7	30630439	Multivariate analysis revealed elevated platelet count (> 400,000/mm3), squamous cell carcinoma subtype, and distant metastasis to be associated with poorer PFS.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (72, 95))	('elevated platelet count', 'Phenotype', 'HP:0001894', (31, 54))	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('squamous cell carcinoma subtype', 'Disease', 'MESH:D002294', (72, 103))	('platelet count', 'MPA', (40, 54))	('distant metastasis', 'CPA', (109, 127))	('squamous cell carcinoma subtype', 'Disease', (72, 103))	('elevated', 'PosReg', (31, 39))	('> 400,000/mm3', 'Var', (56, 69))
8	30630439	Elevated neutrophil count (> 7000/mm3), elevated platelet count (> 400,000/mm3), squamous cell carcinoma subtype, and distant metastasis were found to be associated with poorer OS.	('distant metastasis', 'CPA', (118, 136))	('squamous cell carcinoma subtype', 'Disease', (81, 112))	('poorer', 'Disease', (170, 176))	('Elevated neutrophil count', 'Phenotype', 'HP:0011897', (0, 25))	('OS', 'Chemical', '-', (177, 179))	('> 7000/mm3', 'Var', (27, 37))	('elevated platelet count', 'Phenotype', 'HP:0001894', (40, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('neutrophil count', 'CPA', (9, 25))	('> 400,000/mm3', 'Var', (65, 78))	('platelet count', 'MPA', (49, 63))	('squamous cell carcinoma subtype', 'Disease', 'MESH:D002294', (81, 112))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (81, 104))
43	30630439	Multivariate analysis revealed the following: BMI < 25 kg/m2 showed association with poor overall response rate; high neutrophil count (> 7000/mm3) was identified as a predictor of short OS; and squamous cell carcinoma subtype, distant metastatic disease, and high platelet count (> 400,000/mm3) were found to be individually associated with short PFS and OS.	('high neutrophil count', 'Phenotype', 'HP:0011897', (113, 134))	('> 7000/mm3', 'Var', (136, 146))	('short OS', 'Disease', (181, 189))	('squamous cell carcinoma subtype', 'Disease', (195, 226))	('high platelet count', 'Phenotype', 'HP:0001894', (260, 279))	('> 400,000/mm3', 'Var', (281, 294))	('OS', 'Chemical', '-', (187, 189))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (195, 218))	('carcinoma', 'Phenotype', 'HP:0030731', (209, 218))	('squamous cell carcinoma subtype', 'Disease', 'MESH:D002294', (195, 226))	('associated', 'Reg', (326, 336))	('OS', 'Chemical', '-', (356, 358))	('short PFS', 'Disease', (342, 351))
62	30630439	Moreover, high neutrophil-lymphocyte ratio predicted poorer survival, and high lymphocyte count predicted better survival in ovarian cancer patients.	('ovarian cancer', 'Disease', (125, 139))	('better', 'PosReg', (106, 112))	('ovarian cancer', 'Phenotype', 'HP:0100615', (125, 139))	('ovarian cancer', 'Disease', 'MESH:D010051', (125, 139))	('patients', 'Species', '9606', (140, 148))	('high', 'Var', (10, 14))	('poorer', 'NegReg', (53, 59))	('high lymphocyte count', 'Phenotype', 'HP:0100827', (74, 95))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
76	30630439	A previous study in lung adenocarcinoma reported monocyte count > 430/mm3 to be an independent predictor of recurrence-free survival and OS (HR = 1.765, 95% CI: 1.071-2.910, P = 0.0258, and HR = 4.339, 95% CI: 2.032-9.263, P < 0.001, respectively).	('lung adenocarcinoma', 'Disease', (20, 39))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (20, 39))	('monocyte', 'MPA', (49, 57))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (20, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (30, 39))	('> 430/mm3', 'Var', (64, 73))	('recurrence-free', 'Disease', (108, 123))	('OS', 'Chemical', '-', (137, 139))
77	30630439	A study in 141 patients with stage I-IV endometrial carcinoma found monocyte count > 500/mm3 to be an independent predictor of decreased survival time after recurrence/progression (HR = 3.12, 95% CI: 1.52-6.67, P < 0.001).	('endometrial carcinoma', 'Disease', (40, 61))	('patients', 'Species', '9606', (15, 23))	('decreased', 'NegReg', (127, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (52, 61))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (40, 61))	('survival', 'MPA', (137, 145))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (40, 61))	('> 500/mm3', 'Var', (83, 92))
78	30630439	Subsequent study in 541 patients with stage I-IV endometrial carcinoma reported monocytes > 700/mm3 to be significantly associated with deep myometrial invasion, pelvic lymph node metastasis, and advanced stage.	('associated', 'Reg', (120, 130))	('deep myometrial invasion', 'Disease', (136, 160))	('endometrial carcinoma', 'Disease', (49, 70))	('patients', 'Species', '9606', (24, 32))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (49, 70))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (49, 70))	('advanced', 'Disease', (196, 204))	('lymph node metastasis', 'Disease', (169, 190))	('lymph node metastasis', 'Disease', 'MESH:D009362', (169, 190))	('monocytes > 700/mm3', 'Var', (80, 99))
79	30630439	That study also found monocytes > 700/mm3 to be independently associated with decreased disease-free survival (HR = 1.74, 95% CI: 1.02-2.96, P = 0.041) and decreased OS (HR = 2.63, 95% CI: 1.37-5.05, P = 0.004).	('disease-free survival', 'CPA', (88, 109))	('monocytes > 700/mm3', 'Var', (22, 41))	('decreased', 'NegReg', (156, 165))	('OS', 'Chemical', '-', (166, 168))	('decreased', 'NegReg', (78, 87))
105	30459815	Silencing expression of CCND1, JUN and SPP1 in the human oral cancer cell line OECM-1 confirmed that those genes play essential roles in oral cancer cell invasion.	('oral cancer', 'Disease', (57, 68))	('SPP1', 'Gene', (39, 43))	('oral cancer', 'Disease', (137, 148))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('Silencing', 'Var', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('human', 'Species', '9606', (51, 56))	('CCND1', 'Gene', (24, 29))	('oral cancer', 'Disease', 'MESH:D009062', (57, 68))	('JUN', 'Gene', (31, 34))	('oral cancer', 'Disease', 'MESH:D009062', (137, 148))	('SPP1', 'Gene', '6696', (39, 43))
135	30459815	CCND1 (cyclinD1) is a known critical factor in cell cycle progression, but the function of CCND1 in human cancer cell migration/invasion is not sufficiently understood despite a recent study showing that it directly regulates the focal adhesion pathway and promotes R3327 rat prostatic tumor cell migration/invasion and tumor metastasis and affects cell migration and invasion in breast cancer.	('affects', 'Reg', (341, 348))	('tumor', 'Phenotype', 'HP:0002664', (286, 291))	('breast cancer', 'Phenotype', 'HP:0003002', (380, 393))	('tumor metastasis', 'Disease', 'MESH:D009362', (320, 336))	('rat', 'Species', '10116', (357, 360))	('cancer', 'Disease', (106, 112))	('cancer', 'Disease', 'MESH:D009369', (387, 393))	('invasion', 'CPA', (368, 376))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('breast cancer', 'Disease', 'MESH:D001943', (380, 393))	('breast cancer', 'Disease', (380, 393))	('promotes', 'PosReg', (257, 265))	('regulates', 'Reg', (216, 225))	('prostatic tumor', 'Disease', 'MESH:D011471', (276, 291))	('tumor metastasis', 'Disease', (320, 336))	('focal adhesion pathway', 'Pathway', (230, 252))	('prostatic tumor', 'Disease', (276, 291))	('rat', 'Species', '10116', (300, 303))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('cancer', 'Disease', (387, 393))	('cell migration', 'CPA', (349, 363))	('cancer', 'Phenotype', 'HP:0002664', (387, 393))	('tumor', 'Phenotype', 'HP:0002664', (320, 325))	('human', 'Species', '9606', (100, 105))	('R3327 rat', 'Var', (266, 275))	('rat', 'Species', '10116', (272, 275))	('rat', 'Species', '10116', (121, 124))
151	30459815	In order to find the key genes regulating oral cancer metastasis to lymph nodes, we screened the GEO (gene expression omnibus) database for GSE70604 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE70604) and GSE2280 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE2280) as shown in Additional file 1: Table S1 and Additional file 2: Table S3.	('GSE2280', 'Chemical', '-', (275, 282))	('oral cancer metastasis', 'Disease', (42, 64))	('GSE70604', 'Var', (140, 148))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('GSE2280', 'Chemical', '-', (215, 222))	('oral cancer metastasis', 'Disease', 'MESH:D009362', (42, 64))
152	30459815	In GSE70604, the comparisons of gene expression profiles were made between lymph nodes with metastasis of oral squamous cell carcinoma (OSCC) and normal lymph nodes (comparison 1).	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (111, 134))	('metastasis of oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (92, 134))	('GSE70604', 'Var', (3, 11))	('metastasis of oral squamous cell carcinoma', 'Disease', (92, 134))
166	30459815	CCND1 (cyclinD1), a critical gene regulating cell cycle progress, recently has been reported to directly regulate the focal adhesion pathway and promote R3327 rat prostatic tumor cell migration/invasion and tumor metastasis.	('regulate', 'Reg', (105, 113))	('rat', 'Species', '10116', (187, 190))	('R3327 rat', 'Var', (153, 162))	('rat', 'Species', '10116', (159, 162))	('prostatic tumor', 'Disease', 'MESH:D011471', (163, 178))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('focal adhesion pathway', 'Pathway', (118, 140))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('CCND1', 'Gene', (0, 5))	('tumor metastasis', 'Disease', 'MESH:D009362', (207, 223))	('promote', 'PosReg', (145, 152))	('tumor metastasis', 'Disease', (207, 223))	('prostatic tumor', 'Disease', (163, 178))
170	30459815	Deletion of CCND1, JUN and SPP1 expression in OECM-1 via siRNA interference significantly impaired cell invasion although in varying degrees (Fig.	('impaired', 'NegReg', (90, 98))	('cell invasion', 'CPA', (99, 112))	('CCND1', 'Gene', (12, 17))	('SPP1', 'Gene', '6696', (27, 31))	('JUN', 'Gene', (19, 22))	('SPP1', 'Gene', (27, 31))	('Deletion', 'Var', (0, 8))
190	30459815	High expression of c-Jun is associated with poor prognosis of OSCC.	('c-Jun', 'Gene', (19, 24))	('OSCC', 'Disease', (62, 66))	('c-Jun', 'Gene', '3725', (19, 24))	('High', 'Var', (0, 4))
195	30459815	Its aberrant expression and/or splicing is functionally responsible for many disease pathologies including cancer.	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('splicing', 'MPA', (31, 39))	('aberrant expression', 'Var', (4, 23))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('cancer', 'Disease', (107, 113))	('responsible', 'Reg', (56, 67))
219	29279511	In comparison to conventional cytotoxic chemotherapy, the frequency of adverse events, including hematologic toxicity, is low in patients treated with ICIs.	('ICI', 'Chemical', '-', (151, 154))	('patients', 'Species', '9606', (129, 137))	('ICIs', 'Var', (151, 155))	('toxicity', 'Disease', 'MESH:D064420', (109, 117))	('toxicity', 'Disease', (109, 117))
358	27764819	Tumor recurrence rate is higher and survival rate lower in patients with positive CK19 expression in distant tissue than in those with negative CK19 expression in distant tissue.	('lower', 'NegReg', (50, 55))	('higher', 'PosReg', (25, 31))	('CK19', 'Gene', '3880', (144, 148))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('Tumor recurrence rate', 'CPA', (0, 21))	('positive', 'Var', (73, 81))	('patients', 'Species', '9606', (59, 67))	('CK19', 'Gene', (82, 86))	('CK19', 'Gene', (144, 148))	('CK19', 'Gene', '3880', (82, 86))	('survival rate', 'CPA', (36, 49))
365	27764819	Patients with positive CK19 immunoreactivity also had a significantly worse outcome regarding DSS than patients with negative CK19 immunoreactivity (p=0.001; Figure 2).	('CK19', 'Gene', '3880', (23, 27))	('DSS', 'Gene', '5376', (94, 97))	('CK19', 'Gene', '3880', (126, 130))	('worse', 'NegReg', (70, 75))	('CK19', 'Gene', (23, 27))	('Patients', 'Species', '9606', (0, 8))	('immunoreactivity', 'Var', (28, 44))	('DSS', 'Gene', (94, 97))	('patients', 'Species', '9606', (103, 111))	('CK19', 'Gene', (126, 130))
367	27764819	There is still a significant difference in OS between patients with positive and negative CK19 immunoreactivity, after adjustment for demographic (age, smoking and alcohol) and known prognostic factors (pT, pN, tumor grading) (p=.010, Exp(B)=2.0349, 95% CI 1.231-4.482).	('positive', 'Var', (68, 76))	('negative', 'NegReg', (81, 89))	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('CK19', 'Gene', (90, 94))	('patients', 'Species', '9606', (54, 62))	('men', 'Species', '9606', (125, 128))	('CK19', 'Gene', '3880', (90, 94))	('alcohol', 'Chemical', 'MESH:D000438', (164, 171))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('tumor', 'Disease', (211, 216))
376	27764819	We found that patients with positive CK19 staining in oral tongue HNSCC had a worse outcome regarding overall and disease specific survival than patients with negative CK19 staining.	('patients', 'Species', '9606', (145, 153))	('CK19', 'Gene', (168, 172))	('HNSCC', 'Phenotype', 'HP:0012288', (66, 71))	('CK19', 'Gene', '3880', (168, 172))	('CK19', 'Gene', (37, 41))	('positive', 'Var', (28, 36))	('CK19', 'Gene', '3880', (37, 41))	('patients', 'Species', '9606', (14, 22))	('oral tongue HNSCC', 'Disease', (54, 71))	('staining', 'Var', (42, 50))
397	27764819	In conclusion, our results from 129 patients with oral tongue cancer showed a highly significant association of CK19 positive immunoreactivity to overall survival and disease specific survival.	('patients', 'Species', '9606', (36, 44))	('overall survival', 'CPA', (146, 162))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('oral tongue cancer', 'Disease', 'MESH:D014062', (50, 68))	('disease specific survival', 'CPA', (167, 192))	('CK19', 'Gene', (112, 116))	('positive immunoreactivity', 'Var', (117, 142))	('oral tongue cancer', 'Disease', (50, 68))	('CK19', 'Gene', '3880', (112, 116))
418	25288877	We also show an application to data from a genomic study on lung squamous cell carcinoma, where we identify potential candidates of associations between copy number variants and the transcriptional activity of target genes.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (65, 88))	('lung squamous cell carcinoma', 'Disease', (60, 88))	('associations', 'Interaction', (132, 144))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (60, 88))	('transcriptional', 'MPA', (182, 197))	('copy number variants', 'Var', (153, 173))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (60, 88))
422	25288877	For example, the amplification of a DNA segment in a gene that promotes cell replication may cause the cell to begin dividing excessively, as usually happens in cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('promotes', 'PosReg', (63, 71))	('cause', 'Reg', (93, 98))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('cell replication', 'CPA', (72, 88))	('amplification', 'Var', (17, 30))	('cancer', 'Disease', (161, 167))
438	25288877	The update on R can be made more efficient by selecting at random a subset of the rows and then performing an add/delete or swap move for every row in the subset.	('swap', 'Gene', '6433', (124, 128))	('swap', 'Gene', (124, 128))	('add/delete', 'Var', (110, 120))
450	25288877	For the case of alpha1 = 0 and sigmaepsilon = 0.1, our estimated means and standard deviations were   and   respectively, which are consistent with the values used to simulate the data.	('alpha1', 'Gene', '146', (16, 22))	('alpha1', 'Gene', (16, 22))	('sigmaepsilon = 0.1', 'Var', (31, 49))
454	25288877	Interestingly, one of those genes (DVL3) shows both high-frequency deletion and amplification, and has been recently found to be involved in lung squamous cell carcinoma.	('involved', 'Reg', (129, 137))	('carcinoma', 'Phenotype', 'HP:0030731', (160, 169))	('DVL3', 'Gene', '1857', (35, 39))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (141, 169))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (141, 169))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (146, 169))	('deletion', 'Var', (67, 75))	('amplification', 'MPA', (80, 93))	('lung squamous cell carcinoma', 'Disease', (141, 169))	('DVL3', 'Gene', (35, 39))
522	29072302	Silencing of these viral genes in MCPyV+ MCC cell lines caused cell death; thus, LT and ST have also been referred to as viral oncoproteins.	('LT', 'Gene', '10987417', (81, 83))	('MCPyV', 'Species', '493803', (34, 39))	('cell death', 'CPA', (63, 73))	('Silencing', 'Var', (0, 9))	('ST', 'Gene', '10987419', (88, 90))
529	29072302	Although its exact molecular functions are not well understood, MCPyV ST has strong oncogenic activity.	('oncogenic activity', 'CPA', (84, 102))	('MCPyV', 'Species', '493803', (64, 69))	('MCPyV', 'Var', (64, 69))	('ST', 'Gene', '10987419', (70, 72))
543	29072302	By contrast, MCPyV- MCCs show a very high frequency of DNA mutations associated with UV damage, which are also typically evident in other skin cancers associated with sun exposure, such as melanoma, basal cell carcinoma and cutaneous squamous cell carcinoma (FIG.	('carcinoma', 'Phenotype', 'HP:0030731', (210, 219))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (199, 219))	('cutaneous squamous cell carcinoma', 'Disease', (224, 257))	('basal cell carcinoma', 'Disease', (199, 219))	('cutaneous squamous cell carcinoma', 'Disease', 'MESH:D002294', (224, 257))	('MCPyV', 'Species', '493803', (13, 18))	('skin cancer', 'Phenotype', 'HP:0008069', (138, 149))	('cancers', 'Phenotype', 'HP:0002664', (143, 150))	('melanoma', 'Phenotype', 'HP:0002861', (189, 197))	('melanoma', 'Disease', (189, 197))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('DNA', 'Gene', (55, 58))	('associated', 'Reg', (69, 79))	('skin cancers', 'Phenotype', 'HP:0008069', (138, 150))	('mutations', 'Var', (59, 68))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (234, 257))	('basal cell carcinoma', 'Disease', 'MESH:D002280', (199, 219))	('skin cancers', 'Disease', (138, 150))	('melanoma', 'Disease', 'MESH:D008545', (189, 197))	('skin cancers', 'Disease', 'MESH:D012878', (138, 150))	('carcinoma', 'Phenotype', 'HP:0030731', (248, 257))
546	29072302	UV-damaged MCPyV- MCC had a 25-90-fold increase in the number of mutations compared with MCPyV+ MCC.	('MCPyV', 'Species', '493803', (11, 16))	('increase', 'PosReg', (39, 47))	('MCPyV', 'Species', '493803', (89, 94))	('mutations', 'Var', (65, 74))
547	29072302	In addition, these mutations reflected faulty repair of pyrimidine dimers induced by UV radiation.	('pyrimidine', 'Chemical', 'MESH:C030986', (56, 66))	('pyrimidine', 'Protein', (56, 66))	('repair', 'MPA', (46, 52))	('mutations', 'Var', (19, 28))
549	29072302	MCPyV- MCCs almost invariably contain mutations that disrupt RB1, which regulates cell cycling, whereas most MCPyV+ MCCs contain intact RB1 (REFS).	('cell', 'CPA', (82, 86))	('RB1', 'Gene', (136, 139))	('RB1', 'Gene', '5925', (136, 139))	('MCPyV', 'Species', '493803', (0, 5))	('MCPyV', 'Species', '493803', (109, 114))	('regulates', 'Reg', (72, 81))	('disrupt', 'NegReg', (53, 60))	('mutations', 'Var', (38, 47))	('RB1', 'Gene', (61, 64))	('RB1', 'Gene', '5925', (61, 64))
551	29072302	Furthermore, this observation suggests that inactivation of RB1 function by mutation in RB1 or by the binding of the LXCXE motif of LT to RB1 is required for MCC carcinogenesis (FIG.	('MCC', 'Disease', (158, 161))	('binding', 'Interaction', (102, 109))	('RB1', 'Gene', (138, 141))	('RB1', 'Gene', '5925', (138, 141))	('RB1', 'Gene', (88, 91))	('RB1', 'Gene', (60, 63))	('RB1', 'Gene', '5925', (88, 91))	('carcinogenesis', 'Disease', 'MESH:D063646', (162, 176))	('inactivation', 'NegReg', (44, 56))	('LT', 'Gene', '10987417', (132, 134))	('mutation', 'Var', (76, 84))	('carcinogenesis', 'Disease', (162, 176))	('RB1', 'Gene', '5925', (60, 63))	('function', 'MPA', (64, 72))
552	29072302	When RB1 is mutated or when MCPyV LT is present, RB1 is unable to repress E2F transcription factor-dependent gene expression, and cells are unable to arrest in the G1 phase of the cell cycle (FIG.	('E2F transcription factor-dependent gene', 'Gene', (74, 113))	('RB1', 'Gene', (49, 52))	('unable', 'NegReg', (56, 62))	('RB1', 'Gene', '5925', (49, 52))	('mutated', 'Var', (12, 19))	('LT', 'Gene', '10987417', (34, 36))	('MCPyV', 'Species', '493803', (28, 33))	('RB1', 'Gene', (5, 8))	('RB1', 'Gene', '5925', (5, 8))
553	29072302	Strong genetic evidence suggests that the target of the truncated MCPyV LT is RB1 (REF.).	('RB1', 'Gene', '5925', (78, 81))	('truncated', 'Var', (56, 65))	('MCPyV', 'Gene', (66, 71))	('RB1', 'Gene', (78, 81))	('MCPyV', 'Species', '493803', (66, 71))	('LT', 'Gene', '10987417', (72, 74))
554	29072302	An MCPyV+ MCC cell line with RB1 deletion continued to proliferate after LT was knocked down by RNA interference.	('proliferate', 'PosReg', (55, 66))	('LT', 'Gene', '10987417', (73, 75))	('deletion', 'Var', (33, 41))	('RB1', 'Gene', (29, 32))	('MCPyV', 'Species', '493803', (3, 8))	('rat', 'Species', '10116', (62, 65))	('RB1', 'Gene', '5925', (29, 32))
555	29072302	By contrast, knock down of LT in other MCPyV+ MCC cell lines that contained wild-type RB1 caused growth arrest that could be rescued when RB1 was also knocked down.	('RB1', 'Gene', (86, 89))	('RB1', 'Gene', (138, 141))	('MCPyV', 'Species', '493803', (39, 44))	('growth arrest', 'Phenotype', 'HP:0001510', (97, 110))	('RB1', 'Gene', '5925', (86, 89))	('LT', 'Gene', '10987417', (27, 29))	('RB1', 'Gene', '5925', (138, 141))	('knock down', 'Var', (13, 23))	('growth arrest', 'Disease', (97, 110))	('growth arrest', 'Disease', 'MESH:D006323', (97, 110))
556	29072302	In addition to loss of RB1, MCPyV- MCCs usually have inactivating mutations or deletions of TP53 (REFS 57,63), whereas MCPyV+ MCCs tend to contain wild-type TP53.	('TP53', 'Gene', (157, 161))	('deletions', 'Var', (79, 88))	('MCPyV', 'Species', '493803', (119, 124))	('TP53', 'Gene', (92, 96))	('MCPyV', 'Species', '493803', (28, 33))	('TP53', 'Gene', '7157', (92, 96))	('RB1', 'Gene', (23, 26))	('inactivating', 'MPA', (53, 65))	('RB1', 'Gene', '5925', (23, 26))	('TP53', 'Gene', '7157', (157, 161))
557	29072302	Thus, both RB1 and TP53 are nearly always mutated in MCPyV- MCC and intact in MCPyV+ MCC.	('mutated', 'Var', (42, 49))	('MCPyV', 'Species', '493803', (53, 58))	('RB1', 'Gene', '5925', (11, 14))	('MCPyV', 'Species', '493803', (78, 83))	('MCPyV- MCC', 'Disease', (53, 63))	('TP53', 'Gene', '7157', (19, 23))	('TP53', 'Gene', (19, 23))	('RB1', 'Gene', (11, 14))
560	29072302	MCPyV- MCCs frequently contain inactivating mutations in genes involved in several signalling pathways, including Notch, DNA damage repair and chromatin-modifying pathways (FIG.	('chromatin-modifying pathways', 'Pathway', (143, 171))	('MCPyV', 'Species', '493803', (0, 5))	('inactivating mutations', 'Var', (31, 53))	('DNA damage repair', 'MPA', (121, 138))	('Notch', 'Gene', '4851;4853', (114, 119))	('Notch', 'Gene', (114, 119))	('contain', 'Reg', (23, 30))
561	29072302	Loss-of-function mutations in NOTCH1 and NOTCH2 have been reported in MCPyV- MCCs.	('Loss-of-function', 'NegReg', (0, 16))	('NOTCH2', 'Gene', (41, 47))	('MCPyV- MCCs', 'Disease', (70, 81))	('NOTCH1', 'Gene', '4851', (30, 36))	('NOTCH1', 'Gene', (30, 36))	('NOTCH2', 'Gene', '4853', (41, 47))	('MCPyV', 'Species', '493803', (70, 75))	('mutations', 'Var', (17, 26))
562	29072302	It is possible that, in MCPyV+ MCCs, LT and ST functionally perturb these signalling pathways, thereby bypassing the requirement for the respective inactivating mutations.	('LT', 'Gene', '10987417', (37, 39))	('MCPyV+', 'Var', (24, 30))	('MCPyV', 'Species', '493803', (24, 29))	('perturb', 'NegReg', (60, 67))	('ST', 'Gene', '10987419', (44, 46))
563	29072302	Several studies have noted that both MCPyV+ MCCs and MCPyV- MCCs contain mutations that activate receptor tyrosine kinases (RTKs) and the downstream PI3K-AKT-mTOR growth signalling pathway.	('MCPyV', 'Species', '493803', (53, 58))	('activate', 'PosReg', (88, 96))	('mTOR', 'Gene', (158, 162))	('mutations', 'Var', (73, 82))	('mTOR', 'Gene', '2475', (158, 162))	('MCPyV', 'Species', '493803', (37, 42))
564	29072302	Gain-of-function mutations in AKT1, HRAS and PIK3CA or loss-of-function mutations in PTEN, NF1 and TSC1 have been reported in both MCPyV+ MCCs and MCPyV- MCCs.	('MCPyV+ MCCs', 'Disease', (131, 142))	('mutations', 'Var', (72, 81))	('MCPyV- MCCs', 'Disease', (147, 158))	('AKT1', 'Gene', (30, 34))	('NF1', 'Gene', (91, 94))	('MCPyV', 'Species', '493803', (147, 152))	('PIK3CA', 'Gene', (45, 51))	('loss-of-function', 'NegReg', (55, 71))	('Gain-of-function', 'PosReg', (0, 16))	('TSC1', 'Gene', (99, 103))	('HRAS', 'Disease', (36, 40))	('HRAS', 'Disease', 'None', (36, 40))	('PTEN', 'Gene', (85, 89))	('mutations', 'Var', (17, 26))	('MCPyV', 'Species', '493803', (131, 136))
605	29072302	Positivity for the oncoprotein huntingtin-interacting protein 1 (HIP1) has been observed in the majority of cases.	('observed', 'Reg', (80, 88))	('HIP1', 'Gene', '3092', (65, 69))	('huntingtin-interacting protein 1', 'Gene', (31, 63))	('Positivity', 'Var', (0, 10))	('huntingtin-interacting protein 1', 'Gene', '3092', (31, 63))	('HIP1', 'Gene', (65, 69))
646	29072302	Although a retrospective study suggested that patients with a tumour diameter <10 mm had a lower probability of having regional lymph node metastasis, a systematic review of 36 studies involving 692 patients revealed that 30% of patients had a positive SLNB, consistent with the propensity of MCC to metastasize to lymph nodes even if the primary tumour is small.	('patients', 'Species', '9606', (229, 237))	('patients', 'Species', '9606', (46, 54))	('tumour', 'Phenotype', 'HP:0002664', (62, 68))	('tumour', 'Phenotype', 'HP:0002664', (347, 353))	('positive', 'Var', (244, 252))	('tumour', 'Disease', 'MESH:D009369', (62, 68))	('regional lymph node metastasis', 'CPA', (119, 149))	('tumour', 'Disease', 'MESH:D009369', (347, 353))	('primary tumour', 'Disease', (339, 353))	('tumour', 'Disease', (62, 68))	('patients', 'Species', '9606', (199, 207))	('tumour', 'Disease', (347, 353))	('SLNB', 'Gene', (253, 257))	('primary tumour', 'Disease', 'MESH:D009369', (339, 353))
673	29072302	Several lines of evidence indicate that targeting this pathway could be an effective approach in MCC: MCC was identified as an immunogenic cancer (on the basis of the higher incidence and poorer prognosis in immunosuppressed individuals), immune responses to MCPyV T antigens are present in the blood of patients with MCC and tumour-infiltrating T cells (specific to MCPyV proteins or unspecific) are enriched in some MCCs.	('immunogenic cancer', 'Disease', (127, 145))	('tumour', 'Phenotype', 'HP:0002664', (326, 332))	('MCPyV proteins', 'Var', (367, 381))	('patients', 'Species', '9606', (304, 312))	('tumour', 'Disease', 'MESH:D009369', (326, 332))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('tumour', 'Disease', (326, 332))	('rat', 'Species', '10116', (339, 342))	('MCPyV', 'Species', '493803', (367, 372))	('immunogenic cancer', 'Disease', 'MESH:D009369', (127, 145))	('MCPyV', 'Species', '493803', (259, 264))	('MCC', 'Disease', (318, 321))
674	29072302	MCC immunogenicity is readily explained by the constitutive expression of viral proteins in MCPyV+ MCCs and by the very high frequency of DNA mutations associated with UV damage in MCPyV- MCCs.	('mutations', 'Var', (142, 151))	('MCPyV', 'Species', '493803', (181, 186))	('DNA', 'Gene', (138, 141))	('MCPyV', 'Species', '493803', (92, 97))
675	29072302	Importantly, three phase II open-label clinical trials of therapeutic antibodies against PD1 or PDL1 have demonstrated high and durable response rates (TABLE 2) that are more durable than those reported in historical data of patients treated with chemotherapy.	('patients', 'Species', '9606', (225, 233))	('rat', 'Species', '10116', (113, 116))	('antibodies', 'Var', (70, 80))	('PDL1', 'Gene', (96, 100))	('PD1', 'Gene', '5133', (89, 92))	('PD1', 'Gene', (89, 92))	('rat', 'Species', '10116', (145, 148))
713	29072302	Clonal integration of MCPyV DNA into tumour genome Expression of MCPyV small T antigen (ST) and truncated large T antigen (LT) Wild-type RB1 and TP53 No UV mutational signature Predominantly diploid with minimal number of copy number alterations Minimal number of somatic nucleotide alterations No presence of MCPyV DNA No expression of MCPyV LT and ST RNA or protein Inactivating mutations in RB1 and TP53 High frequency of DNA mutations induced by UV damage High degree of aneuploidy Inactivating mutations in genes involved in various signalling pathways, including DNA damage response and repair genes and chromatin-modifying genes MCC, Merkel cell carcinoma; MCPyV, Merkel cell polyomavirus; RB1, RB transcriptional corepressor 1 (which encodes retinoblastoma-associated protein); TP53, tumour protein p53; UV, ultraviolet light.	('tumour', 'Phenotype', 'HP:0002664', (792, 798))	('RB1', 'Gene', '5925', (137, 140))	('LT', 'Gene', '10987417', (343, 345))	('tumour', 'Disease', (37, 43))	('tumour', 'Disease', 'MESH:D009369', (792, 798))	('TP53', 'Gene', '7157', (145, 149))	('tumour', 'Disease', (792, 798))	('rat', 'Species', '10116', (287, 290))	('RB1', 'Gene', (394, 397))	('TP53', 'Gene', '7157', (786, 790))	('ST', 'Gene', '10987419', (350, 352))	('MCPyV', 'Species', '493803', (664, 669))	('MCPyV', 'Species', '493803', (22, 27))	('RB1', 'Gene', '5925', (697, 700))	('large T antigen', 'Gene', (106, 121))	('TP53', 'Gene', (402, 406))	('Merkel cell polyomavirus', 'Species', '493803', (671, 695))	('aneuploidy', 'Disease', 'MESH:D000782', (475, 485))	('retinoblastoma', 'Phenotype', 'HP:0009919', (750, 764))	('MCPyV', 'Species', '493803', (337, 342))	('retinoblastoma-associated protein', 'Gene', (750, 783))	('tumour', 'Phenotype', 'HP:0002664', (37, 43))	('ST', 'Gene', '10987419', (88, 90))	('p53', 'Gene', '7157', (807, 810))	('retinoblastoma-associated protein', 'Gene', '5925', (750, 783))	('mutations', 'Var', (499, 508))	('RB1', 'Gene', '5925', (394, 397))	('rat', 'Species', '10116', (12, 15))	('Merkel cell carcinoma', 'Disease', 'MESH:D015266', (641, 662))	('small T antigen', 'Gene', '10987419', (71, 86))	('TP53', 'Gene', (145, 149))	('MCPyV', 'Species', '493803', (65, 70))	('p53', 'Gene', (807, 810))	('RB1', 'Gene', (137, 140))	('large T antigen', 'Gene', '10987417', (106, 121))	('aneuploidy', 'Disease', (475, 485))	('TP53', 'Gene', '7157', (402, 406))	('TP53', 'Gene', (786, 790))	('Merkel cell carcinoma', 'Disease', (641, 662))	('MCC', 'Gene', (636, 639))	('LT', 'Gene', '10987417', (123, 125))	('small T antigen', 'Gene', (71, 86))	('MCPyV', 'Species', '493803', (310, 315))	('carcinoma', 'Phenotype', 'HP:0030731', (653, 662))	('RB1', 'Gene', (697, 700))	('tumour', 'Disease', 'MESH:D009369', (37, 43))	('rat', 'Species', '10116', (238, 241))
719	29072302	In severely immunocompromised patients, HPyV6 and HPyV7 can cause pruritic dermatoses characterized by hyperproliferation of dyskeratotic (with premature or altered differentiation) keratinocytes that result in brownish skin plaques.	('HPyV6', 'Var', (40, 45))	('hyperproliferation of dyskeratotic', 'Disease', 'MESH:C562838', (103, 137))	('cause', 'Reg', (60, 65))	('rat', 'Species', '10116', (115, 118))	('rat', 'Species', '10116', (184, 187))	('skin plaques', 'Phenotype', 'HP:0200035', (220, 232))	('pruritic dermatoses', 'Disease', 'MESH:D012871', (66, 85))	('patients', 'Species', '9606', (30, 38))	('HPyV7', 'Var', (50, 55))	('hyperproliferation of dyskeratotic', 'Disease', (103, 137))	('HPyV6', 'Species', '746830', (40, 45))	('rat', 'Species', '10116', (130, 133))	('pruritic dermatoses', 'Disease', (66, 85))	('result in', 'Reg', (201, 210))
720	29072302	TSPyV can cause a hyperkeratotic folliculitis (trichodysplasia spinulosa) in recipients of solid-organ transplant.	('trichodysplasia', 'Phenotype', 'HP:0002552', (47, 62))	('hyperkeratotic folliculitis', 'Phenotype', 'HP:0007502', (18, 45))	('cause', 'Reg', (10, 15))	('hyperkeratotic folliculitis', 'Disease', 'MESH:D005499', (18, 45))	('folliculitis', 'Phenotype', 'HP:0025084', (33, 45))	('hyperkeratotic folliculitis', 'Disease', (18, 45))	('TSPyV', 'Species', '862909', (0, 5))	('trichodysplasia spinulosa', 'Disease', (47, 72))	('trichodysplasia spinulosa', 'Disease', 'MESH:C566032', (47, 72))	('TSPyV', 'Var', (0, 5))
723	29072302	JCPyV can also cause a variety of neurological symptoms including ataxia, paresis, dementia and blindness.	('JCPyV', 'Species', '10632', (0, 5))	('paresis', 'Disease', (74, 81))	('blindness', 'Disease', 'MESH:D001766', (96, 105))	('cause', 'Reg', (15, 20))	('dementia', 'Phenotype', 'HP:0000726', (83, 91))	('ataxia', 'Phenotype', 'HP:0001251', (66, 72))	('ataxia', 'Disease', 'MESH:D001259', (66, 72))	('blindness', 'Phenotype', 'HP:0000618', (96, 105))	('neurological symptoms', 'Disease', 'MESH:D009422', (34, 55))	('ataxia', 'Disease', (66, 72))	('dementia', 'Disease', (83, 91))	('neurological symptoms', 'Disease', (34, 55))	('JCPyV', 'Var', (0, 5))	('blindness', 'Disease', (96, 105))	('dementia', 'Disease', 'MESH:D003704', (83, 91))
750	27602771	Some of them are cancer related, such as POU2F3, NKD1 and CYP2C8, while LINC00189, GCC2 and OR9Q1 genes are rarely reported in human diseases.	('cancer', 'Phenotype', 'HP:0002664', (17, 23))	('human', 'Species', '9606', (127, 132))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('POU2F3', 'Var', (41, 47))	('GCC2', 'Gene', (83, 87))	('GCC2', 'Gene', '9648', (83, 87))	('NKD1', 'Gene', '85407', (49, 53))	('CYP2C8', 'Gene', (58, 64))	('cancer', 'Disease', (17, 23))	('CYP2C8', 'Gene', '1558', (58, 64))	('OR9Q1', 'Gene', (92, 97))	('OR9Q1', 'Gene', '219956', (92, 97))	('LINC00189', 'Gene', (72, 81))	('NKD1', 'Gene', (49, 53))	('LINC00189', 'Gene', '193629', (72, 81))
755	27602771	Alternatively, cells generated from one tumor commonly comprise distinct mutations, or display diverse phenotypic, or epigenetic status.	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('comprise', 'Reg', (55, 63))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('mutations', 'Var', (73, 82))
788	27602771	Previous study identified that ArhGAP15 gene knocking out influences the apoptosis induced by ethanol in bovine fibroblast cells.	('ethanol', 'Chemical', 'MESH:D000431', (94, 101))	('influences', 'Reg', (58, 68))	('apoptosis', 'CPA', (73, 82))	('ArhGAP15 gene', 'Gene', (31, 44))	('bovine', 'Species', '9913', (105, 111))	('knocking out', 'Var', (45, 57))
807	27602771	In addition, POU2F3 was also reported might be a cancer-related tumor suppressor in both intraepithelial neoplasia and cervical cancer, highlighted the importance of POU2F3 in bladder squamous cell carcinoma.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (184, 207))	('bladder squamous cell carcinoma', 'Disease', (176, 207))	('intraepithelial neoplasia and cervical cancer', 'Disease', 'MESH:D018290', (89, 134))	('tumor', 'Disease', (64, 69))	('POU2F3', 'Var', (13, 19))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('carcinoma', 'Phenotype', 'HP:0030731', (198, 207))	('neoplasia', 'Phenotype', 'HP:0002664', (105, 114))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('intraepithelial neoplasia', 'Phenotype', 'HP:0032187', (89, 114))	('bladder squamous cell carcinoma', 'Disease', 'MESH:D002294', (176, 207))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('cancer', 'Disease', (49, 55))	('cancer', 'Disease', (128, 134))
820	25741594	T-cell intracellular antigens function as tumor suppressor genes Knockdown of T-cell intracellular antigens TIA1 and TIAR in transformed cells triggers cell proliferation and tumor growth.	('tumor', 'Disease', (175, 180))	('tumor', 'Disease', (42, 47))	('TIAR', 'Gene', (117, 121))	('Knockdown', 'Var', (65, 74))	('triggers', 'Reg', (143, 151))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('TIA1', 'Gene', (108, 112))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('cell proliferation', 'CPA', (152, 170))
839	25741594	However, ectopic TIA1 or TIAR expression promoted the depletion of endogenous TIA proteins (Figures 1b and Supplementary Figure S2A).	('ectopic', 'Var', (9, 16))	('TIA1', 'Gene', (17, 21))	('TIA', 'Chemical', '-', (78, 81))	('TIAR expression', 'Gene', (25, 40))	('promoted', 'PosReg', (41, 49))	('TIA', 'Chemical', '-', (25, 28))	('TIA', 'Chemical', '-', (17, 20))	('depletion of endogenous TIA proteins', 'MPA', (54, 90))
847	25741594	Ectopic expression of DeltaQ-truncated TIA proteins resulted in a reduced inhibitory effect compared with full-length proteins (Figures 2a and b).	('reduced', 'NegReg', (66, 73))	('inhibitory effect', 'MPA', (74, 91))	('TIA', 'Chemical', '-', (39, 42))	('DeltaQ-truncated', 'Var', (22, 38))
850	25741594	Expression of full-length TIA1 or TIAR but not GFP, HuR, TIA1DeltaQ or TIARDeltaQ, resulted in a significant increase of cells in G0/G1, with a reciprocal decrease in the S phase (Figure 2e).	('S phase', 'CPA', (171, 178))	('TIA1', 'Var', (26, 30))	('cells in G0/G1', 'CPA', (121, 135))	('increase', 'PosReg', (109, 117))	('HuR', 'Gene', '1994', (52, 55))	('decrease', 'NegReg', (155, 163))	('HuR', 'Gene', (52, 55))
874	25741594	Indeed, the G1/S cell cycle regulator cyclin-dependent kinase inhibitor 1A (CDKN1A), a major p53-regulated inhibitor of cyclin-dependent kinases, was significantly induced by TIA expression.	('CDKN1A', 'Gene', '1026', (76, 82))	('induced', 'PosReg', (164, 171))	('cyclin-dependent kinase inhibitor 1A', 'Gene', '1026', (38, 74))	('p53', 'Gene', (93, 96))	('p53', 'Gene', '7157', (93, 96))	('TIA', 'Chemical', '-', (175, 178))	('cyclin-dependent kinase inhibitor 1A', 'Gene', (38, 74))	('TIA expression', 'Var', (175, 189))	('CDKN1A', 'Gene', (76, 82))
876	25741594	Unexpectedly, the protein expression levels of p53 and phosphorylated gammaH2AX (at Ser139) protein, a specific marker of damaged DNA, were similar in cells expressing GFP, HuR, TIA1 or TIAR (Figures 4f and g).	('Ser139', 'Chemical', '-', (84, 90))	('GFP', 'Var', (168, 171))	('HuR', 'Gene', (173, 176))	('HuR', 'Gene', '1994', (173, 176))	('gammaH2AX', 'Protein', (70, 79))	('p53', 'Gene', (47, 50))	('p53', 'Gene', '7157', (47, 50))	('gammaH2AX', 'Chemical', '-', (70, 79))
884	25741594	Inducible FT293 cell extracts expressing GFP, GFP-TIA1, GFP-TIAR or GFP-HuR were immunoprecipitated with an anti-GFP monoclonal antibody coupled to magnetic beads and the immunoprecipitated mRNAs were analyzed by qPCR.	('GFP-TIA1', 'Gene', '7072', (46, 54))	('GFP-TIAR', 'Var', (56, 64))	('FT293', 'CellLine', 'CVCL:6911', (10, 15))	('GFP', 'Var', (41, 44))	('HuR', 'Gene', (72, 75))	('HuR', 'Gene', '1994', (72, 75))	('GFP-TIA1', 'Gene', (46, 54))
886	25741594	Given that the results for mRNA synthesis and/or stability did not conclusively explain the steady-state protein levels, as FT293 cells expressing TIA1 or TIAR present partial inhibition of global cell translation, we estimated the contribution of de novo protein synthesis and/or protein stability in cycloheximide (CHX)-treated FT293 cells (Figure 5b).	('inhibition', 'NegReg', (176, 186))	('CHX', 'Chemical', 'MESH:D003513', (317, 320))	('cycloheximide', 'Chemical', 'MESH:D003513', (302, 315))	('FT293', 'CellLine', 'CVCL:6911', (330, 335))	('TIA1', 'Var', (147, 151))	('FT293', 'CellLine', 'CVCL:6911', (124, 129))	('global cell translation', 'MPA', (190, 213))
905	25741594	Immunohistochemistry analysis revealed that control tumors were highly proliferative, with a cell proliferation index determined by the expression of Ki67 (MIB1 for paraffin) significantly higher in the control group, with a mean expression of 20% compared with TIA1 and TIAR groups (5% Ki67 expression, Figure 6d).	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('MIB1', 'Gene', (156, 160))	('paraffin', 'Chemical', 'MESH:D010232', (165, 173))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('Ki67', 'Var', (150, 154))	('tumors', 'Disease', (52, 58))	('expression', 'MPA', (230, 240))	('cell proliferation index', 'CPA', (93, 117))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('higher', 'PosReg', (189, 195))	('MIB1', 'Gene', '57534', (156, 160))
906	25741594	Further, cells with ectopic TIA1 and TIAR expression exhibited greater apoptosis and necrosis than control cells, as shown by expression of caspase-3 and BCL-2 (Figure 6d).	('BCL-2', 'Gene', '596', (154, 159))	('caspase-3', 'Gene', '836', (140, 149))	('apoptosis', 'CPA', (71, 80))	('BCL-2', 'Gene', (154, 159))	('necrosis', 'Disease', 'MESH:D009336', (85, 93))	('TIA1', 'Gene', (28, 32))	('ectopic', 'Var', (20, 27))	('caspase-3', 'Gene', (140, 149))	('TIAR', 'Gene', (37, 41))	('necrosis', 'Disease', (85, 93))
920	25741594	This replacement of endogenous TIA proteins drives a complex process including reduction of cell proliferation, partial inhibition of global translation (in a phospho eIF2alpha-dependent manner), G1/S arrest and cell death.	('global translation', 'MPA', (134, 152))	('S arrest', 'Disease', (199, 207))	('S arrest', 'Disease', 'MESH:D006323', (199, 207))	('inhibition', 'NegReg', (120, 130))	('cell death', 'CPA', (212, 222))	('TIA', 'Chemical', '-', (31, 34))	('cell proliferation', 'CPA', (92, 110))	('replacement', 'Var', (5, 16))	('reduction', 'NegReg', (79, 88))
938	25741594	Here we showed that TIA expression induced CDKN1A accumulation without apparent major effects on protein expression levels of p53.	('CDKN1A', 'Gene', (43, 49))	('p53', 'Gene', '7157', (126, 129))	('CDKN1A', 'Gene', '1026', (43, 49))	('TIA', 'Chemical', '-', (20, 23))	('accumulation', 'PosReg', (50, 62))	('p53', 'Gene', (126, 129))	('TIA', 'Var', (20, 23))
944	25741594	Human tumors are caused both by genetic and epigenetic events.	('Human', 'Species', '9606', (0, 5))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('epigenetic events', 'Var', (44, 61))	('tumors', 'Disease', (6, 12))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('caused', 'Reg', (17, 23))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))
950	25741594	Thus, the aberrant expression of TIA proteins could facilitate the acquisition of oncogenic phenotypes.	('acquisition of oncogenic phenotypes', 'CPA', (67, 102))	('facilitate', 'PosReg', (52, 62))	('TIA', 'Chemical', '-', (33, 36))	('aberrant', 'Var', (10, 18))	('TIA', 'Gene', (33, 36))
951	25741594	Accordingly, mice with disruption in the tiar gene develop ovarian sex cord stromal tumors.	('mice', 'Species', '10090', (13, 17))	('ovarian sex cord stromal tumors', 'Disease', 'MESH:D018312', (59, 90))	('develop', 'PosReg', (51, 58))	('tiar', 'Gene', (41, 45))	('ovarian sex cord stromal tumors', 'Disease', (59, 90))	('disruption', 'Var', (23, 33))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('ovarian sex cord stromal tumors', 'Phenotype', 'HP:0031918', (59, 90))	('tiar', 'Gene', '21843', (41, 45))
958	25741594	Recent therapies targeting NSCLC subtypes have resulted in encouraging new treatments for LAC, driven by EGFR or EML4-ALK mutations.	('EML4', 'Gene', (113, 117))	('NSCLC', 'Disease', (27, 32))	('EML4', 'Gene', '27436', (113, 117))	('SCLC', 'Phenotype', 'HP:0030357', (28, 32))	('EGFR', 'Gene', '1956', (105, 109))	('NSCLC', 'Disease', 'MESH:D002289', (27, 32))	('ALK', 'Gene', '238', (118, 121))	('NSCLC', 'Phenotype', 'HP:0030358', (27, 32))	('mutations', 'Var', (122, 131))	('EGFR', 'Gene', (105, 109))	('LAC', 'Disease', (90, 93))	('ALK', 'Gene', (118, 121))
962	25741594	TIA1 and TIAR gene disruption or overexpression in murine models provokes early embryonic lethality, similar to other tumor suppressor genes.	('overexpression', 'PosReg', (33, 47))	('gene disruption', 'Var', (14, 29))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('disruption', 'Var', (19, 29))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('TIA1', 'Gene', (0, 4))	('provokes', 'Reg', (65, 73))	('embryonic lethality', 'Disease', 'MESH:D020964', (80, 99))	('tumor', 'Disease', (118, 123))	('TIAR', 'Gene', (9, 13))	('embryonic lethality', 'Disease', (80, 99))	('murine', 'Species', '10090', (51, 57))
965	25741594	and this study), and the identification of somatic mutations in human tumor samples from different origins, strongly suggest that it may advantageous for some human tumors to reduce TIA1 and/or TIAR activity/expression, since these effectors could act under specific environmental circumstances as tumor suppressors and barrier, that is, as cellular gatekeepers, to cancer progression.	('mutations', 'Var', (51, 60))	('cancer', 'Disease', (366, 372))	('TIA1', 'Gene', (182, 186))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('cancer', 'Phenotype', 'HP:0002664', (366, 372))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', (298, 303))	('tumors', 'Phenotype', 'HP:0002664', (165, 171))	('human', 'Species', '9606', (159, 164))	('tumor', 'Disease', 'MESH:D009369', (298, 303))	('gatekeepers', 'Species', '111938', (350, 361))	('human', 'Species', '9606', (64, 69))	('cancer', 'Disease', 'MESH:D009369', (366, 372))	('tumors', 'Disease', (165, 171))	('tumor', 'Phenotype', 'HP:0002664', (298, 303))	('activity/expression', 'MPA', (199, 218))	('tumor', 'Disease', (165, 170))	('tumors', 'Disease', 'MESH:D009369', (165, 171))	('tumor', 'Disease', (70, 75))	('reduce', 'NegReg', (175, 181))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('TIAR', 'Gene', (194, 198))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
968	25741594	Transient RNA interference of human CDKN1A mRNA was carried out with siRNA duplexes (SR300740, Origene, Rockville, MD, USA).	('human', 'Species', '9606', (30, 35))	('CDKN1A', 'Gene', '1026', (36, 42))	('CDKN1A', 'Gene', (36, 42))	('SR300740', 'Var', (85, 93))
991	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))
1018	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))	('lung cancer', 'Disease', 'MESH:D008175', (134, 145))	('cause', 'Reg', (72, 77))	('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))
1037	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))
1050	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))
1054	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))
1055	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))	('PLCE1', 'Gene', '51196', (119, 124))	('1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase epsilon-1', 'Gene', '51196', (141, 208))	('PLCE1', 'Gene', '51196', (54, 59))
1065	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))
1069	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))	('PIK3CA', 'Gene', '5290', (87, 93))	('EP300', 'Gene', '2033', (95, 100))	('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))
1072	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))
1074	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))
1077	32759723	Finally, uniparental disomy and LOH of 9q, gain of 3q and LOH of 17p have been described in normal esophageal mucosa.	('LOH', 'Var', (58, 61))	('LOH of 9q', 'Var', (32, 41))	('age', 'Gene', (104, 107))	('uniparental disomy', 'Disease', (9, 27))	('uniparental disomy', 'Disease', 'MESH:D024182', (9, 27))	('gain', 'PosReg', (43, 47))	('age', 'Gene', '5973', (104, 107))
1078	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.	('variations', 'Var', (122, 132))	('carcinogenesis', 'Disease', 'MESH:D063646', (171, 185))	('carcinogenesis', 'Disease', (171, 185))	('single point mutations', 'Var', (74, 96))	('chromosomal structure', 'CPA', (100, 121))
1079	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))
1080	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))
1084	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))
1085	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.	('mutations', 'Var', (66, 75))	('associated', 'Reg', (122, 132))	('trinucleotides', 'Chemical', '-', (85, 99))	('Apolipoprotein B', 'Gene', (163, 179))	('Apolipoprotein B', 'Gene', '338', (163, 179))	('EC', 'Disease', 'MESH:D005955', (159, 161))	('C>T/C>A mutations', 'Var', (58, 75))	('TpCpX', 'Gene', (79, 84))	('C>G', 'Var', (50, 53))
1086	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))
1087	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))
1090	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))	('mutated', 'Var', (158, 165))	('interaction', 'Interaction', (97, 108))	('CDKN2A', 'Gene', (0, 6))	('p53', 'Gene', '7157', (123, 126))	('ESCCs', 'Disease', (183, 188))	('CDKN2A', 'Gene', '1029', (0, 6))
1091	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))
1094	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.	('PIK3CA', 'Gene', (54, 60))	('PTEN', 'Gene', (76, 80))	('PIK3CA', 'Gene', '5290', (54, 60))	('PTEN', 'Gene', '5728', (76, 80))	('ESCCs', 'Disease', (124, 129))	('mutated', 'Var', (106, 113))
1095	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))
1097	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))
1098	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))
1100	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))	('ESCC', 'Disease', (166, 170))	('FBXW7', 'Gene', '55294', (127, 132))	('NOTCH3', 'Gene', '4854', (116, 122))	('NOTCH', 'Gene', (15, 20))	('ESCCs', 'Disease', (77, 82))	('NOTCH', 'Gene', '4851;4853;4854', (116, 121))	('NOTCH', 'Gene', (116, 121))	('FBXW7', 'Gene', (127, 132))	('mutated', 'Var', (137, 144))	('NOTCH', 'Gene', '4851;4853;4854', (108, 113))	('NOTCH1', 'Gene', '4851', (108, 114))	('NOTCH1', 'Gene', (108, 114))	('Alterations', 'Reg', (0, 11))	('NOTCH', 'Gene', '4851;4853;4854', (15, 20))
1101	32759723	Interestingly, NOTCH1 mutations in ESCC are clustered within epidermal growth factor-like repeats 11-12, involved in ligand binding.	('NOTCH1', 'Gene', '4851', (15, 21))	('NOTCH1', 'Gene', (15, 21))	('mutations', 'Var', (22, 31))	('ESCC', 'Gene', (35, 39))
1106	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))
1107	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))
1109	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))
1112	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))
1114	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))	('CUL3', 'Gene', (13, 17))	('cyclin D1', 'Gene', (173, 182))	('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))
1115	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))
1119	32759723	Of note, TENM3 mutation has been associated with poorer outcome.	('mutation', 'Var', (15, 23))	('TENM3', 'Gene', (9, 14))	('TENM3', 'Gene', '55714', (9, 14))
1122	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))
1123	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))
1125	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))
1126	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))
1130	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))
1131	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))
1134	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))
1138	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))
1141	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))
1142	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.	('poor/lower', 'NegReg', (124, 134))	('Hypermethylation', 'Var', (0, 16))	('ESCCs', 'Disease', (89, 94))	('age', 'Gene', (171, 174))	('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))
1143	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))
1145	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))
1147	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))
1148	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))
1149	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))
1150	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))
1152	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))	('malignancies', 'Disease', (78, 90))	('resulting in', 'Reg', (245, 257))	('genomic instability', 'MPA', (258, 277))	('deletions', 'Var', (138, 147))	('activating', 'PosReg', (94, 104))	('men', 'Species', '9606', (222, 225))	('leading to', 'Reg', (127, 137))	('mitotic recombination', 'CPA', (178, 199))	('chromosomal rearrangements', 'CPA', (201, 227))	('carcinogenesis', 'Disease', (45, 59))	('carcinogenesis', 'Disease', 'MESH:D063646', (45, 59))	('translocations', 'CPA', (152, 166))
1154	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))
1156	32759723	Alterations in miRNA expression are involved in different malignancies, affecting cellular processes of proliferation, motility, invasion and apoptosis.	('malignancies', 'Disease', (58, 70))	('cellular processes', 'CPA', (82, 100))	('Alterations', 'Var', (0, 11))	('invasion', 'CPA', (129, 137))	('malignancies', 'Disease', 'MESH:D009369', (58, 70))	('miRNA', 'Gene', (15, 20))	('affecting', 'Reg', (72, 81))	('apoptosis', 'CPA', (142, 151))	('motility', 'CPA', (119, 127))	('involved', 'Reg', (36, 44))
1158	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-133b', 'Gene', '442890', (168, 176))	('resistance to platinum-based chemotherapy', 'MPA', (80, 121))	('miR-96', 'Gene', (28, 34))	('miR-200c', 'Gene', '406985', (18, 26))	('miR-133b', 'Gene', (168, 176))	('miR-141', 'Gene', (36, 43))	('platinum', 'Chemical', 'MESH:D010984', (94, 102))	('downregulation', 'NegReg', (137, 151))	('increase', 'PosReg', (177, 185))	('miR-141', 'Gene', '406933', (36, 43))	('paclitaxel', 'Chemical', 'MESH:D017239', (205, 215))	('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))
1167	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))
1169	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))
1170	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))
1171	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))
1186	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))
1187	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))
1193	32759723	Mutually exclusive EGFR mutations or amplifications have been reported.	('mutations', 'Var', (24, 33))	('EGFR', 'Gene', '1956', (19, 23))	('EGFR', 'Gene', (19, 23))
1194	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))
1195	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))
1196	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))
1206	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))	('NOTCH1', 'Gene', (81, 87))	('ERBB2', 'Gene', (122, 127))	('SMAD4', 'Gene', (89, 94))	('FAT1', 'Gene', '2195', (75, 79))	('CCND1', 'Gene', '595', (129, 134))	('EGFR', 'Gene', (116, 120))
1208	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))
1210	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))
1211	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))
1213	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))
1216	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))
1217	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))
1218	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))
1220	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))
1221	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))	('HNSCC', 'Disease', (78, 83))	('mutations', 'Var', (40, 49))	('MLL2', 'Gene', '8085', (9, 13))	('ZNF750', 'Gene', (15, 21))	('TGFBR2', 'Gene', (23, 29))
1222	32759723	CDKN2A hypermethylation has been identified in HNSCC.	('hypermethylation', 'Var', (7, 23))	('CDKN2A', 'Gene', (0, 6))	('identified', 'Reg', (33, 43))	('HNSCC', 'Disease', (47, 52))	('CDKN2A', 'Gene', '1029', (0, 6))
1229	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))
1231	30253713	In the current study, we found that moderate heating at 43 C for 2 minutes significantly enhanced in vitro nanosecond pulse stimulation-induced cell death of KLN205 murine squamous cell carcinoma cells by 2.43-fold at 600 V and by 2.32-fold at 900 V, as evidenced by propidium iodide uptake.	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (172, 195))	('KLN205', 'Var', (158, 164))	('squamous cell carcinoma', 'Disease', (172, 195))	('enhanced', 'PosReg', (89, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (186, 195))	('cell death', 'CPA', (144, 154))	('propidium iodide', 'Chemical', 'MESH:D011419', (267, 283))	('rat', 'Species', '10116', (40, 43))	('murine', 'Species', '10090', (165, 171))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (172, 195))
1232	30253713	Furthermore, the ablation zone in KLN205 cells placed in a 3-dimensional cell-culture model and pulsed at a voltage of 900 V at 43 C was 3 times larger than in cells exposed to nanosecond pulse stimulation at room temperature.	('rat', 'Species', '10116', (219, 222))	('KLN205 cells', 'Var', (34, 46))	('larger', 'PosReg', (145, 151))	('ablation', 'MPA', (17, 25))
1258	30253713	KLN205-ATCC CRL1453 (ATCC, Manassas, Virginia) mouse lung squamous cell carcinoma cells were maintained in culture with a complete growth medium of Eagle minimal essential medium with 4 mM l-glutamine, supplemented with 10% heat-inactivated fetal bovine serum, and 5% penicillin/streptomycin.	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (53, 81))	('streptomycin', 'Chemical', 'MESH:D013307', (279, 291))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('bovine', 'Species', '9913', (247, 253))	('lung squamous cell carcinoma', 'Disease', (53, 81))	('KLN205-ATCC', 'Var', (0, 11))	('l-glutamine', 'Chemical', 'MESH:D005973', (189, 200))	('penicillin', 'Chemical', 'MESH:D010406', (268, 278))	('CRL1453', 'Gene', (12, 19))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (53, 81))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (58, 81))	('mouse', 'Species', '10090', (47, 52))
1306	30253713	In a 3-D agarose cell-culture model, nanosecond pulses applied to KLN205 squamous cell carcinoma cells preheated to 43 C were more lethal than against cells pulsed at room temperature (P < .001), as indicated by a higher propidium iodide uptake in the heated condition (Figure 2D, F, H, J, and L).	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (73, 96))	('higher', 'PosReg', (214, 220))	('propidium iodide uptake', 'MPA', (221, 244))	('rat', 'Species', '10116', (177, 180))	('propidium iodide', 'Chemical', 'MESH:D011419', (221, 237))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (73, 96))	('squamous cell carcinoma', 'Disease', (73, 96))	('KLN205', 'Var', (66, 72))	('agarose', 'Chemical', 'MESH:D012685', (9, 16))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))
1313	30253713	In a 3-D agarose cell-culture model, nanosecond pulses applied to KLN205 squamous cell carcinoma cells preheated to 43 C were more lethal than against cells pulsed at room temperature as evidenced by higher propidium iodide uptake.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (73, 96))	('propidium iodide uptake', 'MPA', (207, 230))	('rat', 'Species', '10116', (177, 180))	('propidium iodide', 'Chemical', 'MESH:D011419', (207, 223))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (73, 96))	('squamous cell carcinoma', 'Disease', (73, 96))	('KLN205', 'Var', (66, 72))	('higher', 'PosReg', (200, 206))	('agarose', 'Chemical', 'MESH:D012685', (9, 16))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))
1324	30253713	We did not observe a protective effect in any treatment group when the tumor-free mice were challenged with KLN205 cells on the opposite flank (Figure 4D).	('mice', 'Species', '10090', (82, 86))	('KLN205 cells', 'Var', (108, 120))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Disease', (71, 76))
1330	30253713	Heating KLN205 carcinoma cells in a 3-D culture model did not cause cell death, and MH alone had minimal effect on in vivo tumor growth and no effect on survival.	('carcinoma', 'Disease', 'MESH:D002277', (15, 24))	('tumor', 'Disease', (123, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (15, 24))	('carcinoma', 'Disease', (15, 24))	('KLN205', 'Var', (8, 14))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
1355	32238407	APOB genotypes and CDH13 haplotypes in the cholesterol-related pathway genes predict non-small cell lung cancer survival Several oncogenic signals are involved in the synthesis, metabolism, transportation and modulation of cholesterol.	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (85, 111))	('CDH13', 'Gene', (19, 24))	('APOB', 'Gene', '338', (0, 4))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('cholesterol', 'Chemical', 'MESH:D002784', (43, 54))	('lung cancer', 'Phenotype', 'HP:0100526', (100, 111))	('cholesterol', 'Chemical', 'MESH:D002784', (223, 234))	('APOB', 'Gene', (0, 4))	('predict', 'Reg', (77, 84))	('CDH13', 'Gene', '1012', (19, 24))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (89, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('haplotypes', 'Var', (25, 35))	('cholesterol-related pathway genes', 'Gene', (43, 76))
1357	32238407	We investigated associations between 26,781 common single-nucleotide polymorphisms (SNPs) in 209 genes of the cholesterol pathway and non-small cell lung cancer (NSCLC) survival by utilizing genotyping datasets from two published genome-wide association studies (GWASs).	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (134, 160))	('single-nucleotide polymorphisms', 'Var', (51, 82))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (134, 160))	('NSCLC', 'Disease', (162, 167))	('investigated', 'Reg', (3, 15))	('associations', 'Interaction', (16, 28))	('non-small cell lung cancer', 'Disease', (134, 160))	('NSCLC', 'Disease', 'MESH:D002289', (162, 167))	('lung cancer', 'Phenotype', 'HP:0100526', (149, 160))	('cholesterol', 'Chemical', 'MESH:D002784', (110, 121))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (138, 160))
1358	32238407	We found five independent SNPs (APOB rs1801701C>T; CDH13 rs35859010 C>T, rs1833970 T>A, rs254315 T>C and rs425904 T>C) to be significantly associated with NSCLC survival in both discovery and replication datasets.	('associated with', 'Reg', (139, 154))	('rs1833970 T>A', 'Var', (73, 86))	('rs1833970', 'Mutation', 'rs1833970', (73, 82))	('rs254315 T>C', 'Var', (88, 100))	('CDH13', 'Gene', '1012', (51, 56))	('NSCLC', 'Disease', (155, 160))	('rs1801701C>T', 'DBSNP_MENTION', 'None', (37, 49))	('rs35859010 C>T', 'Var', (57, 71))	('rs1801701C>T', 'Var', (37, 49))	('NSCLC', 'Disease', 'MESH:D002289', (155, 160))	('rs425904', 'Mutation', 'rs425904', (105, 113))	('APOB', 'Gene', (32, 36))	('rs254315', 'Mutation', 'rs254315', (88, 96))	('rs35859010', 'Mutation', 'rs35859010', (57, 67))	('CDH13', 'Gene', (51, 56))	('rs425904 T>C', 'Var', (105, 117))
1359	32238407	When the unfavorable genotype (APOB rs1801701CC) and haplotypes (CDH13 rs35859010-rs1833970-rs254315-rs425904 C-A-T-C and T-T-T-T) were combined into a genetic score as the number of unfavorable genotypes/haplotypes (NUGH) in the multivariate analysis, an increased NUGH was associated with a worse survival (Ptrend < 0.0001).	('C-A-T-C and T-T-T-T', 'Disease', 'MESH:D001260', (110, 129))	('rs425904', 'Mutation', 'rs425904', (101, 109))	('rs1801701', 'Mutation', 'rs1801701', (36, 45))	('rs1801701CC', 'Var', (36, 47))	('NUGH', 'MPA', (266, 270))	('APOB', 'Gene', (31, 35))	('UGH', 'Chemical', '-', (267, 270))	('UGH', 'Chemical', '-', (218, 221))	('rs1833970', 'Mutation', 'rs1833970', (82, 91))	('CDH13', 'Gene', (65, 70))	('CDH13', 'Gene', '1012', (65, 70))	('rs254315', 'Mutation', 'rs254315', (92, 100))	('rs35859010', 'Mutation', 'rs35859010', (71, 81))
1360	32238407	In addition, both APOB rs1801701T<C and CDH13 rs425904C<T were correlated with mRNA expression of the genes in normal lung tissues from the genotype-tissue expression (GTEx) project.	('correlated', 'Reg', (63, 73))	('rs425904C<T', 'Var', (46, 57))	('rs1801701', 'Mutation', 'rs1801701', (23, 32))	('CDH13', 'Gene', (40, 45))	('rs425904', 'Mutation', 'rs425904', (46, 54))	('rs1801701T<C', 'Var', (23, 35))	('APOB', 'Gene', (18, 22))	('CDH13', 'Gene', '1012', (40, 45))	('mRNA expression', 'MPA', (79, 94))	('GTEx', 'Chemical', '-', (168, 172))
1361	32238407	Genetic variants of APOB and CDH13 in the cholesterol pathway were associated with NSCLC survival, possibly by affecting their gene expression.	('cholesterol pathway', 'Pathway', (42, 61))	('CDH13', 'Gene', (29, 34))	('NSCLC', 'Disease', (83, 88))	('NSCLC', 'Disease', 'MESH:D002289', (83, 88))	('variants', 'Var', (8, 16))	('CDH13', 'Gene', '1012', (29, 34))	('APOB', 'Gene', (20, 24))	('cholesterol', 'Chemical', 'MESH:D002784', (42, 53))	('affecting', 'Reg', (111, 120))	('associated with', 'Reg', (67, 82))
1362	32238407	Genetic variants of APOB and CDH13 in the cholesterol pathway may provide new scientific insights into NSCLC prognosis.	('CDH13', 'Gene', (29, 34))	('cholesterol pathway', 'Pathway', (42, 61))	('NSCLC', 'Disease', (103, 108))	('variants', 'Var', (8, 16))	('NSCLC', 'Disease', 'MESH:D002289', (103, 108))	('CDH13', 'Gene', '1012', (29, 34))	('APOB', 'Gene', (20, 24))	('cholesterol', 'Chemical', 'MESH:D002784', (42, 53))	('Genetic variants', 'Var', (0, 16))
1372	32238407	In particular, dietary cholesterol as well as genes involved in its synthesis, metabolism, transportation and modulation have recently been a research focus of epidemiological, preclinical and clinical studies, which indicate that high dietary cholesterol intake may be prone to cancer, even influencing survival of cancer patients.	('patients', 'Species', '9606', (323, 331))	('cancer', 'Phenotype', 'HP:0002664', (316, 322))	('cholesterol', 'Chemical', 'MESH:D002784', (23, 34))	('cancer', 'Phenotype', 'HP:0002664', (279, 285))	('high dietary cholesterol', 'Phenotype', 'HP:0003124', (231, 255))	('prone', 'Reg', (270, 275))	('cancer', 'Disease', 'MESH:D009369', (316, 322))	('high dietary', 'Var', (231, 243))	('cholesterol', 'Chemical', 'MESH:D002784', (244, 255))	('cancer', 'Disease', (279, 285))	('cancer', 'Disease', 'MESH:D009369', (279, 285))	('cancer', 'Disease', (316, 322))
1374	32238407	For example, some studies provided evidence for a correlation between cholesterol synthesis and prognostic outcome, showing that several oncogenic signals, such as PI3K/AKT/mTOR, RTK/RAS and TP53, could modulate cholesterol synthesis in cancer cells.	('RTK/RAS', 'Var', (179, 186))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('AKT', 'Gene', (169, 172))	('TP53', 'Gene', '7157', (191, 195))	('mTOR', 'Gene', '2475', (173, 177))	('TP53', 'Gene', (191, 195))	('modulate', 'Reg', (203, 211))	('cholesterol', 'Chemical', 'MESH:D002784', (212, 223))	('mTOR', 'Gene', (173, 177))	('cancer', 'Disease', 'MESH:D009369', (237, 243))	('cholesterol', 'Chemical', 'MESH:D002784', (70, 81))	('cancer', 'Disease', (237, 243))	('cholesterol synthesis', 'MPA', (212, 233))	('AKT', 'Gene', '207', (169, 172))
1379	32238407	Therefore, we conducted the present study to investigate the associations of genetic variants in the cholesterol pathway and related genes with NSCLC survival by using available genotyping datasets from two previously published genome-wide association studies (GWASs) of lung cancer.	('NSCLC', 'Disease', (144, 149))	('variants', 'Var', (85, 93))	('NSCLC', 'Disease', 'MESH:D002289', (144, 149))	('lung cancer', 'Phenotype', 'HP:0100526', (271, 282))	('lung cancer', 'Disease', (271, 282))	('cancer', 'Phenotype', 'HP:0002664', (276, 282))	('lung cancer', 'Disease', 'MESH:D008175', (271, 282))	('associations', 'Interaction', (61, 73))	('cholesterol', 'Chemical', 'MESH:D002784', (101, 112))
1385	32238407	For the discovery PLCO dataset, we employed a single-locus analysis first with multivariate Cox proportional hazards regression models to assess the association between each of the 26,781 candidate SNPs and NSCLC survival by calculating hazards ratio (HR) and 95% confidence interval (CI).	('NSCLC', 'Disease', (207, 212))	('SNPs', 'Var', (198, 202))	('NSCLC', 'Disease', 'MESH:D002289', (207, 212))	('association', 'Interaction', (149, 160))
1400	32238407	Among the corresponding 26,781 SNPs of the 209 candidate genes in the cholesterol-related pathway, we identified 1,004 SNPs that were significantly associated with the OS in the PLCO dataset with multiple test correction by BFDP after failed by FDR, of which 24 SNPs remained significant after further replication by the HLCS dataset.	('SNPs', 'Var', (119, 123))	('associated', 'Reg', (148, 158))	('cholesterol', 'Chemical', 'MESH:D002784', (70, 81))	('OS', 'Chemical', '-', (168, 170))
1402	32238407	As shown in Table 2, APOB (rs1801701C>T) and CDH13 (rs35859010C>T, rs1833970T>A, rs254315 T>C and rs425904T>C), as well as other demographic and clinical covariates except for radiotherapy, were independently associated with NSCLC survival (all P < 0.05).	('associated with', 'Reg', (209, 224))	('CDH13', 'Gene', '1012', (45, 50))	('rs425904T>C', 'Var', (98, 109))	('rs425904T>C', 'DBSNP_MENTION', 'None', (98, 109))	('rs254315 T>C', 'Var', (81, 93))	('NSCLC', 'Disease', (225, 230))	('APOB', 'Gene', (21, 25))	('rs1833970T>A', 'DBSNP_MENTION', 'None', (67, 79))	('rs1833970T>A', 'Var', (67, 79))	('NSCLC', 'Disease', 'MESH:D002289', (225, 230))	('rs1801701C>T', 'DBSNP_MENTION', 'None', (27, 39))	('rs35859010C>T', 'DBSNP_MENTION', 'None', (52, 65))	('rs35859010C>T', 'Var', (52, 65))	('rs1801701C>T', 'Var', (27, 39))	('CDH13', 'Gene', (45, 50))	('rs254315', 'Mutation', 'rs254315', (81, 89))
1403	32238407	Meanwhile, the pairwise linkage disequilibrium (LD) analysis using HaploView 4.2 software showed that four CDH13 SNPs were in low LD (Supplementary Figure 2F).	('CDH13', 'Gene', (107, 112))	('CDH13', 'Gene', '1012', (107, 112))	('SNPs', 'Var', (113, 117))
1404	32238407	For APOB, the rs1801701 CT+TT genotypes were associated with a better survival (HR = 0.73, 95% CI = 0.60-0.88, P = 0.014 for OS and HR = 0.74, 95% CI = 0.60-0.91, P = 0.004 for DSS), compared with the rs1801701 CC genotype.	('rs1801701', 'Mutation', 'rs1801701', (201, 210))	('survival', 'MPA', (70, 78))	('rs1801701', 'Var', (14, 23))	('OS', 'Chemical', '-', (125, 127))	('APOB', 'Gene', (4, 8))	('better', 'PosReg', (63, 69))	('DSS', 'Chemical', '-', (177, 180))	('rs1801701', 'Mutation', 'rs1801701', (14, 23))
1405	32238407	Therefore, the APOB rs1801701 CC genotype was the unfavorable genotype (Table 3).	('APOB', 'Gene', (15, 19))	('rs1801701 CC', 'Var', (20, 32))	('rs1801701', 'Mutation', 'rs1801701', (20, 29))
1407	32238407	The frequencies of CDH13 haplotypes in the PLCO dataset were first estimated, and there were seven haplotypes named H1 - H7, of which haplotype H1 (C-T-T-T) was the most frequent (39.91%), followed by H2 (C-T-T-C, 18.34%), H3 (C-T-C-T, 11.11%), H4 (C-A-T-T, 10.04%), H5 (C-A-T-C, 9.83%), H6 (T-T-T-T, 6.89%) and H7 (T-T-C-T, 3.87%).	('C-T-C-T', 'Disease', (227, 234))	('H6 (T-T-T-T', 'CellLine', 'CVCL:3174', (288, 299))	('haplotype', 'Var', (134, 143))	('CDH13', 'Gene', (19, 24))	('T-T-C-T', 'Disease', 'MESH:D001260', (316, 323))	('C-T-T-T', 'CellLine', 'CVCL:3174', (148, 155))	('C-T-T-C', 'Disease', 'MESH:C537418', (205, 212))	('C-T-C-T', 'Disease', 'MESH:C537418', (227, 234))	('CDH13', 'Gene', '1012', (19, 24))	('T-T-C-T', 'Disease', (316, 323))	('C-T-T-C', 'Disease', (205, 212))
1408	32238407	Haplotypes H5 and H6 were found to be associated with worst NSCLC OS and DSS; when haplotype H5 and H6 were combined, they remained significantly associated with a worse NSCLC survival (HR = 1.38, 95% CI = 1.21-1.57, P < 0.0001 for OS and HR = 1.36, 95% CI = 1.19-1.56, P < 0.0001 for DSS (Table 3).	('OS', 'Chemical', '-', (66, 68))	('NSCLC OS', 'Disease', 'MESH:C567932', (60, 68))	('NSCLC', 'Disease', (60, 65))	('haplotype H5', 'Var', (83, 95))	('DSS', 'Chemical', '-', (285, 288))	('NSCLC', 'Disease', (170, 175))	('OS', 'Chemical', '-', (232, 234))	('DSS', 'Chemical', '-', (73, 76))	('NSCLC', 'Disease', 'MESH:D002289', (170, 175))	('NSCLC OS', 'Disease', (60, 68))	('Haplotypes', 'Var', (0, 10))	('NSCLC', 'Disease', 'MESH:D002289', (60, 65))
1410	32238407	To further evaluate the combined effect of these UGH on NSCLC OS and DSS in the PLCO dataset, we combined the significant unfavorable genotype (APOB rs1801701 CC) and diplotype (CDH13 H5/H6) into a genetic score as the NUGH.	('UGH', 'Chemical', '-', (220, 223))	('CDH13', 'Gene', '1012', (178, 183))	('rs1801701 CC', 'Var', (149, 161))	('UGH', 'Chemical', '-', (49, 52))	('rs1801701', 'Mutation', 'rs1801701', (149, 158))	('DSS', 'Chemical', '-', (69, 72))	('NSCLC OS', 'Disease', (56, 64))	('APOB', 'Gene', (144, 148))	('CDH13', 'Gene', (178, 183))	('NSCLC OS', 'Disease', 'MESH:C567932', (56, 64))
1414	32238407	As shown in Figure 1, the ROC curves indicated an improved prediction performance with the addition of NUGH to the model with the covariates, compared to the model with the covariates only.	('addition', 'Var', (91, 99))	('UGH', 'Chemical', '-', (104, 107))	('improved', 'PosReg', (50, 58))	('NUGH', 'Gene', (103, 107))
1420	32238407	For APOB, the eQTL analysis of the data from the GTEx project revealed that the rs1801701 T allele was significantly correlated with a lower expression level of APOB in 383 normal lung tissue samples (P = 0.0269; Figure 2A) but not in 369 whole blood samples.	('rs1801701', 'Mutation', 'rs1801701', (80, 89))	('GTEx', 'Chemical', '-', (49, 53))	('rs1801701 T', 'Var', (80, 91))	('APOB', 'Protein', (161, 165))	('expression level', 'MPA', (141, 157))	('lower', 'NegReg', (135, 140))	('lower expression level of APOB', 'Phenotype', 'HP:0031799', (135, 165))
1421	32238407	For CDH13, the eQTL analysis of the data from the GTEx project revealed that the rs425904 C allele was significantly correlated with a lower expression level of CDH13 in 383 normal lung tissue samples (P = 0.0275; Figure 2D) but not in 369 whole blood samples.	('expression level', 'MPA', (141, 157))	('GTEx', 'Chemical', '-', (50, 54))	('CDH13', 'Gene', (161, 166))	('rs425904 C', 'Var', (81, 91))	('lower', 'NegReg', (135, 140))	('CDH13', 'Gene', (4, 9))	('CDH13', 'Gene', '1012', (161, 166))	('rs425904', 'Mutation', 'rs425904', (81, 89))	('CDH13', 'Gene', '1012', (4, 9))
1422	32238407	In the RNA-Seq data of lymphoblastoid cell lines from the 1,000 Genomes Project, none of the four SNPs on CDH13 (i.e., rs35859010, rs1833970, rs254315 and rs425904) showed a significant correlation with the mRNA expression of the gene in all three genetic models (Supplementary Figure 4A-4D); nor were the haplotypes of CDH13 correlated with the mRNA expression levels (Supplementary Figure 4E).	('CDH13', 'Gene', (320, 325))	('rs35859010', 'Var', (119, 129))	('mRNA expression', 'MPA', (207, 222))	('rs1833970', 'Mutation', 'rs1833970', (131, 140))	('mRNA expression levels', 'MPA', (346, 368))	('rs425904', 'Mutation', 'rs425904', (155, 163))	('rs254315', 'Mutation', 'rs254315', (142, 150))	('CDH13', 'Gene', '1012', (320, 325))	('CDH13', 'Gene', (106, 111))	('rs425904', 'Var', (155, 163))	('rs254315', 'Var', (142, 150))	('CDH13', 'Gene', '1012', (106, 111))	('rs1833970', 'Var', (131, 140))	('rs35859010', 'Mutation', 'rs35859010', (119, 129))
1427	32238407	Specifically, APOB rs1801701C>T and CDH13 rs254315T>C are likely to have some effects on enhancer histone marks, DNAse and motifs, while CDH13 rs35859010C>T may have an effect on enhancer histone marks and motifs (Supplementary Table 4).	('CDH13', 'Gene', '1012', (137, 142))	('enhancer', 'PosReg', (179, 187))	('motifs', 'MPA', (123, 129))	('rs254315T>C', 'DBSNP_MENTION', 'None', (42, 53))	('DNAse', 'MPA', (113, 118))	('CDH13', 'Gene', (36, 41))	('rs1801701C>T', 'Var', (19, 31))	('APOB', 'Gene', (14, 18))	('rs35859010C>T', 'DBSNP_MENTION', 'None', (143, 156))	('rs35859010C>T', 'Var', (143, 156))	('rs1801701C>T', 'DBSNP_MENTION', 'None', (19, 31))	('CDH13', 'Gene', '1012', (36, 41))	('CDH13', 'Gene', (137, 142))	('enhancer histone marks', 'MPA', (89, 111))	('rs254315T>C', 'Var', (42, 53))	('effects', 'Reg', (78, 85))
1428	32238407	In the current study, we performed a comprehensive analysis to investigate the associations between SNPs in genes involved in the cholesterol pathway and survival of NSCLC, utilizing two published GWAS datasets with a relatively long median follow-up time and strict quality control procedures.	('associations', 'Interaction', (79, 91))	('cholesterol', 'Chemical', 'MESH:D002784', (130, 141))	('NSCLC', 'Disease', (166, 171))	('NSCLC', 'Disease', 'MESH:D002289', (166, 171))	('SNPs', 'Var', (100, 104))
1429	32238407	Five novel SNPs in two genes were identified, and the APOB genotypes and CDH13 haplotypes were found to be associated with NSCLC survival.	('APOB', 'Gene', (54, 58))	('NSCLC', 'Disease', (123, 128))	('CDH13', 'Gene', (73, 78))	('NSCLC', 'Disease', 'MESH:D002289', (123, 128))	('CDH13', 'Gene', '1012', (73, 78))	('associated with', 'Reg', (107, 122))	('SNPs', 'Var', (11, 15))
1437	32238407	Most of published studies focusing on the methylation of CDH13 observed that the methylation level of CDH13 was higher in NSCLC tumor tissues than in adjacent normal tissues and suggested that CDH13 hypermethylation was associated with early recurrence and worse survival in NSCLC, although another study found that CDH13 mRNA high expression levels were correlated with a better OS in adenocarcinoma patients.	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('CDH13', 'Gene', '1012', (102, 107))	('CDH13', 'Gene', '1012', (316, 321))	('hypermethylation', 'Var', (199, 215))	('CDH13', 'Gene', (193, 198))	('CDH13', 'Gene', (57, 62))	('NSCLC', 'Disease', 'MESH:D002289', (275, 280))	('patients', 'Species', '9606', (401, 409))	('OS', 'Chemical', '-', (380, 382))	('adenocarcinoma', 'Disease', (386, 400))	('NSCLC tumor', 'Disease', (122, 133))	('NSCLC', 'Disease', 'MESH:D002289', (122, 127))	('associated', 'Reg', (220, 230))	('NSCLC', 'Disease', (275, 280))	('CDH13', 'Gene', (102, 107))	('NSCLC tumor', 'Disease', 'MESH:D009369', (122, 133))	('methylation level', 'MPA', (81, 98))	('NSCLC', 'Disease', (122, 127))	('CDH13', 'Gene', (316, 321))	('higher', 'PosReg', (112, 118))	('adenocarcinoma', 'Disease', 'MESH:D000230', (386, 400))	('carcinoma', 'Phenotype', 'HP:0030731', (391, 400))	('CDH13', 'Gene', '1012', (193, 198))	('CDH13', 'Gene', '1012', (57, 62))
1440	32238407	There were several SNPs in CDH13 that were reportedly to affect disease progression by influencing serum adiponectin levels, and the serum adiponectin level was found to be associated with prognosis of lung cancer.	('SNPs', 'Var', (19, 23))	('CDH13', 'Gene', '1012', (27, 32))	('adiponectin', 'Gene', '9370', (105, 116))	('adiponectin', 'Gene', '9370', (139, 150))	('lung cancer', 'Disease', (202, 213))	('lung cancer', 'Phenotype', 'HP:0100526', (202, 213))	('influencing', 'Reg', (87, 98))	('affect', 'Reg', (57, 63))	('adiponectin', 'Gene', (139, 150))	('associated with', 'Reg', (173, 188))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('adiponectin', 'Gene', (105, 116))	('CDH13', 'Gene', (27, 32))	('lung cancer', 'Disease', 'MESH:D008175', (202, 213))
1442	32238407	In the present study, we identified four novel SNPs and confirmed four haplotypes in CDH13 to be associated with survival of NSCLC.	('NSCLC', 'Disease', (125, 130))	('SNPs', 'Var', (47, 51))	('haplotypes', 'Var', (71, 81))	('NSCLC', 'Disease', 'MESH:D002289', (125, 130))	('CDH13', 'Gene', (85, 90))	('CDH13', 'Gene', '1012', (85, 90))	('associated', 'Reg', (97, 107))
1447	32238407	In the present study, we found that smoking status was strongly associated with a worse survival of NSCLC in the presence of the APOB rs1801701 CC genotype as well as CDH13 haplotype H5 (C-A-T-C) and H6 (T-T-T-T) that affected the gene expression.	('NSCLC', 'Disease', (100, 105))	('rs1801701 CC', 'Var', (134, 146))	('NSCLC', 'Disease', 'MESH:D002289', (100, 105))	('CDH13', 'Gene', (167, 172))	('rs1801701', 'Mutation', 'rs1801701', (134, 143))	('CDH13', 'Gene', '1012', (167, 172))	('worse', 'NegReg', (82, 87))	('H6 (T-T-T-T', 'CellLine', 'CVCL:3174', (200, 211))	('APOB', 'Gene', (129, 133))
1451	32238407	Fourth, we only analyzed associations between genetic variants in the identified genes in a selected pathway and survival, more survival-association studies should be called upon on genetic variants in other important biological pathway genes that are likely relevant to tumor phenotypes and treatment response in NSCLC patients.	('tumor', 'Phenotype', 'HP:0002664', (271, 276))	('tumor', 'Disease', (271, 276))	('NSCLC', 'Disease', (314, 319))	('NSCLC', 'Disease', 'MESH:D002289', (314, 319))	('variants', 'Var', (190, 198))	('variants', 'Var', (54, 62))	('tumor', 'Disease', 'MESH:D009369', (271, 276))	('patients', 'Species', '9606', (320, 328))
1453	32238407	In summary, the present study suggested a potential role of genetic variants of the cholesterol pathway genes APOB and CDH13 in NSCLC survival, possibly through the modulation of the synthesis, transport and metabolism of cholesterol by these SNPs and genes, which may provide new scientific insights into NSCLC prognosis and clinical management, once replicated by other investigators.	('variants', 'Var', (68, 76))	('genetic variants', 'Var', (60, 76))	('cholesterol', 'Chemical', 'MESH:D002784', (84, 95))	('metabolism', 'MPA', (208, 218))	('cholesterol', 'Chemical', 'MESH:D002784', (222, 233))	('NSCLC', 'Disease', (128, 133))	('NSCLC', 'Disease', (306, 311))	('APOB', 'Gene', (110, 114))	('CDH13', 'Gene', (119, 124))	('synthesis', 'MPA', (183, 192))	('NSCLC', 'Disease', 'MESH:D002289', (306, 311))	('modulation', 'Reg', (165, 175))	('CDH13', 'Gene', '1012', (119, 124))	('NSCLC', 'Disease', 'MESH:D002289', (128, 133))	('transport', 'MPA', (194, 203))
1454	32238407	APOB            apolipoprotein B AUC area under the receiver operating characteristic curve BFDP Bayesian false discovery probability              CDH13            cadherin 13 CI confidence interval DSS disease-special survival EAF effect allele frequency eQTL expression quantitative trait loci GTEx genotype-tissue expression project GWAS Genome-Wide Association Study HLCS Harvard Lung Cancer Susceptibility HR hazards ratio LD linkage disequilibrium LDL low density lipoprotein LUAD lung adenocarcinoma LUSC lung squamous cell carcinoma NSCLC Non-small cell lung cancer NUGH number of unfavorable genotypes/haplotypes OS overall survival PLCO the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial ROC receiver operating characteristic SNPs single nucleotide polymorphisms              SREBP            sterol regulatory element binding protein TCGA the Cancer Genome Atlas UGH unfavorable genotypes/haplotype	('EAF', 'Disease', (228, 231))	('apolipoprotein B', 'Gene', '338', (16, 32))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (551, 573))	('GTEx', 'Chemical', '-', (296, 300))	('DSS', 'Chemical', '-', (199, 202))	('Harvard Lung Cancer', 'Disease', (376, 395))	('UGH', 'Chemical', '-', (575, 578))	('Ovarian Cancer', 'Phenotype', 'HP:0100615', (682, 696))	('SREBP', 'Gene', (801, 806))	('lung squamous cell carcinoma', 'Disease', (512, 540))	('CDH13', 'Gene', (147, 152))	('Non-small cell lung cancer', 'Disease', 'MESH:D002289', (547, 573))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (512, 540))	('Cancer', 'Phenotype', 'HP:0002664', (869, 875))	('Cancer', 'Disease', 'MESH:D009369', (690, 696))	('Harvard Lung Cancer', 'Disease', 'MESH:D008175', (376, 395))	('single nucleotide polymorphisms', 'Var', (756, 787))	('carcinoma', 'Phenotype', 'HP:0030731', (531, 540))	('Cancer', 'Disease', (869, 875))	('lung adenocarcinoma', 'Disease', (487, 506))	('apolipoprotein B', 'Gene', (16, 32))	('Non-small cell lung cancer', 'Disease', (547, 573))	('cadherin', 'Gene', (164, 172))	('Cancer', 'Phenotype', 'HP:0002664', (389, 395))	('LDL low', 'Phenotype', 'HP:0003563', (454, 461))	('UGH', 'Chemical', '-', (889, 892))	('Lung Cancer', 'Phenotype', 'HP:0100526', (384, 395))	('carcinoma', 'Phenotype', 'HP:0030731', (497, 506))	('Colorectal and Ovarian Cancer', 'Disease', 'MESH:D015179', (667, 696))	('Cancer', 'Disease', (389, 395))	('EAF', 'Disease', 'None', (228, 231))	('Cancer', 'Disease', 'MESH:D009369', (869, 875))	('Non-small cell lung cancer', 'Phenotype', 'HP:0030358', (547, 573))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (487, 506))	('Cancer', 'Phenotype', 'HP:0002664', (690, 696))	('cadherin', 'Gene', '999;1012', (164, 172))	('CDH13', 'Gene', '1012', (147, 152))	('NSCLC', 'Disease', 'MESH:D002289', (541, 546))	('lung cancer', 'Phenotype', 'HP:0100526', (562, 573))	('cancer', 'Phenotype', 'HP:0002664', (567, 573))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (512, 540))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (517, 540))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (487, 506))	('Cancer', 'Disease', (690, 696))	('APOB            apolipoprotein B', 'Phenotype', 'HP:0031798', (0, 32))	('Cancer', 'Disease', 'MESH:D009369', (389, 395))	('NSCLC', 'Disease', (541, 546))	('OS', 'Chemical', '-', (622, 624))
1515	30084036	For instance, determination of new mutations in patients with non-small cell lung cancer (NSCLC) can assist in selection of therapy and provide prognostic information.	('lung cancer', 'Phenotype', 'HP:0100526', (77, 88))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (66, 88))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (62, 88))	('assist', 'Reg', (101, 107))	('NSCLC', 'Disease', (90, 95))	('NSCLC', 'Disease', 'MESH:D002289', (90, 95))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (62, 88))	('patients', 'Species', '9606', (48, 56))	('non-small cell lung cancer', 'Disease', (62, 88))	('NSCLC', 'Phenotype', 'HP:0030358', (90, 95))	('mutations', 'Var', (35, 44))
1518	30084036	Multiple methods, including PCR technologies, have been used to detect known tumor-specific tumor mutations and genome-wide alterations.	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('mutations', 'Var', (98, 107))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Disease', (92, 97))	('tumor', 'Disease', (77, 82))
1544	26892430	Multivariable analysis showed patients with NLR > 5 had shortened OS in both sub-populations but NLR > 5 only predicted RFS in oropharyngeal patients.	('OS', 'Chemical', '-', (66, 68))	('shortened OS', 'MPA', (56, 68))	('RFS', 'Disease', (120, 123))	('RFS', 'Chemical', '-', (120, 123))	('patients', 'Species', '9606', (30, 38))	('NLR > 5', 'Var', (44, 51))	('patients', 'Species', '9606', (141, 149))
1557	26892430	These changes lead to the development of cancer-related syndromes, including fever, night sweats, fatigue, cachexia and bone and muscle pain.	('cachexia', 'Disease', (107, 115))	('changes', 'Var', (6, 13))	('fatigue', 'Disease', 'MESH:D005221', (98, 105))	('cancer', 'Disease', (41, 47))	('lead to', 'Reg', (14, 21))	('sweats', 'Phenotype', 'HP:0000975', (90, 96))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('fever', 'Disease', 'MESH:D005334', (77, 82))	('fever', 'Disease', (77, 82))	('pain', 'Phenotype', 'HP:0012531', (136, 140))	('muscle pain', 'Phenotype', 'HP:0003326', (129, 140))	('fever', 'Phenotype', 'HP:0001945', (77, 82))	('muscle pain', 'Disease', 'MESH:D063806', (129, 140))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('muscle pain', 'Disease', (129, 140))	('cachexia', 'Disease', 'MESH:D002100', (107, 115))	('fatigue', 'Disease', (98, 105))	('night sweats', 'Phenotype', 'HP:0030166', (84, 96))	('fatigue', 'Phenotype', 'HP:0012378', (98, 105))	('night sweats', 'Disease', (84, 96))	('cachexia', 'Phenotype', 'HP:0004326', (107, 115))
1566	26892430	A pilot study in 46 unselected HNSCC patients was conducted by our group and univariate analysis found that NLR was predictive of shorter overall survival.	('overall survival', 'MPA', (138, 154))	('NLR', 'Var', (108, 111))	('HNSCC', 'Phenotype', 'HP:0012288', (31, 36))	('patients', 'Species', '9606', (37, 45))	('shorter', 'NegReg', (130, 137))
1634	26892430	In the total population, patients with high NLR had significantly shorter RFS (p < 0.01) and OS (p < 0.001) and showed a shorter 1-year RFS and OS (62 % vs 87 % and 83 % vs 93 %, respectively).	('high', 'Var', (39, 43))	('RFS', 'Chemical', '-', (74, 77))	('shorter', 'NegReg', (66, 73))	('OS', 'Chemical', '-', (93, 95))	('RFS', 'Chemical', '-', (136, 139))	('RFS', 'MPA', (74, 77))	('shorter', 'NegReg', (121, 128))	('patients', 'Species', '9606', (25, 33))	('RFS', 'MPA', (136, 139))	('OS', 'Chemical', '-', (144, 146))	('NLR', 'Gene', (44, 47))
1635	26892430	In the oropharyngeal sub-population, high NLR patients also showed a poorer RFS (p < 0.01) and OS (p < 0.01) with shorter 1-year RFS and OS (60 % vs 97 % and 94 % vs 98 %, respectively, Fig.	('patients', 'Species', '9606', (46, 54))	('RFS', 'Chemical', '-', (129, 132))	('high', 'Var', (37, 41))	('RFS', 'MPA', (76, 79))	('poorer', 'NegReg', (69, 75))	('shorter', 'NegReg', (114, 121))	('RFS', 'MPA', (129, 132))	('OS', 'Chemical', '-', (95, 97))	('OS', 'Chemical', '-', (137, 139))	('RFS', 'Chemical', '-', (76, 79))
1667	26892430	The results of this study show that on a background of high p16 positive status, elevated NLR was associated with recurrence and survival outcomes under univariate analysis and many of the recurrences and deaths occurred within the first year following radiotherapy.	('p16', 'Gene', (60, 63))	('elevated', 'PosReg', (81, 89))	('NLR', 'Gene', (90, 93))	('survival outcomes', 'CPA', (129, 146))	('p16', 'Gene', '1029', (60, 63))	('high', 'Var', (55, 59))	('associated', 'Reg', (98, 108))	('recurrence', 'CPA', (114, 124))
1675	26892430	Recent analysis conducted by The Cancer Genome Atlas project, shows that within the HPV+ population of HNSCC there is an increase in loss of TNF receptor-associated factor 3 gene and presence of activating mutations in PIK3CA gene, which enhance NF-kappaB signalling and promote a pro-inflammatory microenvironment.	('HNSCC', 'Phenotype', 'HP:0012288', (103, 108))	('mutations', 'Var', (206, 215))	('NF-kappaB', 'Gene', '4790', (246, 255))	('activating', 'PosReg', (195, 205))	('Cancer', 'Phenotype', 'HP:0002664', (33, 39))	('pro-inflammatory microenvironment', 'MPA', (281, 314))	('PIK3CA', 'Gene', (219, 225))	('NF-kappaB', 'Gene', (246, 255))	('TNF', 'Gene', (141, 144))	('loss', 'NegReg', (133, 137))	('enhance', 'PosReg', (238, 245))	('promote', 'PosReg', (271, 278))	('HPV', 'Species', '10566', (84, 87))
1685	26892430	Pharmacological inhibitors of key immunosuppressive mediators (anti-PD1 or PD ligand 1 antibodies, STAT3 and PDE5 inhibitors) have been shown to reduce the number and function of MDSC, Tregs and/or immune T cell-mediated anti-tumour responses in mice and are increasingly being investigated in clinical trials .	('PDE5', 'Gene', (109, 113))	('function', 'CPA', (167, 175))	('PD1', 'Gene', '18566', (68, 71))	('MDSC', 'CPA', (179, 183))	('Tregs', 'CPA', (185, 190))	('inhibitors', 'Var', (16, 26))	('PDE5', 'Gene', '242202', (109, 113))	('tumour', 'Phenotype', 'HP:0002664', (226, 232))	('tumour', 'Disease', 'MESH:D009369', (226, 232))	('STAT3', 'Gene', '20848', (99, 104))	('tumour', 'Disease', (226, 232))	('STAT3', 'Gene', (99, 104))	('reduce', 'NegReg', (145, 151))	('PD1', 'Gene', (68, 71))	('mice', 'Species', '10090', (246, 250))
1686	26892430	New data from the The Cancer Genome Atlas has also suggested novel pathways for intervention, such as the PIK3 pathway due to activating mutations in PI3KCA for HPV+ cancers.	('Cancer', 'Phenotype', 'HP:0002664', (22, 28))	('PI3KCA', 'Gene', (150, 156))	('HPV+ cancers', 'Disease', 'MESH:D030361', (161, 173))	('mutations', 'Var', (137, 146))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('PIK3 pathway', 'Pathway', (106, 118))	('HPV+ cancers', 'Disease', (161, 173))	('cancers', 'Phenotype', 'HP:0002664', (166, 173))	('activating', 'PosReg', (126, 136))
1690	26892430	Patients with poorer ECOG PS had an increased hazard of death in both sub-populations which has been suggested previously in HNSCC and observed in other advanced cancers.	('cancers', 'Disease', 'MESH:D009369', (162, 169))	('poorer', 'Var', (14, 20))	('cancers', 'Disease', (162, 169))	('HNSCC', 'Phenotype', 'HP:0012288', (125, 130))	('HNSCC', 'Disease', (125, 130))	('Patients', 'Species', '9606', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('cancers', 'Phenotype', 'HP:0002664', (162, 169))
1714	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))
1715	26114883	These results suggest that expression of PD-L1 is associated with worse survival in solid tumors.	('associated', 'Reg', (50, 60))	('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))	('solid tumors', 'Disease', (84, 96))	('PD-L1', 'Gene', (41, 46))
1720	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))
1725	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))
1752	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))
1758	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))
1762	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))
1774	24348665	Molecular markers, such as epidermal growth factor receptor (EGFR) mutation and anaplastic lymphoma kinase (ALK) rearrangement, are the best predictors of response to specific tyrosine kinase inhibitor treatment agents.	('anaplastic lymphoma kinase', 'Gene', (80, 106))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (80, 99))	('lymphoma', 'Phenotype', 'HP:0002665', (91, 99))	('ALK', 'Gene', '238', (108, 111))	('mutation', 'Var', (67, 75))	('rearrangement', 'Var', (113, 126))	('epidermal growth factor receptor', 'Gene', (27, 59))	('men', 'Species', '9606', (207, 210))	('epidermal growth factor receptor', 'Gene', '1956', (27, 59))	('anaplastic lymphoma kinase', 'Gene', '238', (80, 106))	('ALK', 'Gene', (108, 111))	('EGFR', 'Gene', '1956', (61, 65))	('men', 'Species', '9606', (122, 125))	('EGFR', 'Gene', (61, 65))
1783	24348665	The epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) gefitinib and erlotinib produce a dramatic response when used as a first-line therapy in NSCLCs carrying an activating EGFR mutation.	('erlotinib', 'Chemical', 'MESH:D000069347', (90, 99))	('NSCLC', 'Disease', 'MESH:D002289', (165, 170))	('EGFR', 'Gene', (195, 199))	('EGFR', 'Gene', '1956', (65, 69))	('EGFR', 'Gene', (65, 69))	('epidermal growth factor receptor', 'Gene', (4, 36))	('gefitinib', 'Chemical', 'MESH:D000077156', (76, 85))	('activating', 'PosReg', (184, 194))	('epidermal growth factor receptor', 'Gene', '1956', (4, 36))	('EGFR', 'Gene', '1956', (195, 199))	('mutation', 'Var', (200, 208))	('NSCLC', 'Disease', (165, 170))
1784	24348665	The anaplastic lymphoma kinase (ALK) inhibitor, crizotinib, is effective in NSCLCs with rearrangement of ALK.	('lymphoma', 'Phenotype', 'HP:0002665', (15, 23))	('ALK', 'Gene', (32, 35))	('ALK', 'Gene', (105, 108))	('anaplastic lymphoma kinase', 'Gene', '238', (4, 30))	('men', 'Species', '9606', (97, 100))	('NSCLC', 'Disease', (76, 81))	('ALK', 'Gene', '238', (32, 35))	('ALK', 'Gene', '238', (105, 108))	('NSCLC', 'Disease', 'MESH:D002289', (76, 81))	('anaplastic lymphoma kinase', 'Gene', (4, 30))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (4, 23))	('crizotinib', 'Chemical', 'MESH:D000077547', (48, 58))	('rearrangement', 'Var', (88, 101))
1785	24348665	Moreover, the molecular markers for targeting of these agents, EGFR mutations and ALK rearrangements, are primarily found in adenocarcinoma.	('EGFR', 'Gene', '1956', (63, 67))	('ALK', 'Gene', (82, 85))	('EGFR', 'Gene', (63, 67))	('rearrangements', 'Var', (86, 100))	('adenocarcinoma', 'Disease', (125, 139))	('found', 'Reg', (116, 121))	('men', 'Species', '9606', (95, 98))	('ALK', 'Gene', '238', (82, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('mutations', 'Var', (68, 77))	('adenocarcinoma', 'Disease', 'MESH:D000230', (125, 139))
1796	24348665	Cytology samples obtained by EBUS-TBNA are sufficient for evaluation of EGFR mutation and ALK rearrangement by molecular testing.	('EGFR', 'Gene', '1956', (72, 76))	('mutation', 'Var', (77, 85))	('ALK', 'Gene', '238', (90, 93))	('men', 'Species', '9606', (103, 106))	('EGFR', 'Gene', (72, 76))	('ALK', 'Gene', (90, 93))
1818	24348665	If molecular analyses are performed sequentially, results should be available for EGFR and KRAS mutation analysis within 5 working days, ALK IHC within 2 working days, and ALK fluorescence in situ hybridization (FISH) test within 3 working days.	('EGFR', 'Gene', (82, 86))	('KRAS', 'Gene', '3845', (91, 95))	('ALK', 'Gene', (137, 140))	('EGFR', 'Gene', '1956', (82, 86))	('ALK', 'Gene', (172, 175))	('KRAS', 'Gene', (91, 95))	('ALK', 'Gene', '238', (137, 140))	('mutation analysis', 'Var', (96, 113))	('ALK', 'Gene', '238', (172, 175))
1821	24348665	It is important to determine which patients should be tested for EGFR mutations, and which tests should be performed.	('mutations', 'Var', (70, 79))	('EGFR', 'Gene', '1956', (65, 69))	('EGFR', 'Gene', (65, 69))	('tested', 'Reg', (54, 60))	('patients', 'Species', '9606', (35, 43))
1822	24348665	The most common EGFR mutations are deletions in exon 19 and the L858R point mutation in exon 21; together these comprise up to 90% of all activating EGFR mutations.	('L858R', 'Mutation', 'rs121434568', (64, 69))	('EGFR', 'Gene', '1956', (149, 153))	('L858R point', 'Var', (64, 75))	('activating', 'PosReg', (138, 148))	('EGFR', 'Gene', (149, 153))	('deletions', 'Var', (35, 44))	('mutations', 'Var', (154, 163))	('EGFR', 'Gene', '1956', (16, 20))	('EGFR', 'Gene', (16, 20))	('mutations', 'Var', (21, 30))
1824	24348665	EGFR mutations are significantly more frequent in never smokers, women, East Asians, and adenocarcinomas, but also occur in smokers, men, and Western; therefore, these clinical characteristics are not absolute markers indicating that EGFR mutation analysis is necessary.	('EGFR', 'Gene', '1956', (234, 238))	('adenocarcinomas', 'Disease', 'MESH:D000230', (89, 104))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('EGFR', 'Gene', (234, 238))	('adenocarcinomas', 'Disease', (89, 104))	('EGFR', 'Gene', (0, 4))	('men', 'Species', '9606', (67, 70))	('carcinomas', 'Phenotype', 'HP:0030731', (94, 104))	('mutations', 'Var', (5, 14))	('men', 'Species', '9606', (133, 136))	('women', 'Species', '9606', (65, 70))	('EGFR', 'Gene', '1956', (0, 4))
1825	24348665	In adenocarcinoma, the prevalence of EGFR mutation is 45% in Pacific Asians and 24% in Caucasians.	('carcinoma', 'Phenotype', 'HP:0030731', (8, 17))	('adenocarcinoma', 'Disease', (3, 17))	('EGFR', 'Gene', '1956', (37, 41))	('mutation', 'Var', (42, 50))	('adenocarcinoma', 'Disease', 'MESH:D000230', (3, 17))	('EGFR', 'Gene', (37, 41))
1826	24348665	A recent Korean nationwide survey reported that the overall EGFR mutation rate was 34.3% in NSCLC and 43.3% in the adenocarcinoma histologic type.	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('EGFR', 'Gene', '1956', (60, 64))	('mutation', 'Var', (65, 73))	('adenocarcinoma', 'Disease', (115, 129))	('NSCLC', 'Disease', (92, 97))	('NSCLC', 'Disease', 'MESH:D002289', (92, 97))	('adenocarcinoma', 'Disease', 'MESH:D000230', (115, 129))	('EGFR', 'Gene', (60, 64))
1827	24348665	EGFR mutations were significantly associated with adenocarcinoma in situ, minimally invasive adenocarcinoma, and lepidic- and papillary-predominant adenocarcinoma subtypes, whereas they were rarely detected in mucinous subtype tumors.	('carcinoma', 'Phenotype', 'HP:0030731', (153, 162))	('adenocarcinoma', 'Disease', 'MESH:D000230', (50, 64))	('invasive adenocarcinoma', 'Disease', 'MESH:D000230', (84, 107))	('adenocarcinoma subtypes', 'Disease', 'MESH:D000230', (148, 171))	('tumors', 'Phenotype', 'HP:0002664', (227, 233))	('adenocarcinoma subtypes', 'Disease', (148, 171))	('adenocarcinoma', 'Disease', (93, 107))	('adenocarcinoma', 'Disease', (148, 162))	('invasive adenocarcinoma', 'Disease', (84, 107))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))	('EGFR', 'Gene', (0, 4))	('carcinoma', 'Phenotype', 'HP:0030731', (55, 64))	('mutations', 'Var', (5, 14))	('lepidic-', 'Disease', (113, 121))	('mucinous subtype tumors', 'Disease', 'MESH:D002288', (210, 233))	('adenocarcinoma', 'Disease', 'MESH:D000230', (148, 162))	('adenocarcinoma', 'Disease', (50, 64))	('adenocarcinoma', 'Disease', 'MESH:D000230', (93, 107))	('associated', 'Reg', (34, 44))	('mucinous subtype tumors', 'Disease', (210, 233))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('EGFR', 'Gene', '1956', (0, 4))
1828	24348665	EGFR mutations have also been found in large cell carcinomas, while the mutation rate in squamous cell carcinoma is generally very low.	('cell carcinomas', 'Disease', 'MESH:C538614', (45, 60))	('EGFR', 'Gene', (0, 4))	('large cell carcinomas', 'Phenotype', 'HP:0030360', (39, 60))	('carcinoma', 'Phenotype', 'HP:0030731', (50, 59))	('found', 'Reg', (30, 35))	('mutations', 'Var', (5, 14))	('carcinomas', 'Phenotype', 'HP:0030731', (50, 60))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (89, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('large cell carcinoma', 'Phenotype', 'HP:0030360', (39, 59))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (89, 112))	('EGFR', 'Gene', '1956', (0, 4))	('cell carcinomas', 'Disease', (45, 60))	('squamous cell carcinoma', 'Disease', (89, 112))
1829	24348665	Therefore, EGFR mutation testing is recommended for adenocarcinoma, large cell carcinoma, NSCLC-NOS, and squamous cell carcinomas of never smokers and where only small biopsy specimens are available.	('carcinoma', 'Phenotype', 'HP:0030731', (57, 66))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('men', 'Species', '9606', (41, 44))	('cell carcinoma', 'Disease', (74, 88))	('EGFR', 'Gene', (11, 15))	('adenocarcinoma', 'Disease', (52, 66))	('NSCLC-NOS', 'Disease', 'MESH:D002289', (90, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('carcinomas', 'Phenotype', 'HP:0030731', (119, 129))	('large cell carcinoma', 'Phenotype', 'HP:0030360', (68, 88))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (105, 129))	('cell carcinoma', 'Disease', 'MESH:C538614', (114, 128))	('adenocarcinoma', 'Disease', 'MESH:D000230', (52, 66))	('cell carcinoma', 'Disease', 'MESH:C538614', (74, 88))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (105, 129))	('mutation', 'Var', (16, 24))	('NSCLC-NOS', 'Disease', (90, 99))	('EGFR', 'Gene', '1956', (11, 15))	('men', 'Species', '9606', (180, 183))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (105, 128))	('squamous cell carcinomas', 'Disease', (105, 129))
1830	24348665	Direct sequencing is widely used for EGFR mutation detection and remains the gold standard for gene mutation analysis, although it has low sensitivity.	('EGFR', 'Gene', '1956', (37, 41))	('mutation', 'Var', (42, 50))	('EGFR', 'Gene', (37, 41))
1831	24348665	In addition to direct sequencing, various other techniques are used to detect EGFR mutations, such as pyrosequencing, Scorpion amplification refractory mutation system, and peptide nucleic acid polymerase chain reaction clamping.	('EGFR', 'Gene', (78, 82))	('mutations', 'Var', (83, 92))	('EGFR', 'Gene', '1956', (78, 82))
1832	24348665	Recently, EGFR mutation-specific antibodies, recognizing the two most common mutations, deletion E746-A750 in exon 19 and the L858R point mutation in exon 21, have been developed and can be used in immunohistochemical staining to identify the expressed mutated EGFR proteins.	('L858R', 'Var', (126, 131))	('EGFR', 'Gene', '1956', (10, 14))	('EGFR', 'Gene', '1956', (261, 265))	('EGFR', 'Gene', (10, 14))	('L858R', 'Mutation', 'rs121434568', (126, 131))	('deletion E746-A750', 'Var', (88, 106))	('EGFR', 'Gene', (261, 265))	('E746-A750', 'Var', (97, 106))
1836	24348665	Cytology samples, such as malignant pleural effusion and fine needle aspirate, are also suitable for EGFR mutation testing.	('EGFR', 'Gene', '1956', (101, 105))	('mutation', 'Var', (106, 114))	('EGFR', 'Gene', (101, 105))	('malignant pleural effusion', 'Disease', (26, 52))	('pleural effusion', 'Phenotype', 'HP:0002202', (36, 52))	('malignant pleural effusion', 'Disease', 'MESH:D016066', (26, 52))
1858	24348665	Ultimately, we expect therapeutic outcomes in NSCLC to improve with personalized therapy, which is driven by the selection of appropriate treatments based on histologic subtype and molecular status, including EGFR mutations and ALK rearrangement.	('men', 'Species', '9606', (241, 244))	('EGFR', 'Gene', (209, 213))	('ALK', 'Gene', '238', (228, 231))	('NSCLC', 'Disease', (46, 51))	('mutations', 'Var', (214, 223))	('NSCLC', 'Disease', 'MESH:D002289', (46, 51))	('men', 'Species', '9606', (143, 146))	('EGFR', 'Gene', '1956', (209, 213))	('ALK', 'Gene', (228, 231))
1866	32468052	We have expanded on our observations by including data relating to mutations and copy number alterations at pan-cancer level.	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('mutations', 'Var', (67, 76))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('copy number alterations', 'Var', (81, 104))
1868	32468052	Based on increasing data, older age and male sex predispose to severe COVID-19, whilst a number of underlying diseases/conditions are also directly related with significantly higher risk for adverse clinical outcomes from COVID-19.	('severe', 'Var', (63, 69))	('COVID-19', 'Disease', (70, 78))	('COVID-19', 'Disease', 'MESH:C000657245', (222, 230))	('COVID-19', 'Disease', (222, 230))	('COVID-19', 'Disease', 'MESH:C000657245', (70, 78))
1880	32468052	On the other hand, TMPRSS2 was upregulated in CESC, COAD, KICH, PRAD, READ, UCEC and UCS, with PRAD and READ exhibiting the highest expression of all cancers (Fig.	('PRAD', 'Disease', (64, 68))	('UCEC', 'Disease', (76, 80))	('READ', 'Disease', (70, 74))	('UCS', 'Disease', (85, 88))	('CESC', 'Disease', (46, 50))	('cancers', 'Phenotype', 'HP:0002664', (150, 157))	('cancers', 'Disease', (150, 157))	('KICH', 'Disease', (58, 62))	('cancers', 'Disease', 'MESH:D009369', (150, 157))	('COAD', 'Disease', (52, 56))	('upregulated', 'PosReg', (31, 42))	('COAD', 'Disease', 'MESH:D029424', (52, 56))	('TMPRSS2', 'Gene', '7113', (19, 26))	('PRAD', 'Var', (95, 99))	('KICH', 'Disease', 'None', (58, 62))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('TMPRSS2', 'Gene', (19, 26))
1888	32468052	Furthermore, using the cBioportal pan-cancer panel, the region and the types of mutations were identified which these two genes have in all the examined cancer types (Figs.	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('cancer', 'Disease', (153, 159))	('mutations', 'Var', (80, 89))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('cancer', 'Disease', (38, 44))
1889	32468052	Most of the CTSL mutations are lying on the peptidase region and are mostly found in CESC, ESCA, Mature B-cell Neoplasms, Melanoma and COAD (Fig.	('ESCA', 'Disease', (91, 95))	('B-cell Neoplasms', 'Disease', 'MESH:D016393', (104, 120))	('Melanoma', 'Disease', 'MESH:D008545', (122, 130))	('Melanoma', 'Phenotype', 'HP:0002861', (122, 130))	('found', 'Reg', (76, 81))	('CTSL', 'Gene', '1514', (12, 16))	('COAD', 'Disease', 'MESH:D029424', (135, 139))	('Melanoma', 'Disease', (122, 130))	('CTSL', 'Gene', (12, 16))	('B-cell Neoplasms', 'Disease', (104, 120))	('Neoplasms', 'Phenotype', 'HP:0002664', (111, 120))	('CESC', 'Disease', (85, 89))	('COAD', 'Disease', (135, 139))	('mutations', 'Var', (17, 26))
1890	32468052	Of note, in most of the cancers the majority of the patients had deletions and partly some gains and amplifications (Fig.	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('gains', 'PosReg', (91, 96))	('cancers', 'Phenotype', 'HP:0002664', (24, 31))	('deletions', 'Var', (65, 74))	('cancers', 'Disease', 'MESH:D009369', (24, 31))	('cancers', 'Disease', (24, 31))	('patients', 'Species', '9606', (52, 60))
1891	32468052	TMPRSS2 mutations were lying across the whole gene region and mostly consist of gene fusions (TMPRSS2-ERG) in prostate adenocarcinoma (Fig.	('TMPRSS2', 'Gene', '7113', (94, 101))	('prostate adenocarcinoma', 'Disease', (110, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('prostate adenocarcinoma', 'Disease', 'MESH:D011471', (110, 133))	('TMPRSS2', 'Gene', (0, 7))	('mutations', 'Var', (8, 17))	('TMPRSS2', 'Gene', (94, 101))	('consist', 'Reg', (69, 76))	('TMPRSS2', 'Gene', '7113', (0, 7))
1899	32468052	In our analysis we also demonstrate that the pancreas is riddled with deep deletions for TMPRSS2 where ACE-2 is co-expressed.	('ACE-2', 'Gene', '59272', (103, 108))	('deletions', 'Var', (75, 84))	('TMPRSS2', 'Gene', (89, 96))	('TMPRSS2', 'Gene', '7113', (89, 96))	('ACE-2', 'Gene', (103, 108))
1904	32133706	Elevation of CD109 promotes metastasis and drug resistance in lung cancer via activation of EGFR-AKT-mTOR signaling Lung cancer is the most commonly diagnosed cancer worldwide, and metastasis in lung cancer is the leading cause of cancer-related deaths.	('Elevation', 'Var', (0, 9))	('mTOR', 'Gene', '2475', (101, 105))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('lung cancer', 'Disease', (62, 73))	('lung cancer', 'Phenotype', 'HP:0100526', (195, 206))	('deaths', 'Disease', 'MESH:D003643', (246, 252))	('cancer', 'Disease', (159, 165))	('AKT', 'Gene', '207', (97, 100))	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('cancer', 'Disease', (231, 237))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('EGFR', 'Gene', '1956', (92, 96))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('cancer', 'Disease', 'MESH:D009369', (200, 206))	('metastasis', 'CPA', (28, 38))	('lung cancer', 'Disease', 'MESH:D008175', (62, 73))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('drug resistance', 'Phenotype', 'HP:0020174', (43, 58))	('promotes', 'PosReg', (19, 27))	('CD109', 'Gene', (13, 18))	('lung cancer', 'Phenotype', 'HP:0100526', (62, 73))	('lung cancer', 'Disease', (195, 206))	('Lung cancer', 'Disease', 'MESH:D008175', (116, 127))	('CD109', 'Chemical', '-', (13, 18))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('Lung cancer', 'Phenotype', 'HP:0100526', (116, 127))	('cancer', 'Disease', (67, 73))	('mTOR', 'Gene', (101, 105))	('cancer', 'Disease', 'MESH:D009369', (231, 237))	('Lung cancer', 'Disease', (116, 127))	('AKT', 'Gene', (97, 100))	('deaths', 'Disease', (246, 252))	('lung cancer', 'Disease', 'MESH:D008175', (195, 206))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('EGFR', 'Gene', (92, 96))	('drug resistance', 'CPA', (43, 58))	('cancer', 'Disease', (121, 127))	('cancer', 'Disease', (200, 206))
1908	32133706	Mechanistically, expression of CD109 regulates protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling via its association with the epidermal growth factor receptor (EGFR).	('protein kinase B', 'Gene', '2185', (47, 63))	('regulates', 'Reg', (37, 46))	('mTOR', 'Gene', (101, 105))	('mTOR', 'Gene', '2475', (101, 105))	('AKT', 'Gene', (65, 68))	('EGFR', 'Gene', '1956', (180, 184))	('EGFR', 'Gene', (180, 184))	('CD109', 'Gene', (31, 36))	('association', 'Interaction', (125, 136))	('protein kinase B', 'Gene', (47, 63))	('expression', 'Var', (17, 27))	('epidermal growth factor receptor', 'Gene', (146, 178))	('mammalian target of rapamycin', 'Gene', '2475', (70, 99))	('epidermal growth factor receptor', 'Gene', '1956', (146, 178))	('AKT', 'Gene', '207', (65, 68))	('mammalian target of rapamycin', 'Gene', (70, 99))	('CD109', 'Chemical', '-', (31, 36))
1909	32133706	Inhibition of CD109 decreases EGFR phosphorylation, diminishes EGF-elicited activation of AKT/mTOR, and sensitizes tumor cells to an EGFR inhibitor.	('EGFR', 'Gene', (30, 34))	('mTOR', 'Gene', '2475', (94, 98))	('tumor', 'Disease', (115, 120))	('EGFR', 'Gene', '1956', (133, 137))	('EGF', 'Gene', (63, 66))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('sensitizes', 'Reg', (104, 114))	('EGF', 'Gene', (30, 33))	('decreases', 'NegReg', (20, 29))	('diminishes', 'NegReg', (52, 62))	('EGF', 'Gene', (133, 136))	('activation', 'MPA', (76, 86))	('CD109', 'Gene', (14, 19))	('CD109', 'Chemical', '-', (14, 19))	('EGFR', 'Gene', '1956', (30, 34))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('AKT', 'Gene', (90, 93))	('Inhibition', 'Var', (0, 10))	('EGF', 'Gene', '1950', (63, 66))	('EGFR', 'Gene', (133, 137))	('mTOR', 'Gene', (94, 98))	('EGF', 'Gene', '1950', (133, 136))	('EGF', 'Gene', '1950', (30, 33))	('phosphorylation', 'MPA', (35, 50))	('AKT', 'Gene', '207', (90, 93))
1911	32133706	CD109 promotes lung cancer metastasis through promoting EGFR-AKT-mTOR signaling and CD109 is an independent prognostic marker for lung adenocarcinoma.	('CD109', 'Gene', (0, 5))	('promotes', 'PosReg', (6, 14))	('EGFR', 'Gene', '1956', (56, 60))	('CD109', 'Chemical', '-', (0, 5))	('lung adenocarcinoma', 'Disease', (130, 149))	('mTOR', 'Gene', (65, 69))	('lung cancer metastasis', 'Disease', 'MESH:D008175', (15, 37))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (130, 149))	('AKT', 'Gene', (61, 64))	('mTOR', 'Gene', '2475', (65, 69))	('CD109', 'Chemical', '-', (84, 89))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (130, 149))	('CD109', 'Var', (84, 89))	('EGFR', 'Gene', (56, 60))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))	('lung cancer', 'Phenotype', 'HP:0100526', (15, 26))	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('AKT', 'Gene', '207', (61, 64))	('promoting', 'PosReg', (46, 55))	('lung cancer metastasis', 'Disease', (15, 37))
1918	32133706	2  Although chemotherapy and radiation therapy show responses during early treatment of NSCLC, molecular changes in NSCLC are a major problem that cause resistance and distant metastasis.	('NSCLC', 'Disease', 'MESH:D002289', (116, 121))	('SCLC', 'Phenotype', 'HP:0030357', (89, 93))	('NSCLC', 'Phenotype', 'HP:0030358', (88, 93))	('changes', 'Var', (105, 112))	('SCLC', 'Phenotype', 'HP:0030357', (117, 121))	('cause', 'Reg', (147, 152))	('NSCLC', 'Phenotype', 'HP:0030358', (116, 121))	('NSCLC', 'Disease', (88, 93))	('NSCLC', 'Disease', 'MESH:D002289', (88, 93))	('NSCLC', 'Disease', (116, 121))
1935	32133706	shRNAs for human CD109 (TRCN0000073649 and TRCN0000073650) were obtained from the National RNAi Core Facility (Academia Sinica, Taipei, Taiwan).	('human', 'Species', '9606', (11, 16))	('TRCN0000073649', 'Var', (24, 38))	('CD109', 'Chemical', '-', (17, 22))	('TRCN0000073650', 'Var', (43, 57))
1960	32133706	Associations of CD109 with oncogenic signatures in three independent cohorts (GSE31210, GSE37745, and GSE8894) 20 ,  21 ,  22  were analyzed using a gene set enrichment analysis (GSEA) algorithm.	('CD109', 'Gene', (16, 21))	('Associations', 'Interaction', (0, 12))	('GSE37745', 'Var', (88, 96))	('CD109', 'Chemical', '-', (16, 21))	('GSEA', 'Chemical', '-', (179, 183))	('oncogenic signatures', 'MPA', (27, 47))
1961	32133706	In order to characterize the role of CD109 in lung tumorigenesis, we analyzed CD109 expression in a panel of lung cancer cell lines, and results showed that CD109 was expressed in A549, H460, and PC9 cells.	('lung cancer', 'Disease', (109, 120))	('PC9', 'Gene', (196, 199))	('CD109', 'Gene', (78, 83))	('PC9', 'Gene', '255738', (196, 199))	('lung cancer', 'Phenotype', 'HP:0100526', (109, 120))	('lung tumor', 'Disease', (46, 56))	('CD109', 'Chemical', '-', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('lung tumor', 'Disease', 'MESH:D008175', (46, 56))	('CD109', 'Chemical', '-', (78, 83))	('CD109', 'Chemical', '-', (157, 162))	('A549', 'CellLine', 'CVCL:0023', (180, 184))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('lung cancer', 'Disease', 'MESH:D008175', (109, 120))	('lung tumor', 'Phenotype', 'HP:0100526', (46, 56))	('H460', 'CellLine', 'CVCL:0459', (186, 190))	('CD109', 'Var', (157, 162))
1964	32133706	We further knocked-down CD109 in A549, CL1-5, and H460 cells (Figure 1C, Figure S1A), and results showed that silencing of CD109 significantly downregulated the migratory and invasive capacities (Figure 1D, Figure S1B), and substantially decreased the growth of tumor cells (Figure 1E, Figure S1C).	('tumor', 'Phenotype', 'HP:0002664', (262, 267))	('downregulated', 'NegReg', (143, 156))	('CD109', 'Gene', (123, 128))	('tumor', 'Disease', (262, 267))	('silencing', 'Var', (110, 119))	('CL1-5', 'Gene', (39, 44))	('CD109', 'Chemical', '-', (123, 128))	('CL1-5', 'Gene', '22859;100862695;23284;100862696', (39, 44))	('decreased', 'NegReg', (238, 247))	('CD109', 'Chemical', '-', (24, 29))	('A549', 'CellLine', 'CVCL:0023', (33, 37))	('H460', 'CellLine', 'CVCL:0459', (50, 54))	('tumor', 'Disease', 'MESH:D009369', (262, 267))
1965	32133706	Conversely, ectopic expression of CD109 enhanced migration and invasion in PC9 cells (Figure S2A and B).	('ectopic expression', 'Var', (12, 30))	('CD109', 'Gene', (34, 39))	('migration', 'CPA', (49, 58))	('CD109', 'Chemical', '-', (34, 39))	('invasion', 'CPA', (63, 71))	('PC9', 'Gene', '255738', (75, 78))	('PC9', 'Gene', (75, 78))	('enhanced', 'PosReg', (40, 48))
1970	32133706	Moreover, high CD109 expression was associated with low overall survival rates in lung adenocarcinoma patients (hazard ratio (HR) = 2.40, P < .001) but not in squamous cell carcinoma patients (Figure 2D, Figure S3).	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (159, 182))	('overall survival', 'MPA', (56, 72))	('CD109', 'Chemical', '-', (15, 20))	('patients', 'Species', '9606', (102, 110))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (82, 101))	('squamous cell carcinoma', 'Disease', (159, 182))	('carcinoma', 'Phenotype', 'HP:0030731', (173, 182))	('expression', 'MPA', (21, 31))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (159, 182))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('high', 'Var', (10, 14))	('lung adenocarcinoma', 'Disease', (82, 101))	('low', 'NegReg', (52, 55))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (82, 101))	('patients', 'Species', '9606', (183, 191))	('CD109', 'Gene', (15, 20))
1971	32133706	Additionally, high CD109 expression was found to be associated with worse recurrence-free probabilities in adenocarcinoma patients (HR = 1.66, P = .023), but not in squamous cell carcinoma patients (Figure 2D).	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (165, 188))	('CD109', 'Chemical', '-', (19, 24))	('worse', 'NegReg', (68, 73))	('squamous cell carcinoma', 'Disease', (165, 188))	('expression', 'MPA', (25, 35))	('high', 'Var', (14, 18))	('recurrence-free probabilities', 'CPA', (74, 103))	('patients', 'Species', '9606', (122, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (179, 188))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('adenocarcinoma', 'Disease', (107, 121))	('patients', 'Species', '9606', (189, 197))	('CD109', 'Gene', (19, 24))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (165, 188))	('adenocarcinoma', 'Disease', 'MESH:D000230', (107, 121))
1973	32133706	To elucidate the mechanism underlying CD109-promoted tumor invasiveness, a protein kinase array was employed in mock- and CD109-silenced A549 cells.	('tumor invasiveness', 'Disease', (53, 71))	('tumor invasiveness', 'Disease', 'MESH:D009361', (53, 71))	('CD109', 'Chemical', '-', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('CD109', 'Chemical', '-', (38, 43))	('A549', 'CellLine', 'CVCL:0023', (137, 141))	('CD109-promoted', 'Var', (38, 52))
1974	32133706	Results showed that the AKT signaling cascade, including mTOR, 70S6K, and GSK3beta, was downregulated after knocking-down CD109 (Figure 3A).	('AKT', 'Gene', (24, 27))	('knocking-down', 'Var', (108, 121))	('CD109', 'Gene', (122, 127))	('GSK3beta', 'Gene', (74, 82))	('CD109', 'Chemical', '-', (122, 127))	('GSK3beta', 'Gene', '2931', (74, 82))	('mTOR', 'Gene', (57, 61))	('mTOR', 'Gene', '2475', (57, 61))	('AKT', 'Gene', '207', (24, 27))	('downregulated', 'NegReg', (88, 101))
1975	32133706	Consistent results were obtained by Western blotting that CD109 silencing suppressed phosphorylation of AKT, mTOR, and 70S6K in A549, H460, and CL1-5 cells (Figure 3B upper panel).	('suppressed', 'NegReg', (74, 84))	('phosphorylation', 'MPA', (85, 100))	('H460', 'CellLine', 'CVCL:0459', (134, 138))	('AKT', 'Gene', (104, 107))	('A549', 'CellLine', 'CVCL:0023', (128, 132))	('mTOR', 'Gene', '2475', (109, 113))	('CD109', 'Gene', (58, 63))	('70S6K', 'Protein', (119, 124))	('mTOR', 'Gene', (109, 113))	('AKT', 'Gene', '207', (104, 107))	('CD109', 'Chemical', '-', (58, 63))	('silencing', 'Var', (64, 73))	('CL1-5', 'Gene', (144, 149))	('CL1-5', 'Gene', '22859;100862695;23284;100862696', (144, 149))
1982	32133706	A previous study reported that CD109 regulates EGFR activity in gliomas, and our aforementioned data identified that suppression of CD109 decreased AKT/mTOR signaling.	('CD109', 'Chemical', '-', (31, 36))	('AKT', 'Gene', '207', (148, 151))	('regulates', 'Reg', (37, 46))	('CD109', 'Chemical', '-', (132, 137))	('mTOR', 'Gene', (152, 156))	('decreased', 'NegReg', (138, 147))	('activity', 'MPA', (52, 60))	('mTOR', 'Gene', '2475', (152, 156))	('AKT', 'Gene', (148, 151))	('gliomas', 'Phenotype', 'HP:0009733', (64, 71))	('gliomas', 'Disease', (64, 71))	('gliomas', 'Disease', 'MESH:D005910', (64, 71))	('EGFR', 'Gene', '1956', (47, 51))	('suppression', 'Var', (117, 128))	('EGFR', 'Gene', (47, 51))	('CD109', 'Gene', (132, 137))
1986	32133706	We hypothesized that the presence of CD109 might enhance activation of the EGFR towards its ligand, including EGF.	('EGF', 'Gene', '1950', (110, 113))	('CD109', 'Gene', (37, 42))	('EGF', 'Gene', (75, 78))	('activation', 'MPA', (57, 67))	('CD109', 'Chemical', '-', (37, 42))	('EGF', 'Gene', '1950', (75, 78))	('enhance', 'PosReg', (49, 56))	('EGF', 'Gene', (110, 113))	('EGFR', 'Gene', '1956', (75, 79))	('presence', 'Var', (25, 33))	('EGFR', 'Gene', (75, 79))
1987	32133706	Indeed, inhibition of CD109 diminished EGF-induced phosphorylation of the EGFR and the downstream AKT (Figure 4C).	('EGF', 'Gene', (74, 77))	('CD109', 'Gene', (22, 27))	('EGF', 'Gene', (39, 42))	('CD109', 'Chemical', '-', (22, 27))	('diminished', 'NegReg', (28, 38))	('EGF', 'Gene', '1950', (74, 77))	('AKT', 'Gene', '207', (98, 101))	('phosphorylation', 'MPA', (51, 66))	('EGFR', 'Gene', '1956', (74, 78))	('EGF', 'Gene', '1950', (39, 42))	('inhibition', 'Var', (8, 18))	('AKT', 'Gene', (98, 101))	('EGFR', 'Gene', (74, 78))
1990	32133706	A549 cells harbor a KRAS mutation which confers resistance to EGFR-TKIs; in contrast, CL1-5 cells exhibit wild-type KRAS and are more sensitive to gefitinib.	('CL1-5', 'Gene', (86, 91))	('EGFR', 'Gene', '1956', (62, 66))	('A549', 'CellLine', 'CVCL:0023', (0, 4))	('CL1-5', 'Gene', '22859;100862695;23284;100862696', (86, 91))	('gefitinib', 'Chemical', 'MESH:D000077156', (147, 156))	('mutation', 'Var', (25, 33))	('EGFR', 'Gene', (62, 66))	('sensitive', 'MPA', (134, 143))	('resistance', 'MPA', (48, 58))	('KRAS', 'Gene', (20, 24))
1991	32133706	Interestingly, CD109 knockdown increased the susceptibility towards gefitinib in both A549 and CL1-5 cells (Figure 4F).	('CL1-5', 'Gene', '22859;100862695;23284;100862696', (95, 100))	('increased', 'PosReg', (31, 40))	('CD109', 'Chemical', '-', (15, 20))	('A549', 'CellLine', 'CVCL:0023', (86, 90))	('susceptibility towards gefitinib', 'MPA', (45, 77))	('CL1-5', 'Gene', (95, 100))	('knockdown', 'Var', (21, 30))	('gefitinib', 'Chemical', 'MESH:D000077156', (68, 77))	('CD109', 'Gene', (15, 20))
1992	32133706	To further evaluate clinical applications of CD109 in patients with lung cancer, we examined the role of CD109 in PC9 cells that harbor an EGFR-activating mutation (exon 19 deletion).	('lung cancer', 'Disease', (68, 79))	('lung cancer', 'Phenotype', 'HP:0100526', (68, 79))	('CD109', 'Chemical', '-', (105, 110))	('patients', 'Species', '9606', (54, 62))	('exon 19 deletion', 'Var', (165, 181))	('PC9', 'Gene', (114, 117))	('PC9', 'Gene', '255738', (114, 117))	('EGFR', 'Gene', '1956', (139, 143))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('lung cancer', 'Disease', 'MESH:D008175', (68, 79))	('EGFR', 'Gene', (139, 143))	('CD109', 'Chemical', '-', (45, 50))
1993	32133706	Results showed that inhibition of CD109 increased sensitivity of EGFR-AKT signaling and cell viability in response to gefitinib (Figure 4G and H).	('AKT', 'Gene', '207', (70, 73))	('EGFR', 'Gene', '1956', (65, 69))	('EGFR', 'Gene', (65, 69))	('inhibition', 'Var', (20, 30))	('CD109', 'Gene', (34, 39))	('AKT', 'Gene', (70, 73))	('gefitinib', 'Chemical', 'MESH:D000077156', (118, 127))	('response to gefitinib', 'MPA', (106, 127))	('CD109', 'Chemical', '-', (34, 39))	('cell viability', 'CPA', (88, 102))	('increased', 'PosReg', (40, 49))	('sensitivity', 'MPA', (50, 61))
1997	32133706	Accordingly, we also found that the responses to phosphatidylinositol 3-kinase signaling and growth factor stimulus were altered after knockdown of CD109 (Figure 5A).	('growth factor stimulus', 'MPA', (93, 115))	('knockdown', 'Var', (135, 144))	('altered', 'Reg', (121, 128))	('CD109', 'Gene', (148, 153))	('CD109', 'Chemical', '-', (148, 153))
1998	32133706	These data echoed findings of the downregulation of AKT/mTOR/GSK3beta signaling by CD109 silencing (Figure 3).	('mTOR', 'Gene', (56, 60))	('mTOR', 'Gene', '2475', (56, 60))	('AKT', 'Gene', (52, 55))	('downregulation', 'NegReg', (34, 48))	('CD109', 'Gene', (83, 88))	('GSK3beta', 'Gene', (61, 69))	('GSK3beta', 'Gene', '2931', (61, 69))	('CD109', 'Chemical', '-', (83, 88))	('silencing', 'Var', (89, 98))	('AKT', 'Gene', '207', (52, 55))
1999	32133706	Moreover, we analyzed CD109-regulated tumorigenic signatures by GSEA, and results revealed that genes associated with cell proliferation and invasion were downregulated by CD109 (Figure 5B).	('invasion', 'CPA', (141, 149))	('tumor', 'Disease', (38, 43))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('CD109', 'Var', (172, 177))	('CD109', 'Chemical', '-', (22, 27))	('GSEA', 'Chemical', '-', (64, 68))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('genes', 'Gene', (96, 101))	('cell proliferation', 'CPA', (118, 136))	('downregulated', 'NegReg', (155, 168))	('CD109', 'Chemical', '-', (172, 177))
2000	32133706	We selected genes which coexisted in the two datasets, and their downregulation by CD109 inhibition was further confirmed by quantitative PCR analysis (Figure 5C).	('downregulation', 'NegReg', (65, 79))	('CD109', 'Chemical', '-', (83, 88))	('CD109', 'Gene', (83, 88))	('inhibition', 'Var', (89, 99))
2009	32133706	24 ,  25  In addition, CD109 binds the TGF-betaR and glucose-regulated protein 78 (GRP78) and promotes lysosomal degradation of the TGF-betaR by inducing Smad7 and Smurf2, resulting in blocking of the transduction of TGF-beta signaling.	('TGF-beta', 'Gene', (132, 140))	('Smurf2', 'Gene', '64750', (164, 170))	('glucose-regulated protein 78', 'Gene', '3309', (53, 81))	('promotes', 'PosReg', (94, 102))	('GRP78', 'Gene', (83, 88))	('blocking', 'NegReg', (185, 193))	('GRP78', 'Gene', '3309', (83, 88))	('CD109', 'Chemical', '-', (23, 28))	('inducing', 'PosReg', (145, 153))	('CD109', 'Var', (23, 28))	('TGF-beta', 'Gene', '7039', (217, 225))	('TGF-beta', 'Gene', (217, 225))	('transduction', 'MPA', (201, 213))	('Smurf2', 'Gene', (164, 170))	('lysosomal degradation', 'MPA', (103, 124))	('Smad7', 'Gene', '4092', (154, 159))	('TGF-beta', 'Gene', '7039', (39, 47))	('Smad7', 'Gene', (154, 159))	('binds', 'Interaction', (29, 34))	('glucose-regulated protein 78', 'Gene', (53, 81))	('TGF-beta', 'Gene', '7039', (132, 140))	('TGF-beta', 'Gene', (39, 47))
2014	32133706	14  In our study, we showed that CD109 was associated with the EGFR and enhanced EGFR downstream signaling including the AKT/mTOR axis.	('EGFR', 'Gene', '1956', (63, 67))	('CD109', 'Chemical', '-', (33, 38))	('mTOR', 'Gene', '2475', (125, 129))	('AKT', 'Gene', (121, 124))	('mTOR', 'Gene', (125, 129))	('EGFR', 'Gene', (63, 67))	('EGFR', 'Gene', '1956', (81, 85))	('enhanced', 'PosReg', (72, 80))	('CD109', 'Var', (33, 38))	('associated', 'Reg', (43, 53))	('AKT', 'Gene', '207', (121, 124))	('EGFR', 'Gene', (81, 85))
2017	32133706	However, a secondary mutation in the EGFR (T790M) or a mutation of KRAS results in acquired resistance to EGFR-TKIs.	('acquired resistance', 'MPA', (83, 102))	('T790M', 'Mutation', 'rs121434569', (43, 48))	('KRAS', 'Gene', (67, 71))	('T790M', 'Var', (43, 48))	('EGFR', 'Gene', '1956', (37, 41))	('EGFR', 'Gene', '1956', (106, 110))	('mutation', 'Var', (55, 63))	('EGFR', 'Gene', (37, 41))	('results in', 'Reg', (72, 82))	('EGFR', 'Gene', (106, 110))
2020	32133706	32  In our study, we found that CD109 expression plays a crucial role in EGFR-TKI sensitivity regardless of whether in KRAS wild-type or mutant lung tumor cells.	('EGFR', 'Gene', '1956', (73, 77))	('CD109', 'Chemical', '-', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('EGFR', 'Gene', (73, 77))	('lung tumor', 'Disease', 'MESH:D008175', (144, 154))	('lung tumor', 'Disease', (144, 154))	('mutant', 'Var', (137, 143))	('lung tumor', 'Phenotype', 'HP:0100526', (144, 154))	('CD109', 'Gene', (32, 37))
2025	32133706	In the present study, we found that high CD109 expression was associated with a poor prognostic value in adenocarcinomas, but not in squamous cell carcinoma, indicating that CD109 expression plays a more-important role in tumorigenesis of adenocarcinomas.	('CD109', 'Gene', (41, 46))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('CD109', 'Chemical', '-', (41, 46))	('CD109', 'Chemical', '-', (174, 179))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (133, 156))	('adenocarcinomas', 'Disease', 'MESH:D000230', (105, 120))	('carcinoma', 'Phenotype', 'HP:0030731', (244, 253))	('high', 'Var', (36, 40))	('adenocarcinomas', 'Disease', (105, 120))	('expression', 'MPA', (47, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('carcinomas', 'Phenotype', 'HP:0030731', (110, 120))	('tumor', 'Disease', (222, 227))	('adenocarcinomas', 'Disease', 'MESH:D000230', (239, 254))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (133, 156))	('adenocarcinomas', 'Disease', (239, 254))	('tumor', 'Disease', 'MESH:D009369', (222, 227))	('carcinomas', 'Phenotype', 'HP:0030731', (244, 254))	('carcinoma', 'Phenotype', 'HP:0030731', (147, 156))	('squamous cell carcinoma', 'Disease', (133, 156))
2026	32133706	Our data were consistent with previous findings that CD109 is the strongest predictor of metastasis and survival in patients with lung adenocarcinoma.	('CD109', 'Chemical', '-', (53, 58))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (130, 149))	('patients', 'Species', '9606', (116, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))	('survival', 'CPA', (104, 112))	('lung adenocarcinoma', 'Disease', (130, 149))	('CD109', 'Var', (53, 58))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (130, 149))	('metastasis', 'CPA', (89, 99))
2029	32133706	Mutations of Ras proteins including H-Ras, K-Ras (KRAS), and N-Ras were identified to be closely associated with tumor progression.	('tumor', 'Disease', (113, 118))	('K-Ras', 'Gene', '16653', (43, 48))	('K-Ras', 'Gene', (43, 48))	('Mutations', 'Var', (0, 9))	('H-Ras', 'Gene', (36, 41))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('H-Ras', 'Gene', '15461', (36, 41))	('N-Ras', 'Gene', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('associated', 'Reg', (97, 107))	('N-Ras', 'Gene', '18176', (61, 66))
2030	32133706	35 ,  36  A previous study found that CD109-knockout mice (CD109-/-) exhibited increased incidences of H-Ras mutations in a skin tumorigenesis model, compared to CD109+/+ mice.	('CD109', 'Chemical', '-', (162, 167))	('H-Ras', 'Gene', (103, 108))	('mice', 'Species', '10090', (171, 175))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('CD109', 'Chemical', '-', (59, 64))	('CD109', 'Chemical', '-', (38, 43))	('mutations', 'Var', (109, 118))	('tumor', 'Disease', (129, 134))	('mice', 'Species', '10090', (53, 57))	('H-Ras', 'Gene', '15461', (103, 108))
2031	32133706	29  Interestingly, our present study found that CD109 was overexpressed in A549, H460, and H441 cells which harbor the KRAS mutant, compared to PC9 and CL1-5 cells that exhibit wild-type KRAS.	('overexpressed', 'PosReg', (58, 71))	('H441', 'CellLine', 'CVCL:1561', (91, 95))	('PC9', 'Gene', '255738', (144, 147))	('H460', 'CellLine', 'CVCL:0459', (81, 85))	('CL1-5', 'Gene', (152, 157))	('CL1-5', 'Gene', '22859;100862695;23284;100862696', (152, 157))	('PC9', 'Gene', (144, 147))	('mutant', 'Var', (124, 130))	('KRAS', 'Gene', (119, 123))	('CD109', 'Chemical', '-', (48, 53))	('A549', 'CellLine', 'CVCL:0023', (75, 79))
2032	32133706	Likewise, it was reported that CD109 was a major driver of lung metastasis in a KrasLSL - G12D/+;Trp53flox/flox mice model.	('G12D', 'Mutation', 'rs121913529', (90, 94))	('CD109', 'Var', (31, 36))	('Trp53', 'Gene', (97, 102))	('Trp53', 'Gene', '22059', (97, 102))	('lung metastasis', 'CPA', (59, 74))	('mice', 'Species', '10090', (112, 116))	('CD109', 'Chemical', '-', (31, 36))
2046	32009633	Moreover, CCAT1 silencing suppressed the ERK/AKT signaling through DDR2 in TCA-8113 cells.	('suppressed', 'NegReg', (26, 36))	('DDR2', 'Gene', '4921', (67, 71))	('AKT', 'Gene', (45, 48))	('TCA', 'Chemical', 'MESH:D014238', (75, 78))	('DDR2', 'Gene', (67, 71))	('silencing', 'Var', (16, 25))	('ERK', 'Gene', '5594', (41, 44))	('CCAT1', 'Gene', '100507056', (10, 15))	('AKT', 'Gene', '207', (45, 48))	('ERK', 'Gene', (41, 44))	('CCAT1', 'Gene', (10, 15))
2062	32009633	In the present study, we assessed CCAT1 expression in OSCC cell lines and the effects of CCAT1 silencing on OSCC cell proliferation, invasion, and migration.	('CCAT1', 'Gene', (34, 39))	('migration', 'CPA', (147, 156))	('invasion', 'CPA', (133, 141))	('OSCC', 'Disease', (54, 58))	('OSCC', 'Disease', 'MESH:D002294', (108, 112))	('CCAT1', 'Gene', '100507056', (89, 94))	('silencing', 'Var', (95, 104))	('OSCC', 'Disease', 'MESH:D002294', (54, 58))	('CCAT1', 'Gene', '100507056', (34, 39))	('CCAT1', 'Gene', (89, 94))	('OSCC', 'Disease', (108, 112))
2092	32009633	To study the role of CCAT1 in OSCC cells, we transfected interfering CCAT1 (shRNA- CCAT1-1/2) or empty vectors into TCA-8113 cells for silencing of CCAT1.	('CCAT1', 'Gene', '100507056', (148, 153))	('OSCC', 'Disease', 'MESH:D002294', (30, 34))	('CCAT1', 'Gene', '100507056', (69, 74))	('CCAT1', 'Gene', (21, 26))	('CCAT1', 'Gene', (83, 88))	('CCAT1', 'Gene', (69, 74))	('CCAT1', 'Gene', (148, 153))	('silencing', 'Var', (135, 144))	('TCA', 'Chemical', 'MESH:D014238', (116, 119))	('OSCC', 'Disease', (30, 34))	('CCAT1', 'Gene', '100507056', (21, 26))	('CCAT1', 'Gene', '100507056', (83, 88))
2095	32009633	As shown in Figure 2B, cell proliferation was remarkably inhibited by knockdown of CCAT1 compared with the shRNA-NC group.	('knockdown', 'Var', (70, 79))	('CCAT1', 'Gene', (83, 88))	('inhibited', 'NegReg', (57, 66))	('cell proliferation', 'CPA', (23, 41))	('CCAT1', 'Gene', '100507056', (83, 88))
2096	32009633	In addition, colony formation assay also showed a decreased number of colonies after transfection with shRNA-CCAT1-1 (Figure 2C).	('colony formation assay', 'CPA', (13, 35))	('transfection', 'Var', (85, 97))	('decreased', 'NegReg', (50, 59))	('CCAT1', 'Gene', '100507056', (109, 114))	('CCAT1', 'Gene', (109, 114))
2098	32009633	To identify the influence of CCAT1 silencing on cell cycle of TCA-8113 cells, cycle distribution was explored by flow cytometry.	('CCAT1', 'Gene', '100507056', (29, 34))	('CCAT1', 'Gene', (29, 34))	('silencing', 'Var', (35, 44))	('TCA', 'Chemical', 'MESH:D014238', (62, 65))
2100	32009633	Moreover, results from Western blot assay showed that transfection with shRNA-CCAT1-1 attenuated the levels of CDK2 and cyclinD1 but elevated the p27 protein level in TCA-8113 cells in comparison with the control or shRNA-NC group (Figure 3B).	('cyclinD1', 'Gene', '595', (120, 128))	('attenuated', 'NegReg', (86, 96))	('TCA', 'Chemical', 'MESH:D014238', (167, 170))	('elevated', 'PosReg', (133, 141))	('CCAT1', 'Gene', '100507056', (78, 83))	('CDK2', 'Gene', (111, 115))	('levels', 'MPA', (101, 107))	('CCAT1', 'Gene', (78, 83))	('p27', 'Gene', '3429', (146, 149))	('p27', 'Gene', (146, 149))	('cyclinD1', 'Gene', (120, 128))	('CDK2', 'Gene', '1017', (111, 115))	('transfection', 'Var', (54, 66))
2101	32009633	These data demonstrate that inhibition of CCAT1 blocks cell cycle progression in TCA-8113 cells.	('CCAT1', 'Gene', (42, 47))	('cell cycle progression', 'CPA', (55, 77))	('blocks', 'NegReg', (48, 54))	('inhibition', 'Var', (28, 38))	('CCAT1', 'Gene', '100507056', (42, 47))	('TCA', 'Chemical', 'MESH:D014238', (81, 84))
2110	32009633	Moreover, a reduction in protein and mRNA expression of DDR2 was observed in TCA-8113 cells upon shRNA-CCAT1-1 transfection (Figure 5B, 5C).	('DDR2', 'Gene', (56, 60))	('TCA', 'Chemical', 'MESH:D014238', (77, 80))	('mRNA expression', 'MPA', (37, 52))	('CCAT1', 'Gene', (103, 108))	('reduction', 'NegReg', (12, 21))	('protein', 'MPA', (25, 32))	('DDR2', 'Gene', '4921', (56, 60))	('transfection', 'Var', (111, 123))	('CCAT1', 'Gene', '100507056', (103, 108))
2129	32009633	CCAT1 silencing suppressed proliferation and clonogenic capacity, while CCAT1 overexpression increased both the cell viability and colony number of SCC cells.	('CCAT1', 'Gene', (0, 5))	('suppressed', 'NegReg', (16, 26))	('CCAT1', 'Gene', (72, 77))	('increased', 'PosReg', (93, 102))	('proliferation', 'CPA', (27, 40))	('SCC', 'Gene', (148, 151))	('CCAT1', 'Gene', '100507056', (0, 5))	('clonogenic capacity', 'CPA', (45, 64))	('colony number of', 'CPA', (131, 147))	('cell viability', 'CPA', (112, 126))	('silencing', 'Var', (6, 15))	('SCC', 'Gene', '6317', (148, 151))	('CCAT1', 'Gene', '100507056', (72, 77))
2131	32009633	The silencing of CCAT1 repressed cell proliferation by inhibiting cell viability, reducing colony numbers, and obstructing the cell cycle.	('CCAT1', 'Gene', (17, 22))	('colony numbers', 'CPA', (91, 105))	('reducing', 'NegReg', (82, 90))	('cell cycle', 'CPA', (127, 137))	('cell viability', 'CPA', (66, 80))	('inhibiting', 'NegReg', (55, 65))	('CCAT1', 'Gene', '100507056', (17, 22))	('obstructing', 'NegReg', (111, 122))	('silencing', 'Var', (4, 13))
2132	32009633	Additionally, CCAT1 silencing attenuated migration and invasion of TCA-8113 cells, which is in agreement with previous reports.	('CCAT1', 'Gene', (14, 19))	('TCA', 'Chemical', 'MESH:D014238', (67, 70))	('CCAT1', 'Gene', '100507056', (14, 19))	('silencing', 'Var', (20, 29))	('attenuated', 'NegReg', (30, 40))
2136	32009633	In addition, studies also found that inhibition of DDR2 diminished migration and invasion in metastatic melanoma cells by repression of MMP2 and MMP9 expression.	('melanoma', 'Phenotype', 'HP:0002861', (104, 112))	('MMP2', 'Gene', (136, 140))	('melanoma', 'Disease', (104, 112))	('inhibition', 'Var', (37, 47))	('MMP2', 'Gene', '4313', (136, 140))	('repression', 'NegReg', (122, 132))	('MMP9', 'Gene', (145, 149))	('DDR2', 'Gene', '4921', (51, 55))	('MMP9', 'Gene', '4318', (145, 149))	('diminished', 'NegReg', (56, 66))	('DDR2', 'Gene', (51, 55))	('melanoma', 'Disease', 'MESH:D008545', (104, 112))
2137	32009633	Based on these previous studies, we speculated that CCAT1 knockdown alleviates invasion and migration of TCA-8113 cells by mediating DDR2 expression.	('DDR2', 'Gene', '4921', (133, 137))	('CCAT1', 'Gene', (52, 57))	('TCA', 'Chemical', 'MESH:D014238', (105, 108))	('mediating', 'Reg', (123, 132))	('alleviates', 'NegReg', (68, 78))	('expression', 'MPA', (138, 148))	('DDR2', 'Gene', (133, 137))	('knockdown', 'Var', (58, 67))	('CCAT1', 'Gene', '100507056', (52, 57))
2145	32009633	reported that FAP silencing inhibited cell proliferation, metastasis, and invasion by blockade of the PTEN/PI3K/AKT and Ras-ERK signaling in OSCC cells.	('ERK', 'Gene', (124, 127))	('OSCC', 'Disease', (141, 145))	('silencing', 'Var', (18, 27))	('cell proliferation', 'CPA', (38, 56))	('invasion', 'CPA', (74, 82))	('PTEN', 'Gene', '5728', (102, 106))	('OSCC', 'Disease', 'MESH:D002294', (141, 145))	('blockade', 'NegReg', (86, 94))	('AKT', 'Gene', '207', (112, 115))	('inhibited', 'NegReg', (28, 37))	('PTEN', 'Gene', (102, 106))	('ERK', 'Gene', '5594', (124, 127))	('AKT', 'Gene', (112, 115))	('FAP', 'Gene', (14, 17))	('metastasis', 'CPA', (58, 68))
2147	32009633	Moreover, the modulation of ERK in cancer is associated with the regulative effect of DDR2.	('ERK', 'Gene', (28, 31))	('DDR2', 'Gene', (86, 90))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('modulation', 'Var', (14, 24))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('ERK', 'Gene', '5594', (28, 31))	('DDR2', 'Gene', '4921', (86, 90))	('cancer', 'Disease', (35, 41))	('regulative effect', 'MPA', (65, 82))
2156	32009633	These results revealed that CCAT1 silencing inhibits cell proliferation, invasion, and migration in TCA-8113 cells through inactivation of the ERK/AKT signaling pathway via repressing DDR2.	('migration', 'CPA', (87, 96))	('CCAT1', 'Gene', (28, 33))	('repressing', 'PosReg', (173, 183))	('DDR2', 'Gene', (184, 188))	('CCAT1', 'Gene', '100507056', (28, 33))	('TCA', 'Chemical', 'MESH:D014238', (100, 103))	('ERK', 'Gene', '5594', (143, 146))	('AKT', 'Gene', '207', (147, 150))	('invasion', 'CPA', (73, 81))	('inhibits', 'NegReg', (44, 52))	('cell proliferation', 'CPA', (53, 71))	('DDR2', 'Gene', '4921', (184, 188))	('silencing', 'Var', (34, 43))	('ERK', 'Gene', (143, 146))	('inactivation', 'NegReg', (123, 135))	('AKT', 'Gene', (147, 150))
2158	28915721	Dramatic response of CTNNB1 and VEGFR-2 mutant temporal bone squamous cell carcinoma to bevacizumab in combination with pemetrexed High recurrence rates and poor survival rates for late stage/advanced temporal bone squamous cell carcinoma with the standard treatments continues to be a significant challenge to otolaryngologists.	('pemetrexed', 'Chemical', 'MESH:D000068437', (120, 130))	('bone squamous cell carcinoma', 'Disease', 'MESH:D002294', (210, 238))	('temporal bone squamous cell carcinoma', 'Disease', (201, 238))	('bone squamous cell carcinoma', 'Disease', 'MESH:D002294', (56, 84))	('VEGFR-2', 'Gene', '3791', (32, 39))	('temporal bone squamous cell carcinoma', 'Disease', 'MESH:D002294', (201, 238))	('bevacizumab', 'Chemical', 'MESH:D000068258', (88, 99))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (61, 84))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (215, 238))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('CTNNB1', 'Gene', (21, 27))	('carcinoma', 'Phenotype', 'HP:0030731', (229, 238))	('temporal bone squamous cell carcinoma', 'Disease', (47, 84))	('temporal bone squamous cell carcinoma', 'Disease', 'MESH:D002294', (47, 84))	('mutant', 'Var', (40, 46))	('VEGFR-2', 'Gene', (32, 39))	('CTNNB1', 'Gene', '1499', (21, 27))
2164	28915721	Our results reveal novel gene mutations of temporal bone squamous cell carcinoma and demonstrate, for the first time, an effective targeted therapy for temporal bone squamous cell carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (180, 189))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (57, 80))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (166, 189))	('temporal bone squamous cell carcinoma', 'Disease', (152, 189))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('temporal bone squamous cell carcinoma', 'Disease', 'MESH:D002294', (152, 189))	('temporal bone squamous cell carcinoma', 'Disease', (43, 80))	('mutations', 'Var', (30, 39))	('temporal bone squamous cell carcinoma', 'Disease', 'MESH:D002294', (43, 80))
2173	28915721	We report herein the first exceptional therapeutic response to bevacizumab targeted therapy in combination with pemetrexed chemotherapy in a multiply recurrent TBSCC with genetically confirmed vascular endothelial growth factor receptor 2 (VEGFR-2) and catenin beta 1 (CTNNB1) mutation.	('CTNNB1', 'Gene', '1499', (269, 275))	('pemetrexed', 'Chemical', 'MESH:D000068437', (112, 122))	('TBSCC', 'Disease', (160, 165))	('vascular endothelial growth factor receptor 2', 'Gene', '3791', (193, 238))	('mutation', 'Var', (277, 285))	('vascular endothelial growth factor receptor 2', 'Gene', (193, 238))	('catenin beta 1', 'Gene', '1499', (253, 267))	('VEGFR-2', 'Gene', '3791', (240, 247))	('VEGFR-2', 'Gene', (240, 247))	('CTNNB1', 'Gene', (269, 275))	('catenin beta 1', 'Gene', (253, 267))	('bevacizumab', 'Chemical', 'MESH:D000068258', (63, 74))
2194	28915721	WES was employed to detect the target gene mutations from patient tumor/normal tissue pairs on the Illumina NextSeq500 sequencing platform and using a TruSeq Rapid Capture Exome Kit for library construction.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Disease', (66, 71))	('patient', 'Species', '9606', (58, 65))	('mutations', 'Var', (43, 52))	('tumor', 'Disease', 'MESH:D009369', (66, 71))
2196	28915721	Specifically, we found a missense mutation p.Met12Leu in exon3 of CTNNB1 and missense mutation p.Gln472His(exon11) in VEGFR-2.	('p.Met12Leu', 'Var', (43, 53))	('VEGFR-2', 'Gene', '3791', (118, 125))	('p.Gln472His', 'Var', (95, 106))	('CTNNB1', 'Gene', (66, 72))	('p.Met12Leu', 'Mutation', 'p.M12L', (43, 53))	('VEGFR-2', 'Gene', (118, 125))	('p.Gln472His', 'Mutation', 'rs1870377', (95, 106))	('CTNNB1', 'Gene', '1499', (66, 72))
2211	28915721	To explore the opportunity and potential benefit of targeted therapy for advanced and recurrent TBSCC, we sequenced the whole exomes of the tumor/normal tissues of the patient in our genetic test lab and identified several novel significantly mutated cancer genes that may be related to TBSCC including CTNNB1 and VEGFR-2 (Table 1).	('TBSCC', 'Disease', (287, 292))	('CTNNB1', 'Gene', '1499', (303, 309))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('patient', 'Species', '9606', (168, 175))	('VEGFR-2', 'Gene', '3791', (314, 321))	('cancer', 'Disease', (251, 257))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('cancer', 'Disease', 'MESH:D009369', (251, 257))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('mutated', 'Var', (243, 250))	('CTNNB1', 'Gene', (303, 309))	('VEGFR-2', 'Gene', (314, 321))	('tumor', 'Disease', (140, 145))
2212	28915721	A few of gene mutation and/expression dysregulation including p16, TP53 mutation, epidermal growth factor receptor (EGFR), pSTAT3, and relaxin-2 have been reported that may be related to the development or progression of different categories of TBSCC.	('epidermal growth factor receptor', 'Gene', (82, 114))	('TBSCC', 'Disease', (245, 250))	('relaxin-2', 'Gene', (135, 144))	('relaxin-2', 'Gene', '6019', (135, 144))	('mutation', 'Var', (72, 80))	('p16', 'Gene', (62, 65))	('epidermal growth factor receptor', 'Gene', '1956', (82, 114))	('pSTAT3', 'Gene', (123, 129))	('dysregulation', 'Var', (38, 51))	('mutation', 'Var', (14, 22))	('TP53', 'Gene', '7157', (67, 71))	('TP53', 'Gene', (67, 71))	('EGFR', 'Gene', '1956', (116, 120))	('p16', 'Gene', '1029', (62, 65))	('EGFR', 'Gene', (116, 120))	('related', 'Reg', (176, 183))
2214	28915721	However, in our case, we found novel mutations in CTNNB1 and VEGFR-2 genes that may be related to TBSCC and overexpression of VEGF and VEGFR-2 genes were observed in the tumor tissue.	('VEGFR-2', 'Gene', (135, 142))	('CTNNB1', 'Gene', (50, 56))	('VEGF', 'Gene', '7422', (61, 65))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('TBSCC', 'Disease', (98, 103))	('VEGFR-2', 'Gene', (61, 68))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('VEGF', 'Gene', '7422', (126, 130))	('VEGF', 'Gene', (135, 139))	('CTNNB1', 'Gene', '1499', (50, 56))	('tumor', 'Disease', (170, 175))	('mutations', 'Var', (37, 46))	('VEGFR-2', 'Gene', '3791', (135, 142))	('VEGF', 'Gene', (61, 65))	('VEGF', 'Gene', (126, 130))	('related', 'Reg', (87, 94))	('VEGF', 'Gene', '7422', (135, 139))	('VEGFR-2', 'Gene', '3791', (61, 68))
2222	28915721	In our case, genetic tests have shown mutation in VEGFR-2 (Table 1) as well as significant overexpression of VEGFR-2 and VEGF in the patient TBSCC tumor tissue (Figure 3).	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('VEGFR-2', 'Gene', (109, 116))	('VEGF', 'Gene', (121, 125))	('overexpression', 'PosReg', (91, 105))	('VEGF', 'Gene', (50, 54))	('patient', 'Species', '9606', (133, 140))	('VEGFR-2', 'Gene', '3791', (50, 57))	('VEGF', 'Gene', (109, 113))	('VEGF', 'Gene', '7422', (121, 125))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('VEGF', 'Gene', '7422', (50, 54))	('mutation', 'Var', (38, 46))	('VEGFR-2', 'Gene', '3791', (109, 116))	('VEGFR-2', 'Gene', (50, 57))	('VEGF', 'Gene', '7422', (109, 113))
2250	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))	('invasion', 'CPA', (166, 174))	('metastasis', 'CPA', (176, 186))	('regulation', 'MPA', (94, 104))	('multi-drug resistance', 'CPA', (202, 223))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('cancer', 'Disease', (58, 64))
2252	28594897	Many studies have shown that high levels of CCAT1 expression may be associated with prognosis of human cancers.	('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))	('high levels', 'Var', (29, 40))	('CCAT1', 'Gene', (44, 49))	('expression', 'MPA', (50, 60))	('cancers', 'Disease', (103, 110))
2273	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))
2312	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))	('UCA1', 'Gene', (165, 169))	('cisplatin resistance', 'MPA', (184, 204))	('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))	('osteosarcoma', 'Disease', (271, 283))	('proliferation', 'CPA', (400, 413))	('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))
2321	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))	('colon cancer', 'Disease', (3, 15))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('CCAT1', 'Gene', '100507056', (60, 65))	('colon cancer', 'Phenotype', 'HP:0003003', (3, 15))	('promotes', 'PosReg', (66, 74))	('migration', 'CPA', (98, 107))	('colon cancer', 'Disease', 'MESH:D015179', (3, 15))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (20, 37))	('CCAT1', 'Gene', (60, 65))	('pancreatic cancer', 'Disease', (20, 37))	('cell proliferation', 'CPA', (75, 93))
2324	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))
2325	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))
2328	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))
2338	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))
2371	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))
2409	27645103	High TROP2 expression had been reported to promote cancer progression and predict of poor prognosis of cancer patients.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('High', 'Var', (0, 4))	('promote', 'PosReg', (43, 50))	('TROP2', 'Gene', (5, 10))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('TROP2', 'Gene', '4070', (5, 10))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('patients', 'Species', '9606', (110, 118))
2414	27645103	Overall, these results clearly show that high TROP2 expression was a poor prognostic factor in solid tumors, with both results of poor OS (pooled HR = 1.896, 95% CI = 1.599-2.247, P < 0.001) and poor DFS (pooled HR = 2.336, 95% CI = 1.596-3.419, P < 0.001).	('solid tumors', 'Disease', (95, 107))	('TROP2', 'Gene', (46, 51))	('solid tumors', 'Disease', 'MESH:D009369', (95, 107))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('TROP2', 'Gene', '4070', (46, 51))	('high', 'Var', (41, 45))	('expression', 'MPA', (52, 62))	('poor', 'NegReg', (130, 134))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))
2418	27645103	Our quantitative results strongly supported the current mainstream viewpoint that an undesirable impact of TROP2 redundancy was correlated with the OS and DFS.	('DFS', 'Disease', (155, 158))	('TROP2', 'Gene', '4070', (107, 112))	('TROP2', 'Gene', (107, 112))	('redundancy', 'Var', (113, 123))
2419	27645103	First, high TROP2 expression may be a general poor prognostic marker in solid tumors.	('solid tumors', 'Disease', 'MESH:D009369', (72, 84))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('TROP2', 'Gene', (12, 17))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('solid tumors', 'Disease', (72, 84))	('TROP2', 'Gene', '4070', (12, 17))	('expression', 'MPA', (18, 28))	('high', 'Var', (7, 11))
2421	27645103	The pooled results from these cancer types demonstrated that high TROP2 expression was associated with poor OS and DFS, and this finding can be extended to all solid tumors.	('DFS', 'Disease', (115, 118))	('TROP2', 'Gene', (66, 71))	('solid tumors', 'Disease', 'MESH:D009369', (160, 172))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('TROP2', 'Gene', '4070', (66, 71))	('high', 'Var', (61, 65))	('cancer', 'Disease', (30, 36))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('associated', 'Reg', (87, 97))	('expression', 'MPA', (72, 82))	('poor OS', 'Disease', (103, 110))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))	('solid tumors', 'Disease', (160, 172))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
2433	26725182	Our purpose was to validate SCT methylation as a potential cancer biomarker for lung cancer.	('methylation', 'Var', (32, 43))	('lung cancer', 'Disease', 'MESH:D008175', (80, 91))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('cancer', 'Disease', (85, 91))	('lung cancer', 'Disease', (80, 91))	('lung cancer', 'Phenotype', 'HP:0100526', (80, 91))	('SCT', 'Gene', (28, 31))	('SCT', 'Gene', '6343', (28, 31))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
2436	26725182	We confirmed the highly discriminative SCT methylation by bisulfite sequencing of lung cancer cell lines and normal blood cells.	('lung cancer', 'Phenotype', 'HP:0100526', (82, 93))	('methylation', 'Var', (43, 54))	('lung cancer', 'Disease', (82, 93))	('SCT', 'Gene', (39, 42))	('SCT', 'Gene', '6343', (39, 42))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('bisulfite', 'Chemical', 'MESH:C042345', (58, 67))	('lung cancer', 'Disease', 'MESH:D008175', (82, 93))
2437	26725182	By applying qMSP, we found that SCT hypermethylation was frequently detected in all major subtypes of malignant NSCLC (AUC=0.92, n=108) and SCLC cancers (AUC=0.93, n=40) but less frequently present in lung carcinoids (AUC=0.54, n=20).	('lung carcinoids', 'Disease', 'MESH:D002276', (201, 216))	('SCT', 'Gene', (32, 35))	('SCT', 'Gene', '6343', (32, 35))	('malignant NSCLC', 'Disease', 'MESH:D009369', (102, 117))	('malignant NSCLC', 'Disease', (102, 117))	('lung carcinoids', 'Disease', (201, 216))	('SCLC cancers', 'Disease', (140, 152))	('carcinoid', 'Phenotype', 'HP:0100570', (206, 215))	('carcinoids', 'Phenotype', 'HP:0100570', (206, 216))	('hypermethylation', 'Var', (36, 52))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('lung carcinoids', 'Phenotype', 'HP:0030445', (201, 216))	('detected', 'Reg', (68, 76))	('SCLC cancers', 'Disease', 'MESH:D018288', (140, 152))	('cancers', 'Phenotype', 'HP:0002664', (145, 152))
2438	26725182	SCT hypermethylation appeared in lung carcinoma in situ samples during multistage pathogenesis and increased in invasive samples.	('carcinoma in situ', 'Phenotype', 'HP:0030075', (38, 55))	('lung carcinoma', 'Disease', (33, 47))	('lung carcinoma', 'Disease', 'MESH:D008175', (33, 47))	('appeared', 'Reg', (21, 29))	('carcinoma in situ', 'Disease', 'MESH:D002278', (38, 55))	('SCT', 'Gene', '6343', (0, 3))	('increased', 'PosReg', (99, 108))	('hypermethylation', 'Var', (4, 20))	('SCT', 'Gene', (0, 3))	('carcinoma', 'Phenotype', 'HP:0030731', (38, 47))	('carcinoma in situ', 'Disease', (38, 55))
2439	26725182	Further analyses of TCGA 450K data showed that SCT hypermethylation is highly discriminative in most types of other malignant tumors but less frequently present in low-grade malignant tumors.	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('hypermethylation', 'Var', (51, 67))	('malignant tumors', 'Disease', (174, 190))	('CG', 'Chemical', 'MESH:C028505', (21, 23))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('malignant tumors', 'Disease', (116, 132))	('tumors', 'Phenotype', 'HP:0002664', (184, 190))	('SCT', 'Gene', (47, 50))	('SCT', 'Gene', '6343', (47, 50))	('malignant tumors', 'Disease', 'MESH:D018198', (116, 132))	('malignant tumors', 'Disease', 'MESH:D018198', (174, 190))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))
2440	26725182	Our findings demonstrated that SCT methylation is a highly discriminative biomarker for lung and other malignant tumors, and less frequently present in low-grade malignant tumors including lung carcinoids, and appears at the carcinoma in situ stage.	('carcinoma in situ', 'Disease', (225, 242))	('carcinoid', 'Phenotype', 'HP:0100570', (194, 203))	('lung carcinoids', 'Disease', 'MESH:D002276', (189, 204))	('lung', 'Disease', (88, 92))	('malignant tumors', 'Disease', 'MESH:D018198', (162, 178))	('tumors', 'Phenotype', 'HP:0002664', (172, 178))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (225, 242))	('malignant tumors', 'Disease', (162, 178))	('SCT', 'Gene', (31, 34))	('SCT', 'Gene', '6343', (31, 34))	('carcinoma in situ', 'Disease', 'MESH:D002278', (225, 242))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('lung carcinoids', 'Disease', (189, 204))	('methylation', 'Var', (35, 46))	('carcinoids', 'Phenotype', 'HP:0100570', (194, 204))	('malignant tumors', 'Disease', 'MESH:D018198', (103, 119))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (225, 234))	('lung carcinoids', 'Phenotype', 'HP:0030445', (189, 204))	('malignant tumors', 'Disease', (103, 119))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))
2443	26725182	The methylation of cytosine adjacent to guanosine in the CpG island sequence in the promoter region may lead to silencing of gene expression including tumor suppressor genes in lung and other cancers.	('cytosine', 'Var', (19, 27))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('cytosine', 'Chemical', 'MESH:D003596', (19, 27))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('tumor', 'Disease', (151, 156))	('cancers', 'Disease', 'MESH:D009369', (192, 199))	('methylation', 'Var', (4, 15))	('cancers', 'Phenotype', 'HP:0002664', (192, 199))	('silencing', 'NegReg', (112, 121))	('cancers', 'Disease', (192, 199))	('guanosine', 'Chemical', 'MESH:D006151', (40, 49))	('gene expression', 'MPA', (125, 140))	('lung', 'Disease', (177, 181))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
2444	26725182	Genome-wide analysis of DNA methylation has showed altered DNA methylation between lung tumor and non-malignant lung affecting expression of multiple genes which play an important role in carcinogenesis.	('lung tumor', 'Disease', (83, 93))	('expression', 'MPA', (127, 137))	('carcinogenesis', 'Disease', 'MESH:D063646', (188, 202))	('lung tumor', 'Phenotype', 'HP:0100526', (83, 93))	('carcinogenesis', 'Disease', (188, 202))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('methylation', 'Var', (63, 74))	('affecting', 'Reg', (117, 126))	('lung tumor', 'Disease', 'MESH:D008175', (83, 93))
2445	26725182	Of interest, the onset and level of aberrant epigenetic DNA methylation changes commences during multistage pathogenesis of lung cancer.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('lung cancer', 'Disease', 'MESH:D008175', (124, 135))	('aberrant epigenetic', 'Var', (36, 55))	('lung cancer', 'Disease', (124, 135))	('lung cancer', 'Phenotype', 'HP:0100526', (124, 135))	('epigenetic', 'Var', (45, 55))
2446	26725182	Aberrant DNA methylation may be useful as biomarkers for early diagnosis, prognosis, and risk assessment as well as therapy management for cancer patients.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('Aberrant', 'Var', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('DNA', 'Protein', (9, 12))	('patients', 'Species', '9606', (146, 154))	('cancer', 'Disease', (139, 145))
2457	26725182	From analysis of The Cancer Genome Atlas (TCGA) methylation 450K array data, authors XM and MQZ observed that the promoter region of SCT gene was selectively hypermethylated in non-small cell lung cancer (NSCLC).	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (177, 203))	('lung cancer', 'Phenotype', 'HP:0100526', (192, 203))	('SCT', 'Gene', '6343', (133, 136))	('non-small cell lung cancer', 'Disease', (177, 203))	('hypermethylated', 'Var', (158, 173))	('SCT', 'Gene', (133, 136))	('Cancer Genome Atlas', 'Disease', (21, 40))	('NSCLC', 'Disease', (205, 210))	('Cancer', 'Phenotype', 'HP:0002664', (21, 27))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (21, 40))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (177, 203))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('CG', 'Chemical', 'MESH:C028505', (43, 45))	('NSCLC', 'Disease', 'MESH:D002289', (205, 210))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (181, 203))
2458	26725182	The purpose of this study was to extend this finding and to validate SCT methylation as a potential cancer biomarker for lung and other cancers.	('cancers', 'Phenotype', 'HP:0002664', (136, 143))	('cancers', 'Disease', (136, 143))	('lung', 'Disease', (121, 125))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('cancers', 'Disease', 'MESH:D009369', (136, 143))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('cancer', 'Disease', (136, 142))	('methylation', 'Var', (73, 84))	('SCT', 'Gene', '6343', (69, 72))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('SCT', 'Gene', (69, 72))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
2467	26725182	To compare all 28 genes, we selected the representative probe from multiple probes of each gene, which had the methylation demonstrating the highest median beta value difference between tumor and non-malignant lung tissues.	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('methylation', 'Var', (111, 122))	('tumor', 'Disease', (186, 191))
2486	26725182	By using Methyl Primer Express software we designed a second SCT qMSP assay, denoted as SCT qMSP-2, to obtain a shorter PCR amplicon thus improve the detection of fragmented DNA from FFPE samples (locations of 80 bp amplicon: from +183 nt to +262 nt using SCT TSS as +1 nt).	('detection', 'MPA', (150, 159))	('SCT', 'Gene', '6343', (256, 259))	('SCT', 'Gene', (88, 91))	('SCT', 'Gene', '6343', (88, 91))	('fragmented', 'Var', (163, 173))	('SCT', 'Gene', (256, 259))	('SCT', 'Gene', (61, 64))	('improve', 'PosReg', (138, 145))	('SCT', 'Gene', '6343', (61, 64))
2506	26725182	Two SCT 450K array probes near the transcription start site of SCT gene (target ID cg25774643 and cg00249511, corresponding to probes 4 and 5 in Fig.	('cg00249511', 'Var', (98, 108))	('cg25774643', 'Var', (83, 93))	('SCT', 'Gene', (4, 7))	('SCT', 'Gene', '6343', (4, 7))	('SCT', 'Gene', '6343', (63, 66))	('SCT', 'Gene', (63, 66))
2515	26725182	S5 in Supplemental Digital Content 3), we found that homozygous deletions of SCT gene were not found in lung squamous cell carcinomas (n=490) and infrequent (<0.8%, n=496) in lung adenocarcinomas, implying that SCT promoter region can be a potential tissue methylation biomarker for nearly all lung adenocarcinoma and squamous cell carcinoma cancers.	('lung squamous cell carcinomas', 'Disease', (104, 133))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (109, 133))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (175, 194))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (294, 313))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (175, 194))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (318, 341))	('cancer', 'Phenotype', 'HP:0002664', (342, 348))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (175, 195))	('cancers', 'Phenotype', 'HP:0002664', (342, 349))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (109, 132))	('carcinoma', 'Phenotype', 'HP:0030731', (332, 341))	('lung adenocarcinomas', 'Disease', (175, 195))	('SCT', 'Gene', (77, 80))	('SCT', 'Gene', '6343', (77, 80))	('lung squamous cell carcinomas', 'Disease', 'MESH:D002294', (104, 133))	('lung adenocarcinoma', 'Disease', (294, 313))	('squamous cell carcinoma cancers', 'Disease', (318, 349))	('carcinomas', 'Phenotype', 'HP:0030731', (123, 133))	('squamous cell carcinoma cancers', 'Disease', 'MESH:D002294', (318, 349))	('SCT', 'Gene', (211, 214))	('SCT', 'Gene', '6343', (211, 214))	('deletions', 'Var', (64, 73))	('carcinoma', 'Phenotype', 'HP:0030731', (304, 313))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('carcinoma', 'Phenotype', 'HP:0030731', (185, 194))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (175, 195))	('carcinomas', 'Phenotype', 'HP:0030731', (185, 195))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (294, 313))
2565	26725182	Our findings were consistent with the previous observation that aberrant DNA methylation commenced at an early stage of lung cancer pathogenesis.	('lung cancer', 'Disease', (120, 131))	('lung cancer', 'Phenotype', 'HP:0100526', (120, 131))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('aberrant DNA methylation', 'Var', (64, 88))	('lung cancer', 'Disease', 'MESH:D008175', (120, 131))
2577	26725182	Additionally, the CDK4/hTERT-immortalized human small airway epithelial cells-1 (HSAEC1-KT) line had increased SCT methylation while further transformed with mutant K-RasV12 and/or mutant TP53 as reflected by PMR increase from 0.13% to 1.37%, 12.99% and 24.68%, respectively (see Fig.	('mutant', 'Var', (181, 187))	('SCT', 'Gene', (111, 114))	('TP53', 'Gene', (188, 192))	('hTERT', 'Gene', (23, 28))	('SCT', 'Gene', '6343', (111, 114))	('increased', 'PosReg', (101, 110))	('human', 'Species', '9606', (42, 47))	('HSAEC1', 'CellLine', 'CVCL:X488', (81, 87))	('PMR', 'Chemical', '-', (209, 212))	('hTERT', 'Gene', '7015', (23, 28))	('increase', 'PosReg', (213, 221))	('increased SCT', 'Phenotype', 'HP:0001899', (101, 114))	('TP53', 'Gene', '7157', (188, 192))	('mutant', 'Var', (158, 164))	('CDK4', 'Gene', '1019', (18, 22))	('CDK4', 'Gene', (18, 22))
2579	26725182	These findings imply that aberrant SCT methylation may commence even when a few transformation-related genes are initiated at the premalignant or early malignant stage of cancer.	('aberrant', 'Var', (26, 34))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('cancer', 'Disease', (171, 177))	('SCT', 'Gene', '6343', (35, 38))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('SCT', 'Gene', (35, 38))
2596	26725182	Our own data indicated that aberrant SCT methylation was present in all highly malignant types of lung cancer including all four of the major NSCLC types and SCLC cancers, implying that SCT methylation biomarker can potentially have wide clinical applications.	('cancers', 'Phenotype', 'HP:0002664', (163, 170))	('SCT', 'Gene', (186, 189))	('SCT', 'Gene', '6343', (186, 189))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('SCT', 'Gene', '6343', (37, 40))	('lung cancer', 'Disease', (98, 109))	('NSCLC', 'Disease', (142, 147))	('lung cancer', 'Phenotype', 'HP:0100526', (98, 109))	('SCT', 'Gene', (37, 40))	('aberrant', 'Var', (28, 36))	('methylation', 'Var', (41, 52))	('SCLC cancers', 'Disease', (158, 170))	('NSCLC', 'Disease', 'MESH:D002289', (142, 147))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('lung cancer', 'Disease', 'MESH:D008175', (98, 109))	('SCLC cancers', 'Disease', 'MESH:D018288', (158, 170))	('present', 'Reg', (57, 64))
2600	26725182	In this study, for both lung adenocarcinomas and squamous cell carcinomas SCT methylation commenced during multistage pathogenesis and progressively increased in frequency and levels, until the in situ and invasive stages.	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (24, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (34, 43))	('carcinomas', 'Phenotype', 'HP:0030731', (63, 73))	('methylation', 'Var', (78, 89))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (49, 72))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (24, 44))	('SCT', 'Gene', (74, 77))	('increased', 'PosReg', (149, 158))	('SCT', 'Gene', '6343', (74, 77))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (24, 43))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (49, 73))	('lung adenocarcinomas', 'Disease', (24, 44))	('carcinomas', 'Phenotype', 'HP:0030731', (34, 44))	('adenocarcinomas and squamous cell carcinomas', 'Disease', 'MESH:D002294', (29, 73))
2601	26725182	The commencement of SCT methylation at early stage of lung cancer was further supported by our findings that the alteration with a few transformation-related genes in the immortalized normal human respiratory cell lines was correlated with an increase of SCT methylation.	('lung cancer', 'Disease', (54, 65))	('lung cancer', 'Phenotype', 'HP:0100526', (54, 65))	('alteration', 'Var', (113, 123))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('lung cancer', 'Disease', 'MESH:D008175', (54, 65))	('increase', 'PosReg', (243, 251))	('SCT', 'Gene', '6343', (20, 23))	('SCT', 'Gene', (255, 258))	('SCT', 'Gene', '6343', (255, 258))	('human', 'Species', '9606', (191, 196))	('SCT', 'Gene', (20, 23))
2602	26725182	Our findings demonstrated that SCT methylation is a promising early diagnostic tissue biomarker for malignant lung cancer with excellent tumor specificity and sensitivity.	('tumor', 'Disease', (137, 142))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('lung cancer', 'Phenotype', 'HP:0100526', (110, 121))	('methylation', 'Var', (35, 46))	('malignant lung cancer', 'Disease', (100, 121))	('malignant lung cancer', 'Disease', 'MESH:D008175', (100, 121))	('SCT', 'Gene', (31, 34))	('SCT', 'Gene', '6343', (31, 34))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
2603	26725182	We previously observed that lung carcinoids had lower frequencies (RARB, CDH1 and RASSF1A genes) or lower levels (p16, APC and CDH13 genes) of aberrant DNA methylation as compared with SCLC tumors and NSCLC tumors, respectively.	('APC', 'Disease', 'MESH:D011125', (119, 122))	('lung carcinoids', 'Phenotype', 'HP:0030445', (28, 43))	('APC', 'Disease', (119, 122))	('NSCLC tumors', 'Disease', (201, 213))	('tumors', 'Phenotype', 'HP:0002664', (207, 213))	('lower', 'NegReg', (100, 105))	('SCLC tumors', 'Disease', (185, 196))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('p16', 'Gene', (114, 117))	('CDH13', 'Gene', '1012', (127, 132))	('aberrant', 'Var', (143, 151))	('p16', 'Gene', '1029', (114, 117))	('RASSF1A', 'Gene', '11186', (82, 89))	('carcinoids', 'Phenotype', 'HP:0100570', (33, 43))	('RARB', 'Gene', (67, 71))	('RARB', 'Gene', '5915', (67, 71))	('carcinoid', 'Phenotype', 'HP:0100570', (33, 42))	('RASSF1A', 'Gene', (82, 89))	('lung carcinoids', 'Disease', 'MESH:D002276', (28, 43))	('NSCLC tumors', 'Disease', 'MESH:D009369', (201, 213))	('SCLC tumors', 'Disease', 'MESH:D018288', (202, 213))	('lower', 'NegReg', (48, 53))	('CDH1', 'Gene', '999', (73, 77))	('CDH13', 'Gene', (127, 132))	('CDH1', 'Gene', '999', (127, 131))	('CDH1', 'Gene', (73, 77))	('lung carcinoids', 'Disease', (28, 43))	('SCLC tumors', 'Disease', 'MESH:D018288', (185, 196))	('tumors', 'Phenotype', 'HP:0002664', (190, 196))	('levels', 'MPA', (106, 112))	('CDH1', 'Gene', (127, 131))
2605	26725182	The difference in the frequency of aberrant SCT methylation among lung tumor histology types was consistent with other findings that the DNA methylation changes may occur in a histology-type specific manner, and may reflect the lower metastatic potential of low grade neuroendocrine tumors.	('metastatic potential', 'CPA', (234, 254))	('SCT', 'Gene', (44, 47))	('neuroendocrine tumors', 'Disease', 'MESH:D018358', (268, 289))	('aberrant', 'Var', (35, 43))	('SCT', 'Gene', '6343', (44, 47))	('lung tumor', 'Phenotype', 'HP:0100526', (66, 76))	('tumor', 'Phenotype', 'HP:0002664', (283, 288))	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (268, 289))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('neuroendocrine tumors', 'Disease', (268, 289))	('lung tumor', 'Disease', (66, 76))	('changes', 'Var', (153, 160))	('tumors', 'Phenotype', 'HP:0002664', (283, 289))	('lung tumor', 'Disease', 'MESH:D008175', (66, 76))
2611	26725182	Thus our observations suggest that SCT methylation may be a potentially useful cancer biomarker to facilitate early diagnosis and prognosis for many types of cancers.	('methylation', 'Var', (39, 50))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('cancers', 'Phenotype', 'HP:0002664', (158, 165))	('cancer', 'Disease', (158, 164))	('cancers', 'Disease', (158, 165))	('cancers', 'Disease', 'MESH:D009369', (158, 165))	('SCT', 'Gene', '6343', (35, 38))	('facilitate', 'PosReg', (99, 109))	('cancer', 'Disease', (79, 85))	('SCT', 'Gene', (35, 38))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
2622	26725182	Previous findings suggest that SCT methylation may play a role of controlling secretin expression in human pancreatic and hepatocellular carcinoma cell lines.	('secretin', 'Gene', '6343', (78, 86))	('controlling', 'Reg', (66, 77))	('human', 'Species', '9606', (101, 106))	('expression', 'MPA', (87, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('methylation', 'Var', (35, 46))	('SCT', 'Gene', '6343', (31, 34))	('SCT', 'Gene', (31, 34))	('secretin', 'Gene', (78, 86))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (122, 146))	('pancreatic and hepatocellular carcinoma', 'Disease', 'MESH:D006528', (107, 146))
2626	26725182	However, the almost universal presence of methylation in many tumor tissues and its virtual absence or minimal methylation in most non-malignant tissues (other than placenta) suggests an important role in tumor biology.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('tumor', 'Disease', (62, 67))	('methylation', 'MPA', (111, 122))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumor', 'Disease', (205, 210))	('methylation', 'Var', (42, 53))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
2632	26725182	In conclusion, we have demonstrated that SCT methylation is a hallmark biomarker of lung cancer tissues across all major histological subtypes and commences during multistage pathogenesis.	('lung cancer', 'Disease', (84, 95))	('lung cancer', 'Phenotype', 'HP:0100526', (84, 95))	('SCT', 'Gene', '6343', (41, 44))	('methylation', 'Var', (45, 56))	('lung cancer', 'Disease', 'MESH:D008175', (84, 95))	('SCT', 'Gene', (41, 44))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
2635	26725182	As SCT methylation is a highly discriminative potential biomarker for many other types of cancers besides lung cancers, clinical applications beyond lung cancer also need to be explored.	('cancers', 'Disease', 'MESH:D009369', (111, 118))	('cancers', 'Disease', (90, 97))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('lung cancers', 'Disease', 'MESH:D008175', (106, 118))	('methylation', 'Var', (7, 18))	('lung cancer', 'Disease', (149, 160))	('lung cancer', 'Disease', 'MESH:D008175', (106, 117))	('lung cancers', 'Disease', (106, 118))	('lung cancer', 'Phenotype', 'HP:0100526', (106, 117))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('lung cancers', 'Phenotype', 'HP:0100526', (106, 118))	('cancers', 'Disease', 'MESH:D009369', (90, 97))	('cancers', 'Phenotype', 'HP:0002664', (111, 118))	('lung cancer', 'Disease', 'MESH:D008175', (149, 160))	('cancers', 'Disease', (111, 118))	('lung cancer', 'Phenotype', 'HP:0100526', (149, 160))	('SCT', 'Gene', (3, 6))	('SCT', 'Gene', '6343', (3, 6))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))
2655	25116943	More recent studies have found that the intronic non-coding RNA (ncRNA) lncRNA-LET plays a role in the regulation of hypoxia-mediated metastasis in squamous cell lung carcinoma, intronic ncRNA AK126698 confers resistance to cisplatin by targeting the Wnt pathway, and the lncRNA SCAL1 (smoke and cancer-associated lncRNA-1) is associated with tobacco-induced lung cancer.	('cancer', 'Phenotype', 'HP:0002664', (296, 302))	('Wnt pathway', 'Pathway', (251, 262))	('carcinoma', 'Phenotype', 'HP:0030731', (167, 176))	('SCAL1', 'Gene', (279, 284))	('squamous cell lung carcinoma', 'Phenotype', 'HP:0030359', (148, 176))	('lung cancer', 'Disease', 'MESH:D008175', (359, 370))	('ncRNA', 'Var', (187, 192))	('cancer', 'Disease', 'MESH:D009369', (296, 302))	('squamous cell lung carcinoma', 'Disease', (148, 176))	('cancer', 'Disease', (364, 370))	('lung cancer', 'Phenotype', 'HP:0100526', (359, 370))	('resistance', 'MPA', (210, 220))	('cancer', 'Phenotype', 'HP:0002664', (364, 370))	('tobacco', 'Species', '4097', (343, 350))	('squamous cell lung carcinoma', 'Disease', 'MESH:D002294', (148, 176))	('hypoxia', 'Disease', (117, 124))	('cisplatin', 'Chemical', 'MESH:D002945', (224, 233))	('AK126698', 'Var', (193, 201))	('targeting', 'Reg', (237, 246))	('cancer', 'Disease', 'MESH:D009369', (364, 370))	('lung cancer', 'Disease', (359, 370))	('hypoxia', 'Disease', 'MESH:D000860', (117, 124))	('cancer', 'Disease', (296, 302))	('SCAL1', 'Gene', '100505994', (279, 284))
2703	25116943	Therefore, to determine if LCAL expression levels are associated with mutational status we focused on 16 protein coding genes that have been reported by TCGA as mutated in at least 10% of lung cancer tumors.	('lung cancer', 'Phenotype', 'HP:0100526', (188, 199))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('tumors', 'Phenotype', 'HP:0002664', (200, 206))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('lung cancer tumors', 'Disease', (188, 206))	('mutated', 'Var', (161, 168))	('lung cancer tumors', 'Disease', 'MESH:D008175', (188, 206))
2705	25116943	In LUSC, NFE2L2 mutational status is associated with six LCALs (Figure 6A).	('associated with', 'Reg', (37, 52))	('six LCALs', 'Disease', (53, 62))	('NFE2L2', 'Gene', '4780', (9, 15))	('mutational status', 'Var', (16, 33))	('LCALs', 'Chemical', '-', (57, 62))	('NFE2L2', 'Gene', (9, 15))
2706	25116943	The mutational status of NFE2L2 and KEAP1, which have been shown to regulate cell response to oxidative damage, is associated with expression levels of multiple LCALs, including LCAL51, or SCAL1 (Figure 6B).	('KEAP1', 'Gene', (36, 41))	('LCAL5', 'Gene', (178, 183))	('SCAL1', 'Gene', (189, 194))	('NFE2L2', 'Gene', '4780', (25, 31))	('associated', 'Reg', (115, 125))	('expression levels', 'MPA', (131, 148))	('cell response to oxidative damage', 'MPA', (77, 110))	('SCAL1', 'Gene', '100505994', (189, 194))	('KEAP1', 'Gene', '9817', (36, 41))	('NFE2L2', 'Gene', (25, 31))	('LCAL5', 'Gene', '400619', (178, 183))	('mutational', 'Var', (4, 14))	('LCALs', 'Chemical', '-', (161, 166))
2716	25116943	Greater than 50% knockdown of LCAL1 in the cell line H322M, which models adenocarcinoma, with two different siRNAs resulted in decreased cell growth as measured by cell counting for six days.	('adenocarcinoma', 'Disease', 'MESH:D000230', (73, 87))	('decreased', 'NegReg', (127, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('LCAL1', 'Gene', (30, 35))	('adenocarcinoma', 'Disease', (73, 87))	('cell growth', 'CPA', (137, 148))	('knockdown', 'Var', (17, 26))	('LCAL1', 'Gene', '80078', (30, 35))
2717	25116943	Both LCAL1 siRNA knockdowns in H322M caused at least a 24% decrease in cell growth starting at day 2 and a 37% or 50% decrease in cell growth in siRNA 1 or siRNA 2, respectively, at day 6 compared to control cells (Figure 7A).	('H322M', 'Var', (31, 36))	('LCAL1', 'Gene', (5, 10))	('cell growth', 'CPA', (71, 82))	('cell growth', 'CPA', (130, 141))	('decrease', 'NegReg', (59, 67))	('decrease', 'NegReg', (118, 126))	('LCAL1', 'Gene', '80078', (5, 10))
2719	25116943	Greater than 50% knockdown of LCAL1 in HCC95 cells recapitulated cell growth observations in the H322M cell.	('HCC95', 'CellLine', 'CVCL:5137', (39, 44))	('cell growth observations', 'CPA', (65, 89))	('LCAL1', 'Gene', (30, 35))	('knockdown', 'Var', (17, 26))	('LCAL1', 'Gene', '80078', (30, 35))
2720	25116943	Both siRNA knockdowns in HCC95 caused at least a 30% decrease in cell growth starting at day 2, which was maintained through to the end of the experiment at day 6 compared with control cells (Figure 7B).	('cell growth', 'CPA', (65, 76))	('decrease', 'NegReg', (53, 61))	('HCC95', 'Gene', (25, 30))	('knockdowns', 'Var', (11, 21))	('HCC95', 'CellLine', 'CVCL:5137', (25, 30))
2734	25116943	This analysis highlights the importance of lncRNAs not only in lung cancer but also as broad oncogenic factors and lays the groundwork for future studies to determine the mechanisms by which these newly discovered non-coding RNAs act in cancer progression.	('act', 'Reg', (230, 233))	('lung cancer', 'Disease', 'MESH:D008175', (63, 74))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('non-coding', 'Var', (214, 224))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('lung cancer', 'Disease', (63, 74))	('lung cancer', 'Phenotype', 'HP:0100526', (63, 74))	('cancer', 'Disease', 'MESH:D009369', (237, 243))	('cancer', 'Disease', (68, 74))	('cancer', 'Disease', (237, 243))
2741	25116943	Here we discovered that some LCALs are also associated with mutational status, thereby implicating them in key oncogenic pathways.	('associated', 'Reg', (44, 54))	('LCALs', 'Disease', (29, 34))	('mutational status', 'Var', (60, 77))	('implicating', 'Reg', (87, 98))	('LCALs', 'Chemical', '-', (29, 34))
2742	25116943	In addition to altered LCAL expression associating with TP53 mutation status, some of the LCALs also associated with mutations in KEAP1 and NFE2L2, which are key players in the oxidative stress pathway.	('NFE2L2', 'Gene', '4780', (140, 146))	('mutations', 'Var', (117, 126))	('KEAP1', 'Gene', (130, 135))	('TP53', 'Gene', '7157', (56, 60))	('NFE2L2', 'Gene', (140, 146))	('LCAL expression', 'MPA', (23, 38))	('TP53', 'Gene', (56, 60))	('LCALs', 'Chemical', '-', (90, 95))	('associated', 'Reg', (101, 111))	('altered', 'Reg', (15, 22))	('KEAP1', 'Gene', '9817', (130, 135))	('LCALs', 'Disease', (90, 95))	('oxidative stress', 'Phenotype', 'HP:0025464', (177, 193))
2743	25116943	For instance, SCAL1 (LCAL51) was found to be associated with KEAP1 mutation status in LUAD and NFE2L2 mutation status in LUSC (Figure 6B) and was recently shown to act downstream of NRF2 and mediate oxidative stress protection in airway epithelial cells.	('KEAP1', 'Gene', (61, 66))	('NFE2L2', 'Gene', '4780', (95, 101))	('LCAL5', 'Gene', (21, 26))	('NRF2', 'Gene', (182, 186))	('mutation status', 'Var', (67, 82))	('NFE2L2', 'Gene', (95, 101))	('SCAL1', 'Gene', (14, 19))	('LCAL5', 'Gene', '400619', (21, 26))	('associated', 'Reg', (45, 55))	('oxidative stress', 'Phenotype', 'HP:0025464', (199, 215))	('SCAL1', 'Gene', '100505994', (14, 19))	('KEAP1', 'Gene', '9817', (61, 66))	('NRF2', 'Gene', '4780', (182, 186))	('mutation status', 'Var', (102, 117))
2747	25116943	Moreover, as proof-of-principle, our LCAL1 overexpression studies highlight increased proliferation compared with control BEAS-2B empty vector cells, suggesting that altered LCAL1 is sufficient for promoting the etiology of the disease.	('LCAL1', 'Gene', '80078', (174, 179))	('increased', 'PosReg', (76, 85))	('LCAL1', 'Gene', (37, 42))	('proliferation', 'CPA', (86, 99))	('BEAS-2B', 'CellLine', 'CVCL:0168', (122, 129))	('altered', 'Var', (166, 173))	('promoting', 'PosReg', (198, 207))	('LCAL1', 'Gene', (174, 179))	('LCAL1', 'Gene', '80078', (37, 42))
2762	25116943	Enrichment for H3K4me3 histone modifications in lung cancer cells was conducted using ENCODE ChIP-Seq data downloaded from the UCSC browser tracks.	('H3K4me3', 'Var', (15, 22))	('lung cancer', 'Disease', 'MESH:D008175', (48, 59))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('lung cancer', 'Disease', (48, 59))	('lung cancer', 'Phenotype', 'HP:0100526', (48, 59))
2774	25116943	LncRNAs with FDR <=10-5, absolute fold change >=2, altered in the same direction as lung, and either average tumor FPKM or average normal FPKM >=1 were called significantly differentially expressed.	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('FDR <=10-5', 'Var', (13, 23))	('tumor', 'Disease', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))
2777	25116943	A549, HOP62, HOP92, NCI-H522, -H32, -H460, -H322M, and -H226 were a kind gift from Dr Van Tine at Washington University.	('A549', 'CellLine', 'CVCL:0023', (0, 4))	('HOP62', 'Var', (6, 11))	('NCI-H522', 'CellLine', 'CVCL:1567', (20, 28))	('A549', 'Var', (0, 4))	('HOP92', 'Var', (13, 18))	('HOP92', 'CellLine', 'CVCL:1286', (13, 18))
2788	25116943	Full-length sequences were uploaded to GenBank under the following accession numbers: KF773845 (LCAL1), KF773846 (LCAL5), KF773847 (LCAL7), and KF773848 (LCAL80).	('KF773847', 'Var', (122, 130))	('LCAL5', 'Gene', '400619', (114, 119))	('KF773848', 'Var', (144, 152))	('KF773846', 'Var', (104, 112))	('LCAL1', 'Gene', '80078', (96, 101))	('LCAL5', 'Gene', (114, 119))	('KF773845', 'Var', (86, 94))	('LCAL1', 'Gene', (96, 101))
2790	25116943	The following siRNA sequences were used for knockdown of LCAL1: siRNA 1 GGACAGGCTGCAGTCATCATATGGA and siRNA 2 GGCATGTGTTCAGACATATCCTAAA.	('LCAL1', 'Gene', '80078', (57, 62))	('LCAL1', 'Gene', (57, 62))	('knockdown', 'Var', (44, 53))
2901	31938577	In general, phosphorylated EIF4EBP1 is considered to be an indicator of tumor activity, indicating a worse prognosis.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Disease', (72, 77))	('EIF4EBP1', 'Gene', (27, 35))	('EIF4EBP1', 'Gene', '1978', (27, 35))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('phosphorylated', 'Var', (12, 26))
2905	31938577	Therefore, the dysregulation of TP63 is closely related to the occurrence of squamous cell carcinoma.	('TP63', 'Gene', '8626', (32, 36))	('TP63', 'Gene', (32, 36))	('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))	('dysregulation', 'Var', (15, 28))	('related', 'Reg', (48, 55))
2906	31938577	The genome-wide analysis suggests that the genetic variant of TP63 may affect susceptibility to LUAD.	('LUAD', 'Phenotype', 'HP:0030078', (96, 100))	('LUAD', 'Disease', (96, 100))	('LUAD', 'Disease', 'MESH:C538231', (96, 100))	('affect susceptibility', 'Reg', (71, 92))	('variant', 'Var', (51, 58))	('TP63', 'Gene', (62, 66))	('TP63', 'Gene', '8626', (62, 66))
2912	31938577	A study on early, operable NSCLC showed that the high expression of BNIP3 was an independent predictor of poor OS.	('poor OS', 'Disease', (106, 113))	('NSCLC', 'Disease', (27, 32))	('SCLC', 'Phenotype', 'HP:0030357', (28, 32))	('BNIP3', 'Gene', (68, 73))	('NSCLC', 'Disease', 'MESH:D002289', (27, 32))	('BNIP3', 'Gene', '664', (68, 73))	('NSCLC', 'Phenotype', 'HP:0030358', (27, 32))	('high', 'Var', (49, 53))
2937	31221178	We found that seven of 24 cases of OSCC showed positive for both PD-L1 and HLA-DR and that PD-L1241-265 peptide efficiently activates HTLs, which showed not only cytokine production but also cytotoxicity against tumor cells in a PD-L1-dependent manner.	('HT', 'Disease', 'MESH:D006973', (134, 136))	('activates', 'PosReg', (124, 133))	('OSCC', 'Phenotype', 'HP:0012182', (35, 39))	('OS', 'Chemical', '-', (35, 37))	('cytotoxicity', 'Disease', 'MESH:D064420', (191, 203))	('SCC', 'Gene', (36, 39))	('tumor', 'Disease', 'MESH:D009369', (212, 217))	('cytokine production', 'MPA', (162, 181))	('PD-L1241-265 peptide', 'Var', (91, 111))	('PD-L1241', 'Chemical', '-', (91, 99))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('SCC', 'Phenotype', 'HP:0002860', (36, 39))	('SCC', 'Gene', '6317', (36, 39))	('cytotoxicity', 'Disease', (191, 203))	('tumor', 'Disease', (212, 217))
2939	31221178	Importantly, T cell responses specific for the PD-L1241-265 peptide were detected in the HNSCC patients.	('patients', 'Species', '9606', (95, 103))	('detected', 'Reg', (73, 81))	('SCC', 'Phenotype', 'HP:0002860', (91, 94))	('SCC', 'Gene', (91, 94))	('HNSCC', 'Phenotype', 'HP:0012288', (89, 94))	('PD-L1241-265 peptide', 'Var', (47, 67))	('PD-L1241', 'Chemical', '-', (47, 55))	('SCC', 'Gene', '6317', (91, 94))
2947	31221178	Indeed, high PD-L1 expression is frequently found in tumor tissues and correlates with poor prognosis.	('expression', 'MPA', (19, 29))	('high', 'Var', (8, 12))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('PD-L1', 'Gene', (13, 18))	('tumor', 'Disease', (53, 58))
2975	31221178	As a result, we selected PD-L1-derived peptides PD-L1189-214 (KLFNVTSTLRINTTTNEIFYCTFRRL) and PD-L1241-265 (LVILGAILLCLGVALTFIFRLRKGR) and commercially synthesized them (GenScript).	('PD-L1189-214', 'Var', (48, 60))	('PD-L1241-265', 'Var', (94, 106))	('PD-L1241', 'Chemical', '-', (94, 102))
2991	31221178	PBMCs (2-3 x 105) of patients with HNSCC were cultured with PD-L1241-265 and PADRE peptides (10 mug/mL) in 96-well plates as described previously.	('SCC', 'Gene', '6317', (37, 40))	('HNSCC', 'Phenotype', 'HP:0012288', (35, 40))	('SCC', 'Phenotype', 'HP:0002860', (37, 40))	('patients', 'Species', '9606', (21, 29))	('PD-L1241', 'Chemical', '-', (60, 68))	('SCC', 'Gene', (37, 40))	('PD-L1241-265', 'Var', (60, 72))
2998	31221178	PD-L1241-265-specific HTLs or control CD4+ T-cells (1-2 x 106) were intravenously injected into the mice on days 20 and 27.	('CD4', 'Gene', (38, 41))	('mice', 'Species', '10090', (100, 104))	('CD4', 'Gene', '920', (38, 41))	('PD-L1241-265-specific', 'Var', (0, 21))	('PD-L1241', 'Chemical', '-', (0, 8))	('HT', 'Disease', 'MESH:D006973', (22, 24))
3010	31221178	To identify a helper epitope peptide for PD-L1, PD-L1189-214 and PD-L1241-265 were selected as candidates for potential MHC class II binding peptide sequences by using computer-based algorithms.	('MHC', 'Gene', '3107', (120, 123))	('PD-L1241-265', 'Var', (65, 77))	('PD-L1241', 'Chemical', '-', (65, 73))	('PD-L1189-214', 'Var', (48, 60))	('MHC', 'Gene', (120, 123))	('binding', 'Interaction', (133, 140))
3013	31221178	No reactions of CD4+ T-cells to PD-L1189-214 peptide were detected.	('PD-L1189-214', 'Var', (32, 44))	('CD4', 'Gene', '920', (16, 19))	('CD4', 'Gene', (16, 19))
3015	31221178	To define their HLA-DR restriction, we evaluated the reactivity of PD-L1241-265-specific CD4+ T-cells to autologous PBMCs in the presence of PD-L1241-265 peptide by using anti-HLA-DR or anti-HLA class I mAbs.	('CD4', 'Gene', '920', (89, 92))	('PD-L1241', 'Chemical', '-', (141, 149))	('PD-L1241-265', 'Var', (141, 153))	('PD-L1241', 'Chemical', '-', (67, 75))	('CD4', 'Gene', (89, 92))
3016	31221178	The IFN-gamma production of both PD-L1241-265-specific CD4+ T-cell lines were inhibited by anti-HLA-DR mAbs, but not by anti-HLA class I mAbs, suggesting that peptide recognition of both PD-L1241-265-specific CD4+ T-cell lines was restricted to HLA-DR (Fig.	('PD-L1241-265-specific', 'Var', (187, 208))	('CD4', 'Gene', '920', (209, 212))	('CD4', 'Gene', (55, 58))	('inhibited', 'NegReg', (78, 87))	('PD-L1241', 'Chemical', '-', (187, 195))	('CD4', 'Gene', '920', (55, 58))	('PD-L1241', 'Chemical', '-', (33, 41))	('CD4', 'Gene', (209, 212))	('IFN-gamma', 'Gene', '3458', (4, 13))	('IFN-gamma', 'Gene', (4, 13))
3021	31221178	Thus, we co-cultured PD-L1241-265-specific CD4+ T-cells with the HLA-DR-matched tumor cell lines expressing PD-L1.	('PD-L1241', 'Chemical', '-', (21, 29))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumor', 'Disease', (80, 85))	('PD-L1241-265-specific', 'Var', (21, 42))	('CD4', 'Gene', (43, 46))	('CD4', 'Gene', '920', (43, 46))
3025	31221178	3c), suggesting that our defined PD-L1241-265 peptide could efficiently stimulate PD-L1-expressing tumor-reactive HTLs.	('tumor', 'Disease', (99, 104))	('PD-L1-expressing', 'Gene', (82, 98))	('HT', 'Disease', 'MESH:D006973', (114, 116))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('PD-L1241', 'Chemical', '-', (33, 41))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('stimulate', 'PosReg', (72, 81))	('PD-L1241-265', 'Var', (33, 45))
3026	31221178	Because PD-L1 is also expressed on non-tumoral cells such as placental cells and DC, we assessed whether PD-L1241-265-specific CD4+ T-cells (G1 and G2) respond to DCs expressing PD-L1.	('CD4', 'Gene', '920', (127, 130))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('PD-L1241', 'Chemical', '-', (105, 113))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumor', 'Disease', (39, 44))	('CD4', 'Gene', (127, 130))	('PD-L1241-265-specific', 'Var', (105, 126))
3027	31221178	Although the response of the T-cell lines to peptide-loaded autologous DCs appeared higher than tumor cell lines, unloaded DCs didn't stimulate PD-L1241-265-specific CD4+ T-cells as much as tumor cell lines (Fig.	('PD-L1241', 'Chemical', '-', (144, 152))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('stimulate', 'PosReg', (134, 143))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('PD-L1241-265-specific', 'Var', (144, 165))	('tumor', 'Disease', (96, 101))	('CD4', 'Gene', (166, 169))	('response', 'MPA', (13, 21))	('tumor', 'Disease', (190, 195))	('CD4', 'Gene', '920', (166, 169))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('higher', 'PosReg', (84, 90))
3028	31221178	We next assessed whether the recognition of PD-L1241-265-specific CD4+ T-cells is surely dependent on PD-L1 expression in tumor cells.	('CD4', 'Gene', (66, 69))	('PD-L1241-265-specific', 'Var', (44, 65))	('CD4', 'Gene', '920', (66, 69))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('PD-L1241', 'Chemical', '-', (44, 52))	('tumor', 'Disease', (122, 127))
3031	31221178	4c), suggesting that PD-L1241-265-specific CD4+ T-cell lines certainly recognize tumor cell lines expressing PD-L1.	('PD-L1241', 'Chemical', '-', (21, 29))	('CD4', 'Gene', '920', (43, 46))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('PD-L1241-265-specific', 'Var', (21, 42))	('PD-L1', 'Var', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('CD4', 'Gene', (43, 46))	('tumor', 'Disease', (81, 86))
3032	31221178	It is important to confirm whether the PD-L1241-265 peptide also shows antigenic activity in patients with HNSCC for clinical applications because HNSCC has been reported to dysregulate immune cells.	('SCC', 'Phenotype', 'HP:0002860', (109, 112))	('SCC', 'Gene', '6317', (109, 112))	('HNSCC', 'Phenotype', 'HP:0012288', (107, 112))	('SCC', 'Gene', (149, 152))	('dysregulate', 'MPA', (174, 185))	('immune', 'CPA', (186, 192))	('SCC', 'Phenotype', 'HP:0002860', (149, 152))	('SCC', 'Gene', '6317', (149, 152))	('PD-L1241', 'Chemical', '-', (39, 47))	('SCC', 'Gene', (109, 112))	('antigenic activity', 'MPA', (71, 89))	('patients', 'Species', '9606', (93, 101))	('PD-L1241-265', 'Var', (39, 51))	('HNSCC', 'Phenotype', 'HP:0012288', (147, 152))
3033	31221178	Thus, we performed a short-term culture of PBMC derived from 5 patients with HNSCC and 2 healthy donors in the presence of the PD-L1241-265 peptide because the volumes of blood obtained from these patients were small.	('patients', 'Species', '9606', (197, 205))	('SCC', 'Gene', (79, 82))	('SCC', 'Phenotype', 'HP:0002860', (79, 82))	('SCC', 'Gene', '6317', (79, 82))	('patients', 'Species', '9606', (63, 71))	('HNSCC', 'Phenotype', 'HP:0012288', (77, 82))	('PD-L1241-265 peptide', 'Var', (127, 147))	('PD-L1241', 'Chemical', '-', (127, 135))
3034	31221178	4d, substantial T-cell responses to PD-L1241-265 peptides were observed not only in healthy donors but also in HNSCC patients (4/5 tested).	('SCC', 'Phenotype', 'HP:0002860', (113, 116))	('T-cell', 'CPA', (16, 22))	('SCC', 'Gene', '6317', (113, 116))	('HNSCC', 'Phenotype', 'HP:0012288', (111, 116))	('PD-L1241', 'Chemical', '-', (36, 44))	('patients', 'Species', '9606', (117, 125))	('SCC', 'Gene', (113, 116))	('PD-L1241-265 peptides', 'Var', (36, 57))
3035	31221178	This means that the precursor of PD-L1241-265-specific CD4+ T-cells surely exists in HNSCC patients.	('PD-L1241-265-specific', 'Var', (33, 54))	('CD4', 'Gene', (55, 58))	('patients', 'Species', '9606', (91, 99))	('SCC', 'Gene', (87, 90))	('CD4', 'Gene', '920', (55, 58))	('SCC', 'Phenotype', 'HP:0002860', (87, 90))	('HNSCC', 'Phenotype', 'HP:0012288', (85, 90))	('SCC', 'Gene', '6317', (87, 90))	('PD-L1241', 'Chemical', '-', (33, 41))
3036	31221178	We then assessed the cytotoxicity of PD-L1241-265-specific CD4+ T-cell line G1 against PD-L1-expressing tumor cell lines.	('PD-L1241-265-specific', 'Var', (37, 58))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('CD4', 'Gene', (59, 62))	('cytotoxicity', 'Disease', (21, 33))	('CD4', 'Gene', '920', (59, 62))	('tumor', 'Disease', (104, 109))	('PD-L1241', 'Chemical', '-', (37, 45))	('cytotoxicity', 'Disease', 'MESH:D064420', (21, 33))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
3038	31221178	Also, PD-L1241-265-specific CD4+ T-cell line G1 produced granzyme B against HLA-DR-matched tumor cell lines pretreated with IFN-gamma (HSC-4 and Lu65), but not against Sa-3 (Fig.	('CD4', 'Gene', (28, 31))	('IFN-gamma', 'Gene', '3458', (124, 133))	('IFN-gamma', 'Gene', (124, 133))	('granzyme B', 'Gene', '3002', (57, 67))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('PD-L1241-265-specific', 'Var', (6, 27))	('CD4', 'Gene', '920', (28, 31))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('granzyme B', 'Gene', (57, 67))	('tumor', 'Disease', (91, 96))	('PD-L1241', 'Chemical', '-', (6, 14))
3039	31221178	Having observed that PD-L1-specific G1 HTLs have ability to kill tumor cells, we further evaluated whether PD-L1241-265-specific CD4+ T-cells exhibit an antitumor effect in vivo setting using an immunodeficient mouse.	('tumor', 'Disease', (157, 162))	('tumor', 'Disease', (65, 70))	('PD-L1241', 'Chemical', '-', (107, 115))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('immunodeficient', 'Disease', 'MESH:D007153', (195, 210))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('immunodeficient', 'Disease', (195, 210))	('mouse', 'Species', '10090', (211, 216))	('PD-L1241-265-specific', 'Var', (107, 128))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('HT', 'Disease', 'MESH:D006973', (39, 41))	('CD4', 'Gene', (129, 132))	('CD4', 'Gene', '920', (129, 132))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
3045	31221178	In the current study, we newly identified a PD-L1-derived helper epitope peptide (PD-L1241-265) and demonstrated the potential use of PD-L1 as a tumor-associated antigen (TAA).	('PD-L1241-265', 'Var', (82, 94))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumor', 'Disease', (145, 150))	('PD-L1241', 'Chemical', '-', (82, 90))
3047	31221178	PD-L1241-265-specific HTLs showed not only cytokine production but also cytotoxicity against tumor cells in a PD-L1-specific manner.	('cytokine production', 'MPA', (43, 62))	('cytotoxicity', 'Disease', 'MESH:D064420', (72, 84))	('HT', 'Disease', 'MESH:D006973', (22, 24))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Disease', (93, 98))	('PD-L1241-265-specific', 'Var', (0, 21))	('cytotoxicity', 'Disease', (72, 84))	('PD-L1241', 'Chemical', '-', (0, 8))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
3048	31221178	Surprisingly, adoptively transfer of PD-L1241-265-specific HTLs into immunodeficient mice significantly inhibited growth of PD-L1-expressing human lung carcinoma.	('mice', 'Species', '10090', (85, 89))	('carcinoma', 'Phenotype', 'HP:0030731', (152, 161))	('PD-L1241-265-specific', 'Var', (37, 58))	('HT', 'Disease', 'MESH:D006973', (59, 61))	('PD-L1241', 'Chemical', '-', (37, 45))	('human', 'Species', '9606', (141, 146))	('immunodeficient', 'Disease', (69, 84))	('lung carcinoma', 'Disease', 'MESH:D008175', (147, 161))	('immunodeficient', 'Disease', 'MESH:D007153', (69, 84))	('lung carcinoma', 'Disease', (147, 161))	('inhibited', 'NegReg', (104, 113))	('growth', 'MPA', (114, 120))
3049	31221178	Because 7 of 24 cases (29.2%) of OSCC were positive for both PD-L1 and HLA-DR expressions, PD-L1-targeted immunotherapy using PD-L1241-265 peptide would be applicable to almost 30% of OSCC patients.	('OSCC', 'Phenotype', 'HP:0012182', (184, 188))	('SCC', 'Gene', (34, 37))	('PD-L1241-265', 'Var', (126, 138))	('SCC', 'Gene', (185, 188))	('OSCC', 'Phenotype', 'HP:0012182', (33, 37))	('SCC', 'Phenotype', 'HP:0002860', (34, 37))	('OS', 'Chemical', '-', (184, 186))	('SCC', 'Phenotype', 'HP:0002860', (185, 188))	('OS', 'Chemical', '-', (33, 35))	('SCC', 'Gene', '6317', (34, 37))	('SCC', 'Gene', '6317', (185, 188))	('patients', 'Species', '9606', (189, 197))	('positive', 'Reg', (43, 51))	('PD-L1241', 'Chemical', '-', (126, 134))
3061	31221178	Furthermore, they tried using PD-L1242-264 peptide to stimulate HLA-A2-restricted CD8+ T-cells and found it impotent.	('CD8', 'Gene', '925', (82, 85))	('stimulate', 'PosReg', (54, 63))	('CD8', 'Gene', (82, 85))	('PD-L1242-264 peptide', 'Var', (30, 50))
3063	31221178	Our defined peptide efficiently induced PD-L1241-265-specific HTLs from several healthy donors in an HLA-DR-restricted manner, HLA-DR4 or HLA-DR9, suggesting that PD-L1241-265 peptide is promiscuous.	('DR4', 'Gene', (131, 134))	('HT', 'Disease', 'MESH:D006973', (62, 64))	('PD-L1241-265-specific', 'Var', (40, 61))	('PD-L1241', 'Chemical', '-', (163, 171))	('DR4', 'Gene', '3126', (131, 134))	('PD-L1241', 'Chemical', '-', (40, 48))	('induced', 'Reg', (32, 39))
3071	31221178	However, in the present study, PD-L1241-265-specific HTLs produced less IFN-gamma against autologous DCs compared with tumor cells.	('tumor', 'Disease', (119, 124))	('IFN-gamma', 'Gene', '3458', (72, 81))	('IFN-gamma', 'Gene', (72, 81))	('less', 'NegReg', (67, 71))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('PD-L1241-265-specific', 'Var', (31, 52))	('HT', 'Disease', 'MESH:D006973', (53, 55))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('PD-L1241', 'Chemical', '-', (31, 39))
3096	30815935	Our finding is of importance for evaluating the potential of TSPY1 in immunotherapy of male tumor patients with TSPY1 expression.	('male tumor', 'Disease', 'MESH:D018567', (87, 97))	('TSPY1', 'Gene', (112, 117))	('expression', 'Var', (118, 128))	('male tumor', 'Disease', (87, 97))	('TSPY1', 'Gene', (61, 66))	('TSPY1', 'Gene', '7258', (61, 66))	('patients', 'Species', '9606', (98, 106))	('TSPY1', 'Gene', '7258', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))
3152	30815935	Collectively, these findings provided evidence to suggest that the ectopic expression of TSPY1 promoted tumor progression.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('promoted', 'PosReg', (95, 103))	('ectopic expression', 'Var', (67, 85))	('TSPY1', 'Gene', (89, 94))	('tumor', 'Disease', (104, 109))	('TSPY1', 'Gene', '7258', (89, 94))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
3182	30815935	Then we knocked down IGFBP3 expression in A549 and HepG2 cells, using both shRNA and siRNA targeted to the IGFBP3 gene (Figures 6B and S6), and observed that the reduction of IGFBP3 was associated with the increase of p-AKT, p-mTOR, BCL2, p-RAF, p-MEK, p-ERK, and JUN (Figures 6B,C and S6).	('RAF', 'Gene', (241, 244))	('knocked', 'Var', (8, 15))	('mTOR', 'Gene', (227, 231))	('A549', 'CellLine', 'CVCL:0023', (42, 46))	('AKT', 'Gene', (220, 223))	('reduction', 'NegReg', (162, 171))	('BCL2', 'Gene', '596', (233, 237))	('mTOR', 'Gene', '2475', (227, 231))	('p-ERK', 'Gene', '9451', (253, 258))	('p-ERK', 'Gene', (253, 258))	('JUN', 'MPA', (264, 267))	('IGFBP3', 'Gene', (21, 27))	('increase', 'PosReg', (206, 214))	('BCL2', 'Gene', (233, 237))	('MEK', 'Gene', '5609', (248, 251))	('AKT', 'Gene', '207', (220, 223))	('RAF', 'Gene', '22882', (241, 244))	('MEK', 'Gene', (248, 251))	('IGFBP3', 'Gene', (175, 181))	('HepG2', 'CellLine', 'CVCL:0027', (51, 56))
3193	30815935	We then investigated the levels of proteins involved in the signaling pathways of PI3K/AKT and RAS in the TSPY1-downregulated LCLC-103H and MHCC97H cells, and observed that the decrease of TSPY1 expression upregulated the IGFBP3 expression (Figures 9A and S7), and contrarily reduced the protein levels of p-AKT, p-mTOR, BCL2, p-RAF, p-MEK, p-ERK, and JUN (Figures 9 and S7).	('AKT', 'Gene', (87, 90))	('IGFBP3', 'Gene', (222, 228))	('AKT', 'Gene', (308, 311))	('mTOR', 'Gene', '2475', (315, 319))	('BCL2', 'Gene', '596', (321, 325))	('p-ERK', 'Gene', '9451', (341, 346))	('decrease', 'Var', (177, 185))	('p-ERK', 'Gene', (341, 346))	('TSPY1', 'Gene', (189, 194))	('MHCC97H', 'CellLine', 'CVCL:4972', (140, 147))	('TSPY1', 'Gene', '7258', (106, 111))	('TSPY1', 'Gene', '7258', (189, 194))	('AKT', 'Gene', '207', (87, 90))	('BCL2', 'Gene', (321, 325))	('MEK', 'Gene', '5609', (336, 339))	('AKT', 'Gene', '207', (308, 311))	('reduced', 'NegReg', (276, 283))	('RAF', 'Gene', '22882', (329, 332))	('expression', 'MPA', (229, 239))	('MEK', 'Gene', (336, 339))	('TSPY1', 'Gene', (106, 111))	('upregulated', 'PosReg', (206, 217))	('mTOR', 'Gene', (315, 319))	('RAF', 'Gene', (329, 332))
3200	30815935	These findings provide evidence that TSPY1 is an upstream modulator of IGFBP3 and the ectopic activation of TSPY1 disrupts the suppressing ability of IGFBP3 on tumor progression.	('TSPY1', 'Gene', '7258', (108, 113))	('tumor', 'Disease', (160, 165))	('TSPY1', 'Gene', '7258', (37, 42))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('TSPY1', 'Gene', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('disrupts', 'NegReg', (114, 122))	('suppressing', 'MPA', (127, 138))	('TSPY1', 'Gene', (37, 42))	('ectopic activation', 'Var', (86, 104))
3207	30815935	In the current study, we confirmed that the ectopic expression of TSPY1 was associated with higher mortality and worse overall survival probability in male patients with LUAD or LIHC, which further provided evidence to suggest that TSPY1 might contribute to the sex disparities in some cancers, particularly LUAD and LIHC.	('TSPY1', 'Gene', (232, 237))	('LUAD', 'Disease', (170, 174))	('LIHC', 'Disease', (178, 182))	('contribute', 'Reg', (244, 254))	('patients', 'Species', '9606', (156, 164))	('higher', 'PosReg', (92, 98))	('cancer', 'Phenotype', 'HP:0002664', (286, 292))	('LUAD', 'Disease', 'None', (170, 174))	('ectopic expression', 'Var', (44, 62))	('LUAD', 'Phenotype', 'HP:0030078', (308, 312))	('TSPY1', 'Gene', '7258', (66, 71))	('cancers', 'Phenotype', 'HP:0002664', (286, 293))	('LIHC', 'Disease', (317, 321))	('cancers', 'Disease', (286, 293))	('TSPY1', 'Gene', '7258', (232, 237))	('LUAD', 'Disease', (308, 312))	('LUAD', 'Phenotype', 'HP:0030078', (170, 174))	('TSPY1', 'Gene', (66, 71))	('LUAD', 'Disease', 'None', (308, 312))	('cancers', 'Disease', 'MESH:D009369', (286, 293))
3256	30061673	Further, GNL1 induced cell proliferation was altered upon knockdown of RPS20 suggesting its critical role in GNL1 function.	('RPS20', 'Gene', (71, 76))	('altered', 'Reg', (45, 52))	('GNL1', 'Gene', '2794', (109, 113))	('GNL1', 'Gene', (109, 113))	('GNL1', 'Gene', (9, 13))	('GNL1', 'Gene', '2794', (9, 13))	('knockdown', 'Var', (58, 67))	('cell proliferation', 'CPA', (22, 40))
3257	30061673	Interestingly, cell proliferation was significantly impaired upon expression of RPS20 interaction deficient GNL1 mutant suggest that GNL1 interaction with RPS20 is critical for cell growth.	('impaired', 'NegReg', (52, 60))	('GNL1', 'Gene', '2794', (133, 137))	('interaction', 'Interaction', (86, 97))	('GNL1', 'Gene', (108, 112))	('GNL1', 'Gene', '2794', (108, 112))	('GNL1', 'Gene', (133, 137))	('cell proliferation', 'CPA', (15, 33))	('mutant', 'Var', (113, 119))
3259	30061673	Collectively, our data provided evidence that cross-talk between GNL1 and RPS20 is critical to promote cell proliferation.	('cross-talk', 'Var', (46, 56))	('GNL1', 'Gene', (65, 69))	('promote', 'PosReg', (95, 102))	('cell proliferation', 'CPA', (103, 121))	('GNL1', 'Gene', '2794', (65, 69))	('RPS20', 'Gene', (74, 79))
3261	30061673	The members of this family have shown to be involved in ribosomal assembly and ribosomal RNA processing and are characterized by the presence of circular permutation of guanine nucleotide binding motifs.	('ribosomal', 'Enzyme', (79, 88))	('involved', 'Reg', (44, 52))	('ribosomal assembly', 'CPA', (56, 74))	('guanine nucleotide', 'Chemical', 'MESH:D006150', (169, 187))	('circular permutation', 'Var', (145, 165))
3262	30061673	The guanine nucleotide motifs G1-G5 of YawG/YIqF GTPases are arranged in G5-G4-G1-G2-G3 order whereas G1-G2-G3-G4-G5 order in classical GTPases.	('G5-G4-G1-G2-G3', 'Var', (73, 87))	('GTP', 'Chemical', 'MESH:D006160', (136, 139))	('GTPases', 'Gene', (49, 56))	('guanine nucleotide', 'Chemical', 'MESH:D006150', (4, 22))	('GTP', 'Chemical', 'MESH:D006160', (49, 52))
3290	30061673	To further understand the mechanism of GNL1 mediated cell cycle progression, GNL11-607 was ectopically expressed in HCT116p53+/+ cells and cell cycle analysis was performed.	('GNL1', 'Gene', '2794', (77, 81))	('GNL1', 'Gene', '2794', (39, 43))	('HCT116p53+/+', 'Var', (116, 128))	('GNL1', 'Gene', (77, 81))	('GNL1', 'Gene', (39, 43))
3299	30061673	Interestingly, the level of pRbS780 was increased in GNL1 expressing cells compared to vector transfected cells without altering total Rb protein levels (Fig.	('expressing', 'Var', (58, 68))	('GNL1', 'Gene', '2794', (53, 57))	('pRbS780', 'Var', (28, 35))	('GNL1', 'Gene', (53, 57))	('increased', 'PosReg', (40, 49))	('level', 'MPA', (19, 24))
3305	30061673	The observed cell cycle arrest at G2/M phase under GNL1 knockdown condition may be due to the changes in cyclins and CDKs levels.	('cell cycle arrest at G2/M phase', 'CPA', (13, 44))	('cyclins', 'Gene', (105, 112))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (13, 30))	('GNL1', 'Gene', '2794', (51, 55))	('changes', 'Reg', (94, 101))	('cyclins', 'Gene', '891', (105, 112))	('CDKs levels', 'MPA', (117, 128))	('GNL1', 'Gene', (51, 55))	('knockdown', 'Var', (56, 65))
3306	30061673	Western blot analysis indicated that the levels of cyclin D1, cyclin B1, CDK4 and CDK1 were significantly downregulated upon GNL1 knockdown (Fig.	('cyclin D1', 'Gene', (51, 60))	('downregulated', 'NegReg', (106, 119))	('GNL1', 'Gene', (125, 129))	('CDK4', 'MPA', (73, 77))	('cyclin B1', 'Gene', (62, 71))	('cyclin B1', 'Gene', '891', (62, 71))	('CDK1', 'Gene', (82, 86))	('knockdown', 'Var', (130, 139))	('GNL1', 'Gene', '2794', (125, 129))	('cyclin D1', 'Gene', '595', (51, 60))	('levels', 'MPA', (41, 47))
3324	30061673	Glutathione-Sepharose beads bound GST-RPS20 were incubated with HEK293T cell lysates containing equal amounts of GFP, full length or indicated variants of GNL11-607 (Supplementary Fig.	('Glutathione', 'Chemical', 'MESH:D005978', (0, 11))	('GNL1', 'Gene', (155, 159))	('HEK293T', 'CellLine', 'CVCL:0063', (64, 71))	('GNL1', 'Gene', '2794', (155, 159))	('Sepharose', 'Chemical', 'MESH:D012685', (12, 21))	('variants', 'Var', (143, 151))
3327	30061673	3b indicate that GNL1 mutant containing amino acids 1 to 50 interacted with RPS20 like GNL11-607.	('GNL1', 'Gene', (87, 91))	('GNL1', 'Gene', '2794', (17, 21))	('GNL1', 'Gene', (17, 21))	('mutant', 'Var', (22, 28))	('GNL1', 'Gene', '2794', (87, 91))	('interacted', 'Interaction', (60, 70))
3330	30061673	Lack of interaction between GFP with GST-RPS20 and GST with variants of GNL11-607 indicated the specificity of interaction between GNL1 and RPS20.	('GNL1', 'Gene', (72, 76))	('GNL1', 'Gene', '2794', (72, 76))	('GNL1', 'Gene', (131, 135))	('interaction', 'Interaction', (8, 19))	('interaction', 'Interaction', (111, 122))	('GNL1', 'Gene', '2794', (131, 135))	('variants', 'Var', (60, 68))
3332	30061673	GST pull down assay was carried out with full length or indicated deletion constructs of GST-RPS20 and HEK293T cell lysates containing GFP or GNL11-607 as described in Materials and Methods.	('GNL1', 'Gene', (142, 146))	('GST-RPS20', 'Gene', (89, 98))	('GNL1', 'Gene', '2794', (142, 146))	('HEK293T', 'CellLine', 'CVCL:0063', (103, 110))	('deletion', 'Var', (66, 74))
3333	30061673	S2c suggest that GNL11-607 interacted with RPS20 full length and the deletion constructs of GST-RPS20 containing amino acids 41 to 60 suggest that amino acids between 41-60 is the minimal domain in RPS20 required for its interaction with GNL1.	('GNL1', 'Gene', '2794', (238, 242))	('GNL1', 'Gene', '2794', (17, 21))	('GNL1', 'Gene', (238, 242))	('amino acids between 41-60', 'Var', (147, 172))	('GNL1', 'Gene', (17, 21))
3340	30061673	As noted from the amino acid sequences, GNL11-50 is rich in lysines and arginines and to identify the amino acids that are critical for GNL1 interaction with RPS20, GNL11-607_R22K23A was generated by exchanging the conserved Arg22 and Lys23 with alanine (Supplementary Fig.	('GNL1', 'Gene', '2794', (40, 44))	('GNL1', 'Gene', '2794', (136, 140))	('Arg22', 'Var', (225, 230))	('GNL1', 'Gene', '2794', (165, 169))	('Arg22 and Lys23 with alanine', 'Mutation', 'p.R,K22,23A', (225, 253))	('GNL1', 'Gene', (40, 44))	('Lys23 with alanine', 'SUBSTITUTION', 'None', (235, 253))	('exchanging', 'Var', (200, 210))	('lysine', 'Chemical', 'MESH:D008239', (60, 66))	('arginine', 'Chemical', 'MESH:D001120', (72, 80))	('GNL1', 'Gene', (136, 140))	('Lys23 with alanine', 'Var', (235, 253))	('GNL1', 'Gene', (165, 169))
3341	30061673	Interestingly, results from the co-immunoprecipitation assay indicate that replacement of Arg22 and Lys23 abrogated GNL1 interaction with RPS20 (Fig.	('Lys23', 'Chemical', '-', (100, 105))	('Arg22', 'Var', (90, 95))	('interaction', 'Interaction', (121, 132))	('GNL1', 'Gene', '2794', (116, 120))	('RPS20', 'Protein', (138, 143))	('abrogated', 'NegReg', (106, 115))	('Arg22', 'Chemical', '-', (90, 95))	('GNL1', 'Gene', (116, 120))	('replacement', 'Var', (75, 86))	('Lys23', 'Var', (100, 105))
3342	30061673	Collectively, data suggests that Arg22 and Lys23 residues within GNL11-50 is critical for its interaction with RPS20.	('GNL1', 'Gene', (65, 69))	('interaction', 'Interaction', (94, 105))	('GNL1', 'Gene', '2794', (65, 69))	('Arg22', 'Var', (33, 38))	('Lys23 residues', 'Var', (43, 57))	('Lys23', 'Chemical', '-', (43, 48))	('Arg22', 'Chemical', '-', (33, 38))	('RPS20', 'Protein', (111, 116))
3343	30061673	To confirm the conservation of GNL1 and RPS20 interaction, a panel of cell lines (HCT116p53+/+, AGS and HEK293T) were selected and tested.	('GNL1', 'Gene', (31, 35))	('GNL1', 'Gene', '2794', (31, 35))	('HEK293T', 'CellLine', 'CVCL:0063', (104, 111))	('HCT116p53+/+', 'Var', (82, 94))
3344	30061673	GNL1 and RPS20 complexes from cells lysates were co-immunoprecipitated with anti-RPS20 antibodies followed by western blot with anti-GNL1 (HCT116p53+/+ and AGS) or anti-GFP (HEK 293T) antibodies.	('HCT116p53+/+', 'Var', (139, 151))	('GNL1', 'Gene', '2794', (133, 137))	('GNL1', 'Gene', (0, 4))	('GNL1', 'Gene', '2794', (0, 4))	('GNL1', 'Gene', (133, 137))	('HEK 293T', 'CellLine', 'CVCL:0063', (174, 182))
3351	30061673	In addition, endogenous GNL1 protein level was significantly increased upon ectopic expression of RPS20-FLAG (here after referred as RPS20) in HCT116p53+/+ and AGS cell lines (Fig.	('GNL1', 'Gene', '2794', (24, 28))	('RPS20-FLAG', 'Var', (98, 108))	('increased', 'PosReg', (61, 70))	('GNL1', 'Gene', (24, 28))
3353	30061673	Furthermore, GNL1 knockdown resulted in reduction of RPS20 protein levels in both HCT116p53+/+ and AGS cell lines (Figs 4f and S3b) and the RPS20 depletion downregulated GNL1 levels in HCT116p53+/+ cells (Fig.	('depletion downregulated', 'NegReg', (146, 169))	('knockdown', 'Var', (18, 27))	('RPS20', 'Protein', (53, 58))	('RPS20', 'Var', (140, 145))	('GNL1', 'Gene', (170, 174))	('GNL1', 'Gene', '2794', (13, 17))	('reduction', 'NegReg', (40, 49))	('GNL1', 'Gene', (13, 17))	('GNL1', 'Gene', '2794', (170, 174))
3355	30061673	The above data lead to the hypothesis that RPS20 increasing GNL1 protein levels by altering its stability.	('GNL1', 'Gene', '2794', (60, 64))	('altering', 'Reg', (83, 91))	('RPS20', 'Var', (43, 48))	('stability', 'MPA', (96, 105))	('GNL1', 'Gene', (60, 64))	('increasing', 'PosReg', (49, 59))
3360	30061673	To further confirm, cell proliferation was measured by MTT and BrdU incorporation assays in RPS20 expressing HCT116p53+/+ cells.	('HCT116p53+/+', 'Var', (109, 121))	('cell proliferation', 'CPA', (20, 38))	('BrdU', 'Chemical', 'MESH:D001973', (63, 67))	('MTT', 'Chemical', 'MESH:C070243', (55, 58))	('RPS20', 'Gene', (92, 97))	('BrdU incorporation assays', 'CPA', (63, 88))
3363	30061673	Western blot analysis indicated that the levels of cyclin D1, cyclinB1, CDK1 and CDK4 were significantly upregulated upon ectopic expression of RPS20 (Fig.	('upregulated', 'PosReg', (105, 116))	('cyclin D1', 'Gene', (51, 60))	('cyclinB1', 'Gene', (62, 70))	('cyclinB1', 'Gene', '891', (62, 70))	('ectopic expression', 'Var', (122, 140))	('CDK4', 'Gene', (81, 85))	('RPS20', 'Var', (144, 149))	('cyclin D1', 'Gene', '595', (51, 60))	('CDK1', 'Gene', (72, 76))	('levels', 'MPA', (41, 47))
3365	30061673	5e indicate that the RPS20 significantly altered the expression of cyclin A2, cyclin E1, cyclin B1 and CDK1.	('cyclin E1', 'Gene', '898', (78, 87))	('altered', 'Reg', (41, 48))	('cyclin E1', 'Gene', (78, 87))	('RPS20', 'Var', (21, 26))	('cyclin A2', 'Gene', (67, 76))	('CDK1', 'Gene', (103, 107))	('expression', 'MPA', (53, 63))	('cyclin A2', 'Gene', '890', (67, 76))	('cyclin B1', 'Gene', '891', (89, 98))	('cyclin B1', 'Gene', (89, 98))
3366	30061673	To further define whether RPS20 knockdown alters cell viability/proliferation, MTT and BrdU incorporation assays were performed.	('RPS20', 'Gene', (26, 31))	('cell viability/proliferation', 'CPA', (49, 77))	('knockdown', 'Var', (32, 41))	('alters', 'Reg', (42, 48))	('MTT', 'Chemical', 'MESH:C070243', (79, 82))	('BrdU', 'Chemical', 'MESH:D001973', (87, 91))	('BrdU incorporation', 'CPA', (87, 105))
3367	30061673	Interestingly, RPS20 knockdown significantly decreased the levels of CDK4 and CDK1 without altering cyclin B1 and cyclin D1 expression (Fig.	('RPS20', 'Gene', (15, 20))	('levels', 'MPA', (59, 65))	('CDK4', 'MPA', (69, 73))	('cyclin D1', 'Gene', '595', (114, 123))	('CDK1', 'Gene', (78, 82))	('cyclin B1', 'Gene', (100, 109))	('cyclin D1', 'Gene', (114, 123))	('decreased', 'NegReg', (45, 54))	('cyclin B1', 'Gene', '891', (100, 109))	('knockdown', 'Var', (21, 30))
3369	30061673	Results from MTT assay clearly indicated that expression of GNL11-607 alone or in combination with RPS20 resulted in increased viability of both HCT116p53+/+ and AGS cells (Fig.	('GNL1', 'Gene', '2794', (60, 64))	('MTT', 'Chemical', 'MESH:C070243', (13, 16))	('increased', 'PosReg', (117, 126))	('viability', 'CPA', (127, 136))	('GNL1', 'Gene', (60, 64))	('HCT116p53+/+', 'Var', (145, 157))
3377	30061673	6c suggest that knockdown of both GNL1 and RPS20 resulted in significant reduction of HCT116p53+/+ cell viability.	('RPS20', 'Gene', (43, 48))	('HCT116p53+/+', 'MPA', (86, 98))	('knockdown', 'Var', (16, 25))	('GNL1', 'Gene', '2794', (34, 38))	('GNL1', 'Gene', (34, 38))	('reduction', 'NegReg', (73, 82))
3386	30061673	To understand the physiological importance of GNL1 and RPS20 interaction during tumorigenesis, the colony formation ability of HCT116p53+/+ or AGS cells were checked upon ectopic expression or knockdown of GNL1 with or without RPS20.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('GNL1', 'Gene', (206, 210))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('GNL1', 'Gene', (46, 50))	('knockdown', 'Var', (193, 202))	('GNL1', 'Gene', '2794', (206, 210))	('tumor', 'Disease', (80, 85))	('GNL1', 'Gene', '2794', (46, 50))
3388	30061673	Results indicate that the number of colonies were significantly increased upon the expression of GNL11-607 or RPS20 alone or in combination (Figs 7a and S4b).	('increased', 'PosReg', (64, 73))	('GNL1', 'Gene', (97, 101))	('GNL1', 'Gene', '2794', (97, 101))	('RPS20', 'Gene', (110, 115))	('expression', 'Var', (83, 93))
3389	30061673	In contrast, the colony numbers were significantly reduced when HCT116p53+/+ or AGS cells were co-expressed with GNL11-607_R22K23A and RPS20 (Figs 7a and S4b).	('HCT116p53+/+', 'Var', (64, 76))	('reduced', 'NegReg', (51, 58))	('GNL1', 'Gene', '2794', (113, 117))	('GNL1', 'Gene', (113, 117))	('colony numbers', 'CPA', (17, 31))	('RPS20', 'Var', (135, 140))
3401	30061673	Kaplan-Meier analysis showed that high mRNA expression of GNL1 and RPS20 was strongly associated with decreased overall survival of gastric cancer patients (Fig.	('GNL1', 'Gene', (58, 62))	('RPS20', 'Gene', (67, 72))	('gastric cancer', 'Disease', (132, 146))	('mRNA expression', 'MPA', (39, 54))	('gastric cancer', 'Disease', 'MESH:D013274', (132, 146))	('high', 'Var', (34, 38))	('GNL1', 'Gene', '2794', (58, 62))	('patients', 'Species', '9606', (147, 155))	('gastric cancer', 'Phenotype', 'HP:0012126', (132, 146))	('overall survival', 'MPA', (112, 128))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('decreased', 'NegReg', (102, 111))
3418	30061673	Results from the current investigation clearly indicates that ectopic expression of GNL1 upregulates RPS20 expression and promotes cell proliferation.	('GNL1', 'Gene', '2794', (84, 88))	('promotes', 'PosReg', (122, 130))	('expression', 'MPA', (107, 117))	('GNL1', 'Gene', (84, 88))	('upregulates', 'PosReg', (89, 100))	('cell proliferation', 'CPA', (131, 149))	('RPS20', 'Protein', (101, 106))	('ectopic expression', 'Var', (62, 80))
3419	30061673	GNL1 function is severely impaired upon RPS20 knockdown which shows the critical role played by RPS20 in GNL1 function.	('RPS20', 'Gene', (40, 45))	('knockdown', 'Var', (46, 55))	('GNL1', 'Gene', '2794', (0, 4))	('GNL1', 'Gene', (105, 109))	('impaired', 'NegReg', (26, 34))	('GNL1', 'Gene', (0, 4))	('function', 'MPA', (5, 13))	('GNL1', 'Gene', '2794', (105, 109))
3426	30061673	The deregulation of G1/S restriction point leads to uncontrolled cell proliferation and contributes to tumorigenesis.	('G1/S', 'Gene', (20, 24))	('deregulation', 'Var', (4, 16))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor', 'Disease', (103, 108))	('uncontrolled', 'MPA', (52, 64))	('contributes to', 'Reg', (88, 102))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('leads to', 'Reg', (43, 51))
3431	30061673	The observed high expression levels of GNL1 and RPS20 in various cancer tissues together with our results from the current study suggests the possibility that the co-operation of GNL1 and RPS20 may favor faster cell proliferation during cancer progression and may be an ideal target for cancer therapeutic intervention.	('favor faster', 'PosReg', (198, 210))	('cancer', 'Disease', (287, 293))	('GNL1', 'Gene', '2794', (39, 43))	('GNL1', 'Gene', '2794', (179, 183))	('cancer', 'Disease', 'MESH:D009369', (287, 293))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('RPS20', 'Gene', (188, 193))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('cancer', 'Phenotype', 'HP:0002664', (287, 293))	('cancer', 'Disease', 'MESH:D009369', (237, 243))	('GNL1', 'Gene', (39, 43))	('co-operation', 'Var', (163, 175))	('cancer', 'Disease', (237, 243))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('GNL1', 'Gene', (179, 183))
3436	30061673	HCT116p53+/+, HCT116p53-/-, AGS and HEK293T cells were cultured in Dulbecco's Modified Eagle's Medium (DMEM) (Thermo Fisher Scientific Inc., USA) with 10% Fetal Bovine Serum (FBS) and 1% antibiotics-antimycotics (Thermo Fisher Scientific Inc., USA).	('Bovine', 'Species', '9913', (161, 167))	('HEK293T', 'CellLine', 'CVCL:0063', (36, 43))	('DMEM', 'Chemical', '-', (103, 107))	('HCT116p53+/+', 'Var', (0, 12))	('FBS', 'Disease', 'MESH:D005198', (175, 178))	('HCT116p53-/-', 'Var', (14, 26))	('FBS', 'Disease', (175, 178))
3443	30061673	Full length and variants of RPS20 were transformed into E. coli BL21DE3 cells and grown overnight at 37  C. Single colony containing GST-RPS20 was inoculated into LB medium and the protein expression was induced with 1 mM IPTG at 18  C for 12-14 hours.	('protein', 'Protein', (181, 188))	('IPTG', 'Chemical', 'MESH:D007544', (222, 226))	('GST-RPS20', 'Gene', (133, 142))	('RPS20', 'Gene', (28, 33))	('LB medium', 'Chemical', '-', (163, 172))	('variants', 'Var', (16, 24))	('E. coli BL21DE3', 'Species', '469008', (56, 71))
3444	30061673	Equal amounts of HCT116p53+/+ and AGS cell lysates were incubated with anti-RPS20 antibodies for 6 hours at 4  C and the antibody-protein complexes were eluted and resolved on SDS-12%PAGE followed by western blotting with anti-GNL1 antibody.	('SDS', 'Chemical', 'MESH:D012967', (176, 179))	('GNL1', 'Gene', (227, 231))	('HCT116p53+/+', 'Var', (17, 29))	('complexes', 'Interaction', (138, 147))	('GNL1', 'Gene', '2794', (227, 231))
3448	30061673	HCT116p53+/+ cells were transfected with GNL11-607, GNL1-shRNA, RPS20-FLAG, RPS20-shRNA, control vectors alone or in combination.	('GNL1', 'Gene', (41, 45))	('GNL1', 'Gene', (52, 56))	('GNL1', 'Gene', '2794', (41, 45))	('RPS20-FLAG', 'Var', (64, 74))	('GNL1', 'Gene', '2794', (52, 56))
3449	30061673	HCT116p53+/+ or AGS cells were transfected with GNL11-607, GNL11-607_R22K23A, RPS20-FLAG, GNL1 shRNA, RPS20 shRNA alone or in combination.	('GNL1', 'Gene', (48, 52))	('GNL1', 'Gene', (90, 94))	('RPS20-FLAG', 'Var', (78, 88))	('GNL1', 'Gene', '2794', (59, 63))	('GNL1', 'Gene', '2794', (90, 94))	('GNL1', 'Gene', '2794', (48, 52))	('GNL1', 'Gene', (59, 63))
3451	30061673	HCT116p53+/+ cells were transfected with GNL11-607, RPS20-FLAG, GNL1 shRNA, RPS20 shRNA alone or in combination.	('GNL1', 'Gene', (41, 45))	('GNL1', 'Gene', '2794', (64, 68))	('GNL1', 'Gene', '2794', (41, 45))	('GNL1', 'Gene', (64, 68))	('RPS20-FLAG', 'Var', (52, 62))	('RPS20', 'Var', (76, 81))
3454	30061673	HCT116p53+/+ and AGS cells were transfected with GNL11-607, GNL11-607_R22K23A, RPS20-FLAG, GNL1 shRNA, RPS20 shRNA alone or in combination.	('GNL1', 'Gene', '2794', (60, 64))	('GNL1', 'Gene', '2794', (91, 95))	('RPS20-FLAG', 'Var', (79, 89))	('GNL1', 'Gene', '2794', (49, 53))	('GNL1', 'Gene', (60, 64))	('GNL1', 'Gene', (91, 95))	('GNL1', 'Gene', (49, 53))
3456	30061673	The surviving fraction of cells was determined by dividing the plating efficiency of cells transfected with GNL11-607, GNL11-607_R22K23A, RPS20-FLAG, GNL1 shRNA, RPS20 shRNA alone or in combination by plating efficiency of control cells.	('GNL1', 'Gene', '2794', (119, 123))	('GNL1', 'Gene', (108, 112))	('GNL1', 'Gene', '2794', (150, 154))	('GNL1', 'Gene', '2794', (108, 112))	('GNL1', 'Gene', (119, 123))	('GNL1', 'Gene', (150, 154))	('RPS20-FLAG', 'Var', (138, 148))
3501	28503090	As a matter of fact, PG490-88, a derivative of triptolide, is part of a phase I clinical trial for treatment of prostate cancer in the USA.	('triptolide', 'Chemical', 'MESH:C001899', (47, 57))	('prostate cancer', 'Phenotype', 'HP:0012125', (112, 127))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('PG490-88', 'Var', (21, 29))	('prostate cancer', 'Disease', (112, 127))	('prostate cancer', 'Disease', 'MESH:D011471', (112, 127))
3516	28503090	Pristimerin was found to induce apoptosis in hormone-sensitive (LNCaP) and hormone-refractory (PC-3) prostate cancer cell lines.	('Pristimerin', 'Chemical', 'MESH:C009043', (0, 11))	('apoptosis', 'CPA', (32, 41))	('prostate cancer', 'Disease', (101, 116))	('induce', 'PosReg', (25, 31))	('Pristimerin', 'Var', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('LNCaP', 'CellLine', 'CVCL:0395', (64, 69))	('prostate cancer', 'Disease', 'MESH:D011471', (101, 116))	('PC-3', 'CellLine', 'CVCL:0035', (95, 99))	('prostate cancer', 'Phenotype', 'HP:0012125', (101, 116))
3517	28503090	Pristimerin increased annexin V-binding and cleavage of PARP-1, procaspases-3 and -9-induced mitochondrial depolarization, cytochrome c release from mitochondria, generation of reactive oxygen species (ROS), and downregulation of BCL-2 and survivin expression via proteasome-dependent degradation.	('cleavage', 'MPA', (44, 52))	('degradation', 'MPA', (285, 296))	('depolarization', 'NegReg', (107, 121))	('Pristimerin', 'Chemical', 'MESH:C009043', (0, 11))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (177, 200))	('generation', 'MPA', (163, 173))	('cytochrome c', 'Gene', (123, 135))	('expression', 'MPA', (249, 259))	('BCL-2', 'Gene', '596', (230, 235))	('BCL-2', 'Gene', (230, 235))	('increased', 'PosReg', (12, 21))	('Pristimerin', 'Var', (0, 11))	('downregulation', 'NegReg', (212, 226))	('annexin V', 'Gene', (22, 31))	('PARP-1, procaspases-3 and -9', 'Gene', '142;836', (56, 84))	('mitochondrial', 'MPA', (93, 106))	('annexin V', 'Gene', '308', (22, 31))	('survivin', 'Protein', (240, 248))	('cytochrome c', 'Gene', '54205', (123, 135))	('ROS', 'Chemical', 'MESH:D017382', (202, 205))
3525	28503090	The work reported that treatment of pancreatic cancer cells with pristimerin resulted in G1-phase arrest associated with a marked decrease in the level of cyclins CCND1 and CCNE, and cyclin-dependent kinases (CDK-2, -4 and -6) with concomitant induction of CDK inhibitors, CDKN1A (p21WAF1) and CDKN1B (p27KIP1).	('CCND1', 'Gene', (163, 168))	('CDKN1A', 'Gene', (273, 279))	('CDKN1A', 'Gene', '1026', (273, 279))	('CCNE', 'Gene', '898', (173, 177))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (36, 53))	('level', 'MPA', (146, 151))	('CDKN1B', 'Gene', '1027', (294, 300))	('pristimerin', 'Chemical', 'MESH:C009043', (65, 76))	('p27KIP1', 'Gene', '1027', (302, 309))	('cyclin', 'Gene', (183, 189))	('p27KIP1', 'Gene', (302, 309))	('G1-phase arrest', 'CPA', (89, 104))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('p21', 'Gene', '1026', (281, 284))	('cyclin', 'Gene', '5111', (155, 161))	('pancreatic cancer', 'Disease', 'MESH:D010190', (36, 53))	('decrease', 'NegReg', (130, 138))	('induction', 'PosReg', (244, 253))	('cyclin', 'Gene', '5111', (183, 189))	('CDKN1B', 'Gene', (294, 300))	('cyclin', 'Gene', (155, 161))	('pancreatic cancer', 'Disease', (36, 53))	('CDK-2, -4 and -6', 'Gene', '1017;1019;1021', (209, 225))	('CCND1', 'Gene', '595', (163, 168))	('pristimerin', 'Var', (65, 76))	('CCNE', 'Gene', (173, 177))	('p21', 'Gene', (281, 284))
3527	28503090	In human pancreatic ductal adenocarcinoma cells (MiaPaCa-2 and Panc-1) pristimerin inhibited the proliferation and induced apoptosis.	('pancreatic ductal adenocarcinoma', 'Disease', (9, 41))	('human', 'Species', '9606', (3, 8))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (9, 41))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (9, 41))	('proliferation', 'CPA', (97, 110))	('carcinoma', 'Phenotype', 'HP:0030731', (32, 41))	('inhibited', 'NegReg', (83, 92))	('Panc-1', 'CellLine', 'CVCL:0480', (63, 69))	('apoptosis', 'CPA', (123, 132))	('MiaPaCa-2', 'CellLine', 'CVCL:0428', (49, 58))	('pristimerin', 'Var', (71, 82))	('pristimerin', 'Chemical', 'MESH:C009043', (71, 82))	('induced', 'Reg', (115, 122))
3529	28503090	The induction of apoptosis was associated with the inhibition of the pro-survival AKT, NF-kappaB and mTOR proteins and downstream targets, such as FOXO3A, CCND1, COX-2, VEGF, p-70S6K1, p-4E-BP1, and protein kinase C-epsilon (PKCepsilon), as well as of anti-apoptotic BCL-2 and survivin (also known as BIRC5) but not BCL-xL.	('mTOR', 'Gene', '2475', (101, 105))	('AKT', 'Gene', '207', (82, 85))	('survivin', 'Protein', (277, 285))	('NF-kappaB', 'Gene', (87, 96))	('protein kinase C-epsilon', 'Gene', '5581', (199, 223))	('BCL-xL', 'Gene', '598', (316, 322))	('NF-kappaB', 'Gene', '4790', (87, 96))	('protein kinase C-epsilon', 'Gene', (199, 223))	('PKCepsilon', 'Gene', '5581', (225, 235))	('FOXO3A', 'Gene', (147, 153))	('apoptosis', 'Disease', (17, 26))	('4E-BP1', 'Gene', '1978', (187, 193))	('COX-2', 'Gene', (162, 167))	('BCL-xL', 'Gene', (316, 322))	('p-70S6K1', 'Var', (175, 183))	('BCL-2', 'Gene', '596', (267, 272))	('AKT', 'Gene', (82, 85))	('COX-2', 'Gene', '4513', (162, 167))	('inhibition', 'NegReg', (51, 61))	('BCL-2', 'Gene', (267, 272))	('anti-apoptotic', 'CPA', (252, 266))	('4E-BP1', 'Gene', (187, 193))	('mTOR', 'Gene', (101, 105))	('BIRC5', 'Gene', '332', (301, 306))	('BIRC5', 'Gene', (301, 306))	('CCND1', 'Gene', '595', (155, 160))	('PKCepsilon', 'Gene', (225, 235))	('FOXO3A', 'Gene', '2309', (147, 153))	('CCND1', 'Gene', (155, 160))
3531	28503090	Pristimerin was found to possess potent cytotoxic effects, inducing apoptosis and inhibiting proliferation in U87 human glioma cells.	('U87', 'Gene', (110, 113))	('glioma', 'Phenotype', 'HP:0009733', (120, 126))	('Pristimerin', 'Chemical', 'MESH:C009043', (0, 11))	('inhibiting', 'NegReg', (82, 92))	('inducing', 'NegReg', (59, 67))	('proliferation', 'CPA', (93, 106))	('apoptosis', 'CPA', (68, 77))	('Pristimerin', 'Var', (0, 11))	('U87', 'Gene', '677775', (110, 113))	('human', 'Species', '9606', (114, 119))	('glioma', 'Disease', (120, 126))	('glioma', 'Disease', 'MESH:D005910', (120, 126))
3534	28503090	In ovarian cancer cells, pristimerin also induced apoptosis through cleavage of PARP-1, procaspases-3, -8 and -9 activity and enhanced mitochondrial depolarization.	('PARP-1, procaspases-3, -8 and -9', 'Gene', '142;836', (80, 112))	('cleavage', 'MPA', (68, 76))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('ovarian cancer', 'Phenotype', 'HP:0100615', (3, 17))	('enhanced', 'PosReg', (126, 134))	('pristimerin', 'Var', (25, 36))	('pristimerin', 'Chemical', 'MESH:C009043', (25, 36))	('ovarian cancer', 'Disease', 'MESH:D010051', (3, 17))	('mitochondrial depolarization', 'MPA', (135, 163))	('ovarian cancer', 'Disease', (3, 17))	('activity', 'MPA', (113, 121))	('apoptosis', 'CPA', (50, 59))
3536	28503090	In a somewhat different approach, pristimerin was shown to inhibit human telomerase reverse transcriptase (hTERT) expression and activity in human pancreatic cancer cells.	('hTERT', 'Gene', '7015', (107, 112))	('pancreatic cancer', 'Disease', 'MESH:D010190', (147, 164))	('pristimerin', 'Var', (34, 45))	('pristimerin', 'Chemical', 'MESH:C009043', (34, 45))	('telomerase reverse transcriptase', 'Gene', (73, 105))	('hTERT', 'Gene', (107, 112))	('telomerase reverse transcriptase', 'Gene', '7015', (73, 105))	('human', 'Species', '9606', (141, 146))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (147, 164))	('activity', 'MPA', (129, 137))	('expression', 'MPA', (114, 124))	('inhibit', 'NegReg', (59, 66))	('human', 'Species', '9606', (67, 72))	('pancreatic cancer', 'Disease', (147, 164))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
3542	28503090	On the one hand, silencing of SENP1 or c-JUN in PC-3 prostate cancer cells decreased cellular viability, suggesting that the cytotoxicity of triptolide could result from triptolide-induced downregulation of SENP1, or c-JUN.	('triptolide', 'Chemical', 'MESH:C001899', (170, 180))	('SENP1', 'Gene', (30, 35))	('downregulation', 'NegReg', (189, 203))	('c-JUN', 'Gene', '3725', (39, 44))	('c-JUN', 'Gene', (39, 44))	('triptolide', 'Chemical', 'MESH:C001899', (141, 151))	('PC-3', 'CellLine', 'CVCL:0035', (48, 52))	('cellular viability', 'CPA', (85, 103))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('SENP1', 'Gene', '29843', (207, 212))	('prostate cancer', 'Disease', 'MESH:D011471', (53, 68))	('prostate cancer', 'Phenotype', 'HP:0012125', (53, 68))	('cytotoxicity', 'Disease', (125, 137))	('prostate cancer', 'Disease', (53, 68))	('SENP1', 'Gene', (207, 212))	('cytotoxicity', 'Disease', 'MESH:D064420', (125, 137))	('c-JUN', 'Gene', '3725', (217, 222))	('c-JUN', 'Gene', (217, 222))	('SENP1', 'Gene', '29843', (30, 35))	('silencing', 'Var', (17, 26))	('decreased', 'NegReg', (75, 84))
3543	28503090	On the other hand, ectopic expression of SENP1, or c-JUN significantly increased the viability of prostate cancer cells upon triptolide exposure, indicating that rescuing these triptolide downregulated proteins could inhibit cell toxicity induced by triptolide.	('toxicity', 'Disease', 'MESH:D064420', (230, 238))	('prostate cancer', 'Disease', 'MESH:D011471', (98, 113))	('proteins', 'Protein', (202, 210))	('prostate cancer', 'Phenotype', 'HP:0012125', (98, 113))	('ectopic expression', 'Var', (19, 37))	('toxicity', 'Disease', (230, 238))	('prostate cancer', 'Disease', (98, 113))	('triptolide', 'Chemical', 'MESH:C001899', (125, 135))	('viability', 'CPA', (85, 94))	('downregulated', 'NegReg', (188, 201))	('SENP1', 'Gene', '29843', (41, 46))	('inhibit', 'NegReg', (217, 224))	('SENP1', 'Gene', (41, 46))	('triptolide', 'Chemical', 'MESH:C001899', (250, 260))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('c-JUN', 'Gene', '3725', (51, 56))	('increased', 'PosReg', (71, 80))	('c-JUN', 'Gene', (51, 56))	('triptolide', 'Chemical', 'MESH:C001899', (177, 187))
3552	28503090	After low-dose combined treatments with triptolide and cisplatin, a decrease in viability with a concomitant increase in apoptosis was observed in SC-M1 cells but not in normal cells.	('triptolide', 'Chemical', 'MESH:C001899', (40, 50))	('decrease', 'NegReg', (68, 76))	('increase', 'PosReg', (109, 117))	('cisplatin', 'Chemical', 'MESH:D002945', (55, 64))	('SC-M1', 'CellLine', 'CVCL:G299', (147, 152))	('viability', 'CPA', (80, 89))	('apoptosis', 'CPA', (121, 130))	('cisplatin', 'Var', (55, 64))
3595	28503090	HNSCC arises from premalignant progenitor cells that progress to invasive malignancy due to cumulative genetic alterations.	('genetic alterations', 'Var', (103, 122))	('invasive malignancy', 'Disease', (65, 84))	('HNSCC', 'Disease', (0, 5))	('HNSCC', 'Phenotype', 'HP:0012288', (0, 5))	('invasive malignancy', 'Disease', 'MESH:D009369', (65, 84))	('progress', 'PosReg', (53, 61))
3602	28503090	However, despite the abundant expression in HNSCC, only a subset of patients responds to EGFR inhibitors since alternative downstream signaling pathways may remain activated.	('responds to', 'MPA', (77, 88))	('EGFR', 'Gene', (89, 93))	('HNSCC', 'Gene', (44, 49))	('patients', 'Species', '9606', (68, 76))	('HNSCC', 'Phenotype', 'HP:0012288', (44, 49))	('EGFR', 'Gene', '1956', (89, 93))	('inhibitors', 'Var', (94, 104))
3604	28503090	Loss of heterozygosity at the chromosomal region 9p21 is found in 70-80% of HNSCC cases, representing the most common genetic alteration in this type of cancer and in early pre-invasive lesions.	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('Loss of heterozygosity', 'Var', (0, 22))	('HNSCC', 'Disease', (76, 81))	('cancer', 'Disease', (153, 159))	('HNSCC', 'Phenotype', 'HP:0012288', (76, 81))	('p21', 'Gene', '1026', (50, 53))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('p21', 'Gene', (50, 53))
3629	28503090	Thus, crosstalk by TGF-beta via TAK1 and NF-kappaB promotes the malignant phenotype of HNSCC.	('HNSCC', 'Phenotype', 'HP:0012288', (87, 92))	('malignant phenotype of', 'CPA', (64, 86))	('TAK1', 'Gene', '6885', (32, 36))	('NF-kappaB', 'Gene', '4790', (41, 50))	('promotes', 'PosReg', (51, 59))	('TAK1', 'Gene', (32, 36))	('NF-kappaB', 'Gene', (41, 50))	('TGF-beta', 'Gene', (19, 27))	('crosstalk', 'Var', (6, 15))	('HNSCC', 'Disease', (87, 92))
3641	26676674	Moreover, overexpressed LOXL2 was confirmed in lung SCC clinical specimens, and silencing of LOXL2 inhibited cancer cell migration and invasion in lung SCC cell lines.	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('silencing', 'Var', (80, 89))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('inhibited', 'NegReg', (99, 108))	('LOXL2', 'Gene', (24, 29))	('cancer', 'Disease', (109, 115))	('SCC', 'Gene', (152, 155))	('SCC', 'Gene', (52, 55))	('SCC', 'Gene', '6317', (152, 155))	('LOXL2', 'Gene', (93, 98))	('LOXL2', 'Gene', '4017', (24, 29))	('SCC', 'Phenotype', 'HP:0002860', (52, 55))	('SCC', 'Phenotype', 'HP:0002860', (152, 155))	('LOXL2', 'Gene', '4017', (93, 98))	('SCC', 'Gene', '6317', (52, 55))	('invasion', 'CPA', (135, 143))
3642	26676674	Our present data suggested that loss of tumor-suppressive miR-29s enhanced cancer cell invasion in lung SCC through direct regulation of oncogenic LOXL2.	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('cancer', 'Disease', (75, 81))	('SCC', 'Gene', (104, 107))	('LOXL2', 'Gene', (147, 152))	('miR', 'Gene', (58, 61))	('enhanced', 'PosReg', (66, 74))	('miR', 'Gene', '220972', (58, 61))	('SCC', 'Phenotype', 'HP:0002860', (104, 107))	('loss', 'Var', (32, 36))	('LOXL2', 'Gene', '4017', (147, 152))	('regulation', 'MPA', (123, 133))	('SCC', 'Gene', '6317', (104, 107))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('tumor', 'Disease', (40, 45))
3662	26676674	Moreover, overexpression of LOXL2 was detected in lung SCC clinical specimens, and silencing of LOXL2 significantly inhibited cell migration and invasion by cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('inhibited', 'NegReg', (116, 125))	('SCC', 'Gene', (55, 58))	('SCC', 'Phenotype', 'HP:0002860', (55, 58))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('LOXL2', 'Gene', (28, 33))	('LOXL2', 'Gene', (96, 101))	('SCC', 'Gene', '6317', (55, 58))	('cancer', 'Disease', (157, 163))	('LOXL2', 'Gene', '4017', (28, 33))	('LOXL2', 'Gene', '4017', (96, 101))	('silencing', 'Var', (83, 92))
3673	26676674	To normalize the data for quantification of mRNA and miRNAs, we used human GUSB (P/N: Hs99999908_m1; Applied Biosystems) and RNU48 (P/N: 001006; Applied Biosystems), respectively.	('miR', 'Gene', '220972', (53, 56))	('miR', 'Gene', (53, 56))	('RNU48', 'Gene', '26801', (125, 130))	('GUSB', 'Gene', (75, 79))	('human', 'Species', '9606', (69, 74))	('GUSB', 'Gene', '2990', (75, 79))	('P/N', 'Var', (81, 84))	('RNU48', 'Gene', (125, 130))
3674	26676674	The following mature miRNA species were used in the present study: Pre-miR  miRNA precursors (hsa-miR-29a-3p, P/N: AM 12499; hsa-miR-29b-3p, P/N: AM 10103; hsa-miR-29c-3p, P/N: AM 10518; and negative control miRNA, P/N: AM 17111), Stealth Select RNAi siRNA, si-LOXL2 (P/N: HSS106124, P/N: HSS106125 and P/N: HSS180848; Invitrogen, Carlsbad, CA, USA), and negative-control siRNA (D-001810-10; Thermo Fisher Scientific, Waltham, MA, USA).	('hsa-miR-29a', 'Gene', '407021', (94, 105))	('miR-29c', 'Gene', (160, 167))	('miR-29b', 'Gene', (129, 136))	('miR', 'Gene', (21, 24))	('miR', 'Gene', '220972', (76, 79))	('LOXL2', 'Gene', '4017', (261, 266))	('P/N: HSS106125', 'Var', (284, 298))	('miR', 'Gene', '220972', (129, 132))	('miR', 'Gene', '220972', (98, 101))	('miR', 'Gene', (76, 79))	('miR', 'Gene', '220972', (71, 74))	('miR', 'Gene', '220972', (160, 163))	('miR', 'Gene', '220972', (208, 211))	('miR', 'Gene', (129, 132))	('miR', 'Gene', (98, 101))	('LOXL2', 'Gene', (261, 266))	('miR-29b', 'Gene', '407024', (129, 136))	('P/N: HSS106124', 'Var', (268, 282))	('miR', 'Gene', (71, 74))	('miR', 'Gene', (208, 211))	('miR', 'Gene', (160, 163))	('P/N: HSS180848', 'Var', (303, 317))	('hsa-miR-29a', 'Gene', (94, 105))	('miR-29c', 'Gene', '407026', (160, 167))	('miR', 'Gene', '220972', (21, 24))
3681	26676674	A partial wild-type sequence of the LOXL2 3'-UTR or those with a deleted miR-29 target site (position 555-561 or position 757-763 of the LOXL2 3'-UTR) was inserted between the XhoI-PmeI restriction sites in the 3'-UTR of the hRluc gene in the psiCHECK-2 vector (C8021; Promega, Madison, WI, USA).	('LOXL2', 'Gene', (36, 41))	('LOXL2', 'Gene', (137, 142))	('LOXL2', 'Gene', '4017', (36, 41))	('miR', 'Gene', '220972', (73, 76))	('C8021;', 'Var', (262, 268))	('miR', 'Gene', (73, 76))	('hRluc', 'Gene', (225, 230))	('LOXL2', 'Gene', '4017', (137, 142))
3706	26676674	The mRNA and protein expression levels of LOXL2 were significantly repressed in miR-29s transfectants in comparison with mock or miR-control transfectants (P<0.001) (Fig.	('miR', 'Gene', '220972', (80, 83))	('transfectants', 'Var', (88, 101))	('miR', 'Gene', (80, 83))	('miR', 'Gene', '220972', (129, 132))	('miR', 'Gene', (129, 132))	('repressed', 'PosReg', (67, 76))	('LOXL2', 'Gene', (42, 47))	('LOXL2', 'Gene', '4017', (42, 47))
3709	26676674	Luciferase activity was significantly decreased in two miR-29 target sites (positions 555-561 and 757-763 in the 3'-UTR of LOXL2) (Fig.	('decreased', 'NegReg', (38, 47))	('757-763', 'Var', (98, 105))	('activity', 'MPA', (11, 19))	('LOXL2', 'Gene', (123, 128))	('miR', 'Gene', '220972', (55, 58))	('miR', 'Gene', (55, 58))	('LOXL2', 'Gene', '4017', (123, 128))	('Luciferase', 'Enzyme', (0, 10))
3713	26676674	XTT assays demonstrated that cell proliferation was not inhibited in si-LOXL2 transfectants in comparison with mock or si-control transfectants in lung SCC cells (Fig.	('SCC', 'Gene', (152, 155))	('cell proliferation', 'CPA', (29, 47))	('LOXL2', 'Gene', (72, 77))	('SCC', 'Phenotype', 'HP:0002860', (152, 155))	('SCC', 'Gene', '6317', (152, 155))	('LOXL2', 'Gene', '4017', (72, 77))	('transfectants', 'Var', (78, 91))
3714	26676674	Wound healing assays showed significant inhibition of cell migration in si-LOXL2 transfectants in comparison with mock or si-control transfectants in lung SCC cells (P<0.0001) (Fig.	('LOXL2', 'Gene', (75, 80))	('transfectants', 'Var', (81, 94))	('SCC', 'Gene', (155, 158))	('LOXL2', 'Gene', '4017', (75, 80))	('SCC', 'Phenotype', 'HP:0002860', (155, 158))	('inhibition', 'NegReg', (40, 50))	('SCC', 'Gene', '6317', (155, 158))	('cell migration', 'CPA', (54, 68))
3719	26676674	Overexpression of extracellular matrix (ECM) components has frequently been observed in cancer lesions and aberrantly expressed ECM-mediated signals have triggered cancer cell metastasis.	('triggered', 'Reg', (154, 163))	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('cancer lesions', 'Disease', 'MESH:D009062', (88, 102))	('cancer', 'Disease', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('cancer lesions', 'Disease', (88, 102))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('aberrantly', 'Var', (107, 117))
3729	26676674	A recent study showed that cancer cells with high c-Myc, low miR-29b, and low FHIT expression had a shorter overall survival and relapse-free survival in NSCLC patients.	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('FHIT', 'Gene', (78, 82))	('low', 'NegReg', (74, 77))	('shorter', 'NegReg', (100, 107))	('expression', 'MPA', (83, 93))	('c-Myc', 'Gene', (50, 55))	('FHIT', 'Gene', '2272', (78, 82))	('overall survival', 'CPA', (108, 124))	('low', 'NegReg', (57, 60))	('c-Myc', 'Gene', '4609', (50, 55))	('high', 'Var', (45, 49))	('miR-29b', 'Gene', '407024', (61, 68))	('cancer', 'Disease', 'MESH:D009369', (27, 33))	('NSCLC', 'Disease', 'MESH:D002289', (154, 159))	('NSCLC', 'Disease', (154, 159))	('patients', 'Species', '9606', (160, 168))	('NSCLC', 'Phenotype', 'HP:0030358', (154, 159))	('miR-29b', 'Gene', (61, 68))	('relapse-free survival', 'CPA', (129, 150))	('cancer', 'Disease', (27, 33))
3731	26676674	Loss of GATA3 is involved in breast cancer pathogenesis.	('GATA3', 'Gene', (8, 13))	('involved', 'Reg', (17, 25))	('GATA3', 'Gene', '2625', (8, 13))	('breast cancer', 'Disease', 'MESH:D001943', (29, 42))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('breast cancer', 'Disease', (29, 42))	('Loss', 'Var', (0, 4))	('breast cancer', 'Phenotype', 'HP:0003002', (29, 42))
3735	26676674	In this study, the restoration of miR-29s into cancer cells significantly inhibited migration and invasion; thus miR-29-mediated novel targets deeply contribute to meta-static pathways.	('inhibited', 'NegReg', (74, 83))	('miR', 'Gene', '220972', (113, 116))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('miR', 'Gene', (113, 116))	('migration and invasion', 'CPA', (84, 106))	('contribute', 'Reg', (150, 160))	('cancer', 'Disease', (47, 53))	('miR', 'Gene', '220972', (34, 37))	('miR', 'Gene', (34, 37))	('restoration', 'Var', (19, 30))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))
3741	26676674	Furthermore, overexpression of LOXL2 was detected in lung SCC clinical specimens, and silencing of LOXL2 expression in lung SCC cells inhibited cancer cell migration and invasion, indicating that LOXL2 acts as an oncogene in the disease.	('SCC', 'Gene', '6317', (124, 127))	('SCC', 'Gene', (58, 61))	('SCC', 'Phenotype', 'HP:0002860', (58, 61))	('silencing', 'Var', (86, 95))	('LOXL2', 'Gene', (99, 104))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('inhibited', 'NegReg', (134, 143))	('SCC', 'Gene', '6317', (58, 61))	('SCC', 'Gene', (124, 127))	('SCC', 'Phenotype', 'HP:0002860', (124, 127))	('cancer', 'Disease', (144, 150))	('LOXL2', 'Gene', (196, 201))	('LOXL2', 'Gene', '4017', (99, 104))	('LOXL2', 'Gene', (31, 36))	('LOXL2', 'Gene', '4017', (196, 201))	('LOXL2', 'Gene', '4017', (31, 36))
3765	25996086	Moreover, patients with Notch1 overexpression and Notch3 overexpression showed significantly poor overall survival (Notch1: HR, 1.29; 95% CI, 1.06-1.57, p = 0.468 and I2 = 0.0%; Notch3: HR, 1.57; 95%CI, 1.04-2.36, p = 0.445 and I2 = 0.0%).	('Notch3', 'Gene', '4854', (178, 184))	('Notch3', 'Gene', (178, 184))	('Notch3', 'Gene', '4854', (50, 56))	('Notch1', 'Var', (24, 30))	('patients', 'Species', '9606', (10, 18))	('poor', 'NegReg', (93, 97))	('overall survival', 'CPA', (98, 114))	('overexpression', 'PosReg', (31, 45))	('Notch3', 'Gene', (50, 56))
3767	25996086	Our meta-analysis supports that Notch signaling is a valuable bio-marker to predict progression and targeting Notch signaling could benefit subpopulation of NSCLC patients.	('patients', 'Species', '9606', (163, 171))	('Notch', 'Gene', '4851;18128;4853;4854;4855', (110, 115))	('benefit', 'PosReg', (132, 139))	('Notch', 'Gene', (110, 115))	('Notch', 'Gene', '4851;18128;4853;4854;4855', (32, 37))	('NSCLC', 'Disease', (157, 162))	('Notch', 'Gene', (32, 37))	('targeting', 'Var', (100, 109))	('NSCLC', 'Disease', 'MESH:D002289', (157, 162))
3772	25996086	Earlier studies also discovered that deregulated Notch signaling led to various diseases, such as T cell leukemia and lung cancer.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('led to', 'Reg', (65, 71))	('deregulated', 'Var', (37, 48))	('lung cancer', 'Disease', 'MESH:D008175', (118, 129))	('Notch', 'Gene', '4851;18128;4853;4854;4855', (49, 54))	('T cell leukemia', 'Phenotype', 'HP:0005517', (98, 113))	('Notch', 'Gene', (49, 54))	('T cell leukemia', 'Disease', (98, 113))	('lung cancer', 'Disease', (118, 129))	('leukemia', 'Phenotype', 'HP:0001909', (105, 113))	('lung cancer', 'Phenotype', 'HP:0100526', (118, 129))	('T cell leukemia', 'Disease', 'MESH:D015458', (98, 113))
3778	25996086	However, the prognostic value of Notch1 and Notch3 for NSCLC has yet to be confirmed.	('Notch3', 'Gene', (44, 50))	('Notch1', 'Var', (33, 39))	('NSCLC', 'Disease', (55, 60))	('NSCLC', 'Disease', 'MESH:D002289', (55, 60))	('Notch3', 'Gene', '4854', (44, 50))
3779	25996086	Some studies suggested that Notch1 and Notch3 overexpression was associated with poor prognosis in NSCLC, but other researchers reported different results.	('overexpression', 'PosReg', (46, 60))	('NSCLC', 'Disease', (99, 104))	('Notch3', 'Gene', '4854', (39, 45))	('Notch1', 'Var', (28, 34))	('Notch3', 'Gene', (39, 45))	('NSCLC', 'Disease', 'MESH:D002289', (99, 104))
3787	25996086	Moreover, greater possibility of lymph node metastasis (LNM) and higher tumor stages were linked with high Notch1 expression in NSCLC (pooled OR = 3.20, 95%CI: 1.81-5.65, p = 0.798 and I2 = 0.0%; pooled OR = 1.62, 95%CI: 1.00-2.62, p = 0.251 and I2 = 25.5%) (Fig.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('high', 'Var', (102, 106))	('tumor', 'Disease', (72, 77))	('Notch1', 'Gene', (107, 113))	('lymph node metastasis', 'CPA', (33, 54))	('NSCLC', 'Disease', (128, 133))	('NSCLC', 'Disease', 'MESH:D002289', (128, 133))	('expression', 'MPA', (114, 124))	('tumor', 'Disease', 'MESH:D009369', (72, 77))
3792	25996086	We found that Notch1 was correlated with the overall survival rate of NSCLC patients (pooled HR = 1.29, 95%CI: 1.06-1.57, p = 0.468 and I2 = 0.0%) (Fig.	('Notch1', 'Var', (14, 20))	('patients', 'Species', '9606', (76, 84))	('NSCLC', 'Disease', (70, 75))	('NSCLC', 'Disease', 'MESH:D002289', (70, 75))	('correlated', 'Reg', (25, 35))
3805	25996086	In the subgroup analysis stratified by cancer histological types, HES1 expression was also associated with both lung adenocarcinoma overall survival rate (pooled HR = 1.85, 95%CI: 1.31-2.60, p = 0.445 and I2 = 0.0%) (Fig.	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (112, 131))	('HES1', 'Gene', '3280', (66, 70))	('cancer', 'Disease', (39, 45))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('expression', 'Var', (71, 81))	('lung adenocarcinoma', 'Disease', (112, 131))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (112, 131))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('HES1', 'Gene', (66, 70))	('associated with', 'Reg', (91, 106))
3808	25996086	Kaplan -Meier survival curve of GSE31210 comprised of 226 NSCLC patients at stage I-II demonstrated that the overall survival rate was lower in patients with higher expression of HES1 (p = 0.007) (Fig.	('NSCLC', 'Disease', (58, 63))	('patients', 'Species', '9606', (64, 72))	('NSCLC', 'Disease', 'MESH:D002289', (58, 63))	('higher', 'PosReg', (158, 164))	('HES1', 'Gene', (179, 183))	('lower', 'NegReg', (135, 140))	('patients', 'Species', '9606', (144, 152))	('HES1', 'Gene', '3280', (179, 183))	('GSE31210', 'Var', (32, 40))
3809	25996086	To explore whether mutation of EGFR interferes with HES1, NSCLC patients were subdivided into EGFR mutation and wild type (wt) group.	('NSCLC', 'Disease', (58, 63))	('EGFR', 'Gene', '1956', (31, 35))	('mutation', 'Var', (19, 27))	('HES1', 'Gene', '3280', (52, 56))	('patients', 'Species', '9606', (64, 72))	('EGFR', 'Gene', '1956', (94, 98))	('NSCLC', 'Disease', 'MESH:D002289', (58, 63))	('EGFR', 'Gene', (31, 35))	('mutation', 'Var', (99, 107))	('EGFR', 'Gene', (94, 98))	('HES1', 'Gene', (52, 56))
3810	25996086	The overall survival rate of patients with EGFR mutation was correlated with the abundance of HES1 expression (p = 0.008) (Fig.	('HES1', 'Gene', (94, 98))	('patients', 'Species', '9606', (29, 37))	('HES1', 'Gene', '3280', (94, 98))	('EGFR', 'Gene', '1956', (43, 47))	('mutation', 'Var', (48, 56))	('EGFR', 'Gene', (43, 47))
3815	25996086	It is generally assumed that Notch1 and Notch3 activity were higher in advanced NSCLC and predicted poor prognosis; However, opposite result was also reported in lung squamous carcinoma.	('Notch3', 'Gene', '4854', (40, 46))	('Notch1', 'Var', (29, 35))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (167, 185))	('Notch3', 'Gene', (40, 46))	('higher', 'PosReg', (61, 67))	('lung squamous carcinoma', 'Disease', (162, 185))	('NSCLC', 'Disease', (80, 85))	('NSCLC', 'Disease', 'MESH:D002289', (80, 85))	('activity', 'MPA', (47, 55))	('lung squamous carcinoma', 'Disease', 'MESH:D002294', (162, 185))	('carcinoma', 'Phenotype', 'HP:0030731', (176, 185))
3816	25996086	Precisely measuring the prognostic value of Notch1 and Notch3 may help to guide an individual therapy for NSCLC patients.	('NSCLC', 'Disease', 'MESH:D002289', (106, 111))	('patients', 'Species', '9606', (112, 120))	('Notch3', 'Gene', '4854', (55, 61))	('Notch1', 'Var', (44, 50))	('Notch3', 'Gene', (55, 61))	('NSCLC', 'Disease', (106, 111))
3824	25996086	Moreover, high Notch3 expression in lung cancer represented a higher possibility of being resistant to chemotherapy.	('lung cancer', 'Disease', (36, 47))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('lung cancer', 'Disease', 'MESH:D008175', (36, 47))	('high', 'Var', (10, 14))	('lung cancer', 'Phenotype', 'HP:0100526', (36, 47))	('Notch3', 'Gene', '4854', (15, 21))	('expression', 'MPA', (22, 32))	('Notch3', 'Gene', (15, 21))
3825	25996086	In support of clinical-pathological observation, experimental study demonstrated that high Notch activity enhanced tumor sphere formation and knockdown of Notch decreased cell proliferation and induced apoptotic cell death.	('Notch', 'Gene', (91, 96))	('cell proliferation', 'CPA', (171, 189))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('decreased', 'NegReg', (161, 170))	('enhanced', 'PosReg', (106, 114))	('induced', 'Reg', (194, 201))	('Notch', 'Gene', '4851;18128;4853;4854;4855', (155, 160))	('tumor', 'Disease', (115, 120))	('Notch', 'Gene', (155, 160))	('apoptotic cell death', 'CPA', (202, 222))	('Notch', 'Gene', '4851;18128;4853;4854;4855', (91, 96))	('knockdown', 'Var', (142, 151))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
3840	25996086	Thus, Notch pathway downstream genes could be used to predict the antitumor activity of RO4929097.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('Notch', 'Gene', (6, 11))	('RO4929097', 'Var', (88, 97))	('tumor', 'Disease', (70, 75))	('Notch', 'Gene', '4851;18128;4853;4854;4855', (6, 11))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
3841	25996086	EGFR mutations are one of the most important active genetic changes yet discovered in NSCLC.	('EGFR', 'Gene', (0, 4))	('NSCLC', 'Disease', (86, 91))	('NSCLC', 'Disease', 'MESH:D002289', (86, 91))	('mutations', 'Var', (5, 14))	('EGFR', 'Gene', '1956', (0, 4))
3843	25996086	It is observed that in human lung cancer cell line NCI-H292 cells, inhibition of the Notch pathway decreased both the Notch and EGFR/ERK pathways, associated with the reduction of proliferative cells.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('Notch', 'Gene', (85, 90))	('inhibition', 'Var', (67, 77))	('decreased', 'NegReg', (99, 108))	('EGFR', 'Gene', '1956', (128, 132))	('EGFR', 'Gene', (128, 132))	('NCI-H292', 'CellLine', 'CVCL:0455', (51, 59))	('proliferative cells', 'CPA', (180, 199))	('reduction', 'NegReg', (167, 176))	('lung cancer', 'Disease', 'MESH:D008175', (29, 40))	('Notch', 'Gene', '4851;18128;4853;4854;4855', (118, 123))	('ERK', 'Gene', (133, 136))	('ERK', 'Gene', '2048', (133, 136))	('human', 'Species', '9606', (23, 28))	('Notch', 'Gene', (118, 123))	('lung cancer', 'Disease', (29, 40))	('Notch', 'Gene', '4851;18128;4853;4854;4855', (85, 90))	('lung cancer', 'Phenotype', 'HP:0100526', (29, 40))
3846	25996086	For example, Notch 1 contributed to the acquired resistance to TKI and inhibition of Notch-1 resulted in effective response to EGFR target therapy (gefitinib).	('inhibition', 'Var', (71, 81))	('Notch-1', 'Gene', (85, 92))	('Notch-1', 'Gene', '4851', (85, 92))	('gefitinib', 'Chemical', 'MESH:D000077156', (148, 157))	('Notch 1', 'Gene', '4851', (13, 20))	('EGFR', 'Gene', '1956', (127, 131))	('Notch 1', 'Gene', (13, 20))	('EGFR', 'Gene', (127, 131))
3862	25996086	The prognosis of NSCLC patients with expressions of Notch1, Notch 3, Notch ligands, Notch downstream target gene HES1 and HEY1was calculated by HRs and 95% CIs, respectively.	('Notch 3', 'Gene', (60, 67))	('Notch', 'Gene', (60, 65))	('HEY1', 'Gene', (122, 126))	('NSCLC', 'Disease', (17, 22))	('Notch', 'Gene', '4851;18128;4853;4854;4855', (52, 57))	('Notch', 'Gene', '4851;18128;4853;4854;4855', (69, 74))	('HES1', 'Gene', (113, 117))	('patients', 'Species', '9606', (23, 31))	('NSCLC', 'Disease', 'MESH:D002289', (17, 22))	('Notch', 'Gene', '4851;18128;4853;4854;4855', (84, 89))	('expressions', 'Var', (37, 48))	('Notch', 'Gene', (52, 57))	('Notch', 'Gene', (69, 74))	('HES1', 'Gene', '3280', (113, 117))	('Notch', 'Gene', '4851;18128;4853;4854;4855', (60, 65))	('Notch', 'Gene', (84, 89))	('HEY1', 'Gene', '23462', (122, 126))	('Notch 3', 'Gene', '4854', (60, 67))
3872	24457962	The main molecular determinants in HNSCC are the abrogation of p53 and retinoblastoma (pRb) pathways that lead to uncontrolled cell replication.	('retinoblastoma', 'Phenotype', 'HP:0009919', (71, 85))	('pRb', 'Gene', '5925', (87, 90))	('pRb', 'Gene', (87, 90))	('p53', 'Pathway', (63, 66))	('HNSCC', 'Disease', (35, 40))	('uncontrolled cell replication', 'MPA', (114, 143))	('lead to', 'Reg', (106, 113))	('retinoblastoma', 'Gene', '5925', (71, 85))	('abrogation', 'Var', (49, 59))	('retinoblastoma', 'Gene', (71, 85))
3873	24457962	Mutations in EGFR-MEK, NOTCH, PI3K, PTEN and AKT pathways are frequently observed in HNSCC.	('AKT', 'Gene', '207', (45, 48))	('AKT', 'Gene', (45, 48))	('NOTCH', 'Gene', (23, 28))	('MEK', 'Gene', (18, 21))	('PI3', 'Gene', '5266', (30, 33))	('PTEN', 'Gene', (36, 40))	('PI3', 'Gene', (30, 33))	('PTEN', 'Gene', '5728', (36, 40))	('Mutations', 'Var', (0, 9))	('MEK', 'Gene', '5609', (18, 21))	('EGFR', 'Gene', '1956', (13, 17))	('HNSCC', 'Disease', (85, 90))	('EGFR', 'Gene', (13, 17))	('observed', 'Reg', (73, 81))
3894	24457962	p53 controls a significant spectrum of genes involved in various pathways; these include recently discovered biochemical pathways, such as the connection of IL-7Ra to telomere erosion, the metabolism of the cell and the silencing of repeats and noncoding RNA.	('silencing', 'Var', (220, 229))	('IL-7Ra', 'Gene', '3575', (157, 163))	('IL-7Ra', 'Gene', (157, 163))	('metabolism', 'MPA', (189, 199))
3905	24457962	Mutations in p53 and pRb pathways result in limitless replicative potential and immortalisation.	('pRb', 'Gene', '5925', (21, 24))	('replicative potential', 'CPA', (54, 75))	('immortalisation', 'CPA', (80, 95))	('Mutations', 'Var', (0, 9))	('p53', 'Gene', (13, 16))	('pRb', 'Gene', (21, 24))
3906	24457962	TP53 mutations can occur throughout the entire gene but the majority are because of a missense mutation in the DNA-binding domain.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('because of', 'Reg', (73, 83))	('missense mutation in', 'Var', (86, 106))	('mutations', 'Var', (5, 14))
3907	24457962	These mutations can result in a number of consequences including inhibition of function, tumour suppressor loss or occasionally gain of function.	('inhibition of function', 'NegReg', (65, 87))	('tumour', 'Phenotype', 'HP:0002664', (89, 95))	('loss', 'NegReg', (107, 111))	('tumour', 'Disease', 'MESH:D009369', (89, 95))	('tumour', 'Disease', (89, 95))	('gain of function', 'PosReg', (128, 144))	('mutations', 'Var', (6, 15))
3908	24457962	Mutation of the TP53 tumour suppressor gene is one of the earliest and most frequently detectable genetic alterations in HNSCC reported in 50-80% of cases, and can also be detected in premalignant dysplastic lesions and in histopathologically negative tumour surgical margins.	('premalignant dysplastic lesions', 'Disease', (184, 215))	('detected', 'Reg', (172, 180))	('HNSCC', 'Disease', (121, 126))	('tumour', 'Phenotype', 'HP:0002664', (21, 27))	('tumour', 'Disease', (252, 258))	('Mutation', 'Var', (0, 8))	('tumour', 'Disease', 'MESH:D009369', (21, 27))	('TP53', 'Gene', '7157', (16, 20))	('premalignant dysplastic lesions', 'Disease', 'MESH:D021782', (184, 215))	('tumour', 'Disease', (21, 27))	('tumour', 'Phenotype', 'HP:0002664', (252, 258))	('TP53', 'Gene', (16, 20))	('tumour', 'Disease', 'MESH:D009369', (252, 258))
3909	24457962	A recent mutational screening in 12 types of cancer has revealed mutations of p53 in 69.8% of HNSCC (Figure 1).	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('HNSCC', 'Disease', (94, 99))	('p53', 'Gene', (78, 81))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('cancer', 'Disease', (45, 51))	('mutations', 'Var', (65, 74))
3911	24457962	Increased TP53 mutation rate is associated with tobacco and alcohol use in HNSCC and also with increased risk of progression to cancer.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('mutation', 'Var', (15, 23))	('alcohol', 'Chemical', 'MESH:D000438', (60, 67))	('TP53', 'Gene', (10, 14))	('tobacco', 'Disease', (48, 55))	('TP53', 'Gene', '7157', (10, 14))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('associated', 'Reg', (32, 42))	('tobacco', 'Species', '4097', (48, 55))	('alcohol use', 'Phenotype', 'HP:0030955', (60, 71))	('cancer', 'Disease', (128, 134))
3912	24457962	In p53 wild-type tumours, p53 function may be inactivated by other mechanisms, such as HPV infection, overexpression or amplification of MDM2 and deletion of the p14ARF gene.	('deletion', 'Var', (146, 154))	('function', 'MPA', (30, 38))	('tumour', 'Phenotype', 'HP:0002664', (17, 23))	('MDM2', 'Gene', (137, 141))	('HPV infection', 'Disease', 'MESH:D030361', (87, 100))	('p14ARF', 'Gene', '1029', (162, 168))	('tumours', 'Phenotype', 'HP:0002664', (17, 24))	('p53', 'Gene', (26, 29))	('amplification', 'Var', (120, 133))	('HPV infection', 'Disease', (87, 100))	('tumours', 'Disease', 'MESH:D009369', (17, 24))	('tumours', 'Disease', (17, 24))	('inactivated', 'NegReg', (46, 57))	('p14ARF', 'Gene', (162, 168))
3913	24457962	pRb is targeted early in the carcinogenesis of HNSCC through inactivation of the tumour-suppressive CDKN2A gene, with mutations seen in 7-9% and copy number losses in a further 20-30% of cases.	('CDKN2A', 'Gene', '1029', (100, 106))	('carcinogenesis', 'Disease', (29, 43))	('copy number losses', 'Var', (145, 163))	('tumour', 'Disease', 'MESH:D009369', (81, 87))	('carcinogenesis', 'Disease', 'MESH:D063646', (29, 43))	('mutations', 'Var', (118, 127))	('tumour', 'Disease', (81, 87))	('CDKN2A', 'Gene', (100, 106))	('HNSCC', 'Disease', (47, 52))	('pRb', 'Gene', '5925', (0, 3))	('inactivation', 'NegReg', (61, 73))	('pRb', 'Gene', (0, 3))	('tumour', 'Phenotype', 'HP:0002664', (81, 87))
3915	24457962	TP53 mutation, loss of p16INK4A and overexpression of cyclin D1 are all associated with reduced survival.	('cyclin D1', 'Gene', '595', (54, 63))	('TP53', 'Gene', '7157', (0, 4))	('p16INK4A', 'Gene', (23, 31))	('TP53', 'Gene', (0, 4))	('survival', 'MPA', (96, 104))	('overexpression', 'PosReg', (36, 50))	('cyclin D1', 'Gene', (54, 63))	('loss', 'NegReg', (15, 19))	('p16INK4A', 'Gene', '1029', (23, 31))	('reduced', 'NegReg', (88, 95))	('mutation', 'Var', (5, 13))
3916	24457962	In addition, TP53 mutation is predictive of poor response to chemotherapy and locoregional recurrence following radiotherapy.	('TP53', 'Gene', '7157', (13, 17))	('TP53', 'Gene', (13, 17))	('mutation', 'Var', (18, 26))	('locoregional recurrence', 'CPA', (78, 101))
3917	24457962	This showed that patients with wild-type p53 had better response to Ad-p53 gene therapy, whereas mutant p53 patients responded better to methotrexate chemotherapy, suggesting a potential of p53 profile as predictive biomarker of response to specific type of therapy.	('response', 'MPA', (56, 64))	('p53', 'Gene', (104, 107))	('Ad-p53', 'Gene', (68, 74))	('mutant', 'Var', (97, 103))	('better', 'PosReg', (49, 55))	('patients', 'Species', '9606', (17, 25))	('patients', 'Species', '9606', (108, 116))	('methotrexate', 'Chemical', 'MESH:D008727', (137, 149))
3928	24457962	EGFR overexpression is mainly at the transcriptional level as there are few EGFR-activating mutations in HNSCC.	('EGFR', 'Gene', (0, 4))	('HNSCC', 'Gene', (105, 110))	('EGFR', 'Gene', '1956', (76, 80))	('mutations', 'Var', (92, 101))	('EGFR', 'Gene', (76, 80))	('EGFR', 'Gene', '1956', (0, 4))
3930	24457962	A mutant form of EGFR, EGFRvIII, resulting from an in-frame deletion of exons 2-7 in the extracellular domain, has been reported in 42% of HNSCC.	('deletion', 'Var', (60, 68))	('EGFR', 'Gene', '1956', (23, 27))	('EGFR', 'Gene', '1956', (17, 21))	('EGFR', 'Gene', (23, 27))	('reported', 'Reg', (120, 128))	('EGFR', 'Gene', (17, 21))
3939	24457962	In HNSCC, a phase III trial of panitumumab in combination with chemotherapy did not show an improvement in survival, although retrospective analysis showed that median overall survival in p16 (surrogate marker for HPV)-negative patients was longer in the panitumumab group than in the control group.	('p16', 'Gene', (188, 191))	('patients', 'Species', '9606', (228, 236))	('longer', 'PosReg', (241, 247))	('panitumumab', 'Chemical', 'MESH:D000077544', (255, 266))	('panitumumab', 'Chemical', 'MESH:D000077544', (31, 42))	('HPV', 'Species', '10566', (214, 217))	('p16', 'Gene', '1029', (188, 191))	('panitumumab', 'Var', (255, 266))	('overall survival', 'MPA', (168, 184))
3948	24457962	Afatinib irreversibly blocks EGFR, HER2 and ErbB4 and is being investigated in the recurrent/metastatic, neoadjuvant and adjuvant settings (NCT 01856478, NCT01538381 and NCT01345669).	('ErbB4', 'Gene', '2066', (44, 49))	('HER2', 'Gene', (35, 39))	('HER2', 'Gene', '2064', (35, 39))	('NCT', 'Var', (140, 143))	('EGFR', 'Gene', '1956', (29, 33))	('EGFR', 'Gene', (29, 33))	('Afatinib', 'Chemical', 'MESH:D000077716', (0, 8))	('blocks', 'NegReg', (22, 28))	('ErbB4', 'Gene', (44, 49))
3954	24457962	One of the novel findings generated from whole-exome sequencing was the discovery that the second most common mutation in HNSCC is in the NOTCH1 gene, accounting for 14-15%, with mutations in the other NOTCH family members occurring in 3-5% of HNSCC.	('NOTCH1', 'Gene', (138, 144))	('HNSCC', 'Gene', (122, 127))	('mutation', 'Var', (110, 118))	('NOTCH1', 'Gene', '4851', (138, 144))
3955	24457962	Mutations in the FBXW7 gene were also identified in 5% of cases that have not been previously observed in HNSCC.	('FBXW7', 'Gene', '55294', (17, 22))	('Mutations', 'Var', (0, 9))	('identified', 'Reg', (38, 48))	('FBXW7', 'Gene', (17, 22))
3958	24457962	NOTCH1 signalling has been reported to be oncogenic, as activating mutations and translocations were found in NOTCH receptor genes in haematological malignancies.	('haematological malignancies', 'Disease', 'MESH:D019337', (134, 161))	('haematological malignancies', 'Disease', (134, 161))	('activating', 'PosReg', (56, 66))	('translocations', 'Var', (81, 95))	('NOTCH1', 'Gene', '4851', (0, 6))	('NOTCH1', 'Gene', (0, 6))	('NOTCH receptor genes', 'Gene', (110, 130))
3959	24457962	However, in HNSCC, the majority were nonsense mutations, predicted to result in truncated NOTCH1 proteins lacking the transcriptional activation domains, therefore suggesting a tumour-suppressor role for this pathway in HNSCC.	('tumour', 'Disease', 'MESH:D009369', (177, 183))	('lacking', 'NegReg', (106, 113))	('tumour', 'Disease', (177, 183))	('proteins', 'Protein', (97, 105))	('transcriptional activation domains', 'MPA', (118, 152))	('nonsense', 'Var', (37, 45))	('HNSCC', 'Disease', (12, 17))	('truncated', 'MPA', (80, 89))	('tumour', 'Phenotype', 'HP:0002664', (177, 183))	('NOTCH1', 'Gene', '4851', (90, 96))	('NOTCH1', 'Gene', (90, 96))
3963	24457962	Overexpression and amplification of TP63 have been observed in the majority of HNSCC.	('HNSCC', 'Disease', (79, 84))	('amplification', 'Var', (19, 32))	('TP63', 'Gene', (36, 40))	('TP63', 'Gene', '8626', (36, 40))
3978	24457962	Genetic aberrations of the PI3K pathway are common in HNSCC.	('PI3', 'Gene', '5266', (27, 30))	('PI3', 'Gene', (27, 30))	('HNSCC', 'Disease', (54, 59))	('Genetic aberrations', 'Var', (0, 19))
3980	24457962	It has been found to be particularly common in HPV-positive HNSCC cases, and specific mutations, such as H1047R in exon 20, may predict higher response rates to treatment with PI3K pathway inhibitors.	('PI3', 'Gene', (176, 179))	('higher', 'PosReg', (136, 142))	('H1047R', 'Var', (105, 111))	('response', 'MPA', (143, 151))	('HNSCC', 'Disease', (60, 65))	('H1047R', 'Mutation', 'rs121913279', (105, 111))	('PI3', 'Gene', '5266', (176, 179))	('HPV', 'Species', '10566', (47, 50))
3981	24457962	In addition, PTEN mutations have been reported in 7% of HNSCC, and the mTOR pathway is frequently activated, independent from activation of EGFR or the presence of mutant p53, particularly in HPV-positive tumours.	('mutant', 'Var', (164, 170))	('HPV-positive tumours', 'Disease', 'MESH:D030361', (192, 212))	('HNSCC', 'Disease', (56, 61))	('activated', 'PosReg', (98, 107))	('HPV-positive tumours', 'Disease', (192, 212))	('EGFR', 'Gene', (140, 144))	('tumour', 'Phenotype', 'HP:0002664', (205, 211))	('mTOR', 'Gene', '2475', (71, 75))	('mTOR', 'Gene', (71, 75))	('PTEN', 'Gene', (13, 17))	('tumours', 'Phenotype', 'HP:0002664', (205, 212))	('PTEN', 'Gene', '5728', (13, 17))	('p53', 'Gene', (171, 174))	('EGFR', 'Gene', '1956', (140, 144))	('mutations', 'Var', (18, 27))
3984	24457962	PI3K inhibitors are being investigated in phase II trials in HNSCC in conjunction with chemotherapy or cetuximab (NCT01252628); AKT inhibitors are being tested in recurrent or metastatic nasopharyngeal cancer (NCT01349933); and the mTOR inhibitors rapamycin, everolimus and temsirolimus are being assessed for HNSCC at the phase II stage in neoadjuvant and recurrent/metastatic settings.	('NCT01349933', 'Var', (210, 221))	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('cetuximab', 'Chemical', 'MESH:D000068818', (103, 112))	('nasopharyngeal cancer', 'Phenotype', 'HP:0100630', (187, 208))	('everolimus', 'Chemical', 'MESH:D000068338', (259, 269))	('PI3', 'Gene', '5266', (0, 3))	('AKT', 'Gene', (128, 131))	('rapamycin', 'Chemical', 'MESH:D020123', (248, 257))	('cancer', 'Disease', 'MESH:D009369', (202, 208))	('mTOR', 'Gene', (232, 236))	('temsirolimus', 'Chemical', 'MESH:C401859', (274, 286))	('mTOR', 'Gene', '2475', (232, 236))	('cancer', 'Disease', (202, 208))	('AKT', 'Gene', '207', (128, 131))	('PI3', 'Gene', (0, 3))
3987	24457962	In the inactivated state, Ras is bound to guanosine diphosphate (GDP) and activation converts Ras to the guanosine triphosphate (GTP)-bound form; Ras-GTP binds to and activates Raf-1.	('Ras-GTP', 'Chemical', '-', (146, 153))	('Raf-1', 'Gene', (177, 182))	('guanosine diphosphate', 'Chemical', 'MESH:D006153', (42, 63))	('GDP', 'Chemical', 'MESH:D006153', (65, 68))	('Raf-1', 'Gene', '5894', (177, 182))	('activates', 'PosReg', (167, 176))	('guanosine triphosphate', 'Chemical', 'MESH:D006160', (105, 127))	('Ras-GTP', 'Var', (146, 153))	('GTP', 'Chemical', 'MESH:D006160', (150, 153))	('binds', 'Interaction', (154, 159))	('GTP', 'Chemical', 'MESH:D006160', (129, 132))
3990	24457962	Mutations in the Ras proto-oncogenes are implicated in 20-30% of all cancers.	('cancers', 'Disease', 'MESH:D009369', (69, 76))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('Mutations', 'Var', (0, 9))	('implicated', 'Reg', (41, 51))	('cancers', 'Phenotype', 'HP:0002664', (69, 76))	('cancers', 'Disease', (69, 76))
3991	24457962	Activating HRAS mutations have been found in 4-5% of HNSCC cases.	('HRAS', 'Gene', '3265', (11, 15))	('Activating', 'PosReg', (0, 10))	('mutations', 'Var', (16, 25))	('HRAS', 'Gene', (11, 15))	('HNSCC', 'Disease', (53, 58))
3992	24457962	KRAS mutations occur in 30-50% of colorectal cancers and are predictive of poor response to panitumumab and cetuximab.	('colorectal cancer', 'Phenotype', 'HP:0003003', (34, 51))	('colorectal cancers', 'Disease', 'MESH:D015179', (34, 52))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('panitumumab', 'Chemical', 'MESH:D000077544', (92, 103))	('colorectal cancers', 'Disease', (34, 52))	('cetuximab', 'Chemical', 'MESH:D000068818', (108, 117))	('mutations', 'Var', (5, 14))	('cancers', 'Phenotype', 'HP:0002664', (45, 52))	('occur', 'Reg', (15, 20))	('KRAS', 'Gene', (0, 4))	('KRAS', 'Gene', '3845', (0, 4))
3999	24457962	Ligand binging activates signalling cascades including the RAS, PI3K, STAT3 and NOTCH pathways, resulting in cell morphogenesis, motility, growth and survival.	('PI3', 'Gene', '5266', (64, 67))	('STAT3', 'Gene', (70, 75))	('survival', 'CPA', (150, 158))	('activates', 'PosReg', (15, 24))	('binging', 'Var', (7, 14))	('signalling cascades', 'Pathway', (25, 44))	('cell morphogenesis', 'CPA', (109, 127))	('motility', 'CPA', (129, 137))	('PI3', 'Gene', (64, 67))	('RAS', 'Pathway', (59, 62))	('NOTCH pathways', 'Pathway', (80, 94))	('STAT3', 'Gene', '6774', (70, 75))
4018	24457962	E2F activates genes responsible for cell cycle progression through the G1 to S phase, including cyclin A, E and DNA polymerase, causing inactivation of checkpoints and regulatory pathways, and ultimately promoting cellular proliferation and transformation (Figure 3).	('E2F', 'Var', (0, 3))	('transformation', 'CPA', (241, 255))	('cellular proliferation', 'CPA', (214, 236))	('cyclin A', 'Gene', (96, 104))	('promoting', 'PosReg', (204, 213))	('genes', 'Gene', (14, 19))	('regulatory pathways', 'Pathway', (168, 187))	('inactivation', 'MPA', (136, 148))	('activates', 'PosReg', (4, 13))	('cyclin A', 'Gene', '890', (96, 104))
4019	24457962	pRb is a negative regulator of the cyclin-dependent kinase inhibitor p16, and therefore inactivation of pRb results in p16 upregulation.	('p16', 'Gene', (119, 122))	('pRb', 'Gene', '5925', (104, 107))	('p16', 'Gene', (69, 72))	('p16', 'Gene', '1029', (119, 122))	('upregulation', 'PosReg', (123, 135))	('p16', 'Gene', '1029', (69, 72))	('pRb', 'Gene', '5925', (0, 3))	('pRb', 'Gene', (0, 3))	('inactivation', 'Var', (88, 100))	('pRb', 'Gene', (104, 107))
4024	24457962	Risk factors for HPV-positive HNSCC are related to sexual behaviour, including young age at first intercourse and high number of sexual partners, in particular oral sex partners, and antibodies against HPV16 viral capsid protein and E6 oncoprotein.	('HPV', 'Species', '10566', (202, 205))	('sexual behaviour', 'Disease', 'MESH:D012735', (51, 67))	('HPV16', 'Species', '333760', (202, 207))	('sexual behaviour', 'Phenotype', 'HP:0030214', (51, 67))	('HNSCC', 'Disease', (30, 35))	('E6 oncoprotein', 'Protein', (233, 247))	('HPV-positive', 'Gene', (17, 29))	('sexual behaviour', 'Disease', (51, 67))	('HPV16', 'Gene', (202, 207))	('antibodies', 'Var', (183, 193))	('HPV', 'Species', '10566', (17, 20))
4032	24457962	HPV-negative HNSCC are typically characterised by TP53 and RB genetic alterations resulting in genomic instability and resistance to apoptosis.	('HPV', 'Species', '10566', (0, 3))	('TP53', 'Gene', '7157', (50, 54))	('resistance to apoptosis', 'CPA', (119, 142))	('TP53', 'Gene', (50, 54))	('genomic instability', 'CPA', (95, 114))	('HNSCC', 'Disease', (13, 18))	('resulting in', 'Reg', (82, 94))	('genetic alterations', 'Var', (62, 81))
4033	24457962	No TP53 mutations were seen in HPV-positive HNSCC on exome sequencing, and the overall mutation rate was approximately half of that seen in HPV-negative samples.	('TP53', 'Gene', '7157', (3, 7))	('TP53', 'Gene', (3, 7))	('HPV', 'Species', '10566', (31, 34))	('mutations', 'Var', (8, 17))	('HNSCC', 'Disease', (44, 49))	('HPV', 'Species', '10566', (140, 143))
4050	24457962	VEGF is the strongest inducer of angiogenesis, and immunohistochemical expression in tumour samples is associated with an increased risk of death.	('tumour', 'Disease', 'MESH:D009369', (85, 91))	('angiogenesis', 'CPA', (33, 45))	('immunohistochemical expression', 'Var', (51, 81))	('death', 'Disease', (140, 145))	('tumour', 'Disease', (85, 91))	('death', 'Disease', 'MESH:D003643', (140, 145))	('VEGF', 'Gene', '7422', (0, 4))	('associated with', 'Reg', (103, 118))	('tumour', 'Phenotype', 'HP:0002664', (85, 91))	('VEGF', 'Gene', (0, 4))
4069	24457962	Aberrant metabolism can be targeted by inhibiting the AKT and mTOR pathways as previously discussed.	('mTOR', 'Gene', '2475', (62, 66))	('Aberrant', 'Var', (0, 8))	('mTOR', 'Gene', (62, 66))	('metabolism', 'CPA', (9, 19))	('AKT', 'Gene', '207', (54, 57))	('AKT', 'Gene', (54, 57))	('inhibiting', 'NegReg', (39, 49))
4072	24457962	Diabetic patients treated with metformin were found to be at lower risk of developing cancer than those on other treatments.	('patients', 'Species', '9606', (9, 17))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('metformin', 'Var', (31, 40))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('Diabetic', 'Disease', (0, 8))	('Diabetic', 'Disease', 'MESH:D003920', (0, 8))	('metformin', 'Chemical', 'MESH:D008687', (31, 40))	('cancer', 'Disease', (86, 92))
4083	24457962	It has been shown that ALDH+ and CD44+ cells form a subpopulation of cells that are highly tumourigenic in immunodeficient mice at very low cell numbers, as well as the ability to self-renew.	('tumour', 'Disease', 'MESH:D009369', (91, 97))	('ALDH', 'Gene', (23, 27))	('tumour', 'Disease', (91, 97))	('ALDH', 'Gene', '216;223', (23, 27))	('CD44+', 'Var', (33, 38))	('immunodeficient', 'Disease', 'MESH:D007153', (107, 122))	('immunodeficient', 'Disease', (107, 122))	('tumour', 'Phenotype', 'HP:0002664', (91, 97))	('mice', 'Species', '10090', (123, 127))
4085	24457962	The concentration of CD44 in the peripheral blood of HNSCC patients has been shown to be significantly higher than healthy controls, and increased CD44+ cell population in the primary tumour correlates with higher rates of recurrence.	('CD44+ cell', 'Var', (147, 157))	('concentration', 'MPA', (4, 17))	('tumour', 'Phenotype', 'HP:0002664', (184, 190))	('increased', 'PosReg', (137, 146))	('patients', 'Species', '9606', (59, 67))	('tumour', 'Disease', 'MESH:D009369', (184, 190))	('higher', 'PosReg', (103, 109))	('tumour', 'Disease', (184, 190))	('CD44', 'MPA', (21, 25))
4092	24457962	The ratio of miR-221 to miR-375 can distinguish between normal and malignant tissue, and high expression of miR-181 and miR-211 in oral SCC has been found to be associated with lymph node metastases, vascular invasion and poor outcome.	('oral SCC', 'Disease', (131, 139))	('associated with', 'Reg', (161, 176))	('miR-375', 'Gene', (24, 31))	('vascular invasion', 'CPA', (200, 217))	('metastases', 'Disease', 'MESH:D009362', (188, 198))	('miR-221', 'Gene', '407006', (13, 20))	('miR-181', 'Var', (108, 115))	('miR-211', 'Gene', '406993', (120, 127))	('miR-375', 'Gene', '494324', (24, 31))	('metastases', 'Disease', (188, 198))	('poor outcome', 'CPA', (222, 234))	('miR-221', 'Gene', (13, 20))	('miR-211', 'Gene', (120, 127))
4099	24457962	The paucity of driver mutations in HNSCC and frequent tumour suppressor loss represents a pharmacological challenge, but increased understanding of the molecular biology through the developments in high-throughput technology heralds a future of personalised medicine.	('loss', 'NegReg', (72, 76))	('tumour', 'Disease', 'MESH:D009369', (54, 60))	('tumour', 'Disease', (54, 60))	('mutations', 'Var', (22, 31))	('tumour', 'Phenotype', 'HP:0002664', (54, 60))	('HNSCC', 'Gene', (35, 40))
4105	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))	('ECRG2', 'Gene', (30, 35))	('defective', 'NegReg', (167, 176))	('p53', 'Gene', (194, 197))	('p53', 'Gene', '7157', (194, 197))	('variant', 'Var', (45, 52))
4106	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))	('ECRG2', 'Gene', '84651', (48, 53))	('expression', 'Species', '29278', (10, 20))	('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))
4112	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))
4127	32681017	Genetic alterations (missense mutations, deletion/frameshift mutations) in the ECRG2 gene were also reported in various human malignancies.	('human', 'Species', '9606', (120, 125))	('reported', 'Reg', (100, 108))	('malignancies', 'Disease', 'MESH:D009369', (126, 138))	('malignancies', 'Disease', (126, 138))	('ECRG2', 'Gene', (79, 84))	('ECRG2', 'Gene', '84651', (79, 84))	('deletion/frameshift mutations', 'Var', (41, 70))
4129	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))
4140	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))
4156	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))
4177	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))
4190	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))	('expression', 'Var', (26, 36))	('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))
4195	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))
4197	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))
4212	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))
4216	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))
4220	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))
4227	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))
4234	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.	('ECRG2', 'Gene', '84651', (60, 65))	('rs3214447', 'Var', (87, 96))	('rs3214447', 'Mutation', 'rs3214447', (87, 96))	('ECRG2', 'Gene', (60, 65))	('ECRG2', 'Gene', '84651', (144, 149))	('ECRG2', 'Gene', (144, 149))	('negatively impacts', 'NegReg', (125, 143))
4235	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))
4236	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))
4239	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))
4247	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))
4277	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))
4289	32269280	The study provides staggered evidence for the significance of GBPs in HNSCC and its potential role as a novel biomarker.	('HNSCC', 'Phenotype', 'HP:0012288', (70, 75))	('GBPs', 'Chemical', '-', (62, 66))	('HNSCC', 'Disease', (70, 75))	('GBPs', 'Var', (62, 66))
4301	32269280	believed that inactivation of the p16 tumor suppressor gene is a common event in HNSCC.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('p16', 'Gene', (34, 37))	('inactivation', 'Var', (14, 26))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('HNSCC', 'Phenotype', 'HP:0012288', (81, 86))	('HNSCC', 'Disease', (81, 86))	('p16', 'Gene', '1029', (34, 37))
4333	32269280	In univariate analysis, we found that tumor stage (HR = 1.80, 95% CI: 1.23-2.66, P < 0.05), T-stage (HR = 1.36, 95% CI: 1.05-1.76, P < 0.05), N-stage (HR = 1.36, 95% CI: 1.10-1.68, P < 0.05), high expressions of GBP1/6/7 were linked to shorter OS of HNSCC patients.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('shorter OS', 'Disease', (236, 246))	('GBP1/6/7', 'Gene', '2633;163351;388646', (212, 220))	('patients', 'Species', '9606', (256, 264))	('HNSCC', 'Phenotype', 'HP:0012288', (250, 255))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('HNSCC', 'Disease', (250, 255))	('GBP1/6/7', 'Gene', (212, 220))	('high expressions', 'Var', (192, 208))
4336	32269280	We next explored the GBPs alterations and networks via the cBioPortal online tool and we further analyzed 50 neighbor genes which were significantly related to GBPs mutations.	('GBPs', 'Chemical', '-', (21, 25))	('GBPs', 'Chemical', '-', (160, 164))	('GBPs', 'Gene', (160, 164))	('mutations', 'Var', (165, 174))
4337	32269280	In the 528 sequenced HNSCC patients, genetic alteration was found in 115 patients and the mutation rate was 22%, GBP5 ranked the highest genes with genetic alterations with the mutation rates were 7% and we also shown the network for GBPs and the 50 most frequently altered neighbor genes (Fig.	('HNSCC', 'Phenotype', 'HP:0012288', (21, 26))	('GBP5', 'Gene', (113, 117))	('patients', 'Species', '9606', (27, 35))	('GBPs', 'Chemical', '-', (234, 238))	('mutation', 'Var', (90, 98))	('patients', 'Species', '9606', (73, 81))	('GBP5', 'Gene', '115362', (113, 117))
4338	32269280	The top 10 type and frequency of GBPs neighbor gene alterations in HNSCC including ADAR, IRF6, IRF9, IRF2, CD44, STAT1, FCGR1A, NFATC2, ICAM1 and STAT2 (Table 2).	('GBPs neighbor', 'Disease', (33, 46))	('ADAR', 'Gene', (83, 87))	('HNSCC', 'Gene', (67, 72))	('HNSCC', 'Phenotype', 'HP:0012288', (67, 72))	('STAT1', 'Gene', (113, 118))	('FCGR1A', 'Gene', (120, 126))	('alterations', 'Var', (52, 63))	('NFATC2', 'Gene', (128, 134))	('IRF2', 'Gene', (101, 105))	('ICAM1', 'Gene', (136, 141))	('IRF9', 'Gene', (95, 99))	('ADAR', 'Gene', '103', (83, 87))	('STAT1', 'Gene', '6772', (113, 118))	('ICAM1', 'Gene', '3383', (136, 141))	('IRF2', 'Gene', '3660', (101, 105))	('IRF9', 'Gene', '10379', (95, 99))	('NFATC2', 'Gene', '4773', (128, 134))	('GBPs neighbor', 'Disease', 'None', (33, 46))	('STAT2', 'Gene', '6773', (146, 151))	('IRF6', 'Gene', (89, 93))	('FCGR1A', 'Gene', '2209', (120, 126))	('CD44', 'Gene', '960', (107, 111))	('IRF6', 'Gene', '3664', (89, 93))	('STAT2', 'Gene', (146, 151))	('CD44', 'Gene', (107, 111))
4341	32269280	Correlation between GBPs in HNSCC expression and abundance of immune infiltrates was statistically significant (P < 0.05, Supplementary Table.	('GBPs', 'Var', (20, 24))	('HNSCC', 'Phenotype', 'HP:0012288', (28, 33))	('HNSCC', 'Gene', (28, 33))	('GBPs', 'Chemical', '-', (20, 24))
4363	32269280	Other study found GPB2/5 shown wide antiviral activity by suppressing the activation of the virus-dependency factor furin.	('GPB2/5', 'Var', (18, 24))	('suppressing', 'NegReg', (58, 69))	('activation', 'MPA', (74, 84))	('furin', 'Gene', '5045', (116, 121))	('furin', 'Gene', (116, 121))	('antiviral activity', 'MPA', (36, 54))
4374	32269280	Our results found the 50 most frequently altered GBPs neighbor gene alterations in HNSCC including interferon regulatory factors 6 (IRF6), IRF9 and IRF2, indicated that IRFs and GBPs coordinate the development of tumors and requires more study.	('GBPs neighbor', 'Disease', 'None', (49, 62))	('tumors', 'Phenotype', 'HP:0002664', (213, 219))	('HNSCC', 'Phenotype', 'HP:0012288', (83, 88))	('IRF9', 'Gene', '10379', (139, 143))	('IRF', 'Gene', '84676', (169, 172))	('alterations', 'Var', (68, 79))	('IRF', 'Gene', '84676', (139, 142))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('GBPs neighbor', 'Disease', (49, 62))	('IRF6', 'Gene', (132, 136))	('IRF6', 'Gene', '3664', (132, 136))	('tumors', 'Disease', (213, 219))	('IRF2', 'Gene', (148, 152))	('IRF9', 'Gene', (139, 143))	('IRF', 'Gene', (132, 135))	('interferon regulatory factors 6', 'Gene', (99, 130))	('tumors', 'Disease', 'MESH:D009369', (213, 219))	('IRF', 'Gene', (148, 151))	('interferon regulatory factors 6', 'Gene', '3664', (99, 130))	('GBPs', 'Chemical', '-', (178, 182))	('GBPs', 'Chemical', '-', (49, 53))	('IRF', 'Gene', (169, 172))	('IRF', 'Gene', (139, 142))	('IRF', 'Gene', '84676', (148, 151))	('IRF', 'Gene', '84676', (132, 135))	('HNSCC', 'Gene', (83, 88))	('IRF2', 'Gene', '3660', (148, 152))
4409	32269280	Functions of GBPs mutations and 50 genes significantly related to GBPs mutations were performed by GO and KEGG in the Database for Annotation, Visualization, and Integrated Discovery (DAVID) online tool.	('GBPs', 'Chemical', '-', (13, 17))	('GBPs', 'Gene', (13, 17))	('GBPs', 'Chemical', '-', (66, 70))	('mutations', 'Var', (18, 27))
4413	32194810	Systematic analysis of genetic variants in cancer-testis genes identified two novel lung cancer susceptibility loci in Chinese population Cancer-testis (CT) genes played important roles in the progression of malignant tumors and were recognized as promising therapeutic targets.	('malignant tumors', 'Disease', (208, 224))	('lung cancer', 'Disease', (84, 95))	('cancer-testis', 'Disease', (43, 56))	('lung cancer', 'Phenotype', 'HP:0100526', (84, 95))	('variants', 'Var', (31, 39))	('Cancer-testis', 'Disease', 'MESH:D013736', (138, 151))	('cancer-testis', 'Disease', 'MESH:D013736', (43, 56))	('malignant tumors', 'Disease', 'MESH:D018198', (208, 224))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('lung cancer', 'Disease', 'MESH:D008175', (84, 95))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('tumors', 'Phenotype', 'HP:0002664', (218, 224))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('Cancer', 'Phenotype', 'HP:0002664', (138, 144))	('Cancer-testis', 'Disease', (138, 151))	('CT', 'Disease', 'MESH:D013736', (153, 155))
4417	32194810	Two variants (rs6941653, OPRM1, T > C, screening: OR = 1.24, 95%CI: 1.12-1.38, P = 2.40x10-5; validation: OR = 1.18, 95%CI: 1.01-1.37, P = 0.039 and rs402969, NLRP8, C > T, screening: OR = 1.15, 95%CI: 1.04-1.26, P = 0.006; validation: OR = 1.16, 95%CI: 1.02-1.33, P = 0.028) were identified as novel lung cancer susceptibility variants.	('OPRM1', 'Gene', '4988', (25, 30))	('NLRP8', 'Gene', (159, 164))	('OPRM1', 'Gene', (25, 30))	('cancer', 'Phenotype', 'HP:0002664', (306, 312))	('lung cancer', 'Disease', 'MESH:D008175', (301, 312))	('NLRP8', 'Gene', '126205', (159, 164))	('rs6941653', 'Var', (14, 23))	('rs402969', 'Mutation', 'rs402969', (149, 157))	('rs402969', 'Var', (149, 157))	('lung cancer', 'Disease', (301, 312))	('lung cancer', 'Phenotype', 'HP:0100526', (301, 312))	('rs6941653', 'Mutation', 'rs6941653', (14, 23))
4418	32194810	Stratification analysis indicated that the effect of rs6941653 was stronger in lung squamous cell carcinoma (OR = 1.36) than that in lung adenocarcinoma (OR = 1.15, I2 = 77%, P = 0.04).	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (79, 107))	('rs6941653', 'Var', (53, 62))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (133, 152))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (79, 107))	('rs6941653', 'Mutation', 'rs6941653', (53, 62))	('lung adenocarcinoma', 'Disease', (133, 152))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (84, 107))	('lung squamous cell carcinoma', 'Disease', (79, 107))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (133, 152))	('carcinoma', 'Phenotype', 'HP:0030731', (143, 152))
4419	32194810	In conclusion, this study identified two novel lung cancer risk variants in Chinese population and provided deeper insight into the roles of CT genes in lung tumorigenesis.	('lung tumor', 'Disease', (153, 163))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('lung cancer', 'Disease', (47, 58))	('lung tumor', 'Disease', 'MESH:D008175', (153, 163))	('lung cancer', 'Phenotype', 'HP:0100526', (47, 58))	('lung tumor', 'Phenotype', 'HP:0100526', (153, 163))	('lung cancer', 'Disease', 'MESH:D008175', (47, 58))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('variants', 'Var', (64, 72))	('CT', 'Disease', 'MESH:D013736', (141, 143))
4423	32194810	However, up till now, GWAS (Genome-Wide Association Study)-reported lung cancer associated single nucleotide polymorphisms (SNPs) could only account for limited lung cancer heritability (less than 1%).	('lung cancer', 'Disease', (68, 79))	('lung cancer', 'Phenotype', 'HP:0100526', (68, 79))	('lung cancer', 'Disease', (161, 172))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('lung cancer', 'Phenotype', 'HP:0100526', (161, 172))	('lung cancer', 'Disease', 'MESH:D008175', (68, 79))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('single nucleotide polymorphisms', 'Var', (91, 122))	('lung cancer', 'Disease', 'MESH:D008175', (161, 172))
4425	32194810	Epigenetic alterations have been recognized as an important feature of tumorigenesis.	('Epigenetic alterations', 'Var', (0, 22))	('tumor', 'Disease', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Disease', 'MESH:D009369', (71, 76))
4426	32194810	Notably, cancer-testis (CT) genes, which were restrictedly expressed in germ cells and malignant tumor cells, were usually activated through epigenetic mechanisms.	('epigenetic', 'Var', (141, 151))	('cancer-testis', 'Disease', 'MESH:D013736', (9, 22))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('tumor', 'Disease', (97, 102))	('activated', 'PosReg', (123, 132))	('cancer-testis', 'Disease', (9, 22))	('CT', 'Disease', 'MESH:D013736', (24, 26))
4428	32194810	In addition, associations between genetic variants in CT genes and the susceptibility of cancers have been described in previous studies.	('cancers', 'Phenotype', 'HP:0002664', (89, 96))	('CT', 'Disease', 'MESH:D013736', (54, 56))	('genetic variants', 'Var', (34, 50))	('cancers', 'Disease', 'MESH:D009369', (89, 96))	('cancers', 'Disease', (89, 96))	('associations', 'Interaction', (13, 25))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
4429	32194810	For example, genetic variants in HORMAD2 and GPATCH2 were reported associated with lung cancer risk, and variants in CTNNA2, CCDC33 and SPAG17 showed significant association with the susceptibility of breast cancer.	('lung cancer', 'Disease', 'MESH:D008175', (83, 94))	('CTNNA2', 'Gene', (117, 123))	('HORMAD2', 'Gene', '150280', (33, 40))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('variants', 'Var', (105, 113))	('lung cancer', 'Phenotype', 'HP:0100526', (83, 94))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('CTNNA2', 'Gene', '1496', (117, 123))	('SPAG17', 'Gene', (136, 142))	('breast cancer', 'Phenotype', 'HP:0003002', (201, 214))	('GPATCH2', 'Gene', '55105', (45, 52))	('SPAG17', 'Gene', '200162', (136, 142))	('CCDC33', 'Gene', (125, 131))	('lung cancer', 'Disease', (83, 94))	('breast cancer', 'Disease', 'MESH:D001943', (201, 214))	('associated', 'Reg', (67, 77))	('breast cancer', 'Disease', (201, 214))	('variants', 'Var', (21, 29))	('CCDC33', 'Gene', '80125', (125, 131))	('association', 'Reg', (162, 173))	('GPATCH2', 'Gene', (45, 52))	('HORMAD2', 'Gene', (33, 40))
4430	32194810	All these studies suggested that genetic variants in CT genes could also contribute to the development of cancers.	('contribute', 'Reg', (73, 83))	('CT', 'Disease', 'MESH:D013736', (53, 55))	('cancers', 'Phenotype', 'HP:0002664', (106, 113))	('cancers', 'Disease', (106, 113))	('cancers', 'Disease', 'MESH:D009369', (106, 113))	('genetic variants', 'Var', (33, 49))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
4431	32194810	Therefore, systematic analysis of the associations between genetic variants in CT genes and lung cancer risk could help identify more novel lung cancer susceptibility loci.	('lung cancer', 'Disease', (92, 103))	('lung cancer', 'Disease', (140, 151))	('CT', 'Disease', 'MESH:D013736', (79, 81))	('lung cancer', 'Phenotype', 'HP:0100526', (92, 103))	('lung cancer', 'Phenotype', 'HP:0100526', (140, 151))	('associations', 'Interaction', (38, 50))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('lung cancer', 'Disease', 'MESH:D008175', (92, 103))	('lung cancer', 'Disease', 'MESH:D008175', (140, 151))	('variants', 'Var', (67, 75))
4435	32194810	This finding provided us an unprecedented opportunity to explore the associations between genetic variants in CT genes and the susceptibility of lung cancer.	('lung cancer', 'Disease', 'MESH:D008175', (145, 156))	('associations', 'Interaction', (69, 81))	('lung cancer', 'Disease', (145, 156))	('genetic variants', 'Var', (90, 106))	('lung cancer', 'Phenotype', 'HP:0100526', (145, 156))	('CT', 'Disease', 'MESH:D013736', (110, 112))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
4436	32194810	The NJMU GWAS, which has been established in our previous study, was used to screen candidate lung cancer risk variants.	('lung cancer', 'Disease', 'MESH:D008175', (94, 105))	('variants', 'Var', (111, 119))	('lung cancer', 'Disease', (94, 105))	('lung cancer', 'Phenotype', 'HP:0100526', (94, 105))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
4437	32194810	These promising variants were further validated in an independent Chinese population with a total of 1,056 lung cancer cases and 1,053 controls based on the Sequenom MassARRAY iPLEX platform.	('lung cancer', 'Disease', 'MESH:D008175', (107, 118))	('lung cancer', 'Disease', (107, 118))	('lung cancer', 'Phenotype', 'HP:0100526', (107, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('variants', 'Var', (16, 24))
4446	32194810	In particular, rs144031443 and rs150492976 were replaced by rs75932085 (r2 = 0.66, Chinese Han population) and rs4726004 (r2 = 1), respectively.	('rs75932085', 'Mutation', 'rs75932085', (60, 70))	('rs4726004', 'Mutation', 'rs4726004', (111, 120))	('rs75932085', 'Var', (60, 70))	('rs150492976', 'Mutation', 'rs150492976', (31, 42))	('rs144031443', 'Mutation', 'rs144031443', (15, 26))	('rs4726004', 'Var', (111, 120))	('rs144031443', 'Var', (15, 26))	('rs150492976', 'Var', (31, 42))
4449	32194810	Associations between genetic variants and lung cancer risk were evaluated (Odd Ratios, OR and 95% confidence intervals, 95%CI) using logistical regression analysis.	('Associations', 'Interaction', (0, 12))	('variants', 'Var', (29, 37))	('lung cancer', 'Disease', (42, 53))	('lung cancer', 'Phenotype', 'HP:0100526', (42, 53))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('lung cancer', 'Disease', 'MESH:D008175', (42, 53))
4457	32194810	Associations between 17 candidate variants and lung cancer risk were shown in Table 2.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('variants', 'Var', (34, 42))	('lung cancer', 'Disease', (47, 58))	('lung cancer', 'Phenotype', 'HP:0100526', (47, 58))	('lung cancer', 'Disease', 'MESH:D008175', (47, 58))
4458	32194810	Notably, only rs6941653 and rs402969 were significant in both screening (rs6941653, OPRM1, T > C, OR = 1.24, 95%CI: 1.12-1.38, P = 2.40x10-5; rs402969, NLRP8, C > T, OR = 1.15, 95%CI: 1.04-1.26, P = 0.006) and validation datasets (rs6941653, OPRM1, T > C, OR = 1.18, 95%CI: 1.01-1.37, P = 0.039; rs402969, NLRP8, C > T, OR = 1.16, 95%CI: 1.02-1.33, P = 0.028).	('rs6941653', 'Mutation', 'rs6941653', (73, 82))	('NLRP8', 'Gene', (152, 157))	('NLRP8', 'Gene', '126205', (152, 157))	('NLRP8', 'Gene', (306, 311))	('rs6941653', 'Var', (231, 240))	('rs6941653', 'Mutation', 'rs6941653', (231, 240))	('rs402969', 'Mutation', 'rs402969', (142, 150))	('OPRM1', 'Gene', (84, 89))	('rs402969', 'Mutation', 'rs402969', (28, 36))	('rs402969', 'Var', (296, 304))	('OPRM1', 'Gene', '4988', (84, 89))	('OPRM1', 'Gene', '4988', (242, 247))	('OPRM1', 'Gene', (242, 247))	('rs402969', 'Mutation', 'rs402969', (296, 304))	('C > T', 'Var', (313, 318))	('NLRP8', 'Gene', '126205', (306, 311))	('rs6941653', 'Var', (73, 82))	('rs6941653', 'Mutation', 'rs6941653', (14, 23))
4459	32194810	Therefore, rs6941653 and rs402969 were considered as novel lung cancer risk variants in Chinese population.	('lung cancer', 'Disease', 'MESH:D008175', (59, 70))	('rs6941653', 'Mutation', 'rs6941653', (11, 20))	('rs402969', 'Mutation', 'rs402969', (25, 33))	('rs402969', 'Var', (25, 33))	('lung cancer', 'Disease', (59, 70))	('lung cancer', 'Phenotype', 'HP:0100526', (59, 70))	('rs6941653', 'Var', (11, 20))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
4461	32194810	Notably, we observed a significantly stronger effect of rs6941653 in SCC (NJMU GWAS: OR = 1.39; Validation: OR = 1.29; Combined: OR = 1.36) than that in LUAD (NJMU GWAS: OR = 1.15; Validation: OR = 1.16; Combined: OR = 1.15, I2 = 77%, P = 0.04, Figure 2A-2B, Figure 3A).	('stronger', 'PosReg', (37, 45))	('LUAD', 'Disease', 'MESH:D000077192', (153, 157))	('rs6941653', 'Mutation', 'rs6941653', (56, 65))	('SCC', 'Phenotype', 'HP:0002860', (69, 72))	('SCC', 'Disease', (69, 72))	('LUAD', 'Disease', (153, 157))	('LUAD', 'Phenotype', 'HP:0030078', (153, 157))	('rs6941653', 'Var', (56, 65))	('SCC', 'Disease', 'MESH:D002294', (69, 72))
4462	32194810	In contrast to rs6941653, SNP rs402969 showed a similar effect on lung cancer risk in various subgroup populations (Figure 2C-D, Figure 3B).	('rs402969', 'Var', (30, 38))	('rs402969', 'Mutation', 'rs402969', (30, 38))	('effect', 'Reg', (56, 62))	('lung cancer', 'Disease', (66, 77))	('lung cancer', 'Phenotype', 'HP:0100526', (66, 77))	('rs6941653', 'Mutation', 'rs6941653', (15, 24))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('lung cancer', 'Disease', 'MESH:D008175', (66, 77))
4463	32194810	In addition, interactions between our identified lung cancer risk variants (rs6941653 and rs402969) and smoking were evaluated.	('lung cancer', 'Disease', 'MESH:D008175', (49, 60))	('rs6941653', 'Mutation', 'rs6941653', (76, 85))	('rs402969', 'Var', (90, 98))	('lung cancer', 'Disease', (49, 60))	('lung cancer', 'Phenotype', 'HP:0100526', (49, 60))	('rs402969', 'Mutation', 'rs402969', (90, 98))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('rs6941653', 'Var', (76, 85))
4464	32194810	Similarly, there was no significant interaction between variant rs6941653 and rs402969 (Supplementary Table 4, P for interaction > 0.05).	('rs6941653', 'Mutation', 'rs6941653', (64, 73))	('rs402969', 'Mutation', 'rs402969', (78, 86))	('rs402969', 'Var', (78, 86))	('rs6941653', 'Var', (64, 73))
4466	32194810	Strikingly, rs9397692 (r2 = 0.70 with rs6941653) was an eQTL and could influence the binding of transcription factor NFATC2.	('rs9397692', 'Var', (12, 21))	('influence', 'Reg', (71, 80))	('rs9397692', 'Mutation', 'rs9397692', (12, 21))	('NFATC2', 'Gene', '4773', (117, 123))	('rs6941653', 'Var', (38, 47))	('rs6941653', 'Mutation', 'rs6941653', (38, 47))	('binding', 'Interaction', (85, 92))	('NFATC2', 'Gene', (117, 123))
4468	32194810	All these results indicated that rs9397692 might be the functional variant, which could affect the binding of specific transcription factor NFATC2.	('rs9397692', 'Var', (33, 42))	('rs9397692', 'Mutation', 'rs9397692', (33, 42))	('NFATC2', 'Gene', '4773', (140, 146))	('affect', 'Reg', (88, 94))	('NFATC2', 'Gene', (140, 146))	('binding', 'Interaction', (99, 106))
4469	32194810	In the second risk loci, rs805165 (r2 = 0.90 with rs402969) was predicted to be an eQTL and could modify the affinity to TF BRCA1.	('rs805165', 'Mutation', 'rs805165', (25, 33))	('affinity', 'Interaction', (109, 117))	('BRCA1', 'Gene', '672', (124, 129))	('rs805165', 'Var', (25, 33))	('modify', 'Reg', (98, 104))	('BRCA1', 'Gene', (124, 129))	('rs402969', 'Mutation', 'rs402969', (50, 58))	('rs402969', 'Var', (50, 58))
4470	32194810	Consistently, the Regulome DB score of rs805165 was 5 (TF binding or DNase peak).	('rs805165', 'Var', (39, 47))	('rs805165', 'Mutation', 'rs805165', (39, 47))	('DNase peak', 'MPA', (69, 79))
4473	32194810	Therefore, associations between our identified variants and the expression of their host genes (OPRM1 and NLRP8) were not evaluated.	('variants', 'Var', (47, 55))	('OPRM1', 'Gene', (96, 101))	('OPRM1', 'Gene', '4988', (96, 101))	('NLRP8', 'Gene', '126205', (106, 111))	('NLRP8', 'Gene', (106, 111))
4474	32194810	Notably, rs805165 was found to be significantly associated with the expression of AC010525.7 and AC024580.1 (Supplementary Figure 1).	('rs805165', 'Var', (9, 17))	('associated', 'Reg', (48, 58))	('rs805165', 'Mutation', 'rs805165', (9, 17))	('AC024580.1', 'Gene', (97, 107))	('AC010525.7', 'Gene', (82, 92))
4486	32194810	In the current study, a two-stage case-control study was performed to systematically evaluate the associations between genetic variants in CT genes and the risk of lung cancer in the Chinese population.	('variants', 'Var', (127, 135))	('lung cancer', 'Disease', (164, 175))	('CT', 'Disease', 'MESH:D013736', (139, 141))	('lung cancer', 'Phenotype', 'HP:0100526', (164, 175))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('associations', 'Interaction', (98, 110))	('lung cancer', 'Disease', 'MESH:D008175', (164, 175))
4488	32194810	Finally, two variants (rs6941653 in OPRM1 and rs402969 in NLRP8) were identified as novel susceptibility loci of lung cancer in Chinese population.	('lung cancer', 'Disease', (113, 124))	('lung cancer', 'Phenotype', 'HP:0100526', (113, 124))	('rs6941653', 'Var', (23, 32))	('NLRP8', 'Gene', '126205', (58, 63))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('rs6941653', 'Mutation', 'rs6941653', (23, 32))	('susceptibility', 'Reg', (90, 104))	('lung cancer', 'Disease', 'MESH:D008175', (113, 124))	('OPRM1', 'Gene', '4988', (36, 41))	('rs402969', 'Mutation', 'rs402969', (46, 54))	('rs402969', 'Var', (46, 54))	('OPRM1', 'Gene', (36, 41))	('NLRP8', 'Gene', (58, 63))
4490	32194810	Previous studies revealed that genetic variants in OPRM1 could modulate the dependence to multiple drugs or chemical agents, including nicotine, cocaine, alcohol.	('cocaine', 'Disease', (145, 152))	('dependence to multiple drugs or', 'MPA', (76, 107))	('OPRM1', 'Gene', '4988', (51, 56))	('nicotine', 'Chemical', 'MESH:D009538', (135, 143))	('alcohol', 'Disease', (154, 161))	('nicotine', 'MPA', (135, 143))	('OPRM1', 'Gene', (51, 56))	('alcohol', 'Chemical', 'MESH:D000438', (154, 161))	('genetic variants', 'Var', (31, 47))	('modulate', 'Reg', (63, 71))	('cocaine', 'Chemical', 'MESH:D003042', (145, 152))
4495	32194810	In the current study, rs6941653 in OPRM1 was further identified associated with lung cancer risk in Chinese population.	('associated', 'Reg', (64, 74))	('lung cancer', 'Disease', 'MESH:D008175', (80, 91))	('OPRM1', 'Gene', '4988', (35, 40))	('OPRM1', 'Gene', (35, 40))	('rs6941653', 'Var', (22, 31))	('rs6941653', 'Mutation', 'rs6941653', (22, 31))	('lung cancer', 'Disease', (80, 91))	('lung cancer', 'Phenotype', 'HP:0100526', (80, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
4496	32194810	Strikingly, stratification analysis indicated that rs6941653 showed a stronger effect in the SCC population.	('SCC', 'Disease', 'MESH:D002294', (93, 96))	('rs6941653', 'Mutation', 'rs6941653', (51, 60))	('SCC', 'Phenotype', 'HP:0002860', (93, 96))	('SCC', 'Disease', (93, 96))	('rs6941653', 'Var', (51, 60))
4498	32194810	Functional annotations for rs6941653 and their LD variants suggested that rs9397692, which was in the DNase peak and could affect the binding of TF NFATC2, might be the functional variant in these loci.	('rs6941653', 'Mutation', 'rs6941653', (27, 36))	('rs9397692', 'Var', (74, 83))	('rs9397692', 'Mutation', 'rs9397692', (74, 83))	('NFATC2', 'Gene', (148, 154))	('binding', 'Interaction', (134, 141))	('NFATC2', 'Gene', '4773', (148, 154))	('affect', 'Reg', (123, 129))	('rs6941653', 'Var', (27, 36))
4499	32194810	The rs402969 was located in the upstream of NLRP8, which belonged to the member of the nucleotide-binding oligomerization domain/ leucine rich repeat/ pyrin domain containing (NLRP) subfamily.	('rs402969', 'Mutation', 'rs402969', (4, 12))	('rs402969', 'Var', (4, 12))	('NLRP8', 'Gene', (44, 49))	('NLRP8', 'Gene', '126205', (44, 49))
4503	32194810	What's more, rs805165 (LD with rs402969) was predicted in the binding sites of TF BRCA1 or DNase peak, suggesting a potential role as a regulator of gene expression.	('BRCA1', 'Gene', (82, 87))	('binding', 'Interaction', (62, 69))	('DNase', 'Gene', (91, 96))	('rs402969', 'Var', (31, 39))	('rs402969', 'Mutation', 'rs402969', (31, 39))	('rs805165', 'Var', (13, 21))	('BRCA1', 'Gene', '672', (82, 87))	('rs805165', 'Mutation', 'rs805165', (13, 21))
4504	32194810	As expected, rs805165 showed a significant association with the expression of AC010525.7 and AC024580.1.	('association', 'Reg', (43, 54))	('rs805165', 'Var', (13, 21))	('AC024580.1', 'Var', (93, 103))	('rs805165', 'Mutation', 'rs805165', (13, 21))	('AC010525.7', 'Gene', (78, 88))
4507	32194810	In conclusion, we performed a systematic evaluation of the associations between genetic variants in CT genes and the risk of lung cancer.	('associations', 'Interaction', (59, 71))	('lung cancer', 'Disease', 'MESH:D008175', (125, 136))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('lung cancer', 'Disease', (125, 136))	('lung cancer', 'Phenotype', 'HP:0100526', (125, 136))	('genetic variants', 'Var', (80, 96))	('CT', 'Disease', 'MESH:D013736', (100, 102))
4585	25013792	In conclusion, this is a first study showing the correlation of Ki-67, PCNA interacted with CDK1 might lead to malignant transformation.	('Ki-67', 'Var', (64, 69))	('interacted', 'Interaction', (76, 86))	('PCNA', 'Gene', (71, 75))	('CDK1', 'Gene', '983', (92, 96))	('CDK1', 'Gene', (92, 96))	('Ki-67', 'Chemical', '-', (64, 69))	('malignant transformation', 'CPA', (111, 135))	('PCNA', 'Gene', '5111', (71, 75))	('lead to', 'Reg', (103, 110))
4606	25013792	We had also surveyed whether possible predicted factors of Ki-67, PCNA, and p27 correlate to CDKs by computational simulation finally to give a possible explanation to the mechanism of Ki-67, PCNA, and p27 to the CDKs in IPs prognosis.	('Ki-67', 'Var', (185, 190))	('CDKs', 'Gene', '983;1017;1019', (213, 217))	('PCNA', 'Gene', (192, 196))	('p27', 'Gene', '3429', (202, 205))	('p27', 'Gene', (202, 205))	('Ki-67', 'Chemical', '-', (59, 64))	('Ki-67', 'Chemical', '-', (185, 190))	('IPs', 'Disease', (221, 224))	('CDKs', 'Gene', (213, 217))	('PCNA', 'Gene', (66, 70))	('CDKs', 'Gene', (93, 97))	('p27', 'Gene', (76, 79))	('p27', 'Gene', '3429', (76, 79))	('PCNA', 'Gene', '5111', (192, 196))	('CDKs', 'Gene', '983;1017;1019', (93, 97))	('PCNA', 'Gene', '5111', (66, 70))
4633	25013792	The key residues are Gly9, Ser10, Ile11, Leu12, Lys13, Lys14, and Val15 which were the major binding domains for both Ki-67 and p27 to the CDK1 shown in red ribbon (Figure 7).	('Val15', 'Var', (66, 71))	('Lys14', 'Chemical', '-', (55, 60))	('Ser10', 'Chemical', '-', (27, 32))	('Lys14', 'Var', (55, 60))	('Ile11', 'Var', (34, 39))	('CDK1', 'Gene', '983', (139, 143))	('Ki-67', 'Chemical', '-', (118, 123))	('CDK1', 'Gene', (139, 143))	('Gly9', 'Var', (21, 25))	('Gly9', 'Chemical', '-', (21, 25))	('Lys13', 'Chemical', '-', (48, 53))	('Ki-67', 'Var', (118, 123))	('Ile11', 'Chemical', '-', (34, 39))	('Leu12', 'Var', (41, 46))	('Lys13', 'Var', (48, 53))	('p27', 'Gene', '3429', (128, 131))	('p27', 'Gene', (128, 131))	('Val15', 'Chemical', '-', (66, 71))	('Ser10', 'Var', (27, 32))
4645	25013792	The key binding residue includes Gly9, Ser10, Ile11, Leu12, Lys13, Lys14, and Val15 on Ki67-CDK1 protein structure dihedrals angle during simulation time of 5000 ps.	('Ile11', 'Var', (46, 51))	('CDK1', 'Gene', '983', (92, 96))	('Gly9', 'Var', (33, 37))	('CDK1', 'Gene', (92, 96))	('Lys14', 'Var', (67, 72))	('Ser10', 'Var', (39, 44))	('Lys13', 'Var', (60, 65))	('Ser10', 'Chemical', '-', (39, 44))	('Ile11', 'Chemical', '-', (46, 51))	('Leu12', 'Var', (53, 58))	('Gly9', 'Chemical', '-', (33, 37))	('Lys14', 'Chemical', '-', (67, 72))	('Lys13', 'Chemical', '-', (60, 65))	('Val15', 'Chemical', '-', (78, 83))	('Val15', 'Var', (78, 83))
4646	25013792	However, there were only stable dihedrals angles in Gly9, Ser10, Leu12, and Val15 on p27-CDK1 protein complexes over all MD simulation time.	('Gly9', 'Var', (52, 56))	('p27', 'Gene', (85, 88))	('Gly9', 'Chemical', '-', (52, 56))	('CDK1', 'Gene', (89, 93))	('CDK1', 'Gene', '983', (89, 93))	('Val15', 'Var', (76, 81))	('Ser10', 'Var', (58, 63))	('Val15', 'Chemical', '-', (76, 81))	('Ser10', 'Chemical', '-', (58, 63))	('p27', 'Gene', '3429', (85, 88))	('Leu12', 'Var', (65, 70))
4647	25013792	Finally, we found that all the key binding residues including Gly9, Ser10, Ile11, Leu12, Lys13, Lys14, and Val15 on PCNA-CDK1 protein structure had stable binding dihedrals angle during the whole MD simulation; no greater changes were found during the process of PCNA binding to CDK1 (Figure 14).	('PCNA', 'Gene', '5111', (116, 120))	('Ser10', 'Chemical', '-', (68, 73))	('Ile11', 'Var', (75, 80))	('PCNA', 'Gene', (263, 267))	('Leu12', 'Var', (82, 87))	('CDK1', 'Gene', '983', (279, 283))	('CDK1', 'Gene', (279, 283))	('CDK1', 'Gene', (121, 125))	('CDK1', 'Gene', '983', (121, 125))	('Gly9', 'Var', (62, 66))	('Gly9', 'Chemical', '-', (62, 66))	('PCNA', 'Gene', '5111', (263, 267))	('Val15', 'Chemical', '-', (107, 112))	('Ile11', 'Chemical', '-', (75, 80))	('PCNA', 'Gene', (116, 120))	('Val15', 'Var', (107, 112))	('Lys14', 'Chemical', '-', (96, 101))	('Lys13', 'Var', (89, 94))	('Ser10', 'Var', (68, 73))	('Lys14', 'Var', (96, 101))	('binding dihedrals angle', 'MPA', (155, 178))	('Lys13', 'Chemical', '-', (89, 94))
4648	25013792	For snapshot comparison assay, the represented structure selected from the last clustering groups for all MD frames of CDK1 complexes of Ki67, P27, and PCNA displaced at 4860 ps, 2740 ps, and 3880 ps, respectively, during simulation time of 5000 ps (Figure 15).	('Ki67', 'Var', (137, 141))	('PCNA', 'Gene', '5111', (152, 156))	('P27', 'Gene', (143, 146))	('2740 ps', 'Var', (179, 186))	('CDK1', 'Gene', (119, 123))	('CDK1', 'Gene', '983', (119, 123))	('P27', 'Gene', '3429', (143, 146))	('PCNA', 'Gene', (152, 156))
4664	25013792	Ki-67 will also affect p21, p27, and CDKs.	('CDKs', 'Gene', '983;1017;1019', (37, 41))	('CDKs', 'Gene', (37, 41))	('Ki-67', 'Var', (0, 5))	('Ki-67', 'Chemical', '-', (0, 5))	('p27', 'Gene', '3429', (28, 31))	('p27', 'Gene', (28, 31))	('p21', 'Gene', '1026', (23, 26))	('affect', 'Reg', (16, 22))	('p21', 'Gene', (23, 26))
4668	25013792	They suggested that testing for p53 may help to screen out papilloma lesions with a potential for dysplasia or carcinoma; however, we did not find it significant in multivariate analysis.	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('papilloma lesions', 'Disease', 'MESH:D010212', (59, 76))	('p53', 'Gene', (32, 35))	('dysplasia or carcinoma', 'Disease', (98, 120))	('p53', 'Gene', '7157', (32, 35))	('dysplasia or carcinoma', 'Disease', 'MESH:D002277', (98, 120))	('papilloma', 'Phenotype', 'HP:0012740', (59, 68))	('papilloma lesions', 'Disease', (59, 76))	('testing', 'Var', (20, 27))
4674	25013792	We suspect that the Ki-67 not only initiated the IPs cells entrance into G1 phase of cell cycle but also caused malignant transformation in cell cores by affecting the CDK1.	('Ki-67', 'Var', (20, 25))	('Ki-67', 'Chemical', '-', (20, 25))	('affecting', 'Reg', (154, 163))	('initiated', 'PosReg', (35, 44))	('malignant transformation', 'CPA', (112, 136))	('caused', 'Reg', (105, 111))	('CDK1', 'Gene', '983', (168, 172))	('CDK1', 'Gene', (168, 172))
4718	24959033	An aberrant expression of MUC4 in various human cancers including breast, lung, pancreas, salivary gland and squamous cell carcinoma of the oral cavity, esophagus and cervix has highlighted its role in the pathogenesis of cancer.	('aberrant', 'Var', (3, 11))	('human', 'Species', '9606', (42, 47))	('esophagus', 'Disease', (153, 162))	('cancer', 'Disease', (48, 54))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('pancreas', 'Disease', 'MESH:D010190', (80, 88))	('cancer', 'Disease', (222, 228))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (109, 132))	('cervix', 'Disease', (167, 173))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('cancers', 'Phenotype', 'HP:0002664', (48, 55))	('salivary gland', 'Disease', (90, 104))	('cancers', 'Disease', (48, 55))	('breast', 'Disease', (66, 72))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (109, 132))	('MUC4', 'Gene', (26, 30))	('carcinoma of the oral cavity', 'Phenotype', 'HP:0100649', (123, 151))	('cancer', 'Disease', 'MESH:D009369', (222, 228))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('squamous cell carcinoma', 'Disease', (109, 132))	('lung', 'Disease', (74, 78))	('cancers', 'Disease', 'MESH:D009369', (48, 55))	('pancreas', 'Disease', (80, 88))
4758	24959033	In the current study, MUC4 positivity in the OSCC samples was highly restricted to the well-differentiated areas and the keratin pearls [Figure 9] of the tumors.	('tumors', 'Disease', (154, 160))	('tumors', 'Disease', 'MESH:D009369', (154, 160))	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('positivity', 'Var', (27, 37))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('MUC4', 'Protein', (22, 26))
4810	24369726	The 11 pathways were also applied to four squamous cell carcinoma datasets, GSE3141, GSE4573, GSE8894, and GSE11969, and no statistical significance was identified for any of 11 pathways and 4 datasets (Additional file 1: Table S3).	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (42, 65))	('GSE11969', 'Var', (107, 115))	('squamous cell carcinoma', 'Disease', (42, 65))	('GSE3141', 'Var', (76, 83))	('GSE8894', 'Var', (94, 101))	('GSE3141', 'Chemical', '-', (76, 83))	('GSE4573', 'Var', (85, 92))	('GSE8894', 'Chemical', '-', (94, 101))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (42, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (56, 65))	('GSE4573', 'Chemical', '-', (85, 92))
4817	24369726	The p-values were consistent with the p-values from the log-rank test; a minor discrepancy is that the dataset GSE3141 has 6 ties at the median score resulting in lower discriminating ability.	('lower', 'NegReg', (163, 168))	('GSE3141', 'Chemical', '-', (111, 118))	('GSE3141', 'Var', (111, 118))	('discriminating ability', 'MPA', (169, 191))
4827	24369726	This suggested that high-risk lung adenocarcinoma patients with poor survival may benefit from receiving ZD-6474 treatment.	('ZD-6474', 'Var', (105, 112))	('patients', 'Species', '9606', (50, 58))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (30, 49))	('men', 'Species', '9606', (118, 121))	('ZD-6474', 'Chemical', 'MESH:C452423', (105, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (40, 49))	('lung adenocarcinoma', 'Disease', (30, 49))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (30, 49))
4842	24369726	Low mRNA and protein expression of MAPT was correlated with high expression of TUBB3, which showed prognostic significance with disease-free survival and overall survival in patients with early breast cancer.	('MAPT', 'Gene', '4137', (35, 39))	('TUBB3', 'Gene', '10381', (79, 84))	('MAPT', 'Gene', (35, 39))	('high', 'Var', (60, 64))	('patients', 'Species', '9606', (174, 182))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('breast cancer', 'Disease', 'MESH:D001943', (194, 207))	('Low', 'NegReg', (0, 3))	('breast cancer', 'Disease', (194, 207))	('TUBB3', 'Gene', (79, 84))	('breast cancer', 'Phenotype', 'HP:0003002', (194, 207))
4844	24369726	PAK2 was a necessary interaction partner of ARHGDIB, and knockdown of PAK2 greatly reduced ARHGDIB-induced cell invasion and ARHGDIB-mediated chemoresistance in gastric cancer, and loss of SATB1 in lung cancer has been shown as a possible marker for poor survival.	('reduced', 'NegReg', (83, 90))	('PAK2', 'Gene', (0, 4))	('ARHGDIB', 'Gene', (125, 132))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('ARHGDIB', 'Gene', (91, 98))	('ARHGDIB', 'Gene', (44, 51))	('gastric cancer', 'Disease', 'MESH:D013274', (161, 175))	('PAK2', 'Gene', '5062', (0, 4))	('loss of SATB1 in lung cancer', 'Disease', (181, 209))	('PAK2', 'Gene', (70, 74))	('ARHGDIB', 'Gene', '397', (125, 132))	('gastric cancer', 'Phenotype', 'HP:0012126', (161, 175))	('PAK2', 'Gene', '5062', (70, 74))	('ARHGDIB', 'Gene', '397', (91, 98))	('ARHGDIB', 'Gene', '397', (44, 51))	('knockdown', 'Var', (57, 66))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('lung cancer', 'Phenotype', 'HP:0100526', (198, 209))	('gastric cancer', 'Disease', (161, 175))	('loss of SATB1 in lung cancer', 'Disease', 'MESH:D008175', (181, 209))
4855	24369726	Although ZD-6474, also known as Vandetanib, targeting EGFR, has not been approved for treatment of NSCLC, it has been used in medullary thyroid cancer.	('thyroid cancer', 'Disease', 'MESH:D013964', (136, 150))	('Vandetanib', 'Chemical', 'MESH:C452423', (32, 42))	('medullary thyroid cancer', 'Phenotype', 'HP:0002865', (126, 150))	('ZD-6474', 'Chemical', 'MESH:C452423', (9, 16))	('thyroid cancer', 'Disease', (136, 150))	('men', 'Species', '9606', (91, 94))	('EGFR', 'Gene', '1956', (54, 58))	('ZD-6474', 'Var', (9, 16))	('thyroid cancer', 'Phenotype', 'HP:0002890', (136, 150))	('NSCLC', 'Disease', (99, 104))	('EGFR', 'Gene', (54, 58))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('NSCLC', 'Disease', 'MESH:D002289', (99, 104))
4856	24369726	One randomized phase 2 clinical trial demonstrated the efficacy of Vandetanib in locally advanced or metastatic differentiated thyroid cancer; another meta-analysis study including 14 trials indicated that NSCLC patients treated by Vandetanib showed better progression-free survival, especially the adenocarcinoma subtype.	('locally advanced', 'Disease', (81, 97))	('thyroid cancer', 'Disease', 'MESH:D013964', (127, 141))	('NSCLC', 'Disease', (206, 211))	('thyroid cancer', 'Disease', (127, 141))	('thyroid cancer', 'Phenotype', 'HP:0002890', (127, 141))	('carcinoma', 'Phenotype', 'HP:0030731', (304, 313))	('patients', 'Species', '9606', (212, 220))	('progression-free survival', 'CPA', (257, 282))	('NSCLC', 'Disease', 'MESH:D002289', (206, 211))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('Vandetanib', 'Chemical', 'MESH:C452423', (67, 77))	('Vandetanib', 'Chemical', 'MESH:C452423', (232, 242))	('adenocarcinoma subtype', 'Disease', (299, 321))	('adenocarcinoma subtype', 'Disease', 'MESH:D000230', (299, 321))	('Vandetanib', 'Var', (232, 242))	('better', 'PosReg', (250, 256))
4885	32916872	Deregulation of HSPGs resulting in malignancy may be due to either their abnormal expression levels or changes in their structure and functions as a result of the altered activity of their biosynthetic or remodeling enzymes.	('resulting in', 'Reg', (22, 34))	('HSPG', 'Gene', '960', (16, 20))	('expression levels', 'MPA', (82, 99))	('Deregulation', 'Var', (0, 12))	('HSPG', 'Gene', (16, 20))	('malignancy', 'Disease', 'MESH:D009369', (35, 45))	('altered', 'Reg', (163, 170))	('malignancy', 'Disease', (35, 45))	('changes', 'Reg', (103, 110))	('functions', 'MPA', (134, 143))	('activity', 'MPA', (171, 179))	('structure', 'MPA', (120, 129))
4904	32916872	Differential expression and structure/activity modifications of HSPGs have been found in several cancers and may correlate with either inhibitory or tumor-promoting activity.	('found', 'Reg', (80, 85))	('cancers', 'Disease', 'MESH:D009369', (97, 104))	('cancers', 'Phenotype', 'HP:0002664', (97, 104))	('HSPG', 'Gene', '960', (64, 68))	('cancers', 'Disease', (97, 104))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('expression', 'MPA', (13, 23))	('HSPG', 'Gene', (64, 68))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('structure/activity', 'MPA', (28, 46))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('tumor', 'Disease', (149, 154))	('modifications', 'Var', (47, 60))
4916	32916872	Then, the HS backbone undergoes modifications involving N-deacetylation and N-sulfation of glucosamine, C-5 epimerization of glucuronic acid to iduronic acid, 2-O-sulfation and 3-O-sulfation of uronic acid and glucosamine, respectively, and 6-O-sulfation of N-acetylated or N-sulfated glucosamine residues.	('glucuronic acid', 'Chemical', 'MESH:D020723', (125, 140))	('glucosamine', 'Chemical', 'MESH:D005944', (210, 221))	('uronic acid', 'Chemical', 'MESH:D014574', (129, 140))	('glucosamine', 'Chemical', 'MESH:D005944', (91, 102))	('iduronic acid', 'Chemical', 'MESH:D007067', (144, 157))	('sulfate', 'Chemical', 'MESH:D013431', (276, 283))	('uronic acid', 'Chemical', 'MESH:D014574', (146, 157))	('HS', 'Chemical', 'MESH:D006497', (10, 12))	('N-deacetylation', 'MPA', (56, 71))	('N-sulfation', 'MPA', (76, 87))	('modifications', 'Var', (32, 45))	('uronic acid', 'Chemical', 'MESH:D014574', (194, 205))	('glucosamine', 'Chemical', 'MESH:D005944', (285, 296))	('C-5', 'Var', (104, 107))
4921	32916872	The genetic loss of NDST4, a member of the N-deacetylase/N-sulfotransferase (NDST) family, correlates with an advanced pathological stage and poor survival in colorectal carcinomas.	('colorectal carcinomas', 'Disease', (159, 180))	('colorectal carcinomas', 'Disease', 'MESH:D015179', (159, 180))	('carcinoma', 'Phenotype', 'HP:0030731', (170, 179))	('NDST4', 'Gene', '64579', (20, 25))	('NDST4', 'Gene', (20, 25))	('genetic loss', 'Var', (4, 16))	('carcinomas', 'Phenotype', 'HP:0030731', (170, 180))
4923	32916872	Defective HS-3-O-sulfation due to methylation-associated repression of HS glucosamine 3-O-sulfotransferase gene (3-OST) results in being associated with chondrosarcoma progression, whereas hypermethylation of the 3-OST gene is associated with poor survival in non-small cell lung cancer.	('methylation-associated', 'Var', (34, 56))	('cancer', 'Phenotype', 'HP:0002664', (280, 286))	('sarcoma', 'Phenotype', 'HP:0100242', (160, 167))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (153, 167))	('3-OST', 'Gene', (213, 218))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (260, 286))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (264, 286))	('3-OST', 'Gene', '9957', (113, 118))	('associated with', 'Reg', (137, 152))	('lung cancer', 'Disease', (275, 286))	('HS', 'Chemical', 'MESH:D006497', (10, 12))	('HS', 'Chemical', 'MESH:D006497', (71, 73))	('HS-3-O-sulfation', 'MPA', (10, 26))	('repression', 'NegReg', (57, 67))	('3-OST', 'Gene', '9957', (213, 218))	('glucosamine', 'Chemical', 'MESH:D005944', (74, 85))	('lung cancer', 'Disease', 'MESH:D008175', (275, 286))	('chondrosarcoma', 'Disease', 'MESH:D002813', (153, 167))	('lung cancer', 'Phenotype', 'HP:0100526', (275, 286))	('chondrosarcoma', 'Disease', (153, 167))	('3-OST', 'Gene', (113, 118))
4926	32916872	Mutations in EXT1 or EXT2, members of the EXT family of glycosyltransferases are responsible for hereditary multiple osteochondromas that may degenerate into chondro- or osteo-sarcomas.	('hereditary multiple osteochondromas', 'Disease', 'MESH:D005097', (97, 132))	('sarcoma', 'Phenotype', 'HP:0100242', (176, 183))	('EXT', 'Gene', (21, 24))	('EXT', 'Gene', (13, 16))	('EXT2', 'Gene', '2132', (21, 25))	('EXT2', 'Gene', (21, 25))	('Mutations', 'Var', (0, 9))	('hereditary multiple osteochondromas', 'Disease', (97, 132))	('EXT1', 'Gene', '2131', (13, 17))	('EXT', 'Gene', '2131', (42, 45))	('osteo-sarcomas', 'Disease', (170, 184))	('responsible', 'Reg', (81, 92))	('osteo-sarcomas', 'Phenotype', 'HP:0002669', (170, 184))	('osteochondromas', 'Phenotype', 'HP:0030431', (117, 132))	('EXT', 'Gene', (42, 45))	('osteo-sarcomas', 'Disease', 'MESH:D012509', (170, 184))	('EXT1', 'Gene', (13, 17))	('sarcomas', 'Phenotype', 'HP:0100242', (176, 184))	('EXT', 'Gene', '2131', (13, 16))	('EXT', 'Gene', '2131', (21, 24))
4927	32916872	Furthermore, mutations in EXT2 have been detected in breast tumor patients, and thyroid cancer.	('thyroid cancer', 'Disease', (80, 94))	('thyroid cancer', 'Phenotype', 'HP:0002890', (80, 94))	('breast tumor', 'Disease', 'MESH:D001943', (53, 65))	('EXT2', 'Gene', (26, 30))	('thyroid cancer', 'Disease', 'MESH:D013964', (80, 94))	('EXT2', 'Gene', '2132', (26, 30))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('breast tumor', 'Disease', (53, 65))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('mutations', 'Var', (13, 22))	('detected', 'Reg', (41, 49))	('patients', 'Species', '9606', (66, 74))	('breast tumor', 'Phenotype', 'HP:0100013', (53, 65))
4928	32916872	Epigenetic inactivation of EXT1 by promoter hyper-methylation preventing HS chain synthesis is observed in leukemia and non-melanoma skin cancer.	('promoter hyper-methylation', 'Var', (35, 61))	('non-melanoma skin cancer', 'Disease', 'MESH:D012878', (120, 144))	('melanoma', 'Phenotype', 'HP:0002861', (124, 132))	('skin cancer', 'Phenotype', 'HP:0008069', (133, 144))	('non-melanoma skin cancer', 'Disease', (120, 144))	('HS chain synthesis', 'MPA', (73, 91))	('leukemia', 'Phenotype', 'HP:0001909', (107, 115))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('leukemia', 'Disease', 'MESH:D007938', (107, 115))	('EXT1', 'Gene', (27, 31))	('leukemia', 'Disease', (107, 115))	('HS', 'Chemical', 'MESH:D006497', (73, 75))	('Epigenetic inactivation', 'Var', (0, 23))	('EXT1', 'Gene', '2131', (27, 31))
4937	32916872	Overexpression of SDC1 correlates with tumor aggressiveness and poor survival in triple-negative breast carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (39, 59))	('breast carcinoma', 'Phenotype', 'HP:0003002', (97, 113))	('poor', 'NegReg', (64, 68))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('SDC1', 'Gene', (18, 22))	('SDC1', 'Gene', '6382', (18, 22))	('breast carcinoma', 'Disease', (97, 113))	('Overexpression', 'Var', (0, 14))	('tumor aggressiveness', 'Disease', (39, 59))	('breast carcinoma', 'Disease', 'MESH:D001943', (97, 113))	('aggressiveness', 'Phenotype', 'HP:0000718', (45, 59))
4943	32916872	Overexpression of GPC1 is a hallmark of breast cancer, esophageal squamous cell carcinoma, and gliomas.	('glioma', 'Phenotype', 'HP:0009733', (95, 101))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (55, 89))	('GPC1', 'Gene', '2817', (18, 22))	('breast cancer', 'Phenotype', 'HP:0003002', (40, 53))	('hallmark of breast cancer', 'Disease', 'MESH:D001943', (28, 53))	('hallmark of breast cancer', 'Disease', (28, 53))	('gliomas', 'Disease', 'MESH:D005910', (95, 102))	('gliomas', 'Phenotype', 'HP:0009733', (95, 102))	('gliomas', 'Disease', (95, 102))	('esophageal squamous cell carcinoma', 'Disease', (55, 89))	('Overexpression', 'Var', (0, 14))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('GPC1', 'Gene', (18, 22))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (66, 89))
4949	32916872	Overexpression of GPC6 is associated with gastric adenocarcinoma and metastatic progression of cutaneous melanoma.	('GPC6', 'Gene', '10082', (18, 22))	('melanoma', 'Phenotype', 'HP:0002861', (105, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (55, 64))	('metastatic progression', 'CPA', (69, 91))	('gastric adenocarcinoma', 'Disease', 'MESH:D013274', (42, 64))	('gastric adenocarcinoma', 'Disease', (42, 64))	('Overexpression', 'Var', (0, 14))	('GPC6', 'Gene', (18, 22))	('cutaneous melanoma', 'Disease', (95, 113))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (95, 113))	('associated with', 'Reg', (26, 41))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (95, 113))
4956	32916872	The aberrant expression of specific HSPGs in the various types of cancers significantly affects HSPG-ligand binding and subsequent signaling, thus determining the malignancy of the tumor phenotype.	('HSPG', 'Gene', (36, 40))	('affects', 'Reg', (88, 95))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('binding', 'Interaction', (108, 115))	('signaling', 'MPA', (131, 140))	('malignancy of the tumor', 'Disease', 'MESH:D009369', (163, 186))	('HSPG', 'Gene', '960', (96, 100))	('determining', 'Reg', (147, 158))	('malignancy of the tumor', 'Disease', (163, 186))	('aberrant expression', 'Var', (4, 23))	('cancers', 'Phenotype', 'HP:0002664', (66, 73))	('HSPG', 'Gene', (96, 100))	('cancers', 'Disease', (66, 73))	('cancers', 'Disease', 'MESH:D009369', (66, 73))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('HSPG', 'Gene', '960', (36, 40))
4961	32916872	Soluble SDC1 promotes the growth of myeloma tumors in vivo, while shed SDC2 enhances colon, lung, and breast cancer progression.	('SDC1', 'Gene', (8, 12))	('SDC1', 'Gene', '6382', (8, 12))	('breast cancer', 'Disease', (102, 115))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('breast cancer', 'Phenotype', 'HP:0003002', (102, 115))	('colon', 'Disease', (85, 90))	('growth', 'MPA', (26, 32))	('promotes', 'PosReg', (13, 21))	('myeloma tumors', 'Disease', 'MESH:D009101', (36, 50))	('myeloma tumors', 'Disease', (36, 50))	('SDC2', 'Gene', (71, 75))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('lung', 'Disease', (92, 96))	('shed', 'Var', (66, 70))	('breast cancer', 'Disease', 'MESH:D001943', (102, 115))	('enhances', 'PosReg', (76, 84))
4962	32916872	SDC-1 shedding is associated with increased mitogenic activity and invasive potential of pancreatic cancer cells, whereas shedding of SDC4 in human endothelial cells promotes wound healing, angiogenesis, and inflammation.	('mitogenic activity', 'CPA', (44, 62))	('invasive potential', 'CPA', (67, 85))	('shedding', 'Var', (122, 130))	('human', 'Species', '9606', (142, 147))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (89, 106))	('increased', 'PosReg', (34, 43))	('angiogenesis', 'CPA', (190, 202))	('SDC-1', 'Gene', '6382', (0, 5))	('SDC-1', 'Gene', (0, 5))	('inflammation', 'Disease', 'MESH:D007249', (208, 220))	('SDC4', 'Gene', '6385', (134, 138))	('SDC4', 'Gene', (134, 138))	('pancreatic cancer', 'Disease', 'MESH:D010190', (89, 106))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('shedding', 'Var', (6, 14))	('inflammation', 'Disease', (208, 220))	('promotes', 'PosReg', (166, 174))	('wound healing', 'CPA', (175, 188))	('pancreatic cancer', 'Disease', (89, 106))
4963	32916872	Furthermore, SDC1 shedding has been shown to trigger a switch from a proliferative to an invasive phenotype of breast cancer cells.	('SDC1', 'Gene', (13, 17))	('SDC1', 'Gene', '6382', (13, 17))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('shedding', 'Var', (18, 26))	('breast cancer', 'Disease', 'MESH:D001943', (111, 124))	('breast cancer', 'Phenotype', 'HP:0003002', (111, 124))	('switch', 'Reg', (55, 61))	('breast cancer', 'Disease', (111, 124))	('trigger', 'Reg', (45, 52))	('proliferative', 'CPA', (69, 82))
4977	32916872	Depending on the tumor type, HSPG-regulated FGF binding and receptor dimerization triggers the activation of four main signaling pathways, including mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK), phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT), Janus kinase (JAK)/signal transducer and activator of transcription (STAT), and protein kinase C (PKC) pathways.	('AKT', 'Gene', '207', (289, 292))	('PKC', 'Gene', '5578;5582', (393, 396))	('PKC', 'Gene', (393, 396))	('extracellular signal-regulated kinase', 'Gene', (189, 226))	('FGF', 'Protein', (44, 47))	('extracellular signal-regulated kinase', 'Gene', '5594', (189, 226))	('phosphatidylinositol 3-kinase', 'Gene', '5293', (234, 263))	('tumor', 'Disease', (17, 22))	('ERK', 'Gene', '5594', (228, 231))	('protein kinase B', 'Gene', '2185', (271, 287))	('AKT', 'Gene', (289, 292))	('activation', 'PosReg', (95, 105))	('STAT', 'Gene', '6774', (364, 368))	('STAT', 'Gene', (364, 368))	('activator of transcription', 'Pathway', (336, 362))	('phosphatidylinositol 3-kinase', 'Gene', (234, 263))	('HSPG', 'Gene', '960', (29, 33))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('protein kinase B', 'Gene', (271, 287))	('binding', 'Var', (48, 55))	('HSPG', 'Gene', (29, 33))	('ERK', 'Gene', (228, 231))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('dimerization', 'Var', (69, 81))
4989	32916872	For example, in myeloma, shed SDC1 promotes HGF paracrine signaling that involves MAPK and PI3K cascade activation resulting in enhanced cell proliferation and survival.	('survival', 'CPA', (160, 168))	('HGF', 'Gene', (44, 47))	('activation', 'PosReg', (104, 114))	('myeloma', 'Disease', (16, 23))	('cell proliferation', 'CPA', (137, 155))	('HGF', 'Gene', '3082', (44, 47))	('SDC1', 'Gene', (30, 34))	('shed', 'Var', (25, 29))	('promotes', 'PosReg', (35, 43))	('SDC1', 'Gene', '6382', (30, 34))	('enhanced', 'PosReg', (128, 136))	('myeloma', 'Disease', 'MESH:D009101', (16, 23))	('MAPK', 'MPA', (82, 86))
4991	32916872	Dysregulation of HSPG-regulated HGF/c-MET signaling in tumor microenvironment plays a key role in hepatocarcinoma.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('c-MET', 'Gene', '4233', (36, 41))	('HSPG', 'Gene', '960', (17, 21))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('Dysregulation', 'Var', (0, 13))	('HSPG', 'Gene', (17, 21))	('tumor', 'Disease', (55, 60))	('hepatocarcinoma', 'Disease', 'None', (98, 113))	('c-MET', 'Gene', (36, 41))	('hepatocarcinoma', 'Disease', (98, 113))	('HGF', 'Gene', (32, 35))	('HGF', 'Gene', '3082', (32, 35))
4992	32916872	Strong evidence demonstrates a role for loss of HB-EGF in the tumor microenvironment in neuroblastoma pathogenesis.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('neuroblastoma', 'Disease', 'MESH:D009447', (88, 101))	('tumor', 'Disease', (62, 67))	('HB-EGF', 'Gene', (48, 54))	('neuroblastoma', 'Disease', (88, 101))	('neuroblastoma', 'Phenotype', 'HP:0003006', (88, 101))	('loss', 'Var', (40, 44))	('HB-EGF', 'Gene', '1839', (48, 54))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
5063	32916872	The HS mimetics OTR4120 and OTR4131 exhibit anti-tumoral effects in human hepatocellular carcinoma by interfering with HSPGs-mediated RANTES signaling.	('human', 'Species', '9606', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('OTR4120', 'Chemical', 'MESH:C533322', (16, 23))	('HS', 'Chemical', 'MESH:D006497', (4, 6))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('HSPG', 'Gene', '960', (119, 123))	('interfering', 'NegReg', (102, 113))	('HSPG', 'Gene', (119, 123))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (74, 98))	('RANTES', 'Gene', (134, 140))	('RANTES', 'Gene', '6352', (134, 140))	('HS', 'Chemical', 'MESH:D006497', (119, 121))	('tumor', 'Disease', (49, 54))	('OTR4131', 'Var', (28, 35))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (74, 98))	('OTR4120', 'Var', (16, 23))	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('OTR4131', 'Chemical', 'MESH:C542264', (28, 35))	('hepatocellular carcinoma', 'Disease', (74, 98))
5072	32916872	Indeed, the HS mimetics PI-88, PG545, and M402 have been shown to exert anti-angiogenic and antimetastatic effects by inhibiting heparanase in several types of cancers.	('PI-88', 'Var', (24, 29))	('cancers', 'Disease', 'MESH:D009369', (160, 167))	('cancers', 'Phenotype', 'HP:0002664', (160, 167))	('PI-88', 'Chemical', 'MESH:C120158', (24, 29))	('cancers', 'Disease', (160, 167))	('anti-angiogenic', 'CPA', (72, 87))	('M402', 'Var', (42, 46))	('M402', 'Chemical', '-', (42, 46))	('heparanase', 'Gene', (129, 139))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('PG545', 'Var', (31, 36))	('antimetastatic effects', 'CPA', (92, 114))	('inhibiting', 'NegReg', (118, 128))	('heparanase', 'Gene', '10855', (129, 139))	('HS', 'Chemical', 'MESH:D006497', (12, 14))	('PG545', 'Chemical', 'MESH:C557899', (31, 36))
5078	32916872	Inhibition of human sulfatase 1 (SULF1) inhibits the malignant phenotype of gallbladder carcinoma cells by hindering the cell response to growth factors.	('human', 'Species', '9606', (14, 19))	('hindering', 'NegReg', (107, 116))	('sulfatase 1', 'Gene', '23213', (20, 31))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('SULF1', 'Gene', '23213', (33, 38))	('SULF1', 'Gene', (33, 38))	('gallbladder carcinoma', 'Disease', 'MESH:D005706', (76, 97))	('inhibits', 'NegReg', (40, 48))	('sulfatase 1', 'Gene', (20, 31))	('Inhibition', 'Var', (0, 10))	('cell response', 'CPA', (121, 134))	('gallbladder carcinoma', 'Disease', (76, 97))	('malignant phenotype of', 'CPA', (53, 75))
5079	32916872	Thus, the modulation of tumor microenvironment by affecting the structure and/or activity of HSPGs represents an effective therapeutic strategy for preventing tumor growth and progression.	('HSPG', 'Gene', (93, 97))	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('structure', 'MPA', (64, 73))	('modulation', 'Var', (10, 20))	('tumor', 'Disease', (24, 29))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('preventing', 'NegReg', (148, 158))	('tumor', 'Disease', (159, 164))	('HSPG', 'Gene', '960', (93, 97))	('activity', 'MPA', (81, 89))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('affecting', 'Reg', (50, 59))
5088	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))
5093	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))
5114	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))
5136	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))
5140	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))
5141	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))
5142	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))
5159	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))
5165	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))	('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))	('STAT1', 'Gene', (85, 90))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('fibrosarcoma', 'Disease', (117, 129))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('tumor', 'Disease', (161, 166))	('murine', 'Species', '10090', (110, 116))	('sarcoma', 'Phenotype', 'HP:0100242', (122, 129))
5166	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))
5167	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))	('breast cancer', 'Disease', (152, 165))	('STAT1 mRNA levels', 'MPA', (61, 78))	('breast cancer', 'Phenotype', 'HP:0003002', (152, 165))	('high', 'Var', (56, 60))
5170	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))
5172	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))
5180	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))	('cyclin D1', 'Gene', '595', (102, 111))	('cyclin D1', 'Gene', (102, 111))	('arrest', 'Disease', 'MESH:D006323', (24, 30))	('interaction', 'Interaction', (85, 96))	('STAT1', 'Var', (14, 19))
5186	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))
5187	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))
5189	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))
5202	31308749	More macrophages were found in lung squamous cell carcinoma (LUSC) patients, patients with wild-type EGFR, and smokers than in patients with lung adenocarcinoma (LUAD), patients with EGFR mutations, and non-smokers.	('LUAD', 'Disease', (162, 166))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (141, 160))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (141, 160))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (31, 59))	('LUAD', 'Disease', 'None', (162, 166))	('EGFR', 'Gene', (183, 187))	('EGFR', 'Gene', '1956', (101, 105))	('patients', 'Species', '9606', (77, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (151, 160))	('patients', 'Species', '9606', (67, 75))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (36, 59))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (31, 59))	('lung squamous cell carcinoma', 'Disease', (31, 59))	('LUSC', 'Phenotype', 'HP:0030359', (61, 65))	('mutations', 'Var', (188, 197))	('lung adenocarcinoma', 'Disease', (141, 160))	('patients', 'Species', '9606', (169, 177))	('EGFR', 'Gene', '1956', (183, 187))	('carcinoma', 'Phenotype', 'HP:0030731', (50, 59))	('EGFR', 'Gene', (101, 105))	('LUAD', 'Phenotype', 'HP:0030078', (162, 166))	('patients', 'Species', '9606', (127, 135))
5203	31308749	Infiltration of centralM2 was an independent prognostic factor of poor overall survival (OS) and disease-free survival (DFS) for NSCLC patients (P<0.05), which was superior to total macrophages and total M2 macrophages.	('patients', 'Species', '9606', (135, 143))	('NSCLC', 'Phenotype', 'HP:0030358', (129, 134))	('NSCLC', 'Disease', (129, 134))	('overall', 'MPA', (71, 78))	('disease-free survival', 'CPA', (97, 118))	('Infiltration', 'Var', (0, 12))	('NSCLC', 'Disease', 'MESH:D002289', (129, 134))	('poor', 'NegReg', (66, 70))
5209	31308749	Smoking, gene mutation, and reprogramming of the immune microenvironment are critical factors that may affect malignancy in lung cancer.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('lung cancer', 'Disease', 'MESH:D008175', (124, 135))	('malignancy', 'Disease', 'MESH:D009369', (110, 120))	('malignancy', 'Disease', (110, 120))	('lung cancer', 'Disease', (124, 135))	('lung cancer', 'Phenotype', 'HP:0100526', (124, 135))	('affect', 'Reg', (103, 109))	('gene mutation', 'Var', (9, 22))
5240	31308749	Fifty-nine (43.1%) patients had EGFR mutations and 78 (56.9%) had wild-type EGFR, which is similar to the known rate of genetic mutations in NSCLC patients in Asia.	('patients', 'Species', '9606', (19, 27))	('EGFR', 'Gene', '1956', (76, 80))	('EGFR', 'Gene', '1956', (32, 36))	('NSCLC', 'Disease', (141, 146))	('mutations', 'Var', (37, 46))	('patients', 'Species', '9606', (147, 155))	('NSCLC', 'Disease', 'MESH:D002289', (141, 146))	('EGFR', 'Gene', (76, 80))	('EGFR', 'Gene', (32, 36))	('NSCLC', 'Phenotype', 'HP:0030358', (141, 146))
5256	31308749	Compared to LUAD patients, patients with EGFR mutations, and non-smokers, higher densities of total macrophages were found in LUSC patients, patients with wild-type EGFR, and smokers, respectively (P<0.05, Figure 3A, 3D, 3G).	('EGFR', 'Gene', (165, 169))	('patients', 'Species', '9606', (131, 139))	('EGFR', 'Gene', (41, 45))	('mutations', 'Var', (46, 55))	('higher', 'PosReg', (74, 80))	('densities', 'MPA', (81, 90))	('patients', 'Species', '9606', (27, 35))	('patients', 'Species', '9606', (17, 25))	('LUAD', 'Phenotype', 'HP:0030078', (12, 16))	('LUAD', 'Disease', 'None', (12, 16))	('LUAD', 'Disease', (12, 16))	('LUSC', 'Phenotype', 'HP:0030359', (126, 130))	('EGFR', 'Gene', '1956', (41, 45))	('patients', 'Species', '9606', (141, 149))	('EGFR', 'Gene', '1956', (165, 169))
5262	31308749	MarginM1 did not affect the OS significantly (P=0.088, Figure 4G), while patients with high infiltration of marginM1 had a better OS than those with low infiltration of marginM1 (P=0.034, Figure 4I).	('better', 'PosReg', (123, 129))	('M1', 'Gene', '100507027', (175, 177))	('high infiltration', 'Var', (87, 104))	('M1', 'Gene', '100507027', (6, 8))	('M1', 'Gene', '100507027', (114, 116))	('patients', 'Species', '9606', (73, 81))
5264	31308749	Patients with centralM2/marginM2high had a worse OS than those with centralM2/marginM2low (P=0.001, Figure 4J), suggesting that centralM2 have a greater impact on the OS of NSCLC patients than marginM2.	('NSCLC', 'Phenotype', 'HP:0030358', (173, 178))	('NSCLC', 'Disease', (173, 178))	('Patients', 'Species', '9606', (0, 8))	('patients', 'Species', '9606', (179, 187))	('NSCLC', 'Disease', 'MESH:D002289', (173, 178))	('centralM2/marginM2high', 'Var', (14, 36))	('centralM2', 'Var', (128, 137))
5265	31308749	Similarly, the analysis of DFS showed that patients with low infiltration of centralM (P=0.023, Figure 5D), especially centralM2 (P=0.006, Figure 5E), had better DFS than patients with high infiltration of centralM and centralM2, and the patients with centralM2/marginM2high had worse DFS than those with centralM2/marginM2low (P=0.005, Figure 5J).	('patients', 'Species', '9606', (43, 51))	('centralM2', 'Var', (119, 128))	('centralM2/marginM2high', 'Var', (252, 274))	('patients', 'Species', '9606', (171, 179))	('better', 'PosReg', (155, 161))	('DFS', 'MPA', (162, 165))	('patients', 'Species', '9606', (238, 246))
5294	31308749	In this study, centralM2 had a stronger effect on tumor development than marginM2.	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('centralM2', 'Var', (15, 24))	('tumor', 'Disease', (50, 55))	('tumor', 'Disease', 'MESH:D009369', (50, 55))
5312	27623437	The prognostic and predictive value of preoperative serum tumor markers and frequency of EGFR mutations in adenosquamous lung carcinoma are unclear.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('EGFR', 'Gene', (89, 93))	('mutations', 'Var', (94, 103))	('adenosquamous lung carcinoma', 'Disease', (107, 135))	('adenosquamous lung carcinoma', 'Disease', 'MESH:D018196', (107, 135))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('EGFR', 'Gene', '1956', (89, 93))
5314	27623437	Correlations between serum tumor marker levels and EGFR mutations as well as survival parameters were analyzed and prognostic factors were identified.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('mutations', 'Var', (56, 65))	('EGFR', 'Gene', (51, 55))	('tumor', 'Disease', (27, 32))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('EGFR', 'Gene', '1956', (51, 55))
5315	27623437	Of the 106 adenosquamous lung carcinoma patients, 29 (27.4%) harbored EGFR mutations.	('harbored', 'Reg', (61, 69))	('adenosquamous lung carcinoma', 'Disease', 'MESH:D018196', (11, 39))	('patients', 'Species', '9606', (40, 48))	('EGFR', 'Gene', '1956', (70, 74))	('EGFR', 'Gene', (70, 74))	('mutations', 'Var', (75, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (30, 39))	('adenosquamous lung carcinoma', 'Disease', (11, 39))
5318	27623437	Adenosquamous lung carcinoma is an aggressive malignancy with relatively high EGFR mutation frequency.	('Adenosquamous lung carcinoma', 'Disease', 'MESH:D018196', (0, 28))	('Adenosquamous lung carcinoma', 'Disease', (0, 28))	('carcinoma', 'Phenotype', 'HP:0030731', (19, 28))	('mutation', 'Var', (83, 91))	('aggressive malignancy', 'Disease', (35, 56))	('EGFR', 'Gene', '1956', (78, 82))	('EGFR', 'Gene', (78, 82))	('aggressive malignancy', 'Disease', 'MESH:D009369', (35, 56))
5327	27623437	Recent advancements in EGFR mutation targeted therapy led to a major paradigm shift in the treatment of non-small cell lung cancer.	('men', 'Species', '9606', (96, 99))	('non-small cell lung cancer', 'Disease', (104, 130))	('men', 'Species', '9606', (14, 17))	('lung cancer', 'Phenotype', 'HP:0100526', (119, 130))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (108, 130))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (104, 130))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('EGFR', 'Gene', '1956', (23, 27))	('mutation', 'Var', (28, 36))	('EGFR', 'Gene', (23, 27))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (104, 130))
5328	27623437	EGFR-sensitizing mutations are strongly associated with robust responses to EGFR tyrosine kinase inhibitors (EGFR-TKI) and improved progression-free survival (PFS).	('responses', 'MPA', (63, 72))	('EGFR', 'Gene', (0, 4))	('EGFR', 'Gene', '1956', (76, 80))	('progression-free survival', 'CPA', (132, 157))	('EGFR', 'Gene', '1956', (109, 113))	('EGFR', 'Gene', (76, 80))	('EGFR', 'Gene', '1956', (0, 4))	('EGFR', 'Gene', (109, 113))	('improved', 'PosReg', (123, 131))	('mutations', 'Var', (17, 26))
5329	27623437	However, EGFR mutations are most common in Asian patients, nonsmokers, females and those with adenocarcinoma histology.	('common', 'Reg', (33, 39))	('EGFR', 'Gene', '1956', (9, 13))	('EGFR', 'Gene', (9, 13))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('patients', 'Species', '9606', (49, 57))	('adenocarcinoma', 'Disease', (94, 108))	('mutations', 'Var', (14, 23))	('adenocarcinoma', 'Disease', 'MESH:D000230', (94, 108))
5330	27623437	In squamous cell carcinoma, the EGFR mutation rate is reported to be approximately 5%.	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (3, 26))	('mutation', 'Var', (37, 45))	('EGFR', 'Gene', '1956', (32, 36))	('EGFR', 'Gene', (32, 36))	('carcinoma', 'Phenotype', 'HP:0030731', (17, 26))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (3, 26))	('squamous cell carcinoma', 'Disease', (3, 26))
5331	27623437	Although several small studies have indicated that the frequency of EGFR mutation in adenosquamous lung carcinoma ranges from 15% to 44% in the East Asian population, the exact prevalence of EGFR mutation in adenosquamous lung carcinoma is still not clear.	('carcinoma', 'Phenotype', 'HP:0030731', (227, 236))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('EGFR', 'Gene', '1956', (191, 195))	('EGFR', 'Gene', (191, 195))	('adenosquamous lung carcinoma', 'Disease', (85, 113))	('adenosquamous lung carcinoma', 'Disease', (208, 236))	('EGFR', 'Gene', '1956', (68, 72))	('adenosquamous lung carcinoma', 'Disease', 'MESH:D018196', (85, 113))	('adenosquamous lung carcinoma', 'Disease', 'MESH:D018196', (208, 236))	('mutation', 'Var', (73, 81))	('EGFR', 'Gene', (68, 72))
5339	27623437	EGFR mutations were detected in 27.4% (29/106) of 106 patients.	('patients', 'Species', '9606', (54, 62))	('EGFR', 'Gene', '1956', (0, 4))	('EGFR', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))
5340	27623437	Among the 29 patients with mutations, 13 harbored exon 19 deletions (del19), 13 had point mutations in exon 21 (12 were L858R, and one was L861Q), two had G719X in exon 18, and one possessed dual mutations of G719X in exon 18 and S768I in exon 20.	('mutations', 'Var', (27, 36))	('point mutations', 'Var', (84, 99))	('L861Q', 'Mutation', 'rs121913444', (139, 144))	('S768I', 'Var', (230, 235))	('del19', 'Mutation', 'c.del19', (69, 74))	('L858R', 'Mutation', 'rs121434568', (120, 125))	('G719X', 'Mutation', 'p.G719X', (209, 214))	('patients', 'Species', '9606', (13, 21))	('G719X', 'Var', (209, 214))	('S768I', 'Mutation', 'rs121913465', (230, 235))	('G719X', 'Mutation', 'p.G719X', (155, 160))	('G719X', 'Var', (155, 160))
5351	27623437	Median levels and positive rates for NSE, CEA, Cyfra21-1 or SCCA were similar regardless of EGFR mutation status in adenosquamous lung carcinoma patients.	('patients', 'Species', '9606', (145, 153))	('NSE', 'Gene', (37, 40))	('CEA', 'Gene', '1084', (42, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('adenosquamous lung carcinoma', 'Disease', (116, 144))	('EGFR', 'Gene', '1956', (92, 96))	('mutation', 'Var', (97, 105))	('EGFR', 'Gene', (92, 96))	('NSE', 'Gene', '2026', (37, 40))	('CEA', 'Gene', (42, 45))	('adenosquamous lung carcinoma', 'Disease', 'MESH:D018196', (116, 144))
5352	27623437	Similarly, no differences were found in positive rates and median levels of these tumor markers between del19 and L858R subtypes.	('levels', 'MPA', (66, 72))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('del19', 'Mutation', 'c.del19', (104, 109))	('L858R', 'Mutation', 'rs121434568', (114, 119))	('L858R', 'Var', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumor', 'Disease', (82, 87))	('del19', 'Var', (104, 109))
5353	27623437	Moreover, as shown in Supplementary Table 1, EGFR mutations were found more frequently in women (48.8% versus 12.7%, chi2 = 16.795, P < 0.001), never-smokers (42.9% versus 17.2%, chi2 = 8.408, P = 0.004) and younger patients (36.0% versus 19.6%, chi2 = 3.556, P = 0.059).	('men', 'Species', '9606', (28, 31))	('EGFR', 'Gene', (45, 49))	('mutations', 'Var', (50, 59))	('patients', 'Species', '9606', (216, 224))	('men', 'Species', '9606', (92, 95))	('EGFR', 'Gene', '1956', (45, 49))	('women', 'Species', '9606', (90, 95))
5356	27623437	Patients with elevated Cyfra21-1 exhibited similar DFS (14.8 versus 15.0 months, log-rank chi2 = 0.017, P = 0.897, Figure 1C) but shorter OS (22.0 versus 37.0 months, log-rank chi2 =3.533, P = 0.060, Figure 1D).	('Patients', 'Species', '9606', (0, 8))	('elevated', 'PosReg', (14, 22))	('Cyfra21-1', 'Var', (23, 32))
5362	27623437	As shown in Table 3, similar DFS and OS were observed in patients regardless of EGFR mutation status (P = 0.893 for DFS; P = 0.642 for OS).	('EGFR', 'Gene', (80, 84))	('patients', 'Species', '9606', (57, 65))	('EGFR', 'Gene', '1956', (80, 84))	('mutation', 'Var', (85, 93))
5363	27623437	Of the 29 adenosquamous lung carcinoma patients with EGFR mutations, no difference was found in DFS and OS between del19 and L858R subgroups (P = 0.595 for DFS; P = 0.778 for OS).	('mutations', 'Var', (58, 67))	('adenosquamous lung carcinoma', 'Disease', 'MESH:D018196', (10, 38))	('patients', 'Species', '9606', (39, 47))	('carcinoma', 'Phenotype', 'HP:0030731', (29, 38))	('del19', 'Mutation', 'c.del19', (115, 120))	('L858R', 'Var', (125, 130))	('L858R', 'Mutation', 'rs121434568', (125, 130))	('EGFR', 'Gene', '1956', (53, 57))	('EGFR', 'Gene', (53, 57))	('del19', 'Var', (115, 120))	('adenosquamous lung carcinoma', 'Disease', (10, 38))
5368	27623437	EGFR mutations are most common in adenocarcinoma, while their frequency in the context of adenosquamous lung carcinoma remains controversial.	('adenosquamous lung carcinoma', 'Disease', (90, 118))	('EGFR', 'Gene', (0, 4))	('adenocarcinoma', 'Disease', (34, 48))	('adenosquamous lung carcinoma', 'Disease', 'MESH:D018196', (90, 118))	('mutations', 'Var', (5, 14))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (39, 48))	('adenocarcinoma', 'Disease', 'MESH:D000230', (34, 48))	('common', 'Reg', (24, 30))	('EGFR', 'Gene', '1956', (0, 4))
5369	27623437	In this study, we found that the EGFR mutation rate (29/106, 27.4%) was relatively high in adenosquamous lung carcinoma patients but had no effect on disease-free survival or overall survival.	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('adenosquamous lung carcinoma', 'Disease', (91, 119))	('EGFR', 'Gene', '1956', (33, 37))	('adenosquamous lung carcinoma', 'Disease', 'MESH:D018196', (91, 119))	('patients', 'Species', '9606', (120, 128))	('mutation', 'Var', (38, 46))	('EGFR', 'Gene', (33, 37))	('high', 'Reg', (83, 87))
5380	27623437	EGFR mutation has been reported to be a good outcome predictor for patients with non-small cell lung cancer.	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (81, 107))	('EGFR', 'Gene', (0, 4))	('patients', 'Species', '9606', (67, 75))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (81, 107))	('lung cancer', 'Phenotype', 'HP:0100526', (96, 107))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (85, 107))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('non-small cell lung cancer', 'Disease', (81, 107))	('EGFR', 'Gene', '1956', (0, 4))	('mutation', 'Var', (5, 13))
5381	27623437	Consistent with previous studies, we observed that EGFR mutation frequency was increased in never-smokers and in females.	('mutation', 'Var', (56, 64))	('EGFR', 'Gene', '1956', (51, 55))	('EGFR', 'Gene', (51, 55))
5383	27623437	Two additional reports were unable to detect a significant association between EGFR mutation and prognosis in patients who did not receive EGFR-TKI therapy.	('EGFR', 'Gene', '1956', (79, 83))	('EGFR', 'Gene', (79, 83))	('EGFR', 'Gene', '1956', (139, 143))	('EGFR', 'Gene', (139, 143))	('patients', 'Species', '9606', (110, 118))	('mutation', 'Var', (84, 92))
5384	27623437	In addition, a prior study showed an adenosquamous lung carcinoma patient harboring EGFR-sensitizing mutation had a remarkable response to gefitinib.	('patient', 'Species', '9606', (66, 73))	('EGFR', 'Gene', '1956', (84, 88))	('gefitinib', 'Chemical', 'MESH:D000077156', (139, 148))	('adenosquamous lung carcinoma', 'Disease', (37, 65))	('response to', 'MPA', (127, 138))	('EGFR', 'Gene', (84, 88))	('mutation', 'Var', (101, 109))	('adenosquamous lung carcinoma', 'Disease', 'MESH:D018196', (37, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (56, 65))
5385	27623437	Therefore EGFR tyrosine kinase inhibitors would be a reasonable therapeutic option to adenosquamous lung carcinoma patients due to the relatively high frequency of EGFR mutations in this cohort.	('adenosquamous lung carcinoma', 'Disease', (86, 114))	('EGFR', 'Gene', '1956', (10, 14))	('patients', 'Species', '9606', (115, 123))	('EGFR', 'Gene', (164, 168))	('mutations', 'Var', (169, 178))	('adenosquamous lung carcinoma', 'Disease', 'MESH:D018196', (86, 114))	('EGFR', 'Gene', (10, 14))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('EGFR', 'Gene', '1956', (164, 168))
5392	27623437	Further, we confirmed that high NSE level in adenosquamous lung carcinoma confers a poorer prognosis.	('adenosquamous lung carcinoma', 'Disease', 'MESH:D018196', (45, 73))	('NSE', 'Gene', (32, 35))	('high', 'Var', (27, 31))	('NSE', 'Gene', '2026', (32, 35))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))	('adenosquamous lung carcinoma', 'Disease', (45, 73))
5398	27623437	Previous studies found that Cyfra21-1 tends to be more useful for squamous cell carcinoma diagnosis while CEA is predictive for adenocarcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('squamous cell carcinoma', 'Disease', (66, 89))	('adenocarcinoma', 'Disease', 'MESH:D000230', (128, 142))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (66, 89))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('Cyfra21-1', 'Var', (28, 37))	('CEA', 'Gene', (106, 109))	('adenocarcinoma', 'Disease', (128, 142))	('CEA', 'Gene', '1084', (106, 109))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (66, 89))
5399	27623437	In our study, elevated levels of neither Cyfra21-1 nor CEA were associated adenosquamous lung carcinoma patient prognosis.	('CEA', 'Gene', (55, 58))	('associated', 'Reg', (64, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('CEA', 'Gene', '1084', (55, 58))	('adenosquamous lung carcinoma', 'Disease', (75, 103))	('patient', 'Species', '9606', (104, 111))	('adenosquamous lung carcinoma', 'Disease', 'MESH:D018196', (75, 103))	('Cyfra21-1', 'Var', (41, 50))
5404	27623437	In addition, we did not investigate the adenosquamous lung carcinoma components separately so it is not known which harbored identified EGFR mutations.	('mutations', 'Var', (141, 150))	('adenosquamous lung carcinoma', 'Disease', (40, 68))	('adenosquamous lung carcinoma', 'Disease', 'MESH:D018196', (40, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (59, 68))	('EGFR', 'Gene', '1956', (136, 140))	('EGFR', 'Gene', (136, 140))
5405	27623437	It has been reported that adenocarcinoma and squamous cell carcinoma components can possess the same EGFR mutation, suggesting that the histologic origin of adenosquamous lung carcinoma can be monoclonal.	('carcinoma', 'Phenotype', 'HP:0030731', (176, 185))	('EGFR', 'Gene', '1956', (101, 105))	('mutation', 'Var', (106, 114))	('EGFR', 'Gene', (101, 105))	('adenosquamous lung carcinoma', 'Disease', (157, 185))	('carcinoma', 'Phenotype', 'HP:0030731', (59, 68))	('adenocarcinoma and squamous cell carcinoma', 'Disease', 'MESH:D002294', (26, 68))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (45, 68))	('adenosquamous lung carcinoma', 'Disease', 'MESH:D018196', (157, 185))	('carcinoma', 'Phenotype', 'HP:0030731', (31, 40))
5407	27623437	In addition, TMI based on serum CEA and Cyfra21-1 is also an independent prognostic for overall survival.	('CEA', 'Gene', '1084', (32, 35))	('TMI', 'Chemical', '-', (13, 16))	('CEA', 'Gene', (32, 35))	('Cyfra21-1', 'Var', (40, 49))
5416	27623437	Based on the manufacturer's recommendation, the following cut-offs for serum marker levels were used: NSE 15.2 ng/ml, CEA 5.0 ng/ml, Cyfra21-1 3.3 ng/ml and SCCA 1.5 ng/ml.	('CEA', 'Gene', (118, 121))	('Cyfra21-1', 'Var', (133, 142))	('CEA', 'Gene', '1084', (118, 121))	('SCCA 1', 'Gene', '6317', (157, 163))	('NSE', 'Gene', (102, 105))	('SCCA 1', 'Gene', (157, 163))	('men', 'Species', '9606', (33, 36))	('NSE', 'Gene', '2026', (102, 105))
5428	33174014	Mechanistically, FEZF1-AS1 expression was influenced by N6-methyladenosine (m6A) modification.	('modification', 'Var', (81, 93))	('AS1', 'Gene', '5729', (23, 26))	('expression', 'MPA', (27, 37))	('AS1', 'Gene', (23, 26))	('FEZF1', 'Gene', '389549', (17, 22))	('N6-methyladenosine', 'Chemical', 'MESH:C010223', (56, 74))	('influenced', 'Reg', (42, 52))	('N6-methyladenosine', 'Var', (56, 74))	('FEZF1', 'Gene', (17, 22))
5438	33174014	In gastric cancer, high FEZF1-AS1 expression promotes cell proliferation.	('cell proliferation', 'CPA', (54, 72))	('high', 'Var', (19, 23))	('expression', 'MPA', (34, 44))	('gastric cancer', 'Phenotype', 'HP:0012126', (3, 17))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('AS1', 'Gene', '5729', (30, 33))	('AS1', 'Gene', (30, 33))	('FEZF1', 'Gene', '389549', (24, 29))	('promotes', 'PosReg', (45, 53))	('gastric cancer', 'Disease', (3, 17))	('FEZF1', 'Gene', (24, 29))	('gastric cancer', 'Disease', 'MESH:D013274', (3, 17))
5439	33174014	In addition, the inhibition of FEZF1-AS1 can suppress the activation of the Wnt/p-catenin signaling pathway.	('suppress', 'NegReg', (45, 53))	('FEZF1', 'Gene', (31, 36))	('inhibition', 'Var', (17, 27))	('AS1', 'Gene', (37, 40))	('AS1', 'Gene', '5729', (37, 40))	('FEZF1', 'Gene', '389549', (31, 36))	('p-catenin', 'Chemical', '-', (80, 89))	('Wnt/p-catenin signaling pathway', 'Pathway', (76, 107))
5494	33174014	The association between the expression levels of FEZF1-AS1, ITGA11 and miR-516b-5p, and the clinicopathological variables of patients with NSCLC was determined using the chi2 test.	('patients', 'Species', '9606', (125, 133))	('miR-516b-5p', 'Chemical', '-', (71, 82))	('NSCLC', 'Phenotype', 'HP:0030358', (139, 144))	('AS1', 'Gene', '5729', (55, 58))	('expression', 'MPA', (28, 38))	('ITGA11', 'Gene', (60, 66))	('NSCLC', 'Disease', (139, 144))	('FEZF1', 'Gene', '389549', (49, 54))	('NSCLC', 'Disease', 'MESH:D002289', (139, 144))	('miR-516b-5p', 'Var', (71, 82))	('ITGA11', 'Gene', '22801', (60, 66))	('FEZF1', 'Gene', (49, 54))	('AS1', 'Gene', (55, 58))
5495	33174014	Paired t-test was used to examine the expression levels of FEZF1-AS1, ITGA11 and miR-516b-5p in normal versus tumor tissue samples.	('miR-516b-5p', 'Chemical', '-', (81, 92))	('tumor', 'Disease', 'MESH:D009369', (110, 115))	('FEZF1', 'Gene', '389549', (59, 64))	('AS1', 'Gene', (65, 68))	('tumor', 'Disease', (110, 115))	('ITGA11', 'Gene', '22801', (70, 76))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('FEZF1', 'Gene', (59, 64))	('AS1', 'Gene', '5729', (65, 68))	('miR-516b-5p', 'Var', (81, 92))	('ITGA11', 'Gene', (70, 76))
5504	33174014	Kaplan-Meier analysis demonstrated that high FEZF1-AS1 expression was significantly associated with a poor OS rate (P=0.045; Fig.	('high', 'Var', (40, 44))	('poor OS rate', 'CPA', (102, 114))	('FEZF1', 'Gene', (45, 50))	('FEZF1', 'Gene', '389549', (45, 50))	('AS1', 'Gene', '5729', (51, 54))	('AS1', 'Gene', (51, 54))
5511	33174014	Additionally, it was observed that FEZF1-AS1 silencing induced G2/M arrest (Figs.	('silencing', 'Var', (45, 54))	('M arrest', 'Disease', (66, 74))	('M arrest', 'Disease', 'MESH:D006323', (66, 74))	('FEZF1', 'Gene', '389549', (35, 40))	('AS1', 'Gene', '5729', (41, 44))	('AS1', 'Gene', (41, 44))	('induced', 'Reg', (55, 62))	('FEZF1', 'Gene', (35, 40))
5514	33174014	3A and B, seven m6A modified sites were predicted, suggesting that FEZF1-AS1 expression may be regulated by m6A modification.	('AS1', 'Gene', '5729', (73, 76))	('m6A', 'Var', (108, 111))	('expression', 'MPA', (77, 87))	('AS1', 'Gene', (73, 76))	('FEZF1', 'Gene', '389549', (67, 72))	('regulated', 'Reg', (95, 104))	('FEZF1', 'Gene', (67, 72))
5521	33174014	The present results suggested that the high expression levels of FEZF1-AS1 in NSCLC cells was positively regulated by m6A methylation.	('m6A methylation', 'Var', (118, 133))	('NSCLC', 'Disease', 'MESH:D002289', (78, 83))	('AS1', 'Gene', '5729', (71, 74))	('AS1', 'Gene', (71, 74))	('methylation', 'Var', (122, 133))	('FEZF1', 'Gene', '389549', (65, 70))	('NSCLC', 'Phenotype', 'HP:0030358', (78, 83))	('NSCLC', 'Disease', (78, 83))	('FEZF1', 'Gene', (65, 70))	('expression levels', 'MPA', (44, 61))
5527	33174014	Following the knockdown of FEZF1-AS1, ITGA11 was the most downregulated mRNA, as revealed using RT-qPCR (Fig.	('mRNA', 'MPA', (72, 76))	('ITGA11', 'Gene', '22801', (38, 44))	('AS1', 'Gene', '5729', (33, 36))	('AS1', 'Gene', (33, 36))	('downregulated', 'NegReg', (58, 71))	('FEZF1', 'Gene', '389549', (27, 32))	('ITGA11', 'Gene', (38, 44))	('knockdown', 'Var', (14, 23))	('FEZF1', 'Gene', (27, 32))
5528	33174014	Compared with BEAS-2B cells, the expression levels of ITGA11 were significantly increased in H358, H1299, H520 and SK-MES-1 cells (Fig.	('SK-MES-1', 'CellLine', 'CVCL:0630', (115, 123))	('increased', 'PosReg', (80, 89))	('ITGA11', 'Gene', (54, 60))	('H520', 'Var', (106, 110))	('BEAS-2B', 'CellLine', 'CVCL:0168', (14, 21))	('expression levels', 'MPA', (33, 50))	('H1299', 'CellLine', 'CVCL:0060', (99, 104))	('H358', 'CellLine', 'CVCL:1559', (93, 97))	('H520', 'CellLine', 'CVCL:1566', (106, 110))	('ITGA11', 'Gene', '22801', (54, 60))
5529	33174014	Additionally, western blot analysis confirmed that ITGA11 protein levels were decreased following FEZF1-AS1 knockdown in H1299 and H520 cells (Fig.	('ITGA11', 'Gene', (51, 57))	('knockdown', 'Var', (108, 117))	('AS1', 'Gene', '5729', (104, 107))	('H1299', 'CellLine', 'CVCL:0060', (121, 126))	('FEZF1', 'Gene', '389549', (98, 103))	('H520', 'CellLine', 'CVCL:1566', (131, 135))	('FEZF1', 'Gene', (98, 103))	('ITGA11', 'Gene', '22801', (51, 57))	('decreased', 'NegReg', (78, 87))	('AS1', 'Gene', (104, 107))
5533	33174014	Based on the present ceRNA networks results and gene ontology analysis in the GSE137445 array dataset, three miRNAs (miR-486, miR-516b-5p and miR-584-3p) binding to both FEZF1-AS1 and ITGA11 were identified.	('AS1', 'Gene', '5729', (176, 179))	('AS1', 'Gene', (176, 179))	('binding', 'Interaction', (154, 161))	('miR-486', 'Gene', '619554', (117, 124))	('miR-584', 'Gene', (142, 149))	('FEZF1', 'Gene', (170, 175))	('miR-516b-5p', 'Var', (126, 137))	('ITGA11', 'Gene', '22801', (184, 190))	('miR-516b-5p', 'Chemical', '-', (126, 137))	('miR-486', 'Gene', (117, 124))	('miR-584', 'Gene', '693169', (142, 149))	('FEZF1', 'Gene', '389549', (170, 175))	('ITGA11', 'Gene', (184, 190))
5534	33174014	Furthermore, three other miRNAs (miR-126a, miR-29b and miR-145) targeting ITGA11 were selected based on previous reports.	('miR-145', 'Gene', '406937', (55, 62))	('miR-29b', 'Gene', (43, 50))	('ITGA11', 'Gene', (74, 80))	('miR-126a', 'Var', (33, 41))	('miR-29b', 'Gene', '407024', (43, 50))	('miR-145', 'Gene', (55, 62))	('ITGA11', 'Gene', '22801', (74, 80))
5535	33174014	After miRNA overexpression, miR-516b-5p significantly downregulated FEZF1-AS1 expression (Fig.	('expression', 'MPA', (78, 88))	('AS1', 'Gene', '5729', (74, 77))	('AS1', 'Gene', (74, 77))	('FEZF1', 'Gene', '389549', (68, 73))	('miR-516b-5p', 'Var', (28, 39))	('FEZF1', 'Gene', (68, 73))	('miR-516b-5p', 'Chemical', '-', (28, 39))	('downregulated', 'NegReg', (54, 67))
5536	33174014	Additionally, it was verified that ITGA11 expression was negatively regulated by miR-516b-5p at both the transcriptional (Fig.	('miR-516b-5p', 'Chemical', '-', (81, 92))	('ITGA11', 'Gene', '22801', (35, 41))	('expression', 'MPA', (42, 52))	('negatively', 'NegReg', (57, 67))	('ITGA11', 'Gene', (35, 41))	('miR-516b-5p', 'Var', (81, 92))
5538	33174014	Compared with BEAS-2B cells, the expression levels of miR-516b-5p were significantly decreased in H358, H1299, H520, A549 and SK-MES-1 cells (Fig.	('decreased', 'NegReg', (85, 94))	('H358', 'CellLine', 'CVCL:1559', (98, 102))	('H520', 'CellLine', 'CVCL:1566', (111, 115))	('miR-516b-5p', 'Chemical', '-', (54, 65))	('H1299', 'CellLine', 'CVCL:0060', (104, 109))	('A549', 'CellLine', 'CVCL:0023', (117, 121))	('BEAS-2B', 'CellLine', 'CVCL:0168', (14, 21))	('expression levels', 'MPA', (33, 50))	('SK-MES-1', 'CellLine', 'CVCL:0630', (126, 134))	('H1299', 'Var', (104, 109))	('miR-516b-5p', 'Var', (54, 65))
5539	33174014	Subsequently, it was examined whether miR-516b-5p-mediated ITGA11 regulation occurred through direct targeting of miRNA-binding sites in the ITGA11 sequence.	('ITGA11', 'Gene', '22801', (141, 147))	('ITGA11', 'Gene', (59, 65))	('ITGA11', 'Gene', '22801', (59, 65))	('regulation', 'MPA', (66, 76))	('miR-516b-5p', 'Chemical', '-', (38, 49))	('ITGA11', 'Gene', (141, 147))	('miR-516b-5p-mediated', 'Var', (38, 58))	('miRNA-binding', 'Protein', (114, 127))
5541	33174014	ITGA11 was subcloned into the pmirGLO dual-luciferase reporter vector, and luciferase assays were performed in H1299 cells by inducing miR-516b-5p overexpression using miR-516b-5p mimics.	('miR-516b-5p', 'Chemical', '-', (135, 146))	('inducing', 'Reg', (126, 134))	('H1299', 'CellLine', 'CVCL:0060', (111, 116))	('ITGA11', 'Gene', '22801', (0, 6))	('miR-516b-5p', 'Chemical', '-', (168, 179))	('overexpression', 'PosReg', (147, 161))	('ITGA11', 'Gene', (0, 6))	('miR-516b-5p', 'Var', (135, 146))
5542	33174014	5F, co-transfection with pmirGLO-ITGA11-WT and miR-516b-5p mimics demonstrated a significant decrease in luciferase reporter activity compared with the negative control (NC) group (P<0.05).	('luciferase', 'Enzyme', (105, 115))	('ITGA11', 'Gene', (33, 39))	('miR-516b-5p', 'Chemical', '-', (47, 58))	('ITGA11', 'Gene', '22801', (33, 39))	('decrease', 'NegReg', (93, 101))	('miR-516b-5p mimics', 'Var', (47, 65))
5543	33174014	This repressive effect was abolished by directed mutagenesis of the miR-516b-5p binding seed region in ITGA11.	('ITGA11', 'Gene', '22801', (103, 109))	('miR-516b-5p', 'Chemical', '-', (68, 79))	('abolished', 'NegReg', (27, 36))	('ITGA11', 'Gene', (103, 109))	('miR-516b-5p', 'Var', (68, 79))
5545	33174014	For the rescue assay, FEZF1-AS1 and miR-516b-5p were overexpressed either alone or together using transfection.	('AS1', 'Gene', '5729', (28, 31))	('FEZF1', 'Gene', '389549', (22, 27))	('miR-516b-5p', 'Chemical', '-', (36, 47))	('FEZF1', 'Gene', (22, 27))	('AS1', 'Gene', (28, 31))	('miR-516b-5p', 'Var', (36, 47))
5546	33174014	Compared with the NC group, the results revealed that overexpression of miR-516b markedly suppressed ITGA11 expression, whereas overexpression of FEZF1-AS1 partly abolished the silencing effect of miR-516b-5p on ITGA11, suggesting that ITGA11 was regulated by miR-516b-5p and FEZF1-AS1 (Fig.	('AS1', 'Gene', '5729', (282, 285))	('FEZF1', 'Gene', (146, 151))	('ITGA11', 'Gene', '22801', (212, 218))	('miR-516b', 'Var', (72, 80))	('ITGA11', 'Gene', '22801', (101, 107))	('FEZF1', 'Gene', '389549', (276, 281))	('AS1', 'Gene', '5729', (152, 155))	('FEZF1', 'Gene', (276, 281))	('AS1', 'Gene', (282, 285))	('miR-516b-5p', 'Chemical', '-', (197, 208))	('miR-516b', 'Chemical', '-', (72, 80))	('miR-516b-5p', 'Chemical', '-', (260, 271))	('ITGA11', 'Gene', (236, 242))	('miR-516b', 'Chemical', '-', (197, 205))	('ITGA11', 'Gene', (212, 218))	('FEZF1', 'Gene', '389549', (146, 151))	('AS1', 'Gene', (152, 155))	('ITGA11', 'Gene', (101, 107))	('suppressed', 'NegReg', (90, 100))	('miR-516b', 'Chemical', '-', (260, 268))	('expression', 'MPA', (108, 118))	('ITGA11', 'Gene', '22801', (236, 242))
5553	33174014	Transwell assays revealed that the knockdown of ITGA11 significantly decreased the migratory and invasive abilities of NSCLC cells (Fig.	('NSCLC', 'Disease', 'MESH:D002289', (119, 124))	('knockdown', 'Var', (35, 44))	('ITGA11', 'Gene', '22801', (48, 54))	('decreased', 'NegReg', (69, 78))	('NSCLC', 'Phenotype', 'HP:0030358', (119, 124))	('ITGA11', 'Gene', (48, 54))	('NSCLC', 'Disease', (119, 124))
5555	33174014	Compared with surrounding healthy tissues, miR-516b-5p expression was significantly inhibited in tumor tissues compared with in normal tissues (Fig.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('miR-516b-5p', 'Chemical', '-', (43, 54))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumor', 'Disease', (97, 102))	('miR-516b-5p', 'Var', (43, 54))	('inhibited', 'NegReg', (84, 93))
5557	33174014	Smoking history (P=0.014) and tumor size (P=0.009) were associated with miR-516b-5p expression using a chi2 test in patients with NSCLC (Table IV).	('NSCLC', 'Disease', 'MESH:D002289', (130, 135))	('patients', 'Species', '9606', (116, 124))	('NSCLC', 'Phenotype', 'HP:0030358', (130, 135))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('miR-516b-5p expression', 'Var', (72, 94))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('miR-516b-5p', 'Chemical', '-', (72, 83))	('NSCLC', 'Disease', (130, 135))	('tumor', 'Disease', (30, 35))
5559	33174014	The CCK-8 assay revealed that overexpression of miR-516b-5p significantly inhibited NSCLC cell proliferation after >72 h (Fig.	('inhibited', 'NegReg', (74, 83))	('NSCLC', 'Phenotype', 'HP:0030358', (84, 89))	('overexpression', 'PosReg', (30, 44))	('miR-516b-5p', 'Var', (48, 59))	('NSCLC', 'Disease', (84, 89))	('NSCLC', 'Disease', 'MESH:D002289', (84, 89))	('miR-516b-5p', 'Chemical', '-', (48, 59))
5560	33174014	Additionally, in the Transwell assay, the migratory and invasive abilities of tumor cells were inhibited in the miR-516b-5p mimic group (Fig.	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('inhibited', 'NegReg', (95, 104))	('miR-516b-5p', 'Chemical', '-', (112, 123))	('miR-516b-5p mimic', 'Var', (112, 129))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Disease', (78, 83))
5561	33174014	The current data indicated that inhibiting ITGA11 or overexpressing miR-516b-5p inhibited cell proliferation and invasion in NSCLC.	('ITGA11', 'Gene', (43, 49))	('NSCLC', 'Disease', (125, 130))	('miR-516b-5p', 'Chemical', '-', (68, 79))	('overexpressing', 'PosReg', (53, 67))	('cell proliferation', 'CPA', (90, 108))	('NSCLC', 'Disease', 'MESH:D002289', (125, 130))	('inhibiting', 'Var', (32, 42))	('ITGA11', 'Gene', '22801', (43, 49))	('NSCLC', 'Phenotype', 'HP:0030358', (125, 130))	('inhibited', 'NegReg', (80, 89))	('miR-516b-5p', 'Var', (68, 79))
5564	33174014	In various types of cancer, FEZF1-AS1 expression in cancer tissues is significantly higher compared with that in normal tissues, and high FEZF1-AS1 expression indicates a poor survival in patients with colon, gastric and cervical cancer.	('cancer', 'Disease', 'MESH:D009369', (20, 26))	('poor', 'NegReg', (171, 175))	('patients', 'Species', '9606', (188, 196))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('AS1', 'Gene', '5729', (34, 37))	('higher', 'PosReg', (84, 90))	('AS1', 'Gene', (144, 147))	('high', 'Var', (133, 137))	('colon', 'Disease', (202, 207))	('cancer', 'Disease', (230, 236))	('AS1', 'Gene', '5729', (144, 147))	('gastric and cervical cancer', 'Disease', 'MESH:D013274', (209, 236))	('expression', 'MPA', (38, 48))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('FEZF1', 'Gene', '389549', (28, 33))	('FEZF1', 'Gene', '389549', (138, 143))	('cancer', 'Disease', (20, 26))	('cancer', 'Disease', (52, 58))	('AS1', 'Gene', (34, 37))	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (230, 236))	('expression', 'MPA', (148, 158))	('FEZF1', 'Gene', (28, 33))	('FEZF1', 'Gene', (138, 143))
5571	33174014	In the present study, knockdown of 'readers' (METTL3 and METTL14) and 'writers' (YTHDF1 and YTHDF2) resulted in the decrease of FEZF1-AS1 expression.	('METTL14', 'Gene', '57721', (57, 64))	('METTL14', 'Gene', (57, 64))	('YTHDF2', 'Gene', (92, 98))	('FEZF1', 'Gene', (128, 133))	('YTHDF1', 'Gene', '54915', (81, 87))	('decrease', 'NegReg', (116, 124))	('knockdown', 'Var', (22, 31))	('YTHDF1', 'Gene', (81, 87))	('AS1', 'Gene', '5729', (134, 137))	('expression', 'MPA', (138, 148))	('AS1', 'Gene', (134, 137))	('METTL3', 'Gene', '56339', (46, 52))	('YTHDF2', 'Gene', '51441', (92, 98))	('METTL3', 'Gene', (46, 52))	('FEZF1', 'Gene', '389549', (128, 133))
5574	33174014	The current results demonstrated that m6A modification may have an important regulatory effect on FEZF1-AS1 expression.	('m6A', 'Var', (38, 41))	('AS1', 'Gene', '5729', (104, 107))	('FEZF1', 'Gene', '389549', (98, 103))	('regulatory', 'MPA', (77, 87))	('FEZF1', 'Gene', (98, 103))	('expression', 'MPA', (108, 118))	('AS1', 'Gene', (104, 107))
5578	33174014	In lung adenocarcinoma A549, H460 and H520 cell lines, tumor growth was significantly higher in A549+WT, compared with A549+Knockout (KO) tumors.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Disease', (138, 143))	('A549', 'CellLine', 'CVCL:0023', (96, 100))	('tumors', 'Disease', 'MESH:D009369', (138, 144))	('higher', 'PosReg', (86, 92))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('H460', 'CellLine', 'CVCL:0459', (29, 33))	('A549', 'CellLine', 'CVCL:0023', (119, 123))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('A549', 'CellLine', 'CVCL:0023', (23, 27))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('A549+WT', 'Var', (96, 103))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (3, 22))	('lung adenocarcinoma A549', 'Disease', (3, 27))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('lung adenocarcinoma A549', 'Disease', 'MESH:D000077192', (3, 27))	('carcinoma', 'Phenotype', 'HP:0030731', (13, 22))	('H520', 'CellLine', 'CVCL:1566', (38, 42))	('tumor', 'Disease', (55, 60))	('tumors', 'Disease', (138, 144))
5582	33174014	miR-516b-5p was selected and validated in the present study as a possible binding miRNA to both FEZF1-AS1 and ITGA11.	('ITGA11', 'Gene', (110, 116))	('miR-516b-5p', 'Var', (0, 11))	('ITGA11', 'Gene', '22801', (110, 116))	('AS1', 'Gene', (102, 105))	('miR-516b-5p', 'Chemical', '-', (0, 11))	('FEZF1', 'Gene', '389549', (96, 101))	('AS1', 'Gene', '5729', (102, 105))	('FEZF1', 'Gene', (96, 101))
5583	33174014	Low miR-516 expression can significantly improve OS in patients with lung squamous cell carcinoma.	('Low miR-516 expression', 'Var', (0, 22))	('miR-516', 'Chemical', '-', (4, 11))	('improve', 'PosReg', (41, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (74, 97))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (69, 97))	('lung squamous cell carcinoma', 'Disease', (69, 97))	('patients', 'Species', '9606', (55, 63))
5584	33174014	In the present study, miR-516b-5p expression in NSCLC tissues was lower compared with in non-neoplastic tissues, and the proliferation, migration and invasion of cells was inhibited following miR-516b-5p upregulation.	('miR-516b-5p', 'Var', (192, 203))	('NSCLC', 'Disease', (48, 53))	('expression', 'MPA', (34, 44))	('miR-516b-5p', 'Chemical', '-', (22, 33))	('NSCLC', 'Phenotype', 'HP:0030358', (48, 53))	('proliferation', 'CPA', (121, 134))	('NSCLC', 'Disease', 'MESH:D002289', (48, 53))	('upregulation', 'PosReg', (204, 216))	('lower', 'NegReg', (66, 71))	('miR-516b-5p', 'Chemical', '-', (192, 203))	('invasion of cells', 'CPA', (150, 167))	('inhibited', 'NegReg', (172, 181))	('miR-516b-5p', 'Gene', (22, 33))
5585	33174014	In the present study, both ITGA11 and miR-516b-5p were involved in cell proliferation, migration and invasion, which is consistent with the biological role in tumor progression of FEZF1-AS1.	('migration', 'CPA', (87, 96))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('AS1', 'Gene', '5729', (186, 189))	('AS1', 'Gene', (186, 189))	('involved', 'Reg', (55, 63))	('ITGA11', 'Gene', '22801', (27, 33))	('miR-516b-5p', 'Chemical', '-', (38, 49))	('tumor', 'Disease', (159, 164))	('invasion', 'CPA', (101, 109))	('FEZF1', 'Gene', '389549', (180, 185))	('cell proliferation', 'CPA', (67, 85))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('ITGA11', 'Gene', (27, 33))	('FEZF1', 'Gene', (180, 185))	('miR-516b-5p', 'Var', (38, 49))
5587	33174014	Additionally, ITGA11 expression was decreased following miR-516b overexpression.	('miR-516b', 'Var', (56, 64))	('ITGA11', 'Gene', '22801', (14, 20))	('expression', 'MPA', (21, 31))	('decreased', 'NegReg', (36, 45))	('ITGA11', 'Gene', (14, 20))	('miR-516b', 'Chemical', '-', (56, 64))
5588	33174014	Therefore, both FEZF1-AS1 and miR-516b may affect ITGA11 expression.	('expression', 'MPA', (57, 67))	('FEZF1', 'Gene', '389549', (16, 21))	('AS1', 'Gene', '5729', (22, 25))	('AS1', 'Gene', (22, 25))	('ITGA11', 'Gene', (50, 56))	('FEZF1', 'Gene', (16, 21))	('affect', 'Reg', (43, 49))	('miR-516b', 'Chemical', '-', (30, 38))	('ITGA11', 'Gene', '22801', (50, 56))	('miR-516b', 'Var', (30, 38))
5589	33174014	Through RIP and RNA pull-down assays, together with the effects of miR-516b-5p upregulation on FEZF1-AS1, it was concluded that miR-516b-5p and FEZF1-AS1 may share a binding site.	('RIP', 'Gene', (8, 11))	('AS1', 'Gene', '5729', (101, 104))	('AS1', 'Gene', (101, 104))	('miR-516b-5p', 'Chemical', '-', (67, 78))	('AS1', 'Gene', '5729', (150, 153))	('AS1', 'Gene', (150, 153))	('RIP', 'Gene', '3267', (8, 11))	('miR-516b-5p', 'Var', (128, 139))	('FEZF1', 'Gene', '389549', (95, 100))	('binding', 'Interaction', (166, 173))	('FEZF1', 'Gene', '389549', (144, 149))	('FEZF1', 'Gene', (95, 100))	('FEZF1', 'Gene', (144, 149))	('miR-516b-5p', 'Chemical', '-', (128, 139))
5590	33174014	Future studies should explore the effects of silencing both ITGA11 and miR-516b-5p, or of overexpressing FEZF1-AS1 and silencing ITGA11, and to observe phenotypic changes in proliferation and invasion.	('FEZF1', 'Gene', '389549', (105, 110))	('silencing', 'Var', (45, 54))	('miR-516b-5p', 'Chemical', '-', (71, 82))	('ITGA11', 'Gene', '22801', (129, 135))	('AS1', 'Gene', '5729', (111, 114))	('AS1', 'Gene', (111, 114))	('ITGA11', 'Gene', (60, 66))	('invasion', 'CPA', (192, 200))	('FEZF1', 'Gene', (105, 110))	('ITGA11', 'Gene', (129, 135))	('miR-516b-5p', 'Gene', (71, 82))	('silencing', 'Var', (119, 128))	('proliferation', 'CPA', (174, 187))	('ITGA11', 'Gene', '22801', (60, 66))
5625	30221145	SCC4, SCC15, SCC25, SCC84, and SCC92 are from the oral cavity, while SCC19 and SCC99 are from the oropharynx (Table 1).	('SCC4', 'Gene', '23383', (0, 4))	('SCC92', 'Gene', (31, 36))	('SCC4', 'Gene', (0, 4))	('SCC84', 'Var', (20, 25))
5651	30221145	GM-CSF and TNF-alpha, both inflammatory biomarkers, were produced by SCC92 at significantly higher levels than all of the other cell lines, while SCC4 and SCC99 produced the lowest amounts of GM-CSF and TNF-alpha (Figure 2).	('TNF-alpha', 'Gene', '7124', (11, 20))	('TNF-alpha', 'Gene', '7124', (203, 212))	('higher', 'PosReg', (92, 98))	('SCC92', 'Var', (69, 74))	('F', 'Chemical', 'MESH:D005461', (5, 6))	('TNF-alpha', 'Gene', (203, 212))	('F', 'Chemical', 'MESH:D005461', (13, 14))	('GM-CSF', 'Gene', (192, 198))	('GM-CSF', 'Gene', (0, 6))	('TNF-alpha', 'Gene', (11, 20))	('GM-CSF', 'Gene', '1437', (192, 198))	('SCC4', 'Gene', '23383', (146, 150))	('GM-CSF', 'Gene', '1437', (0, 6))	('SCC4', 'Gene', (146, 150))	('F', 'Chemical', 'MESH:D005461', (214, 215))	('F', 'Chemical', 'MESH:D005461', (205, 206))	('F', 'Chemical', 'MESH:D005461', (197, 198))
5671	30221145	Several MMPs, including MMP1 and MMP9, can cleave pro-TNF-alpha to activate this proinflammatory cytokine.	('MMP1', 'Gene', '4312', (24, 28))	('TNF-alpha', 'Gene', '7124', (54, 63))	('MMP9', 'Gene', '4318', (33, 37))	('MMP9', 'Gene', (33, 37))	('proinflammatory cytokine', 'MPA', (81, 105))	('MMP1', 'Gene', (24, 28))	('TNF-alpha', 'Gene', (54, 63))	('cleave', 'Var', (43, 49))	('activate', 'PosReg', (67, 75))
5682	30221145	High expression of IL-6 in OSCC cells has been suggested as a predictive factor of poor response to chemoradiotherapy.	('OSCC', 'CellLine', 'CVCL:L894', (27, 31))	('IL-6', 'Gene', (19, 23))	('High', 'Var', (0, 4))	('IL-6', 'Gene', '3569', (19, 23))
5694	30221145	Typically, HPV+ HNSCC has a better survival rate than HPV- HNSCC.	('HPV', 'Species', '10566', (11, 14))	('HNSCC', 'Phenotype', 'HP:0012288', (16, 21))	('survival rate', 'CPA', (35, 48))	('HPV', 'Species', '10566', (54, 57))	('HNSCC', 'Phenotype', 'HP:0012288', (59, 64))	('HPV+ HNSCC', 'Var', (11, 21))
5701	30221145	This is because the E7 HPV oncogene protein will induce p16Ink4a expression.	('E7 HPV', 'Var', (20, 26))	('p16Ink4a', 'Gene', (56, 64))	('induce', 'PosReg', (49, 55))	('p16Ink4a', 'Gene', '1029', (56, 64))	('HPV', 'Species', '10566', (23, 26))
5714	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))
5726	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))
5729	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))
5730	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))
5733	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))	('Hodgkin lymphoma', 'Disease', 'MESH:D006689', (49, 65))	('leukemia', 'Disease', 'MESH:D007938', (70, 78))	('leukemia', 'Phenotype', 'HP:0001909', (70, 78))	('Hodgkin lymphoma', 'Phenotype', 'HP:0012189', (49, 65))
5742	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))
5746	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))
5752	29719615	siRNA based knockdown of SYK significantly decreased (p<0.002) invasion/migration capability of TE11 cells (Figure 4A, 4B).	('knockdown', 'Var', (12, 21))	('SYK', 'Gene', (25, 28))	('TE11', 'Chemical', '-', (96, 100))	('decreased', 'NegReg', (43, 52))	('invasion/migration capability of TE11 cells', 'CPA', (63, 106))
5755	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))
5767	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))
5769	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))
5787	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))
5804	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))
5861	27812105	The Rise of FXR1: Escaping Cellular Senescence in Head and Neck Squamous Cell Carcinoma Cellular senescence is a key tumor-suppressing mechanism in response to numerous cellular threats including oxidative stress, telomere loss, and oncogene activation.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('oncogene', 'CPA', (233, 241))	('Neck Squamous Cell Carcinoma', 'Disease', (59, 87))	('Neck Squamous Cell Carcinoma', 'Disease', 'MESH:D000077195', (59, 87))	('tumor', 'Disease', (117, 122))	('FXR1', 'Gene', '8087', (12, 16))	('oxidative stress', 'Phenotype', 'HP:0025464', (196, 212))	('telomere', 'Var', (214, 222))	('Head and Neck Squamous Cell Carcinoma', 'Phenotype', 'HP:0012288', (50, 87))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('FXR1', 'Gene', (12, 16))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (64, 87))	('Carcinoma', 'Phenotype', 'HP:0030731', (78, 87))
5864	27812105	Aside from its critical role in preventing cancer development, the senescence program also enhances the response to cancer therapy.	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('enhances', 'PosReg', (91, 99))	('cancer', 'Disease', (43, 49))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('senescence program', 'Var', (67, 85))
5872	27812105	have now revealed significant copy number amplification and mRNA overexpression of FXR1 in HNSCC by interrogating cancer genomics databases.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('FXR1', 'Gene', (83, 87))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('HNSCC', 'Disease', (91, 96))	('overexpression', 'PosReg', (65, 79))	('HNSCC', 'Phenotype', 'HP:0012288', (91, 96))	('copy number amplification', 'Var', (30, 55))	('cancer', 'Disease', (114, 120))
5873	27812105	Depletion of FXR1 in HNSCC cell lines caused G1 cell cycle arrest associated with features of cellular senescence, including senescence-associated beta-galactosidase activity and DNA damage foci.	('HNSCC', 'Phenotype', 'HP:0012288', (21, 26))	('FXR1', 'Gene', (13, 17))	('activity', 'MPA', (166, 174))	('G1 cell cycle arrest', 'CPA', (45, 65))	('Depletion', 'Var', (0, 9))	('beta-galactosidase', 'Gene', '2720', (147, 165))	('DNA', 'CPA', (179, 182))	('G1', 'CellLine', 'CVCL:1929', (45, 47))	('beta-galactosidase', 'Gene', (147, 165))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (48, 65))
5874	27812105	The cellular response triggered by FXR1 depletion stimulated p53 levels and activity as indicated by concomitant elevation of p21, a classical p53-target gene mediating senescence.	('p53', 'Gene', '7157', (143, 146))	('depletion', 'Var', (40, 49))	('activity', 'MPA', (76, 84))	('p21', 'Gene', '1026', (126, 129))	('elevation', 'PosReg', (113, 122))	('stimulated', 'PosReg', (50, 60))	('FXR1', 'Gene', (35, 39))	('cellular response', 'MPA', (4, 21))	('p53', 'Gene', '7157', (61, 64))	('p53', 'Gene', (61, 64))	('p53', 'Gene', (143, 146))	('p21', 'Gene', (126, 129))
5875	27812105	Using a p53-mutated HNSCC cell line, the authors demonstrated p53-dependent up-regulation of p21 upon FXR1 knockdown.	('knockdown', 'Var', (107, 116))	('p21', 'Gene', '1026', (93, 96))	('up-regulation', 'PosReg', (76, 89))	('p53', 'Gene', (8, 11))	('HNSCC', 'Phenotype', 'HP:0012288', (20, 25))	('p53', 'Gene', '7157', (8, 11))	('p21', 'Gene', (93, 96))	('p53', 'Gene', (62, 65))	('p53', 'Gene', '7157', (62, 65))
5879	27812105	Ultimately, the decreased TERC levels upon silencing of FXR1 interfered with telomerase activity, thus suggesting a role for FXR1 in acquisition of cell immortality, a critical prerequisite of neoplastic transformation.	('cell immortality', 'CPA', (148, 164))	('TERC', 'Gene', (26, 30))	('telomerase activity', 'MPA', (77, 96))	('silencing', 'Var', (43, 52))	('TERC', 'Gene', '7012', (26, 30))	('interfered', 'NegReg', (61, 71))	('FXR1', 'Gene', (56, 60))	('decreased', 'NegReg', (16, 25))
5880	27812105	The authors also demonstrated that depletion of p21 or ectopic expression of TERC allows bypass of senescence subsequent to loss of FXR1, further supporting their observation regarding FXR1-dependent regulation of p21 and TERC.	('p21', 'Gene', '1026', (48, 51))	('TERC', 'Gene', (77, 81))	('TERC', 'Gene', (222, 226))	('loss', 'Var', (124, 128))	('ectopic expression', 'MPA', (55, 73))	('p21', 'Gene', (48, 51))	('FXR1', 'Gene', (132, 136))	('TERC', 'Gene', '7012', (77, 81))	('TERC', 'Gene', '7012', (222, 226))	('p21', 'Gene', '1026', (214, 217))	('p21', 'Gene', (214, 217))	('depletion', 'MPA', (35, 44))
5883	27812105	Also, further investigation of FXR1 amplification during HPV infection would provide additional clues as to whether FXR1 amplification and E6/E7 HPV proteins are mutually exclusive or cooperate to promote HNSCC.	('HPV infection', 'Disease', (57, 70))	('FXR1', 'Gene', (116, 120))	('HPV', 'Species', '10566', (145, 148))	('HNSCC', 'Disease', (205, 210))	('HPV infection', 'Disease', 'MESH:D030361', (57, 70))	('HNSCC', 'Phenotype', 'HP:0012288', (205, 210))	('E6/E7', 'Var', (139, 144))	('HPV', 'Species', '10566', (57, 60))	('promote', 'PosReg', (197, 204))
5886	27812105	In addition to its amplification in lung, breast, and ovarian as well as head and neck cancers, FXR1 was shown to be down-regulated in other human pathologies such as facioscapulohumeral muscular dystrophy, an inherited myopathy.	('FXR1', 'Gene', (96, 100))	('head and neck cancers', 'Phenotype', 'HP:0012288', (73, 94))	('muscular dystrophy', 'Phenotype', 'HP:0003560', (187, 205))	('amplification', 'Var', (19, 32))	('myopathy', 'Phenotype', 'HP:0003198', (220, 228))	('myopathy', 'Disease', (220, 228))	('down-regulated', 'NegReg', (117, 131))	('cancers', 'Phenotype', 'HP:0002664', (87, 94))	('neck cancers', 'Disease', (82, 94))	('neck cancers', 'Disease', 'MESH:D006258', (82, 94))	('breast', 'Disease', (42, 48))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('facioscapulohumeral muscular dystrophy', 'Phenotype', 'HP:0008970', (167, 205))	('human', 'Species', '9606', (141, 146))	('lung', 'Disease', (36, 40))	('facioscapulohumeral muscular dystrophy', 'Disease', 'MESH:D020391', (167, 205))	('facioscapulohumeral muscular dystrophy', 'Disease', (167, 205))	('ovarian', 'Disease', (54, 61))	('myopathy', 'Disease', 'MESH:D009135', (220, 228))	('ovarian', 'Disease', 'MESH:D010051', (54, 61))
5889	27812105	demonstrated that loss of FXR1 not only leads to senescence in cancer cells, but also in normal cells such as mouse embryonic fibroblasts.	('FXR1', 'Gene', (26, 30))	('loss', 'Var', (18, 22))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('senescence', 'MPA', (49, 59))	('mouse', 'Species', '10090', (110, 115))	('leads to', 'Reg', (40, 48))	('cancer', 'Disease', (63, 69))
5962	29321718	A novel Notch1 missense mutation (C1133Y) in the Abruptex domain exhibits enhanced proliferation and invasion in oral squamous cell carcinoma Notch1 has been regarded as a fundamental regulator in tissue differentiation and stem cell properties.	('proliferation', 'CPA', (83, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('Abruptex', 'Gene', '31293', (49, 57))	('oral squamous cell carcinoma', 'Disease', (113, 141))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (118, 141))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (113, 141))	('Notch1', 'Gene', (8, 14))	('Notch1', 'Gene', (142, 148))	('C1133Y', 'Mutation', 'p.C1133Y', (34, 40))	('Notch1', 'Gene', '4851', (8, 14))	('Notch1', 'Gene', '4851', (142, 148))	('Abruptex', 'Gene', (49, 57))	('C1133Y', 'Var', (34, 40))	('enhanced', 'PosReg', (74, 82))	('invasion', 'CPA', (101, 109))
5963	29321718	Recently, Notch1 mutations have been reported intensively both in solid tumors and in hematopoietic malignancies.	('solid tumors', 'Disease', 'MESH:D009369', (66, 78))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('Notch1', 'Gene', (10, 16))	('hematopoietic malignancies', 'Disease', (86, 112))	('Notch1', 'Gene', '4851', (10, 16))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('solid tumors', 'Disease', (66, 78))	('hematopoietic malignancies', 'Disease', 'MESH:D019337', (86, 112))	('reported', 'Reg', (37, 45))	('mutations', 'Var', (17, 26))
5964	29321718	Previously, we discovered several missense mutations in the Notch1 receptor in a Chinese population with oral squamous cell carcinoma (OSCC).	('Notch1', 'Gene', '4851', (60, 66))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (110, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('oral squamous cell carcinoma', 'Disease', (105, 133))	('missense mutations', 'Var', (34, 52))	('Notch1', 'Gene', (60, 66))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (105, 133))
5965	29321718	We selected a 'hotspot' mutation in the Abruptex domain (C1133Y).	('C1133Y', 'Var', (57, 63))	('Abruptex', 'Gene', '31293', (40, 48))	('Abruptex', 'Gene', (40, 48))	('C1133Y', 'Mutation', 'p.C1133Y', (57, 63))
5967	29321718	The effects of Notch1 C1133Y mutation were analyzed by Immunofluorescence staining and the expression of EGFR-PI3K/AKT signaling.	('AKT', 'Gene', '207', (115, 118))	('C1133Y', 'Mutation', 'p.C1133Y', (22, 28))	('EGFR', 'Gene', '1956', (105, 109))	('AKT', 'Gene', (115, 118))	('C1133Y', 'Var', (22, 28))	('EGFR', 'Gene', (105, 109))	('Notch1', 'Gene', (15, 21))	('Notch1', 'Gene', '4851', (15, 21))
5970	29321718	Importantly, the mutated Notch1 activated the EGFR-PI3K/AKT signaling pathway, which has been confirmed as an overwhelming modulator in OSCC.	('AKT', 'Gene', '207', (56, 59))	('Notch1', 'Gene', (25, 31))	('activated', 'PosReg', (32, 41))	('Notch1', 'Gene', '4851', (25, 31))	('EGFR', 'Gene', '1956', (46, 50))	('AKT', 'Gene', (56, 59))	('OSCC', 'Disease', (136, 140))	('EGFR', 'Gene', (46, 50))	('mutated', 'Var', (17, 24))
5971	29321718	Taken together, our findings revealed for the first time a novel Notch1 mutation that enhances proliferation and invasion in OSCC cell lines.	('invasion', 'CPA', (113, 121))	('Notch1', 'Gene', (65, 71))	('Notch1', 'Gene', '4851', (65, 71))	('mutation', 'Var', (72, 80))	('proliferation', 'CPA', (95, 108))	('enhances', 'PosReg', (86, 94))
5972	29321718	The Notch1 C1133Y mutation impairs the processing of notch1 protein and the critical links between the mutated Notch1 and the activated EGFR-PI3K/AKT signaling pathway.	('processing', 'MPA', (39, 49))	('Notch1', 'Gene', (4, 10))	('mutated', 'Var', (103, 110))	('AKT', 'Gene', '207', (146, 149))	('Notch1', 'Gene', (111, 117))	('C1133Y', 'Var', (11, 17))	('notch1', 'Gene', '4851', (53, 59))	('Notch1', 'Gene', '4851', (4, 10))	('links', 'Interaction', (85, 90))	('AKT', 'Gene', (146, 149))	('impairs', 'NegReg', (27, 34))	('Notch1', 'Gene', '4851', (111, 117))	('notch1', 'Gene', (53, 59))	('C1133Y', 'Mutation', 'p.C1133Y', (11, 17))	('EGFR', 'Gene', '1956', (136, 140))	('EGFR', 'Gene', (136, 140))
5976	29321718	Aberrations in Notch signaling or components of the signaling system underlie various human diseases including carcinogenesis.	('carcinogenesis', 'Disease', (111, 125))	('Notch', 'Gene', '31293', (15, 20))	('Aberrations', 'Var', (0, 11))	('human', 'Species', '9606', (86, 91))	('carcinogenesis', 'Disease', 'MESH:D063646', (111, 125))	('Notch', 'Gene', (15, 20))	('underlie', 'Reg', (69, 77))
5978	29321718	A multitude of mutations in Notch1 has been reported in cutaneous and lung squamous cell carcinoma in Caucasian populations, in OSCC in Japanese populations, and in OSCC in Chinese populations.	('Notch1', 'Gene', (28, 34))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (70, 98))	('Notch1', 'Gene', '4851', (28, 34))	('mutations', 'Var', (15, 24))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (70, 98))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (75, 98))	('lung squamous cell carcinoma', 'Disease', (70, 98))	('reported', 'Reg', (44, 52))
5979	29321718	Although many Notch1 mutations have been discovered by sequencing in numerous malignancies, subsequent functional studies are lacking.	('Notch1', 'Gene', (14, 20))	('Notch1', 'Gene', '4851', (14, 20))	('numerous malignancies', 'Disease', 'MESH:D009369', (69, 90))	('numerous malignancies', 'Disease', (69, 90))	('mutations', 'Var', (21, 30))
5980	29321718	As a result, the oncogenic role of specific Notch1 mutations in tumor progression is still speculative and requires further verification.	('Notch1', 'Gene', '4851', (44, 50))	('tumor', 'Disease', (64, 69))	('mutations', 'Var', (51, 60))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('Notch1', 'Gene', (44, 50))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
5993	29321718	In our previous study, we examined Notch1 mutational status in OSCC in Chinese patients and observed a mutation rate of 43% in the patient population with a poorer clinical outcome.	('Notch1', 'Gene', (35, 41))	('patient', 'Species', '9606', (79, 86))	('Notch1', 'Gene', '4851', (35, 41))	('patients', 'Species', '9606', (79, 87))	('patient', 'Species', '9606', (131, 138))	('mutational', 'Var', (42, 52))	('OSCC', 'Disease', (63, 67))
5994	29321718	We also identified the spectrum of Notch1 mutations.	('mutations', 'Var', (42, 51))	('Notch1', 'Gene', '4851', (35, 41))	('Notch1', 'Gene', (35, 41))
5995	29321718	One of the common domains with mutations is the Abruptex domain (amino acids 907-1143) in the EGF-like repeats (EGF-like repeats 24-29), which has also been observed by other researchers.	('mutations', 'Var', (31, 40))	('Abruptex', 'Gene', '31293', (48, 56))	('Abruptex', 'Gene', (48, 56))
5996	29321718	The Abruptex domain contains the most mutations (13 or 31%), including three nonsense mutations and a hotspot mutation (C1133Y).	('Abruptex', 'Gene', (4, 12))	('C1133Y', 'Mutation', 'p.C1133Y', (120, 126))	('C1133Y', 'Var', (120, 126))	('Abruptex', 'Gene', '31293', (4, 12))
5997	29321718	Because the Abruptex domain plays a role in suppressing cis-inhibition of Notch1 signaling, mutations in this region are thought to be gain-of-function.	('Notch1', 'Gene', '4851', (74, 80))	('Abruptex', 'Gene', (12, 20))	('suppressing', 'NegReg', (44, 55))	('mutations', 'Var', (92, 101))	('Abruptex', 'Gene', '31293', (12, 20))	('Notch1', 'Gene', (74, 80))	('cis-inhibition', 'MPA', (56, 70))
5998	29321718	In this study, we established full-length wild-type Notch1 (Notch1WT) and the Abruptex domain hotspot mutant Notch1 (Notch1C1133Y) vectors and discovered the functional effects of the mutation on Notch1 protein maturation and transportation.	('Notch1', 'Gene', '4851', (60, 66))	('Notch1C1133Y', 'Gene', (117, 129))	('Notch1', 'Gene', (196, 202))	('Notch1', 'Gene', '4851', (196, 202))	('Notch1', 'Gene', (52, 58))	('protein', 'Protein', (203, 210))	('Notch1', 'Gene', (117, 123))	('Abruptex', 'Gene', (78, 86))	('Notch1', 'Gene', '4851', (52, 58))	('Notch1', 'Gene', '4851', (117, 123))	('Notch1C1133Y', 'Gene', '4851', (117, 129))	('transportation', 'MPA', (226, 240))	('Abruptex', 'Gene', '31293', (78, 86))	('Notch1', 'Gene', (60, 66))	('Notch1', 'Gene', (109, 115))	('Notch1', 'Gene', '4851', (109, 115))	('mutation', 'Var', (184, 192))
6005	29321718	For transfection, cells (5 x 105 cells per well in 6-well plates) were cultured to 50% confluence in complete growth medium, and the medium was then replaced with serum-free medium for 12-16 h. The purified pcDNA3.1, pcDNA3.1-Notch1WT and pcDNA3.1-Notch1C1133Y plasmids were transfected into cells using Lipofectamine 2000 (Invitrogen) according to the manufacturer's instructions.	('Notch1C1133Y', 'Gene', (248, 260))	('Notch1', 'Gene', (226, 232))	('Notch1', 'Gene', '4851', (226, 232))	('Lipofectamine 2000', 'Chemical', 'MESH:C086724', (304, 322))	('Notch1', 'Gene', (248, 254))	('Notch1', 'Gene', '4851', (248, 254))	('pcDNA3.1', 'Var', (207, 215))	('Notch1C1133Y', 'Gene', '4851', (248, 260))
6022	29321718	Although missense mutations in Notch1 have previously been identified in OSCC patients in various populations, no functional analysis of any Notch1 alleles associated with OSCC has been elucidated.	('Notch1', 'Gene', (141, 147))	('identified', 'Reg', (59, 69))	('Notch1', 'Gene', (31, 37))	('Notch1', 'Gene', '4851', (31, 37))	('Notch1', 'Gene', '4851', (141, 147))	('patients', 'Species', '9606', (78, 86))	('associated', 'Reg', (156, 166))	('missense mutations', 'Var', (9, 27))	('OSCC', 'Disease', (73, 77))	('OSCC', 'Disease', (172, 176))
6023	29321718	Here, we selected the C1133Y hotspot mutation and assessed its association with Notch1 function in OSCC cell lines with varying levels of endogenous Notch1 expression.	('C1133Y', 'Mutation', 'p.C1133Y', (22, 28))	('Notch1', 'Gene', (149, 155))	('Notch1', 'Gene', (80, 86))	('Notch1', 'Gene', '4851', (80, 86))	('association', 'Interaction', (63, 74))	('function', 'MPA', (87, 95))	('C1133Y', 'Var', (22, 28))	('Notch1', 'Gene', '4851', (149, 155))
6032	29321718	When compared to the cells transfected with wild-type Notch1, cells transfected with the Notch1 C1133Y mutation induced HES1-2 mRNA down-regulated (Fig.	('Notch1', 'Gene', (89, 95))	('Notch1', 'Gene', '4851', (89, 95))	('HES1-2', 'Gene', (120, 126))	('HES1-2', 'Gene', '3280;54626', (120, 126))	('C1133Y', 'Var', (96, 102))	('mRNA', 'MPA', (127, 131))	('Notch1', 'Gene', (54, 60))	('down-regulated', 'NegReg', (132, 146))	('C1133Y', 'Mutation', 'p.C1133Y', (96, 102))	('Notch1', 'Gene', '4851', (54, 60))
6037	29321718	Taken together, these results strongly suggest that the C1133Y mutation in Notch1 inactivates the Notch1 signaling pathway.	('Notch1', 'Gene', (98, 104))	('Notch1', 'Gene', '4851', (98, 104))	('C1133Y', 'Var', (56, 62))	('inactivates', 'NegReg', (82, 93))	('C1133Y', 'Mutation', 'p.C1133Y', (56, 62))	('Notch1', 'Gene', (75, 81))	('Notch1', 'Gene', '4851', (75, 81))
6038	29321718	To test the effect of the Notch1 C1133Y mutation on cell proliferation, CCK-8 assays were utilized.	('Notch1', 'Gene', '4851', (26, 32))	('C1133Y', 'Var', (33, 39))	('C1133Y', 'Mutation', 'p.C1133Y', (33, 39))	('Notch1', 'Gene', (26, 32))
6046	29321718	In HN6 and HN13 transfected cells, no apparent discrepancy has been discovered between wild-type Notch1 and C1133Y-mutant Notch1.	('HN13', 'Gene', '100463500', (11, 15))	('HN13', 'Gene', (11, 15))	('Notch1', 'Gene', '4851', (122, 128))	('C1133Y-mutant', 'Var', (108, 121))	('HN6', 'Gene', (3, 6))	('Notch1', 'Gene', (97, 103))	('Notch1', 'Gene', '4851', (97, 103))	('Notch1', 'Gene', (122, 128))	('C1133Y', 'Mutation', 'p.C1133Y', (108, 114))	('HN6', 'Gene', '100463482', (3, 6))
6052	29321718	Notch1 mutations acting through a similar mechanism may also be involved in the EMT process of OSCC cells.	('involved', 'Reg', (64, 72))	('Notch1', 'Gene', (0, 6))	('Notch1', 'Gene', '4851', (0, 6))	('EMT process', 'CPA', (80, 91))	('OSCC', 'Disease', (95, 99))	('mutations', 'Var', (7, 16))
6055	29321718	An increased expression of mesenchymal markers (N-cadherin and Vimentin) and a decreased expression of the epithelial marker Beta-catenin were observed in Notch1C1133Y-transfected CAL27 and HN6 cells compared with Notch1WT-transfected cells, thus verifying its enhanced status of EMT induced by the C1133Y mutation.	('Vimentin', 'Gene', '7431', (63, 71))	('HN6', 'Gene', '100463482', (190, 193))	('C1133Y', 'Mutation', 'p.C1133Y', (299, 305))	('Vimentin', 'Gene', (63, 71))	('expression', 'MPA', (89, 99))	('decreased', 'NegReg', (79, 88))	('Beta-catenin', 'Gene', '1499', (125, 137))	('Notch1', 'Gene', (214, 220))	('Notch1', 'Gene', '4851', (214, 220))	('Notch1C1133Y', 'Gene', (155, 167))	('increased', 'PosReg', (3, 12))	('CAL27', 'CellLine', 'CVCL:1107', (180, 185))	('HN6', 'Gene', (190, 193))	('C1133Y', 'Var', (299, 305))	('N-cadherin', 'Gene', (48, 58))	('Notch1C1133Y', 'Gene', '4851', (155, 167))	('N-cadherin', 'Gene', '1000', (48, 58))	('C1133Y', 'Mutation', 'p.C1133Y', (161, 167))	('expression', 'MPA', (13, 23))	('Notch1', 'Gene', (155, 161))	('Notch1', 'Gene', '4851', (155, 161))	('Beta-catenin', 'Gene', (125, 137))
6058	29321718	To further elucidate the potential molecular mechanisms of EMT induced by the C1133Y mutation, we analyzed the gene expression levels of the classic EMT-inducers, Zeb (Zeb1 and Zeb2) and Snail (SNAI1 and SNAI2), by real-time qPCR.	('Snail', 'Gene', '6615', (187, 192))	('SNAI1', 'Gene', '6615', (194, 199))	('SNAI1', 'Gene', (194, 199))	('Zeb2', 'Gene', (177, 181))	('Zeb1', 'Gene', (168, 172))	('Zeb1', 'Gene', '6935', (168, 172))	('C1133Y', 'Mutation', 'p.C1133Y', (78, 84))	('Zeb2', 'Gene', '9839', (177, 181))	('Zeb', 'Gene', (177, 180))	('Zeb', 'Gene', (163, 166))	('Zeb', 'Gene', '9839', (168, 171))	('SNAI2', 'Gene', '6591', (204, 209))	('SNAI2', 'Gene', (204, 209))	('Zeb', 'Gene', '9839', (163, 166))	('Snail', 'Gene', (187, 192))	('C1133Y', 'Var', (78, 84))	('Zeb', 'Gene', '9839', (177, 180))	('Zeb', 'Gene', (168, 171))
6064	29321718	One possible explanation for this could be that the C1133Y mutation induces functionally inert S3-cleavage, releasing less Notch1 intracellular domain.	('S3-cleavage', 'Enzyme', (95, 106))	('Notch1', 'Gene', '4851', (123, 129))	('C1133Y', 'Var', (52, 58))	('less', 'NegReg', (118, 122))	('releasing', 'PosReg', (108, 117))	('C1133Y', 'Mutation', 'p.C1133Y', (52, 58))	('Notch1', 'Gene', (123, 129))
6066	29321718	As S1-cleavage in Golgi complex has been described as required for canonical ligand-dependent Notch1 signaling prior to its presentation to the cell surface, the 120 kD band represents Notch1 protein that has undergone S1- or S2-/S3-cleavage, while the 300 kD band is expected to be the full-length Notch1 protein that has not undergone S1-cleavage.	('S1-', 'Var', (219, 222))	('Notch1', 'Gene', (299, 305))	('Notch1', 'Gene', (185, 191))	('Notch1', 'Gene', '4851', (185, 191))	('Notch1', 'Gene', (94, 100))	('Notch1', 'Gene', '4851', (299, 305))	('Notch1', 'Gene', '4851', (94, 100))
6071	29321718	These data strongly imply that the C1133Y mutation causes reduced S1-cleavage.	('S1-cleavage', 'MPA', (66, 77))	('reduced', 'NegReg', (58, 65))	('C1133Y', 'Var', (35, 41))	('C1133Y', 'Mutation', 'p.C1133Y', (35, 41))
6073	29321718	Thus the observed reduced S1-cleavage caused by the Notch1 C1133Y mutation may be attributed to either retention of Notch1 protein in the endoplasmic reticulum (ER) and failure of transporting to the Golgi complex or the functional impairment of S1-cleavage in the Golgi complex.	('Notch1', 'Gene', '4851', (116, 122))	('Notch1', 'Gene', (52, 58))	('transporting', 'MPA', (180, 192))	('C1133Y', 'Var', (59, 65))	('reduced', 'NegReg', (18, 25))	('Notch1', 'Gene', '4851', (52, 58))	('C1133Y', 'Mutation', 'p.C1133Y', (59, 65))	('Notch1', 'Gene', (116, 122))	('S1-cleavage', 'MPA', (26, 37))	('protein', 'Protein', (123, 130))
6076	29321718	In contrast, Notch1 protein in C1133Y-mutated cells was mostly detected in the cytoplasm (Fig.	('detected', 'Reg', (63, 71))	('Notch1', 'Gene', '4851', (13, 19))	('protein', 'Protein', (20, 27))	('C1133Y-mutated', 'Var', (31, 45))	('C1133Y', 'Mutation', 'p.C1133Y', (31, 37))	('Notch1', 'Gene', (13, 19))
6079	29321718	Furthermore, we used a Golgi-specific marker (GM130-CY3) and an endoplasmic reticulum-specific marker (Calnexin-CY3) with immunofluorescence to define Notch1 protein localization.	('Notch1', 'Gene', (151, 157))	('CY3', 'Chemical', '-', (112, 115))	('Notch1', 'Gene', '4851', (151, 157))	('GM130-CY3', 'Chemical', '-', (46, 55))	('GM130-CY3', 'Var', (46, 55))	('Calnexin', 'Gene', (103, 111))	('Calnexin', 'Gene', '821', (103, 111))	('CY3', 'Chemical', '-', (52, 55))
6086	29321718	Overexpression of EGFR, which has been reported in up to 30% of solid tumors including 90% of OSCC, generally correlates with a poor prognosis and promotes tumor proliferation.	('solid tumors', 'Disease', (64, 76))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('OSCC', 'Disease', (94, 98))	('EGFR', 'Gene', '1956', (18, 22))	('promotes', 'PosReg', (147, 155))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('tumor', 'Disease', (70, 75))	('EGFR', 'Gene', (18, 22))	('solid tumors', 'Disease', 'MESH:D009369', (64, 76))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('Overexpression', 'Var', (0, 14))	('tumor', 'Disease', (156, 161))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
6090	29321718	The expression levels of p-EGFR, p-Stat5, p-Shc, and p-Gab1 decreased after cells were transfected with Notch1WT.	('expression levels', 'MPA', (4, 21))	('EGFR', 'Gene', '1956', (27, 31))	('decreased', 'NegReg', (60, 69))	('EGFR', 'Gene', (27, 31))	('p-Stat5', 'Var', (33, 40))	('Shc', 'Gene', (44, 47))	('Gab1', 'Gene', '2549', (55, 59))	('Notch1', 'Gene', (104, 110))	('Gab1', 'Gene', (55, 59))	('Notch1', 'Gene', '4851', (104, 110))	('Shc', 'Gene', '6464', (44, 47))
6096	29321718	In our previous study, we sequenced the entire coding region of the Notch1 gene in 51 OSCC tissues from a Chinese population and discovered that 13 (31%) mutations (including three nonsense mutations and a C1133Y hotspot mutation in three tumors) in the Abruptex region (Fig.	('tumors', 'Disease', (239, 245))	('tumors', 'Disease', 'MESH:D009369', (239, 245))	('tumors', 'Phenotype', 'HP:0002664', (239, 245))	('Abruptex', 'Gene', '31293', (254, 262))	('Notch1', 'Gene', '4851', (68, 74))	('C1133Y', 'Var', (206, 212))	('tumor', 'Phenotype', 'HP:0002664', (239, 244))	('mutations', 'Var', (154, 163))	('C1133Y', 'Mutation', 'p.C1133Y', (206, 212))	('Abruptex', 'Gene', (254, 262))	('Notch1', 'Gene', (68, 74))
6097	29321718	The mammalian Notch extracellular domain has 36 EGF repeats, and six of which (repeats 24-29) are detected by a series of Notch missense mutations in Drosophila, the called Abruptex domain.	('Notch', 'Gene', (122, 127))	('Drosophila', 'Species', '7227', (150, 160))	('Abruptex', 'Gene', (173, 181))	('Notch', 'Gene', (14, 19))	('Abruptex', 'Gene', '31293', (173, 181))	('Notch', 'Gene', '31293', (122, 127))	('missense mutations', 'Var', (128, 146))	('Notch', 'Gene', '31293', (14, 19))	('mammalian', 'Species', '9606', (4, 13))
6098	29321718	These mutations result in amino-acid substitutions in the Abruptex domain and induce phenotypes opposite to those characteristics of decreased Notch expression during Drosophila development.	('induce', 'Reg', (78, 84))	('amino-acid', 'Var', (26, 36))	('Notch', 'Gene', (143, 148))	('Abruptex', 'Gene', '31293', (58, 66))	('Drosophila', 'Species', '7227', (167, 177))	('result in', 'Reg', (16, 25))	('Notch', 'Gene', '31293', (143, 148))	('substitutions', 'Var', (37, 50))	('Abruptex', 'Gene', (58, 66))	('mutations', 'Var', (6, 15))
6103	29321718	Thus, the Abruptex domain may acts as a negative regulator of Notch signaling activation, and any missense mutation in this region may reverse the antagonistic effects on Notch signaling activation.	('Notch', 'Gene', (171, 176))	('Abruptex', 'Gene', '31293', (10, 18))	('Notch', 'Gene', (62, 67))	('Notch', 'Gene', '31293', (171, 176))	('Abruptex', 'Gene', (10, 18))	('activation', 'PosReg', (78, 88))	('Notch', 'Gene', '31293', (62, 67))	('missense mutation', 'Var', (98, 115))	('negative', 'NegReg', (40, 48))
6107	29321718	To detect the molecular mechanisms that may underlie the loss-of-function in Notch1 signaling through the C1133Y mutation, we examined Notch1 protein expression and localization.	('Notch1', 'Gene', '4851', (77, 83))	('C1133Y', 'Var', (106, 112))	('Notch1', 'Gene', (135, 141))	('examined', 'Reg', (126, 134))	('C1133Y', 'Mutation', 'p.C1133Y', (106, 112))	('Notch1', 'Gene', '4851', (135, 141))	('Notch1', 'Gene', (77, 83))
6110	29321718	These data may explain why the estimated gain-of-function mutation in Abruptex domain observed in transient cells adversely inactivated the Notch1 signaling in stable cells: the unexpected inactivation of Notch1 ligand-induced signaling was due to the retention or misfolding of Notch1 protein in the ER, which would lead to reduced transportation of full-length Notch1 protein from the ER to the Golgi complex for presumed S1-cleavage and ultimately presence on the cell surface, on which way the Notch1 signaling pathway was inactivated.	('transportation', 'MPA', (333, 347))	('Abruptex', 'Gene', (70, 78))	('Notch1', 'Gene', (279, 285))	('protein', 'Protein', (286, 293))	('mutation', 'Var', (58, 66))	('Notch1', 'Gene', '4851', (279, 285))	('reduced', 'NegReg', (325, 332))	('S1-cleavage', 'MPA', (424, 435))	('Abruptex', 'Gene', '31293', (70, 78))	('misfolding', 'Var', (265, 275))	('Notch1', 'Gene', (205, 211))	('Notch1', 'Gene', '4851', (205, 211))	('Notch1', 'Gene', (140, 146))	('Notch1', 'Gene', (363, 369))	('Notch1', 'Gene', '4851', (140, 146))	('Notch1', 'Gene', '4851', (363, 369))	('inactivation', 'NegReg', (189, 201))	('Notch1', 'Gene', (498, 504))	('Notch1', 'Gene', '4851', (498, 504))
6111	29321718	Previous evidence has suggested that missense mutations in EGF repeats, not in the Abruptex domain, can cause Notch1 protein retention or misfolding.	('misfolding', 'CPA', (138, 148))	('missense mutations', 'Var', (37, 55))	('EGF repeats', 'Gene', (59, 70))	('Abruptex', 'Gene', '31293', (83, 91))	('protein retention', 'Disease', 'MESH:D016055', (117, 134))	('Notch1', 'Gene', (110, 116))	('Notch1', 'Gene', '4851', (110, 116))	('cause', 'Reg', (104, 109))	('protein retention', 'Disease', (117, 134))	('Abruptex', 'Gene', (83, 91))
6115	29321718	In this study, we selected the C1133Y Abruptex domain mutation and examined its functional effects on Notch1 signaling in OSCC.	('Notch1', 'Gene', '4851', (102, 108))	('Abruptex', 'Gene', '31293', (38, 46))	('C1133Y', 'Var', (31, 37))	('OSCC', 'Disease', (122, 126))	('C1133Y', 'Mutation', 'p.C1133Y', (31, 37))	('Abruptex', 'Gene', (38, 46))	('Notch1', 'Gene', (102, 108))
6117	29321718	These data gave rise to evidence that C1133Y in Abruptex domain could be an 'Abruptex-specific' mutation (as mentioned above) as expected.	('Abruptex', 'Gene', '31293', (48, 56))	('C1133Y', 'Var', (38, 44))	('Abruptex', 'Gene', (77, 85))	('C1133Y', 'Mutation', 'p.C1133Y', (38, 44))	('Abruptex', 'Gene', (48, 56))	('Abruptex', 'Gene', '31293', (77, 85))
6124	29321718	In HN13 cells, Notch1 signaling was drastically activated by wild-type Notch1 transfection, predicting the Notch1-dominant status in HN13, as well as the EGFR-dominant status in HN6.	('EGFR', 'Gene', (154, 158))	('HN13', 'Gene', '100463500', (3, 7))	('transfection', 'Var', (78, 90))	('EGFR', 'Gene', '1956', (154, 158))	('Notch1', 'Gene', (107, 113))	('Notch1', 'Gene', '4851', (107, 113))	('predicting', 'Reg', (92, 102))	('Notch1', 'Gene', (71, 77))	('HN13', 'Gene', '100463500', (133, 137))	('HN6', 'Gene', (178, 181))	('HN13', 'Gene', (133, 137))	('Notch1', 'Gene', (15, 21))	('Notch1', 'Gene', '4851', (71, 77))	('activated', 'PosReg', (48, 57))	('HN13', 'Gene', (3, 7))	('HN6', 'Gene', '100463482', (178, 181))	('Notch1', 'Gene', '4851', (15, 21))
6134	29321718	It is doubtful if the C1133Y mutation-induced AKT activation is attributed to Notch1 retention in cytoplasm directly or to the loss of inhibitory effect on EGFR phosphorylation.	('Notch1', 'Gene', '4851', (78, 84))	('inhibitory effect', 'MPA', (135, 152))	('AKT', 'Gene', '207', (46, 49))	('EGFR', 'Gene', '1956', (156, 160))	('C1133Y', 'Mutation', 'p.C1133Y', (22, 28))	('activation', 'PosReg', (50, 60))	('AKT', 'Gene', (46, 49))	('EGFR', 'Gene', (156, 160))	('C1133Y', 'Var', (22, 28))	('Notch1', 'Gene', (78, 84))
6135	29321718	It's still unclear whether the opposite effect on oncogenic phenotypes induced by C1133Y loss-of-function mutation is AKT signaling-dependent, thus requiring further investigation.	('AKT', 'Gene', '207', (118, 121))	('loss-of-function', 'NegReg', (89, 105))	('C1133Y', 'Mutation', 'p.C1133Y', (82, 88))	('AKT', 'Gene', (118, 121))	('C1133Y', 'Var', (82, 88))
6146	29321718	Further experiments would be implemented to uncover the EMT mechanism in this novel Notch1 mutation.	('Notch1', 'Gene', '4851', (84, 90))	('mutation', 'Var', (91, 99))	('Notch1', 'Gene', (84, 90))
6147	29321718	6b) found evidence for the first time that mutation in Notch1 Abruptex domain can have an inactivated effect on Notch1 signaling pathway and promotive effects on cell oncogenic phenotypes.	('Abruptex', 'Gene', '31293', (62, 70))	('Notch1', 'Gene', '4851', (112, 118))	('mutation', 'Var', (43, 51))	('Notch1', 'Gene', (55, 61))	('Notch1', 'Gene', '4851', (55, 61))	('Notch1', 'Gene', (112, 118))	('Abruptex', 'Gene', (62, 70))	('promotive', 'PosReg', (141, 150))	('cell oncogenic phenotypes', 'CPA', (162, 187))
6148	29321718	Taken together, our data reveal that the Notch1 C1133Y mutation enhances proliferative and invasive ability in OSCC cell lines.	('C1133Y', 'Var', (48, 54))	('Notch1', 'Gene', (41, 47))	('enhances', 'PosReg', (64, 72))	('Notch1', 'Gene', '4851', (41, 47))	('C1133Y', 'Mutation', 'p.C1133Y', (48, 54))
6149	29321718	This novel Notch1 mutation impairs the processing of notch1 protein, and activates the EGFR-PI3K/AKT signaling.	('AKT', 'Gene', '207', (97, 100))	('processing', 'MPA', (39, 49))	('EGFR', 'Gene', '1956', (87, 91))	('Notch1', 'Gene', (11, 17))	('Notch1', 'Gene', '4851', (11, 17))	('notch1', 'Gene', '4851', (53, 59))	('AKT', 'Gene', (97, 100))	('EGFR', 'Gene', (87, 91))	('impairs', 'NegReg', (27, 34))	('notch1', 'Gene', (53, 59))	('mutation', 'Var', (18, 26))	('activates', 'PosReg', (73, 82))
6165	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))
6190	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))
6230	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))
6234	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))	('ly', 'Chemical', '-', (102, 104))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('cancer', 'Disease', (31, 37))
6372	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))
6590	25823023	In sum, both the oncogenic mutation and epithelial cell type in which it is expressed can influence which lung cancer subtypes will form in mice.	('mice', 'Species', '10090', (140, 144))	('lung cancer', 'Disease', (106, 117))	('lung cancer', 'Phenotype', 'HP:0100526', (106, 117))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('mutation', 'Var', (27, 35))	('influence', 'Reg', (90, 99))	('lung cancer', 'Disease', 'MESH:D008175', (106, 117))
6593	25823023	Most human SCLCs harbor inactivating mutations in the prototypical tumor suppressors TP53 and the retinoblastoma 1 (RB1) genes.	('TP53', 'Gene', (85, 89))	('inactivating mutations', 'Var', (24, 46))	('RB1', 'Gene', '5925', (116, 119))	('retinoblastoma 1', 'Gene', '5925', (98, 114))	('SCLC', 'Phenotype', 'HP:0030357', (11, 15))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('retinoblastoma 1', 'Gene', (98, 114))	('TP53', 'Gene', '7157', (85, 89))	('tumor', 'Disease', (67, 72))	('RB1', 'Gene', (116, 119))	('retinoblastoma', 'Phenotype', 'HP:0009919', (98, 112))	('human', 'Species', '9606', (5, 10))	('SCLC', 'Disease', (11, 15))	('SCLC', 'Disease', 'MESH:D018288', (11, 15))
6594	25823023	By using cell-type specific conditional knockouts of these two tumor suppressors, independent groups have confirmed that PNECs are the predominant cells of origin of SCLC.	('tumor', 'Disease', (63, 68))	('SCLC', 'Disease', (166, 170))	('SCLC', 'Disease', 'MESH:D018288', (166, 170))	('PNECs', 'Disease', (121, 126))	('SCLC', 'Phenotype', 'HP:0030357', (166, 170))	('knockouts', 'Var', (40, 49))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
6595	25823023	Interestingly, inactivation of Tp53 and Rb1 in a subset of AT2 cells, but not in club cells, may also lead to SCLC at reduced efficiency.	('Rb1', 'Gene', '5925', (40, 43))	('club', 'Phenotype', 'HP:0001217', (81, 85))	('SCLC', 'Phenotype', 'HP:0030357', (110, 114))	('Rb1', 'Gene', (40, 43))	('Tp53', 'Gene', (31, 35))	('lead to', 'Reg', (102, 109))	('Tp53', 'Gene', '7157', (31, 35))	('SCLC', 'Disease', (110, 114))	('SCLC', 'Disease', 'MESH:D018288', (110, 114))	('inactivation', 'Var', (15, 27))
6600	25823023	Although rarely mutated in human LUSC, inactivation of the tumor suppressor Stk11 (also known as Lkb1) in Kras mutant mice can generate LUSC, but also creates a wide spectrum of NSCLCs including mixed adenosquamous carcinoma and LCC.	('tumor', 'Disease', (59, 64))	('human', 'Species', '9606', (27, 32))	('Stk11', 'Gene', '6794', (76, 81))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('mice', 'Species', '10090', (118, 122))	('SCLC', 'Phenotype', 'HP:0030357', (179, 183))	('LUSC', 'Chemical', '-', (33, 37))	('LCC', 'Phenotype', 'HP:0030360', (229, 232))	('LUSC', 'Chemical', '-', (136, 140))	('mutant', 'Var', (111, 117))	('NSCLCs', 'Disease', 'MESH:D002289', (178, 184))	('carcinoma', 'Phenotype', 'HP:0030731', (215, 224))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('LCC', 'Disease', (229, 232))	('Stk11', 'Gene', (76, 81))	('adenosquamous carcinoma', 'Disease', (201, 224))	('creates', 'Reg', (151, 158))	('NSCLC', 'Phenotype', 'HP:0030358', (178, 183))	('NSCLCs', 'Disease', (178, 184))	('inactivation', 'Var', (39, 51))	('LUSC', 'Disease', (136, 140))	('adenosquamous carcinoma', 'Disease', 'MESH:D018196', (201, 224))
6601	25823023	In addition, IKKalpha kinase inactivation in mice generates spontaneous LUSC exclusively, albeit at a relatively low efficiency.	('mice', 'Species', '10090', (45, 49))	('IKKalpha', 'Gene', (13, 21))	('IKKalpha', 'Gene', '12675', (13, 21))	('spontaneous LUSC exclusively', 'MPA', (60, 88))	('LUSC', 'Chemical', '-', (72, 76))	('inactivation', 'Var', (29, 41))
6602	25823023	The comprehensive catalog of genomic alterations in LUSC identified recurrent PTEN mutations.	('LUSC', 'Chemical', '-', (52, 56))	('mutations', 'Var', (83, 92))	('PTEN', 'Gene', '5728', (78, 82))	('PTEN', 'Gene', (78, 82))
6603	25823023	Concomitant inactivation of Lkb1 and Pten leads to LUSC in GEMM with 100% penetrance.	('leads to', 'Reg', (42, 50))	('Pten', 'Gene', '5728', (37, 41))	('Pten', 'Gene', (37, 41))	('LUSC', 'Chemical', '-', (51, 55))	('LUSC in GEMM', 'CPA', (51, 63))	('Lkb1', 'Gene', (28, 32))	('inactivation', 'Var', (12, 24))
6605	25823023	Given this result, it is expected that the cellular origin(s) of LUSC will soon be identified using conditional knockouts of Lkb1 and Pten in GEMM.	('LUSC', 'Chemical', '-', (65, 69))	('Pten', 'Gene', '5728', (134, 138))	('Pten', 'Gene', (134, 138))	('knockouts', 'Var', (112, 121))	('Lkb1', 'Gene', (125, 129))
6607	25823023	In humans, KRAS is most frequently mutated in tissues of endodermal origin, including the lung epithelium.	('KRAS', 'Gene', (11, 15))	('KRAS', 'Gene', '3845', (11, 15))	('humans', 'Species', '9606', (3, 9))	('mutated', 'Var', (35, 42))
6610	25823023	In principle, tumor progression in the terminal bronchioles can also occur if the Tp53 tumor suppressor gene is concomitantly deleted in CC10+ cells.	('CC10', 'Gene', '7356', (137, 141))	('tumor', 'Disease', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('deleted', 'Var', (126, 133))	('Tp53', 'Gene', '7157', (82, 86))	('tumor', 'Disease', (87, 92))	('occur', 'Reg', (69, 74))	('CC10', 'Gene', (137, 141))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('Tp53', 'Gene', (82, 86))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
6611	25823023	It is also known that mutant Egfr expression in CC10+ cells can give rise to LUAD that rarely metastasizes.	('give rise to', 'Reg', (64, 76))	('Egfr', 'Gene', (29, 33))	('CC10', 'Gene', '7356', (48, 52))	('mutant', 'Var', (22, 28))	('LUAD', 'Disease', (77, 81))	('Egfr', 'Gene', '1956', (29, 33))	('CC10', 'Gene', (48, 52))
6612	25823023	Moreover, the cell surface antigenic profile of tumor-initiating cells varies when comparing LUADs driven by Egfr and Kras mutations.	('Kras', 'Gene', (118, 122))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('tumor', 'Disease', (48, 53))	('Egfr', 'Gene', (109, 113))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('Egfr', 'Gene', '1956', (109, 113))	('mutations', 'Var', (123, 132))
6614	25823023	The function of other driver mutations in LUAD might be equally variable across regional epithelial cell lineages, contributing even further to the heterogeneous nature of this NSCLC subtype.	('NSCLC', 'Phenotype', 'HP:0030358', (177, 182))	('SCLC', 'Phenotype', 'HP:0030357', (178, 182))	('mutations', 'Var', (29, 38))	('LUAD', 'Gene', (42, 46))	('contributing', 'Reg', (115, 127))	('NSCLC', 'Disease', (177, 182))	('NSCLC', 'Disease', 'MESH:D002289', (177, 182))
6619	25823023	Independent of EMT, lung cancer histopathological variations may correlate with cell lineage states that are unique or selective for the airways.	('lung cancer', 'Disease', 'MESH:D008175', (20, 31))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('lung cancer', 'Disease', (20, 31))	('lung cancer', 'Phenotype', 'HP:0100526', (20, 31))	('variations', 'Var', (50, 60))
6632	25823023	Phenotypic conversion of AT2-derived LUADs is seen when mutating the tumor suppressor Stk11 in conjunction with Kras, which generates tumors that transdifferentiate into LUSCs.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumors', 'Disease', (134, 140))	('tumors', 'Disease', 'MESH:D009369', (134, 140))	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('tumor', 'Disease', (69, 74))	('Stk11', 'Gene', '6794', (86, 91))	('mutating', 'Var', (56, 64))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('LUSC', 'Chemical', '-', (170, 174))	('Stk11', 'Gene', (86, 91))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('tumor', 'Disease', (134, 139))
6634	25823023	Mutations in components of this pathway such as APC, GSK3B and CTNNB1 are detected in 15% of human LUADs.	('GSK3B', 'Gene', (53, 58))	('GSK3B', 'Gene', '2932', (53, 58))	('CTNNB1', 'Gene', '1499', (63, 69))	('human', 'Species', '9606', (93, 98))	('detected', 'Reg', (74, 82))	('CTNNB1', 'Gene', (63, 69))	('Mutations', 'Var', (0, 9))	('APC', 'Disease', 'MESH:D011125', (48, 51))	('APC', 'Disease', (48, 51))
6635	25823023	Multiple studies report even more frequent overexpression of various WNT pathway components and epigenetic silencing of WNT pathway antagonists in human LUADs.	('WNT pathway', 'Pathway', (69, 80))	('overexpression', 'PosReg', (43, 57))	('epigenetic silencing', 'Var', (96, 116))	('human', 'Species', '9606', (147, 152))
6636	25823023	Deletion of the WNT antagonist APC cooperates with Kras to induce dedifferentiated invasive LUADs.	('dedifferentiated invasive LUADs', 'Disease', (66, 97))	('induce', 'Reg', (59, 65))	('APC', 'Disease', 'MESH:D011125', (31, 34))	('APC', 'Disease', (31, 34))	('Deletion', 'Var', (0, 8))
6641	25823023	Inactivating mutations in RB1 are ubiquitous to all SCLCs.	('SCLC', 'Phenotype', 'HP:0030357', (52, 56))	('Inactivating mutations', 'Var', (0, 22))	('RB1', 'Gene', (26, 29))	('SCLC', 'Disease', (52, 56))	('RB1', 'Gene', '5925', (26, 29))	('SCLC', 'Disease', 'MESH:D018288', (52, 56))
6643	25823023	Although components of the pRB pathway are frequently inactivated across many cancers, the strong selection for mutations in RB1 exclusively within SCLC suggests that pRb itself is a lineage-specific tumor suppressor.	('SCLC', 'Disease', 'MESH:D018288', (148, 152))	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('pRB', 'Gene', (27, 30))	('SCLC', 'Phenotype', 'HP:0030357', (148, 152))	('RB1', 'Gene', (125, 128))	('cancers', 'Disease', 'MESH:D009369', (78, 85))	('tumor', 'Disease', (200, 205))	('mutations', 'Var', (112, 121))	('cancers', 'Phenotype', 'HP:0002664', (78, 85))	('RB1', 'Gene', '5925', (125, 128))	('cancers', 'Disease', (78, 85))	('pRb', 'Gene', '5925', (167, 170))	('pRb', 'Gene', (167, 170))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('pRB', 'Gene', '5925', (27, 30))	('SCLC', 'Disease', (148, 152))
6645	25823023	This selective requirement for RB1 during mammalian lung development is consistent with the neuroendocrine origins of SCLC and the potent SCLC phenotype generated via Rb and p53 mutations in GEMMs.	('RB1', 'Gene', (31, 34))	('SCLC', 'Disease', (118, 122))	('SCLC', 'Disease', 'MESH:D018288', (118, 122))	('SCLC', 'Phenotype', 'HP:0030357', (138, 142))	('RB1', 'Gene', '5925', (31, 34))	('SCLC', 'Phenotype', 'HP:0030357', (118, 122))	('Rb', 'Gene', '19645', (167, 169))	('p53', 'Gene', (174, 177))	('SCLC', 'Disease', (138, 142))	('mutations', 'Var', (178, 187))	('SCLC', 'Disease', 'MESH:D018288', (138, 142))	('p53', 'Gene', '7157', (174, 177))	('mammalian', 'Species', '9606', (42, 51))
6648	25823023	A combination of genetic alterations, such as the loss of Lkb1, might be required for Sox2-driven LUSC in mice.	('Sox2', 'Gene', '20674', (86, 90))	('mice', 'Species', '10090', (106, 110))	('LUSC', 'Chemical', '-', (98, 102))	('Sox2', 'Gene', (86, 90))	('loss', 'Var', (50, 54))	('Lkb1', 'Gene', (58, 62))
6654	25823023	Induction of Sox9 expression has been observed in murine LUADs harboring activating mutations in Kras and beta-catenin and this over-expression is associated with high grade tumors.	('tumors', 'Disease', (174, 180))	('associated', 'Reg', (147, 157))	('murine', 'Species', '10090', (50, 56))	('tumors', 'Disease', 'MESH:D009369', (174, 180))	('mutations', 'Var', (84, 93))	('tumors', 'Phenotype', 'HP:0002664', (174, 180))	('high', 'Disease', (163, 167))	('beta-catenin', 'Protein', (106, 118))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('Sox9', 'Gene', '20682', (13, 17))	('Kras', 'Gene', (97, 101))	('Sox9', 'Gene', (13, 17))
6655	25823023	Moreover, SOX9 is preferentially upregulated in human KRAS mutant adenomas and is also induced by Notch activation.	('upregulated', 'PosReg', (33, 44))	('adenomas', 'Disease', (66, 74))	('human', 'Species', '9606', (48, 53))	('mutant', 'Var', (59, 65))	('SOX9', 'Gene', (10, 14))	('preferentially', 'PosReg', (18, 32))	('SOX9', 'Gene', '6662', (10, 14))	('KRAS', 'Gene', (54, 58))	('KRAS', 'Gene', '3845', (54, 58))	('adenomas', 'Disease', 'MESH:D000236', (66, 74))	('Notch', 'Gene', '4851;18128', (98, 103))	('Notch', 'Gene', (98, 103))
6659	25823023	About 15% of LUADs harbor NKX2-1 amplification, which correlates with poor outcome and is required for tumor cell viability.	('NKX2-1', 'Gene', '7080', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('amplification', 'Var', (33, 46))	('tumor', 'Disease', (103, 108))	('NKX2-1', 'Gene', (26, 32))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
6660	25823023	NKX2-1 can support pro-tumorigenic signaling downstream of mutant EGFR and is required for EGFR mediated transformation in vivo.	('EGFR', 'Gene', (91, 95))	('EGFR', 'Gene', '1956', (66, 70))	('EGFR', 'Gene', (66, 70))	('mutant', 'Var', (59, 65))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('NKX2-1', 'Gene', '7080', (0, 6))	('tumor', 'Disease', (23, 28))	('support', 'PosReg', (11, 18))	('EGFR', 'Gene', '1956', (91, 95))	('NKX2-1', 'Gene', (0, 6))
6664	25823023	Repression of Nkx2-1 is also required for stochastic dissemination and metastasis by tumors with Kras and p53 mutations.	('p53', 'Gene', '7157', (106, 109))	('mutations', 'Var', (110, 119))	('metastasis by tumors', 'Disease', 'MESH:D009362', (71, 91))	('metastasis by tumors', 'Disease', (71, 91))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('p53', 'Gene', (106, 109))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))
6669	25823023	Conversely, NKX2-1 amplification is often accompanied by overexpression of the lineage TF FOXA1.	('NKX2-1', 'Gene', '7080', (12, 18))	('overexpression', 'PosReg', (57, 71))	('accompanied', 'Reg', (42, 53))	('amplification', 'Var', (19, 32))	('NKX2-1', 'Gene', (12, 18))	('FOXA1', 'Gene', (90, 95))	('FOXA1', 'Gene', '3169', (90, 95))
6681	25823023	Hypermethylation and mutation of GATA6 itself are uncommon in LUADs, but, as in other cancers, alternative mechanisms may contribute to its down-regulation.	('GATA6', 'Gene', (33, 38))	('GATA6', 'Gene', '2627', (33, 38))	('Hypermethylation', 'Var', (0, 16))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('down-regulation', 'NegReg', (140, 155))	('LUADs', 'Disease', (62, 67))	('mutation', 'Var', (21, 29))	('cancers', 'Phenotype', 'HP:0002664', (86, 93))	('cancers', 'Disease', (86, 93))	('cancers', 'Disease', 'MESH:D009369', (86, 93))
6686	25823023	Moreover, ectopic HOPX expression can induce senescence and is preferentially silenced via DNA methylation in the LUAD subtype, where decreased HOPX levels correlate with poor clinical outcome.	('senescence', 'CPA', (45, 55))	('induce', 'PosReg', (38, 44))	('HOPX', 'Gene', '84525', (18, 22))	('ectopic', 'Var', (10, 17))	('HOPX', 'Gene', (144, 148))	('HOPX', 'Gene', (18, 22))	('HOPX', 'Gene', '84525', (144, 148))
6690	25823023	Although rarely mutated in lung cancer, C/EBPalpha is often suppressed by DNA hypermethylation, and its re-expression was shown to inhibit the proliferation and survival of human NSCLC cells.	('inhibit', 'NegReg', (131, 138))	('NSCLC', 'Disease', 'MESH:D002289', (179, 184))	('suppressed', 'NegReg', (60, 70))	('survival', 'CPA', (161, 169))	('lung cancer', 'Disease', (27, 38))	('SCLC', 'Phenotype', 'HP:0030357', (180, 184))	('lung cancer', 'Phenotype', 'HP:0100526', (27, 38))	('NSCLC', 'Phenotype', 'HP:0030358', (179, 184))	('human', 'Species', '9606', (173, 178))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('proliferation', 'CPA', (143, 156))	('lung cancer', 'Disease', 'MESH:D008175', (27, 38))	('NSCLC', 'Disease', (179, 184))	('C/EBPalpha', 'Var', (40, 50))
6703	25823023	RUNX3 methylation status is an independent prognostic factor in NSCLC patients and is associated with chemoresistance.	('methylation status', 'Var', (6, 24))	('NSCLC', 'Disease', 'MESH:D002289', (64, 69))	('patients', 'Species', '9606', (70, 78))	('SCLC', 'Phenotype', 'HP:0030357', (65, 69))	('NSCLC', 'Disease', (64, 69))	('associated', 'Reg', (86, 96))	('NSCLC', 'Phenotype', 'HP:0030358', (64, 69))	('chemoresistance', 'CPA', (102, 117))	('RUNX3', 'Gene', (0, 5))
6705	25823023	In GEMMs, heterozygous loss of Runx3 causes pre-neoplastic lung adenoma.	('heterozygous loss', 'Var', (10, 27))	('lung adenoma', 'Disease', (59, 71))	('Runx3', 'Gene', (31, 36))	('lung adenoma', 'Disease', 'MESH:D000236', (59, 71))	('neoplastic lung', 'Phenotype', 'HP:0100526', (48, 63))	('causes', 'Reg', (37, 43))
6706	25823023	This further suggests that deregulation of cell fate-determining TFs can drive transition to different lung tumor subtypes.	('deregulation', 'Var', (27, 39))	('lung tumor', 'Phenotype', 'HP:0100526', (103, 113))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('lung tumor', 'Disease', (103, 113))	('drive', 'Reg', (73, 78))	('lung tumor', 'Disease', 'MESH:D008175', (103, 113))
6708	25823023	The MYC family proto-oncogenes, which encode C-myc (Myc), N-myc and L-myc, regulate numerous biological processes.	('MYC', 'Gene', (4, 7))	('regulate', 'Reg', (75, 83))	('L-myc', 'Gene', (68, 73))	('Myc', 'Gene', '4609', (52, 55))	('MYC', 'Gene', '4609', (4, 7))	('Myc', 'Gene', (52, 55))	('L-myc', 'Gene', '4610', (68, 73))	('C-myc', 'Var', (45, 50))	('N-myc', 'Var', (58, 63))
6713	25823023	Moreover, recent genomic studies have identified loss of function mutations in MGA and MAX, two genes that encode for MYC inhibitory proteins.	('mutations', 'Var', (66, 75))	('MGA', 'Gene', (79, 82))	('MAX', 'Gene', (87, 90))	('loss of function', 'NegReg', (49, 65))	('MYC', 'Gene', (118, 121))	('MYC', 'Gene', '4609', (118, 121))
6714	25823023	In human lung cancers, alterations in MGA, MAX and MYC are mutually exclusive, indicating a more pervasive activation of the MYC pathway via mutations than was initially appreciated.	('lung cancers', 'Disease', 'MESH:D008175', (9, 21))	('lung cancers', 'Phenotype', 'HP:0100526', (9, 21))	('MYC', 'Gene', '4609', (125, 128))	('lung cancer', 'Phenotype', 'HP:0100526', (9, 20))	('mutations', 'Var', (141, 150))	('human', 'Species', '9606', (3, 8))	('MYC', 'Gene', (51, 54))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('MYC', 'Gene', (125, 128))	('lung cancers', 'Disease', (9, 21))	('alterations', 'Var', (23, 34))	('MYC', 'Gene', '4609', (51, 54))	('cancers', 'Phenotype', 'HP:0002664', (14, 21))	('activation', 'PosReg', (107, 117))
6723	25823023	Finally, human mutations in the MYC pathway are mutually exclusive to SMARCA4 (or BRG1), which encodes a major component of the SWI/SNF chromatin-remodeling complex and is a mediator of SCLC neuroendocrine differentiation.	('SCLC neuroendocrine differentiation', 'Disease', (186, 221))	('SMARCA4', 'Gene', (70, 77))	('mutations', 'Var', (15, 24))	('SMARCA4', 'Gene', '6597', (70, 77))	('SCLC', 'Phenotype', 'HP:0030357', (186, 190))	('BRG1', 'Gene', (82, 86))	('human', 'Species', '9606', (9, 14))	('MYC', 'Gene', (32, 35))	('BRG1', 'Gene', '6597', (82, 86))	('SCLC neuroendocrine differentiation', 'Disease', 'MESH:D018288', (186, 221))	('MYC', 'Gene', '4609', (32, 35))
6734	25823023	Thus, modulation of lineage states by TFs may indirectly influence metastatic potential by controlling intra-tumoral clonal dynamics, presumably via paracrine signals (Figure 3).	('controlling', 'Reg', (91, 102))	('modulation', 'Var', (6, 16))	('metastatic potential', 'CPA', (67, 87))	('influence', 'Reg', (57, 66))	('TFs', 'Gene', (38, 41))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumor', 'Disease', (109, 114))
6741	25823023	Importantly, knockdown of these cytokeratins in their respective disease models inhibits tumor cell invasiveness, suggesting an unexpected direct role for basal/biliary epithelial markers in malignant invasion and metastasis.	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('inhibits', 'NegReg', (80, 88))	('knockdown', 'Var', (13, 22))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
6744	25823023	Nevertheless, exploiting aberrant tumor differentiation states or lineage TFs for therapy has been shown to be clinically beneficial in leukemia and neuroblastoma and pre-clinically feasible in melanoma, glioma, nasopharyngeal carcinoma, and rhabdomyosarcoma.	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (242, 258))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (212, 236))	('leukemia', 'Phenotype', 'HP:0001909', (136, 144))	('aberrant', 'Var', (25, 33))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (242, 258))	('glioma', 'Phenotype', 'HP:0009733', (204, 210))	('carcinoma', 'Disease', 'MESH:D009369', (227, 236))	('leukemia', 'Disease', (136, 144))	('tumor', 'Disease', (34, 39))	('leukemia', 'Disease', 'MESH:D007938', (136, 144))	('melanoma', 'Disease', 'MESH:D008545', (194, 202))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('neuroblastoma', 'Disease', (149, 162))	('neuroblastoma', 'Phenotype', 'HP:0003006', (149, 162))	('rhabdomyosarcoma', 'Disease', (242, 258))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('neuroblastoma', 'Disease', 'MESH:D009447', (149, 162))	('carcinoma', 'Phenotype', 'HP:0030731', (227, 236))	('melanoma', 'Phenotype', 'HP:0002861', (194, 202))	('carcinoma', 'Disease', (227, 236))	('glioma', 'Disease', (204, 210))	('melanoma', 'Disease', (194, 202))	('glioma', 'Disease', 'MESH:D005910', (204, 210))	('beneficial', 'PosReg', (122, 132))
6751	25823023	Notably, a subset of KRAS mutant LUADs that are well-differentiated and retain epithelial markers respond specifically to a combination of drugs that inhibit MAP kinase and BCL-Xl.	('respond', 'Reg', (98, 105))	('KRAS', 'Gene', '3845', (21, 25))	('MAP kinase', 'Pathway', (158, 168))	('KRAS', 'Gene', (21, 25))	('BCL-Xl', 'Gene', '598', (173, 179))	('inhibit', 'NegReg', (150, 157))	('BCL-Xl', 'Gene', (173, 179))	('mutant', 'Var', (26, 32))
6752	25823023	For example, the survival of TKI resistant EGFR mutant tumor cells that are more mesenchymal-like requires activation of the receptor tyrosine kinase AXL, which can be inhibited with small molecules.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('mutant', 'Var', (48, 54))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('AXL', 'Gene', '558', (150, 153))	('tumor', 'Disease', (55, 60))	('receptor tyrosine kinase', 'Gene', (125, 149))	('AXL', 'Gene', (150, 153))	('EGFR', 'Gene', '1956', (43, 47))	('receptor tyrosine kinase', 'Gene', '5979', (125, 149))	('EGFR', 'Gene', (43, 47))	('activation', 'PosReg', (107, 117))
6793	33080755	In these studies, there was no apparent heterogeneity (I2 = 15.60%, P = .291), thus we applied the fixed-effects model, which revealed that high expression of Oct4 was remarkably associated with to poor DFS/RFS/PFS in patients with solid tumors.	('solid tumors', 'Disease', (232, 244))	('associated', 'Reg', (179, 189))	('RFS', 'Disease', 'MESH:D005198', (207, 210))	('patients', 'Species', '9606', (218, 226))	('solid tumors', 'Disease', 'MESH:D009369', (232, 244))	('high', 'Var', (140, 144))	('tumor', 'Phenotype', 'HP:0002664', (238, 243))	('Oct4', 'Gene', (159, 163))	('tumors', 'Phenotype', 'HP:0002664', (238, 244))	('RFS', 'Disease', (207, 210))
6798	33080755	Results indicated that patients overexpressing Oct4 had poorer DFS/RFS/PFS, including HCC (pooled HR: 1.92; 95% CI: 1.30-2.85; P = .001), cervical cancer (pooled HR: 2.77; 95% CI: 1.33-5.79; P = .007), colorectal cancer (pooled HR: 3.22; 95% CI: 1.68-6.16; P < .001), others (pooled HR: 2.39; 95% CI: 1.74-3.27; P < .001).	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('RFS', 'Disease', 'MESH:D005198', (67, 70))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('colorectal cancer', 'Phenotype', 'HP:0003003', (202, 219))	('patients', 'Species', '9606', (23, 31))	('poorer', 'NegReg', (56, 62))	('HCC', 'Phenotype', 'HP:0001402', (86, 89))	('colorectal cancer', 'Disease', (202, 219))	('colorectal cancer', 'Disease', 'MESH:D015179', (202, 219))	('RFS', 'Disease', (67, 70))	('cervical cancer', 'Disease', (138, 153))	('cervical cancer', 'Disease', 'MESH:D002583', (138, 153))	('Oct4', 'Var', (47, 51))	('HCC', 'Disease', (86, 89))
6816	33080755	Interestingly, in HCC, Oct4 has been revealed to confer chemoresistance on HCC cells through protein kinase B Akt-mediated upregulation of ATP-binding cassette transporter G2, while it promoted cancer cell proliferation and migration via the survivin/STAT3 pathway, leading to poor prognosis.	('STAT3', 'Gene', (251, 256))	('HCC', 'Phenotype', 'HP:0001402', (18, 21))	('protein kinase B', 'Gene', (93, 109))	('chemoresistance', 'CPA', (56, 71))	('Akt', 'Gene', (110, 113))	('cancer', 'Disease', (194, 200))	('HCC', 'Phenotype', 'HP:0001402', (75, 78))	('protein kinase B', 'Gene', '2185', (93, 109))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('upregulation', 'PosReg', (123, 135))	('ATP-binding cassette transporter G2', 'Gene', (139, 174))	('promoted', 'PosReg', (185, 193))	('ATP-binding cassette transporter G2', 'Gene', '9429', (139, 174))	('STAT3', 'Gene', '6774', (251, 256))	('Oct4', 'Var', (23, 27))	('Akt', 'Gene', '207', (110, 113))	('migration', 'CPA', (224, 233))	('cancer', 'Disease', 'MESH:D009369', (194, 200))
6824	33080755	On the other hand, Oct4 knockdown could significantly reduce migration and progression in pancreatic cancer and colorectal cancer and cause breast CSC-like cell apoptosis, this strongly suggested that targeting Oct4 might offer vital clinical applications in cancer therapy.	('cancer', 'Disease', 'MESH:D009369', (259, 265))	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('colorectal cancer', 'Disease', 'MESH:D015179', (112, 129))	('Oct4', 'Gene', (19, 23))	('colorectal cancer', 'Disease', (112, 129))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (90, 107))	('cause', 'Reg', (134, 139))	('reduce', 'NegReg', (54, 60))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('breast CSC-like cell apoptosis', 'CPA', (140, 170))	('cancer', 'Disease', (259, 265))	('pancreatic cancer', 'Disease', 'MESH:D010190', (90, 107))	('cancer', 'Phenotype', 'HP:0002664', (259, 265))	('colorectal cancer', 'Phenotype', 'HP:0003003', (112, 129))	('knockdown', 'Var', (24, 33))	('progression', 'CPA', (75, 86))	('cancer', 'Disease', (101, 107))	('pancreatic cancer', 'Disease', (90, 107))	('cancer', 'Disease', (123, 129))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))
6827	33080755	High expression of Oct4 was dramatically associated with worse OS and DFS/RFS/PFS in patients with solid tumors.	('RFS', 'Disease', (74, 77))	('associated', 'Reg', (41, 51))	('High', 'Var', (0, 4))	('RFS', 'Disease', 'MESH:D005198', (74, 77))	('solid tumors', 'Disease', 'MESH:D009369', (99, 111))	('patients', 'Species', '9606', (85, 93))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('worse OS', 'Disease', (57, 65))	('Oct4', 'Gene', (19, 23))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('solid tumors', 'Disease', (99, 111))
6830	33080755	Notably, only 2 studies revealed that patients exhibiting high expression of Oct4 survived longer and had a lower recurrence rate in hypopharyngeal squamous cell carcinoma, and OSCC patients expressing high levels of Oct4 had better cumulative OS, the underlying mechanism is unclear, thus, additional in-depth researches are needed.	('high levels', 'Var', (202, 213))	('hypopharyngeal squamous cell carcinoma', 'Disease', (133, 171))	('cumulative OS', 'CPA', (233, 246))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (148, 171))	('better', 'PosReg', (226, 232))	('high expression', 'Var', (58, 73))	('hypopharyngeal squamous cell carcinoma', 'Disease', 'MESH:D002294', (133, 171))	('hypopharyngeal squamous cell carcinoma', 'Phenotype', 'HP:0012182', (133, 171))	('lower', 'NegReg', (108, 113))	('patients', 'Species', '9606', (182, 190))	('patients', 'Species', '9606', (38, 46))	('Oct4', 'Gene', (77, 81))	('carcinoma', 'Phenotype', 'HP:0030731', (162, 171))
6923	29844819	CD63 protein negativity was significantly associated with larger tumor size, advanced clinicopathological stage and poor patient survival rates (P=0.008); the findings of this study indicated that CD63 could be used as a biomarker to predict the prognosis of patients with early-stages of lung adenocarcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (299, 308))	('tumor', 'Disease', (65, 70))	('patients', 'Species', '9606', (259, 267))	('lung adenocarcinoma', 'Disease', (289, 308))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (289, 308))	('patient', 'Species', '9606', (121, 128))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (289, 308))	('CD63', 'Var', (197, 201))	('patient', 'Species', '9606', (259, 266))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
6931	29844819	However, Stepanenko and Dmitrenko revealed that 293 cells are tumorigenic, whereas acute changes to expression of the cancer-associated genes aggravate tumorigenicity by promoting chromosomal instability.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('cancer', 'Disease', (118, 124))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('changes', 'Var', (89, 96))	('tumor', 'Disease', (62, 67))	('aggravate', 'PosReg', (142, 151))	('tumor', 'Disease', (152, 157))	('promoting', 'PosReg', (170, 179))	('expression', 'MPA', (100, 110))	('293 cells', 'CellLine', 'CVCL:0045', (48, 57))	('chromosomal instability', 'Phenotype', 'HP:0040012', (180, 203))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('chromosomal instability', 'MPA', (180, 203))
6941	29844819	Considering that the changes in expression of MMP-2 and MMP-9 may alter the biological behavior of TCA8113 cells, wound-healing and Transwell invasion assays were used to measure the migratory and invasive ability of TCA8113 cells.	('invasive ability', 'CPA', (197, 213))	('MMP-2', 'Gene', '4313', (46, 51))	('migratory', 'CPA', (183, 192))	('MMP-9', 'Gene', '4318', (56, 61))	('biological behavior', 'CPA', (76, 95))	('MMP-9', 'Gene', (56, 61))	('changes', 'Var', (21, 28))	('alter', 'Reg', (66, 71))	('MMP-2', 'Gene', (46, 51))	('expression', 'MPA', (32, 42))
6961	29805736	Studies have reported that abnormal ASCL2 expression is involved in cell proliferation, invasion, migration, and epithelial-mesenchymal transition (EMT) in colorectal cancer (CRC).	('abnormal', 'Var', (27, 35))	('colorectal cancer', 'Disease', 'MESH:D015179', (156, 173))	('CRC', 'Phenotype', 'HP:0003003', (175, 178))	('invasion', 'CPA', (88, 96))	('cell proliferation', 'CPA', (68, 86))	('colorectal cancer', 'Phenotype', 'HP:0003003', (156, 173))	('ASCL2', 'Gene', (36, 41))	('migration', 'CPA', (98, 107))	('involved', 'Reg', (56, 64))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('colorectal cancer', 'Disease', (156, 173))	('epithelial-mesenchymal transition', 'CPA', (113, 146))
6974	29805736	But there was no difference between the bufalin and oxaliplatin group in 24h, 48h, while in the time of 72h the Oxaliplatin surpress function was more obviously than bufalin (Figure 1C).	('Oxaliplatin', 'Chemical', 'MESH:D000077150', (112, 123))	('Oxaliplatin', 'Var', (112, 123))	('bufalin', 'Chemical', 'MESH:C022777', (166, 173))	('surpress', 'NegReg', (124, 132))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (52, 63))	('bufalin', 'Chemical', 'MESH:C022777', (40, 47))
6989	29805736	Western blot results showed that after XAV939 treatment, beta-catenin and ASCL2 expression were down-regulated, while the expression of the EMT-related gene E-cadherin was up-regulated (Figure 4A).	('expression', 'MPA', (122, 132))	('up-regulated', 'PosReg', (172, 184))	('down-regulated', 'NegReg', (96, 110))	('ASCL2', 'Gene', (74, 79))	('XAV939', 'Var', (39, 45))	('expression', 'MPA', (80, 90))	('E-cadherin', 'Gene', (157, 167))	('E-cadherin', 'Gene', '999', (157, 167))	('beta-catenin', 'Gene', (57, 69))	('beta-catenin', 'Gene', '1499', (57, 69))	('XAV939', 'Chemical', 'MESH:C544261', (39, 45))
7016	29805736	Studies have shown that abnormal expression of ASCL2 can enhance the invasion and metastasis of CRC cells in vitro; that overexpression of ASCL2 correlates with distant metastasis, tumor size and poor overall survival in CRC patients; and that high expression of ASCL2 promotes EMT in CRC.	('tumor', 'Disease', (181, 186))	('patients', 'Species', '9606', (225, 233))	('CRC', 'Phenotype', 'HP:0003003', (96, 99))	('abnormal', 'Var', (24, 32))	('CRC', 'Phenotype', 'HP:0003003', (285, 288))	('ASCL2', 'Gene', (139, 144))	('ASCL2', 'Gene', (263, 268))	('CRC', 'Phenotype', 'HP:0003003', (221, 224))	('ASCL2', 'Gene', (47, 52))	('CRC', 'Disease', (285, 288))	('EMT in', 'CPA', (278, 284))	('overexpression', 'PosReg', (121, 135))	('distant metastasis', 'CPA', (161, 179))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('promotes', 'PosReg', (269, 277))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('enhance', 'PosReg', (57, 64))
7018	29805736	A previous study found that ASCL2 expression was up-regulated and markedly hypomethylated in GC tissues and that ectopic overexpression of ASCL2 increased cell growth and promoted resistance to 5-fluorouracil in GC cells.	('ASCL2', 'Gene', (28, 33))	('GC', 'Phenotype', 'HP:0012126', (212, 214))	('expression', 'MPA', (34, 44))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (194, 208))	('hypomethylated', 'Var', (75, 89))	('increased', 'PosReg', (145, 154))	('promoted', 'PosReg', (171, 179))	('ASCL2', 'Gene', (139, 144))	('resistance to 5-fluorouracil', 'MPA', (180, 208))	('GC', 'Phenotype', 'HP:0012126', (93, 95))	('cell growth', 'CPA', (155, 166))	('up-regulated', 'PosReg', (49, 61))
7026	29805736	Expression of these enzymes is a major characteristic of the malignant invasion and metastasis of cancer cells, as these enzymes degrade the ECM and may promote the penetration of cancer cells into the basement membrane.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('degrade', 'NegReg', (129, 136))	('ECM', 'Gene', '22915', (141, 144))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('metastasis of cancer', 'Disease', 'MESH:D009362', (84, 104))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('metastasis of cancer', 'Disease', (84, 104))	('ECM', 'Gene', (141, 144))	('penetration', 'CPA', (165, 176))	('cancer', 'Disease', (98, 104))	('enzymes', 'Var', (121, 128))	('promote', 'PosReg', (153, 160))	('cancer', 'Disease', (180, 186))
7027	29805736	Our study showed that bufalin and ASCL2 knockdown both inhibited the expression of MMP2 and MMP2, with more pronounced results upon combining bufalin and shRNA-ASCL2 (Figure 3C); these results were verified in animal experiments (Figure 6A).	('MMP2', 'Gene', '4313', (92, 96))	('MMP2', 'Gene', (83, 87))	('bufalin', 'Chemical', 'MESH:C022777', (142, 149))	('knockdown', 'Var', (40, 49))	('expression', 'MPA', (69, 79))	('bufalin', 'Chemical', 'MESH:C022777', (22, 29))	('MMP2', 'Gene', '4313', (83, 87))	('MMP2', 'Gene', (92, 96))	('inhibited', 'NegReg', (55, 64))
7040	29805736	Research suggested that Ascl2 is a master regulator of intestinal stem cell identity:deletion of the Ascl2 gene in the adult small intestine led to the disappearance of Lgr5 stem cells within day:and a Wnt target gene.	('Ascl2', 'Gene', (101, 106))	('Lgr5', 'Gene', (169, 173))	('Ascl2', 'Gene', '430', (24, 29))	('Ascl2', 'Gene', (24, 29))	('deletion', 'Var', (85, 93))	('Ascl2', 'Gene', '430', (101, 106))	('disappearance', 'NegReg', (152, 165))
7041	29805736	Therefore, we inhibited the Wnt signaling pathway with XAV939, which down-regulated beta-catenin and ASCL2 and up-regulated E-cadherin; combining XAV939 with bufalin further decreased the expression of beta-catenin and ASCL2 (Figure 4A).	('beta-catenin', 'Gene', (202, 214))	('decreased', 'NegReg', (174, 183))	('ASCL2', 'MPA', (101, 106))	('beta-catenin', 'Gene', '1499', (202, 214))	('expression', 'MPA', (188, 198))	('Wnt signaling pathway', 'Pathway', (28, 49))	('up-regulated', 'PosReg', (111, 123))	('beta-catenin', 'Gene', (84, 96))	('XAV939', 'Var', (146, 152))	('inhibited', 'NegReg', (14, 23))	('down-regulated', 'NegReg', (69, 83))	('bufalin', 'Chemical', 'MESH:C022777', (158, 165))	('XAV939', 'Chemical', 'MESH:C544261', (55, 61))	('ASCL2', 'MPA', (219, 224))	('XAV939', 'Chemical', 'MESH:C544261', (146, 152))	('beta-catenin', 'Gene', '1499', (84, 96))	('E-cadherin', 'Gene', (124, 134))	('E-cadherin', 'Gene', '999', (124, 134))
7042	29805736	We also found that the migration ability of GC cells obviously decreased after XAV939 treatment, which increased the anti-invasion activity of bufalin (Figure 4B).	('migration ability of GC cells', 'CPA', (23, 52))	('increased', 'PosReg', (103, 112))	('anti-invasion activity', 'MPA', (117, 139))	('decreased', 'NegReg', (63, 72))	('XAV939', 'Var', (79, 85))	('XAV939', 'Chemical', 'MESH:C544261', (79, 85))	('bufalin', 'Chemical', 'MESH:C022777', (143, 150))	('GC', 'Phenotype', 'HP:0012126', (44, 46))
7084	29491376	Silencing of the top differentially expressed and clinically relevant S-phase-enriched lncRNAs in several cancer models affects crucial cancer cell hallmarks.	('crucial cancer', 'Disease', 'MESH:D009369', (128, 142))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('affects', 'Reg', (120, 127))	('cancer', 'Disease', (136, 142))	('cancer', 'Disease', (106, 112))	('Silencing', 'Var', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('crucial cancer', 'Disease', (128, 142))
7088	29491376	Here, the authors identify 633 prognostic markers, 570 S-phase cancer-associated lncRNAs, and show SCAT7 regulates FGF/FGFR and PI3K/AKT/MAPK pathways via interaction with hnRNPK/YBX1 complexes.	('hnRNPK', 'Gene', (172, 178))	('FGF/FGFR', 'Pathway', (115, 123))	('SCAT7', 'Var', (99, 104))	('interaction', 'Interaction', (155, 166))	('regulates', 'Reg', (105, 114))	('YBX1', 'Gene', '4904', (179, 183))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('AKT', 'Gene', '207', (133, 136))	('hnRNPK', 'Gene', '3190', (172, 178))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('AKT', 'Gene', (133, 136))	('YBX1', 'Gene', (179, 183))	('cancer', 'Disease', (63, 69))
7090	29491376	Considering the influence of lncRNAs in a wide-range of biological processes, and that a significant portion of disease-associated single-nucleotide polymorphisms (SNPs) map to lncRNA loci, one could expect a greater role for lncRNAs in human disease.	('single-nucleotide polymorphisms', 'Var', (131, 162))	('disease-associated', 'Reg', (112, 130))	('human', 'Species', '9606', (237, 242))
7108	29491376	Principal component analysis of whole RNA, noncoding RNAs, and lncRNA expression profiles revealed that EtU-labeled RNAs had a better separation across different time points of S-phase compared to unlabeled samples (Fig.	('separation', 'MPA', (134, 144))	('EtU', 'Chemical', '-', (104, 107))	('EtU-labeled', 'Var', (104, 115))
7130	29491376	We utilized the processed CpG methylation data from the catalog of somatic mutations in cancers (COSMIC) for 12 TCGA cancer types (Infinium Human Methylation 450 beadchip platform; ~4000 samples, from international cancer genome consortium (ICGC) release 18) (Supplementary Data 2).	('cancer', 'Disease', (88, 94))	('Human', 'Species', '9606', (140, 145))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('cancer', 'Disease', (215, 221))	('cancer', 'Disease', 'MESH:D009369', (215, 221))	('cancers', 'Disease', 'MESH:D009369', (88, 95))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('cancers', 'Disease', (88, 95))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('mutations', 'Var', (75, 84))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('cancer', 'Disease', (117, 123))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))
7132	29491376	Among these, 22 lncRNAs were hypomethylated with higher expression in tumors, whereas 13 lncRNAs were hypermethylated with lower expression in tumors.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('hypomethylated', 'Var', (29, 43))	('tumors', 'Disease', (143, 149))	('tumors', 'Disease', 'MESH:D009369', (143, 149))	('tumors', 'Disease', (70, 76))	('tumors', 'Disease', 'MESH:D009369', (70, 76))	('expression', 'MPA', (56, 66))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('higher', 'PosReg', (49, 55))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
7133	29491376	Out of 20 lncRNAs, 7 were hypermethylated and highly expressed, whereas 13 lncRNAs were hypomethylated with lower expression in tumors.	('expressed', 'MPA', (53, 62))	('hypermethylated', 'Var', (26, 41))	('highly', 'PosReg', (46, 52))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumors', 'Disease', (128, 134))	('tumors', 'Disease', 'MESH:D009369', (128, 134))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))
7151	29491376	Our clinical investigations revealed CTD-2357A8.3 (SCAT1) and LUCAT1 (SCAT5) as common independent prognostic biomarkers for lung and kidney-derived cancers, respectively (Fig.	('CTD-2357A8.3', 'Var', (37, 49))	('cancers', 'Disease', (149, 156))	('cancers', 'Phenotype', 'HP:0002664', (149, 156))	('lung', 'Disease', (125, 129))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('LUCAT1', 'Gene', '100505994', (62, 68))	('LUCAT1', 'Gene', (62, 68))	('cancers', 'Disease', 'MESH:D009369', (149, 156))
7169	29491376	To this end, both variants of SCAT7 were downregulated in cell lines representing KIRC (Caki-2 and 786-O), LUAD (A549 and H2228), LIHC (HEPG2), and BRCA (MCF7) using siRNA or short hairpin RNA (shRNA).	('BRCA', 'Gene', '672', (148, 152))	('downregulated', 'NegReg', (41, 54))	('SCAT7', 'Gene', (30, 35))	('variants', 'Var', (18, 26))	('BRCA', 'Gene', (148, 152))	('Caki-2', 'CellLine', 'CVCL:0235', (88, 94))	('LIHC', 'Disease', (130, 134))	('A549', 'CellLine', 'CVCL:0023', (113, 117))	('LIHC', 'Disease', 'None', (130, 134))	('MCF7', 'CellLine', 'CVCL:0031', (154, 158))
7171	29491376	Additionally, the knockdown of SCAT7 led to decreased proliferation even in the non-cancerous HEK293 cells (Supplementary Fig.	('knockdown', 'Var', (18, 27))	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('cancer', 'Disease', (84, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('proliferation', 'CPA', (54, 67))	('HEK293', 'CellLine', 'CVCL:0045', (94, 100))	('SCAT7', 'Gene', (31, 36))	('decreased', 'NegReg', (44, 53))
7172	29491376	Furthermore, SCAT7 depletion altered the S-phase progression in multiple cell lines as indicated by the nascent 5-ethynyl-2'-deoxyuridine analog (EdU) incorporation assay (Supplementary Fig.	('depletion', 'Var', (19, 28))	('EdU', 'Chemical', '-', (146, 149))	('SCAT7', 'Gene', (13, 18))	('S-phase progression', 'CPA', (41, 60))	('altered', 'Reg', (29, 36))	("5-ethynyl-2'-deoxyuridine", 'Chemical', 'MESH:C031086', (112, 137))
7174	29491376	SCAT7 knockdown in Caki-2 and A549 cell lines increased caspase 3/7 activity (Fig.	('caspase 3', 'Gene', (56, 65))	('A549', 'CellLine', 'CVCL:0023', (30, 34))	('increased', 'PosReg', (46, 55))	('caspase 3', 'Gene', '836', (56, 65))	('SCAT7', 'Gene', (0, 5))	('Caki-2', 'CellLine', 'CVCL:0235', (19, 25))	('activity', 'MPA', (68, 76))	('knockdown', 'Var', (6, 15))
7175	29491376	The invasion capacity was severely suppressed in Caki-2 and A549 knockdown cells, while the effect was very limited in the case of 786-O knockdown cells.	('invasion capacity', 'CPA', (4, 21))	('Caki-2', 'CellLine', 'CVCL:0235', (49, 55))	('suppressed', 'NegReg', (35, 45))	('knockdown', 'Var', (65, 74))	('A549', 'CellLine', 'CVCL:0023', (60, 64))
7181	29491376	The immortalized BJ-BRAF fibroblasts express the activated form of mouse B-RAF (V600E) under the control of estrogen receptor (ER:B-RAF).	('B-RAF', 'Protein', (73, 78))	('BJ-BRAF', 'CellLine', 'CVCL:6573', (17, 24))	('V600E', 'Var', (80, 85))	('estrogen receptor', 'Gene', (108, 125))	('ER:B', 'Gene', '13983', (127, 131))	('mouse', 'Species', '10090', (67, 72))	('estrogen receptor', 'Gene', '13982', (108, 125))	('V600E', 'Mutation', 'rs113488022', (80, 85))	('ER:B', 'Gene', (127, 131))
7185	29491376	Cells overexpressing SCAT7 were able to bypass the tamoxifen-induced senescence, as indicated by less beta-galactosidase activity and transcriptional repression of the key senescence markers p16, p15, and IL8 (Fig.	('activity', 'MPA', (121, 129))	('IL8', 'Gene', (205, 208))	('SCAT7', 'Var', (21, 26))	('p16', 'Gene', '1029', (191, 194))	('p15', 'Gene', (196, 199))	('IL8', 'Gene', '3576', (205, 208))	('repression', 'NegReg', (150, 160))	('beta-galactosidase', 'Gene', (102, 120))	('p15', 'Gene', '1030', (196, 199))	('transcriptional', 'MPA', (134, 149))	('beta-galactosidase', 'Gene', '2720', (102, 120))	('tamoxifen', 'Chemical', 'MESH:D013629', (51, 60))	('p16', 'Gene', (191, 194))	('less', 'NegReg', (97, 101))
7186	29491376	We next tested the hypothesis that SCAT7 silencing in cancer cell lines may promote senescence.	('tested', 'Reg', (8, 14))	('promote', 'PosReg', (76, 83))	('silencing', 'Var', (41, 50))	('senescence', 'CPA', (84, 94))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('cancer', 'Disease', (54, 60))	('SCAT7', 'Gene', (35, 40))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
7188	29491376	Downregulation of SCAT7 induced the senescence phenotype in both HeLa and A549 cells while Caki-2 cells remained unaffected (Fig.	('Downregulation', 'Var', (0, 14))	('A549', 'CellLine', 'CVCL:0023', (74, 78))	('Caki-2', 'CellLine', 'CVCL:0235', (91, 97))	('SCAT7', 'Gene', (18, 23))	('senescence phenotype', 'MPA', (36, 56))	('HeLa', 'CellLine', 'CVCL:0030', (65, 69))
7193	29491376	CCND1 was downregulated at the transcriptional and translational level upon SCAT7 knockdown while p-RB, but not RB, was downregulated at the protein level.	('downregulated', 'NegReg', (10, 23))	('knockdown', 'Var', (82, 91))	('CCND1', 'Gene', (0, 5))	('SCAT7', 'Gene', (76, 81))	('CCND1', 'Gene', '595', (0, 5))
7199	29491376	For instance, SCAT7 knockdown affected the mRNA levels of FGFR2, FGFR3, FGF7, and FGF21 in HeLa cells while only FGFR2 was downregulated in the Caki-2 and 786-O cells (Fig.	('FGFR3', 'Gene', '2261', (65, 70))	('FGF7', 'Gene', (72, 76))	('FGFR2', 'Gene', (113, 118))	('FGFR2', 'Gene', '2263', (58, 63))	('affected', 'Reg', (30, 38))	('FGFR2', 'Gene', '2263', (113, 118))	('FGFR3', 'Gene', (65, 70))	('HeLa', 'CellLine', 'CVCL:0030', (91, 95))	('SCAT7', 'Gene', (14, 19))	('mRNA levels', 'MPA', (43, 54))	('Caki-2', 'CellLine', 'CVCL:0235', (144, 150))	('FGF21', 'Gene', '26291', (82, 87))	('knockdown', 'Var', (20, 29))	('FGF7', 'Gene', '2252', (72, 76))	('FGF21', 'Gene', (82, 87))	('FGFR2', 'Gene', (58, 63))
7206	29491376	Interestingly, the effects of the FGFR2 depletion on cell cycle, cell proliferation, and vitality phenocopied the effects of the SCAT7 depletion in the HeLa and Caki-2 cells (Fig.	('FGFR2', 'Gene', (34, 39))	('SCAT7', 'Gene', (129, 134))	('depletion', 'Var', (135, 144))	('FGFR2', 'Gene', '2263', (34, 39))	('HeLa', 'CellLine', 'CVCL:0030', (152, 156))	('depletion', 'Var', (40, 49))	('cell proliferation', 'CPA', (65, 83))	('cell cycle', 'CPA', (53, 63))	('Caki-2', 'CellLine', 'CVCL:0235', (161, 167))	('vitality', 'CPA', (89, 97))
7215	29491376	Transient knockdown of hnRNPK or YBX1 by siRNAs (Supplementary Fig.	('hnRNPK', 'Gene', '3190', (23, 29))	('YBX1', 'Gene', (33, 37))	('hnRNPK', 'Gene', (23, 29))	('knockdown', 'Var', (10, 19))	('YBX1', 'Gene', '4904', (33, 37))
7218	29491376	The activities of the MAPK and AKT pathways downstream to FGFRs were also reduced upon hnRNPK or YBX1 knockdown (Fig.	('activities', 'MPA', (4, 14))	('AKT', 'Gene', (31, 34))	('hnRNPK', 'Gene', (87, 93))	('YBX1', 'Gene', (97, 101))	('knockdown', 'Var', (102, 111))	('MAPK', 'Pathway', (22, 26))	('YBX1', 'Gene', '4904', (97, 101))	('reduced', 'NegReg', (74, 81))	('AKT', 'Gene', '207', (31, 34))	('hnRNPK', 'Gene', '3190', (87, 93))
7222	29491376	Our analysis revealed a significant enrichment of SCAT7 at the FGFR2 (-250 to -750 bp relative to TSS (Fig.	('FGFR2', 'Gene', '2263', (63, 68))	('FGFR2', 'Gene', (63, 68))	('-250 to -750 bp', 'Var', (70, 85))	('SCAT7', 'MPA', (50, 55))
7223	29491376	7h) and FGFR3 (-750 bp to -1 kb relative to TSS) (Fig.	('FGFR3', 'Gene', '2261', (8, 13))	('-750 bp', 'Var', (15, 22))	('FGFR3', 'Gene', (8, 13))
7232	29491376	ChOP-qPCR assays in A549 and Caki-2 cells revealed SCAT7 occupancy at the promoter regions of FGFR3 (-750 bp to -1 kb) and FGFR2 (-250 bp to -500 bp), respectively (Fig.	('FGFR2', 'Gene', '2263', (123, 128))	('FGFR2', 'Gene', (123, 128))	('-750', 'Var', (101, 105))	('A549', 'CellLine', 'CVCL:0023', (20, 24))	('FGFR3', 'Gene', '2261', (94, 99))	('Caki-2', 'CellLine', 'CVCL:0235', (29, 35))	('SCAT7', 'MPA', (51, 56))	('FGFR3', 'Gene', (94, 99))
7239	29491376	Eight weeks post-engraftment, both SCAT7 depleted 786-O and A549 xenografts showed a significant decrease in growth parameters compared to control xenografts.	('decrease', 'NegReg', (97, 105))	('SCAT7 depleted 786-O', 'Var', (35, 55))	('growth parameters', 'MPA', (109, 126))	('A549', 'CellLine', 'CVCL:0023', (60, 64))
7240	29491376	Ki67 immunostaining of the dissected tumors confirmed the restricted proliferation capacity of SCAT7 knockdown cells in vivo (Fig.	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('SCAT7', 'Gene', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumors', 'Disease', (37, 43))	('restricted', 'NegReg', (58, 68))	('tumors', 'Disease', 'MESH:D009369', (37, 43))	('knockdown', 'Var', (101, 110))
7243	29491376	We measured the tumor volumes after a course of four injections in two independent experiments and observed 40-50% tumor growth inhibition (TGI) in SCAT7 LNA groups compared to the scrambled LNA control group (Fig.	('SCAT7 LNA groups', 'Var', (148, 164))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('tumor', 'Disease', (115, 120))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('tumor', 'Disease', (16, 21))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
7263	29491376	Therefore, our DNA methylation investigations of S-phase lncRNAs reflect the role of epigenetic alterations in modulating their transcriptional activities during tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('tumor', 'Disease', (162, 167))	('modulating', 'Reg', (111, 121))	('epigenetic alterations', 'Var', (85, 107))	('transcriptional activities', 'MPA', (128, 154))	('tumor', 'Disease', 'MESH:D009369', (162, 167))
7265	29491376	For instance, SCAT8 appeared to be the top prognostic indicator in our studies with the higher hazard ratio in our multivariate models and it also interferes with cancer cell hallmarks, indicating that it may be an oncogenic driver in multiple cancers.	('interferes', 'NegReg', (147, 157))	('cancer', 'Disease', 'MESH:D009369', (163, 169))	('SCAT8', 'Var', (14, 19))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('multiple cancers', 'Disease', (235, 251))	('cancers', 'Phenotype', 'HP:0002664', (244, 251))	('multiple cancers', 'Disease', 'MESH:D009369', (235, 251))	('cancer', 'Disease', (163, 169))	('cancer', 'Disease', (244, 250))	('cancer', 'Disease', 'MESH:D009369', (244, 250))
7272	29491376	Upon SCAT7 knockdown different types of proliferative cell lines exhibit the characteristic features of cellular senescence including beta-galactosidase secretion, cell cycle arrest, and induction of different tumor suppressor genes (p21, p16, and p15).	('cell cycle arrest', 'CPA', (164, 181))	('p16', 'Gene', (239, 242))	('p21', 'Gene', (234, 237))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('p21', 'Gene', '644914', (234, 237))	('beta-galactosidase', 'Gene', '2720', (134, 152))	('tumor', 'Disease', (210, 215))	('p15', 'Gene', (248, 251))	('beta-galactosidase', 'Gene', (134, 152))	('p16', 'Gene', '1029', (239, 242))	('p15', 'Gene', '1030', (248, 251))	('cellular senescence', 'CPA', (104, 123))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (164, 181))	('knockdown', 'Var', (11, 20))	('tumor', 'Disease', 'MESH:D009369', (210, 215))
7277	29491376	The dissection of the regulatory pathways mediated by the action of SCAT7 indicated its crucial involvement in regulating pivotal signaling pathways across multiple cancer models.	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('action', 'Var', (58, 64))	('multiple cancer', 'Disease', 'MESH:D009369', (156, 171))	('SCAT7', 'Gene', (68, 73))	('pivotal signaling pathways', 'Pathway', (122, 148))	('involvement', 'Reg', (96, 107))	('multiple cancer', 'Disease', (156, 171))
7279	29491376	Given that several FGF/FGFR members were deregulated upon SCAT7 knockdown in multiple cancer models, we hypothesized a genuine connection between SCAT7 and FGF signaling in the context of cancer.	('deregulated', 'Reg', (41, 52))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('multiple cancer', 'Disease', (77, 92))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('multiple cancer', 'Disease', 'MESH:D009369', (77, 92))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('SCAT7', 'Gene', (58, 63))	('FGF/FGFR', 'Gene', (19, 27))	('cancer', 'Disease', (188, 194))	('knockdown', 'Var', (64, 73))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('cancer', 'Disease', (86, 92))
7285	29491376	For instance, a SNP in FGFR2 was shown to affect the progression-free survival alone in the metastatic KIRC patients undergoing anti-VEGF-targeted therapy.	('affect', 'Reg', (42, 48))	('VEGF', 'Gene', '7422', (133, 137))	('FGFR2', 'Gene', (23, 28))	('SNP', 'Var', (16, 19))	('VEGF', 'Gene', (133, 137))	('FGFR2', 'Gene', '2263', (23, 28))	('patients', 'Species', '9606', (108, 116))	('progression-free survival', 'CPA', (53, 78))
7286	29491376	Also, a missense mutation in FGFR2 was found to drive a durable response to nucleolin-targeted therapy in metastatic KIRC.	('missense mutation', 'Var', (8, 25))	('FGFR2', 'Gene', '2263', (29, 34))	('response to nucleolin-targeted therapy', 'MPA', (64, 102))	('FGFR2', 'Gene', (29, 34))
7287	29491376	Despite the fact that various FGFR members harbor activating mutations in lung cancer patients and confer acquired resistance to tyrosine kinase inhibitors (TKIs), only a handful of studies have addressed the role of these mutations in LUAD tumorogenesis.	('LUAD tumorogenesis', 'Disease', (236, 254))	('lung cancer', 'Disease', (74, 85))	('lung cancer', 'Phenotype', 'HP:0100526', (74, 85))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('resistance to tyrosine kinase inhibitors', 'MPA', (115, 155))	('mutations', 'Var', (61, 70))	('FGFR members', 'Gene', (30, 42))	('lung cancer', 'Disease', 'MESH:D008175', (74, 85))	('LUAD tumorogenesis', 'Disease', 'MESH:D002471', (236, 254))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))	('activating', 'PosReg', (50, 60))	('patients', 'Species', '9606', (86, 94))
7288	29491376	generated the first genetically engineered lung cancer mouse model harboring an FGFR mutation in p53 null background.	('p53', 'Gene', (97, 100))	('lung cancer', 'Phenotype', 'HP:0100526', (43, 54))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('engineered lung cancer', 'Disease', 'MESH:D008175', (32, 54))	('mutation', 'Var', (85, 93))	('engineered lung cancer', 'Disease', (32, 54))	('mouse', 'Species', '10090', (55, 60))	('p53', 'Gene', '22060', (97, 100))	('FGFR', 'Gene', (80, 84))
7289	29491376	The engineered mouse model showed more than 50% tumor regression when treated with a pan-FGFR inhibitor.	('tumor', 'Disease', (48, 53))	('inhibitor', 'Var', (94, 103))	('mouse', 'Species', '10090', (15, 20))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('pan-FGFR', 'Gene', (85, 93))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
7290	29491376	reported a combinatorial approach including FGFR1 inhibitor to overcome the adaptive resistance to MEK inhibitor in KRAS-mutant LUAD.	('MEK', 'Gene', '5609', (99, 102))	('FGFR1', 'Gene', (44, 49))	('FGFR1', 'Gene', '2260', (44, 49))	('KRAS-mutant', 'Var', (116, 127))	('adaptive resistance', 'MPA', (76, 95))	('MEK', 'Gene', (99, 102))
7291	29491376	Considering the functional nexus between SCAT7 and FGF signaling, targeting SCAT7 alone is sufficient to inhibit tumor progression via repressing different members of the FGF/FGFR pathway.	('tumor', 'Disease', (113, 118))	('repressing', 'NegReg', (135, 145))	('FGF/FGFR pathway', 'Pathway', (171, 187))	('inhibit', 'NegReg', (105, 112))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('targeting', 'Var', (66, 75))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('SCAT7', 'Gene', (76, 81))
7311	29491376	The labeling periods were defined as follows: T0h-T2h (beginning of S-phase), T1.5h-T3.5 h (middle of S-phase), and T3h-T5h (end of S-phase).	('T1.5h-T3.5 h', 'Var', (78, 90))	('T3h-T5h', 'Chemical', '-', (116, 123))	('T0h-T2h', 'Chemical', '-', (46, 53))	('T3h-T5h', 'Var', (116, 123))
7347	29491376	The significant DMRs from COSMIC were assigned to promoter (-2000 bp and +500 bp from TSS) and gene body (TSS + 550 to length of transcript) regions of the cancer-associated lncRNAs from our study.	('cancer', 'Disease', (156, 162))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('-2000', 'Var', (60, 65))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('TSS + 550', 'Var', (106, 115))
7350	29491376	All presented hypo and hypermethylation lncRNAs has FWER < 0.05 obtained with matched normal and tumor comparison in respective cancer types.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('hypo', 'Var', (14, 18))	('tumor', 'Disease', (97, 102))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('hypermethylation', 'Var', (23, 39))	('cancer', 'Disease', (128, 134))
7397	29491376	For each group (n = 6), we injected either 100 pmol of scrambled LNA or SCAT7 LNA1 every three days for a total period of 15 days.	('LNA1', 'Gene', '104188', (78, 82))	('SCAT7', 'Var', (72, 77))	('LNA1', 'Gene', (78, 82))
7417	28379620	As several papers have addressed copy number variation (CNV) patterns in NSCLC, a gain in corresponding knowledge is incremental.	('NSCLC', 'Disease', (73, 78))	('copy number variation', 'Var', (33, 54))	('NSCLC', 'Phenotype', 'HP:0030358', (73, 78))	('NSCLC', 'Disease', 'MESH:D002289', (73, 78))
7443	28379620	LUSC tumors also showed the greatest deflections for gain (chromosome arms 2p, 12p, and part of 22q) and loss (3p, 4p, and 5q).	('tumors', 'Disease', (5, 11))	('tumors', 'Disease', 'MESH:D009369', (5, 11))	('3p', 'Var', (111, 113))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('loss', 'NegReg', (105, 109))	('gain', 'PosReg', (53, 57))	('chromosome arms 2p', 'Var', (59, 77))	('tumors', 'Phenotype', 'HP:0002664', (5, 11))	('LUSC', 'Phenotype', 'HP:0030359', (0, 4))
7444	28379620	Losses of 3p were the first cytogenetic alteration found in lung cancers, occurring early during lung cancer pathogenesis, and multiple tumor suppressor genes are located in this region.	('lung cancers', 'Disease', 'MESH:D008175', (60, 72))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('lung cancer', 'Phenotype', 'HP:0100526', (60, 71))	('Losses of', 'Var', (0, 9))	('lung cancers', 'Phenotype', 'HP:0100526', (60, 72))	('lung cancer', 'Disease', 'MESH:D008175', (97, 108))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('lung cancer', 'Disease', 'MESH:D008175', (60, 71))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('lung cancers', 'Disease', (60, 72))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('cancers', 'Phenotype', 'HP:0002664', (65, 72))	('lung cancer', 'Disease', (97, 108))	('lung cancer', 'Phenotype', 'HP:0100526', (97, 108))	('tumor', 'Disease', (136, 141))
7448	28379620	While mutations in KRAS are characteristic of LUADs, gains of KRAS (12p12.1) were more common in LUSC (33.3%) than in LUAD (21.4%) (P=4.3E-7).	('KRAS', 'Gene', (62, 66))	('KRAS', 'Gene', '103819595', (19, 23))	('gains', 'PosReg', (53, 58))	('LUSC', 'Disease', (97, 101))	('LUSC', 'Phenotype', 'HP:0030359', (97, 101))	('KRAS', 'Gene', (19, 23))	('LUAD', 'Phenotype', 'HP:0030078', (46, 50))	('LUAD', 'Phenotype', 'HP:0030078', (118, 122))	('KRAS', 'Gene', '103819595', (62, 66))	('mutations', 'Var', (6, 15))
7475	28379620	Amplification of the MYC family genes MYC and MYCL (1p34.2) is common in lung cancers, and narrow band gains of both genes were noted in LUADs and LUSCs.	('common', 'Reg', (63, 69))	('LUADs', 'Disease', (137, 142))	('lung cancers', 'Disease', 'MESH:D008175', (73, 85))	('MYC', 'Gene', '103816707', (46, 49))	('lung cancers', 'Disease', (73, 85))	('MYCL', 'Gene', '103823559', (46, 50))	('MYCL', 'Gene', (46, 50))	('MYC', 'Gene', '103816707', (21, 24))	('lung cancer', 'Phenotype', 'HP:0100526', (73, 84))	('lung cancers', 'Phenotype', 'HP:0100526', (73, 85))	('MYC', 'Gene', '103816707', (38, 41))	('cancers', 'Phenotype', 'HP:0002664', (78, 85))	('MYC', 'Gene', (46, 49))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('LUSC', 'Phenotype', 'HP:0030359', (147, 151))	('MYC', 'Gene', (21, 24))	('Amplification', 'Var', (0, 13))	('MYC', 'Gene', (38, 41))	('LUSCs', 'Disease', (147, 152))	('LUAD', 'Phenotype', 'HP:0030078', (137, 141))	('gains', 'PosReg', (103, 108))
7492	28379620	Thus, in addition to the well-described FGFR1 gene, multiple members of the FGF family show copy number gains in SCC tumors.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('gains', 'PosReg', (104, 109))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('FGFR1', 'Gene', (40, 45))	('copy number', 'Var', (92, 103))	('SCC tumors', 'Disease', 'MESH:D009369', (113, 123))	('SCC tumors', 'Disease', (113, 123))	('FGFR1', 'Gene', '103822693', (40, 45))
7493	28379620	While the occurrence of FGFR1 amplification in SCCs is well known, the roles of other FGFR receptors and their ligands in lung cancer are poorly documented.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('SCCs', 'Phenotype', 'HP:0002860', (47, 51))	('lung cancer', 'Disease', (122, 133))	('FGFR1', 'Gene', '103822693', (24, 29))	('lung cancer', 'Phenotype', 'HP:0100526', (122, 133))	('amplification', 'Var', (30, 43))	('FGFR1', 'Gene', (24, 29))	('SCCs', 'Disease', (47, 51))	('lung cancer', 'Disease', 'MESH:D008175', (122, 133))
7495	28379620	Because the magnitude of deflections was greater in LUSC tumors and because the most notable difference between the two cancer types was selective amplification of 3q in LUSCs, the 33-gene list is biased in favor of LUSCs (26 genes, 79%), as well as the chromosomal location on 3q (21 genes, 64%).	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('LUSC', 'Phenotype', 'HP:0030359', (52, 56))	('deflections', 'MPA', (25, 36))	('LUSC', 'Phenotype', 'HP:0030359', (170, 174))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('amplification', 'Var', (147, 160))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('tumors', 'Disease', (57, 63))	('LUSC', 'Phenotype', 'HP:0030359', (216, 220))	('tumors', 'Disease', 'MESH:D009369', (57, 63))
7511	28379620	Tumors with either one of these oncogenic changes failed to exhibit copy number changes that were significantly different from those of wild type tumors.	('type tumors', 'Disease', (141, 152))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('type tumors', 'Disease', 'MESH:D009369', (141, 152))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('changes', 'Var', (42, 49))	('tumors', 'Phenotype', 'HP:0002664', (146, 152))
7556	27286445	Interestingly, we found that both mRNA and protein levels of FAK were decreased in FADD-/- MEFs compared with FADD+/+ MEFs (Figure 2A, 2B and 2C).	('MEFs', 'CellLine', 'CVCL:9115', (118, 122))	('FADD-/- MEFs', 'Var', (83, 95))	('decreased', 'NegReg', (70, 79))	('MEFs', 'CellLine', 'CVCL:9115', (91, 95))
7558	27286445	Similarly, the mRNA and protein levels of FAK were also down-regulated in MEFs transfected with FADD siRNAs (Figure 2D, 2E and 2F).	('down-regulated', 'NegReg', (56, 70))	('MEFs', 'CellLine', 'CVCL:9115', (74, 78))	('transfected', 'Var', (79, 90))	('FADD', 'Var', (96, 100))
7571	27286445	As expected, FADD and FAK showed higher expression level in B16F10 cells than in B16F1 cells, confirmed by both mRNA and protein expression measurements (Figure 4A and 4B).	('higher', 'PosReg', (33, 39))	('B16F10', 'Var', (60, 66))	('expression level', 'MPA', (40, 56))	('B16F1', 'CellLine', 'CVCL:0158', (81, 86))	('B16F1', 'CellLine', 'CVCL:0158', (60, 65))	('B16F10', 'CellLine', 'CVCL:0159', (60, 66))
7572	27286445	Expression of miR-7a, on the contrary, was reduced in B16F10 cells compared to B16F1 cells (Figure 4A).	('B16F10', 'Var', (54, 60))	('miR-7a', 'Chemical', '-', (14, 20))	('Expression', 'MPA', (0, 10))	('B16F1', 'CellLine', 'CVCL:0158', (54, 59))	('reduced', 'NegReg', (43, 50))	('B16F10', 'CellLine', 'CVCL:0159', (54, 60))	('B16F1', 'CellLine', 'CVCL:0158', (79, 84))	('miR-7a', 'Gene', (14, 20))
7576	27286445	FADD knockdown was associated with down-regulation of FAK but up-regulation of miR-7a (Figure 4C, 4D, 4G and 4H) while FADD overexpression was associated with up-regulation of FAK but down-regulation of miR-7a (Figure 4E, 4F, 4I and 4J), consistent with the results from MEF cells.	('miR-7a', 'Chemical', '-', (79, 85))	('FAK', 'Protein', (176, 179))	('knockdown', 'Var', (5, 14))	('up-regulation', 'PosReg', (159, 172))	('FADD', 'Gene', (0, 4))	('MEF', 'Gene', (271, 274))	('down-regulation', 'NegReg', (184, 199))	('FAK', 'CPA', (54, 57))	('MEF', 'Gene', '56501', (271, 274))	('miR-7a', 'Gene', (203, 209))	('miR-7a', 'Chemical', '-', (203, 209))	('down-regulation', 'NegReg', (35, 50))	('up-regulation', 'PosReg', (62, 75))	('miR-7a', 'Gene', (79, 85))
7587	27286445	The luciferase activity was significantly decreased in B16F10 cells co-transfected with FAK-3'-UTR and miR-7a mimic compared to the negative control miRNA.	('decreased', 'NegReg', (42, 51))	('B16F10', 'CellLine', 'CVCL:0159', (55, 61))	('activity', 'MPA', (15, 23))	("FAK-3'-UTR", 'Var', (88, 98))	('luciferase', 'Enzyme', (4, 14))	('miR-7a', 'Chemical', '-', (103, 109))
7596	27286445	After a 24 h period, we found that miR-7a overexpression substantially reduced the rate of cell migration, while miR-7a knockdown increased the rate of migration (Figure 6B).	('migration', 'CPA', (152, 161))	('miR-7a', 'Chemical', '-', (35, 41))	('miR-7a', 'Gene', (113, 119))	('knockdown', 'Var', (120, 129))	('reduced', 'NegReg', (71, 78))	('miR-7a', 'Chemical', '-', (113, 119))	('increased', 'PosReg', (130, 139))	('miR-7a', 'Gene', (35, 41))
7599	27286445	Since B16F10 was highly metastatic with higher FAK expression than B16F1, we co-transfected FADD siRNA (siFADD) with either miR-7a mimic or inhibitor into B16F10 cells.	('B16F1', 'CellLine', 'CVCL:0158', (155, 160))	('B16F10', 'CellLine', 'CVCL:0159', (6, 12))	('higher', 'PosReg', (40, 46))	('B16F10', 'CellLine', 'CVCL:0159', (155, 161))	('miR-7a', 'Chemical', '-', (124, 130))	('B16F1', 'CellLine', 'CVCL:0158', (67, 72))	('FAK expression', 'MPA', (47, 61))	('B16F10', 'Var', (6, 12))	('B16F1', 'CellLine', 'CVCL:0158', (6, 11))	('siFADD', 'Chemical', '-', (104, 110))	('metastatic', 'CPA', (24, 34))
7622	27286445	also demonstrated that FADD was associated with a higher incidence of lymph node metastases and might cause an increased risk of distant metastasis in head and neck squamous cell carcinoma.	('lymph node metastases', 'Disease', 'MESH:D009362', (70, 91))	('cause', 'Reg', (102, 107))	('lymph node metastases', 'Disease', (70, 91))	('neck squamous cell carcinoma', 'Disease', (160, 188))	('distant metastasis', 'CPA', (129, 147))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (151, 188))	('FADD', 'Var', (23, 27))	('carcinoma', 'Phenotype', 'HP:0030731', (179, 188))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (165, 188))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (160, 188))
7633	27286445	The decrease in miR-7a caused by artificial overexpression of FADD in B16F10 was not obvious compared to that in lowly metastatic cell line B16F1, leading to an inconspicuous change in FAK expression in B16F10 (Figure 4E and 4F), compared to a profound change in FAK in B16F1 (Figure 4I and 4J).	('change', 'Reg', (175, 181))	('B16F10', 'CellLine', 'CVCL:0159', (70, 76))	('B16F10', 'Var', (203, 209))	('B16F1', 'CellLine', 'CVCL:0158', (270, 275))	('miR-7a', 'Chemical', '-', (16, 22))	('FAK expression', 'MPA', (185, 199))	('B16F1', 'CellLine', 'CVCL:0158', (140, 145))	('B16F10', 'CellLine', 'CVCL:0159', (203, 209))	('B16F1', 'CellLine', 'CVCL:0158', (203, 208))	('B16F1', 'CellLine', 'CVCL:0158', (70, 75))
7645	27286445	We then cloned FAK-3'UTR and FAK-3'UTR-mutant into luciferase reporter plasmids, co-transfected them with miR-7a mimic and investigated their luciferase activities.	('miR-7a', 'Chemical', '-', (106, 112))	("FAK-3'UTR-mutant", 'Var', (29, 45))	("FAK-3'UTR", 'Var', (15, 24))	('investigated', 'Reg', (123, 135))
7658	27286445	As for the relationship between miR-7a and FAK, miR-7a could suppress FAK expression through binding to 3'UTR of FAK mRNA and lead to subsequent mRNA degradation.	('miR-7a', 'Chemical', '-', (48, 54))	('FAK', 'Protein', (70, 73))	("3'UTR", 'MPA', (104, 109))	('binding', 'Interaction', (93, 100))	('miR-7a', 'Chemical', '-', (32, 38))	('lead to', 'Reg', (126, 133))	('suppress', 'NegReg', (61, 69))	('mRNA degradation', 'MPA', (145, 161))	('miR-7a', 'Var', (48, 54))
7661	27286445	A375, A2058 and Lu1205) have reported similar results, where cell migration can be inhibited by FAK suppression in combination with some other miRNA or small molecule.	('A2058', 'Var', (6, 11))	('A375', 'CellLine', 'CVCL:0132', (0, 4))	('inhibited', 'NegReg', (83, 92))	('cell migration', 'CPA', (61, 75))	('Lu1205', 'Var', (16, 22))	('FAK suppression', 'MPA', (96, 111))
7689	27286445	Antibodies used for Western Blotting were as follows: anti-FADD (Abcam, ab108601), anti-FAK (BD Bioscience, 610088), anti-beta-actin (ABGENT, AM1021B), anti-GAPDH (Santa Cruz biotechnology, L-3113) and anti-alpha-Tubulin (Epitomics, 2871-1).	('beta-actin', 'Gene', '11461', (122, 132))	('anti-FADD', 'Var', (54, 63))	('anti-alpha-Tubulin', 'Protein', (202, 220))	('beta-actin', 'Gene', (122, 132))	('GAPDH', 'Gene', '14433', (157, 162))	('GAPDH', 'Gene', (157, 162))	('anti-FAK', 'Var', (83, 91))
7837	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))	('miR-21', 'Gene', (14, 20))	('migration', 'CPA', (114, 123))	('migration', 'CPA', (29, 38))	('Inhibition', 'Var', (0, 10))	('miR-21', 'Gene', '406991', (98, 104))	('invasion', 'CPA', (128, 136))
7840	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))
7842	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))
7881	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))
7882	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))
7888	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))
7889	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))
7899	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))
7902	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))
7930	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))
7937	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))
7940	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))
7942	30314898	Both epigenetic and genetic changes contribute to the initiation, development and metastasis of NSCLC.	('metastasis of NSCLC', 'Disease', 'MESH:D009362', (82, 101))	('genetic changes', 'Var', (20, 35))	('contribute', 'Reg', (36, 46))	('men', 'Species', '9606', (73, 76))	('development', 'CPA', (66, 77))	('epigenetic', 'Var', (5, 15))	('metastasis of NSCLC', 'Disease', (82, 101))	('NSCLC', 'Phenotype', 'HP:0030358', (96, 101))
7952	30314898	The results revealed that PCAT6 knockdown mitigated NSCLC cell growth by inducing G1-phase cell cycle arrest and apoptosis in vitro and in vivo.	('PCAT6', 'Gene', '100506696', (26, 31))	('arrest', 'Disease', (102, 108))	('mitigated', 'NegReg', (42, 51))	('apoptosis', 'CPA', (113, 122))	('inducing', 'PosReg', (73, 81))	('NSCLC', 'Disease', (52, 57))	('knockdown', 'Var', (32, 41))	('NSCLC', 'Disease', 'MESH:D002289', (52, 57))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (91, 108))	('NSCLC', 'Phenotype', 'HP:0030358', (52, 57))	('arrest', 'Disease', 'MESH:D006323', (102, 108))	('PCAT6', 'Gene', (26, 31))
7963	30314898	Our study provides new insight into the novel mechanism of PCAT6-mediated NSCLC via epigenetically suppressing LATS2, suggesting that PCAT6 might be a potent therapeutic target for patients with NSCLC.	('NSCLC', 'Disease', 'MESH:D002289', (195, 200))	('PCAT6', 'Gene', (59, 64))	('LATS2', 'Gene', (111, 116))	('NSCLC', 'Phenotype', 'HP:0030358', (74, 79))	('PCAT6', 'Gene', '100506696', (134, 139))	('NSCLC', 'Disease', (195, 200))	('PCAT6', 'Gene', '100506696', (59, 64))	('NSCLC', 'Phenotype', 'HP:0030358', (195, 200))	('NSCLC', 'Disease', (74, 79))	('patients', 'Species', '9606', (181, 189))	('NSCLC', 'Disease', 'MESH:D002289', (74, 79))	('epigenetically', 'Var', (84, 98))	('PCAT6', 'Gene', (134, 139))	('LATS2', 'Gene', '26524', (111, 116))
8022	30314898	After siRNA or vector transfection, the cells were harvested in a lysis buffer containing PMSF (Roche), a protease inhibitor cocktail (Roche, Basel, Switzerland) and a mammalian protein extraction reagent RIPA (Beyotime China).	('mammalian', 'Species', '9606', (168, 177))	('RIP', 'Gene', (205, 208))	('transfection', 'Var', (22, 34))	('PMSF', 'Chemical', 'MESH:D010664', (90, 94))	('RIP', 'Gene', '84268', (205, 208))
8041	30314898	With the purpose of manipulating the PCAT6 level in NSCLC cells, we performed loss-of-function study using two discrete chemically synthesized siRNA in A549 (adenocarcinoma cell line) and SK-MES-1 (squamous carcinoma cell line).	('squamous carcinoma', 'Phenotype', 'HP:0002860', (198, 216))	('NSCLC', 'Disease', (52, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (163, 172))	('adenocarcinoma', 'Disease', (158, 172))	('carcinoma', 'Phenotype', 'HP:0030731', (207, 216))	('NSCLC', 'Disease', 'MESH:D002289', (52, 57))	('A549', 'CellLine', 'CVCL:0023', (152, 156))	('adenocarcinoma', 'Disease', 'MESH:D000230', (158, 172))	('manipulating', 'Var', (20, 32))	('SK-MES-1', 'CellLine', 'CVCL:0630', (188, 196))	('squamous carcinoma', 'Disease', 'MESH:D002294', (198, 216))	('PCAT6', 'Gene', (37, 42))	('squamous carcinoma', 'Disease', (198, 216))	('NSCLC', 'Phenotype', 'HP:0030358', (52, 57))	('PCAT6', 'Gene', '100506696', (37, 42))
8045	30314898	An MTT assay demonstrated that PCAT6 knockdown inhibits the proliferation rate of A549 and SK-MES-1 (Fig.	('PCAT6', 'Gene', (31, 36))	('knockdown', 'Var', (37, 46))	('SK-MES-1', 'CellLine', 'CVCL:0630', (91, 99))	('MTT', 'Chemical', 'MESH:C070243', (3, 6))	('PCAT6', 'Gene', '100506696', (31, 36))	('proliferation rate', 'CPA', (60, 78))	('A549', 'CellLine', 'CVCL:0023', (82, 86))	('inhibits', 'NegReg', (47, 55))
8048	30314898	What's more, overexpression PCAT6 could promote cell growth and protect the colony-forming ability (Fig.	('promote', 'PosReg', (40, 47))	('cell growth', 'CPA', (48, 59))	('PCAT6', 'Gene', (28, 33))	('PCAT6', 'Gene', '100506696', (28, 33))	('colony-forming ability', 'CPA', (76, 98))	('protect', 'NegReg', (64, 71))	('overexpression', 'Var', (13, 27))
8052	30314898	3h, PCAT6 knockdown decreased the percentage of cells in the S phase and increased the percentage of cells in the G0/G1 phase compared with control cells.	('increased', 'PosReg', (73, 82))	('3h', 'Chemical', 'MESH:D014316', (0, 2))	('decreased', 'NegReg', (20, 29))	('PCAT6', 'Gene', '100506696', (4, 9))	('knockdown', 'Var', (10, 19))	('PCAT6', 'Gene', (4, 9))
8055	30314898	Accordingly, we proposed that low PCAT6 expression is both important and necessary for apoptosis and normal growth arrest in the NSCLC cell lines.	('expression', 'MPA', (40, 50))	('PCAT6', 'Gene', (34, 39))	('NSCLC', 'Phenotype', 'HP:0030358', (129, 134))	('arrest', 'Disease', 'MESH:D006323', (115, 121))	('growth arrest', 'Phenotype', 'HP:0001510', (108, 121))	('low', 'Var', (30, 33))	('PCAT6', 'Gene', '100506696', (34, 39))	('arrest', 'Disease', (115, 121))	('NSCLC', 'Disease', (129, 134))	('NSCLC', 'Disease', 'MESH:D002289', (129, 134))
8057	30314898	Silencing of PCAT6 strongly inhibited their capability of migration, compared to that in the control cells (Fig.	('Silencing', 'Var', (0, 9))	('inhibited', 'NegReg', (28, 37))	('PCAT6', 'Gene', '100506696', (13, 18))	('PCAT6', 'Gene', (13, 18))
8064	30314898	Moreover, quantitative RT-PCR analysis demonstrated that the expression level of PCAT6 in the tumors after shRNA PCAT6 transfection were lower than that after shRNA transfection (Fig.	('transfection', 'Var', (119, 131))	('shRNA', 'Var', (107, 112))	('PCAT6', 'Gene', '100506696', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('lower', 'NegReg', (137, 142))	('PCAT6', 'Gene', '100506696', (113, 118))	('tumors', 'Disease', (94, 100))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('expression level', 'MPA', (61, 77))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('PCAT6', 'Gene', (81, 86))	('PCAT6', 'Gene', (113, 118))
8073	30314898	To test this hypothesis, we first investigated whether PCAT6 knockdown affected the expression level of LATS2.	('affected', 'Reg', (71, 79))	('PCAT6', 'Gene', (55, 60))	('knockdown', 'Var', (61, 70))	('expression level', 'MPA', (84, 100))	('LATS2', 'Gene', (104, 109))	('LATS2', 'Gene', '26524', (104, 109))	('PCAT6', 'Gene', '100506696', (55, 60))
8083	30314898	Importantly, The MTT and colony formation as says abilities of cell growth and proliferation were partially recovered by LATS2 knockdown (Fig.	('recovered', 'PosReg', (108, 117))	('MTT', 'Chemical', 'MESH:C070243', (17, 20))	('colony formation', 'CPA', (25, 41))	('LATS2', 'Gene', (121, 126))	('LATS2', 'Gene', '26524', (121, 126))	('knockdown', 'Var', (127, 136))	('cell growth', 'CPA', (63, 74))
8085	30314898	Continuing advances in transcriptomics indicate that the study of epigenetic regulation of lncRNAs in cancer is emerging as a potential research field.	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('epigenetic', 'Var', (66, 76))
8087	30314898	Subsequently, multiple lines of evidence demonstrate that lncRNAs lead various chromatin-modifying complexes to specific genomic loci or tumor-cell-specific promoter regions, thereby impacting the cell cycle, differentiation, apoptosis, DNA repair and cell adhesion.	('tumor', 'Disease', (137, 142))	('lncRNAs', 'Var', (58, 65))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('DNA repair', 'CPA', (237, 247))	('apoptosis', 'CPA', (226, 235))	('cell cycle', 'CPA', (197, 207))	('cell adhesion', 'CPA', (252, 265))	('differentiation', 'CPA', (209, 224))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('impacting', 'Reg', (183, 192))
8088	30314898	For instance, our previous studies showed that lincRNA 00673 interacts with the epigenetic repressor LSD1 and represses NCALD expression in NSCLC.	('NSCLC', 'Disease', 'MESH:D002289', (140, 145))	('expression', 'MPA', (126, 136))	('LSD1', 'Gene', (101, 105))	('interacts', 'Interaction', (61, 70))	('represses', 'NegReg', (110, 119))	('NSCLC', 'Disease', (140, 145))	('NCALD', 'Gene', '83988', (120, 125))	('LSD1', 'Gene', '23028', (101, 105))	('NSCLC', 'Phenotype', 'HP:0030358', (140, 145))	('lincRNA 00673', 'Var', (47, 60))	('NCALD', 'Gene', (120, 125))
8093	30314898	To this end, we further explored the potential molecular mechanisms involved and determined that LATS2 was remarkably upregulated after PCAT6 knockdown, as analyzed using bioinformatics and qRT-PCR assays.	('PCAT6', 'Gene', (136, 141))	('PCAT6', 'Gene', '100506696', (136, 141))	('LATS2', 'Gene', '26524', (97, 102))	('upregulated', 'PosReg', (118, 129))	('LATS2', 'Gene', (97, 102))	('knockdown', 'Var', (142, 151))
8096	30314898	Multiple evidence suggested that epigenetic regulation plays a key regulatory role in normal development, and epigenetic imbalance is possibly the beginning of tumorigenesis in patients with NSCLC.	('imbalance', 'Phenotype', 'HP:0002172', (121, 130))	('men', 'Species', '9606', (100, 103))	('NSCLC', 'Phenotype', 'HP:0030358', (191, 196))	('patients', 'Species', '9606', (177, 185))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('NSCLC', 'Disease', (191, 196))	('epigenetic regulation', 'MPA', (33, 54))	('NSCLC', 'Disease', 'MESH:D002289', (191, 196))	('tumor', 'Disease', (160, 165))	('epigenetic imbalance', 'Var', (110, 130))
8098	30314898	It has been revealed that polycomb repressive complex 2 (PRC2) is an essential histone methyltransferase, and the molecular function of PRC2 is responsible for establishing the H3K27me3 mark on specific genes, which promotes transcriptional repression of these genes.	('polycomb', 'Gene', (26, 34))	('H3K27me3', 'Var', (177, 185))	('promotes', 'PosReg', (216, 224))	('polycomb', 'Gene', '12416', (26, 34))	('PRC2', 'Gene', (136, 140))	('transcriptional repression', 'MPA', (225, 251))
8102	30314898	They observed that high expression of EZH2 predicts aggressive tumor behavior, and EZH2 serves as a prognostic marker in patients with surgically resected lung adenocarcinomas, when combined with TTF-1 expression.	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('TTF-1', 'Gene', (196, 201))	('high', 'Var', (19, 23))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (155, 175))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (155, 175))	('expression', 'MPA', (24, 34))	('EZH2', 'Gene', '2146', (38, 42))	('EZH2', 'Gene', '2146', (83, 87))	('predicts', 'Reg', (43, 51))	('EZH2', 'Gene', (38, 42))	('EZH2', 'Gene', (83, 87))	('TTF-1', 'Gene', '7270', (196, 201))	('aggressive tumor behavior', 'Disease', 'MESH:D001523', (52, 77))	('carcinoma', 'Phenotype', 'HP:0030731', (165, 174))	('aggressive tumor behavior', 'Disease', (52, 77))	('patients', 'Species', '9606', (121, 129))	('lung adenocarcinomas', 'Disease', (155, 175))
8104	30314898	May boost the sensitivity of two NSCLC subsets (EGFR mutant or BRG1 mutant) to etoposide.	('NSCLC', 'Phenotype', 'HP:0030358', (33, 38))	('EGFR', 'Gene', '1956', (48, 52))	('BRG1', 'Gene', '6597', (63, 67))	('EGFR', 'Gene', (48, 52))	('sensitivity', 'MPA', (14, 25))	('NSCLC', 'Disease', (33, 38))	('boost', 'PosReg', (4, 9))	('mutant', 'Var', (53, 59))	('etoposide', 'Chemical', 'MESH:D005047', (79, 88))	('NSCLC', 'Disease', 'MESH:D002289', (33, 38))	('BRG1', 'Gene', (63, 67))	('mutant', 'Var', (68, 74))
8117	30314898	Taken together, our study establishes an oncogenic role for PCAT6 deregulation in NSCLC.	('PCAT6', 'Gene', '100506696', (60, 65))	('NSCLC', 'Phenotype', 'HP:0030358', (82, 87))	('deregulation', 'Var', (66, 78))	('PCAT6', 'Gene', (60, 65))	('NSCLC', 'Disease', (82, 87))	('NSCLC', 'Disease', 'MESH:D002289', (82, 87))
8122	30314898	Only by completely elucidating the molecular mechanisms of misregulated PCAT6 in NSCLC can we open avenues for utilizing lncRNAs to identify novel diagnostic or drug targets for NSCLC.	('NSCLC', 'Disease', (178, 183))	('NSCLC', 'Disease', 'MESH:D002289', (178, 183))	('NSCLC', 'Phenotype', 'HP:0030358', (81, 86))	('PCAT6', 'Gene', (72, 77))	('misregulated', 'Var', (59, 71))	('PCAT6', 'Gene', '100506696', (72, 77))	('NSCLC', 'Phenotype', 'HP:0030358', (178, 183))	('NSCLC', 'Disease', (81, 86))	('NSCLC', 'Disease', 'MESH:D002289', (81, 86))
8129	28955754	Furthermore, repression of MAGE-A10 expression increased cell-cell and cell matrix adhesion.	('increased', 'PosReg', (47, 56))	('MAGE-A10', 'Gene', '4109', (27, 35))	('MAGE-A10', 'Gene', (27, 35))	('repression', 'Var', (13, 23))
8149	28955754	Hence it is reasonable to assume that deregulation of the MAGE dependent network can be a co-driver of tumorigenesis and particularly, metastasis.	('metastasis', 'CPA', (135, 145))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('deregulation', 'Var', (38, 50))	('tumor', 'Disease', (103, 108))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
8184	28955754	The secondary antibody was IRDye 800CW goat anti-mouse immunoglobulin.	('mouse', 'Species', '10090', (49, 54))	('goat anti-mouse immunoglobulin', 'Protein', (39, 69))	('IRDye 800CW', 'Var', (27, 38))	('goat', 'Species', '9925', (39, 43))
8186	28955754	Gene expression MAGE-A10 transcripts is clearly higher in LN1 and LN2 cells than in the parental SCC-9 cells as shown by the results in Fig.	('transcripts', 'MPA', (25, 36))	('SCC-9', 'Gene', (97, 102))	('MAGE-A10', 'Gene', '4109', (16, 24))	('LN2', 'Gene', '104123', (66, 69))	('LN2', 'Gene', (66, 69))	('MAGE-A10', 'Gene', (16, 24))	('higher', 'PosReg', (48, 54))	('Gene expression', 'MPA', (0, 15))	('SCC-9', 'Gene', '112207', (97, 102))	('LN1', 'Var', (58, 61))
8199	28955754	These results show that with respect to morphology the more pronounced effect of silencing MAGE-A10 was clearly manifest in LN2 cells.	('MAGE-A10', 'Gene', '4109', (91, 99))	('MAGE-A10', 'Gene', (91, 99))	('LN2', 'Gene', '104123', (124, 127))	('LN2', 'Gene', (124, 127))	('silencing', 'Var', (81, 90))
8203	28955754	2G show that LN1 and LN2 cells transduced with the shControl construct and left to grow for 24-72 h generated cell aggregates that were considerably looser than their knocked down counterparts (#2 and #4), indicating that shMAGEA10 cells displayed a tighter association between cells.	('LN2', 'Gene', (21, 24))	('A10', 'Gene', '28870', (228, 231))	('LN2', 'Gene', '104123', (21, 24))	('A10', 'Gene', (228, 231))	('tighter', 'PosReg', (250, 257))	('association', 'Interaction', (258, 269))	('transduced', 'Var', (31, 41))	('cell aggregates', 'CPA', (110, 125))
8209	28955754	The populations consisting of LN1 and LN2 shControl were significantly less able to form spheroid than their suppressed counterparts.	('LN1', 'Var', (30, 33))	('LN2', 'Gene', '104123', (38, 41))	('LN2', 'Gene', (38, 41))	('less', 'NegReg', (71, 75))
8214	28955754	Again, we observed that silencing of MAGE-A10 affected the migration of both cells lines.	('migration of both cells lines', 'CPA', (59, 88))	('MAGE-A10', 'Gene', '4109', (37, 45))	('MAGE-A10', 'Gene', (37, 45))	('affected', 'Reg', (46, 54))	('silencing', 'Var', (24, 33))
8220	28955754	Finally we asked whether the expression of the adherens junction's proteins E-cadherin and N-cadherin, was affected by the silencing of MAGE-A10 in LN cells.	('N-cadherin', 'Gene', '1000', (91, 101))	('MAGE-A10', 'Gene', '4109', (136, 144))	('affected', 'Reg', (107, 115))	('MAGE-A10', 'Gene', (136, 144))	('expression', 'MPA', (29, 39))	('silencing', 'Var', (123, 132))	('N-cadherin', 'Gene', (91, 101))	('E-cadherin', 'Gene', (76, 86))	('E-cadherin', 'Gene', '999', (76, 86))
8241	28955754	The non-targeted proteome of LN1 and LN2 cells has revealed that a number of non-hair keratin variants are overexpressed in both cell lines (unpublished results).	('LN2', 'Gene', '104123', (37, 40))	('overexpressed', 'PosReg', (107, 120))	('variants', 'Var', (94, 102))	('LN2', 'Gene', (37, 40))	('non-hair keratin', 'Protein', (77, 93))
8267	32286310	PD-L1 is actively expressed on both tumor cells and antigen-presenting cells, and inhibition of PD-1 potentially affects multiple steps in the early stage of lymph node and subsequent immune response in the tumor microenvironment.	('affects', 'Reg', (113, 120))	('PD-1', 'Gene', (96, 100))	('inhibition', 'Var', (82, 92))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('PD-1', 'Gene', '5133', (96, 100))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('PD-L1', 'Gene', (0, 5))	('men', 'Species', '9606', (225, 228))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumor', 'Disease', (207, 212))	('PD-L1', 'Gene', '29126', (0, 5))	('tumor', 'Disease', (36, 41))
8295	32286310	We observed a significantly higher mutation rate for PBRM1 in male patients with clear cell renal cell carcinoma (ccRCC; MWW test, p = 0.040; Fig.	('PBRM1', 'Gene', '55193', (53, 58))	('patients', 'Species', '9606', (67, 75))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (81, 112))	('clear cell renal cell carcinoma', 'Disease', (81, 112))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (92, 112))	('mutation', 'Var', (35, 43))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (81, 112))	('ccRCC', 'Phenotype', 'HP:0006770', (114, 119))	('higher', 'Reg', (28, 34))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('PBRM1', 'Gene', (53, 58))
8342	32286310	We examined the molecular differences of potential biomarkers reported in these studies for potential mechanisms that alter immunotherapy responsiveness, including TMB, individual gene mutations (PBRM1, BRCA2), GEP, neoantigen load, CYT and protein expression of checkpoint mediators (CTLA-4, PD-L1, PD-L2).	('TMB', 'Chemical', '-', (164, 167))	('PD-L1', 'Gene', (293, 298))	('BRCA2', 'Gene', '675', (203, 208))	('CTLA-4', 'Gene', (285, 291))	('CYT', 'MPA', (233, 236))	('PD-L1', 'Gene', '29126', (293, 298))	('CTLA-4', 'Gene', '1493', (285, 291))	('neoantigen load', 'MPA', (216, 231))	('PBRM1', 'Gene', (196, 201))	('GEP', 'MPA', (211, 214))	('PD-L2', 'Gene', '80380', (300, 305))	('PBRM1', 'Gene', '55193', (196, 201))	('mutations', 'Var', (185, 194))	('PD-L2', 'Gene', (300, 305))	('TMB', 'Gene', (164, 167))	('BRCA2', 'Gene', (203, 208))	('alter', 'Reg', (118, 123))
8351	32286310	We obtained two independent data sets with gene expression data for patients with lung cancer (GSE47115) and clear cell renal cell carcinoma (ccRCC) patients (GSE73731).	('GSE73731', 'Var', (159, 167))	('GSE47115', 'Var', (95, 103))	('patients', 'Species', '9606', (149, 157))	('lung cancer', 'Phenotype', 'HP:0100526', (82, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('lung cancer', 'Disease', (82, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (109, 140))	('clear cell renal cell carcinoma', 'Disease', (109, 140))	('patients', 'Species', '9606', (68, 76))	('ccRCC', 'Phenotype', 'HP:0006770', (142, 147))	('lung cancer', 'Disease', 'MESH:D008175', (82, 93))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (120, 140))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (109, 140))
8447	32241264	examined the relationship between individual TMB and prognosis and concluded that high TMB is a poor prognostic factor in non-small cell lung cancer (NSCLC).	('NSCLC', 'Disease', 'MESH:D002289', (150, 155))	('TMB', 'Gene', (87, 90))	('high', 'Var', (82, 86))	('TMB', 'Chemical', '-', (45, 48))	('lung cancer', 'Phenotype', 'HP:0100526', (137, 148))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (122, 148))	('NSCLC', 'Phenotype', 'HP:0030358', (150, 155))	('TMB', 'Chemical', '-', (87, 90))	('non-small cell lung cancer', 'Disease', (122, 148))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (126, 148))	('NSCLC', 'Disease', (150, 155))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (122, 148))
8462	32241264	We found that although TMB and overall survival times are negatively correlated with concordance indices across the cancer types, integrating TMB does not improve the prognosis prediction performance for individual cancers significantly, whereas TMB has a strong correlation with overall survival times.	('cancer', 'Disease', (215, 221))	('cancer', 'Disease', 'MESH:D009369', (215, 221))	('cancers', 'Disease', 'MESH:D009369', (215, 222))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('cancers', 'Phenotype', 'HP:0002664', (215, 222))	('cancers', 'Disease', (215, 222))	('TMB', 'Chemical', '-', (142, 145))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('TMB', 'Chemical', '-', (246, 249))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('TMB', 'Var', (142, 145))	('TMB', 'Chemical', '-', (23, 26))
8472	33391539	Molecular biofunction and mechanistic studies demonstrated that BCL2A1 and AIM2 knockdown inhibited tumorigenesis via the AIM2/NF-kappaB/BCL2A1/MAPK/c-Myc signaling pathway.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('knockdown', 'Var', (80, 89))	('c-Myc', 'Gene', '4609', (149, 154))	('tumor', 'Disease', (100, 105))	('NF-kappaB', 'Gene', '4790', (127, 136))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('AIM2', 'Gene', (75, 79))	('c-Myc', 'Gene', (149, 154))	('NF-kappaB', 'Gene', (127, 136))	('inhibited', 'NegReg', (90, 99))	('BCL2A1', 'Gene', (64, 70))
8488	33391539	The human epidermis keratinocyte cell line (HaCaT), mouse head and neck squamous cell carcinoma (SCC-7) and mouse lung squamous cell carcinoma (KLN205) were obtained from the Type Culture Collection of the Chinese Academy of Sciences (Shanghai, China).	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (72, 95))	('KLN205', 'Var', (144, 150))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (58, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('human', 'Species', '9606', (4, 9))	('mouse', 'Species', '10090', (52, 57))	('HaCaT', 'CellLine', 'CVCL:0038', (44, 49))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (114, 142))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('mouse', 'Species', '10090', (108, 113))	('KLN205', 'CellLine', 'CVCL:3533', (144, 150))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (114, 142))	('neck squamous cell carcinoma', 'Disease', (67, 95))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (119, 142))	('lung squamous cell carcinoma', 'Disease', (114, 142))	('SCC-7', 'CellLine', 'CVCL:V412', (97, 102))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (67, 95))
8493	33391539	The following antibodies and dilutions were used: AIM2 (ab93015, Abcam, 1:1000), BCL2A1 (CY5582, Abways, 1:1000), p44/42 MAPK (137F5, CST, 1:1000), c-Myc (E5Q6W, CST, 1:1000), alpha-tubulin (AF0001, Beyotime, 1:1000), NF-kappaB Pathway Sampler Kit (#9936, CST, 1:1000), Phospho-Erk1/2 Pathway Sampler Kit (#9911, CST, 1:1000), IL-1beta (#12703, CST, 1:1000), cleaved IL-1beta (#83186, CST, 1:1000) and Caspase-1 (#3866, CST, 1:1000).	('#83186', 'Var', (377, 383))	('IL-1beta', 'Gene', '3552', (367, 375))	('alpha-tubulin', 'Gene', (176, 189))	('CST', 'Gene', (385, 388))	('CST', 'Gene', (313, 316))	('IL-1beta', 'Gene', '3552', (327, 335))	('CST', 'Gene', (162, 165))	('CST', 'Gene', (256, 259))	('CST', 'Gene', (345, 348))	('#9911', 'Var', (306, 311))	('#12703', 'Var', (337, 343))	('CST', 'Gene', '106478911', (420, 423))	('Caspase-1', 'Gene', '834', (402, 411))	('CST', 'Gene', '106478911', (134, 137))	('Caspase-1', 'Gene', (402, 411))	('IL-1beta', 'Gene', (367, 375))	('c-Myc', 'Gene', (148, 153))	('alpha-tubulin', 'Gene', '10376', (176, 189))	('CST', 'Gene', (420, 423))	('CST', 'Gene', '106478911', (385, 388))	('IL-1beta', 'Gene', (327, 335))	('CST', 'Gene', '106478911', (313, 316))	('CST', 'Gene', '106478911', (162, 165))	('NF-kappaB', 'Gene', (218, 227))	('c-Myc', 'Gene', '4609', (148, 153))	('CST', 'Gene', (134, 137))	('CST', 'Gene', '106478911', (256, 259))	('CST', 'Gene', '106478911', (345, 348))	('NF-kappaB', 'Gene', '4790', (218, 227))
8507	33391539	Similarly, for the syngeneic tumor model, six- to eight-week-old male C57/BL6 mice (n = 5 per group) was subcutaneously injected with 106 SCC-7 or KLN205 cells transfected with shAIM2 or shNC, and mice were sacrificed two weeks later to measure the tumor volumes and weights.	('KLN205 cells', 'Var', (147, 159))	('tumor', 'Disease', 'MESH:D009369', (249, 254))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (249, 254))	('tumor', 'Disease', (249, 254))	('SCC-7', 'CellLine', 'CVCL:V412', (138, 143))	('tumor', 'Disease', (29, 34))	('KLN205', 'CellLine', 'CVCL:3533', (147, 153))	('mice', 'Species', '10090', (197, 201))	('mice', 'Species', '10090', (78, 82))
8528	33391539	Among the single-positive group, patients with single BCL2A1 overexpression had poorer CSS than those with single AIM2 overexpression (Figure 3H and Table 2).	('single', 'Var', (47, 53))	('CSS', 'Chemical', '-', (87, 90))	('patients', 'Species', '9606', (33, 41))	('CSS', 'CPA', (87, 90))	('poorer', 'NegReg', (80, 86))	('BCL2A1', 'Gene', (54, 60))	('overexpression', 'Var', (61, 75))
8531	33391539	The 5-year CSS rate of PSCC patients with double-positive expression was significantly lower than that of patients with double-negative expression (24.1% vs. 55.1%, p = 0.049), but no difference was detected in the remaining groups (Figure 3I and Table 2).	('double-positive expression', 'Var', (42, 68))	('CSS', 'CPA', (11, 14))	('lower', 'NegReg', (87, 92))	('patients', 'Species', '9606', (106, 114))	('CSS', 'Chemical', '-', (11, 14))	('patients', 'Species', '9606', (28, 36))	('PSCC', 'Disease', (23, 27))
8532	33391539	In addition, pT grade and G grade (both p<0.001) were associated with CSS in the pN+ subset (Figure S3B).	('pN', 'Gene', '79650', (81, 83))	('CSS', 'Chemical', '-', (70, 73))	('pT grade', 'Var', (13, 21))	('CSS', 'Disease', (70, 73))	('associated', 'Reg', (54, 64))
8534	33391539	Colony formation and CCK-8 proliferation assays revealed that the knockdown of BCL2A1 and AIM2 dramatically impaired cell growth, indicating that BCL2A1 and AIM2 are critical for PSCC cell proliferation (Figure 4B and E).	('AIM2', 'Gene', (90, 94))	('BCL2A1', 'Gene', (79, 85))	('CCK', 'Gene', '885', (21, 24))	('CCK', 'Gene', (21, 24))	('cell growth', 'CPA', (117, 128))	('knockdown', 'Var', (66, 75))	('impaired', 'NegReg', (108, 116))
8535	33391539	Moreover, the results of in vivo experiments in nude mice showed that the knockdown of BCL2A1 or AIM2 resulted in lighter and smaller tumors, respectively, than the control (Figure 4F-G).	('tumors', 'Disease', (134, 140))	('tumors', 'Disease', 'MESH:D009369', (134, 140))	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('smaller', 'NegReg', (126, 133))	('knockdown', 'Var', (74, 83))	('BCL2A1', 'Gene', (87, 93))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('nude mice', 'Species', '10090', (48, 57))	('AIM2', 'Gene', (97, 101))
8538	33391539	As expected, knockdown of the AIM2 protein in Penl2 cells significantly decreased the phosphorylation of p65, a dominant protein in the NF-kappaB subunit family, while BCL2A1 silencing reduced the levels of the phosphorylated MEK1/2, Erk1/2 and c-Myc proteins (Figure 5A-B).	('MEK1/2', 'Gene', (226, 232))	('BCL2A1', 'Gene', (168, 174))	('NF-kappaB', 'Gene', '4790', (136, 145))	('p65', 'Gene', (105, 108))	('NF-kappaB', 'Gene', (136, 145))	('decreased', 'NegReg', (72, 81))	('Erk1/2', 'Protein', (234, 240))	('p65', 'Gene', '5970', (105, 108))	('c-Myc', 'Gene', '4609', (245, 250))	('phosphorylation', 'MPA', (86, 101))	('levels', 'MPA', (197, 203))	('phosphorylated', 'MPA', (211, 225))	('c-Myc', 'Gene', (245, 250))	('silencing', 'Var', (175, 184))	('knockdown', 'Var', (13, 22))	('MEK1/2', 'Gene', '5604;5605', (226, 232))	('reduced', 'NegReg', (185, 192))
8547	33391539	We detected that knockdown of AIM2 in SCC-7 cells resulted in smaller and lighter tumors, while no difference in tumors formed by KLN205 cells was observed compared to the control (Figure S5).	('tumors', 'Disease', (82, 88))	('tumors', 'Disease', (113, 119))	('lighter', 'NegReg', (74, 81))	('smaller', 'NegReg', (62, 69))	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('KLN205', 'CellLine', 'CVCL:3533', (130, 136))	('AIM2', 'Gene', (30, 34))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('SCC-7', 'CellLine', 'CVCL:V412', (38, 43))	('knockdown', 'Var', (17, 26))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
8559	33391539	Overexpression of AIM2 has been reported in oral squamous cell carcinoma and non-small cell lung cancer and is associated with shorter survival in patients with oral squamous cell carcinoma.	('lung cancer', 'Phenotype', 'HP:0100526', (92, 103))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (161, 189))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (49, 72))	('oral squamous cell carcinoma', 'Disease', (161, 189))	('Overexpression', 'Var', (0, 14))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (77, 103))	('AIM2', 'Gene', (18, 22))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (166, 189))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (81, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('patients', 'Species', '9606', (147, 155))	('reported', 'Reg', (32, 40))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (77, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (180, 189))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (44, 72))	('shorter', 'NegReg', (127, 134))	('oral squamous cell carcinoma', 'Disease', (44, 72))	('non-small cell lung cancer', 'Disease', (77, 103))
8561	33391539	The results showed that either BCL2A1 or AIM2 staining was significantly associated with PSCC tumor progression, as indicated by clinical features including the pN status, clinical stage and ENE.	('pN', 'Gene', '79650', (161, 163))	('staining', 'Var', (46, 54))	('BCL2A1', 'Gene', (31, 37))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('PSCC tumor', 'Disease', (89, 99))	('PSCC tumor', 'Disease', 'MESH:D009369', (89, 99))	('associated', 'Reg', (73, 83))	('AIM2', 'Gene', (41, 45))
8562	33391539	When correlated with survival data, Kaplan-Meier analysis showed that patients with high BCL2A1 or AIM2 expression experienced shorter CSS, and the worst survival outcomes were observed in patients with double-positive expression.	('shorter', 'NegReg', (127, 134))	('patients', 'Species', '9606', (70, 78))	('BCL2A1', 'Gene', (89, 95))	('CSS', 'MPA', (135, 138))	('high', 'Var', (84, 88))	('CSS', 'Chemical', '-', (135, 138))	('AIM2', 'Gene', (99, 103))	('expression', 'MPA', (104, 114))	('patients', 'Species', '9606', (189, 197))
8566	33391539	However, patients with single-positive expression (5-year CSS rate: 94.9%) and double-negative expression (5-year CSS rate: 100.0%) had a good prognosis, even better than that of the whole pN0 cohort (5-year CSS rate: 90.6% in our cohort and over 85% in cohorts from other centers).	('patients', 'Species', '9606', (9, 17))	('CSS', 'Chemical', '-', (114, 117))	('double-negative expression', 'Var', (79, 105))	('pN', 'Gene', '79650', (189, 191))	('CSS', 'Chemical', '-', (208, 211))	('CSS', 'Chemical', '-', (58, 61))	('single-positive expression', 'Var', (23, 49))
8570	33391539	Similarly, in the pN+ subset, the prognosis of patients with negative BCL2A1 and AIM2 expression was significantly better than that of patients with double-positive expression (5-year CSS rate: 55.1% vs. 24.1%).	('negative', 'NegReg', (61, 69))	('patients', 'Species', '9606', (135, 143))	('BCL2A1', 'Gene', (70, 76))	('patients', 'Species', '9606', (47, 55))	('CSS', 'Chemical', '-', (184, 187))	('better', 'PosReg', (115, 121))	('pN', 'Gene', '79650', (18, 20))	('AIM2', 'Gene', (81, 85))	('expression', 'Var', (86, 96))
8573	33391539	Our results indicate that low-risk pN+ patients with double-negative expression achieve a stable response after lymphadenectomy and a good prognosis, especially those with limited inguinal metastasis.	('double-negative', 'Var', (53, 68))	('pN', 'Gene', '79650', (35, 37))	('patients', 'Species', '9606', (39, 47))	('expression', 'Protein', (69, 79))
8577	33391539	We determined that knocking down BCL2A1 and AIM2 inhibited PSCC cell proliferation, clone formation, migration in vitro and tumor growth in vivo, supporting their critical role in tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('migration', 'CPA', (101, 110))	('AIM2', 'Gene', (44, 48))	('tumor', 'Disease', (124, 129))	('tumor', 'Disease', (180, 185))	('clone formation', 'CPA', (84, 99))	('BCL2A1', 'Gene', (33, 39))	('PSCC cell proliferation', 'CPA', (59, 82))	('knocking down', 'Var', (19, 32))	('inhibited', 'NegReg', (49, 58))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
8578	33391539	Regarding the molecular mechanism, the knockdown of AIM2 significantly decreased BCL2A1 expression via the NF-kappaB pathway, suggesting that BCL2A1 is a dominant downstream oncogene that is not only regulated by AIM2 but also independently influences the progression of PSCC.	('influences', 'Reg', (241, 251))	('knockdown', 'Var', (39, 48))	('PSCC', 'Disease', (271, 275))	('expression', 'MPA', (88, 98))	('NF-kappaB', 'Gene', '4790', (107, 116))	('BCL2A1', 'Gene', (81, 87))	('NF-kappaB', 'Gene', (107, 116))	('decreased', 'NegReg', (71, 80))	('AIM2', 'Gene', (52, 56))
8597	31299995	PIK3CA amplification was associated with significantly higher TMB (P = 0.036).	('TMB', 'Chemical', '-', (62, 65))	('PIK3CA', 'Gene', (0, 6))	('PIK3CA', 'Gene', '5290', (0, 6))	('higher', 'PosReg', (55, 61))	('amplification', 'Var', (7, 20))	('TMB', 'Disease', (62, 65))
8598	31299995	Frequent genetic alterations had no impact on PD-L1 expression but PIK3CA amplification and KEAP1 mutation were independently associated with significantly lower CD8+ TIL density (P < 0.001, P = 0.005, respectively).	('PD-L1', 'Gene', (46, 51))	('KEAP1', 'Gene', (92, 97))	('PIK3CA', 'Gene', '5290', (67, 73))	('mutation', 'Var', (98, 106))	('amplification', 'Var', (74, 87))	('PD-L1', 'Gene', '29126', (46, 51))	('CD8+ TIL density', 'Gene', (162, 178))	('lower', 'NegReg', (156, 161))	('KEAP1', 'Gene', '9817', (92, 97))	('PIK3CA', 'Gene', (67, 73))	('CD8+ TIL density', 'Gene', '925', (162, 178))
8605	31299995	Unlike lung adenocarcinoma (LUAD) with oncogenic driver alterations, therapeutic progress for LUSC is limited and conventional platinum-based chemotherapy remains the standard-of-care for many years.	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (7, 26))	('LUAD', 'Phenotype', 'HP:0030078', (28, 32))	('alterations', 'Var', (56, 67))	('LUSC', 'Phenotype', 'HP:0030359', (94, 98))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (7, 26))	('platinum', 'Chemical', 'MESH:D010984', (127, 135))	('carcinoma', 'Phenotype', 'HP:0030731', (17, 26))	('lung adenocarcinoma', 'Disease', (7, 26))
8626	31299995	The cutoff value was 5% for PD-L1 positivity or negativity (PD-L1+/-).	('PD-L1', 'Gene', '29126', (28, 33))	('positivity', 'Var', (34, 44))	('PD-L1', 'Gene', (60, 65))	('PD-L1', 'Gene', (28, 33))	('PD-L1', 'Gene', '29126', (60, 65))	('negativity', 'NegReg', (48, 58))
8632	31299995	CD8+ TILs density was assessed by using a mouse anti-CD8 monoclonal antibody (M7103, clone C8144B, DAKO).	('C8144B', 'SUBSTITUTION', 'None', (91, 97))	('CD8', 'Gene', (53, 56))	('CD8', 'Gene', '925', (53, 56))	('mouse', 'Species', '10090', (42, 47))	('CD8', 'Gene', (0, 3))	('CD8', 'Gene', '925', (0, 3))	('C8144B', 'Var', (91, 97))
8635	31299995	TMB was defined as the number of somatic, coding, base substitution, and indel mutations per megabase of genome examined by using nonsynonymous and frameshift indels at 5% limit of detection.	('TMB', 'Chemical', '-', (0, 3))	('base substitution', 'Var', (50, 67))	('frameshift', 'Var', (148, 158))	('indel mutations', 'Var', (73, 88))
8648	31299995	TP53 mutation was found in 67% of all cases (TCGA, 81%; Choi et al.	('found', 'Reg', (18, 23))	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('mutation', 'Var', (5, 13))
8651	31299995	PIK3CA and FGFR1 amplifications were found in 23% and 20% of all cases, respectively.	('amplifications', 'Var', (17, 31))	('found', 'Reg', (37, 42))	('PIK3CA', 'Gene', (0, 6))	('FGFR1', 'Gene', (11, 16))	('PIK3CA', 'Gene', '5290', (0, 6))	('FGFR1', 'Gene', '2260', (11, 16))
8653	31299995	There was no significant correlation between EGFR amplification or EML4-ALK fusion and clinicopathological features (Additional file 1: Table S1).	('amplification', 'Var', (50, 63))	('EML4', 'Gene', (67, 71))	('EML4', 'Gene', '27436', (67, 71))	('EGFR', 'Gene', (45, 49))	('ALK', 'Gene', '238', (72, 75))	('EGFR', 'Gene', '1956', (45, 49))	('ALK', 'Gene', (72, 75))
8658	31299995	We observed that only ECOG PS = 0 was associated with a significantly higher rate of samples with low TMB (P = 0.014).	('ECOG', 'Var', (22, 26))	('TMB', 'MPA', (102, 105))	('TMB', 'Chemical', '-', (102, 105))
8660	31299995	Of note, patients with CNVs had significantly higher TMB than those without CNVs (P = 0.008; Additional file 1: Figure S1B).	('patients', 'Species', '9606', (9, 17))	('higher', 'PosReg', (46, 52))	('CNVs', 'Var', (23, 27))	('TMB', 'MPA', (53, 56))	('TMB', 'Chemical', '-', (53, 56))
8662	31299995	A significant correlation of PD-L1 expression score between two assays was found (R2 = 0.782, P < 0.001; Additional file 1: Figure S2B) while E1L3N had a higher mean score (Additional file 1: Figure S2C).	('PD-L1', 'Gene', (29, 34))	('PD-L1', 'Gene', '29126', (29, 34))	('E1L3N', 'Var', (142, 147))	('expression', 'MPA', (35, 45))
8664	31299995	Interestingly, in CHOICE study (includes both Chinese LUSC and LUAD), PD-L1 positivity rate was 23.1% using H-score >= 50, or 63.9% using > 1% tumor cell positive as a cutoff, which is consistent with those in the literature on the Western population.	('PD-L1', 'Gene', '29126', (70, 75))	('LUAD', 'Phenotype', 'HP:0030078', (63, 67))	('tumor', 'Disease', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('H-score >= 50', 'Var', (108, 121))	('LUSC', 'Phenotype', 'HP:0030359', (54, 58))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('PD-L1', 'Gene', (70, 75))
8675	31299995	1, PIK3CA amplification was associated with markedly higher TMB (P = 0.036; Fig.	('higher', 'PosReg', (53, 59))	('PIK3CA', 'Gene', (3, 9))	('TMB', 'CPA', (60, 63))	('PIK3CA', 'Gene', '5290', (3, 9))	('amplification', 'Var', (10, 23))	('TMB', 'Chemical', '-', (60, 63))
8676	31299995	1e) and NFE2L2 mutation was associated with marginally higher TMB than those without (P = 0.069; Fig.	('mutation', 'Var', (15, 23))	('NFE2L2', 'Gene', (8, 14))	('TMB', 'Chemical', '-', (62, 65))	('NFE2L2', 'Gene', '4780', (8, 14))	('TMB', 'MPA', (62, 65))	('higher', 'PosReg', (55, 61))
8679	31299995	KEAP1 mutation was associated with dramatically lower CD8+ TIL density (P = 0.005; Fig.	('CD8+ TIL density', 'Gene', '925', (54, 70))	('KEAP1', 'Gene', (0, 5))	('lower', 'NegReg', (48, 53))	('mutation', 'Var', (6, 14))	('CD8+ TIL density', 'Gene', (54, 70))	('KEAP1', 'Gene', '9817', (0, 5))
8682	31299995	Both TP53 and KEAP1 mutations were independently associated with significantly lower DCs and neutrophil infiltrations (P < 0.05, P < 0.05, respectively; Additional file 1: Figures S5A and S5D).	('DCs', 'CPA', (85, 88))	('KEAP1', 'Gene', '9817', (14, 19))	('lower', 'NegReg', (79, 84))	('KEAP1', 'Gene', (14, 19))	('TP53', 'Gene', '7157', (5, 9))	('TP53', 'Gene', (5, 9))	('mutations', 'Var', (20, 29))
8683	31299995	PIK3CA mutation was associated with significantly lower macrophage infiltration (P < 0.05; Additional file 1: Figure S5F) whereas other somatic mutations had no impact on the six immune infiltrates (Additional file 1: Figure S5).	('lower', 'NegReg', (50, 55))	('PIK3CA', 'Gene', (0, 6))	('macrophage infiltration', 'CPA', (56, 79))	('PIK3CA', 'Gene', '5290', (0, 6))	('mutation', 'Var', (7, 15))
8684	31299995	SOX2 amplification was associated with significantly lower CD8+ T cell abundance (P < 0.01; Additional file 1: Figure S6F).	('SOX2', 'Gene', '6657', (0, 4))	('amplification', 'Var', (5, 18))	('CD8', 'Gene', (59, 62))	('CD8', 'Gene', '925', (59, 62))	('lower', 'NegReg', (53, 58))	('SOX2', 'Gene', (0, 4))
8685	31299995	Additionally, most of frequent CNVs including FGFR1, EGFR, and PIK3CA amplifications and loss of CDKN2A were associated with significantly lower six immune infiltrates (Additional file 1: Figure S6).	('CDKN2A', 'Gene', (97, 103))	('six immune infiltrates', 'MPA', (145, 167))	('CDKN2A', 'Gene', '1029', (97, 103))	('amplifications', 'Var', (70, 84))	('PIK3CA', 'Gene', (63, 69))	('lower', 'NegReg', (139, 144))	('FGFR1', 'Gene', (46, 51))	('PIK3CA', 'Gene', '5290', (63, 69))	('EGFR', 'Gene', (53, 57))	('EGFR', 'Gene', '1956', (53, 57))	('FGFR1', 'Gene', '2260', (46, 51))	('loss', 'NegReg', (89, 93))
8692	31299995	When we combined TMB with PD-L1 and CD8+ TIL, the discriminatory power was significantly improved (Fig.	('improved', 'PosReg', (89, 97))	('TMB', 'Chemical', '-', (17, 20))	('PD-L1', 'Gene', (26, 31))	('discriminatory', 'MPA', (50, 64))	('TMB', 'Var', (17, 20))	('PD-L1', 'Gene', '29126', (26, 31))	('CD8', 'Gene', (36, 39))	('CD8', 'Gene', '925', (36, 39))
8693	31299995	Similarly, the discriminatory power was also improved along with the increase cutoffs of TMB (details in Additional file 1: Figures S7 and S8).	('cutoffs', 'Var', (78, 85))	('increase', 'PosReg', (69, 77))	('improved', 'PosReg', (45, 53))	('discriminatory', 'MPA', (15, 29))	('TMB', 'Gene', (89, 92))	('TMB', 'Chemical', '-', (89, 92))
8696	31299995	CD8+ TIL-, high TMB, PD-L1- plus high TMB, and CD8+ TIL- plus high TMB were independently associated with shorter DFS (P = 0.010, P = 0.040, P = 0.021, P = 0.005, respectively) while CD8+ TIL+ plus lower TMB was associated with longer DFS (P = 0.011).	('shorter', 'NegReg', (106, 113))	('CD8', 'Gene', (47, 50))	('CD8', 'Gene', '925', (47, 50))	('TMB', 'Chemical', '-', (38, 41))	('high TMB', 'Var', (11, 19))	('CD8', 'Gene', (0, 3))	('CD8', 'Gene', '925', (0, 3))	('PD-L1', 'Gene', (21, 26))	('TMB', 'Chemical', '-', (16, 19))	('TMB', 'Chemical', '-', (67, 70))	('TMB', 'Chemical', '-', (204, 207))	('DFS', 'MPA', (114, 117))	('CD8', 'Gene', (183, 186))	('CD8', 'Gene', '925', (183, 186))	('PD-L1', 'Gene', '29126', (21, 26))
8697	31299995	The combination of high TMB and PD-L1- or CD8+ TIL- did not reach the statistical significance in stratifying patients with different OS (P = 0.100, P = 0.078, respectively).	('PD-L1', 'Gene', (32, 37))	('TMB', 'Chemical', '-', (24, 27))	('CD8', 'Gene', (42, 45))	('PD-L1', 'Gene', '29126', (32, 37))	('OS', 'Chemical', '-', (134, 136))	('CD8', 'Gene', '925', (42, 45))	('high TMB', 'Var', (19, 27))	('patients', 'Species', '9606', (110, 118))
8708	31299995	High TMB was correlated with significantly longer DFS (P = 0.021; Fig.	('longer', 'PosReg', (43, 49))	('High', 'Var', (0, 4))	('TMB', 'Gene', (5, 8))	('TMB', 'Chemical', '-', (5, 8))	('DFS', 'MPA', (50, 53))
8719	31299995	Intriguingly, patients with CNVs had significantly higher TMB than those without.	('CNVs', 'Var', (28, 32))	('TMB', 'Chemical', '-', (58, 61))	('TMB', 'MPA', (58, 61))	('higher', 'PosReg', (51, 57))	('patients', 'Species', '9606', (14, 22))
8720	31299995	This were reminiscent of an elegant study that examined the data from 5255 tumor/normal samples representing 12 tumor types from TCGA and found a positive correlation between somatic CNVs level and the total number of mutations, suggesting the potential value of CNVs for predicting the TMB level and its application for predicting who are most likely to benefit from immunotherapy.	('TMB', 'Chemical', '-', (287, 290))	('mutations', 'Var', (218, 227))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('TMB level', 'MPA', (287, 296))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', (112, 117))	('tumor', 'Disease', (75, 80))
8721	31299995	Of note, some kinds of CNVs, such as FGFR1, EGFR, and PIK3CA amplifications and loss of CDKN2A, were associated with significantly lower six immune infiltrates.	('CDKN2A', 'Gene', (88, 94))	('FGFR1', 'Gene', (37, 42))	('FGFR1', 'Gene', '2260', (37, 42))	('six immune infiltrates', 'CPA', (137, 159))	('CDKN2A', 'Gene', '1029', (88, 94))	('PIK3CA', 'Gene', '5290', (54, 60))	('loss', 'Var', (80, 84))	('EGFR', 'Gene', '1956', (44, 48))	('lower', 'NegReg', (131, 136))	('EGFR', 'Gene', (44, 48))	('amplifications', 'Var', (61, 75))	('PIK3CA', 'Gene', (54, 60))
8722	31299995	This finding could partly explain that the fraction of copy number altered genome was highest in NSCLC patients treated with anti-PD-1/PD-L1 therapy but lack of durable benefit due to the importance of these immune infiltrates in antitumor immune response.	('PD-L1', 'Gene', (135, 140))	('tumor', 'Disease', (234, 239))	('NSCLC', 'Disease', (97, 102))	('copy number altered', 'Var', (55, 74))	('PD-L1', 'Gene', '29126', (135, 140))	('highest', 'Reg', (86, 93))	('NSCLC', 'Disease', 'MESH:D002289', (97, 102))	('tumor', 'Disease', 'MESH:D009369', (234, 239))	('patients', 'Species', '9606', (103, 111))	('NSCLC', 'Phenotype', 'HP:0030358', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))
8724	31299995	The results showed that only KEAP1 mutation was significantly associated with lower CD8+ TIL density, and NFE2L2 mutation was associated with marginally higher TMB.	('CD8+ TIL density', 'Gene', (84, 100))	('mutation', 'Var', (113, 121))	('higher', 'PosReg', (153, 159))	('NFE2L2', 'Gene', '4780', (106, 112))	('CD8+ TIL density', 'Gene', '925', (84, 100))	('TMB', 'CPA', (160, 163))	('NFE2L2', 'Gene', (106, 112))	('KEAP1', 'Gene', '9817', (29, 34))	('mutation', 'Var', (35, 43))	('TMB', 'Chemical', '-', (160, 163))	('lower', 'NegReg', (78, 83))	('KEAP1', 'Gene', (29, 34))
8727	31299995	Genetic alterations of KEAP1 or NFE2L2 would destroy this process and lead to oncogenesis and drug and radio resistance in different types of solid tumors.	('Genetic alterations', 'Var', (0, 19))	('solid tumors', 'Disease', 'MESH:D009369', (142, 154))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('NFE2L2', 'Gene', (32, 38))	('oncogenesis', 'CPA', (78, 89))	('lead to', 'Reg', (70, 77))	('KEAP1', 'Gene', '9817', (23, 28))	('solid tumors', 'Disease', (142, 154))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('NFE2L2', 'Gene', '4780', (32, 38))	('KEAP1', 'Gene', (23, 28))	('destroy', 'NegReg', (45, 52))
8728	31299995	Considering these findings, we could infer that tumor with KEAP1 or NFE2L2 mutation would have a higher level of oxidative stress, which could lead to the destruction of immune cells including CD8+ TILs and increased DNA damage level, resulting in the increase of somatic mutations of tumor cells.	('higher', 'PosReg', (97, 103))	('level of oxidative stress', 'MPA', (104, 129))	('somatic', 'CPA', (264, 271))	('DNA damage level', 'MPA', (217, 233))	('CD8', 'Gene', (193, 196))	('NFE2L2', 'Gene', '4780', (68, 74))	('tumor', 'Phenotype', 'HP:0002664', (285, 290))	('mutation', 'Var', (75, 83))	('increase', 'PosReg', (252, 260))	('tumor', 'Disease', (48, 53))	('NFE2L2', 'Gene', (68, 74))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('KEAP1', 'Gene', '9817', (59, 64))	('oxidative stress', 'Phenotype', 'HP:0025464', (113, 129))	('CD8', 'Gene', '925', (193, 196))	('KEAP1', 'Gene', (59, 64))	('lead to', 'Reg', (143, 150))	('tumor', 'Disease', (285, 290))	('increased', 'PosReg', (207, 216))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('tumor', 'Disease', 'MESH:D009369', (285, 290))
8731	31299995	KEAP1 mutation was reported to be associated with poor response to adjuvant chemotherapy in both LUSC and LUAD.	('LUAD', 'Phenotype', 'HP:0030078', (106, 110))	('KEAP1', 'Gene', (0, 5))	('LUSC', 'Disease', (97, 101))	('LUSC', 'Phenotype', 'HP:0030359', (97, 101))	('mutation', 'Var', (6, 14))	('KEAP1', 'Gene', '9817', (0, 5))	('LUAD', 'Disease', (106, 110))
8732	31299995	Whether the relationship between KEAP1 mutation and lower CD8+ T cell infiltration could explain the negative predictive value on adjuvant chemotherapy warrants further examinations.	('mutation', 'Var', (39, 47))	('CD8', 'Gene', (58, 61))	('lower', 'NegReg', (52, 57))	('KEAP1', 'Gene', '9817', (33, 38))	('CD8', 'Gene', '925', (58, 61))	('KEAP1', 'Gene', (33, 38))
8744	31299995	Additionally, we observed that high TMB was correlated with significantly longer DFS in never-smoker but not associated with DFS in former/current smoker.	('DFS', 'MPA', (81, 84))	('longer', 'PosReg', (74, 80))	('TMB', 'Gene', (36, 39))	('TMB', 'Chemical', '-', (36, 39))	('high', 'Var', (31, 35))
8751	31299995	Hence, high TMB was correlated with significantly longer DFS but CD8+ TIL+ was not associated with DFS in never-smoker.	('TMB', 'MPA', (12, 15))	('DFS', 'MPA', (57, 60))	('CD8', 'Gene', (65, 68))	('high', 'Var', (7, 11))	('CD8', 'Gene', '925', (65, 68))	('TMB', 'Chemical', '-', (12, 15))
8757	31299995	In summary, this large-scale study found PIK3CA amplification was associated with higher TMB but lower CD8+ T cells density while the common genetic alterations had no impact on PD-L1 expression.	('CD8', 'Gene', '925', (103, 106))	('PIK3CA', 'Gene', (41, 47))	('higher', 'PosReg', (82, 88))	('TMB', 'MPA', (89, 92))	('CD8', 'Gene', (103, 106))	('PD-L1', 'Gene', (178, 183))	('lower', 'NegReg', (97, 102))	('PIK3CA', 'Gene', '5290', (41, 47))	('PD-L1', 'Gene', '29126', (178, 183))	('TMB', 'Chemical', '-', (89, 92))	('amplification', 'Var', (48, 61))
8766	31144459	Among patients with non-squamous, the EGFR mutation rate was 44.1% and the ALK rearrangement rate was 10.0%.	('EGFR', 'Gene', '1956', (38, 42))	('ALK', 'Gene', (75, 78))	('mutation', 'Var', (43, 51))	('EGFR', 'Gene', (38, 42))	('ALK', 'Gene', '238', (75, 78))	('patients', 'Species', '9606', (6, 14))
8767	31144459	Among patients with squamous cell carcinoma, the EGFR mutation rate was 8.3% and the ALK rearrangement rate was 3.7%.	('EGFR', 'Gene', '1956', (49, 53))	('mutation', 'Var', (54, 62))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (20, 43))	('squamous cell carcinoma', 'Disease', (20, 43))	('EGFR', 'Gene', (49, 53))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (20, 43))	('ALK', 'Gene', (85, 88))	('patients', 'Species', '9606', (6, 14))	('ALK', 'Gene', '238', (85, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (34, 43))
8768	31144459	Among all patients, gender (HR = 1.7, 95%CI = 1.2-2.4, P = 0.006), smoking history (HR = 1.8, 95%CI = 1.3-2.7, P = 0.001), histology (HR = 5.0, 95%CI = 2.4-10.1, P < 0.001), and brain metastases (HR = 1.5, 95%CI = 1.1-2.2, P = 0.017) were independent predictors of EGFR mutation, while age (HR = 2.6, 95%CI = 1.7-4.1, P < 0.001) was an independent predictor of ALK rearrangement.	('brain metastases', 'Disease', (178, 194))	('mutation', 'Var', (270, 278))	('brain metastases', 'Disease', 'MESH:D009362', (178, 194))	('EGFR', 'Gene', '1956', (265, 269))	('ALK', 'Gene', '238', (361, 364))	('EGFR', 'Gene', (265, 269))	('patients', 'Species', '9606', (10, 18))	('ALK', 'Gene', (361, 364))
8771	31144459	There was a negative correlation between the first-line targeted therapy rate and the EGFR mutation detection period (r = -0.152, P = 0.02), while no significant correlation among patients with ALK rearrangement (r = -0.179, P = 0.076).	('mutation', 'Var', (91, 99))	('ALK', 'Gene', (194, 197))	('EGFR', 'Gene', '1956', (86, 90))	('ALK', 'Gene', '238', (194, 197))	('EGFR', 'Gene', (86, 90))	('negative', 'NegReg', (12, 20))	('patients', 'Species', '9606', (180, 188))
8776	31144459	Recent research regarding targeted therapy such as epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) and anaplastic lymphoma kinase inhibitors (ALK-TKIs) has revealed significant improvements in overall survival rates of NSCLC patients harboring EGFR mutation or ALK rearrangement.	('lymphoma', 'Phenotype', 'HP:0002665', (138, 146))	('EGFR', 'Gene', '1956', (268, 272))	('mutation', 'Var', (273, 281))	('EGFR', 'Gene', (112, 116))	('overall survival', 'MPA', (217, 233))	('NSCLC', 'Disease', 'MESH:D002289', (243, 248))	('patients', 'Species', '9606', (249, 257))	('epidermal growth factor receptor', 'Gene', (51, 83))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (127, 146))	('epidermal growth factor receptor', 'Gene', '1956', (51, 83))	('NSCLC', 'Disease', (243, 248))	('ALK', 'Gene', '238', (285, 288))	('anaplastic lymphoma kinase', 'Gene', '238', (127, 153))	('improvements', 'PosReg', (201, 213))	('ALK', 'Gene', '238', (166, 169))	('EGFR', 'Gene', (268, 272))	('NSCLC', 'Phenotype', 'HP:0030358', (243, 248))	('anaplastic lymphoma kinase', 'Gene', (127, 153))	('ALK', 'Gene', (285, 288))	('EGFR', 'Gene', '1956', (112, 116))	('ALK', 'Gene', (166, 169))
8778	31144459	13 analyzed 176 NSCLC patients treated at the First Affiliated Hospital of Wenzhou Medical College, and observed that the total mutation rate of the EGFR gene in exons 19, 20, and 21 was 48.3% (85/176).	('NSCLC', 'Phenotype', 'HP:0030358', (16, 21))	('EGFR', 'Gene', '1956', (149, 153))	('patients', 'Species', '9606', (22, 30))	('NSCLC', 'Disease', (16, 21))	('EGFR', 'Gene', (149, 153))	('mutation', 'Var', (128, 136))	('NSCLC', 'Disease', 'MESH:D002289', (16, 21))
8779	31144459	They further identified several factors, including female gender, adenocarcinoma, distant metastasis, and the chemotherapy, that may increase the probability of EGFR gene mutations.	('EGFR', 'Gene', (161, 165))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('adenocarcinoma', 'Disease', (66, 80))	('adenocarcinoma', 'Disease', 'MESH:D000230', (66, 80))	('mutations', 'Var', (171, 180))	('EGFR', 'Gene', '1956', (161, 165))
8780	31144459	14 analyzed 747 patients with advanced NSCLC among a subset of patients from mainland China with an adenocarcinoma history as part of the PIONEER study, and found that the overall EGFR mutation rate was 50.2% among the 741 patients that were successfully genotyped, while the activating EGFR mutation rate was 48.0% (with 1.3% of patients showing combined activating and resistance mutations).	('NSCLC', 'Phenotype', 'HP:0030358', (39, 44))	('patients', 'Species', '9606', (16, 24))	('EGFR', 'Gene', '1956', (180, 184))	('mutation', 'Var', (185, 193))	('EGFR', 'Gene', (180, 184))	('adenocarcinoma', 'Disease', (100, 114))	('patients', 'Species', '9606', (63, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('NSCLC', 'Disease', (39, 44))	('patients', 'Species', '9606', (330, 338))	('EGFR', 'Gene', (287, 291))	('EGFR', 'Gene', '1956', (287, 291))	('patients', 'Species', '9606', (223, 231))	('NSCLC', 'Disease', 'MESH:D002289', (39, 44))	('adenocarcinoma', 'Disease', 'MESH:D000230', (100, 114))
8781	31144459	Smoking history and regional lymph nodes involvement were identified as independent predictors of EGFR mutation in multivariate analysis.	('EGFR', 'Gene', (98, 102))	('EGFR', 'Gene', '1956', (98, 102))	('mutation', 'Var', (103, 111))
8784	31144459	However, the current evaluation methods and periods of EGFR mutation and/or ALK rearrangement, as well as the first-line targeted therapy rate in patients with NSCLC harboring EGFR mutations or ALK rearrangement in China remain unclear.	('EGFR', 'Gene', '1956', (55, 59))	('ALK', 'Gene', (194, 197))	('ALK', 'Gene', '238', (76, 79))	('EGFR', 'Gene', (55, 59))	('EGFR', 'Gene', '1956', (176, 180))	('NSCLC', 'Phenotype', 'HP:0030358', (160, 165))	('ALK', 'Gene', '238', (194, 197))	('EGFR', 'Gene', (176, 180))	('mutations', 'Var', (181, 190))	('NSCLC', 'Disease', (160, 165))	('ALK', 'Gene', (76, 79))	('patients', 'Species', '9606', (146, 154))	('NSCLC', 'Disease', 'MESH:D002289', (160, 165))
8785	31144459	Therefore, we conducted a prospective multicenter study with the goal of determining the detection methods and detection periods of EGFR mutation and ALK rearrangement, the EGFR mutation rate, ALK rearrangement rate, and first-line targeted therapy rate in patients with NSCLC harboring EGFR mutations or ALK rearrangement in northern China.	('mutations', 'Var', (292, 301))	('ALK', 'Gene', (305, 308))	('ALK', 'Gene', (150, 153))	('NSCLC', 'Disease', (271, 276))	('mutation', 'Var', (137, 145))	('EGFR', 'Gene', '1956', (132, 136))	('EGFR', 'Gene', (132, 136))	('ALK', 'Gene', '238', (305, 308))	('EGFR', 'Gene', '1956', (173, 177))	('ALK', 'Gene', '238', (150, 153))	('NSCLC', 'Disease', 'MESH:D002289', (271, 276))	('ALK', 'Gene', '238', (193, 196))	('patients', 'Species', '9606', (257, 265))	('EGFR', 'Gene', '1956', (287, 291))	('NSCLC', 'Phenotype', 'HP:0030358', (271, 276))	('EGFR', 'Gene', (287, 291))	('EGFR', 'Gene', (173, 177))	('ALK', 'Gene', (193, 196))
8790	31144459	The inclusion criteria were: (i) age >= 18 years, (ii) new diagnosis of NSCLC confirmed using histology or cytology, (iii) locally advanced or metastatic NSCLC (stage IIIb-IV or recurrent cases that were not eligible for surgery or radical chemoradiotherapy), (iv) simultaneous results for EGFR mutation and ALK rearrangement testing, and (v) no previous systemic treatment (except adjuvant chemotherapy).	('NSCLC', 'Disease', 'MESH:D002289', (154, 159))	('NSCLC', 'Disease', (72, 77))	('ALK', 'Gene', (308, 311))	('results', 'Reg', (278, 285))	('mutation', 'Var', (295, 303))	('NSCLC', 'Phenotype', 'HP:0030358', (154, 159))	('NSCLC', 'Disease', 'MESH:D002289', (72, 77))	('EGFR', 'Gene', '1956', (290, 294))	('ALK', 'Gene', '238', (308, 311))	('EGFR', 'Gene', (290, 294))	('NSCLC', 'Phenotype', 'HP:0030358', (72, 77))	('NSCLC', 'Disease', (154, 159))	('rearrangement testing', 'Var', (312, 333))
8791	31144459	Demographic and clinical characteristics of patients were collected, including age at diagnosis, gender, smoking status, date of first pathological diagnosis, method of pathological diagnosis, date that the first EGFR mutation and ALK rearrangement was confirmed, EGFR-mutation/ALK-rearrangement detection period (time from tumor diagnosis to EGFR/ALK status confirmation), detection method of EGFR mutation and ALK rearrangement, distant metastases, and first-line treatment.	('EGFR', 'Gene', (394, 398))	('metastases', 'Disease', (439, 449))	('EGFR', 'Gene', (343, 347))	('metastases', 'Disease', 'MESH:D009362', (439, 449))	('EGFR', 'Gene', '1956', (213, 217))	('patients', 'Species', '9606', (44, 52))	('EGFR', 'Gene', (264, 268))	('tumor', 'Phenotype', 'HP:0002664', (324, 329))	('rearrangement', 'Var', (416, 429))	('EGFR', 'Gene', '1956', (394, 398))	('mutation', 'Var', (399, 407))	('ALK', 'Gene', '238', (231, 234))	('EGFR', 'Gene', '1956', (343, 347))	('ALK', 'Gene', '238', (412, 415))	('ALK', 'Gene', (231, 234))	('ALK', 'Gene', '238', (278, 281))	('EGFR', 'Gene', (213, 217))	('EGFR', 'Gene', '1956', (264, 268))	('ALK', 'Gene', (412, 415))	('tumor', 'Disease', (324, 329))	('ALK', 'Gene', '238', (348, 351))	('ALK', 'Gene', (278, 281))	('tumor', 'Disease', 'MESH:D009369', (324, 329))	('ALK', 'Gene', (348, 351))
8802	31144459	Among all patients, the most commonly used methods of detection for EGFR mutation and ALK rearrangement were ARMS (1029/1134, 90.7%) and IHC targeting D5F3 (692/1134, 61.0%), respectively.	('ALK', 'Gene', '238', (86, 89))	('ALK', 'Gene', (86, 89))	('EGFR', 'Gene', '1956', (68, 72))	('rearrangement', 'Var', (90, 103))	('patients', 'Species', '9606', (10, 18))	('mutation', 'Var', (73, 81))	('EGFR', 'Gene', (68, 72))
8803	31144459	Among patients with non-squamous NSCLC, the most commonly used methods of detection for EGFR mutation and ALK rearrangement were ARMS (933/1025, 91.0%) and IHC targeting D5F3 (637/1025, 62.1%), respectively.	('ALK', 'Gene', '238', (106, 109))	('NSCLC', 'Phenotype', 'HP:0030358', (33, 38))	('ALK', 'Gene', (106, 109))	('EGFR', 'Gene', '1956', (88, 92))	('non-squamous NSCLC', 'Disease', 'MESH:D002294', (20, 38))	('patients', 'Species', '9606', (6, 14))	('mutation', 'Var', (93, 101))	('non-squamous NSCLC', 'Disease', (20, 38))	('EGFR', 'Gene', (88, 92))
8806	31144459	Among patients with squamous NSCLC, the most commonly used methods of detection for EGFR mutation and ALK rearrangement were ARMS (96/109 88.1%) and IHC targeting D5F3 (55/109, 50.1%), respectively.	('NSCLC', 'Phenotype', 'HP:0030358', (29, 34))	('ALK', 'Gene', (102, 105))	('mutation', 'Var', (89, 97))	('EGFR', 'Gene', '1956', (84, 88))	('squamous NSCLC', 'Disease', (20, 34))	('patients', 'Species', '9606', (6, 14))	('ALK', 'Gene', '238', (102, 105))	('squamous NSCLC', 'Disease', 'MESH:D002294', (20, 34))	('EGFR', 'Gene', (84, 88))
8813	31144459	Among all patients, the EGFR mutation rate was 40.7% (461/1134), with the major mutations being 19del and 21L858R.	('EGFR', 'Gene', '1956', (24, 28))	('19del', 'Mutation', 'c.19del', (96, 101))	('EGFR', 'Gene', (24, 28))	('21L858R', 'Var', (106, 113))	('19del', 'Var', (96, 101))	('patients', 'Species', '9606', (10, 18))	('L858R', 'Mutation', 'rs121434568', (108, 113))
8814	31144459	Nineteen patients (1.7%) had double EGFR mutations, with the most common being L858R and T790M (8/19) (Table 2).	('patients', 'Species', '9606', (9, 17))	('L858R', 'Var', (79, 84))	('T790M', 'Mutation', 'rs121434569', (89, 94))	('EGFR', 'Gene', '1956', (36, 40))	('L858R', 'Mutation', 'rs121434568', (79, 84))	('T790M', 'Var', (89, 94))	('EGFR', 'Gene', (36, 40))
8816	31144459	Among patients with non-squamous, the EGFR mutation rate was 44.1% (452/1025) and the ALK rearrangement rate was 10.0% (103/1025).	('EGFR', 'Gene', '1956', (38, 42))	('ALK', 'Gene', '238', (86, 89))	('mutation', 'Var', (43, 51))	('EGFR', 'Gene', (38, 42))	('ALK', 'Gene', (86, 89))	('patients', 'Species', '9606', (6, 14))
8817	31144459	Among patients with squamous cell carcinoma, the EGFR mutation rate was 8.3% (9/109) and the ALK rearrangement rate was 3.7% (4/109).	('EGFR', 'Gene', '1956', (49, 53))	('mutation', 'Var', (54, 62))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (20, 43))	('squamous cell carcinoma', 'Disease', (20, 43))	('ALK', 'Gene', '238', (93, 96))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (20, 43))	('EGFR', 'Gene', (49, 53))	('patients', 'Species', '9606', (6, 14))	('carcinoma', 'Phenotype', 'HP:0030731', (34, 43))	('ALK', 'Gene', (93, 96))
8818	31144459	Among all patients, univariate analyses showed that the EGFR mutation rate was significantly higher in females (P < 0.001), without a smoking history (P < 0.001), non-squamous (P < 0.001), stage IV tumor (P < 0.001), bone metastases (P = 0.014), brain metastases (P = 0.002), pleural effusion (P = 0.016) and pleural nodules (P = 0.014) (Table 3).	('EGFR', 'Gene', '1956', (56, 60))	('mutation', 'Var', (61, 69))	('stage', 'Disease', (189, 194))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('brain metastases', 'Disease', 'MESH:D009362', (246, 262))	('pleural nodules', 'Disease', 'MESH:D010995', (309, 324))	('pleural effusion', 'Disease', (276, 292))	('brain metastases', 'Disease', (246, 262))	('pleural nodules', 'Disease', (309, 324))	('higher', 'Reg', (93, 99))	('pleural effusion', 'Disease', 'MESH:D010996', (276, 292))	('IV tumor', 'Disease', 'MESH:D009369', (195, 203))	('IV tumor', 'Disease', (195, 203))	('bone metastases', 'Disease', 'MESH:D009362', (217, 232))	('EGFR', 'Gene', (56, 60))	('patients', 'Species', '9606', (10, 18))	('pleural effusion', 'Phenotype', 'HP:0002202', (276, 292))	('non-squamous', 'Disease', (163, 175))	('bone metastases', 'Disease', (217, 232))
8819	31144459	Multivariate analysis further identified gender (HR = 1.7, 95%CI = 1.2-2.4, P = 0.006), smoking history (HR = 1.8, 95%CI = 1.3-2.7, P = 0.001), histology (HR = 5.0, 95%CI = 2.4-10.1, P < 0.001), and brain metastases (HR = 1.5, 95%CI = 1.1-2.2, P = 0.017) as independent predictors of EGFR mutation.	('brain metastases', 'Disease', (199, 215))	('brain metastases', 'Disease', 'MESH:D009362', (199, 215))	('EGFR', 'Gene', '1956', (284, 288))	('mutation', 'Var', (289, 297))	('EGFR', 'Gene', (284, 288))
8820	31144459	Among patients with non-squamous , univariate analyses showed that the EGFR mutation rate was significantly higher in females (P < 0.001), without a smoking history (P < 0.001), stage IV tumor (P = 0.002), brain metastases (P = 0.027), and pleural nodules metastases (P = 0.034) (Table 4).	('brain metastases', 'Disease', 'MESH:D009362', (206, 222))	('brain metastases', 'Disease', (206, 222))	('higher', 'Reg', (108, 114))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('pleural nodules metastases', 'Disease', (240, 266))	('IV tumor', 'Disease', (184, 192))	('EGFR', 'Gene', '1956', (71, 75))	('IV tumor', 'Disease', 'MESH:D009369', (184, 192))	('patients', 'Species', '9606', (6, 14))	('mutation', 'Var', (76, 84))	('EGFR', 'Gene', (71, 75))	('pleural nodules metastases', 'Disease', 'MESH:D009362', (240, 266))
8821	31144459	Multivariate analysis further identified female (HR = 1.6, 95%CI = 1.1-2.3, P = 0.013), without a smoking history (HR = 1.9, 95%CI = 1.3-2.7, P = 0.001), and brain metastases (HR = 1.5, 95%CI = 1.1-2.1, P = 0.021) had higher EGFR mutation.	('brain metastases', 'Disease', 'MESH:D009362', (158, 174))	('brain metastases', 'Disease', (158, 174))	('higher', 'PosReg', (218, 224))	('EGFR', 'Gene', '1956', (225, 229))	('mutation', 'Var', (230, 238))	('EGFR', 'Gene', (225, 229))
8822	31144459	Among patients with squamous, univariate analyses showed that the EGFR mutation rate was significantly higher in females (P = 0.004), without a smoking history (P = 0.049), and pleural effusion (P = 0.032) (Table 5).	('pleural effusion', 'Phenotype', 'HP:0002202', (177, 193))	('EGFR', 'Gene', '1956', (66, 70))	('mutation', 'Var', (71, 79))	('EGFR', 'Gene', (66, 70))	('patients', 'Species', '9606', (6, 14))	('pleural effusion', 'Disease', 'MESH:D010996', (177, 193))	('higher', 'Reg', (103, 109))	('pleural effusion', 'Disease', (177, 193))
8823	31144459	Multivariate analysis further identified only gender (HR = 6.0, 95%CI = 1.1-32.6, P = 0.040) as independent predictor of EGFR mutation.	('EGFR', 'Gene', '1956', (121, 125))	('mutation', 'Var', (126, 134))	('EGFR', 'Gene', (121, 125))
8826	31144459	Among patients with non-squamous patients, univariate analyses showed that the ALK rearrangement rate was significantly higher in patients who were <=60 years old (P < 0.001), female (P = 0.007), and without a smoking history (P = 0.001) (Table 7).	('ALK', 'Gene', '238', (79, 82))	('patients', 'Species', '9606', (33, 41))	('rearrangement', 'Var', (83, 96))	('higher', 'PosReg', (120, 126))	('patients', 'Species', '9606', (130, 138))	('ALK', 'Gene', (79, 82))	('patients', 'Species', '9606', (6, 14))
8830	31144459	First-line targeted therapy was 73.8% (340/461) for patients harboring EGFR mutations and 51.4% (55/107) for patients with ALK rearrangements.	('mutations', 'Var', (76, 85))	('ALK', 'Gene', (123, 126))	('patients', 'Species', '9606', (109, 117))	('EGFR', 'Gene', '1956', (71, 75))	('ALK', 'Gene', '238', (123, 126))	('EGFR', 'Gene', (71, 75))	('patients', 'Species', '9606', (52, 60))
8831	31144459	There was a negative correlation between the first-line targeted therapy rate and the EGFR mutation detection period (r = -0.152, P = 0.02), while no significant correlation was detected among patients with ALK rearrangement (r = -0.179, P = 0.076).	('ALK', 'Gene', (207, 210))	('patients', 'Species', '9606', (193, 201))	('mutation', 'Var', (91, 99))	('EGFR', 'Gene', '1956', (86, 90))	('ALK', 'Gene', '238', (207, 210))	('EGFR', 'Gene', (86, 90))	('negative', 'NegReg', (12, 20))
8832	31144459	The present study revealed that although adenocarcinoma was the most common pathological type to be submitted for EGFR/ALK evaluation, patients with squamous carcinoma had an EGFR mutation rate of 8.3% and an ALK rearrangement rate of 3.7%.	('patients', 'Species', '9606', (135, 143))	('EGFR', 'Gene', (175, 179))	('carcinoma', 'Phenotype', 'HP:0030731', (46, 55))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (149, 167))	('ALK', 'Gene', (119, 122))	('ALK', 'Gene', (209, 212))	('EGFR', 'Gene', '1956', (114, 118))	('adenocarcinoma', 'Disease', (41, 55))	('squamous carcinoma', 'Disease', 'MESH:D002294', (149, 167))	('squamous carcinoma', 'Disease', (149, 167))	('adenocarcinoma', 'Disease', 'MESH:D000230', (41, 55))	('ALK', 'Gene', '238', (119, 122))	('EGFR', 'Gene', (114, 118))	('ALK', 'Gene', '238', (209, 212))	('carcinoma', 'Phenotype', 'HP:0030731', (158, 167))	('EGFR', 'Gene', '1956', (175, 179))	('mutation', 'Var', (180, 188))
8834	31144459	Among four patients with squamous harboring ALK rearrangement, two showed inconsistent test results (positive for IHC and negative for FISH).	('ALK', 'Gene', (44, 47))	('IHC', 'Disease', (114, 117))	('rearrangement', 'Var', (48, 61))	('ALK', 'Gene', '238', (44, 47))	('patients', 'Species', '9606', (11, 19))
8838	31144459	The present study revealed that the overall EGFR mutation rate was 40.7%, and gender, smoking history, and histology were independent predictors of EGFR mutation.	('EGFR', 'Gene', '1956', (148, 152))	('EGFR', 'Gene', (148, 152))	('mutation', 'Var', (49, 57))	('EGFR', 'Gene', '1956', (44, 48))	('EGFR', 'Gene', (44, 48))	('mutation', 'Var', (153, 161))
8839	31144459	These findings are consistent with the results of previous studies.13, 14, 18, 19, 20 Furthermore, we found that patients with EGFR mutations were more likely to have baseline brain metastases, which may be related to the downstream effects of EGFR on brain metastases.	('EGFR', 'Gene', '1956', (244, 248))	('EGFR', 'Gene', (244, 248))	('brain metastases', 'Disease', 'MESH:D009362', (176, 192))	('mutations', 'Var', (132, 141))	('patients', 'Species', '9606', (113, 121))	('brain metastases', 'Disease', (176, 192))	('brain metastases', 'Disease', 'MESH:D009362', (252, 268))	('brain metastases', 'Disease', (252, 268))	('EGFR', 'Gene', '1956', (127, 131))	('EGFR', 'Gene', (127, 131))
8842	31144459	Therefore, further studies are needed to better understand the relationship between EGFR mutations and baseline brain metastasis, and clinicians should be aware of this relationship when they encounter cases of EGFR-mutated NSCLC, or cases with brain metastasis.	('NSCLC', 'Disease', (224, 229))	('EGFR', 'Gene', '1956', (211, 215))	('EGFR', 'Gene', '1956', (84, 88))	('NSCLC', 'Disease', 'MESH:D002289', (224, 229))	('mutations', 'Var', (89, 98))	('EGFR', 'Gene', (211, 215))	('EGFR', 'Gene', (84, 88))	('brain metastasis', 'CPA', (112, 128))	('NSCLC', 'Phenotype', 'HP:0030358', (224, 229))
8845	31144459	The present study also revealed that only age was independently associated with ALK rearrangement, which is in line with previous reports.27, 28  The study suggested that first-line targeted therapy rate for patients with NSCLC with EGFR-activating mutation or ALK rearrangement were still low.	('EGFR', 'Gene', '1956', (233, 237))	('ALK', 'Gene', '238', (261, 264))	('patients', 'Species', '9606', (208, 216))	('NSCLC', 'Phenotype', 'HP:0030358', (222, 227))	('EGFR', 'Gene', (233, 237))	('ALK', 'Gene', (261, 264))	('ALK', 'Gene', '238', (80, 83))	('rearrangement', 'Var', (265, 278))	('NSCLC', 'Disease', (222, 227))	('NSCLC', 'Disease', 'MESH:D002289', (222, 227))	('ALK', 'Gene', (80, 83))
8850	31144459	First, these data are preliminary, and thus additional follow-up is needed to examine the effects of targeted therapy in cases of NSCLC harboring EGFR mutation or ALK rearrangement.	('NSCLC', 'Disease', 'MESH:D002289', (130, 135))	('EGFR', 'Gene', '1956', (146, 150))	('ALK', 'Gene', '238', (163, 166))	('mutation', 'Var', (151, 159))	('EGFR', 'Gene', (146, 150))	('NSCLC', 'Phenotype', 'HP:0030358', (130, 135))	('NSCLC', 'Disease', (130, 135))	('ALK', 'Gene', (163, 166))
8861	32548799	Additionally, subgroup analysis demonstrated that high MAGE-A expression was significantly associated with poor prognosis for lung, gastrointestinal, breast, and ovarian cancer in both univariate and multivariate analysis for overall survival.	('lung', 'Disease', (126, 130))	('expression', 'MPA', (62, 72))	('ovarian cancer', 'Phenotype', 'HP:0100615', (162, 176))	('MAGE-A', 'Chemical', '-', (55, 61))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('ovarian cancer', 'Disease', (162, 176))	('MAGE-A', 'Gene', (55, 61))	('ovarian cancer', 'Disease', 'MESH:D010051', (162, 176))	('breast', 'Disease', (150, 156))	('gastrointestinal', 'Disease', (132, 148))	('high', 'Var', (50, 54))
8862	32548799	Overexpression of MAGE-A subfamily members is linked to poor prognosis in multiple cancers.	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('multiple cancers', 'Disease', (74, 90))	('Overexpression', 'Var', (0, 14))	('MAGE-A', 'Chemical', '-', (18, 24))	('cancers', 'Phenotype', 'HP:0002664', (83, 90))	('multiple cancers', 'Disease', 'MESH:D009369', (74, 90))
8869	32548799	Molecular abnormalities (genetic and epigenetic dysregulation) plays a very important role in malignant transformation and can provide vital clinical information about cancer progression.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('epigenetic dysregulation', 'Var', (37, 61))	('malignant transformation', 'CPA', (94, 118))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('cancer', 'Disease', (168, 174))
8888	32548799	High expression of MAGE-A genes is associated with poor survival outcomes in breast cancer, lung cancer, and gastric cancer.	('lung cancer', 'Disease', (92, 103))	('breast cancer', 'Disease', (77, 90))	('lung cancer', 'Phenotype', 'HP:0100526', (92, 103))	('breast cancer', 'Phenotype', 'HP:0003002', (77, 90))	('High', 'Var', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('gastric cancer', 'Disease', (109, 123))	('MAGE-A genes', 'Gene', (19, 31))	('gastric cancer', 'Disease', 'MESH:D013274', (109, 123))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('lung cancer', 'Disease', 'MESH:D008175', (92, 103))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('gastric cancer', 'Phenotype', 'HP:0012126', (109, 123))	('breast cancer', 'Disease', 'MESH:D001943', (77, 90))	('MAGE-A', 'Chemical', '-', (19, 25))
8891	32548799	Patients with cancer and abnormal expression of MAGE-A have a poor prognosis.	('cancer', 'Disease', (14, 20))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('abnormal expression', 'Var', (25, 44))	('MAGE-A', 'Chemical', '-', (48, 54))	('Patients', 'Species', '9606', (0, 8))	('MAGE-A', 'Gene', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (14, 20))
8938	32548799	The association between abnormal expression of MAGE-A members and cancer is now well-established.	('MAGE-A', 'Chemical', '-', (47, 53))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('abnormal expression', 'Var', (24, 43))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('cancer', 'Disease', (66, 72))
8947	32548799	Cancers overexpressing MAGE were more aggressive and showed the worst clinical outcomes.	('aggressive', 'CPA', (38, 48))	('Cancers', 'Disease', (0, 7))	('overexpressing', 'Var', (8, 22))	('Cancers', 'Phenotype', 'HP:0002664', (0, 7))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancers', 'Disease', 'MESH:D009369', (0, 7))
8950	32548799	Aberrant regulation of E3 RING ubiquitin ligases by MAGE members has been reported as contributing to tumorigenesis.	('E3 RING ubiquitin ligases', 'Protein', (23, 48))	('regulation', 'MPA', (9, 19))	('Aberrant', 'Var', (0, 8))	('contributing', 'Reg', (86, 98))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))
8954	32548799	DNA hypomethylation has been shown to induce aberrant expression of MAGE-A genes and is associated with poor survival outcomes in laryngeal squamous cell carcinoma and esophageal squamous cell carcinoma.	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (179, 202))	('hypomethylation', 'Var', (4, 19))	('induce', 'PosReg', (38, 44))	('MAGE-A', 'Chemical', '-', (68, 74))	('esophageal squamous cell carcinoma', 'Disease', (168, 202))	('carcinoma', 'Phenotype', 'HP:0030731', (193, 202))	('aberrant expression', 'MPA', (45, 64))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (140, 163))	('associated', 'Reg', (88, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (154, 163))	('squamous cell carcinoma', 'Disease', (140, 163))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (179, 202))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (140, 163))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (168, 202))
8975	32548799	Overexpression of MAGE-A3 has been shown to enhance the invasive potential of thyroid cancer cells.	('thyroid cancer', 'Disease', 'MESH:D013964', (78, 92))	('MAGE-A3', 'Gene', (18, 25))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('Overexpression', 'Var', (0, 14))	('thyroid cancer', 'Phenotype', 'HP:0002890', (78, 92))	('thyroid cancer', 'Disease', (78, 92))	('MAGE-A3', 'Gene', '4102', (18, 25))	('enhance', 'PosReg', (44, 51))
8981	32548799	Recently, MAGE-A3 overexpression has been shown to induce proliferation and migration of cervical cancer cells by modulating the EMT and Wnt signaling pathways.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('MAGE-A3', 'Gene', (10, 17))	('proliferation', 'CPA', (58, 71))	('migration', 'CPA', (76, 85))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('overexpression', 'Var', (18, 32))	('modulating', 'Reg', (114, 124))	('cancer', 'Disease', (98, 104))	('induce', 'PosReg', (51, 57))	('MAGE-A3', 'Gene', '4102', (10, 17))
8989	32548799	These findings suggest that expression of MAGE-A is associated with proliferation, inhibition of apoptosis, and chemoresistance in cancer cells.	('cancer', 'Disease', (131, 137))	('proliferation', 'CPA', (68, 81))	('inhibition', 'NegReg', (83, 93))	('MAGE-A', 'Chemical', '-', (42, 48))	('associated', 'Reg', (52, 62))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('chemoresistance', 'CPA', (112, 127))	('MAGE-A', 'Gene', (42, 48))	('expression', 'Var', (28, 38))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('apoptosis', 'CPA', (97, 106))
8993	32548799	For instance, MAGE-A family members (A1, A3, A6, A9, and A10) are associated with the worst clinical outcomes, with poor survival rates in lung, breast, and ovarian cancer.	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('ovarian cancer', 'Phenotype', 'HP:0100615', (157, 171))	('ovarian cancer', 'Disease', 'MESH:D010051', (157, 171))	('A10', 'Var', (57, 60))	('breast', 'Disease', (145, 151))	('poor', 'NegReg', (116, 120))	('MAGE-A', 'Chemical', '-', (14, 20))	('lung', 'Disease', (139, 143))	('ovarian cancer', 'Disease', (157, 171))	('A1', 'Var', (37, 39))
8995	32548799	found no association between OS and high MAGE-A expression in gastric cancer and non-Hodgkin lymphoma, respectively.	('non-Hodgkin lymphoma', 'Phenotype', 'HP:0012539', (81, 101))	('gastric cancer', 'Phenotype', 'HP:0012126', (62, 76))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('MAGE-A', 'Chemical', '-', (41, 47))	('Hodgkin lymphoma', 'Phenotype', 'HP:0012189', (85, 101))	('non-Hodgkin lymphoma', 'Disease', 'MESH:D008228', (81, 101))	('non-Hodgkin lymphoma', 'Disease', (81, 101))	('gastric cancer', 'Disease', (62, 76))	('lymphoma', 'Phenotype', 'HP:0002665', (93, 101))	('gastric cancer', 'Disease', 'MESH:D013274', (62, 76))	('high', 'Var', (36, 40))
9010	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.	('Aberrant expression', 'Var', (0, 19))	('autoimmunity', 'CPA', (143, 155))	('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))
9025	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))
9028	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))
9031	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))	('aggressive tumor', 'Disease', 'MESH:D001523', (62, 78))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('oncogenes', 'Gene', (102, 111))	('global DNA hypomethylation', 'Var', (26, 52))	('expression', 'MPA', (132, 142))	('aggressive tumor', 'Disease', (62, 78))
9032	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))
9033	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))
9034	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))
9035	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))
9038	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))
9039	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))	('hypomethylation', 'Var', (59, 74))	('breast cancer', 'Disease', (3, 16))	('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))	('activates', 'PosReg', (75, 84))	('causing', 'Reg', (191, 198))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))
9041	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))
9043	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))
9044	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))
9047	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))	('high', 'Var', (18, 22))	('associated', 'Reg', (53, 63))	('ORF1', 'Gene', '55354', (45, 49))	('distant metastasis', 'CPA', (69, 87))
9061	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))
9062	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))
9063	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))
9066	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))
9067	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))
9070	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))	('carcinomas', 'Disease', (50, 60))	('increased', 'PosReg', (108, 117))	('carcinoma', 'Phenotype', 'HP:0030731', (50, 59))	('ORF2', 'Gene', (123, 127))	('copy', 'MPA', (128, 132))	('ATM', 'Gene', (234, 237))	('carcinomas', 'Disease', 'MESH:D009369', (50, 60))	('ORF2', 'Gene', '100128274', (123, 127))	('retrotransposition', 'MPA', (89, 107))	('LINE-1', 'Gene', (82, 88))	('ATM', 'Gene', (66, 69))	('deficiency', 'Var', (70, 80))	('carcinomas', 'Phenotype', 'HP:0030731', (50, 60))	('increased', 'PosReg', (140, 149))	('ATM', 'Gene', '472', (234, 237))
9071	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))
9073	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))
9074	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))
9078	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))	('choroideremia', 'Phenotype', 'HP:0001139', (79, 92))	('patient', 'Species', '9606', (56, 63))	('choroideremia', 'Gene', (79, 92))	('CHM', 'Gene', (42, 45))
9080	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))
9081	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))
9082	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))
9083	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))
9084	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))	('deficiency', 'Var', (83, 93))	('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))	('upregulated', 'PosReg', (200, 211))	('AGS', 'Disease', 'MESH:C535607', (126, 129))	('Fanconi anemia', 'Phenotype', 'HP:0001994', (48, 62))	('LINE-1', 'Gene', (178, 184))	('Fanconi anemia', 'Disease', (48, 62))	('autosomal recessive genetic disease', 'Disease', 'MESH:D030342', (3, 38))	('Aicardi-Goutieres syndrome', 'Disease', 'MESH:C535607', (98, 124))
9085	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.	('autoimmune diseases', 'Disease', (61, 80))	('found', 'Reg', (52, 57))	('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))	('SLE', 'Disease', (119, 122))	('systemic lupus erythematosus', 'Disease', (89, 117))	('psoriasis', 'Disease', (154, 163))	('SLE', 'Disease', 'MESH:D008180', (119, 122))	('SLE', 'Phenotype', 'HP:0002725', (119, 122))	('systemic lupus erythematosus', 'Phenotype', 'HP:0002725', (89, 117))
9103	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))
9106	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))
9132	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))
9150	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))	('disease', 'Disease', (153, 160))	('disorder', 'MPA', (44, 52))	('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))
9167	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))
9209	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))
9215	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))	('arrest', 'Disease', 'MESH:D006323', (149, 155))	('cell apoptosis', 'CPA', (119, 133))	('MIR31HG', 'Gene', '554202', (9, 16))	('expression', 'MPA', (17, 27))	('knockdown', 'Var', (84, 93))	('MIR31HG', 'Gene', '554202', (97, 104))	('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))
9221	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.	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('cancers', 'Disease', (169, 176))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('high', 'Var', (81, 85))	('lung cancer', 'Disease', (147, 158))	('tumor', 'Disease', (51, 56))	('patients', 'Species', '9606', (133, 141))	('lung cancer', 'Phenotype', 'HP:0100526', (147, 158))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('cancers', 'Phenotype', 'HP:0002664', (169, 176))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('MIR31HG', 'Gene', (86, 93))	('predicted', 'Reg', (105, 114))	('unfavorable', 'Disease', (115, 126))	('MIR31HG', 'Gene', '554202', (86, 93))	('lung cancer', 'Disease', 'MESH:D008175', (147, 158))	('cancers', 'Disease', 'MESH:D009369', (169, 176))
9233	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))
9251	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))
9254	30723410	Here, we review the role of PIN1 in cancer and the regulation of PIN1 expression, and catalog the single nucleotide polymorphisms, and mutations in PIN1 gene associated with cancer.	('associated', 'Reg', (158, 168))	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('cancer', 'Disease', (36, 42))	('mutations', 'Var', (135, 144))	('cancer', 'Disease', (174, 180))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('PIN1', 'Gene', (148, 152))
9261	30723410	Several studies showed that some single nucleotide polymorphisms (SNPs) in PIN1 gene increase the risk of cancer whereas other variants operate as protective factors.	('PIN1', 'Gene', (75, 79))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('single nucleotide polymorphisms', 'Var', (33, 64))	('cancer', 'Disease', (106, 112))	('increase', 'PosReg', (85, 93))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
9281	30723410	PIN1 isomerization of pRb facilitates its binding to CDK-cyclin complexes in mid- to late G1.	('CDK-cyclin complexes', 'Protein', (53, 73))	('pRb', 'Gene', (22, 25))	('binding', 'Interaction', (42, 49))	('pRb', 'Gene', '5925', (22, 25))	('facilitates', 'PosReg', (26, 37))	('isomerization', 'Var', (5, 18))
9284	30723410	Finally, isomerization of MCL-1 causes a conformational change that may stabilize the protein and enhance its anti-apoptotic function.	('enhance', 'PosReg', (98, 105))	('stabilize', 'MPA', (72, 81))	('protein', 'Protein', (86, 93))	('conformational change', 'MPA', (41, 62))	('anti-apoptotic function', 'CPA', (110, 133))	('MCL-1', 'Gene', '4170', (26, 31))	('MCL-1', 'Gene', (26, 31))	('isomerization', 'Var', (9, 22))
9287	30723410	PIN1-mediated isomerization may prevent MCL-1 association with the GSK-3beta-E3 ligase beta-TrCP complex, blocking MCL-1 degradation, but further studies are required.	('beta-TrCP', 'Gene', (87, 96))	('MCL-1', 'Gene', '4170', (115, 120))	('MCL-1', 'Gene', (115, 120))	('PIN1-mediated', 'Var', (0, 13))	('isomerization', 'Var', (14, 27))	('beta-TrCP', 'Gene', '8945', (87, 96))	('GSK-3beta', 'Gene', '2932', (67, 76))	('GSK-3beta', 'Gene', (67, 76))	('association', 'Interaction', (46, 57))	('MCL-1', 'Gene', '4170', (40, 45))	('MCL-1', 'Gene', (40, 45))	('prevent', 'NegReg', (32, 39))	('blocking', 'NegReg', (106, 114))
9293	30723410	In stress conditions, PIN1 induces apoptosis via p53 and p73.	('PIN1', 'Gene', (22, 26))	('induces', 'Reg', (27, 34))	('p73', 'Gene', '7161', (57, 60))	('p53', 'Var', (49, 52))	('p73', 'Gene', (57, 60))	('apoptosis', 'CPA', (35, 44))
9296	30723410	The conformational change facilitates Myc dephosphorylation on Ser62 by protein phosphatase 2 (PP2A), which allows Myc ubiquitination and degradation by the proteasome.	('ubiquitination', 'MPA', (119, 133))	('degradation', 'MPA', (138, 149))	('Myc', 'Gene', '4609', (38, 41))	('PP2A', 'Gene', (95, 99))	('conformational change', 'Var', (4, 25))	('Myc', 'Gene', (38, 41))	('Ser62', 'Chemical', '-', (63, 68))	('Myc', 'Gene', '4609', (115, 118))	('Myc', 'Gene', (115, 118))	('facilitates', 'PosReg', (26, 37))	('PP2A', 'Gene', '5524', (95, 99))	('allows', 'Reg', (108, 114))
9301	30723410	In this way PIN1 sustains the transformed phenotype induced by E2F or Notch1 activation.	('E2F', 'Var', (63, 66))	('Notch1', 'Gene', (70, 76))	('Notch1', 'Gene', '4851', (70, 76))	('activation', 'PosReg', (77, 87))
9306	30723410	Mutations in this region of PIN1 can prevent the repressive effects of miR200c.	('miR200c', 'Gene', (71, 78))	('prevent', 'NegReg', (37, 44))	('miR200c', 'Gene', '406985', (71, 78))	('Mutations', 'Var', (0, 9))	('PIN1', 'Gene', (28, 32))	('repressive effects', 'CPA', (49, 67))
9308	30723410	Phosphorylation of PIN1 on Ser16 in the WW domain suppresses its ability to interact with its substrates.	('PIN1', 'Gene', (19, 23))	('Ser16', 'Var', (27, 32))	('suppresses', 'NegReg', (50, 60))	('interact', 'Interaction', (76, 84))	('Phosphorylation', 'MPA', (0, 15))	('ability', 'MPA', (65, 72))	('Ser16', 'Chemical', '-', (27, 32))
9309	30723410	At least three kinases can phosphorylate this residue: protein kinase A, ribosomal S6 kinase 2, and aurora kinase A. Phosphorylation on Ser71 in the PPIase domain inhibits the protein's enzymatic activity.	('Ser71', 'Chemical', '-', (136, 141))	('ribosomal S6 kinase 2', 'Gene', (73, 94))	('Phosphorylation', 'Var', (117, 132))	('enzymatic activity', 'MPA', (186, 204))	('inhibits', 'NegReg', (163, 171))	('ribosomal S6 kinase 2', 'Gene', '6197', (73, 94))	('Ser71', 'Var', (136, 141))
9312	30723410	It induced PIN1 deubiquitination and stabilization, while the absence of Plk1 enhanced the ubiquitination and degradation of PIN1.	('Plk1', 'Gene', (73, 77))	('degradation', 'MPA', (110, 121))	('stabilization', 'MPA', (37, 50))	('PIN1 deubiquitination', 'Disease', (11, 32))	('absence', 'Var', (62, 69))	('Plk1', 'Gene', '5347', (73, 77))	('PIN1 deubiquitination', 'Disease', 'None', (11, 32))	('PIN1', 'Protein', (125, 129))	('ubiquitination', 'MPA', (91, 105))	('enhanced', 'PosReg', (78, 86))
9313	30723410	SUMOylation of Lys6 in the WW domain and Lys63 in the PPIase domain abolishes PIN1's enzymatic activity and oncogenic functions.	('SUMOylation', 'Var', (0, 11))	('Lys6', 'Chemical', '-', (41, 45))	('Lys6', 'Var', (15, 19))	('PIN1', 'Gene', (78, 82))	('abolishes', 'NegReg', (68, 77))	('Lys6', 'Chemical', '-', (15, 19))	('Lys63', 'Var', (41, 46))	('enzymatic activity', 'MPA', (85, 103))	('Lys63', 'Chemical', '-', (41, 46))	('oncogenic functions', 'CPA', (108, 127))
9314	30723410	However, deSUMOylation of these two domains by SUMO1/sentrin specific peptidase 1 (SENP1) restores PIN1's activity.	('restores', 'PosReg', (90, 98))	('SUMO1', 'Gene', (47, 52))	('SUMO1', 'Gene', '7341', (47, 52))	('sentrin', 'Gene', (53, 60))	('deSUMOylation', 'Var', (9, 22))	('SENP1', 'Gene', (83, 88))	('sentrin', 'Gene', '7341', (53, 60))	('activity', 'MPA', (106, 114))	('PIN1', 'Enzyme', (99, 103))	('SENP1', 'Gene', '29843', (83, 88))
9315	30723410	SENP1 overexpression increases the levels of deSUMOylated PIN1 and in turn the ability of PIN1 to induce centrosome amplification and cell transformation.	('PIN1', 'Gene', (90, 94))	('induce', 'Reg', (98, 104))	('increases', 'PosReg', (21, 30))	('levels', 'MPA', (35, 41))	('SENP1', 'Gene', (0, 5))	('overexpression', 'Var', (6, 20))	('deSUMOylated', 'MPA', (45, 57))	('centrosome amplification', 'MPA', (105, 129))	('PIN1', 'Protein', (58, 62))	('SENP1', 'Gene', '29843', (0, 5))	('cell transformation', 'CPA', (134, 153))
9316	30723410	Finally, under conditions of oxidative stress, PIN1 is oxidized on Cys113 in the catalytic site, inhibiting its enzymatic activity.	('Cys113', 'Chemical', '-', (67, 73))	('PIN1', 'Gene', (47, 51))	('Cys113', 'Var', (67, 73))	('enzymatic activity', 'MPA', (112, 130))	('inhibiting', 'NegReg', (97, 107))	('oxidative stress', 'Phenotype', 'HP:0025464', (29, 45))
9318	30723410	The PIN1 variants rs2233678 (c.-842G>C) and rs2233679 (c.-667T>C), both located in the promoter, and the synonymous change rs2233682 (G>A; p.Gln33Gln) in exon 2 of the coding region, have been widely investigated.	('c.-667T>C', 'Mutation', 'rs2233679', (55, 64))	('p.Gln33Gln', 'Mutation', 'rs2233682', (139, 149))	('rs2233682', 'Mutation', 'rs2233682', (123, 132))	('rs2233679', 'Mutation', 'rs2233679', (44, 53))	('rs2233679 (c.-667T>C', 'Var', (44, 64))	('rs2233682 (G>A; p.Gln33Gln', 'Var', (123, 149))	('PIN1', 'Gene', (4, 8))	('rs2233678', 'Mutation', 'rs2233678', (18, 27))	('rs2233678 (c.-842G>C', 'Var', (18, 38))	('c.-842G>C', 'Mutation', 'rs2233678', (29, 38))
9319	30723410	The -842C allele of rs2233678 was found to confer a significantly lower risk of cancer (odds ratio, 0.75) in a meta-analysis of 11 studies (9280 participants) of patients with esophageal carcinoma, nasopharyngeal carcinoma, laryngeal squamous cell carcinoma, lung cancer, breast cancer, squamous cell carcinoma of the head, and neck or hepatocellular carcinoma (HCC), and matched healthy controls.	('lung cancer', 'Phenotype', 'HP:0100526', (259, 270))	('carcinoma', 'Phenotype', 'HP:0030731', (351, 360))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (234, 257))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (287, 310))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (176, 196))	('cancer', 'Disease', (279, 285))	('cancer', 'Disease', (264, 270))	('cancer', 'Disease', (80, 86))	('laryngeal squamous cell carcinoma', 'Disease', 'MESH:D002294', (224, 257))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancer', 'Phenotype', 'HP:0002664', (264, 270))	('lower', 'NegReg', (66, 71))	('cancer', 'Phenotype', 'HP:0002664', (279, 285))	('carcinoma', 'Phenotype', 'HP:0030731', (301, 310))	('squamous cell carcinoma', 'Disease', (287, 310))	('nasopharyngeal carcinoma', 'Disease', (198, 222))	('rs2233678', 'Var', (20, 29))	('participants', 'Species', '9606', (145, 157))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (336, 360))	('carcinoma', 'Phenotype', 'HP:0030731', (213, 222))	('lung cancer', 'Disease', (259, 270))	('patients', 'Species', '9606', (162, 170))	('HCC', 'Phenotype', 'HP:0001402', (362, 365))	('nasopharyngeal carcinoma', 'Disease', 'MESH:D000077274', (198, 222))	('breast cancer', 'Phenotype', 'HP:0003002', (272, 285))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (176, 196))	('cancer', 'Disease', 'MESH:D009369', (279, 285))	('cancer', 'Disease', 'MESH:D009369', (264, 270))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (336, 360))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (234, 257))	('laryngeal squamous cell carcinoma', 'Disease', (224, 257))	('breast cancer', 'Disease', 'MESH:D001943', (272, 285))	('lung cancer', 'Disease', 'MESH:D008175', (259, 270))	('carcinoma', 'Phenotype', 'HP:0030731', (187, 196))	('esophageal carcinoma', 'Disease', (176, 196))	('breast cancer', 'Disease', (272, 285))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (287, 310))	('rs2233678', 'Mutation', 'rs2233678', (20, 29))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (198, 222))	('carcinoma', 'Phenotype', 'HP:0030731', (248, 257))	('hepatocellular carcinoma', 'Disease', (336, 360))
9320	30723410	Seven of the included studies had found that the allele reduced risk, while four found no association with cancer risk.	('allele', 'Var', (49, 55))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('reduced', 'NegReg', (56, 63))	('risk', 'MPA', (64, 68))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('cancer', 'Disease', (107, 113))
9321	30723410	A study of 209 patients with oral squamous cell carcinoma and 444 controls did not find an association between the -842G>C polymorphism and cancer risk.	('patients', 'Species', '9606', (15, 23))	('oral squamous cell carcinoma', 'Disease', (29, 57))	('cancer', 'Disease', (140, 146))	('the -842G>C', 'Var', (111, 122))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('-842G>C', 'Mutation', 'rs2233678', (115, 122))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (34, 57))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (29, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (48, 57))
9322	30723410	The -667T>C polymorphism has been found to not associate with esophageal carcinoma, breast cancer, or squamous cell carcinoma of the head and neck, whereas it did associate with a lower risk of nasopharyngeal carcinoma, and a higher risk of oral squamous cell carcinoma.	('-667T>C', 'Mutation', 'rs2233679', (4, 11))	('squamous cell carcinoma', 'Disease', (102, 125))	('nasopharyngeal carcinoma', 'Disease', 'MESH:D000077274', (194, 218))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (246, 269))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (62, 82))	('breast cancer', 'Phenotype', 'HP:0003002', (84, 97))	('esophageal carcinoma', 'Disease', (62, 82))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (246, 269))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (102, 125))	('breast cancer', 'Disease', 'MESH:D001943', (84, 97))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (194, 218))	('carcinoma', 'Phenotype', 'HP:0030731', (209, 218))	('breast cancer', 'Disease', (84, 97))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (62, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (260, 269))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (102, 125))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (241, 269))	('The -667T>C', 'Var', (0, 11))	('carcinoma of the head and neck', 'Phenotype', 'HP:0012288', (116, 146))	('lower', 'NegReg', (180, 185))	('nasopharyngeal carcinoma', 'Disease', (194, 218))	('oral squamous cell carcinoma', 'Disease', (241, 269))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
9323	30723410	Finally, the synonymous change Gln33Gln was not found to associate with the risk of breast cancer, or squamous cell carcinoma of the head and neck.	('breast cancer', 'Phenotype', 'HP:0003002', (84, 97))	('squamous cell carcinoma', 'Disease', (102, 125))	('carcinoma of the head and neck', 'Phenotype', 'HP:0012288', (116, 146))	('Gln33Gln', 'Var', (31, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (102, 125))	('breast cancer', 'Disease', 'MESH:D001943', (84, 97))	('breast cancer', 'Disease', (84, 97))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (102, 125))
9324	30723410	Because of the lack of published papers reporting on PIN1 somatic mutations, we obtained deposited genetic data on these mutations in different tumor types from the cBioPortal for Cancer Genomics and COSMIC (Catalog of Somatic Mutations in Cancer).	('tumor', 'Disease', (144, 149))	('mutations', 'Var', (121, 130))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('Cancer', 'Disease', (240, 246))	('Cancer', 'Phenotype', 'HP:0002664', (180, 186))	('Cancer', 'Disease', (180, 186))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('Cancer', 'Phenotype', 'HP:0002664', (240, 246))	('Cancer', 'Disease', 'MESH:D009369', (240, 246))	('Cancer', 'Disease', 'MESH:D009369', (180, 186))
9326	30723410	COSMIC, a database of mutations reported in the scientific literature or from the Cancer Genome Project, permits researchers to explore the effects of somatic mutations in cancer.	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('Cancer', 'Disease', 'MESH:D009369', (82, 88))	('Cancer', 'Disease', (82, 88))	('Cancer', 'Phenotype', 'HP:0002664', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('mutations', 'Var', (22, 31))	('cancer', 'Disease', (172, 178))
9329	30723410	Twenty-three are missense mutations, four are synonymous mutations (they have no effect on PIN1 function), and four are nonsense mutations (R21*, S71*, S108*, and E163*).	('missense', 'Var', (17, 25))	('S108*', 'Var', (152, 157))	('S108*', 'SUBSTITUTION', 'None', (152, 157))	('R21*', 'Var', (140, 144))	('R21*', 'SUBSTITUTION', 'None', (140, 144))	('E163*', 'SUBSTITUTION', 'None', (163, 168))	('E163*', 'Var', (163, 168))	('S71*', 'SUBSTITUTION', 'None', (146, 150))	('S71*', 'Var', (146, 150))
9330	30723410	Overall, 17 mutations were predicted to be pathogenic by the Functional Analysis through Hidden Markov Models (FATHMM) filter in COSMIC and three to be deleterious by the Sorting Intolerant from Tolerant (SIFT) algorithm in cBioPortal.	('pathogenic', 'Reg', (43, 53))	('mutations', 'Var', (12, 21))	('SIFT', 'Disease', 'None', (205, 209))	('SIFT', 'Disease', (205, 209))
9332	30723410	The Q33K and R36P mutations (orange) are in the WW domain, as is G39C that is not shown because it belongs to a peptide loop missing from the X-ray structure.	('Q33K', 'Mutation', 'p.Q33K', (4, 8))	('Q33K', 'Var', (4, 8))	('R36P', 'Mutation', 'p.R36P', (13, 17))	('R36P', 'Var', (13, 17))	('G39C', 'Mutation', 'rs1274409184', (65, 69))
9333	30723410	All the other mutations are found in the PPIase domain: F134S, S154F, and H157Y (magenta) interact with the enzyme's substrates while S71L, D112N, P133L, and T152M (yellow) are indirectly involved in the interaction with substrates.	('S71L', 'Var', (134, 138))	('T152M', 'Var', (158, 163))	('H157Y', 'Var', (74, 79))	('P133L', 'Mutation', 'rs758375227', (147, 152))	('S154F', 'Var', (63, 68))	('interact', 'Interaction', (90, 98))	('D112N', 'Var', (140, 145))	('D112N', 'Mutation', 'rs907464294', (140, 145))	('T152M', 'Mutation', 'p.T152M', (158, 163))	('F134S', 'Var', (56, 61))	('S71L', 'Mutation', 'rs1175807870', (134, 138))	('P133L', 'Var', (147, 152))	('S154F', 'Mutation', 'rs751029251', (63, 68))	('F134S', 'Mutation', 'p.F134S', (56, 61))	('H157Y', 'Mutation', 'p.H157Y', (74, 79))
9334	30723410	Among them, F139S is within the PPIase domain interface (S138 to R142) that is involved in interdomain communication and regulates the function of PIN1 upon substrate binding.	('S138 to R142', 'Var', (57, 69))	('F139S', 'Var', (12, 17))	('PIN1', 'Gene', (147, 151))	('involved', 'Reg', (79, 87))	('regulates', 'Reg', (121, 130))	('function', 'MPA', (135, 143))	('F139S', 'Mutation', 'p.F139S', (12, 17))
9337	30723410	These compounds maintained the carboxylate group, which is the moiety necessary for an optimal interaction in the enzyme binding site, and the aromatic portions were varied, inserting benzimidazole (3), or naphthalene (4), since they lied in a hydrophobic region of the protein.	('naphthalene', 'Chemical', 'MESH:C031721', (206, 217))	('carboxylate', 'Chemical', '-', (31, 42))	('inserting', 'Var', (174, 183))	('binding', 'Interaction', (121, 128))	('carboxylate group', 'MPA', (31, 48))	('interaction', 'Interaction', (95, 106))	('benzimidazole', 'Chemical', 'MESH:C031000', (184, 197))
9356	30723410	Some SNPs in PIN1 gene were found to associate with cancer risk.	('SNPs', 'Var', (5, 9))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('PIN1', 'Gene', (13, 17))	('associate', 'Reg', (37, 46))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))
9360	30723410	Although further studies are required, we believe that investigating the complex pattern of PIN1 gene alterations and their effects on PIN1 protein structure and function is a valid strategy for identifying new biomarkers for susceptibility to cancer and response to anti-PIN1 inhibitors.	('PIN1', 'Gene', (92, 96))	('effects', 'Reg', (124, 131))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('function', 'MPA', (162, 170))	('alterations', 'Var', (102, 113))	('cancer', 'Disease', (244, 250))	('cancer', 'Disease', 'MESH:D009369', (244, 250))
9366	30106450	In addition, high GSDMD expression indicated a poor prognosis in lung adenocarcinoma (LUAD), but not in squamous cell carcinoma (LUSC).	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (104, 127))	('squamous cell carcinoma', 'Disease', (104, 127))	('high', 'Var', (13, 17))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (65, 84))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (104, 127))	('si', 'Chemical', 'MESH:D012825', (30, 32))	('LUAD', 'Phenotype', 'HP:0030078', (86, 90))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('LUSC', 'Phenotype', 'HP:0030359', (129, 133))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (65, 84))	('si', 'Chemical', 'MESH:D012825', (58, 60))	('GSDMD', 'Gene', (18, 23))	('GSDMD', 'Gene', '79792', (18, 23))	('lung adenocarcinoma', 'Disease', (65, 84))
9369	30106450	GSDMD depletion activated the cleavage of caspase-3 and PARP, and promoted cancer cell death via intrinsic mitochondrial apoptotic pathways.	('PARP', 'Gene', '142', (56, 60))	('cleavage', 'MPA', (30, 38))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('caspase-3', 'Gene', '836', (42, 51))	('activated', 'PosReg', (16, 25))	('cancer', 'Disease', (75, 81))	('intrinsic mitochondrial apoptotic pathways', 'Pathway', (97, 139))	('GSDMD', 'Gene', '79792', (0, 5))	('depletion', 'Var', (6, 15))	('PARP', 'Gene', (56, 60))	('GSDMD', 'Gene', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('si', 'Chemical', 'MESH:D012825', (103, 105))	('promoted', 'PosReg', (66, 74))	('caspase-3', 'Gene', (42, 51))
9391	30106450	For example, mice lacking NLRP3 are reported to be hypersusceptible to colitis-associated colorectal cancer as shown by several studies, whereas another study demonstrated that a lack of NLRP3 attenuated DSS-induced colitis in mice.	('colitis-associated colorectal cancer', 'Disease', 'MESH:D015179', (71, 107))	('mice', 'Species', '10090', (13, 17))	('DSS', 'Chemical', 'MESH:D016264', (204, 207))	('NLRP3', 'Gene', (26, 31))	('lack', 'Var', (179, 183))	('mice', 'Species', '10090', (227, 231))	('colitis', 'Disease', 'MESH:D003092', (71, 78))	('colitis-associated colorectal cancer', 'Disease', (71, 107))	('colitis', 'Phenotype', 'HP:0002583', (216, 223))	('colitis', 'Disease', (71, 78))	('attenuated', 'NegReg', (193, 203))	('lacking', 'NegReg', (18, 25))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('colorectal cancer', 'Phenotype', 'HP:0003003', (90, 107))	('colitis', 'Disease', 'MESH:D003092', (216, 223))	('colitis', 'Phenotype', 'HP:0002583', (71, 78))	('NLRP3', 'Gene', (187, 192))	('colitis', 'Disease', (216, 223))
9400	30106450	NSCLC cell lines (PC9, H1703, A549, SPC-A1, H1915, H1975, H1299 and H1650) and a normal human bronchial epithelial cell line (HBE) were purchased from the Institute of Biochemistry and Cell Biology of the Chinese Academy of Sciences (Shanghai, China).	('H1703', 'CellLine', 'CVCL:1490', (23, 28))	('NSCLC', 'Disease', 'MESH:D002289', (0, 5))	('A549', 'CellLine', 'CVCL:0023', (30, 34))	('SPC-A1', 'Gene', (36, 42))	('SPC-A1', 'Gene', '27032', (36, 42))	('H1975', 'Var', (51, 56))	('PC9', 'Gene', '255738', (18, 21))	('H1975', 'CellLine', 'CVCL:1511', (51, 56))	('H1650', 'CellLine', 'CVCL:1483', (68, 73))	('H1915', 'CellLine', 'CVCL:1505', (44, 49))	('PC9', 'Gene', (18, 21))	('NSCLC', 'Phenotype', 'HP:0030358', (0, 5))	('SCLC', 'Phenotype', 'HP:0030357', (1, 5))	('human', 'Species', '9606', (88, 93))	('NSCLC', 'Disease', (0, 5))	('H1299', 'CellLine', 'CVCL:0060', (58, 63))
9469	30106450	Thus, these findings indicated that knockdown of GSDMD inhibited the proliferation of NSCLC cells in vitro.	('GSDMD', 'Gene', (49, 54))	('GSDMD', 'Gene', '79792', (49, 54))	('NSCLC', 'Disease', (86, 91))	('SCLC', 'Phenotype', 'HP:0030357', (87, 91))	('NSCLC', 'Disease', 'MESH:D002289', (86, 91))	('knockdown', 'Var', (36, 45))	('NSCLC', 'Phenotype', 'HP:0030358', (86, 91))	('inhibited', 'NegReg', (55, 64))
9474	30106450	The JC-1 test revealed that the mitochondrial membrane potential (MMP) was decreased following the knockdown of GSDMD (Fig.	('GSDMD', 'Gene', (112, 117))	('GSDMD', 'Gene', '79792', (112, 117))	('mitochondrial membrane potential', 'MPA', (32, 64))	('knockdown', 'Var', (99, 108))	('decreased', 'NegReg', (75, 84))
9475	30106450	These results indicated that siRNA-induced depletion of GSDMD facilitated the intrinsic mitochondrial apoptotic pathway.	('si', 'Chemical', 'MESH:D012825', (29, 31))	('si', 'Chemical', 'MESH:D012825', (84, 86))	('depletion', 'Var', (43, 52))	('facilitated', 'PosReg', (62, 73))	('intrinsic mitochondrial apoptotic pathway', 'Pathway', (78, 119))	('GSDMD', 'Gene', (56, 61))	('GSDMD', 'Gene', '79792', (56, 61))
9497	30106450	Western blotting assay indicated that GSDMD knockdown was associated with the activation of caspase-3 and inactivation of PARP, as indicated by the presence of their cleaved forms (Fig.	('PARP', 'Gene', (122, 126))	('caspase-3', 'Gene', (92, 101))	('caspase-3', 'Gene', '836', (92, 101))	('activation', 'PosReg', (78, 88))	('PARP', 'Gene', '142', (122, 126))	('knockdown', 'Var', (44, 53))	('GSDMD', 'Gene', (38, 43))	('GSDMD', 'Gene', '79792', (38, 43))	('inactivation', 'NegReg', (106, 118))
9500	30106450	At the last time-point (120 h), PC9 cells treated with GSDMD siRNAs demonstrated 33% (si-1031) and 58% (si-1244) cell viability, while PC9 cells which were treated with GSDMD siRNAs and also pretreated with z-VAD-FMK maintained 67% (si-1031) and 81% (si-1244) cell viability, although significant inhibition of proliferation still remained (Fig.	('GSDMD', 'Gene', '79792', (169, 174))	('PC9', 'Gene', (135, 138))	('si', 'Chemical', 'MESH:D012825', (104, 106))	('GSDMD', 'Gene', (169, 174))	('si-1031', 'Var', (233, 240))	('si', 'Chemical', 'MESH:D012825', (175, 177))	('z-VAD-FMK', 'Chemical', 'MESH:C096713', (207, 216))	('si', 'Chemical', 'MESH:D012825', (86, 88))	('si', 'Chemical', 'MESH:D012825', (285, 287))	('GSDMD', 'Gene', '79792', (55, 60))	('inhibition', 'NegReg', (297, 307))	('si', 'Chemical', 'MESH:D012825', (61, 63))	('PC9', 'Gene', '255738', (32, 35))	('si', 'Chemical', 'MESH:D012825', (251, 253))	('cell viability', 'CPA', (260, 274))	('si-1244', 'Var', (251, 258))	('GSDMD', 'Gene', (55, 60))	('PC9', 'Gene', '255738', (135, 138))	('PC9', 'Gene', (32, 35))	('si', 'Chemical', 'MESH:D012825', (233, 235))	('si-1031', 'Var', (86, 93))	('proliferation', 'CPA', (311, 324))
9502	30106450	Collectively, these results revealed that the knockdown of GSDMD led to the induction of apoptosis by activation of caspase-3, which was partially reversed by the caspase inhibition.	('knockdown', 'Var', (46, 55))	('apoptosis', 'CPA', (89, 98))	('si', 'Chemical', 'MESH:D012825', (95, 97))	('caspase-3', 'Gene', (116, 125))	('activation', 'PosReg', (102, 112))	('GSDMD', 'Gene', (59, 64))	('GSDMD', 'Gene', '79792', (59, 64))	('caspase-3', 'Gene', '836', (116, 125))
9512	30106450	Six-week-old male Balb/c nude mice were injected subcutaneously with PC9 cells transduced with shGsd or shNeg.	('PC9', 'Gene', (69, 72))	('PC9', 'Gene', '255738', (69, 72))	('shGsd', 'Var', (95, 100))	('nude mice', 'Species', '10090', (25, 34))
9555	30106450	EGFR mutation and increased copy numbers are common in NSCLC, activating downstream PI3K/Akt/mTOR signaling and resulting in uncontrolled growth and cell proliferation.	('resulting in', 'Reg', (112, 124))	('EGFR', 'Gene', (0, 4))	('NSCLC', 'Disease', (55, 60))	('Akt', 'Gene', '207', (89, 92))	('activating', 'PosReg', (62, 72))	('uncontrolled', 'MPA', (125, 137))	('NSCLC', 'Disease', 'MESH:D002289', (55, 60))	('SCLC', 'Phenotype', 'HP:0030357', (56, 60))	('si', 'Chemical', 'MESH:D012825', (98, 100))	('Akt', 'Gene', (89, 92))	('cell proliferation', 'CPA', (149, 167))	('NSCLC', 'Phenotype', 'HP:0030358', (55, 60))	('copy numbers', 'Var', (28, 40))	('mutation', 'Var', (5, 13))
9558	30106450	It may be that knockdown of GSDMD impairs the inflammatory responses, thus interrupting the negative feedback regulation for activating the PI3K/Akt pathway, but it could also be that the full length GSDMD has a role in regulating this pathway, particularly in cancer cells.	('Akt', 'Gene', (145, 148))	('GSDMD', 'Gene', '79792', (28, 33))	('GSDMD', 'Gene', '79792', (200, 205))	('knockdown', 'Var', (15, 24))	('negative feedback regulation', 'MPA', (92, 120))	('GSDMD', 'Gene', (200, 205))	('cancer', 'Phenotype', 'HP:0002664', (261, 267))	('interrupting', 'NegReg', (75, 87))	('Akt', 'Gene', '207', (145, 148))	('inflammatory responses', 'CPA', (46, 68))	('activating', 'MPA', (125, 135))	('impairs', 'NegReg', (34, 41))	('cancer', 'Disease', (261, 267))	('cancer', 'Disease', 'MESH:D009369', (261, 267))	('GSDMD', 'Gene', (28, 33))
9582	27311570	The 5-year overall survival rate of patients with high PTK6 expression was lower than that of patients with low PTK6 expression (81.3% vs. 96.2%, P = 0.008).	('lower', 'NegReg', (75, 80))	('overall survival', 'CPA', (11, 27))	('patients', 'Species', '9606', (94, 102))	('patients', 'Species', '9606', (36, 44))	('PTK6', 'Gene', (55, 59))	('high', 'Var', (50, 54))
9642	27311570	The 5-year OS rate was significantly lower in patients with high PTK6 expression than in those with low PTK6 expression (81.3% vs. 96.2%, P = 0.008) (Fig.	('high', 'Var', (60, 64))	('patients', 'Species', '9606', (46, 54))	('PTK6', 'Gene', (65, 69))	('lower', 'NegReg', (37, 42))
9666	27311570	In contrast, studies in other types of cancer, including breast cancer and non-small cell lung cancer, showed that high PTK6 expression was significantly associated with low 5-year OS rates.	('breast cancer', 'Disease', (57, 70))	('low', 'NegReg', (170, 173))	('non-small cell lung cancer', 'Disease', (75, 101))	('lung cancer', 'Phenotype', 'HP:0100526', (90, 101))	('cancer', 'Disease', (39, 45))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', (95, 101))	('PTK6', 'Gene', (120, 124))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (79, 101))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (75, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('expression', 'MPA', (125, 135))	('high', 'Var', (115, 119))	('5-year OS rates', 'MPA', (174, 189))	('breast cancer', 'Phenotype', 'HP:0003002', (57, 70))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (75, 101))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('breast cancer', 'Disease', 'MESH:D001943', (57, 70))
9668	27311570	We found that the 5-year OS rate of patients with high PTK6 expression was significantly lower than that of patients with low PTK6 expression (81.3% vs. 96.2%).	('lower', 'NegReg', (89, 94))	('OS rate', 'CPA', (25, 32))	('patients', 'Species', '9606', (36, 44))	('expression', 'Var', (60, 70))	('PTK6', 'Gene', (55, 59))	('patients', 'Species', '9606', (108, 116))	('high', 'Var', (50, 54))
9672	27311570	In the SW620 colorectal adenocarcinoma cell line, targeting nuclear PTK6 negatively regulated endogenous beta-catenin/T cell factor (TCF) transcriptional activity, whereas targeting membrane PTK6 enhanced beta-catenin/TCF-regulated transcription.	('enhanced', 'PosReg', (196, 204))	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (13, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (29, 38))	('PTK6', 'Gene', (68, 72))	('beta-catenin', 'Gene', (205, 217))	('beta-catenin', 'Gene', (105, 117))	('negatively', 'NegReg', (73, 83))	('SW620', 'CellLine', 'CVCL:0547', (7, 12))	('beta-catenin', 'Gene', '1499', (205, 217))	('beta-catenin', 'Gene', '1499', (105, 117))	('TCF', 'Gene', (218, 221))	('TCF', 'Gene', '3172', (218, 221))	('targeting', 'Var', (50, 59))	('TCF', 'Gene', (133, 136))	('TCF', 'Gene', '3172', (133, 136))	('colorectal adenocarcinoma', 'Disease', (13, 38))
9676	27311570	In conclusion, we demonstrated that PTK6 was overexpressed in cervical squamous cell cancer and that high PTK6 expression was associated with short OS.	('associated', 'Reg', (126, 136))	('cervical squamous cell cancer', 'Disease', 'MESH:D002294', (62, 91))	('cervical squamous cell cancer', 'Disease', (62, 91))	('short OS', 'Disease', (142, 150))	('overexpressed', 'PosReg', (45, 58))	('PTK6', 'Gene', (106, 110))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (71, 91))	('expression', 'MPA', (111, 121))	('high', 'Var', (101, 105))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('PTK6', 'Gene', (36, 40))
9694	24434068	A recent analysis of high risk HPV E6/7 expression in 430 oral cancer samples found HPV in only 5.9% of the samples (95% CI, 3.6-8.2).	('HPV', 'Disease', (84, 87))	('HPV', 'Disease', 'MESH:D030361', (31, 34))	('oral cancer', 'Disease', 'MESH:D009062', (58, 69))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('oral cancer', 'Disease', (58, 69))	('E6/7', 'Var', (35, 39))	('HPV', 'Disease', (31, 34))	('HPV', 'Disease', 'MESH:D030361', (84, 87))
9715	24434068	validated the prognostic value of LOH at specific chromosomal loci (3p, 9p, 17p, 4q) in 296 histologic samples with mild or moderate dysplasia.	('LOH', 'Var', (34, 37))	('dysplasia', 'Disease', 'MESH:D004476', (133, 142))	('dysplasia', 'Disease', (133, 142))
9750	24434068	In contrast, a meta-analysis evaluating the safety of pioglitazone, which included 16,390 patients in 19 trials, showed that the hazard ratio (HR) for the composite outcome of death, myocardial infarction or stroke of pioglitazone compare to placebo or other anti-diabetic drug was 0.82 (95% CI, 0.72-0.94; P = 0.005).	('myocardial infarction', 'Phenotype', 'HP:0001658', (183, 204))	('stroke', 'Disease', 'MESH:D020521', (208, 214))	('pioglitazone', 'Chemical', 'MESH:D000077205', (54, 66))	('diabetic', 'Disease', 'MESH:D003920', (264, 272))	('pioglitazone', 'Chemical', 'MESH:D000077205', (218, 230))	('myocardial infarction', 'Disease', 'MESH:D009203', (183, 204))	('stroke', 'Phenotype', 'HP:0001297', (208, 214))	('death', 'Disease', 'MESH:D003643', (176, 181))	('myocardial infarction', 'Disease', (183, 204))	('death', 'Disease', (176, 181))	('pioglitazone', 'Var', (218, 230))	('diabetic', 'Disease', (264, 272))	('stroke', 'Disease', (208, 214))	('patients', 'Species', '9606', (90, 98))
9777	24434068	The same group reported that pioglitazone significantly decreased the adenocarcinoma load by 64% and 50% in wild type or p53 mutant mice, respectively, after exposure by the carcinogen vinyl carbamate.	('mutant', 'Var', (125, 131))	('p53', 'Gene', (121, 124))	('pioglitazone', 'Chemical', 'MESH:D000077205', (29, 41))	('decreased', 'NegReg', (56, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('mice', 'Species', '10090', (132, 136))	('adenocarcinoma', 'Disease', (70, 84))	('p53', 'Gene', '22060', (121, 124))	('adenocarcinoma', 'Disease', 'MESH:D000230', (70, 84))	('carbamate', 'Chemical', 'MESH:D002219', (191, 200))
9797	33946032	Inhomogeneity of stiffness and density of the extracellular matrix within the leukoplakia of human oral mucosa as potential physicochemical factors leading to carcinogenesis Inhomogeneous stiffness might act as mechanoagonist leading to cancer development.	('carcinogenesis', 'Disease', (159, 173))	('leukoplakia', 'Disease', 'MESH:D007971', (78, 89))	('carcinogenesis', 'Disease', 'MESH:D063646', (159, 173))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('human', 'Species', '9606', (93, 98))	('leukoplakia of human oral mucosa', 'Phenotype', 'HP:0002745', (78, 110))	('leukoplakia', 'Disease', (78, 89))	('cancer', 'Disease', 'MESH:D009369', (237, 243))	('cancer', 'Disease', (237, 243))	('Inhomogeneous', 'Var', (174, 187))	('men', 'Species', '9606', (251, 254))
9807	33946032	Inhomogeneous stiffness within leukoplakia might act as "a mechanoagonist" that promotes oncogenesis.	('oncogenesis', 'CPA', (89, 100))	('stiffness within leukoplakia', 'Disease', (14, 42))	('Inhomogeneous', 'Var', (0, 13))	('promotes', 'PosReg', (80, 88))	('stiffness within leukoplakia', 'Disease', 'MESH:D007971', (14, 42))
9816	33946032	Common alterations in chromosomal regions and genes, including FBXL5, UGT2B15, UGT2B28, KANSL1, GSTT1 and DUSP22, as well as some putative genes associated with hallmarks of malignancy are believed to play significant roles in predicting the evolution of lesions in term of leukoplakia to squamous cell carcinoma.	('malignancy', 'Disease', 'MESH:D009369', (174, 184))	('UGT2B28', 'Gene', '54490', (79, 86))	('DUSP22', 'Gene', '56940', (106, 112))	('KANSL1', 'Gene', '284058', (88, 94))	('KANSL1', 'Gene', (88, 94))	('DUSP22', 'Gene', (106, 112))	('FBXL5', 'Gene', (63, 68))	('malignancy', 'Disease', (174, 184))	('UGT2B15', 'Gene', (70, 77))	('GSTT1', 'Gene', '2952', (96, 101))	('UGT2B15', 'Gene', '7366', (70, 77))	('FBXL5', 'Gene', '26234', (63, 68))	('GSTT1', 'Gene', (96, 101))	('alterations', 'Var', (7, 18))	('leukoplakia to squamous cell carcinoma', 'Disease', 'MESH:D002294', (274, 312))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (289, 312))	('leukoplakia to squamous cell carcinoma', 'Disease', (274, 312))	('carcinoma', 'Phenotype', 'HP:0030731', (303, 312))	('UGT2B28', 'Gene', (79, 86))
9817	33946032	Malignant transformation has also been found to be associated with the status of SMAD4 expression, a balance in DNA repair proteins, the presence of keratin 10 in saliva, ALDH1 and podoplanin contents as well as GLUT-1-specific staining with an oral brush biopsy.	('balance in DNA repair', 'MPA', (101, 122))	('podoplanin', 'Gene', '10630', (181, 191))	('SMAD4', 'Gene', (81, 86))	('keratin 10', 'Gene', (149, 159))	('associated', 'Reg', (51, 61))	('presence', 'Var', (137, 145))	('ALDH1', 'Gene', (171, 176))	('expression', 'MPA', (87, 97))	('podoplanin', 'Gene', (181, 191))	('keratin 10', 'Gene', '3858', (149, 159))	('Malignant transformation', 'CPA', (0, 24))	('GLUT-1', 'Gene', (212, 218))	('GLUT-1', 'Gene', '6513', (212, 218))	('ALDH1', 'Gene', '216', (171, 176))	('SMAD4', 'Gene', '4089', (81, 86))
9823	33946032	Thus, high inhomogeneity might be considered as mechanomarker of cancerous transformation, and as a tissue environmental factor (mechanoagonist) associated with cancer development.	('high inhomogeneity', 'Var', (6, 24))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('men', 'Species', '9606', (114, 117))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('cancerous transformation', 'Disease', 'MESH:D009369', (65, 89))	('cancer', 'Disease', (161, 167))	('cancer', 'Disease', (65, 71))	('cancerous transformation', 'Disease', (65, 89))	('men', 'Species', '9606', (175, 178))
9856	33946032	Squamous cell hyperplasia with low grade dysplasia and squamous cell carcinoma samples were significantly stiffer than their normal counterparts, with a mean stiffness equal to 12.9 +- 20.9 kPa (n = 2026) for hyperplasia with dysplasia and 4.0 kPa +- 5.5 kPa (n = 3458) for squamous cell carcinoma tissue.	('carcinoma', 'Phenotype', 'HP:0030731', (288, 297))	('Squamous cell hyperplasia', 'Disease', 'MESH:D002294', (0, 25))	('squamous cell carcinoma', 'Disease', (274, 297))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (55, 78))	('low grade', 'Var', (31, 40))	('dysplasia', 'Disease', 'MESH:C536170', (226, 235))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))	('hyperplasia', 'Disease', (14, 25))	('dysplasia', 'Disease', (41, 50))	('hyperplasia', 'Disease', 'MESH:D006965', (14, 25))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (55, 78))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (274, 297))	('hyperplasia', 'Disease', (209, 220))	('hyperplasia', 'Disease', 'MESH:D006965', (209, 220))	('Squamous cell hyperplasia', 'Disease', (0, 25))	('squamous cell carcinoma', 'Disease', (55, 78))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (274, 297))	('dysplasia', 'Disease', (226, 235))	('dysplasia', 'Disease', 'MESH:C536170', (41, 50))
9858	33946032	Since it is known that the development of premalignancy and malignancy is a multistep process involving the accumulation of genetic, epigenetic and metabolic alterations, we broadened our histopathological examination.	('malignancy', 'Disease', (60, 70))	('malignancy', 'Disease', 'MESH:D009369', (45, 55))	('malignancy', 'Disease', (45, 55))	('epigenetic', 'Var', (133, 143))	('malignancy', 'Disease', 'MESH:D009369', (60, 70))	('men', 'Species', '9606', (34, 37))
9863	33946032	3f, and interestingly, we observed moderate and severe fibrosis in the squamous cell hyperplasia with low grade dysplasia specimens than in the squamous cell cancerous specimens, where the fibrosis was assessed as mild one.	('squamous cell hyperplasia', 'Disease', (71, 96))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('squamous cell cancerous', 'Disease', (144, 167))	('dysplasia', 'Disease', 'MESH:C536170', (112, 121))	('fibrosis', 'Disease', 'MESH:D005355', (55, 63))	('fibrosis', 'Disease', (55, 63))	('fibrosis', 'Disease', (189, 197))	('men', 'Species', '9606', (173, 176))	('fibrosis', 'Disease', 'MESH:D005355', (189, 197))	('dysplasia', 'Disease', (112, 121))	('squamous cell hyperplasia', 'Disease', 'MESH:D002294', (71, 96))	('squamous cell hyperplasia', 'Phenotype', 'HP:0002860', (71, 96))	('squamous cell cancerous', 'Disease', 'MESH:D002294', (144, 167))	('men', 'Species', '9606', (127, 130))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (144, 164))	('low grade', 'Var', (102, 111))
9926	33946032	Importantly, even subtle changes in rigidity of the surrounding ECM were able to induce cell reprogramming leading to tumor emergence, which was determined by disproportional responsiveness of cells to environmental stiffness upon oncogene exposure and regulation of YAP/TAZ activity.	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('TAZ', 'Gene', '6901', (271, 274))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('YAP', 'Gene', '10413', (267, 270))	('TAZ', 'Gene', (271, 274))	('rigidity', 'Disease', (36, 44))	('tumor', 'Disease', (118, 123))	('YAP', 'Gene', (267, 270))	('changes', 'Var', (25, 32))	('cell reprogramming', 'CPA', (88, 106))	('men', 'Species', '9606', (209, 212))	('rigidity', 'Phenotype', 'HP:0002063', (36, 44))	('induce', 'Reg', (81, 87))	('rigidity', 'Disease', 'MESH:D009127', (36, 44))
9949	33886544	For the primary analysis, germline genetic variants in HMGCR, NPC1L1, CETP, PCSK9 and LDLR were used to proxy the effect of low-density lipoprotein cholesterol (LDL-C) lowering therapies.	('CETP', 'Gene', (70, 74))	('CETP', 'Gene', '1071', (70, 74))	('NPC1L1', 'Gene', (62, 68))	('HMGCR', 'Gene', (55, 60))	('low-density lipoprotein cholesterol', 'MPA', (124, 159))	('LDLR', 'Gene', (86, 90))	('LDL-C', 'Gene', (161, 166))	('HMGCR', 'Gene', '3156', (55, 60))	('PCSK9', 'Gene', (76, 81))	('LDL-C', 'Gene', '22796', (161, 166))	('variants', 'Var', (43, 51))	('NPC1L1', 'Gene', '29881', (62, 68))	('cholesterol', 'Chemical', 'MESH:D002784', (148, 159))	('LDLR', 'Gene', '3949', (86, 90))	('PCSK9', 'Gene', '255738', (76, 81))
9957	33886544	LDLR variants, resulting in genetically-proxied reduction in LDL-C equivalent to a 1 mmol/L (38.7 mg/dL), reduced the risk of OC and OPC combined (OR 0.7, 95%CI 0.5, 1.0, p = 0.006).	('OPC', 'Chemical', '-', (133, 136))	('LDLR', 'Gene', (0, 4))	('LDLR', 'Gene', '3949', (0, 4))	('LDL-C', 'Gene', '22796', (61, 66))	('LDL-C', 'Gene', (61, 66))	('variants', 'Var', (5, 13))	('reduction', 'NegReg', (48, 57))	('reduced', 'NegReg', (106, 113))	('OPC', 'Disease', (133, 136))
9959	33886544	There was some evidence that genetically-proxied inhibition of PCSK9 increased risk, while lipid-lowering variants in LDLR, reduced risk of combined OC and OPC.	('LDLR', 'Gene', '3949', (118, 122))	('combined OC', 'Disease', (140, 151))	('lipid-lowering', 'MPA', (91, 105))	('increased', 'PosReg', (69, 78))	('variants', 'Var', (106, 114))	('reduced', 'NegReg', (124, 131))	('PCSK9', 'Gene', (63, 68))	('OPC', 'Disease', (156, 159))	('PCSK9', 'Gene', '255738', (63, 68))	('OPC', 'Chemical', '-', (156, 159))	('LDLR', 'Gene', (118, 122))	('inhibition', 'NegReg', (49, 59))	('lipid', 'Chemical', 'MESH:D008055', (91, 96))
9964	33886544	We did find some evidence that genetically-proxied inhibition of PCSK9 increases, while lipid-lowering variants in LDLR reduce oral and oropharyngeal cancer risk.	('LDLR', 'Gene', '3949', (115, 119))	('inhibition', 'NegReg', (51, 61))	('reduce', 'NegReg', (120, 126))	('PCSK9', 'Gene', (65, 70))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('variants', 'Var', (103, 111))	('cancer', 'Disease', (150, 156))	('PCSK9', 'Gene', '255738', (65, 70))	('increases', 'PosReg', (71, 80))	('LDLR', 'Gene', (115, 119))	('lipid', 'Chemical', 'MESH:D008055', (88, 93))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
9978	33886544	Therefore, modulation of cholesterol synthesis has the potential to influence several hallmarks of tumourigenesis including cell migration and proliferation.	('modulation', 'Var', (11, 21))	('tumour', 'Disease', 'MESH:D009369', (99, 105))	('tumour', 'Disease', (99, 105))	('influence', 'Reg', (68, 77))	('cell migration', 'CPA', (124, 138))	('cholesterol', 'Chemical', 'MESH:D002784', (25, 36))	('tumour', 'Phenotype', 'HP:0002664', (99, 105))	('proliferation', 'CPA', (143, 156))
9986	33886544	Numerous single nucleotide polymorphisms (SNPs) are associated with lower levels of circulating LDL-C and inheriting an LDL-C lowering allele has been proposed to be analogous to being assigned life-long treatment with a cholesterol lowering drug.	('LDL-C lowering', 'Phenotype', 'HP:0003563', (120, 134))	('LDL-C', 'Gene', '22796', (96, 101))	('LDL-C', 'Gene', (96, 101))	('lower', 'NegReg', (68, 73))	('lower levels of circulating LDL', 'Phenotype', 'HP:0003563', (68, 99))	('single nucleotide polymorphisms', 'Var', (9, 40))	('LDL-C', 'Gene', (120, 125))	('men', 'Species', '9606', (209, 212))	('LDL-C', 'Gene', '22796', (120, 125))	('cholesterol lowering', 'Phenotype', 'HP:0003146', (221, 241))	('cholesterol', 'Chemical', 'MESH:D002784', (221, 232))
9987	33886544	MR has previously demonstrated the protective effect of cholesterol-lowering drugs on cardiovascular disease risk, but also that inhibition of HMGCR and PCSK9 may have an adverse effect on diabetes risk.	('HMGCR', 'Gene', (143, 148))	('PCSK9', 'Gene', '255738', (153, 158))	('cardiovascular disease', 'Disease', (86, 108))	('diabetes', 'Disease', (189, 197))	('inhibition', 'Var', (129, 139))	('HMGCR', 'Gene', '3156', (143, 148))	('diabetes', 'Disease', 'MESH:D003920', (189, 197))	('cardiovascular disease', 'Phenotype', 'HP:0001626', (86, 108))	('cardiovascular disease', 'Disease', 'MESH:D002318', (86, 108))	('PCSK9', 'Gene', (153, 158))	('cholesterol', 'Chemical', 'MESH:D002784', (56, 67))
9988	33886544	Of relevance to cancer, some recent MR studies have shown that genetically-proxied inhibition of HMGCR may be protective against overall cancer and epithelial ovarian cancer risk.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('cancer', 'Disease', 'MESH:D009369', (16, 22))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('HMGCR', 'Gene', (97, 102))	('cancer', 'Disease', (16, 22))	('cancer', 'Disease', (167, 173))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('ovarian cancer', 'Phenotype', 'HP:0100615', (159, 173))	('cancer', 'Disease', (137, 143))	('HMGCR', 'Gene', '3156', (97, 102))	('epithelial ovarian cancer', 'Phenotype', 'HP:0025318', (148, 173))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('inhibition', 'Var', (83, 93))	('epithelial ovarian cancer', 'Disease', (148, 173))	('epithelial ovarian cancer', 'Disease', 'MESH:D000077216', (148, 173))
9991	33886544	Variants were robustly associated with LDL-C in a meta-analysis of genome-wide association studies (GWAS) involving 188,578 individuals primarily (96%) of European ancestry in the Global Lipids Genetic Consortium (GLGC).	('Variants', 'Var', (0, 8))	('LDL-C', 'Gene', (39, 44))	('LDL-C', 'Gene', '22796', (39, 44))	('Lipids', 'Chemical', 'MESH:D008055', (187, 193))	('associated', 'Reg', (23, 33))
9995	33886544	We estimated the effects of the cholesterol-lowering genetic variants on risk of OC and OPC using GWAS performed on 6,034 cases and 6,585 controls from 12 studies which were part of the Genetic Associations and Mechanisms in Oncology (GAME-ON) Network.	('Oncology', 'Phenotype', 'HP:0002664', (225, 233))	('cholesterol', 'Chemical', 'MESH:D002784', (32, 43))	('OPC', 'Chemical', '-', (88, 91))	('variants', 'Var', (61, 69))	('OPC', 'Disease', (88, 91))
9997	33886544	Cancer cases comprised the following the International Classification of Diseases (ICD) codes: oral cavity (C02.0-C02.9, C03.0-C03.9, C04.0-C04.9, C05.0-C06.9) oropharynx (C01.9, C02.4, C09.0-C10.9), hypopharynx (C13.0-C13.9), overlapping (C14 and combination of other sites) and 25 cases with unknown ICD code (other).	('C03', 'CellLine', 'CVCL:J167', (127, 130))	('C13.0-C13.9', 'Var', (213, 224))	('C02.0-C02.9', 'Var', (108, 119))	('C03.0-C03.9', 'Var', (121, 132))	('C05.0-C06.9', 'Var', (147, 158))	('C03', 'CellLine', 'CVCL:J167', (121, 124))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('C01.9', 'Var', (172, 177))	('hypopharynx', 'Disease', (200, 211))	('C01.9', 'CellLine', 'CVCL:E303', (172, 177))	('Classification of Diseases', 'Disease', (55, 81))	('oral cavity', 'Disease', (95, 106))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('Classification of Diseases', 'Disease', 'MESH:D008310', (55, 81))	('overlapping', 'Disease', (227, 238))	('C04.0-C04.9', 'Var', (134, 145))	('oropharynx', 'Disease', (160, 170))
10002	33886544	We next performed harmonisation of the direction of effects between the cholesterol-lowering exposures and outcome (OC or OPC) where, for each variant, the allele designated the 'exposure allele' was associated with lower LDL-C levels and palindromic SNPs were aligned when MAFs were <0.3 or were otherwise excluded.	('lower', 'NegReg', (216, 221))	('OPC', 'Chemical', '-', (122, 125))	('lower LDL-C', 'Phenotype', 'HP:0003563', (216, 227))	('variant', 'Var', (143, 150))	('LDL-C', 'Gene', '22796', (222, 227))	('LDL-C', 'Gene', (222, 227))	('cholesterol', 'Chemical', 'MESH:D002784', (72, 83))
10003	33886544	In our primary analysis, four palindromic SNPs, one in HMGCR (rs2006760), the other in PCSK9 (rs2149041) and two in CETP (rs5880, rs9929488) were removed.	('rs2006760', 'Mutation', 'rs2006760', (62, 71))	('rs9929488', 'Mutation', 'rs9929488', (130, 139))	('rs9929488', 'Var', (130, 139))	('HMGCR', 'Gene', (55, 60))	('rs5880', 'Var', (122, 128))	('PCSK9', 'Gene', (87, 92))	('rs2149041', 'Mutation', 'rs2149041', (94, 103))	('CETP', 'Gene', (116, 120))	('rs5880', 'Mutation', 'rs5880', (122, 128))	('HMGCR', 'Gene', '3156', (55, 60))	('CETP', 'Gene', '1071', (116, 120))	('PCSK9', 'Gene', '255738', (87, 92))	('rs2006760', 'Var', (62, 71))	('rs2149041', 'Var', (94, 103))
10004	33886544	In the secondary analysis with other lipid traits, 11 palindromic SNPs (rs1936800, rs2288912, rs7112577, rs964184, rs150617279, rs1883711, rs4722043, rs2156552, rs2954029, rs581080, rs7534572) were removed.	('rs7112577', 'Var', (94, 103))	('rs4722043', 'Var', (139, 148))	('lipid', 'Chemical', 'MESH:D008055', (37, 42))	('rs1883711', 'Mutation', 'rs1883711', (128, 137))	('rs150617279', 'Mutation', 'rs150617279', (115, 126))	('rs4722043', 'Mutation', 'rs4722043', (139, 148))	('rs2156552', 'Mutation', 'rs2156552', (150, 159))	('rs150617279', 'Var', (115, 126))	('rs7534572', 'Mutation', 'rs7534572', (182, 191))	('rs2288912', 'Mutation', 'rs2288912', (83, 92))	('rs964184', 'Mutation', 'rs964184', (105, 113))	('rs581080', 'Var', (172, 180))	('rs964184', 'Var', (105, 113))	('rs1883711', 'Var', (128, 137))	('rs7112577', 'Mutation', 'rs7112577', (94, 103))	('rs1936800', 'Var', (72, 81))	('rs2288912', 'Var', (83, 92))	('rs1936800', 'Mutation', 'rs1936800', (72, 81))	('rs581080', 'Mutation', 'rs581080', (172, 180))	('rs2954029', 'Var', (161, 170))	('rs2954029', 'Mutation', 'rs2954029', (161, 170))	('rs7534572', 'Var', (182, 191))	('rs2156552', 'Var', (150, 159))
10008	33886544	As the instruments for HMGCR, NPC1L1, CETP, PCSK9 and LDLR were in weak LD (r2 <0.2), we accounted for this correlation between SNPs in the primary analysis using LDlink (4.0 Release) which employs Phase 3 (Version 5) of the 1000 Genomes Project and variant rs numbers based on dbSNP.	('LDLR', 'Gene', '3949', (54, 58))	('PCSK9', 'Gene', (44, 49))	('variant', 'Var', (250, 257))	('men', 'Species', '9606', (13, 16))	('PCSK9', 'Gene', '255738', (44, 49))	('NPC1L1', 'Gene', '29881', (30, 36))	('HMGCR', 'Gene', (23, 28))	('CETP', 'Gene', (38, 42))	('LDLR', 'Gene', (54, 58))	('CETP', 'Gene', '1071', (38, 42))	('HMGCR', 'Gene', '3156', (23, 28))	('NPC1L1', 'Gene', (30, 36))
10030	33886544	In total, 5 SNPs in HMGCR (rs12916, rs17238484, rs5909, rs2303152, rs10066707) were used to proxy HMG-CoA reductase inhibition (statins); 5 SNPs in NPC1L1 (rs217386, rs2073547, rs7791240, rs10234070, rs2300414) proxied NPC1L1 inhibition (ezetimibe); 6 SNPs in CETP (rs9989419, rs12708967, rs3764261, rs1800775, rs1864163, rs289714) proxied CETP inhibition; 6 SNPs in PCSK9 (rs11206510, rs2479409, rs2479394, rs10888897, rs7552841, rs562556) proxied PCSK9 inhibition; 3 SNPs proxied cholesterol-lowering in LDLR (rs6511720, rs1122608, rs688) (LDL-receptor inhibition).	('PCSK9', 'Gene', (367, 372))	('HMG-CoA reductase', 'Gene', (98, 115))	('rs5909', 'Mutation', 'rs5909', (48, 54))	('rs562556', 'Mutation', 'rs562556', (431, 439))	('PCSK9', 'Gene', '255738', (367, 372))	('NPC1L1', 'Gene', '29881', (219, 225))	('rs2300414', 'Mutation', 'rs2300414', (200, 209))	('rs10234070', 'Mutation', 'rs10234070', (188, 198))	('cholesterol-lowering', 'MPA', (482, 502))	('LDLR', 'Gene', '3949', (506, 510))	('rs217386', 'Mutation', 'rs217386', (156, 164))	('HMGCR', 'Gene', (20, 25))	('rs562556', 'Var', (431, 439))	('CETP', 'Gene', '1071', (340, 344))	('NPC1L1', 'Gene', (219, 225))	('rs6511720', 'Mutation', 'rs6511720', (512, 521))	('NPC1L1', 'Gene', '29881', (148, 154))	('rs688', 'Var', (534, 539))	('rs10888897', 'Var', (408, 418))	('rs2479409', 'Var', (386, 395))	('NPC1L1', 'Gene', (148, 154))	('rs2479394', 'Mutation', 'rs2479394', (397, 406))	('rs10888897', 'Mutation', 'rs10888897', (408, 418))	('LDL-receptor', 'Gene', '3949', (542, 554))	('ezetimibe', 'Chemical', 'MESH:D000069438', (238, 247))	('rs2073547', 'Mutation', 'rs2073547', (166, 175))	('CETP', 'Gene', '1071', (260, 264))	('rs1800775', 'Mutation', 'rs1800775', (300, 309))	('rs1122608', 'Var', (523, 532))	('cholesterol', 'Chemical', 'MESH:D002784', (482, 493))	('rs7552841', 'Var', (420, 429))	('rs11206510', 'Mutation', 'rs11206510', (374, 384))	('rs2479394', 'Var', (397, 406))	('rs12916', 'Mutation', 'rs12916', (27, 34))	('HMG-CoA reductase', 'Gene', '3156', (98, 115))	('rs2479409', 'Mutation', 'rs2479409', (386, 395))	('CETP', 'Gene', (340, 344))	('rs9989419', 'Mutation', 'rs9989419', (266, 275))	('LDL-receptor', 'Gene', (542, 554))	('rs1864163', 'Mutation', 'rs1864163', (311, 320))	('rs289714', 'Mutation', 'rs289714', (322, 330))	('PCSK9', 'Gene', (449, 454))	('rs11206510', 'Var', (374, 384))	('rs3764261', 'Mutation', 'rs3764261', (289, 298))	('rs6511720', 'Var', (512, 521))	('rs17238484', 'Mutation', 'rs17238484', (36, 46))	('inhibition', 'NegReg', (455, 465))	('rs10066707', 'Mutation', 'rs10066707', (67, 77))	('HMGCR', 'Gene', '3156', (20, 25))	('PCSK9', 'Gene', '255738', (449, 454))	('rs1122608', 'Mutation', 'rs1122608', (523, 532))	('rs7552841', 'Mutation', 'rs7552841', (420, 429))	('rs7791240', 'Mutation', 'rs7791240', (177, 186))	('rs2303152', 'Mutation', 'rs2303152', (56, 65))	('LDLR', 'Gene', (506, 510))	('CETP', 'Gene', (260, 264))	('rs12708967', 'Mutation', 'rs12708967', (277, 287))	('rs688', 'Mutation', 'rs688', (534, 539))
10035	33886544	There was also some evidence that LDLR variants, resulting in genetically-proxied reduction in LDL-C equivalent to a 1 mmol/L (38.7 mg/dL), reduced the risk of combined OC and OPC (OR IVW; 0.7; 95%CI 0.4, 1.0, p = 0.05; Table 2 and Fig 1).	('LDLR', 'Gene', (34, 38))	('reduction', 'NegReg', (82, 91))	('LDLR', 'Gene', '3949', (34, 38))	('OPC', 'Disease', (176, 179))	('LDL-C', 'Gene', (95, 100))	('variants', 'Var', (39, 47))	('OPC', 'Chemical', '-', (176, 179))	('LDL-C', 'Gene', '22796', (95, 100))	('combined OC', 'Disease', (160, 171))	('reduced', 'NegReg', (140, 147))
10055	33886544	We also found some evidence for a protective effect of cholesterol-lowering variants in LDLR on OC and OPC risk in both studies.	('LDLR', 'Gene', '3949', (88, 92))	('OPC', 'Disease', (103, 106))	('OPC', 'Chemical', '-', (103, 106))	('variants', 'Var', (76, 84))	('cholesterol', 'Chemical', 'MESH:D002784', (55, 66))	('LDLR', 'Gene', (88, 92))
10063	33886544	Variants in PCSK9 have been associated with an increased risk of diabetes (OR 1.1, 95%CI 1.0, 1.2 for each 10 mg per decilitre decrease in LDL-C).	('diabetes', 'Disease', (65, 73))	('Variants', 'Var', (0, 8))	('PCSK9', 'Gene', '255738', (12, 17))	('associated', 'Reg', (28, 38))	('LDL-C', 'Gene', '22796', (139, 144))	('LDL-C', 'Gene', (139, 144))	('diabetes', 'Disease', 'MESH:D003920', (65, 73))	('PCSK9', 'Gene', (12, 17))
10067	33886544	One suggested mechanism for a link with cancer progression is that the increased expression of PCSK9 prevents LDL-receptor (LDLR) recycling, leading to hypercholesterolaemia and more exogenous lipid to support the proliferation of the tumour.	('hypercholesterolaemia', 'Disease', 'None', (152, 173))	('LDL-receptor', 'Gene', (110, 122))	('more', 'PosReg', (178, 182))	('LDLR', 'Gene', '3949', (124, 128))	('hypercholesterolaemia', 'Disease', (152, 173))	('tumour', 'Phenotype', 'HP:0002664', (235, 241))	('prevents', 'NegReg', (101, 109))	('tumour', 'Disease', 'MESH:D009369', (235, 241))	('PCSK9', 'Gene', (95, 100))	('tumour', 'Disease', (235, 241))	('cancer', 'Disease', (40, 46))	('PCSK9', 'Gene', '255738', (95, 100))	('lipid', 'Chemical', 'MESH:D008055', (193, 198))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('leading to', 'Reg', (141, 151))	('exogenous lipid', 'MPA', (183, 198))	('expression', 'Var', (81, 91))	('LDL-receptor', 'Gene', '3949', (110, 122))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('LDLR', 'Gene', (124, 128))	('increased', 'PosReg', (71, 80))
10068	33886544	Our study suggests the opposite, that genetically-proxied inhibition of PCSK9 results in an increased risk of OC or OPC.	('OPC', 'Disease', (116, 119))	('OPC', 'Chemical', '-', (116, 119))	('inhibition', 'Var', (58, 68))	('PCSK9', 'Gene', (72, 77))	('PCSK9', 'Gene', '255738', (72, 77))
10070	33886544	Therapies such as statins, ezetimibe, and PCSK9 inhibitors may all lower LDL-C level through the upregulation of LDL-receptors, resulting in elevated intracellular cholesterol.	('upregulation', 'PosReg', (97, 109))	('elevated', 'PosReg', (141, 149))	('intracellular cholesterol', 'MPA', (150, 175))	('LDL-C', 'Gene', (73, 78))	('PCSK9', 'Gene', (42, 47))	('ezetimibe', 'Chemical', 'MESH:D000069438', (27, 36))	('LDL-C', 'Gene', '22796', (73, 78))	('cholesterol', 'Chemical', 'MESH:D002784', (164, 175))	('inhibitors', 'Var', (48, 58))	('LDL-receptor', 'Gene', '3949', (113, 125))	('PCSK9', 'Gene', '255738', (42, 47))	('lower LDL-C', 'Phenotype', 'HP:0003563', (67, 78))	('lower', 'NegReg', (67, 72))	('LDL-receptor', 'Gene', (113, 125))
10084	33886544	Nonetheless, recent MR studies have identified an association between variants in HMGCR with cancer risk, but not alternative cholesterol-lowering treatments or genetically-predicted LDL-C, suggesting that statins may reduce cancer risk through a cholesterol independent pathway.	('reduce', 'NegReg', (218, 224))	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (225, 231))	('LDL-C', 'Gene', '22796', (183, 188))	('cancer', 'Disease', (225, 231))	('LDL-C', 'Gene', (183, 188))	('cholesterol independent pathway', 'Pathway', (247, 278))	('cholesterol', 'Chemical', 'MESH:D002784', (247, 258))	('men', 'Species', '9606', (152, 155))	('cholesterol', 'Chemical', 'MESH:D002784', (126, 137))	('variants', 'Var', (70, 78))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('HMGCR', 'Gene', (82, 87))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('HMGCR', 'Gene', '3156', (82, 87))
10095	33886544	In conclusion, our MR analyses provided little evidence for a role of cholesterol lowering in OC or OPC risk although effects of genetically-proxied inhibition of PCSK9 and cholesterol-lowering variants in LDLR were observed in relation to OPC and OC risk.	('PCSK9', 'Gene', '255738', (163, 168))	('OPC', 'Chemical', '-', (100, 103))	('OPC', 'Chemical', '-', (240, 243))	('OPC', 'Disease', (100, 103))	('LDLR', 'Gene', (206, 210))	('OPC', 'Disease', (240, 243))	('LDLR', 'Gene', '3949', (206, 210))	('cholesterol lowering', 'Phenotype', 'HP:0003146', (70, 90))	('variants', 'Var', (194, 202))	('PCSK9', 'Gene', (163, 168))	('cholesterol', 'Chemical', 'MESH:D002784', (70, 81))	('cholesterol', 'Chemical', 'MESH:D002784', (173, 184))
10157	32398763	Mutations in the Wnt pathway are predominant in human colon cancer and there is also emerging evidence that the Wnt signalling network is involved in the modulation of the inflammatory response, as reviewed recently.	('colon cancer', 'Phenotype', 'HP:0003003', (54, 66))	('colon cancer', 'Disease', 'MESH:D015179', (54, 66))	('Wnt pathway', 'Pathway', (17, 28))	('human', 'Species', '9606', (48, 53))	('colon cancer', 'Disease', (54, 66))	('Mutations', 'Var', (0, 9))	('involved', 'Reg', (138, 146))	('predominant', 'Reg', (33, 44))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
10158	32398763	In this study, we investigated if aberrations in human penile cancer related proteins, thought, generally, although not exclusively, to be under the transcriptional control of the Wnt signalling pathway in horses.	('penile cancer', 'Disease', 'MESH:D010412', (55, 68))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('human', 'Species', '9606', (49, 54))	('penile cancer', 'Disease', (55, 68))	('horses', 'Species', '9796', (206, 212))	('aberrations', 'Var', (34, 45))
10163	32398763	There has been much interest in the role of aberrant expression of Fos proteins in multiple human cancers, including cancers of the liver, pancreas and ovaries.	('cancers of the liver', 'Phenotype', 'HP:0002896', (117, 137))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('cancers', 'Phenotype', 'HP:0002664', (98, 105))	('aberrant expression', 'Var', (44, 63))	('ovaries', 'Disease', 'MESH:D010051', (152, 159))	('Fos', 'Gene', '2353', (67, 70))	('cancers', 'Disease', 'MESH:D009369', (98, 105))	('cancers', 'Disease', (98, 105))	('Fos', 'Gene', (67, 70))	('cancers', 'Phenotype', 'HP:0002664', (117, 124))	('ovaries', 'Disease', (152, 159))	('cancers', 'Disease', 'MESH:D009369', (117, 124))	('human', 'Species', '9606', (92, 97))	('pancreas', 'Disease', (139, 147))	('cancers', 'Disease', (117, 124))
10179	32398763	In EcPV2+ cases, levels of inflammation were significantly higher in both the NT and EpSCC cohorts (p < 0.001) (Fig.	('EcPV2', 'Species', '526413', (3, 8))	('inflammation', 'Disease', 'MESH:D007249', (27, 39))	('higher', 'PosReg', (59, 65))	('EpSCC', 'Disease', (85, 90))	('EcPV2+', 'Var', (3, 9))	('inflammation', 'Disease', (27, 39))
10186	32398763	2G) and a significant increase was also observed in the inflammation in EcPV2+ cores for the NT and EpSCC samples compared to EcPV2- cores (Supplementary Fig.	('inflammation', 'Disease', 'MESH:D007249', (56, 68))	('EcPV2', 'Species', '526413', (72, 77))	('inflammation', 'Disease', (56, 68))	('EcPV2+ cores', 'Var', (72, 84))	('increase', 'PosReg', (22, 30))	('EcPV2', 'Species', '526413', (126, 131))
10200	32398763	There was a significant (p < 0.05) change in the expression of Cyclin D1 and c-Myc in tissue samples that were EcPV2 + (Fig.	('Cyclin D1', 'Protein', (63, 72))	('expression', 'MPA', (49, 59))	('EcPV2 +', 'Var', (111, 118))	('EcPV2', 'Species', '526413', (111, 116))	('c-Myc', 'Gene', '4609', (77, 82))	('change', 'Reg', (35, 41))	('c-Myc', 'Gene', (77, 82))
10202	32398763	The expression of c-Myc was reduced in EpSCC EcPV2+ samples only (Fig.	('reduced', 'NegReg', (28, 35))	('c-Myc', 'Gene', (18, 23))	('EcPV2', 'Species', '526413', (45, 50))	('EpSCC EcPV2+', 'Var', (39, 51))	('expression', 'MPA', (4, 14))	('c-Myc', 'Gene', '4609', (18, 23))
10222	32398763	Additionally, aberrant expression of FRA1 through Wnt activation has also been shown in glioma cells, indicating a linkage.	('glioma', 'Disease', (88, 94))	('aberrant', 'Var', (14, 22))	('FRA1', 'Gene', (37, 41))	('glioma', 'Disease', 'MESH:D005910', (88, 94))	('glioma', 'Phenotype', 'HP:0009733', (88, 94))	('expression', 'MPA', (23, 33))
10228	32398763	FRA1 overexpression in transgenic mice models has been shown to have increased inflammatory cell infiltration in the liver.	('inflammatory cell infiltration', 'CPA', (79, 109))	('increased inflammatory cell', 'Phenotype', 'HP:0012649', (69, 96))	('increased', 'PosReg', (69, 78))	('transgenic mice', 'Species', '10090', (23, 38))	('overexpression', 'Var', (5, 19))	('FRA1', 'Gene', (0, 4))
10244	32398763	There was an increase in inflammation in both NT EcPV2+ and EpSCC EcPV2+ samples compared with EcPV2- samples of the same cohort.	('inflammation', 'Disease', (25, 37))	('EcPV2+', 'Var', (49, 55))	('EcPV2', 'Species', '526413', (66, 71))	('EcPV2', 'Species', '526413', (49, 54))	('EpSCC', 'Disease', (60, 65))	('increase', 'PosReg', (13, 21))	('inflammation', 'Disease', 'MESH:D007249', (25, 37))	('EcPV2+', 'Var', (66, 72))	('EcPV2', 'Species', '526413', (95, 100))
10256	32398763	The antibodies, Cyclin D1 (sc-718 Santa Cruz), MMP7 (ab4044 Abcam), c-Myc (NCL-cmyc Novacastra/Leica), and FRA1 (ab117951 Abcam) were optimised for pH dependence, antigen retrieval, and concentration.	('ab4044', 'Var', (53, 59))	('c-Myc', 'Gene', (68, 73))	('c-Myc', 'Gene', '4609', (68, 73))	('ab117951', 'Var', (113, 121))
10258	32398763	A multi-label stain was performed with Cyclin D1, MMP7, c-Myc, and FRA1 which, after binding to the respective Horse Radish Peroxidase secondary antibody, were visualised following the principle of Toth and Mazey using the following fluorescent tyramides; FITC (488/517 nm), Cy3 (514/565 nm), Cy5 (633/671 nm), and Coumarin (405/470 nm), respectively.	('405/470 nm', 'Var', (325, 335))	('Peroxidase', 'Gene', (124, 134))	('Coumarin', 'Chemical', 'MESH:C030123', (315, 323))	('tyramides', 'Chemical', '-', (245, 254))	('c-Myc', 'Gene', (56, 61))	('FITC', 'Chemical', 'MESH:D016650', (256, 260))	('Radish', 'Species', '3726', (117, 123))	('Peroxidase', 'Gene', '108855023', (124, 134))	('Horse', 'Species', '9796', (111, 116))	('Cy3', 'Chemical', '-', (275, 278))	('binding', 'Interaction', (85, 92))	('Cy5', 'Chemical', 'MESH:C085321', (293, 296))	('c-Myc', 'Gene', '4609', (56, 61))
10278	31368152	Conversely, silencing of EZH2 inhibited tumour glycolysis, EMT, migration and invasion in OSCC cells.	('EMT', 'CPA', (59, 62))	('OSCC', 'Disease', (90, 94))	('tumour glycolysis', 'Disease', 'MESH:C564972', (40, 57))	('invasion', 'CPA', (78, 86))	('inhibited', 'NegReg', (30, 39))	('EZH2', 'Gene', (25, 29))	('silencing', 'Var', (12, 21))	('OSCC', 'Disease', 'MESH:D002294', (90, 94))	('tumour glycolysis', 'Disease', (40, 57))	('migration', 'CPA', (64, 73))	('tumour', 'Phenotype', 'HP:0002664', (40, 46))
10286	31368152	Monoclonal mouse anti-human antibodies to EZH2 (sc-166609), STAT3 (sc-293151), FoxO1 (H-128) and beta-catenin (sc-1496) were obtained from Santa Cruz Biotechnology Inc.	('H-128', 'Chemical', 'MESH:C555346', (86, 91))	('mouse', 'Species', '10090', (11, 16))	('beta-catenin', 'Gene', (97, 109))	('sc-166609', 'Var', (48, 57))	('EZH2', 'Gene', (42, 46))	('beta-catenin', 'Gene', '1499', (97, 109))	('sc-166609', 'Chemical', 'MESH:D012538', (48, 57))	('human', 'Species', '9606', (22, 27))	('sc-293151', 'Var', (67, 76))
10337	31368152	As can be seen in Western blot, EZH2 overexpression led to a significant increase in vimentin, while the up-regulation of N-cadherin and the down-regulation of E-cadherin were mild.	('N-cadherin', 'Gene', (122, 132))	('increase', 'PosReg', (73, 81))	('E-cadherin', 'Gene', (160, 170))	('N-cadherin', 'Gene', '1000', (122, 132))	('E-cadherin', 'Gene', '999', (160, 170))	('up-regulation', 'PosReg', (105, 118))	('overexpression', 'Var', (37, 51))	('EZH2', 'Gene', (32, 36))	('vimentin', 'Gene', '7431', (85, 93))	('vimentin', 'Gene', (85, 93))
10338	31368152	The protein levels of beta-catenin had a slight decrease in EZH2 overexpression cells with no statistical significance.	('EZH2', 'Gene', (60, 64))	('beta-catenin', 'Gene', '1499', (22, 34))	('overexpression', 'Var', (65, 79))	('decrease', 'NegReg', (48, 56))	('beta-catenin', 'Gene', (22, 34))	('protein levels of', 'MPA', (4, 21))
10341	31368152	To further investigate the role of EZH2 in the migration, invasion and EMT of OSCC cells, we applied short hairpin RNAs (shRNAs) to knockdown EZH2 expression in Cal-27 and Tca8113 cells, as confirmed by Western blot and RT-PCR (Figure 3A).	('EZH2', 'Gene', (142, 146))	('OSCC', 'Disease', 'MESH:D002294', (78, 82))	('OSCC', 'Disease', (78, 82))	('knockdown', 'Var', (132, 141))
10347	31368152	Results showed that 2-DG inhibited EZH2-increased glucose consumption and lactate production levels, and the presence of 2-DG suppressed EZH2-induced EMT via down-regulating vimentin and N-cadherin and up-regulating E-cadherin in mRNA levels (Figure 4C).	('2-DG', 'Chemical', 'MESH:D003847', (20, 24))	('up-regulating', 'PosReg', (202, 215))	('N-cadherin', 'Gene', (187, 197))	('N-cadherin', 'Gene', '1000', (187, 197))	('suppressed', 'NegReg', (126, 136))	('glucose', 'CPA', (50, 57))	('vimentin', 'Gene', '7431', (174, 182))	('2-DG', 'Chemical', 'MESH:D003847', (121, 125))	('lactate production levels', 'MPA', (74, 99))	('vimentin', 'Gene', (174, 182))	('glucose', 'Chemical', 'MESH:D005947', (50, 57))	('increased glucose', 'Phenotype', 'HP:0003074', (40, 57))	('down-regulating', 'NegReg', (158, 173))	('E-cadherin', 'Gene', (216, 226))	('E-cadherin', 'Gene', '999', (216, 226))	('inhibited', 'NegReg', (25, 34))	('EZH2-induced', 'Gene', (137, 149))	('lactate', 'Chemical', 'MESH:D019344', (74, 81))	('EMT', 'CPA', (150, 153))	('2-DG', 'Var', (121, 125))
10348	31368152	Thus, we concluded that EZH2 overexpression facilitates EMT mediated by OSCC cells glycolysis, which might provide a competitive environment for OSCC cells migration and invasion.	('glycolysis', 'MPA', (83, 93))	('EMT mediated', 'CPA', (56, 68))	('OSCC', 'Disease', (72, 76))	('OSCC', 'Disease', (145, 149))	('EZH2', 'Gene', (24, 28))	('OSCC', 'Disease', 'MESH:D002294', (72, 76))	('overexpression', 'Var', (29, 43))	('OSCC', 'Disease', 'MESH:D002294', (145, 149))	('facilitates', 'PosReg', (44, 55))
10352	31368152	As a classical cancer signalling pathway, EZH2/STAT3 has pivotal roles in cancer growth and metastasis.14, 19, 32, 33 Western blot showed that STAT3 total expression levels remained unchanged in EZH2-overexpressed OSCC cells, whereas pY-STAT3 was enhanced (Figure 5B).	('metastasis.14', 'Disease', 'MESH:D009362', (92, 105))	('STAT3 total expression levels', 'MPA', (143, 172))	('EZH2-overexpressed', 'PosReg', (195, 213))	('cancer', 'Disease', (15, 21))	('cancer', 'Disease', 'MESH:D009369', (15, 21))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('OSCC', 'Disease', (214, 218))	('cancer', 'Disease', (74, 80))	('metastasis.14', 'Disease', (92, 105))	('OSCC', 'Disease', 'MESH:D002294', (214, 218))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('EZH2-overexpressed', 'Var', (195, 213))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))
10353	31368152	To find out whether the effects of EZH2 on FoxO1 expression were mediated by STAT3, we applied shRNAs to knockdown STAT3 expression in OSCC cells, as confirmed by Western blot and RT-PCR.	('STAT3', 'Gene', (115, 120))	('OSCC', 'Disease', (135, 139))	('FoxO1', 'Gene', (43, 48))	('knockdown', 'Var', (105, 114))	('OSCC', 'Disease', 'MESH:D002294', (135, 139))
10357	31368152	Accumulating evidence suggests that tumour glycolysis, known as 'Warburg effect' and used by most cancer cells to generate energy for rapid growth and cancer metastasis, exerts great influences on EMT and invasion of various cancers.10, 34, 35 Here, we revealed that silencing of EZH2 inhibited the tumour glycolysis, EMT, migration and invasion of OSCC cells.	('tumour glycolysis', 'Disease', 'MESH:C564972', (36, 53))	('cancer', 'Disease', (225, 231))	('cancers', 'Disease', (225, 232))	('tumour', 'Phenotype', 'HP:0002664', (299, 305))	('OSCC', 'Disease', (349, 353))	('cancer', 'Disease', (98, 104))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('tumour', 'Phenotype', 'HP:0002664', (36, 42))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('migration', 'CPA', (323, 332))	('silencing', 'Var', (267, 276))	('cancer', 'Disease', (151, 157))	('cancer metastasis', 'Disease', (151, 168))	('tumour glycolysis', 'Disease', (299, 316))	('cancer', 'Disease', 'MESH:D009369', (225, 231))	('cancers', 'Disease', 'MESH:D009369', (225, 232))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('tumour glycolysis', 'Disease', 'MESH:C564972', (299, 316))	('inhibited', 'NegReg', (285, 294))	('OSCC', 'Disease', 'MESH:D002294', (349, 353))	('cancer metastasis', 'Disease', 'MESH:D009362', (151, 168))	('tumour glycolysis', 'Disease', (36, 53))	('EMT', 'CPA', (318, 321))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('EZH2', 'Gene', (280, 284))	('cancers', 'Phenotype', 'HP:0002664', (225, 232))
10360	31368152	Our data indicated that EZH2 might promote EMT and the metastasis of OSCC through tumour glycolysis, and to our knowledge, this is the first report to reveal the roles of EZH2/STAT3/FoxO1 axis in tumour glycolysis and EMT of OSCC.	('tumour', 'Phenotype', 'HP:0002664', (82, 88))	('tumour glycolysis', 'Disease', 'MESH:C564972', (82, 99))	('OSCC', 'Disease', (225, 229))	('OSCC', 'Disease', 'MESH:D002294', (69, 73))	('tumour glycolysis', 'Disease', 'MESH:C564972', (196, 213))	('tumour', 'Phenotype', 'HP:0002664', (196, 202))	('metastasis of', 'CPA', (55, 68))	('tumour glycolysis', 'Disease', (82, 99))	('OSCC', 'Disease', 'MESH:D002294', (225, 229))	('promote', 'PosReg', (35, 42))	('tumour glycolysis', 'Disease', (196, 213))	('EMT', 'CPA', (43, 46))	('EZH2', 'Var', (24, 28))	('OSCC', 'Disease', (69, 73))
10366	31368152	In this study, we found that EZH2 increased the tumour glycolysis of OSCC cells, thus promoting OSCC metastasis.	('tumour glycolysis', 'Disease', (48, 65))	('OSCC', 'Disease', 'MESH:D002294', (96, 100))	('tumour', 'Phenotype', 'HP:0002664', (48, 54))	('OSCC', 'Disease', 'MESH:D002294', (69, 73))	('EZH2', 'Var', (29, 33))	('promoting', 'PosReg', (86, 95))	('glycolysis of OSCC', 'Disease', (55, 73))	('glycolysis of OSCC', 'Disease', 'MESH:D002294', (55, 73))	('tumour glycolysis', 'Disease', 'MESH:C564972', (48, 65))	('increased', 'PosReg', (34, 43))	('OSCC', 'Disease', (96, 100))	('OSCC', 'Disease', (69, 73))
10368	31368152	As a classical cancer pathway, EZH2/STAT3 axis functions as an oncogenic pathway in most cases, where EZH2 enhances STAT3 activity mainly through methylation.	('enhances', 'PosReg', (107, 115))	('STAT3 activity', 'MPA', (116, 130))	('cancer', 'Disease', (15, 21))	('cancer', 'Disease', 'MESH:D009369', (15, 21))	('methylation', 'MPA', (146, 157))	('EZH2', 'Var', (102, 106))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))
10369	31368152	For example, EZH2 overexpression, induced by transcriptional regulator NF-YA, could enhance STAT3 activity by mediating its lysine methylation to up-regulate VEGF expression and promote angiogenesis in melanoma cells.33 Moreover, EZH2 could also promote phosphorylation of pY705 on STAT3 via other mechanisms independent of STAT3 methylation.	('pY705', 'Var', (273, 278))	('promote', 'PosReg', (246, 253))	('VEGF', 'Gene', '7422', (158, 162))	('melanoma', 'Disease', 'MESH:D008545', (202, 210))	('NF-YA', 'Gene', (71, 76))	('phosphorylation', 'MPA', (254, 269))	('melanoma', 'Phenotype', 'HP:0002861', (202, 210))	('melanoma', 'Disease', (202, 210))	('EZH2', 'Var', (230, 234))	('NF-YA', 'Gene', '4800', (71, 76))	('VEGF', 'Gene', (158, 162))	('lysine', 'Chemical', 'MESH:C114808', (124, 130))
10437	31496355	On the one hand, it has been noted that there are several genes which stimulate the immune system, these include mesotheline and carcinoembryogenic antigen (CEA) which are released by tumour cells through exosomes.	('tumour', 'Phenotype', 'HP:0002664', (184, 190))	('genes', 'Var', (58, 63))	('immune', 'CPA', (84, 90))	('CEA', 'Gene', '1048', (157, 160))	('tumour', 'Disease', (184, 190))	('tumour', 'Disease', 'MESH:D009369', (184, 190))	('CEA', 'Gene', (157, 160))	('stimulate', 'PosReg', (70, 79))
10463	31496355	Modulation of vascular permeability and the stimulation of neo-angiogenesis are key steps during pre-metastatic niche formation which favours the initial extravasation and subsequent metastatic growth of tumour cells in secondary organs.	('Modulation', 'Var', (0, 10))	('favours', 'PosReg', (134, 141))	('tumour', 'Disease', (204, 210))	('extravasation', 'MPA', (154, 167))	('neo-angiogenesis', 'CPA', (59, 75))	('metastatic growth', 'CPA', (183, 200))	('tumour', 'Phenotype', 'HP:0002664', (204, 210))	('tumour', 'Disease', 'MESH:D009369', (204, 210))
10465	31496355	Silencing of the miR-200c-3p targets, CHD9 and WRN, significantly accelerated the invasive potential of SQUU-A cells in squamous tongue carcinoma.	('invasive potential', 'CPA', (82, 100))	('CHD9', 'Gene', '80205', (38, 42))	('squamous tongue carcinoma', 'Phenotype', 'HP:0030413', (120, 145))	('miR', 'Gene', '220972', (17, 20))	('miR', 'Gene', (17, 20))	('squamous tongue carcinoma', 'Disease', 'MESH:D002294', (120, 145))	('CHD9', 'Gene', (38, 42))	('squamous tongue carcinoma', 'Disease', (120, 145))	('tongue carcinoma', 'Phenotype', 'HP:0030415', (129, 145))	('accelerated', 'PosReg', (66, 77))	('WRN', 'Gene', (47, 50))	('WRN', 'Gene', '7486', (47, 50))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('Silencing', 'Var', (0, 9))
10472	31496355	It has become apparent that aberrations within the noncoding genome drive fundamental cancer phenotypes in addition to the best-known protein coding mutations.	('aberrations', 'Var', (28, 39))	('drive', 'Reg', (68, 73))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('cancer', 'Disease', (86, 92))
10476	31496355	On the other hand, exosomes derived from mesenchymal stem cells of human bone marrow that overexpress mi-RNA-101-3p suppress the proliferation, invasion and migration of oral cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('overexpress', 'PosReg', (90, 101))	('proliferation', 'CPA', (129, 142))	('oral cancer', 'Disease', 'MESH:D009062', (170, 181))	('suppress', 'NegReg', (116, 124))	('human', 'Species', '9606', (67, 72))	('mi-RNA-101-3p', 'Var', (102, 115))	('oral cancer', 'Disease', (170, 181))
10486	31496355	Tetraspanins are potential targets for drug development, not only in the area of neoplasias, but also in infectious diseases, given that many tetraspanins are known to facilitate infection processes of various pathogens, for example viral, bacterial and protozoan infections.	('neoplasias', 'Disease', 'MESH:D009369', (81, 91))	('Tetraspanins', 'Chemical', 'MESH:D060185', (0, 12))	('protozoan infections', 'Disease', 'MESH:D011528', (254, 274))	('neoplasias', 'Disease', (81, 91))	('infection', 'Disease', (179, 188))	('infection', 'Disease', (264, 273))	('infectious diseases', 'Disease', (105, 124))	('infection', 'Disease', 'MESH:D007239', (179, 188))	('bacterial', 'Disease', (240, 249))	('tetraspanins', 'Chemical', 'MESH:D060185', (142, 154))	('infectious diseases', 'Disease', 'MESH:D003141', (105, 124))	('infection', 'Disease', 'MESH:D007239', (264, 273))	('protozoan infections', 'Disease', (254, 274))	('neoplasias', 'Phenotype', 'HP:0002664', (81, 91))	('tetraspanins', 'Var', (142, 154))	('viral', 'Disease', (233, 238))	('facilitate', 'PosReg', (168, 178))
10510	31496355	recently revealed that CAF-derived exosomes contain lower miR-3188 levels than normal fibroblasts, and the loss of miR-3188 in exosomes contributes to the malignant phenotypes of HNC cells through the derepression of BCL2.	('malignant phenotypes', 'CPA', (155, 175))	('derepression', 'PosReg', (201, 213))	('CAF', 'Chemical', 'MESH:C035000', (23, 26))	('miR-3188', 'Gene', '100422833', (58, 66))	('miR-3188', 'Gene', (58, 66))	('BCL2', 'Gene', (217, 221))	('loss', 'Var', (107, 111))	('lower', 'NegReg', (52, 57))	('miR-3188', 'Gene', '100422833', (115, 123))	('miR-3188', 'Gene', (115, 123))	('HNC cells', 'Disease', (179, 188))	('BCL2', 'Gene', '596', (217, 221))
10548	31496355	They observed that a large amount of mi-RNA was shared in exosomes from healthy and cancerous cells.	('mi-RNA', 'Var', (37, 43))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('cancerous', 'Disease', (84, 93))	('cancerous', 'Disease', 'MESH:D009369', (84, 93))
10567	26036285	Patients with high c-Met expression had significantly worse survival.	('expression', 'MPA', (25, 35))	('c-Met', 'Gene', (19, 24))	('high', 'Var', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('c-Met', 'Gene', '4233', (19, 24))
10568	26036285	In addition, multivariate analysis identified the high expression of c-Met as an independent prognostic factor.	('c-Met', 'Gene', (69, 74))	('high', 'Var', (50, 54))	('c-Met', 'Gene', '4233', (69, 74))
10579	26036285	In addition, the frequency of c-Met gene amplification and mutation in human malignancies have been reported to range from 1.4 % to 7.2 % for gene amplification and 1.7 % to 3.3 % for mutation in lung cancer, 1.5 % to 10.2 % for amplification in gastric cancer, 2 % for amplification in esophagogastric adenocarcinoma, 13.2 % for mutation in papillary renal carcinoma, and 26.7 % for mutation in head and neck squamous cell carcinoma.	('gastric cancer', 'Disease', (246, 260))	('papillary renal carcinoma', 'Disease', 'MESH:D007681', (342, 367))	('mutation', 'Var', (59, 67))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('c-Met', 'Gene', (30, 35))	('adenocarcinoma', 'Disease', 'MESH:D000230', (303, 317))	('cancer', 'Phenotype', 'HP:0002664', (254, 260))	('neck squamous cell carcinoma', 'Disease', (405, 433))	('carcinoma', 'Phenotype', 'HP:0030731', (358, 367))	('lung cancer', 'Disease', (196, 207))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (405, 433))	('carcinoma', 'Phenotype', 'HP:0030731', (308, 317))	('gastric cancer', 'Disease', 'MESH:D013274', (246, 260))	('human', 'Species', '9606', (71, 76))	('mutation', 'Var', (184, 192))	('esophagogastric adenocarcinoma', 'Phenotype', 'HP:0011459', (287, 317))	('renal carcinoma', 'Phenotype', 'HP:0005584', (352, 367))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (410, 433))	('papillary renal carcinoma', 'Phenotype', 'HP:0006766', (342, 367))	('c-Met', 'Gene', '4233', (30, 35))	('gastric cancer', 'Phenotype', 'HP:0012126', (246, 260))	('lung cancer', 'Disease', 'MESH:D008175', (196, 207))	('to 7', 'Species', '1214577', (129, 133))	('malignancies', 'Disease', 'MESH:D009369', (77, 89))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (396, 433))	('malignancies', 'Disease', (77, 89))	('lung cancer', 'Phenotype', 'HP:0100526', (196, 207))	('carcinoma', 'Phenotype', 'HP:0030731', (424, 433))	('mutation', 'Var', (330, 338))	('adenocarcinoma', 'Disease', (303, 317))	('papillary renal carcinoma', 'Disease', (342, 367))
10604	26036285	A small-molecule inhibitor for c-Met (PF-2341066) was purchased from Selleck Chemicals (Houston, TX, USA).	('PF-2341066', 'Var', (38, 48))	('c-Met', 'Gene', (31, 36))	('c-Met', 'Gene', '4233', (31, 36))
10618	26036285	After the plate was cultured for 24 h in FBS-free medium, the medium was switched to one with or without 50 ng/ml of HGF and PF-2341066.	('PF-2341066', 'Var', (125, 135))	('HGF', 'Gene', '3082', (117, 120))	('HGF', 'Gene', (117, 120))
10630	26036285	On the other hand, HGF status was significantly correlated with tumor differentiation (P = 0.024), tumor depth (P = 0.028), lymph node metastasis (P = 0.014), and pathological stage (P = 0.022).	('tumor', 'Disease', (99, 104))	('HGF', 'Gene', (19, 22))	('tumor', 'Disease', (64, 69))	('HGF', 'Gene', '3082', (19, 22))	('status', 'Var', (23, 29))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('correlated', 'Reg', (48, 58))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('lymph node metastasis', 'CPA', (124, 145))
10636	26036285	In addition, multivariate analysis identified high expression of c-Met (P = 0.033) and lymph node metastasis (P = 0.025) as independent prognostic factors (Table 4).	('c-Met', 'Gene', (65, 70))	('high', 'Var', (46, 50))	('lymph node metastasis', 'CPA', (87, 108))	('c-Met', 'Gene', '4233', (65, 70))
10638	26036285	Patients with high HGF expression tended to have a lower survival rate (Additional file 1), but the difference did not reach statistical significance.	('HGF', 'Gene', (19, 22))	('HGF', 'Gene', '3082', (19, 22))	('survival', 'MPA', (57, 65))	('lower', 'NegReg', (51, 56))	('Patients', 'Species', '9606', (0, 8))	('high', 'Var', (14, 18))
10646	26036285	When both rHGF and PF-2341066 were absent, the number of invaded cells in invasion assay was 31.6 +- 9.0, but that increased to 99.0 +- 25.6 when only rHGF was added (P = 0.0019).	('rHGF', 'Gene', (10, 14))	('PF-2341066', 'Var', (19, 29))	('rHGF', 'Gene', '24446', (151, 155))	('rHGF', 'Gene', '24446', (10, 14))	('rHGF', 'Gene', (151, 155))
10647	26036285	However, the invasion capacity of KYSE 150 cells did not differ significantly under rHGF pre-stimulation and/or PF-2341066 treatment.	('PF-2341066', 'Var', (112, 122))	('rHGF', 'Gene', (84, 88))	('rHGF', 'Gene', '24446', (84, 88))
10648	26036285	The proliferation of the three ESCC cell lines (KYSE150, 170 and 180) under PF-2341066 treatment was evaluated as a decrease percentage compared to control (rHGF+/PF-2341066-).	('proliferation', 'CPA', (4, 17))	('decrease', 'NegReg', (116, 124))	('rHGF', 'Gene', '24446', (157, 161))	('PF-2341066', 'Var', (76, 86))	('rHGF', 'Gene', (157, 161))
10649	26036285	When 1 muM of PF-2341066 was added, the proliferation of KYSE150 cells decreased 16 % (P = 0.001); that of KYSE170 decreased 11 % (P = 0.11), and KYSE180 cell proliferation decreased 16 % (P = 0.003) (Fig.	('KYSE180 cell proliferation', 'CPA', (146, 172))	('decreased', 'NegReg', (71, 80))	('PF-2341066', 'Var', (14, 24))	('decreased', 'NegReg', (173, 182))	('proliferation', 'CPA', (40, 53))	('KYSE180', 'CellLine', 'CVCL:1349', (146, 153))
10655	26036285	Quantitative analysis of immunoblotting results demonstrated that phospho-c-Met expression significantly decreased in a concentration-dependent manner under PF-2341066 treatment (23.7 % decrease at 10 nM; 58.6 % at 100 nM, P < 0.0001; 64.6 % at 500 nM, P < 0.0001; and 65.3 % at 1 muM, P < 0.0001) (Fig.	('PF-2341066', 'Var', (157, 167))	('c-Met', 'Gene', (74, 79))	('c-Met', 'Gene', '4233', (74, 79))	('decreased', 'NegReg', (105, 114))	('decrease', 'NegReg', (186, 194))
10662	26036285	Our survival analysis revealed that patients with high c-Met expression had significantly worse 5-year overall survival and CSS than those without.	('overall survival', 'CPA', (103, 119))	('CSS', 'Chemical', '-', (124, 127))	('patients', 'Species', '9606', (36, 44))	('c-Met', 'Gene', (55, 60))	('CSS', 'CPA', (124, 127))	('c-Met', 'Gene', '4233', (55, 60))	('worse', 'NegReg', (90, 95))	('high', 'Var', (50, 54))
10679	26036285	The results of our in vitro studies demonstrated the important role of HGF as a c-Met activator and the efficacy of the c-Met small-molecule inhibitor PF-2341066, especially in KYSE170 cells with the highest c-Met mRNA expression among the three ESCC cell lines tested.	('highest', 'Reg', (200, 207))	('HGF', 'Gene', '3082', (71, 74))	('c-Met', 'Gene', (80, 85))	('c-Met', 'Gene', (208, 213))	('c-Met', 'Gene', '4233', (208, 213))	('c-Met', 'Gene', '4233', (80, 85))	('PF-2341066', 'Var', (151, 161))	('c-Met', 'Gene', (120, 125))	('c-Met', 'Gene', '4233', (120, 125))	('HGF', 'Gene', (71, 74))
10680	26036285	The invasive potential of KYSE170 cells was significantly increased by rHGF pre-stimulation and decreased by PE-2341066 treatment.	('PE', 'Chemical', '-', (109, 111))	('increased', 'PosReg', (58, 67))	('rHGF', 'Gene', '24446', (71, 75))	('decreased', 'NegReg', (96, 105))	('rHGF', 'Gene', (71, 75))	('invasive potential of KYSE170 cells', 'CPA', (4, 39))	('PE-2341066', 'Var', (109, 119))
10682	26036285	These results indicated that the inhibitory effects of PF-2341066 in ESCC were detected only in c-Met high expression cells, and the drug mainly suppressed cell invasive potential rather than cell proliferation.	('c-Met', 'Gene', (96, 101))	('PF-2341066', 'Var', (55, 65))	('c-Met', 'Gene', '4233', (96, 101))	('suppressed', 'NegReg', (145, 155))	('ESCC', 'Disease', (69, 73))	('cell invasive potential', 'CPA', (156, 179))
10684	26036285	However, in cancer, c-Met was not only activated by the above-mentioned HGF-dependent paracrine and autocrine mechanisms but also via other HGF-dependent or independent fashions such as in cases of c-Met gene amplification or mutations.	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('c-Met', 'Gene', '4233', (20, 25))	('activated', 'PosReg', (39, 48))	('cancer', 'Disease', (12, 18))	('HGF', 'Gene', (140, 143))	('HGF', 'Gene', '3082', (140, 143))	('gene amplification', 'Var', (204, 222))	('c-Met', 'Gene', (198, 203))	('HGF', 'Gene', (72, 75))	('c-Met', 'Gene', '4233', (198, 203))	('mutations', 'Var', (226, 235))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('HGF', 'Gene', '3082', (72, 75))	('c-Met', 'Gene', (20, 25))
10688	26036285	We showed that ESCC cell invasive property was significantly inhibited by PF-2341066 in the presence of rHGF in one of the three ESCC cell lines examined.	('ESCC cell invasive property', 'CPA', (15, 42))	('PF-2341066', 'Var', (74, 84))	('inhibited', 'NegReg', (61, 70))	('rHGF', 'Gene', '24446', (104, 108))	('rHGF', 'Gene', (104, 108))
10689	26036285	In addition, we also demonstrated that the expression levels of phosphorylated c-Met, MAPK, and Akt proteins were all significantly down regulated by treatment with PF-2341066.	('c-Met', 'Gene', (79, 84))	('c-Met', 'Gene', '4233', (79, 84))	('proteins', 'Protein', (100, 108))	('down regulated', 'NegReg', (132, 146))	('PF-2341066', 'Var', (165, 175))	('MAPK', 'Gene', (86, 90))	('Akt', 'Gene', '207', (96, 99))	('expression levels', 'MPA', (43, 60))	('Akt', 'Gene', (96, 99))
10691	26036285	reported the inhibition of MAPK and Akt signaling by PF-2341066 in ovarian cancer cells, which was consistent with our results.	('ovarian cancer', 'Disease', 'MESH:D010051', (67, 81))	('ovarian cancer', 'Disease', (67, 81))	('Akt', 'Gene', (36, 39))	('inhibition', 'NegReg', (13, 23))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('MAPK', 'Pathway', (27, 31))	('ovarian cancer', 'Phenotype', 'HP:0100615', (67, 81))	('Akt', 'Gene', '207', (36, 39))	('PF-2341066', 'Var', (53, 63))
10692	26036285	reported the inhibition of Akt signaling but not of the MAPK cascade by PF-2341066 in head and neck squamous cell carcinoma cells, possibly due to the high basal level of phosphorylated MAPK in these cells prior to HGF stimulation.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (100, 123))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (86, 123))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (95, 123))	('HGF', 'Gene', '3082', (215, 218))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('Akt', 'Gene', '207', (27, 30))	('PF-2341066', 'Var', (72, 82))	('inhibition', 'NegReg', (13, 23))	('neck squamous cell carcinoma', 'Disease', (95, 123))	('Akt', 'Gene', (27, 30))	('HGF', 'Gene', (215, 218))
10697	26036285	PF-2341066 is also known to inhibit the protein activation processes resulted from gene rearrangement of anaplastic lymphoma kinase and ROS1 tyrosine kinase in addition to c-Met inhibition.	('c-Met', 'Gene', (172, 177))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (105, 124))	('ROS1', 'Gene', (136, 140))	('c-Met', 'Gene', '4233', (172, 177))	('lymphoma', 'Phenotype', 'HP:0002665', (116, 124))	('anaplastic lymphoma', 'Disease', (105, 124))	('ROS1', 'Gene', '6098', (136, 140))	('gene rearrangement', 'Var', (83, 101))	('PF-2341066', 'Var', (0, 10))	('anaplastic lymphoma', 'Disease', 'MESH:D017728', (105, 124))	('protein activation', 'MPA', (40, 58))	('inhibit', 'NegReg', (28, 35))
10698	26036285	Additionally, our results demonstrated that the inhibition of cell function by PF-2341066 depended on the presence of HGF, a c-Met specific ligand.	('c-Met', 'Gene', (125, 130))	('c-Met', 'Gene', '4233', (125, 130))	('PF-2341066', 'Var', (79, 89))	('HGF', 'Gene', (118, 121))	('cell function', 'CPA', (62, 75))	('inhibition', 'NegReg', (48, 58))	('HGF', 'Gene', '3082', (118, 121))
10699	26036285	Thus, PF-2341066 functioned as an efficient c-Met inhibitor in the context of our study.	('c-Met', 'Gene', '4233', (44, 49))	('PF-2341066', 'Var', (6, 16))	('c-Met', 'Gene', (44, 49))
10732	33552128	Apart from the above TCGA-LUAD/LUSC cohorts, we also tried to collect the available lung cancer datasets (e.g., CAARRAY, GSE14814, GSE19188, GSE29013, GSE30219, GSE31210, GSE3141, etc.)	('lung cancer', 'Disease', (84, 95))	('lung cancer', 'Phenotype', 'HP:0100526', (84, 95))	('LUSC', 'Phenotype', 'HP:0030359', (31, 35))	('GSE19188', 'Var', (131, 139))	('GSE31210', 'Var', (161, 169))	('GSE30219', 'Var', (151, 159))	('lung cancer', 'Disease', 'MESH:D008175', (84, 95))	('GSE14814', 'Var', (121, 129))	('GSE3141', 'Var', (171, 178))	('GSE29013', 'Var', (141, 149))	('LUAD', 'Phenotype', 'HP:0030078', (26, 30))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
10742	33552128	Thus, we utilized the PhosphoNET to analyze the phosphorylation status and the potential kinases of the two sites (S115 and T131) within the SNRPA protein.	('SNRPA', 'Gene', (141, 146))	('SNRPA', 'Gene', '6627', (141, 146))	('PhosphoNET', 'Chemical', '-', (22, 32))	('S115', 'Var', (115, 119))
10766	33552128	There was no correlation between the genetic alteration of SNRPA and the clinical outcomes of lung adenocarcinoma cases (Figure 3B).	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('lung adenocarcinoma', 'Disease', (94, 113))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (94, 113))	('SNRPA', 'Gene', (59, 64))	('SNRPA', 'Gene', '6627', (59, 64))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (94, 113))	('genetic alteration', 'Var', (37, 55))
10767	33552128	However, for LUSC cases, we observed the 4% alteration rate with the type of "missense mutation," "amplification," and "deep deletion" (Figure 3C), and the correlation between the genetic alteration of SNRPA and the worse OS prognosis (Figure 3D, p = 0.016), suggesting the potential involvement of SNRPA genetic alteration in the clinical prognosis of lung squamous cell carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (372, 381))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (358, 381))	('genetic alteration', 'Var', (305, 323))	('lung squamous cell carcinoma', 'Disease', (353, 381))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (353, 381))	('involvement', 'Reg', (284, 295))	('SNRPA', 'Gene', '6627', (299, 304))	('amplification', 'Var', (99, 112))	('deep deletion', 'Var', (120, 133))	('alteration', 'Reg', (44, 54))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (353, 381))	('LUSC', 'Phenotype', 'HP:0030359', (13, 17))	('genetic alteration', 'Var', (180, 198))	('SNRPA', 'Gene', '6627', (202, 207))	('SNRPA', 'Gene', (299, 304))	('SNRPA', 'Gene', (202, 207))
10771	33552128	This suggested the potential role of SNRPA DNA methylation in the tumorigenesis of lung adenocarcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('SNRPA', 'Gene', '6627', (37, 42))	('SNRPA', 'Gene', (37, 42))	('lung adenocarcinoma', 'Disease', (83, 102))	('tumor', 'Disease', (66, 71))	('methylation', 'Var', (47, 58))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (83, 102))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (83, 102))	('tumor', 'Disease', 'MESH:D009369', (66, 71))
10773	33552128	Besides, the phosphorylation level at the S115 site of SNRPA protein (NP_004587.1) (Figure 5A, p = 0.002), but not the T131 site (p > 0.05), in the primary tumor tissues is higher than that in the normal tissues.	('SNRPA', 'Gene', '6627', (55, 60))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('phosphorylation level', 'MPA', (13, 34))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('higher', 'PosReg', (173, 179))	('S115', 'Var', (42, 46))	('tumor', 'Disease', (156, 161))	('SNRPA', 'Gene', (55, 60))
10787	33552128	Through analyzing the datasets within TCGA and GEO databases, our study aimed to investigate the potential role of SNRPA expression, modification, or genetic mutation in the prognosis of lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) of NSCLC.	('SNRPA', 'Gene', (115, 120))	('lung squamous cell carcinoma', 'Disease', (218, 246))	('NSCLC', 'Disease', (257, 262))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (218, 246))	('SCLC', 'Phenotype', 'HP:0030357', (258, 262))	('NSCLC', 'Phenotype', 'HP:0030358', (257, 262))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (187, 206))	('LUSC', 'Phenotype', 'HP:0030359', (248, 252))	('genetic mutation', 'Var', (150, 166))	('lung adenocarcinoma', 'Disease', (187, 206))	('NSCLC', 'Disease', 'MESH:D002289', (257, 262))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (187, 206))	('carcinoma', 'Phenotype', 'HP:0030731', (197, 206))	('LUAD', 'Phenotype', 'HP:0030078', (208, 212))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (218, 246))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (223, 246))	('carcinoma', 'Phenotype', 'HP:0030731', (237, 246))	('SNRPA', 'Gene', '6627', (115, 120))
10792	33552128	In addition, we found that the LUAD cases with the stages (II, III/IV) or high SNRPA expression were correlated with a poor overall clinical survival prognosis, through our multivariate COX regression analysis.	('expression', 'MPA', (85, 95))	('high', 'Var', (74, 78))	('poor', 'NegReg', (119, 123))	('LUAD', 'Phenotype', 'HP:0030078', (31, 35))	('SNRPA', 'Gene', (79, 84))	('SNRPA', 'Gene', '6627', (79, 84))
10796	33552128	Surprisingly, the high SNRPA expression was detected to be linked to a better first-progression prognosis of lung cancer cases in GEO.	('lung cancer', 'Disease', (109, 120))	('lung cancer', 'Phenotype', 'HP:0100526', (109, 120))	('first-progression prognosis', 'CPA', (78, 105))	('SNRPA', 'Gene', (23, 28))	('SNRPA', 'Gene', '6627', (23, 28))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('lung cancer', 'Disease', 'MESH:D008175', (109, 120))	('high', 'Var', (18, 22))	('better', 'PosReg', (71, 77))	('expression', 'MPA', (29, 39))
10797	33552128	It is likely that the LUSC cases with a lowly expressed SNRPA are prone to suffer from the first disease progression.	('suffer', 'Reg', (75, 81))	('lowly expressed', 'Var', (40, 55))	('LUSC', 'Phenotype', 'HP:0030359', (22, 26))	('SNRPA', 'Gene', (56, 61))	('SNRPA', 'Gene', '6627', (56, 61))
10809	33552128	Herein, we found that the genetic alteration of SNRPA was associated with the overall survival prognosis of LUSC cases, but not LUAD cases.	('LUSC', 'Phenotype', 'HP:0030359', (108, 112))	('genetic alteration', 'Var', (26, 44))	('associated', 'Reg', (58, 68))	('LUSC', 'Disease', (108, 112))	('LUAD', 'Phenotype', 'HP:0030078', (128, 132))	('SNRPA', 'Gene', '6627', (48, 53))	('SNRPA', 'Gene', (48, 53))
10810	33552128	However, it should be noted that the genetic alteration frequency of both LUAD and LUSC is not higher than 5%, which greatly reduces the likelihood of the involvement of SNRPA genetic mutations in the pathogenesis of LUAD.	('SNRPA', 'Gene', (170, 175))	('LUAD', 'Disease', (217, 221))	('LUSC', 'Phenotype', 'HP:0030359', (83, 87))	('SNRPA', 'Gene', '6627', (170, 175))	('LUAD', 'Phenotype', 'HP:0030078', (217, 221))	('reduces', 'NegReg', (125, 132))	('LUAD', 'Phenotype', 'HP:0030078', (74, 78))	('involvement', 'Reg', (155, 166))	('genetic mutations', 'Var', (176, 193))
10822	33552128	The S115 phosphorylation site of SNRPA could be predicted by a kinexus P-site prediction algorithm.	('SNRPA', 'Gene', '6627', (33, 38))	('S115', 'Var', (4, 8))	('SNRPA', 'Gene', (33, 38))
10827	33552128	), ubiquitylation sites (e.g., K20, K50, K88, etc.	('ubiquitylation sites', 'MPA', (3, 23))	('K20', 'Gene', (31, 34))	('K88', 'Var', (41, 44))	('K50', 'Var', (36, 39))	('K20', 'Gene', '54474', (31, 34))
10828	33552128	), acetylation sites (e.g., K122, K80, K96, etc.)	('K122', 'Var', (28, 32))	('acetylation', 'MPA', (3, 14))	('K80', 'Gene', '144501', (34, 37))	('K80', 'Gene', (34, 37))	('K96', 'Var', (39, 42))
10917	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', (98, 132))	('breast cancer', 'Disease', (154, 167))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:C562729', (98, 132))	('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))
10940	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))	('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))
10953	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))
10979	27589834	In addition, mutational profiles of tumors can guide treatment options and help detect resistance to treatments, enabling physicians to evaluate therapeutic options quickly and effectively.	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('mutational', 'Var', (13, 23))	('tumors', 'Disease', (36, 42))	('tumors', 'Disease', 'MESH:D009369', (36, 42))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))
10982	27589834	The ability to extract nucleic acids from tumor samples and detect mutations enables physicians to have access to large amounts of detailed genetic information.	('tumor', 'Disease', (42, 47))	('mutations', 'Var', (67, 76))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('detect', 'Reg', (60, 66))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
10984	27589834	If a patient tests positive for either of these mutations, lung cancer-specific tyrosine kinase inhibitors (TKIs) such as erlotinib, gefitinib, or crizotinib are prescribed.	('lung cancer', 'Disease', 'MESH:D008175', (59, 70))	('patient', 'Species', '9606', (5, 12))	('lung cancer', 'Disease', (59, 70))	('erlotinib', 'Chemical', 'MESH:D000069347', (122, 131))	('lung cancer', 'Phenotype', 'HP:0100526', (59, 70))	('crizotinib', 'Chemical', 'MESH:D000077547', (147, 157))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('gefitinib', 'Chemical', 'MESH:D000077156', (133, 142))	('mutations', 'Var', (48, 57))	('positive', 'Reg', (19, 27))
10995	27589834	showed that murine NIH-3T3 cells incubated with plasma from human colorectal cancer subjects positive for KRAS mutations developed KRAS mutations, and when these NIH-3T3 cells were injected into mice, tumors appeared, and human KRAS mutations were detected in mouse plasma.	('mutations', 'Var', (136, 145))	('tumors', 'Disease', 'MESH:D009369', (201, 207))	('colorectal cancer', 'Disease', (66, 83))	('mutations', 'Var', (111, 120))	('mice', 'Species', '10090', (195, 199))	('KRAS', 'Gene', (131, 135))	('KRAS', 'Gene', (106, 110))	('human', 'Species', '9606', (222, 227))	('mouse', 'Species', '10090', (260, 265))	('murine', 'Species', '10090', (12, 18))	('colorectal cancer', 'Phenotype', 'HP:0003003', (66, 83))	('tumors', 'Phenotype', 'HP:0002664', (201, 207))	('NIH-3T3', 'CellLine', 'CVCL:0594', (162, 169))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('NIH-3T3', 'CellLine', 'CVCL:0594', (19, 26))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('tumors', 'Disease', (201, 207))	('human', 'Species', '9606', (60, 65))	('colorectal cancer', 'Disease', 'MESH:D015179', (66, 83))
10996	27589834	demonstrated that NIH-3T3 cells exposed to DNA from KRAS mutation-positive patient serum or cell supernatant developed a KRAS mutation over time, and when KRAS-positive cells plus the colon cancer carcinogen 1,2-dimethylhydrazine were injected into rats, the rats developed tumors with detectable KRAS mutations.	('colon cancer', 'Phenotype', 'HP:0003003', (184, 196))	('colon cancer', 'Disease', 'MESH:D015179', (184, 196))	('KRAS', 'Gene', (121, 125))	('tumors', 'Disease', 'MESH:D009369', (274, 280))	('mutation-positive', 'Var', (57, 74))	('tumors', 'Phenotype', 'HP:0002664', (274, 280))	('colon cancer', 'Disease', (184, 196))	('mutation', 'Var', (126, 134))	('1,2-dimethylhydrazine', 'Chemical', 'MESH:D019813', (208, 229))	('NIH-3T3', 'CellLine', 'CVCL:0594', (18, 25))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('tumor', 'Phenotype', 'HP:0002664', (274, 279))	('rats', 'Species', '10116', (259, 263))	('rats', 'Species', '10116', (249, 253))	('patient', 'Species', '9606', (75, 82))	('tumors', 'Disease', (274, 280))
11000	27589834	Not only can levels of cfDNA be used to distinguish cancer patients from non-cancer patients, but genomic analysis of cfDNA can also reveal known tumor mutations.	('non-cancer', 'Disease', 'MESH:D009369', (73, 83))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('non-cancer', 'Disease', (73, 83))	('mutations', 'Var', (152, 161))	('patients', 'Species', '9606', (84, 92))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('tumor', 'Disease', (146, 151))	('patients', 'Species', '9606', (59, 67))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('reveal', 'Reg', (133, 139))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
11003	27589834	In 27 of these patients, 28 out of 29 total mutations found in solid biopsy samples were also found in plasma cfDNA.	('found', 'Reg', (94, 99))	('patients', 'Species', '9606', (15, 23))	('mutations', 'Var', (44, 53))
11004	27589834	compared the mutational status of BRAF, EGFR, KRAS, and PIK3CA in plasma cfDNA samples to biopsy tissue samples, most mutations that were detected in the tumor biopsy samples were detected in plasma cfDNA samples: the concordant cases reached 91% for BRAF mutations, 99% for EGFR mutations, 83% for KRAS mutations, and 91% for PIK3CA mutations.	('KRAS', 'Gene', (299, 303))	('mutations', 'Var', (256, 265))	('PIK3CA', 'Gene', '5290', (56, 62))	('tumor', 'Disease', (154, 159))	('mutations', 'Var', (334, 343))	('EGFR', 'Gene', '1956', (275, 279))	('PIK3CA', 'Gene', '5290', (327, 333))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('BRAF', 'Gene', (251, 255))	('BRAF', 'Gene', '673', (251, 255))	('EGFR', 'Gene', (40, 44))	('PIK3CA', 'Gene', (56, 62))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('PIK3CA', 'Gene', (327, 333))	('EGFR', 'Gene', (275, 279))	('mutations', 'Var', (280, 289))	('mutations', 'Var', (304, 313))	('EGFR', 'Gene', '1956', (40, 44))	('BRAF', 'Gene', '673', (34, 38))	('BRAF', 'Gene', (34, 38))
11007	27589834	Moreover, in a genomic analysis of urine cfDNA in patients with urothelial bladder cancer, there was a high rate of concordance between mutations found in urine cfDNA and tumor tissue.	('urothelial bladder cancer', 'Disease', (64, 89))	('patients', 'Species', '9606', (50, 58))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('urothelial bladder cancer', 'Disease', 'MESH:D001749', (64, 89))	('mutations', 'Var', (136, 145))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', (171, 176))	('bladder cancer', 'Phenotype', 'HP:0009725', (75, 89))
11008	27589834	Importantly, circulating tumor DNA in urine had a sensitivity rate of 90% and permitted a better detection of genetic aberrations than urinary cellular DNA.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumor', 'Disease', (25, 30))	('genetic aberrations', 'Var', (110, 129))	('tumor', 'Disease', 'MESH:D009369', (25, 30))
11011	27589834	At inclusion, 44 total mutations were detected in plasma cfDNA samples of 23 out of 39 patients, and at later time-points, four more plasma cfDNA samples harbored mutations.	('mutations', 'Var', (23, 32))	('patients', 'Species', '9606', (87, 95))	('harbored', 'Reg', (154, 162))
11012	27589834	Additionally, in plasma cfDNA from patients who were given targeted therapies, four patients exhibited a mutation allele frequency decrease, and two patients showed a mutation allele increase, indicating that mutations in cfDNA can be helpful in determining a patient's response to treatment.	('patient', 'Species', '9606', (260, 267))	('patients', 'Species', '9606', (149, 157))	('targeted', 'Var', (59, 67))	('patients', 'Species', '9606', (84, 92))	('increase', 'PosReg', (183, 191))	('patient', 'Species', '9606', (35, 42))	('mutation', 'MPA', (167, 175))	('mutations', 'Var', (209, 218))	('mutation allele', 'MPA', (105, 120))	('cfDNA', 'Gene', (222, 227))	('patient', 'Species', '9606', (149, 156))	('decrease', 'NegReg', (131, 139))	('patients', 'Species', '9606', (35, 43))	('patient', 'Species', '9606', (84, 91))
11018	27589834	In addition, determining single nucleotide variants (SNVs) present in cfDNA samples could be useful for diagnosing lung cancer.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('single nucleotide variants', 'Var', (25, 51))	('lung cancer', 'Disease', 'MESH:D008175', (115, 126))	('lung cancer', 'Disease', (115, 126))	('lung cancer', 'Phenotype', 'HP:0100526', (115, 126))
11019	27589834	In a pilot study using four patients with early-stage NSCLC, 16 SNVs were detected in cfDNA samples, and only one cfDNA sample bore 90% of the variants detected, while 22% and 33% of the variants found in the three other tumor samples were also found in cfDNA.	('SCLC', 'Phenotype', 'HP:0030357', (55, 59))	('NSCLC', 'Phenotype', 'HP:0030358', (54, 59))	('tumor', 'Disease', (221, 226))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('tumor', 'Disease', 'MESH:D009369', (221, 226))	('NSCLC', 'Disease', (54, 59))	('patients', 'Species', '9606', (28, 36))	('NSCLC', 'Disease', 'MESH:D002289', (54, 59))	('variants', 'Var', (143, 151))
11029	27589834	Resistance mutations were detected in 27/33 samples, including 11 samples with the T790M EGFR mutation, three samples with a mutation in KRAS, and 13 samples with both mutations.	('EGFR', 'Gene', (89, 93))	('T790M', 'Mutation', 'rs121434569', (83, 88))	('detected', 'Reg', (26, 34))	('EGFR', 'Gene', '1956', (89, 93))	('T790M', 'Var', (83, 88))
11031	27589834	Finally, to evaluate the usefulness of cfDNA for the detection of epigenetic modifications in lung cancer, Lee et al.	('lung cancer', 'Disease', 'MESH:D008175', (94, 105))	('lung cancer', 'Disease', (94, 105))	('lung cancer', 'Phenotype', 'HP:0100526', (94, 105))	('epigenetic modifications', 'Var', (66, 90))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
11033	27589834	They found TMEFF2 methylation in 29/316 samples and no TMEFF2 methylation in control samples, and when compared to corresponding solid tumor samples, three serum cfDNA samples matched tumor DNA samples.	('TMEFF2', 'Gene', '23671', (55, 61))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('solid tumor', 'Disease', (129, 140))	('tumor', 'Disease', (135, 140))	('solid tumor', 'Disease', 'MESH:D009369', (129, 140))	('tumor', 'Disease', (184, 189))	('methylation', 'Var', (18, 29))	('TMEFF2', 'Gene', (11, 17))	('TMEFF2', 'Gene', (55, 61))	('TMEFF2', 'Gene', '23671', (11, 17))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
11035	27589834	In addition, in a study conducted to determine the methylation status of the DCLK1 promoter in plasma cfDNA from lung cancer patients across stages, 49.2% of plasma cfDNA samples were methylated.	('DCLK1', 'Gene', (77, 82))	('lung cancer', 'Disease', (113, 124))	('lung cancer', 'Phenotype', 'HP:0100526', (113, 124))	('DCLK1', 'Gene', '9201', (77, 82))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('methylated', 'Var', (184, 194))	('lung cancer', 'Disease', 'MESH:D008175', (113, 124))	('patients', 'Species', '9606', (125, 133))
11040	27589834	In light of these results, the epigenetic status of plasma cfDNA is a promising biomarker for detecting lung cancer or a risk of lung cancer.	('cfDNA', 'Gene', (59, 64))	('lung cancer', 'Disease', 'MESH:D008175', (104, 115))	('lung cancer', 'Disease', (129, 140))	('lung cancer', 'Phenotype', 'HP:0100526', (129, 140))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('lung cancer', 'Disease', (104, 115))	('epigenetic status', 'Var', (31, 48))	('lung cancer', 'Phenotype', 'HP:0100526', (104, 115))	('lung cancer', 'Disease', 'MESH:D008175', (129, 140))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('detecting', 'Reg', (94, 103))
11044	27589834	Furthermore, a consistent detection of mutations in cfDNA, regardless of tumor stage, is an important step toward widespread physician approval of using cfDNA as a liquid biopsy.	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('cfDNA', 'Gene', (52, 57))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('mutations', 'Var', (39, 48))	('tumor', 'Disease', (73, 78))
11060	27589834	In a study to determine if results from NGS are useful for detecting mutations in tumor tissues, Hagemann et al.	('mutations', 'Var', (69, 78))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumor', 'Disease', (82, 87))	('GS', 'Disease', 'MESH:D011125', (41, 43))
11061	27589834	analyzed the mutations revealed from NGS from the five most common cancer types and calculated a Shannon entropy level for each tumor type to determine if NGS revealed new information.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('cancer', 'Disease', (67, 73))	('GS', 'Disease', 'MESH:D011125', (156, 158))	('GS', 'Disease', 'MESH:D011125', (38, 40))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('tumor', 'Disease', (128, 133))	('mutations', 'Var', (13, 22))	('Shannon entropy level', 'MPA', (97, 118))
11064	27589834	In cancer research, NGS can be used to detect mutations in tumors that might not have been detected with Sanger sequencing.	('mutations', 'Var', (46, 55))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('tumors', 'Disease', (59, 65))	('tumors', 'Disease', 'MESH:D009369', (59, 65))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('cancer', 'Disease', (3, 9))	('GS', 'Disease', 'MESH:D011125', (21, 23))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
11065	27589834	For instance, in a study to determine mutations in lung and colon adenocarcinomas, NGS revealed three novel KRAS and EGFR mutations.	('KRAS', 'Gene', (108, 112))	('colon adenocarcinomas', 'Disease', 'MESH:D003110', (60, 81))	('GS', 'Disease', 'MESH:D011125', (84, 86))	('EGFR', 'Gene', '1956', (117, 121))	('EGFR', 'Gene', (117, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('mutations', 'Var', (122, 131))	('colon adenocarcinomas', 'Disease', (60, 81))
11070	27589834	From the study with squamous cell carcinoma, notable results include a high rate of copy number alterations in SOX2, PDGFRA, KIT, EGFR, FGFR1, WHSC1L1, CCND1, and CDKN2A; a total of 228 non-silent and 360 exonic mutations; the detection of significantly mutated genes, including TP53, CDKN2A, PTEN, PIK3CA, KEAP1, MLL2, HLA-A, NFE2L2, NOTCH1, and RB1; overexpression of SOX2 and TP63; inactivation of CDKN2A in 72% of cases; and EGFR amplifications in 7% of samples.	('CDKN2A', 'Gene', '1029', (285, 291))	('TP53', 'Gene', '7157', (279, 283))	('PDGFRA', 'Gene', (117, 123))	('FGFR1', 'Gene', (136, 141))	('PTEN', 'Gene', '5728', (293, 297))	('EGFR', 'Gene', '1956', (429, 433))	('KEAP1', 'Gene', (307, 312))	('PDGFRA', 'Gene', '5156', (117, 123))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (20, 43))	('NOTCH1', 'Gene', '4851', (335, 341))	('CCND1', 'Gene', '595', (152, 157))	('PIK3CA', 'Gene', (299, 305))	('CDKN2A', 'Gene', '1029', (401, 407))	('EGFR', 'Gene', (130, 134))	('CCND1', 'Gene', (152, 157))	('CDKN2A', 'Gene', '1029', (163, 169))	('RB1', 'Gene', (347, 350))	('squamous cell carcinoma', 'Disease', (20, 43))	('inactivation', 'Var', (385, 397))	('SOX2', 'Gene', '6657', (370, 374))	('MLL2', 'Gene', '9757', (314, 318))	('HLA-A', 'Gene', (320, 325))	('alterations', 'Var', (96, 107))	('overexpression', 'PosReg', (352, 366))	('EGFR', 'Gene', (429, 433))	('SOX2', 'Gene', '6657', (111, 115))	('TP63', 'Gene', (379, 383))	('SOX2', 'Gene', (111, 115))	('TP53', 'Gene', (279, 283))	('FGFR1', 'Gene', '2260', (136, 141))	('WHSC1L1', 'Gene', '54904', (143, 150))	('RB1', 'Gene', '5925', (347, 350))	('NFE2L2', 'Gene', '4780', (327, 333))	('CDKN2A', 'Gene', (285, 291))	('EGFR', 'Gene', '1956', (130, 134))	('PIK3CA', 'Gene', '5290', (299, 305))	('TP63', 'Gene', '8626', (379, 383))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (20, 43))	('WHSC1L1', 'Gene', (143, 150))	('PTEN', 'Gene', (293, 297))	('CDKN2A', 'Gene', (401, 407))	('MLL2', 'Gene', (314, 318))	('KEAP1', 'Gene', '9817', (307, 312))	('NOTCH1', 'Gene', (335, 341))	('HLA-A', 'Gene', '3105', (320, 325))	('carcinoma', 'Phenotype', 'HP:0030731', (34, 43))	('CDKN2A', 'Gene', (163, 169))	('SOX2', 'Gene', (370, 374))	('NFE2L2', 'Gene', (327, 333))
11071	27589834	In addition, notable results from the study with adenocarcinoma include the identification of 18 genes that are commonly mutated in lung adenocarcinoma; determining somatic copy number alterations in NKX2-1, TERT, MDM2, KRAS, EGFR, MET, CCNE1, CCND1, TERC, MECOM, CCND3, and CDKN2A; the detection of MET exon 14 skipping; detecting mutations in KRAS, EGFR, BRAF, ERBB2, and MET that lead to activation of the receptor tyrosine kinase pathways; and determining frequently mutated activated molecular pathways in lung adenocarcinoma, including the RTK/RAS/RAF pathway, PI3K-mTOR pathway, and p53 pathway.	('MECOM', 'Gene', '2122', (257, 262))	('MDM2', 'Gene', '4193', (214, 218))	('p53', 'Gene', '7157', (590, 593))	('receptor tyrosine kinase', 'Gene', '5979', (409, 433))	('RAF', 'Gene', '22882', (358, 361))	('BRAF', 'Gene', (357, 361))	('lung adenocarcinoma', 'Disease', (132, 151))	('BRAF', 'Gene', '673', (357, 361))	('adenocarcinoma', 'Disease', 'MESH:D000230', (137, 151))	('CCNE1', 'Gene', (237, 242))	('PI3K-mTOR pathway', 'Pathway', (567, 584))	('NKX2-1', 'Gene', '7080', (200, 206))	('adenocarcinoma', 'Disease', 'MESH:D000230', (516, 530))	('TERC', 'Gene', '7012', (251, 255))	('adenocarcinoma', 'Disease', 'MESH:D000230', (49, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (142, 151))	('p53', 'Gene', (590, 593))	('CCND3', 'Gene', (264, 269))	('ERBB2', 'Gene', (363, 368))	('CDKN2A', 'Gene', '1029', (275, 281))	('receptor tyrosine kinase', 'Gene', (409, 433))	('activated', 'PosReg', (479, 488))	('KRAS', 'Gene', (345, 349))	('RAF', 'Gene', (358, 361))	('RAF', 'Gene', '22882', (554, 557))	('carcinoma', 'Phenotype', 'HP:0030731', (54, 63))	('EGFR', 'Gene', (351, 355))	('NKX2-1', 'Gene', (200, 206))	('TERC', 'Gene', (251, 255))	('MET', 'Gene', (374, 377))	('CCNE1', 'Gene', '898', (237, 242))	('mutations', 'Var', (332, 341))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (132, 151))	('activation', 'PosReg', (391, 401))	('EGFR', 'Gene', '1956', (226, 230))	('lung adenocarcinoma', 'Disease', (511, 530))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (132, 151))	('mutated', 'Var', (471, 478))	('CCND1', 'Gene', '595', (244, 249))	('ERBB2', 'Gene', '2064', (363, 368))	('RAF', 'Gene', (554, 557))	('carcinoma', 'Phenotype', 'HP:0030731', (521, 530))	('CCND3', 'Gene', '896', (264, 269))	('CCND1', 'Gene', (244, 249))	('TERT', 'Gene', (208, 212))	('TERT', 'Gene', '7015', (208, 212))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (511, 530))	('MDM2', 'Gene', (214, 218))	('adenocarcinoma', 'Disease', (137, 151))	('EGFR', 'Gene', '1956', (351, 355))	('MET exon 14 skipping', 'Var', (300, 320))	('adenocarcinoma', 'Disease', (49, 63))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (511, 530))	('adenocarcinoma', 'Disease', (516, 530))	('MECOM', 'Gene', (257, 262))	('CDKN2A', 'Gene', (275, 281))	('EGFR', 'Gene', (226, 230))
11074	27589834	Overall, low-grade tumors (AC and TC) had fewer mutations than high grade tumors (SCLC and LCNEC), and the following genes were associated with specific tumor types: JAK3, NRAS, RB1, and VHL1 with SCLC; FGFR2 with LCNEC; KIT, PTEN, HNF1A, and SMO with AC; and SMAD4 with TC.	('tumors', 'Disease', (19, 25))	('LCNEC', 'Phenotype', 'HP:0030360', (214, 219))	('SMO', 'Gene', '6608', (243, 246))	('tumor', 'Disease', (74, 79))	('associated', 'Reg', (128, 138))	('tumor', 'Disease', (19, 24))	('PTEN', 'Gene', (226, 230))	('SCLC', 'Phenotype', 'HP:0030357', (197, 201))	('mutations', 'Var', (48, 57))	('tumors', 'Disease', 'MESH:D009369', (74, 80))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('JAK3', 'Gene', (166, 170))	('FGFR2', 'Gene', '2263', (203, 208))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('AC', 'Phenotype', 'HP:0030446', (27, 29))	('tumors', 'Disease', (74, 80))	('SMAD4', 'Gene', (260, 265))	('tumor', 'Disease', (153, 158))	('SCLC', 'Gene', '7864', (197, 201))	('SCLC', 'Gene', (197, 201))	('PTEN', 'Gene', '5728', (226, 230))	('SCLC', 'Phenotype', 'HP:0030357', (82, 86))	('RB1', 'Gene', (178, 181))	('SMO', 'Gene', (243, 246))	('LCNEC', 'Disease', (214, 219))	('HNF1A', 'Gene', '6927', (232, 237))	('fewer', 'NegReg', (42, 47))	('NRAS', 'Gene', '4893', (172, 176))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('VHL1', 'Gene', (187, 191))	('LCNEC', 'Phenotype', 'HP:0030360', (91, 96))	('JAK3', 'Gene', '3718', (166, 170))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('VHL1', 'Gene', '7428', (187, 191))	('HNF1A', 'Gene', (232, 237))	('SCLC', 'Gene', '7864', (82, 86))	('SCLC', 'Gene', (82, 86))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('AC', 'Phenotype', 'HP:0030446', (252, 254))	('SMAD4', 'Gene', '4089', (260, 265))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('RB1', 'Gene', '5925', (178, 181))	('KIT', 'Gene', (221, 224))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('NRAS', 'Gene', (172, 176))	('FGFR2', 'Gene', (203, 208))
11075	27589834	Likewise, in a study that examined the mutational status of tissue samples from patients with AC and TC using a targeted NGS panel, mutations (BRAF, SMAD4, PIK3CA, and KRAS) were only found in one out of 25 patients.	('found', 'Reg', (184, 189))	('patients', 'Species', '9606', (207, 215))	('SMAD4', 'Gene', (149, 154))	('patients', 'Species', '9606', (80, 88))	('PIK3CA', 'Gene', '5290', (156, 162))	('mutations', 'Var', (132, 141))	('BRAF', 'Gene', (143, 147))	('BRAF', 'Gene', '673', (143, 147))	('AC', 'Phenotype', 'HP:0030446', (94, 96))	('GS', 'Disease', 'MESH:D011125', (122, 124))	('SMAD4', 'Gene', '4089', (149, 154))	('PIK3CA', 'Gene', (156, 162))	('KRAS', 'Gene', (168, 172))
11077	27589834	In other studies, NGS has been used to further characterize lung cancer mutations.	('mutations', 'Var', (72, 81))	('lung cancer', 'Disease', (60, 71))	('lung cancer', 'Phenotype', 'HP:0100526', (60, 71))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('lung cancer', 'Disease', 'MESH:D008175', (60, 71))	('GS', 'Disease', 'MESH:D011125', (19, 21))
11078	27589834	used their newly developed targeted NGS system to detect single nucleotide variants and indels in solid tumor samples of patients with lung cancer.	('indels', 'Var', (88, 94))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('GS', 'Disease', 'MESH:D011125', (37, 39))	('solid tumor', 'Disease', (98, 109))	('solid tumor', 'Disease', 'MESH:D009369', (98, 109))	('lung cancer', 'Disease', 'MESH:D008175', (135, 146))	('single nucleotide variants', 'Var', (57, 83))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('patients', 'Species', '9606', (121, 129))	('lung cancer', 'Disease', (135, 146))	('lung cancer', 'Phenotype', 'HP:0100526', (135, 146))
11079	27589834	One hundred and one mutations were found in a total of 168 genes, with KRAS, TP53, EGFR, PIK3CA, BRAF, NRAS, JAK3, CTNNB1, and CKDN2A being the most often mutated genes.	('EGFR', 'Gene', '1956', (83, 87))	('CTNNB1', 'Gene', '1499', (115, 121))	('NRAS', 'Gene', '4893', (103, 107))	('BRAF', 'Gene', '673', (97, 101))	('JAK3', 'Gene', (109, 113))	('PIK3CA', 'Gene', (89, 95))	('EGFR', 'Gene', (83, 87))	('TP53', 'Gene', '7157', (77, 81))	('PIK3CA', 'Gene', '5290', (89, 95))	('KRAS', 'Gene', (71, 75))	('JAK3', 'Gene', '3718', (109, 113))	('NRAS', 'Gene', (103, 107))	('CTNNB1', 'Gene', (115, 121))	('CKDN2A', 'Gene', (127, 133))	('TP53', 'Gene', (77, 81))	('mutations', 'Var', (20, 29))	('BRAF', 'Gene', (97, 101))	('found', 'Reg', (35, 40))
11080	27589834	Moreover, 23 deletions, including deletions in ARID4B and TP53 were detected.	('ARID4B', 'Gene', (47, 53))	('TP53', 'Gene', '7157', (58, 62))	('TP53', 'Gene', (58, 62))	('deletions', 'Var', (34, 43))	('ARID4B', 'Gene', '51742', (47, 53))
11084	27589834	For example, in NSCLC samples, simultaneous detection of ALK, ROS1 and RET fusions and somatic mutations could be achieved in a very sensitive, specific, and tissue-sparing way using targeted NGS.	('fusions', 'Var', (75, 82))	('NSCLC', 'Phenotype', 'HP:0030358', (16, 21))	('ALK', 'Gene', (57, 60))	('GS', 'Disease', 'MESH:D011125', (193, 195))	('SCLC', 'Phenotype', 'HP:0030357', (17, 21))	('ROS1', 'Gene', (62, 66))	('RET', 'Gene', '5979', (71, 74))	('NSCLC', 'Disease', (16, 21))	('ROS1', 'Gene', '6098', (62, 66))	('NSCLC', 'Disease', 'MESH:D002289', (16, 21))	('ALK', 'Gene', '238', (57, 60))	('RET', 'Gene', (71, 74))
11085	27589834	Similarly, a FGFR3-TACC3 fusion was detected in a solid tumor sample from a patient with NSCLC for whom no other oncogenic mutations had been found using reverse transcription PCR, and this fusion was then detected in two more tumor samples that were thought to harbor no oncogenic mutations.	('AC', 'Phenotype', 'HP:0030446', (20, 22))	('solid tumor', 'Disease', (50, 61))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Disease', (227, 232))	('detected', 'Reg', (36, 44))	('NSCLC', 'Phenotype', 'HP:0030358', (89, 94))	('TACC3', 'Gene', '10460', (19, 24))	('tumor', 'Disease', 'MESH:D009369', (227, 232))	('TACC3', 'Gene', (19, 24))	('solid tumor', 'Disease', 'MESH:D009369', (50, 61))	('FGFR3', 'Gene', (13, 18))	('FGFR3', 'Gene', '2261', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))	('fusion', 'Var', (25, 31))	('tumor', 'Disease', (56, 61))	('SCLC', 'Phenotype', 'HP:0030357', (90, 94))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('NSCLC', 'Disease', 'MESH:D002289', (89, 94))	('patient', 'Species', '9606', (76, 83))	('NSCLC', 'Disease', (89, 94))
11086	27589834	Of note, exome sequencing identified a germline mutation in PARK2 that was associated with familial lung cancer.	('PARK2', 'Gene', (60, 65))	('germline mutation', 'Var', (39, 56))	('lung cancer', 'Phenotype', 'HP:0100526', (100, 111))	('familial lung cancer', 'Disease', 'MESH:D008175', (91, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('associated', 'Reg', (75, 85))	('PARK2', 'Gene', '5071', (60, 65))	('familial lung cancer', 'Disease', (91, 111))
11087	27589834	In another study that considered the role of NGS in determining the inherited mutations of lung cancer, mutations were found in the CLTCL1 and PDE4DIP genes in whole blood samples of family members with NSCLC.	('CLTCL1', 'Gene', '8218', (132, 138))	('lung cancer', 'Phenotype', 'HP:0100526', (91, 102))	('NSCLC', 'Disease', (203, 208))	('mutations', 'Var', (104, 113))	('NSCLC', 'Disease', 'MESH:D002289', (203, 208))	('GS', 'Disease', 'MESH:D011125', (46, 48))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('CLTCL1', 'Gene', (132, 138))	('PDE4DIP', 'Gene', (143, 150))	('lung cancer', 'Disease', 'MESH:D008175', (91, 102))	('PDE4DIP', 'Gene', '9659', (143, 150))	('SCLC', 'Phenotype', 'HP:0030357', (204, 208))	('NSCLC', 'Phenotype', 'HP:0030358', (203, 208))	('lung cancer', 'Disease', (91, 102))
11088	27589834	Altogether, data from these studies demonstrate the utility of NGS in finding mutations in lung cancer and the ability to use NGS as a diagnostic tool for patients with lung cancer.	('lung cancer', 'Phenotype', 'HP:0100526', (91, 102))	('lung cancer', 'Disease', 'MESH:D008175', (169, 180))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('mutations', 'Var', (78, 87))	('lung cancer', 'Disease', 'MESH:D008175', (91, 102))	('GS', 'Disease', 'MESH:D011125', (64, 66))	('lung cancer', 'Phenotype', 'HP:0100526', (169, 180))	('patients', 'Species', '9606', (155, 163))	('lung cancer', 'Disease', (169, 180))	('GS', 'Disease', 'MESH:D011125', (127, 129))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('lung cancer', 'Disease', (91, 102))
11092	27589834	First, fine needle aspirates (FNA) have shown some success with detecting lung cancer mutations using NGS.	('mutations', 'Var', (86, 95))	('lung cancer', 'Disease', (74, 85))	('lung cancer', 'Phenotype', 'HP:0100526', (74, 85))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('lung cancer', 'Disease', 'MESH:D008175', (74, 85))	('GS', 'Disease', 'MESH:D011125', (103, 105))
11095	27589834	Therefore, NGS could be used with FNA tissue to detect lung cancer mutations in primary tumors and in metastatic sites.	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('lung cancer', 'Disease', 'MESH:D008175', (55, 66))	('GS', 'Disease', 'MESH:D011125', (12, 14))	('mutations', 'Var', (67, 76))	('lung cancer', 'Disease', (55, 66))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('lung cancer', 'Phenotype', 'HP:0100526', (55, 66))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('tumors', 'Disease', (88, 94))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
11099	27589834	Patients with lung cancer had a higher plasma cfDNA concentration (4.9 ng per 400 muL, range 2.25-26.98 ng per 400 muL versus 2.32 ng per 400 muL, range 1.30-2.81 ng per 400 muL) and a higher PGA score (19.50, range 5.89-64.47 versus 9.28, range 7.38-11.08) than control patients, and targeted NGS revealed 14 point mutations in 12 genes in solid tumor tissue.	('plasma cfDNA concentration', 'MPA', (39, 65))	('solid tumor', 'Disease', 'MESH:D009369', (341, 352))	('higher', 'PosReg', (32, 38))	('PGA score', 'MPA', (192, 201))	('lung cancer', 'Disease', (14, 25))	('lung cancer', 'Phenotype', 'HP:0100526', (14, 25))	('Patients', 'Species', '9606', (0, 8))	('higher', 'PosReg', (185, 191))	('GS', 'Disease', 'MESH:D011125', (295, 297))	('PGA', 'Chemical', '-', (192, 195))	('patients', 'Species', '9606', (271, 279))	('tumor', 'Phenotype', 'HP:0002664', (347, 352))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('point mutations', 'Var', (310, 325))	('solid tumor', 'Disease', (341, 352))	('lung cancer', 'Disease', 'MESH:D008175', (14, 25))
11103	27589834	Mutations found in plasma cfDNA included ALK, ROS1, and RET rearrangements, HER2 insertions, and MET amplification, and mutations in BRAF and KRAS.	('KRAS', 'Gene', (142, 146))	('HER2', 'Gene', (76, 80))	('rearrangements', 'Var', (60, 74))	('HER2', 'Gene', '2064', (76, 80))	('BRAF', 'Gene', '673', (133, 137))	('RET', 'Gene', '5979', (56, 59))	('BRAF', 'Gene', (133, 137))	('ALK', 'Gene', (41, 44))	('mutations', 'Var', (120, 129))	('ROS1', 'Gene', (46, 50))	('MET amplification', 'CPA', (97, 114))	('ALK', 'Gene', '238', (41, 44))	('ROS1', 'Gene', '6098', (46, 50))	('RET', 'Gene', (56, 59))	('insertions', 'Var', (81, 91))
11105	27589834	Moreover, two mutations that were not detected in tumor tissue were detected in cfDNA with the NGS assay (double deletion in exon 19 of EGFR in one patient and high levels of MET amplification in a different patient) and were confirmed with droplet digital PCR (ddPCR) and fluorescent in situ immunohistochemistry, respectively.	('patient', 'Species', '9606', (208, 215))	('EGFR', 'Gene', (136, 140))	('double deletion in', 'Var', (106, 124))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('cfDNA', 'Disease', (80, 85))	('patient', 'Species', '9606', (148, 155))	('GS', 'Disease', 'MESH:D011125', (96, 98))	('EGFR', 'Gene', '1956', (136, 140))	('MET amplification', 'MPA', (175, 192))	('tumor', 'Disease', (50, 55))
11106	27589834	Furthermore, in a different study, there was a 76% concordance rate between mutations found in plasma cfDNA and mutations found in tumor samples from late-stage NSCLC patients, and additional mutations were found in cfDNA in several genes: EGFR, KRAS, PIK3CA, and TP53.	('NSCLC', 'Disease', 'MESH:D002289', (161, 166))	('PIK3CA', 'Gene', '5290', (252, 258))	('mutations', 'Var', (76, 85))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('EGFR', 'Gene', (240, 244))	('TP53', 'Gene', '7157', (264, 268))	('TP53', 'Gene', (264, 268))	('SCLC', 'Phenotype', 'HP:0030357', (162, 166))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('patients', 'Species', '9606', (167, 175))	('NSCLC', 'Phenotype', 'HP:0030358', (161, 166))	('KRAS', 'Gene', (246, 250))	('tumor', 'Disease', (131, 136))	('NSCLC', 'Disease', (161, 166))	('EGFR', 'Gene', '1956', (240, 244))	('cfDNA', 'Gene', (102, 107))	('PIK3CA', 'Gene', (252, 258))
11107	27589834	compared mutations found in plasma cfDNA samples to those found in solid tumor samples from 12 NSCLC patients from various stages using targeted NGS.	('patients', 'Species', '9606', (101, 109))	('NSCLC', 'Disease', 'MESH:D002289', (95, 100))	('SCLC', 'Phenotype', 'HP:0030357', (96, 100))	('solid tumor', 'Disease', 'MESH:D009369', (67, 78))	('GS', 'Disease', 'MESH:D011125', (146, 148))	('mutations', 'Var', (9, 18))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('NSCLC', 'Phenotype', 'HP:0030358', (95, 100))	('NSCLC', 'Disease', (95, 100))	('solid tumor', 'Disease', (67, 78))
11110	27589834	Moreover the NGS assay used in this study allowed the detection of mutations when the allele frequency was >= 5%, in contrast to the detection limit of 0.4% reported by Paweletz et al..	('GS', 'Disease', 'MESH:D011125', (14, 16))	('detection', 'Reg', (54, 63))	('mutations', 'Var', (67, 76))
11111	27589834	For example, mutations in bronchoalveolar lavage (BAL) and pleural fluids have been tested with NGS and yielded promising results.	('pleural fluid', 'Disease', 'MESH:D010995', (59, 72))	('GS', 'Disease', 'MESH:D011125', (97, 99))	('pleural fluid', 'Disease', (59, 72))	('pleural fluid', 'Phenotype', 'HP:0002202', (59, 72))	('mutations', 'Var', (13, 22))
11112	27589834	When NGS was used to test 48 BAL and pleural fluid samples for EGFR mutations, 81% of samples tested positive for EGFR mutations, compared to the 16% of samples that tested positive using Sanger sequencing.	('EGFR', 'Gene', '1956', (63, 67))	('GS', 'Disease', 'MESH:D011125', (6, 8))	('pleural fluid', 'Disease', (37, 50))	('pleural fluid', 'Phenotype', 'HP:0002202', (37, 50))	('pleural fluid', 'Disease', 'MESH:D010995', (37, 50))	('EGFR', 'Gene', (63, 67))	('EGFR', 'Gene', (114, 118))	('EGFR', 'Gene', '1956', (114, 118))	('positive', 'Reg', (101, 109))	('mutations', 'Var', (68, 77))	('mutations', 'Var', (119, 128))
11113	27589834	Finally, given the relative ease of collecting urine samples, early data suggest that using NGS to determine mutations in urine cfDNA shows some promise for diagnosing lung cancer and monitoring response to treatment.	('diagnosing', 'Reg', (157, 167))	('lung cancer', 'Disease', (168, 179))	('GS', 'Disease', 'MESH:D011125', (93, 95))	('lung cancer', 'Phenotype', 'HP:0100526', (168, 179))	('cfDNA', 'Gene', (128, 133))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('mutations', 'Var', (109, 118))	('lung cancer', 'Disease', 'MESH:D008175', (168, 179))
11114	27589834	For example, in TKI-pretreated patients with late stage NSCLC, the T790M mutation was found in 71% of urine cfDNA samples and in 75% of tissue samples, as assessed by the Trovagene quantitative PCR-NGS EGFR T790M assay and the Therascreen  EGFR RGQ polymerase chain reaction test, respectively.	('EGFR', 'Gene', (202, 206))	('T790M', 'Mutation', 'rs121434569', (207, 212))	('EGFR', 'Gene', (240, 244))	('T790M', 'Mutation', 'rs121434569', (67, 72))	('NSCLC', 'Disease', (56, 61))	('T790M', 'Var', (67, 72))	('NSCLC', 'Disease', 'MESH:D002289', (56, 61))	('NSCLC', 'Phenotype', 'HP:0030358', (56, 61))	('patients', 'Species', '9606', (31, 39))	('GS', 'Disease', 'MESH:D011125', (199, 201))	('SCLC', 'Phenotype', 'HP:0030357', (57, 61))	('EGFR', 'Gene', '1956', (202, 206))	('EGFR', 'Gene', '1956', (240, 244))
11115	27589834	Importantly, when tumor tissue was used as a reference, 93% of T790M-positive patients were also positive for this mutation in cfDNA from urine samples >= 90 mL.	('tumor', 'Disease', (18, 23))	('patients', 'Species', '9606', (78, 86))	('positive', 'Reg', (97, 105))	('T790M', 'Mutation', 'rs121434569', (63, 68))	('T790M-positive', 'Var', (63, 77))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
11127	27589834	In order to determine the relevance of using NGS to detect mutations in cancer patients in routine clinical practice, Wong et al.	('GS', 'Disease', 'MESH:D011125', (46, 48))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('patients', 'Species', '9606', (79, 87))	('mutations', 'Var', (59, 68))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('clinical', 'Species', '191496', (99, 107))	('cancer', 'Disease', (72, 78))
11131	27589834	In cancer genomics, the TruSight  Cancer Sequencing Panel targets 94 genes that are thought to contribute to cancer and 284 single nucleotide polymorphisms (SNPs).	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('single nucleotide polymorphisms', 'Var', (124, 155))	('Cancer', 'Phenotype', 'HP:0002664', (34, 40))	('Cancer', 'Disease', (34, 40))	('cancer', 'Disease', (109, 115))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('Cancer', 'Disease', 'MESH:D009369', (34, 40))	('cancer', 'Disease', (3, 9))	('genes', 'Gene', (69, 74))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
11132	27589834	In addition, the TruSight  Tumor 15 targets relevant regions in 15 genes that are often mutated in solid tumors, while the TruSight  Tumor 26, the first commercially available small actionable gene panel, is designed to assess low-frequency mutations in 26 genes involved in lung, gastric, colon, ovarian cancer and melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (316, 324))	('lung', 'Disease', (275, 279))	('melanoma', 'Disease', (316, 324))	('melanoma', 'Disease', 'MESH:D008545', (316, 324))	('Tumor', 'Phenotype', 'HP:0002664', (27, 32))	('gastric', 'Disease', (281, 288))	('solid tumors', 'Disease', 'MESH:D009369', (99, 111))	('ovarian cancer', 'Phenotype', 'HP:0100615', (297, 311))	('colon, ovarian cancer', 'Disease', 'MESH:D010051', (290, 311))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('Tumor', 'Phenotype', 'HP:0002664', (133, 138))	('cancer', 'Phenotype', 'HP:0002664', (305, 311))	('solid tumors', 'Disease', (99, 111))	('mutations', 'Var', (241, 250))
11135	27589834	For example, the Ion AmpliSeq  Cancer Panel v1 that covers 739 hotspot mutations in 46 genes and Panel v2 that covers 2855 hotspot mutations in 50 genes are used with the Ion AmpliSeq  Library Kit 2.0 to generate a multiplex PCR-based library starting with only 10 ng of DNA.	('Cancer', 'Phenotype', 'HP:0002664', (31, 37))	('Cancer', 'Disease', (31, 37))	('mutations', 'Var', (71, 80))	('Cancer', 'Disease', 'MESH:D009369', (31, 37))
11152	27589834	looked for KRAS and EGFR mutations in 25 FFPE samples from lung cancer patients.	('lung cancer', 'Disease', 'MESH:D008175', (59, 70))	('KRAS', 'Gene', (11, 15))	('mutations', 'Var', (25, 34))	('EGFR', 'Gene', (20, 24))	('patients', 'Species', '9606', (71, 79))	('lung cancer', 'Disease', (59, 70))	('lung cancer', 'Phenotype', 'HP:0100526', (59, 70))	('EGFR', 'Gene', '1956', (20, 24))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
11153	27589834	In 14 out of 25 samples, KRAS mutations that had been previously detected by Sanger sequencing combined with high-resolution melting (HRM) were detected by the Cobas , Rotor-Gene, and Ion Torrent  platforms.	('HRM', 'Disease', 'None', (134, 137))	('HRM', 'Disease', (134, 137))	('mutations', 'Var', (30, 39))	('KRAS', 'Gene', (25, 29))	('detected', 'Reg', (144, 152))
11154	27589834	The four other "mutated" samples and one "unmutated" sample could not be analyzed with Roche 454 because of technical sequencing issues (generation of unspecific PCR products), while all of the clinically relevant EGFR mutations that had been detected with HRM and Sanger sequencing were detected with all four platforms.	('HRM', 'Disease', 'None', (257, 260))	('HRM', 'Disease', (257, 260))	('clinical', 'Species', '191496', (194, 202))	('EGFR', 'Gene', '1956', (214, 218))	('EGFR', 'Gene', (214, 218))	('mutations', 'Var', (219, 228))
11156	27589834	compared mutations found in inherited cardiac disease patients on the Illumina MiSeq and the Ion Torrent  PGM platforms.	('patients', 'Species', '9606', (54, 62))	('mutations', 'Var', (9, 18))	('cardiac disease', 'Disease', (38, 53))	('cardiac disease', 'Disease', 'MESH:D006331', (38, 53))
11160	27589834	In addition, targeted NGS identified eight EGFR indels and SNVs that were not detected by the real-time PCR method used.	('EGFR', 'Gene', '1956', (43, 47))	('EGFR', 'Gene', (43, 47))	('indels', 'Var', (48, 54))	('GS', 'Disease', 'MESH:D011125', (23, 25))
11161	27589834	Moreover, when results obtained from targeted NGS were compared to results obtained by immunohistochemistry (IHC) for tumor samples from NSCLC patients with EGFR mutations, the fair sensitivity of the mutant-specific antibodies (58.4%) did not favor the replacement of DNA sequencing by IHC for the detection of EGFR mutations.	('EGFR', 'Gene', (157, 161))	('mutations', 'Var', (162, 171))	('NSCLC', 'Disease', (137, 142))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('NSCLC', 'Disease', 'MESH:D002289', (137, 142))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('SCLC', 'Phenotype', 'HP:0030357', (138, 142))	('patients', 'Species', '9606', (143, 151))	('NSCLC', 'Phenotype', 'HP:0030358', (137, 142))	('GS', 'Disease', 'MESH:D011125', (47, 49))	('tumor', 'Disease', (118, 123))	('EGFR', 'Gene', '1956', (312, 316))	('EGFR', 'Gene', '1956', (157, 161))	('EGFR', 'Gene', (312, 316))
11162	27589834	However, it is noteworthy that the specificity of IHC using mutated EGFR antibodies is excellent (98.0%).	('EGFR', 'Gene', '1956', (68, 72))	('EGFR', 'Gene', (68, 72))	('mutated', 'Var', (60, 67))
11163	27589834	Finally, in a study to compare hybrid capture-based NGS with mass spectrometry genotyping and fluorescence in situ hybridization (FISH), NGS revealed actionable genomic alterations in 65% of solid lung tumors that were classified as negative by the other non-NGS methods.	('genomic alterations', 'Var', (161, 180))	('GS', 'Disease', 'MESH:D011125', (138, 140))	('tumors', 'Phenotype', 'HP:0002664', (202, 208))	('lung tumors', 'Phenotype', 'HP:0100526', (197, 208))	('solid lung tumors', 'Disease', 'MESH:D009369', (191, 208))	('GS', 'Disease', 'MESH:D011125', (53, 55))	('GS', 'Disease', 'MESH:D011125', (260, 262))	('solid lung tumors', 'Disease', (191, 208))	('lung tumor', 'Phenotype', 'HP:0100526', (197, 207))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))
11164	27589834	Based on these studies, NGS is a superior method for detecting targetable mutations in lung tumors and would provide more sensitivity in lung cancer diagnosis.	('GS', 'Disease', 'MESH:D011125', (25, 27))	('lung tumors', 'Phenotype', 'HP:0100526', (87, 98))	('lung cancer', 'Disease', (137, 148))	('lung cancer', 'Phenotype', 'HP:0100526', (137, 148))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('lung tumors', 'Disease', 'MESH:D008175', (87, 98))	('mutations', 'Var', (74, 83))	('lung tumor', 'Phenotype', 'HP:0100526', (87, 97))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('lung cancer', 'Disease', 'MESH:D008175', (137, 148))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('lung tumors', 'Disease', (87, 98))
11167	27589834	Mutations in EGFR result in abnormal receptor activity leading to increased signaling.	('increased', 'PosReg', (66, 75))	('activity', 'MPA', (46, 54))	('receptor', 'Protein', (37, 45))	('Mutations', 'Var', (0, 9))	('signaling', 'MPA', (76, 85))	('EGFR', 'Gene', '1956', (13, 17))	('EGFR', 'Gene', (13, 17))
11168	27589834	These mutations are observed in 10% to 30% of NSCLC cases with higher frequencies in the East Asian population than the Caucasian population.	('NSCLC', 'Disease', (46, 51))	('NSCLC', 'Disease', 'MESH:D002289', (46, 51))	('SCLC', 'Phenotype', 'HP:0030357', (47, 51))	('mutations', 'Var', (6, 15))	('NSCLC', 'Phenotype', 'HP:0030358', (46, 51))
11169	27589834	In patients with EGFR mutations, EGFR tyrosine kinase inhibitors (EGFR TKIs), including erlotinib and gefitinib, are generally given as first-line treatments.	('EGFR', 'Gene', '1956', (66, 70))	('erlotinib', 'Chemical', 'MESH:D000069347', (88, 97))	('EGFR', 'Gene', (66, 70))	('EGFR', 'Gene', '1956', (33, 37))	('patients', 'Species', '9606', (3, 11))	('mutations', 'Var', (22, 31))	('EGFR', 'Gene', '1956', (17, 21))	('EGFR', 'Gene', (33, 37))	('gefitinib', 'Chemical', 'MESH:D000077156', (102, 111))	('EGFR', 'Gene', (17, 21))
11170	27589834	However, some patients develop resistance to TKIs, often related to a mutation in exon 20 of EGFR resulting in a substitution of methionine to threonine at amino acid position 790.	('develop', 'Reg', (23, 30))	('EGFR', 'Gene', '1956', (93, 97))	('substitution', 'Var', (113, 125))	('related', 'Reg', (57, 64))	('EGFR', 'Gene', (93, 97))	('methionine to threonine at amino acid position 790', 'Mutation', 'rs121434569', (129, 179))	('mutation in', 'Var', (70, 81))	('resistance', 'MPA', (31, 41))	('patients', 'Species', '9606', (14, 22))
11171	27589834	In personalized medicine, detecting EGFR-activating mutations and monitoring for resistance mutations enable physicians to prescribe treatments and modify them as necessary.	('mutations', 'Var', (52, 61))	('EGFR', 'Gene', (36, 40))	('EGFR', 'Gene', '1956', (36, 40))
11172	27589834	In order to do this, non-invasive and efficient methods to detect EGFR mutations have been developed using cfDNA as a liquid biopsy sample and NGS as technique for mutational analysis.	('GS', 'Disease', 'MESH:D011125', (144, 146))	('EGFR', 'Gene', (66, 70))	('mutations', 'Var', (71, 80))	('EGFR', 'Gene', '1956', (66, 70))
11173	27589834	First, cfDNA samples can be analyzed to detect and monitor EGFR-activating mutations in patients with lung cancer.	('EGFR', 'Gene', (59, 63))	('lung cancer', 'Phenotype', 'HP:0100526', (102, 113))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('patients', 'Species', '9606', (88, 96))	('lung cancer', 'Disease', (102, 113))	('mutations', 'Var', (75, 84))	('lung cancer', 'Disease', 'MESH:D008175', (102, 113))	('EGFR', 'Gene', '1956', (59, 63))
11174	27589834	used real-time PCR assays to detect EGFR L858R mutations and exon 19 deletions in plasma cfDNA from NSCLC patients.	('NSCLC', 'Disease', (100, 105))	('SCLC', 'Phenotype', 'HP:0030357', (101, 105))	('NSCLC', 'Disease', 'MESH:D002289', (100, 105))	('EGFR', 'Gene', '1956', (36, 40))	('L858R', 'Var', (41, 46))	('L858R', 'Mutation', 'rs121434568', (41, 46))	('patients', 'Species', '9606', (106, 114))	('EGFR', 'Gene', (36, 40))	('NSCLC', 'Phenotype', 'HP:0030358', (100, 105))
11175	27589834	They demonstrated that the Plasma-Therascreen  method (ARMS (Amplification Refractory Mutation System) allele-specific real-time PCR using the fluorescent Scorpions probes) and the Peptide Nucleic Acid (PNA)-clamp approach (inhibition of the amplification of the wild-type allele) have similar sensitivities (65.4% and 61.5%, respectively), specificities (100% for both methods), and concordance rates (90.6% and 89.6%, respectively) for the detection of the same EGFR mutation present in cfDNA and the corresponding primary tumor.	('EGFR', 'Gene', '1956', (464, 468))	('mutation', 'Var', (469, 477))	('tumor', 'Disease', (525, 530))	('EGFR', 'Gene', (464, 468))	('tumor', 'Disease', 'MESH:D009369', (525, 530))	('tumor', 'Phenotype', 'HP:0002664', (525, 530))
11176	27589834	analyzed EGFR mutations in cfDNA from blood samples collected from 97 untreated patients enrolled in the European Tarceva versus Chemotherapy (EURTAC) trial.	('patients', 'Species', '9606', (80, 88))	('AC', 'Phenotype', 'HP:0030446', (147, 149))	('EGFR', 'Gene', '1956', (9, 13))	('EGFR', 'Gene', (9, 13))	('mutations', 'Var', (14, 23))
11177	27589834	The authors demonstrated that in patients with the L858R mutation in tissue, who received erlotinib or standard chemotherapy, the detection of L858R in cfDNA is a negative prognostic factor for overall survival (OS), and patients with the L858R mutation in cfDNA had shorter OS than patients with exon 19 deletions.	('erlotinib', 'Chemical', 'MESH:D000069347', (90, 99))	('L858R', 'Mutation', 'rs121434568', (239, 244))	('patients', 'Species', '9606', (221, 229))	('patients', 'Species', '9606', (33, 41))	('L858R', 'Var', (143, 148))	('overall', 'MPA', (194, 201))	('patients', 'Species', '9606', (283, 291))	('L858R mutation', 'Var', (51, 65))	('L858R', 'Mutation', 'rs121434568', (143, 148))	('L858R', 'Var', (239, 244))	('L858R', 'Mutation', 'rs121434568', (51, 56))	('negative', 'NegReg', (163, 171))	('shorter', 'NegReg', (267, 274))
11178	27589834	EGFR mutation detection in cfDNA was successfully achieved using a PNA-mediated 5' nuclease real-time PCR assay with 78% sensitivity and 100% specificity.	('mutation', 'Var', (5, 13))	('EGFR', 'Gene', '1956', (0, 4))	('EGFR', 'Gene', (0, 4))
11179	27589834	These findings demonstrate the efficacy of this assay in the detection of EGFR mutations in cfDNA and shed light on the need for specific combination therapies for patients bearing the L858R mutation in their blood.	('L858R', 'Var', (185, 190))	('L858R', 'Mutation', 'rs121434568', (185, 190))	('EGFR', 'Gene', '1956', (74, 78))	('patients', 'Species', '9606', (164, 172))	('EGFR', 'Gene', (74, 78))	('mutations', 'Var', (79, 88))	('cfDNA', 'Disease', (92, 97))
11181	27589834	analyzed EGFR mutations in 91 tumor samples and 194 cfDNA samples isolated from patients enrolled in the Iressa Pan-Asia (IPASS) study comparing the efficacy of gefitinib and carboplatin/paclitaxel in patients with lung adenocarcinoma.	('gefitinib', 'Chemical', 'MESH:D000077156', (161, 170))	('patients', 'Species', '9606', (201, 209))	('mutations', 'Var', (14, 23))	('patients', 'Species', '9606', (80, 88))	('carboplatin', 'Chemical', 'MESH:D016190', (175, 186))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (215, 234))	('carcinoma', 'Phenotype', 'HP:0030731', (225, 234))	('paclitaxel', 'Chemical', 'MESH:D017239', (187, 197))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('EGFR', 'Gene', '1956', (9, 13))	('lung adenocarcinoma', 'Disease', (215, 234))	('EGFR', 'Gene', (9, 13))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (215, 234))	('tumor', 'Disease', (30, 35))
11182	27589834	Among the 86 patients who had mutational data for both tissue and cfDNA, the positive predictive value of the cfDNA EGFR mutation test was 100%.	('EGFR', 'Gene', '1956', (116, 120))	('EGFR', 'Gene', (116, 120))	('patients', 'Species', '9606', (13, 21))	('mutation', 'Var', (121, 129))
11184	27589834	study that used the same ARMS-Scorpions PCR approach, the sensitivity of the EGFR mutation detection test in cfDNA in the Goto et al.	('mutation', 'Var', (82, 90))	('EGFR', 'Gene', '1956', (77, 81))	('EGFR', 'Gene', (77, 81))	('cfDNA', 'Disease', (109, 114))
11185	27589834	In another study, in which ARMS-Scorpions PCR was also used, a very low concordance rate was observed between EGFR mutations found in tumor samples and in plasma cfDNA (17.2%); however, this concordance rate increased to 33.3% in later-stage patients and increased to 36.8% in patients with poorly differentiated tumors.	('tumor', 'Phenotype', 'HP:0002664', (313, 318))	('mutations', 'Var', (115, 124))	('tumor', 'Disease', (313, 318))	('EGFR', 'Gene', '1956', (110, 114))	('EGFR', 'Gene', (110, 114))	('patients', 'Species', '9606', (277, 285))	('increased', 'PosReg', (208, 217))	('tumors', 'Disease', (313, 319))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('tumors', 'Disease', 'MESH:D009369', (313, 319))	('tumors', 'Phenotype', 'HP:0002664', (313, 319))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('tumor', 'Disease', 'MESH:D009369', (313, 318))	('tumor', 'Disease', (134, 139))	('patients', 'Species', '9606', (242, 250))
11188	27589834	Taken together, these studies indicate that cfDNA could be used to detect EGFR mutations in patients with late-stage lung cancer using PCR-based assays.	('patients', 'Species', '9606', (92, 100))	('late-stage lung cancer', 'Disease', (106, 128))	('lung cancer', 'Phenotype', 'HP:0100526', (117, 128))	('EGFR', 'Gene', '1956', (74, 78))	('late-stage lung cancer', 'Disease', 'MESH:D008175', (106, 128))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('EGFR', 'Gene', (74, 78))	('mutations', 'Var', (79, 88))
11189	27589834	demonstrated the high sensitivity of this method in detecting EGFR-activating mutations in cfDNA from patients with late-stage NSCLC.	('NSCLC', 'Disease', (127, 132))	('cfDNA', 'Disease', (91, 96))	('EGFR', 'Gene', '1956', (62, 66))	('NSCLC', 'Disease', 'MESH:D002289', (127, 132))	('SCLC', 'Phenotype', 'HP:0030357', (128, 132))	('patients', 'Species', '9606', (102, 110))	('EGFR', 'Gene', (62, 66))	('mutations', 'Var', (78, 87))	('NSCLC', 'Phenotype', 'HP:0030358', (127, 132))
11190	27589834	Next, cfDNA samples can be analyzed for mutations in order to predict tumor response to treatment and to determine if resistance mutations have appeared.	('mutations', 'Var', (40, 49))	('tumor', 'Disease', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))
11191	27589834	compared tumor tissues with known EGFR mutations to plasma cfDNA samples from the same patients and followed the mutational status over time.	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('EGFR', 'Gene', (34, 38))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('mutations', 'Var', (39, 48))	('tumor', 'Disease', (9, 14))	('patients', 'Species', '9606', (87, 95))	('EGFR', 'Gene', '1956', (34, 38))
11193	27589834	Moreover, 40 out of 40 patients who harbored these mutations at baseline showed a decrease in mutant cfDNA after TKI treatment; however, a T790M mutation was detected in 14 patients who progressed after TKI treatment.	('T790M', 'Mutation', 'rs121434569', (139, 144))	('mutations', 'Var', (51, 60))	('T790M', 'Var', (139, 144))	('patients', 'Species', '9606', (173, 181))	('patients', 'Species', '9606', (23, 31))	('decrease', 'NegReg', (82, 90))	('cfDNA', 'Gene', (101, 106))	('mutant', 'Var', (94, 100))
11194	27589834	In a different study, EGFR mutations were detected in 36.4% of tumor tissue samples and 34.7% of plasma cfDNA samples.	('mutations', 'Var', (27, 36))	('tumor', 'Disease', (63, 68))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('EGFR', 'Gene', '1956', (22, 26))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('EGFR', 'Gene', (22, 26))	('detected', 'Reg', (42, 50))
11195	27589834	Furthermore, of the 59 patients who received EGFR-TKIs, patients with known EGFR mutations in tissue and plasma cfDNA had higher ORR than patients who were wild-type for EGFR.	('ORR', 'MPA', (129, 132))	('patients', 'Species', '9606', (56, 64))	('EGFR', 'Gene', (45, 49))	('patients', 'Species', '9606', (23, 31))	('higher', 'PosReg', (122, 128))	('EGFR', 'Gene', '1956', (170, 174))	('EGFR', 'Gene', '1956', (76, 80))	('EGFR', 'Gene', (170, 174))	('EGFR', 'Gene', (76, 80))	('mutations', 'Var', (81, 90))	('EGFR', 'Gene', '1956', (45, 49))	('patients', 'Species', '9606', (138, 146))
11196	27589834	demonstrated that plasma ddPCR is a rapid method to detect EGFR exon 19 deletion, L858R, and T790M mutations with high sensitivity and specificity.	('EGFR', 'Gene', (59, 63))	('L858R', 'Mutation', 'rs121434568', (82, 87))	('T790M', 'Mutation', 'rs121434569', (93, 98))	('L858R', 'Var', (82, 87))	('T790M', 'Var', (93, 98))	('EGFR', 'Gene', '1956', (59, 63))	('deletion', 'Var', (72, 80))
11197	27589834	Importantly, in order to select the most appropriate platform for EGFR mutation detection, in particular T790M, as part of the development process of the irreversible T790M-potent EGFR-TKI AZD9291, Thress et al.	('T790M', 'Mutation', 'rs121434569', (105, 110))	('T790M', 'Mutation', 'rs121434569', (167, 172))	('EGFR', 'Gene', '1956', (66, 70))	('EGFR', 'Gene', (66, 70))	('T790M', 'Var', (105, 110))	('EGFR', 'Gene', '1956', (180, 184))	('AZD9291', 'Chemical', 'MESH:C000596361', (189, 196))	('EGFR', 'Gene', (180, 184))	('T790M-potent', 'Var', (167, 179))
11199	27589834	The authors demonstrated the high and comparable sensitivity and specificity of digital (BioRad ddPCRTM and beads, emulsion, amplification, and magnetics (BEAMing) dPCR) and non-digital (Cobas  EGFR Mutation Test and Therascreen  EGFR Mutation Test) platforms for the detection of EGFR-sensitizing mutations in cfDNA.	('EGFR', 'Gene', '1956', (230, 234))	('EGFR', 'Gene', (230, 234))	('cfDNA', 'Disease', (311, 316))	('EGFR', 'Gene', '1956', (194, 198))	('mutations', 'Var', (298, 307))	('EGFR', 'Gene', (194, 198))	('EGFR', 'Gene', '1956', (281, 285))	('EGFR', 'Gene', (281, 285))
11200	27589834	When comparing the Cobas  EGFR Mutation Test and BEAMing dPCR for EGFR T790M detection in cfDNA, the authors observed a high sensitivity with both tests (73% and 81%, respectively).	('EGFR', 'Gene', (26, 30))	('T790M', 'Mutation', 'rs121434569', (71, 76))	('EGFR', 'Gene', '1956', (66, 70))	('EGFR', 'Gene', (66, 70))	('T790M', 'Var', (71, 76))	('cfDNA', 'Disease', (90, 95))	('EGFR', 'Gene', '1956', (26, 30))
11201	27589834	These results support the use of both platforms for EGFR T790M detection in cfDNA.	('EGFR', 'Gene', '1956', (52, 56))	('EGFR', 'Gene', (52, 56))	('T790M', 'Mutation', 'rs121434569', (57, 62))	('T790M', 'Var', (57, 62))	('cfDNA', 'Disease', (76, 81))
11203	27589834	Although EGFR T790M-positive NSCLC tumors are sensitive to the third generation TKIs such as AZD9291, emergence of resistance to these drugs can still occur.	('SCLC', 'Phenotype', 'HP:0030357', (30, 34))	('NSCLC', 'Phenotype', 'HP:0030358', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('NSCLC tumors', 'Disease', 'MESH:D009369', (29, 41))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('NSCLC tumors', 'Disease', (29, 41))	('AZD9291', 'Chemical', 'MESH:C000596361', (93, 100))	('T790M-positive', 'Var', (14, 28))	('EGFR', 'Gene', '1956', (9, 13))	('EGFR', 'Gene', (9, 13))	('T790M', 'Mutation', 'rs121434569', (14, 19))
11204	27589834	One of the resistance mechanisms is the development of the EGFR C797S mutation which blocks drug binding on EGFR.	('blocks', 'NegReg', (85, 91))	('EGFR', 'Gene', (59, 63))	('EGFR', 'Gene', '1956', (108, 112))	('EGFR', 'Gene', (108, 112))	('C797S', 'Mutation', 'rs1057519861', (64, 69))	('C797S', 'Var', (64, 69))	('drug', 'MPA', (92, 96))	('EGFR', 'Gene', '1956', (59, 63))
11205	27589834	successfully used NGS and ddPCR to detect the EGFR C797S mutation in plasma cfDNA from advanced EGFR-mutant NSCLC patients with acquired resistance to AZD9291.	('C797S', 'Var', (51, 56))	('NSCLC', 'Phenotype', 'HP:0030358', (108, 113))	('EGFR', 'Gene', (96, 100))	('AZD9291', 'Chemical', 'MESH:C000596361', (151, 158))	('EGFR', 'Gene', '1956', (46, 50))	('NSCLC', 'Disease', (108, 113))	('GS', 'Disease', 'MESH:D011125', (19, 21))	('C797S', 'Mutation', 'rs1057519861', (51, 56))	('NSCLC', 'Disease', 'MESH:D002289', (108, 113))	('EGFR', 'Gene', (46, 50))	('SCLC', 'Phenotype', 'HP:0030357', (109, 113))	('patients', 'Species', '9606', (114, 122))	('EGFR', 'Gene', '1956', (96, 100))
11206	27589834	Based on these studies, cfDNA can be used to predict a patient's response to TKIs through the analysis of EGFR mutations over time.	('mutations', 'Var', (111, 120))	('EGFR', 'Gene', '1956', (106, 110))	('patient', 'Species', '9606', (55, 62))	('EGFR', 'Gene', (106, 110))
11207	27589834	Moreover, in tumor tissue, targeted NGS has been used to detect the T790M mutation in patients who had EGFR-activating mutations and were treated with EGFR-TKIs.	('tumor', 'Disease', (13, 18))	('EGFR', 'Gene', '1956', (103, 107))	('EGFR', 'Gene', (151, 155))	('GS', 'Disease', 'MESH:D011125', (37, 39))	('EGFR', 'Gene', (103, 107))	('T790M', 'Mutation', 'rs121434569', (68, 73))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('T790M', 'Var', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('mutations', 'Var', (119, 128))	('EGFR', 'Gene', '1956', (151, 155))	('patients', 'Species', '9606', (86, 94))
11208	27589834	In addition to EGFR T790M, NGS revealed several other acquired resistance mutations, including mutations in TP53, KDR, and KIT, and compound EGFR mutations (i.e.	('compound', 'Var', (132, 140))	('GS', 'Disease', 'MESH:D011125', (28, 30))	('mutations', 'Var', (146, 155))	('EGFR', 'Gene', '1956', (141, 145))	('TP53', 'Gene', '7157', (108, 112))	('KDR', 'Gene', (114, 117))	('TP53', 'Gene', (108, 112))	('acquired resistance', 'MPA', (54, 73))	('EGFR', 'Gene', (141, 145))	('T790M', 'Mutation', 'rs121434569', (20, 25))	('EGFR', 'Gene', '1956', (15, 19))	('EGFR', 'Gene', (15, 19))	('KIT', 'Gene', (123, 126))	('mutations', 'Var', (95, 104))	('KDR', 'Gene', '3791', (114, 117))
11209	27589834	more than one mutation in the EGFR tyrosine kinase domain).	('mutation', 'Var', (14, 22))	('EGFR', 'Gene', '1956', (30, 34))	('EGFR', 'Gene', (30, 34))
11210	27589834	Interestingly, patients with compound EGFR mutations showed significantly lower OS than patients without such mutations (72.8 months versus 83.7 months).	('EGFR', 'Gene', '1956', (38, 42))	('patients', 'Species', '9606', (15, 23))	('EGFR', 'Gene', (38, 42))	('patients', 'Species', '9606', (88, 96))	('mutations', 'Var', (43, 52))	('lower', 'NegReg', (74, 79))
11211	27589834	Additionally, to determine if EGFR mutations could be found in other sample types, Liu et al.	('EGFR', 'Gene', '1956', (30, 34))	('EGFR', 'Gene', (30, 34))	('mutations', 'Var', (35, 44))
11212	27589834	compared mutations found in tumor tissue, plasma cfDNA, and DNA in pleural effusion samples from patients with advanced NSCLC using three different techniques: ARMS PCR, Sanger sequencing, and IHC.	('NSCLC', 'Disease', 'MESH:D002289', (120, 125))	('tumor', 'Disease', (28, 33))	('mutations', 'Var', (9, 18))	('SCLC', 'Phenotype', 'HP:0030357', (121, 125))	('NSCLC', 'Phenotype', 'HP:0030358', (120, 125))	('pleural effusion', 'Disease', 'MESH:D010996', (67, 83))	('pleural effusion', 'Disease', (67, 83))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('pleural effusion', 'Phenotype', 'HP:0002202', (67, 83))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('NSCLC', 'Disease', (120, 125))	('patients', 'Species', '9606', (97, 105))
11213	27589834	Results from this study indicate that pleural effusion samples and plasma cfDNA can be used to determine EGFR mutational status and that of these three techniques, ARMS PCR is the most suitable.	('pleural effusion', 'Disease', 'MESH:D010996', (38, 54))	('pleural effusion', 'Phenotype', 'HP:0002202', (38, 54))	('pleural effusion', 'Disease', (38, 54))	('EGFR', 'Gene', '1956', (105, 109))	('mutational status', 'Var', (110, 127))	('EGFR', 'Gene', (105, 109))
11214	27589834	demonstrated that deep sequencing of plasma cfDNA is highly specific for the detection of EGFR mutations, including T790M.	('T790M', 'Var', (116, 121))	('EGFR', 'Gene', '1956', (90, 94))	('EGFR', 'Gene', (90, 94))	('T790M', 'Mutation', 'rs121434569', (116, 121))
11215	27589834	Given that the detection rate of EGFR mutations can differ significantly between tumor and cfDNA samples, there is a need to address what biopsy sample or combinations of samples provide the most reliable information.	('EGFR', 'Gene', '1956', (33, 37))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('EGFR', 'Gene', (33, 37))	('mutations', 'Var', (38, 47))	('tumor', 'Disease', (81, 86))
11217	27589834	analyzed the EGFR T790M mutation in plasma cfDNA samples, circulating tumor cell (CTC) samples from whole blood, and tissue samples from TKI-treated patients with advanced NSCLC who were known to harbor EGFR-activating mutations..	('EGFR', 'Gene', '1956', (203, 207))	('patients', 'Species', '9606', (149, 157))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('NSCLC', 'Disease', (172, 177))	('tumor', 'Disease', (70, 75))	('EGFR', 'Gene', (203, 207))	('NSCLC', 'Disease', 'MESH:D002289', (172, 177))	('T790M', 'Mutation', 'rs121434569', (18, 23))	('NSCLC', 'Phenotype', 'HP:0030358', (172, 177))	('SCLC', 'Phenotype', 'HP:0030357', (173, 177))	('EGFR', 'Gene', '1956', (13, 17))	('EGFR', 'Gene', (13, 17))	('T790M', 'Var', (18, 23))
11220	27589834	In practice, there is no consensus if one test or another is better suited for the detection of EGFR mutations in the clinic, particularly when using cfDNA.	('EGFR', 'Gene', (96, 100))	('mutations', 'Var', (101, 110))	('EGFR', 'Gene', '1956', (96, 100))
11221	27589834	However, based on the studies mentioned above and on important, multicenter trials in lung cancer such as EURTAC, IPASS and LUX-Lung 3, the allele-specific PCR-based tests have proven efficient and sensitive in the detection of EGFR mutations.	('detection', 'Reg', (215, 224))	('EGFR', 'Gene', '1956', (228, 232))	('lung cancer', 'Phenotype', 'HP:0100526', (86, 97))	('AC', 'Phenotype', 'HP:0030446', (110, 112))	('lung cancer', 'Disease', (86, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('EGFR', 'Gene', (228, 232))	('mutations', 'Var', (233, 242))	('lung cancer', 'Disease', 'MESH:D008175', (86, 97))
11223	27589834	These include, among others, the Cobas  EGFR Mutation test (Roche) (based on real-time allele-specific PCR with Taqman probes) and the Therascreen  EGFR RGQ PCR kit (Qiagen) (based on allele-specific PCR with Scorpions probes) to identify EGFR mutations.	('EGFR', 'Gene', '1956', (148, 152))	('EGFR', 'Gene', (148, 152))	('EGFR', 'Gene', '1956', (40, 44))	('EGFR', 'Gene', (40, 44))	('EGFR', 'Gene', '1956', (239, 243))	('mutations', 'Var', (244, 253))	('EGFR', 'Gene', (239, 243))
11224	27589834	The Cobas  EGFR Mutation test is designed to detect mutations in EGFR exon 19 and the L858R mutation in exon 21.	('mutations', 'Var', (52, 61))	('EGFR', 'Gene', '1956', (65, 69))	('EGFR', 'Gene', (65, 69))	('EGFR', 'Gene', '1956', (11, 15))	('EGFR', 'Gene', (11, 15))	('L858R', 'Var', (86, 91))	('L858R', 'Mutation', 'rs121434568', (86, 91))
11227	27589834	This new version of the original test enables an expanded coverage of EGFR mutations (42 mutations) including exon 19 deletions, L858R substitution (exon 21) and the resistance mutation T790M (exon 20).	('T790M', 'Mutation', 'rs121434569', (186, 191))	('L858R', 'Mutation', 'rs121434568', (129, 134))	('T790M', 'Var', (186, 191))	('L858R substitution', 'Var', (129, 147))	('EGFR', 'Gene', '1956', (70, 74))	('EGFR', 'Gene', (70, 74))
11229	27589834	demonstrated that the Cobas  EGFR Mutation Test v2 and NGS display comparable sensitivities and specificities for the detection of EGFR mutations in plasma cfDNA and tissue.	('EGFR', 'Gene', '1956', (131, 135))	('EGFR', 'Gene', (131, 135))	('EGFR', 'Gene', '1956', (29, 33))	('EGFR', 'Gene', (29, 33))	('mutations', 'Var', (136, 145))	('GS', 'Disease', 'MESH:D011125', (56, 58))
11230	27589834	In addition, the Therascreen  EGFR RGQ PCR kit (Qiagen) covers 29 mutations in the EGFR gene, including exon 19 deletions and the L858R and T790M mutations.	('EGFR', 'Gene', '1956', (83, 87))	('L858R', 'Var', (130, 135))	('EGFR', 'Gene', (30, 34))	('deletions', 'Var', (112, 121))	('L858R', 'Mutation', 'rs121434568', (130, 135))	('T790M', 'Mutation', 'rs121434569', (140, 145))	('EGFR', 'Gene', (83, 87))	('T790M', 'Var', (140, 145))	('EGFR', 'Gene', '1956', (30, 34))
11231	27589834	In 2013, this test was FDA-approved following its use in the LUX-Lung 3 study that showed increased benefits when lung adenocarcinoma patients with EGFR-activating mutations were treated with the TKI afatinib as first-line treatment when compared to cisplatin plus pemetrexed.	('cisplatin', 'Chemical', 'MESH:D002945', (250, 259))	('lung adenocarcinoma', 'Disease', (114, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('EGFR', 'Gene', '1956', (148, 152))	('EGFR', 'Gene', (148, 152))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (114, 133))	('patients', 'Species', '9606', (134, 142))	('afatinib', 'Chemical', 'MESH:D000077716', (200, 208))	('pemetrexed', 'Chemical', 'MESH:D000068437', (265, 275))	('benefits', 'PosReg', (100, 108))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (114, 133))	('mutations', 'Var', (164, 173))
11232	27589834	Furthermore, highly specific and sensitive methods have recently been developed for the detection of rare tumor mutations in cfDNA and would be of interest for clinical application.	('cfDNA', 'Gene', (125, 130))	('clinical', 'Species', '191496', (160, 168))	('mutations', 'Var', (112, 121))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Disease', (106, 111))
11238	27589834	The mesenchymal-epithelial transition factor (MET) gene codes for a receptor tyrosine kinase responsible for activation of signaling cascades downstream of SRC homology 2 domain-containing phosphatase 2 (SHP2), PI3K, CRK-like protein (CRKL), among others, and is often involved in oncogenesis in many cancer types, including lung tumors.	('lung tumors', 'Disease', 'MESH:D008175', (325, 336))	('receptor tyrosine kinase', 'Gene', (68, 92))	('tumors', 'Phenotype', 'HP:0002664', (330, 336))	('lung tumors', 'Phenotype', 'HP:0100526', (325, 336))	('cancer', 'Disease', (301, 307))	('CRK-like protein', 'Gene', '1399', (217, 233))	('CRK-like protein', 'Gene', (217, 233))	('cancer', 'Phenotype', 'HP:0002664', (301, 307))	('MET', 'Gene', (46, 49))	('lung tumor', 'Phenotype', 'HP:0100526', (325, 335))	('CRKL', 'Gene', '1399', (235, 239))	('tumor', 'Phenotype', 'HP:0002664', (330, 335))	('lung tumors', 'Disease', (325, 336))	('SHP2', 'Gene', '5781', (204, 208))	('involved', 'Reg', (269, 277))	('CRKL', 'Gene', (235, 239))	('cancer', 'Disease', 'MESH:D009369', (301, 307))	('activation', 'PosReg', (109, 119))	('SHP2', 'Gene', (204, 208))	('PI3K', 'Var', (211, 215))	('receptor tyrosine kinase', 'Gene', '5979', (68, 92))
11239	27589834	In several cases, MET amplification has been associated with resistance to EGFR-TKI therapy.	('MET amplification', 'Var', (18, 35))	('EGFR', 'Gene', '1956', (75, 79))	('EGFR', 'Gene', (75, 79))	('associated', 'Reg', (45, 55))
11240	27589834	More recently, oncogenic splice-site mutations of MET at exon 14 have been discovered and were shown to activate c-MET in patients with NSCLC and SCLC.	('NSCLC', 'Disease', 'MESH:D002289', (136, 141))	('SCLC', 'Gene', (146, 150))	('c-MET', 'Gene', '4233', (113, 118))	('SCLC', 'Gene', '7864', (146, 150))	('SCLC', 'Phenotype', 'HP:0030357', (146, 150))	('activate', 'PosReg', (104, 112))	('NSCLC', 'Phenotype', 'HP:0030358', (136, 141))	('mutations', 'Var', (37, 46))	('patients', 'Species', '9606', (122, 130))	('SCLC', 'Gene', '7864', (137, 141))	('c-MET', 'Gene', (113, 118))	('SCLC', 'Gene', (137, 141))	('NSCLC', 'Disease', (136, 141))	('SCLC', 'Phenotype', 'HP:0030357', (137, 141))	('MET', 'Gene', (50, 53))
11245	27589834	In a study to characterize MET mutations across many tumor types, MET exon 14 mutations were detected in 3% of non-squamous NSCLC cases, mainly adenocarcinomas, were found specifically in older patients and were frequent in early-stage tumors, suggesting their role in lung tumorigenesis.	('detected', 'Reg', (93, 101))	('MET exon 14', 'Gene', (66, 77))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Disease', 'MESH:D009369', (236, 241))	('SCLC', 'Phenotype', 'HP:0030357', (125, 129))	('tumor', 'Disease', (274, 279))	('tumors', 'Phenotype', 'HP:0002664', (236, 242))	('tumor', 'Disease', 'MESH:D009369', (274, 279))	('mutations', 'Var', (78, 87))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('NSCLC', 'Disease', 'MESH:D002289', (124, 129))	('tumor', 'Phenotype', 'HP:0002664', (236, 241))	('lung tumor', 'Disease', (269, 279))	('tumors', 'Disease', (236, 242))	('adenocarcinomas', 'Disease', 'MESH:D000230', (144, 159))	('adenocarcinomas', 'Disease', (144, 159))	('patients', 'Species', '9606', (194, 202))	('carcinoma', 'Phenotype', 'HP:0030731', (149, 158))	('lung tumor', 'Phenotype', 'HP:0100526', (269, 279))	('NSCLC', 'Disease', (124, 129))	('tumor', 'Phenotype', 'HP:0002664', (274, 279))	('tumors', 'Disease', 'MESH:D009369', (236, 242))	('NSCLC', 'Phenotype', 'HP:0030358', (124, 129))	('tumor', 'Disease', (53, 58))	('tumor', 'Disease', (236, 241))	('lung tumor', 'Disease', 'MESH:D008175', (269, 279))
11246	27589834	Notably, stage IV NSCLC patients whose tumors exhibited MET exon 14 mutations were more likely to display concurrent MET amplification and c-MET overexpression.	('MET amplification', 'MPA', (117, 134))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('NSCLC', 'Disease', (18, 23))	('c-MET', 'Gene', '4233', (139, 144))	('MET exon', 'Var', (56, 64))	('c-MET', 'Gene', (139, 144))	('NSCLC', 'Disease', 'MESH:D002289', (18, 23))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('NSCLC', 'Phenotype', 'HP:0030358', (18, 23))	('SCLC', 'Phenotype', 'HP:0030357', (19, 23))	('patients', 'Species', '9606', (24, 32))	('tumors', 'Disease', (39, 45))
11248	27589834	found that MET exon 14 splicing alterations, but not MET amplification, were often concomitant with the presence of MDM2/CDK4 amplifications in solid tumor samples.	('CDK4', 'Gene', '1019', (121, 125))	('solid tumor', 'Disease', (144, 155))	('MDM2', 'Gene', '4193', (116, 120))	('MDM2', 'Gene', (116, 120))	('concomitant', 'Reg', (83, 94))	('solid tumor', 'Disease', 'MESH:D009369', (144, 155))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('MET exon 14 splicing alterations', 'Var', (11, 43))	('CDK4', 'Gene', (121, 125))
11249	27589834	Taken together, these results indicate that MET mutations can be found in NSCLC and could aid in diagnosis and in treatment decisions.	('MET mutations', 'Var', (44, 57))	('NSCLC', 'Phenotype', 'HP:0030358', (74, 79))	('aid', 'Reg', (90, 93))	('NSCLC', 'Disease', (74, 79))	('NSCLC', 'Disease', 'MESH:D002289', (74, 79))	('SCLC', 'Phenotype', 'HP:0030357', (75, 79))	('mutations', 'Var', (48, 57))
11250	27589834	Importantly, in two separate case reports, NGS detected the presence of a MET exon 14 splice-site mutation in NSCLC tumor tissue, and in each case report, the patient was treated with the MET inhibitor crizotinib and showed a partial response or a significant decrease in tumor size.	('tumor', 'Phenotype', 'HP:0002664', (272, 277))	('tumor', 'Disease', (272, 277))	('decrease', 'NegReg', (260, 268))	('NSCLC tumor', 'Disease', (110, 121))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('SCLC', 'Phenotype', 'HP:0030357', (111, 115))	('NSCLC', 'Phenotype', 'HP:0030358', (110, 115))	('GS', 'Disease', 'MESH:D011125', (44, 46))	('tumor', 'Disease', 'MESH:D009369', (272, 277))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('MET', 'Var', (74, 77))	('patient', 'Species', '9606', (159, 166))	('crizotinib', 'Chemical', 'MESH:D000077547', (202, 212))	('tumor', 'Disease', (116, 121))	('NSCLC tumor', 'Disease', 'MESH:D009369', (110, 121))
11252	27589834	MET exon 14 splice-site mutations were detected in 8 patients, and of the 4 patients who received MET inhibitors, 3 patients exhibited either complete or partial responses.	('patients', 'Species', '9606', (76, 84))	('patients', 'Species', '9606', (53, 61))	('patients', 'Species', '9606', (116, 124))	('detected', 'Reg', (39, 47))	('MET exon', 'Var', (0, 8))
11254	27589834	Interestingly, recent data presented at the 2016 European Lung Cancer Conference (ELCC) highlight the promising use of cfDNA for the detection of MET exon 14 mutations.	('Lung Cancer', 'Disease', 'MESH:D008175', (58, 69))	('MET exon', 'Var', (146, 154))	('Cancer', 'Phenotype', 'HP:0002664', (63, 69))	('Lung Cancer', 'Disease', (58, 69))	('Lung Cancer', 'Phenotype', 'HP:0100526', (58, 69))	('mutations', 'Var', (158, 167))
11256	27589834	This test detects different alterations in 70 cancer-related genes, including MET exon 14 skipping.	('alterations', 'Reg', (28, 39))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('cancer', 'Disease', (46, 52))	('MET exon 14 skipping', 'Var', (78, 98))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))
11257	27589834	The data showed an overall concordance rate of 48% between molecular analyses performed in cfDNA and in tissue, with a higher concordance for EGFR mutations (71%) (Santos et al., poster presented at 2016 European Lung Cancer Conference).	('Lung Cancer', 'Disease', 'MESH:D008175', (213, 224))	('mutations', 'Var', (147, 156))	('Cancer', 'Phenotype', 'HP:0002664', (218, 224))	('EGFR', 'Gene', '1956', (142, 146))	('EGFR', 'Gene', (142, 146))	('Lung Cancer', 'Phenotype', 'HP:0100526', (213, 224))	('Lung Cancer', 'Disease', (213, 224))
11258	27589834	Based on recent studies, about 3 to 5% of NSCLC patients are expected to harbor MET exon 14 skipping, driving cancer progression and metastasis.	('NSCLC', 'Disease', (42, 47))	('cancer', 'Disease', (110, 116))	('NSCLC', 'Disease', 'MESH:D002289', (42, 47))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('MET exon 14 skipping', 'Var', (80, 100))	('NSCLC', 'Phenotype', 'HP:0030358', (42, 47))	('metastasis', 'CPA', (133, 143))	('SCLC', 'Phenotype', 'HP:0030357', (43, 47))	('driving', 'Reg', (102, 109))	('patients', 'Species', '9606', (48, 56))	('cancer', 'Disease', 'MESH:D009369', (110, 116))
11261	27589834	By using cfDNA for liquid biopsies and NGS as a platform to analyze mutations found in cfDNA, lung cancer diagnosis can become less invasive and less expensive.	('lung cancer', 'Disease', 'MESH:D008175', (94, 105))	('cfDNA', 'Gene', (87, 92))	('GS', 'Disease', 'MESH:D011125', (40, 42))	('lung cancer', 'Disease', (94, 105))	('lung cancer', 'Phenotype', 'HP:0100526', (94, 105))	('mutations', 'Var', (68, 77))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
11264	33925911	Genetic Variants of lncRNA GAS5 Are Associated with the Clinicopathologic Development of Oral Cancer The long noncoding RNA, Growth arrest-specific 5 (GAS5) plays a crucial role in the development of oral cancer.	('GAS5', 'Gene', '60674', (27, 31))	('oral cancer', 'Disease', 'MESH:D009369', (200, 211))	('GAS5', 'Gene', (151, 155))	('men', 'Species', '9606', (192, 195))	('Growth arrest', 'Phenotype', 'HP:0001510', (125, 138))	('Oral Cancer', 'Disease', (89, 100))	('Variants', 'Var', (8, 16))	('GAS5', 'Gene', (27, 31))	('men', 'Species', '9606', (81, 84))	('Associated', 'Reg', (36, 46))	('oral cancer', 'Disease', (200, 211))	('Growth arrest-specific 5', 'Gene', (125, 149))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('Oral Cancer', 'Disease', 'MESH:D009369', (89, 100))	('Cancer', 'Phenotype', 'HP:0002664', (94, 100))	('Growth arrest-', 'Phenotype', 'HP:0031164', (125, 139))	('GAS5', 'Gene', '60674', (151, 155))	('Growth arrest-specific 5', 'Gene', '60674', (125, 149))
11265	33925911	However, potential genetic variants in GAS5 that affect the susceptibility and progression of oral cancer have rarely been explored.	('variants', 'Var', (27, 35))	('GAS5', 'Gene', (39, 43))	('affect', 'Reg', (49, 55))	('oral cancer', 'Disease', 'MESH:D009369', (94, 105))	('oral cancer', 'Disease', (94, 105))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
11266	33925911	In this study, two loci of GAS5 single nucleotide polymorphisms (SNPs) (rs145204276 and rs55829688) were genotyped by using the TaqMan allelic discrimination in 1125 oral cancer patients and 1195 non-oral-cancer individuals.	('non-oral-cancer', 'Disease', (196, 211))	('rs145204276', 'Mutation', 'rs145204276', (72, 83))	('rs55829688', 'Mutation', 'rs55829688', (88, 98))	('rs55829688', 'Var', (88, 98))	('oral cancer', 'Disease', 'MESH:D009369', (166, 177))	('patients', 'Species', '9606', (178, 186))	('GAS5', 'Gene', (27, 31))	('rs145204276', 'Var', (72, 83))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('non-oral-cancer', 'Disease', 'MESH:D009369', (196, 211))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('oral cancer', 'Disease', (166, 177))
11268	33925911	However, the patients with GAS5 SNP rs145204276 variants (Ins/Del or Del/Del) showed a higher tendency of moderate to poor cell differentiation of oral cancer (OR: 1.454, 95% CI: 1.041-2.031, p = 0.028).	('oral cancer', 'Disease', 'MESH:D009369', (147, 158))	('rs145204276', 'Var', (36, 47))	('Del/Del', 'Var', (69, 76))	('poor', 'NegReg', (118, 122))	('rs145204276', 'Mutation', 'rs145204276', (36, 47))	('patients', 'Species', '9606', (13, 21))	('GAS5', 'Gene', (27, 31))	('oral cancer', 'Disease', (147, 158))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('cell differentiation', 'CPA', (123, 143))
11269	33925911	Moreover, the GAS5 SNP rs145204276 variants (Ins/Del or Del/Del) in the non-alcohol-drinking population were associated with significantly advanced tumor stage (OR: 1.500, 95% CI: 1.081-2.081, p = 0.015) and larger tumor size (OR: 1.494, 95% CI: 1.076-2.074, p = 0.016).	('GAS5 SNP', 'Gene', (14, 22))	('alcohol', 'Chemical', 'MESH:D000438', (76, 83))	('rs145204276', 'Var', (23, 34))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('alcohol-drinking', 'Phenotype', 'HP:0030955', (76, 92))	('Del/Del', 'Var', (56, 63))	('tumor', 'Disease', 'MESH:D009369', (215, 220))	('tumor', 'Disease', (148, 153))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('rs145204276', 'Mutation', 'rs145204276', (23, 34))	('advanced', 'PosReg', (139, 147))	('tumor', 'Disease', (215, 220))	('tumor', 'Disease', 'MESH:D009369', (148, 153))
11270	33925911	Furthermore, individuals with the GAS5 SNP rs145204276 variant were associated with a higher expression of GAS5 in the GTEx database (p = 0.002), and the higher GAS5 level was associated with poor cell differentiation, advanced tumor stage and larger tumor size in head and neck squamous cell carcinoma from the TCGA database (all p < 0.05).	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (279, 302))	('tumor', 'Disease', (251, 256))	('tumor', 'Disease', 'MESH:D009369', (228, 233))	('poor cell differentiation', 'CPA', (192, 217))	('GAS5', 'Gene', (34, 38))	('higher', 'PosReg', (86, 92))	('tumor', 'Disease', 'MESH:D009369', (251, 256))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (265, 302))	('rs145204276', 'Var', (43, 54))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('tumor', 'Phenotype', 'HP:0002664', (251, 256))	('tumor size in head and neck', 'Phenotype', 'HP:0012288', (251, 278))	('carcinoma', 'Phenotype', 'HP:0030731', (293, 302))	('GAS5', 'Protein', (107, 111))	('rs145204276', 'Mutation', 'rs145204276', (43, 54))	('neck squamous cell carcinoma', 'Disease', (274, 302))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (274, 302))	('TC', 'Chemical', 'MESH:D013667', (312, 314))	('associated', 'Reg', (176, 186))	('expression', 'MPA', (93, 103))	('tumor', 'Disease', (228, 233))
11271	33925911	In conclusion, the GAS5 SNP rs145204276 variant is related to poor-differentiation cell status in oral cancer.	('rs145204276', 'Mutation', 'rs145204276', (28, 39))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('oral cancer', 'Disease', (98, 109))	('poor-differentiation cell status', 'CPA', (62, 94))	('rs145204276', 'Var', (28, 39))	('related', 'Reg', (51, 58))	('oral cancer', 'Disease', 'MESH:D009369', (98, 109))
11272	33925911	Besides, the presence of the GAS5 SNP rs145204276 variant is associated with a worse tumor stage and tumor size in oral cancer patients without alcohol drinking.	('oral cancer', 'Disease', (115, 126))	('tumor', 'Disease', (85, 90))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('tumor size in oral cancer', 'Phenotype', 'HP:0100649', (101, 126))	('alcohol drinking', 'Phenotype', 'HP:0030955', (144, 160))	('tumor', 'Disease', (101, 106))	('rs145204276', 'Var', (38, 49))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('oral cancer', 'Disease', 'MESH:D009369', (115, 126))	('patients', 'Species', '9606', (127, 135))	('alcohol', 'Chemical', 'MESH:D000438', (144, 151))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('rs145204276', 'Mutation', 'rs145204276', (38, 49))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
11280	33925911	Additionally, the genetic polymorphism of chemokine receptor-2 gene enhances the susceptibility of oral cancer development.	('oral cancer', 'Disease', (99, 110))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('chemokine receptor-2', 'Gene', (42, 62))	('enhances', 'PosReg', (68, 76))	('men', 'Species', '9606', (118, 121))	('oral cancer', 'Disease', 'MESH:D009369', (99, 110))	('genetic polymorphism', 'Var', (18, 38))
11281	33925911	In a survey on the gene other than protein, an early study showed that the single nucleotide polymorphism (SNP) of HOX transcript antisense intergenic RNA (HOTAIR) led to large-size tumors and an elevated risk of lymph node metastasis in non-betel quid chewers, implying the relationship between oral cancer and RNA polymorphism.	('single nucleotide polymorphism', 'Var', (75, 105))	('HOX transcript antisense intergenic RNA', 'Gene', '100124700', (115, 154))	('betel', 'Chemical', '-', (242, 247))	('oral cancer', 'Disease', 'MESH:D009369', (296, 307))	('tumors', 'Phenotype', 'HP:0002664', (182, 188))	('tumors', 'Disease', (182, 188))	('HOTAIR', 'Gene', (156, 162))	('tumors', 'Disease', 'MESH:D009369', (182, 188))	('HOTAIR', 'Gene', '100124700', (156, 162))	('HOX transcript antisense intergenic RNA', 'Gene', (115, 154))	('oral cancer', 'Disease', (296, 307))	('cancer', 'Phenotype', 'HP:0002664', (301, 307))	('lymph node metastasis', 'CPA', (213, 234))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
11285	33925911	On the other hand, the genetic polymorphism of GAS5 can lead to different effects on tumorigenesis; the SNP rs145204276 del/del genotype of GAS5 was associated with higher susceptibility of glioma.	('tumor', 'Disease', (85, 90))	('rs145204276', 'Mutation', 'rs145204276', (108, 119))	('glioma', 'Disease', (190, 196))	('GAS5', 'Gene', (140, 144))	('glioma', 'Disease', 'MESH:D005910', (190, 196))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('glioma', 'Phenotype', 'HP:0009733', (190, 196))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('rs145204276 del/del', 'Var', (108, 127))
11296	33925911	Two SNPs of GAS5, meaning the rs145204276 (Ins/Del) and the rs55829688 (T/C), were chosen since their minor allele frequencies were more than 5 percent, and earlier studies indicated their influence in other cancers.	('cancers', 'Phenotype', 'HP:0002664', (208, 215))	('rs145204276', 'Var', (30, 41))	('cancers', 'Disease', (208, 215))	('cancers', 'Disease', 'MESH:D009369', (208, 215))	('rs145204276', 'Mutation', 'rs145204276', (30, 41))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('rs55829688', 'Mutation', 'rs55829688', (60, 70))	('rs55829688', 'Var', (60, 70))
11299	33925911	After that, the genetic polymorphism concerning both the GAS5 SNPs rs145204276 and the rs55829688 (T/C) were evaluated via the application of the ABI StepOne Real-Time PCR System (Applied Biosystems, Foster City, CA, USA).	('rs145204276', 'Mutation', 'rs145204276', (67, 78))	('rs55829688', 'Mutation', 'rs55829688', (87, 97))	('rs145204276', 'Var', (67, 78))	('rs55829688', 'Var', (87, 97))
11301	33925911	To illustrate the relationship between rs145204276 SNP and GAS5 expression, the data from the Genotype-Tissue Expression (GTEx) database were applied to reveal the correlations between rs145204276 SNP and GAS5 expression in esophagus mucosa tissues.	('rs145204276', 'Mutation', 'rs145204276', (185, 196))	('rs145204276 SNP', 'Var', (185, 200))	('expression', 'MPA', (210, 220))	('rs145204276', 'Mutation', 'rs145204276', (39, 50))	('GAS5', 'Gene', (205, 209))	('correlations', 'Interaction', (164, 176))
11309	33925911	Regarding GAS5 SNP rs145204276, 59.1% and 58.7% patients in the study and control groups, respectively, expressed the rs145204276 Ins/Del or Del/Del genotypes, and the distribution of GAS5 SNP rs145204276 frequencies was similar between the study and control groups with similar AOR (Table 2).	('rs145204276', 'Var', (19, 30))	('rs145204276 Ins/Del', 'Var', (118, 137))	('rs145204276', 'Mutation', 'rs145204276', (118, 129))	('rs145204276', 'Mutation', 'rs145204276', (193, 204))	('rs145204276', 'Mutation', 'rs145204276', (19, 30))	('GAS5', 'Gene', (10, 14))	('patients', 'Species', '9606', (48, 56))
11312	33925911	Concerning the clinicopathological characteristics of oral cancers with different genotypes of GAS5 SNP rs145204276, the patients with GAS5 SNP rs145204276 variants (Ins/Del or Del/Del) showed a higher tendency of moderate to poor cell differentiation of oral cancer (OR: 1.454, 95% CI: 1.041-2.031, p = 0.028).	('rs145204276', 'Mutation', 'rs145204276', (104, 115))	('oral cancers', 'Disease', 'MESH:D009369', (54, 66))	('rs145204276', 'Var', (144, 155))	('Ins/Del', 'Var', (166, 173))	('Del/Del', 'Var', (177, 184))	('poor', 'NegReg', (226, 230))	('oral cancer', 'Disease', (255, 266))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('oral cancer', 'Disease', 'MESH:D009369', (54, 65))	('oral cancers', 'Disease', (54, 66))	('cancers', 'Phenotype', 'HP:0002664', (59, 66))	('rs145204276', 'Mutation', 'rs145204276', (144, 155))	('cancer', 'Phenotype', 'HP:0002664', (260, 266))	('patients', 'Species', '9606', (121, 129))	('oral cancer', 'Disease', 'MESH:D009369', (255, 266))
11313	33925911	Nevertheless, the genotypes of GAS5 SNP rs145204276 did not influence the status of clinical stage, tumor size, lymph node invasion or distal metastasis (all p > 0.05) (Table 3).	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('lymph node invasion', 'CPA', (112, 131))	('tumor', 'Disease', (100, 105))	('rs145204276', 'Mutation', 'rs145204276', (40, 51))	('GAS5', 'Gene', (31, 35))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('rs145204276', 'Var', (40, 51))
11314	33925911	Moreover, the genotypes of GAS5 SNP rs55829688 did not influence the clinicopathological characteristics of oral cancer (data not shown).	('oral cancer', 'Disease', 'MESH:D009369', (108, 119))	('rs55829688', 'Mutation', 'rs55829688', (36, 46))	('rs55829688', 'Var', (36, 46))	('oral cancer', 'Disease', (108, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
11315	33925911	In the subgroup analysis that only enrolled the oral cancer patients without alcohol drinking, the GAS5 SNP rs145204276 variants (Ins/Del or Del/Del) in this population were associated with significantly advanced tumor stage (OR: 1.500, 95% CI: 1.081-2.081, p = 0.015) and larger tumor size (OR: 1.494, 95% CI: 1.076-2.074, p = 0.016).	('tumor', 'Disease', (213, 218))	('rs145204276', 'Mutation', 'rs145204276', (108, 119))	('alcohol', 'Chemical', 'MESH:D000438', (77, 84))	('alcohol drinking', 'Phenotype', 'HP:0030955', (77, 93))	('oral cancer', 'Disease', 'MESH:D009369', (48, 59))	('patients', 'Species', '9606', (60, 68))	('tumor', 'Disease', 'MESH:D009369', (280, 285))	('Ins/Del', 'Var', (130, 137))	('tumor', 'Disease', 'MESH:D009369', (213, 218))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('tumor', 'Phenotype', 'HP:0002664', (280, 285))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('GAS5 SNP', 'Gene', (99, 107))	('oral cancer', 'Disease', (48, 59))	('tumor', 'Disease', (280, 285))	('rs145204276', 'Var', (108, 119))	('Del/Del', 'Var', (141, 148))	('advanced', 'PosReg', (204, 212))
11316	33925911	The other clinicopathological characteristics of oral cancer, including lymph node invasion, distal metastasis and cell differentiation, did not relate to the presence of GAS5 SNP rs145204276 variants (all p > 0.05) (Table 4).	('rs145204276', 'Var', (180, 191))	('oral cancer', 'Disease', 'MESH:D009369', (49, 60))	('rs145204276', 'Mutation', 'rs145204276', (180, 191))	('cell differentiation', 'CPA', (115, 135))	('oral cancer', 'Disease', (49, 60))	('lymph node invasion', 'CPA', (72, 91))	('distal metastasis', 'CPA', (93, 110))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
11317	33925911	The results showed that individuals with the GAS5 SNP rs145204276 variant Ins/Del (n = 75) or Del/Del (n = 4) were associated with a higher expression of GAS5 in the esophagus mucosa tissues with statistical significance (p = 0.002) (Figure 1A).	('rs145204276', 'Var', (54, 65))	('Del/Del', 'Var', (94, 101))	('GAS5', 'Protein', (154, 158))	('expression', 'MPA', (140, 150))	('higher', 'PosReg', (133, 139))	('rs145204276', 'Mutation', 'rs145204276', (54, 65))
11322	33925911	In the current study, we found the GAS5 SNP rs145204276 variants (Ins/Del or Del/Del) are related to a poor-differentiation cell character of oral cancer in a male population.	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('oral cancer', 'Disease', 'MESH:D009369', (142, 153))	('rs145204276', 'Var', (44, 55))	('related to', 'Reg', (90, 100))	('rs145204276', 'Mutation', 'rs145204276', (44, 55))	('Del/Del', 'Var', (77, 84))	('poor-differentiation cell character', 'CPA', (103, 138))	('oral cancer', 'Disease', (142, 153))
11324	33925911	The findings of the current study correspond to the results of a real-world database in which the expression of GAS5 is correlated with the GAS5 SNP rs145204276 variants and severe tumor grading of head and neck squamous cell carcinoma.	('rs145204276 variants', 'Var', (149, 169))	('tumor', 'Disease', (181, 186))	('tumor grading of head and neck', 'Phenotype', 'HP:0012288', (181, 211))	('rs145204276', 'Mutation', 'rs145204276', (149, 160))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (198, 235))	('GAS5', 'Gene', (112, 116))	('correlated', 'Reg', (120, 130))	('neck squamous cell carcinoma', 'Disease', (207, 235))	('carcinoma', 'Phenotype', 'HP:0030731', (226, 235))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (212, 235))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (207, 235))	('expression', 'MPA', (98, 108))
11327	33925911	In addition, the higher Insulin-like growth factor 2 mRNA-binding protein 2 was found in head and neck squamous cell carcinoma and correlated with higher cancer stage and larger tumor size, while the presence of ADAMTS14 SNP rs12774070 was significantly associated with the degree of oral tumor cell differentiation.	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (98, 126))	('oral tumor', 'Disease', 'MESH:D009369', (284, 294))	('associated', 'Reg', (254, 264))	('rs12774070', 'Mutation', 'rs12774070', (225, 235))	('tumor', 'Disease', (178, 183))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (103, 126))	('ADAMTS14', 'Gene', (212, 220))	('tumor', 'Disease', (289, 294))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('Insulin-like growth factor 2 mRNA-binding protein 2', 'Gene', '10644', (24, 75))	('tumor', 'Disease', 'MESH:D009369', (289, 294))	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('oral tumor', 'Phenotype', 'HP:0100649', (284, 294))	('higher', 'PosReg', (147, 153))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (89, 126))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('rs12774070', 'Var', (225, 235))	('tumor', 'Phenotype', 'HP:0002664', (289, 294))	('cancer', 'Disease', (154, 160))	('higher', 'PosReg', (17, 23))	('oral tumor', 'Disease', (284, 294))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('ADAMTS14', 'Gene', '140766', (212, 220))	('neck squamous cell carcinoma', 'Disease', (98, 126))
11328	33925911	In addition, gene-environment interactions exist in oral cancer; CD44 polymorphisms and betel quid chewing or tobacco smoking enhance the susceptibility to oral cancer occurrence.	('enhance', 'PosReg', (126, 133))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('oral cancer', 'Disease', 'MESH:D009369', (52, 63))	('betel', 'Chemical', '-', (88, 93))	('men', 'Species', '9606', (25, 28))	('oral cancer', 'Disease', 'MESH:D009369', (156, 167))	('tobacco', 'Species', '4097', (110, 117))	('oral cancer', 'Disease', (52, 63))	('CD44', 'Gene', '960', (65, 69))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('polymorphisms', 'Var', (70, 83))	('oral cancer', 'Disease', (156, 167))	('CD44', 'Gene', (65, 69))
11329	33925911	Additionally, for the factor that controls cell growth, the MIR4435-2HG caused the up-regulation of TGF-beta1 in oral squamous cell carcinoma.	('up-regulation', 'PosReg', (83, 96))	('MIR4435', 'Chemical', '-', (60, 67))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('TGF-beta1', 'Gene', '7040', (100, 109))	('oral squamous cell carcinoma', 'Disease', (113, 141))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (118, 141))	('TGF-beta1', 'Gene', (100, 109))	('MIR4435-2HG', 'Var', (60, 71))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (113, 141))
11331	33925911	Although the majority of malignancies were suppressed via the higher level of GAS5, certain cancers benefited from the presence of GAS5.	('malignancies', 'Disease', 'MESH:D009369', (25, 37))	('cancers', 'Phenotype', 'HP:0002664', (92, 99))	('cancers', 'Disease', 'MESH:D009369', (92, 99))	('cancers', 'Disease', (92, 99))	('malignancies', 'Disease', (25, 37))	('presence', 'Var', (119, 127))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('benefited', 'PosReg', (100, 109))	('GAS5', 'Var', (131, 135))
11332	33925911	In previous research, the GAS5 is associated with the progression of glioma.	('glioma', 'Disease', (69, 75))	('associated with', 'Reg', (34, 49))	('GAS5', 'Var', (26, 30))	('glioma', 'Disease', 'MESH:D005910', (69, 75))	('glioma', 'Phenotype', 'HP:0009733', (69, 75))
11333	33925911	Besides, the GAS5 SNP rs145204276 variant correlated with a poorer five-year survival rate in uterine cervical cancer.	('poorer', 'NegReg', (60, 66))	('rs145204276', 'Var', (22, 33))	('GAS5', 'Gene', (13, 17))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('rs145204276', 'Mutation', 'rs145204276', (22, 33))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))
11334	33925911	According to the above evidences, the GAS5 could lead to tumor development, and SNP rs145204276 might be related to tumor progression, and the GAS5 can lead to proliferation and invasion of esophageal cancer, which is anatomically similar to the development site of oral cancer.	('cancer', 'Disease', (201, 207))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('invasion', 'CPA', (178, 186))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('cancer', 'Disease', (271, 277))	('oral cancer', 'Disease', (266, 277))	('cancer', 'Phenotype', 'HP:0002664', (271, 277))	('GAS5', 'Var', (143, 147))	('rs145204276', 'Mutation', 'rs145204276', (84, 95))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumor', 'Disease', (57, 62))	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('lead to', 'Reg', (49, 56))	('cancer', 'Disease', 'MESH:D009369', (271, 277))	('men', 'Species', '9606', (253, 256))	('lead to', 'Reg', (152, 159))	('men', 'Species', '9606', (70, 73))	('proliferation', 'CPA', (160, 173))	('oral cancer', 'Disease', 'MESH:D009369', (266, 277))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Disease', (116, 121))
11335	33925911	On the other hand, the presence of GAS5 could suppress tumor invasion and proliferation via the miR-21/PTEN axis in the oral squamous cell carcinoma.	('PTEN', 'Gene', (103, 107))	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (125, 148))	('PTEN', 'Gene', '5728', (103, 107))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (120, 148))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('miR-21', 'Gene', (96, 102))	('suppress', 'NegReg', (46, 54))	('carcinoma', 'Phenotype', 'HP:0030731', (139, 148))	('oral squamous cell carcinoma', 'Disease', (120, 148))	('tumor', 'Disease', (55, 60))	('presence', 'Var', (23, 31))	('GAS5', 'Gene', (35, 39))	('miR-21', 'Gene', '406991', (96, 102))
11336	33925911	Moreover, two GAS5 SNPs, which included rs2067079 and rs6790, were associated with a higher possibility of toxic reaction after platinum-based concurrent chemoradiotherapy in patients with nasopharyngeal carcinoma.	('rs2067079', 'Var', (40, 49))	('platinum', 'Chemical', 'MESH:D010984', (128, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (204, 213))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (189, 213))	('carcinoma', 'Disease', 'MESH:D009369', (204, 213))	('toxic', 'Disease', (107, 112))	('rs2067079', 'Mutation', 'rs2067079', (40, 49))	('patients', 'Species', '9606', (175, 183))	('carcinoma', 'Disease', (204, 213))	('associated', 'Reg', (67, 77))	('rs6790', 'Var', (54, 60))	('rs6790', 'Mutation', 'rs6790', (54, 60))
11338	33925911	Consequently, it is possible that the SNP of GAS5 may be associated with the development of oral cancer in a specific gender, which was partially supported by the findings of the current study.	('oral cancer', 'Disease', (92, 103))	('SNP', 'Var', (38, 41))	('GAS5', 'Gene', (45, 49))	('men', 'Species', '9606', (84, 87))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('oral cancer', 'Disease', 'MESH:D009369', (92, 103))	('associated with', 'Reg', (57, 72))
11339	33925911	The expression of the GAS5 SNP rs145204276 variant (Ins/Del or Del/Del) is correlated with the poor-differentiation cell type of oral cancer for males in the current study.	('Del/Del', 'Var', (63, 70))	('oral cancer', 'Disease', (129, 140))	('Ins/Del', 'Var', (52, 59))	('rs145204276', 'Var', (31, 42))	('GAS5 SNP', 'Gene', (22, 30))	('oral cancer', 'Disease', 'MESH:D009369', (129, 140))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('rs145204276', 'Mutation', 'rs145204276', (31, 42))
11342	33925911	The GAS5 SNP rs145204276 Del variant increases the expression of GAS5 mRNA, which proven in the previous research, and the higher concentration of GAS5 may have a prominent effect on the development of oral cancer.	('GAS5 mRNA', 'Protein', (65, 74))	('effect', 'Reg', (173, 179))	('oral cancer', 'Disease', (202, 213))	('men', 'Species', '9606', (194, 197))	('expression', 'MPA', (51, 61))	('GAS5', 'Gene', (4, 8))	('increases', 'PosReg', (37, 46))	('rs145204276', 'Mutation', 'rs145204276', (13, 24))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('rs145204276 Del', 'Var', (13, 28))	('oral cancer', 'Disease', 'MESH:D009369', (202, 213))
11343	33925911	Given the fact that the GAS5 has a different effect, either positive or negative, on the tumor progression, invasion and response to treatment in various types of cancers, our findings suggest that the presence of the GAS5 SNP rs145204276 variant is a positive factor for severe oral cancer in at least a male population, in contrast to the protective effect for oral cancer in a previous study.	('cancers', 'Phenotype', 'HP:0002664', (163, 170))	('oral cancer', 'Disease', 'MESH:D009369', (279, 290))	('cancers', 'Disease', (163, 170))	('GAS5', 'Gene', (218, 222))	('oral cancer', 'Disease', (363, 374))	('men', 'Species', '9606', (138, 141))	('cancer', 'Phenotype', 'HP:0002664', (368, 374))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('oral cancer', 'Disease', (279, 290))	('rs145204276', 'Var', (227, 238))	('oral cancer', 'Disease', 'MESH:D009369', (363, 374))	('cancer', 'Phenotype', 'HP:0002664', (284, 290))	('rs145204276', 'Mutation', 'rs145204276', (227, 238))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))	('cancers', 'Disease', 'MESH:D009369', (163, 170))
11346	33925911	In the subgroup analysis of the oral cancer population without alcohol drinking, the presence of the GAS5 SNP rs145204276 variant is correlated with the advanced cancer stage and larger tumor size.	('oral cancer', 'Disease', (32, 43))	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('rs145204276', 'Mutation', 'rs145204276', (110, 121))	('cancer', 'Disease', (162, 168))	('cancer', 'Disease', (37, 43))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('GAS5 SNP', 'Gene', (101, 109))	('tumor', 'Disease', (186, 191))	('oral cancer', 'Disease', 'MESH:D009369', (32, 43))	('rs145204276', 'Var', (110, 121))	('alcohol drinking', 'Phenotype', 'HP:0030955', (63, 79))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('correlated', 'Reg', (133, 143))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('alcohol', 'Chemical', 'MESH:D000438', (63, 70))
11348	33925911	The possible explanation is that the alcohol-drinking patients have some genetic variations that influence the susceptibility of tumor progression or GAS5 expression.	('GAS5 expression', 'MPA', (150, 165))	('alcohol', 'Chemical', 'MESH:D000438', (37, 44))	('patients', 'Species', '9606', (54, 62))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('influence', 'Reg', (97, 106))	('alcohol-drinking', 'Phenotype', 'HP:0030955', (37, 53))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('tumor', 'Disease', (129, 134))	('variations', 'Var', (81, 91))
11349	33925911	In a previous study, the adulthood patients that did consume alcohol showed a significant correlation with the polymorphisms in 5HTT, DAT1, DRD4, DRD2 and MAOA.	('DAT1', 'Gene', '6531', (134, 138))	('DRD4', 'Gene', '1815', (140, 144))	('5HTT', 'Gene', (128, 132))	('alcohol', 'Chemical', 'MESH:D000438', (61, 68))	('correlation', 'Interaction', (90, 101))	('DRD4', 'Gene', (140, 144))	('MAOA', 'Gene', '4128', (155, 159))	('5HTT', 'Gene', '6532', (128, 132))	('DRD2', 'Gene', (146, 150))	('DRD2', 'Gene', '1813', (146, 150))	('polymorphisms', 'Var', (111, 124))	('MAOA', 'Gene', (155, 159))	('DAT1', 'Gene', (134, 138))	('patients', 'Species', '9606', (35, 43))
11350	33925911	Besides, the deficiency of relaxin-3 was found to increase the alcohol consumption in mice significantly.	('alcohol', 'CPA', (63, 70))	('relaxin-3', 'Gene', '212108', (27, 36))	('relaxin-3', 'Gene', (27, 36))	('deficiency', 'Var', (13, 23))	('mice', 'Species', '10090', (86, 90))	('increase', 'PosReg', (50, 58))	('alcohol', 'Chemical', 'MESH:D000438', (63, 70))
11351	33925911	On the other hand, the severity of lymph node invasion and distal metastasis did not alter with different GAS5 SNP rs145204276 in both the whole group and subgroup analysis, which may indicate the universally minimal effects of GAS5 SNP in the two clinical characters for oral cancer.	('oral cancer', 'Disease', 'MESH:D009369', (272, 283))	('rs145204276', 'Mutation', 'rs145204276', (115, 126))	('distal metastasis', 'CPA', (59, 76))	('lymph node invasion', 'CPA', (35, 54))	('oral cancer', 'Disease', (272, 283))	('cancer', 'Phenotype', 'HP:0002664', (277, 283))	('rs145204276', 'Var', (115, 126))
11353	33925911	These findings correspond to the results in the current study that the expression of GAS5 SNP may lead to worse clinicopathological characteristics of oral cancer and the adjunct tissue.	('expression', 'Var', (71, 81))	('lead to', 'Reg', (98, 105))	('oral cancer', 'Disease', (151, 162))	('GAS5', 'Gene', (85, 89))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('oral cancer', 'Disease', 'MESH:D009369', (151, 162))
11354	33925911	The GAS5 SNP rs145204276 is related to the higher level of GAS5 expression in the GTEx database, which was also proven in previous study.	('expression', 'MPA', (64, 74))	('higher', 'PosReg', (43, 49))	('rs145204276', 'Var', (13, 24))	('GAS5', 'Gene', (59, 63))	('rs145204276', 'Mutation', 'rs145204276', (13, 24))
11355	33925911	Moreover, the advanced tumor stage, larger tumor size and poor-differentiation cell status were observed in head and neck squamous cell carcinoma according to the database of TCGA, and the current study also found such a relationship between the GAS5 SNP rs145204276 and the above clinicopathological characteristics.	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (108, 145))	('neck squamous cell carcinoma', 'Disease', (117, 145))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('TC', 'Chemical', 'MESH:D013667', (175, 177))	('rs145204276', 'Var', (255, 266))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (117, 145))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (122, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Disease', (23, 28))	('tumor', 'Disease', (43, 48))	('rs145204276', 'Mutation', 'rs145204276', (255, 266))
11356	33925911	The similar outcomes in our study and the database of TCGA should further strengthen the relationship between GAS5 SNP rs145204276 and the three clinicopathological characteristics of oral cancer, which may be because of a carcinogenic effect of GAS5 SNP rs145204276.	('TC', 'Chemical', 'MESH:D013667', (54, 56))	('rs145204276', 'Var', (119, 130))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('carcinogenic', 'Disease', 'MESH:D063646', (223, 235))	('oral cancer', 'Disease', 'MESH:D009369', (184, 195))	('carcinogenic', 'Disease', (223, 235))	('rs145204276', 'Var', (255, 266))	('GAS5', 'Gene', (110, 114))	('rs145204276', 'Mutation', 'rs145204276', (119, 130))	('rs145204276', 'Mutation', 'rs145204276', (255, 266))	('oral cancer', 'Disease', (184, 195))
11359	33925911	Such differences may lead to inconsistencies in the significant influence of GAS5 SNP rs145204276 on oral cancers between the current study and the results of TCGA.	('rs145204276', 'Mutation', 'rs145204276', (86, 97))	('oral cancers', 'Disease', (101, 113))	('cancers', 'Phenotype', 'HP:0002664', (106, 113))	('rs145204276', 'Var', (86, 97))	('TC', 'Chemical', 'MESH:D013667', (159, 161))	('oral cancers', 'Disease', 'MESH:D009369', (101, 113))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
11360	33925911	Regarding the differences between the study group and the control group in the current study, no difference of GAS5 SNP distribution frequency was found between the two groups for either GAS5 SNP rs145204276 or GAS5 SNP rs55829688.	('rs55829688', 'Mutation', 'rs55829688', (220, 230))	('rs145204276', 'Mutation', 'rs145204276', (196, 207))	('rs145204276', 'Var', (196, 207))	('rs55829688', 'Var', (220, 230))
11361	33925911	This phenomenon may imply that the GAS5 polymorphism is not a risk factor for oral cancer development in a normal population, but rather a predisposing factor for tumor progression in those with pre-existing oral cancer.	('oral cancer', 'Disease', (208, 219))	('men', 'Species', '9606', (10, 13))	('oral cancer', 'Disease', (78, 89))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('men', 'Species', '9606', (97, 100))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('polymorphism', 'Var', (40, 52))	('oral cancer', 'Disease', 'MESH:D009369', (208, 219))	('tumor', 'Disease', (163, 168))	('oral cancer', 'Disease', 'MESH:D009369', (78, 89))	('GAS5', 'Gene', (35, 39))
11362	33925911	Interestingly, the numbers of GAS5 SNP variant types, whether in rs145204276 or rs55829688, were more than the GAS5 SNP wild type in both the study and control groups, which indicates that the etiology needs further study.	('rs145204276', 'Mutation', 'rs145204276', (65, 76))	('rs55829688', 'Mutation', 'rs55829688', (80, 90))	('rs55829688', 'Var', (80, 90))	('GAS5', 'Gene', (30, 34))	('more', 'PosReg', (97, 101))	('rs145204276', 'Var', (65, 76))
11369	33925911	In conclusion, the presence of the GAS5 SNP rs145204276 variant is correlated with a poor-differentiation cell status in oral cancer in males.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('oral cancer', 'Disease', 'MESH:D009369', (121, 132))	('poor-differentiation cell status', 'CPA', (85, 117))	('rs145204276', 'Var', (44, 55))	('rs145204276', 'Mutation', 'rs145204276', (44, 55))	('oral cancer', 'Disease', (121, 132))
11370	33925911	Furthermore, a worse tumor stage and tumor size was found in the non-alcohol-drinking group with oral cancer and the GAS5 SNP rs145204276 variant.	('rs145204276', 'Mutation', 'rs145204276', (126, 137))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('alcohol-drinking', 'Phenotype', 'HP:0030955', (69, 85))	('tumor', 'Disease', (21, 26))	('oral cancer', 'Disease', 'MESH:D009369', (97, 108))	('rs145204276', 'Var', (126, 137))	('tumor', 'Disease', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('alcohol', 'Chemical', 'MESH:D000438', (69, 76))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('oral cancer', 'Disease', (97, 108))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
11372	33925911	Further randomized-controlled trials to evaluate whether the GAS5 SNP rs145204276 variant will affect the treatment outcome of oral cancer are mandatory.	('oral cancer', 'Disease', (127, 138))	('men', 'Species', '9606', (111, 114))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('affect', 'Reg', (95, 101))	('rs145204276', 'Var', (70, 81))	('oral cancer', 'Disease', 'MESH:D009369', (127, 138))	('rs145204276', 'Mutation', 'rs145204276', (70, 81))
11478	33329726	This happened for GSE14520(U133B), GSE6919(U95B and C), and GSE 6344(U133B).	('GSE', 'Gene', '317782', (18, 21))	('GSE', 'Gene', (18, 21))	('GSE6919', 'Chemical', '-', (35, 42))	('B', 'Chemical', 'MESH:D001895', (73, 74))	('B', 'Chemical', 'MESH:D001895', (46, 47))	('GSE', 'Gene', (60, 63))	('GSE', 'Gene', '317782', (60, 63))	('U133B', 'Var', (27, 32))	('U133B', 'Var', (69, 74))	('GSE', 'Gene', '317782', (35, 38))	('GSE', 'Gene', (35, 38))	('B', 'Chemical', 'MESH:D001895', (31, 32))
11537	33329726	In this sense, the 33 overexpressed genes used as input for the network construction were related to GOs deeply associated to all cancers, like a positive induction of cell cycle, deregulation of DNA repair, proteolysis, and kinase-related signaling pathways (Figure 2C and Supplementary Figure 1, Supplementary Table 16) (Hanahan and Weinberg,; Pickup et al.,; Sanchez-Vega et al.,).	('kinase-related signaling pathways', 'Pathway', (225, 258))	('cancers', 'Phenotype', 'HP:0002664', (130, 137))	('cell cycle', 'CPA', (168, 178))	('to', 'Gene', '6999', (98, 100))	('cancers', 'Disease', (130, 137))	('proteolysis', 'CPA', (208, 219))	('cancers', 'Disease', 'MESH:D009369', (130, 137))	('deregulation', 'Var', (180, 192))	('to', 'Gene', '6999', (123, 125))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('DNA repair', 'Protein', (196, 206))
11601	33329726	BRCA patients with high expression of CTHRC1 had shorter lifespans (HR = 1.7) however.	('CTHRC1', 'Gene', (38, 44))	('pan', 'Gene', '51816', (62, 65))	('patients', 'Species', '9606', (5, 13))	('BRCA', 'Gene', (0, 4))	('high expression', 'Var', (19, 34))	('shorter', 'NegReg', (49, 56))	('CTHRC1', 'Gene', '115908', (38, 44))	('BRCA', 'Phenotype', 'HP:0003002', (0, 4))	('pan', 'Gene', (62, 65))	('BRCA', 'Gene', '672', (0, 4))
11641	32912174	Factors associated with decreased risk of death included female sex and epidermal growth factor receptor gene (EGFR)/anaplastic lymphoma kinase gene (ALK) mutations/rearrangements; factors associated with increased risk of death included older age and stage IV disease.	('decreased', 'NegReg', (24, 33))	('ALK', 'Gene', (150, 153))	('anaplastic lymphoma', 'Disease', 'MESH:D017728', (117, 136))	('epidermal growth factor receptor gene', 'Gene', '1956', (72, 109))	('EGFR', 'Gene', '1956', (111, 115))	('stage IV disease', 'Disease', 'MESH:D058625', (252, 268))	('death', 'Disease', 'MESH:D003643', (42, 47))	('death', 'Disease', 'MESH:D003643', (223, 228))	('mutations/rearrangements', 'Var', (155, 179))	('death', 'Disease', (42, 47))	('EGFR', 'Gene', (111, 115))	('death', 'Disease', (223, 228))	('stage IV disease', 'Disease', (252, 268))	('ALK', 'Gene', '238', (150, 153))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (117, 136))	('epidermal growth factor receptor gene', 'Gene', (72, 109))	('lymphoma', 'Phenotype', 'HP:0002665', (128, 136))	('anaplastic lymphoma', 'Disease', (117, 136))
11643	32912174	Platinum-based chemotherapy was the most common first-line therapy (non-squamous cell carcinoma [NSQ]: 72.9%; squamous cell carcinoma [SQ] 87.3%, 55/63; patients with EGFR/ALK mutations/rearrangements primarily received tyrosine kinase inhibitors).	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (72, 95))	('ALK', 'Gene', (172, 175))	('tyrosine kinase', 'Gene', (220, 235))	('Platinum', 'Chemical', 'MESH:D010984', (0, 8))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (110, 133))	('tyrosine kinase', 'Gene', '7294', (220, 235))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (72, 95))	('SQ', 'Phenotype', 'HP:0002860', (98, 100))	('mutations/rearrangements', 'Var', (176, 200))	('NSQ', 'Chemical', '-', (97, 100))	('EGFR', 'Gene', (167, 171))	('SQ', 'Phenotype', 'HP:0002860', (135, 137))	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('squamous cell carcinoma', 'Disease', (72, 95))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (110, 133))	('patients', 'Species', '9606', (153, 161))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('squamous cell carcinoma', 'Disease', (110, 133))	('EGFR', 'Gene', '1956', (167, 171))	('ALK', 'Gene', '238', (172, 175))
11655	32912174	Tyrosine kinase inhibitors (TKIs) targeting activating mutations in the epidermal growth factor receptor gene (EGFR) or rearrangements in the anaplastic lymphoma kinase gene (ALK) have resulted in improved efficacy versus chemotherapy in patients with NSCLC who have these mutations/rearrangements.	('rearrangements', 'Var', (120, 134))	('anaplastic lymphoma', 'Disease', (142, 161))	('EGFR', 'Gene', '1956', (111, 115))	('Tyrosine kinase', 'Gene', '7294', (0, 15))	('epidermal growth factor receptor gene', 'Gene', (72, 109))	('NSCLC', 'Disease', 'MESH:D002289', (252, 257))	('lymphoma', 'Phenotype', 'HP:0002665', (153, 161))	('epidermal growth factor receptor gene', 'Gene', '1956', (72, 109))	('Tyrosine kinase', 'Gene', (0, 15))	('improved', 'PosReg', (197, 205))	('NSCLC', 'Disease', (252, 257))	('mutations', 'Var', (55, 64))	('NSCLC', 'Phenotype', 'HP:0030358', (252, 257))	('anaplastic lymphoma', 'Disease', 'MESH:D017728', (142, 161))	('EGFR', 'Gene', (111, 115))	('efficacy', 'MPA', (206, 214))	('patients', 'Species', '9606', (238, 246))	('ALK', 'Gene', '238', (175, 178))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (142, 161))	('activating', 'PosReg', (44, 54))	('ALK', 'Gene', (175, 178))	('SCLC', 'Phenotype', 'HP:0030357', (253, 257))
11690	32912174	The impact of age, sex, EGFR/ALK mutational/rearrangement status, histology, disease stage, and brain metastases on OS were also assessed using a multivariate Cox model; hazard ratios (HRs) and 95% CIs were calculated for all variables.	('EGFR', 'Gene', '1956', (24, 28))	('ALK', 'Gene', (29, 32))	('brain metastases', 'Disease', (96, 112))	('EGFR', 'Gene', (24, 28))	('OS', 'Chemical', '-', (116, 118))	('ALK', 'Gene', '238', (29, 32))	('mutational/rearrangement', 'Var', (33, 57))	('brain metastases', 'Disease', 'MESH:D009362', (96, 112))
11698	32912174	The proportion of patients with NSQ who were tested for biomarkers during the study period increased marginally for EGFR mutations (from 83.8% [361/431] in 2012-2014 to 88.6% [256/289] in 2015-2016) and substantially for ALK rearrangements (from 12.3% [53/431] in 2012-2014 to 52.6% [152/289] in 2015-2016).	('ALK', 'Gene', (221, 224))	('SQ', 'Phenotype', 'HP:0002860', (33, 35))	('mutations', 'Var', (121, 130))	('NSQ', 'Disease', (32, 35))	('ALK', 'Gene', '238', (221, 224))	('patients', 'Species', '9606', (18, 26))	('EGFR', 'Gene', '1956', (116, 120))	('EGFR', 'Gene', (116, 120))	('NSQ', 'Chemical', '-', (32, 35))
11699	32912174	Among the 617 patients with NSQ tested for EGFR mutations, 124 (20.1%) had an EGFR mutation (Additional file 1: Table S3).	('SQ', 'Phenotype', 'HP:0002860', (29, 31))	('mutation', 'Var', (83, 91))	('EGFR', 'Gene', '1956', (43, 47))	('NSQ', 'Chemical', '-', (28, 31))	('EGFR', 'Gene', '1956', (78, 82))	('EGFR', 'Gene', (78, 82))	('patients', 'Species', '9606', (14, 22))	('EGFR', 'Gene', (43, 47))	('mutations', 'Var', (48, 57))
11707	32912174	When further stratifying patients with NSQ by EGFR/ALK mutational/rearrangement status, median OS (IQR) was 16.3 (6.3-28.5) months in those with EGFR or ALK mutations/rearrangements and 6.9 (2.8-15.0) months in those with wildtype EGFR and ALK (Fig.	('NSQ', 'Chemical', '-', (39, 42))	('ALK', 'Gene', '238', (51, 54))	('ALK', 'Gene', (153, 156))	('mutations/rearrangements', 'Var', (157, 181))	('ALK', 'Gene', '238', (240, 243))	('EGFR', 'Gene', '1956', (145, 149))	('EGFR', 'Gene', '1956', (46, 50))	('SQ', 'Phenotype', 'HP:0002860', (40, 42))	('EGFR', 'Gene', '1956', (231, 235))	('EGFR', 'Gene', (145, 149))	('ALK', 'Gene', (240, 243))	('ALK', 'Gene', (51, 54))	('EGFR', 'Gene', (46, 50))	('ALK', 'Gene', '238', (153, 156))	('patients', 'Species', '9606', (25, 33))	('EGFR', 'Gene', (231, 235))	('OS', 'Chemical', '-', (95, 97))
11709	32912174	The risk of death within 2 years of diagnosis was reduced for female patients (HR [95% CI]: 0.83 [0.70-0.996]), as well as for patients having NSQ with EGFR or ALK mutations/rearrangements versus wildtype EGFR and ALK (HR [95% CI]: 0.49 [0.38-0.63]).	('ALK', 'Gene', (160, 163))	('ALK', 'Gene', (214, 217))	('mutations/rearrangements', 'Var', (164, 188))	('death', 'Disease', (12, 17))	('NSQ', 'Chemical', '-', (143, 146))	('EGFR', 'Gene', '1956', (152, 156))	('EGFR', 'Gene', '1956', (205, 209))	('EGFR', 'Gene', (205, 209))	('ALK', 'Gene', '238', (160, 163))	('patients', 'Species', '9606', (127, 135))	('patients', 'Species', '9606', (69, 77))	('SQ', 'Phenotype', 'HP:0002860', (144, 146))	('reduced', 'NegReg', (50, 57))	('EGFR', 'Gene', (152, 156))	('ALK', 'Gene', '238', (214, 217))	('NSQ', 'Disease', (143, 146))	('death', 'Disease', 'MESH:D003643', (12, 17))
11718	32912174	The SACT regimens administered to patients with NSQ varied according to EGFR or ALK mutational/rearrangement status.	('SQ', 'Phenotype', 'HP:0002860', (49, 51))	('EGFR', 'Gene', '1956', (72, 76))	('SACT', 'Chemical', '-', (4, 8))	('NSQ', 'Chemical', '-', (48, 51))	('ALK', 'Gene', '238', (80, 83))	('EGFR', 'Gene', (72, 76))	('mutational/rearrangement', 'Var', (84, 108))	('patients', 'Species', '9606', (34, 42))	('ALK', 'Gene', (80, 83))	('NSQ', 'Disease', (48, 51))
11719	32912174	Among the 60 patients with EGFR or ALK mutations/rearrangements, 44 (73.3%) received a TKI alone, including 26 patients (43.3%) receiving erlotinib and 16 (26.7%) receiving gefitinib; the remaining 16 patients (26.7%) received platinum doublet chemotherapy, mainly cisplatin or carboplatin with pemetrexed.	('patients', 'Species', '9606', (201, 209))	('platinum', 'Chemical', 'MESH:D010984', (227, 235))	('EGFR', 'Gene', (27, 31))	('ALK', 'Gene', '238', (35, 38))	('pemetrexed', 'Chemical', 'MESH:D000068437', (295, 305))	('EGFR', 'Gene', '1956', (27, 31))	('cisplatin', 'Chemical', 'MESH:D002945', (265, 274))	('erlotinib', 'Chemical', 'MESH:D000069347', (138, 147))	('patients', 'Species', '9606', (13, 21))	('carboplatin', 'Chemical', 'MESH:D016190', (278, 289))	('gefitinib', 'Chemical', 'MESH:D000077156', (173, 182))	('ALK', 'Gene', (35, 38))	('mutations/rearrangements', 'Var', (39, 63))	('patients', 'Species', '9606', (111, 119))
11729	32912174	In SACT-treated patients with NSQ, median OS (IQR) was 14.4 (4.7-not reached) months for patients with EGFR or ALK mutations/rearrangements (n = 60; EGFR mutation: 48/60; ALK rearrangement: 12/60) and 9.3 (4.4-17.9) months for patients with wildtype phenotype (n = 147).	('EGFR', 'Gene', '1956', (103, 107))	('OS', 'Chemical', '-', (42, 44))	('SACT', 'Chemical', '-', (3, 7))	('EGFR', 'Gene', (103, 107))	('ALK', 'Gene', '238', (111, 114))	('EGFR', 'Gene', '1956', (149, 153))	('ALK', 'Gene', (171, 174))	('NSQ', 'Disease', (30, 33))	('patients', 'Species', '9606', (16, 24))	('SQ', 'Phenotype', 'HP:0002860', (31, 33))	('mutations/rearrangements', 'Var', (115, 139))	('patients', 'Species', '9606', (89, 97))	('EGFR', 'Gene', (149, 153))	('ALK', 'Gene', '238', (171, 174))	('patients', 'Species', '9606', (227, 235))	('ALK', 'Gene', (111, 114))	('NSQ', 'Chemical', '-', (30, 33))
11731	32912174	Female sex and NSQ patients with EGFR or ALK mutations/rearrangements did not show a statistically significant association with a lower risk of death in SACT-treated patients; however, a trend was still apparent (Table 3).	('patients', 'Species', '9606', (19, 27))	('SQ', 'Phenotype', 'HP:0002860', (16, 18))	('death', 'Disease', 'MESH:D003643', (144, 149))	('mutations/rearrangements', 'Var', (45, 69))	('death', 'Disease', (144, 149))	('EGFR', 'Gene', '1956', (33, 37))	('ALK', 'Gene', (41, 44))	('patients', 'Species', '9606', (166, 174))	('EGFR', 'Gene', (33, 37))	('NSQ', 'Chemical', '-', (15, 18))	('ALK', 'Gene', '238', (41, 44))	('SACT', 'Chemical', '-', (153, 157))
11740	32912174	At IPO-Porto, testing for EGFR mutations increased only marginally during the study period because it was already widely used in clinical practice in 2012.	('EGFR', 'Gene', '1956', (26, 30))	('EGFR', 'Gene', (26, 30))	('IPO-Porto', 'Chemical', '-', (3, 12))	('mutations', 'Var', (31, 40))
11742	32912174	It is noteworthy, however, that even in the 2015-2016 period, only approximately 40 to 50% of patients were tested for ALK or ROS rearrangements compared with 89% for EGFR mutations, which may reflect the fact that crizotinib was only reimbursed for second-line treatment in Portugal during this time.	('mutations', 'Var', (172, 181))	('patients', 'Species', '9606', (94, 102))	('ALK', 'Gene', (119, 122))	('crizotinib', 'Chemical', 'MESH:D000077547', (215, 225))	('ROS', 'Gene', (126, 129))	('EGFR', 'Gene', '1956', (167, 171))	('ALK', 'Gene', '238', (119, 122))	('rearrangements', 'Var', (130, 144))	('EGFR', 'Gene', (167, 171))	('ROS', 'Chemical', '-', (126, 129))
11743	32912174	Testing for ALK and/or ROS rearrangements has increased since that time likely as a result of more recent expansions of the reimbursement policy in Portugal (e.g., crizotinib was approved for reimbursement for first-line treatment in December 2017) and is expected to continue this increase as newer targeted agents become available.	('ALK', 'Gene', (12, 15))	('ROS', 'Gene', (23, 26))	('increased', 'PosReg', (46, 55))	('rearrangements', 'Var', (27, 41))	('ALK', 'Gene', '238', (12, 15))	('crizotinib', 'Chemical', 'MESH:D000077547', (164, 174))	('ROS', 'Chemical', '-', (23, 26))	('crizotinib', 'Var', (164, 174))
11745	32912174	Of the patients at IPO-Porto with NSQ who were tested for EGFR or ALK mutations/rearrangements, 20.1 and 8.8%, respectively, were found to have mutations/rearrangements.	('EGFR', 'Gene', '1956', (58, 62))	('ALK', 'Gene', '238', (66, 69))	('mutations/rearrangements', 'Var', (144, 168))	('EGFR', 'Gene', (58, 62))	('NSQ', 'Chemical', '-', (34, 37))	('ALK', 'Gene', (66, 69))	('mutations/rearrangements', 'Var', (70, 94))	('IPO-Porto', 'Chemical', '-', (19, 28))	('SQ', 'Phenotype', 'HP:0002860', (35, 37))	('patients', 'Species', '9606', (7, 15))
11746	32912174	These rates are comparable to those reported in several observational studies conducted in Portugal and elsewhere in Europe in which rates ranged from 10 to 28% for EGFR mutations, and from 3 to 12% for ALK rearrangements.	('EGFR', 'Gene', (165, 169))	('mutations', 'Var', (170, 179))	('ALK', 'Gene', (203, 206))	('ALK', 'Gene', '238', (203, 206))	('EGFR', 'Gene', '1956', (165, 169))
11751	32912174	The presence of EGFR or ALK mutations/rearrangements was also significantly associated with a reduced risk of death in the IPO-Porto patient population.	('IPO-Porto', 'Chemical', '-', (123, 132))	('ALK', 'Gene', '238', (24, 27))	('reduced', 'NegReg', (94, 101))	('patient', 'Species', '9606', (133, 140))	('mutations/rearrangements', 'Var', (28, 52))	('EGFR', 'Gene', '1956', (16, 20))	('ALK', 'Gene', (24, 27))	('death', 'Disease', 'MESH:D003643', (110, 115))	('death', 'Disease', (110, 115))	('presence', 'Var', (4, 12))	('EGFR', 'Gene', (16, 20))
11752	32912174	Other observational studies conducted in Portugal have also reported improved survival outcomes in patients with EGFR or ALK mutations/rearrangements versus in patients with a wildtype phenotype.	('survival', 'CPA', (78, 86))	('patients', 'Species', '9606', (160, 168))	('improved', 'PosReg', (69, 77))	('ALK', 'Gene', '238', (121, 124))	('patients', 'Species', '9606', (99, 107))	('EGFR', 'Gene', '1956', (113, 117))	('EGFR', 'Gene', (113, 117))	('mutations/rearrangements', 'Var', (125, 149))	('ALK', 'Gene', (121, 124))
11761	32912174	The first lines of therapy prescribed were most commonly platinum-based chemotherapy, except in patients with EGFR or ALK mutations/rearrangements, who were mostly treated with a TKI.	('mutations/rearrangements', 'Var', (122, 146))	('EGFR', 'Gene', '1956', (110, 114))	('EGFR', 'Gene', (110, 114))	('platinum', 'Chemical', 'MESH:D010984', (57, 65))	('ALK', 'Gene', '238', (118, 121))	('patients', 'Species', '9606', (96, 104))	('ALK', 'Gene', (118, 121))
11764	32912174	Of the patients receiving a second line of SACT, most received non-platinum-based chemotherapy or, in the case of patients with NSQ and EGFR or ALK mutations/rearrangements, a TKI.	('NSQ', 'Disease', (128, 131))	('EGFR', 'Gene', (136, 140))	('ALK', 'Gene', '238', (144, 147))	('ALK', 'Gene', (144, 147))	('mutations/rearrangements', 'Var', (148, 172))	('platinum', 'Chemical', 'MESH:D010984', (67, 75))	('NSQ', 'Chemical', '-', (128, 131))	('SQ', 'Phenotype', 'HP:0002860', (129, 131))	('patients', 'Species', '9606', (114, 122))	('EGFR', 'Gene', '1956', (136, 140))	('patients', 'Species', '9606', (7, 15))	('SACT', 'Chemical', '-', (43, 47))
11770	32912174	In the current analysis, it was also noted that OS outcomes were better in SACT-treated patients with NSQ who had EGFR or ALK mutations/rearrangements than in those who had wildtype EGFR and ALK (with a median of 14.4 months vs 9.3 months respectively).	('SACT', 'Chemical', '-', (75, 79))	('NSQ', 'Chemical', '-', (102, 105))	('OS', 'Chemical', '-', (48, 50))	('mutations/rearrangements', 'Var', (126, 150))	('EGFR', 'Gene', (182, 186))	('EGFR', 'Gene', '1956', (182, 186))	('patients', 'Species', '9606', (88, 96))	('EGFR', 'Gene', '1956', (114, 118))	('ALK', 'Gene', '238', (191, 194))	('ALK', 'Gene', (122, 125))	('better', 'PosReg', (65, 71))	('NSQ', 'Disease', (102, 105))	('SQ', 'Phenotype', 'HP:0002860', (103, 105))	('EGFR', 'Gene', (114, 118))	('ALK', 'Gene', (191, 194))	('ALK', 'Gene', '238', (122, 125))
11771	32912174	This was not found to be statistically significant in the multivariate model, however it is likely due to the limited sample size of SACT-treated population (adjusted OR of EGFR or ALK mutations/rearrangements vs wildtype being 0.68 [95% CI: 0.44-1.06]).	('SACT', 'Chemical', '-', (133, 137))	('mutations/rearrangements', 'Var', (185, 209))	('EGFR', 'Gene', '1956', (173, 177))	('ALK', 'Gene', (181, 184))	('EGFR', 'Gene', (173, 177))	('ALK', 'Gene', '238', (181, 184))
11772	32912174	This improved survival reflects the effectiveness of TKI therapies targeting EGFR/ALK mutations/rearrangements, which were used as initial treatment in 73% of patients with EGFR/ALK mutations/rearrangements during the study period.	('survival', 'MPA', (14, 22))	('ALK', 'Gene', (82, 85))	('mutations/rearrangements', 'Var', (86, 110))	('ALK', 'Gene', (178, 181))	('EGFR', 'Gene', '1956', (173, 177))	('improved', 'PosReg', (5, 13))	('EGFR', 'Gene', '1956', (77, 81))	('ALK', 'Gene', '238', (82, 85))	('ALK', 'Gene', '238', (178, 181))	('EGFR', 'Gene', (173, 177))	('patients', 'Species', '9606', (159, 167))	('EGFR', 'Gene', (77, 81))
11774	32912174	At IPO-Porto and elsewhere, the availability of second-generation TKIs may further improve survival outcomes in patients with EGFR or ALK mutations/rearrangements.	('EGFR', 'Gene', (126, 130))	('IPO-Porto', 'Chemical', '-', (3, 12))	('ALK', 'Gene', (134, 137))	('mutations/rearrangements', 'Var', (138, 162))	('patients', 'Species', '9606', (112, 120))	('survival outcomes', 'CPA', (91, 108))	('improve', 'PosReg', (83, 90))	('ALK', 'Gene', '238', (134, 137))	('EGFR', 'Gene', '1956', (126, 130))
11816	31811814	Notably, in tumors with mutations in the RAS pathway genes, hyperactivity of autophagy is indispensable to meet extraordinarily high demands of tumor cell metabolism.	('tumor', 'Disease', (144, 149))	('RAS pathway', 'Gene', (41, 52))	('hyperactivity of autophagy', 'Disease', (60, 86))	('hyperactivity', 'Phenotype', 'HP:0000752', (60, 73))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('hyperactivity of autophagy', 'Disease', 'MESH:C564093', (60, 86))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('mutations', 'Var', (24, 33))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('tumors', 'Disease', (12, 18))	('tumor', 'Disease', (12, 17))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('tumors', 'Disease', 'MESH:D009369', (12, 18))
11817	31811814	Consistently, lung tumors driven by the Brafv600E mutation in mouse models were highly sensitive to autophagy inhibition.	('mouse', 'Species', '10090', (62, 67))	('lung tumors', 'Disease', 'MESH:D008175', (14, 25))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('lung tumors', 'Disease', (14, 25))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('lung tumors', 'Phenotype', 'HP:0100526', (14, 25))	('Brafv600E', 'Var', (40, 49))
11819	31811814	Moreover, high expression levels of autophagy-related gene 10 (ATG10) were associated with an unfavorable prognosis in lung cancer.	('lung cancer', 'Disease', (119, 130))	('lung cancer', 'Phenotype', 'HP:0100526', (119, 130))	('autophagy-related gene 10', 'Gene', (36, 61))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('expression levels', 'MPA', (15, 32))	('ATG10', 'Gene', (63, 68))	('high', 'Var', (10, 14))	('autophagy-related gene 10', 'Gene', '83734', (36, 61))	('lung cancer', 'Disease', 'MESH:D008175', (119, 130))	('associated', 'Reg', (75, 85))	('ATG10', 'Gene', '83734', (63, 68))
11840	31811814	The frequent genetic alterations suggested the crucial roles of these genes in the development of lung cancer.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('lung cancer', 'Disease', (98, 109))	('lung cancer', 'Phenotype', 'HP:0100526', (98, 109))	('lung cancer', 'Disease', 'MESH:D008175', (98, 109))	('genetic alterations', 'Var', (13, 32))
11867	31811814	In the Bild cohort of 109 lung cancer patients (GSE3141), patients with smaller risk scores outperformed those with high risk in survival (HR=2.36, 95% CI=1.38-4.03, P=0.001652, maximum AUC=0.743) (Figure 7A, 7C, and 7E).	('GSE3141', 'Var', (48, 55))	('outperformed', 'PosReg', (92, 104))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('lung cancer', 'Disease', 'MESH:D008175', (26, 37))	('patients', 'Species', '9606', (38, 46))	('patients', 'Species', '9606', (58, 66))	('lung cancer', 'Disease', (26, 37))	('lung cancer', 'Phenotype', 'HP:0100526', (26, 37))	('7C', 'Chemical', 'MESH:C079788', (209, 211))
11901	31811814	Salinomycin was reported to induce apoptosis of NSCLC cells through inhibiting the AKT1-mTOR signaling pathway, accompanied by the activation of autophagy; blockage of autophagy augmented salinomycin-mediated apoptosis, suggesting that the autophagic response plays cytoprotective roles.	('autophagy', 'CPA', (168, 177))	('salinomycin', 'Chemical', 'MESH:C010327', (188, 199))	('augmented', 'PosReg', (178, 187))	('NSCLC', 'Disease', (48, 53))	('inhibiting', 'NegReg', (68, 78))	('blockage', 'Var', (156, 164))	('AKT1', 'Gene', '207', (83, 87))	('NSCLC', 'Disease', 'MESH:D002289', (48, 53))	('AKT1', 'Gene', (83, 87))	('autophagy', 'CPA', (145, 154))	('mTOR', 'Gene', (88, 92))	('mTOR', 'Gene', '2475', (88, 92))	('salinomycin-mediated', 'MPA', (188, 208))	('Salinomycin', 'Chemical', 'MESH:C010327', (0, 11))
11921	31811814	The prognostic gene signature was verified in the four independent lung cancer cohorts (GSE31210, GSE30219, GSE3141, and GSE8894).	('GSE31210', 'Var', (88, 96))	('GSE30219', 'Var', (98, 106))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('lung cancer', 'Disease', 'MESH:D008175', (67, 78))	('GSE8894', 'Var', (121, 128))	('GSE8894', 'Chemical', 'MESH:C045330', (121, 128))	('lung cancer', 'Disease', (67, 78))	('lung cancer', 'Phenotype', 'HP:0100526', (67, 78))	('GSE3141', 'Var', (108, 115))
12133	30774636	Our study shows that there is an increase of proportion of macrophages with high HLA-DR expression in tumor compared to distal lung.	('increase of proportion of macrophages', 'Phenotype', 'HP:0004311', (33, 70))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('increase', 'PosReg', (33, 41))	('high', 'Var', (76, 80))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))
12192	30421493	Immunohistochemistry assays showed that CD147 knockdown reduced the expression of Ki67 in xenograft tumors (P < 0.0001) (Figure 4F).	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('xenograft tumors', 'Disease', 'MESH:D009369', (90, 106))	('knockdown', 'Var', (46, 55))	('expression', 'MPA', (68, 78))	('reduced', 'NegReg', (56, 63))	('CD147', 'Gene', (40, 45))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('Ki67', 'Gene', (82, 86))	('xenograft tumors', 'Disease', (90, 106))
12194	30421493	In addition, our study demonstrated that CD147 knockdown significantly impaired the TNF-alpha induced NF-kappa B activation.	('activation', 'MPA', (113, 123))	('impaired', 'NegReg', (71, 79))	('TNF-alpha', 'Gene', '7124', (84, 93))	('knockdown', 'Var', (47, 56))	('TNF-alpha', 'Gene', (84, 93))	('CD147', 'Gene', (41, 46))
12197	28198667	Pan-cancer analysis of frequent DNA co-methylation patterns reveals consistent epigenetic landscape changes in multiple cancers DNA methylation is the major form of epigenetic modifications through which the cell regulates the gene expression and silencing.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('silencing', 'MPA', (247, 256))	('Pan-cancer', 'Disease', (0, 10))	('DNA', 'Var', (128, 131))	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('cancers', 'Phenotype', 'HP:0002664', (120, 127))	('Pan-cancer', 'Disease', 'MESH:C537931', (0, 10))	('regulates', 'Reg', (213, 222))	('cancers', 'Disease', (120, 127))	('cancers', 'Disease', 'MESH:D009369', (120, 127))
12203	28198667	We also found that genes commonly believed to be silenced via hypermethylation in cancers may still display highly variable methylation levels among cancer cells, and should be considered while using them as epigenetic biomarkers.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('cancer', 'Disease', (149, 155))	('hypermethylation', 'Var', (62, 78))	('cancers', 'Phenotype', 'HP:0002664', (82, 89))	('cancers', 'Disease', (82, 89))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('cancers', 'Disease', 'MESH:D009369', (82, 89))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('methylation levels', 'MPA', (124, 142))	('cancer', 'Disease', 'MESH:D009369', (149, 155))
12205	28198667	Aberrant DNA methylation pattern is a hallmark of cancer, and it has been speculated that DNA methylation change may play a role in cancer initiation, development, and drug resistance.	('play', 'Reg', (117, 121))	('role', 'Reg', (124, 128))	('drug resistance', 'Phenotype', 'HP:0020174', (168, 183))	('hallmark of cancer', 'Disease', 'MESH:D009369', (38, 56))	('Aberrant', 'Var', (0, 8))	('cancer initiation', 'Disease', (132, 149))	('cancer initiation', 'Disease', 'MESH:D009369', (132, 149))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('hallmark of cancer', 'Disease', (38, 56))	('DNA', 'MPA', (9, 12))
12207	28198667	It is generally believed that in cancer cells tumor suppressor genes are hypermethylated in the promoter region and are repressed, while oncogenes are hypomethylated and abnormally active.	('cancer', 'Disease', (33, 39))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Disease', (46, 51))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('abnormally active', 'Phenotype', 'HP:0000752', (170, 187))	('hypermethylated', 'Var', (73, 88))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
12223	28198667	These frequently identified co-methylation clusters may indicate common gene regulations in different cancer types.	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('co-methylation', 'Var', (28, 42))
12243	28198667	Figure 1c shows the highly correlated beta values of DNA methylation from Cluster 4 among COAD-450 patients, with each color line representing one gene from Cluster 4.	('patients', 'Species', '9606', (99, 107))	('methylation', 'Var', (57, 68))	('COAD', 'Disease', 'MESH:D029424', (90, 94))	('COAD', 'Disease', (90, 94))
12274	28198667	It is widely accepted that tumor suppressors are hypermethylated in their promoter region and repressed in tumor samples.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('tumor', 'Disease', (27, 32))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('hypermethylated', 'Var', (49, 64))	('tumor', 'Disease', 'MESH:D009369', (27, 32))
12275	28198667	The hypermethylation usually leads to silencing of the genes and a list of commonly repressed and silenced genes from five types of cancer (BRCA, LUCA, PC, Leukemia and CRC) can be found in literature.	('BRCA', 'Gene', '672', (140, 144))	('cancer', 'Disease', (132, 138))	('CRC', 'Disease', (169, 172))	('Leukemia', 'Phenotype', 'HP:0001909', (156, 164))	('silencing', 'MPA', (38, 47))	('BRCA', 'Gene', (140, 144))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('LUCA', 'Disease', (146, 150))	('Leukemia', 'Disease', 'MESH:D007938', (156, 164))	('CRC', 'Disease', 'MESH:D015179', (169, 172))	('leads to', 'Reg', (29, 37))	('Leukemia', 'Disease', (156, 164))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('hypermethylation', 'Var', (4, 20))
12280	28198667	One of the major finings in this study is the existence of pan-cancer co-methylation clusters.	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('co-methylation', 'Var', (70, 84))	('cancer', 'Disease', (63, 69))	('cancer', 'Disease', 'MESH:D009369', (63, 69))
12285	28198667	There are four major co-methylation clusters among the 11 types of cancer studied.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('co-methylation', 'Var', (21, 35))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('cancer', 'Disease', (67, 73))
12288	28198667	Among them, only CDH1 was previously considered to be cancer epigenetic-biomarkers, and reported silenced by hypermethylation in breast, colon, lung, leukemia and prostate cancer (Table 2,).	('lung', 'Disease', (144, 148))	('silenced', 'NegReg', (97, 105))	('CDH1', 'Gene', '999', (17, 21))	('leukemia', 'Phenotype', 'HP:0001909', (150, 158))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('colon', 'Disease', (137, 142))	('cancer', 'Disease', (172, 178))	('cancer', 'Disease', (54, 60))	('leukemia and prostate cancer', 'Disease', 'MESH:D011471', (150, 178))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('prostate cancer', 'Phenotype', 'HP:0012125', (163, 178))	('hypermethylation', 'Var', (109, 125))	('CDH1', 'Gene', (17, 21))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('breast', 'Disease', (129, 135))
12298	28198667	The loss of imprinting of IGF2 and H19 from parental alleles were previously linked to cervical cancer; Loss of imprinting of H19 was also linked to lung cancer and hepatoblastoma.	('lung cancer', 'Disease', 'MESH:D008175', (149, 160))	('H19', 'Gene', (126, 129))	('H19', 'Gene', (35, 38))	('IGF2', 'Gene', '3481', (26, 30))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('linked', 'Reg', (139, 145))	('hepatoblastoma', 'Disease', (165, 179))	('hepatoblastoma', 'Phenotype', 'HP:0002884', (165, 179))	('Loss of', 'Var', (104, 111))	('lung cancer', 'Phenotype', 'HP:0100526', (149, 160))	('lung cancer', 'Disease', (149, 160))	('linked', 'Reg', (77, 83))	('IGF2', 'Gene', (26, 30))	('cervical cancer', 'Disease', 'MESH:D002583', (87, 102))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('hepatoblastoma', 'Disease', 'MESH:D018197', (165, 179))	('cervical cancer', 'Disease', (87, 102))
12306	28198667	The results from this study lead to interesting biological question on the molecular mechanism for co-methylation, while at the same time will provide insights and new directions for potential cancer epigenetic marker and therapeutic target findings.	('cancer', 'Disease', (193, 199))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('co-methylation', 'Var', (99, 113))
12336	24794706	Loss of Lkb1 and Pten Leads to Lung Squamous Cell Carcinoma with Elevated PD-L1 Expression Lung squamous cell carcinoma (SCC) is a deadly disease for which current treatments are inadequate.	('SCC', 'Phenotype', 'HP:0002860', (121, 124))	('Lung Squamous Cell Carcinoma', 'Phenotype', 'HP:0030359', (31, 59))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (96, 119))	('Lung Squamous Cell Carcinoma', 'Disease', (31, 59))	('Pten', 'Gene', '5728', (17, 21))	('Pten', 'Gene', (17, 21))	('Leads to', 'Reg', (22, 30))	('SCC', 'Gene', '6317', (121, 124))	('Carcinoma', 'Phenotype', 'HP:0030731', (50, 59))	('squamous cell carcinoma', 'Disease', (96, 119))	('Lkb1', 'Gene', (8, 12))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('SCC', 'Gene', (121, 124))	('Lkb1', 'Gene', '6794', (8, 12))	('Loss', 'Var', (0, 4))	('Lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (91, 119))	('PD-L1', 'Gene', (74, 79))	('Elevated', 'PosReg', (65, 73))	('PD-L1', 'Gene', '29126', (74, 79))	('Lung Squamous Cell Carcinoma', 'Disease', 'MESH:D002294', (31, 59))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (36, 59))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (96, 119))
12337	24794706	We demonstrate that biallelic inactivation of Lkb1 and Pten in the mouse lung leads to SCC that recapitulates the histology, gene expression, and microenvironment found in human disease.	('leads to', 'Reg', (78, 86))	('biallelic inactivation', 'Var', (20, 42))	('SCC', 'Gene', (87, 90))	('human', 'Species', '9606', (172, 177))	('SCC', 'Phenotype', 'HP:0002860', (87, 90))	('SCC', 'Gene', '6317', (87, 90))	('mouse', 'Species', '10090', (67, 72))	('rat', 'Species', '10116', (10, 13))	('Pten', 'Gene', (55, 59))	('Lkb1', 'Gene', (46, 50))
12347	24794706	Currently, the field lacks a mouse model in which the introduction of genetic alterations found in human squamous lung cancers leads to tumors of purely squamous phenotype.	('tumors', 'Disease', (136, 142))	('tumors', 'Disease', 'MESH:D009369', (136, 142))	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('lung cancers', 'Phenotype', 'HP:0100526', (114, 126))	('leads to', 'Reg', (127, 135))	('cancers', 'Phenotype', 'HP:0002664', (119, 126))	('squamous lung cancers', 'Disease', (105, 126))	('human', 'Species', '9606', (99, 104))	('rat', 'Species', '10116', (82, 85))	('mouse', 'Species', '10090', (29, 34))	('lung cancer', 'Phenotype', 'HP:0100526', (114, 125))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('squamous lung cancers', 'Disease', 'MESH:D008175', (105, 126))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('genetic alterations', 'Var', (70, 89))
12348	24794706	We previously reported that simultaneous activation of KrasG12D(Kras) and inactivation of Lkb1 (also known as serine-threonine kinase 11 [Stk11]) in the lung gave rise to multiple lung cancer histologies, including SCCs; however, KRAS mutations are very rarely found in human squamous lung tumors.	('serine-threonine kinase 11', 'Gene', (110, 136))	('SCC', 'Phenotype', 'HP:0002860', (215, 218))	('Lkb1', 'Gene', (90, 94))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('KrasG12D', 'Var', (55, 63))	('activation', 'PosReg', (41, 51))	('squamous lung tumors', 'Disease', 'MESH:D002294', (276, 296))	('human', 'Species', '9606', (270, 275))	('SCC', 'Gene', '6317', (215, 218))	('squamous lung tumors', 'Disease', (276, 296))	('inactivation', 'Var', (74, 86))	('tumors', 'Phenotype', 'HP:0002664', (290, 296))	('lung tumors', 'Phenotype', 'HP:0100526', (285, 296))	('KRAS', 'Gene', '3845', (230, 234))	('squamous lung tumors', 'Phenotype', 'HP:0030359', (276, 296))	('gave rise to', 'Reg', (158, 170))	('lung tumor', 'Phenotype', 'HP:0100526', (285, 295))	('SCC', 'Gene', (215, 218))	('tumor', 'Phenotype', 'HP:0002664', (290, 295))	('KRAS', 'Gene', (230, 234))	('serine-threonine kinase 11', 'Gene', '6794', (110, 136))	('multiple lung cancer', 'Disease', 'MESH:D008175', (171, 191))	('multiple lung cancer', 'Disease', (171, 191))	('lung cancer', 'Phenotype', 'HP:0100526', (180, 191))
12352	24794706	Despite indications that Lkb1 loss may be central to the generation of squamous cell cancers, deletion of Lkb1 alone is unable to drive tumor formation.	('deletion', 'Var', (94, 102))	('cancers', 'Phenotype', 'HP:0002664', (85, 92))	('Lkb1', 'Gene', (25, 29))	('Lkb1', 'Gene', (106, 110))	('rat', 'Species', '10116', (61, 64))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('squamous cell cancers', 'Disease', (71, 92))	('squamous cell cancers', 'Phenotype', 'HP:0002860', (71, 92))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('loss', 'NegReg', (30, 34))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('squamous cell cancers', 'Disease', 'MESH:D002294', (71, 92))	('tumor', 'Disease', (136, 141))
12353	24794706	PTEN (phosphatase and tensin homolog) is another commonly mutated, deleted, or epigenetically silenced tumor suppressor in human lung cancers.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('lung cancer', 'Phenotype', 'HP:0100526', (129, 140))	('lung cancers', 'Disease', 'MESH:D008175', (129, 141))	('cancers', 'Phenotype', 'HP:0002664', (134, 141))	('human', 'Species', '9606', (123, 128))	('tumor', 'Disease', (103, 108))	('lung cancers', 'Phenotype', 'HP:0100526', (129, 141))	('epigenetically', 'Var', (79, 93))	('lung cancers', 'Disease', (129, 141))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('PTEN', 'Gene', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('PTEN', 'Gene', '5728', (0, 4))
12355	24794706	PTEN negatively regulates the phosphatidylinositol 3-kinase (PI3K)/AKT pathway, and PI3K pathway gene alterations are found in more than half of human lung SCCs.	('AKT', 'Gene', '207', (67, 70))	('regulates', 'Reg', (16, 25))	('PI3K pathway', 'Pathway', (84, 96))	('phosphatidylinositol 3-kinase', 'Gene', '5290', (30, 59))	('rat', 'Species', '10116', (106, 109))	('AKT', 'Gene', (67, 70))	('human', 'Species', '9606', (145, 150))	('negatively', 'NegReg', (5, 15))	('SCC', 'Gene', (156, 159))	('SCC', 'Phenotype', 'HP:0002860', (156, 159))	('phosphatidylinositol 3-kinase', 'Gene', (30, 59))	('alterations', 'Var', (102, 113))	('PTEN', 'Gene', (0, 4))	('SCC', 'Gene', '6317', (156, 159))	('PTEN', 'Gene', '5728', (0, 4))
12356	24794706	In the mouse model, Pten deletion alone in airway basal cells can initiate lung tumor formation, but with low tumor incidence, long latency, and mixed ADC and SCC phenotype.	('initiate', 'PosReg', (66, 74))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('mouse', 'Species', '10090', (7, 12))	('lung tumor', 'Disease', (75, 85))	('SCC', 'Gene', (159, 162))	('SCC', 'Phenotype', 'HP:0002860', (159, 162))	('lung tumor', 'Disease', 'MESH:D008175', (75, 85))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('deletion', 'Var', (25, 33))	('low tumor', 'Disease', 'MESH:D009800', (106, 115))	('SCC', 'Gene', '6317', (159, 162))	('Pten', 'Gene', (20, 24))	('lung tumor', 'Phenotype', 'HP:0100526', (75, 85))	('low tumor', 'Disease', (106, 115))
12363	24794706	In the tumor microenvironment, accumulated MDSCs are thought to promote tumor progression through enhancing matrix degradation, tumor cell proliferation, metastasis, and angiogenesis.	('enhancing', 'PosReg', (98, 107))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('angiogenesis', 'CPA', (170, 182))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('promote', 'PosReg', (64, 71))	('rat', 'Species', '10116', (146, 149))	('tumor', 'Disease', (7, 12))	('tumor', 'Disease', (72, 77))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('metastasis', 'CPA', (154, 164))	('tumor', 'Disease', (128, 133))	('tumor', 'Disease', 'MESH:D009369', (7, 12))	('MDSCs', 'Var', (43, 48))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('matrix degradation', 'CPA', (108, 126))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
12364	24794706	MDSCs have also been shown to antagonize effector T cell function, support the generation of immunosuppressive T cell populations, and inhibit the lysis of tumor cells by cytotoxic T cells or natural killer (NK) cells.	('rat', 'Species', '10116', (83, 86))	('MDSCs', 'Var', (0, 5))	('support', 'PosReg', (67, 74))	('inhibit', 'NegReg', (135, 142))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('immunosuppressive T cell populations', 'MPA', (93, 129))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('antagonize', 'NegReg', (30, 40))	('tumor', 'Disease', (156, 161))	('effector T cell function', 'CPA', (41, 65))
12367	24794706	The PD-1/PD-L1 interaction inhibits CD8+ cytotoxic T lymphocyte (CTL) proliferation, survival, and effector function and can induce apoptosis of tumor-infiltrating T cells; PD-1/PD-L1 interactions can also promote the differentiation of CD4+ T cells into FOXP3+ Tregs, which are known to further suppress the immune system and cause peripheral immune tolerance in lung cancer patients.	('CD4', 'Gene', (237, 240))	('immune system', 'CPA', (309, 322))	('suppress the immune system', 'Phenotype', 'HP:0002721', (296, 322))	('rat', 'Species', '10116', (77, 80))	('lung cancer', 'Disease', (364, 375))	('tumor', 'Disease', (145, 150))	('promote', 'PosReg', (206, 213))	('rat', 'Species', '10116', (157, 160))	('Tregs', 'Chemical', '-', (262, 267))	('interactions', 'Var', (184, 196))	('differentiation', 'CPA', (218, 233))	('CD8', 'Gene', '925', (36, 39))	('apoptosis', 'CPA', (132, 141))	('patients', 'Species', '9606', (376, 384))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('inhibits', 'NegReg', (27, 35))	('FOXP3', 'Gene', (255, 260))	('induce', 'Reg', (125, 131))	('survival', 'CPA', (85, 93))	('CD8', 'Gene', (36, 39))	('lung cancer', 'Disease', 'MESH:D008175', (364, 375))	('CD4', 'Gene', '920', (237, 240))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('lung cancer', 'Phenotype', 'HP:0100526', (364, 375))	('cancer', 'Phenotype', 'HP:0002664', (369, 375))	('FOXP3', 'Gene', '50943', (255, 260))	('cause', 'PosReg', (327, 332))
12368	24794706	Ectopic PD-L1 expression in tumor cells in a syngeneic transplant model facilitated the escape of the tumor cells from CTL control.	('tumor', 'Disease', (28, 33))	('PD-L1', 'Gene', (8, 13))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('Ectopic', 'Var', (0, 7))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('facilitated', 'PosReg', (72, 83))	('escape', 'CPA', (88, 94))	('tumor', 'Disease', (102, 107))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('Ectopic PD', 'Phenotype', 'HP:0006699', (0, 10))
12372	24794706	SCA1+ cells, located at the bronchioalveolar duct junction, are hyperproliferative in response to both oncogenic Kras and deletion of Pten, suggesting that they are susceptible to neoplastic transformation.	('Pten', 'Gene', (134, 138))	('deletion', 'Var', (122, 130))	('rat', 'Species', '10116', (76, 79))
12376	24794706	Using conditional knockout alleles of both Lkb1 and Pten, we found that biallelic inactivation of these two tumor suppressors in the lung resulted in lung tumors with a purely squamous cell phenotype.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('biallelic inactivation', 'Var', (72, 94))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('Lkb1', 'Gene', (43, 47))	('tumors', 'Phenotype', 'HP:0002664', (155, 161))	('lung tumors', 'Phenotype', 'HP:0100526', (150, 161))	('tumor', 'Disease', (155, 160))	('tumor', 'Disease', (108, 113))	('lung tumors', 'Disease', (150, 161))	('lung tumors', 'Disease', 'MESH:D008175', (150, 161))	('resulted in', 'Reg', (138, 149))	('lung tumor', 'Phenotype', 'HP:0100526', (150, 160))
12379	24794706	In order to examine the possibility that Lkb1 and Pten loss would lead to lung SCC formation, 6- to 8-week-old Lkb1fl/fl, Ptenfl/fl (Lkb1, Pten or LP) mice were administered Adenovirus-Cre (Ad-Cre) via intranasal instillation (Figure 1A).	('Pten', 'Gene', (50, 54))	('Lkb1fl/fl', 'Var', (111, 120))	('loss', 'NegReg', (55, 59))	('mice', 'Species', '10090', (151, 155))	('SCC', 'Gene', (79, 82))	('LP', 'Chemical', '-', (147, 149))	('SCC', 'Phenotype', 'HP:0002860', (79, 82))	('SCC', 'Gene', '6317', (79, 82))	('lead', 'Reg', (66, 70))	('Lkb1', 'Gene', (41, 45))
12392	24794706	In contrast, KrasG12D-driven murine ADC and human ADC tissues were p63, KRT5, and SOX2 negative, while TTF1 staining was strongly positive, confirming their ADC phenotype (Figure 2A).	('human', 'Species', '9606', (44, 49))	('murine', 'Species', '10090', (29, 35))	('KrasG12D-driven', 'Var', (13, 28))	('TTF1', 'Gene', (103, 107))	('TTF1', 'Gene', '7270', (103, 107))	('ADC', 'Disease', (36, 39))
12395	24794706	To do this, the gene expression profiles of 34 human SCC tumors with either LKB1 or PTEN alterations from the Cancer Genome Atlas were compared with 35 normal human lung tissue samples to generate a list of genotype-specific SCC genes.	('SCC', 'Gene', '6317', (53, 56))	('PTEN', 'Gene', (84, 88))	('SCC tumors', 'Disease', (53, 63))	('SCC', 'Gene', (53, 56))	('LKB1', 'Gene', '6794', (76, 80))	('SCC', 'Gene', '6317', (225, 228))	('SCC tumors', 'Disease', 'MESH:D009369', (53, 63))	('human', 'Species', '9606', (159, 164))	('LKB1', 'Gene', (76, 80))	('PTEN', 'Gene', '5728', (84, 88))	('SCC', 'Gene', (225, 228))	('human', 'Species', '9606', (47, 52))	('alterations', 'Var', (89, 100))	('rat', 'Species', '10116', (93, 96))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('Cancer', 'Phenotype', 'HP:0002664', (110, 116))	('SCC', 'Phenotype', 'HP:0002860', (53, 56))	('rat', 'Species', '10116', (192, 195))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('SCC', 'Phenotype', 'HP:0002860', (225, 228))
12400	24794706	Comparison of the mouse and human gene sets yielded 893 genes that were significantly differentially expressed in both human tumors with LKB1 and/or PTEN alterations and LP mouse SCCs (Figure S2B).	('LKB1', 'Gene', '6794', (137, 141))	('PTEN', 'Gene', (149, 153))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('SCC', 'Gene', '6317', (179, 182))	('alterations', 'Var', (154, 165))	('rat', 'Species', '10116', (158, 161))	('SCC', 'Gene', (179, 182))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('PTEN', 'Gene', '5728', (149, 153))	('tumors', 'Disease', (125, 131))	('mouse', 'Species', '10090', (173, 178))	('LKB1', 'Gene', (137, 141))	('human', 'Species', '9606', (119, 124))	('tumors', 'Disease', 'MESH:D009369', (125, 131))	('differentially', 'Reg', (86, 100))	('LP', 'Chemical', '-', (170, 172))	('SCC', 'Phenotype', 'HP:0002860', (179, 182))	('mouse', 'Species', '10090', (18, 23))	('human', 'Species', '9606', (28, 33))
12447	24794706	By using two sets of independently derived signatures comparing monocyte/macrophages to neutrophils, we found a clear enrichment for neutrophil signatures in the LP CD45+ cells, while macrophage signatures were significantly enriched in the Kras CD45+ cells (Figure 4G) (p < 0.001).	('LP', 'Chemical', '-', (162, 164))	('LP CD45+', 'Var', (162, 170))	('neutrophil signatures', 'MPA', (133, 154))
12449	24794706	Therefore, we assessed the protein concentrations of these cytokines, including CXCL1, CXCL2, CXCL5, and CXCL7, in bronchoalveolar lavage (BAL) fluid from Lkb1;Pten tumor-bearing mice.	('bronchoalveolar lavage', 'Disease', (115, 137))	('Lkb1', 'Var', (155, 159))	('mice', 'Species', '10090', (179, 183))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('bronchoalveolar lavage', 'Disease', 'None', (115, 137))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('CXCL2', 'MPA', (87, 92))	('rat', 'Species', '10116', (42, 45))	('tumor', 'Disease', (165, 170))
12462	24794706	Because we observed high levels of Pdl1 in the LP EpCAM+ cells by microarray, and published work suggests that PD-L1 can induce Tregs, we further explored the expression of this immunomodulating protein.	('Tregs', 'Chemical', '-', (128, 133))	('LP', 'Chemical', '-', (47, 49))	('induce', 'PosReg', (121, 127))	('Pdl1', 'Gene', (35, 39))	('Pdl1', 'Gene', '29126', (35, 39))	('Tregs', 'CPA', (128, 133))	('PD-L1', 'Var', (111, 116))
12478	24794706	In agreement with previous in vivo results and validating this assay for TPC capacity, SCA1+ cells from Kras;p53 tumors were enriched for tumor colony formation ability (p = 0.0026), but the same was not true for Kras tumors.	('tumor', 'Disease', (113, 118))	('tumors', 'Disease', (113, 119))	('tumor', 'Disease', (138, 143))	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('Kras tumors', 'Disease', (213, 224))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('tumors', 'Disease', 'MESH:D009369', (218, 224))	('tumor', 'Disease', 'MESH:D009369', (218, 223))	('Kras tumors', 'Disease', 'MESH:D009369', (213, 224))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('tumors', 'Phenotype', 'HP:0002664', (218, 224))	('tumor', 'Disease', (218, 223))	('Kras;p53', 'Var', (104, 112))	('tumors', 'Disease', (218, 224))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
12481	24794706	By immunofluorescence, the Lkb1;Pten tumor colonies expressed the squamous marker p63 but not the ADC-associated surfactant protein C (SPC), while both the Kras- and Kras;p53-derived colonies expressed SPC (Figure S6F).	('SPC', 'Gene', (202, 205))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('SPC', 'Gene', '6440', (202, 205))	('SPC', 'Gene', (135, 138))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('SPC', 'Gene', '6440', (135, 138))	('Lkb1;Pten', 'Var', (27, 36))
12483	24794706	Of the four mice that received SCA1+NGFR+ cells, all developed typical SCC with p63+, SOX2+, and KRT5+ staining within 30 to 40 weeks (Figures 6E and 6F).	('SCA1+NGFR+ cells', 'Var', (31, 47))	('SCC', 'Gene', (71, 74))	('mice', 'Species', '10090', (12, 16))	('SCC', 'Phenotype', 'HP:0002860', (71, 74))	('SCC', 'Gene', '6317', (71, 74))
12485	24794706	All mice transplanted with SCA1+NGFR+ developed tertiary SCC within 11 to 27 weeks (Figure 6E, p = 0.001 for secondary, p = 0.002 for tertiary, Fisher's exact test).	('SCC', 'Phenotype', 'HP:0002860', (57, 60))	('SCC', 'Gene', '6317', (57, 60))	('mice', 'Species', '10090', (4, 8))	('SCA1+NGFR+', 'Var', (27, 37))	('SCC', 'Gene', (57, 60))
12491	24794706	Likewise, by real-time RT-PCR for Pdl1 within the sorted LP tumor fractions, SCA1+NGFR+ cells had 7-fold more Pdl1 mRNA than SCA1-NGFR- cells and about 2-fold more than SCA1+NGFR- or SCA1-NGFR+ cells (Figure 7C, p = 0.035).	('NGFR-', 'Gene', (174, 179))	('more', 'PosReg', (105, 109))	('Pdl1', 'Gene', (34, 38))	('mRNA', 'MPA', (115, 119))	('Pdl1', 'Gene', (110, 114))	('tumor', 'Disease', (60, 65))	('Pdl1', 'Gene', '29126', (34, 38))	('Pdl1', 'Gene', '29126', (110, 114))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('NGFR-', 'Gene', '4804', (130, 135))	('NGFR-', 'Gene', '4804', (174, 179))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('SCA1+NGFR+', 'Var', (77, 87))	('NGFR-', 'Gene', (130, 135))	('LP', 'Chemical', '-', (57, 59))
12496	24794706	Using six different PDX samples, PD-L1 staining was 4.2-fold higher in the NGFR+ fraction relative to the NGFR- fraction of the human EpCAM+ tumor cells (Figure 7E, p = 0.02).	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('PD-L1', 'Gene', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('NGFR-', 'Gene', '4804', (106, 111))	('higher', 'PosReg', (61, 67))	('tumor', 'Disease', (141, 146))	('NGFR+', 'Var', (75, 80))	('human', 'Species', '9606', (128, 133))	('NGFR-', 'Gene', (106, 111))
12499	24794706	Therefore, in lung SCC, PD-L1 is most abundantly expressed on tumor cells that express NGFR, and if these cells are analogous to the NGFR+ cells in mouse tumors, they will also be enriched for TPC activity.	('SCC', 'Gene', '6317', (19, 22))	('tumors', 'Disease', (154, 160))	('tumors', 'Disease', 'MESH:D009369', (154, 160))	('NGFR', 'Var', (87, 91))	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', (62, 67))	('mouse', 'Species', '10090', (148, 153))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('PD-L1', 'Gene', (24, 29))	('SCC', 'Gene', (19, 22))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('SCC', 'Phenotype', 'HP:0002860', (19, 22))	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('tumor', 'Disease', (154, 159))
12507	24794706	Several studies have targeted deletion of squamous tumor suppressors, such as Pten, or activation of squamous oncogenes, such as Sox2, but despite these efforts, only partial SCC differentiation was observed in either model.	('squamous tumor', 'Disease', 'MESH:D002294', (42, 56))	('SCC', 'Gene', (175, 178))	('SCC', 'Phenotype', 'HP:0002860', (175, 178))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('Sox2', 'Gene', '6657', (129, 133))	('Pten', 'Gene', (78, 82))	('squamous tumor', 'Disease', (42, 56))	('SCC', 'Gene', '6317', (175, 178))	('deletion', 'Var', (30, 38))	('Sox2', 'Gene', (129, 133))	('squamous tumor', 'Phenotype', 'HP:0002860', (42, 56))
12508	24794706	Here, we demonstrate that deletion of both Pten and Lkb1, via the traditional Ad-Cre inhalation system, is able to produce lung tumors of purely squamous phenotype.	('lung tumor', 'Phenotype', 'HP:0100526', (123, 133))	('produce', 'Reg', (115, 122))	('rat', 'Species', '10116', (16, 19))	('Pten', 'Gene', (43, 47))	('deletion', 'Var', (26, 34))	('lung tumors', 'Phenotype', 'HP:0100526', (123, 134))	('lung tumors', 'Disease', (123, 134))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('Lkb1', 'Gene', (52, 56))	('lung tumors', 'Disease', 'MESH:D008175', (123, 134))
12513	24794706	As expected, the loss of both Lkb1 and Pten in these tumors activated the AKT and mTOR pathways, likely driving cellular proliferation and tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('AKT', 'Gene', '207', (74, 77))	('tumor', 'Disease', (139, 144))	('mTOR', 'Gene', (82, 86))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('activated', 'PosReg', (60, 69))	('mTOR', 'Gene', '2475', (82, 86))	('tumors', 'Disease', (53, 59))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('AKT', 'Gene', (74, 77))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('loss', 'Var', (17, 21))	('driving', 'Reg', (104, 111))	('cellular proliferation', 'CPA', (112, 134))	('Pten', 'Gene', (39, 43))	('Lkb1', 'Gene', (30, 34))	('tumor', 'Disease', (53, 58))	('rat', 'Species', '10116', (128, 131))
12514	24794706	The deletion of these genes was also associated with the upregulation of specific cytokines and other immune-modulating proteins, leading to a unique tumor microenvironment.	('specific cytokines', 'MPA', (73, 91))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('upregulation', 'PosReg', (57, 69))	('deletion', 'Var', (4, 12))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('tumor', 'Disease', (150, 155))
12523	24794706	Thirty-six percent of patients whose tumors showed PD-L1 expression achieved objective response to nivolumab treatment (9 of 25), while none of the 17 patients with PD-L1-negative tumors showed any objective response, although some achieved prolonged stable disease.	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('nivolumab', 'Chemical', 'MESH:D000077594', (99, 108))	('patients', 'Species', '9606', (22, 30))	('tumors', 'Phenotype', 'HP:0002664', (180, 186))	('patients', 'Species', '9606', (151, 159))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumors', 'Disease', (180, 186))	('tumors', 'Disease', 'MESH:D009369', (180, 186))	('tumors', 'Disease', (37, 43))	('PD-L1 expression', 'Var', (51, 67))	('tumors', 'Disease', 'MESH:D009369', (37, 43))
12525	24794706	Strikingly, we found that the SCA1+NGFR1+ cell population had enhanced tumor-propagating activity compared with other tumor cell populations.	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('enhanced', 'PosReg', (62, 70))	('SCA1+NGFR1+', 'Var', (30, 41))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Disease', (118, 123))	('tumor', 'Disease', (71, 76))
12570	33664318	Brachytherapy (7/112 patients, 6.3%) had a slightly higher occurrence rate of distant metastasis than surgery (29/775 patients, 3.7%); however, the difference was not statistically significant (p = 0.202).	('patients', 'Species', '9606', (21, 29))	('distant metastasis', 'CPA', (78, 96))	('Brachytherapy', 'Var', (0, 13))	('patients', 'Species', '9606', (118, 126))
12606	33664318	In conclusion, this study revealed that in OSCC patients, PIOC of the mandible, cervical lymph node metastasis at levels IV and V, and the presence of ENE were significant risk factors for distant metastasis.	('presence', 'Var', (139, 147))	('distant metastasis', 'CPA', (189, 207))	('patients', 'Species', '9606', (48, 56))	('cervical lymph node metastasis', 'Phenotype', 'HP:0025289', (80, 110))
12700	30250539	In addition, Wang et al indicated that the serum concentrations of Cyfra21-1, NSE and CEA may be diagnostic indicators of meningeal carcinomatosis of lung cancer.	('meningeal carcinomatosis of lung cancer', 'Disease', (122, 161))	('lung cancer', 'Phenotype', 'HP:0100526', (150, 161))	('Cyfra21-1', 'Var', (67, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('NSE', 'Gene', (78, 81))	('meningeal carcinomatosis of lung cancer', 'Disease', 'MESH:D055756', (122, 161))	('NSE', 'Gene', '2026', (78, 81))
12722	29725438	Although several molecular mechanisms, such as Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations and the constitutive activation of EGFR and its downstream pathways, have been reported to be involved in cetuximab resistance, histopathological and immunohistochemical changes mediated by cetuximab have not yet been investigated, and the details underlying the mechanisms of resistance remain unclear.	('cetuximab', 'Chemical', 'MESH:D000068818', (213, 222))	('mutations', 'Var', (97, 106))	('sarcoma', 'Disease', (59, 66))	('sarcoma', 'Phenotype', 'HP:0100242', (59, 66))	('EGFR', 'Gene', (142, 146))	('sarcoma', 'Disease', 'MESH:D012509', (59, 66))	('cetuximab', 'Chemical', 'MESH:D000068818', (297, 306))	('involved', 'Reg', (201, 209))	('KRAS', 'Gene', '24525', (91, 95))	('KRAS', 'Gene', (91, 95))	('rat', 'Species', '10116', (55, 58))
12744	29725438	The following primary antibodies were used: EGFR (D38B1; dilution 1:50; CST, Tokyo, Japan), EGFRv3 (9E05M52; dilution 1:200; Bioss Inc., Woburn, MA, USA), CD44v6 (ab78960; dilution 1:100; Abcam, Cambridge, UK), ABCG2 (ab3380; dilution 1:50; Abcam), E-cadherin (M3612; dilution 1:50; Dako; Agilent Technologies, Inc., Glostrup, Denmark), and N-cadherin (M3618; dilution 1:50; Dako; Agilent Technologies, Inc.).	('CST', 'Gene', '106478911', (72, 75))	('E-cadherin', 'Gene', (249, 259))	('N-cadherin', 'Gene', (341, 351))	('E-cadherin', 'Gene', '999', (249, 259))	('CST', 'Gene', (72, 75))	('ABCG2', 'Gene', (211, 216))	('M3618; dilution', 'Var', (353, 368))	('CD44', 'Gene', '960', (155, 159))	('ABCG2', 'Gene', '9429', (211, 216))	('N-cadherin', 'Gene', '1000', (341, 351))	('CD44', 'Gene', (155, 159))
12804	28356747	Further experimentation with TKIs has identified new treatment options such Giotrif  (afatinib), which is approved for second-line treatment without the patient expressing an EGFR mutation.	('EGFR', 'Gene', (175, 179))	('afatinib', 'Chemical', 'MESH:D000077716', (86, 94))	('patient', 'Species', '9606', (153, 160))	('EGFR', 'Gene', '1956', (175, 179))	('mutation', 'Var', (180, 188))
12873	27070449	We next assessed the percentage of tumors that highly expressed MAGE-A (staining of >50% of tumor cells) and found that the majority of malignancies that expressed MAGE-A were indeed high expressers (Table 2).	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('MAGE-A', 'Chemical', '-', (64, 70))	('MAGE-A', 'Var', (164, 170))	('MAGE-A', 'Chemical', '-', (164, 170))	('malignancies', 'Disease', 'MESH:D009369', (136, 148))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('malignancies', 'Disease', (136, 148))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('tumor', 'Disease', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumors', 'Disease', (35, 41))	('tumors', 'Disease', 'MESH:D009369', (35, 41))	('tumor', 'Disease', (92, 97))
12883	27070449	In summary, the expression patterns of MAGE-A and NY-ESO-1 in metastatic lesions are similar to the staining patterns seen in primary lesions with MAGE-A expression being significantly higher than NY-ESO-1 in multiple primary and metastatic malignancies (Table 1, 2, and 3).	('MAGE-A', 'Var', (147, 153))	('MAGE-A', 'Chemical', '-', (147, 153))	('NY-ESO-1', 'Gene', (197, 205))	('NY-ESO-1', 'Gene', '246100', (197, 205))	('NY-ESO-1', 'Gene', '246100', (50, 58))	('malignancies', 'Disease', 'MESH:D009369', (241, 253))	('MAGE-A', 'Chemical', '-', (39, 45))	('NY-ESO-1', 'Gene', (50, 58))	('higher', 'PosReg', (185, 191))	('malignancies', 'Disease', (241, 253))	('expression', 'MPA', (154, 164))
12911	33300283	Genomic characteristics of driver genes in Chinese patients with non-small cell lung cancer The aim of this study was to determine the demographic profile of driver gene alterations, especially low-frequency gene alterations in Chinese patients with non-small cell lung cancer (NSCLC).	('lung cancer', 'Disease', 'MESH:D008175', (265, 276))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (69, 91))	('NSCLC', 'Disease', (278, 283))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('lung cancer', 'Phenotype', 'HP:0100526', (265, 276))	('NSCLC', 'Phenotype', 'HP:0030358', (278, 283))	('lung cancer', 'Disease', 'MESH:D008175', (80, 91))	('patients', 'Species', '9606', (236, 244))	('cancer', 'Disease', (270, 276))	('alterations', 'Var', (170, 181))	('lung cancer', 'Phenotype', 'HP:0100526', (80, 91))	('patients', 'Species', '9606', (51, 59))	('cancer', 'Phenotype', 'HP:0002664', (270, 276))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (254, 276))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (250, 276))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (65, 91))	('cancer', 'Disease', (85, 91))	('lung cancer', 'Disease', (265, 276))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('cancer', 'Disease', 'MESH:D009369', (270, 276))	('NSCLC', 'Disease', 'MESH:D002289', (278, 283))	('lung cancer', 'Disease', (80, 91))
12914	33300283	The frequent genomic alterations found in the study were EGFR mutations (51.7%), KRAS mutations (13.1%), MET alterations (5.6%; 3.2% copy number gains and 0.5% exon 14 skipping mutation), HER2 alterations (7.0%; 2.0% copy number gains and 5.4% mutations), ALK alterations (7.2%; 3.9% rearrangements), RET rearrangements (1.4%), ROS1 rearrangements (0.9%), and NTRK rearrangements (0.6%).	('RET', 'Gene', '5979', (301, 304))	('men', 'Species', '9606', (314, 317))	('NTRK', 'Disease', (360, 364))	('rearrangements', 'Var', (333, 347))	('ROS1', 'Gene', '6098', (328, 332))	('alterations', 'Var', (193, 204))	('HER2', 'Gene', '2064', (188, 192))	('ALK', 'Gene', '238', (256, 259))	('MET', 'Gene', '79811', (105, 108))	('men', 'Species', '9606', (342, 345))	('EGFR', 'Gene', (57, 61))	('mutations', 'Var', (62, 71))	('men', 'Species', '9606', (374, 377))	('mutations', 'Var', (86, 95))	('KRAS', 'Gene', '3845', (81, 85))	('RET', 'Gene', (301, 304))	('ALK', 'Gene', (256, 259))	('men', 'Species', '9606', (293, 296))	('KRAS', 'Gene', (81, 85))	('ROS1', 'Gene', (328, 332))	('HER2', 'Gene', (188, 192))	('EGFR', 'Gene', '1956', (57, 61))	('MET', 'Gene', (105, 108))
12915	33300283	The EGFR mutation rate was found to be significantly higher in women than in men (69.1% vs. 38.5%, P < 0.001), while the KRAS mutation (17.5% vs. 7.3%, P < 0.001) and MET alteration rates (6.5% vs. 4.5%, P < 0.001) were significantly higher in men than in women.	('mutation', 'Var', (9, 17))	('MET', 'Gene', '79811', (167, 170))	('men', 'Species', '9606', (258, 261))	('men', 'Species', '9606', (244, 247))	('KRAS', 'Gene', (121, 125))	('higher', 'PosReg', (53, 59))	('MET', 'Gene', (167, 170))	('men', 'Species', '9606', (65, 68))	('EGFR', 'Gene', (4, 8))	('KRAS', 'Gene', '3845', (121, 125))	('women', 'Species', '9606', (256, 261))	('men', 'Species', '9606', (77, 80))	('women', 'Species', '9606', (63, 68))	('EGFR', 'Gene', '1956', (4, 8))
12916	33300283	The EGFR mutation rate tended to decrease with age in the group aged >40 years, while the KRAS mutation rate tended to increase with age.	('mutation', 'Var', (9, 17))	('decrease', 'NegReg', (33, 41))	('EGFR', 'Gene', (4, 8))	('KRAS', 'Gene', (90, 94))	('KRAS', 'Gene', '3845', (90, 94))	('EGFR', 'Gene', '1956', (4, 8))
12917	33300283	The HER2 mutation (13.9% vs. 6.7%, P < 0.001) and ALK alteration rates (14.3% vs. 6.9%, P < 0.001) were significantly higher in the group aged <40 years than in groups aged 40 years or older.	('higher', 'PosReg', (118, 124))	('mutation', 'Var', (9, 17))	('ALK', 'Gene', (50, 53))	('ALK', 'Gene', '238', (50, 53))	('HER2', 'Gene', (4, 8))	('HER2', 'Gene', '2064', (4, 8))
12924	33300283	The National Comprehensive Cancer Network (NCCN) guideline for NSCLC (Version 1.2020) recommends targeted treatment for EGFR, ALK, ROS1, BRAF, NTRK, RET, HER2, MET amplification and exon 14 skipping mutation.	('NSCLC', 'Disease', (63, 68))	('ALK', 'Gene', '238', (126, 129))	('ALK', 'Gene', (126, 129))	('NSCLC', 'Phenotype', 'HP:0030358', (63, 68))	('Cancer', 'Phenotype', 'HP:0002664', (27, 33))	('MET', 'Gene', (160, 163))	('ROS1', 'Gene', '6098', (131, 135))	('RET', 'Gene', '5979', (149, 152))	('Cancer', 'Disease', (27, 33))	('exon 14 skipping mutation', 'Var', (182, 207))	('HER2', 'Gene', (154, 158))	('EGFR', 'Gene', (120, 124))	('men', 'Species', '9606', (111, 114))	('Cancer', 'Disease', 'MESH:D009369', (27, 33))	('MET', 'Gene', '79811', (160, 163))	('RET', 'Gene', (149, 152))	('ROS1', 'Gene', (131, 135))	('NSCLC', 'Disease', 'MESH:D002289', (63, 68))	('BRAF', 'Gene', (137, 141))	('BRAF', 'Gene', '673', (137, 141))	('men', 'Species', '9606', (91, 94))	('EGFR', 'Gene', '1956', (120, 124))	('HER2', 'Gene', '2064', (154, 158))
12927	33300283	EGFR mutation has been widely and well researched, while alterations of BRAF, HER2, MET, ROS1, RET, and NTRK have not been previously well described due to their low frequency.	('MET', 'Gene', (84, 87))	('RET', 'Gene', (95, 98))	('BRAF', 'Gene', (72, 76))	('EGFR', 'Gene', (0, 4))	('ROS1', 'Gene', (89, 93))	('ROS1', 'Gene', '6098', (89, 93))	('HER2', 'Gene', (78, 82))	('BRAF', 'Gene', '673', (72, 76))	('HER2', 'Gene', '2064', (78, 82))	('MET', 'Gene', '79811', (84, 87))	('RET', 'Gene', '5979', (95, 98))	('NTRK', 'Gene', (104, 108))	('EGFR', 'Gene', '1956', (0, 4))	('mutation', 'Var', (5, 13))
12944	33300283	Frequent genomic alterations found were EGFR mutations (51.7%), KRAS mutations (13.1%), MET alterations (5.6%; 3.2% copy number gains and 0.5% exon 14 skipping), HER2 alterations (7.0%; 2.0% copy number gains and 5.4% mutations), ALK alterations (7.2%; 3.9% rearrangements), RET rearrangements (1.4%), ROS1 rearrangements (0.9%), and NTRK rearrangements (0.6%).	('NTRK', 'Disease', (334, 338))	('men', 'Species', '9606', (288, 291))	('ROS1', 'Gene', (302, 306))	('MET', 'Gene', (88, 91))	('HER2', 'Gene', (162, 166))	('EGFR', 'Gene', (40, 44))	('KRAS', 'Gene', '3845', (64, 68))	('mutations', 'Var', (69, 78))	('men', 'Species', '9606', (316, 319))	('rearrangements', 'Var', (339, 353))	('RET', 'Gene', '5979', (275, 278))	('men', 'Species', '9606', (348, 351))	('KRAS', 'Gene', (64, 68))	('rearrangements', 'Var', (307, 321))	('MET', 'Gene', '79811', (88, 91))	('alterations', 'Var', (167, 178))	('ROS1', 'Gene', '6098', (302, 306))	('ALK', 'Gene', '238', (230, 233))	('HER2', 'Gene', '2064', (162, 166))	('mutations', 'Var', (45, 54))	('ALK', 'Gene', (230, 233))	('EGFR', 'Gene', '1956', (40, 44))	('RET', 'Gene', (275, 278))	('men', 'Species', '9606', (267, 270))
12946	33300283	The National Comprehensive Cancer Network (NCCN) guidelines for NSCLC recommend that biomarker testing should include EGFR mutation, ALK rearrangement, ROS1 rearrangement, NTRK gene fusion, MET amplification, MET exon 14 skipping mutation, RET rearrangement, and HER2 mutation (Table 2).	('NSCLC', 'Disease', 'MESH:D002289', (64, 69))	('RET', 'Gene', '5979', (240, 243))	('mutation', 'Var', (123, 131))	('ALK', 'Gene', (133, 136))	('men', 'Species', '9606', (146, 149))	('HER2', 'Gene', '2064', (263, 267))	('Cancer', 'Phenotype', 'HP:0002664', (27, 33))	('MET', 'Gene', '79811', (209, 212))	('NSCLC', 'Disease', (64, 69))	('Cancer', 'Disease', (27, 33))	('NSCLC', 'Phenotype', 'HP:0030358', (64, 69))	('EGFR', 'Gene', '1956', (118, 122))	('RET', 'Gene', (240, 243))	('MET', 'Gene', (190, 193))	('ROS1', 'Gene', '6098', (152, 156))	('HER2', 'Gene', (263, 267))	('men', 'Species', '9606', (166, 169))	('Cancer', 'Disease', 'MESH:D009369', (27, 33))	('men', 'Species', '9606', (253, 256))	('rearrangement', 'Var', (157, 170))	('skipping mutation', 'Var', (221, 238))	('MET', 'Gene', (209, 212))	('NTRK gene', 'Gene', (172, 181))	('men', 'Species', '9606', (75, 78))	('EGFR', 'Gene', (118, 122))	('MET', 'Gene', '79811', (190, 193))	('ALK', 'Gene', '238', (133, 136))	('ROS1', 'Gene', (152, 156))
12948	33300283	Exon 21 L858R (n = 1645) and exon 19 deletions (n = 1526) accounted for 82.9% of all detected EGFR mutations.	('L858R', 'Mutation', 'rs121434568', (8, 13))	('EGFR', 'Gene', '1956', (94, 98))	('EGFR', 'Gene', (94, 98))	('mutations', 'Var', (99, 108))	('L858R', 'Var', (8, 13))
12949	33300283	Other EGFR mutations included T790M (n = 178, 4.6%), exon 20 insertion (n = 148, 3.8%), G719X (n = 143, 3.7%), L861Q (n = 78, 2.0%), S768I (n = 71, 1.8%), E709X (n = 38, 1.0%), and V834L (n = 22, 0.6%).	('G719X', 'Mutation', 'p.G719X', (88, 93))	('S768I', 'Var', (133, 138))	('EGFR', 'Gene', (6, 10))	('G719X', 'Var', (88, 93))	('E709X', 'Mutation', 'p.E709X', (155, 160))	('S768I', 'Mutation', 'rs121913465', (133, 138))	('T790M', 'Mutation', 'rs121434569', (30, 35))	('V834L', 'Mutation', 'rs397517127', (181, 186))	('L861Q', 'Var', (111, 116))	('T790M', 'Var', (30, 35))	('EGFR', 'Gene', '1956', (6, 10))	('V834L', 'Var', (181, 186))	('E709X', 'Var', (155, 160))	('L861Q', 'Mutation', 'rs121913444', (111, 116))
12950	33300283	A total of 678 patients (17.7% of patients with EGFR mutations) were identified as having complex EGFR mutations.	('EGFR', 'Gene', (98, 102))	('mutations', 'Var', (103, 112))	('patients', 'Species', '9606', (15, 23))	('EGFR', 'Gene', '1956', (48, 52))	('EGFR', 'Gene', (48, 52))	('mutations', 'Var', (53, 62))	('patients', 'Species', '9606', (34, 42))	('EGFR', 'Gene', '1956', (98, 102))
12951	33300283	The most common complex mutation was T790M with another mutation (n = 172, 4.5% of EGFR mutations).	('T790M', 'Var', (37, 42))	('EGFR', 'Gene', '1956', (83, 87))	('EGFR', 'Gene', (83, 87))	('T790M', 'Mutation', 'rs121434569', (37, 42))
12952	33300283	Table 3 identifies the 10 complex EGFR mutation types found with the highest frequency.	('EGFR', 'Gene', '1956', (34, 38))	('mutation', 'Var', (39, 47))	('EGFR', 'Gene', (34, 38))
12953	33300283	HER2 alterations were identified in 517 patients, including HER2 copy number gains (CNGs) in 150 patients, HER2 mutations in 397 patients, and both HER2 CNGs and mutations in 29 patients.	('HER2', 'Gene', (148, 152))	('mutations', 'Var', (162, 171))	('HER2', 'Gene', '2064', (107, 111))	('HER2', 'Gene', '2064', (148, 152))	('patients', 'Species', '9606', (129, 137))	('patients', 'Species', '9606', (40, 48))	('HER2', 'Gene', (60, 64))	('patients', 'Species', '9606', (178, 186))	('gains', 'PosReg', (77, 82))	('CNGs', 'Var', (153, 157))	('mutations', 'Var', (112, 121))	('HER2', 'Gene', '2064', (60, 64))	('alterations', 'Var', (5, 16))	('HER2', 'Gene', (0, 4))	('HER2', 'Gene', '2064', (0, 4))	('copy number', 'Var', (65, 76))	('HER2', 'Gene', (107, 111))	('patients', 'Species', '9606', (97, 105))
12954	33300283	HER2 mutations were distributed in ligand binding domain 1 (n = 6), cysteine-rich domain (n = 28), ligand binding domain 2 (n = 7), growth factor receptor domain (n = 52), transmembrane domain (n = 17), and tyrosine kinase domain (n = 243).	('HER2', 'Gene', '2064', (0, 4))	('cysteine', 'Chemical', 'MESH:D003545', (68, 76))	('HER2', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))
12956	33300283	Y772_G775dupYVMA was the most common exon 20 variant (n = 144), followed by E770delinsEAYVM (n = 32), G776delinsVC (n = 20), G778_P780dupGSP (n = 9), and G776delinsVV (n = 8).	('G775dupYVMA', 'Mutation', 'c.775dupG,YVMA', (5, 16))	('G778_P780dupGSP', 'Var', (125, 140))	('E770delinsEAYVM', 'Var', (76, 91))	('G776delinsVC', 'Var', (102, 114))	('G776delinsVV', 'Mutation', 'c.776delinsG,VV', (154, 166))	('G776delinsVC', 'Mutation', 'c.776delinsG,VC', (102, 114))	('E770delinsEAYVM', 'Mutation', 'c.770delinsE,EAYVM', (76, 91))	('Y772_G775dupYVMA', 'Var', (0, 16))	('G778_P780dupGSP', 'Mutation', 'c.778,780dupP,GSP', (125, 140))	('G776delinsVV', 'Var', (154, 166))
12957	33300283	S310F mutations in the HER2 extracellular region were identified in 13 patients.	('HER2', 'Gene', (23, 27))	('S310F', 'Var', (0, 5))	('patients', 'Species', '9606', (71, 79))	('HER2', 'Gene', '2064', (23, 27))	('S310F', 'Mutation', 'rs1057519816', (0, 5))
12959	33300283	There was no significant difference in the frequency of BRAF mutation, RET rearrangement, ROS1 rearrangement, HER2 alteration, and ALK alteration observed between women and men.	('men', 'Species', '9606', (165, 168))	('women', 'Species', '9606', (163, 168))	('men', 'Species', '9606', (104, 107))	('BRAF', 'Gene', (56, 60))	('BRAF', 'Gene', '673', (56, 60))	('mutation', 'Var', (61, 69))	('ALK', 'Gene', '238', (131, 134))	('men', 'Species', '9606', (173, 176))	('ALK', 'Gene', (131, 134))	('RET', 'Gene', '5979', (71, 74))	('men', 'Species', '9606', (84, 87))	('ROS1', 'Gene', (90, 94))	('HER2', 'Gene', (110, 114))	('ROS1', 'Gene', '6098', (90, 94))	('HER2', 'Gene', '2064', (110, 114))	('rearrangement', 'Var', (95, 108))	('RET', 'Gene', (71, 74))
12960	33300283	We found that the EGFR mutation rate tended to decrease with age in the group aged >40 years, while the KRAS mutation rate tended to increase with age.	('EGFR', 'Gene', '1956', (18, 22))	('mutation', 'Var', (23, 31))	('KRAS', 'Gene', '3845', (104, 108))	('decrease', 'NegReg', (47, 55))	('EGFR', 'Gene', (18, 22))	('KRAS', 'Gene', (104, 108))
12961	33300283	The BRAF mutation rate was 1.0% in the group aged <40 years and approximately 4% in the groups aged >40 years.	('mutation', 'Var', (9, 17))	('BRAF', 'Gene', '673', (4, 8))	('BRAF', 'Gene', (4, 8))
12964	33300283	As 68.5% of patients harboring driver genes can receive matched target agents, it is important to carry out NGS, as in addition to typical EGFR mutations, other genomic alterations can also be focused upon.	('EGFR', 'Gene', (139, 143))	('mutations', 'Var', (144, 153))	('patients', 'Species', '9606', (12, 20))	('EGFR', 'Gene', '1956', (139, 143))
12965	33300283	The frequency of EGFR mutations, KRAS mutations, HER2 alterations, ROS1 rearrangements, RET rearrangements, BRAF mutations and MET alterations in this study was consistent with that reported previously in a study in Asian patients.	('rearrangements', 'Var', (72, 86))	('patients', 'Species', '9606', (222, 230))	('RET', 'Gene', '5979', (88, 91))	('men', 'Species', '9606', (81, 84))	('EGFR', 'Gene', (17, 21))	('ROS1', 'Gene', '6098', (67, 71))	('MET', 'Gene', (127, 130))	('KRAS', 'Gene', '3845', (33, 37))	('BRAF', 'Gene', '673', (108, 112))	('HER2', 'Gene', (49, 53))	('BRAF', 'Gene', (108, 112))	('RET', 'Gene', (88, 91))	('KRAS', 'Gene', (33, 37))	('mutations', 'Var', (22, 31))	('EGFR', 'Gene', '1956', (17, 21))	('MET', 'Gene', '79811', (127, 130))	('ROS1', 'Gene', (67, 71))	('men', 'Species', '9606', (101, 104))	('alterations', 'Var', (54, 65))	('HER2', 'Gene', '2064', (49, 53))
12966	33300283	4 ,  5  Compared with the Western population, the Chinese patients in this study were found to have a higher frequency of EGFR mutation, but a lower frequency of KRAS mutation.	('KRAS', 'Gene', (162, 166))	('mutation', 'Var', (127, 135))	('KRAS', 'Gene', '3845', (162, 166))	('patients', 'Species', '9606', (58, 66))	('EGFR', 'Gene', '1956', (122, 126))	('EGFR', 'Gene', (122, 126))
12967	33300283	6  It has been previously reported that NTRK rearrangements have been found to occur in 0.2% of patients with NSCLC in the Western population, 7  and the frequency of NTRK rearrangements was 0.59% in this study.	('NTRK', 'Gene', (40, 44))	('NSCLC', 'Disease', (110, 115))	('rearrangements', 'Var', (45, 59))	('NSCLC', 'Disease', 'MESH:D002289', (110, 115))	('men', 'Species', '9606', (54, 57))	('patients', 'Species', '9606', (96, 104))	('men', 'Species', '9606', (181, 184))	('NSCLC', 'Phenotype', 'HP:0030358', (110, 115))
12968	33300283	EGFR mutations include typical and atypical EGFR mutations.	('EGFR', 'Gene', (0, 4))	('mutations', 'Var', (49, 58))	('mutations', 'Var', (5, 14))	('EGFR', 'Gene', '1956', (44, 48))	('EGFR', 'Gene', (44, 48))	('EGFR', 'Gene', '1956', (0, 4))
12969	33300283	With the widespread use of NGS, more and more atypical EGFR mutations can be detected.	('mutations', 'Var', (60, 69))	('EGFR', 'Gene', (55, 59))	('EGFR', 'Gene', '1956', (55, 59))
12971	33300283	In addition, NGS could identify more atypical mutations, and might lead to a higher prevalence of EGFR mutations in female patients.	('EGFR', 'Gene', (98, 102))	('atypical mutations', 'MPA', (37, 55))	('mutations', 'Var', (103, 112))	('patients', 'Species', '9606', (123, 131))	('EGFR', 'Gene', '1956', (98, 102))
12972	33300283	Patients with atypical EGFR mutations have been reported to have variable efficacy to EGFR TKIs.	('EGFR', 'Gene', '1956', (86, 90))	('EGFR', 'Gene', (86, 90))	('Patients', 'Species', '9606', (0, 8))	('EGFR', 'Gene', '1956', (23, 27))	('EGFR', 'Gene', (23, 27))	('mutations', 'Var', (28, 37))
12973	33300283	As atypical EGFR mutations account for about 20% of all detected EGFR mutations, and 17.7% of patients harbor complex EGFR mutations, efficacy of EGFR TKIs in patients with different atypical and complex EGFR mutations need to be further researched.	('mutations', 'Var', (70, 79))	('EGFR', 'Gene', '1956', (146, 150))	('patients', 'Species', '9606', (94, 102))	('EGFR', 'Gene', (65, 69))	('EGFR', 'Gene', '1956', (65, 69))	('EGFR', 'Gene', (146, 150))	('EGFR', 'Gene', '1956', (204, 208))	('EGFR', 'Gene', '1956', (118, 122))	('EGFR', 'Gene', '1956', (12, 16))	('EGFR', 'Gene', (118, 122))	('EGFR', 'Gene', (12, 16))	('mutations', 'Var', (17, 26))	('patients', 'Species', '9606', (159, 167))	('EGFR', 'Gene', (204, 208))
12974	33300283	The EGFR mutation rate in our study tended to decrease with age, apart from in the group aged <40 years, which is consistent with previously reported data,4 which implies that patients in the group aged 40-50 had the highest EGFR mutation rate.	('mutation', 'Var', (9, 17))	('patients', 'Species', '9606', (176, 184))	('EGFR', 'Gene', (4, 8))	('EGFR', 'Gene', '1956', (225, 229))	('mutation', 'Var', (230, 238))	('EGFR', 'Gene', (225, 229))	('decrease', 'NegReg', (46, 54))	('EGFR', 'Gene', '1956', (4, 8))
12975	33300283	HER2 mutations in NSCLC are dominated by in-frame insertions in exon 20 of the HER2 kinase domain.	('HER2', 'Gene', '2064', (79, 83))	('NSCLC', 'Disease', (18, 23))	('NSCLC', 'Disease', 'MESH:D002289', (18, 23))	('mutations', 'Var', (5, 14))	('NSCLC', 'Phenotype', 'HP:0030358', (18, 23))	('HER2', 'Gene', (0, 4))	('HER2', 'Gene', '2064', (0, 4))	('HER2', 'Gene', (79, 83))	('insertions in', 'Var', (50, 63))
12976	33300283	8  HER2 mutation is found in 2%-4% of lung cancer patients.	('HER2', 'Gene', '2064', (3, 7))	('lung cancer', 'Disease', (38, 49))	('patients', 'Species', '9606', (50, 58))	('lung cancer', 'Phenotype', 'HP:0100526', (38, 49))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('lung cancer', 'Disease', 'MESH:D008175', (38, 49))	('mutation', 'Var', (8, 16))	('HER2', 'Gene', (3, 7))
12977	33300283	4 ,  9  The frequency of HER2 mutation in this study was 7.0%.	('HER2', 'Gene', '2064', (25, 29))	('mutation', 'Var', (30, 38))	('HER2', 'Gene', (25, 29))
12979	33300283	10  The HER2 extracellular domain mutants were activated by two distinct mechanisms, characterized by elevated C-terminal tail phosphorylation, or by covalent dimerization mediated by intermolecular disulfide bond formation.	('disulfide', 'Chemical', 'MESH:D004220', (199, 208))	('mutants', 'Var', (34, 41))	('C-terminal tail phosphorylation', 'MPA', (111, 142))	('HER2', 'Gene', (8, 12))	('elevated', 'PosReg', (102, 110))	('activated', 'PosReg', (47, 56))	('HER2', 'Gene', '2064', (8, 12))	('covalent dimerization', 'MPA', (150, 171))
12980	33300283	11  Different HER2 variants exhibit divergent sensitivities to anti-HER2 treatments.	('HER2', 'Gene', '2064', (14, 18))	('HER2', 'Gene', (68, 72))	('HER2', 'Gene', '2064', (68, 72))	('men', 'Species', '9606', (78, 81))	('HER2', 'Gene', (14, 18))	('variants', 'Var', (19, 27))
12981	33300283	Afatinib, pyrotinib and poziotinib are regarded as HER2-TKIs.	('Afatinib', 'Chemical', 'MESH:D000077716', (0, 8))	('poziotinib', 'Chemical', 'MESH:C557213', (24, 34))	('pyrotinib', 'Chemical', 'MESH:C000622954', (10, 19))	('HER2', 'Gene', (51, 55))	('pyrotinib', 'Var', (10, 19))	('HER2', 'Gene', '2064', (51, 55))
12982	33300283	Certain variants, G778_P780dup and G776delinsVC, derive sustained clinical benefits from afatinib, whereas the predominant variant, A772_G775dupYVMA, is resistant to most anti-HER2 treatments.	('HER2', 'Gene', (176, 180))	('HER2', 'Gene', '2064', (176, 180))	('afatinib', 'Chemical', 'MESH:D000077716', (89, 97))	('G776delinsVC', 'Var', (35, 47))	('G778_P780dup', 'Mutation', 'p.778,780dupP', (18, 30))	('G776delinsVC', 'Mutation', 'c.776delinsG,VC', (35, 47))	('men', 'Species', '9606', (186, 189))	('A772_G775dupYVMA', 'Var', (132, 148))	('clinical', 'MPA', (66, 74))	('benefits', 'PosReg', (75, 83))	('G775dupYVMA', 'Mutation', 'c.775dupG,YVMA', (137, 148))	('G778_P780dup', 'Var', (18, 30))
12984	33300283	13  Further clinical trials involving variable HER2 mutations are required.	('mutations', 'Var', (52, 61))	('HER2', 'Gene', '2064', (47, 51))	('HER2', 'Gene', (47, 51))
12985	33300283	Although fluorescence in situ hybridization (FISH) has been established as a gold standard method in the detection of ALK and ROS1 rearrangement, NGS is also a reliable technique.	('men', 'Species', '9606', (140, 143))	('ROS1', 'Gene', (126, 130))	('ROS1', 'Gene', '6098', (126, 130))	('ALK', 'Gene', '238', (118, 121))	('rearrangement', 'Var', (131, 144))	('ALK', 'Gene', (118, 121))
12986	33300283	14 ,  15  In addition, NGS has been reported to identify different types of ALK fusions and ALK mutations that mediate resistance to ALK inhibitors.	('ALK', 'Gene', (92, 95))	('fusions', 'Var', (80, 87))	('ALK', 'Gene', '238', (76, 79))	('ALK', 'Gene', (133, 136))	('resistance', 'MPA', (119, 129))	('ALK', 'Gene', '238', (133, 136))	('ALK', 'Gene', '238', (92, 95))	('ALK', 'Gene', (76, 79))	('mutations', 'Var', (96, 105))
12988	33300283	5   Dysregulation of the MET pathway in lung cancer occurs via a variety of mechanisms including gene mutation, amplification, rearrangement, and protein overexpression.	('MET', 'Gene', '79811', (25, 28))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('rearrangement', 'Var', (127, 140))	('amplification', 'Var', (112, 125))	('MET', 'Gene', (25, 28))	('lung cancer', 'Disease', 'MESH:D008175', (40, 51))	('overexpression', 'PosReg', (154, 168))	('protein', 'Protein', (146, 153))	('men', 'Species', '9606', (136, 139))	('lung cancer', 'Disease', (40, 51))	('gene mutation', 'Var', (97, 110))	('lung cancer', 'Phenotype', 'HP:0100526', (40, 51))
12990	33300283	Juxtamenbrane domain mutations that disrupt splice sites flanking MET exon 14 result in MET exon 14 skipping.	('MET', 'Gene', '79811', (66, 69))	('MET', 'Gene', (66, 69))	('men', 'Species', '9606', (5, 8))	('MET', 'Gene', '79811', (88, 91))	('MET', 'Gene', (88, 91))	('skipping', 'NegReg', (100, 108))	('mutations', 'Var', (21, 30))
12991	33300283	The prevalence of MET exon 14 skipping mutations was 0.4% in this study, consistent with a previous report in Chinese patients.	('skipping mutations', 'Var', (30, 48))	('MET', 'Gene', '79811', (18, 21))	('patients', 'Species', '9606', (118, 126))	('MET', 'Gene', (18, 21))
12992	33300283	4  MET copy-number gains arise from two distinct processes: polysomy and amplification.	('copy-number gains', 'Var', (7, 24))	('MET', 'Gene', '79811', (3, 6))	('MET', 'Gene', (3, 6))
12995	33300283	It has been previously reported that BRAF mutations have been observed in 2%-4% of patients with NSCLC.	('BRAF', 'Gene', '673', (37, 41))	('NSCLC', 'Disease', (97, 102))	('BRAF', 'Gene', (37, 41))	('NSCLC', 'Disease', 'MESH:D002289', (97, 102))	('patients', 'Species', '9606', (83, 91))	('NSCLC', 'Phenotype', 'HP:0030358', (97, 102))	('mutations', 'Var', (42, 51))	('observed', 'Reg', (62, 70))
12997	33300283	21  The frequency of BRAF mutation in this study was similar to the frequency reported in other research.	('BRAF', 'Gene', (21, 25))	('BRAF', 'Gene', '673', (21, 25))	('mutation', 'Var', (26, 34))
12999	33300283	BRAF mutations can be divided into V600E and non-V600E.	('V600E', 'Var', (35, 40))	('BRAF', 'Gene', '673', (0, 4))	('BRAF', 'Gene', (0, 4))	('V600E', 'Mutation', 'rs113488022', (49, 54))	('V600E', 'Mutation', 'rs113488022', (35, 40))
13000	33300283	A total of 202 of all patients with BRAF-mutant NSCLC in this study presented with non-V600E mutations.	('BRAF', 'Gene', (36, 40))	('NSCLC', 'Disease', (48, 53))	('presented', 'Reg', (68, 77))	('NSCLC', 'Disease', 'MESH:D002289', (48, 53))	('non-V600E mutations', 'Var', (83, 102))	('patients', 'Species', '9606', (22, 30))	('NSCLC', 'Phenotype', 'HP:0030358', (48, 53))	('V600E', 'Mutation', 'rs113488022', (87, 92))	('BRAF', 'Gene', '673', (36, 40))
13001	33300283	Vemurafenib monotherapy has been reported to be effective for treating patients with BRAF V600-mutated NSCLC, but not those with BRAF non-V600 mutations.	('BRAF', 'Gene', (129, 133))	('BRAF', 'Gene', '673', (129, 133))	('NSCLC', 'Disease', (103, 108))	('patients', 'Species', '9606', (71, 79))	('V600-mutated', 'Var', (90, 102))	('BRAF', 'Gene', (85, 89))	('Vemurafenib', 'Chemical', 'MESH:D000077484', (0, 11))	('NSCLC', 'Disease', 'MESH:D002289', (103, 108))	('BRAF', 'Gene', '673', (85, 89))	('NSCLC', 'Phenotype', 'HP:0030358', (103, 108))
13006	33300283	The frequency of driver gene mutations was found to be much higher in lung adenocarcinoma than in lung squamous cell carcinoma patients.	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (98, 126))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('higher', 'PosReg', (60, 66))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (70, 89))	('lung squamous cell carcinoma', 'Disease', (98, 126))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (103, 126))	('mutations', 'Var', (29, 38))	('patients', 'Species', '9606', (127, 135))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (70, 89))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (98, 126))	('lung adenocarcinoma', 'Disease', (70, 89))
13009	33300283	It has previously been demonstrated that EGFR mutation is highly prevalent in lung cancer patients who were never smokers.	('lung cancer', 'Disease', (78, 89))	('lung cancer', 'Phenotype', 'HP:0100526', (78, 89))	('EGFR', 'Gene', (41, 45))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('lung cancer', 'Disease', 'MESH:D008175', (78, 89))	('EGFR', 'Gene', '1956', (41, 45))	('mutation', 'Var', (46, 54))	('prevalent', 'Reg', (65, 74))	('patients', 'Species', '9606', (90, 98))
13013	31310946	In the present study, we analyzed The Cancer Genome Atlas (TCGA) data, and we found that lncRNA Small Nucleolar RNA Host Gene 17 (SNHG17) was upregulated in NSCLC driven by the amplification of copy number, indicating the special role of SNHG17 in NSCLC.	('NSCLC', 'Disease', (248, 253))	('amplification', 'Var', (177, 190))	('copy number', 'Var', (194, 205))	('NSCLC', 'Disease', 'MESH:D002289', (248, 253))	('Cancer Genome Atlas', 'Disease', (38, 57))	('NSCLC', 'Phenotype', 'HP:0030358', (157, 162))	('Cancer', 'Phenotype', 'HP:0002664', (38, 44))	('SNHG17', 'Gene', (238, 244))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (38, 57))	('SNHG17', 'Gene', (130, 136))	('SNHG17', 'Gene', '388796', (238, 244))	('NSCLC', 'Disease', (157, 162))	('SNHG17', 'Gene', '388796', (130, 136))	('NSCLC', 'Phenotype', 'HP:0030358', (248, 253))	('upregulated', 'PosReg', (142, 153))	('NSCLC', 'Disease', 'MESH:D002289', (157, 162))
13017	31310946	Results showed that the knockdown of SNHG17 inhibited the proliferation and migration and promoted the apoptosis of NSCLC cells.	('NSCLC', 'Disease', 'MESH:D002289', (116, 121))	('proliferation', 'CPA', (58, 71))	('inhibited', 'NegReg', (44, 53))	('NSCLC', 'Phenotype', 'HP:0030358', (116, 121))	('SNHG17', 'Gene', (37, 43))	('apoptosis', 'CPA', (103, 112))	('promoted', 'PosReg', (90, 98))	('NSCLC', 'Disease', (116, 121))	('knockdown', 'Var', (24, 33))	('SNHG17', 'Gene', '388796', (37, 43))
13027	31310946	Aberrant expressions of lncRNAs exert oncogenic and suppressive functions in cancer like breast cancer, gastric cancer, urothelial tract cancer, and NSCLC.	('breast cancer', 'Disease', 'MESH:D001943', (89, 102))	('cancer', 'Disease', (112, 118))	('urothelial tract cancer', 'Phenotype', 'HP:0010786', (120, 143))	('breast cancer', 'Disease', (89, 102))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('cancer', 'Disease', (137, 143))	('NSCLC', 'Disease', 'MESH:D002289', (149, 154))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('cancer', 'Disease', (96, 102))	('urothelial tract cancer', 'Disease', (120, 143))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('gastric cancer', 'Disease', 'MESH:D013274', (104, 118))	('Aberrant', 'Var', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('NSCLC', 'Disease', (149, 154))	('NSCLC', 'Phenotype', 'HP:0030358', (149, 154))	('expressions', 'MPA', (9, 20))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('cancer', 'Disease', (77, 83))	('gastric cancer', 'Phenotype', 'HP:0012126', (104, 118))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('lncRNAs', 'Protein', (24, 31))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('oncogenic', 'CPA', (38, 47))	('suppressive functions', 'CPA', (52, 73))	('urothelial tract cancer', 'Disease', 'MESH:D014523', (120, 143))	('breast cancer', 'Phenotype', 'HP:0003002', (89, 102))	('gastric cancer', 'Disease', (104, 118))
13030	31310946	For example, LINC0026 can regulate activation of the DNA damage response via phosphorylation in NSCLC.	('phosphorylation', 'MPA', (77, 92))	('DNA', 'MPA', (53, 56))	('NSCLC', 'Disease', (96, 101))	('NSCLC', 'Disease', 'MESH:D002289', (96, 101))	('LINC0026', 'Var', (13, 21))	('NSCLC', 'Phenotype', 'HP:0030358', (96, 101))	('activation', 'PosReg', (35, 45))
13032	31310946	It has been reported to be an unfavorable prognostic factor in colorectal cancer (CRC), and it promotes CRC cell proliferation by epigenetically silencing P57.	('CRC', 'Phenotype', 'HP:0003003', (82, 85))	('CRC', 'Disease', (104, 107))	('epigenetically silencing', 'Var', (130, 154))	('P57', 'Gene', '1028', (155, 158))	('P57', 'Gene', (155, 158))	('colorectal cancer', 'Phenotype', 'HP:0003003', (63, 80))	('CRC', 'Phenotype', 'HP:0003003', (104, 107))	('colorectal cancer', 'Disease', (63, 80))	('colorectal cancer', 'Disease', 'MESH:D015179', (63, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('promotes', 'PosReg', (95, 103))
13036	31310946	In this study, we found that gene amplification of SNHG17 could induce the overexpression of SNHG17 in NSCLC, by analyzing The Cancer Genome Atlas (TCGA) database; and, we acquired the exact sequence of SNHG17.	('induce', 'Reg', (64, 70))	('SNHG17', 'Gene', '388796', (203, 209))	('SNHG17', 'Gene', (51, 57))	('NSCLC', 'Disease', (103, 108))	('Cancer Genome Atlas', 'Disease', (127, 146))	('overexpression', 'MPA', (75, 89))	('Cancer', 'Phenotype', 'HP:0002664', (127, 133))	('SNHG17', 'Gene', (93, 99))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (127, 146))	('NSCLC', 'Disease', 'MESH:D002289', (103, 108))	('gene amplification', 'Var', (29, 47))	('NSCLC', 'Phenotype', 'HP:0030358', (103, 108))	('SNHG17', 'Gene', '388796', (93, 99))	('SNHG17', 'Gene', '388796', (51, 57))	('SNHG17', 'Gene', (203, 209))
13037	31310946	Then, we found that knockdown of SNHG17 could inhibit the proliferation and migration and promote the apoptosis of NSCLC cells.	('inhibit', 'NegReg', (46, 53))	('apoptosis', 'CPA', (102, 111))	('NSCLC', 'Disease', (115, 120))	('SNHG17', 'Gene', (33, 39))	('NSCLC', 'Disease', 'MESH:D002289', (115, 120))	('promote', 'PosReg', (90, 97))	('knockdown', 'Var', (20, 29))	('SNHG17', 'Gene', '388796', (33, 39))	('NSCLC', 'Phenotype', 'HP:0030358', (115, 120))
13038	31310946	In addition, we screened out the potential downstream gene of SNHG17 by RNA sequencing (RNA-seq) assays after knockdown of SNHG17 in NSCLC cells.	('SNHG17', 'Gene', (62, 68))	('knockdown', 'Var', (110, 119))	('SNHG17', 'Gene', (123, 129))	('NSCLC', 'Phenotype', 'HP:0030358', (133, 138))	('SNHG17', 'Gene', '388796', (123, 129))	('SNHG17', 'Gene', '388796', (62, 68))	('NSCLC', 'Disease', (133, 138))	('NSCLC', 'Disease', 'MESH:D002289', (133, 138))
13051	31310946	The result of the MTT assay showed that the silencing of SNHG17 greatly inhibited both A549 and PC-9 cell proliferation (Figure 3B).	('PC-9', 'Gene', (96, 100))	('PC-9', 'Gene', '255738', (96, 100))	('MTT', 'Chemical', '-', (18, 21))	('A549', 'CellLine', 'CVCL:0023', (87, 91))	('SNHG17', 'Gene', (57, 63))	('inhibited', 'NegReg', (72, 81))	('silencing', 'Var', (44, 53))	('SNHG17', 'Gene', '388796', (57, 63))
13053	31310946	Ethynyldeoxyuridine (EdU) staining assays also demonstrated that the proliferation capacity of A549 was reduced by the knockdown of SNHG17 (Figure 4A).	('reduced', 'NegReg', (104, 111))	('SNHG17', 'Gene', (132, 138))	('A549', 'CellLine', 'CVCL:0023', (95, 99))	('knockdown', 'Var', (119, 128))	('SNHG17', 'Gene', '388796', (132, 138))	('proliferation capacity', 'CPA', (69, 91))	('EdU', 'Chemical', '-', (21, 24))	('Ethynyldeoxyuridine', 'Chemical', '-', (0, 19))
13055	31310946	As shown in Figure 3D, the migrations of A549 and PC-9 cells were remarkably inhibited after the knockdown of SNHG17.	('knockdown', 'Var', (97, 106))	('A549', 'CellLine', 'CVCL:0023', (41, 45))	('inhibited', 'NegReg', (77, 86))	('PC-9', 'Gene', '255738', (50, 54))	('SNHG17', 'Gene', (110, 116))	('PC-9', 'Gene', (50, 54))	('SNHG17', 'Gene', '388796', (110, 116))
13056	31310946	These results indicated that the inhibition of SNHG17 significantly reduced the NSCLC cell proliferation and migration.	('inhibition', 'Var', (33, 43))	('SNHG17', 'Gene', '388796', (47, 53))	('NSCLC', 'Phenotype', 'HP:0030358', (80, 85))	('NSCLC', 'Disease', (80, 85))	('migration', 'CPA', (109, 118))	('NSCLC', 'Disease', 'MESH:D002289', (80, 85))	('SNHG17', 'Gene', (47, 53))	('reduced', 'NegReg', (68, 75))
13058	31310946	To figure out the role of apoptosis in NSCLC cell proliferation after the knockdown of SNHG17, we used flow cytometry to explore the involvement of SNHG17 in NSCLC cell apoptosis.	('NSCLC', 'Disease', (158, 163))	('NSCLC', 'Phenotype', 'HP:0030358', (39, 44))	('NSCLC', 'Disease', 'MESH:D002289', (158, 163))	('SNHG17', 'Gene', (148, 154))	('SNHG17', 'Gene', (87, 93))	('knockdown', 'Var', (74, 83))	('NSCLC', 'Phenotype', 'HP:0030358', (158, 163))	('SNHG17', 'Gene', '388796', (87, 93))	('NSCLC', 'Disease', (39, 44))	('SNHG17', 'Gene', '388796', (148, 154))	('NSCLC', 'Disease', 'MESH:D002289', (39, 44))
13067	31310946	FOXA1 could be upregulated by lncRNA LOC730100 to promote cancer proliferation.	('FOXA1', 'Gene', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('promote', 'PosReg', (50, 57))	('upregulated', 'PosReg', (15, 26))	('lncRNA LOC730100', 'Var', (30, 46))	('FOXA1', 'Gene', '3169', (0, 5))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('cancer', 'Disease', (58, 64))
13071	31310946	FOXA1 was inhibited while XAF1 and BIK were promoted at the mRNA and protein expression levels after the SNHG17 knockdown (Figures 5B and 5C).	('FOXA1', 'Gene', (0, 5))	('promoted', 'PosReg', (44, 52))	('BIK', 'Gene', (35, 38))	('FOXA1', 'Gene', '3169', (0, 5))	('XAF1', 'Gene', '54739', (26, 30))	('inhibited', 'NegReg', (10, 19))	('knockdown', 'Var', (112, 121))	('SNHG17', 'Gene', (105, 111))	('BIK', 'Gene', '638', (35, 38))	('XAF1', 'Gene', (26, 30))	('SNHG17', 'Gene', '388796', (105, 111))
13077	31310946	The loss-of-function experiments proved that knockdown of SNHG17 inhibited the proliferation and migration of NSCLC cells.	('SNHG17', 'Gene', (58, 64))	('loss-of-function', 'NegReg', (4, 20))	('NSCLC', 'Disease', (110, 115))	('SNHG17', 'Gene', '388796', (58, 64))	('NSCLC', 'Disease', 'MESH:D002289', (110, 115))	('inhibited', 'NegReg', (65, 74))	('knockdown', 'Var', (45, 54))	('NSCLC', 'Phenotype', 'HP:0030358', (110, 115))
13078	31310946	Apoptosis was promoted after the knockdown of SNHG17.	('knockdown', 'Var', (33, 42))	('Apoptosis', 'CPA', (0, 9))	('SNHG17', 'Gene', (46, 52))	('promoted', 'PosReg', (14, 22))	('SNHG17', 'Gene', '388796', (46, 52))
13091	31310946	Our group also revealed that SNHG20 promotes the tumorigenesis of NSCLC by epigenetically silencing P21.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('NSCLC', 'Disease', (66, 71))	('SNHG20', 'Gene', '654434', (29, 35))	('NSCLC', 'Disease', 'MESH:D002289', (66, 71))	('tumor', 'Disease', (49, 54))	('SNHG20', 'Gene', (29, 35))	('P21', 'Gene', '644914', (100, 103))	('epigenetically silencing', 'Var', (75, 99))	('NSCLC', 'Phenotype', 'HP:0030358', (66, 71))	('promotes', 'PosReg', (36, 44))	('P21', 'Gene', (100, 103))
13098	31310946	In our study, FOXA1 was also downregulated along with the knockdown of SNHG17.	('FOXA1', 'Gene', (14, 19))	('FOXA1', 'Gene', '3169', (14, 19))	('SNHG17', 'Gene', (71, 77))	('downregulated', 'NegReg', (29, 42))	('knockdown', 'Var', (58, 67))	('SNHG17', 'Gene', '388796', (71, 77))
13104	31310946	Our result confirmed the upregulation of XAF1 induced by SNHG17 knockdown.	('XAF1', 'Gene', (41, 45))	('XAF1', 'Gene', '54739', (41, 45))	('SNHG17', 'Gene', (57, 63))	('knockdown', 'Var', (64, 73))	('SNHG17', 'Gene', '388796', (57, 63))	('upregulation', 'PosReg', (25, 37))
13110	31310946	Moreover, gene therapy targeted on BikDD, a constitutively active mutant form of BIK, caused immune anticancer response in lung cancer.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('BIK', 'Gene', '638', (81, 84))	('gene', 'Var', (10, 14))	('lung cancer', 'Disease', (123, 134))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('immune', 'PosReg', (93, 99))	('lung cancer', 'Phenotype', 'HP:0100526', (123, 134))	('BIK', 'Gene', (81, 84))	('BikDD', 'Gene', (35, 40))	('lung cancer', 'Disease', 'MESH:D008175', (123, 134))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('cancer', 'Disease', (128, 134))
13111	31310946	Since our results revealed significant upregulation of BIK after SNHG17 knockdown, they indicate that the SNHG17/BIK axis has great potential in NSCLC gene-targeting therapy.	('BIK', 'Gene', (55, 58))	('SNHG17', 'Gene', (65, 71))	('SNHG17', 'Gene', '388796', (106, 112))	('NSCLC', 'Disease', (145, 150))	('BIK', 'Gene', '638', (113, 116))	('NSCLC', 'Phenotype', 'HP:0030358', (145, 150))	('NSCLC', 'Disease', 'MESH:D002289', (145, 150))	('upregulation', 'PosReg', (39, 51))	('BIK', 'Gene', (113, 116))	('SNHG17', 'Gene', '388796', (65, 71))	('BIK', 'Gene', '638', (55, 58))	('knockdown', 'Var', (72, 81))	('SNHG17', 'Gene', (106, 112))
13112	31310946	In summary, we found that SNHG17 was upregulated in lung cancer driven by the amplification of copy number, and we identified its exact sequence.	('lung cancer', 'Disease', 'MESH:D008175', (52, 63))	('upregulated', 'PosReg', (37, 48))	('SNHG17', 'Gene', '388796', (26, 32))	('amplification', 'Var', (78, 91))	('lung cancer', 'Disease', (52, 63))	('lung cancer', 'Phenotype', 'HP:0100526', (52, 63))	('SNHG17', 'Gene', (26, 32))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))
13135	31310946	Total RNAs from the A549 cells with SNHG17 knockdown and control A549 cells were isolated and quantified.	('SNHG17', 'Gene', '388796', (36, 42))	('A549', 'CellLine', 'CVCL:0023', (20, 24))	('A549', 'CellLine', 'CVCL:0023', (65, 69))	('knockdown', 'Var', (43, 52))	('RNAs', 'Protein', (6, 10))	('SNHG17', 'Gene', (36, 42))
13139	31310946	Anti-FOXA1 (ab23738), Anti-BIK (ab52182), and Anti-XAF1 (ab17204) were from Abcam.	('BIK', 'Gene', (27, 30))	('FOXA1', 'Gene', '3169', (5, 10))	('BIK', 'Gene', '638', (27, 30))	('FOXA1', 'Gene', (5, 10))	('ab23738', 'Var', (12, 19))	('XAF1', 'Gene', '54739', (51, 55))	('XAF1', 'Gene', (51, 55))
13147	30634629	By exploring DNA copy number alterations (CNAs) of the KRT8 gene in LUAD, we found that DNA low copy gain (+1 and +2) was associated with elevated KRT8 mRNA expression.	('KRT8', 'Gene', (147, 151))	('low copy', 'Var', (92, 100))	('KRT8', 'Gene', (55, 59))	('LUAD', 'Phenotype', 'HP:0030078', (68, 72))	('KRT8', 'Gene', '3856', (147, 151))	('KRT8', 'Gene', '3856', (55, 59))	('elevated', 'PosReg', (138, 146))
13150	30634629	KRTs contain 54 identified members, that is, 28 of type I (K9-K28) and 26 of type II (K1-K8 and K71-K74).	('K9-K28', 'Var', (59, 65))	('KRT', 'Gene', (0, 3))	('K71-K74', 'Var', (96, 103))	('KRT', 'Gene', '643865', (0, 3))
13157	30634629	KRT8 mRNA and protein expression has been found to be upregulated in gastric cancer (GC) tissues, and its high expression has been observed to promote the cell progression and metastasis of GC cells and produce unfavorable outcomes for patients with GC.	('metastasis', 'CPA', (176, 186))	('gastric cancer', 'Disease', (69, 83))	('upregulated', 'PosReg', (54, 65))	('gastric cancer', 'Disease', 'MESH:D013274', (69, 83))	('KRT8', 'Gene', (0, 4))	('high', 'Var', (106, 110))	('patients', 'Species', '9606', (236, 244))	('promote', 'PosReg', (143, 150))	('gastric cancer', 'Phenotype', 'HP:0012126', (69, 83))	('GC', 'Phenotype', 'HP:0012126', (190, 192))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('KRT8', 'Gene', '3856', (0, 4))	('GC', 'Phenotype', 'HP:0012126', (85, 87))	('GC', 'Phenotype', 'HP:0012126', (250, 252))	('produce', 'Reg', (203, 210))	('cell progression', 'CPA', (155, 171))
13159	30634629	Loss of keratin 8/18 can regulate oncogenic potential by controlling various signaling pathways, including TMS1-NF-kappaB signaling and MARCKSL1-Paxillin1-Rac axis, in skin squamous cell carcinomas (SCC).	('controlling', 'Reg', (57, 68))	('Paxillin1-Rac', 'Gene', '207', (145, 158))	('skin squamous cell carcinomas', 'Disease', 'MESH:D002294', (168, 197))	('TMS1', 'Gene', '29108', (107, 111))	('keratin 8', 'Gene', (8, 17))	('oncogenic', 'CPA', (34, 43))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (173, 196))	('SCC', 'Phenotype', 'HP:0002860', (199, 202))	('TMS1', 'Gene', (107, 111))	('signaling pathways', 'Pathway', (77, 95))	('MARCKSL1', 'Gene', '65108', (136, 144))	('regulate', 'Reg', (25, 33))	('Loss', 'Var', (0, 4))	('Paxillin1-Rac', 'Gene', (145, 158))	('skin squamous cell carcinomas', 'Disease', (168, 197))	('keratin 8', 'Gene', '3856', (8, 17))	('carcinoma', 'Phenotype', 'HP:0030731', (187, 196))	('carcinomas', 'Phenotype', 'HP:0030731', (187, 197))	('skin squamous cell carcinomas', 'Phenotype', 'HP:0006739', (168, 197))	('MARCKSL1', 'Gene', (136, 144))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (173, 197))
13194	30634629	By mapping Kaplan-Meier curves of OS and RFS, we found that LUAD patients with high KRT8 expression had inferior OS (p = 0.0085) and RFS (p = 0.0294) in comparison to patients who had low KRT8 expression (Figure 4a,b).	('KRT8', 'Gene', (188, 192))	('KRT8', 'Gene', '3856', (84, 88))	('patients', 'Species', '9606', (167, 175))	('KRT8', 'Gene', '3856', (188, 192))	('high', 'Var', (79, 83))	('inferior', 'NegReg', (104, 112))	('patients', 'Species', '9606', (65, 73))	('LUAD', 'Phenotype', 'HP:0030078', (60, 64))	('RFS', 'MPA', (133, 136))	('KRT8', 'Gene', (84, 88))
13196	30634629	Results showed that the high KRT8 expression group had inferior OS (HR: 1.29; 95% CI: 1.02-1.63; p = 0.031) for LUAD (Figure S3a), but not for LUSC (Figure S3b).	('KRT8', 'Gene', '3856', (29, 33))	('LUSC', 'Phenotype', 'HP:0030359', (143, 147))	('high', 'Var', (24, 28))	('KRT8', 'Gene', (29, 33))	('LUAD', 'Phenotype', 'HP:0030078', (112, 116))	('LUAD', 'Disease', (112, 116))
13198	30634629	For instance, LUAD patients with or without epidermal growth factor receptor (EGFR) mutation or anaplastic lymphoma kinase (ALK) or c-ros oncogene 1 (ROS-1) rearrangement had different outcomes whether they received tyrosine kinase inhibitors (TKIs) or not.	('rearrangement', 'Var', (157, 170))	('epidermal growth factor receptor', 'Gene', '1956', (44, 76))	('patients', 'Species', '9606', (19, 27))	('LUAD', 'Phenotype', 'HP:0030078', (14, 18))	('c-ros oncogene 1', 'Gene', '6098', (132, 148))	('anaplastic lymphoma kinase', 'Gene', '238', (96, 122))	('ALK', 'Gene', '238', (124, 127))	('ROS-1', 'Gene', (150, 155))	('lymphoma', 'Phenotype', 'HP:0002665', (107, 115))	('ALK', 'Gene', (124, 127))	('EGFR', 'Gene', '1956', (78, 82))	('EGFR', 'Gene', (78, 82))	('anaplastic lymphoma kinase', 'Gene', (96, 122))	('ROS-1', 'Gene', '6098', (150, 155))	('c-ros oncogene 1', 'Gene', (132, 148))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (96, 115))	('epidermal growth factor receptor', 'Gene', (44, 76))	('mutation', 'Var', (84, 92))
13200	30634629	These results showed that LUAD patients with high KRT8 expression also had worse OS and RFS (Figure S4).	('KRT8', 'Gene', '3856', (50, 54))	('RFS', 'CPA', (88, 91))	('high', 'Var', (45, 49))	('patients', 'Species', '9606', (31, 39))	('LUAD', 'Phenotype', 'HP:0030078', (26, 30))	('KRT8', 'Gene', (50, 54))
13207	30634629	By analyzing KRT8 DNA CNAs in 511 cases of LUAD, we found that although low copy gain (+1 and +2, n = 148, 28.96%) was not frequent, it was still associated with significantly increased KRT8 expression compared with the copy-neutral (0) cases (Figure 5).	('low copy', 'Var', (72, 80))	('increased', 'PosReg', (176, 185))	('KRT8', 'Gene', (13, 17))	('KRT8', 'Gene', '3856', (186, 190))	('LUAD', 'Phenotype', 'HP:0030078', (43, 47))	('KRT8', 'Gene', '3856', (13, 17))	('expression', 'MPA', (191, 201))	('KRT8', 'Gene', (186, 190))
13213	30634629	These results show that aberrant KRT8 expression levels might be involved in LUAD cancer treatment.	('expression levels', 'MPA', (38, 55))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('KRT8', 'Gene', '3856', (33, 37))	('LUAD cancer', 'Disease', 'MESH:D009369', (77, 88))	('aberrant', 'Var', (24, 32))	('involved', 'Reg', (65, 73))	('KRT8', 'Gene', (33, 37))	('LUAD', 'Phenotype', 'HP:0030078', (77, 81))	('LUAD cancer', 'Disease', (77, 88))
13216	30634629	KRT8, predominantly expressed in epithelial cells, and its aberrant expression in multiple types of tumors is associated with cell migration, cell adhesion, and drug resistance.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('drug resistance', 'CPA', (161, 176))	('drug resistance', 'Phenotype', 'HP:0020174', (161, 176))	('cell adhesion', 'CPA', (142, 155))	('KRT8', 'Gene', (0, 4))	('aberrant expression', 'Var', (59, 78))	('tumors', 'Disease', (100, 106))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('associated', 'Reg', (110, 120))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('KRT8', 'Gene', '3856', (0, 4))	('cell migration', 'CPA', (126, 140))
13221	30634629	More importantly, we found that patients with high KRT8 expression had worse OS and RFS by setting a median KRT8 mRNA expression.	('high', 'Var', (46, 50))	('KRT8', 'Gene', '3856', (108, 112))	('patients', 'Species', '9606', (32, 40))	('KRT8', 'Gene', (51, 55))	('KRT8', 'Gene', (108, 112))	('KRT8', 'Gene', '3856', (51, 55))	('expression', 'Var', (56, 66))	('RFS', 'Disease', (84, 87))
13222	30634629	Additionally, by performing univariate and multivariate analysis, we discovered that high KRT8 expression was an independent prognostic indicator of poor OS (HR: 1.416, 95% CI: 1.050-1.909, p < 0.022) and RFS (HR: 1.512, 95% CI: 1.077-2.122, p < 0.017) for LUAD.	('LUAD', 'Phenotype', 'HP:0030078', (257, 261))	('LUAD', 'Disease', (257, 261))	('KRT8', 'Gene', '3856', (90, 94))	('poor OS', 'Disease', (149, 156))	('high', 'Var', (85, 89))	('KRT8', 'Gene', (90, 94))	('expression', 'MPA', (95, 105))
13229	30634629	Genetic alterations regulating gene expression are frequently common in LUAD and have significant impacts on tumor phenotypes and patients' survival.	('Genetic alterations', 'Var', (0, 19))	('LUAD', 'Phenotype', 'HP:0030078', (72, 76))	('impacts', 'Reg', (98, 105))	('LUAD', 'Disease', (72, 76))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('patients', 'Species', '9606', (130, 138))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('common', 'Reg', (62, 68))	('tumor', 'Disease', (109, 114))
13230	30634629	For instance, de novo ERBB2 amplification confers intrinsic resistance to erlotinib in EGFR-L858R mutated TKI-naive LUAD.	('ERBB2', 'Gene', '2064', (22, 27))	('L858R', 'Mutation', 'rs121434568', (92, 97))	('EGFR', 'Gene', '1956', (87, 91))	('ERBB2', 'Gene', (22, 27))	('intrinsic resistance to erlotinib', 'MPA', (50, 83))	('EGFR', 'Gene', (87, 91))	('erlotinib', 'Chemical', 'MESH:D000069347', (74, 83))	('mutated', 'Var', (98, 105))	('LUAD', 'Phenotype', 'HP:0030078', (116, 120))	('amplification', 'Var', (28, 41))
13232	30634629	Therefore, it would be worthwhile to exploring the mechanism for genetic alterations of KRT8 influencing LUAD cell behaviors in the future.	('KRT8', 'Gene', (88, 92))	('KRT8', 'Gene', '3856', (88, 92))	('influencing', 'Reg', (93, 104))	('LUAD cell behaviors', 'CPA', (105, 124))	('LUAD', 'Phenotype', 'HP:0030078', (105, 109))	('genetic alterations', 'Var', (65, 84))
13237	30634629	Moreover, KRT8 was significantly increased in the ADC cell line A549 treated with sapphyrin PCI-2050, and in the gemcitabine resistant Calu3 cell line treated with bexarotene, gemcitabine, or a two-drug combination.	('gemcitabine', 'Chemical', 'MESH:C056507', (113, 124))	('PCI-2050', 'Var', (92, 100))	('sapphyrin', 'Var', (82, 91))	('KRT8', 'Gene', (10, 14))	('increased', 'PosReg', (33, 42))	('gemcitabine', 'Chemical', 'MESH:C056507', (176, 187))	('A549', 'CellLine', 'CVCL:0023', (64, 68))	('KRT8', 'Gene', '3856', (10, 14))	('sapphyrin', 'Chemical', 'MESH:C440448', (82, 91))	('bexarotene', 'Chemical', 'MESH:D000077610', (164, 174))
13366	29625055	In the LGG marker paper, analysis of OS showed that patients diagnosed with an IDH1 and IDH2 (two very similar genes, hereafter referred to collectively as IDH) mutation with or without 1p/19q codeletion had substantially longer OS than did patients who had wild-type IDH, proving that IDH-1p/19q status represents a more robust survival predictor than LGG histologic subtype.	('IDH-1p', 'Gene', (286, 292))	('IDH', 'Gene', (88, 91))	('IDH1', 'Gene', (79, 83))	('IDH', 'Gene', (79, 82))	('mutation', 'Var', (161, 169))	('IDH', 'Gene', (286, 289))	('IDH', 'Gene', '3417', (88, 91))	('patients', 'Species', '9606', (52, 60))	('IDH1', 'Gene', '3417', (79, 83))	('IDH', 'Gene', (268, 271))	('IDH', 'Gene', '3417', (79, 82))	('IDH', 'Gene', (156, 159))	('OS', 'Chemical', '-', (229, 231))	('OS', 'Chemical', '-', (37, 39))	('IDH', 'Gene', '3417', (286, 289))	('patients', 'Species', '9606', (241, 249))	('longer', 'PosReg', (222, 228))	('IDH2', 'Gene', (88, 92))	('IDH-1p', 'Gene', '3417', (286, 292))	('IDH2', 'Gene', '3418', (88, 92))	('IDH', 'Gene', '3417', (268, 271))	('IDH', 'Gene', '3417', (156, 159))
13544	28885456	Inhibition of the PD-1/PD-L1 pathway using monoclonal antibodies enhances leukocyte infiltration and increases tumor necrosis factor alpha (TNFalpha) secretion into the oral cancer microenvironment.	('tumor necrosis factor alpha', 'Gene', (111, 138))	('PD-L1', 'Gene', (23, 28))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('increases', 'PosReg', (101, 110))	('oral cancer', 'Disease', 'MESH:D009062', (169, 180))	('PD-L1', 'Gene', '60533', (23, 28))	('oral cancer', 'Disease', (169, 180))	('Inhibition', 'Var', (0, 10))	('tumor necrosis factor alpha', 'Gene', '21926', (111, 138))	('enhances', 'PosReg', (65, 73))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('leukocyte infiltration', 'CPA', (74, 96))	('rat', 'Species', '10116', (90, 93))
13610	28885456	The primary antibodies used were: isolectin B4 FITC conjugate (IB4-FITC (1:1000, Tocris, Bristol, UK), anti-CGRP (1:500, Abcam, Cambridge, UK), anti-NF200 (1:500, Abcam), anti-TNFR1 or TNFR2 (1:250, R&D Systems, Minneapolis, MN)).	('CGRP', 'Gene', (108, 112))	('IB4-FITC', 'Chemical', '-', (63, 71))	('TNFR2', 'Gene', (185, 190))	('TNFR1', 'Gene', (176, 181))	('FITC', 'Chemical', 'MESH:D016650', (47, 51))	('FITC', 'Chemical', 'MESH:D016650', (67, 71))	('TNFR2', 'Gene', '21937', (185, 190))	('1:500', 'Var', (114, 119))	('NF200', 'Gene', (149, 154))	('MN', 'CellLine', 'CVCL:U508', (225, 227))	('NF200', 'Gene', '380684', (149, 154))	('CGRP', 'Gene', '12310', (108, 112))	('TNFR1', 'Gene', '21937', (176, 181))
13631	28885456	Within the CD45+ population, six types of immune cells were detected and quantified: 63.9 +- 1.6% CD11b+CD11c- macrophages/monocytes, 1.1 +- 0.18% CD11b+CD11c- dendritic cells, 3.5 +- 0.4% Ly6G+ neutrophils, 5.3 +- 0.6% CD3+ T cells, 2.6 +- 0.2% CD3-NK1.1+ natural killer (NK) cells, and 9.6 +- 0.4% CD3-B220+ B cells.	('Ly6G', 'Gene', '546644', (189, 193))	('CD11b+CD11c-', 'Var', (98, 110))	('CD3', 'Gene', '28134', (300, 303))	('CD3', 'Gene', (220, 223))	('CD11b+CD11c-', 'Var', (147, 159))	('CD3', 'Gene', '28134', (220, 223))	('CD3', 'Gene', '28134', (246, 249))	('CD3', 'Gene', (300, 303))	('CD3', 'Gene', (246, 249))	('Ly6G', 'Gene', (189, 193))
13634	28885456	However, HSC3 (n = 10), SCC9 (n = 10), and SkMel28 (n = 6) supernatant inoculation resulted in a significant increase in the proportion of total immune cells (CD45+) in the tongue (One-way ANOVA, p < 0.05; Figure 2B).	('CD45+', 'Var', (159, 164))	('increase', 'PosReg', (109, 117))	('SCC9', 'Gene', (24, 28))	('SCC9', 'Gene', '112207', (24, 28))	('HSC3', 'Gene', '150353', (9, 13))	('HSC3', 'Gene', (9, 13))
13642	28885456	Two-way ANOVA analysis identified a significant interaction between treatment and genotype with regard to CD45+ immune cells and CD11b+ and Ly6G+ myeloid subpopulations.	('Ly6G', 'Gene', (140, 144))	('CD11b+', 'Var', (129, 135))	('Ly6G', 'Gene', '546644', (140, 144))	('CD45+ immune cells', 'CPA', (106, 124))
13643	28885456	Consistent with previous findings, C57BL/6 mice treated with HSC3 supernatant had a significant increase in CD45+ immune cells (164.0 +- 21.1%, p < 0.01), CD11b+ macrophages/monocytes (91.0 +- 15.5%, p < 0.01), and Ly6G+ neutrophils (2345.3 +- 20.6%, p < 0.01) compared to HaCaT treatment.	('mice', 'Species', '10090', (43, 47))	('Ly6G', 'Gene', (215, 219))	('HSC3', 'Gene', '150353', (61, 65))	('C57BL/6', 'Var', (35, 42))	('HSC3', 'Gene', (61, 65))	('HaCaT', 'CellLine', 'CVCL:0038', (273, 278))	('Ly6G', 'Gene', '546644', (215, 219))	('increase', 'PosReg', (96, 104))	('CD45+ immune cells', 'MPA', (108, 126))	('CD11b+', 'MPA', (155, 161))
13669	28885456	GM-CSF has shown to be increased in T lymphocytes after nerve injury and when injected directly into the skin results in nociceptive behavior.	('nerve injury', 'Disease', 'MESH:D000080902', (56, 68))	('results in', 'Reg', (110, 120))	('GM-CSF', 'Var', (0, 6))	('increased', 'PosReg', (23, 32))	('nociceptive behavior', 'CPA', (121, 141))	('T lymphocytes', 'CPA', (36, 49))	('nerve injury', 'Disease', (56, 68))
13676	28885456	The molecular events in the 4NQO-induced oSCC closely resemble those observed in human head and neck carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('4NQO-induced', 'Var', (28, 40))	('4NQO', 'Chemical', 'MESH:D015112', (28, 32))	('neck carcinoma', 'Disease', (96, 110))	('oSCC', 'Chemical', '-', (41, 45))	('neck carcinoma', 'Disease', 'MESH:D006258', (96, 110))	('human', 'Species', '9606', (81, 86))	('oSCC', 'Disease', (41, 45))
13683	28885456	Mice that developed oSCC experienced functional allodynia beginning at 4-6 weeks post-4NQO carcinogenesis treatment and continued to worsen for the remaining 6 weeks (Two-way ANOVA, p < 0.05; Figure 8).	('treatment', 'Var', (106, 115))	('carcinogenesis', 'Disease', (91, 105))	('allodynia', 'Phenotype', 'HP:0012533', (48, 57))	('allodynia', 'Disease', (48, 57))	('4NQO', 'Chemical', 'MESH:D015112', (86, 90))	('Mice', 'Species', '10090', (0, 4))	('oSCC', 'Chemical', '-', (20, 24))	('allodynia', 'Disease', 'MESH:D006930', (48, 57))	('carcinogenesis', 'Disease', 'MESH:D063646', (91, 105))
13686	28885456	Using the antibody panel and flow cytometry gating strategy illustrated in Figure 4, we measured the percent of CD45+ cells in the tongue tissue from mice with 4NQO-induced moderate dysplasia (n = 6 mice), severe dysplasia (n = 10 mice), and oSCC (n = 10 mice).	('dysplasia', 'Disease', (182, 191))	('mice', 'Species', '10090', (150, 154))	('dysplasia', 'Disease', 'MESH:D004476', (182, 191))	('mice', 'Species', '10090', (199, 203))	('rat', 'Species', '10116', (177, 180))	('mice', 'Species', '10090', (255, 259))	('oSCC', 'Chemical', '-', (242, 246))	('4NQO-induced', 'Var', (160, 172))	('rat', 'Species', '10116', (53, 56))	('mice', 'Species', '10090', (231, 235))	('4NQO', 'Chemical', 'MESH:D015112', (160, 164))	('dysplasia', 'Disease', (213, 222))	('rat', 'Species', '10116', (66, 69))	('dysplasia', 'Disease', 'MESH:D004476', (213, 222))
13688	28885456	A significant increase in CD45+ cells was detected only in mice with 4NQO-induced oSCC (89.9 +- 2.5%, One-way ANOVA p < 0.05; Figure 9A).	('mice', 'Species', '10090', (59, 63))	('oSCC', 'Chemical', '-', (82, 86))	('4NQO-induced', 'Var', (69, 81))	('CD45+ cells', 'CPA', (26, 37))	('4NQO', 'Chemical', 'MESH:D015112', (69, 73))	('increase', 'PosReg', (14, 22))
13689	28885456	Further characterization of the subpopulations of CD45+ cells revealed a significant increase in the percent of Ly6G+ neutrophils (338.5 +- 53.6%, p < 0.05) and CD3+ T cells (425.9 +- 45.2%, p < 0.05) present in the tongue tissue from mice with 4NQO-induced oSCC (Figure 9B).	('CD3', 'Gene', (161, 164))	('CD45+', 'Var', (50, 55))	('CD3', 'Gene', '28134', (161, 164))	('oSCC', 'Chemical', '-', (258, 262))	('Ly6G', 'Gene', (112, 116))	('4NQO', 'Chemical', 'MESH:D015112', (245, 249))	('mice', 'Species', '10090', (235, 239))	('increase', 'PosReg', (85, 93))	('Ly6G', 'Gene', '546644', (112, 116))
13694	28885456	Using whole cell current clamp electrophysiology, we measured baseline excitability in 99 retrogradely labeled (DiI+) tongue afferent neurons from vehicle-treated mice (n = 4 mice) and mice with 4NQO-induced moderate dysplasia (n = 4 mice), severe dysplasia (n = 4 mice), and oSCC (n = 6 mice).	('mice', 'Species', '10090', (175, 179))	('dysplasia', 'Disease', 'MESH:D004476', (217, 226))	('oSCC', 'Chemical', '-', (276, 280))	('DiI+', 'Chemical', 'MESH:C024286', (112, 116))	('4NQO', 'Chemical', 'MESH:D015112', (195, 199))	('mice', 'Species', '10090', (234, 238))	('4NQO-induced', 'Var', (195, 207))	('dysplasia', 'Disease', 'MESH:D004476', (248, 257))	('mice', 'Species', '10090', (185, 189))	('mice', 'Species', '10090', (265, 269))	('mice', 'Species', '10090', (163, 167))	('rat', 'Species', '10116', (212, 215))	('mice', 'Species', '10090', (288, 292))	('dysplasia', 'Disease', (217, 226))	('dysplasia', 'Disease', (248, 257))
13698	28885456	However, DiI+ neurons from mice with 4NQO-induced severe dysplasia (n = 24 neurons) and oSCC (n = 18 neurons) had more depolarized resting membrane potential (-11.2 +- 3.9% and -15.5 +- 3.9%, respectively, p < 0.05) and significantly decreased rheobase (-24.4 +- 5.0% and -38.9 +- 4.9%, respectively, p < 0.05; Figure 10B) and a more hyperpolarized AP threshold (-30.0 +- 3.7% and -42.1 +- 3.4%, respectively, p < 0.05; Figure 10C).	('4NQO', 'Chemical', 'MESH:D015112', (37, 41))	('decreased', 'NegReg', (234, 243))	('oSCC', 'Chemical', '-', (88, 92))	('DiI+', 'Chemical', 'MESH:C024286', (9, 13))	('mice', 'Species', '10090', (27, 31))	('AP threshold', 'MPA', (349, 361))	('dysplasia', 'Disease', (57, 66))	('4NQO-induced', 'Var', (37, 49))	('depolarized', 'NegReg', (119, 130))	('dysplasia', 'Disease', 'MESH:D004476', (57, 66))	('resting membrane potential', 'MPA', (131, 157))	('rheobase', 'MPA', (244, 252))	('hyperpolarized', 'PosReg', (334, 348))
13701	28885456	Given the more depolarized resting membrane potential, the peak amplitude of the AP (overshoot) was significantly smaller (Two-way ANOVA, p < 0.05) in neurons from mice with 4NQO-induced oSCC (42.6 +- 3.6 mV) compared to neurons from vehicle-treated mice (61.4 +- 1.8 mV).	('4NQO-induced', 'Var', (174, 186))	('oSCC', 'Chemical', '-', (187, 191))	('mice', 'Species', '10090', (164, 168))	('4NQO', 'Chemical', 'MESH:D015112', (174, 178))	('smaller', 'NegReg', (114, 121))	('mice', 'Species', '10090', (250, 254))
13702	28885456	While there was no change in the afterhyperpolarization (AHP) magnitude between groups (p > 0.05), the AHP time constant (tau) of decay was significantly increased (One-way ANOVA, p < 0.05) in neurons from mice with 4NQO-induced oSCC (127.6 +- 16.8 ms) compared to neurons from vehicle-treated mice (61.7 +- 17.7 ms) suggesting increased AP firing potential.	('4NQO', 'Chemical', 'MESH:D015112', (216, 220))	('oSCC', 'Chemical', '-', (229, 233))	('4NQO-induced', 'Var', (216, 228))	('mice', 'Species', '10090', (206, 210))	('decay', 'MPA', (130, 135))	('AHP time constant', 'MPA', (103, 120))	('mice', 'Species', '10090', (294, 298))	('increased', 'PosReg', (154, 163))
13703	28885456	Furthermore, input resistance was lower in neurons from mice with 4NQO-induced oSCC (1389.3 +- 361.0 momega) compared to neurons from vehicle-treated mice (1704.6 +- 212.8 momega); however the groups were not statistically different (One-way ANOVA, p > 0.05).	('mice', 'Species', '10090', (150, 154))	('oSCC', 'Disease', (79, 83))	('input resistance', 'MPA', (13, 29))	('lower', 'NegReg', (34, 39))	('mice', 'Species', '10090', (56, 60))	('4NQO', 'Chemical', 'MESH:D015112', (66, 70))	('4NQO-induced', 'Var', (66, 78))	('oSCC', 'Chemical', '-', (79, 83))
13708	28885456	Consistent with previous studies and our data in the human cancer cells lines, there was a significant increase in TNFalpha (3644.3 +- 22.1%, Student's t test, p < 0.01) in 4NQO-induced oSCC tongue tissue compared to dysplastic tongue tissue (Figure 11A).	('oSCC', 'Chemical', '-', (186, 190))	('4NQO', 'Chemical', 'MESH:D015112', (173, 177))	('increase', 'PosReg', (103, 111))	('dysplastic tongue', 'Disease', (217, 234))	('dysplastic tongue', 'Disease', 'MESH:D014060', (217, 234))	('oSCC', 'Disease', (186, 190))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('TNFalpha', 'Gene', (115, 123))	('human', 'Species', '9606', (53, 58))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('4NQO-induced', 'Var', (173, 185))
13713	28885456	Furthermore, TNFalpha inhibition in oral cancer cell lines has been previously demonstrated to reduce cell viability, activate apoptosis, and inhibit migration.	('inhibition', 'Var', (22, 32))	('rat', 'Species', '10116', (86, 89))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('inhibit', 'NegReg', (142, 149))	('reduce', 'NegReg', (95, 101))	('rat', 'Species', '10116', (153, 156))	('apoptosis', 'CPA', (127, 136))	('activate', 'PosReg', (118, 126))	('oral cancer', 'Disease', 'MESH:D009062', (36, 47))	('migration', 'CPA', (150, 159))	('cell viability', 'CPA', (102, 116))	('oral cancer', 'Disease', (36, 47))	('TNFalpha', 'Gene', (13, 21))
13724	28885456	However, C87+DMEM also resulted in a significant increase in Ly6G+ neutrophils compared to DMEM alone (6.4 +- 1.4% and 0.53 +- 0.1%, p < 0.05; data not shown) suggesting C87 disrupted TNFalpha signaling in response to injection or the compound itself elicited an innate inflammatory reaction.	('Ly6G', 'Gene', '546644', (61, 65))	('increase', 'PosReg', (49, 57))	('elicited', 'Reg', (251, 259))	('DMEM', 'Chemical', '-', (13, 17))	('disrupted', 'NegReg', (174, 183))	('C87', 'Var', (170, 173))	('Ly6G', 'Gene', (61, 65))	('TNFalpha', 'Gene', (184, 192))	('C87+DMEM', 'Var', (9, 17))	('DMEM', 'Chemical', '-', (91, 95))
13736	28885456	Mice with 4NQO-induced severe dysplasia, the final precancerous step before cancer, demonstrated significant nociceptive behavior in the absence of a significant inflammatory response.	('rat', 'Species', '10116', (91, 94))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('dysplasia', 'Disease', 'MESH:D004476', (30, 39))	('4NQO', 'Chemical', 'MESH:D015112', (10, 14))	('4NQO-induced', 'Var', (10, 22))	('cancer', 'Disease', (54, 60))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('dysplasia', 'Disease', (30, 39))	('Mice', 'Species', '10090', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('nociceptive behavior', 'MPA', (109, 129))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))
13738	28885456	Inhibition of TNFalpha signaling with C87 abolished nociception and decreased the number of CD3+ T cells infiltrating into the tongue.	('decreased', 'NegReg', (68, 77))	('rat', 'Species', '10116', (111, 114))	('C87', 'Var', (38, 41))	('TNFalpha', 'Gene', (14, 22))	('CD3', 'Gene', '28134', (92, 95))	('abolished', 'NegReg', (42, 51))	('nociception', 'MPA', (52, 63))	('CD3', 'Gene', (92, 95))
13755	28885456	The 4NQO-induced carcinogenesis model best mimics the natural disease progression of oral cancer in humans; 4NQO causes DNA adduct formation similar to carcinogens found in tobacco.	('oral cancer', 'Disease', (85, 96))	('4NQO', 'Var', (108, 112))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('causes', 'Reg', (113, 119))	('4NQO', 'Chemical', 'MESH:D015112', (4, 8))	('carcinogenesis', 'Disease', 'MESH:D063646', (17, 31))	('carcinogenesis', 'Disease', (17, 31))	('4NQO', 'Chemical', 'MESH:D015112', (108, 112))	('tobacco', 'Species', '4097', (173, 180))	('oral cancer', 'Disease', 'MESH:D009062', (85, 96))	('DNA adduct formation', 'MPA', (120, 140))	('humans', 'Species', '9606', (100, 106))
13756	28885456	Ten to 20 weeks of treatment with 4NQO produces pre-neoplastic (i.e., dysplasia) and neoplastic (i.e., SCC) lesions in mice that exhibit similar histological, molecular, and chromosomal alterations observed in human carcinogenesis.	('4NQO', 'Var', (34, 38))	('mice', 'Species', '10090', (119, 123))	('dysplasia', 'Disease', (70, 79))	('4NQO', 'Chemical', 'MESH:D015112', (34, 38))	('dysplasia', 'Disease', 'MESH:D004476', (70, 79))	('rat', 'Species', '10116', (190, 193))	('carcinogenesis', 'Disease', 'MESH:D063646', (216, 230))	('human', 'Species', '9606', (210, 215))	('carcinogenesis', 'Disease', (216, 230))
13779	28724602	In conclusion, high expression of PLK1 is associated with the aggressive progression and poor prognosis in lung squamous cell carcinoma patients.	('high', 'Var', (15, 19))	('associated', 'Reg', (42, 52))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (107, 135))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (112, 135))	('patients', 'Species', '9606', (136, 144))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (107, 135))	('lung squamous cell carcinoma', 'Disease', (107, 135))	('PLK1', 'Gene', (34, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))
13787	28724602	Polo-like kinase 1 (PLK1) is a member of the mitotic serine/threonine kinases family, which were originally identified in the fruitfly, Drosophila melanogaster from mutants with abnormal spindle poles.	('Polo-like kinase 1', 'Gene', (0, 18))	('mutants', 'Var', (165, 172))	('Drosophila melanogaster', 'Species', '7227', (136, 159))	('PLK1', 'Gene', (20, 24))	('Polo-like kinase 1', 'Gene', '5347', (0, 18))
13790	28724602	In non-small cell lung cancer, silenced PLK1 expression by iNOP-7-PLK1 siRNA reduced tumor growth in vitro and in vivo, and PLK1 was the target for miR-100 to regulate non-small cell lung cancer cell proliferation, apoptosis, and cell cycle.	('tumor', 'Disease', (85, 90))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (172, 194))	('apoptosis', 'CPA', (215, 224))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (168, 194))	('non-small cell lung cancer', 'Disease', (3, 29))	('miR-100', 'Gene', '406892', (148, 155))	('PLK1', 'Gene', (40, 44))	('lung cancer', 'Phenotype', 'HP:0100526', (18, 29))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('lung cancer', 'Phenotype', 'HP:0100526', (183, 194))	('non-small cell lung cancer', 'Disease', (168, 194))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (3, 29))	('cell cycle', 'CPA', (230, 240))	('reduced', 'NegReg', (77, 84))	('regulate', 'Reg', (159, 167))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (7, 29))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (168, 194))	('miR-100', 'Gene', (148, 155))	('iNOP-7-PLK1', 'Var', (59, 70))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (3, 29))	('silenced', 'NegReg', (31, 39))
13849	28724602	reported hepatoblastoma patients with high expression of PLK1 represented obviously poorer outcomes than those with PLK1 low expression.	('hepatoblastoma', 'Disease', 'MESH:D018197', (9, 23))	('high expression', 'Var', (38, 53))	('PLK1', 'Gene', (57, 61))	('hepatoblastoma', 'Disease', (9, 23))	('hepatoblastoma', 'Phenotype', 'HP:0002884', (9, 23))	('patients', 'Species', '9606', (24, 32))	('poorer', 'NegReg', (84, 90))
13854	28724602	In the present study, we further presented the evidence that lung squamous cell carcinoma patients that expressed high level of PLK1 protein had lower overall survival compared with patients with low level of PLK1 protein expression, and PLK1 protein high expression was an independent poor prognostic factor based on univariate and multivariate survival analyses.	('protein', 'Protein', (133, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('PLK1', 'Gene', (128, 132))	('high level', 'Var', (114, 124))	('lung squamous cell carcinoma', 'Disease', (61, 89))	('patients', 'Species', '9606', (182, 190))	('lower', 'NegReg', (145, 150))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (61, 89))	('overall survival', 'MPA', (151, 167))	('patients', 'Species', '9606', (90, 98))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (66, 89))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (61, 89))
13856	28724602	PLK1 inhibitors include BI 2536 (Boehringer Ingelheim Pharma, Germany), Volasertib (BI 6727; Boehringer Ingelheim Pharma, Germany), GSK4661364A (GlaxoSmithKline, U.K.), HMN-214 (Nippon Shinyaku Co. Ltd, Japan), NMS-P937 (Nerviano Medical Science, Italy), TAK-960 (Tekmira Pharmaceuticals Co., Canada), and Rigosertib (Onconova Therapeutics Inc., U.S.A.).	('BI', 'Chemical', 'MESH:D001729', (84, 86))	('NMS', 'Disease', (211, 214))	('NMS', 'Disease', 'MESH:D009459', (211, 214))	('man', 'Species', '9606', (65, 68))	('HMN-214', 'CellLine', 'CVCL:U508', (169, 176))	('BI 2536', 'Chemical', 'MESH:C518477', (24, 31))	('PLK1', 'Gene', (0, 4))	('man', 'Species', '9606', (125, 128))	('BI', 'Chemical', 'MESH:D001729', (24, 26))	('GSK4661364A', 'Var', (132, 143))
13859	28724602	This first-in-man, phase I, dose-escalation study showed that BI 2536 was favorable in terms of manageable toxicity, high distribution into tissue, and favorable efficacy in cancer patients, which initiated further clinical studies.	('distribution', 'MPA', (122, 134))	('man', 'Species', '9606', (96, 99))	('cancer', 'Disease', (174, 180))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('toxicity', 'Disease', 'MESH:D064420', (107, 115))	('patients', 'Species', '9606', (181, 189))	('toxicity', 'Disease', (107, 115))	('BI 2536', 'Chemical', 'MESH:C518477', (62, 69))	('man', 'Species', '9606', (14, 17))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('BI 2536', 'Var', (62, 69))
13865	28724602	This open-label, phase I study showed that BI 2536 (200 mg) combined with standard-dose pemetrexed has an acceptable safety profile, and had a relatively favorable clinical efficacy, with 95.1% patients evaluating tumor response.	('patients', 'Species', '9606', (194, 202))	('tumor', 'Disease', 'MESH:D009369', (214, 219))	('BI 2536', 'Chemical', 'MESH:C518477', (43, 50))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('BI 2536', 'Var', (43, 50))	('tumor', 'Disease', (214, 219))	('pemetrexed', 'Chemical', 'MESH:D000068437', (88, 98))
13945	27535130	These transcriptome changes were validated using RNA-seq data from the knockdown of ESR1 and control in MCF7 cells (Additional file 2: Figure S4a and "Methods").	('ESR1', 'Gene', '2099', (84, 88))	('MCF7', 'CellLine', 'CVCL:0031', (104, 108))	('knockdown', 'Var', (71, 80))	('ESR1', 'Gene', (84, 88))
13956	27535130	Building stage signatures as before for ER+ and ER- independently (Additional file 9), we obtained average accuracies of AUC = 0.794 (ER-) and AUC = 0.756 (ER+) (Fig.	('ER', 'Gene', '2099', (48, 50))	('AUC = 0.756', 'Var', (143, 154))	('ER', 'Gene', '2099', (134, 136))	('ER', 'Gene', '2099', (156, 158))	('ER', 'Gene', '2099', (40, 42))	('AUC = 0.794', 'Var', (121, 132))
13988	27535130	Rather, transcript isoform changes appear linked to tumor-type specific processes, with several of them related to MYC activity, in concordance with recent findings.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumor', 'Disease', (52, 57))	('MYC', 'Gene', (115, 118))	('changes', 'Var', (27, 34))	('transcript isoform', 'MPA', (8, 26))	('MYC', 'Gene', '4609', (115, 118))	('related', 'Reg', (104, 111))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('linked', 'Reg', (42, 48))
14060	33335899	Similarly, CDR1as was found to promote the progression of cholangiocarcinoma and osteoarthritis by sponging miR-641.	('osteoarthritis', 'Disease', 'MESH:D010003', (81, 95))	('CDR1as', 'Gene', '103611090', (11, 17))	('miR-641', 'Gene', (108, 115))	('cholangiocarcinoma', 'Disease', (58, 76))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (58, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (58, 76))	('promote', 'PosReg', (31, 38))	('osteoarthritis', 'Phenotype', 'HP:0002758', (81, 95))	('osteoarthritis', 'Disease', (81, 95))	('miR-641', 'Gene', '693226', (108, 115))	('CDR1as', 'Gene', (11, 17))	('sponging', 'Var', (99, 107))
14061	33335899	Moreover, CDR1as was reported to sponge miR-135b-5p, miR-219a, miR-1299, and miR-876-5p in ovarian cancer, non-small-cell lung cancer and esophageal squamous cell carcinoma, respectively.	('ovarian cancer', 'Disease', 'MESH:D010051', (91, 105))	('miR-876', 'Gene', '100126310', (77, 84))	('miR-1299', 'Gene', (63, 71))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (138, 172))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (149, 172))	('miR-135b-5p', 'Var', (40, 51))	('lung cancer', 'Phenotype', 'HP:0100526', (122, 133))	('ovarian cancer', 'Disease', (91, 105))	('ovarian cancer', 'Phenotype', 'HP:0100615', (91, 105))	('miR-219a', 'Var', (53, 61))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('miR-876', 'Gene', (77, 84))	('CDR1as', 'Gene', (10, 16))	('miR-1299', 'Gene', '100302167', (63, 71))	('CDR1as', 'Gene', '103611090', (10, 16))	('carcinoma', 'Phenotype', 'HP:0030731', (163, 172))	('non-small-cell lung cancer', 'Disease', (107, 133))	('non-small-cell lung cancer', 'Disease', 'MESH:D002289', (107, 133))	('esophageal squamous cell carcinoma', 'Disease', (138, 172))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
14077	33335899	Furthermore, CDR1as knockdown inhibited tumor growth, invasion and metastasis by regulating the miR-219a-5p/SOX5 axis in non-small-cell lung cancer.	('regulating', 'Reg', (81, 91))	('lung cancer', 'Phenotype', 'HP:0100526', (136, 147))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('non-small-cell lung cancer', 'Disease', (121, 147))	('inhibited', 'NegReg', (30, 39))	('SOX5', 'Gene', '6660', (108, 112))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('non-small-cell lung cancer', 'Disease', 'MESH:D002289', (121, 147))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('CDR1as', 'Gene', (13, 19))	('SOX5', 'Gene', (108, 112))	('knockdown', 'Var', (20, 29))	('tumor', 'Disease', (40, 45))	('CDR1as', 'Gene', '103611090', (13, 19))
14078	33335899	Similarly, the knockdown of CDR1as could inhibit tumor growth via miR-135p in ovarian cancer.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('knockdown', 'Var', (15, 24))	('ovarian cancer', 'Disease', 'MESH:D010051', (78, 92))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('tumor', 'Disease', (49, 54))	('miR-135p', 'Var', (66, 74))	('ovarian cancer', 'Disease', (78, 92))	('inhibit', 'NegReg', (41, 48))	('CDR1as', 'Gene', (28, 34))	('miR-135p', 'Chemical', '-', (66, 74))	('CDR1as', 'Gene', '103611090', (28, 34))	('ovarian cancer', 'Phenotype', 'HP:0100615', (78, 92))
14085	33335899	However, CDR1as was found to sponge miR-135b-5p and upregulate the expression of HIF1AN to inhibit the growth, invasion and metastasis of ovarian cancer, which shows that the roles of CDR1as in tumor metastasis vary in different cacer types (Figure 2).	('metastasis of ovarian cancer', 'Disease', (124, 152))	('CDR1as', 'Gene', (9, 15))	('HIF1AN', 'Gene', '55662', (81, 87))	('growth', 'CPA', (103, 109))	('expression', 'Var', (67, 77))	('inhibit', 'NegReg', (91, 98))	('HIF1AN', 'Gene', (81, 87))	('CDR1as', 'Gene', '103611090', (184, 190))	('CDR1as', 'Gene', '103611090', (9, 15))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('metastasis of ovarian cancer', 'Disease', 'MESH:D009362', (124, 152))	('ovarian cancer', 'Phenotype', 'HP:0100615', (138, 152))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('tumor', 'Disease', (194, 199))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('upregulate', 'PosReg', (52, 62))	('CDR1as', 'Gene', (184, 190))
14087	33335899	A number of studies have demonstrated that the dysregulated expression of CDR1as is related to cancer chemoresistance.	('expression', 'MPA', (60, 70))	('related', 'Reg', (84, 91))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('CDR1as', 'Gene', (74, 80))	('cancer', 'Disease', (95, 101))	('CDR1as', 'Gene', '103611090', (74, 80))	('dysregulated', 'Var', (47, 59))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))
14088	33335899	Two studies showed that the knockdown of CDR1as could increase the chemosensitivity of 5-fluorouracyl- and cisplatin-resistant breast cancer cells by sponging miR-7.	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('cisplatin', 'Chemical', 'MESH:D002945', (107, 116))	('breast cancer', 'Disease', 'MESH:D001943', (127, 140))	('increase', 'PosReg', (54, 62))	('breast cancer', 'Disease', (127, 140))	('breast cancer', 'Phenotype', 'HP:0003002', (127, 140))	('knockdown', 'Var', (28, 37))	('CDR1as', 'Gene', (41, 47))	('5-fluorouracyl', 'Chemical', '-', (87, 101))	('CDR1as', 'Gene', '103611090', (41, 47))
14097	33335899	In detail, high CDR1as expression was associated with worse clinicopathological characteristics, including the T status, N status, histological grade, TNM stage and distant metastasis in solid tumors, such as esophageal squamous cell carcinoma (ESCC), non-small cell lung cancer (NSCLC), colorectal cancer (CC), and hepatocellular carcinoma.	('lung cancer', 'Phenotype', 'HP:0100526', (267, 278))	('colorectal cancer', 'Disease', (288, 305))	('cancer', 'Phenotype', 'HP:0002664', (272, 278))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (316, 340))	('esophageal squamous cell carcinoma', 'Disease', (209, 243))	('tumors', 'Disease', 'MESH:D009369', (193, 199))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (252, 278))	('hepatocellular carcinoma', 'Disease', (316, 340))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (256, 278))	('colorectal cancer', 'Phenotype', 'HP:0003003', (288, 305))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (209, 243))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (220, 243))	('carcinoma', 'Phenotype', 'HP:0030731', (331, 340))	('lung cancer', 'Disease', (267, 278))	('tumors', 'Phenotype', 'HP:0002664', (193, 199))	('carcinoma', 'Phenotype', 'HP:0030731', (234, 243))	('distant metastasis', 'CPA', (165, 183))	('NSCLC', 'Disease', 'MESH:D002289', (280, 285))	('expression', 'MPA', (23, 33))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (316, 340))	('CDR1as', 'Gene', (16, 22))	('tumors', 'Disease', (193, 199))	('CDR1as', 'Gene', '103611090', (16, 22))	('cancer', 'Phenotype', 'HP:0002664', (299, 305))	('lung cancer', 'Disease', 'MESH:D008175', (267, 278))	('colorectal cancer', 'Disease', 'MESH:D015179', (288, 305))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('high', 'Var', (11, 15))	('NSCLC', 'Disease', (280, 285))
14099	33335899	In addition, the expression of CDR1as was found to be associated with poor prognosis in cancer patients.	('CDR1as', 'Gene', '103611090', (31, 37))	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('patients', 'Species', '9606', (95, 103))	('expression', 'Var', (17, 27))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('CDR1as', 'Gene', (31, 37))	('associated', 'Reg', (54, 64))
14110	32042337	Conclusion: Our results suggest that ZNF750 may act as a tumor suppressor by directly repressing SNAI1 and inhibiting EMT process in ESCC and other types of SCC.	('SCC', 'Phenotype', 'HP:0002860', (157, 160))	('repressing', 'NegReg', (86, 96))	('SCC', 'Phenotype', 'HP:0002860', (134, 137))	('ESCC', 'Disease', (133, 137))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('ZNF750', 'Var', (37, 43))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('inhibiting', 'NegReg', (107, 117))	('EMT process', 'CPA', (118, 129))	('tumor', 'Disease', (57, 62))	('SNAI1', 'Gene', (97, 102))
14113	32042337	As reported, the frameshift mutation and the variation of the promoter region in ZNF750 gene may lead to lower protein expression and result in the occurrence of seborrheic dermatitis-like psoriasis.	('lower', 'NegReg', (105, 110))	('seborrheic dermatitis-like psoriasis', 'Disease', 'MESH:D012628', (162, 198))	('protein expression', 'MPA', (111, 129))	('result in', 'Reg', (134, 143))	('seborrheic dermatitis-like psoriasis', 'Disease', (162, 198))	('variation', 'Var', (45, 54))	('seborrheic dermatitis', 'Phenotype', 'HP:0001051', (162, 183))	('dermatitis', 'Phenotype', 'HP:0011123', (173, 183))	('frameshift mutation', 'Var', (17, 36))	('psoriasis', 'Phenotype', 'HP:0003765', (189, 198))	('occurrence', 'Reg', (148, 158))	('ZNF750', 'Gene', (81, 87))
14115	32042337	Here, we verified the tumor-suppressor role of ZNF750 in ESCC and elaborated on its possible mechanisms that ZNF750 directly bound to the promoter region of Snail Family Transcriptional Repressor 1 (SNAI1) and down-regulated the expression of SNAI1 to inhibit the epithelial-mesenchymal transition (EMT) of ESCC cells, in order to provide useful clues for clinical treatment of ESCC.	('SCC', 'Phenotype', 'HP:0002860', (58, 61))	('inhibit', 'NegReg', (252, 259))	('ESCC', 'Disease', (57, 61))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('ZNF750', 'Var', (109, 115))	('down-regulated', 'NegReg', (210, 224))	('SNAI1', 'Gene', (243, 248))	('bound', 'Interaction', (125, 130))	('tumor', 'Disease', (22, 27))	('SCC', 'Phenotype', 'HP:0002860', (379, 382))	('SCC', 'Phenotype', 'HP:0002860', (308, 311))	('expression', 'MPA', (229, 239))
14119	32042337	In addition, through cBioPortal based on the Cancer Genome Atlas (TCGA) or other cancer genome database, we found that the inactivating mutation rates of ZNF750 in different squamous cell carcinomas (SCC) were much higher than those in the corresponding adenocarcinomas (Figure 1C).	('ZNF750', 'Gene', (154, 160))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (174, 198))	('squamous cell carcinomas', 'Disease', (174, 198))	('higher', 'PosReg', (215, 221))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('adenocarcinomas', 'Disease', 'MESH:D000230', (254, 269))	('carcinoma', 'Phenotype', 'HP:0030731', (259, 268))	('carcinomas', 'Phenotype', 'HP:0030731', (259, 269))	('cancer', 'Disease', (81, 87))	('inactivating mutation', 'Var', (123, 144))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (174, 198))	('Cancer', 'Phenotype', 'HP:0002664', (45, 51))	('adenocarcinomas', 'Disease', (254, 269))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (174, 197))	('SCC', 'Phenotype', 'HP:0002860', (200, 203))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (188, 197))	('carcinomas', 'Phenotype', 'HP:0030731', (188, 198))
14120	32042337	Similarly, the ratio of truncating and missense mutation was 3.93% (7/178) in lung squamous cell carcinoma (LUSC), however, there was no truncating or missense mutation of ZNF750 gene in lung adenocarcinoma (LUAC).	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (78, 106))	('missense mutation', 'Var', (151, 168))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (187, 206))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (187, 206))	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('LUSC', 'Phenotype', 'HP:0030359', (108, 112))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (83, 106))	('lung squamous cell carcinoma', 'Disease', (78, 106))	('ZNF750', 'Gene', (172, 178))	('lung adenocarcinoma', 'Disease', (187, 206))	('LUAC', 'Phenotype', 'HP:0030078', (208, 212))	('carcinoma', 'Phenotype', 'HP:0030731', (197, 206))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (78, 106))	('missense mutation', 'Var', (39, 56))
14123	32042337	To detect the protein level of ZNF750 in ESCC, we detected its expression in several paired of fresh tumors with or without ZNF750 mutation.	('tumors', 'Disease', 'MESH:D009369', (101, 107))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('SCC', 'Phenotype', 'HP:0002860', (42, 45))	('expression', 'MPA', (63, 73))	('detected', 'Reg', (50, 58))	('ZNF750', 'Gene', (124, 130))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('tumors', 'Disease', (101, 107))	('mutation', 'Var', (131, 139))
14128	32042337	The patients with ZNF750low had a deeper invasion and a worse prognosis compared with the ZNF750high patients.	('deeper invasion', 'Disease', (34, 49))	('deeper invasion', 'Disease', 'MESH:D009361', (34, 49))	('ZNF750low', 'Var', (18, 27))
14138	32042337	The results showed that tumor growth rate of ZNF750wt group was significantly slower than that of the NC group (t-test, P < 0.01, Figure 4F).	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('slower', 'NegReg', (78, 84))	('tumor', 'Disease', (24, 29))	('ZNF750wt', 'Var', (45, 53))	('tumor', 'Disease', 'MESH:D009369', (24, 29))
14139	32042337	The xenograft mice model results showed that the mean tumor volume of the control group, SCR group and the ZNF750wt group were (1212.41 +- 157.84) mm3, (394.74 +- 33.83) mm3, respectively.	('394.74', 'Var', (153, 159))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('1212.41 +-', 'Var', (128, 138))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumor', 'Disease', (54, 59))
14141	32042337	Taken together, the results suggested that ZNF750 gene may act as a tumor suppressor in ESCC and its inactivating-mutation or decreased expression may promote the malignant phenotype of ESCC cells, such as invasion, migration and so on.	('tumor', 'Disease', (68, 73))	('decreased', 'NegReg', (126, 135))	('ESCC', 'Disease', (88, 92))	('expression', 'MPA', (136, 146))	('invasion', 'CPA', (206, 214))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('SCC', 'Phenotype', 'HP:0002860', (187, 190))	('promote', 'PosReg', (151, 158))	('migration', 'CPA', (216, 225))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('malignant phenotype', 'CPA', (163, 182))	('ZNF750', 'Gene', (43, 49))	('ESCC', 'Disease', (186, 190))	('inactivating-mutation', 'Var', (101, 122))	('SCC', 'Phenotype', 'HP:0002860', (89, 92))
14144	32042337	The results showed SNAI1 knockdown decreased the proliferation (Figure 6F), colony formation (Figure 6G), migration (Figure 6H) and invasion (Figure 6I) induced by ZNF750 knockdown in KYSE140 cells.	('KYSE140', 'CellLine', 'CVCL:1347', (184, 191))	('ZNF750', 'Gene', (164, 170))	('colony formation', 'CPA', (76, 92))	('proliferation', 'CPA', (49, 62))	('SNAI1', 'Gene', (19, 24))	('decreased', 'NegReg', (35, 44))	('knockdown', 'Var', (171, 180))	('migration', 'CPA', (106, 115))	('knockdown', 'Var', (25, 34))	('invasion', 'CPA', (132, 140))
14151	32042337	also implicated that ZNF750 harbored many early frameshift and nonsense mutations in head and neck and lung squamous cancers.	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('nonsense mutations', 'Var', (63, 81))	('ZNF750', 'Gene', (21, 27))	('cancers', 'Phenotype', 'HP:0002664', (117, 124))	('lung squamous cancers', 'Disease', 'MESH:D008175', (103, 124))	('lung squamous cancers', 'Disease', (103, 124))	('frameshift', 'Var', (48, 58))
14155	32042337	Its truncation mutation, or copy number loss, or other factors, may cause its inactivation or down-regulation, which may lead to the dedifferentiation and reprogram of squamous epithelium cells and result in tumorigenesis of ESCC.	('truncation mutation', 'Var', (4, 23))	('ESCC', 'Disease', (225, 229))	('SCC', 'Phenotype', 'HP:0002860', (226, 229))	('tumor', 'Disease', 'MESH:D009369', (208, 213))	('dedifferentiation', 'CPA', (133, 150))	('result in', 'Reg', (198, 207))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('reprogram', 'CPA', (155, 164))	('inactivation', 'MPA', (78, 90))	('tumor', 'Disease', (208, 213))	('lead to', 'Reg', (121, 128))	('down-regulation', 'NegReg', (94, 109))	('copy number loss', 'Var', (28, 44))
14158	32042337	Therefore, the decrease or inactivation of ZNF750 may lead SNAI1 to be free from the expression inhibition and trigger the EMT process associated with increased cancer invasion and metastasis.	('increased', 'PosReg', (151, 160))	('decrease', 'NegReg', (15, 23))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('inactivation', 'Var', (27, 39))	('EMT process', 'CPA', (123, 134))	('trigger', 'PosReg', (111, 118))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('SNAI1', 'Gene', (59, 64))	('cancer', 'Disease', (161, 167))	('metastasis', 'CPA', (181, 191))	('ZNF750', 'Gene', (43, 49))
14159	32042337	In conclusion, our work shows that ZNF750, a novel significantly mutated gene in ESCC, may act as a tumor suppressor via directly regulating SNAI1 expression and inhibit the EMT process of ESCC cells.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('ZNF750', 'Var', (35, 41))	('SNAI1', 'Gene', (141, 146))	('SCC', 'Phenotype', 'HP:0002860', (82, 85))	('regulating', 'Reg', (130, 140))	('inhibit', 'NegReg', (162, 169))	('tumor', 'Disease', (100, 105))	('expression', 'MPA', (147, 157))	('ESCC', 'Gene', (81, 85))	('EMT process of ESCC cells', 'CPA', (174, 199))	('SCC', 'Phenotype', 'HP:0002860', (190, 193))	('tumor', 'Disease', 'MESH:D009369', (100, 105))
14160	32042337	Its decrease or inactivation may result in tumorigenesis and progression of ESCC, even in other types of SCC.	('progression', 'CPA', (61, 72))	('result in', 'Reg', (33, 42))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('decrease', 'NegReg', (4, 12))	('inactivation', 'Var', (16, 28))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('SCC', 'Phenotype', 'HP:0002860', (105, 108))	('ESCC', 'Disease', (76, 80))	('tumor', 'Disease', (43, 48))	('SCC', 'Phenotype', 'HP:0002860', (77, 80))
14220	29649929	Podoplanin expression in OSCC was recently shown to be associated with tumor invasion and lymph node metastasis, and podoplanin also possesses prometastatic activities, such as platelet-aggregating activity.	('prometastatic activities', 'CPA', (143, 167))	('lymph node metastasis', 'CPA', (90, 111))	('SCC', 'Gene', '6317', (26, 29))	('Podoplanin', 'Gene', (0, 10))	('associated', 'Reg', (55, 65))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('tumor', 'Disease', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('platelet-aggregating activity', 'CPA', (177, 206))	('SCC', 'Gene', (26, 29))	('podoplanin', 'Var', (117, 127))
14504	33858426	TRIM8 silencing and overexpression further verified the biological effects as those caused by miR-665.	('miR-665', 'Gene', '100126315', (94, 101))	('miR-665', 'Gene', (94, 101))	('silencing', 'Var', (6, 15))	('TRIM8', 'Gene', (0, 5))
14512	33858426	Particularly, silencing TRIM8 led to the similar effects of miR-665 mimics in LUSC cells.	('silencing', 'Var', (14, 23))	('miR-665', 'Gene', (60, 67))	('miR-665', 'Gene', '100126315', (60, 67))	('LUSC', 'Phenotype', 'HP:0030359', (78, 82))	('TRIM8', 'Gene', (24, 29))
14513	33858426	Furthermore, miR-665 promoted LUSC cell proliferation through facilitating the Wnt5a/beta-catenin signaling pathway and restrained apoptosis via inhibiting Caspase-3 signaling pathway, whereas TRIM8 suppressed cell growth by repressing the Wnt5a/beta-catenin signaling pathway and induced apoptosis through activating Caspase-3 signaling pathway.	('repressing', 'PosReg', (225, 235))	('beta-catenin', 'Gene', (246, 258))	('suppressed', 'NegReg', (199, 209))	('Caspase-3 signaling pathway', 'Pathway', (318, 345))	('induced', 'Reg', (281, 288))	('beta-catenin', 'Gene', '1499', (246, 258))	('LUSC cell proliferation', 'CPA', (30, 53))	('TRIM8', 'Var', (193, 198))	('promoted', 'PosReg', (21, 29))	('inhibiting', 'NegReg', (145, 155))	('apoptosis', 'CPA', (131, 140))	('activating', 'PosReg', (307, 317))	('restrained', 'NegReg', (120, 130))	('beta-catenin', 'Gene', (85, 97))	('apoptosis', 'CPA', (289, 298))	('LUSC', 'Phenotype', 'HP:0030359', (30, 34))	('beta-catenin', 'Gene', '1499', (85, 97))	('Caspase-3 signaling pathway', 'Pathway', (156, 183))	('miR-665', 'Gene', (13, 20))	('miR-665', 'Gene', '100126315', (13, 20))	('facilitating', 'PosReg', (62, 74))	('cell growth', 'CPA', (210, 221))
14594	33858426	2e; p < 0.01); nevertheless, miR-665 inhibitor led to the marked accumulation in the G1/G0 phase and the decreasing of proportion of S and G2/M phase (Fig.	('decreasing', 'NegReg', (105, 115))	('accumulation', 'PosReg', (65, 77))	('miR-665', 'Gene', (29, 36))	('G1/G0 phase', 'CPA', (85, 96))	('miR-665', 'Gene', '100126315', (29, 36))	('inhibitor', 'Var', (37, 46))
14601	33858426	To confirm the target relationship between miR-665 and TRIM8, a dual-luciferase reporter system including the wild-type (WT) and mutant-type (MT) 3'-UTR of TRIM8 was fulfilled.	('miR-665', 'Gene', '100126315', (43, 50))	('mutant-type', 'Var', (129, 140))	('miR-665', 'Gene', (43, 50))
14603	33858426	The results showed that miR-665 mimics induced a significant reduction in luciferase activity of the WT 3'-UTR (TRIM8) binding site (p < 0.01), while miR-665 mimics failed to suppress the luciferase activity of the reporter construct containing the MT 3'-UTR (TRIM8) binding site, indicating that miR-665 directly targets the 3'-UTR of TRIM8 (Fig.	('miR-665', 'Gene', (297, 304))	('miR-665', 'Gene', (150, 157))	('miR-665', 'Gene', '100126315', (297, 304))	('reduction', 'NegReg', (61, 70))	('miR-665', 'Gene', '100126315', (150, 157))	('luciferase', 'Enzyme', (74, 84))	('miR-665', 'Gene', '100126315', (24, 31))	('luciferase', 'Enzyme', (188, 198))	('miR-665', 'Gene', (24, 31))	('activity', 'MPA', (85, 93))	('mimics', 'Var', (32, 38))
14615	33858426	TRIM8 knockdown markedly enhanced NCI-H226/SK-MES-1 cell proliferation after transfection with TRIM8 siRNA (Fig.	('NCI-H226/SK-MES-1', 'CellLine', 'CVCL:1544', (34, 51))	('enhanced', 'PosReg', (25, 33))	('NCI-H226/SK-MES-1 cell proliferation', 'CPA', (34, 70))	('TRIM8', 'Gene', (0, 5))	('knockdown', 'Var', (6, 15))
14616	33858426	In addition, TRIM8 siRNA upregulated Wnt5a, beta-Catenin, c-Myc and Cyclin D1 protein expressions, and downregulated active Caspase-3 protein expression in NCI-H226/SK-MES-1 cells (Fig.	('Cyclin', 'MPA', (68, 74))	('beta-Catenin', 'Protein', (44, 56))	('Wnt5a', 'Protein', (37, 42))	('c-Myc', 'Gene', (58, 63))	('TRIM8', 'Var', (13, 18))	('upregulated', 'PosReg', (25, 36))	('NCI-H226/SK-MES-1', 'CellLine', 'CVCL:1544', (156, 173))	('downregulated', 'NegReg', (103, 116))	('active Caspase-3 protein', 'Protein', (117, 141))	('c-Myc', 'Gene', '4609', (58, 63))
14618	33858426	The results showed that TRIM8 siRNA inhibited Wnt5a degradation in NCI-H226/SK-MES-1 cells (Fig.	('TRIM8', 'Var', (24, 29))	('inhibited', 'NegReg', (36, 45))	('NCI-H226/SK-MES-1', 'CellLine', 'CVCL:1544', (67, 84))	('Wnt5a degradation', 'MPA', (46, 63))
14619	33858426	The luciferase activity of TOPFLASH TCF-reporter remarkably increased in TRIM8 siRNA group compared with NC-siRNA group (Fig.	('activity', 'MPA', (15, 23))	('TCF', 'Gene', '3172', (36, 39))	('TCF', 'Gene', (36, 39))	('luciferase', 'Enzyme', (4, 14))	('TRIM8', 'Var', (73, 78))	('increased', 'PosReg', (60, 69))
14623	33858426	TRIM8 overexpression decreased Wnt5a, beta-Catenin, c-Myc and Cyclin D1 protein expressions, and increased active Caspase-3 protein expression in LUSC cells (Fig.	('Cyclin D1 protein expressions', 'MPA', (62, 91))	('c-Myc', 'Gene', '4609', (52, 57))	('increased', 'PosReg', (97, 106))	('LUSC', 'Phenotype', 'HP:0030359', (146, 150))	('overexpression', 'Var', (6, 20))	('c-Myc', 'Gene', (52, 57))	('decreased', 'NegReg', (21, 30))	('Wnt5a', 'MPA', (31, 36))	('TRIM8', 'Gene', (0, 5))	('active Caspase-3', 'MPA', (107, 123))	('beta-Catenin', 'MPA', (38, 50))
14627	33858426	The results of weights and sizes of tumors showed that tumor growth was remarkably restrained by LV-TRIM8 compared to LV-Ctrl (Fig.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumors', 'Disease', 'MESH:D009369', (36, 42))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('restrained', 'NegReg', (83, 93))	('tumor', 'Disease', (55, 60))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('LV-TRIM8', 'Var', (97, 105))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumors', 'Disease', (36, 42))	('tumor', 'Disease', (36, 41))
14633	33858426	Because a single miRNA can regulate multiple gene mRNAs, the disorder of miRNAs can result in the imbalance of RNA network in oncogenesis and development.	('imbalance of RNA network', 'MPA', (98, 122))	('miR', 'Gene', '220972', (17, 20))	('result in', 'Reg', (84, 93))	('miR', 'Gene', (17, 20))	('disorder', 'Var', (61, 69))	('oncogenesis', 'CPA', (126, 137))	('imbalance', 'Phenotype', 'HP:0002172', (98, 107))	('development', 'CPA', (142, 153))	('miR', 'Gene', '220972', (73, 76))	('miR', 'Gene', (73, 76))
14648	33858426	Recently, it is reported that TRIM8 inhibits gliomagenesis through the regulation of JAK-STAT signaling pathway.	('TRIM8', 'Var', (30, 35))	('inhibits', 'NegReg', (36, 44))	('gliomagenesis', 'Disease', (45, 58))	('STAT', 'Gene', '6774', (89, 93))	('STAT', 'Gene', (89, 93))
14663	33858426	The present study demonstrated that miR-665 mimics and silencing TRIM8 promoted LUSC cell proliferation and induced cell cycle G1-S phase transition through facilitating the Wnt5a/beta-catenin signaling pathway, whereas miR-665 inhibitor and TRIM8 overexpression suppressed cell proliferation and led to G1-S phase transition arrest via repressing the Wnt5a/beta-catenin signaling pathway.	('arrest', 'Disease', (326, 332))	('cell proliferation', 'CPA', (274, 292))	('beta-catenin', 'Gene', (358, 370))	('miR-665', 'Gene', (36, 43))	('miR-665', 'Gene', '100126315', (36, 43))	('beta-catenin', 'Gene', '1499', (358, 370))	('promoted', 'PosReg', (71, 79))	('LUSC', 'Phenotype', 'HP:0030359', (80, 84))	('silencing', 'Var', (55, 64))	('arrest', 'Disease', 'MESH:D006323', (326, 332))	('induced', 'PosReg', (108, 115))	('beta-catenin', 'Gene', (180, 192))	('beta-catenin', 'Gene', '1499', (180, 192))	('repressing', 'PosReg', (337, 347))	('cell cycle G1-S phase transition', 'CPA', (116, 148))	('LUSC cell proliferation', 'CPA', (80, 103))	('led to', 'Reg', (297, 303))	('facilitating', 'PosReg', (157, 169))	('miR-665', 'Gene', (220, 227))	('TRIM8', 'Gene', (65, 70))	('miR-665', 'Gene', '100126315', (220, 227))	('suppressed', 'NegReg', (263, 273))
14667	33858426	Some studies have found that TRIM8 can play a variety of biological functions by regulating the protein expressions of STAT3, Caspase-3, IRF3, IRF7, c-MYC, SOX2, NESTIN and CD133.	('regulating', 'Reg', (81, 91))	('IRF3', 'Gene', '3661', (137, 141))	('protein expressions', 'MPA', (96, 115))	('NESTIN', 'Gene', '10763', (162, 168))	('SOX2', 'Gene', (156, 160))	('CD133', 'Gene', (173, 178))	('Caspase-3', 'Protein', (126, 135))	('SOX2', 'Gene', '6657', (156, 160))	('IRF7', 'Gene', '3665', (143, 147))	('c-MYC', 'Gene', (149, 154))	('NESTIN', 'Gene', (162, 168))	('IRF7', 'Gene', (143, 147))	('CD133', 'Gene', '8842', (173, 178))	('STAT3', 'Gene', '6774', (119, 124))	('STAT3', 'Gene', (119, 124))	('c-MYC', 'Gene', '4609', (149, 154))	('IRF3', 'Gene', (137, 141))	('TRIM8', 'Var', (29, 34))
14669	33858426	The results showed that miR-665 mimics or silencing TRIM8 restrained LUSC cell apoptosis via inhibiting Caspase-3 signaling pathway; while miR-665 inhibitor and TRIM8 overexpression promote apoptosis through activating Caspase-3 signaling pathway.	('silencing', 'Var', (42, 51))	('apoptosis', 'CPA', (190, 199))	('LUSC', 'Phenotype', 'HP:0030359', (69, 73))	('miR-665', 'Gene', (139, 146))	('Caspase-3 signaling pathway', 'Pathway', (104, 131))	('promote', 'PosReg', (182, 189))	('miR-665', 'Gene', '100126315', (139, 146))	('miR-665', 'Gene', '100126315', (24, 31))	('activating', 'PosReg', (208, 218))	('Caspase-3 signaling pathway', 'Pathway', (219, 246))	('miR-665', 'Gene', (24, 31))	('LUSC cell apoptosis', 'CPA', (69, 88))	('inhibiting', 'NegReg', (93, 103))	('restrained', 'NegReg', (58, 68))	('TRIM8', 'Gene', (52, 57))
14733	33612111	Some studies have found that T cell depletion is one of the main phenotypes of genetic changes in patients with UTUC.	('patients', 'Species', '9606', (98, 106))	('T cell', 'MPA', (29, 35))	('changes', 'Var', (87, 94))	('UTUC', 'Disease', (112, 116))
14735	33612111	One clinical trial has shown that the FGFR inhibitor erdafitinib has offered significant benefit in the treatment of advanced urothelial cancer patients with FGFR changes, with a remission rate of approximately 40% (complete remission rate 3%, partial remission rate 37%).	('changes', 'Var', (163, 170))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('urothelial cancer', 'Disease', (126, 143))	('FGFR', 'Gene', (158, 162))	('patients', 'Species', '9606', (144, 152))	('urothelial cancer', 'Disease', 'MESH:D014523', (126, 143))	('erdafitinib', 'Chemical', 'MESH:C000604580', (53, 64))
14750	31176655	Chromosomal instability contributes to aneuploidy and is a driving force in carcinogenesis.	('aneuploidy', 'Disease', (39, 49))	('contributes', 'Reg', (24, 35))	('carcinogenesis', 'Disease', 'MESH:D063646', (76, 90))	('aneuploidy', 'Disease', 'MESH:D000782', (39, 49))	('Chromosomal instability', 'Phenotype', 'HP:0040012', (0, 23))	('Chromosomal instability', 'Var', (0, 23))	('carcinogenesis', 'Disease', (76, 90))
14751	31176655	Arsenic causes mitotic arrest and induces aneuploidy.	('aneuploidy', 'Disease', (42, 52))	('mitotic arrest', 'Disease', 'MESH:D006323', (15, 29))	('Arsenic', 'Chemical', 'MESH:D001151', (0, 7))	('aneuploidy', 'Disease', 'MESH:D000782', (42, 52))	('induces', 'Reg', (34, 41))	('Arsenic', 'Var', (0, 7))	('mitotic arrest', 'Disease', (15, 29))	('causes', 'Reg', (8, 14))
14771	31176655	Epidemiological studies from different countries and regions worldwide have confirmed that arsenic exposure via drinking water causes skin cancers.	('skin cancer', 'Phenotype', 'HP:0008069', (134, 145))	('skin cancers', 'Phenotype', 'HP:0008069', (134, 146))	('cancers', 'Phenotype', 'HP:0002664', (139, 146))	('causes', 'Reg', (127, 133))	('water', 'Chemical', 'MESH:D014867', (121, 126))	('skin cancers', 'Disease', (134, 146))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('skin cancers', 'Disease', 'MESH:D012878', (134, 146))	('arsenic', 'Chemical', 'MESH:D001151', (91, 98))	('arsenic', 'Var', (91, 98))
14783	31176655	In some cancers, dysregulated miRNAs promote genomic and chromosomal instability by targeting the mitotic checkpoint or DNA damage repair components.	('cancers', 'Disease', 'MESH:D009369', (8, 15))	('cancers', 'Phenotype', 'HP:0002664', (8, 15))	('cancers', 'Disease', (8, 15))	('promote', 'PosReg', (37, 44))	('miRNAs', 'Protein', (30, 36))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('dysregulated', 'Var', (17, 29))	('chromosomal instability', 'Phenotype', 'HP:0040012', (57, 80))
14805	31176655	HaCaT cells transfected with pEP-hsa-miR-186 Expression Vector or empty vector control were maintained with puromycin (0.9 mug/mL, P7255, Sigma-Aldrich, St Louis, MO, USA).	('puromycin', 'Chemical', 'MESH:D011691', (108, 117))	('HaCaT', 'CellLine', 'CVCL:0038', (0, 5))	('hsa-miR-186', 'Gene', '406962', (33, 44))	('P7255', 'Var', (131, 136))	('hsa-miR-186', 'Gene', (33, 44))
14811	31176655	NEB 5-alpha Competent E. coli cells were transformed with plasmids following 5 Minute Transformation protocol (C2987H/C2987I).	('C2987H', 'Var', (111, 117))	('C2987I', 'SUBSTITUTION', 'None', (118, 124))	('E. coli', 'Species', '562', (22, 29))	('C2987H', 'SUBSTITUTION', 'None', (111, 117))	('C2987I', 'Var', (118, 124))
14826	31176655	The membranes were then incubated with antibodies against BUB1 (1:1000; #ab195268, Abcam, Cambridge, United Kingdom), CDC27 (1:1000; #ab129085, Abcam) and beta-Actin (1:20000, A5441, Sigma-Aldrich).	('BUB1', 'Gene', '699', (58, 62))	('1:1000; #ab195268', 'Var', (64, 81))	('beta-Actin', 'Gene', (155, 165))	('BUB1', 'Gene', (58, 62))	('beta-Actin', 'Gene', '728378', (155, 165))	('CDC27', 'Gene', '996', (118, 123))	('1:1000; #ab129085', 'Var', (125, 142))	('CDC27', 'Gene', (118, 123))
14827	31176655	Subsequently, the membranes were incubated with either anti-rabbit (1:1000; #7074, Cell Signaling Technology, Danvers, MA, USA) or anti-mouse (1:10000; #7076, Cell Signaling Technology) HRP-linked antibodies.	('HRP-linked antibodies', 'Protein', (186, 207))	('1:10000; #7076', 'Var', (143, 157))	('mouse', 'Species', '10090', (136, 141))	('1:1000; #7074', 'Var', (68, 81))
14830	31176655	Aberrant expression of hsa-miR-186 has been reported in a variety of cancers.	('cancers', 'Disease', 'MESH:D009369', (69, 76))	('Aberrant', 'Var', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('hsa-miR-186', 'Gene', '406962', (23, 34))	('reported', 'Reg', (44, 52))	('cancers', 'Phenotype', 'HP:0002664', (69, 76))	('hsa-miR-186', 'Gene', (23, 34))	('cancers', 'Disease', (69, 76))
14844	31176655	Continued culture to 8 weeks further enhanced expression in hsa-miR-186 transfected cells to 4.5-fold and 5.1-fold empty vector control transfected cells incubated with 0 and 100 nM sodium arsenite respectively.	('expression', 'MPA', (46, 56))	('transfected', 'Var', (72, 83))	('sodium arsenite', 'Chemical', 'MESH:C017947', (182, 197))	('hsa-miR-186', 'Gene', '406962', (60, 71))	('enhanced', 'PosReg', (37, 45))	('hsa-miR-186', 'Gene', (60, 71))
14850	31176655	5), suggesting hsa-miR-186 overexpression is inducing endomitosis.	('overexpression', 'Var', (27, 41))	('endomitosis', 'Disease', 'None', (54, 65))	('inducing', 'Reg', (45, 53))	('hsa-miR-186', 'Gene', '406962', (15, 26))	('hsa-miR-186', 'Gene', (15, 26))	('endomitosis', 'Disease', (54, 65))
14853	31176655	6A) can be compared with metaphase spreads of cells from hsa-miR-186 overexpressing clones showing supernumerary chromosomes (152 chromosomes) including dicentrics (Fig.	('hsa-miR-186', 'Gene', '406962', (57, 68))	('hsa-miR-186', 'Gene', (57, 68))	('dicentrics', 'Var', (153, 163))
14869	31176655	Furthermore, dysregulated securin could lead to chromatid segregation defects contributing to aneuploidy, which in turn contributes to carcinogenesis.	('carcinogenesis', 'Disease', (135, 149))	('chromatid segregation defects', 'CPA', (48, 77))	('lead to', 'Reg', (40, 47))	('contributes', 'Reg', (120, 131))	('aneuploidy', 'Disease', (94, 104))	('securin', 'Protein', (26, 33))	('aneuploidy', 'Disease', 'MESH:D000782', (94, 104))	('carcinogenesis', 'Disease', 'MESH:D063646', (135, 149))	('contributing', 'Reg', (78, 90))	('dysregulated', 'Var', (13, 25))
14886	31176655	Mutations and deletion of BUB1 have been identified in some aneuploid tumor cell lines and primary tumors.	('tumors', 'Phenotype', 'HP:0002664', (99, 105))	('aneuploid tumor', 'Disease', 'MESH:D000782', (60, 75))	('aneuploid tumor', 'Disease', (60, 75))	('identified', 'Reg', (41, 51))	('tumors', 'Disease', 'MESH:D009369', (99, 105))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('BUB1', 'Gene', '699', (26, 30))	('Mutations', 'Var', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('deletion', 'Var', (14, 22))	('BUB1', 'Gene', (26, 30))	('tumors', 'Disease', (99, 105))
14899	31176655	Genetic instability including both numerical and structural chromosomal abnormalities is a hallmark of cancer.	('chromosomal abnormalities', 'Disease', (60, 85))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('Genetic instability', 'Var', (0, 19))	('hallmark of cancer', 'Disease', (91, 109))	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (60, 85))	('numerical', 'Var', (35, 44))	('hallmark of cancer', 'Disease', 'MESH:D009369', (91, 109))
14905	31176655	DMs are small fragments of extrachromosomal DNA that can harbor oncogenes, and the amplification of oncogenes is associated with the onset of certain types of carcinogenesis.	('carcinogenesis', 'Disease', (159, 173))	('associated with', 'Reg', (113, 128))	('amplification', 'Var', (83, 96))	('carcinogenesis', 'Disease', 'MESH:D063646', (159, 173))
14914	31176655	Additionally, chronic arsenite exposure for 4 or 8 weeks increases aneuploidy in hsa-miR-186 overexpressing cells but not in the absence of hsa-miR-186 overexpression.	('overexpressing', 'Var', (93, 107))	('arsenite', 'Chemical', 'MESH:C015001', (22, 30))	('aneuploidy', 'Disease', (67, 77))	('hsa-miR-186', 'Gene', '406962', (81, 92))	('hsa-miR-186', 'Gene', '406962', (140, 151))	('increases', 'PosReg', (57, 66))	('hsa-miR-186', 'Gene', (81, 92))	('hsa-miR-186', 'Gene', (140, 151))	('aneuploidy', 'Disease', 'MESH:D000782', (67, 77))
14916	31176655	Finally, dysregulation of cell cycle components such as BUB1 by hsa-miR-186 overexpression likely lead to chromosomal instability.	('BUB1', 'Gene', '699', (56, 60))	('chromosomal instability', 'Phenotype', 'HP:0040012', (106, 129))	('lead to', 'Reg', (98, 105))	('BUB1', 'Gene', (56, 60))	('hsa-miR-186', 'Gene', '406962', (64, 75))	('chromosomal instability', 'MPA', (106, 129))	('hsa-miR-186', 'Gene', (64, 75))	('dysregulation', 'Var', (9, 22))	('overexpression', 'PosReg', (76, 90))
14930	31405076	found that the mutation of TP53 has an impact on the prognosis of breast and several other cancers.	('TP53', 'Gene', '7157', (27, 31))	('mutation', 'Var', (15, 23))	('TP53', 'Gene', (27, 31))	('cancers', 'Disease', 'MESH:D009369', (91, 98))	('cancers', 'Phenotype', 'HP:0002664', (91, 98))	('breast', 'Disease', (66, 72))	('impact', 'Reg', (39, 45))	('cancers', 'Disease', (91, 98))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))
14946	31405076	For example, BRCA1 gene mutation is often found in both breast and ovarian cancers.	('ovarian cancers', 'Phenotype', 'HP:0100615', (67, 82))	('BRCA1', 'Gene', (13, 18))	('cancers', 'Phenotype', 'HP:0002664', (75, 82))	('breast and ovarian cancers', 'Disease', 'MESH:D061325', (56, 82))	('BRCA', 'Phenotype', 'HP:0003002', (13, 17))	('found', 'Reg', (42, 47))	('mutation', 'Var', (24, 32))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('BRCA1', 'Gene', '672', (13, 18))
14961	31405076	adopted a bottom-up approach to quantify the effects of gene expression variations and identified novel recurrent regulatory mutations influencing known cancer genes, such as GRIN2D and NKX2-1, in multiple cancer types.	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('mutations', 'Var', (125, 134))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('cancer', 'Disease', (153, 159))	('GRIN2D', 'Gene', (175, 181))	('cancer type', 'Disease', (206, 217))	('NKX2-1', 'Gene', (186, 192))	('variations', 'Var', (72, 82))	('multiple cancer', 'Disease', 'MESH:D009369', (197, 212))	('GRIN2D', 'Gene', '2906', (175, 181))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('cancer type', 'Disease', 'MESH:D009369', (206, 217))	('NKX2-1', 'Gene', '7080', (186, 192))	('cancer', 'Disease', (206, 212))	('cancer', 'Disease', 'MESH:D009369', (206, 212))	('multiple cancer', 'Disease', (197, 212))
15013	31405076	The dysregulation of transcription factors can alter the expressions of target genes and lead to the tumorigenic process.	('alter', 'Reg', (47, 52))	('lead to', 'Reg', (89, 96))	('dysregulation', 'Var', (4, 17))	('tumor', 'Disease', (101, 106))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('expressions', 'MPA', (57, 68))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
15034	31405076	demonstrated that the expression of CCAR2 is significantly associated with a higher clinical stage and predicted shorter survival in osteosarcoma.	('osteosarcoma', 'Disease', 'MESH:D012516', (133, 145))	('survival', 'MPA', (121, 129))	('CCAR2', 'Gene', (36, 41))	('expression', 'Var', (22, 32))	('higher', 'PosReg', (77, 83))	('associated', 'Reg', (59, 69))	('clinical stage', 'CPA', (84, 98))	('shorter', 'NegReg', (113, 120))	('osteosarcoma', 'Disease', (133, 145))	('CCAR2', 'Gene', '57805', (36, 41))	('osteosarcoma', 'Phenotype', 'HP:0002669', (133, 145))
15038	31405076	on women from northeast China suggested that breast cancer risk and prognosis may be affected by BTLA gene polymorphisms.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('breast cancer', 'Disease', 'MESH:D001943', (45, 58))	('affected', 'Reg', (85, 93))	('breast cancer', 'Disease', (45, 58))	('polymorphisms', 'Var', (107, 120))	('breast cancer', 'Phenotype', 'HP:0003002', (45, 58))	('women', 'Species', '9606', (3, 8))	('BTLA', 'Gene', (97, 101))	('BTLA', 'Gene', '151888', (97, 101))
15046	31405076	It has been demonstrated that protein annexin A1, A2, A4 and A5 play an important role in the occurrence and development of these two cancer types, and BRCA1 and BRCA2 gene mutations are commonly observed in both cancer types.	('cancer type', 'Disease', (213, 224))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('BRCA2', 'Gene', (162, 167))	('BRCA', 'Phenotype', 'HP:0003002', (162, 166))	('BRCA', 'Phenotype', 'HP:0003002', (152, 156))	('annexin A1', 'Gene', '301', (38, 48))	('cancer type', 'Disease', 'MESH:D009369', (134, 145))	('BRCA1', 'Gene', '672', (152, 157))	('cancer type', 'Disease', 'MESH:D009369', (213, 224))	('BRCA2', 'Gene', '675', (162, 167))	('annexin A1', 'Gene', (38, 48))	('mutations', 'Var', (173, 182))	('observed', 'Reg', (196, 204))	('BRCA1', 'Gene', (152, 157))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('cancer type', 'Disease', (134, 145))
15051	31405076	For example, for LUSC, the average C-statistic values are 0.748 (B1), 0.649 (B2), and 0.612 (B3).	('0.612', 'Var', (86, 91))	('LUSC', 'Phenotype', 'HP:0030359', (17, 21))	('0.649', 'Var', (70, 75))	('LUSC', 'Disease', 'MESH:D002294', (17, 21))	('LUSC', 'Disease', (17, 21))
15077	31496806	The expression level of KRT17 was increased or decreased by KRT17 gene transfection or small RNA interference in lung cancer cells, respectively.	('expression level', 'MPA', (4, 20))	('KRT17', 'Gene', (24, 29))	('lung cancer', 'Disease', (113, 124))	('lung cancer', 'Phenotype', 'HP:0100526', (113, 124))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('small RNA interference', 'MPA', (87, 109))	('lung cancer', 'Disease', 'MESH:D008175', (113, 124))	('increased', 'PosReg', (34, 43))	('KRT17', 'Gene', (60, 65))	('gene transfection', 'Var', (66, 83))	('decreased', 'NegReg', (47, 56))
15080	31496806	High expression of KRT17 predicted poor prognosis of patients with NSCLCs, especially lung adenocarcinomas, and was correlated with poor differentiation and lymphatic metastasis.	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (86, 106))	('carcinomas', 'Phenotype', 'HP:0030731', (96, 106))	('poor differentiation', 'CPA', (132, 152))	('especially lung adenocarcinomas', 'Disease', 'MESH:D000077192', (75, 106))	('High', 'Var', (0, 4))	('patients', 'Species', '9606', (53, 61))	('especially lung adenocarcinomas', 'Disease', (75, 106))	('NSCLC', 'Phenotype', 'HP:0030358', (67, 72))	('NSCLCs', 'Disease', (67, 73))	('KRT17', 'Gene', (19, 24))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (86, 105))	('correlated', 'Reg', (116, 126))	('NSCLCs', 'Disease', 'MESH:D002289', (67, 73))
15084	31496806	Overexpression of KRT17 is common in NSCLCs and indicates poor prognosis.	('KRT17', 'Gene', (18, 23))	('NSCLC', 'Phenotype', 'HP:0030358', (37, 42))	('NSCLCs', 'Disease', (37, 43))	('Overexpression', 'Var', (0, 14))	('NSCLCs', 'Disease', 'MESH:D002289', (37, 43))
15099	31496806	In a mouse model of skin basaloid tumors with Gli2 gene transfection, KRT17 gene knockout significantly inhibited tumor development and growth.	('skin basaloid tumors', 'Disease', (20, 40))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('tumor', 'Disease', (34, 39))	('KRT17', 'Gene', (70, 75))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('skin basaloid tumors', 'Disease', 'MESH:D012878', (20, 40))	('mouse', 'Species', '10090', (5, 10))	('basaloid tumors', 'Phenotype', 'HP:0002671', (25, 40))	('knockout', 'Var', (81, 89))	('tumor', 'Disease', (114, 119))	('inhibited', 'NegReg', (104, 113))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('Gli2', 'Gene', (46, 50))	('men', 'Species', '9606', (127, 130))	('Gli2', 'Gene', '14633', (46, 50))
15134	31496806	In LUADs, high KRT17 expression was associated with poor differentiation (P=0.036), advanced TNM stage (P=0.005) and lymph node metastasis (P=0.011).	('lymph node metastasis', 'CPA', (117, 138))	('LUAD', 'Disease', 'None', (3, 7))	('LUAD', 'Disease', (3, 7))	('LUAD', 'Phenotype', 'HP:0030078', (3, 7))	('TNM', 'Gene', '10178', (93, 96))	('expression', 'MPA', (21, 31))	('high', 'Var', (10, 14))	('KRT17', 'Gene', (15, 20))	('TNM', 'Gene', (93, 96))	('poor differentiation', 'CPA', (52, 72))
15138	31496806	In total lung cancers, the survival time was shorter in patients with high KRT17 expression than in patients with low KRT17 expression (P<0.001, Supplementary Figure 1).	('men', 'Species', '9606', (151, 154))	('patients', 'Species', '9606', (56, 64))	('lung cancers', 'Disease', 'MESH:D008175', (9, 21))	('lung cancers', 'Phenotype', 'HP:0100526', (9, 21))	('shorter', 'NegReg', (45, 52))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('lung cancers', 'Disease', (9, 21))	('patients', 'Species', '9606', (100, 108))	('survival time', 'CPA', (27, 40))	('high', 'Var', (70, 74))	('KRT17', 'Gene', (75, 80))	('cancers', 'Phenotype', 'HP:0002664', (14, 21))	('lung cancer', 'Phenotype', 'HP:0100526', (9, 20))
15139	31496806	High expression of KRT17 also indicated poor survival in LUADs (P=0.014, Supplementary Figure 1), which was consistent with total lung cancers.	('lung cancers', 'Disease', (130, 142))	('men', 'Species', '9606', (79, 82))	('poor', 'NegReg', (40, 44))	('lung cancer', 'Phenotype', 'HP:0100526', (130, 141))	('cancers', 'Phenotype', 'HP:0002664', (135, 142))	('High', 'Var', (0, 4))	('lung cancers', 'Disease', 'MESH:D008175', (130, 142))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('lung cancers', 'Phenotype', 'HP:0100526', (130, 142))	('KRT17', 'Gene', (19, 24))	('LUAD', 'Phenotype', 'HP:0030078', (57, 61))	('LUAD', 'Disease', 'None', (57, 61))	('LUAD', 'Disease', (57, 61))
15140	31496806	We elevated KRT17 expression by gene transfection in A549 (A549-KRT17) and H1299 (H1299-KRT17) cells.	('H1299-KRT17', 'CellLine', 'CVCL:0060', (82, 93))	('A549-KRT17', 'CellLine', 'CVCL:0023', (59, 69))	('A549', 'CellLine', 'CVCL:0023', (59, 63))	('gene transfection', 'Var', (32, 49))	('H1299', 'CellLine', 'CVCL:0060', (82, 87))	('H1299', 'CellLine', 'CVCL:0060', (75, 80))	('expression', 'MPA', (18, 28))	('KRT17', 'Gene', (12, 17))	('elevated', 'PosReg', (3, 11))	('A549', 'CellLine', 'CVCL:0023', (53, 57))
15142	31496806	In A549-KRT17 and H1299-KRT17 cells, overexpression of KRT17 promoted proliferation (P<0.05 and P<0.05, respectively) (Figure 2A) colony formation (P=0.010 and P=0.032, respectively) (Figure 2B) and invasiveness (P=0.002 and P=0.001, respectively) (Figure 2C).	('H1299-KRT17', 'Var', (18, 29))	('overexpression', 'PosReg', (37, 51))	('A549-KRT17', 'CellLine', 'CVCL:0023', (3, 13))	('promoted', 'PosReg', (61, 69))	('KRT17', 'Gene', (55, 60))	('proliferation', 'CPA', (70, 83))	('colony formation', 'CPA', (130, 146))	('H1299-KRT17', 'CellLine', 'CVCL:0060', (18, 29))	('invasiveness', 'CPA', (199, 211))
15146	31496806	In contrast, compared to SK-MES-1 control cells, KRT17 expression was down-regulated in SK-siKRT17 cells.	('KRT17', 'Gene', (49, 54))	('expression', 'MPA', (55, 65))	('down-regulated', 'NegReg', (70, 84))	('SK-siKRT17', 'Var', (88, 98))	('SK-MES-1', 'CellLine', 'CVCL:0630', (25, 33))
15147	31496806	The levels of active-beta-catenin, cyclinD1, c-Myc, and MMP7 were also reduced in SK-siKRT17 cells compared to control cells (P<0.05) (Figure 3C and F).	('MMP7', 'Gene', '4316', (56, 60))	('cyclinD1', 'Gene', (35, 43))	('levels', 'MPA', (4, 10))	('beta-catenin', 'Gene', '1499', (21, 33))	('cyclinD1', 'Gene', '595', (35, 43))	('c-Myc', 'Gene', (45, 50))	('reduced', 'NegReg', (71, 78))	('MMP7', 'Gene', (56, 60))	('beta-catenin', 'Gene', (21, 33))	('c-Myc', 'Gene', '4609', (45, 50))	('SK-siKRT17', 'Var', (82, 92))
15148	31496806	However, the expression level of LEF-1 was not significantly changed in A549-KRT17, H1299-KRT17, and SK-siKRT17 cells compared to their respective control cells (P>0.05).	('H1299-KRT17', 'CellLine', 'CVCL:0060', (84, 95))	('A549-KRT17', 'Var', (72, 82))	('LEF-1', 'Gene', '51176', (33, 38))	('expression', 'MPA', (13, 23))	('A549-KRT17', 'CellLine', 'CVCL:0023', (72, 82))	('H1299-KRT17', 'Var', (84, 95))	('LEF-1', 'Gene', (33, 38))
15150	31496806	As shown in Figure 3A, B, D and E, the expression levels of Vimentin, MMP9, and Snail were increased, yet E-cadherin expression was reduced, in A549-KRT17 and H1299-KRT17 cells compared to their control cells (P<0.05).	('expression levels', 'MPA', (39, 56))	('A549-KRT17', 'CellLine', 'CVCL:0023', (144, 154))	('MMP9', 'Gene', (70, 74))	('expression', 'MPA', (117, 127))	('reduced', 'NegReg', (132, 139))	('Snail', 'Gene', '6615', (80, 85))	('MMP9', 'Gene', '4318', (70, 74))	('Vimentin', 'Gene', (60, 68))	('H1299-KRT17', 'CellLine', 'CVCL:0060', (159, 170))	('E-cadherin', 'Gene', (106, 116))	('A549-KRT17', 'Var', (144, 154))	('increased', 'PosReg', (91, 100))	('Snail', 'Gene', (80, 85))	('E-cadherin', 'Gene', '999', (106, 116))	('Vimentin', 'Gene', '7431', (60, 68))	('H1299-KRT17', 'Var', (159, 170))
15164	31496806	Knock-out of the KRT17 gene significantly inhibited the migration and invasion process in areca nut-induced oral squamous cell carcinoma.	('KRT17', 'Gene', (17, 22))	('Knock-out', 'Var', (0, 9))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (108, 136))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (113, 136))	('inhibited', 'NegReg', (42, 51))	('oral squamous cell carcinoma', 'Disease', (108, 136))	('areca nut', 'Species', '184783', (90, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))
15180	31496806	KRT17, keratin 17; EMT, epithelial mesenchymal transition; NSCLC, non-small cell lung cancer; LUAD, lung adenocarcinoma; LUSC, lung squamous cell carcinoma; MMP7, matrix metalloproteinase 7; MMP9, matrix metalloproteinase 9; TCGA, The Cancer Genome Atlas; CK, cytokeratin; NC, negative control; siNC, small interfering RNA negative control; siKRT17, small interfering RNA against keratin 17.	('matrix metalloproteinase 7', 'Gene', '4316', (163, 189))	('lung adenocarcinoma', 'Disease', (100, 119))	('Cancer', 'Phenotype', 'HP:0002664', (235, 241))	('keratin 17', 'Gene', (380, 390))	('LUAD', 'Disease', 'None', (94, 98))	('MMP7', 'Gene', '4316', (157, 161))	('keratin 17', 'Gene', (7, 17))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (127, 155))	('non-small cell lung cancer', 'Disease', (66, 92))	('small interfering RNA', 'Var', (350, 371))	('NSCLC', 'Disease', 'MESH:D002289', (59, 64))	('lung cancer', 'Phenotype', 'HP:0100526', (81, 92))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (100, 119))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (100, 119))	('NSCLC', 'Disease', (59, 64))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (127, 155))	('MMP7', 'Gene', (157, 161))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (235, 254))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (132, 155))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (66, 92))	('lung squamous cell carcinoma', 'Disease', (127, 155))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('NSCLC', 'Phenotype', 'HP:0030358', (59, 64))	('LUAD', 'Phenotype', 'HP:0030078', (94, 98))	('matrix metalloproteinase 7', 'Gene', (163, 189))	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('keratin 17', 'Gene', '3872', (380, 390))	('Cancer Genome Atlas', 'Disease', (235, 254))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (70, 92))	('keratin 17', 'Gene', '3872', (7, 17))	('MMP9', 'Gene', (191, 195))	('LUAD', 'Disease', (94, 98))	('matrix metalloproteinase 9', 'Gene', (197, 223))	('MMP9', 'Gene', '4318', (191, 195))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (66, 92))	('matrix metalloproteinase 9', 'Gene', '4318', (197, 223))
15183	29575229	Differential expression and prognostic value of long non-coding RNA in HPV-negative head and neck squamous cell carcinoma Long non-coding RNA (lncRNA) has emerged as a new avenue of interest due to its various biological functions in cancer.	('Long non-coding', 'Var', (122, 137))	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (84, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('neck squamous cell carcinoma', 'Disease', (93, 121))	('cancer', 'Disease', 'MESH:D009369', (234, 240))	('HPV', 'Species', '10566', (71, 74))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (98, 121))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (93, 121))	('cancer', 'Disease', (234, 240))
15229	29575229	Patients with low MEG3 expression (<0.5 fold change) were found to have a significantly lower 3-year RFS while higher MEG3 expression (> 2 fold change) appeared to have better 3-year RFS, although this did not reach statistical significance (Figure 2 and Table 4).	('MEG3', 'Gene', '55384', (18, 22))	('MEG3', 'Gene', (118, 122))	('RFS', 'MPA', (101, 104))	('Patients', 'Species', '9606', (0, 8))	('MEG3', 'Gene', '55384', (118, 122))	('low', 'NegReg', (14, 17))	('lower', 'NegReg', (88, 93))	('<0.5', 'Var', (35, 39))	('MEG3', 'Gene', (18, 22))
15230	29575229	We also analyzed the associations between the 7 lncRNA and clinical characteristics of HPV-negative HNSCC in the TCGA dataset and found that low MEG3 expression was associated with locally advanced disease and low expression of HANDS-2AS1 correlated with more locally advanced cancer, although this did not appear to have an impact on survival outcomes.	('MEG3', 'Gene', (145, 149))	('expression', 'MPA', (150, 160))	('HNSCC', 'Phenotype', 'HP:0012288', (100, 105))	('cancer', 'Disease', (277, 283))	('associated', 'Reg', (165, 175))	('cancer', 'Disease', 'MESH:D009369', (277, 283))	('low', 'Var', (210, 213))	('HPV', 'Species', '10566', (87, 90))	('AS1', 'Gene', '5729', (235, 238))	('AS1', 'Gene', (235, 238))	('MEG3', 'Gene', '55384', (145, 149))	('low', 'NegReg', (141, 144))	('locally advanced disease', 'Disease', (181, 205))	('cancer', 'Phenotype', 'HP:0002664', (277, 283))
15253	26918037	In addition, CuA also induced lysosomal vacuolation with increased VAC, cytotoxicity, as well as suppressions of both topoisomerase I and II activities in a dose-dependent manner.	('cytotoxicity', 'Disease', 'MESH:D064420', (72, 84))	('induced', 'Reg', (22, 29))	('CuA', 'Var', (13, 16))	('activities', 'MPA', (141, 151))	('CuA', 'Chemical', 'MESH:C007165', (13, 16))	('VAC', 'MPA', (67, 70))	('increased', 'PosReg', (57, 66))	('lysosomal vacuolation', 'MPA', (30, 51))	('cytotoxicity', 'Disease', (72, 84))	('suppressions', 'NegReg', (97, 109))
15265	26918037	These alterations control various signaling pathways that cooperate to endow cancer cells with a wide range of biological capabilities necessary for growing, disseminating and finally killing their host.	('alterations', 'Var', (6, 17))	('signaling pathways', 'Pathway', (34, 52))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('control', 'Reg', (18, 25))
15307	26918037	The assay used here is based on the detection of the chromophore AFC after cleavage from the labeled substrate DEVD- and LEHD-AFC by caspase-3 and caspase-9, respectively.	('caspase-9', 'Gene', '842', (147, 156))	('caspase-3', 'Gene', (133, 142))	('caspase-3', 'Gene', '836', (133, 142))	('LEHD-AFC', 'Var', (121, 129))	('caspase-9', 'Gene', (147, 156))
15328	26918037	3A and B demonstrate that the CuA treatment resulted in acidic vacuoles in NCI-H520 cells, as evidenced by positive neutral red staining.	('CuA', 'Var', (30, 33))	('acidic vacuoles', 'MPA', (56, 71))	('CuA', 'Chemical', 'MESH:C007165', (30, 33))	('resulted in', 'Reg', (44, 55))	('NCI-H520', 'CellLine', 'CVCL:1566', (75, 83))
15371	26918037	Our results suggest that CuA effectively induced apoptosis as indicated by a change in Bax/Bcl-2 ratios, loss of DeltaPsim, release of cytochrome c from the mitochondria into cytosol, activations of caspase-3 and -9 (Fig.	('cytochrome c', 'Gene', (135, 147))	('activations', 'PosReg', (184, 195))	('Bax', 'Gene', '581', (87, 90))	('DeltaPsim', 'MPA', (113, 122))	('loss', 'NegReg', (105, 109))	('cytochrome c', 'Gene', '54205', (135, 147))	('CuA', 'Chemical', 'MESH:C007165', (25, 28))	('Bcl-2', 'Gene', '596', (91, 96))	('CuA', 'Var', (25, 28))	('Bcl-2', 'Gene', (91, 96))	('Bax', 'Gene', (87, 90))	('apoptosis', 'CPA', (49, 58))	('change', 'Reg', (77, 83))
15379	26918037	Regarding the key events in the induction of apoptosis, the present study demonstrates that CuA induced the release of cytochrome c from mitochondria into cytosol in a dose-dependent manner.	('cytochrome c', 'Gene', '54205', (119, 131))	('cytochrome c', 'Gene', (119, 131))	('CuA', 'Chemical', 'MESH:C007165', (92, 95))	('CuA', 'Var', (92, 95))
15395	26918037	These results provide convincing proof of the protective effect of CuA treatment against NCI-H520 xenograft growth in nude mice without any observable toxicity; this suggests that CuA has an antiproliferative action in NCI-H520 cells and can potentially serve as an antiproliferative agent for cancer.	('CuA', 'Chemical', 'MESH:C007165', (180, 183))	('NCI-H520', 'CellLine', 'CVCL:1566', (219, 227))	('CuA', 'Chemical', 'MESH:C007165', (67, 70))	('nude mice', 'Species', '10090', (118, 127))	('toxicity', 'Disease', (151, 159))	('toxicity', 'Disease', 'MESH:D064420', (151, 159))	('cancer', 'Disease', 'MESH:D009369', (294, 300))	('cancer', 'Disease', (294, 300))	('NCI-H520', 'CellLine', 'CVCL:1566', (89, 97))	('antiproliferative action', 'CPA', (191, 215))	('cancer', 'Phenotype', 'HP:0002664', (294, 300))	('CuA', 'Var', (180, 183))
15396	26918037	Collectively, our data clearly indicate that CuA induced apoptosis and also suppressed tumor cells growth and the associated biomarkers.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('apoptosis', 'CPA', (57, 66))	('tumor', 'Disease', (87, 92))	('suppressed', 'NegReg', (76, 86))	('CuA', 'Var', (45, 48))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('CuA', 'Chemical', 'MESH:C007165', (45, 48))
15405	33811752	The median follow-up period was 35.97 +- 30.99 months, perineural invasion was confirmed in 25 patients, and three-year overall and disease-free survival were significantly lower in the perineural invasion group than in the no-perineural invasion group (75.9% vs. 40.0%, p < 0.001; 70.3% vs. 21.6%, p < 0.001).	('patients', 'Species', '9606', (95, 103))	('perineural invasion', 'CPA', (55, 74))	('disease-free survival', 'CPA', (132, 153))	('lower', 'NegReg', (173, 178))	('perineural invasion', 'Var', (186, 205))
15480	33811752	In conclusion, PNI was an independent prognostic factor for shorter DFS in patients with surgically treated ESCC as assessed by multivariable analyses.	('PNI', 'Var', (15, 18))	('DFS', 'MPA', (68, 71))	('patients', 'Species', '9606', (75, 83))	('ESCC', 'Disease', (108, 112))	('shorter', 'NegReg', (60, 67))
15487	31809668	Results: The specificity for SCC of membrane staining for PKP1, KRT15, and DSG3 was 97.4%, 94.6%, and 100%, respectively, and it was 100% when the markers were used together and in combination with the conventional markers (AUCs of 0.7619 for Panel 1 SCC, 0.7375 for Panel 2 SCC, 0.8552 for Panel 1 AC, and 0.8088 for Panel 2 AC).	('SCC', 'Disease', (29, 32))	('0.8088', 'Var', (307, 313))	('SCC', 'Phenotype', 'HP:0002860', (251, 254))	('0.8552', 'Var', (280, 286))	('SCC', 'Phenotype', 'HP:0002860', (29, 32))	('SCC', 'Disease', (251, 254))	('SCC', 'Phenotype', 'HP:0002860', (275, 278))	('SCC', 'Disease', (275, 278))	('SCC', 'Disease', 'MESH:D002294', (29, 32))	('0.7375', 'Var', (256, 262))	('AC', 'Disease', 'MESH:D000230', (326, 328))	('SCC', 'Disease', 'MESH:D002294', (251, 254))	('AC', 'Disease', 'MESH:D000230', (299, 301))	('SCC', 'Disease', 'MESH:D002294', (275, 278))
15488	31809668	In a stepwise multivariate logistic regression model, the combination of CK5/6, p63, and PKP1 in membrane was the optimal panel to differentiate between SCC and AC, with a percentage correct classification of 96.2% overall (94.6% of ACs and 97.6% of SCCs).	('CK5/6', 'Gene', '3852', (73, 78))	('p63', 'Gene', '8626', (80, 83))	('SCC', 'Disease', (250, 253))	('PKP1', 'Var', (89, 93))	('SCC', 'Disease', 'MESH:D002294', (250, 253))	('SCC', 'Disease', 'MESH:D002294', (153, 156))	('CK5/6', 'Gene', (73, 78))	('SCC', 'Phenotype', 'HP:0002860', (250, 253))	('SCC', 'Phenotype', 'HP:0002860', (153, 156))	('p63', 'Gene', (80, 83))	('AC', 'Disease', 'MESH:D000230', (233, 235))	('AC', 'Disease', 'MESH:D000230', (161, 163))	('SCC', 'Disease', (153, 156))
15497	31809668	Moreover, EGFR mutations and gene fusions including ALK and ROS1 are almost exclusively present in non-squamous cancer forms.	('non-squamous cancer', 'Disease', 'MESH:D018307', (99, 118))	('EGFR', 'Gene', '1956', (10, 14))	('squamous cancer', 'Phenotype', 'HP:0002860', (103, 118))	('ROS1', 'Gene', '6098', (60, 64))	('EGFR', 'Gene', (10, 14))	('ALK', 'Gene', '238', (52, 55))	('mutations', 'Var', (15, 24))	('non-squamous cancer', 'Disease', (99, 118))	('gene fusions', 'Var', (29, 41))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('ALK', 'Gene', (52, 55))	('ROS1', 'Gene', (60, 64))	('present', 'Reg', (88, 95))
15536	31809668	Prediluted monoclonal antibodies from Master Diagnostica were used for the remaining determinations: TTF1 (000486QD, clone SPT24), Napsin A (001004QD, clone BS10), CK7 (001004QD, clone OVTL 12/30), CK5/6 (000680QD, clone EP24/EP67/B22-18B231), p63 (000479QD clone 4a4), and p40 (000686QD, clone ZR8).	('CK5/6', 'Gene', '3852', (198, 203))	('p40', 'Gene', '8626', (274, 277))	('p63', 'Gene', (244, 247))	('Napsin A', 'Gene', '9476', (131, 139))	('TTF1', 'Gene', '7080', (101, 105))	('CK5/6', 'Gene', (198, 203))	('CK7', 'Gene', (164, 167))	('TTF1', 'Gene', (101, 105))	('p40', 'Gene', (274, 277))	('p63', 'Gene', '8626', (244, 247))	('CK7', 'Gene', '3855', (164, 167))	('001004QD', 'Var', (141, 149))	('Napsin A', 'Gene', (131, 139))
15541	31809668	Staining for PKP1, CK15, and DSG3 was evaluated semiquantitatively in nucleus, cytoplasm, and membrane as negative (0, <5% cells stained), positive 1+ (6-25% cells stained), positive 2+ (26-50% cells stained), or positive 3+ (>50% cells stained).	('positive 2+', 'Var', (174, 185))	('DSG3', 'Gene', (29, 33))	('CK15', 'Gene', '3866', (19, 23))	('positive 1+', 'Var', (139, 150))	('negative', 'NegReg', (106, 114))	('CK15', 'Gene', (19, 23))
15566	31809668	For AC samples, the combined evaluation of negative membranous staining for PKP1 and DSG3 and positive TTF1, in Panel 1 AC, increased the specificity for AC samples to 100.0% (95% CI = 91.6%-100.0%), but the sensitivity was 24.3% (95% CI = 13.4%-40.1%), with an AUC of 0.8552.	('PKP1', 'Gene', (76, 80))	('TTF1', 'Gene', '7080', (103, 107))	('increased', 'PosReg', (124, 133))	('DSG3', 'Gene', (85, 89))	('TTF1', 'Gene', (103, 107))	('AC', 'Disease', 'MESH:D000230', (120, 122))	('specificity', 'MPA', (138, 149))	('AC', 'Disease', 'MESH:D000230', (154, 156))	('AC', 'Disease', 'MESH:D000230', (4, 6))	('positive', 'Var', (94, 102))	('negative', 'NegReg', (43, 51))
15578	31809668	In the multivariate analyses, the high expression of three SCC markers was associated with better survival: p63 (p = 0.007, HR = 0.93 [0.88-0.98]), PKP1 (p = 0.036, HR = 0.95 [0.91-1.0], as already noted), and CK5 (p = 0.018, HR = 0.95 [0.91-0.99]).	('better', 'PosReg', (91, 97))	('CK5', 'Gene', '3852', (210, 213))	('p63', 'Gene', (108, 111))	('CK5', 'Gene', (210, 213))	('SCC', 'Phenotype', 'HP:0002860', (59, 62))	('high', 'Var', (34, 38))	('SCC', 'Disease', (59, 62))	('PKP1', 'Var', (148, 152))	('SCC', 'Disease', 'MESH:D002294', (59, 62))	('p63', 'Gene', '8626', (108, 111))
15585	31809668	For instance, the most widely used clones of TTF1 monoclonal antibodies are 8G7G3/1 and SPT24, which have been reported to have different sensitivities and specificities, with 8G7G3/1 being more specific and SPT24 more sensitive.	('TTF1', 'Gene', '7080', (45, 49))	('SPT24', 'Gene', (88, 93))	('8G7G3/1', 'Var', (176, 183))	('TTF1', 'Gene', (45, 49))
15588	31809668	negativity for TTF1 and positivity for p63, CK5/6, and 34betaE12.	('34betaE12', 'Protein', (55, 64))	('p63', 'Gene', '8626', (39, 42))	('CK5/6', 'Gene', '3852', (44, 49))	('negativity', 'Var', (0, 10))	('TTF1', 'Gene', '7080', (15, 19))	('CK5/6', 'Gene', (44, 49))	('p63', 'Gene', (39, 42))	('TTF1', 'Gene', (15, 19))
15600	31809668	In our cohort of patients, the relationship of PKP1 staining with better survival of SCC and AC patients did not reach statistical significance; however, we were able to confirm the relationship between high PKP1 mRNA expression and better overall survival in an additional analysis of 495 SCC patients from TCGA.	('SCC', 'Disease', (290, 293))	('AC', 'Disease', 'MESH:D000230', (93, 95))	('better', 'PosReg', (233, 239))	('SCC', 'Disease', (85, 88))	('patients', 'Species', '9606', (294, 302))	('mRNA expression', 'MPA', (213, 228))	('SCC', 'Disease', 'MESH:D002294', (290, 293))	('high', 'Var', (203, 207))	('SCC', 'Disease', 'MESH:D002294', (85, 88))	('patients', 'Species', '9606', (17, 25))	('PKP1', 'Enzyme', (208, 212))	('patients', 'Species', '9606', (96, 104))	('SCC', 'Phenotype', 'HP:0002860', (290, 293))	('SCC', 'Phenotype', 'HP:0002860', (85, 88))	('overall survival', 'MPA', (240, 256))
15601	31809668	This agrees with previous reports that associated positive DSG3 staining with longer survival in lung cancer patients of all histologic subtypes.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('longer', 'PosReg', (78, 84))	('patients', 'Species', '9606', (109, 117))	('lung cancer', 'Disease', 'MESH:D008175', (97, 108))	('DSG3', 'Gene', (59, 63))	('lung cancer', 'Disease', (97, 108))	('lung cancer', 'Phenotype', 'HP:0100526', (97, 108))	('positive', 'Var', (50, 58))
15607	31809668	Despite the small number of samples analyzed, the stepwise multivariate logistic regression model showed that the combination of markers CK5/6, p63, and PKP1 in membrane gave a percentage correct classification of 96.2% overall (94.6% of AC and 97.6% of SCC), being the best immunohistochemical marker panel to distinguish between SCC and AC.	('CK5/6', 'Gene', (137, 142))	('SCC', 'Disease', 'MESH:D002294', (254, 257))	('AC', 'Disease', 'MESH:D000230', (238, 240))	('p63', 'Gene', (144, 147))	('SCC', 'Disease', 'MESH:D002294', (331, 334))	('SCC', 'Phenotype', 'HP:0002860', (254, 257))	('SCC', 'Disease', (254, 257))	('CK5/6', 'Gene', '3852', (137, 142))	('AC', 'Disease', 'MESH:D000230', (339, 341))	('p63', 'Gene', '8626', (144, 147))	('SCC', 'Phenotype', 'HP:0002860', (331, 334))	('PKP1', 'Var', (153, 157))	('SCC', 'Disease', (331, 334))
15613	31576243	Furthermore, the co-expressed networks of dysregulated RBPs with transcriptional factors and lncRNAs also require further investigation.	('ncRNA', 'Gene', '220202', (94, 99))	('ncRNA', 'Gene', (94, 99))	('RBP', 'Gene', (55, 58))	('RBP', 'Gene', '57794', (55, 58))	('dysregulated', 'Var', (42, 54))
15624	31576243	Furthermore, dysregulated expression of some RBPs can lead to disease, including neurological disorders and cancers.	('disease', 'Disease', (62, 69))	('expression', 'MPA', (26, 36))	('lead to', 'Reg', (54, 61))	('neurological disorders', 'Disease', 'MESH:D009422', (81, 103))	('cancers', 'Phenotype', 'HP:0002664', (108, 115))	('RBP', 'Gene', (45, 48))	('RBP', 'Gene', '57794', (45, 48))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('neurological disorders', 'Disease', (81, 103))	('cancers', 'Disease', 'MESH:D009369', (108, 115))	('dysregulated', 'Var', (13, 25))	('cancers', 'Disease', (108, 115))
15630	31576243	Silencing RPL34 plays a blocking role in cell proliferation and metastasis, but promoting cell apoptosis of oral squamous cell carcinomas (OSCCs).	('metastasis', 'CPA', (64, 74))	('RPL34', 'Gene', '6164', (10, 15))	('OSCCs', 'Disease', (139, 144))	('OSCCs', 'Disease', 'MESH:D002294', (139, 144))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (113, 137))	('promoting', 'PosReg', (80, 89))	('Silencing', 'Var', (0, 9))	('RPL34', 'Gene', (10, 15))	('cell apoptosis', 'CPA', (90, 104))	('oral squamous cell carcinomas', 'Disease', (108, 137))	('carcinomas', 'Phenotype', 'HP:0030731', (127, 137))	('oral squamous cell carcinomas', 'Disease', 'MESH:D002294', (108, 137))
15634	31576243	In addition, the silencing of SRSF7 affects the expression of osteopontin splice variants and decreases the proliferation rate of renal cancer cells.	('renal cancer', 'Disease', (130, 142))	('affects', 'Reg', (36, 43))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('SRSF7', 'Gene', (30, 35))	('renal cancer', 'Phenotype', 'HP:0009726', (130, 142))	('SRSF7', 'Gene', '6432', (30, 35))	('expression', 'MPA', (48, 58))	('renal cancer', 'Disease', 'MESH:D007680', (130, 142))	('decreases', 'NegReg', (94, 103))	('silencing', 'Var', (17, 26))	('osteopontin', 'Gene', '6696', (62, 73))	('osteopontin', 'Gene', (62, 73))
15646	31576243	An accumulating genome-wide association study (GWAS) shows that the mutations of TFs or TF-binding sites are closely related to many human cancers (reviewed in), such as gastric cancer, liver cancer, prostate cancer, colorectal cancer and breast cancer.	('breast cancer', 'Disease', (239, 252))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('cancers', 'Phenotype', 'HP:0002664', (139, 146))	('prostate cancer', 'Disease', 'MESH:D011471', (200, 215))	('gastric cancer', 'Phenotype', 'HP:0012126', (170, 184))	('cancers', 'Disease', (139, 146))	('prostate cancer', 'Phenotype', 'HP:0012125', (200, 215))	('colorectal cancer', 'Disease', (217, 234))	('liver cancer', 'Disease', 'MESH:D006528', (186, 198))	('prostate cancer', 'Disease', (200, 215))	('related', 'Reg', (117, 124))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('liver cancer', 'Phenotype', 'HP:0002896', (186, 198))	('human', 'Species', '9606', (133, 138))	('liver cancer', 'Disease', (186, 198))	('TFs', 'Gene', (81, 84))	('gastric cancer', 'Disease', (170, 184))	('cancers', 'Disease', 'MESH:D009369', (139, 146))	('colorectal cancer', 'Phenotype', 'HP:0003003', (217, 234))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('breast cancer', 'Phenotype', 'HP:0003002', (239, 252))	('gastric cancer', 'Disease', 'MESH:D013274', (170, 184))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('mutations', 'Var', (68, 77))	('colorectal cancer', 'Disease', 'MESH:D015179', (217, 234))	('breast cancer', 'Disease', 'MESH:D001943', (239, 252))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
15684	31576243	Generally, in the TNM system, 'T' refers to a primary tumor, 'T1 ~ T4' represents the severity of primary cancer according to the increase in tumor volume and the extent of involvement of adjacent tissues, and 'T0' indicates no primary tumor.	("'T1 ~ T4'", 'Var', (61, 70))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('TNM', 'Disease', 'MESH:D009362', (18, 21))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('tumor', 'Disease', (142, 147))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('tumor', 'Disease', 'MESH:D009369', (236, 241))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('cancer', 'Disease', (106, 112))	('tumor', 'Phenotype', 'HP:0002664', (236, 241))	('increase', 'PosReg', (130, 138))	('tumor', 'Disease', (54, 59))	('tumor', 'Disease', (236, 241))	('TNM', 'Disease', (18, 21))
15745	31576243	These results suggest that dysregulated RBPs play a key role in the regulation of the development of the CHOL and KICH M-stage, which may provide a new perspective for potential prognostic biomarkers and therapeutic targets for patients with cancers at M stages in two cancer types CHOL and KICH.	('cancers', 'Disease', 'MESH:D009369', (242, 249))	('cancers', 'Phenotype', 'HP:0002664', (242, 249))	('cancers', 'Disease', (242, 249))	('cancer', 'Disease', (242, 248))	('cancer', 'Disease', 'MESH:D009369', (242, 248))	('cancer', 'Phenotype', 'HP:0002664', (242, 248))	('cancer', 'Phenotype', 'HP:0002664', (269, 275))	('patients', 'Species', '9606', (228, 236))	('cancer', 'Disease', (269, 275))	('CHOL', 'Phenotype', 'HP:0030153', (282, 286))	('RBP', 'Gene', '57794', (40, 43))	('CHOL', 'Phenotype', 'HP:0030153', (105, 109))	('RBP', 'Gene', (40, 43))	('dysregulated', 'Var', (27, 39))	('cancer', 'Disease', 'MESH:D009369', (269, 275))
15750	31576243	Functional enrichment analyzing demonstrated that cluster 1 and cluster 3 had similar functions and mainly enriched in functional categories involved in gene silencing and negative regulation of translation, such as post transcriptional gene silencing, negative regulation of translation and cellular amide metabolic process, cellular response to dsRNA, miRNA metabolic process.	('negative regulation', 'NegReg', (253, 272))	('translation', 'MPA', (276, 287))	('negative regulation', 'NegReg', (172, 191))	('amide', 'Chemical', 'MESH:D000577', (301, 306))	('miRNA', 'CPA', (354, 359))	('cellular', 'CPA', (326, 334))	('gene silencing', 'Var', (237, 251))	('translation', 'MPA', (195, 206))	('cellular amide metabolic process', 'MPA', (292, 324))	('involved', 'Reg', (141, 149))	('gene silencing', 'Var', (153, 167))
15761	31576243	First, we found the five largest transcription factor families, they are C2H2-ZF, Homeodomain, Nuclear receptor, bHLH and bZIP, and the corresponding proportion is 37%, 17%, 9%, 9% and 9% (Figs.	('C2H2-ZF', 'Var', (73, 80))	('C2H2', 'Chemical', 'MESH:C543495', (73, 77))	('bHLH', 'Gene', (113, 117))
15798	26828791	Polymorphisms in the AKT1 and AKT2 genes and oesophageal squamous cell carcinoma risk in an Eastern Chinese population Ethnic Han Chinese are at high risk of developing oesophageal squamous cell carcinoma (ESCC).	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (181, 204))	('oesophageal squamous cell carcinoma', 'Disease', (45, 80))	('AKT1', 'Gene', (21, 25))	('Polymorphisms', 'Var', (0, 13))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (57, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('oesophageal squamous cell carcinoma', 'Disease', (169, 204))	('oesophageal squamous cell carcinoma', 'Disease', 'MESH:D002294', (45, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (195, 204))	('oesophageal squamous cell carcinoma', 'Disease', 'MESH:D002294', (169, 204))	('AKT2', 'Gene', (30, 34))	('AKT2', 'Gene', '208', (30, 34))	('AKT1', 'Gene', '207', (21, 25))
15799	26828791	Aberrant activation of the AKT signalling pathway is involved in many cancers, including ESCC.	('involved', 'Reg', (53, 61))	('activation', 'PosReg', (9, 19))	('AKT', 'Gene', (27, 30))	('Aberrant', 'Var', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('ESCC', 'Disease', (89, 93))	('AKT', 'Gene', '207', (27, 30))	('cancers', 'Disease', 'MESH:D009369', (70, 77))	('cancers', 'Phenotype', 'HP:0002664', (70, 77))	('cancers', 'Disease', (70, 77))
15800	26828791	We selected five potentially functional SNPs in AKT1 (rs2494750, rs2494752 and rs10138277) and AKT2 (rs7254617 and rs2304186) genes and investigated their associations with ESCC risk in 1117 ESCC cases and 1096 controls in an Eastern Chinese population.	('investigated', 'Reg', (136, 148))	('rs2304186', 'Mutation', 'rs2304186', (115, 124))	('rs2304186', 'Var', (115, 124))	('rs2494750', 'Var', (54, 63))	('ESCC', 'Disease', (173, 177))	('associations', 'Interaction', (155, 167))	('rs10138277', 'Var', (79, 89))	('AKT1', 'Gene', '207', (48, 52))	('rs7254617', 'Var', (101, 110))	('rs10138277', 'Mutation', 'rs10138277', (79, 89))	('AKT1', 'Gene', (48, 52))	('rs2494750', 'Mutation', 'rs2494750', (54, 63))	('rs2494752', 'Var', (65, 74))	('AKT2', 'Gene', (95, 99))	('rs2494752', 'Mutation', 'rs2494752', (65, 74))	('rs7254617', 'Mutation', 'rs7254617', (101, 110))	('AKT2', 'Gene', '208', (95, 99))	('ESCC', 'Disease', (191, 195))
15801	26828791	However, the combined analysis of three AKT1  SNPs suggested that individuals carrying one of AKT1 variant genotypes had a decreased ESCC risk [adjusted odds ratio (OR) = 0.60, 95% CI = 0.42-0.87].	('decreased', 'NegReg', (123, 132))	('ESCC', 'Disease', (133, 137))	('variant', 'Var', (99, 106))	('AKT1', 'Gene', '207', (94, 98))	('AKT1', 'Gene', '207', (40, 44))	('AKT1', 'Gene', (94, 98))	('decreased ESCC', 'Phenotype', 'HP:0025022', (123, 137))	('AKT1', 'Gene', (40, 44))
15802	26828791	Further stratified analysis found that AKT1 rs2294750 SNP was associated with significantly decreased ESCC risk among women (adjusted OR = 0.63, 95% CI = 0.43-0.94) and non-drinkers (OR = 0.79, 95% CI = 0.64-0.99).	('AKT1', 'Gene', (39, 43))	('rs2294750', 'Mutation', 'rs2294750', (44, 53))	('women', 'Species', '9606', (118, 123))	('ESCC', 'Disease', (102, 106))	('rs2294750 SNP', 'Var', (44, 57))	('decreased ESCC', 'Phenotype', 'HP:0025022', (92, 106))	('decreased', 'NegReg', (92, 101))	('AKT1', 'Gene', '207', (39, 43))
15814	26828791	Molecular epidemiological studies have demonstrated that some single nucleotide polymorphisms (SNPs) account, in part, for the variation in cancer susceptibility in the general population 4, 5, 6, including SNPs in inflammatory response, one carbon metabolism, metabolism of chemical carcinogens and DNA repair pathways as well as some other oncogenes and tumour-suppressor genes 7, 8.	('DNA repair pathways', 'Pathway', (300, 319))	('tumour', 'Disease', 'MESH:D009369', (356, 362))	('one carbon', 'Pathway', (238, 248))	('tumour', 'Disease', (356, 362))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('carbon', 'Chemical', 'MESH:D002244', (242, 248))	('tumour', 'Phenotype', 'HP:0002664', (356, 362))	('SNPs', 'Var', (207, 211))
15817	26828791	The PIP3 thereafter recruits AKT to the plasma membrane to facilitate AKT phosphorylation at Thr308 and Ser473.	('AKT', 'Gene', '207', (70, 73))	('Ser473', 'Chemical', '-', (104, 110))	('Thr308', 'Var', (93, 99))	('AKT', 'Gene', '207', (29, 32))	('facilitate', 'PosReg', (59, 69))	('AKT', 'Gene', (70, 73))	('AKT', 'Gene', (29, 32))	('Thr308', 'Chemical', '-', (93, 99))	('Ser473', 'Var', (104, 110))
15821	26828791	Given the important role of AKT in carcinogenesis, it is reasonably speculated that potentially functional SNPs in AKT genes may alter its expression and/or protein function, thereby modifying cancer susceptibility.	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('AKT', 'Gene', '207', (115, 118))	('alter', 'Reg', (129, 134))	('protein function', 'MPA', (157, 173))	('AKT', 'Gene', (28, 31))	('cancer', 'Disease', (193, 199))	('modifying', 'Reg', (183, 192))	('AKT', 'Gene', (115, 118))	('carcinogenesis', 'Disease', 'MESH:D063646', (35, 49))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('expression', 'MPA', (139, 149))	('SNPs', 'Var', (107, 111))	('AKT', 'Gene', '207', (28, 31))	('carcinogenesis', 'Disease', (35, 49))
15832	26828791	We first retrieved available SNPs in target genes from the National Center for Biotechnology Information dbSNP database (http://www.ncbi.nlm.nih.gov/projects/SNP) and then selected common, potentially functional SNPs in accordance with these criteria: (i) positioned in exons, the 5' near gene, 5' untranslated regions (UTR), 3' UTR, 3' near gene or splice sites; (ii) the minor allele frequency (MAF) should be equal or larger than 5% in Chinese Han population; (iii) SNPinfo software (http://snpinfo.niehs.nih.gov/snpfunc.htm)-identified potentially functional SNPs; and (iv) not studied in the published ESCC genome-wide association studies.	('SNPs', 'Var', (563, 567))	('MAF', 'Disease', (397, 400))	('functional', 'MPA', (552, 562))	('MAF', 'Disease', 'None', (397, 400))
15833	26828791	Ultimately, five SNPs (AKT1: rs2494750, rs2494752 and rs10138277; AKT2: rs7254617 and rs2304186) were included in the study.	('AKT1', 'Gene', (23, 27))	('rs10138277', 'Var', (54, 64))	('rs2494750', 'Var', (29, 38))	('rs2494752', 'Var', (40, 49))	('AKT2', 'Gene', '208', (66, 70))	('rs2304186', 'Var', (86, 95))	('rs10138277', 'Mutation', 'rs10138277', (54, 64))	('AKT1', 'Gene', '207', (23, 27))	('rs2494752', 'Mutation', 'rs2494752', (40, 49))	('rs2304186', 'Mutation', 'rs2304186', (86, 95))	('rs2494750', 'Mutation', 'rs2494750', (29, 38))	('rs7254617', 'Mutation', 'rs7254617', (72, 81))	('AKT2', 'Gene', (66, 70))
15838	26828791	Moreover, a combination of rs2494750, rs2494752 and rs10138277 genotypes in the AKT1 gene was considered as a haplotype.	('rs2494750', 'Mutation', 'rs2494750', (27, 36))	('AKT1', 'Gene', '207', (80, 84))	('rs2494752', 'Var', (38, 47))	('rs10138277', 'Var', (52, 62))	('rs2494752', 'Mutation', 'rs2494752', (38, 47))	('rs10138277', 'Mutation', 'rs10138277', (52, 62))	('AKT1', 'Gene', (80, 84))	('rs2494750', 'Var', (27, 36))
15840	26828791	Finally, we performed mini meta-analyses to evaluate the association of AKT1 rs2494750 and AKT2 rs7254617 SNPs with ESCC risk.	('rs7254617', 'Var', (96, 105))	('ESCC', 'Disease', (116, 120))	('rs2494750', 'Var', (77, 86))	('AKT1', 'Gene', '207', (72, 76))	('AKT2', 'Gene', (91, 95))	('AKT1', 'Gene', (72, 76))	('rs7254617', 'Mutation', 'rs7254617', (96, 105))	('association', 'Interaction', (57, 68))	('rs2494750', 'Mutation', 'rs2494750', (77, 86))	('AKT2', 'Gene', '208', (91, 95))
15842	26828791	Second, the MAFs of the genotyped SNPs in controls were comparable to those identified in the CHB data from HapMap or reported in Asians 25: 0.315 versus 0.267 (rs2494750), 0.266 versus 0.220 (rs2494752), 0.104 versus 0.083 (rs10138277), 0.135 versus 0.149 (7254617) and 0.447 versus 0.54 (rs2304186).	('rs10138277', 'Mutation', 'rs10138277', (225, 235))	('rs2494752', 'Var', (193, 202))	('MAF', 'Disease', (12, 15))	('rs2494752', 'Mutation', 'rs2494752', (193, 202))	('rs2304186', 'Mutation', 'rs2304186', (290, 299))	('rs2494750', 'Var', (161, 170))	('7254617', 'Var', (258, 265))	('MAF', 'Disease', 'None', (12, 15))	('rs2304186', 'Var', (290, 299))	('rs2494750', 'Mutation', 'rs2494750', (161, 170))	('rs10138277', 'Var', (225, 235))
15844	26828791	Once again, participants carrying one to five variant genotypes have ESCC risk as high as those carrying wild-type genotypes.	('participants', 'Species', '9606', (12, 24))	('variant', 'Var', (46, 53))	('ESCC', 'Disease', (69, 73))
15846	26828791	However, the combined analysis with only three AKT1 SNPs found that having one AKT1 variant genotype was associated with a protective effect (adjusted OR = 0.60, 95% CI = 0.42-0.87, P = 0.007, statistical power = 0.353) for developing ESCC, which is likely because of a chance.	('ESCC', 'Disease', (235, 239))	('AKT1', 'Gene', '207', (79, 83))	('variant', 'Var', (84, 91))	('AKT1', 'Gene', (79, 83))	('AKT1', 'Gene', '207', (47, 51))	('AKT1', 'Gene', (47, 51))
15848	26828791	Among all the tested SNPs, we found that AKT1 rs2294750 might exert a protective effect on ESCC risk; in particular, this effect was significant for women (adjusted OR = 0.63, 95% CI = 0.43-0.94, P = 0.024, statistical power = 0.925) and non-drinkers (OR = 0.79, 95% CI = 0.64-0.99, P = 0.042, statistical power = 0.995) under the dominant model (Table 3A).	('AKT1', 'Gene', '207', (41, 45))	('women', 'Species', '9606', (149, 154))	('rs2294750', 'Var', (46, 55))	('ESCC', 'Disease', (91, 95))	('AKT1', 'Gene', (41, 45))	('rs2294750', 'Mutation', 'rs2294750', (46, 55))
15851	26828791	Moreover, the protective effect of combined AKT1 SNPs (adjusted OR = 0.56, 95% CI = 0.37-0.83, P = 0.004) was stronger in women than that of each of AKT1 SNP (rs2294750: adjusted OR = 0.63, 95% CI = 0.43-0.94, P = 0.024; rs2294752: OR = 0.70, 95% CI = 0.47-1.03, P = 0.073; OR = 0.77, 95% CI = 0.46-1.2, P = 0.310).	('women', 'Species', '9606', (122, 127))	('rs2294750', 'Mutation', 'rs2294750', (159, 168))	('stronger', 'PosReg', (110, 118))	('AKT1', 'Gene', '207', (149, 153))	('rs2294752', 'Var', (221, 230))	('AKT1', 'Gene', '207', (44, 48))	('AKT1', 'Gene', (149, 153))	('rs2294752', 'Mutation', 'rs2294752', (221, 230))	('AKT1', 'Gene', (44, 48))
15855	26828791	We further investigated whether the haplotypes of three AKT1 SNPs were associated with ESCC risk.	('haplotypes', 'Var', (36, 46))	('AKT1', 'Gene', '207', (56, 60))	('ESCC', 'Disease', (87, 91))	('AKT1', 'Gene', (56, 60))	('associated', 'Reg', (71, 81))
15859	26828791	We found that AKT1 rs2949750 variant C allele was significantly associated with increased AKT1 gene expression levels under the additive model (one-way anova,  P = 0.0006) and recessive model (Student's t-test, P = 0.0001; Fig.	('AKT1', 'Gene', '207', (14, 18))	('rs2949750', 'Var', (19, 28))	('rs2949750', 'Mutation', 'rs2949750', (19, 28))	('increased', 'PosReg', (80, 89))	('AKT1', 'Gene', (14, 18))	('AKT1', 'Gene', '207', (90, 94))	('AKT1', 'Gene', (90, 94))
15860	26828791	Thus far, three publications have reported conflicting results on the associations of AKT1 rs2494750 and AKT2 rs7254617 with cancer risk 9, 14, 19.	('associations', 'Interaction', (70, 82))	('AKT2', 'Gene', (105, 109))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('rs7254617', 'Var', (110, 119))	('rs2494750', 'Var', (91, 100))	('AKT1', 'Gene', '207', (86, 90))	('AKT1', 'Gene', (86, 90))	('AKT2', 'Gene', '208', (105, 109))	('rs2494750', 'Mutation', 'rs2494750', (91, 100))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('rs7254617', 'Mutation', 'rs7254617', (110, 119))
15861	26828791	Pooled analysis provided no evidence of the association of these two SNPs and cancer susceptibility (rs2494750 under dominant model: OR = 0.99, 95% CI = 0.93-1.06; rs7254616 under the dominant model: OR = 1.02, 95% CI = 0.94-1.11) (Fig.	('rs7254616', 'Var', (164, 173))	('rs7254616', 'Mutation', 'rs7254616', (164, 173))	('rs2494750', 'Mutation', 'rs2494750', (101, 110))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('rs2494750', 'Var', (101, 110))
15862	26828791	No publication bias was detected for AKT2 rs7254617, but significant publication bias was detected for rs2494750.	('rs7254617', 'Var', (42, 51))	('AKT2', 'Gene', (37, 41))	('rs7254617', 'Mutation', 'rs7254617', (42, 51))	('AKT2', 'Gene', '208', (37, 41))	('rs2494750', 'Var', (103, 112))	('rs2494750', 'Mutation', 'rs2494750', (103, 112))
15867	26828791	Previous studies have reported that SNPS in PI3K and mTOR genes within the AKT pathway modulate the risk of various cancers 8, 9, 10, 11, 19, 20, 21, 22.	('PI3K', 'Gene', (44, 48))	('modulate', 'Reg', (87, 95))	('AKT', 'Gene', '207', (75, 78))	('mTOR', 'Gene', (53, 57))	('cancers', 'Disease', 'MESH:D009369', (116, 123))	('AKT', 'Gene', (75, 78))	('mTOR', 'Gene', '2475', (53, 57))	('cancers', 'Phenotype', 'HP:0002664', (116, 123))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cancers', 'Disease', (116, 123))	('SNPS', 'Var', (36, 40))
15869	26828791	Therefore, we searched potentially functional SNPs in the AKT genes and studied for their association with ESCC susceptibility.	('SNPs', 'Var', (46, 50))	('AKT', 'Gene', '207', (58, 61))	('ESCC', 'Disease', (107, 111))	('AKT', 'Gene', (58, 61))
15870	26828791	Moreover, our meta-analysis observed no association of AKT1 rs2494750 and AKT2 rs7254617 and ESCC risk.	('rs7254617', 'Var', (79, 88))	('AKT1', 'Gene', '207', (55, 59))	('AKT2', 'Gene', (74, 78))	('AKT1', 'Gene', (55, 59))	('rs2494750', 'Var', (60, 69))	('rs7254617', 'Mutation', 'rs7254617', (79, 88))	('rs2494750', 'Mutation', 'rs2494750', (60, 69))	('AKT2', 'Gene', '208', (74, 78))	('ESCC', 'Disease', (93, 97))
15871	26828791	However, the combined analysis of three AKT1SNPs identified that individuals carrying only one of three AKT1 variant genotypes might have decreased risk to develop ESCC cancer in comparison with non-carriers, but this finding could be because of chance.	('cancer', 'Disease', (169, 175))	('AKT1', 'Gene', '207', (104, 108))	('variant', 'Var', (109, 116))	('decreased', 'NegReg', (138, 147))	('AKT1', 'Gene', (104, 108))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('AKT1', 'Gene', '207', (40, 44))	('AKT1', 'Gene', (40, 44))	('cancer', 'Disease', 'MESH:D009369', (169, 175))
15874	26828791	A study conducted among Caucasians reported that two SNPs in the AKT3 gene had profound effects on bladder cancer susceptibility 20.	('AKT3', 'Gene', (65, 69))	('bladder cancer', 'Phenotype', 'HP:0009725', (99, 113))	('AKT3', 'Gene', '10000', (65, 69))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('SNPs', 'Var', (53, 57))	('bladder cancer', 'Disease', 'MESH:D001749', (99, 113))	('bladder cancer', 'Disease', (99, 113))	('effects', 'Reg', (88, 95))
15875	26828791	AKT3 rs2994329 was shown to significantly increased bladder cancer risk, while AKT3 rs12045585 exhibited reverse association 20.	('increased', 'PosReg', (42, 51))	('AKT3', 'Gene', (79, 83))	('rs12045585', 'Mutation', 'rs12045585', (84, 94))	('AKT3', 'Gene', '10000', (0, 4))	('AKT3', 'Gene', '10000', (79, 83))	('rs2994329', 'Var', (5, 14))	('rs2994329', 'Mutation', 'rs2994329', (5, 14))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('bladder cancer', 'Phenotype', 'HP:0009725', (52, 66))	('rs12045585', 'Var', (84, 94))	('bladder cancer', 'Disease', 'MESH:D001749', (52, 66))	('bladder cancer', 'Disease', (52, 66))	('AKT3', 'Gene', (0, 4))
15876	26828791	The same group also reported that AKT2 3730050 was significantly associated with the survival of muscle invasive and metastatic bladder cancer patients 40.	('bladder cancer', 'Disease', 'MESH:D001749', (128, 142))	('bladder cancer', 'Disease', (128, 142))	('patients', 'Species', '9606', (143, 151))	('associated', 'Reg', (65, 75))	('muscle invasive', 'Disease', (97, 112))	('bladder cancer', 'Phenotype', 'HP:0009725', (128, 142))	('3730050', 'Var', (39, 46))	('AKT2', 'Gene', '208', (34, 38))	('AKT2', 'Gene', (34, 38))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
15877	26828791	When compared with those with the wild-type genotype, patients carrying one or two AKT2 3730050 variant alleles had an increased death risk up to 2.99-fold 40.	('AKT2', 'Gene', '208', (83, 87))	('death', 'Disease', 'MESH:D003643', (129, 134))	('death', 'Disease', (129, 134))	('patients', 'Species', '9606', (54, 62))	('AKT2', 'Gene', (83, 87))	('3730050', 'Var', (88, 95))
15878	26828791	Recently, one study demonstrated that AKT1 rs1130214 and rs3803300 were associated with oral squamous cell carcinoma in Chinese Han Population 21.	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('rs1130214', 'Var', (43, 52))	('AKT1', 'Gene', '207', (38, 42))	('oral squamous cell carcinoma', 'Disease', (88, 116))	('AKT1', 'Gene', (38, 42))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (93, 116))	('associated', 'Reg', (72, 82))	('rs3803300', 'Var', (57, 66))	('rs3803300', 'Mutation', 'rs3803300', (57, 66))	('rs1130214', 'Mutation', 'rs1130214', (43, 52))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (88, 116))
15879	26828791	genotyped five AKT1 SNPs (rs3803300, rs1130214, rs3730358, rs1130233 and rs2494732) in 593 nasopharyngeal carcinoma cases and 480 controls 22.	('rs3730358', 'Mutation', 'rs3730358', (48, 57))	('rs1130214', 'Var', (37, 46))	('rs2494732', 'Var', (73, 82))	('rs2494732', 'Mutation', 'rs2494732', (73, 82))	('nasopharyngeal carcinoma', 'Disease', 'MESH:D000077274', (91, 115))	('AKT1', 'Gene', '207', (15, 19))	('rs3803300', 'Var', (26, 35))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('nasopharyngeal carcinoma', 'Disease', (91, 115))	('rs3803300', 'Mutation', 'rs3803300', (26, 35))	('rs1130233', 'Var', (59, 68))	('rs3730358', 'Var', (48, 57))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (91, 115))	('AKT1', 'Gene', (15, 19))	('rs1130233', 'Mutation', 'rs1130233', (59, 68))	('rs1130214', 'Mutation', 'rs1130214', (37, 46))
15880	26828791	Although none of individual SNP had significant effect on the risk of nasopharyngeal carcinoma, a two-SNP haplotype, consisting variant alleles of AKT1 rs1130233 and rs2494732, was significantly associated with increased nasopharyngeal carcinoma risk 22.	('associated', 'Reg', (195, 205))	('AKT1', 'Gene', '207', (147, 151))	('AKT1', 'Gene', (147, 151))	('nasopharyngeal carcinoma', 'Disease', 'MESH:D000077274', (70, 94))	('rs1130233', 'Mutation', 'rs1130233', (152, 161))	('rs2494732', 'Var', (166, 175))	('nasopharyngeal carcinoma', 'Disease', 'MESH:D000077274', (221, 245))	('carcinoma', 'Phenotype', 'HP:0030731', (236, 245))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (70, 94))	('nasopharyngeal carcinoma', 'Disease', (70, 94))	('increased', 'PosReg', (211, 220))	('nasopharyngeal carcinoma', 'Disease', (221, 245))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('rs2494732', 'Mutation', 'rs2494732', (166, 175))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (221, 245))	('rs1130233', 'Var', (152, 161))
15881	26828791	Moreover, both AKT1 rs2294750 and AKT2 rs7254617 polymorphisms have been investigated in cancers among Chinese populations 9, 19, but results are conflicting.	('rs2294750', 'Mutation', 'rs2294750', (20, 29))	('rs7254617', 'Mutation', 'rs7254617', (39, 48))	('cancers', 'Phenotype', 'HP:0002664', (89, 96))	('cancers', 'Disease', 'MESH:D009369', (89, 96))	('AKT1', 'Gene', '207', (15, 19))	('cancers', 'Disease', (89, 96))	('rs7254617', 'Var', (39, 48))	('rs2294750', 'Var', (20, 29))	('AKT2', 'Gene', (34, 38))	('AKT1', 'Gene', (15, 19))	('AKT2', 'Gene', '208', (34, 38))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
15883	26828791	reported that AKT2 rs7254617, but not AKT1 rs2294750, significantly increased the risk of prostate cancer 9.	('AKT2', 'Gene', '208', (14, 18))	('rs7254617', 'Mutation', 'rs7254617', (19, 28))	('AKT2', 'Gene', (14, 18))	('prostate cancer', 'Disease', 'MESH:D011471', (90, 105))	('AKT1', 'Gene', '207', (38, 42))	('AKT1', 'Gene', (38, 42))	('prostate cancer', 'Phenotype', 'HP:0012125', (90, 105))	('rs7254617', 'Var', (19, 28))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('rs2294750', 'Mutation', 'rs2294750', (43, 52))	('prostate cancer', 'Disease', (90, 105))	('increased', 'PosReg', (68, 77))
15885	26828791	The inconsistency among results may be because of the discrepancies in the sampling, different ethnicity or the fact that polymorphisms in AKT genes may play a tissue-specific role in the carcinogenesis.	('polymorphisms', 'Var', (122, 135))	('AKT', 'Gene', '207', (139, 142))	('play', 'Reg', (153, 157))	('carcinogenesis', 'Disease', 'MESH:D063646', (188, 202))	('carcinogenesis', 'Disease', (188, 202))	('AKT', 'Gene', (139, 142))
15886	26828791	AKT1 rs2294750 SNP show a significantly reverse association with ESCC risk among non-drinkers, but not among drinkers.	('AKT1', 'Gene', '207', (0, 4))	('AKT1', 'Gene', (0, 4))	('rs2294750', 'Mutation', 'rs2294750', (5, 14))	('ESCC', 'Disease', (65, 69))	('rs2294750 SNP', 'Var', (5, 18))
15892	26828791	The protective effects of AKT1 rs2294750 on non-drinker observed in this study is in accordance with the perception of cancer susceptibility, which represents a genetic attribute that modify the possible cancer risk under the influence of environmental conditions or lifestyles, such as smoking, drinking and diet.	('cancer', 'Disease', (204, 210))	('AKT1', 'Gene', (26, 30))	('cancer', 'Disease', 'MESH:D009369', (204, 210))	('rs2294750', 'Mutation', 'rs2294750', (31, 40))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('men', 'Species', '9606', (246, 249))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('cancer', 'Disease', (119, 125))	('non-drinker', 'Disease', (44, 55))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('AKT1', 'Gene', '207', (26, 30))	('rs2294750', 'Var', (31, 40))
15893	26828791	Given the aetiological role of drinking in the development of ESCC, the moderate protective effect of AKT1 rs2294750 on drinker is probably overridden by the potent carcinogenic effect of alcohol.	('AKT1', 'Gene', '207', (102, 106))	('rs2294750', 'Var', (107, 116))	('AKT1', 'Gene', (102, 106))	('carcinogenic', 'Disease', 'MESH:D063646', (165, 177))	('alcohol', 'Chemical', 'MESH:D000438', (188, 195))	('rs2294750', 'Mutation', 'rs2294750', (107, 116))	('carcinogenic', 'Disease', (165, 177))	('men', 'Species', '9606', (54, 57))	('ESCC', 'Disease', (62, 66))
15895	26828791	Moreover, we found that AKT1 rs2294750 had a protective effect on women against ESCC risk.	('AKT1', 'Gene', '207', (24, 28))	('rs2294750', 'Var', (29, 38))	('AKT1', 'Gene', (24, 28))	('rs2294750', 'Mutation', 'rs2294750', (29, 38))	('women', 'Species', '9606', (66, 71))	('ESCC risk', 'Disease', (80, 89))
15897	26828791	Comparable to the results observed in stratified analysis by drinking status, the protective impact of AKT1 rs2294750 was also more predominant in low-risk subgroup (women) than in high-risk subgroup (males).	('women', 'Species', '9606', (166, 171))	('rs2294750', 'Var', (108, 117))	('AKT1', 'Gene', '207', (103, 107))	('AKT1', 'Gene', (103, 107))	('rs2294750', 'Mutation', 'rs2294750', (108, 117))
15900	26828791	The relative gene expression analysis by HapMap genotypes demonstrated that AKT1 rs2949750 variant C allele was significantly associated with elevated AKT1 gene expression levels among the general population and the YRI population but not other three subpopulations.	('AKT1', 'Gene', '207', (151, 155))	('AKT1', 'Gene', (151, 155))	('rs2949750', 'Var', (81, 90))	('rs2949750', 'Mutation', 'rs2949750', (81, 90))	('AKT1', 'Gene', '207', (76, 80))	('AKT1', 'Gene', (76, 80))	('elevated', 'PosReg', (142, 150))
15901	26828791	Finally, although there was no association between ESCC susceptibility and any of AKT1 variants in the single-locus analysis, our results revealed that three AKT1 SNPs might collectively protect individuals from developing ESCC.	('SNPs', 'Var', (163, 167))	('AKT1', 'Gene', '207', (158, 162))	('AKT1', 'Gene', (82, 86))	('AKT1', 'Gene', (158, 162))	('protect', 'Reg', (187, 194))	('ESCC', 'Disease', (223, 227))	('AKT1', 'Gene', '207', (82, 86))
15905	26828791	The lack of main effect of AKT1 variants might suggest that the effect size of any of the variants under investigation was small and the current sample size was not large enough to detect such small effects.	('AKT1', 'Gene', '207', (27, 31))	('variants', 'Var', (32, 40))	('AKT1', 'Gene', (27, 31))
15907	26828791	The identification of multiple risk variants may therefore improve risk prediction and could conceivably be applied to assessment of an individual's ESCC risk.	('ESCC', 'Disease', (149, 153))	('men', 'Species', '9606', (125, 128))	('risk prediction', 'MPA', (67, 82))	('improve', 'PosReg', (59, 66))	('variants', 'Var', (36, 44))
15908	26828791	As indicated by the online tool SNPinfo software, AKT1 rs10138277 and rs2494750 are SNPs in the transcription factor-binding site of the gene and these SNPs may alter the binding capacity of the related transcription factors.	('binding', 'Interaction', (171, 178))	('rs2494750', 'Mutation', 'rs2494750', (70, 79))	('alter', 'Reg', (161, 166))	('rs10138277', 'Var', (55, 65))	('AKT1', 'Gene', '207', (50, 54))	('AKT1', 'Gene', (50, 54))	('transcription factors', 'Interaction', (203, 224))	('rs10138277', 'Mutation', 'rs10138277', (55, 65))	('rs2494750', 'Var', (70, 79))
15909	26828791	AKT1 rs2494752 was selected because that it was reported to be associated with chemotherapy response in advanced non-small cell lung cancer among a Chinese Population 25, and it is also a SNP in the transcription factor-binding site of the AKT1 gene.	('AKT1', 'Gene', '207', (0, 4))	('rs2494752', 'Var', (5, 14))	('AKT1', 'Gene', '207', (240, 244))	('rs2494752', 'Mutation', 'rs2494752', (5, 14))	('AKT1', 'Gene', (0, 4))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (113, 139))	('AKT1', 'Gene', (240, 244))	('non-small cell lung cancer', 'Disease', (113, 139))	('associated with', 'Reg', (63, 78))	('lung cancer', 'Phenotype', 'HP:0100526', (128, 139))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (117, 139))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (113, 139))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
15916	26828791	Moreover, our findings from observational association studies may require in vitro and in vivo experiments to further provide biological evidence of the observed protective effects of AKT1 SNPs on ESCC risk, which would unravel the underlying molecular mechanisms.	('ESCC', 'Disease', (197, 201))	('men', 'Species', '9606', (101, 104))	('AKT1', 'Gene', '207', (184, 188))	('SNPs', 'Var', (189, 193))	('AKT1', 'Gene', (184, 188))
15917	26828791	In summary, we found that AKT1 rs2294750 alone or together with other two AKI SNPs may modify the susceptibility to ESCC risk; nevertheless, these effects were largely dependent on the presence of other risk factors, i.e.	('modify', 'Reg', (87, 93))	('AKT1', 'Gene', (26, 30))	('ESCC', 'Disease', (116, 120))	('rs2294750', 'Mutation', 'rs2294750', (31, 40))	('susceptibility', 'MPA', (98, 112))	('AKT1', 'Gene', '207', (26, 30))	('rs2294750', 'Var', (31, 40))
15931	26352698	Comparative Cox multivariate analysis controlled by N stage and histologic tumor type showed that patients with high HAS-3 expression in pre-neoplastic cells obtained by lung/bronchial biopsy presented a significantly higher risk of death (HR=1.19; P=0.04).	('HAS-3', 'Gene', '3038', (117, 122))	('expression', 'MPA', (123, 133))	('high', 'Var', (112, 116))	('patients', 'Species', '9606', (98, 106))	('C', 'Chemical', 'MESH:D002244', (12, 13))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('death', 'Disease', 'MESH:D003643', (233, 238))	('death', 'Disease', (233, 238))	('HAS-3', 'Gene', (117, 122))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('tumor', 'Disease', (75, 80))
15936	26352698	Lung cancer is the result of a multi-step accumulation of genetic and/or epigenetic alterations.	('epigenetic alterations', 'Var', (73, 95))	('Lung cancer', 'Phenotype', 'HP:0100526', (0, 11))	('Lung cancer', 'Disease', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))	('Lung cancer', 'Disease', 'MESH:D008175', (0, 11))
15937	26352698	Better understanding of the molecular mechanisms by which these alterations affect lung cancer pathogenesis could provide new diagnostic procedures and prognostic factors for detection of early-stage or recurrent disease.	('affect', 'Reg', (76, 82))	('lung cancer', 'Disease', 'MESH:D008175', (83, 94))	('lung cancer', 'Disease', (83, 94))	('alterations', 'Var', (64, 75))	('lung cancer', 'Phenotype', 'HP:0100526', (83, 94))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))
16001	26352698	In fact, heterogeneous hyaluronidase expression has been shown in malignancies, and shows promise as an indicator of disease progression.	('malignancies', 'Disease', 'MESH:D009369', (66, 78))	('malignancies', 'Disease', (66, 78))	('shown', 'Reg', (57, 62))	('expression', 'MPA', (37, 47))	('heterogeneous', 'Var', (9, 22))	('hyaluronidase', 'Protein', (23, 36))
16004	26352698	Additionally, antigens that are nuclear or membranous (e.g., CD3, CD 31, CD117, estrogen and progesterone receptors, Ki67, p53, TTF-1, vimentin) show reduced immunosignals, whereas cytoplasmic antigens (smooth muscle actin, keratins 7, 20, AE1/AE3, 34betaE12, Hyal, and HAS) show little antigen decay.	('C', 'Chemical', 'MESH:D002244', (66, 67))	('CD117', 'Var', (73, 78))	('HA', 'Chemical', 'MESH:D006820', (270, 272))	('p53', 'Var', (123, 126))	('C', 'Chemical', 'MESH:D002244', (73, 74))	('Ki67', 'Var', (117, 121))	('C', 'Chemical', 'MESH:D002244', (61, 62))	('reduced', 'NegReg', (150, 157))	('immunosignals', 'MPA', (158, 171))	('CD 31', 'Var', (66, 71))
16008	26352698	The presence of hyaluronidase in tumor cells has been shown to increase angiogenesis in vivo.	('hyaluronidase', 'Protein', (16, 29))	('increase', 'PosReg', (63, 71))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumor', 'Disease', (33, 38))	('presence', 'Var', (4, 12))	('angiogenesis', 'CPA', (72, 84))
16010	26352698	Interestingly, in a mouse model of prostate cancer, co-expression of a Hyal-1 and a HAS-2 significantly increased angiogenesis.	('increased', 'PosReg', (104, 113))	('prostate cancer', 'Disease', 'MESH:D011471', (35, 50))	('Hyal-1', 'Gene', (71, 77))	('prostate cancer', 'Phenotype', 'HP:0012125', (35, 50))	('angiogenesis', 'CPA', (114, 126))	('co-expression', 'Var', (52, 65))	('HAS-2', 'Gene', (84, 89))	('HAS-2', 'Gene', '3037', (84, 89))	('Hyal-1', 'Gene', '3373', (71, 77))	('prostate cancer', 'Disease', (35, 50))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('mouse', 'Species', '10090', (20, 25))
16022	33303576	EPHA mutation as a predictor of immunotherapeutic efficacy in lung adenocarcinoma Ephrin type-A receptors (EPHA) are members of family of receptor tyrosine kinases and are related to tumor immunogenicity and immune microenvironment, however, the association between EPHA mutation (EPHAmut) and efficacy of immune checkpoint inhibitors (ICIs) has not been investigated in non-small cell lung cancer (NSCLC).	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (62, 81))	('EPH', 'Gene', '2041', (266, 269))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (62, 81))	('EPH', 'Gene', '2041', (107, 110))	('cancer', 'Phenotype', 'HP:0002664', (391, 397))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (375, 397))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (371, 397))	('mutation', 'Var', (271, 279))	('EPH', 'Gene', (266, 269))	('Ephrin', 'Gene', '2041', (82, 88))	('EPH', 'Gene', '2041', (281, 284))	('EPH', 'Gene', (107, 110))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (371, 397))	('EPHAmut', 'Chemical', '-', (281, 288))	('tumor', 'Disease', (183, 188))	('EPH', 'Gene', '2041', (0, 3))	('EPH', 'Gene', (281, 284))	('NSCLC', 'Disease', 'MESH:D002289', (399, 404))	('lung adenocarcinoma', 'Disease', (62, 81))	('Ephrin', 'Gene', (82, 88))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('NSCLC', 'Disease', (399, 404))	('non-small cell lung cancer', 'Disease', (371, 397))	('lung cancer', 'Phenotype', 'HP:0100526', (386, 397))	('EPH', 'Gene', (0, 3))
16027	33303576	Further pooled estimates of the discovery and validation cohorts showed that patients with EPHAmut exhibited a significantly longer PFS and OS in lung adenocarcinoma (LUAD) while not squamous cell lung cancer (LUSC).	('squamous cell lung cancer', 'Phenotype', 'HP:0030359', (183, 208))	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('carcinoma', 'Phenotype', 'HP:0030731', (156, 165))	('EPHAmut', 'Var', (91, 98))	('EPHAmut', 'Chemical', '-', (91, 98))	('squamous cell lung cancer', 'Disease', (183, 208))	('lung adenocarcinoma', 'Disease', (146, 165))	('longer', 'PosReg', (125, 131))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (146, 165))	('patients', 'Species', '9606', (77, 85))	('PFS', 'MPA', (132, 135))	('lung cancer', 'Phenotype', 'HP:0100526', (197, 208))	('squamous cell lung cancer', 'Disease', 'MESH:D002294', (183, 208))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (146, 165))
16042	33303576	Most EPHA3 mutations are loss-of-function missense mutations that inhibit the activating of Eph RTKs by disrupting ephrin binding, kinase activity or cell surface localization, and inactivating of EPHA3 promoted the lung cancer cells proliferation.	('mutations', 'Var', (11, 20))	('disrupting', 'NegReg', (104, 114))	('EPHA3', 'Gene', (197, 202))	('EPHA3', 'Gene', (5, 10))	('lung cancer', 'Disease', 'MESH:D008175', (216, 227))	('kinase activity', 'MPA', (131, 146))	('Eph', 'Gene', (92, 95))	('cell surface localization', 'MPA', (150, 175))	('loss-of-function', 'NegReg', (25, 41))	('lung cancer', 'Phenotype', 'HP:0100526', (216, 227))	('EPHA3', 'Gene', '2042', (5, 10))	('EPHA3', 'Gene', '2042', (197, 202))	('Eph', 'Gene', '2041', (92, 95))	('ephrin', 'Gene', '2041', (115, 121))	('binding', 'Interaction', (122, 129))	('promoted', 'PosReg', (203, 211))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('inhibit', 'NegReg', (66, 73))	('ephrin', 'Gene', (115, 121))	('inactivating', 'Var', (181, 193))	('activating', 'MPA', (78, 88))	('lung cancer', 'Disease', (216, 227))
16078	33303576	The detailed profiles of EPHA (EPHA1-8, EPHA10) mutation in each cohort are listed in the online supplemental figure S1.	('EPHA1-8', 'Gene', '2041;1969;2042;2043;2044;285220;2045;2046', (31, 38))	('EPHA10', 'Gene', (40, 46))	('EPH', 'Gene', '2041', (40, 43))	('EPHA1-8', 'Gene', (31, 38))	('EPH', 'Gene', (40, 43))	('mutation', 'Var', (48, 56))	('EPHA10', 'Gene', '284656', (40, 46))	('EPH', 'Gene', '2041', (25, 28))	('EPH', 'Gene', '2041', (31, 34))	('EPH', 'Gene', (25, 28))	('EPH', 'Gene', (31, 34))
16079	33303576	The non-synonymous mutations including TRUNC (Frameshift del, Frameshift ins, nonsense, nonstop, splice region, splice site), INFRAME (Inframe del and Inframe ins) and MISSENSE mutations of at least one EPHA subtype were defined as EPHA mutation (EPHAmut) in this study.	('MISSENSE mutations', 'Var', (168, 186))	('EPH', 'Gene', '2041', (232, 235))	('EPH', 'Gene', (232, 235))	('EPHAmut', 'Chemical', '-', (247, 254))	('Frameshift ins', 'Var', (62, 76))	('Frameshift del', 'Var', (46, 60))	('EPH', 'Gene', '2041', (247, 250))	('Inframe', 'Var', (135, 142))	('EPH', 'Gene', '2041', (203, 206))	('EPH', 'Gene', (247, 250))	('EPH', 'Gene', (203, 206))
16088	33303576	In the discovery cohort, 22.8% patients with NSCLC harbored EPHA mutations, and most EPHA mutations were missense mutations (92.1%) (online supplemental figure S1).	('missense mutations', 'Var', (105, 123))	('NSCLC', 'Disease', (45, 50))	('EPH', 'Gene', '2041', (60, 63))	('harbored', 'Reg', (51, 59))	('EPH', 'Gene', '2041', (85, 88))	('NSCLC', 'Disease', 'MESH:D002289', (45, 50))	('patients', 'Species', '9606', (31, 39))	('EPH', 'Gene', (60, 63))	('EPH', 'Gene', (85, 88))
16097	33303576	In the multivariable Cox proportional hazards regression model adjusted by PD-L1 expression and TMB (top 20% vs the rest) and other confounding factors, EPHAmut remained an independent predictor for superior PFS (HR 0.59; 95% CI 0.37 to 0.96; p=0.03; online supplemental table S7).	('PFS', 'CPA', (208, 211))	('EPHAmut', 'Var', (153, 160))	('TMB', 'Chemical', '-', (96, 99))	('PD-L1', 'Gene', (75, 80))	('PD-L1', 'Gene', '29126', (75, 80))	('superior', 'PosReg', (199, 207))	('EPHAmut', 'Chemical', '-', (153, 160))
16098	33303576	In the validation cohort 2, which comprised 1662 patients with >10 types of tumors, we further validated the association between EPHAmut and significantly longer OS in NSCLC (HR 0.48; 95% CI 0.33 to 0.71; p<0.001; figure 4A).	('NSCLC', 'Disease', 'MESH:D002289', (168, 173))	('EPHAmut', 'Chemical', '-', (129, 136))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumors', 'Disease', (76, 82))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('EPHAmut', 'Var', (129, 136))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('longer', 'PosReg', (155, 161))	('patients', 'Species', '9606', (49, 57))	('NSCLC', 'Disease', (168, 173))
16106	33303576	The pooled analysis further revealed that EPHAmut was associated with significantly longer PFS (discovery cohort plus validation cohort 1; HR 0.38; 95% CI 0.25 to 0.58; p<0.001; online supplemental figure S4) and OS (validation cohort 2; HR 0.51; 95% CI 0.33 to 0.79; p=0.001; online supplemental figure S4) in LUAD.	('LUAD', 'Disease', (311, 315))	('EPHAmut', 'Chemical', '-', (42, 49))	('PFS', 'MPA', (91, 94))	('EPHAmut', 'Var', (42, 49))	('longer', 'PosReg', (84, 90))
16131	33303576	To our knowledge, our study is the first to propose that the mutation of EPHA might be a predictor favorable for the ICIs delivery.	('ICIs', 'Disease', (117, 121))	('mutation', 'Var', (61, 69))	('EPH', 'Gene', '2041', (73, 76))	('EPH', 'Gene', (73, 76))
16132	33303576	As derived from multiple discovery and the validation cohorts, EPHAmut consistently correlated well with a better clinical benefit in patients with NSCLC, especially LUAD.	('EPHAmut', 'Var', (63, 70))	('NSCLC', 'Disease', (148, 153))	('LUAD', 'Disease', (166, 170))	('patients', 'Species', '9606', (134, 142))	('NSCLC', 'Disease', 'MESH:D002289', (148, 153))	('EPHAmut', 'Chemical', '-', (63, 70))
16138	33303576	Recently, KRAS mutations were identified to represent the generation of neoantigens that reflect an improved immunogenicity, subsequently bringing superior efficacy to ICIs in NSCLC.	('efficacy', 'MPA', (156, 164))	('KRAS', 'Gene', '3845', (10, 14))	('NSCLC', 'Disease', (176, 181))	('mutations', 'Var', (15, 24))	('NSCLC', 'Disease', 'MESH:D002289', (176, 181))	('superior', 'PosReg', (147, 155))	('KRAS', 'Gene', (10, 14))
16139	33303576	In the present study, the more enrichment of KRAS mutations in EPHAmut tumors compared with EPHAwt may be one potential explanation for the distinct performance for ICIs efficacy in LUAD and LUSC (online supplemental figure S6A).	('KRAS', 'Gene', '3845', (45, 49))	('EPH', 'Gene', (63, 66))	('LUAD', 'Disease', (182, 186))	('mutations', 'Var', (50, 59))	('EPH', 'Gene', (92, 95))	('EPH', 'Gene', '2041', (92, 95))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('tumors', 'Disease', (71, 77))	('EPH', 'Gene', '2041', (63, 66))	('EPHAmut', 'Chemical', '-', (63, 70))	('KRAS', 'Gene', (45, 49))	('tumors', 'Disease', 'MESH:D009369', (71, 77))
16140	33303576	The co-occurring mutations in EPHA and KRAS seemed to be associated with the optimal PFS in LUAD in present study, however, the co-mutation between EPHA and KRAS need to be validated in larger population.	('PFS', 'MPA', (85, 88))	('KRAS', 'Gene', '3845', (157, 161))	('EPH', 'Gene', '2041', (148, 151))	('EPH', 'Gene', (148, 151))	('EPH', 'Gene', '2041', (30, 33))	('EPH', 'Gene', (30, 33))	('KRAS', 'Gene', (39, 43))	('KRAS', 'Gene', (157, 161))	('KRAS', 'Gene', '3845', (39, 43))	('mutations', 'Var', (17, 26))	('associated', 'Reg', (57, 67))
16146	33303576	Second, lacking hotspot and difficult to verify the function of each EPHA mutation and indeed influenced the precision of biomarker detection, our attempt to recruit functional EPHA mutations into our EPHA mutation pattern was handicapped by the limited information available regarding the functions of different mutations.	('EPH', 'Gene', (69, 72))	('EPH', 'Gene', '2041', (201, 204))	('EPH', 'Gene', (201, 204))	('EPH', 'Gene', '2041', (177, 180))	('EPH', 'Gene', (177, 180))	('EPH', 'Gene', '2041', (69, 72))	('mutations', 'Var', (182, 191))
16159	31708418	The expanded datasets consist of whole-genome sequencing (WGS), transcriptome sequencing (RNA-seq), whole-genome bisulfite sequencing (WGBS), and DNA methylation array data as well as H3K27me3 and H3K27ac chromatin immunoprecipitation sequencing (ChIP-seq) data (Table S1).	('H3K27me3', 'Var', (184, 192))	('H3K27ac', 'Var', (197, 204))	('bisulfite', 'Chemical', 'MESH:C042345', (113, 122))
16176	31708418	Of 26 cases with SMARCB1 deletions larger than 10 kilobases, a significant overrepresentation (14 out of 26 cases; Fisher's exact p value = 2.12e-08; Figure S3C) was in Group 1.	('deletions', 'Var', (25, 34))	('overrepresentation', 'PosReg', (75, 93))	('SMARCB1', 'Gene', (17, 24))	('S3C', 'Chemical', 'MESH:D013455', (157, 160))
16177	31708418	Group 3 and ATRT-SHH almost exclusively contained cases with somatic nonsense mutations or focal deletions of SMARCB1 (10 out of 12 cases and 11 out of 13 cases, respectively; Figures S3B and S3C).	('SMARCB1', 'Gene', (110, 117))	('S3C', 'Chemical', 'MESH:D013455', (192, 195))	('SHH', 'Gene', '6469', (17, 20))	('deletions', 'Var', (97, 106))	('SHH', 'Gene', (17, 20))
16181	31708418	Our previous study showed that global hypomethylation in ATRT-MYC compared to other ATRT subgroups was linked to the prevalence of partially methylated domains (PMDs).	('MYC', 'Gene', (62, 65))	('partially methylated domains', 'MPA', (131, 159))	('PMDs', 'Disease', 'None', (161, 165))	('global hypomethylation', 'Var', (31, 53))	('MYC', 'Gene', '4609', (62, 65))	('PMDs', 'Disease', (161, 165))
16185	31708418	We also observed a significant enrichment of upregulated genes (e.g., NCOR2, a transcriptional repressor implicated in hematological malignancies) in Group-1-specific DMRs involved in retinoic acid signaling, a pathway that has not been previously associated with MRTs or ATRTs (Figure 3F; Table S3).	('NCOR2', 'Gene', '9612', (70, 75))	('hematological malignancies', 'Disease', (119, 145))	('hematological malignancies', 'Disease', 'MESH:D019337', (119, 145))	('upregulated', 'PosReg', (45, 56))	('NCOR2', 'Gene', (70, 75))	('hematological malignancies', 'Phenotype', 'HP:0004377', (119, 145))	('ATRTs', 'Disease', (272, 277))	('DMRs', 'Var', (167, 171))	('retinoic acid', 'Chemical', 'MESH:D014212', (184, 197))	('MRTs', 'Disease', (264, 268))
16186	31708418	Genes associated with Group-3-specific DMRs were enriched for DNA excision repair, BMP signaling, and pathways implicated in renal cell carcinoma development, consistent with RTK-like characteristics observed in Group 3 (Figure 3D).	('renal cell carcinoma', 'Disease', 'MESH:D002292', (125, 145))	('renal cell carcinoma', 'Disease', (125, 145))	('pathways', 'Pathway', (102, 110))	('BMP signaling', 'Gene', (83, 96))	('DNA excision repair', 'Gene', (62, 81))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (125, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('DMRs', 'Var', (39, 43))
16187	31708418	For Group-4-specific DMRs, the most significantly enriched pathways included focal adhesion, FGFR signaling, and nuclear factor kappaB (NF-kappaB) signaling, a key regulatory pathway for immune and inflammatory processes (Figure 3E).	('enriched', 'Reg', (50, 58))	('DMRs', 'Var', (21, 25))	('NF-kappaB', 'Gene', '4790', (136, 145))	('nuclear factor', 'MPA', (113, 127))	('NF-kappaB', 'Gene', (136, 145))	('focal adhesion', 'MPA', (77, 91))	('FGFR signaling', 'MPA', (93, 107))
16189	31708418	We also observed increased H3K27ac levels in subgroup-specific DMRs (Figure 4B), further supporting upregulation of genes in these regions (e.g., NCOR2).	('increased', 'PosReg', (17, 26))	('DMRs', 'Var', (63, 67))	('NCOR2', 'Gene', '9612', (146, 151))	('NCOR2', 'Gene', (146, 151))	('H3K27ac', 'Protein', (27, 34))	('upregulation', 'PosReg', (100, 112))
16196	31708418	Also enriched within ATRT-MYC and MRT was a TFBS for XBP-1, a TLR-activated TF required for production of proinflammatory cytokines, corroborating our DMR analysis result (above) that indicated epigenetic dysregulation of genes involved in interleukin 1-mediated signaling.	('epigenetic dysregulation', 'Var', (194, 218))	('MYC', 'Gene', '4609', (26, 29))	('XBP-1', 'Gene', (53, 58))	('MYC', 'Gene', (26, 29))	('XBP-1', 'Gene', '7494', (53, 58))
16200	31708418	Our DNA methylation and enhancer data indicated shared epigenetic dysregulation of TFs in ATRT-MYC and MRT, potentially acting on similar gene expression programs.	('MYC', 'Gene', '4609', (95, 98))	('MRT', 'Gene', (103, 106))	('TFs', 'Gene', (83, 86))	('MYC', 'Gene', (95, 98))	('epigenetic dysregulation', 'Var', (55, 79))
16211	31708418	Of these, 11 involved HOX genes, of which five identified MYC as one of the putative direct HOX target genes, supporting the notion that the prominent molecular characteristics of HOX gene overexpression and dysregulation of MYC, another key characteristic of ATRT-MYC and MRT, might be linked (Figure S5C; Table S5).	('MYC', 'Gene', (58, 61))	('MYC', 'Gene', '4609', (225, 228))	('MYC', 'Gene', (265, 268))	('MYC', 'Gene', '4609', (58, 61))	('MYC', 'Gene', (225, 228))	('overexpression', 'PosReg', (189, 203))	('MYC', 'Gene', '4609', (265, 268))	('dysregulation', 'Var', (208, 221))
16241	31708418	A significant increase in PD-L1-expressing CD68+ myeloid cells was also observed in MRTs compared to ATRTs (Wilcoxon p value < 2.2e-16; Figures 7G and S7B; [dummy_Data S1]).	('S7B', 'Chemical', 'MESH:C026625', (151, 154))	('MRTs', 'Var', (84, 88))	('PD-L1', 'Gene', (26, 31))	('CD68', 'Gene', (43, 47))	('PD-L1', 'Gene', '29126', (26, 31))	('CD68', 'Gene', '968', (43, 47))	('increase', 'PosReg', (14, 22))
16249	31708418	ATRT-MYC and MRT showed an enrichment of TFBS in the enhancers of genes involved in type I IFN-induced responses (IRF5/8/9 and STAT1) and antigen presentation (RFX1/5 and XBP-1).	('STAT1', 'Gene', (127, 132))	('type I IFN-induced responses', 'MPA', (84, 112))	('IRF5/8/9', 'Gene', (114, 122))	('XBP-1', 'Gene', (171, 176))	('RFX1/5', 'Gene', '5989;5993', (160, 166))	('MYC', 'Gene', '4609', (5, 8))	('XBP-1', 'Gene', '7494', (171, 176))	('IRF5/8/9', 'Gene', '3663;3394;10379', (114, 122))	('STAT1', 'Gene', '6772', (127, 132))	('TFBS', 'Var', (41, 45))	('MYC', 'Gene', (5, 8))	('RFX1/5', 'Gene', (160, 166))	('enhancers', 'PosReg', (53, 62))
16252	31708418	Although our analysis did not support the notion of epigenetically de-repressed EREs as a potential source of antigens, we did observe increased tumor antigen expression from developmentally silenced genes whose expressions are normally restricted to early embryonic stages or to specific tissue types.	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('embryonic stages', 'Disease', (257, 273))	('embryonic stages', 'Disease', 'MESH:D007676', (257, 273))	('increased', 'PosReg', (135, 144))	('tumor', 'Disease', (145, 150))	('epigenetically de-repressed', 'Var', (52, 79))
16253	31708418	For example, significant under-expression of MIF due to homozygous co-deletion with SMARCB1 in Group1 cases may contribute to increased immunogenicity observed in this subgroup, as suggested by a previous study that demonstrated increased levels of CD8-induced tumor cytotoxicity in MIF double knockout mice compared to wild-type mice.	('immunogenicity', 'MPA', (136, 150))	('CD8', 'Gene', '925', (249, 252))	('tumor cytotoxicity', 'Disease', (261, 279))	('tumor', 'Phenotype', 'HP:0002664', (261, 266))	('mice', 'Species', '10090', (330, 334))	('increased', 'PosReg', (229, 238))	('co-deletion', 'Var', (67, 78))	('SMARCB1', 'Gene', (84, 91))	('mice', 'Species', '10090', (303, 307))	('under-expression', 'NegReg', (25, 41))	('increased', 'PosReg', (126, 135))	('tumor cytotoxicity', 'Disease', 'MESH:D064420', (261, 279))	('CD8', 'Gene', (249, 252))
16258	31708418	Although ICI has emerged as a promising cancer therapy, it frequently has been described to be most effective against cancers with high mutational burdens that are thought to result in neoantigens that provide a substrate for T cell recognition.	('ICI', 'Chemical', 'MESH:C481040', (9, 12))	('cancer', 'Disease', (118, 124))	('cancers', 'Disease', (118, 125))	('cancers', 'Disease', 'MESH:D009369', (118, 125))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('cancer', 'Disease', (40, 46))	('mutational', 'Var', (136, 146))	('result in', 'Reg', (175, 184))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('neoantigens', 'MPA', (185, 196))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('cancers', 'Phenotype', 'HP:0002664', (118, 125))
16259	31708418	However, several recent studies indicated that mutations in the SWI/SNF complex can also increase the immunogenicity of tumors.	('tumors', 'Disease', 'MESH:D009369', (120, 126))	('tumors', 'Disease', (120, 126))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('mutations', 'Var', (47, 56))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('SWI/SNF', 'Gene', (64, 71))	('increase', 'PosReg', (89, 97))
16260	31708418	Our observations of increased cytotoxic T cell infiltration, T cell anergy, and immunosuppressive signaling in immune-responsive MRTs and ATRT-MYC support the notion that T cells may be functionally inhibited by the effects of immune checkpoint signaling and are consistent with accumulating evidence that SWI/SNF mutations can contribute to tumor immunogenicity in ways that may enhance their vulnerability to ICI.	('contribute', 'Reg', (328, 338))	('mutations', 'Var', (314, 323))	('tumor', 'Disease', 'MESH:D009369', (342, 347))	('vulnerability to ICI', 'MPA', (394, 414))	('MYC', 'Gene', '4609', (143, 146))	('tumor', 'Phenotype', 'HP:0002664', (342, 347))	('SWI/SNF', 'Gene', (306, 313))	('ICI', 'Chemical', 'MESH:C481040', (411, 414))	('tumor', 'Disease', (342, 347))	('MYC', 'Gene', (143, 146))	('enhance', 'PosReg', (380, 387))
16308	31708418	These were then followed by Mach2 Double Stain #2 polymer dispensed using the Intellipath FLX  for 30 minutes to put CD8 on IP DAB chromogen and CD3 on IP Warp Red chromogen.	('CD8', 'Gene', '925', (117, 120))	('FLX', 'Chemical', 'None', (90, 93))	('CD3', 'Var', (145, 148))	('CD8', 'Gene', (117, 120))
16315	31708418	To enhance visibility and discrimination between IHC colors, IHC images shown in Figure 7E were adjusted to reduce the blue hematoxylin signals by 50% and were re-colored with the following pseudocolors: CD8+ signals in brown and CD3+ in green.	('CD8', 'Gene', '925', (204, 207))	('enhance', 'PosReg', (3, 10))	('blue hematoxylin signals', 'MPA', (119, 143))	('CD3+', 'Var', (230, 234))	('hematoxylin', 'Chemical', 'MESH:D006416', (124, 135))	('reduce', 'NegReg', (108, 114))	('CD8', 'Gene', (204, 207))
16332	31744190	As a consequence of genetic and/or epigenetic changes, cancer cells are characterized by alteration in their transcriptomes, compared to normal counterparts.	('transcriptomes', 'MPA', (109, 123))	('alteration', 'Reg', (89, 99))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('genetic', 'Var', (20, 27))	('epigenetic changes', 'Var', (35, 53))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('cancer', 'Disease', (55, 61))
16344	31744190	The inactivation of NF-YA by RNAi leads to cell-cycle arrest and apoptosis in different cellular contexts, and no cell line has ever been described lacking NF-Y activity.	('inactivation', 'Var', (4, 16))	('NF-YA', 'Gene', '4800', (20, 25))	('NF-YA', 'Gene', (20, 25))	('apoptosis', 'CPA', (65, 74))	('arrest', 'Disease', 'MESH:D006323', (54, 60))	('RNAi', 'Gene', (29, 33))	('arrest', 'Disease', (54, 60))
16411	31744190	We conclude that the relative levels of the two NF-YA isoforms have an impact on the clinical outcome of LUSC: surprisingly, worst prognosis is observed not only in patients with high NF-YAs/NF-YAl ratios, but equally in those with very low.	('NF-YA', 'Gene', (184, 189))	('impact', 'Reg', (71, 77))	('NF-YA', 'Gene', '4800', (48, 53))	('NF-YA', 'Gene', (191, 196))	('high', 'Var', (179, 183))	('NF-YA', 'Gene', '4800', (184, 189))	('patients', 'Species', '9606', (165, 173))	('NF-YA', 'Gene', (48, 53))	('NF-YA', 'Gene', '4800', (191, 196))
16429	31744190	Structurally, NF-YAl contains 28 additional amino acids at the N-terminal of the protein, within the large glutamine and hydrophobics-rich trans-activation domain (TAD); these 28 aminoacids have the same relative composition (Gln, Ile/Leu and absence of charged residues) as the surrounding part.	('glutamine', 'Chemical', 'MESH:D005973', (107, 116))	('NF-YA', 'Gene', '4800', (14, 19))	('large glutamine', 'Phenotype', 'HP:0003217', (101, 116))	('NF-YA', 'Gene', (14, 19))	('Ile', 'Chemical', 'MESH:D007532', (231, 234))	('Leu', 'Chemical', 'MESH:D007930', (235, 238))	('Gln', 'Var', (226, 229))	('Gln', 'Chemical', 'MESH:D005973', (226, 229))	('Ile/Leu', 'Var', (231, 238))
16464	31796082	Novel findings of this study include identification of (a) potential immunosuppressive effect in OSCC-GB due to significant promoter hypomethylation driven upregulation of CD274 and CD80, (b) significant dysregulation by epigenetic modification of DNMT3B (upregulation) and TET1 (downregulation); and (c) known drugs that can reverse the direction of dysregulation of gene expression caused by promoter methylation.	('promoter methylation', 'Var', (394, 414))	('TET1', 'Gene', '80312', (274, 278))	('SCC', 'Phenotype', 'HP:0002860', (98, 101))	('upregulation', 'PosReg', (156, 168))	('CD80', 'Gene', (182, 186))	('OSCC-GB', 'Gene', (97, 104))	('TET1', 'Gene', (274, 278))	('OSCC-GB', 'Chemical', '-', (97, 104))	('CD274', 'Gene', '29126', (172, 177))	('epigenetic modification', 'Var', (221, 244))	('immunosuppressive', 'MPA', (69, 86))	('CD80', 'Gene', '941', (182, 186))	('DNMT3B', 'Gene', '1789', (248, 254))	('dysregulation', 'Reg', (204, 217))	('CD274', 'Gene', (172, 177))	('DNMT3B', 'Gene', (248, 254))
16476	31796082	In addition to genetic alterations, significant epigenetic alterations have been found to be associated with many cancer types.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('associated', 'Reg', (93, 103))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('epigenetic alterations', 'Var', (48, 70))	('cancer', 'Disease', (114, 120))
16477	31796082	Promoter hypermethylation, mainly in CpG islands, can lead to downregulation of tumor suppressor genes and also dysregulation of downstream signaling pathways; these indications can serve as predictive markers of cancer.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('dysregulation', 'MPA', (112, 125))	('tumor', 'Disease', (80, 85))	('downstream signaling pathways', 'Pathway', (129, 158))	('cancer', 'Disease', 'MESH:D009369', (213, 219))	('downregulation', 'NegReg', (62, 76))	('cancer', 'Disease', (213, 219))	('Promoter hypermethylation', 'Var', (0, 25))
16478	31796082	Global epigenomic alterations during the initiation and progression of cancer are indeed hallmarks of cancer.	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('cancer', 'Disease', (71, 77))	('epigenomic alterations', 'Var', (7, 29))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))
16479	31796082	We have previously identified a set of driver genes for OSCC-GB, with significantly enhanced burden of somatic mutations and copy number alterations, some of which are unique compared to drivers of other subtypes of head and neck cancers.	('SCC', 'Phenotype', 'HP:0002860', (57, 60))	('head and neck cancer', 'Phenotype', 'HP:0012288', (216, 236))	('OSCC-GB', 'Gene', (56, 63))	('head and neck cancers', 'Disease', 'MESH:D006258', (216, 237))	('copy number alterations', 'Var', (125, 148))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('OSCC-GB', 'Chemical', '-', (56, 63))	('head and neck cancers', 'Phenotype', 'HP:0012288', (216, 237))	('cancers', 'Phenotype', 'HP:0002664', (230, 237))	('enhanced', 'PosReg', (84, 92))
16493	31796082	To reduce false positive inference, we have ignored any CpG probe (a) for which detection p was > 0.01; (b) "NA"- masked value; (c) that mapped to multiple locations on the human reference genome (hg19 with decoy sequence) when aligned using Bowtie 2 (v. 2.3.4.1) with "end-to-end" alignment mode and allowing for maximum 2 mismatches; (d) overlapped with a repetitive element [repeat masker (v. 4.0.5) (http://www.repeatmasker.org/) from UCSC hg19]; (e) polymorphic (MAF > 0.01) SNPs (dbSNP build 150) located within 10 bp of the interrogated CpG site; (f) spanned known regions of small insertions and deletions (indels) in the human genome (UCSC hg19); or (g) was located on a sex chromosome.	('men', 'Species', '9606', (372, 375))	('MAF', 'Gene', '4094', (468, 471))	('deletions', 'Var', (604, 613))	('human', 'Species', '9606', (630, 635))	('MAF', 'Gene', (468, 471))	('human', 'Species', '9606', (173, 178))	('men', 'Species', '9606', (287, 290))
16499	31796082	The CpG sites with Benjamini-Hochberg corrected p < 0.05 (merged set) or 0.02 (EPIC only set) and average  Deltabeta  >= 0.2 (tumor vs adjacent normal) were considered as significantly differentially methylated sites (DMPs).	('DMPs', 'Chemical', '-', (218, 222))	('p < 0.05', 'Var', (48, 56))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('0.02', 'Var', (73, 77))	('Deltabeta', 'MPA', (107, 116))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumor', 'Disease', (126, 131))
16517	31796082	Such a gene was further examined to ascertain whether there was an opposite relationship between mean values of promoter methylation and gene expression in tumors compared to normals (i.e., hypomethylation and overexpression, or hypermethylation and underexpression).	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('hypermethylation', 'Var', (229, 245))	('tumors', 'Disease', 'MESH:D009369', (156, 162))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('overexpression', 'PosReg', (210, 224))	('hypomethylation', 'Var', (190, 205))	('tumors', 'Disease', (156, 162))
16521	31796082	Of these 20023 validated DMPs, 11522 (~ 58%) were hypermethylated and 8501 (~ 42%) were hypomethylated (Fig.	('hypermethylated', 'Var', (50, 65))	('hypomethylated', 'Var', (88, 102))	('DMPs', 'Chemical', '-', (25, 29))
16523	31796082	With the exception of chromosomes 8 and 21, on all other chromosomes, the proportion of hypermethylated DMPs was higher than those hypomethylated (Fig.	('DMPs', 'Chemical', '-', (104, 108))	('DMPs', 'Protein', (104, 108))	('hypermethylated', 'Var', (88, 103))	('higher', 'PosReg', (113, 119))
16535	31796082	Of all significantly epigenetically downregulated (upregulated) genes in OSCC-GB, known drugs could upregulate (downregulate) 105 (43) genes.	('OSCC-GB', 'Gene', (73, 80))	('OSCC-GB', 'Chemical', '-', (73, 80))	('epigenetically', 'Var', (21, 35))	('upregulate', 'PosReg', (100, 110))	('SCC', 'Phenotype', 'HP:0002860', (74, 77))	('downregulated', 'NegReg', (36, 49))
16536	31796082	Pathway enrichment analyses using 209 significantly dysregulated genes associated with epigenetic modifications in their promoter regions identified significant (corrected p < 0.05) enrichment of five KEGG pathways (Table 2 and Fig.	('epigenetic modifications', 'Var', (87, 111))	('men', 'Species', '9606', (188, 191))	('KEGG pathways', 'Pathway', (201, 214))	('men', 'Species', '9606', (14, 17))
16537	31796082	Significantly enriched KEGG pathways included PPAR signaling (earlier found with significant gene expression alterations in OSCC-GB and OSCC-tongue), arachidonic acid metabolism (earlier implicated in OSCC using transcriptomic data and in OSCC-GB on post-treatment disease-free survival length using somatic mutation data), and B cell receptor signaling pathway (commonly implicated in chronic lymphocytic leukemia, but also in OSCC).	('SCC', 'Phenotype', 'HP:0002860', (137, 140))	('PPAR', 'Gene', (46, 50))	('SCC', 'Gene', '6317', (202, 205))	('SCC', 'Phenotype', 'HP:0002860', (240, 243))	('SCC', 'Gene', (125, 128))	('B cell receptor signaling pathway', 'Pathway', (328, 361))	('arachidonic acid metabolism', 'MPA', (150, 177))	('SCC', 'Gene', (202, 205))	('SCC', 'Gene', '6317', (137, 140))	('SCC', 'Phenotype', 'HP:0002860', (429, 432))	('SCC', 'Gene', '6317', (240, 243))	('OSCC-GB', 'Chemical', '-', (239, 246))	('PPAR', 'Gene', '5465', (46, 50))	('KEGG pathways', 'Pathway', (23, 36))	('SCC', 'Gene', (137, 140))	('SCC', 'Gene', (240, 243))	('SCC', 'Gene', '6317', (429, 432))	('arachidonic acid', 'Chemical', 'MESH:D016718', (150, 166))	('SCC', 'Phenotype', 'HP:0002860', (125, 128))	('chronic lymphocytic leukemia', 'Disease', 'MESH:D015451', (386, 414))	('men', 'Species', '9606', (260, 263))	('chronic lymphocytic leukemia', 'Disease', (386, 414))	('SCC', 'Gene', (429, 432))	('OSCC-GB', 'Chemical', '-', (124, 131))	('SCC', 'Phenotype', 'HP:0002860', (202, 205))	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (386, 414))	('alterations', 'Var', (109, 120))	('leukemia', 'Phenotype', 'HP:0001909', (406, 414))	('SCC', 'Gene', '6317', (125, 128))
16549	31796082	Epigenomic reprogramming, more specifically epigenomic gene repression, is a significant hallmark of oral cancer.	('epigenomic gene repression', 'Var', (44, 70))	('hallmark of oral cancer', 'Disease', (89, 112))	('Epigenomic reprogramming', 'CPA', (0, 24))	('hallmark of oral cancer', 'Disease', 'MESH:D009369', (89, 112))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
16553	31796082	A cluster of Kruppel-type zinc finger protein genes (including ZNF132 and ZSCAN18, earlier known as ZNF447) on chromosome 19q13 was earlier found significantly epigenetically downregulated in oropharyngeal squamous cell carcinoma.	('ZNF132', 'Gene', (63, 69))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (206, 229))	('epigenetically', 'Var', (160, 174))	('downregulated', 'NegReg', (175, 188))	('squamous cell carcinoma', 'Disease', (206, 229))	('ZNF447', 'Gene', '65982', (100, 106))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (206, 229))	('ZSCAN18', 'Gene', '65982', (74, 81))	('ZNF132', 'Gene', '7691', (63, 69))	('oropharyngeal squamous cell carcinoma', 'Phenotype', 'HP:0012182', (192, 229))	('ZSCAN18', 'Gene', (74, 81))	('carcinoma', 'Phenotype', 'HP:0030731', (220, 229))	('ZNF447', 'Gene', (100, 106))
16558	31796082	ZNF829 hypermethylation is associated with colorectal cancer.	('hypermethylation', 'Var', (7, 23))	('colorectal cancer', 'Disease', (43, 60))	('ZNF829', 'Gene', (0, 6))	('associated', 'Reg', (27, 37))	('colorectal cancer', 'Disease', 'MESH:D015179', (43, 60))	('ZNF829', 'Gene', '374899', (0, 6))	('colorectal cancer', 'Phenotype', 'HP:0003003', (43, 60))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
16559	31796082	Overall, methylation of transcription factor and RNA binding genes and consequent alteration of expression seem important correlates of OSCC-GB.	('methylation', 'Var', (9, 20))	('SCC', 'Phenotype', 'HP:0002860', (137, 140))	('expression', 'MPA', (96, 106))	('OSCC-GB', 'Disease', (136, 143))	('OSCC-GB', 'Chemical', '-', (136, 143))	('alteration', 'Reg', (82, 92))
16561	31796082	Among significantly downregulated genes with promoter hypermethylation, CDON, ID4, and CPEB1 were associated with neuroblastoma, breast cancers, and hepatocellular carcinoma, respectively.	('cancers', 'Phenotype', 'HP:0002664', (136, 143))	('CDON', 'Gene', '50937', (72, 76))	('neuroblastoma', 'Disease', (114, 127))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (149, 173))	('ID4', 'Gene', (78, 81))	('CDON', 'Gene', (72, 76))	('ID4', 'Gene', '3400', (78, 81))	('neuroblastoma', 'Phenotype', 'HP:0003006', (114, 127))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('neuroblastoma', 'Disease', 'MESH:D009447', (114, 127))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (149, 173))	('CPEB1', 'Gene', (87, 92))	('CPEB1', 'Gene', '64506', (87, 92))	('promoter hypermethylation', 'Var', (45, 70))	('breast cancer', 'Phenotype', 'HP:0003002', (129, 142))	('breast cancers', 'Disease', 'MESH:D001943', (129, 143))	('breast cancers', 'Disease', (129, 143))	('hepatocellular carcinoma', 'Disease', (149, 173))	('carcinoma', 'Phenotype', 'HP:0030731', (164, 173))	('breast cancers', 'Phenotype', 'HP:0003002', (129, 143))	('downregulated', 'NegReg', (20, 33))
16567	31796082	Our observation of significant epigenetic upregulation of TRPM2 and LCK is consistent with earlier reports on oral cancer and oral lichen planus (oral pre-cancer).	('LCK', 'Gene', (68, 71))	('cancer', 'Disease', (115, 121))	('LCK', 'Gene', '3932', (68, 71))	('TRPM2', 'Gene', '7226', (58, 63))	('TRPM2', 'Gene', (58, 63))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('cancer', 'Disease', 'MESH:D009369', (155, 161))	('oral lichen planus', 'Disease', (126, 144))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('cancer', 'Disease', (155, 161))	('upregulation', 'PosReg', (42, 54))	('epigenetic', 'Var', (31, 41))
16568	31796082	We have also observed epigenetic upregulations of SULF1 and SEMA3C earlier found upregulated in gastric cancer and breast cancer, respectively.	('upregulated', 'PosReg', (81, 92))	('SEMA3C', 'Gene', '10512', (60, 66))	('upregulations', 'PosReg', (33, 46))	('gastric cancer', 'Phenotype', 'HP:0012126', (96, 110))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('epigenetic', 'Var', (22, 32))	('breast cancer', 'Phenotype', 'HP:0003002', (115, 128))	('SULF1', 'Gene', (50, 55))	('breast cancer', 'Disease', 'MESH:D001943', (115, 128))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('SULF1', 'Gene', '23213', (50, 55))	('gastric cancer', 'Disease', (96, 110))	('breast cancer', 'Disease', (115, 128))	('SEMA3C', 'Gene', (60, 66))	('gastric cancer', 'Disease', 'MESH:D013274', (96, 110))
16570	31796082	Our observations that DNMT3B, a gene responsible for de novo methylation process, is significantly upregulated with promoter hypomethylation and TET1, involved in DNA methylation process and gene activation, and is downregulated with promoter hypermethylation are worthy of further consideration.	('promoter hypomethylation', 'Var', (116, 140))	('upregulated', 'PosReg', (99, 110))	('DNMT3B', 'Gene', (22, 28))	('TET1', 'Gene', (145, 149))	('DNMT3B', 'Gene', '1789', (22, 28))	('TET1', 'Gene', '80312', (145, 149))
16572	31796082	These include epigenetic downregulation of GAS7, OSR1, SELENBP1, TGFBR3, and ZBTB16, earlier found associated with OSCC/HNSCC; epigenetic upregulation of TRPM2 and LCK (a proto-oncogene), earlier observed overexpressed in patients with OSCC or oral lichen planus (oral pre-cancer); altered expression of epigenetically downregulated (CDON, ID4, ZSCAN18, CPEB1, and NUPR1) or epigenetically upregulated (SULF1 and SEMA3C) genes earlier associated with several cancer types.	('LCK', 'Gene', (164, 167))	('TRPM2', 'Gene', '7226', (154, 159))	('cancer', 'Disease', 'MESH:D009369', (459, 465))	('SCC', 'Phenotype', 'HP:0002860', (122, 125))	('epigenetically', 'Var', (304, 318))	('TGFBR3', 'Gene', (65, 71))	('patients', 'Species', '9606', (222, 230))	('SCC', 'Gene', '6317', (116, 119))	('SULF1', 'Gene', (403, 408))	('SELENBP1', 'Gene', '8991', (55, 63))	('ID4', 'Gene', (340, 343))	('ID4', 'Gene', '3400', (340, 343))	('TRPM2', 'Gene', (154, 159))	('OSR1', 'Gene', '130497', (49, 53))	('oral lichen planus', 'Disease', (244, 262))	('SCC', 'Gene', (116, 119))	('TGFBR3', 'Gene', '7049', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (273, 279))	('SCC', 'Phenotype', 'HP:0002860', (237, 240))	('SCC', 'Gene', '6317', (122, 125))	('SEMA3C', 'Gene', (413, 419))	('HNSCC', 'Phenotype', 'HP:0012288', (120, 125))	('ZBTB16', 'Gene', (77, 83))	('NUPR1', 'Gene', (365, 370))	('ZSCAN18', 'Gene', '65982', (345, 352))	('GAS7', 'Gene', '8522', (43, 47))	('SCC', 'Gene', (122, 125))	('LCK', 'Gene', '3932', (164, 167))	('cancer', 'Disease', (459, 465))	('SELENBP1', 'Gene', (55, 63))	('SCC', 'Gene', '6317', (237, 240))	('GAS7', 'Gene', (43, 47))	('SEMA3C', 'Gene', '10512', (413, 419))	('cancer', 'Phenotype', 'HP:0002664', (459, 465))	('epigenetically', 'Var', (375, 389))	('CDON', 'Gene', '50937', (334, 338))	('NUPR1', 'Gene', '26471', (365, 370))	('SCC', 'Gene', (237, 240))	('cancer', 'Disease', (273, 279))	('SCC', 'Phenotype', 'HP:0002860', (116, 119))	('CDON', 'Gene', (334, 338))	('ZSCAN18', 'Gene', (345, 352))	('SULF1', 'Gene', '23213', (403, 408))	('cancer', 'Phenotype', 'HP:0002664', (273, 279))	('ZBTB16', 'Gene', '7704', (77, 83))	('OSR1', 'Gene', (49, 53))	('downregulation', 'NegReg', (25, 39))	('CPEB1', 'Gene', (354, 359))	('CPEB1', 'Gene', '64506', (354, 359))	('expression', 'MPA', (290, 300))
16587	31796082	We have noted upregulation of DNMT3B in OSCC-GB tumor samples driven by promoter hypomethylation.	('OSCC-GB tumor', 'Disease', 'MESH:D009369', (40, 53))	('SCC', 'Phenotype', 'HP:0002860', (41, 44))	('OSCC-GB tumor', 'Disease', (40, 53))	('DNMT3B', 'Gene', (30, 36))	('DNMT3B', 'Gene', '1789', (30, 36))	('promoter hypomethylation', 'Var', (72, 96))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('upregulation', 'PosReg', (14, 26))
16589	31796082	Overexpression of DNMT3B often correlates with the epigenetic inactivation of tumor suppressor genes leading to tumor formation, including oral tumor.	('DNMT3B', 'Gene', (18, 24))	('tumor', 'Disease', (144, 149))	('DNMT3B', 'Gene', '1789', (18, 24))	('leading to', 'Reg', (101, 111))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('epigenetic inactivation', 'Var', (51, 74))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('correlates', 'Reg', (31, 41))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('tumor', 'Disease', (78, 83))	('tumor', 'Disease', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('oral tumor', 'Phenotype', 'HP:0100649', (139, 149))
16593	31796082	Epigenetic downregulation of TET1, observed in OSCC-GB patients, was earlier found associated with head and neck cancer.	('SCC', 'Phenotype', 'HP:0002860', (48, 51))	('TET1', 'Gene', (29, 33))	('head and neck cancer', 'Disease', 'MESH:D006258', (99, 119))	('patients', 'Species', '9606', (55, 63))	('OSCC-GB', 'Disease', (47, 54))	('Epigenetic', 'Var', (0, 10))	('associated', 'Reg', (83, 93))	('head and neck cancer', 'Phenotype', 'HP:0012288', (99, 119))	('OSCC-GB', 'Chemical', '-', (47, 54))	('TET1', 'Gene', '80312', (29, 33))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
16594	31796082	Therefore, our finding that epigenetic modifications upregulate DNMT3B and downregulate TET1, that likely plays an important role in OSCC-GB tumorigenesis, is novel.	('upregulate', 'PosReg', (53, 63))	('SCC', 'Phenotype', 'HP:0002860', (134, 137))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('OSCC-GB tumor', 'Disease', (133, 146))	('downregulate', 'NegReg', (75, 87))	('TET1', 'Gene', (88, 92))	('epigenetic modifications', 'Var', (28, 52))	('DNMT3B', 'Gene', (64, 70))	('DNMT3B', 'Gene', '1789', (64, 70))	('TET1', 'Gene', '80312', (88, 92))	('OSCC-GB tumor', 'Disease', 'MESH:D009369', (133, 146))
16598	31796082	It is interesting that OSCC-GB caused by epigenetic alterations in important cancer genes is potentially actionable by known drugs.	('SCC', 'Phenotype', 'HP:0002860', (24, 27))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('OSCC-GB', 'Disease', (23, 30))	('OSCC-GB', 'Chemical', '-', (23, 30))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('epigenetic alterations', 'Var', (41, 63))	('caused by', 'Reg', (31, 40))
16601	31796082	Epigenetic downregulation of PPARG (from the PPAR signaling pathway) and its ligands have earlier been shown to play a role in tumorigenesis.	('PPAR', 'Gene', '5465', (29, 33))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumor', 'Disease', (127, 132))	('PPARG', 'Gene', '5468', (29, 34))	('PPARG', 'Gene', (29, 34))	('PPAR', 'Gene', '5465', (45, 49))	('PPAR', 'Gene', (29, 33))	('Epigenetic', 'Var', (0, 10))	('PPAR', 'Gene', (45, 49))	('tumor', 'Disease', 'MESH:D009369', (127, 132))
16606	31796082	As a matter of fact, DNMTIs are being used to reverse epigenetic downregulation of PPARG, instead of PPARG ligands that show cytotoxicity.	('PPARG', 'Gene', '5468', (83, 88))	('PPARG', 'Gene', (83, 88))	('PPARG', 'Gene', '5468', (101, 106))	('PPARG', 'Gene', (101, 106))	('cytotoxicity', 'Disease', 'MESH:D064420', (125, 137))	('epigenetic', 'Var', (54, 64))	('downregulation', 'NegReg', (65, 79))	('DNMT', 'Gene', '1786', (21, 25))	('cytotoxicity', 'Disease', (125, 137))	('DNMT', 'Gene', (21, 25))
16607	31796082	We have earlier shown that survival benefits accrue to OSCC-GB patients who carry mutations in genes of the arachidonic acid metabolism (AAM) pathway.	('arachidonic acid', 'Chemical', 'MESH:D016718', (108, 124))	('benefits', 'PosReg', (36, 44))	('OSCC-GB', 'Chemical', '-', (55, 62))	('mutations', 'Var', (82, 91))	('SCC', 'Phenotype', 'HP:0002860', (56, 59))	('patients', 'Species', '9606', (63, 71))
16609	31796082	Some genes that we found to be epigenetically upregulated in OSCC-GB patients, such as PIK3CD and IFITM1, were earlier reported to be upregulated in thyroid cancer and HNSCC.	('thyroid cancer', 'Disease', 'MESH:D013964', (149, 163))	('patients', 'Species', '9606', (69, 77))	('SCC', 'Gene', '6317', (170, 173))	('PIK3CD', 'Gene', (87, 93))	('thyroid cancer', 'Phenotype', 'HP:0002890', (149, 163))	('SCC', 'Phenotype', 'HP:0002860', (62, 65))	('SCC', 'Gene', (170, 173))	('epigenetically', 'Var', (31, 45))	('HNSCC', 'Phenotype', 'HP:0012288', (168, 173))	('SCC', 'Gene', '6317', (62, 65))	('IFITM1', 'Gene', '8519', (98, 104))	('IFITM1', 'Gene', (98, 104))	('SCC', 'Gene', (62, 65))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('thyroid cancer', 'Disease', (149, 163))	('upregulated', 'PosReg', (134, 145))	('OSCC-GB', 'Chemical', '-', (61, 68))	('SCC', 'Phenotype', 'HP:0002860', (170, 173))	('PIK3CD', 'Gene', '5293', (87, 93))	('upregulated', 'PosReg', (46, 57))
16613	31796082	Epigenetic alteration of transcription factor genes and RNA-binding genes and consequently expression dysregulation were strongly associated with OSCC-GB.	('expression', 'MPA', (91, 101))	('SCC', 'Phenotype', 'HP:0002860', (147, 150))	('transcription factor genes', 'Gene', (25, 51))	('OSCC-GB', 'Disease', (146, 153))	('OSCC-GB', 'Chemical', '-', (146, 153))	('RNA-binding genes', 'Gene', (56, 73))	('Epigenetic alteration', 'Var', (0, 21))	('associated', 'Reg', (130, 140))
16614	31796082	Epigenetic activation of immunosuppressive PD-L1/PD-1 and CD80/CTLA4 interactions, which leads to inhibition of the cytotoxic T cells-mediated apoptotic process, was observed in gingivo-buccal oral cancer patients.	('CD80', 'Gene', '941', (58, 62))	('patients', 'Species', '9606', (205, 213))	('CTLA4', 'Gene', '1493', (63, 68))	('PD-L1/PD-1', 'Gene', (43, 53))	('CTLA4', 'Gene', (63, 68))	('inhibition', 'NegReg', (98, 108))	('CD80', 'Gene', (58, 62))	('interactions', 'Interaction', (69, 81))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('cytotoxic T cells-mediated apoptotic process', 'CPA', (116, 160))	('gingivo-buccal oral cancer', 'Disease', (178, 204))	('gingivo-buccal oral cancer', 'Disease', 'MESH:D009369', (178, 204))	('Epigenetic activation', 'Var', (0, 21))
16646	31475242	Additionally, the methods for calculating TMB are inconsistent, especially the inclusion or exclusion of synonymous mutations.	('TMB', 'Chemical', '-', (42, 45))	('synonymous mutations', 'Var', (105, 125))	('TMB', 'MPA', (42, 45))
16669	31475242	For example, the TMB for prostate cancer in TCGA ranged from 0.03 mutations/Mb to 14.13 mutations/Mb, with a mean of 1.23 mutations/Mb (n = 326).	('mutations/Mb', 'Var', (66, 78))	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('TMB', 'Chemical', '-', (17, 20))	('prostate cancer', 'Disease', 'MESH:D011471', (25, 40))	('prostate cancer', 'Phenotype', 'HP:0012125', (25, 40))	('prostate cancer', 'Disease', (25, 40))
16670	31475242	However, the TMB for bladder cancer in TCGA ranged from 0.04 mutations/Mb to 99.68 mutations/Mb with a mean of 6.92 mutations/Mb (n = 375).	('bladder cancer', 'Phenotype', 'HP:0009725', (21, 35))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('mutations/Mb', 'Var', (61, 73))	('bladder cancer', 'Disease', 'MESH:D001749', (21, 35))	('bladder cancer', 'Disease', (21, 35))	('TMB', 'Chemical', '-', (13, 16))
16682	31475242	UCEC also showed significantly improved survival for TMB high patients compared to TMB low when using Chalmers et al (log-rank p-value = 0.023), but did not reach significance when using WCM (log-rank p-value = 0.055) (Supplemental Figure 6).	('improved', 'PosReg', (31, 39))	('high', 'Var', (57, 61))	('TMB', 'Disease', (53, 56))	('TMB', 'Chemical', '-', (83, 86))	('survival', 'MPA', (40, 48))	('patients', 'Species', '9606', (62, 70))	('TMB', 'Chemical', '-', (53, 56))	('WCM', 'Chemical', '-', (187, 190))
16714	31475242	Additionally, patients with low TMB and stage III bladder cancer had the lowest survival rate.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('bladder cancer', 'Disease', 'MESH:D001749', (50, 64))	('survival rate', 'CPA', (80, 93))	('bladder cancer', 'Disease', (50, 64))	('TMB', 'Chemical', '-', (32, 35))	('lowest', 'NegReg', (73, 79))	('low', 'Var', (28, 31))	('bladder cancer', 'Phenotype', 'HP:0009725', (50, 64))	('patients', 'Species', '9606', (14, 22))
16718	31475242	For example, the Chalmers et al cutoff of 20 mutations/Mb is higher than the maximum TMB seen within TCGA prostate cancer (14.13 mutations/Mb), however using a lower threshold might be too lenient for TCGA bladder cancer (maximum TMB of 99.68 mutations/Mb).	('prostate cancer', 'Phenotype', 'HP:0012125', (106, 121))	('TMB', 'Chemical', '-', (230, 233))	('bladder cancer', 'Disease', (206, 220))	('bladder cancer', 'Phenotype', 'HP:0009725', (206, 220))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('prostate cancer', 'Disease', (106, 121))	('bladder cancer', 'Disease', 'MESH:D001749', (206, 220))	('mutations/Mb', 'Var', (45, 57))	('prostate cancer', 'Disease', 'MESH:D011471', (106, 121))	('TMB', 'Chemical', '-', (85, 88))
16737	31475242	Mutational signatures for these samples showed a cluster of patients with POLE deficiency, which leads to a large number of mutations and a TMB distribution with a large IQR, causing the cancer-specific threshold to be strict in this case.	('POLE deficiency', 'Disease', (74, 89))	('cancer', 'Disease', 'MESH:D009369', (187, 193))	('POLE deficiency', 'Disease', 'MESH:D007153', (74, 89))	('TMB', 'Chemical', '-', (140, 143))	('mutations', 'Var', (124, 133))	('cancer', 'Disease', (187, 193))	('patients', 'Species', '9606', (60, 68))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))
16744	31475242	A recent study has shown that melanoma and NSCLC patients with heterozygous HLA class I exhibit improved survival than patients who are homozygous.	('improved', 'PosReg', (96, 104))	('heterozygous', 'Var', (63, 75))	('patients', 'Species', '9606', (119, 127))	('melanoma', 'Disease', 'MESH:D008545', (30, 38))	('melanoma', 'Phenotype', 'HP:0002861', (30, 38))	('patients', 'Species', '9606', (49, 57))	('melanoma', 'Disease', (30, 38))	('NSCLC', 'Disease', (43, 48))	('survival', 'CPA', (105, 113))	('HLA class', 'Gene', (76, 85))	('NSCLC', 'Disease', 'MESH:D002289', (43, 48))
16746	28372346	Metastatic Squamous Cell Carcinoma from Lung Adenocarcinoma after Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Therapy Inhibition of mutated epidermal growth factor receptor (EGFR), EGFR tyrosine kinase inhibitor (TKI), is one of the most successful cancer targeted therapies.	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (11, 34))	('Metastatic Squamous Cell Carcinoma', 'Disease', (0, 34))	('Epidermal Growth Factor Receptor', 'Gene', (66, 98))	('EGFR', 'Gene', '1956', (196, 200))	('cancer', 'Disease', (264, 270))	('Inhibition', 'NegReg', (133, 143))	('Epidermal Growth Factor Receptor', 'Gene', '1956', (66, 98))	('EGFR', 'Gene', '1956', (189, 193))	('Lung Adenocarcinoma', 'Disease', 'MESH:D000077192', (40, 59))	('cancer', 'Phenotype', 'HP:0002664', (264, 270))	('Metastatic Squamous Cell Carcinoma', 'Disease', 'MESH:C538445', (0, 34))	('epidermal growth factor receptor', 'Gene', (155, 187))	('epidermal growth factor receptor', 'Gene', '1956', (155, 187))	('mutated', 'Var', (147, 154))	('Lung Adenocarcinoma', 'Phenotype', 'HP:0030078', (40, 59))	('cancer', 'Disease', 'MESH:D009369', (264, 270))	('EGFR', 'Gene', (196, 200))	('carcinoma', 'Phenotype', 'HP:0030731', (50, 59))	('EGFR', 'Gene', (189, 193))	('Carcinoma', 'Phenotype', 'HP:0030731', (25, 34))	('Lung Adenocarcinoma', 'Disease', (40, 59))
16747	28372346	While this therapy has been beneficial for many non-small cell lung cancer (NSCLC) patients with activated EGFR mutations, almost all patients inevitably develop acquired resistance which limits the median response duration to around 1 year.	('small cell lung cancer', 'Phenotype', 'HP:0030357', (52, 74))	('develop', 'Reg', (154, 161))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('acquired resistance', 'MPA', (162, 181))	('EGFR', 'Gene', '1956', (107, 111))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (48, 74))	('man', 'Species', '9606', (43, 46))	('NSCLC', 'Disease', (76, 81))	('patients', 'Species', '9606', (134, 142))	('EGFR', 'Gene', (107, 111))	('mutations', 'Var', (112, 121))	('NSCLC', 'Disease', 'MESH:D002289', (76, 81))	('lung cancer', 'Phenotype', 'HP:0100526', (63, 74))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (48, 74))	('patients', 'Species', '9606', (83, 91))	('SCLC', 'Phenotype', 'HP:0030357', (77, 81))	('non-small cell lung cancer', 'Disease', (48, 74))	('NSCLC', 'Phenotype', 'HP:0030358', (76, 81))
16760	28372346	EGFR mutation analysis, using a previously resected lobectomy specimen, revealed a deletion at exon 19 of the EGFR gene.	('EGFR', 'Gene', (0, 4))	('EGFR', 'Gene', '1956', (110, 114))	('EGFR', 'Gene', (110, 114))	('EGFR', 'Gene', '1956', (0, 4))	('deletion at', 'Var', (83, 94))
16768	28372346	EGFR mutation analysis, using a biopsied specimen, revealed a deletion at exon 19 of the EGFR gene and an additional T790M point mutation.	('EGFR', 'Gene', (0, 4))	('EGFR', 'Gene', (89, 93))	('deletion at', 'Var', (62, 73))	('T790M', 'Mutation', 'rs121434569', (117, 122))	('EGFR', 'Gene', '1956', (0, 4))	('T790M', 'Var', (117, 122))	('EGFR', 'Gene', '1956', (89, 93))
16775	28372346	Targeting EGFR in patients with activating EGFR mutations has shown initial and significant success in practice.	('EGFR', 'Gene', '1956', (10, 14))	('EGFR', 'Gene', (10, 14))	('EGFR', 'Gene', '1956', (43, 47))	('patients', 'Species', '9606', (18, 26))	('activating', 'PosReg', (32, 42))	('EGFR', 'Gene', (43, 47))	('mutations', 'Var', (48, 57))
16777	28372346	Most of the mechanisms that lead to EGFR TKI resistance involve an additional mutation, such as a T790M mutation, or amplification of alternative pathways.	('T790M mutation', 'Var', (98, 112))	('T790M', 'Mutation', 'rs121434569', (98, 103))	('EGFR', 'Gene', '1956', (36, 40))	('alternative pathways', 'Pathway', (134, 154))	('EGFR', 'Gene', (36, 40))
16781	28372346	The most common EGFR mutation was an L858R point mutation and the most common acquired gene alteration was a T790M point mutation.	('T790M point mutation', 'Var', (109, 129))	('T790M', 'Mutation', 'rs121434569', (109, 114))	('L858R point mutation', 'Var', (37, 57))	('EGFR', 'Gene', '1956', (16, 20))	('EGFR', 'Gene', (16, 20))	('L858R', 'Mutation', 'rs121434568', (37, 42))
16782	28372346	All cases showed the same EGFR mutation in both primary and metastatic carcinomas.	('EGFR', 'Gene', (26, 30))	('mutation', 'Var', (31, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('EGFR', 'Gene', '1956', (26, 30))	('carcinomas', 'Phenotype', 'HP:0030731', (71, 81))	('carcinomas', 'Disease', (71, 81))	('carcinomas', 'Disease', 'MESH:D002277', (71, 81))	('primary', 'Disease', (48, 55))
16784	28372346	Considering that primary adenosquamous carcinoma shows the same mutations in both adenocarcinoma and squamous cell carcinoma components, additional studies are needed and a solution is beyond the scope of this report.	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (101, 124))	('adenosquamous carcinoma', 'Disease', 'MESH:D018196', (25, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (39, 48))	('mutations', 'Var', (64, 73))	('adenosquamous carcinoma', 'Disease', (25, 48))	('adenocarcinoma and squamous cell carcinoma', 'Disease', 'MESH:D002294', (82, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))
16787	25329316	The tumor suppressor serine-threonine kinase LKB1 is mutated in Peutz-Jeghers syndrome and in a spectrum of epithelial cancers whose etiology suggests a cooperation with environmental insults.	('epithelial cancers', 'Disease', (108, 126))	('tumor', 'Disease', (4, 9))	('LKB1', 'Gene', (45, 49))	('Peutz-Jeghers syndrome', 'Disease', 'MESH:D010580', (64, 86))	('cancers', 'Phenotype', 'HP:0002664', (119, 126))	('mutated', 'Var', (53, 60))	('Peutz-Jeghers syndrome', 'Disease', (64, 86))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('rat', 'Species', '10116', (158, 161))	('epithelial cancers', 'Disease', 'MESH:D000077216', (108, 126))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
16791	25329316	Importantly, analysis of human tumor samples suggests that LKB1 mutational status could be a prognostic risk factor for UV-induced skin cancer.	('skin cancer', 'Disease', (131, 142))	('skin cancer', 'Disease', 'MESH:D012878', (131, 142))	('LKB1', 'Gene', (59, 63))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumor', 'Disease', (31, 36))	('human', 'Species', '9606', (25, 30))	('risk', 'Reg', (104, 108))	('mutational status', 'Var', (64, 81))	('skin cancer', 'Phenotype', 'HP:0008069', (131, 142))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
16794	25329316	UV radiation causes modifications in the genetic material of cells (DNA) that if not repaired properly will lead to a mutated DNA (mutated genes) which might trigger the development of cancer.	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('mutated DNA', 'MPA', (118, 129))	('trigger', 'Reg', (158, 165))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('modifications', 'Var', (20, 33))	('lead', 'Reg', (108, 112))	('cancer', 'Disease', (185, 191))
16799	25329316	UV radiation can cause genetic mutations to DNA that if not repaired can lead to skin cancer.	('skin cancer', 'Disease', (81, 92))	('skin cancer', 'Phenotype', 'HP:0008069', (81, 92))	('genetic mutations', 'Var', (23, 40))	('skin cancer', 'Disease', 'MESH:D012878', (81, 92))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('lead to', 'Reg', (73, 80))	('DNA', 'Gene', (44, 47))
16803	25329316	Among these residues Thr-366 is conserved in mammalian, Xenopus and Drosophila LKB1, and is located on a C-terminal non-catalytic moiety of the enzyme.	('Xenopus', 'Species', '8355', (56, 63))	('mammalian', 'Species', '9606', (45, 54))	('LKB1', 'Gene', (79, 83))	('Drosophila', 'Species', '7227', (68, 78))	('Thr', 'Chemical', 'MESH:D013912', (21, 24))	('Thr-366', 'Var', (21, 28))
16805	25329316	Although its function in DNA damage response has not been elucidated, mutation of Thr-366 to Ala or Asp partially inhibits the ability of LKB1 to suppress cell proliferation and it does not affect the nuclear cellular localization of LKB1.	('suppress', 'NegReg', (146, 154))	('inhibits', 'NegReg', (114, 122))	('LKB1', 'Gene', (138, 142))	('Thr-366 to Ala or Asp', 'Mutation', 'p.T366A,D', (82, 103))	('cell proliferation', 'CPA', (155, 173))	('Thr-366 to Ala', 'SUBSTITUTION', 'None', (82, 96))	('Thr-366 to Ala', 'Var', (82, 96))	('rat', 'Species', '10116', (167, 170))	('mutation', 'Var', (70, 78))
16806	25329316	Moreover, phosphorylation of LKB1 at Thr-366 does not directly regulate LKB1 kinase activity.	('LKB1', 'Gene', (29, 33))	('Thr', 'Chemical', 'MESH:D013912', (37, 40))	('Thr-366', 'Var', (37, 44))
16808	25329316	Thus, LKB1 has been found mutated in non-small cell lung carcinomas, head and neck squamous cell carcinoma (SCC), pancreatic cancer and melanomas.	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('SCC', 'Gene', (108, 111))	('LKB1', 'Gene', (6, 10))	('carcinoma', 'Phenotype', 'HP:0030731', (57, 66))	('melanoma', 'Phenotype', 'HP:0002861', (136, 144))	('carcinomas', 'Phenotype', 'HP:0030731', (57, 67))	('non-small cell lung carcinomas', 'Phenotype', 'HP:0030358', (37, 67))	('small cell lung carcinomas', 'Phenotype', 'HP:0030357', (41, 67))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (114, 131))	('melanomas', 'Disease', 'MESH:D008545', (136, 145))	('neck squamous cell carcinoma', 'Disease', (78, 106))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (78, 106))	('melanomas', 'Disease', (136, 145))	('non-small cell lung carcinomas', 'Disease', 'MESH:D002289', (37, 67))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('non-small cell lung carcinomas', 'Disease', (37, 67))	('mutated', 'Var', (26, 33))	('pancreatic cancer', 'Disease', 'MESH:D010190', (114, 131))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (83, 106))	('pancreatic cancer', 'Disease', (114, 131))	('melanomas', 'Phenotype', 'HP:0002861', (136, 145))	('SCC', 'Gene', '6317', (108, 111))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (69, 106))
16811	25329316	Indeed, Lkb1 deficiency sensitizes mice to DMBA-induced skin and lung SCC, and its inactivation in the context of RAS pathway activation facilitates the expansion of melanoma prometastatic tumor cell subpopulations and progression of lung adenomas into carcinomas.	('DMBA', 'Chemical', 'MESH:C082386', (43, 47))	('SCC', 'Gene', (70, 73))	('melanoma prometastatic tumor', 'Disease', (166, 194))	('carcinomas', 'Disease', (253, 263))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('melanoma', 'Phenotype', 'HP:0002861', (166, 174))	('deficiency', 'Var', (13, 23))	('inactivation', 'Var', (83, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (253, 262))	('lung adenomas', 'Disease', 'MESH:D000236', (234, 247))	('facilitates', 'PosReg', (137, 148))	('lung adenomas', 'Disease', (234, 247))	('Lkb1', 'Gene', (8, 12))	('expansion', 'CPA', (153, 162))	('progression', 'CPA', (219, 230))	('mice', 'Species', '10090', (35, 39))	('carcinomas', 'Phenotype', 'HP:0030731', (253, 263))	('carcinomas', 'Disease', 'MESH:D002277', (253, 263))	('SCC', 'Gene', '6317', (70, 73))	('Lkb1', 'Gene', '20869', (8, 12))	('melanoma prometastatic tumor', 'Disease', 'MESH:D008545', (166, 194))
16817	25329316	Our findings suggest that the mutational status of LKB1 can serve as a novel risk factor for UV-induced skin tumors.	('skin tumors', 'Disease', (104, 115))	('LKB1', 'Gene', (51, 55))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('skin tumors', 'Disease', 'MESH:D012878', (104, 115))	('risk factor', 'Reg', (77, 88))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('skin tumor', 'Phenotype', 'HP:0008069', (104, 114))	('mutational status', 'Var', (30, 47))	('skin tumors', 'Phenotype', 'HP:0008069', (104, 115))
16829	25329316	Hence, Lkb1 heterozygosity in an Hgf Tg background sensitizes mice to single-dose UVB-induced skin SCC.	('sensitizes', 'Reg', (51, 61))	('Hgf', 'Gene', '15234', (33, 36))	('SCC', 'Gene', '6317', (99, 102))	('Lkb1', 'Gene', '20869', (7, 11))	('mice', 'Species', '10090', (62, 66))	('Lkb1', 'Gene', (7, 11))	('SCC', 'Gene', (99, 102))	('Hgf', 'Gene', (33, 36))	('heterozygosity', 'Var', (12, 26))
16834	25329316	Consistent with this and the lack of papilloma-SCC progression, no H-Ras mutations were detected in the UVB-induced SCC arising in the Hgf Tg; Lkb1 +/- mice.	('SCC', 'Gene', (116, 119))	('SCC', 'Gene', '6317', (47, 50))	('Lkb1', 'Gene', (143, 147))	('papilloma', 'Phenotype', 'HP:0012740', (37, 46))	('H-Ras', 'Gene', (67, 72))	('SCC', 'Gene', (47, 50))	('SCC', 'Gene', '6317', (116, 119))	('H-Ras', 'Gene', '15461', (67, 72))	('Hgf', 'Gene', (135, 138))	('mice', 'Species', '10090', (152, 156))	('Hgf', 'Gene', '15234', (135, 138))	('papilloma-SCC', 'Disease', (37, 50))	('Lkb1', 'Gene', '20869', (143, 147))	('papilloma-SCC', 'Disease', 'MESH:D010212', (37, 50))	('mutations', 'Var', (73, 82))
16839	25329316	In agreement with previous studies and the heterogeneous LKB1 tumor staining, LKB1 was not expressed in SCC primary tumor-derived cell lines (Figure S1F), suggesting that the Lkb1 wild-type allele (Figure S1G) could be inactivated by multiple mechanisms in SCC, including deletion and possibly point mutation or promoter hypermethylation.	('point mutation', 'Var', (294, 308))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('SCC', 'Gene', '6317', (257, 260))	('inactivated', 'NegReg', (219, 230))	('tumor', 'Disease', (62, 67))	('Lkb1', 'Gene', (175, 179))	('SCC', 'Gene', (104, 107))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('deletion', 'Var', (272, 280))	('SCC', 'Gene', '6317', (104, 107))	('tumor', 'Disease', (116, 121))	('Lkb1', 'Gene', '20869', (175, 179))	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('SCC', 'Gene', (257, 260))
16854	25329316	To investigate the role of LKB1 in response to UVB irradiation regulating CDKN1A protein levels, we knocked down (mRNA) LKB1 in wild type immortalized keratinocytes and in normal human epidermal keratinocytes (NHEK).	('human', 'Species', '9606', (179, 184))	('LKB1', 'Gene', (120, 124))	('rat', 'Species', '10116', (197, 200))	('rat', 'Species', '10116', (153, 156))	('knocked', 'Var', (100, 107))
16857	25329316	In agreement with the previously described role of LKB1 regulating CDKN1A expression, LKB1 knockdown cells showed a significant decrease in the UVB-induced transcriptional regulation of CDKN1A (Figure 2D).	('knockdown', 'Var', (91, 100))	('LKB1', 'Gene', (86, 90))	('CDKN1A', 'Gene', (186, 192))	('decrease', 'NegReg', (128, 136))	('expression', 'Species', '29278', (74, 84))	('UVB-induced transcriptional regulation', 'MPA', (144, 182))
16861	25329316	We reconstituted the system in HeLa cells (deficient for LKB1) and expressed the different LKB1 isoforms (wild type LKB1 or LKB1KD (kinase dead)) in normal human epidermal keratinocytes (NHEK).	('LKB1', 'Gene', (91, 95))	('HeLa', 'CellLine', 'CVCL:0030', (31, 35))	('LKB1KD', 'Var', (124, 130))	('rat', 'Species', '10116', (174, 177))	('human', 'Species', '9606', (156, 161))
16862	25329316	Expression of CDKN1A together with either wild type LKB1 or LKB1KD (kinase dead) in HeLa cells showed that in response to UVB radiation there was an accumulation of CDKN1A in LKB1KD transfected cells, suggesting that LKB1 kinase activity was involved in the regulation of CDKN1A protein amounts in response to UVB irradiation.	('HeLa', 'CellLine', 'CVCL:0030', (84, 88))	('LKB1KD', 'Var', (175, 181))	('Expression', 'Species', '29278', (0, 10))	('CDKN1A', 'Gene', (165, 171))	('accumulation', 'PosReg', (149, 161))
16866	25329316	Construction of two different LKB1 mutants lacking C-terminal 20 (Flag-LBK1Delta416) and 113 (Flag-LBK1Delta323) amino acids, showed that carboxy-terminal region of LKB1 (Figure S4C) seemed to be involved in the binding to CDKN1A and, in a lesser extent to HSP90, a known LKB1 binding protein (Figure S4C).	('lacking', 'NegReg', (43, 50))	('LKB1', 'Gene', (30, 34))	('LKB1', 'Gene', (165, 169))	('involved', 'Reg', (196, 204))	('binding', 'Interaction', (212, 219))	('mutants', 'Var', (35, 42))	('CDKN1A', 'Protein', (223, 229))	('HSP90', 'Gene', (257, 262))	('HSP90', 'Gene', '111042', (257, 262))
16868	25329316	Mass spectrometry analysis of the phosphorylated CDKN1A identified Thr80 as the residue phosphorylated by LKB1 in vitro (Figure 4A and S5A).	('Thr80', 'Var', (67, 72))	('LKB1', 'Gene', (106, 110))	('Thr80', 'Chemical', '-', (67, 72))	('CDKN1A', 'Gene', (49, 55))
16875	25329316	We identified by mass spectrometry phosphorylation of Ser78 in endogenous CDKN1A upon UVB irradiation in mouse melanoma cells (Figure S5D), Phosphorylation on Ser78 was significantly decreased in LKB1 depleted cells (30% vs. 1% of peptide phosphorylated respectively; p<0.0001) (Figure S5E).	('melanoma', 'Disease', 'MESH:D008545', (111, 119))	('melanoma', 'Phenotype', 'HP:0002861', (111, 119))	('Phosphorylation', 'MPA', (140, 155))	('melanoma', 'Disease', (111, 119))	('CDKN1A', 'Gene', (74, 80))	('Ser78', 'Chemical', '-', (159, 164))	('decreased', 'NegReg', (183, 192))	('Ser78', 'Var', (159, 164))	('Ser78', 'Chemical', '-', (54, 59))	('mouse', 'Species', '10090', (105, 110))
16876	25329316	In agreement with the role of LKB1 and NUAK1 regulating CDKN1A degradation upon UVB irradiation, non-phosphorylable human CDKN1A mutants T80A, S146A and double mutant T80A;S146A were accumulated after UVB treatment as compared to the wild type protein.	('T80A', 'Mutation', 'rs1220758921', (137, 141))	('CDKN1A', 'Gene', (122, 128))	('S146A', 'Var', (143, 148))	('S146A', 'Mutation', 'rs1220758921', (143, 148))	('T80A;S146A', 'Var', (167, 177))	('S146A', 'Mutation', 'rs1220758921', (172, 177))	('human', 'Species', '9606', (116, 121))	('T80A', 'Var', (137, 141))	('mutants T80A', 'Var', (129, 141))	('T80A', 'Mutation', 'rs1220758921', (167, 171))
16877	25329316	Interestingly, mutation of both residues (T80A;S146A) caused a synergistic accumulation compared to the single mutations (Figure S6A).	('S146A', 'Mutation', 'rs1220758921', (47, 52))	('synergistic', 'MPA', (63, 74))	('T80A;S146A', 'Var', (42, 52))	('T80A', 'Mutation', 'rs1220758921', (42, 46))	('accumulation', 'PosReg', (75, 87))
16879	25329316	Depletion of NUAK1 partially reproduced the accumulation of CDKN1A in response to UVB observed in the absence of LKB1 (Figure 4D and Figure S6C), and induced phosphorylation of CDKN1A Ser146 upon UVB radiation was absent in NUAK1 knockdown cells (Figure S6C).	('CDKN1A', 'Gene', (177, 183))	('CDKN1A', 'Gene', (60, 66))	('phosphorylation', 'MPA', (158, 173))	('Ser146', 'Chemical', '-', (184, 190))	('Ser146', 'Var', (184, 190))	('response to', 'MPA', (70, 81))	('accumulation', 'PosReg', (44, 56))
16880	25329316	Moreover, expression of mutant HA-NUAK1T211A that cannot be activated by LKB1, led to the accumulation of CDKN1A, upon UVB treatment (Figure 4E) and expression of NUAK1 in LKB1 depleted cells almost totally reconstituted the normal response to UVB (Figure 4F).	('mutant', 'Var', (24, 30))	('HA-NUAK1T211A', 'Gene', (31, 44))	('CDKN1A', 'Gene', (106, 112))	('expression', 'Species', '29278', (149, 159))	('expression', 'Species', '29278', (10, 20))	('accumulation', 'PosReg', (90, 102))
16881	25329316	We observed that LKB1T366 was phosphorylated more efficiently in the skin of WT and Hgf Tg mouse than in the skin of Lkb1 +/- and Hgf Tg; Lkb1 +/- animals (Figure 5A).	('Hgf', 'Gene', (130, 133))	('Hgf', 'Gene', '15234', (130, 133))	('Lkb1', 'Gene', '20869', (138, 142))	('Lkb1', 'Gene', '20869', (117, 121))	('Hgf', 'Gene', (84, 87))	('Lkb1', 'Gene', (138, 142))	('Hgf', 'Gene', '15234', (84, 87))	('Lkb1', 'Gene', (117, 121))	('mouse', 'Species', '10090', (91, 96))	('LKB1T366', 'Var', (17, 25))
16884	25329316	The effect of Flag-Lkb1 T366A mutant on CDKN1A stability in response to UVB, was also partially observed with endogenous protein (Figure 5C), and the number of phospho-LKB1T366 molecules recruited to the CDKN1A immunocomplexes increased in response to UVB (Figure S7D).	('Lkb1', 'Gene', '20869', (19, 23))	('increased', 'PosReg', (227, 236))	('Lkb1', 'Gene', (19, 23))	('CDKN1A', 'Gene', (40, 46))	('response', 'MPA', (60, 68))	('T366A', 'Mutation', 'rs762253780', (24, 29))	('T366A', 'Var', (24, 29))	('stability', 'MPA', (47, 56))
16885	25329316	Moreover, expression of mutant Flag-Lkb1 T366A also impaired the cells ability to repair UVB-induced DNA damage supporting the role of LKB1 and CDKN1A degradation in DNA repair (Figure 5D).	('mutant', 'Var', (24, 30))	('Lkb1', 'Gene', (36, 40))	('impaired', 'NegReg', (52, 60))	('cells ability', 'CPA', (65, 78))	('expression', 'Species', '29278', (10, 20))	('Lkb1', 'Gene', '20869', (36, 40))	('T366A', 'Mutation', 'rs762253780', (41, 46))	('T366A', 'Var', (41, 46))
16896	25329316	Interestingly, analysis of a curated data set of 225 tumors from another relevant UV-induced skin tumor such as cutaneous melanoma (c-Bioportal, MSKCC) showed alterations in LKB1 or NUAK1 in 22.2% of cases that were mutually exclusive (odds ratio 0.625 (no association); 95% Confidence Interval: 0.138438-2.821652; P-value: 0.412752 (Fisher's Exact Test)).	('skin tumor', 'Disease', (93, 103))	('rat', 'Species', '10116', (163, 166))	('LKB1', 'Gene', (174, 178))	('NUAK1', 'Gene', (182, 187))	('alterations', 'Var', (159, 170))	('skin tumor', 'Disease', 'MESH:D012878', (93, 103))	('skin tumor', 'Phenotype', 'HP:0008069', (93, 103))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('cutaneous melanoma', 'Disease', (112, 130))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (112, 130))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (112, 130))	('melanoma', 'Phenotype', 'HP:0002861', (122, 130))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('rat', 'Species', '10116', (241, 244))	('tumors', 'Disease', (53, 59))	('rat', 'Species', '10116', (31, 34))
16898	25329316	This mutual exclusivity of LKB1 or NUAK1 alterations is observed other tumor types including head and neck squamous cells carcinomas (19.7% of data set from 295 tumors), (95% Confidence Interval: 0.552751-5.723118 P-value: 0.250381 (Fisher's Exact Test), cervical squamous cell carcinoma (30.6% of data set from 36 tumors), (95% Confidence Interval: 0.095179-10.506562 P-value: 0.695155 (Fisher's Exact Test) and lung squamous cell carcinoma (15.3% of data set from 177 tumors), (95% Confidence Interval: 0.109684-7.534791 P-value: 0.703561 (Fisher's Exact Test).	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (264, 287))	('tumors', 'Disease', (161, 167))	('tumors', 'Disease', (470, 476))	('tumor', 'Disease', 'MESH:D009369', (315, 320))	('squamous cells carcinomas', 'Phenotype', 'HP:0002860', (107, 132))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Disease', (161, 166))	('tumors', 'Phenotype', 'HP:0002664', (315, 321))	('carcinoma', 'Phenotype', 'HP:0030731', (278, 287))	('tumor', 'Disease', (470, 475))	('tumors', 'Disease', 'MESH:D009369', (470, 476))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (264, 287))	('tumors', 'Disease', 'MESH:D009369', (161, 167))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('tumor', 'Disease', 'MESH:D009369', (470, 475))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (413, 441))	('lung squamous cell carcinoma', 'Disease', (413, 441))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (418, 441))	('tumor', 'Phenotype', 'HP:0002664', (315, 320))	('rat', 'Species', '10116', (45, 48))	('carcinomas', 'Disease', (122, 132))	('tumors', 'Disease', (315, 321))	('squamous cell carcinoma', 'Disease', (264, 287))	('P-value', 'Var', (214, 221))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('tumor', 'Disease', (71, 76))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (418, 441))	('tumor', 'Phenotype', 'HP:0002664', (470, 475))	('tumors', 'Disease', 'MESH:D009369', (315, 321))	('carcinoma', 'Phenotype', 'HP:0030731', (432, 441))	('tumors', 'Phenotype', 'HP:0002664', (161, 167))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('tumors', 'Phenotype', 'HP:0002664', (470, 476))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('carcinomas', 'Phenotype', 'HP:0030731', (122, 132))	('carcinomas', 'Disease', 'MESH:D002277', (122, 132))	('tumor', 'Disease', (315, 320))
16907	25329316	However, it is likely that the requirement for RAS pathway activation for tumor development and progression in humans is achieved in the mouse through the activation of c-MET by HGF over-expression.	('HGF', 'Gene', '15234', (178, 181))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('c-MET', 'Gene', '17295', (169, 174))	('HGF', 'Gene', (178, 181))	('mouse', 'Species', '10090', (137, 142))	('c-MET', 'Gene', (169, 174))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('over-expression', 'Var', (182, 197))	('expression', 'Species', '29278', (187, 197))	('tumor', 'Disease', (74, 79))	('activation', 'PosReg', (155, 165))	('humans', 'Species', '9606', (111, 117))
16910	25329316	Hence, contrary to the previously published DMBA-induced SCC mouse model and in agreement with the benign gastrointestinal polyposis associated with Lkb1 deficiency; in our model malignant SCC pathogenesis seems not to require biallelic inactivation of Lkb1.	('gastrointestinal polyposis', 'Phenotype', 'HP:0200008', (106, 132))	('SCC', 'Gene', (189, 192))	('benign gastrointestinal polyposis', 'Disease', 'MESH:D005767', (99, 132))	('SCC', 'Gene', '6317', (57, 60))	('Lkb1', 'Gene', (253, 257))	('deficiency', 'Var', (154, 164))	('DMBA', 'Chemical', 'MESH:C082386', (44, 48))	('malignant', 'Disease', (179, 188))	('SCC', 'Gene', '6317', (189, 192))	('mouse', 'Species', '10090', (61, 66))	('benign gastrointestinal polyposis', 'Disease', (99, 132))	('Lkb1', 'Gene', '20869', (149, 153))	('Lkb1', 'Gene', '20869', (253, 257))	('SCC', 'Gene', (57, 60))	('benign gastrointestinal polyposis', 'Phenotype', 'HP:0006719', (99, 132))	('Lkb1', 'Gene', (149, 153))
16914	25329316	We show that LKB1 deficiency impedes physiological UVB-induced CDKN1A degradation, impairing DNA damage repair and consequently contributes to mutagenesis and tumor development.	('LKB1', 'Gene', (13, 17))	('impairing', 'NegReg', (83, 92))	('impedes', 'NegReg', (29, 36))	('mutagenesis', 'MPA', (143, 154))	('CDKN1A degradation', 'MPA', (63, 81))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('tumor', 'Disease', (159, 164))	('contributes', 'Reg', (128, 139))	('DNA damage repair', 'MPA', (93, 110))	('deficiency', 'Var', (18, 28))	('tumor', 'Disease', 'MESH:D009369', (159, 164))
16916	25329316	We show that mutation of LKB1 Thr-366 to Ala impaired the cells ability to repair UVB-induced DNA damage by affecting CDKN1A UVB-induced degradation.	('LKB1', 'Gene', (25, 29))	('UVB-induced degradation', 'MPA', (125, 148))	('cells ability', 'CPA', (58, 71))	('mutation', 'Var', (13, 21))	('Thr-366', 'Var', (30, 37))	('affecting', 'Reg', (108, 117))	('Thr-366 to Ala', 'Mutation', 'p.T366A', (30, 44))	('impaired', 'NegReg', (45, 53))	('CDKN1A', 'Gene', (118, 124))
16917	25329316	Furthermore, in humans, LKB1 and its downstream kinase NUAK1 bind and phosphorylate CDKN1A (at Thr80 and Ser146, respectively) contributing to its degradation in response to UVB and DNA repair.	('Ser146', 'Var', (105, 111))	('Thr80', 'Chemical', '-', (95, 100))	('LKB1', 'Gene', (24, 28))	('humans', 'Species', '9606', (16, 22))	('response to UVB', 'MPA', (162, 177))	('DNA repair', 'MPA', (182, 192))	('CDKN1A', 'Gene', (84, 90))	('bind', 'Interaction', (61, 65))	('Ser146', 'Chemical', '-', (105, 111))	('degradation', 'MPA', (147, 158))
16921	25329316	Interestingly, NUAK1 phosphorylates mouse CDKN1A at Ser78 and Ser141, the homologous residues in the human orthologue, and also conserved in the rat protein.	('Ser78', 'Chemical', '-', (52, 57))	('Ser141', 'Chemical', '-', (62, 68))	('human', 'Species', '9606', (101, 106))	('CDKN1A', 'Gene', (42, 48))	('Ser141', 'Var', (62, 68))	('Ser78', 'Var', (52, 57))	('rat', 'Species', '10116', (145, 148))	('mouse', 'Species', '10090', (36, 41))
16926	25329316	Furthermore, LKB1T366A mutant has a diminished binding to CDKN1A compared with LKB1WT and LKB1KD mutant, it does not promote CDKN1A degradation in response to UVB radiation, and impairs DNA damage repair.	('DNA damage', 'MPA', (186, 196))	('LKB1T366A', 'Var', (13, 22))	('diminished', 'NegReg', (36, 46))	('degradation', 'MPA', (132, 143))	('CDKN1A', 'Protein', (58, 64))	('impairs', 'NegReg', (178, 185))	('KD', 'Disease', 'MESH:C537017', (94, 96))	('binding', 'Interaction', (47, 54))
16928	25329316	Although the link between CDKN1A degradation and DNA repair has been extensively demonstrated and our data, and other recent work confirm this connection, how UVB-induced CDKN1A phosphorylation leads to its degradation and whether the concomitant LKB1 degradation is connected needs to be further investigated.	('degradation', 'MPA', (207, 218))	('phosphorylation', 'Var', (178, 193))	('rat', 'Species', '10116', (88, 91))	('CDKN1A', 'Gene', (171, 177))
16930	25329316	Altogether this would ultimately favor the fixation of UVB-induced mutations and tumor development.	('UVB-induced', 'Gene', (55, 66))	('favor', 'PosReg', (33, 38))	('mutations', 'Var', (67, 76))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Disease', (81, 86))
16931	25329316	All these data suggest that in humans silencing a single copy of LKB1 would be sufficient to increase the risk of the acquisition and accumulation of UV-induced mutations, placing LKB1 as an important player in response to environmental insults associated to the acquisition of skin cancer.	('LKB1', 'Gene', (65, 69))	('humans', 'Species', '9606', (31, 37))	('skin cancer', 'Phenotype', 'HP:0008069', (278, 289))	('acquisition', 'MPA', (118, 129))	('cancer', 'Phenotype', 'HP:0002664', (283, 289))	('skin cancer', 'Disease', (278, 289))	('skin cancer', 'Disease', 'MESH:D012878', (278, 289))	('silencing', 'Var', (38, 47))	('single copy', 'Var', (50, 61))
16935	25329316	Since our animal model demonstrates that LKB1 haploinsufficiency is sufficient to cause the accumulation of UVB-induced DNA damage, we posit that the mutational status of LKB1 is a prognostic risk factor for UV-induced skin cancers.	('accumulation', 'MPA', (92, 104))	('cause', 'Reg', (82, 87))	('LKB1', 'Gene', (171, 175))	('skin cancer', 'Phenotype', 'HP:0008069', (219, 230))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('risk', 'Reg', (192, 196))	('skin cancers', 'Phenotype', 'HP:0008069', (219, 231))	('rat', 'Species', '10116', (30, 33))	('LKB1 haploinsufficiency', 'Disease', (41, 64))	('skin cancers', 'Disease', (219, 231))	('cancers', 'Phenotype', 'HP:0002664', (224, 231))	('LKB1 haploinsufficiency', 'Disease', 'MESH:D058495', (41, 64))	('mutational status', 'Var', (150, 167))	('skin cancers', 'Disease', 'MESH:D012878', (219, 231))
16936	25329316	In agreement to this, in melanoma and squamous cell carcinomas, LKB1 is mutated in 2% and 11% of tumor samples, respectively (COSMIC-Wellcome Trust Sanger Institute).	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('mutated', 'Var', (72, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (52, 61))	('carcinomas', 'Phenotype', 'HP:0030731', (52, 62))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumor', 'Disease', (97, 102))	('melanoma and squamous cell carcinomas', 'Disease', 'MESH:D002294', (25, 62))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (38, 62))	('melanoma', 'Phenotype', 'HP:0002861', (25, 33))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (38, 61))	('LKB1', 'Gene', (64, 68))
16937	25329316	Furthermore, our data and results from other studies (c-Bioportal, MSKCC) show that tumors with a clear environmental component including, melanoma, head an neck squamous cell carcinoma, lung squamous cell carcinoma and endometrial squamous cell carcinoma, alterations in LKB1 or NUAK1 are mutually exclusive, reinforcing the role of this molecular axis in DNA damage and genomic instability.	('endometrial squamous cell carcinoma', 'Disease', (220, 255))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('rat', 'Species', '10116', (261, 264))	('alterations', 'Var', (257, 268))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('carcinoma', 'Phenotype', 'HP:0030731', (246, 255))	('melanoma', 'Disease', 'MESH:D008545', (139, 147))	('tumors', 'Disease', (84, 90))	('endometrial squamous cell carcinoma', 'Disease', 'MESH:D002294', (220, 255))	('NUAK1', 'Gene', (280, 285))	('neck squamous cell carcinoma', 'Disease', (157, 185))	('carcinoma', 'Phenotype', 'HP:0030731', (206, 215))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (157, 185))	('LKB1', 'Gene', (272, 276))	('tumors', 'Disease', 'MESH:D009369', (84, 90))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (162, 185))	('melanoma', 'Phenotype', 'HP:0002861', (139, 147))	('melanoma', 'Disease', (139, 147))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (232, 255))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (187, 215))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (192, 215))	('lung squamous cell carcinoma', 'Disease', (187, 215))	('carcinoma', 'Phenotype', 'HP:0030731', (176, 185))
16941	25329316	Thus, deficiencies in LKB1 promotes fixation of UVB-induced mutations, resistance to UVB-induced apoptosis contributing to tumor development.	('fixation', 'MPA', (36, 44))	('deficiencies', 'Var', (6, 18))	('tumor', 'Disease', (123, 128))	('UVB-induced', 'Gene', (48, 59))	('promotes', 'PosReg', (27, 35))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('mutations', 'Var', (60, 69))	('LKB1', 'Gene', (22, 26))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
16957	25329316	Palmer, VHIO, Spain, while LKB1 (D60C5), phosphor-ERK1/2 and total ERK1/2, phospho-Met (Tyr1234/1235), phospho-ATR (Ser428), cleaved caspase-3, PUMA, Bim and phospho-CHK2 antibodies were from Cell Signaling (Danvers, MA USA).	('cleaved', 'MPA', (125, 132))	('ATR', 'Gene', (111, 114))	('ERK1/2', 'Gene', '26413', (50, 56))	('CHK2', 'Gene', '50883', (166, 170))	('ATR', 'Gene', '245000', (111, 114))	('Ser428', 'Chemical', '-', (116, 122))	('caspase-3', 'Gene', (133, 142))	('Tyr1234', 'Chemical', '-', (88, 95))	('ERK1/2', 'Gene', (50, 56))	('ERK1/2', 'Gene', (67, 73))	('ERK1/2', 'Gene', '26413', (67, 73))	('D60C5', 'Var', (33, 38))	('CHK2', 'Gene', (166, 170))	('Bim', 'Gene', '12125', (150, 153))	('caspase-3', 'Gene', '12367', (133, 142))	('Bim', 'Gene', (150, 153))
16959	25329316	G3PDH (GAPDH) was from Trevigen Inc. (Gaithersburg, MD USA).	('GAPDH', 'Gene', (7, 12))	('GAPDH', 'Gene', '14433', (7, 12))	('G3PDH', 'Var', (0, 5))
16960	25329316	Cyclin D1, p27 (C-19), anti-HA (Y-11), and LKB1 were from Santa Cruz (Santa Cruz, CA, USA).	('Cyclin D1', 'Gene', '12443', (0, 9))	('p27', 'Gene', (11, 14))	('p27', 'Gene', '12576', (11, 14))	('anti-HA', 'Var', (23, 30))	('Cyclin D1', 'Gene', (0, 9))	('LKB1', 'Gene', (43, 47))
16982	33488873	Prognostic value of the PIK3CA, AKT, and PTEN mutations in oral squamous cell carcinoma: literature review Over 260,000 (2013) new oral squamous cell carcinoma (OSCC) cases are reported annually worldwide.	('mutations', 'Var', (46, 55))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (59, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (150, 159))	('AKT', 'Gene', (32, 35))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (131, 159))	('oral squamous cell carcinoma', 'Disease', (59, 87))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (136, 159))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (64, 87))	('PTEN', 'Gene', (41, 45))	('oral squamous cell carcinoma', 'Disease', (131, 159))
16992	33488873	The review focused on the PIK3CA, AKT, and PTEN gene mutations as prognostic factors in OSCC, in terms of tumour cell invasion, metastatic capacity, possible re-expression in metastatic tissue, and therapeutic inhibition pathways.	('AKT', 'Gene', (34, 37))	('tumour', 'Phenotype', 'HP:0002664', (106, 112))	('tumour', 'Disease', 'MESH:D009369', (106, 112))	('OSCC', 'Disease', (88, 92))	('mutations', 'Var', (53, 62))	('PTEN', 'Gene', (43, 47))	('tumour', 'Disease', (106, 112))	('metastatic capacity', 'CPA', (128, 147))	('PIK3CA', 'Gene', (26, 32))
17018	33488873	AKT phosphorylation occurs at position T308 of tyrosine and S473 of serine, causing a thousand-fold increase in enzymatic activity.	('serine', 'Chemical', 'MESH:D012694', (68, 74))	('phosphorylation', 'MPA', (4, 19))	('AKT', 'Pathway', (0, 3))	('S473', 'Var', (60, 64))	('enzymatic activity', 'MPA', (112, 130))	('tyrosine', 'Chemical', 'MESH:D014443', (47, 55))	('increase', 'PosReg', (100, 108))
17020	33488873	The impact of PI3K signalling pathway deregulation on tumourigenesis has been recognised since the 1970s.	('tumour', 'Disease', 'MESH:D009369', (54, 60))	('deregulation', 'Var', (38, 50))	('tumour', 'Disease', (54, 60))	('PI3K signalling pathway', 'Pathway', (14, 37))	('tumour', 'Phenotype', 'HP:0002664', (54, 60))
17021	33488873	All of the major elements of this pathway have been found to be mutated or amplified in a broad range of cancers.	('cancers', 'Phenotype', 'HP:0002664', (105, 112))	('amplified', 'Reg', (75, 84))	('cancers', 'Disease', (105, 112))	('cancers', 'Disease', 'MESH:D009369', (105, 112))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('mutated', 'Var', (64, 71))
17022	33488873	Genetic alterations of PI3K/AKT pathway have been shown to promote aberrant cell growth and induce tumourigenesis.	('Genetic alterations', 'Var', (0, 19))	('tumour', 'Disease', 'MESH:D009369', (99, 105))	('tumour', 'Disease', (99, 105))	('promote', 'PosReg', (59, 66))	('aberrant cell growth', 'CPA', (67, 87))	('tumour', 'Phenotype', 'HP:0002664', (99, 105))	('PI3K/AKT pathway', 'Pathway', (23, 39))	('induce', 'PosReg', (92, 98))
17026	33488873	There are three isoforms of the catalytic subunit: p110alpha, p110beta, and p110delta, being expressed by PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha), PIK3CB (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta), and PIK3CD (phosphoinositide-4,5-bisphosphate 3-kinase catalytic subunit delta) genes, respectively.	('phosphatidylinositol', 'Chemical', 'MESH:D010716', (195, 215))	('p110alpha', 'Var', (51, 60))	('PIK3CA', 'Gene', (106, 112))	('phosphatidylinositol', 'Chemical', 'MESH:D010716', (114, 134))	('PIK3CD', 'Gene', (271, 277))	('p110delta', 'Var', (76, 85))	('PIK3CB', 'Gene', (187, 193))
17027	33488873	The oncogenic potential of the PIK3CA gene alterations is associated, inter alia, with tumour insensitivity to insulin and thus to the reduction of energy consumption in the cells.	('reduction', 'NegReg', (135, 144))	('tumour insensitivity to insulin', 'Disease', 'MESH:D009369', (87, 118))	('oncogenic potential', 'CPA', (4, 23))	('PIK3CA', 'Gene', (31, 37))	('tumour insensitivity to insulin', 'Disease', (87, 118))	('tumour', 'Phenotype', 'HP:0002664', (87, 93))	('alterations', 'Var', (43, 54))	('energy consumption in the cells', 'MPA', (148, 179))
17028	33488873	The most common point mutations in a gene that have a proven carcinogenic potential are so-called hotspot mutations: H1047R (exon 20), E542K, and E545K (exon 9) (Table II).	('E545K', 'Mutation', 'p.E545K', (146, 151))	('E542K', 'Var', (135, 140))	('H1047R', 'Mutation', 'p.H1047R', (117, 123))	('carcinogenic', 'Disease', 'MESH:D063646', (61, 73))	('carcinogenic', 'Disease', (61, 73))	('E545K', 'Var', (146, 151))	('H1047R', 'Var', (117, 123))	('E542K', 'Mutation', 'p.E542K', (135, 140))
17029	33488873	The presence of point mutations and amplifications of the PIK3CA gene mapped to the 3q26.32 locus has been demonstrated in numerous malignancies, such as glioblastoma, colorectal cancer, gastric cancer, lung cancer, breast cancer, ovary and cervix cancers, larynx and pharynx cancers, prostate cancer, Hodgkin's lymphoma (Hodgkin's disease), leukaemia, malignant melanoma, or primary liver cancer.	('malignant melanoma', 'Phenotype', 'HP:0002861', (353, 371))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('cancers', 'Disease', 'MESH:D009369', (276, 283))	('malignant melanoma', 'Disease', 'MESH:D008545', (353, 371))	('lymphoma', 'Phenotype', 'HP:0002665', (312, 320))	('lung cancer', 'Phenotype', 'HP:0100526', (203, 214))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('gastric cancer', 'Phenotype', 'HP:0012126', (187, 201))	('cervix cancers', 'Phenotype', 'HP:0030079', (241, 255))	("Hodgkin's lymphoma", 'Disease', (302, 320))	('cancers', 'Phenotype', 'HP:0002664', (248, 255))	('colorectal cancer', 'Disease', 'MESH:D015179', (168, 185))	('cancers', 'Disease', (248, 255))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('liver cancer', 'Disease', 'MESH:D006528', (384, 396))	('cancer', 'Phenotype', 'HP:0002664', (248, 254))	('PIK3CA', 'Gene', (58, 64))	('colorectal cancer', 'Disease', (168, 185))	('glioblastoma', 'Disease', 'MESH:D005909', (154, 166))	('leukaemia', 'Disease', (342, 351))	('liver cancer', 'Phenotype', 'HP:0002896', (384, 396))	('cancers', 'Phenotype', 'HP:0002664', (276, 283))	('demonstrated', 'Reg', (107, 119))	('gastric cancer', 'Disease', (187, 201))	('prostate cancer', 'Disease', 'MESH:D011471', (285, 300))	('malignant melanoma', 'Disease', (353, 371))	("Hodgkin's disease", 'Disease', (322, 339))	('prostate cancer', 'Phenotype', 'HP:0012125', (285, 300))	('glioblastoma', 'Disease', (154, 166))	('breast cancer', 'Phenotype', 'HP:0003002', (216, 229))	('cancers', 'Disease', (276, 283))	('liver cancer', 'Disease', (384, 396))	('malignancies', 'Disease', 'MESH:D009369', (132, 144))	('lung cancer', 'Disease', (203, 214))	('glioblastoma', 'Phenotype', 'HP:0012174', (154, 166))	('prostate cancer', 'Disease', (285, 300))	('malignancies', 'Disease', (132, 144))	("Hodgkin's disease", 'Disease', 'MESH:D006689', (322, 339))	("Hodgkin's disease", 'Phenotype', 'HP:0012189', (322, 339))	('point mutations', 'Var', (16, 31))	('cancers', 'Disease', 'MESH:D009369', (248, 255))	('breast cancer', 'Disease', 'MESH:D001943', (216, 229))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	("Hodgkin's lymphoma", 'Phenotype', 'HP:0012189', (302, 320))	('colorectal cancer', 'Phenotype', 'HP:0003003', (168, 185))	('breast cancer', 'Disease', (216, 229))	('gastric cancer', 'Disease', 'MESH:D013274', (187, 201))	('leukaemia', 'Disease', 'MESH:D007938', (342, 351))	("Hodgkin's lymphoma", 'Disease', 'MESH:D006689', (302, 320))	('ovary and cervix cancers', 'Disease', 'MESH:D010051', (231, 255))	('lung cancer', 'Disease', 'MESH:D008175', (203, 214))
17031	33488873	Additionally, the greatest increase in the PIK3CA gene mutations is observed in early stages of tumour development.	('PIK3CA gene', 'Gene', (43, 54))	('mutations', 'Var', (55, 64))	('tumour', 'Phenotype', 'HP:0002664', (96, 102))	('tumour', 'Disease', 'MESH:D009369', (96, 102))	('increase', 'PosReg', (27, 35))	('tumour', 'Disease', (96, 102))
17033	33488873	The point mutation (nucleotide 49) in the AKT1 gene, which results in the conversion of glutamic acid (E) to lysine (K) in the protein chain, causes the membrane translocation of the AKT1 protein and its constitutive activation.	('membrane translocation', 'MPA', (153, 175))	('AKT1 protein', 'Protein', (183, 195))	('point mutation', 'Var', (4, 18))	('AKT1', 'Gene', (42, 46))	('glutamic acid', 'Chemical', 'MESH:D018698', (88, 101))	('lysine', 'Chemical', 'MESH:D008239', (109, 115))	('constitutive activation', 'MPA', (204, 227))	('causes', 'Reg', (142, 148))
17034	33488873	Correlation between the presence of AKT gene mutations and poor prognosis was observed in cancer of the oral cavity, skin, prostate, pancreas, liver, stomach, endometrium, breast, brain, and haematological neoplasm.	('brain', 'Disease', (180, 185))	('breast', 'Disease', (172, 178))	('haematological neoplasm', 'Disease', (191, 214))	('mutations', 'Var', (45, 54))	('pancreas', 'Disease', (133, 141))	('skin', 'Disease', (117, 121))	('neoplasm', 'Phenotype', 'HP:0002664', (206, 214))	('haematological neoplasm', 'Disease', 'MESH:D019337', (191, 214))	('endometrium', 'Disease', (159, 170))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('prostate', 'Disease', (123, 131))	('liver', 'Disease', (143, 148))	('stomach', 'Disease', (150, 157))	('AKT gene', 'Gene', (36, 44))	('haematological neoplasm', 'Phenotype', 'HP:0004377', (191, 214))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('cancer of the oral cavity', 'Phenotype', 'HP:0100649', (90, 115))
17035	33488873	Polymorphisms rs1130214 and rs3803300 in the AKT1 gene were associated with OSCC susceptibility.	('rs3803300', 'Mutation', 'rs3803300', (28, 37))	('OSCC', 'Disease', (76, 80))	('rs1130214', 'Mutation', 'rs1130214', (14, 23))	('AKT1', 'Gene', (45, 49))	('rs1130214', 'Var', (14, 23))	('rs3803300', 'Var', (28, 37))	('associated', 'Reg', (60, 70))
17036	33488873	Moreover, CT genotype of the SNP rs3730358 was associated with higher risk of OSCC progression in the Chinese Han population.	('rs3730358', 'Var', (33, 42))	('OSCC', 'Disease', (78, 82))	('rs3730358', 'Mutation', 'rs3730358', (33, 42))
17040	33488873	Deletions and missense point mutations leading to PTEN gene inactivation are the most frequently observed genetic aberrations found in a variety of neoplasms such as prostatic, breast, lung, endometrial, and colorectal cancers or glioblastomas.	('lung', 'Disease', (185, 189))	('prostatic', 'Disease', (166, 175))	('neoplasm', 'Phenotype', 'HP:0002664', (148, 156))	('glioblastomas', 'Disease', 'MESH:D005909', (230, 243))	('colorectal cancers', 'Disease', 'MESH:D015179', (208, 226))	('endometrial', 'Disease', (191, 202))	('PTEN', 'Gene', (50, 54))	('neoplasms', 'Disease', 'MESH:D009369', (148, 157))	('missense point mutations', 'Var', (14, 38))	('neoplasms', 'Disease', (148, 157))	('glioblastomas', 'Phenotype', 'HP:0012174', (230, 243))	('cancers', 'Phenotype', 'HP:0002664', (219, 226))	('breast', 'Disease', (177, 183))	('colorectal cancer', 'Phenotype', 'HP:0003003', (208, 225))	('colorectal cancers', 'Disease', (208, 226))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('glioblastomas', 'Disease', (230, 243))	('glioblastoma', 'Phenotype', 'HP:0012174', (230, 242))	('neoplasms', 'Phenotype', 'HP:0002664', (148, 157))	('Deletions', 'Var', (0, 9))
17043	33488873	reported PTEN gene point mutation frequency in 4.65% of cases from which four were identified as missense mutations and one as frameshift mutation in four oral cancers.	('cancers', 'Disease', 'MESH:D009369', (160, 167))	('cancers', 'Phenotype', 'HP:0002664', (160, 167))	('PTEN', 'Gene', (9, 13))	('cancers', 'Disease', (160, 167))	('oral cancer', 'Disease', (155, 166))	('point mutation', 'Var', (19, 33))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('oral cancer', 'Disease', 'MESH:D009369', (155, 166))
17044	33488873	documented PTEN intronic deletions in 3 cases, without any significant correlation with gender, tumour size, stage, or grade.	('PTEN', 'Gene', (11, 15))	('tumour', 'Phenotype', 'HP:0002664', (96, 102))	('deletions', 'Var', (25, 34))	('tumour', 'Disease', 'MESH:D009369', (96, 102))	('tumour', 'Disease', (96, 102))
17058	33488873	PI3K inhibitors have demonstrated antiproliferative, pro-apoptotic, and antitumour activity in a range of preclinical cancer models, as a single agent or in combination with other anticancer therapies.	('cancer', 'Disease', (184, 190))	('cancer', 'Disease', (118, 124))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('inhibitors', 'Var', (5, 15))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('tumour', 'Phenotype', 'HP:0002664', (76, 82))	('PI3K', 'Gene', (0, 4))	('pro-apoptotic', 'CPA', (53, 66))	('tumour', 'Disease', 'MESH:D009369', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('antiproliferative', 'CPA', (34, 51))	('tumour', 'Disease', (76, 82))
17060	33488873	In a randomised phase II trial of cetuximab, with or without PX-866, conducted by Jimeno et al., among patients with PIK3CA gene mutations, none responded to anti-PI3K therapy.	('PX-866', 'Chemical', 'MESH:C496788', (61, 67))	('mutations', 'Var', (129, 138))	('cetuximab', 'Chemical', 'MESH:D000068818', (34, 43))	('PIK3CA', 'Gene', (117, 123))
17070	33488873	In various types of carcinoma, such as lung, prostate, breast, or colon carcinoma, a relationship between the presence of PIK3CA, AKT, or PTEN gene mutations and cancer progression has been demonstrated.	('cancer', 'Disease', (162, 168))	('carcinoma', 'Disease', 'MESH:D009369', (20, 29))	('breast', 'Disease', (55, 61))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('colon carcinoma', 'Disease', 'MESH:D003110', (66, 81))	('presence', 'Var', (110, 118))	('PIK3CA', 'Gene', (122, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('PTEN', 'Gene', (138, 142))	('carcinoma', 'Disease', (72, 81))	('prostate', 'Disease', (45, 53))	('lung', 'Disease', (39, 43))	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('mutations', 'Var', (148, 157))	('carcinoma', 'Disease', 'MESH:D009369', (72, 81))	('carcinoma', 'Phenotype', 'HP:0030731', (20, 29))	('AKT', 'Gene', (130, 133))	('carcinoma', 'Disease', (20, 29))	('colon carcinoma', 'Disease', (66, 81))
17071	33488873	Detection of PIK3CA, AKT, or PTEN genetic alterations could be important in cancer therapy, because their status may be indicative of the resistance of tumour cells to conventional chemotherapy methods, e.g.	('tumour', 'Disease', 'MESH:D009369', (152, 158))	('tumour', 'Disease', (152, 158))	('PIK3CA', 'Gene', (13, 19))	('PTEN', 'Gene', (29, 33))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('tumour', 'Phenotype', 'HP:0002664', (152, 158))	('genetic alterations', 'Var', (34, 53))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('AKT', 'Gene', (21, 24))
17075	33086062	Enhancer Reprogramming Confers Dependence on Glycolysis and IGF Signaling in KMT2D Mutant Melanoma Histone methyltransferase KMT2D harbors frequent loss-of-function somatic point mutations in several tumor types, including melanoma.	('melanoma', 'Disease', (223, 231))	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('KMT2D', 'Gene', '8085', (125, 130))	('melanoma', 'Disease', 'MESH:D008545', (223, 231))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('KMT2D', 'Gene', (77, 82))	('KMT2D', 'Gene', '8085', (77, 82))	('Melanoma', 'Phenotype', 'HP:0002861', (90, 98))	('tumor', 'Disease', (200, 205))	('Melanoma', 'Disease', 'MESH:D008545', (90, 98))	('loss-of-function', 'NegReg', (148, 164))	('Melanoma', 'Disease', (90, 98))	('Histone methyltransferase', 'Gene', '56979', (99, 124))	('Histone methyltransferase', 'Gene', (99, 124))	('Mutant', 'Var', (83, 89))	('melanoma', 'Phenotype', 'HP:0002861', (223, 231))	('KMT2D', 'Gene', (125, 130))
17076	33086062	Here, we identify KMT2D as a potent tumor suppressor in melanoma through an in vivo epigenome-focused pooled RNAi screen and confirm the finding by using a genetically engineered mouse model (GEMM) based on conditional and melanocyte-specific deletion of KMT2D.	('mouse', 'Species', '10090', (179, 184))	('melanoma', 'Disease', 'MESH:D008545', (56, 64))	('melanoma', 'Phenotype', 'HP:0002861', (56, 64))	('melanoma', 'Disease', (56, 64))	('deletion', 'Var', (243, 251))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('KMT2D', 'Gene', (18, 23))	('KMT2D', 'Gene', (255, 260))	('tumor', 'Disease', (36, 41))
17084	33086062	Loss-of-function missense and nonsense point mutations are observed to be highly prevalent across multiple tumor types in two families of chromatin regulators: (1) Histone H3K4 methyltransferase members, including KMT2C and KMT2D; and (2) SWI/SNF complex members, including SMARCA4, ARID1A, and PBRM1.	('Loss-of-function', 'NegReg', (0, 16))	('SMARCA4', 'Gene', '6597', (274, 281))	('missense', 'Var', (17, 25))	('PBRM1', 'Gene', (295, 300))	('tumor', 'Disease', (107, 112))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('KMT2C', 'Gene', '58508', (214, 219))	('KMT2C', 'Gene', (214, 219))	('Histone H3K4 methyltransferase', 'Enzyme', (164, 194))	('PBRM1', 'Gene', '55193', (295, 300))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('ARID1A', 'Gene', '8289', (283, 289))	('nonsense point mutations', 'Var', (30, 54))	('ARID1A', 'Gene', (283, 289))	('SMARCA4', 'Gene', (274, 281))
17085	33086062	Although recent studies have begun to shed light on the roles of these proteins in cancer progression, we still have limited knowledge of why mutations in these proteins are selected over the course of tumor progression.	('mutations', 'Var', (142, 151))	('tumor', 'Disease', (202, 207))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('cancer', 'Disease', (83, 89))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))
17089	33086062	In cutaneous melanoma, mutations in epigenetic regulators, including IDH1/2, EZH2, ARID1A/1B, ARID2, and SMARCA4, have been observed at statistically significant frequencies.	('observed', 'Reg', (124, 132))	('EZH2', 'Gene', (77, 81))	('ARID2', 'Gene', '196528', (94, 99))	('SMARCA4', 'Gene', '6597', (105, 112))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (3, 21))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (3, 21))	('cutaneous melanoma', 'Disease', (3, 21))	('IDH1/2', 'Gene', '3417;3418', (69, 75))	('ARID2', 'Gene', (94, 99))	('ARID1A/1B', 'Gene', (83, 92))	('melanoma', 'Phenotype', 'HP:0002861', (13, 21))	('mutations', 'Var', (23, 32))	('ARID1A/1B', 'Gene', '8289;57492', (83, 92))	('SMARCA4', 'Gene', (105, 112))	('EZH2', 'Gene', '2146', (77, 81))	('IDH1/2', 'Gene', (69, 75))
17090	33086062	However, we have a limited understanding of how specific mutant epigenetic proteins impact melanomagenesis.	('impact', 'Reg', (84, 90))	('epigenetic proteins', 'Protein', (64, 83))	('melanoma', 'Phenotype', 'HP:0002861', (91, 99))	('melanoma', 'Disease', (91, 99))	('melanoma', 'Disease', 'MESH:D008545', (91, 99))	('mutant', 'Var', (57, 63))
17091	33086062	Functional studies have implicated the involvement of other epigenetic factors, such as JARID1B, SETDB1, TET2, and histone variants, in melanoma progression.	('JARID1B', 'Gene', (88, 95))	('TET2', 'Gene', '54790', (105, 109))	('SETDB1', 'Gene', '9869', (97, 103))	('involvement', 'Reg', (39, 50))	('TET2', 'Gene', (105, 109))	('SETDB1', 'Gene', (97, 103))	('melanoma', 'Disease', 'MESH:D008545', (136, 144))	('melanoma', 'Phenotype', 'HP:0002861', (136, 144))	('JARID1B', 'Gene', '10765', (88, 95))	('melanoma', 'Disease', (136, 144))	('variants', 'Var', (123, 131))
17092	33086062	Systematic functional approaches are needed to elucidate how misregulation of epigenetic regulators impact chromatin states and downstream gene expression programs during various stages of tumorigenesis.	('misregulation', 'Var', (61, 74))	('tumor', 'Disease', (189, 194))	('chromatin states', 'MPA', (107, 123))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('impact', 'Reg', (100, 106))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))
17093	33086062	A detailed mechanistic understanding of melanomagenesis and the role of epigenetic regulators will also inform therapeutic strategies for patients whose tumors bear these mutations.	('melanoma', 'Disease', 'MESH:D008545', (40, 48))	('melanoma', 'Phenotype', 'HP:0002861', (40, 48))	('melanoma', 'Disease', (40, 48))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumors', 'Disease', (153, 159))	('tumors', 'Phenotype', 'HP:0002664', (153, 159))	('mutations', 'Var', (171, 180))	('tumors', 'Disease', 'MESH:D009369', (153, 159))	('patients', 'Species', '9606', (138, 146))
17094	33086062	We isolated KMT2D as the top hit in an in vivo RNAi screen focused on identification of epigenetic regulators that play a tumor-suppressive function in melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (152, 160))	('melanoma', 'Disease', (152, 160))	('melanoma', 'Disease', 'MESH:D008545', (152, 160))	('epigenetic regulators', 'Var', (88, 109))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumor', 'Disease', (122, 127))
17095	33086062	KMT2D is a histone H3 lysine 4 (H3K4) methyltransferase that primarily performs monomethylation, H3K4me1, which has been shown to be a marker of enhancer elements.	('lysine', 'Chemical', 'MESH:D008239', (22, 28))	('KMT2D', 'Gene', (0, 5))	('H3K4me1', 'Var', (97, 104))
17100	33086062	We used a well-characterized system of TERT-immortalized human primary foreskin melanocytes that harbor stably integrated dominant negative p53, CDK4R24C, and BRAFV600E (passage, n < 15).	('TERT', 'Gene', (39, 43))	('human', 'Species', '9606', (57, 62))	('TERT', 'Gene', '7015', (39, 43))	('BRAFV600E', 'Var', (159, 168))	('BRAFV600E', 'Mutation', 'rs113488022', (159, 168))	('p53', 'Gene', (140, 143))	('CDK4R24C', 'Var', (145, 153))	('p53', 'Gene', '7157', (140, 143))
17102	33086062	When injected in nude mice, HMEL-BRAFV600E cells form visible tumors only after 22-24 weeks and with low penetrance (~10%-20%) (Figure 1B).	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('HMEL-BRAFV600E', 'Var', (28, 42))	('tumors', 'Disease', (62, 68))	('tumors', 'Disease', 'MESH:D009369', (62, 68))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('BRAFV600E', 'Mutation', 'rs113488022', (33, 42))	('nude mice', 'Species', '10090', (17, 26))
17105	33086062	We had previously used this system for the discovery of pro-tumorigenic epigenomic changes in melanoma.	('epigenomic changes', 'Var', (72, 90))	('melanoma', 'Disease', 'MESH:D008545', (94, 102))	('melanoma', 'Phenotype', 'HP:0002861', (94, 102))	('melanoma', 'Disease', (94, 102))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Disease', (60, 65))
17115	33086062	All eight genes (KMT2D, KDM1A, APOBEC2, HDAC6, KMT2F, SETD4, KAT4, and KDM5B) were validated as tumor suppressor candidates, as knockdown of these genes in both HMEL-BRAFV600E and WM115 cells resulted in accelerated tumor formation (p < 0.05) (Figures 1D-1K and S1J-S1P).	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('BRAFV600E', 'Mutation', 'rs113488022', (166, 175))	('KMT2F', 'Gene', '9739', (47, 52))	('KDM1A', 'Gene', '23028', (24, 29))	('KAT4', 'Gene', '6872', (61, 65))	('accelerated', 'PosReg', (204, 215))	('KMT2F', 'Gene', (47, 52))	('tumor', 'Disease', (216, 221))	('HDAC6', 'Gene', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (216, 221))	('APOBEC2', 'Gene', (31, 38))	('tumor', 'Disease', (96, 101))	('SETD4', 'Gene', (54, 59))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('HDAC6', 'Gene', '10013', (40, 45))	('knockdown', 'Var', (128, 137))	('SETD4', 'Gene', '54093', (54, 59))	('APOBEC2', 'Gene', '10930', (31, 38))	('KDM1A', 'Gene', (24, 29))	('KAT4', 'Gene', (61, 65))
17116	33086062	In addition, knockdown of a subset of these genes in HMEL-BRAFV600E cells also promoted invasion in vitro in a Boyden chamber assay (Figure S1Q).	('invasion in vitro in a', 'CPA', (88, 110))	('knockdown', 'Var', (13, 22))	('BRAFV600E', 'Mutation', 'rs113488022', (58, 67))	('promoted', 'PosReg', (79, 87))
17117	33086062	KMT2D was the most potent hit, as mice injected with cells with stable KMT2D knockdown developed tumor appearance at the earliest interval and with the highest penetrance compared with negative controls (Figures 1C, 1D, and 2A).	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('mice', 'Species', '10090', (34, 38))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('KMT2D', 'Gene', (71, 76))	('knockdown', 'Var', (77, 86))	('tumor', 'Disease', (97, 102))
17119	33086062	We searched published melanoma genomic studies to identify patients whose tumors harbor genetic aberrations in the potential tumor suppressor genes discovered through the screen.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('melanoma', 'Disease', 'MESH:D008545', (22, 30))	('tumor', 'Disease', (125, 130))	('melanoma', 'Phenotype', 'HP:0002861', (22, 30))	('melanoma', 'Disease', (22, 30))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('tumor', 'Disease', (74, 79))	('patients', 'Species', '9606', (59, 67))	('genetic aberrations', 'Var', (88, 107))	('tumors', 'Disease', 'MESH:D009369', (74, 80))	('tumors', 'Disease', (74, 80))
17120	33086062	We observed that ~15% of melanoma cases identified harbored missense mutations in KMT2D, whereas ~5%-8% of patients harbored missense mutations in KAT4 (Figures 2B and S2A).	('KAT4', 'Gene', '6872', (147, 151))	('missense mutations', 'Var', (60, 78))	('KMT2D', 'Gene', (82, 87))	('harbored', 'Reg', (51, 59))	('melanoma', 'Phenotype', 'HP:0002861', (25, 33))	('melanoma', 'Disease', 'MESH:D008545', (25, 33))	('missense mutations', 'Var', (125, 143))	('melanoma', 'Disease', (25, 33))	('patients', 'Species', '9606', (107, 115))	('KAT4', 'Gene', (147, 151))
17121	33086062	As KMT2D mutations are prevalent and this gene is increasingly reported to be a potential tumor suppressor across other tumor types, we next sought to deeply characterize the mechanism of action of KMT2D in melanoma, particularly as the strongest phenotype (fastest tumor growth) in RNAi screen was seen with the KMT2D loss.	('fastest tumor', 'Disease', 'MESH:D009369', (258, 271))	('melanoma', 'Disease', 'MESH:D008545', (207, 215))	('melanoma', 'Phenotype', 'HP:0002861', (207, 215))	('melanoma', 'Disease', (207, 215))	('mutations', 'Var', (9, 18))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('tumor', 'Disease', 'MESH:D009369', (266, 271))	('KMT2D', 'Gene', (313, 318))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('tumor', 'Phenotype', 'HP:0002664', (266, 271))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('tumor', 'Disease', (266, 271))	('KMT2D', 'Gene', (3, 8))	('fastest tumor', 'Disease', (258, 271))	('loss', 'NegReg', (319, 323))	('tumor', 'Disease', (120, 125))
17122	33086062	A subset of the missense mutations in KMT2D were truncating or frameshift insertions/deletions (4.4%) that likely abrogate histone methyltransferase activity (Figure 2B).	('abrogate', 'NegReg', (114, 122))	('missense mutations', 'Var', (16, 34))	('activity', 'MPA', (149, 157))	('histone methyltransferase', 'Gene', '56979', (123, 148))	('frameshift insertions/deletions', 'Var', (63, 94))	('KMT2D', 'Gene', (38, 43))	('histone methyltransferase', 'Gene', (123, 148))
17123	33086062	In addition, 10% of all missense mutations occurred distal to amino acid residue 4700 that were shown to disrupt histone methyltransferase activity in a previous study.	('missense mutations', 'Var', (24, 42))	('histone methyltransferase', 'Gene', '56979', (113, 138))	('activity', 'MPA', (139, 147))	('histone methyltransferase', 'Gene', (113, 138))	('disrupt', 'NegReg', (105, 112))
17128	33086062	Functionally, knockdown of KMT2D by two different shRNAs led to increased tumor burden in two clonal variants of HMEL-BRAFV600E, namely, WM115 and WM266-4 cells (Figures 1D, 2A, 2D, and S2D-S2H).	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('HMEL-BRAFV600E', 'Gene', (113, 127))	('BRAFV600E', 'Mutation', 'rs113488022', (118, 127))	('WM266-4', 'CellLine', 'CVCL:2765', (147, 154))	('tumor', 'Disease', (74, 79))	('knockdown', 'Var', (14, 23))	('increased', 'PosReg', (64, 73))	('KMT2D', 'Gene', (27, 32))
17130	33086062	Melanocyte-specific deletion with Tyr-CreERT2 did not result in the formation of melanomas (data not shown), and thus, these mice were crossed with a previously published doxycycline- and a tamoxifen-inducible mouse model of BRAFV600E melanoma (iBIP = Tyr-CreERT2, Rosa26-rtta, TetO-BRAFV600E, PTENL/L, INK/ARFL/L).	('mice', 'Species', '10090', (125, 129))	('melanoma', 'Phenotype', 'HP:0002861', (81, 89))	('melanoma', 'Disease', (81, 89))	('melanoma', 'Disease', 'MESH:D008545', (235, 243))	('ARFL', 'Disease', 'None', (307, 311))	('Rosa26', 'Gene', '14910', (265, 271))	('tamoxifen', 'Chemical', 'MESH:D013629', (190, 199))	('ARFL', 'Disease', (307, 311))	('doxycycline', 'Chemical', 'MESH:D004318', (171, 182))	('BRAFV600E', 'Mutation', 'rs113488022', (283, 292))	('melanomas', 'Disease', 'MESH:D008545', (81, 90))	('melanomas', 'Disease', (81, 90))	('melanoma', 'Phenotype', 'HP:0002861', (235, 243))	('melanoma', 'Disease', (235, 243))	('PTEN', 'Gene', (294, 298))	('BRAFV600E', 'Mutation', 'rs113488022', (225, 234))	('deletion', 'Var', (20, 28))	('melanoma', 'Disease', 'MESH:D008545', (81, 89))	('Rosa26', 'Gene', (265, 271))	('mouse', 'Species', '10090', (210, 215))	('melanomas', 'Phenotype', 'HP:0002861', (81, 90))	('PTEN', 'Gene', '5728', (294, 298))
17131	33086062	Tamoxifen application on the ears of KMT2D mutant iBIP mice resulted in a drastic acceleration of tumorigenesis compared with KMT2D wild-type (WT) iBIP mice (Figures 2E and 2F).	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('mice', 'Species', '10090', (55, 59))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('mutant', 'Var', (43, 49))	('Tamoxifen', 'Chemical', 'MESH:D013629', (0, 9))	('mice', 'Species', '10090', (152, 156))	('tumor', 'Disease', (98, 103))	('acceleration', 'PosReg', (82, 94))
17136	33086062	The phenotypes observed in KMT2D mutant lines were dependent on the loss of this gene, as overexpression of full-length KMT2D (Figures 2I and S2M) reduced tumor burden in vivo (Figure 2J) in immunodeficient nude mice.	('immunodeficient', 'Disease', (191, 206))	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('nude mice', 'Species', '10090', (207, 216))	('KMT2D', 'Gene', (120, 125))	('tumor', 'Disease', (155, 160))	('mutant', 'Var', (33, 39))	('reduced', 'NegReg', (147, 154))	('overexpression', 'PosReg', (90, 104))	('immunodeficient', 'Disease', 'MESH:D007153', (191, 206))
17139	33086062	To determine the molecular phenotype conferred by KMT2D loss, we performed an RNA sequencing (RNA-seq)-based transcriptome profiling experiment in the KMT2D WT and mutant murine melanoma lines.	('mutant', 'Var', (164, 170))	('loss', 'NegReg', (56, 60))	('murine', 'Species', '10090', (171, 177))	('KMT2D', 'Gene', (50, 55))	('melanoma', 'Phenotype', 'HP:0002861', (178, 186))	('melanoma', 'Disease', (178, 186))	('melanoma', 'Disease', 'MESH:D008545', (178, 186))
17140	33086062	Genes overexpressed in KMT2D mutant cells were enriched for pathways related to immune response, cell adhesion, and epithelial-to-mesenchymal transition, as well as various metabolic pathways, including the "hexose metabolic pathway" or glycolysis (Figures 3A, 3B, S3A, and S3B; Table S2).	('hexose', 'Chemical', 'MESH:D006601', (208, 214))	('KMT2D', 'Gene', (23, 28))	('mutant', 'Var', (29, 35))	('S3A', 'Mutation', 'p.S3A', (265, 268))	('cell adhesion', 'CPA', (97, 110))	('metabolic pathways', 'Pathway', (173, 191))	('epithelial-to-mesenchymal', 'CPA', (116, 141))	('overexpressed', 'PosReg', (6, 19))
17141	33086062	Similar pathways, including glycolysis, were also found to be upregulated in KMT2D mutant human melanomas upon analyses of melanoma tumors from a published TCGA study (Figure 3C; Table S2).	('melanomas', 'Disease', 'MESH:D008545', (96, 105))	('mutant', 'Var', (83, 89))	('KMT2D', 'Gene', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('melanomas', 'Phenotype', 'HP:0002861', (96, 105))	('melanomas', 'Disease', (96, 105))	('human', 'Species', '9606', (90, 95))	('upregulated', 'PosReg', (62, 73))	('melanoma tumors', 'Disease', (123, 138))	('melanoma', 'Phenotype', 'HP:0002861', (123, 131))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('glycolysis', 'MPA', (28, 38))	('melanoma', 'Phenotype', 'HP:0002861', (96, 104))	('melanoma tumors', 'Disease', 'MESH:D008545', (123, 138))
17143	33086062	A survey of pan-cancer TCGA data suggested that energy metabolism pathways, including glycolysis, were activated across 6 other tumor types (BLCA [urothelial bladder carcinoma], CESC [cervical squamous cell carcinoma], endocervical adenocarcinoma, HNSC [head and neck squamous cell carcinoma], LUSC [lung squamous cell carcinoma], UCEC [uterine corpus endometrial carcinoma], and STAD [stomach adenocarcinoma]) that harbor functional KMT2D driver mutations (Figures 3D and S3D; Table S2).	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (305, 328))	('urothelial bladder carcinoma', 'Disease', 'MESH:D001749', (147, 175))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (193, 216))	('neck squamous cell carcinoma', 'Disease', (263, 291))	('urothelial bladder carcinoma', 'Disease', (147, 175))	('glycolysis', 'MPA', (86, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (319, 328))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (263, 291))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (300, 328))	('carcinoma', 'Phenotype', 'HP:0030731', (166, 175))	('cancer', 'Disease', (16, 22))	('carcinoma', 'Phenotype', 'HP:0030731', (207, 216))	('energy metabolism', 'MPA', (48, 65))	('squamous cell carcinoma', 'Disease', (193, 216))	('stomach adenocarcinoma', 'Disease', 'MESH:D000230', (386, 408))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (158, 175))	('endometrial carcinoma', 'Disease', (352, 373))	('carcinoma', 'Phenotype', 'HP:0030731', (237, 246))	('endocervical adenocarcinoma', 'Disease', (219, 246))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (268, 291))	('KMT2D', 'Gene', (434, 439))	('stomach adenocarcinoma', 'Disease', (386, 408))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (300, 328))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (305, 328))	('lung squamous cell carcinoma', 'Disease', (300, 328))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (254, 291))	('tumor', 'Disease', (128, 133))	('activated', 'PosReg', (103, 112))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (352, 373))	('carcinoma', 'Phenotype', 'HP:0030731', (282, 291))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('cancer', 'Disease', 'MESH:D009369', (16, 22))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (193, 216))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (268, 291))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (352, 373))	('endocervical adenocarcinoma', 'Disease', 'MESH:D000230', (219, 246))	('mutations', 'Var', (447, 456))
17144	33086062	We observed drastic upregulation of 10 out of 12 glycolysis pathway enzyme genes (GLUT1, HK1, GPI1, PFKA, ALDOC, TPI1, GAPDH, PGK1, PGAM1, and ENO1) by qPCR in KMT2D mutant lines compared with WT lines in both human and murine models (Figures 3E and 3F).	('PFKA', 'Gene', '5213', (100, 104))	('TPI1', 'Gene', '7167', (113, 117))	('ALDOC', 'Gene', '230', (106, 111))	('human', 'Species', '9606', (210, 215))	('PFKA', 'Gene', (100, 104))	('ALDOC', 'Gene', (106, 111))	('GLUT1', 'Gene', (82, 87))	('TPI1', 'Gene', (113, 117))	('PGAM1', 'Gene', (132, 137))	('HK1', 'Gene', (89, 92))	('qPCR', 'Var', (152, 156))	('KMT2D mutant', 'Var', (160, 172))	('GAPDH', 'Gene', '2597', (119, 124))	('murine', 'Species', '10090', (220, 226))	('ENO1', 'Gene', (143, 147))	('mutant', 'Var', (166, 172))	('GPI1', 'Gene', (94, 98))	('upregulation', 'PosReg', (20, 32))	('PGK1', 'Gene', (126, 130))	('GPI1', 'Gene', '9091', (94, 98))	('GAPDH', 'Gene', (119, 124))	('GLUT1', 'Gene', '6513', (82, 87))	('HK1', 'Gene', '3098', (89, 92))
17145	33086062	Higher expression of ENO1, PGK1, and PGAM1 was confirmed in KMT2D mutant iBIP melanoma tumors by IHC (Figure 3H).	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('mutant', 'Var', (66, 72))	('expression', 'MPA', (7, 17))	('PGAM1', 'Gene', (37, 42))	('KMT2D', 'Gene', (60, 65))	('melanoma tumors', 'Disease', (78, 93))	('melanoma', 'Phenotype', 'HP:0002861', (78, 86))	('Higher', 'PosReg', (0, 6))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('PGK1', 'Gene', (27, 31))	('ENO1', 'Gene', (21, 25))	('melanoma tumors', 'Disease', 'MESH:D008545', (78, 93))
17146	33086062	Quantitation of glucose uptake and lactate production confirmed upregulation of glycolysis in the KMT2D mutant lines (Figures 3I and 3J) that was reduced upon KMT2D overexpression (Figure 3K).	('glycolysis', 'MPA', (80, 90))	('lactate production', 'MPA', (35, 53))	('glucose uptake', 'MPA', (16, 30))	('glucose', 'Chemical', 'MESH:D005947', (16, 23))	('mutant', 'Var', (104, 110))	('KMT2D', 'Gene', (98, 103))	('upregulation', 'PosReg', (64, 76))	('lactate', 'Chemical', 'MESH:D019344', (35, 42))
17147	33086062	In addition, mass-spectrometry-based quantitative measurement of glycolysis intermediate metabolites showed higher levels of fructose-1,6-biphosphate, D-glyceraldehyde-3-phosphate, dihydroxy-acetone-phosphate, 1,3-diphosphateglycerate, and pyruvate in two KMT2D mutant murine lines than those of two WT lines (Figure 3L).	('fructose-1,6-biphosphate', 'Chemical', '-', (125, 149))	('D-glyceraldehyde-3-phosphate', 'Chemical', '-', (151, 179))	('levels', 'MPA', (115, 121))	('mutant', 'Var', (262, 268))	('D-glyceraldehyde-3-phosphate', 'MPA', (151, 179))	('1,3-diphosphateglycerate', 'Chemical', '-', (210, 234))	('dihydroxy-acetone-phosphate', 'Chemical', 'MESH:D004099', (181, 208))	('pyruvate', 'Chemical', 'MESH:D019289', (240, 248))	('dihydroxy-acetone-phosphate', 'MPA', (181, 208))	('murine', 'Species', '10090', (269, 275))	('KMT2D mutant', 'Var', (256, 268))	('higher', 'PosReg', (108, 114))	('pyruvate', 'MPA', (240, 248))
17148	33086062	We also noted a modest increase in some TCA metabolites, amino acids, and sugars, whereas the Pentose Phosphate pathway metabolites either did not change or showed a modest decrease in KMT2D mutant cells compared with WT cells (Figures S3E-S3H).	('decrease', 'NegReg', (173, 181))	('TCA', 'Chemical', 'MESH:D014238', (40, 43))	('sugars', 'Chemical', 'MESH:D000073893', (74, 80))	('amino acids', 'MPA', (57, 68))	('mutant', 'Var', (191, 197))	('sugars', 'MPA', (74, 80))	('Pentose', 'Enzyme', (94, 101))	('increase', 'PosReg', (23, 31))	('Pentose Phosphate', 'Chemical', 'MESH:D010428', (94, 111))	('TCA metabolites', 'MPA', (40, 55))	('KMT2D mutant', 'Var', (185, 197))
17149	33086062	Consistent with this higher glycolysis rate in KMT2D mutants, they grew poorly in low glucose media compared to high glucose media, which likely resulted from rapid exhaustion of glucose in the media (Figures S4A and S4B).	('glucose', 'Chemical', 'MESH:D005947', (117, 124))	('KMT2D', 'Gene', (47, 52))	('mutants', 'Var', (53, 60))	('grew', 'MPA', (67, 71))	('higher', 'PosReg', (21, 27))	('glucose', 'Chemical', 'MESH:D005947', (179, 186))	('high glucose', 'Phenotype', 'HP:0003074', (112, 124))	('glucose', 'Chemical', 'MESH:D005947', (86, 93))	('glycolysis rate', 'MPA', (28, 43))
17150	33086062	However, contradictory to this hypothesis, we observe that KMT2D mutant cells proliferate more slowly than WT cells in vitro (Figures S4A and S4B) despite increased tumorigenesis in vivo.	('increased', 'PosReg', (155, 164))	('slowly', 'NegReg', (95, 101))	('mutant', 'Var', (65, 71))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('KMT2D', 'Gene', (59, 64))	('proliferate', 'CPA', (78, 89))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('tumor', 'Disease', (165, 170))
17151	33086062	Similarly, re-expression of KMT2D in human and mouse KMT2D mutant cells modestly increased their proliferation (Figure S4C).	('KMT2D', 'Gene', (53, 58))	('mutant', 'Var', (59, 65))	('proliferation', 'CPA', (97, 110))	('human', 'Species', '9606', (37, 42))	('increased', 'PosReg', (81, 90))	('mouse', 'Species', '10090', (47, 52))
17152	33086062	Together, these data provide the evidence of activation of glycolysis in KMT2D mutant melanomas (Figure 3M) that likely helps meet the increased biomass and energy requirements for increased tumorigenesis.	('KMT2D', 'Gene', (73, 78))	('melanomas', 'Disease', 'MESH:D008545', (86, 95))	('melanoma', 'Phenotype', 'HP:0002861', (86, 94))	('melanomas', 'Phenotype', 'HP:0002861', (86, 95))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('mutant', 'Var', (79, 85))	('melanomas', 'Disease', (86, 95))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('tumor', 'Disease', (191, 196))	('activation', 'PosReg', (45, 55))	('glycolysis', 'MPA', (59, 69))
17153	33086062	Next, we tested whether the aberrantly activated glycolysis pathway contributed to the increased tumorigenic potential of KMT2D mutant melanomas.	('increased', 'PosReg', (87, 96))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('activated', 'PosReg', (39, 48))	('melanomas', 'Disease', 'MESH:D008545', (135, 144))	('melanoma', 'Phenotype', 'HP:0002861', (135, 143))	('melanomas', 'Phenotype', 'HP:0002861', (135, 144))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('glycolysis pathway', 'Pathway', (49, 67))	('mutant', 'Var', (128, 134))	('tumor', 'Disease', (97, 102))	('KMT2D', 'Gene', (122, 127))	('tested', 'Reg', (9, 15))	('melanomas', 'Disease', (135, 144))
17154	33086062	Inhibition of the glycolysis pathway using three different inhibitors:2-DG (glucose competitor), pomhex (an ENO1 inhibitor), and lonidamine (Hexokinase inhibitor:selectively reduced the proliferation of KMT2D mutant melanoma cells compared with that of KMT2D WT melanoma cells in both murine as well as human systems (Figures 4A-4D, S4D, and S4E; Table S3).	('murine', 'Species', '10090', (285, 291))	('melanoma', 'Phenotype', 'HP:0002861', (262, 270))	('Hexokinase', 'Gene', '3098', (141, 151))	('melanoma', 'Disease', (262, 270))	('human', 'Species', '9606', (303, 308))	('reduced', 'NegReg', (174, 181))	('melanoma', 'Disease', 'MESH:D008545', (216, 224))	('lonidamine', 'Chemical', 'MESH:C016371', (129, 139))	('proliferation', 'CPA', (186, 199))	('glucose', 'Chemical', 'MESH:D005947', (76, 83))	('glycolysis pathway', 'Pathway', (18, 36))	('melanoma', 'Disease', 'MESH:D008545', (262, 270))	('Hexokinase', 'Gene', (141, 151))	('KMT2D mutant', 'Var', (203, 215))	('S4D', 'Mutation', 'p.S4D', (333, 336))	('pomhex', 'Chemical', '-', (97, 103))	('melanoma', 'Phenotype', 'HP:0002861', (216, 224))	('melanoma', 'Disease', (216, 224))	('mutant', 'Var', (209, 215))	('2-DG', 'Chemical', 'MESH:D003847', (70, 74))
17157	33086062	Consistent with the in vitro data, tumors formed by xenotransplantation of KMT2D mutant lines were more sensitive to 2-DG treatment in nude mice (Figures 4G and 4H).	('nude mice', 'Species', '10090', (135, 144))	('sensitive to 2-DG treatment', 'MPA', (104, 131))	('more', 'PosReg', (99, 103))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('KMT2D', 'Gene', (75, 80))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('tumors', 'Disease', (35, 41))	('tumors', 'Disease', 'MESH:D009369', (35, 41))	('mutant', 'Var', (81, 87))	('2-DG', 'Chemical', 'MESH:D003847', (117, 121))
17159	33086062	Together, these data suggest that upregulated glycolysis is an important contributor to enhanced tumorigenesis in KMT2D mutant melanomas and suggest a potential therapeutic strategy in this genetic context.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('glycolysis', 'MPA', (46, 56))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('melanomas', 'Disease', (127, 136))	('upregulated', 'PosReg', (34, 45))	('tumor', 'Disease', (97, 102))	('melanoma', 'Phenotype', 'HP:0002861', (127, 135))	('melanomas', 'Phenotype', 'HP:0002861', (127, 136))	('melanomas', 'Disease', 'MESH:D008545', (127, 136))	('enhanced', 'PosReg', (88, 96))	('mutant', 'Var', (120, 126))	('KMT2D', 'Gene', (114, 119))
17160	33086062	We examined total and genome-wide levels of H3K4 marks, as KMT2D is known to harbor histone methyltransferase activity toward multiple H3K4 methylation states and impacts H3K27ac patterns.	('histone methyltransferase', 'Gene', '56979', (84, 109))	('activity', 'MPA', (110, 118))	('H3K27ac', 'Protein', (171, 178))	('histone methyltransferase', 'Gene', (84, 109))	('KMT2D', 'Var', (59, 64))	('impacts', 'Reg', (163, 170))	('H3K4', 'Protein', (135, 139))
17161	33086062	KMT2D mutant murine cells harbored lower levels of total H3K4me1 and H3K27ac marks than those in WT cells (Figures 5A and S5A), and H3K4me1 levels were elevated upon KMT2D re-expression (Figure S5B).	('S5B', 'Gene', (194, 197))	('S5B', 'Gene', '66998', (194, 197))	('mutant', 'Var', (6, 12))	('elevated', 'PosReg', (152, 160))	('H3K4me1', 'Protein', (57, 64))	('murine', 'Species', '10090', (13, 19))	('lower', 'NegReg', (35, 40))	('KMT2D', 'Gene', (0, 5))	('H3K27ac', 'Protein', (69, 76))	('levels', 'MPA', (41, 47))	('H3K4me1 levels', 'MPA', (132, 146))
17162	33086062	Immunohistochemistry staining of a TCGA melanoma tumor TMA suggests that KMT2D expression levels correlate with those of H3K4me1, H3K27ac, and H3K4me3 (Figures 5B and S5C).	('KMT2D', 'Gene', (73, 78))	('H3K4me1', 'Protein', (121, 128))	('melanoma tumor TMA', 'Disease', 'MESH:D008545', (40, 58))	('expression levels', 'MPA', (79, 96))	('H3K27ac', 'Protein', (130, 137))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('H3K4me3', 'Var', (143, 150))	('melanoma', 'Phenotype', 'HP:0002861', (40, 48))	('melanoma tumor TMA', 'Disease', (40, 58))
17163	33086062	We also observed a significant loss of H3K4me1 but not H3K27Ac in KMT2D mutant Cancer Cell Line Encyclopedia (CCLE) pan-cancer cell lines (Figures 5C and S5D).	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('loss', 'NegReg', (31, 35))	('mutant', 'Var', (72, 78))	('H3K4me1', 'Protein', (39, 46))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('Cancer', 'Disease', (79, 85))	('Cancer', 'Phenotype', 'HP:0002664', (79, 85))	('Cancer', 'Disease', 'MESH:D009369', (79, 85))	('KMT2D', 'Gene', (66, 71))
17164	33086062	Consistently, mass-spectrometry-based quantitation of histone modifications in KMT2D mutant murine cells showed a modest loss of H3K4me1, H3K27ac, and H3K4me3 (Figure S5E).	('murine', 'Species', '10090', (92, 98))	('loss', 'NegReg', (121, 125))	('H3K4me1', 'Protein', (129, 136))	('mutant', 'Var', (85, 91))	('KMT2D', 'Gene', (79, 84))	('H3K27ac', 'Protein', (138, 145))	('H3K4me3', 'Protein', (151, 158))
17165	33086062	Next, we determined chromatin states in murine melanoma KMT2D mutant and WT tumors using chromatin immunoprecipitation sequencing (ChIP-seq) for the histone modifications H3K4Me1 (enhancers), H3K4Me3 (promoters), H3K27Ac (active), H3K79Me2 (transcription), and H3K27Me3 (polycomb-repressed), in line with studies from the NIH Roadmap project.	('mutant', 'Var', (62, 68))	('H3K27Me3', 'Var', (261, 269))	('H3K4Me1', 'Var', (171, 178))	('murine', 'Species', '10090', (40, 46))	('WT tumors', 'Disease', 'MESH:C536751', (73, 82))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('H3K27Ac', 'Var', (213, 220))	('melanoma', 'Phenotype', 'HP:0002861', (47, 55))	('WT tumors', 'Disease', (73, 82))	('melanoma', 'Disease', (47, 55))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('melanoma', 'Disease', 'MESH:D008545', (47, 55))	('H3K79Me2', 'Var', (231, 239))	('KMT2D', 'Gene', (56, 61))	('H3K4Me3', 'Var', (192, 199))
17167	33086062	H3K27me3 peaks also showed modest genome-wide enrichment (Figure S5H) that could be due to loss of function of H3K27me3-specific demethylase, KDM6A, which is known to be an obligate partner of KMT2D.	('KDM6A', 'Gene', (142, 147))	('H3K27me3', 'Var', (0, 8))	('KDM6A', 'Gene', '7403', (142, 147))	('H3K27me3-specific', 'Var', (111, 128))	('loss of function', 'NegReg', (91, 107))
17168	33086062	On the contrary, we did not notice much change in H3K79me2 and H3K4me3 enrichment between KMT2D WT and mutant tumors (Figures S5I and S5J).	('mutant', 'Var', (103, 109))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumors', 'Disease', (110, 116))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('tumors', 'Disease', 'MESH:D009369', (110, 116))
17172	33086062	Of the 7,555 active enhancer loci that display a loss of intensity in KMT2D mutant tumors compared with WT, 1,165 were located nearby (+-200 Kb) genes with decreased expression (Figure 6A).	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('mutant', 'Var', (76, 82))	('tumors', 'Disease', (83, 89))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('tumors', 'Disease', 'MESH:D009369', (83, 89))	('KMT2D', 'Gene', (70, 75))
17175	33086062	Indeed, we observed higher levels of pAKT (S473) and pIGF1R (Y1198) in KMT2D mutant murine and human lines (Figure 6B) as well as KMT2D mutant iBIP tumors (Figure 6C), suggesting aberrant activation of the IGF-AKT-glycolysis pathway.	('murine', 'Species', '10090', (84, 90))	('human', 'Species', '9606', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('iBIP tumors', 'Disease', (143, 154))	('IGF-AKT-glycolysis pathway', 'Pathway', (206, 232))	('higher', 'PosReg', (20, 26))	('iBIP tumors', 'Disease', 'MESH:D009369', (143, 154))	('S473', 'Var', (43, 47))	('mutant', 'Var', (77, 83))	('pAKT', 'MPA', (37, 41))	('KMT2D mutant', 'Var', (71, 83))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('activation', 'PosReg', (188, 198))	('pIGF1R', 'Gene', (53, 59))
17176	33086062	Examination of Reverse Protein Phase Array (RPPA) data from CCLE database across all cancer types showed that KMT2D mutant cell lines (harboring functional driver mutations) showed higher levels of pS473 and pT308 forms of AKT compared to KMT2D WT (and high expressing) lines (Figure 6D).	('KMT2D', 'Gene', (110, 115))	('pS473', 'Var', (198, 203))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('cancer', 'Disease', (85, 91))	('higher', 'PosReg', (181, 187))	('AKT', 'Enzyme', (223, 226))	('mutant', 'Var', (116, 122))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('pT308', 'Var', (208, 213))
17177	33086062	However, in contrast to observations in pancreatic cancer, we observed reduced levels of the phosphorylated form of mTOR (mammalian target of rapamycin) in KMT2D mutant versus WT cells in the CCLE database RPPA data (Figure S6D).	('levels', 'MPA', (79, 85))	('KMT2D mutant', 'Var', (156, 168))	('mammalian target of rapamycin', 'Gene', (122, 151))	('mammalian target of rapamycin', 'Gene', '2475', (122, 151))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('mutant', 'Var', (162, 168))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (40, 57))	('reduced', 'NegReg', (71, 78))	('mTOR', 'Gene', (116, 120))	('mTOR', 'Gene', '2475', (116, 120))	('pancreatic cancer', 'Disease', (40, 57))	('pancreatic cancer', 'Disease', 'MESH:D010190', (40, 57))
17178	33086062	The functional significance of activation of IGF1R signaling was further tested by the treatment of cells with an IGF-1R inhibitor (linsitinib), which reduced the expression of glycolysis genes in KMT2D mutant murine and human cell lines (Figures 6E and 6F).	('mutant', 'Var', (203, 209))	('IGF-1R', 'Gene', '3480', (114, 120))	('reduced', 'NegReg', (151, 158))	('linsitinib', 'Chemical', 'MESH:C551528', (132, 142))	('IGF-1R', 'Gene', (114, 120))	('glycolysis', 'MPA', (177, 187))	('human', 'Species', '9606', (221, 226))	('expression', 'MPA', (163, 173))	('murine', 'Species', '10090', (210, 216))
17179	33086062	Importantly, treatment of KMT2D mutant murine and human cell lines with linsitinib preferentially reduced the proliferation of KMT2D mutant cell lines both in vitro (Figure 6G) and in vivo (Figures 6H and 6I).	('murine', 'Species', '10090', (39, 45))	('proliferation', 'CPA', (110, 123))	('human', 'Species', '9606', (50, 55))	('KMT2D', 'Gene', (127, 132))	('reduced', 'NegReg', (98, 105))	('mutant', 'Var', (133, 139))	('linsitinib', 'Chemical', 'MESH:C551528', (72, 82))
17181	33086062	Cells harboring KMT2D functional driver mutations displayed significantly lower IC50 (half maximal inhibitory concentration) values for linsitinib treatment than for cells that harbor high levels of KMT2D (and have WT protein) (Figure 6J).	('linsitinib', 'Chemical', 'MESH:C551528', (136, 146))	('lower', 'NegReg', (74, 79))	('linsitinib treatment', 'MPA', (136, 156))	('mutations', 'Var', (40, 49))
17184	33086062	We next searched for putative regulators of the IGF signaling that lose active enhancers and gene expression in KMT2D mutants specifically to identify those that may be responsible for the metabolic reprogramming phenotypes observed in KMT2D-deficient tumors.	('lose', 'NegReg', (67, 71))	('mutants', 'Var', (118, 125))	('KMT2D', 'Gene', (112, 117))	('deficient tumors', 'Disease', (242, 258))	('active enhancers', 'MPA', (72, 88))	('deficient tumors', 'Disease', 'MESH:D009369', (242, 258))	('tumor', 'Phenotype', 'HP:0002664', (252, 257))	('tumors', 'Phenotype', 'HP:0002664', (252, 258))	('gene expression', 'MPA', (93, 108))
17186	33086062	We found the loss of H3K4me1 signals on proximal and distal enhancers were associated with IGFBP5 in KMT2D mutant tissues (Figure 7A), whereas other IGFBPs did not show a significant change (Figure S7A).	('mutant', 'Var', (107, 113))	('IGFBP5', 'Gene', (91, 97))	('H3K4me1', 'Protein', (21, 28))	('loss', 'NegReg', (13, 17))	('IGFBPs', 'Gene', (149, 155))	('IGFBPs', 'Gene', '3488;16011', (149, 155))
17188	33086062	Consistently, IGFBP5 expression was also lost in KMT2D mutant murine and human cell lines (Figure 7C), whereas several other IGFBPs showed inconsistent patterns (Figure S7B).	('IGFBP5', 'Gene', (14, 20))	('lost', 'NegReg', (41, 45))	('IGFBPs', 'Gene', (125, 131))	('mutant', 'Var', (55, 61))	('expression', 'MPA', (21, 31))	('human', 'Species', '9606', (73, 78))	('IGFBPs', 'Gene', '3488;16011', (125, 131))	('murine', 'Species', '10090', (62, 68))	('KMT2D', 'Gene', (49, 54))
17189	33086062	Consistently, IGFBP5 expression was significantly reduced in KMT2D mutant human and murine melanoma tumors (Figures 7D, S7C, and S7D).	('murine', 'Species', '10090', (84, 90))	('S7C', 'Mutation', 'p.S7C', (120, 123))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('melanoma', 'Phenotype', 'HP:0002861', (91, 99))	('KMT2D', 'Gene', (61, 66))	('expression', 'MPA', (21, 31))	('melanoma tumors', 'Disease', (91, 106))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('melanoma tumors', 'Disease', 'MESH:D008545', (91, 106))	('mutant', 'Var', (67, 73))	('reduced', 'NegReg', (50, 57))	('human', 'Species', '9606', (74, 79))	('S7D', 'Mutation', 'p.S7D', (129, 132))	('IGFBP5', 'Gene', (14, 20))
17192	33086062	However, we did not find any difference in Per2 expression in KMT2D WT versus mutant murine or human melanoma tumors (Figures S7C and S7D).	('human', 'Species', '9606', (95, 100))	('S7C', 'Mutation', 'p.S7C', (126, 129))	('melanoma', 'Phenotype', 'HP:0002861', (101, 109))	('murine', 'Species', '10090', (85, 91))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('melanoma tumors', 'Disease', (101, 116))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('melanoma tumors', 'Disease', 'MESH:D008545', (101, 116))	('KMT2D', 'Var', (62, 67))	('S7D', 'Mutation', 'p.S7D', (134, 137))	('Per2', 'Gene', (43, 47))
17193	33086062	We also did not observe any change in TSC1 expression in KMT2D mutant versus WT cell lines (Figure S7C).	('mutant', 'Var', (63, 69))	('KMT2D', 'Var', (57, 62))	('TSC1', 'Gene', '7248', (38, 42))	('S7C', 'Mutation', 'p.S7C', (99, 102))	('TSC1', 'Gene', (38, 42))
17195	33086062	Importantly, epistasis experiments revealed that IGFBP5 overexpression in murine melanoma cells decreased levels of IGF1R and AKT phosphorylation (Figure 7E) as well as glycolysis genes (Figures 7F and 7G) in KMT2D mutant murine and human cells compared with their WT counterparts.	('human', 'Species', '9606', (233, 238))	('murine', 'Species', '10090', (222, 228))	('melanoma', 'Disease', 'MESH:D008545', (81, 89))	('decreased', 'NegReg', (96, 105))	('murine', 'Species', '10090', (74, 80))	('melanoma', 'Phenotype', 'HP:0002861', (81, 89))	('melanoma', 'Disease', (81, 89))	('AKT', 'Pathway', (126, 129))	('overexpression', 'PosReg', (56, 70))	('glycolysis genes', 'Gene', (169, 185))	('mutant', 'Var', (215, 221))	('levels', 'MPA', (106, 112))	('IGFBP5', 'Gene', (49, 55))	('IGF1R', 'MPA', (116, 121))
17196	33086062	Taken together, the data presented in this manuscript establish a model of KMT2D function in cancer for which KMT2D acts as a tumor suppressor by enhancer reprogramming on tumor suppressor genes, such as IGFBP5, that regulate key pathways, such as IGF1R signaling, leading to metabolic rewiring (Figure 7H).	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('KMT2D', 'Var', (110, 115))	('tumor', 'Disease', (172, 177))	('enhancer', 'PosReg', (146, 154))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('metabolic rewiring', 'MPA', (276, 294))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('IGFBP5', 'Gene', (204, 210))	('tumor', 'Disease', (126, 131))
17201	33086062	As the strongest phenotypes were observed for KMT2D, we deeply studied its mechanism of action in melanoma.	('melanoma', 'Disease', (98, 106))	('melanoma', 'Disease', 'MESH:D008545', (98, 106))	('melanoma', 'Phenotype', 'HP:0002861', (98, 106))	('KMT2D', 'Var', (46, 51))
17202	33086062	Although the somatic loss-of-function mutations in KMT2D are observed across many malignancies, it is unclear why these mutations are selected over the course of tumor evolution.	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('loss-of-function', 'NegReg', (21, 37))	('malignancies', 'Disease', (82, 94))	('tumor', 'Disease', (162, 167))	('mutations', 'Var', (38, 47))	('KMT2D', 'Gene', (51, 56))	('malignancies', 'Disease', 'MESH:D009369', (82, 94))
17204	33086062	We observed drastic deregulation of multiple metabolic pathways in KMT2D mutant melanomas in both human and murine systems.	('melanomas', 'Phenotype', 'HP:0002861', (80, 89))	('melanomas', 'Disease', 'MESH:D008545', (80, 89))	('melanoma', 'Phenotype', 'HP:0002861', (80, 88))	('KMT2D', 'Gene', (67, 72))	('deregulation', 'Reg', (20, 32))	('mutant', 'Var', (73, 79))	('melanomas', 'Disease', (80, 89))	('human', 'Species', '9606', (98, 103))	('murine', 'Species', '10090', (108, 114))
17207	33086062	Increased pyruvate production due to high glycolysis provides a substrate for the OxPhos pathway (to generate 36 ATPs), which is also upregulated in the KMT2D mutant cells, thereby leading to enhanced ATP production.	('pyruvate production', 'MPA', (10, 29))	('ATPs', 'Chemical', 'MESH:D000255', (113, 117))	('ATP', 'Chemical', 'MESH:D000255', (113, 116))	('enhanced', 'PosReg', (192, 200))	('mutant', 'Var', (159, 165))	('upregulated', 'PosReg', (134, 145))	('KMT2D mutant', 'Var', (153, 165))	('pyruvate', 'Chemical', 'MESH:D019289', (10, 18))	('ATP production', 'MPA', (201, 215))	('Increased', 'PosReg', (0, 9))	('glycolysis', 'MPA', (42, 52))	('Increased pyruvate', 'Phenotype', 'HP:0003542', (0, 18))	('ATP', 'Chemical', 'MESH:D000255', (201, 204))	('OxPhos', 'Enzyme', (82, 88))
17209	33086062	Therefore, upregulated glycolysis in KMT2D mutant cells contributes to several different biomass and energy needs to enhance tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('KMT2D', 'Gene', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('enhance', 'PosReg', (117, 124))	('upregulated', 'PosReg', (11, 22))	('tumor', 'Disease', (125, 130))	('glycolysis', 'MPA', (23, 33))	('mutant', 'Var', (43, 49))
17210	33086062	Data shown here along with our recent data in lung cancer show the dependence of KMT2D mutant cancers on glycolysis and, critically, will inform future clinical studies testing potent glycolysis-blocking inhibitors in this genetic context.	('cancers', 'Disease', 'MESH:D009369', (94, 101))	('glycolysis', 'MPA', (105, 115))	('KMT2D', 'Gene', (81, 86))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('dependence', 'Reg', (67, 77))	('lung cancer', 'Disease', 'MESH:D008175', (46, 57))	('mutant', 'Var', (87, 93))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('cancers', 'Phenotype', 'HP:0002664', (94, 101))	('lung cancer', 'Disease', (46, 57))	('cancers', 'Disease', (94, 101))	('lung cancer', 'Phenotype', 'HP:0100526', (46, 57))
17211	33086062	Our data also suggest the potential use of IGF receptor blocking molecules, such as linsitinib, which is being tested in clinical trials, in the KMT2D mutant patient population.	('KMT2D', 'Gene', (145, 150))	('mutant', 'Var', (151, 157))	('linsitinib', 'Chemical', 'MESH:C551528', (84, 94))	('patient', 'Species', '9606', (158, 165))	('IGF receptor', 'Protein', (43, 55))
17212	33086062	Therefore, some of the observed somatic mutations may be passenger events, especially in cancers with a high mutation burden, such as melanoma and lung cancers.	('lung cancers', 'Disease', (147, 159))	('cancers', 'Disease', (152, 159))	('cancers', 'Disease', 'MESH:D009369', (152, 159))	('cancers', 'Phenotype', 'HP:0002664', (89, 96))	('lung cancers', 'Disease', 'MESH:D008175', (147, 159))	('cancers', 'Disease', 'MESH:D009369', (89, 96))	('lung cancer', 'Phenotype', 'HP:0100526', (147, 158))	('mutations', 'Var', (40, 49))	('melanoma', 'Phenotype', 'HP:0002861', (134, 142))	('cancers', 'Disease', (89, 96))	('melanoma', 'Disease', (134, 142))	('lung cancers', 'Phenotype', 'HP:0100526', (147, 159))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('melanoma', 'Disease', 'MESH:D008545', (134, 142))	('cancers', 'Phenotype', 'HP:0002664', (152, 159))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
17214	33086062	Although we show an important role for glycolysis, many other metabolic pathways, such as oxidative phosphorylation and fatty acid metabolism, are also highly upregulated in KMT2D mutant cancers.	('cancers', 'Disease', 'MESH:D009369', (187, 194))	('metabolic pathways', 'MPA', (62, 80))	('cancers', 'Phenotype', 'HP:0002664', (187, 194))	('cancers', 'Disease', (187, 194))	('fatty acid metabolism', 'MPA', (120, 141))	('oxidative phosphorylation', 'MPA', (90, 115))	('glycolysis', 'MPA', (39, 49))	('mutant', 'Var', (180, 186))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('KMT2D', 'Gene', (174, 179))	('upregulated', 'PosReg', (159, 170))	('fatty acid', 'Chemical', 'MESH:D005227', (120, 130))
17215	33086062	The publicly available CRISPR screening platform Achilles suggests a dependency of KMT2D mutant melanomas on specific genes in these other metabolic pathways that need further exploration.	('melanomas', 'Disease', 'MESH:D008545', (96, 105))	('melanomas', 'Phenotype', 'HP:0002861', (96, 105))	('melanomas', 'Disease', (96, 105))	('KMT2D', 'Gene', (83, 88))	('melanoma', 'Phenotype', 'HP:0002861', (96, 104))	('mutant', 'Var', (89, 95))
17219	33086062	Because it appears that the extent of H3K4me1 loss is more than H3K27ac loss at the global level, it is possible that in a subset of enhancers other histone acetylations (than H3K27ac) may be involved in enhancer activation in KMT2D mutant melanomas.	('mutant', 'Var', (233, 239))	('loss', 'NegReg', (46, 50))	('melanomas', 'Disease', (240, 249))	('melanoma', 'Phenotype', 'HP:0002861', (240, 248))	('KMT2D', 'Gene', (227, 232))	('melanomas', 'Disease', 'MESH:D008545', (240, 249))	('melanomas', 'Phenotype', 'HP:0002861', (240, 249))	('H3K4me1', 'Protein', (38, 45))
17220	33086062	Our previous study also showed drastic losses of chromatin states harboring multiple different histone acetylations, including H2BK5ac and H4K5ac, and H3K4me1/2/3 in early stages of tumorigenic transition in melanoma.	('chromatin states', 'MPA', (49, 65))	('tumor', 'Disease', (182, 187))	('losses', 'NegReg', (39, 45))	('melanoma', 'Phenotype', 'HP:0002861', (208, 216))	('melanoma', 'Disease', (208, 216))	('H4K5ac', 'Var', (139, 145))	('melanoma', 'Disease', 'MESH:D008545', (208, 216))	('H3K4me1/2/3', 'Var', (151, 162))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))	('H2BK5ac', 'Var', (127, 134))
17222	33086062	Because enhancers are shown to be cell type specific, KMT2D-loss-mediated enhancer misregulation could be responsible for different downstream mechanisms upon KMT2D deficiency in different cancer types (such as Per2 in lung cancer, IGFBP5 in melanoma, or SLC2A3 and TSC1 in pancreatic cancer).	('deficiency in different cancer', 'Disease', (165, 195))	('TSC1', 'Gene', (266, 270))	('melanoma', 'Disease', 'MESH:D008545', (242, 250))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (274, 291))	('SLC2A3', 'Gene', (255, 261))	('deficiency in different cancer', 'Disease', 'MESH:D009369', (165, 195))	('TSC1', 'Gene', '7248', (266, 270))	('KMT2D', 'Gene', (159, 164))	('misregulation', 'Var', (83, 96))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('lung cancer', 'Disease', (219, 230))	('SLC2A3', 'Gene', '6515', (255, 261))	('pancreatic cancer', 'Disease', 'MESH:D010190', (274, 291))	('melanoma', 'Phenotype', 'HP:0002861', (242, 250))	('IGFBP5', 'Gene', (232, 238))	('melanoma', 'Disease', (242, 250))	('cancer', 'Phenotype', 'HP:0002664', (285, 291))	('responsible', 'Reg', (106, 117))	('enhancer', 'PosReg', (74, 82))	('lung cancer', 'Disease', 'MESH:D008175', (219, 230))	('pancreatic cancer', 'Disease', (274, 291))	('lung cancer', 'Phenotype', 'HP:0100526', (219, 230))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))
17223	33086062	We noted that KMT2D mutant cells grew slower than WT cells in vitro; however, they proliferated faster in vivo and formed aggressive tumors.	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('proliferated', 'CPA', (83, 95))	('faster', 'PosReg', (96, 102))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('aggressive tumors', 'Disease', 'MESH:D001523', (122, 139))	('KMT2D', 'Gene', (14, 19))	('aggressive tumors', 'Disease', (122, 139))	('mutant', 'Var', (20, 26))
17224	33086062	There may be several reasons for why KMT2D mutant cells did not grow faster than WT cells in vitro; however, they formed aggressive tumors in vivo.	('formed', 'Reg', (114, 120))	('aggressive tumors', 'Disease', (121, 138))	('KMT2D', 'Var', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('mutant', 'Var', (43, 49))	('aggressive tumors', 'Disease', 'MESH:D001523', (121, 138))
17225	33086062	First, due to the rapid consumption of glucose because of their faster metabolism (Figures S4A and S4B), KMT2D mutant cells likely slow once nutrients are exhausted from the media.	('slow', 'NegReg', (131, 135))	('mutant', 'Var', (111, 117))	('KMT2D', 'Gene', (105, 110))	('metabolism', 'MPA', (71, 81))	('glucose', 'Chemical', 'MESH:D005947', (39, 46))	('faster', 'PosReg', (64, 70))
17227	33086062	Second, other factors in the tumor microenvironment (which are lacking in the in vitro culture conditions) may play important roles in supporting the growth of KMT2D mutant cells.	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('KMT2D', 'Gene', (160, 165))	('growth', 'MPA', (150, 156))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('mutant', 'Var', (166, 172))	('tumor', 'Disease', (29, 34))	('supporting', 'PosReg', (135, 145))
17229	33086062	Other events, such as hypoxia, that occur more prominently under in vivo conditions, may also play important roles in promoting the growth of KMT2D mutant cells.	('KMT2D', 'Gene', (142, 147))	('hypoxia', 'Disease', 'MESH:D000860', (22, 29))	('hypoxia', 'Disease', (22, 29))	('promoting', 'PosReg', (118, 127))	('mutant', 'Var', (148, 154))	('growth', 'MPA', (132, 138))
17230	33086062	Indeed, HIF1alpha expression was modestly higher (1.5- to 2-fold) in KMT2D mutant cells compared with WT cells.	('HIF1alpha', 'Gene', '3091', (8, 17))	('higher', 'PosReg', (42, 48))	('expression', 'MPA', (18, 28))	('mutant', 'Var', (75, 81))	('KMT2D', 'Gene', (69, 74))	('HIF1alpha', 'Gene', (8, 17))
17233	33086062	Overall, our study provides evidence for the dependency of the KMT2D mutant melanomas on glycolysis and the IGF pathway by enhancer reprogramming.	('melanomas', 'Phenotype', 'HP:0002861', (76, 85))	('melanomas', 'Disease', 'MESH:D008545', (76, 85))	('mutant', 'Var', (69, 75))	('dependency', 'Reg', (45, 55))	('glycolysis', 'MPA', (89, 99))	('IGF pathway', 'Pathway', (108, 119))	('melanomas', 'Disease', (76, 85))	('enhancer', 'PosReg', (123, 131))	('KMT2D', 'Gene', (63, 68))	('melanoma', 'Phenotype', 'HP:0002861', (76, 84))
17234	33086062	These results suggest a potential therapeutic strategy in the patients with melanoma harboring mutations in this epigenetic regulator.	('melanoma', 'Disease', (76, 84))	('melanoma', 'Disease', 'MESH:D008545', (76, 84))	('mutations', 'Var', (95, 104))	('patients', 'Species', '9606', (62, 70))	('melanoma', 'Phenotype', 'HP:0002861', (76, 84))
17238	33086062	KMT2Dfl/fl mutant mice were crossed with iBIP mice (iBIP = Tyr-CreERT2, Rosa26-rtta, TetO-BRAFV600E, PTENL/L, INK/ARFL/L; mixed genetic background of FVB and B6) to generate iBIP;KMT2DL/+ genotype containing mice.	('mutant', 'Var', (11, 17))	('Rosa26', 'Gene', (72, 78))	('ARFL', 'Disease', (114, 118))	('PTEN', 'Gene', (101, 105))	('PTEN', 'Gene', '5728', (101, 105))	('mice', 'Species', '10090', (18, 22))	('BRAFV600E', 'Mutation', 'rs113488022', (90, 99))	('mice', 'Species', '10090', (46, 50))	('Rosa26', 'Gene', '14910', (72, 78))	('mice', 'Species', '10090', (208, 212))	('ARFL', 'Disease', 'None', (114, 118))
17270	33086062	KMT2D mutant mice were crossed with iBIP mice (iBIP = Tyr-CreERT2, Rosa26-rtta, TetO-BRAFV600E, PTENL/L, INK/ARFL/L; mixed genetic background of FVB and B6) to generate iBIP;KMT2DL/+ genotype containing mice (as assessed by genotyping for all alleles).	('PTEN', 'Gene', '5728', (96, 100))	('mice', 'Species', '10090', (13, 17))	('mutant', 'Var', (6, 12))	('Rosa26', 'Gene', '14910', (67, 73))	('ARFL', 'Disease', (109, 113))	('mice', 'Species', '10090', (41, 45))	('mice', 'Species', '10090', (203, 207))	('Rosa26', 'Gene', (67, 73))	('BRAFV600E', 'Mutation', 'rs113488022', (85, 94))	('PTEN', 'Gene', (96, 100))	('ARFL', 'Disease', 'None', (109, 113))
17277	33086062	Chromatin state models were learnt jointly on all data for all five histone marks (H3K4me1, H3K4me3, H3K27ac, H3K79me2 and H3K27me3) from WT-m1 and Mut-m2 tumor cells and a model with 10 states was chosen for detailed analysis.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('H3K4me1', 'Var', (83, 90))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('H3K4me3', 'Var', (92, 99))	('tumor', 'Disease', (155, 160))	('H3K27me3', 'Var', (123, 131))	('H3K27ac', 'Var', (101, 108))	('H3K79me2', 'Var', (110, 118))
17281	33086062	Ten SKCM primary tumor samples with wild-type copies of KMT2D and expressing high levels and 10 SKCM primary tumor samples with mutant KMT2D (see supplemental data for samples included in the analysis) were compared using DESeq2, the signed fold change *-log10(pvalue) metric was used to pre-rank the gene list and for GSEA pre-rank analysis.	('GSEA', 'Chemical', '-', (319, 323))	('tumor', 'Disease', (17, 22))	('mutant', 'Var', (128, 134))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('KMT2D', 'Gene', (56, 61))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('tumor', 'Disease', (109, 114))
17282	33086062	For the pan cancer analysis, TCGA tumor samples were grouped based on KMT2D gene expression and mutation status: KMT2D mutation free group are samples with high KMT2D expression (among the top quantile) and no somatic mutation; KMT2D mutated group are samples with low KMT2D expression (falling into the bottom quantile) and have either nonsense mutations or missense mutations with the amino acid 4,700.	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('tumor', 'Disease', (34, 39))	('cancer', 'Disease', (12, 18))	('nonsense mutations', 'Var', (337, 355))	('missense mutations', 'Var', (359, 377))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('falling', 'Phenotype', 'HP:0002527', (287, 294))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
17306	33086062	Buffer A was 20 mM NH4OH/20 mM CH3COONH4 (pH = 9.0) in 95:5 water/ACN.	('CH3COONH4', 'Var', (31, 40))	('ACN', 'Chemical', 'MESH:C084683', (66, 69))	('NH4OH', 'Chemical', '-', (19, 24))	('water', 'Chemical', 'MESH:D014867', (60, 65))	('NH4OH/20', 'Var', (19, 27))	('CH3COONH4', 'Chemical', '-', (31, 40))
17313	33086062	TMA was stained with KMT2D (Sigma), H3K4me1 (Abcam ab8895), H3K27ac (Abcam ab4729), H3K4me3 (Abcam ab8580), antibodies.	('H3K4me3', 'Protein', (84, 91))	('H3K4me1', 'Protein', (36, 43))	('D (Sigma)', 'Species', '682535', (25, 34))	('H3K27ac', 'Var', (60, 67))
17332	32794417	Protein p16 expression highly correlates with the presence of HPV16 in oropharyngeal squamous cell carcinoma (OPSCC), and patients with HPV-positive OPSCC exhibit better survival compared with their virus-negative counterparts.	('a', 'Gene', '351', (183, 184))	('better', 'PosReg', (163, 169))	('a', 'Gene', '351', (222, 223))	('SCC', 'Phenotype', 'HP:0002860', (112, 115))	('SCC', 'Phenotype', 'HP:0002860', (151, 154))	('a', 'Gene', '351', (118, 119))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (85, 108))	('p16', 'Gene', (8, 11))	('HPV16', 'Var', (62, 67))	('p16', 'Gene', '1029', (8, 11))	('oropharyngeal squamous cell carcinoma', 'Phenotype', 'HP:0012182', (71, 108))	('a', 'Gene', '351', (107, 108))	('a', 'Gene', '351', (100, 101))	('a', 'Gene', '351', (76, 77))	('patients', 'Species', '9606', (122, 130))	('a', 'Gene', '351', (82, 83))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (85, 108))	('a', 'Gene', '351', (36, 37))	('HPV', 'Species', '10566', (136, 139))	('HPV', 'Species', '10566', (62, 65))	('a', 'Gene', '351', (123, 124))	('OPSCC', 'Phenotype', 'HP:0012182', (149, 154))	('OPSCC', 'Phenotype', 'HP:0012182', (110, 115))	('a', 'Gene', '351', (176, 177))	('presence', 'Var', (50, 58))	('a', 'Gene', '351', (208, 209))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('a', 'Gene', '351', (88, 89))	('HPV16', 'Species', '333760', (62, 67))	('expression', 'MPA', (12, 22))	('squamous cell carcinoma', 'Disease', (85, 108))
17414	32794417	have suggested that vimentin may act as a binding protein for HPV16 pseudovirion and modulate the internalization of HPV16 pseudovirion in cervix carcinoma cell lines; with the results being adverse compared with ours, both HPV-positive and HPV-negative tumor cells were negative for vimentin expression, and we found no relation between stromal vimentin expression and HPV status.	('a', 'Gene', '351', (343, 344))	('a', 'Gene', '351', (17, 18))	('HPV', 'Species', '10566', (117, 120))	('a', 'Gene', '351', (104, 105))	('a', 'Gene', '351', (191, 192))	('a', 'Gene', '351', (40, 41))	('cervix carcinoma', 'Phenotype', 'HP:0030079', (139, 155))	('HPV', 'Species', '10566', (241, 244))	('HPV', 'Species', '10566', (370, 373))	('a', 'Gene', '351', (237, 238))	('a', 'Gene', '351', (324, 325))	('a', 'Gene', '351', (37, 38))	('HPV16', 'Var', (117, 122))	('cervix carcinoma', 'Disease', (139, 155))	('a', 'Gene', '351', (203, 204))	('a', 'Gene', '351', (30, 31))	('tumor', 'Disease', (254, 259))	('HPV', 'Species', '10566', (224, 227))	('a', 'Gene', '351', (376, 377))	('a', 'Gene', '351', (108, 109))	('tumor', 'Disease', 'MESH:D009369', (254, 259))	('a', 'Gene', '351', (154, 155))	('a', 'Gene', '351', (274, 275))	('a', 'Gene', '351', (305, 306))	('HPV', 'Species', '10566', (62, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('a', 'Gene', '351', (147, 148))	('a', 'Gene', '351', (248, 249))	('a', 'Gene', '351', (90, 91))	('a', 'Gene', '351', (1, 2))	('cervix carcinoma', 'Disease', 'MESH:D002583', (139, 155))	('a', 'Gene', '351', (33, 34))	('HPV16', 'Species', '333760', (117, 122))	('HPV16', 'Species', '333760', (62, 67))	('a', 'Gene', '351', (81, 82))	('a', 'Gene', '351', (366, 367))	('tumor', 'Phenotype', 'HP:0002664', (254, 259))
17417	32794417	In addition, we found an association between the high expression of beta-catenin and the presence of regional lymph node metastasis, a relationship that has been earlier identified in breast cancer too.	('a', 'Gene', '351', (25, 26))	('a', 'Gene', '351', (192, 193))	('a', 'Gene', '351', (71, 72))	('a', 'Gene', '351', (150, 151))	('a', 'Gene', '351', (127, 128))	('a', 'Gene', '351', (31, 32))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('a', 'Gene', '351', (22, 23))	('a', 'Gene', '351', (133, 134))	('a', 'Gene', '351', (107, 108))	('a', 'Gene', '351', (138, 139))	('a', 'Gene', '351', (163, 164))	('a', 'Gene', '351', (124, 125))	('a', 'Gene', '351', (187, 188))	('a', 'Gene', '351', (74, 75))	('a', 'Gene', '351', (154, 155))	('breast cancer', 'Phenotype', 'HP:0003002', (184, 197))	('a', 'Gene', '351', (3, 4))	('breast cancer', 'Disease', 'MESH:D001943', (184, 197))	('high', 'Var', (49, 53))	('breast cancer', 'Disease', (184, 197))	('a', 'Gene', '351', (81, 82))
17421	32794417	Thus, the high expression of beta-catenin may hinder the cell-to-cell adhesion function of E-cadherin, increasing the risk of invasion and metastases, although we found no significant relationship between E-cadherin expression and metastasis.	('a', 'Gene', '351', (129, 130))	('a', 'Gene', '351', (142, 143))	('metastases', 'Disease', (139, 149))	('a', 'Gene', '351', (135, 136))	('a', 'Gene', '351', (32, 33))	('a', 'Gene', '351', (70, 71))	('a', 'Gene', '351', (237, 238))	('a', 'Gene', '351', (151, 152))	('a', 'Gene', '351', (180, 181))	('a', 'Gene', '351', (94, 95))	('expression', 'MPA', (15, 25))	('a', 'Gene', '351', (234, 235))	('a', 'Gene', '351', (227, 228))	('a', 'Gene', '351', (108, 109))	('a', 'Gene', '351', (187, 188))	('a', 'Gene', '351', (43, 44))	('a', 'Gene', '351', (35, 36))	('a', 'Gene', '351', (145, 146))	('a', 'Gene', '351', (208, 209))	('metastases', 'Disease', 'MESH:D009362', (139, 149))	('high', 'Var', (10, 14))	('hinder', 'NegReg', (46, 52))
17445	27329590	In vitro, TERF2 knockdown by RNA interference had no effect on cell proliferation, migration, senescence and apoptosis.	('senescence', 'CPA', (94, 104))	('RNA interference', 'MPA', (29, 45))	('rat', 'Species', '10116', (75, 78))	('apoptosis', 'CPA', (109, 118))	('knockdown', 'Var', (16, 25))	('cell proliferation', 'CPA', (63, 81))	('TERF2', 'Gene', (10, 15))	('rat', 'Species', '10116', (86, 89))	('migration', 'CPA', (83, 92))
17446	27329590	Instead, TERF2 knockdown increased the expression of cytokines implicated in inflammation and angiogenesis, except for vascular endothelial growth factor.	('expression of cytokines', 'MPA', (39, 62))	('TERF2', 'Gene', (9, 14))	('increased', 'PosReg', (25, 34))	('knockdown', 'Var', (15, 24))	('vascular endothelial growth factor', 'Gene', (119, 153))	('inflammation', 'Disease', 'MESH:D007249', (77, 89))	('vascular endothelial growth factor', 'Gene', '7422', (119, 153))	('inflammation', 'Disease', (77, 89))
17447	27329590	TERF2 knockdown resulted in a decrease vascularization and growth of xenograft tumors.	('xenograft tumors', 'Disease', 'MESH:D009369', (69, 85))	('decrease', 'NegReg', (30, 38))	('TERF2', 'Gene', (0, 5))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('xenograft tumors', 'Disease', (69, 85))	('knockdown', 'Var', (6, 15))	('vascularization', 'CPA', (39, 54))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
17448	27329590	Finally, response to erlotinib/Tarceva and cetuximab/Erbitux treatment was increased in TRF2 knocked-down cells.	('men', 'Species', '9606', (66, 69))	('Tarceva', 'Chemical', 'MESH:D000069347', (31, 38))	('response', 'MPA', (9, 17))	('Erbitux', 'Chemical', 'MESH:D000068818', (53, 60))	('increased', 'PosReg', (75, 84))	('cetuximab', 'Chemical', 'MESH:D000068818', (43, 52))	('TRF2', 'Gene', '7014', (88, 92))	('TRF2', 'Gene', (88, 92))	('knocked-down', 'Var', (93, 105))	('erlotinib', 'Chemical', 'MESH:D000069347', (21, 30))
17454	27329590	In contrast, over-expression of TERF2 in the skin is associated with increased tumorigenesis.	('increased', 'PosReg', (69, 78))	('tumor', 'Disease', (79, 84))	('TERF2', 'Gene', (32, 37))	('over-expression', 'Var', (13, 28))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
17473	27329590	The above results suggest that the adverse effects linked to high expression of TERF2 on patients' survival may not depend on the intrinsic properties of the tumor cells.	('TERF2', 'Gene', (80, 85))	('high expression', 'Var', (61, 76))	('tumor', 'Disease', (158, 163))	('patients', 'Species', '9606', (89, 97))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))
17475	27329590	Therefore, we measured the cytokine levels in the supernatants of CAL33 cells with or without TERF2 knock-down (Supplementary Figure S3).	('TERF2', 'Gene', (94, 99))	('cytokine levels', 'MPA', (27, 42))	('knock-down', 'Var', (100, 110))	('men', 'Species', '9606', (118, 121))
17476	27329590	TERF2 knock-down in CAL33 resulted in the induction of CXCL1, CXCL8, CXCL9, CXCL10, interleukin 6 (IL6), PDGF-BB and RANTES and a decrease in VEGF expression (Table 2).	('IL6', 'Gene', (99, 102))	('CXCL9', 'Gene', (69, 74))	('induction', 'PosReg', (42, 51))	('CXCL1', 'Gene', '2919', (55, 60))	('PDGF-BB', 'MPA', (105, 112))	('CXCL1', 'Gene', (55, 60))	('CXCL10', 'Gene', (76, 82))	('CXCL9', 'Gene', '4283', (69, 74))	('CXCL8', 'Gene', '3576', (62, 67))	('knock-down', 'Var', (6, 16))	('TERF2', 'Gene', (0, 5))	('CXCL8', 'Gene', (62, 67))	('CXCL1', 'Gene', '2919', (76, 81))	('CXCL1', 'Gene', (76, 81))	('interleukin 6', 'Gene', (84, 97))	('decrease', 'NegReg', (130, 138))	('RANTES', 'Gene', (117, 123))	('VEGF', 'Gene', '7422', (142, 146))	('RANTES', 'Gene', '6352', (117, 123))	('IL6', 'Gene', '3569', (99, 102))	('VEGF', 'Gene', (142, 146))	('interleukin 6', 'Gene', '3569', (84, 97))	('CXCL10', 'Gene', '3627', (76, 82))
17480	27329590	Tumors with TERF2 knock-down were smaller (Figure 4A and 4B).	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('TERF2', 'Gene', (12, 17))	('smaller', 'NegReg', (34, 41))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('knock-down', 'Var', (18, 28))
17481	27329590	The smallest tumors were associated with the highest TERF2 knock-down (sh2 group) (Figure 4A, 4C and 4D).	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('smallest tumors', 'Disease', (4, 19))	('TERF2', 'Gene', (53, 58))	('sh2', 'Gene', '100125854', (71, 74))	('knock-down', 'Var', (59, 69))	('smallest tumors', 'Disease', 'MESH:D009369', (4, 19))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('sh2', 'Gene', (71, 74))
17484	27329590	Moreover, inflammatory and red blood cell extravasation was observed around vessels in TERF2 knocked-down tumors, suggesting the presence of acute inflammation and a disorganized vascular network (Figure 5C and 5H).	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('tumors', 'Disease', (106, 112))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('observed', 'Reg', (60, 68))	('inflammation', 'Disease', 'MESH:D007249', (147, 159))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('inflammation', 'Disease', (147, 159))	('knocked-down', 'Var', (93, 105))	('TERF2', 'Gene', (87, 92))
17492	27329590	We hypothesized that TERF2 expression may influence the response to inhibitors of EGFR erlotinib/Tarceva and cetuximab/Erbitux.	('EGFR', 'Gene', (82, 86))	('TERF2', 'Gene', (21, 26))	('Erbitux', 'Chemical', 'MESH:D000068818', (119, 126))	('cetuximab', 'Chemical', 'MESH:D000068818', (109, 118))	('Tarceva', 'Chemical', 'MESH:D000069347', (97, 104))	('influence', 'Reg', (42, 51))	('expression', 'Var', (27, 37))	('EGFR', 'Gene', '1956', (82, 86))	('erlotinib', 'Chemical', 'MESH:D000069347', (87, 96))	('response to inhibitors', 'MPA', (56, 78))
17494	27329590	The knock-down of TERF2 had no influence on the efficacy of radiotherapy or 5-Fluorouracil treatment (Supplementary Figure S6A and S6B).	('men', 'Species', '9606', (96, 99))	('men', 'Species', '9606', (108, 111))	('5-Fluorouracil', 'Chemical', 'MESH:D005472', (76, 90))	('knock-down', 'Var', (4, 14))	('radiotherapy', 'CPA', (60, 72))	('5-Fluorouracil treatment', 'MPA', (76, 100))	('TERF2', 'Gene', (18, 23))
17496	27329590	MTT assays confirmed that erlotinib/Tarceva inhibited CAL33 cell proliferation when TERF2 was knocked-down (Supplementary Figure S6C).	('rat', 'Species', '10116', (72, 75))	('TERF2', 'Gene', (84, 89))	('inhibited', 'NegReg', (44, 53))	('men', 'Species', '9606', (114, 117))	('MTT', 'Chemical', 'MESH:C070243', (0, 3))	('erlotinib', 'Chemical', 'MESH:D000069347', (26, 35))	('Tarceva', 'Chemical', 'MESH:D000069347', (36, 43))	('CAL33 cell proliferation', 'CPA', (54, 78))	('knocked-down', 'Var', (94, 106))
17497	27329590	The knock-down of TERF2 also increased the efficacy of cetuximab/Erbitux in CAL27 cells (Supplementary Figure S6D).	('Erbitux', 'Chemical', 'MESH:D000068818', (65, 72))	('cetuximab', 'Chemical', 'MESH:D000068818', (55, 64))	('efficacy', 'MPA', (43, 51))	('increased', 'PosReg', (29, 38))	('knock-down', 'Var', (4, 14))	('men', 'Species', '9606', (95, 98))	('TERF2', 'Gene', (18, 23))
17514	27329590	Therefore, high expression of TERF2 in tumors may repress of a panel of cytokines that enhance an anti-tumor immune response.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('tumor', 'Disease', (103, 108))	('TERF2', 'Gene', (30, 35))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('enhance', 'PosReg', (87, 94))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('tumor', 'Disease', (39, 44))	('high', 'Var', (11, 15))	('repress', 'NegReg', (50, 57))	('tumors', 'Disease', (39, 45))
17519	27329590	Hence, an increased pericyte number could account for the lower growth of the tumors with TERF2 knock-down.	('tumors', 'Disease', (78, 84))	('pericyte number', 'CPA', (20, 35))	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('lower', 'NegReg', (58, 63))	('growth', 'MPA', (64, 70))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('knock-down', 'Var', (96, 106))	('TERF2', 'Gene', (90, 95))	('lower growth', 'Phenotype', 'HP:0001510', (58, 70))	('increased', 'PosReg', (10, 19))
17545	27329590	The following antibodies were used: anti-phospho ERK1/2 (Sigma St Louis, MO), anti-phospho AKT, anti-AKT, anti-EGFR (Cell Signaling, Cambridge, UK,), anti-ERK1/2 (Santa Cruz Biotechnology, Santa Cruz, CA), anti-TERF2 (Novus bio, Cambridge, UK) and alpha-tubulin (Fischer scientific, Illkirch France).	('alpha-tubulin', 'Protein', (248, 261))	('AKT', 'Gene', '207', (101, 104))	('AKT', 'Gene', '207', (91, 94))	('EGFR', 'Gene', '1956', (111, 115))	('ERK1/2', 'Gene', (49, 55))	('ERK1/2', 'Gene', (155, 161))	('ERK1/2', 'Gene', '5595;5594', (49, 55))	('ERK1/2', 'Gene', '5595;5594', (155, 161))	('AKT', 'Gene', (101, 104))	('EGFR', 'Gene', (111, 115))	('AKT', 'Gene', (91, 94))	('anti-phospho', 'Var', (78, 90))
17572	33663076	In addition, the number of serum immune cells in patients with high BMI was significantly higher than that in patients with low BMI (all P < .001).	('patients', 'Species', '9606', (110, 118))	('patients', 'Species', '9606', (49, 57))	('higher', 'PosReg', (90, 96))	('high BMI', 'Var', (63, 71))	('low BMI', 'Phenotype', 'HP:0045082', (124, 131))
17573	33663076	The current results showed that high BMI is associated with better prognosis in LSCC patients who received ICIs, which may be related to higher levels of serum immune cells.	('high', 'Var', (32, 36))	('higher', 'PosReg', (137, 143))	('BMI', 'MPA', (37, 40))	('patients', 'Species', '9606', (85, 93))	('LSCC', 'Disease', (80, 84))	('LSCC', 'Phenotype', 'HP:0030359', (80, 84))
17583	33663076	Although obesity can increase the risk of multiple malignancies, high BMI is an independent protective factor against lung cancer-related mortality.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('obesity', 'Disease', 'MESH:D009765', (9, 16))	('obesity', 'Disease', (9, 16))	('lung cancer', 'Disease', 'MESH:D008175', (118, 129))	('malignancies', 'Disease', 'MESH:D009369', (51, 63))	('mortality', 'Disease', 'MESH:D003643', (138, 147))	('obesity', 'Phenotype', 'HP:0001513', (9, 16))	('malignancies', 'Disease', (51, 63))	('lung cancer', 'Disease', (118, 129))	('lung cancer', 'Phenotype', 'HP:0100526', (118, 129))	('mortality', 'Disease', (138, 147))	('high BMI', 'Var', (65, 73))
17589	33663076	Recent studies had shown that ICI therapy is more effective in tumor patients with high PD-L1 expression, high tumor mutation burden, and DNA mismatch-repair deficient /microsatellite instability-high.	('tumor', 'Disease', (63, 68))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('PD-L1', 'Gene', (88, 93))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumor', 'Disease', (111, 116))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('expression', 'MPA', (94, 104))	('high', 'Var', (83, 87))	('patients', 'Species', '9606', (69, 77))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
17633	33663076	In addition, the number of patients with stable disease in high BMI group was 12 (37.5%), compared with 21 (72.4%) in low BMI group after 4 cycles of treatment (P = .006).	('stable disease', 'Disease', (41, 55))	('patients', 'Species', '9606', (27, 35))	('low BMI', 'Phenotype', 'HP:0045082', (118, 125))	('high BMI', 'Var', (59, 67))
17647	33663076	As shown in Figure 8A, compared with low BMI group, the levels of pretreatment CD4+ and CD8+ T cells in high BMI group patients were significantly higher (all P < .0001).	('levels', 'MPA', (56, 62))	('CD8', 'Gene', '925', (88, 91))	('CD4', 'Gene', (79, 82))	('CD4', 'Gene', '920', (79, 82))	('patients', 'Species', '9606', (119, 127))	('high BMI', 'Var', (104, 112))	('low BMI', 'Phenotype', 'HP:0045082', (37, 44))	('higher', 'PosReg', (147, 153))	('CD8', 'Gene', (88, 91))
17648	33663076	Similarly, for post-treatment CD4+ and CD8+ T cells, the numbers of immune cells in the high BMI group were significantly higher than those in the low BMI group (all P < .001) (Fig.	('CD8', 'Gene', (39, 42))	('CD8', 'Gene', '925', (39, 42))	('higher', 'PosReg', (122, 128))	('high BMI', 'Var', (88, 96))	('low BMI', 'Phenotype', 'HP:0045082', (147, 154))	('CD4', 'Gene', (30, 33))	('CD4', 'Gene', '920', (30, 33))
17649	33663076	In addition, for patients with high BMI, the level of post-treatment CD4+ T cells was significantly higher than pretreatment CD4+ T cells (P < .001) (Fig.	('CD4', 'Gene', (69, 72))	('CD4', 'Gene', '920', (69, 72))	('CD4', 'Gene', (125, 128))	('CD4', 'Gene', '920', (125, 128))	('patients', 'Species', '9606', (17, 25))	('higher', 'PosReg', (100, 106))	('high', 'Var', (31, 35))
17650	33663076	Finally, the level of CD8+ T cells in low BMI group was significantly higher than this cell before treatment in the same group (P = .032) (Fig.	('level', 'MPA', (13, 18))	('low BMI', 'Var', (38, 45))	('low BMI', 'Phenotype', 'HP:0045082', (38, 45))	('higher', 'PosReg', (70, 76))	('CD8', 'Gene', (22, 25))	('CD8', 'Gene', '925', (22, 25))
17652	33663076	Similarly, no significant difference was found between pretreatment and post-treatment CD4+ T cells from low BMI group (P = .305).	('CD4', 'Gene', '920', (87, 90))	('low BMI', 'Phenotype', 'HP:0045082', (105, 112))	('CD4', 'Gene', (87, 90))	('low BMI', 'Var', (105, 112))
17658	33663076	The number of serum immune cells of advanced LSCC patients with high pretreatment BMI was greater than that in who with low pretreatment BMI, and high pretreatment BMI was related to longer PFS and OS times.	('advanced LSCC', 'Disease', (36, 49))	('patients', 'Species', '9606', (50, 58))	('greater', 'PosReg', (90, 97))	('LSCC', 'Phenotype', 'HP:0030359', (45, 49))	('high', 'Var', (146, 150))	('longer', 'PosReg', (183, 189))	('PFS', 'CPA', (190, 193))
17664	33663076	ICI therapy, represented by pembrolizumab, has replaced chemotherapy as the first-line treatment for advanced NSCLC patients with PD-L1 expression.	('pembrolizumab', 'Chemical', 'MESH:C582435', (28, 41))	('patients', 'Species', '9606', (116, 124))	('NSCLC', 'Disease', (110, 115))	('SCLC', 'Phenotype', 'HP:0030357', (111, 115))	('PD-L1 expression', 'Var', (130, 146))	('NSCLC', 'Disease', 'MESH:D002289', (110, 115))	('NSCLC', 'Phenotype', 'HP:0030358', (110, 115))
17668	33663076	Although previous studies have shown that patients with high PD-L1, high tumor mutation burden and DNA mismatch-repair deficient/microsatellite instability-high can benefit more from ICI therapy, we need to further explore the clinical factors affecting the therapeutic effect.	('benefit', 'PosReg', (165, 172))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('PD-L1', 'Gene', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Disease', (73, 78))	('patients', 'Species', '9606', (42, 50))	('high', 'Var', (56, 60))
17675	33663076	Many studies have shown that high BMI is closely related to the occurrence and development of a variety of malignant tumors, especially endometrial carcinoma, esophageal adenocarcinoma, renal cell carcinoma, liver cancer, and biliary tract cancer.	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (159, 184))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('carcinoma', 'Phenotype', 'HP:0030731', (175, 184))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('renal cell carcinoma', 'Disease', (186, 206))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (186, 206))	('biliary tract cancer', 'Disease', (226, 246))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('malignant tumors', 'Disease', (107, 123))	('liver cancer', 'Disease', 'MESH:D006528', (208, 220))	('adenocarcinoma', 'Disease', (170, 184))	('carcinoma', 'Phenotype', 'HP:0030731', (148, 157))	('high', 'Var', (29, 33))	('malignant tumors', 'Disease', 'MESH:D009369', (107, 123))	('endometrial carcinoma', 'Disease', (136, 157))	('carcinoma', 'Phenotype', 'HP:0030731', (197, 206))	('related', 'Reg', (49, 56))	('liver cancer', 'Phenotype', 'HP:0002896', (208, 220))	('biliary tract cancer', 'Phenotype', 'HP:0100574', (226, 246))	('adenocarcinoma', 'Disease', 'MESH:D000230', (170, 184))	('liver cancer', 'Disease', (208, 220))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (136, 157))	('biliary tract cancer', 'Disease', 'MESH:D001661', (226, 246))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (186, 206))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (136, 157))
17678	33663076	On the other hand, recent studies have found that high BMI can reduce the surgical mortality, improve the efficacy of ICI therapy and prolong the survival time of lung cancer patients.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('lung cancer', 'Disease', 'MESH:D008175', (163, 174))	('high BMI', 'Var', (50, 58))	('mortality', 'Disease', 'MESH:D003643', (83, 92))	('lung cancer', 'Disease', (163, 174))	('patients', 'Species', '9606', (175, 183))	('lung cancer', 'Phenotype', 'HP:0100526', (163, 174))	('improve', 'PosReg', (94, 101))	('prolong', 'PosReg', (134, 141))	('efficacy', 'MPA', (106, 114))	('reduce', 'NegReg', (63, 69))	('survival time', 'CPA', (146, 159))	('ICI therapy', 'CPA', (118, 129))	('mortality', 'Disease', (83, 92))
17683	33663076	First of all, patients with high BMI have better physical fitness and more energy reserves and stronger antitumor ability.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('stronger', 'PosReg', (95, 103))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('energy reserves', 'MPA', (75, 90))	('better', 'PosReg', (42, 48))	('tumor', 'Disease', (108, 113))	('fitness', 'Disease', (58, 65))	('high', 'Var', (28, 32))	('more', 'PosReg', (70, 74))	('patients', 'Species', '9606', (14, 22))	('fitness', 'Disease', 'MESH:D012640', (58, 65))
17705	33663076	At the same time, this study only revealed that the prognosis of patients with high pretreatment BMI is better, which may be related to more serum immune cells.	('more', 'PosReg', (136, 140))	('high', 'Var', (79, 83))	('patients', 'Species', '9606', (65, 73))	('BMI', 'MPA', (97, 100))
17712	32764415	The Impact of Coilin Nonsynonymous SNP Variants E121K and V145I on Cell Growth and Cajal Body Formation: The First Characterization Coilin is the main component of Cajal body (CB), a membraneless organelle that is involved in the biogenesis of ribonucleoproteins and telomerase, cell cycle, and cell growth.	('Coilin', 'Gene', '8161', (132, 138))	('V145I', 'Var', (58, 63))	('E121K', 'Var', (48, 53))	('Coilin', 'Gene', (14, 20))	('Coilin', 'Gene', (132, 138))	('V145I', 'Mutation', 'rs61731978', (58, 63))	('E121K', 'Mutation', 'rs116022828', (48, 53))	('Coilin', 'Gene', '8161', (14, 20))
17713	32764415	The disruption of CBs is linked to neurodegenerative diseases and potentially cancers.	('neurodegenerative diseases', 'Disease', (35, 61))	('linked', 'Reg', (25, 31))	('neurodegenerative diseases', 'Phenotype', 'HP:0002180', (35, 61))	('cancers', 'Disease', 'MESH:D009369', (78, 85))	('cancers', 'Phenotype', 'HP:0002664', (78, 85))	('CBs', 'Gene', (18, 21))	('cancers', 'Disease', (78, 85))	('neurodegenerative diseases', 'Disease', 'MESH:D019636', (35, 61))	('disruption', 'Var', (4, 14))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))
17714	32764415	The coilin gene (COIL) contains two nonsynonymous SNPs: rs116022828 (E121K) and rs61731978 (V145I).	('E121K', 'Var', (69, 74))	('rs61731978', 'Mutation', 'rs61731978', (80, 90))	('V145I', 'Mutation', 'rs61731978', (92, 97))	('COIL', 'Gene', (17, 21))	('rs116022828 (E121K', 'Var', (56, 74))	('coilin gene', 'Gene', (4, 15))	('coilin gene', 'Gene', '8161', (4, 15))	('COIL', 'Gene', '8161', (17, 21))	('rs61731978', 'Var', (80, 90))	('rs116022828', 'Mutation', 'rs116022828', (56, 67))	('E121K', 'Mutation', 'rs116022828', (69, 74))
17715	32764415	We revealed that both E121K and V145I mutants could disrupt CB formation and result in various patterns of subcellular localization with survival motor neuron protein.	('CB formation', 'CPA', (60, 72))	('V145I', 'Mutation', 'rs61731978', (32, 37))	('disrupt', 'NegReg', (52, 59))	('E121K', 'Mutation', 'rs116022828', (22, 27))	('result in', 'Reg', (77, 86))	('survival motor neuron', 'Gene', '6606', (137, 158))	('subcellular localization', 'MPA', (107, 131))	('E121K', 'Var', (22, 27))	('V145I', 'Var', (32, 37))	('patterns', 'MPA', (95, 103))	('survival motor neuron', 'Gene', (137, 158))
17716	32764415	Noteworthy, many of the E121K cells showed nucleolar coilin accumulation.	('E121K', 'Var', (24, 29))	('nucleolar coilin accumulation', 'MPA', (43, 72))	('E121K', 'Mutation', 'rs116022828', (24, 29))
17717	32764415	The microtubule regrowth and cell cycle assays indicated that the E121K cells appeared to be trapped in the S and G2/M phases of cell cycle, resulting in reduced cell proliferation.	('E121K', 'Var', (66, 71))	('E121K', 'Mutation', 'rs116022828', (66, 71))	('cell proliferation', 'CPA', (162, 180))	('reduced', 'NegReg', (154, 161))
17718	32764415	In silico protein structure prediction suggested that the E121K mutation caused greater destabilization on the coilin structure than the V145I mutation.	('E121K', 'Var', (58, 63))	('coilin structure', 'MPA', (111, 127))	('V145I', 'Mutation', 'rs61731978', (137, 142))	('E121K', 'Mutation', 'rs116022828', (58, 63))	('destabilization', 'NegReg', (88, 103))
17726	32764415	Spinal muscular atrophy (SMA) is a typical example of CB-related disease that is mainly caused by the mutations in the SMN1 gene.	('Spinal muscular atrophy', 'Disease', 'MESH:D009134', (0, 23))	('caused by', 'Reg', (88, 97))	('SMN1', 'Gene', (119, 123))	('SMA', 'Phenotype', 'HP:0007269', (25, 28))	('Spinal muscular atrophy', 'Phenotype', 'HP:0007269', (0, 23))	('muscular atrophy', 'Phenotype', 'HP:0003202', (7, 23))	('mutations', 'Var', (102, 111))	('SMN1', 'Gene', '6606', (119, 123))	('Spinal muscular atrophy', 'Disease', (0, 23))
17733	32764415	According to Single Nucleotide Polymorphism Database (dbSNP; ), the human COIL gene contains two nonsynonymous SNPs: rs116022828 (E121K, c.361G>A, p.Glu121Lys) and rs61731978 (V145I, c.433G>A, p.Val145Ile).	('COIL', 'Gene', (74, 78))	('V145I', 'Mutation', 'rs61731978', (176, 181))	('p.Glu121Lys', 'Mutation', 'rs116022828', (147, 158))	('human', 'Species', '9606', (68, 73))	('c.433G>A', 'Var', (183, 191))	('c.361G>A', 'Var', (137, 145))	('COIL', 'Gene', '8161', (74, 78))	('rs61731978', 'Var', (164, 174))	('E121K', 'Mutation', 'rs116022828', (130, 135))	('rs116022828', 'Mutation', 'rs116022828', (117, 128))	('c.433G>A', 'Mutation', 'rs61731978', (183, 191))	('c.361G>A', 'Mutation', 'rs116022828', (137, 145))	('rs61731978', 'Mutation', 'rs61731978', (164, 174))	('E121K', 'Var', (130, 135))	('p.Val145Ile', 'Mutation', 'rs61731978', (193, 204))
17734	32764415	Here, we constructed HeLa cell lines that expressed wild-type (WT) or mutant forms (E121K and V145I) of coilin, and investigated the functional impacts of these SNPs on CB formation, coilin subcellular localization, microtubule formation, cell cycle, cell proliferation, and coilin expression and protein structure.	('E121K', 'Mutation', 'rs116022828', (84, 89))	('expression', 'MPA', (282, 292))	('cell proliferation', 'CPA', (251, 269))	('microtubule', 'MPA', (216, 227))	('E121K', 'Var', (84, 89))	('V145I', 'Var', (94, 99))	('HeLa', 'CellLine', 'CVCL:0030', (21, 25))	('V145I', 'Mutation', 'rs61731978', (94, 99))
17755	32764415	We searched dbSNP  and analyzed the allele frequencies of both SNPs in different populations to explore the global distributions of rs116022828 (E121K) and rs61731978 (V145I).	('rs61731978', 'Var', (156, 166))	('E121K', 'Mutation', 'rs116022828', (145, 150))	('rs116022828 (E121K', 'Var', (132, 150))	('rs61731978', 'Mutation', 'rs61731978', (156, 166))	('V145I', 'Mutation', 'rs61731978', (168, 173))	('rs116022828', 'Mutation', 'rs116022828', (132, 143))
17759	32764415	The above results indicated that rs61731978 is more globally distributed, whereas rs116022828 is more restricted to the African population.	('rs116022828', 'Mutation', 'rs116022828', (82, 93))	('rs61731978', 'Var', (33, 43))	('rs116022828', 'Var', (82, 93))	('rs61731978', 'Mutation', 'rs61731978', (33, 43))
17767	32764415	Indeed, the results from the immunofluorescence analysis indicated that for transiently transfected cell lines, only less than 50% of WT cells and less than 30% of E121K or V145I cells (n > 100) displayed normal CB formation (Figure 2b).	('E121K', 'Var', (164, 169))	('V145I', 'Mutation', 'rs61731978', (173, 178))	('CB formation', 'CPA', (212, 224))	('V145I', 'Var', (173, 178))	('E121K', 'Mutation', 'rs116022828', (164, 169))
17768	32764415	In contrast, for stably transfected cell lines, more than 89% of the WT, E121K, or V145I cells (n > 140) showed normal CB formation (Figure 2c).	('CB formation', 'CPA', (119, 131))	('E121K', 'Mutation', 'rs116022828', (73, 78))	('E121K', 'Var', (73, 78))	('V145I', 'Var', (83, 88))	('V145I', 'Mutation', 'rs61731978', (83, 88))
17770	32764415	We performed immunofluorescence analysis on the stably transfected cell lines to detect their coilin and SMN co-localization status in order to determine whether the coilin SNP variants have impacts on the subcellular co-localization of coilin and SMN.	('SMN', 'Gene', (248, 251))	('impacts', 'Reg', (191, 198))	('SMN', 'Gene', '6606', (105, 108))	('SMN', 'Gene', '6606', (248, 251))	('SMN', 'Gene', (105, 108))	('subcellular co-localization', 'MPA', (206, 233))	('coilin SNP', 'Gene', (166, 176))	('variants', 'Var', (177, 185))
17773	32764415	Unlike the WT cells, many of the E121K and V145I cells contained coilin foci, but without SMN enrichment (indicated by double arrow).	('SMN', 'Gene', (90, 93))	('V145I', 'Mutation', 'rs61731978', (43, 48))	('SMN', 'Gene', '6606', (90, 93))	('E121K', 'Mutation', 'rs116022828', (33, 38))	('E121K', 'Var', (33, 38))	('coilin foci', 'CPA', (65, 76))	('contained', 'Reg', (55, 64))
17775	32764415	Interestingly, we also observed different patterns of coilin and SMN co-localization that were mainly restricted only to a particular coilin SNP variant cell line.	('SMN', 'Gene', (65, 68))	('SMN', 'Gene', '6606', (65, 68))	('variant', 'Var', (145, 152))
17776	32764415	For instance, in many of the E121K cells, the coilin proteins appeared to be accumulated in the nucleoli (indicated by single arrowhead).	('E121K', 'Mutation', 'rs116022828', (29, 34))	('E121K', 'Var', (29, 34))	('coilin proteins', 'Protein', (46, 61))	('accumulated', 'PosReg', (77, 88))
17778	32764415	The results indicated that about 11-14% of the cells from all three cell lines contained no coilin and SMN co-localization, and it is clear that the WT cells contained a noticeably greater number of canonical CBs than the two coilin SNP variant cells (75.27% vs. 25.87-42.45%) (Figure 3b).	('coilin', 'Protein', (92, 98))	('SMN', 'Gene', (103, 106))	('greater', 'PosReg', (181, 188))	('SMN', 'Gene', '6606', (103, 106))	('variant', 'Var', (237, 244))
17779	32764415	We then investigated whether coilin SNP variants have effects on the growth-related phenotypes of the HeLa cells.	('coilin SNP', 'Gene', (29, 39))	('variants', 'Var', (40, 48))	('effects', 'Reg', (54, 61))	('HeLa', 'CellLine', 'CVCL:0030', (102, 106))
17782	32764415	In cell proliferation assays, we found that the V145I cells had a similar growth rate with the WT cells, and the E121K cells were growing slower than the WT cells, as expected (Figure 4c).	('V145I', 'Var', (48, 53))	('V145I', 'Mutation', 'rs61731978', (48, 53))	('slower', 'NegReg', (138, 144))	('E121K', 'Mutation', 'rs116022828', (113, 118))	('E121K', 'Var', (113, 118))
17783	32764415	We performed immunoblotting to examine the coilin protein expression level (Figure 5a; Figure S4) and RT-qPCR for the detection of COIL gene expression levels (Figure 5b) in order to elucidate whether coilin SNP variants could affect the expression of coilin.	('variants', 'Var', (212, 220))	('coilin', 'Gene', (201, 207))	('affect', 'Reg', (227, 233))	('coilin', 'Gene', (252, 258))	('COIL', 'Gene', '8161', (131, 135))	('expression', 'MPA', (238, 248))	('COIL', 'Gene', (131, 135))
17784	32764415	Notably, the WT and E121K cells showed similar lower coilin expression levels, and the V145I cells had the highest coilin expression.	('coilin expression', 'MPA', (115, 132))	('lower', 'NegReg', (47, 52))	('coilin expression levels', 'MPA', (53, 77))	('E121K', 'Mutation', 'rs116022828', (20, 25))	('V145I', 'Mutation', 'rs61731978', (87, 92))	('E121K', 'Var', (20, 25))
17785	32764415	Additionally, data also indicated that the E121K mutation resulted in the disappearances of the helix structure in the E121K mutant (Figure S5, indicated by red arrow).	('helix structure', 'MPA', (96, 111))	('E121K', 'Mutation', 'rs116022828', (43, 48))	('E121K', 'Var', (43, 48))	('disappearances', 'NegReg', (74, 88))	('E121K', 'Mutation', 'rs116022828', (119, 124))	('E121K', 'Var', (119, 124))
17786	32764415	The results indicated that the E121K mutation had a DeltaDeltaG value of -2.93 while V145I was 0.18 (Figure 6a).	('E121K', 'Mutation', 'rs116022828', (31, 36))	('V145I', 'Mutation', 'rs61731978', (85, 90))	('E121K', 'Var', (31, 36))	('DeltaDeltaG', 'MPA', (52, 63))
17787	32764415	Based on the models with the highest C-scores, it appeared that the E121K mutation had resulted in the most dramatic change in the predicted coilin structure (Figure 6b).	('coilin structure', 'MPA', (141, 157))	('E121K', 'Mutation', 'rs116022828', (68, 73))	('change', 'Reg', (117, 123))	('E121K', 'Var', (68, 73))
17788	32764415	We screened through The Cancer Genome Atlas (TCGA) database searching for cancer patients with coilin mutation at residue 121 or 145 to further investigate the relationships between coilin and cancer.	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('Cancer', 'Disease', (24, 30))	('cancer', 'Disease', (193, 199))	('coilin', 'Gene', (95, 101))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('Cancer', 'Disease', 'MESH:D009369', (24, 30))	('patients', 'Species', '9606', (81, 89))	('Cancer', 'Phenotype', 'HP:0002664', (24, 30))	('cancer', 'Disease', (74, 80))	('mutation at residue 121', 'Var', (102, 125))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
17789	32764415	The data indicated that these coilin mutations were extremely rare in cancer patients, suggesting that coilin SNP variants are likely not cancer risk factors (data not shown).	('cancer', 'Disease', (138, 144))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('variants', 'Var', (114, 122))	('patients', 'Species', '9606', (77, 85))	('coilin', 'Gene', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (138, 144))
17790	32764415	However, since our previous data indicated that coilin SNP variants could give rise to different levels of protein and gene expressions, we then sought to determine the roles of coilin expression in cancer survival.	('levels of protein', 'MPA', (97, 114))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('give rise', 'Reg', (74, 83))	('coilin SNP', 'Gene', (48, 58))	('variants', 'Var', (59, 67))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('cancer', 'Disease', (199, 205))
17791	32764415	Accordingly, we used Kaplan-Meier Plotter database to perform survival analysis on cancer patients with high/low COIL expression across 21 cancer types (Table S2).	('COIL', 'Gene', (113, 117))	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('COIL', 'Gene', '8161', (113, 117))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('patients', 'Species', '9606', (90, 98))	('high/low', 'Var', (104, 112))	('cancer', 'Disease', (83, 89))	('cancer', 'Disease', (139, 145))
17792	32764415	The results showed that high COIL expressions were significantly correlated with lower (HR > 1) or higher (HR < 1) survival outcomes in specific cancer types, as shown in Figure 7a.	('cancer', 'Disease', (145, 151))	('survival outcomes', 'CPA', (115, 132))	('lower', 'NegReg', (81, 86))	('higher', 'PosReg', (99, 105))	('COIL', 'Gene', '8161', (29, 33))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('high', 'Var', (24, 28))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('COIL', 'Gene', (29, 33))
17802	32764415	There are several examples of human diseases that are highly associated with the disruption and loss of CBs, and they usually arise due to mutations in the genes that encode CB-associated proteins.	('human', 'Species', '9606', (30, 35))	('disruption', 'Var', (81, 91))	('mutations', 'Var', (139, 148))	('CBs', 'Gene', (104, 107))	('arise due', 'Reg', (126, 135))	('loss', 'NegReg', (96, 100))
17803	32764415	For instance, SMA, where patients are characterized by progressive degeneration of spinal motor neurons, muscle atrophy, symmetric limb paralysis, and respiratory failure, is caused by mutated SMN1 gene.	('respiratory failure', 'Disease', (151, 170))	('degeneration of spinal motor neurons', 'Disease', 'MESH:D009410', (67, 103))	('respiratory failure', 'Phenotype', 'HP:0002878', (151, 170))	('caused by', 'Reg', (175, 184))	('muscle atrophy', 'Phenotype', 'HP:0003202', (105, 119))	('limb paralysis', 'Disease', 'MESH:D010243', (131, 145))	('SMN1', 'Gene', '6606', (193, 197))	('muscle atrophy', 'Disease', 'MESH:D009133', (105, 119))	('paralysis', 'Phenotype', 'HP:0003470', (136, 145))	('SMA', 'Disease', (14, 17))	('patients', 'Species', '9606', (25, 33))	('symmetric', 'Disease', (121, 130))	('mutated', 'Var', (185, 192))	('SMN1', 'Gene', (193, 197))	('respiratory failure', 'Disease', 'MESH:D012131', (151, 170))	('degeneration of spinal motor neurons', 'Disease', (67, 103))	('SMA', 'Phenotype', 'HP:0007269', (14, 17))	('progressive degeneration of spinal motor', 'Phenotype', 'HP:0009067', (55, 95))	('limb paralysis', 'Disease', (131, 145))	('muscle atrophy', 'Disease', (105, 119))
17805	32764415	Another genetic disease, known as dyskeratosis congenita (DKC), occurs due to mutations in a couple of genes encoding proteins that localize to CBs (e.g., EST1A, NHP2, NOP10, and WRAP53), and resulting in defective ribosome biogenesis and telomere maintenance.	('EST1A', 'Gene', (155, 160))	('dyskeratosis congenita', 'Disease', (34, 56))	('defective', 'NegReg', (205, 214))	('dyskeratosis congenita', 'Disease', 'MESH:D019871', (34, 56))	('WRAP53', 'Gene', (179, 185))	('NOP10', 'Gene', (168, 173))	('WRAP53', 'Gene', '55135', (179, 185))	('ribosome biogenesis', 'MPA', (215, 234))	('NOP10', 'Gene', '55505', (168, 173))	('DKC', 'Gene', '1736', (58, 61))	('mutations', 'Var', (78, 87))	('EST1A', 'Gene', '23293', (155, 160))	('genetic disease', 'Disease', (8, 23))	('genetic disease', 'Disease', 'MESH:D030342', (8, 23))	('NHP2', 'Gene', '55651', (162, 166))	('DKC', 'Gene', (58, 61))	('telomere maintenance', 'CPA', (239, 259))	('NHP2', 'Gene', (162, 166))
17809	32764415	However, the effects of the two nonsynonymous SNPs of COIL gene (rs116022828:E121K and rs61731978:V145I) on CB formation and other cell phenotypes have not been investigated.	('rs61731978', 'Mutation', 'rs61731978', (87, 97))	('rs116022828:E121K', 'Var', (65, 82))	('COIL', 'Gene', '8161', (54, 58))	('V145I', 'Mutation', 'rs61731978', (98, 103))	('E121K', 'Mutation', 'rs116022828', (77, 82))	('E121K', 'Var', (77, 82))	('rs116022828', 'Mutation', 'rs116022828', (65, 76))	('rs61731978', 'Var', (87, 97))	('COIL', 'Gene', (54, 58))
17810	32764415	Here, we constructed HeLa cell lines with coilin WT or coilin SNP variant (E121K or V145I) and investigated, for the first time, how coilin SNPs affect CB formation, co-localization with SMN, cell growth, and coilin expression and structure.	('affect', 'Reg', (145, 151))	('SMN', 'Gene', (187, 190))	('V145I', 'Mutation', 'rs61731978', (84, 89))	('expression', 'MPA', (216, 226))	('SMN', 'Gene', '6606', (187, 190))	('co-localization', 'MPA', (166, 181))	('cell growth', 'CPA', (192, 203))	('V145I', 'Var', (84, 89))	('CB formation', 'CPA', (152, 164))	('E121K', 'Var', (75, 80))	('coilin SNP', 'Gene', (55, 65))	('E121K', 'Mutation', 'rs116022828', (75, 80))	('HeLa', 'CellLine', 'CVCL:0030', (21, 25))
17813	32764415	When comparing the subcellular co-localization of coilin and SMN in the coilin WT and SNP variants, we found that both SNP variant expressing cell lines had lesser cells with canonical CBs (normal CBs that contained both coilin and SMN), but many with residual CBs (coilin foci without SMN).	('SMN', 'Gene', '6606', (61, 64))	('SMN', 'Gene', (286, 289))	('SMN', 'Gene', (232, 235))	('SMN', 'Gene', '6606', (286, 289))	('variant', 'Var', (123, 130))	('SMN', 'Gene', (61, 64))	('SNP', 'Gene', (119, 122))	('SMN', 'Gene', '6606', (232, 235))
17814	32764415	Interestingly, it appeared that the cells with a mutation at coilin residue 121 contained a more diverse pattern of coilin and SMN co-localization.	('SMN', 'Gene', '6606', (127, 130))	('coilin', 'Gene', (61, 67))	('mutation at', 'Var', (49, 60))	('SMN', 'Gene', (127, 130))	('coilin', 'Protein', (116, 122))
17815	32764415	For example, accumulation of coilin in the nucleoli and/or gem structure formation (SMN foci) could frequently be found in the E121K cells but rarely in the WT and V145I cells.	('E121K', 'Var', (127, 132))	('accumulation', 'PosReg', (13, 25))	('SMN', 'Gene', (84, 87))	('gem structure formation', 'CPA', (59, 82))	('V145I', 'Mutation', 'rs61731978', (164, 169))	('SMN', 'Gene', '6606', (84, 87))	('coilin', 'Protein', (29, 35))	('E121K', 'Mutation', 'rs116022828', (127, 132))
17816	32764415	The E121K coilin might be targeted to nucleoli by nucleolar and coiled-body phosphoprotein 1 (NOLC1) since it was previously demonstrated that the N-terminal of coilin interacted strongly with NOLC1.	('NOLC1', 'Gene', (94, 99))	('NOLC1', 'Gene', (193, 198))	('NOLC1', 'Gene', '9221', (94, 99))	('NOLC1', 'Gene', '9221', (193, 198))	('E121K', 'Mutation', 'rs116022828', (4, 9))	('nucleolar and coiled-body phosphoprotein 1', 'Gene', '9221', (50, 92))	('E121K', 'Var', (4, 9))	('interacted', 'Interaction', (168, 178))
17817	32764415	Nevertheless, the findings in our study not only show that coilin SNP variants have impacts on the CB formation and coilin/SMN co-localization, but also indicate that the consequences of E121K and V145I mutations are different.	('CB formation', 'CPA', (99, 111))	('impacts', 'Reg', (84, 91))	('E121K', 'Mutation', 'rs116022828', (187, 192))	('V145I', 'Mutation', 'rs61731978', (197, 202))	('coilin SNP', 'Gene', (59, 69))	('E121K', 'Var', (187, 192))	('variants', 'Var', (70, 78))	('SMN', 'Gene', (123, 126))	('V145I', 'Var', (197, 202))	('SMN', 'Gene', '6606', (123, 126))
17818	32764415	Furthermore, it is indicated that the coilin E121K mutation has greater impacts on the CB formation than the V145I, which warrants further study.	('E121K', 'Mutation', 'rs116022828', (45, 50))	('E121K', 'Var', (45, 50))	('V145I', 'Mutation', 'rs61731978', (109, 114))	('coilin', 'Gene', (38, 44))	('CB formation', 'CPA', (87, 99))	('impacts', 'Reg', (72, 79))
17822	32764415	Moreover, it was shown that a high percentage of HeLa cells stably expressing S489D-mutated coilin (mimic phosphorylation) had their coilin accumulated in the nucleoli, similar to our E121K cells.	('coilin', 'MPA', (133, 139))	('E121K', 'Mutation', 'rs116022828', (184, 189))	('coilin', 'Gene', (92, 98))	('S489D-mutated', 'Var', (78, 91))	('accumulated', 'PosReg', (140, 151))	('S489D', 'Mutation', 'p.S489D', (78, 83))	('HeLa', 'CellLine', 'CVCL:0030', (49, 53))
17823	32764415	HeLa cells with impaired CBs or knocked-down coilin expression showed reduced cell proliferation.	('reduced', 'NegReg', (70, 77))	('expression', 'MPA', (52, 62))	('coilin', 'Gene', (45, 51))	('HeLa', 'CellLine', 'CVCL:0030', (0, 4))	('knocked-down', 'Var', (32, 44))	('cell proliferation', 'CPA', (78, 96))
17825	32764415	It was also showed that the knockdown of coilin caused embryonic lethality in the zebrafish, indicating the essentiality of coilin in embryogenesis.	('embryonic lethality', 'Disease', 'MESH:D020964', (55, 74))	('knockdown', 'Var', (28, 37))	('embryonic lethality', 'Disease', (55, 74))	('coilin', 'Gene', (41, 47))	('zebrafish', 'Species', '7955', (82, 91))
17826	32764415	In the current study, we discovered that coilin E121K variant cells had significant differences in their microtubule formation and cell cycle when compared to coilin WT and V145I cells.	('E121K', 'Var', (48, 53))	('differences', 'Reg', (84, 95))	('microtubule formation', 'MPA', (105, 126))	('V145I', 'Mutation', 'rs61731978', (173, 178))	('cell cycle', 'CPA', (131, 141))	('E121K', 'SUBSTITUTION', 'None', (48, 53))	('coilin', 'Gene', (41, 47))
17827	32764415	Both microtubule regrowth assay and cell cycle assay suggested that a large proportion of E121K cells might be trapped in the S and G2/M phases of cell cycle, and was likely to be the cause of reduced cell proliferation.	('E121K', 'Mutation', 'rs116022828', (90, 95))	('cell proliferation', 'CPA', (201, 219))	('reduced', 'NegReg', (193, 200))	('E121K', 'Var', (90, 95))
17828	32764415	Coincide with the CB formation and coilin/SMN co-localization results, the cell proliferation results indicate that the mutation of coilin residue 121 has greater impacts on the cell growth than residue 145.	('SMN', 'Gene', (42, 45))	('SMN', 'Gene', '6606', (42, 45))	('mutation', 'Var', (120, 128))	('cell growth', 'CPA', (178, 189))	('impacts', 'Reg', (163, 170))	('coilin', 'Gene', (132, 138))
17829	32764415	The results indicated that the coilin with E121K mutation appeared to have a distinctively different predicted protein structure than the others based on the highest C-scores.	('protein structure', 'MPA', (111, 128))	('E121K', 'Var', (43, 48))	('different', 'Reg', (91, 100))	('E121K', 'Mutation', 'rs116022828', (43, 48))
17830	32764415	Furthermore, we used STRUM to predict the effects of E121K or V145I mutation on the coilin stability through assessing the thermodynamics of the protein.	('V145I', 'Var', (62, 67))	('E121K', 'Mutation', 'rs116022828', (53, 58))	('E121K', 'Var', (53, 58))	('V145I', 'Mutation', 'rs61731978', (62, 67))	('coilin stability', 'MPA', (84, 100))
17831	32764415	The results indicated that the E121K mutation caused destabilization on the coilin protein structure, whereas V145I mutation slightly stabilized the protein.	('E121K', 'Mutation', 'rs116022828', (31, 36))	('V145I', 'Mutation', 'rs61731978', (110, 115))	('E121K', 'Var', (31, 36))	('destabilization', 'NegReg', (53, 68))	('V145I', 'Var', (110, 115))	('coilin protein', 'Protein', (76, 90))
17833	32764415	Here, we performed clinical bioinformatic analysis and found that coilin mutation at residue 121 or 145 is rare in patients of various cancer types.	('patients', 'Species', '9606', (115, 123))	('cancer', 'Disease', (135, 141))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('coilin', 'Gene', (66, 72))	('mutation at residue 121', 'Var', (73, 96))	('cancer', 'Disease', 'MESH:D009369', (135, 141))
17835	32764415	Thus, these results indicated that coilin SNP variants are likely not cancer risk factors, but the expression of coilin could be.	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('variants', 'Var', (46, 54))	('coilin', 'Gene', (35, 41))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))
17836	32764415	Overall, findings from our clinical bioinformatic analysis may have potential clinical implications on cancer patients of different populations: the E121K SNP is primarily distributed in the African population, whereas the V145I SNP is mainly distributed in the American population but also observed in African, South Asian, and European populations.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('V145I', 'Var', (223, 228))	('E121K', 'Mutation', 'rs116022828', (149, 154))	('E121K', 'Var', (149, 154))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('V145I', 'Mutation', 'rs61731978', (223, 228))	('patients', 'Species', '9606', (110, 118))
17837	32764415	In conclusion, we demonstrated, for the first time, that coilin SNP variants, E121K and V145I, could differentially impact CB formation, co-localization with SMN, microtubule formation, cell cycle, cell proliferation, and coilin expression.	('SMN', 'Gene', '6606', (158, 161))	('co-localization', 'MPA', (137, 152))	('impact', 'Reg', (116, 122))	('coilin', 'CPA', (222, 228))	('CB formation', 'CPA', (123, 135))	('microtubule formation', 'MPA', (163, 184))	('V145I', 'Mutation', 'rs61731978', (88, 93))	('E121K', 'Mutation', 'rs116022828', (78, 83))	('cell cycle', 'CPA', (186, 196))	('coilin SNP', 'Gene', (57, 67))	('E121K', 'Var', (78, 83))	('SMN', 'Gene', (158, 161))	('cell proliferation', 'CPA', (198, 216))	('V145I', 'Var', (88, 93))	('expression', 'MPA', (229, 239))
17838	32764415	Among the two SNP variants, the E121K variant appeared to have greater detrimental effects on the cells than the V145I variant.	('V145I', 'Mutation', 'rs61731978', (113, 118))	('detrimental', 'NegReg', (71, 82))	('E121K', 'Var', (32, 37))	('E121K', 'SUBSTITUTION', 'None', (32, 37))
17839	32764415	Furthermore, clinical bioinformatic analysis indicates that coilin expression may potentially be a risk factor for cancer, depending on the cancer types and races.	('cancer', 'Disease', (115, 121))	('coilin', 'Protein', (60, 66))	('expression', 'Var', (67, 77))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (115, 121))
17840	32764415	Table S2: Survival analysis of cancer patients with high versus low coilin gene expressions using Kaplan-Meier Plotter database .	('coilin gene', 'Gene', (68, 79))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('coilin gene', 'Gene', '8161', (68, 79))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('high', 'Var', (52, 56))	('patients', 'Species', '9606', (38, 46))	('cancer', 'Disease', (31, 37))
17841	32764415	Figure S1: Global distributions of COIL SNPs, (a) rs116022828 (E121K) and (b) rs61731978 (V145I), analyzed using multiple datasets from various studies in the Single Nucleotide Polymorphism Database (dbSNP; ).	('rs116022828', 'Mutation', 'rs116022828', (50, 61))	('V145I', 'Mutation', 'rs61731978', (90, 95))	('COIL', 'Gene', '8161', (35, 39))	('rs116022828', 'Var', (50, 61))	('rs61731978', 'Var', (78, 88))	('E121K', 'Mutation', 'rs116022828', (63, 68))	('COIL', 'Gene', (35, 39))	('rs61731978', 'Mutation', 'rs61731978', (78, 88))
17847	32764415	Red arrow indicates the position where the predicted helix structure is missing in the E121K mutant.	('E121K', 'Mutation', 'rs116022828', (87, 92))	('missing', 'NegReg', (72, 79))	('helix structure', 'MPA', (53, 68))	('E121K', 'Var', (87, 92))
17848	32764415	Figure S6: Top five models predicted by I-TASSER server  based on the amino acid sequences of the coilin WT and SNP variants (E121K and V145I).	('E121K', 'Var', (126, 131))	('V145I', 'Mutation', 'rs61731978', (136, 141))	('E121K', 'Mutation', 'rs116022828', (126, 131))	('V145I', 'Var', (136, 141))
17852	31863083	Cancer clinical sequencing analyses at a varying scales identify the genotypes of cancers, including the driver mutations in lung adenocarcinoma cells.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('lung adenocarcinoma', 'Disease', (125, 144))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (125, 144))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('cancers', 'Phenotype', 'HP:0002664', (82, 89))	('cancers', 'Disease', (82, 89))	('mutations', 'Var', (112, 121))	('Cancer', 'Disease', (0, 6))	('cancers', 'Disease', 'MESH:D009369', (82, 89))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (125, 144))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))
17853	31863083	For example, EGFR tyrosine kinase inhibitors (e.g., gefitinib and erlotinib) and ALK inhibitors (e.g., crizotinib) are administered to patients with EGFR mutations and ALK fusions, respectively.	('erlotinib', 'Chemical', 'MESH:D000069347', (66, 75))	('patients', 'Species', '9606', (135, 143))	('gefitinib', 'Chemical', 'MESH:D000077156', (52, 61))	('ALK', 'Gene', (81, 84))	('EGFR', 'Gene', '1956', (149, 153))	('ALK', 'Gene', (168, 171))	('ALK', 'Gene', '238', (81, 84))	('EGFR', 'Gene', (149, 153))	('crizotinib', 'Chemical', 'MESH:D000077547', (103, 113))	('mutations', 'Var', (154, 163))	('EGFR', 'Gene', '1956', (13, 17))	('ALK', 'Gene', '238', (168, 171))	('EGFR', 'Gene', (13, 17))
17864	31863083	The resulting dataset, which we generated using whole genome sequencing, comprised the representative patterns of the driver mutations in lung adenocarcinoma, such as EGFR and KRAS point mutations, ALK and RET fusions, and the amplifications of genes such as ERRB2 and MET genes.	('mutations', 'Var', (125, 134))	('RET', 'Gene', '5979', (206, 209))	('ERRB2', 'Gene', (259, 264))	('ALK', 'Gene', (198, 201))	('lung adenocarcinoma', 'Disease', (138, 157))	('carcinoma', 'Phenotype', 'HP:0030731', (148, 157))	('KRAS', 'Gene', (176, 180))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (138, 157))	('KRAS', 'Gene', '3845', (176, 180))	('RET', 'Gene', (206, 209))	('ALK', 'Gene', '238', (198, 201))	('EGFR', 'Gene', '1956', (167, 171))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (138, 157))	('MET genes', 'Gene', (269, 278))	('EGFR', 'Gene', (167, 171))
17867	31863083	Using dataset 1, we deeply examined the transcriptomic and epigenomic changes caused by the representative drugs, including kinase inhibitors, cytotoxic anti-cancer drugs and epigenetic targeting drugs.	('cancer', 'Disease', (158, 164))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('epigenetic targeting', 'Var', (175, 195))
17877	31863083	Genomic KEAP1 mutations were significantly enriched in cells sensitive to the MEK inhibitor PD0325901 (middle and right panels, Fig.	('KEAP1', 'Gene', (8, 13))	('MEK', 'Gene', (78, 81))	('MEK', 'Gene', '5609', (78, 81))	('PD0325901', 'Chemical', 'MESH:C506614', (92, 101))	('KEAP1', 'Gene', '9817', (8, 13))	('mutations', 'Var', (14, 23))
17880	31863083	When KEAP1 is mutated and NFE2L2 signaling is stabilized, cancer cells may be more addicted to MAPK oncogenic and KEAP1-NFE2L2 oxidation reduction (redox) signals and may become sensitive to MEK inhibitors.	('KEAP1', 'Gene', (5, 10))	('addicted', 'MPA', (83, 91))	('NFE2L2', 'Gene', '4780', (120, 126))	('mutated', 'Var', (14, 21))	('NFE2L2', 'Gene', (26, 32))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('NFE2L2', 'Gene', (120, 126))	('KEAP1', 'Gene', '9817', (114, 119))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('KEAP1', 'Gene', '9817', (5, 10))	('cancer', 'Disease', (58, 64))	('MEK', 'Gene', (191, 194))	('KEAP1', 'Gene', (114, 119))	('MEK', 'Gene', '5609', (191, 194))	('NFE2L2', 'Gene', '4780', (26, 32))
17889	31863083	We found that cell lines harboring KEAP1 or NFE2L2 mutations showed significantly increased module activity as represented by their module eigengene (p = 0.0001, Wilcoxon rank sum test) (Fig.	('mutations', 'Var', (51, 60))	('module activity', 'MPA', (92, 107))	('KEAP1', 'Gene', '9817', (35, 40))	('NFE2L2', 'Gene', (44, 50))	('KEAP1', 'Gene', (35, 40))	('increased', 'PosReg', (82, 91))	('NFE2L2', 'Gene', '4780', (44, 50))
17890	31863083	We analyzed the 515 clinical samples of lung adenocarcinoma (TCGA-LUAD) and found that the activity of the "lightcyan" module was strongly correlated with the mutational status of KEAP1 and NFE2L2 (Fig.	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (40, 59))	('KEAP1', 'Gene', '9817', (180, 185))	('mutational status', 'Var', (159, 176))	('correlated', 'Reg', (139, 149))	('carcinoma', 'Phenotype', 'HP:0030731', (50, 59))	('activity', 'MPA', (91, 99))	('KEAP1', 'Gene', (180, 185))	('lung adenocarcinoma', 'Disease', (40, 59))	('NFE2L2', 'Gene', '4780', (190, 196))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (40, 59))	('NFE2L2', 'Gene', (190, 196))
17912	31863083	We analyzed the transcriptome and epigenome perturbation datasets of the compounds with desirable profiles and found that the BET inhibitors (+)-JQ1 and GSK1210151A may be candidates that could downregulate the expression of group 1 genes (Fig.	('downregulate', 'NegReg', (194, 206))	('BET', 'Gene', (126, 129))	('BET', 'Gene', '92737', (126, 129))	('group 1 genes', 'Gene', (225, 238))	('+)-JQ1', 'Var', (142, 148))	('GSK1210151A', 'Var', (153, 164))	('expression', 'MPA', (211, 221))
17922	31863083	S12), and we observed a slight synergistic effect for (+)-JQ1 and vorinostat in some cells (CI40 = 0.61 in H2228 cells and CI40 = 0.80 in H2126 cells) with high activity in the "lightcyan" module (Fig.	('vorinostat', 'Chemical', 'MESH:D000077337', (66, 76))	('S12', 'Gene', (0, 3))	('S12', 'Gene', '6268', (0, 3))	('CI40 = 0.80', 'Var', (123, 134))	('H2228', 'CellLine', 'CVCL:1543', (107, 112))	('H2126', 'CellLine', 'CVCL:1532', (138, 143))	('synergistic effect', 'MPA', (31, 49))
17971	31863083	An aberrant status was defined according to the following: for oncogenes, mutants were defined if the cell lines harbored genomic mutations and the expression was >5 rpkm; for tumor-suppressor genes, mutants were defined if they harbored mutations or showed low expression levels that were <5 rpkm.	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('expression levels', 'MPA', (262, 279))	('tumor', 'Disease', (176, 181))	('mutations', 'Var', (238, 247))	('mutations', 'Var', (130, 139))	('harbored', 'Reg', (229, 237))	('tumor', 'Disease', 'MESH:D009369', (176, 181))
17976	31863083	For the extraction of the gene co-expression modules, we used RNA-seq data (accession numbers DRA001846 and DRA002311) from 27 cultured cell lines (26 lung cancer cell lines and small airway epithelial cells) incubated under basal conditions.	('lung cancer', 'Phenotype', 'HP:0100526', (151, 162))	('lung cancer', 'Disease', (151, 162))	('DRA002311', 'Var', (108, 117))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('lung cancer', 'Disease', 'MESH:D008175', (151, 162))
17978	31863083	A549 cells were seeded (1500 cells/well in 96-well plates) and incubated for 24 h at 37  C. NFE2L2 siRNAs (Silencer Select NFE2L2 s9491 and s9493, Applied Biosystems) and negative control siRNAs (Silencer Select Negative Control #1 siRNA, Applied Biosystems) were used for the transfection of the A549 cells.	('NFE2L2', 'Gene', (92, 98))	('A549', 'CellLine', 'CVCL:0023', (0, 4))	('NFE2L2', 'Gene', '4780', (123, 129))	('NFE2L2', 'Gene', (123, 129))	('s9493', 'Var', (140, 145))	('NFE2L2', 'Gene', '4780', (92, 98))	('A549', 'CellLine', 'CVCL:0023', (297, 301))
17994	31428517	Moreover, the median TIS score for GIST was between the 65th and 70th percentile of the Cancer Genome Atlas dataset, in the same range of tumors responding to anti-PD-1/PD-L1.	('Cancer', 'Phenotype', 'HP:0002664', (88, 94))	('Cancer Genome Atlas', 'Disease', (88, 107))	('TIS score', 'MPA', (21, 30))	('anti-PD-1/PD-L1', 'Var', (159, 174))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (88, 107))	('tumors', 'Disease', (138, 144))	('tumors', 'Disease', 'MESH:D009369', (138, 144))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('GIST', 'Phenotype', 'HP:0100723', (35, 39))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
17996	31428517	Gastrointestinal stromal tumors (GIST) are rare mesenchymal tumors characterized in the vast majority of cases by mutations of KIT proto-oncogene (KIT) and Platelet derived growth factor receptor alpha (PDGFRA) genes that are targets of tyrosine kinase inhibitors (TKI).	('GIST', 'Phenotype', 'HP:0100723', (33, 37))	('PDGFRA', 'Gene', '5156', (203, 209))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('PDGFRA', 'Gene', (203, 209))	('mutations', 'Var', (114, 123))	('tumors', 'Disease', (25, 31))	('Platelet derived growth factor receptor alpha', 'Gene', '5156', (156, 201))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('tumors', 'Disease', 'MESH:D009369', (60, 66))	('tumors', 'Disease', 'MESH:D009369', (25, 31))	('Gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (0, 31))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('Gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (0, 31))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('Gastrointestinal stromal tumors', 'Disease', (0, 31))	('KIT', 'Gene', (147, 150))	('Platelet derived growth factor receptor alpha', 'Gene', (156, 201))	('tumors', 'Disease', (60, 66))
18016	31428517	Overall, the absolute abundance estimation of tumor-infiltrating cells revealed some degree of variability, not due to the different molecular classes (KIT of PDGFRA mutant, Supplementary Figure S1A).	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('PDGFRA', 'Gene', (159, 165))	('tumor', 'Disease', (46, 51))	('PDGFRA', 'Gene', '5156', (159, 165))	('mutant', 'Var', (166, 172))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
18031	31428517	It is already known that imatinib can exert immune modulatory effects, that PD-1/PD-L1 blockade enhances the antitumor efficacy of imatinib in murine GIST model, and that JAK inhibitors and imatinib decrease the expression of PD-L1 in vitro in GIST882 and GIST-T1 cell lines.	('tumor', 'Disease', (113, 118))	('PD-1/PD-L1', 'Gene', (76, 86))	('imatinib', 'Chemical', 'MESH:D000068877', (131, 139))	('GIST-T1', 'CellLine', 'CVCL:4976', (256, 263))	('GIST', 'Phenotype', 'HP:0100723', (256, 260))	('expression', 'MPA', (212, 222))	('GIST', 'Phenotype', 'HP:0100723', (150, 154))	('decrease', 'NegReg', (199, 207))	('imatinib', 'Chemical', 'MESH:D000068877', (190, 198))	('PD-L1', 'Gene', (226, 231))	('GIST', 'Phenotype', 'HP:0100723', (244, 248))	('enhances', 'PosReg', (96, 104))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('murine', 'Species', '10090', (143, 149))	('blockade', 'Var', (87, 95))	('imatinib', 'Chemical', 'MESH:D000068877', (25, 33))
18034	31428517	Analysis conducted on public available GIST data showed that IRF1 and PD-L1 were significantly repressed in imatinib-treated with respect to pre-treatment samples (Figure 6).	('GIST', 'Phenotype', 'HP:0100723', (39, 43))	('imatinib', 'Chemical', 'MESH:D000068877', (108, 116))	('IRF1', 'Gene', (61, 65))	('IRF1', 'Gene', '3659', (61, 65))	('imatinib-treated', 'Var', (108, 124))	('repressed', 'NegReg', (95, 104))	('PD-L1', 'Gene', (70, 75))
18040	31428517	on the immune profiling of GIST reported a difference of immune cell infiltrate, immunological activity and expression of immune-related genes between PDGFRA- and KIT-mutant GIST.	('PDGFRA', 'Gene', '5156', (151, 157))	('PDGFRA', 'Gene', (151, 157))	('GIST', 'Phenotype', 'HP:0100723', (174, 178))	('GIST', 'Phenotype', 'HP:0100723', (27, 31))	('KIT-mutant', 'Var', (163, 173))	('expression', 'MPA', (108, 118))	('difference', 'Reg', (43, 53))
18052	31428517	Indeed, the induced upregulation of PD-L1 was abolished with imatinib and PD-1/PD-L1 blockade enhanced T-cell activity and increased the antitumor effects of imatinib.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('increased', 'PosReg', (123, 132))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('T-cell activity', 'CPA', (103, 118))	('tumor', 'Disease', (141, 146))	('blockade', 'Var', (85, 93))	('imatinib', 'Chemical', 'MESH:D000068877', (61, 69))	('PD-1/PD-L1', 'Gene', (74, 84))	('enhanced', 'PosReg', (94, 102))	('imatinib', 'Chemical', 'MESH:D000068877', (158, 166))
18055	31428517	Moreover, imatinib can synergize with immunotherapy since the treatment with anti-PD-1 or anti-PD-L1 in the Kit V558Delta/+ GIST murine model increases the effect of imatinib by enhancing CD8+ T-cell function.	('imatinib', 'Chemical', 'MESH:D000068877', (10, 18))	('effect', 'MPA', (156, 162))	('CD8', 'Gene', (188, 191))	('anti-PD-L1', 'Var', (90, 100))	('CD8', 'Gene', '925', (188, 191))	('increases', 'PosReg', (142, 151))	('enhancing', 'PosReg', (178, 187))	('imatinib', 'Chemical', 'MESH:D000068877', (166, 174))	('murine', 'Species', '10090', (129, 135))	('GIST', 'Phenotype', 'HP:0100723', (124, 128))	('anti-PD-1', 'Var', (77, 86))
18060	31428517	In fact, despite new TKIs, BLU285, DCC2618, and crenolanib demonstrated good and interesting results in the prolongation of survival in early phase trials, in the future it is expected that TKI resistance develops and thus more efforts are needed to find a cure beyond or along with TKI for long-term advanced GIST.	('BLU285', 'Var', (27, 33))	('DCC2618', 'Var', (35, 42))	('crenolanib', 'Chemical', 'MESH:C577197', (48, 58))	('BLU285', 'Chemical', '-', (27, 33))	('GIST', 'Phenotype', 'HP:0100723', (310, 314))
18064	31428517	All cases were revised by two pathologists with expertise in GIST diagnosis, and all samples were characterized by the presence of KIT or PDGFRA mutation.	('GIST', 'Phenotype', 'HP:0100723', (61, 65))	('KIT', 'Gene', (131, 134))	('PDGFRA', 'Gene', '5156', (138, 144))	('PDGFRA', 'Gene', (138, 144))	('presence', 'Reg', (119, 127))	('mutation', 'Var', (145, 153))
18095	31138322	We found that the TIM-1 expression was increased in human NSCLC tissues compared with the adjacent normal tissues, and the OS rate of NSCLC patients with higher TIM-1 expression was significantly lower compared with the ones with lower TIM-1 expression.	('NSCLC', 'Disease', 'MESH:D002289', (134, 139))	('lower', 'NegReg', (196, 201))	('expression', 'MPA', (167, 177))	('NSCLC', 'Disease', (134, 139))	('SCLC', 'Phenotype', 'HP:0030357', (59, 63))	('higher', 'Var', (154, 160))	('expression', 'MPA', (24, 34))	('NSCLC', 'Phenotype', 'HP:0030358', (134, 139))	('patients', 'Species', '9606', (140, 148))	('TIM-1', 'Gene', (236, 241))	('NSCLC', 'Disease', 'MESH:D002289', (58, 63))	('TIM-1', 'Gene', '26762', (236, 241))	('TIM-1', 'Gene', (161, 166))	('NSCLC', 'Disease', (58, 63))	('TIM-1', 'Gene', (18, 23))	('human', 'Species', '9606', (52, 57))	('SCLC', 'Phenotype', 'HP:0030357', (135, 139))	('increased', 'PosReg', (39, 48))	('TIM-1', 'Gene', '26762', (161, 166))	('NSCLC', 'Phenotype', 'HP:0030358', (58, 63))	('TIM-1', 'Gene', '26762', (18, 23))	('OS', 'Chemical', '-', (123, 125))
18097	31138322	Furthermore, we depleted TIM-1 in NSCLC cell lines A549 and SK-MES-1, and the cellular functional studies also revealed that depletion of TIM-1 could significantly inhibit the cell viability as well as the abilities of migration and invasion.	('NSCLC', 'Disease', (34, 39))	('TIM-1', 'Gene', (138, 143))	('TIM-1', 'Gene', (25, 30))	('A549', 'CellLine', 'CVCL:0023', (51, 55))	('NSCLC', 'Disease', 'MESH:D002289', (34, 39))	('cell viability', 'CPA', (176, 190))	('SK-MES-1', 'CellLine', 'CVCL:0630', (60, 68))	('SCLC', 'Phenotype', 'HP:0030357', (35, 39))	('inhibit', 'NegReg', (164, 171))	('NSCLC', 'Phenotype', 'HP:0030358', (34, 39))	('depletion', 'Var', (125, 134))	('TIM-1', 'Gene', '26762', (138, 143))	('TIM-1', 'Gene', '26762', (25, 30))
18098	31138322	In addition, our microarray data showed that certain signaling pathways were altered and enriched after depletion of TIM-1.	('signaling pathways', 'Pathway', (53, 71))	('TIM-1', 'Gene', (117, 122))	('altered', 'Reg', (77, 84))	('depletion', 'Var', (104, 113))	('TIM-1', 'Gene', '26762', (117, 122))
18112	31138322	have also reported that increased TIM-1 expression is found in human gastric cancer tissues compared with the normal gastric tissues at both the mRNA and protein levels, and high expression of TIM-1 can serve as a novel prognostic factor for gastric cancer.	('expression', 'MPA', (40, 50))	('gastric cancer', 'Disease', (69, 83))	('TIM-1', 'Gene', (34, 39))	('gastric cancer', 'Disease', (242, 256))	('human', 'Species', '9606', (63, 68))	('gastric cancer', 'Disease', 'MESH:D013274', (69, 83))	('gastric cancer', 'Disease', 'MESH:D013274', (242, 256))	('TIM-1', 'Gene', '26762', (193, 198))	('high expression', 'Var', (174, 189))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))	('gastric cancer', 'Phenotype', 'HP:0012126', (242, 256))	('gastric cancer', 'Phenotype', 'HP:0012126', (69, 83))	('TIM-1', 'Gene', (193, 198))	('TIM-1', 'Gene', '26762', (34, 39))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('increased', 'PosReg', (24, 33))
18122	31138322	Rabbit monoclonal antibodies against human PTEN (#9188), human phos-AKT (#9614) and human AKT (#4685) were obtained from Cell Signaling Technology (Danvers, MA, USA).	('#4685', 'Var', (95, 100))	('#9614', 'Var', (73, 78))	('AKT', 'Gene', (90, 93))	('PTEN', 'Gene', (43, 47))	('AKT', 'Gene', '207', (68, 71))	('PTEN', 'Gene', '5728', (43, 47))	('human', 'Species', '9606', (84, 89))	('human', 'Species', '9606', (37, 42))	('AKT', 'Gene', '207', (90, 93))	('Rabbit', 'Species', '9986', (0, 6))	('#9188', 'Var', (49, 54))	('AKT', 'Gene', (68, 71))	('human', 'Species', '9606', (57, 62))
18155	31138322	4a, P = 0.0011), and the OS rate of lung squamous cell carcinoma patients with higher TIM-1 mRNA expression level also trends to be lower than that of the patients with lower TIM-1 mRNA expression level (Fig.	('TIM-1', 'Gene', (175, 180))	('lung squamous cell carcinoma', 'Disease', (36, 64))	('TIM-1', 'Gene', '26762', (86, 91))	('OS', 'Chemical', '-', (25, 27))	('TIM-1', 'Gene', (86, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (55, 64))	('higher', 'Var', (79, 85))	('patients', 'Species', '9606', (65, 73))	('TIM-1', 'Gene', '26762', (175, 180))	('patients', 'Species', '9606', (155, 163))	('lower', 'NegReg', (132, 137))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (36, 64))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (41, 64))
18159	31138322	Moreover, the results of CCK-8 assay showed that the cell proliferation rate was significantly decreased upon depletion of TIM-1.	('decreased', 'NegReg', (95, 104))	('TIM-1', 'Gene', (123, 128))	('TIM-1', 'Gene', '26762', (123, 128))	('cell proliferation rate', 'CPA', (53, 76))	('depletion', 'Var', (110, 119))
18182	31138322	In addition, our microarray data revealed that certain signal pathways were altered and enriched after depletion of TIM-1.	('altered', 'Reg', (76, 83))	('TIM-1', 'Gene', '26762', (116, 121))	('depletion', 'Var', (103, 112))	('TIM-1', 'Gene', (116, 121))	('signal pathways', 'Pathway', (55, 70))
18188	31138322	Our findings demonstrated that abnormal TIM-1 expression was involved in the progression of human NSCLC, and supported the notion that TIM-1 could serve as an important prognostic risk factor for NSCLC patients.	('abnormal', 'Var', (31, 39))	('NSCLC', 'Disease', (196, 201))	('TIM-1', 'Gene', '26762', (135, 140))	('involved', 'Reg', (61, 69))	('TIM-1', 'Gene', (135, 140))	('NSCLC', 'Disease', 'MESH:D002289', (196, 201))	('NSCLC', 'Phenotype', 'HP:0030358', (98, 103))	('patients', 'Species', '9606', (202, 210))	('TIM-1', 'Gene', '26762', (40, 45))	('SCLC', 'Phenotype', 'HP:0030357', (99, 103))	('TIM-1', 'Gene', (40, 45))	('NSCLC', 'Disease', (98, 103))	('NSCLC', 'Phenotype', 'HP:0030358', (196, 201))	('expression', 'MPA', (46, 56))	('human', 'Species', '9606', (92, 97))	('NSCLC', 'Disease', 'MESH:D002289', (98, 103))	('SCLC', 'Phenotype', 'HP:0030357', (197, 201))
18199	30773592	A major goal of these sequencing projects is to identify cancer genes with mutations that drive the cancer phenotype.	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('cancer', 'Disease', (57, 63))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('mutations', 'Var', (75, 84))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))
18200	30773592	Better identification of cancer driver genes would inform potential therapies targeted against the products of these aberrant genomic alterations in addition to fundamentally advancing the knowledge of tumor initiation, promotion and progression.	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('tumor initiation', 'Disease', (202, 218))	('cancer', 'Disease', 'MESH:D009369', (25, 31))	('alterations', 'Var', (134, 145))	('cancer', 'Disease', (25, 31))	('tumor initiation', 'Disease', 'MESH:D009369', (202, 218))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))
18202	30773592	tumor suppressors) resulting randomly from truncated mutations may be missed.	('tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumor', 'Disease', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (0, 5))	('mutations', 'Var', (53, 62))
18216	30773592	It suggests that at least one kind of mutation in the tested gene  has driver effects and that the tested gene is likely a cancer driver.	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('cancer', 'Disease', (123, 129))	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('mutation', 'Var', (38, 46))
18222	30773592	For each type of point nonsilent mutations, different base compositions are considered (Supplementary Figure S1).	('Supplementary Figure S1', 'Disease', (88, 111))	('Supplementary Figure S1', 'Disease', 'MESH:D017034', (88, 111))	('point nonsilent mutations', 'Var', (17, 42))
18255	30773592	The CGC database manually curates a list of genes whose mutations have been causally implicated in cancer.	('mutations', 'Var', (56, 65))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('implicated', 'Reg', (85, 95))	('cancer', 'Disease', (99, 105))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
18269	30773592	To be classified as a tumor suppressor gene, more than 20% of the mutations in the gene need to be inactivating (Supplementary Table S3).	('mutations', 'Var', (66, 75))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('tumor', 'Disease', (22, 27))
18281	30773592	Deacetylation of HSPA5, another identified candidate BRCA driver gene, by HDAC6 reportedly leads to GP78-mediated HSPA5 ubiquitination at K447 and suppresses the metastatic property of breast cancer.	('HSPA5', 'Gene', (114, 119))	('suppresses', 'NegReg', (147, 157))	('BRCA', 'Gene', '672', (53, 57))	('HDAC6', 'Gene', '10013', (74, 79))	('metastatic property', 'CPA', (162, 181))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('ubiquitination', 'MPA', (120, 134))	('GP78', 'Gene', (100, 104))	('HSPA5', 'Gene', (17, 22))	('HSPA5', 'Gene', '3309', (114, 119))	('BRCA', 'Gene', (53, 57))	('HSPA5', 'Gene', '3309', (17, 22))	('GP78', 'Gene', '267', (100, 104))	('Deacetylation', 'Var', (0, 13))	('breast cancer', 'Phenotype', 'HP:0003002', (185, 198))	('leads to', 'Reg', (91, 99))	('HDAC6', 'Gene', (74, 79))	('breast cancer', 'Disease', 'MESH:D001943', (185, 198))	('breast cancer', 'Disease', (185, 198))	('BRCA', 'Phenotype', 'HP:0003002', (53, 57))
18282	30773592	Aberrant expression and activation of EPHA2, identified in CHOL, have been associated with more aggressive metastatic growth and poorer differentiation.	('poorer differentiation', 'CPA', (129, 151))	('Aberrant expression', 'Var', (0, 19))	('EPHA2', 'Gene', '1969', (38, 43))	('more aggressive metastatic growth', 'CPA', (91, 124))	('CHOL', 'Phenotype', 'HP:0030153', (59, 63))	('CHOL', 'CellLine', 'None', (59, 63))	('EPHA2', 'Gene', (38, 43))	('activation', 'PosReg', (24, 34))
18283	30773592	Inhibitors of signal transducer and activator of transcription 3 (STAT3) or DNMT1, identified in PAAD, might be novel strategies for treating pancreatic cancer because activated interleukin-6 (IL-6) /STAT3 signaling can induce cytokine signaling 3 (SOCS3) methylation via DNMT1, which promotes growth and metastasis of pancreatic cancer.	('STAT3', 'Gene', '6774', (200, 205))	('metastasis of pancreatic cancer', 'Disease', 'MESH:D009362', (305, 336))	('pancreatic cancer', 'Disease', (142, 159))	('DNMT1', 'Gene', '1786', (76, 81))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('metastasis of pancreatic cancer', 'Disease', (305, 336))	('interleukin-6', 'Gene', '3569', (178, 191))	('PAAD', 'Phenotype', 'HP:0006725', (97, 101))	('DNMT1', 'Gene', '1786', (272, 277))	('IL-6', 'Gene', '3569', (193, 197))	('interleukin-6', 'Gene', (178, 191))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (319, 336))	('growth', 'CPA', (294, 300))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (142, 159))	('signal transducer and activator of transcription 3', 'Gene', '6774', (14, 64))	('IL-6', 'Gene', (193, 197))	('DNMT1', 'Gene', (76, 81))	('DNMT1', 'Gene', (272, 277))	('STAT3', 'Gene', (66, 71))	('SOCS3', 'Gene', (249, 254))	('methylation', 'Var', (256, 267))	('pancreatic cancer', 'Disease', 'MESH:D010190', (319, 336))	('cancer', 'Phenotype', 'HP:0002664', (330, 336))	('STAT3', 'Gene', (200, 205))	('pancreatic cancer', 'Disease', 'MESH:D010190', (142, 159))	('induce', 'PosReg', (220, 226))	('promotes', 'PosReg', (285, 293))	('SOCS3', 'Gene', '9021', (249, 254))	('STAT3', 'Gene', '6774', (66, 71))
18286	30773592	Seven missense, and one nonsense mutations, and one frameshift indel were observed in NPAT in LUSC from TCGA (Supplementary Figure S4A).	('missense', 'Var', (6, 14))	('LUSC', 'Phenotype', 'HP:0030359', (94, 98))	('frameshift indel', 'Var', (52, 68))	('NPAT', 'Gene', '4863', (86, 90))	('NPAT', 'Gene', (86, 90))
18287	30773592	The majority of somatic mutations in NPAT are missense in the COSMIC (Supplementary Figure S4B).	('NPAT', 'Gene', (37, 41))	('mutations', 'Var', (24, 33))	('missense', 'Var', (46, 54))	('NPAT', 'Gene', '4863', (37, 41))
18294	30773592	Inhibition of NPAT also significantly reduced cell invasion in these LUSC cell lines (Figure 6D).	('LUSC', 'Phenotype', 'HP:0030359', (69, 73))	('NPAT', 'Gene', '4863', (14, 18))	('reduced', 'NegReg', (38, 45))	('NPAT', 'Gene', (14, 18))	('Inhibition', 'Var', (0, 10))	('cell invasion in', 'CPA', (46, 62))
18296	30773592	This was confirmed by western blot analysis in which the protein expression levels of Cyclin A2, Cyclin E2 and p27 were significantly altered upon the knockdown of NPAT in the lung cancer cell lines.	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('Cyclin A2', 'Gene', '890', (86, 95))	('NPAT in the lung cancer', 'Disease', 'MESH:D008175', (164, 187))	('protein expression levels', 'MPA', (57, 82))	('Cyclin E2', 'Gene', '9134', (97, 106))	('Cyclin A2', 'Gene', (86, 95))	('p27', 'Gene', '10671', (111, 114))	('altered', 'Reg', (134, 141))	('p27', 'Gene', (111, 114))	('lung cancer', 'Phenotype', 'HP:0100526', (176, 187))	('NPAT in the lung cancer', 'Disease', (164, 187))	('Cyclin E2', 'Gene', (97, 106))	('knockdown', 'Var', (151, 160))
18298	30773592	The weight parameters in the score statistic measure the functional impact of mutations in cancer.	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('mutations', 'Var', (78, 87))
18309	30773592	A major challenge in cancer genome sequencing is to identify cancer-associated genes with mutations that drive the cancer phenotype.	('cancer', 'Disease', (115, 121))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('mutations', 'Var', (90, 99))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('cancer', 'Disease', (61, 67))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('cancer', 'Disease', (21, 27))	('cancer', 'Disease', 'MESH:D009369', (21, 27))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('cancer', 'Disease', 'MESH:D009369', (115, 121))
18311	30773592	Although many such tools have been actively developed during the past few years, few are robust and powerful in the presence of multiple-level mutational heterogeneity across genomes within a patient, across patients within a given cancer type and across various cancer types.	('cancer', 'Disease', 'MESH:D009369', (232, 238))	('cancer', 'Disease', 'MESH:D009369', (263, 269))	('patients', 'Species', '9606', (208, 216))	('patient', 'Species', '9606', (192, 199))	('patient', 'Species', '9606', (208, 215))	('cancer', 'Disease', (232, 238))	('cancer', 'Disease', (263, 269))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('cancer', 'Phenotype', 'HP:0002664', (263, 269))	('mutational', 'Var', (143, 153))
18312	30773592	In this study, we developed a supervised machine learning approach (DriverML) to score the functional consequences of DNA sequence alterations to identify cancer driver genes (Figure 1B).	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('cancer', 'Disease', (155, 161))	('alterations', 'Var', (131, 142))	('cancer', 'Disease', 'MESH:D009369', (155, 161))
18332	29559623	In vivo animal results showed that overexpressed SOCS2 attenuated the metastatic characteristics of lung adenocarcinoma, including by inhibiting the epithelial-mesenchymal transition (EMT).	('lung adenocarcinoma', 'Disease', (100, 119))	('inhibiting', 'NegReg', (134, 144))	('metastatic characteristics of', 'CPA', (70, 99))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (100, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('attenuated', 'NegReg', (55, 65))	('overexpressed', 'Var', (35, 48))	('SOCS2', 'Gene', (49, 54))	('epithelial-mesenchymal transition', 'CPA', (149, 182))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (100, 119))
18335	29559623	Altogether, our results reveal an important role for SOCS2 dysregulation in the pathogenicity of lung adenocarcinoma, suggest its potential use as a biomarker for diagnosing lung adenocarcinoma, and paves the way to develop novel therapy targets as the axis of SOCS2-IGF1R-STAT in lung adenocarcinoma.	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (281, 300))	('IGF1R', 'Gene', (267, 272))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (97, 116))	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('carcinoma', 'Phenotype', 'HP:0030731', (184, 193))	('lung adenocarcinoma', 'Disease', (97, 116))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (174, 193))	('IGF1R', 'Gene', '3480', (267, 272))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (281, 300))	('carcinoma', 'Phenotype', 'HP:0030731', (291, 300))	('dysregulation', 'Var', (59, 72))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (97, 116))	('SOCS2', 'Gene', (53, 58))	('lung adenocarcinoma', 'Disease', (281, 300))	('lung adenocarcinoma', 'Disease', (174, 193))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (174, 193))
18340	29559623	NSCLC metastasis has been recently reported to be caused by a variety of aberrant molecular changes, including the mutational activation of ROS1, MET, HER2, RET, and ALK oncoproteins and the inactivation of the CDKN2A, RB1, and TP53 tumour suppressor genes.	('mutational', 'Var', (115, 125))	('CDKN2A', 'Gene', (211, 217))	('NSCLC metastasis', 'Disease', (0, 16))	('NSCLC metastasis', 'Disease', 'MESH:D009362', (0, 16))	('ROS1', 'Gene', '6098', (140, 144))	('NSCLC', 'Phenotype', 'HP:0030358', (0, 5))	('caused', 'Reg', (50, 56))	('TP53', 'Gene', (228, 232))	('oncoproteins', 'Protein', (170, 182))	('HER2', 'Gene', '2064', (151, 155))	('tumour', 'Phenotype', 'HP:0002664', (233, 239))	('tumour', 'Disease', 'MESH:D009369', (233, 239))	('CDKN2A', 'Gene', '1029', (211, 217))	('tumour', 'Disease', (233, 239))	('inactivation', 'NegReg', (191, 203))	('RET', 'Gene', '5979', (157, 160))	('RB1', 'Gene', (219, 222))	('ROS1', 'Gene', (140, 144))	('MET', 'Protein', (146, 149))	('activation', 'PosReg', (126, 136))	('SCLC', 'Phenotype', 'HP:0030357', (1, 5))	('TP53', 'Gene', '7157', (228, 232))	('HER2', 'Gene', (151, 155))	('ALK', 'Gene', '238', (166, 169))	('RB1', 'Gene', '5925', (219, 222))	('RET', 'Gene', (157, 160))	('ALK', 'Gene', (166, 169))
18347	29559623	Dysregulation of SOCS protein expression can be one of the mechanisms that induce the metastatic potential of hepatocellular carcinoma (HCC) cells in HCC progression.	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (110, 134))	('Dysregulation', 'Var', (0, 13))	('SOCS', 'Gene', (17, 21))	('hepatocellular carcinoma', 'Disease', (110, 134))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (110, 134))	('HCC', 'Disease', (150, 153))	('SOCS', 'Gene', '1154', (17, 21))	('HCC', 'Phenotype', 'HP:0001402', (150, 153))	('HCC', 'Phenotype', 'HP:0001402', (136, 139))	('induce', 'PosReg', (75, 81))	('metastatic potential', 'CPA', (86, 106))
18351	29559623	IGF1 and its receptor, type 1 insulin-like growth factor receptor (IGF1R), have been implicated in carcinogenesis, and deregulation of the IGF1R signalling cascade has been described in NSCLC.	('NSCLC', 'Phenotype', 'HP:0030358', (186, 191))	('IGF1R', 'Gene', (139, 144))	('carcinogenesis', 'Disease', 'MESH:D063646', (99, 113))	('insulin', 'Gene', (30, 37))	('IGF1R', 'Gene', (67, 72))	('IGF1', 'Gene', (0, 4))	('insulin', 'Gene', '3630', (30, 37))	('IGF1R', 'Gene', '3480', (139, 144))	('NSCLC', 'Disease', (186, 191))	('IGF1R', 'Gene', '3480', (67, 72))	('implicated', 'Reg', (85, 95))	('carcinogenesis', 'Disease', (99, 113))	('SCLC', 'Phenotype', 'HP:0030357', (187, 191))	('NSCLC', 'Disease', 'MESH:D002289', (186, 191))	('deregulation', 'Var', (119, 131))
18378	29559623	Furthermore, knockdown of SOCS2 in both A549-SOCS2 and SPC-A1-SOCS2 cells partially restored migratory and invasive efficiencies compared with that of the corresponding control, as revealed by both the wound healing (Supplementary Figure S3a) and transwell assays (Supplementary Figure S3b).	('invasive efficiencies', 'Disease', (107, 128))	('invasive efficiencies', 'Disease', 'MESH:D009362', (107, 128))	('A549-SOCS2', 'CellLine', 'CVCL:0023', (40, 50))	('restored', 'PosReg', (84, 92))	('rat', 'Species', '10116', (96, 99))	('knockdown', 'Var', (13, 22))	('SOCS2', 'Gene', (26, 31))
18381	29559623	3c, d, the A549-SOCS2 cells-injected mice displayed statistically significantly lower numbers of lung metastases (metastatic nodules) than the mice injected with control cells.	('lung metastases', 'Disease', (97, 112))	('lung metastases', 'Disease', 'MESH:D009362', (97, 112))	('lower', 'NegReg', (80, 85))	('A549-SOCS2 cells', 'CellLine', 'CVCL:0023', (11, 27))	('mice', 'Species', '10090', (143, 147))	('A549-SOCS2', 'Var', (11, 21))	('mice', 'Species', '10090', (37, 41))
18402	29559623	Depletion of SOCS2 in A549-SOCS2 cells substantially restored the phosphorylation of both STAT3 and STAT5 (Supplementary Figure S7), indicating that both STAT3 and STAT5 activity are primarily subjected to negative regulation by SOCS2 in lung adenocarcinoma cells.	('STAT3', 'Gene', '6774', (90, 95))	('A549-SOCS2 cells', 'CellLine', 'CVCL:0023', (22, 38))	('STAT5', 'Gene', (164, 169))	('STAT3', 'Gene', (90, 95))	('STAT5', 'Gene', (100, 105))	('lung adenocarcinoma', 'Disease', (238, 257))	('phosphorylation', 'MPA', (66, 81))	('Depletion', 'Var', (0, 9))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (238, 257))	('STAT5', 'Gene', '6776', (100, 105))	('STAT3', 'Gene', '6774', (154, 159))	('carcinoma', 'Phenotype', 'HP:0030731', (248, 257))	('STAT5', 'Gene', '6776', (164, 169))	('STAT3', 'Gene', (154, 159))	('restored', 'PosReg', (53, 61))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (238, 257))	('SOCS2', 'Gene', (13, 18))
18415	29559623	Overexpression SOCS2 reduced lung adenocarcinoma cell migration and invasion in vitro and inhibited metastasis of lung adenocarcinoma cells in vivo by regulating EMT biomarkers, suggesting that reduced SOCS2 promotes the progression of lung adenocarcinoma.	('invasion', 'CPA', (68, 76))	('SOCS2', 'Gene', (15, 20))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (29, 48))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (236, 255))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (29, 48))	('metastasis of lung adenocarcinoma', 'Disease', 'MESH:D009362', (100, 133))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (236, 255))	('carcinoma', 'Phenotype', 'HP:0030731', (246, 255))	('carcinoma', 'Phenotype', 'HP:0030731', (39, 48))	('lung adenocarcinoma cell migration', 'Disease', 'MESH:D000077192', (29, 63))	('reduced', 'Var', (194, 201))	('inhibited', 'NegReg', (90, 99))	('metastasis of lung adenocarcinoma', 'Disease', (100, 133))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (114, 133))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (114, 133))	('lung adenocarcinoma cell migration', 'Disease', (29, 63))	('promotes', 'PosReg', (208, 216))	('reduced', 'NegReg', (21, 28))	('SOCS2', 'Gene', (202, 207))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('lung adenocarcinoma', 'Disease', (236, 255))
18430	29559623	In the current study, our data show that SOCS2 is involved in attenuating the IGF1-induced STAT3 and STAT5 activity in lung adenocarcinoma cells.	('STAT5', 'Gene', '6776', (101, 106))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (119, 138))	('SOCS2', 'Var', (41, 46))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('STAT5', 'Gene', (101, 106))	('IGF1-induced', 'Gene', (78, 90))	('STAT3', 'Gene', '6774', (91, 96))	('attenuating', 'NegReg', (62, 73))	('lung adenocarcinoma', 'Disease', (119, 138))	('STAT3', 'Gene', (91, 96))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (119, 138))
18438	29559623	Most interestingly, the expression of SOCS2 dose dependently reduced the interaction between IGF1R and STAT3 or STAT5, indicating that SOCS2 acts as a STAT3/STAT5 inhibitor that can competitively bind to IGF1R and thus can attenuate the IGF1-induced STAT3/STAT5 activity in lung adenocarcinoma cells.	('STAT3', 'Gene', (103, 108))	('SOCS2', 'Gene', (135, 140))	('STAT5', 'Gene', '6776', (112, 117))	('STAT5', 'Gene', '6776', (256, 261))	('lung adenocarcinoma', 'Disease', (274, 293))	('STAT3', 'Gene', '6774', (103, 108))	('STAT5', 'Gene', (256, 261))	('STAT5', 'Gene', (112, 117))	('STAT3', 'Gene', (151, 156))	('carcinoma', 'Phenotype', 'HP:0030731', (284, 293))	('STAT5', 'Gene', '6776', (157, 162))	('STAT3', 'Gene', '6774', (151, 156))	('STAT5', 'Gene', (157, 162))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (274, 293))	('IGF1R', 'Gene', '3480', (93, 98))	('IGF1R', 'Gene', '3480', (204, 209))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (274, 293))	('IGF1R', 'Gene', (93, 98))	('STAT3', 'Gene', (250, 255))	('expression', 'Var', (24, 34))	('bind', 'Interaction', (196, 200))	('IGF1R', 'Gene', (204, 209))	('attenuate', 'NegReg', (223, 232))	('interaction', 'Interaction', (73, 84))	('STAT3', 'Gene', '6774', (250, 255))	('reduced', 'NegReg', (61, 68))
18443	29559623	In conclusion, this study presents the pivotal finding that low expression of SOCS2 induces invasion and metastasis of human lung adenocarcinoma cells by regulating EMT both in vitro and in vivo, which is mainly dependent on the IGF1/IGF1R-stimulated STAT3 or STAT5 pathway.	('STAT3', 'Gene', (251, 256))	('EMT', 'CPA', (165, 168))	('lung adenocarcinoma', 'Disease', (125, 144))	('low expression', 'Var', (60, 74))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (125, 144))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('invasion', 'CPA', (92, 100))	('regulating', 'Reg', (154, 164))	('human', 'Species', '9606', (119, 124))	('IGF1R', 'Gene', (234, 239))	('metastasis', 'CPA', (105, 115))	('STAT5', 'Gene', '6776', (260, 265))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (125, 144))	('SOCS2', 'Gene', (78, 83))	('STAT3', 'Gene', '6774', (251, 256))	('IGF1R', 'Gene', '3480', (234, 239))	('STAT5', 'Gene', (260, 265))	('induces', 'Reg', (84, 91))
18484	27994422	Many irreversible changes in deoxyribonucleic acid (DNA) sequence such as mutations, amplifications, and gene deletions may either activate oncogenes or inactivate tumor suppressor genes.	('changes', 'Var', (18, 25))	('amplifications', 'Var', (85, 99))	('inactivate', 'NegReg', (153, 163))	('tumor', 'Disease', (164, 169))	('mutations', 'Var', (74, 83))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('gene deletions', 'Var', (105, 119))	('activate', 'PosReg', (131, 139))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('oncogenes', 'CPA', (140, 149))
18485	27994422	These genetic alterations may lead to the development of oral premalignancy and its progression to oral cancer.	('oral cancer', 'Disease', (99, 110))	('lead to', 'Reg', (30, 37))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('oral premalignancy', 'Disease', (57, 75))	('oral cancer', 'Disease', 'MESH:D009062', (99, 110))	('genetic alterations', 'Var', (6, 25))	('oral premalignancy', 'Disease', 'MESH:D020820', (57, 75))
18489	27994422	The various changes in tumor suppressor genes such as loss of heterozygosity, mutation, and microsatellite instability cause increase in genetic vulnerability for malignant transformation.	('mutation', 'Var', (78, 86))	('genetic vulnerability', 'MPA', (137, 158))	('increase', 'PosReg', (125, 133))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('loss', 'NegReg', (54, 58))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('microsatellite', 'MPA', (92, 106))	('tumor', 'Disease', (23, 28))
18493	27994422	Studies have shown that PTEN mutations along with the loss of heterozygosity of the PTEN locus are seen in some cases of head and neck squamous cell carcinoma.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (135, 158))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (121, 158))	('carcinoma', 'Phenotype', 'HP:0030731', (149, 158))	('mutations', 'Var', (29, 38))	('PTEN', 'Gene', (84, 88))	('neck squamous cell carcinoma', 'Disease', (130, 158))	('seen', 'Reg', (99, 103))	('PTEN', 'Gene', (24, 28))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (130, 158))
18515	27994422	PTEN mutation has been demonstrated in many cancers; however, a rare PTEN mutation has been demonstrated in OSCC.	('mutation', 'Var', (74, 82))	('cancers', 'Phenotype', 'HP:0002664', (44, 51))	('cancers', 'Disease', (44, 51))	('cancers', 'Disease', 'MESH:D009369', (44, 51))	('demonstrated', 'Reg', (92, 104))	('mutation', 'Var', (5, 13))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('OSCC', 'Disease', (108, 112))
18517	27994422	Some studies have shown that PTEN gene alterations have been related to advanced disease.	('PTEN', 'Gene', (29, 33))	('related', 'Reg', (61, 68))	('alterations', 'Var', (39, 50))	('gene alterations', 'Var', (34, 50))	('advanced disease', 'Disease', (72, 88))	('advanced disease', 'Disease', 'MESH:D020178', (72, 88))
18520	27994422	Since AKT pathway involves many downregulations such as inhibition of tumor cell proliferation, apoptosis, and DNA repair and it is also associated with radioresistance mechanisms, inactivation of PTEN can affect the efficiency of anticancer therapy.	('inhibition', 'NegReg', (56, 66))	('AKT', 'Gene', (6, 9))	('associated', 'Reg', (137, 147))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('inactivation', 'Var', (181, 193))	('cancer', 'Disease', (235, 241))	('cancer', 'Disease', 'MESH:D009369', (235, 241))	('tumor', 'Disease', (70, 75))	('PTEN', 'Gene', (197, 201))	('apoptosis', 'CPA', (96, 105))	('AKT', 'Gene', '207', (6, 9))	('downregulations', 'NegReg', (32, 47))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))	('DNA repair', 'CPA', (111, 121))	('affect', 'Reg', (206, 212))
18532	27539087	Overall and cancer-free survival rates were significantly higher in REG-I positive group (p = 0.000434 and 1.0847E-8, respectively).	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('REG', 'Gene', (68, 71))	('cancer', 'Disease', (12, 18))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('Overall', 'CPA', (0, 7))	('higher', 'PosReg', (58, 64))	('REG', 'Gene', '5967', (68, 71))	('positive', 'Var', (74, 82))
18570	27539087	Also, the cancer-free survival rate was significantly higher among patients with a positive REG-I index than among those with a negative index (5-year survival rates were 59 and 8 %, respectively, p = 1.0847E-8).	('REG', 'Gene', (92, 95))	('patients', 'Species', '9606', (67, 75))	('higher', 'PosReg', (54, 60))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('positive', 'Var', (83, 91))	('cancer', 'Disease', 'MESH:D009369', (10, 16))	('cancer', 'Disease', (10, 16))	('REG', 'Gene', '5967', (92, 95))
18577	27539087	We compared those patients with the REG-I negative group (24 patients) and found that the REG-I positive group had a lower incidence of lymphatic permeation (absent in 22 patients (61 %) in the positive group but only six patients (25 %) in the negative group) and vascular invasion (absent in 27 patients (75 %) in the positive group and 11 patients (46 %) in the negative group); and that pathological lymph nodes were absent in 26 patients (72 %) in the positive group, but only nine patients (38 %) in the negative group.	('lymphatic permeation', 'MPA', (136, 156))	('patients', 'Species', '9606', (434, 442))	('REG', 'Gene', '5967', (90, 93))	('vascular invasion', 'CPA', (265, 282))	('patients', 'Species', '9606', (297, 305))	('patients', 'Species', '9606', (342, 350))	('patients', 'Species', '9606', (487, 495))	('patients', 'Species', '9606', (222, 230))	('patients', 'Species', '9606', (61, 69))	('lower', 'NegReg', (117, 122))	('positive', 'Var', (96, 104))	('REG', 'Gene', '5967', (36, 39))	('REG', 'Gene', (90, 93))	('patients', 'Species', '9606', (171, 179))	('patients', 'Species', '9606', (18, 26))	('absent', 'NegReg', (284, 290))	('REG', 'Gene', (36, 39))	('absent', 'NegReg', (158, 164))
18589	27539087	We found that REG-I expression is associated with longer survival in advanced head and neck cancer treated by chemoradiotherapy; our results are consistent with previous results regarding esophageal cancer.	('esophageal cancer', 'Disease', 'MESH:D004938', (188, 205))	('neck cancer', 'Disease', 'MESH:D006258', (87, 98))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('REG', 'Gene', '5967', (14, 17))	('neck cancer', 'Disease', (87, 98))	('expression', 'Var', (20, 30))	('REG', 'Gene', (14, 17))	('head and neck cancer', 'Phenotype', 'HP:0012288', (78, 98))	('esophageal cancer', 'Disease', (188, 205))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('longer', 'PosReg', (50, 56))
18591	27539087	It has also been demonstrated that, REG-I positivity is associated with a worse overall survival rate in patients with surgically treated gastric carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('patients', 'Species', '9606', (105, 113))	('overall survival', 'MPA', (80, 96))	('positivity', 'Var', (42, 52))	('gastric carcinoma', 'Disease', 'MESH:D013274', (138, 155))	('REG', 'Gene', '5967', (36, 39))	('gastric carcinoma', 'Disease', (138, 155))	('worse', 'NegReg', (74, 79))	('REG', 'Gene', (36, 39))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (138, 155))
18598	27539087	The results of our study indicate that REG-I is expressed by advanced head and neck squamous cell carcinoma and that REG-I positivity, in cases treated with chemo-radiotherapy, is associated with a lower incidence of lymphatic permeation, vascular invasion and pathological lymph nodes.	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (70, 107))	('REG', 'Gene', '5967', (117, 120))	('positivity', 'Var', (123, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('neck squamous cell carcinoma', 'Disease', (79, 107))	('REG', 'Gene', (117, 120))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (79, 107))	('lymphatic permeation', 'CPA', (217, 237))	('vascular invasion', 'CPA', (239, 256))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (84, 107))	('REG', 'Gene', '5967', (39, 42))	('REG', 'Gene', (39, 42))	('lower', 'NegReg', (198, 203))
18618	26372838	Retrospective cohort and case-control studies have demonstrated that voriconazole increases the risk for developing SCC in lung transplant recipients.	('SCC', 'Gene', (116, 119))	('SCC', 'Phenotype', 'HP:0002860', (116, 119))	('SCC', 'Gene', '6317', (116, 119))	('voriconazole', 'Var', (69, 81))	('voriconazole', 'Chemical', 'MESH:D065819', (69, 81))
18642	26372838	First, medical records were reviewed for appropriate ICD-9 diagnostic codes (117.3 and 484.6) for invasive aspergillosis.	('invasive aspergillosis', 'Disease', (98, 120))	('invasive aspergillosis', 'Disease', 'MESH:D055744', (98, 120))	('117.3', 'Var', (77, 82))	('invasive aspergillosis', 'Phenotype', 'HP:0020103', (98, 120))
18674	26372838	In our adjusted cumulative incidence model, we found voriconazole exposure was associated with an absolute risk decrease for colonization of 19% at 5 years and 24% at 10 years post-transplant (Table 3).	('voriconazole', 'Var', (53, 65))	('colonization', 'CPA', (125, 137))	('voriconazole', 'Chemical', 'MESH:D065819', (53, 65))	('decrease', 'NegReg', (112, 120))
18678	26372838	In our adjusted cumulative incidence models, we found voriconazole exposure was associated with an absolute risk decrease for invasive aspergillosis of 2% at 1 year, 4% at 5 years and 6% at 10 years post-transplant (Table 3).	('decrease', 'NegReg', (113, 121))	('invasive aspergillosis', 'Disease', (126, 148))	('invasive aspergillosis', 'Disease', 'MESH:D055744', (126, 148))	('invasive aspergillosis', 'Phenotype', 'HP:0020103', (126, 148))	('voriconazole', 'Var', (54, 66))	('voriconazole', 'Chemical', 'MESH:D065819', (54, 66))
18684	26372838	Using unadjusted Kaplan Meier methods, voriconazole exposure was associated with an absolute risk decrease for all-cause mortality of 14% at 5 years and 8% at 10 years (Figure 1b).	('all-cause mortality', 'MPA', (111, 130))	('voriconazole', 'Var', (39, 51))	('voriconazole', 'Chemical', 'MESH:D065819', (39, 51))	('decrease', 'NegReg', (98, 106))
18685	26372838	In this retrospective cohort study of 455 lung transplant recipients, we found that voriconazole exposure is associated with an increased risk of developing SCC, but also significantly reduces risk of developing Aspergillus colonization after lung transplantation, and, among those that become colonizers, all cause-mortality.	('SCC', 'Gene', (157, 160))	('cause-mortality', 'Reg', (310, 325))	('SCC', 'Phenotype', 'HP:0002860', (157, 160))	('reduces', 'NegReg', (185, 192))	('SCC', 'Gene', '6317', (157, 160))	('voriconazole', 'Chemical', 'MESH:D065819', (84, 96))	('voriconazole', 'Var', (84, 96))
18732	32948745	Furthermore, LINC00319 knockdown was found to attenuate the carcinogenic function of CCL18 in OSCC, reducing OSCC proliferation, metastasis, epithelial-mesenchymal transition (EMT), and angiogenesis.	('LINC00319', 'Gene', '284836', (13, 22))	('angiogenesis', 'CPA', (186, 198))	('carcinogenic', 'Disease', (60, 72))	('OSCC', 'Disease', (94, 98))	('LINC00319', 'Gene', (13, 22))	('OSCC', 'Disease', (109, 113))	('knockdown', 'Var', (23, 32))	('reducing', 'NegReg', (100, 108))	('attenuate', 'NegReg', (46, 55))	('CCL18', 'Gene', '6362', (85, 90))	('metastasis', 'CPA', (129, 139))	('epithelial-mesenchymal transition', 'CPA', (141, 174))	('CCL18', 'Gene', (85, 90))	('carcinogenic', 'Disease', 'MESH:D063646', (60, 72))
18733	32948745	LINC00319 was demonstrated to act as a ceRNA in OSCC, which directly responded to miR-199a-5p and rescued the repression of FZD4 by miR-199a-5p.	('LINC00319', 'Gene', (0, 9))	('miR-199a-5p', 'Chemical', '-', (132, 143))	('rescued', 'PosReg', (98, 105))	('repression', 'MPA', (110, 120))	('responded to miR-199a-5p', 'MPA', (69, 93))	('miR-199a-5p', 'Chemical', '-', (82, 93))	('miR-199a-5p', 'Var', (132, 143))	('LINC00319', 'Gene', '284836', (0, 9))	('FZD4', 'Gene', '8322', (124, 128))	('FZD4', 'Gene', (124, 128))
18736	32948745	Importantly, the expression of miR-199a-5p and FZD4 were found to be mediated by CCL18, and miR-199a-5p mimics inhibited the CCL18-promoting effects in oral cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('CCL18', 'Gene', '6362', (125, 130))	('FZD4', 'Gene', '8322', (47, 51))	('CCL18', 'Gene', (125, 130))	('expression', 'MPA', (17, 27))	('miR-199a-5p', 'Gene', (31, 42))	('FZD4', 'Gene', (47, 51))	('miR-199a-5p', 'Chemical', '-', (92, 103))	('oral cancer', 'Disease', 'MESH:D009369', (152, 163))	('CCL18', 'Gene', '6362', (81, 86))	('mediated', 'Reg', (69, 77))	('CCL18', 'Gene', (81, 86))	('inhibited', 'NegReg', (111, 120))	('miR-199a-5p', 'Chemical', '-', (31, 42))	('oral cancer', 'Disease', (152, 163))	('miR-199a-5p', 'Var', (92, 103))
18753	32948745	Recent data has revealed that dysregulated LINC00319 was implicated in the progression of many cancers by involving a ceRNA network.	('involving', 'Reg', (106, 115))	('ceRNA', 'CPA', (118, 123))	('dysregulated', 'Var', (30, 42))	('implicated', 'Reg', (57, 67))	('cancers', 'Phenotype', 'HP:0002664', (95, 102))	('cancers', 'Disease', (95, 102))	('cancers', 'Disease', 'MESH:D009369', (95, 102))	('LINC00319', 'Gene', '284836', (43, 52))	('LINC00319', 'Gene', (43, 52))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))
18757	32948745	The present study hypothesized that the knockdown of LINC00319 could inhibit the oncogenic function of CCL18 in OSCC, and therefore, aimed to investigate CCL18-induced LINC00319 expression as a potential molecular mechanism underpinning OSCC.	('OSCC', 'Disease', (237, 241))	('CCL18', 'Gene', (103, 108))	('CCL18', 'Gene', '6362', (103, 108))	('LINC00319', 'Gene', (168, 177))	('knockdown', 'Var', (40, 49))	('OSCC', 'Disease', (112, 116))	('LINC00319', 'Gene', '284836', (53, 62))	('CCL18', 'Gene', '6362', (154, 159))	('CCL18', 'Gene', (154, 159))	('LINC00319', 'Gene', (53, 62))	('inhibit', 'NegReg', (69, 76))	('LINC00319', 'Gene', '284836', (168, 177))
18773	32948745	An RNA FISH probe mix for LINC00319 with Cy3-labeling and a FISH probe mix for miR-199a-5p with FAM-labeled were each designed (GenePharma, China), and applied to HSC6 cells using a RiboTM Fluorescent In Situ Hybridization Kit (RiboBio, Guangzhou, China) according to kit instructions.	('Kit', 'Gene', (223, 226))	('HSC6', 'CellLine', 'CVCL:A615', (163, 167))	('Cy3-labeling', 'Var', (41, 53))	('kit', 'Gene', (268, 271))	('Kit', 'Gene', '3815', (223, 226))	('kit', 'Gene', '3815', (268, 271))	('LINC00319', 'Gene', '284836', (26, 35))	('miR-199a-5p', 'Chemical', '-', (79, 90))	('LINC00319', 'Gene', (26, 35))
18776	32948745	In all, 4 mumol/L FISH probes for miR-199a-5p and LINC00319 were added on HSC6 cells with the hybridization buffer and incubated at 37  C overnight.	('HSC6', 'CellLine', 'CVCL:A615', (74, 78))	('miR-199a-5p', 'Chemical', '-', (34, 45))	('LINC00319', 'Gene', '284836', (50, 59))	('LINC00319', 'Gene', (50, 59))	('miR-199a-5p', 'Var', (34, 45))
18816	32948745	The percentage of HSC6 cells in rCCL18 + siLINC00319 group was significantly increased in the G0/G1 phase, and the percentage of CAL27 cells in rCCL18 + siLINC00319 group showed to be notably increased in G0/G1 phase and decreased in S phase (Fig.	('G0/G1 phase', 'CPA', (94, 105))	('HSC6', 'CellLine', 'CVCL:A615', (18, 22))	('siLINC00319', 'Chemical', '-', (41, 52))	('rCCL18', 'Chemical', '-', (144, 150))	('rCCL18 + siLINC00319', 'Var', (32, 52))	('siLINC00319', 'Chemical', '-', (153, 164))	('CAL27', 'CellLine', 'CVCL:1107', (129, 134))	('G0/G1 phase', 'CPA', (205, 216))	('decreased', 'NegReg', (221, 230))	('S phase', 'CPA', (234, 241))	('increased', 'PosReg', (77, 86))	('rCCL18', 'Chemical', '-', (32, 38))	('increased', 'PosReg', (192, 201))
18817	32948745	Meanwhile, HSC6 and CAL27 cells apoptosis rate were increased in rCCL18 + siLINC00319 group compared with that in the rCCL18+siNC group (Fig.	('rCCL18 + siLINC00319', 'Var', (65, 85))	('HSC6', 'CellLine', 'CVCL:A615', (11, 15))	('increased', 'PosReg', (52, 61))	('rCCL18', 'Chemical', '-', (65, 71))	('rCCL18', 'Chemical', '-', (118, 124))	('siLINC00319', 'Chemical', '-', (74, 85))	('CAL27', 'CellLine', 'CVCL:1107', (20, 25))	('siNC', 'Chemical', 'MESH:C052464', (125, 129))
18818	32948745	1h and i depicted that the number of cells on the submembrane surface decreased despite the stimulation of rCCL18, in the presence of siLINC00319.	('rCCL18', 'Gene', (107, 113))	('stimulation', 'PosReg', (92, 103))	('siLINC00319', 'Var', (134, 145))	('decreased', 'NegReg', (70, 79))	('rCCL18', 'Chemical', '-', (107, 113))	('siLINC00319', 'Chemical', '-', (134, 145))
18820	32948745	HUVEC cells were cultured with cell culture supernatant of HSC6 and CAL27 cells which were pretreated with rCCL18 + siLINC00319 and rCCL18+siNC.	('rCCL18 + siLINC00319', 'Var', (107, 127))	('HUVEC', 'CellLine', 'CVCL:2959', (0, 5))	('siLINC00319', 'Chemical', '-', (116, 127))	('rCCL18+siNC', 'Var', (132, 143))	('rCCL18', 'Chemical', '-', (107, 113))	('rCCL18', 'Chemical', '-', (132, 138))	('CAL27', 'CellLine', 'CVCL:1107', (68, 73))	('HSC6', 'CellLine', 'CVCL:A615', (59, 63))	('siNC', 'Chemical', 'MESH:C052464', (139, 143))
18821	32948745	Results showed that the angiogenesis (i.e., number of branches, meshes, junctions, and the total mesh area)of HUVEC in the rCCL18 + siLINC00319 group was markedly attenuated compared with the control (Fig.	('rCCL18', 'Chemical', '-', (123, 129))	('siLINC00319', 'Chemical', '-', (132, 143))	('attenuated', 'NegReg', (163, 173))	('HUVEC', 'CellLine', 'CVCL:2959', (110, 115))	('meshes', 'CPA', (64, 70))	('angiogenesis', 'CPA', (24, 36))	('rCCL18', 'Var', (123, 129))
18827	32948745	The results indicated that miR-199a-5p and let-7a-5p may potentially bind to LINC00319 with high conservation.	('bind', 'Interaction', (69, 73))	('miR-199a-5p', 'Var', (27, 38))	('let-7a-5p', 'Var', (43, 52))	('LINC00319', 'Gene', '284836', (77, 86))	('miR-199a-5p', 'Chemical', '-', (27, 38))	('LINC00319', 'Gene', (77, 86))
18829	32948745	The FISH assay confirmed that LINC00319 and miR-199a-5p were primarily expressed in the cytoplasm, and provided a basis indicating their potential interaction (Fig.	('LINC00319', 'Gene', (30, 39))	('interaction', 'Interaction', (147, 158))	('miR-199a-5p', 'Chemical', '-', (44, 55))	('LINC00319', 'Gene', '284836', (30, 39))	('miR-199a-5p', 'Var', (44, 55))
18840	32948745	The CCK8 assay demonstrated that OSCC cells proliferation decreased 72 h after LINC00319 silencing, and that miR-199a-5p inhibitor treatment compensated for the effect of LINC00319 knockdown on OSCC cells proliferation at 72 h (Fig.	('OSCC cells proliferation', 'CPA', (33, 57))	('LINC00319', 'Gene', (79, 88))	('decreased', 'NegReg', (58, 67))	('miR-199a-5p', 'Chemical', '-', (109, 120))	('LINC00319', 'Gene', '284836', (171, 180))	('silencing', 'Var', (89, 98))	('LINC00319', 'Gene', (171, 180))	('LINC00319', 'Gene', '284836', (79, 88))
18846	32948745	In addition, upon LINC00319 depletion, E-cadherin protein levels were found increased, N-cadherin and ZEB2 maintained low expression, and MMP-9 and VEGF-A protein levels were found decreased.	('low', 'NegReg', (118, 121))	('MMP-9', 'Gene', '4318', (138, 143))	('expression', 'MPA', (122, 132))	('ZEB2', 'Gene', '9839', (102, 106))	('LINC00319', 'Gene', '284836', (18, 27))	('E-cadherin', 'Gene', (39, 49))	('MMP-9', 'Gene', (138, 143))	('increased', 'PosReg', (76, 85))	('LINC00319', 'Gene', (18, 27))	('E-cadherin', 'Gene', '999', (39, 49))	('ZEB2', 'Gene', (102, 106))	('depletion', 'Var', (28, 37))	('VEGF-A', 'Gene', '7422', (148, 154))	('N-cadherin', 'Gene', (87, 97))	('VEGF-A', 'Gene', (148, 154))	('N-cadherin', 'Gene', '1000', (87, 97))	('decreased', 'NegReg', (181, 190))
18853	32948745	Figure S3d showed that at 72 h, the CCL18-induced proliferation in OSCC was inhibited by miR-199a-5p upregulation.	('miR-199a-5p', 'Var', (89, 100))	('upregulation', 'PosReg', (101, 113))	('proliferation', 'CPA', (50, 63))	('CCL18', 'Gene', '6362', (36, 41))	('miR-199a-5p', 'Chemical', '-', (89, 100))	('CCL18', 'Gene', (36, 41))	('inhibited', 'NegReg', (76, 85))
18854	32948745	Moreover, miR-199a-5p overexpression was found to attenuate the effects of CCL18 on metastasis, EMT, and angiogenesis of OSCC (Fig.	('EMT', 'CPA', (96, 99))	('OSCC', 'Disease', (121, 125))	('overexpression', 'PosReg', (22, 36))	('angiogenesis', 'CPA', (105, 117))	('miR-199a-5p', 'Var', (10, 21))	('metastasis', 'CPA', (84, 94))	('CCL18', 'Gene', '6362', (75, 80))	('attenuate', 'NegReg', (50, 59))	('CCL18', 'Gene', (75, 80))	('miR-199a-5p', 'Chemical', '-', (10, 21))
18855	32948745	These results suggested that miR-199a-5p is an important component of the CCL18-mediated axis for regulating OSCC development.	('miR-199a-5p', 'Chemical', '-', (29, 40))	('CCL18', 'Gene', (74, 79))	('CCL18', 'Gene', '6362', (74, 79))	('miR-199a-5p', 'Var', (29, 40))	('OSCC development', 'CPA', (109, 125))
18858	32948745	Afterward, qRT-PCR results showed that LINC00319 knockdown could effectively reduce the expression of all these genes, except LAMC1, whose difference in expression was not statistically significant.	('LAMC1', 'Gene', (126, 131))	('knockdown', 'Var', (49, 58))	('reduce', 'NegReg', (77, 83))	('expression', 'MPA', (88, 98))	('LINC00319', 'Gene', '284836', (39, 48))	('LAMC1', 'Gene', '3915', (126, 131))	('LINC00319', 'Gene', (39, 48))
18859	32948745	However, only FZD4 mRNA levels were decreased in the miR-199a-5p-overexpressing HSC6 cells.	('miR-199a-5p', 'Chemical', '-', (53, 64))	('HSC6', 'CellLine', 'CVCL:A615', (80, 84))	('FZD4', 'Gene', (14, 18))	('FZD4', 'Gene', '8322', (14, 18))	('miR-199a-5p-overexpressing', 'Var', (53, 79))	('decreased', 'NegReg', (36, 45))
18863	32948745	Overall, these results implied that LINC00319, miR-199a-5p, and FZD4 constitute a ceRNA network.	('miR-199a-5p', 'Var', (47, 58))	('FZD4', 'Gene', '8322', (64, 68))	('FZD4', 'Gene', (64, 68))	('miR-199a-5p', 'Chemical', '-', (47, 58))	('LINC00319', 'Gene', '284836', (36, 45))	('LINC00319', 'Gene', (36, 45))
18866	32948745	siLINC00319 and siNC were transfected into stable FZD4-overexpressing and NC-overexpressing OSCC cells for 48 h. The results of the CCK8 assay, transwell assay, angiogenesis assay, and western blot showed that FZD4 upregulation promoted the proliferation, migration, invasion, EMT, and angiogenesis of OSCC, and partially reverse the inhibitory those effects of siLINC00319 in OSCC (Fig.	('FZD4', 'Gene', '8322', (50, 54))	('angiogenesis', 'CPA', (286, 298))	('siLINC00319', 'Chemical', '-', (0, 11))	('promoted', 'PosReg', (228, 236))	('FZD4', 'Gene', (50, 54))	('invasion', 'CPA', (267, 275))	('proliferation', 'CPA', (241, 254))	('siNC', 'Chemical', 'MESH:C052464', (16, 20))	('EMT', 'CPA', (277, 280))	('siLINC00319', 'Chemical', '-', (362, 373))	('FZD4', 'Gene', '8322', (210, 214))	('migration', 'CPA', (256, 265))	('FZD4', 'Gene', (210, 214))	('siLINC00319', 'Var', (362, 373))
18873	32948745	As LINC00319 and miR-199a-5p were both mediated by CCL18, we also detected the relationship between CCL18 and FZD4.	('CCL18', 'Gene', '6362', (100, 105))	('mediated', 'Reg', (39, 47))	('CCL18', 'Gene', (51, 56))	('miR-199a-5p', 'Var', (17, 28))	('CCL18', 'Gene', '6362', (51, 56))	('CCL18', 'Gene', (100, 105))	('LINC00319', 'Gene', (3, 12))	('miR-199a-5p', 'Chemical', '-', (17, 28))	('FZD4', 'Gene', '8322', (110, 114))	('LINC00319', 'Gene', '284836', (3, 12))	('FZD4', 'Gene', (110, 114))
18877	32948745	4a, b, tumor growth was inhibited upon LINC00319 knockdown.	('knockdown', 'Var', (49, 58))	('tumor', 'Disease', (7, 12))	('inhibited', 'NegReg', (24, 33))	('LINC00319', 'Gene', '284836', (39, 48))	('tumor', 'Disease', 'MESH:D009369', (7, 12))	('LINC00319', 'Gene', (39, 48))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
18895	32948745	When LINC00319 was silenced, the effect of CCL18 on proliferation, cell cycle, metastasis, and angiogenesis of OSCC cells was markedly inhibited, and the apoptosis inhibition of CCL18 on OSCC cells was alleviated.	('CCL18', 'Gene', (178, 183))	('angiogenesis of', 'CPA', (95, 110))	('metastasis', 'CPA', (79, 89))	('LINC00319', 'Gene', '284836', (5, 14))	('CCL18', 'Gene', (43, 48))	('LINC00319', 'Gene', (5, 14))	('CCL18', 'Gene', '6362', (43, 48))	('cell cycle', 'CPA', (67, 77))	('inhibited', 'NegReg', (135, 144))	('CCL18', 'Gene', '6362', (178, 183))	('silenced', 'Var', (19, 27))
18896	32948745	Moreover, compared with the rCCL18+siNC group, E-cadherin expression was increased, as well as N-cadherin, ZEB2, VEGF-A, and MMP-9 expressions were decreased in the rCCL18 + siLINC00319 group.	('expression', 'MPA', (58, 68))	('MMP-9', 'Gene', (125, 130))	('MMP-9', 'Gene', '4318', (125, 130))	('VEGF-A', 'Gene', (113, 119))	('rCCL18', 'Chemical', '-', (28, 34))	('rCCL18', 'Chemical', '-', (165, 171))	('rCCL18 + siLINC00319', 'Var', (165, 185))	('ZEB2', 'Gene', (107, 111))	('increased', 'PosReg', (73, 82))	('decreased', 'NegReg', (148, 157))	('ZEB2', 'Gene', '9839', (107, 111))	('siLINC00319', 'Chemical', '-', (174, 185))	('expressions', 'MPA', (131, 142))	('N-cadherin', 'Gene', (95, 105))	('VEGF-A', 'Gene', '7422', (113, 119))	('N-cadherin', 'Gene', '1000', (95, 105))	('E-cadherin', 'Gene', (47, 57))	('E-cadherin', 'Gene', '999', (47, 57))	('siNC', 'Chemical', 'MESH:C052464', (35, 39))
18900	32948745	In order to validate the targeting relationship between miR-199a-5p and LINC00319, luciferase reporter assays confirmed a direct interaction between LINC00319 and miR-199a-5p.	('miR-199a-5p', 'Chemical', '-', (56, 67))	('LINC00319', 'Gene', '284836', (72, 81))	('LINC00319', 'Gene', '284836', (149, 158))	('LINC00319', 'Gene', (72, 81))	('miR-199a-5p', 'Var', (163, 174))	('LINC00319', 'Gene', (149, 158))	('miR-199a-5p', 'Chemical', '-', (163, 174))	('interaction', 'Interaction', (129, 140))
18901	32948745	The qRT-PCR results also verified the negative correlation between miR-199a-5p and LINC00319 in OSCC cells.	('LINC00319', 'Gene', '284836', (83, 92))	('miR-199a-5p', 'Chemical', '-', (67, 78))	('LINC00319', 'Gene', (83, 92))	('negative', 'NegReg', (38, 46))	('miR-199a-5p', 'Var', (67, 78))
18903	32948745	The present study verified the dysregulation of miR-199a-5p in OSCC by showing the decreased expression of miR-199a-5p examined in HSC6, CAL27, and SCC9 cells compared with that in HOK cells.	('miR-199a-5p', 'Chemical', '-', (48, 59))	('miR-199a-5p', 'Chemical', '-', (107, 118))	('HSC6', 'CellLine', 'CVCL:A615', (131, 135))	('decreased', 'NegReg', (83, 92))	('expression', 'MPA', (93, 103))	('miR-199a-5p', 'Var', (107, 118))	('CAL27', 'CellLine', 'CVCL:1107', (137, 142))	('SCC9', 'CellLine', 'CVCL:1685', (148, 152))	('OSCC', 'Disease', (63, 67))
18904	32948745	showed that miR-199a-5p could suppress the migration and invasion in OSCC by targeting the EMT-related transcription factor, indicating that the tumor-suppressing role of miR-199a-5p in OSCC progression.	('targeting', 'Reg', (77, 86))	('miR-199a-5p', 'Chemical', '-', (12, 23))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumor', 'Disease', (145, 150))	('miR-199a-5p', 'Var', (12, 23))	('miR-199a-5p', 'Chemical', '-', (171, 182))	('EMT-related', 'Gene', (91, 102))	('suppress', 'NegReg', (30, 38))	('OSCC', 'Disease', (69, 73))
18905	32948745	In accordance with the results shown in the previous study, our study also found that miR-199a-5p mimics suppressed the promoting effects of CCL18 in OSCC development; and vice versa, the miR-199a-5p inhibitor could reverse the proliferation, invasiveness, and angiogenesis of LINC00319-depleted OSCC cells.	('suppressed', 'NegReg', (105, 115))	('miR-199a-5p', 'Var', (188, 199))	('CCL18', 'Gene', '6362', (141, 146))	('CCL18', 'Gene', (141, 146))	('invasiveness', 'CPA', (243, 255))	('miR-199a-5p', 'Chemical', '-', (188, 199))	('proliferation', 'CPA', (228, 241))	('OSCC', 'Disease', (150, 154))	('angiogenesis', 'CPA', (261, 273))	('LINC00319', 'Gene', '284836', (277, 286))	('promoting effects', 'MPA', (120, 137))	('miR-199a-5p', 'Chemical', '-', (86, 97))	('LINC00319', 'Gene', (277, 286))	('reverse', 'NegReg', (216, 223))
18910	32948745	In our study, luciferase reporter assays showed that miR-199a-5p directly binds to the 3'UTR region of FZD4, and thereby inhibit the expression of FZD4.	('inhibit', 'NegReg', (121, 128))	('FZD4', 'Gene', (103, 107))	('expression', 'MPA', (133, 143))	('miR-199a-5p', 'Chemical', '-', (53, 64))	('binds', 'Interaction', (74, 79))	('FZD4', 'Gene', (147, 151))	('FZD4', 'Gene', '8322', (147, 151))	('miR-199a-5p', 'Var', (53, 64))	('FZD4', 'Gene', '8322', (103, 107))
18914	32948745	Silenced FZD4 resulted in a significant decrease of p-ERK and FGF2 in HNSCC and benefited for the anti-VEGF therapy.	('decrease', 'NegReg', (40, 48))	('VEGF', 'Gene', (103, 107))	('Silenced', 'Var', (0, 8))	('FZD4', 'Gene', '8322', (9, 13))	('FGF2', 'Gene', '2247', (62, 66))	('ERK', 'Gene', '2048', (54, 57))	('FZD4', 'Gene', (9, 13))	('ERK', 'Gene', (54, 57))	('VEGF', 'Gene', '7422', (103, 107))	('FGF2', 'Gene', (62, 66))	('benefited', 'PosReg', (80, 89))
18935	31921386	Subsequent analyses also identified MYC binding sites and that co-expression of MYC and p53 leads to synergistic activation of the CLIC4 promoter.	('CLIC4', 'Gene', (131, 136))	('MYC', 'Gene', '4609', (80, 83))	('MYC', 'Gene', '4609', (36, 39))	('co-expression', 'Var', (63, 76))	('p53', 'Gene', (88, 91))	('activation', 'PosReg', (113, 123))	('MYC', 'Gene', (80, 83))	('MYC', 'Gene', (36, 39))
18945	31921386	In total, 25 amplifications, 22 homozygous deletions, 9 fusions (with SLC45A1, CACHD1, UBAP2L, DNAJA4, PLOD1, CCDC28B, ARFGAP3, PACSIN2, and CEP85), 4 frame shift deletions (recurrent, K204Nfs*11), 29 missense mutations (none recurrent), 3 nonsense mutations (S132*, E239*, and E213*), and 1 nonstop mutation (*254Yext*26) were present (Supplementary Table 1).	('DNAJA4', 'Gene', (95, 101))	('CACHD1', 'Gene', (79, 85))	('UBAP2L', 'Gene', '9898', (87, 93))	('E213*', 'SUBSTITUTION', 'None', (278, 283))	('CEP85', 'Gene', (141, 146))	('SLC45A1', 'Gene', (70, 77))	('DNAJA4', 'Gene', '55466', (95, 101))	('PACSIN2', 'Gene', '11252', (128, 135))	('E239*', 'Var', (267, 272))	('PACSIN2', 'Gene', (128, 135))	('S132*', 'SUBSTITUTION', 'None', (260, 265))	('PLOD1', 'Gene', (103, 108))	('K204Nfs*11', 'Var', (185, 195))	('CEP85', 'Gene', '64793', (141, 146))	('ARFGAP3', 'Gene', '26286', (119, 126))	('UBAP2L', 'Gene', (87, 93))	('SLC45A1', 'Gene', '50651', (70, 77))	('E213*', 'Var', (278, 283))	('CCDC28B', 'Gene', (110, 117))	('E239*', 'SUBSTITUTION', 'None', (267, 272))	('CCDC28B', 'Gene', '79140', (110, 117))	('PLOD1', 'Gene', '5351', (103, 108))	('S132*', 'Var', (260, 265))	('K204Nfs*11', 'Mutation', 'p.K204NfsX11', (185, 195))	('ARFGAP3', 'Gene', (119, 126))	('CACHD1', 'Gene', '57685', (79, 85))
18946	31921386	The missense mutations are of unknown significance, but two have the potential to disrupt phosphorylation sites that we previously identified (S27N, putative CK2 site; S38F, putative PKC site).	('S27N', 'Var', (143, 147))	('PKC', 'Gene', (183, 186))	('PKC', 'Gene', '112476', (183, 186))	('S38F', 'Mutation', 'p.S38F', (168, 172))	('phosphorylation sites', 'MPA', (90, 111))	('disrupt', 'Reg', (82, 89))	('S38F', 'Var', (168, 172))	('S27N', 'Mutation', 'p.S27N', (143, 147))
18953	31921386	miR-122 and miR-142-3p induced the strongest repression, which was validated at the CLIC4 protein level in 293T cells (Figure 4C).	('miR-122', 'Gene', '406906', (0, 7))	('miR-142-3p', 'Var', (12, 22))	('repression', 'MPA', (45, 55))	('miR-122', 'Gene', (0, 7))
18954	31921386	miR-122 is largely considered liver-specific and has been implicated in hepatocellular carcinoma, while miR-142-3p is highly expressed in hematopoietic cells and has been investigated in multiple cellular contexts and diseases.	('miR-142-3p', 'Var', (104, 114))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (72, 96))	('hepatocellular carcinoma', 'Disease', (72, 96))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (72, 96))	('miR-122', 'Var', (0, 7))	('implicated', 'Reg', (58, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))
18959	31921386	The more notable inverse relationship between CLIC4 and miR-142-3p in stage III/IV squamous cancers (Figure 6G) suggests that miR-142-3p regulation of CLIC4 may occur predominantly in advanced cancers.	('cancers', 'Phenotype', 'HP:0002664', (193, 200))	('cancers', 'Phenotype', 'HP:0002664', (92, 99))	('squamous cancers', 'Disease', 'MESH:D018307', (83, 99))	('inverse', 'NegReg', (17, 24))	('squamous cancers', 'Disease', (83, 99))	('miR-142-3p', 'Var', (126, 136))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('squamous cancer', 'Phenotype', 'HP:0002860', (83, 98))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('CLIC4', 'Gene', (151, 156))
18969	31921386	Divergent roles for miR-142-3p as both an oncogene and a tumor suppressor are pervasive in the literature, though it is not clear if this is due to cancer-specific intrinsic dependencies or experimental artifacts.	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('intrinsic dependencies', 'Disease', 'MESH:C563242', (164, 186))	('miR-142-3p', 'Var', (20, 30))	('intrinsic dependencies', 'Disease', (164, 186))
18972	31921386	In fact, a recent review defined miR-142-3p as one of a core set of biomarker miRNAs for atopic diseases because of its frequent association with allergic inflammation and immune cell dysfunction.	('association', 'Interaction', (129, 140))	('immune cell dysfunction', 'Disease', (172, 195))	('miR-142-3p', 'Var', (33, 43))	('allergic inflammation', 'Disease', (146, 167))	('atopic diseases', 'Phenotype', 'HP:0001047', (89, 104))	('allergic inflammation', 'Disease', 'MESH:D007249', (146, 167))	('immune cell dysfunction', 'Phenotype', 'HP:0005435', (172, 195))	('inflammation', 'Disease', 'MESH:D007249', (155, 167))	('inflammation', 'Disease', (155, 167))
18975	31921386	However, when considering that HNSCCs are among the most highly immune-infiltrated cancer types and the known abundance of miR-142-3p within immune cells, we sought to determine the source of elevated miR-142-3p detected in bulk HNSCC tumors by leveraging the spatial resolution afforded by ISH.	('HNSCC tumors', 'Disease', 'MESH:C535575', (229, 241))	('HNSCC tumors', 'Disease', (229, 241))	('HNSCCs', 'Disease', (31, 37))	('HNSCC', 'Phenotype', 'HP:0012288', (31, 36))	('HNSCCs', 'Disease', 'MESH:C535575', (31, 37))	('miR-142-3p', 'Var', (201, 211))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('elevated', 'PosReg', (192, 200))	('HNSCC', 'Phenotype', 'HP:0012288', (229, 234))	('SCC', 'Phenotype', 'HP:0002860', (33, 36))	('SCC', 'Phenotype', 'HP:0002860', (231, 234))	('tumors', 'Phenotype', 'HP:0002664', (235, 241))
18977	31921386	In other circumstances of miR-142-3p upregulation in bulk tissue, such as psoriasis and intestinal allograft rejection, ISH has also shown that the source of miR-142-3p is infiltrating immune cells positive for markers of either T cells or monocytes/macrophages.	('psoriasis', 'Disease', 'MESH:D011565', (74, 83))	('miR-142-3p', 'Var', (158, 168))	('upregulation', 'PosReg', (37, 49))	('psoriasis', 'Disease', (74, 83))	('psoriasis', 'Phenotype', 'HP:0003765', (74, 83))	('intestinal allograft rejection', 'Disease', (88, 118))	('miR-142-3p', 'Gene', (26, 36))
18978	31921386	also reported CLIC4 expression in HN4, an additional HNSCC cell line, but suggested that CLIC4 is elevated in HNSCC and its knockdown sensitizes HN4 cells to apoptosis.	('knockdown', 'Var', (124, 133))	('SCC', 'Phenotype', 'HP:0002860', (112, 115))	('HN4', 'Gene', '100463285', (145, 148))	('HNSCC', 'Phenotype', 'HP:0012288', (110, 115))	('HN4', 'Gene', (34, 37))	('SCC', 'Phenotype', 'HP:0002860', (55, 58))	('sensitizes', 'Reg', (134, 144))	('HNSCC', 'Phenotype', 'HP:0012288', (53, 58))	('elevated', 'PosReg', (98, 106))	('apoptosis', 'CPA', (158, 167))	('HN4', 'Gene', (145, 148))	('CLIC4', 'Gene', (89, 94))	('HN4', 'Gene', '100463285', (34, 37))
19001	31360437	The bladder tumor was positive for CK5/6, CK903, and thrombomodulin biomarkers, as well as for high-risk HPV (16, 18, and 31).	('HPV', 'Disease', (105, 108))	('CK903', 'Var', (42, 47))	('CK5/6', 'Gene', (35, 40))	('bladder tumor', 'Disease', (4, 17))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('thrombomodulin', 'Gene', (53, 67))	('HPV', 'Disease', 'MESH:D030361', (105, 108))	('thrombomodulin', 'Gene', '7056', (53, 67))	('bladder tumor', 'Disease', 'MESH:D001749', (4, 17))	('bladder tumor', 'Phenotype', 'HP:0009725', (4, 17))	('CK5/6', 'Gene', '3852', (35, 40))	('positive', 'Reg', (22, 30))
19046	24518808	Deregulation of tissue miRNA expression levels associated with specific genetic alterations has been demonstrated in cancer, where miRNAs function either as oncogenes or as tumor-suppressor genes and are shed from cancer cells into circulation.	('miR', 'Gene', '220972', (23, 26))	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('miR', 'Gene', (23, 26))	('alterations', 'Var', (80, 91))	('cancer', 'Disease', (214, 220))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('Deregulation', 'MPA', (0, 12))	('tumor', 'Disease', (173, 178))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('cancer', 'Disease', (117, 123))	('miR', 'Gene', '220972', (131, 134))	('miR', 'Gene', (131, 134))	('cancer', 'Disease', 'MESH:D009369', (214, 220))
19057	24518808	However, analyses of circulating DNA have allowed the detection of tumor-related genetic and epigenetic alterations that are relevant to cancer development and progression.	('men', 'Species', '9606', (151, 154))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('cancer', 'Disease', (137, 143))	('tumor', 'Disease', (67, 72))	('epigenetic alterations', 'Var', (93, 115))
19081	24518808	High expression level of miR-21 was also associated with poor survival and therapeutic outcome in colon adenocarcinoma patients and correlated with outcome in pancreatic ductal adenocarcinoma patients treated with gemcitabine.	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (159, 191))	('gemcitabine', 'Chemical', 'MESH:C056507', (214, 225))	('carcinoma', 'Phenotype', 'HP:0030731', (182, 191))	('miR-21', 'Gene', (25, 31))	('High', 'Var', (0, 4))	('poor', 'NegReg', (57, 61))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (159, 191))	('patients', 'Species', '9606', (119, 127))	('patients', 'Species', '9606', (192, 200))	('survival', 'CPA', (62, 70))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('colon adenocarcinoma', 'Disease', 'MESH:D003110', (98, 118))	('colon adenocarcinoma', 'Disease', (98, 118))	('pancreatic ductal adenocarcinoma', 'Disease', (159, 191))	('miR-21', 'Gene', '406991', (25, 31))	('therapeutic outcome', 'CPA', (75, 94))
19201	24518808	In that study, the circulating concentrations of miR-21 and miR-106b were significantly reduced post-operatively in patients with high pre-operative plasma miR-21 and miR-106b.	('miR-106b', 'Gene', (167, 175))	('miR-106b', 'Gene', '406900', (60, 68))	('miR-21', 'Gene', '406991', (156, 162))	('high', 'Var', (130, 134))	('patients', 'Species', '9606', (116, 124))	('miR-106b', 'Gene', '406900', (167, 175))	('circulating concentrations', 'MPA', (19, 45))	('miR-21', 'Gene', (49, 55))	('miR-21', 'Gene', (156, 162))	('reduced', 'NegReg', (88, 95))	('miR-21', 'Gene', '406991', (49, 55))	('miR-106b', 'Gene', (60, 68))
19207	24518808	Due to aberrant CpG methylation of its promoter, miR-34a is commonly silenced in human cancers, such as pancreatic cancer, neuroblastoma, breast, lung, colon, kidney, or bladder cancer, and primary melanoma, but serum miR-34a has been reported to be markedly up-regulated in gastric cancer patients and breast cancer patients.	('neuroblastoma', 'Phenotype', 'HP:0003006', (123, 136))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('patients', 'Species', '9606', (317, 325))	('gastric cancer', 'Phenotype', 'HP:0012126', (275, 289))	('pancreatic cancer', 'Disease', (104, 121))	('neuroblastoma', 'Disease', 'MESH:D009447', (123, 136))	('kidney', 'Disease', (159, 165))	('human', 'Species', '9606', (81, 86))	('silenced', 'NegReg', (69, 77))	('colon', 'Disease', 'MESH:D015179', (152, 157))	('patients', 'Species', '9606', (290, 298))	('melanoma', 'Phenotype', 'HP:0002861', (198, 206))	('up-regulated', 'PosReg', (259, 271))	('cancer', 'Phenotype', 'HP:0002664', (310, 316))	('colon', 'Disease', (152, 157))	('miR-34a', 'Gene', (218, 225))	('gastric cancer', 'Disease', (275, 289))	('cancers', 'Phenotype', 'HP:0002664', (87, 94))	('miR-34a', 'Gene', (49, 56))	('cancers', 'Disease', (87, 94))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (104, 121))	('primary melanoma', 'Disease', 'MESH:D008545', (190, 206))	('primary melanoma', 'Disease', (190, 206))	('aberrant', 'Var', (7, 15))	('breast', 'Disease', (138, 144))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('miR-34a', 'Gene', '407040', (218, 225))	('breast cancer', 'Phenotype', 'HP:0003002', (303, 316))	('cancer', 'Phenotype', 'HP:0002664', (283, 289))	('miR-34a', 'Gene', '407040', (49, 56))	('gastric cancer', 'Disease', 'MESH:D013274', (275, 289))	('CpG', 'Var', (16, 19))	('bladder cancer', 'Disease', 'MESH:D001749', (170, 184))	('bladder cancer', 'Disease', (170, 184))	('lung', 'Disease', (146, 150))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('breast cancer', 'Disease', (303, 316))	('pancreatic cancer', 'Disease', 'MESH:D010190', (104, 121))	('breast cancer', 'Disease', 'MESH:D001943', (303, 316))	('bladder cancer', 'Phenotype', 'HP:0009725', (170, 184))	('neuroblastoma', 'Disease', (123, 136))	('cancers', 'Disease', 'MESH:D009369', (87, 94))
19252	33035322	More specifically, they found that an index composed of the presence or absence of tumor infiltrating lymphocytes (TILs), expressing the CD3+ pan-T-cell marker and/or the CD8+ cytotoxic T-cell marker in the tumor center and periphery, provides highly specific and sensitive prognostic information.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumor', 'Disease', (83, 88))	('CD3+', 'Var', (137, 141))	('CD8', 'Gene', (171, 174))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('CD8', 'Gene', '925', (171, 174))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('tumor', 'Disease', (207, 212))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
19255	33035322	In NSCLC, several large studies have established different immune-cell subsets as prognostic indicators, and, as in CRC, the most promising candidate markers up to date are CD3+, CD8+ and CD45RO+ expressing TILs.	('CD45RO', 'Gene', '5788', (188, 194))	('NSCLC', 'Disease', (3, 8))	('NSCLC', 'Disease', 'MESH:D002289', (3, 8))	('CD3+', 'Var', (173, 177))	('CD8', 'Gene', (179, 182))	('CD45RO', 'Gene', (188, 194))	('CD8', 'Gene', '925', (179, 182))
19263	33035322	The stromal and tumor compartments were scored for CD3+, CD4+, CD8+, CD20+ and CD45RO+ separately.	('CD4', 'Gene', '920', (57, 60))	('CD45RO', 'Gene', '5788', (79, 85))	('CD4', 'Gene', (79, 82))	('CD20', 'Gene', '54474', (69, 73))	('CD4', 'Gene', '920', (79, 82))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('CD20', 'Gene', (69, 73))	('CD8', 'Gene', (63, 66))	('men', 'Species', '9606', (29, 32))	('tumor', 'Disease', (16, 21))	('CD8', 'Gene', '925', (63, 66))	('CD3+', 'Var', (51, 55))	('CD45RO', 'Gene', (79, 85))	('CD4', 'Gene', (57, 60))
19292	33035322	The final cutoffs, in cells/mm2, were as follows: CD3 <= 1000; CD4 <= 550; CD8 <= 500; CD20 <= 400; CD45RO <= 250.	('CD4', 'Gene', (63, 66))	('CD4', 'Gene', (100, 103))	('CD8', 'Gene', '925', (75, 78))	('CD45RO', 'Gene', '5788', (100, 106))	('CD20', 'Gene', '54474', (87, 91))	('CD4', 'Gene', '920', (63, 66))	('CD20', 'Gene', (87, 91))	('CD4', 'Gene', '920', (100, 103))	('CD45RO', 'Gene', (100, 106))	('CD3 <= 1000', 'Var', (50, 61))	('CD8', 'Gene', (75, 78))
19299	33035322	Briefly, CD3, CD4, CD8, CD20 and CD45RO were all significant positive prognosticators of DSS in the overall cohort (P-values = <0.001, 0.007, <0.001, <0.001 and <0.001, respectively) and in the LUSC subgroup (P-values = 0.002, 0.009, <0.001, 0.046 and 0.002, respectively), whereas only CD8 and CD20 (P-values = 0.04 and 0.003) were significant positive prognosticators of DSS in the LUAD subgroup.	('CD8', 'Gene', '925', (287, 290))	('CD4', 'Gene', '920', (14, 17))	('CD8', 'Gene', (19, 22))	('CD4', 'Gene', (14, 17))	('DSS', 'Gene', (89, 92))	('CD45RO', 'Gene', (33, 39))	('CD20', 'Gene', (295, 299))	('CD8', 'Gene', (287, 290))	('CD20', 'Gene', (24, 28))	('CD3', 'Var', (9, 12))	('DSS', 'Gene', '5376', (89, 92))	('CD45RO', 'Gene', '5788', (33, 39))	('DSS', 'Gene', (373, 376))	('CD4', 'Gene', '920', (33, 36))	('CD20', 'Gene', '54474', (295, 299))	('CD8', 'Gene', '925', (19, 22))	('CD20', 'Gene', '54474', (24, 28))	('DSS', 'Gene', '5376', (373, 376))	('CD4', 'Gene', (33, 36))
19316	33035322	Comparing DSS data (Table 2; Supplementary Figures S1 and S3), CD3+, CD8+ and CD45RO+ TILs are potential candidate markers for a TNM-I in the overall cohort, and in the LUSC subgroup, while CD8+ and CD20+ TILs are most promising in the LUAD subgroup.	('CD8', 'Gene', '925', (190, 193))	('CD8', 'Gene', '925', (69, 72))	('men', 'Species', '9606', (35, 38))	('CD20', 'Gene', '54474', (199, 203))	('TNM', 'Gene', (129, 132))	('CD45RO', 'Gene', (78, 84))	('CD20', 'Gene', (199, 203))	('TNM', 'Gene', '10178', (129, 132))	('CD8', 'Gene', (69, 72))	('DSS', 'Gene', (10, 13))	('CD45RO', 'Gene', '5788', (78, 84))	('CD3+', 'Var', (63, 67))	('DSS', 'Gene', '5376', (10, 13))	('CD8', 'Gene', (190, 193))
19333	33035322	Interestingly, the mean density of some (CD3+ and CD4+), but not all (CD8+, CD20+ and CD45RO+) TILs were higher in LUAD compared with LUSC patients.	('CD4', 'Gene', (86, 89))	('patients', 'Species', '9606', (139, 147))	('higher', 'PosReg', (105, 111))	('CD45RO', 'Gene', '5788', (86, 92))	('CD4', 'Gene', '920', (86, 89))	('CD4', 'Gene', (50, 53))	('LUAD', 'Disease', (115, 119))	('CD3+', 'Var', (41, 45))	('CD20', 'Gene', (76, 80))	('CD8', 'Gene', (70, 73))	('CD20', 'Gene', '54474', (76, 80))	('CD45RO', 'Gene', (86, 92))	('CD8', 'Gene', '925', (70, 73))	('CD4', 'Gene', '920', (50, 53))
19355	33035322	All possible dichotomized cutoffs for CD3, CD4, CD8, CD20 and CD45RO plotted against P-values indicating significance of disease-specific survival for digital scores (A) and semi-quantitative scores in stroma (B) and tumor (C).	('CD20', 'Gene', (53, 57))	('CD3', 'Var', (38, 41))	('CD4', 'Gene', (62, 65))	('tumor', 'Disease', (217, 222))	('CD4', 'Gene', '920', (62, 65))	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('CD45RO', 'Gene', '5788', (62, 68))	('CD20', 'Gene', '54474', (53, 57))	('CD8', 'Gene', (48, 51))	('CD45RO', 'Gene', (62, 68))	('tumor', 'Disease', 'MESH:D009369', (217, 222))	('CD8', 'Gene', '925', (48, 51))	('CD4', 'Gene', (43, 46))	('CD4', 'Gene', '920', (43, 46))
19358	33035322	All possible dichotomized cutoffs for CD3, CD4, CD8, CD20 and CD45RO plotted against P-values indicating significance of disease-specific survival in pStage I (A), II (B) and III (C).	('CD20', 'Gene', (53, 57))	('CD3', 'Var', (38, 41))	('CD4', 'Gene', (62, 65))	('CD4', 'Gene', '920', (62, 65))	('CD45RO', 'Gene', '5788', (62, 68))	('CD8', 'Gene', '925', (48, 51))	('CD20', 'Gene', '54474', (53, 57))	('CD8', 'Gene', (48, 51))	('CD45RO', 'Gene', (62, 68))	('pStage I', 'Disease', (150, 158))	('CD4', 'Gene', (43, 46))	('CD4', 'Gene', '920', (43, 46))
19360	33035322	Disease-specific survival curves for pStage I-III (panels A-C), and for <=500 vs >500 CD8 TILs per mm2 and <= 400 vs > 400 CD20 TILs per mm2 and their combinations in pStage I-III, panels D-F, G-I and J-L, respectively.	('CD20', 'Gene', (123, 127))	('CD8', 'Gene', (86, 89))	('pStage', 'Gene', (37, 43))	('<= 400 vs > 400', 'Var', (107, 122))	('CD8', 'Gene', '925', (86, 89))	('pStage I-III', 'Disease', (167, 179))	('CD20', 'Gene', '54474', (123, 127))
19374	31611948	Numerous studies have demonstrated that dysregulation of lncRNAs may be involved in the pathological process of several human diseases, including cancer, cardiovascular disease and diseases of the central nervous system.	('cardiovascular disease', 'Phenotype', 'HP:0001626', (154, 176))	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('human', 'Species', '9606', (120, 125))	('diseases of the central nervous system', 'Disease', 'MESH:D002493', (181, 219))	('cardiovascular disease', 'Disease', 'MESH:D002318', (154, 176))	('dysregulation', 'Var', (40, 53))	('lncRNAs', 'Protein', (57, 64))	('diseases of the central nervous system', 'Disease', (181, 219))	('involved', 'Reg', (72, 80))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('cardiovascular disease', 'Disease', (154, 176))
19375	31611948	Through epigenetic modifications, chromatin remodeling and microRNA (miRNA) sponging, lncRNAs modulate cell proliferation, apoptosis, migration and invasion.	('modulate', 'Reg', (94, 102))	('cell proliferation', 'CPA', (103, 121))	('chromatin', 'CPA', (34, 43))	('apoptosis', 'CPA', (123, 132))	('migration', 'CPA', (134, 143))	('miR', 'Gene', '220972', (69, 72))	('miR', 'Gene', (69, 72))	('epigenetic modifications', 'Var', (8, 32))	('invasion', 'CPA', (148, 156))
19378	31611948	The results of two previous meta-analyses have indicated that increased expression of TUG1 is an unfavorable predictor of survival in human cancer, and that TUG1 is closely associated with increased tumor size, advanced pathological stage and distant metastasis.	('tumor', 'Disease', (199, 204))	('increased', 'PosReg', (62, 71))	('human', 'Species', '9606', (134, 139))	('TUG1', 'Var', (157, 161))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('expression', 'MPA', (72, 82))	('advanced pathological stage', 'CPA', (211, 238))	('TUG1', 'Gene', (86, 90))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('associated', 'Reg', (173, 183))	('distant metastasis', 'CPA', (243, 261))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('increased', 'PosReg', (189, 198))
19382	31611948	In addition, previous studies have reported that aberrant expression of TUG1 may affect gene expression through diverse mechanisms, which affect various biological processes, including cell proliferation, invasion, apoptosis, differentiation, migration, drug resistance, radiation resistance, angiogenesis, mitochondrial bioenergetics, epithelial-mesenchymal transition (EMT) and blood tumor barrier permeability regulation.	('blood tumor', 'Phenotype', 'HP:0004377', (380, 391))	('apoptosis', 'CPA', (215, 224))	('gene expression', 'MPA', (88, 103))	('cell proliferation', 'CPA', (185, 203))	('aberrant expression', 'Var', (49, 68))	('blood tumor', 'Disease', (380, 391))	('differentiation', 'CPA', (226, 241))	('epithelial-mesenchymal transition', 'CPA', (336, 369))	('drug resistance', 'CPA', (254, 269))	('blood tumor', 'Disease', 'MESH:D009383', (380, 391))	('migration', 'CPA', (243, 252))	('mitochondrial bioenergetics', 'CPA', (307, 334))	('angiogenesis', 'CPA', (293, 305))	('affect', 'Reg', (138, 144))	('radiation resistance', 'CPA', (271, 291))	('affect', 'Reg', (81, 87))	('tumor', 'Phenotype', 'HP:0002664', (386, 391))	('invasion', 'CPA', (205, 213))	('drug resistance', 'Phenotype', 'HP:0020174', (254, 269))	('TUG1', 'Gene', (72, 76))
19393	31611948	Sirtuin 1 (SIRT1) competes with miR-138-5p and, thus, is upregulated by TUG1.	('miR', 'Gene', (32, 35))	('Sirtuin 1', 'Gene', (0, 9))	('SIRT1', 'Gene', '23411', (11, 16))	('TUG1', 'Var', (72, 76))	('Sirtuin 1', 'Gene', '23411', (0, 9))	('SIRT1', 'Gene', (11, 16))	('miR', 'Gene', '220972', (32, 35))	('upregulated', 'PosReg', (57, 68))
19414	31611948	Furthermore, silencing of TUG1 reduced the expression of the sonic hedgehog protein, known to be associated with the Hedgehog (Hh) signaling pathway, and led to an increase in the expression of miR-132 in hepatocellular carcinoma cells.	('miR-132', 'Gene', '406921', (194, 201))	('reduced', 'NegReg', (31, 38))	('sonic hedgehog protein', 'Gene', (61, 83))	('sonic hedgehog protein', 'Gene', '6469', (61, 83))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (205, 229))	('expression', 'MPA', (180, 190))	('hepatocellular carcinoma', 'Disease', (205, 229))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (205, 229))	('miR-132', 'Gene', (194, 201))	('carcinoma', 'Phenotype', 'HP:0030731', (220, 229))	('expression', 'MPA', (43, 53))	('TUG1', 'Gene', (26, 30))	('increase', 'PosReg', (164, 172))	('silencing', 'Var', (13, 22))
19422	31611948	Furthermore it has been shown that TUG1 contributes to osteosarcoma tumorigenesis by sponging miR-153.	('tumor', 'Disease', (68, 73))	('osteosarcoma', 'Phenotype', 'HP:0002669', (55, 67))	('osteosarcoma', 'Disease', (55, 67))	('osteosarcoma', 'Disease', 'MESH:D012516', (55, 67))	('TUG1', 'Gene', (35, 39))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('miR', 'Gene', '220972', (94, 97))	('miR', 'Gene', (94, 97))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('contributes', 'Reg', (40, 51))	('sponging', 'Var', (85, 93))
19424	31611948	Concordantly, TUG1 upregulates the miR-9-5p downstream target gene, POU class 2 homeobox 1, which is involved in cell proliferation, colony formation, cell cycle arrest and apoptosis.	('POU class 2 homeobox 1', 'Gene', (68, 90))	('TUG1', 'Var', (14, 18))	('upregulates', 'PosReg', (19, 30))	('miR-9-5p', 'Gene', (35, 43))	('miR-9-5p', 'Gene', '407052', (35, 43))	('arrest', 'Disease', 'MESH:D006323', (162, 168))	('arrest', 'Disease', (162, 168))	('POU class 2 homeobox 1', 'Gene', '5451', (68, 90))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (151, 168))
19425	31611948	A recent study has demonstrated that high TUG1 expression in osteosarcoma leads to the downregulation of miR-219a-5p expression via an endogenous sponge adsorption mechanism.	('osteosarcoma', 'Disease', (61, 73))	('osteosarcoma', 'Disease', 'MESH:D012516', (61, 73))	('high', 'Var', (37, 41))	('miR-219', 'Gene', (105, 112))	('TUG1', 'Gene', (42, 46))	('miR-219', 'Gene', '407002', (105, 112))	('downregulation', 'NegReg', (87, 101))	('osteosarcoma', 'Phenotype', 'HP:0002669', (61, 73))
19427	31611948	Modulation of TUG1 alters the level of multiple genes in various cancer cells; the majority of which are PRC2-dependent.	('Modulation', 'Var', (0, 10))	('alters', 'Reg', (19, 25))	('TUG1', 'Gene', (14, 18))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('level of multiple genes', 'MPA', (30, 53))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))
19430	31611948	In addition, knockdown of TUG1 significantly increases the proliferation of NSCLC cells.	('increases', 'PosReg', (45, 54))	('NSCLC', 'Disease', (76, 81))	('NSCLC', 'Disease', 'MESH:D002289', (76, 81))	('knockdown', 'Var', (13, 22))	('SCLC', 'Phenotype', 'HP:0030357', (77, 81))	('TUG1', 'Gene', (26, 30))
19434	31611948	An additional study reported that TUG1 is required to activate PRC2 by occupying its binding site on HOXB7 (a known oncogene), thereby epigenetically modulating its expression and promoting NSCLC cell proliferation.	('PRC2', 'Gene', (63, 67))	('HOXB7', 'Gene', '3217', (101, 106))	('promoting', 'PosReg', (180, 189))	('expression', 'MPA', (165, 175))	('HOXB7', 'Gene', (101, 106))	('SCLC', 'Phenotype', 'HP:0030357', (191, 195))	('NSCLC', 'Disease', (190, 195))	('epigenetically', 'Var', (135, 149))	('NSCLC', 'Disease', 'MESH:D002289', (190, 195))	('modulating', 'Reg', (150, 160))
19436	31611948	In addition, TUG1 recruits EZH2 to target gene promoters and epigenetically represses the expression of cyclin-dependent protein kinase inhibitors, including p15, p16, p21, p27 and p57 in GC.	('epigenetically', 'Var', (61, 75))	('p21', 'Gene', (168, 171))	('p16', 'Gene', '1029', (163, 166))	('p21', 'Gene', '644914', (168, 171))	('p15', 'Gene', (158, 161))	('EZH2', 'Gene', (27, 31))	('p57', 'Gene', '1028', (181, 184))	('represses', 'NegReg', (76, 85))	('p15', 'Gene', '1030', (158, 161))	('EZH2', 'Gene', '2146', (27, 31))	('p57', 'Gene', (181, 184))	('expression', 'MPA', (90, 100))	('p16', 'Gene', (163, 166))	('p27', 'Gene', (173, 176))	('p27', 'Gene', '3429', (173, 176))	('GC', 'Disease', 'MESH:D013274', (188, 190))	('GC', 'Phenotype', 'HP:0012126', (188, 190))
19437	31611948	This leads to TUG1-mediated alterations in the proliferation of GC cells and cell cycle progression.	('alterations', 'Reg', (28, 39))	('GC', 'Disease', 'MESH:D013274', (64, 66))	('cell cycle progression', 'CPA', (77, 99))	('proliferation', 'CPA', (47, 60))	('GC', 'Phenotype', 'HP:0012126', (64, 66))	('TUG1-mediated', 'Var', (14, 27))
19438	31611948	In addition, knockdown of TUG1 in a HCC cell line, Hep3B, led to inhibition of cell proliferation and induction of cell apoptosis in vitro.	('induction', 'Reg', (102, 111))	('inhibition', 'NegReg', (65, 75))	('HCC', 'Disease', 'MESH:D006528', (36, 39))	('HCC', 'Disease', (36, 39))	('cell proliferation', 'CPA', (79, 97))	('HCC', 'Phenotype', 'HP:0001402', (36, 39))	('TUG1', 'Gene', (26, 30))	('cell apoptosis', 'CPA', (115, 129))	('knockdown', 'Var', (13, 22))
19443	31611948	In addition, knockdown of TUG1 in oral squamous cell carcinoma cells leads to decreased proliferation in vitro.	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (34, 62))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (39, 62))	('carcinoma', 'Phenotype', 'HP:0030731', (53, 62))	('oral squamous cell carcinoma', 'Disease', (34, 62))	('knockdown', 'Var', (13, 22))	('proliferation in vitro', 'CPA', (88, 110))	('decreased', 'NegReg', (78, 87))	('TUG1', 'Gene', (26, 30))
19444	31611948	Reverse transcription-quantitative PCR and western blotting results indicated that knockdown of TUG1 leads to downregulation of Wnt/beta-catenin signaling-associated genes, such as beta-catenin, cyclin D1 and c-myc.	('c-myc', 'Gene', '4609', (209, 214))	('c-myc', 'Gene', (209, 214))	('beta-catenin', 'Gene', '1499', (181, 193))	('TUG1', 'Gene', (96, 100))	('beta-catenin', 'Gene', (132, 144))	('knockdown', 'Var', (83, 92))	('beta-catenin', 'Gene', '1499', (132, 144))	('cyclin D1', 'Gene', '595', (195, 204))	('cyclin D1', 'Gene', (195, 204))	('downregulation', 'NegReg', (110, 124))	('beta-catenin', 'Gene', (181, 193))
19449	31611948	When TUG1 expression is knocked down in ovarian cancer cells, E-cadherin expression is high, while vimentin and N-cadherin levels are downregulated.	('N-cadherin', 'Gene', (112, 122))	('vimentin', 'Gene', '7431', (99, 107))	('ovarian cancer', 'Disease', 'MESH:D010051', (40, 54))	('downregulated', 'NegReg', (134, 147))	('N-cadherin', 'Gene', '1000', (112, 122))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('knocked down', 'Var', (24, 36))	('ovarian cancer', 'Disease', (40, 54))	('expression', 'MPA', (73, 83))	('E-cadherin', 'Gene', (62, 72))	('high', 'PosReg', (87, 91))	('TUG1', 'Gene', (5, 9))	('ovarian cancer', 'Phenotype', 'HP:0100615', (40, 54))	('vimentin', 'Gene', (99, 107))	('E-cadherin', 'Gene', '999', (62, 72))
19452	31611948	In addition, overexpression of TUG1 promoted the migration, invasion and EMT of thyroid cancer cell lines, and these effects were primarily dependent on the TUG1-mediated regulation of the miR-145/ZEB1 signaling pathway.	('miR-145', 'Gene', '406937', (189, 196))	('thyroid cancer', 'Disease', (80, 94))	('invasion', 'CPA', (60, 68))	('overexpression', 'Var', (13, 27))	('thyroid cancer', 'Phenotype', 'HP:0002890', (80, 94))	('migration', 'CPA', (49, 58))	('ZEB1', 'Gene', (197, 201))	('TUG1', 'Gene', (31, 35))	('thyroid cancer', 'Disease', 'MESH:D013964', (80, 94))	('ZEB1', 'Gene', '6935', (197, 201))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('promoted', 'PosReg', (36, 44))	('miR-145', 'Gene', (189, 196))
19453	31611948	Furthermore, it was demonstrated that knockdown of TUG1 markedly inhibited the invasion and migration capabilities of prostate cancer cells.	('prostate cancer', 'Disease', (118, 133))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('TUG1', 'Gene', (51, 55))	('prostate cancer', 'Disease', 'MESH:D011471', (118, 133))	('prostate cancer', 'Phenotype', 'HP:0012125', (118, 133))	('inhibited', 'NegReg', (65, 74))	('knockdown', 'Var', (38, 47))
19458	31611948	Following confirmation that miR-219a-5p targets TUG1 using a luciferase assay, it was demonstrated that TUG1 regulates the expression of PIK3CA and activates the AKT signaling pathway to promote the migration and invasion of osteosarcoma cells.	('promote', 'PosReg', (187, 194))	('miR-219', 'Gene', '407002', (28, 35))	('activates', 'PosReg', (148, 157))	('PIK3CA', 'Gene', (137, 143))	('AKT', 'Gene', '207', (162, 165))	('expression', 'MPA', (123, 133))	('regulates', 'Reg', (109, 118))	('TUG1', 'Var', (104, 108))	('AKT', 'Gene', (162, 165))	('PIK3CA', 'Gene', '5290', (137, 143))	('invasion', 'CPA', (213, 221))	('osteosarcoma', 'Disease', (225, 237))	('osteosarcoma', 'Phenotype', 'HP:0002669', (225, 237))	('miR-219', 'Gene', (28, 35))	('osteosarcoma', 'Disease', 'MESH:D012516', (225, 237))	('migration', 'CPA', (199, 208))
19464	31611948	Ji et al demonstrated that TUG1 is markedly upregulated in GC tissues and that silencing of TUG1 leads to the inhibition of c-Met and the inhibition of invasion capabilities of SGC-7901 cells.	('GC', 'Disease', 'MESH:D013274', (59, 61))	('inhibition', 'NegReg', (110, 120))	('inhibition', 'NegReg', (138, 148))	('TUG1', 'Gene', (27, 31))	('GC', 'Phenotype', 'HP:0012126', (178, 180))	('upregulated', 'PosReg', (44, 55))	('GC', 'Phenotype', 'HP:0012126', (59, 61))	('c-Met', 'Gene', (124, 129))	('c-Met', 'Gene', '4233', (124, 129))	('invasion capabilities', 'CPA', (152, 173))	('GC', 'Disease', 'MESH:D013274', (178, 180))	('TUG1', 'Gene', (92, 96))	('silencing', 'Var', (79, 88))
19465	31611948	In HCC, TUG1 competes with miR-144 for binding to the 3'-untranslated region of Janus kinase 2 (JAK2), thereby activating the JAK2/signal transducer and activator of transcription 3 signaling pathway and increasing cell migration in vitro and in vivo.	('HCC', 'Phenotype', 'HP:0001402', (3, 6))	('signal transducer and activator of transcription 3', 'Gene', '6774', (131, 181))	('TUG1', 'Var', (8, 12))	('Janus kinase 2', 'Gene', (80, 94))	('JAK2', 'Gene', '3717', (126, 130))	('JAK2', 'Gene', '3717', (96, 100))	('miR-144', 'Gene', (27, 34))	('activating', 'PosReg', (111, 121))	('HCC', 'Disease', 'MESH:D006528', (3, 6))	('miR-144', 'Gene', '406936', (27, 34))	('Janus kinase 2', 'Gene', '3717', (80, 94))	('JAK2', 'Gene', (126, 130))	('JAK2', 'Gene', (96, 100))	('HCC', 'Disease', (3, 6))	('cell migration', 'CPA', (215, 229))	('binding', 'Interaction', (39, 46))	('increasing', 'PosReg', (204, 214))
19466	31611948	He et al demonstrated that high TUG1 levels were positively associated with cell invasion in HCC.	('HCC', 'Phenotype', 'HP:0001402', (93, 96))	('cell invasion', 'CPA', (76, 89))	('high', 'Var', (27, 31))	('HCC', 'Disease', 'MESH:D006528', (93, 96))	('HCC', 'Disease', (93, 96))	('associated', 'Reg', (60, 70))
19469	31611948	Silencing of TUG1 consequently reduces the expression levels of ZEB1 and EMT-associated proteins.	('reduces', 'NegReg', (31, 38))	('Silencing', 'Var', (0, 9))	('ZEB1', 'Gene', '6935', (64, 68))	('ZEB1', 'Gene', (64, 68))	('expression levels', 'MPA', (43, 60))	('TUG1', 'Gene', (13, 17))
19489	31611948	However, it has been demonstrated that high TUG1 expression may indicate a poor prognosis in the majority of cancer types (Fig.	('high', 'Var', (39, 43))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('cancer', 'Disease', (109, 115))	('expression', 'MPA', (49, 59))	('TUG1', 'Gene', (44, 48))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))
19504	31611948	TUG1, as a novel lncRNA, has been demonstrated to be abnormally expressed in various human cancer types, and its dysregulation is closely associated with carcinogenesis and disease progression.	('TUG1', 'Gene', (0, 4))	('carcinogenesis', 'Disease', 'MESH:D063646', (154, 168))	('cancer', 'Disease', (91, 97))	('dysregulation', 'Var', (113, 126))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('carcinogenesis', 'Disease', (154, 168))	('associated', 'Reg', (138, 148))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('human', 'Species', '9606', (85, 90))
19505	31611948	From a molecular perspective, cancer is a genetic disease that develops due to the aberrant expression and function of tumor suppressor and oncogenic genes.	('tumor', 'Disease', (119, 124))	('genetic disease', 'Disease', 'MESH:D030342', (42, 57))	('genetic disease', 'Disease', (42, 57))	('cancer', 'Disease', (30, 36))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('aberrant', 'Var', (83, 91))	('function', 'MPA', (107, 115))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
19507	31611948	As such, silencing or upregulating TUG1 may inhibit the proliferation, migration and invasion of cancer cells and increase cell apoptosis.	('increase', 'PosReg', (114, 122))	('upregulating', 'PosReg', (22, 34))	('cancer', 'Disease', (97, 103))	('silencing', 'Var', (9, 18))	('inhibit', 'NegReg', (44, 51))	('proliferation', 'CPA', (56, 69))	('TUG1', 'Gene', (35, 39))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('cell apoptosis', 'CPA', (123, 137))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
19518	28220856	Data analysis showed that high expression of CSC markers was associated with poor overall survival (OS) (HR = 1.93; 95% CI: 1.46-2.55, P < 0.001) and disease free survival (DFS) (HR = 4.78; 95% CI: 2.95-7.75, P < 0.001) but not disease specific survival (DSS) (HR = 1.17; 95% CI: 0.74-1.84, P = 0.50) of HNSCC patients.	('patients', 'Species', '9606', (310, 318))	('high', 'Var', (26, 30))	('DSS', 'Chemical', '-', (255, 258))	('poor', 'NegReg', (77, 81))	('OS', 'Chemical', '-', (100, 102))	('expression', 'MPA', (31, 41))	('disease free survival', 'CPA', (150, 171))	('overall survival', 'CPA', (82, 98))
19526	28220856	Furthermore, it has been reported that patients with high expression of ALDH1, CD44 and SOX2 had worse prognosis.	('ALDH1', 'Gene', (72, 77))	('patients', 'Species', '9606', (39, 47))	('ALDH1', 'Gene', '216', (72, 77))	('CD44', 'Gene', '960', (79, 83))	('SOX2', 'Gene', '6657', (88, 92))	('SOX2', 'Gene', (88, 92))	('CD44', 'Gene', (79, 83))	('high expression', 'Var', (53, 68))
19534	28220856	High expression of CSC markers was associated with poor OS (HR = 1.93; 95% CI: 1.46-2.55, P < 0.001) although with heterogeneity (I2 = 59%, Ph < 0.001; Fig.	('OS', 'Chemical', '-', (56, 58))	('poor', 'Disease', (51, 55))	('High', 'Var', (0, 4))
19540	28220856	Interestingly, poor DSS in patients was significantly associated with high expression of Bmi-1 (HR = 1.85, 95%CI: 1.24-2.76, P = 0.002; I2 = 0%, Ph = 0.47).	('DSS', 'Chemical', '-', (20, 23))	('poor DSS', 'Disease', (15, 23))	('Bmi-1', 'Gene', '648', (89, 94))	('patients', 'Species', '9606', (27, 35))	('Bmi-1', 'Gene', (89, 94))	('high', 'Var', (70, 74))
19551	28220856	It has been reported that high expression of Bmi-1 could significantly lead to a poor OS in gastric cancer patients.	('lead to', 'Reg', (71, 78))	('patients', 'Species', '9606', (107, 115))	('high expression', 'Var', (26, 41))	('OS', 'Chemical', '-', (86, 88))	('gastric cancer', 'Disease', (92, 106))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('gastric cancer', 'Disease', 'MESH:D013274', (92, 106))	('Bmi-1', 'Gene', '648', (45, 50))	('gastric cancer', 'Phenotype', 'HP:0012126', (92, 106))	('Bmi-1', 'Gene', (45, 50))	('poor', 'Disease', (81, 85))
19553	28220856	However, poor DSS in HNSCC patients was significantly associated with high expression of Bmi-1 with no heterogeneity (I2 = 0%, Ph = 0.47).	('HNSCC', 'Disease', (21, 26))	('poor DSS', 'Disease', (9, 17))	('DSS', 'Chemical', '-', (14, 17))	('Bmi-1', 'Gene', '648', (89, 94))	('patients', 'Species', '9606', (27, 35))	('Bmi-1', 'Gene', (89, 94))	('high', 'Var', (70, 74))
19555	28220856	When we ruled out the study of Chen 2013, the association of poor OS and high expression of Bmi-1 was changed to be significant, meanwhile the heterogeneity was lower than before.	('OS', 'Chemical', '-', (66, 68))	('Bmi-1', 'Gene', '648', (92, 97))	('Bmi-1', 'Gene', (92, 97))	('high', 'Var', (73, 77))	('poor OS', 'Disease', (61, 68))
19558	28220856	Previous meta-analyses showed that high expression of CD133 was responsible for the reduced OS of ovarian cancer, gastric cancer, non-small cell lung cancer and hepatocellular carcinoma patients.	('hepatocellular carcinoma', 'Disease', (161, 185))	('gastric cancer', 'Disease', 'MESH:D013274', (114, 128))	('non-small cell lung cancer', 'Disease', (130, 156))	('high expression', 'Var', (35, 50))	('lung cancer', 'Phenotype', 'HP:0100526', (145, 156))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('gastric cancer', 'Phenotype', 'HP:0012126', (114, 128))	('ovarian cancer', 'Phenotype', 'HP:0100615', (98, 112))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (161, 185))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (130, 156))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('patients', 'Species', '9606', (186, 194))	('carcinoma', 'Phenotype', 'HP:0030731', (176, 185))	('reduced OS of ovarian cancer', 'Disease', (84, 112))	('CD133', 'Gene', (54, 59))	('CD133', 'Gene', '8842', (54, 59))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (134, 156))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (161, 185))	('gastric cancer', 'Disease', (114, 128))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (130, 156))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('reduced OS of ovarian cancer', 'Disease', 'MESH:C567932', (84, 112))
19559	28220856	Our subgroup analysis revealed that a high expression of CD133 was related to a lower OS in HNSCC patients which was in keeping with those previous analyses.	('OS', 'Chemical', '-', (86, 88))	('patients', 'Species', '9606', (98, 106))	('high', 'Var', (38, 42))	('HNSCC', 'Disease', (92, 97))	('lower', 'NegReg', (80, 85))	('CD133', 'Gene', (57, 62))	('CD133', 'Gene', '8842', (57, 62))
19563	28220856	In the research of Chiou et al., patients with high expression of both Nanog and Oct-4 were associated with lower OS than those with high expression of Nanog or Oct-4 alone.	('patients', 'Species', '9606', (33, 41))	('OS', 'Chemical', '-', (114, 116))	('Nanog', 'Gene', (152, 157))	('Oct-4', 'Gene', (81, 86))	('lower', 'Disease', (108, 113))	('Nanog', 'Gene', '79923', (71, 76))	('high expression', 'Var', (47, 62))	('Oct-4', 'Gene', (161, 166))	('Nanog', 'Gene', (71, 76))	('Oct-4', 'Gene', '5460', (161, 166))	('Oct-4', 'Gene', '5460', (81, 86))	('Nanog', 'Gene', '79923', (152, 157))
19587	24675808	Expression Microarray Analysis Reveals Alternative Splicing of LAMA3 and DST Genes in Head and Neck Squamous Cell Carcinoma Prior studies have demonstrated tumor-specific alternative splicing events in various solid tumor types.	('tumor', 'Disease', (216, 221))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (100, 123))	('Head and Neck Squamous Cell Carcinoma', 'Phenotype', 'HP:0012288', (86, 123))	('Carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumor', 'Disease', (156, 161))	('Neck Squamous Cell Carcinoma', 'Disease', 'MESH:D000077195', (95, 123))	('DST', 'Gene', '667', (73, 76))	('tumor', 'Disease', 'MESH:D009369', (216, 221))	('LAMA3', 'Gene', (63, 68))	('Alternative Splicing', 'Var', (39, 59))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('Neck Squamous Cell Carcinoma', 'Disease', (95, 123))	('DST', 'Gene', (73, 76))	('LAMA3', 'Gene', '3909', (63, 68))
19589	24675808	Our study queried exon-level expression to implicate splice variants in HNSCC tumors.	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('HNSCC tumors', 'Disease', 'MESH:D000077195', (72, 84))	('HNSCC', 'Phenotype', 'HP:0012288', (72, 77))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('splice variants', 'Var', (53, 68))	('HNSCC tumors', 'Disease', (72, 84))
19600	24675808	The most prevalent mutations in HNSCC include TP53 and NOTCH1 genes, found in ~50% and 15% of HNSCC tumors respectively.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('prevalent', 'Reg', (9, 18))	('HNSCC', 'Gene', (32, 37))	('HNSCC tumors', 'Disease', 'MESH:D000077195', (94, 106))	('TP53', 'Gene', '7157', (46, 50))	('HNSCC', 'Phenotype', 'HP:0012288', (94, 99))	('mutations', 'Var', (19, 28))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('HNSCC', 'Phenotype', 'HP:0012288', (32, 37))	('TP53', 'Gene', (46, 50))	('NOTCH1', 'Gene', '4851', (55, 61))	('NOTCH1', 'Gene', (55, 61))	('HNSCC tumors', 'Disease', (94, 106))
19604	24675808	How these prevalent alternative splicing events are implicated in tumorigenesis is not presently clear.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Disease', (66, 71))	('alternative splicing', 'Var', (20, 40))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('implicated', 'Reg', (52, 62))
19606	24675808	The short DeltaNp63 isoform is dominant in both normal epithelial cells and HNSCC, and furthermore DeltaNp63 appears to be selectively overexpressed in HNSCC tumor cells.	('HNSCC tumor', 'Disease', 'MESH:D000077195', (152, 163))	('epithelia', 'Disease', 'None', (55, 64))	('epithelia', 'Disease', (55, 64))	('HNSCC tumor', 'Disease', (152, 163))	('HNSCC', 'Phenotype', 'HP:0012288', (76, 81))	('HNSCC', 'Phenotype', 'HP:0012288', (152, 157))	('overexpressed', 'PosReg', (135, 148))	('DeltaNp63', 'Var', (99, 108))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))
19644	24675808	By examining individual tumor plots we identify putative alternative splicing events that occur in a significant number of individual samples with less 'noise' than may be seen from overall comparisons of tumor and UPPP cohorts.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('tumor', 'Disease', (24, 29))	('alternative splicing', 'Var', (57, 77))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumor', 'Disease', (205, 210))	('tumor', 'Disease', 'MESH:D009369', (24, 29))
19645	24675808	We selected 15 tumors from the discovery set for validation of select alternative splicing candidates from our MMES prediction model.	('tumors', 'Disease', (15, 21))	('alternative splicing', 'Var', (70, 90))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumors', 'Disease', 'MESH:D009369', (15, 21))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))
19660	24675808	Three longer isoforms (TAp63) share ten consecutive exons from the 5'-end (TP63 TA isoforms NM_001114979.1, NM__001114978.1, and NM_003722.4).	('NM_001114979.1', 'Var', (92, 106))	('NM_003722.4', 'Var', (129, 140))	('TP63', 'Gene', '8626', (75, 79))	('TP63', 'Gene', (75, 79))	('NM__001114978.1', 'Var', (108, 123))
19662	24675808	Figure 3 demonstrates select individual tumors with either DeltaNp63 or TAp63 predominant expression (Figure 3A), and a TP63 gene plot comparing all tumors to UPPP normal samples (Figure S4A), predicting that overall tumors have a higher predominance of DeltaNp63 isoform expression.	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('DeltaNp63', 'Var', (254, 263))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('tumors', 'Disease', (217, 223))	('TAp63', 'Gene', (72, 77))	('tumors', 'Disease', 'MESH:D009369', (217, 223))	('tumors', 'Disease', 'MESH:D009369', (40, 46))	('tumors', 'Phenotype', 'HP:0002664', (217, 223))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('TP63', 'Gene', '8626', (120, 124))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumors', 'Disease', (149, 155))	('tumors', 'Disease', 'MESH:D009369', (149, 155))	('TP63', 'Gene', (120, 124))	('tumors', 'Phenotype', 'HP:0002664', (149, 155))	('DeltaNp63', 'Var', (59, 68))	('tumors', 'Disease', (40, 46))
19666	24675808	LAMA3 RefSeq annotations demonstrate four major isoforms of this gene, with the two shorter isoforms (LAMA3A NM_001127718.1 and NM_000227.3) excluding the 36 consecutive most 5' exons, and full-length LAMA3B variants (LAMA3B NM_001127717.1 and NM_198129.1).	('LAMA3', 'Gene', '3909', (102, 107))	('LAMA3', 'Gene', (201, 206))	('LAMA3', 'Gene', (218, 223))	('LAMA3', 'Gene', '3909', (201, 206))	('LAMA3', 'Gene', (102, 107))	('LAMA3', 'Gene', '3909', (218, 223))	('LAMA3', 'Gene', (0, 5))	('NM_198129.1', 'Var', (244, 255))	('NM_001127717.1', 'Var', (225, 239))	('LAMA3', 'Gene', '3909', (0, 5))
19672	24675808	Our manual review of DST gene plots predicted predominant expression of either the short isoform (1e, NM__001723.5):excluding the eight most 3' exons, and including a long sequence that is intronic and not transcribed in the longer isoforms:or one of four longer isoforms that we probed with a 'common' primer/probeset (1eA, NM__183380.3; Isoform 3 NM_001144770.1; Isoform 2, NM__001144769.2; Isoform 1, NM__183380.3).	('DST', 'Gene', '667', (21, 24))	('NM_001144770.1', 'Var', (349, 363))	('DST', 'Gene', (21, 24))	('NM__183380.3', 'Var', (404, 416))	('NM__001144769.2', 'Var', (376, 391))
19677	24675808	Alternative splicing may be relevant in the pathophysiology of various cancers as well.	('cancers', 'Phenotype', 'HP:0002664', (71, 78))	('cancers', 'Disease', 'MESH:D009369', (71, 78))	('cancers', 'Disease', (71, 78))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('Alternative splicing', 'Var', (0, 20))	('relevant', 'Reg', (28, 36))
19681	24675808	Alternative splicing may significantly influence the transcriptional milieu in HNSCC as it does in other tumor types.	('HNSCC', 'Disease', (79, 84))	('influence', 'Reg', (39, 48))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('HNSCC', 'Phenotype', 'HP:0012288', (79, 84))	('Alternative splicing', 'Var', (0, 20))	('tumor', 'Disease', (105, 110))	('transcriptional milieu', 'MPA', (53, 75))
19686	24675808	Often at the validation stage of putative cancer-specific alternative splicing, five to ten genes remain for which RT-PCR validation corroborates array predictions.	('alternative splicing', 'Var', (58, 78))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))
19706	24675808	While BPAG1 mutations are implicated in bullous pemphigoid blistering diseases, little is known about a potential role in cancer.	('mutations', 'Var', (12, 21))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('implicated', 'Reg', (26, 36))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('BPAG1', 'Gene', '667', (6, 11))	('bullous pemphigoid blistering diseases', 'Disease', (40, 78))	('BPAG1', 'Gene', (6, 11))
19739	33936088	Finally, five gene expression microarray datasets were chosen as a training set, including (GSE42568, n=121), (GSE88770, n=117), (GSE16446, n=120), (GSE37751, n=108), and (GSE7390, n=198).	('GSE16446', 'Var', (130, 138))	('GSE7390', 'Var', (172, 179))	('GSE7390', 'Chemical', '-', (172, 179))	('GSE88770', 'Var', (111, 119))	('GSE42568', 'Var', (92, 100))	('GSE37751', 'Var', (149, 157))
19764	33936088	The Kaplan-Meier analysis elucidated that BRCA patients with ATP2C2 low expression had longer survival than those with ATP2C2 high expression (Figure 5A).	('ATP2C2', 'Gene', (61, 67))	('BRCA', 'Phenotype', 'HP:0003002', (42, 46))	('ATP2C2', 'Gene', (119, 125))	('BRCA', 'Gene', '672', (42, 46))	('low expression', 'Var', (68, 82))	('patients', 'Species', '9606', (47, 55))	('BRCA', 'Gene', (42, 46))	('ATP2C2', 'Gene', '9914', (61, 67))	('longer', 'PosReg', (87, 93))	('ATP2C2', 'Gene', '9914', (119, 125))	('survival', 'CPA', (94, 102))
19787	33936088	Through the analysis of the TIDE algorithm, we found that in BRCA patients with low ATP2C2 expression levels, high CTL levels indicate a better prognosis, while the above phenomenon is not observed in BRCA patients with high ATP2C2 expression levels  (Figure 9).	('low', 'Var', (80, 83))	('BRCA', 'Phenotype', 'HP:0003002', (201, 205))	('BRCA', 'Gene', '672', (201, 205))	('ATP2C2', 'Gene', '9914', (84, 90))	('patients', 'Species', '9606', (66, 74))	('patients', 'Species', '9606', (206, 214))	('BRCA', 'Gene', (201, 205))	('ATP2C2', 'Gene', '9914', (225, 231))	('BRCA', 'Phenotype', 'HP:0003002', (61, 65))	('BRCA', 'Gene', '672', (61, 65))	('BRCA', 'Gene', (61, 65))	('ATP2C2', 'Gene', (84, 90))	('high CTL levels', 'MPA', (110, 125))	('ATP2C2', 'Gene', (225, 231))
19814	33936088	Changes in cytosolic Ca2+ trigger events critical for tumorigenesis, such as cellular motility, proliferation, and apoptosis.	('cytosolic Ca2+', 'MPA', (11, 25))	('Ca2+', 'Chemical', 'MESH:D000069285', (21, 25))	('proliferation', 'CPA', (96, 109))	('cellular motility', 'CPA', (77, 94))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor', 'Disease', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('Changes', 'Var', (0, 7))	('apoptosis', 'CPA', (115, 124))
19829	33936088	We found that more M1 macrophages infiltrated in ATP2C2 high-expression group compared with ATP2C2 low-expression group, implying that tumor infiltrated macrophages exert immune response functions and exhibit anti-tumor effects.	('M1 macrophages', 'CPA', (19, 33))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('ATP2C2', 'Gene', '9914', (49, 55))	('tumor', 'Disease', 'MESH:D009369', (214, 219))	('immune response functions', 'CPA', (171, 196))	('tumor', 'Disease', (135, 140))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('ATP2C2', 'Gene', '9914', (92, 98))	('ATP2C2', 'Gene', (49, 55))	('more', 'PosReg', (14, 18))	('high-expression group', 'Var', (56, 77))	('tumor', 'Disease', (214, 219))	('ATP2C2', 'Gene', (92, 98))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
19838	33936088	Previous studies have shown that gammadelta T lymphocytes inhibit angiogenic signalling pathways associated with AKT and ERK, and increase apoptosis.	('ERK', 'Gene', (121, 124))	('gammadelta T', 'Var', (33, 45))	('angiogenic signalling pathways', 'Pathway', (66, 96))	('ERK', 'Gene', '2048', (121, 124))	('AKT', 'Gene', '207', (113, 116))	('increase', 'PosReg', (130, 138))	('inhibit', 'NegReg', (58, 65))	('AKT', 'Gene', (113, 116))	('apoptosis', 'CPA', (139, 148))
19846	33247170	Our results found that high AQP9 expression was significantly correlated with worse prognosis in breast, colon and lung cancers, while predicted better prognosis in gastric cancer.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('lung cancers', 'Phenotype', 'HP:0100526', (115, 127))	('high', 'Var', (23, 27))	('gastric cancer', 'Phenotype', 'HP:0012126', (165, 179))	('AQP9', 'Gene', (28, 32))	('breast', 'Disease', (97, 103))	('cancers', 'Phenotype', 'HP:0002664', (120, 127))	('colon and lung cancers', 'Disease', 'MESH:D008175', (105, 127))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('expression', 'MPA', (33, 43))	('better', 'PosReg', (145, 151))	('gastric cancer', 'Disease', (165, 179))	('gastric cancer', 'Disease', 'MESH:D013274', (165, 179))	('lung cancer', 'Phenotype', 'HP:0100526', (115, 126))
19858	33247170	Lymphocyte activation gene 3 (LAG-3) is expressed in NK cells and activated T cells and blockade of LAG-3 promotes T-cell proliferation, activation and effector function.	('blockade', 'Var', (88, 96))	('Lymphocyte activation gene 3', 'Gene', (0, 28))	('promotes', 'PosReg', (106, 114))	('LAG-3', 'Gene', '3902', (30, 35))	('Lymphocyte activation gene 3', 'Gene', '3902', (0, 28))	('LAG-3', 'Gene', (30, 35))	('T-cell proliferation', 'CPA', (115, 135))	('activation', 'CPA', (137, 147))	('LAG-3', 'Gene', '3902', (100, 105))	('effector function', 'CPA', (152, 169))	('LAG-3', 'Gene', (100, 105))
19866	33247170	AQP9 can inhibit the invasion of liver cancer cells and the proliferation of xenograft tumors.	('liver cancer', 'Disease', (33, 45))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('inhibit', 'NegReg', (9, 16))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('tumors', 'Disease', (87, 93))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('liver cancer', 'Phenotype', 'HP:0002896', (33, 45))	('tumors', 'Disease', 'MESH:D009369', (87, 93))	('AQP9', 'Var', (0, 4))	('liver cancer', 'Disease', 'MESH:D006528', (33, 45))
19868	33247170	Moreover, AQP9 can also activate RAS signal and sensitize tumor cells to chemotherapy drugs in colorectal cancer.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('colorectal cancer', 'Phenotype', 'HP:0003003', (95, 112))	('colorectal cancer', 'Disease', (95, 112))	('colorectal cancer', 'Disease', 'MESH:D015179', (95, 112))	('activate', 'PosReg', (24, 32))	('RAS signal', 'MPA', (33, 43))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('AQP9', 'Var', (10, 14))	('sensitize', 'Reg', (48, 57))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
19884	33247170	It showed that higher AQP9 expression was associated with the mutant of TP53 in BRCA and BRAF in COAD.	('COAD', 'Disease', 'MESH:D029424', (97, 101))	('mutant', 'Var', (62, 68))	('higher', 'PosReg', (15, 21))	('TP53', 'Gene', '7157', (72, 76))	('BRCA', 'Phenotype', 'HP:0003002', (80, 84))	('BRCA', 'Gene', '672', (80, 84))	('expression', 'MPA', (27, 37))	('TP53', 'Gene', (72, 76))	('BRCA', 'Gene', (80, 84))	('COAD', 'Disease', (97, 101))	('BRAF', 'Gene', '673', (89, 93))	('BRAF', 'Gene', (89, 93))	('AQP9', 'Gene', (22, 26))
19892	33247170	In conclusion, the expression of AQP9 can make a profound difference to the prognosis of breast, lung and gastric cancers.	('cancers', 'Phenotype', 'HP:0002664', (114, 121))	('gastric cancers', 'Disease', 'MESH:D013274', (106, 121))	('difference', 'Reg', (58, 68))	('expression', 'Var', (19, 29))	('gastric cancers', 'Disease', (106, 121))	('lung', 'Disease', (97, 101))	('gastric cancers', 'Phenotype', 'HP:0012126', (106, 121))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('AQP9', 'Gene', (33, 37))	('gastric cancer', 'Phenotype', 'HP:0012126', (106, 120))	('breast', 'Disease', (89, 95))
19894	33247170	It was found that the overexpression of AQP9 was correlated with the prognosis at different lymph node status in BRCA, among which high AQP9 expression predicted poorer OS and RFS prognosis in Lymph node negative BRCA, and poorer RFS prognosis in Lymph node positive BRCA (Supplementary Table S2).	('BRCA', 'Gene', (113, 117))	('BRCA', 'Phenotype', 'HP:0003002', (213, 217))	('RFS', 'Gene', (230, 233))	('RFS', 'Gene', '65211', (230, 233))	('BRCA', 'Gene', '672', (213, 217))	('RFS', 'Gene', '65211', (176, 179))	('BRCA', 'Gene', (213, 217))	('RFS', 'Gene', (176, 179))	('BRCA', 'Phenotype', 'HP:0003002', (113, 117))	('BRCA', 'Phenotype', 'HP:0003002', (267, 271))	('expression', 'MPA', (141, 151))	('BRCA', 'Gene', '672', (113, 117))	('BRCA', 'Gene', '672', (267, 271))	('poorer', 'NegReg', (162, 168))	('AQP9', 'Gene', (136, 140))	('high', 'Var', (131, 135))	('BRCA', 'Gene', (267, 271))
19896	33247170	The high AQP9 expression was also found to have better impact on the prognosis of patients at stage N0, N2 and N1+2+3 in gastric cancer.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('AQP9', 'Protein', (9, 13))	('gastric cancer', 'Phenotype', 'HP:0012126', (121, 135))	('patients', 'Species', '9606', (82, 90))	('better', 'PosReg', (48, 54))	('high', 'Var', (4, 8))	('impact', 'Reg', (55, 61))	('gastric cancer', 'Disease', (121, 135))	('N1+2+3', 'Var', (111, 117))	('gastric cancer', 'Disease', 'MESH:D013274', (121, 135))
19899	33247170	The results suggested that high AQP9 expression correlated with the prognosis of patients with lymphatic metastasis in breast, gastric and lung cancers.	('breast', 'Disease', (119, 125))	('lung cancers', 'Disease', 'MESH:D008175', (139, 151))	('gastric', 'Disease', (127, 134))	('lung cancers', 'Phenotype', 'HP:0100526', (139, 151))	('patients', 'Species', '9606', (81, 89))	('high', 'Var', (27, 31))	('cancers', 'Phenotype', 'HP:0002664', (144, 151))	('correlated with', 'Reg', (48, 63))	('lung cancers', 'Disease', (139, 151))	('AQP9', 'Gene', (32, 36))	('lymphatic metastasis', 'CPA', (95, 115))	('expression', 'MPA', (37, 47))	('lung cancer', 'Phenotype', 'HP:0100526', (139, 150))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
19903	33247170	Furthermore, one cohort (GSE17536) revealed that high AQP9 expression predicted worse prognosis for colorectal cancer patients (Fig.	('colorectal cancer', 'Disease', 'MESH:D015179', (100, 117))	('colorectal cancer', 'Phenotype', 'HP:0003003', (100, 117))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('colorectal cancer', 'Disease', (100, 117))	('expression', 'MPA', (59, 69))	('high', 'Var', (49, 53))	('AQP9', 'Gene', (54, 58))	('patients', 'Species', '9606', (118, 126))
19917	33247170	These results strongly indicated that AQP9 might have an important effect on tumor immune infiltration, especially on the infiltrating levels of neutrophils, macrophages and DCs in breast, colorectal, lung and gastric cancers.	('breast', 'Disease', (181, 187))	('gastric cancer', 'Phenotype', 'HP:0012126', (210, 224))	('cancers', 'Phenotype', 'HP:0002664', (218, 225))	('effect', 'Reg', (67, 73))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('gastric cancers', 'Disease', (210, 225))	('lung', 'Disease', (201, 205))	('infiltrating levels of neutrophils', 'MPA', (122, 156))	('gastric cancers', 'Disease', 'MESH:D013274', (210, 225))	('gastric cancers', 'Phenotype', 'HP:0012126', (210, 225))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('AQP9', 'Var', (38, 42))	('tumor', 'Disease', (77, 82))	('colorectal', 'Disease', (189, 199))	('DCs', 'MPA', (174, 177))
19922	33247170	The results suggested that AQP9 might correlate with macrophage polarization in BRCA, COAD, LUAD, LUSC and STAD.	('COAD', 'Disease', 'MESH:D029424', (86, 90))	('BRCA', 'Phenotype', 'HP:0003002', (80, 84))	('BRCA', 'Gene', '672', (80, 84))	('macrophage polarization', 'CPA', (53, 76))	('correlate', 'Reg', (38, 47))	('COAD', 'Disease', (86, 90))	('LUSC', 'Phenotype', 'HP:0030359', (98, 102))	('BRCA', 'Gene', (80, 84))	('LUAD', 'Phenotype', 'HP:0030078', (92, 96))	('AQP9', 'Var', (27, 31))
19939	33247170	As it has been reported in previous studies, AQP9 was required for efficient DCs maturation and affected macrophage function by regulating cell volume, shape and protrusion development via water fluxes.	('macrophage function', 'CPA', (105, 124))	('affected', 'Reg', (96, 104))	('water', 'Chemical', 'MESH:D014867', (189, 194))	('AQP9', 'Var', (45, 49))	('regulating', 'Reg', (128, 138))	('protrusion development', 'CPA', (162, 184))	('cell volume', 'CPA', (139, 150))
19943	33247170	We also found that the mutant TP53 in BRCA and mutant BRAF in COAD were correlated with higher AQP9 expression.	('higher', 'PosReg', (88, 94))	('COAD', 'Disease', 'MESH:D029424', (62, 66))	('TP53', 'Gene', (30, 34))	('BRCA', 'Gene', '672', (38, 42))	('BRAF', 'Gene', (54, 58))	('BRAF', 'Gene', '673', (54, 58))	('BRCA', 'Gene', (38, 42))	('COAD', 'Disease', (62, 66))	('BRCA', 'Phenotype', 'HP:0003002', (38, 42))	('TP53', 'Gene', '7157', (30, 34))	('mutant', 'Var', (47, 53))	('mutant', 'Var', (23, 29))	('AQP9', 'Gene', (95, 99))
19944	33247170	It has been reported that TP53 mutations have different clinical relevance in molecular subtypes of BRCA and TP53 can affect tumor energy metabolism such as increasing glycolysis.	('TP53', 'Gene', (26, 30))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('mutations', 'Var', (31, 40))	('TP53', 'Gene', '7157', (26, 30))	('BRCA', 'Gene', '672', (100, 104))	('affect', 'Reg', (118, 124))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('BRCA', 'Gene', (100, 104))	('increasing', 'PosReg', (157, 167))	('TP53', 'Gene', '7157', (109, 113))	('tumor', 'Disease', (125, 130))	('glycolysis', 'MPA', (168, 178))	('TP53', 'Gene', (109, 113))	('BRCA', 'Phenotype', 'HP:0003002', (100, 104))
19945	33247170	Although TP53 is recognized as a tumor suppressor gene in various cancers, the mutant TP53 does not necessarily represent its inactivation as a tumor suppressor gene, and it's highly likely to have a carcinogenic effect.	('tumor', 'Disease', (144, 149))	('cancers', 'Disease', 'MESH:D009369', (66, 73))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('TP53', 'Gene', '7157', (86, 90))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('mutant', 'Var', (79, 85))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('TP53', 'Gene', (86, 90))	('TP53', 'Gene', '7157', (9, 13))	('TP53', 'Gene', (9, 13))	('cancers', 'Phenotype', 'HP:0002664', (66, 73))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('tumor', 'Disease', (33, 38))	('cancers', 'Disease', (66, 73))	('carcinogenic', 'Disease', 'MESH:D063646', (200, 212))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('carcinogenic', 'Disease', (200, 212))
19946	33247170	BRAF mutations are common in colorectal cancer and confers significant prognosis to advanced diseases.	('colorectal cancer', 'Disease', 'MESH:D015179', (29, 46))	('mutations', 'Var', (5, 14))	('BRAF', 'Gene', '673', (0, 4))	('colorectal cancer', 'Phenotype', 'HP:0003003', (29, 46))	('common', 'Reg', (19, 25))	('BRAF', 'Gene', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('colorectal cancer', 'Disease', (29, 46))
19947	33247170	Our study found that the difference in AQP9 expression was correlated with TP53 and BRAF mutants, which indicated a potential factor that might regulate AQP9 expression in breast and colon cancers.	('expression', 'MPA', (44, 54))	('BRAF', 'Gene', '673', (84, 88))	('expression', 'MPA', (158, 168))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('BRAF', 'Gene', (84, 88))	('regulate', 'Reg', (144, 152))	('colon cancers', 'Phenotype', 'HP:0003003', (183, 196))	('breast and colon cancers', 'Disease', 'MESH:D001943', (172, 196))	('mutants', 'Var', (89, 96))	('cancers', 'Phenotype', 'HP:0002664', (189, 196))	('TP53', 'Gene', '7157', (75, 79))	('TP53', 'Gene', (75, 79))	('AQP9', 'Gene', (39, 43))
19950	33247170	This result suggested that AQP9 expression might also be affected by epigenetics to some extent, but the regulating effect varies from cancer to cancer.	('cancer', 'Disease', (145, 151))	('affected', 'Reg', (57, 65))	('AQP9', 'Gene', (27, 31))	('cancer', 'Disease', (135, 141))	('epigenetics', 'Var', (69, 80))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('expression', 'MPA', (32, 42))	('cancer', 'Disease', 'MESH:D009369', (135, 141))
19951	33247170	Then, we further reported that discrepancies in AQP9 expression level had significant correlations with the prognosis of different tumors.	('correlations', 'Reg', (86, 98))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('AQP9', 'Gene', (48, 52))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('expression level', 'MPA', (53, 69))	('tumors', 'Disease', (131, 137))	('tumors', 'Disease', 'MESH:D009369', (131, 137))	('discrepancies', 'Var', (31, 44))
19955	33247170	Our findings were consistent with the previous study that high expression of AQP9 was associated with favorable OS in all gastric cancer patients including intestinal and diffused types , while high expression of AQP9 was accompanied by worse prognosis in patients with lymph node-negative breast cancer and was increased in higher SBR (Scarff-Bloom-Richardson) grades of all types of breast cancer in particular.	('high expression', 'Var', (58, 73))	('cancer', 'Phenotype', 'HP:0002664', (392, 398))	('gastric cancer', 'Phenotype', 'HP:0012126', (122, 136))	('breast cancer', 'Phenotype', 'HP:0003002', (290, 303))	('high expression', 'Var', (194, 209))	('increased', 'PosReg', (312, 321))	('breast cancer', 'Disease', 'MESH:D001943', (290, 303))	('breast cancer', 'Disease', (290, 303))	('patients', 'Species', '9606', (137, 145))	('gastric cancer', 'Disease', (122, 136))	('breast cancer', 'Phenotype', 'HP:0003002', (385, 398))	('AQP9', 'Var', (213, 217))	('AQP9', 'Gene', (77, 81))	('patients', 'Species', '9606', (256, 264))	('breast cancer', 'Disease', 'MESH:D001943', (385, 398))	('breast cancer', 'Disease', (385, 398))	('gastric cancer', 'Disease', 'MESH:D013274', (122, 136))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('cancer', 'Phenotype', 'HP:0002664', (297, 303))
19956	33247170	However, it may contradict and therefore discredit the results that AQP9 overexpression enhanced the cytotoxic response to 5-FU and promoted the activation of RAS through glycerol transport in CRC cells .	('glycerol transport', 'MPA', (171, 189))	('glycerol', 'Chemical', 'MESH:D005990', (171, 179))	('overexpression', 'Var', (73, 87))	('activation', 'MPA', (145, 155))	('RAS', 'Protein', (159, 162))	('cytotoxic response to 5-FU', 'MPA', (101, 127))	('promoted', 'PosReg', (132, 140))	('AQP9', 'Gene', (68, 72))	('enhanced', 'PosReg', (88, 96))	('5-FU', 'Chemical', 'MESH:D005472', (123, 127))
19960	33247170	It seemed that AQP9 could not only predict the clinical prognosis for tumor patients, but also be used as an indicator for the clinical treatment effect, providing directions for further improving the prognosis of patients.	('patients', 'Species', '9606', (76, 84))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('patients', 'Species', '9606', (214, 222))	('tumor', 'Disease', (70, 75))	('AQP9', 'Var', (15, 19))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('predict', 'Reg', (35, 42))
19962	33247170	Further studies should be conducted to explore whether AQP9 can promote the uptake of specific drugs by tumor cells based on its own transport properties to enhance the sensitivity of chemotherapy.	('enhance', 'PosReg', (157, 164))	('AQP9', 'Var', (55, 59))	('promote', 'PosReg', (64, 71))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('sensitivity of chemotherapy', 'CPA', (169, 196))	('tumor', 'Disease', (104, 109))	('uptake of specific drugs', 'MPA', (76, 100))	('transport properties', 'MPA', (133, 153))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
19968	33247170	These findings revealed the underlying regulatory role AQP9 might play in the polarization of TAMs, indicating AQP9 may be involved in the immunosuppression in the focused cancers.	('involved', 'Reg', (123, 131))	('AQP9', 'Var', (111, 115))	('TAMs', 'Chemical', 'MESH:D013629', (94, 98))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('cancers', 'Disease', 'MESH:D009369', (172, 179))	('cancers', 'Phenotype', 'HP:0002664', (172, 179))	('cancers', 'Disease', (172, 179))
19972	33247170	These findings suggested that AQP9 might affect tumor immune through neutrophils and the correlation with CD11b.	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('tumor', 'Disease', (48, 53))	('correlation', 'Interaction', (89, 100))	('CD11b', 'Gene', (106, 111))	('AQP9', 'Var', (30, 34))	('CD11b', 'Gene', '3684', (106, 111))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('affect', 'Reg', (41, 47))
19979	33247170	It was reported that DCs could increase Treg cells and reduce cytotoxicity of CD8+T cells, thus promoting tumor metastasis.	('cytotoxicity', 'Disease', 'MESH:D064420', (62, 74))	('CD8', 'Gene', (78, 81))	('promoting', 'PosReg', (96, 105))	('CD8', 'Gene', '925', (78, 81))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('Treg cells', 'CPA', (40, 50))	('cytotoxicity', 'Disease', (62, 74))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('increase', 'PosReg', (31, 39))	('reduce', 'NegReg', (55, 61))	('tumor', 'Disease', (106, 111))	('DCs', 'Var', (21, 24))
19985	33247170	In conclusion, AQP9 expression had a significant impact on the regulation of immune infiltration levels and tumor-immune interaction in BRCA, COAD, LUAD, LUSC and STAD.	('COAD', 'Disease', 'MESH:D029424', (142, 146))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('regulation', 'MPA', (63, 73))	('LUAD', 'Phenotype', 'HP:0030078', (148, 152))	('immune infiltration levels', 'MPA', (77, 103))	('expression', 'Var', (20, 30))	('tumor', 'Disease', (108, 113))	('COAD', 'Disease', (142, 146))	('AQP9', 'Gene', (15, 19))	('BRCA', 'Gene', '672', (136, 140))	('BRCA', 'Phenotype', 'HP:0003002', (136, 140))	('impact', 'Reg', (49, 55))	('LUSC', 'Phenotype', 'HP:0030359', (154, 158))	('BRCA', 'Gene', (136, 140))
19998	33247170	IL1RN polymorphism has been reported to promote the development of lung cancer through inflammatory response.	('promote', 'PosReg', (40, 47))	('polymorphism', 'Var', (6, 18))	('inflammatory response', 'CPA', (87, 108))	('IL1RN', 'Gene', '3557', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('IL1RN', 'Gene', (0, 5))	('lung cancer', 'Disease', 'MESH:D008175', (67, 78))	('lung cancer', 'Disease', (67, 78))	('lung cancer', 'Phenotype', 'HP:0100526', (67, 78))
20004	33247170	It should also be addressed through molecular biology techniques to confirm whether AQP9 can be used as a therapeutic target in the immunotherapy of cancers and the specific mechanism in which AQP9 affects the prognosis and immune infiltrates in breast, colon, lung and gastric cancers.	('cancers', 'Disease', 'MESH:D009369', (278, 285))	('AQP9', 'Var', (193, 197))	('affects', 'Reg', (198, 205))	('cancer', 'Phenotype', 'HP:0002664', (278, 284))	('cancers', 'Phenotype', 'HP:0002664', (278, 285))	('cancers', 'Phenotype', 'HP:0002664', (149, 156))	('cancers', 'Disease', (278, 285))	('prognosis', 'CPA', (210, 219))	('gastric cancers', 'Disease', 'MESH:D013274', (270, 285))	('cancers', 'Disease', (149, 156))	('gastric cancers', 'Disease', (270, 285))	('gastric cancers', 'Phenotype', 'HP:0012126', (270, 285))	('colon', 'Disease', (254, 259))	('lung', 'Disease', (261, 265))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('gastric cancer', 'Phenotype', 'HP:0012126', (270, 284))	('immune infiltrates', 'CPA', (224, 242))	('breast', 'Disease', (246, 252))	('cancers', 'Disease', 'MESH:D009369', (149, 156))
20112	31119136	Numerous studies have indicated that aberrant expression levels of exosomal miRNAs are closely related to the onset of multiple diseases, including cancer.	('cancer', 'Disease', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('exosomal miRNAs', 'Protein', (67, 82))	('related', 'Reg', (95, 102))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('expression levels', 'MPA', (46, 63))	('multiple diseases', 'Disease', (119, 136))	('multiple diseases', 'Disease', 'MESH:D000015', (119, 136))	('aberrant', 'Var', (37, 45))
20114	31119136	MiR-93-5p: MicroRNA-93-5p can be transferred between EC9706 cells by exosomes and promote the proliferation of recipient EC9706 cells.	('MiR-93-5p', 'Gene', '100126325', (0, 9))	('promote', 'PosReg', (82, 89))	('MicroRNA-93-5p', 'Var', (11, 25))	('EC9706', 'CellLine', 'CVCL:E307', (121, 127))	('MiR-93-5p', 'Gene', (0, 9))	('proliferation', 'CPA', (94, 107))	('EC9706', 'CellLine', 'CVCL:E307', (53, 59))
20130	31119136	MiR-223-3p: Exo-miRNAs are also important biomarkers for EA diagnosis and progression.	('MiR-223', 'Gene', (0, 7))	('MiR-223', 'Gene', '407008', (0, 7))	('EA', 'Phenotype', 'HP:0011459', (57, 59))	('Exo-miRNAs', 'Var', (12, 22))
20132	31119136	Results showed that a total of eight miRNAs (miR-126-5p, miR-146a-5p, miR-192-5p, miR-196b-5p, miR-223-3p, miR-223-5p, miR-409-3p and miR-483-5p) were significantly overexpressed.	('miR-483-5p', 'Var', (134, 144))	('miR-1', 'Gene', '83856', (70, 75))	('miR-192', 'Gene', '406967', (70, 77))	('miR-223', 'Gene', (95, 102))	('miR-1', 'Gene', (70, 75))	('miR-223', 'Gene', '407008', (107, 114))	('miR-1', 'Gene', '83856', (45, 50))	('miR-126-5p', 'Gene', '100302116', (45, 55))	('miR-126-5p', 'Gene', (45, 55))	('miR-1', 'Gene', '83856', (82, 87))	('miR-1', 'Gene', (45, 50))	('miR-192', 'Gene', (70, 77))	('miR-223', 'Gene', '407008', (95, 102))	('miR-1', 'Gene', (82, 87))	('miR-1', 'Gene', '83856', (57, 62))	('overexpressed', 'PosReg', (165, 178))	('miR-1', 'Gene', (57, 62))	('miR-223', 'Gene', (107, 114))	('miR-409-3p', 'Var', (119, 129))
20133	31119136	Conversely, ten miRNAs (miR-22-3p, miR-23b-5p, miR-27b-3p, miR-149-5p, miR-203-5p, miR-224-5p, miR-452-5p, miR-671-3p, miR-944-5p and miR-1201-5p) were significantly downregulated.	('miR-27b', 'Gene', (47, 54))	('miR-1', 'Gene', (134, 139))	('miR-22-3p', 'Gene', '407008', (24, 33))	('miR-1', 'Gene', '83856', (59, 64))	('miR-203-5p', 'Var', (71, 81))	('miR-27b', 'Gene', '407019', (47, 54))	('miR-224-5p', 'Var', (83, 93))	('miR-944', 'Gene', (119, 126))	('downregulated', 'NegReg', (166, 179))	('miR-22-3p', 'Gene', (24, 33))	('miR-1', 'Gene', (59, 64))	('miR-1201', 'Gene', '100113391', (134, 142))	('miR-671-3p', 'Var', (107, 117))	('miR-23b', 'Gene', '407011', (35, 42))	('miR-944', 'Gene', '100126340', (119, 126))	('miR-452-5p', 'Var', (95, 105))	('miR-1201', 'Gene', (134, 142))	('miR-23b', 'Gene', (35, 42))	('miR-1', 'Gene', '83856', (134, 139))
20135	31119136	There was no statistical difference in the overexpression of miR-223-5p and miR-483-5p in EA and ESCC.	('SCC', 'Phenotype', 'HP:0002860', (98, 101))	('miR-223', 'Gene', (61, 68))	('SCC', 'Gene', '6317', (98, 101))	('EA', 'Phenotype', 'HP:0011459', (90, 92))	('miR-483-5p', 'Var', (76, 86))	('miR-223', 'Gene', '407008', (61, 68))	('SCC', 'Gene', (98, 101))
20136	31119136	MiR-584: A four-stage study including screening, training, testing and validating identified that miR-106a, miR-18a, miR-20b, miR-486-5p and miR-584 were upregulated, but miR-223-3p was downregulated in the plasma of patients with ESCC.	('miR-18a', 'Gene', (108, 115))	('MiR-584', 'Gene', '693169', (0, 7))	('miR-223', 'Gene', '407008', (171, 178))	('SCC', 'Gene', '6317', (232, 235))	('upregulated', 'PosReg', (154, 165))	('miR-20b', 'Gene', (117, 124))	('miR-106a', 'Gene', (98, 106))	('SCC', 'Gene', (232, 235))	('miR-18a', 'Gene', '406953', (108, 115))	('miR-584', 'Gene', '693169', (141, 148))	('MiR-584', 'Gene', (0, 7))	('miR-20b', 'Gene', '574032', (117, 124))	('patients', 'Species', '9606', (217, 225))	('miR-584', 'Gene', (141, 148))	('miR-223', 'Gene', (171, 178))	('miR-106a', 'Gene', '406899', (98, 106))	('miR-486-5p', 'Var', (126, 136))	('SCC', 'Phenotype', 'HP:0002860', (232, 235))	('downregulated', 'NegReg', (186, 199))
20146	31119136	Kang et al demonstrated that long non-coding RNA PART1, as a competitive endogenous RNA, regulated and transported by exosomes, took part in the formation of drug resistance in ESCC patients via the STAT1-long non-coding RNA PART-Bcl-2 pathway in a gefitinib drug-resistant cell line.	('STAT1', 'Gene', (199, 204))	('STAT1', 'Gene', '6772', (199, 204))	('drug resistance', 'Phenotype', 'HP:0020174', (158, 173))	('SCC', 'Phenotype', 'HP:0002860', (178, 181))	('SCC', 'Gene', '6317', (178, 181))	('drug resistance', 'MPA', (158, 173))	('gefitinib', 'Chemical', 'MESH:D000077156', (249, 258))	('long non-coding', 'Var', (29, 44))	('Bcl-2', 'Gene', (230, 235))	('patients', 'Species', '9606', (182, 190))	('Bcl-2', 'Gene', '596', (230, 235))	('formation', 'MPA', (145, 154))	('took part', 'Reg', (128, 137))	('SCC', 'Gene', (178, 181))
20182	28904855	Over-expression of miR-483-3p results in a poor prognosis for patients through promoting ESCC progression as a result of targeting EI24 6.	('promoting', 'PosReg', (79, 88))	('miR-483-3p', 'Var', (19, 29))	('Over-expression', 'PosReg', (0, 15))	('ESCC progression', 'Disease', (89, 105))	('patients', 'Species', '9606', (62, 70))	('EI24 6', 'Gene', (131, 137))
20184	28904855	The expression of protease, serine 8 (PRSS8) with hypermethylation is significantly decreased in ESCC, which predicts a shorter overall survival of patients with ESCC.	('patients', 'Species', '9606', (148, 156))	('overall survival', 'MPA', (128, 144))	('shorter', 'NegReg', (120, 127))	('PRSS8', 'Gene', '5652', (38, 43))	('decreased', 'NegReg', (84, 93))	('expression', 'MPA', (4, 14))	('hypermethylation', 'Var', (50, 66))	('PRSS8', 'Gene', (38, 43))	('ESCC', 'Disease', (97, 101))
20185	28904855	Demethylation of PRSS8 contributes to the inhibition of tumor progression, including cell proliferation, migration and cell cycle arrest 8.	('cell proliferation', 'CPA', (85, 103))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('PRSS8', 'Gene', '5652', (17, 22))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('tumor', 'Disease', (56, 61))	('Demethylation', 'Var', (0, 13))	('cell cycle arrest 8', 'CPA', (119, 138))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (119, 136))	('migration', 'CPA', (105, 114))	('inhibition', 'NegReg', (42, 52))	('PRSS8', 'Gene', (17, 22))
20210	28904855	In total, 1322 genes associated with the tumor grade of ESCC were significantly enriched in 14 signaling pathways, including pathways in cancer (hsa05200), the phospholipase D signaling pathway (hsa04072), small cell lung cancer (hsa05222) and gastric acid secretion (hsa04971) (Table 2).	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('phospholipase D signaling pathway', 'Pathway', (160, 193))	('lung cancer', 'Phenotype', 'HP:0100526', (217, 228))	('cancer', 'Disease', (137, 143))	('small cell lung cancer', 'Disease', 'MESH:D055752', (206, 228))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('signaling pathways', 'Pathway', (95, 113))	('enriched', 'Reg', (80, 88))	('small cell lung cancer', 'Disease', (206, 228))	('cancer', 'Disease', (222, 228))	('gastric acid secretion', 'Disease', (244, 266))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('tumor', 'Disease', (41, 46))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (206, 228))	('ESCC', 'Disease', (56, 60))	('cancer', 'Disease', 'MESH:D009369', (222, 228))	('hsa04072', 'Var', (195, 203))
20235	28904855	Self-aggregation of TIAF1in the human hippocampus leads to the generation of amyloid beta plaques, which results in neurodegeneration in Alzheimer's disease 18.	('TIAF1', 'Gene', '9220', (20, 25))	('amyloid beta plaques', 'MPA', (77, 97))	('Self-aggregation', 'Var', (0, 16))	("Alzheimer's disease", 'Disease', (137, 156))	('TIAF1', 'Gene', (20, 25))	('results in', 'Reg', (105, 115))	('neurodegeneration', 'Phenotype', 'HP:0002180', (116, 133))	('human', 'Species', '9606', (32, 37))	('neurodegeneration', 'Disease', (116, 133))	('neurodegeneration', 'Disease', 'MESH:D019636', (116, 133))	('leads to', 'Reg', (50, 58))	("Alzheimer's disease", 'Disease', 'MESH:D000544', (137, 156))
20255	28904855	However, the expression status of LAMB3 in GSE23400 was in agreement with the previous studies.	('GSE23400', 'Var', (43, 51))	('LAMB3', 'Gene', (34, 39))	('LAMB3', 'Gene', '3914', (34, 39))
20265	28904855	Inhibition of ARNT2 expression promotes NSCLC cell growth in a xenograft model 31.	('ARNT2', 'Gene', '9915', (14, 19))	('promotes', 'PosReg', (31, 39))	('ARNT2', 'Gene', (14, 19))	('Inhibition', 'Var', (0, 10))	('NSCLC', 'Disease', (40, 45))	('NSCLC', 'Disease', 'MESH:D002289', (40, 45))
20269	28904855	However, the expression status of PPARG in GSE23400 was in agreement with previous studies.	('GSE23400', 'Var', (43, 51))	('PPARG', 'Gene', '5468', (34, 39))	('PPARG', 'Gene', (34, 39))
20270	28904855	PPARG is reported to function as an oncogene in ESCC and the activation of PPARG suppresses cell proliferation and induces cell apoptosis of esophageal cancer cells by inhibiting the TLR-4 dependent mitogen-activated protein kinase pathway 33.	('suppresses', 'NegReg', (81, 91))	('esophageal cancer', 'Disease', (141, 158))	('inhibiting', 'NegReg', (168, 178))	('PPARG', 'Gene', '5468', (75, 80))	('TLR-4', 'Gene', '7099', (183, 188))	('cell apoptosis', 'CPA', (123, 137))	('PPARG', 'Gene', '5468', (0, 5))	('induces', 'Reg', (115, 122))	('PPARG', 'Gene', (75, 80))	('PPARG', 'Gene', (0, 5))	('esophageal cancer', 'Disease', 'MESH:D004938', (141, 158))	('cell proliferation', 'CPA', (92, 110))	('activation', 'Var', (61, 71))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('TLR-4', 'Gene', (183, 188))
20315	33363032	These risk factors provoke the development of various genetic instabilities and molecular alterations, including the loss of heterozygosity of chromosomes 3, 4 7, 8, 11, 17, and 19, among others, down-regulation of tumor-suppressor genes such as TP53, RB, CDKN2A, and up-regulation of oncogenes such as cyclin D1.	('men', 'Species', '9606', (38, 41))	('up-regulation', 'PosReg', (268, 281))	('loss', 'Var', (117, 121))	('CDKN2A', 'Gene', (256, 262))	('tumor', 'Disease', 'MESH:D009369', (215, 220))	('instabilities', 'Disease', (62, 75))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('CDKN2A', 'Gene', '1029', (256, 262))	('instabilities', 'Disease', 'MESH:D043171', (62, 75))	('down-regulation', 'NegReg', (196, 211))	('TP53', 'Gene', '7157', (246, 250))	('tumor', 'Disease', (215, 220))	('TP53', 'Gene', (246, 250))	('cyclin D1', 'Gene', '595', (303, 312))	('cyclin D1', 'Gene', (303, 312))
20352	33363032	The presence of CD163 TAMs correlates with lymph node invasion and poor prognosis of patients with OSCC.	('CD163', 'Gene', (16, 21))	('lymph node invasion', 'CPA', (43, 62))	('OSCC', 'Disease', (99, 103))	('patients', 'Species', '9606', (85, 93))	('TAMs', 'Chemical', 'MESH:D013629', (22, 26))	('CD163', 'Gene', '9332', (16, 21))	('presence', 'Var', (4, 12))
20359	33363032	Similar to the anti-inflammatory molecules released from CAFs, IL8 and IL6 are produced in an NFkappaB-dependent manner, suggesting that inhibition of the NFkappaB pathway may be suitable for the treatment of OSCC.	('NFkappaB', 'Gene', '4790', (94, 102))	('CAF', 'Gene', (57, 60))	('men', 'Species', '9606', (201, 204))	('inhibition', 'Var', (137, 147))	('NFkappaB', 'Gene', (155, 163))	('OSCC', 'Disease', (209, 213))	('CAF', 'Gene', '8850', (57, 60))	('NFkappaB', 'Gene', '4790', (155, 163))	('NFkappaB', 'Gene', (94, 102))
20366	33363032	For instance, oral gingival cells exposed to tobacco smoke, alcohol consumption or HPV increase autophagy as a protective mechanism.	('autophagy', 'CPA', (96, 105))	('alcohol', 'Chemical', 'MESH:D000438', (60, 67))	('increase', 'PosReg', (87, 95))	('HPV', 'Species', '10566', (83, 86))	('HPV', 'Var', (83, 86))	('tobacco', 'Species', '4097', (45, 52))
20391	33363032	Spontaneous formation of lung carcinoma and hepatocellular carcinoma is observed in mice with a heterologous deletion of BECN1, suggesting that some components of the autophagic machinery may behave as tumor suppressors.	('lung carcinoma', 'Disease', (25, 39))	('deletion', 'Var', (109, 117))	('tumor', 'Disease', (202, 207))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (44, 68))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('hepatocellular carcinoma', 'Disease', (44, 68))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (44, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (30, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (59, 68))	('lung carcinoma', 'Disease', 'MESH:D008175', (25, 39))	('BECN1', 'Gene', (121, 126))	('mice', 'Species', '10090', (84, 88))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))
20392	33363032	However, breast carcinoma cells knocked down for BECN1 show decreased tumor growth in vivo, indicating that in developed carcinoma cells, BECN1 behaves as an oncogene.	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('decreased tumor', 'Disease', 'MESH:D002303', (60, 75))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('carcinoma', 'Disease', 'MESH:D009369', (16, 25))	('BECN1', 'Gene', (49, 54))	('breast carcinoma', 'Phenotype', 'HP:0003002', (9, 25))	('carcinoma', 'Disease', (121, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (16, 25))	('carcinoma', 'Disease', 'MESH:D009369', (121, 130))	('decreased tumor', 'Disease', (60, 75))	('knocked down', 'Var', (32, 44))	('breast carcinoma', 'Disease', 'MESH:D001943', (9, 25))	('breast carcinoma', 'Disease', (9, 25))	('carcinoma', 'Disease', (16, 25))
20411	33363032	For instance, chemical inhibition of heat shock protein 90, HSP90, which is well-known to inhibit autophagy by decreasing NFkappaB-dependent transcription of autophagic genes like beclin-1 in other cancer models, dramatically reduces the release of the CCL7 chemokine by CAFs, thereby decreasing the invasive rate of OSCC cells.	('reduces', 'NegReg', (226, 233))	('HSP90', 'Gene', '3320', (60, 65))	('cancer', 'Disease', (198, 204))	('NFkappaB', 'Gene', '4790', (122, 130))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('heat shock protein 90', 'Gene', '3320', (37, 58))	('CAF', 'Gene', '8850', (271, 274))	('CCL7', 'Gene', (253, 257))	('NFkappaB', 'Gene', (122, 130))	('CAF', 'Gene', (271, 274))	('beclin-1', 'Gene', '8678', (180, 188))	('invasive rate of OSCC cells', 'CPA', (300, 327))	('release', 'MPA', (238, 245))	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('HSP90', 'Gene', (60, 65))	('inhibition', 'Var', (23, 33))	('beclin-1', 'Gene', (180, 188))	('CCL7', 'Gene', '6354', (253, 257))	('heat shock protein 90', 'Gene', (37, 58))	('decreasing', 'NegReg', (285, 295))	('shock', 'Phenotype', 'HP:0031273', (42, 47))
20424	33363032	In vitro exposure of OSCC cells to cellular stressors such as cadmium or tri-gas hypoxia leads to increased autophagy through mTOR inactivation, suggesting that OSCC cells are still sensitive to autophagy under insults.	('cadmium', 'Chemical', 'MESH:D002104', (62, 69))	('hypoxia', 'Disease', (81, 88))	('hypoxia', 'Disease', 'MESH:D000860', (81, 88))	('autophagy', 'CPA', (108, 117))	('inactivation', 'Var', (131, 143))	('increased', 'PosReg', (98, 107))	('mTOR', 'Gene', (126, 130))	('mTOR', 'Gene', '2475', (126, 130))
20448	33363032	This work was supported by the Agencia Nacional de Investigacion y Desarrollo (ANID, Chile): FONDECYT (3200313 to DP-O) (1200499 to EM) (1201684 to CAR-S) (1180495 to VT) (1171075 to AC); PIA-ANID (ACT172066 to EM and AC); FONDAP (15130011 to SL, VT, and AC); ANID PhD fellowship (21140848 to CK).	('1171075', 'Var', (172, 179))	('CAR-S', 'Gene', '833', (148, 153))	('ANID PhD fellowship', 'Disease', (260, 279))	('21140848', 'Var', (281, 289))	('PIA-ANID', 'Chemical', '-', (188, 196))	('VT', 'Disease', 'MESH:D017180', (167, 169))	('ACT172066', 'Var', (198, 207))	('15130011', 'Var', (231, 239))	('1200499', 'Var', (121, 128))	('1201684', 'Var', (137, 144))	('VT', 'Disease', 'MESH:D017180', (247, 249))	('CAR-S', 'Gene', (148, 153))	('ANID PhD fellowship', 'Disease', 'None', (260, 279))	('1180495', 'Var', (156, 163))	('CK', 'Gene', '51727', (293, 295))
20456	31692283	Among the LUAD subtypes, EGFR sensitizing mutations were most prevalent in the invasive lepidic subtype.	('prevalent', 'Reg', (62, 71))	('LUAD', 'Phenotype', 'HP:0030078', (10, 14))	('EGFR', 'Gene', (25, 29))	('invasive lepidic', 'Disease', (79, 95))	('LUAD', 'Disease', (10, 14))	('LUAD', 'Disease', 'MESH:C538231', (10, 14))	('mutations', 'Var', (42, 51))	('invasive lepidic', 'Disease', 'MESH:D009361', (79, 95))	('EGFR', 'Gene', '1956', (25, 29))
20458	31692283	Patients with colloidal, invasive mucinous, and fetal subtypes had the least number of EGFR mutations.	('Patients', 'Species', '9606', (0, 8))	('EGFR', 'Gene', '1956', (87, 91))	('EGFR', 'Gene', (87, 91))	('mutations', 'Var', (92, 101))
20459	31692283	Moreover, KRAS mutations were prevalent in patients with invasive mucinous, colloid, enteric and solid subtypes.	('invasive mucinous', 'Disease', (57, 74))	('KRAS', 'Gene', '3845', (10, 14))	('solid subtypes', 'Disease', (97, 111))	('patients', 'Species', '9606', (43, 51))	('mutations', 'Var', (15, 24))	('colloid', 'Disease', (76, 83))	('prevalent', 'Reg', (30, 39))	('enteric', 'Disease', (85, 92))	('KRAS', 'Gene', (10, 14))
20460	31692283	A total of 90% of the LUSC patients harbor mutations in TP53, wherein all patients except five with nonkeratinizing were TP53 mutants.	('TP53', 'Gene', '7157', (56, 60))	('patients', 'Species', '9606', (74, 82))	('TP53', 'Gene', '7157', (121, 125))	('TP53', 'Gene', (121, 125))	('patients', 'Species', '9606', (27, 35))	('TP53', 'Gene', (56, 60))	('mutations', 'Var', (43, 52))	('LUSC', 'Disease', 'MESH:D002294', (22, 26))	('LUSC', 'Disease', (22, 26))	('LUSC', 'Phenotype', 'HP:0030359', (22, 26))
20461	31692283	PIK3CA amplifications were most prevalent in keratinizing, followed by basaloid and nonkeratinizing subtypes.	('keratinizing', 'Disease', (45, 57))	('basaloid', 'Disease', (71, 79))	('amplifications', 'Var', (7, 21))	('PIK3CA', 'Gene', (0, 6))	('prevalent', 'Reg', (32, 41))	('PIK3CA', 'Gene', '5290', (0, 6))
20499	31692283	Mutations in the oncogenic drivers were more prevalent in LUAD than LUSC patients (P < 0.001), with 77.2% (166/215) of the LUAD patients harboring alteration in oncogenic driver mutations.	('LUAD', 'Disease', 'MESH:C538231', (123, 127))	('prevalent', 'Reg', (45, 54))	('LUAD', 'Phenotype', 'HP:0030078', (58, 62))	('LUAD', 'Disease', (58, 62))	('LUAD', 'Disease', 'MESH:C538231', (58, 62))	('oncogenic drivers', 'Gene', (17, 34))	('Mutations', 'Var', (0, 9))	('LUSC', 'Disease', 'MESH:D002294', (68, 72))	('LUSC', 'Disease', (68, 72))	('LUSC', 'Phenotype', 'HP:0030359', (68, 72))	('patients', 'Species', '9606', (128, 136))	('LUAD', 'Phenotype', 'HP:0030078', (123, 127))	('patients', 'Species', '9606', (73, 81))	('LUAD', 'Disease', (123, 127))	('harboring', 'Reg', (137, 146))
20500	31692283	Oncogenic drivers included EGFR L858R and exon 19 deletion (19del), KRAS G12, G13 and Q61, BRAF V600E, MET exon14 skipping and amplification, ERBB2 exon 20 insertion, ALK fusions, RET fusions, ROS1 fusions and NRG1 fusions.	('NRG1', 'Gene', '3084', (210, 214))	('EGFR', 'Gene', (27, 31))	('KRAS', 'Gene', (68, 72))	('ERBB2', 'Gene', (142, 147))	('ROS1', 'Gene', '6098', (193, 197))	('L858R', 'Var', (32, 37))	('ERBB2', 'Gene', '2064', (142, 147))	('exon 19', 'Gene', (42, 49))	('EGFR', 'Gene', '1956', (27, 31))	('skipping', 'Var', (114, 122))	('RET', 'Gene', '5979', (180, 183))	('Q61', 'Var', (86, 89))	('19del', 'Mutation', 'c.19del', (60, 65))	('MET exon14 skipping', 'Var', (103, 122))	('ROS1', 'Gene', (193, 197))	('ALK', 'Gene', '238', (167, 170))	('insertion', 'Reg', (156, 165))	('V600E', 'Mutation', 'rs113488022', (96, 101))	('L858R', 'Mutation', 'rs121434568', (32, 37))	('BRAF', 'Gene', '673', (91, 95))	('ALK', 'Gene', (167, 170))	('BRAF', 'Gene', (91, 95))	('NRG1', 'Gene', (210, 214))	('KRAS', 'Gene', '3845', (68, 72))	('amplification', 'Var', (127, 140))	('RET', 'Gene', (180, 183))	('G13', 'Var', (78, 81))
20501	31692283	Among them, 37.7% (81/215) of the patients carried EGFR L858R and 19del mutations.	('EGFR', 'Gene', (51, 55))	('19del mutations', 'Var', (66, 81))	('L858R', 'Var', (56, 61))	('patients', 'Species', '9606', (34, 42))	('L858R', 'Mutation', 'rs121434568', (56, 61))	('EGFR', 'Gene', '1956', (51, 55))	('19del', 'Mutation', 'c.19del', (66, 71))
20502	31692283	Mutual exclusivity was observed among driver mutations in LUAD.	('LUAD', 'Disease', (58, 62))	('LUAD', 'Disease', 'MESH:C538231', (58, 62))	('mutations', 'Var', (45, 54))	('LUAD', 'Phenotype', 'HP:0030078', (58, 62))
20504	31692283	Moreover, we also observed concurrent mutations of EGFR L858R and ERBB2 S310F in two adenocarcinoma patients; EGFR L858R and ERBB2 amplification in three LUAD patients (Table S3).	('LUAD', 'Phenotype', 'HP:0030078', (154, 158))	('EGFR', 'Gene', '1956', (110, 114))	('EGFR', 'Gene', (51, 55))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('L858R', 'Var', (56, 61))	('patients', 'Species', '9606', (100, 108))	('ERBB2', 'Gene', '2064', (66, 71))	('L858R', 'Mutation', 'rs121434568', (115, 120))	('S310F', 'Mutation', 'rs1057519816', (72, 77))	('LUAD', 'Disease', (154, 158))	('adenocarcinoma', 'Disease', (85, 99))	('ERBB2', 'Gene', (125, 130))	('mutations', 'Var', (38, 47))	('EGFR', 'Gene', '1956', (51, 55))	('LUAD', 'Disease', 'MESH:C538231', (154, 158))	('EGFR', 'Gene', (110, 114))	('adenocarcinoma', 'Disease', 'MESH:D000230', (85, 99))	('L858R', 'Var', (115, 120))	('L858R', 'Mutation', 'rs121434568', (56, 61))	('ERBB2', 'Gene', '2064', (125, 130))	('patients', 'Species', '9606', (159, 167))	('S310F', 'Var', (72, 77))	('ERBB2', 'Gene', (66, 71))
20505	31692283	In addition to sensitizing mutations in EGFR, we found three rare EGFR mutations including EGFR G719A detected in a patient and EGFR S758I and L838V concurrently detected in a patient (Table S3).	('S758I', 'Mutation', 'p.S758I', (133, 138))	('EGFR', 'Gene', (91, 95))	('G719A', 'Var', (96, 101))	('EGFR', 'Gene', '1956', (66, 70))	('patient', 'Species', '9606', (116, 123))	('EGFR', 'Gene', (66, 70))	('EGFR', 'Gene', '1956', (128, 132))	('EGFR', 'Gene', (128, 132))	('L838V', 'Mutation', 'rs864621996', (143, 148))	('EGFR', 'Gene', '1956', (40, 44))	('EGFR', 'Gene', (40, 44))	('L838V', 'Var', (143, 148))	('S758I', 'Var', (133, 138))	('patient', 'Species', '9606', (176, 183))	('EGFR', 'Gene', '1956', (91, 95))	('G719A', 'Mutation', 'rs121913428', (96, 101))
20506	31692283	A total of 24 patients (11.2%, 24/215) had EGFR compound mutation.	('EGFR', 'Gene', '1956', (43, 47))	('EGFR', 'Gene', (43, 47))	('patients', 'Species', '9606', (14, 22))	('compound mutation', 'Var', (48, 65))
20507	31692283	KRAS mutations, including G12, G13, Q61, were detected in 17.7% (38/215) of patients.	('G13', 'Var', (31, 34))	('patients', 'Species', '9606', (76, 84))	('G12', 'Var', (26, 29))	('KRAS', 'Gene', (0, 4))	('Q61', 'Var', (36, 39))	('KRAS', 'Gene', '3845', (0, 4))
20508	31692283	Among the BRAF mutations detected in 5.6% (12/215) of patients, no BRAF V600E was found.	('BRAF', 'Gene', '673', (67, 71))	('patients', 'Species', '9606', (54, 62))	('mutations', 'Var', (15, 24))	('BRAF', 'Gene', (67, 71))	('BRAF', 'Gene', (10, 14))	('BRAF', 'Gene', '673', (10, 14))	('V600E', 'Mutation', 'rs113488022', (72, 77))
20509	31692283	A BRAF rare disruptive in-frame insertion R506_K507insVLR was detected in a LUAD patient (Table S4).	('patient', 'Species', '9606', (81, 88))	('BRAF', 'Gene', '673', (2, 6))	('LUAD', 'Phenotype', 'HP:0030078', (76, 80))	('BRAF', 'Gene', (2, 6))	('LUAD', 'Disease', (76, 80))	('R506_K507insVLR', 'Var', (42, 57))	('LUAD', 'Disease', 'MESH:C538231', (76, 80))	('R506_K507insVLR', 'Mutation', 'p.506,507insK,VLR', (42, 57))
20510	31692283	Conversely, mutations in ALK, RET and ROS1, including fusions and other types of mutations, were detected in 25 (11.6%), 8 (3.7%) and 12 (5.6%) LUAD patients, respectively.	('LUAD', 'Disease', (144, 148))	('RET', 'Gene', (30, 33))	('LUAD', 'Disease', 'MESH:C538231', (144, 148))	('patients', 'Species', '9606', (149, 157))	('LUAD', 'Phenotype', 'HP:0030078', (144, 148))	('mutations', 'Var', (12, 21))	('detected', 'Reg', (97, 105))	('ROS1', 'Gene', (38, 42))	('ROS1', 'Gene', '6098', (38, 42))	('ALK', 'Gene', (25, 28))	('RET', 'Gene', '5979', (30, 33))	('ALK', 'Gene', '238', (25, 28))
20516	31692283	In addition, CD74-NRG1 fusions were also detected in three LUAD patients.	('NRG1', 'Gene', '3084', (18, 22))	('LUAD', 'Phenotype', 'HP:0030078', (59, 63))	('LUAD', 'Disease', (59, 63))	('CD74', 'Gene', '972', (13, 17))	('patients', 'Species', '9606', (64, 72))	('LUAD', 'Disease', 'MESH:C538231', (59, 63))	('fusions', 'Var', (23, 30))	('CD74', 'Gene', (13, 17))	('NRG1', 'Gene', (18, 22))	('detected', 'Reg', (41, 49))
20518	31692283	Interestingly, four and one LUSC patients carried EGFR sensitizing and KRAS mutations, respectively.	('mutations', 'Var', (76, 85))	('LUSC', 'Disease', (28, 32))	('LUSC', 'Disease', 'MESH:D002294', (28, 32))	('patients', 'Species', '9606', (33, 41))	('LUSC', 'Phenotype', 'HP:0030359', (28, 32))	('EGFR', 'Gene', '1956', (50, 54))	('KRAS', 'Gene', (71, 75))	('KRAS', 'Gene', '3845', (71, 75))	('EGFR', 'Gene', (50, 54))
20519	31692283	Such mutations were believed to occur exclusively in LUAD.	('LUAD', 'Disease', 'MESH:C538231', (53, 57))	('LUAD', 'Disease', (53, 57))	('LUAD', 'Phenotype', 'HP:0030078', (53, 57))	('mutations', 'Var', (5, 14))
20520	31692283	On the other hand, BRAF mutations were found in four (3.9%, 4/103) LUSC patients; however, no BRAF V600E mutations were detected.	('BRAF', 'Gene', (94, 98))	('BRAF', 'Gene', '673', (19, 23))	('BRAF', 'Gene', (19, 23))	('LUSC', 'Disease', 'MESH:D002294', (67, 71))	('V600E', 'Mutation', 'rs113488022', (99, 104))	('LUSC', 'Phenotype', 'HP:0030359', (67, 71))	('LUSC', 'Disease', (67, 71))	('mutations', 'Var', (24, 33))	('BRAF', 'Gene', '673', (94, 98))	('patients', 'Species', '9606', (72, 80))
20521	31692283	Conversely, EML4-ALK and CD74-ROS1 fusions were found in a patient each; while no RET fusion was found in LUSC patients.	('ALK', 'Gene', '238', (17, 20))	('RET', 'Gene', (82, 85))	('ROS1', 'Gene', (30, 34))	('EML4', 'Gene', '27436', (12, 16))	('patient', 'Species', '9606', (59, 66))	('ALK', 'Gene', (17, 20))	('EML4', 'Gene', (12, 16))	('CD74', 'Gene', '972', (25, 29))	('patients', 'Species', '9606', (111, 119))	('ROS1', 'Gene', '6098', (30, 34))	('LUSC', 'Phenotype', 'HP:0030359', (106, 110))	('LUSC', 'Disease', 'MESH:D002294', (106, 110))	('found', 'Reg', (48, 53))	('RET', 'Gene', '5979', (82, 85))	('LUSC', 'Disease', (106, 110))	('patient', 'Species', '9606', (111, 118))	('fusions', 'Var', (35, 42))	('CD74', 'Gene', (25, 29))
20522	31692283	On the other hand, mutations in TP53 (P < 0.001) and gene amplifications in particular genes (P < 0.001) were more predominant in LUSC.	('TP53', 'Gene', '7157', (32, 36))	('mutations', 'Var', (19, 28))	('predominant', 'Reg', (115, 126))	('TP53', 'Gene', (32, 36))	('LUSC', 'Disease', 'MESH:D002294', (130, 134))	('LUSC', 'Phenotype', 'HP:0030359', (130, 134))	('LUSC', 'Disease', (130, 134))
20523	31692283	TP53 mutations were detected in almost all of the LUSC patients (90%, 93/103) but only 41% (88/215) of LUAD patients.	('detected', 'Reg', (20, 28))	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('patients', 'Species', '9606', (108, 116))	('LUAD', 'Phenotype', 'HP:0030078', (103, 107))	('LUAD', 'Disease', (103, 107))	('LUSC', 'Phenotype', 'HP:0030359', (50, 54))	('LUAD', 'Disease', 'MESH:C538231', (103, 107))	('mutations', 'Var', (5, 14))	('LUSC', 'Disease', 'MESH:D002294', (50, 54))	('LUSC', 'Disease', (50, 54))	('patients', 'Species', '9606', (55, 63))
20524	31692283	In addition, LUSC patients had significantly more mutations in CDKN2 (20/103, P < 0.001), and amplifications in CCND1 (14/103, P < 0.001), PIK3CA (40/103, P < 0.001) and FGFR1 (13/103, P < 0.001) than LUAD patients.	('PIK3CA', 'Gene', '5290', (139, 145))	('FGFR1', 'Gene', '2260', (170, 175))	('mutations', 'Var', (50, 59))	('CDKN2', 'Gene', '1029', (63, 68))	('LUAD', 'Phenotype', 'HP:0030078', (201, 205))	('CCND1', 'Gene', (112, 117))	('LUAD', 'Disease', (201, 205))	('CDKN2', 'Gene', (63, 68))	('patients', 'Species', '9606', (206, 214))	('LUAD', 'Disease', 'MESH:C538231', (201, 205))	('PIK3CA', 'Gene', (139, 145))	('amplifications', 'Var', (94, 108))	('patients', 'Species', '9606', (18, 26))	('LUSC', 'Disease', 'MESH:D002294', (13, 17))	('CCND1', 'Gene', '595', (112, 117))	('FGFR1', 'Gene', (170, 175))	('LUSC', 'Phenotype', 'HP:0030359', (13, 17))	('LUSC', 'Disease', (13, 17))
20525	31692283	Amplifications in FGF19 (10.7%, 11/103), FGF3 (10.7%, 11/103) and FGF4 (2.9%, 3/103) were only found in LUSC patients in our cohort (Fig 1c).	('LUSC', 'Phenotype', 'HP:0030359', (104, 108))	('FGF4', 'Gene', '2249', (66, 70))	('LUSC', 'Disease', (104, 108))	('FGF3', 'Gene', '2248', (41, 45))	('patients', 'Species', '9606', (109, 117))	('FGF19', 'Gene', (18, 23))	('FGF19', 'Gene', '9965', (18, 23))	('FGF4', 'Gene', (66, 70))	('found', 'Reg', (95, 100))	('Amplifications', 'Var', (0, 14))	('FGF3', 'Gene', (41, 45))	('LUSC', 'Disease', 'MESH:D002294', (104, 108))
20526	31692283	Interestingly, a previously unreported FGFR1 fusion with KCNU1 (KCNU1 intergenic: FGFR1 F4) was detected in a patient also harboring concurrent FGFR1 amplification and NTRK1 Q558X stop gain mutation.	('FGFR1', 'Gene', (39, 44))	('NTRK1', 'Gene', (168, 173))	('FGFR1', 'Gene', (82, 87))	('FGFR1', 'Gene', '2260', (39, 44))	('FGFR1', 'Gene', (144, 149))	('fusion', 'Var', (45, 51))	('FGFR1', 'Gene', '2260', (82, 87))	('KCNU1', 'Gene', (57, 62))	('FGFR1', 'Gene', '2260', (144, 149))	('patient', 'Species', '9606', (110, 117))	('KCNU1', 'Gene', '157855', (57, 62))	('amplification', 'Var', (150, 163))	('NTRK1', 'Gene', '4914', (168, 173))	('KCNU1', 'Gene', (64, 69))	('Q558X', 'Mutation', 'p.Q558X', (174, 179))	('KCNU1', 'Gene', '157855', (64, 69))	('Q558X', 'Var', (174, 179))
20527	31692283	Moreover, PIK3CA mutation types between LUAD and LUSC were significantly different, with missense mutations more prevalent in LUAD patients, while amplifications were largely found in LUSC patients (P < 0.001, Fig 1c).	('patients', 'Species', '9606', (131, 139))	('LUSC', 'Disease', 'MESH:D002294', (49, 53))	('LUSC', 'Disease', (49, 53))	('PIK3CA', 'Gene', '5290', (10, 16))	('LUAD', 'Phenotype', 'HP:0030078', (126, 130))	('LUAD', 'Disease', (126, 130))	('LUSC', 'Phenotype', 'HP:0030359', (49, 53))	('LUAD', 'Disease', 'MESH:C538231', (126, 130))	('LUSC', 'Disease', 'MESH:D002294', (184, 188))	('missense mutations', 'Var', (89, 107))	('PIK3CA', 'Gene', (10, 16))	('LUSC', 'Disease', (184, 188))	('LUSC', 'Phenotype', 'HP:0030359', (184, 188))	('LUAD', 'Disease', (40, 44))	('LUAD', 'Disease', 'MESH:C538231', (40, 44))	('LUAD', 'Phenotype', 'HP:0030078', (40, 44))	('prevalent', 'Reg', (113, 122))	('patients', 'Species', '9606', (189, 197))
20529	31692283	Patients with invasive subtypes (ie, acinar, colloid, enteric, fetal, lepidic, micropapillary, invasive mucinous, papillary, and solid adenocarcinomas) harbored more total mutations than preinvasive (ie, adenocarcinoma in situ) and minimally-invasive subtypes (P < 0.001, Fig 2a).	('mutations', 'Var', (172, 181))	('adenocarcinoma in situ', 'Disease', 'MESH:D065311', (204, 226))	('solid adenocarcinomas', 'Disease', (129, 150))	('adenocarcinoma in situ', 'Disease', (204, 226))	('Patients', 'Species', '9606', (0, 8))	('solid adenocarcinomas', 'Disease', 'MESH:D000230', (129, 150))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))	('carcinoma', 'Phenotype', 'HP:0030731', (209, 218))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (209, 226))
20530	31692283	In general, EGFR sensitizing mutations were predominant in LUAD (P < 0.001) with relatively even distribution in preinvasive, minimally invasive and invasive LUAD subtypes (P = 0.515, Fig 2b).	('LUAD', 'Phenotype', 'HP:0030078', (59, 63))	('LUAD', 'Disease', (158, 162))	('LUAD', 'Disease', 'MESH:C538231', (158, 162))	('LUAD', 'Disease', (59, 63))	('LUAD', 'Phenotype', 'HP:0030078', (158, 162))	('LUAD', 'Disease', 'MESH:C538231', (59, 63))	('mutations', 'Var', (29, 38))	('EGFR', 'Gene', '1956', (12, 16))	('sensitizing', 'Reg', (17, 28))	('EGFR', 'Gene', (12, 16))	('predominant', 'Reg', (44, 55))
20533	31692283	Among the patients with preinvasive adenocarcinoma in situ (AIS) subtype, EGFR mutations were detected in 52% (16/31) of the patients (Fig 2b).	('carcinoma', 'Phenotype', 'HP:0030731', (41, 50))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (41, 58))	('invasive adenocarcinoma', 'Disease', (27, 50))	('detected', 'Reg', (94, 102))	('AIS', 'Disease', 'MESH:D065311', (60, 63))	('adenocarcinoma in situ', 'Disease', (36, 58))	('invasive adenocarcinoma', 'Disease', 'MESH:D000230', (27, 50))	('adenocarcinoma in situ', 'Disease', 'MESH:D065311', (36, 58))	('EGFR', 'Gene', '1956', (74, 78))	('patients', 'Species', '9606', (10, 18))	('AIS', 'Disease', (60, 63))	('EGFR', 'Gene', (74, 78))	('mutations', 'Var', (79, 88))	('patients', 'Species', '9606', (125, 133))
20536	31692283	Meanwhile, TP53 mutations were found in 19% (6/31) of the AIS patients (Fig 2c).	('AIS', 'Disease', (58, 61))	('TP53', 'Gene', '7157', (11, 15))	('TP53', 'Gene', (11, 15))	('mutations', 'Var', (16, 25))	('AIS', 'Disease', 'MESH:D065311', (58, 61))	('patients', 'Species', '9606', (62, 70))	('found', 'Reg', (31, 36))
20538	31692283	In patients with minimally invasive adenocarcinoma subtype (MIA), the only oncogenic driver mutations detected were EGFR, ERBB2 and KRAS (Fig 2b) wherein half (4/8) of the MIA patients were EGFR mutants.	('patients', 'Species', '9606', (176, 184))	('carcinoma', 'Phenotype', 'HP:0030731', (41, 50))	('KRAS', 'Gene', (132, 136))	('invasive adenocarcinoma', 'Disease', (27, 50))	('ERBB2', 'Gene', '2064', (122, 127))	('KRAS', 'Gene', '3845', (132, 136))	('EGFR', 'Gene', '1956', (190, 194))	('ERBB2', 'Gene', (122, 127))	('mutations', 'Var', (92, 101))	('invasive adenocarcinoma', 'Disease', 'MESH:D000230', (27, 50))	('EGFR', 'Gene', (190, 194))	('patients', 'Species', '9606', (3, 11))	('MIA', 'Disease', (172, 175))	('EGFR', 'Gene', '1956', (116, 120))	('EGFR', 'Gene', (116, 120))
20543	31692283	In particular, gene alterations in ALK, MET and RET were only found in these patients (Fig 2b).	('MET', 'Gene', (40, 43))	('ALK', 'Gene', '238', (35, 38))	('gene alterations', 'Var', (15, 31))	('RET', 'Gene', '5979', (48, 51))	('patients', 'Species', '9606', (77, 85))	('ALK', 'Gene', (35, 38))	('RET', 'Gene', (48, 51))
20544	31692283	TP53 mutations were also more prevalent in patients with invasive adenocarcinoma (48%, 74/153, Fig 2c).	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('patients', 'Species', '9606', (43, 51))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('mutations', 'Var', (5, 14))	('invasive adenocarcinoma', 'Disease', (57, 80))	('prevalent', 'Reg', (30, 39))	('invasive adenocarcinoma', 'Disease', 'MESH:D000230', (57, 80))
20545	31692283	Not only among invasive subtypes but among all the LUAD subtypes, lepidic adenocarcinoma subtype (LPA) had the most EGFR mutations, with 78.9% (15/19) EGFR positive patients (P = 0.003, Fig 2b) with the majority being sensitizing mutations.	('LUAD', 'Phenotype', 'HP:0030078', (51, 55))	('mutations', 'Var', (121, 130))	('LUAD', 'Disease', (51, 55))	('EGFR', 'Gene', (151, 155))	('lepidic adenocarcinoma subtype', 'Disease', 'MESH:D000230', (66, 96))	('LUAD', 'Disease', 'MESH:C538231', (51, 55))	('LPA', 'Disease', 'MESH:D000230', (98, 101))	('LPA', 'Disease', (98, 101))	('patients', 'Species', '9606', (165, 173))	('lepidic adenocarcinoma subtype', 'Disease', (66, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('EGFR', 'Gene', '1956', (116, 120))	('EGFR', 'Gene', (116, 120))	('EGFR', 'Gene', '1956', (151, 155))
20547	31692283	Mutations in ERBB2, MET and KRAS were found in 1, 1, and 2 LPA patients (Fig 2b); while mutations in TP53 were detected in three LPA patients (Fig 2c).	('LPA', 'Disease', (59, 62))	('KRAS', 'Gene', (28, 32))	('LPA', 'Disease', 'MESH:D000230', (129, 132))	('detected', 'Reg', (111, 119))	('KRAS', 'Gene', '3845', (28, 32))	('TP53', 'Gene', '7157', (101, 105))	('ERBB2', 'Gene', '2064', (13, 18))	('patients', 'Species', '9606', (133, 141))	('MET', 'Gene', (20, 23))	('LPA', 'Disease', 'MESH:D000230', (59, 62))	('ERBB2', 'Gene', (13, 18))	('Mutations', 'Var', (0, 9))	('TP53', 'Gene', (101, 105))	('LPA', 'Disease', (129, 132))	('patients', 'Species', '9606', (63, 71))	('found', 'Reg', (38, 43))
20548	31692283	Patients with acinar subtype (ACI) had mutations in all oncogenic driver genes (Fig 2b).	('acinar subtype', 'Disease', (14, 28))	('Patients', 'Species', '9606', (0, 8))	('Fig 2b', 'Gene', (80, 86))	('mutations', 'Var', (39, 48))
20549	31692283	EGFR mutations were found in 61% (19/31) of these patients (Fig 2b).	('EGFR', 'Gene', (0, 4))	('patients', 'Species', '9606', (50, 58))	('mutations', 'Var', (5, 14))	('found', 'Reg', (20, 25))	('EGFR', 'Gene', '1956', (0, 4))
20550	31692283	TP53 mutations were detected in half of the ACI patients (15/31) (Fig 2c).	('TP53', 'Gene', '7157', (0, 4))	('ACI', 'Disease', (44, 47))	('TP53', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))	('patients', 'Species', '9606', (48, 56))
20552	31692283	Solid adenocarcinoma patients had the most TP53 mutations (87.5%, 21/24) among all LUAD subtypes (Fig 2c).	('LUAD', 'Phenotype', 'HP:0030078', (83, 87))	('LUAD', 'Disease', (83, 87))	('LUAD', 'Disease', 'MESH:C538231', (83, 87))	('adenocarcinoma', 'Disease', (6, 20))	('carcinoma', 'Phenotype', 'HP:0030731', (11, 20))	('patients', 'Species', '9606', (21, 29))	('TP53', 'Gene', '7157', (43, 47))	('adenocarcinoma', 'Disease', 'MESH:D000230', (6, 20))	('TP53', 'Gene', (43, 47))	('mutations', 'Var', (48, 57))
20553	31692283	Mutations in all oncogenic drivers were detected in these patients except ROS1 fusion (Fig 2b).	('ROS1', 'Gene', '6098', (74, 78))	('detected', 'Reg', (40, 48))	('Mutations', 'Var', (0, 9))	('patients', 'Species', '9606', (58, 66))	('ROS1', 'Gene', (74, 78))
20554	31692283	KRAS mutations were found in 25% (6/24) of the patients with solid subtype; while EGFR mutations were only found in 16.7% (4/24) of the patients with solid subtype.	('KRAS', 'Gene', '3845', (0, 4))	('EGFR', 'Gene', (82, 86))	('patients', 'Species', '9606', (47, 55))	('mutations', 'Var', (5, 14))	('patients', 'Species', '9606', (136, 144))	('found', 'Reg', (20, 25))	('EGFR', 'Gene', '1956', (82, 86))	('KRAS', 'Gene', (0, 4))	('solid subtype', 'Disease', (61, 74))
20555	31692283	Patients with enteric adenocarcinoma (ENT) did not have mutations in ALK, BRAF, MET, RET and ROS1.	('ENT', 'Disease', 'MESH:D004751', (38, 41))	('carcinoma', 'Phenotype', 'HP:0030731', (27, 36))	('mutations', 'Var', (56, 65))	('ALK', 'Gene', (69, 72))	('ALK', 'Gene', '238', (69, 72))	('RET', 'Gene', (85, 88))	('enteric adenocarcinoma', 'Disease', (14, 36))	('BRAF', 'Gene', (74, 78))	('enteric adenocarcinoma', 'Disease', 'MESH:D004751', (14, 36))	('BRAF', 'Gene', '673', (74, 78))	('ENT', 'Disease', (38, 41))	('Patients', 'Species', '9606', (0, 8))	('ROS1', 'Gene', (93, 97))	('RET', 'Gene', '5979', (85, 88))	('ROS1', 'Gene', '6098', (93, 97))	('MET', 'Gene', (80, 83))
20557	31692283	Of the 22 ENT patients, 68% (15/22) had TP53 mutations (Fig 2c).	('ENT', 'Disease', 'MESH:D004751', (10, 13))	('mutations', 'Var', (45, 54))	('ENT', 'Disease', (10, 13))	('TP53', 'Gene', '7157', (40, 44))	('TP53', 'Gene', (40, 44))	('patients', 'Species', '9606', (14, 22))
20561	31692283	Patients with invasive mucinous adenocarcinoma subtype (IMA) patients had the most prevalent KRAS mutations, with 40% (6/14) KRAS-positive IMA patients (Fig 2b).	('invasive mucinous adenocarcinoma', 'Disease', 'MESH:D002288', (14, 46))	('KRAS', 'Gene', (93, 97))	('KRAS', 'Gene', (125, 129))	('KRAS', 'Gene', '3845', (125, 129))	('patients', 'Species', '9606', (61, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (37, 46))	('patients', 'Species', '9606', (143, 151))	('mutations', 'Var', (98, 107))	('Patients', 'Species', '9606', (0, 8))	('KRAS', 'Gene', '3845', (93, 97))	('invasive mucinous adenocarcinoma', 'Disease', (14, 46))	('prevalent', 'Reg', (83, 92))
20562	31692283	Instead of sensitizing mutations, only EGFR amplifications were found in two IMA patients (Fig 2b).	('amplifications', 'Var', (44, 58))	('patients', 'Species', '9606', (81, 89))	('found', 'Reg', (64, 69))	('EGFR', 'Gene', '1956', (39, 43))	('EGFR', 'Gene', (39, 43))	('IMA', 'Disease', (77, 80))
20565	31692283	Among the 12 patients with micropapillary adenocarcinoma subtype (MP), 58.3% (7/12) were positive for EGFR sensitizing mutations (Fig 2b).	('sensitizing', 'Reg', (107, 118))	('positive', 'Reg', (89, 97))	('micropapillary adenocarcinoma subtype', 'Disease', (27, 64))	('EGFR', 'Gene', '1956', (102, 106))	('patients', 'Species', '9606', (13, 21))	('carcinoma', 'Phenotype', 'HP:0030731', (47, 56))	('micropapillary adenocarcinoma subtype', 'Disease', 'MESH:D000230', (27, 64))	('mutations', 'Var', (119, 128))	('EGFR', 'Gene', (102, 106))
20566	31692283	Oncogenic driver mutations in MP patients were only detected in EGFR (7/12), ALK (2/12), ERBB2 (2/12) and RET (2/12) (Fig 2b).	('ALK', 'Gene', (77, 80))	('patients', 'Species', '9606', (33, 41))	('ERBB2', 'Gene', (89, 94))	('ERBB2', 'Gene', '2064', (89, 94))	('RET', 'Gene', (106, 109))	('ALK', 'Gene', '238', (77, 80))	('EGFR', 'Gene', '1956', (64, 68))	('EGFR', 'Gene', (64, 68))	('RET', 'Gene', '5979', (106, 109))	('mutations', 'Var', (17, 26))
20567	31692283	The four MP patients with TP53 mutations also coharbored EGFR sensitizing mutations (Figure S1).	('TP53', 'Gene', (26, 30))	('patients', 'Species', '9606', (12, 20))	('mutations', 'Var', (31, 40))	('EGFR', 'Gene', '1956', (57, 61))	('TP53', 'Gene', '7157', (26, 30))	('EGFR', 'Gene', (57, 61))
20570	31692283	Moreover, two patients had ALK fusion; one patient had ERBB2 amplification and one had both EGFR 19del and ERBB2 amplification (Fig 2b).	('patient', 'Species', '9606', (43, 50))	('EGFR 19del', 'Mutation', 'c.19delEGFR', (92, 102))	('ALK', 'Gene', (27, 30))	('amplification', 'Var', (61, 74))	('patient', 'Species', '9606', (14, 21))	('ERBB2', 'Gene', (107, 112))	('ERBB2', 'Gene', (55, 60))	('ERBB2', 'Gene', '2064', (55, 60))	('patients', 'Species', '9606', (14, 22))	('ERBB2', 'Gene', '2064', (107, 112))	('ALK', 'Gene', '238', (27, 30))
20572	31692283	Apart from ERBB2 amplification and KRAS mutation in each of the two fetal adenocarcinoma (FET) patients in the cohort, no other gene alterations in any oncogenic driver and TP53 were detected (Fig 2b,c).	('KRAS', 'Gene', (35, 39))	('patients', 'Species', '9606', (95, 103))	('KRAS', 'Gene', '3845', (35, 39))	('ERBB2', 'Gene', (11, 16))	('ERBB2', 'Gene', '2064', (11, 16))	('TP53', 'Gene', '7157', (173, 177))	('amplification', 'Var', (17, 30))	('TP53', 'Gene', (173, 177))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('fetal adenocarcinoma', 'Disease', 'MESH:D005315', (68, 88))	('fetal adenocarcinoma', 'Disease', (68, 88))	('FET', 'Disease', (90, 93))	('FET', 'Disease', 'MESH:D005315', (90, 93))
20573	31692283	In contrast to LUAD, LUSC had a predominance of mutations in TP53 and copy number variations in particular genes, while oncogenic driver mutations were very few (P < 0.001, Fig 1c, Figure S2).	('LUSC', 'Disease', (21, 25))	('LUSC', 'Phenotype', 'HP:0030359', (21, 25))	('copy', 'MPA', (70, 74))	('LUAD', 'Disease', (15, 19))	('LUAD', 'Disease', 'MESH:C538231', (15, 19))	('LUSC', 'Disease', 'MESH:D002294', (21, 25))	('LUAD', 'Phenotype', 'HP:0030078', (15, 19))	('TP53', 'Gene', (61, 65))	('TP53', 'Gene', '7157', (61, 65))	('mutations', 'Var', (48, 57))
20575	31692283	PIK3CA amplifications were most prevalent in keratinizing squamous cell carcinoma (KSC) patients (64.3%, 27/42, P = 0.015), followed by basaloid squamous cell carcinoma (BSC) (50%, 4/8) and nonkeratinizing squamous cell carcinoma (NKSC) (33.3%, 9/27).	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (58, 81))	('basaloid squamous cell carcinoma', 'Disease', 'MESH:D002294', (136, 168))	('basaloid squamous cell carcinoma', 'Disease', (136, 168))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (145, 168))	('BSC', 'Phenotype', 'HP:0002671', (170, 173))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (206, 229))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('squamous cell carcinoma', 'Disease', (58, 81))	('carcinoma', 'Phenotype', 'HP:0030731', (159, 168))	('amplifications', 'Var', (7, 21))	('prevalent', 'Reg', (32, 41))	('PIK3CA', 'Gene', '5290', (0, 6))	('carcinoma', 'Phenotype', 'HP:0030731', (220, 229))	('BSC', 'Disease', (170, 173))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (206, 229))	('BSC', 'Disease', 'MESH:D002294', (170, 173))	('basaloid squamous cell carcinoma', 'Phenotype', 'HP:0002671', (136, 168))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (58, 81))	('squamous cell carcinoma', 'Disease', (206, 229))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (145, 168))	('patients', 'Species', '9606', (88, 96))	('PIK3CA', 'Gene', (0, 6))
20577	31692283	As expected for LUSC, TP53 mutations were detected in almost all (90%, 93/103) of the LUSC patients, wherein all the patients with KSC (42/42), BSC (8/8) and SIS (1/1) were TP53 mutants.	('mutations', 'Var', (27, 36))	('KSC', 'Disease', (131, 134))	('LUSC', 'Disease', (16, 20))	('TP53', 'Gene', (173, 177))	('patients', 'Species', '9606', (117, 125))	('mutants', 'Var', (178, 185))	('TP53', 'Gene', (22, 26))	('patients', 'Species', '9606', (91, 99))	('LUSC', 'Disease', (86, 90))	('LUSC', 'Disease', 'MESH:D002294', (16, 20))	('LUSC', 'Phenotype', 'HP:0030359', (16, 20))	('detected', 'Reg', (42, 50))	('LUSC', 'Disease', 'MESH:D002294', (86, 90))	('LUSC', 'Phenotype', 'HP:0030359', (86, 90))	('BSC', 'Phenotype', 'HP:0002671', (144, 147))	('TP53', 'Gene', '7157', (22, 26))	('TP53', 'Gene', '7157', (173, 177))	('BSC', 'Disease', (144, 147))	('BSC', 'Disease', 'MESH:D002294', (144, 147))
20578	31692283	Meanwhile, NKSC patients only had 81% (22/27) TP53 mutants (Fig 3c).	('NKSC', 'Disease', (11, 15))	('mutants', 'Var', (51, 58))	('TP53', 'Gene', '7157', (46, 50))	('patients', 'Species', '9606', (16, 24))	('TP53', 'Gene', (46, 50))
20581	31692283	In LUAD patients, TP53 mutations were associated with older patients.	('LUAD', 'Disease', (3, 7))	('associated', 'Reg', (38, 48))	('TP53', 'Gene', '7157', (18, 22))	('LUAD', 'Disease', 'MESH:C538231', (3, 7))	('LUAD', 'Phenotype', 'HP:0030078', (3, 7))	('patients', 'Species', '9606', (60, 68))	('TP53', 'Gene', (18, 22))	('mutations', 'Var', (23, 32))	('patients', 'Species', '9606', (8, 16))
20583	31692283	KRAS mutations were also found to be associated with smoking status (adjusted P = 0.039).	('smoking status', 'Disease', (53, 67))	('mutations', 'Var', (5, 14))	('associated', 'Reg', (37, 47))	('KRAS', 'Gene', (0, 4))	('KRAS', 'Gene', '3845', (0, 4))
20586	31692283	Even with the increasing importance of molecular testing to identify actionable mutations for targeted therapy, histopathological classification of cancer subtypes is still an essential component of clinical diagnosis and making optimal treatment decisions, particularly in patients with no actionable mutations.	('cancer', 'Disease', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('mutations', 'Var', (80, 89))	('patients', 'Species', '9606', (274, 282))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))
20589	31692283	This is in contrast to Caucasian histological prevalence where the top two subtypes were acinar followed by solid subtypes.11, 21 Since previous studies have only used traditional methods of molecular testing, existing literature on the genetic alterations in various histological subtypes are mostly limited to the detection rates of EGFR and KRAS mutations.	('EGFR', 'Gene', (335, 339))	('KRAS', 'Gene', (344, 348))	('KRAS', 'Gene', '3845', (344, 348))	('mutations', 'Var', (349, 358))	('EGFR', 'Gene', '1956', (335, 339))
20591	31692283	A previous study reported that among Chinese LUAD patients, lepidic and micropapillary subtypes had the most EGFR mutations with approximately 70% EGFR-mutant patients from each subtype, while solid subtype had the least number of EGFR mutant patients.18 Meanwhile, another study reported the EGFR mutation detection rates of 68.8%, 70.7%, 69.5%, 22.5%, 80.0%, and 25.0% in Chinese patients with lepidic, papillary, acinar, solid, micropapillary and mucinous subtypes, respectively, with no EGFR mutation detected in the case of fetal adenocarcinoma.23 In contrast, in our cohort, EGFR sensitizing mutations were generally more common in preinvasive and minimally invasive subtypes.	('EGFR', 'Gene', (147, 151))	('LUAD', 'Disease', 'MESH:C538231', (45, 49))	('EGFR', 'Gene', '1956', (293, 297))	('mutations', 'Var', (598, 607))	('fetal adenocarcinoma', 'Disease', (529, 549))	('EGFR', 'Gene', '1956', (109, 113))	('minimally invasive subtypes', 'Disease', (654, 681))	('carcinoma', 'Phenotype', 'HP:0030731', (540, 549))	('EGFR', 'Gene', '1956', (491, 495))	('patients', 'Species', '9606', (243, 251))	('EGFR', 'Gene', (581, 585))	('EGFR', 'Gene', (231, 235))	('EGFR', 'Gene', '1956', (147, 151))	('LUAD', 'Phenotype', 'HP:0030078', (45, 49))	('fetal adenocarcinoma', 'Disease', 'MESH:D005315', (529, 549))	('patients', 'Species', '9606', (50, 58))	('EGFR', 'Gene', (293, 297))	('preinvasive', 'Disease', (638, 649))	('EGFR', 'Gene', (109, 113))	('patients', 'Species', '9606', (159, 167))	('sensitizing', 'Reg', (586, 597))	('common', 'Reg', (628, 634))	('patients', 'Species', '9606', (382, 390))	('LUAD', 'Disease', (45, 49))	('EGFR', 'Gene', '1956', (581, 585))	('EGFR', 'Gene', (491, 495))	('EGFR', 'Gene', '1956', (231, 235))
20592	31692283	Meanwhile, invasive subtypes such as acinar, micropapillary, and papillary also had a substantial number of EGFR mutant patients.	('micropapillary', 'Disease', (45, 59))	('papillary', 'Disease', (65, 74))	('EGFR', 'Gene', '1956', (108, 112))	('EGFR', 'Gene', (108, 112))	('acinar', 'Disease', (37, 43))	('patients', 'Species', '9606', (120, 128))	('mutant', 'Var', (113, 119))
20593	31692283	However, the least number of EGFR sensitizing mutations were in patients of colloidal subtype (1/10), invasive mucinous (0/14) and fetal (0/2) subtypes.	('invasive mucinous', 'Disease', (102, 119))	('mutations', 'Var', (46, 55))	('patients', 'Species', '9606', (64, 72))	('sensitizing', 'Reg', (34, 45))	('colloidal subtype', 'Disease', (76, 93))	('EGFR', 'Gene', '1956', (29, 33))	('EGFR', 'Gene', (29, 33))
20594	31692283	Conversely, KRAS mutations in our cohort were consistent with the reported prevalence.17 In our cohort, KRAS mutations were also more prevalent in invasive mucinous (6/14), colloid (3/10), enteric (4/22) and solid (6/24) subtypes.	('KRAS', 'Gene', '3845', (104, 108))	('invasive mucinous', 'Disease', (147, 164))	('enteric', 'Disease', (189, 196))	('colloid', 'Disease', (173, 180))	('KRAS', 'Gene', (12, 16))	('prevalent', 'Reg', (134, 143))	('KRAS', 'Gene', '3845', (12, 16))	('mutations', 'Var', (109, 118))	('solid', 'Disease', (208, 213))	('KRAS', 'Gene', (104, 108))
20597	31692283	Similar to the findings of the TCGA12 and a study among 104 Korean LUSC patients by Kim et al.,24 significantly fewer EGFR and KRAS mutations were detected in Chinese LUSC than LUAD patients.	('LUSC', 'Phenotype', 'HP:0030359', (167, 171))	('mutations', 'Var', (132, 141))	('TCGA12', 'Chemical', 'MESH:C047031', (31, 37))	('LUSC', 'Disease', 'MESH:D002294', (67, 71))	('LUSC', 'Phenotype', 'HP:0030359', (67, 71))	('KRAS', 'Gene', (127, 131))	('EGFR', 'Gene', '1956', (118, 122))	('fewer', 'NegReg', (112, 117))	('EGFR', 'Gene', (118, 122))	('patients', 'Species', '9606', (182, 190))	('LUSC', 'Disease', (167, 171))	('LUSC', 'Disease', (67, 71))	('LUSC', 'Disease', 'MESH:D002294', (167, 171))	('LUAD', 'Disease', (177, 181))	('LUAD', 'Phenotype', 'HP:0030078', (177, 181))	('LUAD', 'Disease', 'MESH:C538231', (177, 181))	('KRAS', 'Gene', '3845', (127, 131))	('patients', 'Species', '9606', (72, 80))
20599	31692283	Interestingly, we have detected several rare mutations in known oncogenic genes including EGFR and BRAF and unreported fusion partners for RET, FGFR1 and ALK in our cohort.	('RET', 'Gene', (139, 142))	('mutations', 'Var', (45, 54))	('ALK', 'Gene', (154, 157))	('FGFR1', 'Gene', (144, 149))	('EGFR', 'Gene', '1956', (90, 94))	('BRAF', 'Gene', (99, 103))	('BRAF', 'Gene', '673', (99, 103))	('FGFR1', 'Gene', '2260', (144, 149))	('EGFR', 'Gene', (90, 94))	('ALK', 'Gene', '238', (154, 157))	('RET', 'Gene', '5979', (139, 142))
20669	31040254	Of the clinicopathological features analyzed, BMI <=18.5 kg/m2 (27.3% vs. 9.1%, p = .002) and weight loss >=3 kg in the previous 3 months (38.6% vs. 16.1%, p = .001) were more frequently observed in patients with pretreatment lymphopenia compared with those with lymphocyte count >=1,000 cells per mm3.	('lymphopenia', 'Disease', 'MESH:D008231', (226, 237))	('>=3', 'Var', (106, 109))	('lymphopenia', 'Phenotype', 'HP:0001888', (226, 237))	('weight loss', 'Disease', 'MESH:D015431', (94, 105))	('weight loss', 'Disease', (94, 105))	('lymphopenia', 'Disease', (226, 237))	('BMI <=18.5 kg/m2', 'Var', (46, 62))	('weight loss', 'Phenotype', 'HP:0001824', (94, 105))	('patients', 'Species', '9606', (199, 207))
20724	31040254	For example, shrinking radiation fields using limited-field RT for glioblastoma has been correlated with less radiation-related lymphopenia than standard-field RT, and reduction of RT field does not seem to affect patient prognosis [37].	('glioblastoma', 'Disease', (67, 79))	('patient', 'Species', '9606', (214, 221))	('glioblastoma', 'Disease', 'MESH:D005909', (67, 79))	('less', 'NegReg', (105, 109))	('glioblastoma', 'Phenotype', 'HP:0012174', (67, 79))	('lymphopenia', 'Disease', 'MESH:D008231', (128, 139))	('lymphopenia', 'Phenotype', 'HP:0001888', (128, 139))	('limited-field', 'Var', (46, 59))	('lymphopenia', 'Disease', (128, 139))
20741	29764507	ALDOA knockdown inhibited the proliferation and G1/S transition in H520 cells.	('G1/S transition', 'CPA', (48, 63))	('inhibited', 'NegReg', (16, 25))	('H520', 'CellLine', 'CVCL:1566', (67, 71))	('knockdown', 'Var', (6, 15))	('proliferation', 'CPA', (30, 43))
20746	29764507	Additionally, ALDOA knockdown reduced nuclear distribution of PKM2, the extracellular lactate and intracellular adenosine triphosphate concentrations and elevated the extracellular glucose concentration.	('adenosine triphosphate', 'Chemical', 'MESH:D000255', (112, 134))	('extracellular glucose concentration', 'MPA', (167, 202))	('nuclear distribution', 'MPA', (38, 58))	('PKM2', 'Gene', (62, 66))	('reduced', 'NegReg', (30, 37))	('elevated', 'PosReg', (154, 162))	('lactate', 'Chemical', 'MESH:D019344', (86, 93))	('knockdown', 'Var', (20, 29))	('PKM2', 'Gene', '5315', (62, 66))	('ALDOA', 'Gene', (14, 19))	('glucose', 'Chemical', 'MESH:D005947', (181, 188))
20761	29764507	We previously reported that ALDOA is excessively expressed in clinical human lung squamous cell carcinoma compared with adjacent normal tissues and that knockdown of ALDOA impairs the invasion and migration capacities of the lung squamous cell carcinoma cell line H520.	('lung squamous cell carcinoma', 'Disease', (225, 253))	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('knockdown', 'Var', (153, 162))	('human', 'Species', '9606', (71, 76))	('H520', 'CellLine', 'CVCL:1566', (264, 268))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (230, 253))	('impairs', 'NegReg', (172, 179))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (77, 105))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (225, 253))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (82, 105))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (225, 253))	('carcinoma', 'Phenotype', 'HP:0030731', (244, 253))	('ALDOA', 'Gene', (166, 171))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (77, 105))	('lung squamous cell carcinoma', 'Disease', (77, 105))
20772	29764507	Endogenous peroxidase was inhibited with 1% H2O2 and washed in phosphate-buffered saline (PBS).	('PBS', 'Chemical', '-', (90, 93))	('inhibited', 'NegReg', (26, 35))	('phosphate-buffered saline', 'Chemical', '-', (63, 88))	('H2O2', 'Chemical', 'MESH:D006861', (44, 48))	('H2O2', 'Var', (44, 48))
20783	29764507	Primary antibodies for cyclin D1 (1:1000), cyclin E1 (1:500), cyclin-dependent kinase 4 (CDK4, 1:500), CDK6 (1:500), beta-catenin (1:800), pyruvate kinase M2 (PKM2, 1:2000), beta-actin (1:5000), octamer-binding transcription factor-1 (Oct-1) (1:2000), beta-tublin (1:1000) and EGFR (1:1000) were purchased from Proteintech.	('EGFR', 'Gene', '1956', (277, 281))	('PKM2', 'Gene', (159, 163))	('CDK6', 'Gene', '1021', (103, 107))	('octamer-binding transcription factor-1', 'Gene', (195, 233))	('PKM2', 'Gene', '5315', (159, 163))	('Oct-1', 'Gene', (235, 240))	('Oct-1', 'Gene', '5451', (235, 240))	('cyclin-dependent kinase 4', 'Gene', (62, 87))	('1:800', 'Var', (131, 136))	('beta-actin', 'Gene', '728378', (174, 184))	('CDK6', 'Gene', (103, 107))	('beta-catenin', 'Gene', (117, 129))	('cyclin-dependent kinase 4', 'Gene', '1019', (62, 87))	('beta-catenin', 'Gene', '1499', (117, 129))	('CDK4', 'Gene', (89, 93))	('EGFR', 'Gene', (277, 281))	('octamer-binding transcription factor-1', 'Gene', '5451', (195, 233))	('pyruvate kinase M2', 'Gene', (139, 157))	('pyruvate kinase M2', 'Gene', '5315', (139, 157))	('beta-actin', 'Gene', (174, 184))	('CDK4', 'Gene', '1019', (89, 93))
20793	29764507	The glucose and lactate concentrations were measured with specific kits (K686, K627; Biovision, Milpitas, CA US).	('glucose', 'Chemical', 'MESH:D005947', (4, 11))	('K686', 'Var', (73, 77))	('K627', 'Var', (79, 83))	('lactate', 'Chemical', 'MESH:D019344', (16, 23))
20799	29764507	Therefore, H520 cell line was utilized as a model in which we knocked down ALDOA to study its function, and H157 was used as a model for ALDOA overexpression.	('H157', 'CellLine', 'CVCL:2458', (108, 112))	('knocked down', 'Var', (62, 74))	('ALDOA', 'Gene', (75, 80))	('H520', 'CellLine', 'CVCL:1566', (11, 15))
20802	29764507	Our prior study indicated that knockdown of ALDOA inhibited H520 cell growth in nude mice.	('nude mice', 'Species', '10090', (80, 89))	('H520 cell growth', 'CPA', (60, 76))	('H520', 'CellLine', 'CVCL:1566', (60, 64))	('knockdown', 'Var', (31, 40))	('inhibited', 'NegReg', (50, 59))
20808	29764507	First, we performed flow cytometry assays and found that ALDOA knockdown in H520 cells increased the proportion of cells in the G0/G1 phase and reduced the proportion of cells in the S phase (Fig.	('reduced', 'NegReg', (144, 151))	('increased', 'PosReg', (87, 96))	('H520', 'CellLine', 'CVCL:1566', (76, 80))	('ALDOA', 'Gene', (57, 62))	('knockdown', 'Var', (63, 72))
20814	29764507	Moreover, knockdown of ALDOA reduced p-Rb, while total Rb remained unchanged (Fig.	('ALDOA', 'Gene', (23, 28))	('reduced', 'NegReg', (29, 36))	('p-Rb', 'Gene', (37, 41))	('p-Rb', 'Gene', '5925', (37, 41))	('knockdown', 'Var', (10, 19))
20831	29764507	To confirm this assessment, we administrated U0126-EtOH, which is a MEK1/2-specific inhibitor, and tested cyclin D1 expression and colony formation ability.	('expression', 'MPA', (116, 126))	('U0126', 'Chemical', 'MESH:C113580', (45, 50))	('tested', 'Reg', (99, 105))	('U0126-EtOH', 'Var', (45, 55))	('EtOH', 'Chemical', 'MESH:D000431', (51, 55))	('MEK1/2', 'Gene', '5604;5605', (68, 74))	('cyclin D1', 'Protein', (106, 115))	('colony formation ability', 'CPA', (131, 155))	('MEK1/2', 'Gene', (68, 74))
20842	29764507	These results indicated that ALDOA knockdown inhibited EGFR activation, but stimulated ERK1/2 activation.	('knockdown', 'Var', (35, 44))	('EGFR', 'Gene', '1956', (55, 59))	('ERK1/2', 'Protein', (87, 93))	('EGFR', 'Gene', (55, 59))	('activation', 'MPA', (94, 104))	('inhibited', 'NegReg', (45, 54))	('activation', 'MPA', (60, 70))	('stimulated', 'PosReg', (76, 86))
20844	29764507	Here, we examined the distribution of ALDOA after U0126-EtOH treatment and observed that U0126-EtOH administration led to the nuclear translocation of ALDOA (Fig.	('nuclear translocation', 'MPA', (126, 147))	('led to', 'Reg', (115, 121))	('U0126-EtOH', 'Var', (89, 99))	('EtOH', 'Chemical', 'MESH:D000431', (56, 60))	('U0126', 'Chemical', 'MESH:C113580', (50, 55))	('EtOH', 'Chemical', 'MESH:D000431', (95, 99))	('U0126', 'Chemical', 'MESH:C113580', (89, 94))
20850	29764507	As expected, ALDOA knockdown led to reductions in the intracellular ATP concentration (Fig.	('intracellular ATP concentration', 'MPA', (54, 85))	('ATP', 'Chemical', 'MESH:D000255', (68, 71))	('knockdown', 'Var', (19, 28))	('reductions', 'NegReg', (36, 46))	('ALDOA', 'Gene', (13, 18))
20871	29764507	A recent finding suggests that EGFR gene amplification or protein overexpression confers acquired drug resistance to these EGFR TKIs.	('EGFR', 'Gene', (123, 127))	('protein', 'Protein', (58, 65))	('drug resistance', 'Phenotype', 'HP:0020174', (98, 113))	('EGFR', 'Gene', '1956', (31, 35))	('EGFR', 'Gene', (31, 35))	('drug resistance', 'MPA', (98, 113))	('amplification', 'Var', (41, 54))	('EGFR', 'Gene', '1956', (123, 127))	('overexpression', 'PosReg', (66, 80))
20877	29764507	Our findings also revealed that ALDOA knockdown attenuated aerobic glycolysis in NSCLC cells.	('aerobic glycolysis', 'MPA', (59, 77))	('attenuated', 'NegReg', (48, 58))	('NSCLC', 'Phenotype', 'HP:0030358', (81, 86))	('NSCLC', 'Disease', (81, 86))	('knockdown', 'Var', (38, 47))	('NSCLC', 'Disease', 'MESH:D002289', (81, 86))
20879	29764507	Therefore, knock down of ALDOA also help to relieve stress and cut off the energy supply of NSCLC.	('knock down', 'Var', (11, 21))	('relieve stress', 'MPA', (44, 58))	('NSCLC', 'Phenotype', 'HP:0030358', (92, 97))	('NSCLC', 'Disease', 'MESH:D002289', (92, 97))	('NSCLC', 'Disease', (92, 97))	('ALDOA', 'Gene', (25, 30))	('cut off', 'NegReg', (63, 70))
20880	29764507	Another interesting result is that ALDOA knockdown increased the phosphorylation of ERK1/2 at Thr202/Tyr204, whereas the corresponding target (cyclin D1) and the phosphorylation of the upstream kinase MEK1/2 were suppressed.	('Thr202/Tyr204', 'Var', (94, 107))	('increased', 'PosReg', (51, 60))	('MEK1/2', 'Gene', '5604;5605', (201, 207))	('suppressed', 'NegReg', (213, 223))	('ERK1/2', 'Gene', (84, 90))	('MEK1/2', 'Gene', (201, 207))	('Thr202', 'Chemical', '-', (94, 100))	('phosphorylation', 'MPA', (65, 80))	('phosphorylation', 'MPA', (162, 177))	('Tyr204', 'Chemical', '-', (101, 107))
20882	29764507	First, ALDOA was transferred to the nucleus after MEK1/2 inhibition by U0126-EtOH; similarly, ALDOA has been reported to translocate to the nucleus under various conditions that influence cell proliferation.	('U0126-EtOH', 'Var', (71, 81))	('translocate', 'MPA', (121, 132))	('EtOH', 'Chemical', 'MESH:D000431', (77, 81))	('inhibition', 'NegReg', (57, 67))	('MEK1/2', 'Gene', '5604;5605', (50, 56))	('MEK1/2', 'Gene', (50, 56))	('U0126', 'Chemical', 'MESH:C113580', (71, 76))
20892	26762219	Statistically significant risk factors for metastasis were invasion beyond subcutaneous fat (RR [95% CI], 11.21 [3.59-34.97]); Breslow >2 mm (10.76 [2.55-45.31]); Breslow >6 mm (6.93 [4.02-11.94]); diameter >20 mm (6.15 [3.56- 10.65]); poor differentiation (4.98 [3.30-7.49]); PNI (2.95 [2.31-3.75]); location on temple (2.82 [1.72-4.63]), ear (2.33 [1.67-3.23), and lip (RR [1.54-3.37]); and immunosuppression (1.59 [1.07-2.37]).	('Breslow >6', 'Var', (163, 173))	('lip', 'Gene', (367, 370))	('lip', 'Gene', '23049', (367, 370))	('metastasis', 'CPA', (43, 53))
20948	26762219	Poor differentiation, location on the ear or the lip, invasion beyond subcutaneous fat, and PNI were associated with a statistically significant increase ranging from 4- to 6-fold, in the RR of DSD.	('Poor differentiation', 'CPA', (0, 20))	('RR of DSD', 'Disease', (188, 197))	('PNI', 'Disease', (92, 95))	('increase', 'PosReg', (145, 153))	('invasion', 'Var', (54, 62))	('lip', 'Gene', (49, 52))	('lip', 'Gene', '23049', (49, 52))
20959	26438152	ATM kinase inhibition radiosensitizes cells and selectively kills cells with Fanconi anemia (FA) gene mutations.	('Fanconi anemia', 'Disease', (77, 91))	('Fanconi anemia', 'Phenotype', 'HP:0001994', (77, 91))	('mutations', 'Var', (102, 111))	('Fanconi anemia', 'Disease', 'MESH:D005199', (77, 91))	('anemia', 'Phenotype', 'HP:0001903', (85, 91))
20960	26438152	ATR kinase inhibition sensitizes cells to agents that induce replication stress and selectively kills cells with ATM and TP53 mutations.	('ATM', 'Gene', (113, 116))	('TP53', 'Gene', '7157', (121, 125))	('TP53', 'Gene', (121, 125))	('replication stress', 'MPA', (61, 79))	('mutations', 'Var', (126, 135))	('induce', 'Reg', (54, 60))
20961	26438152	ATM mutations and FANCF promoter-methylation are reported in lung carcinomas.	('carcinoma', 'Phenotype', 'HP:0030731', (66, 75))	('FANCF', 'Gene', '2188', (18, 23))	('carcinomas', 'Phenotype', 'HP:0030731', (66, 76))	('lung carcinomas', 'Disease', 'MESH:D008175', (61, 76))	('FANCF', 'Gene', (18, 23))	('lung carcinomas', 'Disease', (61, 76))	('mutations', 'Var', (4, 13))
20964	26438152	In addition, the cancer genome atlas (TCGA) database was interrogated for alterations in: 1) ATM, MRE11A, RAD50 and NBN; 2) ATR, ATRIP and TOPBP1; and 3) 15 FA genes.	('RAD50', 'Gene', (106, 111))	('FA genes', 'Gene', (157, 165))	('ATRIP', 'Gene', (129, 134))	('NBN', 'Gene', '4683', (116, 119))	('cancer genome atlas', 'Disease', 'MESH:D009369', (17, 36))	('ATRIP', 'Gene', '84126', (129, 134))	('cancer genome atlas', 'Disease', (17, 36))	('MRE11A', 'Gene', (98, 104))	('TOPBP1', 'Gene', (139, 145))	('alterations', 'Var', (74, 85))	('ATR', 'Gene', (124, 127))	('ATM', 'Gene', (93, 96))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))	('TOPBP1', 'Gene', '11073', (139, 145))	('NBN', 'Gene', (116, 119))
20966	26438152	Cell lines were radiosensitized by ATM kinase inhibitor KU60019, but no cell killing by ATM kinase inhibitor alone was observed.	('KU60019', 'Chemical', 'MESH:C546193', (56, 63))	('KU60019', 'Var', (56, 63))	('inhibitor KU60019', 'Var', (46, 63))
20973	26438152	While the functional significance of the ATM mutations identified has not been determined, ATM polymorphisms are known to affect lung cancer risk.	('lung cancer', 'Disease', (129, 140))	('lung cancer', 'Phenotype', 'HP:0100526', (129, 140))	('polymorphisms', 'Var', (95, 108))	('affect', 'Reg', (122, 128))	('lung cancer', 'Disease', 'MESH:D008175', (129, 140))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
20974	26438152	Further, since ataxia telangiectasia individuals with mutations in the ATM gene are extremely radiosensitive, ATM kinase inhibition is expected to increase the efficacy of radiotherapy.	('ataxia', 'Phenotype', 'HP:0001251', (15, 21))	('ataxia telangiectasia', 'Disease', (15, 36))	('radiotherapy', 'CPA', (172, 184))	('ATM', 'Gene', (71, 74))	('mutations', 'Var', (54, 63))	('telangiectasia', 'Phenotype', 'HP:0001009', (22, 36))	('ataxia telangiectasia', 'Disease', 'MESH:D001260', (15, 36))	('increase', 'PosReg', (147, 155))
20975	26438152	Thus, up to 7 % of lung adenocarcinomas that have acquired somatic mutations that inactivate ATM may respond extremely well to radiotherapy, while lung cancers that express functional ATM are anticipated to be radiosensitized by ATM kinase inhibitors.	('lung cancers', 'Disease', (147, 159))	('inactivate', 'Var', (82, 92))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (19, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (29, 38))	('lung cancers', 'Disease', 'MESH:D008175', (147, 159))	('respond', 'MPA', (101, 108))	('lung adenocarcinomas', 'Disease', (19, 39))	('lung cancer', 'Phenotype', 'HP:0100526', (147, 158))	('mutations', 'Var', (67, 76))	('carcinomas', 'Phenotype', 'HP:0030731', (29, 39))	('lung cancers', 'Phenotype', 'HP:0100526', (147, 159))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (19, 39))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (19, 39))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('to 7', 'Species', '1214577', (9, 13))	('ATM', 'Gene', (93, 96))	('cancers', 'Phenotype', 'HP:0002664', (152, 159))
20976	26438152	ATM kinase inhibitors also kill cell lines with mutations in genes that cause Fanconi anemia (FA), a multigenic disorder characterized by extreme sensitivity to interstrand crosslinks (ICLs), with greater efficacy than complemented control cell lines.	('multigenic disorder', 'Disease', 'MESH:D030342', (101, 120))	('multigenic disorder', 'Disease', (101, 120))	('anemia', 'Phenotype', 'HP:0001903', (86, 92))	('Fanconi anemia', 'Phenotype', 'HP:0001994', (78, 92))	('Fanconi anemia', 'Disease', (78, 92))	('cause', 'Reg', (72, 77))	('mutations', 'Var', (48, 57))	('Fanconi anemia', 'Disease', 'MESH:D005199', (78, 92))
20977	26438152	Inactivation of the FA pathway through promotor methylation of FANCF was identified previously in 22 of 158 non-small-cell lung carcinomas (NSCLCs) (14 %).	('FANCF', 'Gene', '2188', (63, 68))	('NSCLC', 'Disease', 'MESH:D002289', (140, 145))	('lung carcinomas', 'Disease', 'MESH:D008175', (123, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('small-cell lung carcinomas', 'Phenotype', 'HP:0030357', (112, 138))	('carcinomas', 'Phenotype', 'HP:0030731', (128, 138))	('FANCF', 'Gene', (63, 68))	('non-small-cell lung carcinomas', 'Phenotype', 'HP:0030358', (108, 138))	('Inactivation', 'NegReg', (0, 12))	('methylation', 'Var', (48, 59))	('FA pathway', 'Pathway', (20, 30))	('lung carcinomas', 'Disease', (123, 138))	('NSCLC', 'Disease', (140, 145))
20979	26438152	In contrast to ATM, ATR is an essential protein in mice and ATR disruption by genetic means kills human cells in vitro.	('disruption', 'Var', (64, 74))	('human', 'Species', '9606', (98, 103))	('mice', 'Species', '10090', (51, 55))	('ATR', 'Gene', (60, 63))
20980	26438152	However, Seckel syndrome individuals have a mutation in a splice site that results in the expression of just 10 % of the typical levels of ATR protein, which allows them to survive.	('Seckel syndrome', 'Disease', 'MESH:C537533', (9, 24))	('results in', 'Reg', (75, 85))	('mutation in', 'Var', (44, 55))	('Seckel syndrome', 'Disease', (9, 24))	('expression', 'MPA', (90, 100))
20982	26438152	ATR kinase inhibitors also kill cell lines with mutations in either ATM or TP53 with greater efficacy than complemented control cell lines.	('mutations', 'Var', (48, 57))	('TP53', 'Gene', '7157', (75, 79))	('TP53', 'Gene', (75, 79))	('ATM', 'Gene', (68, 71))
20983	26438152	Thus, up to 7 % of lung adenocarcinomas that have acquired somatic mutations that inactivate ATM may respond to single agent therapy with an ATR kinase inhibitor.	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (19, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (29, 38))	('lung adenocarcinomas', 'Disease', (19, 39))	('mutations', 'Var', (67, 76))	('carcinomas', 'Phenotype', 'HP:0030731', (29, 39))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (19, 39))	('respond', 'Reg', (101, 108))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (19, 39))	('to 7', 'Species', '1214577', (9, 13))	('ATM', 'Gene', (93, 96))
20989	26438152	ATM kinase inhibitors KU55933 and KU60019 (AstraZeneca, Macclesfield, UK) were used at final concentrations of 10 muM and 1 muM, respectively.	('muM', 'Gene', '56925', (124, 127))	('KU60019', 'Chemical', 'MESH:C546193', (34, 41))	('KU60019', 'Var', (34, 41))	('KU55933', 'Var', (22, 29))	('muM', 'Gene', '56925', (114, 117))	('KU55933', 'Chemical', 'MESH:C495818', (22, 29))	('muM', 'Gene', (124, 127))	('muM', 'Gene', (114, 117))
20991	26438152	ETP46464 was synthesized at the Medicinal Chemistry Shared Resource of the Ohio State University Comprehensive Cancer Center (Columbus, OH).	('ETP46464', 'Var', (0, 8))	('ETP46464', 'Chemical', 'MESH:C000598436', (0, 8))	('Cancer', 'Phenotype', 'HP:0002664', (111, 117))	('Cancer', 'Disease', 'MESH:D009369', (111, 117))	('Cancer', 'Disease', (111, 117))
21000	26438152	ATM serine 1981 phosphorylation is associated with ATM kinase activity, and alterations in ATM, MRE11A, RAD50 and NBN may disrupt this biomarker for functionality of ATM kinase activation mechanisms.	('ATM serine 1981 phosphorylation', 'MPA', (0, 31))	('alterations', 'Var', (76, 87))	('MRE11A', 'Gene', (96, 102))	('NBN', 'Gene', '4683', (114, 117))	('ATM', 'Gene', (91, 94))	('serine', 'Chemical', 'MESH:D012694', (4, 10))	('NBN', 'Gene', (114, 117))	('biomarker', 'MPA', (135, 144))	('RAD50', 'Gene', (104, 109))	('disrupt', 'NegReg', (122, 129))
21003	26438152	Calu6 is being sequenced in the Catalogue of Somatic Mutations in Cancer (COSMIC) Cell Lines Project at the Sanger Center, Cambridge, UK and has a homozygous missense point mutation (R196*) in TP53.	('TP53', 'Gene', '7157', (193, 197))	('R196*', 'SUBSTITUTION', 'None', (183, 188))	('TP53', 'Gene', (193, 197))	('Cancer', 'Phenotype', 'HP:0002664', (66, 72))	('Cancer', 'Disease', (66, 72))	('Cancer', 'Disease', 'MESH:D009369', (66, 72))	('R196*', 'Var', (183, 188))
21004	26438152	Of the other cell lines, H460 is a large cell carcinoma with wild-type TP53, 201 T is a lung adenocarcinoma with wild-type TP53, and 54 T and 239 T are lung squamous cell carcinomas with wild-type TP53.	('lung squamous cell carcinomas', 'Disease', (152, 181))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (88, 107))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (157, 181))	('TP53', 'Gene', (197, 201))	('TP53', 'Gene', (123, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (46, 55))	('cell carcinoma', 'Disease', (41, 55))	('TP53', 'Gene', '7157', (71, 75))	('large cell carcinoma', 'Phenotype', 'HP:0030360', (35, 55))	('TP53', 'Gene', '7157', (197, 201))	('lung adenocarcinoma', 'Disease', (88, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (171, 180))	('TP53', 'Gene', '7157', (123, 127))	('carcinomas', 'Phenotype', 'HP:0030731', (171, 181))	('lung squamous cell carcinomas', 'Disease', 'MESH:D002294', (152, 181))	('H460', 'Var', (25, 29))	('cell carcinoma', 'Disease', 'MESH:C538614', (41, 55))	('cell carcinoma', 'Disease', 'MESH:C538614', (166, 180))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (88, 107))	('TP53', 'Gene', (71, 75))
21005	26438152	We selected lung cancer cell lines with wild-type TP53 for this study as we sought to identify the somatic mutations that compromised ATM and ATR kinase-dependent signaling to p53.	('mutations', 'Var', (107, 116))	('ATR kinase-dependent signaling', 'MPA', (142, 172))	('compromised', 'NegReg', (122, 133))	('lung cancer', 'Disease', 'MESH:D008175', (12, 23))	('TP53', 'Gene', '7157', (50, 54))	('lung cancer', 'Disease', (12, 23))	('TP53', 'Gene', (50, 54))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))	('lung cancer', 'Phenotype', 'HP:0100526', (12, 23))
21016	26438152	However, from a therapeutic perspective these two kinases interact as ATM kinase inhibition causes DSBs to accumulate in cells and these activate ATR kinase as they are repaired by homologous recombination repair (HRR).	('DSBs', 'Chemical', 'MESH:C007563', (99, 103))	('accumulate', 'PosReg', (107, 117))	('inhibition', 'Var', (81, 91))	('DSBs', 'Disease', (99, 103))	('ATR', 'Enzyme', (146, 149))	('activate', 'PosReg', (137, 145))
21017	26438152	An ATR kinase-dependent phosphorylation on Chk1 serine-345 is required for Chkl activation, and alterations in ATR, ATRIP and TOPBP1 may disrupt this biomarker for functionality of ATR kinase activation mechanisms.	('ATR', 'Gene', (111, 114))	('TOPBP1', 'Gene', (126, 132))	('alterations', 'Var', (96, 107))	('serine', 'Chemical', 'MESH:D012694', (48, 54))	('TOPBP1', 'Gene', '11073', (126, 132))	('ATRIP', 'Gene', (116, 121))	('Chkl', 'Gene', (75, 79))	('ATRIP', 'Gene', '84126', (116, 121))	('Chkl', 'Gene', '1120', (75, 79))	('phosphorylation', 'MPA', (24, 39))	('biomarker', 'MPA', (150, 159))	('disrupt', 'NegReg', (137, 144))
21027	26438152	Chk1 kinase inhibition was recently reported to increase sensitivity to gemcitabine in two p53 mutant NSCLC cell lines with either high (H1299) or low (H1993) Chk1.	('NSCLC', 'Disease', 'MESH:D002289', (102, 107))	('inhibition', 'NegReg', (12, 22))	('low (H1993', 'Var', (147, 157))	('H1993', 'CellLine', 'CVCL:1512', (152, 157))	('gemcitabine', 'Chemical', 'MESH:C056507', (72, 83))	('Chk1 kinase', 'Enzyme', (0, 11))	('p53', 'Gene', (91, 94))	('H1993', 'Var', (152, 157))	('H1299', 'Var', (137, 142))	('sensitivity to gemcitabine', 'MPA', (57, 83))	('mutant', 'Var', (95, 101))	('NSCLC', 'Disease', (102, 107))	('H1299', 'CellLine', 'CVCL:0060', (137, 142))	('increase', 'PosReg', (48, 56))
21031	26438152	We reasoned that gemcitabine might induce DSBs in lung cancer cell lines due to acquired mutations that disrupt mechanisms that protect stalled replication forks.	('lung cancer', 'Disease', (50, 61))	('gemcitabine', 'Chemical', 'MESH:C056507', (17, 28))	('DSBs', 'Chemical', 'MESH:C007563', (42, 46))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('lung cancer', 'Disease', 'MESH:D008175', (50, 61))	('mutations', 'Var', (89, 98))	('lung cancer', 'Phenotype', 'HP:0100526', (50, 61))	('DSBs', 'Disease', (42, 46))
21039	26438152	To extend these findings we interrogated the publically available database of 212 lung squamous cell carcinomas in the TCGA to determine the incidence of alterations that are predicted to compromise ATM and ATR kinase activation and the FA pathway of ICL repair.	('lung squamous cell carcinomas', 'Disease', 'MESH:D002294', (82, 111))	('FA pathway of ICL repair', 'Pathway', (237, 261))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('ATM', 'MPA', (199, 202))	('carcinomas', 'Phenotype', 'HP:0030731', (101, 111))	('compromise', 'NegReg', (188, 198))	('alterations', 'Var', (154, 165))	('lung squamous cell carcinomas', 'Disease', (82, 111))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (87, 111))
21041	26438152	The TCGA database contains 9 missense point mutations in ATM, 3 in MRE11A, 4 in RAD50, and 1 in NBN (Fig.	('NBN', 'Gene', (96, 99))	('missense point mutations', 'Var', (29, 53))	('MRE11A', 'Gene', (67, 73))	('ATM', 'Gene', (57, 60))	('NBN', 'Gene', '4683', (96, 99))
21047	26438152	The TCGA database contains 13 missense point mutations in ATR, 3 in ATRIP, and 7 in TOPBP1 (Fig.	('missense point mutations', 'Var', (30, 54))	('ATR', 'Gene', (58, 61))	('ATRIP', 'Gene', (68, 73))	('TOPBP1', 'Gene', (84, 90))	('ATRIP', 'Gene', '84126', (68, 73))	('TOPBP1', 'Gene', '11073', (84, 90))
21053	26438152	The striking conclusion from these analyses is that while ATM is mutated in a subset of lung cancers, ATR is amplified in subset of lung cancers.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('lung cancers', 'Disease', 'MESH:D008175', (88, 100))	('lung cancer', 'Phenotype', 'HP:0100526', (88, 99))	('lung cancers', 'Disease', (132, 144))	('lung cancers', 'Phenotype', 'HP:0100526', (88, 100))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('cancers', 'Phenotype', 'HP:0002664', (137, 144))	('lung cancer', 'Phenotype', 'HP:0100526', (132, 143))	('lung cancers', 'Disease', (88, 100))	('lung cancers', 'Disease', 'MESH:D008175', (132, 144))	('lung cancers', 'Phenotype', 'HP:0100526', (132, 144))	('cancers', 'Phenotype', 'HP:0002664', (93, 100))	('mutated', 'Var', (65, 72))
21054	26438152	Together the 15 FA genes are altered by missense point mutation, amplification or homozygous deletion in 72/212 (34 %) of lung squamous cell carcinomas in the publically available TCGA database (Additional file 3: Figure S1).	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('lung squamous cell carcinomas', 'Disease', 'MESH:D002294', (122, 151))	('missense point mutation', 'Var', (40, 63))	('carcinomas', 'Phenotype', 'HP:0030731', (141, 151))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (127, 151))	('altered', 'Reg', (29, 36))	('lung squamous cell carcinomas', 'Disease', (122, 151))	('amplification', 'Var', (65, 78))
21056	26438152	The data are summarized as follows: 6 missense point mutations in FANCA; 4 in FANCB; 2 in FANCC; 1 in FANCE; 3 in FANCF; 5 in FANCG; 1 in FANCL; 10 in FANCM; 1 in FANCI; 12 in BRCA2; 6 in BRIP1; 6 in PALB2 (FANCN); and 14 in SLX4 (FANCP).	('BRCA2', 'Gene', (176, 181))	('FANCN', 'Gene', '79728', (207, 212))	('SLX4', 'Gene', (225, 229))	('FANCP', 'Gene', (231, 236))	('FANCA', 'Gene', (66, 71))	('FANCB', 'Gene', '2187', (78, 83))	('FANCM', 'Gene', '57697', (151, 156))	('FANCN', 'Gene', (207, 212))	('FANCM', 'Gene', (151, 156))	('FANCF', 'Gene', '2188', (114, 119))	('BRCA2', 'Gene', '675', (176, 181))	('SLX4', 'Gene', '84464', (225, 229))	('FANCG', 'Gene', (126, 131))	('missense point mutations', 'Var', (38, 62))	('BRIP1', 'Gene', '83990', (188, 193))	('FANCE', 'Gene', (102, 107))	('FANCC', 'Gene', '2176', (90, 95))	('FANCE', 'Gene', '2178', (102, 107))	('FANCB', 'Gene', (78, 83))	('FANCF', 'Gene', (114, 119))	('FANCL', 'Gene', (138, 143))	('PALB2', 'Gene', (200, 205))	('FANCL', 'Gene', '55120', (138, 143))	('BRIP1', 'Gene', (188, 193))	('FANCI', 'Gene', (163, 168))	('FANCP', 'Gene', '84464', (231, 236))	('FANCG', 'Gene', '2189', (126, 131))	('FANCA', 'Gene', '2175', (66, 71))	('FANCI', 'Gene', '55215', (163, 168))	('FANCC', 'Gene', (90, 95))	('PALB2', 'Gene', '79728', (200, 205))
21057	26438152	Amplifications of 8 FA genes are identified across 22 carcinomas; 2 of the carcinomas contain amplification in two FA genes (FANCG with FANCI and BRIP1 with RAD51C).	('RAD51C', 'Gene', (157, 163))	('amplification', 'Var', (94, 107))	('BRIP1', 'Gene', (146, 151))	('FANCG', 'Gene', '2189', (125, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (54, 63))	('FANCG', 'Gene', (125, 130))	('FANCI', 'Gene', '55215', (136, 141))	('RAD51C', 'Gene', '5889', (157, 163))	('BRIP1', 'Gene', '83990', (146, 151))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('carcinomas', 'Disease', (75, 85))	('carcinomas', 'Phenotype', 'HP:0030731', (75, 85))	('carcinomas', 'Disease', 'MESH:D002277', (75, 85))	('carcinomas', 'Phenotype', 'HP:0030731', (54, 64))	('carcinomas', 'Disease', 'MESH:D002277', (54, 64))	('FANCI', 'Gene', (136, 141))	('carcinomas', 'Disease', (54, 64))
21060	26438152	Since inactivation of the FA pathway through methylation of the FANCF promoter was identified previously in 22 of 158 NSCLCs (14 %), we also examined mRNA expression levels for the FA genes in lung squamous cell carcinomas in the publically available TCGA database.	('carcinomas', 'Phenotype', 'HP:0030731', (212, 222))	('inactivation', 'NegReg', (6, 18))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (198, 222))	('lung squamous cell carcinomas', 'Disease', (193, 222))	('FANCF', 'Gene', (64, 69))	('NSCLC', 'Disease', (118, 123))	('methylation', 'Var', (45, 56))	('carcinoma', 'Phenotype', 'HP:0030731', (212, 221))	('FA pathway', 'Pathway', (26, 36))	('lung squamous cell carcinomas', 'Disease', 'MESH:D002294', (193, 222))	('NSCLC', 'Disease', 'MESH:D002289', (118, 123))	('FANCF', 'Gene', '2188', (64, 69))
21061	26438152	Together the 15 FA genes are altered by missense point mutation, amplification, homozygous deletion, up-regulation (RNA), and down-regulation (RNA) in 102/212 (48 %) of lung squamous cell carcinomas (TCGA) (Additional file 3: Figure S1).	('lung squamous cell carcinomas', 'Disease', 'MESH:D002294', (169, 198))	('lung squamous cell carcinomas', 'Disease', (169, 198))	('up-regulation', 'PosReg', (101, 114))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (174, 198))	('altered', 'Reg', (29, 36))	('amplification', 'Var', (65, 78))	('carcinoma', 'Phenotype', 'HP:0030731', (188, 197))	('down-regulation', 'NegReg', (126, 141))	('carcinomas', 'Phenotype', 'HP:0030731', (188, 198))	('missense point mutation', 'Var', (40, 63))
21065	26438152	Missense point mutations of ATM in 9/212 lung squamous cell carcinomas (4 %) are present in the TCGA database.	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (46, 70))	('lung squamous cell carcinomas', 'Disease', 'MESH:D002294', (41, 70))	('Missense point mutations', 'Var', (0, 24))	('carcinoma', 'Phenotype', 'HP:0030731', (60, 69))	('carcinomas', 'Phenotype', 'HP:0030731', (60, 70))	('ATM', 'Gene', (28, 31))	('lung squamous cell carcinomas', 'Disease', (41, 70))
21066	26438152	These heterozygous mutations span the gene and aside from one mutation in the phosphatidylinositol 3-kinase domain (G2897S) none are judged likely to have a significant impact on kinase activity or expression.	('G2897S', 'Var', (116, 122))	('G2897S', 'Mutation', 'p.G2897S', (116, 122))	('expression', 'MPA', (198, 208))	('kinase activity', 'MPA', (179, 194))	('impact', 'Reg', (169, 175))
21067	26438152	Missense point mutations in an extended analysis of ATM, MRE11A, RAD50 and NBN are present in 16/212 lung squamous cell carcinomas (7 %) are present in the TCGA database.	('RAD50', 'Gene', (65, 70))	('lung squamous cell carcinomas', 'Disease', (101, 130))	('Missense point mutations', 'Var', (0, 24))	('MRE11A', 'Gene', (57, 63))	('NBN', 'Gene', '4683', (75, 78))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (106, 130))	('NBN', 'Gene', (75, 78))	('lung squamous cell carcinomas', 'Disease', 'MESH:D002294', (101, 130))	('carcinomas', 'Phenotype', 'HP:0030731', (120, 130))
21068	26438152	None of the missense point mutations in MRE11A, RAD50 and NBN are judged likely to have a significant impact on ATM kinase activity or expression.	('NBN', 'Gene', (58, 61))	('missense point mutations', 'Var', (12, 36))	('RAD50', 'Gene', (48, 53))	('MRE11A', 'Gene', (40, 46))	('impact', 'Reg', (102, 108))	('expression', 'MPA', (135, 145))	('NBN', 'Gene', '4683', (58, 61))	('ATM kinase activity', 'MPA', (112, 131))
21069	26438152	Thus, our analysis does not suggest that a significant number of lung squamous cell carcinomas will be radiosensitive as a result of acquired missense point mutations that affect ATM kinase activation.	('ATM', 'Enzyme', (179, 182))	('lung squamous cell carcinomas', 'Disease', 'MESH:D002294', (65, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('carcinomas', 'Phenotype', 'HP:0030731', (84, 94))	('activation', 'MPA', (190, 200))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (70, 94))	('lung squamous cell carcinomas', 'Disease', (65, 94))	('missense point mutations', 'Var', (142, 166))
21070	26438152	Inactivation of the FA pathway through promotor methylation of FANCF was also identified previously in 22 of 158 non-small-cell lung carcinomas (NSCLCs) (14 %).	('non-small-cell lung carcinomas', 'Phenotype', 'HP:0030358', (113, 143))	('NSCLC', 'Disease', (145, 150))	('carcinomas', 'Phenotype', 'HP:0030731', (133, 143))	('lung carcinomas', 'Disease', 'MESH:D008175', (128, 143))	('FANCF', 'Gene', (63, 68))	('lung carcinomas', 'Disease', (128, 143))	('NSCLC', 'Disease', 'MESH:D002289', (145, 150))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('small-cell lung carcinomas', 'Phenotype', 'HP:0030357', (117, 143))	('Inactivation', 'NegReg', (0, 12))	('methylation', 'Var', (48, 59))	('FA pathway', 'Pathway', (20, 30))	('FANCF', 'Gene', '2188', (63, 68))
21073	26438152	Together missense point mutation, amplification or homozygous deletion in the 15 FA genes are present in 72/212 lung squamous cell carcinomas (34 %) in the TCGA database.	('lung squamous cell carcinomas', 'Disease', 'MESH:D002294', (112, 141))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('carcinomas', 'Phenotype', 'HP:0030731', (131, 141))	('homozygous deletion', 'Var', (51, 70))	('lung squamous cell carcinomas', 'Disease', (112, 141))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (117, 141))	('amplification', 'Var', (34, 47))	('missense point mutation', 'Var', (9, 32))
21074	26438152	In summation, our analysis does not suggest that a significant number of lung squamous cell carcinomas will be sensitive to ICLs as a result of acquired missense point mutations that affect FA gene products.	('lung squamous cell carcinomas', 'Disease', (73, 102))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (78, 102))	('missense point mutations', 'Var', (153, 177))	('lung squamous cell carcinomas', 'Disease', 'MESH:D002294', (73, 102))	('carcinomas', 'Phenotype', 'HP:0030731', (92, 102))
21075	26438152	Carcinomas with homozygous deletions in either MRE11A, RAD50, ATRIP or PALB2, 4 genes that are essential for mammalian cell viability, are present in the publically available TCGA database.	('ATRIP', 'Gene', '84126', (62, 67))	('Carcinomas', 'Disease', (0, 10))	('PALB2', 'Gene', (71, 76))	('PALB2', 'Gene', '79728', (71, 76))	('RAD50', 'Gene', (55, 60))	('Carcinomas', 'Phenotype', 'HP:0030731', (0, 10))	('mammalian', 'Species', '9606', (109, 118))	('MRE11A', 'Gene', (47, 53))	('deletions', 'Var', (27, 36))	('Carcinomas', 'Disease', 'MESH:D002277', (0, 10))	('ATRIP', 'Gene', (62, 67))
21078	26438152	It is unlikely transformed cells can survive without MRE11A, RAD50, ATRIP or PALB2 although significantly reduced levels may be tolerated, as evidenced by the ATR expression in Seckel syndrome and hypomorphic MRE11A and RAD50 mutations in ATLD and NBS-like disorder patients, respectively.	('patients', 'Species', '9606', (266, 274))	('PALB2', 'Gene', '79728', (77, 82))	('ATLD', 'Disease', (239, 243))	('hypomorphic', 'Disease', (197, 208))	('PALB2', 'Gene', (77, 82))	('ATRIP', 'Gene', (68, 73))	('RAD50', 'Gene', (220, 225))	('Seckel syndrome', 'Disease', (177, 192))	('ATRIP', 'Gene', '84126', (68, 73))	('mutations', 'Var', (226, 235))	('ATLD', 'Disease', 'MESH:C565779', (239, 243))	('NBS-like disorder', 'Disease', 'MESH:D049932', (248, 265))	('MRE11A', 'Gene', (209, 215))	('NBS-like disorder', 'Disease', (248, 265))	('Seckel syndrome', 'Disease', 'MESH:C537533', (177, 192))	('hypomorphic', 'Disease', 'None', (197, 208))
21080	26438152	One frame-shift mutation, one point mutation G736* (in two independent carcinomas), and one point mutation D1687H in ATR are likely to reduce ATR activity.	('G736*', 'Var', (45, 50))	('G736*', 'SUBSTITUTION', 'None', (45, 50))	('D1687H', 'Mutation', 'p.D1687H', (107, 113))	('carcinomas', 'Disease', 'MESH:D002277', (71, 81))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('ATR activity', 'MPA', (142, 154))	('carcinomas', 'Phenotype', 'HP:0030731', (71, 81))	('frame-shift mutation', 'Var', (4, 24))	('carcinomas', 'Disease', (71, 81))	('D1687H', 'Var', (107, 113))	('reduce', 'NegReg', (135, 141))
21081	26438152	In contrast, the co-amplification of ATR (located on human chromosome 3q22-q24) and TOPBP1 (located on human chromosome 3q22.1) in 11 carcinomas may increase ATR activity.	('ATR', 'Gene', (37, 40))	('increase', 'PosReg', (149, 157))	('human', 'Species', '9606', (103, 108))	('ATR activity', 'MPA', (158, 170))	('co-amplification', 'Var', (17, 33))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('human', 'Species', '9606', (53, 58))	('TOPBP1', 'Gene', (84, 90))	('carcinomas', 'Phenotype', 'HP:0030731', (134, 144))	('TOPBP1', 'Gene', '11073', (84, 90))	('carcinomas', 'Disease', (134, 144))	('carcinomas', 'Disease', 'MESH:D002277', (134, 144))
21089	26438152	Finally, ETP-46464 may inhibit a signaling pathway, in addition to that initiated by ATR kinase, that protects cells against the cytotoxic effects of ATR and Chk1 kinase inhibition.	('signaling pathway', 'Pathway', (33, 50))	('ETP-46464', 'Var', (9, 18))	('ETP-46464', 'Chemical', 'MESH:C000598436', (9, 18))	('inhibit', 'NegReg', (23, 30))
21090	26438152	In any event, our data show that ATR kinase inhibition with ETP-46464 does not phenocopy Chk1 kinase inhibition with UCN-01 and as a consequence, ATR and Chk1 inhibitors may different sensitization profiles and this should be considered in the rationale for Phase I clinical trial design with ATR kinase inhibitors.	('different', 'Reg', (174, 183))	('sensitization profiles', 'MPA', (184, 206))	('UCN-01', 'Chemical', 'MESH:C054852', (117, 123))	('ETP-46464', 'Var', (60, 69))	('ETP-46464', 'Chemical', 'MESH:C000598436', (60, 69))
21093	25537079	A Phase I Dose Escalation Trial of MAGE-A3 and HPV16 Specific Peptide Immunomodulatory Vaccines in Patients with Recurrent / Metastatic (RM) Squamous Cell Carcinoma of the Head and Neck (SCCHN) We conducted a phase I dose escalation study to evaluate the safety and immunologic response to peptide immunomodulatory vaccines GL-0810 (HPV16) and GL-0817 (MAGE-A3) in HPV16 and MAGE-A3 positive RM-SCCHN patients, respectively.	('MAGE-A3', 'Gene', (35, 42))	('MAGE-A3', 'Gene', (375, 382))	('GL-0817', 'Var', (344, 351))	('Patients', 'Species', '9606', (99, 107))	('GL-0817', 'Chemical', '-', (344, 351))	('HPV16', 'Gene', (365, 370))	('Carcinoma of the Head and Neck', 'Phenotype', 'HP:0012288', (155, 185))	('patients', 'Species', '9606', (401, 409))	('Squamous Cell Carcinoma', 'Disease', 'MESH:D002294', (141, 164))	('Carcinoma', 'Phenotype', 'HP:0030731', (155, 164))	('MAGE-A3', 'Gene', '4102', (353, 360))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (141, 164))	('GL-0810', 'Chemical', '-', (324, 331))	('MAGE-A3', 'Gene', '4102', (375, 382))	('MAGE-A3', 'Gene', '4102', (35, 42))	('HPV16', 'Species', '333760', (365, 370))	('Squamous Cell Carcinoma', 'Disease', (141, 164))	('HPV16', 'Species', '333760', (47, 52))	('HPV16', 'Species', '333760', (333, 338))	('MAGE-A3', 'Gene', (353, 360))
21094	25537079	Three dose levels (500 mug, 1000 mug, 1500 mug) of GL-0810 or GL-0817 with adjuvants Montanide (1.2ml) and GM-CSF (100mug/m2) were administered subcutaneously q2 weeks for a total of 4 vaccinations in HPV16 and MAGE-A3 positive RM-SCCHN patients, respectively.	('MAGE-A3', 'Gene', '4102', (211, 218))	('HPV16', 'Gene', (201, 206))	('HPV16', 'Species', '333760', (201, 206))	('GL-0810', 'Chemical', '-', (51, 58))	('MAGE-A3', 'Gene', (211, 218))	('GL-0817', 'Var', (62, 69))	('GM-CSF', 'Gene', (107, 113))	('GL-0817', 'Chemical', '-', (62, 69))	('RM-SCCHN', 'Disease', (228, 236))	('500 mug', 'Var', (19, 26))	('GL-0810', 'Gene', (51, 58))	('GM-CSF', 'Gene', '1437', (107, 113))	('patients', 'Species', '9606', (237, 245))	('Montanide', 'Chemical', '-', (85, 94))
21100	25537079	GL-0810 and GL-0817 were well tolerated in patients with RM-SCCHN with T cell and antibody responses observed in the majority of patients who received all 4 vaccinations.	('GL-0810', 'Chemical', '-', (0, 7))	('GL-0810', 'Var', (0, 7))	('patients', 'Species', '9606', (129, 137))	('GL-0817', 'Chemical', '-', (12, 19))	('patients', 'Species', '9606', (43, 51))	('RM-SCCHN', 'Disease', (57, 65))	('GL-0817', 'Var', (12, 19))
21111	25537079	Importantly, MAGE-A3 expression may be associated with a more aggressive course, as several studies suggest that MAGE-A3 may be a negative prognostic indicator in hematologic malignancies.	('hematologic malignancies', 'Disease', (163, 187))	('MAGE-A3', 'Gene', '4102', (113, 120))	('MAGE-A3', 'Gene', '4102', (13, 20))	('associated', 'Reg', (39, 49))	('MAGE-A3', 'Gene', (113, 120))	('expression', 'Var', (21, 31))	('MAGE-A3', 'Gene', (13, 20))	('hematologic malignancies', 'Disease', 'MESH:D019337', (163, 187))
21112	25537079	Additionally, expression has been associated with more advanced stage in squamous cell carcinoma of the larynx.	('expression', 'Var', (14, 24))	('associated', 'Reg', (34, 44))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (73, 96))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (73, 96))	('carcinoma of the larynx', 'Phenotype', 'HP:0012118', (87, 110))	('squamous cell carcinoma', 'Disease', (73, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))
21115	25537079	Furthermore, the inclusion of both HLA-I and HLA-II epitopes facilitates both cytotoxic T cell activation and stimulation of the CD4 T helper cell response, important for development of tumor-specific memory T cell and humoral immunity.	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('tumor', 'Disease', (186, 191))	('cytotoxic T cell activation', 'CPA', (78, 105))	('CD4 T helper cell response', 'CPA', (129, 155))	('inclusion', 'Var', (17, 26))	('facilitates', 'PosReg', (61, 72))	('HLA-I', 'Protein', (35, 40))
21116	25537079	Finally, the combination of Montanide ISA 51 and granulocyte macrophage colony stimulating factor (GM-CSF) is postulated to enhance antigen presentation and promote dendritic cell migration to the site of vaccination.	('Montanide', 'Chemical', '-', (28, 37))	('granulocyte macrophage colony stimulating factor', 'Gene', (49, 97))	('GM-CSF', 'Gene', (99, 105))	('GM-CSF', 'Gene', '1437', (99, 105))	('dendritic cell migration to the', 'CPA', (165, 196))	('enhance', 'PosReg', (124, 131))	('promote', 'PosReg', (157, 164))	('granulocyte macrophage colony stimulating factor', 'Gene', '1437', (49, 97))	('antigen presentation', 'MPA', (132, 152))	('combination', 'Var', (13, 24))
21122	25537079	We conducted a single center phase I dose escalation study at the University of Maryland Greenebaum Cancer Center (UMGCC), to evaluate the effect and safety of three dose levels (500mug, 1000mug, and 1500mug) of HPV16 (GL-0810) or MAGE-A3 (GL-0817) immunomodulatory peptide vaccine in combination with adjuvant montanide and GM-CSF in HPV16 or MAGE-A3 expressing RM-SCCHN patients respectively.	('GL-0817', 'Chemical', '-', (240, 247))	('GL-0810', 'Chemical', '-', (219, 226))	('MAGE-A3', 'Gene', '4102', (231, 238))	('GM-CSF', 'Gene', (325, 331))	('GM-CSF', 'Gene', '1437', (325, 331))	('MAGE-A3', 'Gene', (344, 351))	('HPV16', 'Species', '333760', (212, 217))	('HPV16', 'Species', '333760', (335, 340))	('MAGE-A3', 'Gene', (231, 238))	('500mug', 'Var', (179, 185))	('montanide', 'Chemical', '-', (311, 320))	('RM-SCCHN', 'Disease', (363, 371))	('Cancer', 'Disease', (100, 106))	('Cancer', 'Disease', 'MESH:D009369', (100, 106))	('Cancer', 'Phenotype', 'HP:0002664', (100, 106))	('MAGE-A3', 'Gene', '4102', (344, 351))	('patients', 'Species', '9606', (372, 380))
21173	25537079	HPV16 positive patients were more heavily pretreated with palliative chemotherapy compared to the MAGE-A3 positive patients.	('patients', 'Species', '9606', (115, 123))	('patients', 'Species', '9606', (15, 23))	('HPV16', 'Species', '333760', (0, 5))	('MAGE-A3', 'Gene', '4102', (98, 105))	('positive', 'Var', (6, 14))	('HPV16', 'Gene', (0, 5))	('MAGE-A3', 'Gene', (98, 105))
21190	25537079	One patient (004) did not have a T cell response but had antibody to MAGE-A3 at baseline.	('MAGE-A3', 'Gene', (69, 76))	('MAGE-A3', 'Gene', '4102', (69, 76))	('patient', 'Species', '9606', (4, 11))	('antibody', 'Var', (57, 65))
21200	25537079	Finally, since this trial was conducted in patients with existing disease, if peptide T cells trafficked to the tumor site, their actual numbers could be artificially reduced in the peripheral blood.	('patients', 'Species', '9606', (43, 51))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumor', 'Disease', (112, 117))	('reduced', 'NegReg', (167, 174))	('peptide', 'Var', (78, 85))
21204	25537079	While antibodies to HPV16 E6 have been reported in up to 35% of patients with squamous cell carcinoma of the oropharynx, even upwards of ten years before a diagnosis of cancer, baseline antibodies to MAGE-A3 are rarely found.	('MAGE-A3', 'Gene', '4102', (200, 207))	('cancer', 'Disease', (169, 175))	('patients', 'Species', '9606', (64, 72))	('MAGE-A3', 'Gene', (200, 207))	('HPV16', 'Species', '333760', (20, 25))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('HPV16', 'Gene', (20, 25))	('antibodies', 'Var', (6, 16))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (78, 101))	('reported', 'Reg', (39, 47))	('squamous cell carcinoma', 'Disease', (78, 101))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (78, 101))	('cancer', 'Disease', 'MESH:D009369', (169, 175))
21232	25537079	In conclusion, peptide immunomodulatory vaccines against HPV16 (GL-0810) and MAGE-A3 (GL-0817) in recurrent/metastatic SCCHN are well tolerated and stimulated potentially meaningful T cell and antibody responses in the majority of patients who completed all four vaccinations.	('MAGE-A3', 'Gene', '4102', (77, 84))	('stimulated', 'PosReg', (148, 158))	('HPV16', 'Species', '333760', (57, 62))	('GL-0810', 'Gene', (64, 71))	('GL-0817', 'Var', (86, 93))	('patients', 'Species', '9606', (231, 239))	('MAGE-A3', 'Gene', (77, 84))	('GL-0817', 'Chemical', '-', (86, 93))	('GL-0810', 'Chemical', '-', (64, 71))	('recurrent/metastatic SCCHN', 'Disease', (98, 124))
21255	30038504	Radiotherapy was given after 4 cycles of chemotherapy (primary lung cancer and mediastinum lymphoid region 6MV X-rays D95 PGTV 6450cGy/30F, D95 PTV 5400cGy/30F in 5 fields).	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('primary lung cancer', 'Disease', 'MESH:D008175', (55, 74))	('PTV', 'Chemical', '-', (144, 147))	('lung cancer', 'Phenotype', 'HP:0100526', (63, 74))	('D95 PTV 5400cGy/30F', 'Var', (140, 159))	('rays', 'Species', '255564', (113, 117))	('primary lung cancer', 'Disease', (55, 74))	('D95 PGTV 6450cGy/30F', 'Var', (118, 138))
21290	34006852	Small-molecule inhibition of APE1 induces apoptosis, pyroptosis, and necroptosis in non-small cell lung cancer Apurinic/apyrimidinic endonuclease 1 (APE1) plays a critical role in the base excision repair (BER) pathway, which is responsible for the excision of apurinic sites (AP sites).	('AP', 'Gene', '16870', (29, 31))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('APE1', 'Gene', (29, 33))	('APE1', 'Gene', (149, 153))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (88, 110))	('APE1', 'Gene', '328', (29, 33))	('APE1', 'Gene', '328', (149, 153))	('AP', 'Gene', '16870', (277, 279))	('lung cancer', 'Phenotype', 'HP:0100526', (99, 110))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (84, 110))	('Apurinic/apyrimidinic endonuclease 1', 'Gene', (111, 147))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('inhibition', 'Var', (15, 25))	('AP', 'Gene', '16870', (149, 151))	('Apurinic/apyrimidinic endonuclease 1', 'Gene', '328', (111, 147))
21296	34006852	Treatment with NO.0449-0145 induced DNA damage, apoptosis, pyroptosis, and necroptosis in the NSCLC cell lines A549 and NCI-H460.	('NSCLC', 'Phenotype', 'HP:0030358', (94, 99))	('NCI-H460', 'CellLine', 'CVCL:0459', (120, 128))	('pyroptosis', 'CPA', (59, 69))	('NSCLC', 'Disease', (94, 99))	('DNA damage', 'MPA', (36, 46))	('A549', 'CellLine', 'CVCL:0023', (111, 115))	('NSCLC', 'Disease', 'MESH:D002289', (94, 99))	('NO.0449-0145', 'Var', (15, 27))	('necroptosis', 'CPA', (75, 86))	('apoptosis', 'CPA', (48, 57))
21298	34006852	Moreover, NO.0449-0145 overcame both cisplatin- and erlotinib-resistance in NSCLC cell lines.	('erlotinib-resistance', 'MPA', (52, 72))	('NSCLC', 'Disease', (76, 81))	('NO.0449-0145', 'Var', (10, 22))	('NSCLC', 'Disease', 'MESH:D002289', (76, 81))	('cisplatin-', 'MPA', (37, 47))	('cisplatin', 'Chemical', 'MESH:D002945', (37, 46))	('erlotinib', 'Chemical', 'MESH:D000069347', (52, 61))	('NSCLC', 'Phenotype', 'HP:0030358', (76, 81))	('overcame', 'PosReg', (23, 31))
21310	34006852	APE1, a key enzyme in the BER system, plays a pivotal role in the repair of oxidized and alkylated genomic DNA bases by identifying and cleaving nucleotide chains at 5' apurinic (AP) sites.	('AP', 'Gene', '16870', (0, 2))	('cleaving', 'Var', (136, 144))	('AP', 'Gene', '16870', (179, 181))	('APE1', 'Gene', (0, 4))	('nucleotide chains', 'MPA', (145, 162))	('APE1', 'Gene', '328', (0, 4))
21321	34006852	The blockade of APE1 activity by inhibitors has been demonstrated to induce lethality in breast cancer susceptibility (BRCA)- and ataxia-telangiectasia mutated (ATM)-deficient cells.	('ataxia-telangiectasia mutated', 'Gene', '472', (130, 159))	('CA', 'Gene', '12310', (121, 123))	('blockade', 'NegReg', (4, 12))	('lethality', 'CPA', (76, 85))	('breast cancer', 'Disease', 'MESH:D001943', (89, 102))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('breast cancer', 'Disease', (89, 102))	('breast cancer', 'Phenotype', 'HP:0003002', (89, 102))	('ATM', 'Gene', (161, 164))	('APE1', 'Gene', (16, 20))	('telangiectasia', 'Phenotype', 'HP:0001009', (137, 151))	('APE1', 'Gene', '328', (16, 20))	('ataxia-telangiectasia mutated', 'Gene', (130, 159))	('ataxia', 'Phenotype', 'HP:0001251', (130, 136))	('activity', 'MPA', (21, 29))	('ATM', 'Gene', '472', (161, 164))	('inhibitors', 'Var', (33, 43))
21327	34006852	Low-molecular concentrations of the selective APE1 inhibitor CRT0044876 inhibited the AP endonuclease, 3'-phosphodiesterase, and 3'-phosphatase activities of APE1 and improved the sensitivity of HT1080 cells to methylmethane sulfonate (MMS) and temozolomide (TMZ).	('CRT0044876', 'Var', (61, 71))	('APE1', 'Gene', (46, 50))	('AP', 'Gene', '16870', (158, 160))	('methylmethane sulfonate', 'Chemical', 'MESH:D008741', (211, 234))	('APE1', 'Gene', (158, 162))	('AP', 'Gene', '16870', (86, 88))	('improved', 'PosReg', (167, 175))	("3'-phosphatase activities", 'MPA', (129, 154))	('HT1080', 'CellLine', 'CVCL:0317', (195, 201))	('AP', 'Gene', '16870', (46, 48))	('CRT0044876', 'Chemical', 'MESH:C503406', (61, 71))	('temozolomide', 'Chemical', 'MESH:D000077204', (245, 257))	('TMZ', 'Chemical', 'MESH:D000077204', (259, 262))	('inhibited', 'NegReg', (72, 81))	('APE1', 'Gene', '328', (46, 50))	('MMS', 'Chemical', 'MESH:D008741', (236, 239))	('sensitivity', 'MPA', (180, 191))	('APE1', 'Gene', '328', (158, 162))	("3'-phosphodiesterase", 'MPA', (103, 123))
21329	34006852	Another more widely studied APE1 inhibitor, E3330/APX3330, has been identified as a direct and highly specific inhibitor of the APE1-redox function.	('APE1', 'Gene', (28, 32))	('APE1', 'Gene', '328', (128, 132))	('APE1', 'Gene', '328', (28, 32))	('APX3330', 'Chemical', '-', (50, 57))	('E3330', 'Chemical', 'MESH:C075569', (44, 49))	('E3330/APX3330', 'Var', (44, 57))	('APE1', 'Gene', (128, 132))
21330	34006852	APX3330 impaired tumor growth and blocked the activities of transcription factors, such as NF-kappaB, AP-1, HIF-1alpha, and STAT3.	('STAT3', 'Gene', '6774', (124, 129))	('NF-kappaB', 'Gene', '4790', (91, 100))	('APX3330', 'Var', (0, 7))	('AP-1', 'Gene', '3726', (102, 106))	('STAT3', 'Gene', (124, 129))	('NF-kappaB', 'Gene', (91, 100))	('HIF-1alpha', 'Gene', (108, 118))	('AP-1', 'Gene', (102, 106))	('impaired tumor', 'Disease', (8, 22))	('APX3330', 'Chemical', '-', (0, 7))	('impaired tumor', 'Disease', 'MESH:D060825', (8, 22))	('activities', 'MPA', (46, 56))	('blocked', 'NegReg', (34, 41))	('transcription', 'MPA', (60, 73))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('HIF-1alpha', 'Gene', '3091', (108, 118))
21331	34006852	At the molecular level, APX3330 increases the formation of disulfide bonds between C65 or C93 residues in APE1, which are involved in the redox regulation of AP-1.	('APX3330', 'Chemical', '-', (24, 31))	('AP-1', 'Gene', '3726', (158, 162))	('APX3330', 'Var', (24, 31))	('formation of disulfide bonds', 'MPA', (46, 74))	('C93 residues', 'Var', (90, 102))	('AP-1', 'Gene', (158, 162))	('APE1', 'Gene', (106, 110))	('C65', 'Var', (83, 86))	('APE1', 'Gene', '328', (106, 110))	('increases', 'PosReg', (32, 41))	('disulfide', 'Chemical', 'MESH:D004220', (59, 68))
21334	34006852	Due to the functional significance of APE1 in NSCLC progression, the inhibition of APE1 represents a potential strategy for NSCLC therapy.	('APE1', 'Gene', '328', (38, 42))	('APE1', 'Gene', '328', (83, 87))	('NSCLC', 'Disease', (46, 51))	('NSCLC', 'Disease', (124, 129))	('NSCLC', 'Phenotype', 'HP:0030358', (46, 51))	('NSCLC', 'Disease', 'MESH:D002289', (46, 51))	('NSCLC', 'Disease', 'MESH:D002289', (124, 129))	('inhibition', 'Var', (69, 79))	('APE1', 'Gene', (38, 42))	('APE1', 'Gene', (83, 87))	('NSCLC', 'Phenotype', 'HP:0030358', (124, 129))
21335	34006852	The knockdown of APE1 by small interfering RNA (siRNA) inhibited X-ray irradiation-induced angiogenesis in A549 cells.	('X-ray irradiation-induced angiogenesis', 'CPA', (65, 103))	('A549', 'CellLine', 'CVCL:0023', (107, 111))	('APE1', 'Gene', (17, 21))	('APE1', 'Gene', '328', (17, 21))	('knockdown', 'Var', (4, 13))	('inhibited', 'NegReg', (55, 64))
21337	34006852	APX3330 treatment significantly enhanced the tyrosine kinase inhibitor (TKI)-induced inhibition of cell growth and enhanced apoptosis in TKI-resistant LUAD cells, whereas treatment with an APE1 DNA repair activity inhibitor, APE1 inhibitor III, showed no effect.	('LUAD', 'Phenotype', 'HP:0030078', (151, 155))	('APE1', 'Gene', '328', (189, 193))	('APX3330', 'Var', (0, 7))	('tyrosine kinase inhibitor', 'MPA', (45, 70))	('APE1', 'Gene', (225, 229))	('inhibition', 'NegReg', (85, 95))	('cell growth', 'CPA', (99, 110))	('APE1', 'Gene', '328', (225, 229))	('enhanced', 'PosReg', (115, 123))	('enhanced', 'PosReg', (32, 40))	('APX3330', 'Chemical', '-', (0, 7))	('apoptosis', 'CPA', (124, 133))	('APE1', 'Gene', (189, 193))
21339	34006852	In addition, APX3330 increased the cisplatin-induced cytotoxicity and impairment of cell migration and invasion in NSCLC cells, indicating that APX3330 might represent a promising compound for boosting cisplatin therapy.	('increased', 'PosReg', (21, 30))	('APX3330', 'Var', (13, 20))	('cisplatin', 'Chemical', 'MESH:D002945', (202, 211))	('cytotoxicity and impairment of cell migration', 'Disease', 'MESH:D064420', (53, 98))	('cisplatin', 'Chemical', 'MESH:D002945', (35, 44))	('NSCLC', 'Disease', (115, 120))	('APX3330', 'Var', (144, 151))	('NSCLC', 'Disease', 'MESH:D002289', (115, 120))	('APX3330', 'Chemical', '-', (13, 20))	('APX3330', 'Chemical', '-', (144, 151))	('NSCLC', 'Phenotype', 'HP:0030358', (115, 120))
21341	34006852	In this study, we identified NO.0449-0145 as a novel APE1 endonuclease activity inhibitor using molecular docking and biochemical analyses.	('APE1', 'Gene', '328', (53, 57))	('APE1', 'Gene', (53, 57))	('NO.0449-0145', 'Var', (29, 41))
21342	34006852	We further identified that NO.0449-0145 induces apoptosis, pyroptosis, and necroptosis in NSCLC cells.	('induces', 'Reg', (40, 47))	('NO.0449-0145', 'Var', (27, 39))	('pyroptosis', 'CPA', (59, 69))	('NSCLC', 'Disease', (90, 95))	('NSCLC', 'Disease', 'MESH:D002289', (90, 95))	('necroptosis', 'CPA', (75, 86))	('apoptosis', 'CPA', (48, 57))	('NSCLC', 'Phenotype', 'HP:0030358', (90, 95))
21343	34006852	Furthermore, NO.0449-0145 also efficiently suppressed the proliferation of cisplatin-resistant A549-DDP cells and erlotinib-resistant NCI-H1975 cells by inducing apoptosis, pyroptosis, and necroptosis.	('proliferation', 'CPA', (58, 71))	('DDP', 'Chemical', '-', (100, 103))	('necroptosis', 'CPA', (189, 200))	('erlotinib', 'Chemical', 'MESH:D000069347', (114, 123))	('A549', 'CellLine', 'CVCL:0023', (95, 99))	('inducing', 'PosReg', (153, 161))	('pyroptosis', 'CPA', (173, 183))	('apoptosis', 'CPA', (162, 171))	('cisplatin', 'Chemical', 'MESH:D002945', (75, 84))	('NCI-H1975 cells', 'CellLine', 'CVCL:1511', (134, 149))	('suppressed', 'NegReg', (43, 53))	('NO.0449-0145', 'Var', (13, 25))
21348	34006852	The colony-formation assay showed that A549 and NCI-H460 proliferation was suppressed following APE1 knockdown (Fig.	('APE1', 'Gene', '328', (96, 100))	('suppressed', 'NegReg', (75, 85))	('NCI-H460', 'CellLine', 'CVCL:0459', (48, 56))	('A549', 'CellLine', 'CVCL:0023', (39, 43))	('APE1', 'Gene', (96, 100))	('knockdown', 'Var', (101, 110))
21349	34006852	Consistently, a previous study demonstrated that the median overall survival time and overall survival of NSCLC patients with high-expression APE1 were reduced compared with those of a low APE1 expression group.	('NSCLC', 'Disease', 'MESH:D002289', (106, 111))	('APE1', 'Gene', (189, 193))	('APE1', 'Gene', '328', (189, 193))	('APE1', 'Gene', '328', (142, 146))	('reduced', 'NegReg', (152, 159))	('overall survival time', 'CPA', (60, 81))	('patients', 'Species', '9606', (112, 120))	('NSCLC', 'Phenotype', 'HP:0030358', (106, 111))	('high-expression', 'Var', (126, 141))	('NSCLC', 'Disease', (106, 111))	('APE1', 'Gene', (142, 146))
21356	34006852	In the AP site cleavage assay, fluorescence intensity increases when APE1 cleaves the AP site on the DNA substrate, and the addition of an effective inhibitor represses the rate of increase in fluorescence intensity (Supplementary Fig.	('AP', 'Gene', '16870', (69, 71))	('cleaves', 'Var', (74, 81))	('APE1', 'Gene', '328', (69, 73))	('fluorescence intensity', 'MPA', (31, 53))	('increases', 'PosReg', (54, 63))	('fluorescence intensity', 'MPA', (193, 215))	('AP', 'Gene', '16870', (7, 9))	('AP', 'Gene', '16870', (86, 88))	('APE1', 'Gene', (69, 73))
21360	34006852	Among the eight tested compounds, NO.0449-0145 showed the most effective inhibitory activity with a half-maximal inhibitory concentration (IC50) of 0.1068 microM in A549 cells (Fig.	('A549', 'CellLine', 'CVCL:0023', (165, 169))	('NO.0449-0145', 'Var', (34, 46))	('inhibitory activity', 'MPA', (73, 92))
21363	34006852	In contrast, the previously reported APE1 endonuclease inhibitor CRT0044876 showed no cytotoxic effects in either A549 or NCI-H460 cells even at high concentrations (Supplementary Fig.	('CRT0044876', 'Chemical', 'MESH:C503406', (65, 75))	('APE1', 'Gene', (37, 41))	('A549', 'CellLine', 'CVCL:0023', (114, 118))	('CRT0044876', 'Var', (65, 75))	('APE1', 'Gene', '328', (37, 41))	('NCI-H460 cells', 'CellLine', 'CVCL:0459', (122, 136))
21364	34006852	The molecular simulation assay examining the structures of APE1 and NO.0449-0145 indicated that NO.0449-0145 could directly interact with APE1 (Supplementary Fig.	('APE1', 'Gene', '328', (59, 63))	('APE1', 'Gene', (138, 142))	('NO.0449-0145', 'Var', (96, 108))	('interact', 'Interaction', (124, 132))	('APE1', 'Gene', '328', (138, 142))	('APE1', 'Gene', (59, 63))
21365	34006852	To confirm the binding of NO.0449-0145 with APE1, we performed a circular dichroism spectroscopy analysis.	('APE1', 'Gene', '328', (44, 48))	('APE1', 'Gene', (44, 48))	('binding', 'Interaction', (15, 22))	('NO.0449-0145', 'Var', (26, 38))
21366	34006852	The results showed a clear shift in the spectrum upon the addition of NO.0449-0145 to APE1, indicating a direct physical interaction between the small molecule and APE1 (Fig.	('APE1', 'Gene', (86, 90))	('APE1', 'Gene', '328', (86, 90))	('NO.0449-0145', 'Var', (70, 82))	('physical interaction', 'Interaction', (112, 132))	('shift', 'Reg', (27, 32))	('APE1', 'Gene', (164, 168))	('APE1', 'Gene', '328', (164, 168))
21367	34006852	Furthermore, we examined which APE1 sites were critical for this interaction by performing docking studies, which identified four high-potential sites for the binding of APE1 with NO.0448-0145: R4, K31, R177, and W280 (Fig.	('APE1', 'Gene', (31, 35))	('W280', 'Var', (213, 217))	('K31', 'Var', (198, 201))	('APE1', 'Gene', (170, 174))	('APE1', 'Gene', '328', (31, 35))	('R177', 'Var', (203, 207))	('binding', 'Interaction', (159, 166))	('APE1', 'Gene', '328', (170, 174))
21368	34006852	To further validate whether R4, K31, R177, and W280 were involved in the NO.0449-0145/APE1 interaction, we generated the following APE1 mutations: R4G, K31G, R177G, and W280G.	('R177G', 'Var', (158, 163))	('APE1', 'Gene', (86, 90))	('APE1', 'Gene', (131, 135))	('R177G', 'Mutation', 'p.R177G', (158, 163))	('W280G', 'Mutation', 'p.W280G', (169, 174))	('APE1', 'Gene', '328', (86, 90))	('APE1', 'Gene', '328', (131, 135))	('K31G', 'Mutation', 'p.K31G', (152, 156))	('R4G', 'Var', (147, 150))	('W280G', 'Var', (169, 174))	('K31G', 'Var', (152, 156))
21369	34006852	The AP site cleavage assay performed using these APE1 mutant proteins showed that although the AP site endonuclease activity of the mutants R4G, K31G, and W280G remained mostly intact, the inhibitory effects of NO.0449-0145 were disrupted, at least partially, for these mutants (Fig.	('K31G', 'Var', (145, 149))	('APE1', 'Gene', '328', (49, 53))	('W280G', 'Mutation', 'p.W280G', (155, 160))	('AP', 'Gene', '16870', (95, 97))	('W280G', 'Var', (155, 160))	('activity', 'MPA', (116, 124))	('AP', 'Gene', '16870', (4, 6))	('K31G', 'Mutation', 'p.K31G', (145, 149))	('R4G', 'Var', (140, 143))	('APE1', 'Gene', (49, 53))	('AP', 'Gene', '16870', (49, 51))
21370	34006852	The AP site endonuclease activity of the R177G mutant was almost completely abolished because this residue is essential for substrate binding during DNA repair by APE1.	('R177G', 'Var', (41, 46))	('APE1', 'Gene', (163, 167))	('R177G', 'Mutation', 'p.R177G', (41, 46))	('abolished', 'NegReg', (76, 85))	('APE1', 'Gene', '328', (163, 167))	('AP', 'Gene', '16870', (4, 6))	('AP', 'Gene', '16870', (163, 165))
21371	34006852	These results suggested that these residues are involved in the NO.0449-0145-related inhibition of APE1 endonuclease activity.	('activity', 'MPA', (117, 125))	('NO.0449-0145-related', 'Var', (64, 84))	('inhibition', 'NegReg', (85, 95))	('APE1', 'Gene', (99, 103))	('APE1', 'Gene', '328', (99, 103))
21373	34006852	Our results showed that NO.0449-0145 has no effect on the redox activity of APE1 (Supplementary Fig.	('APE1', 'Gene', (76, 80))	('APE1', 'Gene', '328', (76, 80))	('NO.0449-0145', 'Var', (24, 36))	('redox activity', 'MPA', (58, 72))
21375	34006852	Therefore, we detected the levels of DNA damage in both NCI-H460 and A549 cells following NO.0449-0145 treatment.	('NO.0449-0145', 'Var', (90, 102))	('A549', 'CellLine', 'CVCL:0023', (69, 73))	('NCI-H460', 'CellLine', 'CVCL:0459', (56, 64))	('DNA damage', 'MPA', (37, 47))
21378	34006852	We observed that NO.0449-0145 treatment increased the foci numbers of gamma-H2AX and 53BP1 compared with control conditions in both cell lines (Fig.	('NO.0449-0145', 'Var', (17, 29))	('53BP1', 'Gene', (85, 90))	('gamma-H2AX', 'Gene', '15270', (70, 80))	('foci numbers', 'CPA', (54, 66))	('increased', 'PosReg', (40, 49))	('gamma-H2AX', 'Gene', (70, 80))
21379	34006852	Additionally, the alkaline comet assay, which is frequently used to identify single-stranded breaks (SSBs), revealed that NO.0449-0145 treatment increased the levels of spontaneous DNA strand breaks compared with vehicle (Fig.	('NO.0449-0145', 'Var', (122, 134))	('spontaneous DNA strand breaks', 'MPA', (169, 198))	('SSBs', 'Chemical', '-', (101, 105))	('increased', 'PosReg', (145, 154))
21381	34006852	These results suggested that NO.0449-0145 treatment induced the accumulation of DNA damage in both NCI-H460 and A549 cells.	('A549', 'CellLine', 'CVCL:0023', (112, 116))	('DNA damage', 'MPA', (80, 90))	('NCI-H460', 'CellLine', 'CVCL:0459', (99, 107))	('NO.0449-0145', 'Var', (29, 41))	('accumulation', 'PosReg', (64, 76))
21382	34006852	A cell survival assay demonstrated that NO.0449-0145 could repress NCI-H460 and A549 cell survival at a very low IC50 (Fig.	('NCI-H460', 'CellLine', 'CVCL:0459', (67, 75))	('repress', 'NegReg', (59, 66))	('NCI-H460', 'CPA', (67, 75))	('A549', 'CellLine', 'CVCL:0023', (80, 84))	('NO.0449-0145', 'Var', (40, 52))
21383	34006852	These results were verified by a morphological analysis, which showed that NO.0449-0145 treatment induced cell death in both NCI-H460 and A549 cells in a dose-dependent manner (Fig.	('NCI-H460', 'CellLine', 'CVCL:0459', (125, 133))	('cell death', 'CPA', (106, 116))	('NO.0449-0145 treatment', 'Var', (75, 97))	('A549', 'CellLine', 'CVCL:0023', (138, 142))
21385	34006852	To verify whether NO.0449-0145 induced apoptosis, we performed Annexin V-fluorescein isothiocyanate (FITC)/propidium iodide (PI) staining, which is frequently used to measure apoptosis.	('propidium iodide', 'Chemical', 'MESH:D011419', (107, 123))	('Annexin V', 'Gene', '308', (63, 72))	('FITC', 'Chemical', '-', (101, 105))	('Annexin V', 'Gene', (63, 72))	('NO.0449-0145', 'Var', (18, 30))
21388	34006852	Western blot assay was used to detect whether NO.0449-0145 alters the expression levels of anti- and pro-apoptotic proteins in NCI-H460 and A549 cells.	('A549', 'CellLine', 'CVCL:0023', (140, 144))	('NO.0449-0145', 'Var', (46, 58))	('NCI-H460', 'CellLine', 'CVCL:0459', (127, 135))	('alters', 'Reg', (59, 65))
21392	34006852	The results showed that the MMP decreased in NCI-H460 cells treated with NO.0449-0145 for 24 h, whereas only a slight decrease in the MMP was detected in A549 cells treated with the same dose of NO.0449-0145 (Supplementary Fig.	('A549', 'CellLine', 'CVCL:0023', (154, 158))	('MMP', 'MPA', (28, 31))	('NCI-H460 cells', 'CellLine', 'CVCL:0459', (45, 59))	('NO.0449-0145', 'Var', (73, 85))	('decreased', 'NegReg', (32, 41))
21393	34006852	These results collectively indicated that treatment with NO.0449-0145 potently induced cell apoptosis in NSCLC cells.	('NSCLC', 'Disease', 'MESH:D002289', (105, 110))	('NSCLC', 'Phenotype', 'HP:0030358', (105, 110))	('cell apoptosis', 'CPA', (87, 101))	('induced', 'Reg', (79, 86))	('NSCLC', 'Disease', (105, 110))	('NO.0449-0145', 'Var', (57, 69))
21394	34006852	In addition, the morphological analysis revealed cytoplasmic swelling and plasma membrane bubbles in NCI-H460 and A549 cells treated with NO.0449-0145, indicating that these cells were likely to be undergoing pyroptosis or necroptosis.	('plasma membrane bubbles', 'CPA', (74, 97))	('swelling', 'Disease', (61, 69))	('swelling', 'Disease', 'MESH:D004487', (61, 69))	('NO.0449-0145', 'Var', (138, 150))	('A549', 'CellLine', 'CVCL:0023', (114, 118))	('pyroptosis or necroptosis', 'Disease', 'None', (209, 234))	('NCI-H460', 'CellLine', 'CVCL:0459', (101, 109))	('pyroptosis or necroptosis', 'Disease', (209, 234))
21396	34006852	Hoechst33342 can penetrate the cell membrane and bind DNA, and the fluorescence of apoptotic cells becomes significantly enhanced compared with that of normal cells.	('bind', 'Interaction', (49, 53))	('Hoechst33342', 'Var', (0, 12))	('enhanced', 'PosReg', (121, 129))	('DNA', 'Protein', (54, 57))	('Hoechst33342', 'Chemical', 'MESH:C017807', (0, 12))	('fluorescence', 'MPA', (67, 79))
21400	34006852	Furthermore, the protein levels of caspase-4 and cleaved gasdermin D (GSDMD), which play key roles in cell pyroptosis increased following NO.0449-0145 treatment for 12 h (Fig.	('gasdermin D', 'Gene', (57, 68))	('NO.0449-0145', 'Var', (138, 150))	('increased', 'PosReg', (118, 127))	('caspase-4', 'Gene', (35, 44))	('caspase-4', 'Gene', '837', (35, 44))	('gasdermin D', 'Gene', '79792', (57, 68))	('cleaved', 'MPA', (49, 56))	('protein levels', 'MPA', (17, 31))
21402	34006852	Next, we assessed the antitumor effects of NO.0449-0145 in vivo, using nude mice to perform a xenograft study.	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('nude mice', 'Species', '10090', (71, 80))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('NO.0449-0145', 'Var', (43, 55))
21405	34006852	Our data showed that treatment with NO.0449-0145 suppressed tumor growth in a dose-dependent manner, with both the final tumor volumes and weights decreasing following NO.0449-0145 treatment (Fig.	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('NO.0449-0145', 'Var', (168, 180))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Disease', (121, 126))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('decreasing', 'NegReg', (147, 157))	('NO.0449-0145', 'Var', (36, 48))	('suppressed', 'NegReg', (49, 59))	('tumor', 'Disease', (60, 65))	('weights', 'CPA', (139, 146))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
21407	34006852	These results suggested that NO.0449-0145 could suppress xenograft tumor growth in vivo.	('suppress', 'NegReg', (48, 56))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Disease', (67, 72))	('NO.0449-0145', 'Var', (29, 41))
21408	34006852	To investigate the in vivo mechanism of antitumor action for NO.0449-0145, an immunohistochemistry/immunofluorescence assay was conducted using NCI-H460 tumor samples collected from the various treatment groups.	('NO.0449-0145', 'Var', (61, 73))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('NCI-H460', 'CellLine', 'CVCL:0459', (144, 152))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumor', 'Disease', (44, 49))
21409	34006852	5e, f, NO.0449-0145 treatment increased the positive staining for gamma-H2AX and 53BP1 in tumor tissues and impaired the expression of Ki67, which is a known marker of cell proliferation.	('Ki67', 'Gene', (135, 139))	('positive staining', 'MPA', (44, 61))	('NO.0449-0145', 'Var', (7, 19))	('tumor', 'Disease', (90, 95))	('expression', 'MPA', (121, 131))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('gamma-H2AX', 'Gene', '15270', (66, 76))	('53BP1', 'Gene', (81, 86))	('Ki67', 'Gene', '17345', (135, 139))	('increased', 'PosReg', (30, 39))	('gamma-H2AX', 'Gene', (66, 76))	('impaired', 'NegReg', (108, 116))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
21411	34006852	Additionally, the immunohistochemistry assay identified the upregulation of caspase-4, GSDMD, and phospho-RIPK3 expression in xenograft tumor tissues following NO.0449-0145 treatment (Fig.	('upregulation', 'PosReg', (60, 72))	('caspase-4', 'Gene', (76, 85))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('caspase-4', 'Gene', '837', (76, 85))	('NO.0449-0145', 'Var', (160, 172))	('tumor', 'Disease', (136, 141))	('expression', 'MPA', (112, 122))
21412	34006852	Taken together, these findings suggested that NO.0449-0145 treatment suppressed xenograft growth in nude mice by aggravating DNA damage, inhibiting cell proliferation, and inducing cell death in tumor cells.	('nude mice', 'Species', '10090', (100, 109))	('tumor', 'Disease', (195, 200))	('DNA damage', 'MPA', (125, 135))	('inducing', 'Reg', (172, 180))	('inhibiting', 'NegReg', (137, 147))	('cell death', 'CPA', (181, 191))	('xenograft growth', 'CPA', (80, 96))	('NO.0449-0145', 'Var', (46, 58))	('cell proliferation', 'CPA', (148, 166))	('suppressed', 'NegReg', (69, 79))	('aggravating', 'PosReg', (113, 124))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))
21417	34006852	A cell survival assay indicated that NO.0449-0145 treatment markedly induced cell death in A549-DDP cells (Fig.	('DDP', 'Chemical', '-', (96, 99))	('cell death', 'CPA', (77, 87))	('A549', 'CellLine', 'CVCL:0023', (91, 95))	('NO.0449-0145', 'Var', (37, 49))
21419	34006852	The Hoechst33342/PI staining indicated that plasma membrane permeabilization increased in a dose-dependent manner following NO.0449-0145 treatment (Fig.	('Hoechst33342', 'Chemical', 'MESH:C017807', (4, 16))	('NO.0449-0145', 'Var', (124, 136))	('plasma membrane permeabilization', 'MPA', (44, 76))	('increased', 'PosReg', (77, 86))
21420	34006852	These results indicated that NO.0449-0145 treatment induced cell apoptosis, pyroptosis, and necroptosis in A549-DDP cells.	('DDP', 'Chemical', '-', (112, 115))	('pyroptosis', 'CPA', (76, 86))	('A549', 'CellLine', 'CVCL:0023', (107, 111))	('cell apoptosis', 'CPA', (60, 74))	('NO.0449-0145', 'Var', (29, 41))	('necroptosis', 'CPA', (92, 103))
21422	34006852	A cell survival assay, using various combinations of NO.0449-0145 treatment and different doses of cisplatin, indicated that treatment with NO.0449-0145 was able to overcome DDP-resistance in A549-DDP cells (Fig.	('cisplatin', 'Chemical', 'MESH:D002945', (99, 108))	('NO.0449-0145', 'Var', (140, 152))	('DDP-resistance', 'MPA', (174, 188))	('overcome', 'PosReg', (165, 173))	('DDP', 'Chemical', '-', (197, 200))	('DDP', 'Chemical', '-', (174, 177))	('A549', 'CellLine', 'CVCL:0023', (192, 196))
21428	34006852	Recently, APX3330 became the first APE1-redox inhibitor to complete Phase I clinical trials for cancer treatment.	('APX3330', 'Chemical', '-', (10, 17))	('APE1', 'Gene', (35, 39))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('APE1', 'Gene', '328', (35, 39))	('APX3330', 'Var', (10, 17))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Disease', (96, 102))
21431	34006852	Molecular simulation analysis and circular dichroism spectroscopy analysis confirmed the binding between NO.0449-0145 and APE1.	('binding', 'Interaction', (89, 96))	('NO.0449-0145', 'Var', (105, 117))	('APE1', 'Gene', '328', (122, 126))	('APE1', 'Gene', (122, 126))
21432	34006852	The cell survival assay identified the repressive effects of NO.0449-0145 on the proliferation of various NSCLC cell lines, and a xenograft study further confirmed that NO.0449-0145 repressed NSCLC cells both in vitro and in vivo.	('NO.0449-0145', 'Var', (61, 73))	('NSCLC', 'Disease', (192, 197))	('NSCLC', 'Disease', 'MESH:D002289', (106, 111))	('NSCLC', 'Disease', 'MESH:D002289', (192, 197))	('NSCLC', 'Phenotype', 'HP:0030358', (106, 111))	('NSCLC', 'Phenotype', 'HP:0030358', (192, 197))	('NO.0449-0145', 'Var', (169, 181))	('proliferation', 'CPA', (81, 94))	('NSCLC', 'Disease', (106, 111))
21433	34006852	As expected, the inhibition of APE1 by NO.0449-0145 induced the accumulation of DNA damage in both A549 and NCI-H460 cells, which was consistent with the hypothesis that cancer cells would accumulate DNA damage when treated with inhibitors that target the DNA repair pathway.	('APE1', 'Gene', (31, 35))	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('A549', 'CellLine', 'CVCL:0023', (99, 103))	('accumulate', 'PosReg', (189, 199))	('DNA damage', 'MPA', (80, 90))	('DNA damage', 'MPA', (200, 210))	('cancer', 'Disease', (170, 176))	('APE1', 'Gene', '328', (31, 35))	('NCI-H460 cells', 'CellLine', 'CVCL:0459', (108, 122))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('inhibition', 'NegReg', (17, 27))	('NO.0449-0145', 'Var', (39, 51))	('accumulation', 'PosReg', (64, 76))
21434	34006852	In contrast, the accumulation of gamma-H2AX and recruitment of 53BP1 were reduced in cells treated with the APE1-redox inhibitor APX3330 or with the previously reported APE1 endonuclease inhibitor CRT0044876, which demonstrated no cytotoxic effects in NSCLC cells, even at high concentrations.	('APX3330', 'Var', (129, 136))	('recruitment', 'MPA', (48, 59))	('APE1', 'Gene', '328', (108, 112))	('gamma-H2AX', 'Gene', (33, 43))	('53BP1', 'Gene', (63, 68))	('accumulation', 'MPA', (17, 29))	('APE1', 'Gene', (169, 173))	('NSCLC', 'Phenotype', 'HP:0030358', (252, 257))	('CRT0044876', 'Chemical', 'MESH:C503406', (197, 207))	('APE1', 'Gene', '328', (169, 173))	('APX3330', 'Chemical', '-', (129, 136))	('gamma-H2AX', 'Gene', '15270', (33, 43))	('NSCLC', 'Disease', (252, 257))	('reduced', 'NegReg', (74, 81))	('APE1', 'Gene', (108, 112))	('NSCLC', 'Disease', 'MESH:D002289', (252, 257))
21435	34006852	The alkaline comet assay confirmed the accumulation of SSBs and double-stranded breaks in A549 and NCI-H460 cells following treatments with NO.0449-0145, resulting in the accumulation of DNA fragmentation.	('DNA fragmentation', 'MPA', (187, 204))	('accumulation', 'PosReg', (171, 183))	('SSBs', 'Protein', (55, 59))	('NO.0449-0145', 'Var', (140, 152))	('double-stranded breaks', 'Var', (64, 86))	('A549', 'CellLine', 'CVCL:0023', (90, 94))	('SSBs', 'Chemical', '-', (55, 59))	('NCI-H460 cells', 'CellLine', 'CVCL:0459', (99, 113))	('accumulation', 'PosReg', (39, 51))
21436	34006852	The knockdown of APE1 by RNA interference has been shown to induce apoptosis in human cancer cell lines.	('induce', 'PosReg', (60, 66))	('apoptosis', 'CPA', (67, 76))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('APE1', 'Gene', '328', (17, 21))	('APE1', 'Gene', (17, 21))	('human', 'Species', '9606', (80, 85))	('RNA interference', 'MPA', (25, 41))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('knockdown', 'Var', (4, 13))	('cancer', 'Disease', (86, 92))
21437	34006852	Our data indicated that NO.0449-0145 treatment induced cell apoptosis in both A549 and NCI-H460 cells, consistent with the results reported for other APE1 inhibitors, such as APX3330, which induced apoptosis in multiple tumor cell lines.	('NCI-H460 cells', 'CellLine', 'CVCL:0459', (87, 101))	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('NO.0449-0145', 'Var', (24, 36))	('multiple tumor', 'Disease', (211, 225))	('multiple tumor', 'Disease', 'MESH:D009369', (211, 225))	('APE1', 'Gene', (150, 154))	('A549', 'CellLine', 'CVCL:0023', (78, 82))	('APX3330', 'Chemical', '-', (175, 182))	('cell apoptosis', 'CPA', (55, 69))	('APE1', 'Gene', '328', (150, 154))
21438	34006852	Intriguingly, we also observed some NO.0449-0145 treated cells characterized by cytoplasmic swelling and plasma membrane bubbles, followed by plasma membrane rupture and the subsequent loss of intracellular contents.	('swelling', 'Disease', (92, 100))	('plasma membrane rupture', 'CPA', (142, 165))	('NO.0449-0145', 'Var', (36, 48))	('plasma membrane bubbles', 'CPA', (105, 128))	('loss', 'NegReg', (185, 189))	('swelling', 'Disease', 'MESH:D004487', (92, 100))
21442	34006852	Our western blot analysis showed the increased activation of MLKL and RIPK3, as well as GSDMD-N and caspase-4, in both A549 and NCI-H460 cells treated with NO.0449-0145.	('MLKL', 'Gene', (61, 65))	('RIPK3', 'Gene', (70, 75))	('NCI-H460 cells', 'CellLine', 'CVCL:0459', (128, 142))	('activation', 'PosReg', (47, 57))	('caspase-4', 'Gene', (100, 109))	('A549', 'CellLine', 'CVCL:0023', (119, 123))	('caspase-4', 'Gene', '837', (100, 109))	('NO.0449-0145', 'Var', (156, 168))	('GSDMD-N', 'Gene', (88, 95))
21444	34006852	These data demonstrated that NO.0449-0145 treatment was able to induce pyroptosis and necroptosis in both NSCLC cell lines.	('NO.0449-0145 treatment', 'Var', (29, 51))	('induce', 'PosReg', (64, 70))	('NSCLC', 'Disease', 'MESH:D002289', (106, 111))	('necroptosis', 'CPA', (86, 97))	('NSCLC', 'Phenotype', 'HP:0030358', (106, 111))	('pyroptosis', 'CPA', (71, 81))	('NSCLC', 'Disease', (106, 111))
21450	34006852	A previous study showed that the co-incubation cells with APX3330 and cisplatin significantly decreased cell viability compared with cisplatin alone.	('APX3330', 'Var', (58, 65))	('cisplatin', 'Chemical', 'MESH:D002945', (70, 79))	('cell viability', 'CPA', (104, 118))	('decreased', 'NegReg', (94, 103))	('APX3330', 'Chemical', '-', (58, 65))	('cisplatin', 'Chemical', 'MESH:D002945', (133, 142))
21451	34006852	Our study showed that NO.0449-0145 treatment alone was able to overcome cisplatin resistance in A549-DDP cell and sensitize A549-DDP cells to cisplatin treatment, implying that the inhibition of APE1 by a small-molecule inhibitor may be used to overcome chemotherapeutic resistance in lung cancer treatment.	('NO.0449-0145', 'Var', (22, 34))	('lung cancer', 'Disease', 'MESH:D008175', (285, 296))	('cisplatin', 'Chemical', 'MESH:D002945', (72, 81))	('cisplatin', 'Chemical', 'MESH:D002945', (142, 151))	('A549', 'CellLine', 'CVCL:0023', (96, 100))	('A549', 'CellLine', 'CVCL:0023', (124, 128))	('overcome', 'Reg', (63, 71))	('cancer', 'Phenotype', 'HP:0002664', (290, 296))	('lung cancer', 'Phenotype', 'HP:0100526', (285, 296))	('cisplatin resistance', 'MPA', (72, 92))	('lung cancer', 'Disease', (285, 296))	('DDP', 'Chemical', '-', (101, 104))	('APE1', 'Gene', (195, 199))	('DDP', 'Chemical', '-', (129, 132))	('APE1', 'Gene', '328', (195, 199))
21454	34006852	NSCLC cases associated with specific genomic mutations have benefited from targeted therapies.	('NSCLC', 'Disease', 'MESH:D002289', (0, 5))	('mutations', 'Var', (45, 54))	('NSCLC', 'Disease', (0, 5))	('NSCLC', 'Phenotype', 'HP:0030358', (0, 5))
21455	34006852	Approximately 30-50% of NSCLC cases of east Asian descent harbor EGFR mutations, compared with 10-20% of cases among those who are not of east Asian descent.	('NSCLC', 'Disease', (24, 29))	('mutations', 'Var', (70, 79))	('EGFR', 'Gene', '1956', (65, 69))	('NSCLC', 'Disease', 'MESH:D002289', (24, 29))	('EGFR', 'Gene', (65, 69))	('NSCLC', 'Phenotype', 'HP:0030358', (24, 29))
21458	34006852	However, acquired resistance develops in nearly all patients who receive EGFR-targeted TKI treatments through mechanisms that include the development of secondary EGFR mutations, pathway bypass or alternative activation processes, or histological transformations.	('EGFR', 'Gene', '1956', (73, 77))	('EGFR', 'Gene', '1956', (163, 167))	('EGFR', 'Gene', (73, 77))	('EGFR', 'Gene', (163, 167))	('mutations', 'Var', (168, 177))	('patients', 'Species', '9606', (52, 60))	('acquired resistance', 'Disease', (9, 28))
21461	34006852	We found that NO.0449-0145 treatment induced DNA damage and cytotoxicity in erlotinib-resistant NCI-H1975-ER cells, resulting in cell death (Supplementary Fig.	('erlotinib', 'Chemical', 'MESH:D000069347', (76, 85))	('cytotoxicity', 'Disease', (60, 72))	('cell death', 'CPA', (129, 139))	('NO.0449-0145', 'Var', (14, 26))	('cytotoxicity', 'Disease', 'MESH:D064420', (60, 72))	('NCI-H1975-ER', 'CellLine', 'CVCL:1511', (96, 108))	('DNA damage', 'MPA', (45, 55))
21467	34006852	Our findings suggested that NO.0449-0145 has great potential for the treatment of NSCLC and other tumors.	('tumors', 'Disease', (98, 104))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('NSCLC', 'Phenotype', 'HP:0030358', (82, 87))	('NO.0449-0145', 'Var', (28, 40))	('tumors', 'Disease', 'MESH:D009369', (98, 104))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('NSCLC', 'Disease', (82, 87))	('NSCLC', 'Disease', 'MESH:D002289', (82, 87))
21482	34006852	APE1 was incubated with NO.0449-0145 in reaction buffer (1 mM MgCl2, 50 mM Tris-HCl [pH 8.0], 50 mM NaCl, and 2 mM DTT) at 37  C for 30 min and spectra were scanned at a wavelength of 180-280 nm using 0.001 cm path length quartz cell on circular dichroism (Chirascan, Applied Photophysics).	('MgCl2', 'Chemical', 'MESH:D015636', (62, 67))	('NO.0449-0145', 'Var', (24, 36))	('DTT', 'Chemical', 'MESH:D004229', (115, 118))	('Tris-HCl', 'Chemical', '-', (75, 83))	('NaCl', 'Chemical', 'MESH:D012965', (100, 104))	('APE1', 'Gene', (0, 4))	('APE1', 'Gene', '328', (0, 4))
21484	34006852	The secondary structure for APE1 with NO.0449-0145 or DMSO was analyzed using GraphPad Prism.	('APE1', 'Gene', (28, 32))	('APE1', 'Gene', '328', (28, 32))	('NO.0449-0145', 'Var', (38, 50))	('DMSO', 'Chemical', 'MESH:D004121', (54, 58))
21535	33714956	Previous studies have suggested that iron metabolism dysfunction caused by FPN1 mutations or polymorphisms is involved in hemochromatosis, inflammation, and cancer.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('FPN1', 'Gene', (75, 79))	('inflammation', 'Disease', 'MESH:D007249', (139, 151))	('mutations', 'Var', (80, 89))	('hemochromatosis', 'Disease', (122, 137))	('inflammation', 'Disease', (139, 151))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('involved', 'Reg', (110, 118))	('polymorphisms', 'Var', (93, 106))	('cancer', 'Disease', (157, 163))	('hemochromatosis', 'Disease', 'MESH:D006432', (122, 137))	('iron metabolism dysfunction', 'Disease', (37, 64))	('iron metabolism dysfunction', 'Disease', 'MESH:D019189', (37, 64))
21538	33714956	Downregulated FPN1 might facilitate cancer cell proliferation by reducing iron efflux.	('Downregulated', 'Var', (0, 13))	('facilitate', 'PosReg', (25, 35))	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('reducing', 'NegReg', (65, 73))	('FPN1', 'Gene', (14, 18))	('cancer', 'Disease', (36, 42))	('iron efflux', 'MPA', (74, 85))	('iron', 'Chemical', 'MESH:D007501', (74, 78))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))
21591	33714956	However, there was no significant association between low/high FPN1 expression and LUAD patient prognosis in the B cell, type 1 T helper cell, or type 2 T helper cell cohorts (Figure 10A, 10G, 10H).	('FPN1', 'Gene', (63, 67))	('patient', 'Species', '9606', (88, 95))	('LUAD patient', 'Disease', (83, 95))	('low/high', 'Var', (54, 62))
21595	33714956	Excess free radicals will promote gene mutations that may accelerate tumor initiation.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor', 'Disease', (69, 74))	('accelerate', 'PosReg', (58, 68))	('mutations', 'Var', (39, 48))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('free radicals', 'Chemical', 'MESH:D005609', (7, 20))
21598	33714956	Many kinds of iron chelators, including deferasirox (DFX), deferoxamine (DFO) and Dp44mT, have been developed as anticancer drugs that target iron metabolism.	('Dp44mT', 'Var', (82, 88))	('deferoxamine', 'Chemical', 'MESH:D003676', (59, 71))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('iron', 'Chemical', 'MESH:D007501', (14, 18))	('Dp44mT', 'Chemical', 'MESH:C539263', (82, 88))	('iron', 'Chemical', 'MESH:D007501', (142, 146))	('DFX', 'Chemical', 'MESH:D000077588', (53, 56))	('DFO', 'Chemical', 'MESH:D003676', (73, 76))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('deferasirox', 'Chemical', 'MESH:D000077588', (40, 51))	('cancer', 'Disease', (117, 123))
21601	33714956	For example, sulfasalazine can cause ferroptosis in cancer cells by inhibiting xCT.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('inhibiting', 'NegReg', (68, 78))	('sulfasalazine', 'Var', (13, 26))	('ferroptosis', 'Disease', (37, 48))	('xCT', 'Gene', (79, 82))	('sulfasalazine', 'Chemical', 'MESH:D012460', (13, 26))	('xCT', 'Gene', '23657', (79, 82))	('cause', 'Reg', (31, 36))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))
21603	33714956	In addition, Dp44mT could significantly reverse drug resistance to etoposide in breast cancer cells and vinblastine in epidermal carcinoma cells.	('vinblastine', 'Chemical', 'MESH:D014747', (104, 115))	('carcinoma', 'Disease', 'MESH:D009369', (129, 138))	('Dp44mT', 'Var', (13, 19))	('drug resistance to etoposide', 'MPA', (48, 76))	('Dp44mT', 'Chemical', 'MESH:C539263', (13, 19))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('etoposide', 'Chemical', 'MESH:D005047', (67, 76))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('drug resistance', 'Phenotype', 'HP:0020174', (48, 63))	('breast cancer', 'Disease', 'MESH:D001943', (80, 93))	('carcinoma', 'Disease', (129, 138))	('breast cancer', 'Disease', (80, 93))	('reverse', 'NegReg', (40, 47))	('breast cancer', 'Phenotype', 'HP:0003002', (80, 93))
21618	33714956	Ferroportin disease, also known as type IV hereditary hemochromatosis (HH), is primarily caused by missense mutations in FPN1.	('missense mutations', 'Var', (99, 117))	('type IV hereditary hemochromatosis', 'Disease', (35, 69))	('HH', 'Disease', 'MESH:D006432', (71, 73))	('caused by', 'Reg', (89, 98))	('FPN1', 'Gene', (121, 125))	('Ferroportin disease', 'Disease', (0, 19))	('type IV hereditary hemochromatosis', 'Disease', 'MESH:D006432', (35, 69))
21620	33714956	Currently, numerous FPN1 heterozygous mutations have been identified to be associated with type IV HH.	('associated', 'Reg', (75, 85))	('HH', 'Disease', 'MESH:D006432', (99, 101))	('FPN1', 'Gene', (20, 24))	('heterozygous mutations', 'Var', (25, 47))
21621	33714956	In addition, due to the increased need for phenotypic and genetic testing, rare SLC40A1 variants have been found by chance in patients with secondary causes of hyperferritinemia.	('hyperferritinemia', 'Phenotype', 'HP:0003281', (160, 177))	('SLC40A1', 'Gene', '30061', (80, 87))	('hyperferritinemia', 'Disease', 'MESH:C538137', (160, 177))	('hyperferritinemia', 'Disease', (160, 177))	('patients', 'Species', '9606', (126, 134))	('variants', 'Var', (88, 96))	('SLC40A1', 'Gene', (80, 87))	('found', 'Reg', (107, 112))
21623	33714956	In addition, FPN1 overexpression reduces the growth of xenografted breast cancer cells in vivo.	('breast cancer', 'Phenotype', 'HP:0003002', (67, 80))	('FPN1', 'Gene', (13, 17))	('overexpression', 'Var', (18, 32))	('breast cancer', 'Disease', 'MESH:D001943', (67, 80))	('reduces', 'NegReg', (33, 40))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('breast cancer', 'Disease', (67, 80))
21632	33714956	Although FPN1 profoundly influences cellular iron levels and is essential for systemic iron trafficking, the biological effects of abnormal FPN1 expression on lung cancer development and the connection between FPN1 and immune infiltration remain largely unexplored.	('iron', 'Chemical', 'MESH:D007501', (45, 49))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('lung cancer', 'Disease', 'MESH:D008175', (159, 170))	('iron', 'Chemical', 'MESH:D007501', (87, 91))	('influences', 'Reg', (25, 35))	('FPN1', 'Gene', (140, 144))	('abnormal', 'Var', (131, 139))	('lung cancer', 'Disease', (159, 170))	('lung cancer', 'Phenotype', 'HP:0100526', (159, 170))	('cellular iron levels', 'MPA', (36, 56))
21641	33714956	Recent studies have demonstrated that cancer progression and recurrence are promoted not only by genetic alterations but also by the TME.	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('genetic alterations', 'Var', (97, 116))	('recurrence', 'CPA', (61, 71))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('cancer', 'Disease', (38, 44))	('promoted', 'PosReg', (76, 84))
21644	33714956	PD-1 and CTLA-4 inhibitors exhibit promising anticancer effects in multiple cancers, including NSCLC.	('NSCLC', 'Disease', 'MESH:D002289', (95, 100))	('cancers', 'Phenotype', 'HP:0002664', (76, 83))	('inhibitors', 'Var', (16, 26))	('multiple cancers', 'Disease', (67, 83))	('PD-1', 'Gene', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('CTLA-4', 'Gene', (9, 15))	('NSCLC', 'Disease', (95, 100))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('PD-1', 'Gene', '9825', (0, 4))	('multiple cancers', 'Disease', 'MESH:D009369', (67, 83))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('CTLA-4', 'Gene', '1493', (9, 15))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('cancer', 'Disease', (49, 55))
21651	33714956	In addition, the loss of FPN1 obviously increases the secretion of well-known cytokines, including IL-6 and TNF-alpha, in mouse macrophages.	('mouse', 'Species', '10090', (122, 127))	('secretion of', 'MPA', (54, 66))	('FPN1', 'Gene', (25, 29))	('TNF-alpha', 'Gene', (108, 117))	('IL-6', 'Gene', (99, 103))	('IL-6', 'Gene', '16193', (99, 103))	('increases', 'PosReg', (40, 49))	('loss', 'Var', (17, 21))	('TNF-alpha', 'Gene', '21926', (108, 117))
21700	32824777	Besides tobacco and alcohol consumption, infection with high-risk types of human papillomavirus (HPV), in particular HPV 16, is a risk factor for oropharyngeal squamous cell carcinoma (OPSCC).	('risk', 'Reg', (130, 134))	('HPV', 'Species', '10566', (97, 100))	('HPV', 'Species', '10566', (117, 120))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (160, 183))	('human papillomavirus', 'Species', '10566', (75, 95))	('HPV', 'Var', (117, 120))	('infection', 'Disease', (41, 50))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (160, 183))	('infection', 'Disease', 'MESH:D007239', (41, 50))	('HPV 16', 'Gene', (117, 123))	('alcohol', 'Chemical', 'MESH:D000438', (20, 27))	('squamous cell carcinoma', 'Disease', (160, 183))	('carcinoma', 'Phenotype', 'HP:0030731', (174, 183))	('oropharyngeal squamous cell carcinoma', 'Phenotype', 'HP:0012182', (146, 183))	('HPV 16', 'Species', '333760', (117, 123))	('tobacco', 'Species', '4097', (8, 15))
21880	32824777	Increasing cc-3 expression of fractional irradiated HNSCC13 compared to the mock-treated correlate.	('Increasing', 'PosReg', (0, 10))	('HNSCC13', 'Gene', (52, 59))	('cc-3', 'Gene', '6358', (11, 15))	('fractional irradiated', 'Var', (30, 51))	('cc-3', 'Gene', (11, 15))	('expression', 'MPA', (16, 26))
22039	29435282	A number of studies have reported that alteration in the expression level of clock genes is correlated with several pathological conditions, including cancer.	('alteration', 'Var', (39, 49))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('correlated', 'Reg', (92, 102))	('clock genes', 'Gene', (77, 88))	('expression level', 'MPA', (57, 73))	('cancer', 'Disease', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (151, 157))
22043	29435282	The circadian clock gene period (PER)1 has been associated with oral cancer pathogenesis and it is suggested that changes in the expression of PER1 may exhibit an important role in the development, invasion, and metastasis of oral squamous cell carcinoma.	('metastasis of oral squamous cell carcinoma', 'Disease', (212, 254))	('invasion', 'CPA', (198, 206))	('oral cancer', 'Disease', (64, 75))	('associated', 'Reg', (48, 58))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('PER1', 'Gene', (143, 147))	('carcinoma', 'Phenotype', 'HP:0030731', (245, 254))	('PER', 'Gene', (33, 36))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (231, 254))	('metastasis of oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (212, 254))	('oral cancer', 'Disease', 'MESH:D009062', (64, 75))	('changes', 'Var', (114, 121))
22049	29435282	There are studies showing the effect of dysfunctional circadian machinery in humans, for example mutations, non-standard expression, and translocation of clock genes, which has led to different cancer types including breast, colorectal, gastric, kidney, lung, prostate, pancreatic, and oral cancer.	('mutations', 'Var', (97, 106))	('colorectal', 'Disease', (225, 235))	('cancer', 'Disease', 'MESH:D009369', (291, 297))	('led to', 'Reg', (177, 183))	('kidney', 'Disease', (246, 252))	('dysfunctional', 'Disease', 'MESH:D006331', (40, 53))	('cancer', 'Disease', 'MESH:D009369', (194, 200))	('lung', 'Disease', (254, 258))	('humans', 'Species', '9606', (77, 83))	('translocation', 'Var', (137, 150))	('breast', 'Disease', (217, 223))	('gastric', 'Disease', (237, 244))	('cancer', 'Disease', (291, 297))	('prostate', 'Disease', (260, 268))	('pancreatic', 'Disease', 'MESH:D010195', (270, 280))	('dysfunctional', 'Disease', (40, 53))	('cancer', 'Phenotype', 'HP:0002664', (291, 297))	('cancer', 'Disease', (194, 200))	('pancreatic', 'Disease', (270, 280))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('oral cancer', 'Disease', 'MESH:D009062', (286, 297))	('oral cancer', 'Disease', (286, 297))
22068	29435282	The disruption of the circadian clock has not only been shown to increase the risk of disease, but also to affect the prognosis and treatment outcome of patients.	('increase', 'PosReg', (65, 73))	('affect', 'Reg', (107, 113))	('patients', 'Species', '9606', (153, 161))	('disruption', 'Var', (4, 14))
22070	29435282	Although these findings suggest that the circadian clock undergoes significant changes in human tumorigenesis, the direct links between aberrant circadian clock gene expression and human malignancies, including oral and head and neck carcinomas, remain largely elusive.	('human', 'Species', '9606', (181, 186))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('aberrant', 'Var', (136, 144))	('oral', 'Disease', (211, 215))	('neck carcinomas', 'Disease', (229, 244))	('tumor', 'Disease', (96, 101))	('malignancies', 'Disease', 'MESH:D009369', (187, 199))	('human', 'Species', '9606', (90, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (234, 243))	('neck carcinomas', 'Disease', 'MESH:D006258', (229, 244))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('changes', 'Reg', (79, 86))	('malignancies', 'Disease', (187, 199))	('carcinomas', 'Phenotype', 'HP:0030731', (234, 244))
22096	29435282	The main risk factors are tobacco use and alcohol consumption with combined multiplicative effects possibly leading to DNA damage or mutations.	('tobacco', 'Species', '4097', (26, 33))	('DNA damage', 'Disease', (119, 129))	('leading', 'Reg', (108, 115))	('alcohol', 'Chemical', 'MESH:D000438', (42, 49))	('mutations', 'Var', (133, 142))
22097	29435282	Human papilloma virus infection and genetic polymorphism can also be mentioned as risk factors.	('papilloma virus infection', 'Disease', (6, 31))	('genetic polymorphism', 'Var', (36, 56))	('papilloma virus infection', 'Disease', 'MESH:D010212', (6, 31))	('papilloma', 'Phenotype', 'HP:0012740', (6, 15))
22104	29435282	Studies have confirmed that cyclinbeta1 and p53 are targets of human clock genes where loss of BMAL1 reduces the expression of p53 along with PER1, PER2, and PER3.	('expression', 'MPA', (113, 123))	('loss', 'Var', (87, 91))	('human', 'Species', '9606', (63, 68))	('BMAL1', 'Gene', (95, 100))	('BMAL1', 'Gene', '406', (95, 100))	('PER3', 'Gene', (158, 162))	('reduces', 'NegReg', (101, 108))	('cyclin', 'Gene', '18538', (28, 34))	('cyclin', 'Gene', (28, 34))	('PER3', 'Gene', '8863', (158, 162))	('p53', 'Gene', (127, 130))
22105	29435282	It has also been hypothesized that p53 is involved in regulating PER2 expression by blocking the CLOCK/BMAL1 complex from binding to a promotor region.	('binding', 'Interaction', (122, 129))	('expression', 'MPA', (70, 80))	('BMAL1', 'Gene', (103, 108))	('blocking', 'NegReg', (84, 92))	('BMAL1', 'Gene', '406', (103, 108))	('p53', 'Var', (35, 38))	('PER2', 'Gene', (65, 69))
22121	29435282	PER1 gene knockdown in OSCC cell line SCC15 led to immediate abnormal behavior in terms of cell growth, proliferation, apoptosis resistance, migration and invasion in vitro.	('migration', 'CPA', (141, 150))	('apoptosis resistance', 'CPA', (119, 139))	('SCC15', 'CellLine', 'CVCL:1681', (38, 43))	('cell growth', 'CPA', (91, 102))	('PER1', 'Gene', (0, 4))	('invasion', 'CPA', (155, 163))	('knockdown', 'Var', (10, 19))
22122	29435282	Mice injected with these modified cells subcutaneously experienced enhanced tumor development.	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('modified', 'Var', (25, 33))	('Mice', 'Species', '10090', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('enhanced', 'PosReg', (67, 75))
22124	29435282	Suppression of PER1 leads to disturbance in the cell cycle and inhibits DNA damage control, which again makes clock genes and PER1 a key research subject in the field of carcinogenesis.	('carcinogenesis', 'Disease', (170, 184))	('cell cycle', 'CPA', (48, 58))	('inhibits', 'NegReg', (63, 71))	('Suppression', 'Var', (0, 11))	('carcinogenesis', 'Disease', 'MESH:D063646', (170, 184))	('disturbance', 'Reg', (29, 40))	('DNA damage control', 'MPA', (72, 90))	('PER1', 'Gene', (15, 19))
22129	29435282	This suggests that PER1 not only regulates the downstream genes, but it also plays a role in the synergy of the rest of the clock genes in the circadian machinery in SCC15 cell lines.	('regulates', 'Reg', (33, 42))	('SCC15', 'CellLine', 'CVCL:1681', (166, 171))	('PER1', 'Var', (19, 23))	('plays', 'Reg', (77, 82))
22285	33527860	The sensitivity of ROSE in determining adequacy was highest in the CT-FNA group, followed by the TBB group and the EBUS-TBNA group (Figure 1).	('TBB', 'Chemical', '-', (97, 100))	('sensitivity', 'MPA', (4, 15))	('CT-FNA', 'Var', (67, 73))	('determining adequacy', 'MPA', (27, 47))
22356	33228719	Heat mediated antigen retrieval was performed in a pressure chamber (Pascal; Dako, Carpinteria, CA) with pH 6.0 citrate buffer (Dako) for CD68, CD163 and VEGF-C, but pH 9.0 citrate buffer (Dako) for VEGF-A.	('Dako', 'Chemical', '-', (77, 81))	('CD163', 'Var', (144, 149))	('citrate', 'Chemical', 'MESH:D019343', (173, 180))	('Dako', 'Chemical', '-', (189, 193))	('Dako', 'Chemical', '-', (128, 132))	('citrate', 'Chemical', 'MESH:D019343', (112, 119))	('CD68', 'Var', (138, 142))
22381	33228719	A total of 174 (49.9%) tumors were classified as samples highly expressing CD68 (CD68High), CD163 (CD163High), and VEGF-A (VEGF-AHigh), while 175 (50.1%) tumors were determined to highly express VEGF-C (VEGF-CHigh) (Table 1).	('tumors', 'Disease', (154, 160))	('tumors', 'Disease', (23, 29))	('CD163High', 'Gene', '9332', (99, 108))	('tumors', 'Disease', 'MESH:D009369', (154, 160))	('tumors', 'Disease', 'MESH:D009369', (23, 29))	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('CD68High', 'Gene', '968', (81, 89))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('VEGF-A', 'Gene', (115, 121))	('CD68', 'Gene', (75, 79))	('CD163High', 'Gene', (99, 108))	('CD68High', 'Gene', (81, 89))	('VEGF-C', 'Gene', (195, 201))	('CD163', 'Var', (92, 97))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))
22388	33228719	In the squamous cell carcinoma subgroup, VEGF-CHigh was associated with less differentiation (p = 0.029) (Additional file 1: Table S4).	('squamous cell carcinoma', 'Disease', (7, 30))	('VEGF-CHigh', 'Var', (41, 51))	('less', 'NegReg', (72, 76))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (7, 30))	('carcinoma', 'Phenotype', 'HP:0030731', (21, 30))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (7, 30))
22397	33228719	NSCLC patients with high CD68 expression displayed significantly better overall survival (OS) (log-rank p = 0.023) than those with low CD68 expression (Fig.	('NSCLC', 'Disease', 'MESH:D002289', (0, 5))	('NSCLC', 'Disease', (0, 5))	('overall survival', 'MPA', (72, 88))	('NSCLC', 'Phenotype', 'HP:0030358', (0, 5))	('high', 'Var', (20, 24))	('better', 'PosReg', (65, 71))	('patients', 'Species', '9606', (6, 14))	('CD68', 'Gene', (25, 29))
22399	33228719	In subgroup analyses, adenocarcinoma NSCLC patients with high CD68 expression (log-rank p = 0.034) showed a significant survival advantage (Additional file 2: Fig.	('carcinoma', 'Phenotype', 'HP:0030731', (27, 36))	('CD68', 'Gene', (62, 66))	('NSCLC', 'Phenotype', 'HP:0030358', (37, 42))	('high', 'Var', (57, 61))	('patients', 'Species', '9606', (43, 51))	('adenocarcinoma NSCLC', 'Disease', 'MESH:D000230', (22, 42))	('adenocarcinoma NSCLC', 'Disease', (22, 42))	('advantage', 'PosReg', (129, 138))
22403	33228719	In pairwise comparisons, patients with M2 ratiohighVEGF-Ahigh had significantly worse survival than those with M2 ratiolowVEGF-Ahigh (p = 0.004), while there were no significant survival differences between M2 ratiolowVEGF-Alow (p = 0.728) and M2 ratiohighVEGF-Alow (p = 0.714).	('M2 ratiohighVEGF-Ahigh', 'Var', (39, 61))	('patients', 'Species', '9606', (25, 33))	('worse', 'NegReg', (80, 85))	('survival', 'MPA', (86, 94))
22404	33228719	Kaplan-Meier plots revealed that patients with M2 ratiohighVEGF-Ahigh had a tendency of worse overall survival, but this trend was not significant (log-rank p = 0.056, Fig.	('overall survival', 'MPA', (94, 110))	('worse', 'NegReg', (88, 93))	('M2 ratiohighVEGF-Ahigh', 'Var', (47, 69))	('patients', 'Species', '9606', (33, 41))
22406	33228719	In pairwise comparisons, patient survival in the M2 ratiohighVEGF-Chigh group was significantly worse than that for the M2 ratiolowVEGF-Clow (log-rank p = 0.047) and M2 ratiolowVEGF-Chigh (log-rank p = 0.008) groups.	('patient survival', 'CPA', (25, 41))	('worse', 'NegReg', (96, 101))	('M2 ratiohighVEGF-Chigh', 'Var', (49, 71))	('patient', 'Species', '9606', (25, 32))
22407	33228719	Patients with M2 ratiohighVEGF-Chigh had the worst overall survival compared to patients with M2 ratiolowVEGF-Chigh (OS rate, 62.6% vs. 80.6%, log-rank p = 0.033, Fig.	('patients', 'Species', '9606', (80, 88))	('worst', 'NegReg', (45, 50))	('M2 ratiohighVEGF-Chigh', 'Var', (14, 36))	('Patients', 'Species', '9606', (0, 8))	('overall survival', 'MPA', (51, 67))
22408	33228719	In subgroup analyses, adenocarcinoma NSCLC patients with M2 ratiohighVEGF-Ahigh had shorter survival time than those with M2 ratiolowVEGF-Ahigh (OS rate, 72.7% vs. 93.3%, log-rank p = 0.027) (Additional file 2: Fig.	('carcinoma', 'Phenotype', 'HP:0030731', (27, 36))	('NSCLC', 'Phenotype', 'HP:0030358', (37, 42))	('patients', 'Species', '9606', (43, 51))	('M2 ratiohighVEGF-Ahigh', 'Var', (57, 79))	('survival', 'MPA', (92, 100))	('adenocarcinoma NSCLC', 'Disease', (22, 42))	('shorter', 'NegReg', (84, 91))	('adenocarcinoma NSCLC', 'Disease', 'MESH:D000230', (22, 42))
22409	33228719	Similarly, the survival times of patients with M2 ratiohighVEGF-Chigh were worse than those of patients with M2 ratiolowVEGF-Chigh (OS rate, 69.2% vs. 91.5%, log-rank p = 0.042) (Additional file 2: Fig.	('M2 ratiohighVEGF-Chigh', 'Var', (47, 69))	('patients', 'Species', '9606', (33, 41))	('patients', 'Species', '9606', (95, 103))	('survival times', 'CPA', (15, 29))	('worse', 'NegReg', (75, 80))
22410	33228719	Similarly, there also significant difference of survival rate between groups M2 ratiohighVEGF-Chigh and with M2 ratiolowVEGF-Chigh (pairwise comparison, p = 0.004) expression in adenocarcinomas.	('M2 ratiohighVEGF-Chigh', 'Var', (77, 99))	('difference', 'Reg', (34, 44))	('adenocarcinomas', 'Disease', 'MESH:D000230', (178, 193))	('adenocarcinomas', 'Disease', (178, 193))	('carcinoma', 'Phenotype', 'HP:0030731', (183, 192))	('survival rate', 'CPA', (48, 61))	('carcinomas', 'Phenotype', 'HP:0030731', (183, 193))	('M2 ratiolowVEGF-Chigh', 'Var', (109, 130))
22434	33228719	In this study, we confirmed that patients with high M1 macrophage expression had significantly better overall survival compared to patients with low infiltration of M1 macrophages, while patients with high M2 ratio (CD163+/CD68+) had significantly worse overall survival compared to that of patients with low M2 ratio.	('patients', 'Species', '9606', (131, 139))	('patients', 'Species', '9606', (187, 195))	('patients', 'Species', '9606', (33, 41))	('CD163+/CD68+', 'Var', (216, 228))	('patients', 'Species', '9606', (291, 299))	('overall survival', 'MPA', (102, 118))	('high M1', 'Var', (47, 54))	('better', 'PosReg', (95, 101))
22436	33228719	Notably, the combination of high M2 ratio and high VEGF-C expression was an independent prognostic factor for poor overall survival in NSCLC patients.	('high', 'Var', (46, 50))	('VEGF-C', 'Gene', (51, 57))	('NSCLC', 'Disease', (135, 140))	('NSCLC', 'Disease', 'MESH:D002289', (135, 140))	('M2 ratio', 'MPA', (33, 41))	('high', 'Var', (28, 32))	('patients', 'Species', '9606', (141, 149))	('NSCLC', 'Phenotype', 'HP:0030358', (135, 140))
22449	33228719	High M2 ratio (CD163+/CD68+) was associated with poor prognosis in NSCLC, but there was no meaningful clinical value from the M2 macrophage assessment using only CD163.	('CD163+/CD68+', 'Var', (15, 27))	('NSCLC', 'Disease', 'MESH:D002289', (67, 72))	('NSCLC', 'Disease', (67, 72))	('NSCLC', 'Phenotype', 'HP:0030358', (67, 72))
22450	33228719	Notably, high M2 ratio was an independent prognostic factor for poor overall survival in NSCLC patients.	('NSCLC', 'Disease', 'MESH:D002289', (89, 94))	('M2 ratio', 'MPA', (14, 22))	('overall', 'MPA', (69, 76))	('patients', 'Species', '9606', (95, 103))	('NSCLC', 'Phenotype', 'HP:0030358', (89, 94))	('NSCLC', 'Disease', (89, 94))	('high', 'Var', (9, 13))
22454	33228719	VEGF-A is an endogenous agonist for VEGFR-2 and its signaling is targeted through neutralizing circulating VEGF-A using bevacizumab, or inhibiting downstream signaling pathways.	('inhibiting', 'NegReg', (136, 146))	('VEGFR-2', 'Gene', (36, 43))	('neutralizing', 'Var', (82, 94))	('VEGF-A', 'Gene', (107, 113))	('bevacizumab', 'Chemical', 'MESH:D000068258', (120, 131))	('downstream signaling pathways', 'Pathway', (147, 176))	('VEGFR-2', 'Gene', '3791', (36, 43))
22469	33228719	demonstrated that inhibition of macrophage infiltration in tumors delays the angiogenic switch and malignant transition in a mouse model of breast cancer.	('angiogenic switch', 'CPA', (77, 94))	('breast cancer', 'Disease', 'MESH:D001943', (140, 153))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('breast cancer', 'Disease', (140, 153))	('breast cancer', 'Phenotype', 'HP:0003002', (140, 153))	('mouse', 'Species', '10090', (125, 130))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('tumors delays', 'Disease', (59, 72))	('tumors delays', 'Disease', 'MESH:D009369', (59, 72))	('inhibition', 'Var', (18, 28))	('malignant transition', 'CPA', (99, 119))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
22481	33228719	High M2 ratio (CD163+/CD68+) in the tumor stroma is a potential marker for predicting malignant clinical outcomes in NSCLC patients, and consideration of M2 ratio and VEGF-C expression in combination may enhance the accuracy of prognostic prediction.	('tumor stroma', 'Disease', (36, 48))	('CD163+/CD68+', 'Var', (15, 27))	('NSCLC', 'Disease', (117, 122))	('patients', 'Species', '9606', (123, 131))	('NSCLC', 'Disease', 'MESH:D002289', (117, 122))	('NSCLC', 'Phenotype', 'HP:0030358', (117, 122))	('enhance', 'PosReg', (204, 211))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumor stroma', 'Disease', 'MESH:D009369', (36, 48))
22497	28537888	Dysfunctional regulation of miRNAs in several ailments has been associated with a range of diseases, including cancers.	('cancers', 'Disease', 'MESH:D009369', (111, 118))	('associated', 'Reg', (64, 74))	('cancers', 'Phenotype', 'HP:0002664', (111, 118))	('Dysfunctional regulation', 'Var', (0, 24))	('cancers', 'Disease', (111, 118))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('miRNAs', 'Gene', (28, 34))
22499	28537888	Previous studies have identified various miRNAs in NSCLC patients, including Let-7a, miR-145-3p, miR-30d, miR-499, miR-374a, miR-1254, miR-574-5p, miR-126, miR-210, miR-21 and so on.	('miR-21', 'Gene', '406991', (156, 162))	('miR-210', 'Gene', '406992', (156, 163))	('miR-126', 'Gene', (147, 154))	('miR-21', 'Gene', (165, 171))	('miR-210', 'Gene', (156, 163))	('miR-30d', 'Gene', (97, 104))	('miR-374a', 'Gene', '442919', (115, 123))	('miR-21', 'Gene', (156, 162))	('miR-126', 'Gene', '406913', (147, 154))	('miR-499', 'Gene', '574501', (106, 113))	('NSCLC', 'Disease', 'MESH:D002289', (51, 56))	('miR-30d', 'Gene', '407033', (97, 104))	('miR-145-3p', 'Var', (85, 95))	('miR-374a', 'Gene', (115, 123))	('miR-499', 'Gene', (106, 113))	('NSCLC', 'Phenotype', 'HP:0030358', (51, 56))	('patients', 'Species', '9606', (57, 65))	('NSCLC', 'Disease', (51, 56))	('miR-1254', 'Gene', '100302273', (125, 133))	('miR-574-5p', 'Var', (135, 145))	('Let-7a', 'Var', (77, 83))	('miR-21', 'Gene', '406991', (165, 171))	('miR-1254', 'Gene', (125, 133))
22501	28537888	Recent reports have suggested that down-regulation of miR-138, miR-218, miR-34c-3p were found in NSCLC.	('miR-138', 'Var', (54, 61))	('NSCLC', 'Disease', (97, 102))	('miR-34c-3p', 'Var', (72, 82))	('miR-21', 'Gene', (63, 69))	('NSCLC', 'Disease', 'MESH:D002289', (97, 102))	('NSCLC', 'Phenotype', 'HP:0030358', (97, 102))	('down-regulation', 'NegReg', (35, 50))	('miR-21', 'Gene', '406991', (63, 69))
22522	28537888	The result showed that there were 7 common predicted miRNAs, including miR-455-3p, miR-183-5p, miR-29c-3p, miR-29b-3p, miR-29a-3p miR-124-3p, and miR-493-5p.	('miR-493', 'Gene', (146, 153))	('miR-455-3p', 'Var', (71, 81))	('miR-29b-3p', 'Var', (107, 117))	('miR-493', 'Gene', '574450', (146, 153))	('miR-183', 'Gene', '406959', (83, 90))	('miR-29c-3p', 'Var', (95, 105))	('miR-124-3p', 'Gene', '406909', (130, 140))	('miR-124-3p', 'Gene', (130, 140))	('miR-183', 'Gene', (83, 90))
22523	28537888	Of these 7 genes, miR-455-3p, miR-183-5p and 3 miR-29 family member have been reported and validated to target ITGB1.	('miR-183', 'Gene', '406959', (30, 37))	('miR-183', 'Gene', (30, 37))	('ITGB1', 'Gene', (111, 116))	('ITGB1', 'Gene', '3688', (111, 116))	('miR-455-3p', 'Var', (18, 28))
22548	28537888	However, cellular growth assay revealed that following siITGB1 transfection, the growth rate of A549 cells was significantly inhibited when compared to the control group.	('ITGB1', 'Gene', (57, 62))	('A549', 'CellLine', 'CVCL:0023', (96, 100))	('transfection', 'Var', (63, 75))	('ITGB1', 'Gene', '3688', (57, 62))	('inhibited', 'NegReg', (125, 134))	('growth rate of A549 cells', 'CPA', (81, 106))
22550	28537888	Taken together, these results suggested that miR-493-5p downregulation promoted the proliferation of NSCLC cells and knockdown of ITGB1 inhibited NSCLC cell proliferation in vitro.	('ITGB1', 'Gene', (130, 135))	('miR-493', 'Gene', '574450', (45, 52))	('promoted', 'PosReg', (71, 79))	('inhibited', 'NegReg', (136, 145))	('NSCLC', 'Disease', (101, 106))	('NSCLC', 'Disease', (146, 151))	('downregulation', 'Var', (56, 70))	('ITGB1', 'Gene', '3688', (130, 135))	('NSCLC', 'Disease', 'MESH:D002289', (101, 106))	('NSCLC', 'Disease', 'MESH:D002289', (146, 151))	('proliferation', 'CPA', (84, 97))	('NSCLC', 'Phenotype', 'HP:0030358', (146, 151))	('miR-493', 'Gene', (45, 52))	('knockdown', 'Var', (117, 126))	('NSCLC', 'Phenotype', 'HP:0030358', (101, 106))
22559	28537888	The results showed that NSCLC patients with high ITGB1 expression and low miR-493-5p levels had significantly decreased OS (P < 0.001) (Figure 5G), which suggested that ITGB1 and miR-493-5p might have potential prognostic value and could be useful as tumor biomarkers for the diagnosis of NSCLC patients.	('NSCLC', 'Disease', (24, 29))	('NSCLC', 'Phenotype', 'HP:0030358', (289, 294))	('tumor', 'Disease', (251, 256))	('NSCLC', 'Phenotype', 'HP:0030358', (24, 29))	('ITGB1', 'Gene', (169, 174))	('tumor', 'Disease', 'MESH:D009369', (251, 256))	('ITGB1', 'Gene', (49, 54))	('patients', 'Species', '9606', (30, 38))	('tumor', 'Phenotype', 'HP:0002664', (251, 256))	('ITGB1', 'Gene', '3688', (169, 174))	('high', 'Var', (44, 48))	('decreased', 'NegReg', (110, 119))	('expression', 'MPA', (55, 65))	('miR-493', 'Gene', (179, 186))	('NSCLC', 'Disease', 'MESH:D002289', (289, 294))	('ITGB1', 'Gene', '3688', (49, 54))	('miR-493', 'Gene', '574450', (179, 186))	('low', 'NegReg', (70, 73))	('NSCLC', 'Disease', 'MESH:D002289', (24, 29))	('patients', 'Species', '9606', (295, 303))	('NSCLC', 'Disease', (289, 294))	('miR-493', 'Gene', (74, 81))	('miR-493', 'Gene', '574450', (74, 81))
22565	28537888	examined the miRNA expression profiles for lung cancers to investigate miRNA's involvement in lung carcinogenesis and identified that high hsa-mir-155 and low hsa-let-7a-2 expression correlated with poor survival by univariate analysis as well as multivariate analysis for hsa-mir-155, indicating that miRNA expression profiles are diagnostic and prognostic markers of lung cancer.	('hsa-mir-155', 'Gene', (139, 150))	('hsa-mir-155', 'Gene', (273, 284))	('lung cancers', 'Disease', 'MESH:D008175', (43, 55))	('lung cancer', 'Disease', 'MESH:D008175', (369, 380))	('hsa-let-7a-2', 'Gene', '406882', (159, 171))	('lung cancer', 'Disease', 'MESH:D008175', (43, 54))	('lung cancers', 'Disease', (43, 55))	('lung cancer', 'Phenotype', 'HP:0100526', (369, 380))	('cancer', 'Phenotype', 'HP:0002664', (374, 380))	('lung cancer', 'Phenotype', 'HP:0100526', (43, 54))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('high', 'Var', (134, 138))	('lung carcinogenesis', 'Disease', (94, 113))	('lung cancers', 'Phenotype', 'HP:0100526', (43, 55))	('hsa-let-7a-2', 'Gene', (159, 171))	('cancers', 'Phenotype', 'HP:0002664', (48, 55))	('low', 'NegReg', (155, 158))	('lung carcinogenesis', 'Disease', 'MESH:D063646', (94, 113))	('poor', 'NegReg', (199, 203))	('lung cancer', 'Disease', (369, 380))	('hsa-mir-155', 'Gene', '406947', (139, 150))	('hsa-mir-155', 'Gene', '406947', (273, 284))	('expression', 'MPA', (172, 182))
22590	28537888	The expression levels of mRNAs and miRNAs were investigated from GEO database (GSE41445, GSE67061-GPL6480, GSE61741, and GSE24709) (www.ncbi.nlm.nih.gov/geo/).	('GSE61741', 'Var', (107, 115))	('GPL6480', 'Chemical', '-', (98, 105))	('GSE41445', 'Var', (79, 87))	('GSE67061-GPL6480', 'Var', (89, 105))	('GSE24709', 'Var', (121, 129))
22592	28537888	The human ITGB1 3'-UTR oligonucleotides containing the wild-type (Wt) or mutant (Mut) miR-493-5p binding site were sub-cloned into the XhoI and NotI sites of the pGL3 luciferase reporter plasmid vector (Promega, Madison, WI).	('miR-493', 'Gene', '574450', (86, 93))	('human', 'Species', '9606', (4, 9))	('pGL3', 'Gene', (162, 166))	('ITGB1', 'Gene', (10, 15))	('oligonucleotides', 'Chemical', 'MESH:D009841', (23, 39))	('pGL3', 'Gene', '6391', (162, 166))	('mutant', 'Var', (73, 79))	('ITGB1', 'Gene', '3688', (10, 15))	('miR-493', 'Gene', (86, 93))
22597	28537888	Total protein from HeLa cells on the condition of ITGB1 3'-UTR oligonucleotides containing the wild-type (Wt) or mutant (Mut) miR-493-5p mimics or inhibitor was extracted using cell lysis buffer to detect the expression levels of ITGB1 3'-UTR oligonucleotides containing the wild-type (Wt) or mutant (Mut) miR-493-5p and a reported target molecule FUT4.	('ITGB1', 'Gene', (230, 235))	('miR-493', 'Gene', (306, 313))	('oligonucleotides', 'Chemical', 'MESH:D009841', (243, 259))	('ITGB1', 'Gene', '3688', (50, 55))	('HeLa', 'CellLine', 'CVCL:0030', (19, 23))	('FUT4', 'Gene', (348, 352))	('miR-493', 'Gene', '574450', (306, 313))	('ITGB1', 'Gene', '3688', (230, 235))	('mutant', 'Var', (293, 299))	('miR-493', 'Gene', (126, 133))	('miR-493', 'Gene', '574450', (126, 133))	('oligonucleotides', 'Chemical', 'MESH:D009841', (63, 79))	('FUT4', 'Gene', '2526', (348, 352))	('mutant', 'Var', (113, 119))	('ITGB1', 'Gene', (50, 55))
22609	27281608	High LTBP2 protein level is an independent prognostic marker in HNSCC.	('LTBP2', 'Gene', (5, 10))	('High', 'Var', (0, 4))	('LTBP2', 'Gene', '4053', (5, 10))	('HNSCC', 'Disease', (64, 69))	('HNSCC', 'Phenotype', 'HP:0012288', (64, 69))
22611	27281608	Detection of LTBP2 expression could be a useful prognosis marker and targeting LTBP2 may represent a novel strategy for cancer treatment through regulating activities of TGFbeta.	('TGFbeta', 'Gene', (170, 177))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('TGFbeta', 'Gene', '7040', (170, 177))	('LTBP2', 'Gene', (13, 18))	('activities', 'MPA', (156, 166))	('targeting', 'Var', (69, 78))	('regulating', 'Reg', (145, 155))	('LTBP2', 'Gene', (79, 84))	('LTBP2', 'Gene', '4053', (13, 18))	('LTBP2', 'Gene', '4053', (79, 84))
22629	27281608	LTBP2 mRNA expression level was significantly higher in cancerous tissues (0.2430.02049) than in adjacent normal tissues (0.13110.01190) (P < 0.001) (Figure 1).	('0.2430.02049', 'Var', (75, 87))	('higher', 'PosReg', (46, 52))	('mRNA expression level', 'MPA', (6, 27))	('cancerous', 'Disease', 'MESH:D009369', (56, 65))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('LTBP2', 'Gene', (0, 5))	('LTBP2', 'Gene', '4053', (0, 5))	('cancerous', 'Disease', (56, 65))
22633	27281608	High LTBP2 protein expression was significantly associated with the presence of lymph node metastasis (P = 0.004) and higher stage (pTNM stage III-IV, P = 0.002) (Table 2).	('expression', 'MPA', (19, 29))	('High', 'Var', (0, 4))	('LTBP2', 'Gene', (5, 10))	('protein', 'Protein', (11, 18))	('associated', 'Reg', (48, 58))	('LTBP2', 'Gene', '4053', (5, 10))	('lymph node metastasis', 'Disease', (80, 101))	('lymph node metastasis', 'Disease', 'MESH:D009362', (80, 101))
22635	27281608	In univariate analysis, high LTBP2 expression (HR, 4.602, 95% CI: 2.686-7.883; P < 0.001), older age at diagnosis (HR, 1.657, 95% CI: 1.044-2.630; P = 0.032), T stage (HR, 2.047, 95% CI: 1.227-3.414; P = 0.006), histopathological grade (HR, 1.583, 95% CI: 1.129-2.218; P = 0.008), lymph node metastasis (HR, 5.399, 95% CI: 3.508-8.309; P < 0.001), and pTNM stage (HR, 4.842, 95% CI: 3.097-7.571; P < 0.001) were all significantly associated with overall survival.	('overall', 'MPA', (446, 453))	('LTBP2', 'Gene', (29, 34))	('lymph node metastasis', 'Disease', (281, 302))	('associated', 'Reg', (430, 440))	('LTBP2', 'Gene', '4053', (29, 34))	('high', 'Var', (24, 28))	('lymph node metastasis', 'Disease', 'MESH:D009362', (281, 302))
22636	27281608	In multivariate analysis, high LTBP2 expression (HR, 3.904, 95% CI: 2.253-6.766; P < 0.001) and presence of lymph node metastasis (HR, 2.701, 95% CI: 1.243-5.867; P = 0.012) remain significantly associated with poor overall survival (Table 3).	('LTBP2', 'Gene', '4053', (31, 36))	('poor', 'NegReg', (211, 215))	('high', 'Var', (26, 30))	('lymph node metastasis', 'Disease', (108, 129))	('lymph node metastasis', 'Disease', 'MESH:D009362', (108, 129))	('expression', 'MPA', (37, 47))	('overall survival', 'MPA', (216, 232))	('LTBP2', 'Gene', (31, 36))
22640	27281608	Finally, high LTBP2 protein expression is an independent prognostic marker for poor overall survival in HNSCC patients.	('LTBP2', 'Gene', '4053', (14, 19))	('HNSCC', 'Disease', (104, 109))	('protein', 'Protein', (20, 27))	('HNSCC', 'Phenotype', 'HP:0012288', (104, 109))	('LTBP2', 'Gene', (14, 19))	('overall', 'MPA', (84, 91))	('patients', 'Species', '9606', (110, 118))	('high', 'Var', (9, 13))
22647	27281608	It has been proposed that LTBPs can influence the structure of tumor stroma independent of TGFbeta's activities.	('TGFbeta', 'Gene', (91, 98))	('influence', 'Reg', (36, 45))	('tumor stroma', 'Disease', 'MESH:D009369', (63, 75))	('tumor stroma', 'Disease', (63, 75))	('TGFbeta', 'Gene', '7040', (91, 98))	('structure', 'MPA', (50, 59))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('LTBPs', 'Var', (26, 31))
22652	27281608	High LTBP2 protein expression predicts poor survival in serous ovarian carcinoma.	('High', 'Var', (0, 4))	('LTBP2', 'Gene', (5, 10))	('protein', 'Protein', (11, 18))	('LTBP2', 'Gene', '4053', (5, 10))	('poor', 'NegReg', (39, 43))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('serous ovarian carcinoma', 'Disease', (56, 80))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (63, 80))	('serous ovarian carcinoma', 'Disease', 'MESH:D010051', (56, 80))
22653	27281608	Mechanistic studies demonstrated that LTBP2 knockdown inhibited tumor proliferation and migration, and MAPK, PI3K-AKT, RTK and p53 signaling pathways were involved in cervical carcinogenesis.	('inhibited', 'NegReg', (54, 63))	('MAPK', 'Pathway', (103, 107))	('tumor', 'Disease', (64, 69))	('p53', 'Gene', '7157', (127, 130))	('PI3K-AKT', 'Pathway', (109, 117))	('involved', 'Reg', (155, 163))	('carcinogenesis', 'Disease', 'MESH:D063646', (176, 190))	('knockdown', 'Var', (44, 53))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('LTBP2', 'Gene', (38, 43))	('carcinogenesis', 'Disease', (176, 190))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('LTBP2', 'Gene', '4053', (38, 43))	('p53', 'Gene', (127, 130))
22655	27281608	On the other hand, LTBP2 was epigenetically silenced in several cancer types: LTBP2 is methylated in chronic lymphocytic leukemia (CLL); in melanoma, LTBP2 is epigenetically silenced to promote TGFbeta mediated cell invasion; in NPC, LTBP2 is methylated to inactivate NF-kappaB p65 protein mediated oncogenic signaling pathway.	('promote', 'PosReg', (186, 193))	('LTBP2', 'Gene', (19, 24))	('LTBP2', 'Gene', '4053', (78, 83))	('LTBP2', 'Gene', '4053', (150, 155))	('melanoma', 'Disease', 'MESH:D008545', (140, 148))	('epigenetically', 'Var', (159, 173))	('cancer', 'Disease', (64, 70))	('CLL', 'Phenotype', 'HP:0005550', (131, 134))	('inactivate', 'NegReg', (257, 267))	('LTBP2', 'Gene', '4053', (234, 239))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('LTBP2', 'Gene', (78, 83))	('LTBP2', 'Gene', '4053', (19, 24))	('LTBP2', 'Gene', (150, 155))	('chronic lymphocytic leukemia', 'Disease', 'MESH:D015451', (101, 129))	('melanoma', 'Phenotype', 'HP:0002861', (140, 148))	('melanoma', 'Disease', (140, 148))	('p65', 'Gene', (278, 281))	('chronic lymphocytic leukemia', 'Disease', (101, 129))	('TGFbeta', 'Gene', (194, 201))	('NPC', 'Phenotype', 'HP:0100630', (229, 232))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (101, 129))	('leukemia', 'Phenotype', 'HP:0001909', (121, 129))	('TGFbeta', 'Gene', '7040', (194, 201))	('LTBP2', 'Gene', (234, 239))	('p65', 'Gene', '5970', (278, 281))
22695	31402939	In total, four experiments were selected for inclusion in the present study: GSE3141, GSE37745, GSE30219 and GSE50081.	('GSE50081', 'Var', (109, 117))	('GSE3141', 'Var', (77, 84))	('GSE3141', 'Chemical', '-', (77, 84))	('GSE30219', 'Var', (96, 104))	('GSE37745', 'Var', (86, 94))
22702	31402939	lambda0g(t) is an unknown baseline hazard function for the AC group while lambda0g(t)exp(beta1g) is the baseline hazard function for the SCC group.	('SCC', 'Gene', '6317', (137, 140))	('lambda0g(t)exp', 'Var', (74, 88))	('SCC', 'Gene', (137, 140))
22703	31402939	The two groups have different baseline hazard functions, with beta1g representing the difference between the SCC and AC groups in terms of log baseline hazard function.	('SCC', 'Gene', (109, 112))	('SCC', 'Gene', '6317', (109, 112))	('beta1g', 'Var', (62, 68))
22705	31402939	Both beta2g and beta3g are the parameters of interest, with beta2g representing the change in log hazard rate associated with 1-unit increase in the actual expression value of gene g among AC and beta3g representing the additional change in log hazard rate associated with the SCC subtype.	('SCC', 'Gene', (277, 280))	('SCC', 'Gene', '6317', (277, 280))	('beta2g', 'Var', (60, 66))	('increase', 'PosReg', (133, 141))	('expression', 'MPA', (156, 166))
22717	31402939	In the present study, the data of three microarray experiments (GSE37745, GSE30219 and GSE50081) were used as the training sets, and the GSE3141 dataset and RNA-seq data from the TCGA database were used as the test sets to validate the performance of the resulting prognostic gene signatures.	('GSE3141', 'Chemical', '-', (137, 144))	('GSE50081', 'Var', (87, 95))	('GSE37745', 'Var', (64, 72))	('GSE30219', 'Var', (74, 82))
22730	31402939	Mutations in TP53 are associated with a several types of of human cancer.	('TP53', 'Gene', (13, 17))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('human', 'Species', '9606', (60, 65))	('Mutations', 'Var', (0, 9))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('TP53', 'Gene', '7157', (13, 17))	('associated', 'Reg', (22, 32))	('cancer', 'Disease', (66, 72))
22735	31402939	For example, EGFR was revealed to be involved in the development and progression of lung cancer and VEGF gene polymorphism serves a role in the development of lung cancer.	('lung cancer', 'Disease', (84, 95))	('lung cancer', 'Phenotype', 'HP:0100526', (84, 95))	('polymorphism', 'Var', (110, 122))	('lung cancer', 'Disease', 'MESH:D008175', (159, 170))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('VEGF', 'Gene', '7422', (100, 104))	('lung cancer', 'Disease', 'MESH:D008175', (84, 95))	('lung cancer', 'Disease', (159, 170))	('lung cancer', 'Phenotype', 'HP:0100526', (159, 170))	('EGFR', 'Gene', '1956', (13, 17))	('VEGF', 'Gene', (100, 104))	('EGFR', 'Gene', (13, 17))	('involved', 'Reg', (37, 45))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
22790	33867351	DEFB1 and GNRH1 were primarily affected by deep deletion, while the CTLA-4, DKK1 and EDNRB were frequently amplified.	('GNRH1', 'Gene', '2796', (10, 15))	('EDNRB', 'Gene', (85, 90))	('affected', 'Reg', (31, 39))	('DEFB1', 'Gene', '1672', (0, 5))	('deep deletion', 'Var', (43, 56))	('DEFB1', 'Gene', (0, 5))	('GNRH1', 'Gene', (10, 15))	('DKK1', 'Gene', (76, 80))	('EDNRB', 'Gene', '1910', (85, 90))	('DKK1', 'Gene', '22943', (76, 80))
22799	33867351	Transcription factors regulate gene expression and their dysregulation or mutation is well known to contribute to tumorigenesis.	('mutation', 'Var', (74, 82))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('dysregulation', 'Var', (57, 70))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumor', 'Disease', (114, 119))	('gene expression', 'MPA', (31, 46))	('contribute', 'Reg', (100, 110))
22815	33867351	EDNRB promoter methylation, which is associated with the histologic diagnosis of premalignancy and the presence of malignancy, may be a promising marker for the early detection of premalignant lesions in oral cavity cancer.	('methylation', 'Var', (15, 26))	('malignancy', 'Disease', (84, 94))	('EDNRB', 'Gene', (0, 5))	('cancer', 'Disease', 'MESH:D009369', (216, 222))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('malignancy', 'Disease', 'MESH:D009369', (84, 94))	('malignancy', 'Disease', 'MESH:D009369', (115, 125))	('malignancy', 'Disease', (115, 125))	('EDNRB', 'Gene', '1910', (0, 5))	('lesions in oral cavity', 'Phenotype', 'HP:0100649', (193, 215))	('cancer', 'Disease', (216, 222))	('associated', 'Reg', (37, 47))
22818	33867351	Overexpression of FAM3D-AS1 is demonstrated to inhibit cell proliferation, invasion, EMT, and cell survival rate in colorectal cancer.	('colorectal cancer', 'Phenotype', 'HP:0003003', (116, 133))	('FAM3D', 'Gene', (18, 23))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('invasion', 'CPA', (75, 83))	('colorectal cancer', 'Disease', (116, 133))	('inhibit', 'NegReg', (47, 54))	('cell proliferation', 'CPA', (55, 73))	('colorectal cancer', 'Disease', 'MESH:D015179', (116, 133))	('cell survival rate', 'CPA', (94, 112))	('Overexpression', 'Var', (0, 14))	('FAM3D', 'Gene', '131177', (18, 23))	('EMT', 'CPA', (85, 88))	('AS1', 'Gene', '5729', (24, 27))	('AS1', 'Gene', (24, 27))
22829	33867351	Our study revealed that high CLTA-4 expression was significantly associated with a lower risk score.	('LTA', 'Gene', (30, 33))	('LTA', 'Gene', '4049', (30, 33))	('lower', 'NegReg', (83, 88))	('risk score', 'MPA', (89, 99))	('high', 'Var', (24, 28))	('expression', 'MPA', (36, 46))
22831	33867351	Studies have reported that HNSCC patients exhibiting high PD-L1/PD-1 expression tend to have prolonged survival outcomes and a lower probability of recurrence.	('survival outcomes', 'CPA', (103, 120))	('high', 'Var', (53, 57))	('patients', 'Species', '9606', (33, 41))	('HNSCC', 'Phenotype', 'HP:0012288', (27, 32))	('prolonged', 'PosReg', (93, 102))	('PD-L1/PD-1', 'Gene', (58, 68))
22832	33867351	Studies have found that the genetic variation of HBD-1 contributes to lower RNA expression and may be involved in carcinogenesis of oral squamous cell carcinoma.	('HBD-1', 'Gene', (49, 54))	('genetic variation', 'Var', (28, 45))	('involved', 'Reg', (102, 110))	('HBD-1', 'Gene', '1672', (49, 54))	('lower', 'NegReg', (70, 75))	('carcinoma', 'Phenotype', 'HP:0030731', (151, 160))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (137, 160))	('carcinogenesis of oral squamous cell carcinoma', 'Disease', (114, 160))	('carcinogenesis of oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (114, 160))	('RNA expression', 'MPA', (76, 90))
22833	33867351	The genetic alterations of our 10 immune-related genes may help explain the aberrant expression of these genes to some extent in tumors, and patients that carry such genetic alterations may be more responsive to immunotherapy.	('expression', 'MPA', (85, 95))	('tumors', 'Disease', (129, 135))	('tumors', 'Disease', 'MESH:D009369', (129, 135))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('genetic alterations', 'Var', (166, 185))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('patients', 'Species', '9606', (141, 149))
22872	33858433	The antioxidant activity of chrysin is related to the presence of the double bond between C2-C3 and the carbonyl group on the C4 atom.	('antioxidant activity', 'MPA', (4, 24))	('chrysin', 'Chemical', 'MESH:C043561', (28, 35))	('C2-C3', 'Var', (90, 95))	('presence', 'Var', (54, 62))	('double bond', 'MPA', (70, 81))
22878	33858433	The C30, C40-dichloro substituent in the chrysin molecule was responsible for the suppression of prostaglandin (PG) production.	('PG', 'Chemical', 'MESH:D011453', (112, 114))	('chrysin', 'Chemical', 'MESH:C043561', (41, 48))	('C40-dichloro', 'Var', (9, 21))	('C30', 'Var', (4, 7))	('mole', 'Phenotype', 'HP:0003764', (49, 53))	('prostaglandin', 'Chemical', 'MESH:D011453', (97, 110))	('C40-dichloro', 'Chemical', '-', (9, 21))	('suppression', 'NegReg', (82, 93))
22883	33858433	Methylation of both C5 and C7 resulted in higher effectiveness of this chrysin analog as a feasible chemotherapeutic agent for acute lymphoblastic leukemia.	('leukemia', 'Phenotype', 'HP:0001909', (147, 155))	('acute lymphoblastic leukemia', 'Disease', (127, 155))	('Methylation', 'Var', (0, 11))	('acute lymphoblastic leukemia', 'Disease', 'MESH:D054198', (127, 155))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (133, 155))	('higher', 'PosReg', (42, 48))	('chrysin', 'Chemical', 'MESH:C043561', (71, 78))	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (127, 155))	('effectiveness', 'MPA', (49, 62))
22885	33858433	By in silico screening, a series of C7-hydroxyproton substituted chrysin derivatives exhibited EGFR inhibiting possessions against breast cancer.	('chrysin', 'Chemical', 'MESH:C043561', (65, 72))	('inhibiting', 'NegReg', (100, 110))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('breast cancer', 'Disease', 'MESH:D001943', (131, 144))	('C7-hydroxyproton', 'Chemical', '-', (36, 52))	('EGFR', 'Gene', '1956', (95, 99))	('breast cancer', 'Disease', (131, 144))	('breast cancer', 'Phenotype', 'HP:0003002', (131, 144))	('C7-hydroxyproton substituted', 'Var', (36, 64))	('EGFR', 'Gene', (95, 99))
22903	33858433	Doxorubicin loaded mPEG-PCL-chrysin micelles could significantly show potent anticancer activities in vitro, regarding the pi-pi stacking interactions among the mentioned micelles and doxorubicin.	('doxorubicin', 'Chemical', 'MESH:D004317', (184, 195))	('pi-pi', 'Var', (123, 128))	('mice', 'Species', '10090', (171, 175))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('chrysin', 'Chemical', 'MESH:C043561', (28, 35))	('cancer', 'Disease', (81, 87))	('mPEG-PCL', 'Chemical', 'MESH:C439611', (19, 27))	('mice', 'Species', '10090', (36, 40))	('Doxorubicin', 'Chemical', 'MESH:D004317', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('men', 'Species', '9606', (161, 164))
22939	33858433	By substitution of benzyloxy, dimethylamino, nitro, and fluoro on chrysin structure, potent cytotoxic agents were synthetized that displayed considerable cytotoxicity against MDA-MB-231 and MCF-7.	('chrysin', 'Chemical', 'MESH:C043561', (66, 73))	('nitro', 'Chemical', '-', (45, 50))	('cytotoxicity', 'Disease', (154, 166))	('dimethylamino', 'Chemical', '-', (30, 43))	('MCF-7', 'CellLine', 'CVCL:0031', (190, 195))	('fluoro', 'Chemical', '-', (56, 62))	('substitution', 'Var', (3, 15))	('benzyloxy', 'Chemical', '-', (19, 28))	('cytotoxicity', 'Disease', 'MESH:D064420', (154, 166))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (175, 185))
22943	33858433	Various etiologies have participated in the initializations and progressions of gastric cancer including gene-environment dealings with Helicobacter pylori as the most prevailing reasons for the pathogenesis of gastric cancer, numerous genetic and epigenetic changes have been connected with its carcinogenesis moreover.	('genetic', 'Var', (236, 243))	('gastric cancer', 'Disease', (80, 94))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('gastric cancer', 'Disease', 'MESH:D013274', (80, 94))	('gastric cancer', 'Disease', (211, 225))	('connected', 'Reg', (277, 286))	('men', 'Species', '9606', (117, 120))	('gastric cancer', 'Disease', 'MESH:D013274', (211, 225))	('carcinogenesis', 'Disease', 'MESH:D063646', (296, 310))	('gastric cancer', 'Phenotype', 'HP:0012126', (80, 94))	('Helicobacter pylori', 'Species', '210', (136, 155))	('gastric cancer', 'Phenotype', 'HP:0012126', (211, 225))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('epigenetic changes', 'Var', (248, 266))	('carcinogenesis', 'Disease', (296, 310))
22948	33858433	Cell apoptosis (Bax and Bcl2) and cell cycle altered by G0/G1 arrest and decline in the number of cells in the S phase.	('arrest', 'Disease', 'MESH:D006323', (62, 68))	('Bcl2', 'Gene', (24, 28))	('arrest', 'Disease', (62, 68))	('decline', 'NegReg', (73, 80))	('G0/G1', 'Var', (56, 61))	('Bcl2', 'Gene', '596', (24, 28))	('cell cycle altered', 'CPA', (34, 52))
22950	33858433	CRISPR/Cas9 system was used to generate the TET1 gene knocked out.	('TET1', 'Gene', (44, 48))	('rat', 'Species', '10116', (35, 38))	('knocked out', 'Var', (54, 65))	('TET1', 'Gene', '80312', (44, 48))
23012	33858433	Chrysin pretreatment led to an increase in mitochondrial ROS creation, swelling in isolated mitochondria from hepatocytes, collapse in MMP, and release cytochrome c. Furthermore, Chrysin could elevate caspase-3 activity in the HCC rats group.	('swelling', 'Disease', 'MESH:D004487', (71, 79))	('ROS', 'Chemical', 'MESH:D017382', (57, 60))	('cytochrome c', 'Gene', (152, 164))	('MMP', 'Gene', '4312;4313;17390;4318;17395;4319', (135, 138))	('men', 'Species', '9606', (16, 19))	('activity', 'MPA', (211, 219))	('cytochrome c', 'Gene', '54205', (152, 164))	('mitochondrial ROS creation', 'MPA', (43, 69))	('Chrysin', 'Chemical', 'MESH:C043561', (0, 7))	('MMP', 'Gene', (135, 138))	('Chrysin', 'Var', (179, 186))	('elevate', 'PosReg', (193, 200))	('Chrysin', 'Chemical', 'MESH:C043561', (179, 186))	('rats', 'Species', '10116', (231, 235))	('caspase-3', 'Enzyme', (201, 210))	('swelling', 'Disease', (71, 79))
23049	33858433	One of the main markers indicated the poor prognosis in patients with urinary bladder tumor that is mutation in tumor protein p53 (TP53) gene.	('patients', 'Species', '9606', (56, 64))	('p53', 'Gene', '7157', (126, 129))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('urinary bladder tumor', 'Disease', (70, 91))	('tumor', 'Disease', (86, 91))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('urinary bladder tumor', 'Disease', 'MESH:D001749', (70, 91))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('mutation', 'Var', (100, 108))	('TP53', 'Gene', (131, 135))	('TP53', 'Gene', '7157', (131, 135))	('bladder tumor', 'Phenotype', 'HP:0009725', (78, 91))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumor', 'Disease', (112, 117))	('p53', 'Gene', (126, 129))
23050	33858433	It was found that the progression of bladder tumor cell was inhibited by chrysin at doses 10-100 microM in mutated and wild type TP53 in grade 1-3.	('progression', 'CPA', (22, 33))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('chrysin', 'Chemical', 'MESH:C043561', (73, 80))	('bladder tumor', 'Disease', 'MESH:D001749', (37, 50))	('mutated', 'Var', (107, 114))	('inhibited', 'NegReg', (60, 69))	('TP53', 'Gene', '7157', (129, 133))	('bladder tumor', 'Phenotype', 'HP:0009725', (37, 50))	('TP53', 'Gene', (129, 133))	('bladder tumor', 'Disease', (37, 50))
23052	33858433	Chrysin could affect cell cycle at G2 and M phases and cell morphology following decrease in the expression of PLK1, HOXB3 and SRC genes in mutated TP53 cells,.	('PLK1', 'Gene', (111, 115))	('affect', 'Reg', (14, 20))	('decrease', 'NegReg', (81, 89))	('TP53', 'Gene', '7157', (148, 152))	('HOXB3', 'Gene', '3213', (117, 122))	('TP53', 'Gene', (148, 152))	('PLK1', 'Gene', '5347', (111, 115))	('cell morphology', 'CPA', (55, 70))	('SRC', 'Gene', '6714', (127, 130))	('SRC', 'Gene', (127, 130))	('HOXB3', 'Gene', (117, 122))	('Chrysin', 'Chemical', 'MESH:C043561', (0, 7))	('expression', 'MPA', (97, 107))	('mutated', 'Var', (140, 147))
23076	33858433	8-bromo-7-methoxychrysin led to cell fate in cisplatin-sensitive/resistant A2780 and A2780/DDP cells happened via the regulation of Akt/FOXO3a, resulting in transcription of Bim.	('transcription', 'MPA', (157, 170))	('FOXO3a', 'Gene', '2309', (136, 142))	('FOXO3a', 'Gene', (136, 142))	('8-bromo-7-methoxychrysin', 'Chemical', 'MESH:C552860', (0, 24))	('cisplatin', 'Chemical', 'MESH:D002945', (45, 54))	('Akt', 'Gene', (132, 135))	('Bim', 'MPA', (174, 177))	('A2780/DDP', 'Var', (85, 94))	('cell fate', 'CPA', (32, 41))	('Akt', 'Gene', '207', (132, 135))
23111	33858433	Any abnormality in the production and secretion of mucins causes a pathological condition in the airway such as mucoepidermoid carcinoma.	('mucoepidermoid carcinoma', 'Disease', (112, 136))	('mucin', 'Gene', '100508689', (51, 56))	('production', 'MPA', (23, 33))	('abnormality', 'Var', (4, 15))	('causes', 'Reg', (58, 64))	('secretion', 'MPA', (38, 47))	('mucin', 'Gene', (51, 56))	('mucoepidermoid carcinoma', 'Disease', 'MESH:D018277', (112, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))
23172	33858433	Pretreatment with chrysin exposed S/G2 phase arrest and apoptosis.	('S/G2', 'SUBSTITUTION', 'None', (34, 38))	('arrest', 'Disease', (45, 51))	('men', 'Species', '9606', (8, 11))	('chrysin', 'Chemical', 'MESH:C043561', (18, 25))	('S/G2', 'Var', (34, 38))	('apoptosis', 'CPA', (56, 65))	('arrest', 'Disease', 'MESH:D006323', (45, 51))
23175	33858433	The findings suggested that inhibitory effect of chrysin on ASCL1 was effective for carcinoid management.	('carcinoid', 'Phenotype', 'HP:0100570', (84, 93))	('men', 'Species', '9606', (100, 103))	('carcinoid', 'Disease', 'MESH:D002276', (84, 93))	('chrysin', 'Chemical', 'MESH:C043561', (49, 56))	('inhibitory effect', 'Var', (28, 45))	('ASCL1', 'Gene', (60, 65))	('ASCL1', 'Gene', '429', (60, 65))	('carcinoid', 'Disease', (84, 93))
23191	33858433	Moreover due to this co-treatment declined Akt phosphorylation in addition to intracellular GSH content.	('Akt', 'Gene', '207', (43, 46))	('Akt', 'Gene', (43, 46))	('men', 'Species', '9606', (29, 32))	('GSH', 'Chemical', 'MESH:D005978', (92, 95))	('declined', 'NegReg', (34, 42))	('co-treatment', 'Var', (21, 33))
23223	31270941	Lung cancer patients with EGFR mutations had significantly lower TMB values than those with wild-type EGFR, and increased TMB was significantly associated with dMMR in colorectal cancer (CRC).	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('lower', 'NegReg', (59, 64))	('CRC', 'Phenotype', 'HP:0003003', (187, 190))	('TMB', 'MPA', (122, 125))	('EGFR', 'Gene', '1956', (102, 106))	('colorectal cancer', 'Disease', 'MESH:D015179', (168, 185))	('patients', 'Species', '9606', (12, 20))	('cancer', 'Disease', 'MESH:D009369', (5, 11))	('Lung cancer', 'Phenotype', 'HP:0100526', (0, 11))	('colorectal cancer', 'Disease', (168, 185))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('EGFR', 'Gene', (26, 30))	('mutations', 'Var', (31, 40))	('dMMR', 'Disease', (160, 164))	('TMB', 'Chemical', '-', (122, 125))	('TMB', 'Chemical', '-', (65, 68))	('increased', 'PosReg', (112, 121))	('EGFR', 'Gene', (102, 106))	('dMMR', 'Chemical', '-', (160, 164))	('colorectal cancer', 'Phenotype', 'HP:0003003', (168, 185))	('cancer', 'Disease', (5, 11))	('TMB values', 'MPA', (65, 75))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))	('EGFR', 'Gene', '1956', (26, 30))	('cancer', 'Disease', (179, 185))
23225	31270941	PD-L1 AMP occurred most frequently in lung squamous cell carcinoma and HER2-positive breast cancer.	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (38, 66))	('HER2-positive breast cancer', 'Disease', (71, 98))	('AMP', 'Var', (6, 9))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (38, 66))	('breast cancer', 'Phenotype', 'HP:0003002', (85, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (57, 66))	('PD-L1', 'Gene', (0, 5))	('lung squamous cell carcinoma', 'Disease', (38, 66))	('HER2-positive breast cancer', 'Disease', 'MESH:D001943', (71, 98))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (43, 66))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('PD-L1', 'Gene', '29126', (0, 5))	('AMP', 'Chemical', 'MESH:D000249', (6, 9))
23226	31270941	While MSI and dMMR are associated with higher mutational loads, correlations between TMB-H and other biomarkers, between MSI-H and dMMR, and between PD-L1 AMP and other biomarkers were low, indicating different underlying causes of the four biomarkers.	('PD-L1', 'Gene', (149, 154))	('AMP', 'Chemical', 'MESH:D000249', (155, 158))	('MSI-H', 'Disease', 'MESH:D000848', (121, 126))	('higher', 'PosReg', (39, 45))	('TMB-H', 'Gene', (85, 90))	('dMMR', 'Var', (14, 18))	('mutational loads', 'MPA', (46, 62))	('PD-L1', 'Gene', '29126', (149, 154))	('dMMR', 'Chemical', '-', (14, 18))	('MSI', 'Var', (6, 9))	('TMB-H', 'Chemical', '-', (85, 90))	('MSI-H', 'Disease', (121, 126))	('dMMR', 'Chemical', '-', (131, 135))
23231	31270941	Several studies have analyzed, in detail, the correlation between tumor mutation burden (TMB) and the efficacy of immunotherapy, showing a high association between TMB and treatment efficacy.8, 9, 10 A study involving 151 cancer patients further confirmed a linear relationship between TMB and the clinical outcome of immunotherapy.9 Analysis of almost 1700 cancer patients receiving at least one dose of PD-1/ PD-L1 blockade showed that 20 percent of the patients with the highest TMB in each cancer type had a better overall survival.11 Furthermore, the US Food and Drug Administration (FDA) approved this treatment for unresectable or metastatic solid tumors in patients with high MSI (MSI-H) or dMMR based on five clinical trials.	('patients', 'Species', '9606', (365, 373))	('patients', 'Species', '9606', (229, 237))	('TMB', 'Chemical', '-', (164, 167))	('cancer', 'Disease', (494, 500))	('tumor', 'Disease', 'MESH:D009369', (655, 660))	('cancer', 'Phenotype', 'HP:0002664', (494, 500))	('cancer', 'Disease', (358, 364))	('tumors', 'Phenotype', 'HP:0002664', (655, 661))	('tumor', 'Disease', (66, 71))	('MSI-H', 'Disease', 'MESH:D000848', (689, 694))	('cancer', 'Disease', (222, 228))	('cancer', 'Phenotype', 'HP:0002664', (358, 364))	('patients', 'Species', '9606', (665, 673))	('PD-L1', 'Gene', (411, 416))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('patients', 'Species', '9606', (456, 464))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('TMB', 'Chemical', '-', (89, 92))	('tumor', 'Phenotype', 'HP:0002664', (655, 660))	('PD-L1', 'Gene', '29126', (411, 416))	('tumors', 'Disease', (655, 661))	('PD-1', 'Gene', '5133', (405, 409))	('cancer', 'Disease', 'MESH:D009369', (494, 500))	('high MSI', 'Var', (679, 687))	('PD-1', 'Gene', (405, 409))	('cancer', 'Disease', 'MESH:D009369', (358, 364))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('dMMR', 'Chemical', '-', (699, 703))	('tumors', 'Disease', 'MESH:D009369', (655, 661))	('cancer', 'Disease', 'MESH:D009369', (222, 228))	('unresectable', 'Disease', (622, 634))	('TMB', 'Chemical', '-', (286, 289))	('TMB', 'Chemical', '-', (482, 485))	('MSI-H', 'Disease', (689, 694))	('tumor', 'Disease', (655, 660))
23232	31270941	These trials across 15 cancer types involving 149 patients with high microsatellite instability (MSI-H) or DNA mismatch repair deficiency (dMMR) reported complete or partial response to pembrolizumab in 39.6% of patients.	('high', 'Var', (64, 68))	('MSI-H', 'Disease', 'MESH:D000848', (97, 102))	('patients', 'Species', '9606', (50, 58))	('pembrolizumab', 'Chemical', 'MESH:C582435', (186, 199))	('patients', 'Species', '9606', (212, 220))	('cancer', 'Disease', (23, 29))	('cancer', 'Disease', 'MESH:D009369', (23, 29))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('MSI-H', 'Disease', (97, 102))	('dMMR', 'Chemical', '-', (139, 143))
23259	31270941	Although PD-1/PD-L1 blockade has been approved in Non-small cell lung cancer (NSCLC), some clinical trials have reported that NSCLC patients with EGFR mutations do not benefit from this therapy and that it may even lead to a more rapid disease progression.1, 7, 25 Therefore, we compared the median TMB of LUAD patients with mutant (n = 77) and wild-type (n = 99) EGFR genes.	('NSCLC', 'Disease', 'MESH:D002289', (126, 131))	('TMB', 'Chemical', '-', (299, 302))	('Non-small cell lung cancer', 'Disease', 'MESH:D002289', (50, 76))	('EGFR', 'Gene', (146, 150))	('NSCLC', 'Disease', (78, 83))	('patients', 'Species', '9606', (132, 140))	('NSCLC', 'Disease', (126, 131))	('EGFR', 'Gene', '1956', (364, 368))	('NSCLC', 'Phenotype', 'HP:0030358', (78, 83))	('Non-small cell lung cancer', 'Disease', (50, 76))	('lung cancer', 'Phenotype', 'HP:0100526', (65, 76))	('NSCLC', 'Phenotype', 'HP:0030358', (126, 131))	('PD-L1', 'Gene', (14, 19))	('mutant', 'Var', (325, 331))	('PD-1', 'Gene', (9, 13))	('PD-1', 'Gene', '5133', (9, 13))	('PD-L1', 'Gene', '29126', (14, 19))	('EGFR', 'Gene', '1956', (146, 150))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('Non-small cell lung cancer', 'Phenotype', 'HP:0030358', (50, 76))	('EGFR', 'Gene', (364, 368))	('LUAD', 'Phenotype', 'HP:0030078', (306, 310))	('patients', 'Species', '9606', (311, 319))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (54, 76))	('NSCLC', 'Disease', 'MESH:D002289', (78, 83))
23260	31270941	Patients with EGFR mutations had significantly lower median TMB compared with those with wild-type EGFR (74 vs 113 NSM, respectively; P = 0.0039) (Figure 2B).	('EGFR', 'Gene', (99, 103))	('lower', 'NegReg', (47, 52))	('EGFR', 'Gene', '1956', (14, 18))	('EGFR', 'Gene', (14, 18))	('mutations', 'Var', (19, 28))	('TMB', 'MPA', (60, 63))	('Patients', 'Species', '9606', (0, 8))	('TMB', 'Chemical', '-', (60, 63))	('EGFR', 'Gene', '1956', (99, 103))
23264	31270941	Gastrointestinal stromal tumors exhibited a high frequency of dMMR, while those of hepatocellular carcinoma, sarcoma of soft tissue, and renal cell carcinoma were among the lowest.	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (83, 107))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (83, 107))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('dMMR', 'Var', (62, 66))	('sarcoma', 'Disease', 'MESH:D012509', (109, 116))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('hepatocellular carcinoma', 'Disease', (83, 107))	('renal cell carcinoma', 'Disease', (137, 157))	('Gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (0, 31))	('dMMR', 'Chemical', '-', (62, 66))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (137, 157))	('Gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (0, 31))	('sarcoma', 'Disease', (109, 116))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (137, 157))	('Gastrointestinal stromal tumors', 'Disease', (0, 31))	('sarcoma', 'Phenotype', 'HP:0100242', (109, 116))	('carcinoma', 'Phenotype', 'HP:0030731', (148, 157))
23276	31270941	We also calculated the TMB values of patients with amplified and normal PD-L1.	('amplified', 'Var', (51, 60))	('PD-L1', 'Gene', '29126', (72, 77))	('patients', 'Species', '9606', (37, 45))	('TMB', 'MPA', (23, 26))	('PD-L1', 'Gene', (72, 77))	('TMB', 'Chemical', '-', (23, 26))
23297	31270941	In addition, we found that patients with EGFR mutations had significantly lower median TMB compared with those with wild-type EGFR, consistent with another study in which the TMB value of EGFR-mutant nonsquamous NSCLC was half that of wild-type.37  Moreover, the cut-off value of TMB to predict treatment response has been determined in several studies.	('TMB', 'Chemical', '-', (175, 178))	('EGFR', 'Gene', (41, 45))	('NSCLC', 'Disease', 'MESH:D002289', (212, 217))	('mutations', 'Var', (46, 55))	('TMB', 'MPA', (87, 90))	('EGFR', 'Gene', (126, 130))	('TMB', 'Chemical', '-', (87, 90))	('patients', 'Species', '9606', (27, 35))	('EGFR', 'Gene', '1956', (188, 192))	('NSCLC', 'Phenotype', 'HP:0030358', (212, 217))	('TMB', 'Chemical', '-', (280, 283))	('lower', 'NegReg', (74, 79))	('EGFR', 'Gene', '1956', (41, 45))	('EGFR', 'Gene', (188, 192))	('NSCLC', 'Disease', (212, 217))	('EGFR', 'Gene', '1956', (126, 130))
23312	31270941	This study found that patients with TMB of >100 Mut/Mb may be classified as MSS, but many contain replicative polymerase mutations resulting in replication repair deficiency.	('deficiency', 'NegReg', (163, 173))	('replicative polymerase', 'Enzyme', (98, 120))	('replication repair', 'MPA', (144, 162))	('mutations', 'Var', (121, 130))	('patients', 'Species', '9606', (22, 30))	('TMB', 'Chemical', '-', (36, 39))
23313	31270941	Moreover, TMB values of 10-100 Mut/Mb were mostly associated with MSI-H and had high levels of dMMR.40 This study, therefore, explains to a certain extent why TMB-H, MSI-H, and dMMR do not completely overlap and indicates that there may be several additional underlying causes of TMB-H, for example, replicative polymerase mutations.	('dMMR', 'Chemical', '-', (177, 181))	('mutations', 'Var', (323, 332))	('MSI-H', 'Disease', 'MESH:D000848', (166, 171))	('MSI-H', 'Disease', 'MESH:D000848', (66, 71))	('TMB', 'Chemical', '-', (10, 13))	('TMB-H', 'Chemical', '-', (159, 164))	('TMB', 'Chemical', '-', (159, 162))	('dMMR', 'Chemical', '-', (95, 99))	('TMB-H', 'Chemical', '-', (280, 285))	('replicative polymerase', 'Enzyme', (300, 322))	('MSI-H', 'Disease', (66, 71))	('TMB', 'Chemical', '-', (280, 283))	('MSI-H', 'Disease', (166, 171))
23314	31270941	High TMB and MSI are caused by defects in the DNA damage repair system,41 which is composed of many proteins in addition to MMR components, including the homologous recombination repair element RecA/Rad5142 and the non-homologous end joining repair element Ku70/Ku80.43 Research has shown that in the absence of MSI, mutations in DNA polymerase (POLE) can lead to TMB-H.44 PD-L1 AMP can be caused by the breakage-fusion-bridge cycle, extra replication, and recombination, among other mechanisms, many of which are distinct from the underlying causes attributed to the other biomarkers.	('mutations', 'Var', (317, 326))	('PD-L1', 'Gene', '29126', (373, 378))	('AMP', 'Chemical', 'MESH:D000249', (379, 382))	('TMB', 'Chemical', '-', (364, 367))	('TMB-H.44', 'Disease', (364, 372))	('lead', 'Reg', (356, 360))	('TMB-H', 'Chemical', '-', (364, 369))	('breakage-fusion-bridge cycle', 'Disease', (404, 432))	('caused', 'Reg', (390, 396))	('PD-L1', 'Gene', (373, 378))	('extra replication', 'CPA', (434, 451))	('TMB', 'Chemical', '-', (5, 8))
23433	32923875	In contrast, HPV- vSCCs showed more alterations in TP53 (83% v 6%; P < .0001), TERTp (71% v 9%; P < .0001), CDKN2A (55% v 2%; P < .0001), CCND1 amplification (22% v 2%; P < .0001), FAT1 (25% v 4%; P < .0001), NOTCH1 (19% v 6%; P = .002), and EGFR amplification (11% v 0%; P < .0001), as well as a higher rate of 9p24.1 (PDL1/PDL2) amplification (5% v 1%) and PD-L1 immunohistochemistry high-positive tumor staining (33% v 9%; P = .04).	('amplification', 'Var', (331, 344))	('PD-L1', 'Gene', '29126', (359, 364))	('PDL2', 'Gene', (325, 329))	('tumor', 'Disease', (400, 405))	('EGFR', 'Gene', (242, 246))	('vSCC', 'Phenotype', 'HP:0030417', (18, 22))	('tumor', 'Disease', 'MESH:D009369', (400, 405))	('CDKN2A', 'Gene', '1029', (108, 114))	('PD-L1', 'Gene', (359, 364))	('TP53', 'Gene', (51, 55))	('alterations', 'Reg', (36, 47))	('FAT1', 'Gene', '2195', (181, 185))	('tumor', 'Phenotype', 'HP:0002664', (400, 405))	('EGFR', 'Gene', '1956', (242, 246))	('NOTCH1', 'Gene', (209, 215))	('TP53', 'Gene', '7157', (51, 55))	('PDL1', 'Gene', (320, 324))	('PDL2', 'Gene', '80380', (325, 329))	('TERTp', 'Gene', (79, 84))	('CCND1', 'Gene', '595', (138, 143))	('TERTp', 'Gene', '7015', (79, 84))	('NOTCH1', 'Gene', '4851', (209, 215))	('PDL1', 'Gene', '29126', (320, 324))	('FAT1', 'Gene', (181, 185))	('CCND1', 'Gene', (138, 143))	('HPV', 'Species', '10566', (13, 16))	('CDKN2A', 'Gene', (108, 114))
23450	32923875	Prior studies of the genomic characteristics of vSCC have consistently identified mutations in TP53, with most reporting higher frequencies in human papillomavirus-negative (HPV-) vSCC.	('vSCC', 'Phenotype', 'HP:0030417', (180, 184))	('TP53', 'Gene', '7157', (95, 99))	('papillomavirus-negative', 'Disease', 'MESH:D030361', (149, 172))	('human papillomavirus', 'Species', '10566', (143, 163))	('higher frequencies', 'PosReg', (121, 139))	('mutations', 'Var', (82, 91))	('vSCC', 'Phenotype', 'HP:0030417', (48, 52))	('HPV', 'Species', '10566', (174, 177))	('papillomavirus-negative', 'Disease', (149, 172))	('TP53', 'Gene', (95, 99))
23451	32923875	PIK3CA mutations have been reported, but frequencies have varied widely, from 7% to 60%.	('PIK3CA', 'Gene', '5290', (0, 6))	('mutations', 'Var', (7, 16))	('PIK3CA', 'Gene', (0, 6))
23452	32923875	Other reported mutations in vSCC have involved CDKN2A, FBXW7, HRAS, FAT1, FGFR3, and PTEN, and copy number analyses have reported CCND1 and EGFR amplifications significantly enriched in HPV- tumors.	('HRAS', 'Gene', '3265', (62, 66))	('EGFR', 'Gene', (140, 144))	('HRAS', 'Gene', (62, 66))	('CCND1', 'Gene', (130, 135))	('FAT1', 'Gene', (68, 72))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('PTEN', 'Gene', (85, 89))	('tumors', 'Disease', (191, 197))	('mutations', 'Var', (15, 24))	('HPV', 'Species', '10566', (186, 189))	('tumors', 'Disease', 'MESH:D009369', (191, 197))	('FBXW7', 'Gene', (55, 60))	('PTEN', 'Gene', '5728', (85, 89))	('EGFR', 'Gene', '1956', (140, 144))	('FGFR3', 'Gene', (74, 79))	('CDKN2A', 'Gene', (47, 53))	('FAT1', 'Gene', '2195', (68, 72))	('FGFR3', 'Gene', '2261', (74, 79))	('vSCC', 'Gene', (28, 32))	('FBXW7', 'Gene', '55294', (55, 60))	('amplifications', 'Var', (145, 159))	('CDKN2A', 'Gene', '1029', (47, 53))	('vSCC', 'Phenotype', 'HP:0030417', (28, 32))	('tumors', 'Phenotype', 'HP:0002664', (191, 197))	('CCND1', 'Gene', '595', (130, 135))
23462	32923875	The RefSeq database is comprehensive, and HPV types analyzed for included HPV 6, 11, 16, 18, 26, 31, 33, 35, 39, 40, 42, 43, 44, 45, 51, 52, 53, 54, 55, 56, 58, 59, 61, 62, 64, 66, 67, 68, 69, 70, 71, 72, 73, 81, 82, 83, 84, CP6108, and IS39.	('CP6108', 'Var', (225, 231))	('HPV', 'Species', '10566', (74, 77))	('HPV', 'Gene', (74, 77))	('HPV', 'Species', '10566', (42, 45))
23463	32923875	HPV types identified in this study were stratified according to the HPV classification described by Munoz et al, with HPV 16, 18, 31, 33, and 58 labeled hrHPV+ and HPV 6 labeled low risk.	('HPV', 'Species', '10566', (0, 3))	('HPV 16', 'Species', '333760', (118, 124))	('hrHPV+', 'Disease', (153, 159))	('HPV', 'Species', '10566', (155, 158))	('HPV 16', 'Var', (118, 124))	('HPV', 'Species', '10566', (118, 121))	('HPV', 'Species', '10566', (68, 71))	('HPV', 'Species', '10566', (164, 167))
23469	32923875	A positive signature required a sample to have at least a 40% fit to a characterized mutational process, including APOBEC overexpression, exposure to ultraviolet light, hypofunction of the BRCA tumor suppressor, and defects in mismatch repair.	('mismatch repair', 'CPA', (227, 242))	('hypofunction of the BRCA tumor', 'Disease', (169, 199))	('overexpression', 'PosReg', (122, 136))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('hypofunction of the BRCA tumor', 'Disease', 'MESH:D000309', (169, 199))	('APOBEC', 'Gene', (115, 121))	('defects', 'Var', (216, 223))
23487	32923875	Alterations frequently observed in HPV+ tumors (Table 2) differed from those observed in HPV- tumors (Table 3).	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('HPV', 'Species', '10566', (35, 38))	('tumors', 'Disease', 'MESH:D009369', (40, 46))	('Alterations', 'Var', (0, 11))	('tumors', 'Disease', (94, 100))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('HPV', 'Species', '10566', (89, 92))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumors', 'Disease', (40, 46))
23489	32923875	The only specific point mutation with a significant difference between HPV+ and HPV- was PIK3CA E545K, an activating mutation that was significantly enriched in HPV+ vSCCs (Table 2).	('vSCC', 'Phenotype', 'HP:0030417', (166, 170))	('PIK3CA', 'Gene', (89, 95))	('PIK3CA', 'Gene', '5290', (89, 95))	('E545K', 'Mutation', 'rs104886003', (96, 101))	('HPV', 'Species', '10566', (80, 83))	('E545K', 'Var', (96, 101))	('HPV', 'Species', '10566', (71, 74))	('HPV', 'Species', '10566', (161, 164))
23491	32923875	Of the 73 vSCCs for which PD-L1 IHC was performed, a higher rate of PD-L1 IHC high-positive tumor staining was identified in HPV- versus HPV+ vSCC (33% v 9%; P = .04; Figs 2 and 3).	('PD-L1', 'Gene', '29126', (26, 31))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('PD-L1', 'Gene', (26, 31))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('HPV', 'Species', '10566', (125, 128))	('PD-L1', 'Gene', (68, 73))	('HPV-', 'Var', (125, 129))	('vSCC', 'Phenotype', 'HP:0030417', (10, 14))	('tumor', 'Disease', (92, 97))	('vSCC', 'Phenotype', 'HP:0030417', (142, 146))	('PD-L1', 'Gene', '29126', (68, 73))	('HPV', 'Species', '10566', (137, 140))
23516	32923875	Prior reports of GAs in vSCC have identified trends in mutations between HPV+ and HPV- types, although there has been substantial overlap in mutational profile, possibly owing to limited case volume.	('mutations', 'Var', (55, 64))	('HPV', 'Species', '10566', (73, 76))	('vSCC', 'Phenotype', 'HP:0030417', (24, 28))	('HPV', 'Species', '10566', (82, 85))	('vSCC', 'Disease', (24, 28))
23518	32923875	HPV+ vSCC tended to be enriched in FGFR3 and PTEN mutations, although the rates were not statistically distinguishable from the HPV- vSCC.	('vSCC', 'Phenotype', 'HP:0030417', (5, 9))	('HPV', 'Species', '10566', (0, 3))	('vSCC', 'Phenotype', 'HP:0030417', (133, 137))	('mutations', 'Var', (50, 59))	('FGFR3', 'Gene', '2261', (35, 40))	('HPV', 'Species', '10566', (128, 131))	('FGFR3', 'Gene', (35, 40))	('PTEN', 'Gene', (45, 49))	('PTEN', 'Gene', '5728', (45, 49))
23519	32923875	The HPV- tumors demonstrated significant enrichment for TP53 mutations and showed a nonsignificant tendency toward more HRAS, PI3K, and CDKN2A mutations.	('HPV', 'Species', '10566', (4, 7))	('TP53', 'Gene', '7157', (56, 60))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('mutations', 'Var', (61, 70))	('CDKN2A', 'Gene', (136, 142))	('CDKN2A', 'Gene', '1029', (136, 142))	('PI3K', 'Gene', (126, 130))	('TP53', 'Gene', (56, 60))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('HRAS', 'Gene', '3265', (120, 124))	('tumors', 'Disease', (9, 15))	('tumors', 'Disease', 'MESH:D009369', (9, 15))	('HRAS', 'Gene', (120, 124))	('mutations', 'Var', (143, 152))
23520	32923875	Choschzick et al specifically examined CCND1 copy number changes in 183 vSCCs and identified amplifications in 22%, with a significant association with HPV- tumors.	('tumors', 'Phenotype', 'HP:0002664', (157, 163))	('CCND1', 'Gene', (39, 44))	('association', 'Reg', (135, 146))	('tumors', 'Disease', (157, 163))	('tumors', 'Disease', 'MESH:D009369', (157, 163))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('HPV', 'Species', '10566', (152, 155))	('amplifications', 'Var', (93, 107))	('CCND1', 'Gene', '595', (39, 44))	('copy number changes', 'Var', (45, 64))	('vSCC', 'Phenotype', 'HP:0030417', (72, 76))
23521	32923875	Growdon et al evaluated EGFR amplification in 51 vSCCs, and identified amplification in 12% of tumors, with significant association with poor prognosis and HPV- status.	('EGFR', 'Gene', '1956', (24, 28))	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('EGFR', 'Gene', (24, 28))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('amplification', 'Var', (71, 84))	('HPV', 'Species', '10566', (156, 159))	('vSCC', 'Phenotype', 'HP:0030417', (49, 53))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumors', 'Disease', (95, 101))
23523	32923875	The authors reported TP53 and CDKN2A mutations in both HPV+ and HPV- vSCC, whereas mutations in PIK3CA, FBXW7, HRAS, FGFR3, STK11, AKT1, SMAD4, and PTEN were found at low frequencies in both types of vSCC.	('PTEN', 'Gene', (148, 152))	('TP53', 'Gene', (21, 25))	('CDKN2A', 'Gene', '1029', (30, 36))	('FGFR3', 'Gene', (117, 122))	('STK11', 'Gene', (124, 129))	('PIK3CA', 'Gene', '5290', (96, 102))	('FBXW7', 'Gene', (104, 109))	('vSCC', 'Phenotype', 'HP:0030417', (200, 204))	('SMAD4', 'Gene', '4089', (137, 142))	('PTEN', 'Gene', '5728', (148, 152))	('HPV- vSCC', 'Disease', (64, 73))	('FGFR3', 'Gene', '2261', (117, 122))	('AKT1', 'Gene', '207', (131, 135))	('STK11', 'Gene', '6794', (124, 129))	('TP53', 'Gene', '7157', (21, 25))	('mutations', 'Var', (37, 46))	('PIK3CA', 'Gene', (96, 102))	('FBXW7', 'Gene', '55294', (104, 109))	('vSCC', 'Phenotype', 'HP:0030417', (69, 73))	('AKT1', 'Gene', (131, 135))	('HPV', 'Species', '10566', (64, 67))	('HPV+', 'Disease', (55, 59))	('HRAS', 'Gene', '3265', (111, 115))	('CDKN2A', 'Gene', (30, 36))	('HPV', 'Species', '10566', (55, 58))	('HRAS', 'Gene', (111, 115))	('SMAD4', 'Gene', (137, 142))
23527	32923875	PI3K/mTOR pathway mutations, including STK11, a negative regulator of mTOR signaling, have been described in a wide range of HPV-driven cancers.	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('mTOR', 'Gene', (70, 74))	('described', 'Reg', (96, 105))	('mTOR', 'Gene', '2475', (70, 74))	('STK11', 'Gene', '6794', (39, 44))	('cancers', 'Phenotype', 'HP:0002664', (136, 143))	('cancers', 'Disease', (136, 143))	('cancers', 'Disease', 'MESH:D009369', (136, 143))	('mTOR', 'Gene', (5, 9))	('HPV', 'Species', '10566', (125, 128))	('mTOR', 'Gene', '2475', (5, 9))	('STK11', 'Gene', (39, 44))	('mutations', 'Var', (18, 27))
23530	32923875	It is conceivable that a similar role could exist in HPV+ vSCC as a putative tumor immune-escape mechanism, but additional studies are needed.	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('HPV+ vSCC', 'Var', (53, 62))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('vSCC', 'Phenotype', 'HP:0030417', (58, 62))	('HPV', 'Species', '10566', (53, 56))	('tumor', 'Disease', (77, 82))
23534	32923875	TP53, TERT, and CDKN2A are deregulated by HPV E6 and/or E7, whereas EGFR recycling is altered by HPV E5.	('deregulated', 'Reg', (27, 38))	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('HPV', 'Species', '10566', (42, 45))	('altered', 'Reg', (86, 93))	('CDKN2A', 'Gene', (16, 22))	('CDKN2A', 'Gene', '1029', (16, 22))	('HPV', 'Species', '10566', (97, 100))	('TERT', 'Gene', (6, 10))	('TERT', 'Gene', '7015', (6, 10))	('EGFR', 'Gene', '1956', (68, 72))	('HPV E6', 'Var', (42, 48))	('EGFR', 'Gene', (68, 72))
23536	32923875	HPV induces genomic instability, which may account for the increased TMB in the primary HPV+ cohort.	('HPV', 'Species', '10566', (0, 3))	('HPV', 'Var', (0, 3))	('TMB', 'Chemical', '-', (69, 72))	('genomic instability', 'CPA', (12, 31))	('induces', 'Reg', (4, 11))	('HPV', 'Species', '10566', (88, 91))	('increased', 'PosReg', (59, 68))	('TMB', 'MPA', (69, 72))
23542	32923875	The activating point mutation PIK3CA E545K was significantly enriched in HPV+ vSCC; analysis of specific mutations as part of clinical trials may improve stratification of therapeutic sensitivities.	('PIK3CA', 'Gene', (30, 36))	('vSCC', 'Phenotype', 'HP:0030417', (78, 82))	('PIK3CA', 'Gene', '5290', (30, 36))	('activating', 'PosReg', (4, 14))	('HPV', 'Species', '10566', (73, 76))	('HPV+ vSCC', 'Disease', (73, 82))	('E545K', 'Mutation', 'rs104886003', (37, 42))	('E545K', 'Var', (37, 42))
23580	31799384	Severe dysplasia/carcinoma in situ shows significant nuclear pleomorphism including prominent nucleoli, marked variation in nuclear size and shape, abnormal mitotic figures, and architectural abnormalities such as dyskeratosis, loss of polarity, and a drop-shaped interface with the underlying submucosa (characterized by an irregular interface with the underlying submucosa, often teardrop shaped extending downward; Figure 4C).	('carcinoma in situ', 'Phenotype', 'HP:0030075', (17, 34))	('dysplasia/carcinoma', 'Disease', 'MESH:D002277', (7, 26))	('architectural abnormalities', 'Disease', 'MESH:D002869', (178, 205))	('polarity', 'CPA', (236, 244))	('dyskeratosis', 'Disease', (214, 226))	('dysplasia/carcinoma', 'Disease', (7, 26))	('loss', 'Var', (228, 232))	('carcinoma', 'Phenotype', 'HP:0030731', (17, 26))	('architectural abnormalities', 'Disease', (178, 205))
23595	27473117	In contrast, Silencing Sam68 expression significantly enhanced the sensitivity of oral tongue squamous cell carcinoma cells to apoptosis induced by cisplatin both in vitro and in vivo.	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('oral tongue squamous cell carcinoma', 'Disease', 'MESH:D002294', (82, 117))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (94, 117))	('cisplatin', 'Chemical', 'MESH:D002945', (148, 157))	('tongue squamous cell carcinoma', 'Phenotype', 'HP:0030413', (87, 117))	('oral tongue squamous cell carcinoma', 'Disease', (82, 117))	('sensitivity', 'MPA', (67, 78))	('Sam68', 'Gene', (23, 28))	('enhanced', 'PosReg', (54, 62))	('Silencing', 'Var', (13, 22))
23597	27473117	Sam68 is a potential pharmacologic target for the treatment of oral tongue squamous cell carcinoma and inhibition of Sam68 expression might represent a novel strategy to sensitize oral tongue squamous cell carcinoma to chemotherapy.	('oral tongue squamous cell carcinoma', 'Disease', (180, 215))	('oral tongue squamous cell carcinoma', 'Disease', (63, 98))	('men', 'Species', '9606', (55, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (206, 215))	('oral tongue squamous cell carcinoma', 'Disease', 'MESH:D002294', (180, 215))	('oral tongue squamous cell carcinoma', 'Disease', 'MESH:D002294', (63, 98))	('tongue squamous cell carcinoma', 'Phenotype', 'HP:0030413', (68, 98))	('Sam68', 'Gene', (117, 122))	('inhibition', 'Var', (103, 113))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (75, 98))	('tongue squamous cell carcinoma', 'Phenotype', 'HP:0030413', (185, 215))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (192, 215))
23617	27473117	Stable cell lines expressing Sam68 or Sam68 shRNAs were selected for 10 days with 0.5 mug/mL puromycin.	('Sam68', 'Var', (38, 43))	('Sam68', 'Var', (29, 34))	('puromycin', 'Chemical', 'MESH:D011691', (93, 102))
23622	27473117	Western blotting was performed according to standard methods, as described previously,12 using polyclonal rabbit anti-Sam68 antibodies (sc-733; Santa Cruz Biotechnology, Santa Cruz, CA, USA), anti-caspase-9, anti-cleaved caspase-9, anti-caspase-3, anti-cleaved caspase-3, anti-poly (ADP-ribose) polymerase (PARP), and anti-cleaved PARP antibodies (Cell Signaling Technology, Danvers, MA, USA).	('caspase-9', 'Gene', (221, 230))	('anti-poly', 'Var', (272, 281))	('caspase-3', 'Gene', (261, 270))	('anti-cleaved', 'Var', (208, 220))	('PARP', 'Gene', '142', (307, 311))	('caspase-3', 'Gene', '836', (237, 246))	('caspase-9', 'Gene', (197, 206))	('PARP', 'Gene', '142', (331, 335))	('caspase-3', 'Gene', '836', (261, 270))	('caspase-3', 'Gene', (237, 246))	('anti-cleaved', 'Var', (248, 260))	('PARP', 'Gene', (331, 335))	('caspase-9', 'Gene', '842', (221, 230))	('PARP', 'Gene', (307, 311))	('rabbit', 'Species', '9986', (106, 112))	('caspase-9', 'Gene', '842', (197, 206))
23646	27473117	To further elucidate and characterize the anti-apoptotic activity of Sam68 in OTSCC cells, in vitro studies were performed using OTSCC cell lines with overexpression or silencing of Sam68.	('anti-apoptotic', 'MPA', (42, 56))	('SCC', 'Gene', '6317', (80, 83))	('silencing', 'Var', (169, 178))	('Sam68', 'Gene', (182, 187))	('SCC', 'Gene', (131, 134))	('Sam68', 'Gene', (69, 74))	('SCC', 'Gene', (80, 83))	('SCC', 'Gene', '6317', (131, 134))
23675	27473117	In a previous study, we found that Sam68 is overexpressed in OTSCC and that Sam68 is significantly associated with the clinicopathological characteristics and prognosis of patients.	('Sam68', 'Var', (76, 81))	('SCC', 'Gene', (63, 66))	('SCC', 'Gene', '6317', (63, 66))	('Sam68', 'Gene', (35, 40))	('patients', 'Species', '9606', (172, 180))	('overexpressed', 'PosReg', (44, 57))	('associated', 'Reg', (99, 109))
23677	27473117	In contrast, silencing of Sam68 expression significantly enhanced the sensitivity of OTSCC cells to apoptosis induced by cisplatin both in vitro and in vivo.	('Sam68', 'Gene', (26, 31))	('cisplatin', 'Chemical', 'MESH:D002945', (121, 130))	('SCC', 'Gene', (87, 90))	('sensitivity', 'MPA', (70, 81))	('SCC', 'Gene', '6317', (87, 90))	('enhanced', 'PosReg', (57, 65))	('silencing', 'Var', (13, 22))
23689	24369052	Cancer progression is associated with mutation and differential gene expression.	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('mutation', 'Var', (38, 46))	('associated', 'Reg', (22, 32))
23690	24369052	Many oncogenes and tumor suppressor genes responsible for cancer are linked to mutations.	('oncogenes', 'Gene', (5, 14))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('linked', 'Reg', (69, 75))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('tumor', 'Disease', (19, 24))	('cancer', 'Disease', (58, 64))	('mutations', 'Var', (79, 88))
23691	24369052	Besides these mutations, recent studies correlate epigenetic features to play an important role in cancer development and propagation.	('cancer', 'Disease', (99, 105))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('epigenetic features', 'Var', (50, 69))
23694	24369052	Both hypermethylation and hypomethylation are known to be linked to tumors, autoimmune and other diseases.	('linked', 'Reg', (58, 64))	('tumors', 'Disease', (68, 74))	('tumors', 'Disease', 'MESH:D009369', (68, 74))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('hyper', 'Disease', 'MESH:D053307', (5, 10))	('hyper', 'Disease', (5, 10))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('hypomethylation', 'Var', (26, 41))
23696	24369052	Specific examples of DNA methylation role in cancers include hypermethylation of BRCA1 in breast and ovarian cancer; DOK7 in breast cancer; MYOD1 in hematological neoplasm; APC, HOX2, OTX1 genes in non-small cell lung carcinoma (NSCLC); FEN1 in breast tumor cells; and hypomethylation of TKTL1 in head and neck squamous cell carcinoma.	('OTX1', 'Gene', (184, 188))	('breast and ovarian cancer', 'Disease', 'MESH:D010051', (90, 115))	('FEN1', 'Gene', '2237', (237, 241))	('OTX1', 'Gene', '5013', (184, 188))	('NSCLC', 'Disease', (229, 234))	('cancers', 'Disease', 'MESH:D009369', (45, 52))	('APC', 'Disease', 'MESH:D011125', (173, 176))	('breast cancer', 'Phenotype', 'HP:0003002', (125, 138))	('APC', 'Disease', (173, 176))	('NSCLC', 'Phenotype', 'HP:0030358', (229, 234))	('breast tumor', 'Disease', 'MESH:D001943', (245, 257))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (297, 334))	('HOX2', 'Gene', '3210', (178, 182))	('non-small cell lung carcinoma', 'Disease', 'MESH:D002289', (198, 227))	('HOX2', 'Gene', (178, 182))	('breast cancer', 'Disease', 'MESH:D001943', (125, 138))	('tumor', 'Phenotype', 'HP:0002664', (252, 257))	('neoplasm', 'Phenotype', 'HP:0002664', (163, 171))	('FEN1', 'Gene', (237, 241))	('carcinoma', 'Phenotype', 'HP:0030731', (325, 334))	('breast cancer', 'Disease', (125, 138))	('BRCA1', 'Gene', '672', (81, 86))	('ovarian cancer', 'Phenotype', 'HP:0100615', (101, 115))	('MYOD1', 'Gene', (140, 145))	('hyper', 'Disease', (61, 66))	('DOK7', 'Gene', '285489', (117, 121))	('breast tumor', 'Phenotype', 'HP:0100013', (245, 257))	('BRCA1', 'Gene', (81, 86))	('DOK7', 'Gene', (117, 121))	('breast tumor', 'Disease', (245, 257))	('TKTL1', 'Gene', '8277', (288, 293))	('cancers', 'Phenotype', 'HP:0002664', (45, 52))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('cancers', 'Disease', (45, 52))	('SCLC', 'Phenotype', 'HP:0030357', (230, 234))	('small cell lung carcinoma', 'Phenotype', 'HP:0030357', (202, 227))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('carcinoma', 'Phenotype', 'HP:0030731', (218, 227))	('hypomethylation', 'Var', (269, 284))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('hyper', 'Disease', 'MESH:D053307', (61, 66))	('hematological neoplasm', 'Disease', (149, 171))	('hematological neoplasm', 'Disease', 'MESH:D019337', (149, 171))	('MYOD1', 'Gene', '4654', (140, 145))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (311, 334))	('neck squamous cell carcinoma', 'Disease', (306, 334))	('NSCLC', 'Disease', 'MESH:D002289', (229, 234))	('non-small cell lung carcinoma', 'Phenotype', 'HP:0030358', (198, 227))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (306, 334))	('non-small cell lung carcinoma', 'Disease', (198, 227))	('hematological neoplasm', 'Phenotype', 'HP:0004377', (149, 171))	('TKTL1', 'Gene', (288, 293))
23759	24369052	Early stage HOXA9 methylation has been identified in lung cancer and used in early detection and prognosis.	('HOXA9', 'Gene', (12, 17))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('lung cancer', 'Disease', 'MESH:D008175', (53, 64))	('identified', 'Reg', (39, 49))	('methylation', 'Var', (18, 29))	('HOXA9', 'Gene', '3205', (12, 17))	('lung cancer', 'Disease', (53, 64))	('lung cancer', 'Phenotype', 'HP:0100526', (53, 64))
23760	24369052	Our analysis found HOX genes in all stages, with hypermethylation in Stages I and III, hypomethylation in Stage II.	('hyper', 'Disease', 'MESH:D053307', (49, 54))	('hypomethylation', 'Var', (87, 102))	('HOX genes', 'Gene', (19, 28))	('hyper', 'Disease', (49, 54))
23762	24369052	PTGDR has been negatively correlated with smoking and methylated in colon cancer, however, prior studies have not investigated its role in LUAD.	('PTGDR', 'Gene', (0, 5))	('colon cancer', 'Phenotype', 'HP:0003003', (68, 80))	('colon cancer', 'Disease', 'MESH:D015179', (68, 80))	('negatively', 'NegReg', (15, 25))	('PTGDR', 'Gene', '5729', (0, 5))	('LUAD', 'Phenotype', 'HP:0030078', (139, 143))	('colon cancer', 'Disease', (68, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('methylated', 'Var', (54, 64))
23764	24369052	Previous studies have found them as methylated in leukemia and breast cancer respectively but not in LUAD.	('methylated', 'Var', (36, 46))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('breast cancer', 'Disease', 'MESH:D001943', (63, 76))	('LUAD', 'Phenotype', 'HP:0030078', (101, 105))	('breast cancer', 'Disease', (63, 76))	('breast cancer', 'Phenotype', 'HP:0003002', (63, 76))	('leukemia', 'Disease', (50, 58))	('leukemia', 'Disease', 'MESH:D007938', (50, 58))	('leukemia', 'Phenotype', 'HP:0001909', (50, 58))
23766	24369052	EVX1 and OTX2 (see Table 2) were identified as methylated in NSCLC and lung cancer.	('methylated', 'Var', (47, 57))	('OTX2', 'Gene', '5015', (9, 13))	('EVX1', 'Gene', (0, 4))	('lung cancer', 'Disease', 'MESH:D008175', (71, 82))	('NSCLC', 'Phenotype', 'HP:0030358', (61, 66))	('SCLC', 'Phenotype', 'HP:0030357', (62, 66))	('OTX2', 'Gene', (9, 13))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('NSCLC', 'Disease', (61, 66))	('EVX1', 'Gene', '2128', (0, 4))	('NSCLC', 'Disease', 'MESH:D002289', (61, 66))	('lung cancer', 'Disease', (71, 82))	('lung cancer', 'Phenotype', 'HP:0100526', (71, 82))
23769	24369052	Of the 12 common Significant DNA methylated genes common to Stages I and II, LY96 has been previously associated with lung cancer; ZNF577 and LVRN have been identified as methylated in lung cancer and renal carcinoma, but not in LUAD.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('lung cancer', 'Disease', (118, 129))	('lung cancer', 'Disease', 'MESH:D008175', (185, 196))	('carcinoma', 'Phenotype', 'HP:0030731', (207, 216))	('ZNF577', 'Gene', (131, 137))	('lung cancer', 'Phenotype', 'HP:0100526', (185, 196))	('LUAD', 'Phenotype', 'HP:0030078', (229, 233))	('ZNF577', 'Gene', '84765', (131, 137))	('renal carcinoma', 'Disease', 'MESH:C538614', (201, 216))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('renal carcinoma', 'Disease', (201, 216))	('methylated', 'Var', (171, 181))	('associated', 'Reg', (102, 112))	('renal carcinoma', 'Phenotype', 'HP:0005584', (201, 216))	('lung cancer', 'Disease', 'MESH:D008175', (118, 129))	('lung cancer', 'Phenotype', 'HP:0100526', (118, 129))	('LY96', 'Gene', '23643', (77, 81))	('LVRN', 'Gene', (142, 146))	('LY96', 'Gene', (77, 81))	('lung cancer', 'Disease', (185, 196))	('LVRN', 'Gene', '206338', (142, 146))
23773	24369052	SERPINB5 and TAL1 have been identified as methylated in NSCLC.	('methylated', 'Var', (42, 52))	('SERPINB5', 'Gene', (0, 8))	('NSCLC', 'Disease', (56, 61))	('SERPINB5', 'Gene', '5268', (0, 8))	('TAL1', 'Gene', '6886', (13, 17))	('NSCLC', 'Disease', 'MESH:D002289', (56, 61))	('SCLC', 'Phenotype', 'HP:0030357', (57, 61))	('TAL1', 'Gene', (13, 17))	('NSCLC', 'Phenotype', 'HP:0030358', (56, 61))
23777	24369052	Literature validation of these genes with respect to their importance in LUAD and other cancers found NMUR2 to be overexpressed in pancreatic cancer, AJAP1 epigenetically silenced in Glioblastoma.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (131, 148))	('Glioblastoma', 'Phenotype', 'HP:0012174', (183, 195))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('LUAD', 'Phenotype', 'HP:0030078', (73, 77))	('epigenetically silenced', 'Var', (156, 179))	('cancers', 'Disease', 'MESH:D009369', (88, 95))	('NMUR2', 'Gene', '56923', (102, 107))	('Glioblastoma', 'Disease', (183, 195))	('NMUR2', 'Gene', (102, 107))	('cancers', 'Disease', (88, 95))	('overexpressed', 'PosReg', (114, 127))	('pancreatic cancer', 'Disease', (131, 148))	('pancreatic cancer', 'Disease', 'MESH:D010190', (131, 148))	('AJAP1', 'Gene', '55966', (150, 155))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('Glioblastoma', 'Disease', 'MESH:D005909', (183, 195))	('AJAP1', 'Gene', (150, 155))
23782	24369052	Recent studies have reported SOX17 methylation in lung cancer, but not at the stage level.	('lung cancer', 'Disease', (50, 61))	('SOX17', 'Gene', '64321', (29, 34))	('reported', 'Reg', (20, 28))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('lung cancer', 'Disease', 'MESH:D008175', (50, 61))	('SOX17', 'Gene', (29, 34))	('methylation', 'Var', (35, 46))	('lung cancer', 'Phenotype', 'HP:0100526', (50, 61))
23784	24369052	Of the four Significant hypomethylated genes in Stage I and III, in addition to KRATAP8-1 and MMP26 which were analyzed in the above section, CORO6 was also hypomethylated and has been reported as an epigenetic gene in renal cell carcinoma but not in LUAD.	('LUAD', 'Phenotype', 'HP:0030078', (251, 255))	('MMP26', 'Gene', (94, 99))	('MMP26', 'Gene', '56547', (94, 99))	('CORO6', 'Gene', (142, 147))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (219, 239))	('carcinoma', 'Phenotype', 'HP:0030731', (230, 239))	('hypomethylated', 'Var', (157, 171))	('renal cell carcinoma', 'Disease', (219, 239))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (219, 239))	('CORO6', 'Gene', '84940', (142, 147))
23805	24369052	Chromosome 14 has been associated with genetic variation in lung cancer.	('lung cancer', 'Disease', (60, 71))	('lung cancer', 'Phenotype', 'HP:0100526', (60, 71))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('lung cancer', 'Disease', 'MESH:D008175', (60, 71))	('genetic variation', 'Var', (39, 56))	('associated', 'Reg', (23, 33))
23806	24369052	In Stage III chromosome, 10 was identified with nine hypermethylated genes and these were: LBX1, NKX6-2, PTF1A, SLC18A3, SORC3, SPAG6, C10orf26, and C10orf82.	('PTF1', 'Species', '32651', (105, 109))	('PTF1A', 'Gene', (105, 110))	('NKX6-2', 'Gene', '84504', (97, 103))	('NKX6-2', 'Gene', (97, 103))	('C10orf82', 'Var', (149, 157))	('hyper', 'Disease', 'MESH:D053307', (53, 58))	('SPAG6', 'Gene', (128, 133))	('C10orf26', 'Var', (135, 143))	('SLC18A3', 'Gene', (112, 119))	('LBX1', 'Gene', '10660', (91, 95))	('hyper', 'Disease', (53, 58))	('SPAG6', 'Gene', '9576', (128, 133))	('LBX1', 'Gene', (91, 95))
23807	24369052	The ladybird homeobox 1 (LBX1) gene has been associated with the breakpoint regions involved in T-cell leukemia and methylated in prostate cancer.	('T-cell leukemia', 'Disease', (96, 111))	('prostate cancer', 'Disease', (130, 145))	('ladybird homeobox 1', 'Gene', '10660', (4, 23))	('T-cell leukemia', 'Disease', 'MESH:D015458', (96, 111))	('leukemia', 'Phenotype', 'HP:0001909', (103, 111))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('associated', 'Reg', (45, 55))	('prostate cancer', 'Disease', 'MESH:D011471', (130, 145))	('ladybird homeobox 1', 'Gene', (4, 23))	('prostate cancer', 'Phenotype', 'HP:0012125', (130, 145))	('LBX1', 'Gene', (25, 29))	('LBX1', 'Gene', '10660', (25, 29))	('methylated', 'Var', (116, 126))
23813	24369052	It has been reported that genes silenced due to promoter methylation were mostly tumor suppressor genes, and silencing of these genes can eventually affect all the pathways especially cell cycle, DNA repair genes, apoptosis, signaling etc., which could lead to tumor progression.	('lead to', 'Reg', (253, 260))	('apoptosis', 'CPA', (214, 223))	('DNA repair genes', 'Gene', (196, 212))	('tumor', 'Phenotype', 'HP:0002664', (261, 266))	('tumor', 'Disease', (261, 266))	('affect', 'Reg', (149, 155))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('silencing', 'Var', (109, 118))	('signaling', 'Pathway', (225, 234))	('cell', 'Pathway', (184, 188))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Disease', 'MESH:D009369', (261, 266))	('tumor', 'Disease', (81, 86))
23814	24369052	An example of this propagation was gene LY96 which was identified in our analysis as hypermethylated in Stage I and hypomethylated in Stage II (Table 2).	('hyper', 'Disease', (85, 90))	('LY96', 'Gene', (40, 44))	('hypomethylated', 'Var', (116, 130))	('hyper', 'Disease', 'MESH:D053307', (85, 90))	('LY96', 'Gene', '23643', (40, 44))
23820	24369052	In addition, the focal adhesion pathway associated with Stage II has been reported to be involved with multiple signaling events in lung cancer, suggesting that methylation of this pathway might also affect the signaling pathways.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('focal adhesion pathway', 'Pathway', (17, 39))	('affect', 'Reg', (200, 206))	('lung cancer', 'Disease', 'MESH:D008175', (132, 143))	('methylation', 'Var', (161, 172))	('lung cancer', 'Disease', (132, 143))	('lung cancer', 'Phenotype', 'HP:0100526', (132, 143))	('signaling pathways', 'Pathway', (211, 229))
23826	24369052	EGFR mutations were associated with NSCLC (http://www.egfr.org).	('egfr', 'Gene', '1956', (54, 58))	('associated', 'Reg', (20, 30))	('EGFR', 'Gene', (0, 4))	('NSCLC', 'Phenotype', 'HP:0030358', (36, 41))	('egfr', 'Gene', (54, 58))	('mutations', 'Var', (5, 14))	('NSCLC', 'Disease', (36, 41))	('SCLC', 'Phenotype', 'HP:0030357', (37, 41))	('NSCLC', 'Disease', 'MESH:D002289', (36, 41))	('EGFR', 'Gene', '1956', (0, 4))
23833	24369052	This analysis also confirms that epigenetic genes are not usually hub genes, but have a direct correlation with TF.	('hub', 'Gene', '1993', (66, 69))	('correlation', 'Interaction', (95, 106))	('epigenetic genes', 'Var', (33, 49))	('hub', 'Gene', (66, 69))
23848	24369052	Recent studies have identified BRAF mutations in NSCLC.	('NSCLC', 'Disease', (49, 54))	('NSCLC', 'Disease', 'MESH:D002289', (49, 54))	('mutations', 'Var', (36, 45))	('SCLC', 'Phenotype', 'HP:0030357', (50, 54))	('BRAF', 'Gene', '673', (31, 35))	('NSCLC', 'Phenotype', 'HP:0030358', (49, 54))	('BRAF', 'Gene', (31, 35))
23851	24369052	PIK3CA mutations have been identified in many cancers.	('identified', 'Reg', (27, 37))	('cancers', 'Disease', 'MESH:D009369', (46, 53))	('cancers', 'Phenotype', 'HP:0002664', (46, 53))	('cancers', 'Disease', (46, 53))	('PIK3CA', 'Gene', (0, 6))	('PIK3CA', 'Gene', '5290', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('mutations', 'Var', (7, 16))
23852	24369052	The PIK3CA pathway consist of the KRAS and EGFR genes which are important targets for many cancers, mutations of PIK3CA have been also identified in lung cancer.	('KRAS', 'Gene', '3845', (34, 38))	('mutations', 'Var', (100, 109))	('lung cancer', 'Disease', 'MESH:D008175', (149, 160))	('cancers', 'Disease', 'MESH:D009369', (91, 98))	('PIK3CA', 'Gene', (113, 119))	('cancers', 'Phenotype', 'HP:0002664', (91, 98))	('identified', 'Reg', (135, 145))	('cancers', 'Disease', (91, 98))	('PIK3CA', 'Gene', (4, 10))	('PIK3CA', 'Gene', '5290', (113, 119))	('EGFR', 'Gene', '1956', (43, 47))	('lung cancer', 'Phenotype', 'HP:0100526', (149, 160))	('PIK3CA', 'Gene', '5290', (4, 10))	('lung cancer', 'Disease', (149, 160))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('EGFR', 'Gene', (43, 47))	('KRAS', 'Gene', (34, 38))
23856	24369052	System biology approach stated that epigenetic genes were not the hub nodes but could still affect the hub genes in the networks, eventually playing a critical role in the disease mechanism.	('hub', 'Gene', '1993', (66, 69))	('hub', 'Gene', '1993', (103, 106))	('epigenetic genes', 'Var', (36, 52))	('affect', 'Reg', (92, 98))	('hub', 'Gene', (66, 69))	('hub', 'Gene', (103, 106))
23943	31795956	These accumulated genetic alterations could eventually develop to multiple progressive cancers in the same or independent fields.	('genetic alterations', 'Var', (18, 37))	('cancers', 'Disease', (87, 94))	('develop to', 'Reg', (55, 65))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cancers', 'Phenotype', 'HP:0002664', (87, 94))	('cancers', 'Disease', 'MESH:D009369', (87, 94))
24009	31659178	Similar to TMPRSS4, DDR1 promoter was hypomethylated in NSCLC in 3 independent cohorts and hypomethylation was an independent prognostic factor of disease-free survival.	('NSCLC', 'Disease', (56, 61))	('TMPRSS4', 'Gene', (11, 18))	('NSCLC', 'Disease', 'MESH:D002289', (56, 61))	('DDR1', 'Gene', '780', (20, 24))	('hypomethylated', 'Var', (38, 52))	('TMPRSS4', 'Gene', '56649', (11, 18))	('DDR1', 'Gene', (20, 24))	('hypomethylation', 'Var', (91, 106))	('NSCLC', 'Phenotype', 'HP:0030358', (56, 61))
24016	31659178	Progression of non-small cell lung cancer (NSCLC) is a consequence of both genetic and epigenetic changes that alter intracellular pathways leading to proliferation and invasion.	('lung cancer', 'Phenotype', 'HP:0100526', (30, 41))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (15, 41))	('invasion', 'CPA', (169, 177))	('proliferation', 'CPA', (151, 164))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('non-small cell lung cancer', 'Disease', (15, 41))	('NSCLC', 'Phenotype', 'HP:0030358', (43, 48))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (19, 41))	('intracellular pathways', 'Pathway', (117, 139))	('epigenetic changes', 'Var', (87, 105))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (15, 41))	('NSCLC', 'Disease', (43, 48))	('alter', 'Reg', (111, 116))	('NSCLC', 'Disease', 'MESH:D002289', (43, 48))
24017	31659178	DNA promoter hypomethylation can cause expression of oncogenes, whereas hypermethylation has been associated with silencing of tumor suppressor genes.	('cause', 'Reg', (33, 38))	('hypomethylation', 'Var', (13, 28))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('oncogenes', 'MPA', (53, 62))	('tumor', 'Disease', (127, 132))	('expression', 'MPA', (39, 49))	('tumor', 'Disease', 'MESH:D009369', (127, 132))
24018	31659178	Changes in cell-cell and cell-extracellular matrix (ECM) interactions are crucial for metastasis development, where proteases play a key role in the modification of tumor cells and ECM properties, a reason whereby dysregulation of protease activity is considered as a hallmark of cancer.	('dysregulation', 'Var', (214, 227))	('ECM', 'Gene', '22915', (181, 184))	('hallmark of cancer', 'Disease', 'MESH:D009369', (268, 286))	('ECM', 'Gene', (181, 184))	('ECM', 'Gene', '22915', (52, 55))	('hallmark of cancer', 'Disease', (268, 286))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('cancer', 'Phenotype', 'HP:0002664', (280, 286))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('ECM', 'Gene', (52, 55))	('metastasis', 'CPA', (86, 96))	('tumor', 'Disease', (165, 170))
24020	31659178	We have previously shown that high levels of TMPRSS4 are significantly associated with worse prognosis in patients with squamous NSCLC and that increased expression of this protein is induced by hypomethylation of the TMPRSS4 DNA promoter.	('TMPRSS4', 'Gene', (218, 225))	('NSCLC', 'Phenotype', 'HP:0030358', (129, 134))	('increased', 'PosReg', (144, 153))	('hypomethylation', 'Var', (195, 210))	('TMPRSS4', 'Gene', '56649', (218, 225))	('TMPRSS4', 'Gene', (45, 52))	('high', 'Var', (30, 34))	('NSCLC', 'Disease', (129, 134))	('patients', 'Species', '9606', (106, 114))	('NSCLC', 'Disease', 'MESH:D002289', (129, 134))	('induced by', 'Reg', (184, 194))	('TMPRSS4', 'Gene', '56649', (45, 52))	('associated', 'Reg', (71, 81))	('expression', 'MPA', (154, 164))
24024	31659178	We have also found that both TMPRSS4 and DDR1 are co-regulated by promoter hypomethylation, which is associated with poor prognosis.	('TMPRSS4', 'Gene', '56649', (29, 36))	('promoter hypomethylation', 'Var', (66, 90))	('associated', 'Reg', (101, 111))	('DDR1', 'Gene', '780', (41, 45))	('TMPRSS4', 'Gene', (29, 36))	('DDR1', 'Gene', (41, 45))
24031	31659178	This suggests that tumors with high TMPRSS4 expression may be associated with pathways involving cancer cell-ECM crosstalk in NSCLC, in agreement with the prometastatic role of TMPRSS4.	('tumors', 'Disease', (19, 25))	('ECM', 'Gene', (109, 112))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('NSCLC', 'Disease', 'MESH:D002289', (126, 131))	('cancer', 'Disease', (97, 103))	('associated', 'Reg', (62, 72))	('TMPRSS4', 'Gene', '56649', (177, 184))	('TMPRSS4', 'Gene', '56649', (36, 43))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('NSCLC', 'Disease', (126, 131))	('NSCLC', 'Phenotype', 'HP:0030358', (126, 131))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('ECM', 'Gene', '22915', (109, 112))	('TMPRSS4', 'Gene', (177, 184))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('TMPRSS4', 'Gene', (36, 43))	('high', 'Var', (31, 35))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
24033	31659178	High DDR1 expression has been associated with poor prognosis in NSCLC.	('NSCLC', 'Disease', 'MESH:D002289', (64, 69))	('High', 'Var', (0, 4))	('DDR1', 'Gene', '780', (5, 9))	('expression', 'MPA', (10, 20))	('NSCLC', 'Phenotype', 'HP:0030358', (64, 69))	('DDR1', 'Gene', (5, 9))	('NSCLC', 'Disease', (64, 69))
24040	31659178	Similarly, knock-down of DDR1 did not change levels of TMPRSS4 expression (Supplementary Fig.	('knock-down', 'Var', (11, 21))	('TMPRSS4', 'Gene', (55, 62))	('DDR1', 'Gene', '780', (25, 29))	('DDR1', 'Gene', (25, 29))	('TMPRSS4', 'Gene', '56649', (55, 62))
24045	31659178	High levels of DDR1 were associated with reduced OS in stage I NSCLC (Fig.	('NSCLC', 'Disease', (63, 68))	('reduced', 'NegReg', (41, 48))	('NSCLC', 'Disease', 'MESH:D002289', (63, 68))	('DDR1', 'Gene', '780', (15, 19))	('High levels', 'Var', (0, 11))	('DDR1', 'Gene', (15, 19))	('NSCLC', 'Phenotype', 'HP:0030358', (63, 68))
24046	31659178	When separated by histology, patients with LUAD and high levels of DDR1 showed reduced OS (Fig.	('patients', 'Species', '9606', (29, 37))	('reduced', 'NegReg', (79, 86))	('high levels', 'Var', (52, 63))	('DDR1', 'Gene', '780', (67, 71))	('DDR1', 'Gene', (67, 71))	('LUAD', 'Disease', (43, 47))	('LUAD', 'Disease', 'MESH:C538231', (43, 47))	('LUAD', 'Phenotype', 'HP:0030078', (43, 47))
24049	31659178	DNA promoter hypomethylation is responsible for overexpression of TMPRSS4 in NSCLC.	('NSCLC', 'Disease', 'MESH:D002289', (77, 82))	('hypomethylation', 'Var', (13, 28))	('TMPRSS4', 'Gene', (66, 73))	('NSCLC', 'Phenotype', 'HP:0030358', (77, 82))	('overexpression', 'PosReg', (48, 62))	('TMPRSS4', 'Gene', '56649', (66, 73))	('NSCLC', 'Disease', (77, 82))
24051	31659178	The DDR1 promoter contains a CpG island (from cg23001000 to cg26858073), flanked by a 5' upstream shore (north) and a 3' downstream shore (south).	('cg26858073', 'Var', (60, 70))	('DDR1', 'Gene', (4, 8))	('cg23001000', 'Var', (46, 56))	('DDR1', 'Gene', '780', (4, 8))
24053	31659178	This reflects the presence of consistent hypomethylation in NSCLC.	('hypomethylation', 'Var', (41, 56))	('NSCLC', 'Disease', (60, 65))	('NSCLC', 'Phenotype', 'HP:0030358', (60, 65))	('NSCLC', 'Disease', 'MESH:D002289', (60, 65))
24055	31659178	A specific region comprising 5 consecutive CpGs (from cg23953820 to cg02680487) with consistent hypomethylation in cancer specimens but not in non-malignant lung was identified in the north shore.	('hypomethylation in cancer', 'Disease', (96, 121))	('cg02680487', 'Var', (68, 78))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('hypomethylation in cancer', 'Disease', 'MESH:D009369', (96, 121))	('cg23953820', 'Var', (54, 64))	('CpGs', 'Chemical', 'MESH:C024660', (43, 47))
24056	31659178	Statistical comparisons confirmed that all these CpGs were significantly hypomethylated in LUAD and LUSC with respect to normal samples, for both CURELUNG (Fig.	('CpGs', 'Chemical', 'MESH:C024660', (49, 53))	('hypomethylated', 'Var', (73, 87))	('LUSC', 'Disease', 'MESH:D002294', (100, 104))	('LUSC', 'Disease', (100, 104))	('LUAD', 'Disease', (91, 95))	('LUAD', 'Disease', 'MESH:C538231', (91, 95))	('LUAD', 'Phenotype', 'HP:0030078', (91, 95))
24060	31659178	These results suggest that DDR1 and TMPRSS4 are co-regulated by hypomethylation.	('TMPRSS4', 'Gene', '56649', (36, 43))	('DDR1', 'Gene', '780', (27, 31))	('TMPRSS4', 'Gene', (36, 43))	('hypomethylation', 'Var', (64, 79))	('DDR1', 'Gene', (27, 31))
24063	31659178	When considering all NSCLC patients, hypomethylation was associated with worse DFS for all the CpGs.	('NSCLC', 'Disease', (21, 26))	('NSCLC', 'Disease', 'MESH:D002289', (21, 26))	('worse', 'NegReg', (73, 78))	('DFS', 'Disease', (79, 82))	('patients', 'Species', '9606', (27, 35))	('NSCLC', 'Phenotype', 'HP:0030358', (21, 26))	('CpGs', 'Chemical', 'MESH:C024660', (95, 99))	('hypomethylation', 'Var', (37, 52))
24066	31659178	3D, which shows that DFS was significantly lower in patients with DDR1 hypomethylation (p = 0.016).	('DDR1', 'Gene', (66, 70))	('DFS', 'MPA', (21, 24))	('DDR1', 'Gene', '780', (66, 70))	('hypomethylation', 'Var', (71, 86))	('patients', 'Species', '9606', (52, 60))	('lower', 'NegReg', (43, 48))
24072	31659178	Treatment with the demethylating agent 5'-azacitidine in some cells with DDR1 methylated promoter increased DDR1 levels (Fig.	('DDR1', 'Gene', '780', (108, 112))	('DDR1', 'Gene', (73, 77))	('DDR1', 'Gene', (108, 112))	('increased', 'PosReg', (98, 107))	('promoter', 'Var', (89, 97))	('DDR1', 'Gene', '780', (73, 77))	("5'-azacitidine", 'Chemical', 'MESH:D001374', (39, 53))
24073	31659178	Having demonstrated that both DDR1 and TMPRSS4 are co-expressed and epigenetically co-regulated in NSCLC, we wondered whether these genes could cooperate functionally to maintain a malignant cell behavior.	('TMPRSS4', 'Gene', (39, 46))	('epigenetically', 'Var', (68, 82))	('TMPRSS4', 'Gene', '56649', (39, 46))	('NSCLC', 'Phenotype', 'HP:0030358', (99, 104))	('DDR1', 'Gene', '780', (30, 34))	('DDR1', 'Gene', (30, 34))	('NSCLC', 'Disease', (99, 104))	('NSCLC', 'Disease', 'MESH:D002289', (99, 104))
24083	31659178	Regarding cell cycle related proteins, whereas there were little changes in shDDR1 and shTMPRSS4 clones, a total disappearance of cyclins A and B1 (both involved in S and G2/M transition) was found in double KD cells (Fig.	('cyclins A and B1', 'Gene', '890;891', (130, 146))	('TMPRSS4', 'Gene', (89, 96))	('double KD', 'Var', (201, 210))	('DDR1', 'Gene', '780', (78, 82))	('disappearance', 'NegReg', (113, 126))	('DDR1', 'Gene', (78, 82))	('TMPRSS4', 'Gene', '56649', (89, 96))
24084	31659178	Moreover, cyclin D1 levels were higher in the double KD clone, which could be related with a compensatory mechanism resulting from impaired cell proliferation.	('cyclin D1', 'Gene', '595', (10, 19))	('cyclin D1', 'Gene', (10, 19))	('double KD', 'Var', (46, 55))	('higher', 'PosReg', (32, 38))
24089	31659178	Strikingly, tumors of the double KD group regressed rapidly after administration of doxycycline and were 93% smaller (p < 0.001) than controls at the end of the experiment.	('smaller', 'NegReg', (109, 116))	('doxycycline', 'Chemical', 'MESH:D004318', (84, 95))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('double KD', 'Var', (26, 35))	('tumors', 'Disease', (12, 18))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('tumors', 'Disease', 'MESH:D009369', (12, 18))
24092	31659178	In the double KD, basal apoptosis (without cisplatin) was higher than that found for the single KD and control cells (black bars in Fig.	('double KD', 'Var', (7, 16))	('basal apoptosis', 'CPA', (18, 33))	('higher', 'PosReg', (58, 64))	('cisplatin', 'Chemical', 'MESH:D002945', (43, 52))
24097	31659178	Malignancy of cancer cells is usually maintained by multiple genetic and epigenetic alterations, some of which may cooperate in order to sustain tumor growth.	('epigenetic alterations', 'Var', (73, 95))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('Malignancy of cancer', 'Disease', 'MESH:D009369', (0, 20))	('Malignancy of cancer', 'Disease', (0, 20))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('tumor', 'Disease', (145, 150))
24100	31659178	Moreover, increased TMPRSS4 levels are due to DNA hypomethylation, which is also associated with reduced DFS.	('reduced', 'NegReg', (97, 104))	('TMPRSS4', 'Gene', (20, 27))	('TMPRSS4', 'Gene', '56649', (20, 27))	('increased', 'PosReg', (10, 19))	('hypomethylation', 'Var', (50, 65))
24101	31659178	We have found in the present study that, similar to TMPRSS4, hypomethylation of DDR1 causes DDR1 overexpression and that both expression and methylation status can be used as prognostic indicators in NSCLC.	('overexpression', 'PosReg', (97, 111))	('NSCLC', 'Phenotype', 'HP:0030358', (200, 205))	('TMPRSS4', 'Gene', '56649', (52, 59))	('DDR1', 'Gene', '780', (80, 84))	('DDR1', 'Gene', (80, 84))	('NSCLC', 'Disease', (200, 205))	('DDR1', 'Gene', '780', (92, 96))	('TMPRSS4', 'Gene', (52, 59))	('DDR1', 'Gene', (92, 96))	('NSCLC', 'Disease', 'MESH:D002289', (200, 205))	('hypomethylation', 'Var', (61, 76))
24103	31659178	Importantly, treatment of cells with 5-azacitidine increased levels of DDR1, a result that was also reported for TMPRSS4.	('increased', 'PosReg', (51, 60))	('DDR1', 'Gene', '780', (71, 75))	('DDR1', 'Gene', (71, 75))	('TMPRSS4', 'Gene', '56649', (113, 120))	('5-azacitidine', 'Chemical', 'MESH:D001374', (37, 50))	('5-azacitidine', 'Var', (37, 50))	('TMPRSS4', 'Gene', (113, 120))
24107	31659178	DDR1 may promote cell division depending on the cell type: in H460 NSCLC cells, abrogation of DDR1 levels did not modify proliferation in vitro, but affected invasion and reduced bone metastasis in vivo.	('abrogation', 'Var', (80, 90))	('DDR1', 'Gene', '780', (94, 98))	('NSCLC', 'Phenotype', 'HP:0030358', (67, 72))	('DDR1', 'Gene', (94, 98))	('bone metastasis', 'CPA', (179, 194))	('invasion', 'CPA', (158, 166))	('DDR1', 'Gene', '780', (0, 4))	('NSCLC', 'Disease', (67, 72))	('DDR1', 'Gene', (0, 4))	('affected', 'Reg', (149, 157))	('NSCLC', 'Disease', 'MESH:D002289', (67, 72))	('reduced', 'NegReg', (171, 178))
24109	31659178	Genetic targeting of DDR1 inhibited cell proliferation and subcutaneous tumor growth in glioma.	('Genetic targeting', 'Var', (0, 17))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('inhibited', 'NegReg', (26, 35))	('tumor', 'Disease', (72, 77))	('glioma', 'Disease', (88, 94))	('subcutaneous tumor', 'Phenotype', 'HP:0001482', (59, 77))	('glioma', 'Disease', 'MESH:D005910', (88, 94))	('glioma', 'Phenotype', 'HP:0009733', (88, 94))	('DDR1', 'Gene', '780', (21, 25))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('DDR1', 'Gene', (21, 25))	('cell proliferation', 'CPA', (36, 54))
24110	31659178	Moreover, in human colon carcinoma cells DDR1 depletion caused cell death in response to induced DNA damage.	('colon carcinoma', 'Disease', 'MESH:D015179', (19, 34))	('depletion', 'Var', (46, 55))	('colon carcinoma', 'Disease', (19, 34))	('human', 'Species', '9606', (13, 18))	('cell death', 'CPA', (63, 73))	('DDR1', 'Gene', '780', (41, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (25, 34))	('DDR1', 'Gene', (41, 45))	('response to induced DNA damage', 'MPA', (77, 107))
24112	31659178	Interestingly, lack of TMPRSS4 in these cells caused cisplatin-mediated apoptosis, which was not the case for DDR1.	('lack', 'Var', (15, 19))	('DDR1', 'Gene', (110, 114))	('TMPRSS4', 'Gene', (23, 30))	('cisplatin-mediated apoptosis', 'CPA', (53, 81))	('TMPRSS4', 'Gene', '56649', (23, 30))	('cisplatin', 'Chemical', 'MESH:D002945', (53, 62))	('DDR1', 'Gene', '780', (110, 114))
24113	31659178	Considering the hypothesis of mutual functional cooperation based on co-expression, we treated shTMPRSS4 clones with the DDR1 inhibitor dasatinib and knocked-down both TMPRSS4 and DDR1 in H358 and H2170 cells.	('DDR1', 'Gene', (121, 125))	('dasatinib', 'Chemical', 'MESH:C488369', (136, 145))	('DDR1', 'Gene', '780', (180, 184))	('TMPRSS4', 'Gene', '56649', (97, 104))	('knocked-down', 'Var', (150, 162))	('TMPRSS4', 'Gene', (168, 175))	('DDR1', 'Gene', (180, 184))	('TMPRSS4', 'Gene', '56649', (168, 175))	('TMPRSS4', 'Gene', (97, 104))	('DDR1', 'Gene', '780', (121, 125))
24115	31659178	We have demonstrated that double KD cells suffered G0/G1 cell cycle arrest accompanied by a decrease in the percentage of the cell population in the S and G2/M phases, with loss of cyclins A and B1, but not in cyclins D1 and E. In addition, double KD cells were characterized by loss of E2F1 and increase in p21.	('loss', 'NegReg', (279, 283))	('double', 'Var', (241, 247))	('cyclins A and B1', 'Gene', '890;891', (181, 197))	('p21', 'MPA', (308, 311))	('increase', 'PosReg', (296, 304))	('decrease', 'NegReg', (92, 100))	('E2F1', 'Protein', (287, 291))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (57, 74))	('loss', 'NegReg', (173, 177))	('G0/G1 cell cycle arrest', 'CPA', (51, 74))	('cyclins D1 and E', 'Gene', '595', (210, 226))
24116	31659178	In in vivo experiments, simultaneous abrogation of both genes caused tumor regression and lack of 18-FDG uptake.	('18-FDG', 'Chemical', 'MESH:D019788', (98, 104))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('abrogation', 'Var', (37, 47))	('tumor', 'Disease', (69, 74))	('lack', 'NegReg', (90, 94))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
24118	31659178	Our results show that co-targeting TMPRSS4 and DDR1 produces a synergistic antitumor effect, which fits in the concept of synthetic lethal interaction.	('tumor', 'Disease', (79, 84))	('co-targeting', 'Var', (22, 34))	('DDR1', 'Gene', '780', (47, 51))	('TMPRSS4', 'Gene', (35, 42))	('DDR1', 'Gene', (47, 51))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('TMPRSS4', 'Gene', '56649', (35, 42))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
24120	31659178	The typical example of synthetic lethality is applied to mutations affecting a similar pathway, such as BRCA/PARP, where co-targeting leaves cells unprotected from DNA damage and repair.	('BRCA', 'Gene', '672', (104, 108))	('BRCA', 'Gene', (104, 108))	('mutations', 'Var', (57, 66))	('PARP', 'Gene', '1302', (109, 113))	('PARP', 'Gene', (109, 113))
24123	31659178	As synthetic lethality frequently occurs when targeting genes from parallel pathways involved in similar functions, it is possible that blockade of both TMPRSS4 and DDR1 makes cells succumb to insufficient proliferation/survival signals.	('TMPRSS4', 'Gene', '56649', (153, 160))	('blockade', 'Var', (136, 144))	('TMPRSS4', 'Gene', (153, 160))	('DDR1', 'Gene', '780', (165, 169))	('DDR1', 'Gene', (165, 169))
24125	31659178	Co-inhibition of TMPRSS4 and DDR1 could then constitute a novel therapeutic strategy for NSCLC.	('NSCLC', 'Disease', 'MESH:D002289', (89, 94))	('TMPRSS4', 'Gene', (17, 24))	('DDR1', 'Gene', '780', (29, 33))	('DDR1', 'Gene', (29, 33))	('NSCLC', 'Phenotype', 'HP:0030358', (89, 94))	('TMPRSS4', 'Gene', '56649', (17, 24))	('Co-inhibition', 'Var', (0, 13))	('NSCLC', 'Disease', (89, 94))
24127	31659178	Dasatinib is currently being tested in clinical trials for the treatment of cancer patients (NCT02389309, NCT03216070).	('NCT02389309', 'Var', (93, 104))	('patients', 'Species', '9606', (83, 91))	('Dasatinib', 'Chemical', 'MESH:C488369', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('NCT03216070', 'Var', (106, 117))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))
24133	31659178	In functional in vitro and in vivo experiments we have shown a novel cancer vulnerability based on a synthetic lethal interaction when both genes are absent.	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('synthetic', 'Var', (101, 110))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('cancer', 'Disease', (69, 75))
24142	31659178	Quantitative DNA methylation analysis of the DDR1 promoter was performed by bisulfite pyrosequencing of the following CpG's: cg23953820, cg08469255 and cg14279856.	('cg23953820', 'Var', (125, 135))	('DDR1', 'Gene', '780', (45, 49))	('cg14279856', 'Var', (152, 162))	('DDR1', 'Gene', (45, 49))	('cg08469255', 'Var', (137, 147))	('bisulfite', 'Chemical', 'MESH:C042345', (76, 85))
24158	31659178	CEL files from Gene Expression Omnibus (GEO) were downloaded from the following datasets in the case of lung squamous carcinoma (LUSC): GSE4573, GSE3141, and GSE8894.	('GSE3141', 'Var', (145, 152))	('GSE8894', 'Chemical', 'MESH:C045330', (158, 165))	('lung squamous carcinoma', 'Disease', (104, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (109, 127))	('GSE4573', 'Var', (136, 143))	('LUSC', 'Disease', 'MESH:D002294', (129, 133))	('LUSC', 'Disease', (129, 133))	('lung squamous carcinoma', 'Disease', 'MESH:D002294', (104, 127))	('GSE8894', 'Var', (158, 165))
24159	31659178	For lung adenocarcinoma (LUAD) we used GSE3141, GSE8894 and GSE31210.	('lung adenocarcinoma', 'Disease', (4, 23))	('LUAD', 'Disease', (25, 29))	('GSE31210', 'Var', (60, 68))	('LUAD', 'Disease', 'MESH:C538231', (25, 29))	('GSE8894', 'Var', (48, 55))	('GSE3141', 'Var', (39, 46))	('GSE8894', 'Chemical', 'MESH:C045330', (48, 55))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (4, 23))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (4, 23))	('carcinoma', 'Phenotype', 'HP:0030731', (14, 23))	('LUAD', 'Phenotype', 'HP:0030078', (25, 29))
24237	31184445	Although previous similar studies conflicted and made drawing conclusions about whether COPD was a prognostic factor for NSCLC difficult, our findings supported the view that presence of COPD was a poor prognosis factor for survival in this group of NSCLC.	('NSCLC', 'Disease', 'MESH:D002289', (250, 255))	('COPD', 'Gene', '260431', (187, 191))	('NSCLC', 'Disease', (121, 126))	('COPD', 'Phenotype', 'HP:0006510', (187, 191))	('COPD', 'Gene', (187, 191))	('COPD', 'Gene', '260431', (88, 92))	('NSCLC', 'Disease', 'MESH:D002289', (121, 126))	('presence', 'Var', (175, 183))	('COPD', 'Phenotype', 'HP:0006510', (88, 92))	('COPD', 'Gene', (88, 92))	('NSCLC', 'Disease', (250, 255))
24240	31184445	There were more heavy smokers in CODP group, and they were more prone to cardiovascular, cerebrovascular diseases and chronic renal disease.	('cardiovascular', 'Disease', (73, 87))	('chronic renal disease', 'Disease', 'MESH:D051436', (118, 139))	('cerebrovascular diseases', 'Disease', (89, 113))	('CODP', 'Var', (33, 37))	('renal disease', 'Phenotype', 'HP:0000112', (126, 139))	('chronic renal disease', 'Disease', (118, 139))	('prone', 'Reg', (64, 69))	('cerebrovascular diseases', 'Disease', 'MESH:D002561', (89, 113))	('chronic renal disease', 'Phenotype', 'HP:0003774', (118, 139))
24289	30381562	A repeat bronchoscopic biopsy of mass in the right bronchus intermedius revealed squamous cell carcinoma and staging workup with fluorodeoxyglucose-positron emission tomography (FDG-PET)/CT-detected an FDG avid mass in the right perihilar region with no evidence of distant metastasis and mediastinal lymphadenopathy, suggestive of locoregional recurrence [Figure 3b and c].	('lymphadenopathy', 'Disease', 'MESH:D008206', (301, 316))	('lymphadenopathy', 'Phenotype', 'HP:0002716', (301, 316))	('fluorodeoxyglucose', 'Chemical', 'MESH:D019788', (129, 147))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('FDG avid', 'Var', (202, 210))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (81, 104))	('lymphadenopathy', 'Disease', (301, 316))	('mediastinal lymphadenopathy', 'Phenotype', 'HP:0100721', (289, 316))	('squamous cell carcinoma', 'Disease', (81, 104))	('FDG', 'Chemical', 'MESH:D019788', (178, 181))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (81, 104))	('FDG', 'Chemical', 'MESH:D019788', (202, 205))
24343	33910626	Emerging evidence indicates that some lncRNAs do encode proteins and play roles in transcriptional, and epigenetic gene regulation, and cancer.	('encode', 'Reg', (49, 55))	('transcriptional', 'MPA', (83, 98))	('proteins', 'Protein', (56, 64))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('epigenetic gene', 'Var', (104, 119))	('cancer', 'Disease', (136, 142))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('play roles', 'Reg', (69, 79))
24386	33910626	Multiple studies have demonstrated that functional lncRNA expression can modulate oncognesis via altered regulation of gene expression and signaling within tumor cells.	('modulate', 'Reg', (73, 81))	('regulation of gene expression', 'MPA', (105, 134))	('lncRNA expression', 'Protein', (51, 68))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('altered', 'Reg', (97, 104))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('oncognesis', 'Disease', (82, 92))	('tumor', 'Disease', (156, 161))	('functional', 'Var', (40, 50))	('signaling', 'MPA', (139, 148))
24394	33910626	found that polymorphisms in lncRNA AC016683.6 significantly increased the risk of lung cancer in the smoking population.	('lncRNA AC016683.6', 'Gene', (28, 45))	('lung cancer', 'Phenotype', 'HP:0100526', (82, 93))	('lung cancer', 'Disease', (82, 93))	('increased', 'Reg', (60, 69))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('polymorphisms', 'Var', (11, 24))	('lung cancer', 'Disease', 'MESH:D008175', (82, 93))
24395	33910626	also reported that there were significant interactions of lncRNA AC008392.1 polymorphisms with smoking exposure to lung cancer susceptibility.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('interactions', 'Interaction', (42, 54))	('lung cancer', 'Disease', 'MESH:D008175', (115, 126))	('lncRNA AC008392.1', 'Gene', (58, 75))	('polymorphisms', 'Var', (76, 89))	('lung cancer', 'Disease', (115, 126))	('lung cancer', 'Phenotype', 'HP:0100526', (115, 126))
24504	28824453	Methods: HOXC10 expression was evaluated in 63 primary lung adenocarcinoma tissues from our local hospital, and further systematically confirmed in lung cancer tissues from six GEO datasets (GSE19188, GSE31210, GSE10072, GSE7670, GSE32863, GSE30219), and Kaplan-Meier plotter database.	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('GSE10072', 'Var', (211, 219))	('GSE7670', 'Var', (221, 228))	('lung cancer', 'Disease', 'MESH:D008175', (148, 159))	('GSE19188', 'Var', (191, 199))	('lung adenocarcinoma', 'Disease', (55, 74))	('GSE32863', 'Var', (230, 238))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (55, 74))	('GSE7670', 'Chemical', '-', (221, 228))	('GSE30219', 'Var', (240, 248))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('lung cancer', 'Disease', (148, 159))	('HOXC10', 'Gene', (9, 15))	('lung cancer', 'Phenotype', 'HP:0100526', (148, 159))	('HOXC10', 'Gene', '3226', (9, 15))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (55, 74))	('GSE31210', 'Var', (201, 209))
24577	28824453	qRT-PCR and western blotting analysis revealed H1975 occupied the highest HOXC10 expression and H460 with the lowest (mRNA and protein levels) (Figures 2A,B; p < 0.0001).	('HOXC10', 'Gene', '3226', (74, 80))	('HOXC10', 'Gene', (74, 80))	('H460', 'CellLine', 'CVCL:0459', (96, 100))	('H1975', 'Var', (47, 52))	('H1975', 'CellLine', 'CVCL:1511', (47, 52))	('highest', 'PosReg', (66, 73))	('lowest', 'NegReg', (110, 116))
24583	28824453	In contrast with untreated or scrambled shRNA control transfected H1975 cells, HOXC10 knockdown significantly decreased the migration and invasion of H1975 cells (Figures 3A,B; p < 0.0001).	('knockdown', 'Var', (86, 95))	('H1975', 'CellLine', 'CVCL:1511', (66, 71))	('migration', 'CPA', (124, 133))	('decreased', 'NegReg', (110, 119))	('HOXC10', 'Gene', '3226', (79, 85))	('HOXC10', 'Gene', (79, 85))	('H1975', 'CellLine', 'CVCL:1511', (150, 155))
24591	28824453	Metastasis-associated genes were identified with the significant association with high HOXC10 expression (Figure S1A).	('high', 'Var', (82, 86))	('association', 'Interaction', (65, 76))	('HOXC10', 'Gene', (87, 93))	('expression', 'MPA', (94, 104))	('HOXC10', 'Gene', '3226', (87, 93))	('Metastasis-associated genes', 'Gene', (0, 27))
24595	28824453	The mRNA and protein levels of MMP-2, MMP-9, VCAM-1, and vimentin were decreased remarkably after being treated with HOXC10 shRNA compared to scrambled shRNA control or untreated H1975 cells, and E-cadherin was significantly enhanced in H1975 cells (Figures 5C,E, Figure S1B).	('H1975', 'Var', (237, 242))	('VCAM-1', 'Gene', (45, 51))	('MMP-9', 'Gene', (38, 43))	('H1975', 'CellLine', 'CVCL:1511', (237, 242))	('VCAM-1', 'Gene', '7412', (45, 51))	('E-cadherin', 'Gene', (196, 206))	('HOXC10', 'Gene', (117, 123))	('MMP-2', 'Gene', '4313', (31, 36))	('vimentin', 'Gene', '7431', (57, 65))	('HOXC10', 'Gene', '3226', (117, 123))	('MMP-2', 'Gene', (31, 36))	('MMP-9', 'Gene', '4318', (38, 43))	('vimentin', 'Gene', (57, 65))	('enhanced', 'PosReg', (225, 233))	('E-cadherin', 'Gene', '999', (196, 206))	('decreased', 'NegReg', (71, 80))	('H1975', 'CellLine', 'CVCL:1511', (179, 184))
24598	28824453	Next, to support our conclusion that HOXC10 is upregulated in lung cancer, we further examined the expression of HOXC10 mRNA in lung cancer patients included in six GEO datasets (GSE19188, GSE31210, GSE10072, GSE7670, GSE32863, GSE30219).	('HOXC10', 'Gene', (113, 119))	('GSE32863', 'Var', (218, 226))	('GSE30219', 'Var', (228, 236))	('upregulated', 'PosReg', (47, 58))	('lung cancer', 'Disease', (62, 73))	('GSE31210', 'Var', (189, 197))	('lung cancer', 'Disease', 'MESH:D008175', (128, 139))	('GSE10072', 'Var', (199, 207))	('patients', 'Species', '9606', (140, 148))	('lung cancer', 'Phenotype', 'HP:0100526', (128, 139))	('GSE7670', 'Chemical', '-', (209, 216))	('lung cancer', 'Disease', 'MESH:D008175', (62, 73))	('HOXC10', 'Gene', (37, 43))	('HOXC10', 'Gene', '3226', (113, 119))	('lung cancer', 'Phenotype', 'HP:0100526', (62, 73))	('GSE7670', 'Var', (209, 216))	('GSE19188', 'Var', (179, 187))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('lung cancer', 'Disease', (128, 139))	('HOXC10', 'Gene', '3226', (37, 43))
24607	28824453	Recently, inappropriate HOX gene expression has been associated with different neoplasias occurred in kidney, colon, lung, skin, bladder, liver, breast, and prostate (Cillo et al.,; Calvo et al.,; Abba et al.,; Cantile et al.,; Yuan et al.,).	('neoplasias', 'Phenotype', 'HP:0002664', (79, 89))	('inappropriate', 'Var', (10, 23))	('lung', 'Disease', (117, 121))	('colon', 'Disease', 'MESH:D015179', (110, 115))	('bladder', 'Disease', (129, 136))	('prostate', 'Disease', (157, 165))	('neoplasias', 'Disease', (79, 89))	('kidney', 'Disease', (102, 108))	('neoplasias', 'Disease', 'MESH:D009369', (79, 89))	('breast', 'Disease', (145, 151))	('skin', 'Disease', (123, 127))	('liver', 'Disease', (138, 143))	('HOX gene', 'Gene', (24, 32))	('associated', 'Reg', (53, 63))	('expression', 'MPA', (33, 43))	('colon', 'Disease', (110, 115))
24648	33066414	Of note, combination therapy has been reported to increases the five-year total survival rate by 6.5% compared with a single modality treatment.	('rat', 'Species', '10116', (89, 92))	('increases', 'PosReg', (50, 59))	('combination', 'Var', (9, 20))	('total survival', 'CPA', (74, 88))
24694	33066414	In addition, the level of the anti-apoptosis Bcl-2 protein was significantly decreased in groups treated with Cis and SB and Cis (21.52%, 17.60%) compared to untreated GMSCs (25.20%).	('Cis', 'Var', (125, 128))	('anti-apoptosis Bcl-2 protein', 'MPA', (30, 58))	('SB', 'Chemical', '-', (118, 120))	('level of', 'MPA', (17, 25))	('GMSCs', 'Chemical', '-', (168, 173))	('Cis', 'Var', (110, 113))	('decreased', 'NegReg', (77, 86))
24714	33066414	CD45, CD90, CD105, and CD34 were used as primary antibodies (Abcam, Cambridge, UK).	('CD90', 'Gene', (6, 10))	('CD45', 'Gene', '5788', (0, 4))	('CD34', 'Gene', '947', (23, 27))	('CD34', 'Gene', (23, 27))	('CD105', 'Var', (12, 17))	('CD45', 'Gene', (0, 4))	('CD90', 'Gene', '7070', (6, 10))
24771	33066414	It is usually accepted that initiation of apoptosis is the primary cytotoxic tool of most cancer chemotherapeutic agents, and deviations in the control of the apoptosis process can affect the sensitivity of malignant cells to multiple drugs.	('deviations', 'Var', (126, 136))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('sensitivity of malignant cells', 'CPA', (192, 222))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('affect', 'Reg', (181, 187))
24779	33066414	However, the presence of p53 exacerbates the cytotoxic effect of the complex.	('p53', 'Gene', (25, 28))	('p53', 'Gene', '7157', (25, 28))	('cytotoxic effect', 'CPA', (45, 61))	('exacerbates', 'PosReg', (29, 40))	('presence', 'Var', (13, 21))
24789	33066414	and M.E.-S.; data curation, R.H.A.-S., G.O., M.A.A., E.T.E., M.E.-S. and N.E.	('M.E.-S.', 'Var', (61, 68))	('rat', 'Species', '10116', (20, 23))	('M.A.A.', 'Var', (45, 51))
24826	31988315	PD-L1 expression status on TCs, as represented as TPS, is generally recognized as a potential biomarker to predict the efficacy of antibodies against PD-1 and PD-L1 for advanced NSCLC, as its predictive values have been examined and indicated in many clinical studies.	('NSCLC', 'Disease', (178, 183))	('PD-1', 'Gene', (150, 154))	('NSCLC', 'Disease', 'MESH:D002289', (178, 183))	('PD-L1', 'Gene', '29126', (159, 164))	('PD-1', 'Gene', '5133', (150, 154))	('PD-L1', 'Gene', (0, 5))	('NSCLC', 'Phenotype', 'HP:0030358', (178, 183))	('antibodies', 'Var', (131, 141))	('PD-L1', 'Gene', '29126', (0, 5))	('PD-L1', 'Gene', (159, 164))
24827	31988315	In clinical practice, for patients with advanced NSCLC with high PD-L1 expression (TPS >= 50), single agent first-line treatment with pembrolizumab, an anti-PD-1 antibody, is recommended as the standard treatment of care.	('NSCLC', 'Disease', (49, 54))	('PD-1', 'Gene', '5133', (157, 161))	('high', 'Var', (60, 64))	('PD-1', 'Gene', (157, 161))	('NSCLC', 'Disease', 'MESH:D002289', (49, 54))	('patients', 'Species', '9606', (26, 34))	('PD-L1', 'Gene', (65, 70))	('NSCLC', 'Phenotype', 'HP:0030358', (49, 54))	('PD-L1', 'Gene', '29126', (65, 70))
24829	31988315	In a recent meta-analysis of 38 studies, positive PD-L1 expression on TCs was associated with worse OS (HR, 1.40 [95% CI, 1.20-1.69]) and RFS (HR, 1.67 [95% CI, 1.22-2.29]) overall, but conflicting results were indicated in some studies included in the meta-analysis.	('RFS', 'MPA', (138, 141))	('PD-L1', 'Gene', (50, 55))	('positive', 'Var', (41, 49))	('worse OS', 'Disease', (94, 102))	('PD-L1', 'Gene', '29126', (50, 55))
24830	31988315	PD-L1 positivity was associated with a favorable prognosis in 11 (31.4%) of 35 studies for OS and in 2 (20.0%) of 10 studies for RFS, respectively.	('PD-L1', 'Gene', (0, 5))	('positivity', 'Var', (6, 16))	('PD-L1', 'Gene', '29126', (0, 5))
24867	31632195	The prognostic value of long noncoding RNA SNHG16 on clinical outcomes in human cancers: a systematic review and meta-analysis Cancer has been a worldwide health problem with a high risk of morbidity and mortality, however ideal biomarkers for effective screening and diagnosis of cancer patients are still lacking.	('cancer', 'Phenotype', 'HP:0002664', (281, 287))	('cancer', 'Disease', 'MESH:D009369', (281, 287))	('cancers', 'Disease', 'MESH:D009369', (80, 87))	('patients', 'Species', '9606', (288, 296))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancers', 'Disease', (80, 87))	('cancer', 'Disease', (281, 287))	('Cancer', 'Phenotype', 'HP:0002664', (127, 133))	('Cancer', 'Disease', (127, 133))	('long noncoding RNA', 'Var', (24, 42))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('human', 'Species', '9606', (74, 79))	('SNHG16', 'Gene', (43, 49))	('SNHG16', 'Gene', '100507246', (43, 49))	('cancer', 'Disease', (80, 86))	('cancers', 'Phenotype', 'HP:0002664', (80, 87))
24874	31632195	In the pooled analysis, high SNHG16 expression significantly predicted worse overall survival (OS) in various cancers (HR = 1.87, 95% CI 1.54-2.26, P < 0.001), and recurrence-free survival (RFS) in bladder cancer (HR = 1.68, 95% CI 1.01-2.79, P = 0.045).	('cancers', 'Disease', (110, 117))	('bladder cancer', 'Disease', 'MESH:D001749', (198, 212))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('recurrence-free survival', 'CPA', (164, 188))	('bladder cancer', 'Disease', (198, 212))	('nt', 'Chemical', 'MESH:D009711', (56, 58))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('overall', 'MPA', (77, 84))	('SNHG16', 'Gene', (29, 35))	('high', 'Var', (24, 28))	('SNHG16', 'Gene', '100507246', (29, 35))	('cancers', 'Phenotype', 'HP:0002664', (110, 117))	('worse', 'NegReg', (71, 76))	('bladder cancer', 'Phenotype', 'HP:0009725', (198, 212))	('cancers', 'Disease', 'MESH:D009369', (110, 117))
24876	31632195	In addition, compared to the low SNHG16 expression group, patients with high SNHG16 expression were more prone to worse clinicopathological features, such as larger tumor size, advanced clinical stage, lymph node metastasis (LNM) and distant metastasis (DM).	('nt', 'Chemical', 'MESH:D009711', (239, 241))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('nt', 'Chemical', 'MESH:D009711', (63, 65))	('distant metastasis', 'CPA', (234, 252))	('lymph node metastasis', 'CPA', (202, 223))	('SNHG16', 'Gene', (33, 39))	('patients', 'Species', '9606', (58, 66))	('SNHG16', 'Gene', '100507246', (33, 39))	('SNHG16', 'Gene', (77, 83))	('high', 'Var', (72, 76))	('SNHG16', 'Gene', '100507246', (77, 83))	('tumor', 'Disease', (165, 170))
24878	31632195	The present study implicated that aberrant expression of lncRNA SNHG16 was strongly associated with clinical survival outcomes in various cancers, and therefore might serve as a promising biomarker for predicting prognosis of human cancers.	('SNHG16', 'Gene', '100507246', (64, 70))	('associated with', 'Reg', (84, 99))	('human', 'Species', '9606', (226, 231))	('cancers', 'Disease', 'MESH:D009369', (232, 239))	('cancers', 'Phenotype', 'HP:0002664', (232, 239))	('aberrant expression', 'Var', (34, 53))	('cancers', 'Disease', (232, 239))	('nt', 'Chemical', 'MESH:D009711', (9, 11))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('cancers', 'Disease', 'MESH:D009369', (138, 145))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('cancers', 'Phenotype', 'HP:0002664', (138, 145))	('cancers', 'Disease', (138, 145))	('nt', 'Chemical', 'MESH:D009711', (40, 42))	('SNHG16', 'Gene', (64, 70))
24888	31632195	Moreover, dysregulation of lncRNAs is significantly correlated with cancer cell proliferation, migration, metastasis and recurrence, implicating a crucial role of lncRNAs in regulation of carcinogenesis and cancer progression.	('correlated', 'Reg', (52, 62))	('cancer', 'Disease', 'MESH:D009369', (207, 213))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('nt', 'Chemical', 'MESH:D009711', (47, 49))	('cancer', 'Disease', (207, 213))	('carcinogenesis', 'Disease', 'MESH:D063646', (188, 202))	('dysregulation', 'Var', (10, 23))	('carcinogenesis', 'Disease', (188, 202))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('recurrence', 'CPA', (121, 131))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('cancer', 'Disease', (68, 74))	('metastasis', 'CPA', (106, 116))	('migration', 'CPA', (95, 104))
24894	31632195	Furthermore, emerging studies have demonstrated and emphasized the importance of lncRNA SNHG16 in regulation of cancer-related signaling pathways, including Wnt/beta-catenin, PI3K/Akt, and JAK2/STAT3 pathway.	('beta-catenin', 'Gene', '1499', (161, 173))	('STAT3', 'Gene', '6774', (194, 199))	('Akt', 'Gene', '207', (180, 183))	('nt', 'Chemical', 'MESH:D009711', (158, 160))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('STAT3', 'Gene', (194, 199))	('PI3', 'Gene', '5266', (175, 178))	('Akt', 'Gene', (180, 183))	('JAK2', 'Gene', '3717', (189, 193))	('lncRNA', 'Var', (81, 87))	('PI3', 'Gene', (175, 178))	('SNHG16', 'Gene', (88, 94))	('SNHG16', 'Gene', '100507246', (88, 94))	('JAK2', 'Gene', (189, 193))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('beta-catenin', 'Gene', (161, 173))
24924	31632195	The pooled result demonstrated that high SNHG16 expression significantly associated with worse OS in cancers (HR = 1.87, 95% CI 1.54-2.26, P < 0.001) (Fig.	('cancers', 'Disease', 'MESH:D009369', (101, 108))	('nt', 'Chemical', 'MESH:D009711', (68, 70))	('cancers', 'Phenotype', 'HP:0002664', (101, 108))	('cancers', 'Disease', (101, 108))	('SNHG16', 'Gene', (41, 47))	('SNHG16', 'Gene', '100507246', (41, 47))	('associated', 'Reg', (73, 83))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('high', 'Var', (36, 40))
24926	31632195	2b, the results indicated that high SNHG16 expression in serum predicted unfavorable RFS in bladder cancer (HR = 1.68, 95% CI 1.01-2.79, P = 0.045).	('bladder cancer', 'Disease', 'MESH:D001749', (92, 106))	('bladder cancer', 'Disease', (92, 106))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('bladder cancer', 'Phenotype', 'HP:0009725', (92, 106))	('high', 'Var', (31, 35))	('SNHG16', 'Gene', '100507246', (36, 42))	('SNHG16', 'Gene', (36, 42))
24932	31632195	Notably, high SNHG16 expression was significantly correlated with larger tumor size (OR = 6.36, 95% CI 2.43-16.60, P = 0.0002), poor clinical stage (OR = 2.91, 95% CI 1.60-5.28, P = 0.005), LNM (OR = 4.42, 95% CI 2.66-7.35, P = 0.0001) and DM (OR = 3.86, 95% CI 1.92-7.77, P = 0.002).	('poor clinical stage', 'CPA', (128, 147))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('expression', 'MPA', (21, 31))	('LNM', 'Disease', (190, 193))	('nt', 'Chemical', 'MESH:D009711', (45, 47))	('tumor', 'Disease', (73, 78))	('SNHG16', 'Gene', (14, 20))	('SNHG16', 'Gene', '100507246', (14, 20))	('high', 'Var', (9, 13))
24934	31632195	Subsequently, the pooled HR was calculated again after removing "Lu 2018", and the result showed that high SNHG16 expression still predicted worse OS in multiple cancers (HR = 2.31, 95% CI 1.71-3.13, P < 0.001), which meant that the significance of the pooled result was not altered by the influential study.	('high', 'Var', (102, 106))	('nt', 'Chemical', 'MESH:D009711', (296, 298))	('multiple cancers', 'Disease', (153, 169))	('SNHG16', 'Gene', (107, 113))	('worse OS', 'Disease', (141, 149))	('SNHG16', 'Gene', '100507246', (107, 113))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('nt', 'Chemical', 'MESH:D009711', (221, 223))	('expression', 'MPA', (114, 124))	('multiple cancers', 'Disease', 'MESH:D009369', (153, 169))	('nt', 'Chemical', 'MESH:D009711', (8, 10))	('cancers', 'Phenotype', 'HP:0002664', (162, 169))
24949	31632195	Overexpression of serum PVT1 was markedly associated with larger tumor size, advanced clinical stage, and accurately predicted the disease and poor prognosis.	('tumor', 'Disease', (65, 70))	('predicted', 'Reg', (117, 126))	('associated', 'Reg', (42, 52))	('PVT1', 'Gene', (24, 28))	('Overexpression', 'Var', (0, 14))	('PVT1', 'Gene', '5820', (24, 28))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
24954	31632195	Overexpression of SNHG16 could lead to changes in cancer cell proliferation, apoptosis, migration, invasion, epithelial-mesenchymal transition (EMT) and chemoresistance in a majority of cancers.	('chemoresistance', 'CPA', (153, 168))	('cancer', 'Disease', (50, 56))	('cancers', 'Disease', 'MESH:D009369', (186, 193))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('apoptosis', 'CPA', (77, 86))	('cancers', 'Phenotype', 'HP:0002664', (186, 193))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('cancers', 'Disease', (186, 193))	('lead to changes', 'Reg', (31, 46))	('migration', 'CPA', (88, 97))	('SNHG16', 'Gene', '100507246', (18, 24))	('invasion', 'CPA', (99, 107))	('SNHG16', 'Gene', (18, 24))	('Overexpression', 'Var', (0, 14))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('epithelial-mesenchymal transition', 'CPA', (109, 142))	('cancer', 'Disease', (186, 192))	('cancer', 'Disease', 'MESH:D009369', (186, 192))
24962	31632195	Our pooled results also showed that patients with high SNHG16 expression were more prone to worse clinicopathological features including larger tumor size, advanced clinical tumor stage, LNM and DM.	('tumor', 'Disease', (174, 179))	('tumor', 'Disease', (144, 149))	('patients', 'Species', '9606', (36, 44))	('LNM', 'Disease', (187, 190))	('SNHG16', 'Gene', (55, 61))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('SNHG16', 'Gene', '100507246', (55, 61))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('high', 'Var', (50, 54))
24963	31632195	For instance, cervical patients with high SNHG16 expression had poorer differentiation (P = 0.047) and worse FIGO stage (P = 0.008).	('nt', 'Chemical', 'MESH:D009711', (78, 80))	('high', 'Var', (37, 41))	('SNHG16', 'Gene', '100507246', (42, 48))	('patients', 'Species', '9606', (23, 31))	('cervical', 'Disease', (14, 22))	('SNHG16', 'Gene', (42, 48))	('nt', 'Chemical', 'MESH:D009711', (28, 30))	('differentiation', 'CPA', (71, 86))	('FIGO stage', 'CPA', (109, 119))	('poorer', 'NegReg', (64, 70))
24974	31632195	In conclusion, our results infer that high SNHG16 expression was strongly associated with unfavorable survival outcome of several cancers and therefore might serve as a novel prognostic biomarker and potential therapeutic target in cancer patients.	('cancer', 'Disease', 'MESH:D009369', (232, 238))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('cancers', 'Phenotype', 'HP:0002664', (130, 137))	('cancer', 'Disease', (232, 238))	('cancers', 'Disease', (130, 137))	('cancer', 'Disease', (130, 136))	('cancers', 'Disease', 'MESH:D009369', (130, 137))	('patients', 'Species', '9606', (239, 247))	('high', 'Var', (38, 42))	('nt', 'Chemical', 'MESH:D009711', (244, 246))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('nt', 'Chemical', 'MESH:D009711', (204, 206))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('SNHG16', 'Gene', (43, 49))	('SNHG16', 'Gene', '100507246', (43, 49))	('associated', 'Reg', (74, 84))
24979	31632195	This work was financially supported by the Natural Science Foundation of Hunan Province, China (2017DK2013, 2018JJ3716, and 2018JJ3759), China Scholarship Council (201806375067, 201806375068), National Natural Science Foundation of China (81372180) and Central South University Innovation Foundation for Postgraduate Studies (NO.	('nt', 'Chemical', 'MESH:D009711', (255, 257))	('81372180', 'Var', (239, 247))	('2018JJ3716', 'Var', (108, 118))	('201806375067', 'Var', (164, 176))	('201806375068', 'Var', (178, 190))
24983	29308362	Genetic mutation of p53 gene is common in several head-neck cancers, usually associated with smoking and human papillomavirus (HPV) infection.	('head-neck cancers', 'Disease', 'MESH:D006258', (50, 67))	('p53', 'Gene', (20, 23))	('Genetic mutation', 'Var', (0, 16))	('p53', 'Gene', '7157', (20, 23))	('papillomavirus (HPV) infection', 'Disease', 'MESH:D030361', (111, 141))	('cancers', 'Phenotype', 'HP:0002664', (60, 67))	('head-neck cancers', 'Disease', (50, 67))	('common', 'Reg', (32, 38))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('associated', 'Reg', (77, 87))
24987	29308362	Molecular analysis of p53 codon 72 gene polymorphism was performed by polymerase chain reaction - restriction fragment length polymorphism for Arg/Arg, Arg/Pro, and Pro/Pro.	('Pro', 'Chemical', 'MESH:D011392', (169, 172))	('Pro', 'Chemical', 'MESH:D011392', (156, 159))	('Arg/Arg', 'Var', (143, 150))	('Pro', 'Chemical', 'MESH:D011392', (165, 168))	('Arg', 'Chemical', 'MESH:D001120', (152, 155))	('p53', 'Gene', (22, 25))	('Arg/Pro', 'Var', (152, 159))	('p53', 'Gene', '7157', (22, 25))	('Pro/Pro', 'Var', (165, 172))	('Arg', 'Chemical', 'MESH:D001120', (147, 150))	('Arg', 'Chemical', 'MESH:D001120', (143, 146))
24989	29308362	Genotype frequencies of 35 carcinoma cases of p53 Arg/Arg, Arg/Pro, and Pro/Pro were 23%, 57%, and 20%, respectively, and six leukoplakia cases of p53 Arg/Arg and Arg/Pro genotype were 50% and 50%, respectively.	('Pro', 'Chemical', 'MESH:D011392', (72, 75))	('Arg', 'Chemical', 'MESH:D001120', (59, 62))	('carcinoma', 'Phenotype', 'HP:0030731', (27, 36))	('carcinoma', 'Disease', (27, 36))	('Arg', 'Chemical', 'MESH:D001120', (50, 53))	('Arg/Pro', 'Var', (59, 66))	('leukoplakia', 'Disease', 'MESH:D007971', (126, 137))	('p53', 'Gene', '7157', (46, 49))	('leukoplakia', 'Disease', (126, 137))	('Arg', 'Chemical', 'MESH:D001120', (151, 154))	('Pro', 'Chemical', 'MESH:D011392', (76, 79))	('carcinoma', 'Disease', 'MESH:D002277', (27, 36))	('p53', 'Gene', (46, 49))	('Arg', 'Chemical', 'MESH:D001120', (54, 57))	('p53', 'Gene', '7157', (147, 150))	('Arg', 'Chemical', 'MESH:D001120', (155, 158))	('Arg', 'Chemical', 'MESH:D001120', (163, 166))	('Pro', 'Chemical', 'MESH:D011392', (167, 170))	('Pro', 'Chemical', 'MESH:D011392', (63, 66))	('p53', 'Gene', (147, 150))
25014	29308362	In the present study as shown in Table 2, it was observed that frequency of Arg/Arg genotypes was lower in OSCC patients as compared to controls (P < 0.720), whereas frequency of Arg/Pro and Pro/Pro was elevated in OSCC patients as compared to controls (P < 0.809).	('Pro', 'Chemical', 'MESH:D011392', (183, 186))	('OSCC', 'Disease', (107, 111))	('Pro', 'Chemical', 'MESH:D011392', (191, 194))	('OSCC', 'Disease', (215, 219))	('Arg', 'Chemical', 'MESH:D001120', (76, 79))	('Arg', 'Chemical', 'MESH:D001120', (80, 83))	('patients', 'Species', '9606', (112, 120))	('patients', 'Species', '9606', (220, 228))	('Pro', 'Chemical', 'MESH:D011392', (195, 198))	('Arg/Arg', 'Var', (76, 83))	('Arg', 'Chemical', 'MESH:D001120', (179, 182))	('lower', 'NegReg', (98, 103))
25015	29308362	In leukoplakia patients, frequency of Arg/Arg, Arg/Pro, and Pro/Pro genotype was equal to controls (P < 0.548) [Table 3].	('Arg', 'Chemical', 'MESH:D001120', (42, 45))	('patients', 'Species', '9606', (15, 23))	('leukoplakia', 'Disease', 'MESH:D007971', (3, 14))	('Pro', 'Chemical', 'MESH:D011392', (60, 63))	('Arg', 'Chemical', 'MESH:D001120', (38, 41))	('Arg/Arg', 'Var', (38, 45))	('Pro', 'Chemical', 'MESH:D011392', (64, 67))	('leukoplakia', 'Disease', (3, 14))	('Pro', 'Chemical', 'MESH:D011392', (51, 54))	('Arg', 'Chemical', 'MESH:D001120', (47, 50))	('Arg/Pro', 'Var', (47, 54))
25016	29308362	It was observed in that codon 72 polymorphism was not associated significantly neither with OSCC nor with leukoplakia, associated with tobacco/pan masala consumption.	('tobacco', 'Species', '4097', (135, 142))	('masala consumption', 'Disease', 'MESH:D014397', (147, 165))	('leukoplakia', 'Disease', 'MESH:D007971', (106, 117))	('masala consumption', 'Disease', (147, 165))	('OSCC', 'Disease', (92, 96))	('polymorphism', 'Var', (33, 45))	('leukoplakia', 'Disease', (106, 117))	('codon', 'Var', (24, 29))
25018	29308362	Various genetic studies at molecular level state that a group of protooncogenes and tumor suppressor genes alterations were play an effective role in cancer development.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('alterations', 'Var', (107, 118))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('tumor', 'Disease', (84, 89))	('cancer', 'Disease', (150, 156))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
25021	29308362	Up till now, various studies have provided evidence that p53 polymorphism at codon 72 may be associated with certain cancers such as breast carcinoma, lung cancer, hepatocellular carcinoma, and esophageal carcinoma.	('breast carcinoma', 'Disease', (133, 149))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (194, 214))	('lung cancer', 'Disease', (151, 162))	('cancers', 'Disease', 'MESH:D009369', (117, 124))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (164, 188))	('polymorphism', 'Var', (61, 73))	('p53', 'Gene', '7157', (57, 60))	('p53', 'Gene', (57, 60))	('lung cancer', 'Disease', 'MESH:D008175', (151, 162))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (194, 214))	('hepatocellular carcinoma', 'Disease', (164, 188))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('breast carcinoma', 'Disease', 'MESH:D001943', (133, 149))	('lung cancer', 'Phenotype', 'HP:0100526', (151, 162))	('carcinoma', 'Phenotype', 'HP:0030731', (205, 214))	('associated', 'Reg', (93, 103))	('esophageal carcinoma', 'Disease', (194, 214))	('carcinoma', 'Phenotype', 'HP:0030731', (179, 188))	('cancers', 'Phenotype', 'HP:0002664', (117, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))	('cancers', 'Disease', (117, 124))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('breast carcinoma', 'Phenotype', 'HP:0003002', (133, 149))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (164, 188))
25022	29308362	Specifically both Arg and Pro alleles have been found to be associated with high risk of the development of cancer.	('Arg', 'Var', (18, 21))	('Arg', 'Chemical', 'MESH:D001120', (18, 21))	('Pro', 'Chemical', 'MESH:D011392', (26, 29))	('associated', 'Reg', (60, 70))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
25024	29308362	Occurrence of a single-nucleotide polymorphism at codon 72 of p53 leads to the presence of either Arg or Pro alleles, which in turn could result in three different genotypes: Arg/Arg, Arg/Pro, and Pro/Pro.	('Pro/Pro', 'Disease', (197, 204))	('Arg', 'Chemical', 'MESH:D001120', (175, 178))	('Pro', 'Chemical', 'MESH:D011392', (105, 108))	('Pro', 'Chemical', 'MESH:D011392', (197, 200))	('Arg', 'MPA', (98, 101))	('Arg/Arg', 'Var', (175, 182))	('p53', 'Gene', '7157', (62, 65))	('Pro', 'Chemical', 'MESH:D011392', (188, 191))	('Arg', 'Chemical', 'MESH:D001120', (184, 187))	('Arg/Pro', 'MPA', (184, 191))	('single-nucleotide polymorphism', 'Var', (16, 46))	('Arg', 'Chemical', 'MESH:D001120', (98, 101))	('result in', 'Reg', (138, 147))	('p53', 'Gene', (62, 65))	('Arg', 'Chemical', 'MESH:D001120', (179, 182))	('Pro', 'Chemical', 'MESH:D011392', (201, 204))
25025	29308362	The structure of the p53 protein is affected by substitution of the Arg codon with Pro or vice versa although the mechanism by which this might affect function of p53 remains controversial.	('structure', 'MPA', (4, 13))	('protein', 'Protein', (25, 32))	('p53', 'Gene', (163, 166))	('p53', 'Gene', '7157', (163, 166))	('p53', 'Gene', '7157', (21, 24))	('Arg', 'Var', (68, 71))	('Arg', 'Chemical', 'MESH:D001120', (68, 71))	('substitution', 'Var', (48, 60))	('Pro', 'Chemical', 'MESH:D011392', (83, 86))	('p53', 'Gene', (21, 24))	('affected', 'Reg', (36, 44))
25029	29308362	have found that the heterozygous Arg/Pro genotype is associated with an increased risk of hypopharyngeal squamous cell carcinoma.	('hypopharyngeal squamous cell carcinoma', 'Disease', (90, 128))	('hypopharyngeal squamous cell carcinoma', 'Disease', 'MESH:D002294', (90, 128))	('hypopharyngeal squamous cell carcinoma', 'Phenotype', 'HP:0012182', (90, 128))	('Pro', 'Chemical', 'MESH:D011392', (37, 40))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (105, 128))	('Arg', 'Chemical', 'MESH:D001120', (33, 36))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('Arg/Pro', 'Var', (33, 40))
25031	29308362	reported that the Arg/Arg genotype seems to increase the risk of OSCC by 2.7 fold.	('OSCC', 'Disease', (65, 69))	('Arg', 'Chemical', 'MESH:D001120', (22, 25))	('Arg/Arg', 'Var', (18, 25))	('Arg', 'Chemical', 'MESH:D001120', (18, 21))
25036	29308362	Thus, additional studies with larger sample size might be required in the near future to further evaluate the role of p53 codon 72 gene polymorphism as a risk factor for the development of OSCC.	('p53', 'Gene', '7157', (118, 121))	('p53', 'Gene', (118, 121))	('polymorphism', 'Var', (136, 148))	('OSCC', 'Disease', (189, 193))
25079	31992194	This strengthens the hypothesis that the non-cervical HPV18 that was detected in TCGA samples was likely due to contaminating HeLa cells.	('non-cervical', 'Var', (41, 53))	('HPV', 'Species', '10566', (54, 57))	('HeLa', 'CellLine', 'CVCL:0030', (126, 130))	('HPV18', 'Gene', (54, 59))
25081	31992194	Notably, XMV43 had a median read count of 2, with a maximum read count of 554 in the same KIRC sample with the highest (non-cervical) expression of HPV18 (TCGA-CJ-5681, Fig.	('HPV18', 'Gene', (148, 153))	('HPV', 'Species', '10566', (148, 151))	('XMV43', 'Var', (9, 14))
25082	31992194	XMV43 was also present in 5% of LUSC samples and 3.5% of LUSC samples contained both XMV43 and HPV18 (Fig.	('HPV', 'Species', '10566', (95, 98))	('XMV43', 'Var', (85, 90))	('HPV18', 'Gene', (95, 100))
25084	31992194	For the samples with both XMV43 and HPV18, the expression was correlated (Spearman's rank correlation coefficient = 0.44, p = 0.006, Fig.	('HPV18', 'Var', (36, 41))	('correlated', 'Interaction', (62, 72))	('HPV', 'Species', '10566', (36, 39))	('XMV43', 'Var', (26, 31))	('expression', 'MPA', (47, 57))
25120	31992194	Another example is work by us and others of EBV transcripts in multiple cancers in the TCGA.	('EBV', 'Disease', 'MESH:D020031', (44, 47))	('multiple cancers', 'Disease', 'MESH:D009369', (63, 79))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('EBV', 'Disease', (44, 47))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('transcripts', 'Var', (48, 59))	('multiple cancers', 'Disease', (63, 79))
25166	26503331	Pathways with frequently mutated genes included those of cell-cell adhesion/Wnt/Hippo in 76%, oxidative stress response in 21%, and phosphatidylinositol-3-OH kinase in 36% of the tested tumor samples.	('mutated genes', 'Var', (25, 38))	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('genes', 'Var', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('tumor', 'Disease', (186, 191))	('oxidative', 'MPA', (94, 103))	('oxidative stress', 'Phenotype', 'HP:0025464', (94, 110))
25167	26503331	In functional assays, we observed that knockdown of CDH10 promoted cell proliferation, soft-agar colony formation, cell migration and cell invasion, and overexpression of CDH10 inhibited cell proliferation.	('agar', 'Chemical', 'MESH:D000362', (92, 96))	('CDH10', 'Gene', (171, 176))	('inhibited', 'NegReg', (177, 186))	('knockdown', 'Var', (39, 48))	('cell migration', 'CPA', (115, 129))	('CDH10', 'Gene', (52, 57))	('soft-agar colony formation', 'CPA', (87, 113))	('promoted', 'PosReg', (58, 66))	('cell proliferation', 'CPA', (67, 85))	('cell proliferation', 'CPA', (187, 205))	('cell invasion', 'CPA', (134, 147))
25171	26503331	Novel drugs targeting the 'driver' mutations (e.g., EGFR tyrosine kinase mutations and ALK fusions) have led to prolonged survival and better quality of life for patients with lung adenocarcinoma, in contrast to limited benefits for lung squamous cell carcinoma (SQCC), because current knowledge on lung SQCC tumorigenesis is still limited, especially in Chinese patients.	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (233, 261))	('quality', 'CPA', (142, 149))	('patients', 'Species', '9606', (363, 371))	('EGFR', 'Gene', (52, 56))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (238, 261))	('lung squamous cell carcinoma', 'Disease', (233, 261))	('SQCC', 'Phenotype', 'HP:0002860', (304, 308))	('lung adenocarcinoma', 'Disease', (176, 195))	('SQCC', 'Phenotype', 'HP:0002860', (263, 267))	('patients', 'Species', '9606', (162, 170))	('tumor', 'Disease', (309, 314))	('EGFR', 'Gene', '1956', (52, 56))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (176, 195))	('carcinoma', 'Phenotype', 'HP:0030731', (252, 261))	('better', 'PosReg', (135, 141))	('tumor', 'Disease', 'MESH:D009369', (309, 314))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (176, 195))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (233, 261))	('ALK', 'Gene', '238', (87, 90))	('survival', 'CPA', (122, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (186, 195))	('ALK', 'Gene', (87, 90))	('tumor', 'Phenotype', 'HP:0002664', (309, 314))	('mutations', 'Var', (73, 82))
25172	26503331	Previous studies have identified several mutated genes in lung SQCCs, such as TP53, EPHA2, NFE2L2, AKT1, LKB1, PTEN and ERBB2, as well as copy number gains of SOX2, FGFR1 and PDGFRA, which have served as candidate driver genes for targeted therapy.	('LKB1', 'Gene', '6794', (105, 109))	('lung SQCCs', 'Disease', (58, 68))	('PTEN', 'Gene', '5728', (111, 115))	('ERBB2', 'Gene', (120, 125))	('copy number gains', 'Var', (138, 155))	('EPHA2', 'Gene', (84, 89))	('NFE2L2', 'Gene', '4780', (91, 97))	('ERBB2', 'Gene', '2064', (120, 125))	('FGFR1', 'Gene', (165, 170))	('TP53', 'Gene', '7157', (78, 82))	('LKB1', 'Gene', (105, 109))	('AKT1', 'Gene', '207', (99, 103))	('NFE2L2', 'Gene', (91, 97))	('SQCC', 'Phenotype', 'HP:0002860', (63, 67))	('SOX2', 'Gene', (159, 163))	('EPHA2', 'Gene', '1969', (84, 89))	('SOX2', 'Gene', '6657', (159, 163))	('PDGFRA', 'Gene', '5156', (175, 181))	('PDGFRA', 'Gene', (175, 181))	('mutated', 'Var', (41, 48))	('AKT1', 'Gene', (99, 103))	('PTEN', 'Gene', (111, 115))	('FGFR1', 'Gene', '2260', (165, 170))	('TP53', 'Gene', (78, 82))
25182	26503331	In addition, over 87.3% and 87.0% of the target regions for normal and tumor tissues, respectively, were covered sufficiently for confident variant calling (defined as >=10X).	('tumor', 'Disease', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('variant calling', 'Var', (140, 155))
25188	26503331	Mutations in the pair of CDH10 and CTNNA2 (P = 0.002) or KEAP1 and NFE2L2 (P = 0.026) were mutually exclusive, indicating a functional interaction that is involved in lung tumorigenesis (Fig.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('NFE2L2', 'Gene', (67, 73))	('KEAP1', 'Gene', (57, 62))	('tumor', 'Disease', (172, 177))	('CTNNA2', 'Gene', '1496', (35, 41))	('NFE2L2', 'Gene', '4780', (67, 73))	('CTNNA2', 'Gene', (35, 41))	('involved', 'Reg', (155, 163))	('CDH10', 'Gene', (25, 30))	('Mutations', 'Var', (0, 9))	('KEAP1', 'Gene', '9817', (57, 62))	('tumor', 'Disease', 'MESH:D009369', (172, 177))
25190	26503331	NM_006727:c.C2059T:p.R687W and NM_006727:c.T1883C:p.V628A), and the first was predicted to affect a cadherin domain.	('c.C2059T:p.R687W', 'SUBSTITUTION', 'None', (10, 26))	('c.T1883C:p.V628A', 'SUBSTITUTION', 'None', (41, 57))	('c.C2059T:p.R687W', 'Var', (10, 26))	('cadherin', 'Gene', '999;1008;320873;1016;1016', (100, 108))	('affect', 'Reg', (91, 97))	('c.T1883C:p.V628A', 'Var', (41, 57))	('cadherin', 'Gene', (100, 108))
25193	26503331	Therefore, it is likely that these two mutations may target each of the two alleles separately, leading to the bi-allelic inactivation of CDH10, which meets the requirement of the "two-hits" model of a tumor-suppressor gene.	('bi-allelic', 'MPA', (111, 121))	('tumor-suppressor', 'Gene', '7248', (202, 218))	('mutations', 'Var', (39, 48))	('CDH10', 'Gene', (138, 143))	('tumor-suppressor', 'Gene', (202, 218))	('leading to', 'Reg', (96, 106))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))
25198	26503331	Overexpression of CDH10 significantly inhibited cell proliferation in wild-type mouse embryonic fibroblasts (MEFs) and mouse lung cancer cell line L793 (Supplementary Fig.	('MEFs', 'CellLine', 'CVCL:9115', (109, 113))	('mouse', 'Species', '10090', (119, 124))	('lung cancer', 'Disease', 'MESH:D008175', (125, 136))	('L793', 'CellLine', 'CVCL:8787', (147, 151))	('cell proliferation', 'CPA', (48, 66))	('inhibited', 'NegReg', (38, 47))	('CDH10', 'Gene', (18, 23))	('mouse', 'Species', '10090', (80, 85))	('Overexpression', 'Var', (0, 14))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('lung cancer', 'Disease', (125, 136))	('lung cancer', 'Phenotype', 'HP:0100526', (125, 136))
25200	26503331	Frequent somatic mutations in specific biological pathways indicate their unique roles in tumorigenesis and progression.	('biological pathways', 'Pathway', (39, 58))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('somatic mutations', 'Var', (9, 26))
25202	26503331	In the present study, except for the well-studied TP53 mutations, other pathways with frequently mutated genes included those of cell-cell adhesion/Wnt/Hippo in 76.8%, oxidative stress response in 21.2%, and phosphatidylinositol-3-OH kinase in 36.9% of the tested tumors.	('tumor', 'Phenotype', 'HP:0002664', (264, 269))	('genes', 'Var', (105, 110))	('TP53', 'Gene', '7157', (50, 54))	('oxidative stress', 'Phenotype', 'HP:0025464', (168, 184))	('tumors', 'Disease', 'MESH:D009369', (264, 270))	('tumors', 'Disease', (264, 270))	('tumors', 'Phenotype', 'HP:0002664', (264, 270))	('TP53', 'Gene', (50, 54))
25203	26503331	We observed somatic mutations of several cadherin genes, of which CDH10 (14.6%) was the most frequently mutated, and other mutated cadherin genes included CDH18 (8%), FAT4 (7%) and PCDH15 (8.6%).	('cadherin', 'Gene', (131, 139))	('CDH18', 'Gene', (155, 160))	('mutated', 'Var', (104, 111))	('PCDH15', 'Gene', '65217', (181, 187))	('PCDH15', 'Gene', (181, 187))	('cadherin', 'Gene', '999;1008;320873;1016;1016', (41, 49))	('CDH10', 'Gene', (66, 71))	('FAT4', 'Gene', '79633', (167, 171))	('CDH18', 'Gene', '1016', (155, 160))	('cadherin', 'Gene', (41, 49))	('FAT4', 'Gene', (167, 171))	('cadherin', 'Gene', '999;1008;320873;1016;1016', (131, 139))	('mutations', 'Var', (20, 29))
25204	26503331	Overall, 69.2% of samples had non-silent mutations of the cadherin superfamily genes (data file 8).	('non-silent mutations', 'Var', (30, 50))	('cadherin', 'Gene', (58, 66))	('cadherin', 'Gene', '999;1008;320873;1016;1016', (58, 66))
25205	26503331	It is known that alpha-catenin is a binding partner of the cadherins encoded by CTNNA1, CTNNA2 and CTNNA3, and the latter two genes were mutated in 11.1% and 3% of the tested samples, respectively.	('CTNNA3', 'Gene', '29119', (99, 105))	('CTNNA3', 'Gene', (99, 105))	('CTNNA1', 'Gene', (80, 86))	('CTNNA1', 'Gene', '1495', (80, 86))	('cadherin', 'Gene', '999;1008;320873;1016;1016', (59, 67))	('CTNNA2', 'Gene', '1496', (88, 94))	('CTNNA2', 'Gene', (88, 94))	('alpha-catenin', 'Protein', (17, 30))	('cadherin', 'Gene', (59, 67))	('mutated', 'Var', (137, 144))	('binding', 'Interaction', (36, 43))
25207	26503331	The oxidative stress response pathway protects cells against oxidative and xenobiotic damage, and genetic alterations of NFE2L2 and KEAP1 have been previously reported in NSCLC.	('NSCLC', 'Disease', 'MESH:D002289', (171, 176))	('reported', 'Reg', (159, 167))	('NSCLC', 'Phenotype', 'HP:0030358', (171, 176))	('oxidative stress', 'Phenotype', 'HP:0025464', (4, 20))	('NFE2L2', 'Gene', '4780', (121, 127))	('genetic alterations', 'Var', (98, 117))	('KEAP1', 'Gene', '9817', (132, 137))	('xenobiotic damage', 'Disease', 'MESH:D004194', (75, 92))	('NSCLC', 'Disease', (171, 176))	('NFE2L2', 'Gene', (121, 127))	('alterations', 'Var', (106, 117))	('KEAP1', 'Gene', (132, 137))	('oxidative stress response pathway', 'Pathway', (4, 37))	('xenobiotic damage', 'Disease', (75, 92))
25208	26503331	In the present study, NFE2L2 and KEAP1 were mutually exclusively mutated in 14.6% and 6.6% of the tested samples (P = 0.026), respectively, accounting for 21.2% of the 198 lung SQCC samples (Fig.	('NFE2L2', 'Gene', (22, 28))	('KEAP1', 'Gene', '9817', (33, 38))	('lung SQCC', 'Disease', (172, 181))	('NFE2L2', 'Gene', '4780', (22, 28))	('KEAP1', 'Gene', (33, 38))	('SQCC', 'Phenotype', 'HP:0002860', (177, 181))	('mutated', 'Var', (65, 72))
25210	26503331	All of the eight mutations identified in NFE2L2 in the present study were in exon 2, which is the key region that interacts with KEAP1.	('KEAP1', 'Gene', (129, 134))	('NFE2L2', 'Gene', '4780', (41, 47))	('KEAP1', 'Gene', '9817', (129, 134))	('NFE2L2', 'Gene', (41, 47))	('mutations', 'Var', (17, 26))
25211	26503331	These findings confirmed previous studies that NFE2L2 and KEAP1 were frequently mutated and played important roles in lung SQCCs.	('KEAP1', 'Gene', '9817', (58, 63))	('SQCC', 'Phenotype', 'HP:0002860', (123, 127))	('NFE2L2', 'Gene', (47, 53))	('KEAP1', 'Gene', (58, 63))	('roles', 'Reg', (109, 114))	('mutated', 'Var', (80, 87))	('lung SQCCs', 'Disease', (118, 128))	('played', 'Reg', (92, 98))	('NFE2L2', 'Gene', '4780', (47, 53))
25212	26503331	Mutations of genes in the phosphatidylinositol-3-OH kinase pathway have been previously reported in NSCLC, especially in lung adenocarcinoma.	('lung adenocarcinoma', 'Disease', (121, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('NSCLC', 'Disease', (100, 105))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (121, 140))	('phosphatidylinositol-3-OH kinase pathway', 'Pathway', (26, 66))	('NSCLC', 'Disease', 'MESH:D002289', (100, 105))	('Mutations', 'Var', (0, 9))	('reported', 'Reg', (88, 96))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (121, 140))	('NSCLC', 'Phenotype', 'HP:0030358', (100, 105))
25214	26503331	Genetic alteration of these group of genes have been reported in various types of cancer, mainly including renal cell carcinoma, bladder cancer, endometrium, breast cancer and so on.	('endometrium', 'Disease', (145, 156))	('bladder cancer', 'Disease', 'MESH:D001749', (129, 143))	('breast cancer', 'Phenotype', 'HP:0003002', (158, 171))	('cancer', 'Disease', (82, 88))	('bladder cancer', 'Disease', (129, 143))	('cancer', 'Disease', (137, 143))	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('bladder cancer', 'Phenotype', 'HP:0009725', (129, 143))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('renal cell carcinoma', 'Disease', (107, 127))	('breast cancer', 'Disease', 'MESH:D001943', (158, 171))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (107, 127))	('breast cancer', 'Disease', (158, 171))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('cancer', 'Disease', (165, 171))	('Genetic alteration', 'Var', (0, 18))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (107, 127))	('reported', 'Reg', (53, 61))
25218	26503331	In the present study, we found that mutations in CSMD3 were associated with early TNM stage (P = 0.001) and significantly less frequent in N2 than N0 and N1 tumors (P = 0.007).	('TNM', 'Gene', '10178', (82, 85))	('tumors', 'Phenotype', 'HP:0002664', (157, 163))	('N1 tumors', 'Disease', 'MESH:D009369', (154, 163))	('CSMD3', 'Gene', (49, 54))	('CSMD3', 'Gene', '114788', (49, 54))	('N1 tumors', 'Disease', (154, 163))	('TNM', 'Gene', (82, 85))	('mutations', 'Var', (36, 45))	('frequent', 'Reg', (127, 135))	('less', 'NegReg', (122, 126))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('associated', 'Reg', (60, 70))
25219	26503331	As a gene with very long coding region, CSMD3 mutations were frequently identified but not significantly mutated than background mutation.	('CSMD3', 'Gene', (40, 45))	('CSMD3', 'Gene', '114788', (40, 45))	('mutations', 'Var', (46, 55))
25220	26503331	In a previous study, loss of CSMD3 resulted in increased proliferation of airway epithelial cells.	('loss', 'Var', (21, 25))	('CSMD3', 'Gene', '114788', (29, 34))	('CSMD3', 'Gene', (29, 34))	('increased', 'PosReg', (47, 56))	('proliferation of airway epithelial cells', 'CPA', (57, 97))
25221	26503331	As a potential candidate tumor suppressor, loss of heterozygosity or homozygous deletions may occur in genomic area of CSMD3, however, we did not find loss of copy number in genomic regions of CSMD3 in tumor samples compared with normal lung samples (data file 10).	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumor', 'Disease', (202, 207))	('tumor', 'Disease', (25, 30))	('CSMD3', 'Gene', (193, 198))	('CSMD3', 'Gene', '114788', (193, 198))	('loss', 'NegReg', (43, 47))	('deletions', 'Var', (80, 89))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('CSMD3', 'Gene', (119, 124))	('CSMD3', 'Gene', '114788', (119, 124))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))
25223	26503331	We also found that mutations in PTEN were associated with early TNM stages (P = 0.02) and significantly less frequent in N2 tumors (P = 0.002) (Supplementary Fig.	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('associated', 'Reg', (42, 52))	('PTEN', 'Gene', (32, 36))	('TNM', 'Gene', (64, 67))	('PTEN', 'Gene', '5728', (32, 36))	('mutations', 'Var', (19, 28))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('N2 tumors', 'Disease', (121, 130))	('N2 tumors', 'Disease', 'MESH:D009369', (121, 130))	('less', 'NegReg', (104, 108))	('TNM', 'Gene', '10178', (64, 67))
25228	26503331	Both TCGA and our study on lung SQCC showed high mutation frequencies of TP53, NFE2L2 and PTEN, indicating similar molecular events in squamous carcinogenesis.	('TP53', 'Gene', '7157', (73, 77))	('mutation frequencies', 'Var', (49, 69))	('squamous carcinogenesis', 'Disease', (135, 158))	('PTEN', 'Gene', (90, 94))	('TP53', 'Gene', (73, 77))	('PTEN', 'Gene', '5728', (90, 94))	('NFE2L2', 'Gene', '4780', (79, 85))	('squamous carcinogenesis', 'Disease', 'MESH:D063646', (135, 158))	('SQCC', 'Phenotype', 'HP:0002860', (32, 36))	('NFE2L2', 'Gene', (79, 85))
25229	26503331	CDH10 was found to be frequently mutated in both lung squamous cell carcinoma and adenocarcinoma than other cancer types, which further indicated the importance of CDH10 mutations in NSCLC development.	('NSCLC', 'Phenotype', 'HP:0030358', (183, 188))	('CDH10', 'Gene', (0, 5))	('lung squamous cell carcinoma and adenocarcinoma', 'Disease', 'MESH:D002294', (49, 96))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (49, 77))	('mutations', 'Var', (170, 179))	('CDH10', 'Gene', (164, 169))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))	('NSCLC', 'Disease', (183, 188))	('mutated', 'Var', (33, 40))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (54, 77))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('NSCLC', 'Disease', 'MESH:D002289', (183, 188))	('carcinoma', 'Phenotype', 'HP:0030731', (68, 77))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
25250	26503331	The integrity of the cadherin-catenin complex is negatively regulated by phosphorylation of beta-catenin, receptor tyrosine kinases (RTKs) and cytoplasmic tyrosine kinases, which leads to dissociation of the cadherin-catenin complex.	('phosphorylation', 'Var', (73, 88))	('cadherin', 'Gene', (208, 216))	('integrity', 'MPA', (4, 13))	('negatively', 'NegReg', (49, 59))	('leads to', 'Reg', (179, 187))	('cadherin', 'Gene', '999;1008;320873;1016;1016', (21, 29))	('dissociation', 'MPA', (188, 200))	('cadherin', 'Gene', (21, 29))	('beta-catenin', 'Gene', (92, 104))	('beta-catenin', 'Gene', '1499', (92, 104))	('cadherin', 'Gene', '999;1008;320873;1016;1016', (208, 216))
25253	26503331	Taken together, our results suggest that among other unknown mechanisms, dysregulation of the cadherin-catenin complex caused by somatic mutations may promote lung SQCC formation by modulating multiple signaling pathways.	('cadherin', 'Gene', (94, 102))	('modulating', 'Reg', (182, 192))	('SQCC', 'Phenotype', 'HP:0002860', (164, 168))	('promote', 'PosReg', (151, 158))	('dysregulation', 'Var', (73, 86))	('cadherin', 'Gene', '999;1008;320873;1016;1016', (94, 102))	('lung SQCC', 'Disease', (159, 168))
25254	26503331	In summary, we identified both the well-known and unreported somatic mutations in lung SQCCs by using the exome sequencing of 100 followed by target capture sequencing of 98 paired samples of tumors and their adjacent normal tissues in Chinese patients.	('mutations', 'Var', (69, 78))	('lung SQCCs', 'Gene', (82, 92))	('tumors', 'Disease', (192, 198))	('tumors', 'Disease', 'MESH:D009369', (192, 198))	('tumors', 'Phenotype', 'HP:0002664', (192, 198))	('SQCC', 'Phenotype', 'HP:0002860', (87, 91))	('patients', 'Species', '9606', (244, 252))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))
25271	26503331	TP53, NFE2L2, PTEN, KEAP1, FBXW7 and TMPRSS13) with q-value < 0.1, this probably due to relatively small number of mutations and large number of genes (18,862 in total) being used in MutSigCV, leading to many multiple hypothesis test corrections.	('PTEN', 'Gene', (14, 18))	('TP53', 'Gene', '7157', (0, 4))	('mutations', 'Var', (115, 124))	('TP53', 'Gene', (0, 4))	('PTEN', 'Gene', '5728', (14, 18))	('KEAP1', 'Gene', (20, 25))	('TMPRSS13', 'Gene', (37, 45))	('TMPRSS13', 'Gene', '84000', (37, 45))	('FBXW7', 'Gene', '55294', (27, 32))	('NFE2L2', 'Gene', '4780', (6, 12))	('FBXW7', 'Gene', (27, 32))	('NFE2L2', 'Gene', (6, 12))	('KEAP1', 'Gene', '9817', (20, 25))
25309	26229583	Also p16 mutation and altered expression have been usually seen associated with change in cdk4 expression in cancers.	('mutation', 'Var', (9, 17))	('expression', 'MPA', (30, 40))	('p16', 'Gene', (5, 8))	('cancers', 'Disease', 'MESH:D009369', (109, 116))	('cancers', 'Phenotype', 'HP:0002664', (109, 116))	('cdk4', 'Gene', '1019', (90, 94))	('cancers', 'Disease', (109, 116))	('cdk4', 'Gene', (90, 94))	('p16', 'Gene', '1029', (5, 8))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('expression', 'MPA', (95, 105))
25310	26229583	Inactivation of p16 has been reported by several mechanisms in head and neck SCC.	('p16', 'Gene', '1029', (16, 19))	('SCC', 'Gene', (77, 80))	('p16', 'Gene', (16, 19))	('Inactivation', 'Var', (0, 12))	('SCC', 'Gene', '6317', (77, 80))
25351	26229583	In this context it can be postulated that loss of p16 expression may be an initial sign of malignant transformation in OLP with high cdk4 expression.	('expression', 'MPA', (54, 64))	('OLP', 'Disease', (119, 122))	('p16', 'Gene', '1029', (50, 53))	('malignant transformation', 'CPA', (91, 115))	('cdk4', 'Gene', '1019', (133, 137))	('high', 'Var', (128, 132))	('cdk4', 'Gene', (133, 137))	('p16', 'Gene', (50, 53))	('loss', 'NegReg', (42, 46))
25353	26229583	We observed a significantly higher levels of cytoplasmic cdk4 in EOLP compared to NOLP, in pattern (P = 0.001) (Table 3, Figure 3) as well as prevalence (P = 0.016) (Table 2, Figure 2) of positivity.	('levels', 'MPA', (35, 41))	('EOLP', 'Chemical', '-', (65, 69))	('cytoplasmic', 'MPA', (45, 56))	('EOLP', 'Var', (65, 69))	('higher', 'PosReg', (28, 34))	('cdk4', 'Gene', '1019', (57, 61))	('cdk4', 'Gene', (57, 61))
25357	26229583	Expression of nuclear cdk4 was not significantly increased in EOLP compared to NOLP (Tables 2 and 3), similarly as in case of OLP being compared with normal mucosa.	('Expression', 'MPA', (0, 10))	('increased', 'PosReg', (49, 58))	('EOLP', 'Var', (62, 66))	('EOLP', 'Chemical', '-', (62, 66))	('cdk4', 'Gene', '1019', (22, 26))	('cdk4', 'Gene', (22, 26))
25358	26229583	Also expression of cytoplasmic p16 and nuclear p16 in EOLP was higher than NOLP but it was not achieving statistical significance (Tables 2 and 3).	('p16', 'Gene', '1029', (31, 34))	('expression', 'MPA', (5, 15))	('p16', 'Gene', (47, 50))	('p16', 'Gene', (31, 34))	('p16', 'Gene', '1029', (47, 50))	('higher', 'PosReg', (63, 69))	('EOLP', 'Var', (54, 58))	('EOLP', 'Chemical', '-', (54, 58))
25359	32923698	A defucosylated anti-PD-L1 monoclonal antibody 13-mG2a-f exerts antitumor effects in mouse xenograft models of oral squamous cell carcinoma Programmed cell death ligand-1 (PD-L1) is a type I transmembrane glycoprotein expressed on antigen-presenting cells and several tumor cells, including melanoma and lung cancer cells.	('melanoma', 'Disease', 'MESH:D008545', (291, 299))	('lung cancer', 'Disease', 'MESH:D008175', (304, 315))	('PD-L1', 'Gene', '60533', (21, 26))	('PD-L1', 'Gene', '60533', (172, 177))	('tumor', 'Disease', (68, 73))	('lung cancer', 'Phenotype', 'HP:0100526', (304, 315))	('tumor', 'Phenotype', 'HP:0002664', (268, 273))	('defucosylated', 'Var', (2, 15))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (111, 139))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (116, 139))	('oral squamous cell carcinoma', 'Disease', (111, 139))	('13-mG2a-f', 'Chemical', '-', (47, 56))	('mouse', 'Species', '10090', (85, 90))	('cancer', 'Phenotype', 'HP:0002664', (309, 315))	('PD-L1', 'Gene', (21, 26))	('melanoma', 'Phenotype', 'HP:0002861', (291, 299))	('melanoma', 'Disease', (291, 299))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('PD-L1', 'Gene', (172, 177))	('lung cancer', 'Disease', (304, 315))	('tumor', 'Disease', (268, 273))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('tumor', 'Disease', 'MESH:D009369', (268, 273))
25368	32923698	In vivo analysis revealed that 13-mG2a-f significantly reduced tumor development in SAS and HSC-2 xenografts in comparison to control mouse IgG, even after injection seven days post-tumor inoculation.	('tumor', 'Disease', (63, 68))	('IgG', 'Gene', '668542', (140, 143))	('IgG', 'Gene', (140, 143))	('tumor', 'Disease', (182, 187))	('reduced', 'NegReg', (55, 62))	('13-mG2a-f', 'Chemical', '-', (31, 40))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('SAS', 'Chemical', 'MESH:C012546', (84, 87))	('mouse', 'Species', '10090', (134, 139))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))	('13-mG2a-f', 'Var', (31, 40))
25369	32923698	Taken together, these data demonstrate that treatment with 13-mG2a-f may represent a useful therapy for patients with PD-L1-expressing oral cancers.	('13-mG2a-f', 'Chemical', '-', (59, 68))	('oral cancers', 'Disease', (135, 147))	('cancers', 'Phenotype', 'HP:0002664', (140, 147))	('13-mG2a-f', 'Var', (59, 68))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('patients', 'Species', '9606', (104, 112))	('oral cancers', 'Disease', 'MESH:D009369', (135, 147))
25372	32923698	We converted the subclass of L1Mab-13 from IgG1 into IgG2a (13-mG2a), and defucosylated it (13-mG2a-f).	('mG2a', 'Gene', '56696', (95, 99))	('L1Mab-13', 'Gene', (29, 37))	('defucosylated', 'Var', (74, 87))	('IgG2a', 'Gene', '668478', (53, 58))	('mG2a', 'Gene', '56696', (63, 67))	('IgG1', 'Gene', '16017', (43, 47))	('IgG2a', 'Gene', (53, 58))	('mG2a', 'Gene', (95, 99))	('13-mG2a-f', 'Chemical', '-', (92, 101))	('IgG1', 'Gene', (43, 47))	('mG2a', 'Gene', (63, 67))
25390	32923698	We then investigated whether 13-mG2a-f exhibited ADCC, CDC, and antitumor activities against oral cancers.	('tumor', 'Disease', (68, 73))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('oral cancers', 'Disease', (93, 105))	('cancers', 'Phenotype', 'HP:0002664', (98, 105))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('13-mG2a-f', 'Var', (29, 38))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('13-mG2a-f', 'Chemical', '-', (29, 38))	('oral cancers', 'Disease', 'MESH:D009369', (93, 105))	('ADCC', 'CPA', (49, 53))	('CDC', 'CPA', (55, 58))
25439	32923698	In contrast, the KD for 13-mG2a-f in SAS cells was 2.8 x 10-9 M. The binding affinity of 13-mG2a-f in SAS cells was 1.5-fold higher than that of L1Mab-13.	('-f', 'Chemical', 'MESH:D005461', (31, 33))	('13-mG2a-f', 'Chemical', '-', (89, 98))	('13-mG2a-f', 'Chemical', '-', (24, 33))	('binding', 'Interaction', (69, 76))	('SAS', 'Chemical', 'MESH:C012546', (37, 40))	('higher', 'PosReg', (125, 131))	('SAS', 'Chemical', 'MESH:C012546', (102, 105))	('13-mG2a-f', 'Var', (89, 98))	('-f', 'Chemical', 'MESH:D005461', (119, 121))	('-f', 'Chemical', 'MESH:D005461', (96, 98))
25440	32923698	By contrast, the KD for 13-mG2a-f in HSC-2 cells was 4.8 x 10-9 M. The binding affinity of 13-mG2a-f in HSC-2 cells was 1.8-fold higher than that of L1Mab-13.	('-f', 'Chemical', 'MESH:D005461', (31, 33))	('13-mG2a-f', 'Chemical', '-', (91, 100))	('higher', 'PosReg', (129, 135))	('13-mG2a-f', 'Chemical', '-', (24, 33))	('binding affinity', 'Interaction', (71, 87))	('-f', 'Chemical', 'MESH:D005461', (98, 100))	('13-mG2a-f', 'Var', (91, 100))	('-f', 'Chemical', 'MESH:D005461', (123, 125))
25448	32923698	Because the mouse IgG1 subclass L1Mab-13 does not possess ADCC or CDC activities, we created a mouse IgG2a subclass mAb, and further defucosylated it to enhance those activities.	('IgG2a', 'Gene', '668478', (101, 106))	('defucosylated', 'Var', (133, 146))	('IgG1', 'Gene', (18, 22))	('enhance', 'PosReg', (153, 160))	('IgG2a', 'Gene', (101, 106))	('mouse', 'Species', '10090', (12, 17))	('IgG1', 'Gene', '16017', (18, 22))	('activities', 'MPA', (167, 177))	('mouse', 'Species', '10090', (95, 100))
25449	32923698	In this study, we examined whether the developed 13-mG2a-f induced ADCC and CDC in PD-L1-expressing oral cancer cell lines, such as SAS and HSC-2 cells.	('CDC', 'CPA', (76, 79))	('oral cancer', 'Disease', 'MESH:D009369', (100, 111))	('induced', 'PosReg', (59, 66))	('13-mG2a-f', 'Var', (49, 58))	('ADCC', 'CPA', (67, 71))	('SAS', 'Chemical', 'MESH:C012546', (132, 135))	('oral cancer', 'Disease', (100, 111))	('13-mG2a-f', 'Chemical', '-', (49, 58))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))
25450	32923698	13-mG2a-f exhibited higher ADCC (17% cytotoxicity) in SAS cells compared with that of control mouse IgG2a treatment (6.6% cytotoxicity; P < 0.05) (Fig.	('IgG2a', 'Gene', '668478', (100, 105))	('cytotoxicity', 'Disease', (37, 49))	('ADCC', 'MPA', (27, 31))	('13-mG2a-f', 'Chemical', '-', (0, 9))	('cytotoxicity', 'Disease', (122, 134))	('higher', 'PosReg', (20, 26))	('IgG2a', 'Gene', (100, 105))	('cytotoxicity', 'Disease', 'MESH:D064420', (37, 49))	('SAS', 'Chemical', 'MESH:C012546', (54, 57))	('mouse', 'Species', '10090', (94, 99))	('13-mG2a-f', 'Var', (0, 9))	('cytotoxicity', 'Disease', 'MESH:D064420', (122, 134))
25451	32923698	Similarly, 13-mG2a-f exhibited higher ADCC (8.0% cytotoxicity) in HSC-2 cells compared with that of control mouse IgG2a treatment (2.5% cytotoxicity; P < 0.01) (Fig.	('ADCC', 'MPA', (38, 42))	('13-mG2a-f', 'Var', (11, 20))	('IgG2a', 'Gene', '668478', (114, 119))	('cytotoxicity', 'Disease', (136, 148))	('13-mG2a-f', 'Chemical', '-', (11, 20))	('cytotoxicity', 'Disease', (49, 61))	('mouse', 'Species', '10090', (108, 113))	('IgG2a', 'Gene', (114, 119))	('cytotoxicity', 'Disease', 'MESH:D064420', (136, 148))	('higher', 'PosReg', (31, 37))	('cytotoxicity', 'Disease', 'MESH:D064420', (49, 61))
25452	32923698	Furthermore, 13-mG2a-f exhibited higher CDC activity (27% cytotoxicity) in SAS cells compared with control mouse IgG2a treatment (7.3% cytotoxicity; P < 0.01; Fig.	('higher', 'PosReg', (33, 39))	('CDC activity', 'MPA', (40, 52))	('mouse', 'Species', '10090', (107, 112))	('cytotoxicity', 'Disease', 'MESH:D064420', (135, 147))	('13-mG2a-f', 'Chemical', '-', (13, 22))	('cytotoxicity', 'Disease', (135, 147))	('cytotoxicity', 'Disease', (58, 70))	('IgG2a', 'Gene', '668478', (113, 118))	('SAS', 'Chemical', 'MESH:C012546', (75, 78))	('13-mG2a-f', 'Var', (13, 22))	('IgG2a', 'Gene', (113, 118))	('cytotoxicity', 'Disease', 'MESH:D064420', (58, 70))
25453	32923698	Similarly, 13-mG2a-f exhibited higher CDC activity (15% cytotoxicity) in HSC-2 cells compared with control mouse IgG2a treatment (4.1% cytotoxicity; P < 0.01; Fig.	('13-mG2a-f', 'Var', (11, 20))	('mouse', 'Species', '10090', (107, 112))	('cytotoxicity', 'Disease', 'MESH:D064420', (56, 68))	('cytotoxicity', 'Disease', 'MESH:D064420', (135, 147))	('cytotoxicity', 'Disease', (135, 147))	('13-mG2a-f', 'Chemical', '-', (11, 20))	('CDC activity', 'MPA', (38, 50))	('IgG2a', 'Gene', '668478', (113, 118))	('higher', 'PosReg', (31, 37))	('cytotoxicity', 'Disease', (56, 68))	('IgG2a', 'Gene', (113, 118))
25454	32923698	Although ADCC/CDC activities of 13-mG2a-f in oral cancer cells are not outstanding, it remained to be seen whether 13-mG2a-f may exert antitumor activity against oral cancer cells in vivo.	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('oral cancer', 'Disease', 'MESH:D009369', (45, 56))	('13-mG2a-f', 'Var', (115, 124))	('oral cancer', 'Disease', 'MESH:D009369', (162, 173))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('oral cancer', 'Disease', (45, 56))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('13-mG2a-f', 'Chemical', '-', (115, 124))	('oral cancer', 'Disease', (162, 173))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('13-mG2a-f', 'Chemical', '-', (32, 41))
25457	32923698	On days 8, 14, and 21 after SAS cell injections into the mice, 13-mG2a-f (100 mug) and control mouse IgG (100 mug) were injected i.p.	('mice', 'Species', '10090', (57, 61))	('SAS', 'Chemical', 'MESH:C012546', (28, 31))	('13-mG2a-f', 'Chemical', '-', (63, 72))	('100 mug', 'Var', (74, 81))	('IgG', 'Gene', '668542', (101, 104))	('IgG', 'Gene', (101, 104))	('mouse', 'Species', '10090', (95, 100))
25463	32923698	Tumors from 13-mG2a-f-treated mice weighed significantly less than tumors from IgG-treated control mice (41% reduction, P < 0.05; Fig.	('mice', 'Species', '10090', (99, 103))	('mice', 'Species', '10090', (30, 34))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('13-mG2a-f-treated', 'Var', (12, 29))	('tumors', 'Disease', 'MESH:D009369', (67, 73))	('IgG', 'Gene', '668542', (79, 82))	('IgG', 'Gene', (79, 82))	('reduction', 'NegReg', (109, 118))	('less', 'NegReg', (57, 61))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('tumors', 'Disease', (67, 73))	('13-mG2a-f', 'Chemical', '-', (12, 21))
25470	32923698	Tumors from 13-mG2a-f-treated mice weighed significantly less than tumors from IgG-treated control mice (28% reduction, P < 0.05; Fig.	('mice', 'Species', '10090', (99, 103))	('mice', 'Species', '10090', (30, 34))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('13-mG2a-f-treated', 'Var', (12, 29))	('tumors', 'Disease', 'MESH:D009369', (67, 73))	('IgG', 'Gene', '668542', (79, 82))	('IgG', 'Gene', (79, 82))	('less', 'NegReg', (57, 61))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('tumors', 'Disease', (67, 73))	('13-mG2a-f', 'Chemical', '-', (12, 21))
25485	32923698	These results are consistent with our previous observation that the mouse IgG2a-type mAb 47-mG2a-f also shows a higher affinity for PODXL than the original PcMab-47 (mouse IgG1), indicating that fragment crystallizable (Fc) portion of mouse IgG could be important for the binding affinity for target molecules; or, recombinant mAbs might possess high purity compared to hybridoma-derived mAbs.	('IgG', 'Gene', '668542', (241, 244))	('IgG', 'Gene', (241, 244))	('IgG1', 'Gene', (172, 176))	('47-mG2a-f', 'Var', (89, 98))	('mouse', 'Species', '10090', (166, 171))	('IgG', 'Gene', '668542', (74, 77))	('IgG', 'Gene', (74, 77))	('-mG2a-f', 'Chemical', '-', (91, 98))	('PODXL', 'Gene', '27205', (132, 137))	('affinity', 'Interaction', (119, 127))	('mouse', 'Species', '10090', (235, 240))	('PODXL', 'Gene', (132, 137))	('IgG2a', 'Gene', '668478', (74, 79))	('binding', 'Interaction', (272, 279))	('IgG2a', 'Gene', (74, 79))	('IgG1', 'Gene', '16017', (172, 176))	('mouse', 'Species', '10090', (68, 73))	('higher', 'PosReg', (112, 118))	('IgG', 'Gene', '668542', (172, 175))	('IgG', 'Gene', (172, 175))
25502	31528227	Kaplan-Meier analysis evidenced that a worse overall survival (OS) was correlated to the group with high Wnt3a expression (P = 0.003).	('Wnt3a', 'Gene', (105, 110))	('OS', 'Chemical', '-', (63, 65))	('expression', 'MPA', (111, 121))	('high', 'Var', (100, 104))	('Wnt3a', 'Gene', '89780', (105, 110))	('overall survival', 'MPA', (45, 61))
25503	31528227	When stratified survival analyses were performed, patients with lymph node metastasis/advanced clinical stages and high Wnt3a expression had worse OS rates than patients with other features (P < 0.001).	('high', 'Var', (115, 119))	('OS', 'Chemical', '-', (147, 149))	('patients', 'Species', '9606', (50, 58))	('Wnt3a', 'Gene', (120, 125))	('worse', 'NegReg', (141, 146))	('patients', 'Species', '9606', (161, 169))	('Wnt3a', 'Gene', '89780', (120, 125))
25512	31528227	Dysregulation of this signaling pathway is associated with a series of human diseases, including various human malignancies.	('Dysregulation', 'Var', (0, 13))	('human diseases', 'Disease', (71, 85))	('malignancies', 'Disease', 'MESH:D009369', (111, 123))	('associated', 'Reg', (43, 53))	('human', 'Species', '9606', (105, 110))	('human', 'Species', '9606', (71, 76))	('malignancies', 'Disease', (111, 123))
25550	31528227	Kaplan-Meier survival analysis demonstrated that LSCC patients with high Wnt3a expression had an increased risk of overall mortality (P = 0.005; Fig.	('expression', 'MPA', (79, 89))	('high', 'Var', (68, 72))	('patients', 'Species', '9606', (54, 62))	('Wnt3a', 'Gene', '89780', (73, 78))	('LSCC', 'Disease', (49, 53))	('Wnt3a', 'Gene', (73, 78))
25555	31528227	These results revealed that patients with phenotype of high Wnt3a expression and positive lymph node metastasis had worse OS than those with other characteristics (P < 0.001; Fig.	('Wnt3a', 'Gene', (60, 65))	('expression', 'MPA', (66, 76))	('OS', 'Chemical', '-', (122, 124))	('high', 'Var', (55, 59))	('Wnt3a', 'Gene', '89780', (60, 65))	('patients', 'Species', '9606', (28, 36))
25561	31528227	Finally, we found that high Wnt3a expression was an independent adverse prognostic factor for overall survival, especially when combined with advanced clinical stage and lymph node metastasis status.	('Wnt3a', 'Gene', '89780', (28, 33))	('expression', 'MPA', (34, 44))	('high', 'Var', (23, 27))	('overall survival', 'MPA', (94, 110))	('Wnt3a', 'Gene', (28, 33))
25563	31528227	As previously reported, the aberrant expression of Wnt3a was also found in several human malignancies, including glioblastoma, mammary adenocarcinoma, colon carcinoma, lung cancer, prostate cancer, malignant mesothelioma, esophageal squamous cell carcinoma, hepatocellular carcinoma, and melanoma.	('Wnt3a', 'Gene', '89780', (51, 56))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (198, 220))	('Wnt3a', 'Gene', (51, 56))	('lung cancer', 'Disease', 'MESH:D008175', (168, 179))	('carcinoma', 'Phenotype', 'HP:0030731', (247, 256))	('found', 'Reg', (66, 71))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (258, 282))	('adenocarcinoma', 'Disease', 'MESH:D000230', (135, 149))	('malignancies', 'Disease', 'MESH:D009369', (89, 101))	('glioblastoma', 'Disease', 'MESH:D005909', (113, 125))	('lung cancer', 'Phenotype', 'HP:0100526', (168, 179))	('colon carcinoma', 'Disease', (151, 166))	('melanoma', 'Disease', 'MESH:D008545', (288, 296))	('malignant mesothelioma', 'Disease', (198, 220))	('malignancies', 'Disease', (89, 101))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('carcinoma', 'Phenotype', 'HP:0030731', (157, 166))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (198, 220))	('glioblastoma', 'Disease', (113, 125))	('esophageal squamous cell carcinoma', 'Disease', (222, 256))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (258, 282))	('colon carcinoma', 'Disease', 'MESH:D015179', (151, 166))	('glioblastoma', 'Phenotype', 'HP:0012174', (113, 125))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (233, 256))	('expression', 'MPA', (37, 47))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))	('prostate cancer', 'Disease', 'MESH:D011471', (181, 196))	('hepatocellular carcinoma', 'Disease', (258, 282))	('prostate cancer', 'Phenotype', 'HP:0012125', (181, 196))	('lung cancer', 'Disease', (168, 179))	('human', 'Species', '9606', (83, 88))	('melanoma', 'Phenotype', 'HP:0002861', (288, 296))	('aberrant', 'Var', (28, 36))	('melanoma', 'Disease', (288, 296))	('carcinoma', 'Phenotype', 'HP:0030731', (273, 282))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (222, 256))	('adenocarcinoma', 'Disease', (135, 149))	('prostate cancer', 'Disease', (181, 196))
25577	31528227	This result is consistent with those of previous studies investigating colorectal cancer, hepatocellular carcinoma, lung cancer, and melanoma, in which overexpression of Wnt3a could significantly enhance the invasion and migration potential of tumor cells by inducing epithelial-to-mesenchymal transition (EMT) and the metastasis-related protein matrix metalloproteinases (MMP)-2, -7, and -9.	('matrix metalloproteinases', 'Enzyme', (346, 371))	('lung cancer', 'Phenotype', 'HP:0100526', (116, 127))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('epithelial-to-mesenchymal transition', 'CPA', (268, 304))	('metastasis-related', 'CPA', (319, 337))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('tumor', 'Phenotype', 'HP:0002664', (244, 249))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('enhance', 'PosReg', (196, 203))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (90, 114))	('melanoma', 'Phenotype', 'HP:0002861', (133, 141))	('melanoma', 'Disease', (133, 141))	('colorectal cancer', 'Disease', 'MESH:D015179', (71, 88))	('colorectal cancer', 'Disease', (71, 88))	('lung cancer', 'Disease', (116, 127))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (90, 114))	('overexpression', 'Var', (152, 166))	('tumor', 'Disease', (244, 249))	('Wnt3a', 'Gene', '89780', (170, 175))	('hepatocellular carcinoma', 'Disease', (90, 114))	('inducing', 'PosReg', (259, 267))	('melanoma', 'Disease', 'MESH:D008545', (133, 141))	('lung cancer', 'Disease', 'MESH:D008175', (116, 127))	('colorectal cancer', 'Phenotype', 'HP:0003003', (71, 88))	('tumor', 'Disease', 'MESH:D009369', (244, 249))	('Wnt3a', 'Gene', (170, 175))
25591	31036064	Genes involved in oxygen-sensing are clinically relevant and have significant implications for prognosis.	('oxygen', 'Chemical', 'MESH:D010100', (18, 24))	('implications', 'Reg', (78, 90))	('Genes', 'Var', (0, 5))
25596	31036064	Signature 1 (KDM8, KDM6B, P4HTM, ALKBH4, ALKBH7) and signature 2 (KDM3A, P4HA1, ASPH, PLOD1, PLOD2) were associated with good and poor prognosis.	('KDM6B', 'Gene', (19, 24))	('ASPH', 'Gene', '444', (80, 84))	('ALKBH7', 'Gene', (41, 47))	('ALKBH4', 'Gene', '54784', (33, 39))	('KDM6B', 'Gene', '23135', (19, 24))	('P4HTM', 'Gene', (26, 31))	('PLOD2', 'Gene', (93, 98))	('KDM3A', 'Gene', '55818', (66, 71))	('ALKBH7', 'Gene', '84266', (41, 47))	('P4HTM', 'Gene', '54681', (26, 31))	('ALKBH4', 'Gene', (33, 39))	('KDM8', 'Var', (13, 17))	('ASPH', 'Gene', (80, 84))	('P4HA1', 'Gene', '5033', (73, 78))	('PLOD2', 'Gene', '5352', (93, 98))	('PLOD1', 'Gene', (86, 91))	('KDM3A', 'Gene', (66, 71))	('P4HA1', 'Gene', (73, 78))	('PLOD1', 'Gene', '5351', (86, 91))
25615	31036064	In addition, the epigenetic alterations and inactivating mutations of the Jumonji-C domain-containing lysine demethylase (KDM) family are frequently observed in multiple cancers such as multiple myeloma, esophageal squamous cell carcinoma, renal cell carcinoma, breast cancer, colorectal cancer, and glioblastoma.	('cancers', 'Phenotype', 'HP:0002664', (170, 177))	('multiple cancers', 'Disease', 'MESH:D009369', (161, 177))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (240, 260))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (204, 238))	('breast cancer', 'Disease', 'MESH:D001943', (262, 275))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (215, 238))	('breast cancer', 'Disease', (262, 275))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('glioblastoma', 'Disease', (300, 312))	('cancer', 'Phenotype', 'HP:0002664', (288, 294))	('inactivating mutations', 'Var', (44, 66))	('glioblastoma', 'Phenotype', 'HP:0012174', (300, 312))	('carcinoma', 'Phenotype', 'HP:0030731', (229, 238))	('multiple myeloma', 'Phenotype', 'HP:0006775', (186, 202))	('colorectal cancer', 'Disease', 'MESH:D015179', (277, 294))	('multiple cancers', 'Disease', (161, 177))	('renal cell carcinoma', 'Disease', (240, 260))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (240, 260))	('colorectal cancer', 'Disease', (277, 294))	('observed', 'Reg', (149, 157))	('cancer', 'Phenotype', 'HP:0002664', (269, 275))	('multiple myeloma', 'Disease', 'MESH:D009101', (186, 202))	('epigenetic alterations', 'Var', (17, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (251, 260))	('esophageal squamous cell carcinoma', 'Disease', (204, 238))	('breast cancer', 'Phenotype', 'HP:0003002', (262, 275))	('multiple myeloma', 'Disease', (186, 202))	('glioblastoma', 'Disease', 'MESH:D005909', (300, 312))	('colorectal cancer', 'Phenotype', 'HP:0003003', (277, 294))	('KDM', 'Gene', (122, 125))
25682	31036064	Mutations in PCDHA1, a cell adhesion gene from the cadherin superfamily, were associated with short survival in bladder urothelial carcinoma (BLCA: HR, 1.649; 95% CI 1.058-2.569; P = 0.027) and gastric adenocarcinoma (STAD: HR, 1.525; 95% CI 1.007-2.307; P = 0.046) but with prolonged survival in uterine corpus endometrial carcinoma (UCEC: HR, 0.516; 95% CI 0.272-0.978; P = 0.042) (Additional file 3).	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (324, 333))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (312, 333))	('corpus endometrial carcinoma', 'Disease', (305, 333))	('gastric adenocarcinoma', 'Disease', (194, 216))	('PCDHA1', 'Gene', '56147', (13, 19))	('carcinoma', 'Phenotype', 'HP:0030731', (207, 216))	('corpus endometrial carcinoma', 'Disease', 'MESH:D016889', (305, 333))	('Mutations', 'Var', (0, 9))	('gastric adenocarcinoma', 'Disease', 'MESH:D013274', (194, 216))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (112, 140))	('bladder urothelial carcinoma', 'Disease', (112, 140))	('PCDHA1', 'Gene', (13, 19))
25683	31036064	Mutations in another gene from the protocadherin alpha cluster, PCDHA2, were also associated with adverse outcomes in gastric adenocarcinoma (STAD: HR, 1.604; 95% CI 1.061-2.427; P = 0.025) (Additional file 3).	('associated', 'Reg', (82, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('PCDHA2', 'Gene', '56146', (64, 70))	('Mutations', 'Var', (0, 9))	('PCDHA2', 'Gene', (64, 70))	('gastric adenocarcinoma', 'Disease', 'MESH:D013274', (118, 140))	('gastric adenocarcinoma', 'Disease', (118, 140))
25684	31036064	Mutations in TTN and the tumor suppressor TP53 were associated with short survival in bladder urothelial carcinoma (BLCA: HR, 1.610; 95% CI 1.091-2.376; P = 0.016) and uterine corpus endometrial carcinoma (UCEC: HR, 1.780; 95% CI 1.025-3.090; P = 0.041) (Additional file 3).	('TTN', 'Gene', (13, 16))	('corpus endometrial carcinoma', 'Disease', (176, 204))	('tumor suppressor', 'Gene', '7248', (25, 41))	('TP53', 'Gene', '7157', (42, 46))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('bladder urothelial carcinoma', 'Disease', (86, 114))	('corpus endometrial carcinoma', 'Disease', 'MESH:D016889', (176, 204))	('TP53', 'Gene', (42, 46))	('TTN', 'Gene', '7273', (13, 16))	('Mutations', 'Var', (0, 9))	('tumor suppressor', 'Gene', (25, 41))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('carcinoma', 'Phenotype', 'HP:0030731', (195, 204))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (183, 204))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (86, 114))
25685	31036064	Interestingly, another tumor suppressor PTEN, when mutated, was linked to better outcomes in uterine corpus endometrial carcinoma (UCEC: HR, 0.427; 95% CI 0.234-0.781; P = 0.006) (Additional file 3).	('better', 'PosReg', (74, 80))	('corpus endometrial carcinoma', 'Disease', (101, 129))	('tumor suppressor', 'Gene', (23, 39))	('PTEN', 'Gene', (40, 44))	('PTEN', 'Gene', '5728', (40, 44))	('corpus endometrial carcinoma', 'Disease', 'MESH:D016889', (101, 129))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('tumor suppressor', 'Gene', '7248', (23, 39))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (108, 129))	('mutated', 'Var', (51, 58))
25687	31036064	Likewise, MUC4 mutations prolonged survival in renal clear cell carcinoma patients (KIRC: HR, 0.570; 95% CI 0.370-0.880; P = 0.012) (Additional file 3), an observation that is consistent with another study.	('MUC4', 'Gene', (10, 14))	('patients', 'Species', '9606', (74, 82))	('mutations', 'Var', (15, 24))	('prolonged', 'PosReg', (25, 34))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))	('renal clear cell carcinoma', 'Disease', 'MESH:C538614', (47, 73))	('MUC4', 'Gene', '4585', (10, 14))	('renal clear cell carcinoma', 'Disease', (47, 73))	('survival', 'MPA', (35, 43))
25689	31036064	Signatures 1 or 2 and mutation status were collectively associated with OS (Fig.	('mutation status', 'Var', (22, 37))	('OS', 'Chemical', '-', (72, 74))	('associated with', 'Reg', (56, 71))
25690	31036064	In bladder urothelial carcinoma, high-risk patients (low signature 1 score) harboring mutant alleles of PCDHA1 had ~ 50% increased mortality at 5 years compared to low-risk patients (high signature 1 score) with wild-type PCDHA1 (P = 0.016; Fig.	('PCDHA1', 'Gene', '56147', (222, 228))	('mutant alleles', 'Var', (86, 100))	('patients', 'Species', '9606', (173, 181))	('increased', 'PosReg', (121, 130))	('PCDHA1', 'Gene', (104, 110))	('patients', 'Species', '9606', (43, 51))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('PCDHA1', 'Gene', '56147', (104, 110))	('PCDHA1', 'Gene', (222, 228))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (3, 31))	('bladder urothelial carcinoma', 'Disease', (3, 31))
25692	31036064	In gastric adenocarcinoma, high-risk patients (high signature 2 scores) with mutant PCDHA1 had the worst outcomes (P = 0.002; Fig.	('patients', 'Species', '9606', (37, 45))	('gastric adenocarcinoma', 'Disease', 'MESH:D013274', (3, 25))	('gastric adenocarcinoma', 'Disease', (3, 25))	('PCDHA1', 'Gene', (84, 90))	('carcinoma', 'Phenotype', 'HP:0030731', (16, 25))	('mutant', 'Var', (77, 83))	('PCDHA1', 'Gene', '56147', (84, 90))
25693	31036064	Conversely, PCDHA1 mutation was associated with good prognosis in uterine corpus endometrial carcinoma, hence high-risk patients with wild-type PCDHA1 had the lowest survival rates while survival was prolonged by ~ 20% in low-risk patients with mutant PCDHA1 (P = 0.003; Fig.	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('mutation', 'Var', (19, 27))	('patients', 'Species', '9606', (231, 239))	('PCDHA1', 'Gene', '56147', (144, 150))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (81, 102))	('survival rates', 'MPA', (166, 180))	('PCDHA1', 'Gene', (144, 150))	('PCDHA1', 'Gene', (12, 18))	('PCDHA1', 'Gene', (252, 258))	('corpus endometrial carcinoma', 'Disease', (74, 102))	('corpus endometrial carcinoma', 'Disease', 'MESH:D016889', (74, 102))	('patients', 'Species', '9606', (120, 128))	('mutant', 'Var', (245, 251))	('prolonged', 'PosReg', (200, 209))	('lowest', 'NegReg', (159, 165))	('PCDHA1', 'Gene', '56147', (12, 18))	('PCDHA1', 'Gene', '56147', (252, 258))
25694	31036064	PIK3CA (P < 0.001) and PTEN mutations (P = 0.001) were associated with good outcomes in uterine corpus endometrial carcinoma (Fig.	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('PTEN', 'Gene', (23, 27))	('PIK3CA', 'Gene', (0, 6))	('PTEN', 'Gene', '5728', (23, 27))	('PIK3CA', 'Gene', '5290', (0, 6))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (103, 124))	('corpus endometrial carcinoma', 'Disease', (96, 124))	('mutations', 'Var', (28, 37))	('corpus endometrial carcinoma', 'Disease', 'MESH:D016889', (96, 124))
25695	31036064	Mutations in another cadherin gene PCDHA2 when considered alongside signature 2 were also associated with survival in gastric adenocarcinoma (P < 0.001; Fig.	('PCDHA2', 'Gene', (35, 41))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('associated with', 'Reg', (90, 105))	('Mutations', 'Var', (0, 9))	('PCDHA2', 'Gene', '56146', (35, 41))	('gastric adenocarcinoma', 'Disease', 'MESH:D013274', (118, 140))	('gastric adenocarcinoma', 'Disease', (118, 140))
25696	31036064	Survival rates were reduced by ~ 37% in high-risk patients with mutant PCDHA2 (Fig.	('reduced', 'NegReg', (20, 27))	('patients', 'Species', '9606', (50, 58))	('PCDHA2', 'Gene', (71, 77))	('PCDHA2', 'Gene', '56146', (71, 77))	('Survival rates', 'CPA', (0, 14))	('mutant', 'Var', (64, 70))
25697	31036064	Joint relation between TP53 mutations and signature 1 significantly influenced survival in uterine corpus endometrial carcinoma (P = 0.002; Fig.	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (106, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('corpus endometrial carcinoma', 'Disease', 'MESH:D016889', (99, 127))	('corpus endometrial carcinoma', 'Disease', (99, 127))	('influenced', 'Reg', (68, 78))	('TP53', 'Gene', '7157', (23, 27))	('TP53', 'Gene', (23, 27))	('mutations', 'Var', (28, 37))
25698	31036064	Since MUC4 mutations were associated with good outcomes, survival rates were the lowest in high-risk patients (high signature 2 scores) with wild-type MUC4 (P = 0.003; Fig.	('mutations', 'Var', (11, 20))	('MUC4', 'Gene', (151, 155))	('patients', 'Species', '9606', (101, 109))	('lowest', 'NegReg', (81, 87))	('MUC4', 'Gene', (6, 10))	('survival rates', 'MPA', (57, 71))	('MUC4', 'Gene', '4585', (151, 155))	('MUC4', 'Gene', '4585', (6, 10))
25700	31036064	Patients with high KDM8 levels had a significantly lower risk of death in pancreatic and liver cancer cohorts (Fig.	('liver cancer', 'Phenotype', 'HP:0002896', (89, 101))	('lower', 'NegReg', (51, 56))	('high KDM8 levels', 'Var', (14, 30))	('Patients', 'Species', '9606', (0, 8))	('death in pancreatic and liver cancer', 'Disease', 'MESH:D010190', (65, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))
25703	31036064	Moreover, KDM8 expression was negatively correlated with hypoxia score, indicating that patients with low levels of KDM8 had more hypoxic tumors and poorer survival outcomes (Fig.	('low levels', 'Var', (102, 112))	('survival outcomes', 'CPA', (156, 173))	('hypoxia', 'Disease', (57, 64))	('hypoxia', 'Disease', 'MESH:D000860', (57, 64))	('hypoxic tumors', 'Disease', (130, 144))	('patients', 'Species', '9606', (88, 96))	('KDM8', 'Gene', (116, 120))	('hypoxic tumors', 'Disease', 'MESH:D009369', (130, 144))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('poorer', 'NegReg', (149, 155))	('more', 'PosReg', (125, 129))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
25717	31036064	Our results suggest that dysregulated oxygen sensing in diverse cancer types may activate other oncogenic pathways such as the loss of cell polarity and cell cycle regulation, which collectively influenced clinical outcomes in patients.	('oxygen sensing', 'MPA', (38, 52))	('cell cycle regulation', 'CPA', (153, 174))	('activate', 'PosReg', (81, 89))	('oxygen', 'Chemical', 'MESH:D010100', (38, 44))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('cell polarity', 'CPA', (135, 148))	('influenced', 'Reg', (195, 205))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('loss', 'NegReg', (127, 131))	('oncogenic pathways', 'Pathway', (96, 114))	('patients', 'Species', '9606', (227, 235))	('dysregulated', 'Var', (25, 37))
25720	31036064	In colorectal cancer, high KDM6B expression predicted good prognosis, and knock-down of KDM6B was associated with augmented cell proliferation and inhibited apoptosis.	('KDM6B', 'Gene', '23135', (27, 32))	('knock-down', 'Var', (74, 84))	('apoptosis', 'CPA', (157, 166))	('colorectal cancer', 'Phenotype', 'HP:0003003', (3, 20))	('high', 'Var', (22, 26))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('augmented', 'PosReg', (114, 123))	('KDM6B', 'Gene', (27, 32))	('colorectal cancer', 'Disease', (3, 20))	('KDM6B', 'Gene', '23135', (88, 93))	('cell proliferation', 'CPA', (124, 142))	('inhibited', 'NegReg', (147, 156))	('expression', 'MPA', (33, 43))	('colorectal cancer', 'Disease', 'MESH:D015179', (3, 20))	('KDM6B', 'Gene', (88, 93))
25727	31036064	Moreover, 5-year survival rates dropped to ~ 12% in bladder cancer patients with low expression of signature 1 genes (high-risk), which included KDM8 and PCDHA1 mutations.	('expression', 'MPA', (85, 95))	('low', 'NegReg', (81, 84))	('patients', 'Species', '9606', (67, 75))	('PCDHA1', 'Gene', '56147', (154, 160))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('PCDHA1', 'Gene', (154, 160))	('bladder cancer', 'Phenotype', 'HP:0009725', (52, 66))	('mutations', 'Var', (161, 170))	('bladder cancer', 'Disease', 'MESH:D001749', (52, 66))	('bladder cancer', 'Disease', (52, 66))	('dropped', 'NegReg', (32, 39))	('KDM8', 'Gene', (145, 149))
25728	31036064	Additive effects conferred by mutations in this cell-adhesion protein supports the hypothesis that KDM8 is likely a tumor suppressor and down-regulation of this gene may lead to a loss of epithelial phenotype and cell adhesion to promote cancer invasion.	('cancer', 'Disease', (238, 244))	('cancer', 'Disease', 'MESH:D009369', (238, 244))	('cell adhesion', 'CPA', (213, 226))	('loss', 'NegReg', (180, 184))	('tumor suppressor', 'Gene', (116, 132))	('epithelial phenotype', 'CPA', (188, 208))	('KDM8', 'Gene', (99, 103))	('promote', 'PosReg', (230, 237))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('mutations', 'Var', (30, 39))	('down-regulation', 'NegReg', (137, 152))	('tumor suppressor', 'Gene', '7248', (116, 132))
25734	31036064	Collectively, imbalance in the Jumonji-C subfamily of lysine demethylases such as KDM8 and KDM6B is likely to result in broad-ranging but cell type-specific biological effects.	('imbalance', 'Phenotype', 'HP:0002172', (14, 23))	('KDM6B', 'Gene', (91, 96))	('KDM8', 'Gene', (82, 86))	('KDM6B', 'Gene', '23135', (91, 96))	('result', 'Reg', (110, 116))	('imbalance', 'Var', (14, 23))
25739	30268436	A Pan-Cancer Analysis Reveals High-Frequency Genetic Alterations in Mediators of Signaling by the TGF-beta Superfamily We present an integromic analysis of gene alterations that modulate transforming growth factor beta (TGF-beta)-Smad-mediated signaling in 9,125 tumor samples across 33 cancer types in The Cancer Genome Atlas (TCGA).	('transforming growth factor beta', 'Gene', (187, 218))	('tumor', 'Disease', 'MESH:D009369', (263, 268))	('cancer', 'Disease', (287, 293))	('TGF-beta', 'Gene', (220, 228))	('cancer', 'Disease', 'MESH:D009369', (287, 293))	('tumor', 'Phenotype', 'HP:0002664', (263, 268))	('transforming growth factor beta', 'Gene', '7040', (187, 218))	('TGF-beta', 'Gene', '7040', (98, 106))	('Cancer', 'Phenotype', 'HP:0002664', (6, 12))	('cancer', 'Phenotype', 'HP:0002664', (287, 293))	('tumor', 'Disease', (263, 268))	('modulate', 'Reg', (178, 186))	('TGF-beta', 'Gene', '7040', (220, 228))	('TGF-beta', 'Gene', (98, 106))	('Cancer', 'Phenotype', 'HP:0002664', (307, 313))	('alterations', 'Var', (161, 172))
25740	30268436	Focusing on genes that encode mediators and regulators of TGF-beta signaling, we found at least one genomic alteration (mutation, homozygous deletion, or amplification) in 39% of samples, with highest frequencies in gastrointestinal cancers.	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('TGF-beta', 'Gene', (58, 66))	('mutation', 'Var', (120, 128))	('gastrointestinal cancers', 'Disease', 'MESH:D004067', (216, 240))	('amplification', 'Var', (154, 167))	('cancers', 'Phenotype', 'HP:0002664', (233, 240))	('gastrointestinal cancers', 'Disease', (216, 240))	('frequencies', 'Reg', (201, 212))	('TGF-beta', 'Gene', '7040', (58, 66))
25742	30268436	Alterations in the TGF-beta superfamily correlated positively with expression of metastasis-associated genes and with decreased survival.	('Alterations', 'Var', (0, 11))	('TGF-beta', 'Gene', '7040', (19, 27))	('metastasis-associated genes', 'Gene', (81, 108))	('decreased', 'NegReg', (118, 127))	('survival', 'CPA', (128, 136))	('expression', 'MPA', (67, 77))	('TGF-beta', 'Gene', (19, 27))
25743	30268436	Correlation analyses showed the contributions of mutation, amplification, deletion, DNA methylation, and miRNA expression to transcriptional activity of TGF-beta signaling in each cancer type.	('miR', 'Gene', (105, 108))	('transcriptional', 'MPA', (125, 140))	('TGF-beta', 'Gene', '7040', (153, 161))	('deletion', 'Var', (74, 82))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('TGF-beta', 'Gene', (153, 161))	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('amplification', 'Var', (59, 72))	('cancer', 'Disease', (180, 186))	('miR', 'Gene', '220972', (105, 108))
25759	30268436	We analyzed multiple data types: somatic copy number variation (CNV), point mutation, DNA methylation, mRNA expression (from mRNA-seq), miRNA expression (from miRNA-seq), and, for correlative analyses, protein expression (from reverse-phase protein arrays; RPPA).	('miR', 'Gene', '220972', (136, 139))	('miR', 'Gene', (136, 139))	('point mutation', 'Var', (70, 84))	('miR', 'Gene', '220972', (159, 162))	('miR', 'Gene', (159, 162))	('mRNA expression', 'MPA', (103, 118))
25765	30268436	Using the cBioPortal definitions, genomic alterations were classified as gene amplifications, gains (low-level amplifications), deep deletions (equivalent to homozygous deletions for non-aneuploidy cases), shallow deletions (heterozygous loss), truncating mutations, inframe mutations, or missense mutations.	('non-aneuploidy', 'Disease', (183, 197))	('truncating', 'Disease', (245, 255))	('deep', 'Disease', (128, 132))	('gains', 'Disease', (94, 99))	('inframe mutations', 'Var', (267, 284))	('missense mutations', 'Var', (289, 307))	('shallow', 'Disease', (206, 213))	('non-aneuploidy', 'Disease', 'MESH:D000782', (183, 197))
25767	30268436	Although alteration frequencies were low, 39% of the tumors contained an alteration in at least one of the 43 genes.	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('alteration', 'Var', (73, 83))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('tumors', 'Disease', (53, 59))
25771	30268436	When excluding those six, cumulative mutation frequency (23%) in the TGF-beta core pathways was significantly higher than expected for a randomly selected set of 37 genes (Figure S1C, S1D).	('TGF-beta', 'Gene', '7040', (69, 77))	('higher', 'PosReg', (110, 116))	('mutation frequency', 'Var', (37, 55))	('TGF-beta', 'Gene', (69, 77))
25775	30268436	The frequency and type of genomic alteration varied widely across tumor types (Figure 2A and S2A), from no alterations in testicular germline tumors (TGCT) to all three types of alterations (mutation, deletion, and amplification) in urothelial bladder cancers (BLCA).	('deletion', 'Var', (201, 209))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('cancers', 'Phenotype', 'HP:0002664', (252, 259))	('tumor', 'Disease', (66, 71))	('bladder cancers', 'Phenotype', 'HP:0009725', (244, 259))	('tumor', 'Disease', (142, 147))	('amplification', 'Var', (215, 228))	('urothelial bladder cancers', 'Disease', (233, 259))	('tumors', 'Disease', (142, 148))	('tumors', 'Disease', 'MESH:D009369', (142, 148))	('BLCA', 'Phenotype', 'HP:0009725', (261, 265))	('urothelial bladder cancers', 'Disease', 'MESH:D001749', (233, 259))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('tumor', 'Disease', 'MESH:D009369', (142, 147))
25776	30268436	There were genomic alterations of TGF-beta pathway genes in more than 50% of samples in 12 tumor types (Figure 2A, Tables S2-S4).	('TGF-beta', 'Gene', (34, 42))	('genomic alterations', 'Var', (11, 30))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('TGF-beta', 'Gene', '7040', (34, 42))	('tumor', 'Disease', (91, 96))
25778	30268436	Without adjusting for background alteration burden, among the 39% of TCGA cases that carried TGF-beta pathway gene alterations, SKCM (70%), COAD (65%), and ESCA (65%) had the highest percentages of alterations; THCA (4%), KICH (6%), and TGCT (9%) had the lowest (Table S3).	('TGF-beta', 'Gene', '7040', (93, 101))	('COAD', 'Disease', (140, 144))	('TGF-beta', 'Gene', (93, 101))	('alterations', 'Reg', (198, 209))	('alterations', 'Var', (115, 126))	('KICH', 'Disease', 'None', (222, 226))	('ESCA', 'Phenotype', 'HP:0011459', (156, 160))	('COAD', 'Disease', 'MESH:D029424', (140, 144))	('KICH', 'Disease', (222, 226))
25779	30268436	We observed non-silent SMAD4 mutations in 24% and SMAD4 deletions in 13% of pancreatic adenocarcinoma (PAAD) samples (Figure 2A, 2C; Table S4).	('SMAD4', 'Gene', (23, 28))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('mutations', 'Var', (29, 38))	('SMAD4', 'Gene', (50, 55))	('pancreatic adenocarcinoma', 'Disease', (76, 101))	('deletions', 'Var', (56, 65))	('PAAD', 'Phenotype', 'HP:0006725', (103, 107))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D010190', (76, 101))	('SMAD4', 'Gene', '4089', (23, 28))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (76, 101))	('SMAD4', 'Gene', '4089', (50, 55))
25780	30268436	Because SMAD4 is the Co-Smad required for transducing the Smad signal to downstream effectors, loss of SMAD4 in PAAD by mutation or deletion suggests a tumor-suppressive role for TGF-beta signaling in PAAD, which is consistent with other reports.	('TGF-beta', 'Gene', (179, 187))	('deletion', 'Var', (132, 140))	('SMAD4', 'Gene', (8, 13))	('a tumor', 'Disease', 'MESH:D009369', (150, 157))	('PAAD', 'Phenotype', 'HP:0006725', (112, 116))	('SMAD4', 'Gene', '4089', (103, 108))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('mutation', 'Var', (120, 128))	('a tumor', 'Disease', (150, 157))	('SMAD4', 'Gene', '4089', (8, 13))	('TGF-beta', 'Gene', '7040', (179, 187))	('loss', 'NegReg', (95, 99))	('SMAD4', 'Gene', (103, 108))	('PAAD', 'Disease', (201, 205))	('PAAD', 'Phenotype', 'HP:0006725', (201, 205))
25784	30268436	Diffuse large B-cell lymphoma (DLBC) had a high frequency of deletions spanning different levels of the pathway:: ligands (TGFB2, INHBB, GDF1), receptors or receptor-associated proteins (BMPR1A, ACVR1, ACVR1C, ACV2A, ACVR2B, TGFBRAP1), and Smads (SMAD9):, indicative of a tumor-suppressive role for TGF-beta signaling in these early-stage DLBC cases in the TCGA cohort.	('deletions', 'Var', (61, 70))	('TGF-beta', 'Gene', (299, 307))	('B-cell lymphoma', 'Disease', 'MESH:D016393', (14, 29))	('TGFB2', 'Gene', '7042', (123, 128))	('ACVR1C', 'Gene', (202, 208))	('ACVR1C', 'Gene', '130399', (202, 208))	('INHBB', 'Gene', (130, 135))	('BMPR1A', 'Gene', '657', (187, 193))	('ACV', 'Gene', (195, 198))	('ACV', 'Gene', (210, 213))	('ACV', 'Gene', (202, 205))	('ACVR1', 'Gene', (195, 200))	('a tumor', 'Disease', 'MESH:D009369', (270, 277))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (14, 29))	('TGFB2', 'Gene', (123, 128))	('TGFBRAP1', 'Gene', '9392', (225, 233))	('ACV', 'Gene', '83729', (202, 205))	('ACV', 'Gene', '83729', (195, 198))	('GDF1', 'Gene', (137, 141))	('ACVR2B', 'Gene', '93', (217, 223))	('ACV', 'Gene', '83729', (210, 213))	('ACVR1', 'Gene', '90', (202, 207))	('INHBB', 'Gene', '3625', (130, 135))	('B-cell lymphoma', 'Disease', (14, 29))	('early-stage DLBC', 'Disease', (327, 343))	('ACV', 'Gene', (217, 220))	('a tumor', 'Disease', (270, 277))	('BMPR1A', 'Gene', (187, 193))	('lymphoma', 'Phenotype', 'HP:0002665', (21, 29))	('ACVR1', 'Gene', (202, 207))	('ACVR1', 'Gene', '90', (195, 200))	('SMAD9', 'Gene', (247, 252))	('GDF1', 'Gene', '2657', (137, 141))	('TGF-beta', 'Gene', '7040', (299, 307))	('tumor', 'Phenotype', 'HP:0002664', (272, 277))	('ACV', 'Gene', '83729', (217, 220))	('ACVR2B', 'Gene', (217, 223))	('SMAD9', 'Gene', '4093', (247, 252))	('TGFBRAP1', 'Gene', (225, 233))
25790	30268436	PAAD had deletions associated with 14 TGF-beta core genes, suggesting synergistic effects from ligands (BMP family), receptors (BMPR, TGFBR), and SMAD4.	('TGFBR', 'Gene', '7046;7048;7049', (134, 139))	('TGF-beta', 'Gene', (38, 46))	('BMP', 'Gene', (128, 131))	('BMP', 'Gene', (104, 107))	('TGFBR', 'Gene', (134, 139))	('SMAD4', 'Gene', '4089', (146, 151))	('PAAD', 'Phenotype', 'HP:0006725', (0, 4))	('TGF-beta', 'Gene', '7040', (38, 46))	('deletions', 'Var', (9, 18))	('BMP', 'Gene', '649', (104, 107))	('SMAD4', 'Gene', (146, 151))	('BMP', 'Gene', '649', (128, 131))
25791	30268436	Colorectal cancers (COAD and READ) were marked by SMAD4 and SMAD3 deletions.	('COAD', 'Disease', (20, 24))	('SMAD3', 'Gene', (60, 65))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('Colorectal cancers', 'Disease', (0, 18))	('SMAD4', 'Gene', (50, 55))	('Colorectal cancers', 'Disease', 'MESH:D015179', (0, 18))	('cancers', 'Phenotype', 'HP:0002664', (11, 18))	('COAD', 'Disease', 'MESH:D029424', (20, 24))	('deletions', 'Var', (66, 75))	('SMAD3', 'Gene', '4088', (60, 65))	('SMAD4', 'Gene', '4089', (50, 55))
25792	30268436	Deletions in genomic regions covering all ACVR genes except ACVR2B were identified as significant in DLBC.	('ACV', 'Gene', '83729', (42, 45))	('ACVR2B', 'Gene', (60, 66))	('DLBC', 'Disease', (101, 105))	('ACV', 'Gene', (42, 45))	('ACV', 'Gene', '83729', (60, 63))	('ACV', 'Gene', (60, 63))	('ACVR2B', 'Gene', '93', (60, 66))	('significant', 'Reg', (86, 97))	('Deletions', 'Var', (0, 9))
25793	30268436	To understand how gene alterations affect transcriptional output of the pathways, we analyzed the mRNA expression of 50 downstream targets of Smad signaling with defined roles as tumor promoters or tumor suppressors (Table S1).	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('alterations', 'Var', (23, 34))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('tumor', 'Disease', (198, 203))	('tumor', 'Disease', (179, 184))
25794	30268436	Surprisingly, the directionality of target-gene change was consistent for all mutations, even for mutations in the inhibitors SMAD6/7.	('SMAD6/7', 'Gene', (126, 133))	('SMAD6/7', 'Gene', '4091;4092', (126, 133))	('mutations', 'Var', (78, 87))
25795	30268436	An explanation is that mutations in pathway activators, like TGFB1/2/3 and TGFBR1/2/3, may result in gain of function, whereas mutations in the inhibitors SMAD6 and SMAD7 may result in loss of inhibitory function.	('TGFBR1/2/3', 'Gene', (75, 85))	('gain of function', 'PosReg', (101, 117))	('TGFBR1/2/3', 'Gene', '7046;7048;7049', (75, 85))	('TGFB1/2/3', 'Gene', (61, 70))	('SMAD7', 'Gene', (165, 170))	('mutations', 'Var', (23, 32))	('SMAD7', 'Gene', '4092', (165, 170))	('SMAD6', 'Gene', '4091', (155, 160))	('TGFB1/2/3', 'Gene', '7040;7042;7043', (61, 70))	('SMAD6', 'Gene', (155, 160))	('inhibitory function', 'MPA', (193, 212))
25797	30268436	Similarly, SMAD3 was generally co-amplified with SMAD6; both are in proximal cytogenetic bands, 15q22.33 and 15q22.31, respectively.	('SMAD3', 'Gene', '4088', (11, 16))	('SMAD3', 'Gene', (11, 16))	('SMAD6', 'Gene', '4091', (49, 54))	('15q22.33', 'Var', (96, 104))	('SMAD6', 'Gene', (49, 54))	('15q22.31', 'Var', (109, 117))
25798	30268436	In support of that hypothesis, both the amplification and deletion profiles (rows in Figure 2H-I) of those gene pairs were similar, and, consequently, SMAD2 and SMAD7 are co-clustered, whereas SMAD3 and SMAD6 clustered close to each other.	('SMAD7', 'Gene', (161, 166))	('SMAD7', 'Gene', '4092', (161, 166))	('SMAD2', 'Gene', (151, 156))	('SMAD2', 'Gene', '4087', (151, 156))	('SMAD6', 'Gene', '4091', (203, 208))	('deletion', 'Var', (58, 66))	('SMAD6', 'Gene', (203, 208))	('SMAD3', 'Gene', '4088', (193, 198))	('SMAD3', 'Gene', (193, 198))
25799	30268436	The effect of TGF-beta pathway amplification events on target gene mRNA expression was similar to that of mutations (Figure 2H), suggesting that most mutations in TGF-beta pathway activators are gain of function.	('TGF-beta', 'Gene', '7040', (163, 171))	('TGF-beta', 'Gene', (14, 22))	('gain of function', 'PosReg', (195, 211))	('TGF-beta', 'Gene', (163, 171))	('mutations', 'Var', (150, 159))	('TGF-beta', 'Gene', '7040', (14, 22))
25800	30268436	HMGA2 was overexpressed in samples with either mutations or amplifications in the TGF-beta pathway genes, with the exception of tumors with amplifications in TGFB2, TGFBR2, ACVR2B, SMAD4, SMAD5, or SMAD6.	('TGFBR2', 'Gene', (165, 171))	('SMAD6', 'Gene', (198, 203))	('ACVR2B', 'Gene', '93', (173, 179))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('TGF-beta', 'Gene', '7040', (82, 90))	('SMAD4', 'Gene', (181, 186))	('tumors', 'Disease', (128, 134))	('overexpressed', 'PosReg', (10, 23))	('HMGA2', 'Gene', '8091', (0, 5))	('SMAD5', 'Gene', (188, 193))	('mutations', 'Var', (47, 56))	('tumors', 'Disease', 'MESH:D009369', (128, 134))	('TGF-beta', 'Gene', (82, 90))	('ACVR2B', 'Gene', (173, 179))	('SMAD6', 'Gene', '4091', (198, 203))	('SMAD4', 'Gene', '4089', (181, 186))	('amplifications', 'Var', (140, 154))	('TGFB2', 'Gene', '7042', (158, 163))	('TGFBR2', 'Gene', '7048', (165, 171))	('SMAD5', 'Gene', '4090', (188, 193))	('amplifications', 'Var', (60, 74))	('TGFB2', 'Gene', (158, 163))	('HMGA2', 'Gene', (0, 5))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))
25805	30268436	SMAD5 amplification was associated with increased CDH2 expression; 36 other amplifications were associated with decreased CDH2 expression.	('CDH2', 'Gene', (50, 54))	('CDH2', 'Gene', '1000', (50, 54))	('SMAD5', 'Gene', (0, 5))	('expression', 'MPA', (127, 137))	('CDH2', 'Gene', (122, 126))	('expression', 'MPA', (55, 65))	('CDH2', 'Gene', '1000', (122, 126))	('SMAD5', 'Gene', '4090', (0, 5))	('increased', 'PosReg', (40, 49))	('amplification', 'Var', (6, 19))	('decreased', 'NegReg', (112, 121))
25807	30268436	Another exception was reduced HMGA2 expression in samples with amplifications of SMAD4 or TGFBR2, whereas HMGA2 expression increased in samples with mutations in SMAD4 or TGFBR2 (Figure 2G).	('increased', 'PosReg', (123, 132))	('mutations', 'Var', (149, 158))	('HMGA2', 'Gene', '8091', (30, 35))	('TGFBR2', 'Gene', (90, 96))	('HMGA2', 'Gene', '8091', (106, 111))	('TGFBR2', 'Gene', '7048', (171, 177))	('SMAD4', 'Gene', '4089', (162, 167))	('SMAD4', 'Gene', (81, 86))	('HMGA2', 'Gene', (30, 35))	('HMGA2', 'Gene', (106, 111))	('amplifications', 'Var', (63, 77))	('reduced', 'NegReg', (22, 29))	('TGFBR2', 'Gene', (171, 177))	('TGFBR2', 'Gene', '7048', (90, 96))	('SMAD4', 'Gene', (162, 167))	('expression', 'MPA', (36, 46))	('SMAD4', 'Gene', '4089', (81, 86))	('expression', 'MPA', (112, 122))
25809	30268436	The analysis identified 6genes with hotspot mutations, representing all levels of the TGF-beta pathway (Figure 3A-E).	('TGF-beta', 'Gene', '7040', (86, 94))	('TGF-beta', 'Gene', (86, 94))	('mutations', 'Var', (44, 53))
25811	30268436	Hotspot mutations of BMP5 occurred in 13 cases across 7 cancers.	('cancers', 'Disease', (56, 63))	('cancers', 'Disease', 'MESH:D009369', (56, 63))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('mutations', 'Var', (8, 17))	('occurred', 'Reg', (26, 34))	('BMP5', 'Gene', (21, 25))	('BMP5', 'Gene', '653', (21, 25))	('cancers', 'Phenotype', 'HP:0002664', (56, 63))	('Hotspot', 'PosReg', (0, 7))
25812	30268436	BMP5 is synthesized as a proprotein, and an R321 stop-codon mutation (4 cases) (Figure 3A) results in loss of the functional, secreted ligand.	('R321 stop-codon', 'Var', (44, 59))	('BMP5', 'Gene', '653', (0, 4))	('BMP5', 'Gene', (0, 4))	('loss', 'NegReg', (102, 106))
25813	30268436	Frameshift mutations in ACVR2A at the K437 hotspot generate the variants K437Efs*19 (7 cases in 2 cancers) and K437Rfs*5 (69 cases in 5 cancers), resulting in premature stop codons and deletion of two C-terminal helices of the 4-helix bundle (Figure 3A, 3D), which likely disrupt ACV signaling (; Yosef et al., 2017).	('ACV', 'Gene', '83729', (24, 27))	('cancers', 'Phenotype', 'HP:0002664', (136, 143))	('cancers', 'Phenotype', 'HP:0002664', (98, 105))	('cancers', 'Disease', (136, 143))	('cancers', 'Disease', (98, 105))	('K437Efs*19', 'Var', (73, 83))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('K437Efs', 'Mutation', 'p.K437,FSE', (73, 80))	('ACV', 'Gene', (280, 283))	('disrupt', 'NegReg', (272, 279))	('cancers', 'Disease', 'MESH:D009369', (136, 143))	('ACV', 'Gene', '83729', (280, 283))	('cancers', 'Disease', 'MESH:D009369', (98, 105))	('K437Rfs*5', 'Var', (111, 120))	('stop codons', 'MPA', (169, 180))	('ACVR2A', 'Gene', '92', (24, 30))	('ACV', 'Gene', (24, 27))	('deletion', 'Var', (185, 193))	('ACVR2A', 'Gene', (24, 30))	('K437Rfs', 'Mutation', 'p.K437,FSR', (111, 118))	('Frameshift mutations', 'Var', (0, 20))
25814	30268436	Type I receptors ACVR1B and ACVR1C have similar C-terminal frameshift mutation hotspots at R485 (6 cases) and R441 (5 cases), respectively (Figure S3).	('ACVR1B', 'Gene', '91', (17, 23))	('ACVR1B', 'Gene', (17, 23))	('R441', 'Var', (110, 114))	('ACVR1C', 'Gene', (28, 34))	('ACVR1C', 'Gene', '130399', (28, 34))	('R485', 'Var', (91, 95))
25815	30268436	TGFBR2 R553 to C or H mutations and BMPR2 N583 frameshift might disrupt interaction with other receptor subunits or binding proteins.	('BMPR2', 'Gene', '659', (36, 41))	('binding', 'Interaction', (116, 123))	('N583 frameshift', 'Var', (42, 57))	('interaction', 'Interaction', (72, 83))	('TGFBR2', 'Gene', (0, 6))	('R553 to C or H mutations', 'Var', (7, 31))	('frameshift', 'Var', (47, 57))	('TGFBR2', 'Gene', '7048', (0, 6))	('disrupt', 'NegReg', (64, 71))	('BMPR2', 'Gene', (36, 41))
25816	30268436	Hotspots in SMAD4 at R361 and D537 (two conserved sites in R-Smads) normally stabilize homo- or heterotrimer oligomerization (Figure 3C).	('SMAD4', 'Gene', (12, 17))	('stabilize', 'Reg', (77, 86))	('D537', 'Var', (30, 34))	('homo-', 'MPA', (87, 92))	('SMAD4', 'Gene', '4089', (12, 17))
25817	30268436	Those mutations could have widespread effects, because SMAD4 is a binding partner for all Smad-dependent transcriptional regulation.	('mutations', 'Var', (6, 15))	('SMAD4', 'Gene', '4089', (55, 60))	('SMAD4', 'Gene', (55, 60))
25818	30268436	Mutation at either R361 or D537 in SMAD4 correlates with metastasis and decreased survival in colon cancer.	('survival', 'CPA', (82, 90))	('colon cancer', 'Disease', (94, 106))	('decreased', 'NegReg', (72, 81))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('SMAD4', 'Gene', '4089', (35, 40))	('D537', 'Var', (27, 31))	('metastasis', 'CPA', (57, 67))	('colon cancer', 'Phenotype', 'HP:0003003', (94, 106))	('SMAD4', 'Gene', (35, 40))	('colon cancer', 'Disease', 'MESH:D015179', (94, 106))
25819	30268436	SMAD2 exhibited 13 truncating mutations at S464 (Figure 3A).	('SMAD2', 'Gene', (0, 5))	('SMAD2', 'Gene', '4087', (0, 5))	('S464', 'Var', (43, 47))
25821	30268436	S464 is necessary for proper positioning of SMAD2 for phosphorylation at S465 and S467, both of which mediate interaction of SMAD2 with SMAD4 and dissociation of SMAD2 from TGFBR1 and the adaptor SARA (encoded by ZFYVE9).	('SARA', 'Gene', (196, 200))	('SMAD4', 'Gene', '4089', (136, 141))	('SARA', 'Gene', '9372', (196, 200))	('dissociation', 'MPA', (146, 158))	('ZFYVE9', 'Gene', '9372', (213, 219))	('TGFBR1', 'Gene', '7046', (173, 179))	('mediate', 'Reg', (102, 109))	('TGFBR1', 'Gene', (173, 179))	('SMAD4', 'Gene', (136, 141))	('interaction', 'Interaction', (110, 121))	('SMAD2', 'Gene', (162, 167))	('SMAD2', 'Gene', '4087', (162, 167))	('SMAD2', 'Gene', '4087', (125, 130))	('SMAD2', 'Gene', (125, 130))	('SMAD2', 'Gene', '4087', (44, 49))	('ZFYVE9', 'Gene', (213, 219))	('S467', 'Var', (82, 86))	('SMAD2', 'Gene', (44, 49))
25822	30268436	Hence, S464 mutations may prevent dissociation of SMAD2 from the receptor-adaptor complex, blocking the downstream signal (Figure 3E).	('SMAD2', 'Gene', (50, 55))	('S464 mutations', 'Var', (7, 21))	('downstream signal', 'MPA', (104, 121))	('blocking', 'NegReg', (91, 99))	('SMAD2', 'Gene', '4087', (50, 55))	('dissociation', 'MPA', (34, 46))	('prevent', 'NegReg', (26, 33))
25823	30268436	Of 176 mutations at hotspot sites across 6 genes, 115 (65%) were in cancers of the GI system (Figure S3): 60 in ESCA, 51 in COAD, 3 in PAAD, and 1 in LIHC.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('cancers of the GI system', 'Phenotype', 'HP:0007378', (68, 92))	('PAAD', 'Phenotype', 'HP:0006725', (135, 139))	('cancers', 'Phenotype', 'HP:0002664', (68, 75))	('COAD', 'Disease', (124, 128))	('cancers of the GI system', 'Disease', 'MESH:D009369', (68, 92))	('cancers of the GI system', 'Disease', (68, 92))	('LIHC', 'Disease', (150, 154))	('ESCA', 'Phenotype', 'HP:0011459', (112, 116))	('LIHC', 'Disease', 'None', (150, 154))	('ESCA', 'Disease', (112, 116))	('COAD', 'Disease', 'MESH:D029424', (124, 128))	('mutations', 'Var', (7, 16))
25826	30268436	To determine if GI cancers possess a unique signature of altered TGF-beta pathway activity, we compared changes in the expression of 50 downstream genes related to mutations at hotspot sites (Figure 3B).	('TGF-beta', 'Gene', (65, 73))	('expression', 'MPA', (119, 129))	('GI cancers', 'Disease', (16, 26))	('cancers', 'Phenotype', 'HP:0002664', (19, 26))	('GI cancers', 'Disease', 'MESH:D009369', (16, 26))	('GI cancer', 'Phenotype', 'HP:0007378', (16, 25))	('activity', 'MPA', (82, 90))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('mutations', 'Var', (164, 173))	('TGF-beta', 'Gene', '7040', (65, 73))
25828	30268436	Notably, CDH2 exhibited an overall reduction in expression except in the context of the BMP5 hotspot mutation.	('CDH2', 'Gene', (9, 13))	('CDH2', 'Gene', '1000', (9, 13))	('BMP5', 'Gene', (88, 92))	('expression', 'MPA', (48, 58))	('BMP5', 'Gene', '653', (88, 92))	('mutation', 'Var', (101, 109))	('reduction', 'NegReg', (35, 44))
25832	30268436	Guided by the enrichment of hotspot mutations in GI cancers, we tested for enrichment of TGF-beta pathway point mutations in GI cancers.	('GI cancers', 'Disease', 'MESH:D009369', (49, 59))	('cancers', 'Phenotype', 'HP:0002664', (128, 135))	('GI cancers', 'Disease', 'MESH:D009369', (125, 135))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('GI cancer', 'Phenotype', 'HP:0007378', (49, 58))	('GI cancer', 'Phenotype', 'HP:0007378', (125, 134))	('tested', 'Reg', (64, 70))	('point mutations', 'Var', (106, 121))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('TGF-beta', 'Gene', '7040', (89, 97))	('cancers', 'Phenotype', 'HP:0002664', (52, 59))	('GI cancers', 'Disease', (49, 59))	('GI cancers', 'Disease', (125, 135))	('TGF-beta', 'Gene', (89, 97))
25833	30268436	Non-silent mutations were significantly more common in GI cancers (596 of 1,511) than in the non-GI cancers (1,606 of 7,614).	('GI cancers', 'Disease', 'MESH:D009369', (55, 65))	('common', 'Reg', (45, 51))	('non-GI cancers', 'Disease', 'MESH:D009369', (93, 107))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('GI cancer', 'Phenotype', 'HP:0007378', (55, 64))	('GI cancer', 'Phenotype', 'HP:0007378', (97, 106))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('cancers', 'Phenotype', 'HP:0002664', (58, 65))	('Non-silent mutations', 'Var', (0, 20))	('GI cancers', 'Disease', 'MESH:D009369', (97, 107))	('GI cancers', 'Disease', (55, 65))	('cancers', 'Phenotype', 'HP:0002664', (100, 107))	('non-GI cancers', 'Disease', (93, 107))
25834	30268436	Deep deletions and amplifications were also significantly enriched in GI cancers.	('GI cancer', 'Phenotype', 'HP:0007378', (70, 79))	('GI cancers', 'Disease', 'MESH:D009369', (70, 80))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('GI cancers', 'Disease', (70, 80))	('Deep deletions', 'Var', (0, 14))	('amplifications', 'Var', (19, 33))
25835	30268436	COAD, READ, and STAD had recurrent aberrations in genes at each level of the pathway (ligands, receptors, and SMADs) and all axes (TGFBR, BMPR, ACVR), whereas PAAD had frequent mutations in only SMAD4 and TGFBR2 (Figure S4A).	('TGFBR', 'Gene', (205, 210))	('COAD', 'Disease', (0, 4))	('SMAD4', 'Gene', '4089', (195, 200))	('aberrations', 'Var', (35, 46))	('TGFBR2', 'Gene', '7048', (205, 211))	('ACV', 'Gene', (144, 147))	('mutations', 'Var', (177, 186))	('BMP', 'Gene', (138, 141))	('TGFBR', 'Gene', '7046;7048;7049', (131, 136))	('TGFBR2', 'Gene', (205, 211))	('SMAD4', 'Gene', (195, 200))	('COAD', 'Disease', 'MESH:D029424', (0, 4))	('TGFBR', 'Gene', '7046;7048;7049', (205, 210))	('PAAD', 'Phenotype', 'HP:0006725', (159, 163))	('BMP', 'Gene', '649', (138, 141))	('ACV', 'Gene', '83729', (144, 147))	('TGFBR', 'Gene', (131, 136))
25836	30268436	To compare the TGF-beta pathway transcriptional signatures in GI vs. other cancers, we calculated the target gene expression signatures associated with TGF-beta pathway mutations in both groups (Figure 4A-B).	('TGF-beta', 'Gene', '7040', (152, 160))	('mutations', 'Var', (169, 178))	('cancers', 'Disease', 'MESH:D009369', (75, 82))	('cancers', 'Phenotype', 'HP:0002664', (75, 82))	('TGF-beta', 'Gene', '7040', (15, 23))	('cancers', 'Disease', (75, 82))	('TGF-beta', 'Gene', (15, 23))	('TGF-beta', 'Gene', (152, 160))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))
25838	30268436	Whereas IL6 mRNA was increased in most non-GI cancers with TGF-beta pathway mutations, IL6 upregulation was significantly greater in GI cancers than non-GI cancers (Figure S4B), and within GI cancers IL6 expression was greater in samples with alterations in the TGF-beta pathway genes than those without alterations in the TGF-beta pathway genes.	('non-GI cancers', 'Disease', (39, 53))	('GI cancers than non-GI cancers', 'Disease', 'MESH:D009369', (133, 163))	('GI cancers', 'Disease', 'MESH:D009369', (189, 199))	('non-GI cancers', 'Disease', 'MESH:D009369', (39, 53))	('cancers', 'Phenotype', 'HP:0002664', (136, 143))	('TGF-beta', 'Gene', (323, 331))	('GI cancers', 'Disease', 'MESH:D009369', (43, 53))	('cancers', 'Phenotype', 'HP:0002664', (192, 199))	('IL6', 'Gene', '3569', (8, 11))	('alterations', 'Var', (243, 254))	('IL6', 'Gene', '3569', (200, 203))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('TGF-beta', 'Gene', (59, 67))	('increased', 'PosReg', (21, 30))	('non-GI cancers', 'Disease', 'MESH:D009369', (149, 163))	('GI cancers', 'Disease', 'MESH:D009369', (153, 163))	('IL6', 'Gene', '3569', (87, 90))	('GI cancer', 'Phenotype', 'HP:0007378', (43, 52))	('IL6', 'Gene', (8, 11))	('TGF-beta', 'Gene', '7040', (262, 270))	('IL6', 'Gene', (200, 203))	('GI cancers than non-GI cancers', 'Disease', (133, 163))	('cancers', 'Phenotype', 'HP:0002664', (46, 53))	('GI cancer', 'Phenotype', 'HP:0007378', (153, 162))	('upregulation', 'PosReg', (91, 103))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('IL6', 'Gene', (87, 90))	('expression', 'MPA', (204, 214))	('GI cancers', 'Disease', (189, 199))	('greater', 'PosReg', (122, 129))	('TGF-beta', 'Gene', '7040', (323, 331))	('cancers', 'Phenotype', 'HP:0002664', (156, 163))	('mutations', 'Var', (76, 85))	('TGF-beta', 'Gene', (262, 270))	('GI cancer', 'Phenotype', 'HP:0007378', (133, 142))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('GI cancers', 'Disease', 'MESH:D009369', (133, 143))	('GI cancer', 'Phenotype', 'HP:0007378', (189, 198))	('TGF-beta', 'Gene', '7040', (59, 67))
25839	30268436	Notably, in non-GI cancers associated with GDF1 mutations, IL6 mRNA expression was markedly decreased, suggesting that GDF1 may play different roles in GI and non-GI cancers.	('non-GI cancers', 'Disease', 'MESH:D009369', (159, 173))	('GDF1', 'Gene', (43, 47))	('non-GI cancers', 'Disease', (159, 173))	('GDF1', 'Gene', (119, 123))	('non-GI cancers', 'Disease', (12, 26))	('cancers', 'Phenotype', 'HP:0002664', (19, 26))	('non-GI cancers', 'Disease', 'MESH:D009369', (12, 26))	('GI cancer', 'Phenotype', 'HP:0007378', (163, 172))	('IL6', 'Gene', '3569', (59, 62))	('IL6', 'Gene', (59, 62))	('GI cancer', 'Phenotype', 'HP:0007378', (16, 25))	('cancers', 'Phenotype', 'HP:0002664', (166, 173))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('decreased', 'NegReg', (92, 101))	('GDF1', 'Gene', '2657', (43, 47))	('mutations', 'Var', (48, 57))	('GDF1', 'Gene', '2657', (119, 123))
25841	30268436	In GI cancers, most TGF-beta pathway gene mutations were associated with increased FOS expression; exceptions were TGFBRAP1, SMAD7, SMAD5, GDF1, BMP5, and ACVRL1.	('GI cancers', 'Disease', 'MESH:D009369', (3, 13))	('TGF-beta', 'Gene', (20, 28))	('ACVRL1', 'Gene', (155, 161))	('SMAD7', 'Gene', '4092', (125, 130))	('BMP5', 'Gene', (145, 149))	('BMP5', 'Gene', '653', (145, 149))	('TGFBRAP1', 'Gene', '9392', (115, 123))	('GDF1', 'Gene', (139, 143))	('SMAD5', 'Gene', (132, 137))	('GI cancer', 'Phenotype', 'HP:0007378', (3, 12))	('increased', 'PosReg', (73, 82))	('ACVRL1', 'Gene', '94', (155, 161))	('GDF1', 'Gene', '2657', (139, 143))	('cancers', 'Phenotype', 'HP:0002664', (6, 13))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('SMAD5', 'Gene', '4090', (132, 137))	('FOS', 'Gene', (83, 86))	('SMAD7', 'Gene', (125, 130))	('GI cancers', 'Disease', (3, 13))	('TGF-beta', 'Gene', '7040', (20, 28))	('FOS', 'Gene', '2353', (83, 86))	('TGFBRAP1', 'Gene', (115, 123))	('mutations', 'Var', (42, 51))
25842	30268436	In non-GI cancers, only mutations in TGFBR2 were associated with increased FOS expression; all other TGF-beta pathway gene mutations were associated with decreased FOS expression.	('decreased', 'NegReg', (154, 163))	('increased', 'PosReg', (65, 74))	('FOS', 'Gene', (164, 167))	('TGF-beta', 'Gene', '7040', (101, 109))	('TGFBR2', 'Gene', '7048', (37, 43))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('FOS', 'Gene', '2353', (164, 167))	('TGF-beta', 'Gene', (101, 109))	('non-GI cancers', 'Disease', (3, 17))	('FOS', 'Gene', (75, 78))	('TGFBR2', 'Gene', (37, 43))	('cancers', 'Phenotype', 'HP:0002664', (10, 17))	('mutations', 'Var', (24, 33))	('non-GI cancers', 'Disease', 'MESH:D009369', (3, 17))	('GI cancer', 'Phenotype', 'HP:0007378', (7, 16))	('FOS', 'Gene', '2353', (75, 78))
25843	30268436	To compare the transcriptional output resulting from mutations in GI and non-GI cancers, we calculated differences in expression of the 50 target genes associated with mutations in the 43 genes (Figure 4C).	('non-GI cancers', 'Disease', 'MESH:D009369', (73, 87))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('GI cancer', 'Phenotype', 'HP:0007378', (77, 86))	('differences', 'Reg', (103, 114))	('expression', 'MPA', (118, 128))	('non-GI cancers', 'Disease', (73, 87))	('mutations', 'Var', (168, 177))	('cancers', 'Phenotype', 'HP:0002664', (80, 87))
25844	30268436	The analysis revealed a shift toward repression of transcriptional output in GI cancers with the most significant shifts occurring with mutations in ACVR2B, INHBA, SMAD3, or GDF2.	('GDF2', 'Gene', (174, 178))	('repression', 'NegReg', (37, 47))	('GI cancers', 'Disease', (77, 87))	('SMAD3', 'Gene', '4088', (164, 169))	('ACVR2B', 'Gene', '93', (149, 155))	('INHBA', 'Gene', '3624', (157, 162))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('transcriptional output', 'MPA', (51, 73))	('SMAD3', 'Gene', (164, 169))	('GI cancer', 'Phenotype', 'HP:0007378', (77, 86))	('INHBA', 'Gene', (157, 162))	('mutations', 'Var', (136, 145))	('GI cancers', 'Disease', 'MESH:D009369', (77, 87))	('ACVR2B', 'Gene', (149, 155))	('GDF2', 'Gene', '2658', (174, 178))	('cancers', 'Phenotype', 'HP:0002664', (80, 87))
25845	30268436	In GI cancers, mutations in GDF1 were associated with significantly increased target gene transcription.	('GDF1', 'Gene', '2657', (28, 32))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('GDF1', 'Gene', (28, 32))	('target gene transcription', 'MPA', (78, 103))	('mutations', 'Var', (15, 24))	('GI cancers', 'Disease', (3, 13))	('cancers', 'Phenotype', 'HP:0002664', (6, 13))	('GI cancer', 'Phenotype', 'HP:0007378', (3, 12))	('increased', 'PosReg', (68, 77))	('GI cancers', 'Disease', 'MESH:D009369', (3, 13))
25846	30268436	Mutations in any of the 43 genes were associated with reduced mRNA expression in GI cancers compared with non-GI cancers for most target genes with the largest reductions found for HMGA2 and TERT.	('GI cancer', 'Phenotype', 'HP:0007378', (110, 119))	('GI cancers', 'Disease', 'MESH:D009369', (110, 120))	('GI cancers', 'Disease', (81, 91))	('HMGA2', 'Gene', '8091', (181, 186))	('cancers', 'Phenotype', 'HP:0002664', (84, 91))	('cancers', 'Phenotype', 'HP:0002664', (113, 120))	('non-GI cancers', 'Disease', 'MESH:D009369', (106, 120))	('non-GI cancers', 'Disease', (106, 120))	('GI cancers', 'Disease', 'MESH:D009369', (81, 91))	('mRNA expression', 'MPA', (62, 77))	('Mutations', 'Var', (0, 9))	('HMGA2', 'Gene', (181, 186))	('reduced', 'NegReg', (54, 61))	('GI cancer', 'Phenotype', 'HP:0007378', (81, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('TERT', 'Gene', (191, 195))	('TERT', 'Gene', '7015', (191, 195))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
25847	30268436	Compared to non-GI cancers, GI cancers had fewer genes with increased expression resulting from pathway mutations.	('non-GI cancers', 'Disease', (12, 26))	('mutations', 'Var', (104, 113))	('GI cancers', 'Disease', 'MESH:D009369', (28, 38))	('cancers', 'Phenotype', 'HP:0002664', (19, 26))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('non-GI cancers', 'Disease', 'MESH:D009369', (12, 26))	('GI cancers', 'Disease', 'MESH:D009369', (16, 26))	('expression', 'MPA', (70, 80))	('GI cancer', 'Phenotype', 'HP:0007378', (16, 25))	('GI cancers', 'Disease', (28, 38))	('cancers', 'Phenotype', 'HP:0002664', (31, 38))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('GI cancer', 'Phenotype', 'HP:0007378', (28, 37))	('increased', 'PosReg', (60, 69))
25848	30268436	In GI cancers, mutations in any of the 43 genes were associated with a significantly increased expression of FOS, IL6, ZEB2, and ZEB1 compared to expression changes of the same genes resulting from pathway mutations in non-GI cancers.	('ZEB1', 'Gene', '6935', (129, 133))	('IL6', 'Gene', (114, 117))	('increased', 'PosReg', (85, 94))	('GI cancers', 'Disease', 'MESH:D009369', (3, 13))	('mutations', 'Var', (15, 24))	('non-GI cancers', 'Disease', (219, 233))	('non-GI cancers', 'Disease', 'MESH:D009369', (219, 233))	('FOS', 'Gene', (109, 112))	('GI cancer', 'Phenotype', 'HP:0007378', (3, 12))	('GI cancers', 'Disease', 'MESH:D009369', (223, 233))	('expression', 'MPA', (95, 105))	('FOS', 'Gene', '2353', (109, 112))	('ZEB1', 'Gene', (129, 133))	('cancers', 'Phenotype', 'HP:0002664', (6, 13))	('GI cancer', 'Phenotype', 'HP:0007378', (223, 232))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('ZEB2', 'Gene', (119, 123))	('cancers', 'Phenotype', 'HP:0002664', (226, 233))	('IL6', 'Gene', '3569', (114, 117))	('GI cancers', 'Disease', (3, 13))	('ZEB2', 'Gene', '9839', (119, 123))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
25849	30268436	Finally, we probed for associations between transcriptional output and TGF-beta pathway gene alterations for all cancers and the GI and non-GI subsets (Figure 4E).	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('alterations', 'Var', (93, 104))	('cancers', 'Disease', 'MESH:D009369', (113, 120))	('probed', 'Reg', (12, 18))	('cancers', 'Phenotype', 'HP:0002664', (113, 120))	('cancers', 'Disease', (113, 120))	('TGF-beta', 'Gene', '7040', (71, 79))	('TGF-beta', 'Gene', (71, 79))
25852	30268436	To explore TGF-beta signaling pathway variation across the 33 cancers in the PanCancer cohort, we computed a "pathway activity score" based on mRNA expression of the 43 genes.	('TGF-beta', 'Gene', '7040', (11, 19))	('TGF-beta', 'Gene', (11, 19))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('variation', 'Var', (38, 47))	('Cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancers', 'Disease', 'MESH:D009369', (62, 69))	('cancers', 'Phenotype', 'HP:0002664', (62, 69))	('cancers', 'Disease', (62, 69))
25874	30268436	We attribute this observation to co-occurring amplifications or deletions of SMAD7 and SMAD2 and co-occurring amplifications of SMAD6 and SMAD3 (Figure 1B).	('amplifications', 'Var', (46, 60))	('SMAD7', 'Gene', (77, 82))	('SMAD6', 'Gene', (128, 133))	('SMAD3', 'Gene', '4088', (138, 143))	('SMAD2', 'Gene', '4087', (87, 92))	('deletions', 'Var', (64, 73))	('SMAD7', 'Gene', '4092', (77, 82))	('SMAD2', 'Gene', (87, 92))	('SMAD3', 'Gene', (138, 143))	('SMAD6', 'Gene', '4091', (128, 133))
25881	30268436	We analyzed the combined impact of TGF-beta target gene expression and the 43 core gene alterations on patient survival across the PanCancer cohort.	('TGF-beta', 'Gene', (35, 43))	('Cancer', 'Phenotype', 'HP:0002664', (134, 140))	('alterations', 'Var', (88, 99))	('patient', 'Species', '9606', (103, 110))	('TGF-beta', 'Gene', '7040', (35, 43))
25882	30268436	We compared the survival of patients with 3 different cancer profiles: those with high expression of HMGA2 and alterations in any one of the 43 TGF-beta pathway genes (Figure 6C, High HMGA2/TGF-beta mutant), those with high HMGA2 expression and no alterations in any of the 43 genes (Figure 6C, High HMGA2/TGF-beta wild-type), and those with low expression of HMGA2 without considering alterations in TGF-beta pathway genes (Figure 6C, Low HMGA2 expression).	('TGF-beta', 'Gene', '7040', (306, 314))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('HMGA2', 'Gene', '8091', (360, 365))	('high', 'PosReg', (82, 86))	('HMGA2', 'Gene', '8091', (440, 445))	('HMGA2', 'Gene', '8091', (184, 189))	('HMGA2', 'Gene', (300, 305))	('mutant', 'Var', (199, 205))	('TGF-beta', 'Gene', (401, 409))	('HMGA2', 'Gene', (101, 106))	('TGF-beta', 'Gene', (306, 314))	('HMGA2', 'Gene', '8091', (224, 229))	('TGF-beta', 'Gene', '7040', (144, 152))	('patients', 'Species', '9606', (28, 36))	('TGF-beta', 'Gene', '7040', (190, 198))	('cancer', 'Disease', (54, 60))	('HMGA2', 'Gene', (360, 365))	('HMGA2', 'Gene', '8091', (300, 305))	('HMGA2', 'Gene', '8091', (101, 106))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('TGF-beta', 'Gene', (144, 152))	('HMGA2', 'Gene', (184, 189))	('HMGA2', 'Gene', (440, 445))	('alterations', 'Var', (111, 122))	('TGF-beta', 'Gene', (190, 198))	('TGF-beta', 'Gene', '7040', (401, 409))	('HMGA2', 'Gene', (224, 229))
25886	30268436	We saw the opposite for cancers with downregulated CDH2; the worst outcome was associated with low CDH2 expression and mutations in 43 genes (Figure S6B).	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('low', 'NegReg', (95, 98))	('CDH2', 'Gene', (99, 103))	('CDH2', 'Gene', (51, 55))	('cancers', 'Phenotype', 'HP:0002664', (24, 31))	('expression', 'MPA', (104, 114))	('CDH2', 'Gene', '1000', (99, 103))	('cancers', 'Disease', 'MESH:D009369', (24, 31))	('mutations', 'Var', (119, 128))	('CDH2', 'Gene', '1000', (51, 55))	('cancers', 'Disease', (24, 31))
25887	30268436	Thus, the expression profile of specific target genes and alterations in the TGF-beta superfamily genes cooperated to increase tumor aggressiveness.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumor aggressiveness', 'Disease', (127, 147))	('increase', 'PosReg', (118, 126))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (127, 147))	('TGF-beta', 'Gene', '7040', (77, 85))	('aggressiveness', 'Phenotype', 'HP:0000718', (133, 147))	('TGF-beta', 'Gene', (77, 85))	('alterations', 'Var', (58, 69))
25889	30268436	Because of the association of collagen overexpression and alterations in TGF-beta pathway genes with poor survival, we hypothesize that altered signaling through the TGF-beta superfamily pathways remodels the extracellular matrix to drive metastasis in multiple cancer contexts.	('cancer', 'Disease', (262, 268))	('overexpression', 'PosReg', (39, 53))	('TGF-beta', 'Gene', '7040', (73, 81))	('TGF-beta', 'Gene', '7040', (166, 174))	('TGF-beta', 'Gene', (73, 81))	('remodels', 'Reg', (196, 204))	('cancer', 'Phenotype', 'HP:0002664', (262, 268))	('drive', 'PosReg', (233, 238))	('TGF-beta', 'Gene', (166, 174))	('metastasis', 'CPA', (239, 249))	('cancer', 'Disease', 'MESH:D009369', (262, 268))	('alterations', 'Var', (58, 69))
25891	30268436	In the GI cohort, only ZEB2 combined with TGF-beta pathway gene alteration yielded a significant difference, with low ZEB2 expression corresponding to a survival benefit.	('ZEB2', 'Gene', '9839', (23, 27))	('expression', 'MPA', (123, 133))	('TGF-beta', 'Gene', (42, 50))	('ZEB2', 'Gene', (118, 122))	('ZEB2', 'Gene', (23, 27))	('alteration', 'Var', (64, 74))	('benefit', 'PosReg', (162, 169))	('low', 'NegReg', (114, 117))	('TGF-beta', 'Gene', '7040', (42, 50))	('ZEB2', 'Gene', '9839', (118, 122))
25892	30268436	In non-GI patients, high expression of the TGF-beta pathway target genes IL6, HMGA2, ZEB2, and FOS was associated with reduced survival particularly when combined with TGF-beta pathway mutations.	('TGF-beta', 'Gene', (168, 176))	('HMGA2', 'Gene', '8091', (78, 83))	('ZEB2', 'Gene', '9839', (85, 89))	('survival', 'MPA', (127, 135))	('expression', 'MPA', (25, 35))	('high', 'PosReg', (20, 24))	('HMGA2', 'Gene', (78, 83))	('IL6', 'Gene', '3569', (73, 76))	('TGF-beta', 'Gene', '7040', (43, 51))	('ZEB2', 'Gene', (85, 89))	('TGF-beta', 'Gene', (43, 51))	('IL6', 'Gene', (73, 76))	('FOS', 'Gene', (95, 98))	('mutations', 'Var', (185, 194))	('reduced', 'NegReg', (119, 126))	('TGF-beta', 'Gene', '7040', (168, 176))	('patients', 'Species', '9606', (10, 18))	('FOS', 'Gene', '2353', (95, 98))
25893	30268436	Thus, although TGF-beta pathway mutations may not occur as commonly in non-GI cancers, they may be important contributors to mortality.	('non-GI cancers', 'Disease', (71, 85))	('non-GI cancers', 'Disease', 'MESH:D009369', (71, 85))	('contributors', 'Reg', (109, 121))	('TGF-beta', 'Gene', '7040', (15, 23))	('TGF-beta', 'Gene', (15, 23))	('cancers', 'Phenotype', 'HP:0002664', (78, 85))	('mutations', 'Var', (32, 41))	('GI cancer', 'Phenotype', 'HP:0007378', (75, 84))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))
25911	30268436	We also identified BMPR2 and TGFBR2 as genes with hotspot sites of mutations that were common in STAD and COAD.	('COAD', 'Disease', (106, 110))	('STAD', 'Disease', (97, 101))	('COAD', 'Disease', 'MESH:D029424', (106, 110))	('mutations', 'Var', (67, 76))	('TGFBR2', 'Gene', (29, 35))	('BMPR2', 'Gene', (19, 24))	('BMPR2', 'Gene', '659', (19, 24))	('TGFBR2', 'Gene', '7048', (29, 35))
25912	30268436	The cancers with high frequencies of hotspot mutations in those two genes did not have high expression of miRNA 92a-3p, suggesting that there is little selective pressure for both mutation and downregulation by that miRNA.	('downregulation', 'NegReg', (193, 207))	('mutations', 'Var', (45, 54))	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('miR', 'Gene', (106, 109))	('miR', 'Gene', '220972', (216, 219))	('miR', 'Gene', (216, 219))	('miR', 'Gene', '220972', (106, 109))	('cancers', 'Disease', 'MESH:D009369', (4, 11))	('cancers', 'Phenotype', 'HP:0002664', (4, 11))	('cancers', 'Disease', (4, 11))
25913	30268436	To examine the contribution of mutations, amplifications, deletions, DNA methylation and miRNAs to the pathway activity score across tumor types, we computed Pearson's correlations between the pathway activity score and (i) levels of DNA methylation or miRNA expression and (ii) percentages of mutations or CNVs in each tumor type and plotted the results in order of increasing pathway activity score (Figure 7F).	('miR', 'Gene', '220972', (253, 256))	('miR', 'Gene', (253, 256))	('tumor', 'Disease', 'MESH:D009369', (320, 325))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('CNVs', 'Var', (307, 311))	('miR', 'Gene', '220972', (89, 92))	('miR', 'Gene', (89, 92))	('tumor', 'Phenotype', 'HP:0002664', (320, 325))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumor', 'Disease', (320, 325))	('tumor', 'Disease', (133, 138))	('mutations', 'Var', (294, 303))
25916	30268436	Amplifications positively correlated with activity score and played a dominant role in UCS, SARC, ESCA, CHOL, and OV.	('activity score', 'MPA', (42, 56))	('CHOL', 'CellLine', 'None', (104, 108))	('CHOL', 'Disease', (104, 108))	('Amplifications', 'Var', (0, 14))	('correlated', 'Reg', (26, 36))	('UCS', 'Disease', (87, 90))	('OV', 'Phenotype', 'HP:0100615', (114, 116))	('ESCA', 'Phenotype', 'HP:0011459', (98, 102))	('SARC', 'Disease', (92, 96))	('ESCA', 'Disease', (98, 102))
25920	30268436	Some of the key findings of the study were that (i) 39% of the cancers carried TGF-beta pathway gene alterations; (ii) the genomic alterations appeared to affect expression of metastatic and EMT genes; (iii) six hotspot mutations were identified in six genes; (iv) the pathway was most frequently aberrant in GI cancers, which exhibited 115 of the 176 hotspot mutations identified; (iv) high expression of downstream target genes coupled with mutations in the TGF-beta pathway genes was associated with poor outcome, suggesting a net tumor-promoting role of the superfamily across the PanCancer cohort; (v) apparent gene silencing by DNA methylation and deletion of TGF-beta pathway genes were observed most frequently in DLBC, whereas miRNA silencing was seen most often in LAML.	('gene silencing', 'NegReg', (616, 630))	('cancers', 'Phenotype', 'HP:0002664', (312, 319))	('cancers', 'Disease', (312, 319))	('GI cancers', 'Disease', (309, 319))	('tumor', 'Disease', (534, 539))	('miR', 'Gene', (736, 739))	('cancer', 'Phenotype', 'HP:0002664', (312, 318))	('tumor', 'Disease', 'MESH:D009369', (534, 539))	('DLBC', 'Disease', (722, 726))	('TGF-beta', 'Gene', '7040', (666, 674))	('TGF-beta', 'Gene', '7040', (460, 468))	('cancers', 'Phenotype', 'HP:0002664', (63, 70))	('GI cancers', 'Disease', 'MESH:D009369', (309, 319))	('TGF-beta', 'Gene', '7040', (79, 87))	('cancers', 'Disease', (63, 70))	('Cancer', 'Phenotype', 'HP:0002664', (588, 594))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('methylation', 'Var', (638, 649))	('tumor', 'Phenotype', 'HP:0002664', (534, 539))	('cancers', 'Disease', 'MESH:D009369', (312, 319))	('TGF-beta', 'Gene', (666, 674))	('TGF-beta', 'Gene', (79, 87))	('TGF-beta', 'Gene', (460, 468))	('GI cancer', 'Phenotype', 'HP:0007378', (309, 318))	('deletion', 'Var', (654, 662))	('DNA methylation', 'Var', (634, 649))	('miR', 'Gene', '220972', (736, 739))	('cancers', 'Disease', 'MESH:D009369', (63, 70))
25922	30268436	Although 39% of the cancers had genomic alterations in at least one of the TGF-beta pathway genes, GI cancers were particularly enriched for them.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('GI cancers', 'Disease', (99, 109))	('cancers', 'Disease', 'MESH:D009369', (102, 109))	('GI cancers', 'Disease', 'MESH:D009369', (99, 109))	('genomic alterations', 'Var', (32, 51))	('TGF-beta', 'Gene', '7040', (75, 83))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))	('cancers', 'Disease', (102, 109))	('TGF-beta', 'Gene', (75, 83))	('GI cancer', 'Phenotype', 'HP:0007378', (99, 108))	('cancers', 'Disease', (20, 27))	('cancers', 'Phenotype', 'HP:0002664', (20, 27))	('cancers', 'Disease', 'MESH:D009369', (20, 27))
25923	30268436	GI cancers were most influenced by recurrent hotspot mutations in 6 genes, SMAD4, SMAD2, BMPR2, BMP5, TGFBR2, and ACVR2A.	('BMP5', 'Gene', (96, 100))	('SMAD2', 'Gene', (82, 87))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))	('BMP5', 'Gene', '653', (96, 100))	('BMPR2', 'Gene', (89, 94))	('GI cancers', 'Disease', (0, 10))	('SMAD4', 'Gene', (75, 80))	('TGFBR2', 'Gene', '7048', (102, 108))	('mutations', 'Var', (53, 62))	('hotspot', 'PosReg', (45, 52))	('ACVR2A', 'Gene', '92', (114, 120))	('GI cancer', 'Phenotype', 'HP:0007378', (0, 9))	('influenced', 'Reg', (21, 31))	('GI cancers', 'Disease', 'MESH:D009369', (0, 10))	('BMPR2', 'Gene', '659', (89, 94))	('ACVR2A', 'Gene', (114, 120))	('cancers', 'Phenotype', 'HP:0002664', (3, 10))	('SMAD4', 'Gene', '4089', (75, 80))	('SMAD2', 'Gene', '4087', (82, 87))	('TGFBR2', 'Gene', (102, 108))
25924	30268436	The hotspot mutations in BMP5 and TGFBR2 had not been identified previously, and their function in GI cancer should be explored.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('GI cancer', 'Disease', (99, 108))	('mutations', 'Var', (12, 21))	('TGFBR2', 'Gene', '7048', (34, 40))	('GI cancer', 'Disease', 'MESH:D009369', (99, 108))	('BMP5', 'Gene', (25, 29))	('GI cancer', 'Phenotype', 'HP:0007378', (99, 108))	('TGFBR2', 'Gene', (34, 40))	('BMP5', 'Gene', '653', (25, 29))
25943	30268436	We selected the list of core TGF-beta superfamily genes used in the paper by searching for the keyword "TGF-beta" in 4 databases: (i) BIOCARTA_TGFB_PATHWAY from GSEA (http://software.broadinstitute.org/gsea/msigdb/cards/BIOCARTA_TGFB_PATHWAY), (ii) KEGG_TGF_BETA_SIGNALING_PATHWAY from GSEA (http://software.broadinstitute.org/gsea/msigdb/cards/KEGG_TGF_BETA_SIGNALING_PATHWAY), (iii) GO_0007179 full gene set from BioMart, and (iv) subset of GO_0007179 (filtered by "experimental evidence") from AmiGo.	('AmiGo', 'Gene', '57463', (497, 502))	('TGF-beta', 'Gene', (104, 112))	('AmiGo', 'Gene', (497, 502))	('TGF-beta', 'Gene', '7040', (29, 37))	('TGF-beta', 'Gene', (29, 37))	('TGF-beta', 'Gene', '7040', (104, 112))	('GO_0007179', 'Var', (385, 395))
25944	30268436	(ii) We then performed extensive literature searches and kept only those genes that satisfied any of the following conditions: (a) the gene had previously been implicated in cancer, or (b) the gene was involved in direct binding to and regulation of Smad function, or (c) the gene was phenotypically associated with the TGF-beta superfamily, where mutations or deletions of the gene had resulted in phenotypes similar to those from loss of function of the TGF-beta superfamily pathways.	('TGF-beta', 'Gene', '7040', (320, 328))	('TGF-beta', 'Gene', (456, 464))	('mutations', 'Var', (348, 357))	('implicated', 'Reg', (160, 170))	('TGF-beta', 'Gene', (320, 328))	('involved', 'Reg', (202, 210))	('associated', 'Reg', (300, 310))	('cancer', 'Disease', (174, 180))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('resulted', 'Reg', (387, 395))	('binding', 'Interaction', (221, 228))	('deletions', 'Var', (361, 370))	('TGF-beta', 'Gene', '7040', (456, 464))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))
25961	30268436	Copy-number alterations (CNA) were assessed as deviations in the tumor sample from the paired normal tissue sample, so they only reflected somatic changes.	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumor', 'Disease', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('Copy-number alterations', 'Var', (0, 23))
25969	30268436	This step realigns reads at sites that potentially harbor small insertions or deletions in either the tumor or the matched normal, to decrease the number of false positive single nucleotide variations caused by misaligned reads.	('insertions', 'Var', (64, 74))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('deletions', 'Var', (78, 87))
25972	30268436	Firehose (http://www.broadinstitute.org/cancer/cga/Firehose) takes the BAM files for the tumor and patient- matched normal samples and performs analyses including quality control, local realignment, mutation calling, small insertion and deletion identification, rearrangement detection, coverage calculations and others as described briefly below.	('patient', 'Species', '9606', (99, 106))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('rearrangement', 'Var', (262, 275))	('deletion', 'Var', (237, 245))	('cancer', 'Disease', (40, 46))	('tumor', 'Disease', (89, 94))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('cga', 'Gene', '1113', (47, 50))	('mutation calling', 'Var', (199, 215))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('cga', 'Gene', (47, 50))	('small insertion', 'Var', (217, 232))
25975	30268436	Each oncoprint visualizes and quantifies the somatic mutation and copy number events in 9,125 patients with 33 cancer types for each gene family in the pathway.	('patients', 'Species', '9606', (94, 102))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('copy number', 'Var', (66, 77))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))
25976	30268436	The hotspot mutations are extracted from MC3 MAF file first programmatically for any hotspot site with more than nine counts and validated through a systematic mining in the cBioPortal.	('MC3', 'Gene', '4159', (41, 44))	('mutations', 'Var', (12, 21))	('MAF', 'Gene', '4094', (45, 48))	('MAF', 'Gene', (45, 48))	('MC3', 'Gene', (41, 44))
25977	30268436	For ACVR2A and SMAD4 hotspot mutations are mapped onto the respective protein structures (pdb IDs: 4ASX for ACVR2A and 1DD1 for SMAD4) using the UCSF chimera software.	('ACVR2A', 'Gene', (108, 114))	('SMAD4', 'Gene', (15, 20))	('ACVR2A and 1DD1', 'Gene', '92', (108, 123))	('SMAD4', 'Gene', (128, 133))	('ACVR2A', 'Gene', '92', (4, 10))	('mutations', 'Var', (29, 38))	('ACVR2A', 'Gene', '92', (108, 114))	('SMAD4', 'Gene', '4089', (15, 20))	('SMAD4', 'Gene', '4089', (128, 133))	('ACVR2A', 'Gene', (4, 10))
25987	30268436	Tumor types for which few tumors have been profiled and that have infrequently occurring copy number alterations, GISTIC may fail to identify rare but important somatic events.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('copy number alterations', 'Var', (89, 112))	('tumors', 'Disease', (26, 32))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))
25988	30268436	As more copy number profiles become available through large-scale tumor sequencing efforts, the ability to detect these rare but significant events will increase.	('tumor', 'Disease', (66, 71))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('copy number', 'Var', (8, 19))
25990	30268436	The genomic alteration frequencies for copy number gains or losses and mutations are extracted from the cBioPortal and programmatically form the MC3 MAF file.	('MC3', 'Gene', '4159', (145, 148))	('MC3', 'Gene', (145, 148))	('MAF', 'Gene', '4094', (149, 152))	('mutations', 'Var', (71, 80))	('losses', 'NegReg', (60, 66))	('MAF', 'Gene', (149, 152))	('copy number gains', 'Var', (39, 56))
25992	30268436	The samples with alterations in each core gene and wild type for all TGF-beta pathway genes are extracted from the MC3 MAF file.	('MAF', 'Gene', '4094', (119, 122))	('MAF', 'Gene', (119, 122))	('TGF-beta', 'Gene', (69, 77))	('MC3', 'Gene', '4159', (115, 118))	('MC3', 'Gene', (115, 118))	('TGF-beta', 'Gene', '7040', (69, 77))	('alterations', 'Var', (17, 28))
25993	30268436	The median fold change of transcriptional changes are calculated as the ratio of expression of downstream genes among all core pathway gene mutated, amplified and deleted samples to expression levels in TGF-beta pathway wild type samples.	('TGF-beta', 'Gene', (203, 211))	('deleted', 'Var', (163, 170))	('TGF-beta', 'Gene', '7040', (203, 211))	('expression', 'MPA', (81, 91))	('mutated', 'Var', (140, 147))
25997	30268436	The enrichment of genomic TGF-beta pathway genomic alterations in the GI cancers was statistically assessed using a one tailed Fisher's exact test, where the null hypothesis was the odds ratio of alterations in GI vs other cancers was not greater than 1.	('cancers', 'Disease', (223, 230))	('cancers', 'Disease', (73, 80))	('alterations', 'Var', (51, 62))	('GI cancer', 'Phenotype', 'HP:0007378', (70, 79))	('GI cancers', 'Disease', 'MESH:D009369', (70, 80))	('cancers', 'Phenotype', 'HP:0002664', (223, 230))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('cancers', 'Disease', 'MESH:D009369', (223, 230))	('TGF-beta', 'Gene', '7040', (26, 34))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('GI cancers', 'Disease', (70, 80))	('TGF-beta', 'Gene', (26, 34))	('cancers', 'Disease', 'MESH:D009369', (73, 80))
25998	30268436	The transcriptional outcome of GI cancers with TGF-beta pathway disruptions were quantified using the same method and downstream target gene list as we did in the analysis of transcriptional output from all cancers.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('GI cancer', 'Phenotype', 'HP:0007378', (31, 40))	('cancers', 'Disease', 'MESH:D009369', (207, 214))	('GI cancers', 'Disease', 'MESH:D009369', (31, 41))	('cancers', 'Disease', 'MESH:D009369', (34, 41))	('cancers', 'Phenotype', 'HP:0002664', (207, 214))	('cancers', 'Disease', (207, 214))	('disruptions', 'Var', (64, 75))	('TGF-beta', 'Gene', '7040', (47, 55))	('cancers', 'Phenotype', 'HP:0002664', (34, 41))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('TGF-beta', 'Gene', (47, 55))	('cancers', 'Disease', (34, 41))	('GI cancers', 'Disease', (31, 41))
26022	30268436	We particularly focused on mRNA expression distribution of HMGA2, MMP9, collagens (COL1A1, COL1A2, COL3A1), TERT, FOXP3, CDH2 as the expression of these genes varied significantly between TGF-beta pathway mutated vs. wild type samples.	('mutated', 'Var', (205, 212))	('COL1A2', 'Gene', '1278', (91, 97))	('TERT', 'Gene', (108, 112))	('varied', 'Reg', (159, 165))	('TERT', 'Gene', '7015', (108, 112))	('CDH2', 'Gene', (121, 125))	('FOXP3', 'Gene', (114, 119))	('HMGA2', 'Gene', (59, 64))	('COL1A2', 'Gene', (91, 97))	('COL1A1', 'Gene', '1277', (83, 89))	('CDH2', 'Gene', '1000', (121, 125))	('COL3A1', 'Gene', '1281', (99, 105))	('TGF-beta', 'Gene', '7040', (188, 196))	('FOXP3', 'Gene', '50943', (114, 119))	('expression', 'MPA', (133, 143))	('COL1A1', 'Gene', (83, 89))	('MMP9', 'Gene', (66, 70))	('HMGA2', 'Gene', '8091', (59, 64))	('MMP9', 'Gene', '4318', (66, 70))	('TGF-beta', 'Gene', (188, 196))	('COL3A1', 'Gene', (99, 105))
26024	30268436	The resulting thresholds divided the cohorts into three groups as TGF-beta expression, TGF-beta mutant/high target expression, TGF-beta wt/high target expression and low target gene expression.	('TGF-beta', 'Gene', (87, 95))	('TGF-beta', 'Gene', (66, 74))	('TGF-beta', 'Gene', '7040', (127, 135))	('mutant/high', 'Var', (96, 107))	('TGF-beta', 'Gene', '7040', (87, 95))	('TGF-beta', 'Gene', (127, 135))	('TGF-beta', 'Gene', '7040', (66, 74))
26025	30268436	We merged the TGF-beta mutant/low target expression and TGF-beta wt/low expression cohorts as discriminating between these sets do not inform on the combined effect of TGF-beta mutations and target expression.	('TGF-beta', 'Gene', (168, 176))	('TGF-beta', 'Gene', '7040', (56, 64))	('TGF-beta', 'Gene', (14, 22))	('mutant/low', 'Var', (23, 33))	('mutant/low', 'NegReg', (23, 33))	('TGF-beta', 'Gene', (56, 64))	('TGF-beta', 'Gene', '7040', (14, 22))	('TGF-beta', 'Gene', '7040', (168, 176))
26038	28969096	Aberrant expression of Rab25 was linked to cancer development.	('Aberrant expression', 'Var', (0, 19))	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('cancer', 'Disease', (43, 49))	('Rab25', 'Gene', (23, 28))	('linked', 'Reg', (33, 39))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))
26065	28969096	The inactive Rab proteins located in the cytosol and are recognized by guanine nucleotide exchange factor (GEF), which catalyzes the exchange of GDP for GTP at the guanine nucleotide binding motif to form the active Rab proteins.	('guanine nucleotide', 'Chemical', 'MESH:D006150', (71, 89))	('Rab', 'Gene', '3267', (13, 16))	('GEF', 'Gene', (107, 110))	('exchange', 'Var', (133, 141))	('GTP', 'MPA', (153, 156))	('Rab', 'Gene', '3267', (216, 219))	('GDP', 'MPA', (145, 148))	('GDP', 'Chemical', 'MESH:D006153', (145, 148))	('Rab', 'Gene', (13, 16))	('guanine nucleotide', 'Chemical', 'MESH:D006150', (164, 182))	('GEF', 'Gene', '9181', (107, 110))	('Rab', 'Gene', (216, 219))	('GTP', 'Chemical', 'MESH:D006160', (153, 156))
26076	28969096	Modified Rab25, which does not interact with beta1 integrin, did not promote cell invasion.	('beta1 integrin', 'Gene', '3688', (45, 59))	('beta1 integrin', 'Gene', (45, 59))	('Rab25', 'Gene', (9, 14))	('Modified', 'Var', (0, 8))	('cell invasion', 'CPA', (77, 90))
26085	28969096	Rab25 knockdown reduced phospho-Akt level, leading to the reduction of cell migration/invasion in bladder cancer cell, hepatocellular carcinoma cells and glioblastoma multiforme cells.	('Akt', 'Gene', '207', (32, 35))	('rat', 'Species', '10116', (79, 82))	('hepatocellular carcinoma', 'Disease', (119, 143))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('cell migration/invasion in', 'CPA', (71, 97))	('reduced', 'NegReg', (16, 23))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('reduction', 'NegReg', (58, 67))	('Rab25', 'Gene', (0, 5))	('glioblastoma multiforme', 'Disease', (154, 177))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (119, 143))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (154, 177))	('glioblastoma', 'Phenotype', 'HP:0012174', (154, 166))	('Akt', 'Gene', (32, 35))	('bladder cancer', 'Disease', (98, 112))	('bladder cancer', 'Disease', 'MESH:D001749', (98, 112))	('knockdown', 'Var', (6, 15))	('bladder cancer', 'Phenotype', 'HP:0009725', (98, 112))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (119, 143))
26086	28969096	Rab25 knockdown or Akt inhibitor was found to reduce cisplatin resistance in ovarian cancer cells.	('cisplatin resistance', 'MPA', (53, 73))	('ovarian cancer', 'Phenotype', 'HP:0100615', (77, 91))	('reduce', 'NegReg', (46, 52))	('Akt', 'Gene', '207', (19, 22))	('ovarian cancer', 'Disease', 'MESH:D010051', (77, 91))	('ovarian cancer', 'Disease', (77, 91))	('cisplatin', 'Chemical', 'MESH:D002945', (53, 62))	('Akt', 'Gene', (19, 22))	('knockdown', 'Var', (6, 15))	('Rab25', 'Gene', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
26092	28969096	Knockdown of Rab25 was found to reduce anti-apoptotic protein, Bcl-2, in tobacco carcinogen-induced lung cancer.	('anti-apoptotic protein', 'MPA', (39, 61))	('reduce', 'NegReg', (32, 38))	('Knockdown', 'Var', (0, 9))	('Bcl-2', 'MPA', (63, 68))	('lung cancer', 'Phenotype', 'HP:0100526', (100, 111))	('lung cancer', 'Disease', (100, 111))	('lung cancer', 'Disease', 'MESH:D008175', (100, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('tobacco', 'Species', '4097', (73, 80))	('Rab25', 'Gene', (13, 18))
26106	28969096	Epigenetic regulation also led to down-regulation of Rab25 in oral and oropharyngeal squamous cell carcinoma (OOSCC) and esophageal squamous cell carcinoma (ESCC), in which Rab25 acts as a tumor suppressor.	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('tumor', 'Disease', (189, 194))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (121, 155))	('oropharyngeal squamous cell carcinoma', 'Phenotype', 'HP:0012182', (71, 108))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (132, 155))	('Epigenetic regulation', 'Var', (0, 21))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (132, 155))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (85, 108))	('esophageal squamous cell carcinoma', 'Disease', (121, 155))	('down-regulation', 'NegReg', (34, 49))	('Rab25', 'Gene', (53, 58))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('OOSCC', 'Phenotype', 'HP:0012182', (110, 115))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (85, 108))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('squamous cell carcinoma', 'Disease', (85, 108))	('oral', 'Disease', (62, 66))
26107	28969096	In ESCC, demethylation treatment and bisulfite genomic sequencing analyses revealed that down-regulation of Rab25 expression in both ESCC cell lines and clinical samples was associated with promoter hypermethylation.	('bisulfite', 'Chemical', 'MESH:C042345', (37, 46))	('promoter hypermethylation', 'Var', (190, 215))	('Rab25', 'Gene', (108, 113))	('clinical samples', 'Species', '191496', (153, 169))	('down-regulation', 'NegReg', (89, 104))	('expression', 'MPA', (114, 124))
26117	28969096	Suppression of both in vitro cell growth and in vivo xenograft development were observed after knockdown of Rab25 in glioblastoma multiforme cells (U87MG) and breast cancer cells (MCF7).	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (117, 140))	('breast cancer', 'Disease', (159, 172))	('MCF7', 'CellLine', 'CVCL:0031', (180, 184))	('Rab25', 'Gene', (108, 113))	('knockdown', 'Var', (95, 104))	('breast cancer', 'Disease', 'MESH:D001943', (159, 172))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('Suppression', 'NegReg', (0, 11))	('glioblastoma multiforme', 'Disease', (117, 140))	('breast cancer', 'Phenotype', 'HP:0003002', (159, 172))	('U87MG', 'CellLine', 'CVCL:0022', (148, 153))	('glioblastoma', 'Phenotype', 'HP:0012174', (117, 129))
26118	28969096	Knockdown of Rab25 was reported to inhibit tumor growth in tobacco carcinogen-induced lung cancer model.	('Knockdown', 'Var', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('lung cancer', 'Phenotype', 'HP:0100526', (86, 97))	('tobacco', 'Species', '4097', (59, 66))	('lung cancer', 'Disease', (86, 97))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('lung cancer', 'Disease', 'MESH:D008175', (86, 97))	('tumor', 'Disease', (43, 48))	('inhibit', 'NegReg', (35, 42))	('Rab25', 'Gene', (13, 18))
26120	28969096	Rab25 ectopic overexpression was found to increase development of xenograft derived from breast cancer cells (MCF7) and ovarian cancer cells (A2780, HEY).	('ectopic overexpression', 'Var', (6, 28))	('breast cancer', 'Disease', 'MESH:D001943', (89, 102))	('ovarian cancer', 'Disease', 'MESH:D010051', (120, 134))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('breast cancer', 'Disease', (89, 102))	('breast cancer', 'Phenotype', 'HP:0003002', (89, 102))	('ovarian cancer', 'Disease', (120, 134))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('Rab25', 'Gene', (0, 5))	('development of xenograft derived', 'CPA', (51, 83))	('MCF7', 'CellLine', 'CVCL:0031', (110, 114))	('increase', 'PosReg', (42, 50))	('ovarian cancer', 'Phenotype', 'HP:0100615', (120, 134))
26122	28969096	Knockdown of Rab25 was reported to increase apoptosis in ovarian cancer cells and tobacco carcinogen-induced lung cancer model.	('lung cancer', 'Disease', (109, 120))	('increase', 'PosReg', (35, 43))	('lung cancer', 'Phenotype', 'HP:0100526', (109, 120))	('ovarian cancer', 'Disease', 'MESH:D010051', (57, 71))	('Knockdown', 'Var', (0, 9))	('tobacco', 'Species', '4097', (82, 89))	('apoptosis', 'CPA', (44, 53))	('ovarian cancer', 'Disease', (57, 71))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('lung cancer', 'Disease', 'MESH:D008175', (109, 120))	('ovarian cancer', 'Phenotype', 'HP:0100615', (57, 71))	('Rab25', 'Gene', (13, 18))
26127	28969096	Suppression of cell invasion after Rab25 knockdown was observed in gastric cancer cells.	('gastric cancer', 'Disease', (67, 81))	('Rab25', 'Gene', (35, 40))	('gastric cancer', 'Disease', 'MESH:D013274', (67, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('cell invasion', 'CPA', (15, 28))	('Suppression', 'NegReg', (0, 11))	('gastric cancer', 'Phenotype', 'HP:0012126', (67, 81))	('knockdown', 'Var', (41, 50))
26128	28969096	's study, which showed that Rab25 depletion negatively regulated the invasion ability of hepatocellular carcinoma cells.	('hepatocellular carcinoma', 'Disease', (89, 113))	('Rab25', 'Gene', (28, 33))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (89, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('invasion ability of', 'CPA', (69, 88))	('depletion', 'Var', (34, 43))	('negatively', 'NegReg', (44, 54))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (89, 113))
26129	28969096	In the study of bladder cancer, Rab25 knockdown not only suppress in vitro cell migration but also reduce in vivo tumor metastasis.	('rat', 'Species', '10116', (83, 86))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('bladder cancer', 'Disease', 'MESH:D001749', (16, 30))	('bladder cancer', 'Disease', (16, 30))	('reduce', 'NegReg', (99, 105))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumor metastasis', 'Disease', (114, 130))	('suppress', 'NegReg', (57, 65))	('Rab25', 'Gene', (32, 37))	('tumor metastasis', 'Disease', 'MESH:D009362', (114, 130))	('bladder cancer', 'Phenotype', 'HP:0009725', (16, 30))	('knockdown', 'Var', (38, 47))
26139	28969096	Loss of Rab25 in human colon cancers was associated with poorer patient prognosis.	('colon cancer', 'Phenotype', 'HP:0003003', (23, 35))	('cancers', 'Phenotype', 'HP:0002664', (29, 36))	('patient', 'Species', '9606', (64, 71))	('human', 'Species', '9606', (17, 22))	('colon cancers', 'Disease', (23, 36))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('Rab25', 'Gene', (8, 13))	('colon cancers', 'Phenotype', 'HP:0003003', (23, 36))	('colon cancers', 'Disease', 'MESH:D015179', (23, 36))	('Loss', 'Var', (0, 4))
26140	28969096	Rab25 deficiency promotes intestinal/colon adenoma formation in ApcMin/+ mice.	('promotes', 'PosReg', (17, 25))	('colon adenoma', 'Disease', (37, 50))	('mice', 'Species', '10090', (73, 77))	('deficiency', 'Var', (6, 16))	('colon adenoma', 'Disease', 'MESH:D000236', (37, 50))	('Rab25', 'Gene', (0, 5))
26144	28969096	In the study of head and neck squamous cell carcinoma, Rab25 ectopic overexpression reduced in vitro cell invasion and in vivo tumor metastasis to cervical lymph node.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('neck squamous cell carcinoma', 'Disease', (25, 53))	('tumor metastasis', 'Disease', 'MESH:D009362', (127, 143))	('Rab25', 'Gene', (55, 60))	('ectopic', 'Var', (61, 68))	('tumor metastasis', 'Disease', (127, 143))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (25, 53))	('reduced', 'NegReg', (84, 91))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (30, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (44, 53))
26148	28969096	Pancreatic cancer patients with high Rab25 and high CLIC3 levels were associated with significantly shorter survival time.	('high', 'Var', (32, 36))	('Pancreatic cancer', 'Disease', (0, 17))	('CLIC3', 'Gene', (52, 57))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('Rab25', 'MPA', (37, 42))	('Pancreatic cancer', 'Disease', 'MESH:D010190', (0, 17))	('shorter', 'NegReg', (100, 107))	('patients', 'Species', '9606', (18, 26))	('CLIC3', 'Gene', '9022', (52, 57))	('survival time', 'CPA', (108, 121))	('Pancreatic cancer', 'Phenotype', 'HP:0002894', (0, 17))
26151	28969096	When Rab25 acts as an oncogene, Rab25 enhances alpha5beta1 integrin recycling to the plasma membrane, leading to increase in cancer progression of ovarian cancer.	('ovarian cancer', 'Phenotype', 'HP:0100615', (147, 161))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('ovarian cancer', 'Disease', 'MESH:D010051', (147, 161))	('beta1 integrin', 'Gene', '3688', (53, 67))	('Rab25', 'Var', (32, 37))	('increase', 'PosReg', (113, 121))	('enhances', 'PosReg', (38, 46))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('ovarian cancer', 'Disease', (147, 161))	('beta1 integrin', 'Gene', (53, 67))	('cancer', 'Disease', (155, 161))	('cancer', 'Disease', 'MESH:D009369', (155, 161))
26158	28969096	The role or Rab25 in promoting cancer metastasis is confirmed by in vitro experiments in which knockdown of Rab25 decreased cell migration and invasion of 786-O and A-498 RCC cells.	('rat', 'Species', '10116', (132, 135))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('invasion', 'CPA', (143, 151))	('Rab25', 'Gene', (108, 113))	('cell migration', 'CPA', (124, 138))	('knockdown', 'Var', (95, 104))	('decreased', 'NegReg', (114, 123))	('RCC', 'Phenotype', 'HP:0005584', (171, 174))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('cancer', 'Disease', (31, 37))
26160	28969096	The cisplatin-based chemotherapy response rate of NSCLC patients with Rab25-positive expression was 30%, as opposed to 52% for patients with Rab25-negative expression.	('patients', 'Species', '9606', (56, 64))	('cisplatin-based', 'CPA', (4, 19))	('NSCLC', 'Phenotype', 'HP:0030358', (50, 55))	('Rab25-positive expression', 'Var', (70, 95))	('patients', 'Species', '9606', (127, 135))	('NSCLC', 'Disease', (50, 55))	('NSCLC', 'Disease', 'MESH:D002289', (50, 55))	('cisplatin', 'Chemical', 'MESH:D002945', (4, 13))	('rat', 'Species', '10116', (42, 45))
26161	28969096	Elevated expression of Rab25 may be due to amplification of RAB25 gene located in chromosome 1q22.	('RAB25', 'Gene', '57111', (60, 65))	('amplification', 'Var', (43, 56))	('Rab25', 'Gene', (23, 28))	('Elevated', 'PosReg', (0, 8))	('RAB25', 'Gene', (60, 65))	('expression', 'MPA', (9, 19))
26162	28969096	Amplification of RAB25 was reported to associate with markedly decreased disease-free survival or overall survival in ovarian cancer in Cheng et al.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('Amplification', 'Var', (0, 13))	('ovarian cancer', 'Disease', (118, 132))	('decreased', 'NegReg', (63, 72))	('RAB25', 'Gene', '57111', (17, 22))	('disease-free survival', 'CPA', (73, 94))	('ovarian cancer', 'Phenotype', 'HP:0100615', (118, 132))	('overall survival', 'CPA', (98, 114))	('RAB25', 'Gene', (17, 22))	('ovarian cancer', 'Disease', 'MESH:D010051', (118, 132))
26164	28969096	Ovarian cancer patients with elevated RAB25 amplification either did not enter a disease free state following surgery and chemotherapy or showed very short disease-free survival, implicating RAB25 as potential driver gene correlated with poor prognosis and aggressive behavior of ovarian cancer.	('cancer', 'Phenotype', 'HP:0002664', (288, 294))	('patients', 'Species', '9606', (15, 23))	('elevated', 'PosReg', (29, 37))	('Ovarian cancer', 'Disease', 'MESH:D010051', (0, 14))	('RAB25', 'Gene', '57111', (38, 43))	('aggressive behavior', 'Phenotype', 'HP:0000718', (257, 276))	('RAB25', 'Gene', (191, 196))	('Ovarian cancer', 'Phenotype', 'HP:0100615', (0, 14))	('ovarian cancer', 'Phenotype', 'HP:0100615', (280, 294))	('amplification', 'Var', (44, 57))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('aggressive behavior of ovarian cancer', 'Disease', 'MESH:D001523', (257, 294))	('RAB25', 'Gene', (38, 43))	('aggressive behavior of ovarian cancer', 'Disease', (257, 294))	('RAB25', 'Gene', '57111', (191, 196))	('Ovarian cancer', 'Disease', (0, 14))
26169	28969096	Biological and clinicopathological findings revealed that alteration of Rab25 level has high impact on cancer progression and patient survival.	('patient survival', 'CPA', (126, 142))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('Rab25', 'Gene', (72, 77))	('patient', 'Species', '9606', (126, 133))	('alteration', 'Var', (58, 68))	('rat', 'Species', '10116', (62, 65))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('impact', 'Reg', (93, 99))
26171	28969096	Rab25 overexpression and gene copy number amplification was reported in various types of cancer.	('gene copy number amplification', 'Var', (25, 55))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('cancer', 'Disease', (89, 95))	('overexpression', 'PosReg', (6, 20))	('Rab25', 'Gene', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
26176	28969096	Moreover, it is important to identify the mechanisms that lead to copy number amplification of RAB25 in order to find out the potential methods for cancer prevention.	('cancer', 'Disease', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('RAB25', 'Gene', '57111', (95, 100))	('copy number amplification', 'Var', (66, 91))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('RAB25', 'Gene', (95, 100))
26215	31147570	In a study by Lokeshwar et al., doxycycline inhibited cell proliferation, invasion, and metastasis in prostate cancer while Qin et al.	('Qin', 'Gene', (124, 127))	('cell proliferation', 'CPA', (54, 72))	('invasion', 'CPA', (74, 82))	('metastasis in prostate cancer', 'Disease', (88, 117))	('doxycycline', 'Chemical', 'MESH:D004318', (32, 43))	('inhibited', 'NegReg', (44, 53))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('Qin', 'Gene', '2290', (124, 127))	('doxycycline', 'Var', (32, 43))	('rat', 'Species', '10116', (66, 69))	('metastasis in prostate cancer', 'Disease', 'MESH:D009362', (88, 117))	('prostate cancer', 'Phenotype', 'HP:0012125', (102, 117))
26224	31147570	The directedness (defined in 'Image analysis and data analysis') of the MRC-5, H460 and H520 were -0.39 +- 0.06, 0.87 +- 0.02 and 0.81 +- 0.03 under the dcEF stimulation for 6 h, respectively.	('dcEF', 'Chemical', '-', (153, 157))	('MRC-5', 'CellLine', 'CVCL:0440', (72, 77))	('0.81', 'Var', (130, 134))	('H460', 'CellLine', 'CVCL:0459', (79, 83))	('H520', 'CellLine', 'CVCL:1566', (88, 92))	('0.87', 'Var', (113, 117))	('dcEF', 'MPA', (153, 157))
26227	31147570	Similarly, the migration speeds of the H520 cells in the CTL group were 0.53 +- 0.05 mum/h while those under dcEF stimulation increased to 1.24 +- 0.09 mum/h for 6 h. Overall, the migration speeds of H460 and H520 cells under the dcEF stimulation were higher compared to those of the CTL group.	('rat', 'Species', '10116', (18, 21))	('rat', 'Species', '10116', (183, 186))	('dcEF', 'Chemical', '-', (109, 113))	('dcEF', 'Var', (230, 234))	('mum', 'Gene', (152, 155))	('higher', 'PosReg', (252, 258))	('mum', 'Gene', '56925', (85, 88))	('migration speeds', 'CPA', (180, 196))	('dcEF', 'Chemical', '-', (230, 234))	('mum', 'Gene', (85, 88))	('H520', 'CellLine', 'CVCL:1566', (39, 43))	('H460', 'CellLine', 'CVCL:0459', (200, 204))	('H520', 'CellLine', 'CVCL:1566', (209, 213))	('mum', 'Gene', '56925', (152, 155))
26228	31147570	Conversely, MRC-5 cells migration speeds under dcEF stimulation were lower than those in the CTL group.	('dcEF', 'Chemical', '-', (47, 51))	('MRC-5', 'CellLine', 'CVCL:0440', (12, 17))	('lower', 'NegReg', (69, 74))	('MRC-5 cells migration speeds', 'CPA', (12, 40))	('rat', 'Species', '10116', (27, 30))	('dcEF', 'Var', (47, 51))
26249	31147570	Notably, cell morphology analysis revealed that the cells migrating towards the cathode under dcEF stimulation exhibited epithelial-like morphology (A549, H460 and H520).	('epithelial-like morphology', 'CPA', (121, 147))	('H460', 'CellLine', 'CVCL:0459', (155, 159))	('rat', 'Species', '10116', (61, 64))	('dcEF', 'Gene', (94, 98))	('A549', 'CellLine', 'CVCL:0023', (149, 153))	('H460', 'CPA', (155, 159))	('H520', 'Var', (164, 168))	('dcEF', 'Chemical', '-', (94, 98))	('H520', 'CellLine', 'CVCL:1566', (164, 168))
26286	31147570	The data showed that directedness in H460 cells was significantly different between the H460-EF and the Dox-H460-EF groups.	('H460', 'CellLine', 'CVCL:0459', (37, 41))	('Dox', 'Chemical', 'MESH:D004318', (104, 107))	('directedness', 'CPA', (21, 33))	('different', 'Reg', (66, 75))	('H460-EF', 'Var', (88, 95))	('H460', 'CellLine', 'CVCL:0459', (108, 112))	('H460', 'CellLine', 'CVCL:0459', (88, 92))
26287	31147570	Similarly, directedness in H520 cells was significantly different in both the H520-EF and Dox-H520-EF groups.	('Dox', 'Chemical', 'MESH:D004318', (90, 93))	('H520', 'CellLine', 'CVCL:1566', (94, 98))	('different', 'Reg', (56, 65))	('directedness', 'CPA', (11, 23))	('H520-EF', 'Var', (78, 85))	('H520', 'CellLine', 'CVCL:1566', (78, 82))	('H520', 'CellLine', 'CVCL:1566', (27, 31))
26288	31147570	Doxycycline eliminates cathodal migration in Dox-H460-EF compared to H460-EF groups.	('Dox', 'Chemical', 'MESH:D004318', (0, 3))	('Dox', 'Chemical', 'MESH:D004318', (45, 48))	('H460', 'CellLine', 'CVCL:0459', (49, 53))	('H460', 'CellLine', 'CVCL:0459', (69, 73))	('Dox-H460-EF', 'Var', (45, 56))	('cathodal migration', 'CPA', (23, 41))	('rat', 'Species', '10116', (35, 38))	('eliminates', 'NegReg', (12, 22))	('Doxycycline', 'Chemical', 'MESH:D004318', (0, 11))
26289	31147570	In comparison, doxycycline only partially reduces cathodal migration in Dox-H520-EF groups compared to H520-EF groups.	('H520', 'CellLine', 'CVCL:1566', (76, 80))	('reduces', 'NegReg', (42, 49))	('Dox', 'Chemical', 'MESH:D004318', (72, 75))	('doxycycline', 'Chemical', 'MESH:D004318', (15, 26))	('Dox-H520-EF', 'Var', (72, 83))	('cathodal migration', 'CPA', (50, 68))	('rat', 'Species', '10116', (62, 65))	('H520', 'CellLine', 'CVCL:1566', (103, 107))
26311	31147570	In addition, the migration speed of H460 and H520 cells increased under dcEF stimulation.	('increased', 'PosReg', (56, 65))	('dcEF', 'Var', (72, 76))	('migration speed', 'CPA', (17, 32))	('rat', 'Species', '10116', (20, 23))	('H460', 'CellLine', 'CVCL:0459', (36, 40))	('dcEF', 'Chemical', '-', (72, 76))	('H520', 'CellLine', 'CVCL:1566', (45, 49))
26351	24465403	 MET Genetic Abnormalities Unreliable for Patient Selection for Therapeutic Intervention in Oropharyngeal Squamous Cell Carcinoma Identification of MET genetic alteration, mutation, or amplification in oropharyngeal squamous cell carcinoma (OPSCC) could lead to development of MET selective kinase inhibitors.	('Genetic Abnormalities', 'Disease', (5, 26))	('Genetic Abnormalities', 'Disease', 'MESH:D030342', (5, 26))	('oropharyngeal squamous cell carcinoma', 'Disease', (202, 239))	('Carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (106, 129))	('oropharyngeal squamous cell carcinoma', 'Disease', 'MESH:D002294', (202, 239))	('mutation', 'Var', (172, 180))	('lead to', 'Reg', (254, 261))	('Squamous Cell Carcinoma', 'Disease', 'MESH:D002294', (106, 129))	('oropharyngeal squamous cell carcinoma', 'Phenotype', 'HP:0012182', (202, 239))	('Oropharyngeal Squamous Cell Carcinoma', 'Phenotype', 'HP:0012182', (92, 129))	('carcinoma', 'Phenotype', 'HP:0030731', (230, 239))	('Squamous Cell Carcinoma', 'Disease', (106, 129))	('amplification', 'Var', (185, 198))	('Patient', 'Species', '9606', (42, 49))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (216, 239))
26355	24465403	Six cases (4%) were identified that had a genetic variation, but previously described mutations such as p.Tyr1235Asp (Y1235D) or p.Tyr1230Cys (Y1230C) were not detected.	('p.Tyr1230Cys', 'Var', (129, 141))	('p.Tyr1235Asp (Y1235D', 'Var', (104, 124))	('Y1230C', 'Mutation', 'rs121913246', (143, 149))	('p.Tyr1230Cys', 'Mutation', 'rs121913246', (129, 141))	('p.Tyr1235Asp', 'Mutation', 'rs1057519824', (104, 116))	('Y1235D', 'Mutation', 'rs1057519824', (118, 124))
26374	24465403	MET Y1235D mutation (also known as Y1253D) was found in 15 out of 138 patients (11%) with OPSCC, and in 21 out of 152 patients (14%) with HNSCC, suggesting a relatively high prevalence of this mutant in the OPC.	('patients', 'Species', '9606', (70, 78))	('Y1253D', 'Var', (35, 41))	('Y1235D', 'Mutation', 'rs1057519824', (4, 10))	('OPSCC', 'Disease', (90, 95))	('MET Y1235D', 'Var', (0, 10))	('patients', 'Species', '9606', (118, 126))	('Y1253D', 'Mutation', 'rs1057519824', (35, 41))
26375	24465403	This MET Y1235D mutation and another mutation in the MET activation loop (Y1230C) were also detected in neck lymph nodes metastases from a primary HNSCC tumor.	('metastases', 'Disease', 'MESH:D009362', (121, 131))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('MET Y1235D', 'Var', (5, 15))	('HNSCC tumor', 'Disease', 'MESH:D000077195', (147, 158))	('Y1230C', 'Mutation', 'rs121913246', (74, 80))	('Y1230C', 'Var', (74, 80))	('Y1235D', 'Mutation', 'rs1057519824', (9, 15))	('detected', 'Reg', (92, 100))	('HNSCC tumor', 'Disease', (147, 158))	('metastases', 'Disease', (121, 131))
26376	24465403	The identification of a cancer type in which MET genetic alteration, mutation, or amplification is present in a significant subset such as OPSCC is of high interest.	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('amplification', 'Var', (82, 95))	('cancer', 'Disease', (24, 30))	('cancer', 'Disease', 'MESH:D009369', (24, 30))	('mutation', 'Var', (69, 77))	('OPSCC', 'Disease', (139, 144))
26418	24465403	Eighty-eight tumors (62%) were detected with HPV DNA on qPCR, irrespective of the viral load level, the involved HPV serotype, or the exclusive or combined infection status.	('HPV', 'Species', '10566', (45, 48))	('tumors', 'Disease', (13, 19))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('HPV', 'Species', '10566', (113, 116))	('HPV DNA', 'Var', (45, 52))
26429	24465403	The p.Val136Ile mutation has been previously detected once before in a kidney carcinoma case, and the p.Ala347Thr mutation has been described in lung squamous cell carcinoma.	('p.Ala347Thr', 'Mutation', 'rs200074800', (102, 113))	('p.Ala347Thr', 'Var', (102, 113))	('kidney carcinoma', 'Disease', 'MESH:C538614', (71, 87))	('p.Val136Ile', 'Var', (4, 15))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('described', 'Reg', (132, 141))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (145, 173))	('p.Val136Ile', 'Mutation', 'rs199701987', (4, 15))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (150, 173))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (145, 173))	('lung squamous cell carcinoma', 'Disease', (145, 173))	('carcinoma', 'Phenotype', 'HP:0030731', (164, 173))	('kidney carcinoma', 'Phenotype', 'HP:0005584', (71, 87))	('kidney carcinoma', 'Disease', (71, 87))
26430	24465403	The p.Glu312Lys, p.Thr1036Ile, and p.Cys1210Arg variations have not yet been described in literature and are novel somatic variant with unknown pathogenicity.	('p.Glu312Lys', 'Mutation', 'rs751572663', (4, 15))	('p.Thr1036Ile', 'Mutation', 'rs758440368', (17, 29))	('p.Thr1036Ile', 'Var', (17, 29))	('p.Cys1210Arg', 'Mutation', 'p.C1210R', (35, 47))	('p.Cys1210Arg', 'Var', (35, 47))	('p.Glu312Lys', 'Var', (4, 15))
26431	24465403	Previously described mutations such as p.Tyr1235Asp (Y1235D) or p.Tyr1230Cys (Y1230C) in exon 19 were not found.	('Y1235D', 'Mutation', 'rs1057519824', (53, 59))	('p.Tyr1235Asp', 'Mutation', 'rs1057519824', (39, 51))	('p.Tyr1235Asp (Y1235D', 'Var', (39, 59))	('p.Tyr1230Cys (Y1230C', 'Var', (64, 84))	('Y1230C', 'Mutation', 'rs121913246', (78, 84))	('p.Tyr1230Cys', 'Mutation', 'rs121913246', (64, 76))
26432	24465403	Of the six variations, four were expected to affect protein function based on the SIFT classification system, three of which had predicted damaging effects according to the PolyPhen-2 scoring system.	('affect', 'Reg', (45, 51))	('SIFT', 'Disease', 'None', (82, 86))	('variations', 'Var', (11, 21))	('protein function', 'MPA', (52, 68))	('SIFT', 'Disease', (82, 86))
26437	24465403	Detection of pYY1234-1235 MET was observed in two cases (3%), but in non-tumor cells (at margin of tissue sample).	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Disease', (73, 78))	('pYY1234-1235 MET', 'Var', (13, 29))	('tumor', 'Disease', 'MESH:D009369', (73, 78))
26445	24465403	The aim of this study was to determine the frequency and prognostic value of MET abnormalities including DNA mutations, gene amplification, and protein expression in primary OPSCC.	('MET abnormalities', 'Disease', (77, 94))	('primary OPSCC', 'Disease', (166, 179))	('mutations', 'Var', (109, 118))	('DNA', 'Gene', (105, 108))	('MET abnormalities', 'Disease', 'MESH:D000014', (77, 94))	('gene amplification', 'Var', (120, 138))
26448	24465403	Previously described HNSCC mutations such as p.Tyr1235Asp (Y1235D) and p.Tyr1230Cys (Y1230C) were not detected in our study.	('p.Tyr1235Asp (Y1235D', 'Var', (45, 65))	('p.Tyr1230Cys', 'Var', (71, 83))	('HNSCC', 'Gene', (21, 26))	('p.Tyr1235Asp', 'Mutation', 'rs1057519824', (45, 57))	('Y1235D', 'Mutation', 'rs1057519824', (59, 65))	('Y1230C', 'Mutation', 'rs121913246', (85, 91))	('p.Tyr1230Cys', 'Mutation', 'rs121913246', (71, 83))
26449	24465403	In a study investigating the prevalence and clinical impact of the Y1253D mutation in patients with OPSCC treated by radical RT, the mutation was detected in 15/138 tumors (10.9%).	('Y1253D', 'Var', (67, 73))	('Y1253D', 'Mutation', 'rs1057519824', (67, 73))	('tumors', 'Disease', (165, 171))	('tumors', 'Disease', 'MESH:D009369', (165, 171))	('tumors', 'Phenotype', 'HP:0002664', (165, 171))	('OPSCC', 'Disease', (100, 105))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('patients', 'Species', '9606', (86, 94))
26450	24465403	Also, survival analysis showed a significant correlation between Y1253D mutation and impaired local tumor control.	('impaired local tumor', 'Disease', (85, 105))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('Y1253D', 'Var', (65, 71))	('Y1253D', 'Mutation', 'rs1057519824', (65, 71))	('impaired local tumor', 'Disease', 'MESH:D015417', (85, 105))
26451	24465403	detected Y1253D mutation in 21 tumors in 152 patients (14%) with HNSCC and observed an association with decreased distant metastasis-free survival.	('HNSCC', 'Disease', (65, 70))	('Y1253D', 'Var', (9, 15))	('Y1253D', 'Mutation', 'rs1057519824', (9, 15))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumors', 'Disease', (31, 37))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('decreased', 'NegReg', (104, 113))	('tumors', 'Disease', 'MESH:D009369', (31, 37))	('patients', 'Species', '9606', (45, 53))	('distant metastasis-free survival', 'CPA', (114, 146))
26453	24465403	Nevertheless, our Sanger approach does not detect minor clones representing less than 20% of the tumor cell, but can detect unexpected mutations.	('detect', 'Reg', (117, 123))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('mutations', 'Var', (135, 144))	('tumor', 'Disease', (97, 102))
26457	24465403	recently found 61 MET high polysomy and 13 MET gene amplification cases in a cohort of 438 gastric carcinomas.	('MET gene amplification', 'Var', (43, 65))	('high polysomy', 'Var', (22, 35))	('gastric carcinomas', 'Disease', 'MESH:D013274', (91, 109))	('gastric carcinomas', 'Disease', (91, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('carcinomas', 'Phenotype', 'HP:0030731', (99, 109))
26460	24465403	found that an increase of MET gene copy number, present in 11.1% of patients (high polysomy 8.7% and gene amplification 2.4%), was a negative prognostic factor for survival.	('patients', 'Species', '9606', (68, 76))	('gene amplification', 'Var', (101, 119))	('MET gene', 'Gene', (26, 34))	('increase', 'PosReg', (14, 22))
26461	24465403	The relatively low frequency of MET mutations and amplification in this OPSCC study cohort could be explained, because MET may play a larger role in disease progression in other types of cancer, such as gastric or lung cancer.	('cancer', 'Disease', 'MESH:D009369', (187, 193))	('lung cancer', 'Phenotype', 'HP:0100526', (214, 225))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('cancer', 'Disease', (187, 193))	('gastric or lung cancer', 'Disease', (203, 225))	('gastric or lung cancer', 'Disease', 'MESH:D013274', (203, 225))	('mutations', 'Var', (36, 45))	('cancer', 'Disease', 'MESH:D009369', (219, 225))	('play', 'Reg', (127, 131))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('cancer', 'Disease', (219, 225))
26463	24465403	There is evidence from previous studies that MET mutations are primarily involved in tumor progression to the metastatic phase.	('tumor', 'Disease', (85, 90))	('mutations', 'Var', (49, 58))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('involved', 'Reg', (73, 81))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))
26464	24465403	showed that in 4/15 HNSCC cases, activating MET mutations undergo clonal expansion during metastatic spread, as their frequency increased from 2% in the primary tumors to 50% in the metastases.	('metastases', 'Disease', 'MESH:D009362', (182, 192))	('tumors', 'Disease', (161, 167))	('tumors', 'Phenotype', 'HP:0002664', (161, 167))	('tumors', 'Disease', 'MESH:D009369', (161, 167))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('activating', 'PosReg', (33, 43))	('metastases', 'Disease', (182, 192))	('mutations', 'Var', (48, 57))	('MET', 'Gene', (44, 47))
26468	24465403	This is in contrast with previous studies showing that MET expression is an early event in HNC carcinogenesis, and has an association with a poorer overall survival rate.	('HNC carcinogenesis', 'Disease', (91, 109))	('MET expression', 'Var', (55, 69))	('HNC carcinogenesis', 'Disease', 'MESH:D063646', (91, 109))
26486	24465403	Dysregulation of the MET pathway plays a role in various human cancers, though 'MET addiction' only occurs in a small percentage of these cancers.	('human', 'Species', '9606', (57, 62))	('Dysregulation', 'Var', (0, 13))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('cancers', 'Phenotype', 'HP:0002664', (138, 145))	("'MET addiction'", 'Disease', (79, 94))	('cancers', 'Disease', (138, 145))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('MET pathway', 'Pathway', (21, 32))	('cancers', 'Phenotype', 'HP:0002664', (63, 70))	('role', 'Reg', (41, 45))	('cancers', 'Disease', (63, 70))	('cancers', 'Disease', 'MESH:D009369', (138, 145))	('cancers', 'Disease', 'MESH:D009369', (63, 70))
26505	27485778	Rare mutations in PRDM5 have been identified in Brittle cornea syndrome (BCS), a connective tissue disease characterized by thinning of the cornea, whereas it has also been reported that PRDM5 is silenced due to the promoter hypermethylation in breast cancer, liver cancer, lung cancer, ovarian cancer, cervical cancer, and gastrointestinal cancer 17, 18, 19, 20, 21.	('lung cancer', 'Phenotype', 'HP:0100526', (274, 285))	('silenced', 'NegReg', (196, 204))	('cancer', 'Phenotype', 'HP:0002664', (295, 301))	('liver cancer', 'Phenotype', 'HP:0002896', (260, 272))	('breast cancer', 'Disease', (245, 258))	('cancer', 'Phenotype', 'HP:0002664', (312, 318))	('ovarian cancer', 'Disease', 'MESH:D010051', (287, 301))	('liver cancer', 'Disease', (260, 272))	('Brittle cornea syndrome', 'Disease', (48, 71))	('cancer', 'Phenotype', 'HP:0002664', (279, 285))	('PRDM5', 'Gene', (187, 192))	('thinning of the cornea', 'Phenotype', 'HP:0100689', (124, 146))	('gastrointestinal cancer', 'Disease', 'MESH:D004067', (324, 347))	('gastrointestinal cancer', 'Disease', (324, 347))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (324, 347))	('lung cancer', 'Disease', (274, 285))	('PRDM5', 'Gene', (18, 23))	('mutations', 'Var', (5, 14))	('ovarian cancer', 'Disease', (287, 301))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('ovarian cancer', 'Phenotype', 'HP:0100615', (287, 301))	('Brittle cornea syndrome', 'Disease', 'MESH:C536192', (48, 71))	('identified', 'Reg', (34, 44))	('promoter hypermethylation', 'Var', (216, 241))	('cancer', 'Phenotype', 'HP:0002664', (266, 272))	('breast cancer', 'Phenotype', 'HP:0003002', (245, 258))	('cervical cancer', 'Disease', (303, 318))	('cervical cancer', 'Disease', 'MESH:D002583', (303, 318))
26510	27485778	Two sequences specific to mouse PRDM5 were used to generate siRNAs: target 1 (5'-GCT GTG CAA TAA GGC CTTT-3') and target 2 (5'-GGA TAC ATT AAA CGT TCAT-3').	("5'-GCT", 'Var', (78, 84))	('CGT', 'Gene', (143, 146))	('CGT', 'Gene', '22239', (143, 146))
26530	27485778	Moreover, PRDM5 expression is undetectable in colorectal cancer and gastric cancer due to DNA methylation or trimethylation of Lys27 of histone H3 (H3K27) and PRDM5 overexpression significantly inhibits the colony formation of gastric cancer cells 20.	('gastric cancer', 'Phenotype', 'HP:0012126', (227, 241))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('overexpression', 'PosReg', (165, 179))	('H3K27', 'Protein', (148, 153))	('Lys27', 'Chemical', '-', (127, 132))	('gastric cancer', 'Phenotype', 'HP:0012126', (68, 82))	('colorectal cancer', 'Disease', 'MESH:D015179', (46, 63))	('colorectal cancer', 'Disease', (46, 63))	('gastric cancer', 'Disease', (227, 241))	('DNA', 'Reg', (90, 93))	('PRDM5', 'Gene', (10, 15))	('trimethylation', 'Var', (109, 123))	('gastric cancer', 'Disease', (68, 82))	('inhibits', 'NegReg', (194, 202))	('gastric cancer', 'Disease', 'MESH:D013274', (227, 241))	('colorectal cancer', 'Phenotype', 'HP:0003003', (46, 63))	('undetectable', 'NegReg', (30, 42))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('PRDM5', 'Gene', (159, 164))	('gastric cancer', 'Disease', 'MESH:D013274', (68, 82))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))
26536	32394637	Roles of HOTAIR in lung cancer susceptibility and prognosis Long noncoding (lncRNA) single-nucleotide polymorphisms (SNPs) are associated with the susceptibility to the development of various malignant tumors.	('HOTAIR', 'Gene', (9, 15))	('lung cancer', 'Phenotype', 'HP:0100526', (19, 30))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('tumors', 'Phenotype', 'HP:0002664', (202, 208))	('single-nucleotide polymorphisms', 'Var', (84, 115))	('malignant tumors', 'Disease', (192, 208))	('HOTAIR', 'Gene', '100124700', (9, 15))	('men', 'Species', '9606', (176, 179))	('malignant tumors', 'Disease', 'MESH:D009369', (192, 208))	('lung cancer', 'Disease', 'MESH:D008175', (19, 30))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('lung cancer', 'Disease', (19, 30))
26539	32394637	Three SNPs (rs920778, rs1899663, and rs4759314) of HOTAIR were identified using the MassArray system.	('rs1899663', 'Var', (22, 31))	('HOTAIR', 'Gene', (51, 57))	('rs4759314', 'Var', (37, 46))	('HOTAIR', 'Gene', '100124700', (51, 57))	('rs920778', 'Mutation', 'rs920778', (12, 20))	('rs4759314', 'Mutation', 'rs4759314', (37, 46))	('rs920778', 'Var', (12, 20))	('rs1899663', 'Mutation', 'rs1899663', (22, 31))
26542	32394637	We found that the genotypes of these SNPs (rs920778, rs1899663, and rs4759314) were not significantly associated with lung cancer type, family history, lymph node metastasis, or lung cancer stage.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('rs920778', 'Var', (43, 51))	('lymph node metastasis', 'CPA', (152, 173))	('associated', 'Reg', (102, 112))	('lung cancer', 'Disease', (178, 189))	('lung cancer', 'Disease', 'MESH:D008175', (118, 129))	('lung cancer', 'Phenotype', 'HP:0100526', (178, 189))	('rs4759314', 'Var', (68, 77))	('lung cancer', 'Phenotype', 'HP:0100526', (118, 129))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('lung cancer', 'Disease', (118, 129))	('rs1899663', 'Mutation', 'rs1899663', (53, 62))	('lung cancer', 'Disease', 'MESH:D008175', (178, 189))	('rs1899663', 'Var', (53, 62))	('rs920778', 'Mutation', 'rs920778', (43, 51))	('rs4759314', 'Mutation', 'rs4759314', (68, 77))
26543	32394637	In gender stratification, the results of rs920778 genotypes showed that, compared to genotype AA, the AG (OR = 0.344, 95% CI: 0.133-0.893, p = .028) and AG + GG (OR = 0.378, 95% CI: 0.153-0.932, p = .035) genotypes of rs920778 are protective factors against NSCLC in females.	('NSCLC', 'Disease', (258, 263))	('rs920778', 'Var', (218, 226))	('rs920778', 'Mutation', 'rs920778', (41, 49))	('NSCLC', 'Disease', 'MESH:D002289', (258, 263))	('NSCLC', 'Phenotype', 'HP:0030358', (258, 263))	('rs920778', 'Mutation', 'rs920778', (218, 226))
26544	32394637	In smoking stratification, compared with AA of rs920778, the genotype AG + GG (OR = 0.507, 95% CI: 0.263-0.975, p = .042) was a protective factor against NSCLC in nonsmoking people.	('NSCLC', 'Disease', 'MESH:D002289', (154, 159))	('NSCLC', 'Phenotype', 'HP:0030358', (154, 159))	('AG + GG', 'Var', (70, 77))	('people', 'Species', '9606', (174, 180))	('NSCLC', 'Disease', (154, 159))	('rs920778', 'Mutation', 'rs920778', (47, 55))
26545	32394637	No statistical differences were observed in the classifications of rs1899663 and rs4759314 genotypes.	('rs1899663', 'Var', (67, 76))	('rs1899663', 'Mutation', 'rs1899663', (67, 76))	('rs4759314', 'Var', (81, 90))	('rs4759314', 'Mutation', 'rs4759314', (81, 90))
26546	32394637	Linkage disequilibrium analysis revealed a high linkage disequilibrium between the rs920778 and rs1899663 (D' = 0.99, r 2 = .74), rs920778 and rs4759314 (D' = 0.85, r 2 = .13), and rs1899663 and rs4759314 (D' = 0.79, r 2 = .00).	('rs920778', 'Mutation', 'rs920778', (83, 91))	('rs4759314', 'Mutation', 'rs4759314', (143, 152))	('rs1899663', 'Mutation', 'rs1899663', (96, 105))	('rs1899663', 'Var', (181, 190))	('rs920778', 'Var', (130, 138))	('rs4759314', 'Var', (195, 204))	('rs920778', 'Var', (83, 91))	('rs4759314', 'Var', (143, 152))	('rs1899663', 'Var', (96, 105))	('rs4759314', 'Mutation', 'rs4759314', (195, 204))	('rs920778', 'Mutation', 'rs920778', (130, 138))	('rs1899663', 'Mutation', 'rs1899663', (181, 190))
26547	32394637	Our study demonstrated that HOTAIR expression increased in NSCLC, and that the genotypes of rs920778 could be useful in the diagnosis and prognosis of lung cancer.	('HOTAIR', 'Gene', '100124700', (28, 34))	('NSCLC', 'Disease', 'MESH:D002289', (59, 64))	('rs920778', 'Var', (92, 100))	('increased', 'PosReg', (46, 55))	('lung cancer', 'Phenotype', 'HP:0100526', (151, 162))	('lung cancer', 'Disease', (151, 162))	('NSCLC', 'Phenotype', 'HP:0030358', (59, 64))	('rs920778', 'Mutation', 'rs920778', (92, 100))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('HOTAIR', 'Gene', (28, 34))	('lung cancer', 'Disease', 'MESH:D008175', (151, 162))	('NSCLC', 'Disease', (59, 64))
26549	32394637	We found that HOTAIR increased in nonsmall cell lung cancer, and the genotypes of rs920778 are protective factors for female patients and nonsmoking people, which are useful for screening and prognosis for lung cancer.	('nonsmall cell lung cancer', 'Disease', 'MESH:D002289', (34, 59))	('patients', 'Species', '9606', (125, 133))	('rs920778', 'Var', (82, 90))	('nonsmall cell lung cancer', 'Phenotype', 'HP:0030358', (34, 59))	('lung cancer', 'Disease', 'MESH:D008175', (206, 217))	('lung cancer', 'Disease', 'MESH:D008175', (48, 59))	('HOTAIR', 'Gene', '100124700', (14, 20))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('people', 'Species', '9606', (149, 155))	('lung cancer', 'Disease', (206, 217))	('lung cancer', 'Phenotype', 'HP:0100526', (206, 217))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('lung cancer', 'Phenotype', 'HP:0100526', (48, 59))	('rs920778', 'Mutation', 'rs920778', (82, 90))	('nonsmall cell lung cancer', 'Disease', (34, 59))	('HOTAIR', 'Gene', (14, 20))
26557	32394637	The main pathogenesis of NSCLC is epigenetic variations in chromatin, and the changes in chromatin modification products may alter the growth mode of cells and result in the loss of the original cellular characteristics (Scott, 2018).	('chromatin modification products', 'MPA', (89, 120))	('growth mode of cells', 'CPA', (135, 155))	('NSCLC', 'Disease', (25, 30))	('changes', 'Reg', (78, 85))	('NSCLC', 'Disease', 'MESH:D002289', (25, 30))	('NSCLC', 'Phenotype', 'HP:0030358', (25, 30))	('epigenetic variations', 'Var', (34, 55))	('loss', 'NegReg', (174, 178))	('alter', 'Reg', (125, 130))	('original', 'MPA', (186, 194))
26562	32394637	Single-nucleotide polymorphisms (SNPs) and somatic mutation on lncRNAs might play a critical role in the pathogenesis of cancer, indicating a strong potential for further development of lncRNAs as biomarkers (Tong et al., 2015).	('lncRNAs', 'Gene', (63, 70))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('play', 'Reg', (77, 81))	('Single-nucleotide polymorphisms', 'Var', (0, 31))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('cancer', 'Disease', (121, 127))	('men', 'Species', '9606', (178, 181))
26568	32394637	For example, deleterious nonsynonymous SNPs in the tumor suppressor protein TP53 gene affect the p53-estrogen receptor alpha interaction and are associated with breast cancer (Chitrala, Nagarkatti, Nagarkatti, & Yeguvapalli, 2019).	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('breast cancer', 'Disease', 'MESH:D001943', (161, 174))	('affect', 'Reg', (86, 92))	('breast cancer', 'Phenotype', 'HP:0003002', (161, 174))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('breast cancer', 'Disease', (161, 174))	('TP53', 'Gene', '7157', (76, 80))	('tumor', 'Disease', (51, 56))	('associated', 'Reg', (145, 155))	('p53-estrogen receptor alpha interaction', 'MPA', (97, 136))	('TP53', 'Gene', (76, 80))	('nonsynonymous SNPs', 'Var', (25, 43))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
26569	32394637	Furthermore, the SNP rs915894 in NOTCH4 gene may be a genetic marker for the prognosis of NSCLC in the Chinese population and may have an interactive relationship with epidemiologic factors (Xu, Lin, et al., 2019).	('interactive', 'Interaction', (138, 149))	('NOTCH4', 'Gene', (33, 39))	('NSCLC', 'Disease', (90, 95))	('NOTCH4', 'Gene', '4855', (33, 39))	('rs915894', 'Mutation', 'rs915894', (21, 29))	('NSCLC', 'Disease', 'MESH:D002289', (90, 95))	('SNP rs915894', 'Var', (17, 29))	('NSCLC', 'Phenotype', 'HP:0030358', (90, 95))
26570	32394637	In addition, an association was observed between SNPs in adiponectin gene + 276G/T and breast cancer incidence in postmenopausal women after adjustment for all other variables (Geriki et al., 2019).	('276G/T', 'Var', (76, 82))	('adiponectin', 'Gene', '9370', (57, 68))	('women', 'Species', '9606', (129, 134))	('men', 'Species', '9606', (131, 134))	('breast cancer', 'Disease', 'MESH:D001943', (87, 100))	('men', 'Species', '9606', (118, 121))	('adiponectin', 'Gene', (57, 68))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('breast cancer', 'Disease', (87, 100))	('SNPs', 'Var', (49, 53))	('breast cancer', 'Phenotype', 'HP:0003002', (87, 100))	('276G/T', 'SUBSTITUTION', 'None', (76, 82))	('men', 'Species', '9606', (147, 150))
26571	32394637	The AA genotype of SNP rs10889677 was significantly correlated with increased risk of colorectal cancer (Mosallaei et al., 2019).	('colorectal cancer', 'Disease', 'MESH:D015179', (86, 103))	('colorectal cancer', 'Phenotype', 'HP:0003003', (86, 103))	('colorectal cancer', 'Disease', (86, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('SNP', 'Gene', (19, 22))	('rs10889677', 'Var', (23, 33))	('rs10889677', 'Mutation', 'rs10889677', (23, 33))
26572	32394637	The toll-like receptor gene 2 polymorphism, rs3804100, may be a potential prognostic biomarker for Helicobacter pylori infection-independent gastric cancer (Zhao et al., 2019).	('gastric cancer', 'Disease', (141, 155))	('gastric cancer', 'Phenotype', 'HP:0012126', (141, 155))	('infection', 'Disease', (119, 128))	('infection', 'Disease', 'MESH:D007239', (119, 128))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('rs3804100', 'Mutation', 'rs3804100', (44, 53))	('Helicobacter pylori infection', 'Phenotype', 'HP:0005202', (99, 128))	('Helicobacter pylori', 'Species', '210', (99, 118))	('rs3804100', 'Var', (44, 53))	('gastric cancer', 'Disease', 'MESH:D013274', (141, 155))
26575	32394637	Subsequently, the relationship between HOTAIR gene SNPs (rs920778, rs1899663, and rs4759314) and susceptibility to lung cancer was investigated.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('rs920778', 'Var', (57, 65))	('rs4759314', 'Var', (82, 91))	('HOTAIR', 'Gene', (39, 45))	('HOTAIR', 'Gene', '100124700', (39, 45))	('lung cancer', 'Disease', 'MESH:D008175', (115, 126))	('rs920778', 'Mutation', 'rs920778', (57, 65))	('rs1899663', 'Mutation', 'rs1899663', (67, 76))	('rs4759314', 'Mutation', 'rs4759314', (82, 91))	('rs1899663', 'Var', (67, 76))	('lung cancer', 'Disease', (115, 126))	('lung cancer', 'Phenotype', 'HP:0100526', (115, 126))
26608	32394637	The results showed that there was no significant difference between high and low expression of HOTAIR and the overall survival of patients with LUAD (p = .12, Figure 3a).	('LUAD', 'Disease', (144, 148))	('low', 'NegReg', (77, 80))	('LUAD', 'Phenotype', 'HP:0030078', (144, 148))	('high', 'Var', (68, 72))	('HOTAIR', 'Gene', (95, 101))	('patients', 'Species', '9606', (130, 138))	('HOTAIR', 'Gene', '100124700', (95, 101))	('LUAD', 'Disease', 'None', (144, 148))
26613	32394637	Studies have shown that SNPs can affect the gene expression levels and is closely related to tumorigenesis (Wang et al., 2019).	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('affect', 'Reg', (33, 39))	('tumor', 'Disease', (93, 98))	('related', 'Reg', (82, 89))	('gene expression levels', 'MPA', (44, 66))	('SNPs', 'Var', (24, 28))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
26614	32394637	Therefore, we further explored the relationship between the HOTAIR gene SNPs (rs920778, rs1899663, and rs4759314) and the susceptibility to patients with lung cancer.	('lung cancer', 'Disease', (154, 165))	('lung cancer', 'Phenotype', 'HP:0100526', (154, 165))	('rs920778', 'Var', (78, 86))	('rs4759314', 'Mutation', 'rs4759314', (103, 112))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('HOTAIR', 'Gene', (60, 66))	('rs1899663', 'Mutation', 'rs1899663', (88, 97))	('patients', 'Species', '9606', (140, 148))	('rs4759314', 'Var', (103, 112))	('lung cancer', 'Disease', 'MESH:D008175', (154, 165))	('HOTAIR', 'Gene', '100124700', (60, 66))	('rs920778', 'Mutation', 'rs920778', (78, 86))	('rs1899663', 'Var', (88, 97))
26615	32394637	In order to investigate the relationship between the HOTAIR SNPs (rs920778, rs1899663, and rs4759314) and the susceptibility to lung cancer, we analyzed DNA from 196 cases of patients with NSCLC and 196 healthy controls.	('NSCLC', 'Disease', (189, 194))	('lung cancer', 'Disease', 'MESH:D008175', (128, 139))	('NSCLC', 'Disease', 'MESH:D002289', (189, 194))	('rs920778', 'Mutation', 'rs920778', (66, 74))	('HOTAIR', 'Gene', (53, 59))	('rs1899663', 'Mutation', 'rs1899663', (76, 85))	('rs4759314', 'Var', (91, 100))	('HOTAIR', 'Gene', '100124700', (53, 59))	('patients', 'Species', '9606', (175, 183))	('lung cancer', 'Disease', (128, 139))	('lung cancer', 'Phenotype', 'HP:0100526', (128, 139))	('rs1899663', 'Var', (76, 85))	('rs920778', 'Var', (66, 74))	('NSCLC', 'Phenotype', 'HP:0030358', (189, 194))	('rs4759314', 'Mutation', 'rs4759314', (91, 100))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
26617	32394637	Using a SNP MassArray system, we detected three SNP genotypes at different loci, including rs920778 in 183 controls and 184 cases, rs1899663 in 188 controls and 187 cases, and rs4759314 in 184 controls and 175 cases (Figure 4a-c).	('rs4759314', 'Mutation', 'rs4759314', (176, 185))	('rs1899663', 'Mutation', 'rs1899663', (131, 140))	('rs920778', 'Mutation', 'rs920778', (91, 99))	('rs1899663', 'Var', (131, 140))	('rs4759314', 'Var', (176, 185))	('rs920778', 'Var', (91, 99))
26618	32394637	Genetic variation of SNP rs920778, rs1899663, and rs4759314 within a population was analyzed using the population genetics HWE equilibrium law.	('SNP', 'Gene', (21, 24))	('rs4759314', 'Var', (50, 59))	('rs920778', 'Var', (25, 33))	('rs1899663', 'Mutation', 'rs1899663', (35, 44))	('rs4759314', 'Mutation', 'rs4759314', (50, 59))	('rs1899663', 'Var', (35, 44))	('rs920778', 'Mutation', 'rs920778', (25, 33))
26619	32394637	Chi-square tests were used to analyze alleles of HOTAIR SNP rs920778, rs1899663, and rs4759314 in patients with NSCLC and in healthy controls.	('rs4759314', 'Mutation', 'rs4759314', (85, 94))	('rs920778', 'Var', (60, 68))	('HOTAIR', 'Gene', '100124700', (49, 55))	('NSCLC', 'Phenotype', 'HP:0030358', (112, 117))	('rs1899663', 'Mutation', 'rs1899663', (70, 79))	('rs4759314', 'Var', (85, 94))	('patients', 'Species', '9606', (98, 106))	('rs1899663', 'Var', (70, 79))	('rs920778', 'Mutation', 'rs920778', (60, 68))	('NSCLC', 'Disease', (112, 117))	('HOTAIR', 'Gene', (49, 55))	('NSCLC', 'Disease', 'MESH:D002289', (112, 117))
26620	32394637	Gene frequencies of rs920778 alleles A and G were 78.3% and 21.7% in the NSCLC group, and 75.7% and 24.3% in healthy controls, respectively.	('rs920778', 'Mutation', 'rs920778', (20, 28))	('rs920778', 'Var', (20, 28))	('NSCLC', 'Disease', (73, 78))	('NSCLC', 'Disease', 'MESH:D002289', (73, 78))	('NSCLC', 'Phenotype', 'HP:0030358', (73, 78))
26621	32394637	Gene frequencies of rs1899663 alleles A and C were 16.0% and 84.0% in NSCLC cases, and 18.6% and 81.4% in healthy controls, respectively.	('rs1899663', 'Mutation', 'rs1899663', (20, 29))	('rs1899663', 'Var', (20, 29))	('NSCLC', 'Disease', (70, 75))	('NSCLC', 'Disease', 'MESH:D002289', (70, 75))	('NSCLC', 'Phenotype', 'HP:0030358', (70, 75))
26622	32394637	The gene frequencies of rs4759314 alleles A and G were 95.1% and 4.9% in NSCLC patients, and 95.7% and 4.3% in controls, respectively.	('rs4759314', 'Mutation', 'rs4759314', (24, 33))	('NSCLC', 'Disease', (73, 78))	('rs4759314', 'Var', (24, 33))	('patients', 'Species', '9606', (79, 87))	('NSCLC', 'Disease', 'MESH:D002289', (73, 78))	('NSCLC', 'Phenotype', 'HP:0030358', (73, 78))
26623	32394637	The genotypes of the rs920778, rs1899663, and rs4759314 in NSCLC cases and healthy controls were analyzed using chi-square tests.	('rs4759314', 'Var', (46, 55))	('NSCLC', 'Disease', 'MESH:D002289', (59, 64))	('rs920778', 'Mutation', 'rs920778', (21, 29))	('rs920778', 'Var', (21, 29))	('rs1899663', 'Mutation', 'rs1899663', (31, 40))	('rs1899663', 'Var', (31, 40))	('NSCLC', 'Phenotype', 'HP:0030358', (59, 64))	('rs4759314', 'Mutation', 'rs4759314', (46, 55))	('NSCLC', 'Disease', (59, 64))
26624	32394637	Results demonstrated that the rs920778 locus genotypes AA, AG, GG, and AG + GG, the rs1899663 locus genotypes AA, AC, CC, and AC + CC, and the genotypes AA and AG of the rs4759314 locus between NSCLC and healthy controls were not significantly associated with the susceptibility to lung cancer (Table S2).	('NSCLC', 'Phenotype', 'HP:0030358', (194, 199))	('lung cancer', 'Disease', 'MESH:D008175', (282, 293))	('rs920778', 'Var', (30, 38))	('NSCLC', 'Disease', (194, 199))	('rs4759314', 'Mutation', 'rs4759314', (170, 179))	('cancer', 'Phenotype', 'HP:0002664', (287, 293))	('NSCLC', 'Disease', 'MESH:D002289', (194, 199))	('lung cancer', 'Disease', (282, 293))	('lung cancer', 'Phenotype', 'HP:0100526', (282, 293))	('rs1899663', 'Mutation', 'rs1899663', (84, 93))	('rs1899663', 'Var', (84, 93))	('rs920778', 'Mutation', 'rs920778', (30, 38))
26625	32394637	We further investigated whether the genotypes of locus rs920778, rs1899663, and rs4759314 are associated with lung cancer type, lymph node metastasis, and lung cancer stage, etc.	('lymph node metastasis', 'CPA', (128, 149))	('lung cancer', 'Disease', 'MESH:D008175', (110, 121))	('rs920778', 'Mutation', 'rs920778', (55, 63))	('rs1899663', 'Mutation', 'rs1899663', (65, 74))	('rs1899663', 'Var', (65, 74))	('rs4759314', 'Mutation', 'rs4759314', (80, 89))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('lung cancer', 'Disease', (110, 121))	('lung cancer', 'Disease', (155, 166))	('rs920778', 'Var', (55, 63))	('associated', 'Reg', (94, 104))	('lung cancer', 'Phenotype', 'HP:0100526', (155, 166))	('lung cancer', 'Phenotype', 'HP:0100526', (110, 121))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('rs4759314', 'Var', (80, 89))	('lung cancer', 'Disease', 'MESH:D008175', (155, 166))
26627	32394637	Similarly, the genotypes of rs1899663 (AA, AC, and CC) and of rs4759314 (AA and AG) were not significantly associated with lung cancer type, family history, lymph node metastasis, or lung cancer stage, respectively (p > .05, Tables 4 and 5).	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('rs4759314', 'Mutation', 'rs4759314', (62, 71))	('rs1899663', 'Mutation', 'rs1899663', (28, 37))	('rs1899663', 'Var', (28, 37))	('lung cancer', 'Disease', (123, 134))	('associated', 'Reg', (107, 117))	('lung cancer', 'Disease', 'MESH:D008175', (183, 194))	('lung cancer', 'Phenotype', 'HP:0100526', (123, 134))	('lymph node metastasis', 'CPA', (157, 178))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('lung cancer', 'Disease', 'MESH:D008175', (123, 134))	('rs4759314', 'Var', (62, 71))	('lung cancer', 'Phenotype', 'HP:0100526', (183, 194))	('lung cancer', 'Disease', (183, 194))
26630	32394637	In gender stratification, the results of rs920778 genotypes showed that compared with genotype AA, the AG (OR = 0.344, 95% CI: 0.133-0.893, p = .028) and AG + GG (OR = 0.378, 95% CI: 0.153-0.932, p = .035) genotypes of rs920778 are protective factors against NSCLC in females (Table 4).	('NSCLC', 'Phenotype', 'HP:0030358', (259, 264))	('rs920778', 'Mutation', 'rs920778', (219, 227))	('rs920778', 'Mutation', 'rs920778', (41, 49))	('NSCLC', 'Disease', (259, 264))	('rs920778', 'Var', (219, 227))	('NSCLC', 'Disease', 'MESH:D002289', (259, 264))
26631	32394637	In smoking stratification, compared with AA, the genotype AG + GG (OR = 0.507, 95% CI: 0.263-0.975, p = .042) was a protective factor against NSCLC in nonsmoking people (Table 4).	('NSCLC', 'Disease', (142, 147))	('people', 'Species', '9606', (162, 168))	('NSCLC', 'Disease', 'MESH:D002289', (142, 147))	('AG + GG', 'Var', (58, 65))	('NSCLC', 'Phenotype', 'HP:0030358', (142, 147))
26633	32394637	No statistical differences were observed in the classifications of rs1899663 and rs4759314 genotypes (Tables 5 and 6).	('rs1899663', 'Var', (67, 76))	('rs1899663', 'Mutation', 'rs1899663', (67, 76))	('rs4759314', 'Var', (81, 90))	('rs4759314', 'Mutation', 'rs4759314', (81, 90))
26635	32394637	The results of linkage disequilibrium analysis revealed a high linkage disequilibrium between the rs920778 and rs1899663 (D' = 0.99, r 2 = .74), rs920778 and rs4759314 (D' = 0.85, r 2 = .13), and rs1899663 and rs4759314 (D' = 0.79, r 2 = .00) genotypes, indicating a high linkage disequilibrium between rs920778 and rs1899663.	('rs4759314', 'Mutation', 'rs4759314', (158, 167))	('rs1899663', 'Mutation', 'rs1899663', (196, 205))	('rs920778', 'Var', (98, 106))	('rs1899663', 'Var', (196, 205))	('rs1899663', 'Mutation', 'rs1899663', (111, 120))	('rs920778', 'Mutation', 'rs920778', (303, 311))	('rs4759314', 'Mutation', 'rs4759314', (210, 219))	('rs1899663', 'Mutation', 'rs1899663', (316, 325))	('rs4759314', 'Var', (158, 167))	('rs1899663', 'Var', (316, 325))	('rs1899663', 'Var', (111, 120))	('rs920778', 'Mutation', 'rs920778', (145, 153))	('rs920778', 'Var', (303, 311))	('rs920778', 'Var', (145, 153))	('rs920778', 'Mutation', 'rs920778', (98, 106))
26636	32394637	A linkage disequilibrium was also observed between rs920778 and rs4759314 (Figure 5).	('rs4759314', 'Var', (64, 73))	('rs4759314', 'Mutation', 'rs4759314', (64, 73))	('rs920778', 'Mutation', 'rs920778', (51, 59))	('rs920778', 'Var', (51, 59))
26638	32394637	The results showed that the common alleles in the lung cancer group and control group were A (rs920778), C (rs1899663), and A (rs4759314).	('lung cancer', 'Disease', (50, 61))	('rs4759314', 'Mutation', 'rs4759314', (127, 136))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('lung cancer', 'Disease', 'MESH:D008175', (50, 61))	('rs1899663', 'Mutation', 'rs1899663', (108, 117))	('rs920778', 'Mutation', 'rs920778', (94, 102))	('rs4759314', 'Var', (127, 136))	('lung cancer', 'Phenotype', 'HP:0100526', (50, 61))	('rs920778', 'Var', (94, 102))
26642	32394637	In addition, some change-related motifs were observed at locus rs920778 and locus rs1899663, and they are also were quantitative trait loci for the expression of many genes (Table 7).	('rs920778', 'Mutation', 'rs920778', (63, 71))	('rs920778', 'Var', (63, 71))	('motifs', 'MPA', (33, 39))	('change-related', 'Reg', (18, 32))	('rs1899663', 'Mutation', 'rs1899663', (82, 91))	('rs1899663', 'Var', (82, 91))
26645	32394637	In this case-control study, we explored the relationship between HOTAIR SNPs and susceptibility to lung cancer, and found that the AG and AG + GG genotypes of rs920778 are protective factors against NSCLC in females, and the genotype AG + GG was a protective factor against NSCLC in nonsmoking people.	('HOTAIR', 'Gene', (65, 71))	('lung cancer', 'Disease', (99, 110))	('NSCLC', 'Disease', 'MESH:D002289', (199, 204))	('rs920778', 'Mutation', 'rs920778', (159, 167))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('HOTAIR', 'Gene', '100124700', (65, 71))	('NSCLC', 'Phenotype', 'HP:0030358', (274, 279))	('lung cancer', 'Disease', 'MESH:D008175', (99, 110))	('NSCLC', 'Phenotype', 'HP:0030358', (199, 204))	('rs920778', 'Var', (159, 167))	('lung cancer', 'Phenotype', 'HP:0100526', (99, 110))	('people', 'Species', '9606', (294, 300))	('NSCLC', 'Disease', (274, 279))	('NSCLC', 'Disease', 'MESH:D002289', (274, 279))	('NSCLC', 'Disease', (199, 204))
26656	32394637	SNPs that occur within the lncRNA transcripts can affect the structure and function of multiple RNA molecules (Cairns et al., 2019; Chen et al., 2019), whereas the presence of a SNP in the promoter region of a lncRNA could alter its expression level (Qin et al., 2019).	('function', 'MPA', (75, 83))	('Qin', 'Gene', '2290', (251, 254))	('RNA', 'Protein', (96, 99))	('SNPs', 'Var', (0, 4))	('Qin', 'Gene', (251, 254))	('affect', 'Reg', (50, 56))	('alter', 'Reg', (223, 228))	('expression level', 'MPA', (233, 249))	('structure', 'MPA', (61, 70))
26658	32394637	Previous studies also revealed that SNPs in miR-219-1 (rs213210, rs421446, and rs107822) significantly affect the susceptibility and prognosis of NSCLC (Zheng et al., 2017).	('rs421446', 'Mutation', 'rs421446', (65, 73))	('rs213210', 'Mutation', 'rs213210', (55, 63))	('rs107822', 'Mutation', 'rs107822', (79, 87))	('miR-219-1', 'Gene', '407002', (44, 53))	('NSCLC', 'Disease', (146, 151))	('miR-219-1', 'Gene', (44, 53))	('rs213210', 'Var', (55, 63))	('rs107822', 'Var', (79, 87))	('NSCLC', 'Disease', 'MESH:D002289', (146, 151))	('rs421446', 'Var', (65, 73))	('NSCLC', 'Phenotype', 'HP:0030358', (146, 151))	('affect', 'Reg', (103, 109))
26659	32394637	Genetic variation of HOTAIR may affect its function and is related to the susceptibility of individuals to cancer development (Bayram, Ulger, et al., 2015; Xue et al., 2015).	('function', 'MPA', (43, 51))	('Genetic variation', 'Var', (0, 17))	('men', 'Species', '9606', (121, 124))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('affect', 'Reg', (32, 38))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('cancer', 'Disease', (107, 113))	('related', 'Reg', (59, 66))	('HOTAIR', 'Gene', (21, 27))	('HOTAIR', 'Gene', '100124700', (21, 27))
26660	32394637	The minor alleles of HOTAIR rs4759314 and rs200349340 were significantly associated with pancreatic cancer susceptibility (Jiang et al., 2019).	('pancreatic cancer', 'Disease', 'MESH:D010190', (89, 106))	('rs200349340', 'Mutation', 'rs200349340', (42, 53))	('rs4759314', 'Mutation', 'rs4759314', (28, 37))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('associated', 'Reg', (73, 83))	('rs4759314', 'Var', (28, 37))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (89, 106))	('rs200349340', 'Var', (42, 53))	('HOTAIR', 'Gene', (21, 27))	('pancreatic cancer', 'Disease', (89, 106))	('HOTAIR', 'Gene', '100124700', (21, 27))
26661	32394637	HOTAIR rs920778 was associated with esophageal cancer and esophageal squamous cell carcinoma risk (Tian, Liu, Liu, Zuo, & Chen, 2019).	('HOTAIR', 'Gene', '100124700', (0, 6))	('associated', 'Reg', (20, 30))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (58, 92))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (69, 92))	('rs920778', 'Mutation', 'rs920778', (7, 15))	('cancer', 'Disease', (47, 53))	('rs920778', 'Var', (7, 15))	('esophageal squamous cell carcinoma', 'Disease', (58, 92))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('HOTAIR', 'Gene', (0, 6))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))
26663	32394637	HOTAIR SNPs rs12427129 and rs3816153 were associated with the risk of hepatocellular carcinoma (HCC) in dominant genetic models.	('HOTAIR', 'Gene', '100124700', (0, 6))	('rs12427129', 'Var', (12, 22))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (70, 94))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (70, 94))	('HCC', 'Phenotype', 'HP:0001402', (96, 99))	('hepatocellular carcinoma', 'Disease', (70, 94))	('rs3816153', 'Var', (27, 36))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('HOTAIR', 'Gene', (0, 6))	('rs3816153', 'Mutation', 'rs3816153', (27, 36))	('rs12427129', 'Mutation', 'rs12427129', (12, 22))
26664	32394637	Additionally, SNP-environment interactions for rs12427129, rs3816153, and HBsAg status were found to enhance the risk of HCC (Zhang et al., 2019).	('rs12427129', 'Mutation', 'rs12427129', (47, 57))	('HCC', 'Phenotype', 'HP:0001402', (121, 124))	('rs3816153', 'Var', (59, 68))	('rs12427129', 'Var', (47, 57))	('enhance', 'PosReg', (101, 108))	('rs3816153', 'Mutation', 'rs3816153', (59, 68))	('HCC', 'Disease', (121, 124))	('men', 'Species', '9606', (25, 28))
26665	32394637	Although, HOTAIR rs920778 and rs1899663 significantly increase susceptibility to lung cancer (Wang et al., 2018), the roles of HOTAIR SNPs in lung cancer still need to be further studied.	('rs920778', 'Mutation', 'rs920778', (17, 25))	('lung cancer', 'Disease', (81, 92))	('lung cancer', 'Phenotype', 'HP:0100526', (81, 92))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('HOTAIR', 'Gene', '100124700', (10, 16))	('rs1899663', 'Var', (30, 39))	('rs1899663', 'Mutation', 'rs1899663', (30, 39))	('lung cancer', 'Disease', 'MESH:D008175', (142, 153))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('rs920778', 'Var', (17, 25))	('lung cancer', 'Disease', (142, 153))	('lung cancer', 'Disease', 'MESH:D008175', (81, 92))	('lung cancer', 'Phenotype', 'HP:0100526', (142, 153))	('HOTAIR', 'Gene', (127, 133))	('HOTAIR', 'Gene', (10, 16))	('HOTAIR', 'Gene', '100124700', (127, 133))
26666	32394637	In this study, three SNPs of HOTAIR (rs920778, rs1899663, and rs4759314) were investigated in order to explore the relationship of these SNPs with the pathogenesis of lung cancer.	('rs1899663', 'Var', (47, 56))	('rs920778', 'Var', (37, 45))	('HOTAIR', 'Gene', (29, 35))	('lung cancer', 'Disease', 'MESH:D008175', (167, 178))	('rs4759314', 'Mutation', 'rs4759314', (62, 71))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('lung cancer', 'Disease', (167, 178))	('lung cancer', 'Phenotype', 'HP:0100526', (167, 178))	('HOTAIR', 'Gene', '100124700', (29, 35))	('rs920778', 'Mutation', 'rs920778', (37, 45))	('rs1899663', 'Mutation', 'rs1899663', (47, 56))	('rs4759314', 'Var', (62, 71))
26668	32394637	The allele results of rs920778 is similar to Li's study (Li et al., 2018), but the allele results of rs4759314 is different from Li's study, which report that G allele carriers had a 2.598-fold increased risk of developing lung cancer compared to A allele carriers (Li et al., 2018).	('lung cancer', 'Disease', (223, 234))	('lung cancer', 'Phenotype', 'HP:0100526', (223, 234))	('rs4759314', 'Mutation', 'rs4759314', (101, 110))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('rs920778', 'Mutation', 'rs920778', (22, 30))	('lung cancer', 'Disease', 'MESH:D008175', (223, 234))	('rs4759314', 'Var', (101, 110))
26670	32394637	In the smoking classification, AG + GG genotype of rs920778 was also a protective factor against lung cancer.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('rs920778', 'Mutation', 'rs920778', (51, 59))	('lung cancer', 'Disease', 'MESH:D008175', (97, 108))	('rs920778', 'Var', (51, 59))	('lung cancer', 'Disease', (97, 108))	('lung cancer', 'Phenotype', 'HP:0100526', (97, 108))
26671	32394637	In addition, significant differences were observed among the three genotypes of rs1899663 in the type of lung cancer.	('lung cancer', 'Phenotype', 'HP:0100526', (105, 116))	('rs1899663', 'Mutation', 'rs1899663', (80, 89))	('lung cancer', 'Disease', 'MESH:D008175', (105, 116))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('rs1899663', 'Var', (80, 89))	('differences', 'Reg', (25, 36))	('lung cancer', 'Disease', (105, 116))
26672	32394637	found a significant association between HOTAIR SNP rs920778 and susceptibility to lung cancer (Wang et al., 2018).	('lung cancer', 'Phenotype', 'HP:0100526', (82, 93))	('rs920778', 'Mutation', 'rs920778', (51, 59))	('lung cancer', 'Disease', (82, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('HOTAIR', 'Gene', (40, 46))	('rs920778', 'Var', (51, 59))	('lung cancer', 'Disease', 'MESH:D008175', (82, 93))	('HOTAIR', 'Gene', '100124700', (40, 46))
26673	32394637	The relationship between SNPs in rs920778, rs1899663, and rs4759314 loci of the HOTAIR gene and susceptibility to lung cancer was analyzed from a genetics perspective.	('lung cancer', 'Disease', 'MESH:D008175', (114, 125))	('HOTAIR', 'Gene', '100124700', (80, 86))	('rs4759314', 'Mutation', 'rs4759314', (58, 67))	('HOTAIR', 'Gene', (80, 86))	('lung cancer', 'Disease', (114, 125))	('rs4759314', 'Var', (58, 67))	('lung cancer', 'Phenotype', 'HP:0100526', (114, 125))	('rs920778', 'Mutation', 'rs920778', (33, 41))	('rs1899663', 'Mutation', 'rs1899663', (43, 52))	('rs1899663', 'Var', (43, 52))	('rs920778', 'Var', (33, 41))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
26675	32394637	We found that HOTAIR expression increased in NSCLC, and that the genotypes of rs920778 are protective factors in female patients and nonsmokers; this is useful for screening and prognosis for lung cancer.	('rs920778', 'Var', (78, 86))	('lung cancer', 'Disease', (192, 203))	('HOTAIR', 'Gene', '100124700', (14, 20))	('lung cancer', 'Phenotype', 'HP:0100526', (192, 203))	('NSCLC', 'Disease', (45, 50))	('NSCLC', 'Disease', 'MESH:D002289', (45, 50))	('patients', 'Species', '9606', (120, 128))	('increased', 'PosReg', (32, 41))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('lung cancer', 'Disease', 'MESH:D008175', (192, 203))	('rs920778', 'Mutation', 'rs920778', (78, 86))	('NSCLC', 'Phenotype', 'HP:0030358', (45, 50))	('HOTAIR', 'Gene', (14, 20))
26683	31646712	Forced expression of miR-338-5p in these cells resulted in downregulation of Id-1, and restoration of both in vitro and in vivo sensitivity to 5-FU treatment.	('5-FU', 'Chemical', 'MESH:D005472', (143, 147))	('miR-338-5p', 'Chemical', '-', (21, 31))	('miR-338-5p', 'Var', (21, 31))	('Id-1', 'Gene', (77, 81))	('restoration', 'PosReg', (87, 98))	('downregulation', 'NegReg', (59, 73))	('Id-1', 'Gene', '3397', (77, 81))	('sensitivity to 5-FU treatment', 'MPA', (128, 157))
26685	31646712	In contrast, miR-338-5p knockdown induced 5-FU resistance in chemosensitive esophageal cell lines, and knockdown of both miR-338-5p and Id-1 resensitized the cells to 5-FU.	('miR-338-5p', 'Chemical', '-', (121, 131))	('miR-338-5p', 'Var', (121, 131))	('5-FU', 'Chemical', 'MESH:D005472', (167, 171))	('resensitized', 'NegReg', (141, 153))	('5-FU', 'Chemical', 'MESH:D005472', (42, 46))	('5-FU resistance', 'MPA', (42, 57))	('Id-1', 'Gene', '3397', (136, 140))	('Id-1', 'Gene', (136, 140))	('induced', 'Reg', (34, 41))	('miR-338-5p', 'Chemical', '-', (13, 23))	('knockdown', 'Var', (103, 112))	('miR-338-5p', 'Var', (13, 23))
26686	31646712	In addition, miR-338-5p had suppressive effects on migration and invasion of ESCC cells.	('ESCC', 'Disease', (77, 81))	('invasion of', 'CPA', (65, 76))	('miR-338-5p', 'Var', (13, 23))	('miR-338-5p', 'Chemical', '-', (13, 23))	('suppressive', 'NegReg', (28, 39))
26687	31646712	Luciferase reporter assay confirmed a direct interaction between miR-338-5p and the 3'-UTR of Id-1.	('Id-1', 'Gene', (94, 98))	('miR-338-5p', 'Chemical', '-', (65, 75))	('Id-1', 'Gene', '3397', (94, 98))	('interaction', 'Interaction', (45, 56))	('miR-338-5p', 'Var', (65, 75))
26688	31646712	We also found that miR-338-5p was significantly downregulated in tumor tissue and serum samples of patients with ESCC.	('ESCC', 'Disease', (113, 117))	('tumor', 'Disease', (65, 70))	('downregulated', 'NegReg', (48, 61))	('patients', 'Species', '9606', (99, 107))	('miR-338-5p', 'Chemical', '-', (19, 29))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('miR-338-5p', 'Var', (19, 29))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
26690	31646712	In summary, we found that miR-338-5p can modulate 5-FU chemoresistance and inhibit invasion-related functions in ESCC by negatively regulating Id-1, and that serum miR-338-5p could be a novel noninvasive prognostic and predictive biomarker in ESCC.	('miR-338-5p', 'Var', (164, 174))	('negatively regulating', 'NegReg', (121, 142))	('ESCC', 'Disease', (113, 117))	('invasion-related functions', 'CPA', (83, 109))	('5-FU chemoresistance', 'MPA', (50, 70))	('ESCC', 'Disease', (243, 247))	('inhibit', 'NegReg', (75, 82))	('Id-1', 'Gene', '3397', (143, 147))	('Id-1', 'Gene', (143, 147))	('miR-338-5p', 'Var', (26, 36))	('5-FU', 'Chemical', 'MESH:D005472', (50, 54))	('modulate', 'Reg', (41, 49))	('miR-338-5p', 'Chemical', '-', (26, 36))	('miR-338-5p', 'Chemical', '-', (164, 174))
26691	31646712	We found that microRNA (miR)-338-5p was underexpressed in esophageal squamous cell carcinoma cells with acquired 5-fluorouracil (5-FU) chemoresistance, and that reexpression of miR-338-5p could resensitize them to 5-FU treatment through targeting Id-1.	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (58, 92))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (69, 92))	('-338-5p', 'Chemical', '-', (180, 187))	('5-FU', 'Chemical', 'MESH:D005472', (214, 218))	('esophageal squamous cell carcinoma', 'Disease', (58, 92))	('miR-338-5p', 'Var', (177, 187))	('targeting', 'Reg', (237, 246))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (113, 127))	('Id-1', 'Gene', '3397', (247, 251))	('miR-338-5p', 'Chemical', '-', (177, 187))	('Id-1', 'Gene', (247, 251))	('5-FU', 'Chemical', 'MESH:D005472', (129, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))	('-338-5p', 'Chemical', '-', (28, 35))
26692	31646712	MicroRNA-338-5p was significantly downregulated in tumor tissue and serum of patients with esophageal squamous cell carcinoma.	('esophageal squamous cell carcinoma', 'Disease', (91, 125))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('downregulated', 'NegReg', (34, 47))	('-338-5p', 'Chemical', '-', (8, 15))	('tumor', 'Disease', (51, 56))	('patients', 'Species', '9606', (77, 85))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (91, 125))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('MicroRNA-338-5p', 'Var', (0, 15))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (102, 125))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
26693	31646712	Low serum miR-338-5p was predictive of poor response to 5-FU/cisplatin-based neoadjuvant chemoradiotherapy.	('miR-338-5p', 'Protein', (10, 20))	('miR-338-5p', 'Chemical', '-', (10, 20))	('5-FU', 'Chemical', 'MESH:D005472', (56, 60))	('cisplatin', 'Chemical', 'MESH:D002945', (61, 70))	('Low', 'Var', (0, 3))
26698	31646712	Herein, we present data based on in vitro and in vivo functional experiments, as well as analyses of clinical samples, to show that miR-338-5p is downregulated in ESCC, and that it regulates chemoresistance and invasion-related functions in ESCC cells by negatively regulating Id-1.	('ESCC', 'Disease', (163, 167))	('Id-1', 'Gene', (277, 281))	('regulates', 'Reg', (181, 190))	('chemoresistance', 'CPA', (191, 206))	('miR-338-5p', 'Var', (132, 142))	('miR-338-5p', 'Chemical', '-', (132, 142))	('Id-1', 'Gene', '3397', (277, 281))	('downregulated', 'NegReg', (146, 159))	('invasion-related functions', 'CPA', (211, 237))	('negatively regulating', 'NegReg', (255, 276))
26717	31646712	For in vitro experiments, the mean Ct values of miR-338-5p were normalized to that of the internal reference gene or endogenous control to obtain DeltaCt, and then to that of the corresponding control or parental cell line to obtain the 2-DeltaDeltaCt value as fold change.	('miR-338-5p', 'Var', (48, 58))	('DeltaCt', 'MPA', (146, 153))	('miR-338-5p', 'Chemical', '-', (48, 58))
26741	31646712	The prediction results showed that there were 2 putative binding sites for miR-338-5p within the 3'-UTR of Id-1 (Figure 1A).	('Id-1', 'Gene', (107, 111))	('binding', 'Interaction', (57, 64))	('Id-1', 'Gene', '3397', (107, 111))	('miR-338-5p', 'Var', (75, 85))	('miR-338-5p', 'Chemical', '-', (75, 85))
26742	31646712	The luciferase reporter vectors containing WT and Mut Id-1 3'-UTR were then constructed accordingly (Figure 1A), and dual-luciferase reporter assay was carried out to confirm the direct binding of miR-338-5p to the Id-1 3'-UTR.	('Id-1', 'Gene', '3397', (215, 219))	('Id-1', 'Gene', (215, 219))	('Id-1', 'Gene', (54, 58))	('Id-1', 'Gene', '3397', (54, 58))	('miR-338-5p', 'Var', (197, 207))	('miR-338-5p', 'Chemical', '-', (197, 207))	('binding', 'Interaction', (186, 193))
26743	31646712	Cotransfection of miR-338-5p and the WT psiCHECK-Id-1 3'-UTR into KYSE150 cells led to a significant decrease (P = .004) of the luciferase signal when compared with scrambled miRNA control (Figure 1B).	('Id-1', 'Gene', '3397', (49, 53))	('decrease', 'NegReg', (101, 109))	('miR-338-5p', 'Chemical', '-', (18, 28))	('WT psiCHECK', 'Disease', (37, 48))	('miR-338-5p', 'Var', (18, 28))	('WT psiCHECK', 'Disease', 'MESH:C536751', (37, 48))	('Id-1', 'Gene', (49, 53))	('luciferase', 'Enzyme', (128, 138))
26744	31646712	This inhibitory effect was rescued by mutating the 2 predicted miR-338-5p binding sites (Figure 1B).	('miR-338-5p', 'Chemical', '-', (63, 73))	('mutating', 'Var', (38, 46))	('miR-338-5p', 'Gene', (63, 73))	('binding', 'Interaction', (74, 81))
26745	31646712	These data indicated that Id-1 3'-UTR is a direct target of miR-338-5p.	('Id-1', 'Gene', '3397', (26, 30))	('Id-1', 'Gene', (26, 30))	('miR-338-5p', 'Chemical', '-', (60, 70))	('miR-338-5p', 'Var', (60, 70))
26746	31646712	We determined the miR-338-5p expression level in 42 pairs of esophageal tumor and nonneoplastic tissues (Set B samples), which were previously analyzed for Id-1 protein expression.15 Pearson's correlation analysis showed an inverse relationship (r = -0.214, P = .050) between miR-338-5p and Id-1 (Figure 1C).	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('Id-1', 'Gene', (156, 160))	('miR-338-5p', 'Chemical', '-', (18, 28))	('Id-1', 'Gene', '3397', (156, 160))	('esophageal tumor', 'Disease', (61, 77))	('esophageal tumor', 'Phenotype', 'HP:0100751', (61, 77))	('miR-338-5p', 'Chemical', '-', (276, 286))	('Id-1', 'Gene', '3397', (291, 295))	('Id-1', 'Gene', (291, 295))	('miR-338-5p', 'Var', (276, 286))	('esophageal tumor', 'Disease', 'MESH:D004938', (61, 77))
26747	31646712	Our group previously reported that Id-1 can induce chemoresistance in ESCC.14, 15 We therefore speculated that targeting Id-1 using miR-338-5p could help ESCC cancer cells overcome 5-FU resistance.	('cancer', 'Disease', (159, 165))	('Id-1', 'Gene', (121, 125))	('5-FU', 'Chemical', 'MESH:D005472', (181, 185))	('Id-1', 'Gene', '3397', (121, 125))	('Id-1', 'Gene', '3397', (35, 39))	('Id-1', 'Gene', (35, 39))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('ESCC', 'Disease', (154, 158))	('miR-338-5p', 'Chemical', '-', (132, 142))	('miR-338-5p', 'Var', (132, 142))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('chemoresistance', 'CPA', (51, 66))
26748	31646712	We found that miR-338-5p was downregulated, whereas Id-1 was upregulated, in KYSE410FR and KYSE150FR cells in comparison with their parental ESCC cell lines (Figure 2A,B).	('Id-1', 'Gene', '3397', (52, 56))	('Id-1', 'Gene', (52, 56))	('upregulated', 'PosReg', (61, 72))	('miR-338-5p', 'Gene', (14, 24))	('KYSE150FR', 'Var', (91, 100))	('miR-338-5p', 'Chemical', '-', (14, 24))	('downregulated', 'NegReg', (29, 42))	('KYSE410FR', 'Var', (77, 86))
26749	31646712	We then undertook miR-338-5p knockdown in parental ESCC cell lines using miRZip-338-5p (Figure 2C) and found elevation of Id-1 protein expression levels in both cell lines (Figure 2D).	('miR-338-5p', 'Chemical', '-', (18, 28))	('elevation', 'PosReg', (109, 118))	('-338-5p', 'Chemical', '-', (21, 28))	('Id-1', 'Gene', '3397', (122, 126))	('Id-1', 'Gene', (122, 126))	('miRZip-338-5p', 'Var', (73, 86))	('-338-5p', 'Chemical', '-', (79, 86))
26750	31646712	In contrast, stable miR-338-5p overexpression decreased Id-1 protein levels in KYSE410FR and KYSE150FR cells when compared with their corresponding control cell lines (Figure 2E,F), thus indicating that miR-338-5p can modulate Id-1 function in 5-FU-resistant ESCC cells.	('function', 'MPA', (232, 240))	('Id-1', 'Gene', (227, 231))	('miR-338-5p', 'Var', (203, 213))	('miR-338-5p', 'Chemical', '-', (20, 30))	('Id-1', 'Gene', '3397', (56, 60))	('Id-1', 'Gene', (56, 60))	('miR-338-5p', 'Chemical', '-', (203, 213))	('Id-1', 'Gene', '3397', (227, 231))	('5-FU', 'Chemical', 'MESH:D005472', (244, 248))	('protein levels', 'MPA', (61, 75))	('KYSE410FR', 'Var', (79, 88))	('modulate', 'Reg', (218, 226))	('decreased', 'NegReg', (46, 55))	('KYSE150FR', 'Var', (93, 102))	('miR-338-5p', 'Var', (20, 30))
26752	31646712	The results of MTT cell viability assays showed that overexpression of miR-338-5p sensitized KYSE410FR and KYSE150FR cells to 5-FU treatment, and that this effect was abolished by overexpression of Id-1 (Figure 3A).	('KYSE410FR', 'Var', (93, 102))	('5-FU', 'Chemical', 'MESH:D005472', (126, 130))	('overexpression', 'PosReg', (53, 67))	('Id-1', 'Gene', (198, 202))	('5-FU treatment', 'MPA', (126, 140))	('Id-1', 'Gene', '3397', (198, 202))	('miR-338-5p', 'Chemical', '-', (71, 81))	('miR-338-5p', 'Var', (71, 81))	('KYSE150FR', 'Var', (107, 116))	('MTT', 'Chemical', 'MESH:C070243', (15, 18))	('sensitized', 'Reg', (82, 92))
26753	31646712	Western blot analyses showed that miR-338-5p expression increased the sensitivity of KYSE410FR and KYSE150FR cells to 5-FU-induced apoptosis, as indicated by the increase in cleaved caspase-3 and cleaved PARP; overexpression of Id-1 reversed this effect (Figure 3B).	('increase', 'PosReg', (162, 170))	('increased', 'PosReg', (56, 65))	('Id-1', 'Gene', (228, 232))	('caspase-3', 'Gene', '836', (182, 191))	('PARP', 'Gene', '142', (204, 208))	('sensitivity', 'MPA', (70, 81))	('Id-1', 'Gene', '3397', (228, 232))	('miR-338-5p', 'Chemical', '-', (34, 44))	('caspase-3', 'Gene', (182, 191))	('5-FU', 'Chemical', 'MESH:D005472', (118, 122))	('PARP', 'Gene', (204, 208))	('miR-338-5p expression', 'Var', (34, 55))
26755	31646712	In contrast, data from MTT assays showed that knockdown of miR-338-5p increased the viability of the 5-FU-sensitive parental esophageal cell lines under 5-FU treatment, and that this effect could be abolished by Id-1 knockdown (Figure 3D).	('MTT', 'Chemical', 'MESH:C070243', (23, 26))	('miR-338-5p', 'Chemical', '-', (59, 69))	('viability', 'CPA', (84, 93))	('increased', 'PosReg', (70, 79))	('miR-338-5p', 'Var', (59, 69))	('5-FU', 'Chemical', 'MESH:D005472', (101, 105))	('Id-1', 'Gene', '3397', (212, 216))	('5-FU', 'Chemical', 'MESH:D005472', (153, 157))	('Id-1', 'Gene', (212, 216))
26756	31646712	Western blot analysis of cleaved caspase-3 and cleaved PARP, and flow cytometric analysis of the sub-G1 apoptotic cell population, indicated that knockdown of miR-338-5p made the parental esophageal cells more resistant to 5-FU-induced apoptosis, whereas knockdown of Id-1 could restore 5-FU sensitivity (Figure 3E,F).	('knockdown', 'Var', (146, 155))	('PARP', 'Gene', '142', (55, 59))	('Id-1', 'Gene', '3397', (268, 272))	('miR-338-5p', 'Var', (159, 169))	('resistant', 'CPA', (210, 219))	('caspase-3', 'Gene', (33, 42))	('miR-338-5p', 'Chemical', '-', (159, 169))	('5-FU', 'Chemical', 'MESH:D005472', (223, 227))	('caspase-3', 'Gene', '836', (33, 42))	('PARP', 'Gene', (55, 59))	('more', 'PosReg', (205, 209))	('5-FU', 'Chemical', 'MESH:D005472', (287, 291))	('Id-1', 'Gene', (268, 272))
26757	31646712	Collectively, these data showed that miR-338-5p can modulate 5-FU chemoresistance by downregulating Id-1.	('5-FU', 'Chemical', 'MESH:D005472', (61, 65))	('miR-338-5p', 'Var', (37, 47))	('5-FU chemoresistance', 'MPA', (61, 81))	('miR-338-5p', 'Chemical', '-', (37, 47))	('downregulating', 'NegReg', (85, 99))	('Id-1', 'Gene', '3397', (100, 104))	('Id-1', 'Gene', (100, 104))	('modulate', 'Reg', (52, 60))
26758	31646712	Tumor xenograft experiments were undertaken to determine whether miR-338-5p overexpression could render ESCC tumors more sensitive to 5-FU treatment in vivo (Figure 4A).	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('5-FU', 'Chemical', 'MESH:D005472', (134, 138))	('miR-338-5p', 'Chemical', '-', (65, 75))	('more', 'PosReg', (116, 120))	('miR-338-5p', 'Var', (65, 75))	('ESCC tumors', 'Disease', (104, 115))	('sensitive to 5-FU treatment', 'MPA', (121, 148))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('ESCC tumors', 'Disease', 'MESH:D004938', (104, 115))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))
26759	31646712	Comparison of tumor size showed that miR-338-5p overexpression in KYSE150FR cells significantly increased the sensitivity of the tumors to 5-FU therapy, and that concomitant overexpression of Id-1 significantly restored the 5-FU resistance (Figure 4B,C).	('tumors', 'Disease', (129, 135))	('miR-338-5p', 'Chemical', '-', (37, 47))	('Id-1', 'Gene', '3397', (192, 196))	('Id-1', 'Gene', (192, 196))	('5-FU', 'Chemical', 'MESH:D005472', (139, 143))	('tumor', 'Disease', (129, 134))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('tumors', 'Disease', 'MESH:D009369', (129, 135))	('5-FU', 'Chemical', 'MESH:D005472', (224, 228))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('miR-338-5p', 'Var', (37, 47))	('sensitivity', 'MPA', (110, 121))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('5-FU resistance', 'MPA', (224, 239))	('restored', 'PosReg', (211, 219))	('increased', 'PosReg', (96, 105))	('tumor', 'Disease', (14, 19))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('tumor', 'Disease', 'MESH:D009369', (14, 19))
26760	31646712	Several studies reported that overexpression of Id-1 is associated with tumor invasion and metastasis in different cancer types, including ESCC.20, 23, 24 As our data showed that miR-338-5p could downregulate Id-1, we further speculated that miR-338-5p might play a role in regulating invasion and migration of ESCC cells.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('downregulate', 'NegReg', (196, 208))	('overexpression', 'PosReg', (30, 44))	('associated', 'Reg', (56, 66))	('Id-1', 'Gene', '3397', (209, 213))	('Id-1', 'Gene', (209, 213))	('miR-338-5p', 'Chemical', '-', (179, 189))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('ESCC.20', 'Disease', (139, 146))	('miR-338-5p', 'Chemical', '-', (242, 252))	('miR-338-5p', 'Var', (179, 189))	('Id-1', 'Gene', (48, 52))	('Id-1', 'Gene', '3397', (48, 52))	('tumor', 'Disease', (72, 77))	('metastasis', 'CPA', (91, 101))	('invasion', 'CPA', (285, 293))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('cancer', 'Disease', (115, 121))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))
26761	31646712	The results of the Transwell cell invasion assay indicated that forced expression of miR-338-5p significantly inhibited the invasive activity of ESCC cells in vitro (Figure 5A).	('invasive activity of', 'CPA', (124, 144))	('inhibited', 'NegReg', (110, 119))	('miR-338-5p', 'Chemical', '-', (85, 95))	('miR-338-5p', 'Var', (85, 95))	('ESCC', 'Disease', (145, 149))
26762	31646712	MicroRNA-338-5p also reduced the migration activity of ESCC cells, as shown by the wound healing assay (Figure 5B).	('reduced', 'NegReg', (21, 28))	('ESCC cells', 'CPA', (55, 65))	('-338-5p', 'Chemical', '-', (8, 15))	('migration activity', 'CPA', (33, 51))	('MicroRNA-338-5p', 'Var', (0, 15))
26763	31646712	Reoverexpression of Id-1 attenuated these effects (Figure 5A,B).	('Id-1', 'Gene', (20, 24))	('Reoverexpression', 'Var', (0, 16))	('Id-1', 'Gene', '3397', (20, 24))
26764	31646712	Conversely, silencing miR-338-5p increased the abilities of KYSE270 and T.Tn cells to migrate and invade, and the effects were ameliorated by Id-1 knockdown (Figure 5C,D).	('Id-1', 'Gene', '3397', (142, 146))	('Id-1', 'Gene', (142, 146))	('miR-338-5p', 'Protein', (22, 32))	('silencing', 'Var', (12, 21))	('miR-338-5p', 'Chemical', '-', (22, 32))	('increased', 'PosReg', (33, 42))
26765	31646712	These findings suggest that miR-338-5p has metastasis-inhibiting functions that are mediated by downregulating Id-1.	('miR-338-5p', 'Var', (28, 38))	('Id-1', 'Gene', (111, 115))	('downregulating', 'NegReg', (96, 110))	('metastasis-inhibiting', 'CPA', (43, 64))	('Id-1', 'Gene', '3397', (111, 115))	('miR-338-5p', 'Chemical', '-', (28, 38))
26767	31646712	Among the 30 ESCC samples in Set A, 19 (approximately 63%) had lower expression of miR-338-5p relative to their corresponding nonneoplastic tissues (Figure 6A, upper panel).	('miR-338-5p', 'Chemical', '-', (83, 93))	('miR-338-5p', 'Var', (83, 93))	('lower', 'NegReg', (63, 68))	('expression', 'MPA', (69, 79))
26768	31646712	Similarly, analysis of Set B samples showed that 29 of 42 cases (approximately 69%) had lower expression of miR-338-5p in tumors than in their corresponding nontumor tissues (Figure 6A, lower panel).	('tumors', 'Phenotype', 'HP:0002664', (122, 128))	('tumors', 'Disease', (122, 128))	('tumors', 'Disease', 'MESH:D009369', (122, 128))	('miR-338-5p', 'Chemical', '-', (108, 118))	('miR-338-5p', 'Var', (108, 118))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('expression', 'MPA', (94, 104))	('lower', 'NegReg', (88, 93))	('tumor', 'Disease', (160, 165))	('tumor', 'Disease', (122, 127))
26770	31646712	We also analyzed miR-338-5p expression in other cancers of the gastrointestinal tract using public sources including TCGA database and GEO datasets.	('miR-338-5p', 'Var', (17, 27))	('cancers', 'Disease', (48, 55))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('cancers', 'Phenotype', 'HP:0002664', (48, 55))	('cancers of the gastrointestinal tract', 'Phenotype', 'HP:0007378', (48, 85))	('cancers', 'Disease', 'MESH:D009369', (48, 55))	('miR-338-5p', 'Chemical', '-', (17, 27))
26771	31646712	In TCGA data, the expression level of miR-338-5p in the ESCA data cohort was significantly lower than that in nontumor tissues (Figure S1A).	('lower', 'NegReg', (91, 96))	('tumor', 'Disease', (113, 118))	('miR-338-5p', 'Chemical', '-', (38, 48))	('expression level', 'MPA', (18, 34))	('ESCA', 'Disease', (56, 60))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('miR-338-5p', 'Var', (38, 48))
26773	31646712	Taken together, these results suggest an association between miR-338-5p dysregulation and esophageal cancer.	('miR-338-5p dysregulation', 'Var', (61, 85))	('esophageal cancer', 'Disease', (90, 107))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('miR-338-5p', 'Chemical', '-', (61, 71))	('esophageal cancer', 'Disease', 'MESH:D004938', (90, 107))
26774	31646712	In the GEO datasets, lower expression of miR-338-5p was also found in other gastrointestinal cancers (Figure S1C-F).	('gastrointestinal cancers', 'Disease', 'MESH:D004067', (76, 100))	('miR-338-5p', 'Chemical', '-', (41, 51))	('miR-338-5p', 'Var', (41, 51))	('lower', 'NegReg', (21, 26))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('expression', 'MPA', (27, 37))	('cancers', 'Phenotype', 'HP:0002664', (93, 100))	('gastrointestinal cancers', 'Disease', (76, 100))
26775	31646712	Analysis of TCGA-ESCA data showed that ESCA patients with high miR-338-5p expression in their tumors had longer overall survival time (Figure S1G).	('longer', 'PosReg', (105, 111))	('patients', 'Species', '9606', (44, 52))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('miR-338-5p', 'Chemical', '-', (63, 73))	('overall survival time', 'CPA', (112, 133))	('tumors', 'Disease', (94, 100))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('high miR-338-5p expression', 'Var', (58, 84))	('ESCA', 'Disease', (39, 43))
26776	31646712	To determine whether circulating miR-338-5p could serve as a noninvasive serum biomarker, we analyzed the expression level of miR-338-5p in admission/pretreatment serum samples of 104 patients with ESCC and 50 healthy individuals.	('ESCC', 'Disease', (198, 202))	('patients', 'Species', '9606', (184, 192))	('miR-338-5p', 'Chemical', '-', (33, 43))	('miR-338-5p', 'Chemical', '-', (126, 136))	('miR-338-5p', 'Var', (126, 136))
26783	31646712	The patients with high serum miR-338-5p expression had significantly (P = .013) better survival rates (median survival = 58.00 months) than those with low miR-338-5p expression (median survival = 21.57 months) (Figure 6D).	('miR-338-5p', 'Chemical', '-', (155, 165))	('miR-338-5p expression', 'Var', (29, 50))	('miR-338-5p', 'Chemical', '-', (29, 39))	('high', 'Var', (18, 22))	('better', 'PosReg', (80, 86))	('patients', 'Species', '9606', (4, 12))	('survival rates', 'CPA', (87, 101))
26785	31646712	Correlation with clinicopathologic parameters showed that expression levels of miR-338-5p in pretreatment serum were inversely correlated with posttherapy pathologic ypT-stage (P = .034), ypM-stage (P = .014), overall pathologic stage (ypTNM; P = .017), and histologic grade (P = .026) (Table 1).	('miR-338-5p', 'Chemical', '-', (79, 89))	('miR-338-5p', 'Var', (79, 89))	('expression', 'MPA', (58, 68))	('ypT-stage', 'Disease', (166, 175))	('ypM-stage', 'Disease', (188, 197))	('inversely', 'NegReg', (117, 126))
26786	31646712	Furthermore, high serum miR-338-5p expression was associated with lower percentage of residual viable cells in the primary tumor collected during surgery, and with complete response to therapy (Table 1), which indicated that higher pretreatment serum miR-338-5p level could predict a better response to chemoradiotherapy.	('miR-338-5p', 'Chemical', '-', (24, 34))	('tumor', 'Disease', (123, 128))	('high', 'Var', (13, 17))	('lower', 'NegReg', (66, 71))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('miR-338-5p', 'Chemical', '-', (251, 261))
26788	31646712	Despite 5-FU being an antimetabolic agent widely used in treating gastrointestinal cancers, the response rate of esophageal carcinoma to 5-FU is only 15%.26, 27, 28 Emerging evidence indicates that miRNAs are associated with chemoresistance, but relatively few miRNAs were experimentally validated to have the ability to regulate the sensitivity of ESCC cells to 5-FU treatment.10, 11, 12, 29, 30, 31 Our present study found that miR-338-5p was underexpressed in 5-FU-resistant ESCC cells, and that ectopic overexpression of miR-338-5p in these cells could increase their sensitivity to 5-FU treatment both in vitro and in vivo.	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (113, 133))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('gastrointestinal cancers', 'Disease', 'MESH:D004067', (66, 90))	('5-FU', 'Chemical', 'MESH:D005472', (137, 141))	('sensitivity to 5-FU treatment', 'MPA', (572, 601))	('5-FU', 'Chemical', 'MESH:D005472', (463, 467))	('gastrointestinal cancers', 'Disease', (66, 90))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (113, 133))	('5-FU', 'Chemical', 'MESH:D005472', (587, 591))	('miR-338-5p', 'Chemical', '-', (525, 535))	('5-FU', 'Chemical', 'MESH:D005472', (8, 12))	('esophageal carcinoma', 'Disease', (113, 133))	('5-FU', 'Chemical', 'MESH:D005472', (363, 367))	('miR-338-5p', 'Chemical', '-', (430, 440))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('overexpression', 'PosReg', (507, 521))	('increase', 'PosReg', (557, 565))	('miR-338-5p', 'Var', (525, 535))	('cancers', 'Phenotype', 'HP:0002664', (83, 90))
26789	31646712	We further established that miR-338-5p inhibits 5-FU chemoresistance as well as decreases the invasive and migratory potential of ESCC cells through targeting Id-1.	('miR-338-5p', 'Var', (28, 38))	('5-FU', 'Protein', (48, 52))	('Id-1', 'Gene', (159, 163))	('ESCC', 'Disease', (130, 134))	('Id-1', 'Gene', '3397', (159, 163))	('5-FU', 'Chemical', 'MESH:D005472', (48, 52))	('decreases', 'NegReg', (80, 89))	('inhibits', 'NegReg', (39, 47))	('targeting', 'Reg', (149, 158))	('miR-338-5p', 'Chemical', '-', (28, 38))
26791	31646712	Although miR-338-5p had been reported to be downregulated in non-small-cell lung carcinoma36 and glioblastoma,37, 38 we have found that its expression was reduced in the majority of ESCC.	('downregulated', 'NegReg', (44, 57))	('expression', 'MPA', (140, 150))	('reduced', 'NegReg', (155, 162))	('lung carcinoma36', 'Disease', 'MESH:D008171', (76, 92))	('miR-338-5p', 'Chemical', '-', (9, 19))	('miR-338-5p', 'Var', (9, 19))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('ESCC', 'Disease', (182, 186))	('small-cell lung carcinoma36', 'Phenotype', 'HP:0030357', (65, 92))	('non-small-cell lung carcinoma36', 'Phenotype', 'HP:0030358', (61, 92))	('glioblastoma', 'Disease', (97, 109))	('glioblastoma', 'Disease', 'MESH:D005909', (97, 109))	('lung carcinoma36', 'Disease', (76, 92))
26792	31646712	Analysis of GEO datasets showed the same phenomenon in gastric, colon, and rectal cancers, thus suggesting that miR-338-5p has tumor suppressor functions in the gastrointestinal tract.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('tumor', 'Disease', (127, 132))	('colon', 'Disease', (64, 69))	('rectal cancer', 'Phenotype', 'HP:0100743', (75, 88))	('cancers', 'Phenotype', 'HP:0002664', (82, 89))	('gastric', 'Disease', (55, 62))	('cancers', 'Disease', (82, 89))	('cancers', 'Disease', 'MESH:D009369', (82, 89))	('miR-338-5p', 'Chemical', '-', (112, 122))	('miR-338-5p', 'Var', (112, 122))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('colon', 'Disease', 'MESH:D003110', (64, 69))
26794	31646712	Our results showed that low miR-338-5p levels in serum on admission was significantly associated with poorer survival and advanced posttherapy pathologic staging.	('miR-338-5p', 'Var', (28, 38))	('poorer', 'NegReg', (102, 108))	('low', 'NegReg', (24, 27))	('survival', 'CPA', (109, 117))	('miR-338-5p', 'Chemical', '-', (28, 38))
26814	33665207	The results showed that ZIC2 also acted as a risk prognostic factor in bladder, breast and lung cancer Table 1.	('lung cancer', 'Phenotype', 'HP:0100526', (91, 102))	('bladder', 'Disease', (71, 78))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('lung cancer', 'Disease', 'MESH:D008175', (91, 102))	('ZIC2', 'Var', (24, 28))	('breast and lung cancer', 'Disease', 'MESH:D001943', (80, 102))	('lung cancer', 'Disease', (91, 102))
26821	33665207	The results revealed that multiple tumor- and immune-related pathways were differentially enriched in ZIC2 high or low expression phenotype in a variety of tumors including complement and coagulation cascades, P53 signaling pathway, basal cell carcinoma, PPAR signaling pathway, tight junction, etc (Figure 10).	('carcinoma', 'Disease', (244, 253))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tight junction', 'Disease', (279, 293))	('P53', 'Gene', (210, 213))	('PPAR', 'Gene', '5465', (255, 259))	('carcinoma', 'Disease', 'MESH:D009369', (244, 253))	('ZIC2', 'Gene', (102, 106))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('P53', 'Gene', '7157', (210, 213))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('basal cell carcinoma', 'Disease', 'MESH:D002280', (233, 253))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (233, 253))	('basal cell carcinoma', 'Disease', (233, 253))	('high', 'Var', (107, 111))	('PPAR', 'Gene', (255, 259))	('carcinoma', 'Phenotype', 'HP:0030731', (244, 253))	('enriched', 'Reg', (90, 98))	('low', 'NegReg', (115, 118))
26832	31981860	Accumulating evidence reveals the significance of long non-coding RNAs (lncRNAs) in various cancers.	('cancers', 'Phenotype', 'HP:0002664', (92, 99))	('long non-coding RNAs', 'Var', (50, 70))	('cancers', 'Disease', 'MESH:D009369', (92, 99))	('cancers', 'Disease', (92, 99))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
26838	31981860	Elevated GATA6-AS1 reduced FZD4 expression by recruiting enhancer of zeste homolog 2 (EZH2) and trimethylation at lysine 27 of histone H3 (H3K27me3) to the FZD4 promoter region via the inactivated Wnt/beta-catenin signaling pathway, whereby cell invasion, migration, and proliferation, tumor growth, and LNM in nude mice were reduced.	('trimethylation', 'Var', (96, 110))	('tumor', 'Disease', 'MESH:D009369', (286, 291))	('tumor', 'Phenotype', 'HP:0002664', (286, 291))	('cell invasion', 'CPA', (241, 254))	('tumor', 'Disease', (286, 291))	('GATA6-AS1', 'Gene', (9, 18))	('nude mice', 'Species', '10090', (311, 320))	('enhancer of zeste homolog 2', 'Gene', '14056', (57, 84))	('LNM', 'CPA', (304, 307))	('enhancer of zeste homolog 2', 'Gene', (57, 84))	('reduced', 'NegReg', (19, 26))	('GATA6-AS1', 'Gene', '100128893', (9, 18))	('FZD4', 'Gene', (27, 31))	('expression', 'MPA', (32, 42))	('reduced', 'NegReg', (326, 333))	('lysine', 'Chemical', 'MESH:C114808', (114, 120))
26841	31981860	GC is widely understood to be a multistep process characterized by the involvement of genetic and epigenetic alterations of protein-coding proto-oncogenes as well as tumor-suppressor genes.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('GC', 'Phenotype', 'HP:0012126', (0, 2))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('involvement', 'Reg', (71, 82))	('tumor', 'Disease', (166, 171))	('epigenetic alterations', 'Var', (98, 120))
26846	31981860	lncRNAs, such as HOX antisense intergenic RNA (HOTAIR) and antisense non-coding RNA in the INK4 locus, have been found to participate in GC development.	('INK4', 'Gene', '1029', (91, 95))	('INK4', 'Gene', (91, 95))	('antisense non-coding RNA', 'Var', (59, 83))	('HOTAIR', 'Gene', (47, 53))	('participate', 'Reg', (122, 133))	('HOTAIR', 'Gene', '100124700', (47, 53))	('GC', 'Phenotype', 'HP:0012126', (137, 139))	('GC development', 'CPA', (137, 151))
26853	31981860	The expression of FZD4 in GC from The Cancer Genome Atlas (TCGA) was found at a high level (Figure 1C), and patients displaying high FZD4 expression exhibited considerably low survival rates compared with those with low FZD4 expression (Figure 1D).	('GC', 'Phenotype', 'HP:0012126', (26, 28))	('FZD4', 'Gene', (18, 22))	('Cancer', 'Phenotype', 'HP:0002664', (38, 44))	('low', 'NegReg', (172, 175))	('FZD4', 'Gene', (133, 137))	('high', 'Var', (128, 132))	('patients', 'Species', '9606', (108, 116))	('survival rates', 'CPA', (176, 190))
26865	31981860	The dual-luciferase reporter gene assay results indicated that the luciferase activity in the FZD4-wild-type (WT) group was markedly decreased when compared with the negative control (NC) group (p < 0.05), while the FZD4-mutant (MUT) group did not exhibit any significant differences (p > 0.05), suggesting that GATA6-AS1 could specifically bind to the FZD4 gene (Figure 2D).	('FZD4-wild-type', 'Var', (94, 108))	('GATA6-AS1', 'Gene', '100128893', (312, 321))	('activity', 'MPA', (78, 86))	('luciferase', 'Enzyme', (67, 77))	('bind', 'Interaction', (341, 345))	('FZD4 gene', 'Gene', (353, 362))	('GATA6-AS1', 'Gene', (312, 321))	('FZD4-mutant', 'Gene', (216, 227))	('FZD4-mutant', 'Gene', '4594', (216, 227))	('decreased', 'NegReg', (133, 142))
26868	31981860	Meanwhile, in response to GATA6-AS1 silencing, the intra-nuclear GATA6-AS1 expression was downregulated and FZD4 was highly expressed (p < 0.05, Figures 2E-2G).	('expressed', 'MPA', (124, 133))	('FZD4', 'Gene', (108, 112))	('GATA6-AS1', 'Gene', '100128893', (26, 35))	('GATA6-AS1', 'Gene', '100128893', (65, 74))	('silencing', 'Var', (36, 45))	('downregulated', 'NegReg', (90, 103))	('GATA6-AS1', 'Gene', (26, 35))	('highly', 'PosReg', (117, 123))	('expression', 'MPA', (75, 85))	('GATA6-AS1', 'Gene', (65, 74))
26870	31981860	A RIP assay was subsequently performed in order to detect the protein binding to GATA6-AS1, and results revealed that GATA6-AS1 could significantly enrich histone methyltransferase enhancer of zeste homolog 2 (EZH2) (p < 0.05, Figure 2H), while silencing of EZH2 resulted in a significant increase in the expression of FZD4 (p < 0.05, Figure 2I).	('expression', 'MPA', (305, 315))	('enrich', 'PosReg', (148, 154))	('increase', 'PosReg', (289, 297))	('GATA6-AS1', 'Gene', '100128893', (81, 90))	('enhancer of zeste homolog 2', 'Gene', (181, 208))	('GATA6-AS1', 'Gene', (118, 127))	('silencing', 'Var', (245, 254))	('EZH2', 'Gene', (258, 262))	('2H', 'Chemical', 'MESH:D006859', (234, 236))	('histone methyltransferase', 'MPA', (155, 180))	('GATA6-AS1', 'Gene', '100128893', (118, 127))	('GATA6-AS1', 'Gene', (81, 90))	('FZD4', 'Gene', (319, 323))	('enhancer of zeste homolog 2', 'Gene', '14056', (181, 208))
26871	31981860	In order to verify the enrichment of trimethylation at lysine 27 of histone H3 (H3K27me3) and EZH2 in the FZD4 promoter region, a chromatin immunoprecipitation (ChIP) assay was performed on the FZD4 promoter region in GC cells and results showed that the enrichment of H3K27me3 and EZH2 was significantly elevated by GATA6-AS1 (p < 0.05, Figure 2J).	('lysine', 'Chemical', 'MESH:C114808', (55, 61))	('GATA6-AS1', 'Gene', (317, 326))	('GATA6-AS1', 'Gene', '100128893', (317, 326))	('enrichment', 'MPA', (255, 265))	('elevated', 'PosReg', (305, 313))	('EZH2', 'Gene', (282, 286))	('GC', 'Phenotype', 'HP:0012126', (218, 220))	('H3K27me3', 'Var', (269, 277))
26875	31981860	The TCF binding domains in the TOPFlash plasmid were mutated, while the other sequences were identical to the TOPFlash plasmid and not affected by beta-catenin activity.	('mutated', 'Var', (53, 60))	('binding', 'Interaction', (8, 15))	('TCF', 'Gene', (4, 7))	('TCF', 'Gene', '3172', (4, 7))
26879	31981860	The results revealed that the activity of TOPFlash increased in response to GATA6-AS1 silencing.	('silencing', 'Var', (86, 95))	('increased', 'PosReg', (51, 60))	('GATA6-AS1', 'Gene', (76, 85))	('TOPFlash', 'Protein', (42, 50))	('GATA6-AS1', 'Gene', '100128893', (76, 85))	('activity', 'MPA', (30, 38))
26885	31981860	The protein level of p-GSK-3betaSer9 was decreased in cells treated with silenced GATA6-AS1 and LiCl, highlighting that the activity of GSK-3beta was suppressed.	('protein level', 'MPA', (4, 17))	('suppressed', 'NegReg', (150, 160))	('activity', 'MPA', (124, 132))	('decreased', 'NegReg', (41, 50))	('GSK-3beta', 'Gene', '2931', (23, 32))	('LiCl', 'Chemical', 'MESH:D018021', (96, 100))	('silenced', 'Var', (73, 81))	('GSK-3beta', 'Gene', '2931', (136, 145))	('GATA6-AS1', 'Gene', (82, 91))	('GSK-3beta', 'Gene', (23, 32))	('GSK-3beta', 'Gene', (136, 145))	('GATA6-AS1', 'Gene', '100128893', (82, 91))
26886	31981860	There was no significant change of GSK-3beta activity in the cells treated with GATA6-AS1 silencing + LiCl, cells without any treatment, and cells for NC (Figures 3C-3E).	('activity', 'MPA', (45, 53))	('GSK-3beta', 'Gene', '2931', (35, 44))	('GSK-3beta', 'Gene', (35, 44))	('LiCl', 'Chemical', 'MESH:D018021', (102, 106))	('GATA6-AS1', 'Gene', (80, 89))	('GATA6-AS1', 'Gene', '100128893', (80, 89))	('silencing +', 'Var', (90, 101))
26889	31981860	However, in response to GATA6-AS1 silencing and LiCl, the cells gradually became elongated mesenchymal cells and scattered solitarily with a blurred boundary and migratory synapse (Figure 4A).	('GATA6-AS1', 'Gene', (24, 33))	('LiCl', 'Chemical', 'MESH:D018021', (48, 52))	('silencing', 'Var', (34, 43))	('GATA6-AS1', 'Gene', '100128893', (24, 33))
26894	31981860	Hence, we concluded that the restoration of GATA6-AS1 dampened the progression of EMT.	('dampened', 'NegReg', (54, 62))	('progression of EMT', 'CPA', (67, 85))	('GATA6-AS1', 'Gene', '100128893', (44, 53))	('restoration', 'Var', (29, 40))	('GATA6-AS1', 'Gene', (44, 53))
26896	31981860	The results indicated that the number of invasive cells (Figures 5B-5D) and the migration rate (Figures 5A-5C) and proliferation ability (Figure 5E) were increased following the delivery of GATA6-AS1 silencing and LiCl, while reductions were identified with the delivery of restored GATA6-AS1, when compared to the cells without any treatment and cells for NC (p < 0.05), with no obvious change observed following delivery of GATA6-AS1 + LiCl (p > 0.05).	('migration rate', 'CPA', (80, 94))	('GATA6-AS1', 'Gene', (426, 435))	('GATA6-AS1', 'Gene', (190, 199))	('silencing', 'Var', (200, 209))	('proliferation ability', 'CPA', (115, 136))	('GATA6-AS1', 'Gene', '100128893', (426, 435))	('invasive cells', 'CPA', (41, 55))	('GATA6-AS1', 'Gene', (283, 292))	('GATA6-AS1', 'Gene', '100128893', (190, 199))	('increased', 'PosReg', (154, 163))	('LiCl', 'Chemical', 'MESH:D018021', (214, 218))	('LiCl', 'Chemical', 'MESH:D018021', (438, 442))	('GATA6-AS1', 'Gene', '100128893', (283, 292))
26899	31981860	The results revealed that tumor size and tumor growth were smaller in nude mice bearing overexpressed GATA6-AS1-treated cells but larger among the nude mice bearing cells treated with GATA6-AS1 silencing and LiCl (p < 0.05).	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('LiCl', 'Chemical', 'MESH:D018021', (208, 212))	('tumor', 'Disease', (41, 46))	('GATA6-AS1', 'Gene', (184, 193))	('silencing', 'Var', (194, 203))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('larger', 'PosReg', (130, 136))	('smaller', 'NegReg', (59, 66))	('GATA6-AS1', 'Gene', (102, 111))	('GATA6-AS1', 'Gene', '100128893', (184, 193))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('nude mice', 'Species', '10090', (147, 156))	('nude mice', 'Species', '10090', (70, 79))	('GATA6-AS1', 'Gene', '100128893', (102, 111))
26902	31981860	However, larger tumor cells with a greater number of metastatic tumor cells were detected in the presence of GATA6-AS1 silencing and LiCl (Figure 6D).	('LiCl', 'Chemical', 'MESH:D018021', (133, 137))	('GATA6-AS1', 'Gene', '100128893', (109, 118))	('tumor', 'Disease', (64, 69))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('tumor', 'Disease', (16, 21))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('GATA6-AS1', 'Gene', (109, 118))	('silencing', 'Var', (119, 128))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
26912	31981860	EZH2-mediated H3K27 trimethylation has been reported as a functional mechanism of gene suppression by lncRNA, supporting the notion of the regulatory mechanism of GATA6-AS1 on FZD4.	('lncRNA', 'Gene', (102, 108))	('GATA6-AS1', 'Gene', (163, 172))	('gene suppression', 'MPA', (82, 98))	('GATA6-AS1', 'Gene', '100128893', (163, 172))	('trimethylation', 'Var', (20, 34))	('H3K27', 'Protein', (14, 19))
26916	31981860	Investigative attempts have been made to explore the effects associated with the restoration of GATA6-AS1 on EMT in GC involving the Wnt/beta-catenin signaling pathway.	('GATA6-AS1', 'Gene', '100128893', (96, 105))	('GC', 'Phenotype', 'HP:0012126', (116, 118))	('GATA6-AS1', 'Gene', (96, 105))	('restoration', 'Var', (81, 92))
26925	31981860	Furthermore, we demonstrated that overexpressed GATA6-AS1 inhibited GC cell proliferation, invasion, and migration.	('overexpressed', 'Var', (34, 47))	('GATA6-AS1', 'Gene', (48, 57))	('invasion', 'CPA', (91, 99))	('GATA6-AS1', 'Gene', '100128893', (48, 57))	('GC cell proliferation', 'CPA', (68, 89))	('inhibited', 'NegReg', (58, 67))	('GC', 'Phenotype', 'HP:0012126', (68, 70))	('migration', 'CPA', (105, 114))
26934	31981860	The microarray expression dataset related to GC, GEO: GSE13911 and GSE19826, and corresponding annotation files were downloaded from the GEO database (http://www.ncbi.nlm.nih.gov/geo) through detection using the Affymetrix Human Genome U133 Plus 2.0 Array.	('Human', 'Species', '9606', (223, 228))	('GSE19826', 'Var', (67, 75))	('GC', 'Phenotype', 'HP:0012126', (45, 47))	('GSE13911', 'Var', (54, 62))
26948	31981860	The total RNA was extracted from tissues and cells by TRIzol (Invitrogen, Carlsbad, CA, USA), the ratios of A260/A230 and A260/A280 were measured by a NanoDrop 2000 Micro ultraviolet spectrophotometer (1011U, NanoDrop Technologies, Wilmington, DE, USA), and the concentration and purity of total RNA were determined.	('NanoDrop Technologies', 'Disease', (209, 230))	('A260/A280', 'Var', (122, 131))	('NanoDrop Technologies', 'Disease', 'None', (209, 230))	('1011U', 'Chemical', 'MESH:C514226', (202, 207))	('TRIzol', 'Chemical', 'MESH:C411644', (54, 60))	('A260/A230', 'Var', (108, 117))
26951	31981860	The dual-luciferase reporter gene vector of FZD4 (PGLO-FZD4-WT) as well as the mutation of FZD4 and the GATA6-AS1 binding site (PGLO-FZD4-MUT) was constructed.	('PGLO-FZD4-WT', 'Gene', '8322', (50, 62))	('GATA6-AS1', 'Gene', (104, 113))	('PGLO-FZD4-MUT', 'Chemical', 'MESH:C033127', (128, 141))	('GATA6-AS1', 'Gene', '100128893', (104, 113))	('FZD4', 'Gene', (91, 95))	('mutation', 'Var', (79, 87))	('PGLO-FZD4-WT', 'Gene', (50, 62))
26956	31981860	When the density reached 30%-50%, the SGC7901 cells were transfected with overexpressed GATA6-AS1 plasmid, specific antisense oligonucleotide against GATA6-AS1, LiCl (20 mmol/L, activator of the Wnt/beta-catenin signaling pathway), overexpressed GATA6-AS1 + 20 mmol/L LiCl, or NC in accordance with the instructions of Lipofectamine 2000 (11668019, Thermo Fisher Scientific, Waltham, MA, USA).	('GATA6-AS1', 'Gene', '100128893', (150, 159))	('LiCl', 'Chemical', 'MESH:D018021', (161, 165))	('SGC7901', 'CellLine', 'CVCL:0520', (38, 45))	('LiCl', 'Chemical', 'MESH:D018021', (268, 272))	('GATA6-AS1', 'Gene', (246, 255))	('GATA6-AS1', 'Gene', (88, 97))	('GATA6-AS1', 'Gene', (150, 159))	('GC', 'Phenotype', 'HP:0012126', (39, 41))	('antisense oligonucleotide', 'Var', (116, 141))	('GATA6-AS1', 'Gene', '100128893', (246, 255))	('GATA6-AS1', 'Gene', '100128893', (88, 97))
26986	31754222	Numerous studies have shown cancer genesis is accompanied by an accumulation of harmful mutations, potentiating the identification of cancer based on genomic information.	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('mutations', 'Var', (88, 97))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('cancer', 'Disease', (28, 34))
26987	31754222	We analyzed 6,083 samples' WES (Whole Exon Sequencing) mutations files from 12 cancer types obtained from the TCGA (The Cancer Genome Atlas) and 1,991 healthy samples' WES data from the 1000 Genomes project.	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('mutations', 'Var', (55, 64))	('Cancer', 'Phenotype', 'HP:0002664', (120, 126))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))
26994	31754222	It is known that cancer is mainly caused by harmful mutations in proto-oncogenes, tumor suppressor genes and cell cycle regulator genes.	('mutations', 'Var', (52, 61))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('proto-oncogenes', 'Gene', (65, 80))	('cancer', 'Disease', (17, 23))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumor', 'Disease', (82, 87))	('caused', 'Reg', (34, 40))	('proto-oncogenes', 'Protein', (65, 80))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
26996	31754222	In breast cancer, high penetrance mutations in BRCA1 and BRCA2 cause a loss of tumor suppressive function which correlates with an increased risk of breast cancer.	('BRCA1', 'Gene', (47, 52))	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('loss of tumor', 'Disease', 'MESH:D009369', (71, 84))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('BRCA2', 'Gene', (57, 62))	('breast cancer', 'Disease', (3, 16))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('loss of tumor', 'Disease', (71, 84))	('breast cancer', 'Disease', 'MESH:D001943', (149, 162))	('BRCA2', 'Gene', '675', (57, 62))	('breast cancer', 'Phenotype', 'HP:0003002', (149, 162))	('BRCA1', 'Gene', '672', (47, 52))	('breast cancer', 'Disease', (149, 162))	('mutations', 'Var', (34, 43))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
26998	31754222	There are published reports that stomach cancer may be caused by the accumulation PBLB2 and ATM mutations.	('caused by', 'Reg', (55, 64))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('stomach cancer', 'Disease', 'MESH:D013274', (33, 47))	('ATM', 'Gene', (92, 95))	('stomach cancer', 'Phenotype', 'HP:0012126', (33, 47))	('PBLB2', 'Gene', (82, 87))	('accumulation', 'PosReg', (69, 81))	('stomach cancer', 'Disease', (33, 47))	('ATM', 'Gene', '472', (92, 95))	('mutations', 'Var', (96, 105))
27000	31754222	TCGA researchers have identified many mutated genes that are involved in the cell cycle, DNA repair and chromatin modifications in BLCA.	('BLCA', 'Disease', 'MESH:D001749', (131, 135))	('mutated', 'Var', (38, 45))	('BLCA', 'Disease', (131, 135))
27007	31754222	Kun-Hsing identified thousands of objective features from the images, built and evaluated machine learning classifiers to predict the survival outcomes of lung cancer patient.A deep learning model using non-invasive CT images was used to predict EGFR mutation status for patients with lung adenocarcinoma.	('lung adenocarcinoma', 'Disease', (285, 304))	('patient', 'Species', '9606', (167, 174))	('predict', 'Reg', (238, 245))	('mutation', 'Var', (251, 259))	('patient', 'Species', '9606', (271, 278))	('A deep learning', 'Disease', (175, 190))	('carcinoma', 'Phenotype', 'HP:0030731', (295, 304))	('lung cancer', 'Disease', (155, 166))	('lung cancer', 'Phenotype', 'HP:0100526', (155, 166))	('patients', 'Species', '9606', (271, 279))	('A deep learning', 'Disease', 'MESH:D007859', (175, 190))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('EGFR', 'Gene', '1956', (246, 250))	('EGFR', 'Gene', (246, 250))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (285, 304))	('lung cancer', 'Disease', 'MESH:D008175', (155, 166))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (285, 304))
27011	31754222	Even though GWAS is used to identify associations between single nucleotide variations and cancer, GWAS is based on linkage analysis to find the diseased genes and requires more intimate segregate sites.	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('single nucleotide variations', 'Var', (58, 86))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('associations', 'Interaction', (37, 49))
27017	31754222	If the harmful mutations occur in the oncogene or tumor suppressor genes, the normal cells will become cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('mutations', 'Var', (15, 24))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Disease', (50, 55))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('oncogene', 'Gene', (38, 46))
27018	31754222	Changes in multiple genes are required to transform a normal cell into a cancer cell.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('Changes', 'Var', (0, 7))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))
27024	31754222	To reduce the learning pressure brought about by highly redundant dimensions and to reduce the learning difficulty without affecting the accuracy of the model, we selected point mutations closely related to cancer from the TCGA as the dimension for the model.	('cancer', 'Disease', (207, 213))	('cancer', 'Disease', 'MESH:D009369', (207, 213))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('point mutations', 'Var', (172, 187))
27026	31754222	The accumulation of harmful mutations is the root cause of cancer.	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('mutations', 'Var', (28, 37))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))
27028	31754222	The first part is the accumulation of mutations that occur that lead to the cancer, and the second part is the accumulation of mutations that occur after the cancer develops, which is the cause of tumor heterogeneity.	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('lead to', 'Reg', (64, 71))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('cancer', 'Disease', (158, 164))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('mutations', 'Var', (38, 47))	('cancer', 'Disease', (76, 82))	('tumor', 'Disease', (197, 202))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
27029	31754222	Our goal was to determine the rules that gene mutations follow in converting healthy tissues to cancer, which is reflected in the effect of the mutations on the pathways involved.	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('cancer', 'Disease', (96, 102))	('mutations', 'Var', (46, 55))	('cancer', 'Disease', 'MESH:D009369', (96, 102))
27030	31754222	The difference in genetic mutations between patients with the same type of cancer is large because the effect on different pathways is similar.	('patients', 'Species', '9606', (44, 52))	('type of cancer', 'Disease', 'MESH:D009369', (67, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('type of cancer', 'Disease', (67, 81))	('genetic mutations', 'Var', (18, 35))
27034	31754222	Furthermore, variant sites from healthy people and cancer patients were assigned a score ("0" indicates different from Mutation Collection and "1" indicates the same as Mutation Collection) compared to the Mutation Collection.	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('variant', 'Var', (13, 20))	('people', 'Species', '9606', (40, 46))	('patients', 'Species', '9606', (58, 66))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))
27072	31754222	It was further demonstrated that although cancer tissues vary in form, there are large common genomic variations at the molecular level that lead to lower accuracy in the mixture model than in the specific model.	('variations', 'Var', (102, 112))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('accuracy', 'MPA', (155, 163))	('lower', 'NegReg', (149, 154))
27083	31754222	With the implementation of large genome sequencing projects, more and more cancer associated variations especially the ones at low frequency will be identified so that our model will evolve rapidly and become more and more powerful.	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('variations', 'Var', (93, 103))	('cancer', 'Disease', (75, 81))	('cancer', 'Disease', 'MESH:D009369', (75, 81))
27088	31754222	With the development of biology and deep learning, mass high reliability variants and algorithm will create a better model for cancer risk identification.	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('variants', 'Var', (73, 81))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('cancer', 'Disease', (127, 133))
27118	31289486	The Oncomine database (Version 4.5; ) was used to analyze Okayama  and Beer datasets to identify the associations between SCGB1A1 and EGFR mutation status, echinoderm microtubule associated protein-like 4 (EML4) and anaplastic lymphoma kinase (ALK) gene fusion, expression of TP53 and smoking status.	('ALK', 'Gene', '238', (244, 247))	('mutation', 'Var', (139, 147))	('EGFR', 'Gene', (134, 138))	('EML4', 'Gene', (206, 210))	('anaplastic lymphoma kinase', 'Gene', '238', (216, 242))	('TP53', 'Gene', '7157', (276, 280))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (216, 235))	('associations', 'Interaction', (101, 113))	('anaplastic lymphoma kinase', 'Gene', (216, 242))	('SCGB1A1', 'Gene', (122, 129))	('TP53', 'Gene', (276, 280))	('EML4', 'Gene', '27436', (206, 210))	('ALK', 'Gene', (244, 247))	('echinoderm microtubule associated protein-like 4', 'Gene', '27436', (156, 204))	('Oncomine', 'Chemical', '-', (4, 12))	('echinoderm microtubule associated protein-like 4', 'Gene', (156, 204))	('lymphoma', 'Phenotype', 'HP:0002665', (227, 235))	('EGFR', 'Gene', '1956', (134, 138))
27130	31289486	Oncomine analysis of Okayama and Beer datasets revealed that lower mRNA levels of SCGB1A1 were associated with EGFR mutation, EML4-ALK fusion, expression of TP53 and smoking (Fig.	('TP53', 'Gene', (157, 161))	('lower', 'NegReg', (61, 66))	('EGFR', 'Gene', '1956', (111, 115))	('mutation', 'Var', (116, 124))	('EML4', 'Gene', (126, 130))	('mRNA levels', 'MPA', (67, 78))	('ALK', 'Gene', '238', (131, 134))	('EGFR', 'Gene', (111, 115))	('SCGB1A1', 'Gene', (82, 89))	('smoking', 'Disease', (166, 173))	('EML4', 'Gene', '27436', (126, 130))	('Oncomine', 'Chemical', '-', (0, 8))	('TP53', 'Gene', '7157', (157, 161))	('ALK', 'Gene', (131, 134))
27134	31289486	Individualized targeted therapies for lung cancer are being investigated, and progress has been applied to the clinic, including in TP53, EGFR, KRAS proto-oncogene, GTPase, EML4-ALK rearrangement and MET signal transduction targeted therapies.	('lung cancer', 'Disease', (38, 49))	('KRAS', 'Gene', '3845', (144, 148))	('EML4', 'Gene', '27436', (173, 177))	('EGFR', 'Gene', '1956', (138, 142))	('lung cancer', 'Phenotype', 'HP:0100526', (38, 49))	('ALK', 'Gene', (178, 181))	('TP53', 'Gene', '7157', (132, 136))	('TP53', 'Gene', (132, 136))	('rearrangement', 'Var', (182, 195))	('EGFR', 'Gene', (138, 142))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('lung cancer', 'Disease', 'MESH:D008175', (38, 49))	('ALK', 'Gene', '238', (178, 181))	('KRAS', 'Gene', (144, 148))	('EML4', 'Gene', (173, 177))
27143	31289486	SCGB1A1 knockout mice are more susceptible to lung injury (by bacterial or viral infection, ozone and cigarette smoke) or sensitization, exhibit increased inflammation and remodeling reactions, have more frequent lung tumors, and have a stronger T-helper 2-directed immune response compared with control mice.	('inflammation', 'Disease', (155, 167))	('lung tumors', 'Disease', 'MESH:D008175', (213, 224))	('lung injury', 'Disease', 'MESH:D055370', (46, 57))	('lung tumors', 'Phenotype', 'HP:0100526', (213, 224))	('tumors', 'Phenotype', 'HP:0002664', (218, 224))	('knockout', 'Var', (8, 16))	('mice', 'Species', '10090', (304, 308))	('viral infection', 'Disease', (75, 90))	('T-helper 2-directed immune response', 'CPA', (246, 281))	('mice', 'Species', '10090', (17, 21))	('lung tumors', 'Disease', (213, 224))	('increased', 'PosReg', (145, 154))	('lung injury', 'Disease', (46, 57))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('susceptible', 'Reg', (31, 42))	('SCGB1A1', 'Gene', (0, 7))	('viral infection', 'Disease', 'MESH:D001102', (75, 90))	('stronger', 'PosReg', (237, 245))	('inflammation', 'Disease', 'MESH:D007249', (155, 167))
27144	31289486	In the present study, SCGB1A1 was associated with tumor stage, EGFR mutation, ALK gene fusion and smoking history.	('EGFR', 'Gene', '1956', (63, 67))	('associated', 'Reg', (34, 44))	('ALK', 'Gene', (78, 81))	('SCGB1A1', 'Gene', (22, 29))	('mutation', 'Var', (68, 76))	('EGFR', 'Gene', (63, 67))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('ALK', 'Gene', '238', (78, 81))	('tumor', 'Disease', (50, 55))
27146	31289486	Inducing SCGB1A1 expression may inhibit the expression of c-MYC and C-RAF, which may further inhibit the metastasis of tumors.	('inhibit', 'NegReg', (93, 100))	('C-RAF', 'Gene', '5894', (68, 73))	('metastasis of tumors', 'Disease', 'MESH:D009362', (105, 125))	('expression', 'MPA', (44, 54))	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('inhibit', 'NegReg', (32, 39))	('metastasis of tumors', 'Disease', (105, 125))	('SCGB1A1', 'Gene', (9, 16))	('Inducing', 'Var', (0, 8))	('C-RAF', 'Gene', (68, 73))	('c-MYC', 'Gene', '4609', (58, 63))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('c-MYC', 'Gene', (58, 63))
27150	31289486	A previous study has indicated that hypermethylation and decreased expression of TCF21 are tumor-specific and are frequently observed in NSCLC.	('observed', 'Reg', (125, 133))	('TCF21', 'Gene', (81, 86))	('NSCLC', 'Disease', (137, 142))	('NSCLC', 'Disease', 'MESH:D002289', (137, 142))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('hypermethylation', 'Var', (36, 52))	('NSCLC', 'Phenotype', 'HP:0030358', (137, 142))	('TCF21', 'Gene', '6943', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('expression', 'MPA', (67, 77))	('tumor', 'Disease', (91, 96))	('decreased', 'NegReg', (57, 66))
27152	31289486	A2M regulated tumor cell adhesion, migration and growth by inhibiting tumor-promoting signaling pathways, including the phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) pathway and mothers against decapentaplegic homolog (SMAD) and upregulating phosphatase and tensin homolog via downregulation of microRNA-21 in vitro and in tumor xenografts.	('tumor', 'Disease', 'MESH:D009369', (331, 336))	('migration', 'CPA', (35, 44))	('tumor', 'Disease', (14, 19))	('protein kinase B', 'Gene', (146, 162))	('A2M', 'Var', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Phenotype', 'HP:0002664', (331, 336))	('microRNA-21', 'Gene', (303, 314))	('growth', 'CPA', (49, 55))	('upregulating', 'PosReg', (237, 249))	('tumor', 'Disease', (70, 75))	('tumor', 'Disease', (331, 336))	('inhibiting', 'NegReg', (59, 69))	('protein kinase B', 'Gene', '2185', (146, 162))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('downregulation', 'NegReg', (285, 299))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
27158	31289486	When ITGB8 is silenced, the expression of E-cadherin and cystatin B is increased, whereas the expression of C-X-C motif chemokine ligand CXCL1, CXCL2, CXCL5, matrix metalloproteinase (MMP)-2 and MMP-9 is decreased.	('cystatin B', 'Gene', (57, 67))	('MMP-9', 'Gene', '4318', (195, 200))	('MMP-9', 'Gene', (195, 200))	('CXCL2', 'Gene', (144, 149))	('ITGB8', 'Gene', (5, 10))	('E-cadherin', 'Gene', (42, 52))	('E-cadherin', 'Gene', '999', (42, 52))	('cystatin B', 'Gene', '1476', (57, 67))	('CXCL5', 'Gene', (151, 156))	('expression', 'MPA', (94, 104))	('CXCL5', 'Gene', '6374', (151, 156))	('ITGB8', 'Gene', '3696', (5, 10))	('CXCL1', 'Gene', '2919', (137, 142))	('matrix metalloproteinase (MMP)-2', 'Gene', '4313', (158, 190))	('expression', 'MPA', (28, 38))	('silenced', 'Var', (14, 22))	('CXCL2', 'Gene', '2920', (144, 149))	('CXCL1', 'Gene', (137, 142))	('increased', 'PosReg', (71, 80))
27168	31289486	An increased incidence of lung injury and lung tumors was reported following SCGB1A1 knockout.	('lung injury and lung tumors', 'Disease', 'MESH:D055370', (26, 53))	('lung tumors', 'Phenotype', 'HP:0100526', (42, 53))	('SCGB1A1', 'Gene', (77, 84))	('knockout', 'Var', (85, 93))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))
27170	31289486	Transcriptome analysis of A2M-treated tumor cells, xenografts and mouse liver revealed that A2M modulates tumor cell adhesion, migration and proliferation by inhibiting tumor-promoting signaling pathways, such as PI3K/AKT and SMAD, and by upregulating PTEN via downregulation of miR-21 in vitro and in tumor xenografts.	('tumor', 'Phenotype', 'HP:0002664', (302, 307))	('modulates', 'Reg', (96, 105))	('PTEN', 'Gene', (252, 256))	('downregulation', 'NegReg', (261, 275))	('migration', 'CPA', (127, 136))	('tumor', 'Disease', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('proliferation', 'CPA', (141, 154))	('tumor', 'Disease', (169, 174))	('A2M', 'Var', (92, 95))	('upregulating', 'PosReg', (239, 251))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('tumor', 'Disease', (302, 307))	('PTEN', 'Gene', '19211', (252, 256))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Disease', 'MESH:D009369', (302, 307))	('tumor', 'Disease', (38, 43))	('inhibiting', 'NegReg', (158, 168))	('mouse', 'Species', '10090', (66, 71))	('miR-21', 'Gene', (279, 285))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('SMAD', 'Pathway', (226, 230))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('PI3K/AKT', 'Pathway', (213, 221))	('miR-21', 'Gene', '387140', (279, 285))
27231	29937653	(2008) noticed positive correlation between Oct-4, Nanog and high expression of CD133 with poor prognosis outcome in patients of oral cancer.	('CD133', 'Chemical', '-', (80, 85))	('oral cancer', 'Disease', (129, 140))	('Nanog', 'Gene', (51, 56))	('high', 'Var', (61, 65))	('CD133', 'Gene', (80, 85))	('Oct', 'Chemical', 'MESH:C051883', (44, 47))	('patients', 'Species', '9606', (117, 125))	('Nanog', 'Gene', '79923', (51, 56))	('oral cancer', 'Disease', 'MESH:D009062', (129, 140))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
27245	29937653	These findings suggest that CD133 might represent a useful prognostic indicator with respect to clinical stage of OSCC patients, while Oct-4 findings are less conclusive.	('OSCC', 'Disease', (114, 118))	('Oct', 'Chemical', 'MESH:C051883', (135, 138))	('patients', 'Species', '9606', (119, 127))	('est', 'Gene', '1326', (19, 22))	('CD133', 'Var', (28, 33))	('CD133', 'Chemical', '-', (28, 33))	('est', 'Gene', (19, 22))
27265	25643909	These tumors are characterized by near-universal loss of TP53 and CKDN2A/RB1 by truncating mutation, deletion and/or alternative splicing.	('alternative splicing', 'Var', (117, 137))	('deletion', 'Var', (101, 109))	('truncating', 'MPA', (80, 90))	('loss', 'NegReg', (49, 53))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('tumors', 'Disease', (6, 12))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('CKDN2A/RB1', 'Gene', (66, 76))	('CKDN2A/RB1', 'Gene', '5925', (66, 76))	('TP53', 'Gene', '7157', (57, 61))	('TP53', 'Gene', (57, 61))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))
27267	25643909	Of note, HPV-negative HNSCCs most closely resemble lung squamous cell carcinomas in terms of their spectra of genomic alterations and contain statistically enriched mutations and copy number alterations in genes regulating many of the same pathways in addition to widespread loss of both TP53 and CDKN2A/RB1.	('CDKN2A', 'Gene', (297, 303))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (56, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('copy number alterations', 'Var', (179, 202))	('carcinomas', 'Phenotype', 'HP:0030731', (70, 80))	('CDKN2A', 'Gene', '1029', (297, 303))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (51, 79))	('lung squamous cell carcinomas', 'Disease', 'MESH:D002294', (51, 80))	('HPV', 'Species', '10566', (9, 12))	('TP53', 'Gene', '7157', (288, 292))	('HNSCC', 'Phenotype', 'HP:0012288', (22, 27))	('mutations', 'Var', (165, 174))	('TP53', 'Gene', (288, 292))	('lung squamous cell carcinomas', 'Disease', (51, 80))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (56, 80))
27269	25643909	While twenty percent of HPV-negative HNSCCs in the TCGA cohort displayed amplifications of Receptor Tyrosine Kinase (RTK) genes such as EGFR, ERBB2, MET and FGFR1, there were no recurrent mutations or fusions in RTK genes which have been associated with dramatic responses to small molecule kinase inhibitors in other tumor types such as lung adenocarcinoma.	('RTK', 'Gene', (117, 120))	('lung adenocarcinoma', 'Disease', (338, 357))	('HPV', 'Species', '10566', (24, 27))	('FGFR1', 'Gene', (157, 162))	('tumor', 'Disease', 'MESH:D009369', (318, 323))	('FGFR1', 'Gene', '2260', (157, 162))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (338, 357))	('carcinoma', 'Phenotype', 'HP:0030731', (348, 357))	('MET', 'Gene', (149, 152))	('HNSCC', 'Phenotype', 'HP:0012288', (37, 42))	('amplifications', 'Var', (73, 87))	('tumor', 'Phenotype', 'HP:0002664', (318, 323))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (338, 357))	('tumor', 'Disease', (318, 323))	('ERBB2', 'Gene', (142, 147))	('EGFR', 'Gene', '1956', (136, 140))	('EGFR', 'Gene', (136, 140))
27271	25643909	Mutually exclusive mutations in RAS family genes, notably RHOA, KRAS and HRAS, are present but infrequently found in HNSCC (6% of TCGA cases), though recurrent mutations in RHOA at amino acid position 40 are worth noting; however, the biological significance of these RHOA mutations is unclear.	('HNSCC', 'Phenotype', 'HP:0012288', (117, 122))	('HRAS', 'Gene', '3265', (73, 77))	('mutations', 'Var', (160, 169))	('RHOA', 'Gene', (58, 62))	('RHOA', 'Gene', (268, 272))	('HRAS', 'Gene', (73, 77))	('RHOA', 'Gene', '387', (173, 177))	('KRAS', 'Gene', (64, 68))	('RAS family genes', 'Gene', (32, 48))	('RHOA', 'Gene', (173, 177))	('RHOA', 'Gene', '387', (268, 272))	('KRAS', 'Gene', '3845', (64, 68))	('RHOA', 'Gene', '387', (58, 62))
27272	25643909	Amplification of chromosome 3q, a region containing the TP63, SOX2 and PIK3CA genes, is seen in the majority of both HPV-negative and HPV-positive HNSCCs and PIK3CA mutations are commonly found in both HPV-negative and HPV-positive disease, in agreement with prior studies.	('TP63', 'Gene', (56, 60))	('HPV', 'Species', '10566', (219, 222))	('HPV', 'Species', '10566', (202, 205))	('PIK3CA', 'Gene', '5290', (71, 77))	('SOX2', 'Gene', (62, 66))	('HPV-positive HNSCCs', 'Disease', (134, 153))	('PIK3CA', 'Gene', (158, 164))	('TP63', 'Gene', '8626', (56, 60))	('HNSCC', 'Phenotype', 'HP:0012288', (147, 152))	('HPV', 'Species', '10566', (117, 120))	('PIK3CA', 'Gene', '5290', (158, 164))	('HPV-positive HNSCCs', 'Disease', 'MESH:D000077195', (134, 153))	('HPV-positive disease', 'Disease', (219, 239))	('mutations', 'Var', (165, 174))	('HPV-positive disease', 'Disease', 'MESH:D030361', (219, 239))	('HPV', 'Species', '10566', (134, 137))	('PIK3CA', 'Gene', (71, 77))
27278	25643909	An intriguing mutational pattern identified by TCGA was a subset of HPV-negative HNSCCs originating in the oral cavity with few to no copy number alterations was statistically enriched for HRAS, CASP8 and PIK3CA mutations and lack of TP53 mutation (TCGA Network, Nature, in press).	('PIK3CA', 'Gene', (205, 211))	('HRAS', 'Gene', '3265', (189, 193))	('TP53', 'Gene', '7157', (234, 238))	('TP53', 'Gene', (234, 238))	('PIK3CA', 'Gene', '5290', (205, 211))	('CASP8', 'Gene', '841', (195, 200))	('HRAS', 'Gene', (189, 193))	('CASP8', 'Gene', (195, 200))	('HNSCC', 'Phenotype', 'HP:0012288', (81, 86))	('mutations', 'Var', (212, 221))	('HPV', 'Species', '10566', (68, 71))
27283	25643909	This possibility is supported by the prevalence of both the virally associated Tp*Cp(A/C/T) substitution mutation in the HPV-positive individuals as well as CpG transversions, a mutation class typically associated with smoking.	('Tp*', 'Var', (79, 82))	('HPV', 'Species', '10566', (121, 124))	('CpG transversions', 'Var', (157, 174))	('substitution mutation', 'Var', (92, 113))
27285	25643909	HPV-driven HNSCCs are distinct from HPV-negative disease in that they lack focal RTK amplifications but do display a higher rate of focal PIK3CA amplification and mutation.	('HNSCC', 'Phenotype', 'HP:0012288', (11, 16))	('HNSCCs', 'Disease', (11, 17))	('HPV', 'Species', '10566', (0, 3))	('HPV', 'Species', '10566', (36, 39))	('PIK3CA', 'Gene', (138, 144))	('mutation', 'Var', (163, 171))	('amplification', 'MPA', (145, 158))	('PIK3CA', 'Gene', '5290', (138, 144))
27286	25643909	PIK3CA alterations have been reported as therapeutic biomarkers in this patient population based on cell line and patient-derived xenograft studies.	('PIK3CA', 'Gene', (0, 6))	('patient', 'Species', '9606', (72, 79))	('PIK3CA', 'Gene', '5290', (0, 6))	('patient', 'Species', '9606', (114, 121))	('alterations', 'Var', (7, 18))
27287	25643909	HPV-associated HNSCCs also demonstrate enrichment for copy number gains in TRAF3 and E2F1 and a lack of CCND1 amplification when compared with HPV-negative disease.	('HPV-associated HNSCCs', 'Disease', (0, 21))	('HPV', 'Species', '10566', (143, 146))	('gains', 'PosReg', (66, 71))	('CCND1', 'Gene', (104, 109))	('HPV', 'Species', '10566', (0, 3))	('copy number', 'Var', (54, 65))	('TRAF3', 'Gene', (75, 80))	('CCND1', 'Gene', '595', (104, 109))	('HNSCC', 'Phenotype', 'HP:0012288', (15, 20))	('HNSCCs', 'Disease', (15, 21))	('E2F1', 'Gene', (85, 89))	('TRAF3', 'Gene', '7187', (75, 80))
27288	25643909	HPV-driven cancers display both mutations and fusions in the FGFR3 gene with mutations at position 249 reported at 14% in one study of 50 cases of locoregionally advanced disease and FGFR3-TACC3 fusions have been reported in multiple cases by TCGA and other groups.	('TACC3', 'Gene', '10460', (189, 194))	('HPV-driven cancers', 'Disease', (0, 18))	('FGFR3', 'Gene', (61, 66))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('TACC3', 'Gene', (189, 194))	('fusions', 'Var', (46, 53))	('FGFR3', 'Gene', '2261', (183, 188))	('mutations', 'Var', (32, 41))	('HPV-driven cancers', 'Disease', 'MESH:D030361', (0, 18))	('cancers', 'Phenotype', 'HP:0002664', (11, 18))	('FGFR3', 'Gene', '2261', (61, 66))	('FGFR3', 'Gene', (183, 188))
27289	25643909	These two FGFR3 alterations have been associated with therapeutic response to FGFR small molecule inhibitors in pre-clinical and clinical studies TCGA did not detect any genes displaying statistical enrichment for mutation in HPV-positive individuals as compared to HPV-negative though B2M truncating mutations most closely approached significance.	('FGFR3', 'Gene', '2261', (10, 15))	('associated', 'Reg', (38, 48))	('alterations', 'Var', (16, 27))	('FGFR3', 'Gene', (10, 15))	('HPV', 'Species', '10566', (266, 269))	('HPV', 'Species', '10566', (226, 229))
27295	25643909	HPV integration can have a profound impact on local gene structure and function and result in high-level amplifications, gene disruptions, alternative splicing, novel gene fusions and changes in global promoter methylation and transcription.	('function', 'MPA', (71, 79))	('integration', 'Var', (4, 15))	('changes', 'Reg', (184, 191))	('HPV', 'Species', '10566', (0, 3))	('alternative splicing', 'Var', (139, 159))	('impact', 'Reg', (36, 42))	('local', 'MPA', (46, 51))	('global promoter methylation', 'MPA', (195, 222))	('transcription', 'MPA', (227, 240))	('amplifications', 'MPA', (105, 119))	('gene disruptions', 'Var', (121, 137))
27296	25643909	An intriguing finding in the field of HPV integration is recurrent disruptive integration in the RAD51 gene, perhaps facilitating further HPV integration by hindering DNA repair.	('DNA repair', 'MPA', (167, 177))	('HPV', 'Species', '10566', (138, 141))	('HPV', 'Species', '10566', (38, 41))	('RAD51', 'Gene', (97, 102))	('disruptive integration', 'Var', (67, 89))	('hindering', 'NegReg', (157, 166))
27308	25643909	Prior to the TCGA and other recent studies, earlier reports noted the prevalence of a number of genomic alterations in HNSCCs, which are associated with therapeutic response to targeted agents in other cancers types.	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('HNSCC', 'Phenotype', 'HP:0012288', (119, 124))	('genomic alterations', 'Var', (96, 115))	('HNSCCs', 'Gene', (119, 125))	('cancers', 'Phenotype', 'HP:0002664', (202, 209))	('cancers', 'Disease', (202, 209))	('cancers', 'Disease', 'MESH:D009369', (202, 209))
27309	25643909	These include EGFR mutations and ALK and ROS1 fusions.	('EGFR', 'Gene', '1956', (14, 18))	('ALK', 'Gene', (33, 36))	('EGFR', 'Gene', (14, 18))	('fusions', 'Var', (46, 53))	('ROS1', 'Gene', (41, 45))	('mutations', 'Var', (19, 28))	('ROS1', 'Gene', '6098', (41, 45))	('ALK', 'Gene', '238', (33, 36))
27311	25643909	FGFRs have been shown to be activated by amplification, mutation and translocation in a wide range of cancer types.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('translocation', 'Var', (69, 82))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('activated', 'PosReg', (28, 37))	('amplification', 'Var', (41, 54))	('mutation', 'Var', (56, 64))	('FGFRs', 'Gene', (0, 5))
27312	25643909	In HNSCC FGFR1 amplifications are found in HPV-negative patients at a rate of approximately 10% and appear to be enriched in non-oropharynx tumors.	('patients', 'Species', '9606', (56, 64))	('HNSCC', 'Phenotype', 'HP:0012288', (3, 8))	('FGFR1', 'Gene', '2260', (9, 14))	('tumors', 'Disease', (140, 146))	('tumors', 'Disease', 'MESH:D009369', (140, 146))	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('amplifications', 'Var', (15, 29))	('HPV', 'Species', '10566', (43, 46))	('FGFR1', 'Gene', (9, 14))	('oropharynx tumors', 'Phenotype', 'HP:0100638', (129, 146))
27313	25643909	FGFR1 amplification has been associated with therapeutic response to FGFR TKIs in lung squamous cell cancers, though response rates represent only a modest improvement as compared to chemotherapy.	('cancers', 'Phenotype', 'HP:0002664', (101, 108))	('lung squamous cell cancers', 'Disease', 'MESH:D002294', (82, 108))	('squamous cell cancers', 'Phenotype', 'HP:0002860', (87, 108))	('FGFR', 'Gene', (69, 73))	('FGFR1', 'Gene', (0, 5))	('FGFR1', 'Gene', '2260', (0, 5))	('lung squamous cell cancers', 'Disease', (82, 108))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('associated', 'Reg', (29, 39))	('amplification', 'Var', (6, 19))
27314	25643909	Multiple explanations for this disappointing result have been reported including the presence of co-mutations activating the RAS/MAPK pathway, a lack of correlation with FGFR1 amplification and expression or activation of the protein and difficulty in standardizing assays for detection of amplification by FISH or NGS methods.	('FGFR1', 'Gene', '2260', (170, 175))	('RAS/MAPK pathway', 'Pathway', (125, 141))	('activating', 'PosReg', (110, 120))	('activation', 'MPA', (208, 218))	('FGFR1', 'Gene', (170, 175))	('co-mutations', 'Var', (97, 109))
27315	25643909	Several early-phase clinical trials are ongoing or planned in HNSCC patients with FGFR1 amplifications who have relapsed/refractory HNSCC (eg.	('HNSCC', 'Phenotype', 'HP:0012288', (62, 67))	('FGFR1', 'Gene', (82, 87))	('HNSCC', 'Disease', (62, 67))	('FGFR1', 'Gene', '2260', (82, 87))	('HNSCC', 'Disease', (132, 137))	('patients', 'Species', '9606', (68, 76))	('HNSCC', 'Phenotype', 'HP:0012288', (132, 137))	('amplifications', 'Var', (88, 102))
27316	25643909	Given that FGFR inhibitors appear to be well-tolerated and may also be radiosensitizers, the combination of these agents in the curative treatment setting with the current standard of care may be reasonable in high-risk HPV-negative patients.	('inhibitors', 'Var', (16, 26))	('HPV', 'Species', '10566', (220, 223))	('FGFR', 'Gene', (11, 15))	('patients', 'Species', '9606', (233, 241))
27317	25643909	FGFR2 and FGFR3 mutations and FGFR3-TACC3 fusions are of particular interest as these genetic lesions have been associated with dramatic responses to FGFR TKIs in pre-clinical models and in early phase clinical settings including a case report of a dramatic response to pazopanib in a patient with a FGFR2 mutated tongue cancer.	('TACC3', 'Gene', (36, 41))	('FGFR3', 'Gene', '2261', (10, 15))	('FGFR2', 'Gene', (300, 305))	('FGFR2', 'Gene', '2263', (300, 305))	('mutated', 'Var', (306, 313))	('FGFR3', 'Gene', (30, 35))	('mutations', 'Var', (16, 25))	('cancer', 'Phenotype', 'HP:0002664', (321, 327))	('FGFR3', 'Gene', (10, 15))	('patient', 'Species', '9606', (285, 292))	('pazopanib', 'Chemical', 'MESH:C516667', (270, 279))	('tongue cancer', 'Disease', (314, 327))	('FGFR2', 'Gene', (0, 5))	('TACC3', 'Gene', '10460', (36, 41))	('tongue cancer', 'Disease', 'MESH:D014062', (314, 327))	('FGFR2', 'Gene', '2263', (0, 5))	('FGFR3', 'Gene', '2261', (30, 35))
27318	25643909	In contrast to FGFR1 amplification, FGFR2/3 mutations and FGFR3 fusions appear to occur largely in HPV-positive individuals at a prevalence of 10-20% and clinical trials are currently targeting this patient population.	('FGFR1', 'Gene', '2260', (15, 20))	('FGFR3', 'Gene', '2261', (58, 63))	('fusions', 'Var', (64, 71))	('HPV-positive', 'Gene', (99, 111))	('patient', 'Species', '9606', (199, 206))	('FGFR3', 'Gene', (58, 63))	('FGFR2', 'Gene', '2263', (36, 41))	('mutations', 'Var', (44, 53))	('FGFR2', 'Gene', (36, 41))	('HPV', 'Species', '10566', (99, 102))	('FGFR1', 'Gene', (15, 20))
27320	25643909	PIK3CA is commonly amplified and/or mutated in patients with HNSCCs (37% of cases in TCGA), and PIK3CA alterations are enriched in HPV-positive patients.	('patients', 'Species', '9606', (47, 55))	('PIK3CA', 'Gene', (0, 6))	('mutated', 'Var', (36, 43))	('patients', 'Species', '9606', (144, 152))	('PIK3CA', 'Gene', (96, 102))	('HPV', 'Species', '10566', (131, 134))	('PIK3CA', 'Gene', '5290', (0, 6))	('HNSCCs', 'Disease', (61, 67))	('PIK3CA', 'Gene', '5290', (96, 102))	('HNSCC', 'Phenotype', 'HP:0012288', (61, 66))
27322	25643909	As such, there is tremendous interest in developing small molecule inhibitors of components of this pathway for individuals with HNSCC and ample pre-clinical data suggest that this may be an effective therapeutic strategy, though it should be noted that the activity of PI3K inhibitors as monotherapy in lung squamous cell cancers in patients with PIK3CA or PTEN mutations has been disappointing.	('PIK3CA', 'Gene', '5290', (348, 354))	('lung squamous cell cancers', 'Disease', 'MESH:D002294', (304, 330))	('PTEN', 'Gene', (358, 362))	('squamous cell cancers', 'Phenotype', 'HP:0002860', (309, 330))	('PTEN', 'Gene', '5728', (358, 362))	('HNSCC', 'Phenotype', 'HP:0012288', (129, 134))	('mutations', 'Var', (363, 372))	('lung squamous cell cancers', 'Disease', (304, 330))	('cancer', 'Phenotype', 'HP:0002664', (323, 329))	('PIK3CA', 'Gene', (348, 354))	('patients', 'Species', '9606', (334, 342))	('cancers', 'Phenotype', 'HP:0002664', (323, 330))
27323	25643909	Clinical concepts moving forward include both recruiting patients with relapsed/refractory disease with PI3K pathway lesions as well as using these agents in "window of opportunity" trials in the up-front setting or in combination with chemoradiotherapy (eg, NCT01816984, NCT01195922, NCT01852292, NCT01133678).	('NCT01852292', 'Var', (285, 296))	('NCT01816984', 'Var', (259, 270))	('patients', 'Species', '9606', (57, 65))	('NCT01195922', 'Var', (272, 283))	('relapsed/refractory disease', 'Disease', (71, 98))	('PI3K', 'Gene', (104, 108))	('lesions', 'Var', (117, 124))	('NCT01133678', 'Var', (298, 309))
27324	25643909	Pre-clinical data have shown that inhibition of the PI3K pathway may sensitize cancer cells to radiation and that PI3K inhibitors may be most efficacious as radiosensitizers in patients with NFE2L2 or KEAP1 mutations, genomic events commonly seen in high-risk HPV-negative individuals.	('NFE2L2', 'Gene', (191, 197))	('PI3K pathway', 'Pathway', (52, 64))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('patients', 'Species', '9606', (177, 185))	('KEAP1', 'Gene', (201, 206))	('KEAP1', 'Gene', '9817', (201, 206))	('mutations', 'Var', (207, 216))	('HPV', 'Species', '10566', (260, 263))	('NFE2L2', 'Gene', '4780', (191, 197))	('sensitize', 'Reg', (69, 78))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))
27325	25643909	In the TCGA study 32% of HNSCCs displayed an amplification or mutation of CCDN1, CDK4 or CDK6 with the majority of these alternations found in HPV-negative patients.	('patients', 'Species', '9606', (156, 164))	('HPV', 'Species', '10566', (143, 146))	('HNSCC', 'Phenotype', 'HP:0012288', (25, 30))	('CDK6', 'Gene', (89, 93))	('CDK4', 'Gene', (81, 85))	('CDK6', 'Gene', '1021', (89, 93))	('mutation', 'Var', (62, 70))	('amplification', 'MPA', (45, 58))	('CDK4', 'Gene', '1019', (81, 85))	('CCDN1', 'Gene', (74, 79))
27327	25643909	However, impressive early clinical data in breast cancer have suggested that CDK4/6 inhibitors may be effective in patient cohorts with high rates of CCND1 amplification and that these agents are well-tolerated as both single agents and in combination with other therapies.	('breast cancer', 'Disease', (43, 56))	('amplification', 'Var', (156, 169))	('breast cancer', 'Phenotype', 'HP:0003002', (43, 56))	('CDK4/6', 'Gene', (77, 83))	('CCND1', 'Gene', (150, 155))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('patient', 'Species', '9606', (115, 122))	('breast cancer', 'Disease', 'MESH:D001943', (43, 56))	('CCND1', 'Gene', '595', (150, 155))	('CDK4/6', 'Gene', '1019;1021', (77, 83))
27328	25643909	Clinical trials are moving forward at this time in other cancer types with frequent alterations of CCND1/CDK4/CDK6 and a subset of these trials will include patients with relapsed/refractory HNSCC (NCT02101034).	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('NCT02101034', 'Var', (198, 209))	('CDK4', 'Gene', (105, 109))	('cancer', 'Disease', (57, 63))	('CDK4', 'Gene', '1019', (105, 109))	('patients', 'Species', '9606', (157, 165))	('CDK6', 'Gene', (110, 114))	('CCND1', 'Gene', (99, 104))	('HNSCC', 'Phenotype', 'HP:0012288', (191, 196))	('CDK6', 'Gene', '1021', (110, 114))	('alterations', 'Var', (84, 95))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('CCND1', 'Gene', '595', (99, 104))	('relapsed/refractory HNSCC', 'Disease', (171, 196))
27329	25643909	Many HPV-negative patients with CCND1/CDK4/CDK6 amplifications also harbor RTK amplifications, suggesting that combination strategies may be needed in this setting.	('CDK6', 'Gene', (43, 47))	('CDK6', 'Gene', '1021', (43, 47))	('CCND1', 'Gene', (32, 37))	('amplifications', 'Var', (48, 62))	('RTK amplifications', 'MPA', (75, 93))	('CCND1', 'Gene', '595', (32, 37))	('patients', 'Species', '9606', (18, 26))	('HPV', 'Species', '10566', (5, 8))	('CDK4', 'Gene', '1019', (38, 42))	('CDK4', 'Gene', (38, 42))
27332	25643909	NCT01860430, NCT01935921) with promising data presented recently with pembrolizumab in relapsed/refractory disease.	('pembrolizumab', 'Chemical', 'MESH:C582435', (70, 83))	('NCT01860430', 'Var', (0, 11))	('relapsed/refractory disease', 'Disease', (87, 114))	('NCT01935921', 'Var', (13, 24))
27337	25643909	While the mechanisms governing immune evasion in HNSCCs remain poorly understood it is likely that somatic alterations in these and other genes are likely to play a key role in immune surveillance of HNSCCs and may impact the responsiveness of cancers to specific immunotherapeutic approaches.	('HNSCC', 'Phenotype', 'HP:0012288', (49, 54))	('impact', 'Reg', (215, 221))	('alterations', 'Var', (107, 118))	('role', 'Reg', (169, 173))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('HNSCC', 'Phenotype', 'HP:0012288', (200, 205))	('play', 'Reg', (158, 162))	('responsiveness', 'CPA', (226, 240))	('cancers', 'Disease', 'MESH:D009369', (244, 251))	('cancers', 'Disease', (244, 251))	('cancers', 'Phenotype', 'HP:0002664', (244, 251))
27340	25643909	HNSCCs display frequent degregulation of pro- and anti-apoptotic genes such as CASP8 and cell line studies have suggested that inhibitors of BCL2 family proteins may demonstrate activity against HNSCCs.	('CASP8', 'Gene', '841', (79, 84))	('CASP8', 'Gene', (79, 84))	('HNSCC', 'Phenotype', 'HP:0012288', (0, 5))	('BCL2', 'Protein', (141, 145))	('inhibitors', 'Var', (127, 137))	('HNSCCs', 'Disease', (195, 201))	('activity', 'MPA', (178, 186))	('HNSCC', 'Phenotype', 'HP:0012288', (195, 200))	('degregulation', 'MPA', (24, 37))
27361	25156441	Among the candidate targets, we validated HECW2 (HECT domain ligase W2) and S100PBP (S100P binding protein) as direct targets of miR-944 using luciferase reporter assays and western blot analysis.	('S100PBP', 'Gene', (76, 83))	('S100PBP', 'Gene', '64766', (76, 83))	('miR-944', 'Gene', '100126340', (129, 136))	('S100P', 'Var', (76, 81))	('S100P', 'SUBSTITUTION', 'None', (85, 90))	('HECW2', 'Gene', (42, 47))	('S100P', 'SUBSTITUTION', 'None', (76, 81))	('miR-944', 'Gene', (129, 136))	('HECW2', 'Gene', '57520', (42, 47))	('S100P', 'Var', (85, 90))
27389	25156441	Predesigned TaqMan assays for miR-944 (ID 002189), TP63 (ID Hs00978340_m1), RNU6B (ID 001093) and 18S (ID Hs99999901_s1) were purchased from Applied Biosystems.	('RNU6B', 'Gene', (76, 81))	('ID 001093', 'Var', (83, 92))	('ID Hs99999901_s1', 'Var', (103, 119))	('miR-944', 'Gene', '100126340', (30, 37))	('ID Hs00978340_m1', 'Var', (57, 73))	('miR-944', 'Gene', (30, 37))	('TP63', 'Gene', '8626', (51, 55))	('TP63', 'Gene', (51, 55))	('RNU6B', 'Gene', '26826', (76, 81))	('ID 002189', 'Var', (39, 48))
27393	25156441	For gain-of-function experiments, HeLa, CaSki and SW756 cells were transfected with 10 nM Pre-miR  miR-944 precursor (ID PM12272) or Pre-miR Negative control #1 (ID AM17110).	('SW756', 'CellLine', 'CVCL:1727', (50, 55))	('CaSki', 'CellLine', 'CVCL:1100', (40, 45))	('miR', 'Gene', '220972', (99, 102))	('miR', 'Gene', (99, 102))	('miR', 'Gene', '220972', (137, 140))	('miR', 'Gene', (137, 140))	('miR-944', 'Gene', '100126340', (99, 106))	('miR', 'Gene', '220972', (94, 97))	('miR-944', 'Gene', (99, 106))	('ID PM12272', 'Var', (118, 128))	('miR', 'Gene', (94, 97))	('HeLa', 'CellLine', 'CVCL:0030', (34, 38))
27394	25156441	For loss-of-function experiments, CaSki cells were transfected with 50 nM of Anti-miR  miR-944 inhibitor (ID AM12272) or Anti-miR Negative control #1 (ID AM17010) in parallel.	('miR', 'Gene', '220972', (82, 85))	('miR-944', 'Gene', (87, 94))	('miR', 'Gene', (82, 85))	('ID AM17010', 'Var', (151, 161))	('loss-of-function', 'NegReg', (4, 20))	('miR', 'Gene', '220972', (126, 129))	('miR', 'Gene', (126, 129))	('CaSki', 'CellLine', 'CVCL:1100', (34, 39))	('ID AM12272', 'Var', (106, 116))	('miR', 'Gene', '220972', (87, 90))	('miR', 'Gene', (87, 90))	('miR-944', 'Gene', '100126340', (87, 94))
27466	25156441	In addition, we also measured the effect of miR-944 deregulation on cell proliferation in real-time using the xCELLigence system.	('miR-944', 'Gene', '100126340', (44, 51))	('cell proliferation', 'CPA', (68, 86))	('deregulation', 'Var', (52, 64))	('miR-944', 'Gene', (44, 51))
27472	25156441	Similar results were observed using the transwell cell migration assay, in which cell migration was significantly enhanced in miR-944 overexpressing HeLa (~24%; p = 0.005; Fig.	('transwell cell migration assay', 'CPA', (40, 70))	('HeLa', 'CellLine', 'CVCL:0030', (149, 153))	('overexpressing', 'Var', (134, 148))	('miR-944', 'Gene', '100126340', (126, 133))	('enhanced', 'PosReg', (114, 122))	('cell migration', 'CPA', (81, 95))	('miR-944', 'Gene', (126, 133))
27478	25156441	We did not observe any significant effect in HeLa cells upon miR-944 overexpression or in CaSki cells upon miR-944 overexpression or suppression (Supporting Information Fig.	('overexpression', 'Var', (69, 83))	('miR-944', 'Gene', (107, 114))	('miR-944', 'Gene', '100126340', (61, 68))	('miR-944', 'Gene', (61, 68))	('CaSki', 'CellLine', 'CVCL:1100', (90, 95))	('HeLa', 'CellLine', 'CVCL:0030', (45, 49))	('miR-944', 'Gene', '100126340', (107, 114))
27480	25156441	For cell invasion, we applied the transwell invasion assays to evaluate cell invasion capacity of HeLa and CaSki cells upon modulation of miR-944 expression levels.	('miR-944', 'Gene', (138, 145))	('cell invasion capacity', 'CPA', (72, 94))	('HeLa', 'CellLine', 'CVCL:0030', (98, 102))	('modulation', 'Var', (124, 134))	('CaSki', 'CellLine', 'CVCL:1100', (107, 112))	('miR-944', 'Gene', '100126340', (138, 145))
27493	25156441	We found 58 transcripts (in 64 clusters) present in the miR-944 overexpressing cells and only two of them (i.e., CRYAB and RRBP1) were also present in the control group.	('CRYAB', 'Gene', '1410', (113, 118))	('miR-944', 'Gene', (56, 63))	('overexpressing', 'Var', (64, 78))	('RRBP1', 'Gene', (123, 128))	('RRBP1', 'Gene', '6238', (123, 128))	('CRYAB', 'Gene', (113, 118))	('miR-944', 'Gene', '100126340', (56, 63))
27499	25156441	We constructed the wild-type and mutated (four mismatches in the seed region) putative miR-944 binding sites in the 3'UTR of HECW2 and S100PBP (Figs.	('miR-944', 'Gene', (87, 94))	('S100PBP', 'Gene', (135, 142))	('mutated', 'Var', (33, 40))	('S100PBP', 'Gene', '64766', (135, 142))	('HECW2', 'Gene', (125, 130))	('binding', 'Interaction', (95, 102))	('miR-944', 'Gene', '100126340', (87, 94))	('HECW2', 'Gene', '57520', (125, 130))
27507	25156441	High expression of miR-944 is also associated with tumor recurrence in colorectal cancer, and poor chemotherapy response and survival in bladder cancer.	('colorectal cancer', 'Disease', (71, 88))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('High', 'Var', (0, 4))	('bladder cancer', 'Phenotype', 'HP:0009725', (137, 151))	('miR-944', 'Gene', '100126340', (19, 26))	('tumor', 'Disease', (51, 56))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('associated with', 'Reg', (35, 50))	('bladder cancer', 'Disease', 'MESH:D001749', (137, 151))	('colorectal cancer', 'Disease', 'MESH:D015179', (71, 88))	('survival', 'CPA', (125, 133))	('miR-944', 'Gene', (19, 26))	('colorectal cancer', 'Phenotype', 'HP:0003003', (71, 88))	('bladder cancer', 'Disease', (137, 151))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
27531	25156441	reported that HECW2 is involved in degradation of ATR kinase in HeLa cells with lamin mutants or lamin silenced HeLa cells.	('mutants', 'Var', (86, 93))	('degradation', 'MPA', (35, 46))	('ATR kinase', 'MPA', (50, 60))	('HeLa', 'CellLine', 'CVCL:0030', (64, 68))	('HeLa', 'CellLine', 'CVCL:0030', (112, 116))	('HECW2', 'Gene', (14, 19))	('lamin', 'Gene', (97, 102))	('lamin', 'Gene', (80, 85))	('HECW2', 'Gene', '57520', (14, 19))	('lamin', 'Gene', '4000', (80, 85))	('lamin', 'Gene', '4000', (97, 102))
27771	27076841	Furthermore, p16INK4A positivity has been detected in 16.4 % of HPV-positive patients with ESCC, which is lower than previously published data reporting a range of prevalence between 20 % and 86.2 % .	('SCC', 'Phenotype', 'HP:0002860', (92, 95))	('ESCC', 'Disease', (91, 95))	('p16INK4A', 'Gene', (13, 21))	('HPV-positive', 'Gene', (64, 76))	('p16INK4A', 'Gene', '1029', (13, 21))	('patients', 'Species', '9606', (77, 85))	('positivity', 'Var', (22, 32))	('HPV', 'Species', '10566', (64, 67))	('detected', 'Reg', (42, 50))
27781	27076841	Rb1 alterations and subsequent p16 INK4A overexpression have also been described in non-HPV-driven tumors [.	('INK4A', 'Gene', '1029', (35, 40))	('p16', 'Gene', '1029', (31, 34))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))	('alterations', 'Var', (4, 15))	('tumors', 'Disease', 'MESH:D009369', (99, 105))	('INK4A', 'Gene', (35, 40))	('p16', 'Gene', (31, 34))	('HPV', 'Species', '10566', (88, 91))	('Rb1', 'Gene', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('overexpression', 'PosReg', (41, 55))	('tumors', 'Disease', (99, 105))
27784	27076841	p53 expression may be regarded as an indicator of p53 gene mutation.	('p53', 'Gene', (0, 3))	('p53', 'Gene', '7157', (0, 3))	('expression', 'MPA', (4, 14))	('mutation', 'Var', (59, 67))	('p53', 'Gene', (50, 53))	('p53', 'Gene', '7157', (50, 53))
27786	27076841	However, p53 shows nuclear staining because of the accumulation of mutant p53, which is resistant to degradation.	('p53', 'Gene', (9, 12))	('p53', 'Gene', '7157', (9, 12))	('p53', 'Gene', (74, 77))	('accumulation', 'PosReg', (51, 63))	('mutant', 'Var', (67, 73))	('p53', 'Gene', '7157', (74, 77))
27792	27076841	HPV-associated oropharyngeal SCCs generally show a low level of p53 protein because of degradation through viral E6 protein, whereas HPV-negative tumors show absent or high p53 protein level because of nonsense or missense p53 mutations.	('E6 protein', 'Protein', (113, 123))	('tumors', 'Phenotype', 'HP:0002664', (146, 152))	('HPV', 'Species', '10566', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('p53', 'Gene', (223, 226))	('degradation', 'MPA', (87, 98))	('p53', 'Gene', (173, 176))	('p53', 'Gene', '7157', (223, 226))	('oropharyngeal SCCs', 'Disease', (15, 33))	('p53', 'Gene', '7157', (173, 176))	('tumors', 'Disease', 'MESH:D009369', (146, 152))	('low', 'NegReg', (51, 54))	('nonsense', 'Var', (202, 210))	('tumors', 'Disease', (146, 152))	('p53', 'Gene', (64, 67))	('SCC', 'Phenotype', 'HP:0002860', (29, 32))	('HPV', 'Species', '10566', (133, 136))	('p53', 'Gene', '7157', (64, 67))
27809	25885227	More over, knockdown of ESCCAL-1 expression increases esophageal cancer cell apoptosis and reduces the invasion in vitro.	('ESCCAL-1', 'Gene', (24, 32))	('increases esophageal cancer', 'Disease', (44, 71))	('ESCCAL-1', 'Gene', '101805492', (24, 32))	('invasion in vitro', 'CPA', (103, 120))	('increases esophageal cancer', 'Disease', 'MESH:D004938', (44, 71))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('reduces', 'NegReg', (91, 98))	('knockdown', 'Var', (11, 20))
27821	25885227	Detection of aberrant expression of lncRNAs in various tissue origin of cancers could serve as novel biomarkers for cancer diagnosis and prognosis.	('cancer', 'Disease', (116, 122))	('aberrant expression', 'Var', (13, 32))	('lncRNAs', 'Gene', (36, 43))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cancers', 'Disease', (72, 79))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('cancers', 'Disease', 'MESH:D009369', (72, 79))	('cancer', 'Disease', (72, 78))
27831	25885227	In our previous study, in silico locus control analysis identified lncRNA ESCCAL-337 (chr3:171506370-171528740) and ESCCAL-356 (chr5:1544500-1567142, reverse strand) may modulate lipid metabolism genes contributing to esophageal cancer development.	('contributing', 'Reg', (202, 214))	('modulate', 'Reg', (170, 178))	('lipid', 'Chemical', 'MESH:D008055', (179, 184))	('chr5:1544500-1567142', 'STRUCTURAL_ABNORMALITY', 'None', (128, 148))	('chr3:171506370-171528740', 'STRUCTURAL_ABNORMALITY', 'None', (86, 110))	('esophageal cancer', 'Disease', (218, 235))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('chr3:171506370-171528740', 'Var', (86, 110))	('lipid metabolism genes', 'Gene', (179, 201))	('esophageal cancer', 'Disease', 'MESH:D004938', (218, 235))
27857	25885227	A subset of these differential gene expressions are consistent with the literature, such as aberrant coding gene expression of ARSF, DMRTA1, MAGEA1, ECM1, HIPK2, and PIK3C2G were detected in other studies in esophageal cancer.	('DMRTA1', 'Gene', (133, 139))	('detected', 'Reg', (179, 187))	('aberrant', 'Var', (92, 100))	('ARSF', 'Gene', '416', (127, 131))	('MAGEA1', 'Gene', '4100', (141, 147))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('ECM1', 'Gene', '1893', (149, 153))	('HIPK2', 'Gene', '28996', (155, 160))	('PIK3C2G', 'Gene', (166, 173))	('esophageal cancer', 'Disease', (208, 225))	('ARSF', 'Gene', (127, 131))	('ECM1', 'Gene', (149, 153))	('DMRTA1', 'Gene', '63951', (133, 139))	('MAGEA1', 'Gene', (141, 147))	('HIPK2', 'Gene', (155, 160))	('esophageal cancer', 'Disease', 'MESH:D004938', (208, 225))	('PIK3C2G', 'Gene', '5288', (166, 173))
27861	25885227	HoxA11-AS1 is evolutionary conservation and tissue-specific expression, It was proposed that HOXA11 antisense represses HOXA11 expression by competing for transcription of the common gene, rather than by sense/antisense interaction.	('antisense', 'Var', (100, 109))	('HoxA11', 'Gene', (0, 6))	('competing', 'NegReg', (141, 150))	('HOXA11', 'Gene', '3207', (93, 99))	('expression', 'MPA', (127, 137))	('HoxA11', 'Gene', '3207', (0, 6))	('HOXA11', 'Gene', (93, 99))	('transcription', 'MPA', (155, 168))	('AS1', 'Gene', '5729', (7, 10))	('AS1', 'Gene', (7, 10))	('HOXA11', 'Gene', '3207', (120, 126))	('HOXA11', 'Gene', (120, 126))
27869	25885227	We want to know how esophageal cancer cell behavior changes if knocking down the expression of ESCCAL-1 lncRNA, we therefore designed three small interfering RNAs targeting various region of ESCCAL-1 sequencing.	('esophageal cancer', 'Disease', (20, 37))	('knocking', 'Var', (63, 71))	('ESCCAL-1 lncRNA', 'Gene', (95, 110))	('esophageal cancer', 'Disease', 'MESH:D004938', (20, 37))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('ESCCAL-1', 'Gene', (191, 199))	('ESCCAL-1 lncRNA', 'Gene', '101805492', (95, 110))	('ESCCAL-1', 'Gene', (95, 103))	('ESCCAL-1', 'Gene', '101805492', (191, 199))	('ESCCAL-1', 'Gene', '101805492', (95, 103))	('changes', 'Reg', (52, 59))	('expression', 'MPA', (81, 91))
27874	25885227	Core signaling pathways may be disrupted by these aberrant lncRNA expressions, such as WNT pathway is activated by HOTAIR over expression, TGFbeta1 pathway is inhibited by ANRIL.	('HOTAIR', 'Gene', (115, 121))	('TGFbeta1', 'Gene', '7040', (139, 147))	('TGFbeta1', 'Gene', (139, 147))	('ANRIL', 'Gene', '100048912', (172, 177))	('activated', 'PosReg', (102, 111))	('HOTAIR', 'Gene', '100124700', (115, 121))	('disrupted', 'Reg', (31, 40))	('WNT pathway', 'Pathway', (87, 98))	('Core signaling pathways', 'Pathway', (0, 23))	('ANRIL', 'Gene', (172, 177))	('aberrant', 'Var', (50, 58))	('inhibited', 'NegReg', (159, 168))
27881	24415402	Wound healing and an orthootopic animal model were used to study cells expressing the CSC phenotype (CD44high and ALDH+) and assess mobility, tumorigenesis and metastasis.	('ALDH', 'Gene', (114, 118))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('tumor', 'Disease', (142, 147))	('mobility', 'CPA', (132, 140))	('metastasis', 'CPA', (160, 170))	('ALDH', 'Gene', '11670', (114, 118))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('CD44high', 'Var', (101, 109))
27898	24415402	Additional work using a mouse tail vein injection model of CSC-mediated metastasis demonstrated that HNSCC cells expressing CD44high and ALDH+ have a greater capacity to colonize the lungs compared to CD44low and ALDH- tumor cells which rarely if ever lead to successful lung colonization.	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('mouse', 'Species', '10090', (24, 29))	('ALDH', 'Gene', '11670', (137, 141))	('tumor', 'Disease', (219, 224))	('HNSCC', 'Phenotype', 'HP:0012288', (101, 106))	('ALDH', 'Gene', (137, 141))	('SCC', 'Gene', (103, 106))	('ALDH', 'Gene', '11670', (213, 217))	('ALDH', 'Gene', (213, 217))	('colonize', 'CPA', (170, 178))	('tumor', 'Disease', 'MESH:D009369', (219, 224))	('SCC', 'Gene', '6317', (103, 106))	('CD44high', 'Var', (124, 132))
27918	24415402	Specimens being analyzed for ALDH activity were then counterstained with anti-CD44 (allophycocyanin [APC] conjugated; BD Pharmingen, San Diego, CA) at the appropriate dilution.	('anti-CD44', 'Var', (73, 82))	('ALDH', 'Gene', (29, 33))	('ALDH', 'Gene', '11670', (29, 33))
27923	24415402	(Supplemental Figure 1C and 1D) For double sorts using both CD44 and ALDH, CD44 expression was identified first followed by subsequent ALDH activity.	('CD44', 'Var', (75, 79))	('ALDH', 'Gene', '11670', (69, 73))	('ALDH', 'Gene', '11670', (135, 139))	('ALDH', 'Gene', (69, 73))	('ALDH', 'Gene', (135, 139))
27946	24415402	UM-SCC-47 cells sorted for CD44high expressing cells demonstrated significantly greater mean percent wound closure compared to the CD44low expressing cells at 9, 15, 18 and 20 hours (p=0.0001, 0.001, 0.004 and 0.038 respectively).	('CD44high expressing', 'Var', (27, 46))	('UM-SCC-47', 'CellLine', 'CVCL:7759', (0, 9))	('greater', 'PosReg', (80, 87))
27947	24415402	CD44high UM-SCC-103 cells demonstrated significantly greater mean percentage wound closure compared to CD44low cells at 9, 18 and 20 hours (p=0.012, 0.012, and 0.036 respectively) (Figure 1D).	('CD44high', 'Var', (0, 8))	('SCC', 'Gene', (12, 15))	('SCC', 'Gene', '6317', (12, 15))	('greater', 'PosReg', (53, 60))
27948	24415402	The mean time to closure was significantly shorter in cells sorted for CD44high compared to CD44low sorted cells for both UM-SCC-47 (17.8 hours v. 21 hours; p=0.001) and UM-SCC-103 (20.6 hours v. 25.8 hours; p=0.028) cell lines.	('CD44high', 'Var', (71, 79))	('SCC', 'Gene', (125, 128))	('SCC', 'Gene', (173, 176))	('SCC', 'Gene', '6317', (125, 128))	('UM-SCC-47', 'CellLine', 'CVCL:7759', (122, 131))	('SCC', 'Gene', '6317', (173, 176))	('shorter', 'NegReg', (43, 50))
27954	24415402	Tumor cells were sorted to obtain CD44high, CD44low, CD44high/ALDH+, CD44low/ALDH- and unsorted control populations.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('ALDH', 'Gene', (77, 81))	('ALDH', 'Gene', '11670', (62, 66))	('CD44high/ALDH+', 'Gene', (53, 67))	('CD44high', 'Var', (34, 42))	('ALDH', 'Gene', (62, 66))	('CD44low', 'Var', (44, 51))	('CD44high/ALDH+', 'Gene', '11670', (53, 67))	('ALDH', 'Gene', '11670', (77, 81))
27956	24415402	The minimum number of cells to produce a tumor was 50 fold lower for CD44high UM-SCC-47-luc+ cells compared to the CD44low cells (500 vs. 25,000).	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Disease', (41, 46))	('lower', 'NegReg', (59, 64))	('CD44high', 'Var', (69, 77))	('UM-SCC-47', 'CellLine', 'CVCL:7759', (78, 87))	('tumor', 'Disease', 'MESH:D009369', (41, 46))
27957	24415402	Furthermore primary tumor growth at 28 days was demonstrated in 5/5 mice injected with CD44high cells vs. only 1/4 mice injected with CD44low cells (p=0.047).	('mice', 'Species', '10090', (68, 72))	('demonstrated', 'Reg', (48, 60))	('CD44high cells', 'Var', (87, 101))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('mice', 'Species', '10090', (115, 119))	('tumor', 'Disease', (20, 25))
27959	24415402	(Table 1) The rate of tumor take and growth after injecting 2.5x104 CD44 sorted cells was significantly higher in the CD44high and CD44high/ALDH+ populations compared to CD44low and CD44low/ALDHpopulation (p=0.0011).	('CD44high/ALDH+', 'Gene', (131, 145))	('ALDH', 'Gene', (190, 194))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('higher', 'PosReg', (104, 110))	('ALDH', 'Gene', '11670', (140, 144))	('CD44', 'Gene', (68, 72))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('ALDH', 'Gene', (140, 144))	('tumor', 'Disease', (22, 27))	('growth', 'CPA', (37, 43))	('CD44high/ALDH+', 'Gene', '11670', (131, 145))	('CD44high', 'Var', (118, 126))	('ALDH', 'Gene', '11670', (190, 194))
27960	24415402	Comparison of bioluminescence at individual time points demonstrated a significantly higher levels of luminescence (photons/sec) in the primary tumors generated by CD44high and CD44high/ALDH+ cells at days 21, 28, 36 and 43 compared to CD44low and CD44low/ALDH- cells.	('CD44high/ALDH+', 'Gene', '11670', (177, 191))	('ALDH', 'Gene', (186, 190))	('ALDH', 'Gene', '11670', (256, 260))	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('primary tumors', 'Disease', 'MESH:D009369', (136, 150))	('higher', 'PosReg', (85, 91))	('ALDH', 'Gene', (256, 260))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('CD44high/ALDH+', 'Gene', (177, 191))	('levels', 'MPA', (92, 98))	('CD44high', 'Var', (164, 172))	('ALDH', 'Gene', '11670', (186, 190))	('primary tumors', 'Disease', (136, 150))
27961	24415402	Collectively, CSC (CD44high and CD44high/ALDH+) had significantly greater capacity for tumorigenesis and greater rates of tumor growth compared to non-CSC (CD44low and CD44low/ALDH-).	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('ALDH', 'Gene', '11670', (41, 45))	('greater', 'PosReg', (66, 73))	('CD44high', 'Var', (19, 27))	('tumor', 'Disease', (87, 92))	('CD44high/ALDH+', 'Gene', (32, 46))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('rates', 'CPA', (113, 118))	('ALDH', 'Gene', (41, 45))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('ALDH', 'Gene', '11670', (176, 180))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('greater', 'PosReg', (105, 112))	('tumor', 'Disease', (122, 127))	('ALDH', 'Gene', (176, 180))	('CD44high/ALDH+', 'Gene', '11670', (32, 46))
27962	24415402	(Figure 3A and 3C) Histologic evaluation of the CD44high and CD44high/ALDH+ derived primary tumors demonstrated invasive moderately differentiated squamous cell carcinoma with perineural invasion.	('CD44high/ALDH+', 'Gene', '11670', (61, 75))	('squamous cell carcinoma', 'Disease', (147, 170))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (147, 170))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('CD44high/ALDH+', 'Gene', (61, 75))	('primary tumors', 'Disease', (84, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (161, 170))	('CD44high', 'Var', (48, 56))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (147, 170))	('primary tumors', 'Disease', 'MESH:D009369', (84, 98))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))
27963	24415402	(Figure 3B) These results strongly suggest cells expressing high levels of the cancer stem cell marker CD44 and ALDH have greater tumorigeneic potential compared to cells expressing CD44low or CD44low/ALDH-.	('CD44', 'Gene', (103, 107))	('greater', 'PosReg', (122, 129))	('ALDH', 'Gene', '11670', (112, 116))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('cancer', 'Disease', (79, 85))	('ALDH', 'Gene', (112, 116))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('ALDH', 'Gene', '11670', (201, 205))	('high levels', 'Var', (60, 71))	('tumor', 'Disease', (130, 135))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('ALDH', 'Gene', (201, 205))
27964	24415402	High tumorigeneic potential in CD44highand CD44high/ALDH+ cells further supports CD44 and ALDH as markers for head and neck cancer stem cells.	('CD44highand', 'Var', (31, 42))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('head and neck cancer', 'Phenotype', 'HP:0012288', (110, 130))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('neck cancer', 'Disease', 'MESH:D006258', (119, 130))	('ALDH', 'Gene', '11670', (52, 56))	('CD44high/ALDH+', 'Gene', (43, 57))	('tumor', 'Disease', (5, 10))	('ALDH', 'Gene', '11670', (90, 94))	('neck cancer', 'Disease', (119, 130))	('ALDH', 'Gene', (52, 56))	('ALDH', 'Gene', (90, 94))	('CD44high/ALDH+', 'Gene', '11670', (43, 57))
27965	24415402	Mice injected with 2.5x104 CD44high or CD44high/ALDH+ cells were assessed for metastatic potential relative to CD44low or CD44low/ALDH- cells.	('ALDH', 'Gene', (130, 134))	('CD44high', 'Var', (27, 35))	('ALDH', 'Gene', '11670', (48, 52))	('CD44high/ALDH+', 'Gene', (39, 53))	('metastatic potential', 'CPA', (78, 98))	('Mice', 'Species', '10090', (0, 4))	('ALDH', 'Gene', (48, 52))	('CD44high/ALDH+', 'Gene', '11670', (39, 53))	('ALDH', 'Gene', '11670', (130, 134))
27966	24415402	All mice injected with CD44high or CD44high/ALDH+ had a significantly shorter metastasis-free interval compared to mice injected with CD44low or CD44low/ALDH- cells (mean time to metastasis 21.6 v. 40 days; p=0.005).	('CD44high/ALDH+', 'Gene', (35, 49))	('ALDH', 'Gene', (153, 157))	('ALDH', 'Gene', '11670', (44, 48))	('CD44high', 'Var', (23, 31))	('mice', 'Species', '10090', (4, 8))	('ALDH', 'Gene', (44, 48))	('shorter', 'NegReg', (70, 77))	('metastasis-free interval', 'CPA', (78, 102))	('CD44high/ALDH+', 'Gene', '11670', (35, 49))	('mice', 'Species', '10090', (115, 119))	('ALDH', 'Gene', '11670', (153, 157))
27967	24415402	(Figure 4A) There was significantly greater regional metastatic luminescence in CD44high and CD44high/ALDH+ cells injections at 28, 36 and 43 days compared to CD44low and CD44low/ALDH-.	('CD44high', 'Var', (80, 88))	('CD44high/ALDH+', 'Gene', (93, 107))	('ALDH', 'Gene', '11670', (102, 106))	('ALDH', 'Gene', '11670', (179, 183))	('ALDH', 'Gene', (102, 106))	('ALDH', 'Gene', (179, 183))	('greater', 'PosReg', (36, 43))	('CD44high/ALDH+', 'Gene', '11670', (93, 107))	('regional', 'MPA', (44, 52))
27984	24415402	Cancer stem cells (CD44high and CD44high/ALDH+) have significantly increased in-vitro migration and wound healing and in an orthotopic mouse model are more tumorigenic with a greater rate of spontaneous metastasis compared to non-cancer stem cells (CD44low and CD44low/ALDH-).	('ALDH', 'Gene', (269, 273))	('spontaneous metastasis', 'CPA', (191, 213))	('ALDH', 'Gene', '11670', (41, 45))	('CD44high', 'Var', (19, 27))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('CD44high/ALDH+', 'Gene', (32, 46))	('more', 'PosReg', (151, 155))	('mouse', 'Species', '10090', (135, 140))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('non-cancer', 'Disease', (226, 236))	('increased', 'PosReg', (67, 76))	('ALDH', 'Gene', (41, 45))	('tumor', 'Disease', (156, 161))	('ALDH', 'Gene', '11670', (269, 273))	('non-cancer', 'Disease', 'MESH:D009369', (226, 236))	('CD44high/ALDH+', 'Gene', '11670', (32, 46))
27987	24415402	These findings suggest CSC (CD44high and CD44high/ALDH+) have a greater capacity for spontaneous regional and distant metastatic spread and growth compared to non-CSC (CD44low and CD44low/ALDH-).	('CD44high/ALDH+', 'Gene', (41, 55))	('ALDH', 'Gene', (50, 54))	('ALDH', 'Gene', (188, 192))	('CD44high/ALDH+', 'Gene', '11670', (41, 55))	('CD44high', 'Var', (28, 36))	('ALDH', 'Gene', '11670', (50, 54))	('growth', 'CPA', (140, 146))	('ALDH', 'Gene', '11670', (188, 192))
27988	24415402	In primary patient tumors, CSC enrichment in primary tumors is significantly associated with increased tumor size and tumor stage, while there were trends for association of CD44high content with regional, distant and perineural invasion.	('tumors', 'Disease', (19, 25))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('increased', 'PosReg', (93, 102))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('primary tumors', 'Disease', 'MESH:D009369', (45, 59))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('tumor', 'Disease', (19, 24))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('regional', 'CPA', (196, 204))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumors', 'Disease', (53, 59))	('tumor', 'Disease', (103, 108))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('association', 'Interaction', (159, 170))	('primary tumors', 'Disease', (45, 59))	('patient', 'Species', '9606', (11, 18))	('tumor', 'Disease', (118, 123))	('tumor', 'Disease', (53, 58))	('CD44high content', 'Var', (174, 190))
27995	24415402	We have shown that cells expressing high levels of CD44 alone or jointly with elevated ALDH activity have a greater ability to form primary tumors and regional metastasis compared to cells lacking these two markers.	('regional metastasis', 'CPA', (151, 170))	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('CD44', 'Var', (51, 55))	('ALDH', 'Gene', '11670', (87, 91))	('primary tumors', 'Disease', (132, 146))	('high levels', 'Var', (36, 47))	('ALDH', 'Gene', (87, 91))	('activity', 'MPA', (92, 100))	('primary tumors', 'Disease', 'MESH:D009369', (132, 146))
27998	24415402	However, CD44high may not identify all cells with CSC characteristics and has been shown to be a less selective marker of HNCSC than ALDH expression.	('ALDH', 'Gene', '11670', (133, 137))	('HNCSC', 'Disease', (122, 127))	('CD44high', 'Var', (9, 17))	('ALDH', 'Gene', (133, 137))
27999	24415402	If sufficient numbers of CD44low cells such as the experiments in which 2.5 x 104 CD44low non-CSC cells could eventually yield tumor growth and regional metastasis over longer periods of time compared to the CD44high CSC group, the addition of ALDH as a second marker for CSC identification can help demonstrate a more specific marker for CSC ability to form primary tumors and regional metastasis.	('primary tumors', 'Disease', 'MESH:D009369', (359, 373))	('tumors', 'Phenotype', 'HP:0002664', (367, 373))	('tumor', 'Disease', (367, 372))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumor', 'Disease', (127, 132))	('tumor', 'Phenotype', 'HP:0002664', (367, 372))	('ALDH', 'Gene', '11670', (244, 248))	('primary tumors', 'Disease', (359, 373))	('ALDH', 'Gene', (244, 248))	('tumor', 'Disease', 'MESH:D009369', (367, 372))	('regional metastasis', 'CPA', (144, 163))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('CD44low', 'Var', (82, 89))
28003	24415402	While the in-vitro wound healing assay did not assess CD44high/ALDH+ versus CD44low/ALDH- , we have shown that when using CD44 and ALDH as concurrent CSC markers, there is a greater ability for primary tumor growth and regional metastasis compared to CD44low/ALDH- injections.	('ALDH', 'Gene', (259, 263))	('ALDH', 'Gene', (131, 135))	('ALDH', 'Gene', (84, 88))	('tumor', 'Disease', (202, 207))	('CD44', 'Var', (122, 126))	('ALDH', 'Gene', '11670', (63, 67))	('ALDH', 'Gene', '11670', (84, 88))	('CD44high/ALDH+', 'Gene', (54, 68))	('ALDH', 'Gene', (63, 67))	('ALDH', 'Gene', '11670', (131, 135))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('ALDH', 'Gene', '11670', (259, 263))	('regional metastasis', 'CPA', (219, 238))	('CD44high/ALDH+', 'Gene', '11670', (54, 68))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))
28005	24415402	We did not see an gross differences when evaluating CD44high and CD44high/ALDH+, however the overall group was small and subgroup analysis would require a larger sample size.	('CD44high/ALDH+', 'Gene', '11670', (65, 79))	('CD44high', 'Var', (52, 60))	('CD44high/ALDH+', 'Gene', (65, 79))
28008	24415402	Additionally evaluating for differences between CD44high and CD44high/ALDH+ in the animal model may provide additional insight into the true effect of ALDH on metastasis.	('CD44high/ALDH+', 'Gene', '11670', (61, 75))	('ALDH', 'Gene', '11670', (151, 155))	('CD44high/ALDH+', 'Gene', (61, 75))	('ALDH', 'Gene', (151, 155))	('ALDH', 'Gene', '11670', (70, 74))	('CD44high', 'Var', (48, 56))	('ALDH', 'Gene', (70, 74))
28040	32436117	Related studies have found that the loss of mammalian PCL2 leads to increased self-renewal and delayed differentiation of ESCs.	('self-renewal', 'CPA', (78, 90))	('loss', 'Var', (36, 40))	('mammalian', 'Species', '9606', (44, 53))	('delayed differentiation', 'CPA', (95, 118))	('increased', 'PosReg', (68, 77))
28043	32436117	Cases of GBM with H3F3AK27 mutations show high frequency of TP53 mutations, hypomethylation of DNA, midline location and spread of diffuse pontine glioma, and poor prognosis.	('mutations', 'Var', (27, 36))	('H3F3A', 'Gene', '3020', (18, 23))	('glioma', 'Disease', 'MESH:D005910', (147, 153))	('hypomethylation', 'Var', (76, 91))	('glioma', 'Phenotype', 'HP:0009733', (147, 153))	('TP53', 'Gene', '7157', (60, 64))	('H3F3A', 'Gene', (18, 23))	('glioma', 'Disease', (147, 153))	('TP53', 'Gene', (60, 64))	('mutations', 'Var', (65, 74))
28044	32436117	Mutations in these genes are closely related to the alternate expansions of specific gene expression profiles, leading to the formation of gliomas.	('leading to', 'Reg', (111, 121))	('gliomas', 'Disease', (139, 146))	('gliomas', 'Disease', 'MESH:D005910', (139, 146))	('gliomas', 'Phenotype', 'HP:0009733', (139, 146))	('Mutations', 'Var', (0, 9))	('glioma', 'Phenotype', 'HP:0009733', (139, 145))
28097	32436117	In the colony formation experiment, we could obviously see that the number of colonies was reduced after DZNeP treatment (Fig.	('DZNeP treatment', 'Var', (105, 120))	('reduced', 'NegReg', (91, 98))	('DZNeP', 'Chemical', 'MESH:C048460', (105, 110))
28098	32436117	We demonstrated that in U87 cells, DZNeP reduced the increases in the EZH2 protein level caused by hPCL2 expressions and the protein expression of SUZ12 and EED in PRC2 were reduced compared to that in the control (Fig.	('SUZ12', 'Gene', '23512', (147, 152))	('reduced', 'NegReg', (41, 48))	('hPCL2', 'Gene', '22823', (99, 104))	('PRC2', 'Gene', (164, 168))	('hPCL2', 'Gene', (99, 104))	('U87', 'Gene', '641648', (24, 27))	('DZNeP', 'Chemical', 'MESH:C048460', (35, 40))	('SUZ12', 'Gene', (147, 152))	('protein expression', 'MPA', (125, 143))	('reduced', 'NegReg', (174, 181))	('increases', 'PosReg', (53, 62))	('EZH2', 'Gene', '2146', (70, 74))	('U87', 'Gene', (24, 27))	('EZH2', 'Gene', (70, 74))	('DZNeP', 'Var', (35, 40))	('expressions', 'MPA', (105, 116))
28105	32436117	The phenotypes associated with PCL mutations in Drosophila and Xenopus, as well as the colocalization and interaction of PCLs and PRC2, suggest that PCL proteins play a crucial role in PRC2 function.	('Xenopus', 'Species', '8355', (63, 70))	('interaction', 'Interaction', (106, 117))	('PCL', 'Gene', (31, 34))	('Drosophila', 'Species', '7227', (48, 58))	('mutations', 'Var', (35, 44))
28118	32436117	Studies have shown that the absence of EED can lead to abnormal differentiation and functional defects of hematopoietic stem cells (HSPCs).It has been reported in the literature that CRISPR/Cas9-mediated SUZ12 inactivation and mutant JAK3 synergistically drive T cell transformation and T-cell acute lymphoblastic leukemia (T-ALL) development.	('inactivation', 'NegReg', (210, 222))	('T cell transformation', 'CPA', (261, 282))	('mutant', 'Var', (227, 233))	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (294, 322))	('T-cell acute lymphoblastic leukemia', 'Phenotype', 'HP:0006727', (287, 322))	('T-cell acute lymphoblastic leukemia', 'Disease', 'MESH:D054218', (287, 322))	('T-cell acute lymphoblastic leukemia', 'Disease', (287, 322))	('SUZ12', 'Gene', '23512', (204, 209))	('SUZ12', 'Gene', (204, 209))	('drive', 'PosReg', (255, 260))	('leukemia', 'Phenotype', 'HP:0001909', (314, 322))	('JAK3', 'Gene', (234, 238))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (300, 322))	('JAK3', 'Gene', '3718', (234, 238))
28119	32436117	In contrast, in the study of head and neck squamous cell carcinoma (HNSCC) and non-small cell lung cancer (NSCLC), it was found that shRNA-mediated SUZ12 knock-down significantly inhibited tumor cell proliferation, migration and invasion.	('small cell lung cancer', 'Phenotype', 'HP:0030357', (83, 105))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (29, 66))	('inhibited', 'NegReg', (179, 188))	('carcinoma', 'Phenotype', 'HP:0030731', (57, 66))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (79, 105))	('SUZ12', 'Gene', (148, 153))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('SUZ12', 'Gene', '23512', (148, 153))	('NSCLC', 'Disease', 'MESH:D002289', (107, 112))	('non-small cell lung cancer', 'Disease', (79, 105))	('knock-down', 'Var', (154, 164))	('NSCLC', 'Disease', (107, 112))	('neck squamous cell carcinoma', 'Disease', (38, 66))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (38, 66))	('lung cancer', 'Phenotype', 'HP:0100526', (94, 105))	('HNSC', 'Disease', 'None', (68, 72))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (79, 105))	('tumor', 'Disease', (189, 194))	('invasion', 'CPA', (229, 237))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (43, 66))	('HNSC', 'Disease', (68, 72))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
28124	32436117	H3K9 and H3K27 methylation are related to gene silencing, while H3K4 methylation can activate genes.	('gene', 'MPA', (42, 46))	('methylation', 'Var', (15, 26))	('H3', 'Gene', '126961', (9, 11))	('H3', 'Gene', '126961', (64, 66))	('activate', 'PosReg', (85, 93))	('H3', 'Gene', '126961', (0, 2))
28129	32436117	It has been suggested in the latest research that the mutant H3K27, which is a lethal subunit of glioma, appears in the normal H3.	('H3', 'Gene', '126961', (61, 63))	('glioma', 'Disease', (97, 103))	('H3', 'Gene', '126961', (127, 129))	('glioma', 'Disease', 'MESH:D005910', (97, 103))	('mutant', 'Var', (54, 60))	('glioma', 'Phenotype', 'HP:0009733', (97, 103))
28130	32436117	The ability, recruiting target genes on chromatin by PRC2, does not seem to be affected by the H3K27 mutation, but the transcription will be restricted if the deposition of H3K27me3 and me2 in the whole genome is depleted, and results in affecting gene expression of regulating neurogenesis.	('restricted', 'NegReg', (141, 151))	('affecting', 'Reg', (238, 247))	('regulating neurogenesis', 'CPA', (267, 290))	('H3', 'Gene', '126961', (95, 97))	('deposition', 'MPA', (159, 169))	('me2', 'Gene', '4200', (186, 189))	('me2', 'Gene', (186, 189))	('transcription', 'MPA', (119, 132))	('me3', 'Gene', '109264', (178, 181))	('depleted', 'NegReg', (213, 221))	('gene expression', 'MPA', (248, 263))	('mutation', 'Var', (101, 109))	('H3', 'Gene', '126961', (173, 175))	('me3', 'Gene', (178, 181))
28139	32436117	We found that the expression of PCL2 increased the protein level of EZH2, while DZNeP inhibited the expression of EZH2.	('EZH2', 'Gene', (68, 72))	('DZNeP', 'Chemical', 'MESH:C048460', (80, 85))	('PCL2', 'Gene', (32, 36))	('protein level', 'MPA', (51, 64))	('increased', 'PosReg', (37, 46))	('inhibited', 'NegReg', (86, 95))	('EZH2', 'Gene', '2146', (68, 72))	('EZH2', 'Gene', '2146', (114, 118))	('expression', 'Var', (18, 28))	('EZH2', 'Gene', (114, 118))
28193	32283544	FAM46C knockdown in 22RV1 and DU145 cells significantly inhibited apoptosis and promoted cell proliferation and cell cycle progression as well as activation of AKT.	('promoted', 'PosReg', (80, 88))	('FAM46C knockdown', 'Var', (0, 16))	('activation', 'PosReg', (146, 156))	('cell proliferation', 'CPA', (89, 107))	('22RV1', 'CellLine', 'CVCL:1045', (20, 25))	('AKT', 'Pathway', (160, 163))	('DU145', 'CellLine', 'CVCL:0105', (30, 35))	('cell cycle progression', 'CPA', (112, 134))	('apoptosis', 'CPA', (66, 75))	('inhibited', 'NegReg', (56, 65))	('knockdown', 'Var', (7, 16))
28195	32283544	The prostate cancer cells and patient-derived xenograft (PDX) mice with high-FAM46C-expressing demonstrated an enhanced chemosensitivity to docetaxel.	('prostate cancer', 'Disease', 'MESH:D011471', (4, 19))	('patient', 'Species', '9606', (30, 37))	('prostate cancer', 'Phenotype', 'HP:0012125', (4, 19))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('mice', 'Species', '10090', (62, 66))	('enhanced', 'PosReg', (111, 119))	('prostate cancer', 'Disease', (4, 19))	('high-FAM46C-expressing', 'Var', (72, 94))	('chemosensitivity to docetaxel', 'MPA', (120, 149))	('docetaxel', 'Chemical', 'MESH:D000077143', (140, 149))
28196	32283544	These findings suggest that FAM46C control cell proliferation, cell cycle and apoptosis through PTEN/AKT signaling pathway and is associated with chemosensitivity of prostate cancer.	('apoptosis', 'CPA', (78, 87))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('cell cycle', 'CPA', (63, 73))	('PTEN/AKT signaling pathway', 'Pathway', (96, 122))	('prostate cancer', 'Phenotype', 'HP:0012125', (166, 181))	('cell proliferation', 'CPA', (43, 61))	('control', 'Reg', (35, 42))	('chemosensitivity of prostate cancer', 'Disease', 'MESH:D011471', (146, 181))	('FAM46C', 'Var', (28, 34))	('chemosensitivity of prostate cancer', 'Disease', (146, 181))	('associated with', 'Reg', (130, 145))
28197	32283544	Modulation of their levels may offer a new approach for improving anti-tumor efficacy for chemotherapeutic agents in prostate cancer.	('Modulation', 'Var', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('prostate cancer', 'Disease', 'MESH:D011471', (117, 132))	('prostate cancer', 'Phenotype', 'HP:0012125', (117, 132))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('prostate cancer', 'Disease', (117, 132))	('improving', 'PosReg', (56, 65))	('tumor', 'Disease', (71, 76))
28209	32283544	Deletions of FAM46C have been found in a few cancers, including multiple myeloma, gastric cancer and myeloma, and to be associated with a shorter overall survival.	('associated', 'Reg', (120, 130))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('gastric cancer', 'Disease', 'MESH:D013274', (82, 96))	('cancers', 'Disease', 'MESH:D009369', (45, 52))	('multiple myeloma', 'Disease', (64, 80))	('myeloma', 'Disease', (101, 108))	('myeloma', 'Disease', 'MESH:D009101', (73, 80))	('shorter', 'NegReg', (138, 145))	('gastric cancer', 'Phenotype', 'HP:0012126', (82, 96))	('cancers', 'Phenotype', 'HP:0002664', (45, 52))	('FAM46C', 'Gene', (13, 19))	('multiple myeloma', 'Phenotype', 'HP:0006775', (64, 80))	('myeloma', 'Disease', (73, 80))	('cancers', 'Disease', (45, 52))	('overall survival', 'MPA', (146, 162))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('found', 'Reg', (30, 35))	('myeloma', 'Disease', 'MESH:D009101', (101, 108))	('gastric cancer', 'Disease', (82, 96))	('multiple myeloma', 'Disease', 'MESH:D009101', (64, 80))	('Deletions', 'Var', (0, 9))
28211	32283544	The deletion of FAM46C was identified as an independent risk factor for hepatic recurrence in patients with gastric cancer after curative gastrectomy.	('patients', 'Species', '9606', (94, 102))	('gastric cancer', 'Phenotype', 'HP:0012126', (108, 122))	('FAM46C', 'Gene', (16, 22))	('hepatic recurrence', 'Disease', (72, 90))	('deletion', 'Var', (4, 12))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('risk', 'Reg', (56, 60))	('gastric cancer', 'Disease', (108, 122))	('gastric cancer', 'Disease', 'MESH:D013274', (108, 122))
28215	32283544	PTEN is a tumor suppressor with phosphatase activity and decrease or loss of PTEN expression, due to the methylation, mutation or deletion, may closely relate to the occurrence and development of multiple cancers.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('relate', 'Reg', (152, 158))	('decrease', 'NegReg', (57, 65))	('methylation', 'Var', (105, 116))	('loss', 'NegReg', (69, 73))	('multiple cancers', 'Disease', 'MESH:D009369', (196, 212))	('expression', 'MPA', (82, 92))	('tumor', 'Disease', (10, 15))	('deletion', 'Var', (130, 138))	('PTEN', 'Gene', (77, 81))	('mutation', 'Var', (118, 126))	('multiple cancers', 'Disease', (196, 212))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('men', 'Species', '9606', (188, 191))	('cancers', 'Phenotype', 'HP:0002664', (205, 212))
28218	32283544	Prostate cancer LNCaP cells exhibited PTEN inactivation, leading to constitutive activation of the AKT pathway.	('Prostate cancer', 'Phenotype', 'HP:0012125', (0, 15))	('LNCaP', 'CellLine', 'CVCL:0395', (16, 21))	('Prostate cancer', 'Disease', (0, 15))	('AKT pathway', 'Pathway', (99, 110))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('activation', 'PosReg', (81, 91))	('Prostate cancer', 'Disease', 'MESH:D011471', (0, 15))	('inactivation', 'Var', (43, 55))
28224	32283544	FAM46C promoted cell apoptosis and inhibited cell cycle and cell proliferation of prostate cancer through PTEN/AKT signaling pathway.	('cell apoptosis', 'CPA', (16, 30))	('cell proliferation', 'CPA', (60, 78))	('PTEN/AKT signaling pathway', 'Pathway', (106, 132))	('prostate cancer', 'Disease', 'MESH:D011471', (82, 97))	('cell cycle', 'CPA', (45, 55))	('prostate cancer', 'Disease', (82, 97))	('promoted', 'PosReg', (7, 15))	('inhibited', 'NegReg', (35, 44))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('FAM46C', 'Var', (0, 6))	('prostate cancer', 'Phenotype', 'HP:0012125', (82, 97))
28226	32283544	Bioinformatics analysis based on the TCGA database showed that the transcript level of FAM46A, FAM46B and FAM46C, but not FAM46D, was decreased in prostate cancer tissues compared with noncancerous prostate tissues (Figure 1A).	('decreased', 'NegReg', (134, 143))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('prostate cancer', 'Disease', 'MESH:D011471', (147, 162))	('FAM46B', 'Gene', (95, 101))	('cancer', 'Disease', (156, 162))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('prostate cancer', 'Phenotype', 'HP:0012125', (147, 162))	('FAM46D', 'Gene', (122, 128))	('transcript level', 'MPA', (67, 83))	('prostate cancer', 'Disease', (147, 162))	('FAM46A', 'Gene', (87, 93))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('FAM46C', 'Var', (106, 112))	('FAM46D', 'Gene', '169966', (122, 128))	('cancer', 'Disease', (188, 194))	('FAM46A', 'Gene', '55603', (87, 93))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('FAM46B', 'Gene', '115572', (95, 101))
28227	32283544	Moreover, the mRNA expression of FAM46C, but not FAM46A, FAM46B and FAM46D, in high Gleason score samples was found to be lower than that in low Gleason score samples in hospital cohort (Figure 1B).	('FAM46B', 'Gene', (57, 63))	('lower', 'NegReg', (122, 127))	('FAM46C', 'Var', (33, 39))	('FAM46A', 'Gene', (49, 55))	('FAM46A', 'Gene', '55603', (49, 55))	('mRNA expression', 'MPA', (14, 29))	('FAM46B', 'Gene', '115572', (57, 63))	('FAM46D', 'Gene', (68, 74))	('FAM46D', 'Gene', '169966', (68, 74))
28228	32283544	These data suggest that FAM46C may involve in the prostate cancer progression, and we therefore focused on FAM46C.	('prostate cancer', 'Disease', (50, 65))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('prostate cancer', 'Disease', 'MESH:D011471', (50, 65))	('FAM46C', 'Var', (24, 30))	('involve', 'Reg', (35, 42))	('prostate cancer', 'Phenotype', 'HP:0012125', (50, 65))
28230	32283544	Indeed, the mRNA levels of FAM46C were significantly lower in the prostate cancer tissues compared with the noncancerous prostate tissues in hospital cohort (Figure 1D).	('prostate cancer', 'Disease', 'MESH:D011471', (66, 81))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('mRNA levels', 'MPA', (12, 23))	('prostate cancer', 'Phenotype', 'HP:0012125', (66, 81))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('cancer', 'Disease', (75, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('prostate cancer', 'Disease', (66, 81))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('lower', 'NegReg', (53, 58))	('FAM46C', 'Var', (27, 33))
28231	32283544	The FAM46C mRNA levels were also shown in 30 cases of prostate cancer patients (Figure 1E).	('patients', 'Species', '9606', (70, 78))	('prostate cancer', 'Disease', (54, 69))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('prostate cancer', 'Disease', 'MESH:D011471', (54, 69))	('FAM46C', 'Var', (4, 10))	('prostate cancer', 'Phenotype', 'HP:0012125', (54, 69))
28233	32283544	By comparing the expression of FAM46C in cells, we revealed that, prostate cancer cell lines demonstrated a lower FAM46C expression compared with human prostate epithelial cell line RWPE-2, and 22RV1 cells had the higher expression of FAM46C while DU145 cells had the lower expression of FAM46C (Figure 1F).	('prostate cancer', 'Disease', 'MESH:D011471', (66, 81))	('FAM46C', 'Gene', (114, 120))	('prostate cancer', 'Phenotype', 'HP:0012125', (66, 81))	('expression', 'MPA', (121, 131))	('FAM46C', 'Var', (235, 241))	('human', 'Species', '9606', (146, 151))	('lower', 'NegReg', (108, 113))	('DU145', 'CellLine', 'CVCL:0105', (248, 253))	('prostate cancer', 'Disease', (66, 81))	('22RV1', 'CellLine', 'CVCL:1045', (194, 199))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('RWPE-2', 'CellLine', 'CVCL:3792', (182, 188))
28237	32283544	Patients with prostate cancer in the FAM46C high expression group were also proved to have better overall survival compared with those in the FAM46C low expression group (Figure 2C).	('better', 'PosReg', (91, 97))	('prostate cancer', 'Disease', 'MESH:D011471', (14, 29))	('prostate cancer', 'Phenotype', 'HP:0012125', (14, 29))	('Patients', 'Species', '9606', (0, 8))	('prostate cancer', 'Disease', (14, 29))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('FAM46C high expression', 'Var', (37, 59))	('overall', 'MPA', (98, 105))
28238	32283544	Moreover, it demonstrated that the expression of FAM46C was correlated with the Gleason score and tumor size, but no significant difference could be found regarding the age and pathological grade of patients between FAM46C low and high expression group (Table 1).	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('Gleason score', 'CPA', (80, 93))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('correlated', 'Reg', (60, 70))	('patients', 'Species', '9606', (199, 207))	('low', 'NegReg', (223, 226))	('tumor', 'Disease', (98, 103))	('FAM46C', 'Gene', (216, 222))	('FAM46C', 'Var', (49, 55))
28239	32283544	In terms of overall survival, univariate along with multivariate analysis revealed that FAM46C expression, Gleason score and tumor size were prognostic factors, and FAM46C expression as well as Gleason score was an independent prognostic factor (Figure 2D).	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('FAM46C', 'Gene', (88, 94))	('tumor', 'Disease', (125, 130))	('FAM46C expression', 'Var', (165, 182))
28240	32283544	To assess the role of FAM46C in prostate cancer development, we then transduced pLKO.1-FAM46C shRNAs or pLKO.1-scramble control shRNA (shNC) vector into the 22RV1 and DU145 cells (Figure 3A and 3B).	('prostate cancer', 'Disease', (32, 47))	('men', 'Species', '9606', (55, 58))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('DU145', 'CellLine', 'CVCL:0105', (167, 172))	('prostate cancer', 'Disease', 'MESH:D011471', (32, 47))	('pLKO.1-FAM46C', 'Var', (80, 93))	('prostate cancer', 'Phenotype', 'HP:0012125', (32, 47))	('22RV1', 'CellLine', 'CVCL:1045', (157, 162))
28242	32283544	Our results observed that pLKO.1-shFAM46C#1 and pLKO.1-shFAM46C#3 markedly promoted the cell proliferation of 22RV1 cells by 12.6% and 15.3% at 24 h, by 24.2% and 27.5% at 48 h, and by 33.1% and 37.8% at 72 h, respectively, compared with pLKO.1-shNC (Figure 3B).	('promoted', 'PosReg', (75, 83))	('22RV1', 'CellLine', 'CVCL:1045', (110, 115))	('cell proliferation', 'CPA', (88, 106))	('pLKO.1-shFAM46C#', 'Var', (26, 42))	('pLKO.1-shFAM46C#3', 'Var', (48, 65))
28243	32283544	A colony-formation assay showed that pLKO.1-shFAM46C#1 and pLKO.1-shFAM46C#3 significantly promoted the colony forming growth of 22RV1 cells by 62.4% and 66.4%, respectively, compared with pLKO.1-shNC (Figure 3C).	('colon', 'Disease', (2, 7))	('promoted', 'PosReg', (91, 99))	('colon', 'Disease', 'MESH:D003110', (104, 109))	('22RV1', 'CellLine', 'CVCL:1045', (129, 134))	('colon', 'Disease', 'MESH:D003110', (2, 7))	('colon', 'Disease', (104, 109))	('pLKO.1-shFAM46C', 'Var', (37, 52))	('pLKO.1-shFAM46C#3', 'Var', (59, 76))
28244	32283544	pLKO.1-shFAM46C#1 and pLKO.1-shFAM46C#3 also inhibited 22RV1 cell apoptosis by 61.4% and 68.2%, respectively, compared with pLKO.1-shNC (Figure 3E).	('pLKO.1-shFAM46C', 'Var', (0, 15))	('22RV1', 'CellLine', 'CVCL:1045', (55, 60))	('22RV1 cell apoptosis', 'CPA', (55, 75))	('pLKO.1-shFAM46C#3', 'Var', (22, 39))	('inhibited', 'NegReg', (45, 54))
28246	32283544	After DU145 cells were transduced with pLVX-Puro-FAM46C (Figure 4A), the cell proliferation was significantly inhibited by 16.3%, 23.2% and 28.3% at 24, 48 and 72 h, respectively, compared with vector (Figure 4B).	('pLVX-Puro-FAM46C', 'Var', (39, 55))	('inhibited', 'NegReg', (110, 119))	('cell proliferation', 'CPA', (73, 91))	('DU145', 'CellLine', 'CVCL:0105', (6, 11))
28247	32283544	Colony-formation assay showed that FAM46C overexpression significantly reduced the colony forming growth of DU145 cells by 64.3% compared with vector (Figure 4C).	('DU145', 'CellLine', 'CVCL:0105', (108, 113))	('colon', 'Disease', 'MESH:D003110', (83, 88))	('colon', 'Disease', (83, 88))	('reduced', 'NegReg', (71, 78))	('overexpression', 'PosReg', (42, 56))	('FAM46C', 'Var', (35, 41))
28248	32283544	Moreover, FAM46C overexpression in DU145 cells significantly decreased the cell number in S and G2/M phase and increased the cell number in G0-G1 phase compared with vector (Figure 4D).	('increased', 'PosReg', (111, 120))	('overexpression', 'PosReg', (17, 31))	('decreased', 'NegReg', (61, 70))	('cell number in G0-G1 phase', 'CPA', (125, 151))	('FAM46C', 'Var', (10, 16))	('DU145', 'CellLine', 'CVCL:0105', (35, 40))
28249	32283544	FAM46C overexpression also promoted DU145 cell apoptosis by 25.9-fold compared with vector (Figure 4E).	('DU145 cell apoptosis', 'CPA', (36, 56))	('overexpression', 'Var', (7, 21))	('FAM46C overexpression', 'Var', (0, 21))	('DU145', 'CellLine', 'CVCL:0105', (36, 41))	('promoted', 'PosReg', (27, 35))
28250	32283544	To evaluate the function of FAM46C in prostate cancer in vivo, DU145 cells transduced with pLVX-Puro-FAM46C or blank pLVX-Puro were injected into the nude mice.	('prostate cancer', 'Disease', 'MESH:D011471', (38, 53))	('prostate cancer', 'Phenotype', 'HP:0012125', (38, 53))	('nude mice', 'Species', '10090', (150, 159))	('pLVX-Puro-FAM46C', 'Var', (91, 107))	('prostate cancer', 'Disease', (38, 53))	('DU145', 'CellLine', 'CVCL:0105', (63, 68))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))
28251	32283544	We found that the mice with pLVX-Puro-FAM46C injection showed decreased tumor weight and tumor volume, but increased cell apoptosis (Figure 4F-4H).	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('decreased tumor', 'Disease', 'MESH:D002303', (62, 77))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (72, 77))	('increased', 'PosReg', (107, 116))	('mice', 'Species', '10090', (18, 22))	('tumor', 'Disease', (89, 94))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('cell apoptosis', 'CPA', (117, 131))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('decreased tumor', 'Disease', (62, 77))	('pLVX-Puro-FAM46C', 'Var', (28, 44))
28252	32283544	These data indicated that FAM46C inhibited prostate cancer cell growth, thus playing a critical role in prostate cancer development.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('prostate cancer', 'Disease', 'MESH:D011471', (104, 119))	('prostate cancer', 'Disease', 'MESH:D011471', (43, 58))	('prostate cancer', 'Disease', (43, 58))	('FAM46C', 'Var', (26, 32))	('prostate cancer', 'Phenotype', 'HP:0012125', (104, 119))	('prostate cancer', 'Disease', (104, 119))	('men', 'Species', '9606', (127, 130))	('inhibited', 'NegReg', (33, 42))	('prostate cancer', 'Phenotype', 'HP:0012125', (43, 58))
28254	32283544	As shown in Figure 5B and 5C, FAM46C knockdown in 22RV1 and DU145 cells significantly inhibited the expression of PTEN, P27 and cleaved Caspase-3, but increased phosphorylation level of AKT.	('increased', 'PosReg', (151, 160))	('FAM46C knockdown', 'Var', (30, 46))	('AKT', 'Pathway', (186, 189))	('P27', 'Protein', (120, 123))	('PTEN', 'Protein', (114, 118))	('phosphorylation level', 'MPA', (161, 182))	('knockdown', 'Var', (37, 46))	('DU145', 'CellLine', 'CVCL:0105', (60, 65))	('expression', 'MPA', (100, 110))	('cleaved Caspase-3', 'MPA', (128, 145))	('inhibited', 'NegReg', (86, 95))	('22RV1', 'CellLine', 'CVCL:1045', (50, 55))
28255	32283544	However, FAM46C overexpression in DU145 cells demonstrated an inverse effect (Figure 5D).	('DU145', 'CellLine', 'CVCL:0105', (34, 39))	('FAM46C', 'Var', (9, 15))	('overexpression', 'PosReg', (16, 30))
28256	32283544	Based on the regulatory effect of FAM46C on the expression of PTEN and the level of p-AKT, we hypothesized that the PTEN/AKT signaling pathway may involve in the function of FAM46C in prostate cancer tumorigenesis.	('PTEN/AKT signaling pathway', 'Pathway', (116, 142))	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('prostate cancer', 'Disease', (184, 199))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('tumor', 'Disease', (200, 205))	('FAM46C', 'Var', (174, 180))	('prostate cancer', 'Disease', 'MESH:D011471', (184, 199))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('involve', 'Reg', (147, 154))	('prostate cancer', 'Phenotype', 'HP:0012125', (184, 199))
28258	32283544	As shown in Figure 6A-6F, SF1670 or IGF-1 treatment significantly inhibited FAM46C overexpression-mediated cell growth and the expression of P27 and cleaved Caspase-3.	('Caspase-3', 'Protein', (157, 166))	('expression', 'MPA', (127, 137))	('P27', 'Protein', (141, 144))	('IGF-1', 'Gene', (36, 41))	('SF1670', 'Chemical', 'MESH:C000619508', (26, 32))	('inhibited', 'NegReg', (66, 75))	('men', 'Species', '9606', (47, 50))	('FAM46C', 'Gene', (76, 82))	('SF1670', 'Var', (26, 32))	('cleaved', 'MPA', (149, 156))
28259	32283544	These data indicate that FAM46C may inhibit prostate cancer cell growth through PTEN/AKT signaling pathway.	('prostate cancer', 'Phenotype', 'HP:0012125', (44, 59))	('inhibit', 'NegReg', (36, 43))	('prostate cancer', 'Disease', (44, 59))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('PTEN/AKT signaling pathway', 'Pathway', (80, 106))	('prostate cancer', 'Disease', 'MESH:D011471', (44, 59))	('FAM46C', 'Var', (25, 31))
28260	32283544	Since FAM46C expression did not affect the mRNA expression of PTEN in prostate cancer cells (data not shown), we indicated that FAM46C may increase PTEN expression by the post-transcriptional modification.	('prostate cancer', 'Disease', 'MESH:D011471', (70, 85))	('FAM46C', 'Var', (128, 134))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('prostate cancer', 'Phenotype', 'HP:0012125', (70, 85))	('increase', 'PosReg', (139, 147))	('expression', 'MPA', (153, 163))	('prostate cancer', 'Disease', (70, 85))	('PTEN', 'Protein', (148, 152))
28261	32283544	As shown in Figure 7A, Co-IP analysis demonstrated that FAM46C was interacted with PTEN in DU145 cells.	('FAM46C', 'Var', (56, 62))	('DU145', 'CellLine', 'CVCL:0105', (91, 96))	('interacted', 'Interaction', (67, 77))
28262	32283544	Additionally, FAM46C overexpression in DU145 cells inhibited the ubiquitination of PTEN was significantly inversed by MG132 treatment, suggesting that FAM46C may inhibit the proteasome-dependent ubiquitination of PTEN (Figure 7B).	('inhibit', 'NegReg', (162, 169))	('MG132', 'Chemical', 'MESH:C072553', (118, 123))	('DU145', 'CellLine', 'CVCL:0105', (39, 44))	('ubiquitination', 'MPA', (65, 79))	('inversed', 'NegReg', (106, 114))	('overexpression', 'PosReg', (21, 35))	('men', 'Species', '9606', (129, 132))	('PTEN', 'Protein', (213, 217))	('PTEN', 'Protein', (83, 87))	('inhibited', 'NegReg', (51, 60))	('proteasome-dependent ubiquitination', 'MPA', (174, 209))	('FAM46C', 'Var', (151, 157))
28265	32283544	Linear regression showed that FAM46C protein expression was positively correlated with that of PTEN in prostate cancer tissues (Figure 7D).	('prostate cancer', 'Disease', 'MESH:D011471', (103, 118))	('correlated', 'Reg', (71, 81))	('prostate cancer', 'Phenotype', 'HP:0012125', (103, 118))	('PTEN', 'Disease', (95, 99))	('expression', 'MPA', (45, 55))	('FAM46C', 'Var', (30, 36))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('protein', 'Protein', (37, 44))	('prostate cancer', 'Disease', (103, 118))
28267	32283544	CCK-8 assay showed that DU145 cells with FAM46C overexpression were more sensitive to docetaxel (Figure 8A).	('docetaxel', 'Chemical', 'MESH:D000077143', (86, 95))	('sensitive to docetaxel', 'MPA', (73, 95))	('DU145', 'CellLine', 'CVCL:0105', (24, 29))	('overexpression', 'PosReg', (48, 62))	('CCK-8', 'Chemical', '-', (0, 5))	('FAM46C', 'Var', (41, 47))
28268	32283544	Conversely, 22RV1 cells with FAM46C knockdown resulted in increased resistance to docetaxel (Figure 8B).	('increased', 'PosReg', (58, 67))	('resistance to docetaxel', 'MPA', (68, 91))	('knockdown', 'Var', (36, 45))	('FAM46C knockdown', 'Var', (29, 45))	('docetaxel', 'Chemical', 'MESH:D000077143', (82, 91))	('22RV1', 'CellLine', 'CVCL:1045', (12, 17))
28269	32283544	PDX mice following docetaxel chemotherapy with high-FAM46C-expressing demonstrated smaller tumor size and tumor volume than that with low-FAM46C-expressing (Figure 8C and 8D).	('mice', 'Species', '10090', (4, 8))	('high-FAM46C-expressing', 'Var', (47, 69))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('docetaxel', 'Chemical', 'MESH:D000077143', (19, 28))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('smaller', 'NegReg', (83, 90))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Disease', (91, 96))	('tumor', 'Disease', (106, 111))
28270	32283544	Moreover, the expression of FAM46C in the cells isolated from primary prostate cancer patients in hospital cohort was measured by qRT-PCR and categorized into FAM46C high and low groups (Figure 8E).	('FAM46C', 'Var', (159, 165))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('prostate cancer', 'Phenotype', 'HP:0012125', (70, 85))	('expression', 'MPA', (14, 24))	('primary prostate cancer', 'Disease', (62, 85))	('FAM46C', 'Gene', (28, 34))	('primary prostate cancer', 'Disease', 'MESH:D011471', (62, 85))	('patients', 'Species', '9606', (86, 94))
28271	32283544	In addition, the primary prostate cancer cells with high FAM46C expression were more sensitive to docetaxel than that with low FAM46C expression (Figure 8F).	('sensitive to docetaxel', 'MPA', (85, 107))	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('high FAM46C expression', 'Var', (52, 74))	('prostate cancer', 'Phenotype', 'HP:0012125', (25, 40))	('primary prostate cancer', 'Disease', (17, 40))	('docetaxel', 'Chemical', 'MESH:D000077143', (98, 107))	('primary prostate cancer', 'Disease', 'MESH:D011471', (17, 40))
28272	32283544	These data suggest that FAM46C may involve in chemosensitivity of prostate cancer.	('chemosensitivity of prostate cancer', 'Disease', (46, 81))	('prostate cancer', 'Phenotype', 'HP:0012125', (66, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('FAM46C', 'Var', (24, 30))	('involve', 'Reg', (35, 42))	('chemosensitivity of prostate cancer', 'Disease', 'MESH:D011471', (46, 81))
28275	32283544	Clinical data showed that FAM46C was decreased and correlated with cell cycle, apoptosis and PTEN signaling pathway in prostate cancer.	('prostate cancer', 'Phenotype', 'HP:0012125', (119, 134))	('PTEN signaling pathway', 'Pathway', (93, 115))	('prostate cancer', 'Disease', (119, 134))	('FAM46C', 'Var', (26, 32))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('apoptosis', 'CPA', (79, 88))	('cell cycle', 'CPA', (67, 77))	('decreased', 'NegReg', (37, 46))	('prostate cancer', 'Disease', 'MESH:D011471', (119, 134))	('correlated', 'Reg', (51, 61))
28280	32283544	Previous study reported that FAM46C was identified with potential pathogenic and prognostic significance based on the occurrence of recurrent homozygous deletions and mutations in myeloma.	('FAM46C', 'Gene', (29, 35))	('myeloma', 'Disease', (180, 187))	('myeloma', 'Disease', 'MESH:D009101', (180, 187))	('mutations', 'Var', (167, 176))
28281	32283544	Similarly, our results strongly suggested that FAM46C expression could be of clinical value as a prognostic indicator of several cancer types, such as BLCA, CSCC, HNSC, KIRC, LUAD, OC, PDAD, SARC or UCEC, and may as an independent prognostic factor play important role in prostate cancer.	('prostate cancer', 'Disease', 'MESH:D011471', (272, 287))	('prostate cancer', 'Phenotype', 'HP:0012125', (272, 287))	('cancer', 'Disease', (129, 135))	('prostate cancer', 'Disease', (272, 287))	('HNSC', 'Disease', (163, 167))	('OC', 'Phenotype', 'HP:0100615', (181, 183))	('LUAD', 'Phenotype', 'HP:0030078', (175, 179))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('HNSC', 'Phenotype', 'HP:0012288', (163, 167))	('cancer', 'Disease', 'MESH:D009369', (281, 287))	('FAM46C', 'Var', (47, 53))	('PDAD', 'Disease', (185, 189))	('SARC', 'Disease', (191, 195))	('PDAD', 'Phenotype', 'HP:0006725', (185, 189))	('KIRC', 'Disease', (169, 173))	('LUAD', 'Disease', (175, 179))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('SARC', 'Phenotype', 'HP:0100242', (191, 195))	('cancer', 'Disease', (281, 287))	('BLCA', 'Disease', (151, 155))	('CSCC', 'Disease', (157, 161))	('UCEC', 'Disease', (199, 203))	('cancer', 'Phenotype', 'HP:0002664', (281, 287))	('BLCA', 'Phenotype', 'HP:0002862', (151, 155))
28283	32283544	However, FAM46C overexpression in HCC cells induced the cell cycle G2-M phase arrest, but not the G0-G1 phase.	('arrest', 'Disease', (78, 84))	('FAM46C', 'Var', (9, 15))	('overexpression', 'PosReg', (16, 30))	('arrest', 'Disease', 'MESH:D006323', (78, 84))	('HCC', 'Phenotype', 'HP:0001402', (34, 37))
28286	32283544	Previous study found that the occurrence of prostate cancer and the process of hormone-independent transformation are related to the deletion of PTEN expression.	('related', 'Reg', (118, 125))	('PTEN', 'Gene', (145, 149))	('prostate cancer', 'Disease', (44, 59))	('deletion', 'Var', (133, 141))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('prostate cancer', 'Disease', 'MESH:D011471', (44, 59))	('prostate cancer', 'Phenotype', 'HP:0012125', (44, 59))
28287	32283544	The deletion of PTEN expression occurs during the development of 20%-40% of primary prostate cancer and PTEN expression was observed in 30% of the hormone-independent prostate cancer tissues.	('prostate cancer', 'Phenotype', 'HP:0012125', (167, 182))	('primary prostate cancer', 'Disease', 'MESH:D011471', (76, 99))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('prostate cancer', 'Disease', (167, 182))	('PTEN', 'Gene', (16, 20))	('deletion', 'Var', (4, 12))	('prostate cancer', 'Disease', 'MESH:D011471', (84, 99))	('primary prostate cancer', 'Disease', (76, 99))	('men', 'Species', '9606', (57, 60))	('prostate cancer', 'Phenotype', 'HP:0012125', (84, 99))	('prostate cancer', 'Disease', 'MESH:D011471', (167, 182))
28289	32283544	PTEN inhibiting AKT signaling has been observed in prostate cancer and is associated with cell cycle procession, cell apoptosis and cell proliferation.	('inhibiting', 'NegReg', (5, 15))	('prostate cancer', 'Disease', 'MESH:D011471', (51, 66))	('cell apoptosis', 'CPA', (113, 127))	('prostate cancer', 'Phenotype', 'HP:0012125', (51, 66))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('cell proliferation', 'CPA', (132, 150))	('AKT signaling', 'Pathway', (16, 29))	('prostate cancer', 'Disease', (51, 66))	('PTEN', 'Var', (0, 4))	('cell cycle procession', 'CPA', (90, 111))
28294	32283544	Therefore, we suggest that FAM46C may increase the chemosensitivity of prostate cancer cells to docetaxel through the PTEN/AKT signaling pathway, even though their roles are required for further investigation.	('increase', 'PosReg', (38, 46))	('docetaxel', 'Chemical', 'MESH:D000077143', (96, 105))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('chemosensitivity of prostate cancer', 'Disease', 'MESH:D011471', (51, 86))	('chemosensitivity of prostate cancer', 'Disease', (51, 86))	('prostate cancer', 'Phenotype', 'HP:0012125', (71, 86))	('PTEN/AKT signaling pathway', 'Pathway', (118, 144))	('FAM46C', 'Var', (27, 33))
28297	32283544	Therefore, we may speculate that FAM46C highlighted its anti-metastatic role in prostate cancer.	('FAM46C', 'Var', (33, 39))	('prostate cancer', 'Disease', 'MESH:D011471', (80, 95))	('prostate cancer', 'Phenotype', 'HP:0012125', (80, 95))	('anti-metastatic', 'MPA', (56, 71))	('prostate cancer', 'Disease', (80, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
28299	32283544	In summary, our data indicate that FAM46C was associated with prognosis of prostate cancer patients and its overexpression suppressed cell growth of prostate cancer through PTEN/AKT signaling pathway, which may serves as a mode that mediates prostate cancer cell response to chemotherapy.	('prostate cancer', 'Disease', (75, 90))	('prostate cancer', 'Disease', (242, 257))	('overexpression', 'PosReg', (108, 122))	('patients', 'Species', '9606', (91, 99))	('cell growth', 'CPA', (134, 145))	('associated', 'Reg', (46, 56))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('PTEN/AKT signaling pathway', 'Pathway', (173, 199))	('prognosis', 'Disease', (62, 71))	('prostate cancer', 'Disease', 'MESH:D011471', (149, 164))	('prostate cancer', 'Phenotype', 'HP:0012125', (149, 164))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('prostate cancer', 'Disease', (149, 164))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('suppressed', 'NegReg', (123, 133))	('prostate cancer', 'Disease', 'MESH:D011471', (242, 257))	('prostate cancer', 'Phenotype', 'HP:0012125', (242, 257))	('prostate cancer', 'Disease', 'MESH:D011471', (75, 90))	('prostate cancer', 'Phenotype', 'HP:0012125', (75, 90))	('FAM46C', 'Var', (35, 41))
28300	32283544	This study suggests that FAM46C can be a possible therapeutic agent, particularly in combination with anti-cancer chemotherapy agents.	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('FAM46C', 'Var', (25, 31))	('cancer', 'Disease', (107, 113))	('cancer', 'Disease', 'MESH:D009369', (107, 113))
28331	32283544	A0208, A0181 and A0216; Beyotime Biotechnology, Shanghai, China) for 1 h at 37 C. Protein expression was assessed by an enhanced chemiluminescence (ECL) kit (ECL New England Biolabs, Ltd, Whitby, ON, USA) following the manufacturer's instructions.	('A0181', 'Var', (7, 12))	('A0208', 'Var', (0, 5))	('kit', 'Gene', (153, 156))	('kit', 'Gene', '3815', (153, 156))	('A0216', 'Var', (17, 22))
28336	32283544	For in vivo tumorigenesis assay, a total of 4x106 DU145 cells stably transduced with pLVX-Puro-FAM46C or blank pLVX-Puro were trypsinized, resuspended in PBS, and then subcutaneously injected into the flanks of BALB/c male nude mice (4-5 week-old; 6 per group; Shanghai Experimental Animal Center, Shanghai, China).	('PBS', 'Chemical', 'MESH:D007854', (154, 157))	('men', 'Species', '9606', (276, 279))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('DU145', 'CellLine', 'CVCL:0105', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('nude mice', 'Species', '10090', (223, 232))	('tumor', 'Disease', (12, 17))	('pLVX-Puro-FAM46C', 'Var', (85, 101))
28355	32799882	Previous studies have showed that expression of angiopoietin-2 was significantly associated with angiogenesis and vessel maturation in oral squamous cell carcinoma (SCC).	('angiogenesis', 'CPA', (97, 109))	('oral squamous cell carcinoma', 'Disease', (135, 163))	('SCC', 'Gene', (165, 168))	('SCC', 'Phenotype', 'HP:0002860', (165, 168))	('angiopoietin-2', 'Gene', '285', (48, 62))	('angiopoietin-2', 'Gene', (48, 62))	('expression', 'Var', (34, 44))	('SCC', 'Gene', '6317', (165, 168))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (135, 163))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (140, 163))	('carcinoma', 'Phenotype', 'HP:0030731', (154, 163))	('vessel maturation', 'CPA', (114, 131))	('associated', 'Reg', (81, 91))
28416	32799882	Our results further showed the plasma angiopoietin-2 was also upregulated by surgery in HNSCC.	('angiopoietin-2', 'Gene', '285', (38, 52))	('angiopoietin-2', 'Gene', (38, 52))	('SCC', 'Gene', (90, 93))	('SCC', 'Phenotype', 'HP:0002860', (90, 93))	('upregulated', 'PosReg', (62, 73))	('HNSCC', 'Phenotype', 'HP:0012288', (88, 93))	('surgery', 'Var', (77, 84))	('SCC', 'Gene', '6317', (90, 93))
28419	32799882	The expression of angiopoietin-2 is upregulated at sites of tumor angiogenesis in multiple types of cancer, and overexpression of angiopoietin-2 promoted angiogenesis and tumor growth in experimental models.	('angiopoietin-2', 'Gene', (130, 144))	('upregulated', 'PosReg', (36, 47))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('angiopoietin-2', 'Gene', '285', (130, 144))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('expression', 'MPA', (4, 14))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('angiopoietin-2', 'Gene', '285', (18, 32))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('angiopoietin-2', 'Gene', (18, 32))	('overexpression', 'Var', (112, 126))	('angiogenesis', 'CPA', (154, 166))	('tumor', 'Disease', (171, 176))	('tumor', 'Disease', (60, 65))	('promoted', 'PosReg', (145, 153))
28462	32257046	These changes lead to the accumulation of insults and epigenetic changes that can change the course of a developing or established tumor.	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('change', 'Reg', (82, 88))	('epigenetic changes', 'Var', (54, 72))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('course of a developing', 'CPA', (93, 115))	('changes', 'Var', (6, 13))	('tumor', 'Disease', (131, 136))	('lead to', 'Reg', (14, 21))
28485	32257046	(2018) examined the lung microbiome association with TP53 mutation using 16S rRNA methods and confirmed findings with TCGA lung cancer data.	('lung cancer', 'Disease', (123, 134))	('lung cancer', 'Phenotype', 'HP:0100526', (123, 134))	('mutation', 'Var', (58, 66))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('lung cancer', 'Disease', 'MESH:D008175', (123, 134))	('TP53', 'Gene', '7157', (53, 57))	('examined', 'Reg', (7, 15))	('TP53', 'Gene', (53, 57))
28581	32257046	Overall, Fusobacteria reads represented less than 1% of the total mapped reads in COAD and READ.	('COAD', 'Disease', (82, 86))	('Fusobacteria', 'Var', (9, 21))	('COAD', 'Disease', 'MESH:D029424', (82, 86))
28616	32257046	In TCGA STAD cohort, Selenomonas sputigena had the highest proportion of mapped reads detected in tumor samples compared other species with a prevalence of 18% of tumor compared to 9% of adjacent normal samples.	('Selenomonas', 'Var', (21, 32))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('to 9', 'Species', '1214577', (178, 182))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumor', 'Disease', (163, 168))	('Selenomonas sputigena', 'Species', '69823', (21, 42))	('tumor', 'Disease', (98, 103))
28636	32257046	Interestingly, Selenomonas sputigena has been detected in the tongue coatings of gastric cancer patients and identified as a potential biomarker.	('Selenomonas sputigena', 'Species', '69823', (15, 36))	('gastric cancer', 'Disease', 'MESH:D013274', (81, 95))	('gastric cancer', 'Disease', (81, 95))	('Selenomonas', 'Var', (15, 26))	('patients', 'Species', '9606', (96, 104))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('gastric cancer', 'Phenotype', 'HP:0012126', (81, 95))
28669	32257046	Similarly, Bacteroides vulgatus is believed to have protective anti-tumorigenic effects and one of the most commonly identified species from stool.	('tumor', 'Disease', (68, 73))	('Bacteroides', 'Var', (11, 22))	('Bacteroides vulgatus', 'Species', '821', (11, 31))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))
28675	30081883	LVD was positively associated with the prognosis of NSCLC in the overall analysis (hazard ratio (HR) 1.14, 95% confidence interval (95% CI): 1.02-1.27, p = 0.000, I2 = 73.2%).	('LVD', 'Var', (0, 3))	('NSCLC', 'Disease', 'MESH:D002289', (52, 57))	('NSCLC', 'Disease', (52, 57))
28714	30081883	The study by Zheng and colleagues showed that the VEGF family is important for tumorigenesis and metastasis and that high VEGF and/or VEGFR expression, especially VEGF-C/VEGFR-3 co-expression, is indicative of poor survival in patients with NSCLC.	('VEGFR', 'Gene', '3791', (134, 139))	('VEGFR', 'Gene', (134, 139))	('VEGF', 'Gene', '7422', (50, 54))	('VEGF', 'Gene', '7422', (170, 174))	('VEGF', 'Gene', '7422', (163, 167))	('VEGF', 'Gene', '7422', (122, 126))	('VEGF', 'Gene', (50, 54))	('VEGF', 'Gene', (170, 174))	('VEGF-C', 'Gene', (163, 169))	('VEGF', 'Gene', (163, 167))	('VEGF', 'Gene', (122, 126))	('VEGFR', 'Gene', '3791', (170, 175))	('high', 'Var', (117, 121))	('VEGF-C', 'Gene', '7424', (163, 169))	('patients', 'Species', '9606', (227, 235))	('VEGFR', 'Gene', (170, 175))	('tumor', 'Disease', (79, 84))	('NSCLC', 'Disease', 'MESH:D002289', (241, 246))	('VEGFR-3', 'Gene', '2324', (170, 177))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('VEGF', 'Gene', '7422', (134, 138))	('NSCLC', 'Disease', (241, 246))	('VEGF', 'Gene', (134, 138))	('VEGFR-3', 'Gene', (170, 177))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
28719	30081883	The study by Arinaga demonstrated that the combined expression of VEGF-C and VEGFR-3 has a negative impact on the prognosis of patients with NSCLC.	('VEGF-C', 'Gene', (66, 72))	('NSCLC', 'Disease', (141, 146))	('patients', 'Species', '9606', (127, 135))	('NSCLC', 'Disease', 'MESH:D002289', (141, 146))	('VEGFR-3', 'Gene', '2324', (77, 84))	('VEGF-C', 'Gene', '7424', (66, 72))	('combined', 'Interaction', (43, 51))	('expression', 'Var', (52, 62))	('negative', 'NegReg', (91, 99))	('VEGFR-3', 'Gene', (77, 84))
28720	30081883	In addition, the study by Zhang and colleagues revealed that D2-40-positive peritumoral LVD may be an independent prognostic factor for lung adenocarcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (136, 155))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumor', 'Disease', (80, 85))	('D2-40-positive', 'Var', (61, 75))	('lung adenocarcinoma', 'Disease', (136, 155))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (136, 155))
28721	30081883	Thus, D2-40-positivity may be used to predict patient prognosis in lung adenocarcinoma.	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (67, 86))	('patient', 'Species', '9606', (46, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('lung adenocarcinoma', 'Disease', (67, 86))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (67, 86))	('D2-40-positivity', 'Var', (6, 22))
28724	30081883	Yang and his team demonstrated the role of the epigenetic regulation of desmoplakin in increasing the sensitivity of cancer cells to anticancer drug-induced apoptosis, implying the clinical value of desmoplakin for the treatment of patients with lung cancer.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('desmoplakin', 'Gene', (72, 83))	('sensitivity', 'MPA', (102, 113))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('patients', 'Species', '9606', (232, 240))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('epigenetic regulation', 'Var', (47, 68))	('lung cancer', 'Disease', 'MESH:D008175', (246, 257))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('increasing', 'PosReg', (87, 97))	('cancer', 'Disease', (137, 143))	('cancer', 'Disease', 'MESH:D009369', (251, 257))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('cancer', 'Disease', (117, 123))	('cancer', 'Disease', (251, 257))	('lung cancer', 'Disease', (246, 257))	('lung cancer', 'Phenotype', 'HP:0100526', (246, 257))
28749	26711175	In cancer, oncogenic aberrations of the FGFR3 gene cause sustained cell proliferation, contributing to tumor development 3.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('FGFR3', 'Gene', (40, 45))	('sustained cell proliferation', 'CPA', (57, 85))	('tumor', 'Disease', (103, 108))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('cancer', 'Disease', (3, 9))	('FGFR3', 'Gene', '2261', (40, 45))	('cause', 'Reg', (51, 56))	('rat', 'Species', '10116', (25, 28))	('rat', 'Species', '10116', (79, 82))	('contributing', 'PosReg', (87, 99))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('aberrations', 'Var', (21, 32))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
28750	26711175	Genomic aberrations include FGFR3 driver mutations, FGFR3 gene amplification, and FGFR3 translocations, which frequently occur in bladder cancer, myeloma, and glioblastoma 4, 5.	('myeloma', 'Disease', 'MESH:D009101', (146, 153))	('translocations', 'Var', (88, 102))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('occur', 'Reg', (121, 126))	('mutations', 'Var', (41, 50))	('FGFR3', 'Gene', (28, 33))	('glioblastoma', 'Disease', 'MESH:D005909', (159, 171))	('FGFR3', 'Gene', (52, 57))	('FGFR3', 'Gene', (82, 87))	('myeloma', 'Disease', (146, 153))	('rat', 'Species', '10116', (12, 15))	('FGFR3', 'Gene', '2261', (28, 33))	('FGFR3', 'Gene', '2261', (52, 57))	('glioblastoma', 'Disease', (159, 171))	('FGFR3', 'Gene', '2261', (82, 87))	('glioblastoma', 'Phenotype', 'HP:0012174', (159, 171))	('amplification', 'Var', (63, 76))	('bladder cancer', 'Disease', 'MESH:D001749', (130, 144))	('bladder cancer', 'Disease', (130, 144))	('bladder cancer', 'Phenotype', 'HP:0009725', (130, 144))
28753	26711175	At the moment, early phase clinical trials are conducted with FGFR3-directed targeted therapies on patients with FGFR3-aberrated glioblastoma multiforme, transitional cell carcinoma, multiple myeloma, and other advanced solid malignancies (ClinicalTrials.gov Identifier: NCT01975701, NCT02278978, NCT02401542, NCT02052778).	('NCT02052778', 'Var', (310, 321))	('glioblastoma', 'Disease', (129, 141))	('multiple myeloma', 'Phenotype', 'HP:0006775', (183, 199))	('glioblastoma', 'Disease', 'MESH:D005909', (129, 141))	('FGFR3', 'Gene', (113, 118))	('multiple myeloma', 'Disease', 'MESH:D009101', (183, 199))	('FGFR3', 'Gene', '2261', (62, 67))	('multiple myeloma', 'Disease', (183, 199))	('carcinoma', 'Disease', (172, 181))	('carcinoma', 'Phenotype', 'HP:0030731', (172, 181))	('NCT02401542', 'Var', (297, 308))	('glioblastoma', 'Phenotype', 'HP:0012174', (129, 141))	('patients', 'Species', '9606', (99, 107))	('rat', 'Species', '10116', (123, 126))	('transitional cell carcinoma', 'Phenotype', 'HP:0006740', (154, 181))	('FGFR3', 'Gene', (62, 67))	('carcinoma', 'Disease', 'MESH:D002277', (172, 181))	('FGFR3', 'Gene', '2261', (113, 118))
28791	26711175	A FGFR3/IGH ratio was calculated and defined as: <1.5: normal copy-numbers, 1.5-2.0: copy-number gain and >2.0: gene amplification 13.	('IGH', 'Gene', (8, 11))	('FGFR3', 'Gene', (2, 7))	('copy-number', 'Var', (85, 96))	('rat', 'Species', '10116', (12, 15))	('gain', 'PosReg', (97, 101))	('FGFR3', 'Gene', '2261', (2, 7))	('IGH', 'Gene', '3492', (8, 11))
28826	26711175	For example, targeting FGFR3 with FGFR-inhibitor PD173074 reduced cell proliferation and enhanced radiotherapy sensitivity of resistant OSCC cell lines and xenografts 17.	('FGFR3', 'Gene', (23, 28))	('enhanced', 'PosReg', (89, 97))	('cell proliferation', 'CPA', (66, 84))	('PD173074', 'Chemical', 'MESH:C115711', (49, 57))	('rat', 'Species', '10116', (78, 81))	('PD173074', 'Var', (49, 57))	('FGFR3', 'Gene', '2261', (23, 28))	('radiotherapy sensitivity', 'CPA', (98, 122))	('reduced', 'NegReg', (58, 65))
28841	26711175	Specifically, FGFR3-TACC3 translocations occur predominantly in HPV-positive HNSCC, whereas FGFR3 amplification occurs in HPV-negative HNSCC and FGFR3 mutations occur in both.	('HPV', 'Species', '10566', (122, 125))	('FGFR3', 'Gene', (92, 97))	('FGFR3', 'Gene', '2261', (14, 19))	('TACC3', 'Gene', (20, 25))	('FGFR3', 'Gene', '2261', (145, 150))	('occur', 'Reg', (41, 46))	('FGFR3', 'Gene', (14, 19))	('translocations', 'Var', (26, 40))	('HNSCC', 'Disease', (77, 82))	('HPV-positive HNSCC', 'Disease', (64, 82))	('FGFR3', 'Gene', (145, 150))	('FGFR3', 'Gene', '2261', (92, 97))	('TACC3', 'Gene', '10460', (20, 25))	('HPV', 'Species', '10566', (64, 67))
28842	26711175	Tumors bearing these FGFR3 gene aberrations respond very well to FGFR-inhibitors in preclinical models and early phase clinical studies 37.	('FGFR3', 'Gene', '2261', (21, 26))	('rat', 'Species', '10116', (36, 39))	('FGFR3', 'Gene', (21, 26))	('aberrations', 'Var', (32, 43))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))
28843	26711175	Considering the frequent occurrence of FGFR3 aberrations in HPV-positive HNSCC and impressive response to FGFR-inhibitors, FGFR3 protein might be of therapeutic value in this HNSCC subpopulation.	('FGFR3', 'Gene', '2261', (123, 128))	('aberrations', 'Var', (45, 56))	('FGFR3', 'Gene', (123, 128))	('HNSCC', 'Disease', (73, 78))	('occurrence', 'Reg', (25, 35))	('FGFR3', 'Gene', '2261', (39, 44))	('HPV', 'Species', '10566', (60, 63))	('rat', 'Species', '10116', (49, 52))	('FGFR3', 'Gene', (39, 44))
28845	26711175	The FGFR3 amplification observed by the previous study in a mixed HPV-negative HNSCC cohort was not observed in the OSCC and OPSCC cohorts in this study 30.	('HNSCC', 'Disease', (79, 84))	('HPV', 'Species', '10566', (66, 69))	('FGFR3', 'Gene', (4, 9))	('amplification', 'Var', (10, 23))	('FGFR3', 'Gene', '2261', (4, 9))
28863	25384882	Recently, oncogenic driver mutations including EGFR gene mutation and ALK fusion gene have been found in the majority of ADC.	('mutation', 'Var', (57, 65))	('ALK', 'Gene', '238', (70, 73))	('EGFR', 'Gene', (47, 51))	('ADC', 'Disease', (121, 124))	('EGFR', 'Gene', '1956', (47, 51))	('ALK', 'Gene', (70, 73))	('found', 'Reg', (96, 101))
28864	25384882	Recent randomized trials of gefitinib, erlotinib and crizotinib have demonstrated the significant superiority of these molecular targeted drugs on progression-free survival compared with standard chemotherapies as the key agents for the treatment of advanced ADC with driver mutations.	('mutations', 'Var', (275, 284))	('gefitinib', 'Chemical', 'MESH:D000077156', (28, 37))	('crizotinib', 'Chemical', 'MESH:D000077547', (53, 63))	('erlotinib', 'Chemical', 'MESH:D000069347', (39, 48))	('ADC', 'Disease', (259, 262))
28877	25384882	Multiplex testing for driver mutations in SQCC of the lung (SQ-MAP) using specimens from 40 SQCC patients was reported in 2012.	('SQCC of the lung', 'Disease', (42, 58))	('mutations', 'Var', (29, 38))	('SQCC', 'Phenotype', 'HP:0002860', (42, 46))	('SQCC', 'Phenotype', 'HP:0002860', (92, 96))	('patients', 'Species', '9606', (97, 105))
28878	25384882	FGFR1 amplification was found in 25% and PIK3CA mutation was observed in 11% of SQCC tumors by SQ-MAP.	('SQCC tumors', 'Disease', (80, 91))	('PIK3CA', 'Gene', '5290', (41, 47))	('PIK3CA', 'Gene', (41, 47))	('FGFR1', 'Gene', (0, 5))	('observed', 'Reg', (61, 69))	('FGFR1', 'Gene', '2260', (0, 5))	('mutation', 'Var', (48, 56))	('SQCC tumors', 'Disease', 'MESH:D009369', (80, 91))	('SQCC', 'Phenotype', 'HP:0002860', (80, 84))	('amplification', 'Var', (6, 19))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))
28879	25384882	Based on the SQ-MAP, two approved clinical trials using FGFR1 inhibition and PI3K inhibition have begun.	('clinical', 'Species', '191496', (34, 42))	('FGFR1', 'Gene', '2260', (56, 61))	('FGFR1', 'Gene', (56, 61))	('inhibition', 'Var', (62, 72))
28939	25384882	Recent whole genomic studies indicated frequent amplification at chromosome 3q26 in SQCC, suggesting a potential critical role of this chromosome in carcinogenesis and progression in SQCC.	('carcinogenesis', 'Disease', (149, 163))	('SQCC', 'Phenotype', 'HP:0002860', (183, 187))	('SQCC', 'Disease', (84, 88))	('carcinogenesis', 'Disease', 'MESH:D063646', (149, 163))	('SQCC', 'Phenotype', 'HP:0002860', (84, 88))	('amplification', 'Var', (48, 61))
28941	25384882	PIK3CA gene alteration was found in 16% of lung SQCC samples by The Cancer Genome Atlas, resulting in PI3K pathway alterations.	('alteration', 'Var', (12, 22))	('lung SQCC', 'Disease', (43, 52))	('alterations', 'Reg', (115, 126))	('Cancer', 'Disease', 'MESH:D009369', (68, 74))	('Cancer', 'Disease', (68, 74))	('SQCC', 'Phenotype', 'HP:0002860', (48, 52))	('PIK3CA', 'Gene', (0, 6))	('Cancer', 'Phenotype', 'HP:0002664', (68, 74))	('PI3K pathway', 'Pathway', (102, 114))	('PIK3CA', 'Gene', '5290', (0, 6))
28942	25384882	In addition, PIK3CA gene alteration was more frequently observed in lung SQCC than in ADC.	('observed', 'Reg', (56, 64))	('PIK3CA', 'Gene', (13, 19))	('lung SQCC', 'Disease', (68, 77))	('SQCC', 'Phenotype', 'HP:0002860', (73, 77))	('PIK3CA', 'Gene', '5290', (13, 19))	('alteration', 'Var', (25, 35))
28943	25384882	In Asian patients, PIK3CA copy number gains by FISH were found in 43% of Japanese SQCC patients.	('PIK3CA', 'Gene', (19, 25))	('patients', 'Species', '9606', (9, 17))	('SQCC', 'Phenotype', 'HP:0002860', (82, 86))	('PIK3CA', 'Gene', '5290', (19, 25))	('copy number', 'Var', (26, 37))	('patients', 'Species', '9606', (87, 95))
28946	25384882	The association between PIK3CA gene alteration and the patient prognosis has not been clarified; however, patients with PIK3CA gene mutation tended to have an unfavorable prognosis.	('PIK3CA', 'Gene', (120, 126))	('PIK3CA', 'Gene', (24, 30))	('patient', 'Species', '9606', (106, 113))	('PIK3CA', 'Gene', '5290', (120, 126))	('PIK3CA', 'Gene', '5290', (24, 30))	('patients', 'Species', '9606', (106, 114))	('patient', 'Species', '9606', (55, 62))	('mutation', 'Var', (132, 140))
28948	25384882	These findings suggest that PIK3CA alteration may be involved in the process of carcinogenesis of SQCC and contribute to the prognosis of SQCC.	('carcinogenesis', 'Disease', 'MESH:D063646', (80, 94))	('involved', 'Reg', (53, 61))	('SQCC', 'Phenotype', 'HP:0002860', (98, 102))	('PIK3CA', 'Gene', (28, 34))	('SQCC', 'Phenotype', 'HP:0002860', (138, 142))	('PIK3CA', 'Gene', '5290', (28, 34))	('contribute', 'Reg', (107, 117))	('alteration', 'Var', (35, 45))	('SQCC', 'Disease', (98, 102))	('carcinogenesis', 'Disease', (80, 94))
28964	25384882	EGFR mutations are found at different frequencies in Caucasian and East Asian patients with lung AC.	('EGFR', 'Gene', (0, 4))	('lung AC', 'Disease', (92, 99))	('patients', 'Species', '9606', (78, 86))	('mutations', 'Var', (5, 14))	('EGFR', 'Gene', '1956', (0, 4))
28971	33692839	Cisplatin (DDP) is an effective drug in OSCC treatment, but DDP resistance weakens its therapeutic effect.	('DDP', 'Chemical', '-', (11, 14))	('OSCC', 'Disease', (40, 44))	('therapeutic', 'MPA', (87, 98))	('Cisplatin', 'Chemical', 'MESH:D002945', (0, 9))	('weakens', 'NegReg', (75, 82))	('DDP', 'Var', (60, 63))	('DDP', 'Chemical', '-', (60, 63))
28980	33692839	It was observed that OIP5-AS1 was upregulated in DDP-resistant OSCC cells, and the knockdown of OIP5-AS1 improved DDP sensitivity in DDP-resistant OSCC cells.	('DDP', 'Chemical', '-', (133, 136))	('DDP sensitivity', 'MPA', (114, 129))	('upregulated', 'PosReg', (34, 45))	('DDP', 'Chemical', '-', (49, 52))	('DDP', 'Chemical', '-', (114, 117))	('OIP5-AS1', 'Gene', '729082;11339;5729', (21, 29))	('OIP5-AS1', 'Gene', '729082;11339;5729', (96, 104))	('DDP-resistant', 'Disease', (49, 62))	('improved', 'PosReg', (105, 113))	('OIP5-AS1', 'Gene', (96, 104))	('OIP5-AS1', 'Gene', (21, 29))	('knockdown', 'Var', (83, 92))
28982	33692839	Furthermore, miR-27b-3p silencing reversed the effect of OIP5-AS1 knockdown on DDP sensitivity in DDP-resistant OSCC cells.	('DDP sensitivity', 'MPA', (79, 94))	('DDP', 'Chemical', '-', (98, 101))	('OIP5-AS1', 'Gene', '729082;11339;5729', (57, 65))	('DDP', 'Chemical', '-', (79, 82))	('OIP5-AS1', 'Gene', (57, 65))	('miR-27b-3p', 'Chemical', '-', (13, 23))	('miR-27b-3p', 'Gene', (13, 23))	('knockdown', 'Var', (66, 75))	('silencing', 'Var', (24, 33))
28983	33692839	TRIM14was shown to be a direct target of miR-27b-3p, and TRIM14 overexpression abolished the effect of miR-27b-3p on DDP sensitivity in DDP-resistant OSCC cells.	('DDP sensitivity', 'MPA', (117, 132))	('TRIM14', 'Gene', (57, 63))	('abolished', 'NegReg', (79, 88))	('DDP', 'Chemical', '-', (136, 139))	('overexpression', 'PosReg', (64, 78))	('miR-27b-3p', 'Chemical', '-', (41, 51))	('DDP', 'Chemical', '-', (117, 120))	('miR-27b-3p', 'Chemical', '-', (103, 113))	('miR-27b-3p', 'Var', (103, 113))	('effect', 'MPA', (93, 99))
28985	33692839	In addition, OIP5-AS1 knockdown enhanced DDP sensitivity of OSCC in vivo.	('DDP', 'Chemical', '-', (41, 44))	('OIP5-AS1', 'Gene', '729082;11339;5729', (13, 21))	('knockdown', 'Var', (22, 31))	('OIP5-AS1', 'Gene', (13, 21))	('enhanced', 'PosReg', (32, 40))	('DDP sensitivity', 'MPA', (41, 56))
28986	33692839	Data from the present study indicated that OIP5-AS1 may improve DDP resistance through theupregulationTRIM14 mediated bymiR-27b-3p, providing a possible therapeutic strategy for OSCC treatment.	('DDP', 'Chemical', '-', (64, 67))	('OIP5-AS1', 'Gene', '729082;11339;5729', (43, 51))	('OIP5-AS1', 'Gene', (43, 51))	('DDP resistance', 'MPA', (64, 78))	('theupregulationTRIM14', 'MPA', (87, 108))	('miR-27b-3p', 'Chemical', '-', (120, 130))	('bymiR-27b-3p', 'Var', (118, 130))	('improve', 'PosReg', (56, 63))	('OSCC', 'Disease', (178, 182))
28992	33692839	Previous studies have reported that dysregulation of lncRNAs is implicated in the initiation and development of various tumors, including OSCC.	('dysregulation', 'Var', (36, 49))	('tumors', 'Disease', (120, 126))	('tumors', 'Disease', 'MESH:D009369', (120, 126))	('lncRNAs', 'Protein', (53, 60))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('implicated', 'Reg', (64, 74))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('OSCC', 'Disease', (138, 142))
28996	33692839	miR-27b-3p, a form of mature miR-27b, has been revealed to exert a tumor-suppressive effect by regulating its target genes, including MET and frizzled class receptor 7in OSCC.	('regulating', 'Reg', (95, 105))	('MET', 'Gene', '79811', (134, 137))	('MET', 'Gene', (134, 137))	('miR-27b', 'Gene', (29, 36))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('miR-27b-3p', 'Chemical', '-', (0, 10))	('miR-27b-3p', 'Var', (0, 10))	('tumor', 'Disease', (67, 72))
28997	33692839	Previous studies have suggested that miR-27b-3p could reduce resistance of some drugs in breast cancer and prostate cancer.	('resistance of some drugs', 'MPA', (61, 85))	('prostate cancer', 'Disease', (107, 122))	('miR-27b-3p', 'Chemical', '-', (37, 47))	('miR-27b-3p', 'Var', (37, 47))	('breast cancer', 'Disease', 'MESH:D001943', (89, 102))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('reduce', 'NegReg', (54, 60))	('breast cancer', 'Disease', (89, 102))	('prostate cancer', 'Disease', 'MESH:D011471', (107, 122))	('breast cancer', 'Phenotype', 'HP:0003002', (89, 102))	('prostate cancer', 'Phenotype', 'HP:0012125', (107, 122))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))
28998	33692839	In addition, a recent study reported that miR-27b could improve the chemotherapy sensitivity of OSCC cells to DDP, indicating the involvement of miR-27b-3p in DDP resistance of OSCC.	('chemotherapy sensitivity', 'MPA', (68, 92))	('DDP', 'Chemical', '-', (159, 162))	('DDP', 'Chemical', '-', (110, 113))	('miR-27b', 'Var', (42, 49))	('improve', 'PosReg', (56, 63))	('miR-27b-3p', 'Chemical', '-', (145, 155))
29033	33692839	Partial sequences of OIP5-AS1 and TRIM143'-UTR containing the putative (wild-type; WT) or mutated putative binding sites for miR-27b-3p were amplified and cloned into psiCHECK-2 vector (Promega Corporation), resulting inOIP5-AS1 WT or MUT andTRIM143'-UTRWT or MUT reporter plasmids.	('MUT', 'Var', (235, 238))	('psiCHECK', 'Disease', (167, 175))	('OIP5-AS1', 'Gene', '729082;11339;5729', (21, 29))	('OIP5-AS1', 'Gene', '729082;11339;5729', (220, 228))	('OIP5-AS1', 'Gene', (220, 228))	('miR-27b-3p', 'Chemical', '-', (125, 135))	('OIP5-AS1', 'Gene', (21, 29))	('psiCHECK', 'Disease', 'None', (167, 175))
29034	33692839	Then, SCC-9/DDP and HSC-3/DDP cells (2x105 cells/well) were co-transfected with 100 ng of the constructed reporter plasmids and 100 nM miR-NC or miR-27b-3p and were incubated for 48 h at 37 C. Luciferase activities were measured with the LD400 luminometer (Beckman Coulter, Inc.) at 48 h post-transfection.	('HSC-3', 'Gene', (20, 25))	('DDP', 'Chemical', '-', (12, 15))	('miR-27b-3p', 'Chemical', '-', (145, 155))	('miR-27b-3p', 'Var', (145, 155))	('HSC-3', 'Gene', '150353', (20, 25))	('DDP', 'Chemical', '-', (26, 29))
29046	33692839	The correlation between OIP5-AS1, miR-27b-3p and TRIM14 was detected using Pearson's correlation analysis.	('OIP5-AS1', 'Gene', (24, 32))	('miR-27b-3p', 'Chemical', '-', (34, 44))	('OIP5-AS1', 'Gene', '729082;11339;5729', (24, 32))	('miR-27b-3p', 'Var', (34, 44))
29047	33692839	To investigate the function of OIP5-AS1 with DDP resistance in OSCC, its expression was first measured by RT-qPCR assay.	('DDP', 'Chemical', '-', (45, 48))	('OIP5-AS1', 'Gene', '729082;11339;5729', (31, 39))	('DDP', 'Var', (45, 48))	('OIP5-AS1', 'Gene', (31, 39))
29054	33692839	These data suggested that dysregulation of OIP5-AS1 maybe associated with DDP resistance in OSCC cells.	('dysregulation', 'Var', (26, 39))	('associated', 'Reg', (58, 68))	('OIP5-AS1', 'Gene', '729082;11339;5729', (43, 51))	('OIP5-AS1', 'Gene', (43, 51))	('DDP', 'Chemical', '-', (74, 77))	('DDP resistance', 'Disease', (74, 88))
29059	33692839	2B-D), indicating that the OIP5-AS1 knockdown could reduce the resistance of the cells to DDP.	('OIP5-AS1', 'Gene', '729082;11339;5729', (27, 35))	('knockdown', 'Var', (36, 45))	('reduce', 'NegReg', (52, 58))	('DDP', 'Chemical', '-', (90, 93))	('resistance of the cells to', 'CPA', (63, 89))	('OIP5-AS1', 'Gene', (27, 35))
29060	33692839	Functional analysis suggested that OIP5-AS1 knockdown significantly repressed proliferation (Fig.	('proliferation', 'CPA', (78, 91))	('OIP5-AS1', 'Gene', '729082;11339;5729', (35, 43))	('knockdown', 'Var', (44, 53))	('repressed', 'NegReg', (68, 77))	('OIP5-AS1', 'Gene', (35, 43))
29062	33692839	Moreover, western blot analysis revealed that OIP5-AS1 knockdown significantly increased E-cadherin protein expression, but decreased N-cadherin and Vimentin protein expression levels, indicating that the knockdown of OIP5-AS1 may suppress epithelial-mesenchymal transition (EMT) in SCC-9/DDP and HSC-3/DDP cells (Fig.	('HSC-3', 'Gene', (297, 302))	('knockdown', 'Var', (205, 214))	('OIP5-AS1', 'Gene', '729082;11339;5729', (46, 54))	('OIP5-AS1', 'Gene', (46, 54))	('suppress', 'NegReg', (231, 239))	('epithelial-mesenchymal transition', 'CPA', (240, 273))	('DDP', 'Chemical', '-', (289, 292))	('Vimentin', 'Gene', '7431', (149, 157))	('Vimentin', 'Gene', (149, 157))	('DDP', 'Chemical', '-', (303, 306))	('E-cadherin', 'Gene', (89, 99))	('E-cadherin', 'Gene', '999', (89, 99))	('HSC-3', 'Gene', '150353', (297, 302))	('N-cadherin', 'Gene', (134, 144))	('increased', 'PosReg', (79, 88))	('OIP5-AS1', 'Gene', '729082;11339;5729', (218, 226))	('N-cadherin', 'Gene', '1000', (134, 144))	('decreased', 'NegReg', (124, 133))	('OIP5-AS1', 'Gene', (218, 226))
29063	33692839	Collectively, these data demonstrated that OIP5-AS1 knockdown could decrease DDP resistance, and inhibit cell growth and metastasis in SCC-9/DDP and HSC-3/DDP cells.	('HSC-3', 'Gene', (149, 154))	('inhibit', 'NegReg', (97, 104))	('OIP5-AS1', 'Gene', '729082;11339;5729', (43, 51))	('decrease', 'NegReg', (68, 76))	('DDP resistance', 'MPA', (77, 91))	('OIP5-AS1', 'Gene', (43, 51))	('DDP', 'Chemical', '-', (141, 144))	('DDP', 'Chemical', '-', (155, 158))	('HSC-3', 'Gene', '150353', (149, 154))	('DDP', 'Chemical', '-', (77, 80))	('knockdown', 'Var', (52, 61))
29065	33692839	It was demonstrated that miR-27b-3p overexpression significantly decreased the luciferase activity of OIP5-AS1 WT reporter plasmid, but had no notable effect on the luciferase activity of OIP5-AS1 MUT reporter plasmid in SCC-9/DDP and HSC-3/DDP cells (Fig.	('DDP', 'Chemical', '-', (241, 244))	('HSC-3', 'Gene', (235, 240))	('activity', 'MPA', (90, 98))	('decreased', 'NegReg', (65, 74))	('OIP5-AS1', 'Gene', '729082;11339;5729', (102, 110))	('DDP', 'Chemical', '-', (227, 230))	('OIP5-AS1', 'Gene', '729082;11339;5729', (188, 196))	('miR-27b-3p', 'Chemical', '-', (25, 35))	('HSC-3', 'Gene', '150353', (235, 240))	('OIP5-AS1', 'Gene', (188, 196))	('luciferase', 'Enzyme', (79, 89))	('OIP5-AS1', 'Gene', (102, 110))	('miR-27b-3p', 'Var', (25, 35))
29066	33692839	miR-27b-3p was demonstrated to be expressed at significantly lower levels in OSCC tumors and cell lines compared with the respective control groups (Fig.	('lower', 'NegReg', (61, 66))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('miR-27b-3p', 'Chemical', '-', (0, 10))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('OSCC tumors', 'Disease', (77, 88))	('miR-27b-3p', 'Var', (0, 10))	('OSCC tumors', 'Disease', 'MESH:D009369', (77, 88))
29071	33692839	As an interaction between OIP5-AS1 and miR-27b-3p in DDP-resistant OSCC cells was indicated, it was further investigated whether the effect of OIP5-AS1 on DDP resistance was associated withmiR-27b-3p.	('miR-27b-3p', 'Chemical', '-', (39, 49))	('interaction', 'Interaction', (6, 17))	('DDP', 'Chemical', '-', (155, 158))	('OIP5-AS1', 'Gene', '729082;11339;5729', (26, 34))	('OIP5-AS1', 'Gene', '729082;11339;5729', (143, 151))	('OIP5-AS1', 'Gene', (26, 34))	('miR-27b-3p', 'Chemical', '-', (189, 199))	('withmiR-27b-3p', 'Var', (185, 199))	('OIP5-AS1', 'Gene', (143, 151))	('DDP', 'Chemical', '-', (53, 56))
29073	33692839	Furthermore, the results of IC50 determination suggested that the silencing of miR-27b-3p partly abolished the inhibitory effect of OIP5-AS1 knockdown on DDP resistance in SCC-9/DDP and HSC-3/DDP cells (Fig.	('knockdown', 'Var', (141, 150))	('HSC-3', 'Gene', (186, 191))	('DDP', 'Chemical', '-', (192, 195))	('DDP', 'Chemical', '-', (178, 181))	('silencing', 'Var', (66, 75))	('OIP5-AS1', 'Gene', (132, 140))	('inhibitory effect', 'MPA', (111, 128))	('HSC-3', 'Gene', '150353', (186, 191))	('miR-27b-3p', 'Chemical', '-', (79, 89))	('DDP resistance', 'MPA', (154, 168))	('miR-27b-3p', 'Gene', (79, 89))	('abolished', 'NegReg', (97, 106))	('OIP5-AS1', 'Gene', '729082;11339;5729', (132, 140))	('DDP', 'Chemical', '-', (154, 157))
29074	33692839	Functionally, the knockdown of OIP5-AS1 inhibited proliferation (Fig.	('knockdown', 'Var', (18, 27))	('inhibited', 'NegReg', (40, 49))	('proliferation', 'CPA', (50, 63))	('OIP5-AS1', 'Gene', '729082;11339;5729', (31, 39))	('OIP5-AS1', 'Gene', (31, 39))
29075	33692839	4H) in SCC-9/DDP and HSC-3/DDP cells, while miR-27b-3p silencing significantly reversed the suppressive effect of si-OIP5-AS1 on these biological processes.	('OIP5-AS1', 'Gene', (117, 125))	('HSC-3', 'Gene', '150353', (21, 26))	('DDP', 'Chemical', '-', (27, 30))	('miR-27b-3p', 'Chemical', '-', (44, 54))	('miR-27b-3p', 'Gene', (44, 54))	('silencing', 'Var', (55, 64))	('HSC-3', 'Gene', (21, 26))	('OIP5-AS1', 'Gene', '729082;11339;5729', (117, 125))	('DDP', 'Chemical', '-', (13, 16))
29076	33692839	Western blotting results demonstrated that silencing of miR-27b-3p reversed the si-OIP5-AS1-inducedenhancement in E-cadherin protein expression, as well as the reduction in N-cadherin and Vimentin protein expression levels in SCC-9/DDP and HSC-3/DDP cells (Fig.	('N-cadherin', 'Gene', '1000', (173, 183))	('E-cadherin', 'Gene', (114, 124))	('Vimentin', 'Gene', '7431', (188, 196))	('HSC-3', 'Gene', '150353', (240, 245))	('reduction', 'NegReg', (160, 169))	('miR-27b-3p', 'Chemical', '-', (56, 66))	('E-cadherin', 'Gene', '999', (114, 124))	('silencing', 'Var', (43, 52))	('HSC-3', 'Gene', (240, 245))	('miR-27b-3p', 'Gene', (56, 66))	('Vimentin', 'Gene', (188, 196))	('OIP5-AS1', 'Gene', '729082;11339;5729', (83, 91))	('DDP', 'Chemical', '-', (246, 249))	('N-cadherin', 'Gene', (173, 183))	('OIP5-AS1', 'Gene', (83, 91))	('DDP', 'Chemical', '-', (232, 235))
29077	33692839	Taken together, these results suggested that silencing of miR-27b-3p partly reversed the promotion effect of OIP5-AS1 knockdown on DDP sensitivity in DDP-resistant OSCC cells.	('DDP sensitivity', 'MPA', (131, 146))	('silencing', 'Var', (45, 54))	('OIP5-AS1', 'Gene', '729082;11339;5729', (109, 117))	('OIP5-AS1', 'Gene', (109, 117))	('miR-27b-3p', 'Chemical', '-', (58, 68))	('miR-27b-3p', 'Gene', (58, 68))	('DDP', 'Chemical', '-', (131, 134))	('DDP', 'Chemical', '-', (150, 153))	('promotion', 'PosReg', (89, 98))
29078	33692839	Using the web-based tool starBase, the 3'-UTR of TRIM14 was found to have complementary target sites to miR-27b-3p (Fig.	('miR-27b-3p', 'Chemical', '-', (104, 114))	('miR-27b-3p', 'Var', (104, 114))	('TRIM14', 'Gene', (49, 55))
29080	33692839	The results demonstrated that the luciferase activity was significantly decreased in cells co-transfected with TRIM14 3'-UTR-WT and miR-27b-3p, whereas there was little effect in cells co-transfected withTRIM14 3'-UTR-MUT and miR-27b-3p (Fig.	('activity', 'MPA', (45, 53))	('miR-27b-3p', 'Chemical', '-', (132, 142))	('miR-27b-3p', 'Var', (132, 142))	('decreased', 'NegReg', (72, 81))	("TRIM14 3'-UTR-WT", 'Var', (111, 127))	('miR-27b-3p', 'Chemical', '-', (226, 236))	('luciferase', 'Enzyme', (34, 44))	('miR-27b-3p', 'Var', (226, 236))
29084	33692839	The transfection efficiency of miR-27b-3p overexpression or knockdown was examined and presented in Fig.	('miR-27b-3p', 'Chemical', '-', (31, 41))	('miR-27b-3p', 'Var', (31, 41))	('knockdown', 'Var', (60, 69))
29085	33692839	5K and L) levels TRIM14 expression was significantly decreasedaftermiR-27b-3p overexpression, whereas expression levels were increased by anti-miR-27b-3p transfection in SCC-9/DDP and HSC-3/DDP cells.	('increased', 'PosReg', (125, 134))	('expression', 'MPA', (24, 34))	('HSC-3', 'Gene', (184, 189))	('transfection', 'Var', (154, 166))	('TRIM14', 'Gene', (17, 23))	('miR-27b-3p', 'Chemical', '-', (143, 153))	('overexpression', 'PosReg', (78, 92))	('decreasedaftermiR-27b-3p', 'Var', (53, 77))	('DDP', 'Chemical', '-', (176, 179))	('HSC-3', 'Gene', '150353', (184, 189))	('DDP', 'Chemical', '-', (190, 193))	('decreasedaftermiR-27b-3p', 'NegReg', (53, 77))	('expression levels', 'MPA', (102, 119))	('anti-miR-27b-3p transfection', 'Var', (138, 166))	('miR-27b-3p', 'Chemical', '-', (67, 77))
29086	33692839	Therefore, it was suggested that miR-27b-3p could interact with TRIM14 to inhibit its expression.	('miR-27b-3p', 'Var', (33, 43))	('inhibit', 'NegReg', (74, 81))	('expression', 'MPA', (86, 96))	('interact', 'Interaction', (50, 58))	('miR-27b-3p', 'Chemical', '-', (33, 43))
29087	33692839	As miR-27b-3p was shown to negatively regulate TRIM14 expression, whether the effect of miR-27b-3p on DDP sensitivity was mediated by regulating TRIM14 expression was investigated.	('expression', 'MPA', (54, 64))	('miR-27b-3p', 'Chemical', '-', (88, 98))	('negatively', 'NegReg', (27, 37))	('TRIM14', 'Gene', (47, 53))	('miR-27b-3p', 'Chemical', '-', (3, 13))	('miR-27b-3p', 'Var', (3, 13))	('DDP', 'Chemical', '-', (102, 105))
29088	33692839	The overexpression of miR-27b-3p decreasedTRIM14 expression, which was significantly reversed by co-transfection with TRIM14 overexpression vectors in SCC-9/DDP and HSC-3/DDP cells (Fig.	('decreasedTRIM14', 'Gene', (33, 48))	('DDP', 'Chemical', '-', (157, 160))	('DDP', 'Chemical', '-', (171, 174))	('miR-27b-3p', 'Chemical', '-', (22, 32))	('miR-27b-3p', 'Var', (22, 32))	('decreasedTRIM14', 'NegReg', (33, 48))	('expression', 'MPA', (49, 59))	('HSC-3', 'Gene', (165, 170))	('HSC-3', 'Gene', '150353', (165, 170))
29090	33692839	Moreover, transfection of miR-27b-3p inhibited the proliferation (Fig.	('inhibited', 'NegReg', (37, 46))	('miR-27b-3p', 'Var', (26, 36))	('miR-27b-3p', 'Chemical', '-', (26, 36))	('proliferation', 'CPA', (51, 64))
29093	33692839	Thus, these results suggested that miR-27b-3p may facilitate DDP sensitivity in DDP-resistant OSCC cells by regulating TRIM14.	('DDP', 'Chemical', '-', (61, 64))	('DDP sensitivity', 'MPA', (61, 76))	('TRIM14', 'MPA', (119, 125))	('miR-27b-3p', 'Chemical', '-', (35, 45))	('facilitate', 'PosReg', (50, 60))	('miR-27b-3p', 'Var', (35, 45))	('regulating', 'Reg', (108, 118))	('DDP', 'Chemical', '-', (80, 83))
29096	33692839	RT-qPCR results demonstrated that knockdown of OIP5-AS1 decreasedTRIM14 expression, and introduction of anti-miR-27b-3p effectively reversed this trend in SCC-9/DDP and HSC-3/DDP cells (Fig.	('DDP', 'Chemical', '-', (175, 178))	('HSC-3', 'Gene', (169, 174))	('decreasedTRIM14', 'NegReg', (56, 71))	('DDP', 'Chemical', '-', (161, 164))	('OIP5-AS1', 'Gene', '729082;11339;5729', (47, 55))	('miR-27b-3p', 'Chemical', '-', (109, 119))	('HSC-3', 'Gene', '150353', (169, 174))	('OIP5-AS1', 'Gene', (47, 55))	('decreasedTRIM14', 'Gene', (56, 71))	('knockdown', 'Var', (34, 43))
29097	33692839	Similar to the RT-qPCR results, the protein expression levels of TRIM14 were significantly suppressed in si-OIP5-AS1-transfected SCC-9/DDP and HSC-3/DDP cells, whereas silencing of miR-27b-3p mitigated this inhibitory effect of OIP5-AS1 knockdown (Fig.	('suppressed', 'NegReg', (91, 101))	('OIP5-AS1', 'Gene', (108, 116))	('silencing', 'Var', (168, 177))	('protein expression levels', 'MPA', (36, 61))	('HSC-3', 'Gene', '150353', (143, 148))	('OIP5-AS1', 'Gene', '729082;11339;5729', (228, 236))	('miR-27b-3p', 'Chemical', '-', (181, 191))	('DDP', 'Chemical', '-', (149, 152))	('OIP5-AS1', 'Gene', (228, 236))	('HSC-3', 'Gene', (143, 148))	('TRIM14', 'Gene', (65, 71))	('OIP5-AS1', 'Gene', '729082;11339;5729', (108, 116))	('DDP', 'Chemical', '-', (135, 138))
29101	33692839	The results demonstrated that the tumor size and weight were significantly lower in the sh-OIP5-AS1 group treated DDP compared with the sh-NC group treated DDP, indicating that OIP5-AS1 knockdown hindered tumor growth in OSCC in vivo (Fig.	('hindered', 'NegReg', (196, 204))	('OIP5-AS1', 'Gene', '729082;11339;5729', (177, 185))	('lower', 'NegReg', (75, 80))	('knockdown', 'Var', (186, 195))	('OIP5-AS1', 'Gene', '729082;11339;5729', (91, 99))	('tumor', 'Disease', (34, 39))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('OIP5-AS1', 'Gene', (177, 185))	('OIP5-AS1', 'Gene', (91, 99))	('DDP', 'Chemical', '-', (114, 117))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumor', 'Disease', (205, 210))	('DDP', 'Chemical', '-', (156, 159))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
29103	33692839	8E and F, respectively)expression levels were decreased, whereasmiR-27b-3p expression was enhanced (Fig.	('miR-27b-3p', 'Chemical', '-', (64, 74))	('enhanced', 'PosReg', (90, 98))	('expression levels', 'MPA', (23, 40))	('decreased', 'NegReg', (46, 55))	('whereasmiR-27b-3p', 'Var', (57, 74))
29105	33692839	Collectively, these results indicated that knockdown of OIP5-AS1 repressed tumor growth and enhanced DDP sensitivity partly by regulating the miR-27b-3p/TRIM14 axis in OSCC in vivo.	('OIP5-AS1', 'Gene', (56, 64))	('DDP sensitivity', 'MPA', (101, 116))	('regulating', 'Reg', (127, 137))	('knockdown', 'Var', (43, 52))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('miR-27b-3p/TRIM14 axis', 'MPA', (142, 164))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('DDP', 'Chemical', '-', (101, 104))	('OIP5-AS1', 'Gene', '729082;11339;5729', (56, 64))	('tumor', 'Disease', (75, 80))	('miR-27b-3p', 'Chemical', '-', (142, 152))	('enhanced', 'PosReg', (92, 100))
29108	33692839	For example, it was previously reported that the high expression of OIP5-AS1 was associated with undifferentiated oral tumors and indicated a poor prognosis.	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('OIP5-AS1', 'Gene', '729082;11339;5729', (68, 76))	('undifferentiated oral tumors', 'Disease', (97, 125))	('OIP5-AS1', 'Gene', (68, 76))	('high', 'Var', (49, 53))	('undifferentiated oral tumors', 'Disease', 'MESH:D002277', (97, 125))	('oral tumors', 'Phenotype', 'HP:0100649', (114, 125))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('associated', 'Reg', (81, 91))
29109	33692839	Furthermore, it has been shown that OIP5-AS1 knockdown can reduce the resistance of osteosarcoma cells to DDP.	('DDP', 'Chemical', '-', (106, 109))	('OIP5-AS1', 'Gene', (36, 44))	('reduce', 'NegReg', (59, 65))	('osteosarcoma', 'Disease', (84, 96))	('osteosarcoma', 'Phenotype', 'HP:0002669', (84, 96))	('resistance', 'MPA', (70, 80))	('osteosarcoma', 'Disease', 'MESH:D012516', (84, 96))	('knockdown', 'Var', (45, 54))	('OIP5-AS1', 'Gene', '729082;11339;5729', (36, 44))
29113	33692839	The results showed that OIP5-AS1 knockdown increased DDP sensitivity and repressed proliferation, migration, invasion and EMT in DDP-resistant OSCC cells in vitro.	('OIP5-AS1', 'Gene', (24, 32))	('invasion', 'CPA', (109, 117))	('proliferation', 'CPA', (83, 96))	('knockdown', 'Var', (33, 42))	('DDP sensitivity', 'MPA', (53, 68))	('migration', 'CPA', (98, 107))	('OIP5-AS1', 'Gene', '729082;11339;5729', (24, 32))	('increased', 'PosReg', (43, 52))	('DDP', 'Chemical', '-', (53, 56))	('DDP', 'Chemical', '-', (129, 132))	('EMT', 'CPA', (122, 125))
29114	33692839	Moreover, the current study demonstrated that knockdown of OIP5-AS1 hindered OSCC cell growth, and improved DDP sensitivity in vivo.	('hindered', 'NegReg', (68, 76))	('improved', 'PosReg', (99, 107))	('DDP sensitivity', 'MPA', (108, 123))	('knockdown', 'Var', (46, 55))	('OSCC cell growth', 'CPA', (77, 93))	('DDP', 'Chemical', '-', (108, 111))	('OIP5-AS1', 'Gene', '729082;11339;5729', (59, 67))	('OIP5-AS1', 'Gene', (59, 67))
29115	33692839	Therefore, it was suggested that OIP5-AS1 knockdown may contribute to DDP sensitivity in vitro and in vivo.	('DDP sensitivity', 'MPA', (70, 85))	('OIP5-AS1', 'Gene', '729082;11339;5729', (33, 41))	('DDP', 'Chemical', '-', (70, 73))	('OIP5-AS1', 'Gene', (33, 41))	('contribute', 'Reg', (56, 66))	('knockdown', 'Var', (42, 51))
29116	33692839	In the present study, miR-27b-3p was demonstrated to be a target A of OIP5-AS1.	('OIP5-AS1', 'Gene', '729082;11339;5729', (70, 78))	('miR-27b-3p', 'Chemical', '-', (22, 32))	('OIP5-AS1', 'Gene', (70, 78))	('miR-27b-3p', 'Var', (22, 32))
29117	33692839	It has been shown that miR-27b-3p could exert an inductive effect on drug sensitivity in breast cancer.	('breast cancer', 'Disease', 'MESH:D001943', (89, 102))	('miR-27b-3p', 'Chemical', '-', (23, 33))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('miR-27b-3p', 'Var', (23, 33))	('breast cancer', 'Disease', (89, 102))	('breast cancer', 'Phenotype', 'HP:0003002', (89, 102))	('inductive', 'Reg', (49, 58))	('drug sensitivity', 'Phenotype', 'HP:0020174', (69, 85))	('drug sensitivity', 'MPA', (69, 85))
29119	33692839	Functionally, silencing miR-27b-3p reversedOIP5-AS1-knockdown-induced enhancement of DDP sensitivity, demonstrating that the knockdown of OIP5-AS1 increased DDP sensitivity partly by interacting with miR-27b-3p in DDP-resistant OSCC cells.	('OIP5-AS1', 'Gene', (138, 146))	('silencing', 'Var', (14, 23))	('interacting', 'Interaction', (183, 194))	('DDP', 'Chemical', '-', (157, 160))	('increased', 'PosReg', (147, 156))	('OIP5-AS1', 'Gene', '729082;11339;5729', (43, 51))	('DDP', 'Chemical', '-', (85, 88))	('OIP5-AS1', 'Gene', (43, 51))	('miR-27b-3p', 'Chemical', '-', (24, 34))	('miR-27b-3p', 'Gene', (24, 34))	('miR-27b-3p', 'Chemical', '-', (200, 210))	('OIP5-AS1', 'Gene', '729082;11339;5729', (138, 146))	('DDP sensitivity', 'MPA', (85, 100))	('DDP', 'Chemical', '-', (214, 217))	('DDP sensitivity', 'MPA', (157, 172))	('enhancement', 'PosReg', (70, 81))
29121	33692839	According to previous literature, TRIM14 can affect the activity of Wnt/beta-catenin to promote the drug resistance of tumors.	('affect', 'Reg', (45, 51))	('TRIM14', 'Var', (34, 40))	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('activity', 'MPA', (56, 64))	('tumors', 'Disease', (119, 125))	('beta-catenin', 'Gene', (72, 84))	('promote', 'PosReg', (88, 95))	('tumors', 'Disease', 'MESH:D009369', (119, 125))	('drug resistance', 'Phenotype', 'HP:0020174', (100, 115))	('beta-catenin', 'Gene', '1499', (72, 84))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))
29123	33692839	Therefore, we hypothesize that TRIM14 could induce ABC transporter and MDR1 expression by activating the Wnt/beta-catenin signaling pathway, thus enhancing OSCC resistance to DDP.	('DDP', 'Chemical', '-', (175, 178))	('induce', 'PosReg', (44, 50))	('ABC transporter', 'Gene', (51, 66))	('MDR1', 'Gene', (71, 75))	('TRIM14', 'Var', (31, 37))	('ABC transporter', 'Gene', '9429', (51, 66))	('MDR1', 'Gene', '5243', (71, 75))	('OSCC resistance to DDP', 'MPA', (156, 178))	('enhancing', 'PosReg', (146, 155))	('beta-catenin', 'Gene', (109, 121))	('activating', 'PosReg', (90, 100))	('expression', 'MPA', (76, 86))	('beta-catenin', 'Gene', '1499', (109, 121))
29126	33692839	Functional analysis demonstrated that TRIM14 overexpression reserved the promotion role of miR-27b-3p on DDP sensitivity.	('miR-27b-3p', 'Var', (91, 101))	('promotion', 'PosReg', (73, 82))	('miR-27b-3p', 'Chemical', '-', (91, 101))	('DDP sensitivity', 'Disease', (105, 120))	('DDP', 'Chemical', '-', (105, 108))
29129	33692839	In the present study, the results demonstrated that the downregulation of miR-27b-3p could partly reversed the suppressive action of OIP5-AS1 knockdown on TRIM14 expression in DDP-resistant OSCC cells, verifying the regulatory role of OIP5-AS1/miR-27b-3p/TRIM14 in OSCC.	('OIP5-AS1', 'Gene', '729082;11339;5729', (235, 243))	('miR-27b-3p', 'Chemical', '-', (74, 84))	('OIP5-AS1', 'Gene', '729082;11339;5729', (133, 141))	('miR-27b-3p', 'Gene', (74, 84))	('OIP5-AS1', 'Gene', (235, 243))	('OIP5-AS1', 'Gene', (133, 141))	('DDP', 'Chemical', '-', (176, 179))	('expression', 'MPA', (162, 172))	('downregulation', 'NegReg', (56, 70))	('TRIM14', 'Gene', (155, 161))	('miR-27b-3p', 'Chemical', '-', (244, 254))	('knockdown', 'Var', (142, 151))
29152	32703314	Several mechanisms of erlotinib resistance have been identified, including T790M gatekeeper EGFR-mutation, activation of bypass-signaling (amplification of IGF1R and MET).	('bypass-signaling', 'MPA', (121, 137))	('T790M', 'Mutation', 'rs121434569', (75, 80))	('IGF1R', 'Gene', (156, 161))	('gatekeeper', 'Species', '111938', (81, 91))	('T790M', 'Var', (75, 80))	('IGF1R', 'Gene', '3480', (156, 161))	('erlotinib', 'Chemical', 'MESH:D000069347', (22, 31))	('EGFR', 'Gene', '1956', (92, 96))	('EGFR', 'Gene', (92, 96))
29153	32703314	Besides, 40-60% of acquired resistance mechanism is EGFR T790M mutation in first generation EGFR-TKIs.	('EGFR', 'Gene', '1956', (52, 56))	('EGFR', 'Gene', (52, 56))	('T790M', 'Mutation', 'rs121434569', (57, 62))	('acquired resistance', 'MPA', (19, 38))	('T790M', 'Var', (57, 62))	('EGFR', 'Gene', '1956', (92, 96))	('EGFR', 'Gene', (92, 96))
29154	32703314	However, the erlotinib acquired resistance mechanisms for NSCLC patients without T790M mutation is not clear.	('NSCLC', 'Disease', (58, 63))	('patients', 'Species', '9606', (64, 72))	('NSCLC', 'Disease', 'MESH:D002289', (58, 63))	('T790M', 'Mutation', 'rs121434569', (81, 86))	('T790M', 'Var', (81, 86))	('NSCLC', 'Phenotype', 'HP:0030358', (58, 63))	('erlotinib', 'Chemical', 'MESH:D000069347', (13, 22))
29165	32703314	The erlotinib sensitive and resistant NSCLC dataset GSE38121, GSE69181 and GSE80344 were obtained from the GEO database (https://www.ncbi.nlm.nih.gov/geo), and analyzed by GEO2R ( log2 (Fold change)   > 1 and P < 0.01).	('NSCLC', 'Disease', (38, 43))	('NSCLC', 'Disease', 'MESH:D002289', (38, 43))	('GSE80344', 'Var', (75, 83))	('NSCLC', 'Phenotype', 'HP:0030358', (38, 43))	('erlotinib', 'Chemical', 'MESH:D000069347', (4, 13))	('GSE69181', 'Var', (62, 70))
29166	32703314	And the expression data (GSE7670 and GSE10072) of MMP1 in normal tissues and tumor tissues were obtained by the online analysis website Oncomine (https://www.oncomine.org/resource/login.html).	('MMP1', 'Gene', (50, 54))	('GSE10072', 'Var', (37, 45))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('GSE7670', 'Var', (25, 32))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('Oncomine', 'Chemical', '-', (136, 144))	('MMP1', 'Gene', '4312', (50, 54))	('tumor', 'Disease', (77, 82))	('GSE7670', 'Chemical', '-', (25, 32))
29167	32703314	In detail, GSE7670 (n = 57) is composed of 30 normal lung tissues and 27 lung adenocarcinoma tissues, and GSE10072 consists of 49 normal lung tissues and 58 lung adenocarcinoma tissues.	('lung adenocarcinoma', 'Disease', (73, 92))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (73, 92))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (73, 92))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (157, 176))	('carcinoma', 'Phenotype', 'HP:0030731', (167, 176))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))	('lung adenocarcinoma', 'Disease', (157, 176))	('GSE7670', 'Var', (11, 18))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (157, 176))	('GSE7670', 'Chemical', '-', (11, 18))
29181	32703314	However, erlotinib-acquired resistance is a tough obstacle to effectively treating NSCLC patients with EGFR mutant characteristics.	('mutant characteristics', 'Var', (108, 130))	('EGFR', 'Gene', '1956', (103, 107))	('erlotinib', 'Chemical', 'MESH:D000069347', (9, 18))	('NSCLC', 'Disease', (83, 88))	('EGFR', 'Gene', (103, 107))	('NSCLC', 'Disease', 'MESH:D002289', (83, 88))	('patients', 'Species', '9606', (89, 97))	('NSCLC', 'Phenotype', 'HP:0030358', (83, 88))
29193	32703314	The results revealed that MMP1 was significantly upregulated in the erlotinib resistance dataset GSE38121, GSE69181 and GSE80344.	('MMP1', 'Gene', (26, 30))	('MMP1', 'Gene', '4312', (26, 30))	('upregulated', 'PosReg', (49, 60))	('erlotinib', 'Chemical', 'MESH:D000069347', (68, 77))	('GSE38121', 'Var', (97, 105))	('GSE80344', 'Var', (120, 128))	('erlotinib resistance', 'MPA', (68, 88))	('GSE69181', 'Var', (107, 115))
29194	32703314	And we verified that the expression of MMP1 in NSCLC tissues was significantly higher than that in normal tissues, via the datasets GSE7670 (P = 8.01E-10, Fold Change = 21.925) and GSE10072 (P = 1.12E-15, Fold Change = 7.277) in Oncomine (Fig.	('GSE7670', 'Var', (132, 139))	('GSE7670', 'Chemical', '-', (132, 139))	('NSCLC', 'Phenotype', 'HP:0030358', (47, 52))	('expression', 'MPA', (25, 35))	('MMP1', 'Gene', (39, 43))	('Oncomine', 'Chemical', '-', (229, 237))	('NSCLC', 'Disease', (47, 52))	('GSE10072', 'Var', (181, 189))	('higher', 'PosReg', (79, 85))	('NSCLC', 'Disease', 'MESH:D002289', (47, 52))	('Oncomine', 'Disease', (229, 237))	('MMP1', 'Gene', '4312', (39, 43))
29197	32703314	In addition, survival analysis by Kaplan-Meier plotter indicated that patients with high expression of MMP1 were associated with poor overall survival (GSE50081, HR = 1.87 (1.06-3.31), log-rank P = 0.028; GSE31210, HR = 2.42 (1.19-4.95), log-rank P = 0.012) (Fig.	('patients', 'Species', '9606', (70, 78))	('high expression', 'Var', (84, 99))	('poor', 'NegReg', (129, 133))	('MMP1', 'Gene', '4312', (103, 107))	('overall survival', 'MPA', (134, 150))	('MMP1', 'Gene', (103, 107))
29200	32703314	Among these four genes, Integrin subunit alpha 2 (ITGA2), Basigin (BSG), and Thyroid hormone receptor interactor 6 (TRIP6) were downregulated in the erlotinib resistance dataset GSE80344, while COP9 signalosome subunit 5 (COPS5) was upregulated in this dataset (Fig.	('TRIP6', 'Gene', '7205', (116, 121))	('Basigin', 'Gene', '682', (58, 65))	('ITGA2', 'Gene', '3673', (50, 55))	('BSG', 'Gene', (67, 70))	('BSG', 'Gene', '682', (67, 70))	('downregulated', 'NegReg', (128, 141))	('Integrin subunit alpha 2', 'Gene', (24, 48))	('ITGA2', 'Gene', (50, 55))	('TRIP6', 'Gene', (116, 121))	('COP9 signalosome subunit 5', 'Gene', (194, 220))	('Integrin subunit alpha 2', 'Gene', '3673', (24, 48))	('erlotinib resistance', 'MPA', (149, 169))	('COPS5', 'Gene', (222, 227))	('Basigin', 'Gene', (58, 65))	('COP9 signalosome subunit 5', 'Gene', '10987', (194, 220))	('erlotinib', 'Chemical', 'MESH:D000069347', (149, 158))	('Thyroid hormone receptor interactor 6', 'Gene', '7205', (77, 114))	('GSE80344', 'Var', (178, 186))	('COPS5', 'Gene', '10987', (222, 227))	('Thyroid hormone receptor interactor 6', 'Gene', (77, 114))
29204	32703314	And we further performed the survival analysis by GEPIA2 and found that patients with simultaneous high expression of MMP1 and COPS5 were associated with poor overall survival (HR = 1.7, log-rank P = 0.047) (Fig.	('COPS5', 'Gene', '10987', (127, 132))	('COPS5', 'Gene', (127, 132))	('overall survival', 'MPA', (159, 175))	('MMP1', 'Gene', (118, 122))	('high', 'Var', (99, 103))	('poor', 'NegReg', (154, 158))	('MMP1', 'Gene', '4312', (118, 122))	('patients', 'Species', '9606', (72, 80))
29216	32703314	For example, LEE011, a CDK 4/6 inhibitor, has a good inhibitory effect on the resistance caused by PI3K mutation in breast cancer.	('PI3K', 'Var', (99, 103))	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('breast cancer', 'Disease', (116, 129))	('CDK 4/6', 'Gene', (23, 30))	('CDK 4/6', 'Gene', '1019;1021', (23, 30))	('breast cancer', 'Phenotype', 'HP:0003002', (116, 129))	('inhibitory', 'NegReg', (53, 63))	('LEE011', 'Chemical', 'MESH:C000589651', (13, 19))	('breast cancer', 'Disease', 'MESH:D001943', (116, 129))	('LEE011', 'Var', (13, 19))	('resistance caused', 'MPA', (78, 95))
29229	32703314	And the survival analysis indicated that patients with simultaneous high expression of MMP1 and COPS5 were associated with poor overall survival.	('overall survival', 'MPA', (128, 144))	('high', 'Var', (68, 72))	('COPS5', 'Gene', (96, 101))	('COPS5', 'Gene', '10987', (96, 101))	('MMP1', 'Gene', '4312', (87, 91))	('poor', 'NegReg', (123, 127))	('patients', 'Species', '9606', (41, 49))	('MMP1', 'Gene', (87, 91))
29245	31632477	SK-MES-1 cells were infected with Lenti-virus containing KLF6-SV1 to up-regulate its expression, and the small interfering RNA (siRNA) was designed to knock down KLF6-SV1 transcript level in A549 cells.	('expression', 'MPA', (85, 95))	('KLF6-SV1', 'Gene', '1316', (162, 170))	('KLF6-SV1', 'Gene', (162, 170))	('up-regulate', 'PosReg', (69, 80))	('KLF6-SV1', 'Gene', '1316', (57, 65))	('KLF6-SV1', 'Gene', (57, 65))	('knock', 'Var', (151, 156))
29247	31632477	Furthermore, KLF6-SV1 isoform knockdown triggered caspase-dependent apoptosis of A549 cells through downregulation of the phosphatidylinositol 3-OH kinase (PI3K)/Akt signaling pathway and apoptosis-related protein expression.	('Akt', 'Gene', (162, 165))	('apoptosis-related', 'Protein', (188, 205))	('KLF6-SV1', 'Gene', (13, 21))	('Akt', 'Gene', '207', (162, 165))	('KLF6-SV1', 'Gene', '1316', (13, 21))	('knockdown', 'Var', (30, 39))	('downregulation', 'NegReg', (100, 114))	('phosphatidylinositol 3-OH', 'Chemical', 'MESH:D010716', (122, 147))	('caspase-dependent', 'CPA', (50, 67))
29249	31632477	Our study support KLF6-SV1 might be an important player in modulating the growth, migration, invasion, and survival of NSCLC cells, and that silencing KLF6-SV1 siRNA has the potential to be a powerful gene therapy strategy for NSCLC.	('NSCLC', 'Disease', 'MESH:D002289', (119, 124))	('silencing', 'Var', (141, 150))	('NSCLC', 'Disease', (227, 232))	('NSCLC', 'Disease', 'MESH:D002289', (227, 232))	('KLF6-SV1', 'Gene', (151, 159))	('KLF6-SV1', 'Gene', '1316', (151, 159))	('NSCLC', 'Disease', (119, 124))	('KLF6-SV1', 'Gene', (18, 26))	('KLF6-SV1', 'Gene', '1316', (18, 26))
29263	31632477	Specific knockdown of KLF6-SV1 by small interfering RNA (siRNA) reduces tumor growth in vitro  and in vivo .	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('knockdown', 'Var', (9, 18))	('tumor', 'Disease', (72, 77))	('KLF6-SV1', 'Gene', '1316', (22, 30))	('KLF6-SV1', 'Gene', (22, 30))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('reduces', 'NegReg', (64, 71))
29291	31632477	In si-SV1 transient-transfected cells, KLF6-SV1 expression was reduced by ~85% at 48 h compared with the NC control.	('reduced', 'NegReg', (63, 70))	('expression', 'MPA', (48, 58))	('KLF6-SV1', 'Gene', (39, 47))	('KLF6-SV1', 'Gene', '1316', (39, 47))	('si-SV1', 'Var', (3, 9))
29296	31632477	3A and B indicate that the migration ability of SK-MES-1 cells was significantly enhanced by overexpression of KLF6-SV1 compared to NC cells; in contrast, knocked-down of KLF6-SV1 resulted in inhibition of migration in A549 cells.	('KLF6-SV1', 'Gene', '1316', (111, 119))	('migration in A549 cells', 'CPA', (206, 229))	('enhanced', 'PosReg', (81, 89))	('KLF6-SV1', 'Gene', (111, 119))	('migration ability', 'CPA', (27, 44))	('KLF6-SV1', 'Gene', '1316', (171, 179))	('knocked-down', 'Var', (155, 167))	('KLF6-SV1', 'Gene', (171, 179))	('inhibition', 'NegReg', (192, 202))
29298	31632477	The combination of data suggests that siRNA-induced silencing of KLF6-SV1 expression caused decreased proliferation, cell motility, and invasiveness of NSCLC cells in vitro; whereas, overexpression of KLF6-SV1 promoted the cell proliferation, motility, migration and invasion of SK-MES-1 cells.	('KLF6-SV1', 'Gene', '1316', (201, 209))	('silencing', 'Var', (52, 61))	('cell proliferation', 'CPA', (223, 241))	('KLF6-SV1', 'Gene', '1316', (65, 73))	('KLF6-SV1', 'Gene', (201, 209))	('invasion', 'CPA', (267, 275))	('NSCLC', 'Disease', (152, 157))	('cell motility', 'CPA', (117, 130))	('migration', 'CPA', (253, 262))	('promoted', 'PosReg', (210, 218))	('motility', 'CPA', (243, 251))	('NSCLC', 'Disease', 'MESH:D002289', (152, 157))	('proliferation', 'CPA', (102, 115))	('decreased', 'NegReg', (92, 101))	('invasiveness', 'CPA', (136, 148))	('KLF6-SV1', 'Gene', (65, 73))
29303	31632477	In contrast, E-cadherin expression was upregulated in A549 cells after KLF6-SV1 siRNA transfection, while the expression of N-cadherin, Vimentin, Snail1, and Snail2 was downregulated (Fig.	('Snail1', 'Gene', (146, 152))	('Vimentin', 'Gene', '7431', (136, 144))	('Snail1', 'Gene', '6615', (146, 152))	('expression', 'MPA', (24, 34))	('upregulated', 'PosReg', (39, 50))	('Snail2', 'Gene', (158, 164))	('KLF6-SV1', 'Gene', (71, 79))	('E-cadherin', 'Gene', (13, 23))	('KLF6-SV1', 'Gene', '1316', (71, 79))	('E-cadherin', 'Gene', '999', (13, 23))	('N-cadherin', 'Gene', (124, 134))	('transfection', 'Var', (86, 98))	('Snail2', 'Gene', '6591', (158, 164))	('N-cadherin', 'Gene', '1000', (124, 134))	('downregulated', 'NegReg', (169, 182))	('Vimentin', 'Gene', (136, 144))
29310	31632477	In contrast, the level of p-Akt was inhibited by depletion of KLF6-SV1 in A549 cells compared to NC cells, and the expression of Cyclin D1 was correspondingly downregulated (Fig.	('KLF6-SV1', 'Gene', (62, 70))	('Akt', 'Gene', (28, 31))	('inhibited', 'NegReg', (36, 45))	('Cyclin D1', 'Gene', '595', (129, 138))	('level', 'MPA', (17, 22))	('Cyclin D1', 'Gene', (129, 138))	('expression', 'MPA', (115, 125))	('Akt', 'Gene', '207', (28, 31))	('downregulated', 'NegReg', (159, 172))	('depletion', 'Var', (49, 58))	('KLF6-SV1', 'Gene', '1316', (62, 70))
29311	31632477	5D and E, the expression of anti-apoptotic protein Bcl-2 was increased in SK-MES-1/OE-SV1 cells, while the expression of pro-apoptotic proteins Bax, cleaved Caspase9 and cleaved Caspase3 was decreased (Fig.	('Caspase3', 'Gene', (178, 186))	('Caspase9', 'Gene', (157, 165))	('cleaved', 'MPA', (170, 177))	('Bcl-2', 'Gene', (51, 56))	('Bax', 'Gene', '581', (144, 147))	('Caspase9', 'Gene', '842', (157, 165))	('Bcl-2', 'Gene', '596', (51, 56))	('expression', 'MPA', (107, 117))	('expression', 'MPA', (14, 24))	('increased', 'PosReg', (61, 70))	('decreased', 'NegReg', (191, 200))	('Bax', 'Gene', (144, 147))	('SK-MES-1/OE-SV1', 'Var', (74, 89))	('Caspase3', 'Gene', '836', (178, 186))	('cleaved', 'MPA', (149, 156))
29320	31632477	It has been reported that high expression of KLF6-SV1 transcripts is associated with decreased survival in lung adenocarcinoma patients.	('decreased', 'NegReg', (85, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('lung adenocarcinoma', 'Disease', (107, 126))	('high', 'Var', (26, 30))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (107, 126))	('survival', 'MPA', (95, 103))	('patients', 'Species', '9606', (127, 135))	('KLF6-SV1', 'Gene', (45, 53))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (107, 126))	('KLF6-SV1', 'Gene', '1316', (45, 53))
29336	31632477	Additionally, KLF6-SV1 silencing could reduce activity of the PI3K-AKT pathway, which is a key pathway that is upregulated in human cancers, as well as reduce the expression of Cyclin D1.	('reduce', 'NegReg', (39, 45))	('KLF6-SV1', 'Gene', (14, 22))	('cancers', 'Disease', (132, 139))	('AKT', 'Gene', '207', (67, 70))	('reduce', 'NegReg', (152, 158))	('cancers', 'Disease', 'MESH:D009369', (132, 139))	('human', 'Species', '9606', (126, 131))	('Cyclin D1', 'Gene', '595', (177, 186))	('AKT', 'Gene', (67, 70))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('silencing', 'Var', (23, 32))	('activity', 'MPA', (46, 54))	('Cyclin D1', 'Gene', (177, 186))	('expression', 'MPA', (163, 173))	('KLF6-SV1', 'Gene', '1316', (14, 22))	('cancers', 'Phenotype', 'HP:0002664', (132, 139))
29339	31632477	Here, we further demonstrated that KLF6-SV1 depletion not only promoted apoptosis, but also inhibited migration and invasion in A549 cells.	('inhibited', 'NegReg', (92, 101))	('depletion', 'Var', (44, 53))	('promoted', 'PosReg', (63, 71))	('apoptosis', 'CPA', (72, 81))	('KLF6-SV1', 'Gene', '1316', (35, 43))	('KLF6-SV1', 'Gene', (35, 43))
29348	26949191	Dynamic variations in DNA methylation have been reported in malignant neoplasm and aging; however, the mechanisms remain poorly understood.	('methylation', 'Var', (26, 37))	('neoplasm', 'Phenotype', 'HP:0002664', (70, 78))	('reported', 'Reg', (48, 56))	('DNA', 'Protein', (22, 25))	('malignant neoplasm', 'Disease', (60, 78))	('malignant neoplasm', 'Disease', 'MESH:D009369', (60, 78))
29349	26949191	By constructing an age-associated and cancer-related weighted network (ACWN) based on the correlation of the methylation level and the protein-protein interaction, we found that DNA methylation changes associated with age were closely related to the occurrence of cancer.	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('related', 'Reg', (235, 242))	('changes', 'Reg', (194, 201))	('DNA', 'MPA', (178, 181))	('cancer', 'Phenotype', 'HP:0002664', (264, 270))	('methylation', 'Var', (182, 193))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('cancer', 'Disease', (38, 44))	('cancer', 'Disease', (264, 270))	('cancer', 'Disease', 'MESH:D009369', (264, 270))
29354	26949191	Aging is an intricate and universal physiological process that is affected by many factors, such as telomere shortening, the accumulation of genetic mutations, oxidative stress, and the decay of cells and organs.	('genetic mutations', 'Var', (141, 158))	('man', 'Species', '9606', (78, 81))	('affected', 'Reg', (66, 74))	('telomere', 'Protein', (100, 108))	('telomere shortening', 'Phenotype', 'HP:0031413', (100, 119))	('shortening', 'NegReg', (109, 119))	('oxidative stress', 'Phenotype', 'HP:0025464', (160, 176))
29357	26949191	DNA methylation is a widely studied epigenetic modification that has an important influence on human traits and cancers.	('human', 'Species', '9606', (95, 100))	('influence', 'Reg', (82, 91))	('cancers', 'Phenotype', 'HP:0002664', (112, 119))	('methylation', 'Var', (4, 15))	('cancers', 'Disease', 'MESH:D009369', (112, 119))	('cancers', 'Disease', (112, 119))	('DNA methylation', 'Var', (0, 15))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))
29361	26949191	The occurrence of tumors has been primarily described with regard to genome mutations, but numerous recent researches have demonstrated that aberrant DNA methylation plays a fundamental role in cancer.	('cancer', 'Disease', (194, 200))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('tumors', 'Disease', (18, 24))	('aberrant', 'Var', (141, 149))	('DNA', 'Protein', (150, 153))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('cancer', 'Disease', 'MESH:D009369', (194, 200))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
29364	26949191	This finding demonstrates that tumor suppressor gene promoter methylation elevates tumor susceptibility in aging populations.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumor', 'Disease', (83, 88))	('tumor', 'Disease', (31, 36))	('methylation', 'Var', (62, 73))	('elevates', 'PosReg', (74, 82))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
29366	26949191	Aberrant DNA methylation is a common character in numerous diseases, including cancer.	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('Aberrant DNA methylation', 'Var', (0, 24))	('numerous diseases', 'Disease', (50, 67))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('numerous diseases', 'Disease', 'MESH:D004194', (50, 67))
29367	26949191	Global hypomethylation and site-specific promoter CpG island hypermethylation were previously described in the cancer epigenome.	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('Global hypomethylation', 'Var', (0, 22))
29369	26949191	used whole-genome bisulfite sequencing to demonstrate that the progress of malignancy may be due to DNA methylation of senescence cells if these cells bypass the switch that prevents their growth.	('DNA', 'Var', (100, 103))	('progress', 'PosReg', (63, 71))	('malignancy', 'Disease', 'MESH:D009369', (75, 85))	('bisulfite', 'Chemical', 'MESH:C042345', (18, 27))	('malignancy', 'Disease', (75, 85))
29394	26949191	Previous studies indicated that this transmembrane protein with a single EGF-like and two follistatin domains (TMEFF2) was epigenetically silenced in numerous tumor types, suggesting a potential role as a tumor suppressor.	('numerous tumor', 'Disease', (150, 164))	('TMEFF2', 'Gene', '23671', (111, 117))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('epigenetically', 'Var', (123, 137))	('numerous tumor', 'Disease', 'MESH:D009369', (150, 164))	('tumor', 'Disease', (159, 164))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumor', 'Disease', (205, 210))	('TMEFF2', 'Gene', (111, 117))	('tumor', 'Disease', 'MESH:D009369', (159, 164))
29422	26949191	Furthermore, we hypothesized that the DNA methylation changes associated with age affected cancer risk by clustered in the human interactome.	('human', 'Species', '9606', (123, 128))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('methylation', 'Var', (42, 53))
29426	26949191	Dysregulation of this gene is associated with diseases, such as cancer.	('associated', 'Reg', (30, 40))	('Dysregulation', 'Var', (0, 13))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
29427	26949191	A previous study demonstrated that tumor suppressor NRG1 is frequently subject to epigenetic silencing in epithelial tumors.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('NRG1', 'Gene', '3084', (52, 56))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('epithelial tumors', 'Disease', (106, 123))	('tumor', 'Disease', (117, 122))	('tumor', 'Disease', (35, 40))	('epithelial tumors', 'Disease', 'MESH:D002277', (106, 123))	('NRG1', 'Gene', (52, 56))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('epigenetic silencing', 'Var', (82, 102))
29429	26949191	also showed NRG1 had hypermethylated promoters and reduced expression in colorectal cancer which consistent with our results.	('colorectal cancer', 'Disease', 'MESH:D015179', (73, 90))	('NRG1', 'Gene', (12, 16))	('reduced', 'NegReg', (51, 58))	('colorectal cancer', 'Phenotype', 'HP:0003003', (73, 90))	('expression', 'MPA', (59, 69))	('hypermethylated', 'Var', (21, 36))	('colorectal cancer', 'Disease', (73, 90))	('NRG1', 'Gene', '3084', (12, 16))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))
29431	26949191	The epigenetic silencing of KDR should be considered in the activation of the VEGF-VEGFR signaling pathway in the cancer cells.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('epigenetic silencing', 'Var', (4, 24))	('KDR', 'Gene', (28, 31))	('VEGFR', 'Gene', '3791', (83, 88))	('activation', 'PosReg', (60, 70))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('VEGFR', 'Gene', (83, 88))	('cancer', 'Disease', (114, 120))
29438	26949191	In summary, understanding the trends of methylation changing in aging (hyper-aDMGs or hypo-aDMGs), methylation level (high or low) and differential direction in tumor and normal tissues (differentially hypermethylated or hypomethylated in cancer than normal) is biologically and clinically important.	('tumor', 'Disease', (161, 166))	('hypomethylated', 'Var', (221, 235))	('cancer', 'Disease', 'MESH:D009369', (239, 245))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('cancer', 'Disease', (239, 245))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('methylation level', 'MPA', (99, 116))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))
29446	26949191	In particular, we observed that colon carcinoma (COAD, 11), rectum adenocarcinoma (READ, 8) and kidney renal clear cell carcinoma (KIRC, 8) exhibited more age-associated genes compared with other cancers, suggesting that aging was more likely to be one of the earliest changes marking the risk for neoplasia in these cancers.	('cancers', 'Disease', 'MESH:D009369', (317, 324))	('kidney renal clear cell carcinoma', 'Disease', 'MESH:C538614', (96, 129))	('COAD', 'Disease', (49, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('cancers', 'Disease', 'MESH:D009369', (196, 203))	('colon carcinoma', 'Disease', (32, 47))	('neoplasia', 'Phenotype', 'HP:0002664', (298, 307))	('genes', 'Var', (170, 175))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('kidney renal clear cell carcinoma', 'Disease', (96, 129))	('colon carcinoma', 'Disease', 'MESH:D015179', (32, 47))	('cancers', 'Phenotype', 'HP:0002664', (317, 324))	('carcinoma', 'Phenotype', 'HP:0030731', (38, 47))	('cancers', 'Disease', (317, 324))	('rectum adenocarcinoma', 'Disease', 'MESH:D012004', (60, 81))	('cancers', 'Phenotype', 'HP:0002664', (196, 203))	('cancer', 'Phenotype', 'HP:0002664', (317, 323))	('cancers', 'Disease', (196, 203))	('COAD', 'Disease', 'MESH:D029424', (49, 53))	('neoplasia', 'Disease', 'MESH:D009369', (298, 307))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('neoplasia', 'Disease', (298, 307))	('rectum adenocarcinoma', 'Disease', (60, 81))
29450	26949191	Combining the changes of DNA methylation and gene expression, we identified 28 genes as age-associated cancer markers exhibiting promoter hypermethylation and transcriptional silencing or promoter hypomethylation and transcriptional activation.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('promoter hypermethylation', 'Var', (129, 154))	('transcriptional', 'CPA', (159, 174))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))
29476	26949191	Notably, we identified three survival-associated methylation markers in kidney renal clear cell carcinoma (KIRC).	('kidney renal clear cell carcinoma', 'Disease', (72, 105))	('kidney renal clear cell carcinoma', 'Disease', 'MESH:C538614', (72, 105))	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('methylation', 'Var', (49, 60))
29478	26949191	In the univariate Cox regression, we found that not only methylation signatures, stage and age also could independently predict patient survival (Table 3).	('methylation', 'Var', (57, 68))	('Cox', 'Gene', '1351', (18, 21))	('patient survival', 'CPA', (128, 144))	('Cox', 'Gene', (18, 21))	('patient', 'Species', '9606', (128, 135))	('predict', 'Reg', (120, 127))
29498	26949191	Consistent with this observation, our results demonstrated that hyper-aDMGs were enriched in a variety of developmental processes, thus manifesting a link between aberrant hypermethylation in aging and cancer.	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('enriched', 'Reg', (81, 89))	('man', 'Species', '9606', (136, 139))	('hyper-aDMGs', 'Var', (64, 75))	('cancer', 'Disease', 'MESH:D009369', (202, 208))	('cancer', 'Disease', (202, 208))	('developmental processes', 'CPA', (106, 129))
29504	26949191	We hypothesize that the methylation patterns of these genes in the development of cancer may bypass the mechanism of aging and revert to the initial state of life.	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('methylation patterns', 'Var', (24, 44))	('cancer', 'Disease', (82, 88))
29530	26949191	Thus, the final 4452 differentially methylated gene set we used was the union set of differentially methylated genes of seven cancers, including 1691 DMGs in BRCA, 1817 DMGs in COAD, 1203 DMGs in KIRC, 1077DMGs in KIRP, 1658 DMGs in LUAD, 1869 DMGs in LUSC and 1983 DMGs in READ.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('LUAD', 'Phenotype', 'HP:0030078', (233, 237))	('BRCA', 'Gene', (158, 162))	('DMGs', 'Var', (188, 192))	('1077DMGs', 'Var', (202, 210))	('COAD', 'Disease', 'MESH:D029424', (177, 181))	('DMGs', 'Var', (150, 154))	('cancers', 'Phenotype', 'HP:0002664', (126, 133))	('cancers', 'Disease', (126, 133))	('cancers', 'Disease', 'MESH:D009369', (126, 133))	('1691 DMGs', 'Var', (145, 154))	('COAD', 'Disease', (177, 181))	('BRCA', 'Gene', '672', (158, 162))
29547	33833050	Intratumoral heterogeneity and discrepancy of PD-L1 expression between primary and metastatic lesions may increase the risk of tumor misclassification.	('PD-L1', 'Gene', (46, 51))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumor', 'Disease', (127, 132))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('PD-L1', 'Gene', '29126', (46, 51))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('discrepancy', 'Var', (31, 42))	('expression', 'MPA', (52, 62))	('tumor', 'Disease', (5, 10))	('tumor', 'Disease', 'MESH:D009369', (127, 132))
29555	33833050	KEYNOTE-024 trial showed that patients with high programmed death-ligand 1 (PD-L1) expression and tumor proportion score (TPS) >=50% have significantly improved clinical outcomes when treated with pembrolizumab monotherapy.	('high', 'Var', (44, 48))	('programmed death-ligand 1', 'Gene', (49, 74))	('programmed death-ligand 1', 'Gene', '29126', (49, 74))	('clinical outcomes', 'CPA', (161, 178))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('PD-L1', 'Gene', '29126', (76, 81))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('improved', 'PosReg', (152, 160))	('patients', 'Species', '9606', (30, 38))	('pembrolizumab', 'Chemical', 'MESH:C582435', (197, 210))	('expression', 'MPA', (83, 93))	('tumor', 'Disease', (98, 103))	('PD-L1', 'Gene', (76, 81))
29571	33833050	Among the eight most common metastatic sites, high PD-L1 expression was, statistically significantly, more frequent in samples obtained from lymph nodes (OR, 1.58; 95% CI, 1.43 to 1.74; p<0.001), pleural fluid (OR, 1.48; 95% CI, 1.23 to 1.78; p<0.001), soft tissue (OR, 1.30; 95% CI, 1.08 to 1.58; p=0.007) and adrenal gland (OR, 1.70; 95% CI, 1.30 to 2.22; p<0.001) compared with primary site (table 2, figure 1B).	('expression', 'MPA', (57, 67))	('high', 'Var', (46, 50))	('PD-L1', 'Gene', '29126', (51, 56))	('PD-L1', 'Gene', (51, 56))	('pleural fluid', 'Disease', (196, 209))	('pleural fluid', 'Phenotype', 'HP:0002202', (196, 209))	('adrenal gland', 'Disease', (311, 324))	('lymph nodes', 'Disease', (141, 152))
29667	32383556	In the test cohort, the presence of the 23 immune gene signature was associated with shorter median overall survival (OS) being 18 months for those with the full cancer signature (HR = 2.67, 95% CI 1.55-4.61, P < .001) vs 40 months for those with part of the signature (HR = 1.45, 95% CI 0.88-2.37, P = .137) relative to 90 months for those without the signature (Table 1A).	('shorter', 'NegReg', (85, 92))	('presence', 'Var', (24, 32))	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('cancer', 'Disease', (162, 168))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('overall survival', 'MPA', (100, 116))
29670	32383556	High IL6 expression was associated with higher odds of death in both the HNSCC cohort (HR = 1.14, 95% CI 1.05-1.24, P = .001) and OTSCC subgroup (HR = 1.21, 95% CI 1.03-1.42, P = .021, Table 1E).	('IL6', 'Gene', (5, 8))	('High', 'Var', (0, 4))	('HNSCC', 'Phenotype', 'HP:0012288', (73, 78))	('expression', 'MPA', (9, 19))	('death', 'Disease', 'MESH:D003643', (55, 60))	('death', 'Disease', (55, 60))	('IL6', 'Gene', '3569', (5, 8))
29671	32383556	Similarly, high CCL11 expression was associated with lower odds of death for the HNSCC cohort (HR = 0.92, 95% CI 0.82-0.98, P = .016) and OTSCC subgroup (HR = 0.81, 95% CI 0.70-0.94, P = .005).	('death', 'Disease', 'MESH:D003643', (67, 72))	('death', 'Disease', (67, 72))	('CCL11', 'Gene', (16, 21))	('CCL11', 'Gene', '6356', (16, 21))	('HNSCC', 'Phenotype', 'HP:0012288', (81, 86))	('high', 'Var', (11, 15))	('lower', 'NegReg', (53, 58))	('expression', 'MPA', (22, 32))
29672	32383556	High CD79A expression was associated with lower odds of death for HNSCC only (HR = 0.88, 95% CI 0.82-0.95, P = .001).	('HNSCC', 'Phenotype', 'HP:0012288', (66, 71))	('High', 'Var', (0, 4))	('lower', 'NegReg', (42, 47))	('CD79A', 'Gene', '973', (5, 10))	('HNSCC only', 'Disease', (66, 76))	('CD79A', 'Gene', (5, 10))	('death', 'Disease', 'MESH:D003643', (56, 61))	('death', 'Disease', (56, 61))
29678	32383556	22  Using a FDR of q < 0.05, analyzes revealed that high IL6 expression was associated with higher odds of death for renal clear cell carcinoma (n = 530, HR = 2.49, 95% CI 1.78-3.49, P < .001), as was high CCL11 (HR = 1.91, 95% CI 1.41-2.60, P < .001).	('IL6', 'Gene', '3569', (57, 60))	('CCL11', 'Gene', '6356', (206, 211))	('IL6', 'Gene', (57, 60))	('renal clear cell carcinoma', 'Disease', 'MESH:C538614', (117, 143))	('renal clear cell carcinoma', 'Disease', (117, 143))	('death', 'Disease', 'MESH:D003643', (107, 112))	('CCL11', 'Gene', (206, 211))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('high', 'Var', (52, 56))	('death', 'Disease', (107, 112))	('expression', 'MPA', (61, 71))
29679	32383556	Conversely, high expression of CD79A was associated with higher odds of survival in thymomas (n = 118, HR = 0.11, 95% CI 0.03-0.46, P < .001).	('CD79A', 'Gene', '973', (31, 36))	('CD79A', 'Gene', (31, 36))	('higher', 'PosReg', (57, 63))	('thymomas', 'Disease', (84, 92))	('thymomas', 'Disease', 'MESH:D013945', (84, 92))	('high expression', 'Var', (12, 27))
29720	32383556	Conversely, elevated CCL11 was associated with improved odds of survival in HNSCC and OTSCC subgroup but increased odds of death for renal clear cell carcinoma.	('improved', 'PosReg', (47, 55))	('HNSCC', 'Disease', (76, 81))	('renal clear cell carcinoma', 'Disease', (133, 159))	('HNSCC', 'Phenotype', 'HP:0012288', (76, 81))	('elevated', 'Var', (12, 20))	('CCL11', 'Gene', (21, 26))	('death', 'Disease', 'MESH:D003643', (123, 128))	('death', 'Disease', (123, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (150, 159))	('OTSCC', 'Disease', (86, 91))	('CCL11', 'Gene', '6356', (21, 26))	('renal clear cell carcinoma', 'Disease', 'MESH:C538614', (133, 159))
29725	32383556	25 ,  26 ,  27 ,  28  However, while IL-6 is pro-tumorigenic supporting cellular proliferation, metastases and survival through mechanisms including activation of the JAK/STAT3 signaling pathways, high levels have been reported to be a poor prognostic marker in cancer.	('cancer', 'Disease', (262, 268))	('cellular proliferation', 'CPA', (72, 94))	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('IL-6', 'Gene', (37, 41))	('high', 'Var', (197, 201))	('metastases', 'Disease', 'MESH:D009362', (96, 106))	('cancer', 'Phenotype', 'HP:0002664', (262, 268))	('STAT3', 'Gene', '6774', (171, 176))	('tumor', 'Disease', (49, 54))	('IL-6', 'Gene', '3569', (37, 41))	('survival', 'CPA', (111, 119))	('STAT3', 'Gene', (171, 176))	('cancer', 'Disease', 'MESH:D009369', (262, 268))	('activation', 'PosReg', (149, 159))	('metastases', 'Disease', (96, 106))
29734	32383556	Downregulation of ARG1 activity may occur in relationship to p53-mediated activity suppressing ureagenesis in attempt to hinder tumor growth, 33  although TP53 alterations are the most common mutation identified in HNSCC.	('ARG1', 'Gene', (18, 22))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('TP53', 'Gene', '7157', (155, 159))	('Downregulation', 'NegReg', (0, 14))	('urea', 'Chemical', 'MESH:D014508', (95, 99))	('TP53', 'Gene', (155, 159))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('alterations', 'Var', (160, 171))	('suppressing', 'NegReg', (83, 94))	('HNSCC', 'Phenotype', 'HP:0012288', (215, 220))	('tumor', 'Disease', (128, 133))	('p53', 'Gene', '7157', (61, 64))	('p53', 'Gene', (61, 64))	('ureagenesis', 'MPA', (95, 106))	('ARG1', 'Gene', '383', (18, 22))
29745	32383556	Numerous trials are exploring immunotherapy combination approaches in advanced cancers with a backbone of PD-1/PD-L1/CTLA4 inhibition in conjunction with Treg cell focused agents including those targeting the Inducible T cell Co-Stimulator (ICOS) receptor (NCT02723955), and GITR (NCT03126110).	('cancers', 'Disease', (79, 86))	('ICOS', 'Gene', '29851', (241, 245))	('PD-1', 'Gene', '5133', (106, 110))	('NCT02723955', 'Var', (257, 268))	('CTLA4', 'Gene', '1493', (117, 122))	('PD-1', 'Gene', (106, 110))	('PD-L1', 'Gene', '29126', (111, 116))	('GITR', 'Gene', '8784', (275, 279))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('CTLA4', 'Gene', (117, 122))	('Treg', 'Chemical', '-', (154, 158))	('GITR', 'Gene', (275, 279))	('inhibition', 'NegReg', (123, 133))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('ICOS', 'Gene', (241, 245))	('PD-L1', 'Gene', (111, 116))	('cancers', 'Disease', 'MESH:D009369', (79, 86))	('NCT03126110', 'Var', (281, 292))
29780	32071550	In addition, intron-pairing-driven and RBP-driven circularization events are direct back-splicing mechanisms.	('cir', 'Gene', (50, 53))	('cir', 'Gene', '9541', (50, 53))	('intron-pairing-driven', 'Var', (13, 34))	('RBP', 'Gene', '5950', (39, 42))	('RBP', 'Gene', (39, 42))
29782	32071550	Circular intron RNA biogenesis, which occurs via a lariat-derived mechanism, mainly depends on the conserved motifs at both ends of the intron, i.e., a 7-nt GU-rich element near the 5' splice site and an 11-nt C-rich element near the branch-point site.These motifs can prevent the intron from forming a circular debranching and cause the intron to form a circular structure.	('intron', 'MPA', (281, 287))	('cir', 'Gene', '9541', (303, 306))	('cir', 'Gene', '9541', (355, 358))	('prevent', 'NegReg', (269, 276))	('cir', 'Gene', (303, 306))	('cause', 'Reg', (328, 333))	('cir', 'Gene', (355, 358))	('motifs', 'Var', (258, 264))
29815	32071550	The hsa_circRNA_103809 was overexpressed in LC tissues, and its knockdown significantly inhibited the proliferation and invasion of LC cells and delayed tumor growth in vivo.	('cir', 'Gene', (8, 11))	('LC', 'Disease', 'MESH:D008175', (132, 134))	('inhibited', 'NegReg', (88, 97))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('cir', 'Gene', '9541', (8, 11))	('LC', 'Disease', 'MESH:D008175', (44, 46))	('knockdown', 'Var', (64, 73))	('delayed', 'NegReg', (145, 152))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('invasion', 'CPA', (120, 128))	('tumor', 'Disease', (153, 158))	('LC', 'Phenotype', 'HP:0100526', (132, 134))	('hsa', 'Gene', '213', (4, 7))	('proliferation', 'CPA', (102, 115))	('hsa', 'Gene', (4, 7))	('LC', 'Phenotype', 'HP:0100526', (44, 46))
29823	32071550	Finally, silencing hsa_circ_0020123 by siRNA delivery was shown to suppress NSCLC growth and metastasis in vivo.	('silencing', 'Var', (9, 18))	('cir', 'Gene', (23, 26))	('LC', 'Phenotype', 'HP:0100526', (79, 81))	('NSCLC', 'Disease', (76, 81))	('suppress', 'NegReg', (67, 75))	('hsa', 'Gene', '213', (19, 22))	('hsa', 'Gene', (19, 22))	('NSCLC', 'Disease', 'MESH:D002289', (76, 81))	('cir', 'Gene', '9541', (23, 26))	('SCLC', 'Phenotype', 'HP:0030357', (77, 81))	('NSCLC', 'Phenotype', 'HP:0030358', (76, 81))
29826	32071550	Studies have shown that hsa_circ_0007385 was significantly up-regulated in NSCLC tissue, and its knockdown suppressed the proliferation, migration, and invasion of NSCLC cells in vitro.	('LC', 'Phenotype', 'HP:0100526', (78, 80))	('hsa', 'Gene', '213', (24, 27))	('NSCLC', 'Disease', 'MESH:D002289', (164, 169))	('SCLC', 'Phenotype', 'HP:0030357', (76, 80))	('NSCLC', 'Disease', 'MESH:D002289', (75, 80))	('invasion', 'CPA', (152, 160))	('NSCLC', 'Disease', (164, 169))	('knockdown', 'Var', (97, 106))	('up-regulated', 'PosReg', (59, 71))	('suppressed', 'NegReg', (107, 117))	('migration', 'CPA', (137, 146))	('NSCLC', 'Disease', (75, 80))	('NSCLC', 'Phenotype', 'HP:0030358', (164, 169))	('LC', 'Phenotype', 'HP:0100526', (167, 169))	('proliferation', 'CPA', (122, 135))	('hsa', 'Gene', (24, 27))	('cir', 'Gene', '9541', (28, 31))	('NSCLC', 'Phenotype', 'HP:0030358', (75, 80))	('cir', 'Gene', (28, 31))	('SCLC', 'Phenotype', 'HP:0030357', (165, 169))
29830	32071550	Further analysis indicated that circFADS2 knockdown inhibited the proliferation and invasion ability of the NSCLC cells.	('NSCLC', 'Phenotype', 'HP:0030358', (108, 113))	('cir', 'Gene', (32, 35))	('cir', 'Gene', '9541', (32, 35))	('LC', 'Phenotype', 'HP:0100526', (111, 113))	('NSCLC', 'Disease', (108, 113))	('NSCLC', 'Disease', 'MESH:D002289', (108, 113))	('inhibited', 'NegReg', (52, 61))	('SCLC', 'Phenotype', 'HP:0030357', (109, 113))	('knockdown', 'Var', (42, 51))
29837	32071550	Fusion-circRNA (F-circRNA) has been reported to have tumor-promoting properties in vivo, functioning as a diagnostic marker for the EML4/ALK1 gene fusion mutation in LC.	('cir', 'Gene', '9541', (18, 21))	('LC', 'Disease', 'MESH:D008175', (166, 168))	('ALK1', 'Gene', (137, 141))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('ALK1', 'Gene', '94', (137, 141))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('cir', 'Gene', (18, 21))	('cir', 'Gene', (7, 10))	('EML4', 'Gene', (132, 136))	('LC', 'Phenotype', 'HP:0100526', (166, 168))	('fusion mutation', 'Var', (147, 162))	('tumor', 'Disease', (53, 58))	('EML4', 'Gene', '27436', (132, 136))	('cir', 'Gene', '9541', (7, 10))
29839	32071550	Moreover, LC-associated EML4/ALK1 translocation originated from F-circRNAs, which are functionally relevant (tumor promoting), and represented a novel entry point for LC diagnosis.	('translocation', 'Var', (34, 47))	('ALK1', 'Gene', (29, 33))	('LC', 'Disease', 'MESH:D008175', (167, 169))	('LC', 'Phenotype', 'HP:0100526', (10, 12))	('ALK1', 'Gene', '94', (29, 33))	('EML4', 'Gene', (24, 28))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('cir', 'Gene', (66, 69))	('LC', 'Phenotype', 'HP:0100526', (167, 169))	('LC', 'Disease', 'MESH:D008175', (10, 12))	('EML4', 'Gene', '27436', (24, 28))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('cir', 'Gene', '9541', (66, 69))	('tumor', 'Disease', (109, 114))
29849	32071550	Subsequent experimental results proved that the silencing of circAGFG1 inhibited the proliferation and migration of A549 and H1299 cells.	('silencing', 'Var', (48, 57))	('H1299', 'CellLine', 'CVCL:0060', (125, 130))	('inhibited', 'NegReg', (71, 80))	('cir', 'Gene', (61, 64))	('cir', 'Gene', '9541', (61, 64))	('A549', 'CellLine', 'CVCL:0023', (116, 120))
29852	32071550	As a circRNA, cir-ITCH could regulate the expression of ITCH by sponging miR-7 and miR-214, and consequently, inactivating LC cell proliferation.	('expression', 'MPA', (42, 52))	('miR-214', 'Gene', '406996', (83, 90))	('miR', 'Gene', '220972', (83, 86))	('inactivating', 'NegReg', (110, 122))	('ITCH', 'Gene', (56, 60))	('regulate', 'Reg', (29, 37))	('ITCH', 'Gene', '83737', (18, 22))	('LC', 'Disease', 'MESH:D008175', (123, 125))	('miR', 'Gene', (83, 86))	('miR', 'Gene', '220972', (73, 76))	('LC', 'Phenotype', 'HP:0100526', (123, 125))	('cir', 'Gene', '9541', (14, 17))	('miR-214', 'Gene', (83, 90))	('-ITCH', 'Phenotype', 'HP:0000989', (17, 22))	('ITCH', 'Phenotype', 'HP:0000989', (18, 22))	('ITCH', 'Gene', '83737', (56, 60))	('cir', 'Gene', '9541', (5, 8))	('sponging', 'Var', (64, 72))	('miR', 'Gene', (73, 76))	('cir', 'Gene', (14, 17))	('cir', 'Gene', (5, 8))	('ITCH', 'Phenotype', 'HP:0000989', (56, 60))	('ITCH', 'Gene', (18, 22))
29854	32071550	The Wnt/beta-catenin pathway was reported to play a critical role in tumorigenesis, and aberrant activation of the Wnt/beta-catenin pathway was closely associated with NSCLC progression.	('beta-catenin', 'Gene', '1499', (119, 131))	('aberrant', 'Var', (88, 96))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('activation', 'PosReg', (97, 107))	('beta-catenin', 'Gene', (8, 20))	('tumor', 'Disease', (69, 74))	('NSCLC', 'Disease', 'MESH:D002289', (168, 173))	('NSCLC', 'Phenotype', 'HP:0030358', (168, 173))	('SCLC', 'Phenotype', 'HP:0030357', (169, 173))	('beta-catenin', 'Gene', (119, 131))	('beta-catenin', 'Gene', '1499', (8, 20))	('associated', 'Reg', (152, 162))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('LC', 'Phenotype', 'HP:0100526', (171, 173))	('NSCLC', 'Disease', (168, 173))
29888	32071550	Function assays further confirmed that circRNA_102231 inhibition reduced the LC cells proliferation and invasive ability.	('LC', 'Disease', 'MESH:D008175', (77, 79))	('inhibition', 'Var', (54, 64))	('reduced', 'NegReg', (65, 72))	('cir', 'Gene', (39, 42))	('cir', 'Gene', '9541', (39, 42))	('LC', 'Phenotype', 'HP:0100526', (77, 79))	('invasive ability', 'CPA', (104, 120))
29893	32071550	indicated that hsa_circ_0033155 was significantly downregulated in the NSCLC tissue and its dysregulation can be associated with lymphatic metastasis.	('dysregulation', 'Var', (92, 105))	('NSCLC', 'Phenotype', 'HP:0030358', (71, 76))	('cir', 'Gene', (19, 22))	('hsa', 'Gene', '213', (15, 18))	('lymphatic', 'Disease', (129, 138))	('hsa', 'Gene', (15, 18))	('SCLC', 'Phenotype', 'HP:0030357', (72, 76))	('cir', 'Gene', '9541', (19, 22))	('LC', 'Phenotype', 'HP:0100526', (74, 76))	('downregulated', 'NegReg', (50, 63))	('NSCLC', 'Disease', (71, 76))	('associated', 'Reg', (113, 123))	('NSCLC', 'Disease', 'MESH:D002289', (71, 76))
29900	32071550	Moreover, high plasma hsa_circ_0086414 expression level was related to EGFR mutations.	('mutations', 'Var', (76, 85))	('hsa', 'Gene', '213', (22, 25))	('related', 'Reg', (60, 67))	('hsa', 'Gene', (22, 25))	('cir', 'Gene', (26, 29))	('cir', 'Gene', '9541', (26, 29))	('EGFR', 'Gene', '1956', (71, 75))	('EGFR', 'Gene', (71, 75))
29929	32071550	Functionally, silencing circ-BANP inhibited cell proliferation and migration and induced invasion in vitro and delayed the progression of LC in vivo.	('silencing', 'Var', (14, 23))	('cir', 'Gene', '9541', (24, 27))	('cell proliferation', 'CPA', (44, 62))	('progression', 'CPA', (123, 134))	('BANP', 'Gene', '54971', (29, 33))	('induced', 'Reg', (81, 88))	('LC', 'Phenotype', 'HP:0100526', (138, 140))	('inhibited', 'NegReg', (34, 43))	('invasion', 'CPA', (89, 97))	('BANP', 'Gene', (29, 33))	('delayed', 'NegReg', (111, 118))	('cir', 'Gene', (24, 27))	('LC', 'Disease', 'MESH:D008175', (138, 140))
29941	32071550	also confirmed that the knockdown of circHIPK3 significantly suppressed NSCLC cell proliferation, migration, and invasion and induced macroautophagy/autophagy.	('suppressed', 'NegReg', (61, 71))	('invasion', 'CPA', (113, 121))	('NSCLC', 'Disease', (72, 77))	('cir', 'Gene', (37, 40))	('SCLC', 'Phenotype', 'HP:0030357', (73, 77))	('macroautophagy/autophagy', 'CPA', (134, 158))	('NSCLC', 'Disease', 'MESH:D002289', (72, 77))	('induced', 'Reg', (126, 133))	('migration', 'CPA', (98, 107))	('cir', 'Gene', '9541', (37, 40))	('LC', 'Phenotype', 'HP:0100526', (75, 77))	('knockdown', 'Var', (24, 33))	('NSCLC', 'Phenotype', 'HP:0030358', (72, 77))
29942	32071550	The circHIPK3 silencing was shown to inhibit cell growth and might be partially associated with the induction of autophagy in a subset of LC cell lines.	('silencing', 'Var', (14, 23))	('cir', 'Gene', '9541', (4, 7))	('LC', 'Phenotype', 'HP:0100526', (138, 140))	('inhibit', 'NegReg', (37, 44))	('cir', 'Gene', (4, 7))	('LC', 'Disease', 'MESH:D008175', (138, 140))	('cell growth', 'CPA', (45, 56))	('autophagy', 'CPA', (113, 122))
29945	32071550	Loss-of-function studies indicated that circUBAP2 knockdown suppressed the proliferation and invasion of lung adenocarcinoma.	('invasion of lung adenocarcinoma', 'Disease', 'MESH:C538231', (93, 124))	('Loss-of-function', 'NegReg', (0, 16))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (105, 124))	('suppressed', 'NegReg', (60, 70))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('cir', 'Gene', (40, 43))	('knockdown', 'Var', (50, 59))	('cir', 'Gene', '9541', (40, 43))	('invasion of lung adenocarcinoma', 'Disease', (93, 124))	('proliferation', 'CPA', (75, 88))
29946	32071550	In vitro study showed that circUBAP2 silencing inhibited the expression of CDK6, cyclin D1, c-IAP1, Bcl-2, SuUBRrvivin, FAK, Rac1, and MMP2, while the expression of p27 and Bax was significantly increased.	('SuUBRrvivin', 'Chemical', 'MESH:C035067', (107, 118))	('p27', 'Gene', '10671', (165, 168))	('MMP2', 'Gene', '4313', (135, 139))	('CDK6', 'Gene', (75, 79))	('SuUBRrvivin', 'Gene', (107, 118))	('increased', 'PosReg', (195, 204))	('cyclin D1', 'Gene', (81, 90))	('c-IAP1', 'Gene', '329', (92, 98))	('Rac1', 'Gene', (125, 129))	('Bcl-2', 'Gene', (100, 105))	('cyclin D1', 'Gene', '595', (81, 90))	('c-IAP1', 'Gene', (92, 98))	('silencing', 'Var', (37, 46))	('p27', 'Gene', (165, 168))	('Bax', 'Gene', (173, 176))	('Bcl-2', 'Gene', '596', (100, 105))	('expression', 'MPA', (151, 161))	('MMP2', 'Gene', (135, 139))	('FAK', 'Gene', (120, 123))	('Bax', 'Gene', '581', (173, 176))	('Rac1', 'Gene', '5879', (125, 129))	('expression', 'MPA', (61, 71))	('cir', 'Gene', '9541', (27, 30))	('inhibited', 'NegReg', (47, 56))	('CDK6', 'Gene', '1021', (75, 79))	('cir', 'Gene', (27, 30))	('FAK', 'Gene', '5747', (120, 123))
29947	32071550	Moreover, circUBAP2 knockdown can suppress the activities of Rac1 and FAK.	('Rac1', 'Gene', '5879', (61, 65))	('FAK', 'Gene', '5747', (70, 73))	('Rac1', 'Gene', (61, 65))	('cir', 'Gene', (10, 13))	('suppress', 'NegReg', (34, 42))	('knockdown', 'Var', (20, 29))	('activities', 'MPA', (47, 57))	('cir', 'Gene', '9541', (10, 13))	('FAK', 'Gene', (70, 73))
29952	32071550	Functional assay results indicated that circ_001569 knockdown suppressed the proliferation of NSCLC in vitro.	('NSCLC', 'Phenotype', 'HP:0030358', (94, 99))	('cir', 'Gene', (40, 43))	('LC', 'Phenotype', 'HP:0100526', (97, 99))	('NSCLC', 'Disease', (94, 99))	('cir', 'Gene', '9541', (40, 43))	('suppressed', 'NegReg', (62, 72))	('NSCLC', 'Disease', 'MESH:D002289', (94, 99))	('knockdown', 'Var', (52, 61))	('SCLC', 'Phenotype', 'HP:0030357', (95, 99))
29953	32071550	In addition, circ_001569 knockdown could inhibit the Wnt/beta-catenin signaling pathway in NSCLC cells.	('NSCLC', 'Disease', 'MESH:D002289', (91, 96))	('NSCLC', 'Phenotype', 'HP:0030358', (91, 96))	('cir', 'Gene', (13, 16))	('LC', 'Phenotype', 'HP:0100526', (94, 96))	('inhibit', 'NegReg', (41, 48))	('cir', 'Gene', '9541', (13, 16))	('SCLC', 'Phenotype', 'HP:0030357', (92, 96))	('beta-catenin', 'Gene', (57, 69))	('NSCLC', 'Disease', (91, 96))	('knockdown', 'Var', (25, 34))	('beta-catenin', 'Gene', '1499', (57, 69))
29954	32071550	Therefore, the high expression of circ_001569 might present a risk factor for predicting the prognosis of patients with NSCLC.	('NSCLC', 'Disease', 'MESH:D002289', (120, 125))	('high expression', 'Var', (15, 30))	('SCLC', 'Phenotype', 'HP:0030357', (121, 125))	('NSCLC', 'Phenotype', 'HP:0030358', (120, 125))	('patients', 'Species', '9606', (106, 114))	('cir', 'Gene', (34, 37))	('cir', 'Gene', '9541', (34, 37))	('LC', 'Phenotype', 'HP:0100526', (123, 125))	('NSCLC', 'Disease', (120, 125))
29964	32071550	It has been indicated that altered circRNA expression can affect the tumorigenesis and progression of LC, and these circRNAs hold important clinical relevance due to their advantages in LC diagnosis, therapy, and prognosis.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('altered', 'Var', (27, 34))	('cir', 'Gene', '9541', (35, 38))	('tumor', 'Disease', (69, 74))	('LC', 'Phenotype', 'HP:0100526', (186, 188))	('LC', 'Disease', 'MESH:D008175', (102, 104))	('LC', 'Phenotype', 'HP:0100526', (102, 104))	('cir', 'Gene', (116, 119))	('cir', 'Gene', '9541', (116, 119))	('cir', 'Gene', (35, 38))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('progression', 'CPA', (87, 98))	('LC', 'Disease', 'MESH:D008175', (186, 188))	('affect', 'Reg', (58, 64))	('clinical', 'Species', '191496', (140, 148))
29995	31996191	Thus, the elucidation of aberrantly expressed MMPs and the related miRNA regulatory mechanisms in OSCC progression is critical.	('MMPs', 'Gene', (46, 50))	('OSCC', 'Disease', (98, 102))	('aberrantly', 'Var', (25, 35))	('MMPs', 'Gene', '4312;4313;4314;4316;4317;4318;4319;4320;4321;4322;4323;4324;4326;64066', (46, 50))	('OSCC', 'Disease', 'MESH:D002294', (98, 102))
30028	31996191	MMP13 was regulated by 10 DE-miRNAs (miR-4697-5p, miR-6826-5p, miR-6741-5p, miR-6793-5p, miR-34b, miR-6759-3p, miR-503-5p, miR-6753-3p, miR-7111-3p, and miR-129-1-3p).	('6753-3p', 'Chemical', 'MESH:C020997', (127, 134))	('miR-4697', 'Gene', '100616119', (37, 45))	('miR-129-1-3p', 'Var', (153, 165))	('miR-6741-5p', 'Var', (63, 74))	('miR-4697', 'Gene', (37, 45))	('MMP13', 'Gene', '4322', (0, 5))	('miR-6759-3p', 'Var', (98, 109))	('6741-5p', 'Chemical', 'MESH:C413411', (67, 74))	('miR-503-5p', 'Var', (111, 121))	('miR-6793', 'Gene', '102466737', (76, 84))	('7111-3p', 'Chemical', 'MESH:C031128', (140, 147))	('miR-6826', 'Gene', '102465496', (50, 58))	('miR-34b', 'Gene', '407041', (89, 96))	('miR-6793', 'Gene', (76, 84))	('6759-3p', 'Chemical', 'MESH:C031128', (102, 109))	('miR-6753-3p', 'Var', (123, 134))	('miR-7111-3p', 'Var', (136, 147))	('miR-34b', 'Gene', (89, 96))	('miR-6826', 'Gene', (50, 58))	('MMP13', 'Gene', (0, 5))
30029	31996191	MMP10 was the target gene of miR-20b-5p and miR-6768-5p.	('MMP10', 'Gene', (0, 5))	('MMP10', 'Gene', '4319', (0, 5))	('miR-20b-5p', 'Var', (29, 39))	('miR-6768-5p', 'Var', (44, 55))
30030	31996191	MMP12 was regulated by miR-6090, and MMP9 was regulated by 5 DE-miRNAs (miR-619-5p, miR-3646, miR-4750-3p, miR-4516, and miR-7114-3p) (Table 5).	('regulated', 'Reg', (46, 55))	('miR-6090', 'Gene', '102466104', (23, 31))	('miR-3646', 'Gene', '100500813', (84, 92))	('miR-619-5p', 'Gene', '693204', (72, 82))	('miR-4516', 'Gene', (107, 115))	('miR-7114-3p', 'Var', (121, 132))	('miR-4516', 'Gene', '100616258', (107, 115))	('MMP12', 'Gene', '4321', (0, 5))	('miR-4750-3p', 'Var', (94, 105))	('miR-619-5p', 'Gene', (72, 82))	('miR-6090', 'Gene', (23, 31))	('miR-3646', 'Gene', (84, 92))	('7114-3p', 'Chemical', 'MESH:C071909', (125, 132))	('MMP9', 'Gene', (37, 41))	('MMP12', 'Gene', (0, 5))	('MMP9', 'Gene', '4318', (37, 41))
30093	30809286	Dysregulation of Wnt/beta-catenin signaling, which is necessary for many vital biological processes, such as embryonic development, organogenesis, tissue regeneration, hematopoiesis, cell survival, cellular proliferation and differentiation and stem cell renewal, is associated with many diseases, including osteoporosis, neurodegenerative diseases, and cardiovascular diseases, and numerous human malignancies.	('neurodegenerative diseases', 'Disease', 'MESH:D019636', (322, 348))	('hematopoiesis', 'Disease', (168, 181))	('numerous human malignancies', 'Disease', 'MESH:D009369', (383, 410))	('Dysregulation', 'Var', (0, 13))	('cardiovascular diseases', 'Phenotype', 'HP:0001626', (354, 377))	('numerous human malignancies', 'Disease', (383, 410))	('osteoporosis', 'Phenotype', 'HP:0000939', (308, 320))	('neurodegenerative diseases', 'Disease', (322, 348))	('cardiovascular diseases', 'Disease', (354, 377))	('cardiovascular diseases', 'Disease', 'MESH:D002318', (354, 377))	('neurodegenerative diseases', 'Phenotype', 'HP:0002180', (322, 348))	('osteoporosis', 'Disease', 'MESH:D010024', (308, 320))	('hematopoiesis', 'Disease', 'MESH:C536227', (168, 181))	('associated', 'Reg', (267, 277))	('osteoporosis', 'Disease', (308, 320))
30097	30809286	Further, RPRD1A was found to inhibit chicken DF-1 cell proliferation by downregulating the expression of downstream regulatory genes of the Wnt/beta-catenin pathway, including beta-catenin, TCF4, and cyclin D1.	('expression', 'MPA', (91, 101))	('beta-catenin', 'Protein', (176, 188))	('chicken', 'Species', '9031', (37, 44))	('downregulating', 'NegReg', (72, 86))	('DF-1', 'CellLine', 'CVCL:0570', (45, 49))	('cyclin D1', 'Gene', (200, 209))	('inhibit', 'NegReg', (29, 36))	('TCF4', 'Gene', (190, 194))	('RPRD1A', 'Var', (9, 15))	('chicken DF-1 cell proliferation', 'CPA', (37, 68))
30105	30809286	The breast cancer cell lines ZR-75-30, MCF-7, ZR-75-1, BT-549, BT-474, SKBR3, T47D, MDA-MB-415, MDA-MB-435, MDA-MB-468, MDA-MB-231 and MDA-MB-453 were purchased from the ATCC and maintained in DMEM (Gibco, Grand Island, NY) or RPMI-1640 (Gibco) supplemented with 10% FBS (HyClone, Logan, UT) and 1% penicillin/ streptomycin (Gibco).	('MDA-MB-231', 'CellLine', 'CVCL:0062', (120, 130))	('T47D', 'CellLine', 'CVCL:0553', (78, 82))	('MDA-MB-415', 'Var', (84, 94))	('FBS', 'Disease', 'MESH:D005198', (267, 270))	('breast cancer', 'Disease', 'MESH:D001943', (4, 17))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('MDA-MB-415', 'CellLine', 'CVCL:0621', (84, 94))	('SKBR3', 'CellLine', 'CVCL:0033', (71, 76))	('ZR-75-1', 'CellLine', 'CVCL:0588', (46, 53))	('breast cancer', 'Phenotype', 'HP:0003002', (4, 17))	('breast cancer', 'Disease', (4, 17))	('BT-549', 'CellLine', 'CVCL:1092', (55, 61))	('MDA-MB-468', 'CellLine', 'CVCL:0419', (108, 118))	('FBS', 'Disease', (267, 270))	('MDA-MB-453', 'CellLine', 'CVCL:0418', (135, 145))	('MCF-7', 'CellLine', 'CVCL:0031', (39, 44))	('MDA-MB-435', 'CellLine', 'CVCL:0417', (96, 106))
30124	30809286	Western blotting analysis was performed according to a standard method previously described, using anti-RPRD1A, anti-Axin2, anti-Dkk3, anti-SFRP1 (Abcam) or anti-E-cadherin, anti-alpha-catenin, anti-N-cadherin, anti-vimentin and anti-beta-catenin (Cell Signaling) antibodies.	('E-cadherin', 'Gene', '999', (162, 172))	('Dkk3', 'Gene', (129, 133))	('SFRP1', 'Gene', (140, 145))	('N-cadherin', 'Gene', (199, 209))	('Dkk3', 'Gene', '27122', (129, 133))	('N-cadherin', 'Gene', '1000', (199, 209))	('vimentin', 'Gene', '7431', (216, 224))	('anti-alpha-catenin', 'Protein', (174, 192))	('anti-RPRD1A', 'Var', (99, 110))	('SFRP1', 'Gene', '6422', (140, 145))	('Axin2', 'Gene', (117, 122))	('E-cadherin', 'Gene', (162, 172))	('vimentin', 'Gene', (216, 224))	('Axin2', 'Gene', '8313', (117, 122))
30130	30809286	Stable cell lines expressing miR-454-3p or miRZip-454-3p were generated via retroviral infection using HEK293T cells and selected with 0.5 mug/mL puromycin for 10 days.	('miR-454', 'Gene', (29, 36))	('puromycin', 'Chemical', 'MESH:D011691', (146, 155))	('HEK293T', 'CellLine', 'CVCL:0063', (103, 110))	('miR-454', 'Gene', '768216', (29, 36))	('miRZip-454-3p', 'Var', (43, 56))
30140	30809286	IHC assay was performed using anti-RPRD1A, anti-AXIN2, anti-DKK3, anti-SFRP1 (Abcam) and anti-beta-catenin antibodies (Cell Signaling).	('SFRP1', 'Gene', (71, 76))	('AXIN2', 'Gene', (48, 53))	('AXIN2', 'Gene', '8313', (48, 53))	('anti-beta-catenin', 'Var', (89, 106))	('SFRP1', 'Gene', '6422', (71, 76))	('anti-RPRD1A', 'Var', (30, 41))	('DKK3', 'Gene', '27122', (60, 64))	('DKK3', 'Gene', (60, 64))
30163	30809286	Since previous reports have demonstrated that RPRD1A acts as a negative regulator of Wnt/beta-catenin signaling, we investigated whether Wnt/beta-catenin signaling was involved in the molecular mechanism and found that the transactivity of beta-catenin and the expression of well-known beta-catenin downstream target genes were significantly decreased in the RPRD1A-overexpressing breast cancer cells but increased in the RPRD1A-silenced cells (Figure 1G and Figure S1C).	('cancer', 'Phenotype', 'HP:0002664', (388, 394))	('transactivity', 'MPA', (223, 236))	('breast cancer', 'Disease', 'MESH:D001943', (381, 394))	('decreased', 'NegReg', (342, 351))	('expression', 'MPA', (261, 271))	('breast cancer', 'Disease', (381, 394))	('breast cancer', 'Phenotype', 'HP:0003002', (381, 394))	('RPRD1A-overexpressing', 'Var', (359, 380))	('beta-catenin', 'Protein', (240, 252))
30169	30809286	Furthermore, the luciferase reporter assay showed that the luciferase activity of RPRD1A-3'UTR was drastically decreased in miR-454-3p -overexpressing breast cancer cells but increased in miR-454-silenced cells, whereas forced expression of a mutant miR-454-3p (miR-454-3p-mu: UUCAGCAAUAUUGCUUAUAGGGU) had no inhibitory effect on RPRD1A-3'UTR luciferase activity (Figure 2D).	('miR-454', 'Gene', '768216', (250, 257))	('miR-454', 'Gene', (250, 257))	('miR-454', 'Gene', '768216', (188, 195))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('activity', 'MPA', (70, 78))	('decreased', 'NegReg', (111, 120))	('miR-454', 'Gene', (188, 195))	('breast cancer', 'Disease', 'MESH:D001943', (151, 164))	('miR-454', 'Gene', '768216', (124, 131))	('breast cancer', 'Phenotype', 'HP:0003002', (151, 164))	('breast cancer', 'Disease', (151, 164))	('miR-454', 'Gene', '768216', (262, 269))	('increased', 'PosReg', (175, 184))	('miR-454', 'Gene', (124, 131))	('luciferase', 'Enzyme', (59, 69))	('miR-454', 'Gene', (262, 269))	('mutant', 'Var', (243, 249))
30184	30809286	We also found that overexpression of miR-454-3p reduced the reporter activities driven by the 3'-UTRs of the AXIN2, DKK3 and SFRP1 transcripts, while silencing of miR-454-3p elevated these activities (Figure 3E).	('DKK3', 'Gene', '27122', (116, 120))	('AXIN2', 'Gene', (109, 114))	('miR-454', 'Gene', (163, 170))	('DKK3', 'Gene', (116, 120))	('miR-454', 'Gene', '768216', (37, 44))	('AXIN2', 'Gene', '8313', (109, 114))	('SFRP1', 'Gene', '6422', (125, 130))	('reduced', 'NegReg', (48, 55))	('miR-454', 'Gene', (37, 44))	('elevated', 'PosReg', (174, 182))	('silencing', 'Var', (150, 159))	('miR-454', 'Gene', '768216', (163, 170))	('SFRP1', 'Gene', (125, 130))	('reporter activities driven', 'MPA', (60, 86))
30199	30809286	Further, mice injected with cells with high miR-454-3p expression had shorter survival than those injected with cells that had low miR-454-3p expression, while silencing of miR-454-3p significantly extended their survival (Figure 4G).	('survival', 'CPA', (78, 86))	('extended', 'PosReg', (198, 206))	('miR-454', 'Gene', (44, 51))	('shorter', 'NegReg', (70, 77))	('silencing', 'Var', (160, 169))	('survival', 'CPA', (213, 221))	('miR-454', 'Gene', '768216', (173, 180))	('mice', 'Species', '10090', (9, 13))	('miR-454', 'Gene', '768216', (131, 138))	('miR-454', 'Gene', (131, 138))	('miR-454', 'Gene', (173, 180))	('miR-454', 'Gene', '768216', (44, 51))
30206	30809286	In contrast, silencing of miR-454-3p drastically inhibited the local invasive capability of MDA-MB-231/vector tumors (Figure 5A).	('miR-454', 'Gene', (26, 33))	('local invasive capability', 'CPA', (63, 88))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumors', 'Disease', (110, 116))	('tumors', 'Disease', 'MESH:D009369', (110, 116))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (92, 102))	('miR-454', 'Gene', '768216', (26, 33))	('inhibited', 'NegReg', (49, 58))	('silencing', 'Var', (13, 22))
30214	30809286	Further, the average number of colonies recovered from the blood samples of the tumor-bearing mice was markedly higher in the MDA-MB-231/miRZip-V group (3.4 colonies/100 muL blood) than in the MDA-MB-231/miRZip-454-3p group (1 colony/100 muL blood) (Figure 5E).	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (126, 136))	('MDA-MB-231/miRZip-V', 'Var', (126, 145))	('higher', 'PosReg', (112, 118))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumor', 'Disease', (80, 85))	('mice', 'Species', '10090', (94, 98))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (193, 203))
30225	30809286	As shown in Figure 6B, the number of tumor nests in the lungs formed by the miR-454-3p-transduced MCF-7 cells was significantly higher than that formed by the control cells; further, silencing of miR-454-3p drastically inhibited the capability of MDA-MB-231/vector cells to form lung metastases.	('lung metastases', 'Disease', (279, 294))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (247, 257))	('lung metastases', 'Disease', 'MESH:D009362', (279, 294))	('miR-454', 'Gene', '768216', (196, 203))	('silencing', 'Var', (183, 192))	('inhibited', 'NegReg', (219, 228))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('miR-454', 'Gene', (196, 203))	('tumor', 'Disease', (37, 42))	('MCF-7', 'CellLine', 'CVCL:0031', (98, 103))	('miR-454', 'Gene', '768216', (76, 83))	('miR-454', 'Gene', (76, 83))
30238	30809286	Overexpression of miR-454-3p significantly increased beta-catenin luciferase reporter activity in both the LIHC and KIRC cell lines, while silencing of miR-454-3p decreased this activity.	('miR-454', 'Gene', (152, 159))	('LIHC', 'Disease', 'None', (107, 111))	('silencing', 'Var', (139, 148))	('reporter activity', 'MPA', (77, 94))	('decreased', 'NegReg', (163, 172))	('increased', 'PosReg', (43, 52))	('miR-454', 'Gene', '768216', (18, 25))	('miR-454', 'Gene', (18, 25))	('miR-454', 'Gene', '768216', (152, 159))	('LIHC', 'Disease', (107, 111))	('beta-catenin luciferase', 'Enzyme', (53, 76))
30256	30809286	Moreover, dysregulation of multiple direct target genes of Wnt/beta-catenin signaling in immune cells and tumor cells has been demonstrated to be responsible for the failure of cancer immunotherapy.	('cancer', 'Disease', (177, 183))	('cancer', 'Disease', 'MESH:D009369', (177, 183))	('failure', 'Disease', 'MESH:D017093', (166, 173))	('dysregulation', 'Var', (10, 23))	('failure', 'Disease', (166, 173))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Disease', (106, 111))
30262	30809286	In one such study, inhibition of miR-122 was found to result in a substantial reduction in hepatitis C virus (HCV) infection load and reduction in liver damage.	('reduction in liver damage', 'Disease', (134, 159))	('inhibition', 'Var', (19, 29))	('reduction in hepatitis C virus (HCV) infection', 'Disease', 'MESH:D006526', (78, 124))	('miR-122', 'Gene', (33, 40))	('miR-122', 'Chemical', '-', (33, 40))	('reduction in liver damage', 'Disease', 'MESH:D056486', (134, 159))	('hepatitis', 'Phenotype', 'HP:0012115', (91, 100))
30263	30809286	Recently, two companies (Roche/Santaris and Regulus Therapeutics) have been engaged in clinical trials with anti-miR-122 LNAs as a therapeutic agent against HCV infections, and the projects have reached phase II trials for the treatment of hepatitis.	('hepatitis', 'Disease', (240, 249))	('anti-miR-122', 'Var', (108, 120))	('HCV infections', 'Disease', 'MESH:D006526', (157, 171))	('hepatitis', 'Disease', 'MESH:D056486', (240, 249))	('HCV infections', 'Disease', (157, 171))	('miR-122', 'Chemical', '-', (113, 120))	('hepatitis', 'Phenotype', 'HP:0012115', (240, 249))
30268	30809286	Inhibition of miR-454-3p resulted in inhibition of breast cancer metastasis in a mouse model, indicating its potential clinical applications as a therapeutic target.	('breast cancer metastasis', 'Disease', 'MESH:D009362', (51, 75))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('inhibition', 'NegReg', (37, 47))	('breast cancer metastasis', 'Disease', (51, 75))	('miR-454', 'Gene', '768216', (14, 21))	('Inhibition', 'Var', (0, 10))	('miR-454', 'Gene', (14, 21))	('breast cancer', 'Phenotype', 'HP:0003002', (51, 64))	('mouse', 'Species', '10090', (81, 86))
30269	30809286	Herein, we demonstrated that inhibition of miR-454-3p or ectopic expression of Wnt/beta-catenin antagonists, including RPRD1A, AXIN2, DKK3 and SFRP1, led to Wnt/beta-catenin signaling activity inhibition, which subsequently led to attenuation of breast cancer metastasis.	('miR-454', 'Gene', '768216', (43, 50))	('DKK3', 'Gene', '27122', (134, 138))	('breast cancer', 'Phenotype', 'HP:0003002', (246, 259))	('RPRD1A', 'Gene', (119, 125))	('DKK3', 'Gene', (134, 138))	('AXIN2', 'Gene', (127, 132))	('miR-454', 'Gene', (43, 50))	('SFRP1', 'Gene', (143, 148))	('inhibition', 'NegReg', (193, 203))	('Wnt/beta-catenin signaling activity', 'MPA', (157, 192))	('AXIN2', 'Gene', '8313', (127, 132))	('attenuation of breast cancer metastasis', 'Disease', (231, 270))	('attenuation of breast cancer metastasis', 'Disease', 'MESH:D009362', (231, 270))	('SFRP1', 'Gene', '6422', (143, 148))	('inhibition', 'Var', (29, 39))	('cancer', 'Phenotype', 'HP:0002664', (253, 259))
30274	31484581	RNA-Seq profiling of circular RNA in human lung adenocarcinoma and squamous cell carcinoma Emerging evidences demonstrate that circular RNAs (circRNAs) are abnormally expressed in tumors and could serve as prognostic markers for cancers.	('circular RNAs', 'Var', (127, 140))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('cancers', 'Disease', 'MESH:D009369', (229, 236))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (43, 62))	('cancers', 'Phenotype', 'HP:0002664', (229, 236))	('tumors', 'Phenotype', 'HP:0002664', (180, 186))	('cancers', 'Disease', (229, 236))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (67, 90))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('squamous cell carcinoma', 'Disease', (67, 90))	('tumors', 'Disease', (180, 186))	('tumors', 'Disease', 'MESH:D009369', (180, 186))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (67, 90))	('human', 'Species', '9606', (37, 42))	('carcinoma', 'Phenotype', 'HP:0030731', (53, 62))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('lung adenocarcinoma', 'Disease', (43, 62))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (43, 62))
30293	31484581	Moreover, qPCR data using another divergent primer sets of F3/R3 with one primer crossing the junction site (Additional file 2: Table S6) further verified the differential expressions of hsa_circ_0001821 and hsa_circ_0077837 in both LUAD and LUSC tissues (Additional file 3: Figure S3 m and n), implying they could serve as oncogene or tumor suppressor during NSCLC tumorigenesis.	('tumor', 'Disease', (366, 371))	('LUAD', 'Phenotype', 'HP:0030078', (233, 237))	('NSCLC', 'Disease', 'MESH:D002289', (360, 365))	('tumor', 'Disease', 'MESH:D009369', (336, 341))	('hsa_circ_0001821', 'Var', (187, 203))	('LUSC', 'Phenotype', 'HP:0030359', (242, 246))	('hsa_circ_0077837', 'Var', (208, 224))	('tumor', 'Disease', 'MESH:D009369', (366, 371))	('NSCLC', 'Phenotype', 'HP:0030358', (360, 365))	('tumor', 'Phenotype', 'HP:0002664', (366, 371))	('tumor', 'Phenotype', 'HP:0002664', (336, 341))	('tumor', 'Disease', (336, 341))	('NSCLC', 'Disease', (360, 365))
30295	31484581	For example, hsa_circ_0001821 (circPVT1) plays an oncogenic role in gastric cancer.	('gastric cancer', 'Phenotype', 'HP:0012126', (68, 82))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('gastric cancer', 'Disease', (68, 82))	('gastric cancer', 'Disease', 'MESH:D013274', (68, 82))	('hsa_circ_0001821', 'Var', (13, 29))
30297	31484581	Similarly, hsa_circ_0001073 and hsa_circ_0001495 were confirmed to abnormally express in NSCLC tumors in subtype-specific patterns, i.e., hsa_circ_0001073 was downregulated only in LUAD tissues while hsa_circ_0001495 exhibited higher expression only in LUSC tissues (Additional file 3: Figure S3c-f, i-l).	('NSCLC', 'Phenotype', 'HP:0030358', (89, 94))	('LUSC', 'Phenotype', 'HP:0030359', (253, 257))	('NSCLC tumors', 'Disease', 'MESH:D009369', (89, 101))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('downregulated', 'NegReg', (159, 172))	('hsa_circ_0001073', 'Var', (138, 154))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('NSCLC tumors', 'Disease', (89, 101))	('LUAD', 'Phenotype', 'HP:0030078', (181, 185))
30299	31484581	3a and b, the area under the curve (AUC) to discriminate NSCLC from normal tissues was 0.921 (95% CI: 0.868-0.975) for hsa_circ_0077837 and 0.863 (95% CI: 0.797-0.929) for hsa_circ_0001821, suggesting the high diagnostic potential of these two circRNAs in NSCLC patients.	('NSCLC', 'Disease', 'MESH:D002289', (256, 261))	('hsa_circ_0001821', 'Var', (172, 188))	('NSCLC', 'Phenotype', 'HP:0030358', (256, 261))	('NSCLC', 'Phenotype', 'HP:0030358', (57, 62))	('0.863', 'Var', (140, 145))	('hsa_circ_0077837', 'Var', (119, 135))	('NSCLC', 'Disease', (57, 62))	('patients', 'Species', '9606', (262, 270))	('NSCLC', 'Disease', (256, 261))	('NSCLC', 'Disease', 'MESH:D002289', (57, 62))
30300	31484581	3d), implying that hsa_circ_0001073 and hsa_circ_0001495, which have been shown as above to abnormally express in NSCLC subtype-specific patterns, could serve as diagnostic biomarkers to predict LUAD and LUSC, respectively.	('hsa_circ_0001495', 'Var', (40, 56))	('hsa_circ_0001073', 'Var', (19, 35))	('LUAD', 'Disease', (195, 199))	('NSCLC', 'Phenotype', 'HP:0030358', (114, 119))	('LUSC', 'Phenotype', 'HP:0030359', (204, 208))	('NSCLC', 'Disease', (114, 119))	('LUSC', 'Disease', (204, 208))	('NSCLC', 'Disease', 'MESH:D002289', (114, 119))	('LUAD', 'Phenotype', 'HP:0030078', (195, 199))
30302	31484581	Moreover, ROC analyses demonstrate that hsa_circ_0077837 and hsa_circ_0001821 have the diagnostic potential for NSCLC patients, while hsa_circ_0001073 and hsa_circ_0001495 could act as biomarkers for NSCLC pathological subtyping.	('NSCLC', 'Phenotype', 'HP:0030358', (200, 205))	('NSCLC', 'Phenotype', 'HP:0030358', (112, 117))	('NSCLC', 'Disease', (200, 205))	('hsa_circ_0077837', 'Var', (40, 56))	('NSCLC', 'Disease', 'MESH:D002289', (200, 205))	('NSCLC', 'Disease', (112, 117))	('hsa_circ_0001821', 'Var', (61, 77))	('patients', 'Species', '9606', (118, 126))	('NSCLC', 'Disease', 'MESH:D002289', (112, 117))
30359	25172266	Among men, the incidence of squamous cell carcinoma and adenocarcinoma were higher for NH blacks than for NH whites; among women, differences by race/ethnicity were less pronounced.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (28, 51))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (28, 51))	('men', 'Species', '9606', (125, 128))	('squamous cell carcinoma', 'Disease', (28, 51))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('adenocarcinoma', 'Disease', (56, 70))	('NH blacks', 'Var', (87, 96))	('women', 'Species', '9606', (123, 128))	('adenocarcinoma', 'Disease', 'MESH:D000230', (56, 70))	('carcinoma', 'Phenotype', 'HP:0030731', (42, 51))	('men', 'Species', '9606', (6, 9))
30399	25172266	Consistent with previously reported data, our results showed overall lung cancer rates for NH AI/AN were lower than rates for NH blacks and NH whites.	('lower', 'NegReg', (105, 110))	('NH AI/AN', 'Var', (91, 99))	('lung cancer', 'Disease', 'MESH:D008175', (69, 80))	('lung cancer', 'Disease', (69, 80))	('lung cancer', 'Phenotype', 'HP:0100526', (69, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
30413	27602958	Smoking was negatively associated with methylation levels in cg25771041 (WWTR1, p = 3.6 x 10-9), cg16200496 (NFIX, p = 3.4 x 10-12), cg22515201 (PLA2G6, p = 1.0 x 10-9) and cg24823993 (NHP2L1, p = 5.1 x 10-8) and positively associated with the methylation level in cg11875268 (SMUG1, p = 4.3 x 10-8).	('SMUG1', 'Gene', (277, 282))	('methylation level', 'MPA', (244, 261))	('PLA2G6', 'Gene', (145, 151))	('cg24823993', 'Var', (173, 183))	('WWTR1', 'Gene', '25937', (73, 78))	('negatively', 'NegReg', (12, 22))	('cg11875268', 'Var', (265, 275))	('cg16200496', 'Chemical', '-', (97, 107))	('cg16200496', 'Var', (97, 107))	('SMUG1', 'Gene', '23583', (277, 282))	('cg24823993', 'Chemical', '-', (173, 183))	('WWTR1', 'Gene', (73, 78))	('cg25771041', 'Var', (61, 71))	('cg22515201', 'Var', (133, 143))	('cg11875268', 'Chemical', '-', (265, 275))	('NFIX', 'Gene', '4784', (109, 113))	('PLA2G6', 'Gene', '8398', (145, 151))	('methylation levels', 'MPA', (39, 57))	('cg25771041', 'Chemical', '-', (61, 71))	('cg22515201', 'Chemical', '-', (133, 143))	('NHP2L1', 'Gene', (185, 191))	('NFIX', 'Gene', (109, 113))	('NHP2L1', 'Gene', '4809', (185, 191))
30422	27602958	Differential DNA methylation, hypermethylation and hypomethylation of promoter-specific genes within CpG islands of tumor suppressor and proto-oncogenes, has been correlated with human cancers.	('tumor', 'Disease', (116, 121))	('human', 'Species', '9606', (179, 184))	('correlated', 'Reg', (163, 173))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('hypomethylation', 'Var', (51, 66))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('cancers', 'Phenotype', 'HP:0002664', (185, 192))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('cancers', 'Disease', 'MESH:D009369', (185, 192))	('hypermethylation', 'Var', (30, 46))	('cancers', 'Disease', (185, 192))
30423	27602958	The triggers leading to aberrant epigenetic changes are poorly understood in the cancer genome, but those in blood have been implicated in cigarette smoking.	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('cancer', 'Disease', (81, 87))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('epigenetic changes', 'Var', (33, 51))
30438	27602958	As shown in Table 2, the five externally validated sites and their associated genes were: cg25771041 in WW domain containing transcription regulator 1 gene (WWTR1; pooled p-value = 3.63 x 10-9, external p-value = 0.046), cg11875268 in single-strand-selective monofunctional uracil DNA glycosylase gene (SMUG1; pooled p-value = 4.28 x 10-8, external p-value = 0.0017), cg16200496 in nuclear factor 1 x-type gene (NFIX; pooled p-value = 3.4 x 10-12, external p-value = 0.0344), cg22515201 in phospholipase A2 group VI gene (PLA2G6; pooled p-value = 1.04 x 10-9, external p-value (in LUAD) = 0.016), cg24823993 in NHP2-like protein 1 gene (NHP2L1; pooled p-value = 5.13 x 10-8, external p-value (in LUAD) = 0.047).	('PLA2G6', 'Gene', '8398', (522, 528))	('WWTR1', 'Gene', '25937', (157, 162))	('SMUG1', 'Gene', '23583', (303, 308))	('cg25771041', 'Chemical', '-', (90, 100))	('cg22515201', 'Var', (476, 486))	('phospholipase A2 group VI', 'Gene', (490, 515))	('cg11875268', 'Chemical', '-', (221, 231))	('PLA2G6', 'Gene', (522, 528))	('phospholipase A2 group VI', 'Gene', '8398', (490, 515))	('cg22515201', 'Chemical', '-', (476, 486))	('NHP2-like protein 1', 'Gene', '4809', (611, 630))	('WWTR1', 'Gene', (157, 162))	('NHP2L1', 'Gene', (637, 643))	('NHP2L1', 'Gene', '4809', (637, 643))	('cg24823993', 'Var', (597, 607))	('cg11875268', 'Var', (221, 231))	('NFIX', 'Gene', '4784', (412, 416))	('cg16200496', 'Chemical', '-', (368, 378))	('cg16200496', 'Var', (368, 378))	('SMUG1', 'Gene', (303, 308))	('cg24823993', 'Chemical', '-', (597, 607))	('cg25771041', 'Var', (90, 100))	('NHP2-like protein 1', 'Gene', (611, 630))	('uracil', 'Chemical', 'MESH:D014498', (274, 280))	('NFIX', 'Gene', (412, 416))
30439	27602958	We noted that the three most significant CpG sites that were validated internally: cg16579555 (pooled p = 4.2 x 10-20; located within RNF135 [ring finger protein 135]), cg00032419 (pooled p = 1.8 x 10-19; located within TP53I13 [tumor protein P53 inducible protein 13]) and cg16654732 (pooled p = 8.1 x 10-20; located within FGF18 [fibroblast growth factor 18]) seemed biologically interesting but were not validated by the external data.	('FGF18', 'Gene', '8817', (325, 330))	('fibroblast growth factor 18', 'Gene', '8817', (332, 359))	('FGF18', 'Gene', (325, 330))	('RNF135', 'Gene', '84282', (134, 140))	('cg16579555', 'Var', (83, 93))	('cg16654732', 'Chemical', '-', (274, 284))	('cg16654732', 'Var', (274, 284))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('ring finger protein 135', 'Gene', '84282', (142, 165))	('cg00032419', 'Var', (169, 179))	('tumor protein P53 inducible protein 13', 'Gene', '90313', (229, 267))	('fibroblast growth factor 18', 'Gene', (332, 359))	('tumor protein P53 inducible protein 13', 'Gene', (229, 267))	('TP53I13', 'Gene', (220, 227))	('RNF135', 'Gene', (134, 140))	('ring finger protein 135', 'Gene', (142, 165))	('TP53I13', 'Gene', '90313', (220, 227))
30440	27602958	Higher smoking exposure was associated with decreased methylation at cg25771041, cg16200496, cg22515201, and cg24823993, and increased methylation at cg11875268.	('cg16200496', 'Var', (81, 91))	('cg22515201', 'Chemical', '-', (93, 103))	('cg11875268', 'Chemical', '-', (150, 160))	('increased', 'PosReg', (125, 134))	('cg11875268', 'Var', (150, 160))	('methylation', 'MPA', (135, 146))	('cg24823993', 'Var', (109, 119))	('cg25771041', 'Chemical', '-', (69, 79))	('cg25771041', 'Var', (69, 79))	('cg24823993', 'Chemical', '-', (109, 119))	('methylation', 'MPA', (54, 65))	('cg22515201', 'Var', (93, 103))	('cg16200496', 'Chemical', '-', (81, 91))	('decreased', 'NegReg', (44, 53))
30442	27602958	Associations between CpG site methylation and RNA expression of their associated genes were also assessed for subjects who also had expression data available; only cg25771041 at NHP2L1 demonstrated a significant association between methylation and RNA expression (Supplementary Table S4).	('NHP2L1', 'Gene', (178, 184))	('cg25771041', 'Chemical', '-', (164, 174))	('NHP2L1', 'Gene', '4809', (178, 184))	('men', 'Species', '9606', (270, 273))	('cg25771041', 'Var', (164, 174))	('methylation', 'MPA', (232, 243))	('RNA expression', 'MPA', (248, 262))
30444	27602958	In NFIX, no significant methylation signals other than the externally validated finding at cg16200496 were present.	('NFIX', 'Gene', (3, 7))	('cg16200496', 'Chemical', '-', (91, 101))	('cg16200496', 'Var', (91, 101))	('NFIX', 'Gene', '4784', (3, 7))
30445	27602958	Finally, in SMUG1, several significant methylation loci were present across the gene body but not in the TSS.	('SMUG1', 'Gene', (12, 17))	('SMUG1', 'Gene', '23583', (12, 17))	('methylation', 'Var', (39, 50))
30447	27602958	The most significant association signal between DNA methylation and cigarette smoking in WWTR1 occurred at cg25771041 (Figure 2A).	('WWTR1', 'Gene', '25937', (89, 94))	('cg25771041', 'Chemical', '-', (107, 117))	('cg25771041', 'Var', (107, 117))	('WWTR1', 'Gene', (89, 94))
30450	27602958	cg22515201 in a CpG island within 200 bp of the TSS in PLA2G6 is the most significant CpG locus in the gene associated with cigarette smoking.	('cg22515201', 'Var', (0, 10))	('cg22515201', 'Chemical', '-', (0, 10))	('PLA2G6', 'Gene', (55, 61))	('PLA2G6', 'Gene', '8398', (55, 61))
30451	27602958	The analyses also identified several highly significant methylation loci at the TSS and near exon 1 of PLA2G6 (Figure 2C).	('methylation', 'Var', (56, 67))	('PLA2G6', 'Gene', (103, 109))	('PLA2G6', 'Gene', '8398', (103, 109))
30452	27602958	The analyses of CpG loci within NFIX identified highly significant association with smoking in exon 1 with the most significant signal in cg16200496, but no other regions demonstrate strong enrichment (Figure 2D).	('men', 'Species', '9606', (196, 199))	('NFIX', 'Gene', (32, 36))	('NFIX', 'Gene', '4784', (32, 36))	('cg16200496', 'Chemical', '-', (138, 148))	('smoking', 'MPA', (84, 91))	('cg16200496', 'Var', (138, 148))
30453	27602958	The association with smoking was more prominent in the fourth exon (cg11875268) of SMUG1 (Figure 2E).	('SMUG1', 'Gene', (83, 88))	('cg11875268', 'Var', (68, 78))	('SMUG1', 'Gene', '23583', (83, 88))	('cg11875268', 'Chemical', '-', (68, 78))
30454	27602958	There were statistically significant negative associations for all CpG sites as pack-years increased (cg25771041 [in WWTR1; p = 3.1 x 10-31, R2 = 0.079], cg16200496 [in NFIX; p = 4.8 x 10-39, R2 = 0.098], cg22515201 [in PLA2G6; p = 1.5 x 10-20, R2 = 0.072], cg24823993 [in NHP2L1; p = 0.008, R2 = 0.007]) except in cg11875268 (in SMUG1; p = 1 x 10-14, R2 = 0.068) (Figure 3A).	('cg24823993 [', 'Var', (258, 270))	('negative', 'NegReg', (37, 45))	('WWTR1', 'Gene', '25937', (117, 122))	('cg11875268', 'Chemical', '-', (315, 325))	('PLA2G6', 'Gene', '8398', (220, 226))	('NFIX', 'Gene', '4784', (169, 173))	('SMUG1', 'Gene', (330, 335))	('NHP2L1', 'Gene', (273, 279))	('NHP2L1', 'Gene', '4809', (273, 279))	('cg24823993', 'Chemical', '-', (258, 268))	('cg22515201', 'Var', (205, 215))	('cg16200496 [', 'Var', (154, 166))	('NFIX', 'Gene', (169, 173))	('associations', 'Interaction', (46, 58))	('cg25771041', 'Var', (102, 112))	('SMUG1', 'Gene', '23583', (330, 335))	('WWTR1', 'Gene', (117, 122))	('cg16200496', 'Chemical', '-', (154, 164))	('PLA2G6', 'Gene', (220, 226))	('cg22515201', 'Chemical', '-', (205, 215))	('cg25771041', 'Chemical', '-', (102, 112))	('cg11875268', 'Var', (315, 325))
30455	27602958	Variation in cg22515201 (PLA2G6) was explained the most by smoking pack-years with a marginal R2 = 0.098.	('cg22515201', 'Chemical', '-', (13, 23))	('PLA2G6', 'Gene', (25, 31))	('PLA2G6', 'Gene', '8398', (25, 31))	('cg22515201', 'Var', (13, 23))
30460	27602958	Interestingly, the strength of association was consistently more significant in the LUSC subgroup, with the strongest signal originating from cg16200946 in NFIX (beta = -1.20, p = 6.6 x 10-10, R2 = 0.144) (Supplementary File S3 and Supplementary Figure S1D).	('NFIX', 'Gene', (156, 160))	('cg16200946', 'Var', (142, 152))	('LUSC', 'Disease', (84, 88))	('NFIX', 'Gene', '4784', (156, 160))	('Supplementary File S3 and Supplementary Figure S1D', 'Disease', 'MESH:D017034', (206, 256))
30461	27602958	The cell-type specific association between DNA methylation of the five externally validated loci (cg25771041, cg11875268, cg16200496, cg22515201 and cg24823993) and smoking was presented in Supplementary Tables S2 and S3, and their dose-response relationship was presented in Supplementary Figure S1.	('men', 'Species', '9606', (196, 199))	('cg24823993', 'Var', (149, 159))	('cg16200496', 'Chemical', '-', (122, 132))	('cg22515201', 'Var', (134, 144))	('cg24823993', 'Chemical', '-', (149, 159))	('cg16200496', 'Var', (122, 132))	('cg25771041', 'Var', (98, 108))	('cg22515201', 'Chemical', '-', (134, 144))	('men', 'Species', '9606', (282, 285))	('cg11875268', 'Var', (110, 120))	('cg11875268', 'Chemical', '-', (110, 120))	('cg25771041', 'Chemical', '-', (98, 108))
30463	27602958	Sensitivity analyses were conducted by reanalyzing the main, cell-specific, and external validation datasets after removing cases with KRAS or EGFR mutation from our analytical model.	('EGFR', 'Gene', (143, 147))	('KRAS', 'Gene', (135, 139))	('KRAS', 'Gene', '3845', (135, 139))	('EGFR', 'Gene', '1956', (143, 147))	('mutation', 'Var', (148, 156))
30465	27602958	Of our 98 internally validated CpG sites, five were externally validated in an independent data set: cg16200496 (NFIX), cg25771041 (WWTR1), cg11875268 (SMUG1), cg22515201 (PLA2G6), and cg24823993 (NHP2L1).	('cg25771041', 'Var', (120, 130))	('WWTR1', 'Gene', (132, 137))	('NFIX', 'Gene', '4784', (113, 117))	('NHP2L1', 'Gene', (197, 203))	('NHP2L1', 'Gene', '4809', (197, 203))	('cg22515201', 'Var', (160, 170))	('cg25771041', 'Chemical', '-', (120, 130))	('cg11875268', 'Chemical', '-', (140, 150))	('NFIX', 'Gene', (113, 117))	('PLA2G6', 'Gene', '8398', (172, 178))	('cg24823993', 'Var', (185, 195))	('cg22515201', 'Chemical', '-', (160, 170))	('WWTR1', 'Gene', '25937', (132, 137))	('SMUG1', 'Gene', (152, 157))	('cg16200496', 'Chemical', '-', (101, 111))	('cg24823993', 'Chemical', '-', (185, 195))	('cg16200496', 'Var', (101, 111))	('PLA2G6', 'Gene', (172, 178))	('cg11875268', 'Var', (140, 150))	('SMUG1', 'Gene', '23583', (152, 157))
30475	27602958	Further experimentation with WWTR1/TAZ knockdowns resulted in decreased lung tumor progression, while constitutively active WWTR1/TAZ was found to be sufficient to drive lung tumor progression.	('decreased lung tumor', 'Disease', (62, 82))	('WWTR1', 'Gene', (124, 129))	('lung tumor', 'Disease', (170, 180))	('decreased lung', 'Phenotype', 'HP:0002089', (62, 76))	('lung tumor', 'Phenotype', 'HP:0100526', (170, 180))	('knockdowns', 'Var', (39, 49))	('lung tumor', 'Phenotype', 'HP:0100526', (72, 82))	('WWTR1', 'Gene', '25937', (29, 34))	('TAZ', 'Gene', (35, 38))	('TAZ', 'Gene', '6901', (35, 38))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('TAZ', 'Gene', '6901', (130, 133))	('decreased lung tumor', 'Disease', 'MESH:D008175', (62, 82))	('WWTR1', 'Gene', '25937', (124, 129))	('TAZ', 'Gene', (130, 133))	('lung tumor', 'Disease', 'MESH:D008175', (170, 180))	('lung tumor', 'Disease', 'MESH:D008175', (72, 82))	('men', 'Species', '9606', (14, 17))	('WWTR1', 'Gene', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))
30486	27602958	One candidate gene pathway analysis identified PLA2G6, a member of the cell cycle pathway, as bearing a statistically significant single nucleotide polymorphism associated with lung cancer risk.	('single nucleotide polymorphism', 'Var', (130, 160))	('PLA2G6', 'Gene', '8398', (47, 53))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('lung cancer', 'Disease', 'MESH:D008175', (177, 188))	('PLA2G6', 'Gene', (47, 53))	('lung cancer', 'Disease', (177, 188))	('lung cancer', 'Phenotype', 'HP:0100526', (177, 188))
30492	27602958	In the present analyses, we found that methylation at cg16654732 was negatively associated with smoking, where higher pack years corresponded with lower methylation levels.	('methylation', 'Var', (39, 50))	('cg16654732', 'Chemical', '-', (54, 64))	('cg16654732', 'Var', (54, 64))	('negatively', 'NegReg', (69, 79))	('smoking', 'Disease', (96, 103))	('methylation levels', 'MPA', (153, 171))	('associated', 'Interaction', (80, 90))
30493	27602958	In addition, cg13204512 and cg16579555 (within RNF135) were strongly, negatively associated with smoking pack-years (pooled p-value = 4.8 x 10-15 and 4.2 x 10-20, respectively).	('RNF135', 'Gene', '84282', (47, 53))	('negatively', 'NegReg', (70, 80))	('cg13204512', 'Var', (13, 23))	('RNF135', 'Gene', (47, 53))	('smoking', 'Disease', (97, 104))	('cg16579555', 'Var', (28, 38))
30495	27602958	The TP53I13, TP53 inducible gene 13 also had two strong signals from the analyses of TCGA data (cg00032419, p = 1.8 x 10-19 and cg00265578, p = 1.6 x 10-15).	('TP53I13', 'Gene', '90313', (4, 11))	('cg00265578', 'Var', (128, 138))	('TP53', 'Gene', (13, 17))	('cg00032419', 'Var', (96, 106))	('TP53', 'Gene', (4, 8))	('TP53I13', 'Gene', (4, 11))	('TP53', 'Gene', '7157', (13, 17))	('TP53', 'Gene', '7157', (4, 8))
30497	27602958	Despite the strength of the association in our analyses, cg16654732, cg13204512, cg16579555, cg00032419 and cg00265578 were not found to be statistically significant in the external dataset suggesting this finding may have mechanistic heterogeneity and may not be generalizable to other studies.	('cg00265578', 'Var', (108, 118))	('cg16654732', 'Chemical', '-', (57, 67))	('cg16654732', 'Var', (57, 67))	('cg00032419', 'Var', (93, 103))	('cg16579555', 'Var', (81, 91))	('cg13204512', 'Var', (69, 79))
30518	27602958	Key clinical and demographic variables of interest were re-categorized for analysis: smoking exposure in pack years, sex, age, race, KRAS mutation, EGFR mutation, and cell-type.	('EGFR', 'Gene', '1956', (148, 152))	('EGFR', 'Gene', (148, 152))	('KRAS', 'Gene', (133, 137))	('KRAS', 'Gene', '3845', (133, 137))	('mutation', 'Var', (153, 161))
30519	27602958	Both KRAS and EGFR mutation types were re-categorized into binary variables based on whether any mutations were present: the presence of any mutation (e.g., exon 19 deletion, L858R, and others) or not.	('EGFR', 'Gene', '1956', (14, 18))	('L858R', 'Var', (175, 180))	('EGFR', 'Gene', (14, 18))	('KRAS', 'Gene', (5, 9))	('L858R', 'Mutation', 'rs121434568', (175, 180))	('KRAS', 'Gene', '3845', (5, 9))
30522	27602958	In the first stage, an epigenome-wide association scan was conducted in the discovery subset using a linear model to test the relationship between DNA methylation and smoking at each CpG locus, with adjustments for cell-type, EGFR mutation status, KRAS mutation status, age, sex, and race.	('KRAS', 'Gene', (248, 252))	('KRAS', 'Gene', '3845', (248, 252))	('men', 'Species', '9606', (205, 208))	('EGFR', 'Gene', '1956', (226, 230))	('mutation', 'Var', (231, 239))	('EGFR', 'Gene', (226, 230))
30526	27602958	To examine the robustness of our findings, further sensitivity analyses were conducted by comparing estimates obtained by including vs excluding subjects with documented EGFR (n = 11) or KRAS (n = 12) mutations within the main and cell-type-specific analyses.	('mutations', 'Var', (201, 210))	('men', 'Species', '9606', (163, 166))	('EGFR', 'Gene', '1956', (170, 174))	('KRAS', 'Gene', (187, 191))	('KRAS', 'Gene', '3845', (187, 191))	('EGFR', 'Gene', (170, 174))
30528	27586307	In this paper, knock-down the expression of DDX3X can affect a subset of miRNA expression levels, especially for miR-1, miR-141, miR-145, miR-19b, miR-20a and miR-34a.	('expression', 'Species', '29278', (79, 89))	('miR-141', 'Var', (120, 127))	('expression', 'Var', (30, 40))	('miR-145', 'Var', (129, 136))	('subset of miRNA expression levels', 'MPA', (63, 96))	('miR-34a', 'Var', (159, 166))	('DDX3X', 'Gene', (44, 49))	('affect', 'Reg', (54, 60))	('knock-down', 'Var', (15, 25))	('expression', 'Species', '29278', (30, 40))	('miR-20a', 'Var', (147, 154))	('miR-1', 'Var', (113, 118))	('miR-19b', 'Var', (138, 145))	('DDX3X', 'Gene', '1654', (44, 49))	('miR-145', 'Chemical', '-', (129, 136))	('34a', 'Chemical', '-', (163, 166))
30553	27586307	Compared with two DDX3X KD heatmaps, we can find that there were six miRNAs overlapped in two heatmaps and marked with red asterisk, such as miR-1, miR-141, miR-145, miR-19b, miR-20a and miR-34a (Fig.	('miR-20a', 'Var', (175, 182))	('miR-19b', 'Var', (166, 173))	('miR-145', 'Chemical', '-', (157, 164))	('34a', 'Chemical', '-', (191, 194))	('miR-1', 'Var', (141, 146))	('DDX3X', 'Gene', '1654', (18, 23))	('miR-34a', 'Var', (187, 194))	('miR-145', 'Var', (157, 164))	('DDX3X', 'Gene', (18, 23))	('miR-141', 'Var', (148, 155))
30562	27586307	In the next part, we used the RT-PCR to double check the miRNA array data and test the pri-miRNA and mature miRNA expression levels of six significantly altered miRNAs (miR-1, miR-141, miR-145, miR-19b, miR-20a and miR-34a) in DDX3X KD and OE cell lines respectively.	('miR-20a', 'Var', (203, 210))	('DDX3X', 'Gene', '1654', (227, 232))	('miR-19b', 'Var', (194, 201))	('miR-145', 'Chemical', '-', (185, 192))	('altered', 'Reg', (153, 160))	('miR-1', 'Var', (169, 174))	('34a', 'Chemical', '-', (219, 222))	('expression', 'Species', '29278', (114, 124))	('miR-141', 'Var', (176, 183))	('miR-34a', 'Var', (215, 222))	('miR-145', 'Var', (185, 192))	('DDX3X', 'Gene', (227, 232))
30564	27586307	2C,D) and it demonstrated that knock-down of DDX3X expression could inhibit miRNA biogenesis process and down-regulate mature miRNA expression levels.	('DDX3X', 'Gene', (45, 50))	('miRNA biogenesis process', 'CPA', (76, 100))	('DDX3X', 'Gene', '1654', (45, 50))	('inhibit', 'NegReg', (68, 75))	('knock-down', 'Var', (31, 41))	('expression', 'Species', '29278', (51, 61))	('expression', 'Species', '29278', (132, 142))	('mature miRNA expression levels', 'MPA', (119, 149))	('down-regulate', 'NegReg', (105, 118))
30569	27586307	The data showed that DDX3X-dependent pri-miRNAs (pri-miR-1, pri-miR-141, pri-miR-145, pri-miR-19b, pri-miR-20a and pri-miR-34a) could significantly bind to DDX3X compared with IgG control (**p < 0.01, ***p < 0.001) (Fig.	('pri-miR-19b', 'Var', (86, 97))	('bind', 'Interaction', (148, 152))	('DDX3X', 'Gene', '1654', (21, 26))	('miR-145', 'Chemical', '-', (77, 84))	('pri-miR-145', 'Var', (73, 84))	('DDX3X', 'Gene', (156, 161))	('pri-miR-20a', 'Var', (99, 110))	('34a', 'Chemical', '-', (123, 126))	('DDX3X', 'Gene', (21, 26))	('DDX3X', 'Gene', '1654', (156, 161))	('pri-miR-1', 'Var', (49, 58))	('pri-miR-141', 'Var', (60, 71))
30570	27586307	However, when we knocked down the expression of DDX3X, the DDX3X-dependent pri-miRNAs could not bind to DDX3X anymore (Fig.	('DDX3X', 'Gene', (104, 109))	('DDX3X', 'Gene', '1654', (48, 53))	('DDX3X', 'Gene', '1654', (104, 109))	('expression', 'Species', '29278', (34, 44))	('knocked', 'Var', (17, 24))	('DDX3X', 'Gene', (59, 64))	('DDX3X', 'Gene', (48, 53))	('DDX3X', 'Gene', '1654', (59, 64))	('bind', 'Interaction', (96, 100))
30572	27586307	The data indicated that knock-down the expression of DDX3X could significantly down-regulate the pri-miRNA levels which bind to Drosha, compared with NC group (**p < 0.01) (Fig.	('DDX3X', 'Gene', (53, 58))	('knock-down', 'Var', (24, 34))	('pri-miRNA levels which bind', 'MPA', (97, 124))	('down-regulate', 'NegReg', (79, 92))	('DDX3X', 'Gene', '1654', (53, 58))	('expression', 'Species', '29278', (39, 49))
30579	27586307	All these data suggested that knock-down the expression of DDX3X could inhibit the processing activity of Drosha/DGCR8 complex on pri-miRNAs.	('inhibit', 'NegReg', (71, 78))	('processing activity', 'MPA', (83, 102))	('expression', 'Species', '29278', (45, 55))	('DDX3X', 'Gene', (59, 64))	('expression', 'Var', (45, 55))	('DDX3X', 'Gene', '1654', (59, 64))	('knock-down', 'Var', (30, 40))
30593	27586307	This is because miR-19b and miR-20a both belong to the miR-17-92 family and share the similarity in miRNA sequences, so their expression patterns and biological functions in cancers might be same.	('expression', 'Species', '29278', (126, 136))	('miR-20a', 'Var', (28, 35))	('cancers', 'Phenotype', 'HP:0002664', (174, 181))	('cancers', 'Disease', (174, 181))	('miR-19b', 'Gene', (16, 23))	('cancers', 'Disease', 'MESH:D009369', (174, 181))	('belong', 'Reg', (41, 47))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))
30601	27586307	Whereas, for the expression levels of DDX3X irrelevant miRNAs, such as miR-21 and miR-155, their expression patterns were consistently up-regulated and quite opposite with DDX3X in almost all kinds of cancers (Fig.	('DDX3X', 'Gene', '1654', (38, 43))	('cancers', 'Disease', 'MESH:D009369', (201, 208))	('cancers', 'Phenotype', 'HP:0002664', (201, 208))	('expression', 'Species', '29278', (17, 27))	('cancers', 'Disease', (201, 208))	('DDX3X', 'Gene', '1654', (172, 177))	('up-regulated', 'PosReg', (135, 147))	('expression', 'Species', '29278', (97, 107))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('miR-21', 'Var', (71, 77))	('DDX3X', 'Gene', (38, 43))	('DDX3X', 'Gene', (172, 177))	('miR-155', 'Var', (82, 89))	('expression', 'MPA', (97, 107))
30606	27586307	We can see that for miR-141, miR-19b, miR-20a and miR-34a, they shared part of common targets together.	('miR-20a', 'Var', (38, 45))	('miR-19b', 'Var', (29, 36))	('34a', 'Chemical', '-', (54, 57))	('miR-141', 'Var', (20, 27))	('miR-34a', 'Var', (50, 57))
30607	27586307	For example, the gene MTMR9 (myotubularin related protein 9) can be targeted by miR-141, miR-19b and miR-34a.	('34a', 'Chemical', '-', (105, 108))	('MTMR9', 'Gene', (22, 27))	('miR-19b', 'Var', (89, 96))	('miR-34a', 'Var', (101, 108))	('miR-141', 'Var', (80, 87))
30621	27586307	S2A), so the presence of FUS could down-regulate the expression levels of DDX3X-dependent miRNAs, such as miR-1, miR-141 and miR-145 in SKCM.	('miR-141', 'Var', (113, 120))	('miR-145', 'Var', (125, 132))	('DDX3X', 'Gene', (74, 79))	('expression', 'Species', '29278', (53, 63))	('miR-145', 'Chemical', '-', (125, 132))	('DDX3X', 'Gene', '1654', (74, 79))	('miR-1', 'Var', (106, 111))	('expression levels', 'MPA', (53, 70))	('down-regulate', 'NegReg', (35, 48))
30622	27586307	Whereas, the absence of FUS could otherwise up-regulate the expression levels of these three DDX3X-dependent miRNAs.	('DDX3X', 'Gene', '1654', (93, 98))	('absence', 'Var', (13, 20))	('expression levels', 'MPA', (60, 77))	('expression', 'Species', '29278', (60, 70))	('DDX3X', 'Gene', (93, 98))	('up-regulate', 'PosReg', (44, 55))
30624	27586307	S2B), so the presence of MOV10 could up-regulate the expression levels of DDX3X-dependent miRNAs, such as miR-1 and miR-145 in GBM.	('miR-145', 'Chemical', '-', (116, 123))	('DDX3X', 'Gene', (74, 79))	('MOV10', 'Var', (25, 30))	('expression', 'Species', '29278', (53, 63))	('presence', 'Var', (13, 21))	('miR-145', 'Gene', (116, 123))	('miR-1', 'Gene', (106, 111))	('expression levels', 'MPA', (53, 70))	('DDX3X', 'Gene', '1654', (74, 79))	('up-regulate', 'PosReg', (37, 48))	('OV', 'Phenotype', 'HP:0012887', (26, 28))
30625	27586307	Whereas, the absence of MOV10 could otherwise down-regulate the expression levels of these two DDX3X-dependent miRNAs.	('down-regulate', 'NegReg', (46, 59))	('OV', 'Phenotype', 'HP:0012887', (25, 27))	('absence', 'Var', (13, 20))	('DDX3X', 'Gene', (95, 100))	('MOV10', 'Gene', (24, 29))	('expression', 'Species', '29278', (64, 74))	('expression levels', 'MPA', (64, 81))	('DDX3X', 'Gene', '1654', (95, 100))
30627	27586307	Actually, for the modulation of miRNA biogenesis, various key factors also play an important role in this process, apart from the DEAD-box RNA proteins DDX5 (p68), DDX17 (p72) and DDX3X.	('miRNA biogenesis', 'MPA', (32, 48))	('DDX3X', 'Gene', '1654', (180, 185))	('DDX3X', 'Gene', (180, 185))	('DDX17', 'Var', (164, 169))
30628	27586307	However, if the p53 is mutant at C135Y, R175H, R273H and R248Q sites, the binding of mut-p53 with p68/p72 will lead to the dissociation of Drosha/DGCR8 complex and interfere with Drosha and pri-miRNAs association, so as to hinder the processing of pri-miRNAs and result in miRNA deregulation observed in cancers.	('cancers', 'Phenotype', 'HP:0002664', (304, 311))	('miRNA deregulation', 'MPA', (273, 291))	('cancers', 'Disease', (304, 311))	('dissociation', 'MPA', (123, 135))	('R273H', 'Var', (47, 52))	('processing of pri-miRNAs', 'MPA', (234, 258))	('C135Y', 'Mutation', 'rs587781991', (33, 38))	('cancer', 'Phenotype', 'HP:0002664', (304, 310))	('Drosha/DGCR8 complex', 'Protein', (139, 159))	('R248Q', 'Mutation', 'rs11540652', (57, 62))	('p53', 'Gene', (16, 19))	('interfere', 'NegReg', (164, 173))	('R248Q', 'Var', (57, 62))	('binding', 'Interaction', (74, 81))	('hinder', 'NegReg', (223, 229))	('cancers', 'Disease', 'MESH:D009369', (304, 311))	('C135Y', 'Var', (33, 38))	('mut-p53', 'Gene', (85, 92))	('Drosha', 'Protein', (179, 185))	('R273H', 'Mutation', 'rs28934576', (47, 52))	('R175H', 'Mutation', 'rs28934578', (40, 45))	('R175H', 'Var', (40, 45))	('lead to', 'Reg', (111, 118))
30648	27586307	48 hrs after that, the dual luciferase reporter assay was carried out and the ratios of Firefly and Renilla luciferase were obtained using the Dual-Luciferase Reporter Assay Kit (Cat#: E1910, Promega, USA).	('Renilla luciferase', 'Disease', 'None', (100, 118))	('E1910', 'Var', (185, 190))	('Renilla luciferase', 'Disease', (100, 118))
30658	24874835	In this study, we found that gene-specific mutation and copy number alteration frequencies were similar between young and old SCCOT patients in two independent cohorts.	('SCC', 'Gene', '6317', (126, 129))	('copy number alteration', 'Var', (56, 78))	('SCCOT', 'Phenotype', 'HP:0030413', (126, 131))	('patients', 'Species', '9606', (132, 140))	('SCC', 'Gene', (126, 129))
30659	24874835	TCGA data also demonstrate that the genomic effects of smoking are tumor-site specific, and we find that smoking has only a minor impact on the types of mutations observed in SCCOT.	('SCC', 'Gene', (175, 178))	('SCCOT', 'Phenotype', 'HP:0030413', (175, 180))	('mutations', 'Var', (153, 162))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('SCC', 'Gene', '6317', (175, 178))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Disease', (67, 72))
30679	24874835	A median of 29 and 83 mutations were identified in the YT and OT tumors, respectively.	('YT', 'Chemical', '-', (55, 57))	('OT tumors', 'Disease', 'MESH:D009369', (62, 71))	('OT tumors', 'Disease', (62, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('mutations', 'Var', (22, 31))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
30680	24874835	This finding was validated in The Cancer Genome Atlas (TCGA) cohort, in which the median number of mutations increased from 63 in YT to 112 in OT.	('Cancer', 'Phenotype', 'HP:0002664', (34, 40))	('YT', 'Chemical', '-', (130, 132))	('Cancer Genome Atlas', 'Disease', (34, 53))	('mutations', 'Var', (99, 108))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (34, 53))
30684	24874835	The TP53 mutation frequency was also elevated in the TCGA YT patients (Table 1, Fig 1).	('mutation', 'Var', (9, 17))	('TCGA', 'Disease', (53, 57))	('TP53', 'Gene', (4, 8))	('elevated', 'PosReg', (37, 45))	('patients', 'Species', '9606', (61, 69))	('YT', 'Chemical', '-', (58, 60))	('TP53', 'Gene', '7157', (4, 8))
30687	24874835	The trend of increased TP53 mutations in YT is provocative since the YT lack exposure to cigarette smoke, which has been associated with TP53 mutations.	('YT', 'Chemical', '-', (69, 71))	('YT', 'Chemical', '-', (41, 43))	('TP53', 'Gene', '7157', (137, 141))	('TP53', 'Gene', '7157', (23, 27))	('TP53', 'Gene', (23, 27))	('mutations', 'Var', (28, 37))	('TP53', 'Gene', (137, 141))
30691	24874835	These differences were not statistically significant, although the YT had a smaller mean segment length for copy number gains (p=0.00817) (Table 2) in the MDA cohort.	('YT', 'Chemical', '-', (67, 69))	('segment', 'MPA', (89, 96))	('gains', 'PosReg', (120, 125))	('men', 'Species', '9606', (92, 95))	('smaller', 'NegReg', (76, 83))	('copy number', 'Var', (108, 119))
30697	24874835	Since smoking is known to leave its mark on the genome by causing certain types of mutations, we compared mutation types in the YT and OT patients.	('YT', 'Chemical', '-', (128, 130))	('mutations', 'Var', (83, 92))	('causing', 'Reg', (58, 65))	('patients', 'Species', '9606', (138, 146))
30701	24874835	HPV+ tumors show an increase in C>T mutations (p<0.0001) and decreases in C>A, A>T (both p<0.0001) and A>G (p=0.0074) mutations when compared with HPV- HNSC tumors.	('tumors', 'Phenotype', 'HP:0002664', (157, 163))	('HPV+ tumors', 'Disease', (0, 11))	('HPV+ tumors', 'Disease', 'MESH:D030361', (0, 11))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('HPV- HNSC tumors', 'Disease', (147, 163))	('A>G', 'Var', (103, 106))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('tumors', 'Phenotype', 'HP:0002664', (5, 11))	('decreases', 'NegReg', (61, 70))	('HPV- HNSC tumors', 'Disease', 'MESH:D030361', (147, 163))
30702	24874835	Laryngeal tumors show a decrease in C>T mutations (p<0.0001) and increases in C>A and A>T mutations (both p<0.0001) when compared with non-laryngeal tumors (Fig 2A).	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('non-laryngeal tumors', 'Disease', 'MESH:D007827', (135, 155))	('increases', 'PosReg', (65, 74))	('Laryngeal tumors', 'Phenotype', 'HP:0012118', (0, 16))	('tumors', 'Phenotype', 'HP:0002664', (10, 16))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('decrease', 'NegReg', (24, 32))	('A>T mutations', 'Var', (86, 99))	('non-laryngeal tumors', 'Disease', (135, 155))	('tumors', 'Phenotype', 'HP:0002664', (149, 155))	('Laryngeal tumors', 'Disease', 'MESH:D007822', (0, 16))	('Laryngeal tumors', 'Disease', (0, 16))	('laryngeal tumors', 'Phenotype', 'HP:0012118', (139, 155))
30708	24874835	In LUAD tumors C>A mutations increased 23.7 percentage points in smokers when compared to non-smokers, and C>T mutation decreased 18.7 percentage points (Fig 2B, C).	('decreased', 'NegReg', (120, 129))	('LUAD', 'Phenotype', 'HP:0030078', (3, 7))	('LUAD tumors C', 'Disease', 'MESH:D019698', (3, 16))	('mutations', 'Var', (19, 28))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('tumors', 'Phenotype', 'HP:0002664', (8, 14))	('LUAD tumors C', 'Disease', (3, 16))	('C>T mutation', 'Var', (107, 119))
30710	24874835	BLCA show a much higher frequency of C>T and C>G mutations and a lower frequency of C>A when compared with LUAD (Fig 2B).	('LUAD', 'Phenotype', 'HP:0030078', (107, 111))	('BLCA', 'Chemical', '-', (0, 4))	('C>G mutations', 'Var', (45, 58))	('C>T', 'Var', (37, 40))
30726	24874835	FAT1 is inactivated in a large proportion of oral cavity tumors, either by mutation or copy number deletion.	('mutation', 'Var', (75, 83))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('FAT1', 'Gene', '2195', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('oral cavity tumors', 'Phenotype', 'HP:0100649', (45, 63))	('tumors', 'Disease', (57, 63))	('copy number deletion', 'Var', (87, 107))	('FAT1', 'Gene', (0, 4))	('tumors', 'Disease', 'MESH:D009369', (57, 63))
30728	24874835	The lower frequency of FAT1 mutations in YT could suggest that its inactivation is not necessary for tumor formation or that it is somehow related to smoking status.	('YT', 'Chemical', '-', (41, 43))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('FAT1', 'Gene', '2195', (23, 27))	('FAT1', 'Gene', (23, 27))	('mutations', 'Var', (28, 37))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
30729	24874835	Since TP53 mutations are more frequent in YT patients this result is not likely to be an artifact.	('mutations', 'Var', (11, 20))	('TP53', 'Gene', '7157', (6, 10))	('TP53', 'Gene', (6, 10))	('frequent', 'Reg', (30, 38))	('patients', 'Species', '9606', (45, 53))	('YT', 'Chemical', '-', (42, 44))
30730	24874835	TP53 mutations are likely to be impactful on the tumor progression in YT, but a causative factor leading to increased TP53 mutations in YT is still unknown.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('YT', 'Chemical', '-', (70, 72))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor', 'Disease', (49, 54))	('mutations', 'Var', (5, 14))	('YT', 'Chemical', '-', (136, 138))	('TP53', 'Gene', '7157', (118, 122))	('TP53', 'Gene', (118, 122))	('impactful', 'Reg', (32, 41))
30744	24874835	Since C>T is the most common mutation in many tumor types other factors must also contribute to their frequency.	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('C>T', 'Var', (6, 9))	('tumor', 'Disease', (46, 51))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
30745	24874835	Analysis of the TCGA HNSC data for an alcohol mutation signature resulted in a less dramatic version of the smoking signature with decreases in C>T and increases in C>A in heavy drinkers (data not shown).	('C>A', 'MPA', (165, 168))	('increases', 'PosReg', (152, 161))	('decreases', 'NegReg', (131, 140))	('C>T', 'MPA', (144, 147))	('alcohol', 'Chemical', 'MESH:D000438', (38, 45))	('mutation', 'Var', (46, 54))
30774	24874835	Similarly a factor that disrupts the oral microbiome in YT could promote carcinogenesis in a way similar to the mechanism in OT.	('carcinogenesis', 'Disease', (73, 87))	('carcinogenesis', 'Disease', 'MESH:D063646', (73, 87))	('promote', 'PosReg', (65, 72))	('factor', 'Var', (12, 18))	('YT', 'Chemical', '-', (56, 58))
30776	24874835	SCCOT squamous cell carcinoma of the oral tongue HNSCC head and neck squamous cell carcinoma YT young tongue OT old tongue MDA MD Anderson Cancer Center HNSC TCGA HNSCC project CNA copy number alterations LUAD lung adenocarcinoma BLCA bladder urothelial carcinoma Genomic alterations do not explain the increasing incidence of oral tongue cancer in young patients, and smoking does not dramatically alter the genome of tongue cancer at any age.	('SCC', 'Gene', (165, 168))	('HNSCC', 'Phenotype', 'HP:0012288', (163, 168))	('SCC', 'Gene', '6317', (51, 54))	('carcinoma', 'Phenotype', 'HP:0030731', (254, 263))	('neck squamous cell carcinoma', 'Disease', (64, 92))	('MD Anderson Cancer', 'Disease', 'MESH:C535460', (127, 145))	('lung adenocarcinoma', 'Disease', (210, 229))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (64, 92))	('BLCA', 'Chemical', '-', (230, 234))	('patients', 'Species', '9606', (355, 363))	('carcinoma of the oral', 'Phenotype', 'HP:0100649', (20, 41))	('YT', 'Chemical', '-', (93, 95))	('SCC', 'Gene', (51, 54))	('tongue OT old tongue', 'Phenotype', 'HP:0010808', (102, 122))	('squamous cell carcinoma of the oral tongue', 'Disease', 'MESH:D002294', (6, 48))	('tongue cancer', 'Disease', (419, 432))	('alterations', 'Var', (193, 204))	('LUAD', 'Phenotype', 'HP:0030078', (205, 209))	('oral tongue cancer', 'Disease', (327, 345))	('carcinoma', 'Phenotype', 'HP:0030731', (220, 229))	('squamous cell carcinoma of the oral tongue', 'Phenotype', 'HP:0030413', (6, 48))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (6, 29))	('tongue cancer', 'Disease', 'MESH:D014062', (332, 345))	('HNSCC', 'Phenotype', 'HP:0012288', (49, 54))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (69, 92))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (210, 229))	('tongue cancer', 'Disease', 'MESH:D014062', (419, 432))	('SCC', 'Gene', '6317', (0, 3))	('bladder urothelial carcinoma', 'Disease', (235, 263))	('squamous cell carcinoma of the oral tongue', 'Disease', (6, 48))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (210, 229))	('carcinoma', 'Phenotype', 'HP:0030731', (20, 29))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))	('cancer', 'Phenotype', 'HP:0002664', (339, 345))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (55, 92))	('MD Anderson Cancer', 'Disease', (127, 145))	('SCC', 'Gene', (0, 3))	('cancer', 'Phenotype', 'HP:0002664', (426, 432))	('oral tongue cancer', 'Disease', 'MESH:D014062', (327, 345))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (235, 263))	('SCC', 'Gene', '6317', (165, 168))	('SCCOT', 'Phenotype', 'HP:0030413', (0, 5))	('Cancer', 'Phenotype', 'HP:0002664', (139, 145))
30806	33376529	The Cancer Genome Mapping (derived from TCGA) data portal is the largest and most commonly used public resource, providing datasets, such as somatic mutations, gene expression, gene methylation and copy number variation, for thousands of tumor samples.	('met', 'Gene', (182, 185))	('tumor', 'Disease', 'MESH:D009369', (238, 243))	('tumor', 'Phenotype', 'HP:0002664', (238, 243))	('Cancer', 'Phenotype', 'HP:0002664', (4, 10))	('Cancer', 'Disease', (4, 10))	('tumor', 'Disease', (238, 243))	('Cancer', 'Disease', 'MESH:D009369', (4, 10))	('met', 'Gene', '79811', (182, 185))	('copy number variation', 'Var', (198, 219))
30827	33376529	In the setting of query parameters, mutations, assumed copy number changes from GISTIC and mRNA expression Z-scores (RNASeq V2 RSEM) were selected in 'Select Genomic Profiles', and the z-score threshold was +-2.0.	('met', 'Gene', (28, 31))	('met', 'Gene', '79811', (28, 31))	('copy number', 'Var', (55, 66))	('mRNA', 'MPA', (91, 95))
30882	33376529	For CCNE2, the most common alteration was the amplification in LIHC tumors (Table SIII).	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('LIHC tumors', 'Disease', 'MESH:D009369', (63, 74))	('amplification', 'Var', (46, 59))	('LIHC tumors', 'Disease', (63, 74))	('CCNE2', 'Gene', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('CCNE2', 'Gene', '9134', (4, 9))	('common', 'Reg', (20, 26))
30888	33376529	One group was the altered group: Samples with at least one alteration in the 10 let-7c-5p target genes in the selected profiles, and the other group was the unaltered group: Samples without any alterations in the 10 let-7c-5p target genes in the selected profiles.	('let-7c', 'Gene', (216, 222))	('let-7c', 'Gene', (80, 86))	('let-7c', 'Gene', '406885', (216, 222))	('let-7c', 'Gene', '406885', (80, 86))	('alteration', 'Var', (59, 69))
30889	33376529	Further analysis using the Kaplan-Meier plotter and a log-rank test indicated that the alterations of these 10 genes were associated with worse OS in patients with LIHC (Fig.	('alterations', 'Var', (87, 98))	('worse OS', 'Disease', (138, 146))	('LIHC', 'Chemical', '-', (164, 168))	('associated with', 'Reg', (122, 137))	('patients', 'Species', '9606', (150, 158))	('LIHC', 'Disease', (164, 168))
30890	33376529	These suggested that alterations of these 10 genes could have an impact on the prognosis of patients with LIHC.	('LIHC', 'Chemical', '-', (106, 110))	('patients', 'Species', '9606', (92, 100))	('LIHC', 'Disease', (106, 110))	('impact', 'Reg', (65, 71))	('alterations', 'Var', (21, 32))
30932	33376529	Alterations in either the expression or the activity of these proteins have been associated with the onset and maintenance of tumor phenotypes in LIHC.	('expression', 'MPA', (26, 36))	('Alterations', 'Var', (0, 11))	('LIHC', 'Disease', (146, 150))	('activity', 'MPA', (44, 52))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('LIHC', 'Chemical', '-', (146, 150))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('associated', 'Reg', (81, 91))	('tumor', 'Disease', (126, 131))
30933	33376529	NRAS is a proto-oncogene that is associated with several human cancer types, due to its activating mutation demonstrated marked upregulation of wild-type NRAS in LIHC cell lines and patient tissues, whereas NRAS expression is associated with poor patient survival.	('upregulation', 'PosReg', (128, 140))	('NRAS', 'Gene', (207, 211))	('human', 'Species', '9606', (57, 62))	('patient', 'Species', '9606', (247, 254))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('NRAS', 'Gene', '4893', (207, 211))	('patient', 'Species', '9606', (182, 189))	('mutation', 'Var', (99, 107))	('LIHC', 'Chemical', '-', (162, 166))	('NRAS', 'Gene', (0, 4))	('NRAS', 'Gene', (154, 158))	('NRAS', 'Gene', '4893', (0, 4))	('cancer', 'Disease', (63, 69))	('NRAS', 'Gene', '4893', (154, 158))
30954	32366279	Conclusively, our study for the first time curated both genetic and epigenetic variations of ACE2 in human malignancies.	('epigenetic variations', 'Var', (68, 89))	('human', 'Species', '9606', (101, 106))	('malignancies', 'Disease', 'MESH:D009369', (107, 119))	('ACE2', 'Gene', (93, 97))	('malignancies', 'Disease', (107, 119))	('ACE2', 'Gene', '59272', (93, 97))
30960	32366279	In TCGA pan-cancer panel, the most frequent DNA alteration is mutation.	('cancer', 'Disease', (12, 18))	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('mutation', 'Var', (62, 70))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))
30961	32366279	In another pan-cancer panel, the most frequent DNA alteration is amplification.	('cancer', 'Disease', (15, 21))	('amplification', 'Var', (65, 78))	('cancer', 'Disease', 'MESH:D009369', (15, 21))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))
30962	32366279	Amplifications of ACE2 were observed in NEPC and PRAD patients (Figure S1B).	('NEPC', 'Disease', (40, 44))	('patients', 'Species', '9606', (54, 62))	('ACE2', 'Gene', (18, 22))	('Amplifications', 'Var', (0, 14))	('PRAD', 'Disease', (49, 53))	('observed', 'Reg', (28, 36))	('ACE2', 'Gene', '59272', (18, 22))
30963	32366279	In addition, ACE2 mutations in malignancies were distributed across all exons of ACE2 without hot spot mutation site (Figure S2AC, Table S1).	('ACE2', 'Gene', (13, 17))	('malignancies', 'Disease', 'MESH:D009369', (31, 43))	('ACE2', 'Gene', (81, 85))	('ACE2', 'Gene', '59272', (13, 17))	('malignancies', 'Disease', (31, 43))	('ACE2', 'Gene', '59272', (81, 85))	('mutations', 'Var', (18, 27))
30964	32366279	The most frequent mutation was H195Y/X195_splice (Figure S2B) and X555_splice (Figure S2D).	('H195Y', 'SUBSTITUTION', 'None', (31, 36))	('H195Y', 'Var', (31, 36))	('X555_splice', 'Var', (66, 77))
30982	32366279	Other possibilities, such as histone modifications and glycosylation may give rise in the abnormal expression of ACE2, which requires further explorations.	('abnormal expression', 'MPA', (90, 109))	('ACE2', 'Gene', '59272', (113, 117))	('glycosylation', 'Var', (55, 68))	('give rise', 'Reg', (73, 82))	('ACE2', 'Gene', (113, 117))
30989	32366279	For instance, ACE2 inhibits breast cancer angiogenesis through suppressing VEGFa/VEGFR2/ERK pathway and reduces cell invasion and migration in NSCLC cells.	('NSCLC', 'Disease', (143, 148))	('VEGFR2', 'Gene', (81, 87))	('ERK', 'Gene', '2048', (88, 91))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('reduces', 'NegReg', (104, 111))	('NSCLC', 'Disease', 'MESH:D002289', (143, 148))	('breast cancer', 'Disease', 'MESH:D001943', (28, 41))	('rat', 'Species', '10116', (133, 136))	('VEGFa', 'Gene', '7422', (75, 80))	('ERK', 'Gene', (88, 91))	('ACE2', 'Var', (14, 18))	('breast cancer', 'Disease', (28, 41))	('suppressing', 'NegReg', (63, 74))	('breast cancer', 'Phenotype', 'HP:0003002', (28, 41))	('VEGFa', 'Gene', (75, 80))	('inhibits', 'NegReg', (19, 27))	('VEGFR2', 'Gene', '3791', (81, 87))
31020	30025490	It was also reported that PDT-treated tumor cells tend to induce effective antitumor immunity in vivo compared to tumor cell lysates produced by treatments like ionizing irradiation or freeze-thaw (FT) therapy.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('tumor', 'Disease', (79, 84))	('induce', 'PosReg', (58, 64))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('PDT-treated', 'Var', (26, 37))	('tumor', 'Disease', (114, 119))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
31062	30025490	Splenocytes were harvested as discussed above and stained with the following antibodies: anti-mouse CD3-PE, anti-mouse CD4-FITC, and anti-mouse CD8-PE/Cy5 according to the manufacturer's instructions.	('CD4', 'Gene', '12504', (119, 122))	('CD8-PE', 'Chemical', '-', (144, 150))	('mouse', 'Species', '10090', (138, 143))	('CD3', 'Gene', (100, 103))	('PE', 'Chemical', '-', (104, 106))	('anti-mouse', 'Var', (108, 118))	('mouse', 'Species', '10090', (94, 99))	('PE', 'Chemical', '-', (148, 150))	('CD3', 'Gene', '12501', (100, 103))	('CD4', 'Gene', (119, 122))	('Cy5', 'Chemical', 'MESH:C085321', (151, 154))	('mouse', 'Species', '10090', (113, 118))
31069	30025490	PECA cells treated by PDT have a much greater ability to upregulate expression of CD80, CD86, and MHC-II molecules on the surface of DCs than untreated PECA cells or F/T-treated PECA cells.	('CD80', 'Gene', (82, 86))	('CD86', 'Gene', (88, 92))	('CD86', 'Gene', '12524', (88, 92))	('PE', 'Chemical', '-', (178, 180))	('PE', 'Chemical', '-', (0, 2))	('expression', 'MPA', (68, 78))	('MHC-II', 'Gene', (98, 104))	('upregulate', 'PosReg', (57, 67))	('CD80', 'Gene', '12519', (82, 86))	('PE', 'Chemical', '-', (152, 154))	('PDT', 'Var', (22, 25))
31070	30025490	The expression of CD80, CD86, and MHC-II molecules on DCs induced by PDT-treated PECA cells was significantly higher than that by untreated cells or cells treated by FT (Figure 1).	('PE', 'Chemical', '-', (81, 83))	('MHC-II', 'Gene', (34, 40))	('DCs', 'Disease', (54, 57))	('expression', 'MPA', (4, 14))	('CD80', 'Gene', (18, 22))	('CD86', 'Gene', (24, 28))	('Th', 'Chemical', '-', (0, 2))	('CD86', 'Gene', '12524', (24, 28))	('PECA', 'Var', (81, 85))	('higher', 'PosReg', (110, 116))	('CD80', 'Gene', '12519', (18, 22))	('PDT-treated PECA', 'Var', (69, 85))
31074	30025490	As shown in Figure 2, positive staining for CD4+ and CD8+ T were observed in PDT-DC vaccine group and PDT-PECA group.	('PDT-DC', 'Gene', (77, 83))	('PE', 'Chemical', '-', (106, 108))	('CD8+ T', 'Var', (53, 59))	('CD4', 'Gene', (44, 47))	('CD4', 'Gene', '12504', (44, 47))
31080	30025490	In PDT-DC vaccine group, the percentage of CD4+ T or CD8+ T cells in splenocytes was 72.9% or 25.8%, respectively (Figure 4).	('CD4', 'Gene', (43, 46))	('CD8+ T', 'Var', (53, 59))	('CD4', 'Gene', '12504', (43, 46))
31081	30025490	In the PDT-PECA group, the percentage of CD4+ T or CD8+ T cells in splenocytes was 67.9% or 23.5%, respectively (Figure 4).	('PE', 'Chemical', '-', (11, 13))	('CD8+ T', 'Var', (51, 57))	('CD4', 'Gene', (41, 44))	('CD4', 'Gene', '12504', (41, 44))
31082	30025490	In F/T-DC group, the percentage of CD4+ T or CD8+ T cells was 62.6% or 21.2%, respectively (Figure 3).	('CD4', 'Gene', (35, 38))	('CD8+ T', 'Var', (45, 51))	('CD4', 'Gene', '12504', (35, 38))
31084	30025490	The percentage of CD4+ T or CD8+ T cells in normal splenocytes was 60.4% or 20.6%, respectively (Figure 4).	('CD4', 'Gene', (18, 21))	('CD8+ T', 'Var', (28, 34))	('CD4', 'Gene', '12504', (18, 21))	('Th', 'Chemical', '-', (0, 2))
31088	30025490	As shown in Figure 4, PDT-DC vaccination induced significant high levels of IFN-gamma and IL-12 secretion compared to PDT-PECA, F/T-DC vaccination, or PBS only.	('IFN-gamma', 'Gene', (76, 85))	('high', 'PosReg', (61, 65))	('vaccination', 'Var', (29, 40))	('PBS', 'Chemical', '-', (151, 154))	('IFN-gamma', 'Gene', '15978', (76, 85))	('PDT-DC vaccination', 'Var', (22, 40))	('IL-12 secretion', 'MPA', (90, 105))	('PE', 'Chemical', '-', (122, 124))
31094	30025490	As shown in Figure 6F, the rate of tumor formation of the PDT-DC vaccine group was 0, whereas the PDT-PECA group, F/T-DC vaccine group, and control group represented high rate of tumor formation.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('PE', 'Chemical', '-', (102, 104))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumor', 'Disease', (35, 40))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('PDT-DC', 'Var', (58, 64))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('tumor', 'Disease', (179, 184))
31106	30025490	As shown in Figure 2, PDT-DC vaccination induced an effective CTL response (approximately 50% cell death) compared to PDT tumor lysates alone or F/T DC vaccination.	('PDT tumor', 'Disease', (118, 127))	('vaccination', 'Var', (29, 40))	('CTL response', 'CPA', (62, 74))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('PDT-DC vaccination', 'Var', (22, 40))	('PDT tumor', 'Disease', 'MESH:D009369', (118, 127))
31110	30025490	As shown in Figure 4, the secretion of IFN-gamma and IL-12 from both splenocytes and peripheral blood increased significantly in the PDT-DC vaccine group, whereas IL-10 decreased slightly.	('PDT-DC vaccine', 'Var', (133, 147))	('IFN-gamma', 'Gene', '15978', (39, 48))	('IL-10', 'Gene', (163, 168))	('IL-12', 'Gene', (53, 58))	('IFN-gamma', 'Gene', (39, 48))	('increased', 'PosReg', (102, 111))	('IL-10', 'Gene', '16153', (163, 168))
31119	30025490	Therefore, it was demonstrated that the PDT-DC vaccine prevented SCC growth, while the F/T-DC vaccine did not.	('PDT-DC vaccine', 'Var', (40, 54))	('Th', 'Chemical', '-', (0, 2))	('SCC', 'Phenotype', 'HP:0002860', (65, 68))	('SCC', 'Disease', (65, 68))	('prevented', 'NegReg', (55, 64))
31120	30025490	Interestingly, tumors were observed 7 days after tumor cells challenge in PDT-PECA group but regressed and disappeared 14 days after tumor cells challenge (Figure 5).	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('PDT-PECA', 'Var', (74, 82))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumors', 'Disease', 'MESH:D009369', (15, 21))	('tumor', 'Disease', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumor', 'Disease', (15, 20))	('tumor', 'Disease', (133, 138))	('tumors', 'Disease', (15, 21))	('PE', 'Chemical', '-', (78, 80))
31131	25030904	As an example, the usage of a novel CDH3 splice variant was reported in only a subset (8/20) of adenocarcinoma tumors relative to normal.	('CDH3', 'Gene', (36, 40))	('splice variant', 'Var', (41, 55))	('adenocarcinoma tumors', 'Disease', (96, 117))	('CDH3', 'Gene', '1001', (36, 40))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('adenocarcinoma tumors', 'Disease', 'MESH:D000230', (96, 117))
31137	25030904	We show that SigFuge identifies important transcriptional alterations including alternative splicing of the tumor suppressor gene CDKN2A.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('alternative splicing', 'Var', (80, 100))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('CDKN2A', 'Gene', (130, 136))	('CDKN2A', 'Gene', '1029', (130, 136))	('tumor', 'Disease', (108, 113))
31155	25030904	Reactions were performed using a Bio-Rad C1000 thermocycler and the following cycling conditions: 98o C for 30 seconds, 35 repeats of 98 oC for 30 seconds, 68 oC for 50 seconds and 72 oC for 1 minute, followed by a final extension at 72 oC for 5 minutes.	('Rad', 'Gene', (37, 40))	('98o C', 'Var', (98, 103))	('Rad', 'Gene', '6236', (37, 40))
31178	25030904	Table 4 compares the SigFuge clusters against the three major modes of CDKN2A inactivation identified by the TCGA integrative analysis: homozygous deletion, epigenetic silencing by methylation and inactivation by point mutation.	('epigenetic silencing', 'Var', (157, 177))	('point mutation', 'Var', (213, 227))	('CDKN2A', 'Gene', (71, 77))	('CDKN2A', 'Gene', '1029', (71, 77))	('methylation', 'Var', (181, 192))	('inactivation', 'NegReg', (197, 209))
31199	25030904	The biological relevance of our CDKN2A clusters was validated by observed high concordance with homozygous deletion, methylation and point mutation events at the locus.	('point mutation', 'Var', (133, 147))	('CDKN2A', 'Gene', (32, 38))	('CDKN2A', 'Gene', '1029', (32, 38))	('methylation', 'Var', (117, 128))	('deletion', 'Var', (107, 115))
31201	25030904	The importance of alternative splicing in the development of diseases, including cancer, is well recognized.	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('cancer', 'Disease', (81, 87))	('alternative splicing', 'Var', (18, 38))	('cancer', 'Disease', 'MESH:D009369', (81, 87))
31252	31888623	This method not only assesses mutation's effect on the transcriptional network, but also assesses the differential expression's effect within the transcriptional network.	('mutation', 'Var', (30, 38))	('transcriptional network', 'MPA', (55, 78))	('di', 'Disease', 'MESH:D003643', (102, 104))
31255	31888623	and use them to distinguish driver mutations which contribute to cancer development from passenger mutations that have accumulated in somatic cells but without functional consequences.	('di', 'Disease', 'MESH:D003643', (16, 18))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('mutations', 'Var', (35, 44))
31258	31888623	For instance, CHASM adopts random forest which use alterations trained from known cancer-causing somatic missense mutations to classify driver mutations.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('CHASM', 'Gene', '219537', (14, 19))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('mutations', 'Var', (143, 152))	('CHASM', 'Gene', (14, 19))
31260	31888623	With the developing of the research of cancer, we have recognized that the development and progression of cancer can be promoted by driver mutations or gene perturbing signaling, regulatory or metabolic pathways.	('development', 'CPA', (75, 86))	('progression', 'CPA', (91, 102))	('cancer', 'Disease', (39, 45))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('mutations', 'Var', (139, 148))	('promoted', 'PosReg', (120, 128))	('signaling', 'Pathway', (168, 177))	('regulatory or metabolic pathways', 'Pathway', (179, 211))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('gene perturbing', 'Var', (152, 167))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('cancer', 'Disease', (106, 112))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
31261	31888623	MEMo uses the mutual exclusivity of gene mutations to detect mutated subnetworks critical to carcinogenesis.	('mutations', 'Var', (41, 50))	('carcinogenesis', 'Disease', (93, 107))	('carcinogenesis', 'Disease', 'MESH:D063646', (93, 107))	('mutated', 'MPA', (61, 68))
31265	31888623	Our method not only assess mutation's effect on gene expression, but also assess the differential expression's effect within a transcriptional network.	('gene expression', 'MPA', (48, 63))	('di', 'Disease', 'MESH:D003643', (85, 87))	('mutation', 'Var', (27, 35))
31313	31888623	PolyPhen and SIFT score are predictiors of the harmful effect of a mutation occurring in DNA sequences.	('di', 'Disease', 'MESH:D003643', (31, 33))	('DNA sequences', 'Gene', (89, 102))	('mutation', 'Var', (67, 75))
31328	31888623	When we applied MECoRank to all the three cancer datasets, we finally got a ranking list for each dataset, and the top 100 ranked mutations in the population were selected as the candidate-driver genes.	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('di', 'Disease', 'MESH:D003643', (182, 184))	('mutations', 'Var', (130, 139))
31334	31888623	COSMIC reported mutations in breast cancer most frequently in PIK3CA and TP53 while occasionally in CREBBP.	('TP53', 'Gene', '7157', (73, 77))	('CREBBP', 'Gene', '1387', (100, 106))	('PIK3CA', 'Gene', (62, 68))	('TP53', 'Gene', (73, 77))	('mutations', 'Var', (16, 25))	('breast cancer', 'Disease', 'MESH:D001943', (29, 42))	('PIK3CA', 'Gene', '5290', (62, 68))	('CREBBP', 'Gene', (100, 106))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('breast cancer', 'Disease', (29, 42))	('breast cancer', 'Phenotype', 'HP:0003002', (29, 42))
31338	31888623	For example, miR-181b-3p promotes epithelial-mesenchymal transition in breast cancer cells through Snail stabilization by directly targeting YWHAG.	('YWHAG', 'Gene', '7532', (141, 146))	('breast cancer', 'Disease', (71, 84))	('breast cancer', 'Phenotype', 'HP:0003002', (71, 84))	('promotes', 'PosReg', (25, 33))	('miR-181b-3p', 'Var', (13, 24))	('Snail', 'Gene', (99, 104))	('YWHAG', 'Gene', (141, 146))	('epithelial-mesenchymal transition', 'CPA', (34, 67))	('Snail', 'Gene', '6615', (99, 104))	('di', 'Disease', 'MESH:D003643', (122, 124))	('targeting', 'Reg', (131, 140))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('breast cancer', 'Disease', 'MESH:D001943', (71, 84))
31341	31888623	But recently, a researcher found that a novel variant in UBQLN4 is associated with amyotrophic lateral sclerosis (ALS) and show that its expression compromises motor axon morphogenesis in mouse motor neurons and in zebrafish.	('mouse', 'Species', '10090', (188, 193))	('compromises', 'NegReg', (148, 159))	('variant', 'Var', (46, 53))	('expression', 'MPA', (137, 147))	('ALS', 'Gene', (114, 117))	('ALS', 'Gene', '6647', (114, 117))	('amyotrophic lateral sclerosis', 'Disease', 'MESH:D000690', (83, 112))	('amyotrophic lateral sclerosis', 'Disease', (83, 112))	('ALS', 'Phenotype', 'HP:0007354', (114, 117))	('motor axon morphogenesis', 'CPA', (160, 184))	('associated', 'Reg', (67, 77))	('UBQLN4', 'Gene', (57, 63))	('zebrafish', 'Species', '7955', (215, 224))	('amyotrophic lateral sclerosis', 'Phenotype', 'HP:0007354', (83, 112))
31343	31888623	If SMAD9 have heterozygous mutations, it will cause heritable pulmonary arterial hypertension (HPAH), a serious lung vascular disease.	('cause', 'Reg', (46, 51))	('lung vascular disease', 'Disease', (112, 133))	('pulmonary arterial hypertension', 'Phenotype', 'HP:0002092', (62, 93))	('lung vascular disease', 'Disease', 'MESH:D008171', (112, 133))	('pulmonary arterial hypertension', 'Disease', 'MESH:D000081029', (62, 93))	('pulmonary arterial hypertension', 'Disease', (62, 93))	('HPAH', 'Disease', 'None', (95, 99))	('hypertension', 'Phenotype', 'HP:0000822', (81, 93))	('HPAH', 'Disease', (95, 99))	('SMAD9', 'Gene', (3, 8))	('SMAD9', 'Gene', '4093', (3, 8))	('heterozygous mutations', 'Var', (14, 36))
31353	31888623	The expression of IGF1R is inhibited by miRNA-223 and miRNA-let-7i that negatively associate with KIRC survival.	('miRNA-223', 'Gene', '407008', (40, 49))	('expression', 'MPA', (4, 14))	('miRNA-let-7i', 'Var', (54, 66))	('IGF1R', 'Gene', (18, 23))	('inhibited', 'NegReg', (27, 36))	('miRNA-223', 'Gene', (40, 49))	('IGF1R', 'Gene', '3480', (18, 23))
31354	31888623	Although ATXN1, SMAD9, UBQLN4 and GRB2 are not included in CGC, we have already mentioned that ATXN1, SMAD9 and UBQLN4 are all relate to cancers or pathway in the last paragraph.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('GRB2', 'Gene', '2885', (34, 38))	('ATXN1', 'Gene', (9, 14))	('SMAD9', 'Gene', (16, 21))	('ATXN1', 'Gene', '6310', (9, 14))	('SMAD9', 'Gene', '4093', (16, 21))	('relate', 'Reg', (127, 133))	('SMAD9', 'Gene', (102, 107))	('cancers', 'Disease', 'MESH:D009369', (137, 144))	('cancers', 'Phenotype', 'HP:0002664', (137, 144))	('SMAD9', 'Gene', '4093', (102, 107))	('GRB2', 'Gene', (34, 38))	('cancers', 'Disease', (137, 144))	('ATXN1', 'Gene', (95, 100))	('ATXN1', 'Gene', '6310', (95, 100))	('CGC', 'Chemical', '-', (59, 62))	('UBQLN4', 'Var', (112, 118))	('pathway', 'Pathway', (148, 155))
31360	31888623	ESR1 is known to play a very important role in cancer, and previous research found that ESR1 methylation is associated with concurrent methylation of a group of tumor suppressors.	('ESR1', 'Gene', (0, 4))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('cancer', 'Disease', (47, 53))	('ESR1', 'Gene', '2099', (88, 92))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('methylation', 'MPA', (135, 146))	('associated', 'Reg', (108, 118))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('ESR1', 'Gene', '2099', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('ESR1', 'Gene', (88, 92))	('methylation', 'Var', (93, 104))	('tumor', 'Disease', (161, 166))
31377	31888623	The important contribution of our MECoRank is that we not only assess mutation's effect on gene expression network, but also measure the differential expression's effect within gene expression network.	('gene expression', 'MPA', (91, 106))	('mutation', 'Var', (70, 78))	('effect', 'Reg', (81, 87))	('di', 'Disease', 'MESH:D003643', (137, 139))
31382	31888623	ALS Amyotrophic lateral sclerosisv BRCA Breast cancer dataset CGC Cancer Gene Census CNVs Copy-number variations DGIdb Drug-genes Interaction Database GO Gene Ontology HPAH Heritable pulmonary arterial hypertension HPRD Human Protein Reference Database indels Small insertions or deletions KIRC Kidney renal clear cell carcinoma LUSC Lung squamous cell carcinoma PPI Protein-protein interaction SNVs Single nucleotide variants TGF-beta Transforming growth factor beta Supplementary information accompanies this paper at 10.1186/s12920-019-0582-8.	('ALS', 'Gene', (0, 3))	('Single nucleotide variants', 'Var', (400, 426))	('Breast cancer', 'Disease', 'MESH:D001943', (40, 53))	('Kidney renal clear cell carcinoma', 'Disease', (295, 328))	('Cancer', 'Phenotype', 'HP:0002664', (66, 72))	('Breast cancer', 'Disease', (40, 53))	('pulmonary arterial hypertension', 'Disease', (183, 214))	('ALS', 'Gene', '6647', (0, 3))	('deletions', 'Var', (280, 289))	('carcinoma', 'Phenotype', 'HP:0030731', (319, 328))	('Breast cancer', 'Phenotype', 'HP:0003002', (40, 53))	('HPRD', 'Disease', 'None', (215, 219))	('Amyotrophic lateral sclerosisv', 'Disease', (4, 34))	('hypertension', 'Phenotype', 'HP:0000822', (202, 214))	('Cancer', 'Disease', (66, 72))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('CGC', 'Chemical', '-', (62, 65))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (339, 362))	('ALS', 'Phenotype', 'HP:0007354', (0, 3))	('pulmonary arterial hypertension', 'Phenotype', 'HP:0002092', (183, 214))	('HPRD', 'Disease', (215, 219))	('Kidney renal clear cell carcinoma', 'Disease', 'MESH:C538614', (295, 328))	('Human', 'Species', '9606', (220, 225))	('Lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (334, 362))	('BRCA', 'Gene', '672', (35, 39))	('HPAH', 'Disease', 'None', (168, 172))	('Cancer', 'Disease', 'MESH:D009369', (66, 72))	('TGF-beta', 'Gene', '7039', (427, 435))	('Amyotrophic lateral sclerosisv', 'Disease', 'MESH:D000690', (4, 34))	('Lung squamous cell carcinoma', 'Disease', (334, 362))	('TGF-beta', 'Gene', (427, 435))	('BRCA', 'Gene', (35, 39))	('pulmonary arterial hypertension', 'Disease', 'MESH:D000081029', (183, 214))	('LUSC', 'Phenotype', 'HP:0030359', (329, 333))	('carcinoma', 'Phenotype', 'HP:0030731', (353, 362))	('HPAH', 'Disease', (168, 172))
31506	26123189	Results of our trial suggest that dose density might be an important factor to enhance efficacy of nab-paclitaxel, particularly in the squamous cell population.	('enhance', 'PosReg', (79, 86))	('efficacy', 'MPA', (87, 95))	('nab-paclitaxel', 'Chemical', 'MESH:D017239', (99, 113))	('nab-paclitaxel', 'Var', (99, 113))
31533	26123189	In our trial we demonstrated results similar to the larger phase III study and confirmed the activity of nab-paclitaxel combined with carboplatin, particularly in squamous NSCLC.	('squamous NSCLC', 'Disease', (163, 177))	('carboplatin', 'Chemical', 'MESH:D016190', (134, 145))	('squamous NSCLC', 'Disease', 'MESH:D002294', (163, 177))	('activity', 'MPA', (93, 101))	('nab-paclitaxel', 'Chemical', 'MESH:D017239', (105, 119))	('nab-paclitaxel', 'Var', (105, 119))
31541	26123189	Results of the phase III trial demonstrated a statistically significant improved response rate with nab-paclitaxel, and a nonsignificant improvement in survival.	('nab-paclitaxel', 'Chemical', 'MESH:D017239', (100, 114))	('improved', 'PosReg', (72, 80))	('response', 'MPA', (81, 89))	('nab-paclitaxel', 'Var', (100, 114))
31544	26123189	Our results demonstrated that dosing nab-paclitaxel every 3 weeks had a response rate comparable with weekly dosing.	('response', 'MPA', (72, 80))	('nab-paclitaxel', 'Chemical', 'MESH:D017239', (37, 51))	('nab-paclitaxel', 'Var', (37, 51))
31560	26709519	Patients with high B3GNT3 expression had a shorter overall survival (OS) and disease-free survival (DFS) compared with those with low expression of this protein.	('overall survival', 'CPA', (51, 67))	('disease-free survival', 'CPA', (77, 98))	('B3GNT3', 'Gene', (19, 25))	('high', 'Var', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('B3GNT3', 'Gene', '10331', (19, 25))	('shorter', 'NegReg', (43, 50))
31648	26709519	As summarized in Table 2, high B3GNT3 protein expression tend to be strongly correlated with HPV infection, FIGO stage, tumor size, tumor recurrence, vital status, concurrent chemotherapy and radiotherapy, lymphovascular space involvement and most importantly, lymph node metastasis (Table 2).	('lymphovascular', 'Disease', (206, 220))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('high', 'Var', (26, 30))	('vital status', 'Disease', (150, 162))	('HPV infection', 'Disease', 'MESH:D030361', (93, 106))	('B3GNT3', 'Gene', '10331', (31, 37))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('correlated', 'Reg', (77, 87))	('FIGO stage', 'Disease', (108, 118))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('B3GNT3', 'Gene', (31, 37))	('tumor', 'Disease', (132, 137))	('HPV infection', 'Disease', (93, 106))	('lymph', 'Disease', (261, 266))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('expression', 'MPA', (46, 56))	('tumor', 'Disease', (120, 125))
31651	26709519	The log-rank test showed that the survival time was significantly different between the low and high B3GNT3 protein expression groups (both P < 0.001, Fig 3C).	('B3GNT3', 'Gene', (101, 107))	('expression', 'MPA', (116, 126))	('survival time', 'CPA', (34, 47))	('protein', 'Protein', (108, 115))	('high', 'Var', (96, 100))	('B3GNT3', 'Gene', '10331', (101, 107))
31660	26709519	Furthermore, high B3GNT3 protein expression reduced the OS and DFS of these patients, particularly those who received chemotherapy.	('patients', 'Species', '9606', (76, 84))	('protein', 'Protein', (25, 32))	('high', 'Var', (13, 17))	('DFS', 'Disease', (63, 66))	('B3GNT3', 'Gene', (18, 24))	('reduced', 'NegReg', (44, 51))	('B3GNT3', 'Gene', '10331', (18, 24))
31669	26709519	Therefore, this might be the potential mechanism underlying the association between variants in the B3GNT3 locus and CA19-9 concentrations.	('CA19-9 concentrations', 'MPA', (117, 138))	('B3GNT3', 'Gene', (100, 106))	('B3GNT3', 'Gene', '10331', (100, 106))	('variants', 'Var', (84, 92))	('association', 'Interaction', (64, 75))
31689	26709519	Multivariate analysis demonstrated that PLNM is predictive of the overall survival (OS) of early-stage cervical cancer patients (Table 4).	('overall survival', 'MPA', (66, 82))	('patients', 'Species', '9606', (119, 127))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('cervical cancer', 'Disease', (103, 118))	('cervical cancer', 'Disease', 'MESH:D002583', (103, 118))	('PLNM', 'Var', (40, 44))
31690	26709519	In addition, we observed a correlation between OS and high B3GNT3 protein expression in the "without lymph node metastasis" and "with lymph node metastasis" subgroups.	('B3GNT3', 'Gene', (59, 65))	('B3GNT3', 'Gene', '10331', (59, 65))	('protein', 'Protein', (66, 73))	('high', 'Var', (54, 58))
31691	26709519	Finally, we found a significant association between shorter OS and high B3GNT3 protein expression in the "without lymph node metastasis" subgroup, which suggested that B3GNT3 might be a useful marker to predict poor overall survival of cervical cancer patients without LNM.	('cervical cancer', 'Disease', (236, 251))	('cervical cancer', 'Disease', 'MESH:D002583', (236, 251))	('high', 'Var', (67, 71))	('B3GNT3', 'Gene', '10331', (168, 174))	('patients', 'Species', '9606', (252, 260))	('protein', 'Protein', (79, 86))	('B3GNT3', 'Gene', (168, 174))	('B3GNT3', 'Gene', (72, 78))	('B3GNT3', 'Gene', '10331', (72, 78))	('expression', 'MPA', (87, 97))	('cancer', 'Phenotype', 'HP:0002664', (245, 251))
31705	26709519	To date, more than 200 HPV types have been reported and HPV16 is by far the most carcinogenic in terms of numbers of cases of cervical cancer.	('carcinogenic', 'Disease', 'MESH:D063646', (81, 93))	('HPV', 'Species', '10566', (56, 59))	('carcinogenic', 'Disease', (81, 93))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('cervical cancer', 'Disease', (126, 141))	('cervical cancer', 'Disease', 'MESH:D002583', (126, 141))	('HPV16', 'Species', '333760', (56, 61))	('HPV', 'Species', '10566', (23, 26))	('HPV16', 'Var', (56, 61))
31706	26709519	The time from infection to invasive cancer is shorter for HPV16 than for other HPV types, but the determinants of invasion other than HPV type are unknown.	('infection to invasive cancer', 'Disease', 'MESH:D009362', (14, 42))	('HPV', 'Species', '10566', (79, 82))	('HPV16', 'Species', '333760', (58, 63))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('HPV16', 'Var', (58, 63))	('infection to invasive cancer', 'Disease', (14, 42))	('shorter', 'NegReg', (46, 53))	('HPV', 'Species', '10566', (58, 61))	('HPV', 'Species', '10566', (134, 137))
31731	25578962	Alternative splicing alterations may confer a selective advantage to the tumor, such as angiogenesis, proliferation, cell invasion and avoidance of apoptosis.	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('cell invasion', 'CPA', (117, 130))	('angiogenesis', 'CPA', (88, 100))	('tumor', 'Disease', (73, 78))	('Alternative splicing alterations', 'Var', (0, 32))	('proliferation', 'CPA', (102, 115))	('advantage', 'PosReg', (56, 65))
31760	25578962	The genes with significant isoform-pairs detected include FBLN2, which undergoes an isoform change related to the skipping of a protein coding exon (Supplementary Figure S11) and moreover appears as a single gene model for COAD and is part of the BRCA model (Figure 3A).	('BRCA', 'Gene', (247, 251))	('COAD', 'Disease', (223, 227))	('skipping', 'Var', (114, 122))	('FBLN2', 'Gene', (58, 63))	('protein', 'Protein', (128, 135))	('FBLN2', 'Gene', '2199', (58, 63))	('COAD', 'Disease', 'MESH:D029424', (223, 227))	('BRCA', 'Gene', '672', (247, 251))
31801	25578962	These results suggest that the detected alternative splicing switches may have a functional impact in the cancer cells.	('impact', 'Reg', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('cancer', 'Disease', (106, 112))	('alternative splicing switches', 'Var', (40, 69))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
31812	25578962	This analysis shows that FBLN2, MYH11, FLNA and TNC have the strongest association between mutations and switches (Figure 7A and Supplementary Figure S30).	('TNC', 'Gene', '3371', (48, 51))	('FBLN2', 'Gene', (25, 30))	('TNC', 'Gene', (48, 51))	('MYH11', 'Gene', '4629', (32, 37))	('FBLN2', 'Gene', '2199', (25, 30))	('switches', 'Disease', (105, 113))	('FLNA', 'Gene', (39, 43))	('mutations', 'Var', (91, 100))	('FLNA', 'Gene', '2316', (39, 43))	('MYH11', 'Gene', (32, 37))
31814	25578962	We also found frequent mutations in the alternatively spliced region of the oncogene MYH11.	('mutations', 'Var', (23, 32))	('MYH11', 'Gene', '4629', (85, 90))	('MYH11', 'Gene', (85, 90))
31815	25578962	In particular, we found recurrent deletions and insertions on the alternative exon in COAD and BRCA tumor samples that coincide with the presence of the switch (Figure 7C), which fall on a region of low conservation that is next to a putative binding site for the splicing factor SRSF1 (Supplementary Figure S31).	('COAD', 'Disease', 'MESH:D029424', (86, 90))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('BRCA tumor', 'Disease', 'MESH:D009369', (95, 105))	('deletions', 'Var', (34, 43))	('insertions', 'Var', (48, 58))	('fall', 'Phenotype', 'HP:0002527', (179, 183))	('COAD', 'Disease', (86, 90))	('SRSF1', 'Gene', (280, 285))	('BRCA tumor', 'Disease', (95, 105))	('SRSF1', 'Gene', '6426', (280, 285))
31817	25578962	We therefore tested, for each isoform-switch, whether the presence of mutations in a tumor sample is associated with a larger difference of PSI between the pair of isoforms involved in the switch (Materials and Methods).	('tumor', 'Disease', (85, 90))	('mutations', 'Var', (70, 79))	('PSI', 'MPA', (140, 143))	('tested', 'Reg', (13, 19))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))
31819	25578962	This suggests that, except for a limited number of cases, mutations may not be the main cause of the recurrent splicing switches found in tumors.	('mutations', 'Var', (58, 67))	('tumors', 'Disease', (138, 144))	('tumors', 'Disease', 'MESH:D009369', (138, 144))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('splicing', 'MPA', (111, 119))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
31821	25578962	To test this possibility, we measured how frequently mutations that affect the protein-coding region occur in tumor samples without the isoform switch in the same gene by defining a mutual-exclusion score based on the number of samples with no switch but with protein-affecting mutations (Materials and Methods).	('tumor', 'Disease', 'MESH:D009369', (110, 115))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('mutations', 'Var', (53, 62))
31822	25578962	However, the number of samples with both switch and mutation is generally comparable or higher than the number of samples with mutation and no switch, except for the genes TNC and HECW2 in LUSC, for which we find more samples with a protein-affecting mutation and no switch than with switch and protein-affecting mutation (Supplementary Figure S33).	('TNC', 'Gene', '3371', (172, 175))	('TNC', 'Gene', (172, 175))	('protein-affecting', 'Reg', (233, 250))	('mutation', 'Var', (251, 259))	('HECW2', 'Gene', (180, 185))	('HECW2', 'Gene', '57520', (180, 185))
31823	25578962	This suggests that both types of alterations, mutations and alternative splicing changes, could potentially contribute to cancer.	('mutations', 'Var', (46, 55))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('alternative splicing changes', 'Var', (60, 88))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('contribute', 'Reg', (108, 118))
31827	25578962	When tested on held-out data sets, the predictive models show overall high accuracies, which are comparable to the ones obtained using models based on gene expression patterns and involve different sets of genes; indicating that alternative splicing alterations describe independent cancer signatures, possibly due to cancer-specific splicing regulatory programs.	('cancer', 'Disease', 'MESH:D009369', (318, 324))	('cancer', 'Disease', 'MESH:D009369', (283, 289))	('alternative splicing alterations', 'Var', (229, 261))	('cancer', 'Disease', (318, 324))	('cancer', 'Disease', (283, 289))	('cancer', 'Phenotype', 'HP:0002664', (318, 324))	('cancer', 'Phenotype', 'HP:0002664', (283, 289))
31840	25578962	In particular, 99% of the transcripts analyzed appear mutated in less than 5% of the tumor samples, whereas the switches occur in at least 50% of the samples.	('tumor', 'Disease', (85, 90))	('mutated', 'Var', (54, 61))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))
31842	25578962	Although it has been suggested that synonymous mutations in known cancer drivers may contribute to the oncogenic process, these occur at low frequency and a direct link between the observed mutations and specific splicing changes in the same tumor samples was not provided.	('oncogenic process', 'CPA', (103, 120))	('tumor', 'Disease', 'MESH:D009369', (242, 247))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('tumor', 'Phenotype', 'HP:0002664', (242, 247))	('contribute', 'Reg', (85, 95))	('tumor', 'Disease', (242, 247))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('synonymous mutations', 'Var', (36, 56))	('cancer', 'Disease', (66, 72))
31843	25578962	Although point mutations and indels on splicing factors also occur at low frequency, splicing factors show frequent amplifications, deletions and expression changes in tumors.	('indels', 'Var', (29, 35))	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('splicing factors', 'Gene', (85, 101))	('tumors', 'Disease', (168, 174))	('deletions', 'Var', (132, 141))	('changes', 'Reg', (157, 164))	('tumors', 'Disease', 'MESH:D009369', (168, 174))	('amplifications', 'MPA', (116, 130))	('expression', 'MPA', (146, 156))	('point mutations', 'Var', (9, 24))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
31844	25578962	These alterations are frequent in cancers and they may induce changes in splicing.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('alterations', 'Var', (6, 17))	('changes', 'Reg', (62, 69))	('splicing', 'MPA', (73, 81))	('cancers', 'Phenotype', 'HP:0002664', (34, 41))	('cancers', 'Disease', (34, 41))	('cancers', 'Disease', 'MESH:D009369', (34, 41))
31845	25578962	Interestingly, FBLN2, which presents a switch in various cancers, has been observed frequently methylated in breast and other epithelial tumors.	('FBLN2', 'Gene', '2199', (15, 20))	('methylated', 'Var', (95, 105))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('epithelial tumors', 'Disease', (126, 143))	('cancers', 'Phenotype', 'HP:0002664', (57, 64))	('cancers', 'Disease', (57, 64))	('cancers', 'Disease', 'MESH:D009369', (57, 64))	('epithelial tumors', 'Disease', 'MESH:D002277', (126, 143))	('FBLN2', 'Gene', (15, 20))	('breast', 'Disease', (109, 115))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
31848	25578962	Our analysis of nine cancer types indicate that recurrent changes in splicing may contribute together with mutations and other alterations to explain tumor formation, thereby providing novel signatures for cancer.	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('changes', 'Var', (58, 65))	('contribute', 'Reg', (82, 92))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('splicing', 'MPA', (69, 77))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('cancer', 'Disease', (21, 27))	('cancer', 'Disease', 'MESH:D009369', (21, 27))	('cancer', 'Disease', (206, 212))	('cancer', 'Disease', 'MESH:D009369', (206, 212))	('tumor', 'Disease', (150, 155))
31873	30443493	This membrane Hsp70 (mHsp70) positivity has been identified on a large variety of different primary tumor types such as breast, lung, head and neck, colorectal, pancreas, brain and hematological malignancies, but not on corresponding normal cells and tissues.	('colorectal', 'Disease', (149, 159))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('hematological malignancies', 'Disease', (181, 207))	('tumor', 'Disease', (100, 105))	('pancreas', 'Disease', (161, 169))	('brain', 'Disease', (171, 176))	('lung', 'Disease', (128, 132))	('hematological malignancies', 'Disease', 'MESH:D019337', (181, 207))	('mHsp70', 'Gene', '15511', (21, 27))	('colorectal', 'Disease', 'MESH:D015179', (149, 159))	('hematological malignancies', 'Phenotype', 'HP:0004377', (181, 207))	('mHsp70', 'Gene', (21, 27))	('pancreas', 'Disease', 'MESH:D010190', (161, 169))	('positivity', 'Var', (29, 39))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('breast', 'Disease', (120, 126))
31891	30443493	At the Technische Universitat Munchen, flow cytometric analysis for the expression of mHsp70 and EpCAM on tumor cell lines was undertaken using either an FITC-conjugated cmHsp70.1 mAb (multimmune GmbH, Munich, Germany) and a FITC-conjugated EpCAM (CD326, clone HEA125) and PE-conjugated EpCAM (CD326, clone G8.8) mAb (Acris GmbH, an OriGene Company, Herford, Germany).	('EpCAM', 'Gene', (97, 102))	('mHsp70', 'Gene', (171, 177))	('FITC', 'Chemical', 'MESH:D016650', (225, 229))	('mHsp70', 'Gene', '15511', (171, 177))	('FITC', 'Chemical', 'MESH:D016650', (154, 158))	('EpCAM', 'Gene', '4072', (241, 246))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('EpCAM', 'Gene', '4072', (97, 102))	('tumor', 'Disease', (106, 111))	('EpCAM', 'Gene', (287, 292))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('mHsp70', 'Gene', (86, 92))	('mHsp70', 'Gene', '15511', (86, 92))	('CD326', 'Var', (294, 299))	('EpCAM', 'Gene', (241, 246))	('EpCAM', 'Gene', '4072', (287, 292))
31923	30443493	Following treatment with TGFbeta and L-lactic-acid, the proportion of EpCAM positive cells decreased from 100 to 68% and 24%, respectively, whereas the proportion of cells expressing mHsp70 slightly increased from 76 to 82% and 89%, respectively (Figure 2B).	('TGFbeta', 'Gene', '7040', (25, 32))	('EpCAM', 'Gene', (70, 75))	('mHsp70', 'Gene', (183, 189))	('EpCAM', 'Gene', '4072', (70, 75))	('TGFbeta', 'Gene', (25, 32))	('L-lactic-acid', 'Chemical', 'MESH:D019344', (37, 50))	('L-lactic-acid', 'Var', (37, 50))	('mHsp70', 'Gene', '15511', (183, 189))	('decreased', 'NegReg', (91, 100))
32042	29855390	demonstrated that BC and prostate cancer share similar traits such as DNA repair and N-acetyl transferase polymorphism.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('prostate cancer', 'Disease', 'MESH:D011471', (25, 40))	('prostate cancer', 'Phenotype', 'HP:0012125', (25, 40))	('prostate cancer', 'Disease', (25, 40))	('DNA repair', 'MPA', (70, 80))	('polymorphism', 'Var', (106, 118))
32055	29855390	Recent meta-analyses have shown that patients who received prostate cancer radiotherapy are more likely to have a second malignancy of the bladder, colon and rectum than patients who have not received radiotherapy.	('patients', 'Species', '9606', (170, 178))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('prostate cancer', 'Disease', 'MESH:D011471', (59, 74))	('malignancy', 'Disease', 'MESH:D009369', (121, 131))	('patients', 'Species', '9606', (37, 45))	('prostate cancer', 'Phenotype', 'HP:0012125', (59, 74))	('malignancy', 'Disease', (121, 131))	('radiotherapy', 'Var', (75, 87))	('prostate cancer', 'Disease', (59, 74))
32108	28052061	In EAC, we identified significant mutations in TP53, CDKN2A, ARID1A, SMAD4 and ERBB2, as reported previously21.	('CDKN2A', 'Gene', (53, 59))	('ARID1A', 'Gene', (61, 67))	('SMAD4', 'Gene', '4089', (69, 74))	('TP53', 'Gene', (47, 51))	('CDKN2A', 'Gene', '1029', (53, 59))	('ERBB2', 'Gene', (79, 84))	('ERBB2', 'Gene', '2064', (79, 84))	('TP53', 'Gene', '7157', (47, 51))	('SMAD4', 'Gene', (69, 74))	('ARID1A', 'Gene', '8289', (61, 67))	('mutations', 'Var', (34, 43))
32109	28052061	These findings are consistent with the prominence of CDKN2A and TP53 mutations in dysplastic Barrett's oesophagus, a precursor to EAC.	('mutations', 'Var', (69, 78))	('CDKN2A', 'Gene', (53, 59))	("dysplastic Barrett's oesophagus", 'Disease', 'MESH:D001471', (82, 113))	('CDKN2A', 'Gene', '1029', (53, 59))	("Barrett's oesophagus", 'Phenotype', 'HP:0100580', (93, 113))	('TP53', 'Gene', '7157', (64, 68))	('TP53', 'Gene', (64, 68))	("dysplastic Barrett's oesophagus", 'Disease', (82, 113))
32111	28052061	SCNAs that were recurrent in EAC (but absent in ESCC) included amplifications containing VEGFA (6p21.1), ERBB2 (17p12), GATA6 (18q11.2) and CCNE1 (19q12), and deletion of SMAD4 (18q21.2).	('ERBB2', 'Gene', (105, 110))	('ERBB2', 'Gene', '2064', (105, 110))	('CCNE1', 'Gene', '898', (140, 145))	('CCNE1', 'Gene', (140, 145))	('SMAD4', 'Gene', (171, 176))	('SCC', 'Gene', (49, 52))	('EAC', 'Disease', (29, 32))	('GATA6', 'Gene', (120, 125))	('VEGFA', 'Gene', '7422', (89, 94))	('GATA6', 'Gene', '2627', (120, 125))	('SCC', 'Gene', '6317', (49, 52))	('deletion', 'Var', (159, 167))	('VEGFA', 'Gene', (89, 94))	('SMAD4', 'Gene', '4089', (171, 176))
32112	28052061	Recurring focal SCNAs in ESCC included amplifications of SOX2 (3q26.33), TERT (5p15.33), FGFR1 (8p11.23), MDM2 (12q14.3), NKX2-1 (14q13.2) and deletion of RB1 (13q14.2).	('SCC', 'Gene', '6317', (26, 29))	('RB1', 'Gene', (155, 158))	('NKX2-1', 'Gene', '7080', (122, 128))	('RB1', 'Gene', '5925', (155, 158))	('MDM2', 'Gene', '4193', (106, 110))	('FGFR1', 'Gene', (89, 94))	('deletion', 'Var', (143, 151))	('MDM2', 'Gene', (106, 110))	('TERT', 'Gene', (73, 77))	('FGFR1', 'Gene', '2260', (89, 94))	('SOX2', 'Gene', (57, 61))	('SOX2', 'Gene', '6657', (57, 61))	('NKX2-1', 'Gene', (122, 128))	('TERT', 'Gene', '7015', (73, 77))	('SCC', 'Gene', (26, 29))	('amplifications', 'Var', (39, 53))
32113	28052061	We found novel focal deletions at 3p25.2 in ESCC, encompassing the negative regulator of the Hippo pathway VGLL4 and autophagy factor ATG7.	('VGLL4', 'Gene', (107, 112))	('SCC', 'Gene', (45, 48))	('ATG7', 'Gene', '10533', (134, 138))	('VGLL4', 'Gene', '9686', (107, 112))	('deletions', 'Var', (21, 30))	('SCC', 'Gene', '6317', (45, 48))	('ATG7', 'Gene', (134, 138))
32114	28052061	Inactivation of CDKN2A and amplification of CCND1 were present in 76% and 57% of squamous tumours, respectively; and additional ESCCs had amplification of CDK6 or loss of RB1.	('squamous tumours', 'Disease', (81, 97))	('amplification', 'Var', (27, 40))	('SCC', 'Gene', '6317', (129, 132))	('RB1', 'Gene', '5925', (171, 174))	('CDK6', 'Gene', '1021', (155, 159))	('loss', 'NegReg', (163, 167))	('CDKN2A', 'Gene', (16, 22))	('CDKN2A', 'Gene', '1029', (16, 22))	('CCND1', 'Gene', '595', (44, 49))	('tumour', 'Phenotype', 'HP:0002664', (90, 96))	('tumours', 'Phenotype', 'HP:0002664', (90, 97))	('squamous tumours', 'Disease', 'MESH:D002294', (81, 97))	('CCND1', 'Gene', (44, 49))	('CDK6', 'Gene', (155, 159))	('SCC', 'Gene', (129, 132))	('amplification', 'Var', (138, 151))	('Inactivation', 'Var', (0, 12))	('RB1', 'Gene', (171, 174))
32116	28052061	CDKN2A was inactivated in 76% of EACs by mutation, deletion or epigenetic silencing.	('epigenetic silencing', 'Var', (63, 83))	('inactivated', 'NegReg', (11, 22))	('mutation', 'Var', (41, 49))	('CDKN2A', 'Gene', (0, 6))	('deletion', 'Var', (51, 59))	('CDKN2A', 'Gene', '1029', (0, 6))
32118	28052061	In ESCCs, we identified amplification or mutation of EGFR in 19% of tumours and alterations of PIK3CA, PTEN or PIK3R1, all of which are believed to activate the PI3K pathway, in 24% of tumours.	('PTEN', 'Gene', '5728', (103, 107))	('tumours', 'Phenotype', 'HP:0002664', (68, 75))	('PIK3R1', 'Gene', '5295', (111, 117))	('SCC', 'Gene', '6317', (4, 7))	('tumours', 'Disease', 'MESH:D009369', (68, 75))	('activate', 'PosReg', (148, 156))	('tumours', 'Disease', (185, 192))	('SCC', 'Gene', (4, 7))	('tumour', 'Phenotype', 'HP:0002664', (68, 74))	('PIK3CA', 'Gene', '5290', (95, 101))	('tumours', 'Phenotype', 'HP:0002664', (185, 192))	('mutation', 'Var', (41, 49))	('EGFR', 'Gene', '1956', (53, 57))	('tumours', 'Disease', 'MESH:D009369', (185, 192))	('alterations', 'Var', (80, 91))	('PIK3R1', 'Gene', (111, 117))	('tumour', 'Phenotype', 'HP:0002664', (185, 191))	('amplification', 'Var', (24, 37))	('PI3K pathway', 'Pathway', (161, 173))	('PTEN', 'Gene', (103, 107))	('PIK3CA', 'Gene', (95, 101))	('tumours', 'Disease', (68, 75))	('EGFR', 'Gene', (53, 57))
32121	28052061	Notably, we found mutations of ERBB2 in four tumours lacking ERBB2 amplification, suggesting that more patients may benefit from ERBB2-directed therapy.	('ERBB2', 'Gene', (129, 134))	('ERBB2', 'Gene', '2064', (129, 134))	('ERBB2', 'Gene', (61, 66))	('ERBB2', 'Gene', '2064', (61, 66))	('tumour', 'Phenotype', 'HP:0002664', (45, 51))	('tumours', 'Phenotype', 'HP:0002664', (45, 52))	('tumours', 'Disease', 'MESH:D009369', (45, 52))	('ERBB2', 'Gene', '2064', (31, 36))	('patients', 'Species', '9606', (103, 111))	('ERBB2', 'Gene', (31, 36))	('tumours', 'Disease', (45, 52))	('mutations', 'Var', (18, 27))
32125	28052061	Additional analysis identified dysregulation of the TGF-beta pathway and less frequent CTNNB1 (beta-catenin) activation, both more common in EAC than ESCC.	('EAC', 'Disease', (141, 144))	('CTNNB1', 'Gene', '1499', (87, 93))	('SCC', 'Gene', '6317', (151, 154))	('TGF-beta', 'Gene', (52, 60))	('activation', 'PosReg', (109, 119))	('beta-catenin', 'Gene', (95, 107))	('dysregulation', 'Var', (31, 44))	('CTNNB1', 'Gene', (87, 93))	('TGF-beta', 'Gene', '7040', (52, 60))	('beta-catenin', 'Gene', '1499', (95, 107))	('SCC', 'Gene', (151, 154))
32126	28052061	We found that 6% of ESCCs (but no EACs) had inactivating alterations of PTCH1, as previously described15, suggesting activated hedgehog signalling.	('SCC', 'Gene', (21, 24))	('PTCH1', 'Gene', '5727', (72, 77))	('hedgehog', 'CPA', (127, 135))	('SCC', 'Gene', '6317', (21, 24))	('inactivating alterations', 'Var', (44, 68))	('PTCH1', 'Gene', (72, 77))	('activated', 'PosReg', (117, 126))
32127	28052061	ESCC tumours, like other squamous cancers, had amplifications of chromosome 3q, focused on the SOX2 locus25.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('tumours', 'Phenotype', 'HP:0002664', (5, 12))	('ESCC tumours', 'Disease', 'MESH:D004938', (0, 12))	('squamous cancers', 'Disease', (25, 41))	('squamous cancers', 'Disease', 'MESH:D002294', (25, 41))	('ESCC tumours', 'Disease', (0, 12))	('cancers', 'Phenotype', 'HP:0002664', (34, 41))	('SOX2', 'Gene', (95, 99))	('SOX2', 'Gene', '6657', (95, 99))	('amplifications', 'Var', (47, 61))	('tumour', 'Phenotype', 'HP:0002664', (5, 11))
32129	28052061	Moreover, mutations in ZNF750 and NOTCH1 in ESCCs may similarly modulate squamous cell maturation15-20.	('ZNF750', 'Gene', (23, 29))	('SCC', 'Gene', (45, 48))	('NOTCH1', 'Gene', '4851', (34, 40))	('modulate', 'Reg', (64, 72))	('SCC', 'Gene', '6317', (45, 48))	('NOTCH1', 'Gene', (34, 40))	('ZNF750', 'Gene', '79755', (23, 29))	('squamous cell maturation15-20', 'CPA', (73, 102))	('mutations', 'Var', (10, 19))
32130	28052061	In EACs, however, we found frequent amplifications of genes that encode GATA4 and GATA6 developmental factors, as described in gastric adenocarcinomas26,27 and (for GATA6), experimentally validated in EAC28.	('gastric adenocarcinomas26', 'Disease', 'MESH:D013274', (127, 152))	('gastric adenocarcinomas26', 'Disease', (127, 152))	('GATA4', 'Gene', '2626', (72, 77))	('GATA4', 'Gene', (72, 77))	('GATA6', 'Gene', (82, 87))	('GATA6', 'Gene', '2627', (82, 87))	('GATA6', 'Gene', (165, 170))	('GATA6', 'Gene', '2627', (165, 170))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))	('carcinomas', 'Phenotype', 'HP:0030731', (140, 150))	('amplifications', 'Var', (36, 50))
32132	28052061	Alterations affecting SWI/SNF-encoding genes ARID1A, SMARCA4 and PBRM1 were more common in adenocarcinomas, whereas ESCCs contained more frequent alterations in histone-modifying factors KDM6A (UTX), KMT2D (MLL2) and KMT2C (MLL3).	('KMT2D', 'Gene', (200, 205))	('MLL2', 'Gene', (207, 211))	('ARID1A', 'Gene', '8289', (45, 51))	('Alterations', 'Var', (0, 11))	('SCC', 'Gene', (117, 120))	('PBRM1', 'Gene', (65, 70))	('KMT2C', 'Gene', '58508', (217, 222))	('KMT2C', 'Gene', (217, 222))	('adenocarcinomas', 'Disease', 'MESH:D000230', (91, 106))	('adenocarcinomas', 'Disease', (91, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('carcinomas', 'Phenotype', 'HP:0030731', (96, 106))	('SMARCA4', 'Gene', (53, 60))	('KMT2D', 'Gene', '8085', (200, 205))	('MLL3', 'Gene', '58508', (224, 228))	('alterations', 'Reg', (146, 157))	('KDM6A', 'Gene', '7403', (187, 192))	('UTX', 'Gene', (194, 197))	('SWI/SNF-encoding', 'Gene', (22, 38))	('common', 'Reg', (81, 87))	('UTX', 'Gene', '7403', (194, 197))	('ARID1A', 'Gene', (45, 51))	('PBRM1', 'Gene', '55193', (65, 70))	('MLL3', 'Gene', (224, 228))	('KDM6A', 'Gene', (187, 192))	('SCC', 'Gene', '6317', (117, 120))	('MLL2', 'Gene', '8085', (207, 211))	('SMARCA4', 'Gene', '6597', (53, 60))
32136	28052061	Within iCluster 2, we identified a group of tumours with shared features including mutations in SMARCA4 (encoding the SWI/SNF factor BRG1), increased DNA methylation (Fig.	('mutations', 'Var', (83, 92))	('tumours', 'Phenotype', 'HP:0002664', (44, 51))	('SMARCA4', 'Gene', (96, 103))	('tumours', 'Disease', 'MESH:D009369', (44, 51))	('DNA methylation', 'MPA', (150, 165))	('tumours', 'Disease', (44, 51))	('SMARCA4', 'Gene', '6597', (96, 103))	('BRG1', 'Gene', (133, 137))	('BRG1', 'Gene', '6597', (133, 137))	('increased', 'PosReg', (140, 149))	('tumour', 'Phenotype', 'HP:0002664', (44, 50))
32139	28052061	Mutations in NFE2L2 (NRF2), are associated with poor prognosis and resistance to chemoradiotherapy29.	('NRF2', 'Gene', (21, 25))	('NFE2L2', 'Gene', '4780', (13, 19))	('NFE2L2', 'Gene', (13, 19))	('Mutations', 'Var', (0, 9))	('NRF2', 'Gene', '4780', (21, 25))	('associated', 'Reg', (32, 42))
32143	28052061	ESCC1 showed higher rates of YAP1 (11q22.1) amplification and VGLL4/ATG7 deletion, suggesting activation of Hippo.	('ATG7', 'Gene', '10533', (68, 72))	('VGLL4', 'Gene', (62, 67))	('VGLL4', 'Gene', '9686', (62, 67))	('ATG7', 'Gene', (68, 72))	('amplification', 'Var', (44, 57))	('SCC', 'Gene', (1, 4))	('YAP1', 'Gene', (29, 33))	('YAP1', 'Gene', '10413', (29, 33))	('SCC', 'Gene', '6317', (1, 4))	('deletion', 'Var', (73, 81))	('Hippo', 'CPA', (108, 113))	('activation', 'PosReg', (94, 104))
32144	28052061	ESCC2 showed higher rates of mutation of NOTCH1 or ZNF750 (Extended Data Fig.	('mutation', 'Var', (29, 37))	('ZNF750', 'Gene', (51, 57))	('SCC', 'Gene', (1, 4))	('NOTCH1', 'Gene', '4851', (41, 47))	('NOTCH1', 'Gene', (41, 47))	('SCC', 'Gene', '6317', (1, 4))	('ZNF750', 'Gene', '79755', (51, 57))
32151	28052061	ESCC3 tumours showed no evidence for genetic deregulation of the cell cycle and had TP53 mutations in only one of four samples.	('tumour', 'Phenotype', 'HP:0002664', (6, 12))	('cell cycle', 'CPA', (65, 75))	('TP53', 'Gene', '7157', (84, 88))	('tumours', 'Phenotype', 'HP:0002664', (6, 13))	('SCC', 'Gene', (1, 4))	('tumours', 'Disease', 'MESH:D009369', (6, 13))	('mutations', 'Var', (89, 98))	('SCC', 'Gene', '6317', (1, 4))	('TP53', 'Gene', (84, 88))	('tumours', 'Disease', (6, 13))
32152	28052061	All samples in ESCC3, however, sustained alterations predicted to activate the PI3K pathway (Extended Data Fig.	('PI3K pathway', 'Pathway', (79, 91))	('activate', 'PosReg', (66, 74))	('SCC', 'Gene', (16, 19))	('SCC', 'Gene', '6317', (16, 19))	('alterations', 'Var', (41, 52))
32157	28052061	Tumours from Vietnamese patients were enriched in NFE2L2 mutations (Fig.	('NFE2L2', 'Gene', (50, 56))	('patients', 'Species', '9606', (24, 32))	('mutations', 'Var', (57, 66))	('Tumour', 'Phenotype', 'HP:0002664', (0, 6))	('NFE2L2', 'Gene', '4780', (50, 56))	('Tumours', 'Phenotype', 'HP:0002664', (0, 7))
32159	28052061	This association of NFE2L2 mutations with Vietnamese patients suggests a common oxidative stressor or genetic predisposition.	('mutations', 'Var', (27, 36))	('patients', 'Species', '9606', (53, 61))	('NFE2L2', 'Gene', '4780', (20, 26))	('oxidative stressor', 'Phenotype', 'HP:0025464', (80, 98))	('NFE2L2', 'Gene', (20, 26))	('association', 'Interaction', (5, 16))
32160	28052061	Patients from East Asia have common variants in alcohol-metabolism genes ALDH2 and ADH1B36, which are associated with ESCC risk36, but we could not investigate their association with NFE2L2 mutations as all Vietnamese patients had such variants (Supplementary Fig.	('ALDH2', 'Gene', (73, 78))	('NFE2L2', 'Gene', (183, 189))	('associated', 'Reg', (102, 112))	('SCC', 'Gene', '6317', (119, 122))	('alcohol', 'Chemical', 'MESH:D000438', (48, 55))	('patients', 'Species', '9606', (218, 226))	('Patients', 'Species', '9606', (0, 8))	('ADH1B36', 'Gene', (83, 90))	('ALDH2', 'Gene', '217', (73, 78))	('variants', 'Var', (36, 44))	('NFE2L2', 'Gene', '4780', (183, 189))	('variants', 'Var', (236, 244))	('SCC', 'Gene', (119, 122))
32161	28052061	In comparison to EAC, ESCCs showed enrichment of C> A substitutions and APOBEC (apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like) signatures (P = 7 x 10-7 and 5 x 10-5, respectively, by Wilcoxon rank-sum test).	('SCC', 'Gene', (23, 26))	('C> A substitutions', 'Var', (49, 67))	('SCC', 'Gene', '6317', (23, 26))	('substitutions', 'Var', (54, 67))
32162	28052061	The C>A mutational signature is associated with smoking and chewing tobacco, but did not correlate with ESCC subgroups or clinical variables in our sample set.	('chewing tobacco', 'Disease', (60, 75))	('tobacco', 'Species', '4097', (68, 75))	('C>A', 'Var', (4, 7))	('smoking', 'Disease', (48, 55))	('SCC', 'Gene', (105, 108))	('associated', 'Reg', (32, 42))	('SCC', 'Gene', '6317', (105, 108))
32188	28052061	Unlike hypermethylated gastric CpG island methylator phenotype tumours, no GEA-CIN tumours exhibited epigenetic silencing of MLH1, consistent with their MSI-negative status, but they showed a higher propensity for epigenetic silencing of CDKN2A, (Supplementary Table 6, Fig.	('tumours', 'Disease', (83, 90))	('tumours', 'Phenotype', 'HP:0002664', (83, 90))	('GEA-CIN tumours', 'Disease', (75, 90))	('epigenetic silencing', 'Var', (214, 234))	('MLH1', 'Gene', (125, 129))	('tumours', 'Disease', 'MESH:D009369', (83, 90))	('CIN', 'Phenotype', 'HP:0040012', (79, 82))	('GEA-CIN tumours', 'Disease', 'MESH:D009369', (75, 90))	('tumour', 'Phenotype', 'HP:0002664', (83, 89))	('epigenetic silencing', 'Var', (101, 121))	('MLH1', 'Gene', '4292', (125, 129))	('tumours', 'Disease', (63, 70))	('CDKN2A', 'Gene', (238, 244))	('tumours', 'Phenotype', 'HP:0002664', (63, 70))	('MSI', 'Disease', 'None', (153, 156))	('tumours', 'Disease', 'MESH:D009369', (63, 70))	('MSI', 'Disease', (153, 156))	('CDKN2A', 'Gene', '1029', (238, 244))	('tumour', 'Phenotype', 'HP:0002664', (63, 69))
32191	28052061	EACs had higher rates of mutation of SMARCA4 and deletion of tumour suppressor RUNX1, but lower APC mutation rates relative to gastric tumours, suggesting a less prominent role for Wnt/beta-catenin in EAC.	('tumour', 'Disease', 'MESH:D009369', (61, 67))	('gastric tumours', 'Disease', (127, 142))	('beta-catenin', 'Gene', '1499', (185, 197))	('tumour', 'Disease', (61, 67))	('SMARCA4', 'Gene', '6597', (37, 44))	('mutation', 'Var', (25, 33))	('lower', 'NegReg', (90, 95))	('EACs', 'Disease', (0, 4))	('tumour', 'Phenotype', 'HP:0002664', (135, 141))	('RUNX1', 'Gene', (79, 84))	('tumour', 'Disease', 'MESH:D009369', (135, 141))	('tumour', 'Disease', (135, 141))	('tumours', 'Phenotype', 'HP:0002664', (135, 142))	('RUNX1', 'Gene', '861', (79, 84))	('SMARCA4', 'Gene', (37, 44))	('APC', 'Disease', 'MESH:D011125', (96, 99))	('deletion', 'Var', (49, 57))	('APC', 'Disease', (96, 99))	('gastric tumours', 'Disease', 'MESH:D013274', (127, 142))	('tumour', 'Phenotype', 'HP:0002664', (61, 67))	('beta-catenin', 'Gene', (185, 197))
32192	28052061	Copy-number analysis revealed higher rates of deletions of putative fragile site genes FHIT or WWOX, suggestive of differences in the underlying genomic instability between distal and proximal GEA-CIN tumours.	('GEA-CIN tumours', 'Disease', 'MESH:D009369', (193, 208))	('WWOX', 'Gene', '51741', (95, 99))	('CIN', 'Phenotype', 'HP:0040012', (197, 200))	('tumour', 'Phenotype', 'HP:0002664', (201, 207))	('FHIT', 'Gene', (87, 91))	('GEA-CIN tumours', 'Disease', (193, 208))	('WWOX', 'Gene', (95, 99))	('deletions', 'Var', (46, 55))	('FHIT', 'Gene', '2272', (87, 91))	('tumours', 'Phenotype', 'HP:0002664', (201, 208))
32193	28052061	Analysis of oncogenes identified subtle distinctions, with VEGFA and MYC amplifications being more common in EACs.	('EACs', 'Disease', (109, 113))	('MYC', 'Gene', (69, 72))	('VEGFA', 'Gene', '7422', (59, 64))	('amplifications', 'Var', (73, 87))	('common', 'Reg', (99, 105))	('VEGFA', 'Gene', (59, 64))
32223	28052061	MSI-mono-dinucleotide assay was performed to test a panel of four mononucleotide repeat loci (polyadenine tracts BAT25, BAT26, BAT40 and transforming growth factor receptor type II) and three dinucleotide repeat loci (CA repeats in D2S123, D5S346 and D17S250) as previously described.	('MSI', 'Disease', 'None', (0, 3))	('BAT25', 'Gene', (113, 118))	('D2S123', 'Var', (232, 238))	('BAT26', 'Gene', (120, 125))	('BAT40', 'Var', (127, 132))	('MSI', 'Disease', (0, 3))	('mononucleotide', 'Chemical', '-', (66, 80))	('D17S250', 'Var', (251, 258))	('polyadenine', 'Chemical', 'MESH:C000628261', (94, 105))	('polyadenine tracts', 'Var', (94, 112))	('D5S346', 'Var', (240, 246))
32236	28052061	Tumours were classified as having high chromosomal instability, SCNA-high, if they possessed at least one arm-level loss (apart from that of 18p, 18q or 21, which were recurrent in tumours of both low and high copy-number events) and otherwise as SCNA-low.	('Tumours', 'Phenotype', 'HP:0002664', (0, 7))	('tumour', 'Phenotype', 'HP:0002664', (181, 187))	('tumours', 'Phenotype', 'HP:0002664', (181, 188))	('high', 'MPA', (34, 38))	('tumours', 'Disease', 'MESH:D009369', (181, 188))	('high copy-number events', 'Var', (205, 228))	('loss', 'NegReg', (116, 120))	('Tumour', 'Phenotype', 'HP:0002664', (0, 6))	('chromosomal instability', 'Phenotype', 'HP:0040012', (39, 62))	('tumours', 'Disease', (181, 188))
32238	28052061	CDKN2A (also known as p16INK4) epigenetic silencing calls were made using both DNA methylation and RNA-seq data.	('CDKN2A', 'Gene', (0, 6))	('p16INK4', 'Gene', '1029', (22, 29))	('p16INK4', 'Gene', (22, 29))	('CDKN2A', 'Gene', '1029', (0, 6))	('epigenetic', 'Var', (31, 41))
32239	28052061	CDKN2A DNA methylation status was assessed in each sample based on the probe (cg13601799) located in the p16INK4 promoter CpG island.	('p16INK4', 'Gene', '1029', (105, 112))	('CDKN2A', 'Gene', (0, 6))	('p16INK4', 'Gene', (105, 112))	('CDKN2A', 'Gene', '1029', (0, 6))	('cg13601799', 'Var', (78, 88))
32244	28052061	From these BAM files, four different TCGA analysis sites performed distinct mutation and insertion/deletion detection procedures.	('insertion/deletion', 'Var', (89, 107))	('BAM', 'Gene', (11, 14))	('BAM', 'Gene', '9126', (11, 14))
32253	28052061	Functional annotation of mutations was performed with Oncotator (http://www.broadinstitute.org/cancer/cga/oncotator) using Gencode V18.	('cga', 'Gene', (102, 105))	('mutations', 'Var', (25, 34))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('cancer', 'Disease', (95, 101))	('cga', 'Gene', '1113', (102, 105))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))
32348	26451826	Module 2 is composed of the probes: 206640_x_at, 207086_x_at, 207663_x_at, 207739_s_at, 208155_x_at, 208235_x_at, which correspond to the genes GAGE3, GAGE4, GAGE5, GAGE6, GAGE7, and GAGE8.	('GAGE3', 'Gene', '2575', (144, 149))	('GAGE7', 'Gene', (172, 177))	('206640_x_at', 'Var', (36, 47))	('GAGE5', 'Gene', (158, 163))	('GAGE8', 'Gene', '100101629', (183, 188))	('GAGE3', 'Gene', (144, 149))	('GAGE4', 'Gene', '2576', (151, 156))	('207663_x_at', 'Var', (62, 73))	('GAGE6', 'Gene', '2578', (165, 170))	('GAGE5', 'Gene', '2577', (158, 163))	('GAGE7', 'Gene', '2579', (172, 177))	('GAGE4', 'Gene', (151, 156))	('GAGE8', 'Gene', (183, 188))	('GAGE6', 'Gene', (165, 170))
32377	26451826	Two of them are the same as that enriched by Module 3, which are hsa04115: p53 signaling pathway, and hsa04110: Cell cycle.	('p53', 'Gene', (75, 78))	('Cell cycle', 'CPA', (112, 122))	('p53', 'Gene', '7157', (75, 78))	('hsa04110', 'Var', (102, 110))
32402	26451826	Studies suggested that perturbation of inflammation is critically linked to nutrient metabolic pathways and to other obesity-associated complications such as insulin resistance and type 2 diabetes,,.	('nutrient metabolic pathways', 'Pathway', (76, 103))	('diabetes', 'Disease', 'MESH:D003920', (188, 196))	('linked', 'Reg', (66, 72))	('obesity', 'Phenotype', 'HP:0001513', (117, 124))	('insulin', 'Gene', (158, 165))	('inflammation', 'Disease', 'MESH:D007249', (39, 51))	('perturbation', 'Var', (23, 35))	('insulin resistance', 'Phenotype', 'HP:0000855', (158, 176))	('insulin', 'Gene', '3630', (158, 165))	('inflammation', 'Disease', (39, 51))	('obesity', 'Disease', 'MESH:D009765', (117, 124))	('type 2 diabetes', 'Phenotype', 'HP:0005978', (181, 196))	('diabetes', 'Disease', (188, 196))	('obesity', 'Disease', (117, 124))
32417	26305547	Inhibition of Calcium-Activated Chloride Channel ANO1/TMEM16A Suppresses Tumor Growth and Invasion in Human Lung Cancer Lung cancer or pulmonary carcinoma is primarily derived from epithelial cells that are thin and line on the alveolar surfaces of the lung for gas exchange.	('carcinoma', 'Phenotype', 'HP:0030731', (145, 154))	('ANO1', 'Gene', (49, 53))	('Tumor', 'Phenotype', 'HP:0002664', (73, 78))	('TMEM16A', 'Gene', '55107', (54, 61))	('Human', 'Species', '9606', (102, 107))	('Lung cancer', 'Phenotype', 'HP:0100526', (120, 131))	('Cancer', 'Phenotype', 'HP:0002664', (113, 119))	('ANO1', 'Gene', '55107', (49, 53))	('Invasion', 'CPA', (90, 98))	('cancer', 'Disease', (125, 131))	('Lung Cancer', 'Phenotype', 'HP:0100526', (108, 119))	('Cancer', 'Disease', (113, 119))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('Inhibition', 'Var', (0, 10))	('pulmonary carcinoma', 'Disease', 'MESH:D008175', (135, 154))	('Tumor Growth', 'CPA', (73, 85))	('pulmonary carcinoma', 'Disease', (135, 154))	('Cancer', 'Disease', 'MESH:D009369', (113, 119))	('TMEM16A', 'Gene', (54, 61))	('Suppresses', 'NegReg', (62, 72))	('cancer', 'Disease', 'MESH:D009369', (125, 131))
32421	26305547	In this study, we show that inhibition of calcium-activated chloride channel ANO1/TMEM16A suppresses tumor growth and invasion in human lung cancer.	('suppresses', 'NegReg', (90, 100))	('TMEM16A', 'Gene', '55107', (82, 89))	('lung cancer', 'Phenotype', 'HP:0100526', (136, 147))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('chloride', 'Chemical', 'MESH:D002712', (60, 68))	('tumor', 'Disease', (101, 106))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('inhibition', 'Var', (28, 38))	('TMEM16A', 'Gene', (82, 89))	('lung cancer', 'Disease', 'MESH:D008175', (136, 147))	('human', 'Species', '9606', (130, 135))	('calcium', 'Chemical', 'MESH:D002118', (42, 49))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('lung cancer', 'Disease', (136, 147))
32423	26305547	Knocking-down ANO1 by small hairpin RNAs inhibited proliferation, migration and invasion of GLC82 and NCI-H520 cancel cells evaluated by CCK-8, would-healing, transwell and 3D soft agar assays.	('invasion', 'CPA', (80, 88))	('ANO1', 'Gene', (14, 18))	('migration', 'CPA', (66, 75))	('agar', 'Chemical', 'MESH:D000362', (181, 185))	('Knocking-down', 'Var', (0, 13))	('proliferation', 'CPA', (51, 64))	('inhibited', 'NegReg', (41, 50))	('NCI-H520', 'CellLine', 'CVCL:1566', (102, 110))	('small', 'Gene', (22, 27))
32425	26305547	Furthermore, the tumor growth in nude mice implanted with GLC82 cells was significantly suppressed by ANO1 silencing.	('ANO1', 'Gene', (102, 106))	('silencing', 'Var', (107, 116))	('tumor', 'Disease', (17, 22))	('nude mice', 'Species', '10090', (33, 42))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('suppressed', 'NegReg', (88, 98))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
32435	26305547	Dysregulation of ion channel expression becomes epigenetically abnormal in metastatic cancer cells.	('Dysregulation', 'Var', (0, 13))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('cancer', 'Disease', (86, 92))
32443	26305547	ANO1 overexpression is also correlated with poor prognosis of HNSCC and breast cancer patients, and pharmacological inhibition of CaCC ANO1 activity by CaCCinh-A01 and T16Ainh-A01 can inhibit cancer cell proliferation.	('inhibit', 'NegReg', (184, 191))	('T16Ainh-A01', 'Chemical', 'MESH:C578466', (168, 179))	('T16Ainh-A01', 'Var', (168, 179))	('breast cancer', 'Disease', 'MESH:D001943', (72, 85))	('cancer', 'Disease', (192, 198))	('breast cancer', 'Disease', (72, 85))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('patients', 'Species', '9606', (86, 94))	('overexpression', 'PosReg', (5, 19))	('ANO1', 'Gene', (135, 139))	('cancer', 'Disease', (79, 85))	('CaCC', 'Gene', '55107', (130, 134))	('HNSCC', 'Disease', (62, 67))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('CaCC', 'Gene', '55107', (152, 156))	('cancer', 'Disease', 'MESH:D009369', (192, 198))	('activity', 'MPA', (140, 148))	('CaCC', 'Gene', (130, 134))	('HNSCC', 'Phenotype', 'HP:0012288', (62, 67))	('CaCCinh-A01', 'Chemical', 'MESH:C000607369', (152, 163))	('CaCC', 'Gene', (152, 156))	('breast cancer', 'Phenotype', 'HP:0003002', (72, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))
32451	26305547	Inhibition of ANO1 also suppressed tumor growth in nude mice implanted with stable transfected GLC82 cells.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('ANO1', 'Gene', (14, 18))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('suppressed', 'NegReg', (24, 34))	('tumor', 'Disease', (35, 40))	('Inhibition', 'Var', (0, 10))	('nude mice', 'Species', '10090', (51, 60))
32510	26305547	As shown in Fig 3B, silencing ANO1 significantly slowed down the growth of lung adenocarcinoma GCL82 and lung squamous carcinoma NCI-H520 cells.	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (75, 94))	('ANO1', 'Gene', (30, 34))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (110, 128))	('lung squamous carcinoma', 'Phenotype', 'HP:0030359', (105, 128))	('growth', 'CPA', (65, 71))	('slowed down', 'NegReg', (49, 60))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('NCI-H520 cells', 'CellLine', 'CVCL:1566', (129, 143))	('silencing', 'Var', (20, 29))	('lung adenocarcinoma GCL82 and lung squamous carcinoma NCI-H520', 'Disease', 'MESH:D000077192', (75, 137))
32513	26305547	As shown in Fig 3C, silencing ANO1 resulted in a decrease of 36.2% colony formation in GLC82 cells and 30.7% colony formation in NCI-H520 cells, as compared to scrambled shRNA control.	('ANO1', 'Gene', (30, 34))	('colony formation', 'CPA', (67, 83))	('colony formation', 'CPA', (109, 125))	('decrease', 'NegReg', (49, 57))	('NCI-H520 cells', 'CellLine', 'CVCL:1566', (129, 143))	('silencing', 'Var', (20, 29))
32514	26305547	To further confirm the effect of silencing ANO1 on proliferation, we used the soft agar colony formation assay that monitors anchorage-independent cell growth.	('ANO1', 'Gene', (43, 47))	('agar', 'Chemical', 'MESH:D000362', (83, 87))	('silencing', 'Var', (33, 42))
32516	26305547	These results indicate that silencing endogenous ANO1 can inhibit proliferation of GLC82 and NCI-H520 lung cancer cells.	('ANO1', 'Gene', (49, 53))	('lung cancer', 'Phenotype', 'HP:0100526', (102, 113))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('proliferation', 'CPA', (66, 79))	('endogenous', 'Protein', (38, 48))	('inhibit', 'NegReg', (58, 65))	('silencing', 'Var', (28, 37))	('NCI-H520 lung cancer', 'Disease', (93, 113))	('NCI-H520 lung cancer', 'Disease', 'MESH:D008175', (93, 113))
32518	26305547	As shown in Fig 4A and 4B, transfecting GLC82 lung cancer cells with ANO1 shRNA inhibited the wound filling about 66.8% at 24 h, 67.5% at 48 h and 74.3% at 72 h, as compared with scrambled shRNA.	('inhibited', 'NegReg', (80, 89))	('wound filling', 'CPA', (94, 107))	('ANO1 shRNA', 'Var', (69, 79))	('lung cancer', 'Disease', 'MESH:D008175', (46, 57))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('lung cancer', 'Disease', (46, 57))	('lung cancer', 'Phenotype', 'HP:0100526', (46, 57))
32519	26305547	In NCI-H520 lung cancer cells (Fig 4C and 4D), the wound-healing in ANO1 knockdown group was only about 29.1% at 24 h and 27.6% at 48 h as compared with the scrambled shRNA control group.	('NCI-H520 lung cancer', 'Disease', (3, 23))	('NCI-H520 lung cancer', 'Disease', 'MESH:D008175', (3, 23))	('wound-healing', 'CPA', (51, 64))	('lung cancer', 'Phenotype', 'HP:0100526', (12, 23))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))	('knockdown', 'Var', (73, 82))
32520	26305547	These results show that endogenous ANO1 promotes tumor cell migration, and silencing ANO1 inhibits the migration of lung cancer cells.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('migration of lung cancer', 'Disease', (103, 127))	('lung cancer', 'Phenotype', 'HP:0100526', (116, 127))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('ANO1', 'Gene', (85, 89))	('ANO1', 'Gene', (35, 39))	('tumor', 'Disease', (49, 54))	('inhibits', 'NegReg', (90, 98))	('silencing', 'Var', (75, 84))	('migration of lung cancer', 'Disease', 'MESH:D008175', (103, 127))	('promotes', 'PosReg', (40, 48))
32524	26305547	As shown in Fig 5, the invasion potential of tumor cells was dramatically suppressed by ANO1 knockdown.	('knockdown', 'Var', (93, 102))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('suppressed', 'NegReg', (74, 84))	('tumor', 'Disease', (45, 50))	('ANO1', 'Gene', (88, 92))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
32525	26305547	As shown in Fig 5C and 5D, the relative transwell area of ANO1 knockdown in NCI-H520 cells was 12.2%, as compared with cells transfected by scrambled shRNA.	('knockdown', 'Var', (63, 72))	('NCI-H520 cells', 'CellLine', 'CVCL:1566', (76, 90))	('ANO1', 'Gene', (58, 62))
32526	26305547	These results indicate that silencing ANO1 inhibits the migration and invasion of lung cancer GLC82 and NCI-H520 cells.	('migration', 'CPA', (56, 65))	('lung cancer', 'Phenotype', 'HP:0100526', (82, 93))	('ANO1', 'Gene', (38, 42))	('lung cancer', 'Disease', (82, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('NCI-H520 cells', 'CellLine', 'CVCL:1566', (104, 118))	('lung cancer', 'Disease', 'MESH:D008175', (82, 93))	('silencing', 'Var', (28, 37))	('inhibits', 'NegReg', (43, 51))	('invasion', 'CPA', (70, 78))
32527	26305547	To investigate the effect of ANO1 knockdown on growth of xenograft tumor in vivo, three groups of GLC82 cells were individually transfected with ANO1 shRNA1, ANO1 shRNA2 and scrambled shRNAs, and their knockdown efficiency was confirmed by western blot before injection for formation of tumor xenograft in mice (Fig 6A).	('tumor', 'Disease', (67, 72))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Disease', 'MESH:D009369', (287, 292))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('ANO1', 'Var', (145, 149))	('mice', 'Species', '10090', (306, 310))	('tumor', 'Disease', (287, 292))	('tumor', 'Phenotype', 'HP:0002664', (287, 292))
32530	26305547	As shown in Fig 6B and 6C, ANO1 silencing resulted in a significant reduction of tumor growth by 68.8% in shRNA1 group and 42.1% in shRNA2 group, respectively, as compared with the scrambled group at the observation of day 12.	('ANO1', 'Gene', (27, 31))	('silencing', 'Var', (32, 41))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('reduction', 'NegReg', (68, 77))	('tumor', 'Disease', (81, 86))
32532	26305547	A remarkable reduction of tumor weight in ANO1 shRNA groups was observed (Fig 6D and 6E).	('ANO1 shRNA', 'Var', (42, 52))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('reduction', 'NegReg', (13, 22))	('tumor', 'Disease', (26, 31))
32535	26305547	These results indicate that ANO1 silencing not only inhibits the migration and invasion of lung cancer cells but also significantly suppresses tumor growth.	('suppresses', 'NegReg', (132, 142))	('lung cancer', 'Phenotype', 'HP:0100526', (91, 102))	('migration', 'CPA', (65, 74))	('tumor', 'Disease', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('ANO1', 'Gene', (28, 32))	('silencing', 'Var', (33, 42))	('lung cancer', 'Disease', 'MESH:D008175', (91, 102))	('inhibits', 'NegReg', (52, 60))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('lung cancer', 'Disease', (91, 102))
32538	26305547	Silencing ANO1 suppresses cell proliferation, migration and invasion, and the growth of implanted tumors.	('suppresses', 'NegReg', (15, 25))	('tumors', 'Disease', (98, 104))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('ANO1', 'Gene', (10, 14))	('tumors', 'Disease', 'MESH:D009369', (98, 104))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('Silencing', 'Var', (0, 9))	('cell proliferation', 'CPA', (26, 44))
32541	26305547	It is noticeable that these carcinomas are mostly epithelium originating tumors, indicating not only a crucial role of ANO1 as an ion channel in sensing and transmitting extracellular signals into intracellular machinery in epithelial cells, but also ANO1 dysfunction in alterations of ion homeostasis and volume regulation in epithelial cancer development and progression.	('carcinomas', 'Phenotype', 'HP:0030731', (28, 38))	('tumors', 'Disease', 'MESH:D009369', (73, 79))	('carcinomas', 'Disease', (28, 38))	('ANO1', 'Gene', (251, 255))	('carcinomas', 'Disease', 'MESH:D002277', (28, 38))	('volume regulation', 'MPA', (306, 323))	('carcinoma', 'Phenotype', 'HP:0030731', (28, 37))	('epithelial cancer', 'Disease', (327, 344))	('epithelial cancer', 'Disease', 'MESH:D000077216', (327, 344))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('cancer', 'Phenotype', 'HP:0002664', (338, 344))	('ion homeostasis', 'MPA', (286, 301))	('epithelial cancer', 'Phenotype', 'HP:0031492', (327, 344))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('tumors', 'Disease', (73, 79))	('dysfunction', 'Var', (256, 267))	('alterations of ion homeostasis', 'Phenotype', 'HP:0003111', (271, 301))
32549	26305547	It is not quite clear how overexpression or dysregulation of ANO1 contributes to cancer development.	('dysregulation', 'Var', (44, 57))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('overexpression', 'PosReg', (26, 40))	('contributes', 'Reg', (66, 77))	('cancer', 'Disease', (81, 87))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('ANO1', 'Gene', (61, 65))
32579	33198777	In recent years, the NSCLC patients have been greatly improved in treatment due to the alterations of driver genes, including epidermal growth factor receptor (EGFR) mutations, anaplastic lymphoma kinase (ALK) rearrangements, Kirsten rat sarcoma (KRAS) mutations, etc..	('men', 'Species', '9606', (219, 222))	('sarcoma', 'Phenotype', 'HP:0100242', (238, 245))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (177, 196))	('mutations', 'Var', (166, 175))	('epidermal growth factor receptor', 'Gene', (126, 158))	('NSCLC', 'Disease', 'MESH:D002289', (21, 26))	('mutations', 'Var', (253, 262))	('men', 'Species', '9606', (71, 74))	('patients', 'Species', '9606', (27, 35))	('EGFR', 'Gene', (160, 164))	('epidermal growth factor receptor', 'Gene', '1956', (126, 158))	('anaplastic lymphoma kinase', 'Gene', '238', (177, 203))	('KRAS', 'Gene', (247, 251))	('anaplastic lymphoma kinase', 'Gene', (177, 203))	('NSCLC', 'Disease', (21, 26))	('rat', 'Species', '10116', (91, 94))	('lymphoma', 'Phenotype', 'HP:0002665', (188, 196))	('rat', 'Species', '10116', (234, 237))	('sarcoma', 'Disease', 'MESH:D012509', (238, 245))	('alterations', 'Var', (87, 98))	('sarcoma', 'Disease', (238, 245))	('EGFR', 'Gene', '1956', (160, 164))	('rearrangements', 'Var', (210, 224))	('ALK', 'Gene', '238', (205, 208))	('KRAS', 'Gene', '24525', (247, 251))	('ALK', 'Gene', (205, 208))
32580	33198777	However, the frequency of these genes mutations are low in SCC, and EGFR inhibitors, ALK inhibitors and other genes inhibitors are only effective in few of SCC patients.	('patients', 'Species', '9606', (160, 168))	('SCC', 'Gene', (59, 62))	('ALK', 'Gene', (85, 88))	('SCC', 'Phenotype', 'HP:0002860', (59, 62))	('SCC', 'Gene', '6317', (59, 62))	('SCC', 'Gene', (156, 159))	('EGFR', 'Gene', '1956', (68, 72))	('SCC', 'Phenotype', 'HP:0002860', (156, 159))	('SCC', 'Gene', '6317', (156, 159))	('ALK', 'Gene', '238', (85, 88))	('mutations', 'Var', (38, 47))	('EGFR', 'Gene', (68, 72))
32623	33198777	With the development of molecularly targeted therapy, although it has revolutionized the treatment of patients with EGFR mutation-positive NSCLC, the incidence of this activating mutation of EGFR is lower in SCC patients than in AC patients, which limits the effect of clinical treatment for SCC cases.	('activating', 'PosReg', (168, 178))	('patients', 'Species', '9606', (102, 110))	('patients', 'Species', '9606', (212, 220))	('SCC', 'Phenotype', 'HP:0002860', (208, 211))	('SCC', 'Phenotype', 'HP:0002860', (292, 295))	('EGFR', 'Gene', (191, 195))	('men', 'Species', '9606', (16, 19))	('NSCLC', 'Disease', 'MESH:D002289', (139, 144))	('EGFR', 'Gene', '1956', (116, 120))	('SCC', 'Gene', '6317', (208, 211))	('lower', 'NegReg', (199, 204))	('men', 'Species', '9606', (94, 97))	('SCC', 'Gene', '6317', (292, 295))	('NSCLC', 'Disease', (139, 144))	('SCC', 'Gene', (208, 211))	('SCC', 'Gene', (292, 295))	('patients', 'Species', '9606', (232, 240))	('EGFR', 'Gene', '1956', (191, 195))	('men', 'Species', '9606', (283, 286))	('mutation-positive', 'Var', (121, 138))	('EGFR', 'Gene', (116, 120))
32718	32903763	CCND1 Amplification Contributes to Immunosuppression and Is Associated With a Poor Prognosis to Immune Checkpoint Inhibitors in Solid Tumors Cyclin D1 (CCND1) amplification relevant to malignant biological behavior exists in solid tumors.	('Immunosuppression', 'MPA', (35, 52))	('Tumor', 'Phenotype', 'HP:0002664', (134, 139))	('Cyclin D1', 'Gene', (141, 150))	('amplification', 'Var', (159, 172))	('Tumors', 'Disease', (134, 140))	('Tumors', 'Disease', 'MESH:D009369', (134, 140))	('Tumors', 'Phenotype', 'HP:0002664', (134, 140))	('solid tumors', 'Disease', 'MESH:D009369', (225, 237))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('Amplification', 'Var', (6, 19))	('Contributes', 'Reg', (20, 31))	('CCND1', 'Gene', '595', (152, 157))	('CCND1', 'Gene', '595', (0, 5))	('CCND1', 'Gene', (0, 5))	('solid tumors', 'Disease', (225, 237))	('tumors', 'Phenotype', 'HP:0002664', (231, 237))	('Cyclin D1', 'Gene', '595', (141, 150))	('CCND1', 'Gene', (152, 157))
32719	32903763	The prevalence and utility of CCND1 amplification as a biomarker for the clinical response to treatment with immune checkpoint inhibitors (ICIs) are unknown.	('amplification', 'Var', (36, 49))	('CCND1', 'Gene', (30, 35))	('CCND1', 'Gene', '595', (30, 35))
32720	32903763	Our study is a preliminary investigation mainly focused on the predictive function of CCND1 amplification in the tumor microenvironment (TME) in the aspect of genome and transcriptome.	('CCND1', 'Gene', (86, 91))	('tumor', 'Disease', (113, 118))	('CCND1', 'Gene', '595', (86, 91))	('amplification', 'Var', (92, 105))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))
32722	32903763	Comprehensive profiling was performed to determine the prevalence of CCND1 amplification and the correlation with the prognosis and the response to ICIs.	('amplification', 'Var', (75, 88))	('CCND1', 'Gene', (69, 74))	('CCND1', 'Gene', '595', (69, 74))
32723	32903763	A CCND1 amplification occurs in many cancer types and correlates with shorter overall survival and inferior outcomes with ICI therapy.	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('cancer', 'Disease', (37, 43))	('amplification', 'Var', (8, 21))	('shorter', 'NegReg', (70, 77))	('CCND1', 'Gene', (2, 7))	('overall survival', 'MPA', (78, 94))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('CCND1', 'Gene', '595', (2, 7))
32725	32903763	The gene set enrichment analysis suggested that CCND1 amplification correlates with multiple aggressive, immunosuppressive hallmarks including epithelial-mesenchymal transition, transforming growth factor (TGF)-beta signaling, KRAS signaling, phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling, p53 pathway, and hypoxia signaling in solid tumors.	('hypoxia', 'Disease', (345, 352))	('tumor', 'Phenotype', 'HP:0002664', (372, 377))	('KRAS', 'Gene', '3845', (227, 231))	('transforming growth factor (TGF)-beta', 'Gene', '7039', (178, 215))	('AKT', 'Gene', (276, 279))	('solid tumors', 'Disease', 'MESH:D009369', (366, 378))	('tumors', 'Phenotype', 'HP:0002664', (372, 378))	('p53', 'Gene', (328, 331))	('hypoxia', 'Disease', 'MESH:D000860', (345, 352))	('phosphoinositide 3-kinase', 'Gene', (243, 268))	('KRAS', 'Gene', (227, 231))	('CCND1', 'Gene', '595', (48, 53))	('correlates', 'Reg', (68, 78))	('mTOR', 'Gene', (311, 315))	('CCND1', 'Gene', (48, 53))	('mammalian target of rapamycin', 'Gene', '2475', (280, 309))	('epithelial-mesenchymal transition', 'CPA', (143, 176))	('AKT', 'Gene', '207', (276, 279))	('mTOR', 'Gene', '2475', (311, 315))	('mammalian target of rapamycin', 'Gene', (280, 309))	('amplification', 'Var', (54, 67))	('solid tumors', 'Disease', (366, 378))	('p53', 'Gene', '7157', (328, 331))	('phosphoinositide 3-kinase', 'Gene', '5295', (243, 268))
32726	32903763	These findings indicate that CCND1 amplification may be a key point related to immunosuppression in TME and multiple malignancy hallmarks, and it hinders not only the natural host immune responses but also the efficacy of ICIs.	('amplification', 'Var', (35, 48))	('hinders', 'NegReg', (146, 153))	('CCND1', 'Gene', (29, 34))	('ICIs', 'CPA', (222, 226))	('malignancy hallmarks', 'Disease', (117, 137))	('malignancy hallmarks', 'Disease', 'MESH:D009369', (117, 137))	('CCND1', 'Gene', '595', (29, 34))
32733	32903763	Recently, several studies revealed that CCND1 amplification associates with a negative response to ICIs.	('negative', 'NegReg', (78, 86))	('response to ICIs', 'MPA', (87, 103))	('amplification', 'Var', (46, 59))	('CCND1', 'Gene', (40, 45))	('CCND1', 'Gene', '595', (40, 45))
32738	32903763	We hypothesized that CCND1 amplification may be associated with poor clinical benefits of ICI therapy through suppressing the antitumor immunity in TME.	('amplification', 'Var', (27, 40))	('CCND1', 'Gene', '595', (21, 26))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('suppressing', 'NegReg', (110, 121))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('CCND1', 'Gene', (21, 26))	('tumor', 'Disease', (130, 135))
32739	32903763	We mainly focused on the predictive function of CCND1 amplification in the TME in the aspect of genome and transcriptome.	('CCND1', 'Gene', (48, 53))	('amplification', 'Var', (54, 67))	('CCND1', 'Gene', '595', (48, 53))
32741	32903763	Importantly, we aimed to explore whether CCND1 amplification correlates with a poor response to ICIs in solid tumors, for which the potential mechanism may be correlated with events within the TME.	('CCND1', 'Gene', '595', (41, 46))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('solid tumors', 'Disease', (104, 116))	('amplification', 'Var', (47, 60))	('CCND1', 'Gene', (41, 46))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('solid tumors', 'Disease', 'MESH:D009369', (104, 116))
32746	32903763	Specifically, for the CCND1 gene, samples with chromosome 11q13.3 alterations were further reviewed for CNAs.	('CCND1', 'Gene', '595', (22, 27))	('CCND1', 'Gene', (22, 27))	('alterations', 'Var', (66, 77))	('CNAs', 'Disease', (104, 108))
32749	32903763	Survival information and RSEM-normalized gene-level data from cancers with CCND1 amplification frequency ranked first to 10th were further downloaded.	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('amplification frequency', 'Var', (81, 104))	('CCND1', 'Gene', (75, 80))	('cancers', 'Disease', 'MESH:D009369', (62, 69))	('CCND1', 'Gene', '595', (75, 80))	('cancers', 'Phenotype', 'HP:0002664', (62, 69))	('cancers', 'Disease', (62, 69))
32751	32903763	Patients with CCND1 amplification or neutral phenotypes were further analyzed.	('amplification', 'Var', (20, 33))	('Patients', 'Species', '9606', (0, 8))	('CCND1', 'Gene', (14, 19))	('CCND1', 'Gene', '595', (14, 19))
32755	32903763	Survival information from cancers with CCND1 amplification frequency ranked first to 10th was further downloaded.	('cancers', 'Phenotype', 'HP:0002664', (26, 33))	('CCND1', 'Gene', (39, 44))	('cancers', 'Disease', 'MESH:D009369', (26, 33))	('cancers', 'Disease', (26, 33))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('amplification frequency', 'Var', (45, 68))	('CCND1', 'Gene', '595', (39, 44))
32758	32903763	To explore the association between CCND1 amplification and the clinical outcomes of ICIs, we included CNA and clinical data from four clinical cohorts treated with ICIs.	('amplification', 'Var', (41, 54))	('CCND1', 'Gene', (35, 40))	('CCND1', 'Gene', '595', (35, 40))
32766	32903763	Based on the hallmark gene sets, Gene Set Enrichment Analysis (GSEA) software version 3.0 (Broad Institute) was used to identify the different regulated pathways between the CCND1 amplification and neutral groups in the TCGA pan-cancer cohort ( NES  > 1, NOM P-value <0.10, FDR q-value <0.25).	('GSEA', 'Chemical', '-', (63, 67))	('amplification', 'Var', (180, 193))	('CCND1', 'Gene', '595', (174, 179))	('cancer', 'Disease', (229, 235))	('cancer', 'Disease', 'MESH:D009369', (229, 235))	('CCND1', 'Gene', (174, 179))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))
32772	32903763	Gene expression analysis from the TCGA database showed that CCND1 amplification was significantly related to the upregulation of mRNA expression of CCND1 across the top nine cancer types (TCGA pan-cancer: cancers with CCND1 amplification frequency ranked first to 10th; CHOL was excluded because of the limited number of samples) (Figure 1B).	('cancer', 'Disease', 'MESH:D009369', (205, 211))	('cancer', 'Disease', 'MESH:D009369', (197, 203))	('cancers', 'Disease', 'MESH:D009369', (205, 212))	('CCND1', 'Gene', (218, 223))	('CCND1', 'Gene', (60, 65))	('CHOL', 'Disease', (270, 274))	('mRNA expression', 'MPA', (129, 144))	('cancer', 'Disease', (174, 180))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('cancers', 'Phenotype', 'HP:0002664', (205, 212))	('amplification', 'Var', (66, 79))	('cancer', 'Disease', (205, 211))	('cancer', 'Disease', (197, 203))	('cancers', 'Disease', (205, 212))	('CCND1', 'Gene', '595', (148, 153))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('CCND1', 'Gene', (148, 153))	('upregulation', 'PosReg', (113, 125))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('CHOL', 'Disease', 'None', (270, 274))	('CCND1', 'Gene', '595', (218, 223))	('CCND1', 'Gene', '595', (60, 65))
32773	32903763	Next, we examined the association of CCND1 amplification with clinical outcome for pan-cancer in the TCGA and MSKCC databases.	('cancer', 'Disease', (87, 93))	('CCND1', 'Gene', (37, 42))	('amplification', 'Var', (43, 56))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('CCND1', 'Gene', '595', (37, 42))	('cancer', 'Disease', 'MESH:D009369', (87, 93))
32774	32903763	Kaplan-Meier survival analysis showed that CCND1 amplification was not associated with median OS for pan-cancer in the TCGA database.	('amplification', 'Var', (49, 62))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('CCND1', 'Gene', (43, 48))	('median OS', 'Disease', (87, 96))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('CCND1', 'Gene', '595', (43, 48))
32775	32903763	The median OS for the CCND1 amplification and CCND1 neutral groups was 1,838.0 and 2,133.0 days, respectively [P = 0.1305, HR 1.13 (95% CI 0.96-1.32); Figure 1C].	('CCND1', 'Gene', (46, 51))	('CCND1', 'Gene', (22, 27))	('CCND1', 'Gene', '595', (46, 51))	('CCND1', 'Gene', '595', (22, 27))	('amplification', 'Var', (28, 41))
32779	32903763	For melanoma in the MSKCC database, the median OS for the CCND1 amplification and CCND1 neutral groups was 13.5 months and not reached [P = 0.0139, HR 2.56 (95% CI 0.79-8.29); Figure S1B].	('CCND1', 'Gene', '595', (58, 63))	('CCND1', 'Gene', (58, 63))	('CCND1', 'Gene', (82, 87))	('amplification', 'Var', (64, 77))	('melanoma', 'Disease', 'MESH:D008545', (4, 12))	('melanoma', 'Phenotype', 'HP:0002861', (4, 12))	('CCND1', 'Gene', '595', (82, 87))	('melanoma', 'Disease', (4, 12))
32785	32903763	Based on the impact of CCND1 amplification as a negative prognostic factor for efficacy of ICIs in melanoma, we further investigated its role in patients with a solid tumor.	('patients', 'Species', '9606', (145, 153))	('amplification', 'Var', (29, 42))	('CCND1', 'Gene', (23, 28))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('negative', 'NegReg', (48, 56))	('CCND1', 'Gene', '595', (23, 28))	('melanoma', 'Phenotype', 'HP:0002861', (99, 107))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('melanoma', 'Disease', (99, 107))	('melanoma', 'Disease', 'MESH:D008545', (99, 107))	('tumor', 'Disease', (167, 172))
32786	32903763	To validate CCND1 amplification as a clinical factor associated with poor prognosis in patients with solid tumors treated with ICIs, we performed three analyses.	('solid tumors', 'Disease', 'MESH:D009369', (101, 113))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('CCND1', 'Gene', (12, 17))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('CCND1', 'Gene', '595', (12, 17))	('solid tumors', 'Disease', (101, 113))	('amplification', 'Var', (18, 31))	('patients', 'Species', '9606', (87, 95))
32788	32903763	Fifty-two patients with CCND1 amplification were identified comprising of 14 melanomas, 11 head and neck carcinomas (HNCs), 11 bladder carcinomas, eight non-small-cell lung carcinomas, five breast carcinomas, three esophagogastric carcinomas, and one glioma (Table S3).	('melanomas', 'Disease', (77, 86))	('carcinoma', 'Phenotype', 'HP:0030731', (231, 240))	('glioma', 'Disease', 'MESH:D005910', (251, 257))	('amplification', 'Var', (30, 43))	('carcinomas', 'Disease', 'MESH:D009369', (105, 115))	('lung carcinomas', 'Disease', 'MESH:D008175', (168, 183))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('carcinomas', 'Disease', (173, 183))	('carcinomas', 'Phenotype', 'HP:0030731', (105, 115))	('carcinomas', 'Disease', (197, 207))	('lung carcinomas', 'Disease', (168, 183))	('CCND1', 'Gene', '595', (24, 29))	('carcinomas', 'Disease', 'MESH:D009369', (135, 145))	('glioma', 'Phenotype', 'HP:0009733', (251, 257))	('neck carcinomas', 'Disease', 'MESH:D006258', (100, 115))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('head and neck carcinomas', 'Phenotype', 'HP:0012288', (91, 115))	('carcinomas', 'Phenotype', 'HP:0030731', (135, 145))	('HNCs', 'Phenotype', 'HP:0012288', (117, 121))	('melanomas', 'Phenotype', 'HP:0002861', (77, 86))	('carcinomas', 'Disease', 'MESH:D009369', (231, 241))	('carcinomas', 'Phenotype', 'HP:0030731', (231, 241))	('breast carcinomas', 'Disease', 'MESH:D001943', (190, 207))	('CCND1', 'Gene', (24, 29))	('breast carcinomas', 'Disease', (190, 207))	('neck carcinomas', 'Disease', (100, 115))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (127, 144))	('carcinomas', 'Disease', 'MESH:D009369', (173, 183))	('esophagogastric', 'Disease', (215, 230))	('carcinoma', 'Phenotype', 'HP:0030731', (173, 182))	('carcinomas', 'Phenotype', 'HP:0030731', (173, 183))	('melanoma', 'Phenotype', 'HP:0002861', (77, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (197, 206))	('carcinomas', 'Disease', 'MESH:D009369', (197, 207))	('carcinomas', 'Phenotype', 'HP:0030731', (197, 207))	('bladder carcinomas', 'Phenotype', 'HP:0002862', (127, 145))	('patients', 'Species', '9606', (10, 18))	('carcinomas', 'Disease', (105, 115))	('breast carcinomas', 'Phenotype', 'HP:0003002', (190, 207))	('bladder carcinomas', 'Disease', 'MESH:D001749', (127, 145))	('breast carcinoma', 'Phenotype', 'HP:0003002', (190, 206))	('small-cell lung carcinomas', 'Phenotype', 'HP:0030357', (157, 183))	('melanomas', 'Disease', 'MESH:D008545', (77, 86))	('carcinomas', 'Disease', (135, 145))	('non-small-cell lung carcinomas', 'Phenotype', 'HP:0030358', (153, 183))	('carcinomas', 'Disease', (231, 241))	('glioma', 'Disease', (251, 257))	('bladder carcinomas', 'Disease', (127, 145))
32789	32903763	Across the entire cohort, CCND1 amplification was associated with a decreased OS.	('CCND1', 'Gene', (26, 31))	('decreased', 'NegReg', (68, 77))	('amplification', 'Var', (32, 45))	('CCND1', 'Gene', '595', (26, 31))
32790	32903763	The median OS for the CCND1 amplification and CCND1 neutral groups was 11.0 and 18.0 months, respectively [P = 0.0024, HR 1.63 (95% CI 1.09-2.43); Figure 2B].	('CCND1', 'Gene', (46, 51))	('CCND1', 'Gene', (22, 27))	('CCND1', 'Gene', '595', (46, 51))	('CCND1', 'Gene', '595', (22, 27))	('amplification', 'Var', (28, 41))
32791	32903763	We performed a stratified analysis with the melanoma (n = 231) and bladder carcinoma patients (n = 111) and observed a similar association between CCND1 amplification with a shorter OS.	('CCND1', 'Gene', '595', (147, 152))	('melanoma', 'Phenotype', 'HP:0002861', (44, 52))	('amplification', 'Var', (153, 166))	('melanoma', 'Disease', (44, 52))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (67, 84))	('melanoma', 'Disease', 'MESH:D008545', (44, 52))	('patients', 'Species', '9606', (85, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('bladder carcinoma', 'Disease', 'MESH:D001749', (67, 84))	('CCND1', 'Gene', (147, 152))	('bladder carcinoma', 'Disease', (67, 84))
32792	32903763	In melanoma (n = 231), the median OS for the CCND1 amplification and CCND1 neutral groups was 22.0 and 42.0 months [P = 0.0029, HR 2.48 (95% CI 0.99-6.23); Figure S1D].	('CCND1', 'Gene', (45, 50))	('CCND1', 'Gene', '595', (69, 74))	('CCND1', 'Gene', '595', (45, 50))	('melanoma', 'Disease', (3, 11))	('melanoma', 'Phenotype', 'HP:0002861', (3, 11))	('CCND1', 'Gene', (69, 74))	('melanoma', 'Disease', 'MESH:D008545', (3, 11))	('amplification', 'Var', (51, 64))
32793	32903763	In bladder carcinoma (n = 111), the median OS for the CCND1 amplification and CCND1 neutral groups was 8.0 and 16.0 months, respectively [P = 0.0244, HR 2.17 (95% CI 0.83-5.66); Figure S1E].	('bladder carcinoma', 'Phenotype', 'HP:0002862', (3, 20))	('amplification', 'Var', (60, 73))	('bladder carcinoma', 'Disease', (3, 20))	('bladder carcinoma', 'Disease', 'MESH:D001749', (3, 20))	('CCND1', 'Gene', (78, 83))	('CCND1', 'Gene', (54, 59))	('CCND1', 'Gene', '595', (78, 83))	('CCND1', 'Gene', '595', (54, 59))	('carcinoma', 'Phenotype', 'HP:0030731', (11, 20))
32794	32903763	Recent studies have shown that a high level of TMB associates with improved survival in patients receiving ICIs across a wide variety of cancer types.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('TMB', 'Chemical', '-', (47, 50))	('high', 'Var', (33, 37))	('survival', 'MPA', (76, 84))	('patients', 'Species', '9606', (88, 96))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('cancer', 'Disease', (137, 143))	('TMB', 'MPA', (47, 50))	('improved', 'PosReg', (67, 75))
32797	32903763	The median TMB for the CCND1 amplification and CCND1 neutral groups was 6.79 vs. 5.90 (P = 0.46; Figure S2).	('amplification', 'Var', (29, 42))	('TMB', 'Chemical', '-', (11, 14))	('CCND1', 'Gene', (23, 28))	('CCND1', 'Gene', (47, 52))	('CCND1', 'Gene', '595', (23, 28))	('CCND1', 'Gene', '595', (47, 52))	('TMB', 'MPA', (11, 14))
32800	32903763	Of note, according to a study by Robert M. Samstein et al., in patients treated with ICIs, there is a significant association between a high level of TMB and a better OS.	('high', 'Var', (136, 140))	('better', 'Disease', (160, 166))	('TMB', 'MPA', (150, 153))	('patients', 'Species', '9606', (63, 71))	('TMB', 'Chemical', '-', (150, 153))
32801	32903763	But in our stratified analysis, in spite of a high level of TMB, patients with CCND1 amplification have a significantly decreased median OS [10.0 vs. 41.0 months, HR 2.82 (95% CI 1.11-7.20), P = 0.0003; Figure 2D].	('decreased', 'NegReg', (120, 129))	('CCND1', 'Gene', '595', (79, 84))	('median OS', 'MPA', (130, 139))	('amplification', 'Var', (85, 98))	('patients', 'Species', '9606', (65, 73))	('CCND1', 'Gene', (79, 84))	('TMB', 'Chemical', '-', (60, 63))
32802	32903763	Finally, a multivariable analysis using Cox proportional-hazards regression demonstrated that CCND1 amplification was significantly associated with a shorter median OS [HR 1.60 (95% CI 1.16-2.21), P = 0.0040], with adjustment for TMB, cancer type, age, drug class of ICI, and the year of ICI start (Table S4).	('amplification', 'Var', (100, 113))	('TMB', 'Chemical', '-', (230, 233))	('CCND1', 'Gene', (94, 99))	('cancer', 'Disease', (235, 241))	('cancer', 'Disease', 'MESH:D009369', (235, 241))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))	('median OS [', 'MPA', (158, 169))	('CCND1', 'Gene', '595', (94, 99))	('shorter', 'NegReg', (150, 157))
32804	32903763	reported 319 patients with CCND1 amplification and 46 cases received ICIs.	('CCND1', 'Gene', (27, 32))	('amplification', 'Var', (33, 46))	('CCND1', 'Gene', '595', (27, 32))	('patients', 'Species', '9606', (13, 21))
32815	32903763	For example, the median values of B cells (-0.1870 vs. -0.1691, P < 0.001), T cells (-0.2160 vs. -0.1935, P = 0.0090), CD8+ T cells (0.0914 vs. 0.1009, P < 0.001), and DC cells (-0.1810 vs. -0.1465, P = 0.0170) were significantly attenuated in the CCND1 amplification group in breast cancer, while Th2 cells (0.05419 vs. 0.0148, P < 0.001) and MDSCs (0.0051 vs. -0.0198, P = 0.0094) appear upregulated (Figure S4).	('breast cancer', 'Disease', 'MESH:D001943', (277, 290))	('-0.1870', 'Var', (43, 50))	('CCND1', 'Gene', '595', (248, 253))	('breast cancer', 'Phenotype', 'HP:0003002', (277, 290))	('CD8', 'Gene', (119, 122))	('breast cancer', 'Disease', (277, 290))	('attenuated', 'NegReg', (230, 240))	('CD8', 'Gene', '925', (119, 122))	('0.0051 vs. -0.0198', 'Var', (351, 369))	('cancer', 'Phenotype', 'HP:0002664', (284, 290))	('0.05419', 'Var', (309, 316))	('CCND1', 'Gene', (248, 253))	('upregulated', 'PosReg', (390, 401))	('-0.2160', 'Var', (85, 92))
32816	32903763	The signature of immune cell subsets in HNSCC showed a dramatic decrease in median values of cytotoxic cells (-0.1418 vs. -0.0970, P = 0.0030), T cells (-0.2357 vs. -0.2056, P = 0.0010), CD8+ T cells (0.0730 vs. 0.0761, P = 0.1310), DC cells (-0.2267 vs. -0.1796, P < 0.001), and B cells (-0.1676 vs. -0.1373, P < 0.001), while MDSCs (0.0250 vs. -0.0058, P < 0.001) (Figure S4).	('decrease', 'NegReg', (64, 72))	('-0.1676', 'Var', (289, 296))	('-0.1418', 'Var', (110, 117))	('B cells', 'CPA', (280, 287))	('-0.2357', 'Var', (153, 160))	('DC cells', 'CPA', (233, 241))	('CD8', 'Gene', (187, 190))	('HNSCC', 'Phenotype', 'HP:0012288', (40, 45))	('CD8', 'Gene', '925', (187, 190))	('T cells', 'CPA', (144, 151))	('0.0730 vs. 0.0761', 'Var', (201, 218))
32817	32903763	To investigate signaling pathways activated for CCND1 amplification tumors, we performed GSEA comparing the CCND1 amplification group and the CCND1 neutral group in the TCGA pan-cancer cohort.	('CCND1', 'Gene', (142, 147))	('amplification', 'Var', (114, 127))	('tumors', 'Disease', (68, 74))	('CCND1', 'Gene', (108, 113))	('CCND1', 'Gene', '595', (48, 53))	('tumors', 'Disease', 'MESH:D009369', (68, 74))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('CCND1', 'Gene', '595', (142, 147))	('GSEA', 'Chemical', '-', (89, 93))	('CCND1', 'Gene', '595', (108, 113))	('cancer', 'Disease', (178, 184))	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('CCND1', 'Gene', (48, 53))
32824	32903763	Another study showed that cyclin D1 (encoded by CCND1) may play a key role in the maintenance of VEGFs, and antisense to cyclin D1 could be useful for targeting both cancer cells and blood vessels in tumors.	('antisense', 'Var', (108, 117))	('cyclin D1', 'Gene', (121, 130))	('cancer', 'Disease', (166, 172))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('CCND1', 'Gene', '595', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('tumors', 'Phenotype', 'HP:0002664', (200, 206))	('cyclin D1', 'Gene', '595', (26, 35))	('tumors', 'Disease', (200, 206))	('cyclin D1', 'Gene', (26, 35))	('tumors', 'Disease', 'MESH:D009369', (200, 206))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('cyclin D1', 'Gene', '595', (121, 130))	('CCND1', 'Gene', (48, 53))
32827	32903763	We found that CCND1 amplification can hinder not only the natural host immune response but also the efficacy of ICIs.	('CCND1', 'Gene', '595', (14, 19))	('hinder', 'NegReg', (38, 44))	('ICIs', 'CPA', (112, 116))	('amplification', 'Var', (20, 33))	('CCND1', 'Gene', (14, 19))
32828	32903763	A CCND1 amplification may potentially identify a patient population that will not benefit from ICIs irrespective of TMB status.	('TMB', 'Chemical', '-', (116, 119))	('amplification', 'Var', (8, 21))	('CCND1', 'Gene', (2, 7))	('patient', 'Species', '9606', (49, 56))	('CCND1', 'Gene', '595', (2, 7))
32830	32903763	To our knowledge, our results are the first to reveal that a CCND1 amplification may significantly correlate with tumorigenesis and attenuation of various types of effector immune cells in the TME, including cytotoxic cells, T cells, CD8+ T cells, DC cells, and B cells, and upregulation of Treg cells and MDSCs.	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('attenuation', 'NegReg', (132, 143))	('amplification', 'Var', (67, 80))	('CCND1', 'Gene', (61, 66))	('Treg cells', 'CPA', (291, 301))	('CD8', 'Gene', (234, 237))	('tumor', 'Disease', (114, 119))	('CD8', 'Gene', '925', (234, 237))	('CCND1', 'Gene', '595', (61, 66))	('upregulation', 'PosReg', (275, 287))
32833	32903763	In our analysis of the TCGA pan-cancer cohort, CCND1 amplification showed a statistically significant correlation with high mRNA expression of TGFB1.	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('cancer', 'Disease', (32, 38))	('amplification', 'Var', (53, 66))	('CCND1', 'Gene', (47, 52))	('TGFB1', 'Gene', (143, 148))	('high mRNA expression', 'MPA', (119, 139))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('CCND1', 'Gene', '595', (47, 52))	('TGFB1', 'Gene', '7040', (143, 148))
32834	32903763	More importantly, further study showed significant upregulation of mRNA expression of VEGFA, another known factor inducing tumor immune escape and immunotherapy resistance, associated with the CCND1 amplification phenotype.	('upregulation', 'PosReg', (51, 63))	('tumor', 'Disease', (123, 128))	('VEGFA', 'Gene', (86, 91))	('amplification phenotype', 'Var', (199, 222))	('CCND1', 'Gene', (193, 198))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('VEGFA', 'Gene', '7422', (86, 91))	('CCND1', 'Gene', '595', (193, 198))	('mRNA expression', 'MPA', (67, 82))
32835	32903763	From the survival analysis in TCGA and MSKCC public databases, we found no significant correlation between CCND1 amplification with prognosis in the pan-cancer group.	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('cancer', 'Disease', (153, 159))	('CCND1', 'Gene', '595', (107, 112))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('amplification', 'Var', (113, 126))	('CCND1', 'Gene', (107, 112))
32840	32903763	Meanwhile, the analysis of the transcriptome showed that the amplification of CCND1 was strongly correlated with higher expression level of mRNA.	('expression level of mRNA', 'MPA', (120, 144))	('CCND1', 'Gene', (78, 83))	('higher', 'PosReg', (113, 119))	('amplification', 'Var', (61, 74))	('CCND1', 'Gene', '595', (78, 83))
32841	32903763	Thirdly, according to our investigation, activations of a variety of oncogenes and deactivations of tumor suppressor genes were observed along with the amplification of CCND1 in different cancer types.	('amplification', 'Var', (152, 165))	('deactivations', 'MPA', (83, 96))	('activations', 'PosReg', (41, 52))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('CCND1', 'Gene', (169, 174))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Disease', (100, 105))	('CCND1', 'Gene', '595', (169, 174))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('cancer', 'Disease', (188, 194))	('oncogenes', 'Gene', (69, 78))	('tumor', 'Disease', 'MESH:D009369', (100, 105))
32843	32903763	Nevertheless, the CCND1 amplification is a potential predictive biomarker for the use of ICIs in patients with solid tumors.	('solid tumors', 'Disease', 'MESH:D009369', (111, 123))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('CCND1', 'Gene', '595', (18, 23))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('amplification', 'Var', (24, 37))	('CCND1', 'Gene', (18, 23))	('solid tumors', 'Disease', (111, 123))	('patients', 'Species', '9606', (97, 105))
32844	32903763	In the melanoma pooled cohort, the median OS was shorter in the CCND1 amplification subgroup.	('melanoma', 'Disease', 'MESH:D008545', (7, 15))	('shorter', 'NegReg', (49, 56))	('median OS', 'MPA', (35, 44))	('CCND1', 'Gene', (64, 69))	('CCND1', 'Gene', '595', (64, 69))	('melanoma', 'Phenotype', 'HP:0002861', (7, 15))	('melanoma', 'Disease', (7, 15))	('amplification', 'Var', (70, 83))
32845	32903763	The survival analysis in the MSKCC-IO cohort further verified the negative impact of CCND1 amplification on the efficacy of ICIs.	('ICIs', 'CPA', (124, 128))	('CCND1', 'Gene', '595', (85, 90))	('amplification', 'Var', (91, 104))	('CCND1', 'Gene', (85, 90))	('negative', 'NegReg', (66, 74))
32846	32903763	Strikingly, by comparing CCND1 amplification with TMB in patients with solid tumors from the MSKCC-IO cohort, we found that the association between CCND1 amplification and a worse clinical outcome was more distinct in TMB-high patients.	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('CCND1', 'Gene', (25, 30))	('CCND1', 'Gene', (148, 153))	('solid tumors', 'Disease', (71, 83))	('patients', 'Species', '9606', (57, 65))	('CCND1', 'Gene', '595', (25, 30))	('CCND1', 'Gene', '595', (148, 153))	('patients', 'Species', '9606', (227, 235))	('amplification', 'Var', (154, 167))	('solid tumors', 'Disease', 'MESH:D009369', (71, 83))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('TMB', 'Chemical', '-', (50, 53))	('TMB', 'Chemical', '-', (218, 221))	('TMB-high', 'Disease', (218, 226))
32847	32903763	This indicates that ICIs may not be useful, and even harmful, to patients with CCND1 amplification.	('CCND1', 'Gene', '595', (79, 84))	('amplification', 'Var', (85, 98))	('patients', 'Species', '9606', (65, 73))	('CCND1', 'Gene', (79, 84))
32848	32903763	First, various types of effector immune cell exclusion and immunosuppression in the TME were found in tumors with CCND1 amplification.	('tumors', 'Disease', 'MESH:D009369', (102, 108))	('tumors', 'Disease', (102, 108))	('CCND1', 'Gene', (114, 119))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('CCND1', 'Gene', '595', (114, 119))	('amplification', 'Var', (120, 133))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))
32849	32903763	Second, CCND1 amplification results in high mRNA expression of TGFB1, VEGFA, and HIF1A; these molecules have direct or indirect negative effects on components of the immune system.	('TGFB1', 'Gene', '7040', (63, 68))	('VEGFA', 'Gene', (70, 75))	('HIF1A', 'Gene', (81, 86))	('CCND1', 'Gene', (8, 13))	('HIF1A', 'Gene', '3091', (81, 86))	('mRNA expression', 'MPA', (44, 59))	('TGFB1', 'Gene', (63, 68))	('negative', 'NegReg', (128, 136))	('VEGFA', 'Gene', '7422', (70, 75))	('CCND1', 'Gene', '595', (8, 13))	('amplification', 'Var', (14, 27))
32850	32903763	Finally, some oncogene pathways are activated in CCND1 amplification tumor that may lead to acceleration of tumor growth.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('amplification', 'Var', (55, 68))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('CCND1', 'Gene', '595', (49, 54))	('tumor', 'Disease', (69, 74))	('oncogene pathways', 'Pathway', (14, 31))	('activated', 'PosReg', (36, 45))	('tumor', 'Disease', (108, 113))	('acceleration', 'PosReg', (92, 104))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('CCND1', 'Gene', (49, 54))
32851	32903763	Recently, a study reported on five patients experiencing hyper-progression who had NGS performed on pretreatment tumor tissue, and it confirmed CNAs in MDM2/MDM4, epidermal growth factor receptor (EGFR), and several genes located on 11q13 associated with hyper-progression.	('associated', 'Reg', (239, 249))	('tumor', 'Disease', (113, 118))	('MDM4', 'Gene', (157, 161))	('MDM4', 'Gene', '4194', (157, 161))	('epidermal growth factor receptor', 'Gene', '1956', (163, 195))	('epidermal growth factor receptor', 'Gene', (163, 195))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('EGFR', 'Gene', '1956', (197, 201))	('patients', 'Species', '9606', (35, 43))	('CNAs', 'Var', (144, 148))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('MDM2', 'Gene', '4193', (152, 156))	('EGFR', 'Gene', (197, 201))	('MDM2', 'Gene', (152, 156))
32853	32903763	Considering the immunosuppression in the TME and overexpression of various oncogenes caused by CCND1 amplification, patients with such features should avoid ICI monotherapy.	('patients', 'Species', '9606', (116, 124))	('CCND1', 'Gene', (95, 100))	('amplification', 'Var', (101, 114))	('CCND1', 'Gene', '595', (95, 100))
32856	32903763	The small number of CCND1 amplification tumors and the rarity of the event suggest that further additional data are warranted.	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('amplification', 'Var', (26, 39))	('CCND1', 'Gene', (20, 25))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumors', 'Disease', (40, 46))	('tumors', 'Disease', 'MESH:D009369', (40, 46))	('CCND1', 'Gene', '595', (20, 25))
32857	32903763	Our study is a preliminary investigation mainly focused on the predictive function of CCND1 amplification in the tumor microenvironment in the aspect of genome and transcriptome.	('CCND1', 'Gene', (86, 91))	('tumor', 'Disease', (113, 118))	('CCND1', 'Gene', '595', (86, 91))	('amplification', 'Var', (92, 105))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))
32860	32903763	These findings indicate that CCND1 amplification may be a key point related to immunosuppression in the TME and multiple malignancy hallmark; it may be a common mechanism of resistance to ICIs.	('malignancy hallmark', 'Disease', (121, 140))	('amplification', 'Var', (35, 48))	('malignancy hallmark', 'Disease', 'MESH:D009369', (121, 140))	('CCND1', 'Gene', (29, 34))	('related', 'Reg', (68, 75))	('CCND1', 'Gene', '595', (29, 34))
32891	32082366	Seven patients (TCGA-B8-5552, TCGA-CJ-5679, TCGA-CJ-5680, TCGA-CJ-5681, TCGA-CW-5591, TCGA-CZ-5456, TCGA-CZ-5469) are excluded due to inconsistent expression patterns.	('TCGA-CJ-5679', 'CellLine', 'CVCL:C316', (30, 42))	('TCGA-CJ-5680', 'Var', (44, 56))	('patients', 'Species', '9606', (6, 14))	('TCGA-CJ-5681', 'Var', (58, 70))	('TCGA-CJ-5681', 'CellLine', 'CVCL:C316', (58, 70))
32901	32082366	Notably, many studies have shown that aberrant Akt activation is associated with the development of many tumors.	('tumors', 'Disease', (105, 111))	('tumors', 'Disease', 'MESH:D009369', (105, 111))	('Akt', 'Gene', '207', (47, 50))	('aberrant', 'Var', (38, 46))	('associated', 'Reg', (65, 75))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('Akt', 'Gene', (47, 50))	('activation', 'PosReg', (51, 61))
32925	30760718	Here we comprehensively analyze the genomic alterations of the genes encoding histone acetylation modulator proteins (HAMPs) in the Cancer Genome Atlas cohort and observe that HAMPs have a high frequency of focal copy number alterations and recurrent mutations, whereas transcript fusions of HAMPs are relatively rare genomic events in common adult cancers.	('cancer', 'Phenotype', 'HP:0002664', (349, 355))	('mutations', 'Var', (251, 260))	('Cancer Genome Atlas cohort', 'Disease', 'MESH:D009369', (132, 158))	('cancers', 'Phenotype', 'HP:0002664', (349, 356))	('Cancer Genome Atlas cohort', 'Disease', (132, 158))	('focal', 'MPA', (207, 212))	('adult cancers', 'Disease', (343, 356))	('HAMP', 'Gene', '57817', (292, 296))	('adult cancers', 'Disease', 'MESH:C535836', (343, 356))	('HAMP', 'Gene', (292, 296))	('Cancer', 'Phenotype', 'HP:0002664', (132, 138))	('HAMP', 'Gene', '57817', (176, 180))	('HAMP', 'Gene', '57817', (118, 122))	('HAMP', 'Gene', (176, 180))	('HAMP', 'Gene', (118, 122))
32927	30760718	For example, the recurrent focal amplification of BRD9 is observed in 9 cancer types and genetic depletion of BRD9 inhibits tumor growth.	('genetic depletion', 'Var', (89, 106))	('BRD9', 'Gene', '65980', (50, 54))	('tumor', 'Disease', 'MESH:D009369', (124, 129))	('BRD9', 'Gene', (110, 114))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('tumor', 'Disease', (124, 129))	('BRD9', 'Gene', (50, 54))	('inhibits', 'NegReg', (115, 123))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('BRD9', 'Gene', '65980', (110, 114))	('cancer', 'Disease', (72, 78))
32975	30760718	BRD9, BRD4, KAT6A, ATAD2, CLOCK, ASH1L, and BPTF showed high overall G-scores for copy number gain, whereas HDAC4, BRD1, SIRT3, HDAC10, SP100, SP140L, SP110, and PBRM1 had high overall G-scores for copy number loss (overall G-score > 0.9; Fig.	('BRD4', 'Gene', '23476', (6, 10))	('BPTF', 'Gene', (44, 48))	('SP140L', 'Gene', (143, 149))	('SP110', 'Gene', '3431', (151, 156))	('ATAD2', 'Gene', (19, 24))	('KAT6A', 'Gene', '7994', (12, 17))	('HDAC10', 'Gene', '83933', (128, 134))	('SIRT3', 'Gene', (121, 126))	('ASH1L', 'Gene', (33, 38))	('BRD9', 'Gene', '65980', (0, 4))	('SIRT3', 'Gene', '23410', (121, 126))	('copy number gain', 'Disease', 'MESH:D015430', (82, 98))	('CLOCK', 'Gene', '9575', (26, 31))	('CLOCK', 'Gene', (26, 31))	('BRD1', 'Gene', (115, 119))	('HDAC4', 'Gene', '9759', (108, 113))	('copy number', 'Var', (198, 209))	('ASH1L', 'Gene', '55870', (33, 38))	('copy number gain', 'Disease', (82, 98))	('KAT6A', 'Gene', (12, 17))	('SP110', 'Gene', (151, 156))	('SP100', 'Gene', '6672', (136, 141))	('BRD4', 'Gene', (6, 10))	('SP140L', 'Gene', '93349', (143, 149))	('BRD9', 'Gene', (0, 4))	('PBRM1', 'Gene', '55193', (162, 167))	('ATAD2', 'Gene', '29028', (19, 24))	('BRD1', 'Gene', '23774', (115, 119))	('HDAC10', 'Gene', (128, 134))	('HDAC4', 'Gene', (108, 113))	('BPTF', 'Gene', '2186', (44, 48))	('PBRM1', 'Gene', (162, 167))	('SP100', 'Gene', (136, 141))
32977	30760718	3b); in contrast, high-level alterations (GISTIC status = - 2) were markedly less frequent in HAMPs with copy number loss (0.8-9.4%; Fig.	('HAMP', 'Gene', (94, 98))	('HAMP', 'Gene', '57817', (94, 98))	('copy number loss', 'Var', (105, 121))
32981	30760718	The mutation call set was generated via an ensemble calling strategy by the MC3 (Multi-Center Mutation Calling in Multiple Cancers) project, then we integrated five complementary methods to identify the genes with mutations that have significant signs of positive selection during tumor evolution (Fig.	('Multiple Cancers', 'Disease', (114, 130))	('MC3', 'Gene', (76, 79))	('Multiple Cancers', 'Disease', 'MESH:D009369', (114, 130))	('MC3', 'Gene', '4159', (76, 79))	('Cancer', 'Phenotype', 'HP:0002664', (123, 129))	('Cancers', 'Phenotype', 'HP:0002664', (123, 130))	('mutations', 'Var', (214, 223))	('tumor', 'Disease', 'MESH:D009369', (281, 286))	('tumor', 'Phenotype', 'HP:0002664', (281, 286))	('tumor', 'Disease', (281, 286))
32982	30760718	Collectively, across 33 cancer types, we identified 34 HAMPs that have recurrent mutations in at least one cancer type (Fig.	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('cancer', 'Disease', (24, 30))	('cancer', 'Disease', 'MESH:D009369', (24, 30))	('HAMP', 'Gene', '57817', (55, 59))	('HAMP', 'Gene', (55, 59))	('mutations', 'Var', (81, 90))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('cancer', 'Disease', (107, 113))
32984	30760718	3b), the recurrent mutations of HAMPs were largely cancer type-specific (Fig.	('mutations', 'Var', (19, 28))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('cancer', 'Disease', (51, 57))	('HAMP', 'Gene', '57817', (32, 36))	('HAMP', 'Gene', (32, 36))
32985	30760718	4b): 17 of 34 (50%) HAMPs with recurrent mutations were only observed in one cancer type and no recurrent mutation of HAMPs was found in more than 7 cancer types.	('mutations', 'Var', (41, 50))	('cancer', 'Disease', (149, 155))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('HAMP', 'Gene', '57817', (20, 24))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('HAMP', 'Gene', (20, 24))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('HAMP', 'Gene', '57817', (118, 122))	('cancer', 'Disease', 'MESH:D009369', (149, 155))	('HAMP', 'Gene', (118, 122))
32987	30760718	UCEC (n = 20), SKCM (n = 8), BLCA (n = 6), cervical squamous cell carcinoma, and endocervical adenocarcinoma (CESC; n = 6), and HNSC (n = 6) had the largest numbers of recurrent mutations in HAMPs, whereas ACC, DLBC, ESCA, KICH, LAML, LGG, mesothelioma (MESO), OV, PAAD, PCPG, READ, SARC, TGCT, THCA, THYM, UCS, and UVM had none (Fig.	('READ', 'Disease', 'None', (277, 281))	('carcinoma', 'Phenotype', 'HP:0030731', (66, 75))	('KICH', 'Disease', (223, 227))	('PAAD', 'Phenotype', 'HP:0006725', (265, 269))	('cervical squamous cell carcinoma', 'Disease', (43, 75))	('UCS', 'Phenotype', 'HP:0002891', (307, 310))	('OV', 'Phenotype', 'HP:0012887', (261, 263))	('mesothelioma', 'Disease', (240, 252))	('endocervical adenocarcinoma', 'Disease', 'MESH:D000230', (81, 108))	('cervical squamous cell carcinoma', 'Disease', 'MESH:D002294', (43, 75))	('HAMP', 'Gene', '57817', (191, 195))	('mesothelioma', 'Disease', 'MESH:D008654', (240, 252))	('ACC', 'Phenotype', 'HP:0006744', (206, 209))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (52, 75))	('ESCA', 'Phenotype', 'HP:0011459', (217, 221))	('READ', 'Disease', (277, 281))	('KICH', 'Disease', 'None', (223, 227))	('HAMP', 'Gene', (191, 195))	('THYM', 'Phenotype', 'HP:0100522', (301, 305))	('THCA', 'Phenotype', 'HP:0002890', (295, 299))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('mutations', 'Var', (178, 187))	('endocervical adenocarcinoma', 'Disease', (81, 108))
32988	30760718	Among the three types of HAMPs, BRD proteins and HATs had the highest frequencies of recurrent mutations and HDACs had few recurrent events (Fig.	('HAMP', 'Gene', '57817', (25, 29))	('HDAC', 'Gene', (109, 113))	('HAMP', 'Gene', (25, 29))	('HDAC', 'Gene', '9734', (109, 113))	('mutations', 'Var', (95, 104))
32990	30760718	Among eight HAMPs with M-scores > 0.4, EP300, PBRM1, and CREBBP had the largest overall M-scores across the 33 cancer types (Fig.	('CREBBP', 'Gene', (57, 63))	('HAMP', 'Gene', '57817', (12, 16))	('HAMP', 'Gene', (12, 16))	('M-scores', 'MPA', (88, 96))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('CREBBP', 'Gene', '1387', (57, 63))	('PBRM1', 'Gene', (46, 51))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('EP300', 'Gene', (39, 44))	('EP300', 'Gene', '2033', (39, 44))	('PBRM1', 'Gene', '55193', (46, 51))	('M-scores > 0.4', 'Var', (23, 37))
32992	30760718	At a pan-cancer level, except for PBRM1, the most common mutation category of HAMPs was missense mutation (53.0-77.5%; Fig.	('cancer', 'Disease', (9, 15))	('HAMP', 'Gene', (78, 82))	('PBRM1', 'Gene', (34, 39))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('PBRM1', 'Gene', '55193', (34, 39))	('missense mutation', 'Var', (88, 105))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('HAMP', 'Gene', '57817', (78, 82))
32993	30760718	In contrast, PBRM1 was most commonly affected by truncating mutations (49.1%; Fig.	('affected', 'Reg', (37, 45))	('PBRM1', 'Gene', (13, 18))	('PBRM1', 'Gene', '55193', (13, 18))	('truncating mutations', 'Var', (49, 69))
32994	30760718	Using the ABSOLUTE algorithm, we also determined the timing of the mutational processes and the clonal statuses of the mutations in HAMPs.	('HAMP', 'Gene', (132, 136))	('mutations', 'Var', (119, 128))	('HAMP', 'Gene', '57817', (132, 136))
32995	30760718	More than 50% of mutations in HAMPs were early genomic events (Fig.	('HAMP', 'Gene', '57817', (30, 34))	('mutations', 'Var', (17, 26))	('HAMP', 'Gene', (30, 34))
32996	30760718	5d and Supplementary Data 15) and more than 65% of mutations in HAMPs were clonal mutations (Fig.	('HAMP', 'Gene', (64, 68))	('mutations', 'Var', (51, 60))	('HAMP', 'Gene', '57817', (64, 68))
32998	30760718	We also analyzed the distributions of the mutations across the gene bodies and found that mutations in HAMPs were widely spatially distributed along the entire coding sequences, not concentrated within a specific local region (Fig.	('HAMP', 'Gene', '57817', (103, 107))	('mutations', 'Var', (90, 99))	('HAMP', 'Gene', (103, 107))
33001	30760718	Notably, we observed that PBRM1 mutations showed a unique pattern in KIRC and cholangiocarcinoma (CHOL).	('CHOL', 'Phenotype', 'HP:0030153', (98, 102))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (78, 96))	('PBRM1', 'Gene', (26, 31))	('PBRM1', 'Gene', '55193', (26, 31))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (78, 96))	('mutations', 'Var', (32, 41))	('KIRC', 'Disease', (69, 73))	('cholangiocarcinoma', 'Disease', (78, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))
33002	30760718	Compared with other cancer types, KIRC and CHOL showed higher frequencies of PBRM1 mutations (40.1% in KIRC and 19.4% in CHOL vs. an average of 2.3% among other cancer types).	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('mutations', 'Var', (83, 92))	('PBRM1', 'Gene', (77, 82))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('PBRM1', 'Gene', '55193', (77, 82))	('cancer', 'Disease', 'MESH:D009369', (20, 26))	('CHOL', 'Phenotype', 'HP:0030153', (121, 125))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('cancer', 'Disease', (20, 26))	('cancer', 'Disease', (161, 167))	('CHOL', 'Phenotype', 'HP:0030153', (43, 47))
33003	30760718	Importantly, the dominant PBRM1 mutation category and type in KIRC and CHOL were truncating (83.9% and 85.7%, respectively) and homozygous (85.2% and 71.4%, respectively) mutations, which were remarkably higher than the averages in other cancer types (30.3% and 19.4%, respectively).	('cancer', 'Disease', (238, 244))	('cancer', 'Disease', 'MESH:D009369', (238, 244))	('PBRM1', 'Gene', (26, 31))	('PBRM1', 'Gene', '55193', (26, 31))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('truncating', 'MPA', (81, 91))	('mutation', 'Var', (32, 40))	('CHOL', 'Phenotype', 'HP:0030153', (71, 75))
33004	30760718	Interestingly, we observed that, in both the CREBBP and EP300 genes, the most frequent mutations were located within the catalytic domain, although the mutations were not statistically significant hotspot mutations at the individual gene level based on OncodriveCLUST analysis (Fig.	('CREBBP', 'Gene', '1387', (45, 51))	('EP300', 'Gene', (56, 61))	('EP300', 'Gene', '2033', (56, 61))	('CREBBP', 'Gene', (45, 51))	('mutations', 'Var', (87, 96))
33011	30760718	6a and Supplementary Data 18), which suggests that transcript fusion is a rare genetic alteration compared with SCNAs and mutations in HAMPs in common adult cancers.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('adult cancers', 'Disease', 'MESH:C535836', (151, 164))	('cancers', 'Phenotype', 'HP:0002664', (157, 164))	('adult cancers', 'Disease', (151, 164))	('transcript fusion', 'Var', (51, 68))	('HAMP', 'Gene', '57817', (135, 139))	('HAMP', 'Gene', (135, 139))
33015	30760718	KAT6B-ADK (n = 6), BPTF-PITPNC1 (n = 5), and NCOA3-EYA2 (n = 5) were the most frequent fusions among the common cancer types examined in our study (Fig.	('fusions', 'Var', (87, 94))	('PITPNC1', 'Gene', '26207', (24, 31))	('cancer', 'Disease', (112, 118))	('BPTF', 'Gene', (19, 23))	('PITPNC1', 'Gene', (24, 31))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('NCOA3', 'Gene', '8202', (45, 50))	('EYA2', 'Gene', '2139', (51, 55))	('BPTF', 'Gene', '2186', (19, 23))	('EYA2', 'Gene', (51, 55))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('NCOA3', 'Gene', (45, 50))
33019	30760718	Taken together, these results suggest that, although certain HAMP transcript fusions may be actionable for clinical cancer care, transcript fusion is a rare genomic alteration compared with SCNAs and mutations of HAMPs in common cancers.	('HAMP', 'Gene', '57817', (61, 65))	('transcript fusion', 'Var', (129, 146))	('HAMP', 'Gene', (61, 65))	('cancer', 'Disease', (229, 235))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (229, 235))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('cancers', 'Disease', 'MESH:D009369', (229, 236))	('cancers', 'Disease', (229, 236))	('HAMP', 'Gene', '57817', (213, 217))	('cancers', 'Phenotype', 'HP:0002664', (229, 236))	('HAMP', 'Gene', (213, 217))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))
33023	30760718	Across the different lineages of cancers, three types of alterations were observed: (1) consistent, putative gain-of-function (such as for KAT6A and CLOCK, which were focally amplified in six and five cancer types, respectively); (2) consistent, putative loss-of-function (such as for PBRM1, which is mutated in four and focally deleted in five cancer types, and for CREBBP, which is mutated in four and focally deleted in two cancer types); and (3) diverse alterations (such as for ATAD2, which is mutated in three and focally amplified in five cancer types, and for BPTF, which is mutated in three and focally amplified in five cancer types).	('gain-of-function', 'PosReg', (109, 125))	('cancer', 'Disease', (33, 39))	('cancer', 'Disease', (201, 207))	('cancer', 'Disease', (630, 636))	('cancer', 'Disease', 'MESH:D009369', (427, 433))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('KAT6A', 'Gene', '7994', (139, 144))	('cancer', 'Disease', 'MESH:D009369', (345, 351))	('ATAD2', 'Gene', '29028', (483, 488))	('cancers', 'Phenotype', 'HP:0002664', (33, 40))	('loss-of-function', 'NegReg', (255, 271))	('cancers', 'Disease', (33, 40))	('CREBBP', 'Gene', (367, 373))	('cancer', 'Disease', (546, 552))	('PBRM1', 'Gene', '55193', (285, 290))	('cancer', 'Disease', 'MESH:D009369', (630, 636))	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('cancer', 'Disease', (427, 433))	('KAT6A', 'Gene', (139, 144))	('cancer', 'Phenotype', 'HP:0002664', (546, 552))	('ATAD2', 'Gene', (483, 488))	('PBRM1', 'Gene', (285, 290))	('cancer', 'Phenotype', 'HP:0002664', (427, 433))	('BPTF', 'Gene', '2186', (568, 572))	('CREBBP', 'Gene', '1387', (367, 373))	('cancer', 'Disease', (345, 351))	('CLOCK', 'Gene', '9575', (149, 154))	('cancer', 'Phenotype', 'HP:0002664', (345, 351))	('cancers', 'Disease', 'MESH:D009369', (33, 40))	('CLOCK', 'Gene', (149, 154))	('cancer', 'Disease', 'MESH:D009369', (546, 552))	('BPTF', 'Gene', (568, 572))	('deleted', 'Var', (329, 336))
33024	30760718	This suggests that a large fraction of HAMP alterations may be commonly shared by multiple cancer types, whereas others may be tumor-lineage dependent.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('HAMP', 'Gene', (39, 43))	('HAMP', 'Gene', '57817', (39, 43))	('multiple cancer', 'Disease', (82, 97))	('tumor', 'Disease', (127, 132))	('alterations', 'Var', (44, 55))	('multiple cancer', 'Disease', 'MESH:D009369', (82, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('tumor', 'Disease', 'MESH:D009369', (127, 132))
33053	30760718	Consistent with the GBA prediction, knocking down BRD9 expression dramatically inhibited cancer cell growth in vitro (Fig.	('BRD9', 'Gene', '65980', (50, 54))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('BRD9', 'Gene', (50, 54))	('expression', 'MPA', (55, 65))	('cancer', 'Disease', (89, 95))	('inhibited', 'NegReg', (79, 88))	('knocking down', 'Var', (36, 49))	('GBA', 'Chemical', '-', (20, 23))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
33054	30760718	Finally, we demonstrated that the expression of BRD9 shRNAs significantly suppressed the growth of subcutaneous tumors formed by MDA-MB-231 or OVCAR8 cells in nude mice (Fig.	('subcutaneous tumors', 'Disease', (99, 118))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (129, 139))	('BRD9', 'Gene', (48, 52))	('nude mice', 'Species', '10090', (159, 168))	('OV', 'Phenotype', 'HP:0012887', (143, 145))	('suppressed', 'NegReg', (74, 84))	('subcutaneous tumors', 'Phenotype', 'HP:0001482', (99, 118))	('expression', 'Var', (34, 44))	('subcutaneous tumors', 'Disease', 'MESH:D013352', (99, 118))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('growth', 'CPA', (89, 95))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('BRD9', 'Gene', '65980', (48, 52))
33055	30760718	Collectively, our results demonstrate that genetic depletion of BDR9 expression significantly represses tumor cell growth in vitro and in vivo, suggesting that small molecular compounds targeting BRD9 may have strong clinical application potentials.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('BDR9', 'Gene', (64, 68))	('tumor', 'Disease', (104, 109))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('represses', 'NegReg', (94, 103))	('BRD9', 'Gene', '65980', (196, 200))	('BRD9', 'Gene', (196, 200))	('genetic depletion', 'Var', (43, 60))
33063	30760718	A HAMP with a high score indicates its recurrent alterations are common genomic events across multiple adult cancer types.	('HAMP', 'Gene', '57817', (2, 6))	('alterations', 'Var', (49, 60))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('HAMP', 'Gene', (2, 6))	('cancer', 'Disease', (109, 115))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))
33076	30760718	Furthermore, genetic depletion of HDACs in tumor cells leads to cell cycle arrest, apoptosis, and senescence, suggesting that HDACs are required for the survival and growth of tumor cells.	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('genetic depletion', 'Var', (13, 30))	('tumor', 'Disease', (176, 181))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('senescence', 'CPA', (98, 108))	('HDAC', 'Gene', '9734', (34, 38))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (64, 81))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('apoptosis', 'CPA', (83, 92))	('tumor', 'Disease', (43, 48))	('HDAC', 'Gene', (34, 38))	('HDAC', 'Gene', (126, 130))	('tumor', 'Disease', 'MESH:D009369', (176, 181))	('cell cycle arrest', 'CPA', (64, 81))	('HDAC', 'Gene', '9734', (126, 130))
33079	30760718	For example, CREBBP and EP300 were widely mutated across multiple cancer types at relatively low frequencies; most of these mutations were heterozygous missense mutations.	('mutations', 'Var', (124, 133))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('EP300', 'Gene', (24, 29))	('EP300', 'Gene', '2033', (24, 29))	('multiple cancer', 'Disease', 'MESH:D009369', (57, 72))	('CREBBP', 'Gene', (13, 19))	('multiple cancer', 'Disease', (57, 72))	('CREBBP', 'Gene', '1387', (13, 19))
33080	30760718	In contrast, PBRM1 showed high-frequency, cancer type-specific mutations in KIRC (40.1%).	('mutations', 'Var', (63, 72))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('PBRM1', 'Gene', (13, 18))	('PBRM1', 'Gene', '55193', (13, 18))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))
33086	30760718	Collectively, our comprehensive genomic analysis identified 63 putative cancer-causing HAMPs driven by SCNAs and/or mutations (recurrent score >= 1).	('SCNAs', 'Disease', (103, 108))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('mutations', 'Var', (116, 125))	('HAMP', 'Gene', '57817', (87, 91))	('HAMP', 'Gene', (87, 91))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('cancer', 'Disease', (72, 78))
33089	30760718	For example, the breast and ovarian cancer patients with BRD4 amplifications may be potential candidates for treatment with BET inhibitors that have been successfully developed to the preclinical stage.	('BET', 'Gene', '92737', (124, 127))	('BET', 'Gene', (124, 127))	('ovarian cancer', 'Phenotype', 'HP:0100615', (28, 42))	('patients', 'Species', '9606', (43, 51))	('BRD4', 'Gene', (57, 61))	('amplifications', 'Var', (62, 76))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('BRD4', 'Gene', '23476', (57, 61))	('breast and ovarian cancer', 'Disease', 'MESH:D010051', (17, 42))
33090	30760718	In addition, eight HAMPs focally lost copy numbers (overall G-score > 0.9) and eight HAMPs showed high frequencies of mutations (overall M-score > 0.4), which indicates that their functions may be reduced and/or deficient due to partial loss of wild-type alleles during cancer development.	('HAMP', 'Gene', (19, 23))	('deficient', 'NegReg', (212, 221))	('copy', 'MPA', (38, 42))	('HAMP', 'Gene', '57817', (85, 89))	('functions', 'MPA', (180, 189))	('mutations', 'Var', (118, 127))	('cancer', 'Disease', (270, 276))	('HAMP', 'Gene', (85, 89))	('cancer', 'Disease', 'MESH:D009369', (270, 276))	('cancer', 'Phenotype', 'HP:0002664', (270, 276))	('lost', 'NegReg', (33, 37))	('HAMP', 'Gene', '57817', (19, 23))
33092	30760718	For example, mutations of the BRD-containing protein SMARCA4 in tumor cells results in a unique functional dependence on SMARCA2.	('tumor', 'Disease', (64, 69))	('functional dependence', 'MPA', (96, 117))	('SMARCA4', 'Gene', (53, 60))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('mutations', 'Var', (13, 22))	('SMARCA2', 'Gene', (121, 128))	('SMARCA2', 'Gene', '6595', (121, 128))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('results in', 'Reg', (76, 86))	('SMARCA4', 'Gene', '6597', (53, 60))
33094	30760718	Notably, very few homozygous deletions or mutations of HAMPs (except for PBRM1) were observed in cancer, suggesting that HAMPs may be essential for tumor growth, and that complete loss may be lethal.	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('cancer', 'Disease', (97, 103))	('tumor', 'Disease', (148, 153))	('mutations', 'Var', (42, 51))	('HAMP', 'Gene', '57817', (55, 59))	('PBRM1', 'Gene', '55193', (73, 78))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('HAMP', 'Gene', (55, 59))	('HAMP', 'Gene', '57817', (121, 125))	('HAMP', 'Gene', (121, 125))	('deletions', 'Var', (29, 38))	('PBRM1', 'Gene', (73, 78))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
33108	30760718	Our genomic and functional studies demonstrated that: (1) BRD9 is recurrently and focally amplified in nine cancer types with the highest recurrent score; (2) the expression of BRD9 is significantly increased in cancer specimens compared with that in corresponding normal tissues; (3) computational prediction suggests that BRD9 expression is associated with cell cycle, DNA damage repair, and RNA metabolic pathways in cancer; and (4) genetic depletion of BRD9 by shRNAs reduced cancer cell growth in vitro and in vivo.	('associated', 'Reg', (343, 353))	('genetic depletion', 'Var', (436, 453))	('BRD9', 'Gene', (324, 328))	('cancer', 'Disease', 'MESH:D009369', (212, 218))	('cancer', 'Disease', 'MESH:D009369', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (480, 486))	('cancer', 'Disease', (420, 426))	('BRD9', 'Gene', '65980', (324, 328))	('BRD9', 'Gene', (457, 461))	('cancer', 'Phenotype', 'HP:0002664', (420, 426))	('BRD9', 'Gene', '65980', (457, 461))	('BRD9', 'Gene', (58, 62))	('BRD9', 'Gene', (177, 181))	('cancer', 'Disease', (212, 218))	('BRD9', 'Gene', '65980', (58, 62))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (420, 426))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))	('cancer', 'Disease', (480, 486))	('reduced', 'NegReg', (472, 479))	('BRD9', 'Gene', '65980', (177, 181))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('cancer', 'Phenotype', 'HP:0002664', (480, 486))
33114	30760718	Taken together, our functional studies on BRD9 are the proof-of-concept for the HAMP candidates identified in our study and strongly suggest the clinical potential of targeting BRD9 in common adult solid cancers.	('BRD9', 'Gene', (42, 46))	('cancers', 'Phenotype', 'HP:0002664', (204, 211))	('cancers', 'Disease', (204, 211))	('targeting', 'Var', (167, 176))	('cancers', 'Disease', 'MESH:D009369', (204, 211))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('BRD9', 'Gene', '65980', (177, 181))	('BRD9', 'Gene', (177, 181))	('HAMP', 'Gene', '57817', (80, 84))	('HAMP', 'Gene', (80, 84))	('BRD9', 'Gene', '65980', (42, 46))
33119	30760718	The gene expression data of 2012 cancer cell lines were downloaded through the Expression Atlas (https://www.ebi.ac.uk/gxa/download.html) under the accessions E-MTAB-2770, E-MTAB-3983, and E-MTAB-2706.	('E-MTAB-2770', 'Var', (159, 170))	('cancer', 'Disease', (33, 39))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('MTAB-2706', 'CellLine', 'CVCL:A552', (191, 200))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('E-MTAB-2706', 'Var', (189, 200))
33143	30760718	ABSOLUTE calculated the purity, ploidy, and absolute DNA copy numbers from the segmented copy number alterations and mutation profiles of tumor samples.	('alterations', 'Var', (101, 112))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('tumor', 'Disease', (138, 143))
33146	30760718	The cancer cell fraction of each somatic single-nucleotide variant was extracted from the output.	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('cancer', 'Disease', (4, 10))	('cancer', 'Disease', 'MESH:D009369', (4, 10))	('single-nucleotide variant', 'Var', (41, 66))
33178	29976158	Differential expression of hsa-miR-221, hsa-miR-21, hsa-miR-135b, and hsa-miR-29c suggests a field effect in oral cancer The theory of field effect suggests that the tumor-adjacent area, besides histopathologically normal, undergoes genetic and epigenetic changes that can eventually affect epithelial homeostasis, predisposing the patient to cancer development.	('oral cancer', 'Disease', (109, 120))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('hsa-miR-135b', 'Gene', (52, 64))	('cancer', 'Disease', (343, 349))	('affect', 'Reg', (284, 290))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('miR-221', 'Gene', (31, 38))	('cancer', 'Phenotype', 'HP:0002664', (343, 349))	('hsa-miR-135b', 'Gene', '442891', (52, 64))	('hsa-miR-29', 'Gene', (70, 80))	('miR-221', 'Gene', '407006', (31, 38))	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('epigenetic', 'Var', (245, 255))	('patient', 'Species', '9606', (332, 339))	('tumor', 'Disease', (166, 171))	('cancer', 'Disease', 'MESH:D009369', (343, 349))	('epithelial homeostasis', 'MPA', (291, 313))	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('hsa-miR-21', 'Gene', (40, 50))	('hsa-miR-29', 'Gene', '407021', (70, 80))	('hsa-miR-21', 'Gene', '406991', (40, 50))	('oral cancer', 'Disease', 'MESH:D009062', (109, 120))	('cancer', 'Disease', (114, 120))
33192	29976158	The theory of field effect or field cancerization, firstly described by Slaughter in 1953, shows that the tumor-adjacent area, besides histopathologically normal, undergoes genetic and epigenetic changes that can eventually lead to the development of local recurrence or onset of a second primary tumor.	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('local recurrence', 'CPA', (251, 267))	('cancer', 'Disease', (36, 42))	('tumor', 'Disease', 'MESH:D009369', (297, 302))	('epigenetic changes', 'Var', (185, 203))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('lead to', 'Reg', (224, 231))	('tumor', 'Phenotype', 'HP:0002664', (297, 302))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('tumor', 'Disease', (297, 302))	('tumor', 'Disease', (106, 111))
33195	29976158	Deregulation of miRNA expression contributes to the manifestation of several diseases, including cancer.	('cancer', 'Disease', (97, 103))	('Deregulation', 'Var', (0, 12))	('cancer', 'Disease', 'MESH:D009369', (97, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('miR', 'Gene', '220972', (16, 19))	('miR', 'Gene', (16, 19))	('contributes', 'Reg', (33, 44))
33273	29976158	The aberrant activation of the PI3K/Akt signaling pathway has a significant role in tumorigenesis and tumor metastasis.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('tumor metastasis', 'Disease', 'MESH:D009362', (102, 118))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('aberrant', 'Var', (4, 12))	('tumor metastasis', 'Disease', (102, 118))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('Akt', 'Gene', (36, 39))	('activation', 'PosReg', (13, 23))	('tumor', 'Disease', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('Akt', 'Gene', '207', (36, 39))
33283	29976158	Consequently, inactivation of the APC gene or activation of the WNT-1 pathway causes the nuclear accumulation of beta-catenin, hence it seems to lead to deregulated cell adhesion and other processes such as cell migration, and apoptosis.	('deregulated', 'NegReg', (153, 164))	('APC', 'Gene', (34, 37))	('WNT-1', 'Gene', '7471', (64, 69))	('WNT-1', 'Gene', (64, 69))	('activation', 'PosReg', (46, 56))	('inactivation', 'Var', (14, 26))	('beta-catenin', 'Gene', (113, 125))	('apoptosis', 'CPA', (227, 236))	('APC', 'Gene', '324', (34, 37))	('lead to', 'Reg', (145, 152))	('nuclear accumulation', 'MPA', (89, 109))	('cell migration', 'CPA', (207, 221))	('cell adhesion', 'CPA', (165, 178))	('beta-catenin', 'Gene', '1499', (113, 125))
33284	29976158	Among the alterations in the APC expression, the epigenetic modifications cause a downregulation in its expression in OSCC leading to a blockage of tumor suppressor action and a progress of tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('progress', 'PosReg', (178, 186))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('APC', 'Gene', '324', (29, 32))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('tumor', 'Disease', (148, 153))	('downregulation', 'NegReg', (82, 96))	('epigenetic modifications', 'Var', (49, 73))	('tumor', 'Disease', (190, 195))	('expression', 'MPA', (104, 114))	('blockage', 'NegReg', (136, 144))	('APC', 'Gene', (29, 32))
33289	29976158	The activation of STAT family and the control of aberrantly expressed miRNAs seems in the most basic mechanisms of OSCC.	('OSCC', 'Disease', (115, 119))	('miR', 'Gene', '220972', (70, 73))	('miR', 'Gene', (70, 73))	('aberrantly expressed', 'Var', (49, 69))	('STAT', 'Protein', (18, 22))	('activation', 'PosReg', (4, 14))
33299	26112163	Quantitative analysis of mRNA expression levels and DNA methylation profiles of three neighboring genes: FUS1, NPRL2/G21 and RASSF1A in non-small cell lung cancer patients Tumor suppressor gene (TSG) inactivation plays a crucial role in carcinogenesis.	('TSG', 'Gene', '57045', (195, 198))	('NPRL2', 'Gene', '10641', (111, 116))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (136, 162))	('carcinogenesis', 'Disease', 'MESH:D063646', (237, 251))	('mRNA expression levels', 'MPA', (25, 47))	('RASSF1A', 'Gene', (125, 132))	('TSG', 'Gene', (195, 198))	('Tumor suppressor', 'Gene', (172, 188))	('non-small cell lung cancer', 'Disease', (136, 162))	('NPRL2', 'Gene', (111, 116))	('FUS1', 'Gene', '11334', (105, 109))	('Tumor', 'Phenotype', 'HP:0002664', (172, 177))	('lung cancer', 'Phenotype', 'HP:0100526', (151, 162))	('G21', 'Gene', (117, 120))	('G21', 'Gene', '3350', (117, 120))	('inactivation', 'Var', (200, 212))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (136, 162))	('Tumor suppressor', 'Gene', '7248', (172, 188))	('FUS1', 'Gene', (105, 109))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('carcinogenesis', 'Disease', (237, 251))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (140, 162))	('RASSF1A', 'Gene', '11186', (125, 132))
33316	26112163	The most frequent molecular event in lung cancer pathogenesis is allele loss (loss of heterozygosity, LOH) on short arm of chromosome 3 (3p), in multiple, so called critical regions.	('lung cancer', 'Disease', (37, 48))	('lung cancer', 'Phenotype', 'HP:0100526', (37, 48))	('allele loss', 'Var', (65, 76))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('lung cancer', 'Disease', 'MESH:D008175', (37, 48))	('loss of', 'NegReg', (78, 85))	('short arm', 'Phenotype', 'HP:0009824', (110, 119))
33318	26112163	Inactivation of TSGs is the key event in carcinogenesis and involves two steps, each of them affecting one allele.	('TSG', 'Gene', (16, 19))	('carcinogenesis', 'Disease', 'MESH:D063646', (41, 55))	('TSG', 'Gene', '57045', (16, 19))	('carcinogenesis', 'Disease', (41, 55))	('Inactivation', 'Var', (0, 12))
33319	26112163	Most frequently, one TSG allele is lost due to LOH and the other - to mutation, or, alternatively, epigenetic inactivation via gene promoter hypermethylation.	('epigenetic inactivation', 'Var', (99, 122))	('LOH', 'Var', (47, 50))	('TSG', 'Gene', '57045', (21, 24))	('mutation', 'Var', (70, 78))	('TSG', 'Gene', (21, 24))
33322	26112163	Additionally, low mutation rate, below 10 %, found in lung cell lines and primary tumors, highlighted the significance of epigenetic modifications of TSGs in lung carcinogenesis.	('lung carcinogenesis', 'Disease', (158, 177))	('primary tumors', 'Disease', 'MESH:D009369', (74, 88))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('lung carcinogenesis', 'Disease', 'MESH:D063646', (158, 177))	('epigenetic modifications', 'Var', (122, 146))	('TSG', 'Gene', (150, 153))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('primary tumors', 'Disease', (74, 88))	('TSG', 'Gene', '57045', (150, 153))
33324	26112163	Cancer-related aberrant DNA methylation pattern, e.g., hypermethylation of promoter sequences of TSGs, provide a range of opportunities for risk assessment, early detection, disease progression and prognosis, as well as therapeutic stratification and post-therapeutic monitoring of cancer.	('men', 'Species', '9606', (151, 154))	('TSG', 'Gene', (97, 100))	('cancer', 'Phenotype', 'HP:0002664', (282, 288))	('hypermethylation', 'Var', (55, 71))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('TSG', 'Gene', '57045', (97, 100))	('cancer', 'Disease', 'MESH:D009369', (282, 288))	('cancer', 'Disease', (282, 288))
33327	26112163	DNMT1, possessing a 7- to 21- fold preference for hemimethylated DNA than unmethylated DNA, is the primary enzyme responsible for copping methylation patterns, i.e., for its maintenance.	('hemimethylated', 'Var', (50, 64))	('methylation', 'MPA', (138, 149))	('DNMT1', 'Gene', (0, 5))	('DNMT1', 'Gene', '1786', (0, 5))
33331	26112163	The pre-specified hypothesis tested in the study was that the expression levels of 3 selected TSGs from LUCA region (FUS1, NPRL2/G21 and RASSF1A) were decreased in primary non-small cell lung cancer with promoter hypermethylation as the responsible epigenetic mechanism of their silencing.	('NPRL2', 'Gene', (123, 128))	('FUS1', 'Gene', '11334', (117, 121))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (176, 198))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (172, 198))	('expression levels', 'MPA', (62, 79))	('RASSF1A', 'Gene', '11186', (137, 144))	('RASSF1A', 'Gene', (137, 144))	('promoter hypermethylation', 'Var', (204, 229))	('FUS1', 'Gene', (117, 121))	('decreased', 'NegReg', (151, 160))	('TSG', 'Gene', '57045', (94, 97))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (172, 198))	('TSG', 'Gene', (94, 97))	('NPRL2', 'Gene', '10641', (123, 128))	('G21', 'Gene', (129, 132))	('G21', 'Gene', '3350', (129, 132))	('non-small cell lung cancer', 'Disease', (172, 198))	('lung cancer', 'Phenotype', 'HP:0100526', (187, 198))
33343	26112163	On the other hand, accumulating evidence point to genetic/epigenetic changes occurring in normal tissue adjacent to tumor (the so called "field cancerization" process), which are widely described in literature in various cancer types and highlights the importance of early abnormalities in carcinogenesis.	('cancer', 'Disease', 'MESH:D009369', (221, 227))	('carcinogenesis', 'Disease', 'MESH:D063646', (290, 304))	('cancer', 'Disease', (221, 227))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('carcinogenesis', 'Disease', (290, 304))	('genetic/epigenetic changes', 'Var', (50, 76))	('cancer', 'Disease', (144, 150))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('tumor', 'Disease', (116, 121))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
33410	26112163	Spearman's rank correlation coefficient didn't reveal statistically significant correlations between TSG methylation and DNMT expression (P > 0.05).	('DNMT', 'Gene', '1786', (121, 125))	('methylation', 'Var', (105, 116))	('DNMT', 'Gene', (121, 125))	('TSG', 'Gene', (101, 104))	('TSG', 'Gene', '57045', (101, 104))
33433	26112163	In our study, the frequency of RASSF1A methylated alleles in total NSCLC group was 76 % and gene methylation level was equal to or exceeded 50 %, depending on the histotype.	('NSCLC', 'Phenotype', 'HP:0030358', (67, 72))	('RASSF1A', 'Gene', (31, 38))	('RASSF1A', 'Gene', '11186', (31, 38))	('NSCLC', 'Disease', (67, 72))	('methylated', 'Var', (39, 49))	('NSCLC', 'Disease', 'MESH:D002289', (67, 72))
33435	26112163	In several reports, RASSF1A methylation was associated with poor prognosis in NSCLC patients.	('patients', 'Species', '9606', (84, 92))	('NSCLC', 'Phenotype', 'HP:0030358', (78, 83))	('RASSF1A', 'Gene', (20, 27))	('RASSF1A', 'Gene', '11186', (20, 27))	('NSCLC', 'Disease', (78, 83))	('methylation', 'Var', (28, 39))	('NSCLC', 'Disease', 'MESH:D002289', (78, 83))
33437	26112163	Meta-analysis performed in 2013 confirmed a significant association between RASSF1A methylation and NSCLC, however there were no significant differences in RASSF1A methylation in relation to gender, pathology, TNM stage and smoking behavior among NSCLC cases.	('NSCLC', 'Disease', (247, 252))	('RASSF1A', 'Gene', '11186', (76, 83))	('methylation', 'Var', (84, 95))	('TNM', 'Gene', '10178', (210, 213))	('NSCLC', 'Disease', (100, 105))	('NSCLC', 'Disease', 'MESH:D002289', (247, 252))	('NSCLC', 'Disease', 'MESH:D002289', (100, 105))	('RASSF1A', 'Gene', (76, 83))	('TNM', 'Gene', (210, 213))	('NSCLC', 'Phenotype', 'HP:0030358', (247, 252))	('RASSF1A', 'Gene', (156, 163))	('NSCLC', 'Phenotype', 'HP:0030358', (100, 105))	('RASSF1A', 'Gene', '11186', (156, 163))
33439	26112163	However, the results regarding the utility of RASSF1A epigenetic inactivation as a prognostic marker in NSCLC are still divergent.	('RASSF1A', 'Gene', '11186', (46, 53))	('epigenetic inactivation', 'Var', (54, 77))	('NSCLC', 'Disease', (104, 109))	('NSCLC', 'Disease', 'MESH:D002289', (104, 109))	('RASSF1A', 'Gene', (46, 53))	('NSCLC', 'Phenotype', 'HP:0030358', (104, 109))
33448	26112163	FUS1 promoter methylation analysis in our study revealed the presence of methylated alleles in 58 % NSCLC samples and rather moderate gene methylation status, ranging from 10 to 22 %, depending on histopathological subtype.	('FUS1', 'Gene', (0, 4))	('FUS1', 'Gene', '11334', (0, 4))	('NSCLC', 'Disease', (100, 105))	('NSCLC', 'Disease', 'MESH:D002289', (100, 105))	('methylated', 'Var', (73, 83))	('NSCLC', 'Phenotype', 'HP:0030358', (100, 105))
33454	26112163	Researchers indicate the role of 3'-untranslated regions (UTRs) of the FUS1 gene transcript or the influence of another epigenetic mechanisms, e.g., the role of several miRNAs in the down-regulation of FUS1 protein expression in lung cancer cells or aberrant histone modifications.	('aberrant', 'Var', (250, 258))	('FUS1', 'Gene', '11334', (202, 206))	('down-regulation', 'NegReg', (183, 198))	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('lung cancer', 'Disease', 'MESH:D008175', (229, 240))	('protein', 'Protein', (207, 214))	('histone', 'MPA', (259, 266))	('FUS1', 'Gene', (71, 75))	('FUS1', 'Gene', '11334', (71, 75))	('lung cancer', 'Disease', (229, 240))	('lung cancer', 'Phenotype', 'HP:0100526', (229, 240))	('FUS1', 'Gene', (202, 206))	('expression', 'MPA', (215, 225))
33455	26112163	Thus, the inactivation of FUS1 may occur through abnormal translational control of FUS1 mRNA or aberrant post-translational protein modification resulting in its inactivation despite the absence of mutations and in the presence of high levels of transcript mRNA.	('inactivation', 'MPA', (162, 174))	('FUS1', 'Gene', (83, 87))	('FUS1', 'Gene', '11334', (83, 87))	('aberrant', 'Var', (96, 104))	('mRNA', 'MPA', (88, 92))	('abnormal', 'Reg', (49, 57))	('translational control', 'MPA', (58, 79))	('mutations', 'Var', (198, 207))	('FUS1', 'Gene', (26, 30))	('FUS1', 'Gene', '11334', (26, 30))
33467	26112163	The frequency of gene methylation in NSCLC samples was very low and its methylation status was significantly lower than that of other studied TSGs.	('lower', 'NegReg', (109, 114))	('NSCLC', 'Phenotype', 'HP:0030358', (37, 42))	('TSG', 'Gene', (142, 145))	('methylation status', 'MPA', (72, 90))	('low', 'NegReg', (60, 63))	('NSCLC', 'Disease', (37, 42))	('TSG', 'Gene', '57045', (142, 145))	('gene', 'MPA', (17, 21))	('NSCLC', 'Disease', 'MESH:D002289', (37, 42))	('methylation', 'Var', (22, 33))
33469	26112163	Alternatively, as in the case of other 3p21.3 tumor suppressors, like RASSF1A and FUS1, such mechanisms as chromosome instability, aneuploidy, altered RNA splicing, or defects in transcriptional, translational, and posttranslational modifications that are common in the 3p region, may play a role in the inactivation of NPRL1/G21 in lung tumors.	('altered', 'Var', (143, 150))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('aneuploidy', 'Disease', (131, 141))	('chromosome instability', 'Phenotype', 'HP:0040012', (107, 129))	('inactivation', 'NegReg', (304, 316))	('G21', 'Gene', '3350', (326, 329))	('lung tumors', 'Disease', 'MESH:D008175', (333, 344))	('G21', 'Gene', (326, 329))	('defects', 'Var', (168, 175))	('RNA splicing', 'MPA', (151, 163))	('tumor suppressor', 'Gene', (46, 62))	('tumors', 'Phenotype', 'HP:0002664', (338, 344))	('lung tumors', 'Phenotype', 'HP:0100526', (333, 344))	('lung tumor', 'Phenotype', 'HP:0100526', (333, 343))	('FUS1', 'Gene', '11334', (82, 86))	('chromosome instability', 'CPA', (107, 129))	('tumor', 'Phenotype', 'HP:0002664', (338, 343))	('lung tumors', 'Disease', (333, 344))	('tumor suppressor', 'Gene', '7248', (46, 62))	('RASSF1A', 'Gene', '11186', (70, 77))	('aneuploidy', 'Disease', 'MESH:D000782', (131, 141))	('transcriptional', 'MPA', (179, 194))	('RASSF1A', 'Gene', (70, 77))	('translational', 'MPA', (196, 209))	('FUS1', 'Gene', (82, 86))
33475	26112163	The role of DNMT mediated epigenetic alterations in lung cancer development has been the focus of increasing interest in recent years.	('lung cancer', 'Disease', 'MESH:D008175', (52, 63))	('DNMT', 'Gene', '1786', (12, 16))	('men', 'Species', '9606', (71, 74))	('lung cancer', 'Disease', (52, 63))	('DNMT', 'Gene', (12, 16))	('epigenetic alterations', 'Var', (26, 48))	('lung cancer', 'Phenotype', 'HP:0100526', (52, 63))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))
33480	26112163	However, in other studies, deregulated expression of DNMT1 was an independent prognostic factor in SCC.	('SCC', 'Gene', '6317', (99, 102))	('DNMT1', 'Gene', (53, 58))	('deregulated', 'Var', (27, 38))	('DNMT1', 'Gene', '1786', (53, 58))	('expression', 'MPA', (39, 49))	('SCC', 'Gene', (99, 102))	('SCC', 'Phenotype', 'HP:0002860', (99, 102))
33552	33744857	Moreover, we confirmed the remarkable down-regulation of ITIH1 in LIHC in five GEO datasets (GSE1898, GSE39791, GSE45436, GSE6764, and GSE84598) (Figure 5A).	('GSE6764', 'Var', (122, 129))	('ITIH1', 'Gene', '3697', (57, 62))	('GSE39791', 'Var', (102, 110))	('GSE1898', 'Chemical', '-', (93, 100))	('GSE1898', 'Var', (93, 100))	('GSE6764', 'Chemical', '-', (122, 129))	('ITIH1', 'Gene', (57, 62))	('down-regulation', 'NegReg', (38, 53))	('GSE45436', 'Var', (112, 120))	('GSE84598', 'Var', (135, 143))
33557	33744857	Furthermore, the good prognostic impact of ITIH1 was validated in two independent cohorts of LIHC patients (GSE1898, n = 76; GSE14520, n = 221) (Figure 5D).	('ITIH1', 'Gene', '3697', (43, 48))	('GSE1898', 'Chemical', '-', (108, 115))	('GSE1898', 'Var', (108, 115))	('patients', 'Species', '9606', (98, 106))	('ITIH1', 'Gene', (43, 48))	('GSE14520', 'Var', (125, 133))	('LIHC', 'Disease', (93, 97))
33561	33744857	Melanoma demonstrated the highest frequency of ITIH1 mutation (8.33%), followed by uterine cancer (5.86%) (Figure 6A).	('uterine cancer', 'Phenotype', 'HP:0010784', (83, 97))	('Melanoma', 'Disease', 'MESH:D008545', (0, 8))	('ITIH1', 'Gene', '3697', (47, 52))	('mutation', 'Var', (53, 61))	('Melanoma', 'Phenotype', 'HP:0002861', (0, 8))	('cancer', 'Disease', (91, 97))	('Melanoma', 'Disease', (0, 8))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('ITIH1', 'Gene', (47, 52))
33562	33744857	cBioPortal Oncoprint showed that missense mutation was the main mutation type of ITIH1 and most mutations were C>T (Supplementary Figure 10).	('ITIH1', 'Gene', (81, 86))	('missense mutation', 'Var', (33, 50))	('ITIH1', 'Gene', '3697', (81, 86))	('C>T', 'Var', (111, 114))
33564	33744857	For copy number variations (CNVs) of ITIH1, amplification was most frequently observed in esophagus cancer (1.65%), while deletion event occurred more often in diffusive large B-cell lymphoma (DLBC) (4.17%) (Figure 6A).	('cancer', 'Disease', (100, 106))	('amplification', 'MPA', (44, 57))	('B-cell lymphoma', 'Disease', 'MESH:D016393', (176, 191))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('observed', 'Reg', (78, 86))	('deletion', 'Var', (122, 130))	('B-cell lymphoma', 'Disease', (176, 191))	('ITIH1', 'Gene', (37, 42))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (176, 191))	('copy number variations', 'Var', (4, 26))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('lymphoma', 'Phenotype', 'HP:0002665', (183, 191))	('ITIH1', 'Gene', '3697', (37, 42))
33620	33744857	Our results showed that the mutation frequencies of ITIH1 in cancers appeared to be quite low, and the main mutation type was missense mutation.	('missense mutation', 'Var', (126, 143))	('ITIH1', 'Gene', (52, 57))	('cancers', 'Disease', 'MESH:D009369', (61, 68))	('cancers', 'Phenotype', 'HP:0002664', (61, 68))	('ITIH1', 'Gene', '3697', (52, 57))	('cancers', 'Disease', (61, 68))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))
33622	33744857	The data indicates that dysregulated expression of ITIH1 may be influenced by promoter methylation in LIHC, but was unlikely to be regulated by its mutation status.	('ITIH1', 'Gene', (51, 56))	('LIHC', 'Gene', (102, 106))	('promoter methylation', 'Var', (78, 98))	('influenced by', 'Reg', (64, 77))	('ITIH1', 'Gene', '3697', (51, 56))	('dysregulated expression', 'MPA', (24, 47))
33645	33744857	To validate the differential expression of ITIH1 between LIHC and normal tissue, we further retrieved five datasets from Gene Expression Omnibus (GEO) (https://www.ncbi.nlm.nih.gov/geo/) under accession number GSE1898, GSE39791, GSE45436, GSE6764, and GSE84598.	('ITIH1', 'Gene', '3697', (43, 48))	('GSE84598', 'Var', (252, 260))	('GSE1898', 'Chemical', '-', (210, 217))	('GSE1898', 'Var', (210, 217))	('GSE45436', 'Var', (229, 237))	('GSE6764', 'Chemical', '-', (239, 246))	('GSE39791', 'Var', (219, 227))	('ITIH1', 'Gene', (43, 48))	('GSE6764', 'Var', (239, 246))
33651	33744857	The genetic alterations of ITIH1 in pan-cancers, including somatic mutations, amplification, and deep deletion were assessed through the cbioportal for Cancer Genomics (http://www.cbioportal.org).	('deep deletion', 'Var', (97, 110))	('Cancer', 'Disease', (152, 158))	('ITIH1', 'Gene', (27, 32))	('Cancer', 'Disease', 'MESH:D009369', (152, 158))	('cancers', 'Phenotype', 'HP:0002664', (40, 47))	('Cancer', 'Phenotype', 'HP:0002664', (152, 158))	('amplification', 'Var', (78, 91))	('cancers', 'Disease', 'MESH:D009369', (40, 47))	('cancers', 'Disease', (40, 47))	('ITIH1', 'Gene', '3697', (27, 32))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))
33654	33744857	Oncoprint of ITIH1 mutations in various tumors was drawn through the "OncoPrint" module and the mutated site information of ITIH1 was displayed via the "Mutations" module.	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('tumors', 'Disease', 'MESH:D009369', (40, 46))	('ITIH1', 'Gene', '3697', (13, 18))	('mutations', 'Var', (19, 28))	('ITIH1', 'Gene', (124, 129))	('ITIH1', 'Gene', '3697', (124, 129))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('ITIH1', 'Gene', (13, 18))	('tumors', 'Disease', (40, 46))
33694	32194732	The data describe various characteristics, including miRNA, RNA-seq, single nucleotide polymorphisms, copy number variations and methylation patterns, as well as detailed clinical information.	('miR', 'Gene', (53, 56))	('single nucleotide polymorphisms', 'Var', (69, 100))	('copy number variations', 'Var', (102, 124))	('miR', 'Gene', '22877', (53, 56))	('clinical', 'Species', '191496', (171, 179))
33726	32194732	For upregulated DEmRNAs, the top 10 enriched functions are listed in Table III, such as 'cofactor binding', 'modified amino acid binding' (eg., ADH7, etc.)	('ADH7', 'Gene', (144, 148))	('ADH7', 'Gene', '131', (144, 148))	('upregulated', 'PosReg', (4, 15))	("'modified amino acid", 'Var', (108, 128))
33755	32194732	These data from the present study indicated that genes correlated with retinol metabolism may influence cervical cancer progression.	('retinol', 'Chemical', 'MESH:D014801', (71, 78))	('genes', 'Var', (49, 54))	('cervical cancer', 'Disease', (104, 119))	('cervical cancer', 'Disease', 'MESH:D002583', (104, 119))	('influence', 'Reg', (94, 103))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
33766	32194732	In the present study, miR-299a expression was upregulated in cervical cancer samples and was revealed to downregulate CYP26B1 expression.	('downregulate', 'NegReg', (105, 117))	('cervical cancer', 'Disease', 'MESH:D002583', (61, 76))	('expression', 'MPA', (126, 136))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('cervical cancer', 'Disease', (61, 76))	('CYP26B1', 'Gene', '56603', (118, 125))	('miR-299a', 'Var', (22, 30))	('expression', 'MPA', (31, 41))	('CYP26B1', 'Gene', (118, 125))	('miR-299a', 'Chemical', '-', (22, 30))	('upregulated', 'PosReg', (46, 57))
33793	31138119	To understand how genetic alterations driving tumorigenesis lead to the formation of complex cellular networks and induce biological process variation, recent research into cancer genetics has focused on the identification of molecular differences between cancerous and normal tissues.	('genetic alterations', 'Var', (18, 37))	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('cancer', 'Disease', 'MESH:D009369', (256, 262))	('lead to', 'Reg', (60, 67))	('cancer', 'Disease', (173, 179))	('cancer', 'Disease', (256, 262))	('tumor', 'Disease', (46, 51))	('biological', 'MPA', (122, 132))	('induce', 'Reg', (115, 121))	('cancerous', 'Disease', (256, 265))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('cancer', 'Phenotype', 'HP:0002664', (256, 262))	('cancerous', 'Disease', 'MESH:D009369', (256, 265))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
33797	31138119	However, cancerous tissues often exhibit a higher level of gene expression variability than normal tissues, due to tumor heterogeneity, genetic instability, and the fact that genetic alterations in diverse cancer types may differentially affect cellular processes at the transcriptome level.	('cancer', 'Disease', (9, 15))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('cancerous', 'Disease', (9, 18))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('affect', 'Reg', (238, 244))	('tumor', 'Disease', (115, 120))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('gene expression variability', 'MPA', (59, 86))	('cellular processes', 'CPA', (245, 263))	('cancerous', 'Disease', 'MESH:D009369', (9, 18))	('cancer', 'Disease', (206, 212))	('cancer', 'Disease', 'MESH:D009369', (206, 212))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('genetic alterations', 'Var', (175, 194))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
33816	31138119	Because genetic alterations in diverse cancer types may differentially affect cellular processes at the transcriptome level, we investigated whether reference genes defined by analysis of a single type of cancerous tissue could be applied to other cancer types.	('cancer', 'Disease', (248, 254))	('cellular processes', 'CPA', (78, 96))	('cancer', 'Disease', 'MESH:D009369', (205, 211))	('cancer', 'Disease', (39, 45))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('genetic alterations', 'Var', (8, 27))	('cancer', 'Disease', (205, 211))	('cancer', 'Phenotype', 'HP:0002664', (248, 254))	('cancerous', 'Disease', (205, 214))	('affect', 'Reg', (71, 77))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('cancerous', 'Disease', 'MESH:D009369', (205, 214))	('cancer', 'Disease', 'MESH:D009369', (248, 254))
33884	29616096	A comprehensive analysis of the predicted targets of miR-642b-3p associated with the long non-coding RNA HOXA11-AS in NSCLC cells Long non-coding RNA HOXA11 antisense RNA (HOXA11-AS) has been previously reported to be involved in the tumorigenesis and progression of ovarian cancer and glioma.	('HOXA11-AS', 'Gene', '221883', (105, 114))	('involved', 'Reg', (218, 226))	('ovarian cancer', 'Disease', (267, 281))	('HOXA11', 'Gene', '3207', (105, 111))	('ovarian cancer', 'Phenotype', 'HP:0100615', (267, 281))	('NSCLC', 'Disease', 'MESH:D002289', (118, 123))	('HOXA11', 'Gene', (150, 156))	('HOXA11-AS', 'Gene', (172, 181))	('NSCLC', 'Disease', (118, 123))	('tumorigenesis', 'CPA', (234, 247))	('HOXA11', 'Gene', '3207', (150, 156))	('HOXA11', 'Gene', (172, 178))	('glioma', 'Disease', (286, 292))	('miR-642b', 'Gene', '100500845', (53, 61))	('NSCLC', 'Phenotype', 'HP:0030358', (118, 123))	('HOXA11-AS', 'Gene', '221883', (172, 181))	('glioma', 'Disease', 'MESH:D005910', (286, 292))	('SCLC', 'Phenotype', 'HP:0030357', (119, 123))	('miR-642b', 'Gene', (53, 61))	('HOXA11', 'Gene', '3207', (172, 178))	('ovarian cancer', 'Disease', 'MESH:D010051', (267, 281))	('HOXA11-AS', 'Gene', (105, 114))	('cancer', 'Phenotype', 'HP:0002664', (275, 281))	('antisense', 'Var', (157, 166))	('glioma', 'Phenotype', 'HP:0009733', (286, 292))	('HOXA11', 'Gene', (105, 111))
33886	29616096	Following the knockdown of HOXA11-AS in A549 cells, a microarray analysis was performed in order to detect the differences in microRNA (miRNA/miR) profiles.	('miR', 'Gene', '220972', (136, 139))	('HOXA11-AS', 'Gene', (27, 36))	('miR', 'Gene', (136, 139))	('HOXA11-AS', 'Gene', '221883', (27, 36))	('A549', 'CellLine', 'CVCL:0023', (40, 44))	('miR', 'Gene', '220972', (142, 145))	('miR', 'Gene', (142, 145))	('knockdown', 'Var', (14, 23))
33960	29616096	To date, different lncRNAs have been reported to perform different functions in NSCLC, including lncRNA AK126698, GAS5-AS1 and TUSC7, which may be associated with cell proliferation, metastasis and a poor prognosis in NSCLC.	('NSCLC', 'Phenotype', 'HP:0030358', (80, 85))	('NSCLC', 'Phenotype', 'HP:0030358', (218, 223))	('TUSC7', 'Gene', (127, 132))	('associated', 'Reg', (147, 157))	('SCLC', 'Phenotype', 'HP:0030357', (219, 223))	('TUSC7', 'Gene', '285194', (127, 132))	('GAS5-AS1', 'Gene', (114, 122))	('GAS5-AS1', 'Gene', '100506046;60674;5729', (114, 122))	('NSCLC', 'Disease', (80, 85))	('NSCLC', 'Disease', (218, 223))	('NSCLC', 'Disease', 'MESH:D002289', (80, 85))	('AK126698', 'Var', (104, 112))	('SCLC', 'Phenotype', 'HP:0030357', (81, 85))	('NSCLC', 'Disease', 'MESH:D002289', (218, 223))
33978	29616096	Karachaliou et al revealed that PDE4D was associated with resistant epidermal growth factor receptor (EGFR)-mutant cancer cell lines, and the combination of EGFR tyrosine kinase inhibitors with PDE4D inhibitors may be an effective therapy for patients with EGFR-mutant NSCLC.	('EGFR', 'Gene', (257, 261))	('NSCLC', 'Disease', 'MESH:D002289', (269, 274))	('EGFR', 'Gene', '1956', (157, 161))	('EGFR', 'Gene', '1956', (102, 106))	('PDE4D', 'Gene', '5144', (32, 37))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('patients', 'Species', '9606', (243, 251))	('NSCLC', 'Disease', (269, 274))	('-mutant', 'Var', (107, 114))	('EGFR', 'Gene', '1956', (257, 261))	('PDE4D', 'Gene', (32, 37))	('NSCLC', 'Phenotype', 'HP:0030358', (269, 274))	('epidermal growth factor receptor', 'Gene', (68, 100))	('epidermal growth factor receptor', 'Gene', '1956', (68, 100))	('PDE4D', 'Gene', '5144', (194, 199))	('SCLC', 'Phenotype', 'HP:0030357', (270, 274))	('EGFR', 'Gene', (102, 106))	('EGFR', 'Gene', (157, 161))	('cancer', 'Disease', (115, 121))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('PDE4D', 'Gene', (194, 199))
33994	29204553	We and others have shown that high IL-6 expression independently predicts tumor recurrence, tumor metastasis and poor survival in head and neck cancer patients.	('expression', 'MPA', (40, 50))	('tumor metastasis', 'Disease', (92, 108))	('tumor metastasis', 'Disease', 'MESH:D009362', (92, 108))	('IL-6', 'Gene', (35, 39))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('poor survival', 'CPA', (113, 126))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('neck cancer', 'Disease', 'MESH:D006258', (139, 150))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('neck cancer', 'Disease', (139, 150))	('patients', 'Species', '9606', (151, 159))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('high', 'Var', (30, 34))	('tumor', 'Disease', (74, 79))	('tumor', 'Disease', (92, 97))	('head and neck cancer', 'Phenotype', 'HP:0012288', (130, 150))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('predicts', 'Reg', (65, 73))
34030	29204553	Jinno et al have shown that the high IL-6 expressing group showed significantly poor tumor response to the preoperative chemoradiotherapy as compared to the negative or low IL-6 expressing group.	('tumor', 'Disease', (85, 90))	('high', 'Var', (32, 36))	('poor', 'NegReg', (80, 84))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))
34057	29204553	In contrast, immunodepletion of IL-6 or blocking of gp130 (the signaling unit of the IL-6R complex) abolished STAT3 phosphorylation, thereby confirming IL-6-dependent and EGFR-independent STAT3 activation.	('EGFR', 'Gene', (171, 175))	('gp130', 'Gene', (52, 57))	('IL-6R', 'Gene', (85, 90))	('gp130', 'Gene', '3572', (52, 57))	('abolished', 'NegReg', (100, 109))	('IL-6R', 'Gene', '3570', (85, 90))	('STAT3 phosphorylation', 'MPA', (110, 131))	('EGFR', 'Gene', '1956', (171, 175))	('blocking', 'Var', (40, 48))
34065	29204553	STAT3 knockdown in tumor cells or normal keratinocytes significantly decreased IL-6-mediated cell scattering, cell motility and reversal of EMT phenotype.	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('decreased', 'NegReg', (69, 78))	('IL-6-mediated cell scattering', 'CPA', (79, 108))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('tumor', 'Disease', (19, 24))	('knockdown', 'Var', (6, 15))	('STAT3', 'Gene', (0, 5))	('cell motility', 'CPA', (110, 123))
34086	29204553	H-4073 mediated its anti-tumor effects by inhibiting JAK/STAT3, FAK, Akt and VEGF signaling pathways that play important roles in cell proliferation, migration, survival and angiogenesis.	('Akt', 'Gene', (69, 72))	('H-4073', 'Var', (0, 6))	('VEGF', 'Gene', '7422', (77, 81))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumor', 'Disease', (25, 30))	('inhibiting', 'NegReg', (42, 52))	('FAK', 'Gene', (64, 67))	('FAK', 'Gene', '5747', (64, 67))	('H-4073', 'Chemical', '-', (0, 6))	('JAK/STAT3', 'Pathway', (53, 62))	('VEGF', 'Gene', (77, 81))	('Akt', 'Gene', '207', (69, 72))	('tumor', 'Disease', 'MESH:D009369', (25, 30))
34088	29204553	In the SCID mouse xenograft model, H-4073 significantly enhanced the anti-tumor and anti-angiogenesis effects of cisplatin, with no added systemic toxicity.	('anti-angiogenesis effects', 'CPA', (84, 109))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('toxicity', 'Disease', 'MESH:D064420', (147, 155))	('toxicity', 'Disease', (147, 155))	('H-4073', 'Var', (35, 41))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('SCID', 'Disease', 'MESH:D053632', (7, 11))	('enhanced', 'PosReg', (56, 64))	('tumor', 'Disease', (74, 79))	('SCID', 'Disease', (7, 11))	('mouse', 'Species', '10090', (12, 17))	('H-4073', 'Chemical', '-', (35, 41))	('cisplatin', 'Chemical', 'MESH:D002945', (113, 122))
34099	29204553	Additionally, BMS-911543, a JAK2 selective inhibitor, showed similar suppression of tumor growth.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('suppression', 'NegReg', (69, 80))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumor', 'Disease', (84, 89))	('JAK2', 'Gene', '3717', (28, 32))	('BMS-911543', 'Var', (14, 24))	('JAK2', 'Gene', (28, 32))
34113	33626321	Importantly, Paf knockout markedly suppressed LUAD development in mouse models.	('Paf', 'Gene', (13, 16))	('Paf', 'Gene', '9768', (13, 16))	('mouse', 'Species', '10090', (66, 71))	('knockout', 'Var', (17, 25))	('LUAD', 'Phenotype', 'HP:0030078', (46, 50))	('suppressed', 'NegReg', (35, 45))	('LUAD development', 'CPA', (46, 62))
34114	33626321	PAF depletion induced LUAD cell quiescence and growth arrest.	('PAF', 'Gene', (0, 3))	('growth arrest', 'Disease', 'MESH:D006323', (47, 60))	('growth arrest', 'Disease', (47, 60))	('depletion', 'Var', (4, 13))	('PAF', 'Gene', '9768', (0, 3))	('LUAD cell quiescence', 'CPA', (22, 42))	('growth arrest', 'Phenotype', 'HP:0001510', (47, 60))	('LUAD', 'Phenotype', 'HP:0030078', (22, 26))
34125	33626321	Perturbation of this process can lead to cell quiescence exit and hyperproliferation, which are implicated in cancer.	('lead to', 'Reg', (33, 40))	('cancer', 'Disease', (110, 116))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('cell quiescence exit', 'CPA', (41, 61))	('Perturbation', 'Var', (0, 12))	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('hyperproliferation', 'CPA', (66, 84))
34128	33626321	Upon cell-cycle re-entry stimuli, p130, E2F4, and DP1 are dissociated from the DREAM complex.	('DP1', 'Gene', (50, 53))	('DP1', 'Gene', '21781', (50, 53))	('p130', 'Var', (34, 38))	('E2F4', 'Gene', (40, 44))	('E2F4', 'Gene', '104394', (40, 44))
34129	33626321	The remaining multi-vulval class B (MuvB) core complex composed of LIN9, LIN37, LIN52, LIN54, and RBBP4 subsequently binds to BMYB and FOXM1, which transactivates cell-cycle genes related to S/G2/M phase.	('cell-cycle genes', 'Gene', (163, 179))	('LIN52', 'Gene', '217708', (80, 85))	('LIN37', 'Gene', '75660', (73, 78))	('FOXM1', 'Gene', (135, 140))	('S/G2', 'Var', (191, 195))	('transactivates', 'PosReg', (148, 162))	('binds', 'Interaction', (117, 122))	('LIN9', 'Gene', (67, 71))	('RBBP4', 'Gene', (98, 103))	('S/G2', 'SUBSTITUTION', 'None', (191, 195))	('LIN37', 'Gene', (73, 78))	('LIN9', 'Gene', '72568', (67, 71))	('LIN52', 'Gene', (80, 85))	('LIN54', 'Gene', (87, 92))
34130	33626321	Given that the DREAM complex plays a crucial role in orchestrating the cell cycle, deregulation of this complex is implicated in several cancers.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('implicated', 'Reg', (115, 125))	('deregulation', 'Var', (83, 95))	('cancers', 'Phenotype', 'HP:0002664', (137, 144))	('cancers', 'Disease', 'MESH:D009369', (137, 144))	('cancers', 'Disease', (137, 144))
34152	33626321	Moreover, the transient expression of KRASG12D in non-PAF-expressing and non-transformed cells (3T3, BJ, and IMR-90) induced PAF expression (Figure 1J), implying that PAF expression in LUAD is likely to be associated with oncogenic KRAS signaling.	('LUAD', 'Phenotype', 'HP:0030078', (185, 189))	('expression', 'MPA', (129, 139))	('induced', 'Reg', (117, 124))	('PAF', 'Gene', '9768', (54, 57))	('PAF', 'Gene', '9768', (167, 170))	('PAF', 'Gene', (125, 128))	('KRASG12D', 'Var', (38, 46))	('PAF', 'Gene', (54, 57))	('PAF', 'Gene', (167, 170))	('IMR-90', 'CellLine', 'CVCL:0347', (109, 115))	('PAF', 'Gene', '9768', (125, 128))
34155	33626321	We generated Paf-knockout (KO) mice on KP compound strains (Paf-/-; KrasLSL-G12D/+; Trp53floxed/floxed [PKP]) and administered Ad-Cre to induce oncogenic KrasG12D expression and Trp53 loss in the lungs.	('Paf', 'Gene', (13, 16))	('induce', 'PosReg', (137, 143))	('Paf', 'Gene', '9768', (13, 16))	('KrasG12D expression', 'Var', (154, 173))	('G12D', 'Mutation', 'rs121913529', (76, 80))	('oncogenic', 'CPA', (144, 153))	('loss', 'NegReg', (184, 188))	('Trp53', 'Gene', '22059', (178, 183))	('mice', 'Species', '10090', (31, 35))	('Trp53', 'Gene', (84, 89))	('Trp53', 'Gene', '22059', (84, 89))	('KrasLSL', 'Gene', '16653', (68, 75))	('G12D', 'Mutation', 'rs121913529', (158, 162))	('Paf', 'Gene', (60, 63))	('Paf', 'Gene', '9768', (60, 63))	('KrasLSL', 'Gene', (68, 75))	('Trp53', 'Gene', (178, 183))
34156	33626321	Strikingly, PKP mice exhibited significant suppression of lung tumorigenesis, as assessed by macroscopic, microscopic, and micro-computed tomographic (CT) analyses of lung tumors (Figures 2D-2F, S2C, and S2D).	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('lung tumor', 'Phenotype', 'HP:0100526', (58, 68))	('tumors', 'Phenotype', 'HP:0002664', (172, 178))	('mice', 'Species', '10090', (16, 20))	('lung tumor', 'Disease', 'MESH:D008175', (167, 177))	('lung tumors', 'Disease', (167, 178))	('lung tumors', 'Phenotype', 'HP:0100526', (167, 178))	('lung tumor', 'Disease', (58, 68))	('suppression', 'NegReg', (43, 54))	('lung tumor', 'Disease', 'MESH:D008175', (58, 68))	('PKP', 'Var', (12, 15))	('lung tumors', 'Disease', 'MESH:D008175', (167, 178))	('lung tumor', 'Phenotype', 'HP:0100526', (167, 177))
34157	33626321	The lung tumor numbers and tumor burden were also remarkably lower in PKP mice than in KP mice (Figures 2G and 2H).	('mice', 'Species', '10090', (74, 78))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('lower', 'NegReg', (61, 66))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('tumor', 'Disease', (27, 32))	('lung tumor', 'Phenotype', 'HP:0100526', (4, 14))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumor', 'Disease', (9, 14))	('PKP', 'Var', (70, 73))	('mice', 'Species', '10090', (90, 94))	('lung tumor', 'Disease', (4, 14))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('lung tumor', 'Disease', 'MESH:D008175', (4, 14))
34166	33626321	Paf knockdown (KD) with shRNAs inhibited the growth of lung tumor cells (Figures 3A-3C).	('Paf', 'Gene', '9768', (0, 3))	('Paf', 'Gene', (0, 3))	('lung tumor', 'Phenotype', 'HP:0100526', (55, 65))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('inhibited', 'NegReg', (31, 40))	('knockdown', 'Var', (4, 13))	('lung tumor', 'Disease', (55, 65))	('lung tumor', 'Disease', 'MESH:D008175', (55, 65))
34177	33626321	These results suggest that PAF depletion induces cell quiescence and growth arrest in LUAD cells.	('PAF', 'Gene', (27, 30))	('LUAD', 'Phenotype', 'HP:0030078', (86, 90))	('PAF', 'Gene', '9768', (27, 30))	('growth arrest', 'Disease', (69, 82))	('growth arrest', 'Disease', 'MESH:D006323', (69, 82))	('depletion', 'Var', (31, 40))	('cell quiescence', 'CPA', (49, 64))	('growth arrest', 'Phenotype', 'HP:0001510', (69, 82))
34179	33626321	Previous in vitro studies showed that the PIP motif (62QKGIGEFF69) of PAF is essential for binding to PCNA.	('PCNA', 'Gene', (102, 106))	('PIP', 'Gene', (42, 45))	('PAF', 'Gene', (70, 73))	('QKGIGEFF69', 'CellLine', 'CVCL:4504', (55, 65))	('62QKGIGEFF69', 'Var', (53, 65))	('binding', 'Interaction', (91, 98))	('PAF', 'Gene', '9768', (70, 73))	('PCNA', 'Gene', '18538', (102, 106))	('PIP', 'Gene', '18716', (42, 45))
34182	33626321	We found that, similar to the PAF WT cells (Figure S3G), the ectopic expression of PAF PIP mutant (PAF mutPIP) or PAFK15R, PAFK24R, or PAFK15R/K24R mutants, which no longer interact with PCNA, fully rescued PAF KD-induced cell growth inhibition (Figures S3L and S3M).	('PIP', 'Gene', (87, 90))	('S3M', 'Mutation', 'p.S3M', (262, 265))	('PAF', 'Gene', (135, 138))	('PAF', 'Gene', (30, 33))	('PIP', 'Gene', '18716', (106, 109))	('PAF', 'Gene', '9768', (207, 210))	('PCNA', 'Gene', '18538', (187, 191))	('K24R', 'Mutation', 'p.K24R', (143, 147))	('PAF', 'Gene', (123, 126))	('PAF', 'Gene', (99, 102))	('PIP', 'Gene', '18716', (87, 90))	('PAF', 'Gene', '9768', (135, 138))	('PAF', 'Gene', '9768', (30, 33))	('PAF', 'Gene', (83, 86))	('PAF', 'Gene', (114, 117))	('K24R', 'Mutation', 'p.K24R', (126, 130))	('PCNA', 'Gene', (187, 191))	('PIP', 'Gene', (106, 109))	('PAF', 'Gene', '9768', (99, 102))	('PAF', 'Gene', '9768', (123, 126))	('PAF', 'Gene', (207, 210))	('rescued', 'PosReg', (199, 206))	('PAF', 'Gene', '9768', (83, 86))	('PAF', 'Gene', '9768', (114, 117))	('mutant', 'Var', (91, 97))
34198	33626321	Similar to the harmine treatment results, DYRK1A depletion or LIN52S28A mutant expression reduced the G0/G1 arrest induced by PAF depletion (Figures 5D, 5E, S5F, and S5G).	('S5G', 'Mutation', 'p.S5G', (166, 169))	('reduced', 'NegReg', (90, 97))	('mutant', 'Var', (72, 78))	('G1 arrest', 'Disease', (105, 114))	('harmine', 'Chemical', 'MESH:D006247', (15, 22))	('PAF', 'Gene', '9768', (126, 129))	('S5F', 'Mutation', 'p.S5F', (157, 160))	('G1 arrest', 'Disease', 'MESH:D006323', (105, 114))	('LIN52', 'Gene', (62, 67))	('LIN52', 'Gene', '217708', (62, 67))	('PAF', 'Gene', (126, 129))
34203	33626321	We found that PAF expression reduced cell quiescence induced by serum starvation in 3T3 cells (Figures 5L-5N).	('PAF', 'Gene', (14, 17))	('reduced', 'NegReg', (29, 36))	('PAF', 'Gene', '9768', (14, 17))	('cell quiescence', 'MPA', (37, 52))	('expression', 'Var', (18, 28))
34204	33626321	Moreover, PAF expression diminished the serum starvation-induced recruitment of p130 to the DREAM target gene promoters (Figure 5O).	('PAF', 'Gene', (10, 13))	('expression', 'Var', (14, 24))	('recruitment', 'MPA', (65, 76))	('diminished', 'NegReg', (25, 35))	('PAF', 'Gene', '9768', (10, 13))
34215	33626321	Binding domain mapping analysis showed that this extruded region (S346-E352 AA) of RBBP4 is essential for the PAF-RBBP4 interaction (Figure 6E).	('interaction', 'Interaction', (120, 131))	('PAF', 'Gene', (110, 113))	('S346-E352 AA', 'Var', (66, 78))	('PAF', 'Gene', '9768', (110, 113))	('RBBP4', 'Gene', (83, 88))
34216	33626321	Moreover, we validated that the RBBP4-binding motif (RBM) is required for RBBP4 binding in lung cancer cells by using PAF RBM mutant (mutRBM) (Figures 6F and 6G).	('lung cancer', 'Phenotype', 'HP:0100526', (91, 102))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('PAF', 'Gene', (118, 121))	('mutant', 'Var', (126, 132))	('RB', 'Disease', 'MESH:D012175', (32, 34))	('lung cancer', 'Disease', 'MESH:D008175', (91, 102))	('RB', 'Disease', 'MESH:D012175', (53, 55))	('RB', 'Disease', 'MESH:D012175', (74, 76))	('RB', 'Disease', 'MESH:D012175', (122, 124))	('PAF', 'Gene', '9768', (118, 121))	('RB', 'Disease', 'MESH:D012175', (137, 139))	('lung cancer', 'Disease', (91, 102))
34218	33626321	Chromatin IP (ChIP) experiments showed that PAF depletion increased recruitment of p130, RBBP4, and LIN54 to the promoters of the DREAM target genes (CCNB1, TOP2A, PLK1, and UBE2C) in both human (H1792) and mouse (KP) lung cancer cells (Figures 6H and S6K).	('lung cancer', 'Disease', (218, 229))	('H1792', 'CellLine', 'CVCL:1495', (196, 201))	('PAF', 'Gene', '9768', (44, 47))	('lung cancer', 'Phenotype', 'HP:0100526', (218, 229))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('human', 'Species', '9606', (189, 194))	('p130', 'Gene', (83, 87))	('RBBP4', 'Gene', (89, 94))	('CCNB1', 'Gene', (150, 155))	('recruitment', 'MPA', (68, 79))	('lung cancer', 'Disease', 'MESH:D008175', (218, 229))	('PAF', 'Gene', (44, 47))	('PLK1', 'Gene', (164, 168))	('depletion', 'Var', (48, 57))	('mouse', 'Species', '10090', (207, 212))	('LIN54', 'Gene', (100, 105))	('TOP2A', 'Gene', (157, 162))
34224	33626321	To further validate our hypothesis, we replaced endogenous RBBP4 with a PAF binding-deficient RBBP4 mutant (Delta347-362).	('RBBP4', 'Gene', (94, 99))	('PAF', 'Gene', (72, 75))	('Delta347-362', 'Var', (108, 120))	('Delta347', 'Mutation', 'c.del347', (108, 116))	('PAF', 'Gene', '9768', (72, 75))
34225	33626321	Of note, RBBP4 KD induced severe cell-cycle arrest and induced cell death at a later time point compared with control cells (Figure 6M).	('RBBP4 KD', 'Var', (9, 17))	('death', 'Disease', 'MESH:D003643', (68, 73))	('death', 'Disease', (68, 73))	('arrest', 'Disease', 'MESH:D006323', (44, 50))	('induced', 'Reg', (55, 62))	('arrest', 'Disease', (44, 50))
34226	33626321	Replacement of endogenous RBBP4 by RBBP4 WT rescued the cell-cycle arrest, whereas the RBBP4 Delta347-362 mutant induced cell-cycle arrest at G0/G1, similar to PAF depletion (Figures 6M and 6N), indicating that the PAF-RBBP4 interaction is required for the exit of cell-cycle arrest.	('PAF', 'Gene', '9768', (215, 218))	('rescued', 'PosReg', (44, 51))	('PAF', 'Gene', '9768', (160, 163))	('induced', 'Reg', (113, 120))	('arrest', 'Disease', 'MESH:D006323', (132, 138))	('arrest', 'Disease', 'MESH:D006323', (67, 73))	('arrest', 'Disease', 'MESH:D006323', (276, 282))	('arrest', 'Disease', (276, 282))	('PAF', 'Gene', (215, 218))	('PAF', 'Gene', (160, 163))	('arrest', 'Disease', (132, 138))	('Delta347-362', 'Var', (93, 105))	('RBBP4', 'Gene', (87, 92))	('arrest', 'Disease', (67, 73))	('Delta347', 'Mutation', 'c.del347', (93, 101))
34227	33626321	We confirmed that RBBP4 Delta347-362 mutant maintains the interaction with DREAM complex and its enrichment on the DREAM complex target gene promoters (Figures S6M and S6N).	('interaction', 'Interaction', (58, 69))	('S6N', 'Mutation', 'p.S6N', (168, 171))	('Delta347-362', 'Var', (24, 36))	('Delta347', 'Mutation', 'c.del347', (24, 32))	('RBBP4', 'Gene', (18, 23))
34228	33626321	Moreover, the RBBP4 binding-deficient PAF mutant (Figure 6G) could not rescue the PAF depletion phenotypes, whereas PAF WT and PAF mutPIP did fully rescue the cell-cycle arrest (Figures 6O, 6P, and S6O).	('PAF', 'Gene', (116, 119))	('PAF', 'Gene', (127, 130))	('mutant', 'Var', (42, 48))	('PAF', 'Gene', (38, 41))	('PAF', 'Gene', '9768', (82, 85))	('arrest', 'Disease', 'MESH:D006323', (170, 176))	('PAF', 'Gene', '9768', (116, 119))	('PAF', 'Gene', '9768', (127, 130))	('PIP', 'Gene', '18716', (134, 137))	('PAF', 'Gene', '9768', (38, 41))	('PAF', 'Gene', (82, 85))	('arrest', 'Disease', (170, 176))	('PIP', 'Gene', (134, 137))
34238	33626321	Similarly, p130 KO also rescued pitavastatin- or CsA-induced LUAD cell growth arrest (Figure 7H).	('growth arrest', 'Phenotype', 'HP:0001510', (71, 84))	('LUAD cell growth arrest', 'Disease', 'MESH:D006323', (61, 84))	('pitavastatin', 'Chemical', 'MESH:C108475', (32, 44))	('LUAD cell growth arrest', 'Disease', (61, 84))	('p130 KO', 'Var', (11, 18))	('LUAD', 'Phenotype', 'HP:0030078', (61, 65))
34243	33626321	These results suggest that the pharmacological mimicking of PAF depletion inhibits in vivo lung tumor growth.	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('lung tumor', 'Disease', (91, 101))	('PAF', 'Gene', '9768', (60, 63))	('depletion', 'Var', (64, 73))	('lung tumor', 'Disease', 'MESH:D008175', (91, 101))	('PAF', 'Gene', (60, 63))	('inhibits', 'NegReg', (74, 82))	('lung tumor', 'Phenotype', 'HP:0100526', (91, 101))
34245	33626321	For instance, the deletion of p130, an inhibitory subunit of the DREAM complex, accelerates lung tumorigenesis, but the ablation of Lin9, a core subunit of the MuvB complex, suppresses it.	('p130', 'Gene', (30, 34))	('lung tumor', 'Disease', 'MESH:D008175', (92, 102))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('lung tumor', 'Disease', (92, 102))	('Lin9', 'Gene', '72568', (132, 136))	('ablation', 'Var', (120, 128))	('lung tumor', 'Phenotype', 'HP:0100526', (92, 102))	('Lin9', 'Gene', (132, 136))	('accelerates', 'PosReg', (80, 91))	('deletion', 'Var', (18, 26))
34255	33626321	Moreover, PAF ectopic expression per se accelerates the cell cycle and induces cell transformation.	('PAF', 'Gene', (10, 13))	('accelerates', 'PosReg', (40, 51))	('cell transformation', 'CPA', (79, 98))	('cell cycle', 'CPA', (56, 66))	('PAF', 'Gene', '9768', (10, 13))	('ectopic expression', 'Var', (14, 32))	('induces', 'Reg', (71, 78))
34258	33626321	Importantly, PAF mutants that no longer bind to PCNA are still engaged in LUAD cell proliferation (Figures S3L, S3M, 6G, 6O, 6P, and S6O).	('engaged', 'Reg', (63, 70))	('PCNA', 'Gene', '18538', (48, 52))	('PAF', 'Gene', '9768', (13, 16))	('LUAD cell proliferation', 'CPA', (74, 97))	('PCNA', 'Gene', (48, 52))	('S3M', 'Var', (112, 115))	('LUAD', 'Phenotype', 'HP:0030078', (74, 78))	('PAF', 'Gene', (13, 16))	('S6O', 'Var', (133, 136))	('mutants', 'Var', (17, 24))	('S3M', 'Mutation', 'p.S3M', (112, 115))
34263	33626321	Therefore, molecular targeting of PAF rather than the DREAM complex may be appealing as a cancer therapy because it is likely to have minimal effects on normal cells.	('PAF', 'Gene', (34, 37))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('molecular targeting', 'Var', (11, 30))	('PAF', 'Gene', '9768', (34, 37))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))
34272	33626321	Also, CsA has been recently tested for treatment of several advanced cancers in combination with other drugs (https://clinicaltrials.gov: NCT00983424, NCT02188264, and NCT00003950).	('cancers', 'Disease', 'MESH:D009369', (69, 76))	('NCT00003950', 'Var', (168, 179))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('cancers', 'Phenotype', 'HP:0002664', (69, 76))	('cancers', 'Disease', (69, 76))
34285	33626321	KrasLSL-G12D/+ (#008179) and Trp53floxed/floxed (#008462) mice were obtained from the Jackson Laboratory.	('#008462', 'Var', (49, 56))	('KrasLSL', 'Gene', (0, 7))	('Trp53', 'Gene', '22059', (29, 34))	('G12D', 'Mutation', 'rs121913529', (8, 12))	('mice', 'Species', '10090', (58, 62))	('Trp53', 'Gene', (29, 34))	('KrasLSL', 'Gene', '16653', (0, 7))	('#008179', 'Var', (16, 23))
34296	33626321	For PDXs (Patient-derived xenografts) transplantation, early passages (p < 6) of human LUAD sample TC241, which harbors KRAS oncogenic (G12S) and TP53 inactivating mutations (R209W), were used.	('Patient', 'Species', '9606', (10, 17))	('G12S', 'Var', (136, 140))	('LUAD', 'Phenotype', 'HP:0030078', (87, 91))	('G12S', 'Mutation', 'rs121913530', (136, 140))	('human', 'Species', '9606', (81, 86))	('R209W', 'Var', (175, 180))	('R209W', 'Mutation', 'rs121912651', (175, 180))
34311	33626321	In the lung cancer gene-chip dataset, the correlation analysis was performed with the following options: two probes for PAF/KIAA0101 (202503_s_at and 211713_x_at); splitting patients by median; follow-up threshold: 60 months; restrict analysis to subtypes of histology: NSCLC, LUAD, and LUSC.	('202503_s_at', 'Var', (134, 145))	('NSCLC', 'Disease', 'MESH:D002289', (270, 275))	('NSCLC', 'Phenotype', 'HP:0030358', (270, 275))	('lung cancer', 'Disease', (7, 18))	('PAF', 'Gene', '9768', (120, 123))	('lung cancer', 'Phenotype', 'HP:0100526', (7, 18))	('patients', 'Species', '9606', (174, 182))	('LUSC', 'Phenotype', 'HP:0030359', (287, 291))	('lung cancer', 'Disease', 'MESH:D008175', (7, 18))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('LUSC', 'Disease', (287, 291))	('LUAD', 'Disease', (277, 281))	('LUAD', 'Phenotype', 'HP:0030078', (277, 281))	('211713_x_at', 'Var', (150, 161))	('NSCLC', 'Disease', (270, 275))	('PAF', 'Gene', (120, 123))
34315	33626321	To obtain stable Paf KD murine lung cancer cell lines, shRNAs against Paf (GIPZ mouse Pclaf shRNA, Dharmacon; V2LMM_11233, V2LMM_16348) were used.	('lung cancer', 'Disease', 'MESH:D008175', (31, 42))	('Paf', 'Gene', (17, 20))	('Paf', 'Gene', '9768', (17, 20))	('V2LMM_11233', 'Var', (110, 121))	('lung cancer', 'Disease', (31, 42))	('V2LMM_16348', 'Var', (123, 134))	('Paf', 'Gene', (70, 73))	('mouse', 'Species', '10090', (80, 85))	('murine', 'Species', '10090', (24, 30))	('Paf', 'Gene', '9768', (70, 73))	('lung cancer', 'Phenotype', 'HP:0100526', (31, 42))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))
34373	33375021	Co-Occurrence of Hotspot Point Mutation and Novel Deletion Mutation of TERT Promoter in Solid Variant Papillary Thyroid Carcinoma in a Patient with Synchronous Esophageal Cancer (1) Introduction: Telomerase reverse transcriptase (TERT) promoter mutations are associated with unfavorable clinical outcomes in papillary thyroid carcinomas (PTCs).	('thyroid carcinomas', 'Phenotype', 'HP:0002890', (318, 336))	('TERT', 'Gene', (71, 75))	('Cancer', 'Disease', (171, 177))	('TERT', 'Gene', '7015', (71, 75))	('Patient', 'Species', '9606', (135, 142))	('carcinoma', 'Phenotype', 'HP:0030731', (326, 335))	('carcinomas', 'Phenotype', 'HP:0030731', (326, 336))	('papillary thyroid carcinomas', 'Disease', 'MESH:D000077273', (308, 336))	('mutations', 'Var', (245, 254))	('Papillary Thyroid Carcinoma', 'Disease', 'MESH:D000077273', (102, 129))	('Cancer', 'Disease', 'MESH:D009369', (171, 177))	('Telomerase reverse transcriptase', 'Gene', '7015', (196, 228))	('Deletion Mutation', 'Var', (50, 67))	('associated', 'Reg', (259, 269))	('papillary thyroid carcinoma', 'Phenotype', 'HP:0002895', (308, 335))	('Telomerase reverse transcriptase', 'Gene', (196, 228))	('Thyroid Carcinoma', 'Phenotype', 'HP:0002890', (112, 129))	('PTCs', 'Phenotype', 'HP:0002895', (338, 342))	('PTC', 'Phenotype', 'HP:0002895', (338, 341))	('Cancer', 'Phenotype', 'HP:0002664', (171, 177))	('Carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('Papillary Thyroid Carcinoma', 'Disease', (102, 129))	('TERT', 'Gene', (230, 234))	('TERT', 'Gene', '7015', (230, 234))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (318, 335))	('papillary thyroid carcinomas', 'Disease', (308, 336))	('papillary thyroid carcinomas', 'Phenotype', 'HP:0002895', (308, 336))	('Papillary Thyroid Carcinoma', 'Phenotype', 'HP:0002895', (102, 129))
34374	33375021	Two substitution mutations, C228T (c.1-124C>T) and C250T (c.1-146C>T), make up most of the mutations and occur in a mutually exclusive manner.	('c.1-146C>T', 'SUBSTITUTION', 'None', (58, 68))	('C250T', 'SUBSTITUTION', 'None', (51, 56))	('c.1-124C>T', 'SUBSTITUTION', 'None', (35, 45))	('c.1-124C>T', 'Var', (35, 45))	('c.1-146C>T', 'Var', (58, 68))	('C228T', 'SUBSTITUTION', 'None', (28, 33))	('C250T', 'Var', (51, 56))	('C228T', 'Var', (28, 33))
34377	33375021	Sanger sequencing using DNA from the thyroid tumor showed an indel mutation, c.1-132_1-124delinsT, composed of a deletion (c.1-132_1-125del) as well as a hotspot mutation (c.1-124C>T(C228T)) in the TERT promoter.	('C228T', 'SUBSTITUTION', 'None', (183, 188))	('c.1-124C>T', 'SUBSTITUTION', 'None', (172, 182))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('c.1-132_1-125del', 'Var', (123, 139))	('TERT', 'Gene', '7015', (198, 202))	('c.1-132_1-124delinsT', 'DELETION_INSERTION', 'None', (77, 97))	('c.1-124C>T', 'Var', (172, 182))	('C228T', 'Var', (183, 188))	('thyroid tumor', 'Disease', (37, 50))	('thyroid tumor', 'Phenotype', 'HP:0100031', (37, 50))	('c.1-132_1-125del', 'DELETION', 'None', (123, 139))	('thyroid tumor', 'Disease', 'MESH:D013964', (37, 50))	('TERT', 'Gene', (198, 202))
34378	33375021	(3) Conclusions: This is the first report of PTC harboring a novel deletion along with a hotspot mutation in the TERT promoter in a patient with synchronous esophageal squamous cell carcinoma.	('TERT', 'Gene', '7015', (113, 117))	('synchronous esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (145, 191))	('deletion', 'Var', (67, 75))	('synchronous esophageal squamous cell carcinoma', 'Disease', (145, 191))	('carcinoma', 'Phenotype', 'HP:0030731', (182, 191))	('patient', 'Species', '9606', (132, 139))	('PTC', 'Phenotype', 'HP:0002895', (45, 48))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (168, 191))	('TERT', 'Gene', (113, 117))
34381	33375021	In an effort to finding a biomarker that indicates aggressive biological behavior of the tumor, telomerase reverse transcriptase (TERT) promoter mutations have been suggested as a useful prognostic indicator of clinical aggressiveness and poor outcome in differentiated thyroid carcinomas.	('aggressive biological behavior', 'Phenotype', 'HP:0000718', (51, 81))	('telomerase reverse transcriptase', 'Gene', (96, 128))	('thyroid carcinomas', 'Disease', 'MESH:D013964', (270, 288))	('TERT', 'Gene', (130, 134))	('aggressiveness', 'Disease', 'MESH:D001523', (220, 234))	('thyroid carcinomas', 'Disease', (270, 288))	('mutations', 'Var', (145, 154))	('TERT', 'Gene', '7015', (130, 134))	('telomerase reverse transcriptase', 'Gene', '7015', (96, 128))	('thyroid carcinomas', 'Phenotype', 'HP:0002890', (270, 288))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('aggressiveness', 'Disease', (220, 234))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (270, 287))	('aggressiveness', 'Phenotype', 'HP:0000718', (220, 234))	('carcinoma', 'Phenotype', 'HP:0030731', (278, 287))	('tumor', 'Disease', (89, 94))	('carcinomas', 'Phenotype', 'HP:0030731', (278, 288))
34384	33375021	Two of the most recurrent non-coding mutations, C228T (c.1-124G>A) and C250T (c.1-146G>A), create a de novo binding site (GGAA) for the E26 transformation-specific (ETS) family of transcription factors, specifically the multimeric GA-binding protein (GABP) in the TERT promoter.	('C228T', 'Var', (48, 53))	('c.1-146G>A', 'Var', (78, 88))	('binding', 'Interaction', (108, 115))	('C250T', 'SUBSTITUTION', 'None', (71, 76))	('c.1-124G>A', 'Var', (55, 65))	('TERT', 'Gene', (264, 268))	('TERT', 'Gene', '7015', (264, 268))	('C228T', 'SUBSTITUTION', 'None', (48, 53))	('c.1-124G>A', 'SUBSTITUTION', 'None', (55, 65))	('C250T', 'Var', (71, 76))	('c.1-146G>A', 'SUBSTITUTION', 'None', (78, 88))
34385	33375021	These two TERT promoter mutations occur frequently in poorly differentiated thyroid carcinoma (43.2%) and anaplastic thyroid carcinoma.	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (117, 134))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (76, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('thyroid carcinoma', 'Disease', (76, 93))	('TERT', 'Gene', (10, 14))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('anaplastic thyroid carcinoma', 'Disease', 'MESH:D065646', (106, 134))	('TERT', 'Gene', '7015', (10, 14))	('anaplastic thyroid carcinoma', 'Phenotype', 'HP:0011779', (106, 134))	('anaplastic thyroid carcinoma', 'Disease', (106, 134))	('mutations', 'Var', (24, 33))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (117, 134))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (76, 93))
34386	33375021	Among three major variants of PTC, the tall cell variant shows highest prevalence of TERT promoter mutation, followed by conventional and follicular variants.	('PTC', 'Phenotype', 'HP:0002895', (30, 33))	('TERT', 'Gene', (85, 89))	('TERT', 'Gene', '7015', (85, 89))	('mutation', 'Var', (99, 107))
34389	33375021	Here, we first report the co-occurrence of a novel deletion and hotspot mutation in the TERT promoter in solid variant PTC found in a patient with synchronous primary esophageal cancer.	('hotspot', 'PosReg', (64, 71))	('synchronous primary esophageal cancer', 'Disease', 'MESH:D004938', (147, 184))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('TERT', 'Gene', '7015', (88, 92))	('PTC', 'Phenotype', 'HP:0002895', (119, 122))	('mutation', 'Var', (72, 80))	('synchronous primary esophageal cancer', 'Disease', (147, 184))	('deletion', 'Var', (51, 59))	('patient', 'Species', '9606', (134, 141))	('TERT', 'Gene', (88, 92))
34409	33375021	We carried out Sanger sequencing to identify TERT promoter mutations using a set of primers 5'-AGTGGATTCGCGGGCACAGA-3' (forward) and 5'-AGCACCTCGCGGTAGTGG-3' (reverse).	('TERT', 'Gene', (45, 49))	('TERT', 'Gene', '7015', (45, 49))	('mutations', 'Var', (59, 68))
34410	33375021	The analysis revealed a novel indel mutation, c.1-132_1-124delinsT, composed of a deletion (c.1-132_c.1-125) along with the well-known substitution mutation (c.1-124(G>A)(C228T)) (Figure 3).	('c.1-124', 'Var', (158, 165))	('C228T', 'SUBSTITUTION', 'None', (171, 176))	('c.1-132_c.1-125', 'Var', (92, 107))	('C228T', 'Var', (171, 176))	('c.1-132_1-124delinsT', 'DELETION_INSERTION', 'None', (46, 66))
34412	33375021	TERT promoter mutations are identified in various types of cancers with different frequencies.	('identified', 'Reg', (28, 38))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('TERT', 'Gene', (0, 4))	('TERT', 'Gene', '7015', (0, 4))	('cancers', 'Disease', 'MESH:D009369', (59, 66))	('cancers', 'Phenotype', 'HP:0002664', (59, 66))	('cancers', 'Disease', (59, 66))	('mutations', 'Var', (14, 23))
34414	33375021	As a result of its rarity, the frequency of TERT promoter mutations in SVPTC has not been well known, and only a few studies compared the genetic alterations among subvariants of PTC including SVPTC.	('mutations', 'Var', (58, 67))	('PTC', 'Phenotype', 'HP:0002895', (73, 76))	('TERT', 'Gene', (44, 48))	('TERT', 'Gene', '7015', (44, 48))	('PTC', 'Phenotype', 'HP:0002895', (195, 198))	('PTC', 'Phenotype', 'HP:0002895', (179, 182))
34419	33375021	Two mutations of the TERT core promoter, which cause a cytidine-to-thymidine (CT) dipyrimidine transition at chromosome 5 1,295,228 and 1,295,250 (-124 and -146bp from the ATG), c.1-124C>T(C228T) and c.1-146C>T(C250T), respectively, predominantly occur regardless of tumor type.	('c.1-146C>T', 'Var', (200, 210))	('c.1-124C>T', 'Var', (178, 188))	('tumor', 'Disease', 'MESH:D009369', (267, 272))	('TERT', 'Gene', (21, 25))	('c.1-146C>T', 'SUBSTITUTION', 'None', (200, 210))	('cytidine-to-thymidine', 'MPA', (55, 76))	('cytidine', 'Chemical', 'MESH:D003562', (55, 63))	('TERT', 'Gene', '7015', (21, 25))	('tumor', 'Phenotype', 'HP:0002664', (267, 272))	('C250T', 'SUBSTITUTION', 'None', (211, 216))	('C228T', 'SUBSTITUTION', 'None', (189, 194))	('tumor', 'Disease', (267, 272))	('thymidine', 'Chemical', 'MESH:D013936', (67, 76))	('c.1-124C>T', 'SUBSTITUTION', 'None', (178, 188))	('dipyrimidine', 'Chemical', '-', (82, 94))	('C228T', 'Var', (189, 194))	('C250T', 'Var', (211, 216))
34420	33375021	The C228T mutation is more prevalent than C250T among various malignancies including thyroid cancer.	('C250T', 'SUBSTITUTION', 'None', (42, 47))	('C250T', 'Var', (42, 47))	('malignancies', 'Disease', 'MESH:D009369', (62, 74))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('C228T', 'SUBSTITUTION', 'None', (4, 9))	('thyroid cancer', 'Phenotype', 'HP:0002890', (85, 99))	('thyroid cancer', 'Disease', (85, 99))	('C228T', 'Var', (4, 9))	('malignancies', 'Disease', (62, 74))	('prevalent', 'Reg', (27, 36))	('thyroid cancer', 'Disease', 'MESH:D013964', (85, 99))
34421	33375021	Multiple studies provide evidence that the presence of C228T or C250T mutations promotes telomerase activity both in vivo and in vitro.	('C250T', 'Var', (64, 69))	('C228T', 'Var', (55, 60))	('C250T', 'SUBSTITUTION', 'None', (64, 69))	('telomerase', 'Enzyme', (89, 99))	('C228T', 'SUBSTITUTION', 'None', (55, 60))	('promotes', 'PosReg', (80, 88))
34422	33375021	These mutations generate a de novo binding site for activating the ETS family of transcription factors, including GA-binding proteins (GABP), thereby activating TERT transcription and telomerase activity.	('telomerase', 'CPA', (184, 194))	('activating', 'PosReg', (150, 160))	('TERT', 'Gene', (161, 165))	('activating', 'PosReg', (52, 62))	('TERT', 'Gene', '7015', (161, 165))	('mutations', 'Var', (6, 15))
34423	33375021	Although not a promoter lesion, one previous study reviewing 173 Hurthle cell carcinomas of thyroid cases found a 24 bp deletion in the 5' UTR of exon 1 (c.-53_-29delAGCGCTGCGTCCTGCTGCGCACGT) of TERT in one sample.	('c.-53_-29delAGCGCTGCGTCCTGCTGCGCACGT', 'DELETION', 'None', (154, 190))	('TERT', 'Gene', (195, 199))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('Hurthle cell carcinomas of thyroid', 'Phenotype', 'HP:0006781', (65, 99))	('TERT', 'Gene', '7015', (195, 199))	('carcinomas of thyroid', 'Disease', (78, 99))	('carcinomas', 'Phenotype', 'HP:0030731', (78, 88))	('c.-53_-29delAGCGCTGCGTCCTGCTGCGCACGT', 'Var', (154, 190))	('carcinomas of thyroid', 'Disease', 'MESH:D013964', (78, 99))
34424	33375021	A recent study identified two additional novel mutations in the thyroid tumor: c.-332C>T in one medullary thyroid carcinoma and c.-104_-83dup in one PTC.	('thyroid tumor', 'Phenotype', 'HP:0100031', (64, 77))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('c.-104_-83dup', 'Var', (128, 141))	('c.-332C>T', 'Var', (79, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('PTC', 'Phenotype', 'HP:0002895', (149, 152))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (106, 123))	('c.-332C>T', 'SUBSTITUTION', 'None', (79, 88))	('thyroid tumor', 'Disease', (64, 77))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (106, 123))	('medullary thyroid carcinoma', 'Phenotype', 'HP:0002865', (96, 123))	('thyroid tumor', 'Disease', 'MESH:D013964', (64, 77))	('c.-104_-83dup', 'DUPLICATION', 'None', (128, 141))	('thyroid carcinoma', 'Disease', (106, 123))
34426	33375021	Instead, the mutation deletes the Specificity Protein 1 (SP1) binding site (Figure 4).	('mutation', 'Var', (13, 21))	('Specificity Protein 1', 'Gene', '6667', (34, 55))	('Specificity Protein 1', 'Gene', (34, 55))	('deletes', 'NegReg', (22, 29))
34429	33375021	In a previous study, the authors observed that hotspot mutant promoter activity fluctuated depending on the distance from the native ETS sites, and there was peak activity when two locations were separated by full helical turns of DNA, suggesting that TERT promoter mutation cooperates with native ETSs to recruit GABP.	('TERT', 'Gene', (252, 256))	('TERT', 'Gene', '7015', (252, 256))	('mutant', 'Var', (55, 61))	('mutation', 'Var', (266, 274))	('promoter activity', 'MPA', (62, 79))
34430	33375021	In order to confirm the overall effects of deletion and point mutation of the TERT gene promoter, further studies should be performed through luciferase reporter assay.	('deletion', 'Var', (43, 51))	('TERT', 'Gene', (78, 82))	('TERT', 'Gene', '7015', (78, 82))	('point mutation', 'Var', (56, 70))
34431	33375021	The co-occurrence of different substitution mutations of the TERT promoter has previously been reported.	('substitution', 'Var', (31, 43))	('TERT', 'Gene', '7015', (61, 65))	('TERT', 'Gene', (61, 65))
34432	33375021	One previous PTC cohort study reported that mutations C229T (c.-125C>T) and C232T (c.-128C>T) were simultaneously found in one PTC sample.	('found', 'Reg', (114, 119))	('c.-128C>T', 'SUBSTITUTION', 'None', (83, 92))	('c.-128C>T', 'Var', (83, 92))	('C229T', 'SUBSTITUTION', 'None', (54, 59))	('c.-125C>T', 'SUBSTITUTION', 'None', (61, 70))	('C229T', 'Var', (54, 59))	('C232T', 'SUBSTITUTION', 'None', (76, 81))	('PTC', 'Phenotype', 'HP:0002895', (13, 16))	('c.-125C>T', 'Var', (61, 70))	('PTC', 'Phenotype', 'HP:0002895', (127, 130))	('C232T', 'Var', (76, 81))
34434	33375021	The rs2853669 common allele, a common T>C polymorphism at the -245 bp position from the ATG site, disrupts the pre-existing non-canonical ETS2 binding site in the proximal region of the TERT promoter, reducing the transcriptional activity of TERT.	('ETS2', 'Gene', (138, 142))	('disrupts', 'NegReg', (98, 106))	('TERT', 'Gene', (242, 246))	('binding', 'Interaction', (143, 150))	('rs2853669', 'Var', (4, 13))	('TERT', 'Gene', '7015', (242, 246))	('ETS2', 'Gene', '2114', (138, 142))	('reducing', 'NegReg', (201, 209))	('rs2853669', 'DBSNP_MENTION', 'None', (4, 13))	('TERT', 'Gene', (186, 190))	('transcriptional activity', 'MPA', (214, 238))	('TERT', 'Gene', '7015', (186, 190))
34435	33375021	Several studies reported that the prognostic effect of TERT promoter mutations was modified by the SNP in the TERT promoter.	('mutations', 'Var', (69, 78))	('prognostic', 'MPA', (34, 44))	('TERT', 'Gene', (110, 114))	('TERT', 'Gene', (55, 59))	('TERT', 'Gene', '7015', (110, 114))	('TERT', 'Gene', '7015', (55, 59))	('SNP', 'Var', (99, 102))	('modified', 'Reg', (83, 91))
34436	33375021	In the presence of a somatic TERT promoter mutation in the tumor, patients with the rs2853669 common allele showed poor prognosis in bladder cancer and glioma, although conflicting evidence has been found for the latter.	('TERT', 'Gene', '7015', (29, 33))	('bladder cancer', 'Phenotype', 'HP:0009725', (133, 147))	('tumor', 'Disease', (59, 64))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('glioma', 'Disease', (152, 158))	('rs2853669', 'DBSNP_MENTION', 'None', (84, 93))	('glioma', 'Phenotype', 'HP:0009733', (152, 158))	('patients', 'Species', '9606', (66, 74))	('bladder cancer', 'Disease', 'MESH:D001749', (133, 147))	('bladder cancer', 'Disease', (133, 147))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('glioma', 'Disease', 'MESH:D005910', (152, 158))	('rs2853669', 'Var', (84, 93))	('TERT', 'Gene', (29, 33))
34438	33375021	A previous study evaluating two hotspot TERT promoter mutations in 313 esophageal squamous cell carcinoma samples identified 1.6% occurrence, showing the extremely low frequency compared to that of thyroid cancer (15-50%).	('TERT', 'Gene', '7015', (40, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('esophageal squamous cell carcinoma', 'Disease', (71, 105))	('thyroid cancer', 'Phenotype', 'HP:0002890', (198, 212))	('thyroid cancer', 'Disease', (198, 212))	('mutations', 'Var', (54, 63))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (71, 105))	('thyroid cancer', 'Disease', 'MESH:D013964', (198, 212))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (82, 105))	('TERT', 'Gene', (40, 44))
34439	33375021	Some studies identified a germline mutation in TERT, c.-57T>G in only two melanoma families worldwide, indicating that this inherited mutation is extremely rare.	('TERT', 'Gene', (47, 51))	('c.-57T>G', 'Var', (53, 61))	('TERT', 'Gene', '7015', (47, 51))	('c.-57T>G', 'SUBSTITUTION', 'None', (53, 61))	('melanoma', 'Disease', 'MESH:D008545', (74, 82))	('melanoma', 'Phenotype', 'HP:0002861', (74, 82))	('melanoma', 'Disease', (74, 82))
34448	33375021	In conclusion, this is the first report to describe the co-existing deletion and hotspot TERT promoter mutation of SVPTC in a patient with synchronous esophageal squamous cell carcinoma.	('PTC', 'Phenotype', 'HP:0002895', (117, 120))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (162, 185))	('SVPTC', 'Gene', (115, 120))	('patient', 'Species', '9606', (126, 133))	('TERT', 'Gene', (89, 93))	('deletion', 'Var', (68, 76))	('TERT', 'Gene', '7015', (89, 93))	('synchronous esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (139, 185))	('synchronous esophageal squamous cell carcinoma', 'Disease', (139, 185))	('carcinoma', 'Phenotype', 'HP:0030731', (176, 185))
34449	32547941	Analysis of Genetic Alteration Signatures and Prognostic Values of m6A Regulatory Genes in Head and Neck Squamous Cell Carcinoma Genetic alteration involving N6-methyladenosine (m6A) regulatory genes is a frequent characteristic of multiple tumors.	('Genetic alteration', 'Var', (129, 147))	('m6A', 'Gene', (67, 70))	('N6-methyladenosine', 'Chemical', 'MESH:C010223', (158, 176))	('Carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('tumors', 'Disease', (241, 247))	('Neck Squamous Cell Carcinoma', 'Disease', (100, 128))	('Neck Squamous Cell Carcinoma', 'Disease', 'MESH:D000077195', (100, 128))	('alteration', 'Var', (137, 147))	('tumors', 'Disease', 'MESH:D009369', (241, 247))	('m6A', 'Gene', '56339', (67, 70))	('Head and Neck Squamous Cell Carcinoma', 'Phenotype', 'HP:0012288', (91, 128))	('tumors', 'Phenotype', 'HP:0002664', (241, 247))	('m6A', 'Gene', (178, 181))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (105, 128))	('m6A', 'Gene', '56339', (178, 181))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))
34452	32547941	Correlation analysis involving alteration of m6A regulatory genes, clinicopathological characteristics, and patient survival was performed using R language.	('m6A', 'Gene', (45, 48))	('m6A', 'Gene', '56339', (45, 48))	('alteration', 'Var', (31, 41))	('patient', 'Species', '9606', (108, 115))
34453	32547941	The results suggest that alteration of m6A regulatory genes was correlated with clinical staging.	('m6A', 'Gene', '56339', (39, 42))	('alteration', 'Var', (25, 35))	('m6A', 'Gene', (39, 42))	('correlated', 'Reg', (64, 74))
34454	32547941	Patients with high expression of ALKBH5, FTO, METTL14, WTAP, YTHDC1, YTHDF1, and YTHDF2 had poor overall survival (OS) than those with low expression.	('YTHDF2', 'Gene', '51441', (81, 87))	('YTHDC1', 'Gene', '91746', (61, 67))	('YTHDF1', 'Gene', (69, 75))	('FTO', 'Gene', '79068', (41, 44))	('ALKBH5', 'Gene', '54890', (33, 39))	('overall survival', 'MPA', (97, 113))	('WTAP', 'Gene', '9589', (55, 59))	('YTHDF2', 'Gene', (81, 87))	('WTAP', 'Gene', (55, 59))	('ALKBH5', 'Gene', (33, 39))	('poor', 'NegReg', (92, 96))	('Patients', 'Species', '9606', (0, 8))	('FTO', 'Gene', (41, 44))	('high expression', 'Var', (14, 29))	('METTL14', 'Gene', (46, 53))	('YTHDC1', 'Gene', (61, 67))	('YTHDF1', 'Gene', '54915', (69, 75))	('METTL14', 'Gene', '57721', (46, 53))
34456	32547941	However, patients with high YTHDC2 expression had better OS.	('patients', 'Species', '9606', (9, 17))	('better', 'PosReg', (50, 56))	('high YTHDC2 expression', 'Var', (23, 45))
34458	32547941	Here, we identified alterations to m6A regulatory genes in HNSCC for the first time and found that seven m6A regulators were associated with poor prognosis, especially ALKBH5, whereas YTHDC2 was associated with better prognosis.	('m6A', 'Gene', (35, 38))	('alterations', 'Var', (20, 31))	('m6A', 'Gene', '56339', (35, 38))	('m6A', 'Gene', (105, 108))	('associated', 'Reg', (125, 135))	('m6A', 'Gene', '56339', (105, 108))	('ALKBH5', 'Gene', '54890', (168, 174))	('HNSCC', 'Phenotype', 'HP:0012288', (59, 64))	('ALKBH5', 'Gene', (168, 174))	('HNSCC', 'Disease', (59, 64))
34474	32547941	Emerging evidence shows that m6A modification is related to tumor proliferation, differentiation, occurrence, invasion, and metastasis and plays the role of oncogene or antioncogenes in malignant tumors.	('malignant tumors', 'Disease', (186, 202))	('modification', 'Var', (33, 45))	('malignant tumors', 'Disease', 'MESH:D009369', (186, 202))	('tumors', 'Phenotype', 'HP:0002664', (196, 202))	('tumor', 'Disease', (196, 201))	('metastasis', 'CPA', (124, 134))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('m6A', 'Gene', (29, 32))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('related', 'Reg', (49, 56))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('invasion', 'CPA', (110, 118))	('tumor', 'Disease', (60, 65))	('m6A', 'Gene', '56339', (29, 32))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))
34478	32547941	The deletion of m6A methyltransferase METTL3 leads to selective splicing and gene expression alteration of >20 genes involved in the TP53 signaling pathway in hepatocellular carcinoma (HCC).	('gene expression', 'MPA', (77, 92))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (159, 183))	('carcinoma', 'Phenotype', 'HP:0030731', (174, 183))	('alteration', 'Reg', (93, 103))	('splicing', 'MPA', (64, 72))	('hepatocellular carcinoma', 'Disease', (159, 183))	('METTL3', 'Gene', (38, 44))	('m6A', 'Gene', (16, 19))	('METTL3', 'Gene', '56339', (38, 44))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (159, 183))	('m6A', 'Gene', '56339', (16, 19))	('deletion', 'Var', (4, 12))	('TP53', 'Gene', '7157', (133, 137))	('HCC', 'Phenotype', 'HP:0001402', (185, 188))	('TP53', 'Gene', (133, 137))
34483	32547941	SNP analysis was based on VarScan2 variant aggregation and masking data in TCGA, in particular for mutation analysis of 10 m6A regulatory genes.	('TCGA', 'Gene', (75, 79))	('variant', 'Var', (35, 42))	('m6A', 'Gene', '56339', (123, 126))	('m6A', 'Gene', (123, 126))
34495	32547941	Briefly, paraffin sections were dewaxed, and endogenous peroxidase activity was blocked with 0.3% hydrogen peroxide for 10 min at 37 C. Following antigen retrieval, the tissue sections were incubated with primary antibody YTHDC2 (1:500; EPR21820-49, AB220160; Abcam, Inc., Cambridge, MA, USA) or ALKBH5 (1:2000; EPR18958, ab195377, Abcam, Inc.) at 4 C overnight and then with a secondary antibody at room temperature (25 C) overnight.	('1:2000; EPR18958', 'Var', (304, 320))	('ALKBH5', 'Gene', (296, 302))	('paraffin', 'Chemical', 'MESH:D010232', (9, 17))	('ALKBH5', 'Gene', '54890', (296, 302))
34497	32547941	Of the 506 patients with sequencing data used for SNP mutation analysis, only 41 (8.1%) of the samples had mutation events in any of the 10 m6A regulatory genes as shown in Figure 1.	('patients', 'Species', '9606', (11, 19))	('mutation', 'Var', (107, 115))	('m6A', 'Gene', '56339', (140, 143))	('m6A', 'Gene', (140, 143))
34508	32547941	Additionally, SNP analysis revealed that the most frequent variant classification of m6A regulatory gene mutation was missense mutation, and the largest number of variant types was SNP (Figure S1).	('m6A', 'Gene', '56339', (85, 88))	('m6A', 'Gene', (85, 88))	('mutation', 'Var', (105, 113))	('missense mutation', 'Var', (118, 135))
34509	32547941	The most obvious mutations involved TP53 as mentioned before (66%) and TTN (35%).	('TTN', 'Gene', '7273', (71, 74))	('TP53', 'Gene', '7157', (36, 40))	('TP53', 'Gene', (36, 40))	('TTN', 'Gene', (71, 74))	('mutations', 'Var', (17, 26))
34510	32547941	We then evaluated the relationship between CNV alterations in 10 m6A regulatory genes and clinicopathological features of HNSCC patients.	('m6A', 'Gene', '56339', (65, 68))	('HNSCC', 'Phenotype', 'HP:0012288', (122, 127))	('HNSCC', 'Disease', (122, 127))	('alterations', 'Var', (47, 58))	('patients', 'Species', '9606', (128, 136))	('m6A', 'Gene', (65, 68))
34512	32547941	The results showed that alterations to m6A regulatory genes were significantly related to age, gender, and clinical stage (P < 0.05) (Table 1).	('related', 'Reg', (79, 86))	('m6A', 'Gene', '56339', (39, 42))	('alterations', 'Var', (24, 35))	('m6A', 'Gene', (39, 42))
34515	32547941	With CNV events from deletion to amplification, gene expression of the 10 m6A regulatory genes also showed an upward trend; that is, gene expression increased with increased CNV amplification and decreased with CNV deletion.	('CNV amplification', 'Var', (174, 191))	('decreased', 'NegReg', (196, 205))	('increased', 'PosReg', (149, 158))	('gene expression', 'MPA', (133, 148))	('m6A', 'Gene', (74, 77))	('deletion', 'Var', (21, 29))	('m6A', 'Gene', '56339', (74, 77))
34524	32547941	Combined with the results of the previous analysis (Figure 2A), among the 10 genes, the incidence of CNV events involving YTHDC2 was second only to YTHDF3, and YTHDC2 gene expression and survival prognosis results were also significant.	('YTHDC2', 'Var', (122, 128))	('YTHDF3', 'Gene', (148, 154))	('YTHDF3', 'Gene', '253943', (148, 154))
34529	32547941	GSEA analysis implied that high expression of YTHDC2 is associated with certain key pathways, such as apoptosis, ubiquitin-mediated proteolysis, long-term potentiation, and rig-i-like receptor signaling pathways, revealing the underlying mechanisms involved in HNSCC pathogenesis (Figure 9).	('HNSCC', 'Disease', (261, 266))	('HNSCC', 'Phenotype', 'HP:0012288', (261, 266))	('key pathways', 'Pathway', (80, 92))	('apoptosis', 'MPA', (102, 111))	('rig-i-like receptor signaling pathways', 'Pathway', (173, 211))	('associated', 'Reg', (56, 66))	('long-term potentiation', 'MPA', (145, 167))	('high expression', 'Var', (27, 42))	('ubiquitin-mediated proteolysis', 'MPA', (113, 143))	('GSEA', 'Chemical', '-', (0, 4))	('YTHDC2', 'Gene', (46, 52))
34543	32547941	In the ccRCC cohort, m6A regulatory gene alterations were significantly related to higher Fuhrman nuclear grading.	('m6A', 'Gene', '56339', (21, 24))	('ccRCC', 'Phenotype', 'HP:0006770', (7, 12))	('higher Fuhrman nuclear grading', 'CPA', (83, 113))	('related', 'Reg', (72, 79))	('m6A', 'Gene', (21, 24))	('alterations', 'Var', (41, 52))
34545	32547941	In our HNSCC samples, the alterations to m6A regulatory genes were significantly correlated with age, sex, and clinical stage.	('m6A', 'Gene', '56339', (41, 44))	('HNSCC', 'Phenotype', 'HP:0012288', (7, 12))	('alterations', 'Var', (26, 37))	('correlated', 'Reg', (81, 91))	('m6A', 'Gene', (41, 44))
34546	32547941	This indicated that alterations in m6A CNV may show different clinical characteristics in different tumors.	('m6A', 'Gene', (35, 38))	('alterations', 'Var', (20, 31))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('m6A', 'Gene', '56339', (35, 38))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('tumors', 'Disease', (100, 106))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))
34553	32547941	In HNSCC cases, we observed longer OS with diploid or copy number gain, which is different from the situation in AML but similar to that of ccRCC.	('HNSCC', 'Phenotype', 'HP:0012288', (3, 8))	('copy number', 'Var', (54, 65))	('ccRCC', 'Phenotype', 'HP:0006770', (140, 145))	('gain', 'PosReg', (66, 70))	('AML', 'Disease', 'MESH:D015470', (113, 116))	('AML', 'Phenotype', 'HP:0004808', (113, 116))	('AML', 'Disease', (113, 116))	('diploid', 'Var', (43, 50))	('HNSCC', 'Disease', (3, 8))
34563	32547941	The translation efficiency of Smc3 (target YTHDC2 in spermatogenesis) is significantly decreased in YTHDC2-/- mice compared to YTHDC2 +/+ animals.	('Smc3', 'Gene', '13006', (30, 34))	('decreased', 'NegReg', (87, 96))	('mice', 'Species', '10090', (110, 114))	('Smc3', 'Gene', (30, 34))	('YTHDC2-/-', 'Var', (100, 109))	('translation', 'MPA', (4, 15))
34564	32547941	In addition, the testes and epididymis from adult YTHDC2-/- mice are smaller in size than wild type (YTHDC2 +/+).	('YTHDC2-/-', 'Var', (50, 59))	('mice', 'Species', '10090', (60, 64))	('smaller', 'NegReg', (69, 76))
34575	32547941	The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fonc.2020.00718/full#supplementary-material m6A N6-methyladenosine HNSCC head and neck squamous cell carcinoma CNV copy number variation TCGA The Cancer Genome Atlas GEO Gene Expression Omnibus ccRCC clear cell renal cell carcinoma AML acute myeloid leukemia OS overall survival GSEA gene set enrichment analysis IHC immunohistochemistry.	('AML', 'Disease', 'MESH:D015470', (345, 348))	('clear cell renal cell carcinoma', 'Disease', (313, 344))	('GSEA', 'Chemical', '-', (392, 396))	('AML', 'Disease', (345, 348))	('AML', 'Phenotype', 'HP:0004808', (345, 348))	('acute myeloid leukemia', 'Disease', (349, 371))	('carcinoma', 'Phenotype', 'HP:0030731', (335, 344))	('leukemia', 'Phenotype', 'HP:0001909', (363, 371))	('Cancer', 'Disease', 'MESH:D009369', (259, 265))	('m6A', 'Gene', '56339', (157, 160))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (186, 223))	('carcinoma', 'Phenotype', 'HP:0030731', (214, 223))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (313, 344))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (355, 371))	('m6A', 'Gene', (157, 160))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (349, 371))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (349, 371))	('Cancer', 'Phenotype', 'HP:0002664', (259, 265))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (324, 344))	('neck squamous cell carcinoma', 'Disease', (195, 223))	('copy number variation', 'Var', (228, 249))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (313, 344))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (200, 223))	('HNSCC', 'Phenotype', 'HP:0012288', (180, 185))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (195, 223))	('N6-methyladenosine', 'Chemical', 'MESH:C010223', (161, 179))	('Cancer', 'Disease', (259, 265))	('ccRCC', 'Phenotype', 'HP:0006770', (307, 312))
34601	29378603	All the patients had stage IA disease (pT1aN0M0 or pT1bN0M0), according to the Seventh Edition of the International Union against Cancer TNM classification system.	('Cancer', 'Disease', (130, 136))	('pT1bN0M0', 'Var', (51, 59))	('Cancer', 'Disease', 'MESH:D009369', (130, 136))	('T1a', 'Gene', '10630', (40, 43))	('Cancer', 'Phenotype', 'HP:0002664', (130, 136))	('T1a', 'Gene', (40, 43))	('TNM', 'Gene', (137, 140))	('stage IA disease', 'Disease', 'MESH:C536041', (21, 37))	('stage IA disease', 'Disease', (21, 37))	('TNM', 'Gene', '10178', (137, 140))	('patients', 'Species', '9606', (8, 16))
34695	28881734	Here, we show that overall ALDH activity is increased with cisplatin treatment of HNSCC and that ALDH3A1 protein expression is particularly enriched in cells treated with cisplatin.	('ALDH3A1', 'Gene', (97, 104))	('cisplatin', 'Var', (59, 68))	('activity', 'MPA', (32, 40))	('increased', 'PosReg', (44, 53))	('ALDH', 'Enzyme', (27, 31))	('cisplatin', 'Chemical', 'MESH:D002945', (171, 180))	('cisplatin', 'Chemical', 'MESH:D002945', (59, 68))
34697	28881734	Conversely, treatment with a novel small molecule ALDH inhibitor (Aldi-6) resulted in a marked decrease in cell viability, and the combination of Aldi-6 and cisplatin resulted in a more pronounced reduction of cell viability and a greater reduction in tumor burden in vivo than what was observed with cisplatin alone.	('decrease', 'NegReg', (95, 103))	('combination', 'Interaction', (131, 142))	('reduction', 'NegReg', (239, 248))	('Aldi', 'Gene', (66, 70))	('cisplatin', 'Var', (157, 166))	('reduction', 'NegReg', (197, 206))	('Aldi', 'Gene', (146, 150))	('cell viability', 'CPA', (107, 121))	('cell viability', 'CPA', (210, 224))	('tumor', 'Disease', 'MESH:D009369', (252, 257))	('tumor', 'Phenotype', 'HP:0002664', (252, 257))	('cisplatin', 'Chemical', 'MESH:D002945', (301, 310))	('cisplatin', 'Chemical', 'MESH:D002945', (157, 166))	('tumor', 'Disease', (252, 257))	('Aldi', 'Gene', '196410', (146, 150))	('Aldi', 'Gene', '196410', (66, 70))
34709	28881734	Many chemotherapeutic drugs, including cisplatin and erlotinib, are also known to generate oxidative stress and elevate levels of lipid peroxidation derived aldehydes.	('oxidative stress', 'Phenotype', 'HP:0025464', (91, 107))	('elevate', 'PosReg', (112, 119))	('lipid', 'Chemical', 'MESH:D008055', (130, 135))	('cisplatin', 'Var', (39, 48))	('generate', 'PosReg', (82, 90))	('erlotinib', 'Chemical', 'MESH:D000069347', (53, 62))	('aldehydes', 'Chemical', 'MESH:D000447', (157, 166))	('elevate levels of lipid', 'Phenotype', 'HP:0003077', (112, 135))	('oxidative stress', 'MPA', (91, 107))	('cisplatin', 'Chemical', 'MESH:D002945', (39, 48))	('levels of lipid peroxidation derived aldehydes', 'MPA', (120, 166))	('erlotinib', 'Gene', (53, 62))
34711	28881734	The fact that mutations in various ALDH genes and altered expression of these genes are implicated in multiple cancers highlights the importance of the breakdown of oxidizing aldehydes to non-toxic products as a critical process to reduce oxidative stress.	('cancers', 'Phenotype', 'HP:0002664', (111, 118))	('oxidative stress', 'Phenotype', 'HP:0025464', (239, 255))	('implicated', 'Reg', (88, 98))	('multiple cancers', 'Disease', 'MESH:D009369', (102, 118))	('ALDH genes', 'Gene', (35, 45))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('aldehydes', 'Chemical', 'MESH:D000447', (175, 184))	('altered', 'Reg', (50, 57))	('multiple cancers', 'Disease', (102, 118))	('mutations', 'Var', (14, 23))
34713	28881734	Furthermore, high levels of ALDH1 in patient samples have been correlated with poor prognosis in HNSCC, lung, prostate, breast and pancreatic cancer.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (131, 148))	('high levels', 'Var', (13, 24))	('ALDH1', 'Gene', '216', (28, 33))	('lung', 'Disease', (104, 108))	('patient', 'Species', '9606', (37, 44))	('HNSCC', 'Disease', (97, 102))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('breast and pancreatic cancer', 'Disease', 'MESH:D010190', (120, 148))	('prostate', 'Disease', (110, 118))	('ALDH1', 'Gene', (28, 33))
34716	28881734	Thus, isozyme-selective inhibitors of the relevant ALDHs may reduce resistance to the chemotherapy in cancer cells and sensitize these cells to lower doses of chemotherapeutic agents.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('reduce', 'NegReg', (61, 67))	('ALDHs', 'Gene', (51, 56))	('cancer', 'Disease', (102, 108))	('inhibitors', 'Var', (24, 34))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('sensitize', 'Reg', (119, 128))	('resistance to the chemotherapy in', 'MPA', (68, 101))
34731	28881734	While it is possible that ALDH3A1 protein expression was induced by cisplatin, we also noted that cisplatin, at the concentration (15 muM) used here, was sufficient to result in 40% and 60% cell death in SCC4 and PCI-13, respectively (Supplementary Figure 1A and 1B).	('muM', 'Gene', '56925', (134, 137))	('cisplatin', 'Var', (98, 107))	('expression', 'MPA', (42, 52))	('muM', 'Gene', (134, 137))	('induced', 'Reg', (57, 64))	('ALDH3A1', 'Gene', (26, 33))	('cisplatin', 'Chemical', 'MESH:D002945', (98, 107))	('PCI-13', 'Chemical', '-', (213, 219))	('cell death', 'CPA', (190, 200))	('cisplatin', 'Chemical', 'MESH:D002945', (68, 77))
34739	28881734	Treatment of SCC4 cells with Alda-89 in combination with cisplatin for four consecutive days resulted in a dose-dependent increase in cell survival (Figure 3B, right, black bars), indicating that activation of ALDH3A1 can increase cisplatin resistance in SCC4 cells (Figure 3B).	('cell survival', 'CPA', (134, 147))	('Alda', 'Gene', '226', (29, 33))	('activation', 'Var', (196, 206))	('cisplatin', 'Chemical', 'MESH:D002945', (231, 240))	('Alda', 'Gene', (29, 33))	('increase', 'PosReg', (222, 230))	('cisplatin', 'Chemical', 'MESH:D002945', (57, 66))	('ALDH3A1', 'Gene', (210, 217))	('cisplatin resistance', 'MPA', (231, 251))	('increase', 'PosReg', (122, 130))
34742	28881734	To investigate if the inhibition of ALDH3A1 can enhance cisplatin toxicity, we used a novel ALDH inhibitor (3-(Dimethylamino)-4' bromopropiophenone, MW = 261), discovered by our group and herein, referred to as Aldi-6 (Figure 4A).	('inhibition', 'Var', (22, 32))	('Aldi', 'Gene', '196410', (211, 215))	('cisplatin', 'Chemical', 'MESH:D002945', (56, 65))	('ALDH3A1', 'Gene', (36, 43))	('enhance', 'PosReg', (48, 55))	('toxicity', 'Disease', 'MESH:D064420', (66, 74))	('Aldi', 'Gene', (211, 215))	('toxicity', 'Disease', (66, 74))
34752	28881734	With cisplatin treatment, ALDH activity increased by about two-fold in both SCC4 and PCI-13 cells, as measured by mean fluorescence intensity (MFI) (Figure 5C).	('activity', 'MPA', (31, 39))	('cisplatin', 'Var', (5, 14))	('PCI-13', 'Chemical', '-', (85, 91))	('cisplatin', 'Chemical', 'MESH:D002945', (5, 14))	('increased', 'PosReg', (40, 49))	('ALDH', 'Enzyme', (26, 30))
34758	28881734	Transduction of ALDH3A1 shRNA significantly enhanced cisplatin sensitivity and led to a reduction in cell viability (Figure 6B).	('cisplatin sensitivity', 'MPA', (53, 74))	('Transduction', 'Var', (0, 12))	('ALDH3A1', 'Gene', (16, 23))	('reduction', 'NegReg', (88, 97))	('cell viability', 'CPA', (101, 115))	('cisplatin', 'Chemical', 'MESH:D002945', (53, 62))	('enhanced', 'PosReg', (44, 52))
34763	28881734	The combination of Aldi-6 and cisplatin treatment resulted in an even greater reduction in cell viability (Figure 7A).	('Aldi', 'Gene', '196410', (19, 23))	('cisplatin', 'Var', (30, 39))	('reduction', 'NegReg', (78, 87))	('Aldi', 'Gene', (19, 23))	('cisplatin', 'Chemical', 'MESH:D002945', (30, 39))	('cell viability', 'CPA', (91, 105))
34779	28881734	We hypothesized that inhibition of ALDH activity can effectively increase the oxidative insult from cisplatin and potentiate the efficacy of chemotherapy.	('increase', 'PosReg', (65, 73))	('efficacy of chemotherapy', 'CPA', (129, 153))	('cisplatin', 'Chemical', 'MESH:D002945', (100, 109))	('oxidative insult from cisplatin', 'MPA', (78, 109))	('inhibition', 'Var', (21, 31))	('activity', 'MPA', (40, 48))	('potentiate', 'PosReg', (114, 124))	('ALDH', 'Protein', (35, 39))
34780	28881734	Our data indicate that ALDH3A1 plays a role in cisplatin-resistant cell survival in HNSCC and that inhibition of this enzyme may be a useful strategy in the cisplatin refractory context.	('ALDH3A1', 'Gene', (23, 30))	('HNSCC', 'Disease', (84, 89))	('inhibition', 'Var', (99, 109))	('cisplatin', 'Chemical', 'MESH:D002945', (47, 56))	('cisplatin', 'Chemical', 'MESH:D002945', (157, 166))
34791	28881734	However, CB29 inhibited ALDH3A1 with an IC50 of 16 muM, which is 16 times greater than that of Aldi-6.	('muM', 'Gene', '56925', (51, 54))	('Aldi', 'Gene', '196410', (95, 99))	('inhibited', 'NegReg', (14, 23))	('muM', 'Gene', (51, 54))	('ALDH3A1', 'Protein', (24, 31))	('CB29', 'Var', (9, 13))	('Aldi', 'Gene', (95, 99))
34811	28881734	Aldi-6 (3-(Dimethylamino)-4'-bromopropiophenone, an ALDH1A1, 2 and 3A1 inhibitor) and Alda-89 (S9652, 4-Allyl-1,2-methylenedioxybenzene, an ALDH3A1-activator, Sigma, St. Louis, MO) were identified by our high throughput screening of small molecules.	('Aldi', 'Gene', (0, 4))	('ALDH1A1', 'Gene', (52, 59))	('4-Allyl-1,2-methylenedioxybenzene', 'Chemical', 'MESH:D012451', (102, 135))	("3-(Dimethylamino)-4'-bromopropiophenone", 'Chemical', '-', (8, 47))	('Alda', 'Gene', (86, 90))	('Aldi', 'Gene', '196410', (0, 4))	('ALDH1A1', 'Gene', '216', (52, 59))	('Alda', 'Gene', '226', (86, 90))	('S9652', 'Var', (95, 100))
34845	27650546	We modify the HaCaT keratinocyte cell line model to simulate cancer cells with constitutive activation of EGFR, HRAS, and PI3K in a controlled genetic background.	('PI3K', 'Var', (122, 126))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('activation', 'PosReg', (92, 102))	('cancer', 'Disease', (61, 67))	('HaCaT', 'CellLine', 'CVCL:0038', (14, 19))	('HRAS', 'Gene', '3265', (112, 116))	('EGFR', 'Gene', '1956', (106, 110))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('HRAS', 'Gene', (112, 116))	('EGFR', 'Gene', (106, 110))
34856	27650546	Similar findings have led to the FDA approval and clinical adoption of EGFR inhibitors in other solid tumors.	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('solid tumors', 'Disease', (96, 108))	('EGFR', 'Gene', '1956', (71, 75))	('inhibitors', 'Var', (76, 86))	('solid tumors', 'Disease', 'MESH:D009369', (96, 108))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('EGFR', 'Gene', (71, 75))
34859	27650546	These signaling changes arise from complex feedback between ligand overexpression and receptor crosstalk, changes in miRNA expression, DNA methylation, and genetic alterations.	('DNA methylation', 'MPA', (135, 150))	('changes', 'Reg', (16, 23))	('expression', 'Species', '29278', (71, 81))	('signaling', 'MPA', (6, 15))	('changes', 'Reg', (106, 113))	('genetic', 'Var', (156, 163))	('miRNA expression', 'MPA', (117, 133))	('expression', 'Species', '29278', (123, 133))
34864	27650546	EGFR inhibition is also modeled by knocking-down EGFR expression with siRNA.	('expression', 'MPA', (54, 64))	('EGFR', 'Gene', '1956', (49, 53))	('knocking-down', 'Var', (35, 48))	('EGFR', 'Gene', (0, 4))	('EGFR', 'Gene', (49, 53))	('expression', 'Species', '29278', (54, 64))	('EGFR', 'Gene', '1956', (0, 4))
34866	27650546	We apply the CoGAPS meta-pathway analysis algorithm to delineate genomics signatures for cell-signaling responses to EGFR inhibition with genetic alterations in the EGFR signaling network.	('EGFR', 'Gene', (165, 169))	('genetic alterations', 'Var', (138, 157))	('EGFR', 'Gene', '1956', (117, 121))	('EGFR', 'Gene', (117, 121))	('inhibition', 'NegReg', (122, 132))	('EGFR', 'Gene', '1956', (165, 169))
34876	27650546	EGFR amplifications and mutations occur in only 9% of primary tumors in each subtype, with genetic alterations in the PI3K family (PIK3CA, PIK3CB, PIK3CD, or PIK3CG) (30%) and in the RAS family (HRAS, KRAS, or NRAS) (39%) being most prevalent (Figure 1B).	('HRAS', 'Gene', (195, 199))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('EGFR', 'Gene', (0, 4))	('KRAS', 'Gene', (201, 205))	('tumors', 'Disease', (62, 68))	('tumors', 'Disease', 'MESH:D009369', (62, 68))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('KRAS', 'Gene', '3845', (201, 205))	('PIK3CA', 'Gene', (131, 137))	('mutations', 'Var', (24, 33))	('PIK3CA', 'Gene', '5290', (131, 137))	('HRAS', 'Gene', '3265', (195, 199))	('EGFR', 'Gene', '1956', (0, 4))
34877	27650546	Similar molecular landscapes for the EGFR network are observed for each cancer type (Figure 1C, Supplementary Table S1) with RAS alterations most common in PAAD (86%), LUAD (39%), and COAD (50%) and PI3K alterations most common in LUSC (55%) and HNSCC (41%).	('PAAD', 'Disease', (156, 160))	('COAD', 'Disease', (184, 188))	('LUSC', 'Phenotype', 'HP:0030359', (231, 235))	('cancer', 'Disease', (72, 78))	('LUAD', 'Phenotype', 'HP:0030078', (168, 172))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('RAS', 'Gene', (125, 128))	('EGFR', 'Gene', '1956', (37, 41))	('HNSCC', 'Disease', (246, 251))	('alterations', 'Var', (129, 140))	('LUAD', 'Disease', (168, 172))	('PI3K', 'Var', (199, 203))	('common', 'Reg', (146, 152))	('HNSCC', 'Phenotype', 'HP:0012288', (246, 251))	('PAAD', 'Phenotype', 'HP:0006725', (156, 160))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('COAD', 'Disease', 'MESH:D029424', (184, 188))	('LUSC', 'Disease', (231, 235))	('EGFR', 'Gene', (37, 41))
34878	27650546	Thus, we observe that mutations within EGFR and the RAS and PI3K pathways are the most common genetic alterations in tumors currently treated with EGFR inhibitors.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('EGFR', 'Gene', (147, 151))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('common', 'Reg', (87, 93))	('tumors', 'Disease', (117, 123))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('EGFR', 'Gene', (39, 43))	('mutations', 'Var', (22, 31))	('EGFR', 'Gene', '1956', (39, 43))	('PI3K pathways', 'Pathway', (60, 73))	('EGFR', 'Gene', '1956', (147, 151))
34879	27650546	Because they are downstream of EGFR in the cell-signaling network, both RAS and PI3K alterations confer resistance to EGFR inhibitors.	('EGFR', 'Gene', '1956', (31, 35))	('resistance', 'MPA', (104, 114))	('EGFR', 'Gene', (31, 35))	('RAS', 'Gene', (72, 75))	('EGFR', 'Gene', '1956', (118, 122))	('EGFR', 'Gene', (118, 122))	('alterations', 'Var', (85, 96))	('PI3K', 'Gene', (80, 84))
34886	27650546	Western blot analysis with phospho-specific antibodies further validates the impact of each alteration on cell signaling within the EGFR network (Figure 2B, Supplementary Figure S2).	('alteration', 'Var', (92, 102))	('cell signaling', 'MPA', (106, 120))	('EGFR', 'Gene', '1956', (132, 136))	('EGFR', 'Gene', (132, 136))
34889	27650546	Additionally, HaCaT-HRASV12D exhibits an expected increase in phospho-MAPK levels (Figure 2B).	('increase', 'PosReg', (50, 58))	('HaCaT-HRASV12D', 'CellLine', 'CVCL:0038', (14, 28))	('phospho-MAPK levels', 'MPA', (62, 81))	('HaCaT-HRASV12D', 'Var', (14, 28))
34891	27650546	After validating each modification, we inhibit EGFR in the HaCaT cell lines with three targeted agents with unique mechanisms of action: cetuximab, gefitinib and afatinib.	('modification', 'Var', (22, 34))	('gefitinib', 'Chemical', 'MESH:D000077156', (148, 157))	('inhibit', 'NegReg', (39, 46))	('afatinib', 'Chemical', 'MESH:D000077716', (162, 170))	('HaCaT', 'CellLine', 'CVCL:0038', (59, 64))	('EGFR', 'Gene', '1956', (47, 51))	('cetuximab', 'Chemical', 'MESH:D000068818', (137, 146))	('EGFR', 'Gene', (47, 51))
34895	27650546	Equivalent numbers of cells were cultured in Matrigel colony formation assays and treated with standard concentrations of gefitinib (100nM), cetuximab (100nM), or afatinib (10nM).	('100nM', 'Var', (133, 138))	('cetuximab', 'Chemical', 'MESH:D000068818', (141, 150))	('afatinib', 'Chemical', 'MESH:D000077716', (163, 171))	('gefitinib', 'Chemical', 'MESH:D000077156', (122, 131))	('100nM', 'Var', (152, 157))
34897	27650546	Each oncogenic modification leads to increased cell survival following EGFR inhibition compared to HaCaT-Mock.	('inhibition', 'NegReg', (76, 86))	('modification', 'Var', (15, 27))	('HaCaT-Mock', 'CellLine', 'CVCL:0038', (99, 109))	('EGFR', 'Gene', '1956', (71, 75))	('increased', 'PosReg', (37, 46))	('cell survival', 'CPA', (47, 60))	('EGFR', 'Gene', (71, 75))
34899	27650546	Cell survival is consistently higher in both HaCaT-HRASV12D and HaCaT-PIK3CAH1047R for all three pharmacological agents relative to PBS controls (Figure 2C).	('HaCaT-HRASV12D', 'CellLine', 'CVCL:0038', (45, 59))	('higher', 'PosReg', (30, 36))	('HaCaT-HRASV12D', 'Var', (45, 59))	('HaCaT', 'CellLine', 'CVCL:0038', (64, 69))	('Cell survival', 'CPA', (0, 13))	('HaCaT', 'CellLine', 'CVCL:0038', (45, 50))	('PBS', 'Chemical', 'MESH:D007854', (132, 135))
34901	27650546	We also measure gene expression profiles of the modified HaCaT cell lines before and after 24 hour treatment with EGFR inhibitors (100 nM cetuximab, 100 nM gefitinib, and 10 nM afatinib).	('gene expression profiles', 'MPA', (16, 40))	('100', 'Var', (131, 134))	('cetuximab', 'Chemical', 'MESH:D000068818', (138, 147))	('expression', 'Species', '29278', (21, 31))	('HaCaT', 'CellLine', 'CVCL:0038', (57, 62))	('gefitinib', 'Chemical', 'MESH:D000077156', (156, 165))	('EGFR', 'Gene', '1956', (114, 118))	('afatinib', 'Chemical', 'MESH:D000077716', (177, 185))	('EGFR', 'Gene', (114, 118))
34909	27650546	The overexpression of these genes due to the mutant HRAS and their subsequent decrease after treatment was proportional to the relative cell survival of each modified HaCaT cell line (correlation coefficient of 0.72 and p-value of 0.008).	('mutant', 'Var', (45, 51))	('HRAS', 'Gene', '3265', (52, 56))	('decrease', 'NegReg', (78, 86))	('HaCaT', 'CellLine', 'CVCL:0038', (167, 172))	('HRAS', 'Gene', (52, 56))	('expression', 'Species', '29278', (8, 18))	('overexpression', 'PosReg', (4, 18))
34911	27650546	It also reflects inhibition of that pathway from treatment with EGFR inhibitors in sensitive cells.	('inhibitors', 'Var', (69, 79))	('inhibition', 'NegReg', (17, 27))	('EGFR', 'Gene', (64, 68))	('EGFR', 'Gene', '1956', (64, 68))
34919	27650546	We also performed siRNA knock-down of EGFR with 86% efficiency at 24 hours in HaCaT mock cells.	('EGFR', 'Gene', '1956', (38, 42))	('EGFR', 'Gene', (38, 42))	('knock-down', 'Var', (24, 34))	('HaCaT', 'CellLine', 'CVCL:0038', (78, 83))
34920	27650546	We compare the resulting gene expression changes after siRNA knock-down relative to siRNA scramble in each of the HaCaT cells (Supplementary Figure S6).	('gene expression', 'MPA', (25, 40))	('HaCaT', 'CellLine', 'CVCL:0038', (114, 119))	('expression', 'Species', '29278', (30, 40))	('knock-down', 'Var', (61, 71))
34921	27650546	In this case, HaCaT EGFR knockdown yields an anticipated and statistically significant decrease in EGFR expression (Supplementary Figure S5B; p-value of 9x10-6).	('EGFR', 'Gene', (99, 103))	('EGFR', 'Gene', (20, 24))	('expression', 'Species', '29278', (104, 114))	('EGFR', 'Gene', '1956', (20, 24))	('HaCaT', 'CellLine', 'CVCL:0038', (14, 19))	('expression', 'MPA', (104, 114))	('decrease', 'NegReg', (87, 95))	('EGFR', 'Gene', '1956', (99, 103))	('knockdown', 'Var', (25, 34))
34940	27650546	Similar to the HaCaT cells, HPV-negative HNSCC cell lines (Figure 5A, Supplementary Table S2) without alterations in the EGFR network (UMSCC1, personal communication with the the Carey and Brenner Labs, publication in process; SCC25, Dataset 1 and) or EGFR amplification (SQ20B, Dataset 2) have lower cell survival with cetuximab treatment than cells with PIK3CA mutation (SCC61,).	('SQ20B', 'Var', (272, 277))	('HaCaT', 'CellLine', 'CVCL:0038', (15, 20))	('lower', 'NegReg', (295, 300))	('EGFR', 'Gene', (252, 256))	('EGFR', 'Gene', '1956', (121, 125))	('HNSCC', 'Phenotype', 'HP:0012288', (41, 46))	('PIK3CA', 'Gene', (356, 362))	('cetuximab', 'Chemical', 'MESH:D000068818', (320, 329))	('PIK3CA', 'Gene', '5290', (356, 362))	('EGFR', 'Gene', (121, 125))	('SCC1', 'Gene', (137, 141))	('SCC61', 'CellLine', 'CVCL:7118', (373, 378))	('EGFR', 'Gene', '1956', (252, 256))	('cell survival', 'CPA', (301, 314))	('SCC1', 'Gene', '5795', (137, 141))
34941	27650546	We note that this includes a cell line an HRAS mutation (93VU147T,), although this variant is not an activating hotspot mutation.	('HRAS', 'Gene', '3265', (42, 46))	('HRAS', 'Gene', (42, 46))	('93VU147T', 'CellLine', 'CVCL:L895', (57, 65))	('93VU147T', 'Var', (57, 65))
34942	27650546	The SCC47 cell line has a 3' UTR variant in KRAS and is sensitive to cetuximab, consistent with observations in human HNSCC for this variant.	('cetuximab', 'Chemical', 'MESH:D000068818', (69, 78))	('variant', 'Var', (33, 40))	('SCC47', 'CellLine', 'CVCL:7759', (4, 9))	('HNSCC', 'Phenotype', 'HP:0012288', (118, 123))	('KRAS', 'Gene', (44, 48))	('KRAS', 'Gene', '3845', (44, 48))	('human', 'Species', '9606', (112, 117))
34946	27650546	However, apparent in the gene expression profiles of the panel of HNSCC cells (Figure 5C), the changes in TFAP2A gene expression and AP-2alpha "up" target genes are more strongly associated with changes in EGFR expression in HPV-negative cells (p-values of 0.002 and 0.04, respectively) than HPV-positive (p-values of 0.79 and 0.15, respectively).	('associated', 'Reg', (179, 189))	('EGFR', 'Gene', (206, 210))	('HNSCC', 'Phenotype', 'HP:0012288', (66, 71))	('TFAP2A', 'Gene', (106, 112))	('EGFR', 'Gene', '1956', (206, 210))	('changes', 'Var', (95, 102))	('changes', 'Reg', (195, 202))	('AP-2alpha', 'Gene', '7020', (133, 142))	('expression', 'Species', '29278', (118, 128))	('expression', 'Species', '29278', (211, 221))	('expression', 'MPA', (211, 221))	('expression', 'Species', '29278', (30, 40))	('AP-2alpha', 'Gene', (133, 142))
34966	27650546	Within the TCGA genomics data for pancreatic, lung, head and neck, and colon tumors, mutations or copy number alterations of EGFR network genes are most pervasive in EGFR, RAS, and PI3K.	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('copy number alterations', 'Var', (98, 121))	('pervasive', 'Reg', (153, 162))	('EGFR', 'Gene', '1956', (125, 129))	('EGFR', 'Gene', '1956', (166, 170))	('PI3K', 'Disease', (181, 185))	('EGFR', 'Gene', (166, 170))	('pancreatic', 'Disease', 'MESH:D010195', (34, 44))	('EGFR', 'Gene', (125, 129))	('mutations', 'Var', (85, 94))	('colon tumors', 'Phenotype', 'HP:0100273', (71, 83))	('colon tumors', 'Disease', 'MESH:D015179', (71, 83))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('pancreatic', 'Disease', (34, 44))	('colon tumors', 'Disease', (71, 83))	('RAS', 'Disease', (172, 175))
34967	27650546	Therefore, this study creates a cell line model of EGFR overexpression, mutant HRASV12D, and mutant PIK3CAH1047R in a controlled genetic background.	('EGFR', 'Gene', (51, 55))	('mutant', 'Var', (72, 78))	('HRAS', 'Gene', (79, 83))	('PIK3CAH1047R', 'Gene', (100, 112))	('mutant', 'Var', (93, 99))	('overexpression', 'PosReg', (56, 70))	('expression', 'Species', '29278', (60, 70))	('HRAS', 'Gene', '3265', (79, 83))	('EGFR', 'Gene', '1956', (51, 55))
34968	27650546	In this model system, activation of the RAS pathway by mutant HRASV12D and activation of the PI3K pathway by mutant PIK3CAH1047R reduces sensitivity to EGFR inhibitors compared to EGFR overexpression.	('HRAS', 'Gene', '3265', (62, 66))	('RAS pathway', 'Pathway', (40, 51))	('PI3K pathway', 'Pathway', (93, 105))	('PIK3CAH1047R', 'Gene', (116, 128))	('expression', 'Species', '29278', (189, 199))	('HRAS', 'Gene', (62, 66))	('activation', 'PosReg', (22, 32))	('mutant', 'Var', (55, 61))	('EGFR', 'Gene', (180, 184))	('EGFR', 'Gene', '1956', (180, 184))	('EGFR', 'Gene', '1956', (152, 156))	('EGFR', 'Gene', (152, 156))	('mutant', 'Var', (109, 115))	('reduces', 'NegReg', (129, 136))
34979	27650546	While there is no substitute for genomics profiling of human cancer, pre-clinical models such as the HaCaT cells in this study and mathematical models enable querying of post-treatment genomics changes to numerous therapeutic agents, outgrowth of all possible clones from heterogeneous tumor populations, and delineate therapeutic sensitivity from cellular density and proliferation.	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('changes', 'Var', (194, 201))	('tumor', 'Disease', (286, 291))	('HaCaT', 'CellLine', 'CVCL:0038', (101, 106))	('tumor', 'Phenotype', 'HP:0002664', (286, 291))	('cancer', 'Disease', (61, 67))	('human', 'Species', '9606', (55, 60))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('tumor', 'Disease', 'MESH:D009369', (286, 291))
34984	27650546	This observation is consistent with the association of activating RAS mutations, which are established resistance mechanisms for EGFR inhibitors.	('mutations', 'Var', (70, 79))	('RAS', 'Gene', (66, 69))	('activating', 'PosReg', (55, 65))	('EGFR', 'Gene', '1956', (129, 133))	('EGFR', 'Gene', (129, 133))
34985	27650546	Moreover, our previous study associated a gene expression signature derived from HaCaT-HRASV12D with acquired therapeutic resistance in the HPV-negative HNSCC cell line, UMSCC1, independent of an acquired RAS mutation in this model system.	('HaCaT-HRASV12D', 'Var', (81, 95))	('expression', 'Species', '29278', (47, 57))	('SCC1', 'Gene', (172, 176))	('SCC1', 'Gene', '5795', (172, 176))	('acquired therapeutic resistance', 'MPA', (101, 132))	('HNSCC', 'Phenotype', 'HP:0012288', (153, 158))	('HaCaT-HRASV12D', 'CellLine', 'CVCL:0038', (81, 95))
34994	27650546	This feedback mechanism is consistent with the rapid rewiring of signaling networks associated with adaptive resistance to EGFR inhibitors in non-small-cell lung cancer.	('EGFR', 'Gene', (123, 127))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (146, 168))	('lung cancer', 'Disease', (157, 168))	('lung cancer', 'Phenotype', 'HP:0100526', (157, 168))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (142, 168))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('EGFR', 'Gene', '1956', (123, 127))	('inhibitors', 'Var', (128, 138))	('lung cancer', 'Disease', 'MESH:D008175', (157, 168))
35035	27650546	EGFR and HRAS over-expression was confirmed using EGFR (Hs01076078_m1) and HRAS (Hs00978050_g1) primers by Real time PCR (Applied Biosystems/Life Technologies).	('HRAS', 'Gene', (75, 79))	('EGFR', 'Gene', (0, 4))	('over-expression', 'PosReg', (14, 29))	('HRAS', 'Gene', '3265', (9, 13))	('HRAS', 'Gene', (9, 13))	('EGFR', 'Gene', '1956', (50, 54))	('HRAS', 'Gene', '3265', (75, 79))	('EGFR', 'Gene', (50, 54))	('Hs01076078_m1', 'Var', (56, 69))	('Hs00978050_g1', 'Var', (81, 94))	('EGFR', 'Gene', '1956', (0, 4))	('expression', 'Species', '29278', (19, 29))
35038	27650546	We manually determined the area to be quantified for each of the proteins expressed by the HaCaT cell line and by each of the mutant variants generated.	('HaCaT', 'CellLine', 'CVCL:0038', (91, 96))	('variants', 'Var', (133, 141))	('mutant variants', 'Var', (126, 141))
35046	27650546	Normalized and raw data are available from GEO (HaCaT cells: GSE80667, HNSCC cells: GSE62027, and untreated UMSCC1: GSE21483).	('SCC1', 'Gene', (110, 114))	('GSE62027', 'Var', (84, 92))	('SCC1', 'Gene', '5795', (110, 114))	('HaCaT', 'CellLine', 'CVCL:0038', (48, 53))	('HNSCC', 'Phenotype', 'HP:0012288', (71, 76))	('GSE80667', 'Var', (61, 69))
35048	27650546	These samples were said to be p16 low if the maximum expression value of the probe selected for CDKN2A expression (207039_at) is less than the median average expression value for all pre- and post-treatment samples (5.4).	('CDKN2A', 'Gene', '1029', (96, 102))	('expression', 'Species', '29278', (158, 168))	('expression', 'Species', '29278', (103, 113))	('less', 'NegReg', (129, 133))	('207039_at', 'Var', (115, 124))	('expression', 'MPA', (158, 168))	('expression', 'Species', '29278', (53, 63))	('expression', 'MPA', (53, 63))	('CDKN2A', 'Gene', (96, 102))
35059	27650546	Additional qRT-PCR validation was performed using Taqman probes (Applied Biosystems, Foster City, CA) on AP-2alpha targets for EGFR (HS01076078_m1), ERBB2 (HS01001580_m1), IGF1R (HS00609566_m1), PTEN (HS02621230_s1), BMP2 (HS00154192_m1), BMP4 (HS00370078_m1), VEGFA (HS00900055_m1), TGFA (HS00608187_m1), FGFR4 (HS01169908_m1), and TGFBR3 (HS00234257_m1) and control beta-actin (HS00357333-g1) as described above.	('HS02621230_s1', 'Var', (201, 214))	('HS00900055_m1', 'Var', (268, 281))	('AP-2alpha', 'Gene', (105, 114))	('HS00357333-g1', 'Var', (380, 393))	('HS00608187_m1', 'Var', (290, 303))	('beta-actin', 'MPA', (368, 378))	('HS00154192_m1', 'Var', (223, 236))	('HS01169908_m1', 'Var', (313, 326))	('HS00370078_m1', 'Var', (245, 258))	('HS01076078_m1', 'Var', (133, 146))	('HS00234257_m1', 'Var', (341, 354))	('AP-2alpha', 'Gene', '7020', (105, 114))	('HS01001580_m1', 'Var', (156, 169))	('HS00609566_m1', 'Var', (179, 192))	('EGFR', 'Gene', '1956', (127, 131))	('EGFR', 'Gene', (127, 131))	('TGFBR3', 'Gene', (333, 339))
35078	28220783	An integrative approach unveils FOSL1 as an oncogene vulnerability in KRAS-driven lung and pancreatic cancer KRAS mutated tumours represent a large fraction of human cancers, but the vast majority remains refractory to current clinical therapies.	('lung', 'Disease', (82, 86))	('cancers', 'Disease', 'MESH:D009369', (166, 173))	('KRAS', 'Gene', (70, 74))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (91, 108))	('FOSL1', 'Gene', (32, 37))	('tumours', 'Disease', (122, 129))	('tumour', 'Phenotype', 'HP:0002664', (122, 128))	('tumours', 'Phenotype', 'HP:0002664', (122, 129))	('tumours', 'Disease', 'MESH:D009369', (122, 129))	('FOSL1', 'Gene', '8061', (32, 37))	('cancers', 'Phenotype', 'HP:0002664', (166, 173))	('human', 'Species', '9606', (160, 165))	('pancreatic cancer', 'Disease', 'MESH:D010190', (91, 108))	('cancers', 'Disease', (166, 173))	('mutated', 'Var', (114, 121))	('KRAS', 'Gene', '3845', (109, 113))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('pancreatic cancer', 'Disease', (91, 108))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('KRAS', 'Gene', '3845', (70, 74))	('KRAS', 'Gene', (109, 113))
35079	28220783	Here we report the identification of a common transcriptional signature across mutant KRAS cancers of distinct tissue origin that includes the transcription factor FOSL1.	('KRAS cancers', 'Disease', 'MESH:D009369', (86, 98))	('KRAS cancers', 'Disease', (86, 98))	('cancers', 'Phenotype', 'HP:0002664', (91, 98))	('mutant', 'Var', (79, 85))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))
35080	28220783	High FOSL1 expression identifies mutant KRAS lung and pancreatic cancer patients with the worst survival outcome.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (54, 71))	('KRAS lung', 'Disease', (40, 49))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('pancreatic cancer', 'Disease', (54, 71))	('FOSL1', 'Gene', (5, 10))	('mutant', 'Var', (33, 39))	('pancreatic cancer', 'Disease', 'MESH:D010190', (54, 71))	('patients', 'Species', '9606', (72, 80))
35081	28220783	Furthermore, FOSL1 genetic inhibition is detrimental to both KRAS-driven tumour types.	('tumour', 'Disease', (73, 79))	('tumour', 'Phenotype', 'HP:0002664', (73, 79))	('tumour', 'Disease', 'MESH:D009369', (73, 79))	('genetic inhibition', 'Var', (19, 37))	('FOSL1', 'Gene', (13, 18))
35084	28220783	In this study, the authors show that lung and pancreatic cancers expressing oncogenic KRAS can be targeted by genetic inhibition of FOSL1, which involves downregulation of genes of the mitotic machinery.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (46, 63))	('KRAS', 'Gene', (86, 90))	('pancreatic cancers', 'Disease', 'MESH:D010190', (46, 64))	('pancreatic cancers', 'Disease', (46, 64))	('cancers', 'Phenotype', 'HP:0002664', (57, 64))	('FOSL1', 'Gene', (132, 137))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (46, 64))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('lung', 'Disease', (37, 41))	('oncogenic', 'Var', (76, 85))
35090	28220783	In this regard, loss of WT1, FOXM1 or MYC has been reported to impair initiation of mutant Kras lung or pancreatic tumours in mice.	('MYC', 'Gene', (38, 41))	('Kras lung or pancreatic tumours', 'Disease', (91, 122))	('mice', 'Species', '10090', (126, 130))	('loss of WT1, FOXM1', 'Disease', 'MESH:D009396', (16, 34))	('tumour', 'Phenotype', 'HP:0002664', (115, 121))	('impair', 'NegReg', (63, 69))	('mutant', 'Var', (84, 90))	('Kras lung or pancreatic tumours', 'Disease', 'MESH:D010190', (91, 122))	('initiation', 'CPA', (70, 80))	('tumours', 'Phenotype', 'HP:0002664', (115, 122))
35094	28220783	In this study, we devised an integrative strategy to expose common core elements of KRAS signalling critical for homeostasis of KRAS mutated tumours by combining (1) a cross-tumours gene-expression screen to identify KRAS-dependent candidate genes, and (2) patient outcome to inform selection of candidate genes for functional follow-up.	('tumours', 'Disease', (141, 148))	('tumour', 'Phenotype', 'HP:0002664', (174, 180))	('tumours', 'Phenotype', 'HP:0002664', (174, 181))	('tumour', 'Phenotype', 'HP:0002664', (141, 147))	('cross-tumours', 'Disease', 'MESH:C537866', (168, 181))	('patient', 'Species', '9606', (257, 264))	('tumours', 'Disease', 'MESH:D009369', (174, 181))	('cross-tumours', 'Disease', (168, 181))	('tumours', 'Disease', (174, 181))	('tumours', 'Phenotype', 'HP:0002664', (141, 148))	('mutated', 'Var', (133, 140))	('tumours', 'Disease', 'MESH:D009369', (141, 148))
35097	28220783	First, we screened gene-expression data from in vitro and in vivo experimental systems of epithelial and mesenchymal origin with either wild-type or mutant KRAS allele (human immortalized bronchoepithelial cells, KrasLSLG12D/+ mouse embryo fibroblasts and a mouse model of Kras-driven lung cancer).	('lung cancer', 'Disease', 'MESH:D008175', (285, 296))	('mouse', 'Species', '10090', (258, 263))	('KRAS', 'Gene', (156, 160))	('mouse', 'Species', '10090', (227, 232))	('mutant', 'Var', (149, 155))	('cancer', 'Phenotype', 'HP:0002664', (290, 296))	('lung cancer', 'Phenotype', 'HP:0100526', (285, 296))	('human', 'Species', '9606', (169, 174))	('lung cancer', 'Disease', (285, 296))	('G12D', 'Mutation', 'rs121913529', (220, 224))
35100	28220783	A negative (-) enrichment was observed in mouse lung adenocarcinoma (LAC) and PDAC where mutant KRAS expression was depleted (Supplementary Fig.	('LAC', 'Phenotype', 'HP:0030078', (69, 72))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (48, 67))	('depleted', 'NegReg', (116, 124))	('mouse', 'Species', '10090', (42, 47))	('PDAC', 'Phenotype', 'HP:0006725', (78, 82))	('PDAC', 'Chemical', '-', (78, 82))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (48, 67))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))	('expression', 'MPA', (101, 111))	('mutant', 'Var', (89, 95))	('KRAS', 'Gene', (96, 100))	('lung adenocarcinoma', 'Disease', (48, 67))
35101	28220783	In human cancer, a positive (+) enrichment was observed in mutant KRAS patients compared to wild-type in LAC (n=3), PDAC, colorectal cancer (CRC), cholangiocarcinoma (CCA) and multiple myeloma (MM) (Supplementary Fig.	('cancer', 'Disease', (9, 15))	('human', 'Species', '9606', (3, 8))	('patients', 'Species', '9606', (71, 79))	('mutant', 'Var', (59, 65))	('colorectal cancer', 'Disease', (122, 139))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('multiple myeloma', 'Disease', (176, 192))	('LAC', 'Phenotype', 'HP:0030078', (105, 108))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (147, 165))	('PDAC', 'Chemical', '-', (116, 120))	('CCA', 'Phenotype', 'HP:0030153', (167, 170))	('cholangiocarcinoma', 'Disease', (147, 165))	('PDAC', 'Phenotype', 'HP:0006725', (116, 120))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (147, 165))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('KRAS', 'Gene', (66, 70))	('colorectal cancer', 'Phenotype', 'HP:0003003', (122, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (156, 165))	('multiple myeloma', 'Phenotype', 'HP:0006775', (176, 192))	('cancer', 'Disease', (133, 139))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('CRC', 'Phenotype', 'HP:0003003', (141, 144))	('multiple myeloma', 'Disease', 'MESH:D009101', (176, 192))	('colorectal cancer', 'Disease', 'MESH:D015179', (122, 139))
35106	28220783	Notably, LAMB3 has been reported as a synthetic lethal interaction with oncogenic KRAS in colon cancer, suggesting that other co-identified genes could also display a functional role in mutant KRAS cancer.	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('colon cancer', 'Disease', 'MESH:D015179', (90, 102))	('cancer', 'Disease', (198, 204))	('colon cancer', 'Disease', (90, 102))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('colon cancer', 'Phenotype', 'HP:0003003', (90, 102))	('mutant', 'Var', (186, 192))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('LAMB3', 'Gene', (9, 14))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('LAMB3', 'Gene', '3914', (9, 14))	('cancer', 'Disease', (96, 102))
35108	28220783	A higher geometric mean was representative of LAC (n=3), PDAC and CCA tumours harbouring KRAS mutations (Fig.	('CCA tumours', 'Disease', (66, 77))	('mutations', 'Var', (94, 103))	('PDAC', 'Disease', (57, 61))	('PDAC', 'Phenotype', 'HP:0006725', (57, 61))	('CCA', 'Phenotype', 'HP:0030153', (66, 69))	('LAC', 'Phenotype', 'HP:0030078', (46, 49))	('tumour', 'Phenotype', 'HP:0002664', (70, 76))	('tumours', 'Phenotype', 'HP:0002664', (70, 77))	('CCA tumours', 'Disease', 'MESH:C536211', (66, 77))	('PDAC', 'Chemical', '-', (57, 61))	('KRAS', 'Gene', (89, 93))
35110	28220783	The geometric mean of the eight genes did not discriminate mutant EGFR from wild-type patients in four data sets (Supplementary Fig.	('EGFR', 'Gene', (66, 70))	('mutant', 'Var', (59, 65))	('EGFR', 'Gene', '1956', (66, 70))	('patients', 'Species', '9606', (86, 94))
35111	28220783	Similar results were observed for AML4-ALK, BRAF and DDR2 mutant or MYC amplified tumours in The Cancer Genome Atlas (TCGA) data set (Supplementary Fig.	('Cancer Genome Atlas', 'Disease', (97, 116))	('mutant', 'Var', (58, 64))	('tumour', 'Phenotype', 'HP:0002664', (82, 88))	('BRAF', 'Gene', '673', (44, 48))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (97, 116))	('ALK', 'Gene', (39, 42))	('tumours', 'Phenotype', 'HP:0002664', (82, 89))	('DDR2', 'Gene', '4921', (53, 57))	('BRAF', 'Gene', (44, 48))	('DDR2', 'Gene', (53, 57))	('tumours', 'Disease', 'MESH:D009369', (82, 89))	('tumours', 'Disease', (82, 89))	('ALK', 'Gene', '238', (39, 42))	('Cancer', 'Phenotype', 'HP:0002664', (97, 103))
35115	28220783	Moreover, multivariate analysis of mutant KRAS patients expressing high levels of the eight-gene signature showed that the effect of gene expression on patient survival is irrespective of stage, age and gender (P=0.003, HR=1.599 (1.177-2.172), Cox proportional hazards model), conversely to what was found in wild-type KRAS patients (P=0.883, HR=1.024 (0.748-1.402), Cox proportional hazards model).	('Cox', 'Gene', '1351', (367, 370))	('patients', 'Species', '9606', (324, 332))	('patient', 'Species', '9606', (47, 54))	('Cox', 'Gene', (367, 370))	('Cox', 'Gene', '1351', (244, 247))	('mutant', 'Var', (35, 41))	('patients', 'Species', '9606', (47, 55))	('patient', 'Species', '9606', (324, 331))	('Cox', 'Gene', (244, 247))	('patient', 'Species', '9606', (152, 159))
35117	28220783	1f), whereas no association with patient survival was observed in other tumours where KRAS mutations are rarely found or absent such as squamous cell lung carcinoma or breast cancer (Supplementary Fig.	('carcinoma', 'Phenotype', 'HP:0030731', (155, 164))	('patient', 'Species', '9606', (33, 40))	('KRAS', 'Gene', (86, 90))	('squamous cell lung carcinoma', 'Phenotype', 'HP:0030359', (136, 164))	('squamous cell lung carcinoma or breast cancer', 'Disease', 'MESH:D002294', (136, 181))	('tumour', 'Phenotype', 'HP:0002664', (72, 78))	('tumours', 'Phenotype', 'HP:0002664', (72, 79))	('breast cancer', 'Phenotype', 'HP:0003002', (168, 181))	('mutations', 'Var', (91, 100))	('squamous cell lung carcinoma or breast cancer', 'Disease', (136, 181))	('tumours', 'Disease', 'MESH:D009369', (72, 79))	('tumours', 'Disease', (72, 79))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
35118	28220783	These results argue that high expression of the eight-gene signature is representative of mutant KRAS cancers.	('KRAS cancers', 'Disease', (97, 109))	('expression', 'MPA', (30, 40))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('KRAS cancers', 'Disease', 'MESH:D009369', (97, 109))	('mutant', 'Var', (90, 96))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))
35119	28220783	To further delineate the contribution of the eight candidate genes, we carried out single gene survival analysis to discriminate those genes involved in the clinical outcome of mutant KRAS LAC patients.	('KRAS LAC', 'Gene', (184, 192))	('LAC', 'Phenotype', 'HP:0030078', (189, 192))	('patients', 'Species', '9606', (193, 201))	('mutant', 'Var', (177, 183))
35121	28220783	Only high FOSL1 expression identified a group of patients bearing KRAS mutations with the worst survival outcome and the differences between wild-type and mutant KRAS patients expressing high FOSL1 levels were statistically significant (P=0.016, log-rank test, Mantel Cox) (Fig.	('patients', 'Species', '9606', (167, 175))	('Cox', 'Gene', '1351', (268, 271))	('mutations', 'Var', (71, 80))	('patients', 'Species', '9606', (49, 57))	('Cox', 'Gene', (268, 271))	('KRAS', 'Gene', (66, 70))
35122	28220783	Multivariate analysis including stage, age and sex showed that FOSL1 expression was an independent survival marker in LAC patients with KRAS mutations (P=0.006; HR=5.072 (1.61-15.98), Cox proportional hazards model).	('mutations', 'Var', (141, 150))	('LAC', 'Phenotype', 'HP:0030078', (118, 121))	('patients', 'Species', '9606', (122, 130))	('KRAS', 'Gene', (136, 140))	('Cox', 'Gene', '1351', (184, 187))	('LAC', 'Disease', (118, 121))	('Cox', 'Gene', (184, 187))	('FOSL1', 'Gene', (63, 68))
35128	28220783	Further analysis of patient-derived xenografts revealed upregulation of FOSL1 expression in tumours with KRAS mutations compared to wild type (Supplementary Fig.	('tumours', 'Phenotype', 'HP:0002664', (92, 99))	('expression', 'MPA', (78, 88))	('upregulation', 'PosReg', (56, 68))	('mutations', 'Var', (110, 119))	('FOSL1', 'Gene', (72, 77))	('KRAS', 'Gene', (105, 109))	('tumours', 'Disease', 'MESH:D009369', (92, 99))	('tumours', 'Disease', (92, 99))	('patient', 'Species', '9606', (20, 27))	('tumour', 'Phenotype', 'HP:0002664', (92, 98))
35130	28220783	Pharmacological inhibition of KRAS canonical effectors showed that, in addition to ERK1/2, ERK5 and JNK consistently regulate FOSL1 expression in mutant KRAS cell lines (Fig.	('JNK', 'Gene', '5599', (100, 103))	('ERK1/2', 'Gene', (83, 89))	('ERK1/2', 'Gene', '5595;5594', (83, 89))	('ERK5', 'Gene', (91, 95))	('ERK5', 'Gene', '5598', (91, 95))	('mutant', 'Var', (146, 152))	('regulate', 'Reg', (117, 125))	('JNK', 'Gene', (100, 103))	('expression', 'MPA', (132, 142))	('FOSL1', 'Gene', (126, 131))
35138	28220783	Fosl1 expression was detected in mutant Kras LAC cell lines but not in normal lung tissue or wild-type Kras squamous cell carcinoma cells (Fig.	('Fosl1', 'Gene', (0, 5))	('Kras squamous cell carcinoma', 'Disease', (103, 131))	('LAC', 'Phenotype', 'HP:0030078', (45, 48))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (108, 131))	('expression', 'MPA', (6, 16))	('Kras squamous cell carcinoma', 'Disease', 'MESH:D002294', (103, 131))	('mutant', 'Var', (33, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))
35139	28220783	Moreover, the effect of FOSL1 inhibition was extended to mutant RAS cells from large cell carcinoma (Supplementary Fig.	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('large cell carcinoma', 'Phenotype', 'HP:0030360', (79, 99))	('cell carcinoma', 'Disease', (85, 99))	('mutant', 'Var', (57, 63))	('cell carcinoma', 'Disease', 'MESH:C538614', (85, 99))
35140	28220783	Likewise, FOSL1 depletion in two mouse LAC cell lines derived from a Kras-driven mouse model led to significant decrease in cell viability (Supplementary Fig.	('FOSL1', 'Gene', (10, 15))	('decrease', 'NegReg', (112, 120))	('depletion', 'Var', (16, 25))	('cell viability', 'CPA', (124, 138))	('LAC', 'Phenotype', 'HP:0030078', (39, 42))	('mouse', 'Species', '10090', (33, 38))	('mouse', 'Species', '10090', (81, 86))
35143	28220783	Likewise, FOSL1 depletion in mouse Kras-driven lung cancer cells decreased tumour volume (Fig.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('lung cancer', 'Disease', (47, 58))	('FOSL1', 'Protein', (10, 15))	('depletion', 'Var', (16, 25))	('decreased tumour', 'Disease', 'MESH:D009369', (65, 81))	('lung cancer', 'Phenotype', 'HP:0100526', (47, 58))	('decreased tumour', 'Disease', (65, 81))	('mouse', 'Species', '10090', (29, 34))	('lung cancer', 'Disease', 'MESH:D008175', (47, 58))	('tumour', 'Phenotype', 'HP:0002664', (75, 81))
35144	28220783	To investigate whether FOSL1 was also important in tumour maintenance, mutant KRAS cells were engrafted and grown until average tumour diameter reached 80-100 mm3 prior to doxycycline administration.	('tumour', 'Disease', (128, 134))	('doxycycline', 'Chemical', 'MESH:D004318', (172, 183))	('tumour', 'Phenotype', 'HP:0002664', (51, 57))	('tumour', 'Phenotype', 'HP:0002664', (128, 134))	('mutant', 'Var', (71, 77))	('tumour', 'Disease', 'MESH:D009369', (51, 57))	('tumour', 'Disease', 'MESH:D009369', (128, 134))	('tumour', 'Disease', (51, 57))
35148	28220783	A decrease in tumour burden was observed in KPF mice compared to KP control mice by microcomputed tomography and histology after 12 weeks of AdCre administration (Fig.	('KPF', 'Var', (44, 47))	('decrease', 'NegReg', (2, 10))	('tumour burden', 'Disease', (14, 27))	('tumour burden', 'Disease', 'MESH:D009369', (14, 27))	('mice', 'Species', '10090', (48, 52))	('mice', 'Species', '10090', (76, 80))	('tumour', 'Phenotype', 'HP:0002664', (14, 20))
35149	28220783	Histological analysis revealed a significant decrease of tumour area in KPF compared to KP mice (Fig.	('mice', 'Species', '10090', (91, 95))	('tumour', 'Disease', (57, 63))	('KPF', 'Var', (72, 75))	('decrease', 'NegReg', (45, 53))	('tumour', 'Phenotype', 'HP:0002664', (57, 63))	('tumour', 'Disease', 'MESH:D009369', (57, 63))
35151	28220783	Analysis of total tumour number in KP vs KPF mice showed a significant decrease in the number of tumours initiated in lung epithelial cells depleted of Fosl1 (Fig.	('mice', 'Species', '10090', (45, 49))	('depleted', 'Var', (140, 148))	('tumours', 'Disease', (97, 104))	('decrease', 'NegReg', (71, 79))	('tumour number', 'Disease', 'MESH:D009369', (18, 31))	('tumour', 'Phenotype', 'HP:0002664', (18, 24))	('Fosl1', 'Gene', (152, 157))	('tumour', 'Phenotype', 'HP:0002664', (97, 103))	('tumours', 'Phenotype', 'HP:0002664', (97, 104))	('tumour number', 'Disease', (18, 31))	('tumours', 'Disease', 'MESH:D009369', (97, 104))
35152	28220783	Likewise, analysis of tumour size revealed that tumours in KPF mice were significantly smaller compared to KP (Fig.	('tumour', 'Disease', 'MESH:D009369', (22, 28))	('tumour', 'Phenotype', 'HP:0002664', (22, 28))	('tumours', 'Disease', (48, 55))	('tumour', 'Phenotype', 'HP:0002664', (48, 54))	('tumour', 'Disease', (22, 28))	('KPF', 'Var', (59, 62))	('mice', 'Species', '10090', (63, 67))	('tumour', 'Disease', 'MESH:D009369', (48, 54))	('smaller', 'NegReg', (87, 94))	('tumour', 'Disease', (48, 54))	('tumours', 'Phenotype', 'HP:0002664', (48, 55))	('tumours', 'Disease', 'MESH:D009369', (48, 55))
35154	28220783	Lastly, Fosl1 ablation in KPF mice prolonged overall survival compared to control mice (Fig.	('mice', 'Species', '10090', (82, 86))	('mice', 'Species', '10090', (30, 34))	('prolonged', 'PosReg', (35, 44))	('Fosl1', 'Gene', (8, 13))	('ablation', 'Var', (14, 22))
35155	28220783	These results suggest that Fosl1 functions in initiation and progression of mutant Kras tumours and demonstrate an important role of FOSL1 in Kras-driven LAC oncogenesis in vivo.	('Kras tumours', 'Disease', (83, 95))	('tumours', 'Phenotype', 'HP:0002664', (88, 95))	('progression', 'CPA', (61, 72))	('mutant', 'Var', (76, 82))	('LAC', 'Phenotype', 'HP:0030078', (154, 157))	('tumour', 'Phenotype', 'HP:0002664', (88, 94))	('Kras tumours', 'Disease', 'MESH:D009369', (83, 95))
35164	28220783	Similar results were observed in a mouse model of PDAC (p48+/Cre; KrasLSLG12D, trp53flox/flox (KPC)) (Fig.	('G12D', 'Mutation', 'rs121913529', (73, 77))	('PDAC', 'Disease', (50, 54))	('p48', 'Gene', (56, 59))	('PDAC', 'Phenotype', 'HP:0006725', (50, 54))	('trp53flox/flox', 'Var', (79, 93))	('mouse', 'Species', '10090', (35, 40))	('PDAC', 'Chemical', '-', (50, 54))	('p48', 'Gene', '16391', (56, 59))
35165	28220783	More importantly, high FOSL1 protein expression was a marker of poor patient survival (P=0.002, log-rank test, Mantel-Cox) (Fig.	('FOSL1', 'Gene', (23, 28))	('patient survival', 'CPA', (69, 85))	('poor', 'NegReg', (64, 68))	('Cox', 'Gene', '1351', (118, 121))	('high', 'Var', (18, 22))	('expression', 'MPA', (37, 47))	('patient', 'Species', '9606', (69, 76))	('protein', 'Protein', (29, 36))	('Cox', 'Gene', (118, 121))
35169	28220783	First, we explored FOSL1 function in the transdifferentiation of mouse acinar cells into duct-like cells (acinar-to-ductal metaplasia, ADM) upon mutant Kras expression.	('mouse', 'Species', '10090', (65, 70))	('mutant', 'Var', (145, 151))	('metaplasia', 'Disease', 'MESH:D008679', (123, 133))	('metaplasia', 'Disease', (123, 133))	('Kras', 'Gene', (152, 156))
35181	28220783	To investigate if the FOSL1 signature (FOSL1 sig) was representative of mutant KRAS tumours, GSEA was carried out in LAC and PDAC showing a significant enrichment in mutant KRAS tumours across several human and mouse data sets (Fig.	('tumours', 'Phenotype', 'HP:0002664', (84, 91))	('KRAS tumours', 'Disease', (79, 91))	('GSEA', 'Chemical', '-', (93, 97))	('tumour', 'Phenotype', 'HP:0002664', (178, 184))	('tumours', 'Phenotype', 'HP:0002664', (178, 185))	('LAC', 'Phenotype', 'HP:0030078', (117, 120))	('KRAS tumours', 'Disease', 'MESH:D009369', (79, 91))	('PDAC', 'Chemical', '-', (125, 129))	('tumour', 'Phenotype', 'HP:0002664', (84, 90))	('mutant', 'Var', (166, 172))	('human', 'Species', '9606', (201, 206))	('mouse', 'Species', '10090', (211, 216))	('KRAS tumours', 'Disease', (173, 185))	('KRAS tumours', 'Disease', 'MESH:D009369', (173, 185))	('PDAC', 'Phenotype', 'HP:0006725', (125, 129))
35182	28220783	Interestingly, high expression of the FOSL1 sig was found in LAC patients harbouring KRAS mutations, and was associated with the poorest survival outcome (Fig.	('mutations', 'Var', (90, 99))	('expression', 'MPA', (20, 30))	('high', 'PosReg', (15, 19))	('LAC', 'Phenotype', 'HP:0030078', (61, 64))	('patients', 'Species', '9606', (65, 73))	('KRAS', 'Gene', (85, 89))	('associated with', 'Reg', (109, 124))	('FOSL1', 'Gene', (38, 43))
35185	28220783	Of note, protein expression of AURKA, CCNB1, HURP and TACC3 was decreased upon FOSL1 inhibition in an independent mutant KRAS LAC cell line but not in wild-type cells with similar proliferation rate in vitro and in vivo (Fig.	('CCNB1', 'Gene', '891', (38, 43))	('TACC3', 'Gene', (54, 59))	('FOSL1', 'Gene', (79, 84))	('decreased', 'NegReg', (64, 73))	('AURKA', 'Gene', (31, 36))	('mutant', 'Var', (114, 120))	('inhibition', 'NegReg', (85, 95))	('HURP', 'Gene', '9787', (45, 49))	('protein expression', 'MPA', (9, 27))	('TACC3', 'Gene', '10460', (54, 59))	('CCNB1', 'Gene', (38, 43))	('LAC', 'Phenotype', 'HP:0030078', (126, 129))	('HURP', 'Gene', (45, 49))
35190	28220783	Using taxol, which interferes with mitotic spindle function and blocks cells in mitosis, we found that FOSL1 inhibition led to decreased phospho-HH3 levels in mutant KRAS LAC cells compared to control cells, in concordance with decreased expression of mitotic genes (Supplementary Fig.	('decreased', 'NegReg', (127, 136))	('mitosis', 'Disease', (80, 87))	('FOSL1', 'Gene', (103, 108))	('mutant', 'Var', (159, 165))	('mitosis', 'Disease', 'None', (80, 87))	('inhibition', 'NegReg', (109, 119))	('phospho-HH3 levels', 'MPA', (137, 155))	('LAC', 'Phenotype', 'HP:0030078', (171, 174))	('taxol', 'Chemical', 'MESH:D017239', (6, 11))
35191	28220783	Mutant KRAS tumours undergo a high degree of mitotic stress and, thus, genes contributing to this phenotype may represent cancer vulnerabilities.	('KRAS tumours', 'Disease', (7, 19))	('mitotic stress', 'CPA', (45, 59))	('cancer', 'Disease', (122, 128))	('KRAS tumours', 'Disease', 'MESH:D009369', (7, 19))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('tumours', 'Phenotype', 'HP:0002664', (12, 19))	('Mutant', 'Var', (0, 6))	('tumour', 'Phenotype', 'HP:0002664', (12, 18))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))
35192	28220783	AURKA knockdown led to a profound protein decrease of the mitotic genes CCNB1, HURP and PLK1, while only a partial reduction of TACC3 and FOXM1 was observed (Fig.	('CCNB1', 'Gene', '891', (72, 77))	('mitotic', 'Gene', (58, 65))	('HURP', 'Gene', (79, 83))	('PLK1', 'Gene', (88, 92))	('FOXM1', 'Gene', (138, 143))	('HURP', 'Gene', '9787', (79, 83))	('decrease', 'NegReg', (42, 50))	('TACC3', 'Gene', '10460', (128, 133))	('PLK1', 'Gene', '5347', (88, 92))	('knockdown', 'Var', (6, 15))	('protein', 'MPA', (34, 41))	('TACC3', 'Gene', (128, 133))	('FOXM1', 'Gene', '2305', (138, 143))	('CCNB1', 'Gene', (72, 77))
35195	28220783	Notably, TACC3 inhibition was also preferentially detrimental to proliferation of mutant KRAS LAC cells (Fig.	('inhibition', 'NegReg', (15, 25))	('proliferation', 'CPA', (65, 78))	('detrimental', 'NegReg', (50, 61))	('LAC', 'Phenotype', 'HP:0030078', (94, 97))	('TACC3', 'Gene', '10460', (9, 14))	('TACC3', 'Gene', (9, 14))	('mutant', 'Var', (82, 88))
35199	28220783	Based on the AURKA knockdown results and the fact that its upstream regulator FOSL1 can be regulated by different KRAS effectors, including the MEK-ERK pathway, we posited that combined inactivation of AURKA and MEK would be more deleterious to mutant KRAS cells than single protein inactivation.	('ERK', 'Gene', (148, 151))	('MEK', 'Gene', (212, 215))	('AURKA', 'Gene', (202, 207))	('mutant', 'Var', (245, 251))	('inactivation', 'NegReg', (186, 198))	('ERK', 'Gene', '5594', (148, 151))
35200	28220783	Pharmacological inhibition of AURKA (alisertib) and MEK1/2 (trametinib) was carried out in mutant and wild-type LAC cell lines using drug concentrations equal or lower than the GI25 by MTS analysis (500 nM and 1,000 nM), which achieved complete protein inactivation after a 3-day treatment (Supplementary Fig.	('MTS', 'Gene', '8201', (185, 188))	('MEK1/2', 'Gene', '5604;5605', (52, 58))	('MEK1/2', 'Gene', (52, 58))	('trametinib', 'Chemical', 'MESH:C560077', (60, 70))	('alisertib', 'Chemical', 'MESH:C550258', (37, 46))	('protein', 'Protein', (245, 252))	('inactivation', 'NegReg', (253, 265))	('LAC', 'Phenotype', 'HP:0030078', (112, 115))	('MTS', 'Gene', (185, 188))	('mutant', 'Var', (91, 97))
35203	28220783	Mutant KRAS tumours were treated for 14 days (H2009) or until control tumours reached the largest volume allowed under the ethical protocol (11 days, H1792).	('tumours', 'Disease', 'MESH:D009369', (12, 19))	('KRAS tumours', 'Disease', (7, 19))	('H1792', 'CellLine', 'CVCL:1495', (150, 155))	('tumours', 'Disease', (12, 19))	('KRAS tumours', 'Disease', 'MESH:D009369', (7, 19))	('tumour', 'Phenotype', 'HP:0002664', (70, 76))	('tumours', 'Phenotype', 'HP:0002664', (70, 77))	('tumours', 'Disease', 'MESH:D009369', (70, 77))	('tumours', 'Phenotype', 'HP:0002664', (12, 19))	('Mutant', 'Var', (0, 6))	('tumour', 'Phenotype', 'HP:0002664', (12, 18))	('tumours', 'Disease', (70, 77))
35210	28220783	The fact that loss-of-function experiments demonstrated that FOSL1 is important in mutant KRAS LAC argues that the overall approach integrating gene-expression and survival data is successful to identify genes with a relevant role in KRAS-driven cancer.	('cancer', 'Disease', 'MESH:D009369', (246, 252))	('mutant', 'Var', (83, 89))	('cancer', 'Disease', (246, 252))	('KRAS', 'Gene', (90, 94))	('loss-of-function', 'NegReg', (14, 30))	('LAC', 'Phenotype', 'HP:0030078', (95, 98))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))	('FOSL1', 'Gene', (61, 66))
35212	28220783	Inhibition of early events in the phylogeny of a tumour could attenuate tumour growth and relapse.	('tumour', 'Phenotype', 'HP:0002664', (72, 78))	('tumour could attenuate tumour growth', 'Disease', (49, 85))	('tumour could attenuate tumour growth', 'Disease', 'MESH:D009369', (49, 85))	('tumour', 'Phenotype', 'HP:0002664', (49, 55))	('Inhibition', 'Var', (0, 10))
35217	28220783	However, FOSL1 inhibition experiments later unveiled a role in the control of a motility and invasion programme in human colon cancer cells expressing oncogenic KRASG13D (refs) in vitro.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('colon cancer', 'Disease', (121, 133))	('human', 'Species', '9606', (115, 120))	('motility', 'CPA', (80, 88))	('KRASG13D', 'Var', (161, 169))	('colon cancer', 'Phenotype', 'HP:0003003', (121, 133))	('colon cancer', 'Disease', 'MESH:D015179', (121, 133))
35223	28220783	All in all, these observations indicate that FOSL1 links KRAS oncogene to genes involved in mitotic fitness, and suggest that AURKA and TACC3 may partially mediate the 'synthetic sensitivity' of mutant KRAS tumours to FOSL1 loss.	('mitotic fitness', 'Disease', 'MESH:C536987', (92, 107))	('KRAS tumours to FOSL1 loss', 'Disease', 'MESH:D009369', (202, 228))	('mitotic fitness', 'Disease', (92, 107))	('TACC3', 'Gene', (136, 141))	('tumour', 'Phenotype', 'HP:0002664', (207, 213))	('KRAS tumours to FOSL1 loss', 'Disease', (202, 228))	('TACC3', 'Gene', '10460', (136, 141))	("'synthetic", 'PosReg', (168, 178))	('mutant', 'Var', (195, 201))	('tumours', 'Phenotype', 'HP:0002664', (207, 214))
35224	28220783	Although FOSL1 inhibition involved the regulation of mitotic genes, sensitivity of mutant KRAS cells to FOSL1 loss seems to occur irrespectively of the proliferative rate of tumour cells.	('tumour', 'Phenotype', 'HP:0002664', (174, 180))	('loss', 'NegReg', (110, 114))	('tumour', 'Disease', 'MESH:D009369', (174, 180))	('mutant', 'Var', (83, 89))	('FOSL1', 'Gene', (104, 109))	('tumour', 'Disease', (174, 180))
35225	28220783	Nonetheless, despite the central role of the mitotic machinery to mutant KRAS phenotype, the contribution of other members of the FOSL1 signature to the effect induced by FOSL1 loss remains unexplored and may also help to explain the impact of FOSL1 inhibition in homeostasis of mutant KRAS tumours.	('tumours', 'Phenotype', 'HP:0002664', (291, 298))	('mutant', 'Var', (66, 72))	('KRAS tumours', 'Disease', (286, 298))	('homeostasis', 'MPA', (264, 275))	('loss', 'NegReg', (177, 181))	('KRAS tumours', 'Disease', 'MESH:D009369', (286, 298))	('FOSL1', 'Gene', (171, 176))	('tumour', 'Phenotype', 'HP:0002664', (291, 297))
35226	28220783	This result provides the rationale for novel therapeutic approaches against tumours with KRAS mutations and adds to recently reported combinatorial strategies for the treatment of KRAS-driven tumours involving MEK inhibitors (MEKi) or inhibitors targeting central kinases of mitotic progression, such as PLK1 (ref.).	('tumours', 'Disease', 'MESH:D009369', (76, 83))	('tumour', 'Phenotype', 'HP:0002664', (192, 198))	('mutations', 'Var', (94, 103))	('tumours', 'Phenotype', 'HP:0002664', (192, 199))	('PLK1', 'Gene', (304, 308))	('tumours', 'Disease', (76, 83))	('tumours', 'Disease', 'MESH:D009369', (192, 199))	('tumour', 'Phenotype', 'HP:0002664', (76, 82))	('PLK1', 'Gene', '5347', (304, 308))	('KRAS-driven tumours', 'Disease', 'MESH:D009369', (180, 199))	('tumours', 'Disease', (192, 199))	('KRAS-driven tumours', 'Disease', (180, 199))	('KRAS', 'Gene', (89, 93))	('tumours', 'Phenotype', 'HP:0002664', (76, 83))
35227	28220783	Clinical trials combining alisertib and targeted therapies such as the epidermal growth factor receptor (EGFR) inhibitor (EGFRi) erlotinib, (NCT01471964), the pan-RAFi MLN0128 (NCT02327169), the mTORi MLN1117 (NCT02551055) and sapanisertib (NCT02719691) are being conducted in solid tumours, thus paving the path for combination studies with MEKi in KRAS-driven tumours.	('epidermal growth factor receptor', 'Gene', '1956', (71, 103))	('erlotinib', 'Chemical', 'MESH:D000069347', (129, 138))	('NCT01471964', 'Var', (141, 152))	('solid tumours', 'Disease', (277, 290))	('EGFR', 'Gene', (105, 109))	('NCT02551055', 'Var', (210, 221))	('tumour', 'Phenotype', 'HP:0002664', (362, 368))	('mTOR', 'Gene', '2475', (195, 199))	('EGFR', 'Gene', (122, 126))	('NCT02719691', 'Var', (241, 252))	('sapanisertib', 'Chemical', 'MESH:C572449', (227, 239))	('KRAS-driven tumours', 'Disease', 'MESH:D009369', (350, 369))	('solid tumours', 'Disease', 'MESH:D009369', (277, 290))	('EGFR', 'Gene', '1956', (105, 109))	('NCT02327169', 'Var', (177, 188))	('EGFR', 'Gene', '1956', (122, 126))	('tumours', 'Phenotype', 'HP:0002664', (283, 290))	('KRAS-driven tumours', 'Disease', (350, 369))	('epidermal growth factor receptor', 'Gene', (71, 103))	('tumours', 'Phenotype', 'HP:0002664', (362, 369))	('alisertib', 'Chemical', 'MESH:C550258', (26, 35))	('tumour', 'Phenotype', 'HP:0002664', (283, 289))	('mTOR', 'Gene', (195, 199))
35230	28220783	shRNAs to TACC3: sh1-TRCN0000290485, sh2-TRCN0000308273.	('sh2-TRCN0000308273', 'Var', (37, 55))	('TACC3', 'Gene', (10, 15))	('TACC3', 'Gene', '10460', (10, 15))
35231	28220783	Pharmacological inhibitors: U0126, SP600125, LY294002 and SB203850 were from Sigma; BIX02189 was from Tocris; trametinib and alisertib were from Selleckchem.	('LY294002', 'Var', (45, 53))	('SP600125', 'Var', (35, 43))	('U0126', 'Chemical', 'MESH:C113580', (28, 33))	('BIX02189', 'Chemical', 'MESH:C533207', (84, 92))	('SB203850', 'Var', (58, 66))	('SP600125', 'Chemical', 'MESH:C432165', (35, 43))	('alisertib', 'Chemical', 'MESH:C550258', (125, 134))	('U0126', 'Var', (28, 33))	('LY294002', 'Chemical', 'MESH:C085911', (45, 53))	('trametinib', 'Chemical', 'MESH:C560077', (110, 120))	('BIX02189', 'Var', (84, 92))	('SB203850', 'Chemical', '-', (58, 66))
35235	28220783	Antibodies used were: FOSL1 (1:2,000, #5281, Cell Signaling Technology (CST)), p-FOSL1 (1:1,000, #5841, CST), C-FOS (1:1,1000, #2250, CST), C-JUN (1:1,000, #9165, CST), JUNB (1:1,000, #3753, CST), JUND (1:1,000, #5000, CST), FOSB (1:1,000, #2251, CST), p-AURKA (1:1,000, #2914, CST), p-ERK (1:1,000, #9101, CST), ERK (1:1,000, #9102, CST), FOSL1 (1:500, sc-376148, Santa Cruz Biotechnology (SCB)), KRAS (1:500, sc-30, SCB), AURKA (1:500, sc-56881, SCB), CCNB1 (1:500, sc-245, SCB), FOXM1 (1:500, sc-376471, CST), HURP (1:500, sc-377004, SCB), KIF20A (1:500, sc-374508, SCB), TACC3 (1:1000, sc-376900, SCB), PLK1 (1:500, sc-17783), beta-tubulin (1:2,000, sc-9104, SCB) and FOSL2 (1:1,000, WH0002355M1, Sigma).	('TACC3', 'Gene', '10460', (575, 580))	('1:2,000', 'Var', (645, 652))	('TACC3', 'Gene', (575, 580))	('FOXM1', 'Gene', (482, 487))	('C-FOS', 'Gene', (110, 115))	('JUNB', 'Gene', '3726', (169, 173))	('PLK1', 'Gene', '5347', (607, 611))	('ERK', 'Gene', (313, 316))	('CCNB1', 'Gene', '891', (454, 459))	('HURP', 'Gene', (513, 517))	('FOSB', 'Gene', '2354', (225, 229))	('1:1,000', 'Var', (679, 686))	('C-JUN', 'Gene', '3725', (140, 145))	('JUNB', 'Gene', (169, 173))	('ERK', 'Gene', '5594', (286, 289))	('KIF20A', 'Gene', (543, 549))	('FOSB', 'Gene', (225, 229))	('C-FOS', 'Gene', '2353', (110, 115))	('C-JUN', 'Gene', (140, 145))	('FOXM1', 'Gene', '2305', (482, 487))	('p-ERK', 'Gene', '9451', (284, 289))	('p-ERK', 'Gene', (284, 289))	('CCNB1', 'Gene', (454, 459))	('ERK', 'Gene', (286, 289))	('FOSL2', 'Gene', (672, 677))	('FOSL2', 'Gene', '2355', (672, 677))	('KIF20A', 'Gene', '10112', (543, 549))	('PLK1', 'Gene', (607, 611))	('HURP', 'Gene', '9787', (513, 517))	('ERK', 'Gene', '5594', (313, 316))
35238	28220783	Slides were then incubated with a primary antibody to human and mouse FOSL1 (sc-376148, SCB, human: 1:200; mouse: 1:500) or Ki67 (1:100, RM-9106 (SP6), Thermo) at 4  C overnight.	('SP6', 'Gene', (146, 149))	('mouse', 'Species', '10090', (107, 112))	('FOSL1', 'Gene', (70, 75))	('human', 'Species', '9606', (93, 98))	('Ki67', 'Gene', '17345', (124, 128))	('1:100', 'Var', (130, 135))	('SP6', 'Gene', '83395', (146, 149))	('Ki67', 'Gene', (124, 128))	('human', 'Species', '9606', (54, 59))	('mouse', 'Species', '10090', (64, 69))
35254	28220783	For xenograft experiments, 25 x 103 (LKR13) or 2 x 106 (H358, H2347, H1568 and H1650, H2009 and H1792) cells infected with specified shRNAs were suspended in 200 mul of serum-free medium and injected subcutaneously into the two lower flanks of immune-deficient 8-12-weeks-old Rag2-/- and Balb/cnu/nu mice (for engraftment of human and mouse cells, respectively) (Charles River).	('mouse', 'Species', '10090', (335, 340))	('H2009 and', 'Var', (86, 95))	('H1792', 'CellLine', 'CVCL:1495', (96, 101))	('H358', 'Var', (56, 60))	('Rag2', 'Gene', '5897', (276, 280))	('H1650', 'Var', (79, 84))	('H2347', 'CellLine', 'CVCL:1550', (62, 67))	('H1568', 'CellLine', 'CVCL:1476', (69, 74))	('H2347', 'Var', (62, 67))	('H1650', 'CellLine', 'CVCL:1483', (79, 84))	('H1568', 'Var', (69, 74))	('mice', 'Species', '10090', (300, 304))	('Rag2', 'Gene', (276, 280))	('human', 'Species', '9606', (325, 330))
35259	28220783	For mouse genetics experiments, mice were intercrossed to generate KrasLSL-G12D/+; Trp53f/f; Fosl1+/+ and KrasLSL-G12D/+; Trp53f/f; Fosl1f/f.	('mouse', 'Species', '10090', (4, 9))	('Trp53', 'Gene', (83, 88))	('G12D', 'Mutation', 'rs121913529', (114, 118))	('Trp53', 'Gene', '22059', (122, 127))	('G12D', 'Mutation', 'rs121913529', (75, 79))	('mice', 'Species', '10090', (32, 36))	('Trp53', 'Gene', '22059', (83, 88))	('KrasLSL-G12D/+', 'Var', (67, 81))	('Trp53', 'Gene', (122, 127))
35267	28220783	Mouse lung cancer cell lines LKR10, LKR13 (Julien Sage), LSZ1, LSZ2, LSZ3, LSZ5 (Silve Vicent), 389N1 and 482N1 (Chen-Hua Chuang), and immortalized normal pancreas epithelial cells, KF07, were grown in DMEM supplemented with 10% FBS and 1% penicillin-streptomycin.	('lung cancer', 'Disease', 'MESH:D008175', (6, 17))	('LSZ3', 'Var', (69, 73))	('Sage', 'Gene', (50, 54))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('Sage', 'Gene', '55511', (50, 54))	('lung cancer', 'Disease', (6, 17))	('lung cancer', 'Phenotype', 'HP:0100526', (6, 17))	('FBS', 'Disease', (229, 232))	('Mouse', 'Species', '10090', (0, 5))	('streptomycin', 'Chemical', 'MESH:D013307', (251, 263))	('penicillin', 'Chemical', 'MESH:D010406', (240, 250))	('FBS', 'Disease', 'MESH:D005198', (229, 232))	('DMEM', 'Chemical', '-', (202, 206))
35273	28220783	Samples of the experiments used for KRAS gene signature selection (Sweet-Cordero et al., GSE15325 and GSE17671) were normalized with robust multi-array average (RMA) and after quality assessment and outlier detection with R/Bioconductor, one of the mouse samples was considered an outlier and discarded along with its corresponding control.	('GSE17671', 'Var', (102, 110))	('mouse', 'Species', '10090', (249, 254))	('KRAS', 'Gene', (36, 40))
35274	28220783	Enrichment of the obtained gene set in human patients with mutated KRAS (TCGA LAC, Chitale et al., GSE31210, GSE15471, GSE42284, GSE3225, TCGA MML and GSE36133) or mouse models (GSE15326 and GSE32277) was analysed with GSEA.	('GSEA', 'Chemical', '-', (219, 223))	('mouse', 'Species', '10090', (164, 169))	('GSE31210', 'Var', (99, 107))	('GSE3225', 'Chemical', '-', (129, 136))	('GSE3225', 'Var', (129, 136))	('GSE42284', 'Var', (119, 127))	('patients', 'Species', '9606', (45, 53))	('LAC', 'Phenotype', 'HP:0030078', (78, 81))	('human', 'Species', '9606', (39, 44))
35275	28220783	TCGA processed data for RNA-Seq experiments of LAC samples and microarray raw data for acute myeloid leukemia samples were downloaded for the logFC calculation of the comparison KRAS_mut vs KRAS_wt.	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (87, 109))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (87, 109))	('KRAS_mut', 'Var', (178, 186))	('leukemia', 'Phenotype', 'HP:0001909', (101, 109))	('acute myeloid leukemia', 'Disease', (87, 109))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (93, 109))	('LAC', 'Phenotype', 'HP:0030078', (47, 50))
35278	28220783	Both the classifiers and the corresponding Receiver Operator Characteristics analyses were performed using R. The same methodology was applied to patients or cell lines with mutated EGFR (GSE31210, Nguyen et al.	('mutated', 'Var', (174, 181))	('patients', 'Species', '9606', (146, 154))	('EGFR', 'Gene', '1956', (182, 186))	('EGFR', 'Gene', (182, 186))
35279	28220783	and GSE36133) and LAC patients of the TCGA dataset with mutations in EGFR, BRAF or DDR2, EML-ALK4 fusions, or MYC amplification plus no KRAS mutation (https://tcga-data.nci.nih.gov/tcga/tcgaHome2.jsp).	('EGFR', 'Gene', '1956', (69, 73))	('mutations', 'Var', (56, 65))	('LAC', 'Phenotype', 'HP:0030078', (18, 21))	('ALK4', 'Gene', (93, 97))	('EGFR', 'Gene', (69, 73))	('BRAF', 'Gene', '673', (75, 79))	('patients', 'Species', '9606', (22, 30))	('BRAF', 'Gene', (75, 79))	('DDR2', 'Gene', '4921', (83, 87))	('ALK4', 'Gene', '91', (93, 97))	('DDR2', 'Gene', (83, 87))
35283	28220783	(http://cbio.mskcc.org/Public/lung_array_data/), GSE31210, GSE15471, GSE42284, GSE3225, TCGA MML data set and GSE36133).	('GSE3225', 'Chemical', '-', (79, 86))	('GSE15471', 'Var', (59, 67))	('GSE31210', 'Var', (49, 57))	('GSE3225', 'Var', (79, 86))	('GSE42284', 'Var', (69, 77))
35284	28220783	Enrichment of KRAS-dependent candidates in mouse models: GSE15326 and GSE32277.	('GSE15326', 'Var', (57, 65))	('mouse', 'Species', '10090', (43, 48))	('GSE32277', 'Var', (70, 78))
35344	31786484	KIT-positive melanomas represent a significant diagnostic pitfall; KIT mutations are seen in ~10% melanomas arising at mucosal, acral, and chronically sun-exposed sites, and these tumors tend to overexpress KIT.	('KIT', 'Gene', '3815', (207, 210))	('KIT', 'Gene', (67, 70))	('melanomas', 'Disease', (13, 22))	('tumors', 'Phenotype', 'HP:0002664', (180, 186))	('overexpress', 'PosReg', (195, 206))	('KIT', 'Gene', '3815', (0, 3))	('melanomas', 'Disease', 'MESH:D008545', (98, 107))	('melanomas', 'Disease', (98, 107))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('melanoma', 'Phenotype', 'HP:0002861', (13, 21))	('mutations', 'Var', (71, 80))	('tumors', 'Disease', (180, 186))	('melanomas', 'Phenotype', 'HP:0002861', (13, 22))	('KIT', 'Gene', '3815', (67, 70))	('KIT', 'Gene', (207, 210))	('melanomas', 'Phenotype', 'HP:0002861', (98, 107))	('tumors', 'Disease', 'MESH:D009369', (180, 186))	('KIT', 'Gene', (0, 3))	('melanoma', 'Phenotype', 'HP:0002861', (98, 106))	('melanomas', 'Disease', 'MESH:D008545', (13, 22))
35361	31786484	Often, the diagnostic challenge lies in successfully identifying scant tumor and then distinguishing the deceptively bland glands from reactive change (not the subject of this review, though mutant-pattern p53 staining is useful in this setting).	('p53', 'Gene', (206, 209))	('p53', 'Gene', '7157', (206, 209))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('mutant-pattern', 'Var', (191, 205))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Disease', (71, 76))
35363	31786484	Loss of SMAD4/DPC4 is seen in up to 60% of pancreatic ductal carcinomas (Figure 11), and, although it is less well-studied, is probably seen in no more than 15% of primary small intestinal adenocarcinomas.	('SMAD4', 'Gene', (8, 13))	('DPC4', 'Gene', '4089', (14, 18))	('carcinoma', 'Phenotype', 'HP:0030731', (194, 203))	('DPC4', 'Gene', (14, 18))	('carcinomas', 'Phenotype', 'HP:0030731', (194, 204))	('pancreatic ductal carcinomas', 'Disease', 'MESH:D021441', (43, 71))	('intestinal adenocarcinomas', 'Phenotype', 'HP:0040273', (178, 204))	('intestinal adenocarcinomas', 'Disease', 'MESH:D000230', (178, 204))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('carcinomas', 'Phenotype', 'HP:0030731', (61, 71))	('SMAD4', 'Gene', '4089', (8, 13))	('pancreatic ductal carcinomas', 'Disease', (43, 71))	('Loss', 'Var', (0, 4))	('intestinal adenocarcinomas', 'Disease', (178, 204))
35432	31786484	When faced with diagnostic uncertainty on the initial H&E, it is best to start by trying to assign the broad tumor class with screening markers such as pankeratin, S100 or SOX10, and CD20 or CD45.	('H&E', 'Chemical', '-', (54, 57))	('CD45', 'Gene', (191, 195))	('S100', 'Gene', (164, 168))	('CD20', 'Gene', '54474', (183, 187))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('CD20', 'Gene', (183, 187))	('and', 'Var', (179, 182))	('CD45', 'Gene', '5788', (191, 195))	('S100', 'Gene', '6271', (164, 168))	('pankeratin', 'Chemical', '-', (152, 162))	('SOX10', 'Gene', '6663', (172, 177))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('SOX10', 'Gene', (172, 177))	('tumor', 'Disease', (109, 114))
35443	32327643	As such, downregulation of BTBD9 promoted lung cancer cell migration by upregulating the expression of TNFAIP1, whereas TNFAIP1 deletion abrogated this effect.	('downregulation', 'NegReg', (9, 23))	('TNFAIP1', 'Gene', (103, 110))	('lung cancer', 'Disease', 'MESH:D008175', (42, 53))	('promoted', 'PosReg', (33, 41))	('expression', 'MPA', (89, 99))	('BTBD9', 'Gene', '114781', (27, 32))	('TNFAIP1', 'Gene', '7126', (120, 127))	('upregulating', 'PosReg', (72, 84))	('lung cancer', 'Disease', (42, 53))	('TNFAIP1', 'Gene', (120, 127))	('BTBD9', 'Gene', (27, 32))	('TNFAIP1', 'Gene', '7126', (103, 110))	('lung cancer', 'Phenotype', 'HP:0100526', (42, 53))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('deletion', 'Var', (128, 136))
35452	32327643	NEDD8 modification regulates a variety of biological processes via affecting the subcellular localization, stability, conformation and function of neddylated substrates.	('regulates', 'Reg', (19, 28))	('affecting', 'Reg', (67, 76))	('NEDD8', 'Gene', '4738', (0, 5))	('NEDD8', 'Gene', (0, 5))	('conformation', 'MPA', (118, 130))	('neddylated substrates', 'Protein', (147, 168))	('stability', 'MPA', (107, 116))	('modification', 'Var', (6, 18))	('biological', 'CPA', (42, 52))	('function', 'MPA', (135, 143))	('subcellular localization', 'MPA', (81, 105))
35453	32327643	As a small-molecule inhibitor of NAE, MLN4924 blocks CRL activity, subsequently leading to the accumulation of an abundance of CRL E3 substrates and retarding tumor cell growth in vitro and in vivo.	('accumulation', 'PosReg', (95, 107))	('retarding tumor', 'Disease', (149, 164))	('MLN4924', 'Var', (38, 45))	('NAE', 'Chemical', '-', (33, 36))	('CRL', 'Gene', (127, 130))	('CRL', 'Gene', '133396', (53, 56))	('retarding tumor', 'Disease', 'MESH:D009369', (149, 164))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('MLN4924', 'Chemical', 'MESH:C539933', (38, 45))	('CRL', 'Gene', '133396', (127, 130))	('activity', 'MPA', (57, 65))	('abundance of', 'MPA', (114, 126))	('blocks', 'NegReg', (46, 52))	('CRL', 'Gene', (53, 56))	('leading to', 'Reg', (80, 90))
35471	32327643	The CRISPR/Cas9 system was used to knockdown TNFAIP1 and BTBD9.	('knockdown', 'Var', (35, 44))	('BTBD9', 'Gene', (57, 62))	('TNFAIP1', 'Gene', '7126', (45, 52))	('BTBD9', 'Gene', '114781', (57, 62))	('TNFAIP1', 'Gene', (45, 52))
35473	32327643	TNFAIP1 ubiquitination analysis, including MLN4924 treatment, transfection with siRNA against ROC1 or Cul3, and transfection with sgRNA against BTBD9, was performed in liver and lung cancer cells following our published methods.	('ROC1', 'Gene', '9978', (94, 98))	('lung cancer', 'Disease', (178, 189))	('lung cancer', 'Phenotype', 'HP:0100526', (178, 189))	('Cul3', 'Gene', '8452', (102, 106))	('ROC1', 'Gene', (94, 98))	('MLN4924', 'Chemical', 'MESH:C539933', (43, 50))	('BTBD9', 'Gene', (144, 149))	('TNFAIP1', 'Gene', '7126', (0, 7))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('TNFAIP1', 'Gene', (0, 7))	('lung cancer', 'Disease', 'MESH:D008175', (178, 189))	('ubiquitination', 'MPA', (8, 22))	('Cul3', 'Gene', (102, 106))	('MLN4924', 'Var', (43, 50))	('BTBD9', 'Gene', '114781', (144, 149))
35480	32327643	A label-free quantitative proteomic strategy was carried out to identify up- and downregulated proteins upon neddylation inhibition with MLN4924 (a small-molecule inhibitor of the neddylation pathway) in HepG2 cells (Fig.	('HepG2', 'CellLine', 'CVCL:0027', (204, 209))	('downregulated', 'NegReg', (81, 94))	('neddylation', 'Protein', (109, 120))	('proteins', 'Protein', (95, 103))	('MLN4924', 'Chemical', 'MESH:C539933', (137, 144))	('up-', 'PosReg', (73, 76))	('MLN4924', 'Var', (137, 144))
35481	32327643	A total of 8539 proteins were detected, among which 384 proteins were upregulated more than two-fold, including TNFAIP1, the expression of which was increased by 10.2-fold upon MLN4924 treatment (Fig.	('MLN4924', 'Chemical', 'MESH:C539933', (177, 184))	('increased', 'PosReg', (149, 158))	('TNFAIP1', 'Gene', '7126', (112, 119))	('proteins', 'Protein', (56, 64))	('expression', 'MPA', (125, 135))	('MLN4924', 'Var', (177, 184))	('upregulated', 'PosReg', (70, 81))	('TNFAIP1', 'Gene', (112, 119))	('proteins', 'Protein', (16, 24))
35482	32327643	To further verify the proteomic results, we determined the protein level of TNFAIP1 by western blot analysis and found that TNFAIP1 expression was markedly increased in a dose- and time-dependent manner upon treatment with MLN4924 in multiple cancer cell lines (Fig.	('cancer', 'Phenotype', 'HP:0002664', (243, 249))	('TNFAIP1', 'Gene', (124, 131))	('MLN4924', 'Chemical', 'MESH:C539933', (223, 230))	('MLN4924', 'Var', (223, 230))	('TNFAIP1', 'Gene', (76, 83))	('increased', 'PosReg', (156, 165))	('cancer', 'Disease', (243, 249))	('cancer', 'Disease', 'MESH:D009369', (243, 249))	('TNFAIP1', 'Gene', '7126', (124, 131))	('expression', 'MPA', (132, 142))	('TNFAIP1', 'Gene', '7126', (76, 83))
35484	32327643	To clarify the molecular mechanism of TNFAIP1 accumulation after blockade of the neddylation-CRL pathway, we first determined the TNFAIP1 turnover rate upon MLN4924 treatment.	('TNFAIP1', 'Gene', '7126', (130, 137))	('TNFAIP1', 'Gene', (130, 137))	('TNFAIP1', 'Gene', '7126', (38, 45))	('CRL', 'Gene', (93, 96))	('CRL', 'Gene', '133396', (93, 96))	('MLN4924', 'Chemical', 'MESH:C539933', (157, 164))	('MLN4924', 'Var', (157, 164))	('TNFAIP1', 'Gene', (38, 45))
35485	32327643	1e, f, MLN4924 significantly delayed TNFAIP1 turnover and extended the half-life of TNFAIP1 in four cancer cell lines.	('TNFAIP1', 'Gene', '7126', (84, 91))	('turnover', 'MPA', (45, 53))	('TNFAIP1', 'Gene', '7126', (37, 44))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('TNFAIP1', 'Gene', (84, 91))	('TNFAIP1', 'Gene', (37, 44))	('MLN4924', 'Chemical', 'MESH:C539933', (7, 14))	('extended', 'PosReg', (58, 66))	('half-life', 'MPA', (71, 80))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('delayed', 'NegReg', (29, 36))	('MLN4924', 'Var', (7, 14))
35489	32327643	2a, TNFAIP1 was accumulated only when Cul3 was knocked down, and there was no obvious change in TNFAIP1 expression when the other Cullin family members were silenced under these experimental conditions (Supplementary Fig.	('Cul3', 'Gene', (38, 42))	('knocked down', 'Var', (47, 59))	('Cullin', 'Gene', (130, 136))	('TNFAIP1', 'Gene', '7126', (96, 103))	('TNFAIP1', 'Gene', '7126', (4, 11))	('TNFAIP1', 'Gene', (4, 11))	('Cullin', 'Gene', '143384', (130, 136))	('Cul3', 'Gene', '8452', (38, 42))	('TNFAIP1', 'Gene', (96, 103))
35492	32327643	When ROC1 was knocked down, the activity of CRL was halted, subsequently inducing the accumulation of TNFAIP1 (Fig.	('CRL', 'Gene', '133396', (44, 47))	('ROC1', 'Gene', '9978', (5, 9))	('inducing', 'Reg', (73, 81))	('TNFAIP1', 'Gene', '7126', (102, 109))	('accumulation', 'PosReg', (86, 98))	('ROC1', 'Gene', (5, 9))	('TNFAIP1', 'Gene', (102, 109))	('CRL', 'Gene', (44, 47))	('knocked', 'Var', (14, 21))
35493	32327643	After determining that CRL3 E3 ligase ablation induced TNFAIP1 accumulation, the turnover rate of TNFAIP1 upon CRL3 inactivation was investigated.	('TNFAIP1', 'Gene', (55, 62))	('TNFAIP1', 'Gene', '7126', (55, 62))	('accumulation', 'PosReg', (63, 75))	('TNFAIP1', 'Gene', '7126', (98, 105))	('CRL3', 'Gene', '133396', (111, 115))	('CRL3', 'Gene', '133396', (23, 27))	('CRL3', 'Gene', (111, 115))	('TNFAIP1', 'Gene', (98, 105))	('ablation', 'Var', (38, 46))	('CRL3', 'Gene', (23, 27))
35494	32327643	Notably, we found that when Cul3 or ROC1 was knocked down with siRNA, TNFAIP1 turnover was significantly delayed (Fig.	('ROC1', 'Gene', '9978', (36, 40))	('Cul3', 'Gene', '8452', (28, 32))	('Cul3', 'Gene', (28, 32))	('ROC1', 'Gene', (36, 40))	('TNFAIP1', 'Gene', '7126', (70, 77))	('knocked', 'Var', (45, 52))	('TNFAIP1', 'Gene', (70, 77))	('turnover', 'MPA', (78, 86))	('delayed', 'NegReg', (105, 112))
35497	32327643	2e, silencing Cul3 significantly impaired TNFAIP1 polyubiquitination in both HepG2 and Huh7 cells.	('Cul3', 'Gene', '8452', (14, 18))	('TNFAIP1', 'Gene', (42, 49))	('Cul3', 'Gene', (14, 18))	('polyubiquitination', 'MPA', (50, 68))	('Huh7', 'Gene', (87, 91))	('impaired', 'NegReg', (33, 41))	('Huh7', 'Gene', '284424', (87, 91))	('HepG2', 'CellLine', 'CVCL:0027', (77, 82))	('TNFAIP1', 'Gene', '7126', (42, 49))	('silencing', 'Var', (4, 13))
35506	32327643	Consistently, the half-life of TNFAIP1 was also extended when BTBD9 was silenced with the CRISPR/Cas9 system (Fig.	('half-life', 'MPA', (18, 27))	('BTBD9', 'Gene', '114781', (62, 67))	('TNFAIP1', 'Gene', '7126', (31, 38))	('silenced', 'Var', (72, 80))	('BTBD9', 'Gene', (62, 67))	('extended', 'PosReg', (48, 56))	('TNFAIP1', 'Gene', (31, 38))
35511	32327643	To further elucidate the function of BTBD9 and TNFAIP1 in lung cancer, the CRISPR/Cas9 system was used to knockdown BTBD9 or TNFAIP1 individually and simultaneously (Fig.	('TNFAIP1', 'Gene', (125, 132))	('BTBD9', 'Gene', (116, 121))	('TNFAIP1', 'Gene', '7126', (47, 54))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('lung cancer', 'Disease', (58, 69))	('lung cancer', 'Phenotype', 'HP:0100526', (58, 69))	('BTBD9', 'Gene', '114781', (37, 42))	('knockdown', 'Var', (106, 115))	('TNFAIP1', 'Gene', (47, 54))	('BTBD9', 'Gene', '114781', (116, 121))	('TNFAIP1', 'Gene', '7126', (125, 132))	('lung cancer', 'Disease', 'MESH:D008175', (58, 69))	('BTBD9', 'Gene', (37, 42))
35512	32327643	4c, d, a Transwell assay demonstrated that the migration of lung cancer cells was elevated when BTBD9 was silenced.	('BTBD9', 'Gene', '114781', (96, 101))	('lung cancer', 'Disease', (60, 71))	('silenced', 'Var', (106, 114))	('lung cancer', 'Phenotype', 'HP:0100526', (60, 71))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('lung cancer', 'Disease', 'MESH:D008175', (60, 71))	('elevated', 'PosReg', (82, 90))	('migration', 'CPA', (47, 56))	('BTBD9', 'Gene', (96, 101))
35519	32327643	In addition, Kaplan-Meier analysis showed that the overall survival rate was lower in lung adenocarcinoma and squamous cell carcinoma patients with high TNFAIP1 expression than in patients with low TNFAIP1 expression (in lung adenocarcinoma: p = 0.030; in lung squamous cell carcinoma, p = 0.031, log-rank test) (Fig.	('lower', 'NegReg', (77, 82))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (86, 105))	('carcinoma', 'Phenotype', 'HP:0030731', (231, 240))	('patients', 'Species', '9606', (134, 142))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (221, 240))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (86, 105))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (256, 284))	('TNFAIP1', 'Gene', '7126', (153, 160))	('patients', 'Species', '9606', (180, 188))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (261, 284))	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('lung squamous cell carcinoma', 'Disease', (256, 284))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (221, 240))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (110, 133))	('TNFAIP1', 'Gene', (198, 205))	('high', 'Var', (148, 152))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (261, 284))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (110, 133))	('expression', 'Var', (161, 171))	('carcinoma', 'Phenotype', 'HP:0030731', (275, 284))	('lung adenocarcinoma', 'Disease', (86, 105))	('TNFAIP1', 'Gene', '7126', (198, 205))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('TNFAIP1', 'Gene', (153, 160))	('squamous cell carcinoma', 'Disease', (110, 133))	('lung adenocarcinoma', 'Disease', (221, 240))
35530	32327643	These findings indicate that dysregulation of CRL3BTBD9 may halt TNFAIP1 degradation in lung cancer to regulate the migration and metastasis of lung cancer.	('degradation', 'MPA', (73, 84))	('lung cancer', 'Disease', (88, 99))	('lung cancer', 'Disease', 'MESH:D008175', (144, 155))	('CRL3BTBD9', 'Gene', (46, 55))	('metastasis of lung cancer', 'Disease', 'MESH:D008175', (130, 155))	('lung cancer', 'Phenotype', 'HP:0100526', (144, 155))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('lung cancer', 'Disease', 'MESH:D008175', (88, 99))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('TNFAIP1', 'Gene', '7126', (65, 72))	('regulate', 'Reg', (103, 111))	('migration', 'CPA', (116, 125))	('metastasis of lung cancer', 'Disease', (130, 155))	('dysregulation', 'Var', (29, 42))	('halt', 'NegReg', (60, 64))	('TNFAIP1', 'Gene', (65, 72))	('lung cancer', 'Phenotype', 'HP:0100526', (88, 99))
35533	32327643	In this study, BTBD9 was first identified as an adaptor of CRL3 that regulates the ubiquitination and degradation of its substrate protein TNFAIP1, as demonstrated by the following: (1) TNFAIP1 and BTBD9 interacted, (2) downregulation of BTBD9 delayed the turnover of TNFAIP1, and (3) BTBD9 knockdown diminished the polyubiquitination of TNFAIP1.	('BTBD9', 'Gene', '114781', (285, 290))	('CRL3', 'Gene', (59, 63))	('knockdown', 'Var', (291, 300))	('TNFAIP1', 'Gene', '7126', (186, 193))	('TNFAIP1', 'Gene', '7126', (139, 146))	('downregulation', 'NegReg', (220, 234))	('diminished', 'NegReg', (301, 311))	('TNFAIP1', 'Gene', (268, 275))	('TNFAIP1', 'Gene', (338, 345))	('BTBD9', 'Gene', (198, 203))	('CRL3', 'Gene', '133396', (59, 63))	('BTBD9', 'Gene', (15, 20))	('BTBD9', 'Gene', (238, 243))	('ubiquitination', 'MPA', (83, 97))	('TNFAIP1', 'Gene', (186, 193))	('TNFAIP1', 'Gene', (139, 146))	('BTBD9', 'Gene', '114781', (238, 243))	('BTBD9', 'Gene', '114781', (15, 20))	('BTBD9', 'Gene', '114781', (198, 203))	('TNFAIP1', 'Gene', '7126', (268, 275))	('TNFAIP1', 'Gene', '7126', (338, 345))	('BTBD9', 'Gene', (285, 290))	('turnover', 'MPA', (256, 264))	('polyubiquitination of', 'MPA', (316, 337))
35537	32327643	Unfortunately, in this study, we found that BTBD9 knockdown had no effect on the expression of RhoA.	('BTBD9', 'Gene', (44, 49))	('knockdown', 'Var', (50, 59))	('RhoA', 'Gene', (95, 99))	('BTBD9', 'Gene', '114781', (44, 49))	('RhoA', 'Gene', '387', (95, 99))	('expression', 'MPA', (81, 91))
35544	32327643	Finally, we clarified that TNFAIP1 is overexpressed in the development of lung cancer due to dysfunction of CRL3 adaptor protein BTBD9, which is also associated with poor prognosis in lung cancer patients (Fig.	('TNFAIP1', 'Gene', (27, 34))	('CRL3', 'Gene', '133396', (108, 112))	('lung cancer', 'Disease', (74, 85))	('lung cancer', 'Phenotype', 'HP:0100526', (74, 85))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('overexpressed', 'PosReg', (38, 51))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('lung cancer', 'Disease', 'MESH:D008175', (184, 195))	('CRL3', 'Gene', (108, 112))	('patients', 'Species', '9606', (196, 204))	('lung cancer', 'Disease', 'MESH:D008175', (74, 85))	('dysfunction', 'Var', (93, 104))	('TNFAIP1', 'Gene', '7126', (27, 34))	('BTBD9', 'Gene', '114781', (129, 134))	('lung cancer', 'Disease', (184, 195))	('lung cancer', 'Phenotype', 'HP:0100526', (184, 195))	('BTBD9', 'Gene', (129, 134))
35560	31695721	Cancer initiation and progression involves genetic and epigenetic changes that reprogram complex regulatory circuits.	('reprogram', 'Reg', (79, 88))	('Cancer initiation', 'Disease', 'MESH:D009369', (0, 17))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('epigenetic changes', 'Var', (55, 73))	('Cancer initiation', 'Disease', (0, 17))
35563	31695721	However, molecular diversity increasing with tumor development promotes therapy resistance.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('therapy resistance', 'CPA', (72, 90))	('molecular diversity', 'Var', (9, 28))	('tumor', 'Disease', (45, 50))	('promotes', 'PosReg', (63, 71))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
35571	31695721	This approach was validated experimentally in vitro in MDA-MB-231 (a triple-negative cell line of invasive breast cancer) and showed that the inactivation, by interference RNA, of the five top-ranked targets identified for this cell lineage resulted in a significant reduction of cell proliferation, colony formation, cell growth, cell migration, and cell invasion.	('colony formation', 'CPA', (300, 316))	('invasive breast cancer', 'Disease', 'MESH:D001943', (98, 120))	('cell invasion', 'CPA', (351, 364))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (55, 65))	('reduction', 'NegReg', (267, 276))	('cell growth', 'CPA', (318, 329))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('inactivation', 'Var', (142, 154))	('cell migration', 'CPA', (331, 345))	('breast cancer', 'Phenotype', 'HP:0003002', (107, 120))	('invasive breast cancer', 'Disease', (98, 120))	('cell proliferation', 'CPA', (280, 298))
35572	31695721	Inactivation of these targets in other cell lines, such as MCF-7 (non-invasive breast cancer) and MCF-10A (control), showed little or no effect, respectively.	('MCF-10A', 'CellLine', 'CVCL:0598', (98, 105))	('MCF-7', 'CellLine', 'CVCL:0031', (59, 64))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('invasive breast cancer', 'Disease', (70, 92))	('breast cancer', 'Phenotype', 'HP:0003002', (79, 92))	('invasive breast cancer', 'Disease', 'MESH:D001943', (70, 92))	('Inactivation', 'Var', (0, 12))
35574	31695721	Inactivating multiple hubs may be necessary to shut down alternative pathways that maintain the tumor malignancy.	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumor malignancy', 'Disease', 'MESH:D009369', (96, 112))	('hub', 'Gene', (22, 25))	('Inactivating', 'Var', (0, 12))	('tumor malignancy', 'Disease', (96, 112))	('hub', 'Gene', '1993', (22, 25))
35632	31695721	Their relationship with tumor development is associated with their ability to stabilize mutant proteins, resulting from increased genomic instability, which would be degraded without the chaperones' assistance.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumor', 'Disease', (24, 29))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('proteins', 'Protein', (95, 103))	('mutant', 'Var', (88, 94))	('genomic instability', 'CPA', (130, 149))	('increased', 'PosReg', (120, 129))
35641	31695721	This protein target has prognostic potential, and its overexpression is associated with short OS time in non-squamous-cell lung carcinoma; its knockdown has suppressed tumorigenesis in ovarian cancer cells.	('ovarian cancer', 'Phenotype', 'HP:0100615', (185, 199))	('non-squamous-cell lung carcinoma', 'Disease', (105, 137))	('tumor', 'Disease', (168, 173))	('overexpression', 'PosReg', (54, 68))	('suppressed', 'NegReg', (157, 167))	('ovarian cancer', 'Disease', 'MESH:D010051', (185, 199))	('associated', 'Reg', (72, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('ovarian cancer', 'Disease', (185, 199))	('short OS time', 'Disease', (88, 101))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('knockdown', 'Var', (143, 152))	('non-squamous-cell lung carcinoma', 'Disease', 'MESH:D002294', (105, 137))
35646	31695721	Indeed, the inactivation of five hubs had a significantly higher effect in decreasing entropy than the inactivation of five targets selected at random.	('decreasing', 'NegReg', (75, 85))	('hub', 'Gene', (33, 36))	('entropy', 'MPA', (86, 93))	('inactivation', 'Var', (12, 24))	('hub', 'Gene', '1993', (33, 36))
35693	31695721	The decrease of entropy values after hub inactivation was significantly higher than the decrease of entropy after inactivation of targets selected at random, which confirms the benefit of a targeted attack on scale-free systems as shown by Albert et al..	('hub', 'Gene', '1993', (37, 40))	('inactivation', 'Var', (41, 53))	('entropy values', 'MPA', (16, 30))	('hub', 'Gene', (37, 40))	('decrease', 'NegReg', (4, 12))
35714	31695721	However, the signaling network is dynamic due to regulatory interactions between proteins and genes, and it is possible that the inhibition of a smaller target set may trigger a cascade effect resulting in irreversible tumor cell death as suggested by Tilli et al..	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('tumor', 'Disease', (219, 224))	('inhibition', 'Var', (129, 139))	('trigger', 'Reg', (168, 175))	('tumor', 'Disease', 'MESH:D009369', (219, 224))	('interactions', 'Interaction', (60, 72))
35786	30838028	Obviously, deregulation of the cell cycle may result in aberrant cell proliferation, and the genes involved in the cell cycle may be appropriate biomarkers for cancer detection and prognosis.	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('result in', 'Reg', (46, 55))	('cancer', 'Disease', (160, 166))	('deregulation', 'Var', (11, 23))	('cell cycle', 'CPA', (31, 41))	('cell proliferation', 'CPA', (65, 83))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('aberrant cell proliferation', 'Phenotype', 'HP:0031377', (56, 83))
35791	30838028	Previous studies have reported that dysregulation of RNA processing may drive colorectal and lung cancer, and RNA processing may be a potential therapeutic target in Ewing sarcoma.	('dysregulation', 'Var', (36, 49))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (166, 179))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('colorectal and lung cancer', 'Disease', 'MESH:D015179', (78, 104))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (166, 179))	('sarcoma', 'Phenotype', 'HP:0100242', (172, 179))	('Ewing sarcoma', 'Disease', (166, 179))	('drive', 'PosReg', (72, 77))	('lung cancer', 'Phenotype', 'HP:0100526', (93, 104))	('RNA processing', 'MPA', (53, 67))
35792	30838028	Our results indicate that abnormal RNA processing may be common in cancers and useful in screening for cancer drugs.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('cancers', 'Phenotype', 'HP:0002664', (67, 74))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('cancers', 'Disease', (67, 74))	('cancer', 'Disease', (67, 73))	('cancers', 'Disease', 'MESH:D009369', (67, 74))	('RNA processing', 'MPA', (35, 49))	('common', 'Reg', (57, 63))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('abnormal', 'Var', (26, 34))
35809	30838028	That is, the genes in this hallmark could also be used to predict the prognosis of cancer patients in the COAD data set.	('COAD', 'Disease', (106, 110))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('COAD', 'Disease', 'MESH:D029424', (106, 110))	('genes', 'Var', (13, 18))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('patients', 'Species', '9606', (90, 98))	('cancer', 'Disease', (83, 89))
35839	27821176	Transgenic mouse model demonstrated that deletion of either Six1 or Eya1 genes leads to a defect of mesenchymal cell development and remodeling of the distal lung septae and arteries.	('mesenchymal cell development', 'CPA', (100, 128))	('mouse', 'Species', '10090', (11, 16))	('Eya1', 'Gene', '14048', (68, 72))	('Six1', 'Gene', '20471', (60, 64))	('defect', 'NegReg', (90, 96))	('deletion', 'Var', (41, 49))	('Eya1', 'Gene', (68, 72))	('Six1', 'Gene', (60, 64))
35848	27821176	Sufficient evidences have revealed that aberrant expressions of the SIX genes gave rise to tumorigenesis, tumor progression, and metastasis by promoting proliferation, angiogenesis, migration, and apoptosis.	('SIX', 'Disease', 'None', (68, 71))	('promoting', 'PosReg', (143, 152))	('migration', 'CPA', (182, 191))	('apoptosis', 'CPA', (197, 206))	('aberrant expressions', 'Var', (40, 60))	('gave rise', 'Reg', (78, 87))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('metastasis', 'CPA', (129, 139))	('SIX', 'Disease', (68, 71))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('angiogenesis', 'CPA', (168, 180))	('tumor', 'Disease', (91, 96))	('tumor', 'Disease', (106, 111))
35879	27821176	In GSE32863, only SIX1, SIX2, and SIX4 indicated significant differences between ADC and normal tissues (SIX1: p < 0.0001; SIX2: p = 0.0002; SIX3: p = 0.1021; SIX4: p < 0.0001; SIX5: p = 0.6497; SIX6: p = 0.5539; Fig.	('SIX1', 'Gene', '6495', (105, 109))	('SIX5', 'Gene', '147912', (177, 181))	('SIX3', 'Gene', (141, 145))	('SIX2', 'Gene', (123, 127))	('GSE32863', 'Var', (3, 11))	('SIX6', 'Gene', '4990', (195, 199))	('SIX4', 'Gene', (34, 38))	('SIX1', 'Gene', '6495', (18, 22))	('SIX2', 'Gene', '10736', (24, 28))	('SIX5', 'Gene', (177, 181))	('SIX4', 'Gene', '51804', (159, 163))	('SIX3', 'Gene', '6496', (141, 145))	('SIX1', 'Gene', (105, 109))	('SIX1', 'Gene', (18, 22))	('SIX4', 'Gene', (159, 163))	('SIX2', 'Gene', '10736', (123, 127))	('SIX2', 'Gene', (24, 28))	('SIX6', 'Gene', (195, 199))	('SIX4', 'Gene', '51804', (34, 38))	('ADC', 'Disease', (81, 84))
35886	27821176	The ORs of SIX2 and SIX3 between III-IV and I-II in GSE68793 (SIX2: OR = 1.62; SIX3: OR = 1.62) showed consistent trend with pooled OR.	('SIX2', 'Gene', '10736', (11, 15))	('SIX2', 'Gene', (11, 15))	('SIX2 and SIX3', 'Disease', 'None', (11, 24))	('SIX3', 'Gene', '6496', (20, 24))	('GSE68793', 'Var', (52, 60))	('SIX3', 'Gene', '6496', (79, 83))	('SIX2', 'Gene', (62, 66))	('SIX2', 'Gene', '10736', (62, 66))	('SIX3', 'Gene', (20, 24))	('SIX3', 'Gene', (79, 83))
35911	27821176	For example, novel agents targeting epidermal growth factor receptor (EGFR) mutation and echinoderm microtubule-associated protein-like anaplastic lymphoma kinase (EML4-ALK) fusion benefit the patients with advanced ADC.	('patients', 'Species', '9606', (193, 201))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (136, 155))	('ADC', 'Disease', (216, 219))	('benefit', 'PosReg', (181, 188))	('EML4', 'Gene', (164, 168))	('epidermal growth factor receptor', 'Gene', '1956', (36, 68))	('EGFR', 'Gene', '1956', (70, 74))	('ALK', 'Gene', '238', (169, 172))	('anaplastic lymphoma', 'Disease', (136, 155))	('EML4', 'Gene', '27436', (164, 168))	('lymphoma', 'Phenotype', 'HP:0002665', (147, 155))	('EGFR', 'Gene', (70, 74))	('epidermal growth factor receptor', 'Gene', (36, 68))	('mutation', 'Var', (76, 84))	('anaplastic lymphoma', 'Disease', 'MESH:D017728', (136, 155))	('ALK', 'Gene', (169, 172))
35913	27821176	Aberrant expression of RDGN confers to tumorigenesis.	('Aberrant expression', 'Var', (0, 19))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumor', 'Disease', (39, 44))	('RDGN', 'Gene', (23, 27))
35920	27821176	Thus, inappropriate expression of SIX1 can both induce tumorigenesis and promote metastasis.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('induce', 'PosReg', (48, 54))	('tumor', 'Disease', (55, 60))	('SIX1', 'Gene', (34, 38))	('inappropriate expression', 'Var', (6, 30))	('metastasis', 'CPA', (81, 91))	('SIX1', 'Gene', '6495', (34, 38))	('promote', 'PosReg', (73, 80))
35923	27821176	reported that the expression of SIX1 was associated with heavy tumor burden, including large tumor size, advanced tumor stage, and distant metastasis of NSCLC.	('distant metastasis', 'CPA', (131, 149))	('tumor', 'Disease', (63, 68))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('SIX1', 'Gene', '6495', (32, 36))	('NSCLC', 'Phenotype', 'HP:0030358', (153, 158))	('associated', 'Reg', (41, 51))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumor', 'Disease', (93, 98))	('NSCLC', 'Disease', (153, 158))	('tumor', 'Disease', (114, 119))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('NSCLC', 'Disease', 'MESH:D002289', (153, 158))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('expression', 'Var', (18, 28))	('SIX1', 'Gene', (32, 36))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
35924	27821176	In in vitro study, they demonstrated that silencing of endogenous SIX1 attenuated proliferation and invasion of lung cancer, which supported our clinical analysis.	('silencing', 'Var', (42, 51))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('lung cancer', 'Disease', (112, 123))	('lung cancer', 'Phenotype', 'HP:0100526', (112, 123))	('SIX1', 'Gene', (66, 70))	('lung cancer', 'Disease', 'MESH:D008175', (112, 123))	('attenuated', 'NegReg', (71, 81))	('invasion', 'CPA', (100, 108))	('SIX1', 'Gene', '6495', (66, 70))
35929	27821176	In addition, increased SIX1 protein abundance might derive from enhanced translational regulation and protein stability through modification.	('SIX1', 'Gene', (23, 27))	('translational regulation', 'MPA', (73, 97))	('SIX1', 'Gene', '6495', (23, 27))	('protein', 'MPA', (102, 109))	('modification', 'Var', (128, 140))	('increased', 'PosReg', (13, 22))	('enhanced', 'PosReg', (64, 72))
35930	27821176	Anyway, functional activation of SIX1 may promote tumor progression.	('SIX1', 'Gene', (33, 37))	('SIX1', 'Gene', '6495', (33, 37))	('activation', 'PosReg', (19, 29))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('functional', 'Var', (8, 18))	('promote', 'PosReg', (42, 49))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Disease', (50, 55))
35932	27821176	Furthermore, we found that high SIX2 expression was positively correlated with the high stage which exhibits a greater possibility of invasiveness and poor prognosis in NSCLC.	('invasiveness', 'Disease', 'MESH:D009362', (134, 146))	('SIX2', 'Gene', (32, 36))	('NSCLC', 'Phenotype', 'HP:0030358', (169, 174))	('SIX2', 'Gene', '10736', (32, 36))	('invasiveness', 'Disease', (134, 146))	('NSCLC', 'Disease', (169, 174))	('high stage', 'Disease', (83, 93))	('high', 'Var', (27, 31))	('NSCLC', 'Disease', 'MESH:D002289', (169, 174))	('expression', 'MPA', (37, 47))
35933	27821176	The OS and RFS time were shorter in NSCLC patients with higher expression of SIX2, whereas subgroup analysis did not reach significance in ADC and SQC.	('OS', 'Chemical', '-', (4, 6))	('SIX2', 'Gene', (77, 81))	('shorter', 'NegReg', (25, 32))	('NSCLC', 'Phenotype', 'HP:0030358', (36, 41))	('SIX2', 'Gene', '10736', (77, 81))	('RFS time', 'MPA', (11, 19))	('NSCLC', 'Disease', (36, 41))	('higher', 'PosReg', (56, 62))	('patients', 'Species', '9606', (42, 50))	('NSCLC', 'Disease', 'MESH:D002289', (36, 41))	('expression', 'Var', (63, 73))	('SQC', 'Phenotype', 'HP:0002860', (147, 150))
35956	27821176	High frequency methylation of SIX6 promoter was detected in early stage of NSCLC.	('SIX6', 'Gene', (30, 34))	('methylation', 'Var', (15, 26))	('detected', 'Reg', (48, 56))	('NSCLC', 'Phenotype', 'HP:0030358', (75, 80))	('SIX6', 'Gene', '4990', (30, 34))	('NSCLC', 'Disease', (75, 80))	('NSCLC', 'Disease', 'MESH:D002289', (75, 80))
35957	27821176	Although those methylations were associated with clinical characteristics of NSCLC, the biological functions were not addressed.	('NSCLC', 'Disease', 'MESH:D002289', (77, 82))	('methylations', 'Var', (15, 27))	('NSCLC', 'Phenotype', 'HP:0030358', (77, 82))	('associated', 'Reg', (33, 43))	('NSCLC', 'Disease', (77, 82))
35971	26510908	Epigenetic silencing of HIC1 promotes epithelial-mesenchymal transition and drives progression in esophageal squamous cell carcinoma Downregulation of the novel tumor suppressor gene HIC1 (hypermethylated in cancer 1) occurs frequently in various tumors where it causes tumor progression and metastasis.	('tumor', 'Phenotype', 'HP:0002664', (247, 252))	('esophageal squamous cell carcinoma', 'Disease', (98, 132))	('tumors', 'Disease', (247, 253))	('HIC1', 'Gene', (183, 187))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('tumor', 'Phenotype', 'HP:0002664', (270, 275))	('tumor', 'Disease', (161, 166))	('promotes', 'PosReg', (29, 37))	('HIC1', 'Gene', (24, 28))	('tumors', 'Disease', 'MESH:D009369', (247, 253))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (109, 132))	('hypermethylated in cancer 1', 'Gene', '3090', (189, 216))	('HIC1', 'Gene', '3090', (183, 187))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (98, 132))	('Downregulation', 'NegReg', (133, 147))	('tumor', 'Disease', (247, 252))	('HIC1', 'Gene', '3090', (24, 28))	('Epigenetic silencing', 'Var', (0, 20))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('tumor', 'Disease', 'MESH:D009369', (247, 252))	('tumor', 'Disease', (270, 275))	('tumors', 'Phenotype', 'HP:0002664', (247, 253))	('epithelial-mesenchymal transition', 'CPA', (38, 71))	('hypermethylated in cancer 1', 'Gene', (189, 216))	('tumor', 'Disease', 'MESH:D009369', (270, 275))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))
35977	26510908	Together, loss of the regulation of EphA2 pathway through HIC1 epigenetic silencing could be an important mechanism in the ESCC progression.	('EphA2', 'Gene', '1969', (36, 41))	('epigenetic silencing', 'Var', (63, 83))	('regulation', 'MPA', (22, 32))	('ESCC', 'Disease', (123, 127))	('EphA2', 'Gene', (36, 41))	('HIC1', 'Gene', (58, 62))	('HIC1', 'Gene', '3090', (58, 62))	('loss', 'NegReg', (10, 14))
35984	26510908	It has been proved that this region is frequently affected by genetic alterations such as deletion and epigenetic modifications like hypermethylation in human cancers, including the p53 tumor suppressor gene at 17p13.1.	('cancers', 'Disease', (159, 166))	('deletion', 'Var', (90, 98))	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('p53', 'Gene', '7157', (182, 185))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('tumor', 'Disease', (186, 191))	('human', 'Species', '9606', (153, 158))	('cancers', 'Phenotype', 'HP:0002664', (159, 166))	('hypermethylation', 'Var', (133, 149))	('p53', 'Gene', (182, 185))	('cancers', 'Disease', 'MESH:D009369', (159, 166))
35985	26510908	Accumulating dada showed HIC1 is epigenetically silenced in various types of common human cancers such as prostate cancers, hepatocellular carcinoma, pancreatic cancer, hyperparathyroid tumors, renal cell carcinoma, et al.	('pancreatic cancer', 'Disease', 'MESH:D010190', (150, 167))	('cancers', 'Disease', (90, 97))	('cancers', 'Phenotype', 'HP:0002664', (115, 122))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (124, 148))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('cancers', 'Disease', (115, 122))	('HIC1', 'Gene', (25, 29))	('pancreatic cancer', 'Disease', (150, 167))	('prostate cancer', 'Phenotype', 'HP:0012125', (106, 121))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (124, 148))	('HIC1', 'Gene', '3090', (25, 29))	('renal cell carcinoma', 'Disease', (194, 214))	('prostate cancers', 'Phenotype', 'HP:0012125', (106, 122))	('tumors', 'Phenotype', 'HP:0002664', (186, 192))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (194, 214))	('prostate cancers', 'Disease', (106, 122))	('cancers', 'Disease', 'MESH:D009369', (90, 97))	('cancers', 'Disease', 'MESH:D009369', (115, 122))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('hyperparathyroid tumors', 'Disease', 'MESH:D006961', (169, 192))	('hepatocellular carcinoma', 'Disease', (124, 148))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (150, 167))	('carcinoma', 'Phenotype', 'HP:0030731', (205, 214))	('hyperparathyroid tumors', 'Disease', (169, 192))	('human', 'Species', '9606', (84, 89))	('carcinoma', 'Phenotype', 'HP:0030731', (139, 148))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (194, 214))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('epigenetically', 'Var', (33, 47))	('prostate cancers', 'Disease', 'MESH:D011471', (106, 122))
35988	26510908	These findings suggest that epigenetic HIC1 silencing predisposes tissues to tumorigenesis.	('HIC1', 'Gene', '3090', (39, 43))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('predisposes', 'Reg', (54, 65))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('epigenetic', 'Var', (28, 38))	('silencing', 'Var', (44, 53))	('tumor', 'Disease', (77, 82))	('HIC1', 'Gene', (39, 43))
35989	26510908	However, the status and role of HIC1 by epigenetic modification in ESCC have never been analyzed in detail and thus still remain unsettled.	('HIC1', 'Gene', '3090', (32, 36))	('HIC1', 'Gene', (32, 36))	('epigenetic modification', 'Var', (40, 63))	('ESCC', 'Gene', (67, 71))
35998	26510908	These findings indicate that HIC1 by hypermethylation may play a critical role in facilitating ESCC progression.	('hypermethylation', 'Var', (37, 53))	('HIC1', 'Gene', (29, 33))	('ESCC', 'Disease', (95, 99))	('HIC1', 'Gene', '3090', (29, 33))
36000	26510908	Downregulation of HIC1 was detected in all six ESCC cell lines (KYSE180, KYSE410, KYSE1170, EC1, EC18 and EC109), while the normal expression of HIC1 was detected in human normal esophageal epithelial cell line HEEC (Figure 1A and 1B).	('EC1', 'Gene', '4819', (92, 95))	('EC1', 'Gene', (106, 109))	('EC1', 'Gene', '4819', (106, 109))	('Downregulation', 'NegReg', (0, 14))	('human', 'Species', '9606', (166, 171))	('HIC1', 'Gene', (18, 22))	('KYSE180', 'Var', (64, 71))	('EC1', 'Gene', '4819', (97, 100))	('HIC1', 'Gene', '3090', (18, 22))	('EC1', 'Gene', (97, 100))	('HIC1', 'Gene', (145, 149))	('KYSE1170', 'Var', (82, 90))	('EC1', 'Gene', (92, 95))	('HIC1', 'Gene', '3090', (145, 149))	('HEEC', 'CellLine', 'None', (211, 215))	('KYSE410', 'Var', (73, 80))
36001	26510908	Restoration of HIC1 expression was revealed by 5-Aza-CdR treatment in six ESCC lines (Figure 1B), accompanied by demethylation of HIC1 promoter, while no change in HEEC cells (Figure 1D and 1E), indicating that HIC1 is transcriptionally silenced in these cells by DNA hypermethylation.	('HIC1', 'Gene', (130, 134))	('expression', 'MPA', (20, 30))	('HIC1', 'Gene', '3090', (130, 134))	('demethylation', 'Var', (113, 126))	('HEEC', 'CellLine', 'None', (164, 168))	('HIC1', 'Gene', (15, 19))	('HIC1', 'Gene', '3090', (211, 215))	('HIC1', 'Gene', (211, 215))	('HIC1', 'Gene', '3090', (15, 19))
36005	26510908	The western blot analysis using KYSE410 and HEEC cells, as a model, confirmed the upregulation of HIC1 proteins following the 5-Aza-CdR and 5-Aza-CdR/TSA treatments in KYSE410 cells, while no change in HEEC cells (Figure 1E).	('TSA', 'Chemical', 'MESH:C012589', (150, 153))	('HIC1', 'Gene', '3090', (98, 102))	('HIC1', 'Gene', (98, 102))	('HEEC', 'CellLine', 'None', (44, 48))	('proteins', 'Protein', (103, 111))	('HEEC', 'CellLine', 'None', (202, 206))	('5-Aza-CdR', 'Var', (126, 135))	('upregulation', 'PosReg', (82, 94))
36007	26510908	As shown in Figure 2A, 84.2% (64/76) of ESCCs was methylated, while only 7.9% (6/76) of its corresponding para-cancerous histological normal tissues (PCHNTs) was methylated, showing partial methylation.	('methylated', 'Var', (50, 60))	('ESCCs', 'Disease', (40, 45))	('para-cancerous', 'Disease', 'MESH:D009369', (106, 120))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('PCHNTs', 'Chemical', '-', (150, 156))	('para-cancerous', 'Disease', (106, 120))
36008	26510908	The percentage of HIC1 non-methylation, partial methylation, and complete methylation in 76 ESCC tissues was 15.8% (12/76), 75% (57/76) and 9.2% (7/76), respectively.	('HIC1', 'Gene', (18, 22))	('HIC1', 'Gene', '3090', (18, 22))	('partial methylation', 'Var', (40, 59))	('methylation', 'MPA', (74, 85))	('non-methylation', 'Var', (23, 38))
36009	26510908	The frequency of HIC1 methylation in ESCC tissues was significantly higher as compared with that in paired PCHNTs (P = 0.000).	('HIC1', 'Gene', '3090', (17, 21))	('HIC1', 'Gene', (17, 21))	('higher', 'PosReg', (68, 74))	('PCHNTs', 'Chemical', '-', (107, 113))	('methylation', 'Var', (22, 33))
36015	26510908	Correspondingly, the frequency of HIC1 methylation in all non-cancer controls was very low, even lower than that in adjacent normal tissues.	('methylation', 'Var', (39, 50))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('HIC1', 'Gene', '3090', (34, 38))	('HIC1', 'Gene', (34, 38))	('non-cancer', 'Disease', (58, 68))	('non-cancer', 'Disease', 'MESH:D009369', (58, 68))
36021	26510908	Downregulation of HIC1 at mRNA and protein level by methylation was associated with late stage, vascular invasion and lymph node metastasis, respectively (Table 1, all P < 0.05).	('vascular invasion', 'CPA', (96, 113))	('Downregulation', 'NegReg', (0, 14))	('lymph node metastasis', 'CPA', (118, 139))	('HIC1', 'Gene', (18, 22))	('late stage', 'CPA', (84, 94))	('HIC1', 'Gene', '3090', (18, 22))	('methylation', 'Var', (52, 63))
36026	26510908	Kaplan-Meier analysis demonstrated that no significant correlation was found between patients' OS and HIC1 protein downexpression, or HIC1 mRNA downexpression, or HIC1 methylation.	('HIC1', 'Gene', (102, 106))	('HIC1', 'Gene', (134, 138))	('mRNA', 'MPA', (139, 143))	('HIC1', 'Gene', '3090', (102, 106))	('HIC1', 'Gene', '3090', (134, 138))	('methylation', 'Var', (168, 179))	('patients', 'Species', '9606', (85, 93))	('protein', 'Protein', (107, 114))	('downexpression', 'NegReg', (144, 158))	('HIC1', 'Gene', '3090', (163, 167))	('HIC1', 'Gene', (163, 167))	('downexpression', 'NegReg', (115, 129))
36038	26510908	As analyzed by MTT assay, the cell proliferation rate of KYSE410 cells was significantly inhibited by HIC1 overexpression (Figure 6A).	('HIC1', 'Gene', (102, 106))	('HIC1', 'Gene', '3090', (102, 106))	('inhibited', 'NegReg', (89, 98))	('KYSE410', 'Var', (57, 64))	('overexpression', 'PosReg', (107, 121))	('MTT', 'Chemical', 'MESH:C070243', (15, 18))	('cell proliferation rate', 'CPA', (30, 53))
36055	26510908	This inactivation of HIC1 might impel cancer cells to alter survival and signaling pathways or lineage-specific transcription factors during the early stages of tumorigenesis.	('HIC1 might impel cancer', 'Disease', (21, 44))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('alter', 'Reg', (54, 59))	('HIC1 might impel cancer', 'Disease', 'MESH:D009369', (21, 44))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('inactivation', 'Var', (5, 17))	('lineage-specific', 'Gene', (95, 111))	('tumor', 'Disease', (161, 166))
36064	26510908	Emerging evidence suggests that HIC1 is frequently hypermethylated as a result of silence or low level in a variety of solid tumors.	('HIC1', 'Gene', (32, 36))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('solid tumors', 'Disease', 'MESH:D009369', (119, 131))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('HIC1', 'Gene', '3090', (32, 36))	('low', 'NegReg', (93, 96))	('silence', 'Var', (82, 89))	('solid tumors', 'Disease', (119, 131))
36066	26510908	Here, we showed that the CpG sites in the HIC1 promoter were mostly hypermethylated in primary ESCC tumors and cell lines, whereas those in normal esophageal mucosal tissues remained non-methylated.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('HIC1', 'Gene', '3090', (42, 46))	('HIC1', 'Gene', (42, 46))	('primary ESCC tumors', 'Disease', 'MESH:D004938', (87, 106))	('primary ESCC tumors', 'Disease', (87, 106))	('hypermethylated', 'Var', (68, 83))
36067	26510908	We concluded that the inactivation mediated by promoter methylation might be the major cause of the frequent HIC1 downregulation in ESCC cells.	('inactivation', 'NegReg', (22, 34))	('promoter methylation', 'Var', (47, 67))	('HIC1', 'Gene', '3090', (109, 113))	('HIC1', 'Gene', (109, 113))	('downregulation', 'NegReg', (114, 128))
36072	26510908	Results showed that both HIC1 hypermethylation and HIC1 downregulation both at mRNA and protein level were significantly correlated with vascular invasion, lymph node metastasis and clinical stage, respectively (all P < 0.05), suggesting that frequent dysfunction of HIC1 through its promoter methylation might play crucial roles in malignant progression of human esophageal cancer and might have a important impact on the metastasis and poor survival of ESCC patients.	('HIC1', 'Gene', '3090', (267, 271))	('esophageal cancer', 'Disease', (364, 381))	('HIC1', 'Gene', (25, 29))	('HIC1', 'Gene', '3090', (51, 55))	('cancer', 'Phenotype', 'HP:0002664', (375, 381))	('play', 'Reg', (311, 315))	('promoter', 'MPA', (284, 292))	('impact', 'Reg', (409, 415))	('ESCC', 'Disease', (455, 459))	('HIC1', 'Gene', '3090', (25, 29))	('human', 'Species', '9606', (358, 363))	('malignant progression', 'CPA', (333, 354))	('hypermethylation', 'Var', (30, 46))	('HIC1', 'Gene', (267, 271))	('roles', 'Reg', (324, 329))	('esophageal cancer', 'Disease', 'MESH:D004938', (364, 381))	('HIC1', 'Gene', (51, 55))	('downregulation', 'NegReg', (56, 70))	('patients', 'Species', '9606', (460, 468))	('dysfunction', 'Var', (252, 263))
36073	26510908	It was reported that the loss of suppressive function of HIC1 by promoter hypermethylation was responsible for prostate cancer progression and invasion.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('prostate cancer', 'Disease', (111, 126))	('suppressive function', 'NegReg', (33, 53))	('HIC1', 'Gene', '3090', (57, 61))	('invasion', 'CPA', (143, 151))	('prostate cancer', 'Disease', 'MESH:D011471', (111, 126))	('prostate cancer', 'Phenotype', 'HP:0012125', (111, 126))	('loss', 'NegReg', (25, 29))	('promoter hypermethylation', 'Var', (65, 90))	('HIC1', 'Gene', (57, 61))
36074	26510908	Recently, Eggers H, et al pinpointed that HIC1 hypermethylation was associated with reduced recurrence-free survival in renal cell carcinoma (RCC), suggesting that HIC1 could be seen as a possible marker to improve individualized therapy and risk stratification.	('RCC', 'Disease', 'MESH:C538614', (142, 145))	('RCC', 'Disease', (142, 145))	('RCC', 'Phenotype', 'HP:0005584', (142, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('HIC1', 'Gene', (164, 168))	('recurrence-free survival', 'CPA', (92, 116))	('HIC1', 'Gene', '3090', (164, 168))	('HIC1', 'Gene', '3090', (42, 46))	('reduced', 'NegReg', (84, 91))	('HIC1', 'Gene', (42, 46))	('renal cell carcinoma', 'Disease', (120, 140))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (120, 140))	('hypermethylation', 'Var', (47, 63))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (120, 140))
36079	26510908	The abnormal regulation of Eph pathway via HIC1 epigenetic silencing could be an important mechanism in the pathogenesis of epithelial cancers.	('Eph pathway', 'Pathway', (27, 38))	('regulation', 'Reg', (13, 23))	('cancers', 'Phenotype', 'HP:0002664', (135, 142))	('epithelial cancers', 'Disease', (124, 142))	('HIC1', 'Gene', '3090', (43, 47))	('epigenetic silencing', 'Var', (48, 68))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('epithelial cancers', 'Disease', 'MESH:D000077216', (124, 142))	('HIC1', 'Gene', (43, 47))
36104	26510908	The primers used in PCR are listed as follows: HIC1 sense 5'-cga cga cta caa gag cag cag c-3', and antisense 5'-cag gtt gtc acc gaa gct ctc-3'.	('HIC1', 'Gene', '3090', (47, 51))	('HIC1', 'Gene', (47, 51))	('gaa', 'Gene', (128, 131))	('gag', 'Chemical', 'MESH:D006025', (77, 80))	("antisense 5'-cag", 'Var', (99, 115))	('gaa', 'Gene', '2548', (128, 131))
36105	26510908	EphA2 sense 5'-tgt gcc agg cag gct acg-3', and antisense 5'-ctc caa gca ggg gct ctc a-3'.	('EphA2', 'Gene', '1969', (0, 5))	("antisense 5'-ctc", 'Var', (47, 63))	('EphA2', 'Gene', (0, 5))
36110	26510908	The specific primers for detection of HIC1 CpG island methylation and unmethylation were designed according to previous report.	('methylation', 'Var', (54, 65))	('HIC1', 'Gene', '3090', (38, 42))	('HIC1', 'Gene', (38, 42))
36119	33373873	TNF can induce cell death in cancer cells and has been used as a treatment in certain types of cancer.	('cancer', 'Disease', (29, 35))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('death', 'Disease', 'MESH:D003643', (20, 25))	('death', 'Disease', (20, 25))	('cancer', 'Disease', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('cancer', 'Disease', 'MESH:D009369', (29, 35))	('TNF', 'Var', (0, 3))
36132	33373873	Thus, depending on the cellular context, TNF can promote cell death or tumor growth.	('TNF', 'Var', (41, 44))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('death', 'Disease', 'MESH:D003643', (62, 67))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('promote', 'PosReg', (49, 56))	('death', 'Disease', (62, 67))	('tumor', 'Disease', (71, 76))
36137	33373873	Importantly TNF is known to be secreted by malignant cells as well as cells in the tumor microenvironment, and there is experimental evidence from a variety of models that TNF can promote the growth of tumors.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('TNF', 'Var', (172, 175))	('tumors', 'Phenotype', 'HP:0002664', (202, 208))	('tumor', 'Disease', (202, 207))	('tumor', 'Disease', (83, 88))	('tumors', 'Disease', (202, 208))	('tumors', 'Disease', 'MESH:D009369', (202, 208))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('promote', 'PosReg', (180, 187))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))
36144	33373873	The adenocarcinoma subset of NSCLC (lung adenocarcinoma (LUAD)) includes patients with EGFR activating mutations, the prevalence of which ranges from 15% in Western populations to up to 50% in Asian populations.	('mutations', 'Var', (103, 112))	('NSCLC', 'Phenotype', 'HP:0030358', (29, 34))	('carcinoma', 'Phenotype', 'HP:0030731', (9, 18))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (36, 55))	('carcinoma', 'Phenotype', 'HP:0030731', (46, 55))	('EGFR', 'Gene', (87, 91))	('adenocarcinoma', 'Disease', (4, 18))	('lung adenocarcinoma', 'Disease', (36, 55))	('adenocarcinoma', 'Disease', (41, 55))	('NSCLC', 'Disease', (29, 34))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (36, 55))	('adenocarcinoma', 'Disease', 'MESH:D000230', (41, 55))	('adenocarcinoma', 'Disease', 'MESH:D000230', (4, 18))	('NSCLC', 'Disease', 'MESH:D002289', (29, 34))	('patients', 'Species', '9606', (73, 81))	('activating', 'PosReg', (92, 102))
36145	33373873	Patients with EGFR activating mutations receive treatment with EGFR tyrosine kinase inhibitors (TKIs) since this treatment is effective in early disease control in these patients.	('patients', 'Species', '9606', (170, 178))	('activating', 'PosReg', (19, 29))	('EGFR', 'Gene', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('mutations', 'Var', (30, 39))
36151	33373873	A limitation of the TCGA-LUAD database is that it does not provide the drug treatment history, making it difficult to ascertain treatment with EGFR TKIs, which would affect the EGFR mutant patient's survival.	('affect', 'Reg', (166, 172))	('patient', 'Species', '9606', (189, 196))	('EGFR', 'Gene', (177, 181))	('survival', 'MPA', (199, 207))	('mutant', 'Var', (182, 188))
36157	33373873	The BATTLE trial included about 30 advanced-NSCLC (mostly LUAD) patients harboring active EGFR mutation who were treated with erlotinib after the first diagnosis.	('NSCLC', 'Disease', 'MESH:D002289', (44, 49))	('patients', 'Species', '9606', (64, 72))	('NSCLC', 'Phenotype', 'HP:0030358', (44, 49))	('EGFR', 'Gene', (90, 94))	('erlotinib', 'Chemical', 'MESH:D000069347', (126, 135))	('NSCLC', 'Disease', (44, 49))	('mutation', 'Var', (95, 103))
36158	33373873	As we have previously shown, the BATTLE trial data shows TNF and other target genes are tumor promoting in EGFR mutant patients treated with EGFR TKIs, and we confirmed tumor's TNF was elevated by EGFR TKI therapy in vitro, in vivo, and in patients.	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('patients', 'Species', '9606', (119, 127))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('EGFR', 'Gene', (107, 111))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('patients', 'Species', '9606', (240, 248))	('tumor', 'Disease', (169, 174))	('mutant', 'Var', (112, 118))	('TNF', 'MPA', (177, 180))	('elevated', 'PosReg', (185, 193))	('TNF', 'Gene', (57, 60))	('tumor', 'Disease', (88, 93))
36159	33373873	Per the BATTLE trial data, most TNF superfamily genes and NF-kappaB target genes are oncogenic in EGFR mutant patients treated with EGFR TKIs.	('EGFR', 'Gene', (98, 102))	('mutant', 'Var', (103, 109))	('NF-kappaB', 'Gene', '4790', (58, 67))	('NF-kappaB', 'Gene', (58, 67))	('patients', 'Species', '9606', (110, 118))
36187	33373873	About 10% to 15% of NSCLC patients in Western populations harbor EGFR activating mutations that render the tumors sensitive to EGFR inhibition, and EGFR TKIs are used as a treatment in this subset of patients.	('sensitive', 'MPA', (114, 123))	('NSCLC', 'Disease', 'MESH:D002289', (20, 25))	('patients', 'Species', '9606', (200, 208))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('EGFR', 'Gene', (65, 69))	('activating', 'PosReg', (70, 80))	('tumors', 'Disease', (107, 113))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('patients', 'Species', '9606', (26, 34))	('NSCLC', 'Phenotype', 'HP:0030358', (20, 25))	('tumors', 'Disease', 'MESH:D009369', (107, 113))	('mutations', 'Var', (81, 90))	('NSCLC', 'Disease', (20, 25))
36194	33373873	Similar results were obtained in EGFR mutant NSCLC lines that are EGFR TKI sensitive.	('mutant', 'Var', (38, 44))	('NSCLC', 'Disease', (45, 50))	('NSCLC', 'Disease', 'MESH:D002289', (45, 50))	('EGFR', 'Gene', (33, 37))	('NSCLC', 'Phenotype', 'HP:0030358', (45, 50))
36196	33373873	Importantly, it was demonstrated that a combined EGFR plus TNF inhibition was also synergistic in an immunocompetent transgenic NSCLC model driven by a doxycycline mediated induction of the L858R EGFR mutation.	('EGFR', 'Gene', (196, 200))	('NSCLC', 'Phenotype', 'HP:0030358', (128, 133))	('doxycycline', 'Chemical', 'MESH:D004318', (152, 163))	('NSCLC', 'Disease', (128, 133))	('L858R', 'Var', (190, 195))	('NSCLC', 'Disease', 'MESH:D002289', (128, 133))	('inhibition', 'NegReg', (63, 73))	('L858R', 'Mutation', 'rs121434568', (190, 195))
36208	33373873	However, NSCLCs with EGFR activating mutations appear to be resistant to immunotherapy.	('activating', 'PosReg', (26, 36))	('EGFR', 'Gene', (21, 25))	('NSCLCs', 'Disease', (9, 15))	('mutations', 'Var', (37, 46))	('NSCLCs', 'Disease', 'MESH:D002289', (9, 15))	('NSCLC', 'Phenotype', 'HP:0030358', (9, 14))
36209	33373873	Immunotherapy with PD1 or CTLA4 antibodies or a combination of the 2 is associated with a significant toxicity that is associated with inflammation and immune-related adverse events that may involve TNF production and is commonly treated with glucocorticoids and also with anti-TNF therapies.	('toxicity', 'Disease', 'MESH:D064420', (102, 110))	('antibodies', 'Var', (32, 42))	('toxicity', 'Disease', (102, 110))	('TNF production', 'MPA', (199, 213))	('CTLA4', 'Gene', (26, 31))	('inflammation', 'Disease', 'MESH:D007249', (135, 147))	('inflammation', 'Disease', (135, 147))	('PD1', 'Gene', '5133', (19, 22))	('PD1', 'Gene', (19, 22))	('CTLA4', 'Gene', '1493', (26, 31))
36210	33373873	While this appears to be an effective treatment, experimental studies have suggested that inhibition of TNF may help to overcome resistance to immune checkpoint treatments in murine experimental models.	('inhibition', 'Var', (90, 100))	('murine', 'Species', '10090', (175, 181))	('TNF', 'Gene', (104, 107))
36221	33373873	All primary NSCLC patients from TCGA-LUSC or TCGA-LUAD, the TCGA-LUAD EGFR-activating mutation was defined as harboring L858R or exon 19 deletion, but without T790M mutation.	('NSCLC', 'Phenotype', 'HP:0030358', (12, 17))	('L858R', 'Mutation', 'rs121434568', (120, 125))	('NSCLC', 'Disease', (12, 17))	('LUSC', 'Phenotype', 'HP:0030359', (37, 41))	('patients', 'Species', '9606', (18, 26))	('NSCLC', 'Disease', 'MESH:D002289', (12, 17))	('T790M', 'Mutation', 'rs121434569', (159, 164))	('L858R', 'Var', (120, 125))
36237	30933965	Overexpression of TRAF4 in ESCC was also associated with high expression of ki-67 and p53 (P<0.05).	('p53', 'Gene', '7157', (86, 89))	('expression', 'MPA', (62, 72))	('TRAF4', 'Gene', (18, 23))	('TRAF4', 'Gene', '9618', (18, 23))	('Overexpression', 'Var', (0, 14))	('ki-67', 'Protein', (76, 81))	('p53', 'Gene', (86, 89))
36238	30933965	We also found that patients with high expression of TRAF4 had significantly lower OS than in patients with low TRAF4 expression (P<0.05).	('patients', 'Species', '9606', (93, 101))	('patients', 'Species', '9606', (19, 27))	('high expression', 'Var', (33, 48))	('lower', 'NegReg', (76, 81))	('TRAF4', 'Gene', (52, 57))	('TRAF4', 'Gene', (111, 116))	('low TRAF4', 'Phenotype', 'HP:0040209', (107, 116))	('TRAF4', 'Gene', '9618', (52, 57))	('TRAF4', 'Gene', '9618', (111, 116))
36239	30933965	Overexpression of TRAF4 was an independent risk factor affecting the prognosis of patients (P<0.05).	('patients', 'Species', '9606', (82, 90))	('TRAF4', 'Gene', '9618', (18, 23))	('TRAF4', 'Gene', (18, 23))	('Overexpression', 'Var', (0, 14))
36241	30933965	Overexpression of TRAF4 was an independent risk factor affecting the overall prognosis of patients.	('TRAF4', 'Gene', '9618', (18, 23))	('patients', 'Species', '9606', (90, 98))	('TRAF4', 'Gene', (18, 23))	('Overexpression', 'Var', (0, 14))
36300	30933965	We found that the overall survival (OS) of patients with high expression of TRAF4 was significantly lower than that of patients with low expression of TRAF4 by Kaplan-Meier survival analysis and log-rank statistical test (95%CI 23.337-37.763 vs. 44.409-78.546, P<0.01, Figure 5A).	('overall survival', 'MPA', (18, 34))	('TRAF4', 'Gene', '9618', (76, 81))	('patients', 'Species', '9606', (43, 51))	('patients', 'Species', '9606', (119, 127))	('lower', 'NegReg', (100, 105))	('TRAF4', 'Gene', (151, 156))	('TRAF4', 'Gene', (76, 81))	('TRAF4', 'Gene', '9618', (151, 156))	('high expression', 'Var', (57, 72))
36321	30933965	A high ki-67-positive rate is often accompanied by accelerated tumor growth, poor tissue differentiation, and poor prognosis.	('tumor', 'Disease', (63, 68))	('ki-67-positive', 'Var', (7, 21))	('tissue differentiation', 'CPA', (82, 104))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('accelerated', 'PosReg', (51, 62))
36324	30933965	Therefore, high expression of TRAF4 may lead to the poor prognosis of patients by promoting the growth and proliferation of tumor cells and by inhibiting cell apoptosis.	('patients', 'Species', '9606', (70, 78))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('TRAF4', 'Gene', (30, 35))	('TRAF4', 'Gene', '9618', (30, 35))	('growth', 'CPA', (96, 102))	('inhibiting', 'NegReg', (143, 153))	('tumor', 'Disease', (124, 129))	('high expression', 'Var', (11, 26))	('cell apoptosis', 'CPA', (154, 168))	('promoting', 'PosReg', (82, 91))	('lead', 'Reg', (40, 44))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
36330	30933965	Yao also found that silencing TRAF4 inhibits osteosarcoma cell growth in vivo and in vitro, consistent with these findings.	('osteosarcoma', 'Phenotype', 'HP:0002669', (45, 57))	('TRAF4', 'Gene', (30, 35))	('osteosarcoma', 'Disease', (45, 57))	('osteosarcoma', 'Disease', 'MESH:D012516', (45, 57))	('TRAF4', 'Gene', '9618', (30, 35))	('inhibits', 'NegReg', (36, 44))	('silencing', 'Var', (20, 29))
36334	30933965	Through further Kaplan-Meier and log-rank statistical tests, we found that the overall survival (OS) of patients with high expression of TRAF4 in the cytosol was significantly lower than that of patients with low expression of TRAF4, and the Cox multivariate analysis suggests that TRAF4 is an independent risk factor affecting overall patient survival.	('overall survival', 'CPA', (79, 95))	('patient', 'Species', '9606', (336, 343))	('TRAF4', 'Gene', (137, 142))	('patient', 'Species', '9606', (195, 202))	('patients', 'Species', '9606', (104, 112))	('lower', 'NegReg', (176, 181))	('TRAF4', 'Gene', (282, 287))	('TRAF4', 'Gene', '9618', (137, 142))	('TRAF4', 'Gene', (227, 232))	('Cox', 'Gene', '1351', (242, 245))	('patients', 'Species', '9606', (195, 203))	('patient', 'Species', '9606', (104, 111))	('high expression', 'Var', (118, 133))	('TRAF4', 'Gene', '9618', (227, 232))	('TRAF4', 'Gene', '9618', (282, 287))	('Cox', 'Gene', (242, 245))
36337	30933965	Targeted silencing of TRAF4 may benefit patients with advanced esophageal squamous cell carcinoma.	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (63, 97))	('TRAF4', 'Gene', (22, 27))	('TRAF4', 'Gene', '9618', (22, 27))	('patients', 'Species', '9606', (40, 48))	('esophageal squamous cell carcinoma', 'Disease', (63, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('benefit', 'PosReg', (32, 39))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (74, 97))	('Targeted silencing', 'Var', (0, 18))
36338	30933965	In the future, TRAF4 gene knockout and inhibition of TRAF4 expression may promote apoptosis of esophageal cells, and inhibit proliferation and distant metastasis.	('TRAF4', 'Gene', '9618', (15, 20))	('TRAF4', 'Gene', '9618', (53, 58))	('apoptosis', 'CPA', (82, 91))	('promote', 'PosReg', (74, 81))	('gene knockout', 'Var', (21, 34))	('inhibition', 'NegReg', (39, 49))	('knockout', 'Var', (26, 34))	('expression', 'MPA', (59, 69))	('TRAF4', 'Gene', (53, 58))	('inhibit', 'NegReg', (117, 124))	('TRAF4', 'Gene', (15, 20))
36343	30933965	Patients with high expression of TRAF4 had significantly lower OS than patients with low TRAF4 expression.	('TRAF4', 'Gene', '9618', (33, 38))	('low TRAF4', 'Phenotype', 'HP:0040209', (85, 94))	('TRAF4', 'Gene', (89, 94))	('patients', 'Species', '9606', (71, 79))	('Patients', 'Species', '9606', (0, 8))	('TRAF4', 'Gene', '9618', (89, 94))	('high expression', 'Var', (14, 29))	('TRAF4', 'Gene', (33, 38))	('lower', 'NegReg', (57, 62))
36344	30933965	Overexpression of TRAF4 was an independent risk factor affecting the prognosis of patients, indicating that TRAF4 may become a new target for the treatment of ESCC in the future.	('men', 'Species', '9606', (151, 154))	('patients', 'Species', '9606', (82, 90))	('TRAF4', 'Gene', (18, 23))	('TRAF4', 'Gene', '9618', (108, 113))	('TRAF4', 'Gene', (108, 113))	('Overexpression', 'Var', (0, 14))	('TRAF4', 'Gene', '9618', (18, 23))	('affecting', 'Reg', (55, 64))	('ESCC', 'Disease', (159, 163))
36353	30219035	Dual luciferase assay demonstrated that TUSC2P 3'UTR decoyed miR-17-5p, miR-520a-3p, miR-608, miR-661 from binding to TUSC2.	('miR-661', 'Gene', (94, 101))	('miR-608', 'Gene', '693193', (85, 92))	('miR-661', 'Gene', '724031', (94, 101))	('TUSC2', 'Gene', (118, 123))	('TUSC2P', 'Gene', (40, 46))	('TUSC2P', 'Gene', '11334', (40, 46))	('miR-520a-3p', 'Var', (72, 83))	('TUSC2', 'Gene', (40, 45))	('TUSC2', 'Gene', '11334', (118, 123))	('TUSC2', 'Gene', '11334', (40, 45))	('binding', 'Interaction', (107, 114))	('miR-17-5p', 'Gene', '406952', (61, 70))	('miR-17-5p', 'Gene', (61, 70))	('miR-608', 'Gene', (85, 92))	('decoyed', 'NegReg', (53, 60))
36360	30219035	TUSC2 was firstly reported in a study analyzing frequent deletions in the short arm of chromosome 3p.	('TUSC2', 'Gene', '11334', (0, 5))	('deletions', 'Var', (57, 66))	('TUSC2', 'Gene', (0, 5))	('short arm', 'Phenotype', 'HP:0009824', (74, 83))
36361	30219035	Frequent deletions in the short arm of chromosome 3p occurs in a wide variety of cancers.	('occurs', 'Reg', (53, 59))	('cancers', 'Phenotype', 'HP:0002664', (81, 88))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('short arm', 'Phenotype', 'HP:0009824', (26, 35))	('cancers', 'Disease', (81, 88))	('cancers', 'Disease', 'MESH:D009369', (81, 88))	('deletions', 'Var', (9, 18))
36366	30219035	In addition, they shared binding sites of many miRNAs, including miRNA-17-5p, miRNA-608, miRNA-661, miRNA-520a-3p.	('miRNA-520a-3p', 'Var', (100, 113))	('binding', 'Interaction', (25, 32))	('miRNA-608', 'Var', (78, 87))	('miRNA-17', 'Gene', (65, 73))	('miRNA-661', 'Var', (89, 98))	('miRNA-17', 'Gene', '406952', (65, 73))
36371	30219035	The fragment of 3'UTR of TUSC2 and TUSC2P which contained potential binding sites of miRNA-17-5p, miRNA-608, miRNA-661, miR-520a-3p were synthesized.	('TUSC2', 'Gene', (25, 30))	('miR-520a-3p', 'Var', (120, 131))	('binding', 'Interaction', (68, 75))	('TUSC2', 'Gene', (35, 40))	('TUSC2', 'Gene', '11334', (25, 30))	('miRNA-661', 'Var', (109, 118))	('TUSC2', 'Gene', '11334', (35, 40))	('miRNA-17', 'Gene', (85, 93))	('miRNA-17', 'Gene', '406952', (85, 93))	('TUSC2P', 'Gene', '11334', (35, 41))	('miRNA-608', 'Var', (98, 107))	('TUSC2P', 'Gene', (35, 41))
36373	30219035	To obtain a negative control, the corresponding fragments of 3'UTR of TUSC2 and TUSC2P 3'UTR of which the miRNAs binding sites were mutated was synthesized and cloned to psiCHECK -2 luciferase vector to obtain corresponding mutant luciferase constructs.	('TUSC2', 'Gene', (70, 75))	('TUSC2', 'Gene', (80, 85))	('mutant', 'Var', (224, 230))	('TUSC2', 'Gene', '11334', (70, 75))	('TUSC2', 'Gene', '11334', (80, 85))	('TUSC2P', 'Gene', (80, 86))	('TUSC2P', 'Gene', '11334', (80, 86))
36388	30219035	Cells were cultured at 37  C for 24 h, TUSC2 and TUSC2P luciferase constructs or corresponding mutant constructs were co-transfected with miRNA mimics, or miRNAs controls, respectively using Lipofectamine 2000.	('Lipofectamine 2000', 'Chemical', 'MESH:C086724', (191, 209))	('TUSC2', 'Gene', '11334', (49, 54))	('TUSC2', 'Gene', (39, 44))	('TUSC2', 'Gene', '11334', (39, 44))	('mutant', 'Var', (95, 101))	('TUSC2P', 'Gene', (49, 55))	('TUSC2P', 'Gene', '11334', (49, 55))	('TUSC2', 'Gene', (49, 54))
36399	30219035	When analyzing the sequence of the TUSC2P and TUSC2 3'UTR, miRNA-17-5p, miRNA-608, miRNA-661, miRNA-520a-3p were found to poss conserved binding sites for TUSC2P and TUSC2 (Fig.	('poss', 'NegReg', (122, 126))	('TUSC2', 'Gene', (155, 160))	('TUSC2', 'Gene', '11334', (155, 160))	('miRNA-608', 'Var', (72, 81))	('TUSC2P', 'Gene', '11334', (35, 41))	('miRNA-17', 'Gene', '406952', (59, 67))	('TUSC2P', 'Gene', (35, 41))	('TUSC2', 'Gene', (35, 40))	('miRNA-661', 'Var', (83, 92))	('TUSC2', 'Gene', '11334', (35, 40))	('miRNA-17', 'Gene', (59, 67))	('TUSC2', 'Gene', (46, 51))	('TUSC2', 'Gene', (166, 171))	('TUSC2', 'Gene', '11334', (46, 51))	('TUSC2', 'Gene', '11334', (166, 171))	('miRNA-520a-3p', 'Var', (94, 107))	('binding sites', 'Interaction', (137, 150))	('TUSC2P', 'Gene', '11334', (155, 161))	('TUSC2P', 'Gene', (155, 161))
36437	30219035	Accumulating evidence showed that pseudogenes usually expressed in a cancer specific pattern.	('pseudogenes', 'Var', (34, 45))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('expressed', 'Reg', (54, 63))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Disease', (69, 75))
36439	30219035	However, more and more pseudogenes have been identified, and they exhibit cancer specific expression pattern and are proven to be related to cancer.	('pseudogenes', 'Var', (23, 34))	('related', 'Reg', (130, 137))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Disease', (74, 80))	('expression', 'MPA', (90, 100))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('cancer', 'Disease', (141, 147))
36443	30219035	In light of this, pseudogenes can not only play structural and functional roles in the tumorigenesis, but also in disease diagnosis and prognosis.	('pseudogenes', 'Var', (18, 29))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Disease', (87, 92))	('tumor', 'Disease', 'MESH:D009369', (87, 92))
36459	26798989	Overexpression of serum midkine yielded a relative risk of death of 3.77, with 95% confidence limits ranging from 1.15 to 17.0.	('death', 'Disease', 'MESH:D003643', (59, 64))	('death', 'Disease', (59, 64))	('Overexpression', 'Var', (0, 14))	('midkine', 'Gene', '4192', (24, 31))	('midkine', 'Gene', (24, 31))
36477	26798989	Furthermore, genetic ablation of MK delayed tumor formation and reduced tumor incidence in a transgenic neuroblastoma model through attenuation of the Notch2 signaling pathway 25.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('neuroblastoma', 'Disease', (104, 117))	('genetic ablation', 'Var', (13, 29))	('neuroblastoma', 'Phenotype', 'HP:0003006', (104, 117))	('tumor', 'Disease', (72, 77))	('attenuation', 'NegReg', (132, 143))	('MK', 'Gene', '4192', (33, 35))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('Notch2', 'Gene', (151, 157))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('reduced', 'NegReg', (64, 71))	('Notch2', 'Gene', '4853', (151, 157))	('delayed', 'NegReg', (36, 43))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('tumor', 'Disease', (44, 49))	('neuroblastoma', 'Disease', 'MESH:D009447', (104, 117))
36568	26798989	Additionally, truncated MK lacking exon 3 has been shown to suppress apoptosis and cell death induced by anticancer agents including cisplatin and paclitaxel through cell-protective functions 44.	('MK', 'Gene', '4192', (24, 26))	('cell-protective functions', 'CPA', (166, 191))	('death', 'Disease', (88, 93))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('truncated', 'Var', (14, 23))	('cancer', 'Disease', (109, 115))	('suppress', 'NegReg', (60, 68))	('apoptosis', 'CPA', (69, 78))	('cisplatin', 'Chemical', 'MESH:D002945', (133, 142))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('paclitaxel', 'Chemical', 'MESH:D017239', (147, 157))	('exon 3', 'Protein', (35, 41))	('death', 'Disease', 'MESH:D003643', (88, 93))
36579	28881760	The results indicated that: (1) Patients detected with high expression level of Flotillin-1 protein had a significantly shorter OS (HR =1.64; 95%CI: 1.39-1.88), statistical significance was also observed in subgroup meta-analyses stratified by the cancer type, nationality, detecting method, cutoff value, analysis type, sample size and publication date.	('cancer', 'Disease', (248, 254))	('Patients', 'Species', '9606', (32, 40))	('shorter', 'NegReg', (120, 127))	('high expression level', 'Var', (55, 76))	('OS', 'Chemical', '-', (128, 130))	('cancer', 'Phenotype', 'HP:0002664', (248, 254))	('Flotillin-1', 'Gene', (80, 91))	('Flotillin-1', 'Gene', '10211', (80, 91))	('cancer', 'Disease', 'MESH:D009369', (248, 254))	('protein', 'Protein', (92, 99))
36580	28881760	(2) Patients with high Flotillin-1 protein expression level had a poorer DFS (HR = 2.49; 95%CI: 1.64-3.35), a worse RFS(HR = 3.26; 95%CI: 1.10-5.43) and a potential shorter PFS(HR = 1.84; 95%CI: 0.81-2.87).	('shorter', 'NegReg', (165, 172))	('Flotillin-1', 'Gene', (23, 34))	('poorer', 'NegReg', (66, 72))	('Flotillin-1', 'Gene', '10211', (23, 34))	('high', 'Var', (18, 22))	('Patients', 'Species', '9606', (4, 12))	('PFS', 'MPA', (173, 176))	('RFS', 'MPA', (116, 119))	('DFS', 'MPA', (73, 76))
36600	28881760	In addition, proliferation and tumorigenicity of breast cancer cells would be inhibited by the silence Flotillin-1both in vitro and in vivo.	('Flotillin-1', 'Gene', '10211', (103, 114))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('proliferation', 'CPA', (13, 26))	('inhibited', 'NegReg', (78, 87))	('breast cancer', 'Phenotype', 'HP:0003002', (49, 62))	('tumor', 'Disease', (31, 36))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('breast cancer', 'Disease', 'MESH:D001943', (49, 62))	('breast cancer', 'Disease', (49, 62))	('Flotillin-1', 'Gene', (103, 114))	('silence', 'Var', (95, 102))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
36602	28881760	Several studies have found that high Flotillin-1 expression was associated with shorter overall survival (OS) and disease-free survival(DFS) in various types of cancer.	('cancer', 'Disease', (161, 167))	('high', 'Var', (32, 36))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('Flotillin-1', 'Gene', (37, 48))	('expression', 'MPA', (49, 59))	('Flotillin-1', 'Gene', '10211', (37, 48))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('shorter', 'NegReg', (80, 87))	('overall', 'MPA', (88, 95))	('OS', 'Chemical', '-', (106, 108))	('disease-free survival', 'CPA', (114, 135))
36612	28881760	Overall, the meta-analysis showed that high Flotillin-1 expression level was significantly associated with shorter OS (HR=1.64; 95%CI:1.39-1.88, p<0.001) (Figure 2).	('high', 'Var', (39, 43))	('Flotillin-1', 'Gene', (44, 55))	('OS', 'Chemical', '-', (115, 117))	('expression level', 'MPA', (56, 72))	('Flotillin-1', 'Gene', '10211', (44, 55))	('shorter OS', 'Disease', (107, 117))
36613	28881760	A worse OS was observed in the patients detected with high Flotillin-1 expressionlevel than those of with low Flotillin-1 expression.	('expressionlevel', 'Var', (71, 86))	('high', 'Var', (54, 58))	('Flotillin-1', 'Gene', (59, 70))	('OS', 'Chemical', '-', (8, 10))	('Flotillin-1', 'Gene', '10211', (59, 70))	('Flotillin-1', 'Gene', (110, 121))	('patients', 'Species', '9606', (31, 39))	('Flotillin-1', 'Gene', '10211', (110, 121))
36618	28881760	The pooled result demonstrated a significantly positive association between high Flotillin-1 expression level and poorer DFS (HR = 2.49; 95%CI: 1.64-3.35, p<0.001) (Figure 4).	('Flotillin-1', 'Gene', (81, 92))	('Flotillin-1', 'Gene', '10211', (81, 92))	('expression level', 'MPA', (93, 109))	('high', 'Var', (76, 80))	('poorer', 'Disease', (114, 120))
36625	28881760	Additionally, high expressionlevelof Flotillin-1 was also found to be significantly associated with lymph node metastasis (OR =6.30; 95% CI:3.15-12.59, p<0.001), distant metastasis (OR =6.02; 95% CI: 1.50-24.06, p=0.01) and more advanced TNM stage (OR =4.69; 95% CI: 2.74-8.03, p<0.001).	('Flotillin-1', 'Gene', (37, 48))	('TNM', 'Gene', '10178', (238, 241))	('high expressionlevelof', 'Var', (14, 36))	('Flotillin-1', 'Gene', '10211', (37, 48))	('lymph node metastasis', 'Disease', (100, 121))	('lymph node metastasis', 'Disease', 'MESH:D009362', (100, 121))	('associated', 'Reg', (84, 94))	('TNM', 'Gene', (238, 241))	('distant metastasis', 'CPA', (162, 180))
36638	28881760	Researchers found that knockdown of Flotillin-1 in MCF7 cells resulted in upregulation of EGFR mRNA and protein expression.	('Flotillin-1', 'Gene', '10211', (36, 47))	('EGFR', 'Gene', '1956', (90, 94))	('knockdown', 'Var', (23, 32))	('upregulation', 'PosReg', (74, 86))	('EGFR', 'Gene', (90, 94))	('MCF7', 'CellLine', 'CVCL:0031', (51, 55))	('Flotillin-1', 'Gene', (36, 47))
36640	28881760	The silencing Flotillin-1 would reduce the activity of Akt and then enhance the activity of FOXO3a.	('Akt', 'Gene', (55, 58))	('FOXO3a', 'Gene', (92, 98))	('reduce', 'NegReg', (32, 38))	('FOXO3a', 'Gene', '2309', (92, 98))	('activity', 'MPA', (80, 88))	('Flotillin-1', 'Gene', (14, 25))	('activity', 'MPA', (43, 51))	('Akt', 'Gene', '207', (55, 58))	('Flotillin-1', 'Gene', '10211', (14, 25))	('silencing', 'Var', (4, 13))	('enhance', 'PosReg', (68, 75))
36649	28881760	Our meta-analysis provided strong evidence that high Flotillin-1 protein expression was statistically significant associated with shorter OS in patients with solid tumors.	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('Flotillin-1', 'Gene', '10211', (53, 64))	('tumors', 'Phenotype', 'HP:0002664', (164, 170))	('protein', 'Protein', (65, 72))	('solid tumors', 'Disease', (158, 170))	('OS', 'Chemical', '-', (138, 140))	('shorter OS', 'Disease', (130, 140))	('patients', 'Species', '9606', (144, 152))	('high', 'Var', (48, 52))	('solid tumors', 'Disease', 'MESH:D009369', (158, 170))	('Flotillin-1', 'Gene', (53, 64))
36653	28881760	Additionally, high expression of Flotillin-1 was also found to be significantly associated with metastasis and more advanced TNM stage.	('metastasis', 'CPA', (96, 106))	('Flotillin-1', 'Gene', (33, 44))	('Flotillin-1', 'Gene', '10211', (33, 44))	('TNM', 'Gene', '10178', (125, 128))	('high', 'Var', (14, 18))	('associated', 'Reg', (80, 90))	('TNM', 'Gene', (125, 128))
36664	28881760	The following data and information were retrieved from each publication: the name of first author, the year of publication, original country, cancer type, number of patients, tumor stage, follow-up period, outcome measures, the criteria for high Flotillin-1 expression, assay methods and hazard ratio (HR) as well as corresponding 95% confidence interval (CI).	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('Flotillin-1', 'Gene', (246, 257))	('tumor', 'Disease', (175, 180))	('Flotillin-1', 'Gene', '10211', (246, 257))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('patients', 'Species', '9606', (165, 173))	('high', 'Var', (241, 245))	('cancer', 'Disease', (142, 148))
36696	33712694	UBE2F, TMSB10 and GAPDH were negative coefficients, indicating that patients with higher levels of expression had better outcomes than patients with lower levels of expression.	('patients', 'Species', '9606', (135, 143))	('TMSB10', 'Gene', '9168', (7, 13))	('UBE2F', 'Gene', (0, 5))	('GAPDH', 'Gene', (18, 23))	('UBE2F', 'Gene', '140739', (0, 5))	('TMSB10', 'Gene', (7, 13))	('patients', 'Species', '9606', (68, 76))	('expression', 'Var', (99, 109))	('GAPDH', 'Gene', '2597', (18, 23))
36732	33712694	Previous studies have shown that inhibition of HIF-1 represents a novel approach to cancer therapy.	('inhibition', 'Var', (33, 43))	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('cancer', 'Disease', (84, 90))	('HIF-1', 'Gene', '3091', (47, 52))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('HIF-1', 'Gene', (47, 52))
36746	33712694	Raw microarray data from all data sets were analysed using the Affymetrix human genome U133 plus 2.0 array (GSE31210, GSE30219 and GSE50081), the mRNA expression data were log2 transformed before statistical analysis, and the median value was used when multiple probes existed for a single target.	('human', 'Species', '9606', (74, 79))	('GSE31210', 'Var', (108, 116))	('GSE50081', 'Var', (131, 139))	('GSE30219', 'Var', (118, 126))
36747	33712694	There was a total of 627 stage I/II patients with NSCLC after excluding patients without Recurrence Free Survival(RFS) or clinical data, including 226 from GSE31210, 226 from GSE30219 and 181 from GSE50081.	('patients', 'Species', '9606', (36, 44))	('GSE30219', 'Var', (175, 183))	('NSCLC', 'Disease', (50, 55))	('GSE31210', 'Var', (156, 164))	('NSCLC', 'Disease', 'MESH:D002289', (50, 55))	('patients', 'Species', '9606', (72, 80))
36754	33712694	The relevant antibodies used to detect the target protein are as follows: ADAM10 (dilution 1:1000; Abclone, Wuhan, Hubei, China), ALDOA (dilution 1:10,000; Abclone, Wuhan, Hubei, China), CFB (dilution 1: 1000; Abclone, Wuhan, Hubei, China), FGFR1OP (dilution 1: 1000; Abclone, Wuhan, Hubei, China), GAPDH (dilution 1:1000; Abclone, Wuhan, Hubei, China), HMOX1 (dilution 1:1000; Abclone, Wuhan, Hubei, China), LDHA (dilution 1:1000; Abclone, Wuhan, Hubei, China), MESDC2 (dilution 1:1000; Abclone, Wuhan, Hubei, China), PKM (dilution 1:1000; Abclone, Wuhan, Hubei, China), PML (dilution 1:1000; Abclone, Wuhan, Hubei, China), PPIA (dilution 1:1000; Abclone, Wuhan, Hubei, China), TMSB10 (dilution 1:1000; Sigma-Aldrich Chemicals, St. Louis, MO, USA)), TUBA1B (dilution 1:1000; Abclone, Wuhan, Hubei, China), UBC (dilution 1:1000; Abclone, Wuhan, Hubei, China), UBE2F (dilution 1:1000; Abclone, Wuhan, Hubei, China), Beta Actin (dilution 1:1000; Abclone, Wuhan, Hubei, China).	('dilution 1:1000', 'Var', (927, 942))	('ADAM10', 'Gene', (74, 80))	('CFB', 'Gene', '629', (187, 190))	('TUBA1B', 'Gene', '10376', (751, 757))	('TUBA1B', 'Gene', (751, 757))	('PKM', 'Gene', '5315', (519, 522))	('ALDOA', 'Gene', (130, 135))	('UBE2F', 'Gene', (860, 865))	('TMSB10', 'Gene', '9168', (679, 685))	('ALDOA', 'Gene', '226', (130, 135))	('CFB', 'Gene', (187, 190))	('HMOX1', 'Gene', (354, 359))	('MESDC2', 'Gene', '23184', (463, 469))	('FGFR1OP', 'Gene', '11116', (241, 248))	('MESDC2', 'Gene', (463, 469))	('LDHA', 'Gene', '3939', (409, 413))	('ADAM10', 'Gene', '102', (74, 80))	('Beta Actin', 'Gene', (915, 925))	('FGFR1OP', 'Gene', (241, 248))	('PPIA', 'Gene', '5478', (625, 629))	('PML', 'Gene', (572, 575))	('GAPDH', 'Gene', '2597', (299, 304))	('Beta Actin', 'Gene', '728378', (915, 925))	('UBC', 'Gene', '7316', (807, 810))	('PML', 'Gene', '5371', (572, 575))	('PPIA', 'Gene', (625, 629))	('LDHA', 'Gene', (409, 413))	('HMOX1', 'Gene', '3162', (354, 359))	('GAPDH', 'Gene', (299, 304))	('TMSB10', 'Gene', (679, 685))	('PKM', 'Gene', (519, 522))	('UBC', 'Gene', (807, 810))	('UBE2F', 'Gene', '140739', (860, 865))
36771	33478099	We find that the transcripts encoding PKM2 and three previously unstudied transcripts, namely ENST00000389093, ENST00000568883, and ENST00000561609, exhibited opposite prognostic indications in different cancers.	('cancers', 'Phenotype', 'HP:0002664', (204, 211))	('PKM2', 'Gene', (38, 42))	('cancers', 'Disease', (204, 211))	('cancers', 'Disease', 'MESH:D009369', (204, 211))	('ENST00000561609', 'Var', (132, 147))	('ENST00000568883', 'Var', (111, 126))	('PKM2', 'Gene', '5315', (38, 42))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('ENST00000389093', 'Var', (94, 109))
36773	33478099	Finally, we revealed that ENST00000389093 and ENST00000568883 possess pyruvate kinase enzymatic activity and may have functional roles in metabolism, cell invasion, and hypoxia response in cancer cells.	('cell invasion', 'CPA', (150, 163))	('pyruvate kinase enzymatic activity', 'MPA', (70, 104))	('ENST00000389093', 'Var', (26, 41))	('ENST00000568883', 'Var', (46, 61))	('hypoxia', 'Disease', (169, 176))	('metabolism', 'CPA', (138, 148))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('hypoxia', 'Disease', 'MESH:D000860', (169, 176))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('cancer', 'Disease', (189, 195))
36778	33478099	In the Human Pathology Atlas, high expression of PKM is significantly (log-rank p-value < 0.05) associated with the unfavorable prognoses in liver hepatocellular carcinoma (LIHC), pancreatic adenocarcinoma (PAAD), head and neck squamous cell carcinoma (HNSC), and lung adenocarcinoma (LUAD), whereas it is also associated with favorable prognoses in kidney renal clear-cell carcinoma (KIRC), skin cutaneous melanoma (SKCM), stomach adenocarcinoma (STAD), and thyroid carcinoma (THCA).	('PKM', 'Gene', (49, 52))	('associated', 'Reg', (96, 106))	('melanoma', 'Phenotype', 'HP:0002861', (407, 415))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (459, 476))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (397, 415))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D000230', (180, 205))	('C', 'Chemical', 'MESH:D002244', (480, 481))	('kidney renal clear-cell carcinoma', 'Disease', 'MESH:C538614', (350, 383))	('carcinoma', 'Phenotype', 'HP:0030731', (374, 383))	('PAAD', 'Phenotype', 'HP:0006725', (207, 211))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (147, 171))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (180, 205))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (228, 251))	('C', 'Chemical', 'MESH:D002244', (176, 177))	('LUAD', 'Phenotype', 'HP:0030078', (285, 289))	('neck squamous cell carcinoma', 'Disease', (223, 251))	('kidney renal clear-cell carcinoma', 'Disease', (350, 383))	('Human', 'Species', '9606', (7, 12))	('PKM', 'Gene', '5315', (49, 52))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (223, 251))	('liver hepatocellular carcinoma', 'Disease', 'MESH:D006528', (141, 171))	('stomach adenocarcinoma', 'Disease', 'MESH:D000230', (424, 446))	('C', 'Chemical', 'MESH:D002244', (256, 257))	('lung adenocarcinoma', 'Disease', (264, 283))	('stomach adenocarcinoma', 'Disease', (424, 446))	('THCA', 'Phenotype', 'HP:0002890', (478, 482))	('pancreatic adenocarcinoma', 'Disease', (180, 205))	('carcinoma', 'Phenotype', 'HP:0030731', (196, 205))	('C', 'Chemical', 'MESH:D002244', (388, 389))	('C', 'Chemical', 'MESH:D002244', (419, 420))	('carcinoma', 'Phenotype', 'HP:0030731', (162, 171))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (459, 476))	('high expression', 'Var', (30, 45))	('liver hepatocellular carcinoma', 'Disease', (141, 171))	('renal clear-cell carcinoma', 'Phenotype', 'HP:0006770', (357, 383))	('carcinoma', 'Phenotype', 'HP:0030731', (242, 251))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (392, 415))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (264, 283))	('thyroid carcinoma', 'Disease', (459, 476))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (214, 251))	('HNSC', 'Phenotype', 'HP:0012288', (253, 257))	('carcinoma', 'Phenotype', 'HP:0030731', (274, 283))	('skin cutaneous melanoma', 'Disease', (392, 415))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (264, 283))
36784	33478099	Tetrameric PKM2 exhibits high catalytic activity, which is associated with ATP synthesis and catabolic metabolism, while dimeric PKM2 has low catalytic activity and is the less active state of PKM2.	('PKM2', 'Gene', '5315', (129, 133))	('Tetrameric', 'Var', (0, 10))	('catalytic activity', 'MPA', (30, 48))	('PKM2', 'Gene', (11, 15))	('PKM2', 'Gene', (193, 197))	('PKM2', 'Gene', '5315', (11, 15))	('PKM2', 'Gene', (129, 133))	('PKM2', 'Gene', '5315', (193, 197))	('ATP', 'Chemical', 'MESH:D000255', (75, 78))
36785	33478099	PKM2 activity is also regulated by post-translational modification such as phosphorylation, acetylation, oxidation, and sumoylation, which promote aerobic glycolysis or tumorigenesis.	('promote', 'PosReg', (139, 146))	('acetylation', 'MPA', (92, 103))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('PKM2', 'Gene', (0, 4))	('sumoylation', 'MPA', (120, 131))	('phosphorylation', 'Var', (75, 90))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('PKM2', 'Gene', '5315', (0, 4))	('activity', 'MPA', (5, 13))	('tumor', 'Disease', (169, 174))	('aerobic glycolysis', 'MPA', (147, 165))
36788	33478099	Moreover, it has been reported that methylation or deletion of PKM2 promotes tumor progression in liver cancer, breast cancer, and medulloblastoma.	('breast cancer', 'Disease', 'MESH:D001943', (112, 125))	('breast cancer', 'Disease', (112, 125))	('PKM2', 'Gene', (63, 67))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('PKM2', 'Gene', '5315', (63, 67))	('liver cancer', 'Disease', 'MESH:D006528', (98, 110))	('promotes', 'PosReg', (68, 76))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('medulloblastoma', 'Disease', 'MESH:D008527', (131, 146))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('medulloblastoma', 'Phenotype', 'HP:0002885', (131, 146))	('liver cancer', 'Phenotype', 'HP:0002896', (98, 110))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('methylation', 'Var', (36, 47))	('medulloblastoma', 'Disease', (131, 146))	('liver cancer', 'Disease', (98, 110))	('deletion', 'Var', (51, 59))	('breast cancer', 'Phenotype', 'HP:0003002', (112, 125))	('tumor', 'Disease', (77, 82))
36794	33478099	Both of the two commonly studied transcripts of PKM, ENST00000319622 (encoding PKM1) and ENST00000335181 (encoding PKM2), are composed by 11 exons where 10 of them are shared.	('PKM', 'Gene', (79, 82))	('PKM', 'Gene', '5315', (79, 82))	('ENST00000319622', 'Var', (53, 68))	('PKM', 'Gene', (48, 51))	('PKM', 'Gene', '5315', (48, 51))	('ENST00000335181', 'Var', (89, 104))	('PKM', 'Gene', (115, 118))	('PKM', 'Gene', '5315', (115, 118))	('PKM2', 'Gene', (115, 119))	('PKM2', 'Gene', '5315', (115, 119))
36797	33478099	As shown in Figure 1a, ENST00000561609 (PKM-609), ENST00000568883 (PKM-883), ENST00000565184, ENST00000565154, and ENST00000568459 are composed of different subsequences from PKM1, as well as ENST00000389093 (PKM-093) and ENST00000449901 are composed of different subsequences from PKM2.	('PKM', 'Gene', '5315', (209, 212))	('ENST00000565184', 'Var', (77, 92))	('PKM', 'Gene', (175, 178))	('PKM', 'Gene', '5315', (175, 178))	('PKM2', 'Gene', (282, 286))	('PKM', 'Gene', (282, 285))	('ENST00000449901', 'Var', (222, 237))	('PKM', 'Gene', '5315', (282, 285))	('PKM', 'Gene', (67, 70))	('ENST00000568883', 'Var', (50, 65))	('PKM', 'Gene', '5315', (67, 70))	('PKM', 'Gene', (209, 212))	('PKM2', 'Gene', '5315', (282, 286))	('ENST00000561609', 'Var', (23, 38))	('PKM', 'Gene', (40, 43))	('PKM', 'Gene', '5315', (40, 43))	('ENST00000565154', 'Var', (94, 109))
36800	33478099	As shown in Figure 1b, we found that seven transcripts had mRNA expression (average TPM) > 5 in at least one cancer type, including PKM1, PKM2, PKM-093, PKM-609, PKM-883, ENST00000562997, and ENST00000568459.	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('ENST00000562997', 'Var', (171, 186))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('PKM', 'Gene', (144, 147))	('PKM', 'Gene', '5315', (138, 141))	('PKM', 'Gene', '5315', (144, 147))	('PKM2', 'Gene', (138, 142))	('cancer', 'Disease', (109, 115))	('PKM', 'Gene', (138, 141))	('PKM', 'Gene', '5315', (132, 135))	('ENST00000568459', 'Var', (192, 207))	('PKM', 'Gene', (162, 165))	('PKM', 'Gene', (132, 135))	('PKM', 'Gene', '5315', (162, 165))	('PKM', 'Gene', (153, 156))	('mRNA expression', 'MPA', (59, 74))	('PKM', 'Gene', '5315', (153, 156))	('PKM2', 'Gene', '5315', (138, 142))
36804	33478099	As shown in Figure 2a, the mRNA expression of the PKM indicated opposite survival outcomes in different cancer types.	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('PKM', 'Gene', (50, 53))	('mRNA', 'Var', (27, 31))	('PKM', 'Gene', '5315', (50, 53))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))
36805	33478099	At the transcript level, we found six of these transcripts, including PKM1, PKM2, PKM-609, PKM-093, PKM-883, and ENST00000562997, are significantly associated with patients' survival outcome in at least one cancer.	('PKM', 'Gene', (82, 85))	('ENST00000562997', 'Var', (113, 128))	('cancer', 'Disease', 'MESH:D009369', (207, 213))	('PKM', 'Gene', '5315', (100, 103))	('cancer', 'Disease', (207, 213))	('PKM', 'Gene', (100, 103))	('PKM', 'Gene', '5315', (70, 73))	('PKM', 'Gene', '5315', (76, 79))	('PKM2', 'Gene', (76, 80))	('PKM', 'Gene', (70, 73))	('PKM', 'Gene', (76, 79))	('associated with', 'Reg', (148, 163))	('PKM', 'Gene', (91, 94))	('PKM2', 'Gene', '5315', (76, 80))	('PKM', 'Gene', '5315', (91, 94))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('patients', 'Species', '9606', (164, 172))	('PKM', 'Gene', '5315', (82, 85))
36823	33478099	As shown in Figure 2b, glycolytic process, hypoxia response, nicotinamide adenine dinucleotide hydride (NADH) regeneration pathways are enriched with upregulated genes in patients with high expression of PKM2.	('upregulated', 'PosReg', (150, 161))	('hypoxia', 'Disease', (43, 50))	('hypoxia', 'Disease', 'MESH:D000860', (43, 50))	('patients', 'Species', '9606', (171, 179))	('glycolytic process', 'MPA', (23, 41))	('high expression', 'Var', (185, 200))	('nicotinamide adenine dinucleotide hydride', 'Chemical', '-', (61, 102))	('nicotinamide', 'MPA', (61, 73))	('PKM2', 'Gene', (204, 208))	('PKM2', 'Gene', '5315', (204, 208))	('NADH', 'Chemical', '-', (104, 108))
36858	33478099	We observed that PKM2 has the longest AA sequence with 531aa, followed by the protein products of PKM-609, PKM-093, and PKM-883, which are 485aa, 457aa, and 366aa, respectively.	('PKM', 'Gene', '5315', (17, 20))	('PKM', 'Gene', '5315', (98, 101))	('PKM', 'Gene', '5315', (120, 123))	('PKM2', 'Gene', (17, 21))	('PKM', 'Gene', (17, 20))	('PKM', 'Gene', (120, 123))	('PKM2', 'Gene', '5315', (17, 21))	('PKM', 'Gene', (107, 110))	('366aa', 'Var', (157, 162))	('PKM', 'Gene', '5315', (107, 110))	('457aa', 'Var', (146, 151))	('485aa', 'Var', (139, 144))	('PKM', 'Gene', (98, 101))
36859	33478099	As shown in Figure 4a, we found that proteins of PKM-093 and PKM-883 miss a part of the A1 and B domains (59-132aa and 41-205aa) in PKM2, which may affect the formation of dimer.	('41-205aa', 'Var', (119, 127))	('affect', 'Reg', (148, 154))	('PKM', 'Gene', (49, 52))	('miss', 'NegReg', (69, 73))	('PKM', 'Gene', '5315', (49, 52))	('PKM', 'Gene', '5315', (132, 135))	('formation of dimer', 'MPA', (159, 177))	('PKM2', 'Gene', (132, 136))	('PKM', 'Gene', (132, 135))	('59-132aa', 'Var', (106, 114))	('PKM2', 'Gene', '5315', (132, 136))	('PKM', 'Gene', (61, 64))	('PKM', 'Gene', '5315', (61, 64))
36863	33478099	In this part, K433 is the FBP binding site in PKM2, which activates the association of monomer to form the tetrameric.	('activates', 'PosReg', (58, 67))	('K433', 'Var', (14, 18))	('association', 'Interaction', (72, 83))	('K433', 'Chemical', '-', (14, 18))	('FBP', 'Gene', '2203', (26, 29))	('monomer', 'Protein', (87, 94))	('FBP', 'Gene', (26, 29))	('PKM2', 'Gene', '5315', (46, 50))	('PKM2', 'Gene', (46, 50))	('tetrameric', 'MPA', (107, 117))
36865	33478099	In addition, all protein products of the three transcripts have K270, which is the active site, binding to phosphoenolpyruvate (PEP).	('K270', 'Var', (64, 68))	('PEP', 'Chemical', 'MESH:D010728', (128, 131))	('binding', 'Interaction', (96, 103))	('phosphoenolpyruvate', 'MPA', (107, 126))	('phosphoenolpyruvate', 'Chemical', 'MESH:D010728', (107, 126))
36867	33478099	When compared to the PKM2 structure, we found that the PKM-093 structure is missing the catalytic site for adenosine diphosphate (ADP) binding (59-132aa) and several AA residues, including R73, Q75, H78, G79, H80, E118, and R120 from the missing part are in close contact with ADP (Figure S2).	('adenosine', 'Chemical', 'MESH:D000241', (107, 116))	('missing', 'NegReg', (76, 83))	('catalytic site', 'MPA', (88, 102))	('ADP', 'Chemical', 'MESH:D000244', (130, 133))	('H78', 'Var', (199, 202))	('PKM2', 'Gene', (21, 25))	('PKM', 'Gene', (55, 58))	('PKM2', 'Gene', '5315', (21, 25))	('H80', 'Var', (209, 212))	('contact', 'Interaction', (264, 271))	('PKM', 'Gene', (21, 24))	('R120', 'Var', (224, 228))	('PKM', 'Gene', '5315', (55, 58))	('Q75', 'Var', (194, 197))	('ADP', 'Chemical', 'MESH:D000244', (277, 280))	('G79', 'Var', (204, 207))	('PKM', 'Gene', '5315', (21, 24))	('R73', 'Var', (189, 192))	('binding', 'Interaction', (135, 142))	('E118', 'Var', (214, 218))
36897	33478099	To test whether over-expression of the transcripts increases the pyruvate kinase activity, we extracted the cell lysate from PC3 cell lines with empty vector, PKM-093 over-expression, and PKM-883 over-expression and found that the enzymatic activity is significantly increased in cell lysate with the overexpressed transcripts compared to negative control (Figure 5b).	('PKM', 'Gene', (188, 191))	('over-expression', 'PosReg', (167, 182))	('over-expression', 'PosReg', (196, 211))	('transcripts', 'Var', (315, 326))	('PKM', 'Gene', (159, 162))	('PKM', 'Gene', '5315', (159, 162))	('PC3', 'Gene', '3853', (125, 128))	('increased', 'PosReg', (267, 276))	('overexpressed', 'Var', (301, 314))	('PKM', 'Gene', '5315', (188, 191))	('PC3', 'Gene', (125, 128))	('pyruvate', 'MPA', (65, 73))
36901	33478099	This suggested that the tag in the C-terminal changed the C-C interface structure, thus disturbing the formation of tetramer which is the enzymatically more activated form compared to dimer.	('tag', 'Var', (24, 27))	('C', 'Chemical', 'MESH:D002244', (35, 36))	('disturbing', 'NegReg', (88, 98))	('changed', 'Reg', (46, 53))	('C-C interface structure', 'MPA', (58, 81))	('C', 'Chemical', 'MESH:D002244', (60, 61))	('formation of tetramer', 'MPA', (103, 124))	('C', 'Chemical', 'MESH:D002244', (58, 59))
36915	33478099	In our analysis, SREBF1 is also significantly increased with PKM-883 over-expression, suggesting PKM-883 has potential regulatory function in fatty acid metabolism.	('increased', 'PosReg', (46, 55))	('fatty acid', 'Chemical', 'MESH:D005227', (142, 152))	('SREBF1', 'Gene', '6720', (17, 23))	('PKM', 'Gene', (97, 100))	('PKM', 'Gene', '5315', (97, 100))	('PKM', 'Gene', '5315', (61, 64))	('over-expression', 'Var', (69, 84))	('SREBF1', 'Gene', (17, 23))	('PKM', 'Gene', (61, 64))	('fatty acid metabolism', 'MPA', (142, 163))
36917	33478099	Previous studies have already detected the survival-associated alternative splicing events or differentially splicing events involved in specific exons as the prognostic biomarker or drug response biomarker in different human cancers.	('human', 'Species', '9606', (220, 225))	('cancers', 'Phenotype', 'HP:0002664', (226, 233))	('cancers', 'Disease', (226, 233))	('cancers', 'Disease', 'MESH:D009369', (226, 233))	('alternative splicing events', 'Var', (63, 90))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
36957	33478099	PKM band were detected with ImageQuanattm LAS 500 (29-0050-63, GE) automatic exposure procedure and two PKM isotype band (49.9 kDa and 40.2 kDa) were detected for 5 min exposure.	('PKM', 'Gene', (0, 3))	('PKM', 'Gene', '5315', (0, 3))	('PKM', 'Gene', (104, 107))	('PKM', 'Gene', '5315', (104, 107))	('29-0050-63', 'Var', (51, 61))
36960	33478099	PKM2 antibody (ab137791, abcam) Lamin B1 (ab16048) beta-actin (ab8227) antibody were blotted for 1.5 h. Goat Anti-Rabbit HRP secondary antibody was blotted for 1 h. Cytosolic and nucleus FLAG tagged ENST00000389093 and ENST00000568883 were detected in the same transfer membrane with ImageQuanattm LAS 500 1-min exposure.	('Lamin B1', 'Gene', (32, 40))	('PKM2', 'Gene', (0, 4))	('PKM2', 'Gene', '5315', (0, 4))	('Lamin B1', 'Gene', '4001', (32, 40))	('C', 'Chemical', 'MESH:D002244', (165, 166))	('ENST00000389093', 'Var', (199, 214))
36961	33478099	PC3 cell culture media formulation is F12K Nutrient mix supplemented with 10% FBS and 1% Penicillin/Streptomycin.	('Penicillin', 'Chemical', 'MESH:D010406', (89, 99))	('Streptomycin', 'Chemical', 'MESH:D013307', (100, 112))	('PC3', 'Gene', '3853', (0, 3))	('F12K', 'SUBSTITUTION', 'None', (38, 42))	('F12K', 'Var', (38, 42))	('PC3', 'Gene', (0, 3))
36963	33478099	pCMV6KN empty vector from ORIGENE and pcDNA3.1(+) empty vector from GeneScript were used to clone ENST00000389093 and ENST00000568883 transcripts.	('ENST00000389093', 'Gene', (98, 113))	('ENST00000568883', 'Var', (118, 133))	('C', 'Chemical', 'MESH:D002244', (1, 2))
36977	33478099	The raw files obtained from the MS experiment were analyzed using MaxQuant (version 1.6.1.0) implementing Andromeda to search the MS/MS data against the Ensembl Homo sapiens database (version 83.38, all protein coding transcripts from the primary assembly) as well as a separate database with the two distinct target sequences (ENST00000389093 and ENST00000568883) a list of common contaminants.	('ENST00000389093', 'Var', (328, 343))	('Homo sapiens', 'Species', '9606', (161, 173))	('ENST00000568883', 'Var', (348, 363))
36982	33478099	The homology model of ENST00000561609 was built based on the PKM2 crystal structure (PDB ID: 5X1W), as ENST00000561609 shares 96% sequence similarity to PKM2, compared to 91% to PKM1.	('PKM2', 'Gene', (61, 65))	('PKM2', 'Gene', '5315', (61, 65))	('ENST00000561609', 'Var', (103, 118))	('PKM', 'Gene', (178, 181))	('PKM2', 'Gene', (153, 157))	('PKM', 'Gene', (153, 156))	('PKM', 'Gene', '5315', (153, 156))	('PKM2', 'Gene', '5315', (153, 157))	('PKM', 'Gene', '5315', (178, 181))	('PKM', 'Gene', (61, 64))	('PKM', 'Gene', '5315', (61, 64))
36983	33478099	ENST00000389093 and ENST00000568883 share higher sequence similarity to PKM1, with 100% and 92% correspondingly.	('ENST00000568883', 'Var', (20, 35))	('sequence similarity', 'MPA', (49, 68))	('PKM', 'Gene', (72, 75))	('PKM', 'Gene', '5315', (72, 75))	('ENST00000389093', 'Var', (0, 15))
37010	32872659	Meanwhile, STAT3beta, a STAT3 splicing isoform, is related to the inhibition of tumor growth and chemosensitivity.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumor', 'Disease', (80, 85))	('chemosensitivity', 'CPA', (97, 113))	('STAT3beta', 'Var', (11, 20))	('inhibition', 'NegReg', (66, 76))
37026	32872659	While STAT3 deficiency causes early embryonic lethality, STAT3beta itself can rescue the embryonic lethality.	('embryonic lethality', 'Disease', 'MESH:D020964', (89, 108))	('embryonic lethality', 'Disease', (89, 108))	('early embryonic lethality', 'Disease', (30, 55))	('early embryonic lethality', 'Disease', 'MESH:D020964', (30, 55))	('STAT3', 'Gene', (6, 11))	('deficiency', 'Var', (12, 22))	('embryonic lethality', 'Disease', 'MESH:D020964', (36, 55))
37030	32872659	The development of small-molecule inhibitors has significantly improved progression-free survival against receptor tyrosine kinases (RTKs), but disappointing outcomes remain due to the emergence of drug resistance (Figure 2).	('receptor tyrosine kinase', 'Gene', (106, 130))	('drug resistance', 'Phenotype', 'HP:0020174', (198, 213))	('receptor tyrosine kinase', 'Gene', '5979', (106, 130))	('improved', 'PosReg', (63, 71))	('small-molecule', 'Var', (19, 33))	('progression-free survival', 'CPA', (72, 97))
37031	32872659	Interestingly, erlotinib, as an RTK inhibitor, increases STAT3 phosphorylation (Tyr705) in EGFR-mutant ono-small-cell lung cancer (NSCLC) cells through an autocrine loop, whereas knockdown of STAT3 decreases erlotinib-resistant colony numbers in the presence of erlotinib.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('erlotinib', 'Chemical', 'MESH:D000069347', (15, 24))	('lung cancer', 'Disease', 'MESH:D008175', (118, 129))	('NSCLC', 'Disease', (131, 136))	('erlotinib', 'Chemical', 'MESH:D000069347', (208, 217))	('Tyr705', 'Chemical', '-', (80, 86))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (107, 129))	('EGFR-mutant', 'Var', (91, 102))	('NSCLC', 'Disease', 'MESH:D002289', (131, 136))	('lung cancer', 'Disease', (118, 129))	('increases', 'PosReg', (47, 56))	('lung cancer', 'Phenotype', 'HP:0100526', (118, 129))	('EGFR-mutant', 'Gene', (91, 102))	('erlotinib', 'Chemical', 'MESH:D000069347', (262, 271))
37034	32872659	MEK blockage has poor clinical outcome in KRAS-mutant (KRASMT) colorectal cancer cells, and siRNA-mediated knockdown of macrophage inhibitory factor (MIF) restored sensitivity to refametinib by decreasing STAT3 phosphorylation.	('sensitivity', 'MPA', (164, 175))	('MIF', 'Gene', '4282', (150, 153))	('refametinib', 'Chemical', 'MESH:C544830', (179, 190))	('rectal cancer', 'Phenotype', 'HP:0100743', (67, 80))	('colorectal cancer', 'Phenotype', 'HP:0003003', (63, 80))	('MEK', 'Gene', (0, 3))	('macrophage inhibitory factor', 'Gene', '4282', (120, 148))	('macrophage inhibitory factor', 'Gene', (120, 148))	('MEK', 'Gene', '5609', (0, 3))	('restored', 'PosReg', (155, 163))	('STAT3 phosphorylation', 'MPA', (205, 226))	('colorectal cancer', 'Disease', (63, 80))	('MIF', 'Gene', (150, 153))	('colorectal cancer', 'Disease', 'MESH:D015179', (63, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('blockage', 'Var', (4, 12))	('decreasing', 'NegReg', (194, 204))
37054	32872659	These reports indicate that miRNA-dependent regulation of the STAT3 axis could provide a chance to overcoming the chemoresistance of cancer patients.	('chemoresistance', 'CPA', (114, 129))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('cancer', 'Disease', (133, 139))	('miRNA-dependent', 'Var', (28, 43))	('patients', 'Species', '9606', (140, 148))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
37055	32872659	In addition, STAT3 on Tyr705 correlates with Burkitt lymphoma (BL) chemoresistance.	('lymphoma', 'Phenotype', 'HP:0002665', (53, 61))	('Tyr705', 'Var', (22, 28))	('BL', 'Phenotype', 'HP:0030080', (63, 65))	('Burkitt lymphoma', 'Phenotype', 'HP:0030080', (45, 61))	('Burkitt lymphoma', 'Disease', (45, 61))	('Tyr705', 'Chemical', '-', (22, 28))	('correlates', 'Reg', (29, 39))	('Burkitt lymphoma', 'Disease', 'MESH:D002051', (45, 61))
37059	32872659	Radiotherapy causes DNA damage directly or indirectly through generation of ROS and induces various forms of cancer cell death, including apoptosis, autography, mitotic catastrophe, necrosis and senescence.	('necrosis', 'Disease', (182, 190))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('Radiotherapy', 'Var', (0, 12))	('cancer', 'Disease', (109, 115))	('mitotic catastrophe', 'CPA', (161, 180))	('necrosis', 'Disease', 'MESH:D009336', (182, 190))	('senescence', 'CPA', (195, 205))	('apoptosis', 'CPA', (138, 147))	('ROS', 'Chemical', 'MESH:D017382', (76, 79))	('ROS', 'Protein', (76, 79))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('rat', 'Species', '10116', (66, 69))	('autography', 'CPA', (149, 159))	('induces', 'Reg', (84, 91))
37061	32872659	STAT3 Y705 activation occurs in a dose- and time-dependent manner upon radiation, mediates hepatobiliary malignancies and maintains stem cell self-renewal and tumorigenic potential.	('malignancies', 'Disease', (105, 117))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('stem cell self-renewal', 'CPA', (132, 154))	('STAT3 Y705', 'Var', (0, 10))	('tumor', 'Disease', (159, 164))	('Y705', 'Chemical', '-', (6, 10))	('maintains', 'PosReg', (122, 131))	('mediates', 'Reg', (82, 90))	('malignancies', 'Disease', 'MESH:D009369', (105, 117))	('activation', 'PosReg', (11, 21))	('tumor', 'Disease', 'MESH:D009369', (159, 164))
37065	32872659	STAT3 antisense oligonucleotide (ASO) inhibited the phosphorylation of STAT3.	('inhibited', 'NegReg', (38, 47))	('STAT3', 'Protein', (71, 76))	('ASO', 'Chemical', 'MESH:D016376', (33, 36))	('oligonucleotide', 'Chemical', 'MESH:D009841', (16, 31))	('antisense', 'Var', (6, 15))	('STAT3', 'Gene', (0, 5))	('phosphorylation', 'MPA', (52, 67))
37067	32872659	Constitutive phosphorylation of STAT3 Tyr705 is present in B-1 lymphocytes and contributes to radioresistance.	('STAT3 Tyr705', 'Var', (32, 44))	('radioresistance', 'CPA', (94, 109))	('Tyr705', 'Chemical', '-', (38, 44))	('contributes', 'Reg', (79, 90))
37069	32872659	STAT3 Ser727 phosphorylation is also associated with radioresistance and has been reported to correlate with shortened overall survival and progression-free survival of GBM (glioblastoma) patients.	('shortened', 'NegReg', (109, 118))	('glioblastoma', 'Disease', (174, 186))	('glioblastoma', 'Disease', 'MESH:D005909', (174, 186))	('progression-free', 'CPA', (140, 156))	('Ser727', 'Chemical', '-', (6, 12))	('glioblastoma', 'Phenotype', 'HP:0012174', (174, 186))	('phosphorylation', 'Var', (13, 28))	('patients', 'Species', '9606', (188, 196))	('associated', 'Reg', (37, 47))	('overall survival', 'CPA', (119, 135))	('radioresistance', 'CPA', (53, 68))	('STAT3 Ser727 phosphorylation', 'Var', (0, 28))
37070	32872659	IL6/STAT3/TWIST signaling pathway activation mediates esophageal squamous carcinoma EMT, whereas inactivation of STAT3 by an IL-6 inhibitor or siRNA-mediated downregulation of Twist enhances cancer cell apoptosis and reverses radiation-induced EMT.	('IL-6', 'Gene', '3569', (125, 129))	('downregulation', 'NegReg', (158, 172))	('activation', 'PosReg', (34, 44))	('IL-6', 'Gene', (125, 129))	('cancer', 'Disease', (191, 197))	('IL6', 'Gene', '3569', (0, 3))	('esophageal squamous carcinoma EMT', 'Disease', (54, 87))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('Twist', 'Gene', (176, 181))	('IL6', 'Gene', (0, 3))	('inactivation', 'Var', (97, 109))	('esophageal squamous carcinoma', 'Phenotype', 'HP:0011459', (54, 83))	('enhances', 'PosReg', (182, 190))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (65, 83))	('TWIST', 'Gene', (10, 15))	('cancer', 'Disease', 'MESH:D009369', (191, 197))	('Twist', 'Gene', '7291', (176, 181))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('STAT3', 'Gene', (113, 118))	('TWIST', 'Gene', '7291', (10, 15))	('esophageal squamous carcinoma EMT', 'Disease', 'MESH:D000077277', (54, 87))
37074	32872659	Lip-FLLL32 sensitized pancreatic CSCs to chemotherapy and radiotherapy both in vitro and in vivo.	('pancreatic CSCs', 'Disease', (22, 37))	('Lip-FLLL32', 'Var', (0, 10))	('sensitized', 'Reg', (11, 21))	('FLLL32', 'Chemical', 'MESH:C548902', (4, 10))	('pancreatic CSCs', 'Disease', 'MESH:D010195', (22, 37))
37080	32872659	Both STAT3 Y705 and S727 are potential targets for overcoming clinical radioresistance.	('STAT3 Y705', 'Var', (5, 15))	('S727', 'Var', (20, 24))	('Y705', 'Chemical', '-', (11, 15))
37086	32872659	STAT3 has been shown to significantly enhance Bcl-2 and Bcl-xL promoter activity.	('Bcl-2', 'Gene', (46, 51))	('Bcl-2', 'Gene', '596', (46, 51))	('enhance', 'PosReg', (38, 45))	('STAT3', 'Var', (0, 5))	('Bcl-xL', 'Gene', '598', (56, 62))	('Bcl-xL', 'Gene', (56, 62))
37089	32872659	Thus, aberrant activation of STAT3 can activate Bcl-2 family proteins in various cancer cells.	('Bcl-2', 'Gene', (48, 53))	('activation', 'PosReg', (15, 25))	('Bcl-2', 'Gene', '596', (48, 53))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('aberrant', 'Var', (6, 14))	('cancer', 'Disease', (81, 87))	('STAT3', 'Gene', (29, 34))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('activate', 'PosReg', (39, 47))
37092	32872659	For cisplatin-induced mitochondrial-related apoptosis, knockdown of STAT3, by using siRNA, attenuated the expression of anti-apoptotic proteins Bcl-xL and Bcl-2 and increased the release of cytochrome C and the expression of Bax.	('expression', 'MPA', (211, 221))	('knockdown', 'Var', (55, 64))	('Bcl-2', 'Gene', (155, 160))	('Bax', 'Gene', (225, 228))	('release of cytochrome C', 'MPA', (179, 202))	('Bcl-2', 'Gene', '596', (155, 160))	('Bcl-xL', 'Gene', '598', (144, 150))	('expression', 'MPA', (106, 116))	('Bcl-xL', 'Gene', (144, 150))	('cisplatin', 'Chemical', 'MESH:D002945', (4, 13))	('attenuated', 'NegReg', (91, 101))	('Bax', 'Gene', '581', (225, 228))	('increased', 'PosReg', (165, 174))	('STAT3', 'Gene', (68, 73))
37102	32872659	However, (-)-gossypol also increases the expression levels of Mcl-1, which may result in drug resistance.	('expression levels', 'MPA', (41, 58))	('(-)-gossypol', 'Chemical', 'MESH:D006072', (9, 21))	('increases', 'PosReg', (27, 36))	('Mcl-1', 'Gene', '4170', (62, 67))	('drug resistance', 'MPA', (89, 104))	('Mcl-1', 'Gene', (62, 67))	('result in', 'Reg', (79, 88))	('-)-gossypol', 'Var', (10, 21))	('drug resistance', 'Phenotype', 'HP:0020174', (89, 104))
37122	32872659	Moreover, the blockage of STAT3/Slug also improves survival in GBM-R2I2 xenografts.	('blockage', 'Var', (14, 22))	('GBM-R2I2', 'Gene', (63, 71))	('survival', 'CPA', (51, 59))	('Slug', 'Gene', '6591', (32, 36))	('improves', 'PosReg', (42, 50))	('Slug', 'Gene', (32, 36))
37136	32872659	Inhibition of the IL6/STAT3/Twist signaling pathway could be a useful strategy to reverse radiation -induced EMT and radioresistance in ESCC.	('rat', 'Species', '10116', (72, 75))	('Twist', 'Gene', '7291', (28, 33))	('ESCC', 'Disease', (136, 140))	('IL6', 'Gene', '3569', (18, 21))	('radioresistance', 'CPA', (117, 132))	('Twist', 'Gene', (28, 33))	('IL6', 'Gene', (18, 21))	('Inhibition', 'Var', (0, 10))
37140	32872659	Survivin is an inhibitor of the apoptosis protein family, and its aberrant expression correlates with a poor prognosis and contributes to chemo(radio)resistance.	('Survivin', 'Gene', '11799', (0, 8))	('chemo', 'CPA', (138, 143))	('Survivin', 'Gene', (0, 8))	('aberrant expression', 'Var', (66, 85))	('contributes to', 'Reg', (123, 137))
37143	32872659	Survivin inhibitor MX106 effectively overcomes paclitaxel resistance in ovarian cancer cells.	('overcomes', 'NegReg', (37, 46))	('MX106', 'Var', (19, 24))	('Survivin', 'Gene', '11799', (0, 8))	('MX106', 'Chemical', '-', (19, 24))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('ovarian cancer', 'Phenotype', 'HP:0100615', (72, 86))	('Survivin', 'Gene', (0, 8))	('ovarian cancer', 'Disease', 'MESH:D010051', (72, 86))	('paclitaxel resistance', 'MPA', (47, 68))	('paclitaxel', 'Chemical', 'MESH:D017239', (47, 57))	('ovarian cancer', 'Disease', (72, 86))
37149	32872659	Furthermore, using an inhibitor of JAK2, which is upstream of STAT3, affected survivin expression and sensitized lung cancer to radiation in vitro and in vivo.	('sensitized', 'Reg', (102, 112))	('inhibitor', 'Var', (22, 31))	('JAK2', 'Gene', (35, 39))	('lung cancer', 'Disease', (113, 124))	('lung cancer', 'Phenotype', 'HP:0100526', (113, 124))	('survivin', 'Gene', '11799', (78, 86))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('affected', 'Reg', (69, 77))	('expression', 'MPA', (87, 97))	('JAK2', 'Gene', '3717', (35, 39))	('lung cancer', 'Disease', 'MESH:D008175', (113, 124))	('survivin', 'Gene', (78, 86))
37154	32872659	Several studies reported that inhibition of the STAT3 signaling pathway reduced the expression of cyclin D1 and enhanced the drug sensitivity of the cancer cells, including gastric carcinoma, cholangiocarcinoma, bladder cancer and hepatocellular carcinoma.	('cyclin D1', 'Gene', '595', (98, 107))	('cancer', 'Disease', 'MESH:D009369', (220, 226))	('hepatocellular carcinoma', 'Disease', (231, 255))	('drug sensitivity', 'CPA', (125, 141))	('enhanced', 'PosReg', (112, 120))	('reduced', 'NegReg', (72, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (246, 255))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (192, 210))	('carcinoma', 'Phenotype', 'HP:0030731', (181, 190))	('gastric carcinoma', 'Disease', 'MESH:D013274', (173, 190))	('gastric carcinoma', 'Disease', (173, 190))	('cancer', 'Disease', (149, 155))	('cholangiocarcinoma', 'Disease', (192, 210))	('drug sensitivity', 'Phenotype', 'HP:0020174', (125, 141))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (192, 210))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (231, 255))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (173, 190))	('bladder cancer', 'Disease', 'MESH:D001749', (212, 226))	('bladder cancer', 'Disease', (212, 226))	('expression', 'MPA', (84, 94))	('cancer', 'Disease', (220, 226))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('inhibition', 'Var', (30, 40))	('carcinoma', 'Phenotype', 'HP:0030731', (201, 210))	('bladder cancer', 'Phenotype', 'HP:0009725', (212, 226))	('cyclin D1', 'Gene', (98, 107))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (231, 255))	('STAT3 signaling pathway', 'Pathway', (48, 71))	('cancer', 'Disease', 'MESH:D009369', (149, 155))
37155	32872659	An antisense cyclin D1 sequence in head and neck squamous cell carcinoma (HSNCC) cells inhibits cell growth, induces apoptosis and enhances sensitivity to chemotherapeutic agents both in vitro and in vivo.	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (44, 72))	('sensitivity to chemotherapeutic agents', 'MPA', (140, 178))	('enhances', 'PosReg', (131, 139))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (49, 72))	('cyclin D1', 'Gene', (13, 22))	('inhibits', 'NegReg', (87, 95))	('antisense', 'Var', (3, 12))	('apoptosis', 'CPA', (117, 126))	('cyclin D1', 'Gene', '595', (13, 22))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))	('neck squamous cell carcinoma', 'Disease', (44, 72))	('cell growth', 'CPA', (96, 107))	('induces', 'Reg', (109, 116))
37157	32872659	The researchers also demonstrated that a dominant-negative STAT3 strongly enhanced the cellular sensitivity of HNSCC cells to 5-FU and radiation.	('5-FU', 'Chemical', 'MESH:D005472', (126, 130))	('dominant-negative', 'Var', (41, 58))	('cellular sensitivity', 'MPA', (87, 107))	('STAT3', 'Gene', (59, 64))	('enhanced', 'PosReg', (74, 82))	('rat', 'Species', '10116', (28, 31))
37159	32872659	Inhibition of cyclin D1 using siRNA can inhibit the LDIR-associated anti-apoptotic response and eliminate LDIR-induced adaptive radioresistance.	('adaptive radioresistance', 'CPA', (119, 143))	('eliminate', 'NegReg', (96, 105))	('inhibit', 'NegReg', (40, 47))	('LDIR-associated', 'Disease', (52, 67))	('anti-apoptotic response', 'CPA', (68, 91))	('Inhibition', 'Var', (0, 10))	('cyclin D1', 'Gene', '595', (14, 23))	('cyclin D1', 'Gene', (14, 23))
37161	32872659	Inhibition of cyclin D1 by using siRNA significantly decreased the cell proliferation rate and resulted in G0/G1 arrest, and it also enhanced sensitivity to radiation and reversed EMT.	('arrest', 'Disease', (113, 119))	('cell proliferation rate', 'CPA', (67, 90))	('sensitivity to radiation', 'Phenotype', 'HP:0011133', (142, 166))	('cyclin D1', 'Gene', '595', (14, 23))	('enhanced sensitivity to radiation', 'Phenotype', 'HP:0011133', (133, 166))	('reversed EMT', 'CPA', (171, 183))	('sensitivity', 'CPA', (142, 153))	('Inhibition', 'Var', (0, 10))	('arrest', 'Disease', 'MESH:D006323', (113, 119))	('rat', 'Species', '10116', (79, 82))	('decreased', 'NegReg', (53, 62))	('rat', 'Species', '10116', (86, 89))	('enhanced', 'PosReg', (133, 141))	('cyclin D1', 'Gene', (14, 23))
37164	32872659	Cyclin D1 knockdown using shRNA resulted in a radiation-dose dependent precipitous decline in clonogenic survival.	('decline', 'NegReg', (83, 90))	('Cyclin D1', 'Gene', '595', (0, 9))	('clonogenic survival', 'CPA', (94, 113))	('Cyclin D1', 'Gene', (0, 9))	('knockdown', 'Var', (10, 19))
37167	32872659	Moreover, controlling cyclin D1 by knocking down insulinoma-associated protein1 enhanced the sensitivity of NPC cells to radiation both in vitro and in vivo.	('NPC', 'Phenotype', 'HP:0100630', (108, 111))	('insulinoma-associated protein1', 'Gene', (49, 79))	('knocking down', 'Var', (35, 48))	('cyclin D1', 'Gene', '595', (22, 31))	('sensitivity', 'MPA', (93, 104))	('cyclin D1', 'Gene', (22, 31))	('enhanced', 'PosReg', (80, 88))	('insulinoma-associated protein1', 'Gene', '3642', (49, 79))	('insulinoma', 'Phenotype', 'HP:0012197', (49, 59))
37169	32872659	Yu's study showed that blocking STAT3 signaling with STAT3beta or antisense STAT3 oligonucleotide activated dendritic cells (DCs) by inducing the proinflammatory mediators IL-6, regulated upon activation normal T cell expressed and secreted factor (RANTES) and interferon-inducible protein-10 (IP-10) in tumor cells.	('RANTES', 'Gene', (249, 255))	('interferon-inducible protein-10', 'Gene', (261, 292))	('IL-6', 'Gene', '3569', (172, 176))	('IP-10', 'Gene', (294, 299))	('regulated upon activation normal T cell expressed and secreted factor', 'Gene', '6352', (178, 247))	('inducing', 'PosReg', (133, 141))	('tumor', 'Disease', 'MESH:D009369', (304, 309))	('RANTES', 'Gene', '6352', (249, 255))	('IP-10', 'Gene', '3627', (294, 299))	('interferon-inducible protein-10', 'Gene', '3627', (261, 292))	('tumor', 'Phenotype', 'HP:0002664', (304, 309))	('blocking', 'NegReg', (23, 31))	('IL-6', 'Gene', (172, 176))	('tumor', 'Disease', (304, 309))	('antisense', 'Var', (66, 75))	('oligonucleotide', 'Chemical', 'MESH:D009841', (82, 97))
37183	32872659	Suppressor of cytokine signaling 3 (SOCS3)-deficient CD4+ T cells have a lower type 2 T helper cell (Th2) immune response and considerably increase the expression level of IL-10 and TGF-beta for Th3-like differentiation via the enhanced recruitment of STAT3 to their promoters.	('TGF-beta', 'Gene', (182, 190))	('CD4', 'Gene', '920', (53, 56))	('SOCS3', 'Gene', (36, 41))	('Suppressor of cytokine signaling 3', 'Gene', (0, 34))	('expression level', 'MPA', (152, 168))	('TGF-beta', 'Gene', '7039', (182, 190))	('deficient CD4+ T', 'Phenotype', 'HP:0005407', (43, 59))	('increase', 'PosReg', (139, 147))	('lower', 'NegReg', (73, 78))	('CD4', 'Gene', (53, 56))	('SOCS3', 'Gene', '9021', (36, 41))	('-deficient', 'Var', (42, 52))	('recruitment', 'MPA', (237, 248))	('enhanced', 'PosReg', (228, 236))	('Suppressor of cytokine signaling 3', 'Gene', '9021', (0, 34))
37187	32872659	Recently, Ong and colleagues found that a novel STAT3 mutation (p.D427H, E616G, p.E616K and p.E696K) increased phosphorylation of STAT3 at Tyr705 in STAT3 mutants.	('STAT3', 'Gene', (48, 53))	('p.D427H', 'Mutation', 'p.D427H', (64, 71))	('mutants', 'Var', (155, 162))	('increased', 'PosReg', (101, 110))	('STAT3', 'Gene', (149, 154))	('p.E616K', 'Var', (80, 87))	('E616G', 'Var', (73, 78))	('p.D427H', 'Var', (64, 71))	('Tyr705', 'Chemical', '-', (139, 145))	('p.E616K', 'Mutation', 'p.E616K', (80, 87))	('p.E696K', 'Mutation', 'p.E696K', (92, 99))	('STAT3', 'Protein', (130, 135))	('E616G', 'Mutation', 'p.E616G', (73, 78))	('phosphorylation', 'MPA', (111, 126))	('p.E696K', 'Var', (92, 99))
37188	32872659	Further, p.E616K regulated programmed death-ligand 1(PD-L1) expression via the binding of STAT3 to the promoter of PD-L1 in NK/T-cell lymphoma (NKTL).	('expression', 'MPA', (60, 70))	('PD-L1', 'Gene', (53, 58))	('p.E616K', 'Var', (9, 16))	('PD-L1', 'Gene', (115, 120))	('PD-L1', 'Gene', '29126', (115, 120))	('PD-L1', 'Gene', '29126', (53, 58))	('binding', 'Interaction', (79, 86))	('T-cell lymphoma', 'Phenotype', 'HP:0012190', (127, 142))	('lymphoma', 'Phenotype', 'HP:0002665', (134, 142))	('cell lymphoma', 'Phenotype', 'HP:0012191', (129, 142))	('p.E616K', 'Mutation', 'p.E616K', (9, 16))	('regulated', 'Reg', (17, 26))	('NK/T-cell lymphoma', 'Disease', 'MESH:D054391', (124, 142))	('NK/T-cell lymphoma', 'Disease', (124, 142))
37189	32872659	The team suggested that inhibitors of STAT3 and PD-L1 might be a promising therapeutic strategy for NKTL.	('PD-L1', 'Gene', '29126', (48, 53))	('NKTL', 'Disease', (100, 104))	('rat', 'Species', '10116', (89, 92))	('inhibitors', 'Var', (24, 34))	('PD-L1', 'Gene', (48, 53))	('STAT3', 'Gene', (38, 43))
37191	32872659	Silencing STAT3 signaling can reverse the level of PD-L1 and enhance the susceptibility of CRPC cells to NK cell immunity.	('enhance', 'PosReg', (61, 68))	('susceptibility', 'MPA', (73, 87))	('PD-L1', 'Gene', '29126', (51, 56))	('STAT3', 'Protein', (10, 15))	('Silencing', 'Var', (0, 9))	('PD-L1', 'Gene', (51, 56))
37195	32872659	However, STAT3beta significantly inhibited cell growth in soft agar in a dose-dependent manner, while cell-specific STAT3beta expression in macrophages reduced the invasion and cell mobility of breast cancer cells and significantly suppressed breast tumor growth.	('breast cancer', 'Disease', (194, 207))	('breast tumor', 'Phenotype', 'HP:0100013', (243, 255))	('STAT3beta', 'Var', (116, 125))	('agar', 'Chemical', 'MESH:D000362', (63, 67))	('reduced', 'NegReg', (152, 159))	('breast tumor', 'Disease', 'MESH:D001943', (243, 255))	('cell growth in soft agar', 'CPA', (43, 67))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('tumor', 'Phenotype', 'HP:0002664', (250, 255))	('breast cancer', 'Disease', 'MESH:D001943', (194, 207))	('breast tumor', 'Disease', (243, 255))	('inhibited', 'NegReg', (33, 42))	('suppressed', 'NegReg', (232, 242))	('breast cancer', 'Phenotype', 'HP:0003002', (194, 207))
37198	32872659	Cooperating with c-Jun, STAT3beta increases Fas expression and the sensitization of melanoma cells to Fas ligand-induced apoptosis.	('c-Jun', 'Gene', (17, 22))	('Fas ligand', 'Gene', '356', (102, 112))	('melanoma', 'Disease', 'MESH:D008545', (84, 92))	('melanoma', 'Phenotype', 'HP:0002861', (84, 92))	('expression', 'MPA', (48, 58))	('Fas', 'Protein', (44, 47))	('sensitization', 'CPA', (67, 80))	('melanoma', 'Disease', (84, 92))	('STAT3beta', 'Var', (24, 33))	('rat', 'Species', '10116', (5, 8))	('c-Jun', 'Gene', '3725', (17, 22))	('Fas ligand', 'Gene', (102, 112))	('increases', 'PosReg', (34, 43))
37199	32872659	Zammarchi and colleagues revealed that the STAT3beta switch leads to tumor regression in vivo.	('STAT3beta', 'Var', (43, 52))	('tumor', 'Disease', (69, 74))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))
37203	32872659	In breast cancer cells, STAT3beta mediates cells' growth inhibition and leads to cell cycle arrest and apoptosis.	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('breast cancer', 'Disease', (3, 16))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (81, 98))	('STAT3beta', 'Var', (24, 33))	('arrest', 'Disease', 'MESH:D006323', (92, 98))	('leads to', 'Reg', (72, 80))	('apoptosis', 'CPA', (103, 112))	('arrest', 'Disease', (92, 98))
37205	32872659	Intriguingly, the expression of STAT3beta can rescue the embryonic lethality of STAT3 deficient mice and induce the expression of specific STAT3 target genes.	('induce', 'PosReg', (105, 111))	('expression', 'MPA', (116, 126))	('mice', 'Species', '10090', (96, 100))	('STAT3beta', 'Gene', (32, 41))	('rescue', 'PosReg', (46, 52))	('embryonic lethality', 'Disease', 'MESH:D020964', (57, 76))	('embryonic lethality', 'Disease', (57, 76))	('expression', 'Var', (18, 28))
37206	32872659	STAT3beta has gained attention as a potent tumor suppressor and a favorable prognostic factor in ESCC with or without chemoradiotherapy, and it strongly correlates with longer overall survival and recurrence-free survival.	('recurrence-free survival', 'CPA', (197, 221))	('overall survival', 'CPA', (176, 192))	('STAT3beta', 'Var', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Disease', (43, 48))	('longer', 'PosReg', (169, 175))	('ESCC', 'Disease', (97, 101))
37207	32872659	Recently, it has been found that STAT3beta correlates with a favorable prognosis and prolonged survival, and also has a tumor-suppressive effect in acute myeloid leukemia via the regulation of its target gene, SELL.	('acute myeloid leukemia', 'Disease', (148, 170))	('SELL', 'Gene', (210, 214))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (148, 170))	('SELL', 'Gene', '6402', (210, 214))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (154, 170))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('leukemia', 'Phenotype', 'HP:0001909', (162, 170))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (148, 170))	('STAT3beta', 'Var', (33, 42))	('tumor', 'Disease', (120, 125))
37213	32872659	The splicing reprogramming offers an effective therapeutic approach for cancer.	('splicing', 'Var', (4, 12))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('cancer', 'Disease', (72, 78))
37224	32872659	Furthermore, ST3-H2A2 (LDTRYLEQLHKLY) bound to both phosphorylated and unphosphorylated STAT3 in prostate cancer cells, decreased STAT3 DNA binding ability and induced apoptotic cell death.	('decreased', 'NegReg', (120, 129))	('bound', 'Interaction', (38, 43))	('induced', 'Reg', (160, 167))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('prostate cancer', 'Disease', 'MESH:D011471', (97, 112))	('apoptotic cell death', 'CPA', (168, 188))	('STAT3 DNA binding', 'Interaction', (130, 147))	('prostate cancer', 'Phenotype', 'HP:0012125', (97, 112))	('ST3-H2A2', 'Var', (13, 21))	('prostate cancer', 'Disease', (97, 112))
37229	32872659	showed that it acts as a cysteine reactive inhibitor and binds to one or more cysteines in STAT3 (Cys-367, Cys-468, Cys-542).	('Cys-468', 'Var', (107, 114))	('Cys-367', 'Var', (98, 105))	('cysteines', 'Chemical', 'MESH:D003545', (78, 87))	('Cys', 'Chemical', 'MESH:D003545', (98, 101))	('Cys', 'Chemical', 'MESH:D003545', (116, 119))	('Cys-542', 'Var', (116, 123))	('cysteine', 'Chemical', 'MESH:D003545', (78, 86))	('binds', 'Interaction', (57, 62))	('cysteine', 'Chemical', 'MESH:D003545', (25, 33))	('Cys', 'Chemical', 'MESH:D003545', (107, 110))
37230	32872659	Recently, it was shown to suppress the resistance of prostate cancer cells to enzalutamide, and its analogs SG-1709 (Figure 3b) and SG-1721 (Figure 3c) exhibited even greater effectiveness in blocking STAT3 signaling and inducing apoptosis.	('SG-1721', 'Var', (132, 139))	('prostate cancer', 'Disease', (53, 68))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('resistance', 'MPA', (39, 49))	('STAT3', 'MPA', (201, 206))	('apoptosis', 'CPA', (230, 239))	('prostate cancer', 'Disease', 'MESH:D011471', (53, 68))	('inducing', 'Reg', (221, 229))	('suppress', 'NegReg', (26, 34))	('prostate cancer', 'Phenotype', 'HP:0012125', (53, 68))	('blocking', 'NegReg', (192, 200))	('enzalutamide', 'Chemical', 'MESH:C540278', (78, 90))	('SG-1709', 'Gene', (108, 115))
37246	32872659	found that C48 is a STAT3 inhibitor that selectively binds to Cys468 of STAT3 and blocks phosphorylation of STAT3 to inhibit tumor growth in vivo.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('phosphorylation', 'MPA', (89, 104))	('STAT3', 'Gene', (72, 77))	('C48', 'Gene', (11, 14))	('blocks', 'NegReg', (82, 88))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('Cys468', 'Chemical', '-', (62, 68))	('tumor', 'Disease', (125, 130))	('binds', 'Interaction', (53, 58))	('C48', 'Gene', '55755', (11, 14))	('Cys468', 'Var', (62, 68))	('inhibit', 'NegReg', (117, 124))
37249	32872659	From an analysis by matrix-assisted laser desorption/ionization-mass spectrometry, Cys550 was found to be an important residue for crosslinking between STAT3 and BPMB.	('BPMB', 'Chemical', '-', (162, 166))	('STAT3', 'Gene', (152, 157))	('Cys550', 'Chemical', '-', (83, 89))	('BPMB', 'Gene', (162, 166))	('Cys550', 'Var', (83, 89))	('crosslinking', 'MPA', (131, 143))
37261	32872659	CJ-1383 induced breast cancer cell apoptosis in a dose-dependent manner, while inhibition of tumor growth by the phosphopeptide mimetic PM-73G occurred without apoptosis or changes in the expression of cyclin D1 or survivin in xenograft models.	('cyclin D1', 'Gene', (202, 211))	('breast cancer', 'Disease', (16, 29))	('PM', 'Chemical', 'MESH:D011399', (136, 138))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('survivin', 'Gene', '11799', (215, 223))	('CJ-1383', 'CellLine', 'CVCL:8044', (0, 7))	('tumor', 'Disease', (93, 98))	('breast cancer', 'Phenotype', 'HP:0003002', (16, 29))	('survivin', 'Gene', (215, 223))	('phosphopeptide', 'Chemical', 'MESH:D010748', (113, 127))	('CJ-1383', 'Var', (0, 7))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('cyclin D1', 'Gene', '595', (202, 211))	('breast cancer', 'Disease', 'MESH:D001943', (16, 29))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
37263	32872659	Another study demonstrated that Stattic enhanced radiosensitivity.	('Stattic', 'Var', (32, 39))	('radiosensitivity', 'CPA', (49, 65))	('rat', 'Species', '10116', (21, 24))	('enhanced radiosensitivity', 'Phenotype', 'HP:0010997', (40, 65))	('enhanced', 'PosReg', (40, 48))
37264	32872659	STA-21 (Figure 3g), a natural product analog of tetrangomycin, was discovered via structure-based virtual screening to bind to the SH2 domain and form hydrogen bonds with Arg595, Arg609 and Ile634.	('Ile634', 'Var', (190, 196))	('Arg595', 'Var', (171, 177))	('Arg609', 'Chemical', '-', (179, 185))	('Arg595', 'Chemical', '-', (171, 177))	('form', 'Reg', (146, 150))	('Arg609', 'Var', (179, 185))	('hydrogen', 'Chemical', 'MESH:D006859', (151, 159))	('STA-21', 'Chemical', 'MESH:C500947', (0, 6))	('bind', 'Interaction', (119, 123))	('Ile634', 'Chemical', '-', (190, 196))	('tetrangomycin', 'Chemical', 'MESH:C103671', (48, 61))	('hydrogen', 'Interaction', (151, 159))
37270	32872659	S3I-201 (NSC 74859, Figure 3k) is a selective chemical probe inhibitor of STAT3 and binds to the STAT3 phosphotyrosine peptide (PY*LKT) with the potential to become a radiosensitizer for esophageal cancer radiotherapy.	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('cancer', 'Disease', (198, 204))	('phosphotyrosine', 'Chemical', 'MESH:D019000', (103, 118))	('binds', 'Interaction', (84, 89))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('S3I-201', 'Var', (0, 7))
37271	32872659	S3I-201 alkylates multiple Cys residues of STAT3 (Cys 108, 259, 367, 542 and 687), and is identified as a non-selective alkylating agent due to its leaving group O-tosyl.	('Cys', 'Chemical', 'MESH:D003545', (27, 30))	('alkylates', 'Reg', (8, 17))	('Cys', 'Chemical', 'MESH:D003545', (50, 53))	('S3I-201', 'Var', (0, 7))
37272	32872659	Molecular modeling, using S3I-201 as the lead compound, led to S3I-1757, which could interact with Y705 in the binding site of the SH2 domain and decrease nuclear phosphotyrosine STAT3 levels.	('phosphotyrosine', 'Chemical', 'MESH:D019000', (163, 178))	('nuclear phosphotyrosine STAT3 levels', 'MPA', (155, 191))	('Y705', 'Chemical', '-', (99, 103))	('binding', 'Interaction', (111, 118))	('S3I-1757', 'Var', (63, 71))	('Y705', 'Var', (99, 103))	('decrease', 'NegReg', (146, 154))
37273	32872659	synthesized a large set of S3I-201 analogs, among which SF-1-066 (known as S3I-201.1066, Figure 3l) and SF-1-121 showed impressive potency in whole-cell viability assays, and SF-1-066 also induced an antitumor response in breast tumor xenografts.	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('tumor', 'Disease', 'MESH:D009369', (229, 234))	('breast tumor', 'Phenotype', 'HP:0100013', (222, 234))	('SF-1-066', 'Chemical', 'MESH:C000595191', (56, 64))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('breast tumor', 'Disease', 'MESH:D001943', (222, 234))	('SF-1-066', 'Var', (175, 183))	('tumor', 'Disease', (204, 209))	('tumor', 'Disease', (229, 234))	('induced', 'Reg', (189, 196))	('breast tumor', 'Disease', (222, 234))	('SF-1-066', 'Chemical', 'MESH:C000595191', (175, 183))
37274	32872659	Further improvement of the parent compound SF-1-066 led to BP-5-087 (Figure 3m), a highly potent and selective STAT3 SH2 domain inhibitor, and when used in combination with imatinib, it could reverse TKI-resistant CML.	('BP-5-087', 'Var', (59, 67))	('imatinib', 'Chemical', 'MESH:D000068877', (173, 181))	('SF-1-066', 'Chemical', 'MESH:C000595191', (43, 51))	('TKI-resistant CML', 'Disease', (200, 217))	('BP-5-087', 'Chemical', 'MESH:C000597560', (59, 67))
37278	32872659	To reduce the pharmacokinetic lability of BP-1-102, SH-4-54 was designed as a STAT3 SH2 domain inhibitor, which showed better therapeutic efficacy than BP-1-102, and exhibited blood-brain barrier permeability and controlled glioma tumor growth.	('BP-1-102', 'Chemical', 'MESH:C000595192', (152, 160))	('SH-4-54', 'Var', (52, 59))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('pharmacokinetic lability', 'MPA', (14, 38))	('glioma', 'Phenotype', 'HP:0009733', (224, 230))	('glioma tumor', 'Disease', (224, 236))	('BP-1-102', 'Chemical', 'MESH:C000595192', (42, 50))	('glioma tumor', 'Disease', 'MESH:D005910', (224, 236))
37280	32872659	They interact with the SH2 domain of STAT3 with high affinity and inhibit STAT3 Y705 and S727 phosphorylation.	('S727', 'Var', (89, 93))	('Y705', 'Chemical', '-', (80, 84))	('Y705', 'Var', (80, 84))	('interact', 'Interaction', (5, 13))	('inhibit', 'NegReg', (66, 73))	('STAT3', 'MPA', (74, 79))
37281	32872659	Computational docking and molecular dynamics simulations were used to examine the binding of OPB-31121 to STAT3, and OPB-31121 bound to S636 and V637 residues without overlapping with other STAT3 inhibitors.	('bound', 'Interaction', (127, 132))	('OPB-31121', 'Chemical', '-', (117, 126))	('V637', 'Var', (145, 149))	('OPB-31121', 'Var', (117, 126))	('OPB-31121', 'Chemical', '-', (93, 102))	('S636', 'Var', (136, 140))	('binding', 'Interaction', (82, 89))	('OPB-31121', 'Gene', (93, 102))
37282	32872659	OPB-51602 can directly interfere with mitochondrial STAT3 and induce the formation of STAT3 proteotoxic aggregates that are lethal to cancer cells.	('STAT3 proteotoxic aggregates', 'MPA', (86, 114))	('OPB-51602', 'Var', (0, 9))	('induce', 'Reg', (62, 68))	('interfere', 'NegReg', (23, 32))	('cancer', 'Disease', (134, 140))	('formation', 'MPA', (73, 82))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('mitochondrial STAT3', 'MPA', (38, 57))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('OPB-51602', 'Chemical', '-', (0, 9))
37285	32872659	These include a Phase I clinical trial for OPB-31121 in advanced cancer and solid tumor in Korea (NCT00657176, 18 April 2008) and the USA (NCT00955812, 12 February 2013), a Phase I/II trial in patients with progressive hepatocellular carcinoma (NCT01406574, 8 June 2015), and a Phase I OPB-51602 clinical trial for hematological malignancies in Japan (NCT01344876, 8 June 2015) and for refractory solid tumors (NCT01184807, 26 March 2014).	('tumor', 'Disease', 'MESH:D009369', (403, 408))	('hematological malignancies', 'Disease', 'MESH:D019337', (315, 341))	('OPB-51602', 'Chemical', '-', (286, 295))	('progressive hepatocellular carcinoma', 'Disease', (207, 243))	('tumors', 'Phenotype', 'HP:0002664', (403, 409))	('hematological malignancies', 'Phenotype', 'HP:0004377', (315, 341))	('tumor', 'Disease', (82, 87))	('cancer', 'Disease', (65, 71))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (219, 243))	('OPB-31121', 'Chemical', '-', (43, 52))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (403, 408))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('progressive hepatocellular carcinoma', 'Disease', 'MESH:D006528', (207, 243))	('tumors', 'Disease', (403, 409))	('patients', 'Species', '9606', (193, 201))	('hematological malignancies', 'Disease', (315, 341))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('NCT00657176', 'Var', (98, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (234, 243))	('NCT01344876', 'Var', (352, 363))	('NCT01406574', 'Var', (245, 256))	('tumors', 'Disease', 'MESH:D009369', (403, 409))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('tumor', 'Disease', (403, 408))	('NCT00955812', 'Var', (139, 150))
37286	32872659	Aberrant STAT3 activation is related to cell malignant transformation, tumor proliferation, differentiation and anti-apoptosis.	('activation', 'PosReg', (15, 25))	('cell malignant transformation', 'CPA', (40, 69))	('Aberrant', 'Var', (0, 8))	('STAT3', 'Gene', (9, 14))	('rat', 'Species', '10116', (84, 87))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('anti-apoptosis', 'CPA', (112, 126))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Disease', (71, 76))	('differentiation', 'CPA', (92, 107))
37293	32872659	The team confirmed that K116 both inhibited STAT3 Tyr705 and promoted apoptosis in a dose-dependent manner.	('promoted', 'PosReg', (61, 69))	('inhibited', 'NegReg', (34, 43))	('STAT3 Tyr705', 'MPA', (44, 56))	('apoptosis', 'CPA', (70, 79))	('Tyr705', 'Chemical', '-', (50, 56))	('K116', 'Var', (24, 28))	('K116', 'Chemical', '-', (24, 28))
37294	32872659	In summary, small-molecule STAT3 inhibitors have antitumor activities and inhibit STAT3 phosphorylation but are yet to be approved for clinical cancer therapy.	('small-molecule', 'Var', (12, 26))	('STAT3', 'Gene', (27, 32))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('inhibit', 'NegReg', (74, 81))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('cancer', 'Disease', (144, 150))	('tumor', 'Disease', (53, 58))	('STAT3 phosphorylation', 'MPA', (82, 103))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
37302	32872659	As mentioned above, STAT3beta functions as a tumor suppressor and sensitizes cancer cells and ESCC patients to chemotherapy.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('cancer', 'Disease', (77, 83))	('tumor', 'Disease', (45, 50))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('STAT3beta', 'Var', (20, 29))	('patients', 'Species', '9606', (99, 107))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('sensitizes', 'Reg', (66, 76))
37304	32872659	Interestingly, the ratio of STAT3alpha/STAT3beta impacts the fate of a tumor.	('STAT3alpha/STAT3beta', 'Var', (28, 48))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('rat', 'Species', '10116', (19, 22))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('impacts', 'Reg', (49, 56))	('tumor', 'Disease', (71, 76))
37312	29023197	We identified 281 RBPs to be enriched for mutations (GEMs) in at least one cancer type.	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('cancer', 'Disease', (75, 81))	('RBP', 'Gene', (18, 21))	('RBP', 'Gene', '57794', (18, 21))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('mutations', 'Var', (42, 51))
37313	29023197	GEM RBPs were found to undergo frequent frameshift and inframe deletions as well as missense, nonsense and silent mutations when compared to those that are not enriched for mutations.	('nonsense', 'Var', (94, 102))	('RBP', 'Gene', (4, 7))	('RBP', 'Gene', '57794', (4, 7))	('frameshift', 'Var', (40, 50))	('missense', 'Var', (84, 92))
37315	29023197	Using the OncodriveFM framework, we also identified more than 200 candidate driver RBPs that were found to accumulate functionally impactful mutations in at least one cancer.	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('mutations', 'Var', (141, 150))	('cancer', 'Disease', (167, 173))	('RBP', 'Gene', (83, 86))	('RBP', 'Gene', '57794', (83, 86))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))
37324	29023197	Given the importance of regulatory molecules like RBPs in controlling gene expression, it is evident that any deviation from normal function of these proteins can lead to various disorders including cancer.	('RBP', 'Gene', '57794', (50, 53))	('deviation', 'Var', (110, 119))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('various disorders', 'Disease', (171, 188))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('cancer', 'Disease', (199, 205))	('RBP', 'Gene', (50, 53))	('lead to', 'Reg', (163, 170))	('various disorders', 'Disease', 'MESH:C566351', (171, 188))
37329	29023197	An increased expression of this protein facilitates the inclusion of exon5 in the pre-mRNA of CD44 - a cell surface protein involved in cancer proliferation.	('CD44', 'Gene', (94, 98))	('increased', 'PosReg', (3, 12))	('expression', 'MPA', (13, 23))	('exon5', 'Protein', (69, 74))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('cancer', 'Disease', (136, 142))	('CD44', 'Gene', '960', (94, 98))	('facilitates', 'PosReg', (40, 51))	('inclusion', 'Var', (56, 65))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
37336	29023197	Mutational analysis of all the genes in the human genome across 12 cancer types identified SF3B1, U2AF1 and PCBP1 - RBPs involved in splicing to be significantly mutated in multiple cancers suggesting their role in causing cancer phenotypes.	('human', 'Species', '9606', (44, 49))	('SF3B1', 'Gene', (91, 96))	('PCBP1', 'Gene', (108, 113))	('U2AF1', 'Gene', (98, 103))	('cancer', 'Disease', (223, 229))	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('RBP', 'Gene', (116, 119))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('SF3B1', 'Gene', '23451', (91, 96))	('cancers', 'Phenotype', 'HP:0002664', (182, 189))	('U2AF1', 'Gene', '7307', (98, 103))	('multiple cancers', 'Disease', 'MESH:D009369', (173, 189))	('cancer', 'Disease', (182, 188))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('mutated', 'Var', (162, 169))	('PCBP1', 'Gene', '5093', (108, 113))	('cancer', 'Disease', 'MESH:D009369', (223, 229))	('cancer', 'Disease', (67, 73))	('multiple cancers', 'Disease', (173, 189))	('RBP', 'Gene', '57794', (116, 119))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))
37337	29023197	Furthermore, APOBEC3B - an important protein in the RNA editing mechanism was found to be upregulated and frequently mutated in cancers of bladder, cervix, lung, head and neck and breast.	('cancers', 'Phenotype', 'HP:0002664', (128, 135))	('mutated', 'Var', (117, 124))	('cancers of bladder', 'Disease', (128, 146))	('cervix', 'Disease', (148, 154))	('cancers of bladder', 'Disease', 'MESH:D001749', (128, 146))	('APOBEC3B', 'Gene', (13, 21))	('APOBEC3B', 'Gene', '9582', (13, 21))	('breast', 'Disease', (180, 186))	('lung', 'Disease', (156, 160))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('upregulated', 'PosReg', (90, 101))
37338	29023197	Also notable are the mutations in the gene coding for RBM10 in lung cancer which was found to misregulate the alternative splicing of NUMB protein- a critical regulator of the Notch pathway and hence leading to irregular cell proliferation in lung cancers.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('lung cancer', 'Phenotype', 'HP:0100526', (243, 254))	('lung cancers', 'Phenotype', 'HP:0100526', (243, 255))	('lung cancer', 'Disease', (63, 74))	('RBM10', 'Gene', '8241', (54, 59))	('cancers', 'Phenotype', 'HP:0002664', (248, 255))	('alternative splicing', 'MPA', (110, 130))	('cancer', 'Phenotype', 'HP:0002664', (248, 254))	('NUMB', 'Gene', (134, 138))	('irregular cell proliferation', 'CPA', (211, 239))	('lung cancer', 'Disease', 'MESH:D008175', (63, 74))	('lung cancer', 'Phenotype', 'HP:0100526', (63, 74))	('misregulate', 'Var', (94, 105))	('mutations', 'Var', (21, 30))	('irregular cell proliferation', 'Phenotype', 'HP:0031377', (211, 239))	('NUMB', 'Gene', '8650', (134, 138))	('lung cancers', 'Disease', 'MESH:D008175', (243, 255))	('lung cancer', 'Disease', 'MESH:D008175', (243, 254))	('RBM10', 'Gene', (54, 59))	('lung cancers', 'Disease', (243, 255))	('leading to', 'Reg', (200, 210))
37340	29023197	Hence, to expand the current understanding of mutations in these genes, we performed a systematic analyses of somatic mutations occurring in ~1300 RBPs in ~6000 tumor samples across 26 cancer types.	('tumor', 'Disease', (161, 166))	('RBP', 'Gene', (147, 150))	('RBP', 'Gene', '57794', (147, 150))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('mutations', 'Var', (118, 127))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('cancer', 'Disease', (185, 191))
37342	29023197	We then analyzed the exome sequencing data of 26 cancer types to identify candidate drivers and integrated their transcriptome profiles to assess alterations in their expression due to mutation.	('expression', 'MPA', (167, 177))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('mutation', 'Var', (185, 193))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('cancer', 'Disease', (49, 55))
37346	29023197	Secondly, we identify Genes Enriched for Mutations (GEMs) in a given cancer using a Fisher's exact test that calculates the probability of observing mutations in a given gene against a genomic background (Fig.	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('Mutations', 'Var', (41, 50))	('cancer', 'Disease', (69, 75))
37347	29023197	Finally, we identify RBPs that accumulate high functionally-impactful mutations using OncodriveFM approach (Fig.	('RBP', 'Gene', (21, 24))	('mutations', 'Var', (70, 79))	('RBP', 'Gene', '57794', (21, 24))
37348	29023197	1C) (See Materials and Methods) that relies on SIFT, PPH2 and Mutation Assessor to estimate the functional impact of individual mutations.	('mutations', 'Var', (128, 137))	('SIFT', 'Disease', 'None', (47, 51))	('SIFT', 'Disease', (47, 51))
37349	29023197	It does so by computing the bias towards the accumulation of high-impact mutations across the cancer in the cohort as a signal of their involvement in tumorogenesis.	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumor', 'Disease', (151, 156))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('cancer', 'Disease', (94, 100))	('mutations', 'Var', (73, 82))	('tumor', 'Disease', 'MESH:D009369', (151, 156))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
37353	29023197	Overall, we find the mutational frequency of Non-RBPs to be significantly higher than that of RBPs in ~70% of the cancer types studied (Fig.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('higher', 'PosReg', (74, 80))	('RBP', 'Gene', (49, 52))	('RBP', 'Gene', (94, 97))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('RBP', 'Gene', '57794', (49, 52))	('RBP', 'Gene', '57794', (94, 97))	('mutational', 'Var', (21, 31))	('cancer', 'Disease', (114, 120))
37369	29023197	S1D), suggesting that these observations could reveal common mechanisms of dysregulation at post-transcriptional level with in members of these cancer type clusters due to mutations in RBPs.	('mutations', 'Var', (172, 181))	('cancer type clusters', 'Disease', (144, 164))	('RBP', 'Gene', (185, 188))	('RBP', 'Gene', '57794', (185, 188))	('cancer type clusters', 'Disease', 'MESH:D003027', (144, 164))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
37371	29023197	1B to identify Genes Enriched for Mutations (GEMs) in a given cancer type (see Materials and Methods).	('Mutations', 'Var', (34, 43))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))
37372	29023197	This identified 281 genes encoding for RBPs to be significantly enriched for mutations in at least one cancer (see Fig.	('RBP', 'Gene', '57794', (39, 42))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('mutations', 'Var', (77, 86))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('RBP', 'Gene', (39, 42))
37373	29023197	3A for RBPs enriched for mutations in at least 4 cancers and Fig.	('mutations', 'Var', (25, 34))	('RBP', 'Gene', (7, 10))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('RBP', 'Gene', '57794', (7, 10))	('cancers', 'Disease', 'MESH:D009369', (49, 56))	('cancers', 'Phenotype', 'HP:0002664', (49, 56))	('cancers', 'Disease', (49, 56))
37375	29023197	Comparison of GEM and non-GEM RBPs with corresponding gene sets for non-RBPs, for differences in the GC content and exome length, revealed that while GC content does not contribute to the extent of mutations in RBPs (p = 0.496, Wilcoxon test), it was found to be significantly different (p = 4.21e-08, Wilcoxon test) between GEM and non-GEM groups for non-RBPs (Fig.	('RBP', 'Gene', '57794', (30, 33))	('RBP', 'Gene', (356, 359))	('RBP', 'Gene', '57794', (72, 75))	('RBP', 'Gene', '57794', (356, 359))	('mutations', 'Var', (198, 207))	('RBP', 'Gene', (72, 75))	('RBP', 'Gene', (211, 214))	('RBP', 'Gene', '57794', (211, 214))	('different', 'Reg', (277, 286))	('RBP', 'Gene', (30, 33))
37377	29023197	These observations suggest that while GC content has no significant influence on the extent of mutations in RBPs, exome length might be higher for GEM RBPs, however it does not necessarily determine whether a gene is a GEM since non-RBPs GEMs exhibited significantly lower exome lengths.	('RBP', 'Gene', (233, 236))	('RBP', 'Gene', (151, 154))	('exome length', 'MPA', (114, 126))	('higher', 'PosReg', (136, 142))	('exome lengths', 'MPA', (273, 286))	('RBP', 'Gene', '57794', (151, 154))	('RBP', 'Gene', '57794', (233, 236))	('RBP', 'Gene', (108, 111))	('RBP', 'Gene', '57794', (108, 111))	('mutations', 'Var', (95, 104))	('lower', 'NegReg', (267, 272))
37378	29023197	Among the GEM RBPs, we identified KMT2C (MLL3), a histone 3- lysine 4 methyltransferase with tumor-suppressor properties that belongs to a family of chromatin regulator genes, to be enriched for mutations in 40% of the cancer types (Fig.	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('RBP', 'Gene', (14, 17))	('MLL3', 'Gene', (41, 45))	('tumor', 'Disease', (93, 98))	('cancer', 'Disease', 'MESH:D009369', (219, 225))	('mutations', 'Var', (195, 204))	('KMT2C', 'Gene', '58508', (34, 39))	('cancer', 'Disease', (219, 225))	('KMT2C', 'Gene', (34, 39))	('RBP', 'Gene', '57794', (14, 17))	('MLL3', 'Gene', '58508', (41, 45))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
37380	29023197	Furthermore, PLEC (plectin) - an abundantly expressed versatile protein that links different elements of the cytoskeleton was also seen to be enriched for mutations in 11 cancer types including lung, head and neck, bladder and pancreas.	('plectin', 'Gene', '5339', (19, 26))	('mutations', 'Var', (155, 164))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('cancer', 'Disease', (171, 177))	('PLEC', 'Gene', '5339', (13, 17))	('lung', 'Disease', (194, 198))	('PLEC', 'Gene', (13, 17))	('plectin', 'Gene', (19, 26))	('bladder and pancreas', 'Disease', 'MESH:D001749', (215, 235))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))
37383	29023197	Also notable is the gene encoding for EPPK1 which was seen to be mutated in ~40% of the cancers including cancers of cervix, colon, head and neck, pancreas etc.	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('pancreas', 'Disease', (147, 155))	('cancers', 'Disease', 'MESH:D009369', (88, 95))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('cancers', 'Phenotype', 'HP:0002664', (106, 113))	('cancers', 'Disease', (88, 95))	('EPPK1', 'Gene', '83481', (38, 43))	('cancers', 'Disease', (106, 113))	('EPPK1', 'Gene', (38, 43))	('colon', 'Disease', (125, 130))	('cancers', 'Disease', 'MESH:D009369', (106, 113))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('mutated', 'Var', (65, 72))
37385	29023197	Further, functional analysis of RBPs enriched for mutations identified diverse pathways including translation, mRNA splicing and apoptosis to be over-represented (p < 0.01, Fig.	('apoptosis', 'CPA', (129, 138))	('mutations', 'Var', (50, 59))	('translation', 'MPA', (98, 109))	('over-represented', 'PosReg', (145, 161))	('RBP', 'Gene', (32, 35))	('mRNA splicing', 'MPA', (111, 124))	('RBP', 'Gene', '57794', (32, 35))
37387	29023197	As different genes are susceptible to undergo different kinds of mutations at varied frequency, we aimed to identify mutation types that RBPs enriched for mutations (GEM-RBPs) frequently undergo when compared to RBPs that are not enriched for mutations (NonGEM-RBPs) (See Materials and Methods).	('RBP', 'Gene', (212, 215))	('mutations', 'Var', (155, 164))	('RBP', 'Gene', (137, 140))	('RBP', 'Gene', '57794', (212, 215))	('RBP', 'Gene', (261, 264))	('RBP', 'Gene', '57794', (137, 140))	('RBP', 'Gene', '57794', (261, 264))	('RBP', 'Gene', (170, 173))	('RBP', 'Gene', '57794', (170, 173))
37388	29023197	In particular, we quantified the mutation frequencies of nine different classes of mutations namely Frameshift mutations - Deletion and Insertion, Inframe Deletion, Inframe Insertion, Missense, Nonsense, Nonstop, Silent and Splice Site for all the RBPs across cancer samples (Materials and Methods, Table S2).	('Inframe Deletion', 'Var', (147, 163))	('cancer', 'Disease', 'MESH:D009369', (260, 266))	('RBP', 'Gene', (248, 251))	('cancer', 'Disease', (260, 266))	('Missense', 'Var', (184, 192))	('Nonstop', 'Var', (204, 211))	('RBP', 'Gene', '57794', (248, 251))	('Insertion', 'Var', (136, 145))	('cancer', 'Phenotype', 'HP:0002664', (260, 266))	('Nonsense', 'Var', (194, 202))	('Frameshift mutations - Deletion', 'Var', (100, 131))
37389	29023197	Our analysis clearly revealed that RBPs frequently and significantly undergo Frameshift deletion, Inframe deletion, Missense, Nonsense and Silent mutations (Fig.	('Frameshift deletion', 'Var', (77, 96))	('Silent mutations', 'Var', (139, 155))	('Inframe deletion', 'Var', (98, 114))	('RBP', 'Gene', (35, 38))	('RBP', 'Gene', '57794', (35, 38))	('Missense', 'Var', (116, 124))	('undergo', 'Reg', (69, 76))
37391	29023197	Abundance of Frameshift deletions in GEM-RBPs clearly indicates that deletion mutations causing change in reading frame thereby resulting in different translation than the original polypeptide, could be a frequent mechanism of dysregulation.	('deletion mutations', 'Var', (69, 87))	('RBP', 'Gene', (41, 44))	('RBP', 'Gene', '57794', (41, 44))	('Frameshift deletions', 'Var', (13, 33))	('translation', 'MPA', (151, 162))	('resulting in different', 'Reg', (128, 150))	('reading frame', 'MPA', (106, 119))
37392	29023197	Also, a significant difference in the frequency of nonsense mutations - which introduce a premature termination codon (PTC) in the gene; between the two groups indicate the importance of these mutations in triggering the mechanism of nonsense mediate decay (NMD) of RBPs enriched for mutations in several cancers.	('cancers', 'Disease', 'MESH:D009369', (305, 312))	('cancers', 'Phenotype', 'HP:0002664', (305, 312))	('cancer', 'Phenotype', 'HP:0002664', (305, 311))	('cancers', 'Disease', (305, 312))	('mutations', 'Var', (193, 202))	('RBP', 'Gene', (266, 269))	('RBP', 'Gene', '57794', (266, 269))
37394	29023197	This study showed that mutations that change the reading frame and introduce a premature termination codon cause a severe form of the disease as the whole transcript is eliminated by NMD, whereas mutations that did not give rise to a PTC resulted in a milder form of muscular dystrophy.	('muscular dystrophy', 'Disease', (267, 285))	('muscular dystrophy', 'Disease', 'MESH:D009136', (267, 285))	('cause', 'Reg', (107, 112))	('premature termination codon', 'MPA', (79, 106))	('mutations', 'Var', (23, 32))	('muscular dystrophy', 'Phenotype', 'HP:0003560', (267, 285))	('eliminated', 'NegReg', (169, 179))
37395	29023197	A similar mechanism could be leading to the dysregulation of RBPs that are enriched for mutations in several cancer phenotypes, due to the higher mutational rate of nonsense mutations in GEM-RBPs (Fig.	('nonsense mutations', 'Var', (165, 183))	('RBP', 'Gene', (61, 64))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('RBP', 'Gene', '57794', (61, 64))	('mutational rate', 'MPA', (146, 161))	('cancer', 'Disease', (109, 115))	('dysregulation', 'MPA', (44, 57))	('RBP', 'Gene', (191, 194))	('RBP', 'Gene', '57794', (191, 194))	('higher', 'PosReg', (139, 145))
37396	29023197	Likewise, missense mutations that result in a change in the amino acid composition and inframe deletions which although do not change the frame of transcription but can result in a dysfunctional protein form could contribute to the loss of function phenotypes in RBPs enriched for mutations.	('dysfunctional', 'Disease', (181, 194))	('dysfunctional', 'Disease', 'MESH:D006331', (181, 194))	('protein form', 'MPA', (195, 207))	('amino acid composition', 'MPA', (60, 82))	('result', 'Reg', (169, 175))	('missense mutations', 'Var', (10, 28))	('RBP', 'Gene', '57794', (263, 266))	('RBP', 'Gene', (263, 266))	('change', 'Reg', (46, 52))
37397	29023197	In addition to identifying Genes Enriched for Mutations (GEMs), which can comprise of both synonymous and nonsynonymous somatic mutations in a cancer genome, we aimed to uncover RBPs that exhibit a bias towards the accumulation of nonsynonymous mutations with high functional impact during tumorigenesis, as a means to uncover likely driver RBPs.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('RBP', 'Gene', (178, 181))	('RBP', 'Gene', '57794', (178, 181))	('tumor', 'Disease', 'MESH:D009369', (290, 295))	('RBP', 'Gene', (341, 344))	('cancer', 'Disease', (143, 149))	('nonsynonymous mutations', 'Var', (231, 254))	('RBP', 'Gene', '57794', (341, 344))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('accumulation', 'PosReg', (215, 227))	('tumor', 'Phenotype', 'HP:0002664', (290, 295))	('tumor', 'Disease', (290, 295))
37398	29023197	Driver genes are known to provide a significant growth advantage to cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('cancer', 'Disease', (68, 74))	('genes', 'Var', (7, 12))	('growth advantage', 'CPA', (48, 64))
37400	29023197	A significant trend towards the accumulation of such functional mutations is calculated as FM bias - signal of positive selection during cancer development (See Materials and Methods).	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('cancer', 'Disease', (137, 143))	('mutations', 'Var', (64, 73))	('cancer', 'Disease', 'MESH:D009369', (137, 143))
37407	29023197	We predict AHNAK to be a candidate driver in 12 cancers including head and neck squamous carcinoma, lung adenocarcinoma, lung squamous carcinoma, breast cancers (See Table S3) suggesting the impact of nonsynonymous mutations on protein function and thus misregulating pathways responsible for cellular growth and hence leading to a cancer phenotype.	('lung squamous carcinoma', 'Disease', (121, 144))	('lung adenocarcinoma', 'Disease', (100, 119))	('neck squamous carcinoma', 'Disease', 'MESH:D000077195', (75, 98))	('cancers', 'Disease', (153, 160))	('cancer', 'Disease', (153, 159))	('cancer', 'Disease', 'MESH:D009369', (332, 338))	('lung squamous carcinoma', 'Disease', 'MESH:D002294', (121, 144))	('leading to', 'Reg', (319, 329))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('cancer', 'Disease', (48, 54))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (100, 119))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('nonsynonymous mutations', 'Var', (201, 224))	('pathways', 'Pathway', (268, 276))	('protein', 'Protein', (228, 235))	('breast cancer', 'Phenotype', 'HP:0003002', (146, 159))	('breast cancers', 'Disease', 'MESH:D001943', (146, 160))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (100, 119))	('breast cancers', 'Disease', (146, 160))	('cancers', 'Phenotype', 'HP:0002664', (48, 55))	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('cancers', 'Disease', (48, 55))	('misregulating', 'Reg', (254, 267))	('AHNAK', 'Gene', '79026', (11, 16))	('impact', 'Reg', (191, 197))	('cancers', 'Disease', 'MESH:D009369', (153, 160))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('breast cancers', 'Phenotype', 'HP:0003002', (146, 160))	('cancer', 'Disease', (332, 338))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('AHNAK', 'Gene', (11, 16))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (80, 98))	('cancer', 'Phenotype', 'HP:0002664', (332, 338))	('neck squamous carcinoma', 'Disease', (75, 98))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (126, 144))	('cancers', 'Phenotype', 'HP:0002664', (153, 160))	('cancers', 'Disease', 'MESH:D009369', (48, 55))
37408	29023197	Another striking example is AGO2 which was found to accumulate functional mutations in cancers of breast, skin, lung and stomach.	('cancers of breast', 'Disease', 'MESH:D001943', (87, 104))	('AGO2', 'Gene', '27161', (28, 32))	('stomach', 'Disease', (121, 128))	('mutations', 'Var', (74, 83))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('skin', 'Disease', (106, 110))	('AGO2', 'Gene', (28, 32))	('cancers of breast', 'Disease', (87, 104))	('cancers', 'Phenotype', 'HP:0002664', (87, 94))	('lung', 'Disease', (112, 116))
37415	29023197	Interestingly, we find the gene encoding SF3B1 - an important splicing factor to be frequently mutated and accumulating functional mutations in uveal melanoma (UVM) which is in accordance with a study that showed the impact of SF3B1 mutations on alternative splicing in uveal melanomas.	('uveal melanomas', 'Disease', (270, 285))	('uveal melanomas', 'Phenotype', 'HP:0007716', (270, 285))	('melanomas', 'Phenotype', 'HP:0002861', (276, 285))	('SF3B1', 'Gene', '23451', (227, 232))	('splicing factor', 'Gene', (62, 77))	('melanoma', 'Phenotype', 'HP:0002861', (276, 284))	('SF3B1', 'Gene', (41, 46))	('uveal melanoma', 'Disease', 'MESH:C536494', (144, 158))	('melanoma', 'Phenotype', 'HP:0002861', (150, 158))	('uveal melanoma', 'Disease', (144, 158))	('splicing factor', 'Gene', '10569', (62, 77))	('uveal melanomas', 'Disease', 'MESH:C536494', (270, 285))	('uveal melanoma', 'Disease', 'MESH:C536494', (270, 284))	('uveal melanoma', 'Phenotype', 'HP:0007716', (144, 158))	('SF3B1', 'Gene', '23451', (41, 46))	('mutations', 'Var', (131, 140))	('SF3B1', 'Gene', (227, 232))	('uveal melanoma', 'Phenotype', 'HP:0007716', (270, 284))	('mutations', 'Var', (233, 242))
37416	29023197	Furthermore, recurrent missense mutation at R625 in patients with uveal melanoma was observed suggesting an oncogenic role of this mutation (Fig.	('uveal melanoma', 'Phenotype', 'HP:0007716', (66, 80))	('uveal melanoma', 'Disease', (66, 80))	('uveal melanoma', 'Disease', 'MESH:C536494', (66, 80))	('melanoma', 'Phenotype', 'HP:0002861', (72, 80))	('missense mutation at R625', 'Var', (23, 48))	('patients', 'Species', '9606', (52, 60))
37419	29023197	Also, recurrent missense mutations at S34 in the zf-CCCH domain was observed to be highly recurrent in patients with LAML (Fig.	('missense mutations at S34', 'Var', (16, 41))	('patients', 'Species', '9606', (103, 111))	('LAML', 'Disease', (117, 121))
37420	29023197	To identify if mutations in an RBP gene affects its RNA levels, we performed pan-cancer expression analysis for all the candidate RBP drivers between patient cohorts containing these mutations and cohorts that don't carry such mutations (See Materials and Methods).	('RBP', 'Gene', (130, 133))	('patient', 'Species', '9606', (150, 157))	('mutations', 'Var', (183, 192))	('affects', 'Reg', (40, 47))	('RBP', 'Gene', '57794', (130, 133))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('mutations', 'Var', (15, 24))	('cancer', 'Disease', (81, 87))	('RBP', 'Gene', (31, 34))	('RBP', 'Gene', '57794', (31, 34))	('RNA levels', 'MPA', (52, 62))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))
37422	29023197	Of these, CDKN2A, a cyclin-dependent kinase inhibitor 2A known to stabilize the tumor suppressor protein p53 was observed to have higher levels of RNA in mutated samples when compared to the non-mutated samples (Fold change = 3.9, p = 1.26E-11, Wilcox test).	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('CDKN2A', 'Gene', '1029', (10, 16))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('higher', 'PosReg', (130, 136))	('tumor', 'Disease', (80, 85))	('p53', 'Gene', (105, 108))	('p53', 'Gene', '7157', (105, 108))	('cyclin-dependent kinase inhibitor 2A', 'Gene', (20, 56))	('cyclin-dependent kinase inhibitor 2A', 'Gene', '1029', (20, 56))	('mutated', 'Var', (154, 161))	('levels', 'MPA', (137, 143))	('CDKN2A', 'Gene', (10, 16))	('RNA', 'MPA', (147, 150))
37423	29023197	Additionally, two distinct RNA helicases - DDX5 and DHX9 were found to have significantly different expression profiles between mutated and non-mutated cohorts.	('RNA helicases', 'Protein', (27, 40))	('expression profiles', 'MPA', (100, 119))	('mutated', 'Var', (128, 135))	('different', 'Reg', (90, 99))	('DDX5', 'Gene', (43, 47))	('DHX9', 'Gene', (52, 56))	('DDX5', 'Gene', '1655', (43, 47))	('DHX9', 'Gene', '1660', (52, 56))
37425	29023197	RBM10 was seen to be 2 fold down regulated in mutated samples when compared to the non-mutated samples.	('RBM10', 'Gene', (0, 5))	('down regulated', 'NegReg', (28, 42))	('mutated', 'Var', (46, 53))	('RBM10', 'Gene', '8241', (0, 5))
37426	29023197	We hypothesize that the lower expression in the mutated samples could be a result of the presence of truncated transcripts due to several non-sense mutations in the gene encoding for RBM10 (Fig.	('mutations', 'Var', (148, 157))	('expression', 'MPA', (30, 40))	('lower', 'NegReg', (24, 29))	('RBM10', 'Gene', '8241', (183, 188))	('RBM10', 'Gene', (183, 188))
37427	29023197	Hence, mutations in the RBP gene might not only lead to abnormal subcellular localization, defective binding to RNA but also lead to altered protein-protein interactions and thus conferring a cancer phenotype.	('conferring', 'Reg', (179, 189))	('RNA', 'Protein', (112, 115))	('defective', 'NegReg', (91, 100))	('subcellular localization', 'MPA', (65, 89))	('protein-protein interactions', 'MPA', (141, 169))	('RBP', 'Gene', (24, 27))	('altered', 'Reg', (133, 140))	('cancer', 'Disease', (192, 198))	('RBP', 'Gene', '57794', (24, 27))	('cancer', 'Disease', 'MESH:D009369', (192, 198))	('binding', 'Interaction', (101, 108))	('lead', 'Reg', (48, 52))	('abnormal', 'Reg', (56, 64))	('lead', 'Reg', (125, 129))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('mutations', 'Var', (7, 16))
37437	29023197	Higher degree, betweenness and closeness of drivers when compared to the non-drivers indicates that they form an integral part of the protein-protein interaction network of RBPs and thus mutations in them could significantly contribute to causing lethal phenotypes by potentially disrupting the formation of RNP complexes.	('disrupting', 'NegReg', (280, 290))	('contribute', 'Reg', (225, 235))	('formation', 'MPA', (295, 304))	('RNP', 'Gene', (308, 311))	('mutations', 'Var', (187, 196))	('RNP', 'Gene', '55599', (308, 311))	('RBP', 'Gene', (173, 176))	('causing', 'Reg', (239, 246))	('RBP', 'Gene', '57794', (173, 176))
37440	29023197	Hence, mutations in them may not only affect the expression, defective binding to RNA but can also lead to altered protein-protein interactions and thus conferring a cancer phenotype.	('cancer', 'Disease', (166, 172))	('defective', 'NegReg', (61, 70))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('RNA', 'Protein', (82, 85))	('lead to altered', 'Reg', (99, 114))	('expression', 'MPA', (49, 59))	('conferring', 'Reg', (153, 163))	('binding', 'Interaction', (71, 78))	('protein-protein interactions', 'MPA', (115, 143))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('affect', 'Reg', (38, 44))	('mutations', 'Var', (7, 16))
37448	29023197	This RBP interacts with CDC5L and SF3A1 in LUAD whereas it interacts with SNRNP300 and SF3B3 in COAD suggesting that different combinations of RBP mutated complexes could be contributing to disruption in different post-transcriptional sub-networks leading to varying cancer phenotypes.	('COAD', 'Disease', (96, 100))	('cancer', 'Disease', 'MESH:D009369', (267, 273))	('disruption', 'Reg', (190, 200))	('LUAD', 'Disease', (43, 47))	('RBP', 'Gene', (5, 8))	('leading to', 'Reg', (248, 258))	('RBP', 'Gene', '57794', (143, 146))	('CDC5L', 'Gene', (24, 29))	('post-transcriptional sub-networks', 'Pathway', (214, 247))	('SF3B3', 'Gene', (87, 92))	('mutated', 'Var', (147, 154))	('contributing', 'Reg', (174, 186))	('CDC5L', 'Gene', '988', (24, 29))	('interacts', 'Reg', (9, 18))	('cancer', 'Disease', (267, 273))	('SF3B3', 'Gene', '23450', (87, 92))	('SF3A1', 'Gene', '10291', (34, 39))	('cancer', 'Phenotype', 'HP:0002664', (267, 273))	('COAD', 'Disease', 'MESH:D029424', (96, 100))	('RBP', 'Gene', '57794', (5, 8))	('RNP', 'Gene', '55599', (76, 79))	('RBP', 'Gene', (143, 146))	('SF3A1', 'Gene', (34, 39))	('RNP', 'Gene', (76, 79))
37452	29023197	Hence, to understand if the mutations in these proteins are truly deleterious and/or can have a phenotypic impact in breast cancer, we choose SF3B1 and PRPF8 to study their effect on breast cancer cell lines.	('PRPF8', 'Gene', (152, 157))	('breast cancer', 'Phenotype', 'HP:0003002', (183, 196))	('SF3B1', 'Gene', '23451', (142, 147))	('breast cancer', 'Disease', 'MESH:D001943', (117, 130))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('breast cancer', 'Disease', (117, 130))	('SF3B1', 'Gene', (142, 147))	('breast cancer', 'Phenotype', 'HP:0003002', (117, 130))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('breast cancer', 'Disease', 'MESH:D001943', (183, 196))	('PRPF8', 'Gene', '10594', (152, 157))	('breast cancer', 'Disease', (183, 196))	('mutations', 'Var', (28, 37))
37456	29023197	Despite inefficient knockdown of SF3B1 (Fig.	('knockdown', 'Var', (20, 29))	('SF3B1', 'Gene', (33, 38))	('SF3B1', 'Gene', '23451', (33, 38))
37457	29023197	8A), CD44+/CD24+ cells were reproducibly reduced upon SF3B1 knockdown (Fig.	('SF3B1', 'Gene', (54, 59))	('CD24', 'Gene', (11, 15))	('reduced', 'NegReg', (41, 48))	('CD44', 'Gene', (5, 9))	('SF3B1', 'Gene', '23451', (54, 59))	('knockdown', 'Var', (60, 69))	('CD24', 'Gene', '100133941', (11, 15))	('CD44', 'Gene', '960', (5, 9))
37458	29023197	By contrast, SF3B1 knockdown cells displayed elevated levels of CD24 compared with control luciferase siRNA transfected cells (Fig.	('CD24', 'Gene', '100133941', (64, 68))	('SF3B1', 'Gene', (13, 18))	('knockdown', 'Var', (19, 28))	('CD24', 'Gene', (64, 68))	('SF3B1', 'Gene', '23451', (13, 18))	('elevated', 'PosReg', (45, 53))	('levels', 'MPA', (54, 60))
37459	29023197	Similar results were obtained upon knockdown of PRPF8 in these cells (Fig.	('knockdown', 'Var', (35, 44))	('PRPF8', 'Gene', '10594', (48, 53))	('PRPF8', 'Gene', (48, 53))
37460	29023197	Interestingly, SF3B1 or PRPF8 knockdown in MDA-MB-231 cell line, which represents mesenchymal stem like triple negative breast cancer, had no effect on CD44+/CD24- status (Fig.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('breast cancer', 'Disease', (120, 133))	('CD44', 'Gene', (152, 156))	('breast cancer', 'Disease', 'MESH:D001943', (120, 133))	('SF3B1', 'Gene', '23451', (15, 20))	('breast cancer', 'Phenotype', 'HP:0003002', (120, 133))	('CD24', 'Gene', '100133941', (158, 162))	('CD24', 'Gene', (158, 162))	('PRPF8', 'Gene', '10594', (24, 29))	('PRPF8', 'Gene', (24, 29))	('knockdown', 'Var', (30, 39))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (43, 53))	('SF3B1', 'Gene', (15, 20))	('CD44', 'Gene', '960', (152, 156))
37464	29023197	Consistent with this possibility, recent studies have demonstrated SF3B1 mutation (K700E) in breast cancer, preferentially in estrogen receptor positive breast cancer, to be a driver mutation.	('breast cancer', 'Phenotype', 'HP:0003002', (153, 166))	('SF3B1', 'Gene', '23451', (67, 72))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('breast cancer', 'Disease', 'MESH:D001943', (93, 106))	('K700E', 'Mutation', 'rs559063155', (83, 88))	('breast cancer', 'Disease', (93, 106))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('SF3B1', 'Gene', (67, 72))	('breast cancer', 'Phenotype', 'HP:0003002', (93, 106))	('breast cancer', 'Disease', 'MESH:D001943', (153, 166))	('K700E', 'Var', (83, 88))	('breast cancer', 'Disease', (153, 166))
37468	29023197	Dysregulation of these proteins has been implicated in several disorders including cancer although the causes of such dysregulation is poorly understood.	('Dysregulation', 'Var', (0, 13))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('implicated', 'Reg', (41, 51))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('cancer', 'Disease', (83, 89))
37470	29023197	Our computational analysis revealed that RBPs have an average of ~3 mutations per Mb across 26 cancers and enabled the identification of 281 RBPs to be enriched for mutations in at least one cancer type.	('cancer', 'Disease', (191, 197))	('cancer', 'Disease', 'MESH:D009369', (191, 197))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('cancers', 'Phenotype', 'HP:0002664', (95, 102))	('RBP', 'Gene', (41, 44))	('cancer', 'Disease', (95, 101))	('cancers', 'Disease', (95, 102))	('RBP', 'Gene', '57794', (41, 44))	('RBP', 'Gene', (141, 144))	('cancers', 'Disease', 'MESH:D009369', (95, 102))	('RBP', 'Gene', '57794', (141, 144))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('mutations', 'Var', (68, 77))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))
37471	29023197	Among these, genes encoding for EPPK1, KMT2C, AHNAK and PLEC were found to be enriched for mutations in at least 10 cancers suggesting common players in mediating cancer phenotypes in different tissues.	('PLEC', 'Gene', '5339', (56, 60))	('EPPK1', 'Gene', '83481', (32, 37))	('cancer', 'Disease', 'MESH:D009369', (163, 169))	('PLEC', 'Gene', (56, 60))	('EPPK1', 'Gene', (32, 37))	('AHNAK', 'Gene', '79026', (46, 51))	('KMT2C', 'Gene', '58508', (39, 44))	('cancer', 'Disease', (116, 122))	('KMT2C', 'Gene', (39, 44))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('cancers', 'Disease', 'MESH:D009369', (116, 123))	('mutations', 'Var', (91, 100))	('cancers', 'Phenotype', 'HP:0002664', (116, 123))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cancers', 'Disease', (116, 123))	('cancer', 'Disease', (163, 169))	('AHNAK', 'Gene', (46, 51))
37472	29023197	GC content and exome length were not found to play a major role in contributing to the mutational frequency of RBPs in majority of the studied cancers.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('mutational', 'Var', (87, 97))	('cancers', 'Disease', 'MESH:D009369', (143, 150))	('cancers', 'Phenotype', 'HP:0002664', (143, 150))	('cancers', 'Disease', (143, 150))	('RBP', 'Gene', (111, 114))	('RBP', 'Gene', '57794', (111, 114))
37475	29023197	Our analyses also revealed that RBPs enriched for mutations in atleast one cancer type were seen to be undergoing frequent Frameshift and Inframe deletions, missense, nonsense and silent mutations when compared to those that are not enriched, revealing the abundance of these variant types in mutated RBPs as significant contributor for malfunction in cancer genomes.	('cancer', 'Disease', 'MESH:D009369', (352, 358))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('mutations', 'Var', (50, 59))	('cancer', 'Disease', (352, 358))	('cancer', 'Disease', (75, 81))	('atleast', 'Gene', (63, 70))	('RBP', 'Gene', (32, 35))	('cancer', 'Phenotype', 'HP:0002664', (352, 358))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('RBP', 'Gene', (301, 304))	('RBP', 'Gene', '57794', (301, 304))	('missense', 'Var', (157, 165))	('RBP', 'Gene', '57794', (32, 35))
37479	29023197	We show that the presence of non-synonymous mutations correlate with change in the RNA levels of a significant fraction of driver RBPs (15% of the drivers), when cancer samples are grouped by the presence of mutations in an RBP irrespective of the cancer type.	('cancer', 'Disease', (248, 254))	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('RBP', 'Gene', (130, 133))	('RBP', 'Gene', '57794', (130, 133))	('cancer', 'Disease', (162, 168))	('cancer', 'Phenotype', 'HP:0002664', (248, 254))	('RBP', 'Gene', (224, 227))	('RBP', 'Gene', '57794', (224, 227))	('change', 'Reg', (69, 75))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('presence', 'Var', (17, 25))	('non-synonymous mutations', 'Var', (29, 53))	('cancer', 'Disease', 'MESH:D009369', (248, 254))	('RNA levels', 'MPA', (83, 93))
37482	29023197	Our knock down experiments indicated that deletion of either of these RBPs resulted in MCF7 cells, which are estrogen receptor positive, to exhibit reduced stem cell features.	('MCF7', 'CellLine', 'CVCL:0031', (87, 91))	('stem cell features', 'CPA', (156, 174))	('reduced', 'NegReg', (148, 155))	('RBP', 'Gene', (70, 73))	('RBP', 'Gene', '57794', (70, 73))	('MCF7', 'Gene', (87, 91))	('deletion', 'Var', (42, 50))
37490	29023197	This analysis should form a foundation to help us uncover the mutational spectrum of RBPs and their wiring dynamics in different cancer types thereby leading to dysregulation of post-transcriptional regulatory networks and also emphasizes the potential of various proteins of the splicesomal machinery as possible drug targets in cancer.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('mutational', 'Var', (62, 72))	('RBP', 'Gene', (85, 88))	('RBP', 'Gene', '57794', (85, 88))	('cancer', 'Phenotype', 'HP:0002664', (330, 336))	('leading to', 'Reg', (150, 160))	('cancer', 'Disease', (129, 135))	('dysregulation', 'MPA', (161, 174))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('post-transcriptional', 'Pathway', (178, 198))	('cancer', 'Disease', 'MESH:D009369', (330, 336))	('cancer', 'Disease', (330, 336))
37499	29023197	Genes with corrected p < 0.01 and odds ratio < 1 were classified as Genes Enriched in Mutations (GEMs) in a given cancer.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('Mutations', 'Var', (86, 95))	('cancer', 'Disease', (114, 120))
37501	29023197	We then obtained the mutation frequency of these genes in each cancer type for nine different variant classes viz - Inframe deletion, Inframe insertion, Frameshift deletion, Frameshift Insertion, Missense mutation, Nonsense mutation, Nonstop mutation, Silent and Splice Site mutations.	('Inframe insertion', 'Var', (134, 151))	('Frameshift deletion', 'Var', (153, 172))	('Nonsense mutation', 'Var', (215, 232))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('Nonstop mutation', 'Var', (234, 250))	('Frameshift Insertion', 'Var', (174, 194))	('cancer', 'Disease', (63, 69))	('Missense mutation', 'Var', (196, 213))
37502	29023197	Variants were classified into the above mentioned categories based on the annotations provided in the downloaded MAF files.	('MAF', 'Gene', '4094', (113, 116))	('MAF', 'Gene', (113, 116))	('Variants', 'Var', (0, 8))
37504	29023197	Upon obtaining the mutation frequencies in each cancer type for all the variant classes, we pooled the mutational frequencies of RBPs enriched for mutations across the cancers into one bin named as GEM-RBPs (Fig.	('RBP', 'Gene', (129, 132))	('mutations', 'Var', (147, 156))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('RBP', 'Gene', '57794', (129, 132))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('RBP', 'Gene', (202, 205))	('cancers', 'Disease', 'MESH:D009369', (168, 175))	('RBP', 'Gene', '57794', (202, 205))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('cancers', 'Phenotype', 'HP:0002664', (168, 175))	('cancer', 'Disease', (48, 54))	('cancers', 'Disease', (168, 175))	('cancer', 'Disease', (168, 174))	('cancer', 'Disease', 'MESH:D009369', (48, 54))
37520	29023197	Further, genes were categorized as drivers - if they are predicted to be candidate drivers in at least two cancer types and the remaining RBPs are termed nondrivers.	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('RBP', 'Gene', (138, 141))	('RBP', 'Gene', '57794', (138, 141))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('genes', 'Var', (9, 14))	('cancer', 'Disease', (107, 113))
37531	29023197	Antibodies against SF3B1 (cat# 14434S, Cell Signaling), PRPF8 (Cat#Ab190347, Abcam), CD24 (Cat#555428, BD Biosciences) and CD44 (Cat#559942, BD Biosciences) were used as per instructions from manufacturers.	('Cat#Ab190347', 'Var', (63, 75))	('CD44', 'Gene', '960', (123, 127))	('SF3B1', 'Gene', '23451', (19, 24))	('cat# 14434S', 'Var', (26, 37))	('CD24', 'Gene', '100133941', (85, 89))	('CD24', 'Gene', (85, 89))	('CD44', 'Gene', (123, 127))	('SF3B1', 'Gene', (19, 24))	('PRPF8', 'Gene', '10594', (56, 61))	('PRPF8', 'Gene', (56, 61))
37567	29328386	Proteomics-based investigation of multiple stages of OSCC development indicates that the inhibition of Trx-1 delays oral malignant transformation The majority of cases of oral squamous cell carcinoma (OSCC) develop from oral potentially malignant disorders, which have been confirmed to be involved in chronic oxidative stimulation.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (176, 199))	('carcinoma', 'Phenotype', 'HP:0030731', (190, 199))	('inhibition', 'Var', (89, 99))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (171, 199))	('oral squamous cell carcinoma', 'Disease', (171, 199))	('malignant disorders', 'Disease', (237, 256))	('Trx-1', 'Gene', (103, 108))	('malignant disorders', 'Disease', 'MESH:D009369', (237, 256))	('develop', 'Reg', (207, 214))	('oral malignant transformation', 'CPA', (116, 145))	('Trx-1', 'Gene', '7295', (103, 108))
37570	29328386	Validation experiments confirmed that Trx-1 was overex-pressed both in dysplasia and cancerous tissue samples, and the inhibition of Trx-1 was able to promote the apoptosis of OSCC cells under hypoxic conditions.	('apoptosis', 'CPA', (163, 172))	('Trx-1', 'Gene', (133, 138))	('inhibition', 'Var', (119, 129))	('promote', 'PosReg', (151, 158))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('dysplasia and cancerous', 'Disease', 'MESH:D009369', (71, 94))
37580	29328386	Furthermore, Lan et al demonstrated that 4NQO induced oxidative DNA damage and activated the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway in the mouse tongue.	('mouse', 'Species', '10090', (159, 164))	('4NQO', 'Chemical', 'MESH:D015112', (41, 45))	('rat', 'Species', '10116', (30, 33))	('Nrf2', 'Gene', '18024', (138, 142))	('Nrf2', 'Gene', (138, 142))	('activated', 'PosReg', (79, 88))	('oxidative DNA damage', 'MPA', (54, 74))	('nuclear factor (erythroid-derived 2)-like 2', 'Gene', '18024', (93, 136))	('4NQO', 'Var', (41, 45))
37604	29328386	The normal control, dysplasia and squamous cell carcinoma were labeled with 114, 116 and 119 iTRAQ tags, respectively [normal (N)-114, dysplasia (D)-116 and carcinoma (C)-119].	('squamous cell carcinoma', 'Disease', (34, 57))	('dysplasia', 'Disease', 'MESH:D004476', (20, 29))	('dysplasia', 'Disease', (135, 144))	('carcinoma', 'Disease', (48, 57))	('[normal', 'Var', (118, 125))	('carcinoma', 'Disease', 'MESH:D002277', (157, 166))	('dysplasia', 'Disease', 'MESH:D004476', (135, 144))	('carcinoma', 'Phenotype', 'HP:0030731', (157, 166))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (34, 57))	('dysplasia', 'Disease', (20, 29))	('carcinoma', 'Disease', (157, 166))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (34, 57))	('carcinoma', 'Disease', 'MESH:D002277', (48, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (48, 57))
37606	29328386	The following identification parameters were selected: MS/MS ion search; enzyme, trypsin; fragment mass tolerance, +-0.02 Da; mass values, monoisotopic mass; max missed cleavages, 1; peptide mass tolerance, 10 ppm; variable modifications, Gln-> pyro-Glu (N-termQ), oxidation (M) and iTRAQ8plex (Y); fixed modifications, carbamidomethyl (C), iTRAQ8plex (N-term) and iTRAQ8plex (K).	('iTRAQ8plex', 'Var', (365, 375))	('carbamidomethyl', 'MPA', (320, 335))	('Gln-> pyro-Glu', 'Var', (239, 253))	('oxidation', 'MPA', (265, 274))	('iTRAQ8plex', 'MPA', (283, 293))	('pyro-Glu', 'Chemical', 'MESH:D011761', (245, 253))	('Gln', 'Chemical', 'MESH:D005973', (239, 242))	('iTRAQ8plex', 'Var', (341, 351))
37668	29328386	5, the expression of Bax and Cle-PARP was upregulated and the expression of Bcl-2 was downregulated by PX-12 under hypoxic conditions.	('Bax', 'Gene', '581', (21, 24))	('PX-12', 'Chemical', 'MESH:C412893', (103, 108))	('PX-12', 'Var', (103, 108))	('Bcl-2', 'Gene', (76, 81))	('Bcl-2', 'Gene', '596', (76, 81))	('expression', 'MPA', (62, 72))	('expression', 'MPA', (7, 17))	('PARP', 'Gene', '142', (33, 37))	('downregulated', 'NegReg', (86, 99))	('Bax', 'Gene', (21, 24))	('upregulated', 'PosReg', (42, 53))	('PARP', 'Gene', (33, 37))
37676	29328386	Notably, the PX-12-treated rats had a lower cancerization rate (3/8) than the rats in the disease-control group (7/8) (Fig.	('rats', 'Species', '10116', (78, 82))	('lower', 'NegReg', (38, 43))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('rats', 'Species', '10116', (27, 31))	('rat', 'Species', '10116', (78, 81))	('rat', 'Species', '10116', (27, 30))	('rat', 'Species', '10116', (58, 61))	('PX-12-treated', 'Var', (13, 26))	('PX-12', 'Chemical', 'MESH:C412893', (13, 18))
37677	29328386	In addition, the weights of the rats in the PX-12 treatment group (417.63+-13.22 g) were higher than those of the rats in the disease-control group (356.38+-19.56 g) (P<0.05) (Fig.	('weights', 'CPA', (17, 24))	('higher', 'PosReg', (89, 95))	('rats', 'Species', '10116', (32, 36))	('rats', 'Species', '10116', (114, 118))	('PX-12', 'Var', (44, 49))	('PX-12', 'Chemical', 'MESH:C412893', (44, 49))
37702	29328386	In general, by comparing the gross weight and cancerization rate, the rats treated with PX-12 were in a better condition than the disease controls when exposed to the same carcinogen.	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('rat', 'Species', '10116', (70, 73))	('cancer', 'Disease', (46, 52))	('rat', 'Species', '10116', (60, 63))	('PX-12', 'Chemical', 'MESH:C412893', (88, 93))	('rats', 'Species', '10116', (70, 74))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('PX-12', 'Var', (88, 93))
37704	29328386	The results suggested that the inhibition of Trx-1 may provide a promising chemoprevention strategy with which to interrupt oral malignant transformation.	('Trx-1', 'Gene', (45, 50))	('inhibition', 'Var', (31, 41))	('rat', 'Species', '10116', (93, 96))	('oral', 'Disease', (124, 128))
37825	29292031	The extracted data included samples from three cancer tissues: (1) lung, (2) breast, comprising five biomarker types (EGFR, CK17, CK5/6, ER, and HER2), and (3) bladder with four biomarker types (CK14, GATA3, S0084, and S100P).	('HER2', 'Gene', (145, 149))	('S0084', 'Var', (208, 213))	('S100P', 'Var', (219, 224))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('HER2', 'Gene', '2064', (145, 149))	('CK14', 'Gene', '3861', (195, 199))	('GATA3', 'Gene', (201, 206))	('cancer', 'Disease', (47, 53))	('CK5/6', 'Gene', '3852', (130, 135))	('EGFR', 'Gene', '1956', (118, 122))	('EGFR', 'Gene', (118, 122))	('GATA3', 'Gene', '2625', (201, 206))	('CK17', 'Gene', '3872', (124, 128))	('CK17', 'Gene', (124, 128))	('CK5/6', 'Gene', (130, 135))	('S100P', 'SUBSTITUTION', 'None', (219, 224))	('CK14', 'Gene', (195, 199))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))
37827	29292031	The remaining datasets (BladderBiomarkers, BreastBiomarkers, BladderScores, and BreastScores) are stained by IHC markers including different polyclonal antiserums such as CK14, GATA3, S0084, S100P, EGFR, CK17, CK5/6, ER, and HER2 for their related proteins which play critical roles in tumor progression.	('CK17', 'Gene', '3872', (204, 208))	('CK17', 'Gene', (204, 208))	('CK5/6', 'Gene', '3852', (210, 215))	('S100P', 'SUBSTITUTION', 'None', (191, 196))	('HER2', 'Gene', (225, 229))	('tumor', 'Phenotype', 'HP:0002664', (286, 291))	('tumor', 'Disease', (286, 291))	('CK5/6', 'Gene', (210, 215))	('HER2', 'Gene', '2064', (225, 229))	('CK14', 'Gene', '3861', (171, 175))	('GATA3', 'Gene', (177, 182))	('GATA3', 'Gene', '2625', (177, 182))	('EGFR', 'Gene', '1956', (198, 202))	('S100P', 'Var', (191, 196))	('CK14', 'Gene', (171, 175))	('EGFR', 'Gene', (198, 202))	('tumor', 'Disease', 'MESH:D009369', (286, 291))
37849	29292031	The Log-loss or cross entropy which is defined as  where p(j x) is the probability estimated by the method for example x and class j, and t(j x) is the true probability of class j for x .	('Log-loss', 'Var', (4, 12))	('cross entropy', 'Disease', (16, 29))	('cross entropy', 'Disease', 'MESH:C537866', (16, 29))
37857	29292031	Closer look at the Inception-V1 result of bladder cancer (99%) shows S0084 and S100P were misclassified with GATA3 and S0084, respectively, in two cases out of 200 cases.	('S100P', 'Var', (79, 84))	('bladder cancer', 'Phenotype', 'HP:0009725', (42, 56))	('S0084', 'Var', (119, 124))	('GATA3', 'Gene', (109, 114))	('S100P', 'SUBSTITUTION', 'None', (79, 84))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('S0084', 'Var', (69, 74))	('bladder cancer', 'Disease', 'MESH:D001749', (42, 56))	('bladder cancer', 'Disease', (42, 56))	('GATA3', 'Gene', '2625', (109, 114))
37865	29292031	class score 0 contains GATA3-score 0, CK14-score 0, S100P-score 0, and S0084-score 0).	('S0084-score 0', 'Var', (71, 84))	('S100P', 'Var', (52, 57))	('GATA3', 'Gene', (23, 28))	('CK14', 'Gene', '3861', (38, 42))	('GATA3', 'Gene', '2625', (23, 28))	('S100P', 'SUBSTITUTION', 'None', (52, 57))	('CK14', 'Gene', (38, 42))
37866	29292031	Consequently, S0084 marker had the minimum cases of misclassification in bladder cancer.	('bladder cancer', 'Disease', (73, 87))	('S0084 marker', 'Var', (14, 26))	('bladder cancer', 'Phenotype', 'HP:0009725', (73, 87))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('bladder cancer', 'Disease', 'MESH:D001749', (73, 87))
37888	29292031	The results show that although the colors space for different images have different distributions, our CNN_Smoothie method can successfully identify and register tumor variations and discriminate them consistently and robustly (Fig.	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('tumor', 'Disease', (162, 167))	('variations', 'Var', (168, 178))	('tumor', 'Disease', 'MESH:D009369', (162, 167))
37929	25506701	For the PTV, the values of D98% and D2% (dose received by 98%, and 2% of the target volume) were defined as metrics for minimum and maximum doses.	('D2%', 'Var', (36, 39))	('D98%', 'Var', (27, 31))	('PTV', 'Chemical', '-', (8, 11))
37948	25506701	Because of these changes, from 270  to 0  and 90  to 179.9  in CW, HFQ-VMAT plans may improve efficiency in PTV coverage and brain sparing due to its elliptical annular target volume of squamous cell carcinoma of the scalp; While in HFF-VMAT plans, it would irradiate more healthy tissue (such as brain) in order to irradiate target volume than in HFQ-VMAT plans.	('squamous cell carcinoma of the scalp', 'Disease', 'MESH:D002294', (186, 222))	('squamous cell carcinoma of the scalp', 'Disease', (186, 222))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (186, 209))	('carcinoma', 'Phenotype', 'HP:0030731', (200, 209))	('improve', 'PosReg', (86, 93))	('PTV', 'Chemical', '-', (108, 111))	('changes', 'Var', (17, 24))	('HFF-VMAT plans', 'Disease', 'None', (233, 247))	('HFF-VMAT plans', 'Disease', (233, 247))	('brain sparing', 'CPA', (125, 138))
37966	31762809	Generally, the epigenetic related ncRNAs can be simply separated into two main categories by their size: those with nucleotides less than 30 nts are short ncRNAs, such as microRNAs (miRNAs), piwi-interacting RNAs (piRNAs), and short interfering RNAs (siRNAs), while those longer than 200 nts belong to long ncRNAs (lncRNAs).	('piwi', 'Gene', (191, 195))	('nucleotides less', 'Var', (116, 132))	('piwi', 'Gene', '9271', (191, 195))
38001	31762809	Recent studies have investigated the association between lncRNA BCAR4 and human cancers, and the results show that high expression of BCAR4 indicates aggressiveness and poor prognosis in various carcinomas, including osteosarcoma, breast cancer, non-small cell lung cancer (NSCLC), gastric cancer, prostate cancer, colorectal cancer, and cervical cancer.	('BCAR4', 'Gene', (134, 139))	('prostate cancer', 'Phenotype', 'HP:0012125', (298, 313))	('cancers', 'Disease', 'MESH:D009369', (80, 87))	('gastric cancer', 'Phenotype', 'HP:0012126', (282, 296))	('BCAR4', 'Gene', (64, 69))	('prostate cancer', 'Disease', (298, 313))	('osteosarcoma', 'Phenotype', 'HP:0002669', (217, 229))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (250, 272))	('colorectal cancer', 'Phenotype', 'HP:0003003', (315, 332))	('carcinomas', 'Disease', (195, 205))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (246, 272))	('BCAR4', 'Gene', '400500', (64, 69))	('BCAR4', 'Gene', '400500', (134, 139))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('gastric cancer', 'Disease', (282, 296))	('cervical cancer', 'Disease', 'MESH:D002583', (338, 353))	('NSCLC', 'Disease', 'MESH:D002289', (274, 279))	('cancers', 'Phenotype', 'HP:0002664', (80, 87))	('cervical cancer', 'Disease', (338, 353))	('sarcoma', 'Phenotype', 'HP:0100242', (222, 229))	('aggressiveness', 'Disease', (150, 164))	('osteosarcoma', 'Disease', (217, 229))	('cancers', 'Disease', (80, 87))	('aggressiveness', 'Phenotype', 'HP:0000718', (150, 164))	('lung cancer', 'Phenotype', 'HP:0100526', (261, 272))	('osteosarcoma', 'Disease', 'MESH:D012516', (217, 229))	('non-small cell lung cancer', 'Disease', (246, 272))	('breast cancer', 'Disease', 'MESH:D001943', (231, 244))	('colorectal cancer', 'Disease', 'MESH:D015179', (315, 332))	('carcinoma', 'Phenotype', 'HP:0030731', (195, 204))	('NSCLC', 'Disease', (274, 279))	('aggressiveness', 'Disease', 'MESH:D001523', (150, 164))	('breast cancer', 'Phenotype', 'HP:0003002', (231, 244))	('carcinomas', 'Phenotype', 'HP:0030731', (195, 205))	('gastric cancer', 'Disease', 'MESH:D013274', (282, 296))	('carcinomas', 'Disease', 'MESH:D002277', (195, 205))	('breast cancer', 'Disease', (231, 244))	('high', 'Var', (115, 119))	('colorectal cancer', 'Disease', (315, 332))	('cancer', 'Phenotype', 'HP:0002664', (307, 313))	('cancer', 'Phenotype', 'HP:0002664', (266, 272))	('human', 'Species', '9606', (74, 79))	('cancer', 'Phenotype', 'HP:0002664', (290, 296))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (246, 272))	('prostate cancer', 'Disease', 'MESH:D011471', (298, 313))
38016	31762809	Co-expression of BCAR4 and low level of ERBB2 occurs frequently and indicate a worse PFS outcome for breast cancer patients undergoing tamoxifen resistance.	('patients', 'Species', '9606', (115, 123))	('ERBB2', 'Gene', '2064', (40, 45))	('ERBB2', 'Gene', (40, 45))	('BCAR4', 'Gene', (17, 22))	('BCAR4', 'Gene', '400500', (17, 22))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('Co-expression', 'Var', (0, 13))	('breast cancer', 'Disease', 'MESH:D001943', (101, 114))	('breast cancer', 'Disease', (101, 114))	('tamoxifen', 'Chemical', 'MESH:D013629', (135, 144))	('breast cancer', 'Phenotype', 'HP:0003002', (101, 114))
38018	31762809	Whereas BCAR4 knockdown could significantly suppress tumor cell proliferation, invasion and metastasis, as well as induce cell cycle arrest and increase apoptosis in NSCLC and cervical cancer.	('BCAR4', 'Gene', (8, 13))	('cell cycle arrest', 'CPA', (122, 139))	('BCAR4', 'Gene', '400500', (8, 13))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('NSCLC', 'Disease', (166, 171))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('suppress', 'NegReg', (44, 52))	('tumor', 'Disease', (53, 58))	('induce', 'PosReg', (115, 121))	('NSCLC', 'Disease', 'MESH:D002289', (166, 171))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (122, 139))	('knockdown', 'Var', (14, 23))	('increase', 'PosReg', (144, 152))	('apoptosis', 'CPA', (153, 162))	('cervical cancer', 'Disease', (176, 191))	('cervical cancer', 'Disease', 'MESH:D002583', (176, 191))
38020	31762809	Taken together, the results of our comprehensive meta-analysis have demonstrated that BCAR4 expression is strong associated with unfavorable OS outcome and aggressive clinical features including metastasis and progression, suggesting an independent prognostic value for BCAR4 in human cancers and providing some insights for further research.	('BCAR4', 'Gene', (270, 275))	('cancers', 'Disease', (285, 292))	('expression', 'Var', (92, 102))	('BCAR4', 'Gene', '400500', (270, 275))	('unfavorable OS outcome', 'Disease', (129, 151))	('cancer', 'Phenotype', 'HP:0002664', (285, 291))	('human', 'Species', '9606', (279, 284))	('BCAR4', 'Gene', (86, 91))	('BCAR4', 'Gene', '400500', (86, 91))	('metastasis', 'CPA', (195, 205))	('cancers', 'Phenotype', 'HP:0002664', (285, 292))	('cancers', 'Disease', 'MESH:D009369', (285, 292))	('associated', 'Reg', (113, 123))
38039	31575007	Aberrant STAT3 activity has been reported in various human malignancies such as head and neck, liver, breast, brain, kidney, bladder, pancreas, prostate cancers, and leukemias.	('leukemias', 'Phenotype', 'HP:0001909', (166, 175))	('liver', 'Disease', (95, 100))	('pancreas, prostate cancers', 'Disease', 'MESH:D011471', (134, 160))	('breast', 'Disease', 'MESH:D061325', (102, 108))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('breast', 'Disease', (102, 108))	('bladder', 'Disease', (125, 132))	('leukemias', 'Disease', (166, 175))	('Aberrant', 'Var', (0, 8))	('kidney', 'Disease', (117, 123))	('reported', 'Reg', (33, 41))	('brain', 'Disease', (110, 115))	('prostate cancers', 'Phenotype', 'HP:0012125', (144, 160))	('human', 'Species', '9606', (53, 58))	('STAT3', 'Gene', (9, 14))	('malignancies', 'Disease', 'MESH:D009369', (59, 71))	('leukemias', 'Disease', 'MESH:D007938', (166, 175))	('malignancies', 'Disease', (59, 71))	('cancers', 'Phenotype', 'HP:0002664', (153, 160))	('STAT3', 'Gene', '6774', (9, 14))
38040	31575007	STAT3 is phosphorylated at Tyr-705 by upstream kinases (JAKs and Src) in response to extracellular stimulation with cytokines (IL-6 family) and growth factors (EGF, PDGF).	('Tyr-705', 'Var', (27, 34))	('Src', 'Gene', (65, 68))	('STAT3', 'Gene', '6774', (0, 5))	('Src', 'Gene', '6714', (65, 68))	('JAKs', 'Gene', '3716;3717', (56, 60))	('STAT3', 'Gene', (0, 5))	('JAKs', 'Gene', (56, 60))
38041	31575007	Moreover, hyperactivation of STAT3 has been linked with chronic inflammation and malignant transformation and overexpression of STAT3 has been linked with the negative prognosis in human malignancies.	('hyperactivation', 'Var', (10, 25))	('linked', 'Reg', (143, 149))	('human', 'Species', '9606', (181, 186))	('STAT3', 'Gene', '6774', (128, 133))	('STAT3', 'Gene', '6774', (29, 34))	('STAT3', 'Gene', (128, 133))	('inflammation', 'Disease', 'MESH:D007249', (64, 76))	('malignancies', 'Disease', 'MESH:D009369', (187, 199))	('STAT3', 'Gene', (29, 34))	('inflammation', 'Disease', (64, 76))	('malignant transformation', 'CPA', (81, 105))	('linked', 'Reg', (44, 50))	('malignancies', 'Disease', (187, 199))	('overexpression', 'PosReg', (110, 124))
38042	31575007	Collectively, these pieces of evidence suggest, STAT3 as one of the major contributing factors in the initiation and progression of cancer and blockade of STAT3 signaling can be a suitable therapeutic approach to treat human cancers.	('STAT3', 'Gene', (48, 53))	('cancer', 'Disease', (132, 138))	('cancer', 'Disease', 'MESH:D009369', (225, 231))	('human', 'Species', '9606', (219, 224))	('cancers', 'Disease', 'MESH:D009369', (225, 232))	('STAT3', 'Gene', (155, 160))	('cancer', 'Disease', (225, 231))	('cancers', 'Disease', (225, 232))	('blockade', 'Var', (143, 151))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('STAT3', 'Gene', '6774', (48, 53))	('STAT3', 'Gene', '6774', (155, 160))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('cancers', 'Phenotype', 'HP:0002664', (225, 232))
38095	31575007	Phosphorylation of Tyr705 is a critical event in STAT3 dimerization, nuclear localization and binding to specific response elements to induce gene transcription.	('STAT3', 'Gene', (49, 54))	('Tyr705', 'Var', (19, 25))	('induce', 'Reg', (135, 141))	('gene transcription', 'MPA', (142, 160))	('STAT3', 'Gene', '6774', (49, 54))
38102	31575007	We observed the significant reduction in phosphorylation of JAK1 (Tyr1022/1023), JAK2 (Tyr1007/1008), and Src (Tyr416) on treatment with BT in UD SCC2, JMAR, YD-10B cells but not in LN686 cells (Figure 2B).	('Tyr1022/1023', 'Var', (66, 78))	('JAK2', 'Gene', '3717', (81, 85))	('JAK1', 'Gene', (60, 64))	('Src', 'Gene', (106, 109))	('Tyr1007/1008', 'Var', (87, 99))	('phosphorylation', 'MPA', (41, 56))	('Src', 'Gene', '6714', (106, 109))	('JAK1', 'Gene', '3716', (60, 64))	('JAK2', 'Gene', (81, 85))	('SCC2', 'Gene', '25836', (146, 150))	('Tyr416', 'Chemical', 'MESH:C583569', (111, 117))	('SCC2', 'Gene', (146, 150))	('reduction', 'NegReg', (28, 37))	('BT', 'Chemical', 'MESH:C020237', (137, 139))
38124	31575007	We found that the BT-induced apoptosis was suppressed by the Z-DEVD-FMK treatment, thus indicating the significance of caspase-3 activation in regulating apoptosis upon BT treatment (Figure 4D).	('Z-DEVD-FMK', 'Chemical', 'MESH:C110772', (61, 71))	('caspase-3', 'Gene', '836', (119, 128))	('BT', 'Chemical', 'MESH:C020237', (18, 20))	('BT', 'Chemical', 'MESH:C020237', (169, 171))	('caspase-3', 'Gene', (119, 128))	('Z-DEVD-FMK', 'Var', (61, 71))	('suppressed', 'NegReg', (43, 53))
38131	31575007	The docking results presented that the hydroxyl group of BT is involved in the formation of a hydrogen bond with Asn647 of SH2 domain.	('Asn647', 'Chemical', 'MESH:D004061', (113, 119))	('involved', 'Reg', (63, 71))	('hydrogen bond', 'MPA', (94, 107))	('BT', 'Chemical', 'MESH:C020237', (57, 59))	('SH2', 'Gene', (123, 126))	('Asn647', 'Var', (113, 119))	('hydroxyl', 'Chemical', 'MESH:D017665', (39, 47))	('hydrogen', 'Chemical', 'MESH:D006859', (94, 102))
38132	31575007	The diester sidechain of BT was visualized to be sandwiched between Tyr640 and Phe710 (Figure 5B).	('BT', 'Chemical', 'MESH:C020237', (25, 27))	('Tyr640', 'Var', (68, 74))	('Phe710', 'Chemical', 'MESH:C000588640', (79, 85))	('Phe710', 'Var', (79, 85))
38135	31575007	In an unstimulated cell, STAT3 remains in the cytoplasm in the unphosphorylated form and upon activation, STAT3 monomer can be phosphorylated at Tyr705 followed by its dimerization with another phosphorylated monomer to translocate into the nucleus.	('Tyr705', 'Var', (145, 151))	('STAT3', 'Gene', (25, 30))	('translocate', 'MPA', (220, 231))	('STAT3', 'Gene', '6774', (106, 111))	('STAT3', 'Gene', (106, 111))	('dimerization', 'MPA', (168, 180))	('STAT3', 'Gene', '6774', (25, 30))
38145	31575007	LN686, Tu167, JMAR, and FaDu cells displayed relatively high response rate with IC50 values less than 20 nM, while the others ranged between 21 to 38 nM with a relatively moderate response to BT treatment.	('BT', 'Chemical', 'MESH:C020237', (192, 194))	('IC50 values', 'MPA', (80, 91))	('LN686', 'Var', (0, 5))
38150	31575007	Interestingly, our results suggested that this quassinoid BT inhibited the phosphorylation of JAK1 (Tyr1022/1023), JAK2 (Tyr1007/1008), Src (Tyr416) and STAT3 (Tyr705) indicating BT could inhibit STAT3 via modulating several upstream kinases.	('JAK2', 'Gene', (115, 119))	('Tyr416', 'Var', (141, 147))	('inhibited', 'NegReg', (61, 70))	('JAK1', 'Gene', '3716', (94, 98))	('STAT3', 'Gene', '6774', (153, 158))	('Src', 'Gene', (136, 139))	('Tyr1007/1008', 'Var', (121, 133))	('inhibit', 'NegReg', (188, 195))	('Src', 'Gene', '6714', (136, 139))	('JAK1', 'Gene', (94, 98))	('BT', 'Chemical', 'MESH:C020237', (58, 60))	('STAT3', 'Gene', (196, 201))	('BT', 'Chemical', 'MESH:C020237', (179, 181))	('modulating', 'Reg', (206, 216))	('Tyr705', 'Var', (160, 166))	('Tyr416', 'Chemical', 'MESH:C583569', (141, 147))	('JAK2', 'Gene', '3717', (115, 119))	('STAT3', 'Gene', '6774', (196, 201))	('phosphorylation', 'MPA', (75, 90))	('STAT3', 'Gene', (153, 158))	('Tyr1022/1023', 'Var', (100, 112))
38155	31575007	Previous studies also suggest that the inhibition of STAT3 signaling can regulate apoptosis in tumor cells.	('inhibition', 'Var', (39, 49))	('STAT3', 'Gene', '6774', (53, 58))	('apoptosis', 'CPA', (82, 91))	('STAT3', 'Gene', (53, 58))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('regulate', 'Reg', (73, 81))	('tumor', 'Disease', (95, 100))
38169	31575007	Interestingly, BT downregulated the protein expression of Bcl-2, Bcl-xl, survivin, COX-2, VEGF, cyclin D1, and cyclin E. Overall, aberrant activity STAT3 have been described as a contributing factor for the formation of a tumor, chemoresistance, and poor prognosis in HNSCC.	('chemoresistance', 'CPA', (229, 244))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('BT', 'Chemical', 'MESH:C020237', (15, 17))	('cyclin', 'Gene', (96, 102))	('cyclin', 'Gene', (111, 117))	('cyclin D1', 'Gene', (96, 105))	('STAT3', 'Gene', (148, 153))	('VEGF', 'Gene', '7422', (90, 94))	('cyclin D1', 'Gene', '595', (96, 105))	('COX-2', 'Gene', (83, 88))	('Bcl-2', 'Gene', (58, 63))	('STAT3', 'Gene', '6774', (148, 153))	('VEGF', 'Gene', (90, 94))	('HNSCC', 'Disease', (268, 273))	('aberrant activity', 'Var', (130, 147))	('tumor', 'Disease', (222, 227))	('COX-2', 'Gene', '4513', (83, 88))	('Bcl-2', 'Gene', '596', (58, 63))	('HNSCC', 'Phenotype', 'HP:0012288', (268, 273))	('tumor', 'Disease', 'MESH:D009369', (222, 227))	('Bcl-xl', 'Gene', '598', (65, 71))	('cyclin', 'Gene', '5111', (96, 102))	('cyclin', 'Gene', '5111', (111, 117))	('Bcl-xl', 'Gene', (65, 71))
38231	30522463	Figure 4 (c and d) depicts ROC curve for MPE Hsp90-beta and displays an AUC of 0.839 with a standard error of 0.0468 (Z value = 7.258; P < 0.0001).	('Hsp90-beta', 'Gene', '3326', (45, 55))	('MPE', 'Var', (41, 44))	('Hsp90-beta', 'Gene', (45, 55))
38237	30522463	Previously, we found that Hsp90-beta was higher in H446 cells (1.72 times) and A549 cells (2.19 times) than 16-HBE cells and that increase of Hsp90-beta correlated with postoperative survival time and lymph node metastasis of lung cancer patients.	('Hsp90-beta', 'Gene', '3326', (26, 36))	('16-HBE', 'CellLine', 'CVCL:0112', (108, 114))	('Hsp90-beta', 'Gene', (142, 152))	('A549', 'CellLine', 'CVCL:0023', (79, 83))	('lung cancer', 'Phenotype', 'HP:0100526', (226, 237))	('H446', 'Var', (51, 55))	('Hsp90-beta', 'Gene', (26, 36))	('metastasis of lung cancer', 'Disease', 'MESH:D009362', (212, 237))	('higher', 'PosReg', (41, 47))	('increase', 'PosReg', (130, 138))	('Hsp90-beta', 'Gene', '3326', (142, 152))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('metastasis of lung cancer', 'Disease', (212, 237))	('patients', 'Species', '9606', (238, 246))	('H446', 'CellLine', 'CVCL:1562', (51, 55))
38248	30522463	The chaperone activity of Hsp90 is affected by Mg/ATP.	('chaperone activity', 'MPA', (4, 22))	('Mg/ATP', 'Var', (47, 53))	('Mg', 'Chemical', 'MESH:D008274', (47, 49))	('Hsp90', 'Gene', (26, 31))	('ATP', 'Chemical', 'MESH:D000255', (50, 53))	('Hsp90', 'Gene', '3320', (26, 31))
38261	30522463	Our investigation showed over-expression of MPE Hsp90-beta significantly correlated with malignant biological behavior of lung cancer of lung cancer patients, indicating that the high level of Hsp90-beta is not only closely related to the development of pleural effusion, but also a risk factor for the progression of lung cancer.	('behavior of lung cancer of lung cancer', 'Disease', (110, 148))	('lung cancer', 'Disease', (318, 329))	('pleural effusion', 'Disease', (254, 270))	('Hsp90-beta', 'Gene', '3326', (48, 58))	('lung cancer', 'Disease', 'MESH:D008175', (137, 148))	('lung cancer', 'Disease', 'MESH:D008175', (122, 133))	('patients', 'Species', '9606', (149, 157))	('pleural effusion', 'Disease', 'MESH:D010996', (254, 270))	('lung cancer', 'Phenotype', 'HP:0100526', (122, 133))	('lung cancer', 'Phenotype', 'HP:0100526', (137, 148))	('lung cancer', 'Disease', 'MESH:D008175', (318, 329))	('over-expression', 'PosReg', (25, 40))	('lung cancer', 'Phenotype', 'HP:0100526', (318, 329))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('correlated', 'Reg', (73, 83))	('pleural effusion', 'Phenotype', 'HP:0002202', (254, 270))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('high', 'Var', (179, 183))	('related', 'Reg', (224, 231))	('Hsp90-beta', 'Gene', (193, 203))	('cancer', 'Phenotype', 'HP:0002664', (323, 329))	('Hsp90-beta', 'Gene', '3326', (193, 203))	('Hsp90-beta', 'Gene', (48, 58))	('behavior of lung cancer of lung cancer', 'Disease', 'MESH:D008175', (110, 148))
38262	30522463	A study claims that overall survival rate of lung cancer patients with high Hsp90-beta expression is lower than that of patients with low Hsp90-beta expression, suggesting that Hsp90-beta is an independent prognostic factor for lung cancer.	('lung cancer', 'Disease', 'MESH:D008175', (45, 56))	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('Hsp90-beta', 'Gene', (138, 148))	('high', 'Var', (71, 75))	('patients', 'Species', '9606', (57, 65))	('Hsp90-beta', 'Gene', (177, 187))	('lung cancer', 'Disease', 'MESH:D008175', (228, 239))	('lung cancer', 'Disease', (45, 56))	('lung cancer', 'Phenotype', 'HP:0100526', (45, 56))	('lower', 'NegReg', (101, 106))	('Hsp90-beta', 'Gene', '3326', (76, 86))	('patients', 'Species', '9606', (120, 128))	('Hsp90-beta', 'Gene', '3326', (138, 148))	('lung cancer', 'Phenotype', 'HP:0100526', (228, 239))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('lung cancer', 'Disease', (228, 239))	('Hsp90-beta', 'Gene', '3326', (177, 187))	('Hsp90-beta', 'Gene', (76, 86))
38267	30522463	Using the ROC curve analysis, we obtained that the diagnostic threshold of Hsp90-beta in MPE was 1.659 ng/mL (1.228 ng/mL in serum).	('Hsp90-beta', 'Gene', '3326', (75, 85))	('Hsp90-beta', 'Gene', (75, 85))	('1.659 ng/mL', 'Var', (97, 108))
38308	29854808	One recent study in small cell lung cancer also demonstrated that osteopontin increased chemoresistance to cisplatin in SBC-3 cells by suppressing bcl-2 protein downregulation.	('osteopontin', 'Var', (66, 77))	('small cell lung cancer', 'Disease', (20, 42))	('chemoresistance', 'CPA', (88, 103))	('bcl-2', 'Gene', (147, 152))	('lung cancer', 'Phenotype', 'HP:0100526', (31, 42))	('increased', 'PosReg', (78, 87))	('small cell lung cancer', 'Disease', 'MESH:D055752', (20, 42))	('bcl-2', 'Gene', '596', (147, 152))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (20, 42))	('suppressing', 'NegReg', (135, 146))
38311	29854808	Furthermore, inhibition of osteopontin can sensitize esophageal cancer cells to cisplatin.	('sensitize', 'Reg', (43, 52))	('inhibition', 'Var', (13, 23))	('esophageal cancer', 'Disease', (53, 70))	('osteopontin', 'Protein', (27, 38))	('esophageal cancer', 'Disease', 'MESH:D004938', (53, 70))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
38359	33783864	We found that RFC4 was up-regulated and related to the progression of oral tongue squamous cell carcinoma, and knockdown RFC4 could restrain the proliferation and progression.	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('knockdown', 'Var', (111, 120))	('RFC4', 'Gene', (14, 18))	('related', 'Reg', (40, 47))	('restrain', 'NegReg', (132, 140))	('oral tongue squamous cell carcinoma', 'Disease', 'MESH:D002294', (70, 105))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (82, 105))	('tongue squamous cell carcinoma', 'Phenotype', 'HP:0030413', (75, 105))	('proliferation', 'CPA', (145, 158))	('RFC4', 'Gene', (121, 125))	('up-regulated', 'PosReg', (23, 35))	('progression', 'CPA', (163, 174))	('oral tongue squamous cell carcinoma', 'Disease', (70, 105))
38368	33783864	The mRNA expression of RFC4 in CAL27 and TCA8113 cells transfected with RFC4 shRNA.	('RFC4', 'Gene', (23, 27))	('TCA8113', 'Chemical', '-', (41, 48))	('mRNA expression', 'MPA', (4, 19))	('RFC4', 'Var', (72, 76))
38369	33783864	The protein expression of RFC4 in CAL27 and TCA8113 cells transfected with RFC4 shRNA.	('RFC4', 'Var', (75, 79))	('RFC4', 'Gene', (26, 30))	('protein expression', 'MPA', (4, 22))	('TCA8113', 'Chemical', '-', (44, 51))
38373	33783864	A, B. CAL27 cell transfected with RFC4 shRNA was transplanted subcutaneously in nude mice, the tumor volume was measured with a caliper.	('nude mice', 'Species', '10090', (80, 89))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('RFC4', 'Var', (34, 38))	('tumor', 'Disease', (95, 100))
38386	33783864	7  The dysregulation of RFC4 was associated with many diseases, such as Homologous DNA Pairing and Strand Exchange and Gastric Cancer, the role in the diagnosis and progression of various cancers.	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('Homologous DNA Pairing', 'Disease', (72, 94))	('RFC4', 'Gene', (24, 28))	('cancers', 'Phenotype', 'HP:0002664', (188, 195))	('Strand Exchange', 'Disease', (99, 114))	('Gastric Cancer', 'Phenotype', 'HP:0012126', (119, 133))	('cancers', 'Disease', (188, 195))	('Cancer', 'Phenotype', 'HP:0002664', (127, 133))	('Gastric Cancer', 'Disease', (119, 133))	('dysregulation', 'Var', (7, 20))	('associated', 'Reg', (33, 43))	('Gastric Cancer', 'Disease', 'MESH:D013274', (119, 133))	('cancers', 'Disease', 'MESH:D009369', (188, 195))
38390	33783864	10  All above researches implied that RFC4 was an essential factor, and it was associated with the progression of various cancers.	('associated with', 'Reg', (79, 94))	('cancers', 'Disease', 'MESH:D009369', (122, 129))	('cancers', 'Phenotype', 'HP:0002664', (122, 129))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('cancers', 'Disease', (122, 129))	('RFC4', 'Var', (38, 42))
38426	33783864	To further identify the role of RFC4 in the progression and proliferation of oral tongue squamous cell carcinoma, we knockdown the expression of RFC4 via transfecting oral tongue squamous cell carcinoma CAL27 and TCA8113 cells with RFC4 shRNA.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (179, 202))	('oral tongue squamous cell carcinoma', 'Disease', (77, 112))	('tongue squamous cell carcinoma', 'Phenotype', 'HP:0030413', (82, 112))	('oral tongue squamous cell carcinoma', 'Disease', (167, 202))	('carcinoma', 'Phenotype', 'HP:0030731', (193, 202))	('RFC4', 'Gene', (145, 149))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (89, 112))	('tongue squamous cell carcinoma', 'Phenotype', 'HP:0030413', (172, 202))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('oral tongue squamous cell carcinoma', 'Disease', 'MESH:D002294', (77, 112))	('oral tongue squamous cell carcinoma', 'Disease', 'MESH:D002294', (167, 202))	('TCA8113', 'Chemical', '-', (213, 220))	('knockdown', 'Var', (117, 126))
38429	33783864	The results of CCK-8 assay showed that the proliferation ability of CAL27 and TCA8113 cells was significantly restrained in RFC4 knockdown group compared with the control group (Figure 3C).	('CAL27', 'CPA', (68, 73))	('restrained', 'NegReg', (110, 120))	('CCK-8', 'Chemical', 'MESH:D012844', (15, 20))	('knockdown', 'Var', (129, 138))	('RFC4', 'Gene', (124, 128))	('TCA8113', 'Chemical', '-', (78, 85))	('TCA8113 cells', 'CPA', (78, 91))	('proliferation ability', 'CPA', (43, 64))
38433	33783864	After 25 days of planting cells, we removed these tumors from mice, and we found that the volume of tumors of CAL27 and TCA8113 cells transfected with RFC4 shRNA was restrained obviously compared with the control group (Figure 4A).	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('mice', 'Species', '10090', (62, 66))	('tumors', 'Disease', (100, 106))	('restrained', 'NegReg', (166, 176))	('RFC4 shRNA', 'Var', (151, 161))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('volume', 'CPA', (90, 96))	('TCA8113', 'Chemical', '-', (120, 127))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('tumors', 'Disease', (50, 56))
38434	33783864	And the growth curve of tumors showed that the growth rate of these tumors with RFC4 shRNA group was significantly inhibited than the control group (Figure 4B).	('growth rate', 'CPA', (47, 58))	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumors', 'Disease', (68, 74))	('tumors', 'Disease', (24, 30))	('tumors', 'Disease', 'MESH:D009369', (24, 30))	('tumors', 'Disease', 'MESH:D009369', (68, 74))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('RFC4 shRNA', 'Var', (80, 90))	('inhibited', 'NegReg', (115, 124))
38444	33783864	To explore the relationship between RFC4 and the clinical pathology of oral tongue squamous cell carcinoma, we divided these patients into high and low groups based on the staining intensity of RFC4, and we found that RFC4 was associated with TNM stage.	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('TNM', 'Gene', (243, 246))	('oral tongue squamous cell carcinoma', 'Disease', (71, 106))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (83, 106))	('associated', 'Reg', (227, 237))	('RFC4', 'Var', (218, 222))	('oral tongue squamous cell carcinoma', 'Disease', 'MESH:D002294', (71, 106))	('TNM', 'Gene', '10178', (243, 246))	('tongue squamous cell carcinoma', 'Phenotype', 'HP:0030413', (76, 106))	('patients', 'Species', '9606', (125, 133))
38449	33783864	To explore the possibility of targeting RFC4 for oral tongue squamous cell carcinoma, we knockdown RFC4 and observed the change of proliferation and growth in vitro and vivo.	('oral tongue squamous cell carcinoma', 'Disease', (49, 84))	('RFC4', 'Gene', (99, 103))	('growth', 'CPA', (149, 155))	('oral tongue squamous cell carcinoma', 'Disease', 'MESH:D002294', (49, 84))	('proliferation', 'CPA', (131, 144))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (61, 84))	('tongue squamous cell carcinoma', 'Phenotype', 'HP:0030413', (54, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('change', 'Reg', (121, 127))	('knockdown', 'Var', (89, 98))
38451	33783864	Szymanska Z et al identified that RFC4 was highly expressed throughout the cell circle process of proliferating cells, and tumor proliferation in situ will become slow with the development of the disease, 19  which might be the reason why RFC4 would promote the proliferation of oral tongue squamous cell carcinoma.	('promote', 'PosReg', (250, 257))	('tumor', 'Disease', (123, 128))	('RFC4', 'Gene', (34, 38))	('proliferation', 'CPA', (262, 275))	('tongue squamous cell carcinoma', 'Phenotype', 'HP:0030413', (284, 314))	('oral tongue squamous cell carcinoma', 'Disease', 'MESH:D002294', (279, 314))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (291, 314))	('RFC4', 'Var', (239, 243))	('carcinoma', 'Phenotype', 'HP:0030731', (305, 314))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('oral tongue squamous cell carcinoma', 'Disease', (279, 314))
38452	33783864	Fatima A et al identified that RFC4 was an independent predictor of overall survival in breast cancer.	('RFC4', 'Var', (31, 35))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('overall', 'MPA', (68, 75))	('breast cancer', 'Disease', (88, 101))	('breast cancer', 'Disease', 'MESH:D001943', (88, 101))	('breast cancer', 'Phenotype', 'HP:0003002', (88, 101))
38453	33783864	21  We have enough reasons to predict that RFC4 was also an independent predictor for oral tongue squamous cell carcinoma, and targeting RFC4 was a potential treatment strategy for lots of patients with oral tongue squamous cell carcinoma.	('RFC4', 'Gene', (137, 141))	('tongue squamous cell carcinoma', 'Phenotype', 'HP:0030413', (208, 238))	('tongue squamous cell carcinoma', 'Phenotype', 'HP:0030413', (91, 121))	('oral tongue squamous cell carcinoma', 'Disease', 'MESH:D002294', (86, 121))	('targeting', 'Var', (127, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (229, 238))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (215, 238))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (98, 121))	('oral tongue squamous cell carcinoma', 'Disease', (203, 238))	('patients', 'Species', '9606', (189, 197))	('oral tongue squamous cell carcinoma', 'Disease', (86, 121))	('oral tongue squamous cell carcinoma', 'Disease', 'MESH:D002294', (203, 238))
38454	33783864	In summary, we preliminarily determine that RFC4 promotes the proliferation in vitro and growth in vivo, and RFC4 might be used as a diagnosis-related biomarker and a potential treatment strategy for oral tongue squamous cell carcinoma.	('oral tongue squamous cell carcinoma', 'Disease', (200, 235))	('tongue squamous cell carcinoma', 'Phenotype', 'HP:0030413', (205, 235))	('proliferation', 'CPA', (62, 75))	('oral tongue squamous cell carcinoma', 'Disease', 'MESH:D002294', (200, 235))	('promotes', 'PosReg', (49, 57))	('RFC4', 'Var', (109, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (226, 235))	('RFC4', 'Gene', (44, 48))	('growth', 'CPA', (89, 95))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (212, 235))
38461	32985499	Actionable mutations are enriched in C1 and C2, patients in C3 have a significantly longer overall survival, and C1 and C2 exhibit T-cell inflamed microenvironments.	('mutations', 'Var', (11, 20))	('overall', 'MPA', (91, 98))	('patients', 'Species', '9606', (48, 56))	('longer', 'PosReg', (84, 90))
38468	32985499	Targetable mutations in MET causing exon 14 skipping have been identified in PSC, providing a new treatment option, although present in a minority of cases.	('mutations', 'Var', (11, 20))	('MET', 'Gene', '79811', (24, 27))	('skipping', 'NegReg', (44, 52))	('PSC', 'Disease', (77, 80))	('MET', 'Gene', (24, 27))
38491	32985499	A total of 79% (44/56) of the patients harbored 48 mutations in TP53, and 19% of the mutations were truncation mutations leading to the inactivation of TP53.	('mutations', 'Var', (51, 60))	('TP53', 'Gene', '7157', (152, 156))	('patients', 'Species', '9606', (30, 38))	('TP53', 'Gene', (152, 156))	('inactivation', 'MPA', (136, 148))	('TP53', 'Gene', (64, 68))	('TP53', 'Gene', '7157', (64, 68))
38492	32985499	A total of 57% of the patients harbored mutations in genes of the receptor tyrosine kinase (RTK)/RAS pathway: EGFR (16%), KRAS (14%), MET (13%), BRAF (7%), NF1 (5%), and NRAS (4%); the mutations of the genes were mutually exclusive (P = 0.00065, Monte Carlo simulation).	('NRAS', 'Gene', (170, 174))	('NF1', 'Gene', (156, 159))	('MET', 'Gene', '79811', (134, 137))	('BRAF', 'Gene', (145, 149))	('MET', 'Gene', (134, 137))	('RTK', 'Gene', '5979', (92, 95))	('EGFR', 'Gene', (110, 114))	('NF1', 'Gene', '4763', (156, 159))	('receptor tyrosine kinase', 'Gene', (66, 90))	('EGFR', 'Gene', '1956', (110, 114))	('patients', 'Species', '9606', (22, 30))	('receptor tyrosine kinase', 'Gene', '5979', (66, 90))	('NRAS', 'Gene', '4893', (170, 174))	('mutations', 'Var', (40, 49))	('RTK', 'Gene', (92, 95))	('KRAS', 'Gene', (122, 126))	('BRAF', 'Gene', '673', (145, 149))	('KRAS', 'Gene', '3845', (122, 126))
38493	32985499	EGFR was the most frequently mutated oncogene in the RTK/RAS pathway, and eight out of nine EGFR mutations were common and targetable mutations, including exon 19 deletions and exon 21 L858R.	('mutations', 'Var', (97, 106))	('RTK', 'Gene', '5979', (53, 56))	('exon 21 L858R', 'Var', (177, 190))	('EGFR', 'Gene', (0, 4))	('L858R', 'Var', (185, 190))	('L858R', 'Mutation', 'rs121434568', (185, 190))	('RTK', 'Gene', (53, 56))	('EGFR', 'Gene', '1956', (92, 96))	('EGFR', 'Gene', (92, 96))	('EGFR', 'Gene', '1956', (0, 4))	('exon 19 deletions', 'Var', (155, 172))
38494	32985499	The rare mutation of EGFR was L861Q, located in the tyrosine kinase domain.	('EGFR', 'Gene', '1956', (21, 25))	('L861Q', 'Mutation', 'rs121913444', (30, 35))	('EGFR', 'Gene', (21, 25))	('L861Q', 'Var', (30, 35))
38495	32985499	14% of the patients, less than conventional lung adenocarcinoma (LUAD), harbored KRAS mutations, which mostly involved codon 12.	('KRAS', 'Gene', '3845', (81, 85))	('mutations', 'Var', (86, 95))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (44, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (54, 63))	('AD', 'Disease', 'MESH:D000544', (67, 69))	('LUAD', 'Phenotype', 'HP:0030078', (65, 69))	('AD', 'Disease', (67, 69))	('lung adenocarcinoma', 'Disease', (44, 63))	('involved', 'Reg', (110, 118))	('KRAS', 'Gene', (81, 85))	('harbored', 'Reg', (72, 80))	('patients', 'Species', '9606', (11, 19))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (44, 63))
38498	32985499	Four patients harbored five BRAF mutations, with one N581S mutation and two V600E mutations.	('V600E', 'Mutation', 'rs113488022', (76, 81))	('BRAF', 'Gene', '673', (28, 32))	('patients', 'Species', '9606', (5, 13))	('N581S', 'Mutation', 'rs121913370', (53, 58))	('V600E', 'Var', (76, 81))	('BRAF', 'Gene', (28, 32))	('N581S', 'Var', (53, 58))
38499	32985499	Three mutations identified in NF1, a suppressor of RAS, were all loss-of-function alterations (frameshift or stop gain variants), thus activating the RTK/RAS pathway.	('RTK', 'Gene', '5979', (150, 153))	('NF1', 'Gene', (30, 33))	('NF1', 'Gene', '4763', (30, 33))	('loss-of-function', 'NegReg', (65, 81))	('frameshift', 'Var', (95, 105))	('RTK', 'Gene', (150, 153))	('activating', 'PosReg', (135, 145))
38500	32985499	A total of 27% of the patients harbored one or more mutations in genes of the phosphatidylinositol 3-kinase (PI3K) pathway: PIK3CA (13%), PTEN (9%), AKT3 (5%), and AKT1 (2%).	('mutations', 'Var', (52, 61))	('AKT1', 'Gene', '207', (164, 168))	('PTEN', 'Gene', (138, 142))	('phosphatidylinositol 3-kinase', 'Gene', '5290', (78, 107))	('PTEN', 'Gene', '5728', (138, 142))	('AKT1', 'Gene', (164, 168))	('patients', 'Species', '9606', (22, 30))	('AKT3', 'Gene', (149, 153))	('phosphatidylinositol 3-kinase', 'Gene', (78, 107))	('PIK3CA', 'Gene', (124, 130))	('AKT3', 'Gene', '10000', (149, 153))	('PIK3CA', 'Gene', '5290', (124, 130))
38501	32985499	Two hotspot mutations of PIK3CA, E542K in the helical domain and H1047R in the kinase domain, were each detected in two patients.	('detected', 'Reg', (104, 112))	('E542K', 'Var', (33, 38))	('H1047R', 'Mutation', 'rs121913279', (65, 71))	('PIK3CA', 'Gene', (25, 31))	('PIK3CA', 'Gene', '5290', (25, 31))	('E542K', 'Mutation', 'rs121913273', (33, 38))	('patients', 'Species', '9606', (120, 128))	('H1047R', 'Var', (65, 71))
38502	32985499	Five of the six PTEN mutations were truncation mutations, resulting in the loss of function of PTEN and activating the PI3K pathway.	('loss of function', 'NegReg', (75, 91))	('PTEN', 'Gene', (16, 20))	('activating', 'PosReg', (104, 114))	('PI3K pathway', 'Pathway', (119, 131))	('PTEN', 'Gene', (95, 99))	('PTEN', 'Gene', '5728', (16, 20))	('PTEN', 'Gene', '5728', (95, 99))	('mutations', 'Var', (21, 30))
38503	32985499	In addition, we identified one oncogenic mutation in AKT1: E17K, a candidate therapeutic target for PSC.	('AKT1', 'Gene', (53, 57))	('E17K', 'Var', (59, 63))	('AKT1', 'Gene', '207', (53, 57))	('E17K', 'Mutation', 'rs121434592', (59, 63))	('PSC', 'Disease', (100, 103))
38504	32985499	Analyses of somatic copy number variations (SCNVs) revealed significant amplifications of 11q13.3 (containing CCND1), 8q24.21 (containing MYC), and 7q31.2 (containing MET) and significant deletions of 9p21.3 (containing CDKN2A) and 13q13.1 (containing RB1) (Fig.	('MET', 'Gene', '79811', (167, 170))	('CCND1', 'Gene', (110, 115))	('MET', 'Gene', (167, 170))	('MYC', 'Gene', (138, 141))	('deletions', 'Var', (188, 197))	('CCND1', 'Gene', '595', (110, 115))	('RB1', 'Gene', (252, 255))	('RB1', 'Gene', '5925', (252, 255))	('CDKN2A', 'Gene', (220, 226))	('MYC', 'Gene', '4609', (138, 141))	('CDKN2A', 'Gene', '1029', (220, 226))
38505	32985499	MET amplifications and/or mutations were found in 20% of patients.	('mutations', 'Var', (26, 35))	('MET', 'Gene', '79811', (0, 3))	('MET', 'Gene', (0, 3))	('patients', 'Species', '9606', (57, 65))
38506	32985499	Similar to other types of lung cancer, amplifications or deletions of genes in the cell-cycle pathway (CCND1, CDKN2A, and RB1) were frequently identified in PSC.	('deletions', 'Var', (57, 66))	('identified', 'Reg', (143, 153))	('CDKN2A', 'Gene', (110, 116))	('RB1', 'Gene', '5925', (122, 125))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('CDKN2A', 'Gene', '1029', (110, 116))	('CCND1', 'Gene', '595', (103, 108))	('lung cancer', 'Disease', 'MESH:D008175', (26, 37))	('PSC', 'Disease', (157, 160))	('cell-cycle pathway', 'Pathway', (83, 101))	('RB1', 'Gene', (122, 125))	('CCND1', 'Gene', (103, 108))	('lung cancer', 'Disease', (26, 37))	('amplifications', 'Var', (39, 53))	('lung cancer', 'Phenotype', 'HP:0100526', (26, 37))
38516	32985499	Mutations of TP53, KRAS, and EGFR were all in the trunk, suggesting they were early events in the carcinogenesis of PSC.	('carcinogenesis', 'Disease', 'MESH:D063646', (98, 112))	('TP53', 'Gene', (13, 17))	('carcinogenesis', 'Disease', (98, 112))	('KRAS', 'Gene', (19, 23))	('KRAS', 'Gene', '3845', (19, 23))	('Mutations', 'Var', (0, 9))	('EGFR', 'Gene', '1956', (29, 33))	('EGFR', 'Gene', (29, 33))	('PSC', 'Disease', (116, 119))	('TP53', 'Gene', '7157', (13, 17))
38548	32985499	Most nonsmokers were in C1, and EGFR mutations were significantly enriched in C1 (P = 0.012, Fisher's exact test).	('mutations', 'Var', (37, 46))	('EGFR', 'Gene', '1956', (32, 36))	('EGFR', 'Gene', (32, 36))
38550	32985499	In total, more than 50% of the patients in this group harbored actionable alterations, suggesting targeted therapy could be a good treatment option for patients in C1.	('harbored', 'Reg', (54, 62))	('patients', 'Species', '9606', (31, 39))	('patients', 'Species', '9606', (152, 160))	('alterations', 'Var', (74, 85))
38557	32985499	In addition, we identified distinct mutation pattern between C2 and C3, as C2 had targetable MET exon 14 skipping mutations and BRAF mutations.	('skipping', 'NegReg', (105, 113))	('MET', 'Gene', '79811', (93, 96))	('mutations', 'Var', (133, 142))	('MET', 'Gene', (93, 96))	('BRAF', 'Gene', '673', (128, 132))	('BRAF', 'Gene', (128, 132))
38571	32985499	The somatic mutations of PSC were enriched in the p53, RTK/RAS, and PI3K pathways, and somatic CNVs were commonly observed in the cell-cycle pathway, which was reminiscent of the genomic alterations reported in conventional NSCLC.	('NSCLC', 'Phenotype', 'HP:0030358', (224, 229))	('cell-cycle pathway', 'Pathway', (130, 148))	('mutations', 'Var', (12, 21))	('PI3K pathways', 'Pathway', (68, 81))	('NSCLC', 'Disease', (224, 229))	('PSC', 'Gene', (25, 28))	('RTK', 'Gene', '5979', (55, 58))	('NSCLC', 'Disease', 'MESH:D002289', (224, 229))	('p53', 'Gene', (50, 53))	('p53', 'Gene', '7157', (50, 53))	('observed', 'Reg', (114, 122))	('RTK', 'Gene', (55, 58))
38572	32985499	TP53 mutations were the most common mutation in our cohort, found in 79% of the patients, which was slightly higher than the frequency of 74% reported by Schrock et al.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('patients', 'Species', '9606', (80, 88))	('mutations', 'Var', (5, 14))
38578	32985499	A total of 16% of the patients harbored EGFR mutations, and 89% of them were common mutations and sensitive to EGFR tyrosine kinase inhibitors (TKIs).	('mutations', 'Var', (45, 54))	('EGFR', 'Gene', '1956', (111, 115))	('harbored', 'Reg', (31, 39))	('patients', 'Species', '9606', (22, 30))	('EGFR', 'Gene', (111, 115))	('EGFR', 'Gene', '1956', (40, 44))	('EGFR', 'Gene', (40, 44))
38579	32985499	The frequency of common EGFR mutations was higher than that reported in studies on the Western population, and was similar to that reported for an Asian cohort, suggesting the ethnic differences.	('EGFR', 'Gene', '1956', (24, 28))	('EGFR', 'Gene', (24, 28))	('mutations', 'Var', (29, 38))
38580	32985499	We identified one rare mutation of EGFR, L861Q, which was less sensitive to EGFR-TKIs.	('L861Q', 'Var', (41, 46))	('EGFR', 'Gene', '1956', (76, 80))	('EGFR', 'Gene', '1956', (35, 39))	('EGFR', 'Gene', (35, 39))	('EGFR', 'Gene', (76, 80))	('L861Q', 'Mutation', 'rs121913444', (41, 46))
38581	32985499	However, patients with an L861Q mutation might benefit from the second generation targeted agent afatinib.	('benefit', 'PosReg', (47, 54))	('patients', 'Species', '9606', (9, 17))	('afatinib', 'Chemical', 'MESH:D000077716', (97, 105))	('L861Q', 'Mutation', 'rs121913444', (26, 31))	('L861Q', 'Var', (26, 31))
38583	32985499	MET exon 14 skipping mutations were previously reported in 0% to 22% of PSC cases, and the highly variable frequencies could be due to the different methodologies and limited sample sizes.	('MET', 'Gene', '79811', (0, 3))	('PSC', 'Disease', (72, 75))	('met', 'Gene', '79811', (149, 152))	('MET', 'Gene', (0, 3))	('met', 'Gene', (149, 152))	('skipping mutations', 'Var', (12, 30))
38584	32985499	We identified MET exon 14 skipping mutations and MET DNA alterations in 11% and 20% of our cohort, respectively, making these patients potential beneficiaries of crizotinib.	('MET', 'Gene', '79811', (49, 52))	('MET', 'Gene', '79811', (14, 17))	('MET', 'Gene', (49, 52))	('MET', 'Gene', (14, 17))	('patients', 'Species', '9606', (126, 134))	('skipping mutations', 'Var', (26, 44))	('crizotinib', 'Chemical', 'MESH:D000077547', (162, 172))
38585	32985499	In addition, we found that 7% of the patients harbored BRAF mutations, including two V600E mutations, which were sensitive to the combined therapy of dabrafenib and trametinib.	('patients', 'Species', '9606', (37, 45))	('dabrafenib', 'Chemical', 'MESH:C561627', (150, 160))	('V600E', 'Mutation', 'rs113488022', (85, 90))	('trametinib', 'Chemical', 'MESH:C560077', (165, 175))	('BRAF', 'Gene', '673', (55, 59))	('V600E', 'Var', (85, 90))	('BRAF', 'Gene', (55, 59))
38586	32985499	In total, 27% of the patients had mutations in the PI3K pathway, suggesting the abnormal activation of downstream elements.	('patients', 'Species', '9606', (21, 29))	('activation', 'PosReg', (89, 99))	('mutations', 'Var', (34, 43))	('PI3K pathway', 'Pathway', (51, 63))
38588	32985499	One of the mutations in the PI3K pathway was the E17K mutation of AKT1, which is an oncogenic mutation and could be a therapeutic target for AZD5363, a pan-AKT kinase inhibitor.	('AZD5363', 'Chemical', 'MESH:C575618', (141, 148))	('E17K', 'Mutation', 'rs121434592', (49, 53))	('AKT1', 'Gene', '207', (66, 70))	('E17K', 'Var', (49, 53))	('AKT1', 'Gene', (66, 70))	('PI3K pathway', 'Pathway', (28, 40))
38592	32985499	Although the conclusion was consistent with that of previous studies, which demonstrated that the epithelial and sarcomatoid components shared the same TP53, KRAS, and EGFR mutations, we provided direct evidence based on global genomic profiles with the largest sample size.	('sarcomatoid components', 'Disease', 'MESH:C538614', (113, 135))	('EGFR', 'Gene', '1956', (168, 172))	('KRAS', 'Gene', '3845', (158, 162))	('EGFR', 'Gene', (168, 172))	('sarcomatoid components', 'Disease', (113, 135))	('TP53', 'Gene', '7157', (152, 156))	('mutations', 'Var', (173, 182))	('TP53', 'Gene', (152, 156))	('sarcoma', 'Phenotype', 'HP:0100242', (113, 120))	('KRAS', 'Gene', (158, 162))
38593	32985499	We also showed that the epithelial and sarcomatoid components of the microdissection samples shared driver mutations (such as KRAS and EGFR mutations) that were commonly observed in conventional lung cancer but were rare in sarcoma, further emphasizing the true epithelial nature of PSC and suggesting that the transformation of the epithelial components might occur first.	('sarcomatoid components', 'Disease', (39, 61))	('KRAS', 'Gene', '3845', (126, 130))	('sarcoma', 'Disease', (224, 231))	('sarcoma', 'Disease', 'MESH:D012509', (39, 46))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('sarcoma', 'Phenotype', 'HP:0100242', (39, 46))	('EGFR', 'Gene', '1956', (135, 139))	('lung cancer', 'Disease', (195, 206))	('sarcoma', 'Phenotype', 'HP:0100242', (224, 231))	('lung cancer', 'Phenotype', 'HP:0100526', (195, 206))	('sarcoma', 'Disease', (39, 46))	('EGFR', 'Gene', (135, 139))	('mutations', 'Var', (140, 149))	('lung cancer', 'Disease', 'MESH:D008175', (195, 206))	('sarcoma', 'Disease', 'MESH:D012509', (224, 231))	('sarcomatoid components', 'Disease', 'MESH:C538614', (39, 61))	('KRAS', 'Gene', (126, 130))
38594	32985499	EGFR mutations were all in the trunk of the phylogenetic trees, suggesting the epithelial and sarcomatoid components could both respond to EGFR-TKIs, leading to possible favorable outcomes for these patients regarding targeted therapy.	('EGFR', 'Gene', (0, 4))	('sarcoma', 'Phenotype', 'HP:0100242', (94, 101))	('mutations', 'Var', (5, 14))	('EGFR', 'Gene', '1956', (139, 143))	('sarcomatoid components', 'Disease', 'MESH:C538614', (94, 116))	('respond', 'Reg', (128, 135))	('EGFR', 'Gene', (139, 143))	('patients', 'Species', '9606', (199, 207))	('sarcomatoid components', 'Disease', (94, 116))	('EGFR', 'Gene', '1956', (0, 4))
38599	32985499	As sarcomatoid components had distinct DNA methylation profiles, and the association between DNA methylation levels and expression levels was observed in 26 genes of the 76-gene EMT signature, epigenetic regulation might participate in the EMT process and the carcinogenesis of PSC.	('sarcoma', 'Phenotype', 'HP:0100242', (3, 10))	('met', 'Gene', (43, 46))	('carcinogenesis', 'Disease', 'MESH:D063646', (260, 274))	('participate', 'Reg', (221, 232))	('sarcomatoid components', 'Disease', 'MESH:C538614', (3, 25))	('carcinogenesis', 'Disease', (260, 274))	('epigenetic regulation', 'Var', (193, 214))	('met', 'Gene', '79811', (97, 100))	('sarcomatoid components', 'Disease', (3, 25))	('EMT process', 'CPA', (240, 251))	('met', 'Gene', (97, 100))	('met', 'Gene', '79811', (43, 46))	('PSC', 'Disease', (278, 281))
38608	32985499	EGFR mutations were significantly enriched in C1, and MET and BRAF mutations were also identified, suggesting targeted therapy would be a good treatment option for patients in C1.	('BRAF', 'Gene', '673', (62, 66))	('EGFR', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))	('patients', 'Species', '9606', (164, 172))	('MET', 'Gene', '79811', (54, 57))	('BRAF', 'Gene', (62, 66))	('MET', 'Gene', (54, 57))	('EGFR', 'Gene', '1956', (0, 4))
38632	32985499	The deconstructSigs package (v1.8.0) was used to infer the contributions of 30 published signatures from the Catalog of Somatic Mutations in Cancer (COSMIC) (https://cancer.sanger.ac.uk/cosmic/signatures_v2) in each tumor.	('tumor', 'Disease', (216, 221))	('cancer', 'Disease', (166, 172))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('Mutations', 'Var', (128, 137))	('tumor', 'Disease', 'MESH:D009369', (216, 221))	('Cancer', 'Disease', (141, 147))	('Cancer', 'Phenotype', 'HP:0002664', (141, 147))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('Cancer', 'Disease', 'MESH:D009369', (141, 147))
38637	32985499	For three of the remaining specific mutations, the allele frequencies were much lower in the components, in which WES did not identify the specific mutations, but the tumor purity reviewed by pathologists was similar, indicating the true intratumoral heterogeneity.	('mutations', 'Var', (36, 45))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('tumor', 'Disease', 'MESH:D009369', (243, 248))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('tumor', 'Disease', (167, 172))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))	('tumor', 'Disease', (243, 248))
38681	32985499	Then, SAMtools mpileup and BCFtools (version 1.3.1, https://samtools.github.io/bcftools/) were combined to call SNVs and indels for each tumor and adjacent normal tissue (if available).	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('indels', 'Var', (121, 127))	('tumor', 'Disease', (137, 142))	('tumor', 'Disease', 'MESH:D009369', (137, 142))
38747	31661833	All HNSCC xenograft tumors of the six cell lines reacted with anti ITGB1 and ITGB4 without considerable differences.	('HNSCC xenograft tumors', 'Disease', 'MESH:D000077195', (4, 26))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('ITGB1', 'Gene', '3688', (67, 72))	('anti', 'Var', (62, 66))	('reacted', 'Reg', (49, 56))	('ITGB4', 'Gene', (77, 82))	('HNSCC xenograft tumors', 'Disease', (4, 26))	('ITGB4', 'Gene', '3691', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('ITGB1', 'Gene', (67, 72))
38751	31661833	Figure 6 shows examples of positive and negative tumor samples stained with anti sLeA, sLeX, CD24, CD44 and ITGA5.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('ITGA5', 'Gene', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('anti sLeA', 'Var', (76, 85))	('tumor', 'Disease', (49, 54))	('CD44', 'Gene', (99, 103))	('ITGA5', 'Gene', '3678', (108, 113))	('CD24', 'Gene', '100133941', (93, 97))	('CD24', 'Gene', (93, 97))
38756	31661833	The expression of sLeX was significantly related to higher pT)-stages in 65 cancers of the oropharynx (pT1+2 vs. pT3+4; p = 0.04), whereas analyses of 56 cancers of the oral cavity and 79 larynx carcinomas did not reveal any statistically significant results.	('carcinomas', 'Phenotype', 'HP:0030731', (195, 205))	('cancers', 'Disease', 'MESH:D009369', (76, 83))	('cancers', 'Phenotype', 'HP:0002664', (76, 83))	('cancers', 'Disease', (76, 83))	('cancers', 'Phenotype', 'HP:0002664', (154, 161))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('larynx carcinomas', 'Disease', (188, 205))	('cancers', 'Disease', 'MESH:D009369', (154, 161))	('larynx carcinomas', 'Disease', 'MESH:D007822', (188, 205))	('cancers of the oropharynx', 'Phenotype', 'HP:0100638', (76, 101))	('related', 'Reg', (41, 48))	('expression', 'Var', (4, 14))	('higher', 'PosReg', (52, 58))	('cancers', 'Disease', (154, 161))	('cancers of the oral cavity', 'Phenotype', 'HP:0100649', (154, 180))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('sLeX', 'Gene', (18, 22))	('carcinoma', 'Phenotype', 'HP:0030731', (195, 204))
38775	31661833	Considering previous studies, numbers of CTCs or DTCs in bone marrow seem to have a clinical prognostic relevance in patients with SCC.	('DTCs', 'Var', (49, 53))	('patients', 'Species', '9606', (117, 125))	('SCC', 'Disease', (131, 134))
38784	31661833	The classical (canonical) binding partners of selectins are carbohydrate structures whose minimal recognition motifs are represented by sialyl Lewis X (sLeX) and sialyl Lewis A (sLeA).	('carbohydrate', 'Chemical', 'MESH:D002241', (60, 72))	('sialyl', 'Var', (136, 142))	('sialyl Lewis', 'Var', (162, 174))
38790	31661833	Previous studies have identified sLeX-modified CD24 as a functional P-selectin ligand that can promote rolling and tumor cell colonization to the lung in lung adenocarcinoma cells.	('sLeX-modified', 'Var', (33, 46))	('rolling', 'CPA', (103, 110))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('promote', 'PosReg', (95, 102))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (154, 173))	('P-selectin', 'Gene', (68, 78))	('CD24', 'Gene', '100133941', (47, 51))	('CD24', 'Gene', (47, 51))	('tumor', 'Disease', (115, 120))	('carcinoma', 'Phenotype', 'HP:0030731', (164, 173))	('lung adenocarcinoma', 'Disease', (154, 173))	('P-selectin', 'Gene', '6403', (68, 78))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (154, 173))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
38858	30159341	Therefore, targeting PD-1/PD-L1 signaling can enhance the capacity of activated T cells to recognize and kill tumor cells and subsequently, restore the function of host immune surveillance, by the activation of PI3K/Akt and Ras/MEK/Erk signaling pathways (Figure 1).	('capacity', 'MPA', (58, 66))	('PD-1/PD-L1', 'Gene', (21, 31))	('host immune surveillance', 'MPA', (164, 188))	('restore', 'PosReg', (140, 147))	('Erk', 'Gene', (232, 235))	('activation', 'PosReg', (197, 207))	('tumor', 'Disease', (110, 115))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('MEK', 'Gene', (228, 231))	('function', 'MPA', (152, 160))	('targeting', 'Var', (11, 20))	('Erk', 'Gene', '5594', (232, 235))	('enhance', 'PosReg', (46, 53))	('MEK', 'Gene', '5609', (228, 231))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
38875	30159341	A previously treated patient with >=1% PD-L1-positive cells in tumor might benefit from pembrolizumab as a secondary line therapy, and a previously untreated patient with >=50% PD-L1-positive cells in tumor might benefit from pembrolizumab as the first-line therapy.	('tumor', 'Disease', (63, 68))	('patient', 'Species', '9606', (21, 28))	('patient', 'Species', '9606', (158, 165))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('tumor', 'Disease', (201, 206))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('pembrolizumab', 'Chemical', 'MESH:C582435', (88, 101))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('pembrolizumab', 'Chemical', 'MESH:C582435', (226, 239))	('PD-L1-positive cells', 'Var', (39, 59))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
38876	30159341	PD-L1 IHC 28-8 pharmDx is also an IHC assay for the diagnosis of IHC in clinical trials with nivolumab, by detecting PD-L1 protein in FFPE section of nonsquamous NSCLC and melanoma tissues.	('melanoma', 'Disease', 'MESH:D008545', (172, 180))	('nivolumab', 'Chemical', 'MESH:D000077594', (93, 102))	('squamous NSCLC', 'Disease', 'MESH:D002294', (153, 167))	('melanoma', 'Phenotype', 'HP:0002861', (172, 180))	('NSCLC', 'Phenotype', 'HP:0030358', (162, 167))	('PD-L1', 'Var', (117, 122))	('squamous NSCLC', 'Disease', (153, 167))	('detecting', 'Reg', (107, 116))	('melanoma', 'Disease', (172, 180))	('protein', 'Protein', (123, 130))
38884	30159341	Of note, the SP263 assay could expand the therapeutic range for NSCLC patients.	('patients', 'Species', '9606', (70, 78))	('SP263 assay', 'Var', (13, 24))	('NSCLC', 'Disease', 'MESH:D002289', (64, 69))	('NSCLC', 'Phenotype', 'HP:0030358', (64, 69))	('SP263', 'Chemical', '-', (13, 18))	('NSCLC', 'Disease', (64, 69))
38890	30159341	suggested an equivalent predictive performance of 28-8, 22C3, and SP263 PD-L1 IHC assays, while the SP142 assay exhibited a lower predictive performance in NSCLC.	('SP263', 'Chemical', '-', (66, 71))	('NSCLC', 'Phenotype', 'HP:0030358', (156, 161))	('SP263', 'Var', (66, 71))	('NSCLC', 'Disease', (156, 161))	('NSCLC', 'Disease', 'MESH:D002289', (156, 161))	('SP142', 'Chemical', '-', (100, 105))
38891	30159341	A compelling body of evidence has shown that anti-PD-1/PD-L1 therapy is a promising treatment strategy with unprecedented survival benefits for selected NSCLC patients.	('NSCLC', 'Phenotype', 'HP:0030358', (153, 158))	('anti-PD-1/PD-L1', 'Var', (45, 60))	('NSCLC', 'Disease', (153, 158))	('NSCLC', 'Disease', 'MESH:D002289', (153, 158))	('patients', 'Species', '9606', (159, 167))
38919	30159341	Together, these results indicated that 22C3, 28-8, SP263, and E1L3N were better assays for PD-1 expression in clinical settings.	('SP263', 'Chemical', '-', (51, 56))	('PD-1', 'Gene', (91, 95))	('SP263', 'Var', (51, 56))
38924	30159341	In addition, the high expression of PD-L1 was associated with a low 5-year survival rate in squamous NSCLC.	('squamous NSCLC', 'Disease', (92, 106))	('PD-L1', 'Gene', (36, 41))	('low', 'NegReg', (64, 67))	('high', 'Var', (17, 21))	('squamous NSCLC', 'Disease', 'MESH:D002294', (92, 106))	('NSCLC', 'Phenotype', 'HP:0030358', (101, 106))
38936	30159341	In addition to the PD-L1 as a testing biomarker for anti-PD-1/PD-L1 therapy in NSCLC, several other biomarkers were identified for patient selection in checkpoint blockade therapy.	('NSCLC', 'Disease', 'MESH:D002289', (79, 84))	('anti-PD-1/PD-L1', 'Var', (52, 67))	('NSCLC', 'Phenotype', 'HP:0030358', (79, 84))	('patient', 'Species', '9606', (131, 138))	('NSCLC', 'Disease', (79, 84))
38938	30159341	For instance, NSCLC patients with high nonsynonymous mutation burden showed more durable clinical benefit to treatment with pembrolizumab with a higher PFS and ORR relative to those with less frequent nonsynonymous mutations.	('NSCLC', 'Disease', (14, 19))	('nonsynonymous mutation', 'Var', (39, 61))	('pembrolizumab', 'Chemical', 'MESH:C582435', (124, 137))	('NSCLC', 'Disease', 'MESH:D002289', (14, 19))	('patients', 'Species', '9606', (20, 28))	('NSCLC', 'Phenotype', 'HP:0030358', (14, 19))	('clinical', 'CPA', (89, 97))	('PFS', 'MPA', (152, 155))	('benefit', 'PosReg', (98, 105))	('higher', 'PosReg', (145, 151))
38952	30159341	In this study, the patient group treated with nivolumab resulted in advancing median overall survival (OS) compared to docetaxel (OS 12.2 versus 9.4 months); the OS at one year was 51% (95% CI, 45 to 56) in patients treated with nivolumab versus 39% (95% CI, 33 to 45) in the docetaxel group (NCT01673867).	('advancing', 'PosReg', (68, 77))	('patients', 'Species', '9606', (207, 215))	('OS', 'Chemical', '-', (103, 105))	('nivolumab', 'Chemical', 'MESH:D000077594', (229, 238))	('patient', 'Species', '9606', (19, 26))	('docetaxel', 'Chemical', 'MESH:D000077143', (119, 128))	('OS', 'Chemical', '-', (162, 164))	('nivolumab', 'Var', (46, 55))	('docetaxel', 'Chemical', 'MESH:D000077143', (276, 285))	('OS', 'Chemical', '-', (130, 132))	('patient', 'Species', '9606', (207, 214))	('overall survival', 'MPA', (85, 101))	('nivolumab', 'Chemical', 'MESH:D000077594', (46, 55))
38955	30159341	However, a randomized phase II study in investigation of the efficacy and safety of atezolizumab comparing with docetaxel in previous platinum-treated NSCLC patients (who were PD-L1-positive as determined by SP142 antibody IHC assay) showed that atezolizumab resulted in an enhanced PFS (9.7 versus 3.9 months) and OS compared to docetaxel (12.2 versus 9.4 months) for patients with high levels of PD-L1 expression (NCT01903993).	('PFS', 'MPA', (283, 286))	('NSCLC', 'Phenotype', 'HP:0030358', (151, 156))	('patients', 'Species', '9606', (369, 377))	('NSCLC', 'Disease', (151, 156))	('docetaxel', 'Chemical', 'MESH:D000077143', (330, 339))	('docetaxel', 'Chemical', 'MESH:D000077143', (112, 121))	('NSCLC', 'Disease', 'MESH:D002289', (151, 156))	('SP142', 'Chemical', '-', (208, 213))	('patients', 'Species', '9606', (157, 165))	('NCT01903993', 'Var', (416, 427))	('OS', 'Chemical', '-', (315, 317))	('atezolizumab', 'Chemical', 'MESH:C000594389', (84, 96))	('platinum', 'Chemical', 'MESH:D010984', (134, 142))	('atezolizumab', 'Chemical', 'MESH:C000594389', (246, 258))	('enhanced', 'PosReg', (274, 282))
38961	30159341	Indeed, meta-analysis in randomized clinical trials of anti-PD-1/PD-L1 therapy (atezolizumab, pembrolizumab, and nivolumab) demonstrated the efficacy and safety and could dramatically improve the PFS and OS compared with docetaxel for patients with previously treated NSCLC and enhance the PFS and OS compared to EGFR-TKI alone for NSCLC patients with EGFR wild type.	('NSCLC', 'Disease', 'MESH:D002289', (332, 337))	('EGFR', 'Gene', (313, 317))	('nivolumab', 'Chemical', 'MESH:D000077594', (113, 122))	('enhance', 'PosReg', (278, 285))	('NSCLC', 'Disease', 'MESH:D002289', (268, 273))	('NSCLC', 'Disease', (332, 337))	('patients', 'Species', '9606', (338, 346))	('anti-PD-1/PD-L1', 'Var', (55, 70))	('patients', 'Species', '9606', (235, 243))	('NSCLC', 'Phenotype', 'HP:0030358', (332, 337))	('NSCLC', 'Disease', (268, 273))	('docetaxel', 'Chemical', 'MESH:D000077143', (221, 230))	('atezolizumab', 'Chemical', 'MESH:C000594389', (80, 92))	('NSCLC', 'Phenotype', 'HP:0030358', (268, 273))	('EGFR', 'Gene', (352, 356))	('EGFR', 'Gene', '1956', (313, 317))	('OS', 'Chemical', '-', (204, 206))	('pembrolizumab', 'Chemical', 'MESH:C582435', (94, 107))	('EGFR', 'Gene', '1956', (352, 356))	('improve', 'PosReg', (184, 191))	('OS', 'Chemical', '-', (298, 300))
38962	30159341	Of note, as far as PFS was a concern, an anti-PD-1/PD-L1 therapy was second only to EGFR-TKI therapy for patient with EGFR mutation.	('patient', 'Species', '9606', (105, 112))	('mutation', 'Var', (123, 131))	('EGFR', 'Gene', '1956', (84, 88))	('EGFR', 'Gene', '1956', (118, 122))	('EGFR', 'Gene', (118, 122))	('EGFR', 'Gene', (84, 88))
38963	30159341	These clinical trials clearly demonstrated that inhibition of the PD-1/PD-L1 pathway could clinically improve the ORR, OS, and PFS compared with single-arm chemotherapy alone in nonsquamous and squamous NSCLCs.	('PD-1/PD-L1 pathway', 'Gene', (66, 84))	('improve', 'PosReg', (102, 109))	('OS', 'Chemical', '-', (119, 121))	('inhibition', 'Var', (48, 58))	('squamous NSCLCs', 'Disease', (194, 209))	('NSCLC', 'Phenotype', 'HP:0030358', (203, 208))	('PFS', 'Disease', (127, 130))	('ORR', 'Disease', (114, 117))	('squamous NSCLCs', 'Disease', 'MESH:D002294', (194, 209))
38964	30159341	In addition, these data also showed that PD-1 or PD-L1 could serve as a biomarker to improve the benefit of anti-PD-1/PD-L1 therapy for NSCLC patients.	('NSCLC', 'Disease', 'MESH:D002289', (136, 141))	('anti-PD-1/PD-L1', 'Var', (108, 123))	('NSCLC', 'Phenotype', 'HP:0030358', (136, 141))	('patients', 'Species', '9606', (142, 150))	('NSCLC', 'Disease', (136, 141))
38969	30159341	A compelling body of studies has demonstrated that the PD-L1 expression was associated with EGFR mutation, ALK rearrangements, or KRAS mutation in NSCLC.	('NSCLC', 'Disease', (147, 152))	('PD-L1', 'Gene', (55, 60))	('NSCLC', 'Disease', 'MESH:D002289', (147, 152))	('ALK', 'Gene', '238', (107, 110))	('rearrangements', 'Var', (111, 125))	('associated', 'Reg', (76, 86))	('KRAS', 'Gene', (130, 134))	('NSCLC', 'Phenotype', 'HP:0030358', (147, 152))	('EGFR', 'Gene', '1956', (92, 96))	('mutation', 'Var', (97, 105))	('EGFR', 'Gene', (92, 96))	('ALK', 'Gene', (107, 110))	('KRAS', 'Gene', '3845', (130, 134))
38971	30159341	For example, the PD-L1 expression was linked to KRAS mutations and was significantly associated with EGFR mutations.	('linked', 'Reg', (38, 44))	('KRAS', 'Gene', (48, 52))	('KRAS', 'Gene', '3845', (48, 52))	('EGFR', 'Gene', '1956', (101, 105))	('EGFR', 'Gene', (101, 105))	('mutations', 'Var', (53, 62))	('mutations', 'Var', (106, 115))	('PD-L1', 'Gene', (17, 22))	('associated', 'Reg', (85, 95))
38973	30159341	These studies suggest that a combination of PD-1/PD-L1 blockades with EGFR-TKIs may enhance the outcome of NSCLC treatment.	('outcome', 'MPA', (96, 103))	('NSCLC', 'Disease', (107, 112))	('EGFR', 'Gene', '1956', (70, 74))	('NSCLC', 'Disease', 'MESH:D002289', (107, 112))	('blockades', 'Var', (55, 64))	('EGFR', 'Gene', (70, 74))	('PD-1/PD-L1', 'Gene', (44, 54))	('NSCLC', 'Phenotype', 'HP:0030358', (107, 112))	('enhance', 'PosReg', (84, 91))
38975	30159341	The combinatory therapy of durvalumab and gefitinib (NCT02088112) and durvalumab (NCT0214346) also showed an increased ORR in NSCLC patients with EGFR mutation.	('ORR', 'MPA', (119, 122))	('NCT02088112', 'Var', (53, 64))	('EGFR', 'Gene', '1956', (146, 150))	('NSCLC', 'Disease', 'MESH:D002289', (126, 131))	('gefitinib', 'Chemical', 'MESH:D000077156', (42, 51))	('mutation', 'Var', (151, 159))	('EGFR', 'Gene', (146, 150))	('NSCLC', 'Phenotype', 'HP:0030358', (126, 131))	('durvalumab', 'Chemical', 'MESH:C000613593', (27, 37))	('NCT0214346', 'Var', (82, 92))	('durvalumab', 'Chemical', 'MESH:C000613593', (70, 80))	('increased', 'PosReg', (109, 118))	('patients', 'Species', '9606', (132, 140))	('NSCLC', 'Disease', (126, 131))
38977	30159341	In addition, PD-L1-positive patients exhibited more sensitive to gefitinib or erlotinib than PD-L1-negative patients in terms of TTP and OS.	('gefitinib', 'Chemical', 'MESH:D000077156', (65, 74))	('more', 'PosReg', (47, 51))	('patients', 'Species', '9606', (108, 116))	('erlotinib', 'MPA', (78, 87))	('erlotinib', 'Chemical', 'MESH:D000069347', (78, 87))	('TTP', 'MPA', (129, 132))	('PD-L1-positive', 'Var', (13, 27))	('sensitive', 'MPA', (52, 61))	('patients', 'Species', '9606', (28, 36))	('OS', 'Chemical', '-', (137, 139))
38979	30159341	Similarly, NSCLC patients harboring mutant KRAS treated with immune checkpoint inhibitors (ICIs) had prolonged OS relative to those containing wild-type KRAS.	('NSCLC', 'Disease', (11, 16))	('NSCLC', 'Disease', 'MESH:D002289', (11, 16))	('KRAS', 'Gene', (153, 157))	('OS', 'Chemical', '-', (111, 113))	('KRAS', 'Gene', (43, 47))	('KRAS', 'Gene', '3845', (153, 157))	('prolonged', 'PosReg', (101, 110))	('mutant', 'Var', (36, 42))	('patients', 'Species', '9606', (17, 25))	('NSCLC', 'Phenotype', 'HP:0030358', (11, 16))	('KRAS', 'Gene', '3845', (43, 47))
38980	30159341	These results implied that high mutational rates of EGFR or KRAS mutations enhanced immunogenicity and could serve as potential biomarkers for anti-PD-1/PD-L1 therapy.	('enhanced', 'PosReg', (75, 83))	('EGFR', 'Gene', '1956', (52, 56))	('EGFR', 'Gene', (52, 56))	('immunogenicity', 'CPA', (84, 98))	('mutational', 'Var', (32, 42))	('KRAS', 'Gene', (60, 64))	('KRAS', 'Gene', '3845', (60, 64))	('mutations', 'Var', (65, 74))
38982	30159341	Indeed, NSCLC patients with acquired resistance of EGFR-TKIs and EGFR mutation but not T790M were reported to benefit more from nivolumab than those with T790M mutation.	('NSCLC', 'Phenotype', 'HP:0030358', (8, 13))	('nivolumab', 'MPA', (128, 137))	('EGFR', 'Gene', '1956', (65, 69))	('EGFR', 'Gene', (65, 69))	('EGFR', 'Gene', (51, 55))	('T790M', 'Mutation', 'rs121434569', (154, 159))	('benefit', 'PosReg', (110, 117))	('NSCLC', 'Disease', (8, 13))	('T790M', 'Mutation', 'rs121434569', (87, 92))	('mutation', 'Var', (70, 78))	('patients', 'Species', '9606', (14, 22))	('NSCLC', 'Disease', 'MESH:D002289', (8, 13))	('EGFR', 'Gene', '1956', (51, 55))	('nivolumab', 'Chemical', 'MESH:D000077594', (128, 137))
38984	30159341	The results displayed that the median PFS of patients with the T790M-negative PD-L1 expression level of >=1% and those who had a T790M-positive PD-L1 expression level of <1% were 2.1 and 1.3 months, respectively.	('T790M', 'Mutation', 'rs121434569', (129, 134))	('PD-L1', 'Gene', (78, 83))	('T790M', 'Mutation', 'rs121434569', (63, 68))	('patients', 'Species', '9606', (45, 53))	('T790M-negative', 'Var', (63, 77))
38986	30159341	Further studies on the relationship between driver oncogene mutations (EGFR, ALK, KRAS, MET, and ROS1) and immune-related biomarkers (PD-1, PD-L1, CTLA-4, and CD8) in NSCLC demonstrated that the PD-L1 expression of 26% of SCC and 76% of adenocarcinoma samples was overlapped with driver oncogenes, but a TPS of PD-L1 >= 50% was rarely overlapped with driver oncogenes.	('ALK', 'Gene', (77, 80))	('NSCLC', 'Phenotype', 'HP:0030358', (167, 172))	('adenocarcinoma', 'Disease', (237, 251))	('CTLA-4', 'Gene', '1493', (147, 153))	('EGFR', 'Gene', '1956', (71, 75))	('KRAS', 'Gene', '3845', (82, 86))	('CTLA-4', 'Gene', (147, 153))	('mutations', 'Var', (60, 69))	('CD8', 'Gene', (159, 162))	('adenocarcinoma', 'Disease', 'MESH:D000230', (237, 251))	('ROS1', 'Gene', '6098', (97, 101))	('KRAS', 'Gene', (82, 86))	('EGFR', 'Gene', (71, 75))	('NSCLC', 'Disease', 'MESH:D002289', (167, 172))	('carcinoma', 'Phenotype', 'HP:0030731', (242, 251))	('ALK', 'Gene', '238', (77, 80))	('ROS1', 'Gene', (97, 101))	('CD8', 'Gene', '925', (159, 162))	('NSCLC', 'Disease', (167, 172))
38990	30159341	Both low and high EGFR mutations with PD-L1 expression were reported.	('mutations', 'Var', (23, 32))	('EGFR', 'Gene', '1956', (18, 22))	('EGFR', 'Gene', (18, 22))
38992	30159341	Interestingly, an increased number of evidences unraveled that chemotherapy has an impact on immune microenvironment of tumors, which in turn enhances its antitumor, through mechanisms including reduction of T-regulatory cell activity, selective depletion of myeloid-derived suppressor cells (MDSCs), induction of PD-L2 expression, and the maturation of APCs.	('tumors', 'Disease', (120, 126))	('PD-L2', 'Gene', '80380', (314, 319))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('expression', 'MPA', (320, 330))	('reduction', 'NegReg', (195, 204))	('impact', 'Reg', (83, 89))	('PD-L2', 'Gene', (314, 319))	('T-regulatory cell activity', 'MPA', (208, 234))	('tumors', 'Disease', 'MESH:D009369', (120, 126))	('induction', 'Reg', (301, 310))	('enhances', 'PosReg', (142, 150))	('tumor', 'Disease', (120, 125))	('depletion', 'NegReg', (246, 255))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('tumor', 'Disease', (159, 164))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('chemotherapy', 'Var', (63, 75))	('APCs', 'Gene', (354, 358))	('maturation', 'CPA', (340, 350))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('APCs', 'Gene', '325', (354, 358))
39014	30159341	Several other trials exploring a combination of immune checkpoint blockade and antiangiogenic agents are underway, including the combination of ramucirumab with pembrolizumab (NCT02443324) in patients with advanced solid tumors including NSCLC, pembrolizumab with nintedanib (NCT02856425) in advanced NSCLC, and bevacizumab plus chemotherapy with atezolizumab (NCT02366143) or pembrolizumab (NCT02039674) in the first-line setting for NSCLC treatment (Table 3).	('solid tumors', 'Disease', 'MESH:D009369', (215, 227))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('NSCLC', 'Disease', (238, 243))	('NCT02856425', 'Var', (276, 287))	('NSCLC', 'Disease', (301, 306))	('tumors', 'Phenotype', 'HP:0002664', (221, 227))	('NSCLC', 'Disease', 'MESH:D002289', (435, 440))	('NSCLC', 'Phenotype', 'HP:0030358', (238, 243))	('NSCLC', 'Phenotype', 'HP:0030358', (301, 306))	('pembrolizumab', 'Chemical', 'MESH:C582435', (245, 258))	('NCT02366143', 'Var', (361, 372))	('NSCLC', 'Disease', (435, 440))	('NCT02039674', 'Var', (392, 403))	('nintedanib', 'Chemical', 'MESH:C530716', (264, 274))	('NSCLC', 'Phenotype', 'HP:0030358', (435, 440))	('patients', 'Species', '9606', (192, 200))	('NCT02443324', 'Var', (176, 187))	('atezolizumab', 'Chemical', 'MESH:C000594389', (347, 359))	('bevacizumab', 'Chemical', 'MESH:D000068258', (312, 323))	('pembrolizumab', 'Chemical', 'MESH:C582435', (377, 390))	('solid tumors', 'Disease', (215, 227))	('ramucirumab', 'Chemical', 'MESH:C543333', (144, 155))	('NSCLC', 'Disease', 'MESH:D002289', (238, 243))	('pembrolizumab', 'Chemical', 'MESH:C582435', (161, 174))	('NSCLC', 'Disease', 'MESH:D002289', (301, 306))
39017	30159341	Trials evaluated anti-PD-1/PD-L1 or CTLA-4 antibodies (nivolumab, pembrolizumab, atezolizumab, and durvalumab) in combination with indoximod, BMS-986205, or epacadostat; inhibitors of IDO1 are underway (NCT02327078, NCT03085914, NCT02178722, NCT02862457, NCT02298153, NCT02318277, and NCT02658890).	('NCT02862457', 'Var', (242, 253))	('NCT02327078', 'Var', (203, 214))	('IDO1', 'Gene', '3620', (184, 188))	('atezolizumab', 'Chemical', 'MESH:C000594389', (81, 93))	('NCT03085914', 'Var', (216, 227))	('pembrolizumab', 'Chemical', 'MESH:C582435', (66, 79))	('CTLA-4', 'Gene', '1493', (36, 42))	('NCT02178722', 'Var', (229, 240))	('durvalumab', 'Chemical', 'MESH:C000613593', (99, 109))	('CTLA-4', 'Gene', (36, 42))	('NCT02318277', 'Var', (268, 279))	('IDO1', 'Gene', (184, 188))	('NCT02298153', 'Var', (255, 266))	('nivolumab', 'Chemical', 'MESH:D000077594', (55, 64))
39019	30159341	Apart from combinatory therapies with chemo-, radio-, or targeted therapy, the anti-PD-1/PD-L1 therapy combined with other immunotherapies also is an attractive approach for NSCLC treatment.	('anti-PD-1/PD-L1', 'Var', (79, 94))	('NSCLC', 'Phenotype', 'HP:0030358', (174, 179))	('NSCLC', 'Disease', 'MESH:D002289', (174, 179))	('NSCLC', 'Disease', (174, 179))
39024	30159341	Interestingly, chimeric antigen receptor (CAR) T cell (CAR-T) therapy has demonstrated a promising clinical effect in broad of malignancies including chronic lymphoid leukaemia and lymphomas, despite it still faces a series of challenges in treatments of solid tumors.	('lymphomas', 'Phenotype', 'HP:0002665', (181, 190))	('chimeric', 'Var', (15, 23))	('malignancies', 'Disease', 'MESH:D009369', (127, 139))	('tumor', 'Phenotype', 'HP:0002664', (261, 266))	('malignancies', 'Disease', (127, 139))	('solid tumors', 'Disease', (255, 267))	('tumors', 'Phenotype', 'HP:0002664', (261, 267))	('chronic lymphoid leukaemia', 'Phenotype', 'HP:0005550', (150, 176))	('lymphoid leukaemia', 'Phenotype', 'HP:0005526', (158, 176))	('lymphoma', 'Phenotype', 'HP:0002665', (181, 189))	('lymphoid leukaemia and lymphomas', 'Disease', 'MESH:D008223', (158, 190))	('solid tumors', 'Disease', 'MESH:D009369', (255, 267))
39027	30159341	Therefore, blockading PD-1 signaling in combination with CAR-T cell therapy may potentiate the therapeutic efficacy by overcoming the PD-L1+ tumor-mediated immunosuppressive effect.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('therapeutic efficacy', 'CPA', (95, 115))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('overcoming', 'NegReg', (119, 129))	('tumor', 'Disease', (141, 146))	('potentiate', 'PosReg', (80, 90))	('blockading', 'Var', (11, 21))	('PD-L1+', 'MPA', (134, 140))
39029	30159341	Results from this study showed that the PD-L1 expression of tumor cells suppressed the 4-1BBzeta CAR-T cell function of tumor clearance in a xenograft model, and a disruption of PD-1 by CRISPR/Cas9-mediated gene editing within CAR-T cells led an augmented CAR-T cell antitumor efficacy.	('tumor', 'Phenotype', 'HP:0002664', (271, 276))	('tumor', 'Disease', 'MESH:D009369', (271, 276))	('tumor', 'Disease', (60, 65))	('4-1BBzeta', 'Enzyme', (87, 96))	('tumor', 'Disease', (271, 276))	('PD-L1', 'Gene', (40, 45))	('disruption', 'Var', (164, 174))	('PD-1', 'Gene', (178, 182))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('suppressed', 'NegReg', (72, 82))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('augmented', 'PosReg', (246, 255))	('tumor', 'Disease', (120, 125))
39032	30159341	However, not all patients always benefit from these agents, and the data of preclinical and clinical trials demonstrated that only 20-50% patients benefited from anti-PD-1/PD-L1 therapy for various cancer types.	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('cancer', 'Disease', (198, 204))	('anti-PD-1/PD-L1', 'Var', (162, 177))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('patients', 'Species', '9606', (17, 25))	('patients', 'Species', '9606', (138, 146))
39034	30159341	In addition, little is known about the contributions of exceeding the PD-L1-positive level, the potential antigen load or mutational load in the tumor and the genetic determinants to efficacy, and resistance to anti-PD-1/PD-L1 therapy.	('tumor', 'Disease', (145, 150))	('mutational load', 'Var', (122, 137))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))
39039	30159341	In resistant tumor clones, the authors found that 7 to 18 putative mutation-associated neoantigens were lost and the loss of neoantigens occurred either by an elimination of tumor subclones or by a deletion of truncal chromosome regions.	('tumor', 'Disease', (174, 179))	('tumor', 'Disease', (13, 18))	('loss', 'NegReg', (117, 121))	('deletion', 'Var', (198, 206))	('neoantigens', 'MPA', (87, 98))	('mutation-associated', 'Reg', (67, 86))	('lost', 'NegReg', (104, 108))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
39042	30159341	The introduction of targeting agents, such as EGFR-TKI or ALK inhibitor, further offered significant improvements in NSCLC survival carrying an EGFR mutation or ALK rearrangement.	('NSCLC', 'Disease', (117, 122))	('EGFR', 'Gene', (144, 148))	('improvements', 'PosReg', (101, 113))	('ALK', 'Gene', (161, 164))	('ALK', 'Gene', (58, 61))	('EGFR', 'Gene', '1956', (46, 50))	('NSCLC', 'Disease', 'MESH:D002289', (117, 122))	('EGFR', 'Gene', (46, 50))	('NSCLC', 'Phenotype', 'HP:0030358', (117, 122))	('EGFR', 'Gene', '1956', (144, 148))	('mutation', 'Var', (149, 157))	('ALK', 'Gene', '238', (161, 164))	('ALK', 'Gene', '238', (58, 61))
39051	30159341	For instance, in NSCLC patients with acquired resistance to anti-PD-1/PD-L1 immunotherapies and EGFR or ALK mutations, particularly for patients with high tumor burden or rapid disease progression, a combination of anti-PD-1/PD-L1 therapy and targeted therapy may be an option.	('high tumor', 'Disease', 'MESH:D009369', (150, 160))	('NSCLC', 'Disease', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('mutations', 'Var', (108, 117))	('EGFR', 'Gene', (96, 100))	('NSCLC', 'Disease', 'MESH:D002289', (17, 22))	('ALK', 'Gene', '238', (104, 107))	('patients', 'Species', '9606', (23, 31))	('high tumor', 'Disease', (150, 160))	('patients', 'Species', '9606', (136, 144))	('ALK', 'Gene', (104, 107))	('NSCLC', 'Phenotype', 'HP:0030358', (17, 22))	('EGFR', 'Gene', '1956', (96, 100))
39071	29434143	This approval was based on the results of the CA031 study, in which nab-PC demonstrated a higher ORR than sb-PC (33% vs. 25%, p=0.005).	('sb-PC', 'Chemical', '-', (106, 111))	('ORR', 'MPA', (97, 100))	('nab-PC', 'Var', (68, 74))	('CA031', 'Chemical', '-', (46, 51))	('nab-PC', 'Chemical', '-', (68, 74))
39093	29434143	Carboplatin was administered at a dose of AUC 6 in one patient and AUC 5 in the others, and in five patients, nab-PTX was not administered on day 15 for one whole cycle.	('Carboplatin', 'Chemical', 'MESH:D016190', (0, 11))	('AUC 6', 'Var', (42, 47))	('patient', 'Species', '9606', (100, 107))	('patients', 'Species', '9606', (100, 108))	('AUC 5', 'Var', (67, 72))	('patient', 'Species', '9606', (55, 62))	('nab-PTX', 'Chemical', 'MESH:D017239', (110, 117))
39109	29434143	In the subset analysis for advanced lung SCC, nab-PC produced a significantly higher ORR (41% vs. 24%) and a more than 1-month increase in the OS over sb-PC (median 10.7 vs. 9.5 months) without an improvement in the PFS (median 5.6 months vs. 5.7 months).	('SCC', 'Gene', (41, 44))	('ORR', 'MPA', (85, 88))	('SCC', 'Phenotype', 'HP:0002860', (41, 44))	('nab-PC', 'Var', (46, 52))	('higher', 'PosReg', (78, 84))	('SCC', 'Gene', '6317', (41, 44))	('nab-PC', 'Chemical', '-', (46, 52))	('increase', 'PosReg', (127, 135))	('sb-PC', 'Chemical', '-', (151, 156))
39141	29434143	However, several studies showed that the presence of preexisting ILD was a significant risk for severe radiation pneumonitis and treatment-related death after radiotherapy and concurrent chemoradiotherapy.	('death', 'Disease', 'MESH:D003643', (147, 152))	('ILD', 'Disease', (65, 68))	('ILD', 'Phenotype', 'HP:0006530', (65, 68))	('death', 'Disease', (147, 152))	('pneumonitis', 'Disease', (113, 124))	('presence', 'Var', (41, 49))	('pneumonitis', 'Disease', 'MESH:D011014', (113, 124))
39259	29581778	The anti-tumor effects of dual PI3K/mTOR inhibitor BEZ235 and histone deacetylase inhibitor Trichostatin A on inducing autophagy in esophageal squamous cell carcinoma The effect and regulation of autophagy-related proteins Beclin-1 and LC3 in esophageal squamous cell carcinoma have not been fully studied.	('esophageal squamous cell carcinoma', 'Disease', (132, 166))	('mTOR', 'Gene', '2475', (36, 40))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (243, 277))	('LC3', 'Gene', (236, 239))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (143, 166))	('autophagy', 'CPA', (119, 128))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (254, 277))	('BEZ235', 'Var', (51, 57))	('Trichostatin A', 'Chemical', 'MESH:C012589', (92, 106))	('tumor', 'Disease', (9, 14))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (132, 166))	('carcinoma', 'Phenotype', 'HP:0030731', (157, 166))	('inhibitor BEZ235', 'Var', (41, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (268, 277))	('inducing', 'PosReg', (110, 118))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('LC3', 'Gene', '84557', (236, 239))	('Beclin-1', 'Gene', '8678', (223, 231))	('esophageal squamous cell carcinoma', 'Disease', (243, 277))	('mTOR', 'Gene', (36, 40))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('Beclin-1', 'Gene', (223, 231))	('BEZ235', 'Chemical', 'MESH:C531198', (51, 57))
39268	29581778	In Vitro co-treatment with BEZ235 and TSA showed a synergistic effect on inhibition of ESCC cell viability and induction of autophagy with the increasing expressions of Beclin-1, LC3-II and the ratio of LC3-II/LC3-I.	('LC3', 'Gene', '84557', (179, 182))	('LC3', 'Gene', '84557', (210, 213))	('LC3', 'Gene', '84557', (203, 206))	('inhibition', 'NegReg', (73, 83))	('TSA', 'Chemical', 'MESH:C012589', (38, 41))	('increasing', 'PosReg', (143, 153))	('LC3-II', 'Gene', (179, 185))	('men', 'Species', '9606', (17, 20))	('BEZ235', 'Var', (27, 33))	('LC3-II', 'Gene', '84557', (179, 185))	('induction', 'Reg', (111, 120))	('Beclin-1', 'Gene', '8678', (169, 177))	('expressions', 'MPA', (154, 165))	('LC3', 'Gene', (210, 213))	('autophagy', 'CPA', (124, 133))	('LC3', 'Gene', (203, 206))	('LC3', 'Gene', (179, 182))	('ESCC', 'Disease', (87, 91))	('Beclin-1', 'Gene', (169, 177))	('LC3-II', 'Gene', (203, 209))	('BEZ235', 'Chemical', 'MESH:C531198', (27, 33))	('LC3-II', 'Gene', '84557', (203, 209))
39277	29581778	Both the disturbances of signal transduction pathways and the dysfunction of programmed cell death machinery have been demonstrated to be critical for cancer cells to survive and metastasis.	('disturbances', 'Var', (9, 21))	('dysfunction', 'Var', (62, 73))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('signal transduction pathways', 'Pathway', (25, 53))	('cancer', 'Disease', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('programmed cell death machinery', 'Pathway', (77, 108))
39289	29581778	Histone deacetylases (HDACs) plays a critical role in the regulation of gene expression and has been shown to contribute to carcinogenesis by inducing the aberrant transcription of key genes regulating important cellular functions such as cell proliferation, cell-cycle regulation and PCD.	('PCD', 'Disease', 'MESH:D007619', (285, 288))	('PCD', 'Disease', (285, 288))	('inducing', 'PosReg', (142, 150))	('cell proliferation', 'CPA', (239, 257))	('transcription', 'MPA', (164, 177))	('aberrant', 'Var', (155, 163))	('HDAC', 'Gene', (22, 26))	('cell-cycle regulation', 'CPA', (259, 280))	('HDAC', 'Gene', '9734', (22, 26))	('carcinogenesis', 'Disease', 'MESH:D063646', (124, 138))	('regulation', 'MPA', (58, 68))	('contribute', 'Reg', (110, 120))	('carcinogenesis', 'Disease', (124, 138))
39290	29581778	Inhibitors of HDACs exert anticancer activity by promoting acetylation of histones as well as by promoting acetylation of non-histone protein substrates, and represent promising potential targets for esophageal cancer treatment.	('HDAC', 'Gene', (14, 18))	('HDAC', 'Gene', '9734', (14, 18))	('cancer', 'Disease', 'MESH:D009369', (211, 217))	('men', 'Species', '9606', (223, 226))	('promoting', 'PosReg', (49, 58))	('cancer', 'Disease', (30, 36))	('cancer', 'Disease', (211, 217))	('Inhibitors', 'Var', (0, 10))	('promoting', 'PosReg', (97, 106))	('histones', 'Protein', (74, 82))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('esophageal cancer', 'Disease', (200, 217))	('acetylation', 'MPA', (59, 70))	('esophageal cancer', 'Disease', 'MESH:D004938', (200, 217))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('acetylation', 'MPA', (107, 118))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
39307	29581778	The antibodies against Beclin-1, LC3, p-Akt (Ser473), Akt, p-mTOR (Ser2448), mTOR, Bcl-2, p70S6K, p-p70S6K, Caspase-3, cleaved Caspase-3 and beta-actin were purchased from Santa Cruz Biotechnology (Santa Cruz, CA, USA).	('Beclin-1', 'Gene', (23, 31))	('Akt', 'Gene', '207', (40, 43))	('LC3', 'Gene', (33, 36))	('mTOR', 'Gene', '2475', (77, 81))	('Akt', 'Gene', (54, 57))	('p70S6K', 'Gene', '6198', (100, 106))	('mTOR', 'Gene', '2475', (61, 65))	('Bcl-2', 'Gene', (83, 88))	('Akt', 'Gene', '207', (54, 57))	('Caspase-3, cleaved Caspase-3', 'Gene', '836', (108, 136))	('p70S6K', 'Gene', '6198', (90, 96))	('LC3', 'Gene', '84557', (33, 36))	('beta-actin', 'Gene', '728378', (141, 151))	('Bcl-2', 'Gene', '596', (83, 88))	('Ser2448', 'Chemical', '-', (67, 74))	('p70S6K', 'Gene', (100, 106))	('Ser2448', 'Var', (67, 74))	('Beclin-1', 'Gene', '8678', (23, 31))	('Akt', 'Gene', (40, 43))	('p70S6K', 'Gene', (90, 96))	('mTOR', 'Gene', (77, 81))	('mTOR', 'Gene', (61, 65))	('beta-actin', 'Gene', (141, 151))	('Ser473', 'Chemical', '-', (45, 51))
39344	29581778	Meanwhile, univariate survival analysis for disease-free survival (DFS) also showed similar results, patients with a high expression of Beclin-1 (54.3 % vs. 34.2%, p=0.023) or LC3 (58.6 % vs. 34.1%, p=0.014) had a better 5-year DFS rate.	('patients', 'Species', '9606', (101, 109))	('Beclin-1', 'Gene', (136, 144))	('Beclin-1', 'Gene', '8678', (136, 144))	('DFS', 'CPA', (228, 231))	('LC3', 'Gene', '84557', (176, 179))	('LC3', 'Gene', (176, 179))	('high', 'Var', (117, 121))	('better', 'PosReg', (214, 220))
39348	29581778	As shown in Figure 3, the cell viability was significantly decreased after treatment with BEZ235 or TSA in both Eca-109 and TE-1 cells, indicating that both BEZ235 and TSA had dose dependent anti-tumor effects.	('BEZ235', 'Var', (157, 163))	('TSA', 'Chemical', 'MESH:C012589', (168, 171))	('tumor', 'Disease', (196, 201))	('decreased', 'NegReg', (59, 68))	('BEZ235', 'Var', (90, 96))	('BEZ235', 'Chemical', 'MESH:C531198', (157, 163))	('TSA', 'Chemical', 'MESH:C012589', (100, 103))	('men', 'Species', '9606', (80, 83))	('TE-1', 'CellLine', 'CVCL:1759', (124, 128))	('BEZ235', 'Chemical', 'MESH:C531198', (90, 96))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('cell viability', 'CPA', (26, 40))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))
39354	29581778	The western blot results showed that BEZ235 inhibited the expression of p-mTOR, p-AKT and p-p70S6K in Eca-109 cells (P<0.05).	('p70S6K', 'Gene', '6198', (92, 98))	('p70S6K', 'Gene', (92, 98))	('expression', 'MPA', (58, 68))	('inhibited', 'NegReg', (44, 53))	('mTOR', 'Gene', (74, 78))	('mTOR', 'Gene', '2475', (74, 78))	('AKT', 'Gene', '207', (82, 85))	('BEZ235', 'Var', (37, 43))	('AKT', 'Gene', (82, 85))	('BEZ235', 'Chemical', 'MESH:C531198', (37, 43))
39358	29581778	After the combination with BEZ235 and TSA, it significantly inhibited the phosphorylation of mTOR, AKT and p70S6K in both Eca-109 and TE-1 cells relative to single drug.	('phosphorylation', 'MPA', (74, 89))	('BEZ235', 'Var', (27, 33))	('mTOR', 'Gene', (93, 97))	('TE-1', 'CellLine', 'CVCL:1759', (134, 138))	('mTOR', 'Gene', '2475', (93, 97))	('AKT', 'Gene', '207', (99, 102))	('BEZ235', 'Chemical', 'MESH:C531198', (27, 33))	('TSA', 'Chemical', 'MESH:C012589', (38, 41))	('inhibited', 'NegReg', (60, 69))	('p70S6K', 'Gene', (107, 113))	('AKT', 'Gene', (99, 102))	('p70S6K', 'Gene', '6198', (107, 113))	('combination', 'Interaction', (10, 21))
39363	29581778	These results suggested that co-treatment with BEZ235 and TSA synergistically induced apoptosis through both the mitochondrial pathway and the caspase-dependent pathway for cell death in ESCC cells.	('BEZ235', 'Chemical', 'MESH:C531198', (47, 53))	('caspase-dependent pathway', 'Pathway', (143, 168))	('TSA', 'Chemical', 'MESH:C012589', (58, 61))	('induced', 'Reg', (78, 85))	('men', 'Species', '9606', (37, 40))	('mitochondrial pathway', 'Pathway', (113, 134))	('BEZ235', 'Var', (47, 53))	('apoptosis', 'CPA', (86, 95))
39364	29581778	Compared with treatment with either drug alone, the apoptotic relative proteins LC3-I, LC3-II and Beclin-1 were detected and immunoblotting analysis found co-treatment with BEZ235 and TSA significantly increased the expression of both LC3-II and Beclin-1 in ESCC cells, but the effect on the expression of LC3-I was no obvious (Figure 6).	('Beclin-1', 'Gene', (246, 254))	('LC3', 'Gene', '84557', (306, 309))	('LC3', 'Gene', (87, 90))	('LC3', 'Gene', (80, 83))	('LC3-II', 'Gene', '84557', (235, 241))	('men', 'Species', '9606', (19, 22))	('Beclin-1', 'Gene', '8678', (98, 106))	('expression', 'MPA', (216, 226))	('BEZ235', 'Chemical', 'MESH:C531198', (173, 179))	('LC3', 'Gene', (235, 238))	('Beclin-1', 'Gene', (98, 106))	('increased', 'PosReg', (202, 211))	('LC3', 'Gene', '84557', (87, 90))	('LC3', 'Gene', '84557', (80, 83))	('LC3-II', 'Gene', (87, 93))	('LC3', 'Gene', (306, 309))	('TSA', 'Chemical', 'MESH:C012589', (184, 187))	('men', 'Species', '9606', (163, 166))	('Beclin-1', 'Gene', '8678', (246, 254))	('LC3-II', 'Gene', '84557', (87, 93))	('BEZ235', 'Var', (173, 179))	('LC3', 'Gene', '84557', (235, 238))	('LC3-II', 'Gene', (235, 241))
39366	29581778	Our finding indicated that co-treatment with BEZ235 and TSA exhibited anti-cancer effects through not only autophagy but also apoptosis pathways in ESCC cells.	('men', 'Species', '9606', (35, 38))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('autophagy', 'CPA', (107, 116))	('BEZ235', 'Var', (45, 51))	('cancer', 'Disease', (75, 81))	('BEZ235', 'Chemical', 'MESH:C531198', (45, 51))	('TSA', 'Chemical', 'MESH:C012589', (56, 59))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('ESCC', 'Disease', (148, 152))	('apoptosis pathways', 'CPA', (126, 144))
39368	29581778	Abnormal regulation of PCD is associated with a wide variety of human diseases, including cancer.	('associated', 'Reg', (30, 40))	('human', 'Species', '9606', (64, 69))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('PCD', 'Disease', (23, 26))	('PCD', 'Disease', 'MESH:D007619', (23, 26))	('Abnormal', 'Var', (0, 8))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))
39385	29581778	Patients with a high expression of Beclin-1 or LC3 had a better OS or DFS.	('high expression', 'Var', (16, 31))	('LC3', 'Gene', '84557', (47, 50))	('LC3', 'Gene', (47, 50))	('DFS', 'CPA', (70, 73))	('Beclin-1', 'Gene', (35, 43))	('Patients', 'Species', '9606', (0, 8))	('Beclin-1', 'Gene', '8678', (35, 43))	('better', 'PosReg', (57, 63))	('OS', 'Chemical', 'MESH:D009992', (64, 66))
39388	29581778	The PI3K/mTOR pathway dysregulation has been found in various tumors and plays a crucial role in regulation of cell proliferation, apoptosis and autophagy.	('dysregulation', 'Var', (22, 35))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumors', 'Disease', (62, 68))	('tumors', 'Disease', 'MESH:D009369', (62, 68))	('mTOR', 'Gene', (9, 13))	('autophagy', 'CPA', (145, 154))	('mTOR', 'Gene', '2475', (9, 13))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('cell proliferation', 'CPA', (111, 129))	('apoptosis', 'CPA', (131, 140))
39391	29581778	Our study found BEZ235, the dual inhibitor of mTOR and PI3K can reduce viability of ESCC cells in a dose-dependent manner caused by the significant reduction in p-Akt, p-mTOR and p-p70S6K activity on Eca-109 and TE-1 cells.	('TE-1', 'CellLine', 'CVCL:1759', (212, 216))	('reduction', 'NegReg', (148, 157))	('Akt', 'Gene', (163, 166))	('reduce', 'NegReg', (64, 70))	('mTOR', 'Gene', '2475', (46, 50))	('mTOR', 'Gene', (170, 174))	('BEZ235', 'Chemical', 'MESH:C531198', (16, 22))	('BEZ235', 'Var', (16, 22))	('mTOR', 'Gene', (46, 50))	('PI3K', 'Var', (55, 59))	('p70S6K', 'Gene', (181, 187))	('mTOR', 'Gene', '2475', (170, 174))	('activity', 'MPA', (188, 196))	('p70S6K', 'Gene', '6198', (181, 187))	('viability', 'CPA', (71, 80))	('Akt', 'Gene', '207', (163, 166))
39392	29581778	After BEZ235 intervention, the autophagy or apoptosis-related proteins beclin-1, LC3-II, ratio of LC3-II/LC3-I and cleaved caspase-3 were increased as well as caspase-3 and BCL-2 decreased.	('BEZ235', 'Var', (6, 12))	('caspase-3', 'Gene', '836', (159, 168))	('LC3', 'Gene', '84557', (105, 108))	('ratio of', 'MPA', (89, 97))	('LC3', 'Gene', '84557', (81, 84))	('LC3', 'Gene', '84557', (98, 101))	('LC3-II', 'Gene', (81, 87))	('increased', 'PosReg', (138, 147))	('caspase-3', 'Gene', (159, 168))	('autophagy', 'CPA', (31, 40))	('LC3-II', 'Gene', (98, 104))	('apoptosis-related', 'CPA', (44, 61))	('LC3-II', 'Gene', '84557', (81, 87))	('beclin-1', 'Gene', '8678', (71, 79))	('LC3-II', 'Gene', '84557', (98, 104))	('BEZ235', 'Chemical', 'MESH:C531198', (6, 12))	('BCL-2', 'Gene', '596', (173, 178))	('LC3', 'Gene', (105, 108))	('BCL-2', 'Gene', (173, 178))	('LC3', 'Gene', (98, 101))	('beclin-1', 'Gene', (71, 79))	('LC3', 'Gene', (81, 84))	('decreased', 'NegReg', (179, 188))	('caspase-3', 'Gene', '836', (123, 132))	('caspase-3', 'Gene', (123, 132))
39393	29581778	The study reveals that BEZ235 inhibits the PI3K/mTOR pathway and induces the autophagy and apoptosis in human esophageal cancer cells.	('mTOR', 'Gene', '2475', (48, 52))	('BEZ235', 'Chemical', 'MESH:C531198', (23, 29))	('mTOR', 'Gene', (48, 52))	('apoptosis', 'CPA', (91, 100))	('induces', 'PosReg', (65, 72))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('human', 'Species', '9606', (104, 109))	('esophageal cancer', 'Disease', (110, 127))	('autophagy', 'CPA', (77, 86))	('esophageal cancer', 'Disease', 'MESH:D004938', (110, 127))	('BEZ235', 'Var', (23, 29))	('inhibits', 'NegReg', (30, 38))
39394	29581778	Epigenetic mechanisms, such as modifications of DNA-structure or histone modification play particularly important roles in controlling PCD, such as autophagy, apoptosis and necroptosis in tumor cells.	('tumor', 'Disease', (188, 193))	('DNA-structure', 'Protein', (48, 61))	('PCD', 'Disease', (135, 138))	('modifications', 'Var', (31, 44))	('autophagy', 'CPA', (148, 157))	('PCD', 'Disease', 'MESH:D007619', (135, 138))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('necroptosis', 'CPA', (173, 184))	('histone', 'Protein', (65, 72))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('apoptosis', 'CPA', (159, 168))
39396	29581778	HDAC inhibitors cause changes in the acetylation status of chromatin and other non-histone proteins, resulting in changes in gene expression, induction of apoptosis and inhibition of angiogenesis and metastasis.	('HDAC', 'Gene', (0, 4))	('inhibition', 'NegReg', (169, 179))	('changes', 'Reg', (22, 29))	('HDAC', 'Gene', '9734', (0, 4))	('inhibitors', 'Var', (5, 15))	('acetylation status', 'MPA', (37, 55))	('induction', 'Reg', (142, 151))	('gene expression', 'MPA', (125, 140))	('apoptosis', 'CPA', (155, 164))	('changes', 'Reg', (114, 121))
39399	29581778	Chen et al found co-treatment with BEZ235 and TSA enhanced autophagic cell death and blocked tumor growth without noticeable side effects in breast cancer.	('autophagic cell death', 'CPA', (59, 80))	('breast cancer', 'Phenotype', 'HP:0003002', (141, 154))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('BEZ235', 'Var', (35, 41))	('tumor', 'Disease', (93, 98))	('blocked', 'NegReg', (85, 92))	('breast cancer', 'Disease', 'MESH:D001943', (141, 154))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('BEZ235', 'Chemical', 'MESH:C531198', (35, 41))	('breast cancer', 'Disease', (141, 154))	('enhanced', 'PosReg', (50, 58))	('TSA', 'Chemical', 'MESH:C012589', (46, 49))	('men', 'Species', '9606', (25, 28))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
39403	29581778	Our recently study found co-treatment with BEZ235 and TSA could inhibit the growth and visibility in human esophageal cancer Eca-109 and TE-1 cells and enhanced autophagic cell death by up-regulating the expression of LC3-II and Beclin-1.	('up-regulating', 'PosReg', (186, 199))	('TE-1', 'CellLine', 'CVCL:1759', (137, 141))	('inhibit', 'NegReg', (64, 71))	('esophageal cancer', 'Disease', 'MESH:D004938', (107, 124))	('LC3-II', 'Gene', '84557', (218, 224))	('enhanced', 'PosReg', (152, 160))	('BEZ235', 'Var', (43, 49))	('esophageal cancer', 'Disease', (107, 124))	('men', 'Species', '9606', (33, 36))	('autophagic cell death', 'CPA', (161, 182))	('Beclin-1', 'Gene', (229, 237))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('human', 'Species', '9606', (101, 106))	('expression', 'MPA', (204, 214))	('BEZ235', 'Chemical', 'MESH:C531198', (43, 49))	('Beclin-1', 'Gene', '8678', (229, 237))	('growth', 'CPA', (76, 82))	('LC3-II', 'Gene', (218, 224))	('TSA', 'Chemical', 'MESH:C012589', (54, 57))
39404	29581778	Meanwhile, co-treatment with BEZ235 and TSA can increase the expression of cleaved caspase-3 and decrease the expression of caspase-3 and BCL-2.	('caspase-3', 'Gene', (124, 133))	('caspase-3', 'Gene', '836', (83, 92))	('BCL-2', 'Gene', '596', (138, 143))	('TSA', 'Chemical', 'MESH:C012589', (40, 43))	('BEZ235', 'Chemical', 'MESH:C531198', (29, 35))	('BEZ235', 'Var', (29, 35))	('BCL-2', 'Gene', (138, 143))	('caspase-3', 'Gene', '836', (124, 133))	('expression', 'MPA', (110, 120))	('men', 'Species', '9606', (19, 22))	('decrease', 'NegReg', (97, 105))	('caspase-3', 'Gene', (83, 92))	('expression', 'MPA', (61, 71))	('increase', 'PosReg', (48, 56))
39405	29581778	These results suggested that co-treatment with BEZ235 and TSA synergistically induced apoptosis and autophagy.	('BEZ235', 'Chemical', 'MESH:C531198', (47, 53))	('TSA', 'Chemical', 'MESH:C012589', (58, 61))	('autophagy', 'CPA', (100, 109))	('men', 'Species', '9606', (37, 40))	('induced', 'PosReg', (78, 85))	('BEZ235', 'Var', (47, 53))	('apoptosis', 'CPA', (86, 95))
39411	29581778	Co-treatment with BEZ235 and TSA is more effective than single drug in inhibiting the viability of ESCC cells in Vitro through inducing apoptosis and autophagy, which can be a new effective therapeutic target in ESCCs.	('inhibiting', 'NegReg', (71, 81))	('apoptosis', 'CPA', (136, 145))	('men', 'Species', '9606', (8, 11))	('BEZ235', 'Var', (18, 24))	('viability', 'CPA', (86, 95))	('BEZ235', 'Chemical', 'MESH:C531198', (18, 24))	('autophagy', 'CPA', (150, 159))	('inducing', 'NegReg', (127, 135))	('TSA', 'Chemical', 'MESH:C012589', (29, 32))
39418	29212181	Notably IGF2BP3 was directly associated with a deubiquitinase Ubiquitin specific peptidase 10 (USP10) and attenuated its function in stabilizing p53 protein.	('Ubiquitin specific peptidase 10', 'Gene', (62, 93))	('attenuated', 'NegReg', (106, 116))	('p53', 'Gene', (145, 148))	('p53', 'Gene', '7157', (145, 148))	('Ubiquitin specific peptidase 10', 'Gene', '9100', (62, 93))	('USP10', 'Gene', (95, 100))	('function', 'MPA', (121, 129))	('USP10', 'Gene', '9100', (95, 100))	('associated', 'Reg', (29, 39))	('stabilizing', 'MPA', (133, 144))	('IGF2BP3', 'Var', (8, 15))
39419	29212181	Silencing IGF2BP3 expression in lung cancer cells consistently increased the half-life and protein level of p53 and induced G0/G1 arrest.	('G0/G1 arrest', 'CPA', (124, 136))	('increased', 'PosReg', (63, 72))	('p53', 'Gene', (108, 111))	('p53', 'Gene', '7157', (108, 111))	('induced', 'Reg', (116, 123))	('lung cancer', 'Disease', 'MESH:D008175', (32, 43))	('IGF2BP3', 'Gene', (10, 17))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('half-life', 'MPA', (77, 86))	('Silencing', 'Var', (0, 9))	('protein level', 'MPA', (91, 104))	('lung cancer', 'Disease', (32, 43))	('lung cancer', 'Phenotype', 'HP:0100526', (32, 43))
39420	29212181	Thus, our data together demonstrate that IGF2BP3 promotes lung tumorigenesis via attenuating p53 protein stability.	('tumor', 'Disease', (63, 68))	('p53', 'Gene', (93, 96))	('p53', 'Gene', '7157', (93, 96))	('promotes', 'PosReg', (49, 57))	('IGF2BP3', 'Var', (41, 48))	('attenuating', 'NegReg', (81, 92))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
39433	29212181	It can directly promote the stem-like features in triple-negative breast cancer by modulating SLUG.	('modulating', 'Var', (83, 93))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('breast cancer', 'Disease', 'MESH:D001943', (66, 79))	('breast cancer', 'Disease', (66, 79))	('SLUG', 'Gene', '6591', (94, 98))	('breast cancer', 'Phenotype', 'HP:0003002', (66, 79))	('SLUG', 'Gene', (94, 98))	('stem-like features', 'CPA', (28, 46))	('promote', 'PosReg', (16, 23))
39434	29212181	Thus, IGF2BP3 was supposed to promote tumorigenesis mainly depends on its mRNA binding capacity and positively modulating transcript levels of oncogene.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('promote', 'PosReg', (30, 37))	('mRNA', 'MPA', (74, 78))	('IGF2BP3', 'Var', (6, 13))	('modulating', 'Reg', (111, 121))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('transcript levels', 'MPA', (122, 139))
39441	29212181	In the current study, we identified an unknown function of IGF2BP3 in lung tumorigenesis, by which IGF2BP3 attenuated the protein stability of p53 independent of its mRNA binding activity.	('p53', 'Gene', '7157', (143, 146))	('attenuated', 'NegReg', (107, 117))	('IGF2BP3', 'Var', (99, 106))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('p53', 'Gene', (143, 146))	('tumor', 'Disease', (75, 80))	('protein stability', 'MPA', (122, 139))
39484	29212181	As shown in Figure 5A, IGF2BP3 protein and mRNA levels were significantly reduced in IGF2BP3 knockdown A549 cells.	('knockdown', 'Var', (93, 102))	('IGF2BP3', 'Gene', (23, 30))	('IGF2BP3', 'Gene', (85, 92))	('A549', 'CellLine', 'CVCL:0023', (103, 107))	('mRNA levels', 'MPA', (43, 54))	('reduced', 'NegReg', (74, 81))
39485	29212181	Then CCK-8 assay was used to assess the proliferation potential of A549 cells with IGF2BP3 knockdown.	('A549', 'CellLine', 'CVCL:0023', (67, 71))	('IGF2BP3', 'Gene', (83, 90))	('knockdown', 'Var', (91, 100))
39486	29212181	In HCT116 cells, knockdown of IGF2BP3 expression had the similar results on cell proliferation and colony formation (Supplementary Figure 5.).	('IGF2BP3', 'Gene', (30, 37))	('colony formation', 'CPA', (99, 115))	('HCT116', 'CellLine', 'CVCL:0291', (3, 9))	('cell proliferation', 'CPA', (76, 94))	('knockdown', 'Var', (17, 26))
39487	29212181	These data together indicate that knockdown of IGF2BP3 in lung cancer cells suppresses cell proliferation, migration and invasion.	('IGF2BP3', 'Gene', (47, 54))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('lung cancer', 'Disease', (58, 69))	('cell proliferation', 'CPA', (87, 105))	('lung cancer', 'Phenotype', 'HP:0100526', (58, 69))	('knockdown', 'Var', (34, 43))	('suppresses', 'NegReg', (76, 86))	('lung cancer', 'Disease', 'MESH:D008175', (58, 69))
39488	29212181	To investigate the molecular mechanism by which IGF2BP3 promoted lung tumorigenesis, we performed immunoprecipitation assay followed by mass spectrometry (MS) to identify IGF2BP3-assoicated proteins.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('tumor', 'Disease', (70, 75))	('IGF2BP3', 'Var', (48, 55))	('promoted', 'PosReg', (56, 64))
39495	29212181	Then, to answer which domain of IGF2BP3 is involved in the interaction between IGF2BP3 and USP10, we constructed truncated mutants of IGF2BP3 (Figure 6D).	('IGF2BP3', 'Gene', (134, 141))	('interaction', 'Interaction', (59, 70))	('USP10', 'Gene', (91, 96))	('USP10', 'Gene', '9100', (91, 96))	('mutants', 'Var', (123, 130))
39496	29212181	Co-IP and western blotting analysis revealed that the C-terminal KH domains of IGF2BP3 are required for their interaction with USP10, as deletion of these regions completely abolished their interaction with USP10 (Figure 6E).	('USP10', 'Gene', '9100', (127, 132))	('abolished', 'NegReg', (174, 183))	('USP10', 'Gene', (207, 212))	('interaction', 'Interaction', (110, 121))	('deletion', 'Var', (137, 145))	('USP10', 'Gene', (127, 132))	('IGF2BP3', 'Gene', (79, 86))	('USP10', 'Gene', '9100', (207, 212))	('interaction', 'Interaction', (190, 201))
39500	29212181	In IGF2BP3 overexpressing cells, the half-life of the p53 protein was decreased (Figure 6F).	('IGF2BP3', 'Gene', (3, 10))	('decreased', 'NegReg', (70, 79))	('p53', 'Gene', (54, 57))	('half-life', 'MPA', (37, 46))	('p53', 'Gene', '7157', (54, 57))	('overexpressing', 'Var', (11, 25))
39502	29212181	And the results showed that compared with USP10 alone group, IGF2BP3 coexpression promoted the ubiquitination level of p53 (Figure 6H).	('promoted', 'PosReg', (82, 90))	('IGF2BP3', 'Gene', (61, 68))	('p53', 'Gene', '7157', (119, 122))	('USP10', 'Gene', (42, 47))	('ubiquitination level', 'MPA', (95, 115))	('p53', 'Gene', (119, 122))	('coexpression', 'Var', (69, 81))	('USP10', 'Gene', '9100', (42, 47))
39503	29212181	These data together suggest that IGF2BP3 reduces p53 level by attenuating the deubiquitinating effect of USP10 on p53.	('IGF2BP3', 'Var', (33, 40))	('p53', 'Gene', (49, 52))	('p53', 'Gene', '7157', (49, 52))	('p53', 'Gene', (114, 117))	('reduces', 'NegReg', (41, 48))	('p53', 'Gene', '7157', (114, 117))	('USP10', 'Gene', (105, 110))	('USP10', 'Gene', '9100', (105, 110))	('attenuating', 'NegReg', (62, 73))
39505	29212181	In IGF2BP3 silencing A549 cells, we observed a marked increase of p53 protein level, concurrent with p21 upregulation (Figure 7A).	('silencing', 'Var', (11, 20))	('A549', 'CellLine', 'CVCL:0023', (21, 25))	('p53', 'Gene', '7157', (66, 69))	('upregulation', 'PosReg', (105, 117))	('IGF2BP3', 'Gene', (3, 10))	('increase', 'PosReg', (54, 62))	('p21', 'Gene', (101, 104))	('p21', 'Gene', '644914', (101, 104))	('p53', 'Gene', (66, 69))
39506	29212181	Notably, the mRNA expression of p53 was not changed in IGF2BP3 knockdown cells compared to control cells (Figure 7B).	('mRNA expression', 'MPA', (13, 28))	('p53', 'Gene', (32, 35))	('p53', 'Gene', '7157', (32, 35))	('IGF2BP3', 'Gene', (55, 62))	('knockdown', 'Var', (63, 72))
39507	29212181	Consistently, the half-life of the p53 protein in IGF2BP3 knockdown A549 cells was longer than the control cells (Figure 7C and 7D).	('IGF2BP3', 'Gene', (50, 57))	('p53', 'Gene', (35, 38))	('half-life', 'MPA', (18, 27))	('A549', 'CellLine', 'CVCL:0023', (68, 72))	('p53', 'Gene', '7157', (35, 38))	('longer', 'PosReg', (83, 89))	('protein', 'Protein', (39, 46))	('knockdown', 'Var', (58, 67))
39510	29212181	To further determine whether the function of IGF2BP3 is dependent on p53, we used doxorubicin and etoposide, as DNA damage agents which can induce p53 activation, to treat A549 (p53 positive) and H1299 (p53 negative) lung cancer cell lines in the presence of IGF2BP3 or not.	('IGF2BP3', 'Var', (259, 266))	('p53', 'Gene', '7157', (178, 181))	('p53', 'Gene', (69, 72))	('lung cancer', 'Disease', (217, 228))	('p53', 'Gene', (147, 150))	('p53', 'Gene', '7157', (69, 72))	('lung cancer', 'Phenotype', 'HP:0100526', (217, 228))	('A549', 'CellLine', 'CVCL:0023', (172, 176))	('doxorubicin', 'Chemical', 'MESH:D004317', (82, 93))	('etoposide', 'Chemical', 'MESH:D005047', (98, 107))	('p53', 'Gene', '7157', (147, 150))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('lung cancer', 'Disease', 'MESH:D008175', (217, 228))	('p53', 'Gene', (178, 181))	('p53', 'Gene', '7157', (203, 206))	('H1299', 'CellLine', 'CVCL:0060', (196, 201))	('p53', 'Gene', (203, 206))
39523	29212181	The dysregulation of IGF2BP3 expression in cancer tissue suggests a potential role for this molecule in tumorigenesis.	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('cancer', 'Disease', (43, 49))	('dysregulation', 'Var', (4, 17))	('IGF2BP3', 'Gene', (21, 28))	('tumor', 'Disease', (104, 109))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
39526	29212181	Kaplan-Meier database suggests that lung cancer patients with high IGF2BP3 has relatively short survival time.	('lung cancer', 'Disease', (36, 47))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('lung cancer', 'Disease', 'MESH:D008175', (36, 47))	('lung cancer', 'Phenotype', 'HP:0100526', (36, 47))	('high', 'Var', (62, 66))	('patients', 'Species', '9606', (48, 56))	('IGF2BP3', 'Gene', (67, 74))
39530	29212181	By knocking down the expression of IGF2BP3 in A549 and HCT116 cells, the proliferation, migration and invasion potential of these cells were dramatically inhibited.	('invasion potential', 'CPA', (102, 120))	('knocking', 'Var', (3, 11))	('proliferation', 'CPA', (73, 86))	('inhibited', 'NegReg', (154, 163))	('IGF2BP3', 'Gene', (35, 42))	('HCT116', 'CellLine', 'CVCL:0291', (55, 61))	('A549', 'CellLine', 'CVCL:0023', (46, 50))
39540	29212181	Then our following studies focused on whether IGF2BP3 also regulated the protein stability of p53 via USP10.	('IGF2BP3', 'Var', (46, 53))	('p53', 'Gene', (94, 97))	('p53', 'Gene', '7157', (94, 97))	('protein stability', 'MPA', (73, 90))	('USP10', 'Gene', (102, 107))	('regulated', 'Reg', (59, 68))	('USP10', 'Gene', '9100', (102, 107))
39542	29212181	It suggested that IGF2BP3 indeed reduced the protein expression level of p53.	('p53', 'Gene', (73, 76))	('p53', 'Gene', '7157', (73, 76))	('IGF2BP3', 'Var', (18, 25))	('reduced', 'NegReg', (33, 40))
39546	29212181	The deregulation of p53 expression and function was associated with multiple cancers.	('deregulation', 'Var', (4, 16))	('p53', 'Gene', (20, 23))	('p53', 'Gene', '7157', (20, 23))	('cancers', 'Phenotype', 'HP:0002664', (77, 84))	('expression', 'MPA', (24, 34))	('associated', 'Reg', (52, 62))	('multiple cancers', 'Disease', (68, 84))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('multiple cancers', 'Disease', 'MESH:D009369', (68, 84))	('function', 'MPA', (39, 47))
39547	29212181	Here, we defined a novel mechanism by which IGF2BP3 reduced the p53 level and promoted the tumorigenesis of lung tissues.	('IGF2BP3', 'Var', (44, 51))	('reduced', 'NegReg', (52, 59))	('promoted', 'PosReg', (78, 86))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('p53', 'Gene', (64, 67))	('tumor', 'Disease', (91, 96))	('p53', 'Gene', '7157', (64, 67))
39567	29212181	After growth for 2 weeks, GFP positive cell clones were screened to 24-well plates in RPMI 1640 with 400 mug/ml G418 and 10% FBS.	('G418', 'Chemical', 'MESH:C010680', (112, 116))	('FBS', 'Disease', (125, 128))	('RPMI 1640', 'Chemical', '-', (86, 95))	('G418', 'Var', (112, 116))	('FBS', 'Disease', 'MESH:D005198', (125, 128))
39577	29212181	Antibodies used included anti-IGF2BP3 (Sigma-Aldrich), anti-GAPDH (Proteintech Group Inc, Chicago, Illinois, USA), anti-GFP (MBL Inc, Japan), anti-p53 (Proteintech), anti-p21 (Proteintech), anti-ERK (Cell Signaling Technology, Beverly, MA, USA) anti-Flag and anti-HA(Sigma-Aldrich).	('p21', 'Gene', (171, 174))	('ERK', 'Gene', (195, 198))	('p21', 'Gene', '644914', (171, 174))	('p53', 'Gene', (147, 150))	('anti-GFP', 'Var', (115, 123))	('MBL', 'Gene', '50639', (125, 128))	('anti-IGF2BP3', 'Var', (25, 37))	('p53', 'Gene', '7157', (147, 150))	('ERK', 'Gene', '5594', (195, 198))	('GAPDH', 'Gene', '2597', (60, 65))	('GAPDH', 'Gene', (60, 65))	('MBL', 'Gene', (125, 128))
39613	29212181	IGF2BP3 knockdown or control A549 cells (5 x 104) were harvested and fixed in ice cold 70% ethanol for 30 min.	('IGF2BP3', 'Gene', (0, 7))	('knockdown', 'Var', (8, 17))	('A549', 'CellLine', 'CVCL:0023', (29, 33))	('ethanol', 'Chemical', 'MESH:D000431', (91, 98))
39643	28899363	LJM716 is distinct from other HER2:HER3-targeted therapies in that it binds a conformational epitope that traps HER3 in the inactive conformation preventing its receptor activation, and possesses the unique ability to inhibit both ligand-induced and ligand-independent activation of HER3.	('receptor activation', 'MPA', (161, 180))	('HER3', 'Gene', (35, 39))	('inhibit', 'NegReg', (218, 225))	('HER3', 'Gene', '2065', (35, 39))	('HER3', 'Gene', (283, 287))	('LJM716', 'Chemical', '-', (0, 6))	('HER2', 'Gene', (30, 34))	('HER3', 'Gene', (112, 116))	('HER3', 'Gene', '2065', (283, 287))	('HER2', 'Gene', '2064', (30, 34))	('HER3', 'Gene', '2065', (112, 116))	('LJM716', 'Var', (0, 6))
39708	28899363	NGS studies indicated PI3K pathway activation through PIK3CA mutation (11 patients) and PIK3CA gene amplification (six patients); changes in PTEN genes, either through functional mutation, copy number loss, or frame shift, were also detected in five patients (see Additional file 4: Figure S1B).	('PTEN', 'Gene', (141, 145))	('PIK3CA', 'Gene', '5290', (88, 94))	('PIK3CA', 'Gene', (54, 60))	('PTEN', 'Gene', '5728', (141, 145))	('PI3', 'Gene', (22, 25))	('changes', 'Reg', (130, 137))	('PIK3CA', 'Gene', '5290', (54, 60))	('mutation', 'Var', (61, 69))	('patients', 'Species', '9606', (250, 258))	('patients', 'Species', '9606', (74, 82))	('patients', 'Species', '9606', (119, 127))	('amp', 'Chemical', 'MESH:D000249', (100, 103))	('frame shift', 'Var', (210, 221))	('PIK3CA', 'Gene', (88, 94))	('copy number loss', 'Var', (189, 205))	('activation', 'PosReg', (35, 45))	('PI3', 'Gene', '5266', (22, 25))
39709	28899363	It is noteworthy that tumor shrinkage of >20% was observed in 2 patients with confirmed PIK3CA mutation (Additional file 4: Figure S1B).	('PIK3CA', 'Gene', '5290', (88, 94))	('patients', 'Species', '9606', (64, 72))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('tumor', 'Disease', (22, 27))	('PIK3CA', 'Gene', (88, 94))	('mutation', 'Var', (95, 103))
39719	28899363	Similarly, patients with SCCHN might benefit from combining LJM716 with anti-EGFR therapy.	('LJM716', 'Chemical', '-', (60, 66))	('combining', 'Interaction', (50, 59))	('SCCHN', 'Disease', (25, 30))	('LJM716', 'Var', (60, 66))	('EGFR', 'Gene', '1956', (77, 81))	('patients', 'Species', '9606', (11, 19))	('EGFR', 'Gene', (77, 81))
39720	28899363	Furthermore, although ESCC and SCCHN are considered to have frequent deregulation in HER2/HER3, we did not preselect patients with such aberrations, and patients with other downstream mutations or amplifications were not excluded (11 patients had PIK3CA mutation and six patients had PIK3CA gene amplification).	('PIK3CA', 'Gene', (284, 290))	('deregulation', 'MPA', (69, 81))	('PIK3CA', 'Gene', (247, 253))	('PIK3CA', 'Gene', '5290', (284, 290))	('HER3', 'Gene', (90, 94))	('amp', 'Chemical', 'MESH:D000249', (197, 200))	('patients', 'Species', '9606', (153, 161))	('ESCC', 'Disease', (22, 26))	('HER3', 'Gene', '2065', (90, 94))	('HER2', 'Gene', (85, 89))	('PIK3CA', 'Gene', '5290', (247, 253))	('mutation', 'Var', (254, 262))	('patients', 'Species', '9606', (234, 242))	('patients', 'Species', '9606', (271, 279))	('HER2', 'Gene', '2064', (85, 89))	('amp', 'Chemical', 'MESH:D000249', (296, 299))	('patients', 'Species', '9606', (117, 125))
39722	28899363	Similarly, RG7116 combined with cetuximab or erlotinib has demonstrated preliminary signs of clinical activity in patients with HER3-expressing tumors.	('tumors', 'Disease', (144, 150))	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('HER3', 'Gene', (128, 132))	('tumors', 'Disease', 'MESH:D009369', (144, 150))	('HER3', 'Gene', '2065', (128, 132))	('cetuximab', 'Chemical', 'MESH:D000068818', (32, 41))	('patients', 'Species', '9606', (114, 122))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('RG7116', 'Var', (11, 17))	('erlotinib', 'Chemical', 'MESH:D000069347', (45, 54))
39723	28899363	Future studies of LJM716 will also evaluate LJM716 in combination with other therapeutic agents, including the PI3K inhibitor alpelisib (BYL719) in patients with ESCC, and as part of the triple combination of LJM716, alpelisib, and trastuzumab in patients with HER2-overexpressing breast cancer, in which preliminary data have indicated antitumor activity in patients with PIK3CA mutations.	('tumor', 'Phenotype', 'HP:0002664', (341, 346))	('alpelisib', 'Chemical', 'MESH:C585539', (217, 226))	('ESCC', 'Disease', (162, 166))	('cancer', 'Phenotype', 'HP:0002664', (288, 294))	('patients', 'Species', '9606', (148, 156))	('PIK3CA', 'Gene', '5290', (373, 379))	('mutations', 'Var', (380, 389))	('PI3', 'Gene', '5266', (111, 114))	('LJM716', 'Chemical', '-', (44, 50))	('HER2', 'Gene', '2064', (261, 265))	('breast cancer', 'Phenotype', 'HP:0003002', (281, 294))	('LJM716', 'Chemical', '-', (209, 215))	('tumor', 'Disease', (341, 346))	('alpelisib', 'Chemical', 'MESH:C585539', (126, 135))	('patients', 'Species', '9606', (247, 255))	('trastuzumab', 'Chemical', 'MESH:D000068878', (232, 243))	('breast cancer', 'Disease', 'MESH:D001943', (281, 294))	('patients', 'Species', '9606', (359, 367))	('tumor', 'Disease', 'MESH:D009369', (341, 346))	('breast cancer', 'Disease', (281, 294))	('PIK3CA', 'Gene', (373, 379))	('PI3', 'Gene', (111, 114))	('LJM716', 'Chemical', '-', (18, 24))	('HER2', 'Gene', (261, 265))
39737	31276933	Downregulation of Notch Signaling in Kras-Induced Gastric Metaplasia Activating mutations and amplification of Kras and, more frequently, signatures for Kras activation are noted in stomach cancer.	('Kras', 'Gene', '16653', (111, 115))	('amplification', 'Var', (94, 107))	('stomach cancer', 'Phenotype', 'HP:0012126', (182, 196))	('stomach cancer', 'Disease', (182, 196))	('Kras', 'Gene', (37, 41))	('Metaplasia', 'Disease', (58, 68))	('Downregulation', 'NegReg', (0, 14))	('mutations', 'Var', (80, 89))	('Kras', 'Gene', '16653', (37, 41))	('Kras', 'Gene', '16653', (153, 157))	('Notch', 'Gene', (18, 23))	('Notch', 'Gene', '31293', (18, 23))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('Metaplasia', 'Disease', 'MESH:D008679', (58, 68))	('Kras', 'Gene', (111, 115))	('stomach cancer', 'Disease', 'MESH:D013274', (182, 196))	('Kras', 'Gene', (153, 157))
39738	31276933	Expression of mutant KrasG12D in the mouse gastric mucosa has been shown to induce hyperplasia and metaplasia.	('mutant', 'Var', (14, 20))	('KrasG12D', 'Gene', (21, 29))	('metaplasia', 'Disease', 'MESH:D008679', (99, 109))	('hyperplasia', 'Disease', 'MESH:D006965', (83, 94))	('induce', 'Reg', (76, 82))	('metaplasia', 'Disease', (99, 109))	('mouse', 'Species', '10090', (37, 42))	('hyperplasia', 'Disease', (83, 94))
39739	31276933	However, the mechanisms by which Kras activation leads to gastric metaplasia are not fully understood.	('Kras', 'Gene', (33, 37))	('activation', 'Var', (38, 48))	('gastric metaplasia', 'Disease', 'MESH:D008679', (58, 76))	('leads to', 'Reg', (49, 57))	('gastric metaplasia', 'Disease', (58, 76))
39740	31276933	Here we report that KrasLSL-G12D/+;Pdx1-cre, a mouse model known for pancreatic cancer, also mediates KrasG12D expression in the stomach, causing gastric hyperplasia and metaplasia prior to the pathologic changes in the pancreas.	('G12D', 'Mutation', 'rs121913529', (28, 32))	('gastric hyperplasia', 'Phenotype', 'HP:0005207', (146, 165))	('pancreatic cancer', 'Disease', (69, 86))	('causing', 'Reg', (138, 145))	('metaplasia', 'Disease', 'MESH:D008679', (170, 180))	('pancreatic cancer', 'Disease', 'MESH:D010190', (69, 86))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('pancreas', 'Disease', (220, 228))	('mouse', 'Species', '10090', (47, 52))	('metaplasia', 'Disease', (170, 180))	('G12D', 'Mutation', 'rs121913529', (106, 110))	('gastric hyperplasia', 'Disease', (146, 165))	('pathologic changes in the pancreas', 'Phenotype', 'HP:0001732', (194, 228))	('pancreas', 'Disease', 'MESH:D010190', (220, 228))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (69, 86))	('gastric hyperplasia', 'Disease', 'MESH:D013274', (146, 165))	('KrasG12D', 'Var', (102, 110))
39742	31276933	Notch signaling is decreased in the KrasLSL-G12D/+;Pdx1-cre gastric mucosa, as shown by lower levels of cleaved Notch intracellular domains and downregulation of Notch downstream target genes.	('Notch', 'Gene', (0, 5))	('Notch', 'Gene', '31293', (162, 167))	('Notch', 'Gene', '31293', (112, 117))	('KrasLSL-G12D/+;Pdx1-cre', 'Var', (36, 59))	('downregulation', 'NegReg', (144, 158))	('Notch', 'Gene', '31293', (0, 5))	('Notch', 'Gene', (162, 167))	('G12D', 'Mutation', 'rs121913529', (44, 48))	('decreased', 'NegReg', (19, 28))	('lower', 'NegReg', (88, 93))	('Pdx1-cre', 'Var', (51, 59))	('Notch', 'Gene', (112, 117))
39745	31276933	Finally, deletion of Jagged1 or Notch3 in KrasLSL-G12D/+;Pdx1-cre mice promoted development of squamous cell carcinoma in the forestomach, albeit short of invasive adenocarcinoma in the glandular stomach.	('Notch3', 'Gene', (32, 38))	('invasive adenocarcinoma', 'Disease', (155, 178))	('promoted', 'PosReg', (71, 79))	('deletion', 'Var', (9, 17))	('carcinoma', 'Phenotype', 'HP:0030731', (169, 178))	('G12D', 'Mutation', 'rs121913529', (50, 54))	('mice', 'Species', '10090', (66, 70))	('invasive adenocarcinoma', 'Disease', 'MESH:D000230', (155, 178))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (95, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('Jagged1', 'Gene', (21, 28))	('squamous cell carcinoma', 'Disease', (95, 118))	('carcinoma in the glandular stomach', 'Phenotype', 'HP:0006753', (169, 203))	('Notch3', 'Gene', '18131', (32, 38))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (95, 118))
39748	31276933	In gastric adenocarcinoma, activating mutations or amplification of KRAS are detected in approximately 15% of all cases (http://www.cbioportal.org), and signatures for activation of Kras are noted in at least 40% of gastric cancers.	('activating', 'PosReg', (27, 37))	('gastric cancer', 'Phenotype', 'HP:0012126', (216, 230))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('gastric cancers', 'Disease', 'MESH:D013274', (216, 231))	('gastric adenocarcinoma', 'Disease', 'MESH:D013274', (3, 25))	('gastric adenocarcinoma', 'Disease', (3, 25))	('carcinoma', 'Phenotype', 'HP:0030731', (16, 25))	('gastric cancers', 'Disease', (216, 231))	('KRAS', 'Gene', (68, 72))	('gastric cancers', 'Phenotype', 'HP:0012126', (216, 231))	('activation', 'PosReg', (168, 178))	('cancers', 'Phenotype', 'HP:0002664', (224, 231))	('amplification', 'Var', (51, 64))
39751	31276933	Mist1-CreERT2-mediated expression of constitutively activated Kras (KrasG12D) in the gastric chief cells caused the full spectrum of metaplastic lineage transitions, including spasmolytic polypeptide-expressing metaplasia (SPEM) and intestinal metaplasia (IM), two of the preneoplastic lesions associated with intestinal-type stomach cancer.	('metaplasia', 'Disease', (244, 254))	('intestinal metaplasia', 'Disease', (233, 254))	('metaplasia', 'Disease', 'MESH:D008679', (211, 221))	('intestinal-type stomach cancer', 'Disease', 'MESH:D013274', (310, 340))	('cancer', 'Phenotype', 'HP:0002664', (334, 340))	('metaplasia', 'Disease', (211, 221))	('expression', 'Var', (23, 33))	('intestinal metaplasia', 'Disease', 'MESH:D008679', (233, 254))	('stomach cancer', 'Phenotype', 'HP:0012126', (326, 340))	('Kras', 'Gene', (62, 66))	('metaplastic lineage transitions', 'CPA', (133, 164))	('metaplasia', 'Disease', 'MESH:D008679', (244, 254))	('intestinal-type stomach cancer', 'Disease', (310, 340))	('caused', 'Reg', (105, 111))
39752	31276933	Expression of KrasG12D in the corpus lineages including pit cells and their progenitors through Tff1-Cre caused foveolar hyperplasia, gastric atrophy, and pseudopyloric metaplasia with SPEM.	('foveolar hyperplasia', 'Disease', (112, 132))	('KrasG12D', 'Var', (14, 22))	('metaplasia', 'Disease', (169, 179))	('gastric atrophy', 'Disease', (134, 149))	('foveolar hyperplasia', 'Disease', 'MESH:D006965', (112, 132))	('gastric atrophy', 'Disease', 'MESH:D013274', (134, 149))	('caused', 'Reg', (105, 111))	('metaplasia', 'Disease', 'MESH:D008679', (169, 179))
39754	31276933	KrasG12D expression combined with inactivation of E-cadherin and p53 in the gastric parietal cells gave rise to both intestinal- and diffuse-type tumors, whereas KrasG12D expression in rare Mist1-expressing gastric stem cells, in conjunction with Apc mutation or E-cadherin loss, culminated in intestinal- and diffuse-type carcinomas, respectively.	('tumors', 'Disease', 'MESH:D009369', (146, 152))	('p53', 'Gene', (65, 68))	('carcinomas', 'Disease', (323, 333))	('p53', 'Gene', '22060', (65, 68))	('Apc', 'Gene', (247, 250))	('Apc', 'Gene', '11789', (247, 250))	('E-cadherin', 'Gene', (263, 273))	('carcinoma', 'Phenotype', 'HP:0030731', (323, 332))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('E-cadherin', 'Gene', (50, 60))	('inactivation', 'Var', (34, 46))	('tumors', 'Phenotype', 'HP:0002664', (146, 152))	('intestinal-', 'Disease', (294, 305))	('culminated in', 'Reg', (280, 293))	('E-cadherin', 'Gene', '12550', (263, 273))	('E-cadherin', 'Gene', '12550', (50, 60))	('carcinomas', 'Phenotype', 'HP:0030731', (323, 333))	('intestinal-', 'Disease', (117, 128))	('KrasG12D', 'Var', (162, 170))	('carcinomas', 'Disease', 'MESH:D002277', (323, 333))	('tumors', 'Disease', (146, 152))
39756	31276933	Dysregulation of Notch signaling often leads to expansion of stem and progenitor cell population, impaired differentiation, and increased proliferation, ultimately contributing to tumor initiation and progression.	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('Dysregulation', 'Var', (0, 13))	('contributing to', 'Reg', (164, 179))	('differentiation', 'CPA', (107, 122))	('increased', 'PosReg', (128, 137))	('proliferation', 'CPA', (138, 151))	('Notch', 'Gene', (17, 22))	('tumor initiation', 'Disease', 'MESH:D009369', (180, 196))	('impaired', 'NegReg', (98, 106))	('tumor initiation', 'Disease', (180, 196))	('Notch', 'Gene', '31293', (17, 22))	('expansion', 'PosReg', (48, 57))	('leads to', 'Reg', (39, 47))	('rat', 'Species', '10116', (145, 148))
39757	31276933	Molecular alterations in NOTCH genes, including gain- and loss-of-function mutations and gene amplifications, have been found in approximately 22% of human stomach adenocarcinomas (http://www.cbioportal.org).	('human', 'Species', '9606', (150, 155))	('NOTCH', 'Gene', (25, 30))	('stomach adenocarcinomas', 'Disease', 'MESH:D013274', (156, 179))	('carcinoma', 'Phenotype', 'HP:0030731', (169, 178))	('gain-', 'PosReg', (48, 53))	('carcinomas', 'Phenotype', 'HP:0030731', (169, 179))	('stomach adenocarcinomas', 'Disease', (156, 179))	('loss-of-function', 'NegReg', (58, 74))	('mutations', 'Var', (75, 84))	('NOTCH', 'Gene', '31293', (25, 30))	('rat', 'Species', '10116', (14, 17))
39763	31276933	We previously reported drastic upregulation of Notch signaling during the initiation and progression of Kras-driven pancreatic ductal adenocarcinoma as well as Kras-induced gallbladder adenoma in the same mouse model.	('Notch', 'Gene', '31293', (47, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (139, 148))	('pancreatic ductal adenocarcinoma', 'Disease', (116, 148))	('gallbladder adenoma', 'Disease', 'MESH:D000236', (173, 192))	('gallbladder adenoma', 'Disease', (173, 192))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (116, 148))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (116, 148))	('mouse', 'Species', '10090', (205, 210))	('Kras-driven', 'Var', (104, 115))	('gallbladder adenoma', 'Phenotype', 'HP:0012028', (173, 192))	('Notch', 'Gene', (47, 52))	('upregulation', 'PosReg', (31, 43))
39765	31276933	Furthermore, expression of the chief cell marker Mist1 is lost in the KrasLSL-G12D/+;Pdx1-cre corpus, and activation of Notch upregulates Mist1 in stomach cancer cells, providing insights into the Notch functions in stomach cancer pathogenesis.	('stomach cancer', 'Phenotype', 'HP:0012126', (216, 230))	('Notch', 'Gene', '31293', (120, 125))	('KrasLSL-G12D/+', 'Var', (70, 84))	('stomach cancer', 'Disease', (147, 161))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('Mist1', 'Gene', (49, 54))	('activation', 'PosReg', (106, 116))	('Notch', 'Gene', (120, 125))	('stomach cancer', 'Disease', (216, 230))	('Notch', 'Gene', '31293', (197, 202))	('G12D', 'Mutation', 'rs121913529', (78, 82))	('upregulates', 'PosReg', (126, 137))	('stomach cancer', 'Disease', 'MESH:D013274', (147, 161))	('stomach cancer', 'Phenotype', 'HP:0012126', (147, 161))	('expression', 'MPA', (13, 23))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('lost', 'NegReg', (58, 62))	('Mist1', 'Gene', (138, 143))	('stomach cancer', 'Disease', 'MESH:D013274', (216, 230))	('Notch', 'Gene', (197, 202))
39791	31276933	Interestingly, endogenous Pdx1 expression was previously detected in gastric glands in the distal stomach (gastric antrum), and Pdx1-Cre has been used to delete p53, Smad4, and E-cadherin in the stomach, causing diffuse-type gastric adenocarcinoma.	('Pdx1-Cre', 'Gene', '18609', (128, 136))	('E-cadherin', 'Gene', (177, 187))	('p53', 'Gene', '22060', (161, 164))	('E-cadherin', 'Gene', '12550', (177, 187))	('Smad4', 'Gene', (166, 171))	('Pdx1-Cre', 'Gene', (128, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (238, 247))	('Smad4', 'Gene', '17128', (166, 171))	('causing', 'Reg', (204, 211))	('delete', 'Var', (154, 160))	('Pdx1', 'Gene', (26, 30))	('gastric adenocarcinoma', 'Disease', 'MESH:D013274', (225, 247))	('p53', 'Gene', (161, 164))	('gastric adenocarcinoma', 'Disease', (225, 247))
39793	31276933	While the RosaLSL-LacZ/+ control mice showed no positive staining in the stomach, RosaLSL-LacZ/+;Pdx1-Cre mice showed broad X-gal staining in both corpus and antrum of the glandular stomach, and punctuated staining in the forestomach near the border with corpus (Figure 1A).	('Pdx1-Cre', 'Gene', '18609', (97, 105))	('mice', 'Species', '10090', (106, 110))	('RosaLSL-LacZ/+', 'Var', (82, 96))	('Pdx1-Cre', 'Gene', (97, 105))	('mice', 'Species', '10090', (33, 37))	('gal', 'Chemical', 'MESH:C101993', (126, 129))
39807	31276933	We previously reported upregulation of Notch signaling in the pancreas and gallbladder in KC mice, in which expression of KrasG12D induced development of pancreatic ductal adenocarcinoma and gallbladder adenoma, respectively.	('induced', 'Reg', (131, 138))	('Notch', 'Gene', '31293', (39, 44))	('KrasG12D', 'Gene', (122, 130))	('upregulation', 'PosReg', (23, 35))	('pancreatic ductal adenocarcinoma', 'Disease', (154, 186))	('gal', 'Chemical', 'MESH:C101993', (191, 194))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (154, 186))	('gal', 'Chemical', 'MESH:C101993', (75, 78))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (154, 186))	('pancreas', 'Disease', (62, 70))	('mice', 'Species', '10090', (93, 97))	('gallbladder adenoma', 'Disease', (191, 210))	('gallbladder adenoma', 'Disease', 'MESH:D000236', (191, 210))	('Notch', 'Gene', (39, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (177, 186))	('gallbladder adenoma', 'Phenotype', 'HP:0012028', (191, 210))	('pancreas', 'Disease', 'MESH:D010190', (62, 70))	('expression', 'Var', (108, 118))
39817	31276933	Hs746T and SNU-1 are two of the human stomach cancer cell lines with relatively low JAG1 expression, according to expression data from Cancer Cell Line Encyclopedia.	('low', 'NegReg', (80, 83))	('expression', 'MPA', (89, 99))	('stomach cancer', 'Disease', (38, 52))	('Hs746T', 'Var', (0, 6))	('Cancer Cell Line Encyclopedia', 'Disease', 'MESH:C538614', (135, 164))	('JAG1', 'Gene', '182', (84, 88))	('stomach cancer', 'Disease', 'MESH:D013274', (38, 52))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('human', 'Species', '9606', (32, 37))	('Cancer', 'Phenotype', 'HP:0002664', (135, 141))	('JAG1', 'Gene', (84, 88))	('stomach cancer', 'Phenotype', 'HP:0012126', (38, 52))	('Cancer Cell Line Encyclopedia', 'Disease', (135, 164))
39818	31276933	Hs746T cells plated on Jagged1-precoated plates showed five-fold increase in MIST1 mRNA expression, associated with a drastic upregulation of the Notch downstream target genes HES1, HES5, HEY1, and HEY2 (Figure 3C).	('increase', 'PosReg', (65, 73))	('Hs746T', 'Var', (0, 6))	('Notch', 'Gene', (146, 151))	('mRNA expression', 'MPA', (83, 98))	('upregulation', 'PosReg', (126, 138))	('Notch', 'Gene', '31293', (146, 151))	('MIST1', 'Gene', (77, 82))
39830	31276933	To determine the role of Jagged1-mediated Notch signaling in KrasG12D-induced pathologic changes in the stomach, we crossed a conditional deletion allele of Jag1 into KC mice.	('Jag1', 'Gene', '16449', (157, 161))	('Notch', 'Gene', '31293', (42, 47))	('Notch', 'Gene', (42, 47))	('mice', 'Species', '10090', (170, 174))	('Jag1', 'Gene', (157, 161))	('KrasG12D-induced', 'Var', (61, 77))	('crossed', 'Reg', (116, 123))
39834	31276933	Although the percentage of animals showing gastric metaplasia was similar in age-matched KC and JKC mice, the average area of metaplastic lesions in JKC mice was increased compared with KC mice (49% versus 36% of the examined areas, P << .05).	('increased', 'PosReg', (162, 171))	('mice', 'Species', '10090', (189, 193))	('mice', 'Species', '10090', (100, 104))	('JKC', 'Var', (149, 152))	('mice', 'Species', '10090', (153, 157))	('gastric metaplasia', 'Disease', 'MESH:D008679', (43, 61))	('gastric metaplasia', 'Disease', (43, 61))
39843	31276933	Taken together, deletion of Jagged1 or Notch3 accelerated KrasG12D-initiated metaplasia in the glandular stomach and promoted development of forestomach squamous cell carcinoma, suggesting a tumor-suppressive role for Notch signaling in the initial stages of gastric tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (267, 272))	('metaplasia', 'Disease', 'MESH:D008679', (77, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (167, 176))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('Notch', 'Gene', (218, 223))	('Notch', 'Gene', '31293', (39, 44))	('accelerated', 'PosReg', (46, 57))	('deletion', 'Var', (16, 24))	('tumor', 'Phenotype', 'HP:0002664', (267, 272))	('promoted', 'PosReg', (117, 125))	('Notch3', 'Gene', '18131', (39, 45))	('forestomach squamous cell carcinoma', 'Disease', (141, 176))	('metaplasia', 'Disease', (77, 87))	('development', 'CPA', (126, 137))	('KrasG12D-initiated', 'Gene', (58, 76))	('tumor', 'Disease', (191, 196))	('Notch', 'Gene', (39, 44))	('Jagged1', 'Gene', (28, 35))	('rat', 'Species', '10116', (52, 55))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('Notch', 'Gene', '31293', (218, 223))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (153, 176))	('forestomach squamous cell carcinoma', 'Disease', 'MESH:D002294', (141, 176))	('tumor', 'Disease', (267, 272))	('Notch3', 'Gene', (39, 45))
39845	31276933	While the wild-type mice were completely negative, KC, JKC, and NKC mice all showed ectopic Alcian blue-positive mucins in the corpus gland, suggesting metaplastic changes caused by KrasG12D (Figure 7, A-D).	('mice', 'Species', '10090', (68, 72))	('ectopic Alcian blue-positive mucins', 'MPA', (84, 119))	('KrasG12D', 'Var', (182, 190))	('mice', 'Species', '10090', (20, 24))	('Alcian blue', 'Chemical', 'MESH:D000423', (92, 103))	('metaplastic changes', 'CPA', (152, 171))
39852	31276933	Although no lesion was found in the stomach of Jag1flox/flox;Pdx1-Cre and Notch3beta-Geo/beta-Geo mice (data not shown), deletion of Jagged1 or Notch3 in KC mice promoted development of gastric metaplasia and forestomach squamous cell carcinoma, suggesting that Jagged1 and Notch3 are tumor suppressive in Kras-driven stomach tumorigenesis.	('Notch3', 'Gene', '18131', (274, 280))	('mice', 'Species', '10090', (157, 161))	('gastric metaplasia and forestomach squamous cell carcinoma', 'Disease', 'MESH:D013274', (186, 244))	('Notch3', 'Gene', '18131', (74, 80))	('Pdx1-Cre', 'Gene', (61, 69))	('Notch3', 'Gene', '18131', (144, 150))	('tumor', 'Phenotype', 'HP:0002664', (285, 290))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (221, 244))	('Notch3beta-Geo/beta-Geo', 'Gene', (74, 97))	('Notch3beta-Geo/beta-Geo', 'Gene', '18131', (74, 97))	('Jagged1', 'Gene', (133, 140))	('Pdx1-Cre', 'Gene', '18609', (61, 69))	('tumor', 'Disease', (326, 331))	('mice', 'Species', '10090', (98, 102))	('Notch3', 'Gene', (274, 280))	('tumor', 'Disease', 'MESH:D009369', (326, 331))	('carcinoma', 'Phenotype', 'HP:0030731', (235, 244))	('Jag1', 'Gene', (47, 51))	('promoted', 'PosReg', (162, 170))	('Notch3', 'Gene', (74, 80))	('Notch3', 'Gene', (144, 150))	('tumor', 'Disease', (285, 290))	('development', 'CPA', (171, 182))	('tumor', 'Phenotype', 'HP:0002664', (326, 331))	('Jag1', 'Gene', '16449', (47, 51))	('deletion', 'Var', (121, 129))	('tumor', 'Disease', 'MESH:D009369', (285, 290))
39856	31276933	Interestingly, a recent study found organoids derived from KrasLSL-G12D/+;Tff1-Cre gastric corpus exhibited accelerated growth and abnormal differentiation with a loss of chief cell marker.	('rat', 'Species', '10116', (114, 117))	('chief', 'MPA', (171, 176))	('loss', 'NegReg', (163, 167))	('abnormal differentiation', 'CPA', (131, 155))	('G12D', 'Mutation', 'rs121913529', (67, 71))	('KrasLSL-G12D/+;Tff1-Cre', 'Var', (59, 82))	('growth', 'CPA', (120, 126))	('accelerated', 'PosReg', (108, 119))
39859	31276933	Interestingly, an immunohistochemical study of primarily resected gastric cancer and pretherapeutic biopsies found that NOTCH1-negative tumors demonstrated worse survival, whereas high NOTCH1 expression was associated with early-stage tumors and significantly increased survival in this subgroup.	('tumors', 'Disease', (136, 142))	('survival', 'MPA', (162, 170))	('rat', 'Species', '10116', (150, 153))	('associated', 'Reg', (207, 217))	('increased', 'PosReg', (260, 269))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('tumors', 'Disease', 'MESH:D009369', (136, 142))	('gastric cancer', 'Phenotype', 'HP:0012126', (66, 80))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('survival', 'MPA', (270, 278))	('high', 'Var', (180, 184))	('worse', 'NegReg', (156, 161))	('tumors', 'Phenotype', 'HP:0002664', (235, 241))	('NOTCH1', 'Gene', '18128', (120, 126))	('NOTCH1', 'Gene', '18128', (185, 191))	('gastric cancer', 'Disease', (66, 80))	('tumors', 'Disease', (235, 241))	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('NOTCH1', 'Gene', (120, 126))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('NOTCH1', 'Gene', (185, 191))	('tumors', 'Disease', 'MESH:D009369', (235, 241))	('gastric cancer', 'Disease', 'MESH:D013274', (66, 80))
39866	31276933	Interestingly, deletion of either Jagged1 or Notch3 drastically accelerated the development of squamous cell carcinoma of forestomach.	('rat', 'Species', '10116', (70, 73))	('squamous cell carcinoma of forestomach', 'Disease', 'MESH:D002294', (95, 133))	('deletion', 'Var', (15, 23))	('accelerated', 'PosReg', (64, 75))	('Notch3', 'Gene', '18131', (45, 51))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (95, 118))	('Notch3', 'Gene', (45, 51))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('Jagged1', 'Gene', (34, 41))	('squamous cell carcinoma of forestomach', 'Disease', (95, 133))
39875	31276933	These cells can serve as a cell of origin for intestinal-type cancer with the combination of Kras and Apc mutations as well as for diffuse-type cancer with the loss of E-cadherin.	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('intestinal-type cancer', 'Disease', 'MESH:D007414', (46, 68))	('cancer', 'Disease', (144, 150))	('E-cadherin', 'Gene', '12550', (168, 178))	('cancer', 'Disease', (62, 68))	('Apc', 'Gene', (102, 105))	('mutations', 'Var', (106, 115))	('intestinal-type cancer', 'Disease', (46, 68))	('diffuse-type', 'Disease', (131, 143))	('Apc', 'Gene', '11789', (102, 105))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('Kras', 'Gene', (93, 97))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('E-cadherin', 'Gene', (168, 178))
39881	31276933	Ablation of Jagged1 or Notch3 accelerated Kras-induced gastric metaplasia as well as squamous cell carcinoma of the forestomach.	('squamous cell carcinoma of the forestomach', 'Disease', 'MESH:D002294', (85, 127))	('Notch3', 'Gene', '18131', (23, 29))	('Jagged1', 'Gene', (12, 19))	('Notch3', 'Gene', (23, 29))	('rat', 'Species', '10116', (36, 39))	('accelerated', 'PosReg', (30, 41))	('Ablation', 'Var', (0, 8))	('gastric metaplasia', 'Disease', 'MESH:D008679', (55, 73))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (85, 108))	('gastric metaplasia', 'Disease', (55, 73))	('squamous cell carcinoma of the forestomach', 'Disease', (85, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))
39932	28198666	Of note, the two top-scoring drugs, AICAR and BIBW2992 are drugs that are actively being studied as therapeutics against ER-positive breast cancer.	('breast cancer', 'Disease', (133, 146))	('breast cancer', 'Phenotype', 'HP:0003002', (133, 146))	('BIBW2992', 'Var', (46, 54))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('breast cancer', 'Disease', 'MESH:D001943', (133, 146))
39934	28198666	Further, a Phase II clinical trial demonstrated that BIBW2992 was able to induce stable disease in more than 50% of ER-positive metastatic breast cancer that has progressed on letrozole monotherapy when used in combination with letrozole.	('breast cancer', 'Disease', (139, 152))	('letrozole', 'Chemical', 'MESH:D000077289', (176, 185))	('stable disease', 'Disease', (81, 95))	('breast cancer', 'Disease', 'MESH:D001943', (139, 152))	('letrozole', 'Chemical', 'MESH:D000077289', (228, 237))	('stable disease', 'Disease', 'MESH:D060050', (81, 95))	('BIBW2992', 'Var', (53, 61))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('breast cancer', 'Phenotype', 'HP:0003002', (139, 152))
39939	28198666	Interestingly, BIBW2992, also known as afatinib, a second generation EGFR inhibitor, is ranked second with a significant Connectivity Score of 0.93 (p-value = 0.021).	('BIBW2992', 'Var', (15, 23))	('EGFR', 'Gene', (69, 73))	('afatinib', 'Chemical', 'MESH:D000077716', (39, 47))	('EGFR', 'Gene', '1956', (69, 73))
40003	33478586	Noncoding RNAs in HNSCC-derived EVs are involved in the regulation of tumour progression.	('tumour', 'Phenotype', 'HP:0002664', (70, 76))	('EVs', 'Chemical', '-', (32, 35))	('Noncoding RNAs', 'Var', (0, 14))	('tumour', 'Disease', 'MESH:D009369', (70, 76))	('tumour', 'Disease', (70, 76))	('involved', 'Reg', (40, 48))
40011	33478586	demonstrated that exosomal miRNA-3188 can influence the proliferation of HNSCC cells by directly targeting B-cell lymphoma 2 (BCL2) in vitro and in vivo.	('B-cell lymphoma 2', 'Gene', (107, 124))	('BCL2', 'Gene', '596', (126, 130))	('miRNA-3188', 'Var', (27, 37))	('BCL2', 'Gene', (126, 130))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (107, 122))	('proliferation', 'CPA', (56, 69))	('miRNA-3188', 'Chemical', '-', (27, 37))	('B-cell lymphoma 2', 'Gene', '596', (107, 124))	('targeting', 'Reg', (97, 106))	('influence', 'Reg', (42, 51))	('lymphoma', 'Phenotype', 'HP:0002665', (114, 122))
40019	33478586	Notably, highly metastatic and invasive OSCC can transport EXOs-derived miRNA-1246 and miRNA-200c-3p to parental OSCC cells, which could target and bind the DENN/MADD Domain Containing 2D (DENND2D) and chromodomain helicase DNA 9/Werner, thereby promoting tumour cell proliferation, metastasis and invasion; therefore, it is important to understand the molecular mechanisms of invasion and subsequent metastasis not only to prevent cancer progression but also to detect new therapeutic targets in OSCC.	('DENND2D', 'Gene', '79961', (189, 196))	('tumour', 'Disease', 'MESH:D009369', (256, 262))	('cancer', 'Phenotype', 'HP:0002664', (432, 438))	('tumour', 'Disease', (256, 262))	('invasion', 'CPA', (298, 306))	('metastasis', 'CPA', (283, 293))	('miRNA-200c-3p', 'Var', (87, 100))	('promoting', 'PosReg', (246, 255))	('cancer', 'Disease', 'MESH:D009369', (432, 438))	('DENND2D', 'Gene', (189, 196))	('tumour', 'Phenotype', 'HP:0002664', (256, 262))	('DENN/MADD Domain Containing 2D', 'Gene', (157, 187))	('cancer', 'Disease', (432, 438))	('DENN/MADD Domain Containing 2D', 'Gene', '79961;8567', (157, 187))
40030	33478586	proved that soluble inhibitors of UCH-L1 are effective in reducing lymph node metastasis of HNSCC; therefore, soluble inhibitors of UCH-L1 offer potential forms of treatment for invasive carcinomas, including EBV-positive malignancies.	('invasive carcinomas', 'Disease', (178, 197))	('UCH-L1', 'Gene', '7345', (132, 138))	('soluble inhibitors', 'Var', (110, 128))	('UCH-L1', 'Gene', (132, 138))	('malignancies', 'Disease', (222, 234))	('reducing', 'NegReg', (58, 66))	('lymph node metastasis', 'CPA', (67, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (187, 196))	('UCH-L1', 'Gene', '7345', (34, 40))	('carcinomas', 'Phenotype', 'HP:0030731', (187, 197))	('HNSCC', 'Disease', (92, 97))	('reducing lymph node', 'Phenotype', 'HP:0002732', (58, 77))	('EBV', 'Species', '10376', (209, 212))	('UCH-L1', 'Gene', (34, 40))	('invasive carcinomas', 'Disease', 'MESH:D009361', (178, 197))	('malignancies', 'Disease', 'MESH:D009369', (222, 234))
40052	33478586	Noncoding RNA also plays an important role in tumour angiogenesis; specifically, the level of miRNA-494 is upregulated in OSCC.	('level', 'MPA', (85, 90))	('tumour', 'Disease', (46, 52))	('miRNA-494', 'Var', (94, 103))	('OSCC', 'Disease', (122, 126))	('upregulated', 'PosReg', (107, 118))	('tumour', 'Phenotype', 'HP:0002664', (46, 52))	('tumour', 'Disease', 'MESH:D009369', (46, 52))
40053	33478586	miRNA-494 is delivered to endothelial cells via EVs secreted by tumour cells.	('miRNA-494', 'Var', (0, 9))	('tumour', 'Disease', 'MESH:D009369', (64, 70))	('EVs', 'Chemical', '-', (48, 51))	('tumour', 'Disease', (64, 70))	('tumour', 'Phenotype', 'HP:0002664', (64, 70))
40054	33478586	The angiogenic capacity of miRNA-494 is mediated by the phosphatase and tensin homologue (PTEN)-protein kinase B (KAT)-endothelial nitric oxide synthase (NOS) axis.	('protein kinase B', 'Gene', '2185', (96, 112))	('angiogenic capacity', 'CPA', (4, 23))	('PTEN', 'Gene', (90, 94))	('phosphatase and tensin homologue', 'Gene', '5728', (56, 88))	('PTEN', 'Gene', '5728', (90, 94))	('KAT', 'Gene', '50848', (114, 117))	('miRNA-494', 'Var', (27, 36))	('endothelial nitric oxide synthase', 'Gene', '4846', (119, 152))	('KAT', 'Gene', (114, 117))	('protein kinase B', 'Gene', (96, 112))	('endothelial nitric oxide synthase', 'Gene', (119, 152))
40061	33478586	Thus, we can conclude that miRNA-9 can inhibit tumour angiogenesis, providing a new direction for anticancer treatment.	('tumour', 'Disease', 'MESH:D009369', (47, 53))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('inhibit', 'NegReg', (39, 46))	('tumour', 'Disease', (47, 53))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('miRNA-9', 'Var', (27, 34))	('tumour', 'Phenotype', 'HP:0002664', (47, 53))
40067	33478586	In vitro and in vivo experiments indicated that overexpression of miRNA-34c inhibit malignant behaviours such as invasion, migration, proliferation and EMT in NPCs by targeting beta-Catenin, and in addition, we found alleviated radio resistance upon miRNA-34c overexpression or beta-catenin knockdown in NPCs.	('beta-Catenin', 'Gene', '1499', (177, 189))	('miRNA-34c', 'Gene', '407042', (66, 75))	('NPC', 'Gene', '4864', (159, 162))	('knockdown', 'Var', (291, 300))	('invasion', 'CPA', (113, 121))	('beta-catenin', 'Gene', (278, 290))	('beta-catenin', 'Gene', '1499', (278, 290))	('beta-Catenin', 'Gene', (177, 189))	('NPC', 'Phenotype', 'HP:0100630', (304, 307))	('NPC', 'Phenotype', 'HP:0100630', (159, 162))	('NPC', 'Gene', (304, 307))	('migration', 'CPA', (123, 132))	('alleviated', 'NegReg', (217, 227))	('miRNA-34c', 'Gene', (250, 259))	('NPC', 'Gene', (159, 162))	('radio resistance', 'CPA', (228, 244))	('inhibit', 'NegReg', (76, 83))	('miRNA-34c', 'Gene', (66, 75))	('NPC', 'Gene', '4864', (304, 307))	('malignant behaviours', 'CPA', (84, 104))	('miRNA-34c', 'Gene', '407042', (250, 259))
40083	33478586	Similarly, EXOs induce IL-10 expression in macrophages, thereby inhibiting the development of the immune environment.	('IL-10', 'Gene', (23, 28))	('EXOs', 'Var', (11, 15))	('inhibiting', 'NegReg', (64, 74))	('IL-10', 'Gene', '3586', (23, 28))	('development of the immune environment', 'CPA', (79, 116))	('expression', 'MPA', (29, 39))
40086	33478586	Further investigations revealed that knockout of miRNA-21 in Snail-expressing HNSCC attenuated snail-induced M2 polarization and inhibited angiogenesis and tumour growth.	('inhibited', 'NegReg', (129, 138))	('snail', 'Gene', '6615', (95, 100))	('Snail', 'Gene', '6615', (61, 66))	('Snail', 'Gene', (61, 66))	('miRNA-21', 'Gene', (49, 57))	('tumour', 'Disease', (156, 162))	('miRNA-21', 'Gene', '406991', (49, 57))	('knockout', 'Var', (37, 45))	('attenuated', 'NegReg', (84, 94))	('snail', 'Gene', (95, 100))	('tumour', 'Phenotype', 'HP:0002664', (156, 162))	('tumour', 'Disease', 'MESH:D009369', (156, 162))
40116	33478586	Fortunately, HPV (+) HNSCC responded better to treatment and had a significantly better prognosis than HPV (-) HNSCC.	('better', 'Reg', (81, 87))	('HPV', 'Species', '10566', (103, 106))	('better', 'PosReg', (37, 43))	('HPV (+', 'Var', (13, 19))	('HPV', 'Species', '10566', (13, 16))
40122	33478586	In another study, we found that miRNA-27a-3P and miRNA-27b-3P were enriched in EVs produced by HPV (+) and HPV (-) cells.	('miRNA-27a-3P', 'Var', (32, 44))	('miRNA-27b', 'Gene', '407019', (49, 58))	('EVs', 'Chemical', '-', (79, 82))	('EVs', 'Disease', (79, 82))	('HPV', 'Species', '10566', (107, 110))	('HPV (+', 'Var', (95, 101))	('HPV', 'Var', (107, 110))	('HPV', 'Species', '10566', (95, 98))	('miRNA-27b', 'Gene', (49, 58))
40124	33478586	These results suggest that intercellular communication mediated by HPV (+) EVs might play a dominant role in antitumour immune responses and inhibit tumour proliferation, which may provide a new treatment for HPV (+) head and neck squamous cell carcinoma.	('tumour', 'Phenotype', 'HP:0002664', (113, 119))	('neck squamous cell carcinoma', 'Disease', (226, 254))	('tumour', 'Disease', 'MESH:D009369', (113, 119))	('HPV (+', 'Var', (67, 73))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (226, 254))	('carcinoma', 'Phenotype', 'HP:0030731', (245, 254))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (231, 254))	('intercellular communication', 'MPA', (27, 54))	('tumour', 'Phenotype', 'HP:0002664', (149, 155))	('HPV', 'Species', '10566', (67, 70))	('tumour', 'Disease', (113, 119))	('EVs', 'Chemical', '-', (75, 78))	('tumour', 'Disease', 'MESH:D009369', (149, 155))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (217, 254))	('inhibit', 'NegReg', (141, 148))	('tumour', 'Disease', (149, 155))	('HPV', 'Species', '10566', (209, 212))
40127	33478586	Increased EVs production has been observed in both de novo (H314) and adaptive (H103/cisD2) resistant strains compared with sensitive H103 cells.	('H314', 'Var', (60, 64))	('EVs', 'Chemical', '-', (10, 13))	('cisD2', 'Gene', '493856', (85, 90))	('cisD2', 'Gene', (85, 90))	('EVs production', 'MPA', (10, 24))
40130	33478586	Moreover, TDE rich in miRNA-196a and miRNA-21 mediated cisplatin resistance of oral squamous cell carcinoma by targeting PTEN/PDCD4 (programmed cell death 4) and (cyclin dependent kinase inhibitor 1B)CDKN1B/ING5(inhibitor of growth5), respectively.	('cyclin dependent kinase inhibitor 1B', 'Gene', (163, 199))	('cisplatin resistance', 'MPA', (55, 75))	('CDKN1B', 'Gene', (200, 206))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (79, 107))	('TDE', 'Gene', '10955', (10, 13))	('oral squamous cell carcinoma', 'Disease', (79, 107))	('ING5', 'Gene', '84289', (207, 211))	('PTEN', 'Gene', (121, 125))	('miRNA-21', 'Gene', '406991', (37, 45))	('PDCD4', 'Gene', (126, 131))	('cisplatin', 'Chemical', 'MESH:D002945', (55, 64))	('ING5', 'Gene', (207, 211))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (84, 107))	('targeting', 'Reg', (111, 120))	('miRNA-21', 'Gene', (37, 45))	('mediated', 'Reg', (46, 54))	('CDKN1B', 'Gene', '1027', (200, 206))	('PTEN', 'Gene', '5728', (121, 125))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('PDCD4', 'Gene', '27250', (126, 131))	('miRNA-196a', 'Var', (22, 32))	('cyclin dependent kinase inhibitor 1B', 'Gene', '1027', (163, 199))	('TDE', 'Gene', (10, 13))
40136	33478586	Among miRNANAs in EVs derived from erlotinib-resistant cells, miRNA-7704, miRNA-21-5p and miRNA-3960 were significantly upregulated.	('erlotinib', 'Chemical', 'MESH:D000069347', (35, 44))	('upregulated', 'PosReg', (120, 131))	('miRNA-21', 'Gene', '406991', (74, 82))	('EVs', 'Chemical', '-', (18, 21))	('miRNA-7704', 'Gene', (62, 72))	('miRNA-21', 'Gene', (74, 82))	('miRNA-3960', 'Var', (90, 100))
40143	33478586	The PI3-K/AKT pathway is a carcinogenic pathway with frequent mutations in HNSCC and is a key regulator of radiation resistance and a key driver of cell motility and migration.	('AKT', 'Gene', (10, 13))	('HNSCC', 'Gene', (75, 80))	('carcinogenic', 'Disease', 'MESH:D063646', (27, 39))	('carcinogenic', 'Disease', (27, 39))	('AKT', 'Gene', '207', (10, 13))	('mutations', 'Var', (62, 71))
40157	33478586	demonstrated that COL10A1 was upregulated; however, miRNA-101-3p was downregulated in HNSCC tissues and cell lines, and a dual-luciferase reporter gene assay confirmed that miRNA-101-3P targets COL10A1.	('COL10A1', 'Gene', '1300', (194, 201))	('COL10A1', 'Gene', (18, 25))	('miRNA-101-3p', 'Gene', (52, 64))	('COL10A1', 'Gene', (194, 201))	('downregulated', 'NegReg', (69, 82))	('miRNA-101-3P', 'Var', (173, 185))	('COL10A1', 'Gene', '1300', (18, 25))	('miRNA-101-3p', 'Chemical', '-', (52, 64))
40158	33478586	Subsequently, EXOs derived from human bone marrow mesenchymal stem cells (hBMSCs) were isolated and cocultured with tumour cells, and the results showed that EXOs derived from hBMSCs overexpressing miRNA-101-3p could inhibit the progression of tumours.	('tumours', 'Disease', (244, 251))	('tumour', 'Disease', 'MESH:D009369', (116, 122))	('overexpressing', 'PosReg', (183, 197))	('hBMSCs', 'Chemical', '-', (176, 182))	('miRNA-101-3p', 'Chemical', '-', (198, 210))	('tumour', 'Disease', (116, 122))	('tumour', 'Phenotype', 'HP:0002664', (244, 250))	('inhibit', 'NegReg', (217, 224))	('miRNA-101-3p', 'Var', (198, 210))	('tumours', 'Phenotype', 'HP:0002664', (244, 251))	('hBMSCs', 'Chemical', '-', (74, 80))	('human', 'Species', '9606', (32, 37))	('tumour', 'Disease', 'MESH:D009369', (244, 250))	('tumours', 'Disease', 'MESH:D009369', (244, 251))	('tumour', 'Phenotype', 'HP:0002664', (116, 122))	('tumour', 'Disease', (244, 250))
40159	33478586	In addition, in vitro experiments further confirmed the inhibitory effect of hBMSC-derived EXOs carrying miRNA-101-3p on tumour cell invasion and migration.	('miRNA-101-3p', 'Chemical', '-', (105, 117))	('tumour', 'Phenotype', 'HP:0002664', (121, 127))	('miRNA-101-3p', 'Var', (105, 117))	('tumour', 'Disease', 'MESH:D009369', (121, 127))	('inhibitory effect', 'NegReg', (56, 73))	('tumour', 'Disease', (121, 127))
40163	33478586	Tumour growth in OSCC (SCCVII) cells was inhibited in C3H mice treated with miRNA-138 TDE but not in T-deficient nude mice.	('TDE', 'Gene', (86, 89))	('miRNA-138', 'Var', (76, 85))	('miRNA-138', 'Chemical', '-', (76, 85))	('mice', 'Species', '10090', (58, 62))	('nude mice', 'Species', '10090', (113, 122))	('TDE', 'Gene', '10955', (86, 89))	('inhibited', 'NegReg', (41, 50))	('Tumour', 'Phenotype', 'HP:0002664', (0, 6))	('mice', 'Species', '10090', (118, 122))
40164	33478586	gammadeltaTDEs with miRNA-138 increased IFN-gamma production, CD8 + T cell proliferation, and cytotoxicity against OSCC cells.	('miRNA-138', 'Chemical', '-', (20, 29))	('IFN-gamma', 'Gene', '15978', (40, 49))	('CD8', 'Gene', (62, 65))	('cytotoxicity', 'Disease', 'MESH:D064420', (94, 106))	('CD8', 'Gene', '925', (62, 65))	('increased', 'PosReg', (30, 39))	('gammadeltaTDEs', 'Chemical', '-', (0, 14))	('IFN-gamma', 'Gene', (40, 49))	('miRNA-138', 'Var', (20, 29))	('cytotoxicity', 'Disease', (94, 106))
40181	33478586	However, compared with those in the control group, the exosomal miRNA-486-5p, miRNA-486-3p and miRNA-10b-5p from HNSCC cell lines were strikingly higher.	('higher', 'PosReg', (146, 152))	('miRNA-10b', 'Gene', (95, 104))	('exosomal', 'MPA', (55, 63))	('miRNA-10b', 'Gene', '406903', (95, 104))	('miRNA-486-3p', 'Var', (78, 90))
40182	33478586	Similar studies reported that miRNANA-21, miRNANA-184, miRNA-412-3p, miRNA-512-3p, miRNA-27a-3p, and miRNA-494-3p in salivary EXOs of OSCC patients were significantly higher than those of the healthy control group.	('higher', 'PosReg', (167, 173))	('patients', 'Species', '9606', (139, 147))	('miRNANA-21', 'Var', (30, 40))	('miRNANA-184', 'Var', (42, 53))	('miRNA-412-3p', 'Var', (55, 67))	('salivary EXOs', 'MPA', (117, 130))	('miRNA-27a-3p', 'Var', (83, 95))	('OSCC', 'Disease', (134, 138))	('miRNA-494-3p', 'Var', (101, 113))	('miRNA-512-3p', 'Var', (69, 81))
40183	33478586	In addition, miRNA-302b-3p and miRNA-517b-3p were only expressed in salivary EXOs of OSCC patients.	('miRNA-517b-3p', 'Var', (31, 44))	('patients', 'Species', '9606', (90, 98))	('miRNA-302b-3p', 'Var', (13, 26))
40231	29865971	Immunohistochemical analysis was positive for E-cadherin, Ki-67 (positive region 80%) (Figure 2c) and mutant p53 (Figure 2d), weakly positive for CK5/6, P63, CK7 and CK20, and negative for P40, HPV16, HPV18 and HPV31.	('mutant', 'Var', (102, 108))	('HPV16', 'Species', '333760', (194, 199))	('Ki-67', 'Gene', (58, 63))	('CK5/6', 'Var', (146, 151))	('HPV', 'Species', '10566', (201, 204))	('E-cadherin', 'Protein', (46, 56))	('HPV', 'Species', '10566', (211, 214))	('p53', 'Gene', (109, 112))	('CK7', 'Var', (158, 161))	('p53', 'Gene', '7157', (109, 112))	('HPV', 'Species', '10566', (194, 197))	('CK20', 'Var', (166, 170))	('P63', 'Var', (153, 156))	('positive', 'Reg', (133, 141))	('positive', 'Reg', (33, 41))
40247	29865971	In line with a report by Giordano et al., we also detected mutant p53 expression in our patient, suggesting that mutation of the p53 tumor suppressor gene may be associated with PESCC.	('patient', 'Species', '9606', (88, 95))	('mutation', 'Var', (113, 121))	('p53', 'Gene', '7157', (66, 69))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('associated', 'Reg', (162, 172))	('PESCC', 'Disease', (178, 183))	('tumor', 'Disease', (133, 138))	('p53', 'Gene', (129, 132))	('p53', 'Gene', '7157', (129, 132))	('p53', 'Gene', (66, 69))
40254	29617662	Driver Fusions and Their Implications in the Development and Treatment of Human Cancers Gene fusions represent an important class of somatic alterations in cancer.	('Gene fusions', 'Var', (88, 100))	('Human Cancers', 'Disease', (74, 87))	('Human Cancers', 'Disease', 'MESH:D009369', (74, 87))	('cancer', 'Disease', (156, 162))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('Cancer', 'Phenotype', 'HP:0002664', (80, 86))	('Cancers', 'Phenotype', 'HP:0002664', (80, 87))
40256	29617662	Integration of gene expression, copy number, and fusion annotation data revealed that fusions involving oncogenes tend to exhibit increased expression, whereas fusions involving tumor suppressors have the opposite effect.	('oncogenes', 'Gene', (104, 113))	('tumor', 'Disease', (178, 183))	('expression', 'MPA', (140, 150))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('increased', 'PosReg', (130, 139))	('fusions', 'Var', (86, 93))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))
40262	29617662	To date, many studies have focused on determining the landscape of SNPs, insertions, deletions, and copy number alterations in cancer genomes.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('deletions', 'Var', (85, 94))	('SNPs', 'Var', (67, 71))	('copy number alterations', 'Var', (100, 123))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('insertions', 'Var', (73, 83))	('cancer', 'Disease', (127, 133))
40263	29617662	Although such genomic alterations make up a large fraction of the typical tumor mutation burden, gene fusions also play a critical role in oncogenesis.	('oncogenesis', 'CPA', (139, 150))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('alterations', 'Var', (22, 33))	('tumor', 'Disease', (74, 79))
40265	29617662	Gene fusions function as diagnostic markers for specific cancer types.	('Gene fusions', 'Var', (0, 12))	('cancer', 'Disease', (57, 63))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))
40266	29617662	For example, a frequent translocation between chromosomes 11 and 22 creates a fusion between EWSR1 and FLI1 in Ewing's sarcoma.	('fusion', 'Var', (78, 84))	('translocation', 'Var', (24, 37))	('FLI1', 'Gene', (103, 107))	('EWSR1', 'Gene', (93, 98))	('FLI1', 'Gene', '2313', (103, 107))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (111, 126))	('EWSR1', 'Gene', '2130', (93, 98))	("Ewing's sarcoma", 'Disease', (111, 126))	('sarcoma', 'Phenotype', 'HP:0100242', (119, 126))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (111, 126))
40273	29617662	performed breakpoint analysis on exon microarrays across 974 cancer samples and identified 198 candidate fusions in annotated cancer genes.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('fusions', 'Var', (105, 112))	('cancer', 'Disease', (61, 67))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))
40275	29617662	Some studies focus on important classes of genes, such as kinase fusions, which may have particular structural properties that are selected for during oncogenesis and cancer progression.	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('kinase fusions', 'Var', (58, 72))	('cancer', 'Disease', (167, 173))	('cancer', 'Disease', 'MESH:D009369', (167, 173))
40289	29617662	Fusion events may be associated with altered expression of one or both of the fusion gene partners, a well-known example being multiple myeloma tumors in which translocation t(4;14) fuses the highly expressed IGH locus with the tyrosine protein kinase FGFR3.	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('FGFR3', 'Gene', (252, 257))	('myeloma tumors', 'Disease', 'MESH:D009101', (136, 150))	('IGH', 'Gene', '3492', (209, 212))	('IGH', 'Gene', (209, 212))	('myeloma tumors', 'Disease', (136, 150))	('multiple myeloma', 'Phenotype', 'HP:0006775', (127, 143))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('FGFR3', 'Gene', '2261', (252, 257))	('translocation t', 'Var', (160, 175))
40291	29617662	Figure 2A shows that between 6% (mesothelioma [MESO]) and 28% (KIRP) of kinase fusions displayed outlier overexpression of the kinase partner.	('mesothelioma', 'Disease', 'MESH:D008654', (33, 45))	('fusions', 'Var', (79, 86))	('mesothelioma', 'Disease', (33, 45))	('overexpression', 'PosReg', (105, 119))
40292	29617662	Oncogenes tended to show higher likelihoods of overexpression, whereas TSGs displayed lower likelihoods.	('Oncogenes', 'Var', (0, 9))	('TSG', 'Gene', '57045', (71, 74))	('overexpression', 'MPA', (47, 61))	('TSG', 'Gene', (71, 74))
40293	29617662	Between 3% (breast invasive carcinoma [BRCA]) and 38% (PCPG) of TSG fusions showed outlier underexpression, generally higher than both oncogenes and kinases.	('BRCA', 'Gene', (39, 43))	('fusions', 'Var', (68, 75))	('TSG', 'Gene', (64, 67))	('breast invasive carcinoma', 'Disease', 'MESH:D018270', (12, 37))	('breast invasive carcinoma', 'Phenotype', 'HP:0003002', (12, 37))	('carcinoma', 'Phenotype', 'HP:0030731', (28, 37))	('breast invasive carcinoma', 'Disease', (12, 37))	('BRCA', 'Gene', '672', (39, 43))	('underexpression', 'NegReg', (91, 106))	('TSG', 'Gene', '57045', (64, 67))
40295	29617662	Samples with fusions involving oncogenes, such as EGFR, ERBB2, and RET, showed increased expression of those genes relative to samples without fusions across cancer types.	('increased', 'PosReg', (79, 88))	('expression', 'MPA', (89, 99))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('RET', 'Gene', '5979', (67, 70))	('EGFR', 'Gene', '1956', (50, 54))	('cancer', 'Disease', (158, 164))	('fusions', 'Var', (13, 20))	('ERBB2', 'Gene', '2064', (56, 61))	('EGFR', 'Gene', (50, 54))	('ERBB2', 'Gene', (56, 61))	('RET', 'Gene', (67, 70))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
40299	29617662	For example, TP53 is affected by mutations rather than fusions in most cancer types.	('TP53', 'Gene', (13, 17))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('cancer', 'Disease', (71, 77))	('mutations', 'Var', (33, 42))	('affected', 'Reg', (21, 29))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('TP53', 'Gene', '7157', (13, 17))
40300	29617662	However, in sarcoma (SARC), both fusions and mutations affecting TP53 were detected.	('mutations', 'Var', (45, 54))	('TP53', 'Gene', '7157', (65, 69))	('sarcoma', 'Disease', 'MESH:D012509', (12, 19))	('TP53', 'Gene', (65, 69))	('sarcoma', 'Disease', (12, 19))	('fusions', 'Var', (33, 40))	('sarcoma', 'Phenotype', 'HP:0100242', (12, 19))	('detected', 'Reg', (75, 83))
40301	29617662	In acute myeloid leukemia (LAML), several CBFB fusions but no mutations were observed, yet other cancer types also exhibited CBFB mutations (Table S3; Figure S2).	('CBFB', 'Gene', '865', (125, 129))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (9, 25))	('cancer', 'Disease', (97, 103))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (3, 25))	('leukemia', 'Phenotype', 'HP:0001909', (17, 25))	('CBFB', 'Gene', (42, 46))	('cancer', 'Disease', 'MESH:D009369', (97, 103))	('exhibited', 'Reg', (115, 124))	('CBFB', 'Gene', (125, 129))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('fusions', 'Var', (47, 54))	('mutations', 'Var', (130, 139))	('acute myeloid leukemia', 'Disease', (3, 25))	('CBFB', 'Gene', '865', (42, 46))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (3, 25))
40305	29617662	Recurrent CBFB-MYH11 fusions in LAML are significantly associated with decreased expression of the tumor suppressor CBFB, which functions as a transcriptional regulator (Figure 2D).	('tumor', 'Disease', (99, 104))	('expression', 'MPA', (81, 91))	('CBFB', 'Gene', (10, 14))	('MYH11', 'Gene', '4629', (15, 20))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('CBFB', 'Gene', '865', (116, 120))	('fusions', 'Var', (21, 28))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('CBFB', 'Gene', '865', (10, 14))	('decreased', 'NegReg', (71, 80))	('MYH11', 'Gene', (15, 20))	('CBFB', 'Gene', (116, 120))
40306	29617662	In breast cancer, copy number amplification is a well-known mechanism of ERBB2 overexpression, and treatment of these HER2+ patients with trastuzumab is an established and effective targeted therapy.	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('copy number amplification', 'Var', (18, 43))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('HER2', 'Gene', (118, 122))	('breast cancer', 'Disease', (3, 16))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('trastuzumab', 'Chemical', 'MESH:D000068878', (138, 149))	('HER2', 'Gene', '2064', (118, 122))	('overexpression', 'PosReg', (79, 93))	('ERBB2', 'Gene', (73, 78))	('ERBB2', 'Gene', '2064', (73, 78))	('patients', 'Species', '9606', (124, 132))
40307	29617662	Interestingly, three of four samples with ERBB2 fusions and two samples without a called fusion showed HPV integration within 1 Mb of ERBB2.	('fusions', 'Var', (48, 55))	('ERBB2', 'Gene', '2064', (134, 139))	('ERBB2', 'Gene', (134, 139))	('ERBB2', 'Gene', '2064', (42, 47))	('ERBB2', 'Gene', (42, 47))	('HPV integration', 'CPA', (103, 118))
40310	29617662	Comparison of kinase fusions across different cancer types indicated that kinase fusions are significantly enriched in THCA (35.6%, Fisher's exact test, p < 2.2e-16) (Figure 3B).	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('cancer', 'Disease', (46, 52))	('THCA', 'Disease', (119, 123))	('kinase fusions', 'Var', (74, 88))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))
40314	29617662	For example, there are more TK fusions in THCA and GBM, more CK1 fusions in uterine corpus endometrial carcinoma (UCEC), colon adenocarcinoma (COAD), and esophageal carcinoma (ESCA) and more AGC fusions in liver hepatocellular carcinoma (LIHC).	('colon adenocarcinoma', 'Disease', (121, 141))	('TK fusions', 'Var', (28, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (154, 174))	('COAD', 'Disease', (143, 147))	('liver hepatocellular carcinoma', 'Disease', 'MESH:D006528', (206, 236))	('CK1', 'Gene', (61, 64))	('carcinoma', 'Phenotype', 'HP:0030731', (165, 174))	('esophageal carcinoma', 'Disease', (154, 174))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (91, 112))	('LIHC', 'Disease', (238, 242))	('colon adenocarcinoma', 'Disease', 'MESH:D003110', (121, 141))	('corpus endometrial carcinoma', 'Disease', (84, 112))	('corpus endometrial carcinoma', 'Disease', 'MESH:D016889', (84, 112))	('fusions', 'Var', (65, 72))	('carcinoma', 'Phenotype', 'HP:0030731', (227, 236))	('CK1', 'Species', '2498238', (61, 64))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (154, 174))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('liver hepatocellular carcinoma', 'Disease', (206, 236))	('LIHC', 'Disease', 'None', (238, 242))	('COAD', 'Disease', 'MESH:D029424', (143, 147))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (212, 236))
40315	29617662	Across different cancer types, we found an enrichment of TK and TKL kinase fusions for 3'-kinases but no strong preference for 5'-kinases (Figure S3).	('TKL', 'Gene', (64, 67))	('fusions', 'Var', (75, 82))	("3'-kinases", 'MPA', (87, 97))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('TKL', 'Gene', '7294', (64, 67))	('cancer', 'Disease', (17, 23))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
40317	29617662	As expected, fusions in the FGFR kinase family (FGFR2 and FGFR3) are the most frequent 5'-kinase fusions, given their high recurrence in individual cancer types (Figure 3C).	('cancer', 'Disease', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('FGFR2', 'Gene', (48, 53))	('FGFR2', 'Gene', '2263', (48, 53))	('FGFR3', 'Gene', '2261', (58, 63))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('FGFR3', 'Gene', (58, 63))	('fusions', 'Var', (13, 20))
40327	29617662	For example, we found a TRABD-DDR2 fusion in one head and neck squamous cell carcinoma (HNSC) sample, which fused the stronger TRABD promoter with DDR2, resulting in its overexpression (Figure 4D).	('neck squamous cell carcinoma', 'Disease', (58, 86))	('DDR2', 'Gene', (30, 34))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (63, 86))	('DDR2', 'Gene', '4921', (30, 34))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (58, 86))	('DDR2', 'Gene', '4921', (147, 151))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('fusion', 'Var', (35, 41))	('DDR2', 'Gene', (147, 151))	('overexpression', 'PosReg', (170, 184))
40329	29617662	DDR2 fusions were also detected in another nine samples from five different cancer types, which could be treated similarly given sufficient DDR2 overexpression (Table S1).	('fusions', 'Var', (5, 12))	('DDR2', 'Gene', '4921', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('DDR2', 'Gene', '4921', (140, 144))	('DDR2', 'Gene', (140, 144))	('cancer', 'Disease', (76, 82))	('DDR2', 'Gene', (0, 4))	('overexpression', 'PosReg', (145, 159))	('cancer', 'Disease', 'MESH:D009369', (76, 82))
40330	29617662	Although mutations in oncogenes or TSGs may lead to tumorigenesis, fusions involving those genes are also an important class of cancer driver events.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('lead to', 'Reg', (44, 51))	('tumor', 'Disease', (52, 57))	('TSG', 'Gene', '57045', (35, 38))	('mutations', 'Var', (9, 18))	('oncogenes', 'Gene', (22, 31))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('TSG', 'Gene', (35, 38))	('cancer', 'Disease', (128, 134))
40332	29617662	We characterized patients as having a driver mutation, a mutation in a driver gene, and/or a driver fusion (fusion involving a driver gene).	('mutation', 'Var', (57, 65))	('driver fusion', 'Disease', (93, 106))	('driver gene', 'Gene', (71, 82))	('driver', 'Disease', (38, 44))	('patients', 'Species', '9606', (17, 25))
40333	29617662	Although the majority of cancer cases have known driver mutations (48.6%, mean 6.8 mutations) or mutations in driver genes (28.1%, mean 4.2 mutations), we found that 8.3% have both driver mutations and driver fusion events (mean 5.5 mutations and 1.2 fusions), 6.4% have both mutations and fusions in driver genes (mean 4.2 mutations and 1.3 fusions), and 1.8% have driver fusions only (mean 1.1 fusions) (Figure 5A).	('mutations', 'Var', (97, 106))	('mutations', 'Var', (56, 65))	('mutations', 'Var', (324, 333))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('mutations', 'Var', (276, 285))	('fusions', 'Var', (290, 297))	('cancer', 'Disease', 'MESH:D009369', (25, 31))	('cancer', 'Disease', (25, 31))
40335	29617662	The significant decrease in the numbers of mutations (Mann-Whitney U test, p < 2.2e-16) reflects the functionality of fusions across multiple cancer types.	('multiple cancer', 'Disease', (133, 148))	('decrease', 'NegReg', (16, 24))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('mutations', 'Var', (43, 52))	('multiple cancer', 'Disease', 'MESH:D009369', (133, 148))
40336	29617662	Moreover, within cancer types, we observed a range of 0.2% (HNSC) to 14.0% (LAML) of tumors with fusions but no driver gene mutations.	('cancer', 'Phenotype', 'HP:0002664', (17, 23))	('fusions', 'Var', (97, 104))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('cancer', 'Disease', (17, 23))	('tumors', 'Disease', (85, 91))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('tumors', 'Disease', 'MESH:D009369', (85, 91))
40345	29617662	Several Food and Drug Administration (FDA)-approved drugs exist to target ALK fusions in lung and other cancer types.	('ALK', 'Gene', (74, 77))	('lung', 'Disease', (89, 93))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('fusions', 'Var', (78, 85))	('ALK', 'Gene', '238', (74, 77))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))
40347	29617662	In most cases, fusion status corresponded to copy number neutral overexpression of ALK (Figure 6D).	('ALK', 'Gene', '238', (83, 86))	('copy number neutral', 'Var', (45, 64))	('corresponded', 'Reg', (29, 41))	('overexpression', 'PosReg', (65, 79))	('ALK', 'Gene', (83, 86))
40350	29617662	We detected ESR1 fusions in 16 samples from five different cancer types (9 samples from BRCA).	('ESR1', 'Gene', '2099', (12, 16))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('fusions', 'Var', (17, 24))	('BRCA', 'Gene', '672', (88, 92))	('ESR1', 'Gene', (12, 16))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('BRCA', 'Gene', (88, 92))	('detected', 'Reg', (3, 11))
40352	29617662	We observed strict mutual exclusivity between ESR1 mutations and fusions (Figure 5C).	('ESR1', 'Gene', (46, 50))	('mutations', 'Var', (51, 60))	('ESR1', 'Gene', '2099', (46, 50))
40357	29617662	Similarly, ESR1 expression is higher when ESR1 is mutated in BRCA, CESC, and UCEC, which are all hormone receptor-related cancer types.	('ESR1', 'Gene', '2099', (11, 15))	('higher', 'PosReg', (30, 36))	('ESR1', 'Gene', (42, 46))	('cancer', 'Disease', (122, 128))	('UCEC', 'Disease', (77, 81))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('CESC', 'Disease', (67, 71))	('hormone receptor', 'Gene', (97, 113))	('mutated', 'Var', (50, 57))	('ESR1', 'Gene', (11, 15))	('ESR1', 'Gene', '2099', (42, 46))	('hormone receptor', 'Gene', '3164', (97, 113))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('BRCA', 'Gene', '672', (61, 65))	('expression', 'MPA', (16, 26))	('BRCA', 'Gene', (61, 65))
40358	29617662	Further functional study to determine the mechanism of ESR1 fusions could suggest drug development directions.	('ESR1', 'Gene', (55, 59))	('ESR1', 'Gene', '2099', (55, 59))	('fusions', 'Var', (60, 67))
40361	29617662	However, patients with known driver fusions may be poor candidates for immunotherapy because of their reduced mutational burden, especially without clear evidence of immune cell infiltration and overall immunogenicity.	('patients', 'Species', '9606', (9, 17))	('reduced', 'NegReg', (102, 109))	('mutational burden', 'MPA', (110, 127))	('fusions', 'Var', (36, 43))
40369	29617662	When comparing fusion events with the remainder of the cancer cohort, fusions involving oncogenes such as EGFR, ERBB2, and RET had increased expression.	('ERBB2', 'Gene', '2064', (112, 117))	('increased', 'PosReg', (131, 140))	('ERBB2', 'Gene', (112, 117))	('RET', 'Gene', (123, 126))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('expression', 'MPA', (141, 151))	('RET', 'Gene', '5979', (123, 126))	('EGFR', 'Gene', '1956', (106, 110))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('fusions', 'Var', (70, 77))	('cancer', 'Disease', (55, 61))	('EGFR', 'Gene', (106, 110))
40371	29617662	In addition to well-known recurrent fusions such as FGFR3-TACC3, we also detected 245 kinases with recurrent fusions to different partner genes, which may ultimately prove to be successful drug targets.	('TACC3', 'Gene', '10460', (58, 63))	('FGFR3', 'Gene', '2261', (52, 57))	('TACC3', 'Gene', (58, 63))	('fusions', 'Var', (109, 116))	('FGFR3', 'Gene', (52, 57))
40372	29617662	We showed that a meaningful percentage of patients (1.8%) harbor fusions involving cancer driver genes but have no driver gene mutations.	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('patients', 'Species', '9606', (42, 50))	('fusions', 'Var', (65, 72))	('cancer', 'Disease', (83, 89))
40375	29617662	The significant decrease in mutational burden observed in patients with fusions in driver genes points toward a reduced efficacy of immunotherapy in these patients, despite fusion peptides themselves potentially being good immunogenic targets.	('decrease', 'NegReg', (16, 24))	('efficacy of immunotherapy', 'CPA', (120, 145))	('patients', 'Species', '9606', (155, 163))	('mutational burden', 'MPA', (28, 45))	('reduced', 'NegReg', (112, 119))	('patients', 'Species', '9606', (58, 66))	('fusions', 'Var', (72, 79))
40377	29617662	We sought to prioritize fusions relevant to cancer by highlighting their associations with gene expression, potential for targeted therapy, and roles in cancer hallmark pathways.	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('gene expression', 'MPA', (91, 106))	('cancer', 'Disease', (153, 159))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('associations', 'Interaction', (73, 85))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('fusions', 'Var', (24, 31))
40379	29617662	Fusions play an increasingly appreciated role in tumorigenesis and progression and represent an important source of improved treatment options.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('progression', 'CPA', (67, 78))	('Fusions', 'Var', (0, 7))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor', 'Disease', (49, 54))
40394	29617662	The percentage of kinase genes in each group across different cancer types was defined as the number of kinase genes with fusions in each group divided by their sum, denoted as pg.	('fusions', 'Var', (122, 129))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))
40399	29617662	For TCGA tumor samples where both MC3 (Key Resources Table) mutation calls and gene fusion calls were available, we obtained the genetic alteration events, including fusion, inframe deletion, inframe insertion, missense mutation, nonsense mutation, nonstop mutation, splice site mutation, and translation start site mutation in 299 driver genes.	('nonstop', 'Disease', (249, 256))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('nonsense mutation', 'Var', (230, 247))	('missense mutation', 'Var', (211, 228))	('tumor', 'Disease', (9, 14))	('inframe insertion', 'Var', (192, 209))	('splice', 'MPA', (267, 273))	('MC3', 'Gene', (34, 37))	('fusion', 'Var', (166, 172))	('MC3', 'Gene', '4159', (34, 37))
40401	29617662	Highly recurrent fusions were found in prostate, bladder, breast, and lung cancers Expression increased in oncogene fusions but decreased in tumor suppressor genes Thyroid carcinoma showed significantly higher rates of kinase fusions Tumors with fusion events tend to have lower mutational burden	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('increased', 'PosReg', (94, 103))	('Tumors', 'Disease', 'MESH:D009369', (234, 240))	('Expression', 'MPA', (83, 93))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('prostate', 'Disease', (39, 47))	('Thyroid carcinoma', 'Phenotype', 'HP:0002890', (164, 181))	('fusions', 'Var', (116, 123))	('decreased', 'NegReg', (128, 137))	('breast', 'Disease', (58, 64))	('oncogene', 'Gene', (107, 115))	('lung cancer', 'Phenotype', 'HP:0100526', (70, 81))	('Tumors', 'Phenotype', 'HP:0002664', (234, 240))	('lung cancers', 'Disease', 'MESH:D008175', (70, 82))	('bladder', 'Disease', (49, 56))	('carcinoma', 'Phenotype', 'HP:0030731', (172, 181))	('cancers', 'Phenotype', 'HP:0002664', (75, 82))	('lung cancers', 'Disease', (70, 82))	('tumor', 'Disease', (141, 146))	('Tumors', 'Disease', (234, 240))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('lung cancers', 'Phenotype', 'HP:0100526', (70, 82))	('Thyroid carcinoma', 'Disease', 'MESH:D013964', (164, 181))	('Thyroid carcinoma', 'Disease', (164, 181))
40486	25621024	By contrast, patients treated with targeted therapy demonstrated an improved prognosis compared with those who received no treatment or chemotherapy alone.	('improved', 'PosReg', (68, 76))	('prognosis', 'MPA', (77, 86))	('patients', 'Species', '9606', (13, 21))	('targeted therapy', 'Var', (35, 51))
40514	32161495	The patients with high MAGE-A11 expression had lower 5-year overall survival (OS) rates than those with low MAGE-A11 expression as determined using the Kaplan-Meier method.	('lower', 'NegReg', (47, 52))	('MAGE-A11', 'Gene', '4110', (108, 116))	('expression', 'Var', (32, 42))	('MAGE-A11', 'Gene', (108, 116))	('high', 'Var', (18, 22))	('overall survival', 'MPA', (60, 76))	('patients', 'Species', '9606', (4, 12))	('MAGE-A11', 'Gene', '4110', (23, 31))	('MAGE-A11', 'Gene', (23, 31))
40515	32161495	The univariate and multivariate analyses confirmed that elevated MAGE-A11 was an independent prognostic factor for the OS of HNSCC patients.	('patients', 'Species', '9606', (131, 139))	('MAGE-A11', 'Gene', '4110', (65, 73))	('HNSCC', 'Disease', 'MESH:C535575', (125, 130))	('MAGE-A11', 'Gene', (65, 73))	('HNSCC', 'Disease', (125, 130))	('elevated', 'Var', (56, 64))
40527	32161495	MAGE-A11 is activated through TFCP2/ZEB1 binding sites demethylation as well as histone modification.	('ZEB1', 'Gene', '6935', (36, 40))	('MAGE-A11', 'Gene', (0, 8))	('ZEB1', 'Gene', (36, 40))	('TFCP2', 'Gene', (30, 35))	('TFCP2', 'Gene', '7024', (30, 35))	('histone modification', 'MPA', (80, 100))	('MAGE-A11', 'Gene', '4110', (0, 8))	('demethylation', 'Var', (55, 68))
40565	32161495	As shown in Figure 1C, Kaplan-Meier survival curve showed that patients with high MAGE-A11 expression had worse DFS in HNSCC patients (P = 0.042).	('expression', 'MPA', (91, 101))	('worse', 'NegReg', (106, 111))	('high', 'Var', (77, 81))	('DFS', 'Disease', (112, 115))	('MAGE-A11', 'Gene', '4110', (82, 90))	('patients', 'Species', '9606', (63, 71))	('HNSCC', 'Disease', 'MESH:C535575', (119, 124))	('HNSCC', 'Disease', (119, 124))	('MAGE-A11', 'Gene', (82, 90))	('patients', 'Species', '9606', (125, 133))
40580	32161495	The patients with high MAGE-A11 expression had lower 5-year OS rates than those with low MAGE-A11 expression as determined using the Kaplan-Meier method (P = 0.027, Figure 4).	('lower', 'NegReg', (47, 52))	('OS rates', 'MPA', (60, 68))	('MAGE-A11', 'Gene', (89, 97))	('expression', 'Var', (32, 42))	('high', 'Var', (18, 22))	('MAGE-A11', 'Gene', '4110', (23, 31))	('patients', 'Species', '9606', (4, 12))	('MAGE-A11', 'Gene', '4110', (89, 97))	('MAGE-A11', 'Gene', (23, 31))
40632	30832569	MLP's optimal architectures were 1L_64U for the scenarios of TCGA (stage classification) and NSCLC (adenocarcinoma vs squamous); 1L_128U for the scenarios of TCGA (cancer vs normal), NSCLC (stage classification), and CKD (stage classification).	('NSCLC', 'Phenotype', 'HP:0030358', (183, 188))	('adenocarcinoma', 'Disease', 'MESH:D000230', (100, 114))	('NSCLC', 'Disease', (93, 98))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('NSCLC', 'Disease', 'MESH:D002289', (93, 98))	('NSCLC', 'Disease', (183, 188))	('CKD', 'Phenotype', 'HP:0012622', (217, 220))	('adenocarcinoma', 'Disease', (100, 114))	('cancer', 'Disease', (164, 170))	('NSCLC', 'Disease', 'MESH:D002289', (183, 188))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('NSCLC', 'Phenotype', 'HP:0030358', (93, 98))	('1L_128U', 'Var', (129, 136))
40633	30832569	CNN's best performing architectures were 3L1_64U for all scenarios except for NSCLC (stage classification), which favored 1L_128U.	('1L_128U', 'Var', (122, 129))	('NSCLC', 'Phenotype', 'HP:0030358', (78, 83))	('CNN', 'Chemical', '-', (0, 3))	('NSCLC', 'Disease', (78, 83))	('NSCLC', 'Disease', 'MESH:D002289', (78, 83))	('3L1_64U', 'Var', (41, 48))
40650	30832569	Particularly, at imbalance ratios 4 and 7, the average Kappa of CNN dropped to near zero.	('imbalance', 'Phenotype', 'HP:0002172', (17, 26))	('CNN', 'Chemical', '-', (64, 67))	('dropped', 'NegReg', (68, 75))	('imbalance ratios', 'Var', (17, 33))	('Kappa', 'MPA', (55, 60))
40683	30832569	These five datasets were accessed via IDs GSE10245, GSE11969, GSE19804, GSE41271, and GSE42127, which involved 58, 144, 59, 265, and 174 human subjects, respectively.	('GSE42127', 'Var', (86, 94))	('human', 'Species', '9606', (137, 142))	('GSE11969', 'Var', (52, 60))	('GSE19804', 'Var', (62, 70))	('GSE41271', 'Var', (72, 80))	('GSE10245', 'Var', (42, 50))
40687	30832569	The 703 subjects include 587 CKD patients with five stages (CKD1 = 120, CKD2 = 104, CKD3 = 110, CKD4 = 119, CKD5 = 134) and 116 age-matched normal healthy controls.	('CKD', 'Phenotype', 'HP:0012622', (29, 32))	('CKD', 'Phenotype', 'HP:0012622', (60, 63))	('patients', 'Species', '9606', (33, 41))	('CKD1', 'Var', (60, 64))	('CKD', 'Phenotype', 'HP:0012622', (96, 99))	('CKD2 =', 'Var', (72, 78))	('CKD', 'Phenotype', 'HP:0012622', (72, 75))	('CKD3 =', 'Var', (84, 90))	('CKD', 'Phenotype', 'HP:0012622', (84, 87))
40712	30210526	For instance, DEGs between normal and tumor samples help to study tumorigenesis, and have been routinely applied to identify diagnostic, prognostic, and therapeutic biomarkers for many cancers (Wu et al.,).	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Disease', (66, 71))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('cancers', 'Phenotype', 'HP:0002664', (185, 192))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('cancers', 'Disease', 'MESH:D009369', (185, 192))	('DEGs', 'Var', (14, 18))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('cancers', 'Disease', (185, 192))
40750	30210526	The variance of Zi is , where and  So, , then  can be obtained with sigma2 and sigma'2, the residual variances from normal and cancer groups respectively.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('sigma2', 'Var', (68, 74))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('cancer', 'Disease', (127, 133))	('sigma', 'Var', (79, 84))
40812	30210526	In summary for all tested cancer types, there are 114842 DEGs overlapped between DECtp (with an overall of 151327 DEGs) and t-test (with an overall of 136918 DEGs), 107621 DEGs overlapped between DECtp and limma (with an overall of 121378 DEGs), 112772 DEGs overlapped between t-test and limma, suggesting that the three methods are generally consistent.	('cancer', 'Disease', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('112772 DEGs', 'Var', (246, 257))	('DECtp', 'Chemical', '-', (196, 201))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('DECtp', 'Chemical', '-', (81, 86))	('107621', 'Var', (165, 171))	('114842', 'Var', (50, 56))
40816	30210526	To be specific, for the six cancer types, limma identified 55593 DEGs, edgeR identified 59860 DEGs, and DECtp identified 71115 DEGs, and 44532 DEGs (accounting for 62.6%) in DECtp are overlapped with those identified by limma and edgeR.	('DECtp', 'Chemical', '-', (174, 179))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('44532 DEGs', 'Var', (137, 147))	('DECtp', 'Chemical', '-', (104, 109))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('cancer', 'Disease', (28, 34))
40823	30210526	It is clear that the p-values are not statistically significant for limma, i.e., the p-value is 0.872 for IRF8, 0.959 for CECR1, and 0.867 for IL10RA.	('CECR1', 'Gene', '51816', (122, 127))	('0.959', 'Var', (112, 117))	('IRF8', 'Gene', (106, 110))	('IL10RA', 'Gene', (143, 149))	('0.867', 'Var', (133, 138))	('IL10RA', 'Gene', '3587', (143, 149))	('IRF8', 'Gene', '3394', (106, 110))	('CECR1', 'Gene', (122, 127))
40830	30210526	For example, GO:0006955~immune response is the most enriched Go term for BLCA and PRAD with FDR being 6.161542e-29 and 1.45e-12, respectively.	('BLCA', 'Phenotype', 'HP:0002862', (73, 77))	('BLCA', 'Chemical', '-', (73, 77))	('6.161542e-29', 'Var', (102, 114))	('BLCA', 'Disease', (73, 77))	('GO:0006955~immune', 'Var', (13, 30))
40862	25724524	Sequencing revealed 63% of evaluated BRAFi-cSCCs harbored RAS mutations with PIK3CA, CKIT, ALK and EGFR mutations also detected.	('PIK3CA', 'Gene', (77, 83))	('SCC', 'Gene', '6317', (44, 47))	('EGFR', 'Gene', (99, 103))	('ALK', 'Gene', (91, 94))	('RAS', 'Gene', (58, 61))	('BRAF', 'Gene', '673', (37, 41))	('cSCC', 'Phenotype', 'HP:0006739', (43, 47))	('PIK3CA', 'Gene', '5290', (77, 83))	('BRAF', 'Gene', (37, 41))	('harbored', 'Reg', (49, 57))	('ALK', 'Gene', '238', (91, 94))	('CKIT', 'Gene', '3815', (85, 89))	('SCC', 'Gene', (44, 47))	('EGFR', 'Gene', '1956', (99, 103))	('CKIT', 'Gene', (85, 89))	('mutations', 'Var', (62, 71))
40865	25724524	These findings enhance our understanding of factors cooperating with BRAF inhibition that accelerate keratinocyte oncogenesis as well as broaden the knowledge base of multifactorial mediators of cancer in general.	('inhibition', 'Var', (74, 84))	('cancer', 'Disease', (195, 201))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('accelerate', 'PosReg', (90, 100))	('BRAF', 'Gene', '673', (69, 73))	('keratinocyte oncogenesis', 'CPA', (101, 125))	('BRAF', 'Gene', (69, 73))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
40866	25724524	Molecular inhibition of mutant BRAF protein in advanced melanoma with vemurafenib (Vem) or dabrafenib (Dab) (BRAFi) has improved patient survival but has also caused unanticipated adverse malignancies.	('inhibition', 'NegReg', (10, 20))	('patient survival', 'CPA', (129, 145))	('mutant', 'Var', (24, 30))	('improved', 'PosReg', (120, 128))	('BRAF', 'Gene', (109, 113))	('BRAF', 'Gene', '673', (109, 113))	('melanoma', 'Disease', (56, 64))	('caused', 'Reg', (159, 165))	('melanoma', 'Phenotype', 'HP:0002861', (56, 64))	('Vem', 'Chemical', 'MESH:D000077484', (83, 86))	('BRAF', 'Gene', '673', (31, 35))	('BRAF', 'Gene', (31, 35))	('vemurafenib', 'Chemical', 'MESH:D000077484', (70, 81))	('protein', 'Protein', (36, 43))	('adverse malignancies', 'Disease', 'MESH:D064420', (180, 200))	('melanoma', 'Disease', 'MESH:D008545', (56, 64))	('dabrafenib', 'Chemical', 'MESH:C561627', (91, 101))	('Dab', 'Chemical', 'MESH:C561627', (103, 106))	('adverse malignancies', 'Disease', (180, 200))	('patient', 'Species', '9606', (129, 136))
40871	25724524	The mechanism for cSCC development in otherwise healthy individuals is the result of ultraviolet (UV) radiation-induced transition mutations in host DNA (dipyrimidine or dipurine, e.g.	('SCC', 'Gene', '6317', (19, 22))	('mutations', 'Var', (131, 140))	('cSCC', 'Phenotype', 'HP:0006739', (18, 22))	('dipyrimidine', 'Chemical', '-', (154, 166))	('dipurine', 'Chemical', '-', (170, 178))	('D', 'Chemical', 'MESH:D003903', (149, 150))	('SCC', 'Gene', (19, 22))	('men', 'Species', '9606', (30, 33))
40872	25724524	A<->G or C<->T), which if they occur in tumor suppressor genes, such as TP53, can cause protein inactivation, loss of cell cycle control and cancer growth.	('loss', 'NegReg', (110, 114))	('tumor suppressor', 'Gene', (40, 56))	('inactivation', 'NegReg', (96, 108))	('TP53', 'Gene', '7157', (72, 76))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('TP53', 'Gene', (72, 76))	('tumor suppressor', 'Gene', '7248', (40, 56))	('cell cycle control', 'CPA', (118, 136))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('protein', 'Protein', (88, 95))	('C<->T', 'Var', (9, 14))	('cancer', 'Disease', (141, 147))
40873	25724524	UV radiation (particularly UVB) in conv.-cSCC induces mutations in HRAS.	('SCC', 'Gene', (42, 45))	('mutations', 'Var', (54, 63))	('HRAS', 'Gene', '3265', (67, 71))	('cSCC', 'Phenotype', 'HP:0006739', (41, 45))	('SCC', 'Gene', '6317', (42, 45))	('induces', 'Reg', (46, 53))	('HRAS', 'Gene', (67, 71))
40875	25724524	The data from these efforts demonstrate in part that upstream RAS mutations act in concert with paradoxical activation of MAPK signaling caused by BRAFi in 30-60% of lesions.	('mutations', 'Var', (66, 75))	('MAPK signaling', 'MPA', (122, 136))	('BRAF', 'Gene', (147, 151))	('BRAF', 'Gene', '673', (147, 151))	('upstream RAS', 'Protein', (53, 65))	('activation', 'PosReg', (108, 118))
40894	25724524	Finally, while RAS mutations have been reported frequently in BRAFi-cSCC, identical mutations have been detected in benign epithelial skin lesions, indicating that other factors in addition to RAS may be necessary in the ontogeny of BRAFi-cSCC.	('SCC', 'Gene', (240, 243))	('cSCC', 'Phenotype', 'HP:0006739', (239, 243))	('SCC', 'Gene', (69, 72))	('cSCC', 'Phenotype', 'HP:0006739', (68, 72))	('mutations', 'Var', (19, 28))	('SCC', 'Gene', '6317', (240, 243))	('RAS', 'Gene', (15, 18))	('SCC', 'Gene', '6317', (69, 72))	('BRAF', 'Gene', (233, 237))	('skin lesions', 'Disease', (134, 146))	('BRAF', 'Gene', '673', (62, 66))	('skin lesions', 'Disease', 'MESH:D012871', (134, 146))	('BRAF', 'Gene', (62, 66))	('BRAF', 'Gene', '673', (233, 237))
40898	25724524	Patients were seen by either a medical oncologist (JAS, DBJ, JRI) and/or dermatologist (BRM, WAL) in accordance with the clinical trial protocols (NCT00405587, NCT 00880321, NCT01006980, NCT01107418, NCT01072175, NCT01271803, NCT01037127) for metastatic or unresectable melanoma.	('NCT01271803', 'Var', (213, 224))	('NCT01037127', 'Var', (226, 237))	('NCT01006980', 'Var', (174, 185))	('D', 'Chemical', 'MESH:D003903', (56, 57))	('melanoma', 'Phenotype', 'HP:0002861', (270, 278))	('NCT00405587', 'Var', (147, 158))	('melanoma', 'Disease', (270, 278))	('NCT 00880321', 'Var', (160, 172))	('melanoma', 'Disease', 'MESH:D008545', (270, 278))	('Patients', 'Species', '9606', (0, 8))	('NCT01107418', 'Var', (187, 198))	('NCT01072175', 'Var', (200, 211))
40945	25724524	The majority of patients had metastatic or unresectable melanoma with mutations in the BRAF gene that resulted in valine (V) to glutamate (E) amino acid changes at position 600 (V600E, N = 26 patients).	('mutations', 'Var', (70, 79))	('V600E', 'Var', (178, 183))	('melanoma', 'Disease', 'MESH:D008545', (56, 64))	('melanoma', 'Phenotype', 'HP:0002861', (56, 64))	('melanoma', 'Disease', (56, 64))	('valine', 'Chemical', 'MESH:D014633', (114, 120))	('patients', 'Species', '9606', (16, 24))	('patients', 'Species', '9606', (192, 200))	('resulted in', 'Reg', (102, 113))	('V600E', 'Mutation', 'rs113488022', (178, 183))	('glutamate', 'Chemical', 'MESH:D018698', (128, 137))	('BRAF', 'Gene', (87, 91))	('BRAF', 'Gene', '673', (87, 91))
40946	25724524	Three total patients (one with each mutation) had mutations that caused V600K (valine to lysine), V600D (valine to aspartate) and V600R (valine to arginine) contributing 2, 2 and 3 lesions, respectively (Table 1).	('V600K', 'Var', (72, 77))	('patients', 'Species', '9606', (12, 20))	('V600D', 'Mutation', 'rs121913377', (98, 103))	('arginine', 'Chemical', 'MESH:D001120', (147, 155))	('caused', 'Reg', (65, 71))	('V600K', 'Mutation', 'rs121913227', (72, 77))	('valine', 'Chemical', 'MESH:D014633', (105, 111))	('V600R', 'Mutation', 'rs121913227', (130, 135))	('V600D', 'Var', (98, 103))	('valine', 'Chemical', 'MESH:D014633', (137, 143))	('aspartate', 'Chemical', 'MESH:D001224', (115, 124))	('lysine', 'Chemical', 'MESH:D008239', (89, 95))	('valine', 'Chemical', 'MESH:D014633', (79, 85))	('V600R', 'Var', (130, 135))
40960	25724524	Cutaneous beta-genus HPVs were identified in the BRAFi-cSCC of all morphologic types, with the predominant subtypes being HPV-38 (n=28), HPV-17 (n=21), and HPV-111 (n=11) (Table 1, Fig S1, Table S1).	('HPV', 'Species', '333760', (122, 125))	('HPV', 'Species', '333760', (137, 140))	('HPV', 'Species', '333760', (21, 24))	('SCC', 'Gene', (56, 59))	('BRAF', 'Gene', (49, 53))	('HPV-11', 'Species', '10580', (156, 162))	('SCC', 'Gene', '6317', (56, 59))	('BRAF', 'Gene', '673', (49, 53))	('HPV', 'Species', '333760', (156, 159))	('cSCC', 'Phenotype', 'HP:0006739', (55, 59))	('HPV-111', 'Var', (156, 163))
40964	25724524	Three viral nucleic acid sequences from patients P005, P022, and P028, were unique, each with less than 90% homology to previously reported HPV genotypes in GenBank (NCBI) (Fig.	('HPV', 'Species', '333760', (140, 143))	('patients', 'Species', '9606', (40, 48))	('P005', 'Var', (49, 53))	('P028', 'Var', (65, 69))	('P022', 'Var', (55, 59))
40974	25724524	Nine lesions from 7 patients harbored mutations in major cancer genes (HRAS, KRAS, PIK3CA, CKIT, ALK, EGFR) with mean coverage of 214-fold.	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('cancer', 'Disease', (57, 63))	('ALK', 'Gene', '238', (97, 100))	('PIK3CA', 'Gene', '5290', (83, 89))	('HRAS', 'Gene', (71, 75))	('CKIT', 'Gene', '3815', (91, 95))	('HRAS', 'Gene', '3265', (71, 75))	('KRAS', 'Gene', (77, 81))	('PIK3CA', 'Gene', (83, 89))	('CKIT', 'Gene', (91, 95))	('KRAS', 'Gene', '3845', (77, 81))	('ALK', 'Gene', (97, 100))	('patients', 'Species', '9606', (20, 28))	('mutations', 'Var', (38, 47))	('EGFR', 'Gene', '1956', (102, 106))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('EGFR', 'Gene', (102, 106))
40976	25724524	In the remaining lesions, two had mutations in CKIT (P005, P006), two had mutations in PIK3CA (P008, P070), and one lesion each had mutations in ALK (P041) and EGFR (P071).	('P005', 'Var', (53, 57))	('PIK3CA', 'Gene', '5290', (87, 93))	('ALK', 'Gene', '238', (145, 148))	('P071', 'Var', (166, 170))	('mutations', 'Var', (132, 141))	('mutations', 'Var', (74, 83))	('CKIT', 'Gene', '3815', (47, 51))	('EGFR', 'Gene', '1956', (160, 164))	('P041', 'Var', (150, 154))	('EGFR', 'Gene', (160, 164))	('CKIT', 'Gene', (47, 51))	('ALK', 'Gene', (145, 148))	('mutations', 'Var', (34, 43))	('PIK3CA', 'Gene', (87, 93))
40978	25724524	Two of three PIK3CA mutations and one of two MET SNPs were in samples with sufficient DNA for Sanger confirmation (Table 2, italic font).	('PIK3CA', 'Gene', '5290', (13, 19))	('D', 'Chemical', 'MESH:D003903', (86, 87))	('mutations', 'Var', (20, 29))	('PIK3CA', 'Gene', (13, 19))
40995	25724524	The combination of D+T results in decreased incidence of cSCC; our study shows a trend towards prolongation of latency (52 weeks for D+T vs 16.3 weeks for Vem) which correlates with the effect previously proposed.	('SCC', 'Gene', (58, 61))	('D+T', 'Var', (133, 136))	('D+T', 'Chemical', '-', (19, 22))	('cSCC', 'Phenotype', 'HP:0006739', (57, 61))	('prolongation', 'PosReg', (95, 107))	('D+T', 'Chemical', '-', (133, 136))	('SCC', 'Gene', '6317', (58, 61))	('latency', 'MPA', (111, 118))	('Vem', 'Chemical', 'MESH:D000077484', (155, 158))
40999	25724524	The human papillomaviruses have close homology within the L1 capsid gene that can be amplified by multiple primer sets: PGMY, GP5+/GP6+, FAP, EV-HPV.	('PGMY', 'Var', (120, 124))	('HPV', 'Species', '333760', (145, 148))	('human papillomavirus', 'Species', '10566', (4, 24))	('EV-HPV', 'Var', (142, 148))	('FAP', 'Var', (137, 140))	('GP5+/GP6+', 'Var', (126, 135))
41008	25724524	Examination of cSCC from otherwise healthy individuals identified HPV-38 and HPV-17 in 13.5% (12 of 89) of infected cSCCs using similar methods to our study.	('cSCC', 'Phenotype', 'HP:0006739', (15, 19))	('HPV-17', 'Gene', (77, 83))	('HPV', 'Species', '333760', (66, 69))	('SCC', 'Gene', (117, 120))	('cSCC', 'Phenotype', 'HP:0006739', (116, 120))	('HPV-38', 'Var', (66, 72))	('SCC', 'Gene', (16, 19))	('SCC', 'Gene', '6317', (117, 120))	('SCC', 'Gene', '6317', (16, 19))	('HPV', 'Species', '333760', (77, 80))
41009	25724524	In our study, HPV-38 and HPV-17 composed a significantly higher rate of total infections: 40% (49 of 123, p-value = <0.0001 [2.7e-05], Fisher's exact test [two-sided], Table 1).	('infection', 'Disease', 'MESH:D007239', (78, 87))	('HPV', 'Species', '333760', (25, 28))	('HPV-17', 'Var', (25, 31))	('HPV', 'Species', '333760', (14, 17))	('HPV-38', 'Var', (14, 20))	('infection', 'Disease', (78, 87))
41013	25724524	MCPyV infection and expression of the large T-antigen has been found to interrupt the cell cycle regulatory protein pRB.	('expression', 'Var', (20, 30))	('interrupt', 'NegReg', (72, 81))	('MCPyV infection', 'Disease', 'MESH:D007239', (0, 15))	('cell', 'MPA', (86, 90))	('MCPyV infection', 'Disease', (0, 15))
41020	25724524	The present study adds two examples of HRAS mutation coincident with HPV infection (HRAS G12T with beta-HPV36b - P006 and KRAS G12D beta-HPV 17 and beta-HPV 151 - P144).	('HPV infection', 'Disease', 'MESH:D030361', (69, 82))	('HPV', 'Species', '333760', (137, 140))	('HPV', 'Species', '333760', (153, 156))	('HPV', 'Species', '333760', (69, 72))	('beta-HPV 151 - P144', 'Var', (148, 167))	('beta-HPV36b - P006', 'Var', (99, 117))	('HPV', 'Species', '333760', (104, 107))	('HPV infection', 'Disease', (69, 82))	('HRAS', 'Gene', '3265', (84, 88))	('HPV 151', 'Species', '743812', (153, 160))	('HRAS', 'Gene', '3265', (39, 43))	('G12T', 'Mutation', 'rs773089110', (89, 93))	('HRAS', 'Gene', (84, 88))	('G12D', 'Mutation', 'rs121913529', (127, 131))	('KRAS', 'Gene', (122, 126))	('HRAS', 'Gene', (39, 43))	('KRAS', 'Gene', '3845', (122, 126))
41021	25724524	We also demonstrate the presence of relevent mutations in other cancer-associated proteins not previously reported in BRAFi-cSCC.	('BRAF', 'Gene', '673', (118, 122))	('mutations', 'Var', (45, 54))	('BRAF', 'Gene', (118, 122))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('SCC', 'Gene', (125, 128))	('cSCC', 'Phenotype', 'HP:0006739', (124, 128))	('SCC', 'Gene', '6317', (125, 128))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
41022	25724524	EGFR, ALK, CKIT and PIK3CA mutations are most commonly associated with lung, breast, endometrial and colorectal carcinomas, gastrointestinal stromal tumors and lymphomas.	('mutations', 'Var', (27, 36))	('ALK', 'Gene', '238', (6, 9))	('gastrointestinal stromal tumors', 'Disease', (124, 155))	('PIK3CA', 'Gene', (20, 26))	('lymphomas', 'Disease', (160, 169))	('tumors', 'Phenotype', 'HP:0002664', (149, 155))	('ALK', 'Gene', (6, 9))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('carcinomas', 'Phenotype', 'HP:0030731', (112, 122))	('breast', 'Disease', (77, 83))	('colorectal carcinomas', 'Disease', 'MESH:D015179', (101, 122))	('colorectal carcinomas', 'Disease', (101, 122))	('lymphoma', 'Phenotype', 'HP:0002665', (160, 168))	('CKIT', 'Gene', (11, 15))	('associated', 'Reg', (55, 65))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('lung', 'Disease', (71, 75))	('CKIT', 'Gene', '3815', (11, 15))	('EGFR', 'Gene', (0, 4))	('lymphomas', 'Disease', 'MESH:D008223', (160, 169))	('endometrial', 'Disease', (85, 96))	('PIK3CA', 'Gene', '5290', (20, 26))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (124, 155))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (124, 155))	('lymphomas', 'Phenotype', 'HP:0002665', (160, 169))	('EGFR', 'Gene', '1956', (0, 4))
41023	25724524	Mutations in these oncoproteins are not frequently detected in cutaneous squamous cell carcinoma.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (73, 96))	('cutaneous squamous cell carcinoma', 'Disease', 'MESH:D002294', (63, 96))	('cutaneous squamous cell carcinoma', 'Phenotype', 'HP:0006739', (63, 96))	('cutaneous squamous cell carcinoma', 'Disease', (63, 96))	('Mutations', 'Var', (0, 9))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))
41024	25724524	PIK3CA mutations have been detected in two spontaneous cSCC and one KA lesion and in two BRAFi-cSCC.	('SCC', 'Gene', (96, 99))	('SCC', 'Gene', (56, 59))	('cSCC', 'Phenotype', 'HP:0006739', (95, 99))	('PIK3CA', 'Gene', (0, 6))	('BRAF', 'Gene', '673', (89, 93))	('SCC', 'Gene', '6317', (96, 99))	('PIK3CA', 'Gene', '5290', (0, 6))	('SCC', 'Gene', '6317', (56, 59))	('BRAF', 'Gene', (89, 93))	('cSCC', 'Phenotype', 'HP:0006739', (55, 59))	('detected', 'Reg', (27, 35))	('mutations', 'Var', (7, 16))
41025	25724524	One EGFR R108K mutation has been reported in a single BRAFi-cSCC.	('cSCC', 'Phenotype', 'HP:0006739', (60, 64))	('R108K', 'Mutation', 'rs1057519828', (9, 14))	('SCC', 'Gene', '6317', (61, 64))	('EGFR', 'Gene', (4, 8))	('BRAF', 'Gene', (54, 58))	('BRAF', 'Gene', '673', (54, 58))	('R108K', 'Var', (9, 14))	('SCC', 'Gene', (61, 64))	('EGFR', 'Gene', '1956', (4, 8))
41026	25724524	We report for the first time to our knowledge an ALK F1174L mutation, two tumors with CKIT M541L mutations, and an EGFR V769M mutation in BRAFi-cSCCs.	('EGFR', 'Gene', (115, 119))	('SCC', 'Gene', '6317', (145, 148))	('M541L', 'Mutation', 'rs3822214', (91, 96))	('F1174L', 'Mutation', 'rs863225281', (53, 59))	('tumors', 'Disease', 'MESH:D009369', (74, 80))	('SCC', 'Gene', (145, 148))	('F1174L', 'Var', (53, 59))	('cSCC', 'Phenotype', 'HP:0006739', (144, 148))	('V769M', 'Mutation', 'rs147149347', (120, 125))	('ALK', 'Gene', '238', (49, 52))	('EGFR', 'Gene', '1956', (115, 119))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('ALK', 'Gene', (49, 52))	('BRAF', 'Gene', '673', (138, 142))	('BRAF', 'Gene', (138, 142))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('CKIT', 'Gene', (86, 90))	('CKIT', 'Gene', '3815', (86, 90))	('tumors', 'Disease', (74, 80))
41027	25724524	Prior mechanistic studies of conv.-cSCC have demonstrated a significant role for UV-B via increased rate of mutation in tumor suppressor TP53.	('tumor suppressor', 'Gene', (120, 136))	('SCC', 'Gene', (36, 39))	('TP53', 'Gene', '7157', (137, 141))	('mutation', 'Var', (108, 116))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('SCC', 'Gene', '6317', (36, 39))	('UV-B', 'Gene', (81, 85))	('tumor suppressor', 'Gene', '7248', (120, 136))	('cSCC', 'Phenotype', 'HP:0006739', (35, 39))	('TP53', 'Gene', (137, 141))
41037	25724524	Further, the limitation of sample size prevents demonstration of statistical significance for several parameters suggestive but not definitive of relevance to BRAFi-cSCC carcinogenesis in our study, including coinfection of beta-HPV and MCPyV with and without UV exposure and RAS gene mutation.	('carcinogenesis', 'Disease', (170, 184))	('BRAF', 'Gene', (159, 163))	('SCC', 'Gene', (166, 169))	('cSCC', 'Phenotype', 'HP:0006739', (165, 169))	('RAS', 'Gene', (276, 279))	('MCPyV', 'Species', '493803', (237, 242))	('mutation', 'Var', (285, 293))	('SCC', 'Gene', '6317', (166, 169))	('HPV', 'Species', '333760', (229, 232))	('carcinogenesis', 'Disease', 'MESH:D063646', (170, 184))	('infection', 'Disease', (211, 220))	('BRAF', 'Gene', '673', (159, 163))	('infection', 'Disease', 'MESH:D007239', (211, 220))
41040	25724524	NGS and analysis in our experiments did report HRAS Q61L for P040 that on Sanger was confirmed as Q61R.	('Q61L', 'Mutation', 'rs121913233', (52, 56))	('Q61R', 'Var', (98, 102))	('P040', 'Var', (61, 65))	('HRAS', 'Gene', '3265', (47, 51))	('Q61R', 'Mutation', 'rs121913233', (98, 102))	('men', 'Species', '9606', (30, 33))	('HRAS', 'Gene', (47, 51))
41041	25724524	Additionally, the annotation algorithm misidentified a G12-change in sample P006 that was confirmed G12T by Sanger.	('misidentified', 'Reg', (39, 52))	('G12-change', 'Var', (55, 65))	('G12T', 'Mutation', 'rs773089110', (100, 104))
41042	25724524	A possible double PIK3CA mutation resulting in A1046T (P070) was suggested by the NGS that was not confirmed by Sanger (Table 2).	('A1046T', 'Mutation', 'c.1046A>T', (47, 53))	('PIK3CA', 'Gene', (18, 24))	('A1046T', 'Var', (47, 53))	('PIK3CA', 'Gene', '5290', (18, 24))
41043	25724524	Also, CKIT, EGFR and ALK mutations were within Ampliseq study parameters, however there was insufficient biopsy DNA for further Sanger confirmation.	('insufficient', 'Disease', 'MESH:D000309', (92, 104))	('mutations', 'Var', (25, 34))	('insufficient', 'Disease', (92, 104))	('ALK', 'Gene', (21, 24))	('EGFR', 'Gene', '1956', (12, 16))	('CKIT', 'Gene', '3815', (6, 10))	('D', 'Chemical', 'MESH:D003903', (112, 113))	('EGFR', 'Gene', (12, 16))	('ALK', 'Gene', '238', (21, 24))	('CKIT', 'Gene', (6, 10))
41056	33177501	L1s are expressed and mobilized in different cancers, generating mutagenic insertions that could affect tumor malignancy.	('tumor malignancy', 'Disease', (104, 120))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('affect', 'Reg', (97, 103))	('tumor malignancy', 'Disease', 'MESH:D009369', (104, 120))	('mutagenic insertions', 'Var', (65, 85))	('cancers', 'Disease', 'MESH:D009369', (45, 52))	('cancers', 'Phenotype', 'HP:0002664', (45, 52))	('cancers', 'Disease', (45, 52))
41071	33177501	Remarkably, new L1 insertions accumulate not only during early embryogenesis and in the germline, being transmitted to the next generation, but also in cancer cells, which are characterized by genome instability (thoroughly reviewed recently in refs.	('cancer', 'Disease', (152, 158))	('insertions', 'Var', (19, 29))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('accumulate', 'PosReg', (30, 40))
41073	33177501	Interestingly, several reports have shown that somatic L1 insertions can drive tumorigenesis and may even have initiated the tumor in normal cells.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('tumor', 'Disease', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('insertions', 'Var', (58, 68))	('tumor', 'Disease', (125, 130))	('initiated', 'PosReg', (111, 120))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('drive', 'PosReg', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
41074	33177501	Transcriptional control through methylation of the L1 promoter is one of the main defence mechanisms against L1 activity, and it has been demonstrated that hypomethylation of specific RC-L1s is associated with retrotransposition in early tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (238, 243))	('RC-L1', 'Gene', '10171', (184, 189))	('tumor', 'Phenotype', 'HP:0002664', (238, 243))	('tumor', 'Disease', (238, 243))	('RC-L1', 'Gene', (184, 189))	('hypomethylation', 'Var', (156, 171))	('associated with', 'Reg', (194, 209))
41075	33177501	However, additional post-transcriptional mechanisms that silence and reactivate L1 in somatic normal and tumor cells are not completely understood yet.	('tumor', 'Disease', (105, 110))	('reactivate', 'Var', (69, 79))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))
41078	33177501	Therefore, miRNAs could be influencing essentially all human developmental, physiological, and pathological processes.	('miRNAs', 'Var', (11, 17))	('influencing', 'Reg', (27, 38))	('human', 'Species', '9606', (55, 60))
41081	33177501	Whereas the increase in LINE-1 mRNA levels in the absence of DGCR8 was attributed to reduced noncanonical functions of the Microprocessor, which cleaves stem-loops present in L1 elements, it remains possible that miRNAs regulate L1 expression levels.	('LINE-1 mRNA levels', 'MPA', (24, 42))	('DGCR8', 'Gene', (61, 66))	('absence', 'Var', (50, 57))	('DGCR8', 'Gene', '94223', (61, 66))	('increase', 'PosReg', (12, 20))	('regulate', 'Reg', (220, 228))	('noncanonical functions of', 'MPA', (93, 118))	('reduced', 'NegReg', (85, 92))	('L1 expression levels', 'MPA', (229, 249))
41083	33177501	Thus, we hypothesized that some miRNAs could control L1 retrotransposition and that their misexpression in tumors could contribute to increased LINE-1 mobilization.	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('LINE-1 mobilization', 'CPA', (144, 163))	('L1 retrotransposition', 'CPA', (53, 74))	('misexpression', 'Var', (90, 103))	('tumors', 'Disease', (107, 113))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('tumors', 'Disease', 'MESH:D009369', (107, 113))	('control', 'Reg', (45, 52))	('increased', 'PosReg', (134, 143))
41085	33177501	Notably, we find that samples containing tumor-specific L1 insertions express reduced levels of several members of the tumor suppressor miRNA let-7 family, suggesting that this miRNA could influence retrotransposition in vivo.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Disease', (119, 124))	('levels', 'MPA', (86, 92))	('tumor', 'Disease', (41, 46))	('insertions', 'Var', (59, 69))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('retrotransposition', 'MPA', (199, 217))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('influence', 'Reg', (189, 198))	('reduced', 'NegReg', (78, 85))	('tumor', 'Disease', 'MESH:D009369', (41, 46))
41088	33177501	To identify potential miRNAs whose deregulation could produce a change in L1 retrotransposition in epithelial tumors, we focused on Non-Small Cell Lung Cancer samples (NSCLC) from The Cancer Genome Atlas (TCGA), as endogenous L1s are known to retrotranspose efficiently in this tumor type.	('Cancer', 'Disease', 'MESH:D009369', (152, 158))	('change', 'Reg', (64, 70))	('tumor', 'Phenotype', 'HP:0002664', (278, 283))	('C', 'Chemical', 'MESH:D002244', (170, 171))	('Non-Small Cell Lung Cancer', 'Phenotype', 'HP:0030358', (132, 158))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('Cancer', 'Phenotype', 'HP:0002664', (184, 190))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('C', 'Chemical', 'MESH:D002244', (184, 185))	('tumors', 'Disease', (110, 116))	('Cancer', 'Disease', (184, 190))	('C', 'Chemical', 'MESH:D002244', (142, 143))	('Cancer', 'Phenotype', 'HP:0002664', (152, 158))	('Non-Small Cell Lung Cancer', 'Disease', 'MESH:D002289', (132, 158))	('deregulation', 'Var', (35, 47))	('tumor', 'Disease', (278, 283))	('C', 'Chemical', 'MESH:D002244', (152, 153))	('tumors', 'Disease', 'MESH:D009369', (110, 116))	('Lung Cancer', 'Phenotype', 'HP:0100526', (147, 158))	('NSCLC', 'Disease', (168, 173))	('tumor', 'Disease', 'MESH:D009369', (278, 283))	('Cancer', 'Disease', 'MESH:D009369', (184, 190))	('Cancer', 'Disease', (152, 158))	('C', 'Chemical', 'MESH:D002244', (206, 207))	('NSCLC', 'Disease', 'MESH:D002289', (168, 173))	('tumor', 'Disease', (110, 115))	('Small Cell Lung Cancer', 'Phenotype', 'HP:0030357', (136, 158))	('Non-Small Cell Lung Cancer', 'Disease', (132, 158))	('C', 'Chemical', 'MESH:D002244', (172, 173))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
41090	33177501	We computationally identified tumor-specific somatic L1 retrotransposon insertions from whole-genome sequencing data using the MELT (Mobile Element Locator Tool) software.	('L1 retrotransposon', 'Gene', (53, 71))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('insertions', 'Var', (72, 82))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('tumor', 'Disease', (30, 35))
41091	33177501	First, to rule out possible biases produced by different coverage or quality of sample pairs, we analyzed the polymorphic germline L1 insertions identified by MELT both in tumor and normal tissue.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('tumor', 'Disease', (172, 177))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('insertions', 'Var', (134, 144))
41092	33177501	In the 41 selected samples, the number of polymorphic L1 insertions found in tumor/normal DNA pairs was similar and at least 63% of them were common to both DNAs (Supplementary Table 1).	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Disease', (77, 82))	('insertions', 'Var', (57, 67))	('tumor', 'Disease', 'MESH:D009369', (77, 82))
41093	33177501	After exclusion of polymorphic L1s, we detected 413 putative de novo L1 insertions specific to cancer samples, which were absent in matched normal DNA from the same patient (Supplementary Table 1 and Supplementary Data 1).	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('patient', 'Species', '9606', (165, 172))	('cancer', 'Disease', (95, 101))	('insertions', 'Var', (72, 82))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))
41095	33177501	Consistent with previous studies, 409 of the 413 tumor-specific de novo L1 insertions identified here occurred in intronic and intergenic regions (Supplementary Data 1), likely representing passenger mutations.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor', 'Disease', (49, 54))	('occurred', 'Reg', (102, 110))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('insertions', 'Var', (75, 85))
41096	33177501	To evaluate a possible correlation between L1 retrotransposition in lung cancer and miRNA expression, tumor samples were divided into two groups based on the presence (>=1) or absence (0) of tumor-specific L1 insertions (Fig.	('lung cancer', 'Disease', (68, 79))	('insertions', 'Var', (209, 219))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('lung cancer', 'Phenotype', 'HP:0100526', (68, 79))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('tumor', 'Disease', (191, 196))	('lung cancer', 'Disease', 'MESH:D008175', (68, 79))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))
41098	33177501	Interestingly, we found that several members of the tumor suppressor let-7 family (let-7a, let-7e, and let-7f) were significantly downregulated in the samples with >=1 tumor-specific L1 insertions upon multiple t testing adjusted with False Discovery Rate (FDR) < 0.01 (Fig.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('downregulated', 'NegReg', (130, 143))	('tumor', 'Disease', (168, 173))	('tumor', 'Disease', (52, 57))	('let-7a', 'Gene', (83, 89))	('let-7e', 'Gene', '406887', (91, 97))	('let-7f', 'Gene', (103, 109))	('insertions', 'Var', (186, 196))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('let-7e', 'Gene', (91, 97))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
41099	33177501	Interestingly, reduced expression of let-7a and let-7f has been observed in lung cancer samples.	('lung cancer', 'Disease', 'MESH:D008175', (76, 87))	('let-7f', 'Var', (48, 54))	('lung cancer', 'Disease', (76, 87))	('lung cancer', 'Phenotype', 'HP:0100526', (76, 87))	('reduced', 'NegReg', (15, 22))	('let-7a', 'Gene', (37, 43))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('expression', 'MPA', (23, 33))
41100	33177501	Additionally, miR-34a, another tumor suppressor miRNA, was also significantly reduced in samples with tumor-specific L1 insertions (Fig.	('miR-34a', 'Gene', '407040', (14, 21))	('miR-34a', 'Gene', (14, 21))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumor', 'Disease', (31, 36))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('reduced', 'NegReg', (78, 85))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('insertions', 'Var', (120, 130))
41104	33177501	As expected, L1Hs RNA levels were significantly increased in samples with tumor-specific L1 insertions (Supplementary Fig.	('increased', 'PosReg', (48, 57))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('L1Hs RNA levels', 'MPA', (13, 28))	('tumor', 'Disease', (74, 79))	('insertions', 'Var', (92, 102))
41106	33177501	To further corroborate our results, we analyzed the correlation between miRNA expression and the number of tumor-specific L1 insertions identified by Helman and collaborators in a group of 46 lung tumor samples using Transpo-seq framework (13 of them were also included in the previous analysis using MELT).	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('insertions', 'Var', (125, 135))	('lung tumor', 'Disease', 'MESH:D008175', (192, 202))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('lung tumor', 'Disease', (192, 202))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('tumor', 'Disease', (197, 202))	('lung tumor', 'Phenotype', 'HP:0100526', (192, 202))
41107	33177501	Remarkably, the expression levels of let-7 family members (let-7a and let-7e) and miR-34a were again significantly reduced in those tumors containing tumor-specific L1 insertions when the 26 miRNAs related to lung cancer were analyzed (Supplementary Fig.	('lung cancer', 'Phenotype', 'HP:0100526', (209, 220))	('reduced', 'NegReg', (115, 122))	('tumor', 'Disease', (132, 137))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('expression levels', 'MPA', (16, 33))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('let-7a', 'Gene', (59, 65))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('miR-34a', 'Gene', (82, 89))	('insertions', 'Var', (168, 178))	('lung cancer', 'Disease', (209, 220))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('let-7e', 'Gene', (70, 76))	('miR-34a', 'Gene', '407040', (82, 89))	('tumors', 'Disease', (132, 138))	('tumor', 'Disease', (150, 155))	('let-7e', 'Gene', '406887', (70, 76))	('let-7', 'Gene', (37, 42))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('tumors', 'Disease', 'MESH:D009369', (132, 138))	('lung cancer', 'Disease', 'MESH:D008175', (209, 220))
41108	33177501	Lastly, the same analysis was performed using 36 breast cancer samples which contain a notably smaller number of tumor-specific L1 insertions per sample as determined by Transpo-Seq.	('tumor', 'Disease', (113, 118))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('breast cancer', 'Disease', 'MESH:D001943', (49, 62))	('insertions', 'Var', (131, 141))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('breast cancer', 'Disease', (49, 62))	('breast cancer', 'Phenotype', 'HP:0003002', (49, 62))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))
41112	33177501	To investigate whether there is a causal relationship between the variation in let-7 and miR-34 expression levels and the accumulation of L1 insertions in tumors, we tested the effect of these miRNAs on L1 mobilization using the sRNA/L1 retrotransposition assay, recently developed in our lab.	('miR-34', 'Gene', '407040', (89, 95))	('tested', 'Reg', (166, 172))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('tumors', 'Phenotype', 'HP:0002664', (155, 161))	('variation', 'Var', (66, 75))	('let-7', 'Gene', (79, 84))	('tumors', 'Disease', (155, 161))	('tumors', 'Disease', 'MESH:D009369', (155, 161))	('miR-34', 'Gene', (89, 95))
41113	33177501	Briefly, in this assay, cells are transfected with a plasmid containing an RC-L1 tagged with a reporter cassette (Fig.	('tagged', 'Var', (81, 87))	('RC-L1', 'Gene', '10171', (75, 80))	('RC-L1', 'Gene', (75, 80))
41115	33177501	We next analyzed L1 activity upon overexpressing let-7a and miR-34a, using transfected synthetic miRNA mimics and a neomycin-resistance based retrotransposition assay (using plasmid JM101/L1.3, Fig.	('miR-34a', 'Gene', '407040', (60, 67))	('miR-34a', 'Gene', (60, 67))	('neomycin', 'Chemical', 'MESH:D009355', (116, 124))	('let-7a', 'Var', (49, 55))
41123	33177501	As expected, an inactive L1RP containing two missense mutations in the ORF1-encoded protein did not show luciferase activity (plasmid pYX15, Supplementary Fig.	('luciferase', 'Enzyme', (105, 115))	('missense mutations', 'Var', (45, 63))	('activity', 'MPA', (116, 124))	('ORF1', 'Gene', '55354', (71, 75))	('ORF1', 'Gene', (71, 75))
41130	33177501	Consistent with our previous results, we found that depletion of let-7 in HeLa cells led to a two-fold increase in L1 retrotransposition without affecting the clonability of the cells using the neomycin-resistance cassette described above (Fig.	('L1 retrotransposition', 'MPA', (115, 136))	('increase', 'PosReg', (103, 111))	('HeLa', 'CellLine', 'CVCL:0030', (74, 78))	('let-7', 'Gene', (65, 70))	('depletion', 'Var', (52, 61))	('neomycin', 'Chemical', 'MESH:D009355', (194, 202))	('C', 'Chemical', 'MESH:D002244', (0, 1))
41132	33177501	Furthermore, we confirmed that let-7 knock-down increased L1 retrotransposition in HEK293T using the luciferase reporter vectors pYX014 and pYX017 (Supplementary Fig.	('increased', 'PosReg', (48, 57))	('pYX017', 'Chemical', '-', (140, 146))	('pYX014', 'Chemical', '-', (129, 135))	('L1 retrotransposition', 'MPA', (58, 79))	('HEK293T', 'CellLine', 'CVCL:0063', (83, 90))	('knock-down', 'Var', (37, 47))	('let-7', 'Gene', (31, 36))
41134	33177501	Lastly, since our bioinformatic analysis showed an inverse correlation between let-7 expression and accumulation of L1 insertions in human lung tumor samples, we analyzed whether let-7 could regulate L1 retrotransposition in lung cancer cells.	('regulate', 'Reg', (191, 199))	('lung cancer', 'Phenotype', 'HP:0100526', (225, 236))	('insertions', 'Var', (119, 129))	('lung tumor', 'Disease', (139, 149))	('lung tumor', 'Disease', 'MESH:D008175', (139, 149))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('let-7', 'Gene', (79, 84))	('lung cancer', 'Disease', 'MESH:D008175', (225, 236))	('lung tumor', 'Phenotype', 'HP:0100526', (139, 149))	('human', 'Species', '9606', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('lung cancer', 'Disease', (225, 236))
41135	33177501	To do that, we performed the luciferase-based retrotransposition assay in two lung cancer cell lines with markedly different endogenous levels of let-7, A549, and SK-MES-1 (Supplementary Fig.	('lung cancer', 'Disease', (78, 89))	('let-7', 'Var', (146, 151))	('lung cancer', 'Phenotype', 'HP:0100526', (78, 89))	('SK-MES-1', 'CellLine', 'CVCL:0630', (163, 171))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('A549', 'CellLine', 'CVCL:0023', (153, 157))	('SK-MES-1', 'Var', (163, 171))	('lung cancer', 'Disease', 'MESH:D008175', (78, 89))	('A549', 'Var', (153, 157))
41158	33177501	Accordingly, the introduction of the mutation contained in the "bs2rhmut" sequence, which entails an amino acid change (P to G) in L1-ORF2p, leads to a reduction in RC-L1 mobility (Fig.	('ORF2p', 'Gene', '100128274', (134, 139))	('ORF2p', 'Gene', (134, 139))	('mutation', 'Var', (37, 45))	('RC-L1', 'Gene', (165, 170))	('RC-L1', 'Gene', '10171', (165, 170))	('reduction', 'NegReg', (152, 161))
41161	33177501	However, the fact that mutating this binding site reduced but not abolished the effect of let-7 in L1 mobilization suggests that additional mechanisms mediated by let-7 may work to restrict human L1 retrotransposition.	('mutating', 'Var', (23, 31))	('restrict', 'NegReg', (181, 189))	('human', 'Species', '9606', (190, 195))	('L1 mobilization', 'MPA', (99, 114))
41165	33177501	We found no changes in L1 mRNA levels at 24 and 48 hours after let-7 overexpression, whereas those of other canonical let-7 targets (DICER and HMGA2) were reduced (Fig.	('L1 mRNA levels', 'MPA', (23, 37))	('reduced', 'NegReg', (155, 162))	('DICER', 'Gene', '23405', (133, 138))	('HMGA2', 'Gene', '8091', (143, 148))	('overexpression', 'Var', (69, 83))	('let-7', 'Gene', (63, 68))	('DICER', 'Gene', (133, 138))	('HMGA2', 'Gene', (143, 148))
41174	33177501	Strikingly, we observed an increase in ORF2p upon let-7 depletion and a decrease upon let-7 overexpression in HeLa cells (Fig.	('HeLa', 'CellLine', 'CVCL:0030', (110, 114))	('overexpression', 'PosReg', (92, 106))	('let-7', 'Gene', (50, 55))	('depletion', 'Var', (56, 65))	('decrease', 'NegReg', (72, 80))	('ORF2p', 'Gene', '100128274', (39, 44))	('let-7', 'Gene', (86, 91))	('increase', 'PosReg', (27, 35))	('ORF2p', 'Gene', (39, 44))
41194	33177501	Notably, we found that depleting let-7 led to an increase in the number of mCherry+ cells in the EGFP+ population suggesting an increase in the synthesis of L1-ORF2p-mCherry (Fig.	('ORF2p', 'Gene', (160, 165))	('increase', 'PosReg', (49, 57))	('synthesis', 'MPA', (144, 153))	('increase', 'PosReg', (128, 136))	('let-7', 'Gene', (33, 38))	('C', 'Chemical', 'MESH:D002244', (76, 77))	('C', 'Chemical', 'MESH:D002244', (167, 168))	('ORF2p', 'Gene', '100128274', (160, 165))	('depleting', 'Var', (23, 32))
41197	33177501	In particular, L1 insertions have been found to occur at high frequencies in lung cancer genomes.	('lung cancer', 'Phenotype', 'HP:0100526', (77, 88))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('lung cancer', 'Disease', 'MESH:D008175', (77, 88))	('insertions', 'Var', (18, 28))	('lung cancer', 'Disease', (77, 88))
41199	33177501	In fact, a consistent correlation between the number of somatic L1 insertions in lung cancer and hypomethylation of L1 promoters has been shown, both at a global and at a locus specific level.	('lung cancer', 'Disease', (81, 92))	('hypomethylation', 'MPA', (97, 112))	('lung cancer', 'Phenotype', 'HP:0100526', (81, 92))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('lung cancer', 'Disease', 'MESH:D008175', (81, 92))	('insertions', 'Var', (67, 77))
41204	33177501	First, we found a high frequency of retrotransposition in NSCLC cancer, consistent with previous reports.	('NSCLC cancer', 'Disease', (58, 70))	('NSCLC cancer', 'Disease', 'MESH:D009369', (58, 70))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('retrotransposition', 'Var', (36, 54))
41205	33177501	We further showed that human tumor samples with somatic L1 insertions present reduced let-7 expression.	('let-7', 'Protein', (86, 91))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('insertions', 'Var', (59, 69))	('tumor', 'Disease', (29, 34))	('reduced', 'NegReg', (78, 85))	('human', 'Species', '9606', (23, 28))
41212	33177501	Furthermore, we demonstrate that mutations in this binding site reduce, but not abolish, the effect of let-7 modulation on human L1 mobility.	('reduce', 'NegReg', (64, 70))	('human', 'Species', '9606', (123, 128))	('mutations', 'Var', (33, 42))	('human L1 mobility', 'MPA', (123, 140))	('let-7', 'Gene', (103, 108))
41222	33177501	Notably, even though the let-7 miRNA-L1 mRNA interaction likely occurs in any cell that simultaneously expresses both RNAs, we did not observe any correlation between increased somatic L1 insertions and reduced let-7 levels in human breast cancer samples (Supplementary Fig.	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('insertions', 'Var', (188, 198))	('reduced', 'NegReg', (203, 210))	('breast cancer', 'Disease', 'MESH:D001943', (233, 246))	('human', 'Species', '9606', (227, 232))	('breast cancer', 'Phenotype', 'HP:0003002', (233, 246))	('breast cancer', 'Disease', (233, 246))	('let-7 levels', 'MPA', (211, 223))
41226	33177501	We hypothesize that alterations in let-7 expression in human cancer lead to an increased mobilization of actively transcribed L1s and, moreover L1- mediated retrotransposition of non-autonomous transposable elements like Alu and SVA, increasing genome instability and contributing to tumor progression.	('alterations', 'Var', (20, 31))	('increased', 'PosReg', (79, 88))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('cancer', 'Disease', (61, 67))	('human', 'Species', '9606', (55, 60))	('genome instability', 'MPA', (245, 263))	('contributing', 'Reg', (268, 280))	('mobilization', 'MPA', (89, 101))	('increasing', 'PosReg', (234, 244))	('tumor', 'Disease', 'MESH:D009369', (284, 289))	('tumor', 'Phenotype', 'HP:0002664', (284, 289))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('let-7', 'Gene', (35, 40))	('tumor', 'Disease', (284, 289))
41233	33177501	Four samples in LUSC (TCGA-60-2695, TCGA-60-2722) and LUAD (TCGA-55-1594, TCGA-55-1596) were excluded from analysis because only a low number (<10%) of polymorphic insertions passed all filters.	('TCGA-60-2695', 'Var', (22, 34))	('C', 'Chemical', 'MESH:D002244', (37, 38))	('C', 'Chemical', 'MESH:D002244', (23, 24))	('C', 'Chemical', 'MESH:D002244', (75, 76))	('C', 'Chemical', 'MESH:D002244', (19, 20))	('C', 'Chemical', 'MESH:D002244', (61, 62))	('polymorphic insertions', 'Var', (152, 174))	('TCGA-55-1596', 'Var', (74, 86))	('TCGA-55-1594', 'Var', (60, 72))
41240	33177501	HEK293T, PA-1, HeLa, and U2OS cells were originally obtained from ATCC and were provided by Drs Jose Luis Garcia-Perez (IGMM, Edinburgh, UK) and John V. Moran (University of Michigan, US).	('Jose Luis Garcia-Perez', 'Disease', 'MESH:C536767', (96, 118))	('PA-1', 'CellLine', 'CVCL:T887', (9, 13))	('U2OS', 'CellLine', 'CVCL:0042', (25, 29))	('HeLa', 'CellLine', 'CVCL:0030', (15, 19))	('Jose Luis Garcia-Perez', 'Disease', (96, 118))	('HEK293T', 'CellLine', 'CVCL:0063', (0, 7))	('HEK293T', 'Var', (0, 7))
41242	33177501	Stable Flp-In-293 cells expressing T7-tagged L1-ORF1p were previously generated for a different study.	('ORF1p', 'Gene', '55354', (48, 53))	('T7-tagged', 'Var', (35, 44))	('ORF1p', 'Gene', (48, 53))
41256	33177501	Next day, 200 ng of pYX014, pYX015, or pYX017 were co-transfected with 60 nM of let-7 mimic or 40 nM of let-7 inhibitor (and their respective controls, scr, and c- respectively) using Lipofectamine 2000 (Life).	('let-7', 'Protein', (80, 85))	('pYX017', 'Chemical', '-', (39, 45))	('pYX014', 'Chemical', '-', (20, 26))	('pYX015', 'Chemical', '-', (28, 34))	('pYX017', 'Var', (39, 45))	('Lipofectamine 2000', 'Chemical', 'MESH:C086724', (184, 202))	('let-7', 'Gene', (104, 109))
41260	33177501	Let-7a/b mimic (C-300473-05 and C-300476-05), miR-34 mimic (C-300551-07), let-7a hairpin inhibitor (IH-300474-07), and their respective controls scr and c- (CN-002000-01-05 and IN-002005-01-05), were purchased from Dharmacon.	('C-300551-07', 'Var', (60, 71))	('miR-34', 'Gene', (46, 52))	('C', 'Chemical', 'MESH:D002244', (32, 33))	('C-300473-05', 'Var', (16, 27))	('C', 'Chemical', 'MESH:D002244', (16, 17))	('C', 'Chemical', 'MESH:D002244', (157, 158))	('miR-34', 'Gene', '407040', (46, 52))	('C', 'Chemical', 'MESH:D002244', (60, 61))	('C-300476-05', 'Var', (32, 43))
41273	33177501	Conditions for this PCR were: 95  C 5 min, 10 cycles with (95  C 15 s, 50  C 30 s, 72  C 60 s), 25 cycles with (95  C 15 s, 55  C 30 s, 72  C 60 s), 72  C 10 min.	('C', 'Chemical', 'MESH:D002244', (87, 88))	('C', 'Chemical', 'MESH:D002244', (21, 22))	('95  C 15 s', 'Var', (112, 122))	('C', 'Chemical', 'MESH:D002244', (128, 129))	('C', 'Chemical', 'MESH:D002244', (153, 154))	('C', 'Chemical', 'MESH:D002244', (75, 76))	('C', 'Chemical', 'MESH:D002244', (116, 117))	('95  C 15 s', 'Var', (59, 69))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('C', 'Chemical', 'MESH:D002244', (34, 35))	('C', 'Chemical', 'MESH:D002244', (140, 141))	('C', 'Chemical', 'MESH:D002244', (63, 64))
41274	33177501	The resulting product contained the mutated sequence in ORF2.	('ORF2', 'Gene', (56, 60))	('mutated sequence', 'Var', (36, 52))	('contained', 'Reg', (22, 31))	('ORF2', 'Gene', '100128274', (56, 60))
41275	33177501	This product was purified and cloned into a plasmid containing an active L1 (pJCC5/L1.3) using EcoNI and BsaBI sites, generating pJCC5/bs2mutL1.3.	('pJCC5/L1.3', 'Gene', '28929', (77, 87))	('pJCC5/bs2mutL1.3', 'Var', (129, 145))	('pJCC5/L1.3', 'Gene', (77, 87))
41290	33177501	For blotting we used the following antibodies: a polyclonal rabbit anti-L1-ORF1p (1:1000, provided by Dr. Oliver Weichenrieder, Max-Planck, Germany), a polyclonal rabbit anti-L1ORF1p (1:1000, SE-6798), anti HMGA2 (1:1000, Abcam), anti DICER (1:1000, Cell Signalling), anti-tubulin (1:1000, Santa Cruz), anti-actin (1:10000, Sigma, A2228), anti-GFP (1: 2000, 3H9 clone, Chromotek).	('C', 'Chemical', 'MESH:D002244', (237, 238))	('C', 'Chemical', 'MESH:D002244', (296, 297))	('ORF1p', 'Gene', '55354', (177, 182))	('ORF1p', 'Gene', '55354', (75, 80))	('HMGA2', 'Gene', (207, 212))	('DICER', 'Gene', '23405', (235, 240))	('ORF1p', 'Gene', (177, 182))	('ORF1p', 'Gene', (75, 80))	('1:10000', 'Var', (315, 322))	('C', 'Chemical', 'MESH:D002244', (369, 370))	('C', 'Chemical', 'MESH:D002244', (250, 251))	('DICER', 'Gene', (235, 240))	('Cell Signalling', 'CPA', (250, 265))	('anti-actin', 'Var', (303, 313))	('anti-GFP', 'Var', (339, 347))	('HMGA2', 'Gene', '8091', (207, 212))
41305	33177501	qPCR was performed with primers Let-7a, Let-7b, and miR-34a.	('Let-7b', 'Gene', (40, 46))	('miR-34a', 'Gene', '407040', (52, 59))	('miR-34a', 'Gene', (52, 59))	('Let-7a', 'Var', (32, 38))	('C', 'Chemical', 'MESH:D002244', (2, 3))	('Let-7b', 'Gene', '406884', (40, 46))
41315	33177501	pYX014, pYX015 and pYX017, JM101/L1.3, JM105/L1.3, JJ101/L1.3 and TAM102/L1.3, 99-UB-LRE3, Tgf21-Neo, Zfl2-1-Neo, and Zfl2-2-Neo have been previously described.	('Tgf21-Neo', 'Var', (91, 100))	('TAM102/L1.3', 'Var', (66, 77))	('pYX017', 'Chemical', '-', (19, 25))	('JM105/L1.3', 'Var', (39, 49))	('pYX015', 'Var', (8, 14))	('pYX014', 'Var', (0, 6))	('JJ101/L1.3', 'Var', (51, 61))	('JM101/L1.3', 'Var', (27, 37))	('pYX015', 'Chemical', '-', (8, 14))	('pYX017', 'Var', (19, 25))	('pYX014', 'Chemical', '-', (0, 6))
41334	31554794	Here, the authors show that the ribosylation of LKB1 by tankyrase-RNF146 axis results in attenuation of LKB1 pathway activation.	('LKB1 pathway', 'Pathway', (104, 116))	('LKB1', 'Gene', (48, 52))	('attenuation', 'NegReg', (89, 100))	('tankyrase', 'Gene', '8658', (56, 65))	('tankyrase', 'Gene', (56, 65))	('ribosylation', 'Var', (32, 44))	('activation', 'PosReg', (117, 127))	('RNF146', 'Gene', (66, 72))	('RNF146', 'Gene', '68031', (66, 72))
41337	31554794	Patients with PJS are tumor-prone, and germline mutations in LKB1 are common in patients with sporadic cancers, including lung adenocarcinoma and cervical carcinoma.	('common', 'Reg', (70, 76))	('germline mutations', 'Var', (39, 57))	('patients', 'Species', '9606', (80, 88))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('sporadic cancers', 'Disease', (94, 110))	('LKB1', 'Gene', (61, 65))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('cervical carcinoma', 'Disease', 'MESH:D002583', (146, 164))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('Patients', 'Species', '9606', (0, 8))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (122, 141))	('cancers', 'Phenotype', 'HP:0002664', (103, 110))	('lung adenocarcinoma', 'Disease', (122, 141))	('cervical carcinoma', 'Disease', (146, 164))	('carcinoma', 'Phenotype', 'HP:0030731', (155, 164))	('PJS', 'Disease', 'MESH:D010580', (14, 17))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (122, 141))	('tumor', 'Disease', (22, 27))	('PJS', 'Disease', (14, 17))	('sporadic cancers', 'Disease', 'MESH:D009369', (94, 110))
41341	31554794	LKB1 phosphorylates AMPK at threonine 172 to activate AMPK, activated AMPK then phosphorylates downstream targets involved in fatty acid synthesis, glycolysis, and protein synthesis.	('AMPK', 'Gene', '5563', (20, 24))	('threonine 172', 'Var', (28, 41))	('AMPK', 'Gene', (54, 58))	('LKB1', 'Gene', (0, 4))	('activate', 'PosReg', (45, 53))	('threonine', 'Chemical', 'MESH:C061951', (28, 37))	('AMPK', 'Gene', '5563', (70, 74))	('fatty acid', 'Chemical', 'MESH:D005227', (126, 136))	('AMPK', 'Gene', (20, 24))	('AMPK', 'Gene', '5563', (54, 58))	('AMPK', 'Gene', (70, 74))
41355	31554794	Notably, in addition to metformin/ AICAR, we identified JW55, JW-55, and CHIR-99021 as putative AMPK activators (Fig.	('JW55', 'Var', (56, 60))	('JW-55', 'Var', (62, 67))	('AMPK', 'Gene', '5563', (96, 100))	('CHIR-99021', 'Chemical', 'MESH:C473711', (73, 83))	('AICAR', 'Chemical', 'MESH:C031143', (35, 40))	('metformin', 'Chemical', 'MESH:D008687', (24, 33))	('AMPK', 'Gene', (96, 100))
41356	31554794	The GSK-3 inhibitor CHIR-99021 was previously shown to activate AMPK and both JW55 and JW-55 are inhibitors of tankyrase.	('JW-55', 'Var', (87, 92))	('CHIR-99021', 'Var', (20, 30))	('AMPK', 'Gene', (64, 68))	('activate', 'PosReg', (55, 63))	('JW55', 'Var', (78, 82))	('CHIR-99021', 'Chemical', 'MESH:C473711', (20, 30))	('tankyrase', 'Gene', '8658', (111, 120))	('tankyrase', 'Gene', (111, 120))	('AMPK', 'Gene', '5563', (64, 68))
41362	31554794	Tankyrases were originally discovered as regulator of telomere elongation by ribosylating TRF1, and were recently identified to regulate diverse functions, including in regulation of wnt pathway, PI3K-Akt signaling, Hippo-Yap pathway, and pexophagy.	('pexophagy', 'CPA', (239, 248))	('Yap', 'Gene', '22601', (222, 225))	('ribosylating', 'Var', (77, 89))	('TRF1', 'Gene', (90, 94))	('regulate', 'Reg', (128, 136))	('wnt pathway', 'Pathway', (183, 194))	('Yap', 'Gene', (222, 225))	('PI3K-Akt signaling', 'Pathway', (196, 214))
41364	31554794	Both JW55 and G007-LK led to AMPK activation without changes in LKB1/AMPK levels (Supplementary Fig.	('AMPK', 'Gene', (29, 33))	('JW55', 'Var', (5, 9))	('AMPK', 'Gene', '5563', (69, 73))	('G007-LK', 'Var', (14, 21))	('AMPK', 'Gene', '5563', (29, 33))	('AMPK', 'Gene', (69, 73))
41365	31554794	To confirm this observation, we tested the effects of different tankyrase inhibitors (JW55, WIKI4, XAV939, and G007-LK) on AMPK activation.	('JW55', 'Var', (86, 90))	('tested', 'Reg', (32, 38))	('AMPK', 'Gene', (123, 127))	('tankyrase', 'Gene', '8658', (64, 73))	('tankyrase', 'Gene', (64, 73))	('AMPK', 'Gene', '5563', (123, 127))
41366	31554794	Similar to metformin/AICAR, we found all tankyrase inhibitors increased the phosphorylation of AMPK and the AMPK substrate ACC (acetyl-CoA carboxylase) in HEK293A cells; however, PARP1/2 inhibitor olaparib had no effect (Fig.	('increased', 'PosReg', (62, 71))	('AMPK', 'Gene', '5563', (95, 99))	('AICAR', 'Chemical', 'MESH:C031143', (21, 26))	('inhibitors', 'Var', (51, 61))	('AMPK', 'Gene', (95, 99))	('phosphorylation', 'MPA', (76, 91))	('AMPK', 'Gene', '5563', (108, 112))	('tankyrase', 'Gene', (41, 50))	('tankyrase', 'Gene', '8658', (41, 50))	('acetyl-CoA', 'Chemical', 'MESH:D000105', (128, 138))	('metformin', 'Chemical', 'MESH:D008687', (11, 20))	('AMPK', 'Gene', (108, 112))
41378	31554794	We observed that only TNKS1/2 double-knockdown resulted in AMPK activation (Fig.	('AMPK', 'Gene', (59, 63))	('double-knockdown', 'Var', (30, 46))	('AMPK', 'Gene', '5563', (59, 63))
41381	31554794	Moreover, reintroduction of TNKS1, but not TNKS1-PD could rescue TNKS1/2 double depletion triggered AMPK activation and energy stress-induced cell death (Supplementary Fig.	('reintroduction', 'Var', (10, 24))	('energy', 'CPA', (120, 126))	('AMPK', 'Gene', '5563', (100, 104))	('TNKS1/2', 'Gene', (65, 72))	('AMPK', 'Gene', (100, 104))
41386	31554794	Interestingly, structural analyses of the LKB1/TNKS complex (the crystal structures for LKB1 and the TNKS ANK repeat2 were taken from the RCSB Protein Data Bank) revealed that G47-Y49 and R86-A93 from LKB1 are located proximal to the interface of the LKB1/TNKS-ANK2 complex (Supplementary Fig.	('TNKS-', 'Gene', '21951', (256, 261))	('G47-Y49', 'Var', (176, 183))	('R86', 'Gene', '20706', (188, 191))	('LKB1', 'Gene', (201, 205))	('R86', 'Gene', (188, 191))	('TNKS-', 'Gene', (256, 261))
41393	31554794	We further confirmed that inhibition or knockdown of tankyrases suppressed LKB1 ribosylation levels in vivo (Supplementary Fig.	('tankyrase', 'Gene', (53, 62))	('LKB1 ribosylation levels', 'MPA', (75, 99))	('suppressed', 'NegReg', (64, 74))	('knockdown', 'Var', (40, 49))	('tankyrase', 'Gene', '8658', (53, 62))
41397	31554794	1i), and that LKB1 E138 is located near the ATP-binding pocket of LKB1 (as indicated by the ATP analog AMP-PNP) (Fig.	('ATP', 'Chemical', 'MESH:D000255', (92, 95))	('E138', 'Var', (19, 23))	('LKB1', 'Gene', (14, 18))	('LKB1', 'Gene', (66, 70))	('ATP', 'Chemical', 'MESH:D000255', (44, 47))	('AMP-PNP', 'Chemical', 'MESH:D000266', (103, 110))
41402	31554794	Moreover, tankyrase inhibition suppressed AMPK downstream genes expression (Supplementary Fig.	('inhibition', 'Var', (20, 30))	('AMPK', 'Gene', '5563', (42, 46))	('tankyrase', 'Gene', '8658', (10, 19))	('tankyrase', 'Gene', (10, 19))	('AMPK', 'Gene', (42, 46))	('suppressed', 'NegReg', (31, 41))
41405	31554794	We found the LKB1-E130/138 A and LKB1-R42/138AG47/R86/G91A mutants showed greater phosphorylation of AMPK, but did not respond to tankyrase inhibitor-mediated regulation of AMPK phosphorylation (Fig.	('G91A', 'Mutation', 'c.91G>A', (54, 58))	('tankyrase', 'Gene', '8658', (130, 139))	('LKB1-E130/138 A', 'Var', (13, 28))	('R86', 'Gene', '20706', (50, 53))	('phosphorylation', 'MPA', (82, 97))	('tankyrase', 'Gene', (130, 139))	('R86', 'Gene', (50, 53))	('AMPK', 'Gene', (173, 177))	('AMPK', 'Gene', '5563', (101, 105))	('AMPK', 'Gene', '5563', (173, 177))	('greater', 'PosReg', (74, 81))	('AMPK', 'Gene', (101, 105))
41407	31554794	Moreover, the LKB1-E130/138 A mutant showed more resistant to tankyrase inhibitor-induced decreases in lipid droplets formation (Supplementary Fig.	('decreases', 'NegReg', (90, 99))	('LKB1-E130/138 A', 'Var', (14, 29))	('resistant', 'NegReg', (49, 58))	('tankyrase', 'Gene', '8658', (62, 71))	('tankyrase', 'Gene', (62, 71))	('lipid droplets formation', 'MPA', (103, 127))
41409	31554794	These results suggest that tankyrase-induced LKB1 ribosylation at the E130/E138 sites is critical for tankyrase-dependent LKB1 regulation.	('LKB1', 'Gene', (45, 49))	('tankyrase', 'Gene', (102, 111))	('tankyrase', 'Gene', '8658', (102, 111))	('ribosylation', 'MPA', (50, 62))	('tankyrase', 'Gene', '8658', (27, 36))	('E130/E138', 'Var', (70, 79))	('tankyrase', 'Gene', (27, 36))
41411	31554794	In the LKR13 lung tumor model, LKR13-LKB1-knockout tumors grew much more aggressively than LKR13 tumors (Fig.	('lung tumor', 'Phenotype', 'HP:0100526', (13, 23))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('aggressively', 'PosReg', (73, 85))	('LKR13-LKB1-knockout', 'Var', (31, 50))	('tumors', 'Disease', (51, 57))	('lung tumor', 'Disease', 'MESH:D008175', (13, 23))	('tumors', 'Disease', (97, 103))	('lung tumor', 'Disease', (13, 23))	('tumors', 'Disease', 'MESH:D009369', (51, 57))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('tumors', 'Disease', 'MESH:D009369', (97, 103))	('grew', 'CPA', (58, 62))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
41412	31554794	However, tankyrase inhibitor G007-LK had a substantial tumor-suppressive effect primarily on LKR13 tumors and much less so on LKR13-LKB1-ko tumors (Fig.	('tumors', 'Phenotype', 'HP:0002664', (99, 105))	('tumor', 'Disease', (99, 104))	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumors', 'Disease', 'MESH:D009369', (99, 105))	('tumors', 'Disease', (140, 146))	('tumors', 'Disease', 'MESH:D009369', (140, 146))	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Disease', (55, 60))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumors', 'Disease', (99, 105))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tankyrase', 'Gene', '8658', (9, 18))	('G007-LK', 'Var', (29, 36))	('tankyrase', 'Gene', (9, 18))	('tumor', 'Disease', (140, 145))
41413	31554794	In addition, the anti-tumor effect of G007-LK was observed in Hela-wtLKB1 tumors, but not in Hela or Hela-mtLKB1 tumors (Fig.	('tumor', 'Disease', (113, 118))	('tumors', 'Disease', (113, 119))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('G007-LK', 'Var', (38, 45))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Disease', (74, 79))	('tumor', 'Disease', (22, 27))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('tumors', 'Disease', 'MESH:D009369', (74, 80))	('tumors', 'Disease', (74, 80))
41414	31554794	Collectively, these findings demonstrate that the anti-tumor effect of G007-LK depends on LKB1.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Disease', (55, 60))	('LKB1', 'Gene', (90, 94))	('G007-LK', 'Var', (71, 78))
41416	31554794	Indeed, loss of RNF146 resulted in an increase in AMPK/ACC phosphorylation (Fig.	('increase', 'PosReg', (38, 46))	('AMPK', 'Gene', (50, 54))	('RNF146', 'Gene', (16, 22))	('RNF146', 'Gene', '68031', (16, 22))	('loss', 'Var', (8, 12))	('AMPK', 'Gene', '5563', (50, 54))
41419	31554794	All indicate that the AMPK pathway was activated after RNF146 knockdown.	('RNF146', 'Gene', '68031', (55, 61))	('activated', 'PosReg', (39, 48))	('AMPK', 'Gene', (22, 26))	('AMPK', 'Gene', '5563', (22, 26))	('RNF146', 'Gene', (55, 61))	('knockdown', 'Var', (62, 71))
41420	31554794	We further noted that overexpression of wild-type but not the mutant RNF146 led to suppression of AMPK (Fig.	('mutant', 'Var', (62, 68))	('suppression', 'NegReg', (83, 94))	('RNF146', 'Gene', '68031', (69, 75))	('overexpression', 'PosReg', (22, 36))	('AMPK', 'Gene', (98, 102))	('RNF146', 'Gene', (69, 75))	('AMPK', 'Gene', '5563', (98, 102))
41424	31554794	3d), and found that XAV939, which abolished LKB1 ribosylation, disrupted the RNF146/LKB1 interaction (Fig.	('interaction', 'Interaction', (89, 100))	('RNF146', 'Gene', (77, 83))	('LKB1', 'Gene', (44, 48))	('RNF146', 'Gene', '68031', (77, 83))	('disrupted', 'NegReg', (63, 72))	('XAV939', 'Var', (20, 26))	('ribosylation', 'MPA', (49, 61))
41426	31554794	Notably, because knockdown of RNF146 led to AMPK activation but did not affect LKB1 protein levels (Fig.	('AMPK', 'Gene', (44, 48))	('RNF146', 'Gene', (30, 36))	('RNF146', 'Gene', '68031', (30, 36))	('knockdown', 'Var', (17, 26))	('AMPK', 'Gene', '5563', (44, 48))
41429	31554794	We used K48R and K63R-ubiquitin for an in vivo ubiquitination assay and found that K63R, but not K48R-ubiquitin, blocked RNF146-mediated LKB1 ubiquitination (Fig.	('K48R', 'Mutation', 'p.K48R', (97, 101))	('RNF146', 'Gene', '68031', (121, 127))	('K48R', 'Mutation', 'p.K48R', (8, 12))	('LKB1', 'Protein', (137, 141))	('blocked', 'NegReg', (113, 120))	('K63R', 'Mutation', 'p.K63R', (17, 21))	('K63R', 'Var', (83, 87))	('RNF146', 'Gene', (121, 127))	('K63R', 'Mutation', 'p.K63R', (83, 87))
41431	31554794	4e) and that deletion of RNF146 only decreased K63-ubiquitin-induced LKB1 ubiquitination (Supplementary Fig.	('RNF146', 'Gene', '68031', (25, 31))	('K63-ubiquitin-induced LKB1 ubiquitination', 'MPA', (47, 88))	('deletion', 'Var', (13, 21))	('RNF146', 'Gene', (25, 31))	('decreased', 'NegReg', (37, 46))
41432	31554794	Furthermore, loss of RNF146 led to significant reduction of K63-linked ubiquitination of endogenous LKB1 (Fig.	('LKB1', 'Gene', (100, 104))	('reduction', 'NegReg', (47, 56))	('loss', 'Var', (13, 17))	('RNF146', 'Gene', (21, 27))	('K63-linked ubiquitination', 'MPA', (60, 85))	('RNF146', 'Gene', '68031', (21, 27))
41433	31554794	Given that LKB1 was ribosylated by tankyrase and recognized by RNF146, we examined the response of wild-type and the LKB1-E130/138 A mutant to RNF146 overexpression.	('RNF146', 'Gene', '68031', (63, 69))	('LKB1-E130/138 A', 'Var', (117, 132))	('RNF146', 'Gene', (143, 149))	('tankyrase', 'Gene', '8658', (35, 44))	('tankyrase', 'Gene', (35, 44))	('RNF146', 'Gene', (63, 69))	('RNF146', 'Gene', '68031', (143, 149))
41435	31554794	We also found that the E130/138 A mutant could not interact with RNF146 (Supplementary Fig.	('E130/138 A', 'Var', (23, 33))	('RNF146', 'Gene', '68031', (65, 71))	('interact', 'Interaction', (51, 59))	('RNF146', 'Gene', (65, 71))
41436	31554794	4i), and RNF146 and tankyrase inhibitor treatment did not affect K63-linked ubiquitination levels of the LKB1-E130/138 A mutant (Fig.	('RNF146', 'Gene', (9, 15))	('K63-linked ubiquitination levels', 'MPA', (65, 97))	('RNF146', 'Gene', '68031', (9, 15))	('tankyrase', 'Gene', '8658', (20, 29))	('tankyrase', 'Gene', (20, 29))	('LKB1-E130/138 A', 'Var', (105, 120))
41438	31554794	Given that formation of the LKB1-STRAD-MO25 complex is critical for LKB1 activation, and the fact that one of LKB1 ribosylation site LKB1-E130 is located near the interface of the LKB1/STRAD complex (Fig.	('MO25', 'Gene', (39, 43))	('LKB1-E130', 'Var', (133, 142))	('MO25', 'Gene', '12283', (39, 43))	('LKB1', 'Gene', (68, 72))
41441	31554794	Furthermore, double-knockdown of TNKS1/2 enhanced the formation of the LKB1/STRAD/MO25 complex (Fig.	('double-knockdown', 'Var', (13, 29))	('MO25', 'Gene', '12283', (82, 86))	('enhanced', 'PosReg', (41, 49))	('MO25', 'Gene', (82, 86))	('formation', 'MPA', (54, 63))	('TNKS1/2', 'Gene', (33, 40))
41442	31554794	4b), whereas rescue of wild-type but not the enzymatic-inactive mutant of TNKS1 in TNKS1/2-knockdown cells reversed the increased formation of the LKB1/STRAD/MO25 complex (Fig.	('formation', 'MPA', (130, 139))	('MO25', 'Gene', '12283', (158, 162))	('TNKS1', 'Gene', (74, 79))	('increased', 'PosReg', (120, 129))	('MO25', 'Gene', (158, 162))	('mutant', 'Var', (64, 70))
41444	31554794	Next, we examined the LKB1/STRAD/MO25 complex formation using WT and the E130/138 A mutant of LKB1.	('MO25', 'Gene', '12283', (33, 37))	('LKB1', 'Gene', (94, 98))	('E130/138 A', 'Var', (73, 83))	('MO25', 'Gene', (33, 37))
41445	31554794	We found that the LKB1-E130/138 A mutant formed a stronger complex with STRAD and MO25 (Fig.	('stronger', 'PosReg', (50, 58))	('MO25', 'Gene', (82, 86))	('MO25', 'Gene', '12283', (82, 86))	('LKB1-E130/138 A', 'Var', (18, 33))
41446	31554794	4e, f), and tankyrase inhibitor treatment or RNF146 overexpression had no effect on the complex formation between the LKB1-E130/138 A mutant and STRAD/MO25 (Fig.	('tankyrase', 'Gene', '8658', (12, 21))	('RNF146', 'Gene', '68031', (45, 51))	('tankyrase', 'Gene', (12, 21))	('complex', 'Interaction', (88, 95))	('MO25', 'Gene', '12283', (151, 155))	('LKB1-E130/138 A', 'Var', (118, 133))	('MO25', 'Gene', (151, 155))	('RNF146', 'Gene', (45, 51))
41450	31554794	Phosphorylation of LKB1 at different sites has distinct functions, especially phosphorylation at Ser428 is important for LKB1-induced AMPK activation.	('AMPK', 'Gene', '5563', (134, 138))	('AMPK', 'Gene', (134, 138))	('phosphorylation', 'Var', (78, 93))	('Ser', 'Chemical', 'MESH:C530429', (97, 100))	('Ser428', 'Var', (97, 103))
41453	31554794	As G007-LK was used in xenograft models, we examined whether G007-LK could improve glycemic control in diabetic mice.	('glycemic control', 'MPA', (83, 99))	('G007-LK', 'Var', (61, 68))	('diabetic', 'Disease', 'MESH:D003920', (103, 111))	('diabetic', 'Disease', (103, 111))	('improve', 'PosReg', (75, 82))	('mice', 'Species', '10090', (112, 116))
41454	31554794	Treatment with G007-LK significantly reduced blood glucose levels, as did metformin; interestingly, the combination of G007-LK and metformin had a significantly greater effect (Fig.	('G007-LK', 'Var', (15, 22))	('metformin', 'Chemical', 'MESH:D008687', (74, 83))	('G007-LK', 'Var', (119, 126))	('blood glucose levels', 'MPA', (45, 65))	('metformin', 'Chemical', 'MESH:D008687', (131, 140))	('reduced blood glucose', 'Phenotype', 'HP:0001943', (37, 58))	('glucose', 'Chemical', 'MESH:D005947', (51, 58))
41455	31554794	In addition, the db/db mice had much greater water consumption and urine output than non-diabetic control, and all treatment groups showed drastic reductions in water consumption and urine output (Fig.	('diabetic', 'Disease', 'MESH:D003920', (89, 97))	('urine output', 'MPA', (67, 79))	('greater', 'PosReg', (37, 44))	('water consumption', 'MPA', (161, 178))	('diabetic', 'Disease', (89, 97))	('reductions', 'NegReg', (147, 157))	('db/db', 'Var', (17, 22))	('water consumption', 'MPA', (45, 62))	('urine output', 'MPA', (183, 195))	('mice', 'Species', '10090', (23, 27))
41456	31554794	5c, d), indicating that G007-LK treatment led to remarkable glycemic control in diabetic mice.	('diabetic', 'Disease', (80, 88))	('mice', 'Species', '10090', (89, 93))	('glycemic control', 'MPA', (60, 76))	('diabetic', 'Disease', 'MESH:D003920', (80, 88))	('G007-LK treatment', 'Var', (24, 41))
41458	31554794	5a); the metformin-treated mice showed similar, but the mice treated with G007-LK showed slight losses of body weight (Supplementary Fig.	('metformin', 'Chemical', 'MESH:D008687', (9, 18))	('G007-LK', 'Var', (74, 81))	('mice', 'Species', '10090', (27, 31))	('mice', 'Species', '10090', (56, 60))	('body', 'MPA', (106, 110))	('losses', 'NegReg', (96, 102))
41460	31554794	We also examined metabolic changes in the livers of the db/db mice and found that the G007-LK-treated mice had decreased hepatic triglyceride (Fig.	('mice', 'Species', '10090', (102, 106))	('decreased hepatic triglyceride', 'Disease', 'MESH:D056486', (111, 141))	('mice', 'Species', '10090', (62, 66))	('decreased hepatic triglyceride', 'Phenotype', 'HP:0012153', (111, 141))	('G007-LK-treated', 'Var', (86, 101))	('decreased hepatic triglyceride', 'Disease', (111, 141))
41465	31554794	Taken together, these results suggest that the tankyrase inhibitor G007-LK regulates both liver metabolism and glycemic control in diabetic mice.	('diabetic', 'Disease', (131, 139))	('tankyrase', 'Gene', '8658', (47, 56))	('glycemic control', 'MPA', (111, 127))	('mice', 'Species', '10090', (140, 144))	('regulates', 'Reg', (75, 84))	('tankyrase', 'Gene', (47, 56))	('diabetic', 'Disease', 'MESH:D003920', (131, 139))	('liver metabolism', 'Disease', (90, 106))	('G007-LK', 'Var', (67, 74))	('liver metabolism', 'Disease', 'MESH:D008113', (90, 106))
41470	31554794	6d, e), and injection of G007-LK suppressed TNKS1-induced tumor growth (Fig.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('G007-LK', 'Var', (25, 32))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('TNKS1-induced', 'Gene', (44, 57))	('suppressed', 'NegReg', (33, 43))
41478	31554794	Moreover, Kaplan-Meier analysis of long-term outcomes for overall survival revealed that high expression of TNKS1 was significantly correlated with poorer overall survival in both lung adenocarcinoma and lung squamous cell carcinoma patients (Fig.	('carcinoma', 'Phenotype', 'HP:0030731', (223, 232))	('carcinoma', 'Phenotype', 'HP:0030731', (190, 199))	('high expression', 'Var', (89, 104))	('poorer', 'NegReg', (148, 154))	('TNKS1', 'Gene', (108, 113))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (209, 232))	('patients', 'Species', '9606', (233, 241))	('lung adenocarcinoma and lung squamous cell carcinoma', 'Disease', 'MESH:C538231', (180, 232))	('overall survival', 'MPA', (155, 171))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (180, 199))
41484	31554794	The PARylation subsequently leads to recognition and K63-linked ubiquitination of LKB1 by the E3 ligase RNF146, and this K63-linked ubiquitination disrupts formation of the LKB1-MO25-STRAD complex and thereby suppresses the activation of LKB1.	('MO25', 'Gene', (178, 182))	('RNF146', 'Gene', '68031', (104, 110))	('disrupts', 'NegReg', (147, 155))	('K63-linked', 'Var', (121, 131))	('leads to', 'Reg', (28, 36))	('MO25', 'Gene', '12283', (178, 182))	('activation', 'MPA', (224, 234))	('suppresses', 'NegReg', (209, 219))	('formation', 'MPA', (156, 165))	('RNF146', 'Gene', (104, 110))	('recognition', 'MPA', (37, 48))	('K63-linked ubiquitination', 'MPA', (53, 78))	('LKB1', 'Enzyme', (238, 242))	('LKB1', 'Gene', (82, 86))
41491	31554794	1), which led to K63-linked, non-degradative polyubiquitination of LKB1 by RNF146 (Fig.	('non-degradative polyubiquitination', 'MPA', (29, 63))	('K63-linked', 'Var', (17, 27))	('RNF146', 'Gene', (75, 81))	('RNF146', 'Gene', '68031', (75, 81))	('LKB1', 'Gene', (67, 71))
41493	31554794	Despite the fact that double-knockout of tankyrases TNKS1 and TNKS2 leads to embryonic lethality in mice, TNKS1-deficient mice survive with reduced adiposity, and TNKS2-deficient mice survive with growth defects.	('mice', 'Species', '10090', (100, 104))	('tankyrase', 'Gene', '8658', (41, 50))	('embryonic lethality', 'Disease', (77, 96))	('mice', 'Species', '10090', (179, 183))	('TNKS1-deficient', 'Disease', (106, 121))	('growth defects', 'Disease', (197, 211))	('TNKS2', 'Gene', (62, 67))	('TNKS2-deficient', 'Disease', (163, 178))	('embryonic lethality', 'Disease', 'MESH:D020964', (77, 96))	('mice', 'Species', '10090', (122, 126))	('growth defects', 'Disease', 'MESH:D006130', (197, 211))	('TNKS1', 'Gene', (52, 57))	('double-knockout', 'Var', (22, 37))	('TNKS1-deficient', 'Disease', 'None', (106, 121))	('reduced adiposity', 'Phenotype', 'HP:0040063', (140, 157))	('TNKS2-deficient', 'Disease', 'None', (163, 178))	('tankyrase', 'Gene', (41, 50))	('adiposity', 'MPA', (148, 157))	('reduced', 'NegReg', (140, 147))
41497	31554794	Although the inhibitory activity of the tankyrase inhibitor G007-LK did not seem to wane for the duration of our preclinical experiments, it is uncertain if this activity will not become refractory with longer term treatments.	('inhibitory activity', 'MPA', (13, 32))	('G007-LK', 'Var', (60, 67))	('tankyrase', 'Gene', (40, 49))	('tankyrase', 'Gene', '8658', (40, 49))
41504	31554794	The TNKS1, TNKS2, and TNKS1-PD ("PARP dead", i.e., the H1184A/E1291A mutant) plasmids were kindly provided by Dr. Susan Smith (New York University); the HA-ubiquitin-K48R/K63R/K48/K63 plasmids were provided by Dr. Li Ma (MD Anderson Cancer Center).	('E1291A', 'Mutation', 'p.E1291A', (62, 68))	('MD Anderson Cancer', 'Disease', 'MESH:D009369', (221, 239))	('Cancer', 'Phenotype', 'HP:0002664', (233, 239))	('K48R', 'SUBSTITUTION', 'None', (166, 170))	('H1184A', 'Var', (55, 61))	('K63R', 'Mutation', 'p.K63R', (171, 175))	('H1184A', 'SUBSTITUTION', 'None', (55, 61))	('K48R', 'Var', (166, 170))	('MD Anderson Cancer', 'Disease', (221, 239))
41506	31554794	The RNF146-delta-WWE and RNF146-delta-RING mutants were generated by deleting amino acids 104-159 or amino acids 36-78, respectively, of the RNF146 coding region.	('RNF146', 'Gene', '68031', (25, 31))	('deleting amino acids 104-159', 'Var', (69, 97))	('RNF146', 'Gene', (25, 31))	('RNF146', 'Gene', (4, 10))	('RNF146', 'Gene', (141, 147))	('RNF146', 'Gene', '68031', (4, 10))	('RNF146', 'Gene', '68031', (141, 147))
41530	31554794	Search parameters allowed for a static modification of 57.02146 Da on cysteine and a dynamic modification of addition of 15.0109 Da to aspartic acid and glutamic acid, the stable isotope (10.00827 Da and 8.01420 Da) on arginine and lysine, respectively.	('cysteine', 'Chemical', 'MESH:D003545', (70, 78))	('57.02146 Da', 'Var', (55, 66))	('lysine', 'Chemical', 'MESH:C114808', (232, 238))	('arginine', 'Chemical', 'MESH:D001127', (219, 227))	('glutamic acid', 'Chemical', 'MESH:C030030', (153, 166))	('aspartic acid', 'Chemical', 'MESH:C403564', (135, 148))	('10.00827 Da', 'Var', (188, 199))
41540	31554794	Our power calculations indicated that use of 10 mice per treatment group could identify the expected effect of G007-LK on tumor weight with 100% power.	('mice', 'Species', '10090', (48, 52))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('G007-LK', 'Var', (111, 118))	('tumor', 'Disease', (122, 127))
41543	31554794	When tumor volume of each groups reached a calculated average of 100 mm3, and the animals in each group were randomized into two subgroups (10 mice per group): (1) vehicle control and (2) G007-LK.	('G007-LK', 'Var', (188, 195))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('tumor', 'Disease', (5, 10))	('mice', 'Species', '10090', (143, 147))
41547	31554794	Tumor size was measured as indicated until tumor volume of each groups reached a calculated average of 100 mm3, and the animals in each group were randomized into two subgroups (eight mice per group): (1) vehicle control and (2) G007-LK and treated as previously.	('G007-LK', 'Var', (229, 236))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('mice', 'Species', '10090', (184, 188))	('tumor', 'Disease', (43, 48))
41561	31554794	The following residues were pre-selected as contact points on LKB1: R86, G91, R86 and G91, R86-G91, G47-Y49, and none (blind docking).	('G47-Y49', 'Var', (100, 107))	('R86', 'Gene', (91, 94))	('R86', 'Gene', '20706', (91, 94))	('LKB1', 'Gene', (62, 66))	('R86', 'Gene', '20706', (78, 81))	('G91', 'Var', (86, 89))	('R86', 'Gene', '20706', (68, 71))	('G91', 'Var', (73, 76))	('R86', 'Gene', (78, 81))	('R86', 'Gene', (68, 71))
41563	31554794	While LC20812 TMA contains 126 cases of squamous cell carcinoma, 12 adeno-squamous carcinoma, 54 adenocarcinoma, and 16 normal tissues (some slices missing three cases of squamous cell carcinoma, so we have 205 cases in total for analysis).	('squamous cell carcinoma', 'Disease', (171, 194))	('adenocarcinoma', 'Disease', 'MESH:D000230', (97, 111))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (171, 194))	('adeno-squamous carcinoma', 'Disease', 'MESH:D002294', (68, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (54, 63))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (74, 92))	('adeno-squamous carcinoma', 'Disease', (68, 92))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (40, 63))	('LC20812', 'Var', (6, 13))	('squamous cell carcinoma', 'Disease', (40, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (40, 63))	('adenocarcinoma', 'Disease', (97, 111))	('carcinoma', 'Phenotype', 'HP:0030731', (185, 194))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (171, 194))
41761	33045527	Targeting methyltransferase PRMT5 retards the carcinogenesis and metastasis of HNSCC via epigenetically inhibiting Twist1 transcription Protein arginine methyltransferase 5 (PRMT5) is an important type II arginine methyltransferase that can play roles in cancers in a highly tissue-specific manner, but its role in the carcinogenesis and metastasis of head and neck squamous cell carcinoma (HNSCC) remains unclear.	('epigenetically', 'Var', (89, 103))	('carcinogenesis', 'Disease', (46, 60))	('cancers', 'Phenotype', 'HP:0002664', (255, 262))	('PRMT5', 'Gene', (28, 33))	('cancers', 'Disease', (255, 262))	('HNSCC', 'Phenotype', 'HP:0012288', (391, 396))	('cancer', 'Phenotype', 'HP:0002664', (255, 261))	('retards the carcinogenesis', 'Disease', (34, 60))	('carcinogenesis', 'Disease', 'MESH:D063646', (46, 60))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (352, 389))	('carcinoma', 'Phenotype', 'HP:0030731', (380, 389))	('HNSCC', 'Phenotype', 'HP:0012288', (79, 84))	('PRMT5', 'Gene', '10419', (174, 179))	('retards the carcinogenesis', 'Disease', 'MESH:D063646', (34, 60))	('arginine', 'Chemical', 'MESH:D001120', (144, 152))	('carcinogenesis', 'Disease', (319, 333))	('inhibiting', 'NegReg', (104, 114))	('SCC', 'Phenotype', 'HP:0002860', (393, 396))	('cancers', 'Disease', 'MESH:D009369', (255, 262))	('PRMT5', 'Gene', '10419', (28, 33))	('arginine', 'Chemical', 'MESH:D001120', (205, 213))	('carcinogenesis', 'Disease', 'MESH:D063646', (319, 333))	('SCC', 'Phenotype', 'HP:0002860', (81, 84))	('Twist1', 'Gene', (115, 121))	('Protein arginine methyltransferase 5', 'Gene', '10419', (136, 172))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (366, 389))	('PRMT5', 'Gene', (174, 179))	('neck squamous cell carcinoma', 'Disease', (361, 389))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (361, 389))	('Protein arginine methyltransferase 5', 'Gene', (136, 172))	('Twist1', 'Gene', '7291', (115, 121))
41766	33045527	In summary, this study elucidates that PRMT5 inhibition could reduce H3K4me3-mediated Twist1 transcription and retard the carcinogenesis and metastasis of HNSCC.	('SCC', 'Phenotype', 'HP:0002860', (157, 160))	('retard the carcinogenesis', 'Disease', 'MESH:D063646', (111, 136))	('HNSCC', 'Phenotype', 'HP:0012288', (155, 160))	('HNSCC', 'Disease', (155, 160))	('PRMT5', 'Gene', (39, 44))	('Twist1', 'Gene', (86, 92))	('retard the carcinogenesis', 'Disease', (111, 136))	('reduce', 'NegReg', (62, 68))	('H3K4me3-mediated', 'Protein', (69, 85))	('Twist1', 'Gene', '7291', (86, 92))	('inhibition', 'Var', (45, 55))
41771	33045527	Aberrant expression of PRMT5 could affects cell proliferation, differentiation and movement, which leads to disease progression, especially cancer.	('movement', 'CPA', (83, 91))	('Aberrant expression', 'Var', (0, 19))	('leads to', 'Reg', (99, 107))	('differentiation', 'CPA', (63, 78))	('PRMT5', 'Gene', (23, 28))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('affects', 'Reg', (35, 42))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('rat', 'Species', '10116', (55, 58))	('cell proliferation', 'CPA', (43, 61))
41774	33045527	PRMT5 inhibitors display clinical potential in a variety of tumors, but data on the effects of these inhibitors on HNSCC are not available.	('HNSCC', 'Phenotype', 'HP:0012288', (115, 120))	('PRMT5', 'Gene', (0, 5))	('tumors', 'Disease', (60, 66))	('SCC', 'Phenotype', 'HP:0002860', (117, 120))	('inhibitors', 'Var', (6, 16))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumors', 'Disease', 'MESH:D009369', (60, 66))
41777	33045527	Mechanistically, we revealed that H3R2me2s, catalyzed by PRMT5, promoted the enrichment of H3K4me3 in the Twist1 promoter region by recruiting WDR5, and transcriptional activation of Twist1.	('Twist1', 'Gene', '7291', (183, 189))	('WDR5', 'Gene', '11091', (143, 147))	('enrichment', 'MPA', (77, 87))	('H3R2me2s', 'Chemical', '-', (34, 42))	('promoted', 'PosReg', (64, 72))	('activation', 'PosReg', (169, 179))	('transcriptional', 'MPA', (153, 168))	('H3R2me2s', 'Var', (34, 42))	('PRMT5', 'Gene', (57, 62))	('Twist1', 'Gene', (183, 189))	('Twist1', 'Gene', '7291', (106, 112))	('WDR5', 'Gene', (143, 147))	('Twist1', 'Gene', (106, 112))	('recruiting', 'PosReg', (132, 142))	('H3K4me3', 'Var', (91, 98))
41801	33045527	ChIP was performed with appropriate antibody ratios (H3R2me2s 1:100; H4R3me2s 1:100; H3K4me3 1:50; WDR5 1:50; Set1 1:50) according to the instructions of a ChIP assay kit (Millipore, USA).	('H3R2me2s 1:100', 'Var', (53, 67))	('WDR5', 'Gene', '11091', (99, 103))	('H3K4me3', 'Var', (85, 92))	('Set1', 'Gene', (110, 114))	('WDR5', 'Gene', (99, 103))	('rat', 'Species', '10116', (45, 48))	('H3R2me2s', 'Chemical', '-', (53, 61))	('H4R3me2s', 'Chemical', '-', (69, 77))	('Set1', 'Gene', '9739', (110, 114))	('H4R3me2s 1:100', 'Var', (69, 83))
41802	33045527	Western blot analysis was performed with primary antibody concentration according to the instructions (GAPDH: 1:2000, PRMT5, Twist, E-cadherin, N-cadherin, WDR5, H3R2me2s and H3K4me3 are 1:1000) and performed as previously described.	('WDR5', 'Gene', (156, 160))	('E-cadherin', 'Gene', (132, 142))	('E-cadherin', 'Gene', '999', (132, 142))	('N-cadherin', 'Gene', (144, 154))	('Twist', 'Gene', '7291', (125, 130))	('H3R2me2s', 'Chemical', '-', (162, 170))	('N-cadherin', 'Gene', '1000', (144, 154))	('Twist', 'Gene', (125, 130))	('H3R2me2s', 'Var', (162, 170))	('WDR5', 'Gene', '11091', (156, 160))	('rat', 'Species', '10116', (65, 68))
41819	33045527	Overexpression of PRMT5 promoted migration and invasion in HSC6 and SCC25 cells, and depletion of PRMT5 using shRNA inhibited migration and invasion (Fig.	('SCC', 'Phenotype', 'HP:0002860', (68, 71))	('inhibited', 'NegReg', (116, 125))	('PRMT5', 'Gene', (98, 103))	('migration', 'CPA', (33, 42))	('rat', 'Species', '10116', (36, 39))	('rat', 'Species', '10116', (129, 132))	('depletion', 'Var', (85, 94))	('invasion', 'CPA', (47, 55))	('SCC25', 'CellLine', 'CVCL:1682', (68, 73))	('promoted', 'PosReg', (24, 32))	('PRMT5', 'Gene', (18, 23))
41821	33045527	The shPRMT5 group developed significantly smaller tumor compared to the shCTRL group (Fig.	('smaller', 'NegReg', (42, 49))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('shPRMT5', 'Var', (4, 11))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Disease', (50, 55))
41824	33045527	PRMT5 knockdown inhibited the growth of primary tumors (Fig.	('inhibited', 'NegReg', (16, 25))	('tumors', 'Disease', (48, 54))	('tumors', 'Disease', 'MESH:D009369', (48, 54))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('PRMT5', 'Gene', (0, 5))	('knockdown', 'Var', (6, 15))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
41826	33045527	We showed that PRMT5 knockdown significantly reduced the rate of cervical lymph node metastasis compared with the control group (Fig.	('reduced', 'NegReg', (45, 52))	('PRMT5', 'Gene', (15, 20))	('cervical lymph node metastasis', 'CPA', (65, 95))	('rat', 'Species', '10116', (57, 60))	('knockdown', 'Var', (21, 30))
41828	33045527	To further study the function of endogenous PRMT5 in HNSCC, we used a PRMT5 specific inhibitor that could competitively bind to the substrate of PRMT5, EPZ015666.	('PRMT5', 'Gene', (145, 150))	('SCC', 'Phenotype', 'HP:0002860', (55, 58))	('HNSCC', 'Phenotype', 'HP:0012288', (53, 58))	('rat', 'Species', '10116', (137, 140))	('EPZ015666', 'Chemical', 'MESH:C000599896', (152, 161))	('EPZ015666', 'Var', (152, 161))	('bind', 'Interaction', (120, 124))
41830	33045527	S2A-C, EPZ015666 inhibits the proliferation, migration and invasion of HNSCC cells in vitro.	('inhibits', 'NegReg', (17, 25))	('migration', 'CPA', (45, 54))	('rat', 'Species', '10116', (37, 40))	('EPZ015666', 'Chemical', 'MESH:C000599896', (7, 16))	('SCC', 'Phenotype', 'HP:0002860', (73, 76))	('EPZ015666', 'Var', (7, 16))	('invasion of HNSCC cells', 'CPA', (59, 82))	('HNSCC', 'Phenotype', 'HP:0012288', (71, 76))	('rat', 'Species', '10116', (48, 51))
41831	33045527	To assess the effects of PRMT5 inhibition on HNSCC, we established the 4NQO-induced carcinogenesis model in Sprague Dawley (SD) rats and started administration of EPZ015666 (30 mg/kg) or vehicle control via tail vein injection at week 12 (Fig.	('carcinogenesis', 'Disease', (84, 98))	('4NQO', 'Chemical', 'MESH:D015112', (71, 75))	('SCC', 'Phenotype', 'HP:0002860', (47, 50))	('HNSCC', 'Phenotype', 'HP:0012288', (45, 50))	('rat', 'Species', '10116', (153, 156))	('carcinogenesis', 'Disease', 'MESH:D063646', (84, 98))	('rats', 'Species', '10116', (128, 132))	('EPZ015666', 'Var', (163, 172))	('EPZ015666', 'Chemical', 'MESH:C000599896', (163, 172))	('rat', 'Species', '10116', (128, 131))
41832	33045527	When the experiment was terminated at week 22, we found that EPZ015666 significantly reduced the lesion area on the rat tongue surface (Fig.	('EPZ015666', 'Chemical', 'MESH:C000599896', (61, 70))	('EPZ015666', 'Var', (61, 70))	('rat', 'Species', '10116', (116, 119))	('reduced', 'NegReg', (85, 92))	('lesion area on the rat tongue surface', 'CPA', (97, 134))
41834	33045527	The carcinogenesis rate of EPZ015666-treated group was significantly lower than that of control group (Fig.	('EPZ015666-treated', 'Var', (27, 44))	('lower', 'NegReg', (69, 74))	('carcinogenesis', 'Disease', 'MESH:D063646', (4, 18))	('rat', 'Species', '10116', (19, 22))	('EPZ015666', 'Chemical', 'MESH:C000599896', (27, 36))	('carcinogenesis', 'Disease', (4, 18))
41835	33045527	These data indicate that EPZ015666 inhibits carcinogenesis of HNSCC.	('HNSCC', 'Phenotype', 'HP:0012288', (62, 67))	('inhibits', 'NegReg', (35, 43))	('EPZ015666', 'Chemical', 'MESH:C000599896', (25, 34))	('carcinogenesis of HNSCC', 'Disease', (44, 67))	('carcinogenesis of HNSCC', 'Disease', 'MESH:D000077195', (44, 67))	('EPZ015666', 'Var', (25, 34))	('SCC', 'Phenotype', 'HP:0002860', (64, 67))
41837	33045527	EPZ015666 inhibited the growth of primary tumors (Fig.	('tumors', 'Disease', (42, 48))	('EPZ015666', 'Chemical', 'MESH:C000599896', (0, 9))	('tumors', 'Disease', 'MESH:D009369', (42, 48))	('EPZ015666', 'Var', (0, 9))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('inhibited', 'NegReg', (10, 19))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
41838	33045527	Similarly, EPZ015666 significantly reduced the rate of cervical lymph node metastasis when compared with the control group (Fig.	('reduced', 'NegReg', (35, 42))	('cervical lymph node metastasis', 'CPA', (55, 85))	('rat', 'Species', '10116', (47, 50))	('EPZ015666', 'Chemical', 'MESH:C000599896', (11, 20))	('EPZ015666', 'Var', (11, 20))
41839	33045527	Moreover, EPZ015666 had no significant effect on the body weights of nude mice and showed no obvious toxicity or distant metastasis (Fig.	('EPZ015666', 'Chemical', 'MESH:C000599896', (10, 19))	('distant metastasis', 'CPA', (113, 131))	('EPZ015666', 'Var', (10, 19))	('toxicity', 'Disease', 'MESH:D064420', (101, 109))	('toxicity', 'Disease', (101, 109))	('nude mice', 'Species', '10090', (69, 78))
41840	33045527	We also tested the effects of EPZ015666 in subcutaneous xenograft models using HSC6 in BALB/c nude mice.	('tested', 'Reg', (8, 14))	('EPZ015666', 'Chemical', 'MESH:C000599896', (30, 39))	('EPZ015666', 'Var', (30, 39))	('nude mice', 'Species', '10090', (94, 103))
41841	33045527	EPZ015666 significantly decreased tumor volume compared to the control group and a more dramatic inhibitory effect was observed when a higher dose of EPZ015666 was used (Fig.	('EPZ015666', 'Chemical', 'MESH:C000599896', (150, 159))	('decreased', 'NegReg', (24, 33))	('tumor', 'Disease', (34, 39))	('EPZ015666', 'Chemical', 'MESH:C000599896', (0, 9))	('EPZ015666', 'Var', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
41843	33045527	EPZ015666 inhibited HNSCC cell proliferation, as the number of Ki67+ cells in the EPZ015666 group was significantly lower than that of the control group (Fig.	('lower', 'NegReg', (116, 121))	('EPZ015666', 'Chemical', 'MESH:C000599896', (82, 91))	('EPZ015666', 'Var', (82, 91))	('EPZ015666', 'Chemical', 'MESH:C000599896', (0, 9))	('EPZ015666', 'Var', (0, 9))	('inhibited', 'NegReg', (10, 19))	('HNSCC cell proliferation', 'CPA', (20, 44))	('SCC', 'Phenotype', 'HP:0002860', (22, 25))	('rat', 'Species', '10116', (38, 41))	('HNSCC', 'Phenotype', 'HP:0012288', (20, 25))
41844	33045527	These results demonstrate that EPZ015666 inhibit tumorigenesis and cervical lymph node metastasis of HNSCC.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('HNSCC', 'Disease', (101, 106))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('HNSCC', 'Phenotype', 'HP:0012288', (101, 106))	('tumor', 'Disease', (49, 54))	('EPZ015666', 'Chemical', 'MESH:C000599896', (31, 40))	('SCC', 'Phenotype', 'HP:0002860', (103, 106))	('rat', 'Species', '10116', (21, 24))	('inhibit', 'NegReg', (41, 48))	('cervical lymph node metastasis', 'CPA', (67, 97))	('EPZ015666', 'Var', (31, 40))
41845	33045527	To determine if EPZ015666 is effective for HNSCC patients, we established a Patient-Derived tumor Xenograft (PDX) model using patient tumor tissue expanded in BALB/c nude mice (Fig.	('nude mice', 'Species', '10090', (166, 175))	('EPZ015666', 'Chemical', 'MESH:C000599896', (16, 25))	('EPZ015666', 'Var', (16, 25))	('HNSCC', 'Phenotype', 'HP:0012288', (43, 48))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('patient', 'Species', '9606', (126, 133))	('SCC', 'Phenotype', 'HP:0002860', (45, 48))	('patient', 'Species', '9606', (49, 56))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('patients', 'Species', '9606', (49, 57))	('tumor', 'Disease', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('tumor', 'Disease', (134, 139))
41846	33045527	EPZ015666 significantly inhibited the growth of PDX tumors and showed no significant effect on body weight or liver/kidney toxicity (Fig.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('PDX tumors', 'Disease', (48, 58))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('EPZ015666', 'Chemical', 'MESH:C000599896', (0, 9))	('EPZ015666', 'Var', (0, 9))	('inhibited', 'NegReg', (24, 33))	('liver/kidney toxicity', 'Disease', (110, 131))	('growth', 'MPA', (38, 44))	('liver/kidney toxicity', 'Disease', 'MESH:D007674', (110, 131))	('PDX tumors', 'Disease', 'MESH:D009369', (48, 58))
41847	33045527	In addition, EPZ015666 significantly reduced the number of Ki67+ cells in PDX tumors (Fig.	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('PDX tumors', 'Disease', 'MESH:D009369', (74, 84))	('EPZ015666', 'Chemical', 'MESH:C000599896', (13, 22))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('EPZ015666', 'Var', (13, 22))	('reduced', 'NegReg', (37, 44))	('PDX tumors', 'Disease', (74, 84))
41848	33045527	These data present EPZ015666 as a promising therapeutic reagent for HNSCC patients.	('patients', 'Species', '9606', (74, 82))	('SCC', 'Phenotype', 'HP:0002860', (70, 73))	('HNSCC', 'Disease', (68, 73))	('EPZ015666', 'Chemical', 'MESH:C000599896', (19, 28))	('HNSCC', 'Phenotype', 'HP:0012288', (68, 73))	('EPZ015666', 'Var', (19, 28))
41851	33045527	Twist1 transcription is also repressed by PRMT5 inhibitor EPZ015666 (Fig.	('Twist1', 'Gene', (0, 6))	('transcription', 'MPA', (7, 20))	('EPZ015666', 'Chemical', 'MESH:C000599896', (58, 67))	('EPZ015666', 'Var', (58, 67))	('Twist1', 'Gene', '7291', (0, 6))
41852	33045527	We further examined Twist1 expression at the protein level and demonstrated that overexpressing PRMT5 enhanced Twist1 level, while depleting PRMT5 reduced Twist1 level (Fig.	('enhanced', 'PosReg', (102, 110))	('rat', 'Species', '10116', (70, 73))	('Twist1', 'Gene', (155, 161))	('Twist1', 'Gene', (111, 117))	('depleting', 'Var', (131, 140))	('Twist1', 'Gene', '7291', (20, 26))	('Twist1', 'Gene', '7291', (111, 117))	('Twist1', 'Gene', '7291', (155, 161))	('reduced', 'NegReg', (147, 154))	('Twist1', 'Gene', (20, 26))	('PRMT5', 'Gene', (96, 101))
41854	33045527	On the contrary, depleting PRMT5 increased epithelial marker E-cadherin expression and decreased mesenchymal marker N-cadherin expression (Fig.	('N-cadherin', 'Gene', (116, 126))	('E-cadherin', 'Gene', (61, 71))	('depleting', 'Var', (17, 26))	('decreased', 'NegReg', (87, 96))	('N-cadherin', 'Gene', '1000', (116, 126))	('E-cadherin', 'Gene', '999', (61, 71))	('increased', 'PosReg', (33, 42))	('PRMT5', 'Gene', (27, 32))
41858	33045527	H3R2me2s, H4R3me2s and H3R8me2s were all significantly decreased by depletion or inhibition of PRMT5 (Fig.	('H3R2me2s', 'Chemical', '-', (0, 8))	('H3R2me2s', 'Var', (0, 8))	('inhibition', 'NegReg', (81, 91))	('H4R3me2s', 'Var', (10, 18))	('PRMT5', 'Gene', (95, 100))	('decreased', 'NegReg', (55, 64))	('depletion', 'MPA', (68, 77))	('H3R8me2s', 'Chemical', '-', (23, 31))	('H3R8me2s', 'Var', (23, 31))	('H4R3me2s', 'Chemical', '-', (10, 18))
41859	33045527	H3R2me2s and H4R3me2s was significantly increased by overexpression of PRMT5, but H3R8me2s displayed no obvious change (Fig.	('H3R2me2s', 'Chemical', '-', (0, 8))	('H4R3me2s', 'Var', (13, 21))	('overexpression', 'PosReg', (53, 67))	('H3R2me2s', 'Var', (0, 8))	('PRMT5', 'Gene', (71, 76))	('increased', 'PosReg', (40, 49))	('H4R3me2s', 'Chemical', '-', (13, 21))	('H3R8me2s', 'Chemical', '-', (82, 90))
41860	33045527	We further showed that PRMT5 depletion or inhibition resulted in a significant decrease of H3R2me2s enrichment in Twist1 promoter region (Fig.	('depletion', 'Var', (29, 38))	('PRMT5', 'Gene', (23, 28))	('decrease', 'NegReg', (79, 87))	('Twist1', 'Gene', (114, 120))	('H3R2me2s', 'Protein', (91, 99))	('H3R2me2s', 'Chemical', '-', (91, 99))	('inhibition', 'NegReg', (42, 52))	('Twist1', 'Gene', '7291', (114, 120))
41862	33045527	H3R2me2s enhances the recruitment of WDR5, a core subunit of the human MLL/Set1 complex (COMPASS).	('H3R2me2s', 'Chemical', '-', (0, 8))	('human', 'Species', '9606', (65, 70))	('enhances', 'PosReg', (9, 17))	('Set1', 'Gene', (75, 79))	('WDR5', 'Gene', (37, 41))	('H3R2me2s', 'Var', (0, 8))	('recruitment', 'MPA', (22, 33))	('Set1', 'Gene', '9739', (75, 79))	('WDR5', 'Gene', '11091', (37, 41))	('MLL', 'Gene', '4297', (71, 74))	('MLL', 'Gene', (71, 74))
41863	33045527	To examine whether PRMT5-regulated H3R2me2s controls WDR5 recruitment in HNSCC, we performed Co-immunoprecipitation (Co-IP) assay and showed that PRMT5 knockdown reduced H3R2me2s and its associated WDR5 without changing WDR5 expression (Fig.	('knockdown', 'Var', (152, 161))	('WDR5', 'Gene', '11091', (220, 224))	('H3R2me2s', 'Chemical', '-', (35, 43))	('WDR5', 'Gene', (53, 57))	('WDR5', 'Gene', (198, 202))	('HNSCC', 'Phenotype', 'HP:0012288', (73, 78))	('reduced', 'NegReg', (162, 169))	('SCC', 'Phenotype', 'HP:0002860', (75, 78))	('H3R2me2s', 'Chemical', '-', (170, 178))	('WDR5', 'Gene', '11091', (198, 202))	('WDR5', 'Gene', (220, 224))	('H3R2me2s', 'Enzyme', (170, 178))	('WDR5', 'Gene', '11091', (53, 57))	('PRMT5', 'Gene', (146, 151))
41864	33045527	The WDR5-associated MLL/Set1 complex "write" the H3K4me3 mark at promoter regions, which enables chromatin remodeling and transcription activation.	('transcription', 'MPA', (122, 135))	('WDR5', 'Gene', '11091', (4, 8))	('MLL', 'Gene', (20, 23))	('Set1', 'Gene', (24, 28))	('MLL', 'Gene', '4297', (20, 23))	('H3K4me3', 'Var', (49, 56))	('WDR5', 'Gene', (4, 8))	('Set1', 'Gene', '9739', (24, 28))	('chromatin', 'MPA', (97, 106))
41866	33045527	Focusing on the Twist1 promoter region, we demonstrated that PRMT5 knockdown or inhibition reduced the enrichment of H3K4me3, as well as the occupancy of WDR5 and Set1 at Twist1 promoter region (Fig.	('Twist1', 'Gene', '7291', (16, 22))	('inhibition reduced', 'NegReg', (80, 98))	('Set1', 'Gene', '9739', (163, 167))	('WDR5', 'Gene', '11091', (154, 158))	('rat', 'Species', '10116', (50, 53))	('H3K4me3', 'Protein', (117, 124))	('knockdown', 'Var', (67, 76))	('Twist1', 'Gene', '7291', (171, 177))	('PRMT5', 'Gene', (61, 66))	('WDR5', 'Gene', (154, 158))	('enrichment', 'MPA', (103, 113))	('Twist1', 'Gene', (16, 22))	('occupancy', 'MPA', (141, 150))	('Set1', 'Gene', (163, 167))	('Twist1', 'Gene', (171, 177))
41869	33045527	To determine the requirement of WDR5 in PRMT5-elicited deposition of H3K4me3, we depleted WDR5 using small interfering RNA (SiRNA) and showed that WDR5 knockdown significantly reduced the enrichment of H3K4me3 at Twist1 promoter (Fig.	('H3K4me3', 'Protein', (202, 209))	('knockdown', 'Var', (152, 161))	('WDR5', 'Gene', '11091', (147, 151))	('WDR5', 'Gene', (32, 36))	('depleted', 'NegReg', (81, 89))	('enrichment', 'MPA', (188, 198))	('reduced', 'NegReg', (176, 183))	('Twist1', 'Gene', '7291', (213, 219))	('WDR5', 'Gene', (147, 151))	('WDR5', 'Gene', '11091', (90, 94))	('WDR5', 'Gene', '11091', (32, 36))	('WDR5', 'Gene', (90, 94))	('Twist1', 'Gene', (213, 219))
41871	33045527	OICR9429 also reduced the enrichment of H3K4me3 at Twist1 promoter (Fig.	('reduced', 'NegReg', (14, 21))	('Twist1', 'Gene', (51, 57))	('enrichment of', 'MPA', (26, 39))	('OICR9429', 'Var', (0, 8))	('H3K4me3', 'Protein', (40, 47))	('Twist1', 'Gene', '7291', (51, 57))
41872	33045527	As expected from the above findings, WDR5 knockdown reduced Twist transcription and protein expression (Fig.	('Twist', 'Gene', (60, 65))	('reduced', 'NegReg', (52, 59))	('WDR5', 'Gene', (37, 41))	('protein expression', 'MPA', (84, 102))	('WDR5', 'Gene', '11091', (37, 41))	('knockdown', 'Var', (42, 51))	('Twist', 'Gene', '7291', (60, 65))
41873	33045527	Furthermore, WDR5 knockdown or using OICR-9429 in HSC6 and SCC25 cells decreased the total level of H3K4me3 and expression of mesenchymal marker N-cadherin while increasing the expression of E-cadherin (Figs.	('knockdown', 'Var', (18, 27))	('WDR5', 'Gene', '11091', (13, 17))	('H3K4me3', 'Protein', (100, 107))	('E-cadherin', 'Gene', (191, 201))	('WDR5', 'Gene', (13, 17))	('E-cadherin', 'Gene', '999', (191, 201))	('SCC25', 'CellLine', 'CVCL:1682', (59, 64))	('SCC', 'Phenotype', 'HP:0002860', (59, 62))	('N-cadherin', 'Gene', (145, 155))	('N-cadherin', 'Gene', '1000', (145, 155))	('increasing', 'PosReg', (162, 172))	('expression', 'MPA', (177, 187))	('decreased', 'NegReg', (71, 80))	('expression', 'MPA', (112, 122))
41874	33045527	Taken together, these data demonstrate that PRMT5-deposited H3R2me2s on Twist1 promoter recruits the MLL/Set1/WDR5 complex via WDR5.	('H3R2me2s', 'Var', (60, 68))	('WDR5', 'Gene', '11091', (127, 131))	('rat', 'Species', '10116', (34, 37))	('recruits', 'PosReg', (88, 96))	('Twist1', 'Gene', (72, 78))	('WDR5', 'Gene', (127, 131))	('Set1', 'Gene', '9739', (105, 109))	('WDR5', 'Gene', '11091', (110, 114))	('WDR5', 'Gene', (110, 114))	('H3R2me2s', 'Chemical', '-', (60, 68))	('MLL', 'Gene', '4297', (101, 104))	('Set1', 'Gene', (105, 109))	('Twist1', 'Gene', '7291', (72, 78))	('MLL', 'Gene', (101, 104))
41881	33045527	In addition, EPZ015666 reduced the number of Twist1-positive cells in tumors developed from subcutaneously-implanted HSC6 cells and 4NQO-induced cancerous tissues (Fig.	('Twist1', 'Gene', (45, 51))	('cancerous', 'Disease', (145, 154))	('4NQO', 'Chemical', 'MESH:D015112', (132, 136))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('EPZ015666', 'Chemical', 'MESH:C000599896', (13, 22))	('tumors', 'Disease', (70, 76))	('EPZ015666', 'Var', (13, 22))	('tumors', 'Disease', 'MESH:D009369', (70, 76))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('cancerous', 'Disease', 'MESH:D009369', (145, 154))	('Twist1', 'Gene', '7291', (45, 51))	('reduced', 'NegReg', (23, 30))
41891	33045527	Our results suggested that patients with a high level of PRMT5 expression are more prone to cervical lymph node metastasis.	('prone', 'Reg', (83, 88))	('PRMT5', 'Gene', (57, 62))	('high level', 'Var', (43, 53))	('cervical lymph node metastasis', 'CPA', (92, 122))	('patients', 'Species', '9606', (27, 35))
41893	33045527	Our findings suggested high PRMT5 expression as a potential marker to predict whether a patient needs cervical lymph node dissection.	('high', 'Var', (23, 27))	('patient', 'Species', '9606', (88, 95))	('expression', 'MPA', (34, 44))	('PRMT5', 'Gene', (28, 33))
41894	33045527	As the latest potent and selective inhibitor for PRMT5, EPZ015666 offers highly anticipated therapeutic strategies in mantle cell lymphoma, multiple myeloma, glioblastoma and triple-negative breast cancer.	('PRMT5', 'Gene', (49, 54))	('multiple myeloma', 'Disease', (140, 156))	('glioblastoma', 'Phenotype', 'HP:0012174', (158, 170))	('cell lymphoma', 'Phenotype', 'HP:0012191', (125, 138))	('glioblastoma', 'Disease', (158, 170))	('mantle cell lymphoma', 'Disease', 'MESH:D020522', (118, 138))	('glioblastoma', 'Disease', 'MESH:D005909', (158, 170))	('EPZ015666', 'Chemical', 'MESH:C000599896', (56, 65))	('lymphoma', 'Phenotype', 'HP:0002665', (130, 138))	('mantle cell lymphoma', 'Disease', (118, 138))	('EPZ015666', 'Var', (56, 65))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('rat', 'Species', '10116', (106, 109))	('breast cancer', 'Disease', (191, 204))	('breast cancer', 'Disease', 'MESH:D001943', (191, 204))	('multiple myeloma', 'Phenotype', 'HP:0006775', (140, 156))	('breast cancer', 'Phenotype', 'HP:0003002', (191, 204))	('multiple myeloma', 'Disease', 'MESH:D009101', (140, 156))
41896	33045527	In the present study, we provide the most comprehensive study on the inhibitory effects of EPZ015666 in HNSCC.	('HNSCC', 'Disease', (104, 109))	('SCC', 'Phenotype', 'HP:0002860', (106, 109))	('EPZ015666', 'Chemical', 'MESH:C000599896', (91, 100))	('HNSCC', 'Phenotype', 'HP:0012288', (104, 109))	('EPZ015666', 'Var', (91, 100))
41897	33045527	EPZ015666 can not only inhibit the proliferation of HNSCC in vivo, but also inhibit the regional cervical lymph node metastasis in vivo.	('HNSCC', 'Phenotype', 'HP:0012288', (52, 57))	('inhibit', 'NegReg', (76, 83))	('proliferation', 'CPA', (35, 48))	('EPZ015666', 'Chemical', 'MESH:C000599896', (0, 9))	('inhibit', 'NegReg', (23, 30))	('EPZ015666', 'Var', (0, 9))	('regional cervical lymph node metastasis', 'CPA', (88, 127))	('HNSCC', 'Protein', (52, 57))	('SCC', 'Phenotype', 'HP:0002860', (54, 57))	('rat', 'Species', '10116', (42, 45))
41898	33045527	What's more important, EPZ015666 could inhibit the 4NQO-induced carcinogenesis of rats and the patient-derived tumors of HNSCC.	('tumors of HNSCC', 'Disease', (111, 126))	('SCC', 'Phenotype', 'HP:0002860', (123, 126))	('tumors of HNSCC', 'Disease', 'MESH:D000077195', (111, 126))	('rats', 'Species', '10116', (82, 86))	('patient', 'Species', '9606', (95, 102))	('carcinogenesis', 'Disease', 'MESH:D063646', (64, 78))	('EPZ015666', 'Var', (23, 32))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('inhibit', 'NegReg', (39, 46))	('4NQO', 'Chemical', 'MESH:D015112', (51, 55))	('HNSCC', 'Phenotype', 'HP:0012288', (121, 126))	('carcinogenesis', 'Disease', (64, 78))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('EPZ015666', 'Chemical', 'MESH:C000599896', (23, 32))
41900	33045527	EPZ015666 is expected to become a promising antitumor drug in HNSCC.	('HNSCC', 'Phenotype', 'HP:0012288', (62, 67))	('tumor', 'Disease', (48, 53))	('HNSCC', 'Disease', (62, 67))	('EPZ015666', 'Chemical', 'MESH:C000599896', (0, 9))	('EPZ015666', 'Var', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('SCC', 'Phenotype', 'HP:0002860', (64, 67))
41904	33045527	In our study, we found that overexpressed PRMT5 could repress expression of epithelial gene E-cadherin, and induce expression of mesenchymal gene N-cadherin.	('overexpressed', 'Var', (28, 41))	('N-cadherin', 'Gene', '1000', (146, 156))	('E-cadherin', 'Gene', (92, 102))	('E-cadherin', 'Gene', '999', (92, 102))	('expression', 'MPA', (62, 72))	('expression', 'MPA', (115, 125))	('induce', 'PosReg', (108, 114))	('PRMT5', 'Gene', (42, 47))	('repress', 'NegReg', (54, 61))	('N-cadherin', 'Gene', (146, 156))
41909	33045527	H4R3me2s and H3R8me2s are associated with transcriptional repression, while H3R2me2s is associated with transcriptional activation.	('H3R8me2s', 'Var', (13, 21))	('transcriptional activation', 'MPA', (104, 130))	('H4R3me2s', 'Var', (0, 8))	('H3R2me2s', 'Var', (76, 84))	('transcriptional repression', 'MPA', (42, 68))	('H3R2me2s', 'Chemical', '-', (76, 84))	('H4R3me2s', 'Chemical', '-', (0, 8))	('H3R8me2s', 'Chemical', '-', (13, 21))	('associated', 'Reg', (26, 36))
41910	33045527	In epidermal squamous cell carcinoma, H4R3me2s and H3R8me2s formation depended upon environment.	('carcinoma', 'Phenotype', 'HP:0030731', (27, 36))	('H3R8me2s', 'Chemical', '-', (51, 59))	('H3R8me2s', 'Var', (51, 59))	('H4R3me2s', 'Var', (38, 46))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (13, 36))	('epidermal squamous cell carcinoma', 'Disease', (3, 36))	('epidermal squamous cell carcinoma', 'Disease', 'MESH:D002294', (3, 36))	('H4R3me2s', 'Chemical', '-', (38, 46))
41911	33045527	In lung carcinoma, knockdown PRMT5 could not resulted in downregulation of H3R8me2s but H4R3me2s and H3R2me2s.	('H4R3me2s', 'Var', (88, 96))	('H3R8me2s', 'Protein', (75, 83))	('PRMT5', 'Gene', (29, 34))	('knockdown', 'Var', (19, 28))	('carcinoma', 'Phenotype', 'HP:0030731', (8, 17))	('H4R3me2s', 'Chemical', '-', (88, 96))	('H3R2me2s', 'Chemical', '-', (101, 109))	('lung carcinoma', 'Disease', 'MESH:D008175', (3, 17))	('H3R2me2s', 'Var', (101, 109))	('lung carcinoma', 'Disease', (3, 17))	('H3R8me2s', 'Chemical', '-', (75, 83))
41912	33045527	Our study demonstrated that PRMT5 symmetrically di-methylated H4R3 and H3R2, but not H3R8, in HNSCC.	('SCC', 'Phenotype', 'HP:0002860', (96, 99))	('HNSCC', 'Phenotype', 'HP:0012288', (94, 99))	('di-methylated', 'Var', (48, 61))	('rat', 'Species', '10116', (17, 20))	('H3R2', 'Protein', (71, 75))	('H4R3', 'Protein', (62, 66))
41914	33045527	H3R2me2s is a novel histone marker associated with gene transcriptional activation and that WDR5 can be recruited by it.	('H3R2me2s', 'Var', (0, 8))	('H3R2me2s', 'Chemical', '-', (0, 8))	('WDR5', 'Gene', '11091', (92, 96))	('WDR5', 'Gene', (92, 96))
41916	33045527	Chen et al declared that H3R2me1 but not H3R2me2s could recruit WDR5 and activate snail in A549 cell lines.	('WDR5', 'Gene', (64, 68))	('H3R2me1', 'Var', (25, 32))	('snail', 'Gene', (82, 87))	('activate', 'PosReg', (73, 81))	('A549', 'CellLine', 'CVCL:0023', (91, 95))	('WDR5', 'Gene', '11091', (64, 68))	('snail', 'Gene', '6615', (82, 87))	('H3R2me2s', 'Chemical', '-', (41, 49))
41917	33045527	In our study, we confirmed that H3R2me2s enhances binding of WDR5 to the Twist1 promoter.	('WDR5', 'Gene', '11091', (61, 65))	('Twist1', 'Gene', (73, 79))	('WDR5', 'Gene', (61, 65))	('H3R2me2s', 'Chemical', '-', (32, 40))	('enhances', 'PosReg', (41, 49))	('H3R2me2s', 'Var', (32, 40))	('binding', 'Interaction', (50, 57))	('Twist1', 'Gene', '7291', (73, 79))
41921	33045527	What's more, WDR5, Set1, H3K4me3 all enriched in Twist1 promoter to trans-activate Twist1.	('trans-activate', 'PosReg', (68, 82))	('WDR5', 'Gene', '11091', (13, 17))	('Twist1', 'Gene', (49, 55))	('Twist1', 'Gene', (83, 89))	('WDR5', 'Gene', (13, 17))	('Set1', 'Gene', '9739', (19, 23))	('H3K4me3', 'Var', (25, 32))	('Set1', 'Gene', (19, 23))	('Twist1', 'Gene', '7291', (49, 55))	('Twist1', 'Gene', '7291', (83, 89))
42067	27647989	A bleeding lesion in the tumour appears with hyperintensity in T1WI, which could reflect high vascular invasion characteristics.	('bleeding lesion', 'Disease', 'MESH:D006470', (2, 17))	('bleeding lesion', 'Disease', (2, 17))	('tumour', 'Disease', (25, 31))	('tumour', 'Phenotype', 'HP:0002664', (25, 31))	('tumour', 'Disease', 'MESH:D009369', (25, 31))	('hyperintensity', 'Var', (45, 59))	('T1WI', 'Var', (63, 67))
42111	27605195	Molecular alterations have been associated with the individual risk for lung tissue damage and tumorigenesis.	('associated', 'Reg', (32, 42))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('lung tissue', 'Disease', (72, 83))	('Molecular alterations', 'Var', (0, 21))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Disease', (95, 100))
42114	27605195	Recently, an 8-miRNA signature (miR-96, miR-450a, miR-183, miR-9, miR-577, Let-7i, miR-27b miR-34a) was proposed to diagnose NSCLC in minimal biopsy material.	('SCLC', 'Phenotype', 'HP:0030357', (126, 130))	('miR-183', 'Gene', '406959', (50, 57))	('NSCLC', 'Disease', 'MESH:D002289', (125, 130))	('miR-34a', 'Gene', (91, 98))	('Let-7i', 'Gene', (75, 81))	('NSCLC', 'Disease', (125, 130))	('miR-34a', 'Gene', '407040', (91, 98))	('miR-183', 'Gene', (50, 57))	('miR-96', 'Gene', (32, 38))	('miR-577', 'Gene', '693162', (66, 73))	('NSCLC', 'Phenotype', 'HP:0030358', (125, 130))	('miR-27b', 'Gene', (83, 90))	('diagnose', 'Reg', (116, 124))	('miR-450a', 'Var', (40, 48))	('miR-96', 'Gene', '407053', (32, 38))	('miR-577', 'Gene', (66, 73))	('miR-9', 'Var', (59, 64))	('miR-27b', 'Gene', '407019', (83, 90))	('Let-7i', 'Gene', '406891', (75, 81))
42118	27605195	For example, DNA methylation changes, specific gene and miRNA expression signatures were identified in the presence of cancer cells.	('miRNA expression signatures', 'MPA', (56, 83))	('changes', 'Reg', (29, 36))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('methylation', 'Var', (17, 28))	('cancer', 'Disease', (119, 125))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
42145	27605195	Ongoing comprehensive screening for specific gene expression signatures, driver mutations and other genomic alterations are promising to identify biomarkers and targets for therapeutic intervention in distinct tumor architectures.	('tumor', 'Disease', 'MESH:D009369', (210, 215))	('tumor', 'Disease', (210, 215))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('mutations', 'Var', (80, 89))
42161	27605195	Similarly, Landis and colleagues reported another five miRNA signature (miR-25, miR-34c-5p, miR-191, let-7e, and miR-34a) measured in FFPE tissues predicting survival (p = 0.017) in squamous cell carcinoma patients.	('squamous cell carcinoma', 'Disease', (182, 205))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (182, 205))	('miR-191', 'Gene', (92, 99))	('let-7e', 'Gene', '406887', (101, 107))	('miR-34a', 'Gene', '407040', (113, 120))	('miR-34a', 'Gene', (113, 120))	('patients', 'Species', '9606', (206, 214))	('miR-25', 'Gene', '407014', (72, 78))	('let-7e', 'Gene', (101, 107))	('miR-34c-5p', 'Var', (80, 90))	('miR-191', 'Gene', '406966', (92, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (196, 205))	('miR-25', 'Gene', (72, 78))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (182, 205))	('predicting', 'Reg', (147, 157))
42164	27605195	Of note, five frequently reported miRNAs (miR-21, miR-29b, miR-34a/b/c, miR-155 and let-7a) could not be confirmed as prognostic or predictive biomarker in a large cohort (IALT trial) including 639 patients with resectable NSCLC receiving adjuvant chemotherapy.	('NSCLC', 'Disease', (223, 228))	('miR-34a', 'Gene', (59, 66))	('SCLC', 'Phenotype', 'HP:0030357', (224, 228))	('miR-21', 'Gene', (42, 48))	('miR-29b', 'Gene', (50, 57))	('miR-1', 'Gene', (72, 77))	('let-7a', 'Var', (84, 90))	('NSCLC', 'Disease', 'MESH:D002289', (223, 228))	('patients', 'Species', '9606', (198, 206))	('miR-29b', 'Gene', '407024', (50, 57))	('miR-21', 'Gene', '406991', (42, 48))	('NSCLC', 'Phenotype', 'HP:0030358', (223, 228))	('miR-1', 'Gene', '79187', (72, 77))	('miR-34a', 'Gene', '407040', (59, 66))
42195	27605195	So far, more than 50% of adenocarcinoma and squamous cell carcinoma can be characterized by mutations, fusion genes or amplifications leading to driver activation with potentially effective targeted drugs.	('amplifications', 'Var', (119, 133))	('driver activation', 'PosReg', (145, 162))	('adenocarcinoma and squamous cell carcinoma', 'Disease', 'MESH:D002294', (25, 67))	('fusion genes', 'Var', (103, 115))	('mutations', 'Var', (92, 101))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (44, 67))	('carcinoma', 'Phenotype', 'HP:0030731', (30, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))
42197	27605195	Tumors with EGFR mutations preferentially respond to EGFR tyrosine kinase inhibitors (TKIs), tumors with ALK rearrangements are associated with response to crizotinib.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('EGFR', 'Gene', (53, 57))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('associated', 'Reg', (128, 138))	('EGFR', 'Gene', (12, 16))	('mutations', 'Var', (17, 26))	('crizotinib', 'Chemical', 'MESH:D000077547', (156, 166))	('respond', 'MPA', (42, 49))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('ALK', 'Gene', '238', (105, 108))	('Tumors', 'Disease', (0, 6))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('EGFR', 'Gene', '1956', (53, 57))	('ALK', 'Gene', (105, 108))	('EGFR', 'Gene', '1956', (12, 16))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('tumors', 'Disease', (93, 99))	('preferentially', 'PosReg', (27, 41))	('tumors', 'Disease', 'MESH:D009369', (93, 99))
42199	27605195	Further targeted drugs are investigated in clinical trials for molecular subtypes harboring BRAF, PIK3CA or HER2 mutations, ROS1 or RET rearrangements, or c-MET amplification.	('HER2', 'Gene', (108, 112))	('c-MET', 'Gene', (155, 160))	('BRAF', 'Gene', '673', (92, 96))	('HER2', 'Gene', '2064', (108, 112))	('PIK3CA', 'Gene', (98, 104))	('BRAF', 'Gene', (92, 96))	('RET', 'Gene', '5979', (132, 135))	('PIK3CA', 'Gene', '5290', (98, 104))	('ROS1', 'Gene', (124, 128))	('mutations', 'Var', (113, 122))	('c-MET', 'Gene', '4233', (155, 160))	('ROS1', 'Gene', '6098', (124, 128))	('rearrangements', 'Var', (136, 150))	('RET', 'Gene', (132, 135))
42200	27605195	In about 35% of squamous cell carcinoma, aberrant FGFR1, PDGFRA, AKT1 or DDR2 are putative drug targets for individualized therapy schemes.	('AKT1', 'Gene', '207', (65, 69))	('aberrant', 'Var', (41, 49))	('FGFR1', 'Gene', (50, 55))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (16, 39))	('FGFR1', 'Gene', '2260', (50, 55))	('AKT1', 'Gene', (65, 69))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (16, 39))	('PDGFRA', 'Gene', (57, 63))	('DDR2', 'Gene', '4921', (73, 77))	('carcinoma', 'Phenotype', 'HP:0030731', (30, 39))	('squamous cell carcinoma', 'Disease', (16, 39))	('PDGFRA', 'Gene', '5156', (57, 63))	('DDR2', 'Gene', (73, 77))
42213	27605195	Large comprehensive genomic studies in lung cancer are ongoing to precisely define clinically relevant tumor subtypes by combining histopathology, mutation status, DNA copy number variation, gene and protein expression, and disease outcome.	('lung cancer', 'Phenotype', 'HP:0100526', (39, 50))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('lung cancer', 'Disease', (39, 50))	('tumor', 'Disease', (103, 108))	('mutation', 'Var', (147, 155))	('lung cancer', 'Disease', 'MESH:D008175', (39, 50))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
42226	25884692	Prognostic role of serum p53 antibodies in lung cancer Mutations in the TP53 (Tumour Protein 53) gene can lead to expression of mutant p53 proteins that accumulate in cancer cells and can induce circulating p53 antibodies in cancer patients.	('p53', 'Gene', '7157', (25, 28))	('cancer', 'Disease', (225, 231))	('cancer', 'Disease', (167, 173))	('p53', 'Gene', '7157', (207, 210))	('cancer', 'Disease', (48, 54))	('lung cancer', 'Disease', 'MESH:D008175', (43, 54))	('expression', 'MPA', (114, 124))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('p53', 'Gene', (25, 28))	('lung cancer', 'Phenotype', 'HP:0100526', (43, 54))	('TP53', 'Gene', '7157', (72, 76))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('Tumour', 'Phenotype', 'HP:0002664', (78, 84))	('p53', 'Gene', (207, 210))	('mutant', 'Var', (128, 134))	('proteins', 'Protein', (139, 147))	('p53', 'Gene', '7157', (135, 138))	('cancer', 'Disease', 'MESH:D009369', (225, 231))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('p53', 'Gene', (135, 138))	('accumulate', 'PosReg', (153, 163))	('lead to', 'Reg', (106, 113))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('induce', 'Reg', (188, 194))	('Mutations', 'Var', (55, 64))	('lung cancer', 'Disease', (43, 54))	('patients', 'Species', '9606', (232, 240))	('TP53', 'Gene', (72, 76))
42232	25884692	Survival time of non-small cell lung cancer patients low/negative for serum p53 antibodies was significantly longer compared to patients with positive levels (p = 0.049); in particular, patients with squamous cell carcinoma, but not adenocarcinoma, low/negative for these antibodies show a significant better survival compared to serum-positive patients (p = 0.044).	('longer', 'PosReg', (109, 115))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (200, 223))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (17, 43))	('patients', 'Species', '9606', (44, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (214, 223))	('squamous cell carcinoma', 'Disease', (200, 223))	('carcinoma', 'Phenotype', 'HP:0030731', (238, 247))	('non-small cell lung cancer', 'Disease', (17, 43))	('patients', 'Species', '9606', (186, 194))	('lung cancer', 'Phenotype', 'HP:0100526', (32, 43))	('patients', 'Species', '9606', (345, 353))	('adenocarcinoma', 'Disease', (233, 247))	('better', 'PosReg', (302, 308))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('low/negative', 'Var', (53, 65))	('patients', 'Species', '9606', (128, 136))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (200, 223))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (17, 43))	('adenocarcinoma', 'Disease', 'MESH:D000230', (233, 247))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (21, 43))
42238	25884692	The tumour suppressor p53 is involved in cell growth regulation, cell cycle progression, DNA repair and apoptosis; mutations in the TP53 gene, the most common genetic alterations in human cancers, can lead to production of dysfunctional p53 proteins that may allow the survival of genetically unstable cells that can turn into malignant cells.	('p53 proteins', 'Protein', (237, 249))	('dysfunctional', 'Disease', 'MESH:D006331', (223, 236))	('TP53', 'Gene', (132, 136))	('cancers', 'Disease', 'MESH:D009369', (188, 195))	('tumour', 'Phenotype', 'HP:0002664', (4, 10))	('tumour', 'Disease', 'MESH:D009369', (4, 10))	('tumour', 'Disease', (4, 10))	('survival', 'CPA', (269, 277))	('lead to', 'Reg', (201, 208))	('dysfunctional', 'Disease', (223, 236))	('proteins', 'Protein', (241, 249))	('human', 'Species', '9606', (182, 187))	('TP53', 'Gene', '7157', (132, 136))	('cancers', 'Phenotype', 'HP:0002664', (188, 195))	('cancers', 'Disease', (188, 195))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('mutations', 'Var', (115, 124))	('production', 'MPA', (209, 219))	('allow', 'PosReg', (259, 264))
42239	25884692	Mutant p53 proteins show a longer half-life than wild-type p53, resulting in accumulation in cancer cells; p53 overexpression can in turn induce circulating p53 antibodies (p53Abs) in patients bearing various types of cancer, including lung cancer, presumably because the altered conformation of p53 produced by mutations may trigger an autoimmune response once the protein has been released from tumour cells.	('p53', 'Gene', (107, 110))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('induce', 'Reg', (138, 144))	('lung cancer', 'Disease', (236, 247))	('cancer', 'Disease', 'MESH:D009369', (218, 224))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('autoimmune response', 'Phenotype', 'HP:0002960', (337, 356))	('cancer', 'Disease', 'MESH:D009369', (241, 247))	('lung cancer', 'Disease', 'MESH:D008175', (236, 247))	('tumour', 'Phenotype', 'HP:0002664', (397, 403))	('Mutant', 'Var', (0, 6))	('tumour', 'Disease', 'MESH:D009369', (397, 403))	('overexpression', 'PosReg', (111, 125))	('lung cancer', 'Phenotype', 'HP:0100526', (236, 247))	('cancer', 'Disease', (93, 99))	('tumour', 'Disease', (397, 403))	('patients', 'Species', '9606', (184, 192))	('cancer', 'Disease', (218, 224))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('trigger', 'Reg', (326, 333))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('cancer', 'Disease', (241, 247))	('mutations', 'Var', (312, 321))
42240	25884692	There is a close correlation between serum p53Abs and p53 overexpression in tumour tissues, thus p53Abs can be considered as markers for the presence of TP53 mutations.	('tumour', 'Phenotype', 'HP:0002664', (76, 82))	('TP53', 'Gene', '7157', (153, 157))	('overexpression', 'PosReg', (58, 72))	('TP53', 'Gene', (153, 157))	('tumour', 'Disease', 'MESH:D009369', (76, 82))	('p53', 'MPA', (54, 57))	('mutations', 'Var', (158, 167))	('tumour', 'Disease', (76, 82))
42241	25884692	In lung cancer, TP53 mutations arise early and p53 overexpression was detected in pre-neoplastic lesions, such as bronchial dysplasia.	('bronchial dysplasia', 'Disease', (114, 133))	('lung cancer', 'Disease', (3, 14))	('lung cancer', 'Phenotype', 'HP:0100526', (3, 14))	('neoplastic lesions', 'Phenotype', 'HP:0002664', (86, 104))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('TP53', 'Gene', '7157', (16, 20))	('bronchial dysplasia', 'Disease', 'MESH:D001982', (114, 133))	('lung cancer', 'Disease', 'MESH:D008175', (3, 14))	('TP53', 'Gene', (16, 20))	('overexpression', 'PosReg', (51, 65))	('mutations', 'Var', (21, 30))
42242	25884692	In addition, serum p53Abs were found in heavy smokers several months before the diagnosis of lung cancer.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('lung cancer', 'Disease', 'MESH:D008175', (93, 104))	('p53Abs', 'Var', (19, 25))	('lung cancer', 'Disease', (93, 104))	('lung cancer', 'Phenotype', 'HP:0100526', (93, 104))	('found', 'Reg', (31, 36))
42243	25884692	In a systematic review of published studies, the frequency of serum p53Abs in most of cancer patients resulted higher than in healthy and benign controls; therefore, detection of serum p53Abs may have potential diagnostic value for different types of cancer, including lung cancer.	('lung cancer', 'Disease', 'MESH:D008175', (269, 280))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('cancer', 'Disease', 'MESH:D009369', (274, 280))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('cancer', 'Disease', (274, 280))	('lung cancer', 'Disease', (269, 280))	('lung cancer', 'Phenotype', 'HP:0100526', (269, 280))	('cancer', 'Disease', 'MESH:D009369', (251, 257))	('higher', 'PosReg', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('cancer', 'Disease', (251, 257))	('cancer', 'Phenotype', 'HP:0002664', (274, 280))	('patients', 'Species', '9606', (93, 101))	('p53Abs', 'Var', (185, 191))	('cancer', 'Disease', (86, 92))
42244	25884692	However, another meta-analysis suggested that the low sensitivity of serum p53Abs limited their use in the screening of lung cancer.	('lung cancer', 'Disease', (120, 131))	('lung cancer', 'Phenotype', 'HP:0100526', (120, 131))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('p53Abs', 'Var', (75, 81))	('lung cancer', 'Disease', 'MESH:D008175', (120, 131))	('limited', 'NegReg', (82, 89))
42245	25884692	A combination of serum p53Abs with other conventional markers increased the sensitivity and specificity for detecting lung cancer.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('increased', 'PosReg', (62, 71))	('lung cancer', 'Disease', 'MESH:D008175', (118, 129))	('lung cancer', 'Disease', (118, 129))	('p53Abs', 'Var', (23, 29))	('lung cancer', 'Phenotype', 'HP:0100526', (118, 129))
42247	25884692	Prognostic implications in lung cancer of p53Abs are controversial: in non-small cell lung cancer (NSCLC), p53Abs were found to be related to short survival, but some studies showed the absence of correlation; in small cell lung cancer (SCLC), either a better survival in patients with high levels of p53Abs or a shorter survival in p53Ab positive patients with limited disease, as well as lack of prognostic relevance have been observed.	('patients', 'Species', '9606', (348, 356))	('SCLC', 'Phenotype', 'HP:0030357', (100, 104))	('better', 'PosReg', (253, 259))	('SCLC', 'Phenotype', 'HP:0030357', (237, 241))	('lung cancer', 'Phenotype', 'HP:0100526', (27, 38))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (75, 97))	('small cell lung cancer', 'Disease', 'MESH:D055752', (213, 235))	('SCLC', 'Gene', '7864', (100, 104))	('SCLC', 'Gene', (100, 104))	('SCLC', 'Gene', (237, 241))	('lung cancer', 'Disease', 'MESH:D008175', (224, 235))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (71, 97))	('small cell lung cancer', 'Disease', (213, 235))	('SCLC', 'Gene', '7864', (237, 241))	('p53Abs', 'Var', (301, 307))	('lung cancer', 'Phenotype', 'HP:0100526', (224, 235))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('lung cancer', 'Disease', 'MESH:D008175', (86, 97))	('NSCLC', 'Disease', 'MESH:D002289', (99, 104))	('non-small cell lung cancer', 'Disease', (71, 97))	('lung cancer', 'Disease', (27, 38))	('small cell lung cancer', 'Disease', 'MESH:D055752', (75, 97))	('lung cancer', 'Phenotype', 'HP:0100526', (86, 97))	('patients', 'Species', '9606', (272, 280))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (213, 235))	('NSCLC', 'Disease', (99, 104))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('NSCLC', 'Phenotype', 'HP:0030358', (99, 104))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (71, 97))	('lung cancer', 'Disease', 'MESH:D008175', (27, 38))
42248	25884692	Furthermore, as results of most studies are limited to the prognostic role of serum p53Abs, the aim of our work was not only to determine serum p53Abs in lung cancer patients and evaluate their prognostic role, but also to examine whether these antibodies were associated with p53 protein expression or mutations in corresponding tumour tissues, as p53 overexpression is believed to be an important trigger for the production of serum p53Abs.	('mutations', 'Var', (303, 312))	('lung cancer', 'Disease', (154, 165))	('protein', 'Protein', (281, 288))	('lung cancer', 'Phenotype', 'HP:0100526', (154, 165))	('associated', 'Reg', (261, 271))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('tumour', 'Phenotype', 'HP:0002664', (330, 336))	('tumour', 'Disease', 'MESH:D009369', (330, 336))	('lung cancer', 'Disease', 'MESH:D008175', (154, 165))	('p53', 'Gene', (277, 280))	('patients', 'Species', '9606', (166, 174))	('tumour', 'Disease', (330, 336))
42249	25884692	For these purposes, we simultaneously determined in lung cancer patients serum p53Abs by a highly specific ELISA, p53 protein expression by immunohistochemistry (IHC) and TP53 gene mutations by direct sequencing of exons 2-11, in corresponding tumours.	('TP53', 'Gene', (171, 175))	('tumours', 'Disease', (244, 251))	('p53Abs', 'Gene', (79, 85))	('lung cancer', 'Disease', 'MESH:D008175', (52, 63))	('expression', 'MPA', (126, 136))	('p53', 'Gene', (114, 117))	('patients', 'Species', '9606', (64, 72))	('tumour', 'Phenotype', 'HP:0002664', (244, 250))	('protein', 'Protein', (118, 125))	('lung cancer', 'Disease', (52, 63))	('lung cancer', 'Phenotype', 'HP:0100526', (52, 63))	('tumours', 'Phenotype', 'HP:0002664', (244, 251))	('mutations', 'Var', (181, 190))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('tumours', 'Disease', 'MESH:D009369', (244, 251))	('TP53', 'Gene', '7157', (171, 175))
42261	25884692	p53Abs were detected by a commercially available, highly specific ELISA kit (Anti-p53 ELISA II kit, PharmaCell, Paris, France), using micro-titre plates coated either with human recombinant p53 protein to detect specific p53Abs or with control proteins to reveal non-specific interactions.	('interactions', 'Interaction', (276, 288))	('p53Abs', 'Var', (221, 227))	('human', 'Species', '9606', (172, 177))
42274	25884692	Sera from 201 patients with primary lung carcinoma were evaluated for the presence of p53Abs using a highly specific ELISA kit.	('p53Abs', 'Var', (86, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (41, 50))	('primary lung carcinoma', 'Disease', (28, 50))	('primary lung carcinoma', 'Disease', 'MESH:D008175', (28, 50))	('patients', 'Species', '9606', (14, 22))
42275	25884692	Our results demonstrated that 20.4% of lung cancer patients (41 out of 201) had positive levels of serum p53Abs, while none of the 54 controls resulted positive (Table 3).	('lung cancer', 'Phenotype', 'HP:0100526', (39, 50))	('lung cancer', 'Disease', (39, 50))	('lung cancer', 'Disease', 'MESH:D008175', (39, 50))	('p53Abs', 'Var', (105, 111))	('patients', 'Species', '9606', (51, 59))	('positive', 'PosReg', (80, 88))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
42276	25884692	Our results agree with data from other studies on lung carcinoma where the frequency of p53Abs in serum ranged from 18.8% to 32.1% of the patients.	('carcinoma', 'Phenotype', 'HP:0030731', (55, 64))	('p53Abs', 'Var', (88, 94))	('lung carcinoma', 'Disease', 'MESH:D008175', (50, 64))	('lung carcinoma', 'Disease', (50, 64))	('patients', 'Species', '9606', (138, 146))
42277	25884692	In particular, 36 out of 188 NSCLC patients (19.1%) and 5 out of 13 SCLC patients (38.5%) were positive for serum p53Abs.	('SCLC', 'Gene', '7864', (30, 34))	('SCLC', 'Phenotype', 'HP:0030357', (30, 34))	('NSCLC', 'Phenotype', 'HP:0030358', (29, 34))	('p53Abs', 'Var', (114, 120))	('SCLC', 'Gene', '7864', (68, 72))	('patients', 'Species', '9606', (73, 81))	('SCLC', 'Gene', (68, 72))	('NSCLC', 'Disease', (29, 34))	('patients', 'Species', '9606', (35, 43))	('NSCLC', 'Disease', 'MESH:D002289', (29, 34))	('positive', 'Reg', (95, 103))	('SCLC', 'Gene', (30, 34))	('SCLC', 'Phenotype', 'HP:0030357', (68, 72))
42278	25884692	High levels of p53 tumour expression were demonstrated in 75 out of 131 lung cancer patients (57.3%), for whom tumour tissues were available (Table 3).	('tumour', 'Disease', 'MESH:D009369', (19, 25))	('p53', 'Var', (15, 18))	('patients', 'Species', '9606', (84, 92))	('tumour', 'Phenotype', 'HP:0002664', (111, 117))	('tumour', 'Disease', (19, 25))	('lung cancer', 'Disease', (72, 83))	('tumour', 'Disease', 'MESH:D009369', (111, 117))	('lung cancer', 'Phenotype', 'HP:0100526', (72, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('tumour', 'Disease', (111, 117))	('tumour', 'Phenotype', 'HP:0002664', (19, 25))	('lung cancer', 'Disease', 'MESH:D008175', (72, 83))
42279	25884692	Among these patients, 19 (16 NSCLC and 3 SCLC) out of 22 positive for serum p53Abs resulted also positive for p53 tumour overexpression (86.4%), while 56 (53 NSCLC and 3 SCLC) out of 109 low/negative for serum p53Abs were positive for p53 tumour overexpression (51.4%).	('NSCLC', 'Disease', 'MESH:D002289', (158, 163))	('SCLC', 'Gene', '7864', (159, 163))	('SCLC', 'Gene', (159, 163))	('NSCLC', 'Disease', 'MESH:D002289', (29, 34))	('NSCLC', 'Disease', (158, 163))	('patients', 'Species', '9606', (12, 20))	('SCLC', 'Phenotype', 'HP:0030357', (30, 34))	('SCLC', 'Phenotype', 'HP:0030357', (170, 174))	('tumour', 'Phenotype', 'HP:0002664', (114, 120))	('NSCLC', 'Disease', (29, 34))	('positive', 'Reg', (97, 105))	('NSCLC', 'Phenotype', 'HP:0030358', (158, 163))	('SCLC', 'Gene', (30, 34))	('SCLC', 'Gene', '7864', (30, 34))	('SCLC', 'Phenotype', 'HP:0030357', (41, 45))	('NSCLC', 'Phenotype', 'HP:0030358', (29, 34))	('SCLC', 'Gene', '7864', (170, 174))	('tumour overexpression', 'Disease', 'MESH:D009369', (239, 260))	('SCLC', 'Gene', (170, 174))	('tumour overexpression', 'Disease', 'MESH:D009369', (114, 135))	('tumour', 'Phenotype', 'HP:0002664', (239, 245))	('SCLC', 'Gene', '7864', (41, 45))	('SCLC', 'Gene', (41, 45))	('p53Abs', 'Var', (76, 82))	('SCLC', 'Phenotype', 'HP:0030357', (159, 163))	('tumour overexpression', 'Disease', (239, 260))	('tumour overexpression', 'Disease', (114, 135))
42282	25884692	By histological types, positive levels of p53Abs were more frequently found in patients with squamous cell carcinoma than adenocarcinoma (p = 0.068), while the numbers of other subgroups were too few to draw meaningful conclusions (Table 5).	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('squamous cell carcinoma than adenocarcinoma', 'Disease', 'MESH:D002294', (93, 136))	('squamous cell carcinoma than adenocarcinoma', 'Disease', (93, 136))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (93, 116))	('patients', 'Species', '9606', (79, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('p53Abs', 'Var', (42, 48))	('found', 'Reg', (70, 75))
42283	25884692	In NSCLC, there was a difference of borderline significance (p = 0.054) in the incidence of p53Abs between stage I and the more advanced stages II-IV.	('NSCLC', 'Disease', (3, 8))	('SCLC', 'Phenotype', 'HP:0030357', (4, 8))	('NSCLC', 'Disease', 'MESH:D002289', (3, 8))	('p53Abs', 'Var', (92, 98))	('NSCLC', 'Phenotype', 'HP:0030358', (3, 8))
42284	25884692	Finally, in NSCLC the presence of p53Abs was significantly correlated with tumours showing poorly differentiated grade (p = 0.016).	('NSCLC', 'Phenotype', 'HP:0030358', (12, 17))	('tumours', 'Disease', 'MESH:D009369', (75, 82))	('tumours', 'Disease', (75, 82))	('tumour', 'Phenotype', 'HP:0002664', (75, 81))	('NSCLC', 'Disease', (12, 17))	('p53Abs', 'Var', (34, 40))	('NSCLC', 'Disease', 'MESH:D002289', (12, 17))	('SCLC', 'Phenotype', 'HP:0030357', (13, 17))	('tumours', 'Phenotype', 'HP:0002664', (75, 82))	('correlated', 'Reg', (59, 69))
42286	25884692	From the 75 tumours positively staining for p53 protein, only 53 had enough tumour tissue to be investigated for TP53 gene mutations in exons 2-11.	('tumours', 'Disease', 'MESH:D009369', (12, 19))	('mutations', 'Var', (123, 132))	('tumour', 'Disease', (12, 18))	('tumours', 'Disease', (12, 19))	('tumour', 'Phenotype', 'HP:0002664', (76, 82))	('TP53', 'Gene', '7157', (113, 117))	('tumours', 'Phenotype', 'HP:0002664', (12, 19))	('tumour', 'Disease', 'MESH:D009369', (76, 82))	('tumour', 'Phenotype', 'HP:0002664', (12, 18))	('TP53', 'Gene', (113, 117))	('tumour', 'Disease', (76, 82))	('tumour', 'Disease', 'MESH:D009369', (12, 18))
42287	25884692	Of these 53 tumour samples, 13 (all NSCLC, 24.5%) showed TP53 mutations (9 missense mutations and 4 deletions), while 40 (39 NSCLC and 1 SCLC, 75.5%) showed no mutation; the median rate of tumour cells with p53 overexpression in tumours with mutations was 60%, while in tumours without mutations was 40% (p = 0.04).	('tumour', 'Disease', 'MESH:D009369', (229, 235))	('SCLC', 'Phenotype', 'HP:0030357', (126, 130))	('tumour', 'Disease', (229, 235))	('tumour', 'Phenotype', 'HP:0002664', (189, 195))	('NSCLC', 'Disease', 'MESH:D002289', (125, 130))	('tumour', 'Disease', 'MESH:D009369', (189, 195))	('SCLC', 'Phenotype', 'HP:0030357', (37, 41))	('TP53', 'Gene', '7157', (57, 61))	('tumour', 'Disease', (189, 195))	('tumour', 'Phenotype', 'HP:0002664', (12, 18))	('SCLC', 'Gene', '7864', (126, 130))	('SCLC', 'Gene', (126, 130))	('tumour', 'Disease', 'MESH:D009369', (12, 18))	('overexpression', 'PosReg', (211, 225))	('NSCLC', 'Disease', (125, 130))	('tumour', 'Disease', (12, 18))	('p53', 'Gene', (207, 210))	('tumours', 'Disease', (270, 277))	('SCLC', 'Gene', '7864', (37, 41))	('SCLC', 'Gene', (37, 41))	('NSCLC', 'Disease', 'MESH:D002289', (36, 41))	('NSCLC', 'Phenotype', 'HP:0030358', (125, 130))	('mutations', 'Var', (62, 71))	('SCLC', 'Phenotype', 'HP:0030357', (137, 141))	('tumours', 'Phenotype', 'HP:0002664', (270, 277))	('tumours', 'Disease', 'MESH:D009369', (270, 277))	('tumours', 'Disease', (229, 236))	('NSCLC', 'Disease', (36, 41))	('SCLC', 'Gene', '7864', (137, 141))	('SCLC', 'Gene', (137, 141))	('TP53', 'Gene', (57, 61))	('tumours', 'Phenotype', 'HP:0002664', (229, 236))	('tumour', 'Phenotype', 'HP:0002664', (270, 276))	('tumour', 'Disease', 'MESH:D009369', (270, 276))	('missense mutations', 'Var', (75, 93))	('tumours', 'Disease', 'MESH:D009369', (229, 236))	('NSCLC', 'Phenotype', 'HP:0030358', (36, 41))	('mutations', 'Var', (242, 251))	('tumour', 'Disease', (270, 276))	('tumour', 'Phenotype', 'HP:0002664', (229, 235))
42288	25884692	Mutational analysis was also performed in 12 patients without p53 protein overexpression by IHC (all NSCLC), whose DNA was available for direct sequencing; in this group, compatible with p53 negative staining, we found 9 patients with wild-type p53 and 3 patients with p53 deletions (Figure 2).	('patients', 'Species', '9606', (221, 229))	('p53', 'Gene', (269, 272))	('deletions', 'Var', (273, 282))	('NSCLC', 'Disease', (101, 106))	('patients', 'Species', '9606', (255, 263))	('NSCLC', 'Disease', 'MESH:D002289', (101, 106))	('patients', 'Species', '9606', (45, 53))	('SCLC', 'Phenotype', 'HP:0030357', (102, 106))	('NSCLC', 'Phenotype', 'HP:0030358', (101, 106))
42289	25884692	Of the 16 mutations, 9 (56.2%) were missense mutations and 7 (43.7%) were deletions; 5 out of 9 point mutations (55.6%) were base pair transversions (G = > T 4/9, G = > C 1/9), while 4 (44.4%) were transitions (C = > T).	('mutations', 'Var', (10, 19))	('point mutations', 'Var', (96, 111))	('T 4/9, G = > C 1/9', 'Gene', '10875;7037;10562', (156, 174))
42293	25884692	In our cohort, TP53 mutations were more frequently associated with NSCLC of highest grade, although the difference did not reach a statistical significance, likely due to the small size of the sample.	('NSCLC', 'Phenotype', 'HP:0030358', (67, 72))	('associated', 'Reg', (51, 61))	('TP53', 'Gene', '7157', (15, 19))	('TP53', 'Gene', (15, 19))	('NSCLC', 'Disease', (67, 72))	('SCLC', 'Phenotype', 'HP:0030357', (68, 72))	('NSCLC', 'Disease', 'MESH:D002289', (67, 72))	('mutations', 'Var', (20, 29))
42294	25884692	Other clinicopathologic features, such as age and sex of patients, histological type of tumours and NSCLC stage were not significantly correlated with TP53 mutations (Table 8).	('TP53', 'Gene', (151, 155))	('tumours', 'Phenotype', 'HP:0002664', (88, 95))	('NSCLC', 'Disease', (100, 105))	('mutations', 'Var', (156, 165))	('patients', 'Species', '9606', (57, 65))	('SCLC', 'Phenotype', 'HP:0030357', (101, 105))	('NSCLC', 'Disease', 'MESH:D002289', (100, 105))	('type of tumours', 'Disease', 'MESH:D009369', (80, 95))	('type of tumours', 'Disease', (80, 95))	('tumour', 'Phenotype', 'HP:0002664', (88, 94))	('NSCLC', 'Phenotype', 'HP:0030358', (100, 105))	('TP53', 'Gene', '7157', (151, 155))
42296	25884692	Eleven of these patients (all with NSCLC) were positive for serum p53Abs (20.8%) and three showed missense mutations in the corresponding tumours (27.3%), while ten patients (all with NSCLC) out of the 42 with low/negative-serum (41 with NSCLC and 1 with SCLC) had missense mutations or deletions in their tumours (23.8%).	('NSCLC', 'Phenotype', 'HP:0030358', (184, 189))	('tumours', 'Disease', (306, 313))	('tumour', 'Phenotype', 'HP:0002664', (306, 312))	('patients', 'Species', '9606', (16, 24))	('SCLC', 'Phenotype', 'HP:0030357', (36, 40))	('NSCLC', 'Disease', (238, 243))	('tumours', 'Phenotype', 'HP:0002664', (138, 145))	('patients', 'Species', '9606', (165, 173))	('tumours', 'Phenotype', 'HP:0002664', (306, 313))	('tumours', 'Disease', 'MESH:D009369', (138, 145))	('NSCLC', 'Phenotype', 'HP:0030358', (35, 40))	('NSCLC', 'Phenotype', 'HP:0030358', (238, 243))	('tumours', 'Disease', 'MESH:D009369', (306, 313))	('SCLC', 'Gene', '7864', (36, 40))	('tumour', 'Phenotype', 'HP:0002664', (138, 144))	('SCLC', 'Gene', (36, 40))	('p53Abs', 'Var', (66, 72))	('SCLC', 'Phenotype', 'HP:0030357', (255, 259))	('deletions', 'Var', (287, 296))	('SCLC', 'Phenotype', 'HP:0030357', (185, 189))	('NSCLC', 'Disease', 'MESH:D002289', (35, 40))	('NSCLC', 'Disease', 'MESH:D002289', (184, 189))	('SCLC', 'Phenotype', 'HP:0030357', (239, 243))	('SCLC', 'Gene', '7864', (255, 259))	('SCLC', 'Gene', (185, 189))	('SCLC', 'Gene', (255, 259))	('SCLC', 'Gene', '7864', (185, 189))	('missense mutations', 'Var', (98, 116))	('positive', 'Reg', (47, 55))	('NSCLC', 'Disease', (35, 40))	('NSCLC', 'Disease', (184, 189))	('SCLC', 'Gene', '7864', (239, 243))	('SCLC', 'Gene', (239, 243))	('NSCLC', 'Disease', 'MESH:D002289', (238, 243))	('missense mutations', 'Var', (265, 283))	('tumours', 'Disease', (138, 145))
42298	25884692	In our limited cohort, there was not a statistically significant association between serum p53Abs and the presence of TP53 mutations in the corresponding tumours.	('tumour', 'Phenotype', 'HP:0002664', (154, 160))	('tumours', 'Phenotype', 'HP:0002664', (154, 161))	('tumours', 'Disease', 'MESH:D009369', (154, 161))	('tumours', 'Disease', (154, 161))	('TP53', 'Gene', '7157', (118, 122))	('TP53', 'Gene', (118, 122))	('mutations', 'Var', (123, 132))
42299	25884692	The overall survival time of patients with p53Ab-low/negative-serum and NSCLC was significantly longer compared to serum-positive patients (p = 0.049); the rates of survival at 30 months were 54% versus 31% in patients with low/negative or positive-serum, respectively (Figure 3).	('patients', 'Species', '9606', (29, 37))	('NSCLC', 'Disease', (72, 77))	('SCLC', 'Phenotype', 'HP:0030357', (73, 77))	('p53Ab-low/negative-serum', 'Var', (43, 67))	('NSCLC', 'Disease', 'MESH:D002289', (72, 77))	('patients', 'Species', '9606', (130, 138))	('longer', 'PosReg', (96, 102))	('patients', 'Species', '9606', (210, 218))	('survival', 'CPA', (12, 20))	('NSCLC', 'Phenotype', 'HP:0030358', (72, 77))
42300	25884692	In particular, patients with squamous cell carcinoma and p53Ab-low/negative-serum showed a statistically significant advantage in survival rate at 30 months compared to serum-positive patients, 57% versus 18% respectively (p = 0.044, Figure 4), while no difference was observed in patients with adenocarcinoma (Figure 5); similarly, no difference was found with regard to stage or grade.	('patients', 'Species', '9606', (15, 23))	('carcinoma', 'Phenotype', 'HP:0030731', (300, 309))	('adenocarcinoma', 'Disease', (295, 309))	('patients', 'Species', '9606', (184, 192))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (29, 52))	('adenocarcinoma', 'Disease', 'MESH:D000230', (295, 309))	('patients', 'Species', '9606', (281, 289))	('carcinoma', 'Phenotype', 'HP:0030731', (43, 52))	('squamous cell carcinoma', 'Disease', (29, 52))	('p53Ab-low/negative-serum', 'Var', (57, 81))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (29, 52))	('advantage', 'PosReg', (117, 126))	('survival', 'MPA', (130, 138))
42301	25884692	In this study, there was no correlation between p53 overexpression or TP53 mutations in NSCLC and survival.	('p53', 'Gene', (48, 51))	('SCLC', 'Phenotype', 'HP:0030357', (89, 93))	('NSCLC', 'Phenotype', 'HP:0030358', (88, 93))	('TP53', 'Gene', '7157', (70, 74))	('NSCLC', 'Disease', 'MESH:D002289', (88, 93))	('TP53', 'Gene', (70, 74))	('NSCLC', 'Disease', (88, 93))	('mutations', 'Var', (75, 84))	('overexpression', 'PosReg', (52, 66))
42302	25884692	Our data showed that 20.4% of lung cancer patients had positive levels of serum p53Abs, while none of the controls showed positive levels of these antibodies.	('lung cancer', 'Phenotype', 'HP:0100526', (30, 41))	('lung cancer', 'Disease', (30, 41))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('positive', 'Reg', (55, 63))	('lung cancer', 'Disease', 'MESH:D008175', (30, 41))	('patients', 'Species', '9606', (42, 50))	('p53Abs', 'Var', (80, 86))
42303	25884692	A significant correlation between positive levels of p53Abs and p53 overexpression in the corresponding tumours was observed (p = 0.005), suggesting that the presence of p53Abs is related to the accumulation of p53 protein in the primary tumour.	('tumour', 'Disease', (238, 244))	('accumulation', 'PosReg', (195, 207))	('tumour', 'Phenotype', 'HP:0002664', (104, 110))	('p53Abs', 'Var', (170, 176))	('tumour', 'Disease', 'MESH:D009369', (104, 110))	('tumours', 'Phenotype', 'HP:0002664', (104, 111))	('tumour', 'Phenotype', 'HP:0002664', (238, 244))	('tumour', 'Disease', 'MESH:D009369', (238, 244))	('p53 protein', 'Protein', (211, 222))	('presence', 'Var', (158, 166))	('tumours', 'Disease', 'MESH:D009369', (104, 111))	('tumour', 'Disease', (104, 110))	('tumours', 'Disease', (104, 111))
42304	25884692	In NSCLC, positive levels of p53Abs were associated with squamous cell carcinoma rather than adenocarcinoma (p = 0.068), a different frequency also previously reported.	('adenocarcinoma', 'Disease', 'MESH:D000230', (93, 107))	('p53Abs', 'Var', (29, 35))	('NSCLC', 'Disease', (3, 8))	('associated', 'Reg', (41, 51))	('SCLC', 'Phenotype', 'HP:0030357', (4, 8))	('NSCLC', 'Disease', 'MESH:D002289', (3, 8))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (57, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (57, 80))	('adenocarcinoma', 'Disease', (93, 107))	('squamous cell carcinoma', 'Disease', (57, 80))	('NSCLC', 'Phenotype', 'HP:0030358', (3, 8))
42305	25884692	In our study, p53Abs were correlated with II-IV stages compared to I stage (p = 0.054); similarly, the incidence of p53Abs was previously found higher in lung cancer patients with advanced stages III-IV compared to patients with early stages I-II.	('patients', 'Species', '9606', (215, 223))	('lung cancer', 'Disease', (154, 165))	('lung cancer', 'Phenotype', 'HP:0100526', (154, 165))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('higher', 'PosReg', (144, 150))	('p53Abs', 'Var', (116, 122))	('lung cancer', 'Disease', 'MESH:D008175', (154, 165))	('patients', 'Species', '9606', (166, 174))
42306	25884692	We observed that the presence of p53Abs was significantly related to tumours with poorly differentiated grade (p = 0.016).	('tumours', 'Disease', (69, 76))	('p53Abs', 'Var', (33, 39))	('related', 'Reg', (58, 65))	('tumour', 'Phenotype', 'HP:0002664', (69, 75))	('tumours', 'Phenotype', 'HP:0002664', (69, 76))	('tumours', 'Disease', 'MESH:D009369', (69, 76))
42311	25884692	In particular, TP53 mutations were found in three out of 12 p53 protein-negative samples; the absence of p53 protein expression in these samples may be due to the type of mutations, as they were frameshift mutations.	('frameshift mutations', 'Var', (195, 215))	('p53', 'Gene', (105, 108))	('TP53', 'Gene', '7157', (15, 19))	('TP53', 'Gene', (15, 19))	('absence', 'NegReg', (94, 101))	('mutations', 'Var', (171, 180))	('protein', 'Protein', (109, 116))	('mutations', 'Var', (20, 29))
42314	25884692	In a study by Mack et al., serum p53Abs were significantly correlated with a poor survival in NSCLC patients.	('NSCLC', 'Phenotype', 'HP:0030358', (94, 99))	('SCLC', 'Phenotype', 'HP:0030357', (95, 99))	('p53Abs', 'Var', (33, 39))	('NSCLC', 'Disease', (94, 99))	('patients', 'Species', '9606', (100, 108))	('NSCLC', 'Disease', 'MESH:D002289', (94, 99))	('serum p53Abs', 'Var', (27, 39))	('correlated', 'Reg', (59, 69))
42315	25884692	also showed a significant association between serum p53Abs and poor survival in NSCLC patients, even though in a multivariate analysis only the presence of TP53 mutations remained an independent, significant unfavourable prognostic factor for survival.	('NSCLC', 'Phenotype', 'HP:0030358', (80, 85))	('patients', 'Species', '9606', (86, 94))	('NSCLC', 'Disease', (80, 85))	('TP53', 'Gene', '7157', (156, 160))	('poor survival', 'CPA', (63, 76))	('TP53', 'Gene', (156, 160))	('mutations', 'Var', (161, 170))	('NSCLC', 'Disease', 'MESH:D002289', (80, 85))	('presence', 'Var', (144, 152))	('SCLC', 'Phenotype', 'HP:0030357', (81, 85))	('p53Abs', 'Var', (52, 58))
42316	25884692	Bergqvist et al., in a study regarding patients with advanced NSCLC, reported a significant poor survival in patients positive for serum p53Abs with adenocarcinoma, but not in positive patients with squamous cell carcinoma.	('squamous cell carcinoma', 'Disease', (199, 222))	('adenocarcinoma', 'Disease', 'MESH:D000230', (149, 163))	('NSCLC', 'Disease', (62, 67))	('patients', 'Species', '9606', (39, 47))	('patients', 'Species', '9606', (109, 117))	('SCLC', 'Phenotype', 'HP:0030357', (63, 67))	('NSCLC', 'Disease', 'MESH:D002289', (62, 67))	('serum p53Abs', 'Var', (131, 143))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (199, 222))	('poor', 'NegReg', (92, 96))	('p53Abs', 'Var', (137, 143))	('adenocarcinoma', 'Disease', (149, 163))	('patients', 'Species', '9606', (185, 193))	('NSCLC', 'Phenotype', 'HP:0030358', (62, 67))	('carcinoma', 'Phenotype', 'HP:0030731', (154, 163))	('carcinoma', 'Phenotype', 'HP:0030731', (213, 222))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (199, 222))
42317	25884692	found that in NSCLC the levels of serum p53Abs were significantly higher in stage IV compared to stages I-III.	('NSCLC', 'Disease', (14, 19))	('NSCLC', 'Disease', 'MESH:D002289', (14, 19))	('p53Abs', 'Var', (40, 46))	('SCLC', 'Phenotype', 'HP:0030357', (15, 19))	('higher', 'PosReg', (66, 72))	('levels of serum', 'MPA', (24, 39))	('NSCLC', 'Phenotype', 'HP:0030358', (14, 19))
42318	25884692	However, some groups found no correlation with survival, while others showed a longer survival in lung cancer patients positive for serum p53Abs compared to negative patients, even though the difference did not reach a statistical significance.	('p53Abs', 'Var', (138, 144))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('lung cancer', 'Disease', (98, 109))	('patients', 'Species', '9606', (110, 118))	('lung cancer', 'Phenotype', 'HP:0100526', (98, 109))	('longer', 'PosReg', (79, 85))	('lung cancer', 'Disease', 'MESH:D008175', (98, 109))	('patients', 'Species', '9606', (166, 174))	('positive', 'Reg', (119, 127))
42319	25884692	Usually, these antibodies are considered as markers of TP53 mutations or p53 overexpression in tumours, thus reflecting a poor prognosis; however, the presence of serum p53Abs with a T-cell response may have a favourable impact on survival by destructing tumour cells expressing a dysfunctional p53.	('dysfunctional', 'Disease', (281, 294))	('tumour', 'Disease', 'MESH:D009369', (95, 101))	('tumours', 'Phenotype', 'HP:0002664', (95, 102))	('TP53', 'Gene', '7157', (55, 59))	('tumours', 'Disease', 'MESH:D009369', (95, 102))	('TP53', 'Gene', (55, 59))	('dysfunctional', 'Disease', 'MESH:D006331', (281, 294))	('destructing', 'NegReg', (243, 254))	('p53Abs', 'Var', (169, 175))	('tumour', 'Phenotype', 'HP:0002664', (255, 261))	('tumour', 'Disease', (95, 101))	('tumours', 'Disease', (95, 102))	('tumour', 'Disease', 'MESH:D009369', (255, 261))	('tumour', 'Disease', (255, 261))	('presence', 'Var', (151, 159))	('survival', 'CPA', (231, 239))	('tumour', 'Phenotype', 'HP:0002664', (95, 101))
42320	25884692	However, only 20-40% of cancer patients with TP53 mutations show circulating p53Abs, suggesting that other biological characteristics may be involved in this response, such as specific combination of Major Histocompatibility Complex classes I and II molecules expressed by each patient.	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('TP53', 'Gene', (45, 49))	('mutations', 'Var', (50, 59))	('cancer', 'Disease', (24, 30))	('cancer', 'Disease', 'MESH:D009369', (24, 30))	('patient', 'Species', '9606', (31, 38))	('patients', 'Species', '9606', (31, 39))	('patient', 'Species', '9606', (278, 285))	('p53Abs', 'MPA', (77, 83))	('TP53', 'Gene', '7157', (45, 49))
42321	25884692	Finally, in our study we did not find any significant correlation between p53 overexpression or TP53 mutations and survival in NSCLC, likely because of the reduced number of suitable tumour samples compared to serum samples.	('NSCLC', 'Disease', (127, 132))	('mutations', 'Var', (101, 110))	('tumour', 'Disease', (183, 189))	('TP53', 'Gene', (96, 100))	('NSCLC', 'Disease', 'MESH:D002289', (127, 132))	('SCLC', 'Phenotype', 'HP:0030357', (128, 132))	('p53', 'Gene', (74, 77))	('NSCLC', 'Phenotype', 'HP:0030358', (127, 132))	('tumour', 'Phenotype', 'HP:0002664', (183, 189))	('tumour', 'Disease', 'MESH:D009369', (183, 189))	('TP53', 'Gene', '7157', (96, 100))
42322	25884692	In some studies, p53 accumulation and TP53 mutations have been reported as markers of poor survival in NSCLC.	('accumulation', 'PosReg', (21, 33))	('SCLC', 'Phenotype', 'HP:0030357', (104, 108))	('TP53', 'Gene', (38, 42))	('NSCLC', 'Disease', (103, 108))	('NSCLC', 'Disease', 'MESH:D002289', (103, 108))	('mutations', 'Var', (43, 52))	('p53', 'Protein', (17, 20))	('NSCLC', 'Phenotype', 'HP:0030358', (103, 108))	('TP53', 'Gene', '7157', (38, 42))
42323	25884692	showed that TP53 mutations and p53 overexpression were significantly correlated with poor survival in NSCLC; however, in a multivariate analysis, only the presence of TP53 mutations remained an independent, significant unfavourable prognostic factor for survival.	('NSCLC', 'Disease', 'MESH:D002289', (102, 107))	('p53', 'Gene', (31, 34))	('SCLC', 'Phenotype', 'HP:0030357', (103, 107))	('NSCLC', 'Phenotype', 'HP:0030358', (102, 107))	('poor', 'NegReg', (85, 89))	('TP53', 'Gene', '7157', (12, 16))	('TP53', 'Gene', '7157', (167, 171))	('overexpression', 'PosReg', (35, 49))	('TP53', 'Gene', (12, 16))	('NSCLC', 'Disease', (102, 107))	('mutations', 'Var', (17, 26))	('TP53', 'Gene', (167, 171))
42324	25884692	found that patients with NSCLC overexpressing p53 showed significant shorter survival compared to patients with p53-negative tumours, while TP53 mutations were not prognostic for survival.	('overexpressing', 'PosReg', (31, 45))	('p53', 'Var', (46, 49))	('TP53', 'Gene', (140, 144))	('tumours', 'Disease', (125, 132))	('NSCLC', 'Disease', (25, 30))	('tumour', 'Phenotype', 'HP:0002664', (125, 131))	('shorter', 'NegReg', (69, 76))	('patients', 'Species', '9606', (98, 106))	('NSCLC', 'Disease', 'MESH:D002289', (25, 30))	('SCLC', 'Phenotype', 'HP:0030357', (26, 30))	('survival', 'MPA', (77, 85))	('patients', 'Species', '9606', (11, 19))	('tumours', 'Phenotype', 'HP:0002664', (125, 132))	('NSCLC', 'Phenotype', 'HP:0030358', (25, 30))	('TP53', 'Gene', '7157', (140, 144))	('tumours', 'Disease', 'MESH:D009369', (125, 132))
42325	25884692	However, other groups reported no correlation between p53 accumulation and survival in NSCLC or a not clear role for TP53 mutations as a prognostic marker for survival in NSCLC.	('NSCLC', 'Disease', (87, 92))	('SCLC', 'Phenotype', 'HP:0030357', (172, 176))	('TP53', 'Gene', '7157', (117, 121))	('p53', 'Var', (54, 57))	('accumulation', 'PosReg', (58, 70))	('TP53', 'Gene', (117, 121))	('NSCLC', 'Disease', 'MESH:D002289', (87, 92))	('NSCLC', 'Phenotype', 'HP:0030358', (171, 176))	('SCLC', 'Phenotype', 'HP:0030357', (88, 92))	('mutations', 'Var', (122, 131))	('NSCLC', 'Phenotype', 'HP:0030358', (87, 92))	('NSCLC', 'Disease', (171, 176))	('NSCLC', 'Disease', 'MESH:D002289', (171, 176))
42326	25884692	In our investigation the presence of serum p53Abs, but not p53 tumour overexpression or TP53 mutations, identifies subsets of NSCLC patients with a shorter survival.	('tumour overexpression', 'Disease', 'MESH:D009369', (63, 84))	('NSCLC', 'Disease', 'MESH:D002289', (126, 131))	('tumour overexpression', 'Disease', (63, 84))	('p53Abs', 'Var', (43, 49))	('tumour', 'Phenotype', 'HP:0002664', (63, 69))	('NSCLC', 'Phenotype', 'HP:0030358', (126, 131))	('TP53', 'Gene', '7157', (88, 92))	('SCLC', 'Phenotype', 'HP:0030357', (127, 131))	('TP53', 'Gene', (88, 92))	('patients', 'Species', '9606', (132, 140))	('NSCLC', 'Disease', (126, 131))
42328	25884692	We were unable to find any significant correlation between positive levels of serum p53Abs and TP53 mutations in the corresponding tumours.	('tumours', 'Disease', 'MESH:D009369', (131, 138))	('tumours', 'Phenotype', 'HP:0002664', (131, 138))	('p53Abs', 'Var', (84, 90))	('tumours', 'Disease', (131, 138))	('tumour', 'Phenotype', 'HP:0002664', (131, 137))	('TP53', 'Gene', '7157', (95, 99))	('TP53', 'Gene', (95, 99))
42341	25424420	By associating and deacetylating Smad4, SIRT1 enzyme can influence MMP7 expression, MMP enzyme activity, and consequently, cell migration, invasion, and tumor metastasis in OSCCs.	('tumor metastasis', 'Disease', (153, 169))	('invasion', 'CPA', (139, 147))	('MMP7', 'Gene', (67, 71))	('cell migration', 'CPA', (123, 137))	('influence', 'Reg', (57, 66))	('MMP7', 'Gene', '4316', (67, 71))	('OSCC', 'CellLine', 'CVCL:L894', (173, 177))	('expression', 'MPA', (72, 82))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('activity', 'MPA', (95, 103))	('Smad4', 'Gene', (33, 38))	('tumor metastasis', 'Disease', 'MESH:D009362', (153, 169))	('deacetylating', 'Var', (19, 32))	('MMP enzyme', 'Enzyme', (84, 94))	('OSCCs', 'Disease', (173, 178))
42372	25424420	In contrast, knockdown of SIRT1 in oral cancer cells enhanced EMT and cancer metastasis in vitro.	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('cancer metastasis', 'Disease', (70, 87))	('SIRT1', 'Gene', (26, 31))	('oral cancer', 'Disease', 'MESH:D009062', (35, 46))	('cancer metastasis', 'Disease', 'MESH:D009362', (70, 87))	('oral cancer', 'Disease', (35, 46))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('knockdown', 'Var', (13, 22))	('enhanced', 'PosReg', (53, 61))
42400	25424420	We next investigated the possible regulation of E-cadherin, N-cadherin, and vimentin expression by SIRT1, by using siRNA oligonucleotides to knock down SIRT1 expression in HOK cell lines, and found that SIRT1 silencing clearly down-regulated E-cadherin expression.	('SIRT1', 'Gene', (152, 157))	('N-cadherin', 'Gene', (60, 70))	('expression', 'MPA', (253, 263))	('vimentin', 'Gene', '7431', (76, 84))	('E-cadherin', 'Gene', (242, 252))	('E-cadherin', 'Gene', '999', (242, 252))	('E-cadherin', 'Gene', '999', (48, 58))	('N-cadherin', 'Gene', '1000', (60, 70))	('down-regulated', 'NegReg', (227, 241))	('vimentin', 'Gene', (76, 84))	('SIRT1', 'Gene', (203, 208))	('E-cadherin', 'Gene', (48, 58))	('silencing', 'Var', (209, 218))	('oligonucleotides', 'Chemical', 'MESH:D009841', (121, 137))	('knock', 'Var', (141, 146))
42401	25424420	Additionally, the deletion of SIRT1 led to significantly increased N-cadherin and vimentin expression in knockdown HOK cells.	('expression', 'MPA', (91, 101))	('SIRT1', 'Gene', (30, 35))	('vimentin', 'Gene', '7431', (82, 90))	('increased', 'PosReg', (57, 66))	('vimentin', 'Gene', (82, 90))	('N-cadherin', 'Gene', (67, 77))	('deletion', 'Var', (18, 26))	('N-cadherin', 'Gene', '1000', (67, 77))
42407	25424420	We found that MMP7 transcription and translation were significantly decreased in SIRT1-overexpressing cells compared with their levels in control cells (Figure 4A and B).	('decreased', 'NegReg', (68, 77))	('translation', 'MPA', (37, 48))	('SIRT1-overexpressing', 'Var', (81, 101))	('MMP7', 'Gene', (14, 18))	('MMP7', 'Gene', '4316', (14, 18))	('SIRT1-overexpressing', 'Gene', (81, 101))	('transcription', 'MPA', (19, 32))
42408	25424420	We also compared the enzymatic activity of MMP7 in SIRT1 overexpressing and silencing OSCC cells.	('MMP7', 'Gene', (43, 47))	('silencing', 'Var', (76, 85))	('MMP7', 'Gene', '4316', (43, 47))	('OSCC', 'CellLine', 'CVCL:L894', (86, 90))
42410	25424420	In contrast, SIRT1 silencing produced a significant increase in MMP7 activity (Figure 4C).	('MMP7', 'Gene', (64, 68))	('MMP7', 'Gene', '4316', (64, 68))	('increase', 'PosReg', (52, 60))	('silencing', 'Var', (19, 28))	('SIRT1', 'Gene', (13, 18))
42414	25424420	In contrast, SIRT1 silencing in oral cancer cells resulted in a significant induction of MMP7 secretion.	('oral cancer', 'Disease', (32, 43))	('MMP7', 'Gene', (89, 93))	('silencing', 'Var', (19, 28))	('induction', 'Reg', (76, 85))	('MMP7', 'Gene', '4316', (89, 93))	('SIRT1', 'Gene', (13, 18))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('oral cancer', 'Disease', 'MESH:D009062', (32, 43))
42415	25424420	A similar result was seen in western blot experiments, where MMP7 secretion was significantly suppressed by exogenously produced overexpression of SIRT1 in both OSCC cell lines, whereas repression of SIRT1 by SIRT1 silencing increased MMP7 secretion (Figure 4D).	('MMP7', 'Gene', (235, 239))	('MMP7', 'Gene', '4316', (235, 239))	('MMP7', 'Gene', (61, 65))	('overexpression', 'PosReg', (129, 143))	('increased', 'PosReg', (225, 234))	('MMP7', 'Gene', '4316', (61, 65))	('SIRT1', 'Gene', (209, 214))	('suppressed', 'NegReg', (94, 104))	('silencing', 'Var', (215, 224))	('SIRT1', 'Gene', (147, 152))	('OSCC', 'CellLine', 'CVCL:L894', (161, 165))
42426	25424420	This experiment showed that SIRT1 silencing significantly increased the level of acetylated Smad4 in SIRT1 knockdown OSCC cells.	('increased', 'PosReg', (58, 67))	('OSCC', 'CellLine', 'CVCL:L894', (117, 121))	('SIRT1', 'Gene', (28, 33))	('level of acetylated', 'MPA', (72, 91))	('silencing', 'Var', (34, 43))	('Smad4', 'Protein', (92, 97))	('SIRT1', 'Gene', (101, 106))
42430	25424420	Surprisingly, the acetylation level of Smad4 was highly increased by TGF-beta induction, while overexpression of SIRT1 significantly reduced the acetylation level of TGF-beta induced Smad4 in OSCCs.	('TGF-beta', 'Gene', (69, 77))	('TGF-beta', 'Gene', '7040', (166, 174))	('increased', 'PosReg', (56, 65))	('acetylation', 'MPA', (145, 156))	('TGF-beta', 'Gene', (166, 174))	('OSCC', 'CellLine', 'CVCL:L894', (192, 196))	('TGF-beta', 'Gene', '7040', (69, 77))	('induction', 'Var', (78, 87))	('acetylation level', 'MPA', (18, 35))
42434	25424420	SIRT1 silencing significantly downregulated MMP7 protein expression in both OSCC cell lines (Figure 6A and B).	('MMP7', 'Gene', (44, 48))	('downregulated', 'NegReg', (30, 43))	('MMP7', 'Gene', '4316', (44, 48))	('OSCC', 'CellLine', 'CVCL:L894', (76, 80))	('SIRT1', 'Gene', (0, 5))	('silencing', 'Var', (6, 15))
42435	25424420	A subsequent ELISA analysis of the media showed that MMP7 secretion was significantly decreased in siSmad4 OSCC cells compared with secretion in scrambled control OSCC cells.	('MMP7', 'Gene', (53, 57))	('OSCC', 'CellLine', 'CVCL:L894', (107, 111))	('MMP7', 'Gene', '4316', (53, 57))	('siSmad4 OSCC', 'Var', (99, 111))	('OSCC', 'CellLine', 'CVCL:L894', (163, 167))	('decreased', 'NegReg', (86, 95))
42448	25424420	We generated a flag-tagged Smad4 WT, Smad4-K37R, and Smad4-K428R mutant OECM1 cells, and analyzed their acetylation levels.	('Smad4-K428R', 'Var', (53, 64))	('Smad4-K37R', 'Var', (37, 47))	('acetylation levels', 'MPA', (104, 122))	('K428R', 'Chemical', '-', (59, 64))	('K37R', 'Mutation', 'p.K37R', (43, 47))
42449	25424420	Whereas K428R substitution greatly increased acetylation to levels similar to those observed in wild-type Smad4 (Figure 7C).	('K428R', 'Var', (8, 13))	('increased', 'PosReg', (35, 44))	('acetylation', 'MPA', (45, 56))	('K428R', 'Chemical', '-', (8, 13))
42477	25424420	Additionally SIRT1 involvement has also been suggested in epigenetic silencing of DNA-hypermethylated tumor suppressor genes in breast cancer cells.	('epigenetic silencing', 'Var', (58, 78))	('involvement', 'Reg', (19, 30))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('SIRT1', 'Gene', (13, 18))	('breast cancer', 'Disease', (128, 141))	('breast cancer', 'Disease', 'MESH:D001943', (128, 141))	('breast cancer', 'Phenotype', 'HP:0003002', (128, 141))	('tumor', 'Disease', (102, 107))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))
42479	25424420	Additionally, SIRT1 is highly expressed in various cancers such as prostate cancer, and high levels of SIRT1 expression are associated with a poor prognosis in lung cancer, breast cancer, gastric carcinomas, and B-cell lymphoma.	('prostate cancer', 'Disease', (67, 82))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('high levels', 'Var', (88, 99))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (212, 227))	('breast cancer', 'Phenotype', 'HP:0003002', (173, 186))	('lung cancer', 'Disease', 'MESH:D008175', (160, 171))	('breast cancer', 'Disease', 'MESH:D001943', (173, 186))	('B-cell lymphoma', 'Disease', (212, 227))	('cancers', 'Disease', 'MESH:D009369', (51, 58))	('lung cancer', 'Phenotype', 'HP:0100526', (160, 171))	('breast cancer', 'Disease', (173, 186))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('gastric carcinomas', 'Disease', (188, 206))	('associated', 'Reg', (124, 134))	('gastric carcinomas', 'Disease', 'MESH:D013274', (188, 206))	('carcinoma', 'Phenotype', 'HP:0030731', (196, 205))	('SIRT1', 'Gene', (103, 108))	('carcinomas', 'Phenotype', 'HP:0030731', (196, 206))	('expression', 'MPA', (109, 119))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('prostate cancer', 'Disease', 'MESH:D011471', (67, 82))	('prostate cancer', 'Phenotype', 'HP:0012125', (67, 82))	('cancers', 'Phenotype', 'HP:0002664', (51, 58))	('lymphoma', 'Phenotype', 'HP:0002665', (219, 227))	('cancers', 'Disease', (51, 58))	('B-cell lymphoma', 'Disease', 'MESH:D016393', (212, 227))	('lung cancer', 'Disease', (160, 171))
42486	25424420	found that Sirt1+/-; p53+/- mice develop tumors in multiple tissues, and activation of SIRT1 by resveratrol reduces tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('p53+/-', 'Var', (21, 27))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('tumor', 'Disease', (41, 46))	('Sirt1', 'Gene', '93759', (11, 16))	('mice', 'Species', '10090', (28, 32))	('resveratrol', 'Chemical', 'MESH:D000077185', (96, 107))	('tumors', 'Disease', (41, 47))	('reduces', 'NegReg', (108, 115))	('tumors', 'Disease', 'MESH:D009369', (41, 47))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('develop', 'PosReg', (33, 40))	('SIRT1', 'Gene', (87, 92))	('Sirt1', 'Gene', (11, 16))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('tumor', 'Disease', (116, 121))
42487	25424420	Moreover, several independent investigations have found reduced levels of SIRT1 in Sirt1+/-; p53+/- mice as compared to normal controls, and suggested SIRT1 as an important antagonist of EMT in various types of cancer cells.	('SIRT1', 'MPA', (74, 79))	('cancer', 'Disease', 'MESH:D009369', (211, 217))	('Sirt1', 'Gene', '93759', (83, 88))	('mice', 'Species', '10090', (100, 104))	('reduced', 'NegReg', (56, 63))	('cancer', 'Disease', (211, 217))	('p53+/-', 'Var', (93, 99))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('Sirt1', 'Gene', (83, 88))
42499	25424420	Additionally, we found that SIRT1 knockdown OSCC cells showed increased MMP7 secretion and expression.	('increased', 'PosReg', (62, 71))	('expression', 'MPA', (91, 101))	('OSCC', 'CellLine', 'CVCL:L894', (44, 48))	('MMP7', 'Gene', (72, 76))	('SIRT1', 'Gene', (28, 33))	('knockdown', 'Var', (34, 43))	('MMP7', 'Gene', '4316', (72, 76))
42500	25424420	We examined the interaction between SIRT1 and MMP7 in SIRT1 knockdown OSCC cells by immunoprecipitation, and found no direct interaction of SIRT1 with MMP7 (data not shown).	('MMP7', 'Gene', '4316', (46, 50))	('OSCC', 'CellLine', 'CVCL:L894', (70, 74))	('MMP7', 'Gene', (151, 155))	('SIRT1', 'Gene', (54, 59))	('knockdown', 'Var', (60, 69))	('MMP7', 'Gene', '4316', (151, 155))	('MMP7', 'Gene', (46, 50))
42503	25424420	Smad4 is indispensable for EMT, and RNA interference-mediated knockdown of Smad4 expression results in preserved E-cadherin expression.	('E-cadherin', 'Gene', (113, 123))	('RNA', 'MPA', (36, 39))	('Smad4', 'Gene', (75, 80))	('E-cadherin', 'Gene', '999', (113, 123))	('preserved', 'NegReg', (103, 112))	('knockdown', 'Var', (62, 71))
42517	25424420	Our data revealed that MMP7 expression levels and activity were significantly decreased in the Smad4 knockdown OSCC cells (Figure 6).	('expression levels', 'MPA', (28, 45))	('OSCC', 'CellLine', 'CVCL:L894', (111, 115))	('MMP7', 'Gene', '4316', (23, 27))	('knockdown', 'Var', (101, 110))	('activity', 'MPA', (50, 58))	('decreased', 'NegReg', (78, 87))	('Smad4', 'Gene', (95, 100))	('MMP7', 'Gene', (23, 27))
42521	25424420	SIRT1 was shown to affect Smad4 transcriptional activity by deacetylation, and inhibition of Smad4 function repressed TGF-beta-induced EMT.	('Smad4', 'Gene', (93, 98))	('TGF-beta', 'Gene', (118, 126))	('repressed', 'NegReg', (108, 117))	('deacetylation', 'MPA', (60, 73))	('SIRT1', 'Gene', (0, 5))	('transcriptional activity', 'MPA', (32, 56))	('inhibition', 'Var', (79, 89))	('affect', 'Reg', (19, 25))	('TGF-beta', 'Gene', '7040', (118, 126))	('Smad4', 'Protein', (26, 31))
42522	25424420	These observations clearly show that SIRT1 might influence MMP7 expression, secretion, and activity; and subsequently, cell migration, invasion, and metastasis through Smad4 deacetylation.	('metastasis', 'CPA', (149, 159))	('Smad4', 'Gene', (168, 173))	('expression', 'MPA', (64, 74))	('deacetylation', 'Var', (174, 187))	('SIRT1', 'Gene', (37, 42))	('MMP7', 'Gene', (59, 63))	('activity', 'MPA', (91, 99))	('MMP7', 'Gene', '4316', (59, 63))	('secretion', 'MPA', (76, 85))	('influence', 'Reg', (49, 58))	('cell migration', 'CPA', (119, 133))	('invasion', 'CPA', (135, 143))
42525	25424420	In conclusion, our study identified SIRT1 as a novel metastatic suppressor which acts through deacetylation of TGF-beta-activated transcription factor Smad4 to suppress the effect of TGF-beta signaling on MMP7 transcription, leading to reduced migration and metastasis of OSCC cells.	('TGF-beta', 'Gene', '7040', (111, 119))	('effect', 'MPA', (173, 179))	('metastasis of OSCC cells', 'CPA', (258, 282))	('suppress', 'NegReg', (160, 168))	('TGF-beta', 'Gene', (183, 191))	('TGF-beta', 'Gene', (111, 119))	('transcription', 'MPA', (210, 223))	('MMP7', 'Gene', (205, 209))	('reduced', 'NegReg', (236, 243))	('deacetylation', 'Var', (94, 107))	('MMP7', 'Gene', '4316', (205, 209))	('TGF-beta', 'Gene', '7040', (183, 191))	('migration', 'CPA', (244, 253))	('OSCC', 'CellLine', 'CVCL:L894', (272, 276))
42537	25424420	OECM1 cells were transiently transfected with small interfering RNA (siRNA) (150 nM; a pool of 3 target-specific siRNAs) against SIRT1, or with a nontargeting control (GeneDireX) in Opti-MEM  I reduced serum medium containing Lipofectamine RNAiMAX (Invitrogen).	('small', 'Var', (46, 51))	('SIRT1', 'Gene', (129, 134))	('Lipofectamine', 'Chemical', 'MESH:C086724', (226, 239))	('Opti-MEM  I reduced serum medium', 'Chemical', '-', (182, 214))
42560	25424420	This assay uses a small lysine-acetylated peptide, corresponding to K382 of human p53, as a substrate.	('K382', 'Chemical', '-', (68, 72))	('K382', 'Var', (68, 72))	('human', 'Species', '9606', (76, 81))	('lysine', 'Chemical', 'MESH:D008239', (24, 30))	('p53', 'Gene', (82, 85))
42617	32859951	Comprehensive genomic studies have revealed frequent focal amplifications of the YAP locus in human carcinomas, including head and neck squamous cell carcinoma (HNSCC).	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('carcinomas', 'Phenotype', 'HP:0030731', (100, 110))	('carcinomas', 'Disease', (100, 110))	('YAP locus', 'Gene', (81, 90))	('carcinoma', 'Phenotype', 'HP:0030731', (150, 159))	('neck squamous cell carcinoma', 'Disease', (131, 159))	('amplifications', 'Var', (59, 73))	('human', 'Species', '9606', (94, 99))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (136, 159))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (122, 159))	('HNSCC', 'Phenotype', 'HP:0012288', (161, 166))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (131, 159))	('carcinomas', 'Disease', 'MESH:D009369', (100, 110))
42619	32859951	Abnormal activity of a protein involved in cell proliferation may influence the progression of head and neck cancers.	('cancers', 'Phenotype', 'HP:0002664', (109, 116))	('neck cancers', 'Disease', (104, 116))	('head and neck cancers', 'Phenotype', 'HP:0012288', (95, 116))	('activity', 'MPA', (9, 17))	('neck cancers', 'Disease', 'MESH:D006258', (104, 116))	('influence', 'Reg', (66, 75))	('Abnormal', 'Var', (0, 8))	('protein', 'Protein', (23, 30))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))
42621	32859951	Disruption to the Hippo-YAP signaling pathway, which plays a key role in cell proliferation and differentiation, is implicated in multiple cancers.	('cancers', 'Disease', 'MESH:D009369', (139, 146))	('cancers', 'Phenotype', 'HP:0002664', (139, 146))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('cancers', 'Disease', (139, 146))	('Hippo', 'Gene', (18, 23))	('implicated', 'Reg', (116, 126))	('Hippo', 'Gene', '37247', (18, 23))	('Disruption', 'Var', (0, 10))
42629	32859951	Sequential accumulation of genetic alterations in basal cells is thought to generate preneoplastic lesions that progress into invasive carcinomas.	('invasive carcinomas', 'Disease', (126, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('invasive carcinomas', 'Disease', 'MESH:D009361', (126, 145))	('carcinomas', 'Phenotype', 'HP:0030731', (135, 145))	('genetic alterations', 'Var', (27, 46))
42640	32859951	A number of studies have indicated that the dysregulation of this pathway is deeply implicated in cancer pathogenesis across multiple cancer types.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('dysregulation', 'Var', (44, 57))	('implicated', 'Reg', (84, 94))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('cancer', 'Disease', (98, 104))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
42644	32859951	An analysis of the data revealed recurrent somatic mutations and copy number alterations in HNSCC tumors.	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('HNSCC tumors', 'Disease', (92, 104))	('copy number alterations', 'Var', (65, 88))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('HNSCC tumors', 'Disease', 'MESH:D000077195', (92, 104))	('HNSCC', 'Phenotype', 'HP:0012288', (92, 97))
42645	32859951	Missense or truncating mutations in the TP53 tumor suppressor gene are the most frequent of all somatic genetic changes in HNSCC.	('frequent', 'Reg', (80, 88))	('HNSCC', 'Phenotype', 'HP:0012288', (123, 128))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumor', 'Disease', (45, 50))	('Missense or truncating mutations', 'Var', (0, 32))	('TP53', 'Gene', '7157', (40, 44))	('TP53', 'Gene', (40, 44))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('HNSCC', 'Disease', (123, 128))
42646	32859951	Approximately half of HNSCC patients carry a deletion or truncating mutation in the CDKN2A gene, which encodes tumor suppressors p16/INK4A and p14/ARF, which regulate the cell cycle.	('CDKN2A', 'Gene', '1029', (84, 90))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('ARF', 'Disease', 'MESH:D058186', (147, 150))	('regulate', 'Reg', (158, 166))	('p16', 'Gene', (129, 132))	('p16', 'Gene', '1029', (129, 132))	('deletion', 'Var', (45, 53))	('patients', 'Species', '9606', (28, 36))	('INK4A', 'Gene', '1029', (133, 138))	('p14', 'Gene', '1029', (143, 146))	('tumor', 'Disease', (111, 116))	('HNSCC', 'Disease', (22, 27))	('ARF', 'Disease', (147, 150))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('CDKN2A', 'Gene', (84, 90))	('p14', 'Gene', (143, 146))	('truncating mutation', 'Var', (57, 76))	('INK4A', 'Gene', (133, 138))	('HNSCC', 'Phenotype', 'HP:0012288', (22, 27))
42647	32859951	Mutations in or amplifications of PI3-kinase catalytic subunit alpha (PIK3CA) that can induce the overactivation of the AKT pathway are also frequently found in HNSCC patients.	('AKT', 'Gene', (120, 123))	('overactivation', 'MPA', (98, 112))	('PIK3CA', 'Gene', '5290', (70, 76))	('patients', 'Species', '9606', (167, 175))	('PIK3CA', 'Gene', (70, 76))	('Mutations', 'Var', (0, 9))	('AKT', 'Gene', '207', (120, 123))	('HNSCC', 'Disease', (161, 166))	('HNSCC', 'Phenotype', 'HP:0012288', (161, 166))	('amplifications', 'Var', (16, 30))	('found', 'Reg', (152, 157))
42648	32859951	In addition, TCGA Pan-Cancer Atlas analysis found amplifications of genes encoding EGFR and the cell cycle regulator Cyclin D1 in 11% and 24% of HNSCC patients, respectively.	('EGFR', 'Gene', '1956', (83, 87))	('Cancer', 'Phenotype', 'HP:0002664', (22, 28))	('Cancer', 'Disease', (22, 28))	('HNSCC', 'Disease', (145, 150))	('HNSCC', 'Phenotype', 'HP:0012288', (145, 150))	('Cancer', 'Disease', 'MESH:D009369', (22, 28))	('EGFR', 'Gene', (83, 87))	('patients', 'Species', '9606', (151, 159))	('Cyclin D1', 'Gene', '595', (117, 126))	('amplifications', 'Var', (50, 64))	('Cyclin D1', 'Gene', (117, 126))
42650	32859951	Consistent with the fact that HPV E6 and E7 proteins inactivate p53 and the p16-Cyclin D-RB pathway, alterations in the TP53 and CDKN2A genes are not frequent in HPV-positive HNSCC.	('inactivate', 'NegReg', (53, 63))	('HNSCC', 'Phenotype', 'HP:0012288', (175, 180))	('alterations', 'Var', (101, 112))	('p16', 'Gene', '1029', (76, 79))	('CDKN2A', 'Gene', (129, 135))	('CDKN2A', 'Gene', '1029', (129, 135))	('p16', 'Gene', (76, 79))	('p53', 'Gene', (64, 67))	('TP53', 'Gene', '7157', (120, 124))	('HNSCC', 'Disease', (175, 180))	('TP53', 'Gene', (120, 124))	('p53', 'Gene', '7157', (64, 67))
42651	32859951	By contrast, as in cervical cancer, genetic alterations of PI3-kinase signaling constitute a strong driver for HNSCC, independent of HPV involvement.	('HNSCC', 'Phenotype', 'HP:0012288', (111, 116))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('HNSCC', 'Disease', (111, 116))	('PI3-kinase signaling', 'Pathway', (59, 79))	('genetic alterations', 'Var', (36, 55))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('cancer', 'Disease', (28, 34))
42652	32859951	Mutations in the YAP gene are not frequent, but recurrent YAP1-MAML2 and YAP1-NUTM1 fusions have been identified as activators of Hippo-YAP pathway signaling in skin cancers and several other cancer types.	('Hippo', 'Gene', (130, 135))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('YAP1', 'Gene', (73, 77))	('skin cancers', 'Disease', (161, 173))	('YAP1', 'Gene', (58, 62))	('MAML2', 'Gene', '84441', (63, 68))	('cancer', 'Disease', (192, 198))	('skin cancers', 'Disease', 'MESH:D012878', (161, 173))	('Hippo', 'Gene', '37247', (130, 135))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('fusions', 'Var', (84, 91))	('cancers', 'Phenotype', 'HP:0002664', (166, 173))	('cancer', 'Disease', (166, 172))	('activators', 'PosReg', (116, 126))	('cancer', 'Disease', 'MESH:D009369', (192, 198))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('NUTM1', 'Gene', '256646', (78, 83))	('YAP', 'Gene', (17, 20))	('MAML2', 'Gene', (63, 68))	('NUTM1', 'Gene', (78, 83))	('skin cancers', 'Phenotype', 'HP:0008069', (161, 173))	('YAP1', 'Gene', '10413', (58, 62))	('YAP1', 'Gene', '10413', (73, 77))
42654	32859951	In HNSCC, YAP gene amplification predominates in HPV-negative tumors.	('HNSCC', 'Phenotype', 'HP:0012288', (3, 8))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('YAP gene', 'Gene', (10, 18))	('HPV-negative tumors', 'Disease', 'MESH:D030361', (49, 68))	('amplification', 'Var', (19, 32))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('HPV-negative tumors', 'Disease', (49, 68))
42659	32859951	The amplification of the TAZ gene is frequent in HNSCC and some other types of cancers (Fig.	('cancers', 'Disease', (79, 86))	('HNSCC', 'Phenotype', 'HP:0012288', (49, 54))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('HNSCC', 'Disease', (49, 54))	('frequent', 'Reg', (37, 45))	('TAZ', 'Gene', (25, 28))	('amplification', 'Var', (4, 17))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('cancers', 'Disease', 'MESH:D009369', (79, 86))
42662	32859951	Somatic loss-of-function mutation or deletion in the FAT1 gene is a recurrent event across human cancers, and HNSCC is one of the cancer types with the highest rate of alterations in this gene.	('cancers', 'Disease', 'MESH:D009369', (97, 104))	('cancers', 'Phenotype', 'HP:0002664', (97, 104))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('cancers', 'Disease', (97, 104))	('cancer', 'Disease', (97, 103))	('deletion', 'Var', (37, 45))	('HNSCC', 'Disease', (110, 115))	('cancer', 'Disease', (130, 136))	('mutation', 'Var', (25, 33))	('FAT1', 'Gene', '2195', (53, 57))	('cancer', 'Disease', 'MESH:D009369', (97, 103))	('HNSCC', 'Phenotype', 'HP:0012288', (110, 115))	('FAT1', 'Gene', (53, 57))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('loss-of-function', 'NegReg', (8, 24))	('human', 'Species', '9606', (91, 96))
42672	32859951	Phosphorylation by LATS1/2 can also induce proteasomal degradation of YAP and TAZ.	('LATS1/2', 'Gene', (19, 26))	('Phosphorylation', 'Var', (0, 15))	('LATS1/2', 'Gene', '9113;26524', (19, 26))	('induce', 'Reg', (36, 42))	('proteasomal degradation', 'MPA', (43, 66))
42689	32859951	Mutations in the NF2 gene cause neurofibromatosis type 2, a disorder characterized by the growth of noncancerous tumors in the nervous system.	('cause', 'Reg', (26, 31))	('neurofibromatosis', 'Disease', (32, 49))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (32, 49))	('NF2', 'Gene', '4771', (17, 20))	('neurofibromatosis', 'Disease', 'MESH:C537392', (32, 49))	('Mutations', 'Var', (0, 9))	('noncancerous tumors', 'Disease', 'MESH:D009369', (100, 119))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('noncancerous tumors', 'Disease', (100, 119))	('NF2', 'Gene', (17, 20))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
42698	32859951	Loss-of-function mutations and the deletion of the FAT1 genes may be associated with unrestrained activation of YAP in HNSCC.	('Loss-of-function', 'NegReg', (0, 16))	('YAP', 'MPA', (112, 115))	('FAT1', 'Gene', '2195', (51, 55))	('deletion', 'Var', (35, 43))	('HNSCC', 'Phenotype', 'HP:0012288', (119, 124))	('mutations', 'Var', (17, 26))	('FAT1', 'Gene', (51, 55))
42725	32859951	Thus, alterations in the upstream regulators of YAP/TAZ proteins, especially Hippo signaling, are the prime candidates to mediate the dysregulation of YAP and TAZ in cancer.	('alterations', 'Var', (6, 17))	('Hippo', 'Gene', (77, 82))	('cancer', 'Disease', (166, 172))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('Hippo', 'Gene', '37247', (77, 82))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))
42726	32859951	A recent study demonstrated that the deletion of Mob1a/b in mice rapidly induces the development of invasive OSCC through YAP hyperactivation.	('invasive OSCC', 'Disease', (100, 113))	('Mob1a/b', 'Gene', '232157', (49, 56))	('deletion', 'Var', (37, 45))	('YAP', 'CPA', (122, 125))	('induces', 'Reg', (73, 80))	('Mob1a/b', 'Gene', (49, 56))	('mice', 'Species', '10090', (60, 64))
42727	32859951	However, with the notable exception of the FAT1 gene, loss-of-function mutations or the deletion of the genes encoding Hippo components are not frequently observed in human HNSCCs or cervical cancers (Fig.	('HNSCCs or cervical cancers', 'Disease', 'MESH:D002583', (173, 199))	('Hippo', 'Gene', (119, 124))	('deletion', 'Var', (88, 96))	('cancers', 'Phenotype', 'HP:0002664', (192, 199))	('FAT1', 'Gene', '2195', (43, 47))	('HNSCC', 'Phenotype', 'HP:0012288', (173, 178))	('HNSCCs or cervical cancers', 'Disease', (173, 199))	('mutations', 'Var', (71, 80))	('FAT1', 'Gene', (43, 47))	('Hippo', 'Gene', '37247', (119, 124))	('human', 'Species', '9606', (167, 172))	('loss-of-function', 'NegReg', (54, 70))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))
42728	32859951	It is not known why somatic alterations in FAT1 are more frequent than alterations in the genes encoding the core Hippo kinases and their adapters in squamous cell carcinomas.	('squamous cell carcinomas', 'Disease', (150, 174))	('Hippo', 'Gene', '37247', (114, 119))	('alterations', 'Var', (28, 39))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (150, 174))	('FAT1', 'Gene', '2195', (43, 47))	('FAT1', 'Gene', (43, 47))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (150, 173))	('Hippo', 'Gene', (114, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (164, 173))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (150, 174))	('carcinomas', 'Phenotype', 'HP:0030731', (164, 174))
42729	32859951	The inactivation of FAT1 has previously been linked to the activation of WNT signaling.	('inactivation', 'Var', (4, 16))	('WNT signaling', 'Pathway', (73, 86))	('FAT1', 'Gene', '2195', (20, 24))	('activation', 'PosReg', (59, 69))	('FAT1', 'Gene', (20, 24))
42730	32859951	Currently, there is no conclusive experimental evidence that FAT1 genetic alterations contribute to HNSCC development through the overactivation of WNT signaling.	('overactivation', 'PosReg', (130, 144))	('HNSCC', 'Disease', (100, 105))	('HNSCC', 'Phenotype', 'HP:0012288', (100, 105))	('WNT signaling', 'Pathway', (148, 161))	('FAT1', 'Gene', '2195', (61, 65))	('FAT1', 'Gene', (61, 65))	('contribute', 'Reg', (86, 96))	('genetic alterations', 'Var', (66, 85))
42735	32859951	Studies using mouse models have demonstrated that the hyperactivation of YAP can induce tissue overgrowth and tumorigenesis.	('mouse', 'Species', '10090', (14, 19))	('overgrowth', 'Phenotype', 'HP:0001548', (95, 105))	('YAP', 'Gene', (73, 76))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('hyperactivation', 'Var', (54, 69))	('induce', 'Reg', (81, 87))	('tissue overgrowth', 'CPA', (88, 105))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
42736	32859951	Transgenic overexpression of a mutated version of YAP (YAP-S127A) free from LATS-mediated cytoplasmic retention causes dramatic overgrowth of multiple tissues.	('S127A', 'Mutation', 'rs762471803', (59, 64))	('overgrowth', 'PosReg', (128, 138))	('overgrowth', 'Phenotype', 'HP:0001548', (128, 138))	('overexpression', 'PosReg', (11, 25))	('mutated', 'Var', (31, 38))
42737	32859951	YAP-S127A overexpression in the mouse liver results in massive hepatomegaly, and long-term overexpression induces the formation of hepatocellular carcinomas.	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('YAP-S127A', 'Var', (0, 9))	('induces', 'Reg', (106, 113))	('hepatocellular carcinomas', 'Phenotype', 'HP:0001402', (131, 156))	('S127A', 'Mutation', 'rs762471803', (4, 9))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (131, 155))	('hepatomegaly', 'Phenotype', 'HP:0002240', (63, 75))	('carcinomas', 'Phenotype', 'HP:0030731', (146, 156))	('hepatocellular carcinomas', 'Disease', 'MESH:D006528', (131, 156))	('mouse', 'Species', '10090', (32, 37))	('hepatocellular carcinomas', 'Disease', (131, 156))	('overexpression', 'PosReg', (10, 24))	('hepatomegaly', 'Disease', 'MESH:D006529', (63, 75))	('hepatomegaly', 'Disease', (63, 75))
42738	32859951	In the intestine and skin, the expression of YAP-S127A expands the compartment of undifferentiated stem or progenitor cells.	('S127A', 'Mutation', 'rs762471803', (49, 54))	('YAP-S127A', 'Var', (45, 54))	('expands', 'PosReg', (55, 62))
42739	32859951	Dysplastic changes in the tongue epithelium were also observed after short-term overexpression of YAP-S127A in the basal cell layer of stratified epithelia.	('overexpression', 'PosReg', (80, 94))	('S127A', 'Mutation', 'rs762471803', (102, 107))	('YAP-S127A', 'Var', (98, 107))
42740	32859951	Tissue-specific knockout of the YAP and TAZ genes from the basal cell layer of the mouse skin suppresses the formation of papilloma and squamous cell carcinoma induced by chemical carcinogens.	('formation', 'CPA', (109, 118))	('mouse', 'Species', '10090', (83, 88))	('TAZ genes', 'Gene', (40, 49))	('knockout', 'Var', (16, 24))	('papilloma', 'Phenotype', 'HP:0012740', (122, 131))	('carcinoma', 'Phenotype', 'HP:0030731', (150, 159))	('YAP', 'Gene', (32, 35))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (136, 159))	('squamous cell carcinoma', 'Disease', (136, 159))	('papilloma', 'Disease', (122, 131))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (136, 159))	('suppresses', 'NegReg', (94, 104))	('papilloma', 'Disease', 'MESH:D010212', (122, 131))
42741	32859951	Remarkably, the activation of YAP in the tongue through inducible deletion of the Mob1a and Mob1b genes causes the development of carcinoma in situ within 2 weeks and invasive squamous cell carcinoma within 4 weeks.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (176, 199))	('activation', 'PosReg', (16, 26))	('Mob1a', 'Gene', (82, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (190, 199))	('carcinoma', 'Disease', 'MESH:D009369', (130, 139))	('invasive squamous cell carcinoma', 'Disease', 'MESH:D002294', (167, 199))	('Mob1b', 'Gene', (92, 97))	('Mob1a', 'Gene', '55233', (82, 87))	('invasive squamous cell carcinoma', 'Disease', (167, 199))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (130, 147))	('Mob1b', 'Gene', '92597', (92, 97))	('carcinoma', 'Disease', (190, 199))	('causes', 'Reg', (104, 110))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('carcinoma', 'Disease', 'MESH:D009369', (190, 199))	('deletion', 'Var', (66, 74))	('carcinoma', 'Disease', (130, 139))
42744	32859951	These findings indicate that the dysregulation of endogenous YAP is sufficient to drive tumorigenesis in the oral epithelium.	('dysregulation', 'Var', (33, 46))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor', 'Disease', (88, 93))	('YAP', 'Gene', (61, 64))	('drive', 'Reg', (82, 87))
42750	32859951	Cisplatin-resistant OSCC cell lines were shown to regain cisplatin sensitivity after YAP knockdown.	('cisplatin sensitivity', 'MPA', (57, 78))	('regain', 'PosReg', (50, 56))	('Cisplatin', 'Chemical', 'MESH:D002945', (0, 9))	('cisplatin', 'Chemical', 'MESH:D002945', (57, 66))	('knockdown', 'Var', (89, 98))
42752	32859951	An analysis of the intrinsic cetuximab sensitivity of HNSCC cell lines found that the amplification of the YAP locus is associated with cetuximab resistance.	('amplification', 'Var', (86, 99))	('associated with', 'Reg', (120, 135))	('cetuximab', 'Chemical', 'MESH:D000068818', (29, 38))	('cetuximab', 'Chemical', 'MESH:D000068818', (136, 145))	('HNSCC', 'Phenotype', 'HP:0012288', (54, 59))	('YAP locus', 'Gene', (107, 116))	('cetuximab resistance', 'MPA', (136, 156))
42755	32859951	A subgroup of HNSCC patients with YAP gene amplification and YAP overexpression showed worse prognosis across different HNSCC cohorts.	('gene amplification', 'Var', (38, 56))	('HNSCC', 'Phenotype', 'HP:0012288', (14, 19))	('YAP', 'Gene', (34, 37))	('patients', 'Species', '9606', (20, 28))	('HNSCC', 'Phenotype', 'HP:0012288', (120, 125))
42759	32859951	Most mutations in the NOTCH1 gene in TCGA HNSCC cohorts are considered inactivating, indicating a tumor suppressor role of NOTCH1.	('HNSCC', 'Phenotype', 'HP:0012288', (42, 47))	('NOTCH1', 'Gene', '4851', (22, 28))	('NOTCH1', 'Gene', (22, 28))	('NOTCH1', 'Gene', '4851', (123, 129))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('mutations', 'Var', (5, 14))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('NOTCH1', 'Gene', (123, 129))	('tumor', 'Disease', (98, 103))
42760	32859951	However, frequent activating NOTCH1 mutations have also been detected by analyses of Asian HNSCC patients.	('NOTCH1', 'Gene', (29, 35))	('Asian HNSCC', 'Disease', (85, 96))	('NOTCH1', 'Gene', '4851', (29, 35))	('mutations', 'Var', (36, 45))	('activating', 'PosReg', (18, 28))	('HNSCC', 'Phenotype', 'HP:0012288', (91, 96))	('patients', 'Species', '9606', (97, 105))
42766	32859951	A missense mutation in the TP53 gene is a widespread molecular event in HNSCC.	('TP53', 'Gene', '7157', (27, 31))	('TP53', 'Gene', (27, 31))	('HNSCC', 'Disease', (72, 77))	('HNSCC', 'Phenotype', 'HP:0012288', (72, 77))	('missense mutation', 'Var', (2, 19))
42767	32859951	Most of the mutations are inactivating, but some p53 mutants are thought to gain novel oncogenic function.	('p53', 'Gene', '7157', (49, 52))	('p53', 'Gene', (49, 52))	('gain', 'PosReg', (76, 80))	('mutants', 'Var', (53, 60))	('oncogenic function', 'CPA', (87, 105))
42768	32859951	YAP was shown to directly interact with mutant p53 proteins to regulate the activity of the transcription factor NF-Y.	('proteins', 'Protein', (51, 59))	('activity', 'MPA', (76, 84))	('NF-Y', 'Gene', (113, 117))	('regulate', 'Reg', (63, 71))	('mutant', 'Var', (40, 46))	('p53', 'Gene', (47, 50))	('p53', 'Gene', '7157', (47, 50))
42774	32859951	A recent study reported that p63 interacts with coamplified ACTL6A, a subunit of the chromatin-remodeling complex SWI/SNF.	('ACTL6A', 'Gene', '86', (60, 66))	('interacts', 'Interaction', (33, 42))	('p63', 'Gene', '8626', (29, 32))	('coamplified', 'Var', (48, 59))	('ACTL6A', 'Gene', (60, 66))	('p63', 'Gene', (29, 32))
42778	32859951	Genetic alterations in EGFR are relatively less frequent in HNSCC, but amplification of or mutation in PIK3CA is one of the most common oncogenic drivers in HNSCC.	('amplification of', 'Var', (71, 87))	('mutation', 'Var', (91, 99))	('PIK3CA', 'Gene', (103, 109))	('EGFR', 'Gene', '1956', (23, 27))	('HNSCC', 'Phenotype', 'HP:0012288', (60, 65))	('common', 'Reg', (129, 135))	('PIK3CA', 'Gene', '5290', (103, 109))	('HNSCC', 'Phenotype', 'HP:0012288', (157, 162))	('EGFR', 'Gene', (23, 27))
42779	32859951	Although the interaction between PI3-kinase signaling and YAP/TAZ in HNSCC has not been clearly addressed, activated PI3-kinase was shown to promote YAP activity by inactivating Hippo signaling in other epithelial cell lines (Fig.	('HNSCC', 'Phenotype', 'HP:0012288', (69, 74))	('Hippo', 'Gene', '37247', (178, 183))	('Hippo', 'Gene', (178, 183))	('inactivating', 'NegReg', (165, 177))	('PI3-kinase', 'Var', (117, 127))	('promote', 'PosReg', (141, 148))	('YAP activity', 'MPA', (149, 161))	('activated PI3-kinase', 'Var', (107, 127))
42781	32859951	Upon activation by ligand-bound EGFR, PI3-kinase recruits PDK1 to the plasma membrane, disrupting its interaction with the Hippo kinase complex.	('Hippo', 'Gene', (123, 128))	('activation', 'PosReg', (5, 15))	('EGFR', 'Gene', '1956', (32, 36))	('PI3-kinase', 'Var', (38, 48))	('PDK1', 'Gene', '5163', (58, 62))	('PDK1', 'Gene', (58, 62))	('EGFR', 'Gene', (32, 36))	('Hippo', 'Gene', '37247', (123, 128))	('disrupting', 'NegReg', (87, 97))	('interaction', 'Interaction', (102, 113))
42798	32859951	In addition, consistent with the physical interaction between YAP/TAZ and BRD4, the vulnerability of YAP/TAZ activity to BRD4 inhibitors has been demonstrated.	('BRD4', 'Gene', (74, 78))	('inhibitors', 'Var', (126, 136))	('BRD4', 'Gene', '23476', (121, 125))	('BRD4', 'Gene', '23476', (74, 78))	('BRD4', 'Gene', (121, 125))
42801	30876762	Therefore, this study aimed to explore whether the PLK1 inhibitor BI2536 is able to sensitize ESCC cells to cisplatin (DDP) and determine the underlying mechanisms.	('DDP', 'Gene', (119, 122))	('sensitize', 'Reg', (84, 93))	('BI2536', 'Var', (66, 72))	('cisplatin', 'Chemical', 'MESH:D002945', (108, 117))	('DDP', 'Gene', '1678', (119, 122))	('BI2536', 'Chemical', 'MESH:C518477', (66, 72))	('PLK1', 'Gene', (51, 55))
42802	30876762	Viability, clonogenicity, cell cycle distribution and apoptosis were assessed in ESCC cells treated with BI2536 or DDP alone or in combination.	('DDP', 'Gene', '1678', (115, 118))	('BI2536', 'Chemical', 'MESH:C518477', (105, 111))	('clonogenicity', 'CPA', (11, 24))	('cell cycle distribution', 'CPA', (26, 49))	('DDP', 'Gene', (115, 118))	('BI2536', 'Var', (105, 111))
42804	30876762	We found that the combination of BI2536 and DDP was synergistic in ESCC cells, which induced pyroptosis in ESCC cells at low doses.	('DDP', 'Gene', (44, 47))	('pyroptosis', 'MPA', (93, 103))	('BI2536', 'Chemical', 'MESH:C518477', (33, 39))	('induced', 'Reg', (85, 92))	('DDP', 'Gene', '1678', (44, 47))	('BI2536', 'Var', (33, 39))
42805	30876762	Mechanistic studies revealed that BI2536 significantly induced DNA damage and impaired the DNA damage repair pathway in DDP-treated cells both in vitro and in vivo.	('BI2536', 'Var', (34, 40))	('DNA damage', 'MPA', (63, 73))	('DDP', 'Gene', (120, 123))	('BI2536', 'Chemical', 'MESH:C518477', (34, 40))	('impaired', 'NegReg', (78, 86))	('DNA damage repair pathway', 'Pathway', (91, 116))	('DDP', 'Gene', '1678', (120, 123))	('induced', 'Reg', (55, 62))
42806	30876762	Interestingly, we found that co-treatment with BI2536 and DDP induced pyroptosis in ESCC cells depending on the caspase-3/GSDME pathway.	('BI2536', 'Var', (47, 53))	('GSDME', 'Chemical', '-', (122, 127))	('DDP', 'Gene', (58, 61))	('BI2536', 'Chemical', 'MESH:C518477', (47, 53))	('induced', 'Reg', (62, 69))	('caspase-3', 'Gene', (112, 121))	('DDP', 'Gene', '1678', (58, 61))	('pyroptosis', 'MPA', (70, 80))	('caspase-3', 'Gene', '836', (112, 121))
42808	30876762	BI2536 sensitizes ESCC cells to DDP by inhibiting the DNA damage repair pathway and inducing pyroptosis, which provides new information for understanding pyroptosis.	('BI2536', 'Chemical', 'MESH:C518477', (0, 6))	('pyroptosis', 'MPA', (93, 103))	('DDP', 'Gene', '1678', (32, 35))	('BI2536', 'Var', (0, 6))	('DNA damage repair pathway', 'Pathway', (54, 79))	('inducing', 'Reg', (84, 92))	('DDP', 'Gene', (32, 35))	('inhibiting', 'NegReg', (39, 49))
42809	30876762	Our study also reveals that the PLK1 inhibitor BI2536 may be an attractive candidate for ESCC targeted therapy, especially when combined with DDP for treating the GSDME overexpression subtype.	('BI2536', 'Var', (47, 53))	('PLK1', 'Gene', (32, 36))	('BI2536', 'Chemical', 'MESH:C518477', (47, 53))	('DDP', 'Gene', (142, 145))	('ESCC', 'Disease', (89, 93))	('GSDME', 'Chemical', '-', (163, 168))	('DDP', 'Gene', '1678', (142, 145))
42812	30876762	Lose-dose cisplatin combined with PLK1 inhibitor BI2536, could induce pyroptosis in GSDME-positive oesophageal squamous cell carcinoma cell lines.	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('oesophageal squamous cell carcinoma', 'Disease', 'MESH:D002294', (99, 134))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (111, 134))	('BI2536', 'Var', (49, 55))	('squamous cell carcinom', 'Phenotype', 'HP:0002860', (111, 133))	('induce', 'PosReg', (63, 69))	('GSDME', 'Chemical', '-', (84, 89))	('oesophageal squamous cell carcinoma', 'Disease', (99, 134))	('BI2536', 'Chemical', 'MESH:C518477', (49, 55))	('cisplatin', 'Chemical', 'MESH:D002945', (10, 19))	('pyroptosis', 'MPA', (70, 80))
42815	30876762	We therefore propose BI2536 could enhance the chemosensitivity of cisplatin, which could be a candidate as one of the new drug combination strategy for the clinical treatment of oesophageal squamous cell carcinoma.	('oesophageal squamous cell carcinoma', 'Disease', (178, 213))	('cisplatin', 'Chemical', 'MESH:D002945', (66, 75))	('chemosensitivity of cisplatin', 'MPA', (46, 75))	('carcinoma', 'Phenotype', 'HP:0030731', (204, 213))	('enhance', 'PosReg', (34, 41))	('BI2536', 'Var', (21, 27))	('oesophageal squamous cell carcinoma', 'Disease', 'MESH:D002294', (178, 213))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (190, 213))	('BI2536', 'Chemical', 'MESH:C518477', (21, 27))	('squamous cell carcinom', 'Phenotype', 'HP:0002860', (190, 212))
42819	30876762	Chemotherapy can cause death in multiple ways in tumour cells, one of which is pyroptosis.	('cause', 'Reg', (17, 22))	('tumour', 'Phenotype', 'HP:0002664', (49, 55))	('tumour', 'Disease', 'MESH:D009369', (49, 55))	('Chemotherapy', 'Var', (0, 12))	('tumour', 'Disease', (49, 55))
42829	30876762	BI2536 is an ATP-binding domain inhibitor of PLK1 that inhibits the kinase activity of PLK1 at low nanomolar concentrations.	('ATP', 'Chemical', 'MESH:D000255', (13, 16))	('inhibits', 'NegReg', (55, 63))	('BI2536', 'Var', (0, 6))	('kinase activity', 'MPA', (68, 83))	('BI2536', 'Chemical', 'MESH:C518477', (0, 6))	('PLK1', 'Protein', (87, 91))
42830	30876762	BI2536 treatment can induce apoptosis, which is caused by the activation of caspase-3.	('caspase-3', 'Gene', (76, 85))	('BI2536', 'Var', (0, 6))	('caspase-3', 'Gene', '836', (76, 85))	('apoptosis', 'CPA', (28, 37))	('BI2536', 'Chemical', 'MESH:C518477', (0, 6))	('activation', 'PosReg', (62, 72))
42831	30876762	PLK1 can directly phosphorylate pro-caspase-8 at S305, which inhibits its processing upon Fas stimulation.	('caspase-8', 'Gene', '841', (36, 45))	('processing upon Fas stimulation', 'MPA', (74, 105))	('caspase-8', 'Gene', (36, 45))	('PLK1', 'Gene', (0, 4))	('S305', 'Var', (49, 53))	('inhibits', 'NegReg', (61, 69))
42834	30876762	Therefore, we suspect that in tumour cells expressing high-level GSDME, combined treatment with BI2536 and the chemotherapy drug cisplatin can increase chemosensitivity.	('high-level GSDME', 'Var', (54, 70))	('GSDME', 'Chemical', '-', (65, 70))	('tumour', 'Disease', 'MESH:D009369', (30, 36))	('chemosensitivity', 'CPA', (152, 168))	('tumour', 'Disease', (30, 36))	('cisplatin', 'Chemical', 'MESH:D002945', (129, 138))	('BI2536', 'Var', (96, 102))	('GSDME', 'Var', (65, 70))	('increase', 'PosReg', (143, 151))	('BI2536', 'Chemical', 'MESH:C518477', (96, 102))	('tumour', 'Phenotype', 'HP:0002664', (30, 36))
42835	30876762	In this study, we demonstrated for the first time that low doses of the PLK1 inhibitor BI2536 combined with cisplatin can increase chemosensitivity by inducing pyroptosis in ESCC in vivo and in vitro, and these effects were dependent on the BAX/caspase-3/GSDME pathway.	('BI2536', 'Chemical', 'MESH:C518477', (87, 93))	('PLK1', 'Gene', (72, 76))	('inducing', 'Reg', (151, 159))	('BAX', 'Gene', '581', (241, 244))	('pyroptosis', 'MPA', (160, 170))	('caspase-3', 'Gene', (245, 254))	('BAX', 'Gene', (241, 244))	('cisplatin', 'Chemical', 'MESH:D002945', (108, 117))	('GSDME', 'Chemical', '-', (255, 260))	('caspase-3', 'Gene', '836', (245, 254))	('BI2536', 'Var', (87, 93))	('chemosensitivity', 'MPA', (131, 147))	('increase', 'PosReg', (122, 130))
42837	30876762	These findings raised the possibility that synergistically targeting PLK1 with DDP might be a promising strategy for ESCC treatment and that GSDME might serve as a molecular marker for these regimens.	('DDP', 'Gene', (79, 82))	('GSDME', 'Chemical', '-', (141, 146))	('synergistically', 'Var', (43, 58))	('ESCC', 'Disease', (117, 121))	('DDP', 'Gene', '1678', (79, 82))	('PLK1', 'Gene', (69, 73))
42838	30876762	The human oesophageal squamous cell carcinoma cell lines YES2, KYSE30, KYSE70, KYSE140, KYSE150, KYSE180, KYSE410, KYSE450 and KYSE510 were kindly provided by Dr. Y. Shimada (Kyoto University).	('squamous cell carcinom', 'Phenotype', 'HP:0002860', (22, 44))	('KYSE180', 'Var', (97, 104))	('KYSE70', 'Var', (71, 77))	('human', 'Species', '9606', (4, 9))	('oesophageal squamous cell carcinoma', 'Disease', (10, 45))	('YES2', 'Gene', (57, 61))	('KYSE140', 'Var', (79, 86))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (22, 45))	('KYSE410', 'Var', (106, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (36, 45))	('KYSE150', 'Var', (88, 95))	('KYSE30', 'Var', (63, 69))	('oesophageal squamous cell carcinoma', 'Disease', 'MESH:D002294', (10, 45))	('YES2', 'Gene', '7526', (57, 61))	('KYSE410', 'Chemical', '-', (106, 113))
42841	30876762	The PLK1 inhibitor BI2536 and DDP were purchased from Selleck (America).	('DDP', 'Gene', (30, 33))	('BI2536', 'Chemical', 'MESH:C518477', (19, 25))	('DDP', 'Gene', '1678', (30, 33))	('BI2536', 'Var', (19, 25))
42842	30876762	For the in vitro studies, BI2536 and DDP were prepared as 10 mmol/L stock solutions and stored at -20  C. BI2536 diluted in culture medium (20 nmol/L) and DDP diluted in culture medium (10 mumol/L) were prepared immediately before use.	('DDP', 'Gene', '1678', (155, 158))	('BI2536', 'Chemical', 'MESH:C518477', (26, 32))	('BI2536', 'Var', (106, 112))	('DDP', 'Gene', (155, 158))	('DDP', 'Gene', '1678', (37, 40))	('BI2536', 'Chemical', 'MESH:C518477', (106, 112))	('DDP', 'Gene', (37, 40))
42844	30876762	The antibodies used included cleaved-PARP (#5625), Bcl-2 (#3498), MCL-1 (#39224), caspase-8 (#9746), caspase-9 (#9502), Beclin 1 (#3738), P62 (#23214), LC3 A/B (#4108), phospho-Histono H3 (Ser10, #53348), PLK1 (#4513), phospho-PLK1 (Thr210, #9062), phospho-CDC25C (Ser216, #4901), CDC2 (#28439), phospho-CDC2 (Tyr15, #4539), WEE1 (#13084), phospho-WEE1 (Ser642, #4910), caspase-3 (#9665), cleaved caspase-3 (#9661),gammaH2AX (Ser139; #2577), phospho-BRCA1 (Ser1524, #9009), phospho-ATR (Ser428, #2853), E-cadherin (#14472), Ki-67 (#9027) and GAPDH (#51332), all of which were purchased from Cell Signaling Cytochrome C (ab13575), GSMDE (ab215191), CDC25C (ab32444), GSDMD (ab219800), TOPBP1 (ab2402), RAD51 (ab133534) and 53BP1 (ab36823) antibodies were purchased from Abcam (United Kingdom).	('BRCA1', 'Gene', '672', (450, 455))	('MCL-1', 'Gene', (66, 71))	('RAD51', 'Gene', (701, 706))	('WEE1', 'Gene', (348, 352))	('RAD51', 'Gene', '5888', (701, 706))	('BRCA1', 'Gene', (450, 455))	('Ki-67', 'Gene', '17345', (524, 529))	('P62', 'Gene', '23636', (138, 141))	('caspase-3', 'Gene', '836', (397, 406))	('caspase-8', 'Gene', (82, 91))	('Beclin 1', 'Gene', (120, 128))	('CDC2', 'Gene', '983', (648, 652))	('caspase-9', 'Gene', (101, 110))	('CDC2', 'Gene', (648, 652))	('LC3 A/B', 'Gene', '84557;81631', (152, 159))	('ATR', 'Gene', (482, 485))	('CDC2', 'Gene', (257, 261))	('PARP', 'Gene', (37, 41))	('Beclin 1', 'Gene', '8678', (120, 128))	('caspase-3', 'Gene', (397, 406))	('CDC2', 'Gene', '983', (257, 261))	('E-cadherin', 'Gene', (503, 513))	('E-cadherin', 'Gene', '999', (503, 513))	('TOPBP1', 'Gene', '11073', (684, 690))	('WEE1', 'Gene', '7465', (325, 329))	('CDC2', 'Gene', '983', (304, 308))	('CDC2', 'Gene', (304, 308))	('CDC2', 'Gene', '983', (281, 285))	('caspase-3', 'Gene', '836', (370, 379))	('GSDMD', 'Gene', '79792', (666, 671))	('Ki-67', 'Gene', (524, 529))	('CDC25C', 'Gene', (648, 654))	('P62', 'Gene', (138, 141))	('gammaH2AX', 'Gene', (415, 424))	('CDC2', 'Gene', (281, 285))	('Cytochrome C', 'Gene', (606, 618))	('Bcl-2', 'Gene', (51, 56))	('ab133534', 'Var', (708, 716))	('WEE1', 'Gene', '7465', (348, 352))	('TOPBP1', 'Gene', (684, 690))	('CDC25C', 'Gene', (257, 263))	('CDC25C', 'Gene', '995', (648, 654))	('53BP1', 'Gene', '7158', (722, 727))	('caspase-3', 'Gene', (370, 379))	('CDC25C', 'Gene', '995', (257, 263))	('GSDMD', 'Gene', (666, 671))	('caspase-8', 'Gene', '841', (82, 91))	('ATR', 'Gene', '545', (482, 485))	('MCL-1', 'Gene', '4170', (66, 71))	('Bcl-2', 'Gene', '596', (51, 56))	('53BP1', 'Gene', (722, 727))	('LC3 A/B', 'Gene', (152, 159))	('Cytochrome C', 'Gene', '54205', (606, 618))	('gammaH2AX', 'Gene', '15270', (415, 424))	('WEE1', 'Gene', (325, 329))	('caspase-9', 'Gene', '842', (101, 110))	('PARP', 'Gene', '1302', (37, 41))
42850	30876762	After treatment with BI2536, DDP or their combination for 24 h, 1 x 106 cells were collected, trypsinized, and fixed in 70% ethanol overnight.	('ethanol', 'Chemical', 'MESH:D000431', (124, 131))	('BI2536', 'Var', (21, 27))	('DDP', 'Gene', '1678', (29, 32))	('BI2536', 'Chemical', 'MESH:C518477', (21, 27))	('DDP', 'Gene', (29, 32))
42852	30876762	After treatment with clinically relevant doses of BI2536 (20 nmol/L) or DDP (10 mumol/L) alone or in combination for 24 h, cells were harvested in RIPA buffer (Beyotime, China).	('BI2536', 'Chemical', 'MESH:C518477', (50, 56))	('DDP', 'Gene', '1678', (72, 75))	('DDP', 'Gene', (72, 75))	('RIPA buffer', 'Chemical', '-', (147, 158))	('BI2536', 'Var', (50, 56))
42854	30876762	Cells treated with clinically relevant doses of BI2536 (20 nmol/L) or DDP (10 mumol/L) alone or in combination were placed on glass slides in 6-well plates.	('BI2536', 'Var', (48, 54))	('BI2536', 'Chemical', 'MESH:C518477', (48, 54))	('DDP', 'Gene', (70, 73))	('DDP', 'Gene', '1678', (70, 73))
42868	30876762	Next, 15 mg/kg BI2536 was injected intravenously twice a week, whereas 5 mg/kg DDP was injected intraperitoneally once a week as both single agents and in combination for 4 weeks.	('DDP', 'Gene', (79, 82))	('DDP', 'Gene', '1678', (79, 82))	('BI2536', 'Var', (15, 21))	('BI2536', 'Chemical', 'MESH:C518477', (15, 21))
42884	30876762	KYSE150 and KYSE510 were the cell lines least sensitive to DDP, so we used those two ESCC cell lines for further experiments.	('DDP', 'Gene', (59, 62))	('DDP', 'Gene', '1678', (59, 62))	('KYSE150', 'Var', (0, 7))	('KYSE510', 'Var', (12, 19))
42885	30876762	Then, we measured the cell viability by MTS assay at 72 h treated with BI2536 (1 nM to 100 muM, Supplementary file: Table S3).	('BI2536', 'Chemical', 'MESH:C518477', (71, 77))	('muM', 'Gene', (91, 94))	('BI2536', 'Var', (71, 77))	('muM', 'Gene', '56925', (91, 94))
42886	30876762	To evaluate whether the effects of BI2536 and DDP were synergic, we determined the CI values through the Chou-Talalay method for the cell lines in which the drug combination was found to be effective.	('DDP', 'Gene', (46, 49))	('BI2536', 'Var', (35, 41))	('DDP', 'Gene', '1678', (46, 49))	('BI2536', 'Chemical', 'MESH:C518477', (35, 41))
42888	30876762	1B), and these results suggest that BI2536 enhanced the cytotoxic effect of DDP in a low-dose combination.	('enhanced', 'PosReg', (43, 51))	('BI2536', 'Chemical', 'MESH:C518477', (36, 42))	('DDP', 'Gene', '1678', (76, 79))	('cytotoxic effect', 'CPA', (56, 72))	('DDP', 'Gene', (76, 79))	('BI2536', 'Var', (36, 42))
42889	30876762	Both PLK1 inhibitors and DDP have antitumour properties because they induce apoptosis, so we evaluated the effects of these two drugs on apoptosis by cell staining using flow cytometry.	('DDP', 'Gene', (25, 28))	('PLK1', 'Gene', (5, 9))	('tumour', 'Phenotype', 'HP:0002664', (38, 44))	('induce', 'Reg', (69, 75))	('tumour', 'Disease', 'MESH:D009369', (38, 44))	('DDP', 'Gene', '1678', (25, 28))	('inhibitors', 'Var', (10, 20))	('apoptosis', 'CPA', (76, 85))	('tumour', 'Disease', (38, 44))
42890	30876762	Compared with the single drug treatments, co-treatment with BI2536 and DDP for 24 h significantly increased cell apoptosis in both KYSE150 and KYSE510 cell lines (Fig.	('BI2536', 'Chemical', 'MESH:C518477', (60, 66))	('DDP', 'Gene', '1678', (71, 74))	('increased', 'PosReg', (98, 107))	('BI2536', 'Var', (60, 66))	('DDP', 'Gene', (71, 74))	('cell apoptosis', 'CPA', (108, 122))
42891	30876762	To explore whether co-treatment with BI2536 and DDP impairs the long-term clonogenic survival of ESCC cells, we performed colony assays for 14 days.	('BI2536', 'Chemical', 'MESH:C518477', (37, 43))	('DDP', 'Gene', '1678', (48, 51))	('DDP', 'Gene', (48, 51))	('BI2536', 'Var', (37, 43))	('impairs', 'NegReg', (52, 59))
42892	30876762	Compared to either BI2536 or DDP alone, BI2536 and DDP cooperated to repress the colony formation of ESCC cells (Fig.	('DDP', 'Gene', '1678', (51, 54))	('BI2536', 'Chemical', 'MESH:C518477', (40, 46))	('BI2536', 'Chemical', 'MESH:C518477', (19, 25))	('repress', 'NegReg', (69, 76))	('DDP', 'Gene', '1678', (29, 32))	('DDP', 'Gene', (51, 54))	('colony formation', 'CPA', (81, 97))	('BI2536', 'Var', (40, 46))	('DDP', 'Gene', (29, 32))
42893	30876762	These results indicated that BI2536 enhances the pro-apoptotic and anti-proliferative efficacy of DDP.	('anti-proliferative efficacy', 'CPA', (67, 94))	('BI2536', 'Chemical', 'MESH:C518477', (29, 35))	('enhances', 'PosReg', (36, 44))	('DDP', 'Gene', (98, 101))	('pro-apoptotic', 'CPA', (49, 62))	('DDP', 'Gene', '1678', (98, 101))	('BI2536', 'Var', (29, 35))
42894	30876762	Consistently, we found an increase in G2/M arrest in cells treated with BI2536 and DDP in combination compared to that in cells treated with DDP alone after 24 h (Fig.	('DDP', 'Gene', '1678', (83, 86))	('BI2536', 'Var', (72, 78))	('DDP', 'Gene', (141, 144))	('arrest', 'Disease', 'MESH:D006323', (43, 49))	('DDP', 'Gene', (83, 86))	('arrest', 'Disease', (43, 49))	('BI2536', 'Chemical', 'MESH:C518477', (72, 78))	('increase', 'PosReg', (26, 34))	('DDP', 'Gene', '1678', (141, 144))
42895	30876762	We found that the expression of molecules upstream and downstream of PLK1 was significantly altered in the group to which BI2536 was added (Supplementary file: Fig.	('BI2536', 'Chemical', 'MESH:C518477', (122, 128))	('expression of', 'MPA', (18, 31))	('altered', 'Reg', (92, 99))	('PLK1', 'Gene', (69, 73))	('BI2536', 'Var', (122, 128))
42896	30876762	These results support the hypothesis that ESCC cells treated with BI2536 had impaired cell cycle progression and proliferation.	('cell cycle progression', 'CPA', (86, 108))	('BI2536', 'Var', (66, 72))	('impaired', 'NegReg', (77, 85))	('BI2536', 'Chemical', 'MESH:C518477', (66, 72))	('proliferation', 'CPA', (113, 126))
42897	30876762	Notably, after 16 h of co-treatment with BI2536 and DDP, the dying cells became swollen with evident large bubbles extending from the plasma membrane (Fig.	('BI2536', 'Var', (41, 47))	('DDP', 'Gene', (52, 55))	('DDP', 'Gene', '1678', (52, 55))	('BI2536', 'Chemical', 'MESH:C518477', (41, 47))
42899	30876762	However, ESCC cells treated with BI2536 or DDP alone did not showed apparent pyroptotic morphological changes.	('BI2536', 'Var', (33, 39))	('BI2536', 'Chemical', 'MESH:C518477', (33, 39))	('DDP', 'Gene', (43, 46))	('DDP', 'Gene', '1678', (43, 46))
42900	30876762	Accordingly, these results indicated that BI2536 enhances the efficacy of DDP by inducing pyroptosis.	('BI2536', 'Var', (42, 48))	('efficacy', 'CPA', (62, 70))	('DDP', 'Gene', '1678', (74, 77))	('pyroptosis', 'CPA', (90, 100))	('BI2536', 'Chemical', 'MESH:C518477', (42, 48))	('enhances', 'PosReg', (49, 57))	('inducing', 'Reg', (81, 89))	('DDP', 'Gene', (74, 77))
42902	30876762	Given that BI2536 can intensify the pro-apoptotic effect of DDP, we sought to further explore the mechanism of combination therapy.	('pro-apoptotic effect', 'MPA', (36, 56))	('BI2536', 'Var', (11, 17))	('intensify', 'PosReg', (22, 31))	('DDP', 'Gene', '1678', (60, 63))	('BI2536', 'Chemical', 'MESH:C518477', (11, 17))	('DDP', 'Gene', (60, 63))
42903	30876762	We examined whether BI2536-induced apoptosis in ESCC cells exposed to DDP cytotoxicity is associated with the changes in apoptosis-related proteins, including cleaved-PARP, Bcl-2, BAX, MCL-1 and caspase-8.	('PARP', 'Gene', (167, 171))	('cytotoxicity', 'Disease', (74, 86))	('DDP', 'Gene', '1678', (70, 73))	('caspase-8', 'Gene', '841', (195, 204))	('apoptosis-related', 'MPA', (121, 138))	('Bcl-2', 'Gene', (173, 178))	('BI2536', 'Chemical', 'MESH:C518477', (20, 26))	('Bcl-2', 'Gene', '596', (173, 178))	('cytotoxicity', 'Disease', 'MESH:D064420', (74, 86))	('BI2536-induced', 'Var', (20, 34))	('DDP', 'Gene', (70, 73))	('BAX', 'Gene', '581', (180, 183))	('BAX', 'Gene', (180, 183))	('changes', 'Reg', (110, 117))	('MCL-1', 'Gene', '4170', (185, 190))	('caspase-8', 'Gene', (195, 204))	('PARP', 'Gene', '1302', (167, 171))	('MCL-1', 'Gene', (185, 190))
42906	30876762	These results suggest that BI2536 could indeed increase apoptosis in ESCC cell lines by promoting the caspase-8-mediated activation of the apoptotic pathway and activating PARP, which is a known response to caspase-3 activation.	('caspase-8', 'Gene', '841', (102, 111))	('activating', 'Reg', (161, 171))	('activation', 'MPA', (121, 131))	('PARP', 'Gene', '1302', (172, 176))	('BI2536', 'Var', (27, 33))	('caspase-3', 'Gene', (207, 216))	('PARP', 'Gene', (172, 176))	('apoptotic pathway', 'Pathway', (139, 156))	('promoting', 'PosReg', (88, 97))	('caspase-3', 'Gene', '836', (207, 216))	('apoptosis', 'CPA', (56, 65))	('BI2536', 'Chemical', 'MESH:C518477', (27, 33))	('caspase-8', 'Gene', (102, 111))
42908	30876762	These findings suggest that the pro-apoptotic effect of co-treatment with BI2536 and DDP is dependent on the caspase-8-mediated apoptosis pathway but not the mitochondrial apoptotic pathways or autophagy.	('caspase-8', 'Gene', '841', (109, 118))	('BI2536', 'Chemical', 'MESH:C518477', (74, 80))	('pro-apoptotic effect', 'CPA', (32, 52))	('DDP', 'Gene', '1678', (85, 88))	('BI2536', 'Var', (74, 80))	('caspase-8', 'Gene', (109, 118))	('DDP', 'Gene', (85, 88))
42912	30876762	The results showed that the level of cleaved caspase-3 was increased by BI2536 and DDP combination treatment but weakly induced by single agent treatment (Fig.	('DDP', 'Gene', '1678', (83, 86))	('caspase-3', 'Gene', '836', (45, 54))	('BI2536', 'Var', (72, 78))	('DDP', 'Gene', (83, 86))	('BI2536', 'Chemical', 'MESH:C518477', (72, 78))	('increased', 'PosReg', (59, 68))	('caspase-3', 'Gene', (45, 54))
42916	30876762	The morphological changes of the death cell in KYSE410 presented nucleus shrinkage, which was special in apoptosis (Supplementary file: Fig.	('nucleus', 'CPA', (65, 72))	('KYSE410', 'Chemical', '-', (47, 54))	('KYSE410', 'Var', (47, 54))
42917	30876762	These findings confirmed that the combination of BI2536 and DDP activated caspase-3 to induce the cleavage of GSDME in GSDME high expressed cell lines and thereby led to pyroptosis.	('cleavage', 'MPA', (98, 106))	('GSDME', 'Chemical', '-', (119, 124))	('GSDME', 'Gene', (110, 115))	('led to', 'Reg', (163, 169))	('pyroptosis', 'MPA', (170, 180))	('caspase-3', 'Gene', (74, 83))	('DDP', 'Gene', '1678', (60, 63))	('BI2536', 'Var', (49, 55))	('GSDME', 'Chemical', '-', (110, 115))	('caspase-3', 'Gene', '836', (74, 83))	('BI2536', 'Chemical', 'MESH:C518477', (49, 55))	('DDP', 'Gene', (60, 63))
42918	30876762	To confirm the ability of BI2536 to increase DDP-induced pyroptosis, we evaluated the co-expression of GSDME and E-cadherin by immunofluorescence.	('DDP', 'Gene', '1678', (45, 48))	('BI2536', 'Chemical', 'MESH:C518477', (26, 32))	('increase', 'PosReg', (36, 44))	('E-cadherin', 'Gene', (113, 123))	('GSDME', 'Chemical', '-', (103, 108))	('DDP', 'Gene', (45, 48))	('E-cadherin', 'Gene', '999', (113, 123))	('BI2536', 'Var', (26, 32))
42920	30876762	Compared to the control and DDP therapy cells groups, KYSE150 and KYSE510 cells treated with BI2536 and DDP for 24 h showed GSDME accumulation in the cytoplasm of those cells undergoing mitosis.	('DDP', 'Gene', '1678', (28, 31))	('BI2536', 'Chemical', 'MESH:C518477', (93, 99))	('DDP', 'Gene', '1678', (104, 107))	('accumulation', 'PosReg', (130, 142))	('mitosis', 'Disease', (186, 193))	('GSDME', 'MPA', (124, 129))	('DDP', 'Gene', (28, 31))	('mitosis', 'Disease', 'None', (186, 193))	('DDP', 'Gene', (104, 107))	('GSDME', 'Chemical', '-', (124, 129))	('BI2536', 'Var', (93, 99))
42924	30876762	We observed a very large fraction of cells that were positive for gamma-H2AX staining but negative for RAD51 staining after 24 h of treatment with BI2536 and DDP (Fig.	('RAD51', 'Gene', (103, 108))	('BI2536', 'Var', (147, 153))	('DDP', 'Gene', (158, 161))	('RAD51', 'Gene', '5888', (103, 108))	('gamma-H2AX', 'Gene', '15270', (66, 76))	('BI2536', 'Chemical', 'MESH:C518477', (147, 153))	('DDP', 'Gene', '1678', (158, 161))	('gamma-H2AX', 'Gene', (66, 76))
42925	30876762	These results suggested that BI2536 increased the DNA damage effect of DDP and decreased the DDR ability of ESCC cells.	('BI2536', 'Chemical', 'MESH:C518477', (29, 35))	('decreased', 'NegReg', (79, 88))	('DDP', 'Gene', '1678', (71, 74))	('increased', 'PosReg', (36, 45))	('BI2536', 'Var', (29, 35))	('DDP', 'Gene', (71, 74))	('DNA damage effect', 'MPA', (50, 67))	('DDR ability of ESCC cells', 'CPA', (93, 118))
42926	30876762	Single-cell gel electrophoresis or comet assays were performed to assess the DNA damage induced by BI2536 and DDP.	('DDP', 'Gene', '1678', (110, 113))	('BI2536', 'Chemical', 'MESH:C518477', (99, 105))	('comet', 'Species', '302767', (35, 40))	('DDP', 'Gene', (110, 113))	('BI2536', 'Var', (99, 105))
42929	30876762	The results showed that the DNA damage marker gammaH2AX was remarkably increased when cells were treated with both BI2536 and DDP, while this DNA damage marker was hardly detected in the control and single drug groups.	('DDP', 'Gene', (126, 129))	('gammaH2AX', 'Gene', (46, 55))	('BI2536', 'Var', (115, 121))	('increased', 'PosReg', (71, 80))	('DNA damage', 'MPA', (28, 38))	('BI2536', 'Chemical', 'MESH:C518477', (115, 121))	('DDP', 'Gene', '1678', (126, 129))	('gammaH2AX', 'Gene', '15270', (46, 55))
42933	30876762	Collectively, these results demonstrated that the combination of BI2536 and DDP inhibited the activation of the DDR pathway.	('DDP', 'Gene', '1678', (76, 79))	('DDR pathway', 'Pathway', (112, 123))	('BI2536', 'Var', (65, 71))	('DDP', 'Gene', (76, 79))	('BI2536', 'Chemical', 'MESH:C518477', (65, 71))	('inhibited', 'NegReg', (80, 89))
42934	30876762	To determine whether the induction of pyroptosis by the combination of BI2526 and DDP suppresses tumour growth in vivo, human KYSE150 cells were implanted subcutaneously into the right flanks of immunodeficient BALB/C nude mice.	('tumour', 'Disease', (97, 103))	('human', 'Species', '9606', (120, 125))	('DDP', 'Gene', (82, 85))	('BI', 'Chemical', 'MESH:D001729', (71, 73))	('nude mice', 'Species', '10090', (218, 227))	('DDP', 'Gene', '1678', (82, 85))	('suppresses', 'NegReg', (86, 96))	('tumour', 'Disease', 'MESH:D009369', (97, 103))	('tumour', 'Phenotype', 'HP:0002664', (97, 103))	('BI2526', 'Var', (71, 77))
42935	30876762	Then, the mouse xenograft models were treated with BI2536 (15 mg/kg) twice a week, DDP (5 mg/kg) once a week, or combination therapy, with PBS as a control.	('mouse', 'Species', '10090', (10, 15))	('DDP', 'Gene', '1678', (83, 86))	('BI2536', 'Var', (51, 57))	('DDP', 'Gene', (83, 86))	('BI2536', 'Chemical', 'MESH:C518477', (51, 57))	('PBS', 'Chemical', 'MESH:D007854', (139, 142))
42938	30876762	The lowest overall proliferation rate (Ki-67) and the highest levels of DNA damage (gamma-H2AX) and apoptosis or pyroptosis (cleaved caspase-3) were also observed in the combination group, further validating the improved anticancer efficiency of BI2536 plus DDP in mice bearing ESCC cells (Fig.	('Ki-67', 'Gene', '17345', (39, 44))	('cancer', 'Disease', (225, 231))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('caspase-3', 'Gene', '836', (133, 142))	('levels', 'MPA', (62, 68))	('BI2536', 'Chemical', 'MESH:C518477', (246, 252))	('caspase-3', 'Gene', (133, 142))	('Ki-67', 'Gene', (39, 44))	('gamma-H2AX', 'Gene', '15270', (84, 94))	('DDP', 'Gene', '1678', (258, 261))	('DNA', 'MPA', (72, 75))	('improved', 'PosReg', (212, 220))	('cancer', 'Disease', 'MESH:D009369', (225, 231))	('DDP', 'Gene', (258, 261))	('mice', 'Species', '10090', (265, 269))	('lowest', 'NegReg', (4, 10))	('gamma-H2AX', 'Gene', (84, 94))	('BI2536', 'Var', (246, 252))	('apoptosis', 'MPA', (100, 109))
42950	30876762	Considering these findings, we were interested in whether the PLK1 inhibitor BI2536 could sensitize tumour cells to DDP via inducing DNA damage.	('DDP', 'Gene', (116, 119))	('BI2536', 'Chemical', 'MESH:C518477', (77, 83))	('tumour', 'Phenotype', 'HP:0002664', (100, 106))	('inducing', 'Reg', (124, 132))	('tumour', 'Disease', 'MESH:D009369', (100, 106))	('DNA damage', 'MPA', (133, 143))	('DDP', 'Gene', '1678', (116, 119))	('tumour', 'Disease', (100, 106))	('BI2536', 'Var', (77, 83))
42951	30876762	In our study, we found that the PLK1 inhibitor BI2536 was able to sensitize cells to DDP, thus inducing more DNA damage and pyroptosis to kill the tumour cells.	('BI2536', 'Var', (47, 53))	('inhibitor BI2536', 'Var', (37, 53))	('PLK1', 'Gene', (32, 36))	('tumour', 'Phenotype', 'HP:0002664', (147, 153))	('BI2536', 'Chemical', 'MESH:C518477', (47, 53))	('tumour', 'Disease', 'MESH:D009369', (147, 153))	('DDP', 'Gene', '1678', (85, 88))	('DNA damage', 'MPA', (109, 119))	('inducing', 'PosReg', (95, 103))	('pyroptosis', 'CPA', (124, 134))	('tumour', 'Disease', (147, 153))	('DDP', 'Gene', (85, 88))
42958	30876762	One previous study showed that receiving monotherapy with another PLK1 inhibitor, B6727, led to DNA damage in small cell lung cancer by activating the ATM/ATR-Chk1/Chk2 checkpoint pathway.	('ATM', 'Gene', '472', (151, 154))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('Chk1', 'Gene', '1111', (159, 163))	('activating', 'PosReg', (136, 146))	('small cell lung cancer', 'Disease', 'MESH:D055752', (110, 132))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (110, 132))	('ATR', 'Gene', '545', (155, 158))	('ATM', 'Gene', (151, 154))	('small cell lung cancer', 'Disease', (110, 132))	('Chk2', 'Gene', '11200', (164, 168))	('lung cancer', 'Phenotype', 'HP:0100526', (121, 132))	('B6727', 'Var', (82, 87))	('ATR', 'Gene', (155, 158))	('Chk1', 'Gene', (159, 163))	('Chk2', 'Gene', (164, 168))
42959	30876762	Regrettably, several phase II trials showed that receiving monotherapy with BI2536 had limited antitumour activity and dose-limiting side effects in different types of cancers.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('tumour', 'Disease', 'MESH:D009369', (99, 105))	('tumour', 'Disease', (99, 105))	('BI2536', 'Var', (76, 82))	('cancers', 'Phenotype', 'HP:0002664', (168, 175))	('cancers', 'Disease', (168, 175))	('cancers', 'Disease', 'MESH:D009369', (168, 175))	('BI2536', 'Chemical', 'MESH:C518477', (76, 82))	('tumour', 'Phenotype', 'HP:0002664', (99, 105))
42960	30876762	Nevertheless, BI2536 exhibited impressive antitumour efficacy when combined with chemotherapy drugs in preclinical studies.	('BI2536', 'Chemical', 'MESH:C518477', (14, 20))	('tumour', 'Disease', (46, 52))	('BI2536', 'Var', (14, 20))	('tumour', 'Phenotype', 'HP:0002664', (46, 52))	('tumour', 'Disease', 'MESH:D009369', (46, 52))
42961	30876762	In triple-negative breast cancer, BI-2536 increased tumour cell sensitivity to combination chemotherapy with doxorubicin and cyclophosphamide.	('increased', 'PosReg', (42, 51))	('breast cancer', 'Phenotype', 'HP:0003002', (19, 32))	('doxorubicin', 'Chemical', 'MESH:D004317', (109, 120))	('cyclophosphamide', 'Chemical', 'MESH:D003520', (125, 141))	('tumour', 'Phenotype', 'HP:0002664', (52, 58))	('BI-2536', 'Var', (34, 41))	('tumour', 'Disease', 'MESH:D009369', (52, 58))	('BI', 'Chemical', 'MESH:D001729', (34, 36))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('breast cancer', 'Disease', 'MESH:D001943', (19, 32))	('tumour', 'Disease', (52, 58))	('breast cancer', 'Disease', (19, 32))
42962	30876762	In malignant peripheral nerve sheath tumours, BI2536 and gemcitabine were highly synergistic.	('BI2536', 'Chemical', 'MESH:C518477', (46, 52))	('tumours', 'Phenotype', 'HP:0002664', (37, 44))	('malignant peripheral nerve sheath tumours', 'Disease', 'MESH:D018319', (3, 44))	('malignant peripheral nerve sheath tumours', 'Disease', (3, 44))	('malignant peripheral nerve', 'Phenotype', 'HP:0100697', (3, 29))	('BI2536', 'Var', (46, 52))	('gemcitabine', 'Chemical', 'MESH:C056507', (57, 68))	('tumour', 'Phenotype', 'HP:0002664', (37, 43))
42963	30876762	In gastric cancer, BI2536 increased the anti-tumour of DDP in PLK1 overexpressed tumour cell, the Wnt/ beta -catenin and MEK/ERK/RSK1 signaling pathways changed under the co-treatment.	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('BI2536', 'Chemical', 'MESH:C518477', (19, 25))	('ERK', 'Gene', (125, 128))	('DDP', 'Gene', (55, 58))	('tumour', 'Phenotype', 'HP:0002664', (45, 51))	('tumour', 'Disease', 'MESH:D009369', (45, 51))	('tumour', 'Disease', (45, 51))	('ERK', 'Gene', '2048', (125, 128))	('gastric cancer', 'Phenotype', 'HP:0012126', (3, 17))	('tumour', 'Phenotype', 'HP:0002664', (81, 87))	('tumour', 'Disease', 'MESH:D009369', (81, 87))	('tumour', 'Disease', (81, 87))	('RSK1', 'Gene', (129, 133))	('MEK', 'Gene', '5609', (121, 124))	('increased', 'PosReg', (26, 35))	('gastric cancer', 'Disease', (3, 17))	('PLK1', 'Gene', (62, 66))	('BI2536', 'Var', (19, 25))	('beta -catenin', 'Gene', (103, 116))	('beta -catenin', 'Gene', '1499', (103, 116))	('RSK1', 'Gene', '6195', (129, 133))	('MEK', 'Gene', (121, 124))	('gastric cancer', 'Disease', 'MESH:D013274', (3, 17))	('DDP', 'Gene', '1678', (55, 58))
42965	30876762	Our study is the first to confirm that inhibiting PLK1 could enhance the chemosensitivity of ESCC cells to DDP.	('enhance', 'PosReg', (61, 68))	('DDP', 'Gene', '1678', (107, 110))	('PLK1', 'Gene', (50, 54))	('chemosensitivity', 'CPA', (73, 89))	('DDP', 'Gene', (107, 110))	('inhibiting', 'Var', (39, 49))
42968	30876762	The apoptosis induced by the combination treatment of BI2536 and DDP, however, is multi-factorial and complex.	('BI2536', 'Chemical', 'MESH:C518477', (54, 60))	('apoptosis', 'CPA', (4, 13))	('DDP', 'Gene', (65, 68))	('DDP', 'Gene', '1678', (65, 68))	('BI2536', 'Var', (54, 60))
42972	30876762	Thus, it was reasonable to speculate that the combination of BI2536 and DDP induced pyroptosis.	('BI2536', 'Var', (61, 67))	('DDP', 'Gene', '1678', (72, 75))	('BI2536', 'Chemical', 'MESH:C518477', (61, 67))	('DDP', 'Gene', (72, 75))	('pyroptosis', 'Disease', (84, 94))	('induced', 'Reg', (76, 83))
42973	30876762	We also observed that inhibiting PLK1 induced the upregulation and accumulation of GSDME surrounding the membrane in mitotic cells.	('PLK1', 'Gene', (33, 37))	('upregulation', 'PosReg', (50, 62))	('GSDME', 'Chemical', '-', (83, 88))	('inhibiting', 'Var', (22, 32))	('accumulation', 'PosReg', (67, 79))
42975	30876762	This finding led us to suspect that the inhibition of PLK1 might alter the metabolic pathways of GSDME in cells, and PLK1 inhibitor monotherapy at a high dosage could also induce pyroptosis.	('inhibitor', 'Var', (122, 131))	('inhibition', 'Var', (40, 50))	('PLK1', 'Gene', (117, 121))	('induce', 'Reg', (172, 178))	('pyroptosis', 'CPA', (179, 189))	('PLK1', 'Gene', (54, 58))	('GSDME', 'Chemical', '-', (97, 102))	('alter', 'Reg', (65, 70))	('metabolic pathways', 'Pathway', (75, 93))
42979	30876762	DNA damage induced by BI2536 and DDP activated the downstream apoptotic pathway.	('DDP', 'Gene', (33, 36))	('BI2536', 'Chemical', 'MESH:C518477', (22, 28))	('apoptotic pathway', 'Pathway', (62, 79))	('activated', 'PosReg', (37, 46))	('DDP', 'Gene', '1678', (33, 36))	('BI2536', 'Var', (22, 28))
42989	30876762	GSDME was also methylated in ER-positive breast cancer and was found to be associated with lymph node metastasis.	('associated with', 'Reg', (75, 90))	('breast cancer', 'Disease', 'MESH:D001943', (41, 54))	('GSDME', 'Chemical', '-', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('breast cancer', 'Disease', (41, 54))	('breast cancer', 'Phenotype', 'HP:0003002', (41, 54))	('lymph node metastasis', 'CPA', (91, 112))	('methylated', 'Var', (15, 25))
42994	30876762	In our study, when ESCC cells were treated with both BI2536 and DDP, GSDME, rather than GSDMD, played a role in pyroptosis.	('DDP', 'Gene', (64, 67))	('played', 'Reg', (95, 101))	('BI2536', 'Chemical', 'MESH:C518477', (53, 59))	('GSDME', 'Chemical', '-', (69, 74))	('GSDMD', 'Gene', (88, 93))	('GSDMD', 'Gene', '79792', (88, 93))	('DDP', 'Gene', '1678', (64, 67))	('BI2536', 'Var', (53, 59))	('pyroptosis', 'Disease', (112, 122))
42999	30876762	We hypothesized that high GSDME expression could be a good predictor for ESCC treatment.	('ESCC', 'Disease', (73, 77))	('GSDME', 'Protein', (26, 31))	('GSDME', 'Chemical', '-', (26, 31))	('high', 'Var', (21, 25))
43000	30876762	Patients with high GSDME expression might be more sensitive to the combination treatment of PLK1 inhibitor and DDP, and the antitumour effect of these drugs would be better.	('tumour', 'Disease', (128, 134))	('PLK1', 'Protein', (92, 96))	('combination', 'Interaction', (67, 78))	('DDP', 'Gene', '1678', (111, 114))	('more', 'PosReg', (45, 49))	('high', 'Var', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('tumour', 'Phenotype', 'HP:0002664', (128, 134))	('DDP', 'Gene', (111, 114))	('GSDME', 'Chemical', '-', (19, 24))	('sensitive', 'Reg', (50, 59))	('better', 'PosReg', (166, 172))	('tumour', 'Disease', 'MESH:D009369', (128, 134))
43001	30876762	It is reasonable to speculated that tumour cell with high GSDME expression was vulnerable to suffer pyroptosis when under endogenous or exogenous stresses.	('tumour', 'Disease', 'MESH:D009369', (36, 42))	('high GSDME expression', 'Var', (53, 74))	('tumour', 'Disease', (36, 42))	('GSDME', 'Chemical', '-', (58, 63))	('tumour', 'Phenotype', 'HP:0002664', (36, 42))
43003	30876762	In sum, our study revealed that the PLK1 inhibitor BI2536 may be an attractive candidate for ESCC treatment, especially when combined with DDP.	('PLK1', 'Gene', (36, 40))	('DDP', 'Gene', '1678', (139, 142))	('BI2536', 'Var', (51, 57))	('DDP', 'Gene', (139, 142))	('BI2536', 'Chemical', 'MESH:C518477', (51, 57))	('ESCC', 'Disease', (93, 97))
43004	30876762	Further investigations focusing on the potential antitumour activity of BI2536 and DDP could shed light on the benefit that patients could gain from receiving this well-tolerated chemotherapy regimen and could determine the relevance of GSDME expression to therapeutic effects.	('DDP', 'Gene', '1678', (83, 86))	('tumour', 'Disease', (53, 59))	('GSDME', 'Chemical', '-', (237, 242))	('BI2536', 'Var', (72, 78))	('gain', 'PosReg', (139, 143))	('DDP', 'Gene', (83, 86))	('BI2536', 'Chemical', 'MESH:C518477', (72, 78))	('tumour', 'Phenotype', 'HP:0002664', (53, 59))	('tumour', 'Disease', 'MESH:D009369', (53, 59))	('patients', 'Species', '9606', (124, 132))
43005	30876762	This work is supported by the  (2015CB553904),  (81490753, 81830086, 81702748 and 81802780),  (2017M620010), National Postdoctoral Program for Innovative Talent, Science Foundation of  (2017-27), "" Mission Plan (SML20181101), the (PKU2017RC001), Special Projects for Strengthening Basic Research of  (BMU2018JC006).	('PKU2017RC001', 'Disease', (232, 244))	('81802780', 'Var', (82, 90))	('PKU2017RC001', 'Disease', 'None', (232, 244))
43010	30991713	Mutations and copy number alterations in C1QBP were also analyzed using cBioPortal, and subsequently, the relationship between C1QBP expression and survival probability of cancer patients was explored using the PrognoScan database and the R2: Kaplan Meier Scanner.	('C1QBP', 'Gene', (127, 132))	('C1QBP', 'Gene', '708', (41, 46))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('C1QBP', 'Gene', (41, 46))	('Mutations', 'Var', (0, 9))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('patients', 'Species', '9606', (179, 187))	('cancer', 'Disease', (172, 178))	('C1QBP', 'Gene', '708', (127, 132))
43028	30991713	Moreover, ectopic expression of C1QBP enhances metastasis in melanoma cells.	('C1QBP', 'Gene', '708', (32, 37))	('melanoma', 'Phenotype', 'HP:0002861', (61, 69))	('melanoma', 'Disease', (61, 69))	('C1QBP', 'Gene', (32, 37))	('melanoma', 'Disease', 'MESH:D008545', (61, 69))	('ectopic expression', 'Var', (10, 28))	('enhances', 'PosReg', (38, 46))
43042	30991713	Expression of C1QBP was examined by each alteration status (deep deletion, shallow deletion, diploid, gain, and amplification) and plotted.	('C1QBP', 'Gene', (14, 19))	('deep deletion', 'Var', (60, 73))	('C1QBP', 'Gene', '708', (14, 19))	('shallow deletion', 'Var', (75, 91))
43074	30991713	C1QBP expression was positively associated with the copy number alteration status, significantly (ANOVA, p < 0.0001) (Figure 2e).	('copy number alteration status', 'Var', (52, 81))	('associated', 'Interaction', (32, 42))	('expression', 'MPA', (6, 16))	('C1QBP', 'Gene', '708', (0, 5))	('C1QBP', 'Gene', (0, 5))
43085	30991713	The proportion of genetic alterations (predominantly upregulation) in the C1QBP gene in LUAD (TCGA PanCanAtlas dataset) and LUSC (TCGA Provisional dataset) was around 4% (Figure 3d).	('genetic alterations', 'Var', (18, 37))	('LUSC', 'Phenotype', 'HP:0030359', (124, 128))	('C1QBP', 'Gene', '708', (74, 79))	('C1QBP', 'Gene', (74, 79))	('upregulation', 'PosReg', (53, 65))	('LUAD', 'Phenotype', 'HP:0030078', (88, 92))
43086	30991713	C1QBP mRNA expression showed a significant positive correlation with the copy number alteration status in LUSC (analysis based on TCGA Provisional dataset) (Figure 3e).	('positive', 'PosReg', (43, 51))	('copy number alteration', 'Var', (73, 95))	('mRNA expression', 'MPA', (6, 21))	('C1QBP', 'Gene', '708', (0, 5))	('LUSC', 'Phenotype', 'HP:0030359', (106, 110))	('C1QBP', 'Gene', (0, 5))
43087	30991713	The patient group with a high expression level of C1QBP mRNA showed significantly poor overall survival compared to the low expression group, as revealed by the analysis of the jacob-00182-HLM dataset, accessed from thePrognoScan database (Figure 3f, Supplementary Table S4).	('men', 'Species', '9606', (257, 260))	('overall survival', 'CPA', (87, 103))	('high expression level', 'Var', (25, 46))	('patient', 'Species', '9606', (4, 11))	('C1QBP', 'Gene', '708', (50, 55))	('poor', 'NegReg', (82, 86))	('C1QBP', 'Gene', (50, 55))
43088	30991713	Therefore, these results suggest that C1QBP expression, owing to copy number alterations, is upregulated in lung cancer tissues, and is positively correlated with patient poor survival.	('C1QBP', 'Gene', (38, 43))	('expression', 'MPA', (44, 54))	('lung cancer', 'Disease', 'MESH:D008175', (108, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('copy number alterations', 'Var', (65, 88))	('lung cancer', 'Disease', (108, 119))	('patient', 'Species', '9606', (163, 170))	('lung cancer', 'Phenotype', 'HP:0100526', (108, 119))	('upregulated', 'PosReg', (93, 104))	('C1QBP', 'Gene', '708', (38, 43))	('correlated', 'Reg', (147, 157))
43094	30991713	Alterations in the C1QBP gene (TCGA PanCanAtlas dataset) were found in COAD, mucinous adenocarcinoma of the colon and rectum (MACR), rectal adenocarcinoma (RAD), and colorectal adenocarcinoma (CA) (Figure 4c).	('rectal adenocarcinoma', 'Disease', 'MESH:D012004', (133, 154))	('carcinoma', 'Phenotype', 'HP:0030731', (145, 154))	('mucinous adenocarcinoma of the colon', 'Disease', (77, 113))	('C1QBP', 'Gene', '708', (19, 24))	('Alterations', 'Var', (0, 11))	('COAD', 'Disease', 'MESH:D029424', (71, 75))	('C1QBP', 'Gene', (19, 24))	('RAD', 'Disease', (156, 159))	('RAD', 'Disease', 'MESH:C535729', (156, 159))	('rectal adenocarcinoma', 'Disease', 'MESH:D012004', (170, 191))	('colorectal adenocarcinoma', 'Disease', (166, 191))	('mucinous adenocarcinoma of the colon', 'Disease', 'MESH:D002288', (77, 113))	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (166, 191))	('COAD', 'Disease', (71, 75))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (182, 191))	('rectal adenocarcinoma', 'Disease', (133, 154))	('adenocarcinoma of the colon', 'Phenotype', 'HP:0040276', (86, 113))
43096	30991713	There was a significant difference in C1QBP expression level between shallow deletions and diploid in the copy number alteration status in COAD, according to TCGA PanCanAtlas data-based analysis (Figure 4d).	('C1QBP', 'Gene', (38, 43))	('COAD', 'Disease', 'MESH:D029424', (139, 143))	('shallow deletions', 'Var', (69, 86))	('COAD', 'Disease', (139, 143))	('C1QBP', 'Gene', '708', (38, 43))
43098	30991713	These results suggest that colon cancers have significant C1QBP gene alterations related to augmented C1QBP expression, which are negatively correlated with overall survival in colon cancer patients.	('alterations', 'Var', (69, 80))	('colon cancers', 'Phenotype', 'HP:0003003', (27, 40))	('patients', 'Species', '9606', (190, 198))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('colon cancer', 'Disease', 'MESH:D015179', (27, 39))	('C1QBP', 'Gene', (102, 107))	('colon cancer', 'Phenotype', 'HP:0003003', (177, 189))	('cancers', 'Phenotype', 'HP:0002664', (33, 40))	('colon cancers', 'Disease', 'MESH:D015179', (27, 40))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('men', 'Species', '9606', (95, 98))	('C1QBP', 'Gene', '708', (102, 107))	('colon cancers', 'Disease', (27, 40))	('C1QBP', 'Gene', (58, 63))	('colon cancer', 'Disease', 'MESH:D015179', (177, 189))	('augmented', 'PosReg', (92, 101))	('colon cancer', 'Phenotype', 'HP:0003003', (27, 39))	('colon cancer', 'Disease', (177, 189))	('expression', 'MPA', (108, 118))	('C1QBP', 'Gene', '708', (58, 63))
43104	30991713	The expression level of C1QBP mRNA was positively correlated with copy number alteration status from diploid and amplification (Figure 5e).	('C1QBP', 'Gene', (24, 29))	('expression level', 'MPA', (4, 20))	('copy number alteration', 'Var', (66, 88))	('correlated', 'Reg', (50, 60))	('C1QBP', 'Gene', '708', (24, 29))
43114	30991713	Lymphoma patients' group with a high expression level of C1QBP mRNA showed significantly poor overall survival compared to the low expression group (Figure 6f).	('patients', 'Species', '9606', (9, 17))	('overall survival', 'CPA', (94, 110))	('C1QBP', 'Gene', '708', (57, 62))	('C1QBP', 'Gene', (57, 62))	('poor', 'NegReg', (89, 93))	('high expression level', 'Var', (32, 53))	('Lymphoma', 'Disease', 'MESH:D008223', (0, 8))	('Lymphoma', 'Phenotype', 'HP:0002665', (0, 8))	('Lymphoma', 'Disease', (0, 8))
43132	30991713	Level of C1QBP expression was positively correlated with copy number alterations and negatively correlated with patient survival in breast, lung, colon, and bladder cancers as well as lymphoma.	('C1QBP', 'Gene', '708', (9, 14))	('bladder cancers', 'Disease', 'MESH:D001749', (157, 172))	('colon', 'Disease', (146, 151))	('bladder cancers', 'Disease', (157, 172))	('copy number alterations', 'Var', (57, 80))	('patient', 'Species', '9606', (112, 119))	('lymphoma', 'Phenotype', 'HP:0002665', (184, 192))	('breast', 'Disease', (132, 138))	('correlated', 'Reg', (41, 51))	('correlated', 'Reg', (96, 106))	('C1QBP', 'Gene', (9, 14))	('cancers', 'Phenotype', 'HP:0002664', (165, 172))	('lymphoma', 'Disease', (184, 192))	('lymphoma', 'Disease', 'MESH:D008223', (184, 192))	('bladder cancers', 'Phenotype', 'HP:0009725', (157, 172))	('lung', 'Disease', (140, 144))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('bladder cancer', 'Phenotype', 'HP:0009725', (157, 171))	('negatively', 'NegReg', (85, 95))
43193	29465599	Epidermal growth factor receptor (EGFR) mutations are the major carcinogenic mechanism in non-tobacco induced lung cancers.	('carcinogenic', 'Disease', 'MESH:D063646', (64, 76))	('cancers', 'Phenotype', 'HP:0002664', (115, 122))	('carcinogenic', 'Disease', (64, 76))	('EGFR', 'Gene', (34, 38))	('Epidermal growth factor receptor', 'Gene', (0, 32))	('lung cancers', 'Disease', (110, 122))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('lung cancers', 'Phenotype', 'HP:0100526', (110, 122))	('mutations', 'Var', (40, 49))	('lung cancer', 'Phenotype', 'HP:0100526', (110, 121))	('lung cancers', 'Disease', 'MESH:D008175', (110, 122))	('tobacco', 'Species', '4097', (94, 101))	('Epidermal growth factor receptor', 'Gene', '1956', (0, 32))	('EGFR', 'Gene', '1956', (34, 38))
43194	29465599	The EGFR mutation frequency in Caucasian NSCLC patients is 15%, while East Asian patients nearly 50%.	('mutation', 'Var', (9, 17))	('NSCLC', 'Disease', (41, 46))	('EGFR', 'Gene', (4, 8))	('patients', 'Species', '9606', (47, 55))	('NSCLC', 'Disease', 'MESH:D002289', (41, 46))	('patients', 'Species', '9606', (81, 89))	('NSCLC', 'Phenotype', 'HP:0030358', (41, 46))	('EGFR', 'Gene', '1956', (4, 8))
43196	29465599	Liang et al reported 15 patients underwent mutational analysis of EGFR and all of them had wild type.	('EGFR', 'Gene', (66, 70))	('patients', 'Species', '9606', (24, 32))	('EGFR', 'Gene', '1956', (66, 70))	('mutational analysis', 'Var', (43, 62))
43197	29465599	Tam et al reported that 1 of 11 patients with EGFR mutation, while Liu et al investigated a total of 32 patients but no mutation in axons 19 and 21 was detected.	('patients', 'Species', '9606', (32, 40))	('EGFR', 'Gene', '1956', (46, 50))	('mutation', 'Var', (51, 59))	('EGFR', 'Gene', (46, 50))	('patients', 'Species', '9606', (104, 112))
43198	29465599	Liu et al reported 19 patients underwent surgery without EGFR mutation.	('EGFR', 'Gene', '1956', (57, 61))	('mutation', 'Var', (62, 70))	('patients', 'Species', '9606', (22, 30))	('EGFR', 'Gene', (57, 61))
43199	29465599	Lately, Chang et al reported that 17.4% (8/46) pulmonary LELC patients with EGFR mutations, but none was classical mutation site such as L858R in exon 21.	('L858R', 'Var', (137, 142))	('pulmonary LELC', 'Disease', (47, 61))	('EGFR', 'Gene', '1956', (76, 80))	('L858R', 'Mutation', 'rs121434568', (137, 142))	('EGFR', 'Gene', (76, 80))	('mutations', 'Var', (81, 90))	('patients', 'Species', '9606', (62, 70))
43200	29465599	Comparing to previous reports that nearly half of NSCLC patients in East Asian have EGFR mutations, pulmonary LELC patients with EGFR mutation is very rare.	('patients', 'Species', '9606', (56, 64))	('patients', 'Species', '9606', (115, 123))	('NSCLC', 'Phenotype', 'HP:0030358', (50, 55))	('EGFR', 'Gene', '1956', (84, 88))	('EGFR', 'Gene', '1956', (129, 133))	('NSCLC', 'Disease', (50, 55))	('mutations', 'Var', (89, 98))	('EGFR', 'Gene', (84, 88))	('EGFR', 'Gene', (129, 133))	('NSCLC', 'Disease', 'MESH:D002289', (50, 55))	('pulmonary LELC', 'Disease', (100, 114))
43203	29465599	A large cohort study reported lately shows that 1.8% (2/113) patients with EGFR mutation but none (0/113) with ALK fusion gene.	('ALK', 'Gene', '238', (111, 114))	('patients', 'Species', '9606', (61, 69))	('EGFR', 'Gene', '1956', (75, 79))	('EGFR', 'Gene', (75, 79))	('mutation', 'Var', (80, 88))	('ALK', 'Gene', (111, 114))
43217	29465599	Therefore, we believe that variation of plasma EBV DNA copy quantification in the plasma could be used as a useful tumor marker in pulmonary LELC.	('pulmonary LELC', 'Disease', (131, 145))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumor', 'Disease', (115, 120))	('variation', 'Var', (27, 36))	('EBV DNA', 'Gene', (47, 54))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
43230	27751760	Recent evidence suggests that T cell specificity for cancer cell expressed mutant proteins - termed neoantigens - is an important component of immune mediated tumor rejection.	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('tumor', 'Disease', (159, 164))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('mutant', 'Var', (75, 81))	('proteins', 'Protein', (82, 90))	('tumor', 'Disease', 'MESH:D009369', (159, 164))
43236	27751760	These tumor specific mutant antigens represent viable targets of the immune system underlying the recent successes in checkpoint based immunotherapies and have the potential for both greatly improved immune monitoring and the development of patient specific personalized vaccination.	('mutant', 'Var', (21, 27))	('patient', 'Species', '9606', (241, 248))	('tumor', 'Disease', 'MESH:D009369', (6, 11))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('tumor', 'Disease', (6, 11))
43259	27751760	TSMAs are the byproduct of cancer-specific genomic alterations that result in protein changes and, independent of protein function, persist during tumor clonal expansion.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('alterations', 'Var', (51, 62))	('tumor', 'Disease', (147, 152))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('protein changes', 'MPA', (78, 93))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('cancer', 'Disease', (27, 33))	('cancer', 'Disease', 'MESH:D009369', (27, 33))	('TSMAs', 'Disease', (0, 5))
43276	27751760	One exception to this was a study that used the CTL method and successfully identified a TSMA derived from a mutation in the CASP8 gene in a human oral cavity squamous cell carcinoma (OCSCC).	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (159, 182))	('carcinoma', 'Phenotype', 'HP:0030731', (173, 182))	('squamous cell carcinoma', 'Disease', (159, 182))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (159, 182))	('CASP8', 'Gene', '841', (125, 130))	('human', 'Species', '9606', (141, 146))	('CASP8', 'Gene', (125, 130))	('mutation', 'Var', (109, 117))
43277	27751760	As mutations in the CASP8 gene have been suggested to be driver mutations in HNSCCs, this finding represents an example of an ideal immunotherapy target:a protein critical for tumorigenesis that can be targeted by directed immunotherapy.	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('CASP8', 'Gene', (20, 25))	('CASP8', 'Gene', '841', (20, 25))	('tumor', 'Disease', (176, 181))	('HNSCCs', 'Disease', (77, 83))	('HNSCC', 'Phenotype', 'HP:0012288', (77, 82))	('mutations', 'Var', (3, 12))	('tumor', 'Disease', 'MESH:D009369', (176, 181))
43281	27751760	Whereas conventional thinking about cancer genomic changes focused on driver mutations that contribute to the hallmarks of cancer, Vogelstein and Allison instead proposed that all mutations are relevant for a given cancer depending on their respective affinity for HLA binding.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('mutations', 'Var', (180, 189))	('cancer', 'Disease', (215, 221))	('cancer', 'Disease', 'MESH:D009369', (215, 221))	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('cancer', 'Disease', (36, 42))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('cancer', 'Disease', (123, 129))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('HLA', 'Protein', (265, 268))
43288	27751760	Although less commonly utilized due to poor variant calling results, another approach used to further focus and improve sequence data is to capture RNA from tumor specimens and use this to construct a cDNA library for sequencing.This technique focuses only on those mutations in coding exons and eliminates the need for further RNA-sequencing to eliminate non-expressed mutations.	('tumor', 'Disease', (157, 162))	('mutations', 'Var', (266, 275))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))
43291	27751760	Two groups led by Ugur Sahin and Robert Schreiber independently used sequencing data and in silico neoepitope modeling to identify and validate TSMAs in murine B16-F10 melanoma and methylcholanthrene (MCA)-induced sarcoma cells, respectively.	('murine', 'Species', '10090', (153, 159))	('B16-F10', 'CellLine', 'CVCL:0159', (160, 167))	('sarcoma', 'Disease', 'MESH:D012509', (214, 221))	('methylcholanthrene', 'Chemical', 'MESH:D008748', (181, 199))	('sarcoma', 'Disease', (214, 221))	('TSMAs', 'Var', (144, 149))	('sarcoma', 'Phenotype', 'HP:0100242', (214, 221))	('melanoma', 'Phenotype', 'HP:0002861', (168, 176))	('melanoma', 'Disease', (168, 176))	('melanoma', 'Disease', 'MESH:D008545', (168, 176))
43294	27751760	Using cDNA capture and deep sequencing, it was discovered that a CD8+ T cell response specific for an antigen encoded by the mutant spectrin beta-2 gene was responsible for this immune-mediated tumor rejection.	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('mutant', 'Var', (125, 131))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('CD8', 'Gene', (65, 68))	('CD8', 'Gene', '925', (65, 68))	('tumor', 'Disease', (194, 199))	('spectrin beta-2', 'Gene', (132, 147))
43305	27751760	The patient was found to have CD4+ TIL specific to an epitope from a mutation in the erbb2 interacting protein gene (ERBB2IP).	('erbb2 interacting protein', 'Gene', (85, 110))	('erbb2 interacting protein', 'Gene', '55914', (85, 110))	('patient', 'Species', '9606', (4, 11))	('mutation', 'Var', (69, 77))	('ERBB2IP', 'Gene', (117, 124))	('ERBB2IP', 'Gene', '55914', (117, 124))	('CD4', 'Gene', (30, 33))	('CD4', 'Gene', '920', (30, 33))
43306	27751760	After an initial transfer containing about 25% mutation-specific T cells, the patient developed some decrease in tumor size and disease stabilization but ultimately her cancer progressed.	('tumor', 'Disease', (113, 118))	('cancer', 'Disease', (169, 175))	('patient', 'Species', '9606', (78, 85))	('mutation-specific', 'Var', (47, 64))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('disease stabilization', 'CPA', (128, 149))	('decrease', 'NegReg', (101, 109))	('cancer', 'Disease', 'MESH:D009369', (169, 175))
43312	27751760	In fact, studies have found that tumors with a greater number of nonsynonymous mutations are more likely to possess a higher load of mutation-derived neoepitopes and that immune responses to these epitopes correlate with clinical response.	('nonsynonymous mutations', 'Var', (65, 88))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('tumors', 'Disease', 'MESH:D009369', (33, 39))	('mutation-derived neoepitopes', 'MPA', (133, 161))	('tumors', 'Disease', (33, 39))
43313	27751760	Therefore, tumors with increased genomic instability, which are more likely to develop high numbers of mutations, should correspondingly express a greater number of neoantigens and be more likely to respond to checkpoint blockade.	('greater', 'PosReg', (147, 154))	('mutations', 'Var', (103, 112))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('tumors', 'Phenotype', 'HP:0002664', (11, 17))	('respond', 'Reg', (199, 206))	('neoantigens', 'MPA', (165, 176))	('tumors', 'Disease', (11, 17))	('tumors', 'Disease', 'MESH:D009369', (11, 17))	('checkpoint blockade', 'MPA', (210, 229))
43314	27751760	This was recently confirmed in a study of pembrolizumab in colorectal cancer patients with or without mismatch repair (MMR) deficiency, which results in a 10-100 fold increase in the number of somatic mutations.	('pembrolizumab', 'Chemical', 'MESH:C582435', (42, 55))	('colorectal cancer', 'Phenotype', 'HP:0003003', (59, 76))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('colorectal cancer', 'Disease', (59, 76))	('somatic mutations', 'MPA', (193, 210))	('patients', 'Species', '9606', (77, 85))	('deficiency', 'Var', (124, 134))	('increase', 'PosReg', (167, 175))	('colorectal cancer', 'Disease', 'MESH:D015179', (59, 76))
43316	27751760	This finding was further corroborated by a study of patients with recurrent glioblastoma multiforme (GBM) with biallelic mismatch repair deficiency (bMMRD), which confers an average of 17,740 mutations per tumor.	('glioblastoma', 'Phenotype', 'HP:0012174', (76, 88))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (76, 99))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('biallelic mismatch', 'Var', (111, 129))	('tumor', 'Disease', (206, 211))	('glioblastoma multiforme', 'Disease', (76, 99))	('tumor', 'Disease', 'MESH:D009369', (206, 211))	('patients', 'Species', '9606', (52, 60))
43328	27751760	Therapeutic neoantigen vaccines have begun entering phase I clinical trials in a small number of malignancies including glioblastoma (NCT02510950, NCT02287428), melanoma (NCT01970358), colon cancer (NCT01885702) and breast cancer (NCT02348320, NCT02427581).	('NCT02510950', 'Var', (134, 145))	('colon cancer', 'Phenotype', 'HP:0003003', (185, 197))	('malignancies', 'Disease', 'MESH:D009369', (97, 109))	('NCT02287428', 'Var', (147, 158))	('malignancies', 'Disease', (97, 109))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('NCT01885702', 'Var', (199, 210))	('colon cancer', 'Disease', 'MESH:D015179', (185, 197))	('melanoma', 'Disease', 'MESH:D008545', (161, 169))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('breast cancer', 'Phenotype', 'HP:0003002', (216, 229))	('glioblastoma', 'Disease', 'MESH:D005909', (120, 132))	('NCT02348320', 'Var', (231, 242))	('colon cancer', 'Disease', (185, 197))	('breast cancer', 'Disease', 'MESH:D001943', (216, 229))	('breast cancer', 'Disease', (216, 229))	('glioblastoma', 'Disease', (120, 132))	('glioblastoma', 'Phenotype', 'HP:0012174', (120, 132))	('NCT01970358', 'Var', (171, 182))	('melanoma', 'Phenotype', 'HP:0002861', (161, 169))	('melanoma', 'Disease', (161, 169))
43342	27751760	A second trial utilizes a vaccine targeting the p16/Ink4a protein (NCT01462838).	('p16', 'Gene', '1029', (48, 51))	('Ink4a', 'Gene', '1029', (52, 57))	('p16', 'Gene', (48, 51))	('Ink4a', 'Gene', (52, 57))	('NCT01462838', 'Var', (67, 78))
43349	27751760	It is now well established that the immune system can identify mutation-derived antigens on cancer cells and that these neoantigens represent viable targets for immunotherapies.	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('mutation-derived', 'Var', (63, 79))	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))
43356	24800179	While mutations in transmembrane channel-like 6 (TMC6 / EVER1) and 8 (TMC8 / EVER2) have been causally linked to EV, their molecular functions are unclear.	('EVER2', 'Gene', (77, 82))	('linked', 'Reg', (103, 109))	('EVER2', 'Gene', '147138', (77, 82))	('transmembrane channel-like 6', 'Gene', (19, 47))	('EVER1', 'Gene', (56, 61))	('EVER1', 'Gene', '11322', (56, 61))	('mutations', 'Var', (6, 15))	('transmembrane channel-like 6', 'Gene', '11322', (19, 47))
43400	24800179	Homozygous, invalidating mutations in either gene are found in roughly 75% of EV patients and confer susceptibility to EV.	('mutations', 'Var', (25, 34))	('susceptibility', 'Reg', (101, 115))	('patients', 'Species', '9606', (81, 89))
43402	24800179	A variant of the xeroderma pigmentosum type B (XPB) gene (ERCC3) on 2q21 was found in an EV patient without mutations in TMC6 or TMC8.	('patient', 'Species', '9606', (92, 99))	('ERCC3', 'Gene', '2071', (58, 63))	('variant', 'Var', (2, 9))	('found', 'Reg', (77, 82))	('xeroderma pigmentosum type B (XPB)', 'Gene', '2071', (17, 51))	('ERCC3', 'Gene', (58, 63))	('xeroderma pigmentosum type B (XPB', 'Gene', (17, 50))
43404	24800179	MST1 (macrophage stimulating 1/hepatocyte growth factor-like, or STK4, serine/threonine kinase 4) deficiency was also found to underlie susceptibility to EV-HPV infections.	('deficiency', 'Var', (98, 108))	('MST1', 'Gene', (0, 4))	('susceptibility', 'Reg', (136, 150))	('STK4', 'Gene', (65, 69))	('EV-HPV infections', 'Disease', 'MESH:D004819', (154, 171))	('MST1', 'Gene', '4485', (0, 4))	('EV-HPV infections', 'Disease', (154, 171))
43405	24800179	Located on 20q11.2-q13.2, mutations in this gene lead to T-cell deficiencies, particularly naive CD4+ and CD8+ T-cell lymphopenia.	('lymphopenia', 'Disease', (118, 129))	('T-cell deficiencies', 'Disease', (57, 76))	('CD8', 'Gene', (106, 109))	('lymphopenia', 'Phenotype', 'HP:0001888', (118, 129))	('CD4', 'Gene', (97, 100))	('CD8', 'Gene', '925', (106, 109))	('T-cell lymphopenia', 'Phenotype', 'HP:0005403', (111, 129))	('CD8+ T-cell lymphopenia', 'Phenotype', 'HP:0005415', (106, 129))	('mutations', 'Var', (26, 35))	('lymphopenia', 'Disease', 'MESH:D008231', (118, 129))	('T-cell deficiencies', 'Phenotype', 'HP:0005435', (57, 76))	('lead to', 'Reg', (49, 56))	('CD4', 'Gene', '920', (97, 100))	('T-cell deficiencies', 'Disease', 'MESH:D016399', (57, 76))
43407	24800179	Another mutation in 4p13, encoding the ras homolog gene family member H (RHOH), was also recently shown to cause T cell defects and susceptibility to EV-HPV infections.	('EV-HPV infections', 'Disease', (150, 167))	('RHOH', 'Gene', (73, 77))	('T cell defects', 'Disease', (113, 127))	('cause', 'Reg', (107, 112))	('EV-HPV infections', 'Disease', 'MESH:D004819', (150, 167))	('RHOH', 'Gene', '399', (73, 77))	('mutation', 'Var', (8, 16))	('T cell defects', 'Disease', 'MESH:D016399', (113, 127))	('susceptibility', 'Reg', (132, 146))
43409	24800179	A final case in an EV patient lacking TMC6 or TMC8 mutations identified defective apoptotic Fas function and a perforin (PRF1) missense mutation, which may contribute to decreased viral clearance through impaired T cell-mediated cytotoxicity.	('cytotoxicity', 'Disease', (229, 241))	('missense mutation', 'Var', (127, 144))	('apoptotic Fas function', 'CPA', (82, 104))	('impaired', 'NegReg', (204, 212))	('viral clearance', 'CPA', (180, 195))	('PRF1', 'Gene', '5551', (121, 125))	('cytotoxicity', 'Disease', 'MESH:D064420', (229, 241))	('PRF1', 'Gene', (121, 125))	('decreased', 'NegReg', (170, 179))	('defective', 'NegReg', (72, 81))	('patient', 'Species', '9606', (22, 29))
43411	24800179	This suggests a functional deficiency in the immune response specific to EV-HPVs, and/or to keratinocytes infected with these viruses.	('EV-HPVs', 'Var', (73, 80))	('functional deficiency', 'Disease', (16, 37))	('functional deficiency', 'Disease', 'OMIM:608852', (16, 37))	('functional deficiency in the immune response', 'Phenotype', 'HP:0002721', (16, 60))	('immune', 'MPA', (45, 51))	('EV-HPVs', 'Chemical', '-', (73, 80))
43416	24800179	In general, reports of impaired cell-mediated immunity (CMI) in several EV patients include reduced T-cell responsiveness to mitogens, and anergy to common skin antigens.	('anergy to common skin antigens', 'Phenotype', 'HP:0002965', (139, 169))	('cell-mediated immunity', 'CPA', (32, 54))	('reduced T-cell responsiveness to mitogens', 'Phenotype', 'HP:0031381', (92, 133))	('anergy', 'Var', (139, 145))	('impaired', 'NegReg', (23, 31))	('patients', 'Species', '9606', (75, 83))	('reduced T-cell', 'Phenotype', 'HP:0005403', (92, 106))	('T-cell responsiveness to mitogens', 'MPA', (100, 133))	('reduced', 'NegReg', (92, 99))
43430	24800179	beta-HPV types are more common than other HPV types in NMSC, but only a subset of beta-HPVs is typically associated with malignant conversion, namely, HPV5, as well as occasionally HPV8, 14, 17, 20, or 47.	('HPV', 'Species', '10566', (181, 184))	('HPV5', 'Disease', (151, 155))	('HPV', 'Species', '10566', (42, 45))	('HPV', 'Species', '10566', (87, 90))	('HPV8', 'Var', (181, 185))	('HPV', 'Species', '10566', (5, 8))	('malignant conversion', 'CPA', (121, 141))	('associated with', 'Reg', (105, 120))	('HPV', 'Species', '10566', (151, 154))
43433	24800179	UVB-specific mutations in p53 are seen in the majority of SCCs, with signature UV-induced C T mutations of the p53 gene and abnormal p53 protein expression also associated with EV tumor progression.	('EV tumor', 'Disease', 'MESH:D004819', (177, 185))	('SCC', 'Gene', (58, 61))	('SCC', 'Phenotype', 'HP:0002860', (58, 61))	('associated with', 'Reg', (161, 176))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('mutations', 'Var', (94, 103))	('p53', 'Gene', '7157', (133, 136))	('EV tumor', 'Disease', (177, 185))	('p53', 'Gene', (111, 114))	('SCC', 'Gene', '6317', (58, 61))	('p53', 'Gene', (26, 29))	('p53', 'Gene', '7157', (111, 114))	('expression', 'MPA', (145, 155))	('p53', 'Gene', '7157', (26, 29))	('p53', 'Gene', (133, 136))	('mutations', 'Var', (13, 22))	('protein', 'Protein', (137, 144))
43436	24800179	In addition to damaging keratinocyte DNA, UVB also suppresses the skin's immune system by inhibiting dendritic cells of the skin via the immunosuppressive cytokine interleukin-10 (IL-10).	('interleukin-10', 'Gene', '3586', (164, 178))	('skin', 'CPA', (66, 70))	('UVB', 'Var', (42, 45))	('IL-10', 'Gene', '3586', (180, 185))	('interleukin-10', 'Gene', (164, 178))	('suppresses', 'NegReg', (51, 61))	('inhibiting', 'NegReg', (90, 100))	('dendritic cells of the skin', 'CPA', (101, 128))	('IL-10', 'Gene', (180, 185))
43440	24800179	Others have found no inhibition of UVB-induced apoptosis in keratinocytes transduced with E6 and E7 of HPV5, HPV8, HPV14, HPV24, HPV36, HPV38, and HPV49, even after p53 reactivation.	('apoptosis', 'CPA', (47, 56))	('HPV36', 'Var', (129, 134))	('HPV', 'Species', '10566', (147, 150))	('HPV14', 'Var', (115, 120))	('HPV24', 'Var', (122, 127))	('HPV49', 'Var', (147, 152))	('HPV', 'Species', '10566', (115, 118))	('HPV', 'Species', '10566', (129, 132))	('HPV38', 'Var', (136, 141))	('p53', 'Gene', '7157', (165, 168))	('HPV', 'Species', '10566', (122, 125))	('HPV3', 'Species', '12086', (129, 133))	('HPV1', 'Species', '12080', (115, 119))	('HPV3', 'Species', '12086', (136, 140))	('HPV', 'Species', '10566', (136, 139))	('p53', 'Gene', (165, 168))	('HPV', 'Species', '10566', (103, 106))	('HPV5', 'Gene', (103, 107))	('HPV', 'Species', '10566', (109, 112))
43442	24800179	In addition to inadequate removal of cells by apoptosis, failure to repair damaged DNA can lead to the propagation of somatic mutations and ultimately, to carcinogenesis.	('failure', 'Var', (57, 64))	('lead to', 'Reg', (91, 98))	('carcinogenesis', 'Disease', 'MESH:D063646', (155, 169))	('carcinogenesis', 'Disease', (155, 169))
43455	24800179	These allelic disorders are caused by mutation of TMC1, the mouse ortholog also exhibiting dominant and recessive mutant alleles that cause hearing loss in the Beethoven (Bth) and deafness (dn) mutant mouse strains, respectively.	('Bth', 'Gene', (171, 174))	('deafness', 'Disease', 'MESH:D003638', (180, 188))	('Beethoven', 'Gene', (160, 169))	('TMC1', 'Gene', (50, 54))	('cause', 'Reg', (134, 139))	('Beethoven', 'Gene', '13409', (160, 169))	('hearing loss', 'Phenotype', 'HP:0000365', (140, 152))	('Bth', 'Gene', '13409', (171, 174))	('deafness', 'Phenotype', 'HP:0000365', (180, 188))	('mutant', 'Var', (114, 120))	('deafness', 'Disease', (180, 188))	('mutation', 'Var', (38, 46))	('caused by', 'Reg', (28, 37))	('hearing loss', 'Disease', (140, 152))	('mouse', 'Species', '10090', (201, 206))	('mouse', 'Species', '10090', (60, 65))	('dn', 'Phenotype', 'HP:0000365', (190, 192))	('hearing loss', 'Disease', 'MESH:D034381', (140, 152))
43460	24800179	The cochlear electrophysiologic phenotype of dn mutant mice is consistent with an ion channel defect, and tmc1 has been shown to encode a sodium-sensitive channel required for salt chemosensation in C. elegans.	('tmc1', 'Gene', (106, 110))	('C. elegans', 'Species', '6239', (199, 209))	('mice', 'Species', '10090', (55, 59))	('defect', 'NegReg', (94, 100))	('dn mutant', 'Var', (45, 54))	('dn', 'Phenotype', 'HP:0000365', (45, 47))	('tmc1', 'Gene', '13409', (106, 110))
43471	24800179	All EV-associated TMC6 and TMC8 mutations identified so far eliminate the conserved TMC domain, which is theorized to mediate molecular properties such as cellular ion homeostasis, signal transduction, or homotypic or heterotypic assembly into multimeric complexes.	('TMC', 'Gene', (84, 87))	('TMC', 'Gene', '3703', (27, 30))	('TMC', 'Gene', '3703', (18, 21))	('TMC', 'Gene', (27, 30))	('mutations', 'Var', (32, 41))	('cellular ion homeostasis', 'MPA', (155, 179))	('eliminate', 'NegReg', (60, 69))	('TMC', 'Gene', (18, 21))	('EV-associated', 'Disease', (4, 17))	('TMC', 'Gene', '3703', (84, 87))
43477	24800179	Although the link between TMC6 and TMC8 mutations and EV has now been well established, the molecular role(s) of TMCs in controlling the progression of the disease remains unclear.	('TMC8', 'Gene', (35, 39))	('mutations', 'Var', (40, 49))	('TMC6', 'Gene', (26, 30))	('TMCs', 'Chemical', 'MESH:C039293', (113, 117))
43481	24800179	This may have a pivotal effect on the HPV life cycle, as there are multiple AP-1 binding sites within the LCR of the HPV genome that enhance E6/E7 expression.	('enhance', 'PosReg', (133, 140))	('HPV', 'Species', '10566', (38, 41))	('expression', 'MPA', (147, 157))	('HPV', 'Species', '10566', (117, 120))	('E6/E7', 'Var', (141, 146))	('binding', 'Interaction', (81, 88))	('AP-1', 'Gene', (76, 80))
43485	24800179	It is proposed that in EV patients infected with E5-lacking beta-HPVs, mutations in TMC6 or TMC8 prevent ZnT-1 complex formation, making AP-1 and Zn2+ levels sufficient for viral transcription.	('TMC8', 'Gene', (92, 96))	('HPV', 'Species', '10566', (65, 68))	('Zn2+', 'Chemical', 'MESH:D015032', (146, 150))	('ZnT-1', 'Gene', (105, 110))	('TMC6', 'Gene', (84, 88))	('patients', 'Species', '9606', (26, 34))	('mutations', 'Var', (71, 80))	('making', 'Reg', (130, 136))	('prevent', 'NegReg', (97, 104))	('ZnT-1', 'Gene', '7779', (105, 110))
43486	24800179	However, it is unclear why EV patients with TMC6 or 8 mutations are not more prone to infection with genital HPV types.	('TMC6 or 8', 'Gene', (44, 53))	('prone to infection', 'Phenotype', 'HP:0002719', (77, 95))	('mutations', 'Var', (54, 63))	('infection', 'Disease', (86, 95))	('patients', 'Species', '9606', (30, 38))	('prone', 'Reg', (77, 82))	('infection', 'Disease', 'MESH:D007239', (86, 95))	('HPV', 'Species', '10566', (109, 112))
43488	24800179	It has been hypothesized that mutations in TMC6 or 8 downregulate CMI by decreasing the ability of cells to present EV-HPV antigen-derived peptides to T-lymphocytes triggering the clearance of HPV-infected keratinocytes.	('downregulate', 'NegReg', (53, 65))	('ability', 'MPA', (88, 95))	('HPV-infected', 'Disease', 'MESH:D030361', (193, 205))	('HPV-infected', 'Disease', (193, 205))	('CMI', 'Disease', (66, 69))	('clearance', 'CPA', (180, 189))	('TMC6', 'Gene', (43, 47))	('HPV', 'Species', '10566', (193, 196))	('HPV', 'Species', '10566', (119, 122))	('mutations', 'Var', (30, 39))	('decreasing', 'NegReg', (73, 83))
43496	24800179	Furthermore, the authors showed that a specific TMC8 polymorphism associated with persistence of beta-HPV, EV, and SCC was less effective in triggering TNFalpha-induced apoptosis.	('less', 'NegReg', (123, 127))	('TNFalpha', 'Gene', (152, 160))	('TMC8', 'Gene', (48, 52))	('SCC', 'Gene', (115, 118))	('SCC', 'Phenotype', 'HP:0002860', (115, 118))	('polymorphism', 'Var', (53, 65))	('triggering', 'Reg', (141, 151))	('HPV', 'Species', '10566', (102, 105))	('TNFalpha', 'Gene', '7124', (152, 160))	('SCC', 'Gene', '6317', (115, 118))
43500	24800179	The recent discoveries of several non-TMC mutations associated with EV have revealed functional deficiencies in base excision repair, T cells, keratinocyte proliferation/differentiation, and apoptosis.	('apoptosis', 'CPA', (191, 200))	('base excision repair', 'MPA', (112, 132))	('keratinocyte proliferation/differentiation', 'CPA', (143, 185))	('T cells', 'CPA', (134, 141))	('TMC', 'Gene', '3703', (38, 41))	('TMC', 'Gene', (38, 41))	('functional deficiencies', 'Disease', (85, 108))	('mutations', 'Var', (42, 51))	('functional deficiencies', 'Disease', 'OMIM:608852', (85, 108))
43501	24800179	It is tempting to speculate that TMC proteins may share some overlapping functionalities or phenotypes since mutations in TMC6 and 8 also result in EV pathology.	('TMC', 'Gene', '3703', (122, 125))	('TMC', 'Gene', (122, 125))	('EV pathology', 'Disease', (148, 160))	('mutations', 'Var', (109, 118))	('TMC', 'Gene', '3703', (33, 36))	('result in', 'Reg', (138, 147))	('TMC', 'Gene', (33, 36))
43507	32219437	Genetic manipulation of LKB1 elicits lethal metastatic prostate cancer This study unravels an unprecedented murine model of lethal metastatic prostate cancer, based on the combined deletion of Pten and Lkb1.	('LKB1', 'Gene', (24, 28))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('prostate cancer', 'Disease', (142, 157))	('prostate cancer', 'Disease', 'MESH:D011471', (142, 157))	('prostate cancer', 'Disease', 'MESH:D011471', (55, 70))	('LKB1', 'Gene', '20869', (24, 28))	('prostate cancer', 'Phenotype', 'HP:0012125', (55, 70))	('prostate cancer', 'Phenotype', 'HP:0012125', (142, 157))	('Lkb1', 'Gene', (202, 206))	('prostate cancer', 'Disease', (55, 70))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('elicits', 'Reg', (29, 36))	('deletion', 'Var', (181, 189))	('manipulation', 'Var', (8, 20))	('Pten', 'Gene', (193, 197))	('murine', 'Species', '10090', (108, 114))
43510	32219437	Here, we model an aggressive form of prostate cancer and show the unconventional association of LKB1 dosage to prostate tumorigenesis.	('LKB1', 'Gene', (96, 100))	('prostate tumor', 'Disease', 'MESH:D011471', (111, 125))	('prostate cancer', 'Disease', (37, 52))	('prostate cancer', 'Disease', 'MESH:D011471', (37, 52))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('dosage', 'Var', (101, 107))	('prostate tumor', 'Disease', (111, 125))	('prostate cancer', 'Phenotype', 'HP:0012125', (37, 52))	('prostate tumor', 'Phenotype', 'HP:0100787', (111, 125))
43511	32219437	Whereas loss of Lkb1 alone in the murine prostate epithelium was inconsequential for tumorigenesis, its combination with an oncogenic insult, illustrated by Pten heterozygosity, elicited lethal metastatic prostate cancer.	('prostate cancer', 'Phenotype', 'HP:0012125', (205, 220))	('tumor', 'Disease', (85, 90))	('prostate cancer', 'Disease', (205, 220))	('elicited', 'Reg', (178, 186))	('Lkb1', 'Gene', (16, 20))	('prostate cancer', 'Disease', 'MESH:D011471', (205, 220))	('murine', 'Species', '10090', (34, 40))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('loss', 'Var', (8, 12))	('combination', 'Interaction', (104, 115))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))
43512	32219437	Despite the low frequency of LKB1 deletion in patients, this event was significantly enriched in lung metastasis.	('lung metastasis', 'CPA', (97, 112))	('patients', 'Species', '9606', (46, 54))	('enriched', 'Reg', (85, 93))	('deletion', 'Var', (34, 42))	('LKB1', 'Gene', (29, 33))
43513	32219437	Modeling the role of LKB1 in cellular systems revealed that the residual activity retained in a reported kinase-dead form, LKB1K78I, was sufficient to hamper tumor aggressiveness and metastatic dissemination.	('hamper', 'NegReg', (151, 157))	('activity', 'MPA', (73, 81))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (158, 178))	('LKB1K78I', 'Var', (123, 131))	('aggressiveness', 'Phenotype', 'HP:0000718', (164, 178))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('tumor aggressiveness', 'Disease', (158, 178))
43527	32219437	proposed that genes with such functions would follow the two-hit hypothesis, according to which cancer would emerge upon the loss of the second allele in cells with carrying a mutated gene.	('loss', 'NegReg', (125, 129))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('mutated gene', 'Var', (176, 188))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Disease', (96, 102))
43530	32219437	In this study, we generate an unprecedented model of lethal metastatic PCa by introducing perturbations in Lkb1 in a precancerous setting and demonstrate the high competence of this kinase to suppress biological features of PCa.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('PCa', 'Phenotype', 'HP:0012125', (71, 74))	('biological', 'MPA', (201, 211))	('cancer', 'Disease', (120, 126))	('PCa', 'Disease', (224, 227))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('suppress', 'NegReg', (192, 200))	('PCa', 'Phenotype', 'HP:0012125', (224, 227))	('perturbations', 'Var', (90, 103))	('Lkb1', 'Gene', (107, 111))	('introducing', 'Reg', (78, 89))
43531	32219437	To ascertain the role of LKB1 in PCa, we engineered a series of Lkb1 prostate-specific mutant mice based on a conditional mouse model (Fig.	('Lkb1', 'Gene', (64, 68))	('PCa', 'Phenotype', 'HP:0012125', (33, 36))	('mutant', 'Var', (87, 93))	('mice', 'Species', '10090', (94, 98))	('mouse', 'Species', '10090', (122, 127))
43532	32219437	The survival of mice with prostate-specific Lkb1 (Lkb1pc-/-) deficiency was indistinguishable from that of control counterparts (Fig.	('Lkb1pc-/-', 'Gene', (50, 59))	('mice', 'Species', '10090', (16, 20))	('Lkb1pc-/-', 'Gene', '20869', (50, 59))	('deficiency', 'Var', (61, 71))
43537	32219437	PTLK mice exhibited PCa at full penetrance, whereas none of the other genotypes (Ptenpc+/- Lkb1pc+/+, Ptenpc+/- Lkb1pc+/-) presented lesions beyond PIN at the same age (Fig.	('Ptenpc+/- Lkb1pc+/-', 'Var', (102, 121))	('PCa', 'Disease', (20, 23))	('PCa', 'Phenotype', 'HP:0012125', (20, 23))	('Ptenpc+/- Lkb1pc+/+', 'Var', (81, 100))	('mice', 'Species', '10090', (5, 9))
43540	32219437	The results revealed a lack of this type of alteration in PCa compared with a compendium of datasets from lung adenocarcinoma, a tumor type with frequent alterations in LKB1 (Fig.	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (106, 125))	('PCa', 'Disease', (58, 61))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (106, 125))	('PCa', 'Phenotype', 'HP:0012125', (58, 61))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('LKB1', 'Gene', (169, 173))	('alterations', 'Var', (154, 165))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('tumor', 'Disease', (129, 134))	('lung adenocarcinoma', 'Disease', (106, 125))
43542	32219437	In this dataset, LKB1 heterozygosity was observed in 24.6% of cases (249 out of 1,013), whereas complete loss was restricted to 3.36% of specimens (34 of 1,013; Table S2), in turn suggesting that LKB1 is not a commonly aberrant tumor suppressor in the prostate.	('heterozygosity', 'Var', (22, 36))	('men', 'Species', '9606', (142, 145))	('LKB1', 'Gene', (17, 21))	('tumor', 'Disease', 'MESH:D009369', (228, 233))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('tumor', 'Disease', (228, 233))
43549	32219437	In this regard, we envision the perturbation in Pten used in the mouse model as an illustrative oncogenic signal that would unleash prostate cell proliferation and enable the emergence of Lkb1 loss-dependent phenotypes.	('prostate cell proliferation', 'CPA', (132, 159))	('mouse', 'Species', '10090', (65, 70))	('perturbation', 'Var', (32, 44))	('loss-dependent', 'NegReg', (193, 207))	('Lkb1', 'Gene', (188, 192))	('unleash', 'NegReg', (124, 131))	('Pten', 'Gene', (48, 52))	('unleash prostate', 'Phenotype', 'HP:0008687', (124, 140))
43560	32219437	We then compared the molecular features in PCa with intact Lkb1 (Ptenpc-/-, PIN or adenocarcinoma as indicated) or Lkb1 complete deletion (PTLK mice, squamous cell carcinoma).	('PCa', 'Disease', (43, 46))	('Lkb1', 'Gene', (115, 119))	('PCa', 'Phenotype', 'HP:0012125', (43, 46))	('mice', 'Species', '10090', (144, 148))	('adenocarcinoma', 'Disease', (83, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('Lkb1', 'Gene', (59, 63))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (150, 173))	('complete deletion', 'Var', (120, 137))	('carcinoma', 'Phenotype', 'HP:0030731', (164, 173))	('adenocarcinoma', 'Disease', 'MESH:D000230', (83, 97))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (150, 173))	('squamous cell carcinoma', 'Disease', (150, 173))
43570	32219437	In line with previous reports, DU145 cells lack LKB1 protein expression, due to a frameshift homozygous mutation (; Fig.	('frameshift', 'Var', (82, 92))	('LKB1', 'Gene', (48, 52))	('protein', 'Protein', (53, 60))	('lack', 'NegReg', (43, 47))	('DU145', 'CellLine', 'CVCL:0105', (31, 36))	('expression', 'MPA', (61, 71))
43572	32219437	S2 G), we observed a remarkable inhibition of migration, invasion, invasive growth, and anchorage-independent growth in both WT and K78I mutant LKB1-expressing cells (Fig.	('invasion', 'CPA', (57, 65))	('anchorage-independent growth', 'CPA', (88, 116))	('inhibition', 'NegReg', (32, 42))	('migration', 'CPA', (46, 55))	('LKB1-expressing', 'Gene', (144, 159))	('K78I', 'Mutation', 'p.K78I', (132, 136))	('invasive growth', 'CPA', (67, 82))	('K78I mutant', 'Var', (132, 143))
43574	32219437	The results with LKB1K78I were suggestive of an unprecedented kinase-independent tumor-suppressive activity.	('LKB1K78I', 'Var', (17, 25))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumor', 'Disease', (81, 86))
43575	32219437	By both coimmunoprecipitation coupled to Western blot and mass spectrometry analysis, we could demonstrate that LKB1WT and LKB1K78I presented equivalent protein interaction profiles with core components of its functional complex, including MO25, STE20-related adaptor, HSP90 and CDC37 (Fig.	('HSP90', 'Gene', '111042', (269, 274))	('K78I', 'Mutation', 'p.K78I', (127, 131))	('MO25', 'Gene', '12283', (240, 244))	('CDC37', 'Gene', (279, 284))	('CDC37', 'Gene', '12539', (279, 284))	('LKB1K78I', 'Var', (123, 131))	('STE20', 'Gene', '223255', (246, 251))	('STE20', 'Gene', (246, 251))	('LKB1WT', 'Var', (112, 118))	('HSP90', 'Gene', (269, 274))	('MO25', 'Gene', (240, 244))
43578	32219437	We hypothesized that, if the tumor suppressive activity of both LKB1 constructs relied on the sequestration of MO25, silencing this gene would mimic LKB1 expression and elicit tumor suppression.	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('silencing', 'Var', (117, 126))	('MO25', 'Gene', (111, 115))	('tumor', 'Disease', (176, 181))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('LKB1', 'Gene', (149, 153))	('sequestration', 'MPA', (94, 107))	('tumor', 'Disease', (29, 34))	('MO25', 'Gene', '12283', (111, 115))	('elicit', 'Reg', (169, 175))	('LKB1', 'Gene', (64, 68))	('tumor', 'Disease', 'MESH:D009369', (176, 181))	('expression', 'MPA', (154, 164))
43579	32219437	However, the silencing of this adaptor protein did not reduce two-dimensional or anchorage-independent growth (Fig.	('two-dimensional', 'CPA', (62, 77))	('men', 'Species', '9606', (68, 71))	('silencing', 'Var', (13, 22))
43580	32219437	The lack of evidence supporting a kinase-independent tumor suppressive function of LKB1 prompted us to carefully monitor the impact of K78I mutation on the activity of the kinase.	('LKB1', 'Gene', (83, 87))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('K78I', 'Var', (135, 139))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('K78I', 'Mutation', 'p.K78I', (135, 139))	('tumor', 'Disease', (53, 58))
43581	32219437	In line with our clinical observations, the phosphorylation of SIK1-3 was increased by LKB1WT and to a lower extent by the K78I mutant (Fig.	('K78I', 'Mutation', 'p.K78I', (123, 127))	('phosphorylation', 'MPA', (44, 59))	('LKB1WT', 'Gene', (87, 93))	('increased', 'PosReg', (74, 83))	('K78I', 'Var', (123, 127))	('SIK1-3', 'Gene', '17691;235344;70661', (63, 69))	('SIK1-3', 'Gene', (63, 69))
43582	32219437	To ascertain whether the residual activity of LKB1K78I is sufficient to exert tumor suppression, we generated a second mutant, harboring a nucleotidic change in the magnesium-binding domain (D194A) that we confirmed to be fully devoid of kinase activity (Fig.	('activity', 'MPA', (34, 42))	('LKB1K78I', 'Var', (46, 54))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('D194A', 'Mutation', 'p.D194A', (191, 196))	('tumor', 'Disease', (78, 83))	('magnesium', 'Chemical', 'MESH:D008274', (165, 174))	('D194A', 'Var', (191, 196))
43583	32219437	Importantly, compared with the deleted parental cells, the expression of LKB1D194A neither activated SIK1-3 nor influenced the signaling pattern or the biological response in vitro and in vivo, as opposed to LKB1WT or LKB1K78I mutant (Fig.	('SIK1-3', 'Gene', '17691;235344;70661', (101, 107))	('SIK1-3', 'Gene', (101, 107))	('K78I', 'Mutation', 'p.K78I', (222, 226))	('biological', 'MPA', (152, 162))	('influenced', 'Reg', (112, 122))	('LKB1D194A', 'Var', (73, 82))	('signaling pattern', 'MPA', (127, 144))
43584	32219437	Altogether, our results demonstrate that loss of LKB1 is associated with the emergence of squamous features in murine PCa and that the kinase requires minimal activity to suppress aggressive PCa features in cellular systems.	('PCa', 'Phenotype', 'HP:0012125', (118, 121))	('loss', 'Var', (41, 45))	('PCa', 'Phenotype', 'HP:0012125', (191, 194))	('LKB1', 'Gene', (49, 53))	('murine', 'Species', '10090', (111, 117))	('associated', 'Reg', (57, 67))	('squamous features', 'Disease', (90, 107))
43591	32219437	However, together with the in vitro assays, our data indicate that LKB1 deletion results in the acquisition of aggressiveness features, which would enable prostate tumor cells to gain access to the lung instead of the long metastatic process that underlies bone colonization.	('prostate tumor', 'Phenotype', 'HP:0100787', (155, 169))	('enable', 'Reg', (148, 154))	('results in', 'Reg', (81, 91))	('prostate tumor', 'Disease', 'MESH:D011471', (155, 169))	('aggressiveness', 'Disease', 'MESH:D001523', (111, 125))	('aggressiveness', 'Phenotype', 'HP:0000718', (111, 125))	('aggressiveness', 'Disease', (111, 125))	('prostate tumor', 'Disease', (155, 169))	('acquisition', 'PosReg', (96, 107))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('LKB1', 'Gene', (67, 71))	('deletion', 'Var', (72, 80))
43592	32219437	Lkb1 deletion is associated with the onset of metastatic disease in other tumor types when combined with perturbation of different cancer genes.	('cancer', 'Disease', (131, 137))	('deletion', 'Var', (5, 13))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('metastatic disease', 'Disease', (46, 64))	('associated with', 'Reg', (17, 32))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor', 'Disease', (74, 79))	('Lkb1', 'Gene', (0, 4))	('cancer', 'Disease', 'MESH:D009369', (131, 137))
43593	32219437	Overall, experimental evidence suggests that loss of LKB1 is not an initiating event in cancer, but rather an enhancer of aggressive features once oncogenic signaling is present.	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('enhancer', 'PosReg', (110, 118))	('men', 'Species', '9606', (15, 18))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('aggressive features', 'CPA', (122, 141))	('LKB1', 'Gene', (53, 57))	('loss', 'Var', (45, 49))
43596	32219437	The combination of Pten and Lkb1 deletion in the prostate epithelium performed in this study results in aggressive squamous cell prostate carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('results in', 'Reg', (93, 103))	('Pten', 'Gene', (19, 23))	('deletion', 'Var', (33, 41))	('aggressive squamous cell prostate carcinoma', 'Disease', (104, 147))	('aggressive squamous cell prostate carcinoma', 'Disease', 'MESH:D002294', (104, 147))	('Lkb1', 'Gene', (28, 32))	('prostate carcinoma', 'Phenotype', 'HP:0012125', (129, 147))
43599	32219437	In contrast, deletion in other tumor suppressors such as Tp53 predominantly favors luminal cell renewal and expansion.	('Tp53', 'Gene', '22059', (57, 61))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('expansion', 'CPA', (108, 117))	('luminal', 'Chemical', 'MESH:D010634', (83, 90))	('tumor', 'Disease', (31, 36))	('luminal cell renewal', 'CPA', (83, 103))	('deletion', 'Var', (13, 21))	('Tp53', 'Gene', (57, 61))	('favors', 'PosReg', (76, 82))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
43601	32219437	In addition, several studies report that Lkb1 deletion in different tissues predisposes to squamous lesions.	('deletion', 'Var', (46, 54))	('squamous lesions', 'Disease', (91, 107))	('squamous lesions', 'Disease', 'MESH:D000081483', (91, 107))	('Lkb1', 'Gene', (41, 45))	('predisposes', 'Reg', (76, 87))
43602	32219437	Specifically, combined deletion of Pten and Lkb1 in the lung was recently reported as the first bona fide mouse model of lung squamous cell carcinoma.	('Pten', 'Gene', (35, 39))	('deletion', 'Var', (23, 31))	('Lkb1', 'Gene', (44, 48))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (121, 149))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (121, 149))	('lung squamous cell carcinoma', 'Disease', (121, 149))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (126, 149))	('mouse', 'Species', '10090', (106, 111))
43603	32219437	Interestingly, the existence of compound LKB1 and PTEN deletions in human prostate tumors with squamous pathological and molecular features opens an avenue of research toward better understanding of this disease.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('prostate tumors', 'Disease', (74, 89))	('human', 'Species', '9606', (68, 73))	('LKB1', 'Gene', (41, 45))	('PTEN', 'Gene', (50, 54))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('prostate tumor', 'Phenotype', 'HP:0100787', (74, 88))	('prostate tumors', 'Disease', 'MESH:D011471', (74, 89))	('deletions', 'Var', (55, 64))
43606	32219437	The combined use of conditional mouse models and LKB1 mutant in cells in this study provides strong support for the notion that this kinase is a potent prostate tumor suppressor that can operate at very low doses.	('prostate tumor', 'Phenotype', 'HP:0100787', (152, 166))	('prostate tumor', 'Disease', (152, 166))	('LKB1', 'Gene', (49, 53))	('mouse', 'Species', '10090', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('prostate tumor', 'Disease', 'MESH:D011471', (152, 166))	('mutant', 'Var', (54, 60))
43607	32219437	Moreover, our analysis of the mutant LKB1K78I provides a feasible explanation for the discordance of our results with the elegant study performed by.	('K78I', 'Mutation', 'p.K78I', (41, 45))	('mutant', 'Var', (30, 36))	('LKB1K78I', 'Gene', (37, 45))
43608	32219437	Using a whole-body hypomorphic Lkb1 mutant mouse combined with systemic Pten heterozygous deletion, they observed that there was Lkb1 dose-dependent acceleration of various cancerous lesions.	('deletion', 'Var', (90, 98))	('Lkb1', 'Gene', (129, 133))	('cancerous lesions', 'Disease', 'MESH:D009369', (173, 190))	('acceleration', 'PosReg', (149, 161))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('mutant', 'Var', (36, 42))	('cancerous lesions', 'Disease', (173, 190))	('mouse', 'Species', '10090', (43, 48))	('Lkb1', 'Gene', (31, 35))
43612	32219437	We define standard competence as a continuum of reduction in tumor suppression capacity along with the dosage, which is recapitulated in the prostate phenotype of Pten mutant mice.	('mice', 'Species', '10090', (175, 179))	('mutant', 'Var', (168, 174))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('reduction', 'NegReg', (48, 57))	('tumor', 'Disease', (61, 66))	('Pten', 'Gene', (163, 167))
43613	32219437	We define low competence as a reduction of <50% when a tumor suppressor gene dose results in cancerous lesions, as reported in the mammary tissue with Pten mutants expressing 75% of Pten and at lower gene doses by others.	('cancerous lesions', 'Disease', 'MESH:D009369', (93, 110))	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('cancerous lesions', 'Disease', (93, 110))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('tumor', 'Disease', (55, 60))	('mutants', 'Var', (156, 163))	('Pten', 'Gene', (151, 155))	('Pten', 'Gene', (182, 186))
43617	32219437	Only complete deletion of this gene is associated with the pathogenesis of PCa, a genetic condition that turns a premalignant disease (PIN, typical of Pten+/- mice) into lethal metastatic PCa.	('PCa', 'Phenotype', 'HP:0012125', (75, 78))	('PCa', 'Phenotype', 'HP:0012125', (188, 191))	('associated', 'Reg', (39, 49))	('mice', 'Species', '10090', (159, 163))	('deletion', 'Var', (14, 22))	('PCa', 'Disease', (75, 78))
43625	32219437	The Cre recombinase expression, under the control of androgen-dependent ARR2B probasin promoter (Pb-Cre4), allowed the deletion of Pten in the prostate epithelium at puberty.	('deletion', 'Var', (119, 127))	('Pten', 'Gene', (131, 135))	('AR', 'Gene', '11835', (72, 74))
43629	32219437	DU145 cells expressing WT LKB1 (LKB1WT), LKB1 K78I (LKB1K78I), and LKB1 D194A (LKB1D194A) mutants were generated by retroviral gene transfer.	('D194A', 'Mutation', 'p.D194A', (72, 77))	('D194A', 'Mutation', 'p.D194A', (83, 88))	('mutants', 'Var', (90, 97))	('LKB1', 'Gene', (41, 45))	('DU145', 'CellLine', 'CVCL:0105', (0, 5))	('K78I', 'Mutation', 'p.K78I', (56, 60))	('K78I', 'Mutation', 'p.K78I', (46, 50))	('LKB1', 'Gene', (67, 71))	('LKB1', 'Gene', (26, 30))
43633	32219437	Lentiviral shRNA constructs targeting MO25alpha (TRCN0000044254; TRCN0000044256) were purchased from Sigma-Aldrich, and a scramble shRNA (hairpin sequence: 5'-CCGGCAACAAGATGAAGAGCACCAACTCGAGTTGGTGCTCTTCATCTTGTTG-3') was used as control.	('TRCN0000044256', 'Var', (65, 79))	('MO25alpha', 'Gene', '12283', (38, 47))	('MO25alpha', 'Gene', (38, 47))
43639	32219437	HEK293FT and C4-2 were generously provided by the laboratories of Rosa Barrio (CIC bioGUNE, Derio, Spain) and Pier Paolo Pandolfi, respectively.	('C4-2', 'Gene', '51654', (13, 17))	('C4-2', 'Gene', (13, 17))	('HEK293FT', 'CellLine', 'CVCL:6911', (0, 8))	('HEK293FT', 'Var', (0, 8))
43656	32219437	DU145 cells (pBABE, LKB1WT, LKB1K78I, and LKB1D194A; 4 x 106 cells per site) were resuspended in a final volume of 100 microl cold PBS supplemented with glucose (5 microM) mixed with 50 microl of Matrigel (Corning) and injected subcutaneously in two flanks per 6-12-wk-old male athymic nude mouse.	('men', 'Species', '9606', (141, 144))	('glucose', 'Chemical', 'MESH:D005947', (153, 160))	('cold PBS', 'Disease', (126, 134))	('DU145', 'CellLine', 'CVCL:0105', (0, 5))	('cold PBS', 'Disease', 'MESH:D011535', (126, 134))	('LKB1D194A', 'Var', (42, 51))	('mouse', 'Species', '10090', (291, 296))	('LKB1K78I', 'Var', (28, 36))
43665	32219437	Tissue sample collection (prostate gland, lymph nodes, long bones from lower limbs, lungs, and liver) was performed at 18 mo of age (LKB1pc+/+ and LKB1pc-/- mice) or 10 mo of age (Ptenpc+/- LKB1pc+/+, Ptenpc+/- LKB1pc+/-, and Ptenpc+/- LKB1pc-/-).	('LKB1pc-/-', 'Gene', '20869', (236, 245))	('mice', 'Species', '10090', (157, 161))	('LKB1pc-/-', 'Gene', (147, 156))	('Ptenpc+/- LKB1pc+/+', 'Var', (180, 199))	('lower limbs', 'Phenotype', 'HP:0006385', (71, 82))	('Ptenpc+/- LKB1pc+/-', 'Var', (201, 220))	('LKB1pc-/-', 'Gene', '20869', (147, 156))	('LKB1pc-/-', 'Gene', (236, 245))
43669	32219437	Prostatic lesions were histologically classified according to the criteria of the Consortium Prostate Pathology Committee and scored as 0, no lesion observed; 1, focal or multifocal low-grade PIN; 2, focal or multifocal high-grade PIN; 3, carcinoma affecting <50% of tissue; 4, carcinoma affecting >50% of tissue.	('carcinoma', 'Disease', (239, 248))	('carcinoma', 'Disease', 'MESH:D009369', (239, 248))	('carcinoma', 'Phenotype', 'HP:0030731', (239, 248))	('PIN; 2', 'Gene', (192, 198))	('carcinoma', 'Disease', (278, 287))	('Prostatic lesions', 'Disease', (0, 17))	('carcinoma', 'Disease', 'MESH:D009369', (278, 287))	('PIN; 2', 'Gene', '21749', (192, 198))	('Prostatic lesions', 'Disease', 'MESH:D011472', (0, 17))	('focal or multifocal high-grade PIN', 'Var', (200, 234))	('carcinoma', 'Phenotype', 'HP:0030731', (278, 287))
43673	32219437	Incubation with specific blocking serum for 30 min was followed by incubation with primary antibodies at 4 C overnight using the following concentrations: phospho-AMPK (CST, 2535, 1:50), phospho-S6 (CST, 4858, 1:500), p63 (Abcam, ab735, 1:100), and AR (Santa Cruz Biotechnology, N-20, 1:200).	('p63', 'Gene', '22061', (218, 221))	('phospho-AMPK', 'Var', (155, 167))	('p63', 'Gene', (218, 221))	('AR', 'Gene', '11835', (249, 251))
43683	32219437	Cells stably overexpressing LKB1 WT, K78I, or D194A mutants (FLAG-tagged), were used to immunoprecipitate anti-FLAG-agarose resin, in triplicate.	('K78I', 'Mutation', 'p.K78I', (37, 41))	('D194A', 'Mutation', 'p.D194A', (46, 51))	('LKB1', 'Gene', (28, 32))	('agarose', 'Chemical', 'MESH:D012685', (116, 123))	('K78I', 'Var', (37, 41))	('D194A', 'Var', (46, 51))
43687	32219437	All qRT-PCR data presented were normalized using GAPDH/Gapdh (Applied Biosystems, Hs02758991_g1, Mm99999915_g1).	('Mm99999915_g1', 'Var', (97, 110))	('GAPDH', 'Gene', '14433', (49, 54))	('Gapdh', 'Gene', '14433', (55, 60))	('Gapdh', 'Gene', (55, 60))	('GAPDH', 'Gene', (49, 54))	('Hs02758991_g1', 'Var', (82, 95))
43689	32219437	Antibodies used were phospho-AMPK substrate motif (CST 5759), phospho-ACC (CST 11818), phospho-AMPK (CST 2535), LKB1 (CST 3050), MO25alpha/CAB39 (CST 2716s), PTEN (CST 9559), phospho-Raptor (CST 2083), Raptor (CST 2280), beta-actin (CST 3700S), and HSP90 (CST 4874).	('CST 2535', 'Var', (101, 109))	('Raptor', 'Gene', '74370', (183, 189))	('CAB39', 'Gene', '12283', (139, 144))	('MO25alpha', 'Gene', '12283', (129, 138))	('CST', 'Var', (233, 236))	('HSP90', 'Gene', '111042', (249, 254))	('CST 3050', 'Var', (118, 126))	('CST 9559', 'Var', (164, 172))	('Raptor', 'Gene', (202, 208))	('CST 11818', 'Var', (75, 84))	('Raptor', 'Gene', '74370', (202, 208))	('CAB39', 'Gene', (139, 144))	('MO25alpha', 'Gene', (129, 138))	('CST', 'Var', (146, 149))	('CST', 'Var', (191, 194))	('HSP90', 'Gene', (249, 254))	('Raptor', 'Gene', (183, 189))	('CST 2280', 'Var', (210, 218))
43724	31461649	Loss of the PTEN protein phosphatase upregulates PDHK1 to induce aerobic glycolysis and PDHK1 cellular dependence.	('aerobic glycolysis', 'MPA', (65, 83))	('PDHK1', 'Gene', (49, 54))	('induce', 'PosReg', (58, 64))	('PDHK1', 'Gene', '5163', (49, 54))	('PDHK1', 'Gene', (88, 93))	('upregulates', 'PosReg', (37, 48))	('PTEN', 'Gene', (12, 16))	('PDHK1', 'Gene', '5163', (88, 93))	('Loss', 'Var', (0, 4))
43732	31461649	The modest clinical activity of PI3K and AKT inhibitors in PTEN-deficient cancers coupled with the existence of tumor-derived PTEN Y138 mutants, which specifically lack the protein phosphatase activity, suggest that protein phosphatase-dependent cellular processes may contribute to PTEN-mediated tumor suppression.	('lack', 'NegReg', (164, 168))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('cancers', 'Phenotype', 'HP:0002664', (74, 81))	('PTEN-deficient cancers', 'Disease', 'MESH:D006223', (59, 81))	('tumor', 'Disease', 'MESH:D009369', (297, 302))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('protein', 'Protein', (173, 180))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('AKT', 'Gene', '207', (41, 44))	('tumor', 'Phenotype', 'HP:0002664', (297, 302))	('PTEN-deficient cancers', 'Disease', (59, 81))	('mutants', 'Var', (136, 143))	('tumor', 'Disease', (112, 117))	('tumor', 'Disease', (297, 302))	('PTEN', 'Gene', (126, 130))	('AKT', 'Gene', (41, 44))
43735	31461649	Stable PTEN re-expression suppressed phospho-AKT levels (Figure 1A), as expected.	('suppressed', 'NegReg', (26, 36))	('re-expression', 'Var', (12, 25))	('AKT', 'Gene', (45, 48))	('AKT', 'Gene', '207', (45, 48))	('PTEN', 'Gene', (7, 11))
43739	31461649	Phosphorylation of PDHA1 inhibits PDC activity and blocks pyruvate entry into the tricarboxylic acid (TCA) cycle to uncouple glycolysis from the TCA cycle, contributing to the Warburg effect.	('uncouple glycolysis', 'Phenotype', 'HP:0004366', (116, 135))	('inhibits', 'NegReg', (25, 33))	('PDHA1', 'Gene', (19, 24))	('TCA', 'Chemical', 'MESH:D014233', (102, 105))	('Phosphorylation', 'Var', (0, 15))	('PDHA1', 'Gene', '5160', (19, 24))	('TCA', 'Chemical', 'MESH:D014233', (145, 148))	('tricarboxylic acid', 'Chemical', 'MESH:D014233', (82, 100))	('pyruvate', 'Chemical', 'MESH:D019289', (58, 66))	('Warburg effect', 'Disease', (176, 190))	('blocks', 'NegReg', (51, 57))	('uncouple glycolysis', 'MPA', (116, 135))	('PDC activity', 'MPA', (34, 46))	('contributing to', 'Reg', (156, 171))
43745	31461649	PDHK1 expression was increased upon PTEN silencing in cancer cells and normal (non-cancer) cells that are otherwise PTEN proficient, such as lung adenocarcinoma (HCC827, H1975) and non-cancer cells (Beas2B, HEK293T) (Figures 1C, 1D, and S1A; Table S1).	('HEK293T', 'CellLine', 'CVCL:0063', (207, 214))	('silencing', 'Var', (41, 50))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (141, 160))	('PTEN', 'Gene', (36, 40))	('non-cancer', 'Disease', (181, 191))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (141, 160))	('cancer', 'Disease', (185, 191))	('PDHK1', 'Gene', '5163', (0, 5))	('increased', 'PosReg', (21, 30))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('H1975', 'CellLine', 'CVCL:1511', (170, 175))	('PDHK1', 'Gene', (0, 5))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('carcinoma', 'Phenotype', 'HP:0030731', (151, 160))	('cancer', 'Disease', (54, 60))	('non-cancer', 'Disease', 'MESH:D009369', (79, 89))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('lung adenocarcinoma', 'Disease', (141, 160))	('Beas2B', 'CellLine', 'CVCL:0168', (199, 205))	('expression', 'MPA', (6, 16))	('non-cancer', 'Disease', (79, 89))	('non-cancer', 'Disease', 'MESH:D009369', (181, 191))	('cancer', 'Disease', (83, 89))
43751	31461649	By immunohistochemistry (IHC) analysis, we detected a significant inverse relationship between PDHK1 and PTEN expression levels in multiple human tumor types with frequent PTEN inactivation, including glioblastoma, prostate adenocarcinoma, and lung squamous cell carcinoma (Figures S2A-S2F).	('carcinoma', 'Phenotype', 'HP:0030731', (263, 272))	('tumor', 'Disease', (146, 151))	('tumor', 'Disease', 'MESH:D009369', (146, 151))	('glioblastoma', 'Disease', 'MESH:D005909', (201, 213))	('PTEN', 'Gene', (172, 176))	('carcinoma', 'Phenotype', 'HP:0030731', (229, 238))	('expression levels', 'MPA', (110, 127))	('inverse', 'NegReg', (66, 73))	('glioblastoma', 'Disease', (201, 213))	('prostate adenocarcinoma', 'Disease', (215, 238))	('PDHK1', 'Gene', '5163', (95, 100))	('glioblastoma', 'Phenotype', 'HP:0012174', (201, 213))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (244, 272))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('PDHK1', 'Gene', (95, 100))	('prostate adenocarcinoma', 'Disease', 'MESH:D011471', (215, 238))	('inactivation', 'Var', (177, 189))	('human', 'Species', '9606', (140, 145))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (244, 272))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (249, 272))	('lung squamous cell carcinoma', 'Disease', (244, 272))
43752	31461649	We found a strong association between PTEN inactivation and increased PDHK1 expression in a pan-cancer analysis across 12 different tumor types in The Cancer Genome Atlas (TCGA) dataset (Figure S2G).	('PDHK1', 'Gene', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('PDHK1', 'Gene', '5163', (70, 75))	('inactivation', 'Var', (43, 55))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('increased PDHK1 expression', 'Phenotype', 'HP:0003240', (60, 86))	('Cancer Genome Atlas', 'Disease', (151, 170))	('Cancer', 'Phenotype', 'HP:0002664', (151, 157))	('tumor', 'Disease', (132, 137))	('expression', 'MPA', (76, 86))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (151, 170))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Disease', (96, 102))	('increased', 'PosReg', (60, 69))	('PTEN', 'Gene', (38, 42))
43756	31461649	We investigated whether the PDHK1 upregulation induced by PTEN inactivation in cells is important for growth and survival.	('PDHK1', 'Gene', '5163', (28, 33))	('PTEN', 'Gene', (58, 62))	('inactivation', 'Var', (63, 75))	('PDHK1', 'Gene', (28, 33))	('upregulation', 'PosReg', (34, 46))
43757	31461649	By silencing PDHK1 (using shRNAs to knockdown PDHK1) in PTEN-deficient and PTEN-proficient cells (Figures 2A, 2B, S3A, and S3B), we found that PDHK1 was essential for the survival of PTEN-deficient but not PTEN-expressing normal and cancer cells.	('silencing', 'Var', (3, 12))	('PDHK1', 'Gene', '5163', (13, 18))	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('PDHK1', 'Gene', '5163', (143, 148))	('PDHK1', 'Gene', (46, 51))	('PDHK1', 'Gene', '5163', (46, 51))	('cancer', 'Disease', (233, 239))	('cancer', 'Disease', 'MESH:D009369', (233, 239))	('PDHK1', 'Gene', (13, 18))	('PDHK1', 'Gene', (143, 148))
43758	31461649	The synthetic lethality conferred upon by PDHK1 co-suppression with PTEN loss in PTEN-deficient cells was rescued by re-expression of shRNA-resistant PDHK1 (Figure 2C).	('loss', 'NegReg', (73, 77))	('synthetic lethality', 'MPA', (4, 23))	('PDHK1', 'Gene', '5163', (42, 47))	('PTEN', 'Gene', (68, 72))	('PDHK1', 'Gene', (150, 155))	('co-suppression', 'Var', (48, 62))	('PDHK1', 'Gene', '5163', (150, 155))	('PDHK1', 'Gene', (42, 47))
43762	31461649	PDHK1 knockdown significantly decreased survival in normal and cancer cells specifically during PTEN co-suppression (Figure 2D).	('PDHK1', 'Gene', '5163', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('PDHK1', 'Gene', (0, 5))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('knockdown', 'Var', (6, 15))	('PTEN', 'Gene', (96, 100))	('cancer', 'Disease', (63, 69))	('decreased', 'NegReg', (30, 39))	('survival', 'CPA', (40, 48))
43763	31461649	PDHK1 and PTEN co-suppression was lethal in cancer and normal cells, with evidence of enhanced apoptosis (Figures 2E and 2F).	('PDHK1', 'Gene', '5163', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('cancer', 'Disease', (44, 50))	('apoptosis', 'CPA', (95, 104))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('enhanced', 'PosReg', (86, 94))	('co-suppression', 'Var', (15, 29))	('PDHK1', 'Gene', (0, 5))	('PTEN', 'Gene', (10, 14))
43766	31461649	We investigated the underlying mechanisms of the observed synthetic lethality and apoptosis induction by PTEN and PDHK1 co-suppression in normal and cancer cells.	('cancer', 'Disease', (149, 155))	('apoptosis', 'CPA', (82, 91))	('PDHK1', 'Gene', (114, 119))	('co-suppression', 'Var', (120, 134))	('PTEN', 'Gene', (105, 109))	('PDHK1', 'Gene', '5163', (114, 119))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('synthetic lethality', 'CPA', (58, 77))	('cancer', 'Disease', 'MESH:D009369', (149, 155))
43773	31461649	We also found that the decreased cell viability upon PDHK1 inhibition in PTEN-deficient cells was rescued by the stable overexpression of anti-apoptotic factors Bcl-xL or Bcl2 (Figures S4E and S4F), which can prevent cell death by limiting loss of mitochondrial membrane potential, release of cytochrome c into the cytoplasm, and caspase activation.	('release', 'MPA', (282, 289))	('loss', 'NegReg', (240, 244))	('cytochrome c', 'Gene', (293, 305))	('activation', 'PosReg', (338, 348))	('mitochondrial membrane potential', 'MPA', (248, 280))	('caspase', 'Gene', '834;12371', (330, 337))	('Bcl-xL', 'Gene', '598', (161, 167))	('Bcl-xL', 'Gene', (161, 167))	('cell viability', 'CPA', (33, 47))	('PDHK1', 'Gene', (53, 58))	('Bcl2', 'Gene', '596', (171, 175))	('cytochrome c', 'Gene', '54205', (293, 305))	('inhibition', 'Var', (59, 69))	('PDHK1', 'Gene', '5163', (53, 58))	('caspase', 'Gene', (330, 337))	('decreased', 'NegReg', (23, 32))	('Bcl2', 'Gene', (171, 175))
43778	31461649	We explored the functional consequences of PDHK1 upregulation induced by PTEN inactivation.	('inactivation', 'Var', (78, 90))	('PTEN', 'Gene', (73, 77))	('PDHK1', 'Gene', (43, 48))	('PDHK1', 'Gene', '5163', (43, 48))	('upregulation', 'PosReg', (49, 61))
43782	31461649	Silencing PTEN in cells induced L-lactate secretion, a hallmark of aerobic glycolysis (Figure S6A).	('induced', 'Reg', (24, 31))	('Silencing', 'Var', (0, 9))	('L-lactate secretion', 'MPA', (32, 51))	('L-lactate', 'Chemical', '-', (32, 41))	('PTEN', 'Gene', (10, 14))
43785	31461649	These data suggest that PDHK1 upregulation and activation that occurs upon loss of PTEN promotes aerobic glycolysis in cells.	('promotes', 'PosReg', (88, 96))	('aerobic glycolysis', 'MPA', (97, 115))	('PDHK1', 'Gene', '5163', (24, 29))	('activation', 'PosReg', (47, 57))	('upregulation', 'PosReg', (30, 42))	('PDHK1', 'Gene', (24, 29))	('loss', 'Var', (75, 79))	('PTEN', 'Gene', (83, 87))
43788	31461649	Because increased PDHK1 promoted aerobic glycolysis in PTEN-deficient cells (Figure S6B), we tested whether PTEN inactivation enhances cellular glucose dependence, a hallmark of aerobic glycolysis.	('PDHK1', 'Gene', (18, 23))	('glucose dependence', 'Disease', (144, 162))	('aerobic glycolysis', 'MPA', (33, 51))	('glucose dependence', 'Disease', 'MESH:D019966', (144, 162))	('PDHK1', 'Gene', '5163', (18, 23))	('increased', 'PosReg', (8, 17))	('enhances', 'PosReg', (126, 134))	('promoted', 'PosReg', (24, 32))	('tested', 'Reg', (93, 99))	('inactivation', 'Var', (113, 125))
43792	31461649	We leveraged established cancer-derived PTEN mutants that abrogate either PTEN's lipid phosphatase activity (PTENG129E) or its protein phosphatase activity (PTENY138L) or both (PTENC124S).	('lipid', 'Chemical', 'MESH:D008055', (81, 86))	('mutants', 'Var', (45, 52))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('abrogate', 'NegReg', (58, 66))	('PTEN', 'Gene', (40, 44))	('PTEN', 'Gene', (74, 78))	('lipid phosphatase activity', 'MPA', (81, 107))	('cancer', 'Disease', 'MESH:D009369', (25, 31))	('cancer', 'Disease', (25, 31))	('protein phosphatase activity', 'MPA', (127, 155))
43793	31461649	By stably expressing each of these PTEN mutants or PTENWT in a controlled system of PTEN-deficient cells, we found that the protein phosphatase, but not the lipid phosphatase, activity of PTEN regulates PDHK1 mRNA expression (Figure 3A).	('lipid', 'Chemical', 'MESH:D008055', (157, 162))	('regulates', 'Reg', (193, 202))	('PDHK1', 'Gene', '5163', (203, 208))	('mRNA expression', 'MPA', (209, 224))	('mutants', 'Var', (40, 47))	('PDHK1', 'Gene', (203, 208))
43794	31461649	We confirmed that both mRNA and protein expression levels of PDHK1 were diminished upon expression of PTENWT or the PTEN mutant that retains the protein phosphatase activity only (PTENG129E, lipid phosphatase mutant) in comparison with PTEN-deficient parental cells (Figures 3A and S7A).	('activity', 'MPA', (165, 173))	('mutant', 'Var', (121, 127))	('protein', 'Protein', (145, 152))	('PDHK1', 'Gene', (61, 66))	('diminished', 'NegReg', (72, 82))	('PDHK1', 'Gene', '5163', (61, 66))	('lipid', 'Chemical', 'MESH:D008055', (191, 196))	('PTENG129E', 'Var', (180, 189))
43795	31461649	PDHK1 protein levels were unaffected by expression of the PTEN mutant lacking both phosphatase activities (PTENC124S), suggesting that PDHK1 regulation by PTEN is phosphatase activity dependent and not via other non-enzymatic properties of PTEN (Figure S7A).	('PDHK1', 'Gene', '5163', (0, 5))	('mutant', 'Var', (63, 69))	('PDHK1', 'Gene', (135, 140))	('PDHK1', 'Gene', '5163', (135, 140))	('PDHK1', 'Gene', (0, 5))
43797	31461649	Pharmacologic inhibition of PI3K or AKT in PTEN-deficient cells treated with BKM-120 or MK2206, respectively, suppressed AKT activation (phospho-AKT levels) and expression of hexokinase 2 (HK2) (Figures S7B and S7C), which is upregulated in PTEN-deficient cells.	('PI3K', 'Var', (28, 32))	('BKM-120', 'Var', (77, 84))	('S7C', 'Mutation', 'p.S7C', (211, 214))	('hexokinase 2', 'Gene', '3099', (175, 187))	('AKT', 'Gene', '207', (121, 124))	('expression', 'MPA', (161, 171))	('hexokinase 2', 'Gene', (175, 187))	('AKT', 'Gene', (36, 39))	('MK2206', 'Chemical', 'MESH:C548887', (88, 94))	('suppressed', 'NegReg', (110, 120))	('BKM-120', 'Chemical', 'MESH:C571178', (77, 84))	('AKT', 'Gene', (145, 148))	('HK2', 'Gene', '3099', (189, 192))	('HK2', 'Gene', (189, 192))	('activation', 'PosReg', (125, 135))	('MK2206', 'Var', (88, 94))	('AKT', 'Gene', '207', (36, 39))	('AKT', 'Gene', (121, 124))	('AKT', 'Gene', '207', (145, 148))
43798	31461649	In contrast, the expression of PDHK1 was unaffected under these conditions of PI3K/AKT blockade (Figures 3B and S7B-S7D).	('AKT', 'Gene', '207', (83, 86))	('PDHK1', 'Gene', (31, 36))	('S7B-S7D', 'Var', (112, 119))	('PDHK1', 'Gene', '5163', (31, 36))	('expression', 'MPA', (17, 27))	('AKT', 'Gene', (83, 86))
43801	31461649	Treatment with BKM-120 and another PI3K inhibitor, GDC0941, suppressed phosphorylation of ribosomal protein S6, which is downstream of both AKT and mTORC1, in three different PTEN-deficient cell lines tested and consistent with prior studies, without decreasing PDHK1 levels (Figures S7D and S7E).	('phosphorylation', 'MPA', (71, 86))	('mTORC1', 'Gene', (148, 154))	('AKT', 'Gene', (140, 143))	('GDC0941', 'Var', (51, 58))	('PDHK1', 'Gene', (262, 267))	('ribosomal protein S6', 'Gene', '6194', (90, 110))	('suppressed', 'NegReg', (60, 70))	('GDC0941', 'Chemical', 'MESH:C532162', (51, 58))	('S7E', 'Mutation', 'p.S7E', (292, 295))	('BKM-120', 'Var', (15, 22))	('PDHK1', 'Gene', '5163', (262, 267))	('BKM-120', 'Chemical', 'MESH:C571178', (15, 22))	('mTORC1', 'Gene', '382056', (148, 154))	('AKT', 'Gene', '207', (140, 143))	('ribosomal protein S6', 'Gene', (90, 110))
43804	31461649	We further found that it was the protein phosphatase, but not the lipid phosphatase, activity of PTEN that was required to rescue PTEN-deficient cells from the lethal effects of PDHK1 inhibition (Figure 3D).	('PDHK1', 'Gene', '5163', (178, 183))	('inhibition', 'NegReg', (184, 194))	('lipid', 'Chemical', 'MESH:D008055', (66, 71))	('PTEN-deficient', 'Gene', (130, 144))	('PDHK1', 'Gene', (178, 183))	('PTEN-deficient', 'Var', (130, 144))
43806	31461649	We next investigated the mechanism by which PTEN protein phosphatase inactivation increases PDHK1 gene (and thus protein) expression.	('expression', 'MPA', (122, 132))	('protein', 'MPA', (113, 120))	('inactivation', 'Var', (69, 81))	('PDHK1', 'Gene', (92, 97))	('increases', 'PosReg', (82, 91))	('PDHK1', 'Gene', '5163', (92, 97))
43807	31461649	Although PDHK1 expression can be upregulated by the transcription factor hypoxia-inducible factor 1 (HIF-1), silencing the HIF-1alpha subunit of HIF-1 failed to suppress PDHK1 expression in a panel of PTEN-deficient cell lines, unlike the effects of HIF-1kappa silencing in these cells on carbonic anhydrase 9 (CA9), which is known to be regulated by HIF-1 (Figure S8A).	('HIF-1', 'Gene', (123, 128))	('HIF-1', 'Gene', '3091', (145, 150))	('HIF-1', 'Gene', (351, 356))	('PDHK1', 'Gene', (170, 175))	('HIF-1alpha', 'Gene', '3091', (123, 133))	('HIF-1', 'Gene', (145, 150))	('PDHK1', 'Gene', '5163', (9, 14))	('expression', 'MPA', (176, 186))	('suppress', 'NegReg', (161, 169))	('CA9', 'Gene', '768', (311, 314))	('hypoxia-inducible factor 1', 'Gene', '3091', (73, 99))	('PDHK1', 'Gene', (9, 14))	('carbonic anhydrase 9', 'Gene', '768', (289, 309))	('silencing', 'Var', (109, 118))	('HIF-1alpha', 'Gene', (123, 133))	('HIF-1', 'Gene', '3091', (101, 106))	('hypoxia-inducible factor 1', 'Gene', (73, 99))	('HIF-1', 'Gene', (101, 106))	('upregulated', 'PosReg', (33, 44))	('HIF-1', 'Gene', '3091', (250, 255))	('PDHK1', 'Gene', '5163', (170, 175))	('HIF-1', 'Gene', '3091', (123, 128))	('CA9', 'Gene', (311, 314))	('HIF-1', 'Gene', (250, 255))	('HIF-1', 'Gene', '3091', (351, 356))	('carbonic anhydrase 9', 'Gene', (289, 309))
43809	31461649	To understand the molecular basis of the transcriptional upregulation of PDHK1 induced by PTEN inactivation in cells, we sought to identify the transcription factor(s) involved.	('PTEN', 'Gene', (90, 94))	('PDHK1', 'Gene', (73, 78))	('PDHK1', 'Gene', '5163', (73, 78))	('upregulation', 'PosReg', (57, 69))	('inactivation', 'Var', (95, 107))
43825	31461649	To identify the potential PTEN protein phosphatase-specific effector that links PTEN to downstream NF-kappaB and PDHK1 regulation, we used global mass spectrometry-based phospho-proteomics profiling in a genetically controlled system of PTEN-deficient cell lines with stable GFP or PTENWT or PTENG129E (lipid phosphatase mutant) or PTENY138L (protein phosphatase mutant) re-expression (Figure 5A).	('NF-kappaB', 'Gene', '4790', (99, 108))	('PTENY138L', 'Var', (332, 341))	('NF-kappaB', 'Gene', (99, 108))	('PDHK1', 'Gene', (113, 118))	('lipid', 'Chemical', 'MESH:D008055', (303, 308))	('PTENG129E', 'Var', (292, 301))	('PDHK1', 'Gene', '5163', (113, 118))
43834	31461649	By phosphate affinity (Phos-tag) PAGE analysis, wherein de-phosphorylated NKAP migrates faster than its phosphorylated form, we found enhanced NKAP dephosphorylation in PTEN-deficient cells stably expressing PTENWT or PTENG129E (lipid phosphatase mutant) in comparison with those with stable PTENY138L (protein phosphatase mutant) or GFP expression (Figure 5E).	('enhanced', 'PosReg', (134, 142))	('PTENG129E', 'Var', (218, 227))	('NKAP', 'Protein', (143, 147))	('PTEN-deficient', 'Gene', (169, 183))	('Y138L', 'Mutation', 'p.Y138L', (296, 301))	('PTENWT', 'Var', (208, 214))	('phosphate', 'Chemical', 'MESH:D010710', (3, 12))	('lipid', 'Chemical', 'MESH:D008055', (229, 234))
43838	31461649	To further investigate whether NKAP is a molecular link between PTEN and PDHK1, we examined whether NF-kappaB activation and PDHK1 expression are suppressed by silencing NKAP in PTEN-deficient cells.	('PDHK1', 'Gene', (125, 130))	('activation', 'PosReg', (110, 120))	('NKAP', 'Gene', (170, 174))	('silencing', 'Var', (160, 169))	('PDHK1', 'Gene', (73, 78))	('PDHK1', 'Gene', '5163', (125, 130))	('PDHK1', 'Gene', '5163', (73, 78))	('expression', 'MPA', (131, 141))	('NF-kappaB', 'Gene', '4790', (100, 109))	('NF-kappaB', 'Gene', (100, 109))	('suppressed', 'NegReg', (146, 156))
43839	31461649	NKAP knockdown in different PTEN-deficient cell lines suppressed NF-kappaB transcriptional activity (Figure 6A) without affecting phospho-AKT levels (Figure 6C), consistent with prior work.	('suppressed', 'NegReg', (54, 64))	('knockdown', 'Var', (5, 14))	('AKT', 'Gene', (138, 141))	('NF-kappaB', 'Gene', '4790', (65, 74))	('NF-kappaB', 'Gene', (65, 74))	('transcriptional activity', 'MPA', (75, 99))	('NKAP', 'Gene', (0, 4))	('AKT', 'Gene', '207', (138, 141))
43840	31461649	In concordance, NKAP knockdown suppressed transcriptional activation of the PDHK1 promoter (Figure 6B) and decreased expression of PDHK1 (Figure 6C), which we identified as a NF-kappaB target gene (Figure 4).	('PDHK1', 'Gene', (131, 136))	('PDHK1', 'Gene', (76, 81))	('NF-kappaB', 'Gene', '4790', (175, 184))	('expression', 'MPA', (117, 127))	('decreased', 'NegReg', (107, 116))	('PDHK1', 'Gene', '5163', (131, 136))	('NF-kappaB', 'Gene', (175, 184))	('PDHK1', 'Gene', '5163', (76, 81))	('suppressed', 'NegReg', (31, 41))	('transcriptional activation', 'MPA', (42, 68))	('knockdown', 'Var', (21, 30))
43841	31461649	Stable expression of WT NKAP (NKAPWT), but not de-phosphorylation-deficient mutant NKAP (NKAPS9A-S149A), in PTEN-null cells enhanced NF-kappaB transcriptional activity (Figure S10A) and NF-kappaB nuclear localization (Figure S10B) and increased PDHK1 expression (Figure 6D).	('S10A', 'SUBSTITUTION', 'None', (176, 180))	('transcriptional activity', 'MPA', (143, 167))	('S10B', 'Var', (225, 229))	('PDHK1', 'Gene', (245, 250))	('NF-kappaB', 'Gene', (133, 142))	('expression', 'MPA', (251, 261))	('increased PDHK1 expression', 'Phenotype', 'HP:0003240', (235, 261))	('S10A', 'Var', (176, 180))	('increased', 'PosReg', (235, 244))	('enhanced', 'PosReg', (124, 132))	('S10B', 'SUBSTITUTION', 'None', (225, 229))	('PDHK1', 'Gene', '5163', (245, 250))	('NF-kappaB', 'Gene', '4790', (186, 195))	('nuclear localization', 'MPA', (196, 216))	('S149A', 'Mutation', 'p.S149A', (97, 102))	('NF-kappaB', 'Gene', (186, 195))	('NF-kappaB', 'Gene', '4790', (133, 142))
43842	31461649	Thus, loss of the PTEN protein phosphatase induces NKAP phosphorylation (on S9 and S149) to activate NF-kappaB and increase PDHK1 levels, in a PI3K-AKT-independent manner.	('AKT', 'Gene', '207', (148, 151))	('increase PDHK1 levels', 'Phenotype', 'HP:0003240', (115, 136))	('PTEN', 'Gene', (18, 22))	('loss', 'Var', (6, 10))	('PDHK1', 'Gene', (124, 129))	('increase', 'PosReg', (115, 123))	('AKT', 'Gene', (148, 151))	('PDHK1', 'Gene', '5163', (124, 129))	('NF-kappaB', 'Gene', '4790', (101, 110))	('NF-kappaB', 'Gene', (101, 110))	('NKAP phosphorylation', 'MPA', (51, 71))	('S149', 'Var', (83, 87))	('activate', 'PosReg', (92, 100))
43844	31461649	NKAP knockdown significantly decreased cell viability in PTEN-deficient cells compared with PTEN-expressing cells (Figure 6E), phenocopying the effects of both PDHK1 and NF-kappaB inhibition in PTEN-deficient cells (Figures 2, S4, and S8C).	('PDHK1', 'Gene', '5163', (160, 165))	('knockdown', 'Var', (5, 14))	('NKAP', 'Gene', (0, 4))	('PDHK1', 'Gene', (160, 165))	('NF-kappaB', 'Gene', '4790', (170, 179))	('decreased', 'NegReg', (29, 38))	('cell viability', 'CPA', (39, 53))	('inhibition', 'NegReg', (180, 190))	('NF-kappaB', 'Gene', (170, 179))
43845	31461649	Similar to PDHK1 inhibition (Figure 3D), NKAP silencing significantly decreased the viability of cells specifically lacking the PTEN protein phosphatase activity (Figure 6F).	('lacking', 'NegReg', (116, 123))	('PDHK1', 'Gene', '5163', (11, 16))	('silencing', 'Var', (46, 55))	('decreased', 'NegReg', (70, 79))	('PTEN', 'MPA', (128, 132))	('activity', 'MPA', (153, 161))	('viability', 'CPA', (84, 93))	('NKAP', 'Gene', (41, 45))	('PDHK1', 'Gene', (11, 16))
43846	31461649	PTEN-deficient cells re-constituted with PTENY138L (protein phosphatase mutant) were generally as sensitive as PTEN-deficient cells to NKAP knockdown (Figure 6F).	('sensitive', 'MPA', (98, 107))	('PTENY138L', 'Var', (41, 50))	('Y138L', 'Mutation', 'p.Y138L', (45, 50))
43847	31461649	In contrast, cells re-constituted with PTEN that harbors the protein phosphatase activity (either PTENWT or PTENG129E, the lipid phosphatase mutant) were generally less affected by NKAP suppression (Figure 6F).	('lipid', 'Chemical', 'MESH:D008055', (123, 128))	('activity', 'MPA', (81, 89))	('protein phosphatase', 'Enzyme', (61, 80))	('PTENG129E', 'Var', (108, 117))
43851	31461649	Our study illustrates the importance of defining activity-specific PTEN functions that contribute to physiologic regulation in normal cells and that when dysregulated contribute to genetically driven human diseases such as cancer.	('dysregulated', 'Var', (154, 166))	('contribute', 'Reg', (87, 97))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('contribute', 'Reg', (167, 177))	('physiologic', 'MPA', (101, 112))	('human', 'Species', '9606', (200, 205))	('cancer', 'Disease', 'MESH:D009369', (223, 229))	('cancer', 'Disease', (223, 229))
43868	31461649	High titer pre-made adenovirus expressing PDHK1-HA (Applied Biological Materials) was used to infect PTEN-deficient H1650 cells with stable PDHK1 knockdown for transient overexpression of shRNA-resistant PDHK1-HA.	('knockdown', 'Var', (146, 155))	('PDHK1', 'Gene', '5163', (42, 47))	('PDHK1', 'Gene', (204, 209))	('PDHK1', 'Gene', '5163', (140, 145))	('infect PTEN-deficient', 'Disease', (94, 115))	('PDHK1', 'Gene', '5163', (204, 209))	('infect PTEN-deficient', 'Disease', 'MESH:D006223', (94, 115))	('PDHK1', 'Gene', (140, 145))	('overexpression', 'PosReg', (170, 184))	('PDHK1', 'Gene', (42, 47))
43875	31461649	For each cell line, the degree of cell viability at the highest concentration of DCA (20 mM) was normalized to the vehicle control for each genetic background (cells expressing GFP or PTENWT or PTENMutant).	('PTENWT', 'Var', (184, 190))	('DCA', 'Chemical', 'MESH:D003999', (81, 84))	('GFP', 'Var', (177, 180))
43894	31461649	PDHK1 gene expression regulation by different phosphatase activities of PTEN was also measured by real-time qRT-PCR in PTEN-deficient cell lines stably expressing PTENWT, PTENG129E, PTENY138L or GFP.	('PTENG129E', 'Var', (171, 180))	('PDHK1', 'Gene', '5163', (0, 5))	('PTENY138L', 'Var', (182, 191))	('PDHK1', 'Gene', (0, 5))
43899	31461649	Quantification of NF-kappaB (or RELA) enrichment was done using real-time qPCR with primers designed to amplify a 118 bp region spanning nucleotide position 173420380 in the PDHK1 promoter (EpiTect ChIP qPCR Primer Assay for human PDK1, NM002610.3 (-)01Kb, QIAGEN).	('PDK1', 'Gene', (231, 235))	('PDHK1', 'Gene', '5163', (174, 179))	('NM002610.3', 'Var', (237, 247))	('NF-kappaB', 'Gene', '4790', (18, 27))	('human', 'Species', '9606', (225, 230))	('NF-kappaB', 'Gene', (18, 27))	('PDK1', 'Gene', '5163', (231, 235))	('PDHK1', 'Gene', (174, 179))	('nucleotide', 'Var', (137, 147))	('RELA', 'Gene', (32, 36))	('RELA', 'Gene', '5970', (32, 36))
43900	31461649	pGreenFire1-NF-kappaB (EF1alpha-Puro) lentiviral plasmid containing four NF-kappaB transcription factor response elements fused in tandem upstream of a luciferase gene under a minimal CMV promoter was transfected into PTEN-deficient cancer cells stably expressing either PTENWT or PTENG129E or PTENY138L or GFP to measure the effects of PTEN's protein and / or lipid phosphatase activities on the transcriptional activity of NF-kappaB.	('NF-kappaB', 'Gene', '4790', (425, 434))	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('PTENY138L', 'Var', (294, 303))	('NF-kappaB', 'Gene', (12, 21))	('PTEN-deficient cancer', 'Disease', 'MESH:D006223', (218, 239))	('EF1alpha', 'Gene', '1917', (23, 31))	('PTENG129E', 'Var', (281, 290))	('NF-kappaB', 'Gene', '4790', (73, 82))	('PTEN-deficient cancer', 'Disease', (218, 239))	('NF-kappaB', 'Gene', (425, 434))	('EF1alpha', 'Gene', (23, 31))	('lipid', 'Chemical', 'MESH:D008055', (361, 366))	('NF-kappaB', 'Gene', (73, 82))	('NF-kappaB', 'Gene', '4790', (12, 21))
43901	31461649	pGreenFire1-NF-kappaB (EF1alpha-Puro) reporter plasmid was also transfected into PTEN-deficient cells stably expressing NKAPWT or NKAPs9AS149A or with stable NKAP knockdown to study the effects of NKAP phosphorylation on NF-kappaB activity.	('NF-kappaB', 'Gene', (221, 230))	('NF-kappaB', 'Gene', (12, 21))	('EF1alpha', 'Gene', '1917', (23, 31))	('EF1alpha', 'Gene', (23, 31))	('AS149A', 'CellLine', 'CVCL:B669', (136, 142))	('NF-kappaB', 'Gene', '4790', (221, 230))	('NF-kappaB', 'Gene', '4790', (12, 21))	('NKAPs9AS149A', 'Var', (130, 142))
43904	31461649	5-14 amino acid (SGSRpSPDREA) p-S9-NKAP or 145-154 amino acid (VWGLpSPKNPE) p-S149-NKAP or 68-77 amino acid (ERFQpSLGVAF) p-S72-Rab7 peptide (used as a +ve control) was incubated without or with bacterially expressed and purified (as described before) PTENWT or mutant Y138L PTEN enzyme in reaction buffer (25mM HEPES, pH 7.5, 10 mM MgCl2, 10 mM DTT) at 37 C for 90 min.	('MgCl2', 'Chemical', 'MESH:D015636', (333, 338))	('Y138L', 'Var', (269, 274))	('S149-NKAP', 'Disease', 'None', (78, 87))	('Rab7', 'Gene', (128, 132))	('Rab7', 'Gene', '338382', (128, 132))	('HEPES', 'Chemical', 'MESH:D006531', (312, 317))	('S149-NKAP', 'Disease', (78, 87))	('PTEN', 'Gene', (275, 279))	('Y138L', 'Mutation', 'p.Y138L', (269, 274))
43905	31461649	Following incubation, the released phosphate from each phospho-peptide +- PTENWT or mutant Y138L PTEN enzyme was detected using Malachite Green Assay Kit (Echelon) by measuring the absorbance at 620 nm in a plate reader (SpectraMax M5, Molecular devices).	('Y138L', 'Mutation', 'p.Y138L', (91, 96))	('phosphate', 'Chemical', 'MESH:D010710', (35, 44))	('ice', 'Gene', (249, 252))	('PTEN', 'Gene', (97, 101))	('Y138L', 'Var', (91, 96))	('mutant Y138L', 'Var', (84, 96))	('Malachite', 'Species', '64457', (128, 137))	('ice', 'Gene', '834', (249, 252))	('absorbance at 620 nm', 'MPA', (181, 201))
43906	31461649	Briefly, PTEN-deficient cancer cells stably expressing either PTENWT or PTENG129E or PTENY138L or GFP were lysed and subjected to Zinc-based polyacrylamide gel electrophoresis.	('PTEN-deficient cancer', 'Disease', 'MESH:D006223', (9, 30))	('polyacrylamide', 'Chemical', 'MESH:C016679', (141, 155))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('PTENY138L', 'Var', (85, 94))	('PTEN-deficient cancer', 'Disease', (9, 30))	('Y138L', 'Mutation', 'p.Y138L', (89, 94))	('PTENG129E', 'Var', (72, 81))
43916	31461649	GFP or PTENWT or PTENG129E or PTENY138L was stably introduced in two different PTEN-deficient cancer cell lines H1650 and A2058 with different genetic and histologic backgrounds.	('PTENY138L', 'Var', (30, 39))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('PTENG129E', 'Var', (17, 26))	('PTEN-deficient cancer', 'Disease', 'MESH:D006223', (79, 100))	('PTEN-deficient cancer', 'Disease', (79, 100))
43933	31461649	Expression analysis of patient samples: Expression levels of PDHK1mRNA after normalization were compared between patient samples with single or double copy number loss of PTEN to patients with copy number neutral PTEN by boxplot analysis.	('patient', 'Species', '9606', (113, 120))	('patient', 'Species', '9606', (179, 186))	('PDHK1', 'Gene', (61, 66))	('patients', 'Species', '9606', (179, 187))	('double copy number loss', 'Var', (144, 167))	('PTEN', 'Gene', (171, 175))	('PDHK1', 'Gene', '5163', (61, 66))	('patient', 'Species', '9606', (23, 30))
43956	29221155	In addition, knockdown of CD109 in hBM-MSCs abrogates the anti-malignant activity of hBM-MSC-conditioned medium on A431 and FaDu cells.	('hBM', 'Gene', '3042', (35, 38))	('hBM', 'Gene', (35, 38))	('CD109', 'Gene', (26, 31))	('anti-malignant activity', 'CPA', (58, 81))	('CD109', 'Gene', '135228', (26, 31))	('abrogates', 'NegReg', (44, 53))	('A431', 'CellLine', 'CVCL:0037', (115, 119))	('hBM', 'Gene', '3042', (85, 88))	('hBM', 'Gene', (85, 88))	('knockdown', 'Var', (13, 22))
43992	29221155	Conversely, the sub-G1 peak was markedly reduced in A431 cells treated with hFibro-CM (2.30 +- 3.45%) and DMEM (2.49+- 4.05%) (data not shown).	('reduced', 'NegReg', (41, 48))	('hFibro-CM', 'Var', (76, 85))	('A431', 'CellLine', 'CVCL:0037', (52, 56))	('sub-G1 peak', 'MPA', (16, 27))	('DMEM', 'Chemical', '-', (106, 110))
44029	29221155	To investigate whether the anti-tumor activity of hBM-MSC-CM could be dependent on the released CD109 in the conditioned medium, we knocked down CD109 in hBM-MSCs using small interfering RNA (siRNA).	('CD109', 'Gene', '135228', (145, 150))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('CD109', 'Gene', (96, 101))	('hBM', 'Gene', (50, 53))	('hBM', 'Gene', '3042', (50, 53))	('hBM', 'Gene', (154, 157))	('CD109', 'Gene', (145, 150))	('hBM', 'Gene', '3042', (154, 157))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumor', 'Disease', (32, 37))	('CD109', 'Gene', '135228', (96, 101))	('knocked', 'Var', (132, 139))
44031	29221155	Of note, less than 30% of CD109 was detected in CM derived from CD109 knockdown hBM-MSCs, demonstrating a significant reduction of CD109 in the conditional medium from CD109-knockdown hBM-MSCs (Figure 5C).	('CD109', 'Gene', '135228', (131, 136))	('CD109', 'Gene', (26, 31))	('knockdown', 'Var', (70, 79))	('CD109', 'Gene', (64, 69))	('reduction', 'NegReg', (118, 127))	('CD109', 'Gene', (168, 173))	('hBM', 'Gene', (80, 83))	('hBM', 'Gene', (184, 187))	('CD109', 'Gene', '135228', (26, 31))	('hBM', 'Gene', '3042', (80, 83))	('hBM', 'Gene', '3042', (184, 187))	('CD109', 'Gene', '135228', (64, 69))	('CD109', 'Gene', (131, 136))	('CD109', 'Gene', '135228', (168, 173))
44034	29221155	However, knocking down CD109 with its specific SiRNA significantly reduced the anti-migration activity of hBM-MSC-CM, as demonstrated by a significantly faster closure rate of the wound area, as compared to cells treated with CM derived from hBM-MSCs transfected with scramble siRNA (Figure 5D and 5E).	('hBM', 'Gene', '3042', (106, 109))	('closure rate of the wound area', 'CPA', (160, 190))	('anti-migration activity', 'CPA', (79, 102))	('CD109', 'Gene', '135228', (23, 28))	('hBM', 'Gene', '3042', (242, 245))	('knocking down', 'Var', (9, 22))	('hBM', 'Gene', (242, 245))	('faster', 'PosReg', (153, 159))	('reduced', 'NegReg', (67, 74))	('hBM', 'Gene', (106, 109))	('CD109', 'Gene', (23, 28))
44039	29221155	Crystal violent staining demonstrated that significantly higher number of cells passed through the matrigel coated membrane, as 57.3% invasive cells were detected when cancer cells were treated with CM derived from hBM-MSCs transfected with CD109-specific siRNA, while only 27.3% and 28.7% invasive cells were detected in cells treated from un-transfected hBM-MSCs and from hBM-MSCs transfected with Control siRNA, respectively.	('hBM', 'Gene', '3042', (374, 377))	('hBM', 'Gene', (374, 377))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('transfected', 'Var', (224, 235))	('higher', 'PosReg', (57, 63))	('invasive cells', 'CPA', (134, 148))	('CD109', 'Gene', (241, 246))	('hBM', 'Gene', (215, 218))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('hBM', 'Gene', '3042', (215, 218))	('cancer', 'Disease', (168, 174))	('CD109', 'Gene', '135228', (241, 246))	('hBM', 'Gene', '3042', (356, 359))	('hBM', 'Gene', (356, 359))
44041	29221155	This is consistent with the results presented in Figure 4 and suggests that blocking CD109 in hBM-MSCs abrogates the anti-migration and anti-invasion biological effect of the conditioned media.	('hBM', 'Gene', (94, 97))	('CD109', 'Gene', (85, 90))	('hBM', 'Gene', '3042', (94, 97))	('CD109', 'Gene', '135228', (85, 90))	('blocking', 'Var', (76, 84))	('abrogates', 'NegReg', (103, 112))	('anti-migration', 'CPA', (117, 131))	('anti-invasion biological effect of the', 'CPA', (136, 174))
44042	29221155	Altogether, these results strongly suggest that CD109 released into hBM-MSC-CM is at least partially responsible for the suppression of cancer cell migration and invasiveness, since the knockdown of CD109 in hBM-MSC abrogates the anti-tumor activities of hBM-MSC-CM.	('tumor', 'Disease', 'MESH:D009369', (235, 240))	('invasiveness', 'CPA', (162, 174))	('CD109', 'Gene', (199, 204))	('hBM', 'Gene', '3042', (208, 211))	('CD109', 'Gene', (48, 53))	('cancer', 'Disease', (136, 142))	('CD109', 'Gene', '135228', (199, 204))	('CD109', 'Gene', '135228', (48, 53))	('hBM', 'Gene', (255, 258))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('knockdown', 'Var', (186, 195))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('hBM', 'Gene', (208, 211))	('abrogates', 'NegReg', (216, 225))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('hBM', 'Gene', '3042', (68, 71))	('tumor', 'Disease', (235, 240))	('hBM', 'Gene', (68, 71))	('hBM', 'Gene', '3042', (255, 258))
44048	29221155	Moreover, the capacity to form spheroids was markedly decreased in CD109 overexpressing cells compared to the empty vector transfected cells (Figure 6C and 6D).	('CD109', 'Gene', (67, 72))	('overexpressing', 'Var', (73, 87))	('decreased', 'NegReg', (54, 63))	('CD109', 'Gene', '135228', (67, 72))
44059	29221155	Moreover, siRNA-mediated knockdown of CD109, a TGF-beta co-receptor and potent inhibitor of TGF-beta signaling, reveals a critical role of CD109 in mediating the anti-cancer effects of hBM-MSC-CM.	('hBM', 'Gene', '3042', (185, 188))	('hBM', 'Gene', (185, 188))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('CD109', 'Gene', '135228', (139, 144))	('cancer', 'Disease', (167, 173))	('CD109', 'Gene', (38, 43))	('TGF-beta', 'Gene', '7040', (92, 100))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('TGF-beta', 'Gene', '7040', (47, 55))	('CD109', 'Gene', '135228', (38, 43))	('TGF-beta', 'Gene', (47, 55))	('TGF-beta', 'Gene', (92, 100))	('CD109', 'Gene', (139, 144))	('knockdown', 'Var', (25, 34))
44065	29221155	Our results demonstrating that knockdown of CD109 in hBM-MSCs abrogates the inhibitory effects of hBM-MSC-CM on EMT, migration, invasion and spheroid formation in SCC cells, indicate that CD109 released from hBM-MSCs is essential for these anti-tumor effects.	('SCC', 'Gene', (163, 166))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('hBM', 'Gene', '3042', (208, 211))	('hBM', 'Gene', (98, 101))	('migration', 'CPA', (117, 126))	('hBM', 'Gene', (208, 211))	('invasion', 'CPA', (128, 136))	('inhibitory effects', 'MPA', (76, 94))	('CD109', 'Gene', (188, 193))	('tumor', 'Disease', (245, 250))	('CD109', 'Gene', '135228', (188, 193))	('hBM', 'Gene', '3042', (53, 56))	('CD109', 'Gene', (44, 49))	('spheroid formation', 'CPA', (141, 159))	('tumor', 'Disease', 'MESH:D009369', (245, 250))	('CD109', 'Gene', '135228', (44, 49))	('hBM', 'Gene', (53, 56))	('SCC', 'Gene', '6317', (163, 166))	('hBM', 'Gene', '3042', (98, 101))	('EMT', 'CPA', (112, 115))	('abrogates', 'NegReg', (62, 71))	('knockdown', 'Var', (31, 40))
44142	28841909	This increase is likely related to the higher prevalence of the anal human papilloma virus (HPV) infection, since HPV-related oncoproteins (E6 and E7) are indeed expressed in more than 90% of SCCA.	('HPV', 'Disease', (92, 95))	('HPV', 'Disease', 'MESH:D030361', (114, 117))	('human', 'Species', '9606', (69, 74))	('papilloma', 'Phenotype', 'HP:0012740', (75, 84))	('HPV', 'Disease', 'MESH:D030361', (92, 95))	('papilloma virus (HPV) infection', 'Disease', 'MESH:D030361', (75, 106))	('HPV', 'Disease', (114, 117))	('E7', 'Var', (147, 149))
44156	28841909	In addition, docetaxel has previously shown to increase endoplasmic reticulum stress and to induce an immunogenic cell death of cancer cells.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('docetaxel', 'Chemical', 'MESH:D000077143', (13, 22))	('endoplasmic reticulum stress', 'Disease', 'MESH:D004194', (56, 84))	('endoplasmic reticulum stress', 'Disease', (56, 84))	('death', 'Disease', 'MESH:D003643', (119, 124))	('death', 'Disease', (119, 124))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('increase', 'PosReg', (47, 55))	('induce', 'Reg', (92, 98))	('docetaxel', 'Var', (13, 22))	('cancer', 'Disease', (128, 134))
44404	33078899	We combined genomic heterogeneity with clinical phenotypes analysis and found that subclonal expansion results in the progression and deterioration of the tumor.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('subclonal expansion', 'Var', (83, 102))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('deterioration', 'CPA', (134, 147))	('tumor', 'Disease', (155, 160))
44426	33078899	For each NSCLC patient, a tree was rebuilt using the binary distribution of mutations from the region within the tumor.	('patient', 'Species', '9606', (15, 22))	('tumor', 'Disease', (113, 118))	('mutations', 'Var', (76, 85))	('NSCLC', 'Disease', (9, 14))	('NSCLC', 'Disease', 'MESH:D002289', (9, 14))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('NSCLC', 'Phenotype', 'HP:0030358', (9, 14))
44429	33078899	We used the clonality of mutations that was determined by observed cancer cell fraction (CCF) to calculate the ITH index and characterize the intra-tumor heterogeneity for each patient.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('mutations', 'Var', (25, 34))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('cancer', 'Disease', (67, 73))	('intra-tumor', 'Disease', (142, 153))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('patient', 'Species', '9606', (177, 184))	('intra-tumor', 'Disease', 'MESH:D009369', (142, 153))
44436	33078899	We found that the mutations in lung squamous cell carcinoma (LUSC) were more likely located in the branch (shared and private mutations) of the phylogenetic trees compared to lung adenocarcinoma (LUAD) (p = 0.0017) (Figure 2A).	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (31, 59))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (175, 194))	('carcinoma', 'Phenotype', 'HP:0030731', (50, 59))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (36, 59))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (31, 59))	('lung squamous cell carcinoma', 'Disease', (31, 59))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (175, 194))	('LUSC', 'Phenotype', 'HP:0030359', (61, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (185, 194))	('LUAD', 'Phenotype', 'HP:0030078', (196, 200))	('lung adenocarcinoma', 'Disease', (175, 194))	('mutations', 'Var', (18, 27))
44437	33078899	Also, the driver mutations of LUSC patients showed a consistent phenomenon (Figure 2B), which indicated that LUSC had stronger ITH and evolutionary diversity.	('evolutionary diversity', 'CPA', (135, 157))	('ITH', 'CPA', (127, 130))	('LUSC', 'Phenotype', 'HP:0030359', (109, 113))	('patients', 'Species', '9606', (35, 43))	('stronger', 'PosReg', (118, 126))	('mutations', 'Var', (17, 26))	('LUSC', 'Phenotype', 'HP:0030359', (30, 34))
44438	33078899	Furthermore, we found that driver mutations preferred to present in the trunk in most NSCLC patients (Figure 2C).	('NSCLC', 'Disease', (86, 91))	('patients', 'Species', '9606', (92, 100))	('NSCLC', 'Disease', 'MESH:D002289', (86, 91))	('NSCLC', 'Phenotype', 'HP:0030358', (86, 91))	('mutations', 'Var', (34, 43))
44440	33078899	These results reflected the early potential of driver mutations during tumor evolution.	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Disease', (71, 76))	('mutations', 'Var', (54, 63))	('tumor', 'Disease', 'MESH:D009369', (71, 76))
44441	33078899	For instance, patient CRUK0071 carried driver mutations of CSMD3 at three amino acid positions, including the site p.G612R was located in the trunk of the tree, while both sites p.C543G and p.P3408L were located in shared branches (Figure 2D).	('p.C543G', 'Mutation', 'p.C543G', (178, 185))	('p.C543G', 'Var', (178, 185))	('patient', 'Species', '9606', (14, 21))	('p.P3408L', 'Var', (190, 198))	('p.G612R', 'Mutation', 'p.G612R', (115, 122))	('p.P3408L', 'Mutation', 'p.P3408L', (190, 198))	('p.G612R', 'Var', (115, 122))	('CSMD3', 'Gene', (59, 64))	('CSMD3', 'Gene', '114788', (59, 64))
44442	33078899	Interestingly, parallel evolutionary patterns were exhibited in the phylogenetic trees, including mutations in MLLT10, WDR5, and ERMARD (Figure 2D,E), which indicated the diversity of tumor genome evolution.	('MLLT10', 'Gene', '8028', (111, 117))	('ERMARD', 'Gene', (129, 135))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('ERMARD', 'Gene', '55780', (129, 135))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('WDR5', 'Gene', (119, 123))	('mutations', 'Var', (98, 107))	('tumor', 'Disease', (184, 189))	('MLLT10', 'Gene', (111, 117))	('WDR5', 'Gene', '11091', (119, 123))
44446	33078899	The patients within subtype 1 exhibited higher subclonal diversity mediated through cumulative mutations in the phylogenetic trees, which reflects higher ITH 26 ,  31  (Figure 3B).	('higher', 'PosReg', (40, 46))	('subclonal diversity', 'MPA', (47, 66))	('phylogenetic trees', 'Gene', (112, 130))	('mutations', 'Var', (95, 104))	('patients', 'Species', '9606', (4, 12))
44451	33078899	For instance, in patient CRUK0062, the mutation in TP53 occurred on the trunk, while in NSD1 and UBR5 were shared by branches, and in PLXNB2 was detected only on the private branch (Figure 3E).	('occurred', 'Reg', (56, 64))	('PLXNB2', 'Gene', (134, 140))	('mutation', 'Var', (39, 47))	('TP53', 'Gene', (51, 55))	('UBR5', 'Gene', (97, 101))	('patient', 'Species', '9606', (17, 24))	('PLXNB2', 'Gene', '23654', (134, 140))	('NSD1', 'Gene', '64324', (88, 92))	('UBR5', 'Gene', '51366', (97, 101))	('NSD1', 'Gene', (88, 92))	('TP53', 'Gene', '7157', (51, 55))
44454	33078899	Subsequently, new subclonal lineages formed, in consequence of the positive selection of driver mutations, 33  which can increase the propensity for drug resistance and will cause poorer clinical outcomes for this type of patients.	('clinical outcomes', 'MPA', (187, 204))	('increase', 'PosReg', (121, 129))	('cause', 'Reg', (174, 179))	('patients', 'Species', '9606', (222, 230))	('drug resistance', 'Phenotype', 'HP:0020174', (149, 164))	('mutations', 'Var', (96, 105))	('drug resistance', 'MPA', (149, 164))
44456	33078899	And we found that most driver mutations, such as mutations in PTEN, WT1, KRAS, and STK11, etc., were located in the trunks of the phylogenetic trees.	('PTEN', 'Gene', (62, 66))	('KRAS', 'Gene', (73, 77))	('WT1', 'Gene', '7490', (68, 71))	('PTEN', 'Gene', '5728', (62, 66))	('WT1', 'Gene', (68, 71))	('mutations', 'Var', (49, 58))	('KRAS', 'Gene', '3845', (73, 77))	('STK11', 'Gene', (83, 88))	('STK11', 'Gene', '6794', (83, 88))
44460	33078899	In particular, in patients CRUK0080 and CRUK0024, a small number of mutations were detected in the R2 lesion, and were gradually replaced by newly formed mutations that were distributed in multiple branches of the evolutionary tree.	('CRUK0080', 'Var', (27, 35))	('patients', 'Species', '9606', (18, 26))	('CRUK0024', 'Var', (40, 48))
44461	33078899	This evolutionary pattern suggested that some mutations cannot afford a fitness advantage to allow for additional driver events, which caused a clonal sweep during tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('tumor', 'Disease', (164, 169))	('mutations', 'Var', (46, 55))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('fitness', 'Disease', (72, 79))	('fitness', 'Disease', 'MESH:D012640', (72, 79))
44471	33078899	The results of evolutionary subtypes and clinical phenotypic analysis indicated that a large number of subclonal expansions, which resulted in tumor tissue growth, could lead the tumor cells to invade other tissues (including vascular invasion and pleural invasion), and in turn caused the progression and deterioration of the disease and higher stage.	('resulted in', 'Reg', (131, 142))	('pleural invasion', 'Disease', 'MESH:D010995', (248, 264))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('tumor', 'Disease', (143, 148))	('deterioration of the disease', 'Disease', 'MESH:D009800', (306, 334))	('caused', 'Reg', (279, 285))	('pleural invasion', 'Disease', (248, 264))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('subclonal', 'Var', (103, 112))	('higher stage', 'CPA', (339, 351))	('invade other', 'CPA', (194, 206))	('deterioration of the disease', 'Disease', (306, 334))	('vascular invasion', 'CPA', (226, 243))	('lead', 'Reg', (170, 174))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('tumor', 'Disease', (179, 184))
44474	33078899	17  In this study, we evaluated the global trend in temporal order for driver mutations in NSCLC, by comparing the CCFs of coexisting mutations, which were characterized by their positional distribution on the phylogenetic trees based on the Bradley-Terry model.	('NSCLC', 'Disease', 'MESH:D002289', (91, 96))	('NSCLC', 'Disease', (91, 96))	('NSCLC', 'Phenotype', 'HP:0030358', (91, 96))	('mutations', 'Var', (78, 87))
44475	33078899	37  By showing the relatively earlier evolutionary timing in subtype 1, driver mutations such as PIK3CA,EGFR, and TP53 presented larger CCFs (Figure S6A,B).	('EGFR', 'Gene', '1956', (104, 108))	('EGFR', 'Gene', (104, 108))	('TP53', 'Gene', '7157', (114, 118))	('CCFs', 'MPA', (136, 140))	('TP53', 'Gene', (114, 118))	('larger', 'PosReg', (129, 135))	('PIK3CA', 'Gene', (97, 103))	('mutations', 'Var', (79, 88))	('PIK3CA', 'Gene', '5290', (97, 103))
44476	33078899	Previous studies have shown that driver mutations in EGFR and TP53 played a crucial role in the early stages of lung cancer development.	('TP53', 'Gene', '7157', (62, 66))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('lung cancer', 'Disease', (112, 123))	('lung cancer', 'Phenotype', 'HP:0100526', (112, 123))	('TP53', 'Gene', (62, 66))	('mutations', 'Var', (40, 49))	('lung cancer', 'Disease', 'MESH:D008175', (112, 123))	('EGFR', 'Gene', '1956', (53, 57))	('EGFR', 'Gene', (53, 57))
44477	33078899	38  For subtype 2, however, we found that both early and late driver mutations belonged to ubiquitous events (85/98), such as FBXW7,CMTR2, and STK11 (Figure 4F-H).	('mutations', 'Var', (69, 78))	('FBXW7', 'Gene', '55294', (126, 131))	('CMTR2', 'Gene', '55783', (132, 137))	('FBXW7', 'Gene', (126, 131))	('STK11', 'Gene', (143, 148))	('STK11', 'Gene', '6794', (143, 148))	('CMTR2', 'Gene', (132, 137))
44478	33078899	found that most of the known oncogene mutations occurred in the trunks of the phylogenetic trees, indicating that these mutations were at the early stages of genomic variation in lung cancer evolution.	('lung cancer', 'Disease', (179, 190))	('lung cancer', 'Phenotype', 'HP:0100526', (179, 190))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('mutations', 'Var', (38, 47))	('lung cancer', 'Disease', 'MESH:D008175', (179, 190))
44480	33078899	In subtype 3, the driver mutations of NFE2L2 and TP53 showed a larger CCFs (Figure S6C,D).	('larger', 'PosReg', (63, 69))	('mutations', 'Var', (25, 34))	('TP53', 'Gene', '7157', (49, 53))	('TP53', 'Gene', (49, 53))	('NFE2L2', 'Gene', '4780', (38, 44))	('NFE2L2', 'Gene', (38, 44))	('CCFs', 'CPA', (70, 74))
44484	33078899	For instance, all the driver mutations of KRAS occurred in adenocarcinoma patients (21/61), while not detected in squamous cell carcinoma patients (Figure S5C).	('KRAS', 'Gene', (42, 46))	('KRAS', 'Gene', '3845', (42, 46))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (114, 137))	('patients', 'Species', '9606', (74, 82))	('mutations', 'Var', (29, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('adenocarcinoma', 'Disease', (59, 73))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (114, 137))	('squamous cell carcinoma', 'Disease', (114, 137))	('occurred', 'Reg', (47, 55))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))	('adenocarcinoma', 'Disease', 'MESH:D000230', (59, 73))	('patients', 'Species', '9606', (138, 146))
44485	33078899	All the driver mutations of PTEN occurred just in squamous cell carcinoma patients (7/32).	('PTEN', 'Gene', (28, 32))	('PTEN', 'Gene', '5728', (28, 32))	('patients', 'Species', '9606', (74, 82))	('mutations', 'Var', (15, 24))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (50, 73))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (50, 73))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))	('squamous cell carcinoma', 'Disease', (50, 73))
44487	33078899	Interestingly, whether in adenocarcinoma or squamous cell carcinoma, we found that the mutation of these EDF genes showed significant aggregation in the specific evolutionary subtype.	('EDF genes', 'Gene', (105, 114))	('adenocarcinoma or squamous cell carcinoma', 'Disease', 'MESH:D002294', (26, 67))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (44, 67))	('adenocarcinoma or squamous cell carcinoma', 'Disease', (26, 67))	('mutation', 'Var', (87, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))	('carcinoma', 'Phenotype', 'HP:0030731', (31, 40))
44488	33078899	For example, all the mutations of both TSHR (10/10) and PIK3CA (7/7) occurred in evolutionary subtype 1 (Figure S5C).	('TSHR', 'Gene', (39, 43))	('mutations', 'Var', (21, 30))	('PIK3CA', 'Gene', (56, 62))	('TSHR', 'Gene', '7253', (39, 43))	('PIK3CA', 'Gene', '5290', (56, 62))	('occurred', 'Reg', (69, 77))
44489	33078899	The mutations of WRN (4/4) and COL5A2 (4/4) were only occurred in subtype 2, and the mutations of KEAP1 (7/10), NFE2L2 (4/4), and ARID1A (4/4) were almost only in subtype 3 (Figure S5C).	('ARID1A', 'Gene', '8289', (130, 136))	('KEAP1', 'Gene', (98, 103))	('ARID1A', 'Gene', (130, 136))	('NFE2L2', 'Gene', (112, 118))	('COL5A2', 'Gene', '1290', (31, 37))	('COL5A2', 'Gene', (31, 37))	('KEAP1', 'Gene', '9817', (98, 103))	('mutations', 'Var', (4, 13))	('WRN', 'Gene', '7486', (17, 20))	('NFE2L2', 'Gene', '4780', (112, 118))	('WRN', 'Gene', (17, 20))
44491	33078899	For instance, in all NSCLC patients, the mutation of EDF gene PIK3CA was an early evolutionary event in 89% (8/9) patients within subtype 1 (Figure 5A), which was consistent with the evaluation of the temporal order (Figure S6A,B).	('NSCLC', 'Disease', (21, 26))	('PIK3CA', 'Gene', (62, 68))	('NSCLC', 'Disease', 'MESH:D002289', (21, 26))	('mutation', 'Var', (41, 49))	('patients', 'Species', '9606', (27, 35))	('NSCLC', 'Phenotype', 'HP:0030358', (21, 26))	('PIK3CA', 'Gene', '5290', (62, 68))	('patients', 'Species', '9606', (114, 122))
44492	33078899	While TSHR showed early driver mutations in all subtype 1 patients (10/10).	('TSHR', 'Gene', (6, 10))	('mutations', 'Var', (31, 40))	('TSHR', 'Gene', '7253', (6, 10))	('patients', 'Species', '9606', (58, 66))
44493	33078899	Similarly, the driver mutation of COL5A2 was an early event in 100% (5/5) phylogenetic trees in subtype 2 (Figure 5A).	('COL5A2', 'Gene', '1290', (34, 40))	('COL5A2', 'Gene', (34, 40))	('mutation', 'Var', (22, 30))
44494	33078899	In summary, by the temporal order of the driver mutations in the phylogenetic tree, we identified evolutionary subtype-specific EDF genes, including PIK3CA, NOTCH1, EGFR, and TSHR in subtype 1 patients; KRAS, PTEN, COL5A2, CMTR2, WT1, and WRN in subtype 2; as well as NFE2L2, KEAP1, NIN, ARID1A, and TSC2 in subtype 3 (Figure 5A; Table S2).	('KRAS', 'Gene', '3845', (203, 207))	('TSC2', 'Gene', '7249', (300, 304))	('NFE2L2', 'Gene', '4780', (268, 274))	('COL5A2', 'Gene', '1290', (215, 221))	('mutations', 'Var', (48, 57))	('EGFR', 'Gene', '1956', (165, 169))	('ARID1A', 'Gene', (288, 294))	('KRAS', 'Gene', (203, 207))	('KEAP1', 'Gene', '9817', (276, 281))	('TSC2', 'Gene', (300, 304))	('NOTCH1', 'Gene', (157, 163))	('KEAP1', 'Gene', (276, 281))	('NIN', 'Gene', (283, 286))	('PTEN', 'Gene', (209, 213))	('TSHR', 'Gene', '7253', (175, 179))	('COL5A2', 'Gene', (215, 221))	('NFE2L2', 'Gene', (268, 274))	('ARID1A', 'Gene', '8289', (288, 294))	('PIK3CA', 'Gene', '5290', (149, 155))	('patients', 'Species', '9606', (193, 201))	('CMTR2', 'Gene', (223, 228))	('WT1', 'Gene', (230, 233))	('NOTCH1', 'Gene', '4851', (157, 163))	('PTEN', 'Gene', '5728', (209, 213))	('EGFR', 'Gene', (165, 169))	('TSHR', 'Gene', (175, 179))	('WT1', 'Gene', '7490', (230, 233))	('WRN', 'Gene', '7486', (239, 242))	('PIK3CA', 'Gene', (149, 155))	('EDF', 'PosReg', (128, 131))	('NIN', 'Gene', '51199', (283, 286))	('WRN', 'Gene', (239, 242))	('CMTR2', 'Gene', '55783', (223, 228))
44497	33078899	Researches have shown that gain-of-function mutations of EGFR, KRAS, NFE2L2, and loss-of-function mutations of KEAP1, could produce a convergent activation of NFE2L2  39 ,  40 ,  41  (Figure S7B).	('KRAS', 'Gene', '3845', (63, 67))	('loss-of-function', 'NegReg', (81, 97))	('KEAP1', 'Gene', '9817', (111, 116))	('mutations', 'Var', (98, 107))	('NFE2L2', 'Gene', '4780', (69, 75))	('gain-of-function', 'PosReg', (27, 43))	('KEAP1', 'Gene', (111, 116))	('mutations', 'Var', (44, 53))	('NFE2L2', 'Gene', (159, 165))	('NFE2L2', 'Gene', '4780', (159, 165))	('EGFR', 'Gene', '1956', (57, 61))	('NFE2L2', 'Gene', (69, 75))	('EGFR', 'Gene', (57, 61))	('KRAS', 'Gene', (63, 67))
44499	33078899	42  This indicated that the mutation of these EDF genes among the subtypes could activate NFE2L2 in different ways.	('activate', 'PosReg', (81, 89))	('NFE2L2', 'Gene', '4780', (90, 96))	('mutation', 'Var', (28, 36))	('NFE2L2', 'Gene', (90, 96))	('EDF genes', 'Gene', (46, 55))
44502	33078899	43  By cancer hallmarks associated gene sets, 44  we found that PTEN participated in the apical junction complex, abnormalities in which can cause a decrease in adhesion between cells.	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('cancer', 'Disease', 'MESH:D009369', (7, 13))	('apical junction complex', 'Phenotype', 'HP:0032176', (89, 112))	('participated', 'Reg', (69, 81))	('abnormalities', 'Var', (114, 127))	('PTEN', 'Gene', (64, 68))	('cancer', 'Disease', (7, 13))	('PTEN', 'Gene', '5728', (64, 68))	('decrease', 'NegReg', (149, 157))	('adhesion', 'MPA', (161, 169))
44505	33078899	This result indicated that EDF genes in subtype 2 promoted the development of cancer by obtaining cell stemness, which was consistent with the early accumulation of mutations in this subtype (Figure 3F, Figure 4H).	('development of', 'CPA', (63, 77))	('promoted', 'PosReg', (50, 58))	('EDF', 'Gene', (27, 30))	('cancer', 'Disease', (78, 84))	('cell stemness', 'CPA', (98, 111))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('genes', 'Var', (31, 36))	('obtaining', 'PosReg', (88, 97))
44508	33078899	Besides, the EDF genes within subtype 1 were enriched in functions of cell growth, such as "ERBB2 signaling pathway" and "Constitutive Signaling by Aberrant PI3K in Cancer" (Figure 5F), which could affect tumor cell growth, proliferation, and migration by perturbing the PI3K/AKT/mTOR signaling pathway.	('ERBB2', 'Gene', '2064', (92, 97))	('AKT', 'Gene', '207', (276, 279))	('proliferation', 'CPA', (224, 237))	('perturbing', 'NegReg', (256, 266))	('PI3K', 'Var', (157, 161))	('ERBB2', 'Gene', (92, 97))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('mTOR', 'Gene', '2475', (280, 284))	('Cancer', 'Disease', (165, 171))	('affect', 'Reg', (198, 204))	('mTOR', 'Gene', (280, 284))	('AKT', 'Gene', (276, 279))	('Cancer', 'Disease', 'MESH:D009369', (165, 171))	('Aberrant PI3K', 'Var', (148, 161))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumor', 'Disease', (205, 210))	('migration', 'CPA', (243, 252))	('Cancer', 'Phenotype', 'HP:0002664', (165, 171))
44509	33078899	45 ,  46 ,  47  Taken together, early driving events among evolutionary subtypes determined that genomic variation could perturb the same or subtype-specific functions in multiple ways, drove tumorigenesis and progression in various forms, and ultimately led to diverse evolutionary patterns in cancer patients.	('led to', 'Reg', (255, 261))	('drove', 'Reg', (186, 191))	('tumor', 'Disease', (192, 197))	('genomic variation', 'Var', (97, 114))	('cancer', 'Disease', 'MESH:D009369', (295, 301))	('cancer', 'Disease', (295, 301))	('progression', 'CPA', (210, 221))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('cancer', 'Phenotype', 'HP:0002664', (295, 301))	('perturb', 'Reg', (121, 128))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('patients', 'Species', '9606', (302, 310))
44512	33078899	6 ,  7 ,  9  Intra-tumor heterogeneity may have an important impact on personalized medicine approaches that generally rely on a single-tumor biopsy samples to portray tumor mutations.	('impact', 'Reg', (61, 67))	('tumor', 'Disease', (168, 173))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('tumor', 'Disease', (19, 24))	('mutations', 'Var', (174, 183))	('tumor', 'Disease', (136, 141))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
44527	33078899	Moreover, the driver mutations were more likely to occur on the trunk of the phylogenetic tree, indicating the early stage of tumor evolution in this subtype.	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('tumor', 'Disease', (126, 131))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('mutations', 'Var', (21, 30))
44536	30185546	In human lung adenocarinoma (LUAD) tumors, patients expressing high HORMAD1 exhibited elevated mutational burden and reduced survival.	('elevated', 'PosReg', (86, 94))	('survival', 'MPA', (125, 133))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('human', 'Species', '9606', (3, 8))	('reduced', 'NegReg', (117, 124))	('patients', 'Species', '9606', (43, 51))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('mutational burden', 'MPA', (95, 112))	('lung adenocarinoma', 'Phenotype', 'HP:0030078', (9, 27))	('high', 'Var', (63, 67))	('LUAD', 'Phenotype', 'HP:0030078', (29, 33))	('lung adenocarinoma (LUAD) tumors', 'Disease', 'MESH:D008175', (9, 41))	('HORMAD1', 'Gene', (68, 75))
44561	30185546	Antibodies used were as follows: RAD51 (398587, 1:800, Santa Cruz Biotechnology) and RPA2 (NA19L, 1:500, Millipore, RRID: AB_565123).	('RPA2', 'Gene', (85, 89))	('NA19L', 'Var', (91, 96))	('RAD51', 'Gene', (33, 38))	('RPA2', 'Gene', '6118', (85, 89))	('RAD51', 'Gene', '5888', (33, 38))
44587	30185546	We cultured the S. variabilis strain, SNB-051, on a large scale and obtained fractions used in iterative bioassay analysis with two sensitive NSCLC cell lines (HCC44 and H2122) to identify a single, potent fraction: SNB-051-F36-H7 (see Supplementary Methods; Supplementary Fig.	('NSCLC', 'Disease', (142, 147))	('NSCLC', 'Disease', 'MESH:D002289', (142, 147))	('NSCLC', 'Phenotype', 'HP:0030358', (142, 147))	('SNB-051-F36-H7', 'Var', (216, 230))	('HCC44', 'CellLine', 'CVCL:2060', (160, 165))	('S. variabilis', 'Species', '67372', (16, 29))
44588	30185546	High-resolution ESI-MS analysis of SNB-051-F36-H7 identified a mass/charge consistent with the molecular formula C25H37NO4 (m/z [M+H] 416.2794).	('C25H37NO4', 'Var', (113, 122))	('C25H37NO4', 'Chemical', 'MESH:C039438', (113, 122))	('SNB-051-F36-H7', 'Gene', (35, 49))
44608	30185546	H2O2 is well known to induce oxidation of lipids, proteins, and DNA.	('DNA', 'MPA', (64, 67))	('H2O2', 'Chemical', 'MESH:D014867', (0, 4))	('proteins', 'Protein', (50, 58))	('oxidation', 'MPA', (29, 38))	('induce', 'Reg', (22, 28))	('H2O2', 'Var', (0, 4))
44619	30185546	We also used CRISPR/Cas9 to knockdown HORMAD1 in A549 and H358 cell lines (sgHORMAD1).	('A549', 'CellLine', 'CVCL:0023', (49, 53))	('HORMAD1', 'Gene', (38, 45))	('knockdown', 'Var', (28, 37))
44625	30185546	Furthermore, high HORMAD1 expression also correlated with elevated mutation burden exclusively in the LUAD patient population but not in the LUSC tumors (Fig.	('expression', 'MPA', (26, 36))	('LUSC tumors', 'Disease', (141, 152))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('mutation burden', 'MPA', (67, 82))	('high', 'Var', (13, 17))	('LUSC', 'Phenotype', 'HP:0030359', (141, 145))	('HORMAD1', 'Gene', (18, 25))	('LUSC tumors', 'Disease', 'MESH:D009369', (141, 152))	('tumors', 'Phenotype', 'HP:0002664', (146, 152))	('elevated', 'PosReg', (58, 66))	('patient', 'Species', '9606', (107, 114))	('LUAD', 'Phenotype', 'HP:0030078', (102, 106))
44630	30185546	However, inhibitors of methylation have been successfully used to induce CTA expression in patient populations to boost responses to CTA-based immunotherapy.	('boost', 'PosReg', (114, 119))	('induce', 'Reg', (66, 72))	('CTA expression', 'Protein', (73, 87))	('patient', 'Species', '9606', (91, 98))	('responses', 'MPA', (120, 129))	('inhibitors', 'Var', (9, 19))
44650	30185546	A549 cells are p53 wild-type and KRAS mutant; thus, we tested additional cell lines with opposite mutations: H2126 (p53 mutant, KRAS wild-type) and H2030 (p53 mutant, KRAS mutant).	('KRAS', 'Gene', (128, 132))	('H2126', 'Var', (109, 114))	('p53', 'Gene', (155, 158))	('A549', 'CellLine', 'CVCL:0023', (0, 4))	('p53', 'Gene', '7157', (155, 158))	('H2030', 'Var', (148, 153))	('KRAS', 'Gene', '3845', (128, 132))	('KRAS', 'Gene', (33, 37))	('p53', 'Gene', (15, 18))	('p53', 'Gene', '7157', (15, 18))	('p53', 'Gene', '7157', (116, 119))	('KRAS', 'Gene', '3845', (33, 37))	('KRAS', 'Gene', (167, 171))	('KRAS', 'Gene', '3845', (167, 171))	('p53', 'Gene', (116, 119))
44679	30185546	Importantly, HORMAD1 may predict sensitivity to PD-1 inhibitors in patients with NSCLC that are typically classified as nonresponders due to ROS1 amplification, ALK4 translocation, or EGFR mutation.	('amplification', 'Var', (146, 159))	('predict', 'Reg', (25, 32))	('patients', 'Species', '9606', (67, 75))	('EGFR', 'Gene', '1956', (184, 188))	('NSCLC', 'Phenotype', 'HP:0030358', (81, 86))	('sensitivity', 'MPA', (33, 44))	('ROS1', 'Gene', (141, 145))	('EGFR', 'Gene', (184, 188))	('mutation', 'Var', (189, 197))	('ALK4', 'Gene', '91', (161, 165))	('NSCLC', 'Disease', (81, 86))	('ROS1', 'Gene', '6098', (141, 145))	('ALK4', 'Gene', (161, 165))	('NSCLC', 'Disease', 'MESH:D002289', (81, 86))
44681	30185546	This study uses a chemigenomics approach to demonstrate that anomalous expression of the CTA HORMAD1 specifies resistance to oxidative stress and promotes HR to support tumor cell survival in NSCLC.	('NSCLC', 'Disease', (192, 197))	('CTA HORMAD1', 'Gene', (89, 100))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('NSCLC', 'Disease', 'MESH:D002289', (192, 197))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('anomalous expression', 'Var', (61, 81))	('oxidative stress', 'Phenotype', 'HP:0025464', (125, 141))	('tumor', 'Disease', (169, 174))	('NSCLC', 'Phenotype', 'HP:0030358', (192, 197))	('promotes', 'PosReg', (146, 154))	('support', 'PosReg', (161, 168))	('resistance to oxidative stress', 'MPA', (111, 141))
44733	30333907	Interestingly, the repression of TGIF2 nuclear expression in EMT (+) with siScrbl transfection (Figure 4A; g, Supplementary Figure 8B; b) was rescued when PKM2 was knocked down in EMT (+) with siPKM2 transfection (Figure 4A; h, Supplementary Figure 8B; d) in HSC-4 cells.	('PKM2', 'Gene', (195, 199))	('HSC-4', 'CellLine', 'CVCL:1289', (259, 264))	('TGIF2', 'Gene', '60436', (33, 38))	('PKM2', 'Gene', '5315', (195, 199))	('TGIF2', 'Gene', (33, 38))	('knocked down', 'Var', (164, 176))	('PKM2', 'Gene', (155, 159))	('PKM2', 'Gene', '5315', (155, 159))	('repression', 'MPA', (19, 29))
44735	30333907	Western blotting analyses and LI comparison also showed the same results that the repression of TGIF2 expression in EMT induced HSC-4 cells with siScrbl transfection was rescued when the EMT induction was inhibited by siPKM2 transfection (Figure 4B, 4C).	('HSC-4', 'CellLine', 'CVCL:1289', (128, 133))	('TGIF2', 'Gene', (96, 101))	('PKM2', 'Gene', (220, 224))	('PKM2', 'Gene', '5315', (220, 224))	('transfection', 'Var', (153, 165))	('TGIF2', 'Gene', '60436', (96, 101))
44743	30333907	LI analyses for TGIF2 nuclear expression also showed significant LI decrease in between MG132(-)EMT(-) and MG132(-)EMT(+) and also in between MG132(+)EMT(-) and MG132(+)EMT(+) (Figure 5B for HSC-4, Supplementary Figure 10B for SAS).	('MG132', 'Chemical', 'MESH:C072553', (161, 166))	('HSC-4', 'CellLine', 'CVCL:1289', (191, 196))	('decrease', 'NegReg', (68, 76))	('MG132(-', 'Var', (88, 95))	('TGIF2', 'Gene', '60436', (16, 21))	('MG132', 'Chemical', 'MESH:C072553', (107, 112))	('TGIF2', 'Gene', (16, 21))	('MG132', 'Chemical', 'MESH:C072553', (142, 147))	('MG132', 'Chemical', 'MESH:C072553', (88, 93))	('MG132(-', 'Var', (107, 114))
44744	30333907	Strikingly, this repression of TGIF2 expression in MG132(-)EMT(+) was rescued and the TGIF2 expression was seen mainly in the cytoplasm and focally in the nucleus in HSC-4 and SAS cells in MG132(+)EMT(+) (Figure 5A; c, d, Supplementary Figure 9; b, d for HSC-4, Supplementary Figure 10A; b, d for SAS).	('HSC-4', 'CellLine', 'CVCL:1289', (166, 171))	('TGIF2', 'Gene', '60436', (86, 91))	('TGIF2', 'Gene', (86, 91))	('MG132', 'Chemical', 'MESH:C072553', (189, 194))	('TGIF2', 'Gene', (31, 36))	('TGIF2', 'Gene', '60436', (31, 36))	('MG132(+', 'Var', (189, 196))	('MG132', 'Chemical', 'MESH:C072553', (51, 56))	('MG132', 'Var', (51, 56))	('HSC-4', 'CellLine', 'CVCL:1289', (255, 260))
44745	30333907	In western blotting analyses, the band of TGIF2 in MG132(-)EMT(+) was weaker than that in MG132(-)EMT(-).	('MG132', 'Chemical', 'MESH:C072553', (51, 56))	('weaker', 'NegReg', (70, 76))	('MG132', 'Chemical', 'MESH:C072553', (90, 95))	('MG132(-', 'Var', (51, 58))	('band', 'MPA', (34, 38))	('TGIF2', 'Gene', '60436', (42, 47))	('TGIF2', 'Gene', (42, 47))
44746	30333907	On the other hand, there were no significant changes in the TGIF2 bands in HSC-4 cells in between MG132(+)EMT (-) and MG132(+)EMT(+) (Figure 5C).	('HSC-4', 'CellLine', 'CVCL:1289', (75, 80))	('MG132(+', 'Var', (118, 125))	('TGIF2', 'Gene', '60436', (60, 65))	('TGIF2', 'Gene', (60, 65))	('MG132(+)EMT', 'Var', (98, 109))	('MG132', 'Chemical', 'MESH:C072553', (118, 123))	('MG132', 'Chemical', 'MESH:C072553', (98, 103))
44747	30333907	Ubiquitin- and conjugated ubiquitin-bind bands were also observed, but those bands in MG132 (+) were more distinct than those in MG132 (-), which revealed the inhibitory effect of MG132 against proteasome activity (Figure 5C).	('MG132', 'Var', (86, 91))	('MG132', 'Chemical', 'MESH:C072553', (180, 185))	('Ubiquitin-', 'MPA', (0, 10))	('MG132', 'Chemical', 'MESH:C072553', (86, 91))	('conjugated ubiquitin-bind', 'MPA', (15, 40))	('MG132', 'Chemical', 'MESH:C072553', (129, 134))	('proteasome', 'MPA', (194, 204))
44754	30333907	These results showed that the increased migration activity in the EMT induced HSC-4 and SAS cells was significantly inhibited by the PKM2 knockdown.	('PKM2', 'Gene', (133, 137))	('knockdown', 'Var', (138, 147))	('PKM2', 'Gene', '5315', (133, 137))	('migration activity in', 'CPA', (40, 61))	('inhibited', 'NegReg', (116, 125))	('HSC-4', 'CellLine', 'CVCL:1289', (78, 83))	('increased', 'PosReg', (30, 39))
44755	30333907	The transwell cell migration and invasion assays also showed that PKM2 knockdown significantly repressed the mobility of HSC-4 cells (Figure 6B; a, b).	('PKM2', 'Gene', (66, 70))	('knockdown', 'Var', (71, 80))	('PKM2', 'Gene', '5315', (66, 70))	('repressed', 'NegReg', (95, 104))	('mobility of HSC-4 cells', 'CPA', (109, 132))	('HSC-4', 'CellLine', 'CVCL:1289', (121, 126))
44756	30333907	SAS cells revealed same tendency as repression of migration and invasion by PKM2 knockdown but there was no statistical significance (data not shown).	('knockdown', 'Var', (81, 90))	('PKM2', 'Gene', (76, 80))	('PKM2', 'Gene', '5315', (76, 80))
44762	30333907	We also showed that high scores of PKM2 TS were significantly correlated with the lymphatic and/or vascular permeation and lymph node metastasis.	('high scores', 'Var', (20, 31))	('PKM2', 'Gene', (35, 39))	('lymphatic and/or vascular permeation', 'CPA', (82, 118))	('PKM2', 'Gene', '5315', (35, 39))	('lymph node metastasis', 'CPA', (123, 144))	('correlated', 'Reg', (62, 72))
44766	30333907	The dimer of PKM2 regulates gene transcription by acting as a protein kinase in the cancer cell nucleus, and correlates with cancer cell proliferation.	('PKM2', 'Gene', (13, 17))	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('PKM2', 'Gene', '5315', (13, 17))	('correlates with', 'Reg', (109, 124))	('cancer', 'Disease', (84, 90))	('gene transcription', 'MPA', (28, 46))	('acting', 'Reg', (50, 56))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('dimer', 'Var', (4, 9))	('regulates', 'Reg', (18, 27))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))
44770	30333907	PKM2 is directly bound with EGFR-activated extracellular signal-regulated kinase 2 (ERK2) at PKM2-specific exon 10-encoded Ile 429/Leu 431 through ERK2 docking groove, and is phosphorylated at Ser 37.	('ERK2', 'Gene', (84, 88))	('EGFR', 'Gene', '1956', (28, 32))	('PKM2', 'Gene', (0, 4))	('EGFR', 'Gene', (28, 32))	('ERK2', 'Gene', (147, 151))	('PKM2', 'Gene', '5315', (0, 4))	('ERK2', 'Gene', '5594', (84, 88))	('Ser', 'Chemical', 'MESH:D012694', (193, 196))	('Leu', 'Chemical', 'MESH:D007930', (131, 134))	('PKM2', 'Gene', (93, 97))	('extracellular signal-regulated kinase 2', 'Gene', (43, 82))	('PKM2', 'Gene', '5315', (93, 97))	('ERK2', 'Gene', '5594', (147, 151))	('Ile 429/Leu 431', 'Var', (123, 138))	('Ile', 'Chemical', 'MESH:D007532', (123, 126))	('extracellular signal-regulated kinase 2', 'Gene', '5594', (43, 82))
44776	30333907	Binding of K433 of nuclear PKM2 to c-Src-phosphorylated Y333 of beta-catenin is required for their recruitment to the cyclin D1 gene (CCND1) promoter, leading to HDAC3 removal from the promoter, histone H3 acetylation and cyclin D1 expression.	('Y333', 'Chemical', '-', (56, 60))	('beta-catenin', 'Gene', (64, 76))	('expression', 'MPA', (232, 242))	('beta-catenin', 'Gene', '1499', (64, 76))	('K433', 'Var', (11, 15))	('Y333', 'Var', (56, 60))	('HDAC3', 'Gene', (162, 167))	('cyclin D1', 'Gene', (222, 231))	('CCND1', 'Gene', '595', (134, 139))	('Src', 'Gene', (37, 40))	('PKM2', 'Gene', (27, 31))	('cyclin D1', 'Gene', '595', (222, 231))	('PKM2', 'Gene', '5315', (27, 31))	('cyclin D1', 'Gene', (118, 127))	('CCND1', 'Gene', (134, 139))	('histone H3 acetylation', 'MPA', (195, 217))	('Src', 'Gene', '6714', (37, 40))	('removal from', 'NegReg', (168, 180))	('HDAC3', 'Gene', '8841', (162, 167))	('cyclin D1', 'Gene', '595', (118, 127))
44784	30333907	In addition, EMT induction in HSC-4 and SAS cells was also inhibited by PKM2 knockdown.	('EMT induction', 'CPA', (13, 26))	('inhibited', 'NegReg', (59, 68))	('knockdown', 'Var', (77, 86))	('HSC-4', 'CellLine', 'CVCL:1289', (30, 35))	('PKM2', 'Gene', (72, 76))	('PKM2', 'Gene', '5315', (72, 76))
44802	30333907	Contrary to these reports, in which TGIF2 functioned as an inhibitory manner and loss of TGIF leaded to progression in cancer development, there were a few reports describing the contradictory effect of TGIF2 in cancer development.	('TGIF2', 'Gene', '60436', (36, 41))	('progression', 'PosReg', (104, 115))	('cancer', 'Disease', 'MESH:D009369', (212, 218))	('TGIF2', 'Gene', (203, 208))	('TGIF', 'Gene', '7050', (89, 93))	('cancer', 'Disease', (119, 125))	('TGIF', 'Gene', (89, 93))	('TGIF2', 'Gene', (36, 41))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('TGIF', 'Gene', '7050', (36, 40))	('cancer', 'Disease', (212, 218))	('TGIF', 'Gene', (36, 40))	('leaded to', 'Reg', (94, 103))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))	('TGIF', 'Gene', '7050', (203, 207))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('TGIF', 'Gene', (203, 207))	('TGIF2', 'Gene', '60436', (203, 208))	('loss', 'Var', (81, 85))
44803	30333907	Imoto et al., reported that TGIF2 gene was overexpressed in ovarian cancer cell lines and might play an important role in the development/or progression of some ovarian tumors through a mechanism of gene amplification.	('gene amplification', 'Var', (199, 217))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('ovarian cancer', 'Phenotype', 'HP:0100615', (60, 74))	('ovarian tumors', 'Disease', 'MESH:D010051', (161, 175))	('role', 'Reg', (114, 118))	('ovarian cancer', 'Disease', 'MESH:D010051', (60, 74))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('TGIF2', 'Gene', '60436', (28, 33))	('ovarian tumor', 'Phenotype', 'HP:0100615', (161, 174))	('ovarian cancer', 'Disease', (60, 74))	('tumors', 'Phenotype', 'HP:0002664', (169, 175))	('play', 'Reg', (96, 100))	('overexpressed', 'PosReg', (43, 56))	('ovarian tumors', 'Disease', (161, 175))	('ovarian tumors', 'Phenotype', 'HP:0100615', (161, 175))	('TGIF2', 'Gene', (28, 33))
44855	30333907	HSC-4 and SAS cells cultured in serum free standard medium with or without siPKM2 in EMT (+) condition were seeded into each insert of the 24-well Falcon culture insert (#353097, Corning, NY, USA) for migration assay, or seeded into each insert of the 24-well Biocoat Matrigel Invasion Chamber (#351180, Corning) for invasion assay.	('PKM2', 'Gene', (77, 81))	('PKM2', 'Gene', '5315', (77, 81))	('invasion assay', 'CPA', (317, 331))	('migration assay', 'CPA', (201, 216))	('HSC-4', 'CellLine', 'CVCL:1289', (0, 5))	('#353097', 'Var', (170, 177))
44862	30185897	Furthermore, we demonstrated that downregulation of miR-301a in BEAS-2B attenuates tumor growth in the xenograft model by targeting SMAD4.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('targeting', 'Reg', (122, 131))	('BEAS-2B attenuates tumor', 'Disease', (64, 88))	('SMAD4', 'Protein', (132, 137))	('downregulation', 'NegReg', (34, 48))	('miR-301a', 'Var', (52, 60))	('BEAS-2B attenuates tumor', 'Disease', 'MESH:C538265', (64, 88))
44863	30185897	Of note, the level of miR-301a expression correlated inversely with SMAD4 expression in clinical specimens of human lung cancer.	('expression', 'MPA', (74, 84))	('inversely', 'NegReg', (53, 62))	('lung cancer', 'Disease', (116, 127))	('lung cancer', 'Phenotype', 'HP:0100526', (116, 127))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('SMAD4', 'Gene', (68, 73))	('human', 'Species', '9606', (110, 115))	('expression', 'MPA', (31, 41))	('lung cancer', 'Disease', 'MESH:D008175', (116, 127))	('miR-301a', 'Var', (22, 30))
44864	30185897	Our findings ascertain that miR-301a is an oncogenic miRNA, which targets SMAD4 to establish an essential mechanism for arsenic-induced carcinogenesis, IL-6/STAT3/miR-301a/SMAD4 signaling pathways.	('arsenic', 'Chemical', 'MESH:D001151', (120, 127))	('miR-301a', 'Var', (28, 36))	('IL-6', 'Gene', (152, 156))	('carcinogenesis', 'Disease', 'MESH:D063646', (136, 150))	('IL-6', 'Gene', '3569', (152, 156))	('carcinogenesis', 'Disease', (136, 150))
44868	30185897	Several genotoxic and epigenetic alterations have been tightly associated with the arsenic transformation process, which leads to increased cancer risk.	('associated', 'Reg', (63, 73))	('arsenic', 'Chemical', 'MESH:D001151', (83, 90))	('epigenetic alterations', 'Var', (22, 44))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('arsenic transformation', 'Disease', (83, 105))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))
44875	30185897	Over 1000 human miRNAs have been identified so far, miR-301a is a potential oncogenic miRNA and contributes to tumor formation.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('human', 'Species', '9606', (10, 15))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('miR-301a', 'Var', (52, 60))	('contributes', 'Reg', (96, 107))	('tumor', 'Disease', (111, 116))
44877	30185897	In lung cancer, knockdown of miR-301a reduces anchorage independent colony formation of lung cancer cells and inhibit cellular proliferation, migration and invasion of non-small cell lung cancer cell line.	('small cell lung cancer', 'Phenotype', 'HP:0030357', (172, 194))	('lung cancer', 'Disease', (88, 99))	('lung cancer', 'Phenotype', 'HP:0100526', (3, 14))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (168, 194))	('inhibit', 'NegReg', (110, 117))	('cellular proliferation', 'CPA', (118, 140))	('lung cancer', 'Disease', 'MESH:D008175', (183, 194))	('lung cancer', 'Disease', 'MESH:D008175', (88, 99))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('lung cancer', 'Phenotype', 'HP:0100526', (183, 194))	('non-small cell lung cancer', 'Disease', (168, 194))	('lung cancer', 'Phenotype', 'HP:0100526', (88, 99))	('lung cancer', 'Disease', (3, 14))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('anchorage independent colony formation', 'CPA', (46, 84))	('reduces', 'NegReg', (38, 45))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (168, 194))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('knockdown', 'Var', (16, 25))	('miR-301a', 'Gene', (29, 37))	('lung cancer', 'Disease', 'MESH:D008175', (3, 14))	('invasion', 'CPA', (156, 164))
44880	30185897	Deletion of miR-301a reduced lung tumor development and increases survival in KrasLA2 mice, which correlates with reduced the activation of both NF-kappaB and STAT3.	('reduced', 'NegReg', (21, 28))	('lung tumor', 'Disease', 'MESH:D008175', (29, 39))	('increases', 'PosReg', (56, 65))	('lung tumor', 'Disease', (29, 39))	('NF-kappaB', 'Protein', (145, 154))	('reduced', 'NegReg', (114, 121))	('miR-301a', 'Gene', (12, 20))	('activation', 'PosReg', (126, 136))	('STAT3', 'MPA', (159, 164))	('mice', 'Species', '10090', (86, 90))	('lung tumor', 'Phenotype', 'HP:0100526', (29, 39))	('survival', 'CPA', (66, 74))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('Deletion', 'Var', (0, 8))
44883	30185897	Thus, the mechanisms by which miR-301a modulating STAT3 signaling in the development of arsenic-induced cellular transformation are needed to clarify.	('arsenic', 'Chemical', 'MESH:D001151', (88, 95))	('modulating', 'Reg', (39, 49))	('miR-301a', 'Var', (30, 38))	('STAT3 signaling', 'MPA', (50, 65))
44885	30185897	Further study demonstrated that STAT3/miR-301a/SMAD4 cascade promote the arsenic-induced cellular transformation and tumorigenesis.	('arsenic-induced cellular transformation', 'CPA', (73, 112))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('STAT3/miR-301a/SMAD4', 'Var', (32, 52))	('tumor', 'Disease', (117, 122))	('promote', 'PosReg', (61, 68))	('arsenic', 'Chemical', 'MESH:D001151', (73, 80))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
44886	30185897	Silencing of miR-301a or induction of Smad4 in arsenic transformed BEAS-2B cells reduce the tumorigenesis in xenograft nude mice.	('arsenic', 'Chemical', 'MESH:D001151', (47, 54))	('reduce', 'NegReg', (81, 87))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('nude mice', 'Species', '10090', (119, 128))	('tumor', 'Disease', (92, 97))	('miR-301a', 'Gene', (13, 21))	('Silencing', 'Var', (0, 9))	('BEAS-2B', 'CellLine', 'CVCL:0168', (67, 74))	('Smad4', 'Gene', (38, 43))	('Smad4', 'Gene', '4089', (38, 43))
44901	30185897	miR-301a was significantly increased with IL-6 stimulation, and the effect was abrogated with STAT3 inhibitor, S31-201 treatment (Fig.	('miR-301a', 'Var', (0, 8))	('increased', 'PosReg', (27, 36))	('S31-201', 'Chemical', '-', (111, 118))	('IL-6', 'Gene', (42, 46))	('IL-6', 'Gene', '3569', (42, 46))
44904	30185897	As we expected, arsenic alone treatment results the higher level of miR-301a, while with inhibition of either STAT3 inhibitor or IL-6 inhibition reduced the expression of miR-301a (Fig.	('reduced', 'NegReg', (145, 152))	('expression', 'MPA', (157, 167))	('IL-6', 'Gene', (129, 133))	('miR-301a', 'MPA', (68, 76))	('IL-6', 'Gene', '3569', (129, 133))	('arsenic', 'Chemical', 'MESH:D001151', (16, 23))	('miR-301a', 'Var', (171, 179))
44905	30185897	As miR-301a was reported to be an activator of both STAT3 and NF-kappaB in lung tumorigenesis, we sought to determine whether inhibition of miR-301a leads to reduce the activation of Stat3 or NF-kappaB.	('activation', 'PosReg', (169, 179))	('Stat3', 'Gene', (183, 188))	('Stat3', 'Gene', '6774', (183, 188))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('inhibition', 'Var', (126, 136))	('lung tumor', 'Disease', (75, 85))	('NF-kappaB', 'Pathway', (192, 201))	('reduce', 'NegReg', (158, 164))	('lung tumor', 'Disease', 'MESH:D008175', (75, 85))	('lung tumor', 'Phenotype', 'HP:0100526', (75, 85))	('miR-301a', 'Gene', (140, 148))
44907	30185897	Furthermore, there was no significant differences of IkappaBalpha expression between BEAS-2B cells transfected with anti-control and with anti-miR-301a with arsenic treatment (Fig.	('arsenic', 'Chemical', 'MESH:D001151', (157, 164))	('BEAS-2B', 'CellLine', 'CVCL:0168', (85, 92))	('IkappaBalpha', 'Gene', '4792', (53, 65))	('anti-miR-301a', 'Var', (138, 151))	('IkappaBalpha', 'Gene', (53, 65))
44909	30185897	As an oncogenic miRNA, miR-301a was involved in the regulation of various processes associated with a variety of human malignancies, including cell proliferation, viability, metastasis and invasion.	('cell proliferation', 'CPA', (143, 161))	('malignancies', 'Disease', (119, 131))	('viability', 'CPA', (163, 172))	('invasion', 'CPA', (189, 197))	('miR-301a', 'Var', (23, 31))	('involved', 'Reg', (36, 44))	('metastasis', 'CPA', (174, 184))	('human', 'Species', '9606', (113, 118))	('malignancies', 'Disease', 'MESH:D009369', (119, 131))
44916	30185897	However, inhibition of miR-301a significantly enhanced the chemo-sensitivity of doxorubicin in transformed BEAS-2B.	('BEAS-2B', 'CellLine', 'CVCL:0168', (107, 114))	('chemo-sensitivity of doxorubicin', 'MPA', (59, 91))	('enhanced', 'PosReg', (46, 54))	('miR-301a', 'Gene', (23, 31))	('doxorubicin', 'Chemical', 'MESH:D004317', (80, 91))	('inhibition', 'Var', (9, 19))
44917	30185897	These data confirmed that miR-301a promote cell proliferation and migration of arsenic induced transformed BEAS-2B cells and inhibition of miR-301a would be beneficial in apoptosis-inducing cancer therapies against arsenic-induced tumorigenesis.	('cancer', 'Disease', (190, 196))	('tumor', 'Disease', 'MESH:D009369', (231, 236))	('cancer', 'Disease', 'MESH:D009369', (190, 196))	('migration', 'CPA', (66, 75))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('arsenic', 'Chemical', 'MESH:D001151', (79, 86))	('tumor', 'Disease', (231, 236))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('miR-301a', 'Gene', (139, 147))	('promote', 'PosReg', (35, 42))	('BEAS-2B', 'CellLine', 'CVCL:0168', (107, 114))	('arsenic', 'Chemical', 'MESH:D001151', (215, 222))	('inhibition', 'Var', (125, 135))	('cell proliferation', 'CPA', (43, 61))	('miR-301a', 'Gene', (26, 34))
44920	30185897	Of note, inhibition of miR-301a expression significantly enhanced the expression of SMAD4 in transformed BEAS-2B cells and did not affect the expression level of NKRF.	('SMAD4', 'Gene', (84, 89))	('NKRF', 'Gene', '55922', (162, 166))	('expression', 'MPA', (70, 80))	('miR-301a', 'Gene', (23, 31))	('enhanced', 'PosReg', (57, 65))	('inhibition', 'Var', (9, 19))	('NKRF', 'Gene', (162, 166))	('BEAS-2B', 'CellLine', 'CVCL:0168', (105, 112))
44924	30185897	By using a luciferase reporter system, we sought to determine whether miR-301a directly binds the mRNA encoding Smad4 and down-regulates expression of Smad4.	('Smad4', 'Gene', (151, 156))	('down-regulates', 'NegReg', (122, 136))	('expression', 'MPA', (137, 147))	('miR-301a', 'Var', (70, 78))	('Smad4', 'Gene', '4089', (151, 156))	('binds', 'Interaction', (88, 93))	('Smad4', 'Gene', (112, 117))	('Smad4', 'Gene', '4089', (112, 117))
44927	30185897	These data indicated that miR-301a directly targets the mRNA encoding Smad4 and knockdown of miR-301a leads to elevating SMAD4 protein level in arsenic-induced transformed BEAS-2B cells.	('knockdown', 'Var', (80, 89))	('elevating', 'PosReg', (111, 120))	('arsenic', 'Chemical', 'MESH:D001151', (144, 151))	('Smad4', 'Gene', (70, 75))	('Smad4', 'Gene', '4089', (70, 75))	('miR-301a', 'Gene', (93, 101))	('BEAS-2B', 'CellLine', 'CVCL:0168', (172, 179))	('SMAD4 protein level', 'MPA', (121, 140))
44929	30185897	We first designed three shRNA against Smad4 and found shRNA-02 and shRNA-03 significantly downregulated SMAD4 expression in transformed BEAS-2B cells (Fig.	('BEAS-2B', 'CellLine', 'CVCL:0168', (136, 143))	('shRNA-03', 'Var', (67, 75))	('downregulated', 'NegReg', (90, 103))	('expression', 'MPA', (110, 120))	('SMAD4', 'Gene', (104, 109))	('Smad4', 'Gene', (38, 43))	('Smad4', 'Gene', '4089', (38, 43))
44931	30185897	We then evaluated the cell proliferation by using CCK-8 kit and found that knockdown of Smad4 via short hairpin RNA (shRNA) significantly enhanced cell proliferation (Fig.	('cell proliferation', 'CPA', (147, 165))	('enhanced', 'PosReg', (138, 146))	('knockdown', 'Var', (75, 84))	('Smad4', 'Gene', (88, 93))	('Smad4', 'Gene', '4089', (88, 93))
44934	30185897	Collectively, our results indicated that upregulation of SMAD4 is responsible for the reduced cell proliferation and migration, and enhanced doxorubicin-induced cellular apoptosis observed in transformed BEAS-2B cells with miR-301a inhibition.	('reduced', 'NegReg', (86, 93))	('migration', 'CPA', (117, 126))	('BEAS-2B', 'CellLine', 'CVCL:0168', (204, 211))	('miR-301a', 'Var', (223, 231))	('SMAD4', 'Gene', (57, 62))	('doxorubicin-induced', 'MPA', (141, 160))	('doxorubicin', 'Chemical', 'MESH:D004317', (141, 152))	('enhanced', 'PosReg', (132, 140))	('cell proliferation', 'CPA', (94, 112))	('upregulation', 'PosReg', (41, 53))
44936	30185897	We subcutaneously injected transformed BEAS-2B cells either with Anti-miR-control or Anti-miR-301a into nude mice respectively.	('Anti-miR-control', 'Var', (65, 81))	('BEAS-2B', 'CellLine', 'CVCL:0168', (39, 46))	('nude mice', 'Species', '10090', (104, 113))	('Anti-miR-301a', 'Var', (85, 98))
44939	30185897	To define the impact of SMAD4 on tumor growth with miR-301a inhibition, transformed BEAS-2B cells with anti-miR-301a plus either shRNA control or shRNA-Smad4 were subcutaneously injected into nude mice.	('BEAS-2B', 'CellLine', 'CVCL:0168', (84, 91))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('Smad4', 'Gene', (152, 157))	('Smad4', 'Gene', '4089', (152, 157))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('anti-miR-301a', 'Var', (103, 116))	('nude mice', 'Species', '10090', (192, 201))	('tumor', 'Disease', (33, 38))
44942	30185897	In consistent with this, knockdown of SMAD4 leads to increase the activation of STAT3 in BEAS-2B cells with miR-301a inhibition treated with arsenic (Fig.	('SMAD4', 'Gene', (38, 43))	('miR-301a', 'Gene', (108, 116))	('BEAS-2B', 'CellLine', 'CVCL:0168', (89, 96))	('activation', 'MPA', (66, 76))	('arsenic', 'Chemical', 'MESH:D001151', (141, 148))	('increase', 'PosReg', (53, 61))	('STAT3', 'MPA', (80, 85))	('inhibition', 'NegReg', (117, 127))	('knockdown', 'Var', (25, 34))
44951	30185897	It is generally accepted that epigenetic mechanism may play a key role in arenic-induced tumorigenesis mostly due to its weakly genotoxic carcinogen.	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('epigenetic mechanism', 'Var', (30, 50))	('tumor', 'Disease', (89, 94))	('tumor', 'Disease', 'MESH:D009369', (89, 94))
44953	30185897	For example, knockdown of miR-21 reduces the cell proliferation and xenograft tumors produced by arsenic-induced transformed human embryo lung fibroblast cell (HELFs) and human bronchial epithelial cells (BEAS-2B).	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('reduces', 'NegReg', (33, 40))	('xenograft tumors', 'Disease', (68, 84))	('miR-21', 'Gene', '406991', (26, 32))	('cell proliferation', 'CPA', (45, 63))	('human', 'Species', '9606', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('knockdown', 'Var', (13, 22))	('arsenic', 'Chemical', 'MESH:D001151', (97, 104))	('xenograft tumors', 'Disease', 'MESH:D009369', (68, 84))	('miR-21', 'Gene', (26, 32))	('human', 'Species', '9606', (171, 176))	('BEAS-2B', 'CellLine', 'CVCL:0168', (205, 212))
44955	30185897	In the present work, we investigated the role of miR-301a in arsenic-induced BEAS-2B cellular transformation and tumorigenesis.	('tumor', 'Disease', (113, 118))	('arsenic', 'Chemical', 'MESH:D001151', (61, 68))	('miR-301a', 'Var', (49, 57))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('BEAS-2B', 'CellLine', 'CVCL:0168', (77, 84))
44956	30185897	The major finding of this study is that inhibition of miR-301a reduced the malignance of transformed human bronchial epithelial cells and the activation of STAT3/miR-301a/SMAD4 contribute to the tumorigenesis of arsenic-induced transformed cells.	('arsenic', 'Chemical', 'MESH:D001151', (212, 219))	('inhibition', 'Var', (40, 50))	('tumor', 'Disease', (195, 200))	('activation', 'PosReg', (142, 152))	('reduced', 'NegReg', (63, 70))	('human', 'Species', '9606', (101, 106))	('miR-301a', 'Gene', (54, 62))	('STAT3/miR-301a/SMAD4', 'Gene', (156, 176))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))
44962	30185897	Sustained overproduction of IL-6 and STAT3 was found to contributes to arsenic causes carcinogenesis and STAT3 is also required for cellular transformation and performed pro-tumorigenic functions, including promotion of tumor cell proliferation, survival, invasion, metastasis, and angiogenesis.	('carcinogenesis', 'Disease', (86, 100))	('tumor', 'Disease', (174, 179))	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('IL-6', 'Gene', '3569', (28, 32))	('survival', 'CPA', (246, 254))	('overproduction', 'PosReg', (10, 24))	('tumor', 'Disease', (220, 225))	('STAT3', 'Var', (105, 110))	('invasion', 'CPA', (256, 264))	('metastasis', 'CPA', (266, 276))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('promotion', 'PosReg', (207, 216))	('carcinogenesis', 'Disease', 'MESH:D063646', (86, 100))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('arsenic', 'Chemical', 'MESH:D001151', (71, 78))	('IL-6', 'Gene', (28, 32))	('tumor', 'Disease', 'MESH:D009369', (220, 225))	('angiogenesis', 'CPA', (282, 294))
44963	30185897	Interestingly, miR-301a was shown to be an activator of STAT3 in T cells and lung tumor mouse model through downregulating its target gene, Pias3.	('lung tumor', 'Disease', 'MESH:D008175', (77, 87))	('downregulating', 'NegReg', (108, 122))	('lung tumor', 'Disease', (77, 87))	('miR-301a', 'Var', (15, 23))	('Pias3', 'Gene', '229615', (140, 145))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('mouse', 'Species', '10090', (88, 93))	('lung tumor', 'Phenotype', 'HP:0100526', (77, 87))	('Pias3', 'Gene', (140, 145))
44969	30185897	We for the first time demonstrated that Smad4 is a direct target of miR-301a in arsenic-induced transformed BEAS-2B cells and knockdown of SMAD4 enhanced the malignance of transformed BEAS-2B cells with miR-301a inhibition.	('malignance of', 'CPA', (158, 171))	('enhanced', 'PosReg', (145, 153))	('SMAD4', 'Gene', (139, 144))	('arsenic', 'Chemical', 'MESH:D001151', (80, 87))	('BEAS-2B', 'CellLine', 'CVCL:0168', (108, 115))	('Smad4', 'Gene', (40, 45))	('Smad4', 'Gene', '4089', (40, 45))	('knockdown', 'Var', (126, 135))	('BEAS-2B', 'CellLine', 'CVCL:0168', (184, 191))
44974	30185897	These findings suggest that miR-301a modulates arsenic-induced cellular transformation and tumorigenesis through negative regulation of Smad4, and further supports a key role for miR-301a in metal carcinogen-induced carcinogenesis.	('negative', 'NegReg', (113, 121))	('arsenic', 'Chemical', 'MESH:D001151', (47, 54))	('miR-301a', 'Gene', (28, 36))	('arsenic-induced', 'CPA', (47, 62))	('miR-301a', 'Var', (179, 187))	('modulates', 'Reg', (37, 46))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('carcinogenesis', 'Disease', 'MESH:D063646', (216, 230))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('carcinogenesis', 'Disease', (216, 230))	('Smad4', 'Gene', (136, 141))	('Smad4', 'Gene', '4089', (136, 141))	('tumor', 'Disease', (91, 96))	('metal', 'Chemical', 'MESH:D008670', (191, 196))	('cellular transformation', 'CPA', (63, 86))
44978	30185897	In summary, we present a novel IL-6/STAT3 dependent mechanism for sustained expression of miR-301a during arsenic-induced cellular transformation, and further describe the important role of miR-301a and its target gene, Smad4 in arsenic-induced tumorigenesis.	('IL-6', 'Gene', (31, 35))	('arsenic', 'Chemical', 'MESH:D001151', (106, 113))	('IL-6', 'Gene', '3569', (31, 35))	('Smad4', 'Gene', (220, 225))	('Smad4', 'Gene', '4089', (220, 225))	('tumor', 'Disease', 'MESH:D009369', (245, 250))	('miR-301a', 'Gene', (90, 98))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('miR-301a', 'Var', (190, 198))	('arsenic', 'Chemical', 'MESH:D001151', (229, 236))	('tumor', 'Disease', (245, 250))
45023	29844374	demonstrated that NOS2 ablation or NOS2 null bone marrow (BM) transfer significantly reduces DNA damage, inflammation, and lung SCC incidence, which shows that macrophage NOS2 induction is not only a response to an inflammatory microenvironment but also a promoter of lung carcinogenesis (Fig.	('inflammation', 'Disease', 'MESH:D007249', (105, 117))	('NOS2', 'Gene', (18, 22))	('SCC', 'Gene', (128, 131))	('NOS2', 'Gene', (35, 39))	('ablation', 'Var', (23, 31))	('inflammation', 'Disease', (105, 117))	('lung carcinogenesis', 'Disease', 'MESH:D063646', (268, 287))	('lung carcinogenesis', 'Disease', (268, 287))	('SCC', 'Phenotype', 'HP:0002860', (128, 131))	('SCC', 'Gene', '6317', (128, 131))	('DNA damage', 'CPA', (93, 103))	('NOS2', 'Gene', (171, 175))	('reduces', 'NegReg', (85, 92))
45027	29844374	Because NOS2 depletion significantly decreases lung SCC incidence in KA/KA;Nos2-/- mice, this model offers an opportunity to elucidate the mechanism underlying macrophage NOS2's function in lung carcinogenesis.	('depletion', 'Var', (13, 22))	('SCC', 'Gene', (52, 55))	('mice', 'Species', '10090', (83, 87))	('SCC', 'Phenotype', 'HP:0002860', (52, 55))	('lung carcinogenesis', 'Disease', (190, 209))	('decreases', 'NegReg', (37, 46))	('SCC', 'Gene', '6317', (52, 55))	('lung', 'Disease', (47, 51))	('lung carcinogenesis', 'Disease', 'MESH:D063646', (190, 209))
45028	29844374	NOS2 ablation decreases infiltrating macrophage numbers, pulmonary inflammation, and lung SCC incidence, suggesting that macrophage NOS2 maintains an elevated inflammatory status that promotes carcinogenesis.	('NOS2', 'Gene', (132, 136))	('decreases', 'NegReg', (14, 23))	('macrophage', 'Var', (121, 131))	('pulmonary inflammation', 'Disease', (57, 79))	('carcinogenesis', 'Disease', (193, 207))	('ablation', 'Var', (5, 13))	('SCC', 'Gene', (90, 93))	('SCC', 'Phenotype', 'HP:0002860', (90, 93))	('elevated inflammatory status', 'MPA', (150, 178))	('pulmonary inflammation', 'Disease', 'MESH:D011014', (57, 79))	('elevated inflammatory status', 'Phenotype', 'HP:0012649', (150, 178))	('infiltrating', 'CPA', (24, 36))	('SCC', 'Gene', '6317', (90, 93))	('NOS2', 'Gene', (0, 4))	('carcinogenesis', 'Disease', 'MESH:D063646', (193, 207))	('promotes', 'PosReg', (184, 192))
45030	29844374	Although KA/KA macrophages express increased levels of many cytokines compared to KA/KA;Nos2-/- macrophages, the expression level of IL-13 and IL-4 is higher in KA/KA;Nos2-/- than in KA/KA macrophages, suggesting that macrophage NOS2's effect on tumor promotion is not through altering M1 and M2 macrophage features.	('levels', 'MPA', (45, 51))	('increased', 'PosReg', (35, 44))	('IL-4', 'Gene', (143, 147))	('tumor', 'Disease', 'MESH:D009369', (246, 251))	('IL-4', 'Gene', '3565', (143, 147))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('KA/KA;Nos2-/-', 'Var', (161, 174))	('IL-13', 'Gene', (133, 138))	('expression level', 'MPA', (113, 129))	('higher', 'PosReg', (151, 157))	('tumor', 'Disease', (246, 251))	('IL-13', 'Gene', '3596', (133, 138))
45033	29844374	NOS2 deletion reduces the foamy macrophage and total macrophage number associated with decreased lung SCC incidence.	('SCC', 'Phenotype', 'HP:0002860', (102, 105))	('deletion', 'Var', (5, 13))	('SCC', 'Gene', '6317', (102, 105))	('decreased', 'NegReg', (87, 96))	('reduces', 'NegReg', (14, 21))	('foamy macrophage', 'Phenotype', 'HP:0003651', (26, 42))	('decreased lung', 'Phenotype', 'HP:0002089', (87, 101))	('NOS2', 'Gene', (0, 4))	('SCC', 'Gene', (102, 105))
45035	29844374	We still do not know whether foamy macrophages are present in human lung SCCs, if lung SCCs promote foamy macrophage formation or if foamy macrophages facilitate lung SCC development, and whether IKKalpha inactivation promotes foamy macrophage formation.	('SCC', 'Phenotype', 'HP:0002860', (73, 76))	('foamy macrophage', 'Phenotype', 'HP:0003651', (133, 149))	('foamy macrophage', 'Phenotype', 'HP:0003651', (100, 116))	('foamy macrophage formation', 'CPA', (227, 253))	('foamy macrophage formation', 'CPA', (100, 126))	('SCC', 'Phenotype', 'HP:0002860', (167, 170))	('foamy macrophage', 'Phenotype', 'HP:0003651', (29, 45))	('foamy macrophages', 'Phenotype', 'HP:0003651', (133, 150))	('SCC', 'Phenotype', 'HP:0002860', (87, 90))	('SCC', 'Gene', '6317', (73, 76))	('foamy macrophage', 'Phenotype', 'HP:0003651', (227, 243))	('SCC', 'Gene', '6317', (167, 170))	('human', 'Species', '9606', (62, 67))	('foamy macrophages', 'Phenotype', 'HP:0003651', (29, 46))	('SCC', 'Gene', (73, 76))	('SCC', 'Gene', '6317', (87, 90))	('SCC', 'Gene', (167, 170))	('facilitate', 'PosReg', (151, 161))	('SCC', 'Gene', (87, 90))	('inactivation', 'Var', (205, 217))
45037	29844374	We have shown that deletions of the CHUK locus that encodes IKKalpha significantly reduce the survival time of human patients with KRAS mutation lung ADCs as well as total lung ADCs.	('KRAS', 'Gene', (131, 135))	('CHUK', 'Gene', '1147', (36, 40))	('human', 'Species', '9606', (111, 116))	('KRAS', 'Gene', '3845', (131, 135))	('reduce', 'NegReg', (83, 89))	('patients', 'Species', '9606', (117, 125))	('survival time', 'CPA', (94, 107))	('CHUK', 'Gene', (36, 40))	('deletions', 'Var', (19, 28))
45038	29844374	CHUK deletions are indeed found in human lung SCCs and show a tendency toward the reduced survival time, whereas patients with lung SCCs expressing increased IKKalpha show prolonged survival time (cBioPortal for Cancer Genomics; Fig.	('CHUK', 'Gene', (0, 4))	('prolonged', 'PosReg', (172, 181))	('Cancer', 'Disease', (212, 218))	('human', 'Species', '9606', (35, 40))	('SCC', 'Gene', (132, 135))	('patients', 'Species', '9606', (113, 121))	('Cancer', 'Disease', 'MESH:D009369', (212, 218))	('Cancer', 'Phenotype', 'HP:0002664', (212, 218))	('survival', 'CPA', (182, 190))	('SCC', 'Gene', '6317', (132, 135))	('SCC', 'Gene', (46, 49))	('SCC', 'Phenotype', 'HP:0002860', (132, 135))	('SCC', 'Phenotype', 'HP:0002860', (46, 49))	('survival time', 'CPA', (90, 103))	('reduced', 'NegReg', (82, 89))	('CHUK', 'Gene', '1147', (0, 4))	('deletions', 'Var', (5, 14))	('SCC', 'Gene', '6317', (46, 49))
45048	29844374	All KA/KA mice receiving KA/KA BM developed lung SCCs (positive controls), while all KA/KA;Nos2-/- mice receiving KA/KA;Nos2-/- BM did not develop tumors (negative controls).	('mice', 'Species', '10090', (99, 103))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumors', 'Disease', (147, 153))	('SCC', 'Gene', (49, 52))	('mice', 'Species', '10090', (10, 14))	('SCC', 'Phenotype', 'HP:0002860', (49, 52))	('tumors', 'Phenotype', 'HP:0002664', (147, 153))	('tumors', 'Disease', 'MESH:D009369', (147, 153))	('SCC', 'Gene', '6317', (49, 52))	('KA/KA BM', 'Var', (25, 33))
45049	29844374	Lung SCC incidence is significantly decreased in chimeric KA/KA mice receiving KA/KA;Nos2-/- BM as well as in chimeric KA/KA;Nos2-/- mice receiving KA/KA BM, demonstrating that both macrophage NOS2 and epithelial cell NOS2 are required for carcinogenesis.	('SCC', 'Gene', '6317', (5, 8))	('mice', 'Species', '10090', (133, 137))	('carcinogenesis', 'Disease', 'MESH:D063646', (240, 254))	('SCC', 'Gene', (5, 8))	('decreased', 'NegReg', (36, 45))	('carcinogenesis', 'Disease', (240, 254))	('mice', 'Species', '10090', (64, 68))	('SCC', 'Phenotype', 'HP:0002860', (5, 8))	('KA/KA;Nos2-/- BM', 'Var', (79, 95))
45050	29844374	reported that macrophage NOS2 promotes lung SCC initiation by maintaining circulated inflammatory responses between macrophages and lung epithelial cells, while macrophage NOS2 deletion decreases lung SCC incidence.	('SCC', 'Gene', '6317', (44, 47))	('promotes', 'PosReg', (30, 38))	('deletion', 'Var', (177, 185))	('SCC', 'Gene', (201, 204))	('decreases', 'NegReg', (186, 195))	('circulated inflammatory responses', 'MPA', (74, 107))	('SCC', 'Phenotype', 'HP:0002860', (201, 204))	('SCC', 'Gene', '6317', (201, 204))	('SCC', 'Gene', (44, 47))	('SCC', 'Phenotype', 'HP:0002860', (44, 47))	('NOS2', 'Gene', (172, 176))
45071	27086486	A later meta-analysis by Syrjanen et al found a significant association between HPV 16 and "oral" cancer, to a stronger extent for the presence of oral HPV 16 DNA (OR = 3.9, 95% CI: 2.2-6.9), with between-study heterogeneity.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('HPV 16', 'Species', '333760', (80, 86))	('HPV 16', 'Species', '333760', (152, 158))	('presence', 'Var', (135, 143))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('HPV 16', 'Gene', (80, 86))	('cancer', 'Disease', (98, 104))	('HPV 16', 'Gene', (152, 158))
45087	27086486	After histopathologic verification of SCCOC, paraffin-embedded tumor specimens were assessed for the presence of HPV 16 and HPV 18 DNA.	('tumor', 'Disease', (63, 68))	('SCCOC', 'Phenotype', 'HP:0030413', (38, 43))	('paraffin', 'Chemical', 'MESH:D010232', (45, 53))	('HPV', 'Species', '10566', (124, 127))	('HPV', 'Var', (124, 127))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('HPV 16', 'Species', '333760', (113, 119))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('HPV', 'Species', '10566', (113, 116))	('HPV', 'Var', (113, 116))
45197	32370142	In the context of genetic alterations, the most frequent and mutually exclusive genetic changes in PTCs are BRAF V600E, RAS, and RET/PTC rearrangement, leading to constitutive activation of the signaling pathway of mitogen-activated kinases (MAPK) (Figure 1).	('RET', 'Gene', (129, 132))	('RAS', 'Gene', (120, 123))	('PTC', 'Gene', (99, 102))	('PTC', 'Gene', (133, 136))	('signaling pathway of mitogen-activated kinases', 'Pathway', (194, 240))	('PTC', 'Gene', '5979', (99, 102))	('PTC', 'Gene', '5979', (133, 136))	('V600E', 'Mutation', 'rs113488022', (113, 118))	('RET', 'Gene', '5979', (129, 132))	('BRAF', 'Gene', '673', (108, 112))	('activation', 'PosReg', (176, 186))	('BRAF', 'Gene', (108, 112))	('rearrangement', 'Var', (137, 150))
45198	32370142	BRAF occurs in 45% of PTCs, and in the majority, it is a substitution at the second position of codon 600 (V600E; GTG > GAG), c.1799 T > A) resulting in an amino acid change from valine to glutamic acid that leading to constitutive activation of serine/threonine kinase BRAF.	('PTC', 'Gene', (22, 25))	('BRAF', 'Gene', (270, 274))	('BRAF', 'Gene', '673', (270, 274))	('GAG', 'Chemical', 'MESH:D006025', (120, 123))	('constitutive', 'MPA', (219, 231))	('activation', 'PosReg', (232, 242))	('V600E;', 'Var', (107, 113))	('PTC', 'Gene', '5979', (22, 25))	('c.1799 T > A', 'Mutation', 'rs113488022', (126, 138))	('GTG', 'Gene', '2678', (114, 117))	('V600E', 'Mutation', 'rs113488022', (107, 112))	('BRAF', 'Gene', '673', (0, 4))	('valine', 'Chemical', 'MESH:D014633', (179, 185))	('BRAF', 'Gene', (0, 4))	('c.1799 T > A', 'Var', (126, 138))	('serine', 'Chemical', 'MESH:D012694', (246, 252))	('glutamic acid', 'Chemical', 'MESH:D018698', (189, 202))	('GTG', 'Gene', (114, 117))
45199	32370142	The RAS gene encodes a family of three highly homologous oncogenes: NRAS, HRAS, and KRAS, in which mutations occur in 10%-20% of PTCs.	('occur', 'Reg', (109, 114))	('RAS', 'Gene', (4, 7))	('PTC', 'Gene', (129, 132))	('NRAS', 'Gene', (68, 72))	('PTC', 'Gene', '5979', (129, 132))	('KRAS', 'Gene', (84, 88))	('mutations', 'Var', (99, 108))	('KRAS', 'Gene', '3845', (84, 88))	('HRAS', 'Gene', '3265', (74, 78))	('NRAS', 'Gene', '4893', (68, 72))	('HRAS', 'Gene', (74, 78))
45202	32370142	In contrast, the characteristic genetic modifications that are mutually exclusive in FTC are changes in the RAS, PTEN, and PIK3CA genes, as well as rearrangement of PAX8-PPARgamma, activating the 3-phosphatidylinositol kinase PI kinase (PI3K/Protein Kinase B-AKT).	('PAX8', 'Gene', '7849', (165, 169))	('activating', 'PosReg', (181, 191))	('PPARgamma', 'Gene', '5468', (170, 179))	('PAX8', 'Gene', (165, 169))	('AKT', 'Gene', '207', (259, 262))	('RAS', 'Gene', (108, 111))	('PIK3CA', 'Gene', (123, 129))	('Protein Kinase B', 'Gene', (242, 258))	('PIK3CA', 'Gene', '5290', (123, 129))	('PTEN', 'Gene', (113, 117))	('rearrangement', 'Var', (148, 161))	('AKT', 'Gene', (259, 262))	('PTEN', 'Gene', '5728', (113, 117))	('modifications', 'Var', (40, 53))	('Protein Kinase B', 'Gene', '2185', (242, 258))	('PPARgamma', 'Gene', (170, 179))
45203	32370142	The RAS mutations were observed in approximately 40%-50% of FTC cases, and the modification was predominantly found in the NRAS codon 61, which positively associated with distant metastases of FTC.	('FTC', 'Disease', (193, 196))	('mutations', 'Var', (8, 17))	('NRAS', 'Gene', (123, 127))	('associated with', 'Reg', (155, 170))	('NRAS', 'Gene', '4893', (123, 127))	('metastases', 'Disease', (179, 189))	('metastases', 'Disease', 'MESH:D009362', (179, 189))
45204	32370142	Following, the mutation or deletion of the tumor suppressor gene - PTEN (phosphatase and tensin homolog) and PIK3CA transcript (coding the p110alpha catalytic subunit of PI3K) are the classical genetic alterations that activate the PI3K-AKT pathway in ~10% and 10%-30% of FTC cases, respectively.	('mutation', 'Var', (15, 23))	('AKT', 'Gene', (237, 240))	('PIK3CA', 'Gene', (109, 115))	('PIK3CA', 'Gene', '5290', (109, 115))	('activate', 'PosReg', (219, 227))	('p110alpha', 'Gene', (139, 148))	('phosphatase and tensin homolog', 'Gene', '5728', (73, 103))	('p110alpha', 'Gene', '5290', (139, 148))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('deletion', 'Var', (27, 35))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('PTEN', 'Gene', (67, 71))	('AKT', 'Gene', '207', (237, 240))	('PTEN', 'Gene', '5728', (67, 71))	('tumor', 'Disease', (43, 48))	('FTC', 'Disease', (272, 275))
45206	32370142	The PAX8/PPAR fusion results in significant increases in expression of PAX8/PPAR chimeric protein and, as a result, inhibits the tumor suppressor activity of PPAR.	('expression', 'MPA', (57, 67))	('PAX8', 'Gene', (71, 75))	('inhibits', 'NegReg', (116, 124))	('PAX8', 'Gene', '7849', (4, 8))	('PPAR', 'Gene', (76, 80))	('PPAR', 'Gene', '5465', (158, 162))	('PPAR', 'Gene', (158, 162))	('PPAR', 'Gene', (9, 13))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('PAX8', 'Gene', (4, 8))	('fusion', 'Var', (14, 20))	('PPAR', 'Gene', '5465', (76, 80))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('PAX8', 'Gene', '7849', (71, 75))	('tumor', 'Disease', (129, 134))	('chimeric protein', 'Protein', (81, 97))	('increases', 'PosReg', (44, 53))	('PPAR', 'Gene', '5465', (9, 13))
45211	32370142	Additionally, through whole-genome sequencing, in many malignant THC cases, the mutations in the promoter region of telomerase reverse transcriptase (TERT) were found, contrary to the early stages of thyroid tumors.	('thyroid tumors', 'Disease', 'MESH:D013964', (200, 214))	('mutations in', 'Var', (80, 92))	('TERT', 'Gene', (150, 154))	('found', 'Reg', (161, 166))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('TERT', 'Gene', '7015', (150, 154))	('tumors', 'Phenotype', 'HP:0002664', (208, 214))	('thyroid tumors', 'Disease', (200, 214))	('thyroid tumor', 'Phenotype', 'HP:0100031', (200, 213))	('THC', 'Disease', (65, 68))	('telomerase reverse transcriptase', 'Gene', (116, 148))	('telomerase reverse transcriptase', 'Gene', '7015', (116, 148))
45213	32370142	Two main TERT mutations: 1 295 228 C>T (C228T) and 1 295 250 C>T(C250T) can increase the TERT transcriptional activities.	('increase', 'PosReg', (76, 84))	('228 C>T', 'Var', (31, 38))	('C228T', 'Mutation', 'rs1361898625', (40, 45))	('C250T', 'Mutation', 'c.250C>T', (65, 70))	('TERT', 'Gene', (89, 93))	('TERT', 'Gene', '7015', (89, 93))	('228 C>T', 'SUBSTITUTION', 'None', (31, 38))	('295 250 C>T', 'Mutation', 'g.295250C>T', (53, 64))	('1 295 250 C>T', 'Var', (51, 64))	('TERT', 'Gene', (9, 13))	('TERT', 'Gene', '7015', (9, 13))
45214	32370142	Particularly prevalent in THC is the C228T variant, which appeared in Liu X. et al.	('C228T', 'Mutation', 'rs1361898625', (37, 42))	('C228T', 'Var', (37, 42))	('prevalent', 'Reg', (13, 22))	('THC', 'Disease', (26, 29))
45216	32370142	Moreover, the coexistence of TERT with BRAF or RAS alterations had a synergistic effect on poor clinicopathologic outcomes of PTCs, such as disease recurrence and patient mortality.	('TERT', 'Gene', '7015', (29, 33))	('alterations', 'Var', (51, 62))	('BRAF', 'Gene', '673', (39, 43))	('mortality', 'Disease', 'MESH:D003643', (171, 180))	('BRAF', 'Gene', (39, 43))	('PTC', 'Gene', (126, 129))	('disease recurrence', 'Disease', (140, 158))	('patient', 'Species', '9606', (163, 170))	('mortality', 'Disease', (171, 180))	('PTC', 'Gene', '5979', (126, 129))	('RAS', 'Gene', (47, 50))	('TERT', 'Gene', (29, 33))
45217	32370142	All data suggest that TERT promoter mutations may play a role in the THC de-differentiation, progression, and aggressive behavior.	('TERT', 'Gene', (22, 26))	('aggressive behavior', 'Phenotype', 'HP:0000718', (110, 129))	('play', 'Reg', (50, 54))	('TERT', 'Gene', '7015', (22, 26))	('mutations', 'Var', (36, 45))	('aggressive behavior', 'CPA', (110, 129))	('THC', 'Disease', (69, 72))	('progression', 'CPA', (93, 104))
45221	32370142	The human PROX1 transcript is located on chromosome 1q32.2-q32.3 composed of five exons and four introns and produces two variants: NM_002763 and NM_001270616, both encoding the same protein product, but the NM_002763 transcript is longer by 322 nucleotides.	('NM_001270616', 'Var', (146, 158))	('human', 'Species', '9606', (4, 9))	('NM_002763', 'Var', (132, 141))	('NM_002763', 'Var', (208, 217))
45234	32370142	RNA editing occurs through base modification, by deamination of cytidine (C) to uridine (U) or by deamination of adenosine (A) to inosine (I), in nuclear mRNA.	('deamination', 'Var', (98, 109))	('deamination', 'MPA', (49, 60))	('inosine', 'Chemical', 'MESH:D007288', (130, 137))	('uridine', 'Chemical', 'MESH:D014529', (80, 87))	('base modification', 'MPA', (27, 44))	('adenosine', 'Chemical', 'MESH:D000241', (113, 122))	('cytidine', 'Chemical', 'MESH:D003562', (64, 72))
45236	32370142	In this context, the A-to-G mutation affects PROX1 function in human specimens of pancreatic, colon, and esophageal cancers and A to I in esophageal cancer.	('esophageal cancers', 'Disease', (105, 123))	('esophageal cancers', 'Disease', 'MESH:D004938', (105, 123))	('cancer', 'Disease', (149, 155))	('PROX1', 'Enzyme', (45, 50))	('human', 'Species', '9606', (63, 68))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('affects', 'Reg', (37, 44))	('function', 'MPA', (51, 59))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('pancreatic', 'Disease', 'MESH:D010195', (82, 92))	('cancers', 'Phenotype', 'HP:0002664', (116, 123))	('colon', 'Disease', (94, 99))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('pancreatic', 'Disease', (82, 92))	('A-to-G mutation', 'Var', (21, 36))	('cancer', 'Disease', 'MESH:D009369', (149, 155))
45237	32370142	Importantly, several single nucleotide polymorphisms (SNPs) present in intronic regions of PROX1 were suggested to modulate PROX1 expression levels with potential involvement in the pathogenesis of type 2 diabetes.	('modulate', 'Reg', (115, 123))	('single nucleotide polymorphisms', 'Var', (21, 52))	('PROX1', 'Gene', (91, 96))	('type 2 diabetes', 'Phenotype', 'HP:0005978', (198, 213))	('diabetes', 'Disease', (205, 213))	('PROX1 expression levels', 'MPA', (124, 147))	('diabetes', 'Disease', 'MESH:D003920', (205, 213))	('involvement', 'Reg', (163, 174))
45240	32370142	It is commonly known that inactivation of specific tumor suppressor genes occurs as a consequence of hypermethylation within the promoter regions, and numerous studies have demonstrated a broad range of genes silenced by DNA methylation in different cancer types.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('cancer', 'Disease', 'MESH:D009369', (250, 256))	('hypermethylation', 'Var', (101, 117))	('cancer', 'Disease', (250, 256))	('tumor', 'Disease', (51, 56))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('inactivation', 'NegReg', (26, 38))
45241	32370142	Epigenetic silencing is one of the mechanisms responsible for PROX1 inactivation in tumors.	('PROX1', 'Protein', (62, 67))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('Epigenetic silencing', 'Var', (0, 20))	('tumors', 'Disease', 'MESH:D009369', (84, 90))	('tumors', 'Disease', (84, 90))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('inactivation', 'NegReg', (68, 80))
45242	32370142	For example, hypermethylation of CpG islands was identified as a mechanism for PROX1 inactivation in breast, biliary system, and squamous cell carcinomas.	('inactivation', 'NegReg', (85, 97))	('carcinomas', 'Phenotype', 'HP:0030731', (143, 153))	('squamous cell carcinomas', 'Disease', (129, 153))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (129, 153))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (129, 152))	('PROX1', 'Gene', (79, 84))	('biliary system', 'Disease', (109, 123))	('breast', 'Disease', (101, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (143, 152))	('hypermethylation', 'Var', (13, 29))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (129, 153))
45249	32370142	According to the miRDB database , for example, miR-10527-5p, miR-6867-5p, miR-4262, miR-4668-5p, and miR-3148 may still regulate PROX1 mRNA and thus can be the future research aim, especially in THC cases, due to the lack of published data.	('PROX1 mRNA', 'MPA', (129, 139))	('miR-4668', 'Gene', '100616114', (84, 92))	('regulate', 'Reg', (120, 128))	('miR-10527-5p', 'Var', (47, 59))	('miR-4262', 'Gene', (74, 82))	('miR-4262', 'Gene', '100422996', (74, 82))	('miR-3148', 'Gene', (101, 109))	('THC cases', 'Disease', (195, 204))	('miR-6867', 'Gene', '102465523', (61, 69))	('miR-6867', 'Gene', (61, 69))	('miR-4668', 'Gene', (84, 92))	('miR-3148', 'Gene', '100422876', (101, 109))
45252	32370142	In detail, knockdown of PROX1-AS1 significantly inhibited proliferation, colony formation, migration, and invasion of PTC cells.	('colony formation', 'CPA', (73, 89))	('proliferation', 'CPA', (58, 71))	('PTC', 'Gene', '5979', (118, 121))	('AS1', 'Gene', '5729', (30, 33))	('AS1', 'Gene', (30, 33))	('inhibited', 'NegReg', (48, 57))	('migration', 'CPA', (91, 100))	('knockdown', 'Var', (11, 20))	('PTC', 'Gene', (118, 121))
45270	32370142	The downregulation of PROX1 in PTC-derived cells was a consequence of aberrantly activated Notch signaling.	('Notch signaling', 'Pathway', (91, 106))	('downregulation', 'NegReg', (4, 18))	('PROX1', 'Protein', (22, 27))	('PTC', 'Gene', (31, 34))	('aberrantly', 'Var', (70, 80))	('PTC', 'Gene', '5979', (31, 34))
45271	32370142	Moreover, in PTC cells after transgenic PROX1 reexpression enhanced Wnt/beta-catenin signaling was observed, coupled with and regulation of thyroid cancer 1 (TC-1) protein, Serpina 1, and Fatty acid-binding protein 4 (FABP4), that are known to be associated with PTC.	('TC-1', 'Gene', '56892', (158, 162))	('FABP4', 'Gene', '2167', (218, 223))	('TC-1', 'Gene', (158, 162))	('PTC', 'Gene', (263, 266))	('beta-catenin', 'Gene', (72, 84))	('Fatty acid-binding protein 4', 'Gene', (188, 216))	('PTC', 'Gene', '5979', (263, 266))	('beta-catenin', 'Gene', '1499', (72, 84))	('Serpina 1', 'Gene', '5265', (173, 182))	('thyroid cancer', 'Phenotype', 'HP:0002890', (140, 154))	('Fatty acid-binding protein 4', 'Gene', '2167', (188, 216))	('transgenic', 'Var', (29, 39))	('thyroid cancer 1', 'Gene', (140, 156))	('PTC', 'Gene', (13, 16))	('PTC', 'Gene', '5979', (13, 16))	('FABP4', 'Gene', (218, 223))	('thyroid cancer 1', 'Gene', '56892', (140, 156))	('Serpina 1', 'Gene', (173, 182))	('PROX1', 'Gene', (40, 45))	('enhanced', 'PosReg', (59, 67))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))
45272	32370142	Additionally, notch-induced PROX1 inactivation significantly promoted the malignant phenotype of thyroid cancer cells.	('malignant phenotype of', 'CPA', (74, 96))	('inactivation', 'Var', (34, 46))	('thyroid cancer', 'Disease', (97, 111))	('promoted', 'PosReg', (61, 69))	('thyroid cancer', 'Phenotype', 'HP:0002890', (97, 111))	('thyroid cancer', 'Disease', 'MESH:D013964', (97, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))
45273	32370142	Furthermore, PROX1 knockdown increased the angiogenic potential of FTC- and SCT-derived cells by modulating the expression of genes involved in the angiogenic signaling pathway and was regulated in the opposite direction than pro-angiogenic factor FGF2.	('angiogenic', 'Pathway', (148, 158))	('expression of', 'MPA', (112, 125))	('FGF2', 'Gene', '2247', (248, 252))	('knockdown', 'Var', (19, 28))	('PROX1', 'Gene', (13, 18))	('increased', 'PosReg', (29, 38))	('FGF2', 'Gene', (248, 252))	('angiogenic potential', 'CPA', (43, 63))	('modulating', 'Reg', (97, 107))
45274	32370142	We can hypothesize that the discrepancy between the regulation of PTC and FTC and SCT by PROX1 may result from differences in the origin of cancer cells, mutations, as well as signaling pathways involved.	('result', 'Reg', (99, 105))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('PTC', 'Gene', (66, 69))	('mutations', 'Var', (154, 163))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('PTC', 'Gene', '5979', (66, 69))
45276	32370142	Further, all molecular changes were rigorously confirmed in biological testing where cells after PROX1 knockdown revealed changed actin organization, showed the lower motility, increased invasive potential, and changed the tubularization of human umbilical endothelial cells cultivated in medium conditioned using CGTH-W-1 cells transfected with siPROX1.	('lower', 'NegReg', (161, 166))	('actin', 'MPA', (130, 135))	('CGTH-W-1', 'CellLine', 'CVCL:1120', (314, 322))	('human', 'Species', '9606', (241, 246))	('PROX1', 'Gene', (97, 102))	('changed', 'Reg', (211, 218))	('increased', 'PosReg', (177, 186))	('tubularization', 'CPA', (223, 237))	('motility', 'CPA', (167, 175))	('invasive potential', 'CPA', (187, 205))	('changed', 'Reg', (122, 129))	('knockdown', 'Var', (103, 112))
45291	32370142	Furthermore, defects in the transcription factor SOX18 cause lymphatic dysfunction in the human syndrome hypotrichosis-lymphoedema-telangiectasia.	('telangiectasia', 'Phenotype', 'HP:0001009', (131, 145))	('lymphoedema', 'Phenotype', 'HP:0001004', (119, 130))	('cause', 'Reg', (55, 60))	('SOX18', 'Gene', '54345', (49, 54))	('lymphatic dysfunction in the human syndrome hypotrichosis-lymphoedema-telangiectasia', 'Disease', 'MESH:D013684', (61, 145))	('hypotrichosis', 'Phenotype', 'HP:0001006', (105, 118))	('defects', 'Var', (13, 20))	('SOX18', 'Gene', (49, 54))
45299	32370142	In the PTC-derived cells, PDPN silencing reduces migration, invasion, and adhesion of tested cells through regulating the expression of the ezrin, radixin, and moesin proteins, MMP9 and MMP2 proteins.	('expression', 'MPA', (122, 132))	('invasion', 'CPA', (60, 68))	('migration', 'CPA', (49, 58))	('MMP2', 'Gene', (186, 190))	('PDPN', 'Gene', '10630', (26, 30))	('radixin', 'Protein', (147, 154))	('silencing', 'Var', (31, 40))	('reduces', 'NegReg', (41, 48))	('regulating', 'Reg', (107, 117))	('ezrin', 'Protein', (140, 145))	('PTC', 'Gene', (7, 10))	('PTC', 'Gene', '5979', (7, 10))	('MMP2', 'Gene', '4313', (186, 190))	('adhesion', 'CPA', (74, 82))	('PDPN', 'Gene', (26, 30))	('moesin', 'Gene', (160, 166))	('MMP9', 'Gene', '4318', (177, 181))	('MMP9', 'Gene', (177, 181))	('moesin', 'Gene', '4478', (160, 166))
45308	32370142	Still, further experiments are required to understand how the PROX1 epigenetic regulation and relation with other vascular molecules translate into a tumor setting and development.	('epigenetic regulation', 'Var', (68, 89))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('PROX1', 'Gene', (62, 67))	('tumor', 'Disease', (150, 155))
45328	32296636	Aberrantly expressed HOXA6 and HOXA13 were also observed in breast cancer.	('Aberrantly expressed', 'Var', (0, 20))	('breast cancer', 'Disease', (60, 73))	('HOXA13', 'Gene', (31, 37))	('breast cancer', 'Phenotype', 'HP:0003002', (60, 73))	('HOXA6', 'Gene', '3203', (21, 26))	('HOXA13', 'Gene', '3209', (31, 37))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('HOXA6', 'Gene', (21, 26))	('breast cancer', 'Disease', 'MESH:D001943', (60, 73))	('observed', 'Reg', (48, 56))
45355	32296636	Methylation of gene promoter regions is one of the most common mechanisms that influences gene expression during the progression of human cancer.	('cancer', 'Disease', (138, 144))	('influences', 'Reg', (79, 89))	('Methylation', 'Var', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('gene expression', 'MPA', (90, 105))	('human', 'Species', '9606', (132, 137))	('cancer', 'Disease', 'MESH:D009369', (138, 144))
45386	32296636	Several reports have identified HOXA gene signatures in GBM, and high expression of HOXA9 and HOXA10 were reported to be predictors of poor outcome in patients with GBM.	('HOXA9', 'Gene', (84, 89))	('HOXA', 'Gene', '3197', (94, 98))	('HOXA', 'Gene', (84, 88))	('HOXA', 'Gene', '3197', (32, 36))	('HOXA', 'Gene', '3197', (84, 88))	('GBM', 'Disease', (56, 59))	('patients', 'Species', '9606', (151, 159))	('HOXA10', 'Gene', '3206', (94, 100))	('high', 'Var', (65, 69))	('HOXA9', 'Gene', '3205', (84, 89))	('HOXA', 'Gene', (94, 98))	('HOXA10', 'Gene', (94, 100))	('HOXA', 'Gene', (32, 36))
45387	32296636	Moreover, it was reported that novel methylation markers in HOXA9 also served as an independent indicator of prognosis in invasive bladder cancer.	('invasive bladder', 'Phenotype', 'HP:0100645', (122, 138))	('invasive bladder cancer', 'Disease', (122, 145))	('HOXA9', 'Gene', (60, 65))	('invasive bladder cancer', 'Disease', 'MESH:D001749', (122, 145))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('bladder cancer', 'Phenotype', 'HP:0009725', (131, 145))	('methylation markers', 'Var', (37, 56))	('HOXA9', 'Gene', '3205', (60, 65))
45393	32296636	In breast cancer, HOXA1 knockdown inhibited cell proliferation and increased apoptosis and cell cycle arrest by influencing the aberrant expression of several cell cycle and apoptosis-associated proteins, comprising cyclin D1, B-cell lymphoma 2 (Bcl-2) and Bcl-2-like protein 4.	('cell proliferation', 'CPA', (44, 62))	('cyclin D1, B-cell lymphoma 2', 'Gene', '595', (216, 244))	('Bcl-2', 'Gene', '596', (246, 251))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (91, 108))	('Bcl-2-like protein 4', 'Gene', '581', (257, 277))	('Bcl-2-like protein 4', 'Gene', (257, 277))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (227, 242))	('arrest', 'Disease', (102, 108))	('apoptosis', 'CPA', (77, 86))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('inhibited', 'NegReg', (34, 43))	('increased', 'PosReg', (67, 76))	('Bcl-2', 'Gene', (257, 262))	('HOXA1', 'Gene', '3198', (18, 23))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('aberrant expression', 'MPA', (128, 147))	('knockdown', 'Var', (24, 33))	('arrest', 'Disease', 'MESH:D006323', (102, 108))	('influencing', 'Reg', (112, 123))	('Bcl-2', 'Gene', '596', (257, 262))	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('breast cancer', 'Disease', (3, 16))	('Bcl-2', 'Gene', (246, 251))	('lymphoma', 'Phenotype', 'HP:0002665', (234, 242))	('HOXA1', 'Gene', (18, 23))
45396	32296636	In hepatocellular carcinoma cells, HOXA10 knockdown induced cell cycle arrest at the G0/G1 phase and apoptosis by reducing the expression of Cyclin D1 and Survivin.	('carcinoma', 'Phenotype', 'HP:0030731', (18, 27))	('hepatocellular carcinoma', 'Disease', (3, 27))	('Cyclin D1', 'Gene', (141, 150))	('expression', 'MPA', (127, 137))	('HOXA10', 'Gene', '3206', (35, 41))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (3, 27))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (60, 77))	('arrest', 'Disease', 'MESH:D006323', (71, 77))	('reducing', 'NegReg', (114, 122))	('HOXA10', 'Gene', (35, 41))	('arrest', 'Disease', (71, 77))	('apoptosis', 'CPA', (101, 110))	('Survivin', 'Protein', (155, 163))	('Cyclin D1', 'Gene', '595', (141, 150))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (3, 27))	('knockdown', 'Var', (42, 51))
45397	32296636	Decreased expression of HOXA10 accelerated the acetylation of p53 (Lys382) and suppressed the transcription of histone deacetylase 1 (HDAC1; a potential deacetylase for p53) to activate p53 transcription.	('Lys382', 'Chemical', '-', (67, 73))	('suppressed', 'NegReg', (79, 89))	('HDAC1', 'Gene', (134, 139))	('p53', 'Gene', (169, 172))	('p53', 'Gene', (186, 189))	('histone deacetylase 1', 'Gene', (111, 132))	('accelerated', 'PosReg', (31, 42))	('transcription', 'MPA', (190, 203))	('p53', 'Gene', '7157', (62, 65))	('Lys382', 'Var', (67, 73))	('acetylation', 'MPA', (47, 58))	('HOXA10', 'Gene', (24, 30))	('transcription', 'MPA', (94, 107))	('HDAC1', 'Gene', '3065', (134, 139))	('p53', 'Gene', (62, 65))	('histone deacetylase 1', 'Gene', '3065', (111, 132))	('activate', 'PosReg', (177, 185))	('HOXA10', 'Gene', '3206', (24, 30))	('p53', 'Gene', '7157', (169, 172))	('p53', 'Gene', '7157', (186, 189))
45398	32296636	Additionally, HOXA10 might promote cell proliferation by elevating Bcl-2 expression and inhibiting apoptosis in gastric cancer, and high expression of HOXA10 predicted poor overall survival in gastric cancer patients.	('gastric cancer', 'Disease', 'MESH:D013274', (112, 126))	('gastric cancer', 'Disease', 'MESH:D013274', (193, 207))	('HOXA10', 'Gene', '3206', (151, 157))	('overall survival', 'CPA', (173, 189))	('cell proliferation', 'CPA', (35, 53))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('HOXA10', 'Gene', '3206', (14, 20))	('expression', 'MPA', (73, 83))	('Bcl-2', 'Gene', (67, 72))	('gastric cancer', 'Phenotype', 'HP:0012126', (193, 207))	('gastric cancer', 'Phenotype', 'HP:0012126', (112, 126))	('inhibiting', 'NegReg', (88, 98))	('apoptosis', 'CPA', (99, 108))	('HOXA10', 'Gene', (151, 157))	('elevating', 'PosReg', (57, 66))	('Bcl-2', 'Gene', '596', (67, 72))	('poor', 'NegReg', (168, 172))	('patients', 'Species', '9606', (208, 216))	('gastric cancer', 'Disease', (193, 207))	('gastric cancer', 'Disease', (112, 126))	('promote', 'PosReg', (27, 34))	('HOXA10', 'Gene', (14, 20))	('high expression', 'Var', (132, 147))
45411	32296636	HOXA13 knockdown significantly restored the epithelial characteristics and reduced the mesenchymal characteristics of the cancer cells via the transforming growth factor (TGF)-beta signaling pathway.	('HOXA13', 'Gene', (0, 6))	('transforming growth factor (TGF)-beta', 'Gene', '7039', (143, 180))	('restored', 'PosReg', (31, 39))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('HOXA13', 'Gene', '3209', (0, 6))	('reduced', 'NegReg', (75, 82))	('epithelial characteristics', 'CPA', (44, 70))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('knockdown', 'Var', (7, 16))
45412	32296636	Moreover, HOXA13 expression negatively affects cisplatin sensitivity in human esophageal squamous cells and overall survival in patients with esophageal squamous cell carcinoma.	('cisplatin sensitivity', 'MPA', (47, 68))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (142, 176))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (153, 176))	('affects', 'Reg', (39, 46))	('HOXA13', 'Gene', (10, 16))	('human', 'Species', '9606', (72, 77))	('esophageal squamous cell carcinoma', 'Disease', (142, 176))	('HOXA13', 'Gene', '3209', (10, 16))	('cisplatin', 'Chemical', 'MESH:D002945', (47, 56))	('carcinoma', 'Phenotype', 'HP:0030731', (167, 176))	('expression', 'Var', (17, 27))	('patients', 'Species', '9606', (128, 136))	('negatively', 'NegReg', (28, 38))
45423	31774069	Plasma levels of loc285194 and TGF-beta1 were significantly correlated with the presence of CSCC.	('CSCC', 'Disease', (92, 96))	('TGF-beta1', 'Gene', '7040', (31, 40))	('loc285194', 'Var', (17, 26))	('TGF-beta1', 'Gene', (31, 40))	('correlated', 'Reg', (60, 70))	('Plasma levels', 'MPA', (0, 13))
45424	31774069	In SiHa and C33A cells, TGF-beta1 expression was downregulated, and cell migration was inhibited following lncRNA loc285194 overexpression.	('cell migration', 'CPA', (68, 82))	('TGF-beta1', 'Gene', '7040', (24, 33))	('TGF-beta1', 'Gene', (24, 33))	('expression', 'MPA', (34, 44))	('lncRNA', 'Gene', (107, 113))	('inhibited', 'NegReg', (87, 96))	('downregulated', 'NegReg', (49, 62))	('loc285194', 'Var', (114, 123))	('overexpression', 'PosReg', (124, 138))
45426	31774069	The expression of lncRNA loc285194 inhibited the migration of CSCC cells in vitro through the inactivation of TGF-beta1.	('TGF-beta1', 'Gene', '7040', (110, 119))	('inactivation', 'NegReg', (94, 106))	('TGF-beta1', 'Gene', (110, 119))	('migration of CSCC cells in vitro', 'CPA', (49, 81))	('loc285194', 'Var', (25, 34))	('lncRNA', 'Gene', (18, 24))	('inhibited', 'NegReg', (35, 44))
45433	31774069	Therefore, inhibition of TGF-beta signaling may be a promising target for the treatment of human cancer.	('TGF-beta', 'Gene', (25, 33))	('cancer', 'Disease', (97, 103))	('cancer', 'Disease', 'MESH:D009369', (97, 103))	('TGF-beta', 'Gene', '7039', (25, 33))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('inhibition', 'Var', (11, 21))	('human', 'Species', '9606', (91, 96))
45434	31774069	Previous studies have shown crosstalk between TGF-beta signaling and long noncoding RNA (lncRNA) in the pathogenesis of some human diseases, and lncRNA loc285194, also known as LSAMP antisense RNA 3, has been shown to have a role as a tumor suppressor.	('tumor', 'Disease', 'MESH:D009369', (235, 240))	('lncRNA', 'Var', (145, 151))	('LSAMP', 'Gene', (177, 182))	('long', 'MPA', (69, 73))	('crosstalk', 'Reg', (28, 37))	('human', 'Species', '9606', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('TGF-beta', 'Gene', (46, 54))	('tumor', 'Disease', (235, 240))	('loc285194', 'Var', (152, 161))	('LSAMP', 'Gene', '4045', (177, 182))	('TGF-beta', 'Gene', '7039', (46, 54))
45435	31774069	However, the role lncRNA loc285194 in CSCC and its interaction with TGF-beta signaling are unknown.	('loc285194', 'Var', (25, 34))	('CSCC', 'Disease', (38, 42))	('TGF-beta', 'Gene', '7039', (68, 76))	('TGF-beta', 'Gene', (68, 76))
45436	31774069	Therefore, this study aimed to investigate the expression of lncRNA loc285194 in CSCC biopsy tissue, positive and negative for HPV, and in the human CSCC cell lines SiHa (HPV16-positive) and C33A (HPV-negative) and to investigate overexpression of lncRNA loc285194.	('HPV', 'Species', '10566', (171, 174))	('human', 'Species', '9606', (143, 148))	('HPV16', 'Species', '333760', (171, 176))	('loc285194', 'Var', (68, 77))	('HPV', 'Species', '10566', (197, 200))	('HPV', 'Species', '10566', (127, 130))	('lncRNA', 'Gene', (61, 67))
45439	31774069	Of the 66 cases of CSCC, 22 cases were HPV16-positive, 27 cases were HPV18-positive, and 17 cases were HPV-negative.	('HPV16', 'Species', '333760', (39, 44))	('CSCC', 'Disease', (19, 23))	('HPV', 'Species', '10566', (69, 72))	('HPV', 'Species', '10566', (103, 106))	('HPV', 'Species', '10566', (39, 42))	('HPV16-positive', 'Var', (39, 53))
45459	31774069	Receiver operating curve (ROC) analysis was performed to determine the diagnostic performance of lncRNA loc285194 expression in patients with CSCC compared with controls.	('lncRNA', 'Gene', (97, 103))	('CSCC', 'Disease', (142, 146))	('loc285194', 'Var', (104, 113))	('patients', 'Species', '9606', (128, 136))
45462	31774069	Expression levels of lncRNA loc285194 were not significantly different between the three groups of patients with CSCC, indicating that lncRNA loc285194 expression was associated with CSCC.	('patients', 'Species', '9606', (99, 107))	('CSCC', 'Disease', (183, 187))	('lncRNA loc285194', 'Var', (135, 151))	('associated', 'Reg', (167, 177))
45463	31774069	There was an association between the expression of lncRNA loc285194 and TGF-beta1 in all three groups of patients with CSCC.	('patients', 'Species', '9606', (105, 113))	('TGF-beta1', 'Gene', '7040', (72, 81))	('TGF-beta1', 'Gene', (72, 81))	('CSCC', 'Disease', (119, 123))	('lncRNA', 'Gene', (51, 57))	('loc285194', 'Var', (58, 67))
45464	31774069	Correlations between plasma lncRNA loc285194 and TGF-beta1 were analyzed using Pearson's correlation coefficient.	('TGF-beta1', 'Gene', (49, 58))	('TGF-beta1', 'Gene', '7040', (49, 58))	('loc285194', 'Var', (35, 44))
45465	31774069	As shown in Figure 3, plasma lncRNA loc285194 and TGF-beta1 were correlated in 22 HPV16-positive patients with CSCC (Figure 3A), 27 HPV18-positive patients with CSCC (Figure 3B) and 17 HPV-negative patients (Figure 3C) but not in 20 healthy controls (Figure 3D).	('HPV16-positive', 'Gene', (82, 96))	('HPV16', 'Species', '333760', (82, 87))	('HPV', 'Species', '10566', (185, 188))	('patients', 'Species', '9606', (198, 206))	('HPV', 'Species', '10566', (132, 135))	('TGF-beta1', 'Gene', '7040', (50, 59))	('TGF-beta1', 'Gene', (50, 59))	('patients', 'Species', '9606', (147, 155))	('patients', 'Species', '9606', (97, 105))	('HPV', 'Species', '10566', (82, 85))	('CSCC', 'Disease', (111, 115))	('loc285194', 'Var', (36, 45))	('correlated', 'Reg', (65, 75))
45466	31774069	Also, expression of lncRNA loc285194 inhibited TGF-beta1.	('lncRNA', 'Gene', (20, 26))	('inhibited', 'NegReg', (37, 46))	('loc285194', 'Var', (27, 36))	('TGF-beta1', 'Gene', '7040', (47, 56))	('TGF-beta1', 'Gene', (47, 56))
45468	31774069	As shown in Figure 4, compared with the control groups, lncRNA loc285194 overexpression significantly downregulated TGF-beta1 (p<0.05).	('downregulated', 'NegReg', (102, 115))	('loc285194', 'Var', (63, 72))	('TGF-beta1', 'Gene', '7040', (116, 125))	('overexpression', 'PosReg', (73, 87))	('TGF-beta1', 'Gene', (116, 125))
45470	31774069	As shown in Figure 5, compared with the control groups, lncRNA loc285194 overexpression significantly inhibited SiHa and C33A cell migration, and treatment with exogenous TGF-beta1 at a dose of 10 ng/ml, promoted cell migration (Figure 5A, 5B) (p<0.05).	('cell migration', 'CPA', (213, 227))	('inhibited', 'NegReg', (102, 111))	('loc285194', 'Var', (63, 72))	('TGF-beta1', 'Gene', '7040', (171, 180))	('TGF-beta1', 'Gene', (171, 180))	('overexpression', 'PosReg', (73, 87))	('promoted', 'PosReg', (204, 212))
45473	31774069	The hypothesis that drove this study was that lncRNA loc285194 might play a role as a tumor suppressor in CSCC.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Disease', (86, 91))	('CSCC', 'Disease', (106, 110))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('loc285194', 'Var', (53, 62))
45474	31774069	The downregulation of TGF-beta1 expression at least partially mediated the action of lncRNA loc285194 in CSCC.	('CSCC', 'Disease', (105, 109))	('downregulation', 'NegReg', (4, 18))	('TGF-beta1', 'Gene', '7040', (22, 31))	('TGF-beta1', 'Gene', (22, 31))	('expression', 'MPA', (32, 42))	('loc285194', 'Var', (92, 101))
45475	31774069	The expression patterns and functionality of lncRNA loc285194 have been previously investigated in several types of human cancer.	('lncRNA', 'Gene', (45, 51))	('investigated', 'Reg', (83, 95))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('loc285194', 'Var', (52, 61))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('human', 'Species', '9606', (116, 121))
45482	31774069	The detection of downregulated lncRNA loc285194 is a potentially promising diagnostic biomarker for colorectal cancer.	('colorectal cancer', 'Disease', 'MESH:D015179', (100, 117))	('colorectal cancer', 'Phenotype', 'HP:0003003', (100, 117))	('loc285194', 'Var', (38, 47))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('downregulated', 'NegReg', (17, 30))	('lncRNA', 'Protein', (31, 37))	('colorectal cancer', 'Disease', (100, 117))
45484	31774069	However, because lncRNA loc285194 is downregulated in multiple cancers, for future studies to evaluate the role of lncRNA loc285194 in CSCC, detection of lncRNA loc285194 should be combined with other diagnostic markers to improve diagnostic specificity.	('downregulated', 'NegReg', (37, 50))	('multiple cancers', 'Disease', (54, 70))	('lncRNA loc285194', 'Gene', (17, 33))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('lncRNA loc285194', 'Var', (154, 170))	('multiple cancers', 'Disease', 'MESH:D009369', (54, 70))	('cancers', 'Phenotype', 'HP:0002664', (63, 70))	('CSCC', 'Disease', (135, 139))
45486	31774069	Expression of TGF-beta suppresses tumor growth at the early stages of tumor development but promotes tumor metastasis in more advanced stages of malignancy.	('promotes', 'PosReg', (92, 100))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', (34, 39))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('Expression', 'Var', (0, 10))	('tumor', 'Disease', (70, 75))	('tumor', 'Disease', (101, 106))	('malignancy', 'Disease', 'MESH:D009369', (145, 155))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('malignancy', 'Disease', (145, 155))	('TGF-beta suppresses tumor', 'Disease', 'MESH:D007340', (14, 39))	('tumor metastasis', 'Disease', 'MESH:D009362', (101, 117))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('tumor metastasis', 'Disease', (101, 117))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('TGF-beta suppresses tumor', 'Disease', (14, 39))
45487	31774069	lncRNA loc285194 is a tumor-suppressor lncRNA regulated by p53, which interacts with TGF-beta signaling to exert its role in the pathogenesis of malignancy.	('p53', 'Gene', (59, 62))	('p53', 'Gene', '7157', (59, 62))	('TGF-beta', 'Gene', (85, 93))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('TGF-beta', 'Gene', '7039', (85, 93))	('malignancy', 'Disease', 'MESH:D009369', (145, 155))	('loc285194', 'Var', (7, 16))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('malignancy', 'Disease', (145, 155))	('tumor', 'Disease', (22, 27))	('lncRNA', 'Var', (0, 6))
45488	31774069	Therefore, lncRNA loc285194 may also show crosstalk with TGF-beta signaling.	('TGF-beta', 'Gene', '7039', (57, 65))	('crosstalk', 'Reg', (42, 51))	('TGF-beta', 'Gene', (57, 65))	('loc285194', 'Var', (18, 27))
45490	31774069	The results also showed that treatment with exogenous TGF-beta1 promoted cell migration of SiHa and C33A CSCC cells, which supported the role of TGF-beta signaling on promoting metastasis in CSCC.	('promoted', 'PosReg', (64, 72))	('TGF-beta', 'Gene', (145, 153))	('metastasis', 'CPA', (177, 187))	('cell migration', 'CPA', (73, 87))	('TGF-beta1', 'Gene', '7040', (54, 63))	('TGF-beta1', 'Gene', (54, 63))	('TGF-beta', 'Gene', (54, 62))	('exogenous', 'Var', (44, 53))	('TGF-beta', 'Gene', '7039', (145, 153))	('TGF-beta', 'Gene', '7039', (54, 62))
45491	31774069	The study findings also showed that lncRNA loc285194 was likely to be an upstream inhibitor of TGF-beta1 as lncRNA loc285194 overexpression resulted in increased expression levels of TGF-beta1 and treatment with exogenous TGF-beta1 showed no significant effects on lncRNA loc285194 expression.	('TGF-beta1', 'Gene', (95, 104))	('increased', 'PosReg', (152, 161))	('expression levels', 'MPA', (162, 179))	('TGF-beta1', 'Gene', '7040', (183, 192))	('TGF-beta1', 'Gene', (183, 192))	('lncRNA', 'Gene', (108, 114))	('loc285194', 'Var', (115, 124))	('TGF-beta1', 'Gene', '7040', (222, 231))	('TGF-beta1', 'Gene', (222, 231))	('overexpression', 'PosReg', (125, 139))	('TGF-beta1', 'Gene', '7040', (95, 104))
45492	31774069	Also, the effects of lncRNA loc285194 overexpression on CSCC cell behaviors were reduced by treatment with exogenous TGF-beta1.	('lncRNA', 'Gene', (21, 27))	('TGF-beta1', 'Gene', '7040', (117, 126))	('loc285194', 'Var', (28, 37))	('TGF-beta1', 'Gene', (117, 126))	('overexpression', 'PosReg', (38, 52))	('reduced', 'NegReg', (81, 88))	('CSCC cell behaviors', 'CPA', (56, 75))
45493	31774069	However, the impact of lncRNA loc285194 on TGF-beta1 might have been indirect, due to the lack of a significant correlation between lncRNA loc285194 and TGF-beta1 in healthy controls.	('TGF-beta1', 'Gene', '7040', (153, 162))	('lack', 'NegReg', (90, 94))	('TGF-beta1', 'Gene', (153, 162))	('lncRNA', 'Gene', (132, 138))	('loc285194', 'Var', (139, 148))	('TGF-beta1', 'Gene', '7040', (43, 52))	('TGF-beta1', 'Gene', (43, 52))
45494	31774069	CSCC-specific mediators may exist between lncRNA loc285194 and TGF-beta1, as it has previously been shown that specific lncRNAs may regulate the methylation of protein-coding genes and affect gene expression.	('TGF-beta1', 'Gene', '7040', (63, 72))	('affect', 'Reg', (185, 191))	('TGF-beta1', 'Gene', (63, 72))	('gene expression', 'MPA', (192, 207))	('methylation', 'MPA', (145, 156))	('loc285194', 'Var', (49, 58))	('regulate', 'Reg', (132, 140))
45495	31774069	The role of lncRNA loc285194 on methylation of the TGF-beta1 gene requires future study.	('methylation', 'MPA', (32, 43))	('TGF-beta1', 'Gene', '7040', (51, 60))	('loc285194', 'Var', (19, 28))	('TGF-beta1', 'Gene', (51, 60))
45497	31774069	The findings showed that lncRNA loc285194 was downregulated in both HPV-positive and HPV-negative CSCC.	('loc285194', 'Var', (32, 41))	('lncRNA', 'Gene', (25, 31))	('CSCC', 'Disease', (98, 102))	('downregulated', 'NegReg', (46, 59))	('HPV', 'Species', '10566', (68, 71))	('HPV', 'Species', '10566', (85, 88))
45498	31774069	The expression of lncRNA loc285194 also inhibited the migration of CSCC cells in vitro through the inactivation of TGF-beta1, which indicated that lncRNA loc285194 might inhibit the metastasis in CSCC by downregulating TGF-beta1.	('TGF-beta1', 'Gene', '7040', (219, 228))	('migration of CSCC cells in vitro', 'CPA', (54, 86))	('TGF-beta1', 'Gene', (219, 228))	('inhibit', 'NegReg', (170, 177))	('inhibited', 'NegReg', (40, 49))	('downregulating', 'NegReg', (204, 218))	('TGF-beta1', 'Gene', '7040', (115, 124))	('TGF-beta1', 'Gene', (115, 124))	('lncRNA', 'Gene', (18, 24))	('lncRNA loc285194', 'Var', (147, 163))	('CSCC', 'Disease', (196, 200))	('loc285194', 'Var', (25, 34))	('inactivation', 'NegReg', (99, 111))	('metastasis', 'CPA', (182, 192))
45511	30642553	The biology of non-small cell lung (NSCLC) cancer is complex with considerable variation in the clinical behavior and treatment of tumors with specific genetic mutations, rearrangements, high/low PD-L1 expression, and variable histologies.	('high/low', 'Var', (187, 195))	('PD-L1', 'Gene', '29126', (196, 201))	('mutations', 'Var', (160, 169))	('non-small cell lung (NSCLC) cancer', 'Disease', 'MESH:D002289', (15, 49))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('expression', 'MPA', (202, 212))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('tumors', 'Disease', (131, 137))	('tumors', 'Disease', 'MESH:D009369', (131, 137))	('PD-L1', 'Gene', (196, 201))	('rearrangements', 'Var', (171, 185))	('high/low', 'NegReg', (187, 195))
45516	30642553	Published guidelines now underscore the importance of identifying PDL-1 expression, EGFR mutations, ALK and ROS-1 rearrangements, and histological classification.	('ROS-1', 'Gene', (108, 113))	('ROS-1', 'Gene', '6098', (108, 113))	('EGFR', 'Gene', '1956', (84, 88))	('ALK', 'Gene', (100, 103))	('PDL-1', 'Gene', '29126', (66, 71))	('mutations', 'Var', (89, 98))	('PDL-1', 'Gene', (66, 71))	('EGFR', 'Gene', (84, 88))	('ALK', 'Gene', '238', (100, 103))
45567	30642553	Small cell carcinoma was also more commonly identified with EBUS and cTBNA as opposed to TTFNA at the time of diagnosis (Figure 2).	('Small cell carcinoma', 'Disease', (0, 20))	('EBUS', 'Disease', (60, 64))	('Small cell carcinoma', 'Disease', 'MESH:D018288', (0, 20))	('Small cell carcinoma', 'Phenotype', 'HP:0030357', (0, 20))	('cTBNA', 'Var', (69, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (11, 20))
45585	30642553	The intraclass correlation (ICC) coefficients were 0.801 (95% CI: 0.7131147, 0.8646188; p-value: 8e-21) and 0.776 (95% CI: 0.6787765, 0.8467928; p-value: 1.4e-18) for the LUAD and LUSC subtypes, respectively.	('0.8646188', 'Var', (77, 86))	('LUAD', 'Disease', 'MESH:C538231', (171, 175))	('LUAD', 'Disease', (171, 175))	('LUSC', 'Disease', (180, 184))
45586	30642553	The Pearson's correlation coefficients were 0.801 (95% CI: 0.7131147, 0.8646188, p-value: < 2.2e-16) and 0.776 (95% CI: 0.6787765, 0.8467928; p-value: < 2.2e-16) for LUAD and LUSC subtypes, respectively.	('0.8646188', 'Var', (70, 79))	('0.776', 'Var', (105, 110))	('LUAD', 'Disease', (166, 170))	('LUAD', 'Disease', 'MESH:C538231', (166, 170))	('0.8467928', 'Var', (131, 140))	('LUSC', 'Disease', (175, 179))
45616	30642553	Current clinical practice presents many competing demands for tumor tissue, as immunohistochemical markers and molecular characterization of EGFR mutations, ALK and ROS rearrangements, with PDL-1 testing are all being requested.	('PDL-1', 'Gene', (190, 195))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('mutations', 'Var', (146, 155))	('EGFR', 'Gene', '1956', (141, 145))	('tumor', 'Disease', (62, 67))	('ALK', 'Gene', (157, 160))	('EGFR', 'Gene', (141, 145))	('PDL-1', 'Gene', '29126', (190, 195))	('ALK', 'Gene', '238', (157, 160))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
45623	32971994	Scientific evidence about the presence of genetic and epigenetic abnormalities of the KEAP1 gene was firstly reported in non-small-cell lung cancer (NSCLC) and then described in other tumors.	('tumors', 'Disease', 'MESH:D009369', (184, 190))	('lung cancer', 'Disease', 'MESH:D008175', (136, 147))	('NSCLC', 'Disease', 'MESH:D002289', (149, 154))	('epigenetic abnormalities', 'Disease', 'MESH:D018376', (54, 78))	('lung cancer', 'Phenotype', 'HP:0100526', (136, 147))	('NSCLC', 'Disease', (149, 154))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (125, 147))	('NSCLC', 'Phenotype', 'HP:0030358', (149, 154))	('KEAP1', 'Gene', '9817', (86, 91))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (121, 147))	('tumors', 'Phenotype', 'HP:0002664', (184, 190))	('KEAP1', 'Gene', (86, 91))	('reported', 'Reg', (109, 117))	('lung cancer', 'Disease', (136, 147))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('genetic', 'Var', (42, 49))	('tumors', 'Disease', (184, 190))	('epigenetic abnormalities', 'Disease', (54, 78))
45624	32971994	At present, the prognostic role of aberrant methylation at cytosine-guanine dinucleotide (CpG) sites of the KEAP1 gene promoter is debated in NSCLC, and its correlation with transcriptional changes and protein levels remains to be defined in large sample cohorts.	('NSCLC', 'Disease', (142, 147))	('cytosine-guanine dinucleotide', 'Chemical', 'MESH:C015772', (59, 88))	('KEAP1', 'Gene', '9817', (108, 113))	('NSCLC', 'Disease', 'MESH:D002289', (142, 147))	('aberrant methylation', 'Var', (35, 55))	('KEAP1', 'Gene', (108, 113))	('NSCLC', 'Phenotype', 'HP:0030358', (142, 147))
45628	32971994	Interestingly, these results were limited to the KRAS wild-type LUSC and LUAD cohorts, whereas in LUAD the effect of the epigenetic silencing of KEAP1 on its transcription was also observed in the EGFR mutated subpopulation.	('transcription', 'MPA', (158, 171))	('KRAS', 'Gene', '3845', (49, 53))	('LUAD', 'Phenotype', 'HP:0030078', (73, 77))	('KEAP1', 'Gene', '9817', (145, 150))	('epigenetic silencing', 'Var', (121, 141))	('LUSC', 'Phenotype', 'HP:0030359', (64, 68))	('KEAP1', 'Gene', (145, 150))	('EGFR', 'Gene', '1956', (197, 201))	('LUAD', 'Phenotype', 'HP:0030078', (98, 102))	('EGFR', 'Gene', (197, 201))	('KRAS', 'Gene', (49, 53))
45630	32971994	Moreover, the observed impact of epigenetic silencing on KEAP1 expression in specific KRAS and EGFR settings may suggest a potential role of KEAP1 methylation as a predictive marker for NSCLC patients for whom anti-EGFR treatments are considered.	('NSCLC', 'Phenotype', 'HP:0030358', (186, 191))	('KEAP1', 'Gene', (57, 62))	('KEAP1', 'Gene', '9817', (141, 146))	('KRAS', 'Gene', (86, 90))	('KRAS', 'Gene', '3845', (86, 90))	('patients', 'Species', '9606', (192, 200))	('NSCLC', 'Disease', (186, 191))	('EGFR', 'Gene', '1956', (215, 219))	('EGFR', 'Gene', (215, 219))	('NSCLC', 'Disease', 'MESH:D002289', (186, 191))	('EGFR', 'Gene', '1956', (95, 99))	('KEAP1', 'Gene', (141, 146))	('KEAP1', 'Gene', '9817', (57, 62))	('epigenetic silencing', 'Var', (33, 53))	('EGFR', 'Gene', (95, 99))
45633	32971994	Interestingly, a significant translational impact in terms of increased risk of cancer progression and shorter overall survival was documented for alterations in the Kelch-like ECH-associated protein 1 (KEAP1) gene.	('KEAP1', 'Gene', '9817', (203, 208))	('Kelch-like ECH-associated protein 1', 'Gene', '9817', (166, 201))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('KEAP1', 'Gene', (203, 208))	('overall', 'MPA', (111, 118))	('shorter', 'NegReg', (103, 110))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('Kelch-like ECH-associated protein 1', 'Gene', (166, 201))	('cancer', 'Disease', (80, 86))	('alterations', 'Var', (147, 158))
45635	32971994	In cancer, loss of KEAP1 function leads to enhanced activity of NRF2 and antioxidant-related element (ARE)-driven gene expression, thus promoting cellular resistance to oxidative stress, rapid proliferation, and metabolic deregulation.	('KEAP1', 'Gene', (19, 24))	('enhanced', 'PosReg', (43, 51))	('loss', 'Var', (11, 15))	('activity', 'MPA', (52, 60))	('rapid proliferation', 'CPA', (187, 206))	('NRF2', 'Gene', '4780', (64, 68))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('KEAP1', 'Gene', '9817', (19, 24))	('metabolic deregulation', 'CPA', (212, 234))	('cancer', 'Disease', (3, 9))	('oxidative stress', 'Phenotype', 'HP:0025464', (169, 185))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))	('NRF2', 'Gene', (64, 68))	('promoting', 'PosReg', (136, 145))	('cellular resistance', 'CPA', (146, 165))
45636	32971994	Among the genetic lesions that affect KEAP1/NRF2 activity, point mutations were the first reported mechanism of deregulation in NSCLC and other solid tumors.	('KEAP1', 'Gene', '9817', (38, 43))	('tumors', 'Disease', (150, 156))	('tumors', 'Disease', 'MESH:D009369', (150, 156))	('NSCLC', 'Phenotype', 'HP:0030358', (128, 133))	('tumors', 'Phenotype', 'HP:0002664', (150, 156))	('NRF2', 'Gene', '4780', (44, 48))	('KEAP1', 'Gene', (38, 43))	('NSCLC', 'Disease', (128, 133))	('point mutations', 'Var', (59, 74))	('deregulation', 'MPA', (112, 124))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('NRF2', 'Gene', (44, 48))	('NSCLC', 'Disease', 'MESH:D002289', (128, 133))
45638	32971994	Mutations in the KEAP1 or NFE2L2 genes are mutually exclusive and occur in NSCLC patients with a variable incidence (3.5-15% for KEAP1; 12-17% for NFE2L2), with the first ones mainly clustered with the lung adenocarcinoma (LUAD) histology.	('occur', 'Reg', (66, 71))	('lung adenocarcinoma', 'Disease', (202, 221))	('KEAP1', 'Gene', '9817', (17, 22))	('LUAD', 'Phenotype', 'HP:0030078', (223, 227))	('NFE2L2', 'Gene', '4780', (147, 153))	('KEAP1', 'Gene', (17, 22))	('carcinoma', 'Phenotype', 'HP:0030731', (212, 221))	('Mutations', 'Var', (0, 9))	('NSCLC', 'Disease', 'MESH:D002289', (75, 80))	('NFE2L2', 'Gene', '4780', (26, 32))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (202, 221))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (202, 221))	('NFE2L2', 'Gene', (147, 153))	('NSCLC', 'Disease', (75, 80))	('NFE2L2', 'Gene', (26, 32))	('NSCLC', 'Phenotype', 'HP:0030358', (75, 80))	('patients', 'Species', '9606', (81, 89))	('KEAP1', 'Gene', '9817', (129, 134))	('clustered', 'Reg', (183, 192))	('KEAP1', 'Gene', (129, 134))
45639	32971994	In addition to the genetic lesions, epigenetic abnormalities, such as aberrant cytosine-guanine dinucleotide (CpG) methylation at the KEAP1 promoter island, have been widely reported as one of the main mechanisms of KEAP1 silencing in tumors.	('tumors', 'Disease', 'MESH:D009369', (235, 241))	('KEAP1', 'Gene', (134, 139))	('KEAP1', 'Gene', (216, 221))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('aberrant', 'Var', (70, 78))	('tumors', 'Phenotype', 'HP:0002664', (235, 241))	('epigenetic abnormalities', 'Disease', (36, 60))	('epigenetic abnormalities', 'Disease', 'MESH:D018376', (36, 60))	('KEAP1', 'Gene', '9817', (134, 139))	('KEAP1', 'Gene', '9817', (216, 221))	('cytosine-guanine dinucleotide', 'Chemical', 'MESH:C015772', (79, 108))	('tumors', 'Disease', (235, 241))
45640	32971994	Aberrant methylation at the KEAP1 promoter was firstly described in human NSCLC cell lines and tissues and involves the CpGs grouped into one main island located near the transcriptional start site (TSS).	('methylation', 'Var', (9, 20))	('KEAP1', 'Gene', '9817', (28, 33))	('human', 'Species', '9606', (68, 73))	('NSCLC', 'Phenotype', 'HP:0030358', (74, 79))	('KEAP1', 'Gene', (28, 33))	('NSCLC', 'Disease', (74, 79))	('Aberrant methylation', 'Var', (0, 20))	('NSCLC', 'Disease', 'MESH:D002289', (74, 79))
45641	32971994	In consequence, the observed effect of KEAP1 methylation was to suppress gene expression by abrogating the Sp1 transcription factor binding sites in the promoter region.	('KEAP1', 'Gene', (39, 44))	('abrogating', 'NegReg', (92, 102))	('suppress', 'NegReg', (64, 72))	('KEAP1', 'Gene', '9817', (39, 44))	('Sp1', 'Protein', (107, 110))	('methylation', 'Var', (45, 56))	('gene expression', 'MPA', (73, 88))
45642	32971994	This mechanism of KEAP1 epigenetic silencing was also reported in neoplastic tissues of patients affected by NSCLC and carcinoid tumors, and it was associated with increased risk of lung cancer progression in surgically resected NSCLC patients.	('epigenetic silencing', 'Var', (24, 44))	('lung cancer', 'Disease', (182, 193))	('NSCLC', 'Disease', (229, 234))	('KEAP1', 'Gene', (18, 23))	('carcinoid tumors', 'Disease', 'MESH:D002276', (119, 135))	('NSCLC', 'Disease', 'MESH:D002289', (109, 114))	('NSCLC', 'Phenotype', 'HP:0030358', (229, 234))	('patients', 'Species', '9606', (235, 243))	('carcinoid tumors', 'Disease', (119, 135))	('lung cancer', 'Disease', 'MESH:D008175', (182, 193))	('NSCLC', 'Disease', (109, 114))	('lung cancer', 'Phenotype', 'HP:0100526', (182, 193))	('NSCLC', 'Phenotype', 'HP:0030358', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('associated', 'Reg', (148, 158))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('carcinoid', 'Phenotype', 'HP:0100570', (119, 128))	('patients', 'Species', '9606', (88, 96))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('NSCLC', 'Disease', 'MESH:D002289', (229, 234))	('KEAP1', 'Gene', '9817', (18, 23))
45643	32971994	In clear-cell renal cell carcinoma (ccRCC), the epigenetic modulation of KEAP1 was shown to be the leading mechanism of KEAP1 deregulation, and it was able to strongly predict patient survival.	('epigenetic modulation', 'Var', (48, 69))	('KEAP1', 'Gene', '9817', (120, 125))	('ccRCC', 'Phenotype', 'HP:0006770', (36, 41))	('KEAP1', 'Gene', (120, 125))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (14, 34))	('KEAP1', 'Gene', '9817', (73, 78))	('carcinoma', 'Phenotype', 'HP:0030731', (25, 34))	('KEAP1', 'Gene', (73, 78))	('clear-cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (3, 34))	('clear-cell renal cell carcinoma', 'Disease', (3, 34))	('deregulation', 'MPA', (126, 138))	('patient', 'Species', '9606', (176, 183))	('predict', 'Reg', (168, 175))	('clear-cell renal cell carcinoma', 'Disease', 'MESH:C538614', (3, 34))
45644	32971994	In primary breast cancers and pre-invasive lesions, aberrant KEAP1 promoter methylation was seen to be associated to the estrogen receptor (ER)-positive status and was hypothesized to be a prognostic marker of mortality risk.	('KEAP1', 'Gene', (61, 66))	('mortality', 'Disease', (210, 219))	('breast cancers', 'Phenotype', 'HP:0003002', (11, 25))	('associated', 'Reg', (103, 113))	('estrogen receptor', 'Gene', (121, 138))	('estrogen receptor', 'Gene', '2099', (121, 138))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('breast cancers', 'Disease', 'MESH:D001943', (11, 25))	('breast cancers', 'Disease', (11, 25))	('aberrant', 'Var', (52, 60))	('mortality', 'Disease', 'MESH:D003643', (210, 219))	('KEAP1', 'Gene', '9817', (61, 66))	('ER', 'Gene', '2099', (140, 142))	('cancers', 'Phenotype', 'HP:0002664', (18, 25))
45645	32971994	Aberrant KEAP1 methylation was also reported in colorectal cancer cells and cancer tissues and was linked to a downregulation of its transcriptional activity and an upregulation of NRF2 and its target genes' expression.	('NRF2', 'Gene', (181, 185))	('KEAP1', 'Gene', '9817', (9, 14))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('expression', 'MPA', (208, 218))	('KEAP1', 'Gene', (9, 14))	('colorectal cancer', 'Disease', 'MESH:D015179', (48, 65))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('methylation', 'Var', (15, 26))	('Aberrant', 'Var', (0, 8))	('colorectal cancer', 'Disease', (48, 65))	('upregulation', 'PosReg', (165, 177))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('cancer', 'Disease', (59, 65))	('NRF2', 'Gene', '4780', (181, 185))	('cancer', 'Disease', (76, 82))	('colorectal cancer', 'Phenotype', 'HP:0003003', (48, 65))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('downregulation', 'NegReg', (111, 125))	('transcriptional activity', 'MPA', (133, 157))
45648	32971994	Despite the well-documented clinical impact of KEAP1 and NFE2L2 mutations, the role of aberrant KEAP1 methylation was not fully elucidated in NSCLC, and its clinical prognostic significance in many solid tumors remains controversial.	('KEAP1', 'Gene', (47, 52))	('tumors', 'Disease', 'MESH:D009369', (204, 210))	('KEAP1', 'Gene', '9817', (96, 101))	('NFE2L2', 'Gene', (57, 63))	('NSCLC', 'Disease', (142, 147))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('NSCLC', 'Disease', 'MESH:D002289', (142, 147))	('KEAP1', 'Gene', (96, 101))	('mutations', 'Var', (64, 73))	('KEAP1', 'Gene', '9817', (47, 52))	('tumors', 'Disease', (204, 210))	('NSCLC', 'Phenotype', 'HP:0030358', (142, 147))	('NFE2L2', 'Gene', '4780', (57, 63))	('tumors', 'Phenotype', 'HP:0002664', (204, 210))
45649	32971994	Studies on chemoresistance suggested that selective inhibition of KEAP1 methylation in adenocarcinoma cells could represent a marker of radiosensitizing effects in lung cancer.	('lung cancer', 'Disease', (164, 175))	('KEAP1', 'Gene', '9817', (66, 71))	('lung cancer', 'Phenotype', 'HP:0100526', (164, 175))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('adenocarcinoma', 'Disease', (87, 101))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('methylation', 'Var', (72, 83))	('KEAP1', 'Gene', (66, 71))	('lung cancer', 'Disease', 'MESH:D008175', (164, 175))	('adenocarcinoma', 'Disease', 'MESH:D000230', (87, 101))	('inhibition', 'NegReg', (52, 62))
45650	32971994	More recently, our group observed that epigenetic deregulation of the KEAP1/NRF2 system by methylation at the KEAP1 promoter could involve only some CpGs at the P1a region, thus suggesting that an evaluation of each single CpG methylation status might give more information and have more translational utility than a semi-quantitative evaluation of an entire CpG island.	('information', 'MPA', (262, 273))	('methylation', 'Var', (91, 102))	('epigenetic deregulation', 'MPA', (39, 62))	('NRF2', 'Gene', '4780', (76, 80))	('KEAP1', 'Gene', '9817', (70, 75))	('NRF2', 'Gene', (76, 80))	('KEAP1', 'Gene', '9817', (110, 115))	('KEAP1', 'Gene', (70, 75))	('KEAP1', 'Gene', (110, 115))
45651	32971994	Less information is available in NSCLC about additional mechanisms of epigenetic modulation, such as alteration in poorly investigated intragenic methylation sites of the KEAP1 gene.	('NSCLC', 'Phenotype', 'HP:0030358', (33, 38))	('KEAP1', 'Gene', (171, 176))	('NSCLC', 'Disease', (33, 38))	('KEAP1', 'Gene', '9817', (171, 176))	('NSCLC', 'Disease', 'MESH:D002289', (33, 38))	('epigenetic', 'Var', (70, 80))
45652	32971994	The latest emerging roles of non-promoter CpG islands of cancer-related genes and the translational impact of KEAP1/NRF2 point mutations in predicting resistance to treatment further beg the question of the translational utility of KEAP1 methylation in the clinical context.	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('resistance to treatment', 'MPA', (151, 174))	('cancer', 'Disease', (57, 63))	('KEAP1', 'Gene', '9817', (110, 115))	('NRF2', 'Gene', '4780', (116, 120))	('KEAP1', 'Gene', '9817', (232, 237))	('point mutations', 'Var', (121, 136))	('predicting', 'Reg', (140, 150))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('KEAP1', 'Gene', (110, 115))	('NRF2', 'Gene', (116, 120))	('KEAP1', 'Gene', (232, 237))
45664	32971994	Data related to EGFR, KRAS, and smoking status were also obtained, and patients were divided into the following cohorts: LUAD smokers (all stages, n = 508; early stages, n = 124), LUAD non-smokers (all stages, n = 14; early stages, n = 2); LUAD EGFR mutated (all stages, n = 63; early stages, n = 5), LUAD EGFR wild-type (all stages, n = 459; early stages, n = 98); LUAD KRAS mutated (all stages, n = 447; early stages, n = 101), LUAD KRAS wild-type (all stages, n = 75; early stages, n = 25).	('LUAD', 'Phenotype', 'HP:0030078', (240, 244))	('LUAD', 'Phenotype', 'HP:0030078', (121, 125))	('patients', 'Species', '9606', (71, 79))	('EGFR', 'Gene', '1956', (245, 249))	('EGFR', 'Gene', (306, 310))	('KRAS', 'Gene', (22, 26))	('EGFR', 'Gene', '1956', (16, 20))	('KRAS', 'Gene', (435, 439))	('LUAD', 'Phenotype', 'HP:0030078', (366, 370))	('LUAD', 'Phenotype', 'HP:0030078', (301, 305))	('EGFR', 'Gene', '1956', (306, 310))	('mutated', 'Var', (376, 383))	('LUAD', 'Phenotype', 'HP:0030078', (180, 184))	('EGFR', 'Gene', (245, 249))	('EGFR', 'Gene', (16, 20))	('KRAS', 'Gene', '3845', (371, 375))	('KRAS', 'Gene', (371, 375))	('KRAS', 'Gene', '3845', (22, 26))	('KRAS', 'Gene', '3845', (435, 439))
45665	32971994	A total of 60 LUAD patients of all stages (95% EGFR mutated and 80% KRAS wild-type) shared the EGFR mutated/KRAS wild-type molecular subsets.	('KRAS', 'Gene', (108, 112))	('patients', 'Species', '9606', (19, 27))	('LUAD', 'Phenotype', 'HP:0030078', (14, 18))	('mutated', 'Var', (52, 59))	('KRAS', 'Gene', '3845', (108, 112))	('KRAS', 'Gene', (68, 72))	('KRAS', 'Gene', '3845', (68, 72))	('EGFR', 'Gene', '1956', (47, 51))	('EGFR', 'Gene', '1956', (95, 99))	('EGFR', 'Gene', (47, 51))	('EGFR', 'Gene', (95, 99))
45666	32971994	Ninety-five LUAD subjects were not annotated with any information about KRAS/EGFR mutations and smoking habits.	('KRAS', 'Gene', (72, 76))	('KRAS', 'Gene', '3845', (72, 76))	('mutations', 'Var', (82, 91))	('EGFR', 'Gene', '1956', (77, 81))	('LUAD', 'Phenotype', 'HP:0030078', (12, 16))	('EGFR', 'Gene', (77, 81))
45667	32971994	Finally, there were 15 LUSC KRAS mutated patients (all stages) and 246 LUSC KRAS wild-type patients (all stages).	('KRAS', 'Gene', (28, 32))	('patients', 'Species', '9606', (91, 99))	('KRAS', 'Gene', '3845', (28, 32))	('KRAS', 'Gene', (76, 80))	('KRAS', 'Gene', '3845', (76, 80))	('mutated', 'Var', (33, 40))	('patients', 'Species', '9606', (41, 49))	('LUSC', 'Phenotype', 'HP:0030359', (23, 27))	('LUSC', 'Phenotype', 'HP:0030359', (71, 75))
45671	32971994	For the analysis of KEAP1 CpGs methylation within the TCGA cohort, Illumina Infinium Human Methylation 450 BeadChip beads (cg25801292, cg02428100, cg06911149, cg26500801, cg03890664, cg15676203, cg15204119, cg26988016, cg20226327, cg10505024, cg07695362, cg00522555, cg01018726, cg22779878, cg02337283, cg01586432) were used.	('cg00522555', 'Var', (255, 265))	('cg07695362', 'Var', (243, 253))	('cg25801292', 'Chemical', '-', (123, 133))	('Human', 'Species', '9606', (85, 90))	('KEAP1', 'Gene', (20, 25))	('cg25801292', 'Var', (123, 133))	('cg15204119', 'Var', (195, 205))	('cg26500801', 'Var', (159, 169))	('cg26988016', 'Var', (207, 217))	('cg03890664', 'Var', (171, 181))	('KEAP1', 'Gene', '9817', (20, 25))	('cg15676203', 'Var', (183, 193))	('cg20226327', 'Var', (219, 229))	('cg10505024', 'Var', (231, 241))	('cg22779878', 'Var', (279, 289))	('cg01586432', 'Var', (303, 313))	('cg01018726', 'Var', (267, 277))	('cg02337283', 'Var', (291, 301))
45672	32971994	Both in non-neoplastic and in tumor tissues of LUAD and LUSC, CpG-sites targeted by beads located peripherally in the CpG-dense area of KEAP1 (which includes the GCI-1 island) showed lower methylation levels, than the beads located in the central position of KEAP1 gene, including the CGI-2 island; the only exception was cg25801292 (Figure 2).	('cg25801292', 'Var', (322, 332))	('KEAP1', 'Gene', (259, 264))	('LUSC', 'Phenotype', 'HP:0030359', (56, 60))	('KEAP1', 'Gene', (136, 141))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('KEAP1', 'Gene', '9817', (259, 264))	('methylation levels', 'MPA', (189, 207))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('LUAD', 'Phenotype', 'HP:0030078', (47, 51))	('cg25801292', 'Chemical', '-', (322, 332))	('lower', 'NegReg', (183, 188))	('KEAP1', 'Gene', '9817', (136, 141))	('tumor', 'Disease', (30, 35))
45675	32971994	Considering all-stages of LUAD patients, we found that only two predicted KEAP1 CpG sites, are located in the CGI-1 and CGI-2 islands (cg15204119, R = -0,18, p = 8 x 10-0.5; cg10505024, R = -0,12, p = 0.0097), were significantly and inversely correlated with KEAP1 mRNA levels (Figure 4A,B).	('cg10505024', 'Var', (174, 184))	('KEAP1', 'Gene', '9817', (259, 264))	('KEAP1', 'Gene', '9817', (74, 79))	('patients', 'Species', '9606', (31, 39))	('cg15204119', 'Var', (135, 145))	('inversely', 'NegReg', (233, 242))	('KEAP1', 'Gene', (259, 264))	('LUAD', 'Phenotype', 'HP:0030078', (26, 30))	('KEAP1', 'Gene', (74, 79))
45676	32971994	More surprisingly, we observed a clear and inverse association between six KEAP1 CpG sites (cg25801292, R = -0.18, p = 0.001; cg20226327, R = -0.18, p = 0.0005; cg10505024, R =-0.21, p =3.9 x 10-0.5; cg07695362, R = -0.3, p = 6 x 10-0.9; cg22779878, R = -0.33 p = 1.40 x 10-10; cg02337283, R = -0.17, p = 0.001) and mRNA levels in the LUSC group (all stages) (Figure 4C,D).	('KEAP1', 'Gene', (75, 80))	('LUSC', 'Phenotype', 'HP:0030359', (335, 339))	('mRNA levels', 'MPA', (316, 327))	('cg25801292', 'Var', (92, 102))	('cg10505024', 'Var', (161, 171))	('cg02337283', 'Var', (278, 288))	('cg22779878', 'Var', (238, 248))	('inverse', 'NegReg', (43, 50))	('cg07695362', 'Var', (200, 210))	('cg20226327', 'Var', (126, 136))	('KEAP1', 'Gene', '9817', (75, 80))	('cg25801292', 'Chemical', '-', (92, 102))
45677	32971994	As for the LUAD cohort, three out of these CpGs are located in the CGI-1 (cg25801292) and CGI-2 (cg10505024 and cg07695362) regions.	('cg25801292', 'Var', (74, 84))	('LUAD', 'Phenotype', 'HP:0030078', (11, 15))	('cg10505024', 'Var', (97, 107))	('cg07695362', 'Var', (112, 122))	('cg25801292', 'Chemical', '-', (74, 84))
45679	32971994	Almost half of the KEAP1 CpG sites related to the LUSC cohort exhibited a significant correlation with KEAP1 expression (cg25801292 and cg02428100, exon 1-CGI-1; cg20226327, intron 2; cg10505024 and cg07695362, exon 3-CGI-2; cg22779878, exon 4; cg02337283, exon 5; Figure 5A,B),whereas KEAP1 methylated CpG sites did not show any significant correlation in the LUAD non-metastatic cohort.	('KEAP1', 'Gene', (19, 24))	('cg20226327', 'Var', (162, 172))	('KEAP1', 'Gene', '9817', (103, 108))	('cg07695362', 'Var', (199, 209))	('KEAP1', 'Gene', '9817', (286, 291))	('cg22779878', 'Var', (225, 235))	('LUSC', 'Phenotype', 'HP:0030359', (50, 54))	('cg02428100', 'Var', (136, 146))	('cg25801292', 'Chemical', '-', (121, 131))	('KEAP1', 'Gene', (103, 108))	('KEAP1', 'Gene', '9817', (19, 24))	('LUAD', 'Phenotype', 'HP:0030078', (361, 365))	('KEAP1', 'Gene', (286, 291))	('cg10505024', 'Var', (184, 194))	('cg02337283', 'Var', (245, 255))	('cg25801292', 'Var', (121, 131))
45680	32971994	Results were slightly different when the LUAD smoker all-stages cohort was examined, where a significant inverse correlation between KEAP1 methylation and its expression emerged for the cg22779878 (exon 4), cg07695362 (exon 3-CGI-2), and cg15676203, (intron 1-CGI-1), (Supplemental Table S2).	('inverse', 'NegReg', (105, 112))	('LUAD', 'Phenotype', 'HP:0030078', (41, 45))	('expression', 'MPA', (159, 169))	('KEAP1', 'Gene', '9817', (133, 138))	('methylation', 'MPA', (139, 150))	('cg15676203', 'Var', (238, 248))	('cg22779878', 'Var', (186, 196))	('cg07695362', 'Var', (207, 217))	('KEAP1', 'Gene', (133, 138))
45682	32971994	The effect of the KEAP1 methylation on its transcript level was observed only in the EGFR mutated cohort, strictly related to the cg22779878 (exon 4), a block of 3 CpGs of the CGI-2 intragenic island (cg07695362, cg10505024, and cg20226327) an only one CpG of the CGI-1 promoter island (cg15676203).	('cg10505024', 'Var', (213, 223))	('transcript', 'MPA', (43, 53))	('EGFR', 'Gene', (85, 89))	('cg20226327', 'Var', (229, 239))	('KEAP1', 'Gene', (18, 23))	('cg07695362', 'Var', (201, 211))	('EGFR', 'Gene', '1956', (85, 89))	('KEAP1', 'Gene', '9817', (18, 23))
45683	32971994	Conversely, in the subpopulation of KRAS wild-type all-stages LUAD, correlation was observed at the cg22779878 (exon 4), in only one CpG located in the CGI-2 intragenic island (cg07695362), but in three CpGs located in the CGI-1 promoter island (cg06911149, cg15676203, and cg03890664).	('LUAD', 'Phenotype', 'HP:0030078', (62, 66))	('cg15676203', 'Var', (258, 268))	('cg03890664', 'Var', (274, 284))	('KRAS', 'Gene', (36, 40))	('KRAS', 'Gene', '3845', (36, 40))	('cg22779878', 'Var', (100, 110))	('cg06911149', 'Var', (246, 256))
45685	32971994	In this cohort, a large number of CpGs located in the CGI-1 (cg25801292, cg02428100, cg15204119, cg15676203) and CGI-2 islands (cg2022637, cg10505024, cg07695362, cg01018726) showed a negative correlation between KEAP1 methylation and transcript expression, but only in the group of KRAS wild-type tumors (Supplemental Table S2).	('tumors', 'Disease', 'MESH:D009369', (298, 304))	('cg2022637', 'Var', (128, 137))	('KRAS', 'Gene', (283, 287))	('cg10505024', 'Var', (139, 149))	('cg15204119', 'Var', (85, 95))	('transcript expression', 'MPA', (235, 256))	('KEAP1', 'Gene', '9817', (213, 218))	('cg02428100', 'Var', (73, 83))	('tumors', 'Phenotype', 'HP:0002664', (298, 304))	('cg25801292', 'Var', (61, 71))	('KEAP1', 'Gene', (213, 218))	('negative', 'NegReg', (184, 192))	('cg01018726', 'Var', (163, 173))	('tumor', 'Phenotype', 'HP:0002664', (298, 303))	('tumors', 'Disease', (298, 304))	('cg07695362', 'Var', (151, 161))	('KRAS', 'Gene', '3845', (283, 287))	('cg25801292', 'Chemical', '-', (61, 71))	('cg15676203', 'Var', (97, 107))
45686	32971994	We then investigated the possibility that patterns of methylation may interfere with the transcription of KEAP1 through modulation of the accessibility of transcription factor binding sites (TFBSs).	('transcription', 'MPA', (89, 102))	('methylation', 'Var', (54, 65))	('KEAP1', 'Gene', (106, 111))	('modulation', 'Reg', (120, 130))	('patterns', 'Var', (42, 50))	('accessibility of transcription', 'MPA', (138, 168))	('interfere', 'NegReg', (70, 79))	('KEAP1', 'Gene', '9817', (106, 111))
45689	32971994	Concerning the KEAP1 exon 3 and the CGI-2, we observed the presence of CTCF sites at the position chr19: 1062751-10603103 (ENCODE V3 cell lines) and chr19:10602731-10603130 (ENCODE V2).	('chr19:10602731-10603130', 'Var', (149, 172))	('CTCF', 'Gene', '10664', (71, 75))	('chr19: 1062751-10603103', 'Var', (98, 121))	('chr19:10602731-10603130', 'STRUCTURAL_ABNORMALITY', 'None', (149, 172))	('KEAP1', 'Gene', '9817', (15, 20))	('CTCF', 'Gene', (71, 75))	('KEAP1', 'Gene', (15, 20))
45695	32971994	An inverse, strong correlation between KEAP1 methylation and mRNA expression levels of NRF2 and its targets was observed in both the LUAD and LUSC cohorts.	('NRF2', 'Gene', '4780', (87, 91))	('KEAP1', 'Gene', (39, 44))	('NRF2', 'Gene', (87, 91))	('LUSC', 'Phenotype', 'HP:0030359', (142, 146))	('mRNA expression levels', 'MPA', (61, 83))	('KEAP1', 'Gene', '9817', (39, 44))	('methylation', 'Var', (45, 56))	('LUAD', 'Phenotype', 'HP:0030078', (133, 137))
45696	32971994	In the LUAD cohort, a common pattern of correlation emerged between the methylation of cg227799878 (exon 4) and the expression of NRF2 and its targets.	('cg227799878', 'Chemical', '-', (87, 98))	('expression', 'MPA', (116, 126))	('LUAD', 'Phenotype', 'HP:0030078', (7, 11))	('methylation', 'MPA', (72, 83))	('cg227799878', 'Var', (87, 98))	('NRF2', 'Gene', '4780', (130, 134))	('NRF2', 'Gene', (130, 134))
45700	32971994	Among these, hypermethylation of cg15204119 (CGI-I island), cg07695362 (CGI-2 island), and cg22779878 (exon 4) correlated with both KEAP1 mRNA downregulation and NRF2/ARE-driven target genes upregulation.	('cg07695362', 'Var', (60, 70))	('upregulation', 'PosReg', (191, 203))	('cg22779878', 'Var', (91, 101))	('NRF2', 'Gene', (162, 166))	('downregulation', 'NegReg', (143, 157))	('KEAP1', 'Gene', '9817', (132, 137))	('hypermethylation', 'Var', (13, 29))	('KEAP1', 'Gene', (132, 137))	('cg15204119', 'Var', (33, 43))	('NRF2', 'Gene', '4780', (162, 166))
45702	32971994	Among these, hypermethylation of cg15204119, cg02428100, cg15676203, cg15204119 (all located in the CGI-I island), cg20226327 (intron 2), cg10505024 and cg07695362 (all located in the CGI-2 island), cg22779878 (exon 4), and cg02337283 (exon 5) correlated with both KEAP1 mRNA downregulation and NRF2/ARE-driven target genes downregulation.	('cg15676203', 'Var', (57, 67))	('cg20226327', 'Var', (115, 125))	('downregulation', 'NegReg', (276, 290))	('downregulation', 'NegReg', (324, 338))	('cg02337283', 'Var', (224, 234))	('KEAP1', 'Gene', '9817', (265, 270))	('cg22779878', 'Var', (199, 209))	('cg10505024', 'Var', (138, 148))	('NRF2', 'Gene', '4780', (295, 299))	('cg02428100', 'Var', (45, 55))	('cg07695362', 'Var', (153, 163))	('KEAP1', 'Gene', (265, 270))	('cg15204119', 'Var', (69, 79))	('hypermethylation', 'Var', (13, 29))	('NRF2', 'Gene', (295, 299))	('cg15204119', 'Var', (33, 43))
45703	32971994	As a result of their frequency and plasticity, epigenetic alterations are now emerging as innovative cancer biomarkers.	('cancer', 'Disease', (101, 107))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('epigenetic alterations', 'Var', (47, 69))
45706	32971994	The presence of genetic and epigenetic abnormalities in this pathway, such as point mutations in functional domains of KEAP1 and NFE2L2 and methylation at the KEAP1 promoter region, was firstly described in NSCLC and then widely reported in many solid tumors, with the hypothesis that the lack of KEAP1 transcription induced high NRF2 activity and aberrant overexpression of ARE-driven target genes.	('NRF2', 'Gene', (330, 334))	('NSCLC', 'Disease', (207, 212))	('tumors', 'Phenotype', 'HP:0002664', (252, 258))	('activity', 'MPA', (335, 343))	('NSCLC', 'Phenotype', 'HP:0030358', (207, 212))	('epigenetic abnormalities', 'Disease', (28, 52))	('KEAP1', 'Gene', '9817', (159, 164))	('tumor', 'Phenotype', 'HP:0002664', (252, 257))	('KEAP1', 'Gene', (159, 164))	('KEAP1', 'Gene', '9817', (119, 124))	('tumors', 'Disease', (252, 258))	('NFE2L2', 'Gene', '4780', (129, 135))	('KEAP1', 'Gene', (119, 124))	('epigenetic abnormalities', 'Disease', 'MESH:D018376', (28, 52))	('lack', 'Var', (289, 293))	('KEAP1', 'Gene', (297, 302))	('NRF2', 'Gene', '4780', (330, 334))	('tumors', 'Disease', 'MESH:D009369', (252, 258))	('NFE2L2', 'Gene', (129, 135))	('overexpression', 'PosReg', (357, 371))	('KEAP1', 'Gene', '9817', (297, 302))	('NSCLC', 'Disease', 'MESH:D002289', (207, 212))
45708	32971994	This notion is also supported by a clear co-occurrence with STK11 and KRAS gene alterations with a suggested synergic role of these genes in enhancement of tumorigenesis and lung cancer progression.	('STK11', 'Gene', (60, 65))	('enhancement', 'PosReg', (141, 152))	('lung cancer', 'Disease', (174, 185))	('alterations', 'Var', (80, 91))	('lung cancer', 'Phenotype', 'HP:0100526', (174, 185))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('KRAS', 'Gene', (70, 74))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('STK11', 'Gene', '6794', (60, 65))	('KRAS', 'Gene', '3845', (70, 74))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('lung cancer', 'Disease', 'MESH:D008175', (174, 185))	('tumor', 'Disease', (156, 161))
45719	32971994	These findings were corroborated by the fact that, regardless of non-metastatic and metastatic stages, no strong correlation appeared between KEAP1 CpGs methylation and mRNA levels in LUAD, while this occurred instead in LUSC (both in all-stages and in non-metastatic stages).	('mRNA levels', 'MPA', (169, 180))	('LUSC', 'Phenotype', 'HP:0030359', (221, 225))	('KEAP1', 'Gene', '9817', (142, 147))	('LUAD', 'Phenotype', 'HP:0030078', (184, 188))	('KEAP1', 'Gene', (142, 147))	('methylation', 'Var', (153, 164))
45720	32971994	A novel and unexpected finding is that, when we stratified the LUAD population on the basis of the EGFR and KRAS status, the effects of KEAP1 methylation on KEAP1 transcription strongly re-emerged, strictly linked to an EGFR mutated and KRAS wild-type context.	('KRAS', 'Gene', (108, 112))	('KRAS', 'Gene', (237, 241))	('KEAP1', 'Gene', (157, 162))	('EGFR', 'Gene', (99, 103))	('EGFR', 'Gene', (220, 224))	('KEAP1', 'Gene', (136, 141))	('KRAS', 'Gene', '3845', (237, 241))	('LUAD', 'Phenotype', 'HP:0030078', (63, 67))	('re-emerged', 'PosReg', (186, 196))	('KEAP1', 'Gene', '9817', (157, 162))	('KRAS', 'Gene', '3845', (108, 112))	('effects', 'Reg', (125, 132))	('methylation', 'Var', (142, 153))	('EGFR', 'Gene', '1956', (99, 103))	('KEAP1', 'Gene', '9817', (136, 141))	('EGFR', 'Gene', '1956', (220, 224))
45721	32971994	The link between the epigenetic silencing of KEAP1 and KRAS wild-type status was also confirmed in LUSC, being present in the KRAS wild-type subpopulation and absent in KRAS mutated patients.	('KRAS', 'Gene', (55, 59))	('KRAS', 'Gene', '3845', (126, 130))	('epigenetic silencing', 'Var', (21, 41))	('KEAP1', 'Gene', '9817', (45, 50))	('KRAS', 'Gene', '3845', (55, 59))	('KRAS', 'Gene', (169, 173))	('KRAS', 'Gene', '3845', (169, 173))	('KEAP1', 'Gene', (45, 50))	('patients', 'Species', '9606', (182, 190))	('LUSC', 'Phenotype', 'HP:0030359', (99, 103))	('KRAS', 'Gene', (126, 130))
45722	32971994	Our results support the documented link between KEAP1, EGFR, and KRAS mutations and open the debate on the role of KEAP1 methylation in the context of anti-EGFR treatments.	('EGFR', 'Gene', '1956', (55, 59))	('mutations', 'Var', (70, 79))	('KEAP1', 'Gene', '9817', (48, 53))	('KRAS', 'Gene', '3845', (65, 69))	('EGFR', 'Gene', '1956', (156, 160))	('EGFR', 'Gene', (55, 59))	('KEAP1', 'Gene', '9817', (115, 120))	('KEAP1', 'Gene', (48, 53))	('EGFR', 'Gene', (156, 160))	('KEAP1', 'Gene', (115, 120))	('KRAS', 'Gene', (65, 69))	('link', 'Interaction', (35, 39))
45723	32971994	For NSCLC patients whose tumors harbor mutations in EGFR, disruption of the KEAP1/NRF2 pathway is of the most recently reported mechanisms by which EGFR-tyrosine kinase inhibitors (EGFR-TKI) resistance occurs.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumors', 'Disease', (25, 31))	('EGFR', 'Gene', (52, 56))	('NRF2', 'Gene', '4780', (82, 86))	('EGFR', 'Gene', '1956', (181, 185))	('NSCLC', 'Disease', 'MESH:D002289', (4, 9))	('EGFR', 'Gene', '1956', (148, 152))	('mutations', 'Var', (39, 48))	('tumors', 'Disease', 'MESH:D009369', (25, 31))	('NRF2', 'Gene', (82, 86))	('NSCLC', 'Disease', (4, 9))	('EGFR', 'Gene', '1956', (52, 56))	('NSCLC', 'Phenotype', 'HP:0030358', (4, 9))	('patients', 'Species', '9606', (10, 18))	('EGFR', 'Gene', (181, 185))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('KEAP1', 'Gene', '9817', (76, 81))	('EGFR', 'Gene', (148, 152))	('KEAP1', 'Gene', (76, 81))
45724	32971994	Coexisting mutations in the KEAP1/NFE2L2/CUL3 genes were in fact reported to be associated with significantly decreased time to TKI treatment failure.	('NFE2L2', 'Gene', '4780', (34, 40))	('mutations', 'Var', (11, 20))	('KEAP1', 'Gene', '9817', (28, 33))	('TKI', 'Disease', (128, 131))	('CUL3', 'Gene', '8452', (41, 45))	('time', 'CPA', (120, 124))	('KEAP1', 'Gene', (28, 33))	('decreased', 'NegReg', (110, 119))	('NFE2L2', 'Gene', (34, 40))	('CUL3', 'Gene', (41, 45))
45725	32971994	Taking into account our findings of a clear connection between KEAP1 methylation and an EGFR mutated condition, we speculate that KEAP1 methylation might represent an additional mechanism of TKI resistance in the context of oxidative stress modulation.	('KEAP1', 'Gene', '9817', (63, 68))	('methylation', 'Var', (136, 147))	('KEAP1', 'Gene', (130, 135))	('KEAP1', 'Gene', (63, 68))	('oxidative stress', 'Phenotype', 'HP:0025464', (224, 240))	('EGFR', 'Gene', '1956', (88, 92))	('KEAP1', 'Gene', '9817', (130, 135))	('EGFR', 'Gene', (88, 92))
45727	32971994	First, oncogenic KRAS mutations were associated with chemoresistance and poor prognosis in NSCLC, also by controlling the NFE2L2 gene transcription through a direct link of KRAS to a TPA response element (TRE) located in the NFE2L2 promoter.	('NSCLC', 'Disease', 'MESH:D002289', (91, 96))	('transcription', 'MPA', (134, 147))	('NSCLC', 'Phenotype', 'HP:0030358', (91, 96))	('NFE2L2', 'Gene', (122, 128))	('NFE2L2', 'Gene', (225, 231))	('chemoresistance', 'CPA', (53, 68))	('controlling', 'Reg', (106, 117))	('link', 'Interaction', (165, 169))	('KRAS', 'Gene', (173, 177))	('NFE2L2', 'Gene', '4780', (225, 231))	('KRAS', 'Gene', '3845', (173, 177))	('TPA', 'Chemical', '-', (183, 186))	('KRAS', 'Gene', (17, 21))	('associated', 'Reg', (37, 47))	('mutations', 'Var', (22, 31))	('KRAS', 'Gene', '3845', (17, 21))	('NSCLC', 'Disease', (91, 96))	('NFE2L2', 'Gene', '4780', (122, 128))
45728	32971994	Second, KRAS-mutant tumors with coexisting TP53 or KEAP1 mutations were associated with a more aggressive tumor phenotype, and loss of KEAP1 in tumors exhibits unique characteristics dictated by their cellular origin and metabolic program.	('tumors', 'Disease', (144, 150))	('KEAP1', 'Gene', '9817', (51, 56))	('associated', 'Reg', (72, 82))	('mutations', 'Var', (57, 66))	('KEAP1', 'Gene', (51, 56))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('tumors', 'Disease', 'MESH:D009369', (144, 150))	('KEAP1', 'Gene', '9817', (135, 140))	('aggressive tumor', 'Disease', 'MESH:D001523', (95, 111))	('KEAP1', 'Gene', (135, 140))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('TP53', 'Gene', (43, 47))	('tumors', 'Disease', (20, 26))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('KRAS', 'Gene', '3845', (8, 12))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('aggressive tumor', 'Disease', (95, 111))	('tumors', 'Disease', 'MESH:D009369', (20, 26))	('KRAS', 'Gene', (8, 12))	('TP53', 'Gene', '7157', (43, 47))	('loss', 'Var', (127, 131))
45730	32971994	Alternatively, given that in our study no clear inverse correlation was observed between KEAP1 methylation and NFE2L2 transcription, the epigenetic silencing of KEAP1 could represent an alternative or synergic way for NRF2 modulation of chemoresistance in NSCLC mediated by the KRAS gene status.	('KRAS', 'Gene', (278, 282))	('NSCLC', 'Disease', 'MESH:D002289', (256, 261))	('chemoresistance', 'CPA', (237, 252))	('KEAP1', 'Gene', '9817', (89, 94))	('KEAP1', 'Gene', (161, 166))	('KEAP1', 'Gene', (89, 94))	('NSCLC', 'Phenotype', 'HP:0030358', (256, 261))	('NFE2L2', 'Gene', '4780', (111, 117))	('KRAS', 'Gene', '3845', (278, 282))	('NRF2', 'Gene', '4780', (218, 222))	('NFE2L2', 'Gene', (111, 117))	('modulation', 'Reg', (223, 233))	('NRF2', 'Gene', (218, 222))	('KEAP1', 'Gene', '9817', (161, 166))	('NSCLC', 'Disease', (256, 261))	('epigenetic silencing', 'Var', (137, 157))
45733	32971994	In fact, we hypothesized that a non-canonical epigenetic regulation may exist for KEAP1 at the exonic level, and specifically at exon 3, where a short CpG island (CGI-2 in our work) was predicted that starts from chr19:10602253 and ends at 10602938, according to the UCSC CpG Island track (human genome build: hg19).	('10602938', 'Var', (240, 248))	('human', 'Species', '9606', (290, 295))	('KEAP1', 'Gene', (82, 87))	('KEAP1', 'Gene', '9817', (82, 87))
45735	32971994	At the protein level, an aberrant transcript without exon 3 should produce a shorter KEAP1 protein (624 amino acids in its canonical form), lacking amino acids 214-536.	('KEAP1', 'Gene', (85, 90))	('lacking', 'NegReg', (140, 147))	('aberrant', 'Var', (25, 33))	('amino acids 214-536', 'MPA', (148, 167))	('KEAP1', 'Gene', '9817', (85, 90))	('shorter', 'NegReg', (77, 84))
45736	32971994	This would lead to partial loss of IVR and KELCH domains, both responsible for NRF2 interaction (fundamental arginine residues would be deleted, including Arg-380, Arg-415, and Arg-483).	('NRF2', 'Gene', (79, 83))	('Arg', 'Chemical', 'MESH:D001120', (155, 158))	('IVR', 'MPA', (35, 38))	('Arg', 'Chemical', 'MESH:D001120', (177, 180))	('Arg', 'Chemical', 'MESH:D001120', (164, 167))	('Arg-483', 'Var', (177, 184))	('Arg-415', 'Var', (164, 171))	('NRF2', 'Gene', '4780', (79, 83))	('Arg-380', 'Var', (155, 162))	('loss', 'NegReg', (27, 31))	('arginine', 'Chemical', 'MESH:D001120', (109, 117))
45737	32971994	At the cellular level, intragenic KEAP1 hypermethylation would increase the dosage of aberrant KEAP1 proteins at the expense of its canonical form, thereby contributing to enhance the levels of un-sequestered NRF2.	('increase', 'PosReg', (63, 71))	('levels', 'MPA', (184, 190))	('enhance', 'PosReg', (172, 179))	('KEAP1', 'Gene', (34, 39))	('KEAP1', 'Gene', (95, 100))	('proteins', 'Protein', (101, 109))	('hypermethylation', 'Var', (40, 56))	('aberrant', 'Var', (86, 94))	('dosage', 'MPA', (76, 82))	('NRF2', 'Gene', '4780', (209, 213))	('NRF2', 'Gene', (209, 213))	('KEAP1', 'Gene', '9817', (34, 39))	('KEAP1', 'Gene', '9817', (95, 100))
45738	32971994	To test this hypothesis, experimental assays are warranted to verify CpG methylation levels for the KEAP1 genomic region, the presence of an exon 3-skipped transcript variant, and the dosage balance between normal and aberrant KEAP1 protein.	('KEAP1', 'Gene', '9817', (227, 232))	('KEAP1', 'Gene', '9817', (100, 105))	('variant', 'Var', (167, 174))	('KEAP1', 'Gene', (227, 232))	('KEAP1', 'Gene', (100, 105))
45739	32971994	Surprisingly, we also observed that one KEAP1 CpG (cg02337283), predicted in exon 5, was significantly recurrent in all bioinformatics analysis on non-metastatic LUAD and LUSC correlations; we thus wonder if DNA methylation might facilitate KEAP1 exon inclusion in other settings by recruiting methyl-binding domain (MBD) proteins.	('methyl-binding domain', 'MPA', (294, 315))	('KEAP1', 'Gene', (40, 45))	('KEAP1', 'Gene', '9817', (241, 246))	('facilitate', 'PosReg', (230, 240))	('methylation', 'Var', (212, 223))	('LUAD', 'Phenotype', 'HP:0030078', (162, 166))	('KEAP1', 'Gene', (241, 246))	('KEAP1', 'Gene', '9817', (40, 45))	('LUSC', 'Phenotype', 'HP:0030359', (171, 175))	('recruiting', 'PosReg', (283, 293))
45740	32971994	Strong correlations were observed between many CpGs located both in the KEAP1 promoter and in the KEAP1 gene body CGI and the mRNA transcript levels of NRF2 and some of its target genes, both in LUAD and in LUSC; this evidence confirms the strong link between epigenetic KEAP1 silencing and NRF2 activity modulation.	('NRF2', 'Gene', (291, 295))	('KEAP1', 'Gene', (98, 103))	('NRF2', 'Gene', '4780', (152, 156))	('KEAP1', 'Gene', '9817', (271, 276))	('LUSC', 'Phenotype', 'HP:0030359', (207, 211))	('activity', 'MPA', (296, 304))	('KEAP1', 'Gene', '9817', (72, 77))	('silencing', 'NegReg', (277, 286))	('NRF2', 'Gene', (152, 156))	('KEAP1', 'Gene', (271, 276))	('mRNA transcript levels', 'MPA', (126, 148))	('KEAP1', 'Gene', (72, 77))	('epigenetic', 'Var', (260, 270))	('NRF2', 'Gene', '4780', (291, 295))	('KEAP1', 'Gene', '9817', (98, 103))	('LUAD', 'Phenotype', 'HP:0030078', (195, 199))
45742	32971994	Globally, a complex link emerges between KEAP1 methylation and NRF2 deregulation that needs to be confirmed on large independent NSCLC cohorts.	('NSCLC', 'Phenotype', 'HP:0030358', (129, 134))	('NRF2', 'Gene', (63, 67))	('KEAP1', 'Gene', '9817', (41, 46))	('methylation', 'Var', (47, 58))	('NSCLC', 'Disease', (129, 134))	('KEAP1', 'Gene', (41, 46))	('deregulation', 'MPA', (68, 80))	('NSCLC', 'Disease', 'MESH:D002289', (129, 134))	('NRF2', 'Gene', '4780', (63, 67))
45743	32971994	Epigenetic deregulation has been increasingly recognized as one of the major mechanisms of the KEAP1 gene deregulation in lung cancer.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('lung cancer', 'Disease', (122, 133))	('Epigenetic deregulation', 'Var', (0, 23))	('KEAP1', 'Gene', (95, 100))	('lung cancer', 'Phenotype', 'HP:0100526', (122, 133))	('lung cancer', 'Disease', 'MESH:D008175', (122, 133))	('KEAP1', 'Gene', '9817', (95, 100))	('deregulation', 'Var', (106, 118))
45765	31205522	TCGA (The Cancer Genome Atlas, https://cancergenome.nih.gov/) data was reviewed to analyze the expression of PTPRZ1 gene and PTPRZ1 gene mutations.	('PTPRZ1', 'Gene', (125, 131))	('cancer', 'Disease', (39, 45))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('mutations', 'Var', (137, 146))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('Cancer', 'Phenotype', 'HP:0002664', (10, 16))	('PTPRZ1', 'Gene', (109, 115))
45769	31205522	The rates of PTPRZ1 gene mutations were different across tumors, and uterine corpus endometrial carcinoma (UCEC) (16.79%) has the highest rate of PTPRZ1 gene mutation, followed by lung adenocarcinoma (LUAD) (12.87%) and skin cutaneous melanoma (SKCM) (12.15%) (Figure 2).	('lung adenocarcinoma', 'Disease', (180, 199))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (84, 105))	('tumors', 'Disease', 'MESH:D009369', (57, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('carcinoma', 'Phenotype', 'HP:0030731', (190, 199))	('corpus endometrial carcinoma', 'Disease', (77, 105))	('corpus endometrial carcinoma', 'Disease', 'MESH:D016889', (77, 105))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (180, 199))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (180, 199))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (220, 243))	('melanoma', 'Phenotype', 'HP:0002861', (235, 243))	('skin cutaneous melanoma', 'Disease', (220, 243))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('rat', 'Species', '10116', (4, 7))	('rat', 'Species', '10116', (138, 141))	('LUAD', 'Phenotype', 'HP:0030078', (201, 205))	('PTPRZ1', 'Gene', (146, 152))	('mutation', 'Var', (158, 166))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumors', 'Disease', (57, 63))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (225, 243))
45770	31205522	Fusion genes combine parts of two or more original genes, generating from chromosomal rearrangement or abnormal transcription.	('rat', 'Species', '10116', (62, 65))	('abnormal transcription', 'Var', (103, 125))	('chromosomal rearrangement', 'Var', (74, 99))
45773	31205522	PTPRZ1-MET induces gliomas through elevated expression levels of MET mRNA, preserve fundamental properties of wild-type MET, and enhance phosphorylation.	('MET mRNA', 'MPA', (65, 73))	('induces', 'Reg', (11, 18))	('phosphorylation', 'MPA', (137, 152))	('fundamental properties', 'MPA', (84, 106))	('gliomas', 'Disease', 'MESH:D005910', (19, 26))	('gliomas', 'Phenotype', 'HP:0009733', (19, 26))	('gliomas', 'Disease', (19, 26))	('PTPRZ1-MET', 'Var', (0, 10))	('elevated', 'PosReg', (35, 43))	('expression levels', 'MPA', (44, 61))	('enhance', 'PosReg', (129, 136))	('glioma', 'Phenotype', 'HP:0009733', (19, 25))
45776	31205522	Several splice variants of PTPRZ1 have been discovered, including PTPRZ1-A (9.4 kb), a full-length transmembrane receptor form; PTPRZ1-B (6.4 kb), a short transmembrane receptor form with a deletion in the extracellular region; the other two are soluble secreted forms that lack both a transmembrane region and tyrosine phosphatase activity (phosphacan, short (4 kb) and long (8.4 kb; also known as phosphacan, PTPRZ-S)).	('phosphacan', 'Gene', '5803', (342, 352))	('PTPRZ', 'Gene', (66, 71))	('phosphacan', 'Gene', (399, 409))	('PTPRZ', 'Gene', (27, 32))	('PTPRZ', 'Gene', '5803', (66, 71))	('PTPRZ', 'Gene', '5803', (128, 133))	('deletion', 'Var', (190, 198))	('PTPRZ', 'Gene', (128, 133))	('phosphacan', 'Gene', '5803', (399, 409))	('PTPRZ', 'Gene', '5803', (411, 416))	('tyrosine', 'Chemical', 'MESH:D014443', (311, 319))	('PTPRZ', 'Gene', '5803', (27, 32))	('lack', 'NegReg', (274, 278))	('PTPRZ', 'Gene', (411, 416))	('phosphacan', 'Gene', (342, 352))
45783	31205522	PTPRZ1-PTN interaction results in accumulation of tyrosine phosphorylation of multiple downstream proteins including SRC kinase, calmodulin, anaplastic lymphoma kinase (ALK), GIT1/Cat1, beta-catenin, beta-adducin, Fyn, GIT1/Cat-1, and P190RhoGAP, which in turn have been related to activation of multiple pro-tumorigenic signaling cascades.	('beta-adducin', 'Gene', (200, 212))	('lymphoma', 'Phenotype', 'HP:0002665', (152, 160))	('Fyn', 'Gene', '2534', (214, 217))	('GIT1', 'Gene', (175, 179))	('GIT1', 'Gene', '850462', (219, 223))	('Cat-1', 'Species', '717647', (224, 229))	('ALK', 'Gene', '238', (169, 172))	('accumulation', 'PosReg', (34, 46))	('P190RhoGAP', 'Gene', '2909', (235, 245))	('tyrosine phosphorylation', 'MPA', (50, 74))	('ALK', 'Gene', (169, 172))	('SRC', 'Gene', '6714', (117, 120))	('calmodulin', 'MPA', (129, 139))	('beta-adducin', 'Gene', '119', (200, 212))	('tumor', 'Disease', (309, 314))	('anaplastic lymphoma', 'Disease', 'MESH:D017728', (141, 160))	('tyrosine', 'Chemical', 'MESH:D014443', (50, 58))	('tumor', 'Disease', 'MESH:D009369', (309, 314))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (141, 160))	('SRC', 'Gene', (117, 120))	('interaction', 'Var', (11, 22))	('GIT1', 'Gene', '850462', (175, 179))	('Cat1', 'Species', '717647', (180, 184))	('Fyn', 'Gene', (214, 217))	('GIT1', 'Gene', (219, 223))	('PTPRZ1-PTN', 'Gene', (0, 10))	('beta-catenin', 'Gene', (186, 198))	('P190RhoGAP', 'Gene', (235, 245))	('beta-catenin', 'Gene', '1499', (186, 198))	('tumor', 'Phenotype', 'HP:0002664', (309, 314))	('anaplastic lymphoma', 'Disease', (141, 160))
45789	31205522	PTN has been shown to activate both the mitogen- activated protein kinase (MAPK) and the phosphatidylinositol 3-kinase (PI3K)-Akt signaling axes, and inhibitors of Erk1/2 or PI3K inhibit DNA synthesis stimulated by PTN.	('Erk1/2', 'Gene', '5595;5594', (164, 170))	('phosphatidylinositol 3-kinase', 'Gene', '5295', (89, 118))	('DNA synthesis', 'MPA', (187, 200))	('Erk1/2', 'Gene', (164, 170))	('inhibitors', 'Var', (150, 160))	('Akt', 'Gene', '207', (126, 129))	('phosphatidylinositol 3-kinase', 'Gene', (89, 118))	('inhibit', 'NegReg', (179, 186))	('activate', 'PosReg', (22, 30))	('Akt', 'Gene', (126, 129))
45805	31205522	found PTPRZ1 inhibition also potentiated GSK3beta-regulated beta-catenin translocation and two pools of beta-catenin, which are regulated by PTPRZ1 and GSK3beta are partially but incompletely overlapping, with GSK3beta appearing to regulate beta-catenin availability beyond that influenced by PTPRZ1.	('PTPRZ1', 'Gene', (6, 12))	('GSK3beta', 'Gene', '2932', (210, 218))	('GSK3beta', 'Gene', '2932', (41, 49))	('GSK3beta', 'Gene', (152, 160))	('beta-catenin', 'Gene', (104, 116))	('beta-catenin', 'Gene', (241, 253))	('beta-catenin', 'Gene', '1499', (104, 116))	('inhibition', 'Var', (13, 23))	('potentiated', 'PosReg', (29, 40))	('GSK3beta', 'Gene', '2932', (152, 160))	('beta-catenin', 'Gene', '1499', (241, 253))	('beta-catenin', 'Gene', (60, 72))	('beta-catenin', 'Gene', '1499', (60, 72))	('GSK3beta', 'Gene', (41, 49))	('GSK3beta', 'Gene', (210, 218))
45822	31205522	PTPRZ1 seems to be important for maximum tumor growth in situations of contact independence or in complex cellular environments, and blocking the PTPRZ1-PTN signaling potently suppressed glioblastoma growth and prolonged animal survival.	('glioblastoma growth', 'Disease', 'MESH:D005909', (187, 206))	('glioblastoma', 'Phenotype', 'HP:0012174', (187, 199))	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('blocking', 'Var', (133, 141))	('tumor', 'Disease', (41, 46))	('glioblastoma growth', 'Disease', (187, 206))	('suppressed', 'NegReg', (176, 186))	('animal survival', 'CPA', (221, 236))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('prolonged', 'PosReg', (211, 220))
45829	31205522	PTPRZ1 gene knockdown increased the ability of human prostate cancer cells to migrate and invade in vitro and to metastasize in vivo .	('PTPRZ1', 'Gene', (0, 6))	('prostate cancer', 'Disease', (53, 68))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('rat', 'Species', '10116', (81, 84))	('knockdown', 'Var', (12, 21))	('prostate cancer', 'Disease', 'MESH:D011471', (53, 68))	('increased', 'PosReg', (22, 31))	('prostate cancer', 'Phenotype', 'HP:0012125', (53, 68))	('metastasize', 'CPA', (113, 124))	('migrate', 'CPA', (78, 85))	('human', 'Species', '9606', (47, 52))
45830	31205522	PTPRZ1 gene knockdown interrupts hydrogen peroxide-induced cell migration and PTPRZ1 gene knockdown in human umbilical vein endothelial cells (HUVEC) inhibited PTN-induced migration and tube formation on matrigel.	('tube formation on matrigel', 'CPA', (186, 212))	('PTPRZ1', 'Gene', (0, 6))	('interrupts', 'NegReg', (22, 32))	('rat', 'Species', '10116', (67, 70))	('hydrogen peroxide-induced', 'MPA', (33, 58))	('knockdown', 'Var', (90, 99))	('human', 'Species', '9606', (103, 108))	('inhibited', 'NegReg', (150, 159))	('cell migration', 'CPA', (59, 73))	('PTPRZ1', 'Gene', (78, 84))	('hydrogen peroxide', 'Chemical', 'MESH:D006861', (33, 50))	('rat', 'Species', '10116', (175, 178))
45835	31205522	In prostate cancer, the loss of PTPRZ1 gene expression initiated EMT and increased the ability of the cells to migrate and invade.	('loss', 'Var', (24, 28))	('increased', 'PosReg', (73, 82))	('EMT', 'CPA', (65, 68))	('rat', 'Species', '10116', (114, 117))	('prostate cancer', 'Phenotype', 'HP:0012125', (3, 18))	('PTPRZ1', 'Gene', (32, 38))	('prostate cancer', 'Disease', (3, 18))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('initiated', 'PosReg', (55, 64))	('prostate cancer', 'Disease', 'MESH:D011471', (3, 18))
45837	31205522	Tumor-associated macrophages (TAMs) secrete abundant PTN to stimulate glioma stem cells (GSCs) through PTPRZ1 thus promoting GBM malignant growth, and disrupting PTPRZ1 abrogated GSC maintenance and tumorigenic potential.	('PTPRZ1', 'Gene', (103, 109))	('tumor', 'Disease', (199, 204))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('glioma', 'Disease', (70, 76))	('promoting', 'PosReg', (115, 124))	('disrupting', 'Var', (151, 161))	('stimulate', 'PosReg', (60, 69))	('glioma', 'Disease', 'MESH:D005910', (70, 76))	('abrogated', 'NegReg', (169, 178))	('PTPRZ1', 'Gene', (162, 168))	('glioma', 'Phenotype', 'HP:0009733', (70, 76))	('GBM malignant growth', 'CPA', (125, 145))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('GSC maintenance', 'CPA', (179, 194))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))
45838	31205522	Knocking down PTPRZ1 gene altered the expression levels of SOX2, OLIG2, and POU3F2 and decreased the sphere- forming abilities in glioblastoma cells.	('expression levels', 'MPA', (38, 55))	('PTPRZ1', 'Gene', (14, 20))	('glioblastoma', 'Disease', (130, 142))	('decreased', 'NegReg', (87, 96))	('POU3F2', 'Gene', '5454', (76, 82))	('glioblastoma', 'Disease', 'MESH:D005909', (130, 142))	('POU3F2', 'Gene', (76, 82))	('OLIG2', 'Gene', (65, 70))	('glioblastoma', 'Phenotype', 'HP:0012174', (130, 142))	('SOX2', 'Gene', '6657', (59, 63))	('altered', 'Reg', (26, 33))	('OLIG2', 'Gene', '10215', (65, 70))	('SOX2', 'Gene', (59, 63))	('Knocking', 'Var', (0, 8))
45839	31205522	Another study found the knockdown of PTPRZ1 gene led to reduction of OCT4 and SOX2 transcripts by approximately 40%.	('OCT4', 'Gene', (69, 73))	('PTPRZ1', 'Gene', (37, 43))	('SOX2', 'Gene', '6657', (78, 82))	('reduction', 'NegReg', (56, 65))	('SOX2', 'Gene', (78, 82))	('knockdown', 'Var', (24, 33))	('OCT4', 'Gene', '5460', (69, 73))
45840	31205522	OCT4 knockdown also resulted in 90% decrease of PTPRZ1 gene transcripts, consistent with the marked decrease of PTPRZ1 in differentiating embryonic stem cells.	('PTPRZ1 gene', 'Gene', (48, 59))	('knockdown', 'Var', (5, 14))	('transcripts', 'MPA', (60, 71))	('OCT4', 'Gene', '5460', (0, 4))	('OCT4', 'Gene', (0, 4))	('decrease', 'NegReg', (36, 44))
45847	31205522	Ectopic menin expression significantly repressed PTN transcription, and indirectly inhibited PTPRZ1 expression through repressing PTN expression, and further inhibits FAK and ERK1/2 phosphorylation.	('expression', 'Var', (14, 24))	('PTN expression', 'MPA', (130, 144))	('menin', 'Gene', '4221', (8, 13))	('inhibits', 'NegReg', (158, 166))	('PTN transcription', 'MPA', (49, 66))	('PTPRZ1', 'Gene', (93, 99))	('FAK', 'Gene', '5747', (167, 170))	('menin', 'Gene', (8, 13))	('repressed', 'NegReg', (39, 48))	('expression', 'MPA', (100, 110))	('inhibited', 'NegReg', (83, 92))	('FAK', 'Gene', (167, 170))	('repressing', 'NegReg', (119, 129))	('Ectopic', 'Var', (0, 7))	('ERK1/2', 'Gene', (175, 181))	('ERK1/2', 'Gene', '5595;5594', (175, 181))
45850	31205522	identified several other substrates: Git1, p190, PIST, MAGI-3, Veli-3, Synj2bp, Syntrophin acidic1, Syntrophin basic1, MUPP1, Cardiac troponin T, hDKFZp434G232, KIAA0167, SPOP by a genetic method named the ''yeast substrate-trapping system''.	('Synj2bp', 'Var', (71, 78))	('MAGI-3', 'Gene', (55, 61))	('PIST', 'Gene', '57120', (49, 53))	('p190', 'Var', (43, 47))	('rat', 'Species', '10116', (30, 33))	('PIST', 'Gene', (49, 53))	('MAGI-3', 'Gene', '260425', (55, 61))	('rat', 'Species', '10116', (219, 222))	('Cardiac troponin', 'MPA', (126, 142))	('yeast', 'Species', '4932', (208, 213))
45853	31205522	High PTPRZ1 gene expression might be associated with better OS in BRCA, CESC, LUAD, PAAD, and SKCM, and low PTPRZ1 expression might be associated with better OS in BLCA, COAD, GBM, LGG, LIHC.	('LIHC', 'Disease', (186, 190))	('associated', 'Reg', (135, 145))	('low', 'NegReg', (104, 107))	('BRCA', 'Phenotype', 'HP:0003002', (66, 70))	('High', 'Var', (0, 4))	('LIHC', 'Disease', 'None', (186, 190))	('expression', 'MPA', (17, 27))	('GBM', 'Disease', (176, 179))	('BLCA', 'Disease', (164, 168))	('better OS', 'Disease', (151, 160))	('associated', 'Reg', (37, 47))	('LUAD', 'Phenotype', 'HP:0030078', (78, 82))	('CESC', 'Disease', (72, 76))	('COAD', 'Disease', 'MESH:D029424', (170, 174))	('LGG', 'Disease', (181, 184))	('PTPRZ1', 'Gene', (108, 114))	('BRCA', 'Gene', '672', (66, 70))	('PTPRZ1', 'Gene', (5, 11))	('LUAD', 'Disease', (78, 82))	('PAAD', 'Phenotype', 'HP:0006725', (84, 88))	('BRCA', 'Gene', (66, 70))	('expression', 'MPA', (115, 125))	('COAD', 'Disease', (170, 174))
45855	31205522	In human breast cancer, high expression of PTPRZ1 may be an independent risk indicator for triple- negative breast cancer (TNBC) recurrence and metastasis.	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('human', 'Species', '9606', (3, 8))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('TNBC', 'Disease', 'None', (123, 127))	('PTPRZ1', 'Gene', (43, 49))	('high expression', 'Var', (24, 39))	('breast cancer', 'Disease', 'MESH:D001943', (9, 22))	('breast cancer', 'Disease', 'MESH:D001943', (108, 121))	('breast cancer', 'Disease', (9, 22))	('TNBC', 'Disease', (123, 127))	('breast cancer', 'Phenotype', 'HP:0003002', (9, 22))	('breast cancer', 'Disease', (108, 121))	('breast cancer', 'Phenotype', 'HP:0003002', (108, 121))
45856	31205522	PTPRZ1 has a significant impact on survival of patients with oral squamous cell carcinoma, and patients with positive PTPRZ1 was associated with 8 times lower risk of death within 5 years than those with negative PTPRZ1.	('positive', 'Var', (109, 117))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('death', 'Disease', 'MESH:D003643', (167, 172))	('patients', 'Species', '9606', (95, 103))	('death', 'Disease', (167, 172))	('PTPRZ1', 'Gene', (118, 124))	('oral squamous cell carcinoma', 'Disease', (61, 89))	('patients', 'Species', '9606', (47, 55))	('impact', 'Reg', (25, 31))	('lower', 'NegReg', (153, 158))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (61, 89))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (66, 89))
45859	31205522	identified NAZ2329, a cell-permeable small molecule that allosterically inhibits PTPRZ1, which reduced the expression of SOX2 and abrogated the sphere-forming abilities in glioblastoma cells.	('SOX2', 'Gene', (121, 125))	('SOX2', 'Gene', '6657', (121, 125))	('NAZ2329', 'Chemical', '-', (11, 18))	('expression', 'MPA', (107, 117))	('glioblastoma', 'Disease', 'MESH:D005909', (172, 184))	('inhibits', 'NegReg', (72, 80))	('abrogated', 'NegReg', (130, 139))	('PTPRZ1', 'Gene', (81, 87))	('glioblastoma', 'Disease', (172, 184))	('reduced', 'NegReg', (95, 102))	('NAZ2329', 'Var', (11, 18))	('glioblastoma', 'Phenotype', 'HP:0012174', (172, 184))
45863	31205522	showed the intracellular delivery of SCB4380, the first potent inhibitor for PTPRZ1, by liposome carriers inhibited PTPRZ1 activity in glioblastoma cells, and thereby suppressed cell migration and proliferation in vitro and tumor growth in a rat allograft model.	('SCB4380', 'Var', (37, 44))	('cell migration', 'CPA', (178, 192))	('suppressed', 'NegReg', (167, 177))	('rat', 'Species', '10116', (242, 245))	('glioblastoma', 'Phenotype', 'HP:0012174', (135, 147))	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('rat', 'Species', '10116', (186, 189))	('rat', 'Species', '10116', (204, 207))	('inhibited', 'NegReg', (106, 115))	('tumor', 'Disease', (224, 229))	('SCB4380', 'Chemical', '-', (37, 44))	('PTPRZ1', 'Gene', (116, 122))	('PTPRZ1', 'Gene', (77, 83))	('glioblastoma', 'Disease', (135, 147))	('activity', 'MPA', (123, 131))	('glioblastoma', 'Disease', 'MESH:D005909', (135, 147))	('tumor', 'Disease', 'MESH:D009369', (224, 229))
45867	31205522	Given the strong up-regulation of PTPRZ1, antagonization of PTPRZ1 expression and/or signaling may be a promising strategy to inhibit the tumor growth.	('tumor', 'Disease', (138, 143))	('antagonization', 'Var', (42, 56))	('inhibit', 'NegReg', (126, 133))	('rat', 'Species', '10116', (116, 119))	('PTPRZ1', 'Gene', (60, 66))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('PTPRZ1', 'Gene', (34, 40))	('up-regulation', 'PosReg', (17, 30))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
45873	31205522	PTPRZ1 gene mutation accounts for a high proportion of cancer patients, especially in UCEC, the proportion could be up to 16.79%.	('PTPRZ1', 'Gene', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('mutation', 'Var', (12, 20))	('patients', 'Species', '9606', (62, 70))	('cancer', 'Disease', (55, 61))	('UCEC', 'Disease', (86, 90))
45874	31205522	Such a high proportion of cancer patients have PTPRZ1 mutations, so whether PTPRZ1 mutations could predict therapy efficacy or not deserved further research.	('patients', 'Species', '9606', (33, 41))	('cancer', 'Disease', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('mutations', 'Var', (54, 63))	('PTPRZ1', 'Gene', (47, 53))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))
45877	31205522	In the future, the value of PTPRZ1 gene mutation in cancer therapy deserved to be researched and drugs that target patients with PTPRZ1 mutations were studied in literature.	('PTPRZ1', 'Gene', (28, 34))	('mutation', 'Var', (40, 48))	('patients', 'Species', '9606', (115, 123))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('rat', 'Species', '10116', (166, 169))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))
45878	31205522	Tumors from patients harboring PTPRZ1-MET-fused glioblastoma are resistant to temozolomide therapy and have significantly compromised overall survival rates.	('temozolomide', 'Chemical', 'MESH:D000077204', (78, 90))	('glioblastoma', 'Phenotype', 'HP:0012174', (48, 60))	('patients', 'Species', '9606', (12, 20))	('PTPRZ1-MET-fused', 'Var', (31, 47))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('compromised', 'NegReg', (122, 133))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('overall', 'MPA', (134, 141))	('rat', 'Species', '10116', (151, 154))	('glioblastoma', 'Disease', (48, 60))	('glioblastoma', 'Disease', 'MESH:D005909', (48, 60))	('resistant to temozolomide therapy', 'MPA', (65, 98))
45888	31205522	Our previous study showed high expression of PTPRZ1 may be an independent risk indicator for triple negative breast cancer recurrence and metastasis.	('PTPRZ1', 'Gene', (45, 51))	('metastasis', 'CPA', (138, 148))	('high expression', 'Var', (26, 41))	('breast cancer', 'Disease', (109, 122))	('breast cancer', 'Phenotype', 'HP:0003002', (109, 122))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('breast cancer', 'Disease', 'MESH:D001943', (109, 122))
45889	31205522	PTPRZ1 has a significant impact on survival in patients with oral squamous cell carcinoma, and patients with positive PTPRZ1 was associated with 8 times lower risk of death within 5 years than those with negative PTPRZ1.	('positive', 'Var', (109, 117))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('death', 'Disease', 'MESH:D003643', (167, 172))	('patients', 'Species', '9606', (95, 103))	('death', 'Disease', (167, 172))	('PTPRZ1', 'Gene', (118, 124))	('oral squamous cell carcinoma', 'Disease', (61, 89))	('patients', 'Species', '9606', (47, 55))	('impact', 'Reg', (25, 31))	('lower', 'NegReg', (153, 158))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (61, 89))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (66, 89))
45892	31205522	Future studies should screen drugs for patients with PTPRZ1 gene mutations, PTPRZ1 fusion genes, and PTPRZ1 protein positivity.	('PTPRZ1', 'Gene', (76, 82))	('patients', 'Species', '9606', (39, 47))	('PTPRZ1', 'Gene', (53, 59))	('mutations', 'Var', (65, 74))
45893	31205522	Second, pharmacological inhibition or activation of PTPRZ1 is a promising strategy for the treatment of several tumors.	('activation', 'Var', (38, 48))	('rat', 'Species', '10116', (76, 79))	('tumors', 'Disease', (112, 118))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumors', 'Disease', 'MESH:D009369', (112, 118))	('PTPRZ1', 'Gene', (52, 58))
45943	30103707	In the same way, the AUCs and 95%CI of postoperative NLR, PLR, MLR, ALP and LDH were 0.568 (0.509-0.627, P = 0.025), 0.605 (0.542-0.688, P = 0.001), 0.614 (0.550-0.678, P <  0.001), 0.495 (0.423-0.568, P = 0.895) and 0.524 (0.460-0.587, P = 0.466), respectively.	('ALP', 'Gene', (68, 71))	('ALP', 'Gene', '250', (68, 71))	('0.614', 'Var', (149, 154))	('0.605', 'Var', (117, 122))
45982	30103707	The published studies concluded that low PLR was independently associated with better OS, CSS and DFS in multivariate analyses.	('better', 'Disease', (79, 85))	('CSS', 'Chemical', '-', (90, 93))	('low', 'Var', (37, 40))	('OS', 'Chemical', '-', (86, 88))	('PLR', 'MPA', (41, 44))	('DFS', 'CPA', (98, 101))	('CSS', 'Disease', (90, 93))
45985	30103707	The high preoperative ALP was prominently related with worse OS and PFS according to this univariate analyses.	('worse OS', 'Disease', (55, 63))	('ALP', 'Gene', (22, 25))	('ALP', 'Gene', '250', (22, 25))	('high', 'Var', (4, 8))	('OS', 'Chemical', '-', (61, 63))	('related', 'Reg', (42, 49))	('high preoperative ALP', 'Phenotype', 'HP:0003155', (4, 25))	('PFS', 'Disease', (68, 71))
45995	30103707	In this study, the high postoperative NLR, PLR and MLR were significantly associated with increased risk of death and tumor progression.	('death', 'Disease', (108, 113))	('high', 'Var', (19, 23))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('PLR', 'MPA', (43, 46))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('MLR', 'Gene', (51, 54))	('tumor', 'Disease', (118, 123))	('death', 'Disease', 'MESH:D003643', (108, 113))	('NLR', 'MPA', (38, 41))	('associated', 'Reg', (74, 84))
46030	27965308	Cells (Cal27 control, Cal27-c-Fos, MDA1386Tu control and MDA1386Tu-c-Fos) were seeded in triplicates, and cells were trypsinized at 24, 48 and 72 h. All cells were counted by Trypan blue exclusion method using a haemocytometer.	('Trypan blue', 'Chemical', 'MESH:D014343', (175, 186))	('Cal27-c-Fos', 'Gene', '2353', (22, 33))	('MDA1386Tu', 'CellLine', 'CVCL:H542', (35, 44))	('MDA1386Tu-c-Fos', 'Var', (57, 72))	('MDA1386Tu', 'CellLine', 'CVCL:H542', (57, 66))	('Cal27-c-Fos', 'Gene', (22, 33))
46031	27965308	For sphere formation, Cal27 control, Cal27-c-Fos, MDA1386Tu control and MDA1386Tu-c-Fos cells (5000 cells/well) were seeded in single cells suspension on ultralow attachment plates (Corning) as described previously.	('MDA1386Tu', 'CellLine', 'CVCL:H542', (72, 81))	('MDA1386Tu', 'Var', (50, 59))	('Cal27-c-Fos', 'Gene', '2353', (37, 48))	('MDA1386Tu-c-Fos', 'Var', (72, 87))	('MDA1386Tu', 'CellLine', 'CVCL:H542', (50, 59))	('Cal27-c-Fos', 'Gene', (37, 48))
46037	27965308	We used mouse monoclonal antibodies for Cytokeratin 19 (A53-B/A2.26) from Cell Marque (CA) and Vimentin (V9) from Ventana (AR).	('A53-B/A2.26', 'Var', (56, 67))	('Cytokeratin 19', 'Gene', (40, 54))	('Vimentin', 'Gene', (95, 103))	('Vimentin', 'Gene', '7431', (95, 103))	('Cytokeratin 19', 'Gene', '3880', (40, 54))	('mouse', 'Species', '10090', (8, 13))
46038	27965308	MDA1386Tu control and MDA1386Tu-c-Fos cells were transfected with pGL2 basic vector (Promega) containing full-length VEGF promoter sequence (-2361 to +298 bp or -350 to +298 bp) relative to the transcription start site).	('VEGF', 'Gene', (117, 121))	('MDA1386Tu', 'CellLine', 'CVCL:H542', (0, 9))	('-2361 to +298 bp', 'Var', (141, 157))	('VEGF', 'Gene', '7422', (117, 121))	('MDA1386Tu', 'CellLine', 'CVCL:H542', (22, 31))	('pGL2', 'Gene', (66, 70))	('MDA1386Tu-c-Fos', 'Var', (22, 37))	('pGL2', 'Gene', '54949', (66, 70))
46040	27965308	Cal27 control, Cal27-c-Fos, MDA1386Tu control and MDA1386Tu-c-Fos cells were resuspended in 100 mul serum free medium, mixed with 40% BD-Matrigel (BD Bioscience) and implanted (2x106 /site) subcutaneously into the flank (right flanks with control cells and left flanks with c-Fos overexpressing cells) of each mouse (n=5).	('MDA1386Tu', 'CellLine', 'CVCL:H542', (28, 37))	('Cal27-c-Fos', 'Gene', '2353', (15, 26))	('mouse', 'Species', '10090', (310, 315))	('MDA1386Tu', 'CellLine', 'CVCL:H542', (50, 59))	('Cal27-c-Fos', 'Gene', (15, 26))	('MDA1386Tu-c-Fos', 'Var', (50, 65))	('MDA1386Tu', 'Var', (28, 37))
46041	27965308	We also implanted higher number of MDA1386Tu control and MDA1386Tu-c-Fos cells (1x107) similarly in 3 nude mice.	('MDA1386Tu', 'Var', (35, 44))	('nude mice', 'Species', '10090', (102, 111))	('MDA1386Tu', 'CellLine', 'CVCL:H542', (35, 44))	('MDA1386Tu-c-Fos', 'Var', (57, 72))	('MDA1386Tu', 'CellLine', 'CVCL:H542', (57, 66))
46057	27965308	c-Fos overexpressing Cal27 and MDA1386Tu and their respective control cells were injected into the flanks of each nude mice.	('nude mice', 'Species', '10090', (114, 123))	('MDA1386Tu', 'CellLine', 'CVCL:H542', (31, 40))	('MDA1386Tu', 'Var', (31, 40))	('Cal27', 'Var', (21, 26))
46059	27965308	We observed that tumor size was significantly larger in those flanks of mice injected with c-Fos overexpressing cells as compared to control Cal27 cells (Fig.	('tumor', 'Disease', (17, 22))	('larger', 'PosReg', (46, 52))	('c-Fos overexpressing cells', 'Var', (91, 117))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('mice', 'Species', '10090', (72, 76))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
46061	27965308	MDA1386Tu cells represented a previously untreated squamous cell carcinoma originating in the hypopharynx of a 72-year-man (T4N3M0).	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('MDA1386Tu', 'CellLine', 'CVCL:H542', (0, 9))	('squamous cell carcinoma', 'Disease', (51, 74))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (51, 74))	('man', 'Species', '9606', (119, 122))	('MDA1386Tu', 'Var', (0, 9))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (51, 74))
46062	27965308	MDA1386Tu cells when implanted in the orthotopic nude mouse model did not form tumor till day 32.	('MDA1386Tu', 'CellLine', 'CVCL:H542', (0, 9))	('tumor', 'Disease', (79, 84))	('MDA1386Tu', 'Var', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('mouse', 'Species', '10090', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
46063	27965308	In c-Fos overexpressing MDA1386Tu cells, we observed only one mouse display tumor from 2x106 injected cells.	('MDA1386Tu', 'Var', (24, 33))	('mouse', 'Species', '10090', (62, 67))	('MDA1386Tu', 'CellLine', 'CVCL:H542', (24, 33))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
46071	27965308	Interestingly, we observed significantly higher expression of vimentin in tumor lysates from MDA1386Tu-c-Fos implanted cells (Fig.	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('vimentin', 'Gene', (62, 70))	('expression', 'MPA', (48, 58))	('MDA1386Tu', 'CellLine', 'CVCL:H542', (93, 102))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor', 'Disease', (74, 79))	('higher', 'PosReg', (41, 47))	('MDA1386Tu-c-Fos', 'Var', (93, 108))	('vimentin', 'Gene', '7431', (62, 70))
46072	27965308	Immunohistochemistry data demonstrated a strong expression of vimentin, but weak expression of cytokeratin19 from MDA1386Tu-c-Fos implanted cells (Fig.	('vimentin', 'Gene', (62, 70))	('weak', 'NegReg', (76, 80))	('expression', 'MPA', (48, 58))	('cytokeratin19', 'Gene', '3880', (95, 108))	('MDA1386Tu-c-Fos', 'Var', (114, 129))	('MDA1386Tu', 'CellLine', 'CVCL:H542', (114, 123))	('cytokeratin19', 'Gene', (95, 108))	('vimentin', 'Gene', '7431', (62, 70))	('expression', 'MPA', (81, 91))
46073	27965308	Together, our results suggest that introduction of c-Fos in HNSCC cells enhances the tumor growth.	('tumor', 'Disease', (85, 90))	('introduction', 'Var', (35, 47))	('c-Fos', 'Var', (51, 56))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('enhances', 'PosReg', (72, 80))
46079	27965308	We observed that the protein level of pERK1/2 was increased only in Cal27 c-Fos overexpressing cells (Fig.	('overexpressing', 'PosReg', (80, 94))	('pERK', 'Gene', (38, 42))	('protein level', 'MPA', (21, 34))	('Cal27 c-Fos', 'Var', (68, 79))	('pERK', 'Gene', '9451', (38, 42))	('increased', 'PosReg', (50, 59))
46088	27965308	We observed a significant increase in the numbers and size of oralspheres in c-Fos overexpressing cells as compared to control MDA1386Tu cells (Fig.	('MDA1386Tu', 'CellLine', 'CVCL:H542', (127, 136))	('c-Fos', 'Gene', (77, 82))	('overexpressing', 'Var', (83, 97))	('increase', 'PosReg', (26, 34))
46090	27965308	Our results indicated that A-Fos expression significantly inhibited oralspheres formation as compared to control cells (data not shown).	('expression', 'Var', (33, 43))	('Fos', 'Gene', '2353', (29, 32))	('inhibited', 'NegReg', (58, 67))	('oralspheres formation', 'CPA', (68, 89))	('Fos', 'Gene', (29, 32))
46092	27965308	A significant upregulation of Notch1 protein was noted in both Cal27 and MDA1386Tu-c-Fos overexpressing cells (Fig.	('Notch1', 'Gene', '4851', (30, 36))	('MDA1386Tu', 'CellLine', 'CVCL:H542', (73, 82))	('MDA1386Tu-c-Fos', 'Var', (73, 88))	('Notch1', 'Gene', (30, 36))	('protein', 'Protein', (37, 44))	('upregulation', 'PosReg', (14, 26))
46096	27965308	On the other hand, Nanog and c-Myc protein level was increased in c-Fos overexpressing MDA1386Tu or Cal27 cells compared with control cells (Fig.	('overexpressing', 'PosReg', (72, 86))	('MDA1386Tu', 'Var', (87, 96))	('c-Myc', 'Gene', '4609', (29, 34))	('Nanog', 'Gene', '79923', (19, 24))	('MDA1386Tu', 'CellLine', 'CVCL:H542', (87, 96))	('c-Fos', 'Protein', (66, 71))	('increased', 'PosReg', (53, 62))	('Nanog', 'Gene', (19, 24))	('c-Myc', 'Gene', (29, 34))
46100	27965308	MDA1386Tu cells expressing c-Fos were proficient in closing an artificial wound created over a confluent monolayer as compared to control cells (Fig.	('c-Fos', 'Var', (27, 32))	('MDA1386Tu', 'CellLine', 'CVCL:H542', (0, 9))	('closing an artificial wound', 'CPA', (52, 79))
46101	27965308	We also observed upregulation of vimentin in MDA1386Tu-c-Fos expressing cells (Fig.	('MDA1386Tu', 'CellLine', 'CVCL:H542', (45, 54))	('vimentin', 'Gene', '7431', (33, 41))	('MDA1386Tu-c-Fos', 'Var', (45, 60))	('vimentin', 'Gene', (33, 41))	('upregulation', 'PosReg', (17, 29))
46104	27965308	We transiently transfected the MDA1386Tu control or c-Fos expressing cells with 2.6-kb VEGF promoter-luciferase construct in pGL2 basic vector.	('MDA1386Tu', 'Var', (31, 40))	('MDA1386Tu', 'CellLine', 'CVCL:H542', (31, 40))	('VEGF', 'Gene', '7422', (87, 91))	('pGL2', 'Gene', (125, 129))	('VEGF', 'Gene', (87, 91))	('pGL2', 'Gene', '54949', (125, 129))
46105	27965308	We observed that VEGF-A promoter (2.6 kb) is highly increased in c-Fos overexpressing MDA1386Tu cells (Fig.	('increased', 'PosReg', (52, 61))	('c-Fos', 'Protein', (65, 70))	('MDA1386Tu', 'Var', (86, 95))	('MDA1386Tu', 'CellLine', 'CVCL:H542', (86, 95))	('overexpressing', 'PosReg', (71, 85))	('VEGF-A promoter', 'Gene', (17, 32))
46112	27965308	Recent study demonstrated that c-Fos enhances IL-6 and VEGF-A expression in colon cancer.	('IL-6', 'Gene', (46, 50))	('colon cancer', 'Disease', 'MESH:D015179', (76, 88))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('colon cancer', 'Disease', (76, 88))	('expression', 'MPA', (62, 72))	('enhances', 'PosReg', (37, 45))	('c-Fos', 'Var', (31, 36))	('IL-6', 'Gene', '3569', (46, 50))	('VEGF-A', 'Gene', (55, 61))	('colon cancer', 'Phenotype', 'HP:0003003', (76, 88))
46116	27965308	However, we have observed enhancement of cyclin D1 in Cal27 cells overexpressing c-Fos.	('c-Fos', 'Var', (81, 86))	('cyclin D1', 'Gene', '595', (41, 50))	('cyclin D1', 'Gene', (41, 50))	('enhancement', 'PosReg', (26, 37))
46119	27965308	Notch1 mutations occur in approximately 15% of patients with HNSCC, implicating a critical role of NOTCH signaling pathways in HNSCC tumors.	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('Notch1', 'Gene', (0, 6))	('Notch1', 'Gene', '4851', (0, 6))	('HNSCC tumors', 'Disease', (127, 139))	('patients', 'Species', '9606', (47, 55))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('HNSCC tumors', 'Disease', 'MESH:D000077195', (127, 139))	('HNSCC', 'Disease', (61, 66))	('mutations', 'Var', (7, 16))
46128	27965308	In fact, CSC markers are also enhanced on both Cal27 and MDA1386Tu cells, although cell type specificity is noted.	('MDA1386Tu', 'CellLine', 'CVCL:H542', (57, 66))	('enhanced', 'PosReg', (30, 38))	('CSC markers', 'MPA', (9, 20))	('MDA1386Tu', 'Var', (57, 66))
46133	27965308	We have also observed that VEGF, one of the downstream targets of c-Fos, is upregulated in c-Fos overexpressing HNSCC.	('VEGF', 'Gene', '7422', (27, 31))	('overexpressing', 'PosReg', (97, 111))	('upregulated', 'PosReg', (76, 87))	('VEGF', 'Gene', (27, 31))	('c-Fos', 'Var', (91, 96))
46244	29514610	High CD73 expression was significantly correlated with shorter overall survival (OS) in various cancers (high risk [HR] = 1.48; P < 0.05).	('overall survival', 'MPA', (63, 79))	('CD73', 'Gene', (5, 9))	('cancers', 'Phenotype', 'HP:0002664', (96, 103))	('High', 'Var', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('shorter', 'NegReg', (55, 62))	('expression', 'MPA', (10, 20))	('cancers', 'Disease', 'MESH:D009369', (96, 103))	('OS', 'Chemical', '-', (81, 83))	('cancers', 'Disease', (96, 103))
46245	29514610	Subgroup analysis using online database demonstrated that high CD73 expression was significantly correlated with poor OS in breast (HR = 1.23; P < 0.05) and ovarian cancer (HR = 1.14; P < 0.05), but favorable OS in lung (HR = 0.80; P < 0.05) and gastric cancer (HR = 0.71; P < 0.05).	('cancer', 'Phenotype', 'HP:0002664', (254, 260))	('expression', 'MPA', (68, 78))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('ovarian cancer', 'Disease', 'MESH:D010051', (157, 171))	('ovarian cancer', 'Phenotype', 'HP:0100615', (157, 171))	('gastric cancer', 'Disease', (246, 260))	('breast', 'Disease', (124, 130))	('OS', 'Chemical', '-', (118, 120))	('gastric cancer', 'Disease', 'MESH:D013274', (246, 260))	('CD73', 'Gene', (63, 67))	('high', 'Var', (58, 62))	('ovarian cancer', 'Disease', (157, 171))	('lung', 'Disease', (215, 219))	('OS', 'Chemical', '-', (209, 211))	('gastric cancer', 'Phenotype', 'HP:0012126', (246, 260))
46260	29514610	Even some studies indicated that high CD73 expression was associated with favorable prognosis in patients with gastric cancer or rectal adenocarcinoma.	('gastric cancer', 'Disease', 'MESH:D013274', (111, 125))	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('high', 'Var', (33, 37))	('gastric cancer', 'Phenotype', 'HP:0012126', (111, 125))	('rectal adenocarcinoma', 'Disease', (129, 150))	('CD73', 'Protein', (38, 42))	('rectal adenocarcinoma', 'Disease', 'MESH:D012004', (129, 150))	('expression', 'MPA', (43, 53))	('gastric cancer', 'Disease', (111, 125))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('patients', 'Species', '9606', (97, 105))
46264	29514610	Furthermore, we performed subgroup analysis on the association of high CD73 expression with prognosis in breast, lung, gastric and ovarian cancer by using the published data on KM plotter (http://www.kmplot.com).	('CD73', 'Gene', (71, 75))	('gastric and ovarian cancer', 'Disease', 'MESH:D013274', (119, 145))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('ovarian cancer', 'Phenotype', 'HP:0100615', (131, 145))	('expression', 'MPA', (76, 86))	('high', 'Var', (66, 70))	('lung', 'Disease', (113, 117))	('breast', 'Disease', (105, 111))
46265	29514610	We aimed to provide an overview of the current status of high CD73 expression in tumor prognosis and future immunotherapy.	('high', 'Var', (57, 61))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('CD73', 'Gene', (62, 66))	('tumor', 'Disease', (81, 86))
46278	29514610	As shown in Supplemental Material, median CD73 expression level in tumor tissues was significantly higher than that in normal tissues in most kinds of cancers including bladder, brain, invasive lobular breast, esophageal, gastric, pancreatic cancer, rectal mucinous, renal cell, lung large cell, oral cavity squamous cell carcinoma, melanoma, and lung adenocarcinoma (P < 0.05) (Additional file 1: Figures S1, S2, S3, S5, S6, S7, S8, S11, S12, S13, S15, S17).	('S15', 'Gene', '6209', (449, 452))	('S12', 'Gene', (439, 442))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (347, 366))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (347, 366))	('S13', 'Var', (444, 447))	('S15', 'Gene', (449, 452))	('tumor', 'Disease', (67, 72))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (231, 248))	('S11', 'Gene', '6267', (434, 437))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('S17', 'Gene', (454, 457))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (308, 331))	('melanoma', 'Phenotype', 'HP:0002861', (333, 341))	('melanoma', 'Disease', (333, 341))	('cancers', 'Phenotype', 'HP:0002664', (151, 158))	('carcinoma', 'Phenotype', 'HP:0030731', (357, 366))	('cancers', 'Disease', (151, 158))	('expression', 'MPA', (47, 57))	('lung large cell', 'Disease', (279, 294))	('bladder', 'Disease', (169, 176))	('higher', 'PosReg', (99, 105))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('S12', 'Gene', '6268', (439, 442))	('carcinoma', 'Phenotype', 'HP:0030731', (322, 331))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('S11', 'Gene', (434, 437))	('esophageal', 'Disease', (210, 220))	('pancreatic cancer', 'Disease', 'MESH:D010190', (231, 248))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (308, 331))	('gastric', 'Disease', (222, 229))	('lung adenocarcinoma', 'Disease', (347, 366))	('pancreatic cancer', 'Disease', (231, 248))	('brain', 'Disease', (178, 183))	('CD73', 'Gene', (42, 46))	('cancers', 'Disease', 'MESH:D009369', (151, 158))	('cancer', 'Phenotype', 'HP:0002664', (242, 248))	('S17', 'Gene', '6218', (454, 457))	('melanoma', 'Disease', 'MESH:D008545', (333, 341))	('squamous cell carcinoma', 'Disease', (308, 331))
46279	29514610	However, several types of tumors (cervical, liver, colorectal, prostate invasive ductal breast, small cell lung cancer and lung squamous cell carcinoma) showed similar CD73 expression level compared to the level in matched normal tissues (P > 0.05) (Additional file 1: Figures S3, S4, S5, S9, S10, S11, S12, S14, S18, S19).	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (123, 151))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (128, 151))	('lung squamous cell carcinoma', 'Disease', (123, 151))	('small cell lung cancer', 'Disease', (96, 118))	('lung cancer', 'Phenotype', 'HP:0100526', (107, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (142, 151))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('S18', 'Gene', '6222', (313, 316))	('S12', 'Gene', (303, 306))	('S11', 'Gene', '6267', (298, 301))	('S10', 'Gene', '6204', (293, 296))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (96, 118))	('liver', 'Disease', (44, 49))	('S19', 'Var', (318, 321))	('tumors', 'Disease', (26, 32))	('S14', 'Gene', '6208', (308, 311))	('S11', 'Gene', (298, 301))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('S18', 'Gene', (313, 316))	('S14', 'Gene', (308, 311))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('prostate invasive ductal breast', 'Disease', (63, 94))	('S10', 'Gene', (293, 296))	('S12', 'Gene', '6268', (303, 306))	('small cell lung cancer', 'Disease', 'MESH:D055752', (96, 118))	('colorectal', 'Disease', (51, 61))
46284	29514610	The results showed that high CD73 expression was significantly correlated with poorer OS in various cancers [HR 1.48 (95% CI: 1.04-2.10); P = 0.030] but large heterogeneity existed (I2 = 78.0%; P < 0.05; Fig.	('expression', 'MPA', (34, 44))	('cancers', 'Phenotype', 'HP:0002664', (100, 107))	('OS', 'Chemical', '-', (86, 88))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('high', 'Var', (24, 28))	('cancers', 'Disease', 'MESH:D009369', (100, 107))	('poorer', 'Disease', (79, 85))	('CD73', 'Gene', (29, 33))	('cancers', 'Disease', (100, 107))
46286	29514610	In addition, we carried out the subgroup analysis of association between high CD73 expression and prognosis in breast, lung, gastric and ovarian cancer by using online database.	('CD73', 'Gene', (78, 82))	('ovarian cancer', 'Phenotype', 'HP:0100615', (137, 151))	('breast', 'Disease', (111, 117))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('expression', 'MPA', (83, 93))	('gastric and ovarian cancer', 'Disease', 'MESH:D013274', (125, 151))	('high', 'Var', (73, 77))	('lung', 'Disease', (119, 123))
46288	29514610	Consistent with the meta-analysis, the results from database showed that high CD73 expression was significantly correlated with poor OS in breast [HR: 1.23 (95% CI: 1.11-1.38); P < 0.05; Fig.	('CD73', 'Gene', (78, 82))	('breast [HR', 'Disease', (139, 149))	('poor OS', 'Disease', (128, 135))	('expression', 'MPA', (83, 93))	('high', 'Var', (73, 77))	('OS', 'Chemical', '-', (133, 135))
46290	29514610	However, high CD73 expression was correlated with favorable OS in lung [HR: 0.80 (95% CI: 0.71-0.91); P < 0.05; Fig.	('expression', 'MPA', (19, 29))	('lung [', 'MPA', (66, 72))	('CD73', 'Gene', (14, 18))	('OS', 'Chemical', '-', (60, 62))	('high', 'Var', (9, 13))
46306	29514610	The results of all included studies demonstrated that high CD73 expression was significantly associated with poor OS but not RFS.	('expression', 'MPA', (64, 74))	('high', 'Var', (54, 58))	('OS', 'Chemical', '-', (114, 116))	('CD73', 'Gene', (59, 63))	('associated', 'Reg', (93, 103))	('poor OS', 'Disease', (109, 116))	('RFS', 'Chemical', '-', (125, 128))
46308	29514610	The pooled results showed that high CD73 expression was markedly associated with poor OS in breast and ovarian cancer but favorable OS in lung and gastric cancer.	('gastric cancer', 'Phenotype', 'HP:0012126', (147, 161))	('CD73', 'Protein', (36, 40))	('expression', 'MPA', (41, 51))	('OS', 'Chemical', '-', (86, 88))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('OS', 'Chemical', '-', (132, 134))	('lung', 'Disease', (138, 142))	('ovarian cancer', 'Phenotype', 'HP:0100615', (103, 117))	('breast and ovarian cancer', 'Disease', 'MESH:D010051', (92, 117))	('gastric cancer', 'Disease', (147, 161))	('high', 'Var', (31, 35))	('gastric cancer', 'Disease', 'MESH:D013274', (147, 161))
46309	29514610	In breast cancer, a previous study demonstrated that positive CD73 expression was correlated with longer DFS and OS, which was opposite to the results from KM plotter.	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('breast cancer', 'Disease', (3, 16))	('longer', 'PosReg', (98, 104))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('DFS', 'CPA', (105, 108))	('CD73', 'Gene', (62, 66))	('OS', 'Chemical', '-', (113, 115))	('expression', 'MPA', (67, 77))	('positive', 'Var', (53, 61))
46310	29514610	Theoretically, cancer cells with high CD73 expression possessed higher aggressiveness and invasiveness.	('aggressiveness', 'Disease', (71, 85))	('high', 'Var', (33, 37))	('cancer', 'Disease', (15, 21))	('cancer', 'Disease', 'MESH:D009369', (15, 21))	('invasiveness', 'CPA', (90, 102))	('higher', 'PosReg', (64, 70))	('aggressiveness', 'Phenotype', 'HP:0000718', (71, 85))	('CD73', 'Protein', (38, 42))	('aggressiveness', 'Disease', 'MESH:D001523', (71, 85))	('expression', 'MPA', (43, 53))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))
46312	29514610	Hence, it seems that high CD73 expression was likely to be associated with poor prognosis in breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('CD73', 'Protein', (26, 30))	('breast cancer', 'Disease', 'MESH:D001943', (93, 106))	('high', 'Var', (21, 25))	('expression', 'MPA', (31, 41))	('breast cancer', 'Disease', (93, 106))	('breast cancer', 'Phenotype', 'HP:0003002', (93, 106))
46321	29514610	They further demonstrated that CD73 could promote HNSCC migration and invasion via adenosine A3R stimulation and the activation of EGF/EGFR signaling.	('adenosine', 'Chemical', 'MESH:D000241', (83, 92))	('HNSCC migration', 'CPA', (50, 65))	('CD73', 'Var', (31, 35))	('EGFR', 'Gene', '1956', (135, 139))	('promote', 'PosReg', (42, 49))	('adenosine A3R', 'MPA', (83, 96))	('EGFR', 'Gene', (135, 139))	('stimulation', 'PosReg', (97, 108))	('invasion', 'CPA', (70, 78))
46324	29514610	A series of studies suggested that CD73-derived adenosine could help to form immunosuppressive environment via dampening anti-tumor effect of immune cells, such as CD8+ positive T cells and NK cells.	('adenosine', 'Chemical', 'MESH:D000241', (48, 57))	('CD8', 'Gene', (164, 167))	('CD8', 'Gene', '925', (164, 167))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('CD73-derived', 'Var', (35, 47))	('dampening', 'NegReg', (111, 120))	('tumor', 'Disease', (126, 131))
46326	29514610	Recently, several studies showed that CD73 expression on tumor cells weakened the immune response to PD-1/PD-L1 inhibitors.	('expression', 'Var', (43, 53))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('PD-L1', 'Gene', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('weakened', 'NegReg', (69, 77))	('CD73 expression', 'Var', (38, 53))	('tumor', 'Disease', (57, 62))	('PD-L1', 'Gene', '29126', (106, 111))
46327	29514610	reported that anti-CD73 mono-antibody (mAb) dramatically enhanced the effect of anti-CTLA-4 and PD-1 inhibitors against colon, prostate and breast cancers in mice model.	('breast cancers', 'Phenotype', 'HP:0003002', (140, 154))	('colon', 'Disease', (120, 125))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('breast cancers', 'Disease', 'MESH:D001943', (140, 154))	('breast cancers', 'Disease', (140, 154))	('mice', 'Species', '10090', (158, 162))	('breast cancer', 'Phenotype', 'HP:0003002', (140, 153))	('PD-1', 'Gene', (96, 100))	('anti-CD73', 'Var', (14, 23))	('prostate', 'Disease', (127, 135))	('cancers', 'Phenotype', 'HP:0002664', (147, 154))	('enhanced', 'PosReg', (57, 65))	('anti-CTLA-4', 'Gene', (80, 91))	('effect', 'MPA', (70, 76))
46328	29514610	Iannone and colleagues also found that blockade of CD73 could enhance efficacy of anti-CTLA-4 in melanoma model.	('efficacy', 'MPA', (70, 78))	('melanoma', 'Disease', 'MESH:D008545', (97, 105))	('melanoma', 'Phenotype', 'HP:0002861', (97, 105))	('blockade', 'Var', (39, 47))	('melanoma', 'Disease', (97, 105))	('anti-CTLA-4', 'Var', (82, 93))	('enhance', 'PosReg', (62, 69))	('CD73', 'Gene', (51, 55))	('Iannone', 'Chemical', '-', (0, 7))	('anti-CTLA-4', 'Gene', (82, 93))
46333	29514610	MEDI9447 could enhance the activity of PD-1 antibody in a syngeneic tumor model through increasing CD8+ T cells and reducing MDSC and Tregs in the tumor microenvironment.	('tumor', 'Disease', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('reducing', 'NegReg', (116, 124))	('CD8', 'Gene', (99, 102))	('CD8', 'Gene', '925', (99, 102))	('PD-1 antibody', 'Protein', (39, 52))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('MEDI9447', 'Var', (0, 8))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('MEDI9447', 'Chemical', '-', (0, 8))	('increasing', 'PosReg', (88, 98))	('activity', 'MPA', (27, 35))	('enhance', 'PosReg', (15, 22))	('MDSC', 'MPA', (125, 129))
46337	29514610	In summary, the current study indicates that high CD73 expression would be a potential prognostic factor to human solid tumors, especially the lung, breast, gastric and ovarian cancer.	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('gastric and ovarian cancer', 'Disease', 'MESH:D013274', (157, 183))	('breast', 'Disease', (149, 155))	('expression', 'MPA', (55, 65))	('high', 'Var', (45, 49))	('solid tumors', 'Disease', (114, 126))	('human', 'Species', '9606', (108, 113))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('ovarian cancer', 'Phenotype', 'HP:0100615', (169, 183))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('CD73', 'Gene', (50, 54))	('solid tumors', 'Disease', 'MESH:D009369', (114, 126))	('lung', 'Disease', (143, 147))
46360	29299514	He underwent a PEG tube placement prior to definitive chemoradiotherapy for a T3N2c squamous cell carcinoma of the oropharynx.	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('T3N2c', 'Var', (78, 83))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (84, 107))	('N2c', 'CellLine', 'CVCL:0529', (80, 83))	('squamous cell carcinoma', 'Disease', (84, 107))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (84, 107))	('PEG tube', 'Chemical', '-', (15, 23))
46396	28087642	In line with this, shRNA mediated STXBP4 and PDGFRA knockdown suppressed tumor growth in soft agar and xenograft assays.	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('PDGFRA', 'Gene', (45, 51))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('suppressed', 'NegReg', (62, 72))	('tumor', 'Disease', (73, 78))	('agar', 'Chemical', 'MESH:D000362', (94, 98))	('knockdown', 'Var', (52, 61))
46397	28087642	STXBP4 plays a crucial role in driving SCC growth and is an independent prognostic factor for predicting worse outcome in lung SCC.	('SCC', 'Gene', '6317', (39, 42))	('SCC', 'Gene', (127, 130))	('SCC', 'Phenotype', 'HP:0002860', (127, 130))	('SCC', 'Gene', '6317', (127, 130))	('STXBP4', 'Var', (0, 6))	('SCC', 'Gene', (39, 42))	('SCC', 'Phenotype', 'HP:0002860', (39, 42))
46413	28087642	Initially, we assessed the expression of STXBP4 and DeltaNp63 in SCC tumors by immunohistochemistry, and found that positive STXBP4 expression signified worse Overall Survival (OS) and Progression-Free Survival (PFS).	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('Progression-Free Survival', 'CPA', (185, 210))	('positive', 'Var', (116, 124))	('Overall Survival', 'CPA', (159, 175))	('SCC tumors', 'Disease', 'MESH:D009369', (65, 75))	('p63', 'Gene', (58, 61))	('SCC tumors', 'Disease', (65, 75))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('p63', 'Gene', '8626', (58, 61))	('SCC', 'Phenotype', 'HP:0002860', (65, 68))	('worse', 'NegReg', (153, 158))	('STXBP4', 'Gene', (125, 131))
46415	28087642	In line with this, shRNA mediated depletion of PDGFRalpha suppressed the growth of a lung SCC cell line in soft agar and xenograft tumor assays, similar to the findings obtained when the expression of STXBP4 or DeltaNp63 were knocked down.	('agar', 'Chemical', 'MESH:D000362', (112, 116))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('p63', 'Gene', (217, 220))	('suppressed', 'NegReg', (58, 68))	('SCC', 'Gene', (90, 93))	('SCC', 'Phenotype', 'HP:0002860', (90, 93))	('tumor', 'Disease', (131, 136))	('depletion', 'Var', (34, 43))	('p63', 'Gene', '8626', (217, 220))	('SCC', 'Gene', '6317', (90, 93))	('PDGFRalpha', 'Gene', '5156', (47, 57))	('PDGFRalpha', 'Gene', (47, 57))
46427	28087642	We used antibodies specific for p63 (4A4) (Santa Cruz Biotechnology, Dallas, TX) and STXBP4 (Abcam, Cambridge, MA).	('p63', 'Gene', '8626', (32, 35))	('STXBP4', 'Var', (85, 91))	('p63', 'Gene', (32, 35))
46456	28087642	Statistical correlation analysis between STXBP4 expression and clinicopathological features revealed that pathological local tumor factor stage (Disease stage), pathological tumor-node-metastasis (TNM) stage, and pleural involvement as a local invasion factor, were correlated with STXBP4-positivity (Table 1).	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('pleural involvement', 'Disease', (213, 232))	('local tumor', 'Disease', (119, 130))	('STXBP4-positivity', 'Var', (282, 299))	('tumor-node-metastasis', 'Disease', (174, 195))	('pleural involvement', 'Disease', 'MESH:D010995', (213, 232))	('tumor-node-metastasis', 'Disease', 'MESH:D009362', (174, 195))	('local tumor', 'Disease', 'MESH:D009364', (119, 130))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))
46462	28087642	The median PFS and OS (21.2 months versus 52.2 months; P < 0.05) were shorter in STXBP4-positive patients compared with STXBP4-negative patients (Fig.	('shorter', 'NegReg', (70, 77))	('STXBP4-positive', 'Var', (81, 96))	('PFS', 'CPA', (11, 14))	('patients', 'Species', '9606', (136, 144))	('patients', 'Species', '9606', (97, 105))
46468	28087642	Interestingly, high mammalian target of rapamycin (mTOR), a major controller of growth and is often deregulated in cancer, was significantly correlated with STXBP4-positivity (Spearman's rho = 0.220; P < 0.05), while other tumor markers, including CD147, a member of the immunoglobulin superfamily involved in angiogenesis (P < 0.5), and Ki-67, a general marker for cell division (P < 0.1), were not significantly correlated (Fig.	('mTOR', 'Gene', (51, 55))	('STXBP4-positivity', 'Var', (157, 174))	('cancer', 'Disease', (115, 121))	('tumor', 'Disease', (223, 228))	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('CD147', 'Gene', '682', (248, 253))	('mammalian target of rapamycin', 'Gene', '2475', (20, 49))	('mammalian target of rapamycin', 'Gene', (20, 49))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('tumor', 'Disease', 'MESH:D009369', (223, 228))	('CD147', 'Gene', (248, 253))	('mTOR', 'Gene', '2475', (51, 55))	('cancer', 'Disease', 'MESH:D009369', (115, 121))
46471	28087642	This finding supported our experimental observations that STXBP4 could be linked to the poor prognosis of lung SCC (Fig.	('SCC', 'Gene', (111, 114))	('STXBP4', 'Var', (58, 64))	('SCC', 'Gene', '6317', (111, 114))	('SCC', 'Phenotype', 'HP:0002860', (111, 114))
46477	28087642	Indeed, the oncogenic properties of mutated or amplified PDGFRalpha have been studied in several tumor types, and PDGFRbeta has been linked to not only tumor angiogenesis via paracrine effects, but also cancer metastasis.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('PDGFRbeta', 'Gene', '5159', (114, 123))	('cancer metastasis', 'Disease', (203, 220))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('PDGFRbeta', 'Gene', (114, 123))	('tumor', 'Disease', (152, 157))	('mutated', 'Var', (36, 43))	('tumor', 'Disease', (97, 102))	('cancer metastasis', 'Disease', 'MESH:D009362', (203, 220))	('PDGFRalpha', 'Gene', '5156', (57, 67))	('amplified', 'Var', (47, 56))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('linked', 'Reg', (133, 139))	('PDGFRalpha', 'Gene', (57, 67))
46480	28087642	Interestingly, we observed that PDGFRA expression was significantly up-regulated in STXBP4-positive lung SCC samples compared with STXBP4-negative samples (P < 0.05) (Fig.	('STXBP4-positive', 'Var', (84, 99))	('PDGFRA', 'Gene', (32, 38))	('SCC', 'Gene', (105, 108))	('SCC', 'Phenotype', 'HP:0002860', (105, 108))	('expression', 'MPA', (39, 49))	('up-regulated', 'PosReg', (68, 80))	('SCC', 'Gene', '6317', (105, 108))
46489	28087642	Two independent siRNAs against STXBP4 (STXBP4#1 and STXBP4#2) were transfected into the lung SCC cell line, RERF-LC-Sq1, and a siRNA targeting luciferase (siLUC) was used as a control.	('SCC', 'Gene', '6317', (93, 96))	('SCC', 'Gene', (93, 96))	('SCC', 'Phenotype', 'HP:0002860', (93, 96))	('STXBP4', 'Var', (52, 58))
46492	28087642	In order to evaluate the functional relevance of STXBP4 and PDGFRalpha expression during tumor formation, we monitored the colony formation of RERF-LC-Sq1 cells lentivirally transduced with STXBP4, DeltaNp63 or PDGFRalpha shRNAs.	('p63', 'Gene', '8626', (204, 207))	('PDGFRalpha', 'Gene', (211, 221))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('PDGFRalpha', 'Gene', '5156', (211, 221))	('p63', 'Gene', (204, 207))	('PDGFRalpha', 'Gene', '5156', (60, 70))	('STXBP4', 'Var', (190, 196))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))	('PDGFRalpha', 'Gene', (60, 70))
46493	28087642	4C, PDGFRalpha, STXBP4 or DeltaNp63 knockdown in RERF-LC-Sq1 cells, led to decreased anchorage-independent colony formation in soft agar.	('p63', 'Gene', '8626', (32, 35))	('PDGFRalpha', 'Gene', '5156', (4, 14))	('PDGFRalpha', 'Gene', (4, 14))	('agar', 'Chemical', 'MESH:D000362', (132, 136))	('knockdown', 'Var', (36, 45))	('p63', 'Gene', (32, 35))	('decreased', 'NegReg', (75, 84))
46495	28087642	Additionally, the knockdown effect of STXBP4 and suppression of tumorigenesis are more marked in high STXBP4 expressing RERF-LC-Sq1 cells compared with low STXBP4 expressing EBC-1 cells (Fig.	('tumor', 'Disease', (64, 69))	('suppression', 'NegReg', (49, 60))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('high STXBP4', 'Var', (97, 108))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
46497	28087642	Overall, our results indicate that STXBP4 has oncogenic activity both in vitro and in vivo, and further suggest that STXBP4 could be a critical driver of tumor propagation through regulating the PDGFRalpha pathway.	('PDGFRalpha', 'Gene', (195, 205))	('PDGFRalpha', 'Gene', '5156', (195, 205))	('STXBP4', 'Var', (117, 123))	('oncogenic activity', 'CPA', (46, 64))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('STXBP4', 'Var', (35, 41))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('regulating', 'Reg', (180, 190))	('tumor', 'Disease', (154, 159))
46501	28087642	Polymorphisms of STXBP4/COX11 (rs6504950; AA/AG-genotype) were associated with a significantly decreased risk of carcinogenesis in a meta-analysis of breast cancer patients.	('decreased', 'NegReg', (95, 104))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('carcinogenesis', 'Disease', 'MESH:D063646', (113, 127))	('breast cancer', 'Disease', 'MESH:D001943', (150, 163))	('COX11', 'Gene', (24, 29))	('breast cancer', 'Phenotype', 'HP:0003002', (150, 163))	('breast cancer', 'Disease', (150, 163))	('Polymorphisms', 'Var', (0, 13))	('rs6504950', 'Mutation', 'rs6504950', (31, 40))	('COX11', 'Gene', '1353', (24, 29))	('carcinogenesis', 'Disease', (113, 127))	('rs6504950;', 'Var', (31, 41))	('patients', 'Species', '9606', (164, 172))
46502	28087642	Although functional assessments of these polymorphisms were not undertaken, and the extent of loss of STXBP4 function in tumors was not studied, the data suggested that STXBP4 could play a role in carcinogenesis and tumor progression in breast cancer patients.	('carcinogenesis', 'Disease', (197, 211))	('tumors', 'Disease', 'MESH:D009369', (121, 127))	('patients', 'Species', '9606', (251, 259))	('breast cancer', 'Phenotype', 'HP:0003002', (237, 250))	('role', 'Reg', (189, 193))	('carcinogenesis', 'Disease', 'MESH:D063646', (197, 211))	('tumor', 'Disease', (216, 221))	('breast cancer', 'Disease', 'MESH:D001943', (237, 250))	('tumor', 'Disease', (121, 126))	('breast cancer', 'Disease', (237, 250))	('tumor', 'Disease', 'MESH:D009369', (216, 221))	('play', 'Reg', (182, 186))	('tumor', 'Disease', 'MESH:D009369', (121, 126))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('tumors', 'Disease', (121, 127))	('STXBP4', 'Var', (169, 175))
46503	28087642	Our study provides diagnostic role of STXBP4 alongside DeltaNp63 in lung SCC.	('p63', 'Gene', (61, 64))	('STXBP4', 'Var', (38, 44))	('SCC', 'Gene', (73, 76))	('SCC', 'Phenotype', 'HP:0002860', (73, 76))	('p63', 'Gene', '8626', (61, 64))	('SCC', 'Gene', '6317', (73, 76))
46509	28087642	Thus, STXBP4 may contribute to the susceptibility and severity of cancer in a p63-dependent and independent manner.	('p63', 'Gene', (78, 81))	('p63', 'Gene', '8626', (78, 81))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('STXBP4', 'Var', (6, 12))	('contribute', 'Reg', (17, 27))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('cancer', 'Disease', (66, 72))
46510	28087642	Indeed, amplification and overexpression of p63 has frequently been observed in a variety of SCCs, including lung cancers and head and neck cancers.	('cancers', 'Phenotype', 'HP:0002664', (114, 121))	('lung cancer', 'Phenotype', 'HP:0100526', (109, 120))	('lung cancers', 'Disease', 'MESH:D008175', (109, 121))	('head and neck cancers', 'Disease', 'MESH:D006258', (126, 147))	('p63', 'Gene', '8626', (44, 47))	('amplification', 'Var', (8, 21))	('overexpression', 'PosReg', (26, 40))	('head and neck cancers', 'Phenotype', 'HP:0012288', (126, 147))	('observed', 'Reg', (68, 76))	('SCC', 'Gene', (93, 96))	('SCC', 'Phenotype', 'HP:0002860', (93, 96))	('cancers', 'Phenotype', 'HP:0002664', (140, 147))	('lung cancers', 'Phenotype', 'HP:0100526', (109, 121))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('lung cancers', 'Disease', (109, 121))	('SCC', 'Gene', '6317', (93, 96))	('p63', 'Gene', (44, 47))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))
46511	28087642	However, p63 expression is decreased during progression to invasion and metastasis of lung, breast and bladder cancer, and loss of p63 expression is associated with worse prognosis in some cases.	('p63', 'Gene', '8626', (131, 134))	('p63', 'Gene', '8626', (9, 12))	('metastasis', 'CPA', (72, 82))	('expression', 'MPA', (13, 23))	('decreased', 'NegReg', (27, 36))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('bladder cancer', 'Phenotype', 'HP:0009725', (103, 117))	('lung', 'Disease', (86, 90))	('breast and bladder cancer', 'Disease', 'MESH:D001749', (92, 117))	('p63', 'Gene', (131, 134))	('expression', 'MPA', (135, 145))	('p63', 'Gene', (9, 12))	('invasion', 'CPA', (59, 67))	('loss', 'Var', (123, 127))
46519	28087642	Based on recent evidence, inhibition of the p53/NF-Y complex by mutant gain of function p53 enhances PDGFRbeta expression and promotes metastasis in a subset of pancreatic cancers.	('PDGFRbeta', 'Gene', '5159', (101, 110))	('metastasis', 'CPA', (135, 145))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (161, 179))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('PDGFRbeta', 'Gene', (101, 110))	('gain of function', 'PosReg', (71, 87))	('enhances', 'PosReg', (92, 100))	('promotes', 'PosReg', (126, 134))	('p53', 'Gene', (88, 91))	('expression', 'MPA', (111, 121))	('p53', 'Gene', (44, 47))	('p53', 'Gene', '7157', (88, 91))	('p53', 'Gene', '7157', (44, 47))	('cancers', 'Phenotype', 'HP:0002664', (172, 179))	('pancreatic cancers', 'Disease', 'MESH:D010190', (161, 179))	('pancreatic cancers', 'Disease', (161, 179))	('mutant', 'Var', (64, 70))
46520	28087642	In addition, the interaction of mutant p53 with p63 regulates the expression of p63 target genes to enhance invasion and metastasis.	('p63', 'Gene', '8626', (80, 83))	('interaction', 'Interaction', (17, 28))	('enhance', 'PosReg', (100, 107))	('expression', 'MPA', (66, 76))	('p63', 'Gene', (48, 51))	('mutant', 'Var', (32, 38))	('p53', 'Gene', (39, 42))	('regulates', 'Reg', (52, 61))	('p53', 'Gene', '7157', (39, 42))	('p63', 'Gene', '8626', (48, 51))	('p63', 'Gene', (80, 83))
46521	28087642	Hence, the oncogenic activity of mutant p53 is a consequence of the physical association between mutant p53 and the p53 family members, p63 and p73.	('oncogenic activity', 'CPA', (11, 29))	('p53', 'Gene', (104, 107))	('p73', 'Gene', '7161', (144, 147))	('p63', 'Gene', (136, 139))	('p73', 'Gene', (144, 147))	('p53', 'Gene', '7157', (104, 107))	('mutant', 'Var', (97, 103))	('p53', 'Gene', (40, 43))	('p63', 'Gene', '8626', (136, 139))	('p53', 'Gene', '7157', (116, 119))	('mutant', 'Var', (33, 39))	('p53', 'Gene', '7157', (40, 43))	('p53', 'Gene', (116, 119))
46524	28087642	In particular, targeted agents that inhibit the epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) are approved for the treatment of NSCLC harboring genetic alterations in the genes encoding these proteins.	('NSCLC', 'Disease', (158, 163))	('EGFR', 'Gene', (82, 86))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (91, 110))	('anaplastic lymphoma kinase', 'Gene', (91, 117))	('NSCLC', 'Disease', 'MESH:D002289', (158, 163))	('lymphoma', 'Phenotype', 'HP:0002665', (102, 110))	('ALK', 'Gene', (119, 122))	('inhibit', 'NegReg', (36, 43))	('epidermal growth factor receptor', 'Gene', (48, 80))	('NSCLC', 'Phenotype', 'HP:0030358', (158, 163))	('ALK', 'Gene', '238', (119, 122))	('EGFR', 'Gene', '1956', (82, 86))	('genetic alterations', 'Var', (174, 193))	('epidermal growth factor receptor', 'Gene', '1956', (48, 80))	('anaplastic lymphoma kinase', 'Gene', '238', (91, 117))
46525	28087642	EGFR inhibitors, such as erlotinib and gefitinib, are only effective against NSCLCs with EGFR mutations, which occur almost exclusively in lung AC.	('NSCLC', 'Disease', 'MESH:D002289', (77, 82))	('lung AC', 'Disease', (139, 146))	('EGFR', 'Gene', '1956', (89, 93))	('EGFR', 'Gene', (0, 4))	('EGFR', 'Gene', (89, 93))	('mutations', 'Var', (94, 103))	('NSCLC', 'Phenotype', 'HP:0030358', (77, 82))	('gefitinib', 'Chemical', 'MESH:D000077156', (39, 48))	('NSCLC', 'Disease', (77, 82))	('EGFR', 'Gene', '1956', (0, 4))	('erlotinib', 'Chemical', 'MESH:D000069347', (25, 34))
46565	26473842	Deregulation of the microenvironment during the wound healing results in delayed healing in venous ulcers or in diabetic foot syndrome.	('diabetic foot syndrome', 'Disease', (112, 134))	('Deregulation', 'Var', (0, 12))	('venous ulcers', 'Disease', (92, 105))	('delayed', 'NegReg', (73, 80))	('diabetic foot syndrome', 'Disease', 'MESH:D017719', (112, 134))	('delayed healing', 'Phenotype', 'HP:0001058', (73, 88))	('venous ulcers', 'Disease', 'MESH:D014647', (92, 105))
46667	26473842	More recently, antibodies unblocking immune response are used in tumors escaping immune destruction (e.g., anti-CTLA-4 or anti-PD-1 in melanoma).	('melanoma', 'Disease', 'MESH:D008545', (135, 143))	('CTLA-4', 'Gene', '1493', (112, 118))	('melanoma', 'Phenotype', 'HP:0002861', (135, 143))	('melanoma', 'Disease', (135, 143))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('tumors', 'Disease', (65, 71))	('CTLA-4', 'Gene', (112, 118))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('anti-PD-1', 'Var', (122, 131))
46750	25635388	Generally, chemotherapy and radiotherapy are considered to have cytotoxic effects on other organs and thus increase sequential cancer risk.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('increase', 'PosReg', (107, 115))	('chemotherapy', 'Var', (11, 23))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('cancer', 'Disease', (127, 133))	('radiotherapy', 'Var', (28, 40))
46760	24853421	P53-regulated long non-coding RNA TUG1 affects cell proliferation in human non-small cell lung cancer, partly through epigenetically regulating HOXB7 expression Recently, a novel class of transcripts, long non-coding RNAs (lncRNAs), is being identified at a rapid pace.	('HOXB7', 'Gene', (144, 149))	('HOXB7', 'Gene', '3217', (144, 149))	('epigenetically', 'Var', (118, 132))	('TUG1', 'Gene', (34, 38))	('ncRNA', 'Gene', '54719', (224, 229))	('affects', 'Reg', (39, 46))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (75, 101))	('non-small cell lung cancer', 'Disease', (75, 101))	('human', 'Species', '9606', (69, 74))	('TUG1', 'Gene', '55000', (34, 38))	('P53', 'Gene', (0, 3))	('lung cancer', 'Phenotype', 'HP:0100526', (90, 101))	('P53', 'Gene', '7157', (0, 3))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (79, 101))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (75, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('ncRNA', 'Gene', (224, 229))	('cell proliferation', 'CPA', (47, 65))
46766	24853421	Interestingly, inhibition of TUG1 could upregulate homeobox B7 (HOXB7) expression; ChIP assays demonstrated that the promoter of HOXB7 locus was bound by EZH2 (enhancer of zeste homolog 2), a key component of PRC2, and was H3K27 trimethylated.	('enhancer of zeste homolog 2', 'Gene', (160, 187))	('homeobox B7', 'Gene', (51, 62))	('EZH2', 'Gene', (154, 158))	('EZH2', 'Gene', '2146', (154, 158))	('upregulate', 'PosReg', (40, 50))	('bound', 'Interaction', (145, 150))	('HOXB7', 'Gene', '3217', (129, 134))	('enhancer of zeste homolog 2', 'Gene', '2146', (160, 187))	('HOXB7', 'Gene', (129, 134))	('TUG1', 'Gene', (29, 33))	('HOXB7', 'Gene', '3217', (64, 69))	('inhibition', 'Var', (15, 25))	('HOXB7', 'Gene', (64, 69))
46779	24853421	The aberrant expressions of lncRNAs have also been shown in various types of cancer, including NSCLC.	('ncRNA', 'Gene', (29, 34))	('NSCLC', 'Disease', 'MESH:D002289', (95, 100))	('cancer', 'Disease', (77, 83))	('shown', 'Reg', (51, 56))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('ncRNA', 'Gene', '54719', (29, 34))	('NSCLC', 'Phenotype', 'HP:0030358', (95, 100))	('aberrant expressions', 'Var', (4, 24))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('NSCLC', 'Disease', (95, 100))
46783	24853421	These lncRNAs epigenetically regulate gene expression through binding to PRC2 in various biological processes, especially in cancer.	('ncRNA', 'Gene', '54719', (7, 12))	('PRC2', 'Gene', (73, 77))	('binding', 'Interaction', (62, 69))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('gene expression', 'MPA', (38, 53))	('epigenetically', 'Var', (14, 28))	('ncRNA', 'Gene', (7, 12))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('regulate', 'Reg', (29, 37))
46786	24853421	These show that many lncRNAs are associated with PRC2 complex, and that the dysregulation of PRC2-related lncRNAs participate in various pathological processes, including cancer.	('participate', 'Reg', (114, 125))	('ncRNA', 'Gene', (22, 27))	('ncRNA', 'Gene', '54719', (107, 112))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('cancer', 'Disease', (171, 177))	('PRC2-related', 'Gene', (93, 105))	('ncRNA', 'Gene', '54719', (22, 27))	('associated', 'Reg', (33, 43))	('ncRNA', 'Gene', (107, 112))	('dysregulation', 'Var', (76, 89))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))
46789	24853421	The depletion of TUG1 in the developing mouse eye was found to block retinal development.	('TUG1', 'Gene', (17, 21))	('depletion', 'Var', (4, 13))	('mouse', 'Species', '10090', (40, 45))	('retinal development', 'CPA', (69, 88))	('block', 'NegReg', (63, 68))
46790	24853421	These results indicate that TUG1 may be necessary for development, and that its dysregulation may participate in human disease progression.	('dysregulation', 'Var', (80, 93))	('participate', 'Reg', (98, 109))	('human', 'Species', '9606', (113, 118))
46794	24853421	In addition, we demonstrated that TUG1 could epigenetically modulate homeobox B7 (HOXB7), which may partly account for TUG1-mediated proliferation regulation, thus affecting the proliferation of NSCLC both in vitro and in vivo.	('account', 'Reg', (107, 114))	('homeobox B7', 'Gene', (69, 80))	('NSCLC', 'Disease', 'MESH:D002289', (195, 200))	('proliferation', 'CPA', (178, 191))	('TUG1', 'Gene', (34, 38))	('affecting', 'Reg', (164, 173))	('modulate', 'Reg', (60, 68))	('HOXB7', 'Gene', '3217', (82, 87))	('NSCLC', 'Phenotype', 'HP:0030358', (195, 200))	('epigenetically', 'Var', (45, 59))	('HOXB7', 'Gene', (82, 87))	('NSCLC', 'Disease', (195, 200))
46800	24853421	From the Kaplan-Meier survival curve, we observed that patients with high levels of TUG1 expression had remarkably longer survival time than those with low levels (P<0.001, log-rank test; Figure 1d).	('expression', 'MPA', (89, 99))	('TUG1', 'Gene', (84, 88))	('high levels', 'Var', (69, 80))	('survival time', 'CPA', (122, 135))	('patients', 'Species', '9606', (55, 63))	('longer', 'PosReg', (115, 121))
46815	24853421	Next, we sought to determine whether p53 mutation could regulate TUG1 expression.	('TUG1', 'Gene', (65, 69))	('mutation', 'Var', (41, 49))	('expression', 'MPA', (70, 80))	('p53', 'Gene', (37, 40))	('p53', 'Gene', '7157', (37, 40))	('regulate', 'Reg', (56, 64))
46816	24853421	Toward this end, p53 with a point mutation (R175H) at the DNA-binding domain, a frequent mutant in diverse cancer, had no impact on TUG1 expression, indicating that TUG1 is specifically induced by WT p53.	('expression', 'MPA', (137, 147))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('p53', 'Gene', (200, 203))	('TUG1', 'Gene', (132, 136))	('p53', 'Gene', '7157', (200, 203))	('R175H', 'Mutation', 'rs28934578', (44, 49))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('p53', 'Gene', (17, 20))	('R175H', 'Var', (44, 49))	('cancer', 'Disease', (107, 113))	('p53', 'Gene', '7157', (17, 20))
46819	24853421	In addition, we found that mutant p53 had no impact on the promoter activity of TUG1 (Figure 2e).	('p53', 'Gene', (34, 37))	('p53', 'Gene', '7157', (34, 37))	('mutant', 'Var', (27, 33))	('TUG1', 'Gene', (80, 84))	('promoter activity', 'MPA', (59, 76))
46820	24853421	To further determine the function of this p53RE, we made deletion at the promoter of TUG1 (Figure 2f).	('p53', 'Gene', (42, 45))	('deletion', 'Var', (57, 65))	('TUG1', 'Gene', (85, 89))	('p53', 'Gene', '7157', (42, 45))
46821	24853421	After transfection by p53 expression plasmid, the deletion (not containing the p53RE) caused significant reduction of promoter activity compared with the full-length promoter construct (Figure 2f).	('p53', 'Gene', (79, 82))	('p53', 'Gene', '7157', (79, 82))	('promoter activity', 'MPA', (118, 135))	('deletion', 'Var', (50, 58))	('p53', 'Gene', (22, 25))	('reduction', 'NegReg', (105, 114))	('p53', 'Gene', '7157', (22, 25))
46822	24853421	Furthermore, site-directed mutagenesis involving the conserved C and G of the p53RE (Figure 2b) also significantly reduced luciferase activity (Figure 2f).	('mutagenesis', 'Var', (27, 38))	('reduced', 'NegReg', (115, 122))	('p53', 'Gene', (78, 81))	('luciferase', 'Enzyme', (123, 133))	('activity', 'MPA', (134, 142))	('p53', 'Gene', '7157', (78, 81))
46829	24853421	Next, MTT assay showed that knockdown of TUG1 expression significantly increased cell proliferation both in SPC-A1 and NCI-H1650 cell lines compared with the control cells (Figure 3b).	('cell proliferation', 'CPA', (81, 99))	('TUG1', 'Gene', (41, 45))	('MTT', 'Chemical', 'MESH:C070243', (6, 9))	('increased', 'PosReg', (71, 80))	('knockdown', 'Var', (28, 37))	('NCI-H1650', 'CellLine', 'CVCL:1483', (119, 128))	('SPC-A1', 'Gene', '27032', (108, 114))	('SPC-A1', 'Gene', (108, 114))
46830	24853421	As shown in Figure 3c, the colony numbers of SPC-A1 and NCI-H1650 cells transfected with si-TUG1 were evidently higher than those transfected with si-NC.	('NCI-H1650', 'CellLine', 'CVCL:1483', (56, 65))	('higher', 'PosReg', (112, 118))	('si-TUG1', 'Var', (89, 96))	('SPC-A1', 'Gene', '27032', (45, 51))	('colony numbers', 'CPA', (27, 41))	('SPC-A1', 'Gene', (45, 51))
46837	24853421	As shown in Figures 4a and b, tumor growth in the shTUG1 group was significantly more rapid than that in the control group.	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('shTUG1', 'Var', (50, 56))	('tumor', 'Disease', (30, 35))	('more rapid', 'PosReg', (81, 91))
46843	24853421	Moreover, large number of aberrant Hox gene expression have been found in various cancers.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('expression', 'MPA', (44, 54))	('aberrant', 'Var', (26, 34))	('cancers', 'Phenotype', 'HP:0002664', (82, 89))	('cancers', 'Disease', (82, 89))	('cancers', 'Disease', 'MESH:D009369', (82, 89))	('Hox gene', 'Gene', (35, 43))	('found', 'Reg', (65, 70))
46845	24853421	The results showed that HOXB7, HOXD4, HOXD9 and HOXD10 mRNA expression were induced in SPC-A1 cells transfected with si-TUG1 (Figure 5a).	('SPC-A1', 'Gene', (87, 93))	('HOXB7', 'Gene', (24, 29))	('SPC-A1', 'Gene', '27032', (87, 93))	('HOXD10', 'Gene', '3236', (48, 54))	('HOXD4', 'Gene', '3233', (31, 36))	('HOXD9', 'Gene', (38, 43))	('induced', 'PosReg', (76, 83))	('HOXD10', 'Gene', (48, 54))	('si-TUG1', 'Var', (117, 124))	('HOXD9', 'Gene', '3235', (38, 43))	('HOXB7', 'Gene', '3217', (24, 29))	('HOXD4', 'Gene', (31, 36))
46848	24853421	In addition, knockdown TUG1 also increased the expression of HOXB7 also in NCI-H1650 cell line.	('HOXB7', 'Gene', '3217', (61, 66))	('increased', 'PosReg', (33, 42))	('NCI-H1650', 'CellLine', 'CVCL:1483', (75, 84))	('knockdown', 'Var', (13, 22))	('HOXB7', 'Gene', (61, 66))	('TUG1', 'Gene', (23, 27))	('expression', 'MPA', (47, 57))
46849	24853421	IHC analysis found that tumors developed from shTUG1 cells showed stronger HOXB7 staining than that in control (Figure 5a).	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumors', 'Disease', 'MESH:D009369', (24, 30))	('tumors', 'Disease', (24, 30))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('HOXB7', 'Gene', '3217', (75, 80))	('shTUG1', 'Var', (46, 52))	('HOXB7', 'Gene', (75, 80))	('stronger', 'PosReg', (66, 74))
46854	24853421	The cells then transfect with an siRNA targeting the key catalytic subunit of PRC2 histone methyltransferase, EZH2, H3K27-trimethylated, which efficiently reduced the EZH2 level (Supplementary Figure S2B).	('EZH2', 'Gene', (167, 171))	('reduced', 'NegReg', (155, 162))	('H3K27-trimethylated', 'Var', (116, 135))	('EZH2', 'Gene', (110, 114))	('EZH2', 'Gene', '2146', (110, 114))	('EZH2', 'Gene', '2146', (167, 171))
46855	24853421	The ChIP results show that primers directed at +-200 bp from the transcription start site of HOXB7 promoter detected H3K27 trimethylation and PRC2 binding in SPC-A1 cells transfected with si-NC.	('H3K27', 'Protein', (117, 122))	('HOXB7', 'Gene', '3217', (93, 98))	('si-NC', 'Var', (188, 193))	('binding', 'Interaction', (147, 154))	('HOXB7', 'Gene', (93, 98))	('PRC2', 'Gene', (142, 146))	('trimethylation', 'MPA', (123, 137))	('SPC-A1', 'Gene', (158, 164))	('SPC-A1', 'Gene', '27032', (158, 164))
46857	24853421	These results suggested that TUG1 could epigenetically modulate the expression of HOXB7 by binding to PRC2.	('modulate', 'Reg', (55, 63))	('epigenetically', 'Var', (40, 54))	('expression', 'MPA', (68, 78))	('HOXB7', 'Gene', '3217', (82, 87))	('binding', 'Interaction', (91, 98))	('HOXB7', 'Gene', (82, 87))	('PRC2', 'Gene', (102, 106))
46861	24853421	Next, flow cytometric analysis indicated that the cell cycle progression of si-HOXB7 cells was stalled at the G1-G0 phases compared with cells transfected with si-NC and knockdown HOXB7 could induce apoptosis (Figure 6A).	('HOXB7', 'Gene', (79, 84))	('HOXB7', 'Gene', '3217', (180, 185))	('knockdown', 'Var', (170, 179))	('induce', 'Reg', (192, 198))	('HOXB7', 'Gene', (180, 185))	('apoptosis', 'CPA', (199, 208))	('cell cycle progression', 'CPA', (50, 72))	('HOXB7', 'Gene', '3217', (79, 84))
46862	24853421	Importantly, overexpression of p53 could inhibit HOXB7 expression and co-transfection (p53 and si-TUG1) could partially abrogate p53-induced HOXB7 inhibition (Figure 6B).	('p53', 'Gene', (31, 34))	('HOXB7', 'Gene', '3217', (141, 146))	('si-TUG1', 'Var', (95, 102))	('HOXB7', 'Gene', '3217', (49, 54))	('p53', 'Gene', '7157', (31, 34))	('HOXB7', 'Gene', (49, 54))	('p53', 'Gene', (87, 90))	('p53', 'Gene', '7157', (87, 90))	('HOXB7', 'Gene', (141, 146))	('overexpression', 'PosReg', (13, 27))	('inhibit', 'NegReg', (41, 48))	('p53', 'Gene', (129, 132))	('abrogate', 'NegReg', (120, 128))	('p53', 'Gene', '7157', (129, 132))
46864	24853421	The western blotting revealed that the levels of p-ERK, p-AKT and p-GSK3beta were decreased by knocking down of HOXB7 and were increased by knockdown of TUG1 in SPC-A1 cells, respectively (Figure 6C).	('p-ERK', 'Gene', '9451', (49, 54))	('SPC-A1', 'Gene', (161, 167))	('SPC-A1', 'Gene', '27032', (161, 167))	('p-ERK', 'Gene', (49, 54))	('levels', 'MPA', (39, 45))	('GSK3beta', 'Gene', (68, 76))	('TUG1', 'Gene', (153, 157))	('AKT', 'Gene', '207', (58, 61))	('HOXB7', 'Gene', '3217', (112, 117))	('knocking down', 'Var', (95, 108))	('knockdown', 'Var', (140, 149))	('GSK3beta', 'Gene', '2932', (68, 76))	('decreased', 'NegReg', (82, 91))	('increased', 'PosReg', (127, 136))	('HOXB7', 'Gene', (112, 117))	('AKT', 'Gene', (58, 61))
46869	24853421	These results suggest that TUG1 can participate in AKT and MAPK pathway through the modulation of HOXB7, by the binding to PRC2, indicating that TUG1 affects NSCLC cell growth at least partly through the epigenetic regulation of HOXB7.	('MAPK pathway', 'Pathway', (59, 71))	('NSCLC', 'Disease', (158, 163))	('epigenetic regulation', 'Var', (204, 225))	('binding', 'Interaction', (112, 119))	('participate', 'Reg', (36, 47))	('NSCLC', 'Disease', 'MESH:D002289', (158, 163))	('affects', 'Reg', (150, 157))	('AKT', 'Gene', (51, 54))	('HOXB7', 'Gene', '3217', (229, 234))	('modulation', 'Var', (84, 94))	('HOXB7', 'Gene', (229, 234))	('TUG1', 'Gene', (145, 149))	('HOXB7', 'Gene', '3217', (98, 103))	('NSCLC', 'Phenotype', 'HP:0030358', (158, 163))	('PRC2', 'Gene', (123, 127))	('HOXB7', 'Gene', (98, 103))	('AKT', 'Gene', '207', (51, 54))
46872	24853421	To date, increasing evidence links dysregulation of lncRNAs to diverse human diseases including tumors.	('ncRNA', 'Gene', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumors', 'Disease', (96, 102))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('ncRNA', 'Gene', '54719', (53, 58))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('dysregulation', 'Var', (35, 48))	('human', 'Species', '9606', (71, 76))
46873	24853421	In our current study, we found that the average level of TUG1 in NSCLC tissues was significantly lower than those in corresponding non-tumor tissues.	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('NSCLC', 'Disease', 'MESH:D002289', (65, 70))	('tumor', 'Disease', (135, 140))	('NSCLC', 'Phenotype', 'HP:0030358', (65, 70))	('lower', 'NegReg', (97, 102))	('TUG1', 'Var', (57, 61))	('NSCLC', 'Disease', (65, 70))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
46885	24853421	As a result, inhibition of TUG1 could promote NSCLC cell proliferation both in vitro and in vivo.	('TUG1', 'Gene', (27, 31))	('inhibition', 'Var', (13, 23))	('NSCLC', 'Disease', (46, 51))	('NSCLC', 'Disease', 'MESH:D002289', (46, 51))	('promote', 'PosReg', (38, 45))	('NSCLC', 'Phenotype', 'HP:0030358', (46, 51))
46892	24853421	The dysregulation of HOX gene expression has been shown in many diverse cancers.	('dysregulation', 'Var', (4, 17))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('HOX gene', 'Gene', (21, 29))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('cancers', 'Disease', (72, 79))	('cancers', 'Disease', 'MESH:D009369', (72, 79))
46893	24853421	showed that H3K4me3 and H3K27me3 switches in HOX gene clusters between normal and prostate cancer cells through a genome-wide analysis of H3K4me3 and H3K27me3 modifications.	('prostate cancer', 'Disease', 'MESH:D011471', (82, 97))	('H3K27me3', 'Var', (24, 32))	('prostate cancer', 'Disease', (82, 97))	('H3K27me3', 'Var', (150, 158))	('HOX gene clusters', 'Gene', (45, 62))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('H3K4me3', 'Var', (138, 145))	('switches', 'Reg', (33, 41))	('H3K4me3', 'Var', (12, 19))	('prostate cancer', 'Phenotype', 'HP:0012125', (82, 97))
46895	24853421	In addition, RIP assays confirmed that TUG1 could bind to PRC2 and ChIP assays validated that knockdown of TUG1 resulted in the loss of H3K27 trimethylation and PRC2 binding to the genomic loci of HOXB7, confirming that HOXB7 was a bona target of TUG1/PRC2-regulated genes.	('knockdown', 'Var', (94, 103))	('loss', 'NegReg', (128, 132))	('HOXB7', 'Gene', (220, 225))	('TUG1', 'Gene', (107, 111))	('binding', 'Interaction', (166, 173))	('HOXB7', 'Gene', '3217', (197, 202))	('H3K27', 'Protein', (136, 141))	('HOXB7', 'Gene', (197, 202))	('trimethylation', 'MPA', (142, 156))	('PRC2', 'Gene', (161, 165))	('HOXB7', 'Gene', '3217', (220, 225))
46898	24853421	TUG1 knockdown could also increase the levels of p-ERK, p-AKT and p-GSK3beta.	('p-ERK', 'Gene', '9451', (49, 54))	('TUG1', 'Gene', (0, 4))	('knockdown', 'Var', (5, 14))	('p-ERK', 'Gene', (49, 54))	('GSK3beta', 'Gene', (68, 76))	('AKT', 'Gene', '207', (58, 61))	('increase', 'PosReg', (26, 34))	('GSK3beta', 'Gene', '2932', (68, 76))	('AKT', 'Gene', (58, 61))
46902	24853421	Our results showed a considerable increase in TUG1 expression in the nucleus compared with the cytosol (Figure 5b) and that TUG1 could epigenetically regulate HOXB7 (Figure 5c).	('HOXB7', 'Gene', '3217', (159, 164))	('HOXB7', 'Gene', (159, 164))	('regulate', 'Reg', (150, 158))	('expression', 'MPA', (51, 61))	('TUG1', 'Gene', (46, 50))	('epigenetically', 'Var', (135, 149))	('increase', 'PosReg', (34, 42))
46903	24853421	In our study, the knockdown of TUG1 was found to result in anti-apoptotic activity; the lower expression of TUG1 strengthens this effect due to the loss of PRC2 binding and H3K27 trimethylation occupancy at the HOXB7 locus, similarly to the function of ncRNA intSMYD3.	('knockdown', 'Var', (18, 27))	('loss', 'NegReg', (148, 152))	('anti-apoptotic', 'MPA', (59, 73))	('H3K27', 'Protein', (173, 178))	('ncRNA', 'Gene', (253, 258))	('TUG1', 'Gene', (108, 112))	('PRC2', 'Protein', (156, 160))	('TUG1', 'Gene', (31, 35))	('ncRNA', 'Gene', '54719', (253, 258))	('HOXB7', 'Gene', '3217', (211, 216))	('HOXB7', 'Gene', (211, 216))	('expression', 'MPA', (94, 104))	('lower', 'NegReg', (88, 93))	('occupancy', 'MPA', (194, 203))
46904	24853421	Moreover, epigenetic deregulation, especially histone modification, contributes to the deregulation of HOX genes in cancer.	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('histone', 'MPA', (46, 53))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('epigenetic deregulation', 'Var', (10, 33))	('HOX genes', 'Gene', (103, 112))	('deregulation', 'MPA', (87, 99))
46909	24853421	In addition, we demonstrated that the co-transfection (p53 and si-TUG1) could partially abrogate p53-mediated HOXB7 inhibition.	('p53', 'Gene', (97, 100))	('p53', 'Gene', (55, 58))	('p53', 'Gene', '7157', (55, 58))	('HOXB7', 'Gene', '3217', (110, 115))	('abrogate', 'NegReg', (88, 96))	('p53', 'Gene', '7157', (97, 100))	('HOXB7', 'Gene', (110, 115))	('si-TUG1', 'Var', (63, 70))
46932	24853421	The promoter region of TUG1 was PCR-amplified by TaKaRa LA Taq (Takara) with the primers TUG1-p-F (Kpn1 site) and TUG1-p-R (Xho1 site), and was subcloned into the pGL3 basic firefly luciferase reporter.	('pGL3', 'Gene', (163, 167))	('TUG1-p-F', 'Var', (89, 97))	('TUG1-p-R', 'Var', (114, 122))	('pGL3', 'Gene', '6391', (163, 167))	('TUG1', 'Gene', (23, 27))
46974	32127929	revealed that in KRAS mutation-induced pancreatic cancer, GPC1 is the key molecule for tumor growth and angiogenesis; exosomes containing GPC1 in peripheral blood can be used as biomarkers for the diagnosis of pancreatic cancer.	('mutation-induced', 'Var', (22, 38))	('GPC1', 'Gene', '2817', (58, 62))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (39, 56))	('GPC1', 'Gene', '2817', (138, 142))	('tumor', 'Disease', (87, 92))	('pancreatic cancer', 'Disease', (210, 227))	('pancreatic cancer', 'Disease', 'MESH:D010190', (210, 227))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('pancreatic cancer', 'Disease', 'MESH:D010190', (39, 56))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('KRAS', 'Gene', (17, 21))	('pancreatic cancer', 'Disease', (39, 56))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('GPC1', 'Gene', (138, 142))	('KRAS', 'Gene', '3845', (17, 21))	('GPC1', 'Gene', (58, 62))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (210, 227))
46984	32127929	The polypeptide contains a Furin restriction enzyme site, and by cleavage of the peptide bond between Arg358 and Cys359, the GPC3 protein is cleaved into two fragments: N-terminal at 40kD and C-terminal at 30kD; These two subunits can be connected by one or more disulfide bonds, and the N-terminal subunit can be further sheared to form sGPC3 in the peripheral circulation; Heparan sulfate modification occurs at two sites of GPC3: Cys495 and Cys508; Ser560 is anchored to the lipid raft on cell membrane by phosphatidylinositol (Figure 1).	('Heparan sulfate modification', 'MPA', (375, 403))	('Cys495', 'Var', (433, 439))	('Hep', 'CellLine', 'CVCL:1906', (375, 378))	('Cys508; Ser560', 'Var', (444, 458))	('Ser560', 'Var', (452, 458))
46988	32127929	GPC3 mutation causes simpson golabi behmel syndrome (SGBS) in humans, i.e.	('SGBS', 'Gene', '2719', (53, 57))	('simpson golabi behmel syndrome', 'Disease', (21, 51))	('simpson golabi behmel syndrome', 'Disease', 'MESH:C537340', (21, 51))	('SGBS', 'Gene', (53, 57))	('GPC3', 'Gene', (0, 4))	('causes', 'Reg', (14, 20))	('humans', 'Species', '9606', (62, 68))	('mutation', 'Var', (5, 13))
46990	32127929	Knockout of GPC3 in mice also causes symptoms similar to SGBS, manifested as excessive growth of somatic cells before and after birth.	('GPC3', 'Gene', (12, 16))	('causes', 'Reg', (30, 36))	('SGBS', 'Gene', '2719', (57, 61))	('mice', 'Species', '10090', (20, 24))	('SGBS', 'Gene', (57, 61))	('Knockout', 'Var', (0, 8))	('excessive', 'PosReg', (77, 86))
46992	32127929	Studies have shown that the loss of GPC3 during development leads to changes in downstream signals such as WNT and Hedgehog.	('GPC3', 'Gene', (36, 40))	('loss', 'Var', (28, 32))	('downstream signals', 'MPA', (80, 98))	('WNT', 'Gene', '35975', (107, 110))	('WNT', 'Gene', (107, 110))	('Hedgehog', 'CPA', (115, 123))	('changes', 'Reg', (69, 76))
47004	32127929	Studies have shown that GPC3 can help the activation of WNT signaling by promoting the formation of membrane surface complexes in liver cancer.	('liver cancer', 'Disease', 'MESH:D006528', (130, 142))	('formation of membrane surface complexes', 'MPA', (87, 126))	('liver cancer', 'Disease', (130, 142))	('GPC3', 'Var', (24, 28))	('promoting', 'PosReg', (73, 82))	('activation', 'MPA', (42, 52))	('WNT', 'Gene', '35975', (56, 59))	('WNT', 'Gene', (56, 59))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('liver cancer', 'Phenotype', 'HP:0002896', (130, 142))
47005	32127929	Both the GPC3 protein and the heparan sulfate side chain can interact with FZD and WNTs, and play as a "signal recruiter" in the initial activation-stage of the WNT signaling; in addition, the presence of GPC3 can further stabilize the binding of WNTs to FZD, thereby positively regulate WNTs downstream signal transduction (Figure 5).	('WNT', 'Gene', '35975', (247, 250))	('WNT', 'Gene', (247, 250))	('WNT', 'Gene', (161, 164))	('WNT', 'Gene', '35975', (161, 164))	('WNT', 'Gene', '35975', (288, 291))	('presence', 'Var', (193, 201))	('heparan sulfate', 'Chemical', 'MESH:D006497', (30, 45))	('trans', 'Chemical', 'MESH:C057348', (311, 316))	('WNT', 'Gene', '35975', (83, 86))	('WNT', 'Gene', (83, 86))	('WNT', 'Gene', (288, 291))	('regulate', 'Reg', (279, 287))	('binding', 'Interaction', (236, 243))	('GPC3', 'Gene', (205, 209))	('stabilize', 'MPA', (222, 231))	('positively', 'PosReg', (268, 278))
47006	32127929	The Hedgehog (Hh) signaling pathway plays a key role in embryo morphogenesis, and the abnormal activation of this pathway in adults can lead to the progression of multiple tumors.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('tumors', 'Phenotype', 'HP:0002664', (172, 178))	('lead to', 'Reg', (136, 143))	('activation', 'PosReg', (95, 105))	('multiple tumors', 'Disease', (163, 178))	('abnormal', 'Var', (86, 94))	('multiple tumors', 'Disease', 'MESH:D009369', (163, 178))	('progression', 'CPA', (148, 159))
47012	32127929	There is an interpretation about GPC3 loss-of-function mutation resulting in SGBS attributed to excessive activation of the Hh signaling pathway.	('GPC3', 'Gene', (33, 37))	('SGBS', 'Gene', '2719', (77, 81))	('Hh signaling pathway', 'Pathway', (124, 144))	('loss-of-function', 'NegReg', (38, 54))	('SGBS', 'Gene', (77, 81))	('mutation', 'Var', (55, 63))
47018	32127929	In addition, intervention of GPC3 expression in the HCC cell line promotes TGF-beta2 expression, thereby inhibiting cell proliferation.	('cell proliferation', 'CPA', (116, 134))	('inhibiting', 'NegReg', (105, 115))	('expression', 'MPA', (85, 95))	('HCC', 'Phenotype', 'HP:0001402', (52, 55))	('TGF-beta2', 'Gene', (75, 84))	('HCC', 'Gene', (52, 55))	('promotes', 'PosReg', (66, 74))	('GPC3', 'Gene', (29, 33))	('TGF-beta2', 'Gene', '7042', (75, 84))	('HCC', 'Gene', '619501', (52, 55))	('intervention', 'Var', (13, 25))
47022	32127929	In addition, studies have shown that GPC3 expression is negatively correlated with E-cadherin in HCC cell lines; a similar correlation is also found in pathological examination, and GPC3 overexpression can activate ERK signaling pathway to induce EMT.	('E-cadherin', 'Gene', (83, 93))	('E-cadherin', 'Gene', '999', (83, 93))	('overexpression', 'PosReg', (187, 201))	('EMT', 'Gene', (247, 250))	('HCC', 'Phenotype', 'HP:0001402', (97, 100))	('ERK', 'Gene', '2048', (215, 218))	('EMT', 'Gene', '3702', (247, 250))	('GPC3', 'Var', (182, 186))	('activate', 'PosReg', (206, 214))	('ERK', 'Gene', (215, 218))	('induce', 'PosReg', (240, 246))	('HCC', 'Gene', (97, 100))	('HCC', 'Gene', '619501', (97, 100))
47024	32127929	confirmed that GPC3 was highly correlated with macrophage recruitment in liver cancer tissues.	('macrophage recruitment', 'CPA', (47, 69))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('liver cancer', 'Phenotype', 'HP:0002896', (73, 85))	('liver cancer', 'Disease', 'MESH:D006528', (73, 85))	('liver cancer', 'Disease', (73, 85))	('GPC3', 'Var', (15, 19))	('correlated', 'Reg', (31, 41))
47035	32127929	A large number of studies have shown that GPC3 is more sensitive than AFP in the diagnosis of liver cancer.	('GPC3', 'Var', (42, 46))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('AFP', 'Gene', '174', (70, 73))	('liver cancer', 'Phenotype', 'HP:0002896', (94, 106))	('liver cancer', 'Disease', 'MESH:D006528', (94, 106))	('liver cancer', 'Disease', (94, 106))	('AFP', 'Gene', (70, 73))
47039	32127929	Furthermore, the subcellular location of GPC3 was studied, and results showed that GPC3 is mainly located in the membrane and cytoplasm of HCC cells, and the most common subtype in tumors is isoform 2 (NM_004484.3).	('tumors', 'Disease', (181, 187))	('tumors', 'Disease', 'MESH:D009369', (181, 187))	('tumors', 'Phenotype', 'HP:0002664', (181, 187))	('HCC', 'Gene', '619501', (139, 142))	('HCC', 'Phenotype', 'HP:0001402', (139, 142))	('GPC3', 'Gene', (83, 87))	('NM_004484.3', 'Var', (202, 213))	('HCC', 'Gene', (139, 142))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))
47050	32127929	carried out a meta-analysis of 22 studies for HCC diagnosis by sGPC3 levels, and 18 studies showed that serum GPC3 was a specific biomarker for HCC, with a sensitivity and specificity in combination with other markers of 69% and 93%, respectively.	('HCC', 'Gene', '619501', (46, 49))	('serum GPC3', 'Var', (104, 114))	('HCC', 'Phenotype', 'HP:0001402', (46, 49))	('HCC', 'Gene', (144, 147))	('HCC', 'Gene', '619501', (144, 147))	('HCC', 'Gene', (46, 49))	('HCC', 'Phenotype', 'HP:0001402', (144, 147))
47053	32127929	The 5-year survival rate of GPC3-positive HCC patients was significantly lower than that of GPC3-negative HCC patients (54.5% vs 87.7%).	('patients', 'Species', '9606', (46, 54))	('HCC', 'Gene', (106, 109))	('HCC', 'Gene', (42, 45))	('survival', 'CPA', (11, 19))	('HCC', 'Gene', '619501', (106, 109))	('lower', 'NegReg', (73, 78))	('HCC', 'Gene', '619501', (42, 45))	('HCC', 'Phenotype', 'HP:0001402', (106, 109))	('GPC3-positive', 'Var', (28, 41))	('patients', 'Species', '9606', (110, 118))	('HCC', 'Phenotype', 'HP:0001402', (42, 45))
47054	32127929	In HBV-positive HCC patients, the survival rate of patients with high expression of GPC3 was significantly lower than that of patients with low or no expression of GPC3; and the expression of GPC3 was positively correlated with poor tumor differentiation, portal vein tumor thrombus and tumor lymphatic metastasis.	('HCC', 'Gene', '619501', (16, 19))	('HCC', 'Phenotype', 'HP:0001402', (16, 19))	('lower', 'NegReg', (107, 112))	('vein tumor thrombus', 'Disease', 'MESH:D013927', (263, 282))	('patients', 'Species', '9606', (126, 134))	('HCC', 'Gene', (16, 19))	('HBV-positive', 'Gene', (3, 15))	('GPC3', 'Var', (192, 196))	('tumor', 'Phenotype', 'HP:0002664', (268, 273))	('tumor', 'Disease', (233, 238))	('patients', 'Species', '9606', (20, 28))	('patients', 'Species', '9606', (51, 59))	('vein tumor thrombus', 'Disease', (263, 282))	('tumor', 'Disease', (287, 292))	('high expression', 'Var', (65, 80))	('tumor', 'Disease', 'MESH:D009369', (233, 238))	('portal vein tumor thrombus', 'Phenotype', 'HP:0030242', (256, 282))	('survival rate', 'CPA', (34, 47))	('tumor', 'Disease', 'MESH:D009369', (287, 292))	('correlated', 'Reg', (212, 222))	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('GPC3', 'Gene', (84, 88))	('tumor', 'Disease', (268, 273))	('tumor', 'Phenotype', 'HP:0002664', (287, 292))	('vein tumor thrombus', 'Phenotype', 'HP:0004936', (263, 282))	('tumor', 'Disease', 'MESH:D009369', (268, 273))
47057	32127929	The high expression of GPC3 was significantly associated with malignant events such as poor tumor differentiation, advanced stage of tumor, vascular invasion, and HBV infection.	('GPC3', 'Gene', (23, 27))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Disease', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('high', 'Var', (4, 8))	('HBV infection', 'Disease', (163, 176))	('tumor', 'Disease', (133, 138))	('associated', 'Reg', (46, 56))	('vascular invasion', 'CPA', (140, 157))	('HBV infection', 'Disease', 'MESH:D006509', (163, 176))
47061	32127929	GPC3 has a higher positive rate in lung squamous cell carcinoma, but has a lower positive rate in lung adenocarcinoma.	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (35, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('carcinoma', 'Phenotype', 'HP:0030731', (54, 63))	('GPC3', 'Var', (0, 4))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (98, 117))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (35, 63))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (98, 117))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (40, 63))	('lung squamous cell carcinoma', 'Disease', (35, 63))	('higher', 'PosReg', (11, 17))	('lung adenocarcinoma', 'Disease', (98, 117))
47064	32127929	In urothelial carcinoma (UC), GPC3 has a higher positive rate in malignant UC (43.6% vs 13.3%), which is not expressed in normal urothelium.	('GPC3', 'Var', (30, 34))	('UC', 'Disease', 'MESH:D014523', (75, 77))	('urothelial carcinoma', 'Disease', (3, 23))	('UC', 'Disease', 'MESH:D014523', (25, 27))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (3, 23))	('carcinoma', 'Phenotype', 'HP:0030731', (14, 23))
47069	32127929	In mouse ectopic and in situ GPC3-positive HCC xenograft models, GC33 can significantly inhibit tumor growth; its tumor inhibition efficacy is mainly through antibody-dependent cell-mediated cytotoxicity (ADCC).	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('GC33', 'Chemical', '-', (65, 69))	('mouse', 'Species', '10090', (3, 8))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('cytotoxicity', 'Disease', 'MESH:D064420', (191, 203))	('tumor', 'Disease', (96, 101))	('inhibit', 'NegReg', (88, 95))	('GC33', 'Var', (65, 69))	('tumor', 'Disease', (114, 119))	('HCC', 'Gene', '619501', (43, 46))	('HCC', 'Phenotype', 'HP:0001402', (43, 46))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('HCC', 'Gene', (43, 46))	('cytotoxicity', 'Disease', (191, 203))
47074	32127929	ERY974 has a good killing effect on a variety of GPC3 high expression tumors, and can convert "cold tumor" into a highly inflammatory state "hot tumor".	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('tumor', 'Disease', (100, 105))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumor', 'Disease', (70, 75))	('tumors', 'Disease', (70, 76))	('tumor', 'Disease', (145, 150))	('GPC3', 'Gene', (49, 53))	('tumors', 'Disease', 'MESH:D009369', (70, 76))	('ERY974', 'Var', (0, 6))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('killing', 'CPA', (18, 25))
47078	32127929	identified antibody HS20 targeting heparan sulfate chain of GPC3, which blocked Wnt/beta-catenin signaling, and inhibited WNT3a-dependent cell proliferation and HCC xenografts growth by blocking the interaction between Wnt3a and its ligand.	('Wnt', 'Gene', (80, 83))	('HCC', 'Gene', (161, 164))	('blocking', 'NegReg', (186, 194))	('interaction', 'Interaction', (199, 210))	('Wnt', 'Gene', '35975', (219, 222))	('heparan sulfate', 'Chemical', 'MESH:D006497', (35, 50))	('WNT3a', 'Gene', '89780', (122, 127))	('Wnt', 'Gene', (219, 222))	('WNT3a', 'Gene', (122, 127))	('heparan', 'Protein', (35, 42))	('inhibited', 'NegReg', (112, 121))	('beta-catenin', 'Gene', (84, 96))	('blocked', 'NegReg', (72, 79))	('HS20', 'Var', (20, 24))	('beta-catenin', 'Gene', '1499', (84, 96))	('Wnt3a', 'Gene', '89780', (219, 224))	('GPC3', 'Gene', (60, 64))	('HCC', 'Gene', '619501', (161, 164))	('HS', 'Chemical', 'MESH:D006859', (20, 22))	('Wnt3a', 'Gene', (219, 224))	('HCC', 'Phenotype', 'HP:0001402', (161, 164))	('Wnt', 'Gene', '35975', (80, 83))
47083	32127929	constructed immunotoxins YP7-PE38 and HN3-PE38, both have good anti-tumor activity in vivo and in vitro, and can induce regression of GPC3 positive xenografts.	('tumor', 'Disease', (68, 73))	('HN3', 'Gene', '100462983', (38, 41))	('induce', 'PosReg', (113, 119))	('YP7-PE38', 'Var', (25, 33))	('GPC3', 'Protein', (134, 138))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('HN3', 'Gene', (38, 41))	('regression', 'CPA', (120, 130))
47084	32127929	The same research team truncated the PE-A protein molecule to construct the immunotoxin HN3-mPE24, which also significantly prolonged the survival time of tumor-bearing mice.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('tumor', 'Disease', (155, 160))	('HN3', 'Gene', (88, 91))	('HN3', 'Gene', '100462983', (88, 91))	('survival time', 'CPA', (138, 151))	('mice', 'Species', '10090', (169, 173))	('prolonged', 'PosReg', (124, 133))	('truncated', 'Var', (23, 32))
47086	32127929	was coupled with Pseudomonas Exotoxin A (PE38KDEL), it showed a potent anti-tumor effect in a nude mouse xenograft model.	('mouse', 'Species', '10090', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('PE38KDEL', 'Var', (41, 49))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
47088	32127929	The team designed two kinds of photoimmunotherapy agents, IR700-YP7 and IR700-HN3, based on YP7 antibody and NH3, both of which can significantly inhibit tumor growth.	('inhibit', 'NegReg', (146, 153))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('HN3', 'Gene', (78, 81))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('HN3', 'Gene', '100462983', (78, 81))	('IR700-YP7', 'Var', (58, 67))	('tumor', 'Disease', (154, 159))
47095	32127929	In order to further enhance the killing effect of GPC3 CAR-T, Pan Z et al.	('CAR-T', 'Gene', '9607', (55, 60))	('enhance', 'PosReg', (20, 27))	('killing', 'MPA', (32, 39))	('GPC3', 'Var', (50, 54))	('CAR-T', 'Gene', (55, 60))
47097	32127929	found that knockout PD1 in CAR-T by CAS9 can block the downstream signaling of PD1 and significantly enhance the expression of Akt phosphorylation and anti-apoptotic protein Bcl-xL, improving its anti-tumor effect.	('PD1', 'Gene', (79, 82))	('expression', 'MPA', (113, 123))	('block', 'NegReg', (45, 50))	('CAR-T', 'Gene', (27, 32))	('enhance', 'PosReg', (101, 108))	('tumor', 'Disease', (201, 206))	('knockout', 'Var', (11, 19))	('improving', 'PosReg', (182, 191))	('PD1', 'Gene', (20, 23))	('PD1', 'Gene', '5133', (79, 82))	('downstream signaling', 'MPA', (55, 75))	('Bcl-xL', 'Gene', (174, 180))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('Akt', 'Pathway', (127, 130))	('Bcl-xL', 'Gene', '598', (174, 180))	('CAR-T', 'Gene', '9607', (27, 32))	('CAS9', 'CellLine', 'CVCL:8537', (36, 40))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('PD1', 'Gene', '5133', (20, 23))
47111	32127929	firstly identified a specific GPC3 linear epitope GPC3298-306 (EYILSLEEL) peptide in BALB/c mice, which can induce tumor rejection and large numbers of CD8+ T cells into the tumor after xenograft in mice of the tumor cells transfected with this epitope; later this group identified the linear epitope GPC3144-152 (FVGEFFTDV) peptide, which induces peptide-reactive CTLs in HLA-A2.1 transgenic mice without inducing autoimmunity, and activates CTLs in HCC patients, and these CTLs can significantly kill tumors in the PDX model.	('autoimmunity', 'Disease', 'MESH:D001327', (415, 427))	('peptide-reactive', 'MPA', (348, 364))	('transgenic mice', 'Species', '10090', (382, 397))	('tumor', 'Disease', (115, 120))	('autoimmunity', 'Phenotype', 'HP:0002960', (415, 427))	('tumor', 'Disease', (211, 216))	('trans', 'Chemical', 'MESH:C057348', (382, 387))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('tumor', 'Disease', (503, 508))	('mice', 'Species', '10090', (92, 96))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('HCC', 'Gene', '619501', (451, 454))	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('HCC', 'Phenotype', 'HP:0001402', (451, 454))	('tumor', 'Disease', 'MESH:D009369', (503, 508))	('trans', 'Chemical', 'MESH:C057348', (223, 228))	('mice', 'Species', '10090', (393, 397))	('CD8', 'Gene', (152, 155))	('HCC', 'Gene', (451, 454))	('tumors', 'Phenotype', 'HP:0002664', (503, 509))	('activates', 'PosReg', (433, 442))	('induces', 'PosReg', (340, 347))	('patients', 'Species', '9606', (455, 463))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumor', 'Phenotype', 'HP:0002664', (503, 508))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('tumors', 'Disease', (503, 509))	('autoimmunity', 'Disease', (415, 427))	('tumor', 'Disease', (174, 179))	('mice', 'Species', '10090', (199, 203))	('GPC3298-306', 'CellLine', 'CVCL:9P26', (50, 61))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('tumors', 'Disease', 'MESH:D009369', (503, 509))	('CD8', 'Gene', '925', (152, 155))	('GPC3144-152', 'Var', (301, 312))
47137	32127929	Subsequently, is the most essential question is that the absence of GPC3 is not lethal to tumor cells.	('absence', 'Var', (57, 64))	('tumor', 'Disease', (90, 95))	('GPC3', 'Protein', (68, 72))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
47140	30556200	PI3-kinase Pathway Biomarkers in Oral Cancer and Tumor Immune Cells This study investigated the hypothesis that PI3-kinase pathway dysregulation in either head and neck cancer cells and/or tumor infiltrating immune cells would influence outcomes of patients with surgically treated oral tongue squamous cell carcinomas (SCC).	('oral tongue squamous cell carcinomas', 'Disease', 'MESH:D002294', (282, 318))	('head and neck cancer', 'Phenotype', 'HP:0012288', (155, 175))	('Tumor', 'Phenotype', 'HP:0002664', (49, 54))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (294, 317))	('SCC', 'Gene', '6317', (320, 323))	('dysregulation', 'Var', (131, 144))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('Oral Cancer', 'Disease', 'MESH:D009062', (33, 44))	('tongue squamous cell carcinoma', 'Phenotype', 'HP:0030413', (287, 317))	('PI3', 'Gene', '5266', (112, 115))	('SCC', 'Gene', (320, 323))	('PI3', 'Gene', '5266', (0, 3))	('carcinoma', 'Phenotype', 'HP:0030731', (308, 317))	('head and neck cancer', 'Disease', 'MESH:D006258', (155, 175))	('oral tongue squamous cell carcinomas', 'Disease', (282, 318))	('patients', 'Species', '9606', (249, 257))	('Tumor', 'Disease', 'MESH:D009369', (49, 54))	('Cancer', 'Phenotype', 'HP:0002664', (38, 44))	('PI3', 'Gene', (112, 115))	('influence', 'Reg', (227, 236))	('PI3', 'Gene', (0, 3))	('carcinomas', 'Phenotype', 'HP:0030731', (308, 318))	('tumor', 'Disease', (189, 194))	('Oral Cancer', 'Disease', (33, 44))	('tongue squamous cell carcinomas', 'Phenotype', 'HP:0030413', (287, 318))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (294, 318))	('SCC', 'Phenotype', 'HP:0002860', (320, 323))	('Tumor', 'Disease', (49, 54))	('tumor', 'Disease', 'MESH:D009369', (189, 194))
47151	30556200	In The Cancer Genome Atlas project, mutations in the p110-alpha gene (PIK3CA) were identified in 18% of human papilloma virus (HPV)-negative and 37% of HPV-positive head and neck cancers.	('head and neck cancer', 'Phenotype', 'HP:0012288', (165, 185))	('p110-alpha', 'Gene', (53, 63))	('head and neck cancers', 'Disease', 'MESH:D006258', (165, 186))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('PIK3CA', 'Gene', '5290', (70, 76))	('human papilloma', 'Disease', (104, 119))	('identified', 'Reg', (83, 93))	('p110-alpha', 'Gene', '5290', (53, 63))	('mutations', 'Var', (36, 45))	('HPV', 'Species', '10566', (152, 155))	('PIK3CA', 'Gene', (70, 76))	('head and neck cancers', 'Phenotype', 'HP:0012288', (165, 186))	('Cancer', 'Phenotype', 'HP:0002664', (7, 13))	('cancers', 'Phenotype', 'HP:0002664', (179, 186))	('HPV', 'Species', '10566', (127, 130))	('human papilloma virus', 'Species', '10566', (104, 125))	('papilloma', 'Phenotype', 'HP:0012740', (110, 119))
47154	30556200	Of note, PTEN loss can result from genetic, as well as epigenetic events, such as promoter methylation, alternative splicing of pre-messenger mRNA, and post-translational modification.	('PTEN', 'Gene', (9, 13))	('result', 'Reg', (23, 29))	('PTEN', 'Gene', '5728', (9, 13))	('post-translational modification', 'Var', (152, 183))	('alternative splicing of pre-messenger mRNA', 'MPA', (104, 146))	('promoter', 'MPA', (82, 90))	('loss', 'NegReg', (14, 18))
47156	30556200	Identifying a prognostic role of potentially targetable molecular alterations may serve as a useful approach to assist in cancer drug development, and has been used, for example, to support the decision to study epidermal growth factor receptor (EGFR) inhibitors for head and neck cancer treatment.	('cancer', 'Phenotype', 'HP:0002664', (281, 287))	('epidermal growth factor receptor', 'Gene', (212, 244))	('cancer', 'Disease', 'MESH:D009369', (281, 287))	('decision', 'Disease', 'MESH:D020195', (194, 202))	('head and neck cancer', 'Disease', 'MESH:D006258', (267, 287))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', (281, 287))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('epidermal growth factor receptor', 'Gene', '1956', (212, 244))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('EGFR', 'Gene', '1956', (246, 250))	('EGFR', 'Gene', (246, 250))	('decision', 'Disease', (194, 202))	('head and neck cancer', 'Phenotype', 'HP:0012288', (267, 287))	('alterations', 'Var', (66, 77))
47161	30556200	We therefore designed this study to investigate the hypothesis that PI3-kinase pathway dysregulation in either head and neck cancer cells and/or tumor infiltrating immune cells would influence long-term outcomes of patients with oral tongue squamous cell carcinomas treated with surgical resection.	('oral tongue squamous cell carcinomas', 'Disease', (229, 265))	('PI3', 'Gene', (68, 71))	('head and neck cancer', 'Disease', 'MESH:D006258', (111, 131))	('influence', 'Reg', (183, 192))	('carcinoma', 'Phenotype', 'HP:0030731', (255, 264))	('carcinomas', 'Phenotype', 'HP:0030731', (255, 265))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (241, 265))	('tumor', 'Disease', (145, 150))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('oral tongue squamous cell carcinomas', 'Disease', 'MESH:D002294', (229, 265))	('dysregulation', 'Var', (87, 100))	('tongue squamous cell carcinomas', 'Phenotype', 'HP:0030413', (234, 265))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (241, 264))	('patients', 'Species', '9606', (215, 223))	('PI3', 'Gene', '5266', (68, 71))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('head and neck cancer', 'Phenotype', 'HP:0012288', (111, 131))	('tongue squamous cell carcinoma', 'Phenotype', 'HP:0030413', (234, 264))
47167	30556200	Endogenous peroxidase activity was blocked prior to antibody immunostaining with 3% H2O2 in methanol for 30 min, followed by a 30-minute incubation with 10% fetal bovine serum in Tris-buffered saline solution with Tween 20 to block non-specific antibody binding.	('Tris-buffered saline', 'Chemical', '-', (179, 199))	('binding', 'Interaction', (254, 261))	('H2O2', 'Chemical', 'MESH:D006861', (84, 88))	('H2O2', 'Var', (84, 88))	('methanol', 'Chemical', 'MESH:D000432', (92, 100))	('Tween 20', 'Chemical', 'MESH:D011136', (214, 222))
47197	30556200	Appendix Figure 3 shows representative tissue sections of no/low or high PTEN staining in immune cells and cancer cells.	('PTEN', 'Gene', (73, 77))	('PTEN', 'Gene', '5728', (73, 77))	('high', 'Var', (68, 72))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('no/low', 'NegReg', (58, 64))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('cancer', 'Disease', (107, 113))
47198	30556200	In this study, we identified a non-statistically significant trend towards inferior recurrence-free and overall survival of patients with resected oral tongue squamous cell carcinoma exhibiting higher levels of cancer cell expression of p-Akt (nuclear and membrane), p-mTOR (cytoplasmic), Ki67 (nuclear), and lower levels of cancer cell expression of PTEN (cytoplasmic).	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (159, 182))	('Akt', 'Gene', '207', (239, 242))	('mTOR', 'Gene', '2475', (269, 273))	('inferior', 'NegReg', (75, 83))	('tongue squamous cell carcinoma', 'Phenotype', 'HP:0030413', (152, 182))	('patients', 'Species', '9606', (124, 132))	('cancer', 'Disease', 'MESH:D009369', (211, 217))	('cancer', 'Disease', (325, 331))	('cancer', 'Phenotype', 'HP:0002664', (325, 331))	('higher', 'PosReg', (194, 200))	('oral tongue squamous cell carcinoma', 'Disease', 'MESH:D002294', (147, 182))	('PTEN', 'Gene', (351, 355))	('carcinoma', 'Phenotype', 'HP:0030731', (173, 182))	('oral tongue squamous cell carcinoma', 'Disease', (147, 182))	('overall survival', 'CPA', (104, 120))	('recurrence-free', 'CPA', (84, 99))	('mTOR', 'Gene', (269, 273))	('PTEN', 'Gene', '5728', (351, 355))	('cancer', 'Disease', (211, 217))	('cancer', 'Disease', 'MESH:D009369', (325, 331))	('Ki67', 'Var', (289, 293))	('Akt', 'Gene', (239, 242))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))
47204	30556200	Overexpression of p-Akt has been shown to be associated with shorter disease-free survival independently of stage and nodal status in a cohort of 52 tongue cancer cases and shorter overall survival in two cohorts of 84 and 191 oral squamous cell carcinoma cases.	('shorter', 'NegReg', (61, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (246, 255))	('Akt', 'Gene', (20, 23))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (227, 255))	('disease-free survival', 'CPA', (69, 90))	('shorter', 'NegReg', (173, 180))	('Akt', 'Gene', '207', (20, 23))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (232, 255))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('Overexpression', 'Var', (0, 14))	('tongue cancer', 'Disease', (149, 162))	('tongue cancer', 'Disease', 'MESH:D014062', (149, 162))	('oral squamous cell carcinoma', 'Disease', (227, 255))
47205	30556200	demonstrated lower disease-free and overall survival in patients with oral squamous cell carcinoma with high p-mTOR expression.	('patients', 'Species', '9606', (56, 64))	('mTOR', 'Gene', '2475', (111, 115))	('lower', 'NegReg', (13, 18))	('mTOR', 'Gene', (111, 115))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (70, 98))	('overall survival', 'CPA', (36, 52))	('high', 'Var', (104, 108))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (75, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('oral squamous cell carcinoma', 'Disease', (70, 98))
47219	30556200	Notably, we identified that no/low PTEN protein expression in immune cells (which consisted primarily of lymphocytes) was associated with inferior recurrence-free and overall survival on univariate (Table 6, Appendix Figure 2) and multi-covariate analysis (Appendix Table 3).	('recurrence-free', 'CPA', (147, 162))	('PTEN', 'Gene', (35, 39))	('expression', 'MPA', (48, 58))	('no/low', 'Var', (28, 34))	('PTEN', 'Gene', '5728', (35, 39))	('inferior', 'NegReg', (138, 146))	('overall survival', 'CPA', (167, 183))
47286	30361422	Cisplatin treatment is associated with severe hematologic toxicities such as myelosuppression as well as nonhematologic toxicities including nephrotoxicity, nausea, and nephropathy, which can result in treatment disruption in patients with advanced esophageal cancer who are likely to be especially susceptible to such toxicities.	('n', 'Chemical', 'MESH:D009584', (132, 133))	('nephropathy', 'Disease', 'MESH:D007674', (169, 180))	('nephrotoxicity', 'Disease', 'MESH:D007674', (141, 155))	('myelosuppression', 'Disease', 'MESH:D001855', (77, 93))	('nausea', 'Disease', 'MESH:D009325', (157, 163))	('toxicities', 'Disease', 'MESH:D064420', (58, 68))	('result', 'Reg', (192, 198))	('n', 'Chemical', 'MESH:D009584', (209, 210))	('esophageal cancer', 'Disease', 'MESH:D004938', (249, 266))	('toxicities', 'Disease', (58, 68))	('n', 'Chemical', 'MESH:D009584', (200, 201))	('n', 'Chemical', 'MESH:D009584', (231, 232))	('n', 'Chemical', 'MESH:D009584', (169, 170))	('toxicities', 'Disease', 'MESH:D064420', (120, 130))	('n', 'Chemical', 'MESH:D009584', (105, 106))	('toxicities', 'Disease', 'MESH:D064420', (319, 329))	('hematologic toxicities', 'Disease', 'MESH:D006402', (46, 68))	('nephropathy', 'Phenotype', 'HP:0000112', (169, 180))	('n', 'Chemical', 'MESH:D009584', (262, 263))	('n', 'Chemical', 'MESH:D009584', (17, 18))	('n', 'Chemical', 'MESH:D009584', (224, 225))	('patients', 'Species', '9606', (226, 234))	('esophageal cancer', 'Disease', (249, 266))	('toxicities', 'Disease', (120, 130))	('toxicities', 'Disease', (319, 329))	('n', 'Chemical', 'MESH:D009584', (8, 9))	('n', 'Chemical', 'MESH:D009584', (166, 167))	('n', 'Chemical', 'MESH:D009584', (190, 191))	('n', 'Chemical', 'MESH:D009584', (221, 222))	('hematologic toxicities', 'Disease', 'MESH:D006402', (108, 130))	('hematologic toxicities', 'Disease', (46, 68))	('nausea', 'Phenotype', 'HP:0002018', (157, 163))	('myelosuppression', 'Disease', (77, 93))	('n', 'Chemical', 'MESH:D009584', (157, 158))	('n', 'Chemical', 'MESH:D009584', (244, 245))	('treatment', 'Disease', (202, 211))	('n', 'Chemical', 'MESH:D009584', (141, 142))	('cancer', 'Phenotype', 'HP:0002664', (260, 266))	('hematologic toxicities', 'Disease', (108, 130))	('nephrotoxicity', 'Disease', (141, 155))	('n', 'Chemical', 'MESH:D009584', (92, 93))	('nausea', 'Disease', (157, 163))	('Cisplatin', 'Chemical', 'MESH:D002945', (0, 9))	('nephropathy', 'Disease', (169, 180))	('n', 'Chemical', 'MESH:D009584', (138, 139))	('Cisplatin', 'Var', (0, 9))	('n', 'Chemical', 'MESH:D009584', (107, 108))
47326	30662330	Kaplan-Meier survival analysis showed that high levels of MEOX1 were significantly associated with unfavorable survival in NSCLC patients, and MEOX1 nucleus staining had worse survival, than did patients with overall expression in lung squamous cell carcinoma patients.	('high levels', 'Var', (43, 54))	('lung squamous cell carcinoma', 'Disease', (231, 259))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (231, 259))	('NSCLC', 'Disease', (123, 128))	('patients', 'Species', '9606', (129, 137))	('NSCLC', 'Disease', 'MESH:D002289', (123, 128))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (236, 259))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (231, 259))	('patients', 'Species', '9606', (260, 268))	('NSCLC', 'Phenotype', 'HP:0030358', (123, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (250, 259))	('associated', 'Reg', (83, 93))	('patients', 'Species', '9606', (195, 203))	('MEOX1', 'Gene', (58, 63))	('worse', 'NegReg', (170, 175))	('MEOX1', 'Gene', (143, 148))
47328	30662330	Silencing of MEOX1 by specific SiRNA significantly inhibited H460 and H1299 cell proliferation and sphere formation in serum-free medium.	('H1299', 'CellLine', 'CVCL:0060', (70, 75))	('H460', 'CellLine', 'CVCL:0459', (61, 65))	('sphere formation', 'CPA', (99, 115))	('Silencing', 'Var', (0, 9))	('MEOX1', 'Gene', (13, 18))	('inhibited', 'NegReg', (51, 60))
47329	30662330	Conclusions: Our results firstly indentified that high levels of MEOX1 especially nuclear staining was an independent prognostic factor for NSCLC, and it served a essential roles in the regulation of cell proliferation and colony formation in vitro.	('NSCLC', 'Disease', 'MESH:D002289', (140, 145))	('cell proliferation', 'CPA', (200, 218))	('NSCLC', 'Phenotype', 'HP:0030358', (140, 145))	('high levels', 'Var', (50, 61))	('colony formation', 'CPA', (223, 239))	('MEOX1', 'Gene', (65, 70))	('NSCLC', 'Disease', (140, 145))
47335	30662330	Several studies have proved that dysregulation of MEOX1 is associated with cancer progression.	('dysregulation', 'Var', (33, 46))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('cancer', 'Disease', (75, 81))	('associated', 'Reg', (59, 69))	('MEOX1', 'Gene', (50, 55))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))
47363	30662330	Kaplan-Meier analysis showed that the overall survival time of lung cancer patients with high levels of MEOX1 was markedly shorter than those with MEOX1-negative expression (Figure.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('lung cancer', 'Disease', 'MESH:D008175', (63, 74))	('shorter', 'NegReg', (123, 130))	('patients', 'Species', '9606', (75, 83))	('lung cancer', 'Disease', (63, 74))	('lung cancer', 'Phenotype', 'HP:0100526', (63, 74))	('survival time', 'CPA', (46, 59))	('MEOX1', 'Var', (104, 109))	('high levels', 'Var', (89, 100))
47364	30662330	Further analysis indicated that MEOX1 nucleus staining had worse survival, than did patients with overall expression in squamous cell lung cancer patients (Figure.	('squamous cell lung cancer', 'Disease', (120, 145))	('MEOX1', 'Var', (32, 37))	('worse', 'NegReg', (59, 64))	('lung cancer', 'Phenotype', 'HP:0100526', (134, 145))	('patients', 'Species', '9606', (84, 92))	('squamous cell lung cancer', 'Disease', 'MESH:D002294', (120, 145))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('patients', 'Species', '9606', (146, 154))	('survival', 'MPA', (65, 73))
47368	30662330	The results showed that inhibition of MEOX1 dramatically suppressed the mammosphere formation number by 89.1% and 79.6% in H1299 and H460 cells over 14 days.	('H460', 'CellLine', 'CVCL:0459', (133, 137))	('inhibition', 'Var', (24, 34))	('MEOX1', 'Gene', (38, 43))	('H1299', 'CellLine', 'CVCL:0060', (123, 128))	('mammosphere formation number', 'CPA', (72, 100))	('suppressed', 'NegReg', (57, 67))
47369	30662330	MTS assay indicated that knockdown of MEOX1 in H1299 cells grew at a rate 71.2% slower than control cells.	('H1299', 'CellLine', 'CVCL:0060', (47, 52))	('MTS', 'Gene', (0, 3))	('MEOX1', 'Gene', (38, 43))	('slower', 'NegReg', (80, 86))	('grew', 'CPA', (59, 63))	('knockdown', 'Var', (25, 34))	('MTS', 'Gene', '8201', (0, 3))
47370	30662330	Consistently, inhibition of MEOX1 also attenuated lung cancer cell H460 proliferation, and the inhibitory rate was approximately 51.2% (Figure 4B).	('attenuated lung cancer', 'Disease', 'MESH:D008175', (39, 61))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('lung cancer', 'Phenotype', 'HP:0100526', (50, 61))	('MEOX1', 'Gene', (28, 33))	('inhibition', 'Var', (14, 24))	('attenuated lung cancer', 'Disease', (39, 61))	('H460', 'CellLine', 'CVCL:0459', (67, 71))
47376	30662330	Mutations in MEOX1 are associated with Klippel-Feil Syndrome.	('Klippel-Feil Syndrome', 'Disease', 'MESH:D007714', (39, 60))	('Klippel-Feil Syndrome', 'Phenotype', 'HP:0004602', (39, 60))	('Mutations', 'Var', (0, 9))	('MEOX1', 'Gene', (13, 18))	('associated', 'Reg', (23, 33))	('Klippel-Feil Syndrome', 'Disease', (39, 60))
47377	30662330	It has been reported that aberrant expression of MEOX1 might involve in cancer progression.	('MEOX1', 'Gene', (49, 54))	('aberrant expression', 'Var', (26, 45))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('involve', 'Reg', (61, 68))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('cancer', 'Disease', (72, 78))
47390	30662330	Kaplan-Meier analysis indicated that lung cancer patients with high levels of MEOX1 had significantly shorter time than those with MEOX1-negative expression.	('shorter', 'NegReg', (102, 109))	('lung cancer', 'Disease', (37, 48))	('time', 'MPA', (110, 114))	('lung cancer', 'Phenotype', 'HP:0100526', (37, 48))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('high levels', 'Var', (63, 74))	('MEOX1', 'Gene', (78, 83))	('lung cancer', 'Disease', 'MESH:D008175', (37, 48))	('patients', 'Species', '9606', (49, 57))
47398	29980786	Epigenetically regulated PAX6 drives cancer cells toward a stem-like state via GLI-SOX2 signaling axis in lung adenocarcinoma It remains unclear whether PAX6 acts as a crucial transcription factor for lung cancer stem cell (CSC) traits.	('SOX2', 'Gene', (83, 87))	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('SOX2', 'Gene', '6657', (83, 87))	('lung cancer', 'Disease', 'MESH:D008175', (201, 212))	('PAX6', 'Gene', (25, 29))	('PAX6', 'Gene', '5080', (25, 29))	('lung cancer', 'Phenotype', 'HP:0100526', (201, 212))	('PAX6', 'Gene', (153, 157))	('PAX6', 'Gene', '5080', (153, 157))	('cancer', 'Disease', (206, 212))	('GLI', 'Gene', (79, 82))	('lung adenocarcinoma', 'Disease', (106, 125))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('cancer', 'Disease', (37, 43))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('Epigenetically regulated', 'Var', (0, 24))	('lung cancer', 'Disease', (201, 212))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (106, 125))	('GLI', 'Gene', '2735', (79, 82))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (106, 125))	('cancer', 'Disease', 'MESH:D009369', (206, 212))
47403	29980786	Therapeutically, the blockade of the PAX6-GLI-SOX2 signaling axis elicits a long-lasting therapeutic efficacy by limiting CSC expansion following chemotherapy.	('GLI', 'Gene', '2735', (42, 45))	('SOX2', 'Gene', '6657', (46, 50))	('SOX2', 'Gene', (46, 50))	('blockade', 'Var', (21, 29))	('CSC expansion', 'CPA', (122, 135))	('limiting', 'NegReg', (113, 121))	('GLI', 'Gene', (42, 45))
47410	29980786	Paired box 6 (PAX6), which belongs to homeobox gene superfamily, is an essential transcription factor for embryonic development , and the dysregulation of PAX6 expression results in developmental disorders and formation of tumors .	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('developmental disorders', 'Disease', 'MESH:D002658', (182, 205))	('Paired box 6', 'Gene', '5080', (0, 12))	('tumors', 'Disease', (223, 229))	('tumors', 'Disease', 'MESH:D009369', (223, 229))	('results in', 'Reg', (171, 181))	('tumors', 'Phenotype', 'HP:0002664', (223, 229))	('dysregulation', 'Var', (138, 151))	('PAX6', 'Gene', (155, 159))	('Paired box 6', 'Gene', (0, 12))	('developmental disorders', 'Disease', (182, 205))
47420	29980786	Promoter methylation (PM) is one of the most common epigenetic alterations, and aberrant PM of candidate genes can be an early event in cancer progression, indicating its potential as a biomarker for early cancer detection .	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('cancer', 'Disease', (136, 142))	('cancer', 'Disease', (206, 212))	('cancer', 'Disease', 'MESH:D009369', (206, 212))	('Promoter', 'Disease', (0, 8))	('aberrant', 'Var', (80, 88))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
47424	29980786	Our study provides a rationale for targeting PAX6-GLI-SOX2 signaling axis and reveal the clinical utility of PAX6 PM as a serum biomarker for early lung cancer detection.	('GLI', 'Gene', (50, 53))	('lung cancer', 'Disease', 'MESH:D008175', (148, 159))	('SOX2', 'Gene', '6657', (54, 58))	('GLI', 'Gene', '2735', (50, 53))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('SOX2', 'Gene', (54, 58))	('lung cancer', 'Disease', (148, 159))	('lung cancer', 'Phenotype', 'HP:0100526', (148, 159))	('PAX6', 'Var', (109, 113))
47426	29980786	The promoter CpG islands were frequently methylated in the tumor samples compared with matched normal samples.	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('methylated', 'Var', (41, 51))	('tumor', 'Disease', (59, 64))	('tumor', 'Disease', 'MESH:D009369', (59, 64))
47428	29980786	In all the NSCLC cell lines with PAX6 PM, the expression levels of PAX6 were mostly absent (Supplementary Fig.	('NSCLC', 'Disease', (11, 16))	('PAX6 PM', 'Var', (33, 40))	('NSCLC', 'Disease', 'MESH:D002289', (11, 16))	('absent', 'NegReg', (84, 90))	('expression levels', 'MPA', (46, 63))
47433	29980786	A remarkable reduction in tumor volume was observed in mice injected with PAX6-sh cells compared with PAX6-Ctrl cells, while enhanced tumorigenesis was observed in PAX6-LV cells (Fig.	('PAX6-sh cells', 'Var', (74, 87))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('mice', 'Species', '10090', (55, 59))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('reduction', 'NegReg', (13, 22))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('enhanced', 'PosReg', (125, 133))	('tumor', 'Disease', (26, 31))	('tumor', 'Disease', (134, 139))
47439	29980786	In contrast, SOX2 knockdown attenuated the PAX6-induced stemness properties in PAX6-LV NCI-H1975 cells (Fig.	('knockdown', 'Var', (18, 27))	('NCI-H1975', 'CellLine', 'CVCL:1511', (87, 96))	('attenuated', 'NegReg', (28, 38))	('PAX6-induced stemness properties', 'CPA', (43, 75))	('SOX2', 'Gene', '6657', (13, 17))	('SOX2', 'Gene', (13, 17))
47455	29980786	S4C and S4G), indicating that PAX6 activates Hh signaling in a SMO-independent manner.	('SMO', 'Gene', '6608', (63, 66))	('SMO', 'Gene', (63, 66))	('activates', 'PosReg', (35, 44))	('PAX6', 'Var', (30, 34))	('Hh signaling', 'MPA', (45, 57))
47457	29980786	To test whether the expression status of PAX6 is associated with these molecular subtypes, we assessed molecular subtype-related genes using their individual enrichment scores from results of GSEA in the groups with high and low PAX6 expression in the TCGA LUAD cohort (Supplementary Table S1).	('low', 'NegReg', (225, 228))	('expression', 'MPA', (234, 244))	('high', 'Var', (216, 220))	('GSEA', 'Chemical', '-', (192, 196))	('PAX6', 'Gene', (229, 233))
47462	29980786	GLI1 knockdown induced the expression of HOPX and NKX2-1, and the dual knockdown of GLI1 and GLI2 further upregulated their expression.	('GLI1', 'Gene', (0, 4))	('GLI2', 'Gene', (93, 97))	('GLI2', 'Gene', '2736', (93, 97))	('upregulated', 'PosReg', (106, 117))	('knockdown', 'Var', (5, 14))	('GLI1', 'Gene', '2735', (84, 88))	('knockdown', 'Var', (71, 80))	('expression', 'MPA', (27, 37))	('NKX2-1', 'Gene', (50, 56))	('HOPX', 'Gene', (41, 45))	('expression', 'MPA', (124, 134))	('GLI1', 'Gene', (84, 88))	('GLI1', 'Gene', '2735', (0, 4))	('HOPX', 'Gene', '84525', (41, 45))	('NKX2-1', 'Gene', '7080', (50, 56))
47466	29980786	Collectively, PAX6 not only enhanced the key pluripotent factors but also repressed differentiation lineage factors via SOX2-GLI signaling.	('key pluripotent factors', 'MPA', (41, 64))	('GLI', 'Gene', (125, 128))	('enhanced', 'PosReg', (28, 36))	('repressed', 'NegReg', (74, 83))	('PAX6', 'Var', (14, 18))	('GLI', 'Gene', '2735', (125, 128))	('SOX2', 'Gene', (120, 124))	('SOX2', 'Gene', '6657', (120, 124))	('differentiation lineage factors', 'CPA', (84, 115))
47471	29980786	Furthermore, we observed that tumors with PAX6 PM have higher expression levels of HOPX and NKX2-1 and lower levels of SOX2 and GLI than those without PM (Fig.	('tumors', 'Disease', (30, 36))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('HOPX', 'Gene', '84525', (83, 87))	('GLI', 'Gene', '2735', (128, 131))	('expression levels', 'MPA', (62, 79))	('lower', 'NegReg', (103, 108))	('HOPX', 'Gene', (83, 87))	('NKX2-1', 'Gene', (92, 98))	('PAX6 PM', 'Var', (42, 49))	('SOX2', 'Gene', (119, 123))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('SOX2', 'Gene', '6657', (119, 123))	('higher', 'PosReg', (55, 61))	('GLI', 'Gene', (128, 131))	('NKX2-1', 'Gene', '7080', (92, 98))
47476	29980786	In contrast to PAX6-Ctrl tumors, PAX6-sh tumors retained their low sphere-forming ability along with reduced PAX6-GLI-SOX2 signaling, even after treatment with Pem-Cis chemotherapy (Fig.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('low sphere-forming ability', 'CPA', (63, 89))	('tumors', 'Disease', (25, 31))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('GLI', 'Gene', '2735', (114, 117))	('Pem-Cis', 'Chemical', '-', (160, 167))	('tumors', 'Disease', (41, 47))	('tumors', 'Disease', 'MESH:D009369', (41, 47))	('SOX2', 'Gene', '6657', (118, 122))	('tumors', 'Disease', 'MESH:D009369', (25, 31))	('PAX6-sh', 'Var', (33, 40))	('reduced', 'NegReg', (101, 108))	('SOX2', 'Gene', (118, 122))	('PAX6-Ctrl tumors', 'Disease', (15, 31))	('PAX6-Ctrl tumors', 'Disease', 'MESH:D015783', (15, 31))	('GLI', 'Gene', (114, 117))
47479	29980786	Thus, the chemotherapy-induced demethylation of the PAX6 promoter may expand LUAD CSCs via the activation of PAX6-GLI-SOX2 signaling.	('GLI', 'Gene', '2735', (114, 117))	('PAX6 promoter', 'Gene', (52, 65))	('activation', 'PosReg', (95, 105))	('expand', 'PosReg', (70, 76))	('SOX2', 'Gene', '6657', (118, 122))	('SOX2', 'Gene', (118, 122))	('demethylation', 'Var', (31, 44))	('LUAD CSCs', 'Disease', (77, 86))	('GLI', 'Gene', (114, 117))
47504	29980786	Here, we provide a rationale for targeting the PAX6-GLI-SOX2 signaling axis and support the clinical utility of PAX6 PM as a serum biomarker for early cancer detection.	('PAX6 PM', 'Var', (112, 119))	('SOX2', 'Gene', '6657', (56, 60))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('GLI', 'Gene', '2735', (52, 55))	('SOX2', 'Gene', (56, 60))	('cancer', 'Disease', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('GLI', 'Gene', (52, 55))
47515	29980786	Thus, PAX6 not only enhanced the key pluripotent factors but also repressed the differentiation lineage factors via SOX2, driving lung cancer cells toward a stem-like state in LUAD.	('lung cancer', 'Phenotype', 'HP:0100526', (130, 141))	('enhanced', 'PosReg', (20, 28))	('PAX6', 'Var', (6, 10))	('driving', 'PosReg', (122, 129))	('key pluripotent factors', 'MPA', (33, 56))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('lung cancer', 'Disease', 'MESH:D008175', (130, 141))	('SOX2', 'Gene', '6657', (116, 120))	('SOX2', 'Gene', (116, 120))	('lung cancer', 'Disease', (130, 141))
47520	29980786	Hh signaling is a stemness-related pathway tightly regulated during development, and its aberrant activation plays a critical role in maintaining CSCs in several cancer types .	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('CSCs', 'Disease', (146, 150))	('cancer', 'Disease', (162, 168))	('activation', 'PosReg', (98, 108))	('aberrant', 'Var', (89, 97))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))
47525	29980786	Thus, our findings suggest that PAX6 promotes the activation of the Hh signaling pathway in the noncanonical manner and subsequent SOX2 overexpression.	('SOX2', 'Gene', (131, 135))	('overexpression', 'PosReg', (136, 150))	('activation', 'PosReg', (50, 60))	('SOX2', 'Gene', '6657', (131, 135))	('Hh signaling pathway', 'Pathway', (68, 88))	('PAX6', 'Var', (32, 36))
47526	29980786	Therapeutically, the blockade of the PAX6-GLI-SOX2 signaling axis elicits a long-lasting therapeutic efficacy by limiting CSC expansion following chemotherapy, indicating these transcription factors are promising target molecules for LUAD CSCs.	('GLI', 'Gene', '2735', (42, 45))	('SOX2', 'Gene', '6657', (46, 50))	('SOX2', 'Gene', (46, 50))	('blockade', 'Var', (21, 29))	('CSC expansion', 'CPA', (122, 135))	('limiting', 'NegReg', (113, 121))	('GLI', 'Gene', (42, 45))
47533	29980786	Our combination panel of three homeobox genes (PAX6, HOXA9, and UNCX) showed comparable sensitivity (79.1% vs. 71.1%) and superior specificity (83.3% vs. 62.7%) in serum samples from stage IA LUAD compared with the CT screening cohort .	('stage', 'Disease', (183, 188))	('PAX6', 'Var', (47, 51))	('UNCX', 'Gene', '340260', (64, 68))	('HOXA9', 'Gene', '3205', (53, 58))	('UNCX', 'Gene', (64, 68))	('HOXA9', 'Gene', (53, 58))
47536	29980786	In summary, we demonstrate that PAX6 drives cancer cells toward a stem-like state via the GLI-SOX2 signaling axis and the blockade of this axis suppresses CSC expansion following chemotherapy in LUAD.	('CSC expansion', 'CPA', (155, 168))	('GLI', 'Gene', '2735', (90, 93))	('SOX2', 'Gene', (94, 98))	('blockade', 'Var', (122, 130))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('SOX2', 'Gene', '6657', (94, 98))	('suppresses', 'NegReg', (144, 154))	('PAX6', 'Gene', (32, 36))	('GLI', 'Gene', (90, 93))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
47538	29980786	Our findings provide a clinical rationale for targeting the PAX6-GLI-SOX2 signaling axis and demonstrate the clinical utility of PAX6 PM as a biomarker for early cancer detection.	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('SOX2', 'Gene', (69, 73))	('SOX2', 'Gene', '6657', (69, 73))	('cancer', 'Disease', (162, 168))	('PAX6 PM', 'Var', (129, 136))	('GLI', 'Gene', '2735', (65, 68))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('GLI', 'Gene', (65, 68))
47563	29980786	SOX2 shRNA pGFP-C-shLenti Vector (Cat # TL309173) for SOX2 knockdown (SOX2-sh) and Non-effective 29-mer scrambled shRNA pGFP-C-shLenti Vector (Cat # TR30021) for a control (SOX2-Ctrl) were purchased from Origene (Rockville, USA).	('SOX2', 'Gene', '6657', (0, 4))	('SOX2', 'Gene', '6657', (70, 74))	('SOX2', 'Gene', (70, 74))	('SOX2', 'Gene', '6657', (54, 58))	('SOX2', 'Gene', (173, 177))	('SOX2', 'Gene', (54, 58))	('SOX2', 'Gene', '6657', (173, 177))	('knockdown', 'Var', (59, 68))	('SOX2', 'Gene', (0, 4))
47646	28166815	In line with this assumption, ESR2-positive oropharyngeal squamous cell carcinoma (OPSCC) with high SMR3A expression had an unfavorable progression-free and disease-specific survival as compared to those tumors with low SMR3A expression.	('OPSCC', 'Phenotype', 'HP:0012182', (83, 88))	('tumors', 'Disease', 'MESH:D009369', (204, 210))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('oropharyngeal squamous cell carcinoma', 'Phenotype', 'HP:0012182', (44, 81))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('high', 'Var', (95, 99))	('disease-specific', 'CPA', (157, 173))	('SMR3A', 'Gene', (220, 225))	('tumors', 'Disease', (204, 210))	('SMR3A', 'Gene', (100, 105))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (58, 81))	('ESR2-positive oropharyngeal squamous cell carcinoma', 'Disease', 'MESH:D002294', (30, 81))	('tumors', 'Phenotype', 'HP:0002664', (204, 210))	('SMR3A', 'Gene', '26952', (100, 105))	('SMR3A', 'Gene', '26952', (220, 225))
47717	28166815	However, patients with ESR2pos tumors had a significantly shorter PFS and DSS in the presence of high SMR3A expression, similar to the ESR2neg subgroup, while ESR2posSMR3Alow tumors exhibited the most favorable clinical outcome (Fig.	('tumors', 'Disease', (175, 181))	('ESR2pos tumors', 'Disease', 'MESH:D009369', (23, 37))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('ESR2', 'Gene', '2100', (159, 163))	('ESR2', 'Gene', '2100', (135, 139))	('SMR3A', 'Gene', (166, 171))	('ESR2', 'Gene', '2100', (23, 27))	('ESR2', 'Gene', (159, 163))	('shorter', 'NegReg', (58, 65))	('tumors', 'Disease', 'MESH:D009369', (175, 181))	('ESR2', 'Gene', (135, 139))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumors', 'Disease', (31, 37))	('SMR3A', 'Gene', (102, 107))	('DSS', 'Gene', (74, 77))	('PFS', 'MPA', (66, 69))	('ESR2', 'Gene', (23, 27))	('ESR2pos tumors', 'Disease', (23, 37))	('SMR3A', 'Gene', '26952', (166, 171))	('DSS', 'Gene', '5376', (74, 77))	('tumors', 'Disease', 'MESH:D009369', (31, 37))	('SMR3A', 'Gene', '26952', (102, 107))	('patients', 'Species', '9606', (9, 17))	('tumors', 'Phenotype', 'HP:0002664', (175, 181))	('expression', 'MPA', (108, 118))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('high', 'Var', (97, 101))
47722	28166815	Although ectopic SMR3A expression had no significant impact on tumor-relevant processes under normal growth conditions in vitro, presented data provide compelling experimental evidence that it might serve as a surrogate marker for a subpopulation of resistant cells as a putative source for tumor relapse after radiotherapy.	('tumor', 'Disease', (63, 68))	('ectopic', 'Var', (9, 16))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('tumor', 'Disease', 'MESH:D009369', (291, 296))	('tumor', 'Phenotype', 'HP:0002664', (291, 296))	('SMR3A', 'Gene', (17, 22))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('SMR3A', 'Gene', '26952', (17, 22))	('tumor', 'Disease', (291, 296))
47723	28166815	In line with this assumption, a previous retrospective study unraveled high SMR3A expression as a risk factor for unfavorable progression-free and overall survival in a cohort of OPSCC patients.	('high', 'Var', (71, 75))	('expression', 'MPA', (82, 92))	('OPSCC', 'Disease', (179, 184))	('SMR3A', 'Gene', '26952', (76, 81))	('patients', 'Species', '9606', (185, 193))	('SMR3A', 'Gene', (76, 81))	('OPSCC', 'Phenotype', 'HP:0012182', (179, 184))
47725	28166815	This assumption is further supported by recent reports demonstrating that the presence of ESR2 modulates response to several therapeutic agents in breast and lung cancer cells.	('response to several therapeutic agents', 'MPA', (105, 143))	('ESR2', 'Gene', (90, 94))	('lung cancer', 'Phenotype', 'HP:0100526', (158, 169))	('breast and lung cancer', 'Disease', 'MESH:D001943', (147, 169))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('ESR2', 'Gene', '2100', (90, 94))	('presence', 'Var', (78, 86))	('modulates', 'Reg', (95, 104))
47740	28166815	In summary, our data suggest that HNSC'C with a combined ESR2 and SMR3A expression are at a higher risk for treatment failure upon radiotherapy, but might benefit from treatment with TAM or Fulvestrant, two clinically well-established inhibitors targeting estrogen receptor signaling.	('TAM', 'Chemical', '-', (183, 186))	("HNSC'C", 'Disease', (34, 40))	('estrogen receptor', 'Gene', '2099', (256, 273))	('SMR3A', 'Gene', '26952', (66, 71))	('Fulvestrant', 'Chemical', 'MESH:D000077267', (190, 201))	("HNSC'C", 'Disease', 'MESH:C537418', (34, 40))	('ESR2', 'Gene', (57, 61))	('treatment failure', 'Disease', 'MESH:D016609', (108, 125))	('treatment failure', 'Disease', (108, 125))	('SMR3A', 'Gene', (66, 71))	('ESR2', 'Gene', '2100', (57, 61))	('expression', 'Var', (72, 82))	('estrogen receptor', 'Gene', (256, 273))
47776	27162546	The primary antibodies included: Angiogenin (Sc-74528, Santa cruz), HMGA2 (ab52039, Abcam) and Lamin B2 (ab151735, Abcam).	('Angiogenin', 'Gene', '283', (33, 43))	('Angiogenin', 'Gene', (33, 43))	('Lamin B2', 'Gene', (95, 103))	('Sc-74528', 'Var', (45, 53))	('Lamin B2', 'Gene', '84823', (95, 103))	('ab151735', 'Var', (105, 113))
47807	27162546	Results showed that Ad-ANG SK-MES-1s presented not only significantly increased migration but also invasion capability (Figure 2, B, C, E, and F), as compared with the Ad-GFP cells.	('SK-MES-1s', 'Var', (27, 36))	('increased', 'PosReg', (70, 79))	('migration', 'CPA', (80, 89))	('invasion capability', 'CPA', (99, 118))	('ANG', 'Gene', (23, 26))	('ANG', 'Gene', '283', (23, 26))	('SK-MES-1', 'CellLine', 'CVCL:0630', (27, 35))
47839	27162546	However, knocking down of HMGA2 did not enhance the apoptotic rate in Ad-ANG SK-MES-1 cells (Figure 6, H).	('ANG', 'Gene', '283', (73, 76))	('ANG', 'Gene', (73, 76))	('knocking down', 'Var', (9, 22))	('apoptotic', 'CPA', (52, 61))	('HMGA2', 'Gene', (26, 31))	('SK-MES-1', 'CellLine', 'CVCL:0630', (77, 85))
47857	27162546	To extend our clinical studies and investigate its biological function, we employed adenovirus to over-express ANG and siRNA to knockdown ANG expression in SQCLC cell line SK-MES-1, which thus suggested that knockdowning of ANG could become a negative factor for expression of HMGA2.	('over-express', 'PosReg', (98, 110))	('ANG', 'Gene', (138, 141))	('ANG', 'Gene', (224, 227))	('ANG', 'Gene', '283', (111, 114))	('knockdown', 'Var', (128, 137))	('ANG', 'Gene', '283', (224, 227))	('ANG', 'Gene', (111, 114))	('SK-MES-1', 'CellLine', 'CVCL:0630', (172, 180))	('ANG', 'Gene', '283', (138, 141))
47859	27162546	But when over-expressed ANG along with silencing HMGA2, the ability of cells could weaken.	('ANG', 'Gene', (24, 27))	('silencing', 'Var', (39, 48))	('weaken', 'NegReg', (83, 89))	('HMGA2', 'Gene', (49, 54))	('ANG', 'Gene', '283', (24, 27))
47870	24520074	Inhibition of angiogenesis by neutralization of VEGF is effective at reducing progression of certain tumors despite having little effect on most tumor cells.	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('VEGF', 'Gene', (48, 52))	('tumors', 'Disease', 'MESH:D009369', (101, 107))	('progression', 'CPA', (78, 89))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('reducing', 'NegReg', (69, 77))	('neutralization', 'Var', (30, 44))	('tumor', 'Disease', (145, 150))	('VEGF', 'Gene', '22339', (48, 52))	('angiogenesis', 'CPA', (14, 26))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('tumors', 'Disease', (101, 107))
47942	24520074	We sorted WT and Gfi1-null CD11b+Ly6C+Ly6G- cells from LLC1 tumor cell suspensions to measure expression levels of Notch1, Notch4, Dll4, Hey1 and Hey2 (Figure S3A).	('Hey1', 'Gene', (137, 141))	('Hey2', 'Gene', (146, 150))	('Dll4', 'Gene', (131, 135))	('Dll4', 'Gene', '54485', (131, 135))	('Notch1', 'Var', (115, 121))	('Ly6G', 'Gene', '546644', (38, 42))	('LLC1 tumor', 'Disease', 'MESH:D009369', (55, 65))	('Notch4', 'Var', (123, 129))	('expression levels', 'MPA', (94, 111))	('Ly6C', 'Gene', (33, 37))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('LLC1 tumor', 'Disease', (55, 65))	('Ly6C', 'Gene', '17067', (33, 37))	('Ly6G', 'Gene', (38, 42))
47948	24520074	By contrast, Dll4 did not induce Hey1 and Hey2 expression in EL4 cells, which express Notch1 and Notch4 at considerably lower levels than LLC1 cells (Figure 3E).	('Notch1', 'Var', (86, 92))	('EL4', 'Gene', (61, 64))	('EL4', 'Gene', '111979', (61, 64))	('Dll4', 'Gene', '54485', (13, 17))	('Dll4', 'Gene', (13, 17))	('LLC1', 'Gene', '128602', (138, 142))	('Notch4', 'Var', (97, 103))	('LLC1', 'Gene', (138, 142))
47996	24520074	Such functional change is attributed to inactivating mutations of TGF-BetaR2 and SMAD4 preventing TGF-beta tumor-suppressive signaling in gastrointestinal and pancreatic tumors.	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('preventing', 'NegReg', (87, 97))	('TGF-BetaR2', 'Gene', (66, 76))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('SMAD4', 'Gene', (81, 86))	('tumor', 'Disease', (170, 175))	('tumors', 'Phenotype', 'HP:0002664', (170, 176))	('gastrointestinal and pancreatic tumors', 'Disease', 'MESH:D004067', (138, 176))	('pancreatic tumors', 'Phenotype', 'HP:0002894', (159, 176))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('inactivating mutations', 'Var', (40, 62))	('SMAD4', 'Gene', '17128', (81, 86))
48007	24520074	Recent reports and the current work show that Notch activity is a contributor to progression of some cancers, albeit not all cancers.	('cancers', 'Disease', 'MESH:D009369', (125, 132))	('cancers', 'Phenotype', 'HP:0002664', (125, 132))	('cancers', 'Disease', 'MESH:D009369', (101, 108))	('cancers', 'Phenotype', 'HP:0002664', (101, 108))	('cancers', 'Disease', (125, 132))	('Notch', 'Var', (46, 51))	('cancers', 'Disease', (101, 108))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))
48020	24741319	The expression of two miRNAs (miR-21-3p and miR-106b-3p) was upregulated in both microarray and quantitative real-time polymerase chain-reaction analyses, whereas the expression of six miRNAs (let-7f-5p, miR-10a-5p, miR-125a-5p, miR-144-3p, miR-195-5p, and miR-203) was downregulated.	('miR', 'Gene', '220972', (44, 47))	('miR', 'Gene', (30, 33))	('upregulated', 'PosReg', (61, 72))	('miR-195', 'Gene', '406971', (241, 248))	('miR', 'Gene', '220972', (241, 244))	('expression', 'MPA', (4, 14))	('miR-10a', 'Gene', '406902', (204, 211))	('miR', 'Gene', '220972', (257, 260))	('miR-203', 'Gene', (257, 264))	('expression', 'MPA', (167, 177))	('miR', 'Gene', (204, 207))	('miR', 'Gene', (44, 47))	('miR-195', 'Gene', (241, 248))	('let-7f-5p', 'Var', (193, 202))	('miR', 'Gene', (257, 260))	('miR', 'Gene', '220972', (216, 219))	('miR', 'Gene', (241, 244))	('miR-21-3p', 'Gene', '406995', (30, 39))	('miR', 'Gene', '220972', (185, 188))	('miR-203', 'Gene', '406986', (257, 264))	('miR', 'Gene', '220972', (204, 207))	('miR-10a', 'Gene', (204, 211))	('downregulated', 'NegReg', (270, 283))	('miR', 'Gene', (216, 219))	('miR', 'Gene', (185, 188))	('miR', 'Gene', '220972', (229, 232))	('miR', 'Gene', '220972', (30, 33))	('miR', 'Gene', '220972', (22, 25))	('miR-21-3p', 'Gene', (30, 39))	('miR', 'Gene', (22, 25))	('miR', 'Gene', (229, 232))
48032	24741319	The pathogenesis of laryngeal carcinoma is related to the activation of oncogenes, including BCL2 and c-MYC, and the inactivation of tumor-suppressor genes, including p53 and RB.	('tumor-suppressor', 'Gene', '7248', (133, 149))	('BCL2', 'Gene', '596', (93, 97))	('c-MYC', 'Gene', '4609', (102, 107))	('oncogenes', 'Gene', (72, 81))	('inactivation', 'Var', (117, 129))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('p53', 'Gene', '7157', (167, 170))	('laryngeal carcinoma', 'Disease', (20, 39))	('BCL2', 'Gene', (93, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (30, 39))	('tumor-suppressor', 'Gene', (133, 149))	('activation', 'PosReg', (58, 68))	('laryngeal carcinoma', 'Disease', 'MESH:D007827', (20, 39))	('laryngeal carcinoma', 'Phenotype', 'HP:0012118', (20, 39))	('c-MYC', 'Gene', (102, 107))	('p53', 'Gene', (167, 170))
48066	24741319	Eight miRNAs (miR-21-3p, miR-106b-3p, let-7f-5p, miR-10a-5p, miR-125a-5p, miR-144-3p, miR-195-5p, and miR-203) were validated with qRT-PCR.	('miR', 'Gene', (102, 105))	('miR', 'Gene', '220972', (61, 64))	('miR', 'Gene', (6, 9))	('miR-21-3p', 'Gene', '406995', (14, 23))	('miR-203', 'Gene', '406986', (102, 109))	('miR', 'Gene', (14, 17))	('miR', 'Gene', '220972', (74, 77))	('miR', 'Gene', (61, 64))	('miR', 'Gene', '220972', (25, 28))	('miR', 'Gene', '220972', (49, 52))	('miR-10a', 'Gene', '406902', (49, 56))	('miR', 'Gene', (74, 77))	('miR-195', 'Gene', '406971', (86, 93))	('miR', 'Gene', '220972', (86, 89))	('miR', 'Gene', (25, 28))	('let-7f-5p', 'Var', (38, 47))	('miR', 'Gene', (49, 52))	('miR-21-3p', 'Gene', (14, 23))	('miR', 'Gene', '220972', (102, 105))	('miR-195', 'Gene', (86, 93))	('miR', 'Gene', (86, 89))	('miR', 'Gene', '220972', (6, 9))	('miR-10a', 'Gene', (49, 56))	('miR', 'Gene', '220972', (14, 17))	('miR-203', 'Gene', (102, 109))
48071	24741319	miR-21-3p and miR-106b-3p were upregulated, and let-7f-5p, miR-10a-5p, miR-125a-5p, miR-144-3p, miR-195-5p, and miR-203 were downregulated in the microarray and qRT-PCR analyses.	('miR', 'Gene', '220972', (84, 87))	('miR', 'Gene', '220972', (59, 62))	('miR', 'Gene', (14, 17))	('miR-10a', 'Gene', '406902', (59, 66))	('miR', 'Gene', (84, 87))	('miR-195', 'Gene', '406971', (96, 103))	('miR', 'Gene', (59, 62))	('miR', 'Gene', '220972', (96, 99))	('miR-21-3p', 'Gene', (0, 9))	('let-7f-5p', 'Var', (48, 57))	('miR', 'Gene', '220972', (71, 74))	('miR-195', 'Gene', (96, 103))	('miR', 'Gene', '220972', (112, 115))	('miR-203', 'Gene', (112, 119))	('miR', 'Gene', '220972', (0, 3))	('miR', 'Gene', (96, 99))	('miR-10a', 'Gene', (59, 66))	('downregulated', 'NegReg', (125, 138))	('miR', 'Gene', (71, 74))	('miR', 'Gene', (112, 115))	('miR-21-3p', 'Gene', '406995', (0, 9))	('miR', 'Gene', (0, 3))	('upregulated', 'PosReg', (31, 42))	('miR-203', 'Gene', '406986', (112, 119))	('miR', 'Gene', '220972', (14, 17))
48086	24741319	In addition, miRNAs not previously reported or inconsistent with previous head and neck squamous cell carcinoma or laryngeal carcinoma studies were also identified, and included let-7f-5p and miR-195-5p.	('laryngeal carcinoma', 'Disease', (115, 134))	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('laryngeal carcinoma', 'Phenotype', 'HP:0012118', (115, 134))	('miR', 'Gene', '220972', (13, 16))	('miR', 'Gene', (13, 16))	('miR', 'Gene', '220972', (192, 195))	('miR', 'Gene', (192, 195))	('laryngeal carcinoma', 'Disease', 'MESH:D007827', (115, 134))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (74, 111))	('neck squamous cell carcinoma', 'Disease', (83, 111))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (88, 111))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (83, 111))	('let-7f-5p', 'Var', (178, 187))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('miR-195', 'Gene', (192, 199))	('miR-195', 'Gene', '406971', (192, 199))
48116	33953163	For example, the KRAS G12C inhibitors seemed to induce tumor responses in the majority of lung cancers but much less in pancreatic cancers, which differ in their tumor micromilieu dominated by cancer-associated fibroblasts.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('cancers', 'Phenotype', 'HP:0002664', (131, 138))	('cancer', 'Disease', (193, 199))	('tumor', 'Disease', (162, 167))	('pancreatic cancers', 'Disease', 'MESH:D010190', (120, 138))	('lung cancer', 'Phenotype', 'HP:0100526', (90, 101))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('KRAS', 'Gene', '3845', (17, 21))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('lung cancers', 'Disease', 'MESH:D008175', (90, 102))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('cancers', 'Phenotype', 'HP:0002664', (95, 102))	('induce', 'PosReg', (48, 54))	('cancer', 'Disease', (95, 101))	('lung cancers', 'Disease', (90, 102))	('KRAS', 'Gene', (17, 21))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('G12C', 'Mutation', 'rs121913530', (22, 26))	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('lung cancers', 'Phenotype', 'HP:0100526', (90, 102))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (120, 138))	('cancer', 'Disease', (131, 137))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('pancreatic cancers', 'Disease', (120, 138))	('tumor', 'Disease', (55, 60))	('inhibitors', 'Var', (27, 37))
48132	33953163	We identify distinct cell populations and cellular signals that are differentially enriched in tumors depending on the pathological types, presence or absence of driver mutations, and degree of tumor heterogeneity.	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('mutations', 'Var', (169, 178))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Disease', (194, 199))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumors', 'Disease', (95, 101))	('tumor', 'Disease', (95, 100))
48139	33953163	Next, we used the scRNA-seq data to infer copy number alterations (CNAs) in cancer cell populations.	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('copy number alterations', 'Var', (42, 65))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))
48141	33953163	For LUAD patients, prominent arm-level insertions were found in chromosome 7 and 8q, with deletions in chromosome 10.	('insertions', 'Var', (39, 49))	('patients', 'Species', '9606', (9, 17))	('deletions', 'Var', (90, 99))	('LUAD', 'Phenotype', 'HP:0030078', (4, 8))
48142	33953163	In contrast, LUSC patients mostly have 3q insertions and 5q deletions.	('LUSC', 'Disease', (13, 17))	('LUSC', 'Phenotype', 'HP:0030359', (13, 17))	('patients', 'Species', '9606', (18, 26))	('3q insertions', 'Var', (39, 52))
48147	33953163	Most patients, especially patients with LUAD e.g., P16, P20, and P32, had dominant clones, while in a few LUSC such as P27 and P37 the malignant cells spread across multiple clusters (Fig.	('patients', 'Species', '9606', (5, 13))	('P16', 'Var', (51, 54))	('P20', 'Var', (56, 59))	('P32', 'Var', (65, 68))	('patients', 'Species', '9606', (26, 34))	('LUAD', 'Phenotype', 'HP:0030078', (40, 44))	('LUSC', 'Phenotype', 'HP:0030359', (106, 110))
48233	33953163	Reverse transcription PCR (RT-PCR) was performed for testing of EGFR mutation, KRAS mutation, ALK fusion, ROS1 fusion, RET fusion, HER2 mutation, BRAF mutation, and MET exon14 skipping for all adenocarcinoma, some squamous carcinoma and some NSCLC patients.	('MET', 'Gene', '79811', (165, 168))	('adenocarcinoma', 'Disease', 'MESH:D000230', (193, 207))	('RET', 'Gene', '5979', (119, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (223, 232))	('ROS1', 'Gene', '6098', (106, 110))	('HER2', 'Gene', (131, 135))	('carcinoma', 'Phenotype', 'HP:0030731', (198, 207))	('EGFR', 'Gene', (64, 68))	('NSCLC', 'Disease', 'MESH:D002289', (242, 247))	('squamous carcinoma', 'Disease', (214, 232))	('RET', 'Gene', (119, 122))	('KRAS', 'Gene', '3845', (79, 83))	('mutation', 'Var', (136, 144))	('MET', 'Gene', (165, 168))	('NSCLC', 'Disease', (242, 247))	('patients', 'Species', '9606', (248, 256))	('BRAF', 'Gene', '673', (146, 150))	('adenocarcinoma', 'Disease', (193, 207))	('KRAS', 'Gene', (79, 83))	('ROS1', 'Gene', (106, 110))	('BRAF', 'Gene', (146, 150))	('ALK', 'Gene', '238', (94, 97))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (214, 232))	('NSCLC', 'Phenotype', 'HP:0030358', (242, 247))	('HER2', 'Gene', '2064', (131, 135))	('mutation', 'Var', (69, 77))	('EGFR', 'Gene', '1956', (64, 68))	('ALK', 'Gene', (94, 97))	('squamous carcinoma', 'Disease', 'MESH:D002294', (214, 232))	('mutation', 'Var', (84, 92))
48292	32400056	3  The mutation burden in lung adenocarcinoma has been reported to be lower in driver-gene-alteration-positive cases than in pan-negative driver gene cases.	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (26, 45))	('driver-gene-alteration-positive', 'Var', (79, 110))	('lower', 'NegReg', (70, 75))	('carcinoma', 'Phenotype', 'HP:0030731', (36, 45))	('lung adenocarcinoma', 'Disease', (26, 45))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (26, 45))	('mutation burden', 'MPA', (7, 22))
48306	32400056	14 ,  15 ,  16   It is unclear which IME factors, if any, quantified by digital pathology in surgical samples by means of a machine learning algorithm, are associated with mutation burden.	('IME', 'Chemical', '-', (37, 40))	('mutation burden', 'Var', (172, 187))	('associated', 'Reg', (156, 166))
48345	32400056	WES and variant calling were performed using an Ion Proton AmpliSeq Exome kit and Ion Torrent server as previously reported.	('variant', 'Var', (8, 15))	('kit', 'Gene', (74, 77))	('kit', 'Gene', '3815', (74, 77))
48348	32400056	The SNVs of the total exonic mutations for each sequenced tumor included nonsynonymous, synonymous, and indel/frameshift mutations.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('synonymous', 'Var', (88, 98))	('indel/frameshift mutations', 'Var', (104, 130))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('nonsynonymous', 'Var', (73, 86))
48361	32400056	Six patients (2.4%) had both EML4-ALK gene rearrangements and BRAF mutations, and 61 patients (31%) had mutations that conferred sensitivity to EGFR tyrosine kinase inhibitor.	('ALK', 'Gene', '238', (34, 37))	('EML4', 'Gene', '27436', (29, 33))	('sensitivity', 'MPA', (129, 140))	('mutations', 'Var', (104, 113))	('men', 'Species', '9606', (52, 55))	('mutations', 'Var', (67, 76))	('patients', 'Species', '9606', (85, 93))	('ALK', 'Gene', (34, 37))	('patients', 'Species', '9606', (4, 12))	('BRAF', 'Gene', '673', (62, 66))	('EML4', 'Gene', (29, 33))	('BRAF', 'Gene', (62, 66))	('rearrangements', 'Var', (43, 57))
48362	32400056	The median serum CEA level (range) was 3.4 (0.5-144.3) ng/mL, median serum CYFRA 21-1 level (range) 1.2 (1-38) ng/mL, median exonic mutation burden (range) 2.19 mt/Mb (0.1-64.3), and median tumor purity 27.2% (20-99.9).	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('exonic mutation', 'Var', (125, 140))	('tumor', 'Disease', (190, 195))	('CEA', 'Gene', (17, 20))	('CEA', 'Gene', '1084', (17, 20))
48372	32400056	The exonic mutation burden was significantly higher in men (median: 3.3/Mb, range: 0.2-64.3, P < .0001, Wilcoxon test), patients with squamous histology (median: 5.1, range: 0.6-18.4, P < .0001), smokers (median: 3.2, range: 0.2-64.3, P < .0001), patients without an actionable mutation (median: 3.3, range: 0.1-50.4, P = .0001), patients with a serum CEA level above 5 ng/mL (median: 4.0, range: 0.3-50.4, P < .0001), and patients with a serum CYFRA21-1 level above 3.5 ng/mL(median: 4.0, range: 0.6-50.4, P = .0005).	('men', 'Species', '9606', (55, 58))	('CEA', 'Gene', (352, 355))	('exonic mutation', 'Var', (4, 19))	('CEA', 'Gene', '1084', (352, 355))	('patients', 'Species', '9606', (247, 255))	('patients', 'Species', '9606', (120, 128))	('patients', 'Species', '9606', (330, 338))	('higher', 'PosReg', (45, 51))	('patients', 'Species', '9606', (423, 431))
48373	32400056	In a previous study, lung squamous cell carcinomas were found to have a higher mutation burden than lung adenocarcinomas, 23  and the results of the present study are consistent with that finding (median value 5.1 mutations/Mb vs 1.6 mutations/Mb, P < .0001; Wilcoxon's test).	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (21, 49))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (100, 120))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (100, 120))	('lung squamous cell carcinomas', 'Disease', 'MESH:D002294', (21, 50))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (26, 50))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('carcinomas', 'Phenotype', 'HP:0030731', (110, 120))	('mutations/Mb', 'Var', (214, 226))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (26, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (40, 49))	('carcinomas', 'Phenotype', 'HP:0030731', (40, 50))	('lung squamous cell carcinomas', 'Disease', (21, 50))	('lung adenocarcinomas', 'Disease', (100, 120))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (100, 119))	('mutation burden', 'MPA', (79, 94))
48374	32400056	Interestingly, the range of mutation burdens in the adenocarcinomas (0.1-64.4 mutations/Mb) was wider than that in the squamous cell carcinomas (0.6-18.4 mutations/Mb).	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (119, 143))	('carcinomas', 'Phenotype', 'HP:0030731', (133, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (57, 66))	('mutations/Mb', 'Var', (78, 90))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('adenocarcinomas', 'Disease', 'MESH:D000230', (52, 67))	('carcinomas', 'Phenotype', 'HP:0030731', (57, 67))	('adenocarcinomas', 'Disease', (52, 67))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (119, 142))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (119, 143))	('squamous cell carcinomas', 'Disease', (119, 143))
48380	32400056	The clinical variables identified as being associated with exonic mutation burden in the univariate linear regression were: male gender (P < .001), smoker status (P < .001), PET SUV-max (P < .001), actionable mutation (P = .004), squamous histology (P < .001), elevated CEA level (P < .001), and elevated CYFRA 21-1 level (P <.001) (Table 1).	('actionable mutation', 'Var', (198, 217))	('squamous', 'Disease', (230, 238))	('CYFRA 21-1 level', 'MPA', (305, 321))	('CEA', 'Gene', (270, 273))	('CEA', 'Gene', '1084', (270, 273))	('elevated', 'PosReg', (261, 269))	('exonic mutation burden', 'Var', (59, 81))	('elevated', 'PosReg', (296, 304))	('elevated CEA', 'Phenotype', 'HP:0031029', (261, 273))
48387	32400056	Several clinical factors were shown to be confounders that influenced the association between actionable mutations and mutation burden, whereas smoking status, PET SUV-max, and elevated CEA level were found to be independently and significantly associated with mutation burden in patients with resected NSCLC.	('NSCLC', 'Phenotype', 'HP:0030358', (303, 308))	('patients', 'Species', '9606', (280, 288))	('mutation', 'MPA', (119, 127))	('NSCLC', 'Disease', (303, 308))	('CEA', 'Gene', (186, 189))	('mutations', 'Var', (105, 114))	('associated', 'Reg', (245, 255))	('CEA', 'Gene', '1084', (186, 189))	('NSCLC', 'Disease', 'MESH:D002289', (303, 308))	('elevated CEA', 'Phenotype', 'HP:0031029', (177, 189))	('association', 'Interaction', (74, 85))	('influenced', 'Reg', (59, 69))
48389	32400056	In evaluations of TMB, the total number of mutations identified using a targeted NGS has been shown to be strongly correlated with the total exome mutation number.	('mutations', 'Var', (43, 52))	('TMB', 'Chemical', '-', (18, 21))	('correlated', 'Reg', (115, 125))
48390	32400056	24 ,  25  However, WES remains a proven method for analyzing genetic alterations in adequate specimens of NSCLC.	('NSCLC', 'Disease', 'MESH:D002289', (106, 111))	('genetic alterations', 'Var', (61, 80))	('NSCLC', 'Phenotype', 'HP:0030358', (106, 111))	('men', 'Species', '9606', (98, 101))	('NSCLC', 'Disease', (106, 111))
48405	32400056	23  An East-Asian study, however, reported a median of 25 mutations in lung adenocarcinoma patients who had undergone resections.	('mutations', 'Var', (58, 67))	('patients', 'Species', '9606', (91, 99))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (71, 90))	('lung adenocarcinoma', 'Disease', (71, 90))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (71, 90))
48432	32400056	We propose to conduct a prospective study to evaluate the IME factors quantitatively and predict the genotype (ie, the presence or absence of other actionable mutations) from the phenotype (ie, histological observations) using deep learning algorithms based on training and validation test sets.	('IME', 'Chemical', '-', (58, 61))	('mutations', 'Var', (159, 168))	('deep learning algorithms', 'Disease', (227, 251))	('deep learning algorithms', 'Disease', 'MESH:D007859', (227, 251))
48580	25344376	Because high HSPA2 expression was associated with negative prognosis in esophageal SCC, non-small cell lung cancer (NSCLC), and liver hepatocellular cancer (HCC) patients (Zhang et al.	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (88, 114))	('SCC', 'Gene', '6317', (83, 86))	('NSCLC', 'Disease', 'MESH:D002289', (116, 121))	('expression', 'MPA', (19, 29))	('high', 'Var', (8, 12))	('SCC', 'Gene', (83, 86))	('non-small cell lung cancer', 'Disease', (88, 114))	('HCC', 'Disease', (157, 160))	('HCC', 'Phenotype', 'HP:0001402', (157, 160))	('hepatocellular cancer', 'Phenotype', 'HP:0001402', (134, 155))	('NSCLC', 'Disease', (116, 121))	('patients', 'Species', '9606', (162, 170))	('liver hepatocellular cancer', 'Disease', (128, 155))	('NSCLC', 'Phenotype', 'HP:0030358', (116, 121))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('lung cancer', 'Phenotype', 'HP:0100526', (103, 114))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (88, 114))	('HCC', 'Disease', 'MESH:D006528', (157, 160))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (92, 114))	('liver hepatocellular cancer', 'Disease', 'MESH:D006528', (128, 155))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('SCC', 'Phenotype', 'HP:0002860', (83, 86))	('HSPA2', 'Protein', (13, 18))
48596	25344376	Within this region, we identified two short stretches which we termed box A (nt -346 to -325) and box B (nt -260 to -235) sharing the highest degree of nucleotide sequence homology between the mouse and rat genes.	('nt -260 to -235', 'Var', (105, 120))	('mouse', 'Species', '10090', (193, 198))	('rat', 'Species', '10116', (203, 206))	('nt -346 to -325', 'Var', (77, 92))
48607	25344376	Aberrant expression of HuR protein (either deficiency or overexpression) in mice testis led to defective spermatogenesis manifested by massive death of spermatocytes (Chi et al.).	('death', 'NegReg', (143, 148))	('overexpression', 'PosReg', (57, 71))	('Aberrant', 'Var', (0, 8))	('HuR protein', 'Protein', (23, 34))	('defective', 'NegReg', (95, 104))	('mice', 'Species', '10090', (76, 80))	('defective spermatogenesis', 'Phenotype', 'HP:0008669', (95, 120))	('spermatogenesis', 'CPA', (105, 120))
48613	25344376	Such a Bat3-dependent regulatory mechanism seems to exist because depletion of Bat3 was associated with decreased stability of HSPA2 in mouse embryonic fibroblasts (MEFs) and human teratocarcinoma cells (Sasaki et al.).	('human', 'Species', '9606', (175, 180))	('teratocarcinoma', 'Disease', 'MESH:D018243', (181, 196))	('teratocarcinoma', 'Disease', (181, 196))	('decreased', 'NegReg', (104, 113))	('MEFs', 'CellLine', 'CVCL:9115', (165, 169))	('Bat3', 'Gene', (79, 83))	('stability', 'MPA', (114, 123))	('depletion', 'Var', (66, 75))	('mouse', 'Species', '10090', (136, 141))	('HSPA2', 'Protein', (127, 132))
48615	25344376	Missense mutation in exon 36 of the mouse Eif4g3 gene causes a failure of spermatocytes to exit meiotic prophase.	('causes', 'Reg', (54, 60))	('Missense mutation in', 'Var', (0, 20))	('Eif4g3', 'Gene', (42, 48))	('failure', 'CPA', (63, 70))	('mouse', 'Species', '10090', (36, 41))
48616	25344376	Interestingly, the HSPA2 protein is absent from spermatocytes of Eif4g3 mutant mice in spite of the presence of Bat3 and normal levels of the HSPA2 mRNA (Sun et al.).	('HSPA2', 'Protein', (142, 147))	('levels', 'MPA', (128, 134))	('mutant', 'Var', (72, 78))	('mice', 'Species', '10090', (79, 83))	('Bat3', 'MPA', (112, 116))	('Eif4g3', 'Gene', (65, 71))	('absent', 'NegReg', (36, 42))	('HSPA2 protein', 'Protein', (19, 32))
48619	25344376	The accumulating evidence points to DNA methylation as one of the most important epigenetic mechanisms modulating the HSPA2 expression level in human cells.	('expression level', 'MPA', (124, 140))	('methylation', 'Var', (40, 51))	('human', 'Species', '9606', (144, 149))	('HSPA2', 'Protein', (118, 123))	('DNA', 'Var', (36, 39))
48620	25344376	HSPA2 gene methylation was detected in numerous breast, cervical, bladder, and renal cancer cell lines (Ye et al.	('HSPA2', 'Gene', (0, 5))	('renal cancer', 'Disease', (79, 91))	('breast', 'Disease', (48, 54))	('renal cancer', 'Phenotype', 'HP:0009726', (79, 91))	('renal cancer', 'Disease', 'MESH:D007680', (79, 91))	('methylation', 'Var', (11, 22))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('detected', 'Reg', (27, 35))
48623	25344376	The frequent cancer-specific hypermethylation of the gene was also detected in endometrial and invasive cervical cancers (Fiegl et al.	('endometrial', 'Disease', (79, 90))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('invasive cervical cancers', 'Disease', 'MESH:D002583', (95, 120))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('cancers', 'Phenotype', 'HP:0002664', (113, 120))	('cancer', 'Disease', (113, 119))	('cancer', 'Disease', (13, 19))	('hypermethylation', 'Var', (29, 45))	('detected', 'Reg', (67, 75))	('cancer', 'Disease', 'MESH:D009369', (13, 19))	('invasive cervical cancers', 'Disease', (95, 120))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
48624	25344376	Although the above-mentioned observations strongly suggest that epigenetic modification could be important for regulation of HSPA2 gene expression, there are some controversies regarding this issue.	('epigenetic modification', 'Var', (64, 87))	('expression', 'MPA', (136, 146))	('HSPA2', 'Gene', (125, 130))	('men', 'Species', '9606', (19, 22))
48625	25344376	While hypermethylation-related repression of the HSPA2 gene in primary bladder tumors has been reported (Costa et al.	('bladder tumors', 'Disease', 'MESH:D001749', (71, 85))	('HSPA2', 'Gene', (49, 54))	('bladder tumors', 'Phenotype', 'HP:0009725', (71, 85))	('bladder tumors', 'Disease', (71, 85))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('hypermethylation-related', 'Var', (6, 30))	('repression', 'NegReg', (31, 41))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
48634	25344376	Similarly, a marked reduction of the HSPA2 expression level occurred in parallel with rapid degeneration of seminiferous epithelium due to massive apoptosis of spermatocytes when the constitutively active mutant of HSF1 was overexpressed in testes of transgenic mice (Nakai et al.	('HSF1', 'Gene', (215, 219))	('overexpressed', 'PosReg', (224, 237))	('HSPA2', 'Protein', (37, 42))	('expression level', 'MPA', (43, 59))	('mutant', 'Var', (205, 211))	('degeneration of seminiferous epithelium', 'Disease', (92, 131))	('apoptosis', 'CPA', (147, 156))	('reduction', 'NegReg', (20, 29))	('transgenic mice', 'Species', '10090', (251, 266))	('degeneration of seminiferous epithelium', 'Disease', 'MESH:C536309', (92, 131))
48646	25344376	Profiling the expression of molecular markers specific for defined stages of spermatogenesis established that HSPA2 depletion severely impaired the late stages of spermatocyte development (Dix et al.).	('late stages of spermatocyte development', 'CPA', (148, 187))	('impaired', 'NegReg', (135, 143))	('men', 'Species', '9606', (183, 186))	('HSPA2', 'Protein', (110, 115))	('depletion', 'Var', (116, 125))
48657	25344376	Concomitant, massive hyperacetylation of chromatin is believed to destabilize its nucleosomal structure and to facilitate the replacement of testis-specific histones by transition proteins (TPs) and finally by other basic DNA-packaging proteins (Gaucher et al.).	('facilitate', 'PosReg', (111, 121))	('destabilize', 'NegReg', (66, 77))	('men', 'Species', '9606', (133, 136))	('replacement', 'MPA', (126, 137))	('nucleosomal', 'MPA', (82, 93))	('hyperacetylation', 'Var', (21, 37))
48666	25344376	Disruption of the Ppp1cc gene results in aberrant spermiogenesis manifested by abnormal chromatin packing (histone retention), increased germ cell apoptosis, and, consequently, deficiency of condensing and elongating spermatids (Varmuza et al.	('chromatin', 'MPA', (88, 97))	('deficiency', 'NegReg', (177, 187))	('germ cell apoptosis', 'CPA', (137, 156))	('spermiogenesis', 'CPA', (50, 64))	('Ppp1cc', 'Gene', (18, 24))	('Ppp1cc', 'Gene', '5501', (18, 24))	('aberrant spermiogenesis', 'Phenotype', 'HP:0008669', (41, 64))	('abnormal', 'Reg', (79, 87))	('increased', 'PosReg', (127, 136))	('Disruption', 'Var', (0, 10))
48667	25344376	Taking into account that PPP1CC2 can directly interact with HSPA2 and PPP1CC2 depletion leads to the accumulation of hyperphosphorylated HSPA2 in testis, it was proposed that the PPP1CC2-dependent modulation of HSPA2 structure/activity could contribute to chromatin remodeling during spermiogenesis in mouse (Henderson et al.).	('depletion', 'Var', (78, 87))	('contribute', 'Reg', (242, 252))	('hyperphosphorylated', 'MPA', (117, 136))	('interact', 'Interaction', (46, 54))	('mouse', 'Species', '10090', (302, 307))	('PPP1CC2-dependent', 'Var', (179, 196))	('accumulation', 'PosReg', (101, 113))	('PPP1CC2', 'Gene', (70, 77))
48681	25344376	have shown that sperm maturation is associated with rearrangements of HSPA2 localization from intracellular in non-capacitated sperm, to superficial in capacitated spermatozoa.	('HSPA2', 'Protein', (70, 75))	('rearrangements', 'Var', (52, 66))	('rat', 'Species', '10116', (26, 29))	('sperm maturation', 'CPA', (16, 32))	('localization', 'MPA', (76, 88))	('men', 'Species', '9606', (61, 64))
48702	25344376	reported that HSPA2 knockdown decreased migration of cancer cells.	('HSPA2', 'Gene', (14, 19))	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('rat', 'Species', '10116', (43, 46))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('knockdown', 'Var', (20, 29))	('decreased', 'NegReg', (30, 39))
48705	25344376	Because each study cited above exploited a different cancer cell line and different gene silencing strategies, it is evident that more systematic studies are needed in order to understand the cause of the variable effects of HSPA2 deficit on growth of cancer cells.	('cancer', 'Disease', 'MESH:D009369', (252, 258))	('rat', 'Species', '10116', (101, 104))	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('cancer', 'Disease', (252, 258))	('deficit', 'Var', (231, 238))	('HSPA2', 'Gene', (225, 230))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))
48715	25344376	While HSPA2-depleted cells acquired a senescent-like phenotype and were arrested in G1 of the cell cycle, silencing of the HSPA1 gene resulted in G2/M arrest and immediate entry of cells into apoptosis.	('HSPA1', 'Gene', (123, 128))	('G2/M arrest', 'CPA', (146, 157))	('senescent-like', 'CPA', (38, 52))	('silencing', 'Var', (106, 115))	('HSPA1', 'Gene', '3303', (123, 128))
48719	25344376	Although these results would indicate an involvement of HSPA2 in multiple processes during mouse embryogenesis, the deletion of the HSPA2 gene from mouse genome was not associated with reduced litter size, developmental abnormalities in newborn mice, or increased perinatal mortality as shown earlier by Dix et al., indicating that HSPA2 is dispensable for mouse embryo development.	('developmental abnormalities', 'Disease', 'MESH:D006130', (206, 233))	('involvement', 'Reg', (41, 52))	('men', 'Species', '9606', (48, 51))	('mouse', 'Species', '10090', (357, 362))	('mouse', 'Species', '10090', (148, 153))	('HSPA2', 'Gene', (132, 137))	('deletion', 'Var', (116, 124))	('developmental abnormalities', 'Phenotype', 'HP:0001263', (206, 233))	('mice', 'Species', '10090', (245, 249))	('developmental abnormalities', 'Disease', (206, 233))	('men', 'Species', '9606', (377, 380))	('men', 'Species', '9606', (213, 216))	('mouse', 'Species', '10090', (91, 96))	('reduced', 'NegReg', (185, 192))
48798	24959221	Secondly, impairment in the DNA repair proteins could lead to an increased susceptibility to radiation-induced carcinogenesis.	('carcinogenesis', 'Disease', (111, 125))	('lead', 'Reg', (54, 58))	('DNA repair proteins', 'Protein', (28, 47))	('impairment', 'Var', (10, 20))	('carcinogenesis', 'Disease', 'MESH:D063646', (111, 125))	('susceptibility to radiation', 'Phenotype', 'HP:0011133', (75, 102))	('radiation-induced', 'CPA', (93, 110))
48806	24959221	In a large study, patients with MFH of the extremities who underwent limb sparing surgery followed by radiation experienced a 10-year relapse-free survival rate of 62% and an overall survival rate of 80%, which was higher than that in earlier studies.	('relapse-free survival', 'CPA', (134, 155))	('patients', 'Species', '9606', (18, 26))	('MFH', 'Var', (32, 35))
48820	31815134	Furthermore, RNAi-mediated knockdown of genes in the flavoprotein signature led to decreased proliferation and migration of ESCC cells.	('knockdown', 'Var', (27, 36))	('proliferation', 'CPA', (93, 106))	('ESCC', 'Disease', 'MESH:C562729', (124, 128))	('decreased', 'NegReg', (83, 92))	('flavoprotein', 'Gene', (53, 65))	('N', 'Chemical', 'MESH:D009584', (14, 15))	('ESCC', 'Disease', (124, 128))
48842	31815134	A number of recent studies indicate that abnormal expression of flavoproteins and their interacting proteins lead to a variety of clinical abnormalities, which range from degenerative changes in the skin lesions, to the growth retardation, or nervous system and peripheral neuropathy; it also affects the proliferation and mobility of various cancer cells.	('skin lesions', 'Disease', (199, 211))	('lead to', 'Reg', (109, 116))	('cancer', 'Disease', (343, 349))	('growth retardation', 'Disease', 'MESH:D006130', (220, 238))	('peripheral neuropathy', 'Disease', (262, 283))	('growth retardation', 'Disease', (220, 238))	('peripheral neuropathy', 'Disease', 'MESH:D010523', (262, 283))	('cancer', 'Phenotype', 'HP:0002664', (343, 349))	('degenerative changes', 'Phenotype', 'HP:0002180', (171, 191))	('mobility', 'CPA', (323, 331))	('nervous system', 'Disease', (243, 257))	('peripheral neuropathy', 'Phenotype', 'HP:0009830', (262, 283))	('expression', 'Var', (50, 60))	('cancer', 'Disease', 'MESH:D009369', (343, 349))	('skin lesions', 'Disease', 'MESH:D012871', (199, 211))	('proliferation', 'CPA', (305, 318))	('growth retardation', 'Phenotype', 'HP:0001510', (220, 238))	('abnormal expression', 'Var', (41, 60))	('flavoproteins', 'Protein', (64, 77))	('affects', 'Reg', (293, 300))
48856	31815134	In brief, KYSE150 and KYSE510 esophageal carcinoma cells were grown in RPMI 1640 medium (Thermo Fisher Scientific) supplemented with 10% fetal bovine serum (GIBCO), penicillin-G (100 units/mL), and streptomycin (100 mug/mL).	('KYSE510', 'Var', (22, 29))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (30, 50))	('carcinoma', 'Phenotype', 'HP:0030731', (41, 50))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (30, 50))	('bovine', 'Species', '9913', (143, 149))	('KYSE510', 'CellLine', 'CVCL:1354', (22, 29))	('penicillin-G', 'Chemical', 'MESH:D010400', (165, 177))	('streptomycin', 'Chemical', 'MESH:D013307', (198, 210))	('esophageal carcinoma', 'Disease', (30, 50))
48887	31815134	Figure 2(a) shows that the relative mRNA expression of the flavoprotein signature in KYSE150 cells and KYSE510 cells in the si-flavoprotein signature group was lower than the si-negative control (NC) group (P < 0.01).	('KYSE510', 'CellLine', 'CVCL:1354', (103, 110))	('mRNA expression', 'MPA', (36, 51))	('si-flavoprotein', 'Var', (124, 139))	('N', 'Chemical', 'MESH:D009584', (196, 197))	('N', 'Chemical', 'MESH:D009584', (38, 39))	('KYSE510', 'Var', (103, 110))	('flavoprotein signature', 'MPA', (59, 81))	('lower', 'NegReg', (160, 165))
48888	31815134	Colony formation assay showed that knockdown of the flavoprotein signature genes significantly inhibited the growth of KYSE150 cells and KYSE510 cells (Figure 2(b)).	('knockdown', 'Var', (35, 44))	('inhibited', 'NegReg', (95, 104))	('KYSE510', 'CellLine', 'CVCL:1354', (137, 144))	('flavoprotein signature genes', 'Gene', (52, 80))	('growth of KYSE150 cells and', 'CPA', (109, 136))
48889	31815134	Compared with the siNC group, ESCC cell growth in the si-flavoprotein signature group was generally suppressed (P < 0.0001, one-way ANOVA).	('N', 'Chemical', 'MESH:D009584', (133, 134))	('N', 'Chemical', 'MESH:D009584', (20, 21))	('ESCC', 'Disease', (30, 34))	('suppressed', 'NegReg', (100, 110))	('si-flavoprotein', 'Var', (54, 69))	('ESCC', 'Disease', 'MESH:C562729', (30, 34))
48891	31815134	As shown in Figures 3 and 4, siRNA-mediated knockdown of CTTN, GGH, GPD2, PYROXD2, SRC, or SYNJ2BP in KYSE150 cells and KYSE510 cells conferred reduced migration, compared with the siNC group (P < 0.01, one-way ANOVA).	('SRC', 'Gene', (83, 86))	('SYNJ2BP', 'Gene', '55333', (91, 98))	('KYSE510', 'CellLine', 'CVCL:1354', (120, 127))	('N', 'Chemical', 'MESH:D009584', (212, 213))	('PYROXD2', 'Gene', '84795', (74, 81))	('CTTN', 'Gene', (57, 61))	('GGH', 'Gene', '8836', (63, 66))	('N', 'Chemical', 'MESH:D009584', (60, 61))	('GPD2', 'Gene', (68, 72))	('knockdown', 'Var', (44, 53))	('reduced', 'NegReg', (144, 151))	('GPD2', 'Gene', '2820', (68, 72))	('GGH', 'Gene', (63, 66))	('SRC', 'Gene', '6714', (83, 86))	('N', 'Chemical', 'MESH:D009584', (183, 184))	('migration', 'CPA', (152, 161))	('SYNJ2BP', 'Gene', (91, 98))	('N', 'Chemical', 'MESH:D009584', (32, 33))	('CTTN', 'Gene', '2017', (57, 61))	('N', 'Chemical', 'MESH:D009584', (93, 94))	('PYROXD2', 'Gene', (74, 81))
48893	31815134	And six genes also play different roles in KYSE150 and KYSE510 cells.	('KYSE150', 'Var', (43, 50))	('KYSE510', 'Var', (55, 62))	('play', 'Reg', (19, 23))	('KYSE510', 'CellLine', 'CVCL:1354', (55, 62))
48894	31815134	After knocking down the PYROXD2 gene in KYSE150 cells, the cell proliferation ability was most significantly reduced (P < 0.0001, one-way ANOVA), while wound healing and transwell assay showed that knockdown of the PYROXD2 gene in KYSE150 cells had the least effect on cell migration compared to other genes (P < 0.01, one-way ANOVA).	('N', 'Chemical', 'MESH:D009584', (139, 140))	('PYROXD2', 'Gene', (24, 31))	('PYROXD2', 'Gene', '84795', (215, 222))	('N', 'Chemical', 'MESH:D009584', (328, 329))	('knockdown', 'Var', (198, 207))	('cell migration', 'CPA', (269, 283))	('cell proliferation ability', 'CPA', (59, 85))	('PYROXD2', 'Gene', '84795', (24, 31))	('PYROXD2', 'Gene', (215, 222))	('reduced', 'NegReg', (109, 116))	('knocking down', 'Var', (6, 19))
48895	31815134	In KYSE510 cells, the significant effect of inhibiting cell proliferation is knocking down the SYNJ2BP gene (P < 0.0001, one-way ANOVA).	('inhibiting', 'NegReg', (44, 54))	('N', 'Chemical', 'MESH:D009584', (130, 131))	('SYNJ2BP', 'Gene', (95, 102))	('cell proliferation', 'CPA', (55, 73))	('SYNJ2BP', 'Gene', '55333', (95, 102))	('KYSE510', 'CellLine', 'CVCL:1354', (3, 10))	('N', 'Chemical', 'MESH:D009584', (97, 98))	('knocking', 'Var', (77, 85))
48896	31815134	In KYSE150 and KYSE510 cells, the effect of GGH on cell proliferation was minimal compared to other genes (P < 0.01, one-way ANOVA).	('KYSE150', 'Var', (3, 10))	('GGH', 'Gene', (44, 47))	('minimal', 'NegReg', (74, 81))	('KYSE510', 'CellLine', 'CVCL:1354', (15, 22))	('N', 'Chemical', 'MESH:D009584', (126, 127))	('cell proliferation', 'CPA', (51, 69))	('GGH', 'Gene', '8836', (44, 47))	('KYSE510', 'Var', (15, 22))
48897	31815134	However, after knockdown of GGH, wound healing and transwell assay showed that the GGH gene has a great influence on the mobility of ESCC cells (P < 0.0001, one-way ANOVA).	('N', 'Chemical', 'MESH:D009584', (166, 167))	('knockdown', 'Var', (15, 24))	('ESCC', 'Disease', (133, 137))	('GGH', 'Gene', '8836', (83, 86))	('mobility', 'CPA', (121, 129))	('GGH', 'Gene', '8836', (28, 31))	('GGH', 'Gene', (28, 31))	('influence', 'Reg', (104, 113))	('GGH', 'Gene', (83, 86))	('ESCC', 'Disease', 'MESH:C562729', (133, 137))
48922	31815134	confirmed the effect of PYROXD2 polymorphisms on trimethylamine metabolism.	('polymorphisms', 'Var', (32, 45))	('PYROXD2', 'Gene', (24, 31))	('effect', 'Reg', (14, 20))	('PYROXD2', 'Gene', '84795', (24, 31))	('trimethylamine metabolism', 'MPA', (49, 74))	('trimethylamine', 'Chemical', 'MESH:C023336', (49, 63))
48934	31815134	Similar to knockdown of CTTN and SRC, ESCC cell growth and motility are significantly reduced following knockdown of GGH, GPD2, PYROXD2, and SYNJ2BP.	('motility', 'CPA', (59, 67))	('reduced', 'NegReg', (86, 93))	('ESCC', 'Disease', 'MESH:C562729', (38, 42))	('GPD2', 'Gene', '2820', (122, 126))	('GGH', 'Gene', (117, 120))	('CTTN', 'Gene', '2017', (24, 28))	('SYNJ2BP', 'Gene', '55333', (141, 148))	('SRC', 'Gene', '6714', (33, 36))	('GGH', 'Gene', '8836', (117, 120))	('SRC', 'Gene', (33, 36))	('PYROXD2', 'Gene', (128, 135))	('ESCC', 'Disease', (38, 42))	('PYROXD2', 'Gene', '84795', (128, 135))	('SYNJ2BP', 'Gene', (141, 148))	('CTTN', 'Gene', (24, 28))	('GPD2', 'Gene', (122, 126))	('knockdown', 'Var', (104, 113))
48935	31815134	Among these genes, GPD2 knockdown has the most significant effect on inhibiting the proliferation and migration of ESCC cells.	('ESCC', 'Disease', (115, 119))	('ESCC', 'Disease', 'MESH:C562729', (115, 119))	('GPD2', 'Gene', (19, 23))	('inhibiting', 'NegReg', (69, 79))	('knockdown', 'Var', (24, 33))	('GPD2', 'Gene', '2820', (19, 23))
48943	31815134	Furthermore, abnormal expression of the flavoprotein signature promotes proliferation and migration of ESCC cells.	('flavoprotein signature', 'Gene', (40, 62))	('ESCC', 'Disease', 'MESH:C562729', (103, 107))	('migration', 'CPA', (90, 99))	('proliferation', 'CPA', (72, 85))	('promotes', 'PosReg', (63, 71))	('ESCC', 'Disease', (103, 107))	('abnormal', 'Var', (13, 21))	('expression', 'MPA', (22, 32))
48971	31367490	For instance, the overexpression of RP11-169D4.1, which is a target of miR-205-5p, inhibits the proliferation, migration, and invasion of LSCC cell lines as well as promotes apoptosis.	('RP11-169D4.1', 'Var', (36, 48))	('migration', 'CPA', (111, 120))	('miR-205', 'Gene', (71, 78))	('inhibits', 'NegReg', (83, 91))	('promotes', 'PosReg', (165, 173))	('apoptosis', 'CPA', (174, 183))	('miR-205', 'Gene', '406988', (71, 78))	('invasion', 'CPA', (126, 134))	('LSCC cell lines', 'CPA', (138, 153))	('overexpression', 'PosReg', (18, 32))
49015	31367490	These results suggests that the potential regulatory roles of aberrantly expressed miRNAs in LSCC might be one of the mechanisms of LSCC tumorigenesis.	('tumor', 'Disease', (137, 142))	('LSCC', 'Disease', (132, 136))	('miR', 'Gene', '220972', (83, 86))	('miR', 'Gene', (83, 86))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('LSCC', 'Disease', (93, 97))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('aberrantly expressed', 'Var', (62, 82))
49039	31367490	For example, used agonist of stromal vitamin D receptor to reprogram ECM by reducing fibrosis and increasing angiogenesis, and hence enhances the efficacy of gemcitabine treatment in pancreatic cancer.	('gemcitabine', 'Chemical', 'MESH:C056507', (158, 169))	('vitamin D receptor', 'Gene', '7421', (37, 55))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (183, 200))	('fibrosis', 'Disease', (85, 93))	('increasing', 'PosReg', (98, 108))	('enhances', 'PosReg', (133, 141))	('ECM', 'Gene', '22915', (69, 72))	('angiogenesis', 'CPA', (109, 121))	('vitamin D receptor', 'Gene', (37, 55))	('fibrosis', 'Disease', 'MESH:D005355', (85, 93))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('pancreatic cancer', 'Disease', 'MESH:D010190', (183, 200))	('ECM', 'Gene', (69, 72))	('pancreatic cancer', 'Disease', (183, 200))	('reducing', 'NegReg', (76, 84))	('agonist', 'Var', (18, 25))
49055	31367490	Inhibitors of TRPV6, the highly Ca2+ selective ion channel, has now undergone phase I clinical trials in patients with advanced tumors.	('patients', 'Species', '9606', (105, 113))	('TRPV6', 'Gene', '55503', (14, 19))	('Inhibitors', 'Var', (0, 10))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('TRPV6', 'Gene', (14, 19))	('tumors', 'Disease', (128, 134))	('tumors', 'Disease', 'MESH:D009369', (128, 134))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))
49059	31367490	Previous profiling studies suggest that the aberrant expression of lncRNA in LSCC may be a potential mechanism of tumorigenesis and development, and might become biomarkers for diagnosis and prognosis.	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('LSCC', 'Gene', (77, 81))	('mechanism', 'Reg', (101, 110))	('tumor', 'Disease', (114, 119))	('development', 'CPA', (132, 143))	('lncRNA', 'Protein', (67, 73))	('aberrant expression', 'Var', (44, 63))
49063	31367490	As described in previous studies, high lncRNA PART1 expression is associated with poor prognosis and tumor recurrence in non-small cell lung cancer.	('lung cancer', 'Phenotype', 'HP:0100526', (136, 147))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (125, 147))	('non-small cell lung cancer', 'Disease', (121, 147))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('lncRNA PART1', 'Protein', (39, 51))	('expression', 'MPA', (52, 62))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (121, 147))	('high', 'Var', (34, 38))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (121, 147))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
49070	31367490	LSAMP-AS1 inhibits proliferation by sponging miR-211 in colorectal cancer.	('LSAMP-AS1', 'Gene', '101926903', (0, 9))	('inhibits', 'NegReg', (10, 18))	('miR-211', 'Gene', '406993', (45, 52))	('miR-211', 'Gene', (45, 52))	('colorectal cancer', 'Disease', 'MESH:D015179', (56, 73))	('colorectal cancer', 'Phenotype', 'HP:0003003', (56, 73))	('proliferation', 'CPA', (19, 32))	('sponging', 'Var', (36, 44))	('colorectal cancer', 'Disease', (56, 73))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('LSAMP-AS1', 'Gene', (0, 9))
49109	33692955	275 DEGs were significantly associated with TME.	('275 DEGs', 'Var', (0, 8))	('associated', 'Reg', (28, 38))	('DEGs', 'Chemical', '-', (4, 8))	('TME', 'Disease', (44, 47))
49229	33692955	This is further evidence that these genes influence the immune system and the tumor microenvironment by influencing the immune system and, thus, tumorigenesis, progression, and prognosis.	('men', 'Species', '9606', (96, 99))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('prognosis', 'CPA', (177, 186))	('influencing', 'Reg', (104, 115))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('immune system', 'CPA', (120, 133))	('genes', 'Var', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumor', 'Disease', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Disease', (145, 150))	('influence', 'Reg', (42, 51))	('progression', 'CPA', (160, 171))
49265	33692955	We found that both in CCR4, CCR8, and P2RY14, the abundance of CD8 T-lymphocytes was significantly higher in the group with high expression of these genes than in the lower expression group.	('CCR8', 'Gene', (28, 32))	('higher', 'PosReg', (99, 105))	('CD8', 'Gene', (63, 66))	('P2RY14', 'Gene', '9934', (38, 44))	('CD8', 'Gene', '925', (63, 66))	('high expression', 'Var', (124, 139))	('CCR8', 'Gene', '1237', (28, 32))	('P2RY14', 'Gene', (38, 44))
49268	33692955	In all of the three hub genes, we also found that the content of M0 macrophages was significantly lower in the high-expression group of the gene.	('high-expression', 'Var', (111, 126))	('content of M0 macrophages', 'MPA', (54, 79))	('hub', 'Gene', '1993', (20, 23))	('hub', 'Gene', (20, 23))	('lower', 'NegReg', (98, 103))
49272	33692955	In this study, we found that the content of M0 macrophages was significantly reduced in the high expression group while M1 macrophages were increased although there was no significant difference, while there was no significant change in M2 macrophages, which suggested an enhanced anti-tumor immune response in the high expression group.	('content', 'MPA', (33, 40))	('tumor', 'Phenotype', 'HP:0002664', (286, 291))	('high expression', 'Var', (92, 107))	('tumor', 'Disease', (286, 291))	('enhanced', 'PosReg', (272, 280))	('reduced', 'NegReg', (77, 84))	('tumor', 'Disease', 'MESH:D009369', (286, 291))	('increased', 'PosReg', (140, 149))
49305	31248382	Research demonstrated that ZEB-1 promotes the process of EMT through regulation of the relevant protein binding domains, such as the p300-P/CAF binding domain, Smad interaction domain, and C-terminal-binding protein interaction domain.	('promotes', 'PosReg', (33, 41))	('C-terminal-binding protein interaction', 'MPA', (189, 227))	('protein', 'Protein', (96, 103))	('p300-P/CAF', 'Var', (133, 143))	('Smad interaction', 'Protein', (160, 176))	('ZEB-1', 'Gene', (27, 32))	('EMT', 'CPA', (57, 60))	('CAF', 'Chemical', '-', (140, 143))	('ZEB-1', 'Gene', '6935', (27, 32))	('regulation', 'MPA', (69, 79))
49308	31248382	suggested that aberrant expression of ZEB-1in gastric cancer was associated with tumor stage, depth of invasion and poor differentiation.	('aberrant expression', 'Var', (15, 34))	('gastric cancer', 'Disease', (46, 60))	('ZEB-1', 'Gene', (38, 43))	('gastric cancer', 'Disease', 'MESH:D013274', (46, 60))	('associated', 'Reg', (65, 75))	('poor differentiation', 'CPA', (116, 136))	('depth of invasion', 'CPA', (94, 111))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('ZEB-1', 'Gene', '6935', (38, 43))	('gastric cancer', 'Phenotype', 'HP:0012126', (46, 60))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('tumor', 'Disease', (81, 86))
49330	31248382	The results indicated a negative effect of high ZEB-1 expression on OS (univariable analysis) in patients with colorectal cancer (pooled HR: 1.80; 95% CI: 1.28-2.54) (Fig.	('expression', 'MPA', (54, 64))	('high', 'Var', (43, 47))	('colorectal cancer', 'Disease', 'MESH:D015179', (111, 128))	('ZEB-1', 'Gene', (48, 53))	('negative', 'NegReg', (24, 32))	('colorectal cancer', 'Phenotype', 'HP:0003003', (111, 128))	('ZEB-1', 'Gene', '6935', (48, 53))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('colorectal cancer', 'Disease', (111, 128))	('OS', 'Chemical', '-', (68, 70))	('patients', 'Species', '9606', (97, 105))
49342	31248382	revealed that high expression of ZEB-1 may have an impact on cell-cell interactions resulting in endometrial cancer cell invasion and metastasis.	('cell-cell interactions', 'CPA', (61, 83))	('endometrial cancer', 'Disease', (97, 115))	('metastasis', 'CPA', (134, 144))	('high expression', 'Var', (14, 29))	('endometrial cancer', 'Disease', 'MESH:D016889', (97, 115))	('endometrial cancer', 'Phenotype', 'HP:0012114', (97, 115))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('impact', 'Reg', (51, 57))	('ZEB-1', 'Gene', (33, 38))	('ZEB-1', 'Gene', '6935', (33, 38))
49344	31248382	Knockdown of ZEB-1 may induce cell apoptosis, while high ZEB-1 expression may drastically suppress lung cancer cells, as shown through soft agar colony formation assays.	('ZEB-1', 'Gene', (57, 62))	('lung cancer', 'Disease', (99, 110))	('Knockdown', 'Var', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('suppress', 'NegReg', (90, 98))	('ZEB-1', 'Gene', (13, 18))	('cell apoptosis', 'CPA', (30, 44))	('ZEB-1', 'Gene', '6935', (57, 62))	('expression', 'MPA', (63, 73))	('lung cancer', 'Disease', 'MESH:D008175', (99, 110))	('ZEB-1', 'Gene', '6935', (13, 18))	('high', 'Var', (52, 56))	('lung cancer', 'Phenotype', 'HP:0100526', (99, 110))
49350	31248382	In vitro, high expression of ZEB-1 was associated with poor OS in patients with esophageal squamous cell carcinoma.	('ZEB-1', 'Gene', '6935', (29, 34))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (80, 114))	('poor OS', 'Disease', (55, 62))	('patients', 'Species', '9606', (66, 74))	('high expression', 'Var', (10, 25))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (91, 114))	('associated', 'Reg', (39, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('ZEB-1', 'Gene', (29, 34))	('esophageal squamous cell carcinoma', 'Disease', (80, 114))	('OS', 'Chemical', '-', (60, 62))
49352	31248382	identified that high level of ZEB-1 expression was associated with recurrence, lymph node metastasis, worse pathologic grading and low survival rates in oral cavity carcinoma.	('carcinoma', 'Disease', (165, 174))	('ZEB-1', 'Gene', (30, 35))	('recurrence', 'CPA', (67, 77))	('ZEB-1', 'Gene', '6935', (30, 35))	('low', 'NegReg', (131, 134))	('associated', 'Reg', (51, 61))	('high level', 'Var', (16, 26))	('carcinoma', 'Disease', 'MESH:D002277', (165, 174))	('carcinoma', 'Phenotype', 'HP:0030731', (165, 174))	('lymph node metastasis', 'CPA', (79, 100))	('expression', 'MPA', (36, 46))
49357	31248382	Regarding the types of tumors, our study indicated that high expression of ZEB-1 was also significantly associated with worse OS in colorectal cancer, esophageal squamous cell carcinoma, pancreatic cancer, gastric cancer and hepatocellular carcinoma.	('ZEB-1', 'Gene', (75, 80))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (151, 185))	('ZEB-1', 'Gene', '6935', (75, 80))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (187, 204))	('colorectal cancer', 'Phenotype', 'HP:0003003', (132, 149))	('associated', 'Reg', (104, 114))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('gastric cancer', 'Disease', (206, 220))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (225, 249))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('pancreatic cancer', 'Disease', 'MESH:D010190', (187, 204))	('OS', 'Chemical', '-', (126, 128))	('gastric cancer', 'Disease', 'MESH:D013274', (206, 220))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('tumors', 'Disease', (23, 29))	('colorectal cancer', 'Disease', 'MESH:D015179', (132, 149))	('pancreatic cancer', 'Disease', (187, 204))	('esophageal squamous cell carcinoma', 'Disease', (151, 185))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (225, 249))	('colorectal cancer', 'Disease', (132, 149))	('high expression', 'Var', (56, 71))	('tumors', 'Disease', 'MESH:D009369', (23, 29))	('gastric cancer', 'Phenotype', 'HP:0012126', (206, 220))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (162, 185))	('hepatocellular carcinoma', 'Disease', (225, 249))	('carcinoma', 'Phenotype', 'HP:0030731', (240, 249))	('carcinoma', 'Phenotype', 'HP:0030731', (176, 185))
49406	26130668	Nucleotide Excision Repair Gene ERCC2 and ERCC5 Variants Increase Risk of Uterine Cervical Cancer Defects in the DNA damage repair process can cause genomic instability and play an important role in cervical carcinogenesis.	('Cancer', 'Disease', (91, 97))	('ERCC5', 'Gene', '2073', (42, 47))	('carcinogenesis', 'Disease', (208, 222))	('Defects', 'Var', (98, 105))	('Cancer', 'Disease', 'MESH:D009369', (91, 97))	('ERCC2', 'Gene', '2068', (32, 37))	('Cancer', 'Phenotype', 'HP:0002664', (91, 97))	('Variants', 'Var', (48, 56))	('cause', 'Reg', (143, 148))	('ERCC2', 'Gene', (32, 37))	('ERCC5', 'Gene', (42, 47))	('genomic instability', 'MPA', (149, 168))	('carcinogenesis', 'Disease', 'MESH:D063646', (208, 222))
49407	26130668	The purpose of this study was to analyze the association of 29 candidate single nucleotide polymorphisms (SNPs) in genes in the DNA repair pathway, TP53, and TP53BP1 with the risk of cervical cancer.	('TP53', 'Gene', '7157', (158, 162))	('cervical cancer', 'Disease', (183, 198))	('TP53', 'Gene', (158, 162))	('DNA repair pathway', 'Pathway', (128, 146))	('association', 'Interaction', (45, 56))	('TP53', 'Gene', '7157', (148, 152))	('TP53BP1', 'Gene', (158, 165))	('TP53', 'Gene', (148, 152))	('single nucleotide polymorphisms', 'Var', (73, 104))	('TP53BP1', 'Gene', '7158', (158, 165))	('cervical cancer', 'Disease', 'MESH:D002583', (183, 198))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))
49409	26130668	The most significant association was found for rs17655 in ERCC5, with an age-adjusted p-value < 0.0001, for which a strong additive effect of the risk allele C was observed (odds ratio, 2.01 for CC to GG).	('ERCC5', 'Gene', '2073', (58, 63))	('ERCC5', 'Gene', (58, 63))	('rs17655', 'Var', (47, 54))	('rs17655', 'Mutation', 'rs17655', (47, 54))
49410	26130668	On the other hand, another significant polymorphism rs454421 in ERCC2 showed a dominant effect (odds ratio, 1.68 for GA+AA to GG) with an age-adjusted p-value of 0.0009.	('rs454421', 'Mutation', 'rs454421', (52, 60))	('ERCC2', 'Gene', '2068', (64, 69))	('rs454421', 'Var', (52, 60))	('ERCC2', 'Gene', (64, 69))
49412	26130668	However, for rs454421, the association was observed only in patients with squamous cell carcinoma and non-HPV 18 type.	('patients', 'Species', '9606', (60, 68))	('rs454421', 'Mutation', 'rs454421', (13, 21))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('rs454421', 'Var', (13, 21))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (74, 97))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (74, 97))	('squamous cell carcinoma', 'Disease', (74, 97))	('HPV', 'Species', '10566', (106, 109))
49425	26130668	TP53 is a major activator of ATM upon DNA damage signal, and functional polymorphisms in TP53 and TP53BP1 are known to be associated with genetic instability as well as cancer risk.	('associated', 'Reg', (122, 132))	('TP53', 'Gene', '7157', (89, 93))	('TP53', 'Gene', '7157', (0, 4))	('cancer', 'Disease', (169, 175))	('TP53', 'Gene', (89, 93))	('TP53', 'Gene', (0, 4))	('ATM', 'Gene', (29, 32))	('genetic instability', 'CPA', (138, 157))	('TP53BP1', 'Gene', '7158', (98, 105))	('TP53BP1', 'Gene', (98, 105))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('ATM', 'Gene', '472', (29, 32))	('TP53', 'Gene', '7157', (98, 102))	('polymorphisms', 'Var', (72, 85))	('cancer', 'Disease', 'MESH:D009369', (169, 175))	('TP53', 'Gene', (98, 102))
49426	26130668	Several common and putative functional single nucleotide polymorphisms (SNPs) of these DNA repair genes were reported as genetic factors associated with HPV persistence and cervical cancer progression.	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('associated', 'Reg', (137, 147))	('cervical cancer', 'Disease', (173, 188))	('HPV persistence', 'Disease', (153, 168))	('DNA repair genes', 'Gene', (87, 103))	('single nucleotide polymorphisms', 'Var', (39, 70))	('HPV', 'Species', '10566', (153, 156))	('cervical cancer', 'Disease', 'MESH:D002583', (173, 188))
49433	26130668	The candidate polymorphisms in the six genes, including eight non-synonymous SNPs, were selected on the basis of previously reported associations with cancer risk or prognosis.	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('polymorphisms', 'Var', (14, 27))	('cancer', 'Disease', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('associations', 'Interaction', (133, 145))
49444	26130668	From the results of the association analysis, four of the six SNPs in the ERCC2 gene, rs454421, rs238417, rs238406, and rs3710366, showed associations with p-value under 0.05 (Supplementary Table 1).	('rs454421', 'Mutation', 'rs454421', (86, 94))	('associations', 'Reg', (138, 150))	('ERCC2', 'Gene', '2068', (74, 79))	('rs3710366', 'Var', (120, 129))	('rs238417', 'Var', (96, 104))	('rs3710366', 'Mutation', 'rs3710366', (120, 129))	('rs238417', 'Mutation', 'rs238417', (96, 104))	('ERCC2', 'Gene', (74, 79))	('rs238406', 'Mutation', 'rs238406', (106, 114))	('rs238406', 'Var', (106, 114))	('rs454421', 'Var', (86, 94))
49445	26130668	Applying a conservative Bonferroni correction (p < 0.05/29), two SNPs of rs454421 and rs17655 were found to show significant association with the risk of cervical cancer.	('rs454421', 'Var', (73, 81))	('association', 'Reg', (125, 136))	('rs17655', 'Mutation', 'rs17655', (86, 93))	('rs17655', 'Var', (86, 93))	('cervical cancer', 'Disease', (154, 169))	('cervical cancer', 'Disease', 'MESH:D002583', (154, 169))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('rs454421', 'Mutation', 'rs454421', (73, 81))
49448	26130668	On the other hand, the dominant genotypes of rs454421 (GA+AA) contribute to an increased risk of cervical cancer.	('cervical cancer', 'Disease', (97, 112))	('rs454421', 'Mutation', 'rs454421', (45, 53))	('rs454421', 'Var', (45, 53))	('cervical cancer', 'Disease', 'MESH:D002583', (97, 112))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
49452	26130668	Using the split-sample approach, rs454421 and rs17655 were found to show significant association with the risk of cervical cancer in 9 and 10 split-sample procedures out of 10 repetitions, respectively.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('rs454421', 'Var', (33, 41))	('association', 'Reg', (85, 96))	('rs454421', 'Mutation', 'rs454421', (33, 41))	('rs17655', 'Mutation', 'rs17655', (46, 53))	('rs17655', 'Var', (46, 53))	('cervical cancer', 'Disease', (114, 129))	('cervical cancer', 'Disease', 'MESH:D002583', (114, 129))
49453	26130668	In addition, rs454421 and rs17655 were found to show significant association with the disease 781 and 887 times out of 1,000 bootstrap samples, respectively.	('association', 'Reg', (65, 76))	('rs454421', 'Mutation', 'rs454421', (13, 21))	('rs454421', 'Var', (13, 21))	('rs17655', 'Mutation', 'rs17655', (26, 33))	('rs17655', 'Var', (26, 33))
49454	26130668	The associations of both rs454421 and rs17655 were examined separately in subgroups of patients with early onset (<= 40) and late onset (> 40) (Supplementary Table 2).	('rs17655', 'Var', (38, 45))	('rs17655', 'Mutation', 'rs17655', (38, 45))	('rs454421', 'Var', (25, 33))	('rs454421', 'Mutation', 'rs454421', (25, 33))	('patients', 'Species', '9606', (87, 95))
49457	26130668	For both SNPs, stronger association in terms of the magnitude of the odds ratio was observed for those in the early onset group, as evidenced by the significant p-values, which are based on the proportional odds model with ordered disease status according to the age of onset (p=0.0002 for rs454421 and p < 0.0001 for rs17655) (Supplementary Table 3).	('ordered disease', 'Disease', (223, 238))	('rs454421', 'Mutation', 'rs454421', (290, 298))	('ordered disease', 'Disease', 'MESH:D004194', (223, 238))	('rs17655', 'Mutation', 'rs17655', (318, 325))	('rs454421', 'Var', (290, 298))	('rs17655', 'Var', (318, 325))
49460	26130668	For rs454421, the association was only observed in squamous cell carcinoma (p=0.0004) and non-HPV 18 type (p=0.0043).	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('squamous cell carcinoma', 'Disease', (51, 74))	('HPV', 'Species', '10566', (94, 97))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (51, 74))	('rs454421', 'Var', (4, 12))	('rs454421', 'Mutation', 'rs454421', (4, 12))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (51, 74))
49461	26130668	On the other hand, for rs17655, significant association was found in all subgroups (p-value in squamous cell carcinoma, 0.0002; in adenocarcinoma, 0.0326; p-value in HPV 18 type, 0.0127; in non-HPV 18 type, 0.0009).	('rs17655', 'Mutation', 'rs17655', (23, 30))	('HPV', 'Species', '10566', (166, 169))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (95, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('adenocarcinoma', 'Disease', (131, 145))	('HPV', 'Species', '10566', (194, 197))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('squamous cell carcinoma', 'Disease', (95, 118))	('rs17655', 'Var', (23, 30))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (95, 118))	('adenocarcinoma', 'Disease', 'MESH:D000230', (131, 145))
49462	26130668	When multiple testing was adjusted for, similar to the case of rs454421, the association was observed only in squamous cell carcinoma and non-HPV 18 type.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (110, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('squamous cell carcinoma', 'Disease', (110, 133))	('HPV', 'Species', '10566', (142, 145))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (110, 133))	('rs454421', 'Var', (63, 71))	('rs454421', 'Mutation', 'rs454421', (63, 71))
49464	26130668	Because DNA repair plays a fundamental role in maintaining genomic integrity, disruption of DNA repair allows genomic instability and cancer development.	('genomic instability', 'CPA', (110, 129))	('cancer', 'Disease', (134, 140))	('disruption', 'Var', (78, 88))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('DNA repair', 'Gene', (92, 102))	('allows', 'Reg', (103, 109))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
49466	26130668	Genetic variants of ERCC genes were also widely studied as risk factors for cancer as well as predictors of treatment outcomes in cancer.	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('cancer', 'Disease', (130, 136))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('ERCC', 'Gene', (20, 24))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('Genetic variants', 'Var', (0, 16))
49467	26130668	Our results show highly significant associations of rs454421 in ERCC2 and rs17655 in ERCC5 with cervical cancer.	('rs454421', 'Mutation', 'rs454421', (52, 60))	('ERCC2', 'Gene', '2068', (64, 69))	('ERCC5', 'Gene', (85, 90))	('cervical cancer', 'Disease', 'MESH:D002583', (96, 111))	('rs17655', 'Mutation', 'rs17655', (74, 81))	('significant associations', 'Reg', (24, 48))	('ERCC5', 'Gene', '2073', (85, 90))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('cervical cancer', 'Disease', (96, 111))	('rs17655', 'Var', (74, 81))	('rs454421', 'Var', (52, 60))	('ERCC2', 'Gene', (64, 69))
49470	26130668	The association of polymorphisms in HPV 18 type was difficult to test due to the small size of the group.	('HPV', 'Species', '10566', (36, 39))	('polymorphisms', 'Var', (19, 32))	('HPV 18', 'Gene', (36, 42))
49471	26130668	Non-synonymous polymorphism rs17655 (Asp1104His) in ERCC5 has been reported as a risk factor for various cancers, including lung cancer and bladder cancer.	('Asp1104His', 'SUBSTITUTION', 'None', (37, 47))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('lung cancer', 'Disease', 'MESH:D008175', (124, 135))	('Asp1104His', 'Var', (37, 47))	('rs17655', 'Mutation', 'rs17655', (28, 35))	('cancers', 'Phenotype', 'HP:0002664', (105, 112))	('ERCC5', 'Gene', '2073', (52, 57))	('bladder cancer', 'Phenotype', 'HP:0009725', (140, 154))	('cancers', 'Disease', (105, 112))	('risk', 'Reg', (81, 85))	('cancers', 'Disease', 'MESH:D009369', (105, 112))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('bladder cancer', 'Disease', 'MESH:D001749', (140, 154))	('bladder cancer', 'Disease', (140, 154))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('lung cancer', 'Disease', (124, 135))	('lung cancer', 'Phenotype', 'HP:0100526', (124, 135))	('ERCC5', 'Gene', (52, 57))
49474	26130668	Three 53BP1 variant genotypes (Glu353Asp [rs560191], T-885G [rs1869258], and Gln1136Lys [rs2602141]) increased the risk of progesterone receptor-negative breast cancer, and the two latter variants significantly increased estrogen receptor-negative breast cancer in the Chinese population.	('Glu353Asp', 'Var', (31, 40))	('53BP1', 'Gene', (6, 11))	('increased', 'PosReg', (101, 110))	('T-885G [rs1869258]', 'Var', (53, 71))	('Gln1136Lys', 'Var', (77, 87))	('progesterone receptor', 'Gene', (123, 144))	('progesterone receptor', 'Gene', '5241', (123, 144))	('cancer', 'Phenotype', 'HP:0002664', (255, 261))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('increased estrogen receptor', 'Phenotype', 'HP:0025134', (211, 238))	('increased', 'PosReg', (211, 220))	('breast cancer', 'Phenotype', 'HP:0003002', (154, 167))	('T-885G', 'Mutation', 'rs1869258', (53, 59))	('breast cancer', 'Phenotype', 'HP:0003002', (248, 261))	('rs560191', 'Mutation', 'rs560191', (42, 50))	('breast cancer', 'Disease', 'MESH:D001943', (154, 167))	('breast cancer', 'Disease', (154, 167))	('breast cancer', 'Disease', 'MESH:D001943', (248, 261))	('Glu353Asp', 'SUBSTITUTION', 'None', (31, 40))	('breast cancer', 'Disease', (248, 261))	('Gln1136Lys', 'SUBSTITUTION', 'None', (77, 87))	('rs2602141', 'Mutation', 'rs2602141', (89, 98))	('rs1869258', 'Mutation', 'rs1869258', (61, 70))
49475	26130668	In addition, TP53BP1 Gln1136Lys (rs2602141) and TP53 Arg72Pro (rs1042522) showed gene-gene interaction with increased breast cancer risk in patients.	('TP53', 'Gene', (13, 17))	('Gln1136Lys', 'SUBSTITUTION', 'None', (21, 31))	('Arg72Pro', 'Var', (53, 61))	('rs2602141', 'Var', (33, 42))	('breast cancer', 'Phenotype', 'HP:0003002', (118, 131))	('TP53', 'Gene', '7157', (48, 52))	('Gln1136Lys', 'Var', (21, 31))	('breast cancer', 'Disease', 'MESH:D001943', (118, 131))	('patients', 'Species', '9606', (140, 148))	('Arg72Pro', 'SUBSTITUTION', 'None', (53, 61))	('TP53BP1', 'Gene', '7158', (13, 20))	('TP53', 'Gene', '7157', (13, 17))	('breast cancer', 'Disease', (118, 131))	('rs1042522', 'Var', (63, 72))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('TP53BP1', 'Gene', (13, 20))	('rs1042522', 'Mutation', 'rs1042522', (63, 72))	('TP53', 'Gene', (48, 52))	('rs2602141', 'Mutation', 'rs2602141', (33, 42))
49476	26130668	TP53 codon 72 polymorphism causes different biochemical functions of TP53.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('TP53', 'Gene', '7157', (69, 73))	('TP53', 'Gene', (69, 73))	('polymorphism', 'Var', (14, 26))	('causes', 'Reg', (27, 33))	('biochemical functions', 'MPA', (44, 65))
49478	26130668	However, a meta-analysis concluded no association of Pro72Arg variant with incidence of cervical cancer.	('cervical cancer', 'Disease', (88, 103))	('cervical cancer', 'Disease', 'MESH:D002583', (88, 103))	('Pro72Arg', 'Var', (53, 61))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('Pro72Arg', 'Mutation', 'rs1042522', (53, 61))
49479	26130668	In addition, Arg variant was previously found to be more susceptible to degradation by the HPV 18 E6 protein.	('Arg', 'Chemical', 'MESH:D001120', (13, 16))	('Arg variant', 'Var', (13, 24))	('HPV', 'Species', '10566', (91, 94))	('degradation', 'MPA', (72, 83))
49480	26130668	In our subgroup analysis of rs1042522, a tendency toward an association with the risk of cervical cancer was observed for patients with younger age of onset (OR, 1.72; p=0.07), and for patients with HPV 18 infection (OR, 2.09; p=0.03).	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('HPV 18 infection', 'Disease', 'MESH:D030361', (199, 215))	('rs1042522', 'Var', (28, 37))	('cervical cancer', 'Disease', 'MESH:D002583', (89, 104))	('HPV 18 infection', 'Disease', (199, 215))	('cervical cancer', 'Disease', (89, 104))	('patients', 'Species', '9606', (122, 130))	('patients', 'Species', '9606', (185, 193))	('rs1042522', 'Mutation', 'rs1042522', (28, 37))	('association', 'Interaction', (60, 71))
49483	26130668	XRCC1 Arg399Gln (rs25487) also showed an association with differential prognostic factor for progression-free survival in patients with adenocarcinoma of the lung treated with gefitinib chemotherapy.	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('Arg399Gln', 'Var', (6, 15))	('Arg399Gln', 'SUBSTITUTION', 'None', (6, 15))	('gefitinib', 'Chemical', 'MESH:D000077156', (176, 185))	('adenocarcinoma of the lung', 'Disease', (136, 162))	('XRCC1', 'Gene', (0, 5))	('adenocarcinoma of the lung', 'Disease', 'MESH:D000077192', (136, 162))	('rs25487', 'Mutation', 'rs25487', (17, 24))	('patients', 'Species', '9606', (122, 130))	('XRCC1', 'Gene', '7515', (0, 5))
49484	26130668	However, in the current study no significant association with cervical cancer risk was observed for polymorphisms in XRCC1 in the BER pathway or NBS1 in the DNA DSBs repair pathway.	('NBS1', 'Gene', (145, 149))	('XRCC1', 'Gene', '7515', (117, 122))	('BER pathway', 'Pathway', (130, 141))	('DNA DSBs repair pathway', 'Pathway', (157, 180))	('NBS1', 'Gene', '55655', (145, 149))	('cervical cancer', 'Disease', (62, 77))	('cervical cancer', 'Disease', 'MESH:D002583', (62, 77))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('XRCC1', 'Gene', (117, 122))	('polymorphisms', 'Var', (100, 113))	('DSBs', 'Chemical', 'MESH:C007563', (161, 165))
49485	26130668	Our findings suggest that the polymorphisms in ERCC2 and ERCC5 may contribute to the etiology of cervical cancer, showing an additive effect.	('cervical cancer', 'Disease', (97, 112))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('polymorphisms', 'Var', (30, 43))	('ERCC5', 'Gene', (57, 62))	('ERCC5', 'Gene', '2073', (57, 62))	('ERCC2', 'Gene', '2068', (47, 52))	('ERCC2', 'Gene', (47, 52))	('cervical cancer', 'Disease', 'MESH:D002583', (97, 112))	('contribute', 'Reg', (67, 77))
49489	26130668	More comprehensive screening based on a large number of genetic variants related to cervical cancer susceptibility is expected to provide evidence for addressing cervical cancer-related public health issues such as defining the high risk population for aggressive cancer screening and the use of preventive vaccines.	('cervical cancer', 'Disease', 'MESH:D002583', (84, 99))	('cervical cancer', 'Disease', (162, 177))	('cancer', 'Phenotype', 'HP:0002664', (264, 270))	('cervical cancer', 'Disease', (84, 99))	('aggressive cancer', 'Disease', 'MESH:D009369', (253, 270))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('aggressive cancer', 'Disease', (253, 270))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('variants', 'Var', (64, 72))	('cervical cancer', 'Disease', 'MESH:D002583', (162, 177))
49527	33023117	The 5-year cause-specific survival rates of the m1/m2, m3/sm1, and sm2 groups were 98%, 93%, and 100%, respectively.	('sm1', 'Gene', (58, 61))	('m1/m2', 'Var', (48, 53))	('sm1', 'Gene', '7911', (58, 61))	('sm2', 'Gene', (67, 70))	('sm2', 'Gene', '53366', (67, 70))
49535	33023117	The 5-year overall survival rates of the m1/m2, m3/sm1, and sm2 groups were 95%, 84%, and 75%, respectively.	('sm2', 'Gene', (60, 63))	('sm1', 'Gene', (51, 54))	('sm2', 'Gene', '53366', (60, 63))	('m1/m2', 'Var', (41, 46))	('sm1', 'Gene', '7911', (51, 54))
49628	32284758	The predicted AUC of EGFR mutation reached 0.83, and then the universality of the model was verified.	('EGFR', 'Gene', '1956', (21, 25))	('EGFR', 'Gene', (21, 25))	('AUC', 'MPA', (14, 17))	('mutation', 'Var', (26, 34))
49629	32284758	The appearance of this model can preliminarily predict gene mutation by only inputting H&E stained images, overcome the shortcomings of human naked eye recognition and summary of features, and has the advantages of low cost and high efficiency.	('human', 'Species', '9606', (136, 141))	('predict', 'Reg', (47, 54))	('gene mutation', 'Var', (55, 68))	('H&E', 'Chemical', 'MESH:D006371', (87, 90))
49684	31413738	Verteporfin significantly inhibited HNSCC cell proliferation, migration and invasion, induced apoptosis, and arrested the cell cycle at the S/G2 phase.	('arrested', 'NegReg', (109, 117))	('migration', 'CPA', (62, 71))	('inhibited', 'NegReg', (26, 35))	('HNSCC cell proliferation', 'CPA', (36, 60))	('Verteporfin', 'Chemical', 'MESH:D000077362', (0, 11))	('HNSCC', 'Phenotype', 'HP:0012288', (36, 41))	('induced', 'Reg', (86, 93))	('S/G2', 'Var', (140, 144))	('S/G2', 'SUBSTITUTION', 'None', (140, 144))	('apoptosis', 'CPA', (94, 103))	('invasion', 'CPA', (76, 84))
49696	31413738	Dysregulation of the Hippo pathway has been implicated in many human diseases, including cancer.	('human', 'Species', '9606', (63, 68))	('Dysregulation', 'Var', (0, 13))	('implicated', 'Reg', (44, 54))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('cancer', 'Disease', (89, 95))	('Hippo pathway', 'Pathway', (21, 34))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
49765	31413738	In the present study, the migration of cells treated with 0.25 and 0.5 microM VP was significantly decreased in a dose-dependent manner compared with the DMSO group cells (Fig.	('migration of cells', 'CPA', (26, 44))	('decreased', 'NegReg', (99, 108))	('VP', 'Chemical', 'MESH:D000077362', (78, 80))	('DMSO', 'Chemical', 'MESH:D004121', (154, 158))	('0.25', 'Var', (58, 62))
49779	31413738	Moreover, our data showed that YAP1 expression was highest in UM-SCC-47 cells, moderate in UPCI-SCC-090 cells and lowest in 93-VU-147T cells in the three HPV-positive HNSCC cell lines, consistent with a previous report, in which authors show that UM-SCC-47 cell line has YAP1 gene amplification and 93-VU-147T cell line has YAP1 gene deep deletion.	('YAP1', 'Gene', (271, 275))	('YAP1', 'Gene', '10413', (271, 275))	('deep deletion', 'Var', (334, 347))	('UM-SCC-47', 'CellLine', 'CVCL:7759', (247, 256))	('UM-SCC-47', 'CellLine', 'CVCL:7759', (62, 71))	('YAP1', 'Gene', (31, 35))	('YAP1', 'Gene', '10413', (31, 35))	('93-VU-147T', 'CellLine', 'CVCL:L895', (299, 309))	('93-VU-147T', 'CellLine', 'CVCL:L895', (124, 134))	('HNSCC', 'Phenotype', 'HP:0012288', (167, 172))	('YAP1', 'Gene', (324, 328))	('YAP1', 'Gene', '10413', (324, 328))	('HPV', 'Species', '10566', (154, 157))	('expression', 'MPA', (36, 46))
49846	30410368	In addition, silencing of APC11 decreased cell migrative and invasive abilities.	('APC11', 'Gene', '51529', (26, 31))	('invasive abilities', 'CPA', (61, 79))	('APC11', 'Gene', (26, 31))	('si', 'Chemical', 'MESH:D012825', (13, 15))	('si', 'Chemical', 'MESH:D012825', (65, 67))	('decreased', 'NegReg', (32, 41))	('silencing', 'Var', (13, 22))
49850	30410368	The E3 ligases are classified into two groups, the homologous to the E6-AP carboxyl terminus domain containing E3s and the Really Interesting New Gene (RING) domain containing E3s.	('E6-AP', 'Var', (69, 74))	('si', 'Chemical', 'MESH:D012825', (23, 25))	('E3s', 'Var', (111, 114))
49854	30410368	A dysfunctional APC11 influenced the cell cycle process and mainly caused mitosis arrest.	('mitosis arrest', 'Disease', 'MESH:D006323', (74, 88))	('mitosis arrest', 'Disease', (74, 88))	('dysfunctional', 'Var', (2, 15))	('APC11', 'Gene', (16, 21))	('influenced', 'Reg', (22, 32))	('caused', 'Reg', (67, 73))	('cell cycle process', 'CPA', (37, 55))	('APC11', 'Gene', '51529', (16, 21))
49855	30410368	Silencing the APC11 gene in nematode embryonic cells resulted in cell cycle arrest during the first meiotic division.	('APC11', 'Gene', '51529', (14, 19))	('si', 'Chemical', 'MESH:D012825', (112, 114))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (65, 82))	('APC11', 'Gene', (14, 19))	('Silencing', 'Var', (0, 9))
49862	30410368	In this study, we found that APC11 could be served as a prognostic biomarker for lung adenocarcinoma, knockdown of APC11 significantly inhibited lung adenocarcinoma cell growth, colon formation, migration, and invasion.	('APC11', 'Gene', (29, 34))	('invasion', 'CPA', (210, 218))	('APC11', 'Gene', '51529', (115, 120))	('APC11', 'Gene', (115, 120))	('lung adenocarcinoma', 'Disease', (145, 164))	('si', 'Chemical', 'MESH:D012825', (214, 216))	('lung adenocarcinoma', 'Disease', (81, 100))	('migration', 'CPA', (195, 204))	('colon formation', 'CPA', (178, 193))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (145, 164))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (81, 100))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (145, 164))	('inhibited', 'NegReg', (135, 144))	('carcinoma', 'Phenotype', 'HP:0030731', (155, 164))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (81, 100))	('knockdown', 'Var', (102, 111))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('APC11', 'Gene', '51529', (29, 34))	('si', 'Chemical', 'MESH:D012825', (121, 123))
49876	30410368	Briefly, NCI-H1299 cells transfected with si-Control or si-APC11 were cultured in RPMI-1640 medium for 24 hours and plated on the top surface of the transwell chambers (Corning Inc., Corning, NY, USA) and incubated in humidified environment with 5% CO2 at 37 C for 48 hours.	('NCI-H1299', 'CellLine', 'CVCL:0060', (9, 18))	('si', 'Chemical', 'MESH:D012825', (56, 58))	('si', 'Chemical', 'MESH:D012825', (42, 44))	('CO2', 'Chemical', '-', (249, 252))	('APC11', 'Gene', '51529', (59, 64))	('RPMI-1640 medium', 'Chemical', '-', (82, 98))	('APC11', 'Gene', (59, 64))	('si-Control', 'Var', (42, 52))
49885	30410368	As a result, high mRNA expression of APC11 was significantly associated with worse survival in lung cancer patients (Figure 1A).	('lung cancer', 'Disease', (95, 106))	('si', 'Chemical', 'MESH:D012825', (29, 31))	('lung cancer', 'Phenotype', 'HP:0100526', (95, 106))	('APC11', 'Gene', (37, 42))	('high', 'Var', (13, 17))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('mRNA expression', 'MPA', (18, 33))	('si', 'Chemical', 'MESH:D012825', (47, 49))	('lung cancer', 'Disease', 'MESH:D008175', (95, 106))	('worse', 'NegReg', (77, 82))	('associated', 'Reg', (61, 71))	('patients', 'Species', '9606', (107, 115))	('APC11', 'Gene', '51529', (37, 42))	('survival', 'MPA', (83, 91))
49888	30410368	As the online data analysis indicated that high APC11 mRNA expression predicated only worse prognosis for lung adenocarcinoma, but not for lung squamous cell carcinoma.	('lung squamous cell carcinoma', 'Disease', (139, 167))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (106, 125))	('lung adenocarcinoma', 'Disease', (106, 125))	('high', 'Var', (43, 47))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (144, 167))	('APC11', 'Gene', '51529', (48, 53))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (106, 125))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (139, 167))	('si', 'Chemical', 'MESH:D012825', (98, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (158, 167))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('APC11', 'Gene', (48, 53))	('si', 'Chemical', 'MESH:D012825', (65, 67))	('si', 'Chemical', 'MESH:D012825', (24, 26))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (139, 167))
49894	30410368	In addition, knockdown of APC11 inhibited colony forming ability of both H1299 and H358 cells (Figure 3C and D).	('APC11', 'Gene', '51529', (26, 31))	('inhibited', 'NegReg', (32, 41))	('H1299', 'CellLine', 'CVCL:0060', (73, 78))	('APC11', 'Gene', (26, 31))	('H358', 'CellLine', 'CVCL:1559', (83, 87))	('colony forming ability', 'CPA', (42, 64))	('knockdown', 'Var', (13, 22))
49897	30410368	As expected, silencing of APC11 caused mitosis arrest in both H1299 and H358 cells (Figure 4A).	('APC11', 'Gene', '51529', (26, 31))	('H1299', 'CellLine', 'CVCL:0060', (62, 67))	('si', 'Chemical', 'MESH:D012825', (43, 45))	('APC11', 'Gene', (26, 31))	('mitosis arrest', 'Disease', 'MESH:D006323', (39, 53))	('si', 'Chemical', 'MESH:D012825', (13, 15))	('mitosis arrest', 'Disease', (39, 53))	('H358', 'CellLine', 'CVCL:1559', (72, 76))	('silencing', 'Var', (13, 22))
49899	30410368	Of note, the results of Transwell assay showed that knockdown of APC11 caused an apparent reduction of migrative and invasive capacity in both H1299 and H358 cells (Figure 4B and C).	('reduction', 'NegReg', (90, 99))	('APC11', 'Gene', '51529', (65, 70))	('si', 'Chemical', 'MESH:D012825', (121, 123))	('H1299', 'CellLine', 'CVCL:0060', (143, 148))	('APC11', 'Gene', (65, 70))	('knockdown', 'Var', (52, 61))	('H358', 'CellLine', 'CVCL:1559', (153, 157))
49900	30410368	The in vitro experiments revealed that silencing of APC11 significantly inhibited lung adenocarcinoma cell proliferation, migration, and invasion.	('si', 'Chemical', 'MESH:D012825', (39, 41))	('si', 'Chemical', 'MESH:D012825', (141, 143))	('invasion', 'CPA', (137, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (82, 101))	('APC11', 'Gene', '51529', (52, 57))	('silencing', 'Var', (39, 48))	('si', 'Chemical', 'MESH:D012825', (58, 60))	('inhibited', 'NegReg', (72, 81))	('migration', 'CPA', (122, 131))	('lung adenocarcinoma', 'Disease', (82, 101))	('APC11', 'Gene', (52, 57))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (82, 101))
49904	30410368	We further divided patients into two groups, the weak and moderate staining of APC11 as negative expression group and the strong staining as positive expression group.	('patients', 'Species', '9606', (19, 27))	('si', 'Chemical', 'MESH:D012825', (156, 158))	('weak', 'Var', (49, 53))	('APC11', 'Gene', '51529', (79, 84))	('APC11', 'Gene', (79, 84))	('si', 'Chemical', 'MESH:D012825', (143, 145))	('si', 'Chemical', 'MESH:D012825', (103, 105))
49907	30410368	As shown in Figure 5B, high APC11 levels apparently affected the OS of all NSCLC patients.	('high', 'Var', (23, 27))	('APC11', 'Gene', '51529', (28, 33))	('patients', 'Species', '9606', (81, 89))	('NSCLC', 'Disease', (75, 80))	('affected', 'Reg', (52, 60))	('APC11', 'Gene', (28, 33))	('NSCLC', 'Disease', 'MESH:D002289', (75, 80))
49911	30410368	It ubiquitinates the anaphase inhibitor securin to initiate sister chromatid separation and ubiquitinates the CyclinB1 to exit from mitosis.	('mitosis', 'Disease', (132, 139))	('sister chromatid separation', 'CPA', (60, 87))	('mitosis', 'Disease', 'None', (132, 139))	('si', 'Chemical', 'MESH:D012825', (136, 138))	('si', 'Chemical', 'MESH:D012825', (60, 62))	('CyclinB1', 'Gene', '891', (110, 118))	('securin', 'Gene', (40, 47))	('securin', 'Gene', '9232', (40, 47))	('ubiquitinates', 'Var', (92, 105))	('CyclinB1', 'Gene', (110, 118))
49913	30410368	APC11 silencing arrested lung cancer cells in M phase and inhibited cell proliferation and colon formation.	('APC11', 'Gene', '51529', (0, 5))	('M phase', 'CPA', (46, 53))	('cell proliferation', 'CPA', (68, 86))	('lung cancer', 'Disease', (25, 36))	('lung cancer', 'Phenotype', 'HP:0100526', (25, 36))	('APC11', 'Gene', (0, 5))	('inhibited', 'NegReg', (58, 67))	('si', 'Chemical', 'MESH:D012825', (6, 8))	('silencing', 'Var', (6, 15))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('lung cancer', 'Disease', 'MESH:D008175', (25, 36))
49914	30410368	Furthermore, knockdown of APC11 decreased cell migrative and invasive capacities.	('APC11', 'Gene', '51529', (26, 31))	('APC11', 'Gene', (26, 31))	('knockdown', 'Var', (13, 22))	('si', 'Chemical', 'MESH:D012825', (65, 67))	('decreased', 'NegReg', (32, 41))
49917	30410368	Mutations in several subunits of APC/C had been reported in cancer samples and were implied as the cause for carcinogenesis.	('APC', 'Gene', (33, 36))	('APC', 'Gene', '324', (33, 36))	('carcinogenesis', 'Disease', 'MESH:D063646', (109, 123))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('cause', 'Reg', (99, 104))	('reported', 'Reg', (48, 56))	('carcinogenesis', 'Disease', (109, 123))	('cancer', 'Disease', (60, 66))	('Mutations', 'Var', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
49923	30410368	In the present study, we found that silencing of APC11 significantly impaired the cell proliferative and colon forming abilities.	('si', 'Chemical', 'MESH:D012825', (36, 38))	('silencing', 'Var', (36, 45))	('APC11', 'Gene', '51529', (49, 54))	('APC11', 'Gene', (49, 54))	('impaired', 'NegReg', (69, 77))	('si', 'Chemical', 'MESH:D012825', (55, 57))
49924	30410368	Furthermore, APC11 silencing induced cell apoptosis and cell cycle arrest.	('cell cycle arrest', 'Phenotype', 'HP:0011018', (56, 73))	('cell apoptosis', 'CPA', (37, 51))	('APC11', 'Gene', '51529', (13, 18))	('si', 'Chemical', 'MESH:D012825', (19, 21))	('cell cycle arrest', 'CPA', (56, 73))	('silencing', 'Var', (19, 28))	('APC11', 'Gene', (13, 18))	('si', 'Chemical', 'MESH:D012825', (48, 50))
49926	30410368	Interestingly, we also found that knockdown of APC11 inhibited lung cancer cell migration and invasion, which implicated the role of APC11 in controlling cell motility.	('invasion', 'CPA', (94, 102))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('lung cancer', 'Disease', 'MESH:D008175', (63, 74))	('APC11', 'Gene', '51529', (47, 52))	('inhibited', 'NegReg', (53, 62))	('APC11', 'Gene', (133, 138))	('APC11', 'Gene', (47, 52))	('lung cancer', 'Disease', (63, 74))	('lung cancer', 'Phenotype', 'HP:0100526', (63, 74))	('si', 'Chemical', 'MESH:D012825', (98, 100))	('knockdown', 'Var', (34, 43))	('APC11', 'Gene', '51529', (133, 138))
49929	30410368	In summary, our data indicated that overexpression of APC11 was significantly associated with unfavorable outcome, and it was also suggested that overexpression of APC11 could be an independent prognostic factor for lung adenocarcinoma patients.	('APC11', 'Gene', '51529', (54, 59))	('associated', 'Reg', (78, 88))	('lung adenocarcinoma', 'Disease', (216, 235))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (216, 235))	('si', 'Chemical', 'MESH:D012825', (156, 158))	('si', 'Chemical', 'MESH:D012825', (46, 48))	('APC11', 'Gene', '51529', (164, 169))	('patients', 'Species', '9606', (236, 244))	('APC11', 'Gene', (54, 59))	('overexpression', 'Var', (146, 160))	('carcinoma', 'Phenotype', 'HP:0030731', (226, 235))	('si', 'Chemical', 'MESH:D012825', (64, 66))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (216, 235))	('APC11', 'Gene', (164, 169))	('overexpression', 'Var', (36, 50))
49930	30410368	In addition, knockdown of APC11 could significantly inhibit lung cancer cell proliferation, colon formation, migration, and invasion by in vitro study.	('APC11', 'Gene', '51529', (26, 31))	('inhibit', 'NegReg', (52, 59))	('lung cancer', 'Disease', (60, 71))	('si', 'Chemical', 'MESH:D012825', (128, 130))	('lung cancer', 'Phenotype', 'HP:0100526', (60, 71))	('APC11', 'Gene', (26, 31))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('lung cancer', 'Disease', 'MESH:D008175', (60, 71))	('migration', 'CPA', (109, 118))	('si', 'Chemical', 'MESH:D012825', (38, 40))	('invasion', 'CPA', (124, 132))	('knockdown', 'Var', (13, 22))	('colon formation', 'CPA', (92, 107))
50039	28294568	Systems Pharmacology-Based Discovery of Natural Products for Precision Oncology Through Targeting Cancer Mutated Genes Massive cancer genomics data have facilitated the rapid revolution of a novel oncology drug discovery paradigm through targeting clinically relevant driver genes or mutations for the development of precision oncology.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('Cancer', 'Phenotype', 'HP:0002664', (98, 104))	('Oncology', 'Phenotype', 'HP:0002664', (71, 79))	('mutations', 'Var', (284, 293))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('oncology', 'Phenotype', 'HP:0002664', (327, 335))	('cancer', 'Disease', (127, 133))	('oncology', 'Phenotype', 'HP:0002664', (197, 205))
50042	28294568	In case studies, we computationally identified novel anticancer indications for several US Food and Drug Administration-approved or clinically investigational natural products (e.g., resveratrol, quercetin, genistein, and fisetin) through targeting significantly mutated genes in multiple cancer types.	('multiple cancer', 'Disease', (280, 295))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('cancer', 'Disease', (57, 63))	('cancer', 'Phenotype', 'HP:0002664', (289, 295))	('multiple cancer', 'Disease', 'MESH:D009369', (280, 295))	('quercetin', 'Chemical', 'MESH:D011794', (196, 205))	('fisetin', 'Chemical', 'MESH:C017875', (222, 229))	('genes', 'Gene', (271, 276))	('mutated', 'Var', (263, 270))	('resveratrol', 'Chemical', 'MESH:D000077185', (183, 194))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('cancer', 'Disease', 'MESH:D009369', (289, 295))	('genistein', 'Chemical', 'MESH:D019833', (207, 216))	('cancer', 'Disease', (289, 295))
50044	28294568	Massive cancer genomic data has facilitated the revolution of a novel oncology drug discovery paradigm through targeting clinically relevant driver genes or mutations for the development of precision oncology.	('cancer', 'Disease', (8, 14))	('mutations', 'Var', (157, 166))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('oncology', 'Phenotype', 'HP:0002664', (70, 78))	('oncology', 'Phenotype', 'HP:0002664', (200, 208))	('cancer', 'Disease', 'MESH:D009369', (8, 14))
50047	28294568	WHAT THIS STUDY ADDS TO OUR KNOWLEDGE    This study demonstrates that a systems pharmacology framework that integrates drug-target interaction network of natural products and cancer mutant genes from the cancer genome projects would be useful for the development of novel targeted cancer therapies.	('cancer', 'Disease', (204, 210))	('cancer', 'Disease', 'MESH:D009369', (204, 210))	('cancer', 'Disease', 'MESH:D009369', (281, 287))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('cancer', 'Disease', (175, 181))	('cancer', 'Disease', (281, 287))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('cancer', 'Phenotype', 'HP:0002664', (281, 287))	('mutant', 'Var', (182, 188))
50048	28294568	In the past several decades, traditional oncology drug discovery that focused on synthesized compounds has shown high risk in clinical trials.1 A recent study revealed that ~7.5% of the oncology drugs were able to enter phase I trials and only 33.2% of the drugs that entered phase III trials were eventually approved.1 Compared with traditional oncology drugs, natural products are better templates with ideal pharmacokinetics/pharmacodynamics (PK/PD) properties, of which scaffolds are repeatedly considered "privileged" in drug discovery.2 So far, more than half of the new drugs introduced after 1990 could be traced to naturally derived products or their analogs.3, 4 Since natural products possess enormous structural and chemical diversity and are abundant, they have served as great inspiration for the next generation of cancer therapeutics.5, 6  With rapidly growing, revolutionary next-generation sequencing technologies, several large-scale cancer genome projects, such as The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC), have generated massive amounts of somatic mutation profiles.7 Such massive amounts of cancer genomic data have helped us better understand cancer biology and improve cancer prognosis, diagnosis, and treatment.8, 9 For most solid tumors, their genomes harbor hundreds of DNA-level genetic alterations, which are composed of massive bystander mutations ("passenger mutations") with no oncogenic potential and few cancer-driving genomic aberrations ("driver mutations").10 Driver mutations represent mutations that have a selective growth advantage in tumor cells, further contributing to tumor initiation, progression, and drug resistance via activating oncogenes or inactivating tumor suppressor genes.11 Therefore, cancer drugs that target clinically relevant driver mutations, such as kinase inhibitors, have shown high selectivity on tumor cells and demonstrated valuable opportunities for precision oncology.12 For example, BCR-ABL mutations have been found to predict clinical responses to imatinib, the first US Food and Drug Administration (FDA)-approved targeted agent, in chronic myelogenous leukemia (CML).	('cancer', 'Disease', 'MESH:D009369', (1237, 1243))	('cancer', 'Disease', 'MESH:D009369', (1482, 1488))	('myelogenous leukemia', 'Phenotype', 'HP:0012324', (2159, 2179))	('oncology', 'Phenotype', 'HP:0002664', (1973, 1981))	('oncology', 'Phenotype', 'HP:0002664', (346, 354))	('tumor', 'Disease', 'MESH:D009369', (1657, 1662))	('cancer', 'Disease', 'MESH:D009369', (830, 836))	('tumor', 'Disease', 'MESH:D009369', (1300, 1305))	('tumor', 'Disease', (1749, 1754))	('predict', 'Reg', (2035, 2042))	('chronic myelogenous leukemia', 'Phenotype', 'HP:0005506', (2151, 2179))	('solid tumors', 'Disease', 'MESH:D009369', (1294, 1306))	('cancer', 'Disease', (1786, 1792))	('tumors', 'Phenotype', 'HP:0002664', (1300, 1306))	('cancer', 'Disease', 'MESH:D009369', (1210, 1216))	('oncology', 'Phenotype', 'HP:0002664', (186, 194))	('tumor', 'Disease', 'MESH:D009369', (1749, 1754))	('oncology', 'Phenotype', 'HP:0002664', (41, 49))	('BCR-ABL', 'Gene', '25', (1998, 2005))	('tumor', 'Phenotype', 'HP:0002664', (1657, 1662))	('cancer', 'Disease', (953, 959))	('cancer', 'Disease', (1157, 1163))	('tumor', 'Disease', (1907, 1912))	('tumor', 'Phenotype', 'HP:0002664', (1300, 1305))	('tumor', 'Disease', (1620, 1625))	('cancer', 'Phenotype', 'HP:0002664', (953, 959))	('cancer', 'Phenotype', 'HP:0002664', (1157, 1163))	('drug resistance', 'Phenotype', 'HP:0020174', (1692, 1707))	('mutations', 'Var', (2006, 2015))	('cancer', 'Disease', (1237, 1243))	('cancer', 'Disease', (1482, 1488))	('tumor', 'Disease', 'MESH:D009369', (1907, 1912))	('tumor', 'Phenotype', 'HP:0002664', (1749, 1754))	('cancer', 'Disease', (830, 836))	('tumor', 'Disease', 'MESH:D009369', (1620, 1625))	('CML', 'Disease', 'MESH:D015464', (2181, 2184))	('chronic myelogenous leukemia', 'Disease', (2151, 2179))	('chronic myelogenous leukemia', 'Disease', 'MESH:D015464', (2151, 2179))	('leukemia', 'Phenotype', 'HP:0001909', (2171, 2179))	('cancer', 'Phenotype', 'HP:0002664', (1237, 1243))	('cancer', 'Disease', 'MESH:D009369', (1786, 1792))	('CML', 'Disease', (2181, 2184))	('cancer', 'Disease', (1210, 1216))	('cancer', 'Phenotype', 'HP:0002664', (830, 836))	('Cancer', 'Phenotype', 'HP:0002664', (1038, 1044))	('PD', 'Disease', 'MESH:D010300', (449, 451))	('tumor initiation', 'Disease', 'MESH:D009369', (1657, 1673))	('solid tumors', 'Disease', (1294, 1306))	('Cancer', 'Phenotype', 'HP:0002664', (989, 995))	('BCR-ABL', 'Gene', (1998, 2005))	('cancer', 'Disease', 'MESH:D009369', (953, 959))	('cancer', 'Phenotype', 'HP:0002664', (1210, 1216))	('tumor', 'Phenotype', 'HP:0002664', (1907, 1912))	('tumor initiation', 'Disease', (1657, 1673))	('tumor', 'Phenotype', 'HP:0002664', (1620, 1625))	('cancer', 'Disease', 'MESH:D009369', (1157, 1163))	('tumor', 'Disease', (1657, 1662))	('tumor', 'Disease', (1300, 1305))
50071	28294568	The alternative hypothesis asserts that cancer drug target proteins are more likely to be protein products of SMGs than other proteins for a natural product that has a potential anticancer indication.	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('SMGs', 'Var', (110, 114))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('cancer', 'Disease', (40, 46))	('cancer', 'Disease', (182, 188))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))
50076	28294568	Among the 409 FDA-approved or clinically investigational natural products, eight are linked by over 100 target proteins: DB04077 (glycerol), DB04216 (quercetin), DB02709 (resveratrol), DB00396 (progesterone), DB04272 (citric acid), DB07352 (apigenin), DB01645 (genistein), and DB00131 (adenosine monophosphate).	('DB00131', 'Gene', (277, 284))	('resveratrol', 'Chemical', 'MESH:D000077185', (171, 182))	('adenosine monophosphate', 'Chemical', 'MESH:D000249', (286, 309))	('DB07352', 'Var', (232, 239))	('apigenin', 'Chemical', 'MESH:D047310', (241, 249))	('progesterone', 'Chemical', 'MESH:D011374', (194, 206))	('DB01645', 'Var', (252, 259))	('DB04272', 'Var', (209, 216))	('DB04077', 'Var', (121, 128))	('DB00396', 'Var', (185, 192))	('DB07352', 'Chemical', '-', (232, 239))	('DB04077', 'Chemical', '-', (121, 128))	('quercetin', 'Chemical', 'MESH:D011794', (150, 159))	('DB04216', 'Chemical', '-', (141, 148))	('DB04272', 'Chemical', '-', (209, 216))	('DB00396', 'Chemical', '-', (185, 192))	('DB02709', 'Var', (162, 169))	('DB02709', 'Chemical', '-', (162, 169))	('genistein', 'Chemical', 'MESH:D019833', (261, 270))	('citric acid', 'Chemical', 'MESH:D019343', (218, 229))	('glycerol', 'Chemical', 'MESH:D005990', (130, 138))	('DB04216', 'Var', (141, 148))	('DB01645', 'Chemical', '-', (252, 259))	('DB00131', 'Chemical', '-', (277, 284))
50085	28294568	We further developed an integrated statistical systems pharmacology framework with the permutation test for prioritizing new anticancer indications of natural products via targeting cancer relevant mutations and mutant genes.	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('mutant genes', 'Var', (212, 224))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('cancer', 'Disease', (182, 188))
50088	28294568	Resveratrol is a non-flavonoid polyphenol in grape skin and has been reported to have antioxidative and proapoptotic effects in several cancer cell lines.31 Several ongoing or completed clinical trials (http://clinicaltrials.gov/) for resveratrol are being conducted to treat various cancers, such as colon cancer (NCT00256334), neuroendocrine tumor (NCT01476592), and liver cancer (NCT02261844).	('NCT02261844', 'Var', (383, 394))	('cancer', 'Disease', 'MESH:D009369', (284, 290))	('cancers', 'Disease', 'MESH:D009369', (284, 291))	('Resveratrol', 'Chemical', 'MESH:D000077185', (0, 11))	('neuroendocrine tumor', 'Disease', (329, 349))	('cancer', 'Phenotype', 'HP:0002664', (375, 381))	('cancer', 'Disease', (136, 142))	('colon cancer', 'Disease', (301, 313))	('flavonoid', 'Chemical', 'MESH:D005419', (21, 30))	('liver cancer', 'Disease', 'MESH:D006528', (369, 381))	('neuroendocrine tumor', 'Phenotype', 'HP:0100634', (329, 349))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('cancer', 'Disease', 'MESH:D009369', (307, 313))	('NCT00256334', 'Var', (315, 326))	('liver cancer', 'Phenotype', 'HP:0002896', (369, 381))	('neuroendocrine tumor', 'Disease', 'MESH:D018358', (329, 349))	('cancer', 'Disease', 'MESH:D009369', (375, 381))	('liver cancer', 'Disease', (369, 381))	('colon cancer', 'Phenotype', 'HP:0003003', (301, 313))	('cancers', 'Phenotype', 'HP:0002664', (284, 291))	('cancer', 'Disease', (284, 290))	('NCT01476592', 'Var', (351, 362))	('cancers', 'Disease', (284, 291))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('cancer', 'Phenotype', 'HP:0002664', (284, 290))	('cancer', 'Disease', (307, 313))	('colon cancer', 'Disease', 'MESH:D015179', (301, 313))	('polyphenol', 'Chemical', 'MESH:D059808', (31, 41))	('tumor', 'Phenotype', 'HP:0002664', (344, 349))	('cancer', 'Phenotype', 'HP:0002664', (307, 313))	('resveratrol', 'Chemical', 'MESH:D000077185', (235, 246))	('cancer', 'Disease', (375, 381))
50093	28294568	Recently, several clinical trials for quercetin to treat or prevent various cancers are ongoing or completed, including prostate cancer (NCT01912820), colorectal cancer (NCT00003365), renal cell carcinoma (NCT02446795), and advanced pancreatic cancer (NCT01879878).	('cancers', 'Phenotype', 'HP:0002664', (76, 83))	('cancers', 'Disease', (76, 83))	('NCT01912820', 'Var', (137, 148))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (184, 204))	('NCT00003365', 'Var', (170, 181))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('colorectal cancer', 'Disease', 'MESH:D015179', (151, 168))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (233, 250))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('colorectal cancer', 'Disease', (151, 168))	('prostate cancer', 'Disease', 'MESH:D011471', (120, 135))	('prostate cancer', 'Phenotype', 'HP:0012125', (120, 135))	('cancers', 'Disease', 'MESH:D009369', (76, 83))	('pancreatic cancer', 'Disease', 'MESH:D010190', (233, 250))	('renal cell carcinoma', 'Disease', (184, 204))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (184, 204))	('prostate cancer', 'Disease', (120, 135))	('quercetin', 'Chemical', 'MESH:D011794', (38, 47))	('carcinoma', 'Phenotype', 'HP:0030731', (195, 204))	('colorectal cancer', 'Phenotype', 'HP:0003003', (151, 168))	('pancreatic cancer', 'Disease', (233, 250))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('NCT02446795', 'Var', (206, 217))
50097	28294568	Figure 4 c shows that genistein is predicted to have potential anticancer indications for 11 cancer types, such as BLCA (Z = 6.24, q < 1.0 x 10-5), BRCA (Z = 7.03, q < 1.0 x 10-5), and LUAD (Z = 9.74, q < 1.0 x 10-5).	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('cancer', 'Disease', (67, 73))	('LUAD', 'Disease', (185, 189))	('BRCA', 'Gene', '672', (148, 152))	('BRCA', 'Gene', (148, 152))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('BLCA', 'Chemical', '-', (115, 119))	('genistein', 'Var', (22, 31))	('BLCA', 'Disease', (115, 119))	('genistein', 'Chemical', 'MESH:D019833', (22, 31))
50098	28294568	A recent study has reported that genistein acted as a chemotherapeutic agent against different types of cancers via altering apoptosis, cell cycle, and angiogenesis or inhibiting metastasis.39 In addition, genistein has been widely used and tested in several clinical cancer studies, such as breast cancer (NCT00244933), bladder cancer (NCT00118040), prostate cancer (NCT01325311), and lung cancer (NCT01628471).	('cancer', 'Phenotype', 'HP:0002664', (329, 335))	('cancer', 'Phenotype', 'HP:0002664', (360, 366))	('prostate cancer', 'Disease', 'MESH:D011471', (351, 366))	('prostate cancer', 'Phenotype', 'HP:0012125', (351, 366))	('breast cancer', 'Phenotype', 'HP:0003002', (292, 305))	('cancer', 'Disease', (391, 397))	('cancers', 'Phenotype', 'HP:0002664', (104, 111))	('prostate cancer', 'Disease', (351, 366))	('cancer', 'Disease', (104, 110))	('cancers', 'Disease', (104, 111))	('cancer', 'Disease', 'MESH:D009369', (299, 305))	('cancer', 'Disease', 'MESH:D009369', (268, 274))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('NCT01325311', 'Var', (368, 379))	('breast cancer', 'Disease', 'MESH:D001943', (292, 305))	('cancer', 'Disease', 'MESH:D009369', (329, 335))	('cancer', 'Disease', 'MESH:D009369', (360, 366))	('breast cancer', 'Disease', (292, 305))	('genistein', 'Chemical', 'MESH:D019833', (33, 42))	('NCT00118040', 'Var', (337, 348))	('lung cancer', 'Disease', (386, 397))	('bladder cancer', 'Phenotype', 'HP:0009725', (321, 335))	('cancer', 'Disease', 'MESH:D009369', (391, 397))	('cancer', 'Disease', (299, 305))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('cancers', 'Disease', 'MESH:D009369', (104, 111))	('cancer', 'Disease', (268, 274))	('lung cancer', 'Disease', 'MESH:D008175', (386, 397))	('bladder cancer', 'Disease', 'MESH:D001749', (321, 335))	('bladder cancer', 'Disease', (321, 335))	('cancer', 'Disease', (329, 335))	('cancer', 'Disease', (360, 366))	('NCT00244933', 'Var', (307, 318))	('genistein', 'Chemical', 'MESH:D019833', (206, 215))	('cancer', 'Phenotype', 'HP:0002664', (268, 274))	('cancer', 'Phenotype', 'HP:0002664', (299, 305))	('lung cancer', 'Phenotype', 'HP:0100526', (386, 397))
50107	28294568	Data quality and data incompleteness of the cancer mutant genes may be influenced by the limited cohorts of cancer genome projects and tumor heterogeneity.	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('cancer', 'Disease', (44, 50))	('mutant', 'Var', (51, 57))	('tumor', 'Disease', (135, 140))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))	('cancer', 'Disease', (108, 114))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
50110	28294568	Fourth, it is commonly known that most cancer significantly mutated genes are not targetable by current small molecular drugs, owing to the "undruggable" properties of certain cancer mutant genes (e.g., KRAS).	('KRAS', 'Gene', (203, 207))	('KRAS', 'Gene', '3845', (203, 207))	('cancer', 'Disease', (39, 45))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('mutant', 'Var', (183, 189))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('cancer', 'Disease', (176, 182))	('cancer', 'Disease', 'MESH:D009369', (176, 182))
50177	25654522	Polycyclic aromatic hydrocarbons and higher aldehydes have been detected in the breathing zone of cooks during frying.	('Polycyclic', 'Var', (0, 10))	('Polycyclic aromatic hydrocarbons', 'Chemical', 'MESH:D011084', (0, 32))	('higher aldehydes', 'MPA', (37, 53))	('aldehydes', 'Chemical', 'MESH:D000447', (44, 53))
50207	32215870	Moreover, high ratios of CD8+ T cells over CD68+ myeloid cells or CD163+ TAMs bear favorable predictive and prognostic implications in patients with various cancers.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('patients', 'Species', '9606', (135, 143))	('CD8', 'Gene', (25, 28))	('TAMs', 'Chemical', '-', (73, 77))	('CD163+', 'Var', (66, 72))	('cancers', 'Disease', 'MESH:D009369', (157, 164))	('cancers', 'Phenotype', 'HP:0002664', (157, 164))	('CD8', 'Gene', '925', (25, 28))	('cancers', 'Disease', (157, 164))
50223	32215870	The tissue specimens were categorized according to the number of cells per mm2 in three spatial compartments: outer invasive margin (0-500 mum outside the tumor invasion front), inner invasive margin (0-500 mum inside the tumor invasion front), and in the tumor core (>500 mum inside the invasion front).	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('0-500 mum', 'Var', (133, 142))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('tumor', 'Disease', 'MESH:D009369', (222, 227))	('tumor', 'Disease', (155, 160))	('tumor', 'Disease', 'MESH:D009369', (256, 261))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('tumor', 'Disease', (222, 227))	('tumor', 'Phenotype', 'HP:0002664', (256, 261))	('0-500 mum', 'Var', (201, 210))	('tumor', 'Disease', (256, 261))
50272	32215870	Epithelial to mesenchymal transition is not the only way in which TGF activity may lead to fibrosis mediated in cancer.	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('lead to', 'Reg', (83, 90))	('activity', 'Var', (70, 78))	('fibrosis', 'Disease', 'MESH:D005355', (91, 99))	('fibrosis', 'Disease', (91, 99))
50283	32215870	According to this view, the metabolic impairment of oxidative phosphorylation triggers a cascade of events that include the fractal shape of tumors, the secretion of collagen by CAFs, the production of lactic acid that elicits an acidic TME with direct and indirect effects on innate and adaptive immune functions.	('impairment', 'Var', (38, 48))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumors', 'Disease', (141, 147))	('CAFs', 'Gene', (178, 182))	('triggers', 'Reg', (78, 86))	('metabolic impairment', 'Var', (28, 48))	('tumors', 'Disease', 'MESH:D009369', (141, 147))	('lactic acid', 'Chemical', 'MESH:D019344', (202, 213))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('fractal shape', 'CPA', (124, 137))	('CAFs', 'Gene', '6899', (178, 182))	('secretion', 'MPA', (153, 162))	('elicits', 'Reg', (219, 226))
50293	32215870	It is likely that hypoxia is at least a cause of increased VEGF family members including VEGF-A, -C, and -D presence in the TME.	('presence', 'Var', (108, 116))	('VEGF', 'Gene', '7422', (89, 93))	('VEGF', 'Gene', '7422', (59, 63))	('VEGF-A, -C, and -D', 'Gene', '7422;7424;2277', (89, 107))	('hypoxia', 'Disease', 'MESH:D000860', (18, 25))	('VEGF', 'Gene', (89, 93))	('VEGF', 'Gene', (59, 63))	('hypoxia', 'Disease', (18, 25))
50304	32215870	It is, therefore, possible that for unknown reasons an abrupt reduction in the gradient of chemo-attraction from the center to the periphery, such as expression of CXCR3 and CCR5 associated chemokines, may reduce the chemo-attractive propulsion that occurs at the periphery.	('CCR5', 'Gene', (174, 178))	('expression', 'Var', (150, 160))	('CXCR3', 'Gene', (164, 169))	('reduce', 'NegReg', (206, 212))	('CXCR3', 'Gene', '2833', (164, 169))	('chemo-attractive propulsion', 'CPA', (217, 244))	('reduction', 'NegReg', (62, 71))	('gradient of chemo-attraction', 'MPA', (79, 107))	('CCR5', 'Gene', '1234', (174, 178))
50319	32215870	Consequently, their targeting promotes the activation of immune responses against cancer as well exemplified by the potentiation of radiation effects by the inhibition of Mertk.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('Mertk', 'Gene', (171, 176))	('potentiation', 'PosReg', (116, 128))	('activation', 'PosReg', (43, 53))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('targeting', 'Var', (20, 29))	('inhibition', 'NegReg', (157, 167))	('radiation effects', 'CPA', (132, 149))	('immune responses', 'CPA', (57, 73))	('Mertk', 'Gene', '10461', (171, 176))
50325	32215870	Interestingly, both PI3K and STAT-3 signaling are prominent features of myeloid cell activation and, therefore, their role in immune modulation is often confused with the genuine alteration of intrinsic cancer pathways.	('myeloid cell', 'CPA', (72, 84))	('STAT-3', 'Gene', (29, 35))	('PI3K', 'Var', (20, 24))	('activation', 'PosReg', (85, 95))	('cancer', 'Disease', (203, 209))	('cancer', 'Disease', 'MESH:D009369', (203, 209))	('STAT-3', 'Gene', '6774', (29, 35))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))
50326	32215870	Interestingly, most studies referring to dysregulation of the PI3K pathway refer to mutations of genes involved in cancer cell signaling.	('cancer', 'Disease', (115, 121))	('PI3K pathway', 'Pathway', (62, 74))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('mutations', 'Var', (84, 93))	('cancer', 'Disease', 'MESH:D009369', (115, 121))
50330	32215870	Conversely, beta-catenin and MAPK activation have been associated with mutational status of genes within the respective pathways and are, therefore, to be considered purely related to activation of cancer cell-intrinsic pathways.	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('cancer', 'Disease', (198, 204))	('beta-catenin', 'Gene', (12, 24))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('activation', 'PosReg', (34, 44))	('beta-catenin', 'Gene', '1499', (12, 24))	('MAPK', 'Gene', (29, 33))	('mutational status', 'Var', (71, 88))
50377	32528035	Likewise, miR-410 was found to increase the levels of phosphorylated Akt in NSCLC.	('Akt', 'Gene', (69, 72))	('NSCLC', 'Disease', (76, 81))	('NSCLC', 'Disease', 'MESH:D002289', (76, 81))	('miR-410', 'Var', (10, 17))	('Akt', 'Gene', '207', (69, 72))	('levels of phosphorylated', 'MPA', (44, 68))	('NSCLC', 'Phenotype', 'HP:0030358', (76, 81))	('increase', 'PosReg', (31, 39))
50380	32528035	In addition, cancer stem cells (CSCs) and Akt phosphorylation are positively correlated with radioresistance and EMT.	('Akt', 'Gene', (42, 45))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('phosphorylation', 'Var', (46, 61))	('correlated', 'Reg', (77, 87))	('cancer', 'Disease', (13, 19))	('Akt', 'Gene', '207', (42, 45))	('cancer', 'Disease', 'MESH:D009369', (13, 19))	('EMT', 'CPA', (113, 116))	('radioresistance', 'CPA', (93, 108))
50381	32528035	Consequently, mounting evidence indicates that miR-410 might be a promoter of EMT and radioresistance in NSCLC.	('NSCLC', 'Disease', 'MESH:D002289', (105, 110))	('EMT', 'CPA', (78, 81))	('NSCLC', 'Phenotype', 'HP:0030358', (105, 110))	('miR-410', 'Var', (47, 54))	('radioresistance', 'CPA', (86, 101))	('NSCLC', 'Disease', (105, 110))	('promoter', 'PosReg', (66, 74))
50383	32528035	Moreover, the data also suggested that miR-410-induced EMT might significantly contribute to the enhanced radioresistance, which might be a novel mechanism of radioresistance in NSCLC.	('NSCLC', 'Disease', (178, 183))	('miR-410-induced', 'Var', (39, 54))	('EMT', 'CPA', (55, 58))	('NSCLC', 'Disease', 'MESH:D002289', (178, 183))	('radioresistance', 'CPA', (106, 121))	('enhanced', 'PosReg', (97, 105))	('NSCLC', 'Phenotype', 'HP:0030358', (178, 183))
50384	32528035	Further investigation with NSCLC specimens also demonstrated that miR-410 was positively correlated with EMT.	('NSCLC', 'Disease', (27, 32))	('NSCLC', 'Disease', 'MESH:D002289', (27, 32))	('EMT', 'CPA', (105, 108))	('NSCLC', 'Phenotype', 'HP:0030358', (27, 32))	('miR-410', 'Var', (66, 73))	('correlated', 'Reg', (89, 99))
50390	32528035	Interestingly, morphological changes from the typical spindle-like shape of A549 and H1299 cells to a cobblestone-like shape were observed upon miR-410 knockdown, whereas ectopic expression of miR-410 resulted in more PC9 and SPC-A1 cells with a spindle-like shape (Fig.	('knockdown', 'Var', (152, 161))	('miR-410', 'Gene', (144, 151))	('A549', 'CellLine', 'CVCL:0023', (76, 80))	('more', 'PosReg', (213, 217))	('PC9', 'Gene', (218, 221))	('SPC-A1', 'Gene', (226, 232))	('SPC-A1', 'Gene', '27032', (226, 232))	('H1299', 'CellLine', 'CVCL:0060', (85, 90))	('PC9', 'Gene', '255738', (218, 221))	('spindle-like shape', 'CPA', (246, 264))
50391	32528035	In addition, the protein levels of epithelial marker (E-cadherin) were notably increased, and mesenchymal markers (N-cadherin, Vimentin, and Slug) were significantly decreased in A549-Inh and H1299-Inh cells.	('A549', 'CellLine', 'CVCL:0023', (179, 183))	('increased', 'PosReg', (79, 88))	('Slug', 'Gene', '6591', (141, 145))	('Vimentin', 'MPA', (127, 135))	('decreased', 'NegReg', (166, 175))	('N-cadherin', 'Gene', (115, 125))	('A549-Inh', 'Var', (179, 187))	('Slug', 'Gene', (141, 145))	('H1299-Inh', 'CellLine', 'CVCL:0060', (192, 201))	('N-cadherin', 'Gene', '1000', (115, 125))	('H1299-Inh', 'Var', (192, 201))	('mesenchymal', 'CPA', (94, 105))
50394	32528035	Our results showed that radioresistance was significantly decreased in A549-Inh and H1299-Inh cells but significantly increased in PC9-miR-410 and SPC-A1-miR-410 cells (Fig.	('H1299-Inh', 'CellLine', 'CVCL:0060', (84, 93))	('A549-Inh', 'Var', (71, 79))	('H1299-Inh', 'Var', (84, 93))	('decreased', 'NegReg', (58, 67))	('PC9', 'Gene', '255738', (131, 134))	('SPC-A1', 'Gene', '27032', (147, 153))	('increased', 'PosReg', (118, 127))	('radioresistance', 'CPA', (24, 39))	('PC9', 'Gene', (131, 134))	('SPC-A1', 'Gene', (147, 153))	('A549', 'CellLine', 'CVCL:0023', (71, 75))
50396	32528035	The protein levels of gamma-H2AX at 4 h after irradiation were significantly higher in A549-Inh and H1299-Inh cells but significantly lower in PC9-miR-410 and SPC-A1-miR-410 cells (Fig.	('SPC-A1', 'Gene', (159, 165))	('PC9', 'Gene', (143, 146))	('protein levels', 'MPA', (4, 18))	('lower', 'NegReg', (134, 139))	('H1299-Inh', 'Var', (100, 109))	('SPC-A1', 'Gene', '27032', (159, 165))	('A549', 'CellLine', 'CVCL:0023', (87, 91))	('higher', 'PosReg', (77, 83))	('gamma-H2AX', 'Chemical', '-', (22, 32))	('PC9', 'Gene', '255738', (143, 146))	('H1299-Inh', 'CellLine', 'CVCL:0060', (100, 109))
50398	32528035	Thus, the data revealed that miR-410 increased radioresistance and might be associated with enhanced DSB repair in NSCLC cells.	('miR-410', 'Var', (29, 36))	('radioresistance', 'CPA', (47, 62))	('NSCLC', 'Disease', (115, 120))	('NSCLC', 'Disease', 'MESH:D002289', (115, 120))	('increased', 'PosReg', (37, 46))	('DSB repair', 'CPA', (101, 111))	('DSB', 'Chemical', '-', (101, 104))	('NSCLC', 'Phenotype', 'HP:0030358', (115, 120))	('enhanced', 'PosReg', (92, 100))
50404	32528035	The direct interaction between miR-410 and the 3'-UTR of PTEN was then confirmed by a dual-luciferase reporter assay (Fig.	('PTEN', 'Gene', (57, 61))	('PTEN', 'Gene', '5728', (57, 61))	('miR-410', 'Var', (31, 38))
50405	32528035	Moreover, elevated protein levels of PTEN were observed in A549-Inh and H1299-Inh cells, whereas reduced expression of PTEN was detected in PC9-miR-410 and SPC-A1-miR-410 cells (Fig.	('PC9', 'Gene', '255738', (140, 143))	('H1299-Inh', 'Var', (72, 81))	('A549', 'CellLine', 'CVCL:0023', (59, 63))	('SPC-A1', 'Gene', (156, 162))	('PC9', 'Gene', (140, 143))	('SPC-A1', 'Gene', '27032', (156, 162))	('protein levels', 'MPA', (19, 33))	('PTEN', 'Gene', (37, 41))	('PTEN', 'Gene', (119, 123))	('PTEN', 'Gene', '5728', (37, 41))	('PTEN', 'Gene', '5728', (119, 123))	('elevated', 'PosReg', (10, 18))	('expression', 'MPA', (105, 115))	('H1299-Inh', 'CellLine', 'CVCL:0060', (72, 81))
50407	32528035	Collectively, these results confirmed that PTEN was a direct target of miR-410 and that it was posttranscriptionally regulated by miR-410 in NSCLC cells.	('miR-410', 'Var', (130, 137))	('miR-410', 'Gene', (71, 78))	('NSCLC', 'Disease', (141, 146))	('PTEN', 'Gene', (43, 47))	('PTEN', 'Gene', '5728', (43, 47))	('NSCLC', 'Disease', 'MESH:D002289', (141, 146))	('NSCLC', 'Phenotype', 'HP:0030358', (141, 146))
50409	32528035	Therefore, based on the results above, we tested whether miR-410 might exert its biological functions by activating the PI3K/mTOR pathway.	('mTOR', 'Gene', '2475', (125, 129))	('mTOR', 'Gene', (125, 129))	('miR-410', 'Var', (57, 64))	('tested', 'Reg', (42, 48))	('activating', 'Reg', (105, 115))
50411	32528035	In contrast, miR-410 knockdown in A549 and H1299 cells remarkably decreased the levels of phosphorylated Akt, mTOR, P70S6K, and 4E-BP1 (Fig.	('P70S6K', 'Gene', '6198', (116, 122))	('mTOR', 'Gene', (110, 114))	('Akt', 'Gene', '207', (105, 108))	('mTOR', 'Gene', '2475', (110, 114))	('4E-BP1', 'Gene', (128, 134))	('A549', 'CellLine', 'CVCL:0023', (34, 38))	('P70S6K', 'Gene', (116, 122))	('decreased', 'NegReg', (66, 75))	('Akt', 'Gene', (105, 108))	('H1299', 'CellLine', 'CVCL:0060', (43, 48))	('4E-BP1', 'Gene', '1978', (128, 134))	('knockdown', 'Var', (21, 30))	('miR-410', 'Gene', (13, 20))	('levels of phosphorylated', 'MPA', (80, 104))
50412	32528035	These results suggested that miR-410 indeed activated the PI3K/mTOR pathway in NSCLC cells.	('mTOR', 'Gene', (63, 67))	('NSCLC', 'Disease', 'MESH:D002289', (79, 84))	('miR-410', 'Var', (29, 36))	('NSCLC', 'Phenotype', 'HP:0030358', (79, 84))	('activated', 'PosReg', (44, 53))	('mTOR', 'Gene', '2475', (63, 67))	('NSCLC', 'Disease', (79, 84))
50413	32528035	Based on the results above that overexpression of miR-410 could promote both EMT and radioresistance in vitro, we next investigated the effects of specific blockade of the PI3K, Akt, or mTOR pathway on miR-410-induced EMT and radioresistance in miR-410-overexpressing PC9 and SPC-A1 cells.	('miR-410', 'Var', (50, 57))	('promote', 'PosReg', (64, 71))	('radioresistance', 'CPA', (85, 100))	('SPC-A1', 'Gene', (276, 282))	('SPC-A1', 'Gene', '27032', (276, 282))	('mTOR', 'Gene', (186, 190))	('Akt', 'Gene', '207', (178, 181))	('mTOR', 'Gene', '2475', (186, 190))	('PC9', 'Gene', (268, 271))	('PC9', 'Gene', '255738', (268, 271))	('blockade', 'NegReg', (156, 164))	('EMT', 'CPA', (218, 221))	('Akt', 'Gene', (178, 181))	('miR-410-induced', 'Gene', (202, 217))
50414	32528035	The effectiveness of different doses of PI3K inhibitor (LY294002), Akt inhibitor (MK-2206), and mTOR inhibitor (rapamycin) was confirmed first (Fig.	('mTOR', 'Gene', (96, 100))	('Akt', 'Gene', (67, 70))	('rapamycin', 'Chemical', 'MESH:D020123', (112, 121))	('LY294002', 'Var', (56, 64))	('mTOR', 'Gene', '2475', (96, 100))	('MK-2206', 'Chemical', 'MESH:C548887', (82, 89))	('LY294002', 'Chemical', 'MESH:C085911', (56, 64))	('Akt', 'Gene', '207', (67, 70))
50415	32528035	Further results showed that treatment with the specific PI3K, Akt or mTOR inhibitor drastically decreased the expression of N-cadherin, Vimentin, and Slug while elevating the expression of E-cadherin in PC9-miR-410 and SPC-A1-miR-410 cells (Fig.	('Akt', 'Gene', '207', (62, 65))	('N-cadherin', 'Gene', (124, 134))	('N-cadherin', 'Gene', '1000', (124, 134))	('expression', 'MPA', (175, 185))	('PC9', 'Gene', '255738', (203, 206))	('decreased', 'NegReg', (96, 105))	('Slug', 'Gene', (150, 154))	('SPC-A1', 'Gene', '27032', (219, 225))	('elevating', 'PosReg', (161, 170))	('SPC-A1', 'Gene', (219, 225))	('PC9', 'Gene', (203, 206))	('PI3K', 'Var', (56, 60))	('expression', 'MPA', (110, 120))	('Vimentin', 'Protein', (136, 144))	('Slug', 'Gene', '6591', (150, 154))	('E-cadherin', 'Protein', (189, 199))	('mTOR', 'Gene', (69, 73))	('Akt', 'Gene', (62, 65))	('mTOR', 'Gene', '2475', (69, 73))
50417	32528035	Similarly, the radioresistance of PC9-miR-410 and SPC-A1-miR-410 cells was significantly decreased after treatment with the PI3K, Akt, or mTOR inhibitor (Fig.	('PC9', 'Gene', '255738', (34, 37))	('mTOR', 'Gene', (138, 142))	('mTOR', 'Gene', '2475', (138, 142))	('SPC-A1', 'Gene', (50, 56))	('PC9', 'Gene', (34, 37))	('SPC-A1', 'Gene', '27032', (50, 56))	('PI3K', 'Var', (124, 128))	('Akt', 'Gene', '207', (130, 133))	('Akt', 'Gene', (130, 133))	('radioresistance', 'CPA', (15, 30))	('decreased', 'NegReg', (89, 98))
50418	32528035	Hence, these data illustrated that miR-410 promoted both the EMT process and radioresistance in NSCLC cells by activating PI3K/mTOR signaling.	('EMT process', 'CPA', (61, 72))	('radioresistance', 'CPA', (77, 92))	('NSCLC', 'Disease', (96, 101))	('promoted', 'PosReg', (43, 51))	('NSCLC', 'Disease', 'MESH:D002289', (96, 101))	('activating', 'PosReg', (111, 121))	('miR-410', 'Var', (35, 42))	('mTOR', 'Gene', (127, 131))	('mTOR', 'Gene', '2475', (127, 131))	('NSCLC', 'Phenotype', 'HP:0030358', (96, 101))
50422	32528035	In addition, the effectiveness of pVax-PTEN and siPTEN was further confirmed in miR-410 overexpression or knockdown NSCLC cells, respectively (Fig.	('NSCLC', 'Disease', 'MESH:D002289', (116, 121))	('overexpression', 'PosReg', (88, 102))	('PTEN', 'Gene', (50, 54))	('miR-410', 'Gene', (80, 87))	('NSCLC', 'Phenotype', 'HP:0030358', (116, 121))	('PTEN', 'Gene', '5728', (50, 54))	('knockdown', 'Var', (106, 115))	('PTEN', 'Gene', (39, 43))	('PTEN', 'Gene', '5728', (39, 43))	('NSCLC', 'Disease', (116, 121))
50424	32528035	Moreover, restoration of PTEN expression drastically decreased the levels of phosphorylated Akt, mTOR, P70S6K, and 4E-BP1 in PC9-miR-410 and SPC-A1-miR-410 cells (Fig.	('4E-BP1', 'Gene', (115, 121))	('phosphorylated', 'MPA', (77, 91))	('mTOR', 'Gene', '2475', (97, 101))	('restoration', 'Var', (10, 21))	('mTOR', 'Gene', (97, 101))	('PC9', 'Gene', '255738', (125, 128))	('levels', 'MPA', (67, 73))	('Akt', 'Gene', '207', (92, 95))	('P70S6K', 'Gene', '6198', (103, 109))	('PC9', 'Gene', (125, 128))	('4E-BP1', 'Gene', '1978', (115, 121))	('Akt', 'Gene', (92, 95))	('SPC-A1', 'Gene', '27032', (141, 147))	('P70S6K', 'Gene', (103, 109))	('decreased', 'NegReg', (53, 62))	('PTEN', 'Gene', (25, 29))	('PTEN', 'Gene', '5728', (25, 29))	('SPC-A1', 'Gene', (141, 147))
50426	32528035	Conversely, transfecting siPTEN in A549-Inh and H1299-Inh cells resulted in the opposite effects (Fig.	('A549', 'CellLine', 'CVCL:0023', (35, 39))	('transfecting', 'Var', (12, 24))	('PTEN', 'Gene', (27, 31))	('H1299-Inh', 'CellLine', 'CVCL:0060', (48, 57))	('PTEN', 'Gene', '5728', (27, 31))
50434	32528035	Thus, these data suggested that miR-410 overexpression could enhance the EMT process in vivo and was associated with targeting PTEN while activating the PI3K/mTOR pathway.	('enhance', 'PosReg', (61, 68))	('overexpression', 'PosReg', (40, 54))	('activating', 'PosReg', (138, 148))	('EMT process in vivo', 'CPA', (73, 92))	('PTEN', 'Gene', (127, 131))	('PTEN', 'Gene', '5728', (127, 131))	('mTOR', 'Gene', (158, 162))	('mTOR', 'Gene', '2475', (158, 162))	('miR-410', 'Var', (32, 39))
50439	32528035	In an effort to explore the clinical relevance of miR-410 and the EMT process, 62 NSCLC samples were collected.	('NSCLC', 'Disease', (82, 87))	('miR-410', 'Var', (50, 57))	('NSCLC', 'Phenotype', 'HP:0030358', (82, 87))	('NSCLC', 'Disease', 'MESH:D002289', (82, 87))
50440	32528035	Consequently, mesenchymal and EMT phenotypes were more likely found in patients with high miR-410 expression (Fig.	('miR-410', 'Gene', (90, 97))	('patients', 'Species', '9606', (71, 79))	('high', 'Var', (85, 89))	('more', 'PosReg', (50, 54))	('expression', 'MPA', (98, 108))
50442	32528035	Moreover, 80.65% of high miR-410 expression specimens showed low expression of PTEN, and 58.06% of low miR-410 expression specimens showed high expression of PTEN (Fig.	('low', 'NegReg', (61, 64))	('expression', 'MPA', (65, 75))	('PTEN', 'Gene', (158, 162))	('high miR-410', 'Var', (20, 32))	('PTEN', 'Gene', '5728', (158, 162))	('PTEN', 'Gene', (79, 83))	('PTEN', 'Gene', '5728', (79, 83))
50443	32528035	This result indicated that the inverse correlation between miR-410 and PTEN was also clinically relevant in NSCLC.	('NSCLC', 'Phenotype', 'HP:0030358', (108, 113))	('NSCLC', 'Disease', (108, 113))	('PTEN', 'Gene', (71, 75))	('miR-410', 'Var', (59, 66))	('PTEN', 'Gene', '5728', (71, 75))	('NSCLC', 'Disease', 'MESH:D002289', (108, 113))
50447	32528035	Furthermore, patients with high miR-410 expression tended to show poorer overall survival in 542 cases of lung adenocarcinoma tissues (TCGA_LUAD), whereas no significant difference was observed in 416 cases of lung squamous carcinoma tissues (TCGA_LUSC), which were analyzed by PROGmiRV2 (Supplemental Fig.	('miR', 'Gene', (32, 35))	('lung squamous carcinoma', 'Disease', (210, 233))	('miR', 'Gene', '751557', (282, 285))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (106, 125))	('lung adenocarcinoma', 'Disease', (106, 125))	('LUAD', 'Phenotype', 'HP:0030078', (140, 144))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (215, 233))	('miR', 'Gene', '751557', (32, 35))	('patients', 'Species', '9606', (13, 21))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (106, 125))	('poorer', 'NegReg', (66, 72))	('high', 'Var', (27, 31))	('lung squamous carcinoma', 'Disease', 'MESH:D002294', (210, 233))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('lung squamous carcinoma', 'Phenotype', 'HP:0030359', (210, 233))	('miR', 'Gene', (282, 285))	('carcinoma', 'Phenotype', 'HP:0030731', (224, 233))	('overall survival', 'MPA', (73, 89))
50450	32528035	However, little is known about whether the abnormal expression of miRNAs promotes both EMT and radioresistance.	('radioresistance', 'CPA', (95, 110))	('EMT', 'CPA', (87, 90))	('miR', 'Gene', (66, 69))	('promotes', 'PosReg', (73, 81))	('abnormal', 'Var', (43, 51))	('miR', 'Gene', '751557', (66, 69))
50455	32528035	On the one hand, NSCLC cells that survived radiation and grew in spheres showed mesenchymal phenotypes, and inhibition of radiation-induced EMT could enhance the radiosensitivity of cells.	('NSCLC', 'Disease', (17, 22))	('radiosensitivity of cells', 'CPA', (162, 187))	('NSCLC', 'Disease', 'MESH:D002289', (17, 22))	('mesenchymal phenotypes', 'CPA', (80, 102))	('NSCLC', 'Phenotype', 'HP:0030358', (17, 22))	('inhibition', 'Var', (108, 118))	('enhance', 'PosReg', (150, 157))
50458	32528035	In our study, assessments of the radioresponse in miR-410 overexpression or knockdown cells demonstrated that miR-410 could increase radioresistance, as well as promote EMT, which also indicated that the occurrence of EMT was accompanied by radioresistance in NSCLC cells.	('increase', 'PosReg', (124, 132))	('radioresistance', 'CPA', (133, 148))	('EMT', 'CPA', (169, 172))	('NSCLC', 'Phenotype', 'HP:0030358', (260, 265))	('promote', 'PosReg', (161, 168))	('NSCLC', 'Disease', (260, 265))	('miR-410', 'Var', (110, 117))	('NSCLC', 'Disease', 'MESH:D002289', (260, 265))
50463	32528035	The data suggested that miR-410-increased radioresistance might be associated with enhanced DSB repair in NSCLC cells.	('miR-410-increased', 'PosReg', (24, 41))	('DSB', 'Chemical', '-', (92, 95))	('NSCLC', 'Disease', 'MESH:D002289', (106, 111))	('enhanced', 'PosReg', (83, 91))	('radioresistance', 'CPA', (42, 57))	('NSCLC', 'Phenotype', 'HP:0030358', (106, 111))	('DSB repair', 'CPA', (92, 102))	('miR-410-increased', 'Var', (24, 41))	('NSCLC', 'Disease', (106, 111))
50466	32528035	miR-410 was also reported to enhance proliferation by targeting BDR7 in NSCLC.	('targeting', 'Reg', (54, 63))	('NSCLC', 'Disease', (72, 77))	('BDR7', 'Protein', (64, 68))	('NSCLC', 'Disease', 'MESH:D002289', (72, 77))	('miR-410', 'Var', (0, 7))	('proliferation', 'CPA', (37, 50))	('enhance', 'PosReg', (29, 36))	('NSCLC', 'Phenotype', 'HP:0030358', (72, 77))
50471	32528035	In the present study, the direct interaction between miR-410 and PTEN was confirmed by dual-luciferase reporter assays, and PTEN was found to be posttranscriptionally regulated by miR-410.	('miR-410', 'Var', (180, 187))	('PTEN', 'Gene', (65, 69))	('PTEN', 'Gene', (124, 128))	('PTEN', 'Gene', '5728', (65, 69))	('PTEN', 'Gene', '5728', (124, 128))	('miR-410', 'Gene', (53, 60))
50472	32528035	These results indicated that PTEN was a direct target of miR-410 in NSCLC cells.	('NSCLC', 'Disease', 'MESH:D002289', (68, 73))	('PTEN', 'Gene', (29, 33))	('miR-410', 'Var', (57, 64))	('PTEN', 'Gene', '5728', (29, 33))	('NSCLC', 'Phenotype', 'HP:0030358', (68, 73))	('NSCLC', 'Disease', (68, 73))
50476	32528035	Loss of PTEN in NSCLC drives the hyperactivation of PI3K/Akt and downstream mTOR, thus regulating multiple cellular functions.	('mTOR', 'Gene', (76, 80))	('Akt', 'Gene', '207', (57, 60))	('mTOR', 'Gene', '2475', (76, 80))	('NSCLC', 'Phenotype', 'HP:0030358', (16, 21))	('PTEN', 'Gene', (8, 12))	('PTEN', 'Gene', '5728', (8, 12))	('hyperactivation', 'PosReg', (33, 48))	('NSCLC', 'Disease', (16, 21))	('Akt', 'Gene', (57, 60))	('NSCLC', 'Disease', 'MESH:D002289', (16, 21))	('Loss', 'Var', (0, 4))	('regulating', 'Reg', (87, 97))
50480	32528035	Therefore, we hypothesized that miR-410 exerts its biological effects on EMT and radioresistance by activating the PI3K/mTOR pathway.	('activating', 'PosReg', (100, 110))	('mTOR', 'Gene', (120, 124))	('mTOR', 'Gene', '2475', (120, 124))	('miR-410', 'Var', (32, 39))
50481	32528035	Indeed, we found that overexpression of miR-410 in NSCLC cells robustly increased the levels of phosphorylated Akt, mTOR, P70S6K, and 4E-BP1.	('P70S6K', 'Gene', '6198', (122, 128))	('phosphorylated', 'MPA', (96, 110))	('4E-BP1', 'Gene', '1978', (134, 140))	('miR-410', 'Var', (40, 47))	('increased', 'PosReg', (72, 81))	('overexpression', 'PosReg', (22, 36))	('Akt', 'Gene', (111, 114))	('levels', 'MPA', (86, 92))	('P70S6K', 'Gene', (122, 128))	('NSCLC', 'Disease', (51, 56))	('NSCLC', 'Disease', 'MESH:D002289', (51, 56))	('4E-BP1', 'Gene', (134, 140))	('mTOR', 'Gene', (116, 120))	('mTOR', 'Gene', '2475', (116, 120))	('Akt', 'Gene', '207', (111, 114))	('NSCLC', 'Phenotype', 'HP:0030358', (51, 56))
50483	32528035	In addition, restoration of PTEN expression in PC9-miR-410 and SPC-A1-miR-410 cells significantly decreased miR-410-induced EMT and radioresistance, whereas transfecting siPTEN in A549-Inh and H1299-Inh cells resulted in the opposite effects.	('PTEN', 'Gene', (28, 32))	('PTEN', 'Gene', '5728', (172, 176))	('PTEN', 'Gene', '5728', (28, 32))	('radioresistance', 'CPA', (132, 147))	('SPC-A1', 'Gene', '27032', (63, 69))	('H1299-Inh', 'CellLine', 'CVCL:0060', (193, 202))	('A549', 'CellLine', 'CVCL:0023', (180, 184))	('PTEN', 'Gene', (172, 176))	('miR-410-induced', 'Var', (108, 123))	('expression', 'MPA', (33, 43))	('PC9', 'Gene', '255738', (47, 50))	('decreased', 'NegReg', (98, 107))	('SPC-A1', 'Gene', (63, 69))	('PC9', 'Gene', (47, 50))
50486	32528035	reported that miR-410-3p exerted oncogenic functions in prostate cancer via the PTEN/AKT/mTOR pathway.	('mTOR', 'Gene', '2475', (89, 93))	('miR-410-3p', 'Chemical', '-', (14, 24))	('PTEN', 'Gene', (80, 84))	('PTEN', 'Gene', '5728', (80, 84))	('AKT', 'Gene', '207', (85, 88))	('prostate cancer', 'Disease', 'MESH:D011471', (56, 71))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('prostate cancer', 'Phenotype', 'HP:0012125', (56, 71))	('oncogenic functions', 'MPA', (33, 52))	('miR-410-3p', 'Var', (14, 24))	('AKT', 'Gene', (85, 88))	('mTOR', 'Gene', (89, 93))	('prostate cancer', 'Disease', (56, 71))
50487	32528035	showed that loss of lncRNA OIP5-AS1 induced miR-410 accumulation and regulated its target KLF10/PTEN/AKT-mediated cellular behaviors in multiple myeloma cells.	('lncRNA', 'Gene', (20, 26))	('PTEN', 'Gene', '5728', (96, 100))	('AKT', 'Gene', '207', (101, 104))	('KLF10', 'Gene', '7071', (90, 95))	('myeloma', 'Disease', 'MESH:D009101', (145, 152))	('miR-410', 'Gene', (44, 51))	('AKT', 'Gene', (101, 104))	('accumulation', 'PosReg', (52, 64))	('loss', 'Var', (12, 16))	('OIP5-AS1', 'Gene', '729082;11339;5729', (27, 35))	('regulated', 'Reg', (69, 78))	('myeloma', 'Disease', (145, 152))	('multiple myeloma', 'Phenotype', 'HP:0006775', (136, 152))	('OIP5-AS1', 'Gene', (27, 35))	('KLF10', 'Gene', (90, 95))	('PTEN', 'Gene', (96, 100))
50489	32528035	Studies showed that the expression of E-cadherin increased the radiosensitivity of breast cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('radiosensitivity', 'CPA', (63, 79))	('increased', 'PosReg', (49, 58))	('breast cancer', 'Disease', 'MESH:D001943', (83, 96))	('breast cancer', 'Disease', (83, 96))	('breast cancer', 'Phenotype', 'HP:0003002', (83, 96))	('expression', 'Var', (24, 34))	('E-cadherin', 'Protein', (38, 48))
50493	32528035	Consequently, we inferred that in NSCLC cells, radioresistance with enhanced DNA damage repair might be promoted by the miR-410-induced EMT process.	('enhanced', 'PosReg', (68, 76))	('NSCLC', 'Disease', (34, 39))	('radioresistance', 'CPA', (47, 62))	('NSCLC', 'Disease', 'MESH:D002289', (34, 39))	('miR-410-induced', 'Var', (120, 135))	('DNA damage', 'MPA', (77, 87))	('NSCLC', 'Phenotype', 'HP:0030358', (34, 39))	('promoted', 'PosReg', (104, 112))
50504	32528035	Consistent with these findings, high miR-410 expression tended to be associated with poorer overall survival in lung adenocarcinoma patients in the current study, which further indicated the oncogenic role of miR-410.	('poorer', 'NegReg', (85, 91))	('high', 'Var', (32, 36))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (112, 131))	('miR-410', 'Gene', (37, 44))	('expression', 'MPA', (45, 55))	('lung adenocarcinoma', 'Disease', (112, 131))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (112, 131))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('overall', 'MPA', (92, 99))	('patients', 'Species', '9606', (132, 140))
50505	32528035	Moreover, mesenchymal and EMT phenotypes and high vimentin expression were more likely to be found in NSCLC patients with high miR-410 expression, and the protein levels of PTEN were positively associated with E-cadherin levels in TCGA NSCLC specimens.	('NSCLC', 'Disease', 'MESH:D002289', (102, 107))	('NSCLC', 'Disease', 'MESH:D002289', (236, 241))	('E-cadherin levels', 'MPA', (210, 227))	('NSCLC', 'Phenotype', 'HP:0030358', (236, 241))	('high', 'Var', (122, 126))	('vimentin', 'Gene', '7431', (50, 58))	('PTEN', 'Gene', (173, 177))	('miR-410', 'Gene', (127, 134))	('NSCLC', 'Phenotype', 'HP:0030358', (102, 107))	('PTEN', 'Gene', '5728', (173, 177))	('associated', 'Reg', (194, 204))	('vimentin', 'Gene', (50, 58))	('expression', 'MPA', (59, 69))	('patients', 'Species', '9606', (108, 116))	('NSCLC', 'Disease', (102, 107))	('NSCLC', 'Disease', (236, 241))
50509	32528035	Further investigation in NSCLC specimens also demonstrated that miR-410 was positively correlated with EMT.	('correlated', 'Reg', (87, 97))	('EMT', 'CPA', (103, 106))	('miR-410', 'Var', (64, 71))	('NSCLC', 'Disease', (25, 30))	('NSCLC', 'Disease', 'MESH:D002289', (25, 30))	('NSCLC', 'Phenotype', 'HP:0030358', (25, 30))
50519	32528035	qRT-PCR was performed with the SYBR Green Real-Time PCR Master Mix Kit protocol (Bio-Rad, Hercules, CA, USA) on a CFX96 Real-Time System (Bio-Rad) to quantify the miR-410 or PTEN mRNA level using U6 or beta-actin as an internal control, respectively.	('PTEN', 'Gene', '5728', (174, 178))	('Rad', 'Gene', (142, 145))	('Rad', 'Gene', '6236', (85, 88))	('Rad', 'Gene', (85, 88))	('beta-actin', 'Gene', '728378', (202, 212))	('miR-410', 'Var', (163, 170))	('beta-actin', 'Gene', (202, 212))	('PTEN', 'Gene', (174, 178))	('Rad', 'Gene', '6236', (142, 145))
50527	32528035	The wild-type and mutant 3'-UTR sequences of PTEN were cloned into the pmirGLO vector (Promega, Madison, WI, USA) respectively, and validated by sequencing.	('PTEN', 'Gene', (45, 49))	('mutant', 'Var', (18, 24))	('PTEN', 'Gene', '5728', (45, 49))
50531	32528035	To validate the direct interaction between miR-410 and the 3'-UTR of PTEN, 293T cells were seeded in 96-well plates the day before transfection and then co-transfected with ~100 ng of wild-type or mutant PTEN 3'-UTR and with miR-410 mimics (50 nm) or inhibitors (100 nm) or negative control (50 nm) (RiboBio Co. Ltd).	('PTEN', 'Gene', '5728', (69, 73))	('miR-410', 'Gene', (225, 232))	('PTEN', 'Gene', (204, 208))	('PTEN', 'Gene', '5728', (204, 208))	('mutant', 'Var', (197, 203))	('100 nm', 'Var', (263, 269))	('293T', 'CellLine', 'CVCL:0063', (75, 79))	('PTEN', 'Gene', (69, 73))
50550	32216017	LNCAROD is stabilized by m6A methylation and promotes cancer progression via forming a ternary complex with HSPA1A and YBX1 in head and neck squamous cell carcinoma Head and neck squamous cell carcinoma (HNSCC) constitute approximately 4% of all cancers worldwide.	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('carcinoma', 'Phenotype', 'HP:0030731', (193, 202))	('promotes', 'PosReg', (45, 53))	('YBX1', 'Gene', (119, 123))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (141, 164))	('neck squamous cell carcinoma', 'Disease', (174, 202))	('neck squamous cell carcinoma', 'Disease', (136, 164))	('cancers', 'Phenotype', 'HP:0002664', (246, 253))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (174, 202))	('YBX1', 'Gene', '4904', (119, 123))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (136, 164))	('cancers', 'Disease', (246, 253))	('cancer', 'Disease', (246, 252))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))	('methylation', 'Var', (29, 40))	('HSPA1A', 'Gene', (108, 114))	('cancer', 'Disease', (54, 60))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (127, 164))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (179, 202))	('carcinoma', 'Phenotype', 'HP:0030731', (155, 164))	('cancer', 'Disease', 'MESH:D009369', (246, 252))	('cancers', 'Disease', 'MESH:D009369', (246, 253))	('HSPA1A', 'Gene', '3303', (108, 114))	('HNSCC', 'Phenotype', 'HP:0012288', (204, 209))	('Head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (165, 202))
50555	32216017	Silencing either YBX1 or HSPA1A did not affect the level of LNCAROD.	('YBX1', 'Gene', (17, 21))	('Silencing', 'Var', (0, 9))	('HSPA1A', 'Gene', (25, 31))	('YBX1', 'Gene', '4904', (17, 21))
50562	32216017	Dysregulation of long noncoding RNAs (lncRNAs) is implicated in cancer development and progression.	('Dysregulation', 'Var', (0, 13))	('implicated', 'Reg', (50, 60))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('cancer', 'Disease', (64, 70))	('long noncoding RNAs', 'Protein', (17, 36))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
50563	32216017	demonstrated that an oncogenic lncRNA, LNCAROD, is stabilized by m6A methylation and overexpressed in head and neck squamous cell carcinoma (HNSCC).	('m6A', 'Chemical', '-', (65, 68))	('HNSCC', 'Phenotype', 'HP:0012288', (141, 146))	('neck squamous cell carcinoma', 'Disease', (111, 139))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (116, 139))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (102, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('methylation', 'Var', (69, 80))	('m6A', 'Protein', (65, 68))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (111, 139))	('overexpressed', 'PosReg', (85, 98))
50571	32216017	The m6A modification affects various aspects of RNA metabolism, including structure, maturation, stability, splicing, export, translation, and decay (Chen et al., 2019; Lan et al., 2019).	('m6A', 'Chemical', '-', (4, 7))	('m6A modification', 'Var', (4, 20))	('affects', 'Reg', (21, 28))	('stability', 'MPA', (97, 106))	('translation', 'MPA', (126, 137))	('maturation', 'MPA', (85, 95))	('splicing', 'MPA', (108, 116))	('RNA metabolism', 'MPA', (48, 62))	('modification', 'Var', (8, 20))	('decay', 'MPA', (143, 148))	('structure', 'MPA', (74, 83))	('export', 'MPA', (118, 124))
50572	32216017	To date, most of the studies focus on effects of m6A modification on mRNAs.	('m6A', 'Gene', (49, 52))	('modification', 'Var', (53, 65))	('mRNAs', 'MPA', (69, 74))	('m6A', 'Chemical', '-', (49, 52))
50573	32216017	LNCAROD is stabilized with m6A methylation in HNSCC cells.	('m6A', 'Chemical', '-', (27, 30))	('HNSCC', 'Phenotype', 'HP:0012288', (46, 51))	('methylation', 'Var', (31, 42))	('m6A methylation', 'Var', (27, 42))
50583	32216017	HK1 is a well-differentiated SCC cell line of nasopharynx (Huang et al., 1980), whereas NP69 is an immortalized nasopharyngeal epithelial cell line (Tsao et al., 2002), and C666-1 is an undifferentiated nasopharyngeal carcinoma cell line (Cheung et al., 1999).	('undifferentiated nasopharyngeal carcinoma', 'Disease', (186, 227))	('carcinoma', 'Phenotype', 'HP:0030731', (218, 227))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (203, 227))	('C666-1', 'Var', (173, 179))	('undifferentiated nasopharyngeal carcinoma', 'Disease', 'MESH:D002277', (186, 227))	('C666-1', 'CellLine', 'CVCL:7949', (173, 179))
50609	32216017	The m6A modification of noncoding RNAs is emerging as a fundamental role in their regulation and functions (Coker et al., 2019).	('m6A', 'Var', (4, 7))	('noncoding', 'Protein', (24, 33))	('m6A', 'Chemical', '-', (4, 7))
50616	32216017	Silencing either METTL3 or METTL14 leads to moderate decrease of LNCAROD level (Fig.	('METTL3', 'Gene', '56339', (17, 23))	('decrease', 'NegReg', (53, 61))	('METTL14', 'Gene', '57721', (27, 34))	('METTL3', 'Gene', (17, 23))	('METTL14', 'Gene', (27, 34))	('LNCAROD level', 'MPA', (65, 78))	('Silencing', 'Var', (0, 9))
50617	32216017	Moreover, pulse-chase assay showed that loss of METTL3 and METTL14 significantly shortened the half-life of LNCAROD (Fig.	('METTL3', 'Gene', '56339', (48, 54))	('shortened', 'NegReg', (81, 90))	('METTL14', 'Gene', (59, 66))	('METTL3', 'Gene', (48, 54))	('METTL14', 'Gene', '57721', (59, 66))	('loss', 'Var', (40, 44))	('half-life', 'MPA', (95, 104))
50618	32216017	2F), suggesting that m6A methylation enhances the stability of LNCAROD.	('m6A', 'Chemical', '-', (21, 24))	('stability of LNCAROD', 'CPA', (50, 70))	('enhances', 'PosReg', (37, 45))	('methylation', 'Var', (25, 36))	('m6A methylation', 'Var', (21, 36))
50627	32216017	Moreover, RIP assays demonstrated that LNCAROD RNA was precipitated with by anti-YBX1 and anti-HSPA1A in HK1 cell (Fig.	('LNCAROD RNA', 'Disease', (39, 50))	('YBX1', 'Gene', (81, 85))	('YBX1', 'Gene', '4904', (81, 85))	('anti-HSPA1A', 'Var', (90, 101))
50629	32216017	Deletion mutant assays demonstrated LNCAROD binds with HSP1A1 through a region of its 3' terminus (751-972 nt), whereas binds with YBX1 through its internal region (251-500 nt) (Fig.	('HSP1A1', 'Protein', (55, 61))	('YBX1', 'Gene', (131, 135))	('YBX1', 'Gene', '4904', (131, 135))	('binds', 'Interaction', (44, 49))	('751-972 nt', 'Var', (99, 109))	('binds', 'Interaction', (120, 125))	('Deletion', 'Var', (0, 8))
50632	32216017	Furthermore, silencing LNCAROD in HK1 cells hindered the protein-protein interaction between YBX1 and HSPA1A, whereas overexpression of LNCAROD enhanced YBX1-HSPA1A proteins interaction (Fig.	('YBX1', 'Gene', (93, 97))	('YBX1', 'Gene', (153, 157))	('silencing', 'Var', (13, 22))	('protein-protein interaction', 'MPA', (57, 84))	('HSPA1A', 'Protein', (102, 108))	('YBX1', 'Gene', '4904', (93, 97))	('YBX1', 'Gene', '4904', (153, 157))	('hindered', 'NegReg', (44, 52))	('interaction', 'Interaction', (174, 185))	('LNCAROD', 'Gene', (23, 30))
50635	32216017	Silencing either YBX1 or HSPA1A in HK1 and FaDu cells exert little effect on the level of LNCAROD (Fig.	('YBX1', 'Gene', '4904', (17, 21))	('Silencing', 'Var', (0, 9))	('YBX1', 'Gene', (17, 21))	('HSPA1A', 'Gene', (25, 31))	('level of LNCAROD', 'MPA', (81, 97))
50640	32216017	We further demonstrated that loss of LNCAROD shortened the half-life of YBX1 protein (Fig.	('half-life', 'MPA', (59, 68))	('LNCAROD', 'Protein', (37, 44))	('YBX1', 'Gene', (72, 76))	('protein', 'Protein', (77, 84))	('loss', 'Var', (29, 33))	('shortened', 'NegReg', (45, 54))	('YBX1', 'Gene', '4904', (72, 76))
50642	32216017	5P), suggesting loss of LNCAROD promotes proteasomal degradation of YBX1 protein.	('YBX1', 'Gene', '4904', (68, 72))	('proteasomal degradation', 'MPA', (41, 64))	('protein', 'Protein', (73, 80))	('LNCAROD', 'Gene', (24, 31))	('loss', 'Var', (16, 20))	('YBX1', 'Gene', (68, 72))	('promotes', 'PosReg', (32, 40))
50644	32216017	As expected, silencing HSPA1A in HK1 cell resulted in reduction of YBX1 protein level (Fig.	('YBX1', 'Gene', '4904', (67, 71))	('reduction', 'NegReg', (54, 63))	('YBX1', 'Gene', (67, 71))	('HSPA1A', 'Gene', (23, 29))	('silencing', 'Var', (13, 22))
50646	32216017	5S), indicating that HSPA1A inhibits proteasomal degradation of YBX1 protein.	('YBX1', 'Gene', '4904', (64, 68))	('inhibits', 'NegReg', (28, 36))	('HSPA1A', 'Var', (21, 27))	('YBX1', 'Gene', (64, 68))	('proteasomal degradation', 'MPA', (37, 60))
50647	32216017	Furthermore, silencing HSPA1A led to reduction of YBX1 protein in LNCAROD-overexpressing Tca8113 cell, suggesting that HSPA1A is required for LNCAROD-mediated YBX1 protein stabilization (Fig.	('reduction', 'NegReg', (37, 46))	('YBX1', 'Gene', (50, 54))	('protein', 'Protein', (55, 62))	('YBX1', 'Gene', (159, 163))	('HSPA1A', 'Protein', (23, 29))	('YBX1', 'Gene', '4904', (50, 54))	('YBX1', 'Gene', '4904', (159, 163))	('silencing', 'Var', (13, 22))
50655	32216017	Xenograft tumor growth assays showed that loss of LNCAROD in HK1 cells delayed xenograft formation in nude mice (Fig.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('loss', 'Var', (42, 46))	('xenograft formation in', 'CPA', (79, 101))	('tumor', 'Disease', (10, 15))	('nude mice', 'Species', '10090', (102, 111))	('delayed', 'NegReg', (71, 78))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('LNCAROD', 'Gene', (50, 57))
50659	32216017	Immunohistochemical staining showed there are less Ki67+ cells in tumors from sh-LNCAROD/HK1 cells (Fig.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('less', 'NegReg', (46, 50))	('tumors', 'Disease', (66, 72))	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('LNCAROD/HK1', 'CellLine', 'CVCL:7047', (81, 92))	('Ki67+', 'Var', (51, 56))
50660	32216017	Furthermore, the protein level of YBX1 was remarkably reduced upon silencing LNCAROD.	('YBX1', 'Gene', (34, 38))	('protein level', 'MPA', (17, 30))	('YBX1', 'Gene', '4904', (34, 38))	('reduced', 'NegReg', (54, 61))	('silencing', 'Var', (67, 76))	('LNCAROD', 'Gene', (77, 84))
50661	32216017	LNCAROD is primarily distributed in nucleus and is regulated by METT3- and METTL14-mediated m6A methylation in HNSCC.	('HNSCC', 'Phenotype', 'HP:0012288', (111, 116))	('LNCAROD', 'Gene', (0, 7))	('METT3-', 'Var', (64, 70))	('methylation', 'Var', (96, 107))	('METTL14', 'Gene', '57721', (75, 82))	('METTL14', 'Gene', (75, 82))	('regulated', 'Reg', (51, 60))	('m6A', 'Chemical', '-', (92, 95))
50668	32216017	Similar to protein-coding genes, we demonstrated that m6A modification increased the half-life of LNCAROD in HNSCC cells, suggesting m6A marks of LNCAROD mediated by RNA m6A methyltransferases might account for high expression of LNCAROD in HNSCC.	('HNSCC', 'Phenotype', 'HP:0012288', (241, 246))	('m6A', 'Var', (54, 57))	('modification', 'Var', (58, 70))	('HNSCC', 'Phenotype', 'HP:0012288', (109, 114))	('increased', 'PosReg', (71, 80))	('m6A', 'Chemical', '-', (170, 173))	('m6A', 'Chemical', '-', (54, 57))	('m6A', 'Chemical', '-', (133, 136))	('half-life', 'MPA', (85, 94))
50669	32216017	Though silencing either METTL3 or METTL14 in HK1 cell led to reduction of LNCAROD.	('METTL14', 'Gene', (34, 41))	('METTL3', 'Gene', (24, 30))	('LNCAROD', 'CPA', (74, 81))	('METTL14', 'Gene', '57721', (34, 41))	('reduction', 'NegReg', (61, 70))	('silencing', 'Var', (7, 16))	('METTL3', 'Gene', '56339', (24, 30))
50672	32216017	Dysregulation of m6A methylation is intensively involved in squamous cell carcinoma progression.	('m6A', 'Chemical', '-', (17, 20))	('Dysregulation', 'Var', (0, 13))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('methylation', 'Var', (21, 32))	('m6A', 'Protein', (17, 20))	('involved', 'Reg', (48, 56))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (60, 83))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (60, 83))	('squamous cell carcinoma', 'Disease', (60, 83))
50675	32216017	Thus, our data along with other observations unveiled a critical role of m6A modification on the fate and function of lncRNAs.	('m6A', 'Chemical', '-', (73, 76))	('m6A', 'Gene', (73, 76))	('modification', 'Var', (77, 89))
50678	32216017	We speculated that m6A modification probably protects LNCAROD from degradation through enhancing its recognition by IGF2BPs family members.	('modification', 'Var', (23, 35))	('recognition', 'MPA', (101, 112))	('degradation', 'MPA', (67, 78))	('enhancing', 'PosReg', (87, 96))	('m6A', 'Var', (19, 22))	('m6A', 'Chemical', '-', (19, 22))
50680	32216017	However, silencing LNCAROD did not alter DKK1 level in our systems (data not shown).	('silencing', 'Var', (9, 18))	('DKK1', 'Gene', '22943', (41, 45))	('DKK1', 'Gene', (41, 45))	('LNCAROD', 'Gene', (19, 26))
50685	32216017	We demonstrated that LNCAROD binds with YBX1 or HSPA1A through different fragments, 251-500 nt for YBX1 and 751-972 nt for HSPA1A, respectively, making it as a scaffold for YBX1-HSPA1A interaction.	('YBX1', 'Gene', '4904', (173, 177))	('751-972 nt', 'Var', (108, 118))	('YBX1', 'Gene', '4904', (99, 103))	('interaction', 'Interaction', (185, 196))	('YBX1', 'Gene', (40, 44))	('binds', 'Interaction', (29, 34))	('YBX1', 'Gene', (173, 177))	('YBX1', 'Gene', '4904', (40, 44))	('YBX1', 'Gene', (99, 103))
50696	32216017	We provide evidence that m6A methylation mediated by METTL3 and METTL14 contributes to increased stability of LNCAROD.	('METTL14', 'Gene', (64, 71))	('methylation', 'Var', (29, 40))	('increased', 'PosReg', (87, 96))	('stability of LNCAROD', 'CPA', (97, 117))	('m6A', 'Chemical', '-', (25, 28))	('METTL3', 'Gene', '56339', (53, 59))	('m6A', 'Protein', (25, 28))	('METTL3', 'Gene', (53, 59))	('METTL14', 'Gene', '57721', (64, 71))
50720	31516564	It has also been observed that when individually investigated, the genes potentially responsible for the disease may not result in disease in certain patients.	('not', 'NegReg', (117, 120))	('patients', 'Species', '9606', (150, 158))	('genes', 'Var', (67, 72))	('result in', 'Reg', (121, 130))
50725	31516564	It has been reported that CDK4 activity can increase the transcriptional activity of FOXM1 without phosphorylating FOXM1, while the expression of FOXM1 has been suggested to contribute to the development or progression of LSCC.	('FOXM1', 'Gene', (146, 151))	('FOXM1', 'Gene', '2305', (115, 120))	('FOXM1', 'Gene', '2305', (146, 151))	('FOXM1', 'Gene', (115, 120))	('LSCC', 'Disease', (222, 226))	('activity', 'Var', (31, 39))	('contribute', 'Reg', (174, 184))	('increase', 'PosReg', (44, 52))	('CDK4', 'Gene', (26, 30))	('CDK4', 'Gene', '1019', (26, 30))	('FOXM1', 'Gene', (85, 90))	('FOXM1', 'Gene', '2305', (85, 90))	('transcriptional activity', 'MPA', (57, 81))
50758	30832674	MicroRNA-144-3p (miR-144-3p), having various functions in different types of cancers, is one of the miRNAs related to cancer.	('cancer', 'Disease', (118, 124))	('miR-144', 'Gene', (17, 24))	('cancers', 'Disease', 'MESH:D009369', (77, 84))	('cancers', 'Phenotype', 'HP:0002664', (77, 84))	('cancer', 'Disease', (77, 83))	('cancers', 'Disease', (77, 84))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('miR-144', 'Gene', '406936', (17, 24))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('MicroRNA-144-3p', 'Var', (0, 15))	('cancer', 'Disease', 'MESH:D009369', (118, 124))
50784	30832674	With respect to the data from the tissue samples, the NSCLC groups had a significantly lower level of miR-144-3p expression than the control groups in GSE25508, GSE48414, GSE51853, GSE56036, GSE63805, GSE72526, GSE74190, and GSE102286 (p = 0.0202, p <  0.0001, p <  0.0001, p = 0.0011, p <  0.0001, p = 0.0102, p <  0.0001, and p <  0.0001, respectively (Fig.	('GSE72526', 'Var', (201, 209))	('GSE51853', 'Var', (171, 179))	('miR-144', 'Gene', (102, 109))	('lower', 'NegReg', (87, 92))	('miR-144', 'Gene', '406936', (102, 109))	('NSCLC', 'Phenotype', 'HP:0030358', (54, 59))	('GSE56036', 'Var', (181, 189))	('GSE63805', 'Var', (191, 199))	('GSE25508', 'Var', (151, 159))	('LC', 'Phenotype', 'HP:0100526', (57, 59))	('GSE74190', 'Var', (211, 219))	('GSE48414', 'Var', (161, 169))	('NSCLC', 'Disease', (54, 59))	('NSCLC', 'Disease', 'MESH:D002289', (54, 59))	('GSE102286', 'Var', (225, 234))
50785	30832674	In contrast, no notable distinction in miR-144-3p expression was detected between the NSCLC and the control groups in the other microarrays (GSE14936, GSE29248, GSE36681, GSE47525, GSE53882, and GSE77380).	('GSE14936', 'Var', (141, 149))	('miR-144', 'Gene', '406936', (39, 46))	('NSCLC', 'Disease', (86, 91))	('GSE77380', 'Var', (195, 203))	('GSE47525', 'Var', (171, 179))	('NSCLC', 'Disease', 'MESH:D002289', (86, 91))	('LC', 'Phenotype', 'HP:0100526', (89, 91))	('GSE36681', 'Var', (161, 169))	('GSE53882', 'Var', (181, 189))	('GSE29248', 'Var', (151, 159))	('NSCLC', 'Phenotype', 'HP:0030358', (86, 91))	('miR-144', 'Gene', (39, 46))
50786	30832674	Regarding the data from the blood samples, miR-144-3p expression in NSCLC was found to decrease significantly in GSE27486 and GSE40738 (p = 0.0196, p = 0.0036, respectively (Fig.	('NSCLC', 'Disease', 'MESH:D002289', (68, 73))	('GSE27486', 'Var', (113, 121))	('miR-144', 'Gene', (43, 50))	('miR-144', 'Gene', '406936', (43, 50))	('LC', 'Phenotype', 'HP:0100526', (71, 73))	('NSCLC', 'Phenotype', 'HP:0030358', (68, 73))	('GSE40738', 'Var', (126, 134))	('decrease', 'NegReg', (87, 95))	('NSCLC', 'Disease', (68, 73))
50802	30832674	LUSC patients in Stages III-IV (2.4469 +- 1.41079) had a lower expression of miR-144-3p than those in Stages I-II (2.8878 +- 1.39556).	('miR-144', 'Gene', '406936', (77, 84))	('patients', 'Species', '9606', (5, 13))	('expression', 'MPA', (63, 73))	('miR-144', 'Gene', (77, 84))	('2.4469 +- 1.41079', 'Var', (32, 49))	('LUSC', 'Phenotype', 'HP:0030359', (0, 4))	('lower', 'NegReg', (57, 62))
50803	30832674	The miR-144-3p expression of LUSC in T3-T4 (2.5088 +- 1.36178) was more significantly decreased than T1-T2 (2.9023 +- 1.40854).	('miR-144', 'Gene', (4, 11))	('LUSC', 'Phenotype', 'HP:0030359', (29, 33))	('2.5088 +- 1.36178', 'Var', (44, 61))	('miR-144', 'Gene', '406936', (4, 11))	('decreased', 'NegReg', (86, 95))
50805	30832674	Patients in Stages III-IV (3.1868 +- 1.45395) had higher expression values of miR-144-3p.	('higher', 'PosReg', (50, 56))	('miR-144', 'Gene', (78, 85))	('miR-144', 'Gene', '406936', (78, 85))	('3.1868 +- 1.45395', 'Var', (27, 44))	('expression values', 'MPA', (57, 74))	('Patients', 'Species', '9606', (0, 8))
50806	30832674	As is illustrated in Table 4, the significance in the statistics for the T stage was based on the lower miR-144-3p expression in patients in T3-T4 (p <  0.05).	('T3-T4', 'Var', (141, 146))	('patients', 'Species', '9606', (129, 137))	('miR-144', 'Gene', (104, 111))	('miR-144', 'Gene', '406936', (104, 111))	('lower', 'NegReg', (98, 103))
50878	30123356	An aberrant exaltation of the serum SCC antigen level is an effective predictor of advanced esophageal cancer correlative to poor survival after esophagostomy.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('aberrant exaltation', 'Var', (3, 22))	('SCC', 'Gene', (36, 39))	('esophageal cancer', 'Disease', (92, 109))	('SCC', 'Gene', '6317', (36, 39))	('esophageal cancer', 'Disease', 'MESH:D004938', (92, 109))
50891	30123356	Studies that reported dysregulated microRNAs in ESCC cases compared with healthy controls, together with the corresponding AUC and sensitivity and specificity for the very microRNA, were enrolled in the meta-analysis.	('SCC', 'Gene', (49, 52))	('SCC', 'Gene', '6317', (49, 52))	('microRNAs', 'MPA', (35, 44))	('dysregulated', 'Var', (22, 34))
50892	30123356	The overall pooled sensitivity, specificity and AUC of all the 43 microRNAs in the diagnosis of ESCC were 0.794 (95%CI: 0.765 - 0.820), 0.779 (95%CI: 0.746 - 0.808) and 0.86 (95%CI: 0.82 - 0.88), respectively.	('SCC', 'Gene', (97, 100))	('0.779', 'Var', (136, 141))	('SCC', 'Gene', '6317', (97, 100))
50930	27149479	CA125 had the highest positive rate in I and II stage of NSCLC, and CYFRA21-1 had the highest positive rate in III and IV stage of NSCLC.	('CYFRA21-1', 'Var', (68, 77))	('SCLC', 'Phenotype', 'HP:0030357', (58, 62))	('CA125', 'Gene', '94025', (0, 5))	('NSCLC', 'Disease', (131, 136))	('SCLC', 'Phenotype', 'HP:0030357', (132, 136))	('NSCLC', 'Phenotype', 'HP:0030358', (57, 62))	('NSCLC', 'Disease', 'MESH:D002289', (131, 136))	('CA125', 'Gene', (0, 5))	('NSCLC', 'Disease', (57, 62))	('NSCLC', 'Phenotype', 'HP:0030358', (131, 136))	('NSCLC', 'Disease', 'MESH:D002289', (57, 62))
50977	27149479	At last, in this study, NSCLC was divided into adenocarcinoma and squamous cell carcinoma, CEA, CA125, CYFRA21-1, and SCC were used to identified the 2 histopathological type (in Figure 5), CEA and CA125 had higher positive rate for adenocarcinoma, CYFRA21-1, and SCC had higher positive rate in squamous cell carcinoma.	('NSCLC', 'Disease', (24, 29))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (296, 319))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (66, 89))	('SCC', 'Phenotype', 'HP:0002860', (264, 267))	('CEA', 'Gene', (91, 94))	('CEA', 'Gene', '1084', (190, 193))	('CA125', 'Gene', '94025', (96, 101))	('NSCLC', 'Phenotype', 'HP:0030358', (24, 29))	('CA125', 'Gene', '94025', (198, 203))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('squamous cell carcinoma', 'Disease', (66, 89))	('carcinoma', 'Phenotype', 'HP:0030731', (310, 319))	('squamous cell carcinoma', 'Disease', (296, 319))	('adenocarcinoma', 'Disease', 'MESH:D000230', (47, 61))	('carcinoma', 'Phenotype', 'HP:0030731', (238, 247))	('CEA', 'Gene', '1084', (91, 94))	('SCC', 'Gene', '6317', (264, 267))	('SCC', 'Phenotype', 'HP:0002860', (118, 121))	('SCLC', 'Phenotype', 'HP:0030357', (25, 29))	('SCC', 'Gene', (264, 267))	('adenocarcinoma', 'Disease', (233, 247))	('CYFRA21-1', 'Var', (249, 258))	('SCC', 'Gene', '6317', (118, 121))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (296, 319))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (66, 89))	('CA125', 'Gene', (96, 101))	('higher', 'PosReg', (208, 214))	('carcinoma', 'Phenotype', 'HP:0030731', (52, 61))	('NSCLC', 'Disease', 'MESH:D002289', (24, 29))	('CEA', 'Gene', (190, 193))	('CA125', 'Gene', (198, 203))	('SCC', 'Gene', (118, 121))	('adenocarcinoma', 'Disease', 'MESH:D000230', (233, 247))	('adenocarcinoma', 'Disease', (47, 61))
50998	27149479	CEA and CA125 were beneficial to diagnosis adenocarcinoma, CYFRA21-1 and SCC are squamous cancer, CA125 and CYFRA21-1 were beneficial for the diagnosis clinical stage of NSCLC.	('CEA', 'Gene', '1084', (0, 3))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('SCC', 'Phenotype', 'HP:0002860', (73, 76))	('squamous cancer', 'Disease', 'MESH:D002294', (81, 96))	('CA125', 'Gene', '94025', (8, 13))	('SCLC', 'Phenotype', 'HP:0030357', (171, 175))	('carcinoma', 'Phenotype', 'HP:0030731', (48, 57))	('CA125', 'Gene', (98, 103))	('NSCLC', 'Disease', 'MESH:D002289', (170, 175))	('SCC', 'Gene', '6317', (73, 76))	('adenocarcinoma', 'Disease', (43, 57))	('SCC', 'Gene', (73, 76))	('CYFRA21-1', 'Var', (108, 117))	('NSCLC', 'Disease', (170, 175))	('CEA', 'Gene', (0, 3))	('CA125', 'Gene', '94025', (98, 103))	('NSCLC', 'Phenotype', 'HP:0030358', (170, 175))	('squamous cancer', 'Phenotype', 'HP:0002860', (81, 96))	('adenocarcinoma', 'Disease', 'MESH:D000230', (43, 57))	('CA125', 'Gene', (8, 13))	('squamous cancer', 'Disease', (81, 96))
51023	25250788	LnRNAAK126698 was found to confer cisplatin resistance by targeting the Wnt pathway.	('cisplatin', 'Chemical', 'MESH:D002945', (34, 43))	('confer', 'Reg', (27, 33))	('cisplatin resistance', 'MPA', (34, 54))	('LnRNAAK126698', 'Var', (0, 13))	('targeting', 'Reg', (58, 67))	('Wnt pathway', 'Pathway', (72, 83))
51066	25250788	The results demonstrated that lncRNA ENST00000584612 and ENST00000579363 were downregulated and that NR_038200, ENST00000466677 and ENST00000562112 were upregulated in the PR samples compared with PD samples (Figure 2A).	('ENST00000562112', 'Var', (132, 147))	('ENST00000466677', 'Var', (112, 127))	('NR_038200', 'Gene', (101, 110))	('ts d', 'Gene', (9, 13))	('PD', 'Disease', 'MESH:D010300', (197, 199))	('ts d', 'Gene', '3073', (9, 13))	('PR', 'Chemical', '-', (172, 174))	('upregulated', 'PosReg', (153, 164))	('ENST00000579363', 'Gene', (57, 72))	('downregulated', 'NegReg', (78, 91))
51067	25250788	For mRNA, NM_020299 and ENST00000171111 were downregulated and that NM_001098517, NM_001306 and NM_001904 were upregulated in the PR samples compared with PD samples (Figure 2B).	('NM_020299', 'Var', (10, 19))	('PR', 'Chemical', '-', (130, 132))	('NM_001098517', 'Var', (68, 80))	('PD', 'Disease', 'MESH:D010300', (155, 157))	('downregulated', 'NegReg', (45, 58))	('NM_001904', 'Var', (96, 105))	('NM_001306', 'Var', (82, 91))	('upregulated', 'PosReg', (111, 122))	('ENST00000171111', 'Var', (24, 39))
51077	25250788	The results indicated that many lncRNAs such as AC006050.3, NAPSB, KRT16P2, XLOC_005280 and MI0000285 potentially play important role in the network.	('AC006050.3', 'Var', (48, 58))	('XLOC_005280', 'Var', (76, 87))	('NAPSB', 'Gene', '256236', (60, 65))	('NAPSB', 'Gene', (60, 65))	('play', 'Reg', (114, 118))	('KRT16P2', 'Gene', (67, 74))	('MI0000285', 'Var', (92, 101))
51081	25250788	The expression of lncRNA AC006050.3-003 was next detected by qPCR in the other 60 lung SCC patients received cisplatin based chemotherapy (Figure 5A).	('lncRNA AC006050.3-003', 'Var', (18, 39))	('patients', 'Species', '9606', (91, 99))	('lung SCC', 'Disease', (82, 90))	('SCC', 'Phenotype', 'HP:0002860', (87, 90))	('cisplatin', 'Chemical', 'MESH:D002945', (109, 118))
51082	25250788	The expression of lncRNA AC006050.3-003 was significantly lower in PR samples compared with the PD samples.	('PR', 'Chemical', '-', (67, 69))	('lower', 'NegReg', (58, 63))	('expression', 'MPA', (4, 14))	('lncRNA', 'Gene', (18, 24))	('PD', 'Disease', 'MESH:D010300', (96, 98))	('AC006050.3-003', 'Var', (25, 39))
51085	25250788	As shown in Figure 5B, ROC curve analysis revealed that lncRNA AC006050.3-003 was a valuable biomarker for differentiating PR patients from PD patients with an area under the curve (AUC) of 0.887 (95% confidence interval 0.779, 0.954).	('AC006050.3-003', 'Var', (63, 77))	('lncRNA AC006050.3-003', 'Var', (56, 77))	('PD', 'Disease', 'MESH:D010300', (140, 142))	('PR', 'Chemical', '-', (123, 125))	('patients', 'Species', '9606', (143, 151))	('patients', 'Species', '9606', (126, 134))
51093	25250788	Previous studies have shown that there is deregulation of HOX gene expression in various of cancers including lung cancer.	('lung cancer', 'Disease', 'MESH:D008175', (110, 121))	('deregulation', 'Var', (42, 54))	('cancers', 'Phenotype', 'HP:0002664', (92, 99))	('cancers', 'Disease', 'MESH:D009369', (92, 99))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('lung cancer', 'Disease', (110, 121))	('lung cancer', 'Phenotype', 'HP:0100526', (110, 121))	('cancers', 'Disease', (92, 99))	('HOX gene', 'Gene', (58, 66))	('expression', 'MPA', (67, 77))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
51099	25250788	Depletion of a number of enhancer lncRNAs could lead to decreased expression of their neighboring protein-coding genes, such as TAL1, Snai1 and Snai2.	('Snai1', 'Gene', (134, 139))	('Snai2', 'Gene', (144, 149))	('Snai2', 'Gene', '6591', (144, 149))	('TAL1', 'Gene', (128, 132))	('decreased', 'NegReg', (56, 65))	('expression', 'MPA', (66, 76))	('Depletion', 'Var', (0, 9))	('Snai1', 'Gene', '6615', (134, 139))
51110	25250788	Gene co-expression network identified that lncRNAs including BX648420, ENST00000366408, and AK126698 potentially played a key role in cisplatin resistance.	('cisplatin resistance', 'MPA', (134, 154))	('played', 'Reg', (113, 119))	('AK126698', 'Var', (92, 100))	('n ne', 'Gene', (17, 21))	('n ne', 'Gene', '2023', (17, 21))	('e co-', 'Gene', '22858', (3, 8))	('cisplatin', 'Chemical', 'MESH:D002945', (134, 143))	('e co-', 'Gene', (3, 8))	('BX648420', 'Var', (61, 69))
51114	25250788	The centrality of lncRNA AC006050.3 indicates its relative importance in the lncRNA-mRNA co-expression network.	('n ne', 'Gene', (101, 105))	('lncRNA', 'Var', (18, 24))	('AC006050.3', 'Var', (25, 35))	('n ne', 'Gene', '2023', (101, 105))
51115	25250788	With co-expression network, we found AC006050.3-003 expression level correlated with many members of the NER pathway.	('expression level', 'MPA', (52, 68))	('correlated', 'Reg', (69, 79))	('n ne', 'Gene', (17, 21))	('NER pathway', 'Pathway', (105, 116))	('AC006050.3-003', 'Var', (37, 51))	('n ne', 'Gene', '2023', (17, 21))
51118	25250788	Based on the co-expression network analysis, lncRNA AC006050.3-003 was selected to further evaluate the predictor value in determining clinical response of lung SCC patients receiving cisplatin based chemotherapy by qPCR through additional 60 lung SCC samples.	('e co-', 'Gene', (11, 16))	('lung SCC', 'Disease', (156, 164))	('SCC', 'Phenotype', 'HP:0002860', (161, 164))	('SCC', 'Phenotype', 'HP:0002860', (248, 251))	('cisplatin', 'Chemical', 'MESH:D002945', (184, 193))	('n ne', 'Gene', (25, 29))	('patients', 'Species', '9606', (165, 173))	('e co-', 'Gene', '22858', (11, 16))	('n ne', 'Gene', '2023', (25, 29))	('lncRNA AC006050.3-003', 'Var', (45, 66))
51183	33437754	The newly obtained prediction accuracies caused by a gene were compared to the original prediction accuracy from the model for the cancer type labeled by TCGA data.	('cancer', 'Disease', (131, 137))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('gene', 'Var', (53, 57))
51201	33437754	The GCNN model with the PPI+singleton graph included all the 7,091 genes and demonstrated a >5% increase in prediction accuracy compared with the PPI graph with a smaller accuracy variation as shown in Table 2, suggesting that the additional 2,647 genes could be important in determining cancer type.	('GCNN', 'Chemical', '-', (4, 8))	('cancer', 'Disease', 'MESH:D009369', (288, 294))	('cancer', 'Disease', (288, 294))	('prediction', 'MPA', (108, 118))	('PPI+singleton', 'Var', (24, 37))	('increase', 'PosReg', (96, 104))	('cancer', 'Phenotype', 'HP:0002664', (288, 294))
51208	33437754	A total of 68%, 16%, 95.2%, and 72.9%, out of 166 READ samples were classified into COAD cancer type by the co-expression, co-expression+singleton, PPI, and PPI+singleton GCNN model respectively (confusion matrices in Figure 7 and, Figure 8, and further illustrated in Supplement 2, 3, 4, and 5).	('GCNN', 'Chemical', '-', (171, 175))	('D', 'Chemical', 'MESH:D003903', (87, 88))	('PPI+singleton', 'Var', (157, 170))	('COAD cancer', 'Disease', 'MESH:D029424', (84, 95))	('confusion', 'Phenotype', 'HP:0001289', (196, 205))	('D', 'Chemical', 'MESH:D003903', (53, 54))	('COAD cancer', 'Disease', (84, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
51216	33437754	UCS classification performed poorly (misclassification rate of 25%, 25%, 58.9%, and 21.4% for co-expression, co-expression+singleton, PPI model, and PPI+singleton GCNN model, respectively), and most of these misclassified samples were in UCEC as expected.	('PPI+singleton', 'Var', (149, 162))	('co-expression+singleton', 'Var', (109, 132))	('UCEC', 'Disease', (238, 242))	('GCNN', 'Chemical', '-', (163, 167))	('co-expression', 'Var', (94, 107))	('UCS', 'Phenotype', 'HP:0002891', (0, 3))
51261	32939323	Lung cancer patients with positive Siglec-15 expression showed significantly short survival rates in progression-free survival concomitant with reduced infiltration of CD20 + B, and dendritic cells by immunohistochemistry.	('short', 'NegReg', (77, 82))	('reduced', 'NegReg', (144, 151))	('patients', 'Species', '9606', (12, 20))	('positive', 'Var', (26, 34))	('Siglec-15', 'Gene', (35, 44))	('Lung cancer', 'Phenotype', 'HP:0100526', (0, 11))	('CD20', 'Gene', '54474', (168, 172))	('CD20', 'Gene', (168, 172))	('Lung cancer', 'Disease', (0, 11))	('progression-free survival', 'CPA', (101, 126))	('Lung cancer', 'Disease', 'MESH:D008175', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))	('expression', 'Var', (45, 55))	('infiltration', 'MPA', (152, 164))	('Siglec-15', 'Gene', '284266', (35, 44))
51292	32939323	We investigated the copy number alterations (CNA) and mutations of Siglec-15 in different cancers.	('cancers', 'Disease', (90, 97))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('mutations', 'Var', (54, 63))	('copy number alterations', 'Var', (20, 43))	('Siglec-15', 'Gene', '284266', (67, 76))	('Siglec-15', 'Gene', (67, 76))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('cancers', 'Disease', 'MESH:D009369', (90, 97))
51327	32939323	Genetic and epigenetic changes play a critical role in regulating cancer development and immune tolerance.	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('Genetic', 'Var', (0, 7))	('immune tolerance', 'CPA', (89, 105))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('epigenetic changes', 'Var', (12, 30))	('cancer', 'Disease', (66, 72))
51329	32939323	We found that patients with high Siglec-15 expression were accompanied by gene alterations in OV, HNSC, sarcoma (SARC), UCEC, BLCA, BRCA, SKCM, and lymphoid neoplasm diffuse large B-cell lymphoma (DLBC) (Figure 2a, Supplementary Figure S2a).	('neoplasm', 'Phenotype', 'HP:0002664', (157, 165))	('alterations', 'Reg', (79, 90))	('sarcoma', 'Phenotype', 'HP:0100242', (104, 111))	('B-cell lymphoma', 'Disease', 'MESH:D016393', (180, 195))	('patients', 'Species', '9606', (14, 22))	('HNSC', 'Disease', (98, 102))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (180, 195))	('OV', 'Phenotype', 'HP:0012887', (94, 96))	('lymphoid neoplasm', 'Disease', (148, 165))	('SARC', 'Phenotype', 'HP:0100242', (113, 117))	('B-cell lymphoma', 'Disease', (180, 195))	('Siglec-15', 'Gene', (33, 42))	('sarcoma', 'Disease', 'MESH:D012509', (104, 111))	('high', 'Var', (28, 32))	('lymphoma', 'Phenotype', 'HP:0002665', (187, 195))	('lymphoid neoplasm', 'Disease', 'MESH:D008223', (148, 165))	('sarcoma', 'Disease', (104, 111))	('BRCA', 'Phenotype', 'HP:0003002', (132, 136))	('lymphoid neoplasm', 'Phenotype', 'HP:0002665', (148, 165))	('Siglec-15', 'Gene', '284266', (33, 42))	('expression', 'MPA', (43, 53))
51330	32939323	The trends in Siglec-15 genetic alteration were consistent with its mRNA levels in these cancers.	('Siglec-15', 'Gene', (14, 23))	('cancers', 'Phenotype', 'HP:0002664', (89, 96))	('genetic alteration', 'Var', (24, 42))	('cancers', 'Disease', 'MESH:D009369', (89, 96))	('cancers', 'Disease', (89, 96))	('Siglec-15', 'Gene', '284266', (14, 23))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
51347	32939323	We found that high mRNA expression of Siglec-15 indicated a better prognosis for BRCA-luminal A, BRCA-luminal B, OV and STAD-diffuse (Figure 3c).	('STAD-diffuse', 'Disease', (120, 132))	('luminal', 'Chemical', 'MESH:D010634', (86, 93))	('mRNA expression', 'MPA', (19, 34))	('BRCA-luminal A', 'Disease', (81, 95))	('BRCA', 'Phenotype', 'HP:0003002', (97, 101))	('high', 'Var', (14, 18))	('BRCA', 'Phenotype', 'HP:0003002', (81, 85))	('Siglec-15', 'Gene', '284266', (38, 47))	('BRCA-luminal', 'Disease', (97, 109))	('luminal', 'Chemical', 'MESH:D010634', (102, 109))	('OV', 'Phenotype', 'HP:0012887', (113, 115))	('Siglec-15', 'Gene', (38, 47))
51349	32939323	High Siglec-15 expression predicted worse outcomes in LUAD, BRCA-basal, BRCA-Her2+ ,and STAD (Figure 3d).	('High', 'Var', (0, 4))	('BRCA', 'Phenotype', 'HP:0003002', (72, 76))	('Her2', 'Gene', (77, 81))	('Siglec-15', 'Gene', '284266', (5, 14))	('Her2', 'Gene', '2064', (77, 81))	('Siglec-15', 'Gene', (5, 14))	('expression', 'MPA', (15, 25))	('LUAD', 'Phenotype', 'HP:0030078', (54, 58))	('BRCA', 'Phenotype', 'HP:0003002', (60, 64))	('STAD', 'Disease', (88, 92))	('LUAD', 'Disease', (54, 58))	('BRCA-basal', 'Disease', (60, 70))
51350	32939323	Furthermore, high Siglec-15 expression was associated with poor OS and FP in LUAD; poor OS in BRCA-basal; poor RFS in BRCA-Her2+; poor OS and PPS in STAD-intestinal; and poor OS in STAD-mixed.	('Siglec-15', 'Gene', (18, 27))	('high', 'Var', (13, 17))	('BRCA', 'Phenotype', 'HP:0003002', (94, 98))	('Her2', 'Gene', (123, 127))	('expression', 'MPA', (28, 38))	('BRCA', 'Phenotype', 'HP:0003002', (118, 122))	('Her2', 'Gene', '2064', (123, 127))	('LUAD', 'Phenotype', 'HP:0030078', (77, 81))	('PPS', 'Chemical', '-', (142, 145))	('Siglec-15', 'Gene', '284266', (18, 27))
51367	32939323	Siglec-15 was positively associated with naive B cells, neutrophils, and activated mast cells and negatively associated with follicular helper T cells in metastatic SKCM in GSE8401 compared to the associations in primary SKCM.	('positively', 'PosReg', (14, 24))	('follicular helper T cells', 'CPA', (125, 150))	('associated', 'Interaction', (109, 119))	('associated', 'Interaction', (25, 35))	('negatively', 'NegReg', (98, 108))	('Siglec-15', 'Gene', '284266', (0, 9))	('GSE8401', 'Var', (173, 180))	('Siglec-15', 'Gene', (0, 9))	('metastatic SKCM', 'Disease', (154, 169))
51389	32939323	And PI3 K was significantly positively associated with Siglec-15 expression (Pearson r = 0.54, p = .01).	('expression', 'MPA', (65, 75))	('Siglec-15', 'Gene', (55, 64))	('PI3 K', 'Var', (4, 9))	('Siglec-15', 'Gene', '284266', (55, 64))
51391	32939323	PI3 K was highly expressed in the Siglec-15 high group (p < .05).	('Siglec-15', 'Gene', (34, 43))	('Siglec-15', 'Gene', '284266', (34, 43))	('PI3', 'Var', (0, 3))
51422	32939323	For example, mutant PD-L1 with structural variations leads to aberrant PD-L1 expression and immunosuppression.	('mutant', 'Var', (13, 19))	('expression', 'MPA', (77, 87))	('PD-L1', 'Gene', (71, 76))	('PD-L1', 'Gene', (20, 25))	('PD-L1', 'Gene', '29126', (71, 76))	('leads to', 'Reg', (53, 61))	('PD-L1', 'Gene', '29126', (20, 25))
51423	32939323	JAK2/PD-L1/PD-L2 (9p24.1) amplifications can also bring about constitutive overexpression of PD-L1 and a significant response to checkpoint inhibitors.	('PD-L1', 'Gene', '29126', (93, 98))	('overexpression', 'PosReg', (75, 89))	('PD-L1', 'Gene', (5, 10))	('JAK2', 'Gene', '3717', (0, 4))	('response to checkpoint inhibitors', 'MPA', (117, 150))	('PD-L1', 'Gene', '29126', (5, 10))	('JAK2', 'Gene', (0, 4))	('bring about', 'Reg', (50, 61))	('PD-L1', 'Gene', (93, 98))	('PD-L2', 'Gene', (11, 16))	('PD-L2', 'Gene', '80380', (11, 16))	('amplifications', 'Var', (26, 40))
51425	32939323	Preliminary analysis suggested that Siglec-15 expression was genetically and epigenetically regulated through CNA and promoter methylation.	('expression', 'MPA', (46, 56))	('Siglec-15', 'Gene', (36, 45))	('Siglec-15', 'Gene', '284266', (36, 45))	('promoter methylation', 'Var', (118, 138))
51442	32939323	There is an increasing trend for CXCR3 and MMP9 in patients with overexpressed Siglec-15, which may recruit Treg.	('overexpressed', 'Var', (65, 78))	('Siglec-15', 'Gene', (79, 88))	('CXCR3', 'Gene', '2833', (33, 38))	('patients', 'Species', '9606', (51, 59))	('MMP9', 'Gene', (43, 47))	('CXCR3', 'Gene', (33, 38))	('MMP9', 'Gene', '4318', (43, 47))	('Siglec-15', 'Gene', '284266', (79, 88))
51462	32463792	Kaplan-Meier plotter showed that high PTGIS was associated with poor overall survival and progression-free survival in lung, ovarian, and gastric cancers.	('overall survival', 'CPA', (69, 85))	('high', 'Var', (33, 37))	('PTGIS', 'Gene', (38, 43))	('PTGIS', 'Gene', '5740', (38, 43))	('poor', 'NegReg', (64, 68))	('progression-free survival', 'CPA', (90, 115))	('gastric cancer', 'Phenotype', 'HP:0012126', (138, 152))	('ovarian', 'Disease', 'MESH:D010049', (125, 132))	('gastric cancers', 'Disease', 'MESH:D013274', (138, 153))	('ovarian', 'Disease', (125, 132))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('gastric cancers', 'Disease', (138, 153))	('gastric cancers', 'Phenotype', 'HP:0012126', (138, 153))	('lung', 'Disease', (119, 123))	('cancers', 'Phenotype', 'HP:0002664', (146, 153))
51464	32463792	Conclusions: High expression of PTGIS could promote the infiltration of TAMs and Tregs in the tumor microenvironment and deteriorate outcomes of patients with lung, ovarian, and gastric cancers.	('ovarian', 'Disease', (165, 172))	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('deteriorate', 'NegReg', (121, 132))	('cancers', 'Phenotype', 'HP:0002664', (186, 193))	('gastric cancers', 'Disease', 'MESH:D013274', (178, 193))	('gastric cancers', 'Disease', (178, 193))	('gastric cancers', 'Phenotype', 'HP:0012126', (178, 193))	('TAMs', 'Chemical', '-', (72, 76))	('gastric cancer', 'Phenotype', 'HP:0012126', (178, 192))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('Tregs', 'Chemical', '-', (81, 86))	('iron', 'Chemical', 'MESH:D007501', (108, 112))	('lung', 'Disease', (159, 163))	('PTGIS', 'Gene', '5740', (32, 37))	('infiltration', 'CPA', (56, 68))	('High expression', 'Var', (13, 28))	('ovarian', 'Disease', 'MESH:D010049', (165, 172))	('TAMs', 'Protein', (72, 76))	('PTGIS', 'Gene', (32, 37))	('patients', 'Species', '9606', (145, 153))	('outcomes', 'CPA', (133, 141))	('promote', 'PosReg', (44, 51))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('tumor', 'Disease', (94, 99))
51478	32463792	A previous study observed that hypermethylation of the PTGIS promotor was associated with diminished gene expression in colorectal carcinogenesis.	('hypermethylation', 'Var', (31, 47))	('colorectal carcinogenesis', 'Disease', 'MESH:D015179', (120, 145))	('PTGIS', 'Gene', (55, 60))	('PTGIS', 'Gene', '5740', (55, 60))	('colorectal carcinogenesis', 'Disease', (120, 145))	('diminished', 'NegReg', (90, 100))	('gene expression', 'MPA', (101, 116))
51479	32463792	Furthermore, other studies suggested that PTGIS variants may affect breast cancer susceptibility, and elevated PTGIS was associated with liver metastasis and poor survival outcomes for patients with colon cancer.	('liver metastasis', 'Disease', 'MESH:D009362', (137, 153))	('associated with', 'Reg', (121, 136))	('PTGIS', 'Gene', '5740', (42, 47))	('affect', 'Reg', (61, 67))	('PTGIS', 'Gene', (42, 47))	('colon cancer', 'Phenotype', 'HP:0003003', (199, 211))	('PTGIS', 'Gene', '5740', (111, 116))	('liver metastasis', 'Disease', (137, 153))	('breast cancer', 'Phenotype', 'HP:0003002', (68, 81))	('variants', 'Var', (48, 56))	('colon cancer', 'Disease', 'MESH:D015179', (199, 211))	('PTGIS', 'Gene', (111, 116))	('patients', 'Species', '9606', (185, 193))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('elevated PTGIS', 'Phenotype', 'HP:0008151', (102, 116))	('breast cancer', 'Disease', 'MESH:D001943', (68, 81))	('elevated', 'PosReg', (102, 110))	('breast cancer', 'Disease', (68, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('colon cancer', 'Disease', (199, 211))
51498	32463792	Interestingly, compared with low PTGIS expression, high expression of PTGIS indicated a better survival prognosis for overall survival (OS) (hazard ratio [HR]=0.63, 95% confidence interval [CI]=0.44 to 0.90, P=0.012) and disease specific survival (DSS) (HR=0.60, 95% CI=0.40 to 0.90, P=0.013) in breast cancer (Figure 2A and 2B).	('disease specific survival', 'CPA', (221, 246))	('overall survival', 'CPA', (118, 134))	('PTGIS', 'Gene', (70, 75))	('breast cancer', 'Disease', 'MESH:D001943', (296, 309))	('PTGIS', 'Gene', '5740', (70, 75))	('cancer', 'Phenotype', 'HP:0002664', (303, 309))	('breast cancer', 'Disease', (296, 309))	('breast cancer', 'Phenotype', 'HP:0003002', (296, 309))	('high expression', 'Var', (51, 66))	('PTGIS', 'Gene', (33, 38))	('better', 'PosReg', (88, 94))	('PTGIS', 'Gene', '5740', (33, 38))
51499	32463792	However, among the other three common solid tumors (colorectal cancer, ovarian cancer, and lung cancer), high PTGIS expression was associated with a worse prognosis than low PTGIS expression (Figure 2C-2H).	('lung cancer', 'Phenotype', 'HP:0100526', (91, 102))	('solid tumors', 'Disease', (38, 50))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('colorectal cancer', 'Phenotype', 'HP:0003003', (52, 69))	('solid tumors', 'Disease', 'MESH:D009369', (38, 50))	('lung cancer', 'Disease', (91, 102))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('ovarian cancer', 'Disease', 'MESH:D010051', (71, 85))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('PTGIS', 'Gene', '5740', (174, 179))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('PTGIS', 'Gene', '5740', (110, 115))	('colorectal cancer', 'Disease', 'MESH:D015179', (52, 69))	('PTGIS', 'Gene', (174, 179))	('high', 'Var', (105, 109))	('ovarian cancer', 'Disease', (71, 85))	('PTGIS', 'Gene', (110, 115))	('lung cancer', 'Disease', 'MESH:D008175', (91, 102))	('colorectal cancer', 'Disease', (52, 69))	('ovarian cancer', 'Phenotype', 'HP:0100615', (71, 85))
51502	32463792	Notably, PTGIS had less influence on OS in this analysis than it had been shown to have in the PrognoScan analysis for breast cancer (HR=0.89, 95% CI=0.72 to 1.1, P=0.28) (Figure 3A), and high PTGIS expression was correlated with poor prognosis in gastric cancer (OS HR=2.03, 95% CI=1.69 to 2.44, P=7.8e-15; progression-free survival [PFS] HR=2.05, 95% CI=1.65 to 2.54, P=2.5e-11) (Figure 3C and 3D).	('gastric cancer', 'Disease', 'MESH:D013274', (248, 262))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('breast cancer', 'Disease', 'MESH:D001943', (119, 132))	('gastric cancer', 'Disease', (248, 262))	('high', 'Var', (188, 192))	('breast cancer', 'Disease', (119, 132))	('breast cancer', 'Phenotype', 'HP:0003002', (119, 132))	('gastric cancer', 'Phenotype', 'HP:0012126', (248, 262))	('PTGIS', 'Gene', (9, 14))	('PTGIS', 'Gene', '5740', (9, 14))	('cancer', 'Phenotype', 'HP:0002664', (256, 262))	('PTGIS', 'Gene', (193, 198))	('PTGIS', 'Gene', '5740', (193, 198))
51503	32463792	Consistent with previous results, patients with high expression of PTGIS had a poor prognosis in both lung cancer (OS HR=1.47, 95% CI=1.28 to 1.69, P=4.8e-08; PFS HR=2.13, 95% CI=1.74 to 2.6, P=3.5e-14) and ovarian cancer (OS HR=1.23, 95% CI=1.08 to 1.4, P=0.002; PFS HR=1.26, 95% CI=1.11 to 1.43, P=3.1e-4) (Figure 3E-3H).	('PTGIS', 'Gene', '5740', (67, 72))	('lung cancer', 'Phenotype', 'HP:0100526', (102, 113))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('ovarian cancer', 'Disease', (207, 221))	('lung cancer', 'Disease', (102, 113))	('patients', 'Species', '9606', (34, 42))	('lung cancer', 'Disease', 'MESH:D008175', (102, 113))	('high expression', 'Var', (48, 63))	('PTGIS', 'Gene', (67, 72))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('ovarian cancer', 'Disease', 'MESH:D010051', (207, 221))	('ovarian cancer', 'Phenotype', 'HP:0100615', (207, 221))
51504	32463792	Based on this large-sample validation analysis, these results suggest that high PTGIS expression implies reduced survival in ovarian, lung and gastric cancer.	('gastric cancer', 'Phenotype', 'HP:0012126', (143, 157))	('lung', 'Disease', (134, 138))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('high', 'Var', (75, 79))	('ovarian', 'Disease', 'MESH:D010049', (125, 132))	('PTGIS', 'Gene', (80, 85))	('ovarian', 'Disease', (125, 132))	('survival', 'MPA', (113, 121))	('reduced', 'NegReg', (105, 112))	('gastric cancer', 'Disease', (143, 157))	('gastric cancer', 'Disease', 'MESH:D013274', (143, 157))	('PTGIS', 'Gene', '5740', (80, 85))
51512	32463792	For serous ovarian cancer, high expression of PTGIS was related to reduced OS and PFS.	('serous ovarian cancer', 'Disease', 'MESH:D018284', (4, 25))	('ovarian cancer', 'Phenotype', 'HP:0100615', (11, 25))	('high', 'Var', (27, 31))	('reduced', 'NegReg', (67, 74))	('PTGIS', 'Gene', (46, 51))	('PFS', 'Disease', (82, 85))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('PTGIS', 'Gene', '5740', (46, 51))	('serous ovarian cancer', 'Disease', (4, 25))
51513	32463792	Specifically, compared with low PTGIS mRNA expression, high PTGIS mRNA expression was correlated with worse OS and PFS only in stage 3 disease (OS HR = 1.2, P = 0.0398; PFS HR = 1.28, P = 0.0025), which includes involvement of retroperitoneal lymph nodes.	('PTGIS', 'Gene', '5740', (60, 65))	('PFS', 'Disease', (115, 118))	('PTGIS', 'Gene', (32, 37))	('high', 'Var', (55, 59))	('PTGIS', 'Gene', (60, 65))	('worse OS', 'Disease', (102, 110))	('PTGIS', 'Gene', '5740', (32, 37))
51547	32463792	Interestingly, PTGIS expression also has a positive correlation with TIM-3, an important gene mediating T cell exhaustion and macrophage activation; the presence of the exhausted phenotype downregulates the immune response in tumor-bearing hosts.	('T cell exhaustion', 'Phenotype', 'HP:0005435', (104, 121))	('immune response', 'CPA', (207, 222))	('PTGIS', 'Gene', '5740', (15, 20))	('TIM-3', 'Gene', '84868', (69, 74))	('TIM-3', 'Gene', (69, 74))	('presence', 'Var', (153, 161))	('tumor', 'Disease', 'MESH:D009369', (226, 231))	('downregulates', 'NegReg', (189, 202))	('PTGIS', 'Gene', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('tumor', 'Disease', (226, 231))
51557	32463792	Notably, high expression of PTGIS could significantly impair the prognosis of patients with lymph node metastasis in ovarian or gastric cancer.	('impair', 'NegReg', (54, 60))	('high expression', 'Var', (9, 24))	('lymph node metastasis in ovarian or gastric cancer', 'Disease', 'MESH:D000072717', (92, 142))	('PTGIS', 'Gene', (28, 33))	('patients', 'Species', '9606', (78, 86))	('PTGIS', 'Gene', '5740', (28, 33))	('gastric cancer', 'Phenotype', 'HP:0012126', (128, 142))	('prognosis', 'CPA', (65, 74))	('lymph node metastasis in ovarian or gastric cancer', 'Disease', (92, 142))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
51563	32463792	It has been reported in the literature that hypermethylation of gene promoters leads to transcriptional silencing as a common event in cancer, and hypermethylation of the PTGIS promoter was also detected in colorectal cancer.	('cancer', 'Disease', 'MESH:D009369', (218, 224))	('cancer', 'Disease', (135, 141))	('colorectal cancer', 'Disease', 'MESH:D015179', (207, 224))	('PTGIS', 'Gene', '5740', (171, 176))	('cancer', 'Disease', (218, 224))	('transcriptional silencing', 'MPA', (88, 113))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('colorectal cancer', 'Phenotype', 'HP:0003003', (207, 224))	('PTGIS', 'Gene', (171, 176))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('hypermethylation', 'Var', (44, 60))	('colorectal cancer', 'Disease', (207, 224))	('cancer', 'Disease', 'MESH:D009369', (135, 141))	('detected', 'Reg', (195, 203))
51565	32463792	For example, high expression of PTGIS was associated with a good prognosis for breast cancer patients in PrognoScan, while there was no significant effect on prognosis in Kaplan-Meier-plotter and the GEPIA database.	('breast cancer', 'Disease', 'MESH:D001943', (79, 92))	('high', 'Var', (13, 17))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('breast cancer', 'Disease', (79, 92))	('breast cancer', 'Phenotype', 'HP:0003002', (79, 92))	('PTGIS', 'Gene', (32, 37))	('patients', 'Species', '9606', (93, 101))	('PTGIS', 'Gene', '5740', (32, 37))
51567	32463792	Moreover, compared with low expression of PTGIS, elevated expression of PTGIS was revealed to be associated with poorer survival outcomes for patients with stage 3 disease, patients with wild-type TP53, and patients treated with suboptimal debulking surgery in ovarian cancer, as well as for patients with advanced-stage disease or lymph node metastasis in gastric cancer.	('ovarian cancer', 'Disease', (261, 275))	('expression', 'MPA', (58, 68))	('ovarian cancer', 'Phenotype', 'HP:0100615', (261, 275))	('advanced-stage disease', 'Disease', (306, 328))	('PTGIS', 'Gene', '5740', (42, 47))	('gastric cancer', 'Disease', (357, 371))	('patients', 'Species', '9606', (292, 300))	('TP53', 'Gene', (197, 201))	('PTGIS', 'Gene', (42, 47))	('patients', 'Species', '9606', (173, 181))	('suboptimal', 'Var', (229, 239))	('cancer', 'Phenotype', 'HP:0002664', (365, 371))	('PTGIS', 'Gene', '5740', (72, 77))	('gastric cancer', 'Disease', 'MESH:D013274', (357, 371))	('elevated', 'PosReg', (49, 57))	('advanced-stage disease', 'Disease', 'MESH:D006223', (306, 328))	('poorer', 'NegReg', (113, 119))	('cancer', 'Phenotype', 'HP:0002664', (269, 275))	('PTGIS', 'Gene', (72, 77))	('ovarian cancer', 'Disease', 'MESH:D010051', (261, 275))	('TP53', 'Gene', '7157', (197, 201))	('survival outcomes', 'CPA', (120, 137))	('gastric cancer', 'Phenotype', 'HP:0012126', (357, 371))	('patients', 'Species', '9606', (207, 215))	('patients', 'Species', '9606', (142, 150))
51581	32463792	PGI2 is the primary metabolite of PTGIS, and the 5-year survival rate of lung cancer patients with high expression of PGI2 is significantly worse than that of lung cancer patients with low expression of PGI2.	('high expression', 'Var', (99, 114))	('PGI2', 'Chemical', 'MESH:D011464', (0, 4))	('PTGIS', 'Gene', '5740', (34, 39))	('worse', 'NegReg', (140, 145))	('lung cancer', 'Disease', 'MESH:D008175', (73, 84))	('lung cancer', 'Disease', 'MESH:D008175', (159, 170))	('PTGIS', 'Gene', (34, 39))	('patients', 'Species', '9606', (171, 179))	('patients', 'Species', '9606', (85, 93))	('PGI2', 'Chemical', 'MESH:D011464', (118, 122))	('lung cancer', 'Phenotype', 'HP:0100526', (159, 170))	('lung cancer', 'Phenotype', 'HP:0100526', (73, 84))	('PGI2', 'Chemical', 'MESH:D011464', (203, 207))	('PGI2', 'Gene', (118, 122))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('survival rate', 'CPA', (56, 69))	('lung cancer', 'Disease', (159, 170))	('lung cancer', 'Disease', (73, 84))
51616	32120229	While vascular invasion, pleural invasion and genetic mutations are histologic markers that suggest higher risk disease, there is no consensus regarding their use in making decisions about adjuvant therapy.	('genetic mutations', 'Var', (46, 63))	('vascular invasion', 'CPA', (6, 23))	('pleural invasion', 'Disease', 'MESH:D010995', (25, 41))	('pleural invasion', 'Disease', (25, 41))
51666	32120229	Radiomic features extracted from lung CT have been shown to be representative of many facets of lung cancer biology, such as clinical receptor status, molecular subtype identified by gene expression, and gene mutations and have hence shown immense value in predicting outcomes.	('lung cancer', 'Disease', 'MESH:D008175', (96, 107))	('gene mutations', 'Var', (204, 218))	('lung cancer', 'Disease', (96, 107))	('lung cancer', 'Phenotype', 'HP:0100526', (96, 107))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))
51697	32669708	This strategy was first realized for the treatment of NSCLC when mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) were identified as the molecular basis of the clinical responses observed in patients treated with the EGFR tyrosine kinase inhibitor gefitinib.	('epidermal growth factor receptor', 'Gene', (112, 144))	('patients', 'Species', '9606', (229, 237))	('EGFR', 'Gene', (255, 259))	('EGFR', 'Gene', '1956', (255, 259))	('EGFR', 'Gene', '1956', (146, 150))	('NSCLC', 'Phenotype', 'HP:0030358', (54, 59))	('gefitinib', 'Chemical', 'MESH:D000077156', (286, 295))	('EGFR', 'Gene', (146, 150))	('epidermal growth factor receptor', 'Gene', '1956', (112, 144))	('NSCLC', 'Disease', (54, 59))	('mutations in', 'Var', (65, 77))	('NSCLC', 'Disease', 'MESH:D002289', (54, 59))
51698	32669708	In NSCLC, the majority of targetable alterations tend to occur in the cancers of patients who have never smoked or who are former light smokers.	('NSCLC', 'Disease', (3, 8))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('NSCLC', 'Disease', 'MESH:D002289', (3, 8))	('patients', 'Species', '9606', (81, 89))	('alterations', 'Var', (37, 48))	('cancers', 'Disease', 'MESH:D009369', (70, 77))	('NSCLC', 'Phenotype', 'HP:0030358', (3, 8))	('cancers', 'Phenotype', 'HP:0002664', (70, 77))	('cancers', 'Disease', (70, 77))	('occur', 'Reg', (57, 62))
51721	32669708	Results for the 19 cohorts are grouped into 4 modules of genomic aberrations on the basis of pathways identified from the analyses of lung cancers undertaken by The Cancer Genome Atlas (TCGA) (1) a cell cycle progression gene module, encompassing alterations in CDKN2A, CCND1 and CDK4; (2) an activated RAS module, including mutation of KRAS and loss of NF1; (3) an altered receptor tyrosine kinase (RTK) module, encompassing genomic aberrations in FGFR2 and FGFR3 (mutation and translocation), MET (amplification and mutation), ROS1 (fusion) and EGFR T790M mutation; and (4) a PI3K/PTEN/AKT/mTOR module encompassing mutation or amplification of PIK3CA, loss of PTEN, and mutations in AKT1-3 and in TSC1 and TSC2.	('mTOR', 'Gene', '2475', (592, 596))	('EGFR', 'Gene', '1956', (547, 551))	('CDKN2A', 'Gene', '1029', (262, 268))	('AKT', 'Gene', '207', (685, 688))	('cancers', 'Phenotype', 'HP:0002664', (139, 146))	('T790M', 'Mutation', 'rs121434569', (552, 557))	('Cancer', 'Disease', (165, 171))	('RTK', 'Gene', (400, 403))	('KRAS', 'Gene', '3845', (337, 341))	('FGFR3', 'Gene', '2261', (459, 464))	('PTEN', 'Gene', (583, 587))	('PTEN', 'Gene', (662, 666))	('RTK', 'Gene', '5979', (400, 403))	('FGFR2', 'Gene', (449, 454))	('AKT', 'Gene', '207', (588, 591))	('NF1', 'Gene', '4763', (354, 357))	('CDK4', 'Gene', (280, 284))	('MET', 'Gene', '79811', (495, 498))	('KRAS', 'Gene', (337, 341))	('AKT1-3', 'Gene', '207;208;10000', (685, 691))	('ROS1', 'Gene', (529, 533))	('PIK3CA', 'Gene', (646, 652))	('loss', 'NegReg', (654, 658))	('Cancer', 'Disease', 'MESH:D009369', (165, 171))	('amplification', 'Var', (629, 642))	('PTEN', 'Gene', '5728', (583, 587))	('PTEN', 'Gene', '5728', (662, 666))	('FGFR2', 'Gene', '2263', (449, 454))	('NF1', 'Gene', (354, 357))	('CCND1', 'Gene', '595', (270, 275))	('mutation', 'Var', (325, 333))	('lung cancer', 'Phenotype', 'HP:0100526', (134, 145))	('TSC2', 'Gene', '7249', (708, 712))	('mutations', 'Var', (672, 681))	('CDK4', 'Gene', '1019', (280, 284))	('receptor tyrosine kinase', 'Gene', '5979', (374, 398))	('CCND1', 'Gene', (270, 275))	('EGFR', 'Gene', (547, 551))	('lung cancers', 'Disease', 'MESH:D008175', (134, 146))	('TSC1', 'Gene', (699, 703))	('AKT', 'Gene', (685, 688))	('lung cancers', 'Disease', (134, 146))	('CDKN2A', 'Gene', (262, 268))	('TSC1', 'Gene', '7248', (699, 703))	('AKT1-3', 'Gene', (685, 691))	('receptor tyrosine kinase', 'Gene', (374, 398))	('mutation', 'Var', (617, 625))	('TSC2', 'Gene', (708, 712))	('mTOR', 'Gene', (592, 596))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('lung cancers', 'Phenotype', 'HP:0100526', (134, 146))	('AKT', 'Gene', (588, 591))	('MET', 'Gene', (495, 498))	('ROS1', 'Gene', '6098', (529, 533))	('PIK3CA', 'Gene', '5290', (646, 652))	('Cancer', 'Phenotype', 'HP:0002664', (165, 171))	('FGFR3', 'Gene', (459, 464))
51725	32669708	In patients with cancers that harboured aberrations in cell cycle progression genes, we assessed the effect of inhibiting CDK4 and CDK6 using palbociclib.	('cell cycle progression genes', 'Gene', (55, 83))	('palbociclib', 'Chemical', 'MESH:C500026', (142, 153))	('cancers', 'Phenotype', 'HP:0002664', (17, 24))	('aberrations', 'Var', (40, 51))	('cancers', 'Disease', (17, 24))	('CDK4', 'Gene', (122, 126))	('cancers', 'Disease', 'MESH:D009369', (17, 24))	('inhibiting', 'NegReg', (111, 121))	('patients', 'Species', '9606', (3, 11))	('CDK4', 'Gene', '1019', (122, 126))	('CDK6', 'Gene', (131, 135))	('CDK6', 'Gene', '1021', (131, 135))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
51728	32669708	The current Bayesian estimates for median PFS (the primary outcome measure) range from 2.2 months (95% credible interval: 1.1-5.2) for patients with CDK4 amplification to 4.2 months (95% credible interval: 2.7-7.2) for patients with LUSC with CDKN2A loss, wherein 4 out of 18 patients obtained DCB.	('patients', 'Species', '9606', (276, 284))	('patients', 'Species', '9606', (135, 143))	('CDK4', 'Gene', (149, 153))	('CDK4', 'Gene', '1019', (149, 153))	('CDKN2A', 'Gene', (243, 249))	('loss', 'NegReg', (250, 254))	('amplification', 'Var', (154, 167))	('CDKN2A', 'Gene', '1029', (243, 249))	('patients', 'Species', '9606', (219, 227))	('DCB', 'Chemical', 'MESH:D015101', (294, 297))
51732	32669708	The cohorts in this module are as follows: palbociclib - KRAS mutation with no concomitant aberration activating AKT (AKT activation abrogates RAS-induced senescence mediated by CDK4 loss (Supplementary Information)) (C6), palbociclib -KRAS mutation/dual STK11 loss (C5), vistusertib (inhibitor of mTORC1 and mTORC2) -KRAS mutation/dual STK11 loss (B2D), vistusertib - STK11 loss only (B2S) and docetaxel + selumetinib (MEK inhibitor) - LUAD NF1 loss (E2).	('AKT', 'Gene', '207', (113, 116))	('LUAD', 'Phenotype', 'HP:0030078', (437, 441))	('AKT', 'Gene', (118, 121))	('STK11', 'Gene', (337, 342))	('mTORC1', 'Gene', (298, 304))	('KRAS', 'Gene', (236, 240))	('MEK', 'Gene', (420, 423))	('STK11', 'Gene', (369, 374))	('vistusertib', 'Chemical', 'MESH:C585537', (272, 283))	('mTORC1', 'Gene', '382056', (298, 304))	('selumetinib', 'Chemical', 'MESH:C517975', (407, 418))	('loss', 'NegReg', (343, 347))	('NF1', 'Gene', '4763', (442, 445))	('KRAS', 'Gene', '3845', (318, 322))	('KRAS', 'Gene', '3845', (57, 61))	('mTORC2', 'Gene', (309, 315))	('loss', 'NegReg', (446, 450))	('CDK4', 'Gene', (178, 182))	('docetaxel', 'Chemical', 'MESH:D000077143', (395, 404))	('palbociclib', 'Chemical', 'MESH:C500026', (43, 54))	('STK11', 'Gene', '6794', (337, 342))	('palbociclib', 'Chemical', 'MESH:C500026', (223, 234))	('AKT', 'Gene', '207', (118, 121))	('STK11', 'Gene', '6794', (369, 374))	('NF1', 'Gene', (442, 445))	('KRAS', 'Gene', (318, 322))	('STK11', 'Gene', (255, 260))	('KRAS', 'Gene', (57, 61))	('AKT', 'Gene', (113, 116))	('CDK4', 'Gene', '1019', (178, 182))	('vistusertib', 'Chemical', 'MESH:C585537', (355, 366))	('mTORC2', 'Gene', '74343', (309, 315))	('RAS-induced senescence', 'MPA', (143, 165))	('mutation', 'Var', (62, 70))	('KRAS', 'Gene', '3845', (236, 240))	('STK11', 'Gene', '6794', (255, 260))	('MEK', 'Gene', '5609', (420, 423))
51733	32669708	The Food and Drug Administration have recently approved selumetinib for paediatric patients with germline loss of NF1 who develop symptomatic inoperable plexiform neurofibromas.	('develop', 'PosReg', (122, 129))	('NF1', 'Gene', '4763', (114, 117))	('neurofibromas', 'Disease', 'MESH:D009455', (163, 176))	('selumetinib', 'Chemical', 'MESH:C517975', (56, 67))	('loss', 'Var', (106, 110))	('plexiform neurofibromas', 'Phenotype', 'HP:0009732', (153, 176))	('patients', 'Species', '9606', (83, 91))	('NF1', 'Gene', (114, 117))	('neurofibromas', 'Disease', (163, 176))	('neurofibromas', 'Phenotype', 'HP:0001067', (163, 176))
51734	32669708	Numerically, the highest median PFS of all the palbociclib-treated cohorts is the closed RAS mutant cohort (C6), at 5.3 months (95% credible interval: 3.8-7.9, PP > 0.99) with DCB rate 40% (95% credible interval: 25-58%).	('PFS', 'MPA', (32, 35))	('mutant', 'Var', (93, 99))	('DCB', 'Chemical', 'MESH:D015101', (176, 179))	('palbociclib', 'Chemical', 'MESH:C500026', (47, 58))
51735	32669708	The dual STK11 loss/RAS mutant palbociclib cohort (C5) currently has a median PFS of 2.6 months (95% credible interval: 1.5-5.0) and continues to recruit with PPoS of 0.27.	('mutant', 'Var', (24, 30))	('palbociclib', 'Gene', (31, 42))	('STK11', 'Gene', '6794', (9, 14))	('palbociclib', 'Chemical', 'MESH:C500026', (31, 42))	('loss/RAS', 'NegReg', (15, 23))	('STK11', 'Gene', (9, 14))
51741	32669708	The cohorts in this module are as follows: AZD4547 (FGFR inhibitor) - FGFR2 and FGFR3 mutations and translocations (A1), crizotinib (Met inhibitor) - MET amplification (D1), crizotinib (also ROS inhibitor) - ROS1 fusion (D2), crizotinib - MET exon 14 skipping mutations (D3) and osimertinib (EGFR inhibitor) - EGFR T790M mutation (G1).	('AZD4547', 'Chemical', 'MESH:C572463', (43, 50))	('FGFR2', 'Gene', '2263', (70, 75))	('EGFR', 'Gene', '1956', (310, 314))	('T790M', 'Mutation', 'rs121434569', (315, 320))	('FGFR3', 'Gene', '2261', (80, 85))	('Met', 'Gene', (133, 136))	('MET', 'Gene', (239, 242))	('MET', 'Gene', (150, 153))	('EGFR', 'Gene', '1956', (292, 296))	('crizotinib', 'Chemical', 'MESH:D000077547', (226, 236))	('crizotinib', 'Chemical', 'MESH:D000077547', (121, 131))	('mutations', 'Var', (86, 95))	('AZD4547', 'Gene', (43, 50))	('ROS1', 'Gene', '6098', (208, 212))	('skipping mutations', 'Var', (251, 269))	('T790M mutation', 'Var', (315, 329))	('osimertinib', 'Chemical', '-', (279, 290))	('EGFR', 'Gene', (310, 314))	('Met', 'Gene', '79811', (133, 136))	('MET', 'Gene', '79811', (239, 242))	('MET', 'Gene', '79811', (150, 153))	('translocations', 'Var', (100, 114))	('FGFR2', 'Gene', (70, 75))	('EGFR', 'Gene', (292, 296))	('crizotinib', 'Chemical', 'MESH:D000077547', (174, 184))	('FGFR3', 'Gene', (80, 85))	('ROS1', 'Gene', (208, 212))
51742	32669708	One out of five patients had a confirmed response to FGFR inhibition using AZD4547, with the response ongoing after more than 20 months.	('FGFR', 'Gene', (53, 57))	('patients', 'Species', '9606', (16, 24))	('AZD4547', 'Var', (75, 82))	('inhibition', 'NegReg', (58, 68))	('AZD4547', 'Chemical', 'MESH:C572463', (75, 82))
51745	32669708	In the MET exon 14 skipping mutation cohort (D3), the estimated confirmed OR rate is currently 65% (8 out of 12 patients responded, 95% credible interval: 39-86%) and the DCB rate is 68% (95% credible interval: 39-89%).	('MET', 'Gene', '79811', (7, 10))	('skipping mutation', 'Var', (19, 36))	('MET', 'Gene', (7, 10))	('patients', 'Species', '9606', (112, 120))	('DCB', 'Chemical', 'MESH:D015101', (171, 174))
51748	32669708	We assessed the effect of inhibiting mTOR (activated via a TSC1 or TSC2 mutation mutation) using vistusertib or inhibiting AKT using capivasertib in patients with cancers harbouring genomic aberrations that activated AKT.	('mutation mutation', 'Var', (72, 89))	('mTOR', 'Gene', '2475', (37, 41))	('TSC1', 'Gene', (59, 63))	('AKT', 'Gene', '207', (217, 220))	('cancers', 'Disease', 'MESH:D009369', (163, 170))	('vistusertib', 'Chemical', 'MESH:C585537', (97, 108))	('patients', 'Species', '9606', (149, 157))	('TSC1', 'Gene', '7248', (59, 63))	('TSC2', 'Gene', '7249', (67, 71))	('AKT', 'Gene', (123, 126))	('inhibiting', 'NegReg', (112, 122))	('inhibiting', 'NegReg', (26, 36))	('capivasertib', 'Chemical', 'MESH:C575618', (133, 145))	('TSC2', 'Gene', (67, 71))	('cancers', 'Phenotype', 'HP:0002664', (163, 170))	('cancers', 'Disease', (163, 170))	('AKT', 'Gene', (217, 220))	('AKT', 'Gene', '207', (123, 126))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('mTOR', 'Gene', (37, 41))
51750	32669708	The cohorts in this module are as follows: vistusertib - TSC1 and TSC2 mutation (B1), capivasertib - LUSC PIK3CA mutation (F1), capivasertib - LUSC PIK3CA amplification (F2), capivasertib - LUSC PTEN loss (F4) and capivasertib - LUAD with aberrations of PI3K/PTEN or AKT genes (F3).	('PTEN', 'Gene', (259, 263))	('PIK3CA', 'Gene', '5290', (106, 112))	('vistusertib', 'Chemical', 'MESH:C585537', (43, 54))	('PIK3CA', 'Gene', (148, 154))	('PTEN', 'Gene', (195, 199))	('PTEN loss', 'Disease', (195, 204))	('capivasertib', 'Chemical', 'MESH:C575618', (128, 140))	('PTEN', 'Gene', '5728', (259, 263))	('LUAD', 'Phenotype', 'HP:0030078', (229, 233))	('AKT', 'Gene', (267, 270))	('PTEN', 'Gene', '5728', (195, 199))	('capivasertib', 'Chemical', 'MESH:C575618', (175, 187))	('TSC2', 'Gene', '7249', (66, 70))	('PIK3CA', 'Gene', (106, 112))	('TSC1', 'Gene', (57, 61))	('capivasertib', 'Chemical', 'MESH:C575618', (214, 226))	('PIK3CA', 'Gene', '5290', (148, 154))	('TSC1', 'Gene', '7248', (57, 61))	('mutation', 'Var', (71, 79))	('TSC2', 'Gene', (66, 70))	('capivasertib', 'Chemical', 'MESH:C575618', (86, 98))	('AKT', 'Gene', '207', (267, 270))	('PTEN loss', 'Disease', 'MESH:D006223', (195, 204))
51751	32669708	Zero out of five patients with cancers harbouring TSC1 and TSC2 mutations responded or obtained DCB using vistusertib.	('TSC2', 'Gene', '7249', (59, 63))	('DCB', 'Chemical', 'MESH:D015101', (96, 99))	('TSC2', 'Gene', (59, 63))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('DCB', 'MPA', (96, 99))	('TSC1', 'Gene', (50, 54))	('vistusertib', 'Chemical', 'MESH:C585537', (106, 117))	('patients', 'Species', '9606', (17, 25))	('mutations', 'Var', (64, 73))	('cancers', 'Phenotype', 'HP:0002664', (31, 38))	('responded', 'Reg', (74, 83))	('cancers', 'Disease', (31, 38))	('TSC1', 'Gene', '7248', (50, 54))	('cancers', 'Disease', 'MESH:D009369', (31, 38))
51752	32669708	Of 28 patients across 4 cohorts with cancers harbouring PIK3CA or PTEN aberrations, no patient responded to AKT inhibition using capivasertib, and only one patient obtained a DCB.	('AKT', 'Gene', '207', (108, 111))	('PTEN', 'Gene', (66, 70))	('PTEN', 'Gene', '5728', (66, 70))	('cancers', 'Phenotype', 'HP:0002664', (37, 44))	('patient', 'Species', '9606', (6, 13))	('AKT', 'Gene', (108, 111))	('cancers', 'Disease', (37, 44))	('PIK3CA', 'Gene', (56, 62))	('aberrations', 'Var', (71, 82))	('patient', 'Species', '9606', (87, 94))	('cancers', 'Disease', 'MESH:D009369', (37, 44))	('patients', 'Species', '9606', (6, 14))	('DCB', 'Chemical', 'MESH:D015101', (175, 178))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('capivasertib', 'Chemical', 'MESH:C575618', (129, 141))	('PIK3CA', 'Gene', '5290', (56, 62))	('patient', 'Species', '9606', (156, 163))
51763	32669708	A reduction in clinical benefit with increasing cumulative smoking duration and higher complexity of the mutational landscape has been demonstrated in patients with EGFR mutations treated with EGFR tyrosine kinase inhibitors.	('EGFR', 'Gene', (165, 169))	('clinical benefit', 'MPA', (15, 31))	('mutations', 'Var', (170, 179))	('EGFR', 'Gene', '1956', (193, 197))	('reduction', 'NegReg', (2, 11))	('patients', 'Species', '9606', (151, 159))	('EGFR', 'Gene', (193, 197))	('EGFR', 'Gene', '1956', (165, 169))
51790	32669708	Illumina sequencing libraries were generated from 50 ng of DNA samples (FFPE and blood) using Nextera transposons which simultaneously fragment and add sequencing adapters to the DNA.	('transposons', 'Species', '2387', (102, 113))	('sequencing adapters', 'MPA', (152, 171))	('fragment', 'Var', (135, 143))
51795	32669708	Finally, we added targets for single-nucleotide polymorphisms (SNPs) common in the population to confirm that tumour and normal samples were derived from the same individual.	('single-nucleotide', 'Var', (30, 47))	('tumour', 'Disease', 'MESH:D009369', (110, 116))	('tumour', 'Disease', (110, 116))	('tumour', 'Phenotype', 'HP:0002664', (110, 116))
51797	32669708	SCNA calling was attempted on all tumours that were NGS-tested, although SCNAs could be confidently detected by NGS in samples with a high tumour percentage (>60% tumour content) and if the SCNA was large.	('tumour', 'Disease', (139, 145))	('tumour', 'Disease', 'MESH:D009369', (34, 40))	('NGS', 'Var', (112, 115))	('tumour', 'Phenotype', 'HP:0002664', (163, 169))	('tumour', 'Disease', (34, 40))	('tumours', 'Phenotype', 'HP:0002664', (34, 41))	('tumour', 'Phenotype', 'HP:0002664', (139, 145))	('tumours', 'Disease', 'MESH:D009369', (34, 41))	('tumour', 'Disease', 'MESH:D009369', (163, 169))	('tumour', 'Disease', 'MESH:D009369', (139, 145))	('tumours', 'Disease', (34, 41))	('tumour', 'Disease', (163, 169))	('tumour', 'Phenotype', 'HP:0002664', (34, 40))
51799	32669708	FISH analyses were performed for the following genes to confirm SCNAs and deletions identified by NGS and were divided between the 3 THs: MET and ROS1 (performed by RMH TH), PIK3CA, PTEN and CCND1 (performed by Cardiff TH), and CDK4 and CDKN2A (performed by BMH TH).	('deletions', 'Var', (74, 83))	('PIK3CA', 'Gene', (174, 180))	('CDK4', 'Gene', (228, 232))	('CCND1', 'Gene', (191, 196))	('MET', 'Gene', '79811', (138, 141))	('CDK4', 'Gene', '1019', (228, 232))	('MET', 'Gene', (138, 141))	('ROS1', 'Gene', (146, 150))	('PIK3CA', 'Gene', '5290', (174, 180))	('CDKN2A', 'Gene', '1029', (237, 243))	('THs', 'Chemical', '-', (133, 136))	('ROS1', 'Gene', '6098', (146, 150))	('CCND1', 'Gene', '595', (191, 196))	('CDKN2A', 'Gene', (237, 243))	('PTEN', 'Gene', (182, 186))	('PTEN', 'Gene', '5728', (182, 186))
51815	32669708	For treatment arm C the primary outcome measure is PFS, defined as the time from commencement of trial treatment to the date of the CT scan at which progressive disease is first recorded, or date of death without previously recorded progression.	('death', 'Disease', 'MESH:D003643', (199, 204))	('death', 'Disease', (199, 204))	('PFS', 'Var', (51, 54))
51829	32669708	SCNA segments demonstrating amplification/gain involving PIK3CA in any sample of an individual tumour were isolated for analysis, and oncogenes within them annotated.	('tumour', 'Disease', 'MESH:D009369', (95, 101))	('PIK3CA', 'Gene', '5290', (57, 63))	('tumour', 'Phenotype', 'HP:0002664', (95, 101))	('tumour', 'Disease', (95, 101))	('amplification/gain', 'Var', (28, 46))	('amplification/gain', 'PosReg', (28, 46))	('PIK3CA', 'Gene', (57, 63))
51831	32669708	TCGA SCNA segments harbouring an amplification/gain involving PIK3CA were isolated for analysis, and oncogenes within them annotated.	('PIK3CA', 'Gene', (62, 68))	('amplification/gain', 'PosReg', (33, 51))	('PIK3CA', 'Gene', '5290', (62, 68))	('amplification/gain', 'Var', (33, 51))
51910	29973636	Several studies indicated an association between high blood glucose and an increased risk of cancer overall.	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('high blood', 'Var', (49, 59))	('glucose', 'Chemical', 'MESH:D005947', (60, 67))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('high blood glucose', 'Phenotype', 'HP:0003074', (49, 67))
51957	29434870	The overall survival (OS) of patients in the serum miR-590 low expression group was significantly lower than that of the serum miR-590 high expression group (P=0.012), and the low expression of miR-590 was an independent risk factor for the prognosis of patients [hazard ratio (HR)=2.152, 95% CI=1.285-3.233, P=0.004].	('low', 'Var', (176, 179))	('patients', 'Species', '9606', (29, 37))	('miR-590', 'Chemical', '-', (194, 201))	('serum miR-590', 'Gene', (45, 58))	('overall', 'CPA', (4, 11))	('miR-590', 'Chemical', '-', (127, 134))	('low expression', 'NegReg', (59, 73))	('patients', 'Species', '9606', (254, 262))	('lower', 'NegReg', (98, 103))	('miR-590', 'Chemical', '-', (51, 58))
51962	29434870	Notably, even when patients in the late stage undergo chemotherapy, molecular-targeted therapy or radiotherapy and chemotherapy, they do not survive for more than 5 years.	(' und', 'Gene', '7373', (45, 49))	(' und', 'Gene', (45, 49))	('molecular-targeted therapy', 'Var', (68, 94))	('patients', 'Species', '9606', (19, 27))
51985	29434870	The ROC curve was further applied, which showed that the risk of predicting LUSC using miR-590 was high, the area under curve (AUC) was 0.882, and the 95% confidence interval (CI) was 0.829-0.9334 (Fig.	(' und', 'Gene', '7373', (113, 117))	('miR-590', 'Chemical', '-', (87, 94))	('LUSC', 'Phenotype', 'HP:0030359', (76, 80))	('miR-590', 'Var', (87, 94))	(' und', 'Gene', (113, 117))	('LUSC', 'Disease', (76, 80))
51987	29434870	Based on the median value (0.513) of the expression level of miR-590 in all 237 LUSC patients, these patients were divided into the high expression group (miR-590>0.513) and the low expression group (miR-590<0.513).	('miR-590', 'Chemical', '-', (155, 162))	('patients', 'Species', '9606', (101, 109))	('miR-590', 'Chemical', '-', (200, 207))	('LUSC', 'Phenotype', 'HP:0030359', (80, 84))	('miR-590>0.513', 'Var', (155, 168))	('patients', 'Species', '9606', (85, 93))	('miR-590', 'Chemical', '-', (61, 68))	('miR-590', 'Gene', (61, 68))
52001	29434870	The abnormal expression of miRNAs is closely related to tumour formation, and certain key factors can promote or inhibit cell proliferation by regulating the pathways thereof.	('abnormal', 'Var', (4, 12))	('expression', 'MPA', (13, 23))	('tumour', 'Phenotype', 'HP:0002664', (56, 62))	('inhibit', 'NegReg', (113, 120))	('cell proliferation', 'CPA', (121, 139))	('promote', 'PosReg', (102, 109))	('pathways', 'Pathway', (158, 166))	('regulating', 'Reg', (143, 153))	('miRNAs', 'Gene', (27, 33))	('tumour', 'Disease', 'MESH:D009369', (56, 62))	('tumour', 'Disease', (56, 62))
52002	29434870	miR-590 is mainly composed of two genes, miR-590-3p and miR-590-5p.	('miR-590', 'Chemical', '-', (56, 63))	('miR-590', 'Chemical', '-', (41, 48))	('miR-590-5p', 'Var', (56, 66))	('miR-590-3p', 'Var', (41, 51))	('miR-590', 'Chemical', '-', (0, 7))
52006	29434870	In a related study, it was shown that decreased miR-590 upregulates transforming growth factor-beta1 (TGF-beta1) and TGF-TGF-betaRII proteins removed, translated and inhibited by these miRNAs.	('removed', 'NegReg', (142, 149))	('miR-590', 'Chemical', '-', (48, 55))	('upregulates', 'PosReg', (56, 67))	('miR-590', 'Gene', (48, 55))	('TGF-beta', 'Gene', (121, 129))	('decreased', 'Var', (38, 47))	('TGF-beta', 'Gene', '7040', (121, 129))	('TGF-beta', 'Gene', '7040', (102, 110))	('proteins', 'Protein', (133, 141))	('translated', 'MPA', (151, 161))	('transforming growth factor-beta1', 'Gene', (68, 100))	('inhibited', 'NegReg', (166, 175))	('TGF-beta', 'Gene', (102, 110))
52010	29434870	The sample size was relatively small, and miR-590 affected LUSC clinicopathological staging as well as prognosis by regulating which target gene has yet to be explored.	('miR-590', 'Var', (42, 49))	('LUSC', 'Disease', (59, 63))	('miR-590', 'Chemical', '-', (42, 49))	('affected', 'Reg', (50, 58))	('LUSC', 'Phenotype', 'HP:0030359', (59, 63))
52014	29434870	The aforementioned results demonstrate that the miR-590 expression level can be used as a biomarker for onset risk, disease staging and prognosis of LUSC patients.	('miR-590', 'Chemical', '-', (48, 55))	('miR-590', 'Var', (48, 55))	('patients', 'Species', '9606', (154, 162))	('LUSC', 'Phenotype', 'HP:0030359', (149, 153))	('LUSC', 'Disease', (149, 153))
52021	29096676	Circular RNAs (circRNAs) are a class of RNA molecules that lack 5'-3' ends and poly A tail and covalently form closed loops.	('cir', 'Gene', '3762', (15, 18))	("5'-3' ends", 'MPA', (64, 74))	('lack', 'NegReg', (59, 63))	('cir', 'Gene', (15, 18))	('poly', 'Var', (79, 83))	('Cir', 'Gene', (0, 3))	('Cir', 'Gene', '3762', (0, 3))	('form', 'Reg', (106, 110))
52034	29096676	In addition, all the four types of alternative splicing (namely cassette exon, intron retention, alternative donor site and alternative acceptor site) that have been identified in linear mRNA are found in circRNAs, which adds more complexity to the biogenesis of circRNAs.	('cir', 'Gene', '3762', (205, 208))	('cassette exon', 'Var', (64, 77))	('cir', 'Gene', (205, 208))	('cir', 'Gene', '3762', (263, 266))	('cir', 'Gene', (263, 266))	('donor', 'Species', '9606', (109, 114))
52054	29096676	However, circular RNA can be cleaved by endonucleases; therefore, RNA interference can be used to knock down circRNA expression.	('cir', 'Gene', '3762', (9, 12))	('cir', 'Gene', (9, 12))	('RNA', 'MPA', (66, 69))	('cir', 'Gene', '3762', (109, 112))	('cir', 'Gene', (109, 112))	('knock', 'Var', (98, 103))
52067	29096676	In addtion, when the efficiency of linear splicing increases, circRNA abundance decreases, which suggests that there is a genome-wide competition between canonical splicing and circRNA generation.	('increases', 'PosReg', (51, 60))	('decreases', 'NegReg', (80, 89))	('linear splicing', 'Var', (35, 50))	('cir', 'Gene', (62, 65))	('cir', 'Gene', '3762', (62, 65))	('cir', 'Gene', '3762', (177, 180))	('cir', 'Gene', (177, 180))
52119	29096676	These findings suggest that the deregulated expression of circRNAs is closely associated with the development and progression of ESCC.	('associated', 'Reg', (78, 88))	('deregulated', 'Var', (32, 43))	('expression', 'MPA', (44, 54))	('ESCC', 'Disease', (129, 133))	('cir', 'Gene', '3762', (58, 61))	('cir', 'Gene', (58, 61))
52136	29096676	These results indicate that the abnormal expression of circRNAs may be novel and non-invasive biomarkers for the diagnosis and prognosis of gastric cancer.	('gastric cancer', 'Phenotype', 'HP:0012126', (140, 154))	('expression', 'MPA', (41, 51))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('gastric cancer', 'Disease', (140, 154))	('abnormal', 'Var', (32, 40))	('gastric cancer', 'Disease', 'MESH:D013274', (140, 154))	('cir', 'Gene', '3762', (55, 58))	('cir', 'Gene', (55, 58))
52149	29096676	The knockdown of circ-BANP could significantly attenuate the proliferation of colorectal cancer cells.	('BANP', 'Gene', '54971', (22, 26))	('cir', 'Gene', (17, 20))	('colorectal cancer', 'Disease', 'MESH:D015179', (78, 95))	('BANP', 'Gene', (22, 26))	('cir', 'Gene', '3762', (17, 20))	('colorectal cancer', 'Phenotype', 'HP:0003003', (78, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('proliferation', 'CPA', (61, 74))	('knockdown', 'Var', (4, 13))	('attenuate', 'NegReg', (47, 56))	('colorectal cancer', 'Disease', (78, 95))
52159	29096676	CDR1as knockdown suppressed colorectal cancer cell proliferation and invasion via inhibiting the activities of miR-7 targets including EGFR and IGF-1R.	('CDR1as', 'Gene', '103611090', (0, 6))	('colorectal cancer', 'Phenotype', 'HP:0003003', (28, 45))	('inhibiting', 'NegReg', (82, 92))	('miR-7', 'Gene', (111, 116))	('colorectal cancer', 'Disease', (28, 45))	('EGFR', 'Gene', '1956', (135, 139))	('IGF-1R', 'Gene', '3480', (144, 150))	('suppressed', 'NegReg', (17, 27))	('colorectal cancer', 'Disease', 'MESH:D015179', (28, 45))	('IGF-1R', 'Gene', (144, 150))	('activities', 'MPA', (97, 107))	('EGFR', 'Gene', (135, 139))	('invasion', 'CPA', (69, 77))	('miR-7', 'Gene', '10859', (111, 116))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('knockdown', 'Var', (7, 16))	('CDR1as', 'Gene', (0, 6))
52178	29096676	CDR1as interacts with miR-7 to derepress the expression of CCNE1 and PIK3CD genes, thereby promoting the proliferation and invasiveness of liver cancer cells.	('CDR1as', 'Gene', '103611090', (0, 6))	('derepress', 'Var', (31, 40))	('invasiveness of liver cancer', 'Disease', 'MESH:D006528', (123, 151))	('CDR1as', 'Gene', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('CCNE1', 'Gene', '898', (59, 64))	('miR-7', 'Gene', (22, 27))	('CCNE1', 'Gene', (59, 64))	('proliferation', 'CPA', (105, 118))	('expression', 'MPA', (45, 55))	('liver cancer', 'Phenotype', 'HP:0002896', (139, 151))	('PIK3CD', 'Gene', '5293', (69, 75))	('miR-7', 'Gene', '10859', (22, 27))	('PIK3CD', 'Gene', (69, 75))	('promoting', 'PosReg', (91, 100))	('invasiveness of liver cancer', 'Disease', (123, 151))
52209	29096676	found that cZNF292 was also expressed in glioma cells and that the silencing of cZNF292 expression could inhibit glioma cell proliferation.	('glioma', 'Disease', 'MESH:D005910', (113, 119))	('glioma', 'Phenotype', 'HP:0009733', (113, 119))	('inhibit', 'NegReg', (105, 112))	('glioma', 'Disease', 'MESH:D005910', (41, 47))	('cZNF292', 'Gene', (80, 87))	('glioma', 'Phenotype', 'HP:0009733', (41, 47))	('glioma', 'Disease', (113, 119))	('silencing', 'Var', (67, 76))	('glioma', 'Disease', (41, 47))	('expression', 'MPA', (88, 98))
52234	29096676	For functional study, the researchers generally use gene over-expression and knockdown strategies to manipulate circRNA expression.	('manipulate', 'Reg', (101, 111))	('cir', 'Gene', '3762', (112, 115))	('knockdown', 'Var', (77, 86))	('cir', 'Gene', (112, 115))
52236	29096676	To study the protein-coding potential of a circRNA, the researchers could predict N6-methyladenosin, internal ribozyme entry site (IRES), and open reading frame in circRNA by bioinformatic analyses.	('cir', 'Gene', '3762', (43, 46))	('cir', 'Gene', (43, 46))	('cir', 'Gene', '3762', (164, 167))	('cir', 'Gene', (164, 167))	('N6-methyladenosin', 'Var', (82, 99))	('N6-methyladenosin', 'Chemical', '-', (82, 99))
52329	33618069	Interestingly, higher PRF1 expression was observed in HPV+ HNSCC than in HPV- HNSCC (p < 0.01).	('PRF1', 'Gene', (22, 26))	('higher', 'PosReg', (15, 21))	('HPV', 'Species', '10566', (73, 76))	('expression', 'MPA', (27, 37))	('HPV', 'Species', '10566', (54, 57))	('HNSCC', 'Phenotype', 'HP:0012288', (78, 83))	('HPV+ HNSCC', 'Var', (54, 64))	('HNSCC', 'Phenotype', 'HP:0012288', (59, 64))	('PRF1', 'Gene', '5551', (22, 26))
52335	33618069	High PRF1 expression was related to better OS in HNSCC significantly, as analyzed by TIMER (HR = 0.854, p = 0.0129) (Fig.	('HNSCC', 'Phenotype', 'HP:0012288', (49, 54))	('High', 'Var', (0, 4))	('HNSCC', 'Disease', (49, 54))	('expression', 'MPA', (10, 20))	('PRF1', 'Gene', '5551', (5, 9))	('PRF1', 'Gene', (5, 9))	('better', 'PosReg', (36, 42))
52336	33618069	Consistent results were obtained in Kaplan-Meier plotter, wherein better OS in HNSCC was significantly associated with high PRF1 expression (HR = 0.65, p = 0.0031) (Fig.	('expression', 'MPA', (129, 139))	('high', 'Var', (119, 123))	('PRF1', 'Gene', '5551', (124, 128))	('PRF1', 'Gene', (124, 128))	('HNSCC', 'Phenotype', 'HP:0012288', (79, 84))
52339	33618069	There was a significant association between high PRF1 expression and better prognosis in HPV+ HNSCC (HR = 0.676, p = 0.00858), while in HPV- HNSCC, no obvious correlation was observed (Fig.	('expression', 'MPA', (54, 64))	('high', 'Var', (44, 48))	('PRF1', 'Gene', '5551', (49, 53))	('HNSCC', 'Phenotype', 'HP:0012288', (141, 146))	('HNSCC', 'Phenotype', 'HP:0012288', (94, 99))	('PRF1', 'Gene', (49, 53))	('better', 'PosReg', (69, 75))	('HPV', 'Species', '10566', (89, 92))	('HPV+ HNSCC', 'Var', (89, 99))	('HPV', 'Species', '10566', (136, 139))
52341	33618069	High P16 expression was significantly related to better OS in HNSCC according to TIMER (HR = 0.842, p = 0.00658) (Fig.	('HNSCC', 'Phenotype', 'HP:0012288', (62, 67))	('P16', 'Gene', (5, 8))	('High', 'Var', (0, 4))	('P16', 'Gene', '1029', (5, 8))	('HNSCC', 'Disease', (62, 67))
52343	33618069	Moreover, univariate analysis displayed that age, sex, PRF1, N stage and T stage were significantly related to OS (p < 0.05) (Table S1), and further multivariate analysis showed that high PRF1 expression was a favorable independent prognostic factor (HR = 0.36, p < 0.05) (Fig.	('PRF1', 'Gene', '5551', (55, 59))	('PRF1', 'Gene', (55, 59))	('high', 'Var', (183, 187))	('related', 'Reg', (100, 107))	('expression', 'MPA', (193, 203))	('PRF1', 'Gene', '5551', (188, 192))	('PRF1', 'Gene', (188, 192))
52344	33618069	The Kaplan-Meier survival curves showed high PRF1 expression correlated with better prognosis.	('high', 'Var', (40, 44))	('PRF1', 'Gene', (45, 49))	('expression', 'MPA', (50, 60))	('PRF1', 'Gene', '5551', (45, 49))
52368	33618069	High PRF1 expression indicated a better survival rate in HNSCC, the prognostic value of which was stronger in HPV+ HNSCC.	('HNSCC', 'Phenotype', 'HP:0012288', (57, 62))	('High', 'Var', (0, 4))	('HPV', 'Species', '10566', (110, 113))	('HNSCC', 'Phenotype', 'HP:0012288', (115, 120))	('expression', 'MPA', (10, 20))	('HNSCC', 'Disease', (57, 62))	('PRF1', 'Gene', '5551', (5, 9))	('PRF1', 'Gene', (5, 9))	('better', 'PosReg', (33, 39))	('survival rate', 'CPA', (40, 53))
52373	33618069	Further analysis of 505 cases of HNSCC from TCGA showed that high PRF1 expression was remarkably related to advanced HNSCC.	('HNSCC', 'Phenotype', 'HP:0012288', (117, 122))	('expression', 'MPA', (71, 81))	('related', 'Reg', (97, 104))	('PRF1', 'Gene', '5551', (66, 70))	('high', 'Var', (61, 65))	('HNSCC', 'Phenotype', 'HP:0012288', (33, 38))	('PRF1', 'Gene', (66, 70))	('advanced HNSCC', 'Disease', (108, 122))
52374	33618069	Survival analysis via TIMER and Kaplan-Meier plotter displayed that high PRF1 expression predicted better prognosis of HNSCC.	('better', 'PosReg', (99, 105))	('expression', 'MPA', (78, 88))	('high', 'Var', (68, 72))	('PRF1', 'Gene', '5551', (73, 77))	('PRF1', 'Gene', (73, 77))	('HNSCC', 'Phenotype', 'HP:0012288', (119, 124))	('HNSCC', 'Disease', (119, 124))
52382	33618069	In our study, high P16 expression was also found to be associated with better OS in HNSCC.	('P16', 'Gene', '1029', (19, 22))	('HNSCC', 'Disease', (84, 89))	('HNSCC', 'Phenotype', 'HP:0012288', (84, 89))	('high', 'Var', (14, 18))	('P16', 'Gene', (19, 22))	('expression', 'MPA', (23, 33))
52389	33618069	By comparing the differences of TILs between the PRF1high group and PRF1low group, we showed that tumors with high PRF1 expression had elevated levels of CD8+ T cell, CD4+ T cell, NK cell and M1 macrophage infiltration.	('CD4', 'Gene', '920', (167, 170))	('tumors', 'Disease', (98, 104))	('CD8', 'Gene', (154, 157))	('elevated', 'PosReg', (135, 143))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('CD8', 'Gene', '925', (154, 157))	('PRF1', 'Gene', '5551', (49, 53))	('tumors', 'Disease', 'MESH:D009369', (98, 104))	('M1 macrophage infiltration', 'CPA', (192, 218))	('PRF1', 'Gene', (49, 53))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('high', 'Var', (110, 114))	('PRF1', 'Gene', '5551', (115, 119))	('NK cell', 'CPA', (180, 187))	('CD4', 'Gene', (167, 170))	('PRF1', 'Gene', (115, 119))	('PRF1', 'Gene', '5551', (68, 72))	('PRF1', 'Gene', (68, 72))
52396	33618069	Moreover, the strong correlation between PRF1 expression and CD8+ T cell infiltration suggested that CD8+ T cells had higher cytotoxicity in HPV+ HNSCC than in HPV- HNSCC, which was related to favorable prognosis.	('higher', 'PosReg', (118, 124))	('CD8', 'Gene', '925', (101, 104))	('PRF1', 'Gene', '5551', (41, 45))	('HNSCC', 'Phenotype', 'HP:0012288', (146, 151))	('cytotoxicity', 'Disease', 'MESH:D064420', (125, 137))	('PRF1', 'Gene', (41, 45))	('CD8', 'Gene', (61, 64))	('HPV', 'Species', '10566', (141, 144))	('HPV+ HNSCC', 'Var', (141, 151))	('CD8', 'Gene', '925', (61, 64))	('HPV', 'Species', '10566', (160, 163))	('cytotoxicity', 'Disease', (125, 137))	('HNSCC', 'Phenotype', 'HP:0012288', (165, 170))	('CD8', 'Gene', (101, 104))
52403	33618069	To summarize, high PRF1 expression had significant associations with improved survival and with CD8+ T cell, CD4+ T cell, DC and neutrophil infiltration in HNSCC, especially in HPV+ HNSCC.	('survival', 'CPA', (78, 86))	('HNSCC', 'Phenotype', 'HP:0012288', (182, 187))	('improved', 'PosReg', (69, 77))	('expression', 'MPA', (24, 34))	('CD8', 'Gene', (96, 99))	('CD4', 'Gene', (109, 112))	('HPV', 'Species', '10566', (177, 180))	('high', 'Var', (14, 18))	('HNSCC', 'Phenotype', 'HP:0012288', (156, 161))	('CD8', 'Gene', '925', (96, 99))	('PRF1', 'Gene', '5551', (19, 23))	('neutrophil infiltration', 'CPA', (129, 152))	('PRF1', 'Gene', (19, 23))	('CD4', 'Gene', '920', (109, 112))
52442	32519819	For each patient, the demographic and clinical variables were recorded, including age at diagnosis, race (black, white, other), marital status (married, unmarried, unknown), Tumor grade (grade I, grade II, grade III, grade IV, unknown), T classification (T1, T2, T3, T4), N classification (N0, N1, N2, N3), chemotherapy (yes, no/unknown), radiotherapy (yes, no), regional lymph node examined, regional positive lymph nodes, survival time, and vital status.	('patient', 'Species', '9606', (9, 16))	('T1', 'Var', (255, 257))	('Tumor', 'Phenotype', 'HP:0002664', (174, 179))	('N0', 'Var', (290, 292))
52501	32519819	The C-index of the predictive model with LODDS (0.745, 95% CI: 0.701-0.789) was higher than those of the models with NPLN (0.715, 95% CI: 0.678-0.766) and LNR (0.737, 95% CI: 0.692-0.782), though statistical significance was not achieved.	('LODDS', 'Chemical', '-', (41, 46))	('LODDS', 'Var', (41, 46))	('higher', 'PosReg', (80, 86))	('C-index', 'MPA', (4, 11))
52544	31344359	Deviant genes generally appeared with greater frequency in cancer types having large numbers of copy number alterations (LUSC, LUAD, ESCA, SARC, BLCA, OV), whereas fewer disagreements tended to occur within cancer types harboring fewer copy number alterations (THCA, LAML, KIRP, UVM, THYM, KIRC) (Figure 2C).	('ESCA', 'Disease', (133, 137))	('cancer', 'Disease', 'MESH:D009369', (207, 213))	('THCA', 'Chemical', '-', (261, 265))	('copy number alterations', 'Var', (96, 119))	('cancer', 'Disease', (207, 213))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('cancer', 'Disease', (59, 65))	('SARC', 'Disease', (139, 143))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('LUAD', 'Disease', (127, 131))	('cancer', 'Disease', 'MESH:D009369', (59, 65))
52546	31344359	Almost all (93%; 482/521) of these driver alterations in both marker papers and hg19 GISTIC analyses were matched in the analysis of the hg38 data, meaning they were either found in both hg19 and hg38 or not present in either (Data S2.6).	('hg38', 'Gene', (196, 200))	('hg38', 'Gene', '8549', (196, 200))	('alterations', 'Var', (42, 53))	('S2.6', 'Gene', (232, 236))	('hg38', 'Gene', (137, 141))	('hg38', 'Gene', '8549', (137, 141))	('S2.6', 'Gene', '6231', (232, 236))
52550	31344359	"beta") values was not altered, and thus methylation beta values for individual probes were identical between the hg19 and hg38 versions.	('hg38', 'Gene', (123, 127))	('hg38', 'Gene', '8549', (123, 127))	('hg19', 'Var', (114, 118))	('methylation', 'MPA', (41, 52))
52556	31344359	Some of the new protein coding associations involved alternative promoters of known cancer genes that were not represented in the hg19 version, such as epigenetic regulation of the PAX8 gene in a subset of CHOL tumors (Figure 3D-E).	('PAX8', 'Gene', '7849', (181, 185))	('involved', 'Reg', (44, 52))	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('cancer', 'Disease', (84, 90))	('CHOL tumors', 'Disease', (206, 217))	('PAX8', 'Gene', (181, 185))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('tumors', 'Phenotype', 'HP:0002664', (211, 217))	('CHOL tumors', 'Disease', 'MESH:D009369', (206, 217))	('epigenetic regulation', 'Var', (152, 173))
52561	31344359	These differences:in alignment, quantification, normalization, and references (Figure 4A):are expected to introduce bias between the hg19 and hg38 abundance estimates.	('differences', 'Var', (6, 17))	('hg38', 'Gene', '8549', (142, 146))	('hg38', 'Gene', (142, 146))	('introduce', 'Reg', (106, 115))	('hg19', 'Gene', (133, 137))
52575	31344359	Across 1,902 shared tumor samples, the mutation overlap between GDC and MC3 contained a total of 488,138 public somatic SNV calls from 21,535 genes (Figure 5B).	('mutation', 'Var', (39, 47))	('GDC', 'Gene', (64, 67))	('MC3', 'Gene', '4159', (72, 75))	('MC3', 'Gene', (72, 75))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('tumor', 'Disease', (20, 25))
52578	31344359	The stringent one-caller mutation removal in MC3 contributed to the majority of the recoverable GDC-unique calls (59.0%).	('MC3', 'Gene', (45, 48))	('MC3', 'Gene', '4159', (45, 48))	('mutation removal', 'Var', (25, 41))
52579	31344359	The gene annotation changes can also alter the exonic definition (at least 2.1% of all recoverable GDC-unique calls), such as genes CCDC168 and EFCAB8 (Figure S4C, D).	('CCDC168', 'Gene', '643677', (132, 139))	('EFCAB8', 'Gene', (144, 150))	('exonic definition', 'MPA', (47, 64))	('alter', 'Reg', (37, 42))	('CCDC168', 'Gene', (132, 139))	('EFCAB8', 'Gene', '388795', (144, 150))	('changes', 'Var', (20, 27))
52580	31344359	The GDC labels a mutation call 'public' when it is also found in the validation sequencing, regardless of the filter status, whereas MC3 calling did not utilize validation status.	('MC3', 'Gene', (133, 136))	('MC3', 'Gene', '4159', (133, 136))	('mutation', 'Var', (17, 25))
52617	31344359	The main differences between the hg19 and hg38 versions of the pipeline involve the versions of some software components, and the reference data files used (Figure 1A).	('hg38', 'Gene', (42, 46))	('hg38', 'Gene', '8549', (42, 46))	('hg19', 'Var', (33, 37))
52637	31344359	As described in the main text, copy number alterations were identified from TCGA Level 3 segmented copy number profiles, generated from the same pipeline for both hg19 and hg38.	('hg38', 'Gene', (172, 176))	('hg38', 'Gene', '8549', (172, 176))	('copy number alterations', 'Var', (31, 54))	('TCGA', 'Gene', (76, 80))
52651	31344359	Similarly, among focal deletions in COAD, only 1519 genes were called in both runs' peaks compared to 938 and 809 genes found only in the hg19-aligned and hg38-aligned GISTIC2.0 deletion peaks, respectively.	('deletions', 'Var', (23, 32))	('COAD', 'Disease', 'MESH:D029424', (36, 40))	('hg38', 'Gene', (155, 159))	('hg38', 'Gene', '8549', (155, 159))	('COAD', 'Disease', (36, 40))
52657	31344359	Forty drivers were absent from both hg19 and hg38 GISTIC2.0 runs and likely stem from multiple causes: the marker papers often used smaller sets of TCGA samples to discover these drivers, utilized manual inspection and rescue of drivers proximal to identified copy number peaks but not explicitly called within these peaks, and used earlier versions of GISTIC running on hg18-aligned copy number data.	('hg38', 'Gene', '8549', (45, 49))	('copy', 'Var', (260, 264))	('hg38', 'Gene', (45, 49))
52667	31344359	In addition, "experiment-specific" probe masking is performed, based on weak signal or high background due to array quality, experimental failure, or genomic deletions in the sample.	('genomic deletions', 'Var', (150, 167))	('experimental failure', 'Disease', (125, 145))	('experimental failure', 'Disease', 'MESH:D006333', (125, 145))
52680	31344359	The vast majority of probes remained validly mapped without mismatches in hg38 (98.0% of HM27 and 98.9% of HM450, Table S4).	('HM27', 'CellLine', 'CVCL:8807', (89, 93))	('hg38', 'Gene', (74, 78))	('hg38', 'Gene', '8549', (74, 78))	('mismatches', 'Var', (60, 70))
52684	31344359	Most probes (64% HM27 and 67% HM450 probes) were completely concordant between hg19 and hg38, meaning that the gene(s) annotated were completely identical between the two releases (Figure S2A,B).	('hg19', 'Gene', (79, 83))	('hg38', 'Gene', (88, 92))	('HM27', 'Var', (17, 21))	('hg38', 'Gene', '8549', (88, 92))	('HM27', 'CellLine', 'CVCL:8807', (17, 21))
52686	31344359	Gene name changes also contributed to these differences: for roughly 25k probes (23,508 HM450 and 1,467 HM27), the probe was associated with the same gene in both hg19 and hg38 releases, but the gene symbol was updated in hg38.	('hg38', 'Gene', (172, 176))	('hg38', 'Gene', '8549', (172, 176))	('HM450', 'Var', (88, 93))	('hg38', 'Gene', (222, 226))	('hg38', 'Gene', '8549', (222, 226))	('HM27', 'CellLine', 'CVCL:8807', (104, 108))
52689	31344359	This approach was commonly used in TCGA to infer epigenetic silencing of genes such as BRCA1 in ovarian cancer.	('epigenetic silencing', 'Var', (49, 69))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('ovarian cancer', 'Phenotype', 'HP:0100615', (96, 110))	('BRCA1 in ovarian cancer', 'Disease', 'OMIM:604370', (87, 110))	('BRCA1 in ovarian cancer', 'Disease', (87, 110))
52691	31344359	Because the newer gene associations contained more genes and alternative transcripts, and associated CpG probes both upstream and downstream of the TSS (illustrated in Figure 3B), we were able to identify substantially more significant associations in the hg38 methylation data than in its hg19 predecessor (Figure 3C).	('methylation', 'Var', (261, 272))	('hg38', 'Gene', (256, 260))	('hg38', 'Gene', '8549', (256, 260))
52694	31344359	De-methylation of the associated promoter CpG is associated with increased expression in a subset of TCGA-CHOL tumors (Figure 3E).	('increased', 'PosReg', (65, 74))	('De-methylation', 'Var', (0, 14))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('TCGA-CHOL tumors', 'Disease', (101, 117))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('TCGA-CHOL tumors', 'Disease', 'MESH:D009369', (101, 117))	('expression', 'MPA', (75, 85))
52704	31344359	This explains the small subsets for some data types such as simple nucleotide variation, and data formats such as VCF, FA, and TAR.	('VCF', 'Disease', (114, 117))	('TAR', 'Disease', (127, 130))	('simple nucleotide variation', 'Var', (60, 87))	('TAR', 'Disease', 'MESH:C536940', (127, 130))
52725	31344359	The genomic coordinates of MC3 variant calls were lifted over from hg19 to hg38 using CrossMap v0.2.7 and chain files from University of California, Santa Cruz (UCSC).	('MC3', 'Gene', '4159', (27, 30))	('hg38', 'Gene', (75, 79))	('MC3', 'Gene', (27, 30))	('variant', 'Var', (31, 38))	('hg38', 'Gene', '8549', (75, 79))
52754	30975211	To date, the FDA has approved more than 20 small-molecule inhibitors for clinical use in the treatment of cancer.	('small-molecule', 'Var', (43, 57))	('cancer', 'Disease', (106, 112))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
52759	30975211	These utilize several different mechanisms, some of which include: targeting the immune system, e.g., alemtuzumab (Campath , Sanofi, France), which binds CD52 inducing an immune response; targeting antigens on cancer cells that are involved in cell growth and proliferation, e.g., trastuzumab (Herceptin , Genentech, USA) for HER2; and immune check-point inhibitors, e.g., ipilimumab (Yervoy , Bristol-Myers Squibb, USA) for cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4).	('ipilimumab', 'Chemical', 'MESH:D000074324', (373, 383))	('targeting', 'Var', (67, 76))	('trastuzumab', 'Chemical', 'MESH:D000068878', (281, 292))	('CD52', 'Gene', (154, 158))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('inducing', 'Reg', (159, 167))	('HER2', 'Gene', (326, 330))	('rat', 'Species', '10116', (267, 270))	('immune response', 'MPA', (171, 186))	('HER2', 'Gene', '2064', (326, 330))	('CD52', 'Gene', '1043', (154, 158))	('cancer', 'Disease', 'MESH:D009369', (210, 216))	('cancer', 'Disease', (210, 216))
52774	30975211	The EGFR family has been implicated in the development and progression of many cancers, notably NSCLCs, glioblastomas, colorectal cancers (CRCs), breast cancers, and ovarian tumors, through specific driver mutations.	('cancers', 'Disease', (153, 160))	('ovarian tumors', 'Phenotype', 'HP:0100615', (166, 180))	('colorectal cancers', 'Disease', (119, 137))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('NSCLC', 'Phenotype', 'HP:0030358', (96, 101))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('glioblastomas', 'Disease', 'MESH:D005909', (104, 117))	('NSCLCs', 'Disease', (96, 102))	('cancers', 'Disease', 'MESH:D009369', (130, 137))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('breast cancer', 'Phenotype', 'HP:0003002', (146, 159))	('breast cancers', 'Disease', 'MESH:D001943', (146, 160))	('implicated', 'Reg', (25, 35))	('breast cancers', 'Disease', (146, 160))	('ovarian tumors', 'Disease', (166, 180))	('cancers', 'Disease', (79, 86))	('mutations', 'Var', (206, 215))	('colorectal cancers', 'Disease', 'MESH:D015179', (119, 137))	('cancers', 'Disease', 'MESH:D009369', (153, 160))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('ovarian tumors', 'Disease', 'MESH:D010051', (166, 180))	('NSCLCs', 'Disease', 'MESH:D002289', (96, 102))	('breast cancers', 'Phenotype', 'HP:0003002', (146, 160))	('glioblastomas', 'Phenotype', 'HP:0012174', (104, 117))	('EGFR family', 'Gene', (4, 15))	('glioblastoma', 'Phenotype', 'HP:0012174', (104, 116))	('cancers', 'Phenotype', 'HP:0002664', (130, 137))	('cancers', 'Disease', (130, 137))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('cancers', 'Phenotype', 'HP:0002664', (153, 160))	('cancers', 'Disease', 'MESH:D009369', (79, 86))	('tumors', 'Phenotype', 'HP:0002664', (174, 180))	('glioblastomas', 'Disease', (104, 117))
52775	30975211	Notably, kinase domain hotspot mutations, which are often found in NSCLC patients of Eastern Asian origin, frequently have the L858R point mutation.	('kinase', 'Gene', (9, 15))	('L858R', 'Var', (127, 132))	('NSCLC', 'Phenotype', 'HP:0030358', (67, 72))	('L858R', 'Mutation', 'rs121434568', (127, 132))	('NSCLC', 'Disease', (67, 72))	('patients', 'Species', '9606', (73, 81))	('NSCLC', 'Disease', 'MESH:D002289', (67, 72))
52777	30975211	Consequently, these mutations tend to confer inappropriate activation of the downstream, anti-apoptotic Ras signaling cascade, leading to uncontrolled cell proliferation.	('rat', 'Species', '10116', (163, 166))	('uncontrolled cell proliferation', 'CPA', (138, 169))	('leading to', 'Reg', (127, 137))	('activation', 'PosReg', (59, 69))	('mutations', 'Var', (20, 29))
52783	30975211	Positive results from pre-clinical studies prompted extensive clinical studies in NSCLC patients, which have demonstrated anti-cancer activity against EGFR mutated cancers.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('NSCLC', 'Phenotype', 'HP:0030358', (82, 87))	('EGFR', 'Gene', (151, 155))	('patients', 'Species', '9606', (88, 96))	('cancers', 'Phenotype', 'HP:0002664', (164, 171))	('mutated', 'Var', (156, 163))	('cancers', 'Disease', (164, 171))	('cancer', 'Disease', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('rat', 'Species', '10116', (116, 119))	('cancer', 'Disease', (127, 133))	('cancers', 'Disease', 'MESH:D009369', (164, 171))	('NSCLC', 'Disease', (82, 87))	('NSCLC', 'Disease', 'MESH:D002289', (82, 87))
52785	30975211	Since its initial introduction into the Japanese market in 2002, gefitinib has since been FDA approved as a first-line treatment for metastatic, EGFR-mutated (exon 19 deletions or exon 21 L858R substitutions) NSCLC.	('exon 19 deletions', 'Var', (159, 176))	('NSCLC', 'Disease', 'MESH:D002289', (209, 214))	('gefitinib', 'Chemical', 'MESH:D000077156', (65, 74))	('L858R', 'Mutation', 'rs121434568', (188, 193))	('NSCLC', 'Phenotype', 'HP:0030358', (209, 214))	('L858R substitutions', 'Var', (188, 207))	('NSCLC', 'Disease', (209, 214))
52786	30975211	This was based on data from the 'IPASS' clinical trials and the follow-up 'IFUM' studies, in which gefitinib improved median overall survival (OS; 18.6 vs. 17.3 months), median progression-free survival (PFS; 24.9 vs. 6.7%; p < 0.001) and objective response rates (ORR; 43.0 vs. 32.2%; p < 0.001), when compared with standard treatment of carboplatin and paclitaxel (Table 1).	('carboplatin', 'Chemical', 'MESH:D016190', (339, 350))	('paclitaxel', 'Chemical', 'MESH:D017239', (355, 365))	('PF', 'Chemical', 'MESH:C002997', (204, 206))	('overall', 'MPA', (125, 132))	('gefitinib', 'Var', (99, 108))	('OS', 'Chemical', '-', (143, 145))	('improved', 'PosReg', (109, 117))	('progression-free survival', 'CPA', (177, 202))	('rat', 'Species', '10116', (258, 261))	('gefitinib', 'Chemical', 'MESH:D000077156', (99, 108))	('objective response rates', 'CPA', (239, 263))
52791	30975211	These clinical trials have revealed that, in addition to the common side effects of diarrhea and skin reactions, gefitinib can cause more serious adverse effects, including interstitial lung disease, liver damage, gastrointestinal perforation, severe diarrhea and ocular disorders.	('diarrhea', 'Disease', (251, 259))	('lung disease', 'Phenotype', 'HP:0002088', (186, 198))	('ocular disorders', 'Phenotype', 'HP:0000478', (264, 280))	('gefitinib', 'Var', (113, 122))	('liver damage', 'Disease', (200, 212))	('diarrhea', 'Disease', (84, 92))	('gastrointestinal perforation', 'Disease', (214, 242))	('rat', 'Species', '10116', (236, 239))	('diarrhea', 'Disease', 'MESH:D003967', (251, 259))	('diarrhea', 'Disease', 'MESH:D003967', (84, 92))	('liver damage', 'Disease', 'MESH:D056486', (200, 212))	('interstitial lung disease', 'Phenotype', 'HP:0006530', (173, 198))	('interstitial lung disease', 'Disease', 'MESH:D017563', (173, 198))	('ocular disorders', 'Disease', 'MESH:D005128', (264, 280))	('severe diarrhea', 'Phenotype', 'HP:0002028', (244, 259))	('interstitial lung disease', 'Disease', (173, 198))	('skin reactions', 'Phenotype', 'HP:0011123', (97, 111))	('diarrhea', 'Phenotype', 'HP:0002014', (251, 259))	('ocular disorders', 'Disease', (264, 280))	('diarrhea', 'Phenotype', 'HP:0002014', (84, 92))	('gefitinib', 'Chemical', 'MESH:D000077156', (113, 122))
52796	30975211	The 'SATURN' trial showed that erlotinib significantly extended median OS (12.4 vs. 11.0 months; p < 0.01) and PFS (12.3 vs. 11.1 weeks; p < 0.0001) in a broad patient population, including squamous and non-squamous histology, compared with the placebo (Table 1).	('PF', 'Chemical', 'MESH:C002997', (111, 113))	('erlotinib', 'Var', (31, 40))	('OS', 'Chemical', '-', (71, 73))	('PFS', 'MPA', (111, 114))	('extended', 'PosReg', (55, 63))	('patient', 'Species', '9606', (160, 167))	('erlotinib', 'Chemical', 'MESH:D000069347', (31, 40))
52798	30975211	This led to modification of the indication for erlotinib, limiting treatment to metastatic NSCLC that have specific EGFR mutants, and as a maintenance therapy if there is no progression after platinum based first-line treatment.	('NSCLC', 'Disease', 'MESH:D002289', (91, 96))	('NSCLC', 'Phenotype', 'HP:0030358', (91, 96))	('mutants', 'Var', (121, 128))	('erlotinib', 'Chemical', 'MESH:D000069347', (47, 56))	('platinum', 'Chemical', 'MESH:D010984', (192, 200))	('NSCLC', 'Disease', (91, 96))	('EGFR', 'Gene', (116, 120))
52807	30975211	However, the success of the first generation TKIs has been limited by acquired resistance, developing at around 12-16 months, mediated mostly by a T790 M missense mutation on exon 20 of EGFR.	('EGFR', 'Gene', (186, 190))	('T790 M missense', 'Var', (147, 162))	('rat', 'Species', '10116', (38, 41))	('T790 M', 'Mutation', 'rs121434569', (147, 153))
52815	30975211	These treatment benefits were greatest in EGFR-mutant patients.	('patients', 'Species', '9606', (54, 62))	('EGFR-mutant', 'Gene', (42, 53))	('EGFR-mutant', 'Var', (42, 53))
52816	30975211	The FDA has approved afatinib as a first-line treatment for metastatic NSCLC EGFR-mutant cancers, as well as for advanced squamous cell carcinoma of the lung following failure of platinum-based chemotherapy.	('afatinib', 'Chemical', 'MESH:D000077716', (21, 29))	('NSCLC', 'Phenotype', 'HP:0030358', (71, 76))	('cancers', 'Phenotype', 'HP:0002664', (89, 96))	('squamous cell carcinoma of the lung', 'Disease', (122, 157))	('EGFR-mutant', 'Var', (77, 88))	('cancers', 'Disease', 'MESH:D009369', (89, 96))	('squamous cell carcinoma of the lung', 'Disease', 'MESH:D002294', (122, 157))	('cancers', 'Disease', (89, 96))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (122, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('NSCLC', 'Disease', (71, 76))	('platinum', 'Chemical', 'MESH:D010984', (179, 187))	('EGFR-mutant', 'Gene', (77, 88))	('NSCLC', 'Disease', 'MESH:D002289', (71, 76))
52817	30975211	Approval was based on the clinical trials, 'LUX-Lung 2', 'LUX-Lung 3', and 'LUX-Lung 6', in NSCLC harboring non-resistant EGFR mutations (S768I, L861Q, and/or G719X) and the 'LUX-Lung 8' in patients with advanced squamous cell carcinomas of the lung (Table 1).	('carcinoma', 'Phenotype', 'HP:0030731', (227, 236))	('carcinomas', 'Phenotype', 'HP:0030731', (227, 237))	('squamous cell carcinomas of the lung', 'Disease', (213, 249))	('squamous cell carcinomas of the lung', 'Disease', 'MESH:D002294', (213, 249))	('patients', 'Species', '9606', (190, 198))	('L861Q', 'Mutation', 'rs121913444', (145, 150))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (213, 236))	('L861Q', 'Var', (145, 150))	('NSCLC', 'Phenotype', 'HP:0030358', (92, 97))	('S768I', 'Mutation', 'rs121913465', (138, 143))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (213, 237))	('S768I', 'Var', (138, 143))	('NSCLC', 'Disease', (92, 97))	('G719X', 'Mutation', 'p.G719X', (159, 164))	('NSCLC', 'Disease', 'MESH:D002289', (92, 97))	('EGFR', 'Gene', (122, 126))	('G719X', 'Var', (159, 164))
52821	30975211	In vitro studies in HER2-amplified breast cancer cell lines and EGFR mutant NSCLC cell lines have demonstrated the strong anti-proliferative activity of dacomitinib, providing a rational for its progression into clinical testing against HER2 positive and EGFR mutant cancers.	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('HER2', 'Gene', (20, 24))	('anti-proliferative activity', 'MPA', (122, 149))	('cancers', 'Disease', 'MESH:D009369', (267, 274))	('NSCLC', 'Disease', 'MESH:D002289', (76, 81))	('dacomitinib', 'Chemical', 'MESH:C525726', (153, 164))	('rat', 'Species', '10116', (134, 137))	('EGFR', 'Gene', (64, 68))	('HER2', 'Gene', '2064', (237, 241))	('NSCLC', 'Disease', (76, 81))	('cancer', 'Phenotype', 'HP:0002664', (267, 273))	('rat', 'Species', '10116', (178, 181))	('breast cancer', 'Phenotype', 'HP:0003002', (35, 48))	('HER2', 'Gene', '2064', (20, 24))	('NSCLC', 'Phenotype', 'HP:0030358', (76, 81))	('mutant', 'Var', (69, 75))	('rat', 'Species', '10116', (105, 108))	('cancers', 'Phenotype', 'HP:0002664', (267, 274))	('breast cancer', 'Disease', 'MESH:D001943', (35, 48))	('cancers', 'Disease', (267, 274))	('breast cancer', 'Disease', (35, 48))	('HER2', 'Gene', (237, 241))
52822	30975211	In September 2018, dacomitinib received its first FDA approval as a first-line treatment of patients with metastatic NSCLC with EGFR exon 19 deletion or exon 21 L858R substitution mutations.	('NSCLC', 'Disease', (117, 122))	('dacomitinib', 'Chemical', 'MESH:C525726', (19, 30))	('L858R', 'Mutation', 'rs121434568', (161, 166))	('EGFR', 'Gene', (128, 132))	('patients', 'Species', '9606', (92, 100))	('NSCLC', 'Disease', 'MESH:D002289', (117, 122))	('NSCLC', 'Phenotype', 'HP:0030358', (117, 122))	('L858R', 'Var', (161, 166))
52838	30975211	These agents include osimertinib (AZD9291/ Tagrisso ; AstraZeneca; formerly mereletinib), rociletinib (CO-1686; Clovis Oncology, USA), olmutinib (HM61713; Hanmi Pharmaceutical, South Korea), naquotinib (ASP8273; Astellas Pharma Inc., Japan), tesevatinib (XL647/KD019; Kadmon Corporation, USA), nazartinib (Novartis, Switzerland; EGF816), and PF-06747775.	('EGF', 'Gene', (329, 332))	('rociletinib', 'Chemical', 'MESH:C000589977', (90, 101))	('Oncology', 'Phenotype', 'HP:0002664', (119, 127))	('osimertinib', 'Chemical', 'MESH:C000603933', (21, 32))	('rat', 'Species', '10116', (280, 283))	('PF', 'Chemical', 'MESH:C002997', (342, 344))	('EGF', 'Gene', '1950', (329, 332))	('nazartinib', 'Chemical', 'MESH:C000619734', (294, 304))	('olmutinib', 'Chemical', 'MESH:C000617753', (135, 144))	('PF-06747775', 'Var', (342, 353))	('naquotinib', 'Chemical', 'MESH:C000627869', (191, 201))
52840	30975211	Osimertinib is an irreversible T790 M-EGFR mutant-selective TKI that is also able to bind irreversibly to EGFR that hold a L858R mutation or an exon 19 deletion.	('L858R', 'Var', (123, 128))	('Osimertinib', 'Chemical', 'MESH:C000603933', (0, 11))	('T790 M', 'Mutation', 'rs121434569', (31, 37))	('L858R', 'Mutation', 'rs121434568', (123, 128))	('T790', 'Var', (31, 35))
52841	30975211	More than 50% of NSCLC patients that are EGFR mutation-positive and who have experienced disease progression following EGFR-TKI treatment, have developed a T790 M resistance mutation, for which there has been few treatment options.	('T790 M', 'Var', (156, 162))	('NSCLC', 'Disease', (17, 22))	('patients', 'Species', '9606', (23, 31))	('NSCLC', 'Disease', 'MESH:D002289', (17, 22))	('NSCLC', 'Phenotype', 'HP:0030358', (17, 22))	('T790 M', 'Mutation', 'rs121434569', (156, 162))
52842	30975211	Following the results of the Phase II 'AURA2' and the Phase III 'AURA3' clinical trials, in 2015, the FDA accelerated approval of osimertinib for the treatment of EGFR-T790 M mutant NSCLC patients following EGFR-TKI therapy (Table 1).	('NSCLC', 'Disease', (182, 187))	('AURA2', 'Gene', '1326', (39, 44))	('T790 M', 'Mutation', 'rs121434569', (168, 174))	('EGFR-T790 M mutant', 'Var', (163, 181))	('NSCLC', 'Disease', 'MESH:D002289', (182, 187))	('patients', 'Species', '9606', (188, 196))	('rat', 'Species', '10116', (112, 115))	('AURA2', 'Gene', (39, 44))	('NSCLC', 'Phenotype', 'HP:0030358', (182, 187))	('osimertinib', 'Chemical', 'MESH:C000603933', (130, 141))
52845	30975211	Rociletinib is also an irreversible mutant-selective inhibitor of commonly mutated forms of EGFR (exon 19 deletion, L858R, and T790 M) that has been assessed in early Phase I-II clinical trials.	('L858R', 'Var', (116, 121))	('Rociletinib', 'Chemical', 'MESH:C000589977', (0, 11))	('L858R', 'Mutation', 'rs121434568', (116, 121))	('T790 M', 'Mutation', 'rs121434569', (127, 133))	('T790 M', 'Var', (127, 133))
52846	30975211	In these studies, rociletinib was associated with tumor responses and sustained disease control among patients with heavily pretreated EGFR-mutated NSCLC (NCT01526928; Table 1).	('NSCLC', 'Disease', (148, 153))	('patients', 'Species', '9606', (102, 110))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('disease control', 'CPA', (80, 95))	('NSCLC', 'Disease', 'MESH:D002289', (148, 153))	('rociletinib', 'Chemical', 'MESH:C000589977', (18, 29))	('NSCLC', 'Phenotype', 'HP:0030358', (148, 153))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('rociletinib', 'Var', (18, 29))	('tumor', 'Disease', (50, 55))
52852	30975211	Naquotinib has also been assessed for activity against NSCLC with EGFR mutations in the phase III 'SOLAR' trial.	('NSCLC', 'Disease', (55, 60))	('EGFR', 'Gene', (66, 70))	('NSCLC', 'Disease', 'MESH:D002289', (55, 60))	('mutations', 'Var', (71, 80))	('Naquotinib', 'Chemical', 'MESH:C000627869', (0, 10))	('NSCLC', 'Phenotype', 'HP:0030358', (55, 60))
52854	30975211	Tesevatinib, nazartinib and PF-06747775 are currently in phase II/III trials to assess their activity against NSCLCs.	('PF', 'Chemical', 'MESH:C002997', (28, 30))	('NSCLCs', 'Disease', (110, 116))	('PF-06747775', 'Var', (28, 39))	('Tesevatinib', 'Chemical', 'MESH:C571826', (0, 11))	('NSCLCs', 'Disease', 'MESH:D002289', (110, 116))	('nazartinib', 'Chemical', 'MESH:C000619734', (13, 23))	('NSCLC', 'Phenotype', 'HP:0030358', (110, 115))
52862	30975211	This was based on data from the 'EXTREME' clinical trial of cetuximab treatment in head and neck cancer patients, where patients receiving the cetuximab combination therapy had a significantly longer median OS (10.1 vs. 7.4 months; p < 0.05) and PFS (5.6 vs. 3.3 months; p < 0.0001) compared to those receiving chemotherapy only (Table 2).	('longer', 'PosReg', (193, 199))	('head and neck cancer', 'Phenotype', 'HP:0012288', (83, 103))	('patients', 'Species', '9606', (104, 112))	('PF', 'Chemical', 'MESH:C002997', (246, 248))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('OS', 'Chemical', '-', (207, 209))	('cetuximab', 'Var', (143, 152))	('patients', 'Species', '9606', (120, 128))	('PFS', 'MPA', (246, 249))	('cetuximab', 'Chemical', 'MESH:D000068818', (60, 69))	('head and neck cancer', 'Disease', 'MESH:D006258', (83, 103))	('cetuximab', 'Chemical', 'MESH:D000068818', (143, 152))
52865	30975211	Cancers may acquire activating mutations in exon 2 of KRAS, thus isolating the signaling pathway from the effect of upstream EGFR2, rendering the EGFR inhibitors ineffective.	('signaling pathway', 'Pathway', (79, 96))	('mutations', 'Var', (31, 40))	('activating', 'PosReg', (20, 30))	('Cancers', 'Disease', (0, 7))	('Cancers', 'Phenotype', 'HP:0002664', (0, 7))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('KRAS', 'Gene', (54, 58))	('Cancers', 'Disease', 'MESH:D009369', (0, 7))
52866	30975211	Indeed, the mutation status of KRAS in CRCs is predictive of the patient's response to therapy.	('mutation', 'Var', (12, 20))	('KRAS', 'Gene', (31, 35))	('patient', 'Species', '9606', (65, 72))
52873	30975211	Therefore, like cetuximab, panitumumab monotherapy efficacy in mutant CRC is limited to patients with wild-type KRAS tumors.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('mutant', 'Var', (63, 69))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('patients', 'Species', '9606', (88, 96))	('panitumumab', 'Chemical', 'MESH:D000077544', (27, 38))	('cetuximab', 'Chemical', 'MESH:D000068818', (16, 25))	('KRAS tumors', 'Disease', 'MESH:D009369', (112, 123))	('KRAS tumors', 'Disease', (112, 123))	('CRC', 'Disease', (70, 73))
52889	30975211	Overexpression of VEGF has been correlated with advanced tumor stages and invasiveness and is, therefore, a target for cancer therapeutics.	('invasiveness', 'Disease', (74, 86))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('VEGF', 'Gene', '7422', (18, 22))	('correlated', 'Reg', (32, 42))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('cancer', 'Disease', (119, 125))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('Overexpression', 'Var', (0, 14))	('invasiveness', 'Disease', 'MESH:D009361', (74, 86))	('tumor', 'Disease', (57, 62))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('VEGF', 'Gene', (18, 22))
52890	30975211	Mutations in oncogenes, such as ras or p53, and the inhibition of several tumor suppressor genes, such as PTEN or WT1, can result in the up-regulation of VEGF.	('VEGF', 'Gene', '7422', (154, 158))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('ras', 'Gene', (32, 35))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('up-regulation', 'PosReg', (137, 150))	('Mutations', 'Var', (0, 9))	('p53', 'Gene', (39, 42))	('tumor', 'Disease', (74, 79))	('PTEN', 'Gene', (106, 110))	('WT1', 'Gene', (114, 117))	('VEGF', 'Gene', (154, 158))	('PTEN', 'Gene', '5728', (106, 110))	('p53', 'Gene', '7157', (39, 42))	('WT1', 'Gene', '7490', (114, 117))	('inhibition', 'NegReg', (52, 62))
52915	30975211	Following its success in clinical trials, bevacizumab is currently approved for the treatment of CRC (NCT01169558), glioblastoma (NCT00345163), ovarian cancer (GOG-0213, OCEANS, NCT01239732), renal cancer (AVOREN), breast cancer (E2100, BEATRICE) and cervical cancer (GOG-240).	('breast cancer', 'Phenotype', 'HP:0003002', (215, 228))	('cancer', 'Disease', 'MESH:D009369', (260, 266))	('glioblastoma', 'Disease', 'MESH:D005909', (116, 128))	('breast cancer', 'Disease', 'MESH:D001943', (215, 228))	('cancer', 'Disease', (152, 158))	('breast cancer', 'Disease', (215, 228))	('glioblastoma', 'Disease', (116, 128))	('cancer', 'Disease', (198, 204))	('cancer', 'Disease', (222, 228))	('ovarian cancer', 'Disease', 'MESH:D010051', (144, 158))	('glioblastoma', 'Phenotype', 'HP:0012174', (116, 128))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('renal cancer', 'Disease', (192, 204))	('renal cancer', 'Phenotype', 'HP:0009726', (192, 204))	('CRC', 'Disease', (97, 100))	('cancer', 'Disease', (260, 266))	('ovarian cancer', 'Disease', (144, 158))	('cancer', 'Phenotype', 'HP:0002664', (260, 266))	('bevacizumab', 'Chemical', 'MESH:D000068258', (42, 53))	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('ovarian cancer', 'Phenotype', 'HP:0100615', (144, 158))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (222, 228))	('renal cancer', 'Disease', 'MESH:D007680', (192, 204))	('NCT01169558', 'Var', (102, 113))
52974	30975211	T-DM1 is therefore able to bind to HER2-overexpressing cells and is internalized by the cell where the tubulin inhibitor is released (Fig.	('T-DM1', 'Var', (0, 5))	('HER2', 'Gene', (35, 39))	('T-DM1', 'Chemical', 'MESH:C550911', (0, 5))	('HER2', 'Gene', '2064', (35, 39))	('bind', 'Interaction', (27, 31))
52976	30975211	Clinical trials of the drug have shown that T-DM1 has low toxicity and can be used in combination with lapatinib and nab-paclitaxel for significant anti-tumor activity and, is therefore, a promising drug candidate for HER2-overexpressing breast cancer (Table 4).	('paclitaxel', 'Chemical', 'MESH:D017239', (121, 131))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('T-DM1', 'Var', (44, 49))	('lapatinib', 'Chemical', 'MESH:D000077341', (103, 112))	('HER2', 'Gene', (218, 222))	('toxicity', 'Disease', 'MESH:D064420', (58, 66))	('HER2', 'Gene', '2064', (218, 222))	('tumor', 'Disease', (153, 158))	('toxicity', 'Disease', (58, 66))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('breast cancer', 'Disease', 'MESH:D001943', (238, 251))	('cancer', 'Phenotype', 'HP:0002664', (245, 251))	('breast cancer', 'Disease', (238, 251))	('breast cancer', 'Phenotype', 'HP:0003002', (238, 251))	('T-DM1', 'Chemical', 'MESH:C550911', (44, 49))
52994	30975211	Importantly, trastuzumab, T-DM1, pertuzumab and lapatinib have shown clinical importance in the treatment of HER2 overexpressing breast cancer and the application of these drugs have shown significant improvement in patient outcomes.	('breast cancer', 'Disease', (129, 142))	('T-DM1', 'Var', (26, 31))	('T-DM1', 'Chemical', 'MESH:C550911', (26, 31))	('trastuzumab', 'Chemical', 'MESH:D000068878', (13, 24))	('breast cancer', 'Phenotype', 'HP:0003002', (129, 142))	('overexpressing', 'PosReg', (114, 128))	('HER2', 'Gene', (109, 113))	('lapatinib', 'Chemical', 'MESH:D000077341', (48, 57))	('HER2', 'Gene', '2064', (109, 113))	('patient', 'Species', '9606', (216, 223))	('pertuzumab', 'Chemical', 'MESH:C485206', (33, 43))	('breast cancer', 'Disease', 'MESH:D001943', (129, 142))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
52998	30975211	In cancer, translocations involving the ALK gene form nearly 30 different fusion oncogenes.	('ALK', 'Gene', (40, 43))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('cancer', 'Disease', (3, 9))	('ALK', 'Gene', '238', (40, 43))	('translocations', 'Var', (11, 25))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
53000	30975211	ALK alterations have been found in several cancers, such as anaplastic large cell lymphoma, NSCLC, inflammatory myofibroblastic tumor, diffuse large B-cell lymphomas, esophageal squamous cell carcinoma, renal medulla carcinoma, RCC, breast cancer, colon carcinoma, serous ovarian carcinoma, and anaplastic thyroid carcinoma.	('rat', 'Species', '10116', (8, 11))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (149, 164))	('RCC', 'Disease', 'MESH:D002292', (228, 231))	('lymphomas', 'Disease', 'MESH:D008223', (156, 165))	('B-cell lymphomas', 'Phenotype', 'HP:0012191', (149, 165))	('cancers', 'Phenotype', 'HP:0002664', (43, 50))	('lymphoma', 'Phenotype', 'HP:0002665', (82, 90))	('cell lymphoma', 'Phenotype', 'HP:0012191', (151, 164))	('cancers', 'Disease', (43, 50))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('colon carcinoma', 'Disease', (248, 263))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (272, 289))	('lymphoma', 'Disease', (156, 164))	('anaplastic thyroid carcinoma', 'Phenotype', 'HP:0011779', (295, 323))	('lymphomas', 'Phenotype', 'HP:0002665', (156, 165))	('carcinoma', 'Phenotype', 'HP:0030731', (254, 263))	('NSCLC', 'Disease', 'MESH:D002289', (92, 97))	('lymphoma', 'Disease', 'MESH:D008223', (156, 164))	('carcinoma', 'Phenotype', 'HP:0030731', (192, 201))	('cell lymphoma', 'Phenotype', 'HP:0012191', (77, 90))	('ovarian carcinoma', 'Disease', (272, 289))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (306, 323))	('esophageal squamous cell carcinoma', 'Disease', (167, 201))	('alterations', 'Var', (4, 15))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('thyroid carcinoma', 'Disease', (306, 323))	('B-cell lymphoma', 'Disease', (149, 164))	('colon carcinoma', 'Disease', 'MESH:D015179', (248, 263))	('found', 'Reg', (26, 31))	('NSCLC', 'Disease', (92, 97))	('renal medulla carcinoma', 'Disease', (203, 226))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (272, 289))	('lymphoma', 'Disease', (82, 90))	('lymphoma', 'Disease', 'MESH:D008223', (82, 90))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (306, 323))	('lymphomas', 'Disease', (156, 165))	('NSCLC', 'Phenotype', 'HP:0030358', (92, 97))	('breast cancer', 'Phenotype', 'HP:0003002', (233, 246))	('cancers', 'Disease', 'MESH:D009369', (43, 50))	('tumor', 'Disease', (128, 133))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (178, 201))	('ALK', 'Gene', '238', (0, 3))	('lymphoma', 'Phenotype', 'HP:0002665', (156, 164))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('B-cell lymphoma', 'Disease', 'MESH:D016393', (149, 164))	('myofibroblastic tumor', 'Phenotype', 'HP:0020135', (112, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (280, 289))	('RCC', 'Disease', (228, 231))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:C562729', (167, 201))	('breast cancer', 'Disease', 'MESH:D001943', (233, 246))	('carcinoma', 'Phenotype', 'HP:0030731', (314, 323))	('RCC', 'Phenotype', 'HP:0005584', (228, 231))	('breast cancer', 'Disease', (233, 246))	('ALK', 'Gene', (0, 3))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('renal medulla carcinoma', 'Disease', 'MESH:D002292', (203, 226))	('carcinoma', 'Phenotype', 'HP:0030731', (217, 226))
53009	30975211	These include: the first-generation ALK inhibitor, crizotinib (Xalkori , formerly PF-02341066, Pfizer); the second-generation inhibitors, ceritinib (Zykadia , formerly LDK378; Novartis), alectinib (Alcensa , formerly RO5424802/CH5424802, Hoffmann-La Roche, Inc./Genentech, Inc.), and brigatinib (Alunbrig , formerly AP26113, Takeda Pharmaceutical Company, Ltd); and the third-generation inhibitor, lorlatinib (PF-06463922; Pfizer; Fig.	('crizotinib', 'Chemical', 'MESH:D000077547', (51, 61))	('ceritinib', 'Chemical', 'MESH:C586847', (138, 147))	('brigatinib', 'Chemical', 'MESH:C000598580', (284, 294))	('ALK', 'Gene', '238', (36, 39))	('ALK', 'Gene', (36, 39))	('rat', 'Species', '10116', (29, 32))	('rat', 'Species', '10116', (119, 122))	('rat', 'Species', '10116', (380, 383))	('alectinib', 'Chemical', 'MESH:C582670', (187, 196))	('PF', 'Chemical', 'MESH:C002997', (410, 412))	('PF', 'Chemical', 'MESH:C002997', (82, 84))	('lorlatinib', 'Chemical', 'MESH:C000590786', (398, 408))	('PF-06463922;', 'Var', (410, 422))
53013	30975211	Furthermore, the 'PROFILE 1014' trial showed crizotinib to be superior, compared to standard first-line platinum/pemetrexed chemotherapy in patients with untreated, advanced, NSCLC; for which it is now an approved treatment.	('platinum', 'Chemical', 'MESH:D010984', (104, 112))	('NSCLC', 'Disease', 'MESH:D002289', (175, 180))	('crizotinib', 'Var', (45, 55))	('pemetrexed', 'Chemical', 'MESH:D000068437', (113, 123))	('NSCLC', 'Phenotype', 'HP:0030358', (175, 180))	('patients', 'Species', '9606', (140, 148))	('NSCLC', 'Disease', (175, 180))	('crizotinib', 'Chemical', 'MESH:D000077547', (45, 55))
53018	30975211	Secondary resistance has been attributed to point mutations in the ALK gene, gene amplification, and modification of downstream signaling pathways to bypass ALK inhibition.	('downstream signaling pathways', 'Pathway', (117, 146))	('point mutations', 'Var', (44, 59))	('ALK', 'Gene', '238', (67, 70))	('ALK', 'Gene', (157, 160))	('modification', 'Reg', (101, 113))	('ALK', 'Gene', '238', (157, 160))	('ALK', 'Gene', (67, 70))
53031	30975211	Only 12% of patients treated with alectinib developed CNS progression, compared with 45% of those treated with crizotinib.	('CNS progression', 'CPA', (54, 69))	('patients', 'Species', '9606', (12, 20))	('alectinib', 'Var', (34, 43))	('crizotinib', 'Chemical', 'MESH:D000077547', (111, 121))	('alectinib', 'Chemical', 'MESH:C582670', (34, 43))
53036	30975211	Lorlatinib, a third generation ALK-inhibitor, was designed to inhibit ALK resistant mutants and penetrate the blood brain barrier (BBB).	('ALK', 'Gene', '238', (31, 34))	('rat', 'Species', '10116', (101, 104))	('ALK', 'Gene', '238', (70, 73))	('Lorlatinib', 'Chemical', 'MESH:C000590786', (0, 10))	('mutants', 'Var', (84, 91))	('ALK', 'Gene', (31, 34))	('inhibit', 'NegReg', (62, 69))	('rat', 'Species', '10116', (24, 27))	('ALK', 'Gene', (70, 73))
53050	30975211	BRAF mutations have been extensively reported in numerous cancers, including melanomas (50-66%), papillary thyroid tumors (45-50%), CRCs (10%), prostate tumors (10%), and NSCLCs (3%).	('NSCLCs', 'Disease', 'MESH:D002289', (171, 177))	('melanomas', 'Disease', (77, 86))	('prostate tumors', 'Disease', (144, 159))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('CRCs', 'Disease', (132, 136))	('BRAF', 'Gene', '673', (0, 4))	('prostate tumors', 'Disease', 'MESH:D011471', (144, 159))	('BRAF', 'Gene', (0, 4))	('melanomas', 'Phenotype', 'HP:0002861', (77, 86))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('cancers', 'Disease', 'MESH:D009369', (58, 65))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('NSCLC', 'Phenotype', 'HP:0030358', (171, 176))	('mutations', 'Var', (5, 14))	('melanoma', 'Phenotype', 'HP:0002861', (77, 85))	('NSCLCs', 'Disease', (171, 177))	('tumors', 'Phenotype', 'HP:0002664', (153, 159))	('papillary thyroid tumors', 'Disease', 'MESH:C536915', (97, 121))	('papillary thyroid tumors', 'Phenotype', 'HP:0002895', (97, 121))	('cancers', 'Phenotype', 'HP:0002664', (58, 65))	('melanomas', 'Disease', 'MESH:D008545', (77, 86))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('papillary thyroid tumors', 'Disease', (97, 121))	('cancers', 'Disease', (58, 65))	('reported', 'Reg', (37, 45))
53051	30975211	Studies have reported a V600E hotspot mutation in malignant melanomas and CRCs which increases BRAF kinase activity.	('V600E', 'Var', (24, 29))	('BRAF', 'Gene', '673', (95, 99))	('malignant melanomas', 'Phenotype', 'HP:0002861', (50, 69))	('melanoma', 'Phenotype', 'HP:0002861', (60, 68))	('BRAF', 'Gene', (95, 99))	('malignant melanomas', 'Disease', 'MESH:D008545', (50, 69))	('melanomas', 'Phenotype', 'HP:0002861', (60, 69))	('V600E', 'Mutation', 'rs113488022', (24, 29))	('malignant melanomas', 'Disease', (50, 69))	('increases', 'PosReg', (85, 94))
53052	30975211	This mutation represents about 70-90% of all BRAF mutations.	('mutations', 'Var', (50, 59))	('BRAF', 'Gene', (45, 49))	('BRAF', 'Gene', '673', (45, 49))
53054	30975211	These BRAF mutant cancers have been associated with poor patient prognosis.	('mutant', 'Var', (11, 17))	('cancers', 'Disease', (18, 25))	('cancers', 'Phenotype', 'HP:0002664', (18, 25))	('patient', 'Species', '9606', (57, 64))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('BRAF', 'Gene', '673', (6, 10))	('BRAF', 'Gene', (6, 10))	('cancers', 'Disease', 'MESH:D009369', (18, 25))
53059	30975211	Sorafenib was the first RAF inhibitor to enter clinical trials, which occurred prior to the discovery of BRAF mutations in cancer.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('BRAF', 'Gene', '673', (105, 109))	('mutations', 'Var', (110, 119))	('RAF', 'Gene', '22882', (24, 27))	('RAF', 'Gene', (24, 27))	('BRAF', 'Gene', (105, 109))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('cancer', 'Disease', (123, 129))	('Sorafenib', 'Chemical', 'MESH:D000077157', (0, 9))	('RAF', 'Gene', '22882', (106, 109))	('RAF', 'Gene', (106, 109))
53060	30975211	Molecular characterization studies of NSCLC and HCC lesions has since revealed a BRAF exon 11 mutation (G469 V) that may be responsible in part for some of the observed sensitivity to sorafenib.	('NSCLC and HCC lesions', 'Disease', 'MESH:D006528', (38, 59))	('HCC', 'Phenotype', 'HP:0001402', (48, 51))	('G469 V', 'Mutation', 'rs121913355', (104, 110))	('BRAF', 'Gene', '673', (81, 85))	('sorafenib', 'Chemical', 'MESH:D000077157', (184, 193))	('BRAF', 'Gene', (81, 85))	('NSCLC', 'Phenotype', 'HP:0030358', (38, 43))	('G469 V', 'Var', (104, 110))
53062	30975211	However, when sorafenib was studied in Phase II trials for the treatment of melanoma, no relationship between V600E BRAF status and disease stability was observed (Table 6).	('melanoma', 'Disease', (76, 84))	('V600E', 'Mutation', 'rs113488022', (110, 115))	('melanoma', 'Disease', 'MESH:D008545', (76, 84))	('BRAF', 'Gene', '673', (116, 120))	('V600E', 'Var', (110, 115))	('BRAF', 'Gene', (116, 120))	('melanoma', 'Phenotype', 'HP:0002861', (76, 84))	('sorafenib', 'Chemical', 'MESH:D000077157', (14, 23))
53068	30975211	Vemurafenib is a potent small-molecule inhibitor of BRAF V600E among other BRAF mutations.	('V600E', 'Mutation', 'rs113488022', (57, 62))	('BRAF', 'Gene', '673', (75, 79))	('Vemurafenib', 'Chemical', 'MESH:D000077484', (0, 11))	('BRAF', 'Gene', (75, 79))	('V600E', 'Var', (57, 62))	('BRAF', 'Gene', '673', (52, 56))	('BRAF', 'Gene', (52, 56))
53069	30975211	The FDA approved vemurafenib for the treatment of patients with mutant-V600E BRAF metastatic melanomas in 2011.	('melanoma', 'Phenotype', 'HP:0002861', (93, 101))	('melanomas', 'Phenotype', 'HP:0002861', (93, 102))	('patients', 'Species', '9606', (50, 58))	('melanomas', 'Disease', 'MESH:D008545', (93, 102))	('BRAF', 'Gene', '673', (77, 81))	('mutant-V600E', 'Var', (64, 76))	('V600E', 'Mutation', 'rs113488022', (71, 76))	('BRAF', 'Gene', (77, 81))	('melanomas', 'Disease', (93, 102))	('vemurafenib', 'Chemical', 'MESH:D000077484', (17, 28))
53071	30975211	In these studies, melanoma patients bearing mutant-V600E BRAF had partial or complete response rates to vemurafenib between 48 and 81% with the median PFS extending beyond 7 months.	('melanoma', 'Disease', 'MESH:D008545', (18, 26))	('PF', 'Chemical', 'MESH:C002997', (151, 153))	('BRAF', 'Gene', '673', (57, 61))	('rat', 'Species', '10116', (95, 98))	('vemurafenib', 'Chemical', 'MESH:D000077484', (104, 115))	('BRAF', 'Gene', (57, 61))	('patients', 'Species', '9606', (27, 35))	('melanoma', 'Phenotype', 'HP:0002861', (18, 26))	('V600E', 'Mutation', 'rs113488022', (51, 56))	('melanoma', 'Disease', (18, 26))	('mutant-V600E', 'Var', (44, 56))
53074	30975211	Dabrafenib is also an extremely potent inhibitor of V600E-mutated BRAF, which has shown efficacy in melanoma and CRC both in vitro and in vivo.	('Dabrafenib', 'Chemical', 'MESH:C561627', (0, 10))	('melanoma', 'Disease', 'MESH:D008545', (100, 108))	('efficacy', 'PosReg', (88, 96))	('CRC', 'Disease', (113, 116))	('BRAF', 'Gene', '673', (66, 70))	('melanoma', 'Phenotype', 'HP:0002861', (100, 108))	('V600E-mutated', 'Var', (52, 65))	('melanoma', 'Disease', (100, 108))	('BRAF', 'Gene', (66, 70))	('V600E', 'Mutation', 'rs113488022', (52, 57))
53075	30975211	In addition to V600E, dabrafenib also has demonstrated activity against V600D+ and V600R+ cancers.	('cancers', 'Disease', (90, 97))	('activity', 'MPA', (55, 63))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('dabrafenib', 'Chemical', 'MESH:C561627', (22, 32))	('V600E', 'Mutation', 'rs113488022', (15, 20))	('V600R', 'Mutation', 'rs121913227', (83, 88))	('V600R+', 'Var', (83, 89))	('V600D', 'Mutation', 'rs121913377', (72, 77))	('V600E', 'Var', (15, 20))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('V600D+', 'Var', (72, 78))	('rat', 'Species', '10116', (49, 52))	('cancers', 'Disease', 'MESH:D009369', (90, 97))
53076	30975211	In Phase I and II clinical trials, dabrafenib demonstrated a 53-78% partial or complete response rate in melanoma patients bearing mutant V600E BRAF.	('dabrafenib', 'Chemical', 'MESH:C561627', (35, 45))	('rat', 'Species', '10116', (97, 100))	('V600E', 'Var', (138, 143))	('melanoma', 'Phenotype', 'HP:0002861', (105, 113))	('melanoma', 'Disease', (105, 113))	('melanoma', 'Disease', 'MESH:D008545', (105, 113))	('BRAF', 'Gene', '673', (144, 148))	('rat', 'Species', '10116', (53, 56))	('BRAF', 'Gene', (144, 148))	('V600E', 'Mutation', 'rs113488022', (138, 143))	('patients', 'Species', '9606', (114, 122))	('partial', 'NegReg', (68, 75))
53079	30975211	Following the success of the Phase II clinical trials, dabrafenib has been approved for the treatment of V600E mutant-BRAF NSCLC (NCT01336634) and BRAF+ anaplastic thyroid cancers (NCT01723202).	('BRAF', 'Gene', '673', (118, 122))	('dabrafenib', 'Chemical', 'MESH:C561627', (55, 65))	('thyroid cancers', 'Disease', (164, 179))	('NSCLC', 'Disease', (123, 128))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('BRAF', 'Gene', (118, 122))	('thyroid cancers', 'Disease', 'MESH:D013964', (164, 179))	('NSCLC', 'Disease', 'MESH:D002289', (123, 128))	('V600E', 'Mutation', 'rs113488022', (105, 110))	('BRAF', 'Gene', (147, 151))	('BRAF', 'Gene', '673', (147, 151))	('NSCLC', 'Phenotype', 'HP:0030358', (123, 128))	('cancers', 'Phenotype', 'HP:0002664', (172, 179))	('V600E', 'Var', (105, 110))	('thyroid cancer', 'Phenotype', 'HP:0002890', (164, 178))	('anaplastic thyroid cancers', 'Phenotype', 'HP:0011779', (153, 179))
53082	30975211	Regorafenib is a multi-kinase inhibitor, which has been shown to inhibit both wild-type and mutant V600E BRAF in vitro.	('BRAF', 'Gene', '673', (105, 109))	('Regorafenib', 'Chemical', 'MESH:C559147', (0, 11))	('BRAF', 'Gene', (105, 109))	('V600E', 'Mutation', 'rs113488022', (99, 104))	('inhibit', 'NegReg', (65, 72))	('V600E', 'Var', (99, 104))	('mutant V600E', 'Var', (92, 104))
53087	30975211	In this trial, patients receiving regorafenib had a significantly longer median PFS longer than patients given the placebo (4.8 vs. 0.9 months; p < 0.000001, Table 6).	('patients', 'Species', '9606', (15, 23))	('regorafenib', 'Chemical', 'MESH:C559147', (34, 45))	('PF', 'Chemical', 'MESH:C002997', (80, 82))	('regorafenib', 'Var', (34, 45))	('patients', 'Species', '9606', (96, 104))	('longer', 'PosReg', (66, 72))	('PFS', 'MPA', (80, 83))
53091	30975211	A number of other small molecule inhibitors targeting BRAF have also been evaluated in vitro and are currently in clinical development for their anti-tumor activity against V600E mutant cancers.	('cancers', 'Disease', 'MESH:D009369', (186, 193))	('BRAF', 'Gene', (54, 58))	('V600E', 'Mutation', 'rs113488022', (173, 178))	('BRAF', 'Gene', '673', (54, 58))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('cancers', 'Disease', (186, 193))	('cancers', 'Phenotype', 'HP:0002664', (186, 193))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('V600E mutant', 'Var', (173, 185))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('tumor', 'Disease', (150, 155))
53092	30975211	These include encorafenib (LGX818), XL281 (BMS-908662), ARQ736, PLX4720, PLX3603 (RO5212054), SB-590885, GDC-0879 and RAF265.	('SB-590885', 'Chemical', 'MESH:C508204', (94, 103))	('RO5212054', 'Var', (82, 91))	('RAF', 'Gene', '22882', (118, 121))	('GDC-0879', 'Chemical', 'MESH:C540167', (105, 113))	('RAF', 'Gene', (118, 121))	('encorafenib', 'Chemical', 'MESH:C000601108', (14, 25))
53096	30975211	Cobimetinib was FDA approved in 2015 for the use in combination with vemurafenib for the treatment of advanced melanomas with BRAF V600E or V600K mutations.	('V600E', 'Mutation', 'rs113488022', (131, 136))	('V600K', 'Mutation', 'rs121913227', (140, 145))	('melanomas', 'Disease', 'MESH:D008545', (111, 120))	('melanoma', 'Phenotype', 'HP:0002861', (111, 119))	('vemurafenib', 'Chemical', 'MESH:D000077484', (69, 80))	('melanomas', 'Disease', (111, 120))	('BRAF', 'Gene', (126, 130))	('BRAF', 'Gene', '673', (126, 130))	('V600K', 'Var', (140, 145))	('Cobimetinib', 'Chemical', 'MESH:C574276', (0, 11))	('melanomas', 'Phenotype', 'HP:0002861', (111, 120))
53098	30975211	Similarly, trametinib prolonged the survival of melanoma patients in the Phase III clinical trials 'COMBI-AD', and was FDA approved in 2018 for use in combination with dabrafenib for patients with melanomas with BRAF V600E or V600K mutations (Table 6).	('dabrafenib', 'Chemical', 'MESH:C561627', (168, 178))	('melanoma', 'Phenotype', 'HP:0002861', (48, 56))	('melanoma', 'Disease', (48, 56))	('V600K', 'Mutation', 'rs121913227', (226, 231))	('melanoma', 'Phenotype', 'HP:0002861', (197, 205))	('melanomas', 'Phenotype', 'HP:0002861', (197, 206))	('melanoma', 'Disease', (197, 205))	('BRAF', 'Gene', '673', (212, 216))	('COMBI-AD', 'Chemical', '-', (100, 108))	('BRAF', 'Gene', (212, 216))	('V600E', 'Mutation', 'rs113488022', (217, 222))	('survival', 'CPA', (36, 44))	('prolonged', 'PosReg', (22, 31))	('trametinib', 'Chemical', 'MESH:C560077', (11, 21))	('V600K', 'Var', (226, 231))	('melanoma', 'Disease', 'MESH:D008545', (48, 56))	('patients', 'Species', '9606', (183, 191))	('melanoma', 'Disease', 'MESH:D008545', (197, 205))	('patients', 'Species', '9606', (57, 65))	('melanomas', 'Disease', 'MESH:D008545', (197, 206))	('melanomas', 'Disease', (197, 206))
53111	30975211	Therefore, inhibition of CTLA-4 can shift this balance towards T-cell activation, resulting in destruction of the antigens expressed on tumor cells.	('destruction', 'NegReg', (95, 106))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('inhibition', 'Var', (11, 21))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('tumor', 'Disease', (136, 141))	('CTLA-4', 'Gene', (25, 31))
53113	30975211	Preclinical and clinical data has shown that the inhibition of CTLA-4 directly activates CD4+ and CD8+ effector T-cells.	('CD4', 'Gene', '920', (89, 92))	('CD8', 'Gene', (98, 101))	('CTLA-4', 'Gene', (63, 69))	('CD8', 'Gene', '925', (98, 101))	('inhibition', 'Var', (49, 59))	('CD4', 'Gene', (89, 92))	('activates', 'PosReg', (79, 88))
53129	30975211	Despite this, ipilimumab has since been approved for BRAF V600 wild-type melanomas, melanomas after surgery (NCT00636168), unresectable or metastatic melanomas (CHECKMATE-067/ NCT01696045), intermediate or poor-risk advanced RCCs (CHECKMATE-214), and metastatic CRC (CHECKMATE-142) (Table 7).	('melanomas', 'Disease', (84, 93))	('melanomas', 'Phenotype', 'HP:0002861', (150, 159))	('melanomas', 'Disease', 'MESH:D008545', (73, 82))	('RCC', 'Disease', (225, 228))	('RCC', 'Phenotype', 'HP:0005584', (225, 228))	('melanomas', 'Phenotype', 'HP:0002861', (84, 93))	('melanomas', 'Disease', (73, 82))	('melanoma', 'Phenotype', 'HP:0002861', (150, 158))	('BRAF', 'Gene', '673', (53, 57))	('BRAF', 'Gene', (53, 57))	('melanoma', 'Phenotype', 'HP:0002861', (84, 92))	('NCT00636168', 'Var', (109, 120))	('RCC', 'Disease', 'MESH:D002292', (225, 228))	('melanomas', 'Disease', 'MESH:D008545', (150, 159))	('melanomas', 'Phenotype', 'HP:0002861', (73, 82))	('melanomas', 'Disease', (150, 159))	('ipilimumab', 'Chemical', 'MESH:D000074324', (14, 24))	('melanomas', 'Disease', 'MESH:D008545', (84, 93))	('metastatic CRC', 'Disease', (251, 265))	('melanoma', 'Phenotype', 'HP:0002861', (73, 81))
53147	30975211	In 2015, pembrolizumab received an expanded first-line indication to include previously untreated advanced melanomas regardless of their BRAF mutation status, following the results of the 'KEYNOTE-006' clinical trial (Table 7).	('melanoma', 'Phenotype', 'HP:0002861', (107, 115))	('melanomas', 'Phenotype', 'HP:0002861', (107, 116))	('melanomas regardless', 'Disease', (107, 127))	('pembrolizumab', 'Chemical', 'MESH:C582435', (9, 22))	('melanomas regardless', 'Disease', 'MESH:D008545', (107, 127))	('BRAF', 'Gene', (137, 141))	('BRAF', 'Gene', '673', (137, 141))	('mutation', 'Var', (142, 150))
53148	30975211	One-year OS and ORR rates were significantly improved in patients receiving pembrolizumab compared to ipilimumab.	('ipilimumab', 'Chemical', 'MESH:D000074324', (102, 112))	('pembrolizumab', 'Var', (76, 89))	('improved', 'PosReg', (45, 53))	('pembrolizumab', 'Chemical', 'MESH:C582435', (76, 89))	('patients', 'Species', '9606', (57, 65))	('OS', 'Chemical', '-', (9, 11))	('ORR rates', 'CPA', (16, 25))	('rat', 'Species', '10116', (20, 23))
53151	30975211	Since 2015, the FDA has approved pembrolizumab for the treatment of advanced/metastatic NSCLC (KEYNOTE-001), recurrent/metastatic head and neck squamous cell carcinoma (KEYNOTE-012), high PD-1 expressing metastatic NSCLC (KEYNOTE-024), classical Hodgkin lymphoma (KEYNOTE-087), first-line metastatic non-squamous NSCLC irrespective of PD-L1 expression (KEYNOTE-021), locally advanced/metastatic urothelial carcinoma (KEYNOTE-052), unresectable or metastatic solid tumors with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors (KEYNOTE-016, - 164, - 012, - 028, and - 158), advanced/metastatic gastric or gastroesophageal junction cancers expressing PD-L1 (KEYNOTE-059), metastatic cervical cancers expressing PD-L1 (KEYNOTE-158), refractory or relapsed primary mediastinal large B-Cell lymphomas (PMBCL; KEYNOTE-170), and metastatic non-squamous NSCLCs with no EGFR or ALK mutations (KEYNOTE-189; Table 7).	('NSCLC', 'Phenotype', 'HP:0030358', (88, 93))	('cancers', 'Disease', 'MESH:D009369', (696, 703))	('cancer', 'Phenotype', 'HP:0002664', (756, 762))	('carcinoma', 'Phenotype', 'HP:0030731', (406, 415))	('solid tumors', 'Disease', 'MESH:D009369', (579, 591))	('tumors', 'Phenotype', 'HP:0002664', (585, 591))	('lymphoma', 'Phenotype', 'HP:0002665', (852, 860))	('B-Cell lymphomas', 'Disease', (845, 861))	('pembrolizumab', 'Chemical', 'MESH:C582435', (33, 46))	('mismatch repair deficient (dMMR) solid tumors', 'Disease', 'MESH:C536928', (546, 591))	('NSCLC', 'Disease', (215, 220))	('NSCLC', 'Disease', (912, 917))	('gastroesophageal junction cancers', 'Disease', 'MESH:D009369', (670, 703))	('B-Cell lymphomas', 'Disease', 'MESH:D016393', (845, 861))	('solid tumors', 'Disease', (458, 470))	('Hodgkin lymphoma', 'Disease', 'MESH:D006689', (246, 262))	('PD-L1', 'Gene', (715, 720))	('Hodgkin lymphoma', 'Phenotype', 'HP:0012189', (246, 262))	('non-squamous NSCLC', 'Disease', (300, 318))	('tumor', 'Phenotype', 'HP:0002664', (585, 590))	('NSCLC', 'Phenotype', 'HP:0030358', (215, 220))	('gastroesophageal junction cancers', 'Disease', (670, 703))	('NSCLC', 'Disease', 'MESH:D002289', (313, 318))	('NSCLC', 'Phenotype', 'HP:0030358', (912, 917))	('NSCLCs', 'Disease', (912, 918))	('non-squamous NSCLC', 'Disease', 'MESH:D002294', (899, 917))	('carcinoma', 'Phenotype', 'HP:0030731', (158, 167))	('cancers', 'Disease', 'MESH:D009369', (756, 763))	('tumor', 'Phenotype', 'HP:0002664', (464, 469))	('lymphoma', 'Phenotype', 'HP:0002665', (254, 262))	('gastric or gastroesophageal junction cancer', 'Disease', 'MESH:D013274', (659, 702))	('B-Cell lymphomas', 'Phenotype', 'HP:0012191', (845, 861))	('NSCLC', 'Disease', (313, 318))	('cancers', 'Phenotype', 'HP:0002664', (696, 703))	('gastric or gastroesophageal junction cancer', 'Disease', (659, 702))	('lymphomas', 'Phenotype', 'HP:0002665', (852, 861))	('cancers', 'Disease', (696, 703))	('solid tumors', 'Disease', 'MESH:D009369', (458, 470))	('tumors', 'Phenotype', 'HP:0002664', (464, 470))	('PD-L1', 'Var', (775, 780))	('cancer', 'Phenotype', 'HP:0002664', (696, 702))	('NSCLC', 'Disease', 'MESH:D002289', (88, 93))	('NSCLC', 'Phenotype', 'HP:0030358', (313, 318))	('NSCLCs', 'Disease', 'MESH:D002289', (912, 918))	('non-squamous NSCLC', 'Disease', 'MESH:D002294', (300, 318))	('solid tumors', 'Disease', (579, 591))	('PD-1', 'Gene', '5133', (188, 192))	('PD-1', 'Gene', (188, 192))	('ALK', 'Gene', '238', (935, 938))	('ALK', 'Gene', (935, 938))	('cancers', 'Phenotype', 'HP:0002664', (756, 763))	('NSCLC', 'Disease', (88, 93))	('neck squamous cell carcinoma', 'Disease', 'MESH:C535575', (139, 167))	('neck squamous cell carcinoma', 'Disease', (139, 167))	('metastatic urothelial carcinoma', 'Disease', 'MESH:C538445', (384, 415))	('Hodgkin lymphoma', 'Disease', (246, 262))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (144, 167))	('non-squamous NSCLC', 'Disease', (899, 917))	('cancers', 'Disease', (756, 763))	('NSCLC', 'Disease', 'MESH:D002289', (215, 220))	('metastatic urothelial carcinoma', 'Disease', (384, 415))	('NSCLC', 'Disease', 'MESH:D002289', (912, 917))
53161	30975211	Later in 2015, nivolumab was also approved for the treatment of advanced non-squamous NSCLC, as patients treated with nivolumab in the 'CHECKMATE-057' trials lived an average of 12.2 months compared to 9.4 months in those treated with docetaxel.	('non-squamous NSCLC', 'Disease', 'MESH:D002294', (73, 91))	('nivolumab', 'Chemical', 'MESH:D000077594', (15, 24))	('nivolumab', 'Chemical', 'MESH:D000077594', (118, 127))	('non-squamous NSCLC', 'Disease', (73, 91))	('nivolumab', 'Var', (118, 127))	('docetaxel', 'Chemical', 'MESH:D000077143', (235, 244))	('to 9', 'Species', '1214577', (199, 203))	('patients', 'Species', '9606', (96, 104))	('NSCLC', 'Phenotype', 'HP:0030358', (86, 91))
53172	30975211	In patients with positive PD-L1 expression, 26% experienced a tumor response, compared with 9.5% in those that were PD-L1 negative (Table 7).	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('positive', 'Var', (17, 25))	('expression', 'Var', (32, 42))	('tumor', 'Disease', (62, 67))	('PD-L1', 'Gene', (26, 31))	('patients', 'Species', '9606', (3, 11))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
53179	30975211	The ORR of this study was 26.3% in patients with highly PD-L1 expressing tumors, compared with 17.0% in all evaluable patients regardless of their PD-L1 status.	('highly', 'Var', (49, 55))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('tumors', 'Disease', (73, 79))	('tumors', 'Disease', 'MESH:D009369', (73, 79))	('patients', 'Species', '9606', (35, 43))	('patients', 'Species', '9606', (118, 126))	('PD-L1', 'Gene', (56, 61))
53182	30975211	Early in 2018, durvalumab was also approved for the treatment of stage III unresectable NSCLC following the success of the 'PACIFIC' Phase III trials, which showed a median PFS for patients taking durvalumab of 16.8 months compared to 5.6 months for patients receiving the placebo (Table 7).	('durvalumab', 'Chemical', 'MESH:C000613593', (15, 25))	('durvalumab', 'Chemical', 'MESH:C000613593', (197, 207))	('NSCLC', 'Phenotype', 'HP:0030358', (88, 93))	('durvalumab', 'Var', (197, 207))	('patients', 'Species', '9606', (250, 258))	('PF', 'Chemical', 'MESH:C002997', (173, 175))	('patients', 'Species', '9606', (181, 189))	('NSCLC', 'Disease', (88, 93))	('NSCLC', 'Disease', 'MESH:D002289', (88, 93))
53220	30302893	Framework for microRNA variant annotation and prioritization using human population and disease datasets MicroRNA (miRNA) expression is frequently deregulated in human disease, in contrast, disease-associated miRNA mutations are understudied.	('variant', 'Var', (23, 30))	('human', 'Species', '9606', (67, 72))	('deregulated', 'PosReg', (147, 158))	('human', 'Species', '9606', (162, 167))
53224	30302893	In addition to known somatic miR-142 mutations in hematologic cancers, we describe novel somatic miR-21 mutations in esophageal cancers impacting downstream miRNA targets.	('cancers', 'Disease', 'MESH:D009369', (128, 135))	('cancers', 'Phenotype', 'HP:0002664', (128, 135))	('miRNA targets', 'MPA', (157, 170))	('mutations', 'Var', (104, 113))	('impacting', 'Reg', (136, 145))	('cancers', 'Disease', (128, 135))	('miR-21', 'Gene', '406991', (97, 103))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('esophageal cancers', 'Disease', (117, 135))	('esophageal cancers', 'Disease', 'MESH:D004938', (117, 135))	('miR-21', 'Gene', (97, 103))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('miR-142', 'Gene', '406934', (29, 36))	('cancers', 'Disease', 'MESH:D009369', (62, 69))	('cancers', 'Phenotype', 'HP:0002664', (62, 69))	('miR-142', 'Gene', (29, 36))	('cancers', 'Disease', (62, 69))
53226	30302893	Dysregulation of miRNAs leads to altered expression of their downstream target genes as seen in a wide variety of human diseases such as cancer, cardiovascular and developmental diseases.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('cardiovascular and developmental diseases', 'Disease', 'MESH:D002318', (145, 186))	('expression', 'MPA', (41, 51))	('Dysregulation', 'Var', (0, 13))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('miRNAs', 'Gene', (17, 23))	('altered', 'Reg', (33, 40))	('cancer', 'Disease', (137, 143))	('human', 'Species', '9606', (114, 119))
53228	30302893	Ablation of the miRNA repertoire in Dicer1-/- mutant zebrafish and mice leads to lethality in model organisms and heterozygous loss leads to cancer predisposition in humans.	('mice', 'Species', '10090', (67, 71))	('humans', 'Species', '9606', (166, 172))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('Ablation', 'Var', (0, 8))	('miRNA', 'Protein', (16, 21))	('leads to', 'Reg', (132, 140))	('Dicer1', 'Gene', '324724', (36, 42))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('lethality', 'CPA', (81, 90))	('zebrafish', 'Species', '7955', (53, 62))	('Dicer1', 'Gene', (36, 42))	('cancer', 'Disease', (141, 147))
53230	30302893	Three out of the four known Mendelian disorders shown to be caused by mutations in miRNAs (OMIM (McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University) are due to seed domain mutations: miR-96 in hearing loss, miR-184 in familial keratoconus, and miR-204 in inherited retinal dystrophy.	('inherited retinal dystrophy', 'Disease', (277, 304))	('miR-204', 'Gene', (266, 273))	('mutations', 'Var', (70, 79))	('Mendelian disorders', 'Disease', (28, 47))	('hearing loss', 'Disease', (215, 227))	('familial keratoconus', 'Disease', (240, 260))	('miR-96', 'Gene', '407053', (205, 211))	('keratoconus', 'Phenotype', 'HP:0000563', (249, 260))	('miR-96', 'Gene', (205, 211))	('miR-184', 'Gene', (229, 236))	('retinal dystrophy', 'Phenotype', 'HP:0000556', (287, 304))	('due', 'Reg', (175, 178))	('miR-184', 'Gene', '406960', (229, 236))	('miR-204', 'Gene', '406987', (266, 273))	('caused', 'Reg', (60, 66))	('miRNAs', 'Gene', (83, 89))	('hearing loss', 'Phenotype', 'HP:0000365', (215, 227))
53232	30302893	Most of these variants ascribed to cancer predisposition or somatic mechanisms are primary or precursor miRNA transcript variants and alter the expression levels of mature miRNAs by interfering with the miRNA processing.	('interfering', 'NegReg', (182, 193))	('miRNA processing', 'MPA', (203, 219))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('variants', 'Var', (14, 22))	('alter', 'Reg', (134, 139))	('expression levels of mature miRNAs', 'MPA', (144, 178))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('cancer', 'Disease', (35, 41))
53236	30302893	Annotation of variants within protein-coding genes utilize several criteria including but not limited to, predicted protein truncations, change in the amino acid code, evolutionary conservation and/or on sequence constraint metrics such as those developed using large human population datasets of protein-coding sequences like ExAC.	('truncations', 'NegReg', (124, 135))	('human', 'Species', '9606', (268, 273))	('variants', 'Var', (14, 22))	('protein', 'Protein', (116, 123))
53248	30302893	We used BEDTools intersect tool to subset the whole exome germline variant calls to the miRNA regions that corresponded to the mature and precursor miRNA sequences (miRBase v21).	('variant', 'Var', (67, 74))	('v21', 'Gene', (173, 176))	('v21', 'Gene', '28809', (173, 176))
53256	30302893	On average, 55% of all miRNAs listed in miRBase v21 (>90% precursor bases in capture bed file) were targeted either directly, as per the miRBase release at the time of capture design, or indirectly as a result of miRNAs overlapping the protein-coding exons.	('v21', 'Gene', '28809', (48, 51))	('protein-coding', 'Protein', (236, 250))	('miRNAs', 'Var', (213, 219))	('v21', 'Gene', (48, 51))
53259	30302893	The majority of mature miRNAs contain 0-2 variants in the entire gnomAD WGS dataset, with a few outlier miRNAs accumulating relatively high sequence variation (Figure 5 D).	('gnomAD WGS dataset', 'Disease', (65, 83))	('variants', 'Var', (42, 50))	('gnomAD WGS dataset', 'Disease', 'None', (65, 83))
53267	30302893	Among the mature miRNA variants, 1,267 were rare germline variants (as defined by ExAC nonTCGA AF <0.1%) found in approximately 11% of all PanCancerAtlas samples and 1,492 were somatic mutations in 8% of all samples (Table 2).	('variants', 'Var', (23, 31))	('Cancer', 'Phenotype', 'HP:0002664', (142, 148))	('PanCancerAtlas', 'Disease', (139, 153))	('AF', 'Disease', 'MESH:D001281', (95, 97))
53268	30302893	We first analyzed those variants found in miRNAs in the KEGG pathway 'MicroRNAs in Cancer' that catalogues differentially expressed miRNAs across 10 cancer types.	('cancer type', 'Disease', 'MESH:D009369', (149, 160))	('variants', 'Var', (24, 32))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('cancer type', 'Disease', (149, 160))	('KEGG', 'Pathway', (56, 60))	('Cancer', 'Phenotype', 'HP:0002664', (83, 89))
53270	30302893	miR-10, let-7, miR-17, miR-30, and miR-15 harbor frequent somatic and rare germline variants in the above mentioned 10 cancer types as well as some other cancer types in the PanCancerAtlas dataset, (Figure 8).	('Cancer', 'Phenotype', 'HP:0002664', (177, 183))	('let-7', 'Gene', (8, 13))	('cancer type', 'Disease', (119, 130))	('miR-10', 'Gene', '10288', (0, 6))	('cancer type', 'Disease', 'MESH:D009369', (154, 165))	('miR-17', 'Gene', (15, 21))	('cancer type', 'Disease', 'MESH:D009369', (119, 130))	('miR-30', 'Gene', (23, 29))	('miR-10', 'Gene', (0, 6))	('variants', 'Var', (84, 92))	('miR-17', 'Gene', '406952', (15, 21))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('miR-15', 'Gene', (35, 41))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('cancer type', 'Disease', (154, 165))
53273	30302893	There were 1,267 rare germline variants spread among 631 miRNAs, however, variation within many miRNAs did not significantly cluster within one tumor type (Supplementary Data).	('tumor', 'Disease', (144, 149))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('variants', 'Var', (31, 39))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))
53278	30302893	Overall, our analysis of rare germline miRNA variants in the TCGA PanCancerAtlas Dataset compared with gnomAD suggests that rare germline variation plays little to no role in predisposition to the most common histologic types of adult cancers, however, this does not preclude smaller effects of common variants, or miRNA variation in other tumors types or histopathologic subtypes.	('tumors', 'Disease', (340, 346))	('tumors', 'Disease', 'MESH:D009369', (340, 346))	('variants', 'Var', (45, 53))	('cancers', 'Disease', 'MESH:D009369', (235, 242))	('cancers', 'Phenotype', 'HP:0002664', (235, 242))	('variation', 'Var', (138, 147))	('cancers', 'Disease', (235, 242))	('tumors', 'Phenotype', 'HP:0002664', (340, 346))	('Cancer', 'Phenotype', 'HP:0002664', (69, 75))	('tumor', 'Phenotype', 'HP:0002664', (340, 345))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))
53280	30302893	We identified the 10 most frequently mutated miRNAs within each cancer type (Figure 9 A).	('cancer type', 'Disease', 'MESH:D009369', (64, 75))	('mutated', 'Var', (37, 44))	('cancer type', 'Disease', (64, 75))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
53281	30302893	We found that the majority of miRNAs were mutated in <1% of samples in the respective cancer type.	('mutated', 'Var', (42, 49))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('miRNAs', 'Gene', (30, 36))	('cancer type', 'Disease', (86, 97))	('cancer type', 'Disease', 'MESH:D009369', (86, 97))
53283	30302893	The tumor types with at least 1% somatic mutation in a specific miRNA (Figure 9 A) included diffuse large B-cell lymphoma (DLBC) and acute myeloid leukemia (LAML) with miR-142 mutations, 6.2%, and 1.3% respectively.	('tumor', 'Disease', (4, 9))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (139, 155))	('B-cell lymphoma', 'Disease', (106, 121))	('mutations', 'Var', (176, 185))	('leukemia', 'Phenotype', 'HP:0001909', (147, 155))	('miR-142', 'Gene', (168, 175))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (133, 155))	('lymphoma', 'Phenotype', 'HP:0002665', (113, 121))	('acute myeloid leukemia', 'Disease', (133, 155))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (133, 155))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('miR-142', 'Gene', '406934', (168, 175))	('B-cell lymphoma', 'Disease', 'MESH:D016393', (106, 121))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (106, 121))
53285	30302893	This result is consistent with the previously reported association of somatic mutations of miR-142 (miR142) mutations in hematologic malignancies, lymphoma (20% DLBC) and leukemia (2% LAML) (Figure 9 B).	('leukemia', 'Phenotype', 'HP:0001909', (171, 179))	('leukemia', 'Disease', 'MESH:D007938', (171, 179))	('mutations', 'Var', (108, 117))	('leukemia', 'Disease', (171, 179))	('miR-142', 'Gene', '406934', (91, 98))	('miR142', 'Gene', '406934', (100, 106))	('miR142', 'Gene', (100, 106))	('lymphoma', 'Phenotype', 'HP:0002665', (147, 155))	('miR-142', 'Gene', (91, 98))	('hematologic malignancies, lymphoma', 'Disease', 'MESH:D019337', (121, 155))
53289	30302893	Indeed, expression of 5 miR-21 target genes, APAF1, BASP1, PDCD4, RASA1, and RASGRP1, show significantly altered expression in mutated samples as compared to the rest of the samples in this cancer type (Wilcoxon test p<0.05) suggesting the miRNA variants impact miR-21 function (Figure 9 C).	('RASA1', 'Gene', (66, 71))	('miR-21', 'Gene', (262, 268))	('PDCD4', 'Gene', '27250', (59, 64))	('expression', 'MPA', (113, 123))	('APAF1', 'Gene', '317', (45, 50))	('miR-21', 'Gene', '406991', (24, 30))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('expression', 'MPA', (8, 18))	('impact', 'Reg', (255, 261))	('BASP1', 'Gene', (52, 57))	('APAF1', 'Gene', (45, 50))	('BASP1', 'Gene', '10409', (52, 57))	('RASGRP1', 'Gene', '10125', (77, 84))	('function', 'MPA', (269, 277))	('variants', 'Var', (246, 254))	('cancer type', 'Disease', (190, 201))	('RASGRP1', 'Gene', (77, 84))	('miR-21', 'Gene', '406991', (262, 268))	('RASA1', 'Gene', '5921', (66, 71))	('miR-21', 'Gene', (24, 30))	('cancer type', 'Disease', 'MESH:D009369', (190, 201))	('PDCD4', 'Gene', (59, 64))	('altered', 'Reg', (105, 112))
53297	30302893	Despite this difference in the genomic environment, we found comparable variant AF distribution of intragenic and intergenic miRNA genes and similar conservation profiles of the mature miRNA sequence.	('AF', 'Disease', 'MESH:D001281', (80, 82))	('variant', 'Var', (72, 79))	('miRNA genes', 'Gene', (125, 136))
53306	30302893	Further study is needed to determine the potential role of germline variants in miRNA genes in rare pathologic subtypes, other rare adult cancers, pediatric cancers and those miRNAs not effectively sequenced by WES.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('germline variants', 'Var', (59, 76))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('cancers', 'Disease', 'MESH:D009369', (157, 164))	('cancers', 'Phenotype', 'HP:0002664', (157, 164))	('miRNA genes', 'Gene', (80, 91))	('cancers', 'Disease', (157, 164))	('cancers', 'Phenotype', 'HP:0002664', (138, 145))	('cancers', 'Disease', (138, 145))	('cancers', 'Disease', 'MESH:D009369', (138, 145))
53307	30302893	Genome-wide association approaches could also be explored by focusing on the common miRNAs variants (AF >5%) described here, as some of these common variants are predicted to alter miRNA target gene expression.	('expression', 'MPA', (199, 209))	('alter', 'Reg', (175, 180))	('variants', 'Var', (149, 157))	('AF', 'Disease', 'MESH:D001281', (101, 103))	('variants', 'Var', (91, 99))
53308	30302893	Analysis of somatic mutations in miRNAs demonstrated higher specificity with cancer type including the previously described association of miR-142 somatic mutations in hematologic malignancies such as lymphoma (DLBC) and leukemia (LAML).	('lymphoma', 'Phenotype', 'HP:0002665', (201, 209))	('mutations', 'Var', (155, 164))	('cancer type', 'Disease', 'MESH:D009369', (77, 88))	('association', 'Interaction', (124, 135))	('hematologic malignancies', 'Disease', 'MESH:D019337', (168, 192))	('miR-142', 'Gene', '406934', (139, 146))	('lymphoma', 'Disease', (201, 209))	('leukemia', 'Phenotype', 'HP:0001909', (221, 229))	('miR-142', 'Gene', (139, 146))	('leukemia', 'Disease', 'MESH:D007938', (221, 229))	('hematologic malignancies', 'Disease', (168, 192))	('lymphoma', 'Disease', 'MESH:D008223', (201, 209))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('cancer type', 'Disease', (77, 88))	('leukemia', 'Disease', (221, 229))
53380	28367064	The protein and mRNA expressions of Nrf2, HO1, NQO1 and GST in the HSC-4-RR-Nrf2 siRNA group were upregulated compared with those in the HSC-4-Nrf2 siRNA group (all P<0.05).	('HSC-4-RR-Nrf2', 'Var', (67, 80))	('GST', 'Gene', (56, 59))	('upregulated', 'PosReg', (98, 109))	('NQO1', 'Gene', (47, 51))	('HO1', 'Gene', (42, 45))	('mRNA expressions', 'MPA', (16, 32))	('NQO1', 'Gene', '1728', (47, 51))	('GST', 'Gene', '373156', (56, 59))	('protein', 'MPA', (4, 11))	('HO1', 'Gene', '3162', (42, 45))	('Nrf2', 'Gene', (36, 40))
53384	28367064	While the tumor volume in the RT and RT + Nrf2 siRNA groups evidently decreased (both P<0.05), the RT + Nrf2 siRNA group had smaller tumor volume compared with that of the RT group (P<0.05).	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumor', 'Disease', (10, 15))	('decreased', 'NegReg', (70, 79))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumor', 'Disease', (133, 138))	('RT + Nrf2 siRNA', 'Var', (99, 114))	('smaller', 'NegReg', (125, 132))	('tumor', 'Disease', 'MESH:D009369', (10, 15))
53385	28367064	The results suggested that RT could inhibit tumor growth, and nude mice were more radiation sensitive after transfected with Nrf2 siRNA.	('inhibit', 'NegReg', (36, 43))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('transfected', 'Var', (108, 119))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumor', 'Disease', (44, 49))	('Nrf2', 'Gene', (125, 129))	('nude mice', 'Species', '10090', (62, 71))
53400	28367064	It was also reported that NQO1 expression is closely correlated with the progression and prognosis of patients with HNSCC, and high expression of NQO1 may be used as an important indicator for poor prognosis of patients with HNSCC.	('patients', 'Species', '9606', (211, 219))	('NQO1', 'Gene', '1728', (146, 150))	('correlated', 'Reg', (53, 63))	('patients', 'Species', '9606', (102, 110))	('high expression', 'Var', (127, 142))	('NQO1', 'Gene', (26, 30))	('NQO1', 'Gene', '1728', (26, 30))	('HNSCC', 'Disease', (116, 121))	('NQO1', 'Gene', (146, 150))
53403	28367064	Consistent with our study, Shibata et al investigated the role of Nrf2 mutation in the resistance of therapy in esophageal squamous cancer (ESC) and found that downregulation of mutant Nrf2 is very likely to enhance radiation sensitivity in ESC cells.	('downregulation', 'NegReg', (160, 174))	('mutant', 'Var', (178, 184))	('esophageal squamous cancer', 'Disease', 'MESH:D004938', (112, 138))	('esophageal squamous cancer', 'Disease', (112, 138))	('squamous cancer', 'Phenotype', 'HP:0002860', (123, 138))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('Nrf2', 'Gene', (185, 189))	('Nrf2', 'Gene', (66, 70))	('radiation sensitivity', 'CPA', (216, 237))	('enhance', 'PosReg', (208, 215))
53406	28367064	A growing body of evidence suggests that dysregulation of DNA repair genes affects the response of cells to DNA-damaging anticancer treatment and upregulation of DNA damage response, as well as repair genes can cause cancer development by the increasing cancer cells, and also resulting in the increasing resistance to chemotherapy and radiotherapy.	('cancer', 'Phenotype', 'HP:0002664', (254, 260))	('affects', 'Reg', (75, 82))	('resulting in', 'Reg', (277, 289))	('upregulation', 'PosReg', (146, 158))	('increasing', 'PosReg', (294, 304))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('dysregulation', 'Var', (41, 54))	('cancer', 'Disease', 'MESH:D009369', (254, 260))	('cancer', 'Disease', (217, 223))	('cancer', 'Disease', 'MESH:D009369', (217, 223))	('cancer', 'Disease', (254, 260))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('response', 'MPA', (87, 95))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))	('cause', 'Reg', (211, 216))
53410	28367064	Hence, after transfected with Nrf2 siRNA, the protein and mRNA expressions of Nrf2, HO1, NQO1 and GST and cell viability of HSC-4-RR-Nrf2 siRNA were decreased.	('transfected', 'Var', (13, 24))	('HO1', 'Gene', (84, 87))	('Nrf2', 'Gene', (78, 82))	('protein', 'MPA', (46, 53))	('mRNA expressions', 'MPA', (58, 74))	('HO1', 'Gene', '3162', (84, 87))	('Nrf2', 'Gene', (30, 34))	('NQO1', 'Gene', (89, 93))	('GST', 'Gene', (98, 101))	('decreased', 'NegReg', (149, 158))	('NQO1', 'Gene', '1728', (89, 93))	('GST', 'Gene', '373156', (98, 101))	('cell viability', 'CPA', (106, 120))
53413	28367064	These results confirmed our previous presumptions that RT could inhibit tumor growth, and nude mice were more sensitive to radiation after transfected with Nrf2 siRNA.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Disease', (72, 77))	('inhibit', 'NegReg', (64, 71))	('transfected', 'Var', (139, 150))	('nude mice', 'Species', '10090', (90, 99))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('Nrf2', 'Gene', (156, 160))
53420	32458657	Immunohistochemistry was performed by using Rabbit monoclonal antibody against HER-2/neu (EP700Y, cell marquee and diluted 1:50).	('EP700Y', 'Var', (90, 96))	('HER-2/neu', 'Gene', (79, 88))	('HER-2/neu', 'Gene', '2064', (79, 88))
53445	32458657	In a similar report, Ohashi et al., (2017) reported that approximately 5% of NSCLC tumors possess HER2 alterations, and Trastuzumab emtansine (an anti-HER2 antibody conjugated with a vinca alkaloid) has shown excellent antitumor effects against HER2/neu.	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('tumor', 'Disease', (83, 88))	('Trastuzumab', 'Chemical', 'MESH:D000068878', (120, 131))	('HER2/neu', 'Gene', (245, 253))	('emtansine', 'Chemical', 'MESH:D008453', (132, 141))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('HER2', 'Gene', '2064', (151, 155))	('HER2', 'Gene', '2064', (245, 249))	('HER2', 'Gene', (98, 102))	('NSCLC tumors', 'Disease', 'MESH:D009369', (77, 89))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumor', 'Disease', (223, 228))	('HER2/neu', 'Gene', '2064', (245, 253))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('HER2', 'Gene', (151, 155))	('tumor', 'Disease', 'MESH:D009369', (223, 228))	('alterations', 'Var', (103, 114))	('HER2', 'Gene', (245, 249))	('HER2', 'Gene', '2064', (98, 102))	('NSCLC tumors', 'Disease', (77, 89))
53452	32458657	Immunohistochemistry evaluation  Immunohistochemistry was performed by using Rabbit monoclonal antibody against HER-2/Neu (EP700Y, cell marquee and diluted 1:50).	('Neu', 'Gene', '2064', (118, 121))	('HER-2', 'Gene', '2064', (112, 117))	('EP700Y', 'Var', (123, 129))	('HER-2', 'Gene', (112, 117))	('Neu', 'Gene', (118, 121))
53460	32458657	Negative (not amplified) - Average Her2 copy number < 4.0 signals/ cell.	('Her2', 'Gene', (35, 39))	('Her2', 'Gene', '2064', (35, 39))	('copy number <', 'Var', (40, 53))
53461	32458657	Equivocal - Average Her2 copy number >= 4.0 and < 6.0 signals/ cell.	('Her2', 'Gene', (20, 24))	('copy number', 'Var', (25, 36))	('Her2', 'Gene', '2064', (20, 24))
53462	32458657	Positive (amplified) - Average Her2 copy number >= 6.0 signals/cell.	('Her2', 'Gene', '2064', (31, 35))	('copy number', 'Var', (36, 47))	('Her2', 'Gene', (31, 35))
53514	31336999	We summarize the emerging roles of long non-coding RNAs in HNC and LC development and their possible use in early diagnosis.	('HNC', 'CPA', (59, 62))	('LC development', 'CPA', (67, 81))	('LC', 'Phenotype', 'HP:0012118', (67, 69))	('men', 'Species', '9606', (77, 80))	('HNC', 'Phenotype', 'HP:0012288', (59, 62))	('long non-coding RNAs', 'Var', (35, 55))
53540	31336999	HPV tumor positivity can lead to mutations in the PIK3CA gene, loss of the TRAF3 gene, and amplification of the E2F1 gene.	('PIK3CA', 'Gene', '5290', (50, 56))	('TRAF3 gene', 'Gene', (75, 85))	('amplification', 'Var', (91, 104))	('mutations', 'Var', (33, 42))	('lead to', 'Reg', (25, 32))	('E2F1', 'Gene', (112, 116))	('HPV tumor', 'Disease', 'MESH:D030361', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('HPV tumor', 'Disease', (0, 9))	('PIK3CA', 'Gene', (50, 56))	('loss', 'NegReg', (63, 67))
53541	31336999	On the other hand, tumors that are negative for HPV can have mutations in CCND1, FADD, BIRC2, YAP1, CASP8 or HRAS and in other genes involved in the regulation of cell cycle, cell death and NF-kB.	('tumors', 'Disease', (19, 25))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('FADD', 'Gene', (81, 85))	('HPV', 'Disease', 'MESH:D030361', (48, 51))	('CCND1', 'Gene', (74, 79))	('mutations', 'Var', (61, 70))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('CASP8', 'Gene', (100, 105))	('YAP1', 'Gene', (94, 98))	('CASP8', 'Gene', '841', (100, 105))	('YAP1', 'Gene', '10413', (94, 98))	('HPV', 'Disease', (48, 51))	('HRAS', 'Disease', (109, 113))	('BIRC2', 'Gene', (87, 92))	('HRAS', 'Disease', 'None', (109, 113))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))
53542	31336999	Mutations of TP53 are associated with tobacco consumption, inactivation of CDKN2A and changes in genes associated with oxidative stress.	('tobacco consumption', 'Disease', (38, 57))	('TP53', 'Gene', (13, 17))	('inactivation', 'NegReg', (59, 71))	('oxidative stress', 'Phenotype', 'HP:0025464', (119, 135))	('CDKN2A', 'Gene', (75, 81))	('tobacco', 'Species', '4097', (38, 45))	('genes', 'MPA', (97, 102))	('Mutations', 'Var', (0, 9))	('changes', 'Reg', (86, 93))	('TP53', 'Gene', '7157', (13, 17))	('associated', 'Reg', (22, 32))
53543	31336999	A recent evidence has reported the presence of different mutations in PIK3CA, CASP8, NOTCH1 or TP53 genes in oral tumors with better treatment response and mutations in NSD1, WNT and NFE2L2 genes in LC.Molecular profiling of genes that influence HNSCC and LC proteins is very important, as it represents a valid tool for testing selected biomarkers.	('NFE2L2', 'Gene', (183, 189))	('NSD1', 'Gene', '64324', (169, 173))	('men', 'Species', '9606', (138, 141))	('SCC', 'Phenotype', 'HP:0002860', (248, 251))	('oral tumors', 'Disease', (109, 120))	('mutations', 'Var', (57, 66))	('CASP8', 'Gene', '841', (78, 83))	('LC', 'Phenotype', 'HP:0012118', (256, 258))	('NOTCH1', 'Gene', (85, 91))	('LC', 'Phenotype', 'HP:0012118', (199, 201))	('PIK3CA', 'Gene', '5290', (70, 76))	('TP53', 'Gene', '7157', (95, 99))	('CASP8', 'Gene', (78, 83))	('NOTCH1', 'Gene', '4851', (85, 91))	('HNSCC', 'Phenotype', 'HP:0012288', (246, 251))	('NSD1', 'Gene', (169, 173))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('NFE2L2', 'Gene', '4780', (183, 189))	('oral tumors', 'Phenotype', 'HP:0100649', (109, 120))	('oral tumors', 'Disease', 'MESH:D020820', (109, 120))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('PIK3CA', 'Gene', (70, 76))	('TP53', 'Gene', (95, 99))
53548	31336999	Abnormal miRNA expression determines a wide variety of cellular pathways governing human malignancies, such as cell proliferation, apoptosis, metastasis, and drug response.	('determines', 'Reg', (26, 36))	('malignancies', 'Disease', 'MESH:D009369', (89, 101))	('metastasis', 'CPA', (142, 152))	('human', 'Species', '9606', (83, 88))	('cell proliferation', 'CPA', (111, 129))	('malignancies', 'Disease', (89, 101))	('Abnormal', 'Var', (0, 8))	('apoptosis', 'CPA', (131, 140))	('miR', 'Gene', '220972', (9, 12))	('cellular pathways', 'Pathway', (55, 72))	('miR', 'Gene', (9, 12))
53562	31336999	The long non-coding HOX transcript antisense RNA (HOTAIR) with 2158-nucleotidesis located at chromosome 12q13.13.	('antisense', 'Var', (35, 44))	('HOTAIR', 'Gene', (50, 56))	('HOTAIR', 'Gene', '100124700', (50, 56))
53569	31336999	In fact, HOTAIR knockdown significantly inhibited both in vitro and in vivo tumor cell growth and angiogenesis (Table 1).	('HOTAIR', 'Gene', (9, 15))	('inhibited', 'NegReg', (40, 49))	('HOTAIR', 'Gene', '100124700', (9, 15))	('angiogenesis', 'CPA', (98, 110))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('knockdown', 'Var', (16, 25))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
53573	31336999	Over-expression of UCA1 lncRNA could promote metastatic but not proliferation ability of TSCC cells (Table 1).	('metastatic', 'CPA', (45, 55))	('ncRNA', 'Gene', '220202', (25, 30))	('promote', 'PosReg', (37, 44))	('UCA1', 'Gene', '652995', (19, 23))	('UCA1', 'Gene', (19, 23))	('SCC', 'Phenotype', 'HP:0002860', (90, 93))	('Over-expression', 'Var', (0, 15))	('ncRNA', 'Gene', (25, 30))
53579	31336999	Indeed, FOXCUT silencing reduces FOXC1 expression both at mRNA and protein level (Table 1).	('reduces', 'NegReg', (25, 32))	('FOXCUT', 'Gene', (8, 14))	('silencing', 'Var', (15, 24))	('FOXC1', 'Gene', (33, 38))	('FOXCUT', 'Gene', '101927703', (8, 14))	('expression', 'MPA', (39, 49))	('FOXC1', 'Gene', '2296', (33, 38))
53581	31336999	In vitro experiments demonstrated that AFAP1-AS1 knockdown significantly inhibited NPC cell migration and invasion.	('knockdown', 'Var', (49, 58))	('AFAP1-AS1', 'Gene', '84740;60312;5729', (39, 48))	('men', 'Species', '9606', (15, 18))	('AFAP1-AS1', 'Gene', (39, 48))	('inhibited', 'NegReg', (73, 82))	('NPC', 'Phenotype', 'HP:0100630', (83, 86))
53582	31336999	AFAP1-AS1 knockdown also increased AFAP1 protein expression.	('increased', 'PosReg', (25, 34))	('protein expression', 'MPA', (41, 59))	('AFAP1-AS1', 'Gene', '84740;60312;5729', (0, 9))	('AFAP1-AS1', 'Gene', (0, 9))	('AFAP1', 'Gene', (35, 40))	('knockdown', 'Var', (10, 19))
53585	31336999	In nude mice, AFAP1-AS1 knockdown represses cell invasion and inhibits NPC lung metastasis (Table 1).	('NPC lung metastasis', 'Disease', (71, 90))	('cell invasion', 'CPA', (44, 57))	('represses', 'NegReg', (34, 43))	('inhibits', 'NegReg', (62, 70))	('NPC lung metastasis', 'Disease', 'MESH:D052556', (71, 90))	('NPC', 'Phenotype', 'HP:0100630', (71, 74))	('AFAP1-AS1', 'Gene', '84740;60312;5729', (14, 23))	('nude mice', 'Species', '10090', (3, 12))	('knockdown', 'Var', (24, 33))	('AFAP1-AS1', 'Gene', (14, 23))
53587	31336999	Lentivirus-mediated HNF1A-AS knockdown suppressed cell proliferation and migration abilities of NPC cells.	('HNF1A', 'Gene', '6927', (20, 25))	('knockdown', 'Var', (29, 38))	('HNF1A', 'Gene', (20, 25))	('migration abilities of NPC cells', 'CPA', (73, 105))	('suppressed', 'NegReg', (39, 49))	('NPC', 'Phenotype', 'HP:0100630', (96, 99))	('cell proliferation', 'CPA', (50, 68))
53588	31336999	In mice injected with CNE-2 and SUNE-1, depletion of HNF1A-AS caused inhibition of tumor growth, whereas cell cycle analysis showed that HNF1A-AS-knockdown resulted in cell accumulation in the G0/G1 phase.	('cell accumulation in the G0/G1 phase', 'CPA', (168, 204))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('depletion', 'Var', (40, 49))	('tumor', 'Disease', (83, 88))	('mice', 'Species', '10090', (3, 7))	('HNF1A', 'Gene', '6927', (137, 142))	('HNF1A', 'Gene', (53, 58))	('HNF1A', 'Gene', '6927', (53, 58))	('CNE-2', 'CellLine', 'CVCL:6889', (22, 27))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('HNF1A', 'Gene', (137, 142))	('inhibition', 'NegReg', (69, 79))
53592	31336999	In fact, inhibition of the expression of ROR increased G1 phase (from 59.91% to 70.11%), and decreased the S and G2 phase (from 40.01% to 29.89%) in NPC CNE2 cells.	('NPC', 'Phenotype', 'HP:0100630', (149, 152))	('ROR', 'Gene', '100885779', (41, 44))	('increased', 'PosReg', (45, 54))	('NPC CNE2', 'CellLine', 'CVCL:6889', (149, 157))	('decreased', 'NegReg', (93, 102))	('G1 phase', 'CPA', (55, 63))	('inhibition', 'Var', (9, 19))	('ROR', 'Gene', (41, 44))
53597	31336999	Notably, knockdown of ROR leads to an increase in the activation of p53 pathways (Table 1.).	('increase', 'PosReg', (38, 46))	('knockdown', 'Var', (9, 18))	('ROR', 'Gene', (22, 25))	('activation', 'PosReg', (54, 64))	('p53', 'Gene', (68, 71))	('p53', 'Gene', '7157', (68, 71))	('ROR', 'Gene', '100885779', (22, 25))
53601	31336999	Moreover, lncRNA-LET is transcriptionally repressed by EZH2-mediated H3K27 histone methylation on the LET promoter.	('histone', 'Reg', (75, 82))	('lncRNA-LET', 'Gene', '101241892', (10, 20))	('EZH2', 'Gene', '2146', (55, 59))	('lncRNA-LET', 'Gene', (10, 20))	('EZH2', 'Gene', (55, 59))	('methylation', 'Var', (83, 94))	('H3K27', 'Protein', (69, 74))
53607	31336999	Furthermore, knockdown of PlncRNA-1 reduced cell proliferation and increased the apoptosis in vitro (Table 1).	('PlncRNA-1', 'Gene', '100506428', (26, 35))	('cell proliferation', 'CPA', (44, 62))	('apoptosis in vitro', 'CPA', (81, 99))	('PlncRNA-1', 'Gene', (26, 35))	('increased', 'PosReg', (67, 76))	('reduced', 'NegReg', (36, 43))	('knockdown', 'Var', (13, 22))
53611	31336999	As mutation hotspot, the c.713A>G/714T>C dinucleotide substitution was found among 89.1% patients with GAS8-AS1 mutations and associated with advanced PTC disease (p = 0.009).	('714T>C', 'SUBSTITUTION', 'None', (34, 40))	('dinucleotide', 'Chemical', 'MESH:D015226', (41, 53))	('associated with', 'Reg', (126, 141))	('PTC disease', 'Disease', (151, 162))	('mutations', 'Var', (112, 121))	('714T>C', 'Var', (34, 40))	('c.713A>G', 'Mutation', 'rs1182784713', (25, 33))	('patients', 'Species', '9606', (89, 97))	('PTC disease', 'Disease', 'MESH:D000077273', (151, 162))	('PTC', 'Phenotype', 'HP:0002895', (151, 154))	('GAS8', 'Gene', '2622', (103, 107))	('GAS8', 'Gene', (103, 107))
53612	31336999	Interestingly, the wild-type lncRNA GAS8-AS1 (A713T714) showed consistently higher capability to inhibit cancer cell growth compared to the mutated lncRNA (G713C714).	('inhibit', 'NegReg', (97, 104))	('A713T714', 'Var', (46, 54))	('ncRNA', 'Gene', '220202', (149, 154))	('GAS8', 'Gene', (36, 40))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('ncRNA', 'Gene', (30, 35))	('G713C714', 'Var', (156, 164))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('ncRNA', 'Gene', '220202', (30, 35))	('higher', 'PosReg', (76, 82))	('ncRNA', 'Gene', (149, 154))	('GAS8', 'Gene', '2622', (36, 40))
53613	31336999	Further studies also elucidated the oncogene nature of the G protein-coupled receptor LPAR4 and its c.872T>G (p.Ile291Ser) mutation in PTC malignant transformation.	('LPAR4', 'Gene', '2846', (86, 91))	('p.Ile291Ser', 'Mutation', 'p.I291S', (110, 121))	('c.872T>G', 'Mutation', 'c.872T>G', (100, 108))	('LPAR4', 'Gene', (86, 91))	('G protein-coupled receptor', 'Protein', (59, 85))	('PTC', 'Phenotype', 'HP:0002895', (135, 138))	('c.872T>G', 'Var', (100, 108))	('PTC', 'Gene', '8030', (135, 138))	('PTC', 'Gene', (135, 138))
53615	31336999	Furthermore, GAS8-AS1 mutations in PTC are associated with an advanced clinical stage (Table 1).	('GAS8', 'Gene', '2622', (13, 17))	('PTC', 'Gene', '8030', (35, 38))	('GAS8', 'Gene', (13, 17))	('mutations', 'Var', (22, 31))	('associated', 'Reg', (43, 53))	('PTC', 'Gene', (35, 38))	('PTC', 'Phenotype', 'HP:0002895', (35, 38))
53617	31336999	Furthermore, ADAMTS9-AS2 knockdown in TSCC cells leads to the inhibition of cell migration and invasion and reverses TGF-beta1 induced EMT.	('reverses', 'NegReg', (108, 116))	('TGF-beta1', 'Gene', '7040', (117, 126))	('TGF-beta1', 'Gene', (117, 126))	('ADAMTS9', 'Gene', '56999', (13, 20))	('EMT', 'CPA', (135, 138))	('ADAMTS9', 'Gene', (13, 20))	('inhibition', 'NegReg', (62, 72))	('knockdown', 'Var', (25, 34))	('SCC', 'Phenotype', 'HP:0002860', (39, 42))
53618	31336999	ADAMTS9-AS2 knockdown also inhibits TSCC cell growth in vitro and in vivo.	('TSCC cell growth', 'CPA', (36, 52))	('inhibits', 'NegReg', (27, 35))	('knockdown', 'Var', (12, 21))	('ADAMTS9', 'Gene', '56999', (0, 7))	('ADAMTS9', 'Gene', (0, 7))	('SCC', 'Phenotype', 'HP:0002860', (37, 40))
53625	31336999	Moreover, knockdown of ESCCAL-1 expression increases esophageal cancer cell apoptosis and reduces the invasion in vitro (Table 1).	('increases esophageal cancer', 'Disease', (43, 70))	('ESCCAL-1', 'Gene', '101805492', (23, 31))	('increases esophageal cancer', 'Disease', 'MESH:D004938', (43, 70))	('reduces', 'NegReg', (90, 97))	('SCC', 'Phenotype', 'HP:0002860', (24, 27))	('ESCCAL-1', 'Gene', (23, 31))	('knockdown', 'Var', (10, 19))	('invasion in vitro', 'CPA', (102, 119))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
53632	31336999	Moreover, lncRNA PVT1 could be enriched by EZH2, and silencing PVT1 resulted in the decreased recruitment of EZH2.	('recruitment', 'MPA', (94, 105))	('EZH2', 'Gene', (43, 47))	('ncRNA', 'Gene', '220202', (11, 16))	('PVT1', 'Gene', (17, 21))	('men', 'Species', '9606', (101, 104))	('EZH2', 'Gene', '2146', (43, 47))	('PVT1', 'Gene', (63, 67))	('ncRNA', 'Gene', (11, 16))	('silencing', 'Var', (53, 62))	('PVT1', 'Gene', '5820', (17, 21))	('EZH2', 'Gene', '2146', (109, 113))	('decreased', 'NegReg', (84, 93))	('PVT1', 'Gene', '5820', (63, 67))	('EZH2', 'Gene', (109, 113))
53636	31336999	The risk allele [A] of rs965513 was significantly associated with low expression of unspliced PTCSC2, FOXE1, and TSHR in unaffected thyroid tissue.	('PTCSC2', 'Gene', '101928337', (94, 100))	('FOXE1', 'Gene', '2304', (102, 107))	('PTCSC2', 'Gene', (94, 100))	('FOXE1', 'Gene', (102, 107))	('PTC', 'Phenotype', 'HP:0002895', (94, 97))	('expression', 'MPA', (70, 80))	('TSHR', 'Gene', '7253', (113, 117))	('low', 'NegReg', (66, 69))	('rs965513', 'Var', (23, 31))	('rs965513', 'Mutation', 'rs965513', (23, 31))	('TSHR', 'Gene', (113, 117))
53638	31336999	The correlation between the rs965513 genotype and the PTCSC2 unspliced transcript levels remained significant after adjusting for age, gender, and CLT.	('rs965513', 'Mutation', 'rs965513', (28, 36))	('rs965513', 'Var', (28, 36))	('PTCSC2', 'Gene', '101928337', (54, 60))	('PTC', 'Phenotype', 'HP:0002895', (54, 57))	('PTCSC2', 'Gene', (54, 60))
53640	31336999	Similarly, a unique, long, intergenic, noncoding RNA gene (lincRNA) named Papillary Thyroid Carcinoma Susceptibility Candidate 3 (PTCSC3) located 3.2 kb downstream of rs944289 at 14q.13.3 and its expression is strictly thyroid specific.	('rs944289', 'Var', (167, 175))	('ncRNA', 'Gene', (61, 66))	('Thyroid Carcinoma', 'Phenotype', 'HP:0002890', (84, 101))	('rs944289', 'Mutation', 'rs944289', (167, 175))	('PTCSC3', 'Gene', '100886964', (130, 136))	('PTCSC3', 'Gene', (130, 136))	('ncRNA', 'Gene', '220202', (61, 66))	('PTC', 'Phenotype', 'HP:0002895', (130, 133))	('Papillary Thyroid Carcinoma', 'Phenotype', 'HP:0002895', (74, 101))	('Papillary Thyroid Carcinoma Susceptibility Candidate 3', 'Gene', '100886964', (74, 128))	('Carcinoma', 'Phenotype', 'HP:0030731', (92, 101))
53642	31336999	The SNP rs944289 was located in a binding site for the CCAAT/enhancer binding proteins (C/EBP) alpha and beta.	('C/EBP) alpha', 'Gene', '1050', (88, 100))	('beta', 'Protein', (105, 109))	('rs944289', 'Mutation', 'rs944289', (8, 16))	('rs944289', 'Var', (8, 16))
53649	31336999	Thirty lncRNA transcripts were differentially expressed between TP53 mutated and TP53 wild type tumors.	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('ncRNA', 'Gene', (8, 13))	('mutated', 'Var', (69, 76))	('ncRNA', 'Gene', '220202', (8, 13))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('differentially', 'Reg', (31, 45))	('type tumors', 'Disease', 'MESH:D009369', (91, 102))	('TP53', 'Gene', '7157', (64, 68))	('TP53', 'Gene', (64, 68))	('type tumors', 'Disease', (91, 102))	('TP53', 'Gene', '7157', (81, 85))	('TP53', 'Gene', (81, 85))
53653	31336999	Both genomic excision of FIRRE locus and knockdown of hnRNPU shows decreased co-localization of these trans-chromosomal interacting loci.	('FIRRE', 'Gene', (25, 30))	('decreased', 'NegReg', (67, 76))	('hnRNPU', 'Gene', '3192', (54, 60))	('FIRRE', 'Gene', '286467', (25, 30))	('hnRNPU', 'Gene', (54, 60))	('co-localization', 'MPA', (77, 92))	('knockdown', 'Var', (41, 50))
53654	31336999	Thus, aberrant epigenetic alterations caused by deregulated FIRRE levels may represent a novel HNSCC oncogenic mechanism, which should be clarified in future experimental studies (Table 1).	('aberrant epigenetic alterations', 'Var', (6, 37))	('FIRRE', 'Gene', '286467', (60, 65))	('SCC', 'Phenotype', 'HP:0002860', (97, 100))	('HNSCC', 'Disease', (95, 100))	('FIRRE', 'Gene', (60, 65))	('deregulated', 'Var', (48, 59))	('HNSCC', 'Phenotype', 'HP:0012288', (95, 100))	('men', 'Species', '9606', (164, 167))
53659	31336999	The long non-coding RNA (lncRNA) H19 is overexpressed also in NPC tissues; knockdown of H19 significantly inhibited the invasive ability of NPC cells.	('invasive ability of NPC cells', 'CPA', (120, 149))	('ncRNA', 'Gene', (26, 31))	('inhibited', 'NegReg', (106, 115))	('knockdown', 'Var', (75, 84))	('H19', 'Gene', '283120', (88, 91))	('ncRNA', 'Gene', '220202', (26, 31))	('H19', 'Gene', '283120', (33, 36))	('NPC', 'Phenotype', 'HP:0100630', (62, 65))	('NPC', 'Phenotype', 'HP:0100630', (140, 143))	('H19', 'Gene', (88, 91))	('H19', 'Gene', (33, 36))
53664	31336999	The loss of MEG3 expression promotes tumor progression but its re-expression inhibits proliferation and induces apoptosis.	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('apoptosis', 'CPA', (112, 121))	('MEG3', 'Gene', (12, 16))	('proliferation', 'CPA', (86, 99))	('promotes', 'PosReg', (28, 36))	('MEG3', 'Gene', '55384', (12, 16))	('tumor', 'Disease', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('induces', 'Reg', (104, 111))	('re-expression', 'PosReg', (63, 76))	('inhibits', 'NegReg', (77, 85))	('loss', 'Var', (4, 8))
53671	31336999	DNA microarray analysis showed that several members of small proline rich proteins (SPRR) were up-regulated by knockdown of MALAT-1 in TSCC cells.	('knockdown', 'Var', (111, 120))	('SCC', 'Phenotype', 'HP:0002860', (136, 139))	('up-regulated', 'PosReg', (95, 107))	('MALAT-1', 'Gene', '378938', (124, 131))	('MALAT-1', 'Gene', (124, 131))
53673	31336999	Consequently, knockdown of MALAT-1 lncRNA in TSCC cells led to impaired migration and proliferation in vitro and less metastases in vivo (Table 1).	('ncRNA', 'Gene', (36, 41))	('impaired migration', 'Disease', 'MESH:D054081', (63, 81))	('less', 'NegReg', (113, 117))	('metastases', 'Disease', (118, 128))	('metastases', 'Disease', 'MESH:D009362', (118, 128))	('ncRNA', 'Gene', '220202', (36, 41))	('MALAT-1', 'Gene', '378938', (27, 34))	('SCC', 'Phenotype', 'HP:0002860', (46, 49))	('knockdown', 'Var', (14, 23))	('impaired migration', 'Disease', (63, 81))	('MALAT-1', 'Gene', (27, 34))
53675	31336999	An independent t-test identified that the expression level of lncRNA LOC541471 was significantly increased in tumor tissues compared to healthy tissues.	('expression level', 'MPA', (42, 58))	('increased', 'PosReg', (97, 106))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('ncRNA', 'Gene', (63, 68))	('ncRNA', 'Gene', '220202', (63, 68))	('LOC541471', 'Var', (69, 78))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
53676	31336999	Additionally, high lncRNA LOC541471 expression was significantly associated to increasing lymph node metastasis and perineural invasion.	('lymph node metastasis', 'CPA', (90, 111))	('increasing', 'PosReg', (79, 89))	('LOC541471', 'Var', (26, 35))	('ncRNA', 'Gene', (20, 25))	('high', 'Var', (14, 18))	('perineural invasion', 'CPA', (116, 135))	('ncRNA', 'Gene', '220202', (20, 25))	('expression', 'MPA', (36, 46))
53677	31336999	A multivariate Cox regression analysis revealed that high lncRNA LOC541471 expression was an independent predictor for reduced overall survival (n = 487) and relapse-free survival (n = 355).	('high', 'Var', (53, 57))	('ncRNA', 'Gene', (59, 64))	('LOC541471', 'Var', (65, 74))	('relapse-free survival', 'CPA', (158, 179))	('ncRNA', 'Gene', '220202', (59, 64))	('reduced', 'NegReg', (119, 126))	('overall survival', 'CPA', (127, 143))
53683	31336999	In human larynx squamous carcinoma cell lines, Hep-2R, lncRNA DiGeorge syndrome critical region gene 5 (DGCR5) is upregulated and microRNA-506 is down-regulated.	('DGCR5', 'Gene', (104, 109))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (16, 34))	('microRNA-506', 'Var', (130, 142))	('squamous carcinoma', 'Disease', 'MESH:D002294', (16, 34))	('DiGeorge syndrome critical region gene 5', 'Gene', '26220', (62, 102))	('human', 'Species', '9606', (3, 8))	('larynx squamous carcinoma', 'Phenotype', 'HP:0012118', (9, 34))	('carcinoma', 'Phenotype', 'HP:0030731', (25, 34))	('DGCR5', 'Gene', '26220', (104, 109))	('ncRNA', 'Gene', '220202', (56, 61))	('Hep-2R', 'CellLine', 'CVCL:1906', (47, 53))	('down-regulated', 'NegReg', (146, 160))	('ncRNA', 'Gene', (56, 61))	('upregulated', 'PosReg', (114, 125))	('squamous carcinoma', 'Disease', (16, 34))	('DiGeorge syndrome critical region gene 5', 'Gene', (62, 102))
53684	31336999	In addition, silencing of DGCR5 inhibited the stemness and enhanced the radiosensitivity of Hep-2R cells.	('DGCR5', 'Gene', '26220', (26, 31))	('inhibited', 'NegReg', (32, 41))	('enhanced', 'PosReg', (59, 67))	('radiosensitivity', 'CPA', (72, 88))	('Hep-2R', 'CellLine', 'CVCL:1906', (92, 98))	('DGCR5', 'Gene', (26, 31))	('stemness', 'Disease', 'MESH:D020295', (46, 54))	('silencing', 'Var', (13, 22))	('stemness', 'Disease', (46, 54))
53691	31336999	Using LC cell lines Hep-2 and AMC-HN-8, it was demonstrated that knockdown of PCAT19 decreased cell proliferation, increased mitochondrial respiration, and inhibited glycolysis.	('cell proliferation', 'CPA', (95, 113))	('PCAT19', 'Gene', (78, 84))	('decreased', 'NegReg', (85, 94))	('glycolysis', 'MPA', (166, 176))	('increased', 'PosReg', (115, 124))	('Hep-2', 'CellLine', 'CVCL:1906', (20, 25))	('PCAT19', 'Gene', '100505495', (78, 84))	('mitochondrial respiration', 'MPA', (125, 150))	('LC', 'Phenotype', 'HP:0012118', (6, 8))	('knockdown', 'Var', (65, 74))	('inhibited', 'NegReg', (156, 165))
53692	31336999	In detail, pyruvate dehydrogenase kinase 4 (PDK4) expression and PDHE1alpha phosphorylation levels were decreased upon PCAT19 knockdown.	('PDK4', 'Gene', (44, 48))	('PCAT19', 'Gene', (119, 125))	('PDHE1alpha phosphorylation levels', 'MPA', (65, 98))	('PCAT19', 'Gene', '100505495', (119, 125))	('decreased', 'NegReg', (104, 113))	('PDK4', 'Gene', '5166', (44, 48))	('pyruvate dehydrogenase kinase 4', 'Gene', '5166', (11, 42))	('knockdown', 'Var', (126, 135))	('pyruvate dehydrogenase kinase 4', 'Gene', (11, 42))	('expression', 'MPA', (50, 60))
53695	31336999	Finally, PCAT19 knockdown decreased the tumor growth in vivo, possibly by regulating the miR-182/PDK4 axis.	('regulating', 'Reg', (74, 84))	('miR-182', 'Gene', (89, 96))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('knockdown', 'Var', (16, 25))	('PDK4', 'Gene', '5166', (97, 101))	('miR-182', 'Gene', '406958', (89, 96))	('PDK4', 'Gene', (97, 101))	('PCAT19', 'Gene', (9, 15))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('decreased', 'NegReg', (26, 35))	('PCAT19', 'Gene', '100505495', (9, 15))
53702	31336999	The inhibition of LSCC progression induced by H19 knockdown required the activity of miR-148a-3p.	('miR', 'Gene', '220972', (85, 88))	('miR', 'Gene', (85, 88))	('activity', 'MPA', (73, 81))	('knockdown', 'Var', (50, 59))	('H19', 'Gene', '283120', (46, 49))	('H19', 'Gene', (46, 49))	('LSCC', 'Disease', (18, 22))	('inhibition', 'NegReg', (4, 14))	('SCC', 'Phenotype', 'HP:0002860', (19, 22))
53704	31336999	Cellular DNA methylation levels were inhibited by both miR-148a-3p overexpression and H19 knockdown.	('H19', 'Gene', '283120', (86, 89))	('knockdown', 'Var', (90, 99))	('inhibited', 'NegReg', (37, 46))	('overexpression', 'PosReg', (67, 81))	('H19', 'Gene', (86, 89))	('miR', 'Gene', '220972', (55, 58))	('miR', 'Gene', (55, 58))	('Cellular DNA methylation levels', 'MPA', (0, 31))
53715	31336999	The growth of LSCC xenograft was significantly inhibited in mice treated with NEAT1 siRNA lentivirus, compared with mice treated with GFP lentivirus.	('mice', 'Species', '10090', (116, 120))	('NEAT1', 'Var', (78, 83))	('inhibited', 'NegReg', (47, 56))	('growth of LSCC xenograft', 'CPA', (4, 28))	('mice', 'Species', '10090', (60, 64))	('SCC', 'Phenotype', 'HP:0002860', (15, 18))
53722	31336999	UCA1 overexpression promoted, whereas UCA1 knockdown inhibited the proliferation, migration and invasion of LSCC cells.	('SCC', 'Phenotype', 'HP:0002860', (109, 112))	('inhibited', 'NegReg', (53, 62))	('knockdown', 'Var', (43, 52))	('migration', 'CPA', (82, 91))	('promoted', 'PosReg', (20, 28))	('proliferation', 'CPA', (67, 80))	('UCA1', 'Gene', '652995', (0, 4))	('invasion of LSCC cells', 'CPA', (96, 118))	('UCA1', 'Gene', (0, 4))	('UCA1', 'Gene', '652995', (38, 42))	('UCA1', 'Gene', (38, 42))
53736	31336999	Moreover, a series of bioinformatics tools and in vitro experiments proved that knockdown of LINC00668 inhibited the proliferation, migration and invasion ability of LSCC cells (Table 2).	('men', 'Species', '9606', (62, 65))	('knockdown', 'Var', (80, 89))	('LINC00668', 'Gene', '400643', (93, 102))	('SCC', 'Phenotype', 'HP:0002860', (167, 170))	('proliferation', 'CPA', (117, 130))	('migration', 'CPA', (132, 141))	('inhibited', 'NegReg', (103, 112))	('LINC00668', 'Gene', (93, 102))	('invasion ability', 'CPA', (146, 162))	('LSCC cells', 'CPA', (166, 176))
53740	31336999	In addition, knockdown of SNHG1 inhibited LSCC growth and metastasis in vivo.	('SCC', 'Phenotype', 'HP:0002860', (43, 46))	('inhibited', 'NegReg', (32, 41))	('SNHG1', 'Gene', '23642', (26, 31))	('knockdown', 'Var', (13, 22))	('SNHG1', 'Gene', (26, 31))
53745	31336999	Furthermore, high TUG1 expression was positively associated with advanced T category, worse lymph node metastasis and late clinical stage.	('high', 'Var', (13, 17))	('TUG1', 'Gene', (18, 22))	('associated', 'Reg', (49, 59))	('TUG1', 'Gene', '55000', (18, 22))	('worse lymph node metastasis', 'CPA', (86, 113))	('advanced T category', 'CPA', (65, 84))	('expression', 'MPA', (23, 33))
53746	31336999	In vitro experiments with silencing of TUG1 demonstrated that it markedly inhibited viability, invasive and migratory properties of LC Hep-2 cells.	('LC', 'Phenotype', 'HP:0012118', (132, 134))	('inhibited', 'NegReg', (74, 83))	('Hep-2', 'CellLine', 'CVCL:1906', (135, 140))	('men', 'Species', '9606', (15, 18))	('TUG1', 'Gene', '55000', (39, 43))	('silencing', 'Var', (26, 35))	('viability', 'CPA', (84, 93))	('TUG1', 'Gene', (39, 43))
53756	31336999	Notably, LINC00460 expression in T1+T2 stages patients was significantly lower than T3+T4 stages (p < 0.05).	('T1+T2 stages', 'Var', (33, 45))	('expression', 'MPA', (19, 29))	('patients', 'Species', '9606', (46, 54))	('LINC00460', 'Gene', (9, 18))	('lower', 'NegReg', (73, 78))	('LINC00460', 'Gene', '728192', (9, 18))
53763	31336999	Interestingly, the LINC00520 level in LSCC with lymph node metastasis was significantly higher than that in patients without lymph node metastasis (p < 0.01).	('higher', 'PosReg', (88, 94))	('LINC00520', 'Gene', (19, 28))	('LSCC', 'Disease', (38, 42))	('patients', 'Species', '9606', (108, 116))	('lymph node metastasis', 'Var', (48, 69))	('LINC00520', 'Gene', '645687', (19, 28))	('SCC', 'Phenotype', 'HP:0002860', (39, 42))
53765	31336999	Interestingly, among them, 27 cases (27/40, 67.5%) had higher expression level of LOC554202 in PTC samples compared to the adjacent normal samples.	('PTC', 'Gene', '8030', (95, 98))	('PTC', 'Gene', (95, 98))	('expression level', 'MPA', (62, 78))	('PTC', 'Phenotype', 'HP:0002895', (95, 98))	('LOC554202', 'Var', (82, 91))	('higher', 'PosReg', (55, 61))
53766	31336999	Moreover, the LOC554202 expression was higher in patients with early stage LSCC than in advanced stage LSCC.	('higher', 'PosReg', (39, 45))	('LOC554202', 'Var', (14, 23))	('expression', 'MPA', (24, 34))	('early stage LSCC', 'Disease', (63, 79))	('SCC', 'Phenotype', 'HP:0002860', (104, 107))	('SCC', 'Phenotype', 'HP:0002860', (76, 79))	('patients', 'Species', '9606', (49, 57))
53767	31336999	LOC554202 expression inversely correlated with mi31 expression in LSCC tissues and in order to prove the mechanistic correlation between LOC554202 expression and biological functions in tumours, the LC Hep-2 cells were transfected with cDNA-LOC55420, causing cell growth and increase of percentage population in the S phase of the cell cycle.	('LOC554202', 'Gene', (0, 9))	('tumours', 'Disease', 'MESH:D009369', (186, 193))	('tumours', 'Disease', (186, 193))	('cDNA-LOC55420', 'Var', (236, 249))	('cell growth', 'CPA', (259, 270))	('LC', 'Phenotype', 'HP:0012118', (199, 201))	('Hep-2', 'CellLine', 'CVCL:1906', (202, 207))	('SCC', 'Phenotype', 'HP:0002860', (67, 70))	('causing', 'PosReg', (251, 258))	('tumours', 'Phenotype', 'HP:0002664', (186, 193))	('increase', 'PosReg', (275, 283))
53768	31336999	Opposite effects were caused by the ectopic overexpression of miR31 that was, in turn, down regulated by LOC554202 overexpression.	('miR31', 'Gene', '407035', (62, 67))	('miR31', 'Gene', (62, 67))	('down regulated', 'NegReg', (87, 101))	('LOC554202', 'Var', (105, 114))
53769	31336999	Therefore, a new loop among these two ncRNAs was found that associated LOC554202 with tumorigenic and aggressive phenotype of LSCC (Table 2).	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('SCC', 'Phenotype', 'HP:0002860', (127, 130))	('tumor', 'Disease', (86, 91))	('LSCC', 'Disease', (126, 130))	('ncRNA', 'Gene', (38, 43))	('LOC554202', 'Var', (71, 80))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('ncRNA', 'Gene', '220202', (38, 43))	('aggressive phenotype', 'CPA', (102, 122))
53773	31336999	Long noncoding RNA HOXA11 antisense RNA (HOXA11-AS) is involved in tumorigenesis and development of some human cancers.	('cancers', 'Disease', 'MESH:D009369', (111, 118))	('cancers', 'Phenotype', 'HP:0002664', (111, 118))	('cancers', 'Disease', (111, 118))	('HOXA11', 'Gene', (41, 47))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('antisense', 'Var', (26, 35))	('men', 'Species', '9606', (92, 95))	('involved', 'Reg', (55, 63))	('HOXA11-AS', 'Gene', (41, 50))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('HOXA11-AS', 'Gene', '221883', (41, 50))	('HOXA11', 'Gene', '3207', (19, 25))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('HOXA11', 'Gene', (19, 25))	('tumor', 'Disease', (67, 72))	('human', 'Species', '9606', (105, 110))	('HOXA11', 'Gene', '3207', (41, 47))
53776	31336999	Patients with T3-4 grade, neck nodal metastasis, or advanced clinical stage presented higher HOXA11-AS expression.	('neck nodal metastasis', 'CPA', (26, 47))	('Patients', 'Species', '9606', (0, 8))	('HOXA11-AS', 'Gene', (93, 102))	('HOXA11-AS', 'Gene', '221883', (93, 102))	('higher', 'PosReg', (86, 92))	('T3-4 grade', 'Var', (14, 24))
53777	31336999	Kaplan-Meier analysis showed that high HOXA11-AS expression could predict a poor prognosis in LSCC patients.	('patients', 'Species', '9606', (99, 107))	('high', 'Var', (34, 38))	('SCC', 'Phenotype', 'HP:0002860', (95, 98))	('LSCC', 'Disease', (94, 98))	('HOXA11-AS', 'Gene', (39, 48))	('HOXA11-AS', 'Gene', '221883', (39, 48))
53778	31336999	Furthermore, HOXA11-AS knockdown significantly inhibited the growth, migration, and invasion of LSCC cells.	('invasion of LSCC cells', 'CPA', (84, 106))	('inhibited', 'NegReg', (47, 56))	('HOXA11-AS', 'Gene', (13, 22))	('HOXA11-AS', 'Gene', '221883', (13, 22))	('knockdown', 'Var', (23, 32))	('SCC', 'Phenotype', 'HP:0002860', (97, 100))	('growth', 'CPA', (61, 67))
53783	31336999	Moreover, long non-coding RNA CCAT1 silencing inhibits xenograft tumor growth in vivo providing a promising therapeutic target for laryngeal squamous cell cancer patients (Table 2).	('patients', 'Species', '9606', (162, 170))	('tumor', 'Disease', (65, 70))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('laryngeal squamous cell cancer', 'Disease', 'MESH:D002294', (131, 161))	('inhibits', 'NegReg', (46, 54))	('laryngeal squamous cell cancer', 'Disease', (131, 161))	('CCAT1', 'Gene', '100507056', (30, 35))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (141, 161))	('silencing', 'Var', (36, 45))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('CCAT1', 'Gene', (30, 35))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
53791	31336999	LncRNAs NR027340, and SOX2-OT and their correlated mRNAs ITGB1, HIF1A, DDIT4 are overexpressed and identified as potential biomarkers in advanced LSCC.	('ITGB1', 'Gene', (57, 62))	('HIF1A', 'Gene', (64, 69))	('HIF1A', 'Gene', '3091', (64, 69))	('advanced LSCC', 'Disease', (137, 150))	('ncRNA', 'Gene', '220202', (1, 6))	('SCC', 'Phenotype', 'HP:0002860', (147, 150))	('DDIT4', 'Gene', (71, 76))	('SOX2-OT', 'Gene', (22, 29))	('ITGB1', 'Gene', '3688', (57, 62))	('NR027340', 'Var', (8, 16))	('DDIT4', 'Gene', '54541', (71, 76))	('SOX2-OT', 'Gene', '347689', (22, 29))	('ncRNA', 'Gene', (1, 6))
53794	31336999	On the other hand, HOTAIR knockdown reduces tumor invasion and increases cell apoptosis in vitro and inhibits LSCC xenograft growth in vivo.	('cell apoptosis', 'CPA', (73, 87))	('increases', 'PosReg', (63, 72))	('HOTAIR', 'Gene', (19, 25))	('LSCC xenograft growth in vivo', 'CPA', (110, 139))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('knockdown', 'Var', (26, 35))	('HOTAIR', 'Gene', '100124700', (19, 25))	('reduces', 'NegReg', (36, 43))	('inhibits', 'NegReg', (101, 109))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('SCC', 'Phenotype', 'HP:0002860', (111, 114))	('tumor', 'Disease', (44, 49))
53795	31336999	HOTAIR serves as an oncogene by inducing hypermethylation of CpG islands in the PTEN gene, reducing the expression of PTEN at mRNA and protein level.	('hypermethylation', 'Var', (41, 57))	('HOTAIR', 'Gene', '100124700', (0, 6))	('PTEN', 'Gene', (80, 84))	('reducing', 'NegReg', (91, 99))	('PTEN', 'Gene', '5728', (80, 84))	('PTEN', 'Gene', '5728', (118, 122))	('PTEN', 'Gene', (118, 122))	('inducing', 'Reg', (32, 40))	('expression', 'MPA', (104, 114))	('HOTAIR', 'Gene', (0, 6))
53798	31336999	HOTAIR expression silencing stimulates EZH2 expressing, promotes the cell proliferation, and increased the sensitivity to cis-platinum of the LSCC cells (Table 2).	('HOTAIR', 'Gene', '100124700', (0, 6))	('SCC', 'Phenotype', 'HP:0002860', (143, 146))	('silencing', 'Var', (18, 27))	('sensitivity to cis-platinum', 'MPA', (107, 134))	('expressing', 'MPA', (44, 54))	('increased', 'PosReg', (93, 102))	('stimulates', 'PosReg', (28, 38))	('cell proliferation', 'CPA', (69, 87))	('promotes', 'PosReg', (56, 64))	('HOTAIR', 'Gene', (0, 6))	('cis-platinum', 'Chemical', 'MESH:D002945', (122, 134))	('EZH2', 'Gene', (39, 43))	('EZH2', 'Gene', '2146', (39, 43))
53801	31336999	Recognized as a genome disease, cancer can be caused by mutations, amplifications, deletions or deregulation of genomic products.	('deregulation', 'Var', (96, 108))	('mutations', 'Var', (56, 65))	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('genome disease', 'Disease', (16, 30))	('cancer', 'Disease', (32, 38))	('deletions', 'Var', (83, 92))	('caused', 'Reg', (46, 52))	('genome disease', 'Disease', 'MESH:D042822', (16, 30))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('amplifications', 'Var', (67, 81))
53805	31336999	Based on the target genes, recent studies suggest that lncRNAs are implicated in numerous biological processes such as cell cycle control, apoptosis, development and differentiation, as well as in epigenetic regulation of gene expression.	('implicated', 'Reg', (67, 77))	('development', 'CPA', (150, 161))	('epigenetic regulation', 'Var', (197, 218))	('cell cycle', 'CPA', (119, 129))	('differentiation', 'CPA', (166, 181))	('men', 'Species', '9606', (157, 160))	('ncRNA', 'Gene', (56, 61))	('apoptosis', 'CPA', (139, 148))	('ncRNA', 'Gene', '220202', (56, 61))
53807	31336999	In fact, the aberrant expression of lncRNAs in different tumor types has been correlated with the specific bio-pathological characteristics of the tumor itself, the outcome of the disease and the response to pharmacological treatments.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('ncRNA', 'Gene', (37, 42))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('ncRNA', 'Gene', '220202', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('men', 'Species', '9606', (229, 232))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('correlated', 'Reg', (78, 88))	('tumor', 'Disease', (57, 62))	('aberrant', 'Var', (13, 21))
53815	31336999	Cells with MALAT1 deficiency exhibited severe migration deficits.	('migration deficits', 'Disease', (46, 64))	('migration deficits', 'Disease', 'MESH:D014085', (46, 64))	('MALAT1', 'Gene', (11, 17))	('deficiency', 'Var', (18, 28))
53816	31336999	In a murine model of metastasis MALAT1 knock down significantly reduced tumor nodules in number and size.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Disease', (72, 77))	('murine', 'Species', '10090', (5, 11))	('knock down', 'Var', (39, 49))	('reduced', 'NegReg', (64, 71))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('MALAT1', 'Gene', (32, 38))
53817	31336999	Also, the alternative inhibition of MALAT1 in cells by means of antisense oligonucleotides caused a drastic reduction of metastasis.	('metastasis', 'CPA', (121, 131))	('oligonucleotides', 'Chemical', 'MESH:D009841', (74, 90))	('inhibition', 'NegReg', (22, 32))	('antisense oligonucleotides', 'Var', (64, 90))	('reduction', 'NegReg', (108, 117))
53835	31375661	Recent technological and computational advances in genomics and systems biology have now made it possible to identify new druggable targets and therapeutic agents by uniquely targeting cancer type-specific mechanisms (e.g., perturbed pathways in the disease module) that cause or contribute to human disease.	('human', 'Species', '9606', (294, 299))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('contribute', 'Reg', (280, 290))	('pathways', 'Pathway', (234, 242))	('perturbed', 'Var', (224, 233))	('cause', 'Reg', (271, 276))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('cancer', 'Disease', (185, 191))	('human disease', 'Disease', (294, 307))
53843	31375661	Yet, whether the mutant proteins directly derived from individual patient sequencing data (e.g., whole-exome sequencing) form a statistically significant module in the human protein-protein interactome (or subnetwork in a disease module) remains unknown.	('proteins', 'Protein', (24, 32))	('human', 'Species', '9606', (168, 173))	('mutant', 'Var', (17, 23))	('patient', 'Species', '9606', (66, 73))
53915	31375661	Moreover, knockdown of HIF1A by two distinct shRNAs reduces the response of ouabain in A549 cells approximately 17-fold (Fig.	('A549', 'CellLine', 'CVCL:0023', (87, 91))	('reduces', 'NegReg', (52, 59))	('ouabain', 'Chemical', 'MESH:D010042', (76, 83))	('HIF1A', 'Gene', (23, 28))	('knockdown', 'Var', (10, 19))	('HIF1A', 'Gene', '3091', (23, 28))	('response of ouabain', 'MPA', (64, 83))
53933	31375661	However, patients treated with those targeted agents often develop drug resistance due to clinically actionable genetic and epigenetic events in individuals, with survival typically prolonged by only a few months.	('patients', 'Species', '9606', (9, 17))	('drug resistance', 'MPA', (67, 82))	('genetic', 'Var', (112, 119))	('develop', 'Reg', (59, 66))	('drug resistance', 'Phenotype', 'HP:0020174', (67, 82))	('epigenetic events', 'Var', (124, 141))
53963	31375661	After extracting the bioactivity data related to the drugs from the prepared bioactivity databases, only those items meeting the following four criteria were retained: (i) binding affinities, including Ki, Kd, IC50, or EC50, <=10 muM; (ii) proteins represented by unique UniProt accession number; (iii) proteins marked as "reviewed" in the UniProt database; and (iv) proteins of human origin.	('IC50', 'Var', (210, 214))	('muM', 'Gene', '56925', (230, 233))	('binding', 'Interaction', (172, 179))	('EC50', 'Var', (219, 223))	('muM', 'Gene', (230, 233))	('<=10', 'Var', (225, 229))	('human', 'Species', '9606', (379, 384))
53995	31375661	: CY5197, 1:1000 dilution), purchased from Abways Technology (Shanghai, China); and anti-LEO1 (Catalog No.	('LEO1', 'Gene', (89, 93))	('CY5197', 'Var', (2, 8))	('LEO1', 'Gene', '123169', (89, 93))
54003	31375661	HIF1A knockdown was confirmed by a RT-qPCR.	('knockdown', 'Var', (6, 15))	('HIF1A', 'Gene', '3091', (0, 5))	('HIF1A', 'Gene', (0, 5))
54074	30564890	We previously identified a head and neck squamous cell carcinoma with human papilloma virus integration in the PD-L1 locus upstream of the transmembrane domain-encoding region, suggesting expression of a truncated form of PD-L1.	('carcinoma', 'Phenotype', 'HP:0030731', (55, 64))	('integration', 'Var', (92, 103))	('neck squamous cell carcinoma', 'Disease', 'MESH:C535575', (36, 64))	('neck squamous cell carcinoma', 'Disease', (36, 64))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (27, 64))	('PD-L1', 'Gene', (111, 116))	('human papilloma virus', 'Species', '10566', (70, 91))	('papilloma', 'Phenotype', 'HP:0012740', (76, 85))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (41, 64))
54078	30564890	Overall, we have demonstrated that truncated forms of PD-L1 exist in numerous cancer types, and have validated that truncated PD-L1 can be secreted and negatively regulate T cell function.	('regulate', 'Reg', (163, 171))	('PD-L1', 'Gene', (54, 59))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('negatively', 'NegReg', (152, 162))	('PD-L1', 'Gene', (126, 131))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('T cell function', 'CPA', (172, 187))	('truncated', 'Var', (116, 125))
54083	30564890	Although there has been considerable success in treating patients using anti-PD-1/PD-L1 therapies, only a subset of patients respond to this treatment and our knowledge of the diverse mechanisms driving cancer immune evasion is limited.	('anti-PD-1/PD-L1', 'Var', (72, 87))	('patients', 'Species', '9606', (57, 65))	('patients', 'Species', '9606', (116, 124))	('cancer', 'Disease', (203, 209))	('cancer', 'Disease', 'MESH:D009369', (203, 209))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))
54088	30564890	HPV E6 and E7) and induce immune tolerance to prevent an anti-tumor T cell response to viral antigens.	('prevent', 'NegReg', (46, 53))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', (62, 67))	('E7', 'Var', (11, 13))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
54089	30564890	One recently reported mechanism governing anti-viral immune escape is PD-L1/PD-L2 locus amplification in Epstein-Barr virus (EBV) associated lymphomas and gastric cancers, as well as PD-L1 overexpression with HPV infection in head and neck cancer.	('lymphomas', 'Disease', 'MESH:D008223', (141, 150))	('PD-L2', 'Gene', '80380', (76, 81))	('gastric cancer', 'Phenotype', 'HP:0012126', (155, 169))	('lymphomas', 'Phenotype', 'HP:0002665', (141, 150))	('head and neck cancer', 'Phenotype', 'HP:0012288', (226, 246))	('PD-L1', 'Gene', (183, 188))	('PD-L2', 'Gene', (76, 81))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('Epstein-Barr virus', 'Disease', (105, 123))	('locus amplification', 'Var', (82, 101))	('Epstein-Barr virus', 'Disease', 'MESH:D020031', (105, 123))	('lymphomas', 'Disease', (141, 150))	('amplification', 'Var', (88, 101))	('HPV infection in head and neck cancer', 'Disease', 'MESH:D006258', (209, 246))	('cancers', 'Phenotype', 'HP:0002664', (163, 170))	('EBV', 'Disease', (125, 128))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('gastric cancers', 'Disease', 'MESH:D013274', (155, 170))	('overexpression', 'PosReg', (189, 203))	('gastric cancers', 'Disease', (155, 170))	('gastric cancers', 'Phenotype', 'HP:0012126', (155, 170))	('EBV', 'Disease', 'MESH:D020031', (125, 128))
54090	30564890	We previously reported pan-cancer computational analyses of HPV integration sites in the human genome, and while we did not observe amplification of PD-L1/PD-L2 in HPV-associated cancers, we did identify a novel potential mechanism of immune evasion represented by a case in which integration of HPV into the CD274 (PD-L1) locus between exons 4 and 5 drove overexpression of the 5' exons (exons 1-4) of PD-L1, suggesting the production of a truncated form of PD-L1.	('PD-L1', 'Gene', (403, 408))	('immune evasion', 'MPA', (235, 249))	('PD-L2', 'Gene', (155, 160))	('PD-L2', 'Gene', '80380', (155, 160))	('human', 'Species', '9606', (89, 94))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('overexpression', 'PosReg', (357, 371))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('cancers', 'Disease', 'MESH:D009369', (179, 186))	('cancer', 'Disease', (27, 33))	('integration', 'Var', (281, 292))	('cancers', 'Phenotype', 'HP:0002664', (179, 186))	('cancer', 'Disease', 'MESH:D009369', (27, 33))	('cancers', 'Disease', (179, 186))	('cancer', 'Disease', (179, 185))
54168	30564890	We next sought to further define the localization of truncated PD-L1 using the HEK293T cell line model which does not express detectable baseline PD-L1.	('truncated', 'Var', (53, 62))	('PD-L1', 'Gene', (63, 68))	('HEK293T', 'CellLine', 'CVCL:0063', (79, 86))
54179	30564890	IL-2 levels were found to be decreased with sec-PD-L1-long incubation in a dose dependent manner, with a 1.2 and 1.4 fold decrease in IL2 secretion with 20ug/ml and 40ug/ml sec-PD-L1-long incubation, respectively (Fig.	('IL-2', 'Gene', (0, 4))	('IL-2', 'Gene', '3558', (0, 4))	('IL2', 'Gene', '3558', (134, 137))	('decrease', 'NegReg', (122, 130))	('sec-PD-L1-long', 'Var', (173, 187))	('IL2', 'Gene', (134, 137))	('decreased', 'NegReg', (29, 38))	('sec-PD-L1-long', 'Var', (44, 58))
54182	30564890	In this study we extended observations made in our previous computational analysis of genomic sites of HPV integration, where we identified HPV integration in the PD-L1 locus in a HNSCC tumor, suggesting expression of a truncated form of PD-L1.	('PD-L1', 'Gene', (163, 168))	('HNSCC tumor', 'Disease', 'MESH:C535575', (180, 191))	('HNSCC tumor', 'Disease', (180, 191))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('integration', 'Var', (144, 155))
54183	30564890	We performed computational de novo assembly of this truncated form that led to the identification of a novel expressed PD-L1 variant and identified additional truncated forms of PD-L1 in multiple human cancers and cancer cell lines.	('variant', 'Var', (125, 132))	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('cancer', 'Disease', (214, 220))	('human', 'Species', '9606', (196, 201))	('PD-L1', 'Gene', (119, 124))	('cancer', 'Disease', 'MESH:D009369', (202, 208))	('cancers', 'Phenotype', 'HP:0002664', (202, 209))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('cancer', 'Disease', (202, 208))	('cancers', 'Disease', (202, 209))	('cancers', 'Disease', 'MESH:D009369', (202, 209))	('cancer', 'Disease', 'MESH:D009369', (214, 220))
54185	30564890	In their work, titled "A secreted PD-L1 splice variant that covalently dimerizes and mediates immunosuppression", the authors describe a similarly-spliced variant of PD-L1 with a readthrough into the fourth intron, which negatively effects T cell function and is widely expressed in various human cancers as well as normal tissues.	('cancers', 'Disease', 'MESH:D009369', (297, 304))	('cancers', 'Phenotype', 'HP:0002664', (297, 304))	('negatively effects', 'NegReg', (221, 239))	('cancers', 'Disease', (297, 304))	('cancer', 'Phenotype', 'HP:0002664', (297, 303))	('variant', 'Var', (155, 162))	('PD-L1', 'Gene', (166, 171))	('T cell function', 'CPA', (240, 255))	('human', 'Species', '9606', (291, 296))
54193	30564890	Circulating PD-L1 in patients could be short secreted versions lacking the transmembrane domain similar to that described herein, cleaved extracellular PDL-L1 as described by others, or even full-length PD-L1 in exosomes.	('transmembrane domain', 'MPA', (75, 95))	('lacking', 'NegReg', (63, 70))	('patients', 'Species', '9606', (21, 29))	('cleaved', 'Var', (130, 137))	('PDL-L1', 'Gene', (152, 158))
54194	30564890	Nevertheless, there have been mixed reports on the implications of circulating PD-L1 on the prognosis of patients.	('PD-L1', 'Gene', (79, 84))	('patients', 'Species', '9606', (105, 113))	('circulating', 'Var', (67, 78))
54199	30564890	Our experiments using human T cell blasts to measure the effect of sec-PD-L1-long on T cell function did support that there is a preservation of a negative regulatory effect of sec-PD-L1-long on T cells.	('human', 'Species', '9606', (22, 27))	('sec-PD-L1-long', 'Var', (177, 191))	('negative regulatory effect', 'MPA', (147, 173))
54206	29577639	Overexpression of stathmin-1 has been observed to be associated with metastasis, poor prognosis, and chemoresistance in various human cancers.	('metastasis', 'CPA', (69, 79))	('cancers', 'Disease', 'MESH:D009369', (134, 141))	('cancers', 'Phenotype', 'HP:0002664', (134, 141))	('chemoresistance', 'CPA', (101, 116))	('cancers', 'Disease', (134, 141))	('stathmin-1', 'Gene', (18, 28))	('stathmin-1', 'Gene', '3925', (18, 28))	('poor prognosis', 'CPA', (81, 95))	('Overexpression', 'Var', (0, 14))	('associated', 'Reg', (53, 63))	('human', 'Species', '9606', (128, 133))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
54242	29577639	Subsequently, 100 muL of 3P9, 1B16-B, 3B19-B or commercial rabbit anti-stathmin-1 antibody (Cat.	('rabbit', 'Species', '9986', (59, 65))	('muL', 'Gene', '4591', (18, 21))	('3B19-B', 'Var', (38, 44))	('muL', 'Gene', (18, 21))	('stathmin-1', 'Gene', (71, 81))	('stathmin-1', 'Gene', '3925', (71, 81))
54313	29577639	Actually, stathmin-1 knockdown had been found to cause cell cycle arrest and promote apoptosis in numerous tumors 31.	('promote', 'PosReg', (77, 84))	('arrest', 'Disease', 'MESH:D006323', (66, 72))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('arrest', 'Disease', (66, 72))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('apoptosis', 'CPA', (85, 94))	('stathmin-1', 'Gene', (10, 20))	('numerous tumors', 'Disease', (98, 113))	('stathmin-1', 'Gene', '3925', (10, 20))	('numerous tumors', 'Disease', 'MESH:D009369', (98, 113))	('knockdown', 'Var', (21, 30))	('cause', 'PosReg', (49, 54))
54324	29577639	The analysis further indicated that malignant cells, which aberrantly overexpressed stathmin-1, produce oncogenic exosomes, leading to raised levels of stathmin-1 in serum.	('aberrantly', 'Var', (59, 69))	('raised', 'PosReg', (135, 141))	('overexpressed', 'PosReg', (70, 83))	('stathmin-1', 'Gene', (84, 94))	('oncogenic exosomes', 'MPA', (104, 122))	('stathmin-1', 'Gene', (152, 162))	('stathmin-1', 'Gene', '3925', (152, 162))	('stathmin-1', 'Gene', '3925', (84, 94))
54365	26172508	Intracellular pH changes reverse the inhibitory interaction of cofilin and cortactin, allowing cofilin to sever F-actin, which induces actin polymerization, leading to membrane protrusion at invadopodia.	('cofilin', 'Gene', '1072', (63, 70))	('induces', 'Reg', (127, 134))	('changes', 'Var', (17, 24))	('cortactin', 'Gene', (75, 84))	('cofilin', 'Gene', (63, 70))	('leading to', 'Reg', (157, 167))	('actin polymerization', 'MPA', (135, 155))	('cofilin', 'Gene', '1072', (95, 102))	('cortactin', 'Gene', '2017', (75, 84))	('membrane protrusion', 'MPA', (168, 187))	('cofilin', 'Gene', (95, 102))
54405	26172508	927-40000 [LI-COR Biosciences]) for 1 hour at room temperature and incubated with primary antibodies (beta-tubulin [1:1000] and Tks5 [1:1000] or cortactin [1:1000]; beta-actin [1:20 000] and fascin [1:1000]) overnight at 4 C. The membranes were washed 3 times with 1x Tris Buffered Saline-Tween (TBS-T) and incubated with secondary antibodies (IRDye 680RD anti-mouse and IRDye 800CW anti-rabbit [1:5000]) for 1 hour at room temperature.	('Tks5', 'Gene', '9644', (128, 132))	('Tks5', 'Gene', (128, 132))	('fascin', 'Gene', (191, 197))	('cortactin', 'Gene', (145, 154))	('TBS-T', 'Disease', (296, 301))	('cortactin', 'Gene', '2017', (145, 154))	('IRDye', 'Var', (344, 349))	('mouse', 'Species', '10090', (361, 366))	('beta-actin', 'Gene', '728378', (165, 175))	('rabbit', 'Species', '9986', (388, 394))	('beta-actin', 'Gene', (165, 175))	('TBS-T', 'Disease', 'MESH:D001260', (296, 301))	('fascin', 'Gene', '6624', (191, 197))
54423	26172508	TaqMan Gene Expression assays used were Hs00160519_m1 (kallikrein 6, KLK6), Hs00173611_m1 (kallikrein 10, KLK10), Hs00234579_m1 (matrix metalloproteinase 9, MMP9) and Hs99999905_m1 (glyceraldehyde 3-phosphate dehydrogenase, GAPDH).	('glyceraldehyde 3-phosphate dehydrogenase', 'Gene', '2597', (182, 222))	('glyceraldehyde 3-phosphate dehydrogenase', 'Gene', (182, 222))	('kallikrein 6', 'Gene', '5653', (55, 67))	('Hs00160519_m1', 'Var', (40, 53))	('kallikrein 10', 'Gene', (91, 104))	('KLK6', 'Gene', '5653', (69, 73))	('KLK6', 'Gene', (69, 73))	('MMP9', 'Gene', (157, 161))	('MMP9', 'Gene', '4318', (157, 161))	('GAPDH', 'Gene', '2597', (224, 229))	('matrix metalloproteinase 9', 'Gene', (129, 155))	('kallikrein 6', 'Gene', (55, 67))	('Hs00173611_m1', 'Var', (76, 89))	('matrix metalloproteinase 9', 'Gene', '4318', (129, 155))	('KLK10', 'Gene', (106, 111))	('GAPDH', 'Gene', (224, 229))	('Hs00234579_m1', 'Var', (114, 127))	('KLK10', 'Gene', '5655', (106, 111))	('kallikrein 10', 'Gene', '5655', (91, 104))	('Hs99999905_m1', 'Var', (167, 180))
54441	26172508	OSC19 cells with increased miR-375 expression showed an 81% reduction in the number of mature invadopodia per cell, as well as a 48% reduction in invadopodium precursors, compared to OSC19 control cells (Figure 2, A through H).	('invadopodium precursors', 'CPA', (146, 169))	('increased', 'PosReg', (17, 26))	('miR-375', 'Gene', (27, 34))	('OSC19', 'CellLine', 'CVCL:3086', (183, 188))	('reduction', 'NegReg', (133, 142))	('reduction', 'NegReg', (60, 69))	('OSC19', 'CellLine', 'CVCL:3086', (0, 5))	('miR-375', 'Gene', '494324', (27, 34))	('expression', 'Var', (35, 45))
54462	26172508	In the conditioned medium from UMSCC1 cells with increased expression of miR-375 there was also significant reductions in the secreted levels of MMP-9 and ADAMTS-1, which were diminished by 70% and 64%, respectively (Figure 6, A and B).	('reductions', 'NegReg', (108, 118))	('UMSCC1', 'CellLine', 'CVCL:7707', (31, 37))	('miR-375', 'Gene', (73, 80))	('increased', 'PosReg', (49, 58))	('MMP-9', 'Gene', (145, 150))	('MMP-9', 'Gene', '4318', (145, 150))	('ADAMTS-1', 'Gene', (155, 163))	('ADAMTS-1', 'Gene', '9510', (155, 163))	('diminished', 'NegReg', (176, 186))	('miR-375', 'Gene', '494324', (73, 80))	('expression', 'Var', (59, 69))
54500	26172508	In HNSCC cells with regulated (wild-type) PI3 kinase activity, protein kinase C alpha stimulates invadopodium formation.	('HNSCC', 'Phenotype', 'HP:0012288', (3, 8))	('invadopodium formation', 'CPA', (97, 119))	('stimulates', 'PosReg', (86, 96))	('protein kinase C alpha', 'Gene', '5578', (63, 85))	('protein kinase C alpha', 'Gene', (63, 85))	('PI3', 'Var', (42, 45))
54523	26172508	The promoters of kallikrein 5, kallikrein 6, kallikrein 10, kallikrein 11, and kallikrein 12 are epigenetically regulated by DNA methylation.	('kallikrein 11', 'Gene', (60, 73))	('kallikrein 12', 'Gene', (79, 92))	('kallikrein 10', 'Gene', (45, 58))	('kallikrein 6', 'Gene', '5653', (31, 43))	('promoters', 'MPA', (4, 13))	('kallikrein 5', 'Gene', (17, 29))	('kallikrein 11', 'Gene', '11012', (60, 73))	('kallikrein 10', 'Gene', '5655', (45, 58))	('kallikrein 12', 'Gene', '43849', (79, 92))	('kallikrein 5', 'Gene', '25818', (17, 29))	('kallikrein 6', 'Gene', (31, 43))	('DNA methylation', 'Var', (125, 140))
54534	26295053	EPHX1 Tyr113His, XPD C156A, and GSTT1 null genotypes were associated with skin cancer risk (OR = 2.99, 95% CI = 1.01-8.83; OR = 2.04, 95% CI = 0.99-4.27; OR = 1.74, 95% CI = 1.00-3.02, resp.).	('Tyr113His', 'SUBSTITUTION', 'None', (6, 15))	('XPD', 'Gene', (17, 20))	('Tyr113His', 'Var', (6, 15))	('skin cancer', 'Disease', (74, 85))	('GSTT1', 'Gene', (32, 37))	('associated', 'Reg', (58, 68))	('EPHX1', 'Gene', (0, 5))	('GSTT1', 'Gene', '2952', (32, 37))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('XPD', 'Gene', '2068', (17, 20))	('skin cancer', 'Disease', 'MESH:D012878', (74, 85))	('EPHX1', 'Gene', '2052', (0, 5))	('skin cancer', 'Phenotype', 'HP:0008069', (74, 85))	('C156A', 'Mutation', 'rs238406', (21, 26))
54536	26295053	Individuals carrying three risk polymorphisms of EPHX1 Tyr113His, XPD C156A, and GSTs presented a 400% increased skin cancer risk when compared to those with less than or equal to one polymorphism.	('C156A', 'Mutation', 'rs238406', (70, 75))	('skin cancer', 'Phenotype', 'HP:0008069', (113, 124))	('XPD', 'Gene', (66, 69))	('increased', 'PosReg', (103, 112))	('GSTs', 'Gene', '373156', (81, 85))	('EPHX1', 'Gene', '2052', (49, 54))	('skin cancer', 'Disease', (113, 124))	('Tyr113His', 'Var', (55, 64))	('Tyr113His', 'SUBSTITUTION', 'None', (55, 64))	('skin cancer', 'Disease', 'MESH:D012878', (113, 124))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('XPD', 'Gene', '2068', (66, 69))	('EPHX1', 'Gene', (49, 54))	('GSTs', 'Gene', (81, 85))
54549	26295053	Genetic factors, nutritional status, ethnicity, an early age of exposure and variations in arsenic biotransformation are all potentially responsible for differences in individual susceptibility to arsenic-induced skin carcinogenesis.	('variations', 'Var', (77, 87))	('skin carcinogenesis', 'Disease', (213, 232))	('responsible', 'Reg', (137, 148))	('arsenic', 'Chemical', 'MESH:D001151', (197, 204))	('arsenic', 'Chemical', 'MESH:D001151', (91, 98))	('skin carcinogenesis', 'Disease', 'MESH:D063646', (213, 232))
54552	26295053	Arsenic has been demonstrated to induce ROS formation in many cell types and thus cause DNA damage, protein modification, and lipid peroxidation in these cells.	('ROS formation', 'MPA', (40, 53))	('lipid', 'Chemical', 'MESH:D008055', (126, 131))	('cause', 'Reg', (82, 87))	('ROS', 'Phenotype', 'HP:0025464', (40, 43))	('DNA damage', 'MPA', (88, 98))	('Arsenic', 'Chemical', 'MESH:D001151', (0, 7))	('protein modification', 'MPA', (100, 120))	('Arsenic', 'Var', (0, 7))	('lipid peroxidation', 'MPA', (126, 144))	('induce', 'Reg', (33, 39))	('ROS', 'Chemical', 'MESH:D017382', (40, 43))
54558	26295053	Our previous studies have shown that shorter (GT)n repeats of HO-1 were associated with reduced arsenic-associated carotid atherosclerosis and cardiovascular mortality.	('cardiovascular mortality', 'CPA', (143, 167))	('arsenic', 'Chemical', 'MESH:D001151', (96, 103))	('HO-1', 'Gene', '3162', (62, 66))	('carotid atherosclerosis', 'Disease', 'MESH:D002340', (115, 138))	('atherosclerosis', 'Phenotype', 'HP:0002621', (123, 138))	('shorter', 'Var', (37, 44))	('carotid atherosclerosis', 'Disease', (115, 138))	('reduced', 'NegReg', (88, 95))	('HO-1', 'Gene', (62, 66))
54559	26295053	One meta-analysis suggests that longer HO-1 (GT)n repeats are potential genetic factors for developing squamous cell carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (103, 126))	('squamous cell carcinoma', 'Disease', (103, 126))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (103, 126))	('HO-1', 'Gene', (39, 43))	('HO-1', 'Gene', '3162', (39, 43))	('longer', 'Var', (32, 38))
54561	26295053	The C609T (Pro187Ser) polymorphism has been shown to have strong impact on gene product stability and enzyme activity.	('C609T', 'Mutation', 'rs1800566', (4, 9))	('activity', 'MPA', (109, 117))	('Pro187Ser', 'Chemical', '-', (11, 20))	('C609T', 'Var', (4, 9))	('gene product stability', 'CPA', (75, 97))	('impact', 'Reg', (65, 71))
54562	26295053	One comprehensive meta-analysis involving 92 studies suggests that C609T is an important genetic factor for overall cancer risk as well as bladder and gastric cancer risk.	('cancer', 'Disease', (159, 165))	('gastric cancer', 'Phenotype', 'HP:0012126', (151, 165))	('bladder', 'Disease', (139, 146))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('C609T', 'Var', (67, 72))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('gastric cancer', 'Disease', (151, 165))	('C609T', 'Mutation', 'rs1800566', (67, 72))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('gastric cancer', 'Disease', 'MESH:D013274', (151, 165))
54565	26295053	The T337G Tyr113His and A415G His139Arg polymorphisms have been reported associated with 40% decreased and 25% increased enzyme activity.	('His139Arg', 'SUBSTITUTION', 'None', (30, 39))	('increased', 'PosReg', (111, 120))	('Tyr113His', 'SUBSTITUTION', 'None', (10, 19))	('T337G', 'SUBSTITUTION', 'None', (4, 9))	('A415G', 'Var', (24, 29))	('A415G', 'SUBSTITUTION', 'None', (24, 29))	('decreased', 'NegReg', (93, 102))	('T337G', 'Var', (4, 9))	('enzyme activity', 'MPA', (121, 136))	('Tyr113His', 'Var', (10, 19))	('His139Arg', 'Var', (30, 39))
54566	26295053	Polymorphisms in DNA repair genes may result in differential DNA repair activity and further contribute to individual susceptibility for various cancer developments.	('cancer', 'Disease', (145, 151))	('DNA repair genes', 'Gene', (17, 33))	('DNA repair activity', 'MPA', (61, 80))	('Polymorphisms', 'Var', (0, 13))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('result in', 'Reg', (38, 47))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('contribute to', 'Reg', (93, 106))
54568	26295053	Several SNPs in the XRCC1 have been reported for amino acid changes, including Arg399Gln G>A and Arg280His G>A.	('Arg399Gln', 'Var', (79, 88))	('Arg399Gln', 'SUBSTITUTION', 'None', (79, 88))	('Arg280His', 'SUBSTITUTION', 'None', (97, 106))	('XRCC1', 'Gene', (20, 25))	('Arg280His', 'Var', (97, 106))	('XRCC1', 'Gene', '7515', (20, 25))
54571	26295053	There is a C>G transversion in exon 7, resulting in an amino acid change from serine to cysteine (Ser326Cys).	('serine', 'Chemical', 'MESH:D012694', (78, 84))	('amino acid change from serine to cysteine', 'MPA', (55, 96))	('Ser326Cys', 'SUBSTITUTION', 'None', (98, 107))	('Ser326Cys', 'Var', (98, 107))	('C>G transversion', 'Var', (11, 27))	('cysteine', 'Chemical', 'MESH:D003545', (88, 96))
54572	26295053	hOGG1 Ser326Cys polymorphism has been reported associated with various types of malignancy including lung, esophageal, bladder, and prostate cancer.	('hOGG1', 'Gene', '4968', (0, 5))	('prostate cancer', 'Disease', (132, 147))	('malignancy', 'Disease', 'MESH:D009369', (80, 90))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('hOGG1', 'Gene', (0, 5))	('prostate cancer', 'Disease', 'MESH:D011471', (132, 147))	('bladder', 'Disease', (119, 126))	('Ser326Cys', 'SUBSTITUTION', 'None', (6, 15))	('esophageal', 'Disease', (107, 117))	('lung', 'Disease', (101, 105))	('prostate cancer', 'Phenotype', 'HP:0012125', (132, 147))	('Ser326Cys', 'Var', (6, 15))	('malignancy', 'Disease', (80, 90))	('associated', 'Reg', (47, 57))
54574	26295053	Xeroderma pigmentosum group D (XPD) involved in NER and mutations in the gene leads to NER defect.	('leads to', 'Reg', (78, 86))	('mutations', 'Var', (56, 65))	('NER defect', 'Disease', (87, 97))	('XPD', 'Gene', (31, 34))	('Xeroderma pigmentosum', 'Disease', (0, 21))	('XPD', 'Gene', '2068', (31, 34))	('Xeroderma pigmentosum', 'Disease', 'MESH:D014983', (0, 21))
54575	26295053	It has been consistently documented that nonsynonymous polymorphism at XPD codon 156 is associated with NMSC.	('XPD', 'Gene', '2068', (71, 74))	('NMSC', 'Disease', (104, 108))	('nonsynonymous polymorphism', 'Var', (41, 67))	('XPD', 'Gene', (71, 74))	('associated', 'Reg', (88, 98))
54576	26295053	One study has also shown that XPD polymorphisms modify the association between arsenic exposure and NMSC.	('XPD', 'Gene', '2068', (30, 33))	('NMSC', 'Disease', (100, 104))	('association', 'Interaction', (59, 70))	('arsenic', 'Chemical', 'MESH:D001151', (79, 86))	('polymorphisms', 'Var', (34, 47))	('XPD', 'Gene', (30, 33))	('modify', 'Reg', (48, 54))
54579	26295053	The polymorphisms of interests were classified into three groups according to their functions: (i) xenobiotic metabolic genes: glutathione S-transferases (GSTs) M1, T1, and P1 Ile105Val (rs1695); (ii) reactive oxidative stress (ROS) related genes: NQO1 C609T (rs1800566), EPHX1 Tyr113His (rs1051740) and His139Arg (rs2234922), and HO-1 5'-franking region GT repeats; (iii) DNA repair genes: XRCC1 Arg280His (rs25489) and Arg399Gln (rs25487), XPD C156A (rs238406), hOGG1 Ser326Cys (rs1052133), and ataxia-telangiectasia mutated (ATM) IVS48 +238C>G (rs609429).	('XPD', 'Gene', '2068', (442, 445))	('rs1052133', 'Mutation', 'rs1052133', (481, 490))	('rs609429', 'Mutation', 'rs609429', (548, 556))	('ROS', 'Phenotype', 'HP:0025464', (228, 231))	('rs25487', 'Var', (432, 439))	('rs1051740', 'Mutation', 'rs1051740', (289, 298))	('rs25489', 'Var', (408, 415))	('Arg280His', 'SUBSTITUTION', 'None', (397, 406))	('His139Arg', 'SUBSTITUTION', 'None', (304, 313))	('Arg280His', 'Var', (397, 406))	('rs25489', 'Mutation', 'rs25489', (408, 415))	('GSTs', 'Gene', (155, 159))	('hOGG1', 'Gene', '4968', (464, 469))	('glutathione S-transferases', 'Gene', '373156', (127, 153))	('+238C>G', 'SUBSTITUTION', 'None', (539, 546))	('reactive oxidative stress', 'Phenotype', 'HP:0025464', (201, 226))	('hOGG1', 'Gene', (464, 469))	('ataxia-telangiectasia mutated', 'Gene', (497, 526))	('ROS', 'Chemical', 'MESH:D017382', (228, 231))	('ATM', 'Gene', '472', (528, 531))	('+238C>G', 'Var', (539, 546))	('XPD', 'Gene', (442, 445))	('Arg399Gln (rs25487', 'Var', (421, 439))	('C609T', 'Mutation', 'rs1800566', (253, 258))	('rs238406', 'Mutation', 'rs238406', (453, 461))	('rs1695', 'Mutation', 'rs1695', (187, 193))	('Tyr113His', 'Var', (278, 287))	('rs1052133', 'Var', (481, 490))	('Tyr113His', 'SUBSTITUTION', 'None', (278, 287))	('rs238406', 'Var', (453, 461))	('NQO1', 'Gene', '1728', (248, 252))	('XRCC1', 'Gene', (391, 396))	('glutathione S-transferases', 'Gene', (127, 153))	('HO-1', 'Gene', '3162', (331, 335))	('GSTs', 'Gene', '373156', (155, 159))	('rs25487', 'Mutation', 'rs25487', (432, 439))	('Ser326Cys', 'SUBSTITUTION', 'None', (470, 479))	('EPHX1', 'Gene', '2052', (272, 277))	('Arg399Gln', 'Chemical', '-', (421, 430))	('NQO1', 'Gene', (248, 252))	('IVS48 +238C>G', 'Mutation', 'rs609429', (533, 546))	('ataxia', 'Phenotype', 'HP:0001251', (497, 503))	('rs1800566', 'Mutation', 'rs1800566', (260, 269))	('HO-1', 'Gene', (331, 335))	('rs2234922', 'Mutation', 'rs2234922', (315, 324))	('EPHX1', 'Gene', (272, 277))	('ATM', 'Gene', (528, 531))	('Ile105Val', 'Mutation', 'rs1695', (176, 185))	('telangiectasia', 'Phenotype', 'HP:0001009', (504, 518))	('ataxia-telangiectasia mutated', 'Gene', '472', (497, 526))	('Ser326Cys', 'Var', (470, 479))	('His139Arg', 'Var', (304, 313))	('XRCC1', 'Gene', '7515', (391, 396))	('C156A', 'Mutation', 'rs238406', (446, 451))
54603	26295053	The ORs of EPHX1 exon 3 T/C and C/C polymorphisms were 3.74 (1.20-11.66) and 2.58 (0.85-7.85), respectively.	('EPHX1', 'Gene', '2052', (11, 16))	('3 T/C', 'Var', (22, 27))	('EPHX1', 'Gene', (11, 16))	('3 T/C', 'SUBSTITUTION', 'None', (22, 27))	('C/C polymorphisms', 'Var', (32, 49))
54604	26295053	In addition, the ORs of A/C and A/A polymorphisms in XPD exon 6 were found to be 1.96 (0.91-4.22) and 2.24 (0.93-5.40), though the difference was not statistically significant.	('XPD', 'Gene', (53, 56))	('A/A polymorphisms', 'Var', (32, 49))	('XPD', 'Gene', '2068', (53, 56))	('A/C', 'Var', (24, 27))
54612	26295053	Although the group having a high MMA percentage also had a higher OR, the data was not completely comparable to former case control studies on arsenic-induced skin cancer.	('MMA', 'Chemical', 'MESH:C020300', (33, 36))	('arsenic', 'Chemical', 'MESH:D001151', (143, 150))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('skin cancer', 'Phenotype', 'HP:0008069', (159, 170))	('MMA percentage', 'Var', (33, 47))	('skin cancer', 'Disease', (159, 170))	('skin cancer', 'Disease', 'MESH:D012878', (159, 170))
54616	26295053	In the GST group, the GSTM1 subtype was reported to correlate with cervical neoplasia and chronic obstructive pulmonary disease, while GSTT1 subtype had a higher incidence or percentage of bladder cancer and the GSTP1 Ile105Val polymorphism was related with squamous cell carcinoma (SCC) and colorectal cancer.	('cervical neoplasia', 'Disease', 'MESH:D018290', (67, 85))	('SCC', 'Gene', '6317', (283, 286))	('colorectal cancer', 'Phenotype', 'HP:0003003', (292, 309))	('related', 'Reg', (245, 252))	('GSTM1', 'Gene', (22, 27))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (258, 281))	('neoplasia', 'Phenotype', 'HP:0002664', (76, 85))	('chronic obstructive pulmonary disease', 'Disease', (90, 127))	('SCC', 'Gene', (283, 286))	('obstructive pulmonary disease', 'Phenotype', 'HP:0006536', (98, 127))	('squamous cell carcinoma', 'Disease', (258, 281))	('cervical neoplasia', 'Disease', (67, 85))	('cancer', 'Phenotype', 'HP:0002664', (303, 309))	('bladder cancer', 'Disease', 'MESH:D001749', (189, 203))	('bladder cancer', 'Disease', (189, 203))	('GSTT1', 'Gene', '2952', (135, 140))	('colorectal cancer', 'Disease', 'MESH:D015179', (292, 309))	('GSTM1', 'Gene', '2944', (22, 27))	('bladder cancer', 'Phenotype', 'HP:0009725', (189, 203))	('cervical neoplasia', 'Phenotype', 'HP:0032241', (67, 85))	('colorectal cancer', 'Disease', (292, 309))	('GSTP1', 'Gene', '2950', (212, 217))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('SCC', 'Phenotype', 'HP:0002860', (283, 286))	('Ile105Val', 'Mutation', 'rs1695', (218, 227))	('GSTT1', 'Gene', (135, 140))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (258, 281))	('GSTP1', 'Gene', (212, 217))	('Ile105Val', 'Var', (218, 227))	('chronic obstructive pulmonary disease', 'Phenotype', 'HP:0006510', (90, 127))	('chronic obstructive pulmonary disease', 'Disease', 'MESH:D029424', (90, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (272, 281))
54617	26295053	NQO1 C609T was reported in many diseases, including lung cancer, bladder cancer, and esophageal squamous cell carcinoma.	('bladder cancer', 'Disease', (65, 79))	('lung cancer', 'Disease', 'MESH:D008175', (52, 63))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (96, 119))	('esophageal squamous cell carcinoma', 'Disease', (85, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('C609T', 'Var', (5, 10))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('bladder cancer', 'Phenotype', 'HP:0009725', (65, 79))	('lung cancer', 'Disease', (52, 63))	('NQO1', 'Gene', (0, 4))	('reported', 'Reg', (15, 23))	('lung cancer', 'Phenotype', 'HP:0100526', (52, 63))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('C609T', 'Mutation', 'rs1800566', (5, 10))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (85, 119))	('NQO1', 'Gene', '1728', (0, 4))	('bladder cancer', 'Disease', 'MESH:D001749', (65, 79))
54618	26295053	Both EPHX1 polymorphisms in Tyr113His and His139Arg revealed significantly high risks in developing lung cancer and polycystic ovary syndrome.	('Tyr113His', 'Var', (28, 37))	('polycystic ovary syndrome', 'Disease', (116, 141))	('EPHX1', 'Gene', (5, 10))	('ovary syndrome', 'Phenotype', 'HP:0000137', (127, 141))	('polycystic ovary syndrome', 'Disease', 'MESH:D011085', (116, 141))	('His139Arg', 'Var', (42, 51))	('polycystic ovary', 'Phenotype', 'HP:0000147', (116, 132))	('His139Arg', 'SUBSTITUTION', 'None', (42, 51))	('EPHX1', 'Gene', '2052', (5, 10))	('lung cancer', 'Phenotype', 'HP:0100526', (100, 111))	('lung cancer', 'Disease', (100, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('lung cancer', 'Disease', 'MESH:D008175', (100, 111))	('Tyr113His', 'SUBSTITUTION', 'None', (28, 37))
54619	26295053	Furthermore, the correlation between the long HO-1 (GT) repeat and oral squamous cell carcinoma has been identified.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (72, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('HO-1', 'Gene', (46, 50))	('repeat', 'Var', (56, 62))	('HO-1', 'Gene', '3162', (46, 50))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (67, 95))	('oral squamous cell carcinoma', 'Disease', (67, 95))
54620	26295053	Among DNA repair genes, XRCC1 Arg399Gln has been reported in breast cancer and skin cancer, while XPD C156A was correlated with basal cell carcinoma, and the hOGG1 Ser326Cys polymorphism has been studied as a causal factor in lung and esophageal cancers.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('Arg399Gln', 'Chemical', '-', (30, 39))	('basal cell carcinoma', 'Disease', (128, 148))	('hOGG1', 'Gene', (158, 163))	('skin cancer', 'Disease', 'MESH:D012878', (79, 90))	('cancers', 'Phenotype', 'HP:0002664', (246, 253))	('XRCC1', 'Gene', '7515', (24, 29))	('esophageal cancers', 'Disease', 'MESH:D004938', (235, 253))	('XPD', 'Gene', '2068', (98, 101))	('breast cancer', 'Phenotype', 'HP:0003002', (61, 74))	('reported', 'Reg', (49, 57))	('correlated', 'Reg', (112, 122))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))	('C156A', 'Mutation', 'rs238406', (102, 107))	('breast cancer', 'Disease', 'MESH:D001943', (61, 74))	('breast cancer', 'Disease', (61, 74))	('basal cell carcinoma', 'Disease', 'MESH:D002280', (128, 148))	('esophageal cancers', 'Disease', (235, 253))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('skin cancer', 'Disease', (79, 90))	('Ser326Cys', 'SUBSTITUTION', 'None', (164, 173))	('Ser326Cys', 'Var', (164, 173))	('XPD', 'Gene', (98, 101))	('lung', 'Disease', (226, 230))	('Arg399Gln', 'Var', (30, 39))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (128, 148))	('carcinoma', 'Phenotype', 'HP:0030731', (139, 148))	('XRCC1', 'Gene', (24, 29))	('skin cancer', 'Phenotype', 'HP:0008069', (79, 90))	('hOGG1', 'Gene', '4968', (158, 163))
54621	26295053	In the univariate analysis, GSTT1 genotype, EPHX1 Tyr113His, and XPD C156A polymorphisms showed significant differences between skin cancer patients and controls.	('C156A', 'Mutation', 'rs238406', (69, 74))	('EPHX1', 'Gene', (44, 49))	('XPD', 'Gene', (65, 68))	('Tyr113His', 'SUBSTITUTION', 'None', (50, 59))	('Tyr113His', 'Var', (50, 59))	('GSTT1', 'Gene', '2952', (28, 33))	('XPD', 'Gene', '2068', (65, 68))	('EPHX1', 'Gene', '2052', (44, 49))	('GSTT1', 'Gene', (28, 33))	('patients', 'Species', '9606', (140, 148))	('differences', 'Reg', (108, 119))	('skin cancer', 'Phenotype', 'HP:0008069', (128, 139))	('skin cancer', 'Disease', (128, 139))	('skin cancer', 'Disease', 'MESH:D012878', (128, 139))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
54625	26295053	These results indicated that the GST polymorphisms may exert strong effects in arsenic-induced skin cancer.	('polymorphisms', 'Var', (37, 50))	('skin cancer', 'Disease', (95, 106))	('skin cancer', 'Disease', 'MESH:D012878', (95, 106))	('arsenic', 'Chemical', 'MESH:D001151', (79, 86))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('GST', 'Gene', (33, 36))	('effects', 'Reg', (68, 75))	('skin cancer', 'Phenotype', 'HP:0008069', (95, 106))
54627	26295053	When considering GST family genes, EPHX1 Tyr113His and XPD C156A together, we found that the higher the polymorphism number among these genes, the higher the risk for skin cancer development.	('Tyr113His', 'SUBSTITUTION', 'None', (41, 50))	('Tyr113His', 'Var', (41, 50))	('skin cancer', 'Disease', (167, 178))	('EPHX1', 'Gene', '2052', (35, 40))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('polymorphism number', 'Var', (104, 123))	('XPD', 'Gene', (55, 58))	('skin cancer', 'Disease', 'MESH:D012878', (167, 178))	('XPD', 'Gene', '2068', (55, 58))	('EPHX1', 'Gene', (35, 40))	('higher', 'Reg', (147, 153))	('C156A', 'Mutation', 'rs238406', (59, 64))	('skin cancer', 'Phenotype', 'HP:0008069', (167, 178))
54630	26295053	For example, when considering the association of ROS genes with skin cancer, we did not include catalase or superoxide dismutase in the present study; (iii) many of the genes in this study belonged to different pathways involved in cellular activities and therefore their corresponding effects and impact might not be in concert.	('catalase', 'Gene', (96, 104))	('skin cancer', 'Disease', (64, 75))	('superoxide', 'Chemical', 'MESH:D013481', (108, 118))	('skin cancer', 'Disease', 'MESH:D012878', (64, 75))	('catalase', 'Gene', '847', (96, 104))	('ROS', 'Chemical', 'MESH:D017382', (49, 52))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('ROS', 'Phenotype', 'HP:0025464', (49, 52))	('skin cancer', 'Phenotype', 'HP:0008069', (64, 75))	('genes', 'Var', (169, 174))	('belonged to', 'Reg', (189, 200))
54634	26295053	In conclusion, we suggest that GSTT1, EPHX1 Tyr113His, and XPD C156A polymorphisms are potential genetic factors for arsenic-induced skin carcinogenesis.	('C156A', 'Mutation', 'rs238406', (63, 68))	('EPHX1', 'Gene', '2052', (38, 43))	('XPD', 'Gene', (59, 62))	('EPHX1', 'Gene', (38, 43))	('arsenic', 'Chemical', 'MESH:D001151', (117, 124))	('polymorphisms', 'Var', (69, 82))	('skin carcinogenesis', 'Disease', 'MESH:D063646', (133, 152))	('XPD', 'Gene', '2068', (59, 62))	('Tyr113His', 'SUBSTITUTION', 'None', (44, 53))	('Tyr113His', 'Var', (44, 53))	('GSTT1', 'Gene', '2952', (31, 36))	('GSTT1', 'Gene', (31, 36))	('factors', 'Reg', (105, 112))	('skin carcinogenesis', 'Disease', (133, 152))
54635	26295053	Individuals who carried all the 3 risk polymorphisms, including any risk variant of GSTs, EPHX1 Tyr113His, and XPD C156A polymorphisms, had a 4.86-fold risk for the development of arsenic-related skin cancers compared to those with less than 2 polymorphisms.	('Tyr113His', 'SUBSTITUTION', 'None', (96, 105))	('Tyr113His', 'Var', (96, 105))	('EPHX1', 'Gene', '2052', (90, 95))	('cancers', 'Phenotype', 'HP:0002664', (201, 208))	('skin cancers', 'Phenotype', 'HP:0008069', (196, 208))	('skin cancer', 'Phenotype', 'HP:0008069', (196, 207))	('C156A', 'Mutation', 'rs238406', (115, 120))	('GSTs', 'Gene', (84, 88))	('skin cancers', 'Disease', (196, 208))	('arsenic', 'Chemical', 'MESH:D001151', (180, 187))	('XPD', 'Gene', (111, 114))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('EPHX1', 'Gene', (90, 95))	('skin cancers', 'Disease', 'MESH:D012878', (196, 208))	('XPD', 'Gene', '2068', (111, 114))	('GSTs', 'Gene', '373156', (84, 88))
54654	32214852	Because of the molecular heterogeneity of NSCLC, up to 69% of patients with mNSCLC could have a potentially actionable molecular target, and the presence of different gene mutations could result in differences in the optimal treatment regimen.	('NSCLC', 'Disease', 'MESH:D002289', (77, 82))	('mutations', 'Var', (172, 181))	('NSCLC', 'Disease', (42, 47))	('NSCLC', 'Disease', 'MESH:D002289', (42, 47))	('presence', 'Var', (145, 153))	('result in differences', 'Reg', (188, 209))	('NSCLC', 'Disease', (77, 82))	('patients', 'Species', '9606', (62, 70))
54673	32214852	Clinical data were collected on patients who received antitumor treatment, such as sex, age, pathological type, genetic mutations, and major metastatic sites.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('patients', 'Species', '9606', (32, 40))	('genetic mutations', 'Var', (112, 129))	('tumor', 'Disease', 'MESH:D009369', (58, 63))
54689	32214852	Driver gene detection was tested in 108 patients, while revealed 77 patients with an epidermal growth factor receptor (EGFR) mutation, three patients with anaplastic lymphoma kinase (ALK) rearrangement positivity, and 28 patients with no gene mutation.	('patients', 'Species', '9606', (221, 229))	('patients', 'Species', '9606', (40, 48))	('epidermal growth factor receptor', 'Gene', '1956', (85, 117))	('patients', 'Species', '9606', (141, 149))	('ALK', 'Gene', (183, 186))	('anaplastic lymphoma kinase', 'Gene', '238', (155, 181))	('ALK', 'Gene', '238', (183, 186))	('lymphoma', 'Phenotype', 'HP:0002665', (166, 174))	('patients', 'Species', '9606', (68, 76))	('EGFR', 'Gene', '1956', (119, 123))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (155, 174))	('anaplastic lymphoma kinase', 'Gene', (155, 181))	('epidermal growth factor receptor', 'Gene', (85, 117))	('EGFR', 'Gene', (119, 123))	('mutation', 'Var', (125, 133))
54695	32214852	Mutation of adenocarcinoma is also important factor influencing the consistency of treatment regimens (P<0.001, Figure 2).	('carcinoma', 'Phenotype', 'HP:0030731', (17, 26))	('adenocarcinoma', 'Disease', (12, 26))	('Mutation', 'Var', (0, 8))	('adenocarcinoma', 'Disease', 'MESH:D000230', (12, 26))
54699	32214852	In particular, the rate of inconsistency was significantly higher (P<0.001) in the two treatment regimens for the adenocarcinoma patients with detected mutation (ie, EGFR or ALK), at 18.75% (15/80), than for the patients with no mutation detected or unknown mutation status (Figure 3).	('adenocarcinoma', 'Disease', 'MESH:D000230', (114, 128))	('ALK', 'Gene', (174, 177))	('patients', 'Species', '9606', (129, 137))	('EGFR', 'Gene', '1956', (166, 170))	('patients', 'Species', '9606', (212, 220))	('EGFR', 'Gene', (166, 170))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('higher', 'PosReg', (59, 65))	('adenocarcinoma', 'Disease', (114, 128))	('mutation', 'Var', (152, 160))	('ALK', 'Gene', '238', (174, 177))
54703	32214852	Compared with the "for consideration" and "not recommended" of WFO treatment regimens, the univariate logistic regression analysis showed that the concordance of "recommended" regimen differed significantly for various gender, EOCG scores, N stage, pathological types, gene mutations between the two treatment regimens (Table 2).	('gene mutations', 'Var', (269, 283))	('WFO', 'Chemical', '-', (63, 66))	('differed', 'Reg', (184, 192))
54704	32214852	Whereas, compared with the agreement rate for concordance of "recommended" and "for consideration" regimens, there was a statistically significant difference in the "not recommended" patients of gender, gene mutation in univariate logistic regression analysis (Table 3).	('gene mutation', 'Var', (203, 216))	('significant difference', 'Reg', (135, 157))	('patients', 'Species', '9606', (183, 191))
54705	32214852	Table 4 shows that these adenocarcinoma patients with EGFR mutation should have chosen osimertinib according to the WFO system, but they actually chose other targeted drugs or chemotherapy drugs.	('patients', 'Species', '9606', (40, 48))	('EGFR', 'Gene', '1956', (54, 58))	('mutation', 'Var', (59, 67))	('adenocarcinoma', 'Disease', (25, 39))	('osimertinib', 'Chemical', 'MESH:C000603933', (87, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (30, 39))	('adenocarcinoma', 'Disease', 'MESH:D000230', (25, 39))	('EGFR', 'Gene', (54, 58))	('WFO', 'Chemical', '-', (116, 119))
54709	32214852	There was discordance between the WFO and medical-team regimens in 10.26% of patients (4/39) with deletion mutations in exon 19 of EGFR, in 71.2% of patients (5/7) with insertions in exon 20, and in 19.23% of patients (5/26) with mutations in exon 21 (Figure 2 and Table 4).	('WFO', 'Chemical', '-', (34, 37))	('patients', 'Species', '9606', (149, 157))	('EGFR', 'Gene', '1956', (131, 135))	('patients', 'Species', '9606', (77, 85))	('deletion mutations in', 'Var', (98, 119))	('EGFR', 'Gene', (131, 135))	('patients', 'Species', '9606', (209, 217))
54711	32214852	Three patients with ALK rearrangement positivity showed consistency in the two treatment regimens.	('rearrangement positivity', 'Var', (24, 48))	('ALK', 'Gene', '238', (20, 23))	('ALK', 'Gene', (20, 23))	('patients', 'Species', '9606', (6, 14))
54718	32214852	The clinical strategy has been based on a molecularly driven approach due to the development of targeted therapies against the driver gene mutations, which has improved the outcomes for patients.	('mutations', 'Var', (139, 148))	('patients', 'Species', '9606', (186, 194))	('improved', 'PosReg', (160, 168))
54726	32214852	The consensus rate was lower for patients with gene mutations than for those without gene mutations (80.52% vs 85.71%).	('patients', 'Species', '9606', (33, 41))	('gene mutations', 'Var', (47, 61))	('lower', 'NegReg', (23, 28))
54727	32214852	The inconsistency rate was 18.75% for patients with mutations (Figure 2), which might be related to different EGFR inhibitor (icotinib) in Chinese patients and clinical and social factors, including medical insurance coverage.	('mutations', 'Var', (52, 61))	('EGFR', 'Gene', '1956', (110, 114))	('EGFR', 'Gene', (110, 114))	('icotinib', 'Chemical', 'MESH:C531470', (126, 134))	('patients', 'Species', '9606', (147, 155))	('patients', 'Species', '9606', (38, 46))
54728	32214852	The prevalence of lung cancer patients with the EGFR gene mutation phenotype is higher in China (50%) than in European and American countries (approximately 15%).	('lung cancer', 'Disease', 'MESH:D008175', (18, 29))	('EGFR', 'Gene', '1956', (48, 52))	('EGFR', 'Gene', (48, 52))	('mutation', 'Var', (58, 66))	('patients', 'Species', '9606', (30, 38))	('lung cancer', 'Phenotype', 'HP:0100526', (18, 29))	('lung cancer', 'Disease', (18, 29))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('higher', 'PosReg', (80, 86))
54733	32214852	The Chinese National Essential Drugs List (2018 edition) had incorporated some oral targeted drugs including gefitinib and icotinib, which may increase the rate of gene detection and the treatment rate of patients with EGFR mutations, thereby improving the consensus rate of WFO recommendations.	('EGFR', 'Gene', '1956', (219, 223))	('patients', 'Species', '9606', (205, 213))	('WFO', 'Chemical', '-', (275, 278))	('icotinib', 'Chemical', 'MESH:C531470', (123, 131))	('EGFR', 'Gene', (219, 223))	('improving', 'PosReg', (243, 252))	('consensus', 'MPA', (257, 266))	('mutations', 'Var', (224, 233))	('gene', 'MPA', (164, 168))	('increase', 'PosReg', (143, 151))	('gefitinib', 'Chemical', 'MESH:D000077156', (109, 118))
54735	32214852	Adenocarcinoma patients with a high rate of genetic mutations might lead to differences in treatment.	('Adenocarcinoma', 'Disease', (0, 14))	('patients', 'Species', '9606', (15, 23))	('lead', 'Reg', (68, 72))	('Adenocarcinoma', 'Disease', 'MESH:D000230', (0, 14))	('carcinoma', 'Phenotype', 'HP:0030731', (5, 14))	('genetic mutations', 'Var', (44, 61))
54736	32214852	The adenocarcinoma patients with no EGFR mutation had a lower rate of "recommended" regimens (P<0.001, Figure 2 and Table 2) with 14.28% (4/28) and a higher rate of "recommended" and "for consideration" regimens (P=0.066, Figure 3 and Table 3) with 85.71% (24/28).	('patients', 'Species', '9606', (19, 27))	('carcinoma', 'Phenotype', 'HP:0030731', (9, 18))	('adenocarcinoma', 'Disease', (4, 18))	('mutation', 'Var', (41, 49))	('lower', 'NegReg', (56, 61))	('EGFR', 'Gene', '1956', (36, 40))	('EGFR', 'Gene', (36, 40))	('adenocarcinoma', 'Disease', 'MESH:D000230', (4, 18))
54773	30374364	For example, aberrant expression of the lncRNA H19 occurs in ovarian cancer and other types of cancers (Yoshimura et al.,).	('ovarian cancer', 'Disease', 'MESH:D010051', (61, 75))	('H19', 'Gene', (47, 50))	('cancers', 'Phenotype', 'HP:0002664', (95, 102))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('cancers', 'Disease', (95, 102))	('ovarian cancer', 'Disease', (61, 75))	('cancers', 'Disease', 'MESH:D009369', (95, 102))	('occurs', 'Reg', (51, 57))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('H19', 'Gene', '283120', (47, 50))	('expression', 'MPA', (22, 32))	('ovarian cancer', 'Phenotype', 'HP:0100615', (61, 75))	('aberrant', 'Var', (13, 21))
54781	30374364	However, another study reported that genetic ablation of NEAT1 resulted in aberrant mammary gland morphogenesis and lactation defects (Standaert et al.,).	('genetic ablation', 'Var', (37, 53))	('NEAT1', 'Gene', (57, 62))	('lactation defects', 'Disease', (116, 133))	('lactation defects', 'Disease', 'MESH:D007775', (116, 133))	('aberrant mammary gland morphogenesis', 'CPA', (75, 111))	('resulted in', 'Reg', (63, 74))
54782	30374364	NEAT1 displays typical characteristics of cancer drivers, because it is responsible for tumor initiation and progression, and its frequent dysregulation in cancers correlates with clinical features such as metastasis, recurrence rate and patient survival (Lanzos et al.,).	('cancers', 'Phenotype', 'HP:0002664', (156, 163))	('cancers', 'Disease', (156, 163))	('recurrence rate', 'CPA', (218, 233))	('NEAT1', 'Gene', (0, 5))	('cancer', 'Disease', (156, 162))	('clinical', 'Species', '191496', (180, 188))	('cancers', 'Disease', 'MESH:D009369', (156, 163))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('tumor initiation', 'Disease', 'MESH:D009369', (88, 104))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('patient', 'Species', '9606', (238, 245))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('dysregulation', 'Var', (139, 152))	('tumor initiation', 'Disease', (88, 104))	('metastasis', 'CPA', (206, 216))
54787	30374364	The expression of NEAT1 in cancer cells is controlled by the following mechanisms: genetic alterations (such as copy number gain and gene mutation), transcription factors, DNA methylation, miRNAs and RNA-binding protein (Figure 3B).	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('gain', 'PosReg', (124, 128))	('gene mutation', 'Var', (133, 146))	('RNA-binding protein', 'Gene', '27303', (200, 219))	('RNA-binding protein', 'Gene', (200, 219))	('copy number', 'Var', (112, 123))	('miR', 'Gene', '220972', (189, 192))	('miR', 'Gene', (189, 192))	('NEAT1', 'Gene', (18, 23))	('cancer', 'Disease', (27, 33))	('cancer', 'Disease', 'MESH:D009369', (27, 33))
54788	30374364	The Cancer Genome Atlas (TCGA, a large-scale cancer genomics project) has revealed molecular alterations such as gene mutations, copy-number changes, upregulation or downregulation of mRNA and lncRNA across diverse tumor types.	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('mRNA', 'Protein', (184, 188))	('tumor', 'Disease', 'MESH:D009369', (215, 220))	('mutations', 'Var', (118, 127))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('Cancer', 'Phenotype', 'HP:0002664', (4, 10))	('copy-number changes', 'Var', (129, 148))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('upregulation', 'PosReg', (150, 162))	('Cancer Genome Atlas', 'Disease', (4, 23))	('tumor', 'Disease', (215, 220))	('cancer', 'Disease', (45, 51))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (4, 23))	('downregulation', 'NegReg', (166, 180))	('lncRNA', 'Protein', (193, 199))
54789	30374364	A comprehensive study analyzing lncRNA alterations in the TCGA datasets covering 5,860 tumor samples from 13 cancer types revealed that on average 13.16% of lncRNAs underwent copy number gains and 13.53% of lncRNAs underwent copy number loss (Yan et al.,).	('copy number gains', 'Var', (175, 192))	('copy number', 'Var', (225, 236))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('tumor', 'Disease', (87, 92))	('cancer', 'Disease', (109, 115))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))
54790	30374364	Here, we used the TCGA cervical, endometrial and ovarian cancer datasets to annotate genetic alterations of NEAT1 in these gynecological cancers via the cBioPortal online application (http://www.cbioportal.org).	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('endometrial and ovarian cancer', 'Disease', 'MESH:D016889', (33, 63))	('cancers', 'Disease', 'MESH:D009369', (137, 144))	('cancers', 'Phenotype', 'HP:0002664', (137, 144))	('ovarian cancer', 'Phenotype', 'HP:0100615', (49, 63))	('genetic alterations', 'Var', (85, 104))	('cancers', 'Disease', (137, 144))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('NEAT1', 'Gene', (108, 113))
54791	30374364	Consistent with previous observations (Kim et al.,; Chen Z. J. et al.,; Li Z. et al.,; Han et al.,; Wang J. et al.,), we found that genetic alterations occur in 5-11% of cervical, endometrial and ovarian cancers, and the predominant alterations were amplification and RNA upregulation (Figure 3C).	('cancers', 'Phenotype', 'HP:0002664', (204, 211))	('genetic alterations', 'Var', (132, 151))	('ovarian cancer', 'Phenotype', 'HP:0100615', (196, 210))	('ovarian cancers', 'Phenotype', 'HP:0100615', (196, 211))	('RNA', 'CPA', (268, 271))	('endometrial and ovarian cancers', 'Disease', 'MESH:D016889', (180, 211))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('amplification', 'Var', (250, 263))	('cervical', 'Disease', (170, 178))
54792	30374364	The presence of copy number gain in NEAT1 gene might provide a possible explanation for high NEAT1 expression in these cancers.	('expression', 'MPA', (99, 109))	('high', 'PosReg', (88, 92))	('NEAT1', 'Gene', (36, 41))	('copy number gain', 'Var', (16, 32))	('cancers', 'Disease', 'MESH:D009369', (119, 126))	('cancers', 'Phenotype', 'HP:0002664', (119, 126))	('cancers', 'Disease', (119, 126))	('NEAT1', 'Gene', (93, 98))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
54793	30374364	In addition, deep sequencing analysis of breast cancers has indicated mutations in the NEAT1 promoter region (Rheinbay et al.,).	('mutations', 'Var', (70, 79))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('breast cancers', 'Phenotype', 'HP:0003002', (41, 55))	('breast cancer', 'Phenotype', 'HP:0003002', (41, 54))	('breast cancers', 'Disease', 'MESH:D001943', (41, 55))	('indicated', 'Reg', (60, 69))	('breast cancers', 'Disease', (41, 55))	('NEAT1', 'Gene', (87, 92))	('cancers', 'Phenotype', 'HP:0002664', (48, 55))
54794	30374364	Another group also found an elevation of mutations in the NEAT1 promoter in renal cell carcinoma, and these mutations were associated with increased NEAT1 expression and unfavorable patient survival (Li S. et al.,).	('mutations', 'Var', (41, 50))	('renal cell carcinoma', 'Disease', (76, 96))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (76, 96))	('mutations', 'Var', (108, 117))	('NEAT1', 'Gene', (58, 63))	('increased', 'PosReg', (139, 148))	('expression', 'MPA', (155, 165))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (76, 96))	('patient', 'Species', '9606', (182, 189))	('elevation', 'PosReg', (28, 37))	('NEAT1', 'Gene', (149, 154))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))
54799	30374364	Epigenetic mechanisms such as aberrant DNA methylation and miRNA dysregulation account for the aberrant expression of lncRNAs in tumors (Choudhry et al.,; Yan et al.,).	('tumors', 'Disease', (129, 135))	('tumors', 'Disease', 'MESH:D009369', (129, 135))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('aberrant', 'Var', (30, 38))	('miR', 'Gene', '220972', (59, 62))	('miR', 'Gene', (59, 62))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))
54800	30374364	The expression of NEAT1 was increased by the treatment with 5-AZA in hepatocellular carcinoma cells, indicating that DNA methylation is an important determinant of NEAT1 expression (Fang et al.,).	('increased', 'PosReg', (28, 37))	('5-AZA', 'Chemical', 'MESH:D001374', (60, 65))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (69, 93))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (69, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('hepatocellular carcinoma', 'Disease', (69, 93))	('expression', 'MPA', (4, 14))	('5-AZA', 'Var', (60, 65))	('NEAT1', 'Gene', (18, 23))
54802	30374364	NEAT1 inhibits cell cycle arrest and apoptosis, but promotes migration, invasion, metastasis, epithelial-to-mesenchymal transition (EMT), stem cell-like phenotype, chemoresistance and radioresistance, through at least three different molecular mechanisms (Figure 4 and Table 1): (i) NEAT1 functions as a scaffold RNA molecule by interacting with EZH2 (a subunit of the polycomb repressive complex) to influence the expression of downstream effectors of EZH2, (ii) NEAT1 acts as miRNA sponges to antagonize the interactions between multiple tumor suppressor miRNAs and target mRNAs, and (iii) NEAT1 suppresses the expression of miR-129 by promoting the DNA methylation of the miR-129 promoter region.	('tumor', 'Phenotype', 'HP:0002664', (540, 545))	('DNA methylation', 'MPA', (652, 667))	('arrest', 'Disease', 'MESH:D006323', (26, 32))	('expression', 'MPA', (613, 623))	('suppresses', 'NegReg', (598, 608))	('EZH2', 'Gene', '2146', (453, 457))	('EZH2', 'Gene', (453, 457))	('miR', 'Gene', '220972', (478, 481))	('miR', 'Gene', '220972', (627, 630))	('miR', 'Gene', '220972', (557, 560))	('miR', 'Gene', '220972', (675, 678))	('promoting', 'PosReg', (638, 647))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (15, 32))	('influence', 'Reg', (401, 410))	('tumor', 'Disease', (540, 545))	('miR', 'Gene', (478, 481))	('miR', 'Gene', (627, 630))	('arrest', 'Disease', (26, 32))	('miR', 'Gene', (557, 560))	('miR', 'Gene', (675, 678))	('EZH2', 'Gene', '2146', (346, 350))	('tumor', 'Disease', 'MESH:D009369', (540, 545))	('EZH2', 'Gene', (346, 350))	('NEAT1', 'Var', (592, 597))
54803	30374364	In gastric cancer, laryngeal squamous cell cancer, pancreatic cancer, oral squamous cell carcinoma, nasopharyngeal carcinoma and breast cancer, knockdown of NEAT1 via small interfering RNA (siRNA) inhibited cell proliferation (Ma et al.,; Wang P. et al.,; Cheng and Guo,; Huang et al.,; Qian et al.,).	('inhibited', 'NegReg', (197, 206))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (100, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (51, 68))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('gastric cancer', 'Phenotype', 'HP:0012126', (3, 17))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (70, 98))	('oral squamous cell carcinoma', 'Disease', (70, 98))	('cell proliferation', 'CPA', (207, 225))	('breast cancer', 'Phenotype', 'HP:0003002', (129, 142))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('nasopharyngeal carcinoma', 'Disease', (100, 124))	('laryngeal squamous cell cancer', 'Disease', (19, 49))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (29, 49))	('pancreatic cancer', 'Disease', 'MESH:D010190', (51, 68))	('laryngeal squamous cell cancer', 'Disease', 'MESH:D002294', (19, 49))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (75, 98))	('knockdown', 'Var', (144, 153))	('gastric cancer', 'Disease', (3, 17))	('breast cancer', 'Disease', 'MESH:D001943', (129, 142))	('nasopharyngeal carcinoma', 'Disease', 'MESH:D000077274', (100, 124))	('breast cancer', 'Disease', (129, 142))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('pancreatic cancer', 'Disease', (51, 68))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('gastric cancer', 'Disease', 'MESH:D013274', (3, 17))
54805	30374364	Furthermore, short hairpin RNA (shRNA)-mediated silencing of NEAT1 significantly impaired cell proliferation, migration and invasion in cholangiocarcinoma (Zhang C. et al.,).	('silencing', 'Var', (48, 57))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (136, 154))	('carcinoma', 'Phenotype', 'HP:0030731', (145, 154))	('NEAT1', 'Gene', (61, 66))	('migration', 'CPA', (110, 119))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (136, 154))	('cell proliferation', 'CPA', (90, 108))	('impaired', 'NegReg', (81, 89))	('invasion', 'CPA', (124, 132))	('cholangiocarcinoma', 'Disease', (136, 154))
54807	30374364	EMT is a complex process in which epithelial cells acquire the characteristics of invasive mesenchymal cells and has been shown to contribute to tumorigenesis, invasion, metastasis, resistance to conventional chemotherapy, radiotherapy and small-molecule-targeted therapy (Dong et al.,; Nieto et al.,; Huo et al.,).	('small-molecule-targeted', 'Var', (240, 263))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('resistance', 'CPA', (182, 192))	('invasion', 'CPA', (160, 168))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('metastasis', 'CPA', (170, 180))	('tumor', 'Disease', (145, 150))	('contribute', 'Reg', (131, 141))
54811	30374364	Importantly, NEAT1 was found to be overexpressed in CD133+ glioma stem cells and knockdown of NEAT1 by siRNA reduced the ability of these cells to form colonies in soft agar (Yang et al.,).	('CD133', 'Gene', (52, 57))	('glioma', 'Disease', (59, 65))	('CD133', 'Gene', '8842', (52, 57))	('glioma', 'Disease', 'MESH:D005910', (59, 65))	('glioma', 'Phenotype', 'HP:0009733', (59, 65))	('knockdown', 'Var', (81, 90))	('reduced', 'NegReg', (109, 116))	('NEAT1', 'Gene', (94, 99))
54812	30374364	Glioma stem cells transfected with NEAT1 shRNA exhibited weaker proliferation, migration and invasion than that of those cells transfected with control shRNA (Gong et al.,).	('migration', 'CPA', (79, 88))	('weaker', 'NegReg', (57, 63))	('Glioma', 'Phenotype', 'HP:0009733', (0, 6))	('Glioma', 'Disease', 'MESH:D005910', (0, 6))	('Glioma', 'Disease', (0, 6))	('invasion', 'CPA', (93, 101))	('NEAT1', 'Var', (35, 40))
54817	30374364	For example, in colorectal cancer cell lines, knockdown of NEAT1-1 could inhibit cell invasion and proliferation, whereas knockdown of NEAT1-2 promoted cell growth (Wu et al.,).	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('cell invasion', 'CPA', (81, 94))	('knockdown', 'Var', (46, 55))	('cell growth', 'CPA', (152, 163))	('colorectal cancer', 'Disease', 'MESH:D015179', (16, 33))	('promoted', 'PosReg', (143, 151))	('NEAT1-1', 'Gene', (59, 66))	('colorectal cancer', 'Phenotype', 'HP:0003003', (16, 33))	('colorectal cancer', 'Disease', (16, 33))	('inhibit', 'NegReg', (73, 80))
54839	30374364	In vivo studies also confirmed that knockdown of NEAT1 sensitized tumor cells to cisplatin/paclitaxel- or radio-induced tumor regression (An et al.,; Han et al.,; Hu et al.,).	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Disease', (66, 71))	('sensitized', 'Reg', (55, 65))	('knockdown', 'Var', (36, 45))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('paclitaxel', 'Chemical', 'MESH:D017239', (91, 101))	('cisplatin/paclitaxel-', 'MPA', (81, 102))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('NEAT1', 'Gene', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('cisplatin', 'Chemical', 'MESH:D002945', (81, 90))	('tumor', 'Disease', (120, 125))
54853	28380452	Detection of oncogenic mutations in resected bronchial margins by next-generation sequencing indicates early relapse in stage IA lung adenocarcinoma patients Stage I non-small cell lung cancer (NSCLC) patients experience a relatively high rate of recurrence, ranging from about 30-35%.	('patients', 'Species', '9606', (201, 209))	('patients', 'Species', '9606', (149, 157))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (129, 148))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('carcinoma', 'Phenotype', 'HP:0030731', (139, 148))	('IA lung adenocarcinoma', 'Disease', (126, 148))	('NSCLC', 'Disease', (194, 199))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (170, 192))	('lung cancer', 'Phenotype', 'HP:0100526', (181, 192))	('IA lung adenocarcinoma', 'Disease', 'MESH:D000077192', (126, 148))	('mutations', 'Var', (23, 32))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (166, 192))	('NSCLC', 'Disease', 'MESH:D002289', (194, 199))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (166, 192))	('non-small cell lung cancer', 'Disease', (166, 192))
54861	28380452	Moreover, according to the gene mutation status in marginal tissue, 87.5% (7/8) of patients with at least one gene mutation in the bronchial margins had local recurrence or metastasis, whereas only 16.7% (1/6) of patients without any mutation detected had signs of relapse, the recurrence rate was significantly higher than that of the negative mutation margin group ((p (log-rank) = 0.023).	('local recurrence', 'CPA', (153, 169))	('metastasis', 'CPA', (173, 183))	('higher', 'PosReg', (312, 318))	('patients', 'Species', '9606', (213, 221))	('patients', 'Species', '9606', (83, 91))	('mutation', 'Var', (115, 123))
54862	28380452	The existence of oncogenic mutations in bronchial margins may represent occult residual tumor and elevated risk of recurrence in early stage NSCLC patients.	('mutations', 'Var', (27, 36))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('NSCLC', 'Disease', (141, 146))	('patients', 'Species', '9606', (147, 155))	('NSCLC', 'Disease', 'MESH:D002289', (141, 146))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('bronchial margins', 'Gene', (40, 57))	('tumor', 'Disease', (88, 93))
54873	28380452	Hancock et al identified 54512 NSCLC patients who underwent curative surgery between 2003 and 2006, of note, 5-year survival rate of stage pI patients with R1 margins decreased from 62% to 37% compared to patients with complete resection.	('patients', 'Species', '9606', (205, 213))	('patients', 'Species', '9606', (37, 45))	('NSCLC', 'Disease', (31, 36))	('R1 margins', 'Var', (156, 166))	('NSCLC', 'Disease', 'MESH:D002289', (31, 36))	('stage pI', 'Disease', (133, 141))	('patients', 'Species', '9606', (142, 150))	('decreased', 'NegReg', (167, 176))
54874	28380452	Similarly, another study also showed that patients with R1 margins have worse disease-free survival and 5-year survival.	('worse', 'NegReg', (72, 77))	('R1 margins', 'Var', (56, 66))	('5-year survival', 'CPA', (104, 119))	('patients', 'Species', '9606', (42, 50))	('disease-free survival', 'CPA', (78, 99))
54878	28380452	By detecting mutations of the k-ras proto-oncogene, Masasyesva et al found that high local recurrence rates of sublobar resection were associated with the occult presence of tumor cells at resection margins.	('tumor', 'Disease', (174, 179))	('local recurrence', 'CPA', (85, 101))	('sublobar resection', 'Disease', (111, 129))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('mutations', 'Var', (13, 22))	('k-ras', 'Gene', '3845', (30, 35))	('k-ras', 'Gene', (30, 35))
54879	28380452	Vatan et al examined p53 gene mutations and k-ras codon 12 mutations from the tumor samples and surgical margins of 34 NSCLC patients, and their mutation rate was found to be much lower than the range given in the literature.	('NSCLC', 'Disease', 'MESH:D002289', (119, 124))	('patients', 'Species', '9606', (125, 133))	('k-ras', 'Gene', '3845', (44, 49))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('p53', 'Gene', '7157', (21, 24))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('mutations', 'Var', (30, 39))	('tumor', 'Disease', (78, 83))	('NSCLC', 'Disease', (119, 124))	('p53', 'Gene', (21, 24))	('k-ras', 'Gene', (44, 49))
54890	28380452	TP53 was the most common mutation identified in the tumor tissue of ER group, accounting for 62.5% (5/8) of the patients; K-ras and EGFR mutations were the second most common, accounting for 37.5% (3/8) of the patients.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('EGFR', 'Gene', '1956', (132, 136))	('tumor', 'Disease', (52, 57))	('EGFR', 'Gene', (132, 136))	('patients', 'Species', '9606', (112, 120))	('mutations', 'Var', (137, 146))	('K-ras', 'Gene', (122, 127))	('patients', 'Species', '9606', (210, 218))	('K-ras', 'Gene', '3845', (122, 127))	('tumor', 'Disease', 'MESH:D009369', (52, 57))
54891	28380452	Among the 3 patients with EGFR mutation, one had a 19-Del mutation, one had a 19-Del mutation and PSH-EGFR fusion, and one had a L858R mutation.	('EGFR', 'Gene', (26, 30))	('patients', 'Species', '9606', (12, 20))	('a 19', 'Gene', '28921', (49, 53))	('L858R', 'Mutation', 'rs121434568', (129, 134))	('mutation', 'Var', (31, 39))	('a 19', 'Gene', (49, 53))	('a 19', 'Gene', '28921', (76, 80))	('a 19', 'Gene', (76, 80))	('EGFR', 'Gene', '1956', (26, 30))	('EGFR', 'Gene', '1956', (102, 106))	('EGFR', 'Gene', (102, 106))
54892	28380452	Moreover, mutations of EGFR, TP53, and SMARCA4 were the common mutations identified in marginal tissue of ER group, and the detection rates were all 28.6% (2/7) (Figure 3 and Supplementary Table 1)..	('EGFR', 'Gene', '1956', (23, 27))	('TP53', 'Gene', '7157', (29, 33))	('TP53', 'Gene', (29, 33))	('mutations', 'Var', (10, 19))	('EGFR', 'Gene', (23, 27))	('SMARCA4', 'Gene', (39, 46))	('SMARCA4', 'Gene', '6597', (39, 46))
54895	28380452	The EGFR mutation was the most common mutation detected in the tumor tissue of NR group and was identified in all of the 6 cases (100%), including 3 cases of EGFR 19-Del, 1 case of a co-mutation of EGFR L858R and EGFR V689V, 1 case of EGFR 746-756 Del and ZNF385D-ROS1 fusion, and 1 case of EGFR M766 delins MASV.	('EGFR', 'Gene', (291, 295))	('EGFR', 'Gene', (4, 8))	('L858R', 'Mutation', 'rs121434568', (203, 208))	('EGFR', 'Gene', '1956', (198, 202))	('EGFR', 'Gene', '1956', (158, 162))	('EGFR', 'Gene', '1956', (213, 217))	('V689V', 'Var', (218, 223))	('EGFR', 'Gene', '1956', (235, 239))	('ROS1', 'Gene', '6098', (264, 268))	('EGFR', 'Gene', '1956', (291, 295))	('ZNF385D', 'Gene', '79750', (256, 263))	('EGFR', 'Gene', '1956', (4, 8))	('mutation', 'Var', (9, 17))	('tumor', 'Disease', (63, 68))	('M766 delins', 'Mutation', 'p.766delinsM', (296, 307))	('L858R', 'Var', (203, 208))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('EGFR', 'Gene', (198, 202))	('EGFR', 'Gene', (158, 162))	('EGFR', 'Gene', (213, 217))	('V689V', 'Mutation', 'rs773835994', (218, 223))	('ROS1', 'Gene', (264, 268))	('EGFR', 'Gene', (235, 239))	('M766', 'Var', (296, 300))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('ZNF385D', 'Gene', (256, 263))
54898	28380452	Although another mutation ARID1A was discovered in tumor tissue, no key mutation, such as EGFR or TP53, was identified in corresponding marginal tissue (Figure 3 and Table 4).	('ARID1A', 'Gene', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('EGFR', 'Gene', '1956', (90, 94))	('mutation', 'Var', (17, 25))	('tumor', 'Disease', (51, 56))	('EGFR', 'Gene', (90, 94))	('TP53', 'Gene', '7157', (98, 102))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('ARID1A', 'Gene', '8289', (26, 32))	('TP53', 'Gene', (98, 102))
54900	28380452	EGFR Mutation of Tumors tissue were also tested by amplification-refractory mutation system (ARMS).	('EGFR', 'Gene', (0, 4))	('Tumors', 'Disease', (17, 23))	('Tumors', 'Disease', 'MESH:D009369', (17, 23))	('Tumors', 'Phenotype', 'HP:0002664', (17, 23))	('tested', 'Reg', (41, 47))	('EGFR', 'Gene', '1956', (0, 4))	('Mutation', 'Var', (5, 13))
54901	28380452	All of patient underwent EGFR mutation test.	('mutation', 'Var', (30, 38))	('EGFR', 'Gene', '1956', (25, 29))	('EGFR', 'Gene', (25, 29))	('patient', 'Species', '9606', (7, 14))
54902	28380452	Of note, EGFR (n=6) mutations were detected by conventional sequencing.	('EGFR', 'Gene', '1956', (9, 13))	('EGFR', 'Gene', (9, 13))	('mutations', 'Var', (20, 29))
54904	28380452	There were totally 5 of EGFR mutations not previously covered by the amplification-refractory mutation system (NO7.	('EGFR', 'Gene', '1956', (24, 28))	('EGFR', 'Gene', (24, 28))	('mutations', 'Var', (29, 38))
54908	28380452	EGFR M766delinsMASV, NO12.	('EGFR', 'Gene', '1956', (0, 4))	('EGFR', 'Gene', (0, 4))	('M766delinsMASV', 'Var', (5, 19))
54910	28380452	Detailed information regarding the patients is provided in Supplementary Table 2 Based on the results of high-throughput sequencing, 7 out of 8 (87.5%) tumor specific gene mutations were identified in the marginal tissue in the ER group, while genetic mutation in the marginal tissue was only observed in 1 out of 6 patients (12.5%) in the NR group.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('mutations', 'Var', (172, 181))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('tumor', 'Disease', (152, 157))	('patients', 'Species', '9606', (35, 43))	('patients', 'Species', '9606', (316, 324))
54919	28380452	Compared to NR patients, oncogene mutations were detected more frequently in resected bronchial margins of ER patients.	('oncogene', 'Gene', (25, 33))	('patients', 'Species', '9606', (15, 23))	('mutations', 'Var', (34, 43))	('patients', 'Species', '9606', (110, 118))
54925	28380452	Given the unsatisfactory survival rates, many researchers have been searching for possible methods that could help predict the outcome of stage I patients, such as analysis of the standard uptake value (SUVmax) in positron emission tomography or carcinoembryonic antigen (CEA) serum levels, or detection of genetic alterations, epigenetic modifications, and gene-expression profiles.	('CEA', 'Gene', (272, 275))	('epigenetic modifications', 'Var', (328, 352))	('genetic alterations', 'Var', (307, 326))	('carcinoembryonic antigen', 'Gene', (246, 270))	('detection', 'Reg', (294, 303))	('CEA', 'Gene', '1048', (272, 275))	('patients', 'Species', '9606', (146, 154))	('carcinoembryonic antigen', 'Gene', '1048', (246, 270))
54927	28380452	Despite histologically tumor-free surgical margins, they found that k-ras mutant cells could be detected in these surgical margins and that the presence of these cells was associated with a higher incidence of local recurrence and disease progression.	('k-ras', 'Gene', (68, 73))	('k-ras', 'Gene', '3845', (68, 73))	('local recurrence', 'CPA', (210, 226))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('tumor', 'Disease', (23, 28))	('associated', 'Reg', (172, 182))	('disease progression', 'CPA', (231, 250))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('mutant', 'Var', (74, 80))	('presence', 'Var', (144, 152))
54932	28380452	However, they did find that recurrence only occurred in patients with methylation-positive bronchial margins.	('patients', 'Species', '9606', (56, 64))	('methylation-positive', 'Var', (70, 90))	('bronchial', 'Disease', (91, 100))
54942	28380452	In sum, we can conclude that the detection of oncogenes in microscopically negative bronchial margins increased the risk of relapse in stage I lung adenocarcinoma patients.	('patients', 'Species', '9606', (163, 171))	('detection', 'Var', (33, 42))	('I lung adenocarcinoma', 'Disease', (141, 162))	('oncogenes', 'Protein', (46, 55))	('relapse', 'Disease', (124, 131))	('carcinoma', 'Phenotype', 'HP:0030731', (153, 162))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (143, 162))	('I lung adenocarcinoma', 'Disease', 'MESH:D000077192', (141, 162))
54971	27537898	Defective autophagy might contribute to tumorigenesis via accumulation of damaged mitochondria and protein aggregates, leading to a production of reactive oxygen species and causing DNA damage, and subsequently genomic instability.	('reactive oxygen species', 'Chemical', 'MESH:D017382', (146, 169))	('production of reactive oxygen species', 'MPA', (132, 169))	('contribute', 'Reg', (26, 36))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('accumulation', 'PosReg', (58, 70))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('tumor', 'Disease', (40, 45))	('Defective', 'Var', (0, 9))	('protein', 'Protein', (99, 106))	('causing', 'Reg', (174, 181))	('DNA damage', 'MPA', (182, 192))	('autophagy', 'CPA', (10, 19))
54972	27537898	Manipulating autophagy for induction of cell death, inhibition of protective autophagy, and its crosstalk with tissue-specific apoptosis might yield promising anticancer chemotherapeutic venues.	('cancer', 'Disease', 'MESH:D009369', (163, 169))	('inhibition', 'NegReg', (52, 62))	('Manipulating', 'Var', (0, 12))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('protective autophagy', 'CPA', (66, 86))	('cancer', 'Disease', (163, 169))	('autophagy', 'CPA', (13, 22))
54985	27537898	Transcription of the AEN gene can be regulated by all three TP53 family members (TP53, TP63, and TP73) and AEN knockdown decreases levels of autophagic vacuoles and LC3B-II protein after genotoxic stress, strengthening the connection between TP53 signaling and autophagy.	('LC3B', 'Gene', (165, 169))	('levels of autophagic vacuoles', 'MPA', (131, 160))	('knockdown', 'Var', (111, 120))	('AEN', 'Gene', (21, 24))	('decreases', 'NegReg', (121, 130))	('TP73', 'Gene', '7161', (97, 101))	('TP73', 'Gene', (97, 101))	('AEN', 'Gene', (107, 110))	('TP53', 'Gene', '7157', (60, 64))	('TP63', 'Gene', (87, 91))	('TP53', 'Gene', '7157', (242, 246))	('TP53', 'Gene', (242, 246))	('LC3B', 'Gene', '81631', (165, 169))	('autophagic vacuoles', 'Phenotype', 'HP:0003736', (141, 160))	('TP63', 'Gene', '8626', (87, 91))	('TP53', 'Gene', (60, 64))	('TP53', 'Gene', '7157', (81, 85))	('TP53', 'Gene', (81, 85))
54988	27537898	Although TP73 was found to induce expression of ATG5 and ATG7 genes, TP73 knockdown increased the UVRAG expression levels.	('TP73', 'Gene', '7161', (69, 73))	('TP73', 'Gene', (69, 73))	('ATG5', 'Gene', (48, 52))	('UVRAG expression levels', 'MPA', (98, 121))	('knockdown', 'Var', (74, 83))	('TP73', 'Gene', '7161', (9, 13))	('TP73', 'Gene', (9, 13))	('increased', 'PosReg', (84, 93))	('ATG7 genes', 'Gene', (57, 67))
54991	27537898	The DeltaNp63alpha is the most predominantly expressed isotype in head and neck squamous cell carcinoma (SCC) cells.	('neck squamous cell carcinoma', 'Disease', (75, 103))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (75, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (80, 103))	('SCC', 'Phenotype', 'HP:0002860', (105, 108))	('DeltaNp63alpha', 'Var', (4, 18))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (66, 103))
54992	27537898	DeltaNp63alpha was shown to activate ATM transcription, thereby contributing to the ATM-TSC2-mTOR complex 1-dependent autophagic pathway.	('ATM', 'Gene', (84, 87))	('ATM', 'Gene', (37, 40))	('autophagic pathway', 'CPA', (118, 136))	('mTOR', 'Gene', (93, 97))	('mTOR', 'Gene', '2475', (93, 97))	('activate', 'PosReg', (28, 36))	('ATM', 'Gene', '472', (84, 87))	('ATM', 'Gene', '472', (37, 40))	('DeltaNp63alpha', 'Var', (0, 14))	('contributing', 'Reg', (64, 76))
55021	27537898	While phosphorylation of TP53 family members is often critical for the activation of TP53 proteins as transcription factors, the specific phosphorylation events (S385 for DeltaNp63alpha Y99 for TP73alpha, and S15 and S46 for TP53) have also been found to serve as biomarkers underlying the role of TP53 family members in reducing tumor cell survival and inducing cell death via multiple mechanisms.	('tumor', 'Disease', (330, 335))	('TP53', 'Gene', (298, 302))	('tumor', 'Disease', 'MESH:D009369', (330, 335))	('TP53', 'Gene', (85, 89))	('S385', 'Var', (162, 166))	('TP53', 'Gene', (225, 229))	('TP53', 'Gene', (25, 29))	('tumor', 'Phenotype', 'HP:0002664', (330, 335))	('inducing', 'Reg', (354, 362))	('TP73', 'Gene', '7161', (194, 198))	('TP53', 'Gene', '7157', (298, 302))	('TP53', 'Gene', '7157', (85, 89))	('S46', 'Var', (217, 220))	('reducing', 'NegReg', (321, 329))	('Y99', 'Var', (186, 189))	('cell death', 'CPA', (363, 373))	('TP53', 'Gene', '7157', (225, 229))	('TP73', 'Gene', (194, 198))	('DeltaNp63alpha Y99', 'Var', (171, 189))	('TP53', 'Gene', '7157', (25, 29))
55030	27537898	We first found that the treatment with CA2, PMA, and ILQ lead to a marked increase in the LC3B-II/LC3B-II ratio in tested tumor cells (up to 2.8-3.2 x fold).	('CA2', 'Gene', '760', (39, 42))	('LC3B', 'Gene', (98, 102))	('LC3B', 'Gene', '81631', (90, 94))	('PMA', 'Chemical', 'MESH:C098378', (44, 47))	('CA2', 'Gene', (39, 42))	('increase', 'PosReg', (74, 82))	('LC3B', 'Gene', (90, 94))	('LC3B', 'Gene', '81631', (98, 102))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('PMA', 'Var', (44, 47))	('tumor', 'Disease', (122, 127))
55037	27537898	Thus, selected tumor cells (SCC-11, U87-MG, and RKO) previously transfected with the luciferase reporter plasmids carrying promoter sequences for ATG7, ATG10, ATG5, UVRAG, BECN1, ULK1, or control luciferase plasmid were treated with CA2, PMA, or ILQ, as indicated in Figure 4B.	('ATG7', 'Var', (146, 150))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('CA2', 'Gene', (233, 236))	('CA2', 'Gene', '760', (233, 236))	('SCC', 'Phenotype', 'HP:0002860', (28, 31))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumor', 'Disease', (15, 20))	('U87-MG', 'CellLine', 'CVCL:0022', (36, 42))	('PMA', 'Chemical', 'MESH:C098378', (238, 241))
55046	27537898	We found that in contrast to the scrambled RNA (Scr RNA), siRNA against TP63, TP73, and TP53 markedly decreased the protein levels of predominant isoforms DeltaNp63alpha, TP73alpha, and TP53 in the tested tumor cells (SCC-11, U87-MG, and RKO) even upon subsequent exposure of the tumor cells to the selected marine compounds (CA2, PMA, and ILQ), as shown in Figure 7.	('SCC', 'Phenotype', 'HP:0002860', (218, 221))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('CA2', 'Gene', (326, 329))	('TP53', 'Gene', '7157', (88, 92))	('TP73', 'Gene', '7161', (78, 82))	('TP63', 'Gene', (72, 76))	('CA2', 'Gene', '760', (326, 329))	('protein levels', 'MPA', (116, 130))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('TP73', 'Gene', (78, 82))	('TP53', 'Gene', (186, 190))	('tumor', 'Disease', (280, 285))	('TP73', 'Gene', '7161', (171, 175))	('decreased', 'NegReg', (102, 111))	('DeltaNp63alpha', 'Var', (155, 169))	('TP63', 'Gene', '8626', (72, 76))	('U87-MG', 'CellLine', 'CVCL:0022', (226, 232))	('tumor', 'Disease', 'MESH:D009369', (280, 285))	('TP53', 'Gene', (88, 92))	('TP73', 'Gene', (171, 175))	('TP53', 'Gene', '7157', (186, 190))	('tumor', 'Phenotype', 'HP:0002664', (280, 285))	('tumor', 'Disease', (205, 210))	('PMA', 'Chemical', 'MESH:C098378', (331, 334))
55067	27537898	Specific genotoxic stimuli are known to promote a series of reversible post-translational modifications of the TP53 protein including multisite phosphorylation events (e.g., S15 and S46) of the transactivation domain (N-terminus) leading to activation of TP53 as a transcriptional factor.	('phosphorylation', 'MPA', (144, 159))	('TP53', 'Gene', (255, 259))	('TP53', 'Gene', '7157', (111, 115))	('S46', 'Var', (182, 185))	('S15', 'Var', (174, 177))	('TP53', 'Gene', (111, 115))	('activation', 'PosReg', (241, 251))	('TP53', 'Gene', '7157', (255, 259))
55068	27537898	The phosphorylation at the S15 and S46 positions could stimulate association of TP53 with critical chromatin-associated proteins, such as histone/lysine acetyltransferases, as reviewed in.	('stimulate', 'PosReg', (55, 64))	('TP53', 'Gene', '7157', (80, 84))	('association', 'Interaction', (65, 76))	('TP53', 'Gene', (80, 84))	('S15', 'Var', (27, 30))	('phosphorylation', 'Var', (4, 19))	('S46', 'Var', (35, 38))
55070	27537898	Similarly, phosphorylation of DeltaNp63alpha at the S385 position and TP73 at the Y99 position were also found to be critical for the transcriptional role for DeltaNp63alpha and TP73, respectively.	('TP73', 'Gene', (178, 182))	('DeltaNp63alpha', 'Var', (159, 173))	('DeltaNp63alpha', 'Protein', (30, 44))	('TP73', 'Gene', '7161', (70, 74))	('TP73', 'Gene', (70, 74))	('phosphorylation', 'MPA', (11, 26))	('TP73', 'Gene', '7161', (178, 182))
55071	27537898	Therefore, our observations that ILQ could induce the phosphorylation of TP53 at the S15 and S46 positions, as well as that CA2 and PMA could induce the phosphorylation of DeltaNp63alpha at the S385 position, and TP73 at the Y99 position, respectively, might reflect their roles in transcriptional activation of downstream target genes, as indicated in.	('TP53', 'Gene', '7157', (73, 77))	('TP73', 'Gene', '7161', (213, 217))	('TP73', 'Gene', (213, 217))	('TP53', 'Gene', (73, 77))	('phosphorylation', 'MPA', (153, 168))	('CA2', 'Gene', (124, 127))	('DeltaNp63alpha', 'Var', (172, 186))	('PMA', 'Chemical', 'MESH:C098378', (132, 135))	('CA2', 'Gene', '760', (124, 127))	('phosphorylation', 'MPA', (54, 69))
55074	27537898	Finally, we found that silencing of TP53 family proteins with siRNA modulated the induction of autophagic gene expression in tested tumor cells upon exposure to CA2, PMA, and ILQ.	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('induction', 'MPA', (82, 91))	('autophagic gene', 'Gene', (95, 110))	('CA2', 'Gene', (161, 164))	('modulated', 'Reg', (68, 77))	('CA2', 'Gene', '760', (161, 164))	('silencing', 'Var', (23, 32))	('TP53', 'Gene', '7157', (36, 40))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumor', 'Disease', (132, 137))	('TP53', 'Gene', (36, 40))	('PMA', 'Chemical', 'MESH:C098378', (166, 169))
55080	27537898	For example, Helenalin, a sesquiterpene lactone; in addition to inducing cell cycle arrest and apoptosis, it also increased the levels of the autophagic markers.	('Helenalin', 'Chemical', 'MESH:C001329', (13, 22))	('apoptosis', 'CPA', (95, 104))	('increased', 'PosReg', (114, 123))	('cell cycle arrest', 'CPA', (73, 90))	('inducing', 'PosReg', (64, 72))	('Helenalin', 'Var', (13, 22))	('sesquiterpene lactone', 'Chemical', '-', (26, 47))	('levels of the autophagic markers', 'MPA', (128, 160))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (73, 90))
55092	27537898	Peiminine enhances the autophagic flux by repressing the phosphorylation of mTOR.	('Peiminine', 'Var', (0, 9))	('mTOR', 'Gene', (76, 80))	('mTOR', 'Gene', '2475', (76, 80))	('autophagic flux', 'CPA', (23, 38))	('Peiminine', 'Chemical', 'MESH:C047331', (0, 9))	('enhances', 'PosReg', (10, 18))	('phosphorylation', 'MPA', (57, 72))	('repressing', 'NegReg', (42, 52))
55093	27537898	Silencing of ATG5 expression greatly reduced the peiminine-induced cell death in wild-type HCT-116 cells, while treating BAX/BAK-deficient cells with peiminine resulted in significant cell death, suggesting a pathway independent of classical apoptosis.	('ATG5', 'Gene', (13, 17))	('peiminine-induced', 'MPA', (49, 66))	('HCT-116', 'CellLine', 'CVCL:0291', (91, 98))	('peiminine', 'Chemical', 'MESH:C047331', (150, 159))	('BAK', 'Gene', (125, 128))	('BAX', 'Gene', (121, 124))	('BAX', 'Gene', '581', (121, 124))	('reduced', 'NegReg', (37, 44))	('Silencing', 'Var', (0, 9))	('BAK', 'Gene', '578', (125, 128))	('peiminine', 'Chemical', 'MESH:C047331', (49, 58))
55096	27537898	All cell lines were authenticated by a short tandem repeat profiling analysis using the AmpFISTR Identifier PCR Amplification Lit (Applied Biosystems/Life Technologies, Carlsbad, CA, USA) with the following markers: Amelogenin X, CSF1PO, D13S317, D16S539, D5S818, D7S820, THO1, TPOX, and vWA at the JHMI Fragment Analysis Facility.	('D5S818', 'Var', (256, 262))	('CSF1PO', 'Var', (230, 236))	('D16S539', 'Var', (247, 254))	('D7S820', 'Var', (264, 270))	('THO1', 'Gene', (272, 276))	('THO1', 'Gene', '9984', (272, 276))	('D13S317', 'Var', (238, 245))
55107	27537898	5 x 106 cell chromatin equivalents were immunoprecipitated with 5 microg of the antibody against DeltaNp63alpha (PC-373, EMD/Millipore) ChIP-grade antibody against wild-type TP53 (GAH-112, Qiagen, Gaithersburg, MD, USA), and ChIP-grade TP73 antibody (#39941, Active Motif, Carlsbad, CA, USA), as described elsewhere.	('TP53', 'Gene', '7157', (174, 178))	('EMD', 'Disease', (121, 124))	('TP53', 'Gene', (174, 178))	('EMD', 'Disease', 'None', (121, 124))	('DeltaNp63alpha', 'Gene', (97, 111))	('TP73', 'Gene', '7161', (236, 240))	('TP73', 'Gene', (236, 240))	('#39941', 'Var', (251, 257))
55109	27537898	Specific regions for the ATG1/ULK1 promoter (Figure S1) sense, (-1850) 5'-GGTGCAATCTTTGCTCTTCT-3' (-1831), and antisense, (-1520) 5'-CCCTTCCAGCTCGGTGGCTT-3' (-1501); for the ATG5 promoter (Figure S2), sense, (-1900) 5'-CAGGGTCTCTCTCTGTTACC-3' (-1881), and antisense, (-1669) 5'-CCCAAAGTGCTGGGATTACA-3' (-1651); for the ARG6 (BECN1) promoter (Figure S3), sense, (-600) 5'-ATCCGCCCGCCTCGGCCTCC-3' (-581), and antisense, (-520) 5'-GTTCTGAGATGGAGCCTTGC-3' (501); for the ATG7 promoter (Figure S4), sense, (-1250) 5'-TCTGCTATTGCACGGTTCCT-3' (-1231), and antisense, (-1000) 5'-TTTCACCGTTTTAGCCGGGA-3' (-981); for the ATG10 promoter (Figure 5), sense, (-1070) 5'-ATAATCTAAATTGGCAGCTA-3' (-1051), and antisense, (870) 5'-CAGTCACCCCCTTCCTCCAG-3' (-851); and for the UVRAG promoter (Figure S6), sense, (-1900) 5'-AGTGACTCCTTTCTCAACAA-3' (-1981), and antisense, (-1670) 5'-TACTATATGCCAGGTCCTGT-3' (-1651).	('-1670', 'Var', (852, 857))	('ATG1', 'Gene', '8408', (25, 29))	('ATG1', 'Gene', (611, 615))	('ATG1', 'Gene', '8408', (611, 615))	('ATG1', 'Gene', (25, 29))	('-1900', 'Var', (793, 798))
55110	27537898	Non-specific regions were amplified with the following primers: for the ATG1/ULK1 promoter (Figure S1) sense, (-1350) 5'-TGCACGTGGTGAAAGCCATT-3' (-1331), and antisense, (-1220) 5'-TGGCTGCCGGCGGTGTGACT-3' (-1201); for the ATG5 promoter (Figure S2), sense, (-1500) 5'-CTACCATTATATTTTACTAT-3' (-1481), and antisense, (-1370) 5'-GCACCTTAATCCCACAAGCT-3' (-1351); for the ATG6 (BECN1) promoter (Figure S3), sense, (-200) 5'-GGAGCCTCCCCATTCTCTGC-3' (-181), and antisense, (-120) 5'-CCCAGCCCGGCCTCTGGGGG-3' (-101); for the ATG7 promoter (Figure S4), sense, (-500) 5'-GAATAACTTTATCTCACTGA-3' (-481), and antisense, (-370) 5'-GCCACCCTGATGGCCCCTGT-3' (-351); for the ATG10 promoter (Figure 5), sense, (-1550) 5'-CATTCTTTGCCATGAGGGAT-3' (-1531), and antisense, (-1420) 5'-TTTAAATTAACATGGTGGTT-3' (-1401); and for the UVRAG promoter (Figure S6), sense, (-1650) 5'-GTGGGCACTTTACATATGTT-3' (-1631), and antisense, (-1470) 5'-TGTTCATCCAGGTGGTGGAA-3' (-1451).	('ATG1', 'Gene', (72, 76))	('-1650', 'Var', (841, 846))	('-1470', 'Var', (900, 905))	('ATG6', 'Gene', '8678', (366, 370))	('ATG1', 'Gene', (656, 660))	('ATG1', 'Gene', '8408', (656, 660))	('ATG6', 'Gene', (366, 370))	('ATG1', 'Gene', '8408', (72, 76))
55141	26184314	MCPyV genome integration, for example, is associated with cancer progression.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('associated', 'Reg', (42, 52))	('MCPyV', 'Species', '493803', (0, 5))	('MCPyV genome integration', 'Var', (0, 24))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('cancer', 'Disease', (58, 64))
55147	26184314	Most importantly, all HPyV contain a potentially oncogenic Tag variant.	('variant', 'Var', (63, 70))	('oncogenic', 'Reg', (49, 58))	('PyV', 'Species', '36362', (23, 26))	('Tag', 'Gene', (59, 62))	('Tag', 'Gene', '404663', (59, 62))
55149	26184314	For example, MCPyV encodes a 57k Tag and JCPyV encodes T'135, T'136, and T'165.	('Tag', 'Gene', (33, 36))	('JCPyV', 'Species', '10632', (41, 46))	('Tag', 'Gene', '404663', (33, 36))	('MCPyV', 'Species', '493803', (13, 18))	("T'135", 'Var', (55, 60))
55153	26184314	Soon after, SV40 was revealed to induce salivary gland carcinomas in murine neonates and mesotheliomas, lymphomas, brain tumors, bone tumors, and sarcomas in hamsters.	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('lymphoma', 'Phenotype', 'HP:0002665', (104, 112))	('induce', 'PosReg', (33, 39))	('mesotheliomas', 'Disease', (89, 102))	('lymphomas', 'Disease', (104, 113))	('salivary gland carcinomas', 'Disease', 'MESH:D012468', (40, 65))	('brain tumors', 'Disease', (115, 127))	('salivary gland carcinomas', 'Disease', (40, 65))	('murine', 'Species', '10090', (69, 75))	('mesotheliomas', 'Disease', 'MESH:D008654', (89, 102))	('bone tumors', 'Disease', (129, 140))	('carcinomas', 'Phenotype', 'HP:0030731', (55, 65))	('bone tumors', 'Phenotype', 'HP:0010622', (129, 140))	('sarcomas', 'Disease', 'MESH:D012509', (146, 154))	('carcinoma', 'Phenotype', 'HP:0030731', (55, 64))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('sarcomas', 'Phenotype', 'HP:0100242', (146, 154))	('SV40', 'Var', (12, 16))	('sarcomas', 'Disease', (146, 154))	('bone tumors', 'Disease', 'MESH:D001859', (129, 140))	('brain tumors', 'Phenotype', 'HP:0030692', (115, 127))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('lymphomas', 'Disease', 'MESH:D008223', (104, 113))	('sarcoma', 'Phenotype', 'HP:0100242', (146, 153))	('lymphomas', 'Phenotype', 'HP:0002665', (104, 113))	('hamster', 'Species', '10034', (158, 165))	('salivary gland carcinomas', 'Phenotype', 'HP:0100684', (40, 65))	('brain tumors', 'Disease', 'MESH:D001932', (115, 127))
55154	26184314	In human biopsies, tumors equivalent to the hamster types have been found to contain SV40 DNA and proteins, which is why mesotheliomas and brain tumors have been most consistently linked with SV40.	('tumors', 'Disease', (19, 25))	('brain tumors', 'Disease', 'MESH:D001932', (139, 151))	('brain tumors', 'Phenotype', 'HP:0030692', (139, 151))	('human', 'Species', '9606', (3, 8))	('mesotheliomas', 'Disease', (121, 134))	('tumors', 'Disease', 'MESH:D009369', (145, 151))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('mesotheliomas', 'Disease', 'MESH:D008654', (121, 134))	('brain tumors', 'Disease', (139, 151))	('hamster', 'Species', '10034', (44, 51))	('SV40', 'Gene', (85, 89))	('proteins', 'Protein', (98, 106))	('linked', 'Reg', (180, 186))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('SV40', 'Var', (192, 196))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumors', 'Disease', (145, 151))
55158	26184314	Thanks to SV40, transcriptional regulation enhancers, alternative splicing, eukaryotic chromosomal DNA replication characterization, identification of tumor suppressor protein p53, elucidation of viral effects on cell cycle regulation, and identification of a protein nuclear localization signal was achieved.	('SV40', 'Var', (10, 14))	('enhancers', 'PosReg', (43, 52))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('p53', 'Gene', (176, 179))	('tumor', 'Disease', (151, 156))	('p53', 'Gene', '7157', (176, 179))	('alternative', 'Var', (54, 65))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
55159	26184314	Moreover, the extensive studies focusing on SV40 identified the two major viral oncoproteins, large Tag (90-100 kDa nuclear protein) and small tag (17-22 kDa), which are present in all human polyomaviruses (HPyV).	('PyV', 'Species', '36362', (208, 211))	('polyomaviruses', 'Species', '36362', (191, 205))	('human', 'Species', '9606', (185, 190))	('tag', 'Gene', '404663', (143, 146))	('Tag', 'Gene', '404663', (100, 103))	('Tag', 'Gene', (100, 103))	('tag', 'Gene', (143, 146))	('90-100 kDa', 'Var', (105, 115))
55177	26184314	Hence, Tag gene expression, leading to inactivation of p53, without evidence of a productive infection (i.e., viral protein expression, genome replication, etc.	('p53', 'Gene', (55, 58))	('p53', 'Gene', '7157', (55, 58))	('infection', 'Disease', (93, 102))	('infection', 'Disease', 'MESH:D007239', (93, 102))	('Tag', 'Gene', (7, 10))	('Tag', 'Gene', '404663', (7, 10))	('inactivation', 'Var', (39, 51))
55178	26184314	Causality based on this theory is hard to prove experimentally since the complete disappearance of the virus in tumor cells is likely, as HPyV Tag paves the way for tumorigenic transformation without the host cell actually supporting a full viral life cycle.	('PyV', 'Species', '36362', (139, 142))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('HPyV', 'Var', (138, 142))	('Tag', 'Gene', (143, 146))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('men', 'Species', '9606', (54, 57))	('Tag', 'Gene', '404663', (143, 146))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('tumor', 'Disease', (112, 117))	('tumor', 'Disease', (165, 170))
55195	26184314	MCPyV genomes are clonally integrated in approximately 85% of all MCC cases and all recuperated integrated genomes and MCC cell lines carry the same signature mutations in the early gene transcripts encoding for Tag.	('MCC', 'Disease', (66, 69))	('mutations', 'Var', (159, 168))	('MCPyV', 'Species', '493803', (0, 5))	('Tag', 'Gene', (212, 215))	('Tag', 'Gene', '404663', (212, 215))
55196	26184314	These mutations are important because they selectively abolish viral replication but maintain the oncogene Rb-binding ability, suggesting that the Rb fragment found within the viral protein Tag plays a crucial role during MCC pathogenesis.	('Tag', 'Gene', (190, 193))	('Rb-binding', 'Protein', (107, 117))	('viral replication', 'CPA', (63, 80))	('Tag', 'Gene', '404663', (190, 193))	('abolish', 'NegReg', (55, 62))	('men', 'Species', '9606', (154, 157))	('MCC', 'Disease', (222, 225))	('mutations', 'Var', (6, 15))
55197	26184314	Similar mutations that potentially lead to oncogenesis may be identified among other HPyVs in the future.	('oncogenesis', 'CPA', (43, 54))	('lead to', 'Reg', (35, 42))	('mutations', 'Var', (8, 17))	('PyV', 'Species', '36362', (86, 89))
55202	26184314	While the difference between MCPyV positivity in different types of CNS malignancies was not statistically significant (p =  0.066), a multiple linear regression analysis revealed statistically significant differences in MCPyV copy number between meningioma and other CNS tumor types, when the model was adjusted for age and sex (p =  0.024).	('MCPyV', 'Species', '493803', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (272, 277))	('tumor', 'Disease', (272, 277))	('meningioma', 'Disease', (247, 257))	('significant differences', 'Reg', (194, 217))	('CNS malignancies', 'Disease', (68, 84))	('CNS tumor', 'Phenotype', 'HP:0100006', (268, 277))	('tumor', 'Disease', 'MESH:D009369', (272, 277))	('CNS malignancies', 'Disease', 'MESH:D009369', (68, 84))	('copy number', 'Var', (227, 238))	('meningioma', 'Phenotype', 'HP:0002858', (247, 257))	('MCPyV', 'Gene', (221, 226))	('MCPyV', 'Species', '493803', (221, 226))	('meningioma', 'Disease', 'MESH:D008577', (247, 257))
55209	26184314	Data suggests that in an infected human colon, partial JCPyV DNA integration, along with additional events may lead to tumorigenesis and cancer progression.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('tumor', 'Disease', (119, 124))	('human', 'Species', '9606', (34, 39))	('JCPyV', 'Species', '10632', (55, 60))	('partial JCPyV DNA integration', 'Var', (47, 76))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('cancer', 'Disease', (137, 143))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('lead to', 'Reg', (111, 118))
55221	26184314	Prostate cancer is a common tumor in Western countries and abrogated p53 function is thought to contribute to prostate cancer risk.	('Prostate cancer', 'Phenotype', 'HP:0012125', (0, 15))	('tumor', 'Disease', (28, 33))	('p53', 'Gene', (69, 72))	('p53', 'Gene', '7157', (69, 72))	('prostate cancer', 'Disease', 'MESH:D011471', (110, 125))	('Prostate cancer', 'Disease', (0, 15))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('abrogated', 'Var', (59, 68))	('prostate cancer', 'Phenotype', 'HP:0012125', (110, 125))	('contribute', 'Reg', (96, 106))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('prostate cancer', 'Disease', (110, 125))	('Prostate cancer', 'Disease', 'MESH:D011471', (0, 15))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
55223	26184314	Indeed a quantitative PCR-based study searching for BKPyV viral DNA among clinical prostate cancer samples found that viral DNA copy numbers were higher in cancer tissues taken from higher Gleason score patients as compared to patients with lower Gleason scores.	('higher', 'PosReg', (146, 152))	('cancer', 'Disease', (156, 162))	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('prostate cancer', 'Disease', 'MESH:D011471', (83, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('viral', 'MPA', (118, 123))	('higher', 'Var', (182, 188))	('prostate cancer', 'Phenotype', 'HP:0012125', (83, 98))	('patients', 'Species', '9606', (203, 211))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('prostate cancer', 'Disease', (83, 98))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('BKPyV', 'Species', '1891762', (52, 57))	('patients', 'Species', '9606', (227, 235))
55229	26184314	The study further showed that the p53 gene from atrophic cells expressing Tag were wild type, whereas tumor cells expressing detectable nuclear p53 contain a mix of wild-type and mutant p53 genes, suggesting that Tag may inactivate p53 in the atrophic cells.	('p53', 'Gene', (34, 37))	('inactivate', 'NegReg', (221, 231))	('p53', 'Gene', '7157', (34, 37))	('mutant', 'Var', (179, 185))	('Tag', 'Gene', (74, 77))	('p53', 'Gene', '7157', (144, 147))	('Tag', 'Gene', (213, 216))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('p53', 'Gene', (232, 235))	('p53', 'Gene', '7157', (232, 235))	('Tag', 'Gene', '404663', (74, 77))	('p53', 'Gene', (186, 189))	('p53', 'Gene', '7157', (186, 189))	('Tag', 'Gene', '404663', (213, 216))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('p53', 'Gene', (144, 147))
55236	26184314	Importantly, a study evaluating the presence of SV40, BKPyV and JCPyV DNA among oral squamous cell carcinoma specimens did not find a significant difference between the cases and the controls, contraindicating a major role of any of these PyV in the etiology of oral squamous cell carcinoma.	('JCPyV', 'Species', '10632', (64, 69))	('SV40', 'Var', (48, 52))	('oral squamous cell carcinoma', 'Disease', (80, 108))	('PyV', 'Species', '36362', (239, 242))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (262, 290))	('men', 'Species', '9606', (114, 117))	('BKPyV', 'Species', '1891762', (54, 59))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (267, 290))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (85, 108))	('carcinoma', 'Phenotype', 'HP:0030731', (281, 290))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (80, 108))	('PyV', 'Species', '36362', (66, 69))	('oral squamous cell carcinoma', 'Disease', (262, 290))	('PyV', 'Species', '36362', (56, 59))
55296	26184314	The study found highest BKPyV VLs in patients diagnosed with HIVSGD (n = 11) as compared to patients who were HIV positive without HIVSGD (n = 46) and HIV negative individuals (n = 12).	('HIVSGD', 'Var', (61, 67))	('BKPyV VLs', 'MPA', (24, 33))	('highest', 'PosReg', (16, 23))	('patients', 'Species', '9606', (37, 45))	('patients', 'Species', '9606', (92, 100))	('BKPyV', 'Species', '1891762', (24, 29))
55319	26184314	The in vitro experiments show that a lysine to serine mutation of this residue switches the receptor specificity of BKPyV from GD3 to GM1.	('serine', 'Chemical', 'MESH:D012694', (47, 53))	('switches', 'Reg', (79, 87))	('BKPyV', 'Gene', (116, 121))	('lysine', 'Chemical', 'MESH:D008239', (37, 43))	('BKPyV', 'Species', '1891762', (116, 121))	('GM1', 'Chemical', 'MESH:D005677', (134, 137))	('lysine to', 'Var', (37, 46))	('men', 'Species', '9606', (19, 22))	('receptor specificity', 'MPA', (92, 112))
55326	26184314	The NCCR is a hypervariable region and comparative studies have suggested that it may regulate host cell tropism mainly due to the rearrangement, duplication or deletion of TFBS.	('men', 'Species', '9606', (140, 143))	('host cell tropism', 'CPA', (95, 112))	('TFBS', 'Chemical', '-', (173, 177))	('deletion', 'Var', (161, 169))	('rearrangement', 'Var', (131, 144))	('duplication', 'Var', (146, 157))	('regulate', 'Reg', (86, 94))	('TFBS', 'Gene', (173, 177))
55328	26184314	The BKPyV NCCR commonly undergoes block deletions and/or duplications as compared to the archetype.	('undergoes', 'Reg', (24, 33))	('duplications', 'Var', (57, 69))	('block', 'CPA', (34, 39))	('BKPyV', 'Gene', (4, 9))	('BKPyV', 'Species', '1891762', (4, 9))
55331	26184314	It has been shown that NCCR block rearrangements bestow remarkable differences in transforming potential and host cell permissiveness.	('rearrangements', 'Var', (34, 48))	('transforming potential', 'CPA', (82, 104))	('men', 'Species', '9606', (43, 46))	('host cell permissiveness', 'CPA', (109, 133))
55332	26184314	Clinical studies determined that the emergence of rr NCCR BKPyV variants in the plasma samples from immune suppressed kidney transplant recipients were correlated to increased replication efficiencies and pathogenesis.	('replication efficiencies', 'CPA', (176, 200))	('increased', 'PosReg', (166, 175))	('rr NCCR BKPyV', 'Gene', (50, 63))	('BKPyV', 'Species', '1891762', (58, 63))	('variants', 'Var', (64, 72))
55338	26184314	While host factors contribute to the viral pathogenic capacity and likely fluctuate between individuals and over time both JCPyV and BKPyV promoter rearrangements are likely to drive viral replication and therefore pathogenicity in vivo.	('JCPyV', 'Species', '10632', (123, 128))	('drive', 'PosReg', (177, 182))	('viral replication', 'MPA', (183, 200))	('BKPyV', 'Species', '1891762', (133, 138))	('BKPyV', 'Gene', (133, 138))	('JCPyV', 'Gene', (123, 128))	('rearrangements', 'Var', (148, 162))	('men', 'Species', '9606', (157, 160))
55339	26184314	Whether BKPyV rr NCCR variants are more efficient at in vivo disease development is debated but not unlikely since JCPyV promoter rearrangements have also been suggested to drive neural tropism and bestow increased virulence as discussed above.	('neural tropism', 'Disease', 'MESH:C565640', (179, 193))	('neural tropism', 'Disease', (179, 193))	('JCPyV', 'Species', '10632', (115, 120))	('BKPyV', 'Species', '1891762', (8, 13))	('men', 'Species', '9606', (76, 79))	('increased', 'PosReg', (205, 214))	('virulence', 'MPA', (215, 224))	('men', 'Species', '9606', (139, 142))	('JCPyV', 'Gene', (115, 120))	('variants', 'Var', (22, 30))	('drive', 'PosReg', (173, 178))
55340	26184314	It is important to conclusively determine whether BKPyV promoter rearrangements truly endow higher replication levels and increased virulence in order to understand BKPyV pathogenesis and prevent disease development effectively.	('endow', 'Reg', (86, 91))	('higher', 'PosReg', (92, 98))	('virulence', 'MPA', (132, 141))	('rearrangements', 'Var', (65, 79))	('men', 'Species', '9606', (211, 214))	('BKPyV', 'Species', '1891762', (50, 55))	('BKPyV', 'Species', '1891762', (165, 170))	('men', 'Species', '9606', (74, 77))	('increased', 'PosReg', (122, 131))	('BKPyV promoter', 'Gene', (50, 64))	('replication levels', 'MPA', (99, 117))
55344	26184314	In the past 15 years renewed interest in HPyV and its prevalence and pathology has been sparked as a result of novel HPyV identifications and the accumulation of evidence suggesting that more than just the HPyV MCPyV may cause cancer.	('PyV', 'Species', '36362', (207, 210))	('PyV', 'Species', '36362', (118, 121))	('HPyV', 'Gene', (117, 121))	('MCPyV', 'Species', '493803', (211, 216))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('PyV', 'Species', '36362', (213, 216))	('cancer', 'Disease', 'MESH:D009369', (227, 233))	('MCPyV', 'Var', (211, 216))	('cancer', 'Disease', (227, 233))	('cause', 'Reg', (221, 226))	('PyV', 'Species', '36362', (42, 45))
55347	26184314	For BKPyV in particular, there is no specific antiviral treatment available, despite BKVN often resulting in chronic allograft dysfunction and failure.	('allograft dysfunction and failure', 'Disease', 'MESH:D007676', (117, 150))	('resulting in', 'Reg', (96, 108))	('BKPyV', 'Species', '1891762', (4, 9))	('men', 'Species', '9606', (61, 64))	('BKVN', 'Var', (85, 89))
55350	24945674	Genetic Variants of EGF and VEGF Predict Prognosis of Patients with Advanced Esophageal Squamous Cell Carcinoma To investigate the association between genetic polymorphisms of growth factor-related genes and prognosis in patients with advanced esophageal squamous cell carcinoma (ESCC).	('EGF', 'Gene', (29, 32))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (244, 278))	('VEGF', 'Gene', (28, 32))	('patients', 'Species', '9606', (221, 229))	('Carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('Patients', 'Species', '9606', (54, 62))	('carcinoma', 'Phenotype', 'HP:0030731', (269, 278))	('Advanced Esophageal Squamous Cell Carcinoma', 'Disease', 'MESH:D000077277', (68, 111))	('esophageal squamous cell carcinoma', 'Disease', (244, 278))	('Variants', 'Var', (8, 16))	('EGF', 'Gene', '1950', (29, 32))	('VEGF', 'Gene', '7422', (28, 32))	('EGF', 'Gene', (20, 23))	('Predict', 'Reg', (33, 40))	('EGF', 'Gene', '1950', (20, 23))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (88, 111))	('Advanced Esophageal Squamous Cell Carcinoma', 'Disease', (68, 111))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (255, 278))
55352	24945674	The genotypes of 14 candidate single nucleotide polymorphisms (SNPs) involved in growth factor-related functions were analyzed using iPLEX Gold technology from the genomic DNA of peripheral leukocytes, and were correlated with the clinical outcome of patients.	('single nucleotide polymorphisms', 'Var', (30, 61))	('patients', 'Species', '9606', (251, 259))	('correlated', 'Reg', (211, 221))
55353	24945674	The genetic polymorphisms of EGF:rs4444903, EGF:rs2237051 and VEGF:rs2010963 showed significant associations with overall survival (OS) of advanced ESCC patients (A/A+ A/G vs. GG, [HR = 0.77, 95% CI = 0.60-0.99, P = 0.039 for rs4444903; A/G+ G/G vs. A/A, [HR = 0.74, 95% CI = 0.58-0.95, P = 0.019 for rs2237051; G/G+G/C vs. C/C, [HR] inves = 0.69, 95% CI = 0.50-0.95, P = 0.023 for rs2010963).	('EGF', 'Gene', (29, 32))	('patients', 'Species', '9606', (153, 161))	('rs2237051; G/G+G/C vs.', 'Var', (301, 323))	('rs4444903', 'Var', (33, 42))	('rs2010963', 'Mutation', 'rs2010963', (382, 391))	('rs4444903', 'Mutation', 'rs4444903', (33, 42))	('overall', 'MPA', (114, 121))	('rs2237051', 'Mutation', 'rs2237051', (48, 57))	('rs2010963', 'Mutation', 'rs2010963', (67, 76))	('rs4444903', 'Var', (226, 235))	('VEGF', 'Gene', '7422', (62, 66))	('rs4444903', 'Mutation', 'rs4444903', (226, 235))	('rs2237051', 'Var', (48, 57))	('ESCC', 'Disease', (148, 152))	('VEGF', 'Gene', (62, 66))	('associations', 'Interaction', (96, 108))	('rs2237051', 'Mutation', 'rs2237051', (301, 310))
55354	24945674	EGFR:rs2227983 and 3 SNPs of PIK3CA also showed borderline significant correlation with OS of advanced ESCC patients (P = 0.058 for rs2227983; P = 0.069, 0.091 and 0.067 for rs6443624, rs7651265 and rs7621329 of PIK3CA respectively).	('rs6443624', 'Mutation', 'rs6443624', (174, 183))	('rs2227983', 'Var', (132, 141))	('EGFR', 'Gene', (0, 4))	('rs2227983', 'Var', (5, 14))	('rs7651265', 'Var', (185, 194))	('patients', 'Species', '9606', (108, 116))	('PIK3CA', 'Gene', (212, 218))	('rs2227983', 'Mutation', 'rs2227983', (132, 141))	('rs2227983', 'Mutation', 'rs2227983', (5, 14))	('EGFR', 'Gene', '1956', (0, 4))	('rs6443624', 'Var', (174, 183))	('rs7621329', 'Var', (199, 208))	('PIK3CA', 'Gene', '5290', (212, 218))	('advanced ESCC patients', 'Disease', (94, 116))	('PIK3CA', 'Gene', (29, 35))	('PIK3CA', 'Gene', '5290', (29, 35))	('rs7651265', 'Mutation', 'rs7651265', (185, 194))	('rs7621329', 'Mutation', 'rs7621329', (199, 208))
55369	24945674	Genetic variants of EGFR have also been shown to influence clinical outcome of many different types of cancer including non-small-cell lung cancer (NSCLC), prostate cancer, metastatic colorectal cancer (mCRC), and pancreatic cancer.	('prostate cancer', 'Disease', (156, 171))	('EGFR', 'Gene', (20, 24))	('colorectal cancer', 'Disease', 'MESH:D015179', (184, 201))	('cancer', 'Disease', (225, 231))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('NSCLC', 'Disease', 'MESH:D002289', (148, 153))	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('pancreatic cancer', 'Disease', (214, 231))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('cancer', 'Disease', (103, 109))	('colorectal cancer', 'Disease', (184, 201))	('influence', 'Reg', (49, 58))	('non-small-cell lung cancer', 'Disease', (120, 146))	('non-small-cell lung cancer', 'Disease', 'MESH:D002289', (120, 146))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('NSCLC', 'Disease', (148, 153))	('variants', 'Var', (8, 16))	('EGFR', 'Gene', '1956', (20, 24))	('NSCLC', 'Phenotype', 'HP:0030358', (148, 153))	('cancer', 'Disease', 'MESH:D009369', (225, 231))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (214, 231))	('cancer', 'Disease', (195, 201))	('cancer', 'Disease', (140, 146))	('colorectal cancer', 'Phenotype', 'HP:0003003', (184, 201))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (124, 146))	('cancer', 'Disease', (165, 171))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (120, 146))	('lung cancer', 'Phenotype', 'HP:0100526', (135, 146))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('prostate cancer', 'Disease', 'MESH:D011471', (156, 171))	('prostate cancer', 'Phenotype', 'HP:0012125', (156, 171))	('pancreatic cancer', 'Disease', 'MESH:D010190', (214, 231))
55370	24945674	Most studies have focused on the R497K (rs2227983) and the CA repeat polymorphisms within intron 1, as EGFR R497K is known to attenuate the binding of the ligand EGF while the CA repeat polymorphism appears to significantly influence the transcription of EGFR .	('EGFR', 'Gene', '1956', (255, 259))	('EGFR', 'Gene', (255, 259))	('R497K', 'Var', (108, 113))	('ligand', 'Interaction', (155, 161))	('attenuate', 'NegReg', (126, 135))	('EGF', 'Protein', (162, 165))	('EGFR', 'Gene', '1956', (103, 107))	('binding', 'Interaction', (140, 147))	('rs2227983', 'Var', (40, 49))	('EGFR', 'Gene', (103, 107))	('rs2227983', 'Mutation', 'rs2227983', (40, 49))	('R497K', 'Mutation', 'rs2227983', (108, 113))	('influence', 'Reg', (224, 233))	('R497K', 'Mutation', 'rs2227983', (33, 38))	('transcription', 'MPA', (238, 251))
55371	24945674	The interaction of EGFR R497K with EGF at the +61A/G (rs4444903) polymorphism has been shown to enhance the risk of esophageal cancer.	('esophageal cancer', 'Disease', 'MESH:D004938', (116, 133))	('R497K', 'Mutation', 'rs2227983', (24, 29))	('interaction', 'Interaction', (4, 15))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('rs4444903', 'Var', (54, 63))	('rs4444903', 'Mutation', 'rs4444903', (54, 63))	('enhance', 'PosReg', (96, 103))	('EGFR', 'Gene', '1956', (19, 23))	('R497K', 'Var', (24, 29))	('+61A/G', 'Mutation', 'rs4444903', (46, 52))	('EGFR', 'Gene', (19, 23))	('esophageal cancer', 'Disease', (116, 133))
55372	24945674	We also found that the polymorphism in EGFR intron 1 was able to predict the prognosis of our patients with esophageal cancer after chemoradiation and surgery previously.	('predict', 'Reg', (65, 72))	('patients', 'Species', '9606', (94, 102))	('esophageal cancer', 'Disease', (108, 125))	('esophageal cancer', 'Disease', 'MESH:D004938', (108, 125))	('EGFR', 'Gene', '1956', (39, 43))	('polymorphism', 'Var', (23, 35))	('EGFR', 'Gene', (39, 43))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
55379	24945674	The genetic polymorphisms of the insulin-related pathway are associated with the risk of colorectal cancer and prostate cancer.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('colorectal cancer', 'Phenotype', 'HP:0003003', (89, 106))	('prostate cancer', 'Disease', (111, 126))	('insulin', 'Gene', (33, 40))	('insulin', 'Gene', '3630', (33, 40))	('colorectal cancer', 'Disease', (89, 106))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('prostate cancer', 'Disease', 'MESH:D011471', (111, 126))	('colorectal cancer', 'Disease', 'MESH:D015179', (89, 106))	('prostate cancer', 'Phenotype', 'HP:0012125', (111, 126))	('genetic polymorphisms', 'Var', (4, 25))	('associated', 'Reg', (61, 71))
55382	24945674	The SNPs of the genes involved in the PI3K/PTEN/AKT/mTOR pathway have recently been demonstrated to be associated with treatment outcome in esophageal cancer patients who have undergone surgery and chemoradiotherapy.	('mTOR', 'Gene', (52, 56))	('mTOR', 'Gene', '2475', (52, 56))	('esophageal cancer', 'Disease', 'MESH:D004938', (140, 157))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('AKT', 'Gene', (48, 51))	('men', 'Species', '9606', (124, 127))	('PTEN', 'Gene', (43, 47))	('associated with', 'Reg', (103, 118))	('SNPs', 'Var', (4, 8))	('PTEN', 'Gene', '5728', (43, 47))	('AKT', 'Gene', '207', (48, 51))	('patients', 'Species', '9606', (158, 166))	('esophageal cancer', 'Disease', (140, 157))
55384	24945674	Two SNPs within the genes AKT2 and FRAP1 (encoding mTOR) were correlated with poor treatment response, while a better response was associated with heterozygosity for AKT1 rs3803304.	('mTOR', 'Gene', (51, 55))	('AKT2', 'Gene', '208', (26, 30))	('AKT1', 'Gene', '207', (166, 170))	('FRAP1', 'Gene', '2475', (35, 40))	('AKT2', 'Gene', (26, 30))	('treatment response', 'CPA', (83, 101))	('men', 'Species', '9606', (88, 91))	('rs3803304', 'Var', (171, 180))	('rs3803304', 'Mutation', 'rs3803304', (171, 180))	('mTOR', 'Gene', '2475', (51, 55))	('AKT1', 'Gene', (166, 170))	('FRAP1', 'Gene', (35, 40))
55385	24945674	Growing reports revealed the significant prognostic relevance of the SNPs among the genes involved in growth factor-mediated pathways in cancers.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('cancers', 'Phenotype', 'HP:0002664', (137, 144))	('cancers', 'Disease', 'MESH:D009369', (137, 144))	('cancers', 'Disease', (137, 144))	('SNPs', 'Var', (69, 73))
55415	24945674	To select potential prognostically relevant SNPs, we randomly selected 95 subjects to conduct a pre-test by analyzing 26 growth-factor related SNPs, including 8 SNPs in EGFR; 2 SNPs in EGF; 2 SNPs in IGF1R; 2 SNPs in IGF; 4 SNPs in VEGF; 3 SNPs in PIK3CA; and a single SNP in AKT1, AKT2, FRAP1 and PTEN (Table S1).	('IGF1R', 'Gene', (200, 205))	('AKT2', 'Gene', (282, 286))	('AKT2', 'Gene', '208', (282, 286))	('PTEN', 'Gene', '5728', (298, 302))	('IGF1R', 'Gene', '3480', (200, 205))	('SNPs', 'Var', (177, 181))	('PIK3CA', 'Gene', '5290', (248, 254))	('EGFR', 'Gene', '1956', (169, 173))	('AKT1', 'Gene', '207', (276, 280))	('SNPs', 'Var', (192, 196))	('VEGF', 'Gene', (232, 236))	('FRAP1', 'Gene', (288, 293))	('PTEN', 'Gene', (298, 302))	('PIK3CA', 'Gene', (248, 254))	('EGFR', 'Gene', (169, 173))	('AKT1', 'Gene', (276, 280))	('VEGF', 'Gene', '7422', (232, 236))	('FRAP1', 'Gene', '2475', (288, 293))
55418	24945674	Both SNPs in EGF, rs4444903 and rs2237051, exhibited significance for overall survival (Table 2).	('rs4444903', 'Var', (18, 27))	('rs4444903', 'Mutation', 'rs4444903', (18, 27))	('rs2237051', 'Var', (32, 41))	('rs2237051', 'Mutation', 'rs2237051', (32, 41))
55419	24945674	Patients carrying major allele A in EGF:rs4444903 exhibited obvious reduced risk for death ([HR] = 0.77, 95% CI = 0.60-0.99, P = 0.039; Table 2), whereas patients with the minor allele G in EGF:rs2237051 showed significantly better survival ([HR] = 0.74, 95% CI = 0.58-0.95, P = 0.019, Table 2).	('death', 'Disease', 'MESH:D003643', (85, 90))	('death', 'Disease', (85, 90))	('rs4444903', 'Var', (40, 49))	('patients', 'Species', '9606', (154, 162))	('rs4444903', 'Mutation', 'rs4444903', (40, 49))	('Patients', 'Species', '9606', (0, 8))	('rs2237051', 'Mutation', 'rs2237051', (194, 203))	('reduced', 'NegReg', (68, 75))	('better', 'PosReg', (225, 231))	('EGF', 'Gene', (36, 39))
55420	24945674	The wildtype genotype of VEGF:rs2010963 was also significantly associated with improved survival ([HR] = 0.69, 95% CI = 0.50-0.95, P = 0.023; Table 2).	('survival', 'CPA', (88, 96))	('improved', 'PosReg', (79, 87))	('rs2010963', 'Var', (30, 39))	('VEGF', 'Gene', '7422', (25, 29))	('VEGF', 'Gene', (25, 29))	('rs2010963', 'Mutation', 'rs2010963', (30, 39))
55421	24945674	EGFR:rs2227983 and 3 SNPs in PIK3CA also exhibited borderline significant correlation with survival (P = 0.058 for EGFR:rs2227983; P = 0.069 for PIK3CA:rs6443624; P = 0.091 for PIK3CA:rs7651265; P = 0.067 for PIK3CA:rs7621329; Table 2).	('PIK3CA', 'Gene', '5290', (177, 183))	('rs2227983', 'Var', (5, 14))	('EGFR', 'Gene', (115, 119))	('rs7651265', 'Mutation', 'rs7651265', (184, 193))	('rs6443624', 'Mutation', 'rs6443624', (152, 161))	('PIK3CA', 'Gene', (209, 215))	('rs2227983', 'Mutation', 'rs2227983', (120, 129))	('PIK3CA', 'Gene', (145, 151))	('rs7651265', 'Var', (184, 193))	('PIK3CA', 'Gene', (177, 183))	('PIK3CA', 'Gene', '5290', (29, 35))	('EGFR', 'Gene', (0, 4))	('EGFR', 'Gene', '1956', (115, 119))	('rs2227983', 'Mutation', 'rs2227983', (5, 14))	('PIK3CA', 'Gene', '5290', (209, 215))	('rs6443624', 'Var', (152, 161))	('PIK3CA', 'Gene', (29, 35))	('PIK3CA', 'Gene', '5290', (145, 151))	('EGFR', 'Gene', '1956', (0, 4))	('rs7621329', 'Mutation', 'rs7621329', (216, 225))
55422	24945674	Even though none of these genetic polymorphisms significantly predicted tumor recurrence among these patients, EGFR:rs2227983, VEGF:rs2010963, and EGF:rs2237051 showed borderline significance for disease progression (P = 0.058 for EGFR:rs2227983, P = 0.073 for VEGF:rs2010963, and P = 0.104 for EGF:rs2237051; Table 2).	('VEGF', 'Gene', (261, 265))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('EGFR', 'Gene', '1956', (111, 115))	('rs2227983', 'Var', (116, 125))	('rs2010963', 'Mutation', 'rs2010963', (132, 141))	('rs2237051', 'Mutation', 'rs2237051', (151, 160))	('rs2237051', 'Mutation', 'rs2237051', (299, 308))	('rs2010963', 'Mutation', 'rs2010963', (266, 275))	('patients', 'Species', '9606', (101, 109))	('EGFR', 'Gene', (231, 235))	('VEGF', 'Gene', '7422', (127, 131))	('tumor', 'Disease', (72, 77))	('EGFR', 'Gene', (111, 115))	('VEGF', 'Gene', (127, 131))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('VEGF', 'Gene', '7422', (261, 265))	('EGFR', 'Gene', '1956', (231, 235))	('rs2227983', 'Mutation', 'rs2227983', (116, 125))	('rs2227983', 'Mutation', 'rs2227983', (236, 245))
55424	24945674	These two EGF SNPs separately analyzed in combination with VEGF:rs2010963 resulted in more significant joint effects.	('joint effects', 'CPA', (103, 116))	('VEGF', 'Gene', '7422', (59, 63))	('rs2010963', 'Var', (64, 73))	('VEGF', 'Gene', (59, 63))	('rs2010963', 'Mutation', 'rs2010963', (64, 73))
55425	24945674	Patients with both unfavorable genotypes of VEGF:rs2010963 and either EGF:rs4444903 or EGF:rs2237051 had an approximately 1.7-fold increased risk of death ([HR] = 1.70, 95% CI = 1.06-2.72, P = 0.027, P trend = 0.003 for EGF:rs4444903 with VEGF:rs2010963; [HR] = 1.74, 95% CI = 1.09-2.80, P = 0.022, P trend = 0.002 for EGF:rs2237051 with VEGF:rs2010963; Table 4).	('VEGF', 'Gene', (338, 342))	('rs4444903', 'Mutation', 'rs4444903', (74, 83))	('VEGF', 'Gene', (44, 48))	('rs2237051', 'Mutation', 'rs2237051', (323, 332))	('rs4444903', 'Mutation', 'rs4444903', (224, 233))	('rs4444903', 'Var', (74, 83))	('Patients', 'Species', '9606', (0, 8))	('rs2010963', 'Var', (49, 58))	('rs2010963', 'Mutation', 'rs2010963', (343, 352))	('death', 'Disease', (149, 154))	('VEGF', 'Gene', '7422', (239, 243))	('rs2237051', 'Mutation', 'rs2237051', (91, 100))	('rs2010963', 'Mutation', 'rs2010963', (49, 58))	('VEGF', 'Gene', (239, 243))	('EGF', 'Var', (70, 73))	('rs2010963', 'Mutation', 'rs2010963', (244, 253))	('VEGF', 'Gene', '7422', (338, 342))	('VEGF', 'Gene', '7422', (44, 48))	('death', 'Disease', 'MESH:D003643', (149, 154))
55426	24945674	The cumulative effect of VEGF:rs2010963 with either EGF:rs4444903 or EGF:rs2010963 is better than the effect of all the 3 SNPs combined (P = 0.075).	('rs4444903', 'Mutation', 'rs4444903', (56, 65))	('rs2010963', 'Mutation', 'rs2010963', (73, 82))	('VEGF', 'Gene', '7422', (25, 29))	('rs2010963', 'Var', (30, 39))	('better', 'PosReg', (86, 92))	('VEGF', 'Gene', (25, 29))	('rs2010963', 'Mutation', 'rs2010963', (30, 39))
55427	24945674	We further jointly analyzed EGFR:rs2227983 and PIK3CA:rs6443624.	('PIK3CA', 'Gene', (47, 53))	('EGFR', 'Gene', '1956', (28, 32))	('rs2227983', 'Var', (33, 42))	('PIK3CA', 'Gene', '5290', (47, 53))	('rs2227983', 'Mutation', 'rs2227983', (33, 42))	('EGFR', 'Gene', (28, 32))	('rs6443624', 'Mutation', 'rs6443624', (54, 63))	('rs6443624', 'Var', (54, 63))
55428	24945674	The hazard for death further increased to 3.29 or 3.14-fold in patients carrying the four unfavorable genotypes of VEGF, EGFR, PIK3CA and either EGF:rs2237051 or EGF:rs4444903 ([HR] = 3.29, 95% CI = 1.36-7.96, P = 0.008 and [HR] = 3.14, 95% CI = 1.12-8.19, P = 0.008, respectively; Table 4).	('rs4444903', 'Mutation', 'rs4444903', (166, 175))	('EGFR', 'Gene', '1956', (121, 125))	('VEGF', 'Gene', (115, 119))	('EGF', 'Var', (145, 148))	('PIK3CA', 'Gene', (127, 133))	('EGFR', 'Gene', (121, 125))	('PIK3CA', 'Gene', '5290', (127, 133))	('rs2237051', 'Mutation', 'rs2237051', (149, 158))	('patients', 'Species', '9606', (63, 71))	('VEGF', 'Gene', '7422', (115, 119))	('death', 'Disease', 'MESH:D003643', (15, 20))	('death', 'Disease', (15, 20))
55431	24945674	Compared with those carrying favorable genotypes, patients with the adverse genotypes had a significantly reduced survival duration (MST = 12.53 vs. 8.62 months, log-rank P = 0.025 for EGF:rs4444903, Fig.	('patients', 'Species', '9606', (50, 58))	('EGF', 'Var', (185, 188))	('survival duration', 'CPA', (114, 131))	('rs4444903', 'Mutation', 'rs4444903', (189, 198))	('reduced', 'NegReg', (106, 113))
55433	24945674	Overall survival also differed significantly among the group of advanced ESCC patients according to the accumulated number of unfavorable genotypes within EGF, VEGF, EGFR and PIK3CA (log-rank P = 0.013 in EGF:rs4444903-containing set, and log-rank P = 0.007 in EGF:rs2237051-containing set, Fig.	('PIK3CA', 'Gene', (175, 181))	('differed', 'Reg', (22, 30))	('VEGF', 'Gene', (160, 164))	('EGFR', 'Gene', '1956', (166, 170))	('rs4444903-containing', 'Var', (209, 229))	('EGFR', 'Gene', (166, 170))	('PIK3CA', 'Gene', '5290', (175, 181))	('rs2237051', 'Mutation', 'rs2237051', (265, 274))	('patients', 'Species', '9606', (78, 86))	('rs4444903', 'Mutation', 'rs4444903', (209, 218))	('VEGF', 'Gene', '7422', (160, 164))
55434	24945674	Patients carrying all of the unfavorable genotypes exhibited significantly increased risk of death compared with those carrying none of the adverse genotypes (MST = 17.51 vs. 5.21 months in EGF:rs4444903-containing set, and MST = 14.72 vs. 5.21 months in EGF:rs2237051-containing set, Fig.	('rs2237051', 'Mutation', 'rs2237051', (259, 268))	('rs4444903', 'Mutation', 'rs4444903', (194, 203))	('death', 'Disease', 'MESH:D003643', (93, 98))	('Patients', 'Species', '9606', (0, 8))	('death', 'Disease', (93, 98))	('rs4444903-containing', 'Var', (194, 214))
55437	24945674	The rs4444903 SNP, localized at position 61 in the 5'-untranslated region (5'UTR) of EGF, has been found to be correlated with production level of EGF measured in peripheral-blood mononuclear cells in-vitro .	('rs4444903 SNP', 'Var', (4, 17))	('production level', 'MPA', (127, 143))	('correlated', 'Reg', (111, 121))	('EGF', 'Gene', (85, 88))	('rs4444903', 'Mutation', 'rs4444903', (4, 13))
55438	24945674	Meanwhile, rs2010963 at the 5'-UTR of VEGF has also been suggested to modulate VEGF level.	('modulate', 'Reg', (70, 78))	('rs2010963', 'Mutation', 'rs2010963', (11, 20))	('VEGF', 'Gene', '7422', (38, 42))	('VEGF', 'Gene', '7422', (79, 83))	('rs2010963', 'Var', (11, 20))	('VEGF', 'Gene', (38, 42))	('VEGF', 'Gene', (79, 83))
55442	24945674	As expected, homozygous GG carriers of rs4444903 showed a trend of increased EGF level compared with AA carriers (Fig.	('rs4444903', 'Var', (39, 48))	('rs4444903', 'Mutation', 'rs4444903', (39, 48))	('increased', 'PosReg', (67, 76))	('increased EGF level', 'Phenotype', 'HP:0003496', (67, 86))	('EGF level', 'MPA', (77, 86))
55443	24945674	However, we did not find an association between the genotypes of rs2010963 and serum VEGF level (Fig.	('rs2010963', 'Mutation', 'rs2010963', (65, 74))	('VEGF', 'Gene', (85, 89))	('rs2010963', 'Var', (65, 74))	('VEGF', 'Gene', '7422', (85, 89))
55446	24945674	Kaplan-Meier survival analysis revealed that the group with detectable levels of EGF had a significantly increased risk of death compared to the group with undetectable levels (MST = 36.92 vs. 9.12 months, log-rank P = 0.010, Fig.	('death', 'Disease', (123, 128))	('death', 'Disease', 'MESH:D003643', (123, 128))	('detectable levels', 'Var', (60, 77))	('EGF', 'Gene', (81, 84))
55450	24945674	A growing body of research shows a significant association between SNPs of the genes involved in growth factor mediated pathways and prognosis of esophageal adenocarcinoma cancer.	('esophageal adenocarcinoma cancer', 'Disease', 'MESH:D004938', (146, 178))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('esophageal adenocarcinoma cancer', 'Disease', (146, 178))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (146, 171))	('SNPs', 'Var', (67, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (162, 171))
55451	24945674	We here have demonstrated that the genetic polymorphisms rs4444903 and rs2237051 in EGF and rs2010963 in VEGF were significantly correlated with the clinical outcome of patients with advanced ESCC (Table 2).	('patients', 'Species', '9606', (169, 177))	('rs2237051', 'Var', (71, 80))	('correlated with', 'Reg', (129, 144))	('ESCC', 'Disease', (192, 196))	('VEGF', 'Gene', (105, 109))	('rs4444903', 'Var', (57, 66))	('rs4444903', 'Mutation', 'rs4444903', (57, 66))	('rs2010963', 'Mutation', 'rs2010963', (92, 101))	('VEGF', 'Gene', '7422', (105, 109))	('rs2237051', 'Mutation', 'rs2237051', (71, 80))	('rs2010963', 'Var', (92, 101))
55452	24945674	Meanwhile, the SNPs in EGFR and PIK3CA also showed a borderline significant effect for prognosis.	('PIK3CA', 'Gene', '5290', (32, 38))	('SNPs', 'Var', (15, 19))	('EGFR', 'Gene', '1956', (23, 27))	('EGFR', 'Gene', (23, 27))	('PIK3CA', 'Gene', (32, 38))
55456	24945674	The G/G genotype of the EGF +61A/G polymorphism has been observed to correlate with a greater risk of esophageal adenocarcinoma and increased levels of EGF in gastroesophageal reflux disease patients compared with A/A or A/G.	('gastroesophageal reflux disease', 'Disease', 'MESH:D005764', (159, 190))	('patients', 'Species', '9606', (191, 199))	('levels', 'MPA', (142, 148))	('EGF +61A/G', 'Gene', (24, 34))	('G/G', 'Var', (4, 7))	('esophageal adenocarcinoma', 'Disease', (102, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (102, 127))	('increased', 'PosReg', (132, 141))	('+61A/G', 'Mutation', 'rs4444903', (28, 34))	('EGF', 'MPA', (152, 155))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (102, 127))	('gastroesophageal reflux disease', 'Disease', (159, 190))	('gastroesophageal reflux', 'Phenotype', 'HP:0002020', (159, 182))
55458	24945674	In the current study, we demonstrated that the G/G genotype of rs4444903 was significantly associated with increased risk of adverse clinical outcomes in ESCC patients with advanced tumor stages.	('G/G', 'Var', (47, 50))	('tumor', 'Disease', (182, 187))	('ESCC', 'Disease', (154, 158))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('patients', 'Species', '9606', (159, 167))	('rs4444903', 'Var', (63, 72))	('rs4444903', 'Mutation', 'rs4444903', (63, 72))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
55459	24945674	We also observed that G/G showed a trend to correlate with elevated serum EGF levels in these patients.	('serum EGF levels', 'MPA', (68, 84))	('G/G', 'Var', (22, 25))	('elevated', 'PosReg', (59, 67))	('patients', 'Species', '9606', (94, 102))
55462	24945674	It is released by its precursor prepro-EGF by cleavage of Arg-Asn and Arg-His bonds.	('Asn', 'Chemical', 'MESH:D001216', (62, 65))	('Arg', 'Chemical', 'MESH:D001120', (70, 73))	('Arg-His bonds', 'Protein', (70, 83))	('Arg-Asn', 'Protein', (58, 65))	('cleavage', 'Var', (46, 54))	('Arg', 'Chemical', 'MESH:D001120', (58, 61))	('His', 'Chemical', 'MESH:D006639', (74, 77))
55463	24945674	The EGF:rs2237051, I708M, is located within one of eight EGF-like repeat domains of prepro-EGF encoded by exons 6, 7, 8, 9, 15, 17, 18 and 19.	('rs2237051', 'Var', (8, 17))	('I708M', 'Var', (19, 24))	('I708M', 'Mutation', 'rs2237051', (19, 24))	('rs2237051', 'Mutation', 'rs2237051', (8, 17))
55464	24945674	The variant carriers of EGF:rs2237051 have been reported to be associated with a markedly decreased risk of lung cancer.	('lung cancer', 'Disease', 'MESH:D008175', (108, 119))	('rs2237051', 'Mutation', 'rs2237051', (28, 37))	('decreased', 'NegReg', (90, 99))	('lung cancer', 'Disease', (108, 119))	('lung cancer', 'Phenotype', 'HP:0100526', (108, 119))	('EGF', 'Gene', (24, 27))	('rs2237051', 'Var', (28, 37))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
55465	24945674	In our results, we also demonstrated that the variant allele G of EGF:rs2237051 was associated with favorable prognosis in advanced ESCC patients.	('patients', 'Species', '9606', (137, 145))	('EGF', 'Gene', (66, 69))	('rs2237051', 'Mutation', 'rs2237051', (70, 79))	('ESCC', 'Disease', (132, 136))	('rs2237051', 'Var', (70, 79))
55467	24945674	Whether or not the genetic variants of EGF:rs2237051 correlated with the function of prepro-EGF needs further investigation.	('correlated', 'Reg', (53, 63))	('rs2237051', 'Mutation', 'rs2237051', (43, 52))	('EGF', 'Gene', (39, 42))	('rs2237051', 'Var', (43, 52))
55468	24945674	The association of the SNPs of VEGF at -460T/C (rs833061), 405G/C (rs2010963 or -634G/C), and 936C/T (rs3025039) with clinical outcome of patients with esophageal cancer has been investigated previously.	('VEGF', 'Gene', (31, 35))	('405G/C', 'Var', (59, 65))	('rs3025039', 'Mutation', 'rs3025039', (102, 111))	('esophageal cancer', 'Disease', (152, 169))	('936C/T', 'Mutation', 'rs3025039', (94, 100))	('-634G/C', 'Mutation', 'rs2010963', (80, 87))	('rs833061', 'Var', (48, 56))	('-460T/C', 'Mutation', 'rs833061', (39, 46))	('rs2010963', 'Mutation', 'rs2010963', (67, 76))	('405G/C', 'SUBSTITUTION', 'None', (59, 65))	('rs833061', 'Mutation', 'rs833061', (48, 56))	('esophageal cancer', 'Disease', 'MESH:D004938', (152, 169))	('VEGF', 'Gene', '7422', (31, 35))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('patients', 'Species', '9606', (138, 146))	('rs2010963 or -634G/C', 'Var', (67, 87))
55470	24945674	The combined CGC haplotype of the three VEGF SNPs (-460T/C, 405G/C, and 936C/T) was associated with worse overall survival of esophageal cancer patients.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('405G/C', 'SUBSTITUTION', 'None', (60, 66))	('overall', 'MPA', (106, 113))	('esophageal cancer', 'Disease', 'MESH:D004938', (126, 143))	('CG', 'Chemical', 'MESH:C028505', (13, 15))	('936C/T', 'Mutation', 'rs3025039', (72, 78))	('VEGF', 'Gene', (40, 44))	('-460T/C', 'Var', (51, 58))	('worse', 'NegReg', (100, 105))	('patients', 'Species', '9606', (144, 152))	('936C/T', 'Var', (72, 78))	('VEGF', 'Gene', '7422', (40, 44))	('405G/C', 'Var', (60, 66))	('esophageal cancer', 'Disease', (126, 143))	('-460T/C', 'Mutation', 'rs833061', (51, 58))
55471	24945674	In the current study, we demonstrated that VEGF rs2010963 independently correlated with prognosis of patients with advanced ESCC.	('patients', 'Species', '9606', (101, 109))	('correlated', 'Reg', (72, 82))	('rs2010963', 'Mutation', 'rs2010963', (48, 57))	('VEGF', 'Gene', (43, 47))	('rs2010963', 'Var', (48, 57))	('ESCC', 'Disease', (124, 128))	('VEGF', 'Gene', '7422', (43, 47))
55472	24945674	VEGF rs2010963 405G/C has been found to correlate with VEGF protein production stimulated by lipopolysaccharide.	('405G/C', 'SUBSTITUTION', 'None', (15, 21))	('VEGF', 'Gene', (55, 59))	('lipopolysaccharide', 'Chemical', 'MESH:D008070', (93, 111))	('VEGF', 'Gene', '7422', (0, 4))	('rs2010963', 'DBSNP_MENTION', 'None', (5, 14))	('VEGF', 'Gene', '7422', (55, 59))	('405G/C', 'Var', (15, 21))	('stimulated', 'PosReg', (79, 89))	('VEGF', 'Gene', (0, 4))	('rs2010963', 'Var', (5, 14))	('lipopolysaccharide', 'MPA', (93, 111))
55473	24945674	However, we did not find an association between the genotypes of rs2010963 and serum VEGF levels in patients with ESCC (Fig.	('rs2010963', 'Mutation', 'rs2010963', (65, 74))	('ESCC', 'Disease', (114, 118))	('VEGF', 'Gene', '7422', (85, 89))	('rs2010963', 'Var', (65, 74))	('patients', 'Species', '9606', (100, 108))	('VEGF', 'Gene', (85, 89))
55474	24945674	Because the sera were collected before patients received treatment, we suggest that the genotypes of rs2010963 may be associated with post-treatment expression of VEGF and thereby influence the survival outcome of patients.	('men', 'Species', '9606', (62, 65))	('survival', 'CPA', (194, 202))	('men', 'Species', '9606', (144, 147))	('patients', 'Species', '9606', (214, 222))	('rs2010963', 'Mutation', 'rs2010963', (101, 110))	('patients', 'Species', '9606', (39, 47))	('VEGF', 'Gene', (163, 167))	('rs2010963', 'Var', (101, 110))	('expression', 'MPA', (149, 159))	('associated', 'Reg', (118, 128))	('VEGF', 'Gene', '7422', (163, 167))	('influence', 'Reg', (180, 189))
55475	24945674	Even though EGF:rs4444903, EGF:rs2237051 and VEGF:rs2010963 were each significantly associated with a better prognosis of advanced ESCC, we found the cumulative effect of VEGF:rs2010963 with either EGF:rs4444903 or EGF:rs2010963 to be even better than the cumulative effect of these 3 SNPs combined (Table 4).	('rs2010963', 'Mutation', 'rs2010963', (219, 228))	('EGF', 'Var', (27, 30))	('VEGF', 'Gene', '7422', (171, 175))	('rs4444903', 'Mutation', 'rs4444903', (202, 211))	('better', 'PosReg', (102, 108))	('rs2010963', 'Mutation', 'rs2010963', (176, 185))	('rs2010963', 'Mutation', 'rs2010963', (50, 59))	('VEGF', 'Gene', '7422', (45, 49))	('rs4444903', 'Mutation', 'rs4444903', (16, 25))	('rs2237051', 'Mutation', 'rs2237051', (31, 40))	('EGF', 'Var', (12, 15))	('VEGF', 'Gene', (171, 175))	('VEGF', 'Gene', (45, 49))	('ESCC', 'Disease', (131, 135))
55476	24945674	Joint analysis of EGFR:rs2227983 and the SNPs of the downstream signaling factor PIK3CA, revealed strong cumulative effects for both increased risk of death and for recurrence with increasing numbers of unfavorable genotypes in both EGF:rs2237051 and EGF:rs4444903 sets (Table 4).	('PIK3CA', 'Gene', (81, 87))	('EGFR', 'Gene', '1956', (18, 22))	('PIK3CA', 'Gene', '5290', (81, 87))	('rs2227983', 'Var', (23, 32))	('rs2237051', 'Mutation', 'rs2237051', (237, 246))	('rs2227983', 'Mutation', 'rs2227983', (23, 32))	('EGFR', 'Gene', (18, 22))	('EGF', 'Gene', (233, 236))	('death', 'Disease', 'MESH:D003643', (151, 156))	('death', 'Disease', (151, 156))	('rs4444903', 'Mutation', 'rs4444903', (255, 264))
55477	24945674	The minor allele frequencies of the 3 SNPs of PIK3CA, rs6333624, rs7651263 and rs7621329 were similar (1.5%) in our study population.	('rs7651263', 'Var', (65, 74))	('PIK3CA', 'Gene', '5290', (46, 52))	('rs7621329', 'Mutation', 'rs7621329', (79, 88))	('rs7651263', 'Mutation', 'rs7651263', (65, 74))	('rs6333624', 'Mutation', 'rs6333624', (54, 63))	('rs6333624', 'Var', (54, 63))	('rs7621329', 'Var', (79, 88))	('PIK3CA', 'Gene', (46, 52))
55478	24945674	In a previous study, the minor allele homozygous AA of PIK3CA:rs6443624 was associated with risk of recurrence, but none of these PIK3CA SNPs were found to correlate with recurrence in esophageal cancer patients.	('PIK3CA', 'Gene', (130, 136))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('esophageal cancer', 'Disease', (185, 202))	('PIK3CA', 'Gene', '5290', (130, 136))	('esophageal cancer', 'Disease', 'MESH:D004938', (185, 202))	('rs6443624', 'Mutation', 'rs6443624', (62, 71))	('associated', 'Reg', (76, 86))	('patients', 'Species', '9606', (203, 211))	('rs6443624', 'Var', (62, 71))	('PIK3CA', 'Gene', (55, 61))	('PIK3CA', 'Gene', '5290', (55, 61))
55480	24945674	Meanwhile, the minor allele of PIK3CA:rs6443624 had a cumulative effect with the unfavorable genotypes of EGF, VEGF and EGFR.	('VEGF', 'Gene', (111, 115))	('rs6443624', 'Mutation', 'rs6443624', (38, 47))	('PIK3CA', 'Gene', (31, 37))	('rs6443624', 'Var', (38, 47))	('PIK3CA', 'Gene', '5290', (31, 37))	('VEGF', 'Gene', '7422', (111, 115))	('EGFR', 'Gene', '1956', (120, 124))	('EGF', 'Disease', (106, 109))	('EGFR', 'Gene', (120, 124))
55481	24945674	The role of EGFR:rs2227983 (G to A, R497K) in cancer has been extensively investigated.	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('cancer', 'Disease', (46, 52))	('EGFR', 'Gene', '1956', (12, 16))	('rs2227983', 'Var', (17, 26))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('rs2227983', 'Mutation', 'rs2227983', (17, 26))	('EGFR', 'Gene', (12, 16))	('R497K', 'Mutation', 'rs2227983', (36, 41))
55482	24945674	EGFR with an argnine-to-lysine substitution has been reported to exhibit a significantly reduced growth response to EGF and TGF-alpha.	('TGF-alpha', 'Gene', (124, 133))	('EGFR', 'Gene', (0, 4))	('argnine-to-lysine substitution', 'Var', (13, 43))	('argnine', 'Chemical', '-', (13, 20))	('TGF-alpha', 'Gene', '7039', (124, 133))	('lysine', 'Chemical', 'MESH:D008239', (24, 30))	('reduced', 'NegReg', (89, 96))	('EGFR', 'Gene', '1956', (0, 4))	('growth', 'MPA', (97, 103))
55483	24945674	The homozygous argnine allele has been suggested to associate with favorable prognosis in patients with colorectal carcinoma, whereas it has no evident effect on the outcome of esophageal cancer patients.	('esophageal cancer', 'Disease', 'MESH:D004938', (177, 194))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('esophageal cancer', 'Disease', (177, 194))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (104, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('argnine', 'Var', (15, 22))	('patients', 'Species', '9606', (195, 203))	('colorectal carcinoma', 'Disease', (104, 124))	('patients', 'Species', '9606', (90, 98))	('argnine', 'Chemical', '-', (15, 22))
55484	24945674	R497K alone does not significantly associate with risks of esophageal cancer and gastric cancer; however, the arginine allele has shown a cumulative effect of increasing hazard of death in combination with other SNPs.	('esophageal cancer', 'Disease', (59, 76))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('arginine', 'Var', (110, 118))	('esophageal cancer', 'Disease', 'MESH:D004938', (59, 76))	('gastric cancer', 'Disease', 'MESH:D013274', (81, 95))	('R497K', 'Var', (0, 5))	('gastric cancer', 'Disease', (81, 95))	('arginine', 'Chemical', 'MESH:D001120', (110, 118))	('death', 'Disease', 'MESH:D003643', (180, 185))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('death', 'Disease', (180, 185))	('gastric cancer', 'Phenotype', 'HP:0012126', (81, 95))	('R497K', 'Mutation', 'rs2227983', (0, 5))
55485	24945674	We found, unexpectedly, that patients carrying the lysine allele (GA or AA genotypes) showed an increased trend of risk for death and disease recurrence, though without reaching statistical significance (P = 0.058, Table 2).	('lysine', 'Chemical', 'MESH:D008239', (51, 57))	('patients', 'Species', '9606', (29, 37))	('disease recurrence', 'CPA', (134, 152))	('lysine', 'Var', (51, 57))	('death', 'Disease', 'MESH:D003643', (124, 129))	('death', 'Disease', (124, 129))
55487	24945674	The function of R497K in ESCC cells is not clear and merits further investigation.	('R497K', 'Var', (16, 21))	('ESCC', 'Disease', (25, 29))	('R497K', 'Mutation', 'rs2227983', (16, 21))
55496	24945674	However, unlike non-small cell lung cancer (NSCLC), where useful markers such as EGFR gene mutation have already been established, the molecular markers regulating sensitivity to EGF/EGFR as well as those targeting VEGF/VEGFR in ESCC are hardly known.	('mutation', 'Var', (91, 99))	('EGFR', 'Gene', '1956', (221, 225))	('cell lung cancer', 'Disease', 'MESH:D008175', (26, 42))	('EGFR', 'Gene', (183, 187))	('VEGFR', 'Gene', '3791', (220, 225))	('VEGF', 'Gene', '7422', (215, 219))	('VEGFR', 'Gene', (220, 225))	('cell lung cancer', 'Disease', (26, 42))	('EGFR', 'Gene', (81, 85))	('NSCLC', 'Disease', 'MESH:D002289', (44, 49))	('VEGF', 'Gene', (215, 219))	('lung cancer', 'Phenotype', 'HP:0100526', (31, 42))	('EGFR', 'Gene', (221, 225))	('NSCLC', 'Disease', (44, 49))	('EGFR', 'Gene', '1956', (183, 187))	('VEGF', 'Gene', '7422', (220, 224))	('NSCLC', 'Phenotype', 'HP:0030358', (44, 49))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (20, 42))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (16, 42))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('VEGF', 'Gene', (220, 224))	('EGFR', 'Gene', '1956', (81, 85))
55499	33565239	EXT1 methylation promotes proliferation and migration and predicts the clinical outcome of non-small cell lung carcinoma via WNT signalling pathway DNA methylation is important for lung cancer prognosis.	('EXT1', 'Gene', '2131', (0, 4))	('small cell lung carcinoma', 'Phenotype', 'HP:0030357', (95, 120))	('methylation', 'Var', (5, 16))	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('promotes', 'PosReg', (17, 25))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('lung cancer', 'Disease', (181, 192))	('lung carcinoma', 'Disease', 'MESH:D008175', (106, 120))	('lung cancer', 'Phenotype', 'HP:0100526', (181, 192))	('non-small cell lung carcinoma', 'Phenotype', 'HP:0030358', (91, 120))	('lung carcinoma', 'Disease', (106, 120))	('EXT1', 'Gene', (0, 4))	('migration', 'CPA', (44, 53))	('proliferation', 'CPA', (26, 39))	('lung cancer', 'Disease', 'MESH:D008175', (181, 192))
55501	33565239	Gene body methylation of three CpG sites (cg03276982, cg11592677, cg16286281) on EXT1 was significantly associated with clinical outcome, and the EXT1 gene expression also predicted prognosis.	('EXT1', 'Gene', '2131', (146, 150))	('predicted', 'Reg', (172, 181))	('associated with', 'Reg', (104, 119))	('EXT1', 'Gene', (81, 85))	('cg16286281', 'Var', (66, 76))	('cg03276982', 'Chemical', '-', (42, 52))	('cg16286281', 'Chemical', '-', (66, 76))	('cg11592677', 'Var', (54, 64))	('cg03276982', 'Var', (42, 52))	('cg11592677', 'Chemical', '-', (54, 64))	('EXT1', 'Gene', '2131', (81, 85))	('EXT1', 'Gene', (146, 150))
55503	33565239	Knocking down of EXT1 resulted in decreased proliferation and migration.	('EXT1', 'Gene', '2131', (17, 21))	('decreased', 'NegReg', (34, 43))	('Knocking down', 'Var', (0, 13))	('EXT1', 'Gene', (17, 21))
55508	33565239	In summary, EXT1 methylation regulates the gene expression, effects the proliferation and migration via WNT pathway and predicted a poor prognosis for NSCLC.	('EXT1', 'Gene', (12, 16))	('NSCLC', 'Disease', (151, 156))	('gene expression', 'MPA', (43, 58))	('migration', 'CPA', (90, 99))	('NSCLC', 'Disease', 'MESH:D002289', (151, 156))	('methylation', 'Var', (17, 28))	('proliferation', 'CPA', (72, 85))	('WNT pathway', 'Pathway', (104, 115))	('EXT1', 'Gene', '2131', (12, 16))	('effects', 'Reg', (60, 67))	('regulates', 'Reg', (29, 38))
55513	33565239	2 ,  3   DNA methylation is the most well-known epigenetic modification on mammal DNA, and the methylation pattern across genome significantly influence the DNA long-term interaction, and chromatin structure and thus play vital roles in many biological processes, including carcinogenesis and cancer development.	('cancer', 'Disease', (293, 299))	('cancer', 'Disease', 'MESH:D009369', (293, 299))	('mammal', 'Species', '9606', (75, 81))	('methylation', 'Var', (95, 106))	('roles', 'Reg', (228, 233))	('carcinogenesis', 'Disease', 'MESH:D063646', (274, 288))	('DNA', 'MPA', (157, 160))	('carcinogenesis', 'Disease', (274, 288))	('influence', 'Reg', (143, 152))	('cancer', 'Phenotype', 'HP:0002664', (293, 299))	('play', 'Reg', (217, 221))
55515	33565239	4  Similarly, the promoter methylation of hOGG1 was shown to increase the risk of NSCLC carcinogenesis.	('promoter methylation', 'Var', (18, 38))	('hOGG1', 'Gene', '4968', (42, 47))	('NSCLC carcinogenesis', 'Disease', 'MESH:D063646', (82, 102))	('NSCLC carcinogenesis', 'Disease', (82, 102))	('hOGG1', 'Gene', (42, 47))	('increase', 'PosReg', (61, 69))
55517	33565239	6  Additionally, LRP12 methylation was shown to predict the clinical response of NSCLC to carboplatin.	('methylation', 'Var', (23, 34))	('predict', 'Reg', (48, 55))	('carboplatin', 'Chemical', 'MESH:D016190', (90, 101))	('LRP12', 'Gene', '29967', (17, 22))	('NSCLC', 'Disease', (81, 86))	('LRP12', 'Gene', (17, 22))	('NSCLC', 'Disease', 'MESH:D002289', (81, 86))
55518	33565239	The aim of this study was to screen the genes that effect the cancer development via DNA methylation alteration in non-small cell lung carcinoma.	('small cell lung carcinoma', 'Phenotype', 'HP:0030357', (119, 144))	('alteration', 'Var', (101, 111))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('non-small cell lung carcinoma', 'Phenotype', 'HP:0030358', (115, 144))	('lung carcinoma', 'Disease', 'MESH:D008175', (130, 144))	('lung carcinoma', 'Disease', (130, 144))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))
55520	33565239	Subsequent analyses revealed that the DNA methylation of EXT1 regulates the expression level of EXT1 and thus promotes proliferation and migration.	('EXT1', 'Gene', (57, 61))	('expression level', 'MPA', (76, 92))	('promotes', 'PosReg', (110, 118))	('migration', 'CPA', (137, 146))	('regulates', 'Reg', (62, 71))	('EXT1', 'Gene', '2131', (57, 61))	('EXT1', 'Gene', (96, 100))	('methylation', 'Var', (42, 53))	('EXT1', 'Gene', '2131', (96, 100))	('proliferation', 'CPA', (119, 132))
55550	33565239	The prognostic values of cg03276982, cg11592677 and cg16286281 methylation were also evaluated.	('cg11592677', 'Var', (37, 47))	('cg16286281', 'Var', (52, 62))	('cg11592677', 'Chemical', '-', (37, 47))	('cg03276982', 'Chemical', '-', (25, 35))	('cg03276982', 'Var', (25, 35))	('cg16286281', 'Chemical', '-', (52, 62))
55551	33565239	As shown in Figure 1B-D, the patients with hypomethylation of these sites had a significantly shorter survival period than the hypermethylated.	('hypomethylation', 'Var', (43, 58))	('patients', 'Species', '9606', (29, 37))	('survival period', 'CPA', (102, 117))	('shorter', 'NegReg', (94, 101))
55553	33565239	The mRNA abundance of EXT1 was negatively correlated with DNA methylation of cg11592677 and cg16286281 (Figure 2E,F, P < 1e-16), but not cg03276982 (not shown).	('negatively', 'NegReg', (31, 41))	('cg16286281', 'Chemical', '-', (92, 102))	('EXT1', 'Gene', (22, 26))	('DNA methylation', 'MPA', (58, 73))	('cg03276982', 'Chemical', '-', (137, 147))	('EXT1', 'Gene', '2131', (22, 26))	('cg11592677', 'Chemical', '-', (77, 87))	('cg16286281', 'Var', (92, 102))	('cg11592677', 'Var', (77, 87))	('mRNA abundance', 'MPA', (4, 18))
55559	33565239	Gene expression and DNA methylation levels of cg03276982, cg11592677 and cg16286281 were quantified using qRT-PCR and Pyrosequencing methods, respectively.	('cg11592677', 'Var', (58, 68))	('cg16286281', 'Chemical', '-', (73, 83))	('cg11592677', 'Chemical', '-', (58, 68))	('cg03276982', 'Chemical', '-', (46, 56))	('cg03276982', 'Var', (46, 56))	('cg16286281', 'Var', (73, 83))
55560	33565239	As expected, the expression of EXT1 was significantly associated overall survival of NSCLC (Figure 2A), and the similar DNA methylation pattern was observed in these three CpG sites (Figure 2B-D).	('NSCLC', 'Disease', (85, 90))	('NSCLC', 'Disease', 'MESH:D002289', (85, 90))	('EXT1', 'Gene', '2131', (31, 35))	('expression', 'Var', (17, 27))	('EXT1', 'Gene', (31, 35))	('associated', 'Reg', (54, 64))
55561	33565239	In consistent with previous results, the mRNA level of EXT1 was significantly and negatively associated with DNA methylation level of cg11592677 and cg16286281 (Figure 2E,F), but not cg03276982 (not shown).	('cg03276982', 'Chemical', '-', (183, 193))	('associated', 'Interaction', (93, 103))	('EXT1', 'Gene', '2131', (55, 59))	('mRNA level', 'MPA', (41, 51))	('DNA methylation level', 'MPA', (109, 130))	('cg16286281', 'Var', (149, 159))	('cg11592677', 'Chemical', '-', (134, 144))	('EXT1', 'Gene', (55, 59))	('negatively', 'NegReg', (82, 92))	('cg11592677', 'Var', (134, 144))	('cg16286281', 'Chemical', '-', (149, 159))
55572	33565239	After knocking down of EXT1 in H520 and A549 (Figure 4A), the proliferation rate of both cell lines was determined and compared with the control group, using CCK9 assay in several days.	('proliferation rate', 'CPA', (62, 80))	('EXT1', 'Gene', (23, 27))	('A549', 'CellLine', 'CVCL:0023', (40, 44))	('EXT1', 'Gene', '2131', (23, 27))	('knocking down', 'Var', (6, 19))
55573	33565239	As expected, the cell lines with EXT1 knocking down has a significantly lower proliferation rate than the control group (Figure 4B) from the 2nd day since culturing, indicating the role of EXT1 in cell cycle.	('EXT1', 'Gene', '2131', (189, 193))	('knocking down', 'Var', (38, 51))	('EXT1', 'Gene', (33, 37))	('EXT1', 'Gene', '2131', (33, 37))	('lower', 'NegReg', (72, 77))	('EXT1', 'Gene', (189, 193))	('proliferation rate', 'CPA', (78, 96))
55574	33565239	Afterwards, the migration ability was also evaluated and compared between experimental and control group, and the migration rate of EXT1 knocking down group has a significantly less migration ability than the control (Figure 4C).	('migration rate', 'CPA', (114, 128))	('less', 'NegReg', (177, 181))	('EXT1', 'Gene', '2131', (132, 136))	('migration ability', 'CPA', (182, 199))	('knocking down', 'Var', (137, 150))	('EXT1', 'Gene', (132, 136))
55575	33565239	All results above indicate that the EXT1 gene expression facilitates cell proliferation and migration in NSCLC cell lines.	('NSCLC', 'Disease', 'MESH:D002289', (105, 110))	('EXT1', 'Gene', (36, 40))	('expression', 'Var', (46, 56))	('EXT1', 'Gene', '2131', (36, 40))	('cell proliferation', 'CPA', (69, 87))	('NSCLC', 'Disease', (105, 110))	('facilitates', 'PosReg', (57, 68))
55579	33565239	After knocking down of EXT1 by siRNA, the active beta-catenin protein abundance was compared with the control group.	('beta-catenin', 'Gene', (49, 61))	('EXT1', 'Gene', (23, 27))	('beta-catenin', 'Gene', '1499', (49, 61))	('EXT1', 'Gene', '2131', (23, 27))	('knocking down', 'Var', (6, 19))
55588	33565239	17  In hepatocellular carcinoma, increased copy number of EXT1 results in more mRNA abundance and thus predicted a shorter disease-free survival rate without vascular invasion.	('more', 'PosReg', (74, 78))	('disease-free survival rate', 'CPA', (123, 149))	('EXT1', 'Gene', '2131', (58, 62))	('copy number', 'Var', (43, 54))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('shorter', 'NegReg', (115, 122))	('increased', 'PosReg', (33, 42))	('mRNA abundance', 'MPA', (79, 93))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (7, 31))	('EXT1', 'Gene', (58, 62))	('hepatocellular carcinoma', 'Disease', (7, 31))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (7, 31))
55589	33565239	18  In breast cancer, EXT1 gene expression was shown to predict a risk of metastasis, 19  and knocking down of EXT1 reduced the colony formation of breast cancer, and effect the therapy resistance.	('therapy resistance', 'CPA', (178, 196))	('EXT1', 'Gene', (111, 115))	('EXT1', 'Gene', '2131', (111, 115))	('breast cancer', 'Disease', 'MESH:D001943', (7, 20))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('breast cancer', 'Disease', 'MESH:D001943', (148, 161))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('EXT1', 'Gene', (22, 26))	('metastasis', 'CPA', (74, 84))	('knocking down', 'Var', (94, 107))	('breast cancer', 'Disease', (7, 20))	('breast cancer', 'Disease', (148, 161))	('effect', 'Reg', (167, 173))	('EXT1', 'Gene', '2131', (22, 26))	('breast cancer', 'Phenotype', 'HP:0003002', (148, 161))	('breast cancer', 'Phenotype', 'HP:0003002', (7, 20))	('reduced', 'NegReg', (116, 123))	('colony formation', 'CPA', (128, 144))
55591	33565239	21   In previous report, EXT1 has been reported as to enhance canonical WNT signalling activity during chondrogenic differentiation, 12  in addition, knock-down of EXT1 using CRISPR/Cas9 resulted in aberrant WNT signalling in multiple myeloma.	('EXT1', 'Gene', '2131', (164, 168))	('multiple myeloma', 'Disease', (226, 242))	('WNT signalling', 'MPA', (208, 222))	('knock-down', 'Var', (150, 160))	('multiple myeloma', 'Disease', 'MESH:D009101', (226, 242))	('EXT1', 'Gene', (164, 168))	('EXT1', 'Gene', (25, 29))	('enhance', 'PosReg', (54, 61))	('EXT1', 'Gene', '2131', (25, 29))	('canonical WNT signalling activity', 'MPA', (62, 95))	('multiple myeloma', 'Phenotype', 'HP:0006775', (226, 242))	('aberrant', 'Reg', (199, 207))
55595	33565239	23  Furthermore, the methylation status of EXT1 and the gene expression of EXT1 is significantly associated with overall survival of NSCLC.	('methylation status', 'Var', (21, 39))	('EXT1', 'Gene', (43, 47))	('EXT1', 'Gene', (75, 79))	('associated with', 'Reg', (97, 112))	('EXT1', 'Gene', '2131', (75, 79))	('NSCLC', 'Disease', (133, 138))	('EXT1', 'Gene', '2131', (43, 47))	('NSCLC', 'Disease', 'MESH:D002289', (133, 138))	('gene expression', 'MPA', (56, 71))
55596	33565239	Both mRNA and DNA methylation performed better in survival prediction, compared with age, gender, pathological stages and primary tumour size.	('survival', 'CPA', (50, 58))	('primary tumour', 'Disease', (122, 136))	('methylation', 'Var', (18, 29))	('primary tumour', 'Disease', 'MESH:D009369', (122, 136))	('tumour', 'Phenotype', 'HP:0002664', (130, 136))
55597	33565239	Generally, DNA hypermethylation on promoter regions is correlated with depressed gene expression, 24  whereas hypermethylation at gene body regions resulted in overexpression.	('gene expression', 'MPA', (81, 96))	('overexpression', 'PosReg', (160, 174))	('hypermethylation', 'Var', (110, 126))	('depressed', 'Disease', 'MESH:D000275', (71, 80))	('hypermethylation', 'Var', (15, 31))	('depressed', 'Disease', (71, 80))
55598	33565239	25  cg03276982, cg11592677 and cg16286281 are all located in gene body and none of these sites located in CpG island.	('cg16286281', 'Var', (31, 41))	('cg11592677', 'Chemical', '-', (16, 26))	('cg11592677', 'Var', (16, 26))	('cg03276982', 'Chemical', '-', (4, 14))	('cg03276982', 'Var', (4, 14))	('cg16286281', 'Chemical', '-', (31, 41))
55604	33565239	Collectively, this study revealed that gene body hypermethylation of EXT1 results in EXT1 overexpression, activates WNT signalling pathway and predicts the survival of NSCLC.	('EXT1', 'Gene', '2131', (69, 73))	('hypermethylation', 'Var', (49, 65))	('NSCLC', 'Disease', 'MESH:D002289', (168, 173))	('predicts', 'Reg', (143, 151))	('EXT1', 'Gene', (85, 89))	('WNT signalling pathway', 'Pathway', (116, 138))	('activates', 'PosReg', (106, 115))	('EXT1', 'Gene', '2131', (85, 89))	('EXT1', 'Gene', (69, 73))	('overexpression', 'PosReg', (90, 104))	('NSCLC', 'Disease', (168, 173))
55612	33634070	Moreover, carbon ion treatment, in combination with FAK silencing, markedly blocked the phosphorylation levels of FAK, and paxillin, which partly contributed to the reduced motility of tongue squamous cell carcinoma CAL27 cells.	('silencing', 'Var', (56, 65))	('reduced motility of tongue', 'Phenotype', 'HP:0000183', (165, 191))	('tongue squamous cell carcinoma', 'Phenotype', 'HP:0030413', (185, 215))	('FAK', 'Gene', (52, 55))	('FAK', 'Gene', (114, 117))	('FAK', 'Gene', '5747', (114, 117))	('FAK', 'Gene', '5747', (52, 55))	('tongue squamous cell carcinoma', 'Disease', 'MESH:D002294', (185, 215))	('carcinoma', 'Phenotype', 'HP:0030731', (206, 215))	('phosphorylation levels', 'MPA', (88, 110))	('blocked', 'NegReg', (76, 83))	('paxillin', 'Gene', '5829', (123, 131))	('motility', 'CPA', (173, 181))	('reduced', 'NegReg', (165, 172))	('tongue squamous cell carcinoma', 'Disease', (185, 215))	('reduced motility of tongue squamous', 'Phenotype', 'HP:0010298', (165, 200))	('carbon', 'Chemical', 'MESH:D002244', (10, 16))	('CAL27', 'CellLine', 'CVCL:1107', (216, 221))	('paxillin', 'Gene', (123, 131))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (192, 215))
55623	33634070	Knockdown of FAK has been found to inhibit the survival, invasion, and metastasis of oral cancer.	('metastasis of oral cancer', 'Disease', 'MESH:D009362', (71, 96))	('invasion', 'CPA', (57, 65))	('Knockdown', 'Var', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('FAK', 'Gene', '5747', (13, 16))	('survival', 'CPA', (47, 55))	('FAK', 'Gene', (13, 16))	('metastasis of oral cancer', 'Disease', (71, 96))	('inhibit', 'NegReg', (35, 42))
55637	33634070	Following FAK silencing and/or irradiation, CAL27 cells were seeded into the upper culture compartments supplemented with serum-free medium.	('FAK', 'Gene', '5747', (10, 13))	('silencing', 'Var', (14, 23))	('FAK', 'Gene', (10, 13))	('CAL27', 'CellLine', 'CVCL:1107', (44, 49))
55642	33634070	Tissue microarray chips containing 20 tissues of TSCC were obtained from Shanghai Biochip Co., Ltd (HOraC060PG01 and Horac080PG01, and the ID of ethics approval was T20-0361).	('HOraC060PG01', 'CellLine', 'CVCL:9069', (100, 112))	('HOraC060PG01', 'Var', (100, 112))	('Horac080PG01', 'Var', (117, 129))	('TSCC', 'Phenotype', 'HP:0030413', (49, 53))
55645	33634070	Total protein samples were blotted with the following antibodies: anti-FAK, anti-phospho-FAK (Y397), anti-phospho-paxillin (Y118), and anti-beta-actin (GeneTex, Irvine, CA).	('FAK', 'Gene', (71, 74))	('paxillin', 'Gene', '5829', (114, 122))	('FAK', 'Gene', '5747', (71, 74))	('Y397', 'Var', (94, 98))	('paxillin', 'Gene', (114, 122))	('FAK', 'Gene', (89, 92))	('FAK', 'Gene', '5747', (89, 92))	('beta-actin', 'Gene', '728378', (140, 150))	('beta-actin', 'Gene', (140, 150))	('Y118', 'Var', (124, 128))
55654	33634070	To test the contribution of FAK signaling in tumor inhibition during carbon ion radiation therapy, we knocked down FAK expression in CAL27 cells using lentivirus carrying FAK shRNA.	('FAK', 'Gene', (115, 118))	('FAK', 'Gene', '5747', (115, 118))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('FAK', 'Gene', '5747', (28, 31))	('tumor', 'Disease', (45, 50))	('carbon', 'Chemical', 'MESH:D002244', (69, 75))	('FAK', 'Gene', (171, 174))	('CAL27', 'CellLine', 'CVCL:1107', (133, 138))	('FAK', 'Gene', '5747', (171, 174))	('knocked', 'Var', (102, 109))	('FAK', 'Gene', (28, 31))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
55659	33634070	Compared to the irradiation alone treatment, the relative number of colonies formed by CAL27 cells after treatment with irradiation plus FAK knockdown was reduced by 47.2% (Figures 2C,D).	('knockdown', 'Var', (141, 150))	('reduced', 'NegReg', (155, 162))	('FAK', 'Gene', '5747', (137, 140))	('FAK', 'Gene', (137, 140))	('CAL27', 'CellLine', 'CVCL:1107', (87, 92))
55661	33634070	Moreover, the quantitative results of cells taken at 24 h after scratching indicated a markedly significant decline in the wound area by 44.6, 52.4, and 77.2% in irradiated, FAK-/-, and FAK-/- irradiated cells compared to that in control cells (Figure 3D).	('FAK', 'Gene', (186, 189))	('FAK', 'Gene', '5747', (186, 189))	('decline', 'NegReg', (108, 115))	('irradiated', 'Var', (162, 172))	('FAK', 'Gene', (174, 177))	('FAK', 'Gene', '5747', (174, 177))	('wound area', 'CPA', (123, 133))
55662	33634070	Further data revealed that a reduction in wound healing ability was significantly found in the FAK silencing and irradiation groups compared to the irradiation group (P < 0.01).	('irradiation', 'Var', (113, 124))	('FAK', 'Gene', '5747', (95, 98))	('FAK', 'Gene', (95, 98))	('reduction', 'NegReg', (29, 38))	('reduction in wound healing ability', 'Phenotype', 'HP:0001058', (29, 63))	('wound healing ability', 'CPA', (42, 63))
55671	33634070	Our data from nine patients with stage I TSCC (N0) and 47 patients with stage IV TSCC (>=N1) using public databases showed that genomic alteration of FAK closely modulated the malignant progression of TSSC, including histological differentiation, TNM stage, and lymph node metastasis (Figure 1).	('lymph node metastasis', 'CPA', (262, 283))	('genomic alteration', 'Var', (128, 146))	('modulated', 'Reg', (162, 171))	('TNM', 'Gene', '10178', (247, 250))	('patients', 'Species', '9606', (19, 27))	('FAK', 'Gene', (150, 153))	('histological differentiation', 'CPA', (217, 245))	('FAK', 'Gene', '5747', (150, 153))	('TNM', 'Gene', (247, 250))	('patients', 'Species', '9606', (58, 66))	('malignant progression', 'CPA', (176, 197))	('TSCC', 'Phenotype', 'HP:0030413', (81, 85))	('TSSC', 'Disease', (201, 205))	('TSCC', 'Phenotype', 'HP:0030413', (41, 45))
55677	33634070	Our data showed that carbon ion irradiation remarkably repressed the expression of FAK and phosphorylation of FAK on Tyr397 and paxillin on Tyr118 in CAL27 cells.	('phosphorylation', 'MPA', (91, 106))	('paxillin', 'Gene', '5829', (128, 136))	('Tyr397', 'Var', (117, 123))	('carbon', 'Chemical', 'MESH:D002244', (21, 27))	('Tyr397', 'Chemical', '-', (117, 123))	('paxillin', 'Gene', (128, 136))	('Tyr118', 'Chemical', '-', (140, 146))	('FAK', 'Gene', '5747', (110, 113))	('CAL27', 'CellLine', 'CVCL:1107', (150, 155))	('FAK', 'Gene', '5747', (83, 86))	('FAK', 'Gene', (110, 113))	('FAK', 'Gene', (83, 86))
55679	33634070	In agreement with previous findings, glioblastoma, colon cancer, and head and neck cancer cells showed enhanced cell-killing effects in response to ionizing radiation by FAK deletion.	('colon cancer', 'Disease', (51, 63))	('FAK', 'Gene', (170, 173))	('FAK', 'Gene', '5747', (170, 173))	('glioblastoma', 'Disease', 'MESH:D005909', (37, 49))	('head and neck cancer', 'Phenotype', 'HP:0012288', (69, 89))	('glioblastoma', 'Phenotype', 'HP:0012174', (37, 49))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('cell-killing effects', 'CPA', (112, 132))	('deletion', 'Var', (174, 182))	('response to ionizing radiation', 'MPA', (136, 166))	('enhanced', 'PosReg', (103, 111))	('colon cancer', 'Phenotype', 'HP:0003003', (51, 63))	('colon cancer', 'Disease', 'MESH:D015179', (51, 63))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('head and neck cancer', 'Disease', 'MESH:D006258', (69, 89))	('glioblastoma', 'Disease', (37, 49))
55682	33634070	It is worth noting that, after FAK knockdown, the migratory and invasive abilities of CAL27 cells were more prominently inhibited when compared to cells treated with radiation alone.	('knockdown', 'Var', (35, 44))	('CAL27', 'CellLine', 'CVCL:1107', (86, 91))	('inhibited', 'NegReg', (120, 129))	('FAK', 'Gene', '5747', (31, 34))	('FAK', 'Gene', (31, 34))
55683	33634070	Here, the precise role of the combination of FAK knockdown and carbon ion irradiation was confirmed to suppress the high-motility capability of the TSCC cell line CAL27.	('knockdown', 'Var', (49, 58))	('suppress', 'NegReg', (103, 111))	('CAL27', 'CellLine', 'CVCL:1107', (163, 168))	('TSCC', 'Phenotype', 'HP:0030413', (148, 152))	('carbon', 'Chemical', 'MESH:D002244', (63, 69))	('high-motility capability', 'CPA', (116, 140))	('FAK', 'Gene', '5747', (45, 48))	('FAK', 'Gene', (45, 48))
55687	33634070	Furthermore, compared to control cells, FAK silencing resulted in reduced adhesion energy to the substrates in the irradiated cells, FAK shRNA-infected cells, or cells treated with FAK shRNA combined with irradiation, which was consistent with changes in cell motility and phosphorylation of adhesion proteins.	('reduced', 'NegReg', (66, 73))	('FAK', 'Gene', (40, 43))	('FAK', 'Gene', '5747', (40, 43))	('FAK', 'Gene', (133, 136))	('FAK', 'Gene', '5747', (133, 136))	('infected', 'Disease', (143, 151))	('FAK', 'Gene', (181, 184))	('FAK', 'Gene', '5747', (181, 184))	('silencing', 'Var', (44, 53))	('adhesion energy to the substrates', 'MPA', (74, 107))	('infected', 'Disease', 'MESH:D007239', (143, 151))
55729	33391452	Therefore, we aimed to determine which patient and tumor characteristics, including concurrent T2DM, are related to high glucose uptake in the majority of tumor lesions in NSCLC patients as measured by 2-deoxy-2-[fluorine-18]fluoro-D-glucose (18F-FDG) positron emission tomography (PET)/computed tomography (CT) scans.	('18F-FDG', 'Chemical', 'MESH:D019788', (243, 250))	('tumor', 'Disease', (155, 160))	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('tumor', 'Disease', (51, 56))	('patients', 'Species', '9606', (178, 186))	('NSCLC', 'Disease', 'MESH:D002289', (172, 177))	('tumor lesions', 'Disease', 'MESH:D009369', (155, 168))	('glucose uptake', 'MPA', (121, 135))	('glucose', 'Chemical', 'MESH:D005947', (234, 241))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('patient', 'Species', '9606', (39, 46))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('NSCLC', 'Disease', (172, 177))	('tumor lesions', 'Disease', (155, 168))	('NSCLC', 'Phenotype', 'HP:0030358', (172, 177))	('high glucose', 'Phenotype', 'HP:0003074', (116, 128))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('glucose', 'Chemical', 'MESH:D005947', (121, 128))	('patient', 'Species', '9606', (178, 185))	('high', 'PosReg', (116, 120))	('T2DM', 'Var', (95, 99))
55735	33391452	T2DM patients had higher median glucose uptake in individual tumor lesions and per patient compared to non-diabetic NSCLC patients (SUVmean 4.3 vs 2.8, P < 0.001 and SUVmean 5.4 vs 3.7, P = 0.009, respectively).	('glucose uptake', 'MPA', (32, 46))	('tumor lesions', 'Disease', (61, 74))	('patient', 'Species', '9606', (5, 12))	('patients', 'Species', '9606', (5, 13))	('glucose', 'Chemical', 'MESH:D005947', (32, 39))	('diabetic NSCLC', 'Disease', (107, 121))	('patient', 'Species', '9606', (122, 129))	('tumor lesions', 'Disease', 'MESH:D009369', (61, 74))	('diabetic NSCLC', 'Disease', 'MESH:D003920', (107, 121))	('NSCLC', 'Phenotype', 'HP:0030358', (116, 121))	('patients', 'Species', '9606', (122, 130))	('T2DM', 'Var', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('patient', 'Species', '9606', (83, 90))	('higher', 'PosReg', (18, 24))
55783	33391452	A region of interest (ROI) was drawn around each visible 18F-FDG avid tumor lesion.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('18F-FDG', 'Chemical', 'MESH:D019788', (57, 64))	('avid tumor lesion', 'Disease', 'MESH:D009369', (65, 82))	('18F-FDG', 'Var', (57, 64))	('avid tumor lesion', 'Disease', (65, 82))
55813	33391452	The median glucose uptake was higher in tumor lesions of NSCLC patients with T2DM than in tumor lesions of non-diabetic NSCLC patients (SUVmean 4.3 vs. 2.8, P < 0.001) (Fig.	('tumor lesions', 'Disease', 'MESH:D009369', (40, 53))	('T2DM', 'Var', (77, 81))	('NSCLC', 'Phenotype', 'HP:0030358', (57, 62))	('NSCLC', 'Phenotype', 'HP:0030358', (120, 125))	('patients', 'Species', '9606', (126, 134))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor lesions', 'Disease', (40, 53))	('tumor lesions of non-diabetic NSCLC', 'Disease', 'MESH:D003920', (90, 125))	('higher', 'PosReg', (30, 36))	('glucose uptake', 'MPA', (11, 25))	('glucose', 'Chemical', 'MESH:D005947', (11, 18))	('tumor lesions of non-diabetic NSCLC', 'Disease', (90, 125))	('tumor lesions', 'Disease', 'MESH:D009369', (90, 103))	('NSCLC', 'Disease', 'MESH:D002289', (57, 62))	('NSCLC', 'Disease', 'MESH:D002289', (120, 125))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('patients', 'Species', '9606', (63, 71))	('NSCLC', 'Disease', (57, 62))	('NSCLC', 'Disease', (120, 125))
55814	33391452	Median tumor lesion glucose uptake per patient was also higher for T2DM than for non-diabetic patients (SUVmean 5.4 vs 3.7, P = 0.009) (Fig.	('patient', 'Species', '9606', (39, 46))	('patients', 'Species', '9606', (94, 102))	('diabetic', 'Disease', 'MESH:D003920', (85, 93))	('T2DM', 'Var', (67, 71))	('diabetic', 'Disease', (85, 93))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))	('patient', 'Species', '9606', (94, 101))	('higher', 'PosReg', (56, 62))	('tumor lesion glucose uptake', 'Disease', 'MESH:C536778', (7, 34))	('tumor lesion glucose uptake', 'Disease', (7, 34))
55815	33391452	Univariable logistic regression showed that T2DM patients are more likely to have high tumor lesion glucose uptake (SUVmean >5) in at least half of the tumor lesions than non-diabetic NSCLC patients (OR 2.9, 95% CI 1.1-7.5) (Table 2).	('NSCLC', 'Phenotype', 'HP:0030358', (184, 189))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('T2DM', 'Var', (44, 48))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('patients', 'Species', '9606', (190, 198))	('high tumor lesion glucose uptake', 'Disease', (82, 114))	('tumor lesions', 'Disease', (152, 165))	('high tumor lesion glucose uptake', 'Disease', 'MESH:C536778', (82, 114))	('patients', 'Species', '9606', (49, 57))	('diabetic NSCLC', 'Disease', 'MESH:D003920', (175, 189))	('tumor lesions', 'Disease', 'MESH:D009369', (152, 165))	('diabetic NSCLC', 'Disease', (175, 189))
55817	33391452	To determine whether T2DM was independently associated with high tumor lesion glucose uptake, univariable logistic regression was used to determine the OR of other potentially relevant patient characteristics on high tumor lesion glucose uptake.	('associated', 'Reg', (44, 54))	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('patient', 'Species', '9606', (185, 192))	('high tumor lesion glucose uptake', 'Disease', (60, 92))	('T2DM', 'Var', (21, 25))	('high tumor lesion glucose uptake', 'Disease', 'MESH:C536778', (60, 92))	('high tumor lesion glucose uptake', 'Disease', (212, 244))	('high tumor lesion glucose uptake', 'Disease', 'MESH:C536778', (212, 244))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
55823	33391452	T2DM NSCLC patients had higher median glucose uptake in individual tumor lesions and per patient compared to non-diabetic NSCLC patients.	('patient', 'Species', '9606', (89, 96))	('patient', 'Species', '9606', (128, 135))	('NSCLC', 'Disease', 'MESH:D002289', (5, 10))	('glucose', 'Chemical', 'MESH:D005947', (38, 45))	('NSCLC', 'Disease', (5, 10))	('NSCLC', 'Disease', 'MESH:D002289', (122, 127))	('tumor lesions', 'Disease', 'MESH:D009369', (67, 80))	('NSCLC', 'Phenotype', 'HP:0030358', (5, 10))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('T2DM', 'Var', (0, 4))	('patients', 'Species', '9606', (128, 136))	('patients', 'Species', '9606', (11, 19))	('NSCLC', 'Disease', (122, 127))	('diabetic NSCLC', 'Disease', (113, 127))	('tumor lesions', 'Disease', (67, 80))	('higher', 'PosReg', (24, 30))	('NSCLC', 'Phenotype', 'HP:0030358', (122, 127))	('glucose uptake', 'MPA', (38, 52))	('patient', 'Species', '9606', (11, 18))	('diabetic NSCLC', 'Disease', 'MESH:D003920', (113, 127))
55839	33391452	The median number of tumor lesions was lower in T2DM than in non-diabetic patients and also lower in patients with squamous cell carcinoma than in those with adenocarcinoma histology (Figure S3).	('patients', 'Species', '9606', (101, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (163, 172))	('patients', 'Species', '9606', (74, 82))	('adenocarcinoma', 'Disease', (158, 172))	('diabetic', 'Disease', 'MESH:D003920', (65, 73))	('tumor lesions', 'Disease', (21, 34))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('adenocarcinoma', 'Disease', 'MESH:D000230', (158, 172))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (115, 138))	('tumor lesions', 'Disease', 'MESH:D009369', (21, 34))	('squamous cell carcinoma', 'Disease', (115, 138))	('diabetic', 'Disease', (65, 73))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (115, 138))	('T2DM', 'Var', (48, 52))	('lower', 'NegReg', (92, 97))	('lower', 'NegReg', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
55842	33391452	Higher tumor lesion glucose uptake in squamous cell carcinoma as compared to adenocarcinoma histology has been previously reported and may be caused by high GLUT-1 expression.	('carcinoma', 'Phenotype', 'HP:0030731', (52, 61))	('caused by', 'Reg', (142, 151))	('adenocarcinoma', 'Disease', 'MESH:D000230', (77, 91))	('tumor lesion glucose uptake in squamous cell carcinoma', 'Disease', 'MESH:D002294', (7, 61))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('Higher', 'PosReg', (0, 6))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (38, 61))	('GLUT-1', 'Gene', '6513', (157, 163))	('high', 'Var', (152, 156))	('GLUT-1', 'Gene', (157, 163))	('adenocarcinoma', 'Disease', (77, 91))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
55859	33391452	Although this was not independent of other factors such as the histological subtype and number of tumor lesions per patient, our data may suggest that tumors from T2DM NSCLC patients have a different biology than tumors from non-diabetic NSCLC patients.	('tumors', 'Phenotype', 'HP:0002664', (213, 219))	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('NSCLC', 'Phenotype', 'HP:0030358', (168, 173))	('NSCLC', 'Disease', (238, 243))	('patients', 'Species', '9606', (244, 252))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('diabetic NSCLC', 'Disease', (229, 243))	('T2DM', 'Var', (163, 167))	('tumors', 'Disease', (213, 219))	('NSCLC', 'Phenotype', 'HP:0030358', (238, 243))	('patient', 'Species', '9606', (174, 181))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumors', 'Disease', (151, 157))	('diabetic NSCLC', 'Disease', 'MESH:D003920', (229, 243))	('tumor lesions', 'Disease', 'MESH:D009369', (98, 111))	('tumors', 'Disease', 'MESH:D009369', (213, 219))	('tumors', 'Disease', 'MESH:D009369', (151, 157))	('patient', 'Species', '9606', (244, 251))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumor lesions', 'Disease', (98, 111))	('patient', 'Species', '9606', (116, 123))	('NSCLC', 'Disease', 'MESH:D002289', (168, 173))	('patients', 'Species', '9606', (174, 182))	('NSCLC', 'Disease', 'MESH:D002289', (238, 243))	('NSCLC', 'Disease', (168, 173))
55861	33391452	2-DG 2-deoxyglucose 95% CI 95% confidence interval CT computed tomography EARL European Association of Nuclear Medicine Research Ltd 18F-FDG 2-deoxy-2-[fluorine-18]fluoro-D-glucose GLUT-1 glucose transporter 1 MTV metabolic tumor volume MTVpatient sum of the metabolic tumor volume measured in all tumor lesions per patient NSCLC non-small cell lung cancer OR odds ratio PET positron emission tomography PVE partial volume effect ROI region of interest SUVmax maximum measured standardized uptake value SUVmean mean standardized uptake value T1DM type 1 diabetes mellitus T2DM type 2 diabetes mellitus	('2-deoxyglucose', 'Chemical', 'MESH:D003847', (5, 19))	('non-small cell lung cancer', 'Disease', (330, 356))	('glucose', 'Chemical', 'MESH:D005947', (173, 180))	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('diabetes mellitus', 'Phenotype', 'HP:0000819', (554, 571))	('diabetes mellitus', 'Phenotype', 'HP:0000819', (584, 601))	('glucose transporter 1', 'Gene', '6513', (188, 209))	('patient', 'Species', '9606', (240, 247))	('glucose', 'Chemical', 'MESH:D005947', (188, 195))	('NSCLC', 'Disease', 'MESH:D002289', (324, 329))	('lung cancer', 'Phenotype', 'HP:0100526', (345, 356))	('cancer', 'Phenotype', 'HP:0002664', (350, 356))	('T1DM', 'Var', (542, 546))	('MTV', 'Chemical', '-', (210, 213))	('glucose transporter 1', 'Gene', (188, 209))	('metabolic tumor', 'Disease', (259, 274))	('tumor', 'Phenotype', 'HP:0002664', (269, 274))	('NSCLC', 'Disease', (324, 329))	('glucose', 'Chemical', 'MESH:D005947', (12, 19))	('metabolic tumor', 'Disease', 'MESH:D008659', (214, 229))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (330, 356))	('patient', 'Species', '9606', (316, 323))	('diabetes mellitus T2DM', 'Phenotype', 'HP:0005978', (554, 576))	('NSCLC', 'Phenotype', 'HP:0030358', (324, 329))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (334, 356))	('diabetes mellitus', 'Disease', (554, 571))	('T2DM', 'Var', (572, 576))	('2-DG', 'Chemical', 'MESH:D003847', (0, 4))	('tumor lesions', 'Disease', 'MESH:D009369', (298, 311))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (330, 356))	('type 2 diabetes', 'Phenotype', 'HP:0005978', (577, 592))	('diabetes mellitus', 'Disease', (584, 601))	('metabolic tumor', 'Disease', (214, 229))	('GLUT-1', 'Gene', '6513', (181, 187))	('tumor', 'Phenotype', 'HP:0002664', (298, 303))	('MTV', 'Chemical', '-', (237, 240))	('GLUT-1', 'Gene', (181, 187))	('18F-FDG', 'Chemical', 'MESH:D019788', (133, 140))	('tumor lesions', 'Disease', (298, 311))	('type 1 diabetes', 'Phenotype', 'HP:0100651', (547, 562))	('diabetes mellitus', 'Disease', 'MESH:D003920', (554, 571))	('metabolic tumor', 'Disease', 'MESH:D008659', (259, 274))	('diabetes mellitus', 'Disease', 'MESH:D003920', (584, 601))
55862	31319977	Homologous recombination and DNA repair mutations in patients treated with carboplatin and nab-paclitaxel for metastatic non-small cell lung cancer Chemotherapy remains a cornerstone treatment in non-small cell lung cancer either in combination with checkpoint inhibitors or as subsequent therapy.	('carboplatin', 'Chemical', 'MESH:D016190', (75, 86))	('lung cancer', 'Phenotype', 'HP:0100526', (211, 222))	('cancer', 'Disease', (216, 222))	('lung cancer', 'Phenotype', 'HP:0100526', (136, 147))	('non-small cell lung cancer', 'Disease', (121, 147))	('nab', 'Chemical', '-', (91, 94))	('patients', 'Species', '9606', (53, 61))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (196, 222))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (200, 222))	('mutations', 'Var', (40, 49))	('cancer', 'Disease', (141, 147))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (196, 222))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (121, 147))	('paclitaxel', 'Chemical', 'MESH:D017239', (95, 105))	('cancer', 'Disease', 'MESH:D009369', (216, 222))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (125, 147))	('DNA repair', 'Gene', (29, 39))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (121, 147))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('non-small cell lung cancer', 'Disease', (196, 222))
55863	31319977	We performed genomic analysis on tumor samples of patients treated with carboplatin and nab-paclitaxel as part of a phase II trial to evaluate the prognostic and predictive value of mutations in DNA repair pathway in patients treated with this regimen.	('nab', 'Chemical', '-', (88, 91))	('patients', 'Species', '9606', (50, 58))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('carboplatin', 'Chemical', 'MESH:D016190', (72, 83))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('paclitaxel', 'Chemical', 'MESH:D017239', (92, 102))	('DNA repair pathway', 'Pathway', (195, 213))	('tumor', 'Disease', (33, 38))	('patients', 'Species', '9606', (217, 225))	('mutations', 'Var', (182, 191))
55867	31319977	Four patients with mutations in homologous recombination mutations had a shorter PFS (hazard ratio [HR] = 4.54, 95% CI 1.2, 17.1, p = 0.026) and OS (HR = 6.3, 95% CI 1.8, 21.3, p = 0.003).	('shorter', 'NegReg', (73, 80))	('patients', 'Species', '9606', (5, 13))	('PFS', 'MPA', (81, 84))	('mutations', 'Var', (19, 28))
55868	31319977	In this analysis of patients with predominantly squamous cell non-small cell lung cancer treated with carboplatin and nab-paclitaxel in a phase II trial, patients with mutations in homologous recombination pathways had shorter overall and progression-free survival.	('lung cancer', 'Phenotype', 'HP:0100526', (77, 88))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (66, 88))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('carboplatin', 'Chemical', 'MESH:D016190', (102, 113))	('shorter', 'NegReg', (219, 226))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (62, 88))	('nab', 'Chemical', '-', (118, 121))	('patients', 'Species', '9606', (154, 162))	('homologous recombination pathways', 'Pathway', (181, 214))	('patients', 'Species', '9606', (20, 28))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (62, 88))	('paclitaxel', 'Chemical', 'MESH:D017239', (122, 132))	('progression-free survival', 'CPA', (239, 264))	('overall', 'CPA', (227, 234))	('non-small cell lung cancer', 'Disease', (62, 88))	('mutations', 'Var', (168, 177))
55875	31319977	EGFR, ALK, ROS, and BRAF among others), and in many cases targeted therapy offers improved response rates compared to chemotherapy.	('ALK', 'Gene', '238', (6, 9))	('EGFR', 'Gene', (0, 4))	('targeted', 'Var', (58, 66))	('BRAF', 'Gene', '673', (20, 24))	('ALK', 'Gene', (6, 9))	('BRAF', 'Gene', (20, 24))	('EGFR', 'Gene', '1956', (0, 4))
55876	31319977	Targeted therapies have so far shown clinical benefit primarily in patients with lung adenocarcinoma where driver mutations are more common than in patients with LSCC.	('patients', 'Species', '9606', (148, 156))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (81, 100))	('patients', 'Species', '9606', (67, 75))	('mutations', 'Var', (114, 123))	('lung adenocarcinoma', 'Disease', (81, 100))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (81, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('LSCC', 'Phenotype', 'HP:0030359', (162, 166))
55877	31319977	Mutations in TP53 represent the most common alteration in LSCC; mutations in CDKN2A, PIK3CA, KEAP1, MLL2, NFE2L2, and RB1 are also frequently observed.	('TP53', 'Gene', (13, 17))	('KEAP1', 'Gene', '9817', (93, 98))	('NFE2L2', 'Gene', '4780', (106, 112))	('CDKN2A', 'Gene', (77, 83))	('RB1', 'Gene', (118, 121))	('PIK3CA', 'Gene', '5290', (85, 91))	('CDKN2A', 'Gene', '1029', (77, 83))	('KEAP1', 'Gene', (93, 98))	('NFE2L2', 'Gene', (106, 112))	('Mutations', 'Var', (0, 9))	('MLL2', 'Gene', '9757', (100, 104))	('mutations', 'Var', (64, 73))	('RB1', 'Gene', '5925', (118, 121))	('LSCC', 'Phenotype', 'HP:0030359', (58, 62))	('MLL2', 'Gene', (100, 104))	('TP53', 'Gene', '7157', (13, 17))	('observed', 'Reg', (142, 150))	('PIK3CA', 'Gene', (85, 91))
55878	31319977	Mutations in MLL2, CDH8, NFE2L2 or RB1 have been associated with a worse prognosis for patients with early stage LSCC.	('RB1', 'Gene', (35, 38))	('CDH8', 'Gene', '1006', (19, 23))	('LSCC', 'Phenotype', 'HP:0030359', (113, 117))	('MLL2', 'Gene', '9757', (13, 17))	('RB1', 'Gene', '5925', (35, 38))	('associated', 'Reg', (49, 59))	('NFE2L2', 'Gene', '4780', (25, 31))	('MLL2', 'Gene', (13, 17))	('early stage LSCC', 'Disease', (101, 117))	('Mutations', 'Var', (0, 9))	('CDH8', 'Gene', (19, 23))	('NFE2L2', 'Gene', (25, 31))	('patients', 'Species', '9606', (87, 95))
55879	31319977	Mutations in NFE2L2 and KEAP1 have also been associated with resistance to chemotherapy and targeted therapies as well as radiation therapy.	('KEAP1', 'Gene', '9817', (24, 29))	('NFE2L2', 'Gene', '4780', (13, 19))	('KEAP1', 'Gene', (24, 29))	('resistance to chemotherapy', 'CPA', (61, 87))	('NFE2L2', 'Gene', (13, 19))	('associated', 'Reg', (45, 55))	('Mutations', 'Var', (0, 9))
55880	31319977	For patients whose tumors do not harbor actionable driver mutations, platinum-based chemotherapy remains a backbone of treatment with or without ICI.	('mutations', 'Var', (58, 67))	('tumors', 'Disease', (19, 25))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('nab', 'Chemical', '-', (45, 48))	('patients', 'Species', '9606', (4, 12))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('platinum', 'Chemical', 'MESH:D010984', (69, 77))
55886	31319977	Understanding the role of DNA repair pathway mutations in response to platinum based chemotherapy is vital to determine optimal treatment approaches for patients with NSCLC.	('NSCLC', 'Disease', 'MESH:D002289', (167, 172))	('mutations', 'Var', (45, 54))	('patients', 'Species', '9606', (153, 161))	('platinum', 'Chemical', 'MESH:D010984', (70, 78))	('NSCLC', 'Phenotype', 'HP:0030358', (167, 172))	('NSCLC', 'Disease', (167, 172))
55887	31319977	In this study we retrospectively performed next-generation DNA-sequencing on NSCLC patients who received first-line chemotherapy with carboplatin and nanoparticle albumin-bound (nab)-paclitaxel on an NCCN-sponsored clinical trial to evaluate the predictive value of DNA repair pathway mutations in this patient population.	('NSCLC', 'Disease', 'MESH:D002289', (77, 82))	('carboplatin', 'Chemical', 'MESH:D016190', (134, 145))	('mutations', 'Var', (285, 294))	('NSCLC', 'Phenotype', 'HP:0030358', (77, 82))	('nab', 'Chemical', '-', (178, 181))	('DNA repair pathway', 'Pathway', (266, 284))	('paclitaxel', 'Chemical', 'MESH:D017239', (183, 193))	('patient', 'Species', '9606', (83, 90))	('patient', 'Species', '9606', (303, 310))	('patients', 'Species', '9606', (83, 91))	('NSCLC', 'Disease', (77, 82))
55895	31319977	Ensembl Variant Effect Predictor (VEP) was used to annotate and determine functional consequences of tumor specific variants.	('variants', 'Var', (116, 124))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
55903	31319977	The most frequent mutations were in TP53, occurring in 13 patients (52%).	('TP53', 'Gene', (36, 40))	('patients', 'Species', '9606', (58, 66))	('TP53', 'Gene', '7157', (36, 40))	('mutations', 'Var', (18, 27))
55906	31319977	For example, 11 patients' tumors with MAPK-ERK pathway mutations had median OS 17.7 compared to median OS 9.6 months for 14 patients' tumors without MAPK-ERK mutations (HR 0.69, 95% CI 0.3, 1.6, p = 0.378).	('tumors', 'Disease', (134, 140))	('tumors', 'Disease', 'MESH:D009369', (134, 140))	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('mutations', 'Var', (55, 64))	('patients', 'Species', '9606', (16, 24))	('ERK', 'Gene', '5594', (154, 157))	('ERK', 'Gene', '5594', (43, 46))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('ERK', 'Gene', (43, 46))	('ERK', 'Gene', (154, 157))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('patients', 'Species', '9606', (124, 132))	('tumors', 'Disease', (26, 32))
55907	31319977	Five patients whose tumors had mutations in IGF-1 pathway had median OS of 14.6 months compared to 13.2 months in 20 those without IGF-1 mutations (HR 0.72, 95% CI 0.24, 2.2, p = 0.5635).	('mutations', 'Var', (31, 40))	('IGF-1', 'Gene', (131, 136))	('tumors', 'Disease', (20, 26))	('tumors', 'Disease', 'MESH:D009369', (20, 26))	('patients', 'Species', '9606', (5, 13))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('IGF-1', 'Gene', '3479', (44, 49))	('IGF-1', 'Gene', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('IGF-1', 'Gene', '3479', (131, 136))
55909	31319977	Furthermore, alterations in JAK-STAT, IGF-1, or MAPK-ERK were not associated with significant differences in response rates.	('JAK', 'Gene', '3717', (28, 31))	('ERK', 'Gene', '5594', (53, 56))	('IGF-1', 'Gene', '3479', (38, 43))	('ERK', 'Gene', (53, 56))	('IGF-1', 'Gene', (38, 43))	('alterations', 'Var', (13, 24))	('JAK', 'Gene', (28, 31))
55911	31319977	Interestingly, patients whose tumors harbored DNA repair pathway mutations had a lower rate of partial response to treatment by RECIST (11% vs 50%), although this did not meet statistical significance (Table 1, p = 0.069).	('tumors', 'Disease', (30, 36))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('lower', 'NegReg', (81, 86))	('patients', 'Species', '9606', (15, 23))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('partial response to treatment', 'MPA', (95, 124))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('DNA', 'Gene', (46, 49))	('mutations', 'Var', (65, 74))
55912	31319977	More specifically, in 18 patients with squamous cell carcinoma evaluable for a response, mutations in the DNA repair pathway (p = 0.382) and homologous recombination pathway (BLM, RAD50, BRCA2; p = 0.446) were not associated with objective response to treatment (Fig.	('BRCA2', 'Gene', (187, 192))	('BLM', 'Gene', '641', (175, 178))	('DNA', 'Pathway', (106, 109))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (39, 62))	('carcinoma', 'Phenotype', 'HP:0030731', (53, 62))	('squamous cell carcinoma', 'Disease', (39, 62))	('patients', 'Species', '9606', (25, 33))	('BRCA2', 'Gene', '675', (187, 192))	('mutations', 'Var', (89, 98))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (39, 62))	('BLM', 'Gene', (175, 178))
55915	31319977	Thus, these homologous recombination alterations may be contributing to the trend in differences in response rate between tumors with and without DNA repair pathway mutations (Fig.	('tumors', 'Disease', (122, 128))	('tumors', 'Disease', 'MESH:D009369', (122, 128))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('mutations', 'Var', (165, 174))	('tumors', 'Phenotype', 'HP:0002664', (122, 128))
55916	31319977	Overall, within the GEP, there was no difference in PFS or OS in 10 patients with DNA repair mutations (Fig.	('GEP', 'Gene', '2896', (20, 23))	('mutations', 'Var', (93, 102))	('PFS', 'Disease', (52, 55))	('GEP', 'Gene', (20, 23))	('patients', 'Species', '9606', (68, 76))	('DNA repair', 'Gene', (82, 92))
55917	31319977	2A, C), and there was no difference in PFS or OS in three patients with mutations in the FA pathway.	('patients', 'Species', '9606', (58, 66))	('mutations', 'Var', (72, 81))	('FA pathway', 'Pathway', (89, 99))
55920	31319977	Two patients with RAD50 mutations had significantly worse OS (p = 0.003).	('mutations', 'Var', (24, 33))	('RAD50', 'Gene', (18, 23))	('patients', 'Species', '9606', (4, 12))
55921	31319977	For those patients within the GEP with squamous cell histology, homologous recombination mutations remained significantly associated with OS (HR 4.2, 95% CI 1.1, 16.1, p = 0.035, Fig.	('GEP', 'Gene', (30, 33))	('associated with', 'Reg', (122, 137))	('GEP', 'Gene', '2896', (30, 33))	('patients', 'Species', '9606', (10, 18))	('homologous recombination mutations', 'Var', (64, 98))
55922	31319977	Finally, an analysis of response and survival based on the presence or absence of TP53 alterations revealed no change in response rate (Table 1) or overall survival (Fig.	('alterations', 'Var', (87, 98))	('TP53', 'Gene', (82, 86))	('TP53', 'Gene', '7157', (82, 86))
55924	31319977	For patients with LSCC, treatment with carboplatin and nab-paclitaxel has been shown to have increase rate of response compared to carboplatin and paclitaxel, and improvement in survival has been reported in some patient populations.	('carboplatin', 'Chemical', 'MESH:D016190', (39, 50))	('nab-paclitaxel', 'Var', (55, 69))	('paclitaxel', 'Chemical', 'MESH:D017239', (59, 69))	('improvement', 'PosReg', (163, 174))	('increase', 'PosReg', (93, 101))	('patient', 'Species', '9606', (213, 220))	('LSCC', 'Phenotype', 'HP:0030359', (18, 22))	('patient', 'Species', '9606', (4, 11))	('LSCC', 'Disease', (18, 22))	('survival', 'MPA', (178, 186))	('patients', 'Species', '9606', (4, 12))	('nab', 'Chemical', '-', (55, 58))	('carboplatin', 'Chemical', 'MESH:D016190', (131, 142))	('paclitaxel', 'Chemical', 'MESH:D017239', (147, 157))	('response', 'MPA', (110, 118))
55931	31319977	We found that patients whose tumors have mutations in homologous recombination DNA repair pathways had shorter PFS and OS than those without homologous recombination mutations, as well as a trend toward lower response rate.	('mutations', 'Var', (41, 50))	('lower', 'NegReg', (203, 208))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('shorter', 'NegReg', (103, 110))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('tumors', 'Disease', 'MESH:D009369', (29, 35))	('tumors', 'Disease', (29, 35))	('response rate', 'CPA', (209, 222))	('patients', 'Species', '9606', (14, 22))
55932	31319977	Mutations in other pathways including JAK-STAT, MAPK-ERK, and IGF-1 were not associated with survival or response to treatment.	('JAK', 'Gene', '3717', (38, 41))	('ERK', 'Gene', '5594', (53, 56))	('Mutations', 'Var', (0, 9))	('ERK', 'Gene', (53, 56))	('IGF-1', 'Gene', '3479', (62, 67))	('IGF-1', 'Gene', (62, 67))	('JAK', 'Gene', (38, 41))	('associated', 'Reg', (77, 87))
55933	31319977	Aberrations in the genes involved in DNA repair can lead to the development of cancer, and ineffective or defective DNA repair has long been evaluated as a biomarker or target for anti-neoplastic therapy.	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('lead to', 'Reg', (52, 59))	('Aberrations', 'Var', (0, 11))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))
55937	31319977	DNA repair pathway mutations have been shown to play a role in response to platinum-based chemotherapy in NSCLC including RAD50.	('role', 'Reg', (55, 59))	('NSCLC', 'Disease', 'MESH:D002289', (106, 111))	('RAD50', 'Disease', (122, 127))	('mutations', 'Var', (19, 28))	('NSCLC', 'Phenotype', 'HP:0030358', (106, 111))	('platinum', 'Chemical', 'MESH:D010984', (75, 83))	('DNA repair pathway', 'Pathway', (0, 18))	('NSCLC', 'Disease', (106, 111))
55938	31319977	Mutations in DNA repair pathways have also been associated with increased neo-antigen load and T-cell infiltration, as well as with overall tumor mutational burden in several cancers, including NSCLC.	('NSCLC', 'Phenotype', 'HP:0030358', (194, 199))	('T-cell infiltration', 'CPA', (95, 114))	('tumor', 'Disease', (140, 145))	('associated', 'Reg', (48, 58))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('NSCLC', 'Disease', (194, 199))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('Mutations', 'Var', (0, 9))	('NSCLC', 'Disease', 'MESH:D002289', (194, 199))	('cancers', 'Disease', 'MESH:D009369', (175, 182))	('cancers', 'Phenotype', 'HP:0002664', (175, 182))	('neo-antigen load', 'MPA', (74, 90))	('cancers', 'Disease', (175, 182))	('increased', 'PosReg', (64, 73))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('DNA repair pathways', 'Pathway', (13, 32))
55939	31319977	It is well established that mutations in germline homologous recombination genes such as BRCA1 and BRCA2 are associated with the development with several cancers including most notably breast and ovarian cancer.	('ovarian cancer', 'Phenotype', 'HP:0100615', (196, 210))	('cancers', 'Phenotype', 'HP:0002664', (154, 161))	('BRCA1', 'Gene', (89, 94))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('cancers', 'Disease', 'MESH:D009369', (154, 161))	('BRCA2', 'Gene', (99, 104))	('cancers', 'Disease', (154, 161))	('breast and ovarian cancer', 'Disease', 'MESH:D001943', (185, 210))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('BRCA1', 'Gene', '672', (89, 94))	('associated with', 'Reg', (109, 124))	('mutations', 'Var', (28, 37))	('BRCA2', 'Gene', '675', (99, 104))
55943	31319977	Disruption of the MRN complex due to mutant RAD50 led to increased tumor sensitivity to cisplatin in a murine squamous cell xenograft model.	('MRN complex', 'Protein', (18, 29))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('cisplatin', 'Chemical', 'MESH:D002945', (88, 97))	('mutant', 'Var', (37, 43))	('increased', 'PosReg', (57, 66))	('tumor', 'Disease', (67, 72))	('murine', 'Species', '10090', (103, 109))	('RAD50', 'Gene', (44, 49))
55945	31319977	In our study, the two RAD50 mutations identified included R1198G and E605Q.	('R1198G', 'Var', (58, 64))	('E605Q', 'Mutation', 'p.E605Q', (69, 74))	('R1198G', 'Mutation', 'p.R1198G', (58, 64))	('RAD50', 'Gene', (22, 27))	('E605Q', 'Var', (69, 74))
55946	31319977	To our knowledge, the association between mutations in HR repair genes including RAD50 being associated with decreased response to treatment, PFS, and OS with carboplatin and nab-paclitaxel combination therapy in patients with NSCLC has not previously been reported.	('decreased', 'NegReg', (109, 118))	('NSCLC', 'Phenotype', 'HP:0030358', (227, 232))	('response to treatment', 'MPA', (119, 140))	('NSCLC', 'Disease', (227, 232))	('NSCLC', 'Disease', 'MESH:D002289', (227, 232))	('nab', 'Chemical', '-', (175, 178))	('carboplatin', 'Chemical', 'MESH:D016190', (159, 170))	('patients', 'Species', '9606', (213, 221))	('paclitaxel', 'Chemical', 'MESH:D017239', (179, 189))	('RAD50', 'Gene', (81, 86))	('mutations', 'Var', (42, 51))
55948	31319977	On the other hand, defects in homologous recombination might lead to compensatory activation of other repair pathways such as non-homologous end-joining or nucleotide excision repair that ultimately lead to tumors that are "primed" for DNA repair in the face of DNA damaging chemotherapy.	('nucleotide', 'Enzyme', (156, 166))	('tumors', 'Phenotype', 'HP:0002664', (207, 213))	('activation', 'PosReg', (82, 92))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('lead to', 'Reg', (199, 206))	('defects', 'Var', (19, 26))	('tumors', 'Disease', 'MESH:D009369', (207, 213))	('tumors', 'Disease', (207, 213))
55952	31319977	Lastly, the fact that we observed differences in PFS and OS but not response rate in patients with homologous recombination mutations raises the possibility of these mutations being prognostic but not specifically predictive of response to platinum-based treatment.	('mutations', 'Var', (124, 133))	('differences', 'Reg', (34, 45))	('PFS', 'MPA', (49, 52))	('patients', 'Species', '9606', (85, 93))	('platinum', 'Chemical', 'MESH:D010984', (240, 248))
55954	31319977	In a clinical study of patients with metastatic NSCLC treated with first-line carboplatin and nab-paclitaxel with predominantly squamous cell histology, patients with mutations in homologous recombination mutations had shorter overall and progression-free survival.	('carboplatin', 'Chemical', 'MESH:D016190', (78, 89))	('NSCLC', 'Disease', (48, 53))	('patients', 'Species', '9606', (153, 161))	('shorter', 'NegReg', (219, 226))	('patients', 'Species', '9606', (23, 31))	('NSCLC', 'Disease', 'MESH:D002289', (48, 53))	('mutations', 'Var', (167, 176))	('paclitaxel', 'Chemical', 'MESH:D017239', (98, 108))	('NSCLC', 'Phenotype', 'HP:0030358', (48, 53))	('nab', 'Chemical', '-', (94, 97))
55955	31319977	Patients with mutations in DNA repair genes had a trend toward lower response rate.	('lower', 'NegReg', (63, 68))	('DNA repair genes', 'Gene', (27, 43))	('Patients', 'Species', '9606', (0, 8))	('response', 'MPA', (69, 77))	('mutations', 'Var', (14, 23))
55976	32183719	There is substantial indirect evidence of immune activation resulting from anti-PD-1 antibody treatment.	('PD-1', 'Gene', (80, 84))	('antibody', 'Var', (85, 93))	('immune', 'MPA', (42, 48))	('PD-1', 'Gene', '5133', (80, 84))
56055	32183719	In contrast to the lack of nivolumab treatment effect on CD4+ cell expression of IFN-gamma, nivolumab caused an increase in the proportion of Foxp3+CD4+ T-cells.	('CD4', 'Gene', '920', (57, 60))	('nivolumab', 'Chemical', 'MESH:D000077594', (92, 101))	('Foxp3', 'Gene', '50943', (142, 147))	('Foxp3', 'Gene', (142, 147))	('CD4', 'Gene', (148, 151))	('nivolumab', 'Var', (92, 101))	('increase', 'PosReg', (112, 120))	('IFN-gamma', 'Gene', '3458', (81, 90))	('CD4', 'Gene', '920', (148, 151))	('nivolumab', 'Chemical', 'MESH:D000077594', (27, 36))	('CD4', 'Gene', (57, 60))	('IFN-gamma', 'Gene', (81, 90))
56058	32183719	In this setting increased CD4+FoxP3+ expressing T cells following PD-1 inhibition are associated with hyperprogression in patients with gastric cancer.	('hyperprogression', 'Disease', (102, 118))	('inhibition', 'Var', (71, 81))	('FoxP3', 'Gene', (30, 35))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('associated with', 'Reg', (86, 101))	('gastric cancer', 'Disease', (136, 150))	('increased', 'PosReg', (16, 25))	('PD-1', 'Gene', (66, 70))	('patients', 'Species', '9606', (122, 130))	('gastric cancer', 'Disease', 'MESH:D013274', (136, 150))	('CD4', 'Gene', (26, 29))	('PD-1', 'Gene', '5133', (66, 70))	('FoxP3', 'Gene', '50943', (30, 35))	('gastric cancer', 'Phenotype', 'HP:0012126', (136, 150))	('CD4', 'Gene', '920', (26, 29))
56079	32183719	These stimulatory responses prominently included nivolumab increasing blood levels of CD8+ T-cells, and increasing levels of T-cell subpopulations expressing IFN-gamma and granzyme B in most of the OCSCC patients.	('patients', 'Species', '9606', (204, 212))	('granzyme B', 'Gene', (172, 182))	('levels', 'MPA', (115, 121))	('nivolumab', 'Var', (49, 58))	('granzyme B', 'Gene', '3002', (172, 182))	('CD8', 'Gene', (86, 89))	('CD8', 'Gene', '925', (86, 89))	('increasing', 'PosReg', (59, 69))	('OCSCC', 'Disease', (198, 203))	('IFN-gamma', 'Gene', '3458', (158, 167))	('IFN-gamma', 'Gene', (158, 167))	('increasing', 'PosReg', (104, 114))	('nivolumab', 'Chemical', 'MESH:D000077594', (49, 58))
56093	25979927	The discovery of EGFR mutations that confer sensitivity to tyrosine kinase inhibitors in lung adenocarcinomas in 2004 heralded the beginning of the era of precision medicine for lung cancer.	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (89, 109))	('lung cancer', 'Disease', (178, 189))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (89, 108))	('lung cancer', 'Phenotype', 'HP:0100526', (178, 189))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('sensitivity to tyrosine kinase inhibitors', 'MPA', (44, 85))	('mutations', 'Var', (22, 31))	('EGFR', 'Gene', '1956', (17, 21))	('lung cancer', 'Disease', 'MESH:D008175', (178, 189))	('lung adenocarcinomas', 'Disease', (89, 109))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (89, 109))	('EGFR', 'Gene', (17, 21))
56095	25979927	The fruits of these efforts are visible every day now in lung cancer clinics: patients receive molecular testing to determine whether their tumor harbors an actionable mutation, new and improved targeted therapies that can overcome resistance to first-generation drugs are in clinical trials and drugs targeting the immune system are showing activity in patients.	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('lung cancer', 'Phenotype', 'HP:0100526', (57, 68))	('patients', 'Species', '9606', (78, 86))	('lung cancer', 'Disease', 'MESH:D008175', (57, 68))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('mutation', 'Var', (168, 176))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('patients', 'Species', '9606', (354, 362))	('lung cancer', 'Disease', (57, 68))	('tumor', 'Disease', (140, 145))
56106	25979927	EGFR mutations and ALK-rearrangements were the first molecular alterations in lung adenocarcinoma -- discovered in 2004 and 2007, respectively-- that were shown to confer sensitivity to specific targeted therapies, namely tyrosine kinase inhibitors (TKIs, Fig.	('ALK', 'Gene', (19, 22))	('EGFR', 'Gene', (0, 4))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (78, 97))	('men', 'Species', '9606', (32, 35))	('mutations', 'Var', (5, 14))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('ALK', 'Gene', '238', (19, 22))	('lung adenocarcinoma', 'Disease', (78, 97))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (78, 97))	('EGFR', 'Gene', '1956', (0, 4))
56109	25979927	Conversely, it has also been shown that patients with non-EGFR mutant lung cancers rarely respond to EGFR TKIs and are more likely to benefit from chemotherapy supporting the importance of matching tumor genotype to therapy.	('EGFR', 'Gene', '1956', (58, 62))	('mutant', 'Var', (63, 69))	('cancers', 'Phenotype', 'HP:0002664', (75, 82))	('lung cancers', 'Disease', (70, 82))	('EGFR', 'Gene', (58, 62))	('EGFR', 'Gene', '1956', (101, 105))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('EGFR', 'Gene', (101, 105))	('patients', 'Species', '9606', (40, 48))	('lung cancer', 'Phenotype', 'HP:0100526', (70, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('tumor', 'Disease', (198, 203))	('lung cancers', 'Disease', 'MESH:D008175', (70, 82))	('lung cancers', 'Phenotype', 'HP:0100526', (70, 82))	('benefit', 'PosReg', (134, 141))
56110	25979927	Nevertheless, spurred by these early successes, investigators have since identified and further characterized additional oncogenic driver mutations in lung adenocarcinoma.	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (151, 170))	('carcinoma', 'Phenotype', 'HP:0030731', (161, 170))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (151, 170))	('lung adenocarcinoma', 'Disease', (151, 170))	('mutations', 'Var', (138, 147))
56111	25979927	In addition to mutations in KRAS, that were first described in lung cancer in the 1980s and are observed in 25-30% of lung adenocarcinomas (but uncommon in other subtypes), mutations in ERBB2 (3%), BRAF (2%), PIK3CA (1%), MAP2K1 (1%) and NRAS (1%) are also observed.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (118, 138))	('KRAS', 'Gene', '3845', (28, 32))	('MAP2K1', 'Gene', '5604', (222, 228))	('lung cancer', 'Disease', (63, 74))	('NRAS', 'Gene', '4893', (238, 242))	('MAP2K1', 'Gene', (222, 228))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (118, 137))	('KRAS', 'Gene', (28, 32))	('BRAF', 'Gene', '673', (198, 202))	('PIK3CA', 'Gene', (209, 215))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (118, 138))	('BRAF', 'Gene', (198, 202))	('lung cancer', 'Disease', 'MESH:D008175', (63, 74))	('lung adenocarcinomas', 'Disease', (118, 138))	('NRAS', 'Gene', (238, 242))	('mutations', 'Var', (173, 182))	('lung cancer', 'Phenotype', 'HP:0100526', (63, 74))	('ERBB2', 'Gene', (186, 191))	('PIK3CA', 'Gene', '5290', (209, 215))	('ERBB2', 'Gene', '2064', (186, 191))
56112	25979927	KRAS mutant cancers, including lung cancers, have been historically especially difficult to target and are the focus of a new NCI initiative directed towards tackling RAS mutant cancers.	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('cancers', 'Disease', 'MESH:D009369', (12, 19))	('cancers', 'Disease', 'MESH:D009369', (36, 43))	('cancers', 'Disease', 'MESH:D009369', (178, 185))	('lung cancers', 'Disease', 'MESH:D008175', (31, 43))	('KRAS', 'Gene', '3845', (0, 4))	('lung cancers', 'Disease', (31, 43))	('lung cancer', 'Phenotype', 'HP:0100526', (31, 42))	('lung cancers', 'Phenotype', 'HP:0100526', (31, 43))	('KRAS', 'Gene', (0, 4))	('cancers', 'Phenotype', 'HP:0002664', (12, 19))	('cancers', 'Phenotype', 'HP:0002664', (36, 43))	('cancers', 'Disease', (12, 19))	('cancers', 'Disease', (36, 43))	('cancers', 'Phenotype', 'HP:0002664', (178, 185))	('cancers', 'Disease', (178, 185))	('mutant', 'Var', (5, 11))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))
56114	25979927	Clinical trials to assess the efficacy of targeted therapies in tumors harboring the less common oncogenic driver mutations are ongoing (e.g., NCT01336634).	('tumors', 'Disease', (64, 70))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('mutations', 'Var', (114, 123))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
56115	25979927	One of the most surprising revelations of the past decade has been the discovery of recurrent gene fusions in NSCLC in addition to ALK-rearrangements.	('men', 'Species', '9606', (144, 147))	('NSCLC', 'Disease', (110, 115))	('ALK', 'Gene', '238', (131, 134))	('gene fusions', 'Var', (94, 106))	('NSCLC', 'Disease', 'MESH:D002289', (110, 115))	('ALK', 'Gene', (131, 134))
56116	25979927	Gene fusions involving the tyrosine kinases ROS1 and RET are found in 1-2% of lung adenocarcinomas.	('ROS1', 'Gene', (44, 48))	('RET', 'Gene', (53, 56))	('ROS1', 'Gene', '6098', (44, 48))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (78, 97))	('Gene fusions', 'Var', (0, 12))	('found', 'Reg', (61, 66))	('lung adenocarcinomas', 'Disease', (78, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('RET', 'Gene', '5979', (53, 56))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (78, 98))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (78, 98))
56117	25979927	Tumors harboring ROS1 fusions were recently shown to have a 72% response rate to crizotinib demonstrating the sensitivity of these tumors to TKIs (NCT00585195).	('ROS1', 'Gene', (17, 21))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('ROS1', 'Gene', '6098', (17, 21))	('crizotinib', 'Chemical', 'MESH:D000077547', (81, 91))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('fusions', 'Var', (22, 29))	('response', 'MPA', (64, 72))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('tumors', 'Disease', (131, 137))	('tumors', 'Disease', 'MESH:D009369', (131, 137))
56119	25979927	Fusions involving the receptor tyrosine kinase NTRK1 were also recently reported in lung adenocarcinoma.	('Fusions', 'Var', (0, 7))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (84, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('NTRK1', 'Gene', '4914', (47, 52))	('reported', 'Reg', (72, 80))	('lung adenocarcinoma', 'Disease', (84, 103))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (84, 103))	('NTRK1', 'Gene', (47, 52))
56121	25979927	Finally, CD74-NRG1 fusions have been detected in invasive mucinous lung adenocarcinomas and could potentially be targeted using drugs to block ERBB receptors and their downstream signaling molecules.	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (67, 86))	('ERBB', 'Gene', '1956;2064', (143, 147))	('ERBB', 'Gene', (143, 147))	('fusions', 'Var', (19, 26))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (67, 87))	('NRG1', 'Gene', (14, 18))	('invasive mucinous lung adenocarcinomas', 'Disease', 'MESH:D002288', (49, 87))	('CD74', 'Gene', (9, 13))	('detected', 'Reg', (37, 45))	('targeted', 'Reg', (113, 121))	('invasive mucinous lung adenocarcinomas', 'Disease', (49, 87))	('CD74', 'Gene', '972', (9, 13))	('NRG1', 'Gene', '3084', (14, 18))
56126	25979927	To date, none of the recurrent molecular alterations--including amplification and/or mutation of FGFR family members, which are commonly altered in lung squamous cell carcinoma--have proven to be as predictive for response to therapy as EGFR or ALK alterations in lung adenocarcinoma.	('lung adenocarcinoma', 'Disease', (264, 283))	('EGFR', 'Gene', '1956', (237, 241))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (153, 176))	('EGFR', 'Gene', (237, 241))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (264, 283))	('mutation', 'Var', (85, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (167, 176))	('ALK', 'Gene', '238', (245, 248))	('carcinoma', 'Phenotype', 'HP:0030731', (274, 283))	('FGFR', 'Gene', (97, 101))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (148, 176))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (264, 283))	('altered', 'Reg', (137, 144))	('lung squamous cell carcinoma', 'Disease', (148, 176))	('ALK', 'Gene', (245, 248))
56128	25979927	LUNG-MAP focuses on determining the efficacy of therapies targeting: 1) the FGFR family of receptor tyrosine kinases in tumors with mutation or amplification in genes encoding these receptors, 2) PI3K in tumors with PIK3CA mutations and, 3) CDK4/6 in tumors with amplification of CDK4 or CCND1/2/3.	('tumors', 'Disease', (120, 126))	('CCND1/2/3', 'Gene', '595;894;896', (288, 297))	('CDK4/6', 'Gene', '1019;1021', (241, 247))	('PIK3CA', 'Gene', '5290', (216, 222))	('tumors', 'Phenotype', 'HP:0002664', (204, 210))	('mutations', 'Var', (223, 232))	('tumors', 'Disease', 'MESH:D009369', (120, 126))	('CDK4', 'Gene', (280, 284))	('tumors', 'Phenotype', 'HP:0002664', (251, 257))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('CCND1/2/3', 'Gene', (288, 297))	('tumors', 'Disease', (204, 210))	('tumor', 'Phenotype', 'HP:0002664', (251, 256))	('CDK4', 'Gene', (241, 245))	('tumors', 'Disease', (251, 257))	('CDK4', 'Gene', '1019', (280, 284))	('PIK3CA', 'Gene', (216, 222))	('amplification', 'Var', (263, 276))	('amplification', 'Var', (144, 157))	('tumors', 'Disease', 'MESH:D009369', (204, 210))	('FGFR', 'Gene', (76, 80))	('CDK4/6', 'Gene', (241, 247))	('CDK4', 'Gene', '1019', (241, 245))	('PI3K', 'Var', (196, 200))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('tumors', 'Disease', 'MESH:D009369', (251, 257))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('mutation', 'Var', (132, 140))
56131	25979927	These include tumors with FGFR1 amplification, PARP overexpression or MYC amplification that could be responsive to FGFR, PARP and Aurora kinase inhibitors respectively.	('PARP', 'Gene', (47, 51))	('PARP', 'Gene', (122, 126))	('FGFR1', 'Gene', (26, 31))	('FGFR1', 'Gene', '2260', (26, 31))	('amplification', 'Var', (32, 45))	('tumors', 'Disease', (14, 20))	('MYC', 'Gene', (70, 73))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('overexpression', 'PosReg', (52, 66))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('PARP', 'Gene', '1302', (122, 126))	('PARP', 'Gene', '1302', (47, 51))
56135	25979927	To better understand the biological landscape of lung cancers, national and international large-scale -omic studies were undertaken shortly after the discovery of EGFR mutations.	('cancers', 'Phenotype', 'HP:0002664', (54, 61))	('lung cancers', 'Disease', (49, 61))	('EGFR', 'Gene', '1956', (163, 167))	('lung cancer', 'Phenotype', 'HP:0100526', (49, 60))	('EGFR', 'Gene', (163, 167))	('lung cancers', 'Disease', 'MESH:D008175', (49, 61))	('lung cancers', 'Phenotype', 'HP:0100526', (49, 61))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('mutations', 'Var', (168, 177))
56139	25979927	Collectively these efforts have contributed to the identification of new driver mutations and potential therapeutic targets in lung cancer.	('lung cancer', 'Disease', (127, 138))	('lung cancer', 'Phenotype', 'HP:0100526', (127, 138))	('mutations', 'Var', (80, 89))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('lung cancer', 'Disease', 'MESH:D008175', (127, 138))
56143	25979927	A recent report described the increased sensitivity of lung cancer cell lines with SMARCA4 mutations to inhibition of the methyltransferase EZH2 and etoposide highlighting how targeting epigenetic regulators in the appropriate genomic context could represent a valid therapeutic strategy.	('lung cancer', 'Disease', 'MESH:D008175', (55, 66))	('EZH2', 'Gene', '2146', (140, 144))	('etoposide', 'Chemical', 'MESH:D005047', (149, 158))	('EZH2', 'Gene', (140, 144))	('inhibition', 'MPA', (104, 114))	('SMARCA4', 'Gene', (83, 90))	('SMARCA4', 'Gene', '6597', (83, 90))	('lung cancer', 'Disease', (55, 66))	('methyltransferase', 'Enzyme', (122, 139))	('mutations', 'Var', (91, 100))	('lung cancer', 'Phenotype', 'HP:0100526', (55, 66))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('sensitivity', 'MPA', (40, 51))
56145	25979927	For example, according to data from the genomic characterization of lung squamous cell carcinoma by the TCGA, mutations in the KEAP1-CUL3-NFE2L2 oxidative stress response pathway are found in 34% of these cancers.	('NFE2L2', 'Gene', (138, 144))	('KEAP1', 'Gene', '9817', (127, 132))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (73, 96))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (68, 96))	('lung squamous cell carcinoma', 'Disease', (68, 96))	('mutations', 'Var', (110, 119))	('found', 'Reg', (183, 188))	('CUL3', 'Gene', (133, 137))	('cancers', 'Disease', 'MESH:D009369', (205, 212))	('CUL3', 'Gene', '8452', (133, 137))	('cancers', 'Disease', (205, 212))	('KEAP1', 'Gene', (127, 132))	('NFE2L2', 'Gene', '4780', (138, 144))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('oxidative stress', 'Phenotype', 'HP:0025464', (145, 161))	('cancers', 'Phenotype', 'HP:0002664', (205, 212))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))
56148	25979927	SOX2 is also frequently amplified in SCLC and has been shown to be a potential driver in these tumor since SOX2 knock-down in SCLC cell lines with high SOX2 expression, led to a decrease in cell viability.	('SOX2', 'Gene', '6657', (0, 4))	('SCLC', 'Gene', (126, 130))	('SOX2', 'Gene', (107, 111))	('SOX2', 'Gene', '6657', (107, 111))	('SOX2', 'Gene', '6657', (152, 156))	('decrease', 'NegReg', (178, 186))	('SOX2', 'Gene', (152, 156))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('cell viability', 'CPA', (190, 204))	('SCLC', 'Gene', '7864', (37, 41))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('SCLC', 'Gene', (37, 41))	('knock-down', 'Var', (112, 122))	('SCLC', 'Gene', '7864', (126, 130))	('SOX2', 'Gene', (0, 4))	('tumor', 'Disease', (95, 100))
56149	25979927	In lung adenocarcinoma, amplification of the lineage-specific transcription factor NKX2.1 has been described, although recent data indicate that it may have dual oncogenic and suppressive functions depending on the context complicating therapeutic considerations.	('NKX2.1', 'Gene', (83, 89))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (3, 22))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (3, 22))	('amplification', 'Var', (24, 37))	('NKX2.1', 'Gene', '7080', (83, 89))	('carcinoma', 'Phenotype', 'HP:0030731', (13, 22))	('lung adenocarcinoma', 'Disease', (3, 22))
56153	25979927	It is likely that this will at a minimum include mutational analysis of a panel of cancer genes, along with determination of copy number alterations and rearrangements.	('mutational', 'Var', (49, 59))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('men', 'Species', '9606', (162, 165))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('cancer', 'Disease', (83, 89))
56162	25979927	Much of our current understanding of acquired drug resistance has come from the molecular analysis of repeat biopsies at progression in patients with EGFR mutant or ALK-rearranged lung cancer following treatment with a TKI.	('ALK', 'Gene', '238', (165, 168))	('EGFR', 'Gene', (150, 154))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('lung cancer', 'Disease', 'MESH:D008175', (180, 191))	('mutant', 'Var', (155, 161))	('men', 'Species', '9606', (207, 210))	('patients', 'Species', '9606', (136, 144))	('ALK', 'Gene', (165, 168))	('drug resistance', 'Phenotype', 'HP:0020174', (46, 61))	('lung cancer', 'Disease', (180, 191))	('lung cancer', 'Phenotype', 'HP:0100526', (180, 191))	('EGFR', 'Gene', '1956', (150, 154))
56163	25979927	In 2004 when EGFR mutations were discovered, it was very uncommon to perform a re-biopsy if a patient with lung cancer developed progressive disease.	('lung cancer', 'Phenotype', 'HP:0100526', (107, 118))	('lung cancer', 'Disease', 'MESH:D008175', (107, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('progressive disease', 'Disease', 'MESH:D018450', (129, 148))	('lung cancer', 'Disease', (107, 118))	('patient', 'Species', '9606', (94, 101))	('progressive disease', 'Disease', (129, 148))	('EGFR', 'Gene', '1956', (13, 17))	('EGFR', 'Gene', (13, 17))	('mutations', 'Var', (18, 27))
56165	25979927	Shortly after the discovery of EGFR mutations in EGFR TKI-sensitive lung adenocarcinomas, groups at Memorial Sloan-Kettering and Harvard described a secondary mutation in EGFR, the EGFRT790M mutation, in tumors that had acquired resistance to TKIs in patients who had undergone a repeat biopsy at the time of progression.	('EGFR', 'Gene', (171, 175))	('patients', 'Species', '9606', (251, 259))	('tumors', 'Phenotype', 'HP:0002664', (204, 210))	('EGFR', 'Gene', '1956', (181, 185))	('EGFR', 'Gene', '1956', (31, 35))	('EGFR', 'Gene', (49, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('mutation', 'Var', (159, 167))	('tumors', 'Disease', (204, 210))	('EGFR', 'Gene', '1956', (171, 175))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (68, 88))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (68, 87))	('tumors', 'Disease', 'MESH:D009369', (204, 210))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (68, 88))	('EGFRT790M', 'Mutation', 'rs121434569', (181, 190))	('EGFR', 'Gene', '1956', (49, 53))	('EGFR', 'Gene', (181, 185))	('EGFR', 'Gene', (31, 35))	('mutations', 'Var', (36, 45))	('lung adenocarcinomas', 'Disease', (68, 88))
56167	25979927	Additional mechanisms of resistance to EGFR TKIs were also uncovered through analysis of repeat biopsies including the transformation to SCLC, HER2 and MET amplification, PIK3CA and BRAF mutations and NF1 down-regulation as described in this CCR Focus by Riely and Yu.	('NF1', 'Gene', '4763', (201, 204))	('BRAF', 'Gene', (182, 186))	('PIK3CA', 'Gene', (171, 177))	('PIK3CA', 'Gene', '5290', (171, 177))	('down-regulation', 'NegReg', (205, 220))	('HER2', 'Gene', (143, 147))	('mutations', 'Var', (187, 196))	('BRAF', 'Gene', '673', (182, 186))	('SCLC', 'Gene', '7864', (137, 141))	('EGFR', 'Gene', '1956', (39, 43))	('SCLC', 'Gene', (137, 141))	('EGFR', 'Gene', (39, 43))	('HER2', 'Gene', '2064', (143, 147))	('CCR', 'Disease', (242, 245))	('NF1', 'Gene', (201, 204))
56169	25979927	Approximately 25% of crizotinib-resistant tumors harbor secondary mutations in ALK.	('mutations', 'Var', (66, 75))	('ALK', 'Gene', '238', (79, 82))	('tumors', 'Disease', (42, 48))	('tumors', 'Disease', 'MESH:D009369', (42, 48))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('crizotinib', 'Chemical', 'MESH:D000077547', (21, 31))	('ALK', 'Gene', (79, 82))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
56170	25979927	Newly developed agents with higher potency including alectinib, ceritinib and AP26113 have the ability to inhibit the activity of several crizotinib-resistant mutants (including the L1196M gatekeeper mutation).	('activity', 'MPA', (118, 126))	('AP26113', 'Chemical', 'MESH:C000598580', (78, 85))	('L1196M', 'Mutation', 'rs1057519784', (182, 188))	('L1196M', 'Var', (182, 188))	('inhibit', 'NegReg', (106, 113))	('crizotinib-resistant', 'MPA', (138, 158))	('alectinib', 'Chemical', 'MESH:C582670', (53, 62))	('gatekeeper', 'Species', '111938', (189, 199))	('ceritinib', 'Chemical', 'MESH:C586847', (64, 73))	('crizotinib', 'Chemical', 'MESH:D000077547', (138, 148))
56171	25979927	In this regard a recent study showed that tumors resistant to ceritinib harbored mutations that confer resistance to this drug even though these were not detected after treatment with crizotinib in the same patient.	('ceritinib', 'Chemical', 'MESH:C586847', (62, 71))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('tumors', 'Disease', (42, 48))	('tumors', 'Disease', 'MESH:D009369', (42, 48))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('men', 'Species', '9606', (174, 177))	('mutations', 'Var', (81, 90))	('patient', 'Species', '9606', (207, 214))	('resistance', 'MPA', (103, 113))	('crizotinib', 'Chemical', 'MESH:D000077547', (184, 194))
56172	25979927	The NCCN guidelines recommend that a biopsy be performed at the time of disease progression in EGFR mutant TKI-resistant lung cancers.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('mutant', 'Var', (100, 106))	('lung cancers', 'Disease', (121, 133))	('cancers', 'Phenotype', 'HP:0002664', (126, 133))	('lung cancer', 'Phenotype', 'HP:0100526', (121, 132))	('EGFR', 'Gene', '1956', (95, 99))	('lung cancers', 'Disease', 'MESH:D008175', (121, 133))	('lung cancers', 'Phenotype', 'HP:0100526', (121, 133))	('men', 'Species', '9606', (25, 28))	('EGFR', 'Gene', (95, 99))
56174	25979927	Moreover, the presence of EGFRT790M has been shown to have prognostic value with EGFRT790M mutations portending to better outcomes.	('EGFRT790M', 'Gene', (81, 90))	('EGFRT790M', 'Var', (26, 35))	('better', 'PosReg', (115, 121))	('EGFRT790M', 'Mutation', 'rs121434569', (26, 35))	('EGFRT790M', 'Mutation', 'rs121434569', (81, 90))
56176	25979927	Similarly, in ALK-rearranged lung cancer the presence of a secondary ALK mutation at the time of acquired TKI resistance could determine whether the patient receives an ALK inhibitor in second-line or is treated with a different regimen altogether.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('ALK', 'Gene', '238', (69, 72))	('ALK', 'Gene', '238', (14, 17))	('men', 'Species', '9606', (233, 236))	('determine', 'Reg', (127, 136))	('ALK', 'Gene', '238', (169, 172))	('lung cancer', 'Disease', 'MESH:D008175', (29, 40))	('ALK', 'Gene', (14, 17))	('patient', 'Species', '9606', (149, 156))	('ALK', 'Gene', (69, 72))	('mutation', 'Var', (73, 81))	('lung cancer', 'Disease', (29, 40))	('ALK', 'Gene', (169, 172))	('lung cancer', 'Phenotype', 'HP:0100526', (29, 40))
56177	25979927	Further, recent findings have unveiled how new ALK inhibitors have unique patterns of specificity, therefore the nature of the specific secondary ALK mutation present could further narrow down the choice of subsequent TKI therapy.	('TKI therapy', 'Disease', (218, 229))	('ALK', 'Gene', '238', (146, 149))	('mutation', 'Var', (150, 158))	('ALK', 'Gene', (47, 50))	('ALK', 'Gene', '238', (47, 50))	('narrow down', 'NegReg', (181, 192))	('ALK', 'Gene', (146, 149))
56178	25979927	The results from studies of TKI-resistant EGFR and ALK mutant lung cancer support the use and incorporation of repeat biopsies into routine clinical practice to assist with determination of future treatment strategies (Fig.	('ALK', 'Gene', '238', (51, 54))	('men', 'Species', '9606', (202, 205))	('EGFR', 'Gene', '1956', (42, 46))	('lung cancer', 'Phenotype', 'HP:0100526', (62, 73))	('EGFR', 'Gene', (42, 46))	('mutant', 'Var', (55, 61))	('lung cancer', 'Disease', (62, 73))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('ALK', 'Gene', (51, 54))	('lung cancer', 'Disease', 'MESH:D008175', (62, 73))
56180	25979927	In 2013, investigators at MSKCC reported on the molecular analysis of 155 cases of EGFR mutant TKI resistant lung cancer.	('lung cancer', 'Disease', (109, 120))	('EGFR', 'Gene', '1956', (83, 87))	('lung cancer', 'Phenotype', 'HP:0100526', (109, 120))	('EGFR', 'Gene', (83, 87))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('mutant', 'Var', (88, 94))	('lung cancer', 'Disease', 'MESH:D008175', (109, 120))
56190	25979927	This design facilitates a particular targeted therapeutic strategy (i.e., inhibition of an oncogenically mutated kinase) across multiple cancer types.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('inhibition', 'Var', (74, 84))	('cancer', 'Disease', (137, 143))	('cancer', 'Disease', 'MESH:D009369', (137, 143))
56193	25979927	Examples are Investigation of Serial Studies to Predict Your Therapeutic Response with Imaging And molecular Analysis 2 (I-SPY TRIAL 2, I-SPY 2, NCT01042379), the FOCUS4 study in advanced colorectal cancer, and the phase 2 adaptive randomization design Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE) and BATTLE-2 in NSCLC (NCT00409968 and NCT01248247).	('Lung Cancer', 'Phenotype', 'HP:0100526', (309, 320))	('colorectal cancer', 'Disease', (188, 205))	('NCT00409968', 'Var', (365, 376))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('colorectal cancer', 'Disease', 'MESH:D015179', (188, 205))	('NSCLC', 'Disease', (358, 363))	('Lung Cancer Elimination', 'Disease', (309, 332))	('colorectal cancer', 'Phenotype', 'HP:0003003', (188, 205))	('NSCLC', 'Disease', 'MESH:D002289', (358, 363))	('Cancer', 'Phenotype', 'HP:0002664', (314, 320))	('NCT01248247', 'Var', (381, 392))
56201	33363004	Monoacylglycerol Lipase Knockdown Inhibits Cell Proliferation and Metastasis in Lung Adenocarcinoma Abnormal metabolism is one of the hallmarks of cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('Monoacylglycerol Lipase', 'Gene', (0, 23))	('Abnormal metabolism', 'Disease', 'MESH:D008659', (100, 119))	('Abnormal metabolism', 'Phenotype', 'HP:0032245', (100, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('Knockdown', 'Var', (24, 33))	('Metastasis in Lung Adenocarcinoma', 'Disease', 'MESH:D009362', (66, 99))	('Abnormal metabolism', 'Disease', (100, 119))	('Metastasis in Lung Adenocarcinoma', 'Disease', (66, 99))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('Inhibits', 'NegReg', (34, 42))	('Monoacylglycerol Lipase', 'Gene', '11343', (0, 23))	('cancer', 'Disease', (147, 153))	('Cell Proliferation', 'CPA', (43, 61))	('Lung Adenocarcinoma', 'Phenotype', 'HP:0030078', (80, 99))
56206	33363004	Functional studies further demonstrated that stable short hairpin RNA (shRNA)-mediated knockdown of MGLL inhibits tumor proliferation and metastasis, both in vitro and in vivo, and mechanistically, our data indicate that MGLL regulates Cyclin D1 and Cyclin B1 in LUAD cells.	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('MGLL', 'Gene', (221, 225))	('regulates', 'Reg', (226, 235))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('Cyclin D1', 'Gene', '595', (236, 245))	('tumor', 'Disease', (114, 119))	('Cyclin D1', 'Gene', (236, 245))	('Cyclin B1', 'Gene', '891', (250, 259))	('LUAD', 'Phenotype', 'HP:0030078', (263, 267))	('inhibits', 'NegReg', (105, 113))	('Cyclin B1', 'Gene', (250, 259))	('MGLL', 'Gene', (100, 104))	('knockdown', 'Var', (87, 96))
56207	33363004	Moreover, we found that knockdown of MGLL suppresses the expression of matrix metalloproteinase 14 (MMP14) in A549 and H322 cells, and in clinical samples, expression of MMP14 is significantly correlated with MGLL expression.	('MMP14', 'Gene', (170, 175))	('expression', 'MPA', (57, 67))	('MGLL', 'Gene', (209, 213))	('MMP14', 'Gene', '4323', (170, 175))	('matrix metalloproteinase 14', 'Gene', '4323', (71, 98))	('A549', 'CellLine', 'CVCL:0023', (110, 114))	('MGLL', 'Gene', (37, 41))	('H322', 'CellLine', 'CVCL:1556', (119, 123))	('suppresses', 'NegReg', (42, 52))	('MMP14', 'Gene', '4323', (100, 105))	('correlated', 'Interaction', (193, 203))	('MMP14', 'Gene', (100, 105))	('matrix metalloproteinase 14', 'Gene', (71, 98))	('knockdown', 'Var', (24, 33))	('expression', 'MPA', (214, 224))
56211	33363004	Emerging evidences have revealed that dysregulated metabolic pathways involved in cancer development, and metabolic reprogramming can regulate cancer cell stemness, proliferation, metastasis, and drug resistance.	('drug resistance', 'CPA', (196, 211))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('dysregulated', 'Var', (38, 50))	('metastasis', 'CPA', (180, 190))	('drug resistance', 'Phenotype', 'HP:0020174', (196, 211))	('regulate', 'Reg', (134, 142))	('metabolic', 'CPA', (51, 60))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('proliferation', 'CPA', (165, 178))
56213	33363004	Recently, a number of studies have further demonstrated that aberrantly activated lipid metabolic pathways can promote cancer cell proliferation and metastasis, and intriguingly, disordered lipid metabolism has been detected in lung cancer.	('lipid metabolic pathways', 'Pathway', (82, 106))	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('disordered lipid metabolism', 'Disease', 'MESH:D052439', (179, 206))	('aberrantly', 'Var', (61, 71))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('lung cancer', 'Disease', 'MESH:D008175', (228, 239))	('cancer', 'Disease', (233, 239))	('cancer', 'Disease', (119, 125))	('cancer', 'Disease', 'MESH:D009369', (233, 239))	('disordered lipid metabolism', 'Phenotype', 'HP:0003119', (179, 206))	('lipid', 'Chemical', 'MESH:D008055', (190, 195))	('disordered lipid metabolism', 'Disease', (179, 206))	('lung cancer', 'Disease', (228, 239))	('lung cancer', 'Phenotype', 'HP:0100526', (228, 239))	('detected', 'Reg', (216, 224))	('lipid', 'Chemical', 'MESH:D008055', (82, 87))	('promote', 'PosReg', (111, 118))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
56227	33363004	Sections were incubated with MGLL (1:200, Proteintech) or MMP14 (1:200, Abclonal) antibodies overnight at 4 C and then incubated with appropriate secondary antibodies.	('MMP14', 'Gene', (58, 63))	('1:200', 'Var', (65, 70))	('MMP14', 'Gene', '4323', (58, 63))
56236	33363004	RNA-seq was used to measure mRNA expression profiles after knockdown of MGLL in A549 cells.	('MGLL', 'Gene', (72, 76))	('mRNA expression profiles', 'MPA', (28, 52))	('knockdown', 'Var', (59, 68))	('A549', 'CellLine', 'CVCL:0023', (80, 84))
56249	33363004	To investigate the effect of MGLL on the malignant phenotypes of LUAD cells, we used shRNA to stably knockdown MGLL expression in the A549 and H322 cell lines, which display higher endogenous MGLL expression ( Figures 2A, B ).	('MGLL', 'Gene', (111, 115))	('endogenous', 'MPA', (181, 191))	('LUAD', 'Phenotype', 'HP:0030078', (65, 69))	('A549', 'CellLine', 'CVCL:0023', (134, 138))	('higher', 'PosReg', (174, 180))	('H322', 'CellLine', 'CVCL:1556', (143, 147))	('MGLL', 'Protein', (192, 196))	('expression', 'MPA', (197, 207))	('knockdown', 'Var', (101, 110))
56250	33363004	Our data show that MGLL depletion significantly attenuates both cell proliferation and colony formation in A549 and H322 cells, as compared to cells transfected with empty vector control ( Figures 2C, D ).	('colony formation', 'CPA', (87, 103))	('cell proliferation', 'CPA', (64, 82))	('attenuates', 'NegReg', (48, 58))	('MGLL', 'Gene', (19, 23))	('depletion', 'Var', (24, 33))	('A549', 'CellLine', 'CVCL:0023', (107, 111))	('H322', 'CellLine', 'CVCL:1556', (116, 120))
56252	33363004	Consistent with our in vitro data, we found that tumor size and weight were markedly reduced in the A549-shMGLL group compared to the control group ( Figures 2E, F ).	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('A549', 'CellLine', 'CVCL:0023', (100, 104))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor', 'Disease', (49, 54))	('reduced', 'NegReg', (85, 92))	('A549-shMGLL', 'Var', (100, 111))
56253	33363004	A previous study reported that knockdown of MGLL in colorectal cancer cells inhibits tumor cell proliferation and induces apoptosis via downregulation of Cyclin D1 and BCL-2.	('tumor', 'Disease', (85, 90))	('BCL-2', 'Gene', '596', (168, 173))	('apoptosis', 'CPA', (122, 131))	('downregulation', 'NegReg', (136, 150))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('Cyclin D1', 'Gene', '595', (154, 163))	('inhibits', 'NegReg', (76, 84))	('colorectal cancer', 'Phenotype', 'HP:0003003', (52, 69))	('MGLL', 'Gene', (44, 48))	('BCL-2', 'Gene', (168, 173))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('colorectal cancer', 'Disease', (52, 69))	('induces', 'Reg', (114, 121))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('Cyclin D1', 'Gene', (154, 163))	('knockdown', 'Var', (31, 40))	('colorectal cancer', 'Disease', 'MESH:D015179', (52, 69))
56255	33363004	We then measured the protein levels of cell proliferation and apoptosis-related proteins by western blot and found that MGLL knockdown attenuates the expression of both Cyclin D1 and Cyclin B1; whereas the expression levels of the apoptosis-related proteins BCL-2 and BAX are not significantly affected by MGLL knockdown ( Figure 2I ).	('knockdown', 'Var', (125, 134))	('expression', 'MPA', (150, 160))	('Cyclin D1', 'Gene', '595', (169, 178))	('BCL-2', 'Gene', '596', (258, 263))	('Cyclin D1', 'Gene', (169, 178))	('Cyclin B1', 'Gene', '891', (183, 192))	('BCL-2', 'Gene', (258, 263))	('attenuates', 'NegReg', (135, 145))	('MGLL', 'Gene', (120, 124))	('Cyclin B1', 'Gene', (183, 192))	('BAX', 'Gene', '581', (268, 271))	('BAX', 'Gene', (268, 271))
56257	33363004	We found that both the migratory and invasive capabilities of A549 and H322 cells are significantly suppressed by MGLL knockdown relative to the control ( Figures 3A, B ).	('A549', 'CellLine', 'CVCL:0023', (62, 66))	('MGLL', 'Gene', (114, 118))	('suppressed', 'NegReg', (100, 110))	('knockdown', 'Var', (119, 128))	('H322', 'CellLine', 'CVCL:1556', (71, 75))
56259	33363004	We found that mice injected with A549-shMGLL cells displayed fewer pulmonary metastatic nodules compared to those injected with the vector control cells ( Figure 3C ).	('pulmonary metastatic nodules', 'CPA', (67, 95))	('mice', 'Species', '10090', (14, 18))	('A549-shMGLL cells', 'Var', (33, 50))	('fewer', 'NegReg', (61, 66))	('A549', 'CellLine', 'CVCL:0023', (33, 37))
56262	33363004	To better understand the molecular mechanisms underlying the role of MGLL in LUAD proliferation and metastasis, we performed RNA-seq analysis to uncover the transcriptional profiles of A549 cells following MGLL knockdown ( Figures 4A, B ,  Supplementary Data1 ).	('A549', 'CellLine', 'CVCL:0023', (185, 189))	('LUAD', 'Phenotype', 'HP:0030078', (77, 81))	('MGLL', 'Gene', (206, 210))	('knockdown', 'Var', (211, 220))
56264	33363004	We then carefully examined the list of upregulated and downregulated mRNAs and found that expression of MMP14 is significantly decreased following MGLL knockdown ( Figure 4A ).	('knockdown', 'Var', (152, 161))	('MMP14', 'Gene', (104, 109))	('decreased', 'NegReg', (127, 136))	('expression', 'MPA', (90, 100))	('MGLL', 'Gene', (147, 151))	('MMP14', 'Gene', '4323', (104, 109))
56266	33363004	Consistent with our transcriptional profiling, western blot analysis revealed that expression of MMP14 is significantly decreased following MGLL knockdown in A549 and H322 cells ( Figure 4D ).	('decreased', 'NegReg', (120, 129))	('A549', 'CellLine', 'CVCL:0023', (158, 162))	('knockdown', 'Var', (145, 154))	('H322', 'CellLine', 'CVCL:1556', (167, 171))	('MMP14', 'Gene', '4323', (97, 102))	('expression', 'MPA', (83, 93))	('MGLL', 'Gene', (140, 144))	('MMP14', 'Gene', (97, 102))
56269	33363004	Our results revealed that MMP14 is significantly overexpressed in tumor tissues compared to non-tumor tissues ( Figures 5A, B ), and high MMP14 expression is significantly correlated with poor overall survival (P = 0.019,  Figure 5C ).	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('MMP14', 'Gene', '4323', (26, 31))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumor', 'Disease', (66, 71))	('expression', 'MPA', (144, 154))	('poor', 'NegReg', (188, 192))	('high', 'Var', (133, 137))	('tumor', 'Disease', (96, 101))	('overall survival', 'CPA', (193, 209))	('MMP14', 'Gene', (26, 31))	('overexpressed', 'PosReg', (49, 62))	('MMP14', 'Gene', '4323', (138, 143))	('MMP14', 'Gene', (138, 143))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('tumor', 'Disease', 'MESH:D009369', (66, 71))
56272	33363004	In particular, it has become well recognized that aberrant expression of genes involved in fatty acid synthesis or fatty acid oxidation correlate with malignant phenotypes, including metastasis and drug resistance.	('aberrant expression', 'Var', (50, 69))	('drug resistance', 'Phenotype', 'HP:0020174', (198, 213))	('fatty acid', 'Chemical', 'MESH:D005227', (115, 125))	('metastasis', 'CPA', (183, 193))	('fatty acid', 'Chemical', 'MESH:D005227', (91, 101))	('drug resistance', 'CPA', (198, 213))
56277	33363004	We therefore evaluated the role of MGLL in cell proliferation in A549 and H322 cells and found that MGLL knockdown inhibits cancer cell proliferation both in vitro and in vivo.	('cancer', 'Disease', (124, 130))	('A549', 'CellLine', 'CVCL:0023', (65, 69))	('knockdown', 'Var', (105, 114))	('H322', 'CellLine', 'CVCL:1556', (74, 78))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('inhibits', 'NegReg', (115, 123))	('MGLL', 'Gene', (100, 104))	('cancer', 'Disease', 'MESH:D009369', (124, 130))
56279	33363004	Interestingly, the expression of apoptosis-related proteins BCL-2 and BAX was not significantly affected following MGLL knockdown, suggesting that MGLL may not affect apoptosis in LUAD cells.	('BCL-2', 'Gene', (60, 65))	('LUAD', 'Phenotype', 'HP:0030078', (180, 184))	('knockdown', 'Var', (120, 129))	('BAX', 'Gene', (70, 73))	('BAX', 'Gene', '581', (70, 73))	('BCL-2', 'Gene', '596', (60, 65))
56284	33363004	Here, our data indicate that MGLL can promote lung cancer cell metastasis, both in vitro and in vivo.	('MGLL', 'Var', (29, 33))	('lung cancer', 'Disease', 'MESH:D008175', (46, 57))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('promote', 'PosReg', (38, 45))	('lung cancer', 'Disease', (46, 57))	('lung cancer', 'Phenotype', 'HP:0100526', (46, 57))
56285	33363004	However, we found that expression of EMT markers, including E-cadherin and N-cadherin, was not significantly affected following MGLL knockdown in A549 and H322 cells.	('MGLL', 'Gene', (128, 132))	('N-cadherin', 'Gene', '1000', (75, 85))	('H322', 'CellLine', 'CVCL:1556', (155, 159))	('E-cadherin', 'Gene', (60, 70))	('E-cadherin', 'Gene', '999', (60, 70))	('A549', 'CellLine', 'CVCL:0023', (146, 150))	('knockdown', 'Var', (133, 142))	('N-cadherin', 'Gene', (75, 85))
56289	33363004	Among the MGLL-regulated genes uncovered via RNA-seq, we found that MMP14 is significantly downregulated following MGLL knockdown.	('downregulated', 'NegReg', (91, 104))	('MGLL', 'Gene', (115, 119))	('MMP14', 'Gene', '4323', (68, 73))	('MMP14', 'Gene', (68, 73))	('knockdown', 'Var', (120, 129))
56294	33363004	Critically, we find that knockdown of MGLL inhibits the expression level of Cyclin B1, Cyclin D1 and MMP14.	('Critically', 'Disease', (0, 10))	('Cyclin D1', 'Gene', (87, 96))	('MMP14', 'Gene', (101, 106))	('Cyclin B1', 'Gene', '891', (76, 85))	('expression level', 'MPA', (56, 72))	('Cyclin B1', 'Gene', (76, 85))	('Critically', 'Disease', 'MESH:D016638', (0, 10))	('MMP14', 'Gene', '4323', (101, 106))	('Cyclin D1', 'Gene', '595', (87, 96))	('MGLL', 'Gene', (38, 42))	('inhibits', 'NegReg', (43, 51))	('knockdown', 'Var', (25, 34))
56303	33195415	However, the characterization of aberrant ACE2 expression in malignant tumors has not been elucidated.	('malignant tumors', 'Disease', (61, 77))	('malignant tumors', 'Disease', 'MESH:D009369', (61, 77))	('ACE2', 'Gene', (42, 46))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('aberrant', 'Var', (33, 41))	('ACE2', 'Gene', '59272', (42, 46))
56316	33195415	GSEA analysis which was carried out to determine the effect of ACE2 on tumors indicated that several cancer-associated pathways and immune-related pathways were hyperactivated in the high ACE2 expression group of most tumors.	('hyperactivated', 'PosReg', (161, 175))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Disease', (71, 77))	('expression', 'MPA', (193, 203))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('tumors', 'Phenotype', 'HP:0002664', (218, 224))	('tumors', 'Disease', 'MESH:D009369', (71, 77))	('GSEA', 'Chemical', '-', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('ACE2', 'Gene', '59272', (63, 67))	('tumors', 'Disease', (218, 224))	('cancer', 'Disease', (101, 107))	('ACE2', 'Gene', '59272', (188, 192))	('ACE2', 'Gene', (63, 67))	('immune-related pathways', 'Pathway', (132, 155))	('ACE2', 'Gene', (188, 192))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('high', 'Var', (183, 187))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('tumors', 'Disease', 'MESH:D009369', (218, 224))
56351	33195415	Neoantigen is a neonatal antigen that is encoded by a mutant gene of a tumor cell.	('mutant', 'Var', (54, 60))	('tumor', 'Disease', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Disease', 'MESH:D009369', (71, 76))
56353	33195415	Neoantigen vaccines can be developed using the immune activity of tumor neoantigens, according to a specific mutation in the tumor cells, then administered to patients to achieve the required therapeutic effect.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('tumor', 'Disease', (66, 71))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumor', 'Disease', (125, 130))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('patients', 'Species', '9606', (159, 167))	('mutation', 'Var', (109, 117))
56356	33195415	The Tumor Mutational Burden (TMB) is usually measured by the number of somatic mutations that occur within an average of 1 Mb in the coding region (exon region) of the tumor cell genome (non-synonymous mutations).	('tumor', 'Disease', (168, 173))	('mutations', 'Var', (79, 88))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('TMB', 'Chemical', '-', (29, 32))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('Tumor', 'Phenotype', 'HP:0002664', (4, 9))
56360	33195415	Microsatellite Instability (MSI) refers to any change in the length of a microsatellite due to the insertion or deletion of a repeating unit in a tumor compared to normal tissue.	('change', 'Reg', (47, 53))	('S', 'Gene', '43740568', (29, 30))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('length', 'MPA', (61, 67))	('insertion', 'Var', (99, 108))	('deletion', 'Var', (112, 120))	('tumor', 'Disease', (146, 151))	('Microsatellite Instability', 'Disease', (0, 26))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
56366	33195415	We visualized the tumor with the most ACE2 mutations using an R data package, maftools.	('tumor', 'Disease', (18, 23))	('ACE2', 'Gene', (38, 42))	('mutations', 'Var', (43, 52))	('ACE2', 'Gene', '59272', (38, 42))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
56367	33195415	Therefore, TCGA expression profiling was used to evaluate the relationship between ACE2 and five MMRs genes: MLH1, MSH2, MSH6, PMS2, and EPCAM mutations.	('PMS2', 'Gene', (127, 131))	('MLH1', 'Gene', '4292', (109, 113))	('MLH1', 'Gene', (109, 113))	('MSH6', 'Gene', (121, 125))	('PMS2', 'Gene', '5395', (127, 131))	('ACE2', 'Gene', (83, 87))	('MMRs genes', 'Gene', (97, 107))	('EPCAM', 'Gene', (137, 142))	('MSH6', 'Gene', '2956', (121, 125))	('MSH2', 'Gene', (115, 119))	('ACE2', 'Gene', '59272', (83, 87))	('MSH2', 'Gene', '4436', (115, 119))	('EPCAM', 'Gene', '4072', (137, 142))	('mutations', 'Var', (143, 152))
56426	33195415	A schematic diagram of the tumor with the highest number of mutations is shown in Figure 12.	('tumor', 'Disease', (27, 32))	('mutations', 'Var', (60, 69))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))
56427	33195415	Notably, ACE2 mutations were only observed in BLCA, BRCA, COAD, HNSC, LAML, LGG, LUAD, LUSC, OV, SKCM, STAD, and UCEC.	('S', 'Gene', '43740568', (66, 67))	('S', 'Gene', '43740568', (97, 98))	('S', 'Gene', '43740568', (103, 104))	('ACE2', 'Gene', '59272', (9, 13))	('BRCA', 'Gene', (52, 56))	('BRCA', 'Gene', '672', (52, 56))	('COAD', 'Disease', (58, 62))	('S', 'Gene', '43740568', (89, 90))	('COAD', 'Disease', 'MESH:D029424', (58, 62))	('mutations', 'Var', (14, 23))	('ACE2', 'Gene', (9, 13))
56428	33195415	These findings indicate that ACE2 mutations seldom occur in most tumors.	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('ACE2', 'Gene', '59272', (29, 33))	('tumors', 'Disease', (65, 71))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('mutations', 'Var', (34, 43))	('ACE2', 'Gene', (29, 33))
56433	33195415	DNA hypermethylation in the promoter region of a tumor suppressor gene leads to gene silencing, which in turn leads to dysregulation of multiple signaling pathways associated with human malignancy.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('multiple signaling pathways', 'Pathway', (136, 163))	('gene', 'MPA', (80, 84))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('malignancy', 'Disease', 'MESH:D009369', (186, 196))	('leads to', 'Reg', (110, 118))	('human', 'Species', '9606', (180, 185))	('tumor', 'Disease', (49, 54))	('dysregulation', 'MPA', (119, 132))	('malignancy', 'Disease', (186, 196))	('hypermethylation', 'Var', (4, 20))
56473	33195415	It has been demonstrated that overexpressed ACE2 may inhibit cell growth and vascular endothelial growth factor production in lung cancer, breast cancer, colon cancer, and pancreatic cancer.	('ACE2', 'Gene', '59272', (44, 48))	('colon cancer', 'Phenotype', 'HP:0003003', (154, 166))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('ACE2', 'Gene', (44, 48))	('inhibit', 'NegReg', (53, 60))	('vascular endothelial growth factor', 'Gene', '7422', (77, 111))	('pancreatic cancer', 'Disease', 'MESH:D010190', (172, 189))	('lung cancer', 'Disease', (126, 137))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('colon cancer', 'Disease', 'MESH:D015179', (154, 166))	('breast cancer', 'Phenotype', 'HP:0003002', (139, 152))	('vascular endothelial growth factor', 'Gene', (77, 111))	('pancreatic cancer', 'Disease', (172, 189))	('cell growth', 'CPA', (61, 72))	('breast cancer', 'Disease', 'MESH:D001943', (139, 152))	('breast cancer', 'Disease', (139, 152))	('overexpressed', 'Var', (30, 43))	('lung cancer', 'Disease', 'MESH:D008175', (126, 137))	('colon cancer', 'Disease', (154, 166))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('lung cancer', 'Phenotype', 'HP:0100526', (126, 137))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (172, 189))
56474	33195415	On the other hand, overexpressed ACE2 may promote the migration and invasion of human renal carcinoma cells.	('ACE2', 'Gene', '59272', (33, 37))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('renal carcinoma', 'Disease', 'MESH:C538614', (86, 101))	('migration', 'CPA', (54, 63))	('overexpressed', 'Var', (19, 32))	('promote', 'PosReg', (42, 49))	('human', 'Species', '9606', (80, 85))	('renal carcinoma', 'Disease', (86, 101))	('ACE2', 'Gene', (33, 37))	('renal carcinoma', 'Phenotype', 'HP:0005584', (86, 101))
56483	33195415	ACE2 expression also has a significantly positive correlation with the infiltrating levels of dendritic cells, macrophages M0, mast cells resting, and neutrophils in multiple cancers.	('ACE2', 'Gene', (0, 4))	('multiple cancers', 'Disease', (166, 182))	('expression', 'Var', (5, 15))	('infiltrating levels of dendritic cells', 'MPA', (71, 109))	('cancers', 'Phenotype', 'HP:0002664', (175, 182))	('ACE2', 'Gene', '59272', (0, 4))	('multiple cancers', 'Disease', 'MESH:D009369', (166, 182))	('positive correlation', 'Reg', (41, 61))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
56487	33195415	We found that increased ACE2 expression correlates with immune infiltration levels in most tumors and that higher ACE2 expression was related to immune neoantigen, TMB, and microsatellite instability.	('tumors', 'Disease', (91, 97))	('increased', 'PosReg', (14, 23))	('expression', 'MPA', (119, 129))	('tumors', 'Disease', 'MESH:D009369', (91, 97))	('TMB', 'Chemical', '-', (164, 167))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('ACE2', 'Gene', '59272', (114, 118))	('related', 'Reg', (134, 141))	('ACE2', 'Gene', (24, 28))	('microsatellite instability', 'Var', (173, 199))	('higher', 'PosReg', (107, 113))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('ACE2', 'Gene', '59272', (24, 28))	('expression', 'MPA', (29, 39))	('ACE2', 'Gene', (114, 118))	('immune infiltration levels', 'MPA', (56, 82))
56510	32334476	Other factors that positively affect the signal for angiogenesis are protein action arising from oncogenes, hypoxia, low pH, poor nutrition and activity of reactive oxygen species (Viallard and Larrivee, 2017).	('low', 'Var', (117, 120))	('poor nutrition and activity of reactive oxygen species', 'Phenotype', 'HP:0025464', (125, 179))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (156, 179))	('poor nutrition and activity', 'Phenotype', 'HP:0011968', (125, 152))	('hypoxia', 'Disease', 'MESH:D000860', (108, 115))	('hypoxia', 'Disease', (108, 115))	('protein', 'MPA', (69, 76))
56523	32334476	As primary antibodies, anti-tryptase (M7052, Dako ) diluted 1:1000 was used for the evaluation of mast cells, and anti-CD34 (M7165, Dako ) and anti-CD31 (M0823, Dako ), both 1:100 for evaluation of angiogenesis.	('CD31', 'Gene', '5175', (148, 152))	('M7165', 'Var', (125, 130))	('angiogenesis', 'CPA', (198, 210))	('Dako', 'Chemical', '-', (161, 165))	('CD34', 'Gene', (119, 123))	('CD34', 'Gene', '947', (119, 123))	('Dako', 'Chemical', '-', (45, 49))	('Dako', 'Chemical', '-', (132, 136))	('M0823', 'Var', (154, 159))	('M7052', 'Var', (38, 43))	('CD31', 'Gene', (148, 152))
56544	32334476	Currently, the most used markers for endothelial cells are the anti-CD31, anti-CD34, anti- VWF, anti- CD105 and VEGF antibodies.	('anti- CD105', 'Var', (96, 107))	('VEGF', 'Gene', '7422', (112, 116))	('CD31', 'Gene', (68, 72))	('VEGF', 'Gene', (112, 116))	('CD34', 'Gene', '947', (79, 83))	('VWF', 'Gene', '7450', (91, 94))	('CD31', 'Gene', '5175', (68, 72))	('CD34', 'Gene', (79, 83))	('VWF', 'Gene', (91, 94))
56560	32334476	A study that evaluated the effects of tobacco on oral mucosa showed that the carcinogen 4-nitroquinoline-N-oxide (4-NQO), present in tobacco, may cause a decrease in mast cells, which may explain the findings of this study (Sand et al., 2002).	('tobacco', 'Species', '4097', (133, 140))	('tobacco', 'Species', '4097', (38, 45))	('decrease', 'NegReg', (154, 162))	('4-NQO', 'Chemical', 'MESH:D015112', (114, 119))	('4-nitroquinoline-N-oxide', 'Chemical', 'MESH:D015112', (88, 112))	('4-nitroquinoline-N-oxide', 'Var', (88, 112))	('mast cells', 'CPA', (166, 176))
56579	32718341	We profiled the variants in ctDNA from 24 CC patients who were being treated with systemic chemotherapy and local radiotherapy at the Jeonbuk National University Hospital, Korea.	('ctDNA', 'Gene', (28, 33))	('variants', 'Var', (16, 24))	('patients', 'Species', '9606', (45, 53))	('CC', 'Phenotype', 'HP:0002664', (42, 44))
56580	32718341	Eighteen out of 24 genes in our NGS CC panel had mutations across the 24 CC patients, including somatic alterations of mutated genes (ZFHX3-83%, KMT2C-79%, KMT2D-79%, NSD1-67%, ATM-38% and RNF213-27%).	('CC', 'Phenotype', 'HP:0002664', (36, 38))	('ATM', 'Gene', (177, 180))	('patients', 'Species', '9606', (76, 84))	('KMT2C', 'Gene', '58508', (145, 150))	('ZFHX3', 'Gene', '463', (134, 139))	('mutations', 'Var', (49, 58))	('ZFHX3', 'Gene', (134, 139))	('KMT2D', 'Gene', (156, 161))	('KMT2D', 'Gene', '8085', (156, 161))	('ATM', 'Gene', '472', (177, 180))	('NSD1', 'Gene', '64324', (167, 171))	('RNF213', 'Gene', (189, 195))	('CC', 'Phenotype', 'HP:0002664', (73, 75))	('NSD1', 'Gene', (167, 171))	('KMT2C', 'Gene', (145, 150))	('RNF213', 'Gene', '57674', (189, 195))
56582	32718341	We developed our NGS CC panel and demostrated that our NGS panel can be useful for the diagnosis and monitoring of the CC, since the panel detected the common somatic variations in CC patients and we observed how these genetic variations change according to the treatment pattern of the patient.	('patient', 'Species', '9606', (287, 294))	('CC', 'Phenotype', 'HP:0002664', (119, 121))	('patients', 'Species', '9606', (184, 192))	('CC', 'Phenotype', 'HP:0002664', (21, 23))	('CC', 'Phenotype', 'HP:0002664', (181, 183))	('change', 'Reg', (238, 244))	('variations', 'Var', (167, 177))	('patient', 'Species', '9606', (184, 191))
56594	32718341	In this study, we assessed the clinical utility of analyzing gene mutations in CC patients who have a medical history of chemotherapy and radiotherapy, profiling the genetic variations in cfDNA from 24 patients.	('genetic variations', 'Var', (166, 184))	('patients', 'Species', '9606', (82, 90))	('patients', 'Species', '9606', (202, 210))	('CC', 'Phenotype', 'HP:0002664', (79, 81))	('cfDNA', 'Gene', (188, 193))
56595	32718341	As a result, we were able to obtain the mutational variations in ctDNA and observe their patterns over time, which can be used to detect the phases of CC, monitor the tumor status, and predict therapeutic responses.	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('CC', 'Phenotype', 'HP:0002664', (151, 153))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('mutational', 'Var', (40, 50))	('ctDNA', 'Gene', (65, 70))	('tumor', 'Disease', (167, 172))
56617	32718341	The standard material (Horizon Discovery, Cambridge, UK) contains mutations in PIK3CA(E545K) and KRAS(G12D) genes.	('mutations', 'Var', (66, 75))	('KRAS', 'Gene', (97, 101))	('KRAS', 'Gene', '3845', (97, 101))	('PIK3CA', 'Gene', (79, 85))	('E545K', 'Mutation', 'rs104886003', (86, 91))	('G12D', 'Mutation', 'rs121913529', (102, 106))	('PIK3CA', 'Gene', '5290', (79, 85))
56638	32718341	Genetic mutations in ZFHX3, KMT2C/D, and NDS1 were detected in 20 (83%), 19 (79%), and 16 (67%) women with CC, respectively (Fig.	('detected', 'Reg', (51, 59))	('KMT2C/D', 'Gene', (28, 35))	('KMT2C/D', 'Gene', '58508', (28, 35))	('ZFHX3', 'Gene', '463', (21, 26))	('CC', 'Phenotype', 'HP:0002664', (107, 109))	('ZFHX3', 'Gene', (21, 26))	('NDS1', 'Gene', (41, 45))	('Genetic mutations', 'Var', (0, 17))	('women', 'Species', '9606', (96, 101))
56641	32718341	Mutation patterns with two or more mutation types (such as missense and frameshift) were found in 15 patients.	('frameshift', 'Var', (72, 82))	('patients', 'Species', '9606', (101, 109))	('missense', 'Var', (59, 67))
56642	32718341	Frameshift insertions and deletions were found in only five patients.	('patients', 'Species', '9606', (60, 68))	('Frameshift insertions', 'Var', (0, 21))	('deletions', 'Var', (26, 35))
56646	32718341	After analyzing all variants of each gene, the most commonly detected variations were located in KMT2D, followed by the KMT2C, FAT4, RNF213, and ZFHX3 variants (Fig.	('RNF213', 'Gene', (133, 139))	('KMT2D', 'Gene', '8085', (97, 102))	('variations', 'Var', (70, 80))	('KMT2C', 'Gene', (120, 125))	('RNF213', 'Gene', '57674', (133, 139))	('ZFHX3', 'Gene', '463', (145, 150))	('FAT4', 'Gene', (127, 131))	('ZFHX3', 'Gene', (145, 150))	('KMT2C', 'Gene', '58508', (120, 125))	('FAT4', 'Gene', '79633', (127, 131))	('KMT2D', 'Gene', (97, 102))
56647	32718341	Most mutations in cancer suppressor genes were evenly detected across all stages of cancer, whereas cancer driver gene variants were found mainly in the early stages of cancer (stage I and II).	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('cancer', 'Disease', (169, 175))	('cancer', 'Disease', (84, 90))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('mutations', 'Var', (5, 14))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('variants', 'Var', (119, 127))	('cancer', 'Disease', (18, 24))	('cancer', 'Disease', 'MESH:D009369', (18, 24))	('cancer', 'Disease', 'MESH:D009369', (169, 175))
56652	32718341	In addition to KMT2C and ZFHX3 mutations found in most patients, PIK3CA and RNF213 mutations were also detected, and RNF213 mutations changed over 18 months of the examination.	('mutations', 'Var', (83, 92))	('RNF213', 'Gene', '57674', (76, 82))	('mutations', 'Var', (31, 40))	('KMT2C', 'Gene', '58508', (15, 20))	('KMT2C', 'Gene', (15, 20))	('RNF213', 'Gene', '57674', (117, 123))	('RNF213', 'Gene', (117, 123))	('PIK3CA', 'Gene', (65, 71))	('ZFHX3', 'Gene', '463', (25, 30))	('ZFHX3', 'Gene', (25, 30))	('RNF213', 'Gene', (76, 82))	('patients', 'Species', '9606', (55, 63))	('PIK3CA', 'Gene', '5290', (65, 71))
56662	32718341	The mutation of KMT2D gene, which is considered as pathologic (0.84) according to the FATHMM prediction, was detected in the first screening but disappeared in the second screening and then reappeared in the third screening.	('disappeared', 'NegReg', (145, 156))	('KMT2D', 'Gene', (16, 21))	('KMT2D', 'Gene', '8085', (16, 21))	('mutation', 'Var', (4, 12))
56663	32718341	The genetic variation of ZFHX3 was found to decrease in the early phase of chemotherapy (2.1%), but increased over time (7.2%).	('decrease', 'NegReg', (44, 52))	('increased', 'PosReg', (100, 109))	('ZFHX3', 'Gene', '463', (25, 30))	('ZFHX3', 'Gene', (25, 30))	('genetic variation', 'Var', (4, 21))
56666	32718341	The patient had mutations in two genes (KMT2D and ZFHX3); the KMT2D mutation, which is considered as pathogenic (score 0.84), disappeared by the second and third screening (Fig.	('ZFHX3', 'Gene', (50, 55))	('KMT2D', 'Gene', '8085', (62, 67))	('mutation', 'Var', (68, 76))	('patient', 'Species', '9606', (4, 11))	('KMT2D', 'Gene', (40, 45))	('KMT2D', 'Gene', '8085', (40, 45))	('disappeared', 'NegReg', (126, 137))	('KMT2D', 'Gene', (62, 67))	('ZFHX3', 'Gene', '463', (50, 55))
56684	32718341	Although we minimized the technical errors and germline variants, there were approximately five mutations in 52 Mbp.	('Mbp', 'Gene', '4155', (112, 115))	('mutations', 'Var', (96, 105))	('Mbp', 'Gene', (112, 115))
56685	32718341	The levels of mutations in PIK3CA, KRAS, and TP53, the most relevant mutated genes in CC, were lower than expected.	('TP53', 'Gene', (45, 49))	('KRAS', 'Gene', (35, 39))	('TP53', 'Gene', '7157', (45, 49))	('PIK3CA', 'Gene', (27, 33))	('KRAS', 'Gene', '3845', (35, 39))	('CC', 'Phenotype', 'HP:0002664', (86, 88))	('PIK3CA', 'Gene', '5290', (27, 33))	('mutations', 'Var', (14, 23))
56689	32718341	showed that the frequency of KMT2C/D gene mutation was also notable in patients with histology of Cutaneous squamous cell carcinoma (SCC), head and neck SCC, lung SCC, esophageal SCC, and cervical SCC.	('CC', 'Phenotype', 'HP:0002664', (198, 200))	('CC', 'Phenotype', 'HP:0002664', (164, 166))	('patients', 'Species', '9606', (71, 79))	('SCC', 'Gene', (163, 166))	('SCC', 'Gene', '6317', (179, 182))	('KMT2C/D', 'Gene', '58508', (29, 36))	('SCC', 'Phenotype', 'HP:0002860', (153, 156))	('SCC', 'Gene', (179, 182))	('CC', 'Phenotype', 'HP:0002664', (154, 156))	('KMT2C/D', 'Gene', (29, 36))	('mutation', 'Var', (42, 50))	('Cutaneous squamous cell carcinoma', 'Disease', (98, 131))	('SCC', 'Phenotype', 'HP:0002860', (197, 200))	('SCC', 'Phenotype', 'HP:0002860', (133, 136))	('SCC', 'Gene', '6317', (153, 156))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (108, 131))	('SCC', 'Phenotype', 'HP:0002860', (163, 166))	('Cutaneous squamous cell carcinoma', 'Disease', 'MESH:D002294', (98, 131))	('SCC', 'Gene', (153, 156))	('SCC', 'Gene', '6317', (197, 200))	('CC', 'Phenotype', 'HP:0002664', (134, 136))	('SCC', 'Gene', '6317', (133, 136))	('SCC', 'Phenotype', 'HP:0002860', (179, 182))	('CC', 'Phenotype', 'HP:0002664', (180, 182))	('SCC', 'Gene', (197, 200))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('SCC', 'Gene', '6317', (163, 166))	('SCC', 'Gene', (133, 136))
56690	32718341	In similar to these studies, our results indicate that mutation rates of ZFHX3, KMT2C, KMT2D, NSD1, and RNF213 genes have existed at a high frequency in CC patients in despite of the characteristics of these genetic mutations that have not been clearly identified in CC patients.	('patients', 'Species', '9606', (156, 164))	('KMT2C', 'Gene', '58508', (80, 85))	('KMT2C', 'Gene', (80, 85))	('CC', 'Phenotype', 'HP:0002664', (267, 269))	('patients', 'Species', '9606', (270, 278))	('NSD1', 'Gene', '64324', (94, 98))	('NSD1', 'Gene', (94, 98))	('KMT2D', 'Gene', '8085', (87, 92))	('CC', 'Phenotype', 'HP:0002664', (153, 155))	('RNF213', 'Gene', (104, 110))	('mutation', 'Var', (55, 63))	('ZFHX3', 'Gene', '463', (73, 78))	('RNF213', 'Gene', '57674', (104, 110))	('KMT2D', 'Gene', (87, 92))	('ZFHX3', 'Gene', (73, 78))
56693	32718341	In addition, RNF213 mutation, which was employed as a monitoring marker for CC patients in our study, is currently little known about its function and role in cancer.	('cancer', 'Disease', (159, 165))	('RNF213', 'Gene', (13, 19))	('mutation', 'Var', (20, 28))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('patients', 'Species', '9606', (79, 87))	('RNF213', 'Gene', '57674', (13, 19))	('CC', 'Phenotype', 'HP:0002664', (76, 78))	('cancer', 'Disease', 'MESH:D009369', (159, 165))
56697	32718341	We report several important aspects regarding the promising application of cfDNA for early diagnosis and monitoring of CC: (i) Gene mutation can serve as a prognostic biomarker for detecting CC by the profiling of the tumor suppressor and cancer driver genes.	('CC', 'Phenotype', 'HP:0002664', (119, 121))	('tumor', 'Disease', 'MESH:D009369', (218, 223))	('cancer', 'Disease', 'MESH:D009369', (239, 245))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('cancer', 'Disease', (239, 245))	('tumor', 'Disease', (218, 223))	('mutation', 'Var', (132, 140))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))	('CC', 'Phenotype', 'HP:0002664', (191, 193))
56698	32718341	(ii) Mutations in tumor suppressor genes are prevalent in all stages of CC, and (iii) Chemotherapy and radiotherapy affect the allele frequency, which can be utilized for monitoring cancer.	('prevalent', 'Reg', (45, 54))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('Mutations', 'Var', (5, 14))	('allele frequency', 'MPA', (127, 143))	('tumor', 'Disease', (18, 23))	('CC', 'Phenotype', 'HP:0002664', (72, 74))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('affect', 'Reg', (116, 122))	('cancer', 'Disease', (182, 188))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
56705	32718341	AF Allele Frequency CC Cervical Cancer cfDNA Cell-free DNA ctDNA Circulating tumor DNA CR Complete Response FDG Fluordeoxyglucose HR-HPV High-risk Human papillomavirus ICR Intracavity Radiation LN Lymph node NGS Next-Generation-Sequencing PBMC Peripheral Blood Mononuclear Cell PR Partial Response SCC Squamous cell carcinoma SNP Single Nucleotide Polymorphism TCGA The Cancer Genome Atlas Supplementary information accompanies this paper at 10.1186/s12885-020-07161-0.	('Cancer', 'Disease', 'MESH:D009369', (32, 38))	('SCC', 'Gene', '6317', (298, 301))	('Cancer', 'Disease', (370, 376))	('Squamous cell carcinoma', 'Disease', 'MESH:D002294', (302, 325))	('CC', 'Phenotype', 'HP:0002664', (20, 22))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('CC', 'Phenotype', 'HP:0002664', (299, 301))	('Fluordeoxyglucose', 'Chemical', '-', (112, 129))	('SCC', 'Gene', (298, 301))	('CR', 'Chemical', 'MESH:D002857', (169, 171))	('Cancer', 'Disease', 'MESH:D009369', (370, 376))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('papillomavirus', 'Disease', 'MESH:D030361', (153, 167))	('Cancer', 'Phenotype', 'HP:0002664', (32, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (316, 325))	('AF', 'Disease', 'MESH:D001281', (0, 2))	('FDG', 'Chemical', 'MESH:D019788', (108, 111))	('Single Nucleotide Polymorphism', 'Var', (330, 360))	('papillomavirus', 'Disease', (153, 167))	('SCC', 'Phenotype', 'HP:0002860', (298, 301))	('Cancer', 'Disease', (32, 38))	('CR', 'Chemical', 'MESH:D002857', (87, 89))	('Cancer', 'Phenotype', 'HP:0002664', (370, 376))	('Squamous cell carcinoma', 'Phenotype', 'HP:0002860', (302, 325))	('Squamous cell carcinoma', 'Disease', (302, 325))	('tumor', 'Disease', (77, 82))	('HPV', 'Species', '10566', (133, 136))
56713	31801551	Alteration of m6A levels participates in cancer pathogenesis and development via regulating expression of tumor-related genes like BRD4, MYC, SOCS2 and EGFR.	('BRD4', 'Gene', (131, 135))	('SOCS2', 'Gene', (142, 147))	('Alteration', 'Var', (0, 10))	('cancer', 'Disease', (41, 47))	('MYC', 'Gene', (137, 140))	('tumor', 'Disease', (106, 111))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('m6A', 'Gene', '56339', (14, 17))	('BRD4', 'Gene', '23476', (131, 135))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('EGFR', 'Gene', (152, 156))	('m6A', 'Gene', (14, 17))	('MYC', 'Gene', '4609', (137, 140))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('participates', 'Reg', (25, 37))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('expression', 'MPA', (92, 102))	('regulating', 'Reg', (81, 91))	('EGFR', 'Gene', '1956', (152, 156))	('SOCS2', 'Gene', '8835', (142, 147))
56717	31801551	Among numerous RNA modifications, N6-methyladenosine (m6A) is the most abundant mRNA modification.	('m6A', 'Gene', (54, 57))	('m6A', 'Gene', '56339', (54, 57))	('N6-methyladenosine', 'Chemical', 'MESH:C010223', (34, 52))	('N6-methyladenosine', 'Var', (34, 52))
56732	31801551	Crosslink among writers, erasers and readers, is involved in cancer pathogenesis and progression.	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('involved', 'Reg', (49, 57))	('cancer', 'Disease', (61, 67))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('Crosslink', 'Var', (0, 9))
56741	31801551	Loss of METTL3 results in higher level of BCL-XS isoform and NCOR2alpha isoform and inhibition of GSC growth and self-renewal.	('GSC', 'Gene', (98, 101))	('higher', 'PosReg', (26, 32))	('inhibition', 'NegReg', (84, 94))	('METTL3', 'Gene', (8, 14))	('NCOR2alpha', 'Protein', (61, 71))	('Loss', 'Var', (0, 4))	('GSC', 'Gene', '145258', (98, 101))	('level of BCL-XS isoform', 'MPA', (33, 56))
56757	31801551	Loss of METTL14 impairs the priming and further differentiation competence of embryonic stem cells.	('METTL14', 'Gene', (8, 15))	('Loss', 'Var', (0, 4))	('impairs', 'NegReg', (16, 23))	('METTL14', 'Gene', '57721', (8, 15))
56759	31801551	METTL16 binds a subset of mRNAs and methylates long noncoding RNA (lncRNA) and U6 small nuclear RNA (U6 snRNA).	('METTL16', 'Gene', (0, 7))	('methylates', 'Var', (36, 46))	('METTL16', 'Gene', '79066', (0, 7))	('mRNAs', 'Protein', (26, 31))	('binds', 'Interaction', (8, 13))
56790	31801551	In prostate cancer, YTHDF2 expression can be suppressed by miR-493-3p, therefore impairing cell proliferation and migration.	('prostate cancer', 'Phenotype', 'HP:0012125', (3, 18))	('YTHDF2', 'Gene', '51441', (20, 26))	('YTHDF2', 'Gene', (20, 26))	('expression', 'MPA', (27, 37))	('suppressed', 'NegReg', (45, 55))	('prostate cancer', 'Disease', (3, 18))	('miR-493-3p', 'Var', (59, 69))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('impairing', 'NegReg', (81, 90))	('prostate cancer', 'Disease', 'MESH:D011471', (3, 18))
56792	31801551	YTHDF2 deficiency prevents degradation of mRNAs of both survival-related genes and Wnt target genes during hematopoietic stresses, which synergistically enhances the regenerative capacity of HSCs.	('hematopoietic stresses', 'Disease', 'MESH:D000079225', (107, 129))	('regenerative capacity of HSCs', 'CPA', (166, 195))	('enhances', 'PosReg', (153, 161))	('mRNAs', 'MPA', (42, 47))	('YTHDF2', 'Gene', '51441', (0, 6))	('deficiency', 'Var', (7, 17))	('YTHDF2', 'Gene', (0, 6))	('hematopoietic stresses', 'Disease', (107, 129))	('prevents', 'NegReg', (18, 26))	('degradation', 'MPA', (27, 38))
56794	31801551	Unmodified circRNA forms a complex with activated pattern recognization receptor RIG-I and K63-polyubiquitin, resulting in MAVS filamentation, IRF3 dimerization, and interferon production.	('interferon production', 'MPA', (166, 187))	('RIG-I', 'Gene', '23586', (81, 86))	('K63-polyubiquitin', 'Var', (91, 108))	('complex', 'Interaction', (27, 34))	('RIG-I', 'Gene', (81, 86))	('MAVS', 'Gene', (123, 127))	('MAVS', 'Gene', '57506', (123, 127))	('IRF3', 'Gene', (143, 147))	('IRF3', 'Gene', '3661', (143, 147))
56822	31801551	EIF3 knockdown promotes autophagy.	('EIF3', 'Gene', '8661', (0, 4))	('promotes', 'PosReg', (15, 23))	('knockdown', 'Var', (5, 14))	('autophagy', 'CPA', (24, 33))	('EIF3', 'Gene', (0, 4))
56829	31801551	METTL3 elevated m6A level of CDCP1, thus promoting its translation modulated by YTHDF1.	('promoting', 'PosReg', (41, 50))	('YTHDF1', 'Gene', (80, 86))	('m6A', 'Gene', (16, 19))	('elevated', 'PosReg', (7, 15))	('m6A', 'Gene', '56339', (16, 19))	('translation', 'MPA', (55, 66))	('METTL3', 'Var', (0, 6))	('YTHDF1', 'Gene', '54915', (80, 86))	('CDCP1', 'Gene', '64866', (29, 34))	('CDCP1', 'Gene', (29, 34))
56832	31801551	Inhibition of METTL3 significantly hampered bladder tumor cell proliferation, migration, invasion, and survival in vitro and impairs cell proliferation in vivo.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('cell proliferation', 'CPA', (133, 151))	('bladder tumor', 'Disease', (44, 57))	('hampered', 'NegReg', (35, 43))	('invasion', 'CPA', (89, 97))	('METTL3', 'Gene', (14, 20))	('migration', 'CPA', (78, 87))	('Inhibition', 'Var', (0, 10))	('survival', 'CPA', (103, 111))	('bladder tumor', 'Disease', 'MESH:D001749', (44, 57))	('impairs', 'NegReg', (125, 132))	('bladder tumor', 'Phenotype', 'HP:0009725', (44, 57))
56837	31801551	METTL3 depletion leads to increased cell apoptosis and decreased cell growth and invasion, impairing tumorigenicity in mouse xenografts.	('mouse', 'Species', '10090', (119, 124))	('cell apoptosis', 'CPA', (36, 50))	('invasion', 'CPA', (81, 89))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('decreased', 'NegReg', (55, 64))	('METTL3', 'Gene', (0, 6))	('depletion', 'Var', (7, 16))	('increased', 'PosReg', (26, 35))	('impairing', 'NegReg', (91, 100))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
56853	31801551	In pancreatic tumors and in smokers, expression of miR-25-3p is elevated, associated with worse prognosis.	('elevated', 'PosReg', (64, 72))	('pancreatic tumors', 'Disease', (3, 20))	('miR-25-3p', 'Var', (51, 60))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('pancreatic tumor', 'Phenotype', 'HP:0002894', (3, 19))	('pancreatic tumors', 'Phenotype', 'HP:0002894', (3, 20))	('expression', 'MPA', (37, 47))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('pancreatic tumors', 'Disease', 'MESH:D010190', (3, 20))
56855	31801551	MiR-25-3p inhibits PH domain leucine-rich repeat protein phosphatase 2 (PHLPP2), leading to the activation of oncogenic AKT-p70S6K signaling.	('AKT', 'Gene', (120, 123))	('PHLPP2', 'Gene', '23035', (72, 78))	('inhibits', 'NegReg', (10, 18))	('PHLPP2', 'Gene', (72, 78))	('MiR-25-3p', 'Var', (0, 9))	('MiR-25-3p', 'Chemical', '-', (0, 9))	('AKT', 'Gene', '207', (120, 123))	('PH domain leucine-rich repeat protein phosphatase 2', 'Gene', '23035', (19, 70))	('p70S6K', 'Gene', (124, 130))	('activation', 'PosReg', (96, 106))	('p70S6K', 'Gene', '6198', (124, 130))
56866	31801551	Depletion of METTL3 results in a decrease in cell proliferation, colony formation, and migration in vitro and inhibits tumor cell proliferation and metastasis in vivo.	('migration', 'CPA', (87, 96))	('tumor', 'Disease', (119, 124))	('decrease', 'NegReg', (33, 41))	('METTL3', 'Gene', (13, 19))	('inhibits', 'NegReg', (110, 118))	('cell proliferation', 'CPA', (45, 63))	('Depletion', 'Var', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('colony formation', 'CPA', (65, 81))
56872	31801551	In endometrial tumors, the m6A level is lower which is caused by reduced METTL3 expression or METTL14 mutation.	('m6A', 'Gene', '56339', (27, 30))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('reduced', 'NegReg', (65, 72))	('mutation', 'Var', (102, 110))	('endometrial tumors', 'Disease', 'MESH:D016889', (3, 21))	('METTL14', 'Gene', (94, 101))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('METTL14', 'Gene', '57721', (94, 101))	('METTL3', 'Protein', (73, 79))	('lower', 'NegReg', (40, 45))	('expression', 'MPA', (80, 90))	('m6A', 'Gene', (27, 30))	('endometrial tumors', 'Disease', (3, 21))
56873	31801551	M6A methylation inhibits activation of the AKT pathway through YTHDF2-mediated degradation of the positive AKT regulator mTORC2.	('degradation', 'MPA', (79, 90))	('M6A', 'Gene', '56339', (0, 3))	('AKT', 'Gene', (107, 110))	('AKT', 'Gene', '207', (43, 46))	('M6A', 'Gene', (0, 3))	('methylation', 'Var', (4, 15))	('YTHDF2', 'Gene', '51441', (63, 69))	('AKT', 'Gene', (43, 46))	('inhibits', 'NegReg', (16, 24))	('mTORC2', 'Gene', (121, 127))	('YTHDF2', 'Gene', (63, 69))	('mTORC2', 'Gene', '74343', (121, 127))	('AKT', 'Gene', '207', (107, 110))
56874	31801551	Attenuated m6A methylation leads to enhanced cell proliferation, colony formation, migration and invasion.	('methylation', 'Var', (15, 26))	('m6A', 'Gene', '56339', (11, 14))	('Attenuated', 'NegReg', (0, 10))	('cell proliferation', 'CPA', (45, 63))	('enhanced', 'PosReg', (36, 44))	('colony formation', 'CPA', (65, 81))	('invasion', 'CPA', (97, 105))	('m6A', 'Gene', (11, 14))	('migration', 'CPA', (83, 92))
56884	31801551	In endometrial tumors, m6A methylation inhibits activation of the AKT pathway through YTHDF1-mediated translation of the negative AKT regulator PHLPP2.	('AKT', 'Gene', '207', (66, 69))	('PHLPP2', 'Gene', (144, 150))	('m6A', 'Gene', '56339', (23, 26))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('AKT', 'Gene', (66, 69))	('activation', 'MPA', (48, 58))	('endometrial tumors', 'Disease', 'MESH:D016889', (3, 21))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('AKT', 'Gene', (130, 133))	('methylation', 'Var', (27, 38))	('m6A', 'Gene', (23, 26))	('AKT', 'Gene', '207', (130, 133))	('PHLPP2', 'Gene', '23035', (144, 150))	('inhibits', 'NegReg', (39, 47))	('YTHDF1', 'Gene', '54915', (86, 92))	('YTHDF1', 'Gene', (86, 92))	('endometrial tumors', 'Disease', (3, 21))
56887	31801551	Premature polyadenylation (pPA) of tumor suppressor genes frequently truncates these genes, leading to inhibition of their functions.	('functions', 'MPA', (123, 132))	('truncates', 'NegReg', (69, 78))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('pPA', 'Chemical', '-', (27, 30))	('Premature polyadenylation', 'Var', (0, 25))	('tumor suppressor', 'Gene', '7248', (35, 51))	('tumor suppressor', 'Gene', (35, 51))	('inhibition', 'NegReg', (103, 113))
56891	31801551	Overexpression of METTL14 inhibits the migration and invasiveness of HepG2 cells in vitro and restrains cell proliferation and metastasis in vivo.	('inhibits', 'NegReg', (26, 34))	('restrains', 'NegReg', (94, 103))	('invasiveness', 'CPA', (53, 65))	('METTL14', 'Gene', (18, 25))	('migration', 'CPA', (39, 48))	('Overexpression', 'Var', (0, 14))	('METTL14', 'Gene', '57721', (18, 25))	('HepG2', 'CellLine', 'CVCL:0027', (69, 74))
56898	31801551	The aberrant m6A level in cancer (which is decided by the change of expression or activity of writer or eraser); (3).	('cancer', 'Disease', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('aberrant', 'Var', (4, 12))	('m6A', 'Gene', (13, 16))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('m6A', 'Gene', '56339', (13, 16))
56905	31801551	In lung cancer, sumoylation reduces activity of METTL3 catalyzing m6A, resulting in enhanced tumorigenesis.	('m6A', 'Gene', '56339', (66, 69))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('METTL3 catalyzing', 'Enzyme', (48, 65))	('lung cancer', 'Disease', (3, 14))	('reduces', 'NegReg', (28, 35))	('lung cancer', 'Phenotype', 'HP:0100526', (3, 14))	('activity', 'MPA', (36, 44))	('sumoylation', 'Var', (16, 27))	('tumor', 'Disease', (93, 98))	('lung cancer', 'Disease', 'MESH:D008175', (3, 14))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('enhanced', 'PosReg', (84, 92))	('m6A', 'Gene', (66, 69))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
56911	31801551	NNMT-modulated CD44 m6A methylation improves the RNA stability by impairing ubiquitin-mediated degradation.	('impairing', 'NegReg', (66, 75))	('improves', 'PosReg', (36, 44))	('CD44', 'Gene', '960', (15, 19))	('CD44', 'Gene', (15, 19))	('NNMT', 'Gene', (0, 4))	('m6A', 'Gene', '56339', (20, 23))	('NNMT', 'Gene', '4837', (0, 4))	('methylation', 'Var', (24, 35))	('ubiquitin-mediated degradation', 'MPA', (76, 106))	('m6A', 'Gene', (20, 23))	('RNA stability', 'CPA', (49, 62))
56916	31801551	As a metabolite by mutant IDH1/2 enzymes, R-2-hydroxyglutarate (R-2HG) elevates m6A level and enhances the YTHDF2-mediated-degradation of MYC, ASB2, and RARA.	('enhances', 'PosReg', (94, 102))	('ASB2', 'Gene', '51676', (143, 147))	('R-2-hydroxyglutarate', 'Chemical', '-', (42, 62))	('m6A', 'Gene', (80, 83))	('MYC', 'Gene', '4609', (138, 141))	('IDH1/2', 'Gene', (26, 32))	('MYC', 'Gene', (138, 141))	('elevates', 'PosReg', (71, 79))	('ASB2', 'Gene', (143, 147))	('RARA', 'Gene', '5914', (153, 157))	('YTHDF2', 'Gene', '51441', (107, 113))	('mutant', 'Var', (19, 25))	('m6A', 'Gene', '56339', (80, 83))	('RARA', 'Gene', (153, 157))	('R-2-hydroxyglutarate', 'Var', (42, 62))	('YTHDF2', 'Gene', (107, 113))	('IDH1/2', 'Gene', '3417;3418', (26, 32))
56922	31801551	The FTO-mediated demethylation promotes stability of proliferation-related genes Table 3.	('FTO', 'Gene', '79068', (4, 7))	('proliferation-related genes Table', 'Gene', (53, 86))	('promotes', 'PosReg', (31, 39))	('demethylation', 'Var', (17, 30))	('FTO', 'Gene', (4, 7))	('stability', 'MPA', (40, 49))
56924	31801551	The m6A methylation participates in regulation of cancer malignant phenotype by controlling the expression of cancer-related genes.	('m6A', 'Gene', '56339', (4, 7))	('cancer malignant', 'Disease', 'MESH:D009369', (50, 66))	('cancer', 'Disease', (110, 116))	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('expression', 'MPA', (96, 106))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('cancer malignant', 'Disease', (50, 66))	('controlling', 'Reg', (80, 91))	('m6A', 'Gene', (4, 7))	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('methylation', 'Var', (8, 19))
56964	31205553	The wild type (WT) and mutant type (MT) of CCR7 3'UTR sequences were generated by PCR amplification from human genomic DNA using specific primers (Table 2) and cloned into pmirGLO- reporter (Promega), respectively.	('human', 'Species', '9606', (105, 110))	('CCR7', 'Gene', (43, 47))	('CCR7', 'Gene', '1236', (43, 47))	('mutant', 'Var', (23, 29))
56988	31205553	As shown in Figure 1E, co-transfection with hsa-let-7e-5p mimic and the plasmid for wild-type of CCR7 3'UTR-regualted luciferase significantly reduced the luciferase activities in PCI-37B cells, relative to the controls transfected with hsa-let-7e-5p mimic and the plasmid for the mutant CCR7 3'UTR-regulated luciferase and the cells transfected with the plasmid and control miRNA (NC) or the cells transfected with the plasmid alone (p<0.01).	('37B', 'Chemical', '-', (184, 187))	('luciferase', 'Enzyme', (155, 165))	('hsa-let-7e', 'Gene', (237, 247))	('CCR7', 'Gene', '1236', (97, 101))	('activities', 'MPA', (166, 176))	('hsa-let-7e', 'Gene', '406887', (44, 54))	('CCR7', 'Gene', (97, 101))	('hsa-let-7e', 'Gene', (44, 54))	('CCR7', 'Gene', '1236', (288, 292))	('hsa-let-7e', 'Gene', '406887', (237, 247))	('mutant', 'Var', (281, 287))	('CCR7', 'Gene', (288, 292))	('reduced', 'NegReg', (143, 150))
57000	31205553	Previous studies have shown the levels of has-let-7e-5p expression in different types of malignant tumors remain controversial.	('has-let-7e-5p', 'Var', (42, 55))	('malignant tumors', 'Disease', (89, 105))	('malignant tumors', 'Disease', 'MESH:D018198', (89, 105))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))
57001	31205553	These data suggest that has-let-7e-5p may act as a tumor suppressor and its down-regulated expression may promote the development and progression of HNSCC, extending previous observations in NSCLC, breast cancer and glioma.	('expression', 'MPA', (91, 101))	('has-let-7e-5p', 'Var', (24, 37))	('breast cancer', 'Phenotype', 'HP:0003002', (198, 211))	('promote', 'PosReg', (106, 113))	('NSCLC', 'Disease', (191, 196))	('breast cancer', 'Disease', 'MESH:D001943', (198, 211))	('breast cancer', 'Disease', (198, 211))	('NSCLC', 'Phenotype', 'HP:0030358', (191, 196))	('progression', 'CPA', (134, 145))	('tumor', 'Disease', (51, 56))	('development', 'CPA', (118, 129))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('glioma', 'Disease', (216, 222))	('glioma', 'Disease', 'MESH:D005910', (216, 222))	('HNSCC', 'Disease', (149, 154))	('down-regulated', 'NegReg', (76, 90))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('HNSCC', 'Phenotype', 'HP:0012288', (149, 154))	('glioma', 'Phenotype', 'HP:0009733', (216, 222))	('NSCLC', 'Disease', 'MESH:D002289', (191, 196))
57004	31205553	These contradictory findings suggest that has-let-7e-5p expression may be regulated by specific tumor type, stage and its host age and has-let-7e-5p may have different roles during the pathogenesis of different types of malignant tumors by targeting different gene expression.	('tumor', 'Disease', (230, 235))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumors', 'Phenotype', 'HP:0002664', (230, 236))	('tumor', 'Disease', (96, 101))	('malignant tumors', 'Disease', (220, 236))	('has-let-7e-5p', 'Var', (135, 148))	('targeting', 'Reg', (240, 249))	('has-let-7e-5p', 'Gene', (42, 55))	('tumor', 'Disease', 'MESH:D009369', (230, 235))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))	('malignant tumors', 'Disease', 'MESH:D018198', (220, 236))
57006	31205553	While hsa-let-7e-5p can inhibit the proliferation and metastasis of glioma stem cells and colorectal cancer, hsa-let- 7e-5p, together with miR-99b and miR-125a, acts as a pro-metastasis oncomir to promote ESCC cell migration and invasion in vitro .	('colorectal cancer', 'Disease', 'MESH:D015179', (90, 107))	('miR-99b', 'Gene', '407056', (139, 146))	('glioma', 'Disease', (68, 74))	('hsa-let-7e', 'Gene', '406887', (6, 16))	('colorectal cancer', 'Disease', (90, 107))	('inhibit', 'NegReg', (24, 31))	('glioma', 'Disease', 'MESH:D005910', (68, 74))	('metastasis', 'CPA', (54, 64))	('promote', 'PosReg', (197, 204))	('miR-125a', 'Gene', '406910', (151, 159))	('glioma', 'Phenotype', 'HP:0009733', (68, 74))	('miR-99b', 'Gene', (139, 146))	('colorectal cancer', 'Phenotype', 'HP:0003003', (90, 107))	('miR-125a', 'Gene', (151, 159))	('proliferation', 'CPA', (36, 49))	('hsa-let- 7e-5p', 'Var', (109, 123))	('ESCC cell migration', 'CPA', (205, 224))	('hsa-let-7e', 'Gene', (6, 16))	('invasion', 'CPA', (229, 237))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))
57019	31205553	Our data were consistent with a recent report and support the notion that high levels of CCR7 expression promote the invasion and metastasis of HNSCC and esophageal squamous cell carcinoma.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (165, 188))	('promote', 'PosReg', (105, 112))	('esophageal squamous cell carcinoma', 'Disease', (154, 188))	('HNSCC', 'Disease', (144, 149))	('CCR7', 'Gene', (89, 93))	('CCR7', 'Gene', '1236', (89, 93))	('metastasis', 'CPA', (130, 140))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (154, 188))	('carcinoma', 'Phenotype', 'HP:0030731', (179, 188))	('high levels', 'Var', (74, 85))	('invasion', 'CPA', (117, 125))	('HNSCC', 'Phenotype', 'HP:0012288', (144, 149))
57027	31205553	Hsa-let-7e-5p inhibited the proliferation, wound healing, migration and invasion of HNSCC cells in vitro and the growth of HNSCC tumors in vivo.	('HNSCC', 'Phenotype', 'HP:0012288', (123, 128))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('proliferation', 'CPA', (28, 41))	('HNSCC tumors', 'Disease', (123, 135))	('Hsa-let-7e-5p', 'Var', (0, 13))	('growth', 'CPA', (113, 119))	('HNSCC', 'Phenotype', 'HP:0012288', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('inhibited', 'NegReg', (14, 23))	('HNSCC tumors', 'Disease', 'MESH:D000077195', (123, 135))	('invasion of HNSCC cells', 'CPA', (72, 95))	('wound healing', 'CPA', (43, 56))	('migration', 'CPA', (58, 67))
57040	29805594	Overall, PDTXS of LSCC altered the lncRNA profile and increased the proliferative activity of cancer cells, whilst retaining responsiveness to cisplatin.	('SCC', 'Gene', '6317', (19, 22))	('SCC', 'Phenotype', 'HP:0002860', (19, 22))	('cisplatin', 'Chemical', 'MESH:D002945', (143, 152))	('LSCC', 'Phenotype', 'HP:0030359', (18, 22))	('lncRNA profile', 'MPA', (35, 49))	('increased', 'PosReg', (54, 63))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('altered', 'Reg', (23, 30))	('SCC', 'Gene', (19, 22))	('responsiveness to cisplatin', 'MPA', (125, 152))	('PDTXS', 'Var', (9, 14))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
57053	29805594	Moreover, emerging evidence supports the notion that aberrant expression of lncRNAs plays a significant role in various human malignant diseases, including NSCLC.	('role', 'Reg', (104, 108))	('human', 'Species', '9606', (120, 125))	('lncRNAs', 'Gene', (76, 83))	('malignant diseases', 'Disease', 'MESH:D009369', (126, 144))	('NSCLC', 'Phenotype', 'HP:0030358', (156, 161))	('malignant diseases', 'Disease', (126, 144))	('NSCLC', 'Disease', (156, 161))	('aberrant expression', 'Var', (53, 72))	('NSCLC', 'Disease', 'MESH:D002289', (156, 161))
57099	29805594	In multivariate analysis, poor differentiation and larger tumor volume were independently associated with increased rates of engraftment.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('poor', 'Var', (26, 30))	('engraftment', 'CPA', (125, 136))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('increased', 'PosReg', (106, 115))
57144	29805594	The relationship between SCC engraftment in nude mice and clinicopathological parameters of patients was analyzed retrospectively, and we found that tumor volume and differentiation were closely correlated with the take rate of PDTXs, which was similar to that of a prior study in NSCLC In addition, our results showed that the expression of Ki67 in original SCC patient tumors was a predictive factor for implanted tumor growth and the success of serial passages in PDTX mice, as reported previously for prostate cancer and hepatic metastasis uveal melanoma.	('tumor', 'Disease', (371, 376))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('melanoma', 'Phenotype', 'HP:0002861', (550, 558))	('SCC', 'Phenotype', 'HP:0002860', (25, 28))	('tumor', 'Disease', 'MESH:D009369', (371, 376))	('SCC', 'Phenotype', 'HP:0002860', (359, 362))	('Ki67', 'Var', (342, 346))	('tumor', 'Disease', (416, 421))	('hepatic metastasis uveal melanoma', 'Disease', 'MESH:C536494', (525, 558))	('tumors', 'Phenotype', 'HP:0002664', (371, 377))	('uveal melanoma', 'Phenotype', 'HP:0007716', (544, 558))	('patients', 'Species', '9606', (92, 100))	('SCC', 'Gene', '6317', (25, 28))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('tumor', 'Disease', 'MESH:D009369', (416, 421))	('SCC', 'Gene', '6317', (359, 362))	('tumor', 'Phenotype', 'HP:0002664', (371, 376))	('mice', 'Species', '10090', (472, 476))	('NSCLC', 'Disease', 'MESH:D002289', (281, 286))	('SCC', 'Gene', (25, 28))	('patient', 'Species', '9606', (363, 370))	('tumors', 'Disease', (371, 377))	('mice', 'Species', '10090', (49, 53))	('SCC', 'Gene', (359, 362))	('NSCLC', 'Disease', (281, 286))	('cancer', 'Phenotype', 'HP:0002664', (514, 520))	('tumor', 'Phenotype', 'HP:0002664', (416, 421))	('hepatic metastasis uveal melanoma', 'Disease', (525, 558))	('patient', 'Species', '9606', (92, 99))	('prostate cancer', 'Disease', 'MESH:D011471', (505, 520))	('NSCLC', 'Phenotype', 'HP:0030358', (281, 286))	('tumors', 'Disease', 'MESH:D009369', (371, 377))	('prostate cancer', 'Phenotype', 'HP:0012125', (505, 520))	('tumor', 'Disease', (149, 154))	('nude mice', 'Species', '10090', (44, 53))	('prostate cancer', 'Disease', (505, 520))	('serial passages', 'CPA', (448, 463))
57145	29805594	Moreover we observed that the average time for xenograft tumors to reach a volume of 500 mm3 in the first generation was longer than that of the other two passages (9.2, 6.8 and 6.3 weeks, respectively), which suggested that passaging xenograft tumors were more proliferative than first-generation tumors and that PDTXs increased cancer cell proliferative activity, as reported previously in human malignant pleural mesothelioma.	('tumors', 'Disease', 'MESH:D009369', (298, 304))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('malignant pleural mesothelioma', 'Disease', (398, 428))	('xenograft tumors', 'Disease', 'MESH:D009369', (235, 251))	('cancer', 'Disease', 'MESH:D009369', (330, 336))	('tumors', 'Phenotype', 'HP:0002664', (245, 251))	('tumors', 'Disease', 'MESH:D009369', (57, 63))	('PDTXs', 'Var', (314, 319))	('tumors', 'Disease', (245, 251))	('proliferative', 'CPA', (262, 275))	('tumors', 'Phenotype', 'HP:0002664', (298, 304))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (408, 428))	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (398, 428))	('increased', 'PosReg', (320, 329))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('tumors', 'Disease', 'MESH:D009369', (245, 251))	('cancer', 'Disease', (330, 336))	('tumor', 'Phenotype', 'HP:0002664', (298, 303))	('cancer', 'Phenotype', 'HP:0002664', (330, 336))	('xenograft tumors', 'Disease', (47, 63))	('tumors', 'Disease', (298, 304))	('human', 'Species', '9606', (392, 397))	('more', 'PosReg', (257, 261))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumors', 'Disease', (57, 63))	('xenograft tumors', 'Disease', 'MESH:D009369', (47, 63))	('xenograft tumors', 'Disease', (235, 251))
57210	27854242	CPI are being investigated in a number of malignancies, including squamous cell carcinoma of the head and neck and esophageal cancer, with a plan to isolate specific markers that might predict response and survival benefits to specific cancer populations such as the microsatellite instable colon and gastrointestinal malignancies.	('cancer', 'Disease', 'MESH:D009369', (236, 242))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (66, 89))	('malignancies', 'Disease', 'MESH:D009369', (42, 54))	('esophageal cancer', 'Disease', 'MESH:D004938', (115, 132))	('malignancies', 'Disease', (42, 54))	('malignancies', 'Disease', 'MESH:D009369', (318, 330))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('squamous cell carcinoma', 'Disease', (66, 89))	('malignancies', 'Disease', (318, 330))	('cancer', 'Disease', (126, 132))	('esophageal cancer', 'Disease', (115, 132))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('carcinoma of the head and neck', 'Phenotype', 'HP:0012288', (80, 110))	('CPI', 'Chemical', '-', (0, 3))	('cancer', 'Disease', (236, 242))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('colon and gastrointestinal malignancies', 'Disease', 'MESH:D005767', (291, 330))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (66, 89))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('microsatellite', 'Var', (267, 281))
57304	33937258	Wallenda-Nmo Axis Regulates Growth via Hippo Signaling Both Hippo signaling pathways and cell polarity regulation are critical for cell proliferation and the maintenance of tissue homeostasis, despite the well-established connections between cell polarity disruption and Hippo inactivation, the molecular mechanism by which aberrant cell polarity induces Hippo-mediated overgrowth remains underexplored.	('Hippo', 'Gene', (60, 65))	('overgrowth', 'Phenotype', 'HP:0001548', (370, 380))	('Hippo', 'Gene', '37247', (355, 360))	('Hippo', 'Gene', '37247', (39, 44))	('Hippo', 'Gene', '37247', (60, 65))	('Hippo', 'Gene', (271, 276))	('Hippo', 'Gene', (355, 360))	('induces', 'Reg', (347, 354))	('aberrant', 'Var', (324, 332))	('Hippo', 'Gene', '37247', (271, 276))	('Hippo', 'Gene', (39, 44))
57305	33937258	Here we use Drosophila wing discs as a model and identify the Wnd-Nmo axis as an important molecular link that bridges loss-of-cell polarity-triggered Hippo inactivation and overgrowth.	('loss-of-cell', 'Var', (119, 131))	('Drosophila', 'Species', '7227', (12, 22))	('overgrowth', 'Phenotype', 'HP:0001548', (174, 184))	('Wnd', 'Gene', '40143', (62, 65))	('Hippo', 'Gene', (151, 156))	('Wnd', 'Gene', (62, 65))	('Nmo', 'Chemical', '-', (66, 69))	('Hippo', 'Gene', '37247', (151, 156))	('inactivation', 'NegReg', (157, 169))
57309	33937258	Proper control of cell proliferation is fundamental for correct organ development, disruption of which would cause tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('cause', 'Reg', (109, 114))	('tumor', 'Disease', (115, 120))	('disruption', 'Var', (83, 93))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
57314	33937258	Cell polarity maintenance is essential for tissue homeostasis, and dysregulation of apical-basal polarity has been linked to various developmental disorders and cancer.	('dysregulation', 'Var', (67, 80))	('developmental disorders', 'Disease', 'MESH:D002658', (133, 156))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('linked', 'Reg', (115, 121))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('cancer', 'Disease', (161, 167))	('developmental disorders', 'Disease', (133, 156))
57317	33937258	We also identified Wallenda (Wnd), a member of mitogen activated protein kinase kinase kinase (MAPKKK) family, as an essential downstream component that links loss-of-polarity-induced cell invasion phenotype to JNK pathway activation.	('Wnd', 'Gene', (29, 32))	('loss-of-polarity-induced', 'Var', (159, 183))	('JNK', 'Gene', (211, 214))	('JNK', 'Gene', '44801', (211, 214))	('activation', 'PosReg', (223, 233))	('Wnd', 'Gene', '40143', (29, 32))
57327	33937258	We found that copy number variants (CNV) of MAP3K13 are dysregulated in various human cancers (Figure 1A), especially in lung squamous cell carcinoma (LUSC) and ovarian serous cystadenocarcinoma (OV).	('copy number variants', 'Var', (14, 34))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (121, 149))	('ovarian serous cystadenocarcinoma', 'Disease', (161, 194))	('dysregulated', 'Reg', (56, 68))	('LUSC', 'Phenotype', 'HP:0030359', (151, 155))	('ovarian serous cystadenocarcinoma', 'Disease', 'MESH:D018284', (161, 194))	('human', 'Species', '9606', (80, 85))	('cancers', 'Phenotype', 'HP:0002664', (86, 93))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (121, 149))	('lung squamous cell carcinoma', 'Disease', (121, 149))	('cancers', 'Disease', (86, 93))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (126, 149))	('cancers', 'Disease', 'MESH:D009369', (86, 93))	('OV', 'Phenotype', 'HP:0012887', (196, 198))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('MAP3K13', 'Gene', '9175', (44, 51))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))	('MAP3K13', 'Gene', (44, 51))	('ovarian serous cystadenocarcinoma', 'Phenotype', 'HP:0012887', (161, 194))	('carcinoma', 'Phenotype', 'HP:0030731', (185, 194))
57331	33937258	Given that ectopic wnd expression can induce the up-regulation of wingless (wg) and cycE, two known downstream target genes of the Hippo pathway, we tested the possibility that wnd could regulate the Hippo pathway in Drosophila.	('Hippo', 'Gene', '37247', (131, 136))	('wnd', 'Gene', (177, 180))	('Hippo', 'Gene', '37247', (200, 205))	('tested', 'Reg', (149, 155))	('up-regulation', 'PosReg', (49, 62))	('wnd', 'Gene', (19, 22))	('wnd', 'Gene', '40143', (177, 180))	('Drosophila', 'Species', '7227', (217, 227))	('wingless', 'Gene', (66, 74))	('ectopic', 'Var', (11, 18))	('wnd', 'Gene', '40143', (19, 22))	('Hippo', 'Gene', (200, 205))	('cycE', 'Gene', (84, 88))	('Hippo', 'Gene', (131, 136))	('regulate', 'Reg', (187, 195))
57333	33937258	Given that ectopic expression of Wnd also leads to apoptosis as reported previously, we inhibited apoptosis simultaneously by co-expression of P35 with wnd and observed a stronger up-regulation of ban-lacZ (Figures 1G,G').	('Wnd', 'Gene', '40143', (33, 36))	('inhibited', 'NegReg', (88, 97))	('P35', 'Var', (143, 146))	('wnd', 'Gene', (152, 155))	('apoptosis', 'CPA', (98, 107))	('up-regulation', 'PosReg', (180, 193))	('ban-lacZ', 'Gene', (197, 205))	('Wnd', 'Gene', (33, 36))	('wnd', 'Gene', '40143', (152, 155))	('ban', 'Species', '9031', (197, 200))	('apoptosis', 'CPA', (51, 60))
57341	33937258	Overexpression of Rho1 with P35 by ptc-Gal4 in wing imaginal discs induces obvious cell proliferation and enhanced Yki nuclear localization (Figures 2B,B'), both of which are significantly impeded by knockdown of wnd (Figures 2C,C').	('enhanced', 'PosReg', (106, 114))	('P35', 'Var', (28, 31))	('Gal4', 'Gene', (39, 43))	('Gal4', 'Gene', '414342', (39, 43))	('Yki nuclear localization', 'MPA', (115, 139))	('cell proliferation', 'CPA', (83, 101))	('wnd', 'Gene', (213, 216))	('Rho1', 'Gene', (18, 22))	('Rho1', 'Gene', '36775', (18, 22))	('wnd', 'Gene', '40143', (213, 216))
57342	33937258	Consistently with this, we found that compared with the wild type control (Figures 2D,D'), knockdown of wnd also reduces Rho1 overexpression-induced ban-lacZ up-regulation (Figures 2E-F' and Supplementary Figure 2), suggesting that Wnd is required for Rho1-induced Hippo signaling inactivation.	('Wnd', 'Gene', (232, 235))	('Rho1', 'Gene', (252, 256))	('Hippo', 'Gene', '37247', (265, 270))	('Rho1', 'Gene', '36775', (252, 256))	('wnd', 'Gene', '40143', (104, 107))	('overexpression-induced', 'PosReg', (126, 148))	('ban-lacZ', 'Gene', (149, 157))	('ban', 'Species', '9031', (149, 152))	('knockdown', 'Var', (91, 100))	('Hippo', 'Gene', (265, 270))	('Rho1', 'Gene', (121, 125))	('Rho1', 'Gene', '36775', (121, 125))	('reduces', 'NegReg', (113, 120))	('up-regulation', 'PosReg', (158, 171))	('wnd', 'Gene', (104, 107))	('Wnd', 'Gene', '40143', (232, 235))
57343	33937258	Loss of scrib has been reported to upregulate Yki target genes.	('scrib', 'Gene', (8, 13))	('scrib', 'Gene', '44448', (8, 13))	('Yki target genes', 'Gene', (46, 62))	('upregulate', 'PosReg', (35, 45))	('Loss', 'Var', (0, 4))
57346	33937258	Additionally, knockdown of scrib by nub-Gal4 leads to significant overgrowth of the wing pouch region (Figure 2J), which is also inhibited by wnd knockdown (Figures 2K,L).	('wnd', 'Gene', (142, 145))	('Gal4', 'Gene', (40, 44))	('Gal4', 'Gene', '414342', (40, 44))	('wnd', 'Gene', '40143', (142, 145))	('overgrowth', 'Phenotype', 'HP:0001548', (66, 76))	('nub', 'Gene', (36, 39))	('scrib', 'Gene', '44448', (27, 32))	('scrib', 'Gene', (27, 32))	('knockdown', 'Var', (14, 23))	('overgrowth of the wing pouch region', 'CPA', (66, 101))	('nub', 'Gene', '34669', (36, 39))
57353	33937258	It is worth noting that both Wnd and Nmo are essential for the overgrowth phenotype of neuromuscular junction (NMJ) caused by a mutation in a ubiquitin E3 ligase named Highwire, indicating a potential genetic interaction between wnd and nmo.	('neuromuscular junction', 'Disease', (87, 109))	('Wnd', 'Gene', (29, 32))	('wnd', 'Gene', (229, 232))	('ubiquitin', 'Gene', (142, 151))	('ubiquitin', 'Gene', '38456', (142, 151))	('caused by', 'Reg', (116, 125))	('wnd', 'Gene', '40143', (229, 232))	('Nmo', 'Chemical', '-', (37, 40))	('overgrowth', 'Phenotype', 'HP:0001548', (63, 73))	('mutation', 'Var', (128, 136))	('Wnd', 'Gene', '40143', (29, 32))	('Highwire', 'Gene', (168, 176))
57356	33937258	Overexpression of P35 alone by ptc-Gal4 leads to no change on Wg level comparing to the wild type (Figures 3A-B'), iwhile co-expression of wnd and P35 and observed a significant up-regulation of wg expression along the ptc stripe (GFP positive) (Figures 3D,D'), which was dramatically reduced by simultaneously knocking down nmo (Figures 3E,E').	('Gal4', 'Gene', '414342', (35, 39))	('wg expression', 'MPA', (195, 208))	('wnd', 'Gene', (139, 142))	('Wg level', 'MPA', (62, 70))	('up-regulation', 'PosReg', (178, 191))	('wnd', 'Gene', '40143', (139, 142))	('nmo', 'Gene', (325, 328))	('knocking down', 'Var', (311, 324))	('Gal4', 'Gene', (35, 39))
57357	33937258	Strikingly, we found that nmo knockdown not only reduced the nuclear Yki accumulation induced by co-expression of wnd and P35, but also caused sharp decrease of Yki protein level (Figures 3I-J''), whereas knockdown of nmo alone did not cause obvious phenotypes (Figures 3C,C',H-H'', and Supplementary Figure 4).	('wnd', 'Gene', (114, 117))	('nuclear Yki accumulation', 'MPA', (61, 85))	('Yki protein level', 'MPA', (161, 178))	('reduced', 'NegReg', (49, 56))	('wnd', 'Gene', '40143', (114, 117))	('nmo', 'Gene', (26, 29))	('knockdown', 'Var', (30, 39))	('decrease', 'NegReg', (149, 157))	('P35', 'Var', (122, 125))
57358	33937258	We found that though there is no significant difference of proliferation rate in P35 overexpression and nmo knockdown wing discs compared with the wild type control (Figures 3P-R',U), the increased proliferation caused by wnd and P35 co-expression was significantly suppressed by nmo knockdown (Figures 3S-U).	('knockdown', 'Var', (108, 117))	('suppressed', 'NegReg', (266, 276))	('nmo', 'Gene', (104, 107))	('wnd', 'Gene', (222, 225))	('proliferation', 'CPA', (198, 211))	('wnd', 'Gene', '40143', (222, 225))	('increased', 'PosReg', (188, 197))
57363	33937258	Given that loss of Yki activity facilitates cell death, we speculate that in the Wnd and P35 co-expressing wing disc, nmo knockdown leads to the downregulation of Yki level and therefore increases apoptosis.	('apoptosis', 'CPA', (197, 206))	('Wnd', 'Gene', '40143', (81, 84))	('cell death', 'CPA', (44, 54))	('Wnd', 'Gene', (81, 84))	('Yki level', 'MPA', (163, 172))	('knockdown', 'Var', (122, 131))	('nmo', 'Gene', (118, 121))	('increases', 'PosReg', (187, 196))	('downregulation', 'NegReg', (145, 159))
57382	33937258	Taking advantage of the Drosophila model, our findings here suggest the exciting prospect that similar mechanisms may exist in human cancer progression, and further investigation is required to elucidate the potential link between MAP3K13-NLK axis and polarity loss induced YAP/TAZ activation in tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (296, 301))	('human', 'Species', '9606', (127, 132))	('polarity loss', 'Var', (252, 265))	('YAP', 'Gene', '10413', (274, 277))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('MAP3K13', 'Gene', (231, 238))	('tumor', 'Disease', (296, 301))	('Drosophila', 'Species', '7227', (24, 34))	('cancer', 'Disease', (133, 139))	('MAP3K13', 'Gene', '9175', (231, 238))	('TAZ', 'Gene', (278, 281))	('TAZ', 'Gene', '6901', (278, 281))	('YAP', 'Gene', (274, 277))	('activation', 'PosReg', (282, 292))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('tumor', 'Disease', 'MESH:D009369', (296, 301))
57397	33937258	This platform automatically found three cancer types that show significant difference in prognosis under low or high MAP3K13 expression level.	('low', 'NegReg', (105, 108))	('MAP3K13', 'Gene', '9175', (117, 124))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('high', 'Var', (112, 116))	('cancer', 'Disease', (40, 46))	('expression', 'MPA', (125, 135))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('MAP3K13', 'Gene', (117, 124))
57423	33280522	Hence, 125I radiotherapy can maximally inactivating the tumor cells, ultimately attaining the treatment purpose.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('inactivating', 'NegReg', (39, 51))	('tumor', 'Disease', (56, 61))	('125I', 'Var', (7, 11))	('men', 'Species', '9606', (99, 102))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
57470	33280522	The PFS and OS of LUAD patients were significant increased compared with LUSC patients (P < 0.05, Figure 3E, F).	('patients', 'Species', '9606', (23, 31))	('LUAD', 'Phenotype', 'HP:0030078', (18, 22))	('increased', 'PosReg', (49, 58))	('PFS', 'CPA', (4, 7))	('patients', 'Species', '9606', (78, 86))	('LUAD', 'Var', (18, 22))	('LUSC', 'Phenotype', 'HP:0030359', (73, 77))
57481	33280522	In recent years, with the development of nuclear medicine and the improvement of medical equipment, radioactive seed implantation (125I, 131I, 103Pd) has been widely applied in treatment of various tumors.	('125I', 'Var', (131, 135))	('men', 'Species', '9606', (73, 76))	('men', 'Species', '9606', (94, 97))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('tumors', 'Disease', (198, 204))	('tumors', 'Disease', 'MESH:D009369', (198, 204))	('tumors', 'Phenotype', 'HP:0002664', (198, 204))	('men', 'Species', '9606', (182, 185))	('men', 'Species', '9606', (33, 36))
57514	30388102	Our results show that some somatic mutations affect gene expression in several cancer types.	('affect', 'Reg', (45, 51))	('gene expression', 'MPA', (52, 67))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('mutations', 'Var', (35, 44))
57515	30388102	In particular, we show that the associations between gene expression traits and TP53 gene level mutation reveal some similarities across a few cancer types.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('associations', 'Interaction', (32, 44))	('TP53', 'Gene', '7157', (80, 84))	('mutation', 'Var', (96, 104))	('TP53', 'Gene', (80, 84))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('mi', 'Chemical', 'MESH:C011506', (119, 121))
57518	30388102	First, since somatic mutation data are relatively new, most efforts were spent on bioinformatic challenges such as somatic mutation calling and functional annotations, e.g., inference of driver mutations, or estimation of cancer subtypes using somatic mutations.	('cancer', 'Disease', (222, 228))	('mutations', 'Var', (194, 203))	('cancer', 'Disease', 'MESH:D009369', (222, 228))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))
57540	30388102	When Di >= d0 = 20, we simulated Ai by a beta-binomial distribution specified in equation (2) of S1 Appendix, with parameters (pi00, pi01, pi10, pi11) = (0.001, 0.002, 0.1179, 0.3207) and (phi00, phi01, phi10, phi11) = (0.0006, 0.3457, 0.0001, 0.1018).	('a beta', 'Gene', '351', (39, 45))	('pi11', 'Gene', (145, 149))	('a beta', 'Gene', (39, 45))	('pi10', 'Gene', (139, 143))	('pi11', 'Gene', '6318', (145, 149))	('pi10', 'Gene', '5273', (139, 143))	('mi', 'Chemical', 'MESH:C011506', (50, 52))	('phi11', 'Var', (210, 215))	('pi00', 'Var', (127, 131))	('phi10', 'Var', (203, 208))	('0.001', 'Var', (154, 159))	('0.3207', 'Var', (176, 182))	('phi00', 'Var', (189, 194))
57541	30388102	When Di < 20, the number of alternative reads Ai was generated by a beta-binomial distribution (see equation (4) of S1 Appendix) with parameters pi0 = 0.001, phi0 = 0.001, pi1 = 0.146, and phi1 = 0.10.	('Di < 20', 'Var', (5, 12))	('mi', 'Chemical', 'MESH:C011506', (77, 79))	('pi0', 'Var', (145, 148))	('a beta', 'Gene', '351', (66, 72))	('phi0', 'Var', (158, 162))	('a beta', 'Gene', (66, 72))
57548	30388102	We called somatic mutations using the intersection of MuTect and Strelka, followed by the read-depth filter to keep those mutations with read-depth >=20 in both tumor and paired-normal samples (Section 3.1 in S3 Appendix).	('mutations', 'Var', (122, 131))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('tumor', 'Disease', (161, 166))	('tumor', 'Disease', 'MESH:D009369', (161, 166))
57555	30388102	Most of these significant associations (100 out of 109) are with respect to the BRAF V600E mutation (chr7:140753336), which is a single nucleotide variant that results in an amino acid change from a valine (V) to a glutamic acid (E).	('mi', 'Chemical', 'MESH:C011506', (220, 222))	('BRAF', 'Gene', (80, 84))	('amino acid change', 'MPA', (174, 191))	('V600E', 'Mutation', 'rs113488022', (85, 90))	('glutamic acid', 'Chemical', 'MESH:D018698', (215, 228))	('valine', 'Chemical', 'MESH:D014633', (199, 205))	('V600E', 'Var', (85, 90))	('BRAF', 'Gene', '673', (80, 84))	('mi', 'Chemical', 'MESH:C011506', (175, 177))
57556	30388102	The high frequency of BRAF V600E mutation associations is partly due to its high mutation frequency (11.66%).	('BRAF', 'Gene', (22, 26))	('V600E', 'Var', (27, 32))	('BRAF', 'Gene', '673', (22, 26))	('V600E', 'Mutation', 'rs113488022', (27, 32))
57559	30388102	The first example is that the TP53 mutation "chr17:7673803" is associated with the gene expression CDX1.	('TP53', 'Gene', (30, 34))	('associated', 'Reg', (63, 73))	('CDX1', 'Gene', '1044', (99, 103))	('mutation', 'Var', (35, 43))	('TP53', 'Gene', '7157', (30, 34))	('CDX1', 'Gene', (99, 103))
57560	30388102	Previous work has indicated that the gene expression of CDX1 is abnormally down-regulated in colon cancer-derived cell lines, and our finding suggests that this TP53 somatic mutation is partly responsible for dysregulation of CDX1's expression in colon cancer.	('colon cancer', 'Disease', (93, 105))	('TP53', 'Gene', (161, 165))	('gene expression', 'MPA', (37, 52))	('expression', 'MPA', (233, 243))	('mutation', 'Var', (174, 182))	('CDX1', 'Gene', '1044', (226, 230))	('colon cancer', 'Disease', 'MESH:D015179', (247, 259))	('colon cancer', 'Phenotype', 'HP:0003003', (247, 259))	('CDX1', 'Gene', (56, 60))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('CDX1', 'Gene', '1044', (56, 60))	('colon cancer', 'Disease', (247, 259))	('colon cancer', 'Phenotype', 'HP:0003003', (93, 105))	('TP53', 'Gene', '7157', (161, 165))	('CDX1', 'Gene', (226, 230))	('down-regulated', 'NegReg', (75, 89))	('colon cancer', 'Disease', 'MESH:D015179', (93, 105))	('cancer', 'Phenotype', 'HP:0002664', (253, 259))
57561	30388102	The second example is that TP53 mutation "chr17:7674894" associated with its own gene expression.	('TP53', 'Gene', '7157', (27, 31))	('TP53', 'Gene', (27, 31))	('mutation', 'Var', (32, 40))	('associated', 'Reg', (57, 67))
57562	30388102	Among these mutations, we conducted the association analysis for 180 genes that are mutated in at least 5 samples and are known to be associated with colon cancer.	('associated', 'Reg', (134, 144))	('mutations', 'Var', (12, 21))	('colon cancer', 'Phenotype', 'HP:0003003', (150, 162))	('colon cancer', 'Disease', 'MESH:D015179', (150, 162))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('colon cancer', 'Disease', (150, 162))
57565	30388102	Gene-level mutation status of BRAF is associated with the expression of 36 genes and all of these associations have been identified in mutation-level analysis with respect to the V600E mutation.	('V600E', 'Var', (179, 184))	('associated', 'Reg', (38, 48))	('expression', 'MPA', (58, 68))	('BRAF', 'Gene', (30, 34))	('BRAF', 'Gene', '673', (30, 34))	('V600E', 'Mutation', 'rs113488022', (179, 184))	('mutation status', 'Var', (11, 26))
57566	30388102	This may not be surprising because V600E mutation is present in more than 80% of the samples with at least one BRAF mutation.	('V600E', 'Var', (35, 40))	('BRAF', 'Gene', (111, 115))	('BRAF', 'Gene', '673', (111, 115))	('V600E', 'Mutation', 'rs113488022', (35, 40))
57568	30388102	Each of the 68 individual mutations within TP53 has relatively low mutation frequency (the highest frequency is 5.70%), however, after aggregating all the mutations, the gene-level mutation TP53 is present in 39.38% of the samples.	('TP53', 'Gene', '7157', (190, 194))	('mutations', 'Var', (26, 35))	('TP53', 'Gene', (190, 194))	('TP53', 'Gene', '7157', (43, 47))	('TP53', 'Gene', (43, 47))
57574	30388102	To illustrate somatic mutation association analysis using dichotomous outcomes, we applied both mSAME and gSAME to identify somatic mutations associated with colon cancer subtypes defined by DNA methylation data.	('gSAME', 'Chemical', '-', (106, 111))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('mutations', 'Var', (132, 141))	('colon cancer subtype', 'Disease', (158, 178))	('colon cancer', 'Phenotype', 'HP:0003003', (158, 170))	('associated', 'Reg', (142, 152))	('colon cancer subtype', 'Disease', 'MESH:D015179', (158, 178))
57582	30388102	Our results suggest that the mutations of KMT2C are associated with DNA methylation, which is consistent with its role as histone methyltransferases because DNA methylation and histone methylation often work together to establish epigenetic landscape for gene expression regulation.	('DNA methylation', 'Disease', (68, 83))	('mutations', 'Var', (29, 38))	('associated', 'Reg', (52, 62))	('KMT2C', 'Gene', '58508', (42, 47))	('KMT2C', 'Gene', (42, 47))
57590	30388102	For LGG, we further adjusted for cancer subtype defined based on the IDH1 or IDH2 mutation and chromosome 1p and 19q co-deletion.	('IDH1', 'Gene', '3417', (69, 73))	('cancer', 'Disease', (33, 39))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('mutation', 'Var', (82, 90))	('IDH2', 'Gene', (77, 81))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('IDH2', 'Gene', '3418', (77, 81))	('IDH1', 'Gene', (69, 73))
57592	30388102	However, one exception is gene-level TP53 mutation (Fig 3), which is among the significant eQTLs in 7 out of the 12 cancer types.	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('mutation', 'Var', (42, 50))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('TP53', 'Gene', '7157', (37, 41))	('TP53', 'Gene', (37, 41))
57597	30388102	Next we examine the eGenes (genes whose expression are associated with an eQTL) associated with TP53 gene level mutation across cancer types.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('mi', 'Chemical', 'MESH:C011506', (11, 13))	('mutation', 'Var', (112, 120))	('TP53', 'Gene', (96, 100))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('TP53', 'Gene', '7157', (96, 100))	('cancer', 'Disease', (128, 134))
57601	30388102	The difference of gSAME and GLM results are most due to potential mutation calling errors in TP53 (Fig S17 in S3 Appendix).	('mutation calling errors', 'Var', (66, 89))	('errors', 'Var', (83, 89))	('gSAME', 'Chemical', '-', (18, 23))	('TP53', 'Gene', '7157', (93, 97))	('TP53', 'Gene', (93, 97))
57614	30388102	This is because an oncogene is often activated by some specific "gain of function" mutations that drive tumor growth, and such driver mutations are often recurrent across patients.	('mutations', 'Var', (83, 92))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('activated', 'PosReg', (37, 46))	('tumor', 'Disease', (104, 109))	('patients', 'Species', '9606', (171, 179))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
57617	30388102	This is indeed the pattern observed when we compare the eQTL results for BRAF V600E mutation versus BRAF gene level mutations (Fig 5).	('BRAF', 'Gene', '673', (73, 77))	('V600E', 'Mutation', 'rs113488022', (78, 83))	('BRAF', 'Gene', '673', (100, 104))	('BRAF', 'Gene', (100, 104))	('V600E', 'Var', (78, 83))	('BRAF', 'Gene', (73, 77))
57619	30388102	The function of a tumor suppressor gene may be perturbed by multiple "loss of function" mutations and thus there is no evolutionary pressure to select a specific one.	('tumor', 'Disease', (18, 23))	('function', 'MPA', (4, 12))	('perturbed', 'Reg', (47, 56))	('mutations', 'Var', (88, 97))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
57620	30388102	Since all the loss of function mutations have similar functional consequence, gene-level association can have much larger power than mutation-level analysis.	('mi', 'Chemical', 'MESH:C011506', (48, 50))	('mutations', 'Var', (31, 40))	('loss of function', 'NegReg', (14, 30))
57621	30388102	For example, TP53 has 68 individual mutations in TCGA colon cancer dataset, among which only 6 mutations occur at more than 2% of the samples and are significant eQTLs with transcriptome-wide multiple testing correction.	('TP53', 'Gene', (13, 17))	('colon cancer', 'Disease', 'MESH:D015179', (54, 66))	('colon cancer', 'Phenotype', 'HP:0003003', (54, 66))	('mutations', 'Var', (36, 45))	('colon cancer', 'Disease', (54, 66))	('TP53', 'Gene', '7157', (13, 17))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
57626	30388102	Somatic mutation association is a new field with great potential to deliver key findings for precision cancer therapy.	('Somatic mutation association', 'Var', (0, 28))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))
57638	26459875	Masuda et al demonstrated that INFc(+) was significantly associated with venous invasion, the scirrhous stromal tumor type and a lower postoperative survival in patients with lung SqCC.	('venous invasion', 'CPA', (73, 88))	('lower', 'NegReg', (129, 134))	('lung SqCC', 'Disease', (175, 184))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('patients', 'Species', '9606', (161, 169))	('scirrhous stromal tumor', 'Disease', (94, 117))	('INFc(+', 'Var', (31, 37))	('scirrhous stromal tumor', 'Disease', 'MESH:D002293', (94, 117))	('postoperative survival', 'CPA', (135, 157))	('associated', 'Reg', (57, 67))	('SqCC', 'Phenotype', 'HP:0002860', (180, 184))
57649	26459875	Therefore, SqCC tissue specimens were further classified into seven categories: INFa, INFa>b, INFa<b, INFb, INFb>c, INFb<c and INFc.	('INFb>c', 'Var', (108, 114))	('INFa', 'Gene', (80, 84))	('INFa', 'Gene', '3451', (94, 98))	('INFa', 'Gene', '3451', (86, 90))	('SqCC', 'Phenotype', 'HP:0002860', (11, 15))	('INFa', 'Gene', '3451', (80, 84))	('INFa', 'Gene', (86, 90))	('INFa', 'Gene', (94, 98))
57665	26459875	The patients with INFc(+) (INFb>c, b<c, c) had a poor outcome, compared with the patients with INFc(-) (INFa,a>b, a<b, b) (Table II).	('INFa', 'Gene', '3451', (104, 108))	('INFc(+) (INFb>c', 'Var', (18, 33))	('patients', 'Species', '9606', (81, 89))	('patients', 'Species', '9606', (4, 12))	('INFa', 'Gene', (104, 108))
57701	33669819	Female lung cancer patients tend to have genetic abnormalities in EGFR and ALK, etc., while the male patients tend to have mutated versions of KRAS and BRAF, etc..	('KRAS', 'Gene', '3845', (143, 147))	('BRAF', 'Gene', (152, 156))	('patients', 'Species', '9606', (101, 109))	('ALK', 'Gene', (75, 78))	('patients', 'Species', '9606', (19, 27))	('EGFR', 'Gene', '1956', (66, 70))	('EGFR', 'Gene', (66, 70))	('lung cancer', 'Disease', (7, 18))	('genetic abnormalities', 'Disease', 'MESH:D030342', (41, 62))	('lung cancer', 'Phenotype', 'HP:0100526', (7, 18))	('ALK', 'Gene', '238', (75, 78))	('genetic abnormalities', 'Disease', (41, 62))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('KRAS', 'Gene', (143, 147))	('mutated', 'Var', (123, 130))	('BRAF', 'Gene', '673', (152, 156))	('lung cancer', 'Disease', 'MESH:D008175', (7, 18))
57723	33669819	The 10FCV classification performance of the classifier "C" was calculated on dsMale and denoted as C(dsMale).	('as C', 'Gene', (96, 100))	('as C', 'Gene', '412', (96, 100))	('10FCV', 'Chemical', '-', (4, 9))	('dsMale', 'Var', (77, 83))
57766	32705252	However, PGK1 knockdown reversed hypoxia-mediated glycolysis, stem cell-like properties, EMT in addition to inhibiting OSCC cell invasion and migration.	('hypoxia', 'Disease', (33, 40))	('PGK1', 'Gene', (9, 13))	('hypoxia', 'Disease', 'MESH:D000860', (33, 40))	('inhibiting', 'NegReg', (108, 118))	('knockdown', 'Var', (14, 23))	('EMT', 'CPA', (89, 92))	('reversed', 'PosReg', (24, 32))	('stem cell-like properties', 'CPA', (62, 87))
57767	32705252	PGK1 knockdown also inhibited tumour growth, whilst the overexpression of PGK1 was demonstrated to promote tumour growth in mouse xenograft models in vivo.	('tumour', 'Disease', 'MESH:D009369', (30, 36))	('knockdown', 'Var', (5, 14))	('promote', 'PosReg', (99, 106))	('tumour', 'Disease', (30, 36))	('mouse', 'Species', '10090', (124, 129))	('tumour', 'Phenotype', 'HP:0002664', (107, 113))	('PGK1', 'Gene', (74, 78))	('tumour', 'Disease', 'MESH:D009369', (107, 113))	('inhibited', 'NegReg', (20, 29))	('PGK1', 'Gene', (0, 4))	('tumour', 'Phenotype', 'HP:0002664', (30, 36))	('tumour', 'Disease', (107, 113))
57768	32705252	Downstream, activation of the AKT signalling pathway reversed the series of changes induced by PGK1 knockdown.	('knockdown', 'Var', (100, 109))	('PGK1', 'Gene', (95, 99))	('AKT', 'Gene', '207', (30, 33))	('AKT', 'Gene', (30, 33))
57784	32705252	In OSCC, pyruvate kinase M1/2 dephosphorylation has been previously demonstrated to promote the Warburg effect and tumorigenesis, whilst silencing phosphofructokinase, platelet (PFKP) expression inhibited starvation-induced autophagy, glycolysis and EMT.	('glycolysis', 'CPA', (235, 245))	('PFKP', 'Gene', (178, 182))	('starvation-induced autophagy', 'CPA', (205, 233))	('promote', 'PosReg', (84, 91))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('inhibited', 'NegReg', (195, 204))	('tumor', 'Disease', (115, 120))	('EMT', 'CPA', (250, 253))	('silencing', 'Var', (137, 146))	('PFKP', 'Gene', '5214', (178, 182))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('Warburg effect', 'CPA', (96, 110))
57786	32705252	Phosphoglycerate kinase (PGK) is an essential enzyme that is associated with the survival of every organism, where mutations in PGK results in a number of metabolic disorders, including mental retardation, neurological disorders and rhabdomyolysis.	('mental retardation', 'Phenotype', 'HP:0001249', (186, 204))	('mental retardation', 'Disease', (186, 204))	('mutations', 'Var', (115, 124))	('results in', 'Reg', (132, 142))	('rhabdomyolysis', 'Disease', 'MESH:D012206', (233, 247))	('mental retardation', 'Disease', 'MESH:D008607', (186, 204))	('PGK', 'Gene', (128, 131))	('rhabdomyolysis', 'Disease', (233, 247))	('metabolic disorders', 'Disease', 'MESH:D008659', (155, 174))	('neurological disorders', 'Disease', 'MESH:D009422', (206, 228))	('neurological disorders', 'Disease', (206, 228))	('rhabdomyolysis', 'Phenotype', 'HP:0003201', (233, 247))	('metabolic disorders', 'Disease', (155, 174))
57788	32705252	Aberrant PGK1 expression has been previously associated with the occurrence of a number of diseases, including Parkinson's disease and hereditary non-spherical hemolytic anemia.	("Parkinson's disease", 'Disease', (111, 130))	('Aberrant', 'Var', (0, 8))	('PGK1', 'Gene', (9, 13))	('hemolytic anemia', 'Disease', 'MESH:D000743', (160, 176))	('hemolytic anemia', 'Phenotype', 'HP:0001878', (160, 176))	("Parkinson's disease", 'Disease', 'MESH:D010300', (111, 130))	('associated', 'Reg', (45, 55))	('anemia', 'Phenotype', 'HP:0001903', (170, 176))	('expression', 'MPA', (14, 24))	('hemolytic anemia', 'Disease', (160, 176))
57789	32705252	By contrast, the PGK2 gene is only expressed in spermatogenic cells, where its only known function is to compensate for the inhibition of PGK1 expression caused by the inactivation of X chromosomes in spermatocytes.	('PGK1', 'Gene', (138, 142))	('expression', 'MPA', (143, 153))	('inactivation', 'Var', (168, 180))	('PGK2', 'Gene', '5232', (17, 21))	('PGK2', 'Gene', (17, 21))
57797	32705252	Anti-PGK1 (cat.	('cat', 'Gene', (11, 14))	('cat', 'Gene', '847', (11, 14))	('Anti-PGK1', 'Var', (0, 9))
57818	32705252	The multiplicity of infection of both PGK1 knockdown and overexpression was 10.	('infection', 'Disease', 'MESH:D007239', (20, 29))	('infection', 'Disease', (20, 29))	('knockdown', 'Var', (43, 52))	('PGK1', 'Gene', (38, 42))
57828	32705252	An Axio Imager Z2 light microscope (magnifications, x100 and x400; Zeiss AG) was used for image acquisition.	('x400', 'Var', (61, 65))	('cat', 'Gene', '847', (43, 46))	('cat', 'Gene', (43, 46))
57844	32705252	SCID mice were randomly divided into the following four groups (n=5 in each group): i) Overexpression control (Vector); ii) overexpression (PGK1); iii) knockdown control group (shVector); and iv) knockdown (shPGK1).	('knockdown', 'Var', (196, 205))	('SCID', 'Disease', (0, 4))	('mice', 'Species', '10090', (5, 9))	('SCID', 'Disease', 'MESH:D053632', (0, 4))
57868	32705252	To study the effect of hypoxia treatment on OSCC cells after PGK1 knockdown, the effect of siRNA transfection on the PGK1 expression under normoxic conditions was first verified by western blotting (Fig.	('hypoxia', 'Disease', (23, 30))	('PGK1', 'Gene', (61, 65))	('knockdown', 'Var', (66, 75))	('hypoxia', 'Disease', 'MESH:D000860', (23, 30))
57869	32705252	PGK1 knockdown using PGK si-01 was found to partially but significantly reverse the positive effects of hypoxia on glucose consumption (Fig.	('si-01', 'Chemical', '-', (25, 30))	('PGK', 'Gene', (21, 24))	('reverse', 'NegReg', (72, 79))	('knockdown', 'Var', (5, 14))	('glucose', 'Chemical', 'MESH:D005947', (115, 122))	('hypoxia', 'Disease', (104, 111))	('hypoxia', 'Disease', 'MESH:D000860', (104, 111))	('glucose consumption', 'MPA', (115, 134))	('PGK1', 'Gene', (0, 4))
57871	32705252	In terms of EMT, PGK1 knockdown markedly reversed the increases in the expression of EMT markers vimentin and Slug whilst markedly preventing the reduction in E-cadherin caused by hypoxia (Fig.	('expression', 'MPA', (71, 81))	('E-cadherin', 'Protein', (159, 169))	('vimentin', 'Protein', (97, 105))	('preventing', 'NegReg', (131, 141))	('hypoxia', 'Disease', 'MESH:D000860', (180, 187))	('knockdown', 'Var', (22, 31))	('PGK1', 'Gene', (17, 21))	('increases', 'PosReg', (54, 63))	('reduction', 'NegReg', (146, 155))	('hypoxia', 'Disease', (180, 187))
57872	32705252	PGK1 knockdown did not significantly affect HIF-1alpha expression, which was upregulated by hypoxia (Fig.	('hypoxia', 'Disease', (92, 99))	('upregulated', 'PosReg', (77, 88))	('knockdown', 'Var', (5, 14))	('hypoxia', 'Disease', 'MESH:D000860', (92, 99))	('HIF-1alpha', 'Gene', '3091', (44, 54))	('expression', 'MPA', (55, 65))	('HIF-1alpha', 'Gene', (44, 54))	('PGK1', 'Gene', (0, 4))
57873	32705252	PGK1 knockdown was found to markedly suppress the expression of stem cell markers Sox2, Oct4 and Nanog in addition to reversing the hypoxia-induced upregulation of these stem cell markers (Fig.	('hypoxia', 'Disease', (132, 139))	('upregulation', 'PosReg', (148, 160))	('hypoxia', 'Disease', 'MESH:D000860', (132, 139))	('knockdown', 'Var', (5, 14))	('Nanog', 'Gene', (97, 102))	('suppress', 'NegReg', (37, 45))	('PGK1', 'Gene', (0, 4))	('reversing', 'NegReg', (118, 127))	('Oct4', 'Gene', (88, 92))	('expression', 'MPA', (50, 60))	('Sox2', 'Gene', (82, 86))
57879	32705252	PGK1 knockdown was found to reduce p-AKT phosphorylation (Fig.	('knockdown', 'Var', (5, 14))	('AKT', 'Gene', '207', (37, 40))	('reduce', 'NegReg', (28, 34))	('AKT', 'Gene', (37, 40))	('PGK1', 'Gene', (0, 4))
57881	32705252	SC79 treatment was revealed to increase AKT phosphorylation whilst reversing the inhibitory effects of PGK1 knockdown on vimentin, Slug, Sox2, Oct4 and Nanog expression (Fig.	('knockdown', 'Var', (108, 117))	('AKT', 'Gene', '207', (40, 43))	('AKT', 'Gene', (40, 43))	('increase', 'PosReg', (31, 39))	('SC79', 'Chemical', '-', (0, 4))	('PGK1', 'Gene', (103, 107))
57882	32705252	In addition, increases in E-cadherin expression induced by PGK1 knockdown was also found to be reversed by SC79 treatment (Fig.	('increases', 'PosReg', (13, 22))	('SC79', 'Chemical', '-', (107, 111))	('E-cadherin', 'Protein', (26, 36))	('knockdown', 'Var', (64, 73))	('expression', 'MPA', (37, 47))	('PGK1', 'Gene', (59, 63))
57883	32705252	SC79 was found to promote significantly potentiate sphere formation, migration and invasion in HN6 and HSC3 cells following PGK1 knockdown (Fig.	('potentiate', 'PosReg', (40, 50))	('PGK1', 'Gene', (124, 128))	('knockdown', 'Var', (129, 138))	('HSC3', 'Gene', '150353', (103, 107))	('invasion', 'CPA', (83, 91))	('HSC3', 'Gene', (103, 107))	('sphere formation', 'CPA', (51, 67))	('promote', 'PosReg', (18, 25))	('SC79', 'Chemical', '-', (0, 4))	('migration', 'CPA', (69, 78))
57888	32705252	Survival analysis showed that the overall survival rate of patients with high expression of PGK1 was significantly reduced compared with those with low PGK1 expression (Fig.	('reduced', 'NegReg', (115, 122))	('PGK1', 'Gene', (92, 96))	('patients', 'Species', '9606', (59, 67))	('high expression', 'Var', (73, 88))
57899	32705252	A number of studies previously found that PGK1 expression is significantly associated with the survival and prognosis of patients with hepatocellular carcinoma, where PGK1 knockdown can inhibit the proliferation of hepatocellular carcinoma cell lines.	('PGK1', 'Gene', (42, 46))	('inhibit', 'NegReg', (186, 193))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (215, 239))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (135, 159))	('carcinoma', 'Phenotype', 'HP:0030731', (150, 159))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (215, 239))	('hepatocellular carcinoma', 'Disease', (135, 159))	('PGK1', 'Gene', (167, 171))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (135, 159))	('proliferation', 'CPA', (198, 211))	('carcinoma', 'Phenotype', 'HP:0030731', (230, 239))	('hepatocellular carcinoma', 'Disease', (215, 239))	('associated', 'Reg', (75, 85))	('knockdown', 'Var', (172, 181))	('patients', 'Species', '9606', (121, 129))
57903	32705252	PGK1 overexpression can promote the development and metastasis of gastric cancer by activating the C-X-C motif chemokine receptor 4/C-X-C motif chemokine 12/beta-catenin signalling pathway.	('metastasis of gastric cancer', 'Disease', (52, 80))	('C-X-C motif', 'MPA', (99, 110))	('development', 'CPA', (36, 47))	('beta-catenin', 'Gene', '1499', (157, 169))	('metastasis of gastric cancer', 'Disease', 'MESH:D013274', (52, 80))	('gastric cancer', 'Phenotype', 'HP:0012126', (66, 80))	('promote', 'PosReg', (24, 31))	('activating', 'PosReg', (84, 94))	('PGK1', 'Gene', (0, 4))	('overexpression', 'Var', (5, 19))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('beta-catenin', 'Gene', (157, 169))
57908	32705252	Further investigation found that PGK1 knockdown partially reversed the invasion and migration of oral cancer cells under hypoxic conditions.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('PGK1', 'Gene', (33, 37))	('invasion', 'CPA', (71, 79))	('oral cancer', 'Disease', 'MESH:D009369', (97, 108))	('reversed', 'NegReg', (58, 66))	('knockdown', 'Var', (38, 47))	('oral cancer', 'Disease', (97, 108))
57910	32705252	Aberrant activation of the AKT signalling pathway has been previously shown to serve an important role in the malignant progression of cancer.	('activation', 'PosReg', (9, 19))	('cancer', 'Disease', (135, 141))	('AKT', 'Gene', (27, 30))	('Aberrant', 'Var', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('AKT', 'Gene', '207', (27, 30))	('cancer', 'Disease', 'MESH:D009369', (135, 141))
57920	32479426	Alterations in glycolytic/cholesterogenic gene expression in hepatocellular carcinoma Metabolic reprogramming is a hallmark of tumors, including hepatocellular carcinoma (HCC).	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('HCC', 'Gene', (171, 174))	('hallmark of tumors', 'Disease', 'MESH:D009369', (115, 133))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (145, 169))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (160, 169))	('hepatocellular carcinoma', 'Disease', (145, 169))	('hallmark of tumors', 'Disease', (115, 133))	('Alterations', 'Var', (0, 11))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (145, 169))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('HCC', 'Gene', '619501', (171, 174))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (61, 85))	('hepatocellular carcinoma', 'Disease', (61, 85))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (61, 85))	('glycolytic/cholesterogenic', 'MPA', (15, 41))
57921	32479426	We used data from The Cancer Genome Atlas and the International Cancer Genome Consortium to assess the alterations in glycolytic and cholesterogenic genes in HCC and to determine their association with clinical features in HCC patients.	('Cancer', 'Phenotype', 'HP:0002664', (22, 28))	('Cancer', 'Disease', (22, 28))	('Cancer', 'Disease', (64, 70))	('cholesterogenic genes', 'Gene', (133, 154))	('HCC', 'Gene', (158, 161))	('alterations', 'Var', (103, 114))	('glycolytic', 'Gene', (118, 128))	('Cancer', 'Disease', 'MESH:D009369', (22, 28))	('Cancer', 'Disease', 'MESH:D009369', (64, 70))	('Cancer', 'Phenotype', 'HP:0002664', (64, 70))	('HCC', 'Gene', (223, 226))	('HCC', 'Gene', '619501', (158, 161))	('patients', 'Species', '9606', (227, 235))	('HCC', 'Gene', '619501', (223, 226))
57926	32479426	Whole-genome analyses indicated that aberrant amplification of TP53 and MYC in HCC were associated with abnormal anabolic cholesterol metabolism.	('TP53', 'Gene', '7157', (63, 67))	('aberrant amplification', 'Var', (37, 59))	('TP53', 'Gene', (63, 67))	('MYC', 'Gene', (72, 75))	('abnormal anabolic cholesterol metabolism', 'Disease', 'MESH:D008659', (104, 144))	('HCC', 'Gene', (79, 82))	('abnormal anabolic cholesterol metabolism', 'Disease', (104, 144))	('associated', 'Reg', (88, 98))	('HCC', 'Gene', '619501', (79, 82))	('MYC', 'Gene', '4609', (72, 75))
57941	32479426	Although disruptions in certain signaling pathways are known to contribute to metabolic reprogramming in cancer, alterations in glycolipid metabolism have rarely been reported in liver cancer.	('disruptions', 'Var', (9, 20))	('liver cancer', 'Disease', 'MESH:D006528', (179, 191))	('liver cancer', 'Phenotype', 'HP:0002896', (179, 191))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('liver cancer', 'Disease', (179, 191))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('contribute', 'Reg', (64, 74))	('glycolipid', 'Chemical', 'MESH:D006017', (128, 138))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('cancer', 'Disease', (185, 191))	('signaling pathways', 'Pathway', (32, 50))
57969	32479426	We next investigated the frequency of single nucleotide variations (SNVs), insertion-deletion mutations (INDELs) and copy number variations (CNVs) in genes associated with the different metabolic subtypes of liver hepatocellular carcinoma (LIHC) cohorts (Figure 2A).	('carcinoma', 'Phenotype', 'HP:0030731', (229, 238))	('single nucleotide variations', 'Var', (38, 66))	('liver hepatocellular carcinoma', 'Disease', 'MESH:D006528', (208, 238))	('liver hepatocellular carcinoma', 'Disease', (208, 238))	('insertion-deletion mutations', 'Var', (75, 103))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (214, 238))	('copy number variations', 'Var', (117, 139))
57973	32479426	These findings are consistent with the high mutational frequency of TP53 and MYC, and support the notion that mutations in TP53 and MYC promote tumor progression by inducing abnormal glucose utilization.	('abnormal glucose', 'Disease', 'MESH:D044882', (174, 190))	('tumor', 'Disease', (144, 149))	('abnormal glucose', 'Phenotype', 'HP:0001952', (174, 190))	('promote', 'PosReg', (136, 143))	('inducing', 'Reg', (165, 173))	('mutations', 'Var', (110, 119))	('MYC', 'Gene', '4609', (77, 80))	('MYC', 'Gene', '4609', (132, 135))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('abnormal glucose', 'Disease', (174, 190))	('MYC', 'Gene', (132, 135))	('MYC', 'Gene', (77, 80))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('TP53', 'Gene', '7157', (123, 127))	('TP53', 'Gene', '7157', (68, 72))	('TP53', 'Gene', (68, 72))	('TP53', 'Gene', (123, 127))
57986	32479426	To explore the association of MPC1 and MPC2 with the different metabolic phenotypes, we assessed the metabolic subpopulations for SNVs, INDELs, CNVs and mRNA expression changes in these genes.	('MPC2', 'Gene', (39, 43))	('MPC2', 'Gene', '25874', (39, 43))	('MPC1', 'Gene', '51660', (30, 34))	('MPC1', 'Gene', (30, 34))	('CNVs', 'Var', (144, 148))	('INDELs', 'Var', (136, 142))	('changes', 'Reg', (169, 176))
57987	32479426	The CNVs in MPC1 and MPC2 differed significantly among the metabolic subgroups; however, the CNVs in MPC1 were deletions in almost all of the HCC samples, while the CNVs in MPC2 were mostly amplifications (Figure 4A).	('MPC2', 'Gene', (173, 177))	('MPC1', 'Gene', (12, 16))	('MPC2', 'Gene', '25874', (173, 177))	('MPC1', 'Gene', '51660', (101, 105))	('MPC1', 'Gene', '51660', (12, 16))	('MPC2', 'Gene', (21, 25))	('MPC2', 'Gene', '25874', (21, 25))	('HCC', 'Gene', (142, 145))	('deletions', 'Var', (111, 120))	('MPC1', 'Gene', (101, 105))	('HCC', 'Gene', '619501', (142, 145))
57991	32479426	Thus, the dysregulation of mitochondrial pyruvate transport at the mRNA level may be associated with the metabolic tumor subtypes.	('metabolic tumor', 'Disease', (105, 120))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('pyruvate', 'Chemical', 'MESH:D019289', (41, 49))	('dysregulation', 'Var', (10, 23))	('mitochondrial pyruvate transport', 'MPA', (27, 59))	('metabolic tumor', 'Disease', 'MESH:D008659', (105, 120))	('associated', 'Reg', (85, 95))
58019	32479426	illustrated that inhibiting glycolysis could transform conventional tolerogenic cancer cells into immunogenic ones, thus providing a novel approach for immunogenic chemotherapy.	('inhibiting', 'Var', (17, 27))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('glycolysis', 'MPA', (28, 38))	('transform', 'Reg', (45, 54))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('cancer', 'Disease', (80, 86))
58036	32479426	Thus, abnormal expression of TP53 and MYC may promote the malignant process of tumors by enhancing cholesterol synthesis and altering cholesterol use.	('promote', 'PosReg', (46, 53))	('abnormal', 'Var', (6, 14))	('MYC', 'Gene', (38, 41))	('enhancing', 'PosReg', (89, 98))	('cholesterol', 'Chemical', 'MESH:D002784', (99, 110))	('cholesterol', 'Chemical', 'MESH:D002784', (134, 145))	('cholesterol use', 'MPA', (134, 149))	('tumors', 'Disease', (79, 85))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('TP53', 'Gene', (29, 33))	('TP53', 'Gene', '7157', (29, 33))	('altering', 'Reg', (125, 133))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('cholesterol synthesis', 'MPA', (99, 120))	('MYC', 'Gene', '4609', (38, 41))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
58037	32479426	In addition, by detecting mutated genes in metabolic pathways, we found that the MPC complexes regulating pyruvate flux were mutated and abnormally expressed in HCC, suggesting that changes in MPC are associated with HCC progression.	('pyruvate', 'Chemical', 'MESH:D019289', (106, 114))	('HCC', 'Gene', (161, 164))	('HCC', 'Gene', (217, 220))	('HCC', 'Gene', '619501', (161, 164))	('changes', 'Var', (182, 189))	('associated', 'Reg', (201, 211))	('HCC', 'Gene', '619501', (217, 220))
58039	32479426	Our in-depth investigation demonstrated that the mutation of different metabolic genes and the expression of specific enzymes contribute to the unique metabolic characteristics and clinical prognoses of different cancer types.	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('metabolic genes', 'Gene', (71, 86))	('contribute', 'Reg', (126, 136))	('mutation', 'Var', (49, 57))	('cancer', 'Disease', 'MESH:D009369', (213, 219))	('cancer', 'Disease', (213, 219))
58060	32479426	In order to identify oncogenic molecular events in the HCC metabolic subtypes, we investigated the frequency of SNVs, INDELs and CNVs in commonly mutated HCC genes and explored their relationship with the HCC metabolic subtypes.	('HCC', 'Gene', '619501', (205, 208))	('HCC', 'Gene', (154, 157))	('INDELs', 'Var', (118, 124))	('HCC', 'Gene', (55, 58))	('HCC', 'Gene', '619501', (154, 157))	('CNVs', 'Var', (129, 133))	('HCC', 'Gene', (205, 208))	('HCC', 'Gene', '619501', (55, 58))
58090	32265992	In fact, dy-regulations of peroxisomal enzymes and/or their effects were shown in numerous tumor types including prostate cancer, colorectal carcinoma, liver cancer, oral squamous cell carcinoma, pancreatic cancer, breast cancer, and lymphoma.	('breast cancer', 'Phenotype', 'HP:0003002', (215, 228))	('pancreatic cancer', 'Disease', 'MESH:D010190', (196, 213))	('prostate cancer', 'Disease', 'MESH:D011471', (113, 128))	('tumor', 'Disease', (91, 96))	('prostate cancer', 'Phenotype', 'HP:0012125', (113, 128))	('pancreatic cancer', 'Disease', (196, 213))	('breast cancer', 'Disease', 'MESH:D001943', (215, 228))	('lymphoma', 'Disease', (234, 242))	('breast cancer', 'Disease', (215, 228))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('prostate cancer', 'Disease', (113, 128))	('lymphoma', 'Disease', 'MESH:D008223', (234, 242))	('liver cancer', 'Disease', 'MESH:D006528', (152, 164))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (166, 194))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('oral squamous cell carcinoma', 'Disease', (166, 194))	('dy-regulations', 'Var', (9, 23))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (196, 213))	('liver cancer', 'Phenotype', 'HP:0002896', (152, 164))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('colorectal carcinoma', 'Disease', (130, 150))	('liver cancer', 'Disease', (152, 164))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (130, 150))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (171, 194))	('lymphoma', 'Phenotype', 'HP:0002665', (234, 242))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('peroxisomal enzymes', 'Enzyme', (27, 46))	('carcinoma', 'Phenotype', 'HP:0030731', (185, 194))
58135	32265992	Furthermore, through their comparisons between different grades (Figures 6D-F), a lower trend of ACAA1 expression (p = 0.084, 0.05 < p < 0.1) and a significant lower expression of PXMP4 (p = 0.02, p < 0.05) was shown in the poor differentiation tumors than the ones with well-moderate differentiation while no significant difference of HSD17B4 was shown.	('tumors', 'Phenotype', 'HP:0002664', (245, 251))	('lower', 'NegReg', (160, 165))	('ACAA1', 'Gene', '30', (97, 102))	('PXMP4', 'Gene', (180, 185))	('expression', 'MPA', (103, 113))	('poor', 'Var', (224, 228))	('tumors', 'Disease', 'MESH:D009369', (245, 251))	('rat', 'Species', '10116', (280, 283))	('expression', 'MPA', (166, 176))	('ACAA1', 'Gene', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('tumors', 'Disease', (245, 251))	('lower', 'NegReg', (82, 87))
58138	32265992	In contrast, significant negative correlations were shown between ACAA1 expression and its methylation value of CpG site cg10548708 in LUSC (Pearson r = -0.234, p = 4.412E-06) and LUAD (Pearson r = -0.411, p = 1.002E-18).	('cg10548708', 'Var', (121, 131))	('methylation value', 'MPA', (91, 108))	('ACAA1', 'Gene', (66, 71))	('negative', 'NegReg', (25, 33))	('cg10548708', 'Chemical', '-', (121, 131))	('LUSC', 'Phenotype', 'HP:0030359', (135, 139))	('expression', 'MPA', (72, 82))	('LUAD', 'Phenotype', 'HP:0030078', (180, 184))	('ACAA1', 'Gene', '30', (66, 71))
58143	32265992	However, both in LUSC and LUAD, HSD17B4 was found to have positive correlations with infiltrations of B cell, CD8+ T cell, Macrophage and dendritic cell.	('rat', 'Species', '10116', (91, 94))	('infiltrations of B cell', 'CPA', (85, 108))	('CD8', 'Gene', (110, 113))	('HSD17B4', 'Var', (32, 39))	('LUSC', 'Phenotype', 'HP:0030359', (17, 21))	('LUAD', 'Phenotype', 'HP:0030078', (26, 30))	('CD8', 'Gene', '925', (110, 113))
58153	32265992	Through correlation analyses (Supplementary Table S6), ACAA1 expression was shown to be negatively correlated with the IC50 values of five anti-cancer drugs including AZD0530 (r = -0.261, p = 0.014), AZD6244 (r = -0.281, p = 0.008), Erlotinib (r = -0.211, p = 0.047), Lapatinib (r = -0.234, p = 0.028), and ZD-6474 (r = -0.285, p = 0.007) while no significant correlation was shown for HSD17B4 or PXMP4 expression with the IC50 values of all the 24 drugs (p > 0.05).	('ACAA1', 'Gene', '30', (55, 60))	('HSD17B4', 'Gene', (386, 393))	('AZD6244', 'Var', (200, 207))	('Erlotinib', 'Chemical', 'MESH:D000069347', (233, 242))	('PXMP4', 'Gene', (397, 402))	('Lapatinib', 'Chemical', 'MESH:D000077341', (268, 277))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('AZD6244', 'Chemical', 'MESH:C517975', (200, 207))	('ACAA1', 'Gene', (55, 60))	('negatively', 'NegReg', (88, 98))	('cancer', 'Disease', (144, 150))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
58159	32265992	However, although dysfunctions of peroxisomes were shown in many tumors, their roles in lung cancer were rarely explored.	('lung cancer', 'Disease', (88, 99))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('lung cancer', 'Disease', 'MESH:D008175', (88, 99))	('tumors', 'Disease', (65, 71))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('dysfunctions', 'Var', (18, 30))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('lung cancer', 'Phenotype', 'HP:0100526', (88, 99))
58174	32265992	In addition, as one of the innate immunity genes, the single nucleotide polymorphisms (SNPs) of ACAA1 have been reported to be associated with pathogenesis of childhood asthma and the protective effects of its exposure to endotoxin.	('associated', 'Reg', (127, 137))	('ACAA1', 'Gene', (96, 101))	('asthma', 'Disease', (169, 175))	('asthma', 'Disease', 'MESH:D001249', (169, 175))	('single nucleotide polymorphisms', 'Var', (54, 85))	('ACAA1', 'Gene', '30', (96, 101))	('asthma', 'Phenotype', 'HP:0002099', (169, 175))
58182	32265992	In summary, dy-regulation of peroxisome pathway was common in NSCLC and more than 30% of peroxisome pathway genes were consistently down- or up-regulated in LUSC and LUAD, indicating their crucial roles in NSCLC.	('NSCLC', 'Disease', (62, 67))	('peroxisome pathway genes', 'Gene', (89, 113))	('LUSC', 'Phenotype', 'HP:0030359', (157, 161))	('NSCLC', 'Disease', (206, 211))	('NSCLC', 'Disease', 'MESH:D002289', (62, 67))	('up-regulated', 'PosReg', (141, 153))	('NSCLC', 'Disease', 'MESH:D002289', (206, 211))	('LUAD', 'Phenotype', 'HP:0030078', (166, 170))	('peroxisome pathway', 'Pathway', (29, 47))	('NSCLC', 'Phenotype', 'HP:0030358', (206, 211))	('NSCLC', 'Phenotype', 'HP:0030358', (62, 67))	('down-', 'NegReg', (132, 137))	('dy-regulation', 'Var', (12, 25))
58193	31096457	The expression level of alpha7 nAChR (encoded by CHRNA7) in 141 patients was measured by IHC and a high expression of alpha7 nAChR was associated with unfavorable prognosis (P = .008).	('high expression', 'Var', (99, 114))	('patients', 'Species', '9606', (64, 72))	('CHRNA7', 'Gene', '1139', (49, 55))	('nAChR', 'Gene', '1137', (31, 36))	('nAChR', 'Gene', '1137', (125, 130))	('CHRNA7', 'Gene', (49, 55))	('nAChR', 'Gene', (31, 36))	('nAChR', 'Gene', (125, 130))	('alpha7', 'Var', (118, 124))
58204	31096457	Nicotine can also promote cancer cell survival, proliferation, angiogenesis, invasion, and epithelial to mesenchymal transition (EMT) through nAChRs.	('cancer', 'Disease', (26, 32))	('epithelial to mesenchymal transition', 'CPA', (91, 127))	('proliferation', 'CPA', (48, 61))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('Nicotine', 'Var', (0, 8))	('invasion', 'CPA', (77, 85))	('Nicotine', 'Chemical', 'MESH:D009538', (0, 8))	('nAChR', 'Gene', '1137', (142, 147))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('nAChR', 'Gene', (142, 147))	('angiogenesis', 'CPA', (63, 75))	('promote', 'PosReg', (18, 25))
58206	31096457	Genome-wide association studies (GWAS) proved for the first time that variations in genomic regions located on chromosome 15q24-25 are associated with nicotine dependence and lung cancer risk.	('nicotine dependence', 'Disease', (151, 170))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('lung cancer', 'Disease', (175, 186))	('lung cancer', 'Phenotype', 'HP:0100526', (175, 186))	('variations', 'Var', (70, 80))	('associated', 'Reg', (135, 145))	('nicotine', 'Chemical', 'MESH:D009538', (151, 159))	('lung cancer', 'Disease', 'MESH:D008175', (175, 186))
58207	31096457	Although there have been several genomic variation studies investigating the relationships between the single-nucleotide polymorphisms (SNPs) of AChR and lung cancer risk, the functions of the AChR gene family are still unclear.	('lung cancer', 'Disease', (154, 165))	('lung cancer', 'Phenotype', 'HP:0100526', (154, 165))	('ACh', 'Chemical', 'MESH:D000109', (145, 148))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('ACh', 'Chemical', 'MESH:D000109', (193, 196))	('lung cancer', 'Disease', 'MESH:D008175', (154, 165))	('AChR', 'Gene', (145, 149))	('single-nucleotide polymorphisms', 'Var', (103, 134))
58212	31096457	We found that only alpha7 nAChR was associated with survival in both adenocarcinoma and squamous carcinoma.	('nAChR', 'Gene', '1137', (26, 31))	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (88, 106))	('adenocarcinoma and squamous carcinoma', 'Disease', 'MESH:D002294', (69, 106))	('alpha7', 'Var', (19, 25))	('nAChR', 'Gene', (26, 31))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('associated with', 'Reg', (36, 51))
58214	31096457	We studied the genomic alterations (amplification, deep deletion, missense mutation, mRNA upregulation, mRNA downregulation) that occurred in the AChR gene family in Lung Adenocarcinoma (TCGA, Nature 2014) and Lung Squamous Cell Carcinoma (TCGA, Nature 2012) case sets using cBioPortal (http://www.cbioportal.org/).	('Lung Adenocarcinoma', 'Phenotype', 'HP:0030078', (166, 185))	('deep deletion', 'Var', (51, 64))	('Lung Squamous Cell Carcinoma', 'Phenotype', 'HP:0030359', (210, 238))	('upregulation', 'PosReg', (90, 102))	('missense mutation', 'Var', (66, 83))	('Carcinoma', 'Phenotype', 'HP:0030731', (229, 238))	('Lung Squamous Cell Carcinoma', 'Disease', (210, 238))	('AChR', 'Gene', (146, 150))	('ACh', 'Chemical', 'MESH:D000109', (146, 149))	('Lung Adenocarcinoma', 'Disease', (166, 185))	('Lung Squamous Cell Carcinoma', 'Disease', 'MESH:D002294', (210, 238))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (215, 238))	('mRNA', 'MPA', (104, 108))	('Lung Adenocarcinoma', 'Disease', 'MESH:D000077192', (166, 185))	('carcinoma', 'Phenotype', 'HP:0030731', (176, 185))
58268	31096457	As shown in Figure 2C, Kaplan-Meier survival analysis showed that high expression of alpha7 nAChR in NSCLC was associated with unfavorable prognosis (P = .008) and early recurrence (P = .003).	('nAChR', 'Gene', '1137', (92, 97))	('nAChR', 'Gene', (92, 97))	('NSCLC', 'Disease', (101, 106))	('associated', 'Reg', (111, 121))	('NSCLC', 'Disease', 'MESH:D002289', (101, 106))	('high', 'Var', (66, 70))	('NSCLC', 'Phenotype', 'HP:0030358', (101, 106))
58280	31096457	IHC data analysis of the present patient cohort showed that alpha7 nAChR was an independent prognostic factor in NSCLC.	('nAChR', 'Gene', '1137', (67, 72))	('nAChR', 'Gene', (67, 72))	('patient', 'Species', '9606', (33, 40))	('NSCLC', 'Phenotype', 'HP:0030358', (113, 118))	('alpha7', 'Var', (60, 66))	('NSCLC', 'Disease', (113, 118))	('NSCLC', 'Disease', 'MESH:D002289', (113, 118))
58282	31096457	Interestingly, mutual exclusivity and co-occurrence analysis showed that that CHRM3 and CHRNB2, or CHRM5 and CHRNA7, tend to have co-occurrent alterations (amplification) in LUAD (P < .001).	('CHRNA7', 'Gene', (109, 115))	('CHRM3', 'Gene', (78, 83))	('CHRNA7', 'Gene', '1139', (109, 115))	('CHRM5', 'Gene', '1133', (99, 104))	('CHRNB2', 'Gene', (88, 94))	('CHRM5', 'Gene', (99, 104))	('CHRM3', 'Gene', '1131', (78, 83))	('CHRNB2', 'Gene', '1141', (88, 94))	('alterations', 'Var', (143, 154))	('LUAD', 'Disease', (174, 178))
58288	31096457	In addition, blocking M2 AChR signaling inhibits tumor growth and reverses EMT in NSCLC.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('ACh', 'Chemical', 'MESH:D000109', (25, 28))	('blocking', 'Var', (13, 21))	('NSCLC', 'Phenotype', 'HP:0030358', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('M2 AChR', 'Protein', (22, 29))	('reverses', 'NegReg', (66, 74))	('tumor', 'Disease', (49, 54))	('EMT', 'CPA', (75, 78))	('inhibits', 'NegReg', (40, 48))	('NSCLC', 'Disease', (82, 87))	('NSCLC', 'Disease', 'MESH:D002289', (82, 87))
58291	31096457	GWAS have shown for the first time with strong evidence that variations in genomic regions located on chromosome 15q24-25 are associated with nicotine dependence and lung cancer risk.	('associated', 'Reg', (126, 136))	('lung cancer', 'Disease', 'MESH:D008175', (166, 177))	('nicotine dependence', 'Disease', (142, 161))	('lung cancer', 'Disease', (166, 177))	('lung cancer', 'Phenotype', 'HP:0100526', (166, 177))	('nicotine', 'Chemical', 'MESH:D009538', (142, 150))	('variations', 'Var', (61, 71))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))
58293	31096457	Although several studies have shown that gene variations at this cluster are associated with lung cancer risk, little research has focused on their expression and lung cancer mortality risk.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('lung cancer', 'Disease', 'MESH:D008175', (163, 174))	('lung cancer', 'Disease', 'MESH:D008175', (93, 104))	('lung cancer', 'Phenotype', 'HP:0100526', (93, 104))	('lung cancer', 'Phenotype', 'HP:0100526', (163, 174))	('lung cancer', 'Disease', (93, 104))	('lung cancer', 'Disease', (163, 174))	('gene variations', 'Var', (41, 56))	('associated', 'Reg', (77, 87))
58297	31096457	Seung et al showed that the unmethylation of the CHRNB4 gene was an unfavorable prognostic factor in NSCLC.	('NSCLC', 'Disease', (101, 106))	('unmethylation', 'Var', (28, 41))	('NSCLC', 'Disease', 'MESH:D002289', (101, 106))	('CHRNB4', 'Gene', '1143', (49, 55))	('CHRNB4', 'Gene', (49, 55))	('NSCLC', 'Phenotype', 'HP:0030358', (101, 106))
58299	31096457	SNPs rs421629 on 5p15.33 and rs1948, rs660652, rs8040868, and rs2036527 on 15q25.1 previously identified as lung cancer risk or nicotine-addiction modifiers were associated with tumor DNA methylation levels in the promoters of TERT and CHRNB4.	('rs421629', 'Var', (5, 13))	('rs2036527', 'Var', (62, 71))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('tumor', 'Disease', (178, 183))	('rs8040868', 'Var', (47, 56))	('rs1948', 'Var', (29, 35))	('rs1948', 'Mutation', 'rs1948', (29, 35))	('TERT', 'Gene', (227, 231))	('lung cancer', 'Disease', (108, 119))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('nicotine', 'Chemical', 'MESH:D009538', (128, 136))	('TERT', 'Gene', '7015', (227, 231))	('CHRNB4', 'Gene', (236, 242))	('rs2036527', 'Mutation', 'rs2036527', (62, 71))	('associated', 'Reg', (162, 172))	('rs421629', 'Mutation', 'rs421629', (5, 13))	('rs660652', 'Mutation', 'rs660652', (37, 45))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('lung cancer', 'Disease', 'MESH:D008175', (108, 119))	('rs660652', 'Var', (37, 45))	('rs8040868', 'Mutation', 'rs8040868', (47, 56))	('lung cancer', 'Phenotype', 'HP:0100526', (108, 119))	('CHRNB4', 'Gene', '1143', (236, 242))
58300	31096457	In addition, CHRNB4 knockdown in NSCLC cell lines resulted in a reduced proliferation and propensity to form colonies.	('NSCLC', 'Phenotype', 'HP:0030358', (33, 38))	('CHRNB4', 'Gene', '1143', (13, 19))	('CHRNB4', 'Gene', (13, 19))	('NSCLC', 'Disease', (33, 38))	('reduced', 'NegReg', (64, 71))	('knockdown', 'Var', (20, 29))	('NSCLC', 'Disease', 'MESH:D002289', (33, 38))
58305	31096457	In non-transformed bronchial cells and in lung cancer cell lines, silencing CHRNA5 or inhibiting receptors containing alpha5 nAChR with a-conotoxin MII exerted a nicotine-like effect, with increased motility and invasiveness in vitro and increased calcium influx.	('exerted', 'MPA', (152, 159))	('CHRNA5', 'Gene', '1138', (76, 82))	('lung cancer', 'Disease', 'MESH:D008175', (42, 53))	('CHRNA5', 'Gene', (76, 82))	('motility', 'CPA', (199, 207))	('nicotine', 'Chemical', 'MESH:D009538', (162, 170))	('lung cancer', 'Phenotype', 'HP:0100526', (42, 53))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('calcium influx', 'CPA', (248, 262))	('calcium', 'Chemical', 'MESH:D002118', (248, 255))	('nAChR', 'Gene', '1137', (125, 130))	('invasiveness', 'CPA', (212, 224))	('nAChR', 'Gene', (125, 130))	('nicotine-like effect', 'MPA', (162, 182))	('silencing', 'Var', (66, 75))	('increased', 'PosReg', (238, 247))	('inhibiting', 'NegReg', (86, 96))	('lung cancer', 'Disease', (42, 53))	('increased', 'PosReg', (189, 198))
58308	31096457	Another study showed that all lung cancer tissues expressed mRNA encoding alpha7 nAChR and the resultant proteins in the following rank: squamous carcinoma more than > adenocarcinoma > squamous carcinoma from non-smokers > large cell carcinoma > carnification > and pulmonary chondroid hamartoma.	('large cell carcinoma', 'Phenotype', 'HP:0030360', (223, 243))	('squamous carcinoma', 'Disease', (185, 203))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('carnification', 'Disease', (246, 259))	('pulmonary chondroid hamartoma', 'Disease', (266, 295))	('pulmonary chondroid hamartoma', 'Disease', 'MESH:D006222', (266, 295))	('adenocarcinoma', 'Disease', 'MESH:D000230', (168, 182))	('cell carcinoma', 'Disease', 'MESH:C538614', (229, 243))	('nAChR', 'Gene', '1137', (81, 86))	('lung cancer', 'Disease', (30, 41))	('squamous carcinoma', 'Disease', (137, 155))	('mRNA', 'Var', (60, 64))	('nAChR', 'Gene', (81, 86))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (185, 203))	('squamous carcinoma', 'Disease', 'MESH:D002294', (185, 203))	('carcinoma', 'Phenotype', 'HP:0030731', (173, 182))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (137, 155))	('lung cancer', 'Disease', 'MESH:D008175', (30, 41))	('carcinoma', 'Phenotype', 'HP:0030731', (234, 243))	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('lung cancer', 'Phenotype', 'HP:0100526', (30, 41))	('squamous carcinoma', 'Disease', 'MESH:D002294', (137, 155))	('cell carcinoma', 'Disease', (229, 243))	('carcinoma', 'Phenotype', 'HP:0030731', (194, 203))	('hamartoma', 'Phenotype', 'HP:0010566', (286, 295))	('expressed', 'Reg', (50, 59))	('adenocarcinoma', 'Disease', (168, 182))
58327	31096457	High expression of alpha7 nAChR was associated with unfavorable prognosis in lung cancer.	('lung cancer', 'Phenotype', 'HP:0100526', (77, 88))	('nAChR', 'Gene', '1137', (26, 31))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('High', 'Var', (0, 4))	('nAChR', 'Gene', (26, 31))	('lung cancer', 'Disease', 'MESH:D008175', (77, 88))	('associated', 'Reg', (36, 46))	('lung cancer', 'Disease', (77, 88))
58330	31096457	Because of its high calcium permeability, which modulates intracellular signaling molecules, alpha7 nAChR has been implicated in lung tumorigenesis.	('implicated', 'Reg', (115, 125))	('modulates', 'Reg', (48, 57))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('nAChR', 'Gene', '1137', (100, 105))	('nAChR', 'Gene', (100, 105))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('calcium permeability', 'MPA', (20, 40))	('calcium', 'Chemical', 'MESH:D002118', (20, 27))	('tumor', 'Disease', (134, 139))	('alpha7', 'Var', (93, 99))
58331	31096457	The copy number variations (CNV-3956) of alpha7 nAChR was associated with an increased risk of lung cancer and the poor survival of lung cancer patients.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('lung cancer', 'Disease', (95, 106))	('lung cancer', 'Phenotype', 'HP:0100526', (95, 106))	('associated', 'Reg', (58, 68))	('lung cancer', 'Disease', 'MESH:D008175', (132, 143))	('copy number variations (CNV-3956', 'Var', (4, 36))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('nAChR', 'Gene', '1137', (48, 53))	('CNV-3956', 'Var', (28, 36))	('nAChR', 'Gene', (48, 53))	('patients', 'Species', '9606', (144, 152))	('lung cancer', 'Disease', 'MESH:D008175', (95, 106))	('lung cancer', 'Disease', (132, 143))	('lung cancer', 'Phenotype', 'HP:0100526', (132, 143))
58333	31096457	For the first time, we found that alpha7 nAChR was upregulated in tumor tissues compared with matched normal tissues and proved that alpha7 nAChR was an independent prognostic factor.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('nAChR', 'Gene', '1137', (140, 145))	('tumor', 'Disease', (66, 71))	('nAChR', 'Gene', (140, 145))	('alpha7', 'Var', (133, 139))	('nAChR', 'Gene', '1137', (41, 46))	('upregulated', 'PosReg', (51, 62))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('nAChR', 'Gene', (41, 46))
58418	25191856	ERCC1 Single Nucleotide Polymorphism C8092A, but Not Its Expression Is Associated with Survival of Esophageal Squamous Cell Carcinoma Patients from Fujian Province, China Esophageal carcinoma is one of the world's deadliest cancers.	('deadliest cancers', 'Disease', (214, 231))	('C8092A', 'Var', (37, 43))	('Esophageal carcinoma', 'Disease', 'MESH:D004938', (171, 191))	('Esophageal carcinoma', 'Phenotype', 'HP:0011459', (171, 191))	('cancers', 'Phenotype', 'HP:0002664', (224, 231))	('ERCC1', 'Gene', '2067', (0, 5))	('Single Nucleotide Polymorphism', 'Var', (6, 36))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('Esophageal Squamous Cell Carcinoma', 'Disease', 'MESH:D000077277', (99, 133))	('C8092A', 'Mutation', 'rs3212986', (37, 43))	('Carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (182, 191))	('Esophageal carcinoma', 'Disease', (171, 191))	('ERCC1', 'Gene', (0, 5))	('Esophageal Squamous Cell Carcinoma', 'Disease', (99, 133))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (110, 133))	('Patients', 'Species', '9606', (134, 142))	('deadliest cancers', 'Disease', 'MESH:D009369', (214, 231))	('Associated', 'Reg', (71, 81))
58421	25191856	Evidence suggests polymorphisms in genes encoding excision repair cross-complementing group 1 (ERCC1), a protein involved in nuclear excision repair (NER), may help predict response to cisplatin and other platinum-based chemotherapeutics.	('ERCC1', 'Gene', '2067', (95, 100))	('ERCC1', 'Gene', (95, 100))	('response', 'MPA', (173, 181))	('excision repair cross-complementing group 1', 'Gene', '2067', (50, 93))	('platinum', 'Chemical', 'MESH:D010984', (205, 213))	('polymorphisms', 'Var', (18, 31))	('excision repair cross-complementing group 1', 'Gene', (50, 93))	('cisplatin', 'Chemical', 'MESH:D002945', (185, 194))	('help predict', 'Reg', (160, 172))
58422	25191856	Multiple ERCC1 single nucleotide polymorphisms (SNPs) have been associated with platinum chemotherapy response.	('associated', 'Reg', (64, 74))	('platinum chemotherapy response', 'CPA', (80, 110))	('platinum', 'Chemical', 'MESH:D010984', (80, 88))	('ERCC1', 'Gene', (9, 14))	('ERCC1', 'Gene', '2067', (9, 14))	('single nucleotide polymorphisms', 'Var', (15, 46))
58423	25191856	Two common SNPs occur at the C8092A and C118T loci.	('C118T', 'Mutation', 'rs11615', (40, 45))	('C118T', 'Var', (40, 45))	('C8092A', 'Var', (29, 35))	('C8092A', 'Mutation', 'rs3212986', (29, 35))
58429	25191856	Interestingly, C8092A SNP showed significant association with patient survival (P = 0.01), with patients homozygous for the mutant allele showing the most significantly reduced survival (P = 0.04) compared to those homozygous for the dominant allele (CC).	('patient survival', 'CPA', (62, 78))	('C8092A', 'Var', (15, 21))	('patient', 'Species', '9606', (62, 69))	('patient', 'Species', '9606', (96, 103))	('reduced', 'NegReg', (169, 176))	('survival', 'MPA', (177, 185))	('patients', 'Species', '9606', (96, 104))	('C8092A', 'Mutation', 'rs3212986', (15, 21))
58438	25191856	In non-small cell lung cancer (NSCLC), ERCC1 SNP has been linked to reduced survival time and increased risk of comorbid complications in specific populations of chemotherapy patients.	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (3, 29))	('SNP', 'Var', (45, 48))	('NSCLC', 'Disease', (31, 36))	('NSCLC', 'Disease', 'MESH:D002289', (31, 36))	('patients', 'Species', '9606', (175, 183))	('lung cancer', 'Phenotype', 'HP:0100526', (18, 29))	('ERCC1', 'Gene', (39, 44))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (3, 29))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('survival time', 'CPA', (76, 89))	('reduced', 'NegReg', (68, 75))	('ERCC1', 'Gene', '2067', (39, 44))	('non-small cell lung cancer', 'Disease', (3, 29))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (7, 29))
58440	25191856	Single nucleotide polymorphisms (SNP) of ERCC1 could affect potential for genetic repair, which highly influences the efficacy and individual sensitivity to these chemotherapeutic agents.	('Single nucleotide polymorphisms', 'Var', (0, 31))	('influences', 'Reg', (103, 113))	('ERCC1', 'Gene', '2067', (41, 46))	('affect', 'Reg', (53, 59))	('ERCC1', 'Gene', (41, 46))	('potential for genetic repair', 'CPA', (60, 88))
58441	25191856	Evidence suggests that the ERCC1 C118T SNP could affect mRNA and protein expression of ERCC1, therefore altering sensitivity to platinum-based therapeutics.	('affect', 'Reg', (49, 55))	('ERCC1', 'Gene', (27, 32))	('platinum', 'Chemical', 'MESH:D010984', (128, 136))	('ERCC1', 'Gene', (87, 92))	('altering', 'Reg', (104, 112))	('C118T SNP', 'Var', (33, 42))	('ERCC1', 'Gene', '2067', (27, 32))	('ERCC1', 'Gene', '2067', (87, 92))	('C118T', 'Mutation', 'rs11615', (33, 38))	('sensitivity to platinum-based therapeutics', 'MPA', (113, 155))
58442	25191856	Meta-analysis suggests that certain ERCC1 SNPs may also be predictive of cancer susceptibility, further highlighting potential importance of this genetic alteration in cancer detection and therapeutics.	('ERCC1', 'Gene', '2067', (36, 41))	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('cancer', 'Disease', (168, 174))	('SNPs', 'Var', (42, 46))	('ERCC1', 'Gene', (36, 41))
58443	25191856	Although the link between platinum-based chemotherapeutics and ERCC1 is debatable, the predictive aspect of assessing ERCC1 polymorphisms is attractive for assessing risk of cancer development in esophageal cancer due to the high latency of detection and resulting poor outcomes in this disease.	('cancer', 'Disease', 'MESH:D009369', (207, 213))	('ERCC1', 'Gene', '2067', (63, 68))	('ERCC1', 'Gene', (63, 68))	('esophageal cancer', 'Disease', 'MESH:D004938', (196, 213))	('cancer', 'Disease', (207, 213))	('cancer', 'Disease', (174, 180))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('platinum', 'Chemical', 'MESH:D010984', (26, 34))	('polymorphisms', 'Var', (124, 137))	('ERCC1', 'Gene', '2067', (118, 123))	('ERCC1', 'Gene', (118, 123))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('esophageal cancer', 'Disease', (196, 213))
58475	25191856	In brief, allelic frequencies of C8092A and C118T polymorphisms were entered into a software calculator based on the equation, p2+2pq+q2 = 1, where p represents the major allele, q the minor allele, and pq the heterozygous condition.	('C8092A', 'Var', (33, 39))	('C8092A', 'Mutation', 'rs3212986', (33, 39))	('C118T', 'Mutation', 'rs11615', (44, 49))	('C118T', 'Var', (44, 49))
58488	25191856	For ERCC1 polymorphism C8092A, approximately 40% of patients were homozygous for the major allele (CC = 40.7%) or heterozygous (CA = 41.7%) while only 17.6% were homozygous for the recessive allele (AA).	('ERCC1', 'Gene', '2067', (4, 9))	('ERCC1', 'Gene', (4, 9))	('C8092A', 'Var', (23, 29))	('C8092A', 'Mutation', 'rs3212986', (23, 29))	('patients', 'Species', '9606', (52, 60))
58491	25191856	No significant relationship was identified between ERCC1 staining and allelic distribution of SNP C8092A (P = 0.56) (Table 2).	('C8092A', 'Mutation', 'rs3212986', (98, 104))	('SNP', 'Gene', (94, 97))	('ERCC1', 'Gene', '2067', (51, 56))	('C8092A', 'Var', (98, 104))	('ERCC1', 'Gene', (51, 56))
58496	25191856	Ultimately, statistical analysis revealed no significant association between ERCC1 status and allelic distribution for polymorphism C118T (P = 0.37) (Table 2).	('ERCC1', 'Gene', (77, 82))	('ERCC1', 'Gene', '2067', (77, 82))	('C118T', 'Var', (132, 137))	('C118T', 'Mutation', 'rs11615', (132, 137))
58497	25191856	Unlike ERCC1 histological classification, genotype analysis for the C8092A polymorphism exhibited a significant association with patient outcomes and overall and progression-free (PFS) survival.	('C8092A', 'Mutation', 'rs3212986', (68, 74))	('patient outcomes', 'CPA', (129, 145))	('ERCC1', 'Gene', (7, 12))	('ERCC1', 'Gene', '2067', (7, 12))	('C8092A', 'Var', (68, 74))	('progression-free', 'CPA', (162, 178))	('patient', 'Species', '9606', (129, 136))
58500	25191856	There was also no significant trend observed for SNP allele variations of C118T concerning association with overall survival (P = 0.78) or PFS (chi-square  = 0.15, P = 0.93).	('PFS', 'Disease', (139, 142))	('overall survival', 'CPA', (108, 124))	('C118T', 'Mutation', 'rs11615', (74, 79))	('C118T', 'Var', (74, 79))
58501	25191856	Kaplan-Meier survival curves for C8092A are illustrated in Figure 6A & B, and C118T in Figure 6C & D. Platinum-based chemotherapeutics target and damage DNA, advancing cell death of affected tumorigenic, as well as normal cells.	('DNA', 'PosReg', (153, 156))	('and', 'Var', (74, 77))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('C8092A', 'Var', (33, 39))	('C8092A', 'Mutation', 'rs3212986', (33, 39))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('tumor', 'Disease', (191, 196))	('Platinum', 'Chemical', 'MESH:D010984', (102, 110))	('C118T', 'Mutation', 'rs11615', (78, 83))
58504	25191856	Polymorphisms in ERCC1 gene affect mRNA expression and have received much attention as potential predictors of cisplatin and platinum adjuvant therapy outcome, and patient prognosis in lung cancer, melanoma, bladder cancer, in addition to esophageal cancer.	('bladder cancer', 'Disease', 'MESH:D001749', (208, 222))	('bladder cancer', 'Disease', (208, 222))	('mRNA expression', 'MPA', (35, 50))	('bladder cancer', 'Phenotype', 'HP:0009725', (208, 222))	('affect', 'Reg', (28, 34))	('lung cancer', 'Disease', 'MESH:D008175', (185, 196))	('cisplatin', 'Chemical', 'MESH:D002945', (111, 120))	('ERCC1', 'Gene', '2067', (17, 22))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('Polymorphisms', 'Var', (0, 13))	('melanoma', 'Phenotype', 'HP:0002861', (198, 206))	('melanoma', 'Disease', (198, 206))	('lung cancer', 'Phenotype', 'HP:0100526', (185, 196))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('esophageal cancer', 'Disease', 'MESH:D004938', (239, 256))	('ERCC1', 'Gene', (17, 22))	('patient', 'Species', '9606', (164, 171))	('esophageal cancer', 'Disease', (239, 256))	('platinum', 'Chemical', 'MESH:D010984', (125, 133))	('melanoma', 'Disease', 'MESH:D008545', (198, 206))	('lung cancer', 'Disease', (185, 196))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))
58515	25191856	Contrary to what we observed for ERCC1 H-score classification and adjuvant therapy, some polymorphic ERCC1 influence on overall patient survival was identified.	('polymorphic', 'Var', (89, 100))	('ERCC1', 'Gene', '2067', (101, 106))	('ERCC1', 'Gene', (101, 106))	('ERCC1', 'Gene', '2067', (33, 38))	('ERCC1', 'Gene', (33, 38))	('patient', 'Species', '9606', (128, 135))	('influence', 'Reg', (107, 116))
58516	25191856	Two commonly studied ERCC1 SNPs occur at loci C8092A and C118T, and both have been suggested to predict treatment response or patient outcome in esophageal cancer.	('ERCC1', 'Gene', (21, 26))	('C8092A', 'Var', (46, 52))	('ERCC1', 'Gene', '2067', (21, 26))	('patient', 'Species', '9606', (126, 133))	('C118T', 'Var', (57, 62))	('esophageal cancer', 'Disease', (145, 162))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('C8092A', 'Mutation', 'rs3212986', (46, 52))	('esophageal cancer', 'Disease', 'MESH:D004938', (145, 162))	('C118T', 'Mutation', 'rs11615', (57, 62))	('predict', 'Reg', (96, 103))
58517	25191856	Of the two, the C8092A SNP showed a significant association with overall and progression-free patient survival.	('C8092A', 'Var', (16, 22))	('progression-free patient survival', 'CPA', (77, 110))	('patient', 'Species', '9606', (94, 101))	('C8092A', 'Mutation', 'rs3212986', (16, 22))	('overall', 'CPA', (65, 72))
58518	25191856	It is documented that polymorphisms that disrupt DNA base repair increase risk of ESCC.	('SCC', 'Gene', (83, 86))	('SCC', 'Gene', '6317', (83, 86))	('polymorphisms', 'Var', (22, 35))
58519	25191856	In our study, the C   A mutation at ERCC1 residue 8092 appears to diminish overall survival and PFS, which is reasonable if this mutation is associated with increased risk of ESCC development.	('ERCC1', 'Gene', '2067', (36, 41))	('C   A mutation at', 'Var', (18, 35))	('PFS', 'CPA', (96, 99))	('SCC', 'Gene', (176, 179))	('overall survival', 'CPA', (75, 91))	('ERCC1', 'Gene', (36, 41))	('SCC', 'Gene', '6317', (176, 179))	('diminish', 'NegReg', (66, 74))
58522	25191856	Upon review of the literature, many recent studies investigating polymorphic variations in ERCC1 and the predictive potential for patient and platinum-based treatment effects take place in Europe or the United States where ESCC is far less common than esophageal adenocarcinoma.	('patient', 'Species', '9606', (130, 137))	('platinum', 'Chemical', 'MESH:D010984', (142, 150))	('SCC', 'Gene', (224, 227))	('esophageal adenocarcinoma', 'Disease', (252, 277))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (252, 277))	('polymorphic variations', 'Var', (65, 87))	('SCC', 'Gene', '6317', (224, 227))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (252, 277))	('ERCC1', 'Gene', (91, 96))	('ERCC1', 'Gene', '2067', (91, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (268, 277))
58526	25191856	One recent study explored ERCC1-C8092A polymorphic predictive value of ESCC susceptibility in North Xinjiang, China.	('polymorphic', 'Var', (39, 50))	('SCC', 'Gene', (72, 75))	('C8092A', 'Mutation', 'rs3212986', (32, 38))	('SCC', 'Gene', '6317', (72, 75))	('ERCC1', 'Gene', '2067', (26, 31))	('ERCC1', 'Gene', (26, 31))
58529	25191856	Here, when all three allelic combinations were statistically compared, those with the AA genotype showed a trend in reduced overall survival, and when two homozygous allelic combinations (AA vs. CC) were compared there was a clear significant influence on survival, with patients homozygous for the mutant allele (AA) exhibiting reduced overall survival than those homozygous for the dominant allele, CC (P = 0.07, Hazard Ratio  = 4.496, 95%CI  = 1.507 to 13.42).	('overall survival', 'MPA', (337, 353))	('mutant', 'Var', (299, 305))	('overall', 'MPA', (124, 131))	('patients', 'Species', '9606', (271, 279))	('reduced', 'NegReg', (329, 336))	('reduced', 'NegReg', (116, 123))
58531	25191856	Similar to our findings, the recessive mutant allele (A) in their study was directly related to overall patient survival in both the homozygous mutant (AA) and heterozygous (CA) genotypes.	('mutant', 'Var', (144, 150))	('related to', 'Reg', (85, 95))	('patient', 'Species', '9606', (104, 111))
58533	25191856	As such, the C   A mutation decreases overall survival in our study patient population, but actual ERCC1 expression level within analyzed tumor tissue was not associated with any genotypic variation at this loci.	('decreases', 'NegReg', (28, 37))	('mutation', 'Var', (19, 27))	('ERCC1', 'Gene', '2067', (99, 104))	('tumor', 'Disease', (138, 143))	('patient', 'Species', '9606', (68, 75))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('overall survival', 'MPA', (38, 54))	('C   A mutation', 'Var', (13, 27))	('ERCC1', 'Gene', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
58546	25191856	In line with these findings, Yang and Xian performed a meta-analysis on clinical studies of various ERCC1 SNPs including C118T in non-small cell lung cancer and found overall reduced survival in ERCC1+ patients, as well as reduced sensitivity to platinum-based chemotherapy.	('C118T', 'Var', (121, 126))	('ERCC1', 'Gene', (195, 200))	('reduced', 'NegReg', (175, 182))	('survival', 'MPA', (183, 191))	('ERCC1', 'Gene', '2067', (195, 200))	('reduced', 'NegReg', (223, 230))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (130, 156))	('ERCC1', 'Gene', '2067', (100, 105))	('ERCC1', 'Gene', (100, 105))	('platinum', 'Chemical', 'MESH:D010984', (246, 254))	('patients', 'Species', '9606', (202, 210))	('C118T', 'Mutation', 'rs11615', (121, 126))	('non-small cell lung cancer', 'Disease', (130, 156))	('lung cancer', 'Phenotype', 'HP:0100526', (145, 156))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (134, 156))	('sensitivity', 'MPA', (231, 242))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (130, 156))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
58548	25191856	To our knowledge this is the first clinical analysis of ERCC1 expression and polymorphic variation in esophageal cancer patients in Fujian Province.	('esophageal cancer', 'Disease', 'MESH:D004938', (102, 119))	('ERCC1', 'Gene', '2067', (56, 61))	('ERCC1', 'Gene', (56, 61))	('polymorphic variation', 'Var', (77, 98))	('patients', 'Species', '9606', (120, 128))	('esophageal cancer', 'Disease', (102, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
58549	25191856	Only two other studies from this province have involved examination of ERCC1 polymorphisms and cancer, however these were focused on colorectal and liver cancer.	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('polymorphisms', 'Var', (77, 90))	('cancer', 'Disease', (95, 101))	('cancer', 'Disease', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('liver cancer', 'Phenotype', 'HP:0002896', (148, 160))	('colorectal and liver cancer', 'Disease', 'MESH:D015179', (133, 160))	('ERCC1', 'Gene', (71, 76))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('ERCC1', 'Gene', '2067', (71, 76))
58551	25191856	Few studies have targeted tumor cell-specific expression of ERCC1 as a potential correlate for the progression of squamous cell carcinoma of the esophagus, and our findings yield interesting potential associations between ERCC1 SNP C8092A and survival of patients with this disease.	('SNP C8092A', 'Var', (228, 238))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (114, 137))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('C8092A', 'Var', (232, 238))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('squamous cell carcinoma of the esophagus', 'Disease', (114, 154))	('associations', 'Interaction', (201, 213))	('patients', 'Species', '9606', (255, 263))	('tumor', 'Disease', (26, 31))	('C8092A', 'Mutation', 'rs3212986', (232, 238))	('squamous cell carcinoma of the esophagus', 'Disease', 'MESH:D002294', (114, 154))	('ERCC1', 'Gene', '2067', (222, 227))	('ERCC1', 'Gene', (222, 227))	('carcinoma of the esophagus', 'Phenotype', 'HP:0011459', (128, 154))	('ERCC1', 'Gene', '2067', (60, 65))	('ERCC1', 'Gene', (60, 65))
58552	25191856	This might prove valuable for assessment of other allelic variations or SNPs of ERCC1 in regards to treatment response and survival outcomes in this form of the disease.	('ERCC1', 'Gene', '2067', (80, 85))	('ERCC1', 'Gene', (80, 85))	('SNPs', 'Var', (72, 76))
58554	25191856	This is the first study to investigate this regional population of Chinese with ESCC, and linked ERCC1 polymorphism to esophageal carcinoma in these patients that impacted overall survival.	('SCC', 'Gene', '6317', (81, 84))	('patients', 'Species', '9606', (149, 157))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (119, 139))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (119, 139))	('polymorphism', 'Var', (103, 115))	('ERCC1', 'Gene', (97, 102))	('impacted', 'Reg', (163, 171))	('ERCC1', 'Gene', '2067', (97, 102))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('SCC', 'Gene', (81, 84))	('esophageal carcinoma', 'Disease', (119, 139))
58558	32556556	p16 overexpression is also known to be induced by deregulation of RB1 in neuroendocrine carcinomas.	('neuroendocrine carcinomas', 'Disease', 'MESH:D018278', (73, 98))	('neuroendocrine carcinomas', 'Disease', (73, 98))	('neuroendocrine carcinomas', 'Phenotype', 'HP:0100634', (73, 98))	('p16', 'Gene', (0, 3))	('RB1', 'Gene', '5925', (66, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('carcinomas', 'Phenotype', 'HP:0030731', (88, 98))	('overexpression', 'PosReg', (4, 18))	('deregulation', 'Var', (50, 62))	('p16', 'Gene', '1029', (0, 3))	('RB1', 'Gene', (66, 69))
58573	32556556	In general, CDKN2A is frequently inactivated in human malignant tumors by its gene aberrations, such as deletions or mutations, but diffuse p16 expression was also reported in various human malignancies, e.g., high-grade breast and lung cancers and/or undifferentiated pleomorphic sarcoma without significant association with its gene alteration status.	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('CDKN2A', 'Gene', (12, 18))	('malignant tumors', 'Disease', 'MESH:D009369', (54, 70))	('reported', 'Reg', (164, 172))	('p16', 'Gene', (140, 143))	('human', 'Species', '9606', (184, 189))	('p16', 'Gene', '1029', (140, 143))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('lung cancer', 'Phenotype', 'HP:0100526', (232, 243))	('human', 'Species', '9606', (48, 53))	('CDKN2A', 'Gene', '1029', (12, 18))	('cancers', 'Phenotype', 'HP:0002664', (237, 244))	('malignancies', 'Disease', 'MESH:D009369', (190, 202))	('malignancies', 'Disease', (190, 202))	('mutations', 'Var', (117, 126))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('lung cancers', 'Phenotype', 'HP:0100526', (232, 244))	('undifferentiated pleomorphic sarcoma', 'Disease', 'MESH:D002277', (252, 288))	('breast and lung cancers', 'Disease', 'MESH:D001943', (221, 244))	('deletions', 'Var', (104, 113))	('undifferentiated pleomorphic sarcoma', 'Disease', (252, 288))	('malignant tumors', 'Disease', (54, 70))	('sarcoma', 'Phenotype', 'HP:0100242', (281, 288))
58574	32556556	In these neoplasms, p16 was reported to be induced by deregulation of RB1 as positive feedback.	('RB1', 'Gene', (70, 73))	('p16', 'Gene', (20, 23))	('neoplasms', 'Disease', (9, 18))	('deregulation', 'Var', (54, 66))	('neoplasms', 'Disease', 'MESH:D009369', (9, 18))	('RB1', 'Gene', '5925', (70, 73))	('p16', 'Gene', '1029', (20, 23))	('neoplasms', 'Phenotype', 'HP:0002664', (9, 18))
58575	32556556	The p16 overexpression via RB1 alteration was on the one hand demonstrated in highly aggressive tumors, such as small-cell carcinomas of the lung and esophagus.	('overexpression', 'PosReg', (8, 22))	('small-cell carcinomas of the lung', 'Disease', 'MESH:D055752', (112, 145))	('small-cell carcinomas of the lung', 'Phenotype', 'HP:0030357', (112, 145))	('RB1', 'Gene', '5925', (27, 30))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('p16', 'Gene', '1029', (4, 7))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('p16', 'Gene', (4, 7))	('carcinomas', 'Phenotype', 'HP:0030731', (123, 133))	('aggressive tumors', 'Disease', 'MESH:D001523', (85, 102))	('carcinomas of the lung', 'Phenotype', 'HP:0100526', (123, 145))	('alteration', 'Var', (31, 41))	('esophagus', 'Disease', (150, 159))	('aggressive tumors', 'Disease', (85, 102))	('small-cell carcinoma', 'Phenotype', 'HP:0030357', (112, 132))	('small-cell carcinomas of the lung', 'Disease', (112, 145))	('RB1', 'Gene', (27, 30))
58595	32556556	Tumors with the following conditions were excluded: (i) located at the esophagogastric junction or concomitant Barrett's esophagus and (ii) eradication of more than two thirds of the tumor with preoperative therapy.	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (111, 130))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('tumor', 'Disease', (183, 188))	('eradication', 'Var', (140, 151))
58652	32556556	CDKN2A was inactivated mostly by deletion (44-72%), occasionally by mutation (2-8%).	('inactivated', 'NegReg', (11, 22))	('deletion', 'Var', (33, 41))	('CDKN2A', 'Gene', '1029', (0, 6))	('CDKN2A', 'Gene', (0, 6))
58653	32556556	CDKN2A DNA hypermethylation could also contribute to its inactivation, and the aberrant methylation of 5' CpG islands of the CDKN2A promoter region leads to repression of its gene transcription.	('methylation', 'Var', (88, 99))	('gene transcription', 'MPA', (175, 193))	('repression', 'NegReg', (157, 167))	('inactivation', 'MPA', (57, 69))	('aberrant methylation', 'Var', (79, 99))	('CDKN2A', 'Gene', (125, 131))	('CDKN2A', 'Gene', (0, 6))	('CDKN2A', 'Gene', '1029', (125, 131))	('CDKN2A', 'Gene', '1029', (0, 6))
58658	32556556	Although the frequency of inactivation of p16 in basaloid squamous cell carcinomas has not been fully studied at this juncture, an inactivation of the p16 gene might correlate with high-grade neoplasms.	('p16', 'Gene', '1029', (42, 45))	('inactivation', 'Var', (26, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (58, 82))	('squamous cell carcinomas', 'Disease', (58, 82))	('neoplasms', 'Disease', (192, 201))	('neoplasms', 'Disease', 'MESH:D009369', (192, 201))	('basaloid squamous cell carcinomas', 'Phenotype', 'HP:0002671', (49, 82))	('p16', 'Gene', '1029', (151, 154))	('carcinomas', 'Phenotype', 'HP:0030731', (72, 82))	('p16', 'Gene', (151, 154))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (58, 82))	('p16', 'Gene', (42, 45))	('inactivation', 'Var', (131, 143))	('neoplasms', 'Phenotype', 'HP:0002664', (192, 201))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (58, 81))	('correlate', 'Reg', (166, 175))	('basaloid squamous cell carcinoma', 'Phenotype', 'HP:0002671', (49, 81))
58659	32556556	Whether p16 immunoreactivity can serve as a predictive marker for genetic or epigenetic inactivation of CDKN2A gene is controversial, and further investigations are required for clarification at this juncture.	('CDKN2A', 'Gene', '1029', (104, 110))	('p16', 'Gene', '1029', (8, 11))	('p16', 'Gene', (8, 11))	('CDKN2A', 'Gene', (104, 110))	('epigenetic inactivation', 'Var', (77, 100))
58662	32556556	The p16 overexpression is considered as positive feedback by deregulation of RB1.	('p16', 'Gene', (4, 7))	('RB1', 'Gene', (77, 80))	('RB1', 'Gene', '5925', (77, 80))	('p16', 'Gene', '1029', (4, 7))	('deregulation', 'Var', (61, 73))
58663	32556556	An inactivation of RB1 was reported to play a pivotal role in carcinogenesis of neuroendocrine carcinomas, and Rb1 protein loss was proposed to be a characteristic in gastroenteropancreatic and pulmonary neuroendocrine carcinomas.	('Rb1', 'Gene', (111, 114))	('gastroenteropancreatic and pulmonary neuroendocrine carcinomas', 'Disease', 'MESH:C535650', (167, 229))	('neuroendocrine carcinomas', 'Phenotype', 'HP:0100634', (80, 105))	('inactivation', 'Var', (3, 15))	('carcinogenesis of neuroendocrine carcinomas', 'Disease', (62, 105))	('protein', 'Protein', (115, 122))	('carcinogenesis of neuroendocrine carcinomas', 'Disease', 'MESH:D063646', (62, 105))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('RB1', 'Gene', (19, 22))	('loss', 'NegReg', (123, 127))	('neuroendocrine carcinomas', 'Phenotype', 'HP:0100634', (204, 229))	('Rb1', 'Gene', '5925', (111, 114))	('carcinomas', 'Phenotype', 'HP:0030731', (95, 105))	('carcinoma', 'Phenotype', 'HP:0030731', (219, 228))	('carcinomas', 'Phenotype', 'HP:0030731', (219, 229))	('RB1', 'Gene', '5925', (19, 22))
58664	32556556	In small-cell lung cancer, the mechanism has been shown that at least one allele of RB1 was affected by different genomic alterations (i.e., hemizygous deletion, loss of heterozygosity, or mutation, including rearrangements).	('affected', 'Reg', (92, 100))	('small-cell lung cancer', 'Disease', (3, 25))	('small-cell lung cancer', 'Disease', 'MESH:D055752', (3, 25))	('loss of heterozygosity', 'Var', (162, 184))	('RB1', 'Gene', (84, 87))	('lung cancer', 'Phenotype', 'HP:0100526', (14, 25))	('mutation', 'Var', (189, 197))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('RB1', 'Gene', '5925', (84, 87))	('rearrangements', 'Var', (209, 223))
58670	32556556	However, in this study, p16 positivity in high-grade squamous cell carcinoma was not associated with tumor size, TNM stage, and patients' clinical outcome.	('p16', 'Gene', '1029', (24, 27))	('TNM', 'Gene', (113, 116))	('positivity', 'Var', (28, 38))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('p16', 'Gene', (24, 27))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (53, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('squamous cell carcinoma', 'Disease', (53, 76))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (53, 76))	('patients', 'Species', '9606', (128, 136))	('TNM', 'Gene', '10178', (113, 116))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
58672	32556556	Interestingly, the p16 overexpression induced by dysregulation of RB1 appeared to have an association with tumor aggressiveness in high-grade squamous cell carcinoma.	('association', 'Reg', (90, 101))	('p16', 'Gene', (19, 22))	('overexpression', 'PosReg', (23, 37))	('carcinoma', 'Phenotype', 'HP:0030731', (156, 165))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (142, 165))	('aggressiveness', 'Phenotype', 'HP:0000718', (113, 127))	('squamous cell carcinoma', 'Disease', (142, 165))	('RB1', 'Gene', '5925', (66, 69))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (142, 165))	('tumor aggressiveness', 'Disease', (107, 127))	('p16', 'Gene', '1029', (19, 22))	('dysregulation', 'Var', (49, 62))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (107, 127))	('RB1', 'Gene', (66, 69))
58680	32556556	However, p16 can be induced by dysregulation of the RB1 pathway without HPV infection.	('RB1', 'Gene', (52, 55))	('HPV infection', 'Disease', 'MESH:D030361', (72, 85))	('induced by', 'Reg', (20, 30))	('p16', 'Gene', '1029', (9, 12))	('RB1', 'Gene', '5925', (52, 55))	('dysregulation', 'Var', (31, 44))	('HPV infection', 'Disease', (72, 85))	('p16', 'Gene', (9, 12))
58700	33485341	EGFR-dependent human and murine HNSCC cell lines were treated with the EGFR/ERBB inhibitors, gefitinib and AZD8931, and submitted to RNAseq, GSEA, and qRT-PCR.	('GSEA', 'Chemical', '-', (141, 145))	('EGFR/ERBB', 'Gene', (71, 80))	('gefitinib', 'Chemical', 'MESH:D000077156', (93, 102))	('AZD8931', 'Chemical', 'MESH:C548875', (107, 114))	('AZD8931', 'Var', (107, 114))	('SCC', 'CellLine', 'CVCL:1R13', (34, 37))
58705	33485341	Similarly, AZD8931 exerted potent growth inhibition, IFNalpha/IFNgamma pathway activation, and CXCL10 induction in murine B4B8 HNSCC cells.	('AZD8931', 'Chemical', 'MESH:C548875', (11, 18))	('IFNalpha', 'Chemical', '-', (53, 61))	('AZD8931', 'Var', (11, 18))	('IFNalpha/IFNgamma pathway', 'Pathway', (53, 78))	('growth inhibition', 'CPA', (34, 51))	('activation', 'PosReg', (79, 89))	('CXCL10 induction', 'MPA', (95, 111))	('B4B8 HNSCC', 'CellLine', 'CVCL:0B35', (122, 132))
58713	33485341	Distinct from lung adenocarcinoma, the HNSCC genomic landscape has not unveiled gain-of-function mutations or gene amplification events that serve as biomarkers of clinical activity of cetuximab, either alone or when combined with chemotherapy or radiotherapy.	('mutations', 'Var', (97, 106))	('lung adenocarcinoma', 'Disease', (14, 33))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (14, 33))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (14, 33))	('cetuximab', 'Chemical', 'MESH:D000068818', (185, 194))	('carcinoma', 'Phenotype', 'HP:0030731', (24, 33))	('SCC', 'CellLine', 'CVCL:1R13', (41, 44))	('gain-of-function', 'PosReg', (80, 96))
58714	33485341	The mechanisms accounting for the broad range of clinical response to EGFR-targeted inhibitors in HNSCC patients remain largely unknown and this knowledge gap represents a significant hurdle to their deployment as precision oncology agents.	('inhibitors', 'Var', (84, 94))	('oncology', 'Phenotype', 'HP:0002664', (224, 232))	('HNSCC', 'Disease', (98, 103))	('EGFR-targeted', 'Gene', (70, 83))	('SCC', 'CellLine', 'CVCL:1R13', (100, 103))
58717	33485341	The literature also demonstrates the ability of EGFR inhibitors to increase MHC expression and antigen presentation on tumor cells.	('inhibitors', 'Var', (53, 63))	('tumor', 'Disease', (119, 124))	('increase MHC expression', 'Phenotype', 'HP:0031391', (67, 90))	('MHC', 'Protein', (76, 79))	('EGFR', 'Gene', (48, 52))	('increase', 'PosReg', (67, 75))	('increase MHC', 'Phenotype', 'HP:0025548', (67, 79))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('antigen presentation', 'MPA', (95, 115))
58719	33485341	Combined, this literature supports the idea that EGFR/ERBB inhibition promotes the participation of the tumor immune microenvironment via induction of an interferon response program.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumor', 'Disease', (104, 109))	('inhibition', 'Var', (59, 69))	('promotes', 'PosReg', (70, 78))	('EGFR/ERBB', 'Gene', (49, 58))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
58722	33485341	Still, even within oncogene-defined subsets of lung cancers driven by mutant EGFR or ALK, the individual responses to targeted TKIs ranges widely.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('driven by', 'Reg', (60, 69))	('lung cancer', 'Phenotype', 'HP:0100526', (47, 58))	('ALK', 'Gene', (85, 88))	('mutant', 'Var', (70, 76))	('lung cancers', 'Disease', 'MESH:D008175', (47, 59))	('lung cancers', 'Phenotype', 'HP:0100526', (47, 59))	('lung cancers', 'Disease', (47, 59))	('EGFR', 'Gene', (77, 81))	('cancers', 'Phenotype', 'HP:0002664', (52, 59))
58724	33485341	Thus, a deeper understanding of the biology underlying variation in response may unveil novel means to deepen tumor shrinkage responses with rational combinations of therapeutics.	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('deepen tumor', 'Disease', 'MESH:D009369', (103, 115))	('variation', 'Var', (55, 64))	('deepen tumor', 'Disease', (103, 115))
58765	33485341	Notably, none of the members of the interferon family of factors was induced at the mRNA levels in these cell lines, indicating that the mechanism by which gefitinib induced the IFNalpha and IFNgamma pathways did not involve activation of IFN receptors through autocrine IFNs.	('induced', 'PosReg', (166, 173))	('IFNalpha', 'Chemical', '-', (178, 186))	('gefitinib', 'Chemical', 'MESH:D000077156', (156, 165))	('gefitinib', 'Var', (156, 165))
58769	33485341	The levels of mRNAs for CXCL10, CCL28 and C3 were more highly induced by gefitinib in UMSCC8 cells while IL6, CCL5 and TGFbeta2 mRNAs were more strongly regulated in UMSCC25 (Additional file 1: Fig.	('levels', 'MPA', (4, 10))	('induced', 'PosReg', (62, 69))	('mRNAs', 'MPA', (14, 19))	('gefitinib', 'Chemical', 'MESH:D000077156', (73, 82))	('SCC', 'CellLine', 'CVCL:1R13', (168, 171))	('SCC', 'CellLine', 'CVCL:1R13', (88, 91))	('CCL28', 'MPA', (32, 37))	('gefitinib', 'Var', (73, 82))	('CXCL10', 'MPA', (24, 30))
58771	33485341	CXCL10 protein was strongly induced by the pan-ERBB inhibitor, AZD8931, and the MEK inhibitor, trametinib, in UMSCC8 cells relative to UMSCC25 cells.	('trametinib', 'Chemical', 'MESH:C560077', (95, 105))	('induced', 'PosReg', (28, 35))	('SCC', 'CellLine', 'CVCL:1R13', (137, 140))	('AZD8931', 'Chemical', 'MESH:C548875', (63, 70))	('AZD8931', 'Var', (63, 70))	('SCC', 'CellLine', 'CVCL:1R13', (112, 115))	('CXCL10 protein', 'MPA', (0, 14))
58774	33485341	In addition to UMSCC8, Cal27 cells exhibited marked induction of CXCL10 protein in response to AZD8931 while HN6, HN12, JHU-011 and UMSCC25 showed more modest induction, and HN31 cells exhibited little or no CXCL10 induction.	('CXCL10 protein', 'MPA', (65, 79))	('AZD8931', 'Var', (95, 102))	('AZD8931', 'Chemical', 'MESH:C548875', (95, 102))	('induction', 'PosReg', (52, 61))	('SCC', 'CellLine', 'CVCL:1R13', (134, 137))	('SCC', 'CellLine', 'CVCL:1R13', (17, 20))
58775	33485341	By contrast, IL6 was induced by AZD8931 in UMSCC25 and Cal27 cells.	('IL6', 'Disease', (13, 16))	('AZD8931', 'Chemical', 'MESH:C548875', (32, 39))	('induced', 'Reg', (21, 28))	('AZD8931', 'Var', (32, 39))	('SCC', 'CellLine', 'CVCL:1R13', (45, 48))
58777	33485341	For example, CCL5 and CSF1 are induced by AZD8931 in all three cell lines while CXCL2 is induced only in Cal27 and UMSCC25 and CXCL6 is induced only in Cal27 and UMSCC8 cells.	('SCC', 'CellLine', 'CVCL:1R13', (117, 120))	('AZD8931', 'Chemical', 'MESH:C548875', (42, 49))	('SCC', 'CellLine', 'CVCL:1R13', (164, 167))	('AZD8931', 'Var', (42, 49))	('CCL5', 'Disease', (13, 17))	('CSF1', 'Disease', (22, 26))	('induced', 'Reg', (31, 38))	('CXCL2', 'MPA', (80, 85))
58784	33485341	3a, treatment with AZD8931 rapidly halts B4B8 tumor progression and causes significant shrinkage of tumors (Fig.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('AZD8931', 'Var', (19, 26))	('B4B8', 'Gene', (41, 45))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Disease', (100, 105))	('shrinkage', 'NegReg', (87, 96))	('tumor', 'Disease', (46, 51))	('tumors', 'Disease', (100, 106))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('AZD8931', 'Chemical', 'MESH:C548875', (19, 26))	('halts', 'NegReg', (35, 40))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
58795	33485341	To determine if B4B8 tumors treated in vivo with AZD8931 show changes in IFN pathway activity, tumor-bearing mice were sacrificed after 3, 7, and 14 days of treatment, RNA was isolated and submitted to RNAseq.	('AZD8931', 'Chemical', 'MESH:C548875', (49, 56))	('tumor', 'Disease', (21, 26))	('tumor', 'Disease', (95, 100))	('tumors', 'Disease', (21, 27))	('tumors', 'Disease', 'MESH:D009369', (21, 27))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('changes', 'Reg', (62, 69))	('AZD8931', 'Var', (49, 56))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('activity', 'MPA', (85, 93))	('IFN pathway', 'Pathway', (73, 84))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
58805	33485341	S5B) is reduced by ruxolitinib and IKK16 while IL6, TGFB2 and CCL5 mRNA induction are reduced only by IKK16.	('IL6', 'Gene', (47, 50))	('reduced', 'NegReg', (8, 15))	('TGFB2', 'Gene', (52, 57))	('IKK16', 'Var', (35, 40))	('ruxolitinib', 'Chemical', 'MESH:C540383', (19, 30))
58806	33485341	Similar to UMSCC25 cells, AZD8931 induced CXCL10 protein in murine B4B8 HNSCC cells was blocked by both ruxolitinib and IKK16 (Additional file 1: Fig.	('AZD8931', 'Var', (26, 33))	('ruxolitinib', 'Chemical', 'MESH:C540383', (104, 115))	('B4B8 HNSCC', 'CellLine', 'CVCL:0B35', (67, 77))	('AZD8931', 'Chemical', 'MESH:C548875', (26, 33))	('SCC', 'CellLine', 'CVCL:1R13', (74, 77))	('SCC', 'CellLine', 'CVCL:1R13', (13, 16))	('CXCL10 protein', 'MPA', (42, 56))
58807	33485341	S5D) where IKK16, but not ruxolitinib, reduced AZD8931-induced reporter activity.	('IKK16', 'Var', (11, 16))	('AZD8931-induced reporter activity', 'MPA', (47, 80))	('AZD8931', 'Chemical', 'MESH:C548875', (47, 54))	('reduced', 'NegReg', (39, 46))	('ruxolitinib', 'Chemical', 'MESH:C540383', (26, 37))
58810	33485341	To explore changes in immune cell content within murine HNSCC tumors, B4B8 tumors treated for 3, 7 and 14 days with AZD8931 were stained for CD3e and either CD4 or CD8alpha by immunofluorescence.	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('AZD8931', 'Var', (116, 123))	('CD3e', 'Protein', (141, 145))	('tumors', 'Disease', (62, 68))	('tumors', 'Disease', 'MESH:D009369', (62, 68))	('CD8alpha', 'Protein', (164, 172))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('tumors', 'Disease', (75, 81))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('AZD8931', 'Chemical', 'MESH:C548875', (116, 123))	('HNSCC tumors', 'Disease', (56, 68))	('CD4', 'Protein', (157, 160))	('HNSCC tumors', 'Disease', 'MESH:D000077195', (56, 68))
58811	33485341	CD3 + cells were significantly increased at all times following AZD8931 treatment (Fig.	('AZD8931', 'Chemical', 'MESH:C548875', (64, 71))	('AZD8931', 'Var', (64, 71))	('increased', 'PosReg', (31, 40))
58822	33485341	While numbers of CD14 + and CD19 + cells did not change between pre- and post-cetuximab treated samples regardless of responder status, the pre-treated biopsies of the non-responder patients exhibited significantly greater number of CD19 + B cells compared to responders (Fig.	('cetuximab', 'Chemical', 'MESH:D000068818', (78, 87))	('CD19 +', 'Var', (233, 239))	('greater', 'PosReg', (215, 222))
58832	33485341	showed that EGFR inhibition can augment expression of CIITA and antigen presenting machinery (APC).	('expression', 'MPA', (40, 50))	('antigen presenting machinery', 'MPA', (64, 92))	('inhibition', 'Var', (17, 27))	('EGFR', 'Protein', (12, 16))	('augment', 'PosReg', (32, 39))	('APC', 'Disease', 'MESH:D011125', (94, 97))	('APC', 'Disease', (94, 97))
58834	33485341	Likewise, treatment of murine B4B8 HNSCC cells with AZD8931 induced classic MHC class I and II genes (Additional file 1: Fig.	('induced', 'PosReg', (60, 67))	('AZD8931', 'Var', (52, 59))	('AZD8931', 'Chemical', 'MESH:C548875', (52, 59))	('B4B8 HNSCC', 'CellLine', 'CVCL:0B35', (30, 40))
58838	33485341	While we did not explore the induction of the IFN program by combinations of EGFR/ERBB inhibitors and IFNgamma or TNFalpha, it is likely that additive or synergistic activation of this pathway occurs and may more fully capture the response to oncogene inhibitors observed in vivo where paracrine interactions between tumor cells and immune cells can occur.	('tumor', 'Phenotype', 'HP:0002664', (317, 322))	('tumor', 'Disease', 'MESH:D009369', (317, 322))	('tumor', 'Disease', (317, 322))	('EGFR/ERBB', 'Gene', (77, 86))	('inhibitors', 'Var', (87, 97))	('combinations', 'Interaction', (61, 73))
58839	33485341	Our findings reveal EGFR/ERBB inhibitor-stimulated influx of T cells into orthotopic B4B8 tumors propagated in syngeneic mice and reduced anti-tumor activity of AZD8931 on tumors propagated in immune-deficient mice (Fig.	('tumor', 'Disease', (172, 177))	('tumors', 'Disease', 'MESH:D009369', (90, 96))	('influx', 'PosReg', (51, 57))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('tumors', 'Phenotype', 'HP:0002664', (172, 178))	('tumor', 'Disease', (90, 95))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('tumors', 'Disease', (172, 178))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('EGFR/ERBB', 'Gene', (20, 29))	('AZD8931', 'Chemical', 'MESH:C548875', (161, 168))	('B4B8', 'Gene', (85, 89))	('tumor', 'Disease', (143, 148))	('tumors', 'Disease', 'MESH:D009369', (172, 178))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('AZD8931', 'Var', (161, 168))	('tumors', 'Disease', (90, 96))	('reduced', 'NegReg', (130, 137))	('tumor', 'Disease', 'MESH:D009369', (143, 148))
58841	33485341	reported several published studies that show oncogene-targeted therapies in melanoma and breast cancer can affect the immune tumor microenvironment, where MEK or BRAF inhibitors resulted in production of immune stimulatory cytokines (IFNgamma, TNFalpha, IL12) capable of recruiting and activating anti-tumorigenic T cells, or by reducing immunosuppressive cytokines (IL6 and CCL2) that keep pro-tumorigenic cell types, such as MDSCs, at bay.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (302, 307))	('inhibitors', 'Var', (167, 177))	('reducing', 'NegReg', (329, 337))	('activating', 'PosReg', (286, 296))	('melanoma and breast cancer', 'Disease', 'MESH:D001943', (76, 102))	('tumor', 'Phenotype', 'HP:0002664', (395, 400))	('affect', 'Reg', (107, 113))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('MEK', 'Gene', (155, 158))	('tumor', 'Disease', (302, 307))	('recruiting', 'PosReg', (271, 281))	('tumor', 'Disease', 'MESH:D009369', (302, 307))	('melanoma', 'Phenotype', 'HP:0002861', (76, 84))	('BRAF', 'Gene', (162, 166))	('tumor', 'Disease', (395, 400))	('breast cancer', 'Phenotype', 'HP:0003002', (89, 102))	('tumor', 'Disease', (125, 130))	('tumor', 'Disease', 'MESH:D009369', (395, 400))
58842	33485341	The immunological effects of targeted therapy have also been documented in HNSCCs where inhibition of the mTOR, VEGF, and CDK pathways have been shown to promote anti-tumor immunity, including the recruitment of T cells.	('promote', 'PosReg', (154, 161))	('CDK pathways', 'Pathway', (122, 134))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('VEGF', 'Pathway', (112, 116))	('SCC', 'CellLine', 'CVCL:1R13', (77, 80))	('HNSCCs', 'Disease', (75, 81))	('T cells', 'CPA', (212, 219))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('mTOR', 'Pathway', (106, 110))	('recruitment', 'CPA', (197, 208))	('tumor', 'Disease', (167, 172))	('inhibition', 'Var', (88, 98))
58846	33485341	In agreement with these findings, our study found a significant increase in the number of CD8 + T cells in on-treatment specimens from cetuximab responders, while those that were defined as non-responders did not.	('responders', 'Var', (145, 155))	('cetuximab', 'Chemical', 'MESH:D000068818', (135, 144))	('cetuximab', 'Gene', (135, 144))	('increase', 'PosReg', (64, 72))	('CD8 + T cells', 'CPA', (90, 103))
58850	33485341	Due to cetuximab's documented stimulatory effects on the immune system, there are currently over 20 studies planned or underway to investigate the safety and efficacy of cetuximab immunotherapy combinations, including anti-PD1/PDL1/CTLA-4 (T cell modulation), TLR agonists, anti-NKG2A (NK cell modulation) and recombinant IL12.	('cetuximab', 'Chemical', 'MESH:D000068818', (7, 16))	('anti-PD1/PDL1/CTLA-4', 'Var', (218, 238))	('anti-NKG2A', 'Var', (274, 284))	('cetuximab', 'Chemical', 'MESH:D000068818', (170, 179))	('TLR', 'Gene', (260, 263))
58854	33485341	While the majority of the studies have focused on cetuximab's ability to modulate the immune microenvironment due to the effector function intrinsic to the monoclonal antibody, herein we provide evidence that inhibition of the EGFR/ERBB receptors can contribute to immune stimulatory effects via transcriptional induction of an IFN response.	('cetuximab', 'Chemical', 'MESH:D000068818', (50, 59))	('inhibition', 'Var', (209, 219))	('immune stimulatory effects', 'MPA', (265, 291))	('EGFR/ERBB', 'Gene', (227, 236))	('IFN response', 'MPA', (328, 340))	('transcriptional', 'MPA', (296, 311))
58937	33308216	Identification of LINC02310 as an enhancer in lung adenocarcinoma and investigation of its regulatory network via comprehensive analyses Lung adenocarcinoma (LADC) is a major subtype of non-small cell lung cancer and has one of the highest mortality rates.	('LINC02310', 'Var', (18, 27))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('lung cancer', 'Disease', 'MESH:D008175', (201, 212))	('LADC', 'Phenotype', 'HP:0030078', (158, 162))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (190, 212))	('mortality', 'Disease', 'MESH:D003643', (240, 249))	('lung adenocarcinoma', 'Disease', (46, 65))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (46, 65))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (186, 212))	('Lung adenocarcinoma', 'Phenotype', 'HP:0030078', (137, 156))	('Lung adenocarcinoma', 'Disease', (137, 156))	('Lung adenocarcinoma', 'Disease', 'MESH:D000077192', (137, 156))	('lung cancer', 'Phenotype', 'HP:0100526', (201, 212))	('mortality', 'Disease', (240, 249))	('lung cancer', 'Disease', (201, 212))	('carcinoma', 'Phenotype', 'HP:0030731', (147, 156))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (46, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (56, 65))
58938	33308216	An increasing number of long non-coding RNAs (LncRNAs) were reported to be associated with the occurrence and progression of LADC.	('long non-coding', 'Var', (24, 39))	('si', 'Chemical', 'MESH:D012825', (9, 11))	('LADC', 'Phenotype', 'HP:0030078', (125, 129))	('si', 'Chemical', 'MESH:D012825', (117, 119))	('associated', 'Reg', (75, 85))	('LADC', 'Disease', (125, 129))
58945	33308216	PCR experiments and clinical feature analysis suggested that LINC02310 was significantly correlated with TNM-stage and T-stage.	('TNM', 'Gene', (105, 108))	('LINC02310', 'Chemical', '-', (61, 70))	('si', 'Chemical', 'MESH:D012825', (75, 77))	('LINC02310', 'Var', (61, 70))	('TNM', 'Gene', '10178', (105, 108))	('correlated', 'Reg', (89, 99))	('T-stage', 'Disease', (119, 126))	('si', 'Chemical', 'MESH:D012825', (42, 44))
58946	33308216	CCK-8 assay and colony formation assay demonstrated that LINC02310 acted as an enhancer in LADC.	('LINC02310', 'Chemical', '-', (57, 66))	('LADC', 'Phenotype', 'HP:0030078', (91, 95))	('enhancer', 'PosReg', (79, 87))	('LADC', 'Disease', (91, 95))	('CCK-8', 'Chemical', 'MESH:D012844', (0, 5))	('LINC02310', 'Var', (57, 66))
58948	33308216	This study verified LINC02310 as an enhancer in LADC and performed comprehensive analyses on its downstream regulatory network, which might benefit LADC prognoses and therapies.	('benefit', 'PosReg', (140, 147))	('si', 'Chemical', 'MESH:D012825', (76, 78))	('LINC02310', 'Chemical', '-', (20, 29))	('enhancer', 'PosReg', (36, 44))	('LADC', 'Phenotype', 'HP:0030078', (148, 152))	('LADC', 'Phenotype', 'HP:0030078', (48, 52))	('LADC', 'Disease', (48, 52))	('LINC02310', 'Var', (20, 29))	('LADC', 'Disease', (148, 152))
58958	33308216	This study identified LINC02310 as an enhancer in LADC and investigated its regulatory network through bioinformatic analyses and experimental validation.	('LINC02310', 'Chemical', '-', (22, 31))	('LADC', 'Disease', (50, 54))	('enhancer', 'PosReg', (38, 46))	('LINC02310', 'Var', (22, 31))	('LADC', 'Phenotype', 'HP:0030078', (50, 54))
58963	33308216	Moreover, CCK-8 assays and colony formation assays were performed to demonstrate that LINC02310 acted as an enhancer in LADC.	('LADC', 'Phenotype', 'HP:0030078', (120, 124))	('LINC02310', 'Var', (86, 95))	('enhancer', 'PosReg', (108, 116))	('LADC', 'Disease', (120, 124))	('LINC02310', 'Chemical', '-', (86, 95))	('CCK-8', 'Chemical', 'MESH:D012844', (10, 15))
59002	33308216	Then, the LADC samples were divided into two groups: high expression (LINC02310 expression > median expression) and low expression (LINC02310 expression < median expression).	('LINC02310', 'Var', (70, 79))	('si', 'Chemical', 'MESH:D012825', (148, 150))	('si', 'Chemical', 'MESH:D012825', (126, 128))	('LINC02310', 'Var', (132, 141))	('LADC', 'Phenotype', 'HP:0030078', (10, 14))	('si', 'Chemical', 'MESH:D012825', (64, 66))	('si', 'Chemical', 'MESH:D012825', (106, 108))	('si', 'Chemical', 'MESH:D012825', (168, 170))	('LINC02310', 'Chemical', '-', (70, 79))	('LINC02310', 'Chemical', '-', (132, 141))	('si', 'Chemical', 'MESH:D012825', (86, 88))
59005	33308216	OE: the primers G0157014-1F (AGGATCGCTAGCGCTACCGGACTCAGATCTCGAGAGTCTCCTCTTG CAGATCAGATACCACC) and G0157014-1R (TACCCGGTAGAATTATCTAGAGTCGCGGGATCCAGATAC CTAAAAGGCACAAATCCTTCTG) were synthesized.	('G0157014-1R', 'Var', (98, 109))	('si', 'Chemical', 'MESH:D012825', (186, 188))	('G0157014-1F', 'Var', (16, 27))
59009	33308216	CCK-8 assay: 100 muL of OE, NC, si-02310 and si-NC of H1299 and PC-9 (1 x 103/mL) were transplanted in 96-well plate.	('si', 'Chemical', 'MESH:D012825', (32, 34))	('PC-9', 'CellLine', 'CVCL:B260', (64, 68))	('CCK-8', 'Chemical', 'MESH:D012844', (0, 5))	('si-NC of H1299', 'Var', (45, 59))	('si-02310', 'Var', (32, 40))	('si', 'Chemical', 'MESH:D012825', (45, 47))
59011	33308216	Colony formation assay: OE, NC, si-02310 and si-NC of H1299 (1 x 103) were transplanted into 6-well plate and then incubated at 37  C for 10 days.	('si-NC', 'Var', (45, 50))	('si', 'Chemical', 'MESH:D012825', (32, 34))	('si', 'Chemical', 'MESH:D012825', (45, 47))	('si-02310', 'Var', (32, 40))
59036	33308216	It can be observed that LINC02310 had the most significant effect on tumor proliferation.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor', 'Disease', (69, 74))	('LINC02310', 'Chemical', '-', (24, 33))	('si', 'Chemical', 'MESH:D012825', (47, 49))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('LINC02310', 'Var', (24, 33))
59039	33308216	Based on the above results, LINC02310 was screened out and reasonably assumed to act as an enhancer in LADC.	('LINC02310', 'Var', (28, 37))	('LINC02310', 'Chemical', '-', (28, 37))	('LADC', 'Phenotype', 'HP:0030078', (103, 107))	('enhancer', 'PosReg', (91, 99))	('LADC', 'Disease', (103, 107))
59048	33308216	As a result, has-miR-1270, has-miR-506-3p and has-miR-330-3p were involved in 561 interactions with 414 downstream DEmRNAs (Additional file 4: Table S4).	('interactions', 'Interaction', (82, 94))	('miR-1270', 'Gene', (17, 25))	('has-miR-506-3p', 'Var', (27, 41))	('miR-506-3p', 'Chemical', '-', (31, 41))	('involved', 'Reg', (66, 74))	('miR-330-3p', 'Chemical', '-', (50, 60))	('has-miR-330-3p', 'Var', (46, 60))	('miR-1270', 'Gene', '100302179', (17, 25))
59064	33308216	This study identified LINC02310 as an enhancer and promising biomarker in LADC via comprehensive analyses of TCGA data and experimental validation.	('LADC', 'Phenotype', 'HP:0030078', (74, 78))	('LINC02310', 'Chemical', '-', (22, 31))	('enhancer', 'PosReg', (38, 46))	('LADC', 'Disease', (74, 78))	('LINC02310', 'Var', (22, 31))	('si', 'Chemical', 'MESH:D012825', (92, 94))	('si', 'Chemical', 'MESH:D012825', (56, 58))
59066	33308216	However, they simply identified LINC02310 as one of the ten prognostic markers in LADC through a Cox regression model.	('si', 'Chemical', 'MESH:D012825', (14, 16))	('LINC02310', 'Chemical', '-', (32, 41))	('LADC', 'Phenotype', 'HP:0030078', (82, 86))	('LADC', 'Disease', (82, 86))	('LINC02310', 'Var', (32, 41))	('si', 'Chemical', 'MESH:D012825', (107, 109))
59070	33308216	The clinical feature analysis of the 22 pairs of LADC tissues showed that LINC02310 was significantly associated with T-stage and TNM-stage in LADC, which was further verified by analysis of TCGA clinical data.	('si', 'Chemical', 'MESH:D012825', (184, 186))	('TNM', 'Gene', '10178', (130, 133))	('LINC02310', 'Chemical', '-', (74, 83))	('associated', 'Reg', (102, 112))	('LADC', 'Phenotype', 'HP:0030078', (143, 147))	('TNM', 'Gene', (130, 133))	('si', 'Chemical', 'MESH:D012825', (26, 28))	('LINC02310', 'Var', (74, 83))	('T-stage', 'Disease', (118, 125))	('si', 'Chemical', 'MESH:D012825', (88, 90))	('LADC', 'Phenotype', 'HP:0030078', (49, 53))
59071	33308216	These results indicated that LINC02310 acted as an enhancer in LADC.	('enhancer', 'PosReg', (51, 59))	('LADC', 'Phenotype', 'HP:0030078', (63, 67))	('LINC02310', 'Var', (29, 38))	('LADC', 'Disease', (63, 67))	('LINC02310', 'Chemical', '-', (29, 38))
59073	33308216	On the contrary, after down-regulating the expression of LINC02310, the growth and proliferation of the two cell lines were inhibited.	('LINC02310', 'Chemical', '-', (57, 66))	('expression', 'Var', (43, 53))	('LINC02310', 'Gene', (57, 66))	('down-regulating', 'NegReg', (23, 38))	('inhibited', 'NegReg', (124, 133))	('si', 'Chemical', 'MESH:D012825', (49, 51))
59074	33308216	In conclusion, LINC02310 was identified as an enhancer in LADC in this study.	('si', 'Chemical', 'MESH:D012825', (9, 11))	('LINC02310', 'Var', (15, 24))	('LADC', 'Phenotype', 'HP:0030078', (58, 62))	('enhancer', 'PosReg', (46, 54))	('LADC', 'Disease', (58, 62))	('LINC02310', 'Chemical', '-', (15, 24))
59076	33308216	3 targeted miRNAs (has-miR-1270, has-miR-506-3p and has-miR-330-3p) and 414 downstream DEmRNAs were predicted via the lncRNASNP2 website and starBase database.	('si', 'Chemical', 'MESH:D012825', (132, 134))	('has-miR-330-3p', 'Var', (52, 66))	('miR-330-3p', 'Chemical', '-', (56, 66))	('has-miR-506-3p', 'Var', (33, 47))	('miR-506-3p', 'Chemical', '-', (37, 47))	('miR-1270', 'Gene', '100302179', (23, 31))	('miR-1270', 'Gene', (23, 31))
59078	33308216	Has-miR-506-3p was identified as a tumor suppressor in several cancers, including NSCLC and colorectal cancer.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('miR-506-3p', 'Chemical', '-', (4, 14))	('NSCLC', 'Disease', 'MESH:D002289', (82, 87))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('cancers', 'Disease', 'MESH:D009369', (63, 70))	('Has-miR-506-3p', 'Var', (0, 14))	('tumor', 'Disease', (35, 40))	('colorectal cancer', 'Disease', 'MESH:D015179', (92, 109))	('colorectal cancer', 'Phenotype', 'HP:0003003', (92, 109))	('cancers', 'Phenotype', 'HP:0002664', (63, 70))	('NSCLC', 'Disease', (82, 87))	('cancers', 'Disease', (63, 70))	('colorectal cancer', 'Disease', (92, 109))
59080	33308216	Has-miR-330-3p promoted cell invasion and metastasis and controlled cell proliferation in NSCLC.	('promoted', 'PosReg', (15, 23))	('cell invasion', 'CPA', (24, 37))	('miR-330-3p', 'Chemical', '-', (4, 14))	('si', 'Chemical', 'MESH:D012825', (33, 35))	('Has-miR-330-3p', 'Var', (0, 14))	('controlled', 'PosReg', (57, 67))	('cell proliferation', 'CPA', (68, 86))	('NSCLC', 'Disease', (90, 95))	('NSCLC', 'Disease', 'MESH:D002289', (90, 95))	('metastasis', 'CPA', (42, 52))	('si', 'Chemical', 'MESH:D012825', (49, 51))
59092	33308216	In addition, the mutations of TOP2A are associated with chemotherapy resistance in lung cancer.	('lung cancer', 'Disease', 'MESH:D008175', (83, 94))	('associated with', 'Reg', (40, 55))	('si', 'Chemical', 'MESH:D012825', (71, 73))	('chemotherapy resistance', 'CPA', (56, 79))	('lung cancer', 'Disease', (83, 94))	('lung cancer', 'Phenotype', 'HP:0100526', (83, 94))	('TOP2A', 'Gene', '7153', (30, 35))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('TOP2A', 'Gene', (30, 35))	('mutations', 'Var', (17, 26))
59095	33308216	In summary, this study verified that LINC02310 significantly promoted the growth and proliferation of LADC cells, and was closely related to the clinical features of LADC patients.	('LADC', 'Phenotype', 'HP:0030078', (102, 106))	('LADC', 'Disease', (166, 170))	('related', 'Reg', (130, 137))	('promoted', 'PosReg', (61, 69))	('patients', 'Species', '9606', (171, 179))	('si', 'Chemical', 'MESH:D012825', (47, 49))	('LADC', 'Phenotype', 'HP:0030078', (166, 170))	('LINC02310', 'Var', (37, 46))	('growth', 'CPA', (74, 80))	('proliferation', 'CPA', (85, 98))	('LINC02310', 'Chemical', '-', (37, 46))
59100	33308216	In this study, LINC02310, which has rarely been investigated previously, was identified as an enhancer in LADC through bioinformatic analyses and experiments, including PCR experiment, CCK-8 assays and colony formation assays.	('LADC', 'Phenotype', 'HP:0030078', (106, 110))	('LADC', 'Disease', (106, 110))	('enhancer', 'PosReg', (94, 102))	('LINC02310', 'Var', (15, 24))	('CCK-8', 'Chemical', 'MESH:D012844', (185, 190))	('LINC02310', 'Chemical', '-', (15, 24))
59102	33308216	In conclusion, this research identified LINC02310 as a promising prognostic biomarker for LADC therapies and provided comprehensive analyses on its regulatory network.	('LADC', 'Disease', (90, 94))	('LINC02310', 'Chemical', '-', (40, 49))	('si', 'Chemical', 'MESH:D012825', (9, 11))	('si', 'Chemical', 'MESH:D012825', (60, 62))	('LINC02310', 'Var', (40, 49))	('si', 'Chemical', 'MESH:D012825', (127, 129))	('LADC', 'Phenotype', 'HP:0030078', (90, 94))
59141	24864260	A key point of EMT is the reduction of cell-cell adhesion by transcriptional repression of cadherins (adherens junctions), occludin and claudin (tight junctions), and desmoplakin (desmosomes).	('repression', 'NegReg', (77, 87))	('occludin', 'Gene', '100506658', (123, 131))	('reduction', 'NegReg', (26, 35))	('claudin', 'Protein', (136, 143))	('transcriptional', 'Var', (61, 76))	('occludin', 'Gene', (123, 131))	('cell-cell adhesion', 'CPA', (39, 57))	('cadherins', 'Protein', (91, 100))
59146	24864260	which promoted VM formation through dephosphorylation of FAK and remodeling of extracellular matrix in VM formation in melanoma.	('VM formation', 'CPA', (15, 27))	('FAK', 'Gene', '5747', (57, 60))	('FAK', 'Gene', (57, 60))	('melanoma', 'Phenotype', 'HP:0002861', (119, 127))	('promoted', 'PosReg', (6, 14))	('dephosphorylation', 'Var', (36, 53))
59148	31950163	Prevalence and architecture of posttranscriptionally impaired synonymous mutations in 8,320 genomes across 22 cancer types Somatic synonymous mutations are one of the most frequent genetic variants occurring in the coding region of cancer genomes, while their contributions to cancer development remain largely unknown.	('mutations', 'Var', (142, 151))	('cancer', 'Disease', (110, 116))	('cancer', 'Disease', 'MESH:D009369', (232, 238))	('cancer', 'Disease', (232, 238))	('cancer', 'Disease', (277, 283))	('cancer', 'Disease', 'MESH:D009369', (277, 283))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('synonymous mutations', 'Var', (62, 82))	('cancer', 'Phenotype', 'HP:0002664', (277, 283))	('cancer', 'Disease', 'MESH:D009369', (110, 116))
59149	31950163	To assess whether synonymous mutations involved in post-transcriptional regulation contribute to the genetic etiology of cancers, we collected whole exome data from 8,320 patients across 22 cancer types.	('cancer', 'Disease', (190, 196))	('cancers', 'Disease', (121, 128))	('cancer', 'Disease', 'MESH:D009369', (190, 196))	('cancers', 'Disease', 'MESH:D009369', (121, 128))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('patients', 'Species', '9606', (171, 179))	('synonymous mutations', 'Var', (18, 38))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('cancer', 'Disease', (121, 127))	('cancers', 'Phenotype', 'HP:0002664', (121, 128))
59154	31950163	Somatic synonymous mutations, which do not alter the protein sequences of their host genes, are one of the most frequent but rarely investigated genetic changes that occur in the coding regions of human cancer genomes.	('cancer', 'Disease', (203, 209))	('cancer', 'Disease', 'MESH:D009369', (203, 209))	('human', 'Species', '9606', (197, 202))	('synonymous mutations', 'Var', (8, 28))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))
59155	31950163	Recent studies have shown that they can act as drivers of cancers by altering RNA splicing, RNA stability and protein translation, which suggests the existence of uncovered regulatory effects of these 'silent' mutations and highlights the significance to adjust our focus beyond the damaging protein-coding mutations.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('mutations', 'Var', (210, 219))	('cancers', 'Phenotype', 'HP:0002664', (58, 65))	('altering', 'Reg', (69, 77))	('RNA stability', 'MPA', (92, 105))	('cancers', 'Disease', 'MESH:D009369', (58, 65))	('RNA splicing', 'MPA', (78, 90))	('protein translation', 'MPA', (110, 129))	('cancers', 'Disease', (58, 65))
59157	31950163	RNA-binding proteins (RBPs) play versatile roles in posttranscriptional RNA regulation, including splicing, polyadenylation, mRNA stabilization, RNA structure, subcellular localization and transcription, and their aberrant expression may lead to chaos within the whole regulation network.	('lead to', 'Reg', (238, 245))	('mRNA', 'MPA', (125, 129))	('chaos', 'MPA', (246, 251))	('expression', 'MPA', (223, 233))	('RBP', 'Gene', (22, 25))	('aberrant', 'Var', (214, 222))	('RBP', 'Gene', '57794', (22, 25))
59158	31950163	In several cancer types, the abnormal expression of RBPs was associated with patient prognosis, and numerous mutations occurred in coding regions of RBPs had been implicated in tumorigenesis and progression, such as KHDRBS1 and ELAVL1 (also known as HuR).	('implicated', 'Reg', (163, 173))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('HuR', 'Gene', '1994', (250, 253))	('ELAVL1', 'Gene', (228, 234))	('RBP', 'Gene', (52, 55))	('abnormal', 'Var', (29, 37))	('RBP', 'Gene', '57794', (149, 152))	('cancer', 'Disease', 'MESH:D009369', (11, 17))	('associated', 'Reg', (61, 71))	('tumor', 'Disease', (177, 182))	('patient', 'Species', '9606', (77, 84))	('KHDRBS1', 'Gene', '10657', (216, 223))	('expression', 'MPA', (38, 48))	('KHDRBS1', 'Gene', (216, 223))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('ELAVL1', 'Gene', '1994', (228, 234))	('mutations', 'Var', (109, 118))	('progression', 'CPA', (195, 206))	('RBP', 'Gene', (149, 152))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('HuR', 'Gene', (250, 253))	('cancer', 'Disease', (11, 17))	('RBP', 'Gene', '57794', (52, 55))
59163	31950163	It has been demonstrated that RBPs can recognize their RNA substrate via sequence-specific binding motifs; therefore, genetic mutations occurred in the binding motifs may disrupt the recognition between RBPs and RNA substrates, resulting in various human diseases.	('resulting in', 'Reg', (228, 240))	('RBP', 'Gene', '57794', (30, 33))	('genetic mutations', 'Var', (118, 135))	('recognition', 'MPA', (183, 194))	('RBP', 'Gene', (203, 206))	('RBP', 'Gene', '57794', (203, 206))	('human diseases', 'Disease', (249, 263))	('human', 'Species', '9606', (249, 254))	('mutations', 'Var', (126, 135))	('disrupt', 'NegReg', (171, 178))	('RBP', 'Gene', (30, 33))
59164	31950163	For example, a mutation in the 3' untranslated region of FMR1 decreased neuronal activity-dependent translation of FMRP by disrupting the binding of HuR, leading to developmental delay in patients.	('FMR1', 'Gene', (57, 61))	('neuronal activity-dependent translation', 'MPA', (72, 111))	('FMRP', 'Gene', (115, 119))	('developmental delay', 'CPA', (165, 184))	('decreased', 'NegReg', (62, 71))	('mutation in', 'Var', (15, 26))	('HuR', 'Gene', (149, 152))	('disrupting', 'NegReg', (123, 133))	('HuR', 'Gene', '1994', (149, 152))	('leading to', 'Reg', (154, 164))	('binding', 'Interaction', (138, 145))	('patients', 'Species', '9606', (188, 196))	('developmental delay', 'Phenotype', 'HP:0001263', (165, 184))	('FMRP', 'Gene', '2332', (115, 119))	('FMR1', 'Gene', '2332', (57, 61))
59166	31950163	To test whether synonymous mutations involved in posttranscriptional regulation contribute to the genetic etiology of cancers, we collected whole exome data from 8,320 patients across 22 cancer types.	('cancer', 'Disease', 'MESH:D009369', (187, 193))	('cancer', 'Disease', (118, 124))	('cancers', 'Disease', (118, 125))	('cancers', 'Disease', 'MESH:D009369', (118, 125))	('cancer', 'Disease', (187, 193))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('patients', 'Species', '9606', (168, 176))	('synonymous mutations', 'Var', (16, 36))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('cancers', 'Phenotype', 'HP:0002664', (118, 125))
59198	31950163	All genetic mutations occurred in 2,042 pisSNV-hosted genes across 22 cancer types were curated, and their functional consequences on protein were predicted using Varcards.	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('genetic mutations', 'Var', (4, 21))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))
59199	31950163	Protein damage mutations were then defined by loss-of-function mutations or missense mutations with a damaging score >=0.8 predicted using ReVe.	('mutations', 'Var', (63, 72))	('missense mutations', 'Var', (76, 94))	('Protein damage', 'Disease', (0, 14))	('Protein damage', 'Disease', 'MESH:D058495', (0, 14))	('loss-of-function', 'NegReg', (46, 62))
59208	31950163	Seventeen (62.96%) piSNVs and 11 (73.33%) pisSNVs obtained through our pipeline were overlapped with the allele-specific RBP-RNA interaction sites identified by ASPRIN (Figure 1B; Supplementary Table S3), which suggests that PIVar was more stringent for identifying the impact of genetic mutations on posttranscriptional regulation network.	('mutations', 'Var', (288, 297))	('PIVar', 'Chemical', '-', (225, 230))	('RBP', 'Gene', '57794', (121, 124))	('RBP', 'Gene', (121, 124))
59209	31950163	Inspired by previous studies in which genetic mutations can disrupt the RBP recognition of RNA substrates and many RBPs play important roles in tumorigenesis, we then employed PIVar (Figure 1A) to analyze the somatic mutation spectrum of 22 cancer types to explore the correlation between mutations and binding of RBPs.	('tumor', 'Disease', (144, 149))	('mutations', 'Var', (46, 55))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('cancer', 'Disease', 'MESH:D009369', (241, 247))	('RBP', 'Gene', (72, 75))	('RBP', 'Gene', (115, 118))	('RBP', 'Gene', (314, 317))	('cancer', 'Disease', (241, 247))	('disrupt', 'NegReg', (60, 67))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('RBP', 'Gene', '57794', (314, 317))	('RBP', 'Gene', '57794', (72, 75))	('PIVar', 'Chemical', '-', (176, 181))	('RBP', 'Gene', '57794', (115, 118))
59211	31950163	Synonymous mutations can function as driver mutations in human cancers by disrupting RNA splicing or RBP binding instead of altering the sequence of encoded proteins directly; thus, we focused on the previously neglected 'silent' mutations and observed a total of 22,948 synonymous piSNVs (pisSNVs) across 22 cancer types (Figure 1C; Supplementary Table S4).	('mutations', 'Var', (11, 20))	('human', 'Species', '9606', (57, 62))	('disrupting', 'NegReg', (74, 84))	('cancer', 'Disease', (63, 69))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('cancers', 'Disease', 'MESH:D009369', (63, 70))	('altering', 'Reg', (124, 132))	('cancer', 'Phenotype', 'HP:0002664', (309, 315))	('cancer', 'Disease', (309, 315))	('RBP', 'Gene', (101, 104))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('cancers', 'Phenotype', 'HP:0002664', (63, 70))	('cancer', 'Disease', 'MESH:D009369', (309, 315))	('cancers', 'Disease', (63, 70))	('RBP', 'Gene', '57794', (101, 104))	('RNA splicing', 'MPA', (85, 97))
59213	31950163	Also, we observed synonymous mutations had a higher mutation load on posttranscriptional regulation comparing to non-synonymous mutations in 15 cancer types (Supplementary Figure S1).	('Supplementary Figure S1', 'Disease', (158, 181))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('synonymous mutations', 'Var', (18, 38))	('cancer', 'Disease', (144, 150))	('posttranscriptional regulation', 'MPA', (69, 99))	('mutation load', 'MPA', (52, 65))	('higher', 'PosReg', (45, 51))	('Supplementary Figure S1', 'Disease', 'MESH:D017034', (158, 181))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
59214	31950163	The significant distinction between cancer and normal control samples unveiled the prevalence of posttranscriptionally impaired synonymous mutations in cancer genomes, implying their contribution to cancer etiology.	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('cancer', 'Disease', (36, 42))	('posttranscriptionally', 'MPA', (97, 118))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('synonymous mutations', 'Var', (128, 148))	('cancer', 'Disease', (199, 205))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))
59220	31950163	It has been demonstrated that genetic mutations on RNA substrates can disrupt the RBP recognition toward them.	('genetic mutations', 'Var', (30, 47))	('RBP', 'Gene', (82, 85))	('disrupt', 'NegReg', (70, 77))	('RBP', 'Gene', '57794', (82, 85))
59227	31950163	By screening the identified pisSNVs, we found that ADCY7, whose expression significantly correlated with the overall survival of acute myeloid leukemia patients, had a mutation from G to A at the second position of the above motif.	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (129, 151))	('leukemia', 'Phenotype', 'HP:0001909', (143, 151))	('expression', 'MPA', (64, 74))	('acute myeloid leukemia', 'Disease', (129, 151))	('mutation from G to A', 'Var', (168, 188))	('ADCY7', 'Gene', '113', (51, 56))	('ADCY7', 'Gene', (51, 56))	('correlated', 'Reg', (89, 99))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (129, 151))	('patients', 'Species', '9606', (152, 160))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (135, 151))
59240	31950163	LRP1B was thought to function as a tumor suppressor, and microRNA-mediated inactivation of LRP1B could increase the growth and invasive capacity of cancer cells.	('inactivation', 'Var', (75, 87))	('cancer', 'Disease', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('increase', 'PosReg', (103, 111))	('LRP1B', 'Gene', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('LRP1B', 'Gene', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('tumor', 'Disease', (35, 40))	('LRP1B', 'Gene', '53353', (91, 96))	('LRP1B', 'Gene', '53353', (0, 5))
59246	31950163	When we summarized the gene-length corrected frequency of occurrence of 2,042 genes based on the status of posttranscriptional impact and/or function damage (Figure 4C), we found that 470 of 8,320 cancer patients carried protein-damaging mutations in LRP1B, the highest frequently occurred pisSNV-hosted gene.	('patients', 'Species', '9606', (204, 212))	('cancer', 'Disease', 'MESH:D009369', (197, 203))	('mutations', 'Var', (238, 247))	('cancer', 'Disease', (197, 203))	('protein-damaging', 'NegReg', (221, 237))	('LRP1B', 'Gene', (251, 256))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('LRP1B', 'Gene', '53353', (251, 256))
59257	31950163	Posttranscriptionally impaired synonymous mutations of MTOR, a reported oncogene in multiple cancers, co-occurred in 14 cancer types.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('cancers', 'Disease', (93, 100))	('cancer', 'Disease', (93, 99))	('MTOR', 'Gene', '2475', (55, 59))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('co-occurred', 'Reg', (102, 113))	('cancers', 'Phenotype', 'HP:0002664', (93, 100))	('cancer', 'Disease', (120, 126))	('synonymous mutations', 'Var', (31, 51))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('cancers', 'Disease', 'MESH:D009369', (93, 100))	('MTOR', 'Gene', (55, 59))
59261	31950163	As shown in Figure 6A, high sensitivity (low IC50 value) for CAY10566, a steroyl-CoA desaturase 1 (SCD1) inhibitor which inhibits the conversion from saturated to monounsaturated, long-chain fatty acyl-CoAs, was significantly associated with IGSF3 c.891 G>A mutation.	('SCD1', 'Gene', '6319', (99, 103))	('long-chain fatty acyl-CoAs', 'Chemical', '-', (180, 206))	('SCD1', 'Gene', (99, 103))	('associated', 'Reg', (226, 236))	('inhibits', 'NegReg', (121, 129))	('IGSF3', 'Gene', (242, 247))	('c.891 G>A mutation', 'Var', (248, 266))	('conversion', 'MPA', (134, 144))	('CAY10566', 'Var', (61, 69))	('steroyl-CoA desaturase 1', 'Gene', (73, 97))	('steroyl-CoA desaturase 1', 'Gene', '6319', (73, 97))	('c.891 G>A', 'Mutation', 'rs61730485', (248, 257))	('CAY10566', 'Chemical', '-', (61, 69))	('IGSF3', 'Gene', '3321', (242, 247))
59262	31950163	In addition, Ara-G and SGC0946 had higher response to TTN c.22323 C>T mutated cell lines in comparison with wild-type cell lines (Figure 6B).	('TTN', 'Gene', (54, 57))	('TTN', 'Gene', '7273', (54, 57))	('c.22323 C>T', 'Mutation', 'c.22323C>T', (58, 69))	('Ara-G', 'Chemical', 'MESH:C028771', (13, 18))	('c.22323 C>T', 'Var', (58, 69))	('higher', 'PosReg', (35, 41))
59268	31950163	Recent studies have shown that synonymous mutations could function as cancer drivers by altering RNA splicing, RNA stability and protein translation.	('RNA stability', 'MPA', (111, 124))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('protein translation', 'MPA', (129, 148))	('synonymous mutations', 'Var', (31, 51))	('RNA splicing', 'MPA', (97, 109))	('altering', 'Reg', (88, 96))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))
59270	31950163	Numerous studies have found that RBPs play an important role in posttranscriptional regulation, and in the cancer genome, abnormal expression of RBPs has a significant effect on cancer phenotype.	('RBP', 'Gene', '57794', (33, 36))	('abnormal', 'Var', (122, 130))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('effect', 'Reg', (168, 174))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('posttranscriptional regulation', 'MPA', (64, 94))	('RBP', 'Gene', (145, 148))	('cancer', 'Disease', (178, 184))	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('RBP', 'Gene', '57794', (145, 148))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('cancer', 'Disease', (107, 113))	('RBP', 'Gene', (33, 36))
59271	31950163	Therefore, we speculated that the synonymous mutations present in the cancer genome may disrupt the binding of RBPs by altering the secondary structure of RNA, thereby affecting the translation, transportation or degradation of the RNA and ultimately resulting in the carcinogenesis and progression of cancer.	('progression', 'CPA', (287, 298))	('binding', 'Interaction', (100, 107))	('carcinogenesis', 'Disease', 'MESH:D063646', (268, 282))	('RNA', 'Protein', (155, 158))	('cancer', 'Disease', (302, 308))	('cancer', 'Phenotype', 'HP:0002664', (302, 308))	('secondary structure', 'MPA', (132, 151))	('cancer', 'Disease', (70, 76))	('RBP', 'Gene', '57794', (111, 114))	('transportation', 'MPA', (195, 209))	('resulting in', 'Reg', (251, 263))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('translation', 'MPA', (182, 193))	('cancer', 'Disease', 'MESH:D009369', (302, 308))	('disrupt', 'NegReg', (88, 95))	('altering', 'Reg', (119, 127))	('mutations', 'Var', (45, 54))	('affecting', 'Reg', (168, 177))	('degradation', 'MPA', (213, 224))	('RBP', 'Gene', (111, 114))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('carcinogenesis', 'Disease', (268, 282))
59275	31950163	Thus, we provided an efficient and reliable tool for genome-wide deciphering of the role of these synonymous mutations in the development of cancers at the posttranscriptional regulation level.	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('cancers', 'Phenotype', 'HP:0002664', (141, 148))	('mutations', 'Var', (109, 118))	('cancers', 'Disease', 'MESH:D009369', (141, 148))	('cancers', 'Disease', (141, 148))
59280	31950163	For example, LRP1B, a member of low density lipoprotein receptor-related protein family, had the highest gene-length corrected frequency of occurrence as a pisSNV-hosted gene, while 470 of 8,320 cancer patients was also identified to carry protein damaging mutations of LRP1B.	('mutations', 'Var', (257, 266))	('LRP1B', 'Gene', (270, 275))	('LRP1B', 'Gene', (13, 18))	('cancer', 'Disease', (195, 201))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('patients', 'Species', '9606', (202, 210))	('LRP1B', 'Gene', '53353', (270, 275))	('LRP1B', 'Gene', '53353', (13, 18))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
59281	31950163	Down-regulation of LRP1B was reported to promote the growth and migration of colon cancer cells, and its deletion was associated with acquired chemotherapy resistance to liposomal doxorubicin in high-grade serous ovarian cancers.	('LRP1B', 'Gene', (19, 24))	('doxorubicin', 'Chemical', 'MESH:D004317', (180, 191))	('deletion', 'Var', (105, 113))	('cancers', 'Phenotype', 'HP:0002664', (221, 228))	('growth', 'MPA', (53, 59))	('serous ovarian cancers', 'Disease', 'MESH:D010051', (206, 228))	('colon cancer', 'Phenotype', 'HP:0003003', (77, 89))	('colon cancer', 'Disease', 'MESH:D015179', (77, 89))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('serous ovarian cancers', 'Disease', (206, 228))	('LRP1B', 'Gene', '53353', (19, 24))	('ovarian cancers', 'Phenotype', 'HP:0100615', (213, 228))	('promote', 'PosReg', (41, 48))	('Down-regulation', 'NegReg', (0, 15))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('colon cancer', 'Disease', (77, 89))	('associated', 'Reg', (118, 128))
59285	31950163	Clinical implication analysis unveiled two drug-response associated pisSNVs and three pisSNV-associated compounds including CAY10566, Ara-G and SGC0946.	('Ara-G', 'Chemical', 'MESH:C028771', (134, 139))	('drug-response', 'Disease', (43, 56))	('CAY10566', 'Var', (124, 132))	('CAY10566', 'Chemical', '-', (124, 132))
59286	31950163	Of the compounds responding to TTN c.22323 C>T synonymous mutation, Ara-G is a metabolite of nelarabine, which could be used for chemotherapy in T-cell acute lymphoblastic leukemia.	('lymphoblastic leukemia', 'Disease', (158, 180))	('T-cell acute lymphoblastic leukemia', 'Phenotype', 'HP:0006727', (145, 180))	('TTN', 'Gene', (31, 34))	('leukemia', 'Phenotype', 'HP:0001909', (172, 180))	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (152, 180))	('Ara-G', 'Chemical', 'MESH:C028771', (68, 73))	('nelarabine', 'Chemical', 'MESH:C104457', (93, 103))	('c.22323 C>T synonymous', 'Var', (35, 57))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (158, 180))	('TTN', 'Gene', '7273', (31, 34))	('lymphoblastic leukemia', 'Disease', 'MESH:D054198', (158, 180))	('c.22323 C>T', 'Mutation', 'c.22323C>T', (35, 46))
59287	31950163	In addition, SGC0946 can work as an inhibitor of histone lysine methyltransferase for H3K79 and selectively kill mixed lineage leukemia cells.	('leukemia', 'Disease', (127, 135))	('leukemia', 'Phenotype', 'HP:0001909', (127, 135))	('leukemia', 'Disease', 'MESH:D007938', (127, 135))	('kill', 'NegReg', (108, 112))	('H3K79', 'Protein', (86, 91))	('SGC0946', 'Var', (13, 20))
59295	31993547	Nonetheless, any alteration in their expression level has been reported to be directly associated with the incidence and aggressiveness of several diseases.	('alteration', 'Var', (17, 27))	('aggressiveness of several diseases', 'Disease', (121, 155))	('associated', 'Reg', (87, 97))	('expression level', 'MPA', (37, 53))	('aggressiveness of several diseases', 'Disease', 'MESH:D001523', (121, 155))	('aggressiveness', 'Phenotype', 'HP:0000718', (121, 135))
59312	31993547	Secondly, the regulatory ncRNAs that can regulate the expression pattern of other coding transcripts includes long non-coding RNAs (lncRNAs) >=200 nucleotides and short non-coding RNAs (sncRNAs) < 200 nucleotides as shown in Table 1.	('expression', 'MPA', (54, 64))	('ncRNA', 'Gene', (187, 192))	('ncRNA', 'Gene', (133, 138))	('ncRNA', 'Gene', '220202', (25, 30))	('ncRNA', 'Gene', '220202', (187, 192))	('ncRNA', 'Gene', '220202', (133, 138))	('>=200 nucleotides', 'Var', (141, 158))	('ncRNA', 'Gene', (25, 30))
59313	31993547	SncRNAs are divided into microRNAs (miRNAs), small interfering RNAs (siRNAs) and piwi-associated RNAs (piRNAs).	('ncRNA', 'Gene', '220202', (1, 6))	('small interfering', 'Var', (45, 62))	('miR', 'Gene', (36, 39))	('miR', 'Gene', '220972', (36, 39))	('ncRNA', 'Gene', (1, 6))
59314	31993547	However, antisense RNAs and enhancer RNAs (eRNAs) are intermediate-sized ncRNA molecules lying at the bay between both classes of lncRNAs and sncRNAs.	('antisense', 'Var', (9, 18))	('ncRNA', 'Gene', '220202', (131, 136))	('ncRNA', 'Gene', '220202', (73, 78))	('enhancer', 'PosReg', (28, 36))	('ncRNA', 'Gene', '220202', (143, 148))	('ncRNA', 'Gene', (143, 148))	('ncRNA', 'Gene', (131, 136))	('ncRNA', 'Gene', (73, 78))
59340	31993547	Drosha/DGCR8-independent pathway includes splicing of mRNA introns and their conversion into mirtrons transcripts.	('DGCR8', 'Gene', '54487', (7, 12))	('mRNA introns', 'MPA', (54, 66))	('mirtrons transcripts', 'MPA', (93, 113))	('Drosha', 'Gene', '29102', (0, 6))	('conversion', 'MPA', (77, 87))	('Drosha', 'Gene', (0, 6))	('DGCR8', 'Gene', (7, 12))	('splicing', 'Var', (42, 50))
59404	31993547	Collectively, exosomal miR-486-5p is believed to act as a circulating marker for high-risk LARC.	('LARC', 'Disease', (91, 95))	('exosomal', 'Var', (14, 22))	('miR-486', 'Gene', '619554', (23, 30))	('miR-486', 'Gene', (23, 30))
59421	31993547	Our research group has found that miR-486-5p was down-regulated in HCC liver tissues and cell lines (Huh-7 cells), where its ectopic expression was found to block one of the most aggressive deregulated oncogenic signaling pathway in HCC patients.	('ectopic expression', 'Var', (125, 143))	('HCC', 'Disease', (67, 70))	('CC', 'Phenotype', 'HP:0002664', (68, 70))	('HCC', 'Phenotype', 'HP:0001402', (67, 70))	('down-regulated', 'NegReg', (49, 63))	('HCC', 'Disease', 'MESH:D006528', (233, 236))	('CC', 'Phenotype', 'HP:0002664', (234, 236))	('Huh-7', 'CellLine', 'CVCL:0336', (101, 106))	('HCC', 'Disease', (233, 236))	('miR-486', 'Gene', (34, 41))	('deregulated oncogenic signaling pathway', 'Pathway', (190, 229))	('HCC', 'Phenotype', 'HP:0001402', (233, 236))	('patients', 'Species', '9606', (237, 245))	('HCC', 'Disease', 'MESH:D006528', (67, 70))	('miR-486', 'Gene', '619554', (34, 41))	('block', 'NegReg', (157, 162))
59447	31993547	It has been found that the hyper-activation of estrogen receptor alpha (ERalpha) causes changes on the genetic and epigenetic levels in ovarian cancer cells.	('ovarian cancer', 'Disease', 'MESH:D010051', (136, 150))	('changes', 'Reg', (88, 95))	('hyper-activation', 'Var', (27, 43))	('ERalpha', 'Gene', '2099', (72, 79))	('ovarian cancer', 'Disease', (136, 150))	('ERalpha', 'Gene', (72, 79))	('estrogen receptor alpha', 'Gene', (47, 70))	('estrogen receptor alpha', 'Gene', '2099', (47, 70))	('ovarian cancer', 'Phenotype', 'HP:0100615', (136, 150))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
59450	31993547	Impairment of the expression of ERalpha-mediated OLFM4 facilitates malignant development of ovarian serous adenocarcinoma.	('OLFM4', 'Gene', '10562', (49, 54))	('ovarian serous adenocarcinoma', 'Disease', 'MESH:D010051', (92, 121))	('OLFM4', 'Gene', (49, 54))	('facilitates', 'PosReg', (55, 66))	('ovarian serous adenocarcinoma', 'Disease', (92, 121))	('men', 'Species', '9606', (84, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('expression', 'MPA', (18, 28))	('ERalpha', 'Gene', (32, 39))	('malignant development', 'CPA', (67, 88))	('Impairment', 'Var', (0, 10))	('ERalpha', 'Gene', '2099', (32, 39))	('men', 'Species', '9606', (6, 9))
59457	31993547	Thus miR-486-5p ectopic-expression leads to an increase in the apoptosis of leukemia cells by targeting FOXO1.	('increase', 'PosReg', (47, 55))	('miR-486', 'Gene', (5, 12))	('miR-486', 'Gene', '619554', (5, 12))	('ectopic-expression', 'Var', (16, 34))	('apoptosis', 'CPA', (63, 72))	('leukemia', 'Disease', (76, 84))	('FOXO1', 'Gene', (104, 109))	('leukemia', 'Phenotype', 'HP:0001909', (76, 84))	('leukemia', 'Disease', 'MESH:D007938', (76, 84))	('targeting', 'Reg', (94, 103))	('FOXO1', 'Gene', '2308', (104, 109))
59471	31993547	As it was mentioned above that ANK1 irregular epigenetic modifications could lead to suppression of miR-486-5p in NSCLC.	('ANK1', 'Gene', (31, 35))	('miR-486', 'Gene', '619554', (100, 107))	('men', 'Species', '9606', (10, 13))	('ANK1', 'Gene', '286', (31, 35))	('NSCLC', 'Phenotype', 'HP:0030358', (114, 119))	('NSCLC', 'Disease', (114, 119))	('NSCLC', 'Disease', 'MESH:D002289', (114, 119))	('suppression', 'NegReg', (85, 96))	('miR-486', 'Gene', (100, 107))	('epigenetic modifications', 'Var', (46, 70))
59472	31993547	Accordingly, hyper-methylation of ANK1 promoter by DNMT3B which is found in arecoline (a major component of betel quid chewing) leads to a reduction of ANK1 and miR-486-3p expression subsequently leading to DDR1 expression.	('DNMT3B', 'Gene', (51, 57))	('DNMT3B', 'Gene', '1789', (51, 57))	('DDR1', 'Gene', '780', (207, 211))	('reduction', 'NegReg', (139, 148))	('DDR1', 'Gene', (207, 211))	('ANK1', 'Gene', '286', (152, 156))	('expression', 'MPA', (212, 222))	('ANK1', 'Gene', (152, 156))	('miR-486', 'Gene', (161, 168))	('arecoline', 'Chemical', 'MESH:D001115', (76, 85))	('hyper-methylation', 'Var', (13, 30))	('leading to', 'Reg', (196, 206))	('ANK1', 'Gene', '286', (34, 38))	('miR-486', 'Gene', '619554', (161, 168))	('ANK1', 'Gene', (34, 38))
59483	31993547	Eventually, cell growth and metastasis were inhibited by miR-486-3p ectopic-expression.	('miR-486', 'Gene', (57, 64))	('inhibited', 'NegReg', (44, 53))	('miR-486', 'Gene', '619554', (57, 64))	('ectopic-expression', 'Var', (68, 86))
59511	31993547	CF is a genetic disease caused by mutations in the gene of cystic fibrosis conductance regulator (CFTR).	('cystic fibrosis conductance regulator', 'Gene', '1080', (59, 96))	('CFTR', 'Gene', (98, 102))	('cystic fibrosis conductance regulator', 'Gene', (59, 96))	('CF', 'Disease', 'MESH:D003550', (98, 100))	('CF', 'Disease', 'MESH:D003550', (0, 2))	('genetic disease', 'Disease', (8, 23))	('caused by', 'Reg', (24, 33))	('genetic disease', 'Disease', 'MESH:D030342', (8, 23))	('CFTR', 'Gene', '1080', (98, 102))	('mutations', 'Var', (34, 43))
59550	31993547	Collectively, those few studies highlight a clear research gap in connecting the lines between different classes of ncRNAs and the assembly of the ceRNAs circuits that when dys-regulated lead to several malignant and non-malignant phenotypes.	('malignant', 'CPA', (203, 212))	('dys-regulated', 'Var', (173, 186))	('ncRNA', 'Gene', (116, 121))	('ncRNA', 'Gene', '220202', (116, 121))	('lead to', 'Reg', (187, 194))
59568	25794680	Global gene expression profiles associated with YAP and TAZ knockdown revealed changes in the control of gene expression implicated in pro-tumorigenic signaling, including those required for cell cycle progression and survival.	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('YAP and TAZ', 'Gene', '10413;6901', (48, 59))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('control of gene expression', 'MPA', (94, 120))	('knockdown', 'Var', (60, 69))	('changes', 'Reg', (79, 86))
59571	25794680	Recent studies have shown that aberrant activation of the transcriptional regulators YAP and TAZ (YAP/TAZ) contributes to the onset and progression of a range of cancers.	('cancers', 'Disease', 'MESH:D009369', (162, 169))	('cancers', 'Disease', (162, 169))	('aberrant', 'Var', (31, 39))	('activation', 'PosReg', (40, 50))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('cancers', 'Phenotype', 'HP:0002664', (162, 169))	('YAP and TAZ', 'Gene', '10413;6901', (85, 96))
59575	25794680	Dysregulated YAP/TAZ activity has been implicated in head and neck cancers.	('cancers', 'Phenotype', 'HP:0002664', (67, 74))	('head and neck cancers', 'Phenotype', 'HP:0012288', (53, 74))	('implicated', 'Reg', (39, 49))	('neck cancers', 'Disease', (62, 74))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('neck cancers', 'Disease', 'MESH:D006258', (62, 74))	('Dysregulated', 'Var', (0, 12))	('YAP/TAZ', 'Protein', (13, 20))
59590	25794680	3xFLAG-tagged mutants of YAP (5SA: S61A, S109A, S127A, S164A, S97A or 5SA/S94A) were generated by site-directed mutagenesis and cloned into the pLVX-Tight-Puro plasmid (#632162, Clontech).	('S164A', 'Mutation', 'p.S164A', (55, 60))	('S97A or', 'Var', (62, 69))	('S97A', 'Mutation', 'p.S97A', (62, 66))	('S109A', 'Var', (41, 46))	('S127A', 'Mutation', 'rs762471803', (48, 53))	('S164A', 'Var', (55, 60))	('S127A', 'Var', (48, 53))	('S94A', 'Mutation', 'p.S94A', (74, 78))	('S109A', 'Mutation', 'p.S109A', (41, 46))	('S61A', 'Mutation', 'p.S61A', (35, 39))
59592	25794680	SCC2-dsRED cells were subsequently infected with lentivirus transducing the expression of control shRNA (shCTL), shRNA targeting YAP (shYAP-2, pLKO1-shYAP-2 was a gift from Kunliang Guan, Addgene plasmid # 27369) and/or TAZ (shTAZ) from either the pLKO1-puro (gift from Bob Weinberg) or pLKO1-neo plasmids (gift from Sheila Stewart).	('pLKO1-shYAP-2', 'Var', (143, 156))	('Bob', 'Gene', '2838', (270, 273))	('shCTL', 'Chemical', '-', (105, 110))	('Bob', 'Gene', (270, 273))
59593	25794680	The following SCC2-dsRED stable cells were generated and selected with 2 mg/mL G-418 sulfate and 1 mug/mL Puromycin: Neo-shCTL+Puro-shCTL (shCTL), Neo-shYAP+Puro-shCTL (shYAP), Neo-shYAP+Puro-shTAZ (shY/T).	('shCTL', 'Chemical', '-', (132, 137))	('Puromycin', 'Chemical', 'MESH:D011691', (106, 115))	('Neo-shYAP+Puro-shTAZ', 'Var', (177, 197))	('G-418 sulfate', 'Chemical', 'MESH:C010680', (79, 92))	('shCTL', 'Chemical', '-', (121, 126))	('shCTL', 'Chemical', '-', (162, 167))	('Neo-shYAP+Puro-shCTL', 'Var', (147, 167))	('Neo-shCTL+Puro-shCTL', 'Var', (117, 137))	('shCTL', 'Chemical', '-', (139, 144))
59603	25794680	CAL27 doxycycline-inducible cells were treated with doxycycline (100 ng/mL) for 24 hours to induce the expression of YAP-5SA, or 5SA/S94A.	('doxycycline', 'Chemical', 'MESH:D004318', (6, 17))	('doxycycline', 'Chemical', 'MESH:D004318', (52, 63))	('YAP-5SA', 'Gene', (117, 124))	('5SA/S94A', 'Var', (129, 137))	('S94A', 'Mutation', 'p.S94A', (133, 137))	('CAL27', 'CellLine', 'CVCL:1107', (0, 5))
59604	25794680	CAL27 doxycycline-inducible cells were pretreated with doxycycline (100 ng/mL) for 24 hours to induce the expression of YAP-5SA, or 5SA/S94A.	('doxycycline', 'Chemical', 'MESH:D004318', (6, 17))	('YAP-5SA', 'Gene', (120, 127))	('doxycycline', 'Chemical', 'MESH:D004318', (55, 66))	('5SA/S94A', 'Var', (132, 140))	('S94A', 'Mutation', 'p.S94A', (136, 140))	('CAL27', 'CellLine', 'CVCL:1107', (0, 5))
59623	25794680	Prior studies have suggested that amplification of the chromosomal region encoding YAP contributes to its aberrant expression in human head and neck squamous cell carcinoma cells.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (149, 172))	('carcinoma', 'Phenotype', 'HP:0030731', (163, 172))	('YAP', 'Gene', (83, 86))	('neck squamous cell carcinoma', 'Disease', (144, 172))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (144, 172))	('expression', 'MPA', (115, 125))	('human', 'Species', '9606', (129, 134))	('amplification', 'Var', (34, 47))
59625	25794680	We found no evidence of amplification, deletion, or mutation of the genomic region encompassing YAP or TAZ in cancers originating from the oral cavity (using the Genomic Identification of Significant Targets in Cancer tool; data not shown).	('Cancer', 'Phenotype', 'HP:0002664', (211, 217))	('cancers', 'Disease', (110, 117))	('YAP', 'Gene', (96, 99))	('deletion', 'Var', (39, 47))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('mutation', 'Var', (52, 60))	('cancers', 'Phenotype', 'HP:0002664', (110, 117))	('TAZ', 'Gene', (103, 106))	('cancers', 'Disease', 'MESH:D009369', (110, 117))
59629	25794680	Phosphorylation of YAP on Serine 127 (pS127-YAP) induces the cytoplasmic sequestration of YAP, and correlates with YAP degradation.	('pS127-YAP', 'Var', (38, 47))	('YAP degradation', 'MPA', (115, 130))	('Serine', 'Chemical', 'MESH:D012694', (26, 32))	('correlates with', 'Reg', (99, 114))	('Phosphorylation', 'Var', (0, 15))	('cytoplasmic sequestration', 'MPA', (61, 86))	('induces', 'Reg', (49, 56))
59631	25794680	The other six tumors we examined, which were characterized as moderately differentiated, showed no differences in YAP or pS127-YAP (Fig.	('YAP', 'MPA', (114, 117))	('pS127-YAP', 'Var', (121, 130))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('tumors', 'Disease', (14, 20))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
59636	25794680	Furthermore, knockdown of either YAP or TAZ decreased the ability of SCC2 cells to migrate in wound closure scratch assays, with knockdown of both YAP and TAZ almost completely halting cell migration (Fig.	('cell migration', 'CPA', (185, 199))	('YAP and TAZ', 'Gene', '10413;6901', (147, 158))	('halting', 'NegReg', (177, 184))	('knockdown', 'Var', (129, 138))	('decreased', 'NegReg', (44, 53))
59638	25794680	For these studies, CAL27 cells were engineered to express, in a doxycycline-inducible manner, the nuclear-localized YAP-5SA mutant (S61A, S109A, S127A, S164A, S397A), or YAP-5SA/S94A, which has an additional mutation that disrupts binding to the TEAD transcription factors (Fig.	('YAP-5SA', 'Gene', (116, 123))	('S61A', 'Var', (132, 136))	('S164A', 'Mutation', 'p.S164A', (152, 157))	('S109A', 'Var', (138, 143))	('CAL27', 'CellLine', 'CVCL:1107', (19, 24))	('S109A', 'Mutation', 'p.S109A', (138, 143))	('S397A', 'Mutation', 'p.S397A', (159, 164))	('S94A', 'Mutation', 'p.S94A', (178, 182))	('doxycycline', 'Chemical', 'MESH:D004318', (64, 75))	('S127A', 'Mutation', 'rs762471803', (145, 150))	('S164A', 'Var', (152, 157))	('S61A', 'Mutation', 'p.S61A', (132, 136))	('S397A', 'Var', (159, 164))	('binding', 'Interaction', (231, 238))	('S127A', 'Var', (145, 150))	('disrupts', 'NegReg', (222, 230))
59641	25794680	Expression of YAP-5SA, but not YAP-5SA/S94A, also reduced Caspase 3/7 activity in the CAL27 cells (Fig.	('CAL27', 'CellLine', 'CVCL:1107', (86, 91))	('activity', 'MPA', (70, 78))	('YAP-5SA', 'Var', (14, 21))	('S94A', 'Mutation', 'p.S94A', (39, 43))	('Caspase 3', 'Gene', (58, 67))	('reduced', 'NegReg', (50, 57))	('Caspase 3', 'Gene', '836', (58, 67))
59642	25794680	Moreover, YAP-5SA, but not YAP-5SA/S94A, increased the ability of CAL27 cells to migrate (Fig.	('S94A', 'Mutation', 'p.S94A', (35, 39))	('CAL27', 'CellLine', 'CVCL:1107', (66, 71))	('increased', 'PosReg', (41, 50))	('YAP-5SA', 'Var', (10, 17))
59644	25794680	To test whether YAP and TAZ drive pro-tumorigenic properties in OSCC cells in vivo, we knocked down YAP or YAP/TAZ in SCC2 cells and used them in tongue orthotopic xenograft tumor experiments in immunocompromised mice.	('YAP/TAZ', 'Gene', (107, 114))	('tumor', 'Disease', (38, 43))	('YAP', 'Gene', (100, 103))	('tumor', 'Disease', (174, 179))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('mice', 'Species', '10090', (213, 217))	('YAP and TAZ', 'Gene', '10413;6901', (16, 27))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('knocked', 'Var', (87, 94))
59645	25794680	To easily track tumor development and metastasis, we generated SCC2 cells expressing dsRED (SCC2-dsRED) and then engineered them to express control shRNA (shCTL), shRNA targeting YAP (shYAP), or shRNA targeting both YAP and TAZ (shYAP/TAZ).	('YAP and TAZ', 'Gene', '10413;6901', (216, 227))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('dsRED', 'Var', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('tumor', 'Disease', (16, 21))	('shCTL', 'Chemical', '-', (155, 160))
59648	25794680	We found that YAP or YAP/TAZ knockdown decreased primary tumor volume, with YAP/TAZ suppressing tumor growth more dramatically (Fig.	('suppressing', 'NegReg', (84, 95))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('knockdown', 'Var', (29, 38))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Disease', (96, 101))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('decreased', 'NegReg', (39, 48))	('tumor', 'Disease', (57, 62))
59649	25794680	Thus, our mouse experiments indicated that YAP and TAZ have important roles in OSCC tumor growth and metastasis, suggesting that dysregulated nuclear YAP in oral tissues is relevant for OSCC onset and progression.	('mouse', 'Species', '10090', (10, 15))	('OSCC', 'Disease', (186, 190))	('OSCC tumor', 'Disease', 'MESH:D009369', (79, 89))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('dysregulated', 'Var', (129, 141))	('YAP and TAZ', 'Gene', '10413;6901', (43, 54))	('OSCC tumor', 'Disease', (79, 89))
59653	25794680	Our GSEA analysis revealed a significant enrichment (nominal p-values <=0.05) for genes activated by YAP or YAP/TAZ (i.e.	('activated', 'PosReg', (88, 97))	('YAP', 'Var', (101, 104))	('YAP/TAZ', 'Var', (108, 115))	('GSEA', 'Chemical', '-', (4, 8))
59668	25794680	To validate whether the genes identified in Clusters A and B were indeed regulated by YAP and TAZ, we examined the expression of subset of these genes by quantitative real-time PCR (qPCR) in SCC2 cells transfected with control siRNA, or siRNA targeting TAZ, YAP, or both YAP/TAZ, as well as in CAL27 cells that expressed (24 h of ectopic expression) the nuclear YAP-5SA mutant or the transcriptionally defective YAP-5SA-S94A mutant.	('YAP and TAZ', 'Gene', '10413;6901', (86, 97))	('S94A', 'Mutation', 'p.S94A', (420, 424))	('YAP-5SA', 'Gene', (362, 369))	('CAL27', 'CellLine', 'CVCL:1107', (294, 299))	('mutant', 'Var', (370, 376))	('YAP-5SA-S94A', 'Gene', (412, 424))
59673	25794680	Interestingly, the exception was the regulation of TEAD1 and TEAD4, as the expression of both of these TEAD family members was increased by YAP-5SA, but not by the YAP-5SA/S94A mutant, in CAL27 cells (Fig.	('S94A', 'Mutation', 'p.S94A', (172, 176))	('YAP-5SA', 'Var', (140, 147))	('expression', 'MPA', (75, 85))	('TEAD1', 'Gene', '7003', (51, 56))	('TEAD4', 'Gene', '7004', (61, 66))	('TEAD1', 'Gene', (51, 56))	('TEAD4', 'Gene', (61, 66))	('CAL27', 'CellLine', 'CVCL:1107', (188, 193))	('increased', 'PosReg', (127, 136))
59679	25794680	Indeed, knockdown of YAP in SCC2 cells inhibited the ability of these cells to proliferate in vitro, and reduced the ability of these cells to generate tongue tumors in vivo.	('YAP', 'Gene', (21, 24))	('tongue tumors', 'Phenotype', 'HP:0100648', (152, 165))	('inhibited', 'NegReg', (39, 48))	('knockdown', 'Var', (8, 17))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('tongue tumors', 'Disease', 'MESH:D014062', (152, 165))	('tumors', 'Phenotype', 'HP:0002664', (159, 165))	('tongue tumor', 'Phenotype', 'HP:0100648', (152, 164))	('reduced', 'NegReg', (105, 112))	('tongue tumors', 'Disease', (152, 165))
59680	25794680	YAP knockdown in CAL27 cells also inhibited cell proliferation and anchorage-independent growth.	('YAP', 'Gene', (0, 3))	('cell proliferation', 'CPA', (44, 62))	('inhibited', 'NegReg', (34, 43))	('knockdown', 'Var', (4, 13))	('CAL27', 'CellLine', 'CVCL:1107', (17, 22))	('anchorage-independent growth', 'CPA', (67, 95))
59681	25794680	Moreover, ectopic expression of a nuclear-localized YAP mutant in CAL27 cells promoted cell proliferation, indicating that nuclear YAP is sufficient to drive cell proliferation.	('CAL27', 'CellLine', 'CVCL:1107', (66, 71))	('cell proliferation', 'CPA', (158, 176))	('mutant', 'Var', (56, 62))	('promoted', 'PosReg', (78, 86))	('cell proliferation', 'CPA', (87, 105))	('YAP', 'Gene', (52, 55))
59683	25794680	Due to technical issues we were unable to similarly examine the localization of TAZ in human tissues, but given that common regulatory signals control YAP and TAZ localization, and that TAZ plays an important role in other cancer cells, it is likely that dysregulated TAZ localization also contributes to early OSCC development.	('YAP and TAZ', 'Gene', '10413;6901', (151, 162))	('contributes', 'Reg', (290, 301))	('dysregulated', 'Var', (255, 267))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('early OSCC', 'Disease', (305, 315))	('human', 'Species', '9606', (87, 92))	('cancer', 'Disease', 'MESH:D009369', (223, 229))	('cancer', 'Disease', (223, 229))
59684	25794680	Supporting this premise, we found that knockdown of both YAP and TAZ in SCC2 OSCC cells severely reduced their proliferation, induced pro-apoptotic cues, and halted their wound closure potential in vitro, beyond the knockdown of either YAP or TAZ alone.	('SCC2 OSCC', 'CellLine', 'CVCL:L894', (72, 81))	('halted', 'NegReg', (158, 164))	('knockdown', 'Var', (39, 48))	('proliferation', 'CPA', (111, 124))	('reduced', 'NegReg', (97, 104))	('wound closure potential', 'CPA', (171, 194))	('induced', 'Reg', (126, 133))	('pro-apoptotic cues', 'MPA', (134, 152))	('YAP and TAZ', 'Gene', '10413;6901', (57, 68))	('SCC2', 'Gene', (72, 76))
59685	25794680	Additionally, knockdown of both YAP and TAZ dramatically reduced primary tumor growth in vivo, more so than YAP knockdown alone.	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Disease', (73, 78))	('YAP and TAZ', 'Gene', '10413;6901', (32, 43))	('knockdown', 'Var', (14, 23))	('reduced', 'NegReg', (57, 64))
59690	25794680	Phosphorylation of YAP on S127 was reduced in tumors with elevated YAP, suggesting that defective Hippo pathway signaling likely contributes to these aberrant YAP levels.	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('S127', 'Var', (26, 30))	('reduced', 'NegReg', (35, 42))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('Phosphorylation', 'MPA', (0, 15))	('tumors', 'Disease', (46, 52))	('YAP', 'Protein', (19, 22))	('tumors', 'Disease', 'MESH:D009369', (46, 52))
59692	25794680	Thus, nuclear YAP activity may facilitate the oral epithelial progenitor state and possibly contribute to stem cell-like properties observed in aggressive OSCCs.	('aggressive OSCC', 'Disease', 'MESH:D001523', (144, 159))	('contribute', 'Reg', (92, 102))	('oral epithelial progenitor state', 'CPA', (46, 78))	('facilitate', 'PosReg', (31, 41))	('stem cell-like properties', 'CPA', (106, 131))	('nuclear', 'Var', (6, 13))	('aggressive OSCC', 'Disease', (144, 159))
59711	33080677	Three independent datasets (GSE2379, GSE20347, and GSE75241) were screened out from the Gene Expression Omnibus (GEO) database and the overlapping differentially expressed genes (DEGs) were identified using GEO2R online platform.	('GSE2379', 'Var', (28, 35))	('GSE2379', 'Chemical', '-', (28, 35))	('GSE20347', 'Var', (37, 45))	('GSE75241', 'Var', (51, 59))
59717	33080677	Finally, hsa-miR-29c-3p, hsa-miR-29a-3p, and hsa-miR-29b-3p were confirmed as the top 3 interactive miRNAs that target the most hub genes according to the interaction network of miRNAs and hub genes.	('hub', 'Gene', '1993', (128, 131))	('hub', 'Gene', '1993', (189, 192))	('hub', 'Gene', (189, 192))	('hsa-miR-29b-3p', 'Var', (45, 59))	('hub', 'Gene', (128, 131))
59737	33080677	After the rigorous screening of all relevant datasets, 3 gene expression datasets including GSE2379, GSE20347, and GSE75241 met the inclusion criteria.	('GSE2379', 'Var', (92, 99))	('GSE75241', 'Var', (115, 123))	('GSE20347', 'Var', (101, 109))	('GSE2379', 'Chemical', '-', (92, 99))
59740	33080677	The original data of 3 datasets (GSE2379, GSE20347, GSE75241) were obtained from GEO and then subjected to differential expression analysis by the GEO2R online platform.	('GSE75241', 'Var', (52, 60))	('GSE2379', 'Var', (33, 40))	('GSE2379', 'Chemical', '-', (33, 40))	('GSE20347', 'Var', (42, 50))
59741	33080677	Based on the predefined cut-off values, DEGs (254 in GSE2379, 292 in GSE20347, and 257 in GSE75241) were identified (Fig.	('GSE20347', 'Var', (69, 77))	('GSE75241', 'Var', (90, 98))	('GSE2379', 'Var', (53, 60))	('GSE2379', 'Chemical', '-', (53, 60))
59764	33080677	In addition, aberrant adhesion of tumor cells to the extracellular matrix also plays a critical role in tumor invasion and metastasis.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumor', 'Disease', (34, 39))	('tumor', 'Disease', (104, 109))	('adhesion', 'CPA', (22, 30))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('metastasis', 'CPA', (123, 133))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('aberrant', 'Var', (13, 21))
59784	33080677	Previous studies have demonstrated ESCC cells could produce COL1A1 endogenously, and miR-133a-3p could inhibit the ESCC cell proliferation, invasion, and migration by targeting COL1A1.	('ESCC', 'Disease', (115, 119))	('targeting', 'Reg', (167, 176))	('COL1A1', 'Gene', (177, 183))	('miR-133a-3p', 'Var', (85, 96))	('COL1A1', 'Gene', '1277', (177, 183))	('miR-133a-3p', 'Chemical', '-', (85, 96))	('invasion', 'CPA', (140, 148))	('COL1A1', 'Gene', '1277', (60, 66))	('COL1A1', 'Gene', (60, 66))	('migration', 'CPA', (154, 163))	('inhibit', 'NegReg', (103, 110))
59787	33080677	However, in other malignancies such as ovarian cancer, pancreatic cancer, and head and neck cancer, overexpressed COL1A2 was found to promote tumor cell invasion and migration.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('migration', 'CPA', (166, 175))	('malignancies', 'Disease', 'MESH:D009369', (18, 30))	('pancreatic cancer', 'Disease', 'MESH:D010190', (55, 72))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('malignancies', 'Disease', (18, 30))	('promote', 'PosReg', (134, 141))	('head and neck cancer', 'Disease', 'MESH:D006258', (78, 98))	('pancreatic cancer', 'Disease', (55, 72))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('ovarian cancer', 'Disease', 'MESH:D010051', (39, 53))	('tumor', 'Disease', (142, 147))	('COL1A2', 'Gene', (114, 120))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (55, 72))	('overexpressed', 'Var', (100, 113))	('ovarian cancer', 'Disease', (39, 53))	('head and neck cancer', 'Phenotype', 'HP:0012288', (78, 98))	('ovarian cancer', 'Phenotype', 'HP:0100615', (39, 53))
59812	33080677	Meanwhile, the interaction network of miRNAs and hub genes illustrates the regulatory relationships of the hub genes and miRNA, and hsa-miR-29c-3p, hsa-miR-29a-3p, and hsa-miR-29b-3p were confirmed as the top 3 interactive miRNAs that target the most hub genes.	('hsa-miR-29a-3p', 'Var', (148, 162))	('hub', 'Gene', (107, 110))	('hsa-miR-29c-3p', 'Var', (132, 146))	('regulatory', 'MPA', (75, 85))	('hub', 'Gene', '1993', (251, 254))	('hub', 'Gene', '1993', (49, 52))	('hub', 'Gene', '1993', (107, 110))	('hub', 'Gene', (251, 254))	('hub', 'Gene', (49, 52))
59815	31275450	The disease-free survival (DFS) was higher in low SCC-Ag expression patients than in high SCC-Ag expression patients (HR = 2.17, 95% CI = 1.84 - 2.57, P < 0.001).	('higher', 'PosReg', (36, 42))	('patient', 'Species', '9606', (68, 75))	('disease-free survival', 'CPA', (4, 25))	('patients', 'Species', '9606', (68, 76))	('patient', 'Species', '9606', (108, 115))	('patients', 'Species', '9606', (108, 116))	('low SCC-Ag expression', 'Var', (46, 67))
59831	30609649	Polymorphisms in ERCC5 rs17655 and ERCC1 rs735482 Genes Associated with the Survival of Male Patients with Postoperative Oral Squamous Cell Carcinoma Treated with Adjuvant Concurrent Chemoradiotherapy The nucleotide excision repair (NER) pathway plays a major role in the repair of DNA damaged by exogenous agents, such as chemotherapeutic and radiotherapeutic agents.	('Patients', 'Species', '9606', (93, 101))	('rs735482', 'Mutation', 'rs735482', (41, 49))	('ERCC5', 'Gene', '2073', (17, 22))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (126, 149))	('rs17655', 'Mutation', 'rs17655', (23, 30))	('Carcinoma', 'Phenotype', 'HP:0030731', (140, 149))	('Polymorphisms', 'Var', (0, 13))	('ERCC1', 'Gene', (35, 40))	('ERCC1', 'Gene', '2067', (35, 40))	('Associated with', 'Reg', (56, 71))	('ERCC5', 'Gene', (17, 22))	('Postoperative Oral Squamous Cell Carcinoma', 'Disease', (107, 149))	('rs17655', 'Var', (23, 30))	('Postoperative Oral Squamous Cell Carcinoma', 'Disease', 'MESH:D002294', (107, 149))	('rs735482', 'Var', (41, 49))
59832	30609649	Thus, we investigated the association between key potentially functional single nucleotide polymorphisms (SNPs) in the NER pathway and clinical outcomes in oral squamous cell carcinoma (OSCC) patients treated with concurrent chemoradiotherapy (CCRT).	('oral squamous cell carcinoma', 'Disease', (156, 184))	('patients', 'Species', '9606', (192, 200))	('single nucleotide polymorphisms', 'Var', (73, 104))	('investigated', 'Reg', (9, 21))	('NER pathway', 'Pathway', (119, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (175, 184))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (156, 184))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (161, 184))
59835	30609649	Carriers of the XPC rs2228000 TT genotype showed a borderline significant increased risk of poor overall survival under the recessive model (hazard ratio (HR) = 1.81, 95% confidence interval (CI) = 0.99-3.29).	('XPC', 'Gene', (16, 19))	('overall survival', 'MPA', (97, 113))	('poor', 'NegReg', (92, 96))	('XPC', 'Gene', '7508', (16, 19))	('rs2228000', 'Var', (20, 29))	('rs2228000', 'Mutation', 'rs2228000', (20, 29))
59836	30609649	The CC genotypes of ERCC5 rs17655 (HR = 1.54, 95% CI = 1.03-2.29) and ERCC1 rs735482 (HR = 1.65, 95% CI = 1.06-2.58) were associated with an increased risk of worse disease-free survival under the recessive model.	('rs735482', 'Var', (76, 84))	('ERCC1', 'Gene', (70, 75))	('ERCC1', 'Gene', '2067', (70, 75))	('worse', 'NegReg', (159, 164))	('ERCC5', 'Gene', (20, 25))	('rs735482', 'Mutation', 'rs735482', (76, 84))	('rs17655', 'Mutation', 'rs17655', (26, 33))	('rs17655', 'Var', (26, 33))	('ERCC5', 'Gene', '2073', (20, 25))
59837	30609649	In addition, participants carrying both the CC genotypes of ERCC5 rs17655 and ERCC1 rs735482 exhibited an enhanced susceptibility for recurrence (HR = 2.60, 95% CI = 1.11-6.09).	('rs17655', 'Var', (66, 73))	('rs17655', 'Mutation', 'rs17655', (66, 73))	('ERCC1', 'Gene', '2067', (78, 83))	('participants', 'Species', '9606', (13, 25))	('rs735482', 'Var', (84, 92))	('ERCC5', 'Gene', (60, 65))	('rs735482', 'Mutation', 'rs735482', (84, 92))	('ERCC5', 'Gene', '2073', (60, 65))	('ERCC1', 'Gene', (78, 83))	('recurrence', 'MPA', (134, 144))
59838	30609649	Our findings reveal that the ERCC5 rs17655 CC and ERCC1 rs735482 CC genotypes were associated with an increased risk of recurrence in male patients with OSCC treated with CCRT.	('ERCC1', 'Gene', '2067', (50, 55))	('ERCC5', 'Gene', (29, 34))	('OSCC', 'Disease', (153, 157))	('patients', 'Species', '9606', (139, 147))	('rs17655', 'Mutation', 'rs17655', (35, 42))	('rs735482', 'Mutation', 'rs735482', (56, 64))	('associated', 'Reg', (83, 93))	('ERCC5', 'Gene', '2073', (29, 34))	('rs735482 CC', 'Var', (56, 67))	('rs17655 CC', 'Var', (35, 45))	('recurrence', 'Disease', (120, 130))	('ERCC1', 'Gene', (50, 55))
59845	30609649	Genetic variations in DNA repair genes affect susceptibility to the efficacy and survival outcome of a certain treatment.	('efficacy', 'CPA', (68, 76))	('survival outcome', 'CPA', (81, 97))	('affect', 'Reg', (39, 45))	('Genetic variations', 'Var', (0, 18))	('susceptibility', 'MPA', (46, 60))	('men', 'Species', '9606', (116, 119))	('DNA repair genes', 'Gene', (22, 38))
59847	30609649	Single nucleotide polymorphism (SNP) in genes involved in the nucleotide excision repair (NER) pathway may modulate DNA repair capacity by influencing gene expression or activity, thereby affecting the anticancer effects of therapeutic agents and treatment response.	('modulate', 'Reg', (107, 115))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('Single nucleotide polymorphism', 'Var', (0, 30))	('gene expression', 'MPA', (151, 166))	('activity', 'MPA', (170, 178))	('affecting', 'Reg', (188, 197))	('men', 'Species', '9606', (252, 255))	('treatment response', 'CPA', (247, 265))	('cancer', 'Disease', (206, 212))	('cancer', 'Disease', 'MESH:D009369', (206, 212))	('influencing', 'Reg', (139, 150))	('DNA repair capacity', 'MPA', (116, 135))
59852	30609649	Therefore, identifying genetic markers in the NER pathway may help develop personalized management strategies, thereby maximizing treatment success and improving survival.	('genetic', 'Var', (23, 30))	('treatment success', 'CPA', (130, 147))	('men', 'Species', '9606', (94, 97))	('men', 'Species', '9606', (135, 138))	('maximizing', 'NegReg', (119, 129))	('person', 'Species', '9606', (75, 81))	('survival', 'CPA', (162, 170))	('improving', 'PosReg', (152, 161))
59853	30609649	Thus, we conducted a retrospective cohort study to test whether SNPs in genes involved in the NER pathway are associated with prognosis in male patients with OSCC treated with adjuvant CCRT.	('OSCC', 'Disease', (158, 162))	('associated', 'Reg', (110, 120))	('SNPs', 'Var', (64, 68))	('patients', 'Species', '9606', (144, 152))
59866	30609649	SNPs in the NER pathway were selected from studies that indicated that SNPs were associated with the risk or prognosis of malignancies in ethnic Chinese.	('associated', 'Reg', (81, 91))	('malignancies', 'Disease', (122, 134))	('SNPs', 'Var', (71, 75))	('malignancies', 'Disease', 'MESH:D009369', (122, 134))
59867	30609649	A total of 13 potentially functional SNPs in ERCC5 (rs2094258, rs1047768, rs17655, and rs873601), ERCC2 (rs13181 and rs1799793), ERCC1 (rs735482, rs3212986, and rs11615), XPC (rs2228001 and rs2228000), and XPA (rs1800975 and rs10817938) genes were genotyped using the Sequenom iPLEX MassARRAY system (Sequenom, Inc., San Diego, CA, USA).	('rs735482', 'Mutation', 'rs735482', (136, 144))	('rs2228000', 'Mutation', 'rs2228000', (190, 199))	('rs2228001', 'Mutation', 'rs2228001', (176, 185))	('ERCC2', 'Gene', '2068', (98, 103))	('rs2228001', 'Var', (176, 185))	('rs3212986', 'Mutation', 'rs3212986', (146, 155))	('ERCC1', 'Gene', (129, 134))	('rs13181', 'Mutation', 'rs13181', (105, 112))	('XPA', 'Gene', (206, 209))	('XPA', 'Gene', '7507', (206, 209))	('rs2094258', 'Mutation', 'rs2094258', (52, 61))	('rs1047768', 'Mutation', 'rs1047768', (63, 72))	('XPC', 'Gene', '7508', (171, 174))	('rs13181', 'Var', (105, 112))	('rs1800975', 'Mutation', 'rs1800975', (211, 220))	('rs10817938', 'Var', (225, 235))	('XPC', 'Gene', (171, 174))	('rs1047768', 'Var', (63, 72))	('rs873601', 'Mutation', 'rs873601', (87, 95))	('rs873601', 'Var', (87, 95))	('rs2094258', 'Var', (52, 61))	('rs11615', 'Var', (161, 168))	('ERCC5', 'Gene', '2073', (45, 50))	('ERCC1', 'Gene', '2067', (129, 134))	('rs17655', 'Mutation', 'rs17655', (74, 81))	('ERCC5', 'Gene', (45, 50))	('rs10817938', 'Mutation', 'rs10817938', (225, 235))	('rs2228000', 'Var', (190, 199))	('rs1800975', 'Var', (211, 220))	('rs1799793', 'Mutation', 'rs1799793', (117, 126))	('rs11615', 'Mutation', 'rs11615', (161, 168))	('rs735482', 'Var', (136, 144))	('rs3212986', 'Var', (146, 155))	('ERCC2', 'Gene', (98, 103))	('rs17655', 'Var', (74, 81))
59872	30609649	Postoperative RT was administered to patients with pT4 stage tumor, pathologically close margins (<=4 mm), or pathologically positive lymph nodes.	('pT4 stage', 'Var', (51, 60))	('patients', 'Species', '9606', (37, 45))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Disease', (61, 66))
59886	30609649	The genotype frequency distribution analysis showed a statistically significant difference in genotypes of ERCC1 rs11615 in terms of tumor differentiation (p = 0.039), XPC rs2228000 in terms of vascular invasion (p = 0.045), ERCC1 rs3212986 and XPA rs10817938 in terms of lymphatic invasion (p = 0.046 and 0.033, respectively), XPC rs2228001 in terms of pathologic TNM stage (p = 0.039), and ERCC5 rs17655 in terms of DFS (p = 0.049) (Table S1).	('ERCC1', 'Gene', (107, 112))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('ERCC1', 'Gene', (225, 230))	('lymphatic invasion', 'CPA', (272, 290))	('rs3212986', 'Var', (231, 240))	('vascular invasion', 'CPA', (194, 211))	('XPA', 'Gene', '7507', (245, 248))	('XPA', 'Gene', (245, 248))	('rs2228001', 'Mutation', 'rs2228001', (332, 341))	('rs3212986', 'Mutation', 'rs3212986', (231, 240))	('XPC', 'Gene', '7508', (328, 331))	('rs2228000', 'Mutation', 'rs2228000', (172, 181))	('XPC', 'Gene', '7508', (168, 171))	('rs11615', 'Var', (113, 120))	('ERCC5', 'Gene', '2073', (392, 397))	('XPC', 'Gene', (328, 331))	('tumor', 'Disease', (133, 138))	('XPC', 'Gene', (168, 171))	('rs17655', 'Mutation', 'rs17655', (398, 405))	('ERCC5', 'Gene', (392, 397))	('rs10817938', 'Mutation', 'rs10817938', (249, 259))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('ERCC1', 'Gene', '2067', (107, 112))	('rs11615', 'Mutation', 'rs11615', (113, 120))	('TNM', 'Gene', '10178', (365, 368))	('ERCC1', 'Gene', '2067', (225, 230))	('TNM', 'Gene', (365, 368))
59888	30609649	In the univariate Cox proportional hazards models, the ERCC1 rs735482 CC genotype was marginally significantly associated with poor DFS (HR = 1.53, 95% CI = 0.99-2.38; p = 0.058).	('ERCC1', 'Gene', (55, 60))	('poor', 'NegReg', (127, 131))	('ERCC1', 'Gene', '2067', (55, 60))	('rs735482', 'Mutation', 'rs735482', (61, 69))	('rs735482 CC', 'Var', (61, 72))	('DFS', 'MPA', (132, 135))
59889	30609649	The XPA rs10817938 CC genotype was significantly associated with an increased risk of worse OS (HR = 2.97, 95% CI = 1.20-7.35; p = 0.019), and DFS (HR = 2.61, 95% CI = 1.06-6.41; p = 0.037), respectively (Table S2).	('XPA', 'Gene', (4, 7))	('rs10817938 CC', 'Var', (8, 21))	('DFS', 'Disease', (143, 146))	('worse OS', 'Disease', (86, 94))	('rs10817938', 'Mutation', 'rs10817938', (8, 18))	('XPA', 'Gene', '7507', (4, 7))
59890	30609649	Only the XPC rs2228000 TT genotype (HR = 1.81, 95% CI = 0.99-3.29, p = 0.053) showed an increased risk of poor OS at borderline significance compared with the CC+CT genotypes.	('poor OS', 'Disease', (106, 113))	('XPC', 'Gene', (9, 12))	('XPC', 'Gene', '7508', (9, 12))	('rs2228000', 'Var', (13, 22))	('rs2228000', 'Mutation', 'rs2228000', (13, 22))
59891	30609649	The ERCC5 rs17655 CC (HR = 1.50, 95% CI = 1.01-2.24; p = 0.045) and ERCC1 rs735482 CC (HR = 1.61, 95% CI = 1.04-2.51; p = 0.034) genotypes were significantly associated with an increased risk of DFS compared with their counterparts with the GG+GC and AA+AC genotypes, respectively, in the recessive models.	('ERCC5', 'Gene', '2073', (4, 9))	('ERCC1', 'Gene', '2067', (68, 73))	('ERCC1', 'Gene', (68, 73))	('rs17655', 'Mutation', 'rs17655', (10, 17))	('DFS', 'Disease', (195, 198))	('ERCC5', 'Gene', (4, 9))	('rs17655 CC', 'Var', (10, 20))	('rs735482', 'Mutation', 'rs735482', (74, 82))	('rs735482 CC', 'Var', (74, 85))
59892	30609649	The test of LD show that SNPs in ERCC5 block 1 (rs2094258 and rs1047768; D' = 0.97, R2 = 0.19) and block 2 (rs17655 and rs873601; D' = 0.98, R2 = 0.89), ERCC1 block (rs3212986 and rs11615; D' = 1.00, R2 = 0.18), XPC block (rs2228001 and rs2228000; D' = 1.00, R2 = 0.28), and XPA block (rs1800975 and rs10817938; D' = 1.00, R2 = 0.24) were in LD with each other (Figure S1).	('rs2094258', 'Var', (48, 57))	('XPC', 'Gene', '7508', (212, 215))	('ERCC5', 'Gene', (33, 38))	('rs10817938', 'Mutation', 'rs10817938', (300, 310))	('ERCC1', 'Gene', '2067', (153, 158))	('XPC', 'Gene', (212, 215))	('rs2228000', 'Mutation', 'rs2228000', (237, 246))	('rs2228001', 'Mutation', 'rs2228001', (223, 232))	('rs10817938; D', 'Var', (300, 313))	('rs1800975', 'Var', (286, 295))	('rs17655', 'Mutation', 'rs17655', (108, 115))	('rs2228001', 'Var', (223, 232))	('ERCC1', 'Gene', (153, 158))	('rs873601', 'Mutation', 'rs873601', (120, 128))	('rs873601', 'Var', (120, 128))	('XPA', 'Gene', '7507', (275, 278))	('rs1047768', 'Mutation', 'rs1047768', (62, 71))	('rs3212986', 'Var', (166, 175))	('XPA', 'Gene', (275, 278))	('rs11615', 'Mutation', 'rs11615', (180, 187))	('rs17655', 'Var', (108, 115))	('rs3212986', 'Mutation', 'rs3212986', (166, 175))	('rs1047768', 'Var', (62, 71))	('rs2094258', 'Mutation', 'rs2094258', (48, 57))	('rs1800975', 'Mutation', 'rs1800975', (286, 295))	('ERCC5', 'Gene', '2073', (33, 38))	("rs11615; D'", 'Var', (180, 191))	('rs2228000', 'Var', (237, 246))
59894	30609649	We further conducted a combination analysis for the ERCC5 rs17655 and ERCC1 rs735482 polymorphisms and DSF in patients with OSCC.	('rs17655', 'Var', (58, 65))	('rs735482', 'Var', (76, 84))	('ERCC1', 'Gene', (70, 75))	('patients', 'Species', '9606', (110, 118))	('ERCC5', 'Gene', '2073', (52, 57))	('ERCC1', 'Gene', '2067', (70, 75))	('rs735482', 'Mutation', 'rs735482', (76, 84))	('rs17655', 'Mutation', 'rs17655', (58, 65))	('ERCC5', 'Gene', (52, 57))	('OSCC', 'Disease', (124, 128))
59895	30609649	The multivariate Cox proportional models indicated that patients with the combination of ERCC5 rs17655 CC and ERCC1 rs735482 CC genotypes exhibited a higher risk of disease recurrence than those with the combination of ERCC5 rs17655 GG+GC and ERCC1 rs735482 AA+AC genotypes (HR = 2.60, 95% CI = 1.11-6.09; p = 0.027) (Table 4).	('patients', 'Species', '9606', (56, 64))	('ERCC5', 'Gene', '2073', (219, 224))	('ERCC1', 'Gene', (243, 248))	('ERCC1', 'Gene', '2067', (243, 248))	('rs17655 CC', 'Var', (95, 105))	('rs735482', 'Mutation', 'rs735482', (249, 257))	('disease recurrence', 'CPA', (165, 183))	('ERCC1', 'Gene', '2067', (110, 115))	('ERCC1', 'Gene', (110, 115))	('rs17655', 'Mutation', 'rs17655', (225, 232))	('ERCC5', 'Gene', (89, 94))	('rs17655', 'Mutation', 'rs17655', (95, 102))	('rs735482', 'Mutation', 'rs735482', (116, 124))	('ERCC5', 'Gene', (219, 224))	('ERCC5', 'Gene', '2073', (89, 94))	('rs735482 CC', 'Var', (116, 127))
59896	30609649	Results show a significant interaction between ERCC5 rs17655 polymorphism and perineural invasion on the risk for DFS (interaction p = 0.008).	('ERCC5', 'Gene', (47, 52))	('rs17655 polymorphism', 'Var', (53, 73))	('rs17655', 'Mutation', 'rs17655', (53, 60))	('DFS', 'Disease', (114, 117))	('perineural invasion', 'CPA', (78, 97))	('ERCC5', 'Gene', '2073', (47, 52))
59897	30609649	The ERCC5 rs17655 CC genotype individuals with perineural invasion (HR = 2.46, 95% CI = 1.46-4.15; p < 0.001) had an increased risk for DFS compared to their counterparts with no perineural invasion.	('ERCC5', 'Gene', '2073', (4, 9))	('rs17655', 'Mutation', 'rs17655', (10, 17))	('DFS', 'Disease', (136, 139))	('ERCC5', 'Gene', (4, 9))	('rs17655 CC', 'Var', (10, 20))
59898	30609649	Although a significant interaction between ERCC1 rs735482 polymorphism and vascular invasion was also observed (interaction p < 0.001), the harmful effect of CC genotype on recurrence was not present in any subgroup of vascular invasion.	('rs735482', 'Var', (49, 57))	('rs735482', 'Mutation', 'rs735482', (49, 57))	('vascular invasion', 'CPA', (75, 92))	('ERCC1', 'Gene', '2067', (43, 48))	('ERCC1', 'Gene', (43, 48))
59899	30609649	In this study, we investigated the association between potentially functional SNPs in the NER pathway genes and clinical outcomes in male patients with OSCC treated with CCRT.	('SNPs', 'Var', (78, 82))	('patients', 'Species', '9606', (138, 146))	('NER pathway genes', 'Gene', (90, 107))
59900	30609649	Our findings suggest that the XPC rs2228000 TT genotype was marginally significantly associated with increased risk of death, whereas the ERCC5 rs17655 CC and ERCC1 rs735482 CC genotypes were significantly associated with the increased risk of relapse.	('ERCC5', 'Gene', '2073', (138, 143))	('rs17655', 'Mutation', 'rs17655', (144, 151))	('rs735482', 'Mutation', 'rs735482', (165, 173))	('relapse', 'Disease', (244, 251))	('associated', 'Reg', (206, 216))	('rs735482 CC', 'Var', (165, 176))	('death', 'Disease', 'MESH:D003643', (119, 124))	('death', 'Disease', (119, 124))	('XPC', 'Gene', (30, 33))	('ERCC1', 'Gene', (159, 164))	('ERCC1', 'Gene', '2067', (159, 164))	('rs17655 CC', 'Var', (144, 154))	('rs2228000', 'Var', (34, 43))	('XPC', 'Gene', '7508', (30, 33))	('ERCC5', 'Gene', (138, 143))	('rs2228000', 'Mutation', 'rs2228000', (34, 43))
59902	30609649	Studies have revealed that variations in DNA-repair capacity are related to cancer risk and prognosis.	('variations', 'Var', (27, 37))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('related', 'Reg', (65, 72))	('DNA-repair', 'MPA', (41, 51))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))
59903	30609649	In addition, SNPs in the NER genes modulate susceptibility to efficacy and survival outcome of the treatment in certain types of cancers.	('NER genes', 'Gene', (25, 34))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('men', 'Species', '9606', (104, 107))	('modulate', 'Reg', (35, 43))	('cancers', 'Disease', 'MESH:D009369', (129, 136))	('cancers', 'Phenotype', 'HP:0002664', (129, 136))	('SNPs', 'Var', (13, 17))	('cancers', 'Disease', (129, 136))	('susceptibility', 'MPA', (44, 58))	('survival outcome', 'CPA', (75, 91))
59907	30609649	SNPs in this gene have been found to affect clinical outcomes in various cancer types.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('clinical outcomes', 'CPA', (44, 61))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('affect', 'Reg', (37, 43))	('SNPs', 'Var', (0, 4))
59908	30609649	Li and colleagues observed that the XPC rs2228000 TT genotypes were associated with shorter OS than the CC+CT genotype individuals in a study of Japanese gastric cancer patients.	('gastric cancer', 'Phenotype', 'HP:0012126', (154, 168))	('patients', 'Species', '9606', (169, 177))	('XPC', 'Gene', (36, 39))	('gastric cancer', 'Disease', (154, 168))	('rs2228000', 'Var', (40, 49))	('XPC', 'Gene', '7508', (36, 39))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('gastric cancer', 'Disease', 'MESH:D013274', (154, 168))	('shorter', 'Disease', (84, 91))	('rs2228000', 'Mutation', 'rs2228000', (40, 49))
59909	30609649	Another Chinese study demonstrated that patients with the CC genotype of XPC rs2228000 have a borderline significant decreased risk of developing gastric cancer compared with those with the CT+TT genotype.	('XPC', 'Gene', (73, 76))	('gastric cancer', 'Disease', 'MESH:D013274', (146, 160))	('gastric cancer', 'Disease', (146, 160))	('patients', 'Species', '9606', (40, 48))	('decreased', 'NegReg', (117, 126))	('rs2228000', 'Var', (77, 86))	('XPC', 'Gene', '7508', (73, 76))	('rs2228000', 'Mutation', 'rs2228000', (77, 86))	('gastric cancer', 'Phenotype', 'HP:0012126', (146, 160))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))
59910	30609649	Similarly, in our study, the XPC rs2228000 TT genotype shows an increased risk of death compared with the CC+CT genotype.	('death', 'Disease', 'MESH:D003643', (82, 87))	('death', 'Disease', (82, 87))	('rs2228000', 'Var', (33, 42))	('rs2228000', 'Mutation', 'rs2228000', (33, 42))	('XPC', 'Gene', (29, 32))	('XPC', 'Gene', '7508', (29, 32))
59911	30609649	Given the importance of the XPC gene in the NER pathway, it is possible that variants of XPC alter the DNA repair capacity and thereby affect sensitivity to therapeutic agents.	('XPC', 'Gene', '7508', (89, 92))	('variants', 'Var', (77, 85))	('XPC', 'Gene', (28, 31))	('affect', 'Reg', (135, 141))	('XPC', 'Gene', '7508', (28, 31))	('DNA repair capacity', 'MPA', (103, 122))	('XPC', 'Gene', (89, 92))	('sensitivity to therapeutic agents', 'MPA', (142, 175))	('alter', 'Reg', (93, 98))
59912	30609649	We also observed that those with the ERCC5 rs17655 CC and ERCC1 rs735482 CC genotypes have an increased risk of relapse compared with individuals with the GG+GC and AA+AC genotypes, respectively.	('rs17655 CC', 'Var', (43, 53))	('ERCC1', 'Gene', '2067', (58, 63))	('ERCC1', 'Gene', (58, 63))	('ERCC5', 'Gene', (37, 42))	('relapse', 'CPA', (112, 119))	('ERCC5', 'Gene', '2073', (37, 42))	('rs735482', 'Mutation', 'rs735482', (64, 72))	('rs735482 CC', 'Var', (64, 75))	('rs17655', 'Mutation', 'rs17655', (43, 50))
59914	30609649	Evidence has linked ERCC5 polymorphism to chemotherapeutic response and prognosis of tumors.	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('ERCC5', 'Gene', '2073', (20, 25))	('ERCC5', 'Gene', (20, 25))	('tumors', 'Disease', (85, 91))	('linked', 'Reg', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('polymorphism', 'Var', (26, 38))	('tumors', 'Disease', 'MESH:D009369', (85, 91))
59916	30609649	Additionally, the rs17655 leads to an amino-acid substitution from histidine to aspartic acid, which may lead to differential interacting abilities, thus, influencing the DNA repair efficacy.	('rs17655', 'Mutation', 'rs17655', (18, 25))	('histidine', 'Chemical', 'MESH:D006639', (67, 76))	('influencing', 'Reg', (155, 166))	('rs17655', 'Var', (18, 25))	('DNA repair efficacy', 'CPA', (171, 190))	('aspartic acid', 'Chemical', 'MESH:D001224', (80, 93))	('interacting', 'Interaction', (126, 137))
59917	30609649	also observed that ERCC5 rs17655 polymorphism has a moderately increased risk of recurrence in squamous cell carcinoma of the oropharynx.	('rs17655', 'Var', (25, 32))	('rs17655', 'Mutation', 'rs17655', (25, 32))	('ERCC5', 'Gene', (19, 24))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (95, 118))	('ERCC5', 'Gene', '2073', (19, 24))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('squamous cell carcinoma', 'Disease', (95, 118))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (95, 118))
59920	30609649	On the basis of these study results, we speculate that the CC genotypes of ERCC5 rs17655 and ERCC1 rs735482 may increase the DNA-repair capacity of cancer cells, leading to increased susceptibility to recurrence.	('cancer', 'Disease', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('rs735482', 'Mutation', 'rs735482', (99, 107))	('ERCC1', 'Gene', (93, 98))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('ERCC5', 'Gene', (75, 80))	('rs17655', 'Mutation', 'rs17655', (81, 88))	('increase', 'PosReg', (112, 120))	('ERCC1', 'Gene', '2067', (93, 98))	('DNA-repair capacity', 'MPA', (125, 144))	('ERCC5', 'Gene', '2073', (75, 80))	('rs17655', 'Var', (81, 88))	('rs735482', 'Var', (99, 107))	('recurrence', 'CPA', (201, 211))
59926	30609649	We investigated the association between key potentially functional SNPs in the NER pathway and susceptibility for death or relapse in male patients with advanced OSCC who were treated with adjuvant CCRT.	('NER pathway', 'Pathway', (79, 90))	('patients', 'Species', '9606', (139, 147))	('SNPs', 'Var', (67, 71))	('death', 'Disease', 'MESH:D003643', (114, 119))	('death', 'Disease', (114, 119))
59927	30609649	Our findings showed that the CC genotypes of ERCC5 rs17655 and ERCC1 rs735482 were associated with an increased risk of recurrence.	('ERCC1', 'Gene', '2067', (63, 68))	('ERCC1', 'Gene', (63, 68))	('rs17655', 'Var', (51, 58))	('rs735482', 'Mutation', 'rs735482', (69, 77))	('rs17655', 'Mutation', 'rs17655', (51, 58))	('ERCC5', 'Gene', '2073', (45, 50))	('recurrence', 'CPA', (120, 130))	('associated', 'Reg', (83, 93))	('rs735482', 'Var', (69, 77))	('ERCC5', 'Gene', (45, 50))
59931	29902298	Prevalence of PDL1 Amplification and Preliminary Response to Immune Checkpoint Blockade in Solid Tumors Copy number alterations in programmed cell death ligand 1 (PDL1 or CD274), programmed cell death 1 ligand 2 (PDCD1LG2 or PDL2), and Janus kinase 2 (JAK2) genes (chromosome 9p24.1) characterize Hodgkin lymphoma, resulting in high response rates to programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) blockade.	('programmed cell death 1 ligand 2', 'Gene', '102160127', (179, 211))	('Copy', 'Var', (104, 108))	('lymphoma', 'Phenotype', 'HP:0002665', (305, 313))	('PDL1', 'Gene', (14, 18))	('PD-1', 'Gene', (376, 380))	('programmed cell death 1 ligand 2', 'Gene', (179, 211))	('alterations', 'Var', (116, 127))	('PD-1', 'Gene', '5133', (376, 380))	('Tumors', 'Disease', (97, 103))	('PDL1', 'Gene', '29126', (14, 18))	('Hodgkin lymphoma', 'Disease', (297, 313))	('Tumors', 'Disease', 'MESH:D009369', (97, 103))	('PDL1', 'Gene', (163, 167))	('PDL1', 'Gene', '29126', (163, 167))	('response', 'MPA', (333, 341))	('Hodgkin lymphoma', 'Disease', 'MESH:D006689', (297, 313))	('Hodgkin lymphoma', 'Phenotype', 'HP:0012189', (297, 313))	('Tumor', 'Phenotype', 'HP:0002664', (97, 102))	('Tumors', 'Phenotype', 'HP:0002664', (97, 103))
59933	29902298	To examine the prevalence of PDL1 amplification and its utility as a response biomarker to PD-1/PD-L1 blockade in solid tumors.	('PDL1', 'Gene', (29, 33))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('PD-1', 'Gene', (91, 95))	('PD-1', 'Gene', '5133', (91, 95))	('solid tumors', 'Disease', (114, 126))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('amplification', 'Var', (34, 47))	('solid tumors', 'Disease', 'MESH:D009369', (114, 126))
59940	29902298	Of the 118 187 deidentified tumor samples, PDL1 amplifications were identified in 843 (0.7%), including more than 100 types of solid tumors.	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('solid tumors', 'Disease', (127, 139))	('tumor', 'Disease', (28, 33))	('PDL1', 'Gene', (43, 47))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('amplifications', 'Var', (48, 62))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('solid tumors', 'Disease', 'MESH:D009369', (127, 139))	('tumor', 'Disease', (133, 138))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('identified', 'Reg', (68, 78))
59945	29902298	The results of this study suggest that PDL1 amplification occurs in a small subset of malignant tumors.	('PDL1', 'Gene', (39, 43))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('amplification', 'Var', (44, 57))	('malignant tumors', 'Disease', (86, 102))	('malignant tumors', 'Disease', 'MESH:D018198', (86, 102))
59952	29902298	Overall, 105 of 108 biopsy specimens (97.2%) from patients with newly diagnosed classic Hodgkin lymphoma have had increased PDL1 and PDCD1LG2 copy numbers.	('copy numbers', 'Var', (142, 154))	('classic Hodgkin lymphoma', 'Disease', (80, 104))	('PDCD1LG2', 'Gene', (133, 141))	('Hodgkin lymphoma', 'Phenotype', 'HP:0012189', (88, 104))	('patients', 'Species', '9606', (50, 58))	('increased', 'PosReg', (114, 123))	('classic Hodgkin lymphoma', 'Disease', 'MESH:D006689', (80, 104))	('lymphoma', 'Phenotype', 'HP:0002665', (96, 104))	('increased PD', 'Phenotype', 'HP:0008151', (114, 126))	('PDL1', 'Gene', (124, 128))
59953	29902298	This increase is attributable to 9p24.1 amplifications, copy number alterations (CNAs), or polysomy of chromosome 9p.	('copy number alterations', 'Var', (56, 79))	('increase', 'PosReg', (5, 13))	('to 9', 'Species', '1214577', (30, 34))	('polysomy', 'Var', (91, 99))	('9p24.1', 'Protein', (33, 39))	('amplifications', 'Var', (40, 54))
59957	29902298	Taken together, in certain lymphomas, chromosome 9p24.1 alterations, which include PDL1, are relatively common and are associated with high susceptibility to PD-1 blockade.	('lymphomas', 'Disease', (27, 36))	('alterations', 'Var', (56, 67))	('susceptibility', 'Reg', (140, 154))	('lymphomas', 'Disease', 'MESH:D008223', (27, 36))	('PD-1', 'Gene', '5133', (158, 162))	('PD-1', 'Gene', (158, 162))	('lymphomas', 'Phenotype', 'HP:0002665', (27, 36))	('lymphoma', 'Phenotype', 'HP:0002665', (27, 35))	('PDL1', 'Gene', (83, 87))
59968	29902298	Ranges of MSI scores were assigned as high MSI (MSI-H), microsatellite stable, or intermediate or ambiguous MSI.	('microsatellite', 'Var', (56, 70))	('MSI-H', 'Disease', 'MESH:D000848', (48, 53))	('MSI-H', 'Disease', (48, 53))
59969	29902298	To understand the large-scale prevalence of PDL1 amplification and its relevant associations, we analyzed 118 187 patient samples with cancer from the Foundation Medicine deiden-tified database.	('amplification', 'Var', (49, 62))	('cancer', 'Disease', (135, 141))	('PDL1', 'Gene', (44, 48))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('patient', 'Species', '9606', (114, 121))	('cancer', 'Disease', 'MESH:D009369', (135, 141))
59970	29902298	Only patients with chromosome 9p24.1 alterations in PDL1, PDL2, and/or JAK2 alterations were further reviewed (eFigure 1 in Supplement 1 and Supplement 2).	('patients', 'Species', '9606', (5, 13))	('PDL1', 'Gene', (52, 56))	('PDL2', 'Gene', (58, 62))	('alterations', 'Var', (37, 48))
59977	29902298	Overall, 843 of 118 187 patient samples (0.7%) that had undergone comprehensive genomic profiling had 6 or more CNAs in PDL1 (Table).	('PDL1', 'Gene', (120, 124))	('CNAs', 'Var', (112, 116))	('patient', 'Species', '9606', (24, 31))
59980	29902298	The tumor type with the highest percentage of PDL1 amplification was mixed hepatocellular cholangiocarcinoma (10.5% of samples).	('tumor', 'Disease', (4, 9))	('PDL1', 'Gene', (46, 50))	('hepatocellular cholangiocarcinoma', 'Disease', 'MESH:D018281', (75, 108))	('hepatocellular cholangiocarcinoma', 'Disease', (75, 108))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (90, 108))	('amplification', 'Var', (51, 64))
59983	29902298	The mean TMB for PDLl-amplified tumors was 13.3 mutations per megabase, and the median was 6.3 mutations per megabase.	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('TMB', 'Chemical', '-', (9, 12))	('PDLl-amplified', 'Gene', (17, 31))	('tumors', 'Disease', (32, 38))	('mutations', 'Var', (48, 57))	('tumors', 'Disease', 'MESH:D009369', (32, 38))
59984	29902298	For unamplified tumors, the mean was 7.4 mutations per megabase and the median was 3.6 mutations per megabase (eTable 3 in Supplement 1).	('mutations', 'Var', (41, 50))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('tumors', 'Disease', 'MESH:D009369', (16, 22))	('tumors', 'Disease', (16, 22))
59989	29902298	Five of 741 patients (0.7%) with PDL1 amplification (2 gastrointestinal tumors and 3 carcinomas of unknown primary) who were tested for microsatellite status were MSI-H; 1435 of 103 373 patients (1.4%) who did not have PDL1 amplification and were tested for microsatellite status were MSI-H.	('MSI-H', 'Disease', 'MESH:D000848', (285, 290))	('patients', 'Species', '9606', (12, 20))	('PDL1', 'Gene', (33, 37))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('patients', 'Species', '9606', (186, 194))	('MSI-H', 'Disease', 'MESH:D000848', (163, 168))	('gastrointestinal tumors', 'Phenotype', 'HP:0007378', (55, 78))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('gastrointestinal tumors', 'Disease', 'MESH:D004067', (55, 78))	('gastrointestinal tumors', 'Disease', (55, 78))	('MSI-H', 'Disease', (285, 290))	('carcinomas', 'Disease', 'MESH:D002277', (85, 95))	('amplification', 'Var', (38, 51))	('carcinomas', 'Phenotype', 'HP:0030731', (85, 95))	('MSI-H', 'Disease', (163, 168))	('carcinomas', 'Disease', (85, 95))
59990	29902298	In the UCSD cohort (n = 13), the median TMB for PDLl-amplified tumors was 9 mutations per megabase vs 4 mutations per megabase for non-PDLl-amplified tumors (P = .007).	('tumors', 'Disease', (150, 156))	('tumors', 'Disease', 'MESH:D009369', (150, 156))	('tumors', 'Phenotype', 'HP:0002664', (150, 156))	('mutations', 'Var', (76, 85))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('tumors', 'Disease', (63, 69))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('TMB', 'Chemical', '-', (40, 43))	('PDLl-amplified', 'Gene', (48, 62))
59994	29902298	All 13 patients had coamplification of PDCD1LG2 (PDL2), and all but 1 (92.3%) had coamplification of JAK2.	('coamplification', 'Var', (20, 35))	('patients', 'Species', '9606', (7, 15))	('PDCD1LG2', 'Gene', (39, 47))
59998	29902298	A total of 70 genes with 143 alterations were identified among the 13 patients with PDL1 CNAs (Figure 1 and eTable 5 in Supplement 1).	('patients', 'Species', '9606', (70, 78))	('PDL1', 'Gene', (84, 88))	('alterations', 'Var', (29, 40))
60002	29902298	One patient had metastatic head and neck squamous cell carcinoma that harbored a PDL1 exon 7 truncation.	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (36, 64))	('truncation', 'Var', (93, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (55, 64))	('patient', 'Species', '9606', (4, 11))	('neck squamous cell carcinoma', 'Disease', (36, 64))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (27, 64))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (41, 64))
60005	29902298	Nine of the 13 patients (69.2%) with PDL1 amplification were treated with checkpoint blockade (all solid tumors) (eTable 5 in Supplement 1).	('patients', 'Species', '9606', (15, 23))	('PDL1', 'Gene', (37, 41))	('solid tumors', 'Disease', 'MESH:D009369', (99, 111))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('amplification', 'Var', (42, 55))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('solid tumors', 'Disease', (99, 111))
60012	29902298	The case was presented at the molecular tumor board, and treatment with checkpoint inhibition was debated because of the presence of MDM2 amplification, which has been associated with hyperprogression.	('associated with', 'Reg', (168, 183))	('MDM2', 'Gene', (133, 137))	('molecular tumor', 'Disease', 'MESH:D030342', (30, 45))	('hyperprogression', 'Disease', (184, 200))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('amplification', 'Var', (138, 151))	('molecular tumor', 'Disease', (30, 45))
60016	29902298	These alterations were identified in a small subset of multiple solid tumor types, including rare neoplasms, such as bladder squamous cell carcinoma, undifferentiated soft-tissue sarcomas, and sarcomatoid renal cell carcinoma.	('alterations', 'Var', (6, 17))	('soft-tissue sarcomas', 'Phenotype', 'HP:0030448', (167, 187))	('bladder squamous cell carcinoma', 'Disease', (117, 148))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (125, 148))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('neoplasms', 'Phenotype', 'HP:0002664', (98, 107))	('sarcomatoid renal cell carcinoma', 'Disease', (193, 225))	('sarcomas', 'Disease', 'MESH:D012509', (179, 187))	('sarcomas', 'Phenotype', 'HP:0100242', (179, 187))	('sarcomas', 'Disease', (179, 187))	('sarcomatoid renal cell carcinoma', 'Disease', 'MESH:C538614', (193, 225))	('neoplasms', 'Disease', 'MESH:D009369', (98, 107))	('identified', 'Reg', (23, 33))	('soft-tissue sarcoma', 'Phenotype', 'HP:0030448', (167, 186))	('sarcoma', 'Phenotype', 'HP:0100242', (179, 186))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (205, 225))	('carcinoma', 'Phenotype', 'HP:0030731', (139, 148))	('tumor', 'Disease', (70, 75))	('carcinoma', 'Phenotype', 'HP:0030731', (216, 225))	('neoplasms', 'Disease', (98, 107))	('bladder squamous cell carcinoma', 'Disease', 'MESH:D002294', (117, 148))	('sarcoma', 'Phenotype', 'HP:0100242', (193, 200))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
60018	29902298	Six of 9 patients (66.7%) with PDL1 amplification responded to immunotherapy vs 45 of 151 patients (29.8%) in the overall UCSD-treated cohort (P = .03).	('patients', 'Species', '9606', (9, 17))	('amplification', 'Var', (36, 49))	('responded', 'Reg', (50, 59))	('PDL1', 'Gene', (31, 35))	('patients', 'Species', '9606', (90, 98))
60019	29902298	Although rare outside certain lymphomas, identification of amplifications in PDL1 is important because this subset of tumors appears to have a high likelihood of responding to checkpoint blockade.	('lymphomas', 'Phenotype', 'HP:0002665', (30, 39))	('PDL1', 'Gene', (77, 81))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('responding to checkpoint blockade', 'MPA', (162, 195))	('amplifications', 'Var', (59, 73))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('lymphoma', 'Phenotype', 'HP:0002665', (30, 38))	('lymphomas', 'Disease', (30, 39))	('tumors', 'Disease', (118, 124))	('lymphomas', 'Disease', 'MESH:D008223', (30, 39))	('tumors', 'Disease', 'MESH:D009369', (118, 124))
60020	29902298	This situation is analogous to that in patients withlungcancerthat harbors anaplastic lymphoma kinase (ALK) (OMIM 105590) and V-ROS avian UR2 sarcoma virus oncogene homolog 1 ROS1 (OMIM 165020) alterations, which both confer sensitivity to ALK inhibitors.	('ALK', 'Gene', '238', (103, 106))	('ROS1', 'Gene', (175, 179))	('ALK', 'Gene', '238', (240, 243))	('anaplastic lymphoma kinase', 'Gene', (75, 101))	('patients', 'Species', '9606', (39, 47))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (75, 94))	('ROS1', 'Gene', '6098', (175, 179))	('sarcoma', 'Phenotype', 'HP:0100242', (142, 149))	('UR2 sarcoma virus', 'Species', '354090', (138, 155))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('alterations', 'Var', (194, 205))	('ALK', 'Gene', (240, 243))	('ALK', 'Gene', (103, 106))	('anaplastic lymphoma kinase', 'Gene', '238', (75, 101))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('lymphoma', 'Phenotype', 'HP:0002665', (86, 94))
60022	29902298	Infection has been implicated in certain types of neoplasms identified to have a higher prevalence of PDL1 amplifications.	('neoplasms', 'Phenotype', 'HP:0002664', (50, 59))	('PDL1', 'Gene', (102, 106))	('neoplasms', 'Disease', 'MESH:D009369', (50, 59))	('implicated', 'Reg', (19, 29))	('amplifications', 'Var', (107, 121))	('neoplasms', 'Disease', (50, 59))
60025	29902298	It is plausible that these tumors are using PDL1 amplification as a mechanism of immune escape from an endogenous immune response.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('amplification', 'Var', (49, 62))	('PDL1', 'Gene', (44, 48))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('tumors', 'Disease', (27, 33))	('tumors', 'Disease', 'MESH:D009369', (27, 33))
60039	29902298	Of interest, in addition to the 13 patients in the UCSD cohort who had PDL1 amplification, 2 patients harbored alterations that involved PDL1 and PDCD1LG2 (eTable 4 in Supplement 1) that were not CNAs.	('PDL1', 'Gene', (137, 141))	('PDL1', 'Gene', (71, 75))	('PDCD1LG2', 'Gene', (146, 154))	('involved', 'Reg', (128, 136))	('patients', 'Species', '9606', (35, 43))	('patients', 'Species', '9606', (93, 101))	('amplification', 'Var', (76, 89))
60042	29902298	However, translocations that involve PDCD1LG2 and numerous partners have been highly characterized in primary mediastinal large B-cell lymphoma and result in increased PD-L2 expression.	('PDCD1LG2', 'Gene', (37, 45))	('lymphoma', 'Phenotype', 'HP:0002665', (135, 143))	('translocations', 'Var', (9, 23))	('expression', 'MPA', (174, 184))	('B-cell lymphoma', 'Disease', (128, 143))	('B-cell lymphoma', 'Disease', 'MESH:D016393', (128, 143))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (128, 143))	('increased PD', 'Phenotype', 'HP:0008151', (158, 170))	('PD-L2', 'Gene', (168, 173))	('PD-L2', 'Gene', '80380', (168, 173))	('increased', 'PosReg', (158, 167))
60047	29902298	Findings In this study of 118 187 tumor samples from a deidentified database, including a subset of 2039 samples from a clinically annotated database, the prevalence of PDL1 amplification was 0.7%.	('PDL1', 'Gene', (169, 173))	('tumor', 'Disease', (34, 39))	('amplification', 'Var', (174, 187))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
60048	29902298	The objective response rate for patients with solid tumors that harbored PDL1 amplification was 66.7%, with a median progression-free survival of 15.2 months.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('patients', 'Species', '9606', (32, 40))	('solid tumors', 'Disease', 'MESH:D009369', (46, 58))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('amplification', 'Var', (78, 91))	('solid tumors', 'Disease', (46, 58))	('PDL1', 'Gene', (73, 77))
60049	29902298	Meaning The results of this study suggest that PDL1 amplification occurs in a small subset of malignant tumors; however, testing for this alteration may be warranted because of the frequent and durable responses to programmed cell death/programmed cell death ligand 1 blockade.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('malignant tumors', 'Disease', 'MESH:D018198', (94, 110))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('PDL1', 'Gene', (47, 51))	('malignant tumors', 'Disease', (94, 110))	('amplification', 'Var', (52, 65))
60056	28881626	CCL3-/- and CCR5-/- mice presented reduced incidence of tongue tumours compared to wild-type (WT) and CCR1-/- mice.	('tongue tumours', 'Disease', 'MESH:D014062', (56, 70))	('reduced', 'NegReg', (35, 42))	('mice', 'Species', '10090', (20, 24))	('tongue tumours', 'Disease', (56, 70))	('mice', 'Species', '10090', (110, 114))	('tongue tumour', 'Phenotype', 'HP:0100648', (56, 69))	('tumour', 'Phenotype', 'HP:0002664', (63, 69))	('tumours', 'Phenotype', 'HP:0002664', (63, 70))	('CCL3-/-', 'Var', (0, 7))	('reduced incidence of tongue', 'Phenotype', 'HP:0000171', (35, 62))
60057	28881626	Consistently, attenuated cytomorphological atypia and reduced cell proliferation were observed in lesions of CCL3-/- and CCR5-/- mice.	('attenuated', 'NegReg', (14, 24))	('CCL3-/-', 'Var', (109, 116))	('cell proliferation', 'CPA', (62, 80))	('rat', 'Species', '10116', (74, 77))	('reduced', 'NegReg', (54, 61))	('cytomorphological atypia', 'CPA', (25, 49))	('mice', 'Species', '10090', (129, 133))
60058	28881626	OSCC from CCL3-/- mice exhibited lower infiltration of eosinophils and reduced expression of Egf, Fgf1, Tgf-beta1, Vegfa, Vegfb, Itga-4, Vtn, Mmp-1a, Mmp-2 and Mmp-9 than WT mice.	('lower infiltration of eosinophils', 'Phenotype', 'HP:0031891', (33, 66))	('mice', 'Species', '10090', (174, 178))	('OSCC', 'Chemical', '-', (0, 4))	('Tgf-beta1', 'Gene', (104, 113))	('Itga-4', 'Gene', '16401', (129, 135))	('Itga-4', 'Gene', (129, 135))	('Egf', 'Gene', (93, 96))	('Fgf1', 'Gene', (98, 102))	('CCL3-/-', 'Var', (10, 17))	('Egf', 'Gene', '13645', (93, 96))	('expression', 'MPA', (79, 89))	('Fgf1', 'Gene', '14164', (98, 102))	('Mmp-1a', 'Gene', (142, 148))	('Vegfa', 'Gene', '22339', (115, 120))	('Vtn', 'Gene', (137, 140))	('reduced', 'NegReg', (71, 78))	('Vegfa', 'Gene', (115, 120))	('Mmp-2', 'Gene', '17390', (150, 155))	('lower', 'NegReg', (33, 38))	('rat', 'Species', '10116', (45, 48))	('Mmp-2', 'Gene', (150, 155))	('Mmp-9', 'Gene', (160, 165))	('mice', 'Species', '10090', (18, 22))	('Vtn', 'Gene', '22370', (137, 140))	('infiltration of eosinophils', 'MPA', (39, 66))	('Mmp-1a', 'Gene', '83995', (142, 148))	('Mmp-9', 'Gene', '17395', (160, 165))	('Tgf-beta1', 'Gene', '21803', (104, 113))	('Vegfb', 'Gene', (122, 127))	('Vegfb', 'Gene', '22340', (122, 127))
60079	28881626	The expression of Ccl3 (4.0 fold) and its receptors Ccr1 and Ccr5 (3.5 and 5.0 fold, respectively) was significantly increased in 4NQO-induced oral tumours (p<0.05) (Figure 1).	('4NQO-induced', 'Var', (130, 142))	('increased', 'PosReg', (117, 126))	('4NQO', 'Chemical', 'MESH:D015112', (130, 134))	('Ccr5', 'Gene', '12774', (61, 65))	('oral tumours', 'Disease', (143, 155))	('Ccr1', 'Gene', '12768', (52, 56))	('Ccr5', 'Gene', (61, 65))	('expression', 'MPA', (4, 14))	('Ccl3', 'Gene', '20302', (18, 22))	('Ccl3', 'Gene', (18, 22))	('tumour', 'Phenotype', 'HP:0002664', (148, 154))	('tumours', 'Phenotype', 'HP:0002664', (148, 155))	('Ccr1', 'Gene', (52, 56))	('oral tumours', 'Disease', 'MESH:D009062', (143, 155))
60096	28881626	Accordingly, the CCL3-/- group treated with 4NQO had a significantly reduced Ki67 immunopositivity when compared with the WT mice (Figure 2F, 2C and 2N).	('4NQO', 'Chemical', 'MESH:D015112', (44, 48))	('reduced', 'NegReg', (69, 76))	('Ki67', 'Gene', (77, 81))	('mice', 'Species', '10090', (125, 129))	('4NQO', 'Var', (44, 48))	('Ki67', 'Gene', '17345', (77, 81))
60097	28881626	CCR1-/- mice treated with 4NQO presented a similar production of tumours (Figure 2G) and histopathological score (Figure 2H, 2M) in comparison with the WT mice (Figure 2M).	('histopathological score', 'CPA', (89, 112))	('4NQO', 'Chemical', 'MESH:D015112', (26, 30))	('tumour', 'Phenotype', 'HP:0002664', (65, 71))	('tumours', 'Phenotype', 'HP:0002664', (65, 72))	('mice', 'Species', '10090', (155, 159))	('4NQO', 'Var', (26, 30))	('tumours', 'Disease', 'MESH:D009369', (65, 72))	('mice', 'Species', '10090', (8, 12))	('tumours', 'Disease', (65, 72))
60098	28881626	In contrast, CCR5-/- mice treated with 4NQO exhibited a reduced incidence of tumour formation (Figure 2J) and lower histopathological scores (Figure 2K and 2M), which was similar to the CCL3-/- mice (Figure 2M).	('4NQO', 'Chemical', 'MESH:D015112', (39, 43))	('histopathological scores', 'CPA', (116, 140))	('mice', 'Species', '10090', (21, 25))	('tumour', 'Disease', 'MESH:D009369', (77, 83))	('reduced', 'NegReg', (56, 63))	('tumour', 'Disease', (77, 83))	('lower', 'NegReg', (110, 115))	('4NQO', 'Var', (39, 43))	('mice', 'Species', '10090', (194, 198))	('tumour', 'Phenotype', 'HP:0002664', (77, 83))
60099	28881626	Moreover, the proliferative activity was decreased in the SCC lesions from CCR5-/- mice treated with 4NQO compared with the CCR1-/- mice (Figure 2L, 2I and 2N).	('SCC', 'Gene', (58, 61))	('4NQO', 'Var', (101, 105))	('decreased', 'NegReg', (41, 50))	('SCC', 'Gene', '6317', (58, 61))	('mice', 'Species', '10090', (83, 87))	('mice', 'Species', '10090', (132, 136))	('proliferative activity', 'CPA', (14, 36))	('rat', 'Species', '10116', (21, 24))	('4NQO', 'Chemical', 'MESH:D015112', (101, 105))
60100	28881626	To confirm the relative protection of CCL3 deletion in oral carcinogenesis, a more "aggressive" OSCC model using a high dose of 4NQO (200 microg/mL) was used.	('CCL3', 'Gene', (38, 42))	('OSCC', 'Chemical', '-', (96, 100))	('deletion', 'Var', (43, 51))	('4NQO', 'Chemical', 'MESH:D015112', (128, 132))	('oral carcinogenesis', 'Disease', 'MESH:D063646', (55, 74))	('oral carcinogenesis', 'Disease', (55, 74))
60108	28881626	We next determined if CCL3 deletion modifies the inflammatory cell infiltrate in SCC lesions.	('SCC', 'Gene', '6317', (81, 84))	('modifies', 'Reg', (36, 44))	('deletion', 'Var', (27, 35))	('CCL3', 'Gene', (22, 26))	('SCC', 'Gene', (81, 84))	('rat', 'Species', '10116', (73, 76))
60111	28881626	Because we have observed reduced SCC formation in the CCL3-/- mice, we then evaluated whether the expression of angiogenic factors, cytokines and ECM components would be consistently diminished in the tumour milieu by the absence of CCL3.	('CCL3', 'Gene', (233, 237))	('diminished', 'NegReg', (183, 193))	('tumour', 'Disease', (201, 207))	('reduced', 'NegReg', (25, 32))	('SCC', 'Gene', '6317', (33, 36))	('mice', 'Species', '10090', (62, 66))	('ECM', 'Gene', '22915', (146, 149))	('absence', 'Var', (222, 229))	('tumour', 'Phenotype', 'HP:0002664', (201, 207))	('SCC', 'Gene', (33, 36))	('ECM', 'Gene', (146, 149))	('tumour', 'Disease', 'MESH:D009369', (201, 207))	('expression', 'MPA', (98, 108))
60112	28881626	SCC lesions of WT mice treated with 4NQO presented a significantly increased expression of the proliferative and angiogenic factors Egf, Fgf1, Tgfbeta1, Vegfa and Vegfb and the inflammatory cytokines Il-6 and Tnf-alpha.	('Il-6', 'Gene', (200, 204))	('Tnf-alpha', 'Gene', '21926', (209, 218))	('Egf', 'Gene', (132, 135))	('Fgf1', 'Gene', (137, 141))	('4NQO', 'Chemical', 'MESH:D015112', (36, 40))	('Egf', 'Gene', '13645', (132, 135))	('Fgf1', 'Gene', '14164', (137, 141))	('increased', 'PosReg', (67, 76))	('rat', 'Species', '10116', (102, 105))	('Il-6', 'Gene', '16193', (200, 204))	('mice', 'Species', '10090', (18, 22))	('Tgfbeta1', 'Gene', '21803', (143, 151))	('SCC', 'Gene', '6317', (0, 3))	('Vegfa', 'Gene', '22339', (153, 158))	('Vegfa', 'Gene', (153, 158))	('Tgfbeta1', 'Gene', (143, 151))	('expression', 'MPA', (77, 87))	('Tnf-alpha', 'Gene', (209, 218))	('SCC', 'Gene', (0, 3))	('Vegfb', 'Gene', (163, 168))	('Vegfb', 'Gene', '22340', (163, 168))	('4NQO', 'Var', (36, 40))
60113	28881626	Additionally, there was an increased expression of the matrix components Col1a1, Mmp-1a, Mmp-2, Mmp-9 and the adhesion molecules Itga4 and Vtn in the WT mice treated with 4NQO in relation to the WT control group (Figure 4A).	('increased', 'PosReg', (27, 36))	('Itga4', 'Gene', (129, 134))	('Mmp-2', 'Gene', (89, 94))	('Mmp-1a', 'Gene', '83995', (81, 87))	('Col1a1', 'Gene', '12842', (73, 79))	('Mmp-2', 'Gene', '17390', (89, 94))	('Vtn', 'Gene', '22370', (139, 142))	('4NQO', 'Chemical', 'MESH:D015112', (171, 175))	('Itga4', 'Gene', '16401', (129, 134))	('Mmp-1a', 'Gene', (81, 87))	('Mmp-9', 'Gene', '17395', (96, 101))	('Col1a1', 'Gene', (73, 79))	('mice', 'Species', '10090', (153, 157))	('expression', 'MPA', (37, 47))	('4NQO', 'Var', (171, 175))	('Mmp-9', 'Gene', (96, 101))	('Vtn', 'Gene', (139, 142))
60114	28881626	On the other hand, the CCL3-/- mice treated with 4NQO had a significantly decreased expression of the angiogenic factors Egf, Fgf1, Tgfbeta1, Vegfa, and Vegfb, the inflammatory cytokines Il-6 and Tnf-alpha, the matrix components Mmp-1a, Mmp-2, and Mmp-9, and the adhesion molecules Itga4 and Vtn (Figure 4B).	('Il-6', 'Gene', '16193', (187, 191))	('Vegfb', 'Gene', '22340', (153, 158))	('Vegfb', 'Gene', (153, 158))	('Tgfbeta1', 'Gene', (132, 140))	('mice', 'Species', '10090', (31, 35))	('Mmp-9', 'Gene', (248, 253))	('4NQO', 'Var', (49, 53))	('angiogenic', 'CPA', (102, 112))	('Mmp-9', 'Gene', '17395', (248, 253))	('Mmp-1a', 'Gene', (229, 235))	('Mmp-2', 'Gene', '17390', (237, 242))	('Il-6', 'Gene', (187, 191))	('Tnf-alpha', 'Gene', (196, 205))	('Mmp-2', 'Gene', (237, 242))	('Egf', 'Gene', (121, 124))	('Vtn', 'Gene', (292, 295))	('4NQO', 'Chemical', 'MESH:D015112', (49, 53))	('Itga4', 'Gene', (282, 287))	('expression', 'MPA', (84, 94))	('Itga4', 'Gene', '16401', (282, 287))	('Fgf1', 'Gene', (126, 130))	('Mmp-1a', 'Gene', '83995', (229, 235))	('Egf', 'Gene', '13645', (121, 124))	('Vegfa', 'Gene', '22339', (142, 147))	('Tnf-alpha', 'Gene', '21926', (196, 205))	('Fgf1', 'Gene', '14164', (126, 130))	('Vegfa', 'Gene', (142, 147))	('Vtn', 'Gene', '22370', (292, 295))	('decreased', 'NegReg', (74, 83))	('Tgfbeta1', 'Gene', '21803', (132, 140))
60115	28881626	The evidence obtained in our previous experiments suggested that a lack of CCL3 turned down pathways associated with invasiveness and proliferation in SCC.	('invasiveness', 'CPA', (117, 129))	('rat', 'Species', '10116', (141, 144))	('pathways', 'Pathway', (92, 100))	('lack', 'Var', (67, 71))	('SCC', 'Gene', '6317', (151, 154))	('turned', 'Reg', (80, 86))	('CCL3', 'Gene', (75, 79))	('proliferation', 'CPA', (134, 147))	('SCC', 'Gene', (151, 154))
60123	28881626	On the other hand, HN12 cultures stimulated with CCL3 had similar proliferation levels, as measured by the expression of Ki67, in comparison with the control (non-stimulated HN12 cells in DMEM-serum free media) (Figure 5H).	('CCL3', 'Var', (49, 53))	('HN12', 'Gene', '100463498', (174, 178))	('DMEM', 'Chemical', '-', (188, 192))	('expression', 'MPA', (107, 117))	('HN12', 'Gene', (19, 23))	('Ki67', 'Gene', '17345', (121, 125))	('HN12', 'Gene', '100463498', (19, 23))	('HN12', 'Gene', (174, 178))	('Ki67', 'Gene', (121, 125))	('rat', 'Species', '10116', (73, 76))
60139	28881626	Previous data from our group showed that CCL3 expression in primary OSCC was related with poor cumulative survival rates.	('cumulative survival', 'CPA', (95, 114))	('rat', 'Species', '10116', (115, 118))	('CCL3 expression', 'Var', (41, 56))	('primary OSCC', 'Disease', (60, 72))	('OSCC', 'Chemical', '-', (68, 72))
60142	28881626	In the absence of CCL3 and CCR5, but not of CCR1, SCC formation was significantly reduced.	('SCC', 'Gene', '6317', (50, 53))	('reduced', 'NegReg', (82, 89))	('CCR5', 'Var', (27, 31))	('SCC', 'Gene', (50, 53))
60146	28881626	It is a limitation of this study because the long-time treatment with 4NQO for producing tumours and consequently its toxicity precludes its use as a model to analyse tumour progression or response to treatments.	('tumour', 'Disease', 'MESH:D009369', (167, 173))	('tumours', 'Phenotype', 'HP:0002664', (89, 96))	('tumour', 'Phenotype', 'HP:0002664', (89, 95))	('4NQO', 'Var', (70, 74))	('tumour', 'Disease', (167, 173))	('tumour', 'Disease', 'MESH:D009369', (89, 95))	('tumours', 'Disease', 'MESH:D009369', (89, 96))	('tumour', 'Disease', (89, 95))	('tumours', 'Disease', (89, 96))	('toxicity', 'Disease', 'MESH:D064420', (118, 126))	('toxicity', 'Disease', (118, 126))	('4NQO', 'Chemical', 'MESH:D015112', (70, 74))	('tumour', 'Phenotype', 'HP:0002664', (167, 173))
60147	28881626	Similarly to our findings, previous studies found that deficiency of the CCL3/CCR5 system resulted in a significantly reduced tumour formation and a reduced lung metastasis.	('tumour', 'Phenotype', 'HP:0002664', (126, 132))	('tumour', 'Disease', 'MESH:D009369', (126, 132))	('reduced', 'NegReg', (118, 125))	('reduced', 'NegReg', (149, 156))	('tumour', 'Disease', (126, 132))	('deficiency', 'Var', (55, 65))	('lung metastasis', 'Disease', (157, 172))	('lung metastasis', 'Disease', 'MESH:D009362', (157, 172))
60148	28881626	On the other hand, a study demonstrated that the absence of CCL3/CCR1, but not CCL3/CCR5, resulted in a decreased incidence of hepatocellular carcinoma.	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (127, 151))	('decreased', 'NegReg', (104, 113))	('CCL3/CCR1', 'Gene', (60, 69))	('rat', 'Species', '10116', (34, 37))	('absence', 'Var', (49, 56))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (127, 151))	('carcinoma', 'Phenotype', 'HP:0030731', (142, 151))	('hepatocellular carcinoma', 'Disease', (127, 151))
60160	28881626	Our results are corroborated by previous findings showing that tumours from CCL3-/- and CCR5-/- mice presented reduced vascularisation.	('tumours', 'Disease', (63, 70))	('vascularisation', 'CPA', (119, 134))	('mice', 'Species', '10090', (96, 100))	('CCL3-/-', 'Var', (76, 83))	('rat', 'Species', '10116', (23, 26))	('reduced', 'NegReg', (111, 118))	('tumour', 'Phenotype', 'HP:0002664', (63, 69))	('tumours', 'Phenotype', 'HP:0002664', (63, 70))	('tumours', 'Disease', 'MESH:D009369', (63, 70))
60161	28881626	The decreased expression of the adhesion molecules Itga4 and Vtn in the SCC lesions from the CCL3-/- mice may be indicative of the fact that CCL3 activate neoplastic cell adhesion and motility within the tumour microenvironment as described for other tumours.	('tumour', 'Phenotype', 'HP:0002664', (251, 257))	('motility within the tumour', 'Disease', (184, 210))	('Vtn', 'Gene', (61, 64))	('mice', 'Species', '10090', (101, 105))	('motility within the tumour', 'Disease', 'MESH:D001929', (184, 210))	('Vtn', 'Gene', '22370', (61, 64))	('activate', 'PosReg', (146, 154))	('tumours', 'Disease', (251, 258))	('SCC', 'Gene', '6317', (72, 75))	('decreased', 'NegReg', (4, 13))	('CCL3', 'Var', (141, 145))	('tumours', 'Phenotype', 'HP:0002664', (251, 258))	('SCC', 'Gene', (72, 75))	('expression', 'MPA', (14, 24))	('tumour', 'Phenotype', 'HP:0002664', (204, 210))	('tumours', 'Disease', 'MESH:D009369', (251, 258))	('Itga4', 'Gene', (51, 56))	('Itga4', 'Gene', '16401', (51, 56))	('neoplastic cell adhesion', 'CPA', (155, 179))
60163	28881626	In line with these findings, blockade of the IL-6 receptor reduces tumour growth and angiogenesis in vivo, and the expression of IL-6 and TNF-alpha in OSCC cell lines correlated with the metastatic phenotype.	('blockade', 'Var', (29, 37))	('tumour growth', 'Disease', 'MESH:D006130', (67, 80))	('OSCC', 'Chemical', '-', (151, 155))	('IL-6', 'Gene', (129, 133))	('reduces', 'NegReg', (59, 66))	('correlated with', 'Reg', (167, 182))	('TNF-alpha', 'Gene', (138, 147))	('metastatic', 'CPA', (187, 197))	('IL-6', 'Gene', (45, 49))	('angiogenesis', 'CPA', (85, 97))	('tumour', 'Phenotype', 'HP:0002664', (67, 73))	('tumour growth', 'Disease', (67, 80))
60164	28881626	Therefore, changes in inflammatory and angiogenic factors appear to be the underlying mechanism explaining the OSCC phenotype in CCL3 deficient mice.	('deficient', 'Var', (134, 143))	('mice', 'Species', '10090', (144, 148))	('OSCC', 'Chemical', '-', (111, 115))	('CCL3', 'Gene', (129, 133))	('changes', 'Reg', (11, 18))	('OSCC', 'Disease', (111, 115))
60230	28387377	These insults produce mutations in genes that might alter their expression and/or function, deregulating many physiological pathways and provoke chromosomal damage, events that drive oncogenic transformation and tumour progression.	('expression', 'MPA', (64, 74))	('tumour', 'Phenotype', 'HP:0002664', (212, 218))	('physiological pathways', 'Pathway', (110, 132))	('chromosomal damage', 'MPA', (145, 163))	('tumour', 'Disease', 'MESH:D009369', (212, 218))	('oncogenic transformation', 'CPA', (183, 207))	('mutations', 'Var', (22, 31))	('tumour', 'Disease', (212, 218))	('genes', 'Gene', (35, 40))	('provoke', 'Reg', (137, 144))	('deregulating', 'Reg', (92, 104))	('drive', 'Reg', (177, 182))
60231	28387377	Different levels of damage produce different responses, such that mild DNA damage induces a reparative response, while severe damage activates cell death in a regulated manner.	('induces', 'Reg', (82, 89))	('damage activates cell death', 'Disease', (126, 153))	('reparative response', 'CPA', (92, 111))	('mild DNA damage', 'Var', (66, 81))	('damage activates cell death', 'Disease', 'MESH:D001926', (126, 153))
60240	28387377	TP53 or FOS are examples of tumour suppressor genes where mutations, deletions and/or repression are implicated in processes related to cancer development.	('mutations', 'Var', (58, 67))	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('tumour', 'Phenotype', 'HP:0002664', (28, 34))	('implicated', 'Reg', (101, 111))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('FOS', 'Gene', (8, 11))	('deletions', 'Var', (69, 78))	('tumour', 'Disease', 'MESH:D009369', (28, 34))	('cancer', 'Disease', (136, 142))	('tumour', 'Disease', (28, 34))	('FOS', 'Gene', '2353', (8, 11))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
60241	28387377	Similarly, the oncogenes E2F3 and AURKA induce cell growth and proliferation when mutated or over-expressed, driving cells through the cell cycle checkpoints.	('AURKA', 'Gene', (34, 39))	('E2F3', 'Gene', '398159', (25, 29))	('mutated', 'Var', (82, 89))	('cell growth', 'CPA', (47, 58))	('E2F3', 'Gene', (25, 29))	('induce', 'PosReg', (40, 46))
60250	28387377	The miR-143/145 cluster targets a large number of genes and their deregulation is thought to be one of the earliest events in cancer development.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('deregulation', 'Var', (66, 78))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('miR-143', 'Gene', '406935', (4, 11))	('miR-143', 'Gene', (4, 11))	('targets', 'Reg', (24, 31))
60253	28387377	Some techniques measure mRNA expression upon the modification of miRNA expression using luciferase assays or other proteomic assays like pulsed stable isotope labelling with amino acids in cell culture (pSILAC).	('miR', 'Gene', '220972', (65, 68))	('miR', 'Gene', (65, 68))	('modification', 'Var', (49, 61))	('mRNA expression', 'MPA', (24, 39))	('measure', 'Reg', (16, 23))
60259	28387377	In addition, the analyses of these signatures in different tumours, accounting for additional factors like gene methylation (MET) and copy number alterations (CNAs), could provide relevant information regarding the signature's stability.	('tumour', 'Phenotype', 'HP:0002664', (59, 65))	('tumours', 'Phenotype', 'HP:0002664', (59, 66))	('tumours', 'Disease', 'MESH:D009369', (59, 66))	('tumours', 'Disease', (59, 66))	('copy number alterations', 'Var', (134, 157))
60271	28387377	One such example is the aforementioned TP53, which is often over-expressed in cancer when it carries mutations, although many of these overexpressed mutated variants have lost their original function.	('over-expressed', 'PosReg', (60, 74))	('mutations', 'Var', (101, 110))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('TP53', 'Gene', '7157', (39, 43))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('TP53', 'Gene', (39, 43))
60338	28387377	SYNE1 is the most significantly repressed gene and its dysregulation has been related to glioblastoma and ovarian cancer, among others.	('SYNE1', 'Gene', (0, 5))	('glioblastoma and ovarian cancer', 'Disease', 'MESH:D005909', (89, 120))	('related', 'Reg', (78, 85))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('glioblastoma', 'Phenotype', 'HP:0012174', (89, 101))	('SYNE1', 'Gene', '23345', (0, 5))	('dysregulation', 'Var', (55, 68))	('ovarian cancer', 'Phenotype', 'HP:0100615', (106, 120))
60347	28387377	It is well known that methylation and copy number alterations affect gene expression, especially in cancer.	('affect', 'Reg', (62, 68))	('copy number alterations', 'Var', (38, 61))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('gene expression', 'MPA', (69, 84))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('methylation', 'Var', (22, 33))
60433	28387377	In prostate cancer, the classification was performed based on tumour grade instead of tumour stage, where good prognosis involved tumours with Gleason score of 6 or 7, and bad prognosis tumours with Gleason score >= 8.	('tumours', 'Phenotype', 'HP:0002664', (130, 137))	('prostate cancer', 'Phenotype', 'HP:0012125', (3, 18))	('tumours', 'Disease', (186, 193))	('tumours', 'Disease', 'MESH:D009369', (130, 137))	('tumour', 'Phenotype', 'HP:0002664', (186, 192))	('prostate cancer', 'Disease', (3, 18))	('tumour', 'Disease', 'MESH:D009369', (186, 192))	('tumours', 'Phenotype', 'HP:0002664', (186, 193))	('tumour', 'Phenotype', 'HP:0002664', (130, 136))	('Gleason', 'Var', (143, 150))	('tumour', 'Disease', (186, 192))	('tumour', 'Disease', 'MESH:D009369', (130, 136))	('tumours', 'Disease', 'MESH:D009369', (186, 193))	('tumour', 'Disease', (130, 136))	('bad prognosis tumours', 'Disease', 'MESH:D009369', (172, 193))	('tumour', 'Phenotype', 'HP:0002664', (62, 68))	('tumour', 'Phenotype', 'HP:0002664', (86, 92))	('tumours', 'Disease', (130, 137))	('tumour', 'Disease', 'MESH:D009369', (62, 68))	('bad prognosis tumours', 'Disease', (172, 193))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('tumour', 'Disease', 'MESH:D009369', (86, 92))	('tumour', 'Disease', (62, 68))	('tumour', 'Disease', (86, 92))	('prostate cancer', 'Disease', 'MESH:D011471', (3, 18))
60477	27429973	Furthermore, miR-146a was shown to be a negative regulator of TLR-NFkappaB pathway in human periodontal ligament cells after P. gingivalis LPS stimulation, therefore being involved in inflammatory response.	('TLR-NFkappaB pathway', 'Pathway', (62, 82))	('involved', 'Reg', (172, 180))	('human', 'Species', '9606', (86, 91))	('P. gingivalis', 'Species', '837', (125, 138))	('miR-146a', 'Var', (13, 21))	('negative', 'NegReg', (40, 48))
60481	27429973	In this in vitro study THP-1 macrophages that were stimulated with LPS from Aggregatibacter actinomycetemcomitans, P.g., and also P.g.	('Aggregatibacter actinomycetemcomitans', 'Species', '714', (76, 113))	('THP-1', 'Gene', '2736', (23, 28))	('THP-1', 'Gene', (23, 28))	('P.g.', 'Var', (115, 119))
60533	27429973	MiR-146a and miR-155 were dominant in in vitro studies.	('MiR-146a', 'Gene', (0, 8))	('MiR-146a', 'Gene', '406938', (0, 8))	('miR-155', 'Var', (13, 20))
60617	33926541	devised a 'suitability score' as a metric of the molecular similarity of CCLs to high-grade serous ovarian carcinoma based on a heuristic weighting of copy number alterations, mutation status of several genes that distinguish ovarian cancer subtypes, and hypermutation status.	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('serous ovarian carcinoma', 'Disease', (92, 116))	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('copy number alterations', 'Var', (151, 174))	('serous ovarian carcinoma', 'Disease', 'MESH:D010051', (92, 116))	('ovarian cancer', 'Disease', 'MESH:D010051', (226, 240))	('CCLs', 'Chemical', '-', (73, 77))	('ovarian cancer', 'Disease', (226, 240))	('CCLs', 'Disease', (73, 77))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (99, 116))	('mutation', 'Var', (176, 184))	('ovarian cancer', 'Phenotype', 'HP:0100615', (226, 240))
60618	33926541	transcriptomic and copy number alterations) to quantify the similarity of cell lines to tumors.	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumors', 'Disease', (88, 94))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('copy number alterations', 'Var', (19, 42))
60621	33926541	have developed methods to assess CCLs using molecular traits such as copy number alterations (CNA), somatic mutations, DNA methylation, and transcriptomics.	('copy number alterations', 'Var', (69, 92))	('CCLs', 'Chemical', '-', (33, 37))	('CCLs', 'Disease', (33, 37))
60692	33926541	SK-OV-3, Vcap, and RT4 were cultured in Dulbecco's modified Eagle medium (DMEM, high glucose, 11960069, Gibco) with 1% penicillin-streptomycin-glutamine (10378016, Life Technologies); Caov-4, PC-3, NCCIT, and A2780 were cultured using RPMI-1640 medium (11875093, Gibco) while HEC-59 was in Iscove's modified Dulbecco's medium (IMDM, 12440053, Gibco).	('11875093', 'Var', (253, 261))	('penicillin', 'Chemical', 'MESH:D010406', (119, 129))	('PC-3', 'Gene', (192, 196))	('PC-3', 'Gene', '57332', (192, 196))	('high glucose', 'Phenotype', 'HP:0003074', (80, 92))	('SK-OV-3', 'Chemical', '-', (0, 7))	('glucose', 'Chemical', 'MESH:D005947', (85, 92))	('HEC-59', 'CellLine', 'CVCL:2930', (276, 282))	('streptomycin', 'Chemical', 'MESH:D013307', (130, 142))	('Vcap', 'Chemical', '-', (9, 13))
60774	33926541	We reasoned that if SK-OV-3, A2780, and PC-3 were classified most strongly as UCEC, TGCT, and BLCA, respectively, then they would express proteins that are indicative of these cancer types.	('PC-3', 'Gene', (40, 44))	('PC-3', 'Gene', '57332', (40, 44))	('proteins', 'Protein', (138, 146))	('UCEC', 'Disease', (78, 82))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('express', 'Reg', (130, 137))	('A2780', 'Var', (29, 34))	('SK-OV-3', 'Chemical', '-', (20, 27))	('BLCA', 'Phenotype', 'HP:0009725', (94, 98))	('cancer', 'Disease', (176, 182))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('TGCT', 'Disease', (84, 88))
60779	33926541	From our computational analysis and experimental validation, SK-OV-3 is most likely an endometrioid subtype of ovarian cancer.	('ovarian cancer', 'Disease', (111, 125))	('SK-OV-3', 'Var', (61, 68))	('ovarian cancer', 'Phenotype', 'HP:0100615', (111, 125))	('ovarian cancer', 'Disease', 'MESH:D010051', (111, 125))	('SK-OV-3', 'Chemical', '-', (61, 68))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
60780	33926541	This result is also consistent with prior classification of SK-OV-3, and the fact that SK-OV-3 lacks p53 mutations, which is prevalent in high-grade serous ovarian cancer, and it harbors an endometrioid-associated mutation in ARID1A.	('SK-OV-3', 'Chemical', '-', (87, 94))	('lacks', 'NegReg', (95, 100))	('prevalent', 'Reg', (125, 134))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('ARID1A', 'Gene', '8289', (226, 232))	('SK-OV-3', 'Chemical', '-', (60, 67))	('serous ovarian cancer', 'Disease', (149, 170))	('ARID1A', 'Gene', (226, 232))	('p53', 'Gene', (101, 104))	('p53', 'Gene', '7157', (101, 104))	('serous ovarian cancer', 'Disease', 'MESH:D018284', (149, 170))	('mutations', 'Var', (105, 114))	('ovarian cancer', 'Phenotype', 'HP:0100615', (156, 170))	('high-grade', 'Disease', (138, 148))
60782	33926541	The OV marker WT1 was also expressed in fewer A2780 cells as compared to Caov-4 (48% vs 85%), which suggests that A2780 could be a germ cell-derived ovarian tumor.	('ovarian tumor', 'Phenotype', 'HP:0100615', (149, 162))	('ovarian tumor', 'Disease', 'MESH:D010051', (149, 162))	('A2780', 'Var', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('ovarian tumor', 'Disease', (149, 162))
60783	33926541	Taken together, our results suggest that SK-OV-3 and A2780 could represent OV subtypes that are not well represented in TCGA training data, which resulted in a low OV score and higher CCN score in other categories.	('low', 'NegReg', (160, 163))	('higher', 'PosReg', (177, 183))	('OV score', 'MPA', (164, 172))	('CCN', 'Chemical', '-', (184, 187))	('CCN score', 'MPA', (184, 193))	('SK-OV-3', 'Var', (41, 48))	('SK-OV-3', 'Chemical', '-', (41, 48))	('A2780', 'Var', (53, 58))
60794	33926541	For example, HEC-1A, HEC-1B, and KLE were previously characterized as type II endometrial cancer, which includes a serous histological subtype.	('type II endometrial cancer', 'Disease', 'MESH:D016889', (70, 96))	('HEC-1A', 'Disease', (13, 19))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('KLE', 'Disease', (33, 36))	('HEC-1B', 'Var', (21, 27))	('endometrial cancer', 'Phenotype', 'HP:0012114', (78, 96))	('type II endometrial cancer', 'Disease', (70, 96))
60801	33926541	Similarly, LUDLU-1 and EPLC-272H, previously reported as classical and basal respectively, had maximal tumor subtype CCN scores for these subtypes (0.323 and 0.256) (Fig.	('CCN', 'Chemical', '-', (117, 120))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('EPLC-272H', 'Var', (23, 32))	('tumor', 'Disease', (103, 108))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
60824	33926541	In contrast to LGG CCLs, LGG GEMMs, generated by Nf1 mutations expressed in different neural progenitors in combination with Pten deletion, consistently were classified as LGG (Fig.	('LGG', 'Disease', (172, 175))	('Nf1', 'Gene', '4763', (49, 52))	('Nf1', 'Gene', (49, 52))	('mutations', 'Var', (53, 62))	('CCLs', 'Chemical', '-', (19, 23))	('Pten', 'Gene', '5728', (125, 129))	('Pten', 'Gene', (125, 129))
60827	33926541	GEMMs sharing genotypes across studies, such as LUAD GEMMs driven by Kras mutation and loss of p53, also received similar general and subtype classification scores (Fig.	('mutation', 'Var', (74, 82))	('loss', 'Var', (87, 91))	('LUAD', 'Phenotype', 'HP:0030078', (48, 52))	('p53', 'Gene', (95, 98))	('p53', 'Gene', '7157', (95, 98))	('Kras', 'Gene', (69, 73))	('Kras', 'Gene', '3845', (69, 73))
60841	33926541	Most of the LUAD GEMMs, which were generated using various combinations of activating Kras mutation, loss of Trp53, and loss of Smarca4L, were correctly classified (Fig.	('mutation', 'Var', (91, 99))	('Kras', 'Gene', '3845', (86, 90))	('loss', 'NegReg', (101, 105))	('Trp53', 'Gene', '7157', (109, 114))	('Smarca4L', 'Gene', (128, 136))	('LUAD', 'Phenotype', 'HP:0030078', (12, 16))	('activating', 'PosReg', (75, 85))	('Trp53', 'Gene', (109, 114))	('loss', 'Var', (120, 124))	('Kras', 'Gene', (86, 90))
60929	33926541	Microarray tumor validation data: Microarray tumor datasets used for validation are available in the GEO database: GSE36771, GSE21653, GSE20685, GSE50948, GSE23177, GSE26639, GSE12276, GSE31448, GSE32646, GSE65194, GSE42568, GSE26682, GSE17536, GSE41328, GSE33114, GSE26906, GSE39582, GSE62080, GSE20916, GSE18088, GSE17537, GSE23878, GSE60697, GSE37892, GSE30540, GSE50161, GSE4290, GSE60184, GSE36245, GSE53733, GSE32374, GSE34824, GSE41137, GSE53757, GSE46699, GSE36895, GSE2109, GSE45436, GSE9843, GSE6222, GSE19665, GSE41804, GSE10245, GSE12667, GSE37745, GSE19188, GSE40595, GSE12172, GSE20565, GSE18520, GSE10971, GSE51373, GSE14001, GSE26193, GSE55512, GSE42404, GSE16515, GSE17891, GSE15471, GSE22780, GSE32688, GSE17951, GSE32448, GSE7307, GSE32982, GSE3325, GSE26910, GSE55945, GSE7553, GSE10282, GSE19293, GSE19234, GSE35640, GSE22968, GSE34599, and GSE23376.	('GSE23376', 'Var', (862, 870))	('GSE35640', 'Var', (828, 836))	('GSE22968', 'Var', (838, 846))	('tumor', 'Disease', (45, 50))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('GSE10282', 'Var', (798, 806))	('tumor', 'Disease', (11, 16))	('GSE7307', 'Var', (741, 748))	('GSE32982', 'Var', (750, 758))	('GSE19234', 'Var', (818, 826))	('tumor', 'Disease', 'MESH:D009369', (11, 16))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('GSE55945', 'Var', (779, 787))	('GSE34599', 'Var', (848, 856))	('GSE7553', 'Var', (789, 796))	('GSE32448', 'Var', (731, 739))	('GSE3325', 'Var', (760, 767))	('GSE19293', 'Var', (808, 816))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('GSE26910', 'Var', (769, 777))
60932	33926541	The other tumoroid datasets are available in the GEO database: GSE84073, GSE103990, and GSE109982.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('GSE84073', 'Var', (63, 71))	('GSE103990', 'Var', (73, 82))	('tumor', 'Disease', (10, 15))	('GSE109982', 'Var', (88, 97))	('tumor', 'Disease', 'MESH:D009369', (10, 15))
61003	29943286	has suggested that using the more tumor-specific tracer L-[3-18F]-alpha-methyltyrosine in an FDG-PET/CT scan may be an effective method to distinguish sarcoidosis from malignancy.	('malignancy', 'Disease', 'MESH:D009369', (168, 178))	('L-[3-18F]-alpha-methyltyrosine', 'Chemical', '-', (56, 86))	('sarcoidosis', 'Disease', 'MESH:D012507', (151, 162))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('malignancy', 'Disease', (168, 178))	('tumor', 'Disease', (34, 39))	('L-[3-18F]-alpha-methyltyrosine', 'Var', (56, 86))	('sarcoidosis', 'Disease', (151, 162))	('FDG', 'Gene', '23583', (93, 96))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('FDG', 'Gene', (93, 96))
61024	25835715	Mutant p53 expression decreased gradually from cancerous to normal mucosae, whereas p21 CIP1/WAF1  expression displayed an opposite trend.	('expression', 'MPA', (11, 21))	('p21 CIP1', 'Gene', (84, 92))	('p53', 'Gene', '7157', (7, 10))	('WAF1', 'Gene', '1026', (93, 97))	('cancerous', 'Disease', (47, 56))	('p21 CIP1', 'Gene', '1026', (84, 92))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('Mutant', 'Var', (0, 6))	('WAF1', 'Gene', (93, 97))	('cancerous', 'Disease', 'MESH:D009369', (47, 56))	('p53', 'Gene', (7, 10))	('decreased', 'NegReg', (22, 31))
61035	25835715	reported that a mutated p53 gene was overexpressed in the adjacent 'normal' or hyperplastic mucosa of laryngeal cancer and stated that p53 abnormalities most likely occur extremely early in laryngeal squamous cell carcinoma development.	('p53', 'Gene', (24, 27))	('p53', 'Gene', '7157', (24, 27))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (200, 223))	('carcinoma', 'Phenotype', 'HP:0030731', (214, 223))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('laryngeal squamous cell carcinoma', 'Disease', 'MESH:D002294', (190, 223))	('laryngeal cancer', 'Disease', 'MESH:D007822', (102, 118))	('mutated', 'Var', (16, 23))	('p53', 'Gene', (135, 138))	('p53', 'Gene', '7157', (135, 138))	('laryngeal squamous cell carcinoma', 'Disease', (190, 223))	('laryngeal cancer', 'Disease', (102, 118))	('overexpressed', 'PosReg', (37, 50))	('laryngeal cancer', 'Phenotype', 'HP:0012118', (102, 118))
61114	25835715	The mutation and inactivation of p53 may be a critical event in the origin and progression of head and neck carcinoma, and p53 mutations are among the most common genetic changes in oral squamous cell carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('carcinoma', 'Phenotype', 'HP:0030731', (201, 210))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (182, 210))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (187, 210))	('mutation', 'Var', (4, 12))	('oral squamous cell carcinoma', 'Disease', (182, 210))	('p53', 'Gene', (33, 36))	('neck carcinoma', 'Disease', 'MESH:D006258', (103, 117))	('p53', 'Gene', (123, 126))	('p53', 'Gene', '7157', (33, 36))	('head and neck carcinoma', 'Phenotype', 'HP:0012288', (94, 117))	('neck carcinoma', 'Disease', (103, 117))	('mutations', 'Var', (127, 136))	('p53', 'Gene', '7157', (123, 126))	('inactivation', 'NegReg', (17, 29))
61125	25835715	Despite this dependence, loss-of-function p21 mutations do not accumulate in cancer nor do they predispose individuals to cancer incidence.	('p21', 'Gene', '1026', (42, 45))	('mutations', 'Var', (46, 55))	('cancer', 'Disease', (77, 83))	('p21', 'Gene', (42, 45))	('cancer', 'Disease', (122, 128))	('loss-of-function', 'NegReg', (25, 41))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))
61133	25835715	eIF4E gene amplification and overexpression appeared to progress from the 'tumour-free' margin to the tumour core.	('tumour-free', 'Disease', (75, 86))	('tumour', 'Disease', 'MESH:D009369', (75, 81))	('overexpression', 'PosReg', (29, 43))	('tumour', 'Phenotype', 'HP:0002664', (102, 108))	('tumour', 'Disease', 'MESH:D009369', (102, 108))	('tumour', 'Disease', (75, 81))	('eIF4E', 'Gene', '1977', (0, 5))	('tumour', 'Disease', (102, 108))	('progress', 'PosReg', (56, 64))	('eIF4E', 'Gene', (0, 5))	('tumour-free', 'Disease', 'MESH:D000072662', (75, 86))	('amplification', 'Var', (11, 24))	('tumour', 'Phenotype', 'HP:0002664', (75, 81))
61155	25835715	Most (>90%) HPV-associated head and neck squamous cell cancers are caused by HPV 16.	('HPV-associated', 'Gene', (12, 26))	('squamous cell cancers', 'Phenotype', 'HP:0002860', (41, 62))	('cancers', 'Phenotype', 'HP:0002664', (55, 62))	('caused by', 'Reg', (67, 76))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('HPV 16', 'Species', '333760', (77, 83))	('HPV', 'Species', '10566', (12, 15))	('neck squamous cell cancers', 'Disease', (36, 62))	('HPV', 'Species', '10566', (77, 80))	('neck squamous cell cancers', 'Disease', 'MESH:D002294', (36, 62))	('HPV', 'Var', (77, 80))
61178	32916258	We found the low survival rate in high expression of ACE2 in lung cancer patients and 16 mutational positions.	('lung cancer', 'Disease', (61, 72))	('ACE2', 'Gene', (53, 57))	('lung cancer', 'Phenotype', 'HP:0100526', (61, 72))	('low', 'NegReg', (13, 16))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('rat', 'Species', '10116', (26, 29))	('patients', 'Species', '9606', (73, 81))	('high', 'Var', (34, 38))	('lung cancer', 'Disease', 'MESH:D008175', (61, 72))	('survival', 'MPA', (17, 25))
61252	32916258	We found both overall (OS) and relapse-free survival (RFS) had a low survival rate in high mRNA expression of ACE2 and higher HR value in lung cancer patients.	('relapse-free survival', 'CPA', (31, 52))	('RFS', 'Disease', (54, 57))	('lung cancer', 'Disease', 'MESH:D008175', (138, 149))	('S', 'Gene', '43740568', (56, 57))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('RFS', 'Disease', 'MESH:D005198', (54, 57))	('lung cancer', 'Phenotype', 'HP:0100526', (138, 149))	('higher', 'PosReg', (119, 125))	('rat', 'Species', '10116', (78, 81))	('low', 'NegReg', (65, 68))	('patients', 'Species', '9606', (150, 158))	('ACE2', 'Protein', (110, 114))	('lung cancer', 'Disease', (138, 149))	('S', 'Gene', '43740568', (24, 25))	('high', 'Var', (86, 90))	('HR value', 'MPA', (126, 134))
61253	32916258	Therefore, we also investigated the mutational analysis of ACE2 protein, where in total 16 mutations in lung cancer were observed - 9 missense mutations in LUAD, while 4 missenses, 2 splice, and 1 frameshift mutations in LUSC (Table 2 ).	('lung cancer', 'Disease', 'MESH:D008175', (104, 115))	('missense mutations', 'Var', (134, 152))	('LUSC', 'Phenotype', 'HP:0030359', (221, 225))	('lung cancer', 'Disease', (104, 115))	('lung cancer', 'Phenotype', 'HP:0100526', (104, 115))	('LUAD', 'Phenotype', 'HP:0030078', (156, 160))	('S', 'Gene', '43740568', (223, 224))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('LUAD', 'Gene', (156, 160))
61262	32916258	The protein-protein interaction of ACE2, ABCA13, UGT1A6, KLF5, LCN2, TSPN3, AASS, and CYP2C18 form a protein network was consisting themselves and keratin 7 (KRT7), CEA cell adhesion molecule 5 (CEACAM5), transmembrane 4 six family member 4 (TM4SF4), tripartite motif-containing 31 (TRIM31), glutathione S-transferase Mu 3 (GSTM3), E74 Like ETS transcription factor 3 (ELF3), peptidase inhibitor 3 (PI3), olfactomedin 4 (OLFM4), galectin 4 (LGALS4), chromosome 1 open reading frame 106 (C1orf106), Cbl proto-oncogene C (CBLC), argininosuccinate synthase 1 (ASS1), serine peptidase inhibitor kazal type 1 (SPINK1), S100 calcium-binding protein P (S100P), tetraspanin 8 (TSPAN8), paraoxonase 1 (PON1), fyn related src family tyrosine kinase (FRK), ATPase secretory pathway Ca2+ transporting 2 (ATP2C2), suppressor of cytokine signaling 6 (SOCS6), and secretory leukocyte peptidase inhibitor (SLPI).	('LGALS4', 'Gene', '3960', (441, 447))	('OLFM4', 'Gene', '10562', (421, 426))	('tetraspanin 8', 'Gene', (654, 667))	('S', 'Gene', '43740568', (614, 615))	('SPINK1', 'Gene', '6690', (605, 611))	('CYP2C18', 'Gene', (86, 93))	('FRK', 'Gene', '2444', (740, 743))	('tripartite motif-containing 31', 'Gene', (251, 281))	('suppressor of cytokine signaling 6', 'Gene', (801, 835))	('Cbl proto-oncogene C', 'Gene', '23624', (498, 518))	('tetraspanin 8', 'Gene', '7103', (654, 667))	('CEA cell adhesion molecule 5', 'Gene', '1048', (165, 193))	('peptidase inhibitor 3', 'Gene', '5266', (376, 397))	('KLF5', 'Gene', '688', (57, 61))	('S', 'Gene', '43740568', (79, 80))	('S', 'Gene', '43740568', (890, 891))	('galectin 4', 'Gene', '3960', (429, 439))	('peptidase inhibitor 3', 'Gene', (376, 397))	('LCN2', 'Gene', '3934', (63, 67))	('SLPI', 'Gene', '6590', (890, 894))	('PON1', 'Gene', (693, 697))	('glutathione S-transferase Mu 3', 'Gene', '2947', (292, 322))	('S', 'Gene', '43740568', (70, 71))	('ASS1', 'Gene', '445', (557, 561))	('suppressor of cytokine signaling 6', 'Gene', '9306', (801, 835))	('GSTM3', 'Gene', (324, 329))	('LCN2', 'Gene', (63, 67))	('S', 'Gene', '43740568', (304, 305))	('C1orf106', 'Gene', '55765', (487, 495))	('KRT7', 'Gene', (158, 162))	('fyn', 'Gene', '2534', (700, 703))	('secretory leukocyte peptidase inhibitor', 'Gene', '6590', (849, 888))	('S', 'Gene', '43740568', (646, 647))	('S', 'Gene', '43740568', (670, 671))	('secretory leukocyte peptidase inhibitor', 'Gene', (849, 888))	('keratin 7', 'Gene', '3855', (147, 156))	('TRIM31', 'Gene', (283, 289))	('KRT7', 'Gene', '3855', (158, 162))	('CEA cell adhesion molecule 5', 'Gene', (165, 193))	('SLPI', 'Gene', (890, 894))	('TM4SF4', 'Gene', '7104', (242, 248))	('KLF5', 'Gene', (57, 61))	('TRIM31', 'Gene', '11074', (283, 289))	('transmembrane 4 six family member 4', 'Gene', (205, 240))	('PI3', 'Gene', '5266', (399, 402))	('transmembrane 4 six family member 4', 'Gene', '7104', (205, 240))	('UGT1A6', 'Gene', (49, 55))	('ABCA13', 'Gene', '154664', (41, 47))	('serine peptidase inhibitor kazal type 1', 'Gene', '6690', (564, 603))	('FRK', 'Gene', (740, 743))	('CEACAM5', 'Gene', '1048', (195, 202))	('TSPAN8', 'Gene', (669, 675))	('S', 'Gene', '43740568', (559, 560))	('CYP2C18', 'Gene', '1562', (86, 93))	('AASS', 'Gene', (76, 80))	('SOCS6', 'Gene', (837, 842))	('S100 calcium-binding protein P', 'Gene', (614, 644))	('S', 'Gene', '43740568', (343, 344))	('ATP2C2', 'Gene', '9914', (792, 798))	('C1orf106', 'Gene', (487, 495))	('GSTM3', 'Gene', '2947', (324, 329))	('S', 'Gene', '43740568', (245, 246))	('S', 'Gene', '43740568', (78, 79))	('S', 'Gene', '43740568', (325, 326))	('S100P', 'Var', (646, 651))	('paraoxonase 1', 'Gene', '5444', (678, 691))	('LGALS4', 'Gene', (441, 447))	('CBLC', 'Gene', '23624', (520, 524))	('S', 'Gene', '43740568', (840, 841))	('CEACAM5', 'Gene', (195, 202))	('UGT1A6', 'Gene', '54578', (49, 55))	('galectin 4', 'Gene', (429, 439))	('TM4SF4', 'Gene', (242, 248))	('SPINK1', 'Gene', (605, 611))	('Cbl proto-oncogene C', 'Gene', (498, 518))	('ABCA13', 'Gene', (41, 47))	('ELF3', 'Gene', (369, 373))	('keratin 7', 'Gene', (147, 156))	('argininosuccinate synthase 1', 'Gene', (527, 555))	('PON1', 'Gene', '5444', (693, 697))	('S', 'Gene', '43740568', (837, 838))	('olfactomedin 4', 'Gene', '10562', (405, 419))	('S', 'Gene', '43740568', (605, 606))	('PI3', 'Gene', (399, 402))	('S', 'Gene', '43740568', (558, 559))	('ATP2C2', 'Gene', (792, 798))	('AASS', 'Gene', '10157', (76, 80))	('serine peptidase inhibitor kazal type 1', 'Gene', (564, 603))	('S100P', 'SUBSTITUTION', 'None', (646, 651))	('OLFM4', 'Gene', (421, 426))	('SOCS6', 'Gene', '9306', (837, 842))	('CBLC', 'Gene', (520, 524))	('S', 'Gene', '43740568', (445, 446))	('S100 calcium-binding protein P', 'Gene', '6286', (614, 644))	('tripartite motif-containing 31', 'Gene', '11074', (251, 281))	('glutathione S-transferase Mu 3', 'Gene', (292, 322))	('olfactomedin 4', 'Gene', (405, 419))	('TSPAN8', 'Gene', '7103', (669, 675))	('ASS1', 'Gene', (557, 561))	('ELF3', 'Gene', '1999', (369, 373))	('argininosuccinate synthase 1', 'Gene', '445', (527, 555))	('fyn', 'Gene', (700, 703))	('paraoxonase 1', 'Gene', (678, 691))
61264	32916258	From the 219 miRNAs ACE2 shares has-mir-26b-5p with TSPN3 and KLF5, has-mir-10b-5p with KLF5 and AASS, has-mir-499a with TSPN3, has-mir-100-5p with CYP2C18, has-mir-520c-3p with KLF5, has-mir-99a-5p with CYP2C18, has-mir-210-3p with CYP2C18 and has-mir-449a with TSPN3.	('S', 'Gene', '43740568', (100, 101))	('KLF5', 'Gene', (62, 66))	('has-mir-10b-5p', 'Var', (68, 82))	('S', 'Gene', '43740568', (122, 123))	('S', 'Gene', '43740568', (99, 100))	('S', 'Gene', '43740568', (264, 265))	('KLF5', 'Gene', '688', (178, 182))	('mir-26b', 'Gene', '407017', (36, 43))	('KLF5', 'Gene', '688', (88, 92))	('KLF5', 'Gene', (178, 182))	('AASS', 'Gene', (97, 101))	('CYP2C18', 'Gene', (148, 155))	('CYP2C18', 'Gene', (204, 211))	('CYP2C18', 'Gene', '1562', (148, 155))	('CYP2C18', 'Gene', '1562', (204, 211))	('AASS', 'Gene', '10157', (97, 101))	('KLF5', 'Gene', (88, 92))	('CYP2C18', 'Gene', (233, 240))	('has-mir-210-3p', 'Var', (213, 227))	('CYP2C18', 'Gene', '1562', (233, 240))	('has-mir-449a', 'Var', (245, 257))	('mir-26b', 'Gene', (36, 43))	('has-mir-520c-3p', 'Var', (157, 172))	('KLF5', 'Gene', '688', (62, 66))	('S', 'Gene', '43740568', (53, 54))
30989	32916258	For instance, ACE2 inhibits breast cancer angiogenesis through suppressing VEGFa/VEGFR2/ERK pathway and reduces cell invasion and migration in NSCLC cells.	('NSCLC', 'Disease', (143, 148))	('VEGFR2', 'Gene', (81, 87))	('ERK', 'Gene', '2048', (88, 91))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('reduces', 'NegReg', (104, 111))	('NSCLC', 'Disease', 'MESH:D002289', (143, 148))	('breast cancer', 'Disease', 'MESH:D001943', (28, 41))	('rat', 'Species', '10116', (133, 136))	('VEGFa', 'Gene', '7422', (75, 80))	('ERK', 'Gene', (88, 91))	('ACE2', 'Var', (14, 18))	('breast cancer', 'Disease', (28, 41))	('suppressing', 'NegReg', (63, 74))	('breast cancer', 'Phenotype', 'HP:0003002', (28, 41))	('VEGFa', 'Gene', (75, 80))	('inhibits', 'NegReg', (19, 27))	('VEGFR2', 'Gene', '3791', (81, 87))
61297	32916258	Furthermore, we also found 16 mutations in the ACE2 gene in lung cancer patients that may aid in COVID-19 virus entry or disease severity depending on the mutations type and position.	('ACE2', 'Gene', (47, 51))	('lung cancer', 'Disease', (60, 71))	('lung cancer', 'Phenotype', 'HP:0100526', (60, 71))	('aid', 'Reg', (90, 93))	('COVID-19 virus entry', 'Disease', (97, 117))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('lung cancer', 'Disease', 'MESH:D008175', (60, 71))	('mutations', 'Var', (30, 39))	('COVID-19 virus entry', 'Disease', 'MESH:C000657245', (97, 117))	('patients', 'Species', '9606', (72, 80))
61305	32916258	So, in our study, the moderated co-expression of LCN2 still bears significance in the clinical outcome of LUAD and LUSC because of non-responsiveness to radiotherapy.	('LUAD', 'Phenotype', 'HP:0030078', (106, 110))	('S', 'Gene', '43740568', (117, 118))	('significance', 'Reg', (66, 78))	('rat', 'Species', '10116', (26, 29))	('LUSC', 'Phenotype', 'HP:0030359', (115, 119))	('LCN2', 'Gene', '3934', (49, 53))	('S', 'Gene', '43740568', (0, 1))	('LCN2', 'Gene', (49, 53))	('LUAD', 'Disease', (106, 110))	('co-expression', 'Var', (32, 45))
61310	32916258	So, ACE2 helping in the entry of the COVID-19 virus into the cell may lead to lung cancer, as evident in the co-expressed genes contributing to lung cancer progression and its upregulation in LUAD and LUSC.	('lung cancer', 'Disease', (78, 89))	('lung cancer', 'Phenotype', 'HP:0100526', (78, 89))	('upregulation', 'PosReg', (176, 188))	('lung cancer', 'Disease', (144, 155))	('lung cancer', 'Phenotype', 'HP:0100526', (144, 155))	('LUSC', 'Phenotype', 'HP:0030359', (201, 205))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('ACE2', 'Var', (4, 8))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('COVID-19 virus', 'Species', '2697049', (37, 51))	('lead to', 'Reg', (70, 77))	('lung cancer', 'Disease', 'MESH:D008175', (78, 89))	('S', 'Gene', '43740568', (0, 1))	('lung cancer', 'Disease', 'MESH:D008175', (144, 155))	('COVID-19', 'Gene', (37, 45))	('S', 'Gene', '43740568', (203, 204))	('LUAD', 'Phenotype', 'HP:0030078', (192, 196))
61339	31296250	The inhibition of LEF1 might therefore be a novel therapeutic target to inactivate CSCs and inhibit tumor progression.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Disease', (100, 105))	('CSCs', 'Protein', (83, 87))	('inhibition', 'Var', (4, 14))	('inhibit', 'NegReg', (92, 99))	('inactivate', 'NegReg', (72, 82))	('LEF1', 'Gene', (18, 22))	('tumor', 'Disease', 'MESH:D009369', (100, 105))
61348	31296250	In our previous study, we demonstrated that OV6 expression was also closely associated with the clinical outcome and prognosis of ESCC patients and contributed to tumorigenesis and chemotherapy resistance.	('patients', 'Species', '9606', (135, 143))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('ESCC', 'Disease', (130, 134))	('chemotherapy resistance', 'CPA', (181, 204))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('contributed to', 'Reg', (148, 162))	('rat', 'Species', '10116', (33, 36))	('associated', 'Reg', (76, 86))	('tumor', 'Disease', (163, 168))	('OV6 expression', 'Var', (44, 58))
61350	31296250	Several studies indicated that LEF1 was overexpressed in lung adenocarcinomas and oral squamous cell carcinoma, and its aberrant expression was closely associated with tumor progression and poor prognosis.	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (82, 110))	('aberrant', 'Var', (120, 128))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (87, 110))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (57, 77))	('tumor', 'Disease', (168, 173))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('oral squamous cell carcinoma', 'Disease', (82, 110))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('lung adenocarcinomas', 'Disease', (57, 77))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (57, 77))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('associated', 'Reg', (152, 162))	('overexpressed', 'PosReg', (40, 53))	('LEF1', 'Gene', (31, 35))
61355	31296250	The aberrant activation of the TGF-beta signaling pathway is responsible for the self-renewal properties and drug resistance of various cancers, including hepatocellular carcinoma, esophageal squamous cell carcinoma, and colorectal cancer.	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (155, 179))	('cancers', 'Phenotype', 'HP:0002664', (136, 143))	('cancers', 'Disease', (136, 143))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('colorectal cancer', 'Disease', 'MESH:D015179', (221, 238))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (155, 179))	('TGF-beta', 'Gene', '7040', (31, 39))	('colorectal cancer', 'Disease', (221, 238))	('carcinoma', 'Phenotype', 'HP:0030731', (206, 215))	('hepatocellular carcinoma', 'Disease', (155, 179))	('esophageal squamous cell carcinoma', 'Disease', (181, 215))	('cancers', 'Disease', 'MESH:D009369', (136, 143))	('TGF-beta', 'Gene', (31, 39))	('rectal cancer', 'Phenotype', 'HP:0100743', (225, 238))	('carcinoma', 'Phenotype', 'HP:0030731', (170, 179))	('aberrant', 'Var', (4, 12))	('activation', 'PosReg', (13, 23))	('colorectal cancer', 'Phenotype', 'HP:0003003', (221, 238))	('drug resistance', 'Phenotype', 'HP:0020174', (109, 124))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (192, 215))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (181, 215))
61358	31296250	A recent study reported that the application of a TGF-beta inhibitor prevents the development of CSCs, which promotes the chemotherapeutic effect against triple-negative breast cancer.	('CSCs', 'Disease', (97, 101))	('TGF-beta', 'Gene', '7040', (50, 58))	('inhibitor', 'Var', (59, 68))	('development', 'CPA', (82, 93))	('TGF-beta', 'Gene', (50, 58))	('breast cancer', 'Disease', 'MESH:D001943', (170, 183))	('prevents', 'NegReg', (69, 77))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('breast cancer', 'Disease', (170, 183))	('breast cancer', 'Phenotype', 'HP:0003002', (170, 183))	('promotes', 'PosReg', (109, 117))
61378	31296250	The lentiviral vectors were transfected into the HCC cells with a multiplicity of infection (MOI) 5 in the presence of polybrene (5 mug/ml) for 6 h. Stable Eca109 and TE-1 cells knockdown of LEF1 were generated using lentiviral constructs expressing shLEF1(shLEF11#CCCATCCCGAGAACATCAA; shLEF12#CCTCATCCAGCTATTGTAA; shLEF13#GCTACATATGCAGCTTTAT) and negative control (HeYuan Bio-technology Co., Shanghai, China), and incubated with 2 mug/ml puromycin (Sigma, St Louis, USA).	('rat', 'Species', '10116', (205, 208))	('HCC', 'CellLine', 'CVCL:0C54', (49, 52))	('shLEF13#GCTACATATGCAGCTTTAT', 'Var', (315, 342))	('shLEF12#CCTCATCCAGCTATTGTAA', 'Var', (286, 313))	('infection', 'Disease', (82, 91))	('infection', 'Disease', 'MESH:D007239', (82, 91))
61411	31296250	A Kaplan-Meier curve unveiled that patients with high expression levels of LEF1 were associated with a lower overall survival rate (Fig.	('lower', 'NegReg', (103, 108))	('LEF1', 'Gene', (75, 79))	('high expression levels', 'Var', (49, 71))	('overall survival', 'MPA', (109, 125))	('patients', 'Species', '9606', (35, 43))	('rat', 'Species', '10116', (126, 129))
61414	31296250	Our previous study reported that OV6 was a possible CSC marker for ESCC and was associated with poor prognosis in ESCC patients.	('patients', 'Species', '9606', (119, 127))	('ESCC', 'Disease', (114, 118))	('ESCC', 'Disease', (67, 71))	('OV6', 'Var', (33, 36))
61473	31296250	In addition, a significant correlation between LEF1 and ID1 expression was observed in clinical ESCC patients, strongly suggesting that LEF1 regulation of the CSC phenotype is associated with ID1 expression.	('patients', 'Species', '9606', (101, 109))	('ID1', 'Gene', (56, 59))	('LEF1', 'Var', (136, 140))	('ID1', 'Gene', '3397', (192, 195))	('ESCC', 'Disease', (96, 100))	('ID1', 'Gene', (192, 195))	('ID1', 'Gene', '3397', (56, 59))
61480	31296250	Mechanically, LEF1 overexpression in ESCC directly upregulates ID1 and activates TGF-beta pathway.	('upregulates', 'PosReg', (51, 62))	('ID1', 'Gene', (63, 66))	('activates', 'PosReg', (71, 80))	('overexpression', 'Var', (19, 33))	('ID1', 'Gene', '3397', (63, 66))	('TGF-beta', 'Gene', '7040', (81, 89))	('LEF1', 'Gene', (14, 18))	('TGF-beta', 'Gene', (81, 89))
61486	32911687	Additionally, by reporting the molecular mechanisms of drug sensitivity and resistance in which non-coding RNAs are involved, we highlighted their potential role as druggable targets and suggested new therapeutic options for CSCC patients.	('CSCC', 'Disease', (225, 229))	('non-coding', 'Var', (96, 106))	('involved', 'Reg', (116, 124))	('RNAs', 'Gene', (107, 111))	('patients', 'Species', '9606', (230, 238))	('drug sensitivity', 'Phenotype', 'HP:0020174', (55, 71))	('CSCC', 'Phenotype', 'HP:0006739', (225, 229))
61506	32911687	Specifically, the aberrant alterations of ncRNA intracellular networks can lead to the development of pathological conditions, such as tumorigenesis.	('lead to', 'Reg', (75, 82))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('aberrant alterations', 'Var', (18, 38))	('tumor', 'Disease', (135, 140))	('tumor', 'Disease', 'MESH:D009369', (135, 140))	('ncRNA', 'Gene', (42, 47))	('ncRNA', 'Gene', '220202', (42, 47))
61515	32911687	Whole exome sequencing (WES) analysis has revealed that CSCC is also a tumor with the "UVR mutational signature", showing a marked mutation burden with about 50 mutations per megabase pair DNA with a prevalence of cytosine > thymine (C > T) transitions at pyrimidine sites that represent the 68% of all somatic mutations induced by UVR damage.	('thymine', 'Chemical', 'MESH:D013941', (225, 232))	('pyrimidine', 'Chemical', 'MESH:C030986', (256, 266))	('cytosine', 'Chemical', 'MESH:D003596', (214, 222))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('mutations', 'Var', (161, 170))	('CSCC', 'Phenotype', 'HP:0006739', (56, 60))	('tumor', 'Disease', (71, 76))	('CSCC', 'Disease', (56, 60))
61516	32911687	Interestingly, significant evidence shows that sun-exposed epidermal cells carry many of the CSCC-specific mutations such as TP53 and NOTCH1/2 mutations, with an incidence rate 10-fold lower than CSCC cells.	('NOTCH1/2', 'Gene', '4851;4853', (134, 142))	('mutations', 'Var', (107, 116))	('TP53', 'Gene', '7157', (125, 129))	('CSCC', 'Phenotype', 'HP:0006739', (196, 200))	('TP53', 'Gene', (125, 129))	('CSCC', 'Phenotype', 'HP:0006739', (93, 97))	('NOTCH1/2', 'Gene', (134, 142))	('CSCC-specific', 'Gene', (93, 106))	('mutations', 'Var', (143, 152))
61517	32911687	Probably, the continuous accumulation of UVR-induced mutations and the constant renewal of damaged epidermal cells support the multiple mutational events that lead to the activation of oncogenes or the inactivation of tumor suppression genes with resultant CSCC development.	('inactivation', 'NegReg', (202, 214))	('UVR-induced', 'Gene', (41, 52))	('tumor', 'Disease', 'MESH:D009369', (218, 223))	('CSCC', 'Phenotype', 'HP:0006739', (257, 261))	('mutations', 'Var', (53, 62))	('activation', 'PosReg', (171, 181))	('CSCC', 'Disease', (257, 261))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('oncogenes', 'Gene', (185, 194))	('tumor', 'Disease', (218, 223))
61523	32911687	Probably, following the damage, HOTAIR up-regulates double-stranded RNA-dependent protein kinase (PKR) expression, activating the PI3K/AKT and NF-kB pathway and promoting the inflammatory process.	('AKT', 'Gene', '207', (135, 138))	('NF-kB pathway', 'Pathway', (143, 156))	('HOTAIR', 'Gene', (32, 38))	('PKR', 'Gene', (98, 101))	('expression', 'MPA', (103, 113))	('PKR', 'Gene', '5610', (98, 101))	('AKT', 'Gene', (135, 138))	('HOTAIR', 'Gene', '100124700', (32, 38))	('AK', 'Phenotype', 'HP:0025127', (135, 137))	('activating', 'PosReg', (115, 125))	('up-regulates', 'PosReg', (39, 51))	('inflammatory process', 'CPA', (175, 195))	('double-stranded', 'Var', (52, 67))	('promoting', 'PosReg', (161, 170))
61533	32911687	The aberrant alterations of these networks can lead to the development of pathological cell conditions, including tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('lead to', 'Reg', (47, 54))	('tumor', 'Disease', (114, 119))	('aberrant alterations', 'Var', (4, 24))
61537	32911687	miRNAs could act as oncogenes (oncomiRs) or tumour suppressors, depending on the roles of their target genes.	('tumour', 'Disease', 'MESH:D009369', (44, 50))	('tumour', 'Disease', (44, 50))	('miRNAs', 'Var', (0, 6))	('oncogenes', 'CPA', (20, 29))	('tumour', 'Phenotype', 'HP:0002664', (44, 50))
61540	32911687	Moreover, recent studies have discovered novel oncomiRs (miR-506 and miR-664) and tumor suppressor miRNAs (miR-216b, miR-125b, and miR-3619-5p) involved in the pathogenesis of CSCC, and understanding their role as biomarkers and potential targets for the treatment of CSCC is of great interest in oncology research.	('miR-3619', 'Gene', '100500828', (131, 139))	('oncology', 'Phenotype', 'HP:0002664', (297, 305))	('miR-125b', 'Chemical', '-', (117, 125))	('miR-216b', 'Var', (107, 115))	('involved', 'Reg', (144, 152))	('miR-506', 'Gene', '574511', (57, 64))	('miR-664', 'Var', (69, 76))	('miR-506', 'Gene', (57, 64))	('tumor suppressor', 'Gene', (82, 98))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('CSCC', 'Phenotype', 'HP:0006739', (268, 272))	('miR-125b', 'Var', (117, 125))	('tumor suppressor', 'Gene', '7248', (82, 98))	('CSCC', 'Phenotype', 'HP:0006739', (176, 180))	('miR-3619', 'Gene', (131, 139))	('CSCC', 'Disease', (176, 180))
61542	32911687	Molecular assays have revealed that the silencing of miR-506 reduces cell proliferation, invasion, and migration ability in CSCC cells, suggesting its involvement in regulating cell survival and apoptosis.	('miR-506', 'Gene', '574511', (53, 60))	('miR-506', 'Gene', (53, 60))	('apoptosis', 'CPA', (195, 204))	('invasion', 'CPA', (89, 97))	('migration ability', 'CPA', (103, 120))	('cell proliferation', 'CPA', (69, 87))	('involvement', 'Reg', (151, 162))	('CSCC', 'Phenotype', 'HP:0006739', (124, 128))	('silencing', 'Var', (40, 49))	('cell survival', 'CPA', (177, 190))	('reduces', 'NegReg', (61, 68))	('regulating', 'Reg', (166, 176))
61549	32911687	IRF2 is inhibited by miR-664 and its expression in CSCC is strongly reduced compared to healthy skin tissues.	('inhibited', 'NegReg', (8, 17))	('IRF2', 'Gene', (0, 4))	('CSCC', 'Phenotype', 'HP:0006739', (51, 55))	('expression', 'MPA', (37, 47))	('miR-664', 'Var', (21, 28))	('IRF2', 'Gene', '3660', (0, 4))	('reduced', 'NegReg', (68, 75))
61552	32911687	Further investigations have also shown a correlation between miR-216b and p53 expression, suggesting that the over-expression of miRNA-216b can inhibit cell proliferation and promotes cell apoptosis by negatively regulating TPX2 and promoting the activation of p53 signaling.	('negatively', 'NegReg', (202, 212))	('promoting', 'PosReg', (233, 242))	('p53', 'Gene', (261, 264))	('p53', 'Gene', '7157', (261, 264))	('promotes', 'PosReg', (175, 183))	('over-expression', 'PosReg', (110, 125))	('miRNA-216b', 'Var', (129, 139))	('p53', 'Gene', (74, 77))	('TPX2', 'Gene', (224, 228))	('inhibit', 'NegReg', (144, 151))	('p53', 'Gene', '7157', (74, 77))	('TPX2', 'Gene', '22974', (224, 228))	('cell proliferation', 'CPA', (152, 170))	('cell apoptosis', 'CPA', (184, 198))
61555	32911687	miR-125b inhibits the tumor growth and progression in two ways: (i) by influencing the STAT3 pathway, and (ii) by negatively regulating the downstream targets Cyclin D1 and Bcl2, involved in the cell cycle and apoptosis processes, respectively.	('STAT3', 'Gene', (87, 92))	('Bcl2', 'Gene', '596', (173, 177))	('negatively regulating', 'NegReg', (114, 135))	('Cyclin D1', 'Gene', (159, 168))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('miR-125b', 'Var', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('inhibits', 'NegReg', (9, 17))	('Bcl2', 'Gene', (173, 177))	('tumor', 'Disease', (22, 27))	('influencing', 'Reg', (71, 82))	('miR-125b', 'Chemical', '-', (0, 8))	('STAT3', 'Gene', '6774', (87, 92))	('Cyclin D1', 'Gene', '595', (159, 168))
61567	32911687	In order to suggest possible therapeutic applications of the novel oncomiRs (miR-506 and miR664) and tumor suppressor miRNAs (miR-215b, miR-216b, and miR-3619-5p) in CSCC, we focused on the evidence, reported in other tumor pathologies, on their role in the modulation of response/resistance to drugs used in the treatment of CSCC.	('miR-506', 'Gene', (77, 84))	('miR-216b', 'Var', (136, 144))	('tumor', 'Disease', (218, 223))	('tumor', 'Disease', 'MESH:D009369', (218, 223))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('miR-3619', 'Gene', (150, 158))	('miR-3619', 'Gene', '100500828', (150, 158))	('tumor suppressor', 'Gene', (101, 117))	('CSCC', 'Phenotype', 'HP:0006739', (326, 330))	('miR664', 'Gene', (89, 95))	('miR-506', 'Gene', '574511', (77, 84))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('CSCC', 'Phenotype', 'HP:0006739', (166, 170))	('CSCC', 'Disease', (166, 170))	('tumor suppressor', 'Gene', '7248', (101, 117))	('tumor', 'Disease', (101, 106))	('miR-215b', 'Var', (126, 134))	('miR664', 'Gene', '100302234', (89, 95))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
61571	32911687	Therefore, it could be hypothesized that the limited and unsuccessful efficacy of the platin-based pharmacological treatment may depend on a lack of correct stratification of patients on a genetic basis; probably the subset of patients with high levels of miRNA-506 or miRNA-664 could respond to cisplatin.	('cisplatin', 'Chemical', 'MESH:D002945', (296, 305))	('miRNA-664', 'Var', (269, 278))	('respond', 'Reg', (285, 292))	('platin', 'Chemical', '-', (86, 92))	('patients', 'Species', '9606', (175, 183))	('platin', 'Chemical', '-', (299, 305))	('patients', 'Species', '9606', (227, 235))
61572	32911687	Despite the interaction with drugs of the two tumor suppressor miRNAs, miR-216b and miR-125b have already been characterised in several cancer diseases.	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('cancer diseases', 'Disease', (136, 151))	('tumor suppressor', 'Gene', (46, 62))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('cancer diseases', 'Disease', 'MESH:D009369', (136, 151))	('miR-125b', 'Chemical', '-', (84, 92))	('interaction', 'Interaction', (12, 23))	('tumor suppressor', 'Gene', '7248', (46, 62))	('miR-216b', 'Var', (71, 79))	('miR-125b', 'Var', (84, 92))
61573	32911687	The reduced levels of miR-216b appear to be responsible for the reduced sensitivity to cisplatin through an up-regulation of PARP-1 in ovarian cancer cells and via c-Jun/Bcl-xl in NSCLC.	('cisplatin', 'Chemical', 'MESH:D002945', (87, 96))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('Bcl-xl', 'Gene', (170, 176))	('PARP-1', 'Gene', (125, 131))	('ovarian cancer', 'Disease', (135, 149))	('NSCLC', 'Disease', (180, 185))	('reduced', 'NegReg', (4, 11))	('up-regulation', 'PosReg', (108, 121))	('PARP-1', 'Gene', '142', (125, 131))	('sensitivity to cisplatin', 'MPA', (72, 96))	('c-Jun', 'Gene', '3725', (164, 169))	('miR-216b', 'Var', (22, 30))	('NSCLC', 'Disease', 'MESH:D002289', (180, 185))	('ovarian cancer', 'Phenotype', 'HP:0100615', (135, 149))	('reduced', 'NegReg', (64, 71))	('Bcl-xl', 'Gene', '598', (170, 176))	('ovarian cancer', 'Disease', 'MESH:D010051', (135, 149))	('c-Jun', 'Gene', (164, 169))
61575	32911687	Low levels of miR-125b are also correlated with resistance to 5-FU in colorectal cancer and to doxorubicin in breast cancer.	('colorectal cancer', 'Disease', 'MESH:D015179', (70, 87))	('doxorubicin', 'Chemical', 'MESH:D004317', (95, 106))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('colorectal cancer', 'Phenotype', 'HP:0003003', (70, 87))	('5-FU', 'Chemical', 'MESH:D005472', (62, 66))	('resistance to 5-FU', 'MPA', (48, 66))	('miR-125b', 'Var', (14, 22))	('colorectal cancer', 'Disease', (70, 87))	('breast cancer', 'Disease', 'MESH:D001943', (110, 123))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('breast cancer', 'Disease', (110, 123))	('breast cancer', 'Phenotype', 'HP:0003002', (110, 123))	('miR-125b', 'Chemical', '-', (14, 22))
61576	32911687	Moreover, as demonstrated by Chen, low levels of miR-216b up-regulate Beclin-1 by reducing sensitivity to cetuximab through the induction of autophagy in CRC cells.	('miR-216b', 'Var', (49, 57))	('up-regulate', 'PosReg', (58, 69))	('reducing', 'NegReg', (82, 90))	('sensitivity to cetuximab', 'MPA', (91, 115))	('autophagy', 'CPA', (141, 150))	('Beclin-1', 'Gene', (70, 78))	('cetuximab', 'Chemical', 'MESH:D000068818', (106, 115))	('Beclin-1', 'Gene', '8678', (70, 78))
61578	32911687	Furthermore, as reported above, the over-expression of miRNA-3619-5p is involved in drug response in CSCC by reducing KPNA4 expression and increasing cisplatin sensitivity.	('cisplatin sensitivity', 'MPA', (150, 171))	('KPNA4', 'Gene', '3840', (118, 123))	('expression', 'MPA', (124, 134))	('over-expression', 'PosReg', (36, 51))	('cisplatin', 'Chemical', 'MESH:D002945', (150, 159))	('CSCC', 'Disease', (101, 105))	('CSCC', 'Phenotype', 'HP:0006739', (101, 105))	('reducing', 'NegReg', (109, 117))	('miRNA-3619-5p', 'Var', (55, 68))	('KPNA4', 'Gene', (118, 123))	('increasing', 'PosReg', (139, 149))
61580	32911687	Indeed, it is part of a set of miRNAs in plasma which, when present at high levels, correlates with shorter PFS and OS in melanoma patients treated with anti-PD1, nivolumab, and pembrolizumab.	('patients', 'Species', '9606', (131, 139))	('pembrolizumab', 'Chemical', 'MESH:C582435', (178, 191))	('melanoma', 'Disease', 'MESH:D008545', (122, 130))	('shorter', 'NegReg', (100, 107))	('PFS', 'CPA', (108, 111))	('melanoma', 'Phenotype', 'HP:0002861', (122, 130))	('melanoma', 'Disease', (122, 130))	('nivolumab', 'Chemical', 'MESH:D000077594', (163, 172))	('anti-PD1', 'Var', (153, 161))
61590	32911687	have identified a novel circRNA (circ_0070934) highly expressed in CSCC tissue specimens and cell lines which promotes the proliferation, migration, and invasiveness in CSCC cells by sponging and negatively regulating miR-1238 and miR-1247e5p, two microRNAs that act as tumor suppressors.	('proliferation', 'CPA', (123, 136))	('miR-1238', 'Gene', '100302226', (218, 226))	('migration', 'CPA', (138, 147))	('CSCC', 'Phenotype', 'HP:0006739', (67, 71))	('tumor suppressor', 'Gene', (270, 286))	('miR-1247e5p', 'Var', (231, 242))	('invasiveness', 'CPA', (153, 165))	('tumor suppressor', 'Gene', '7248', (270, 286))	('negatively regulating', 'NegReg', (196, 217))	('promotes', 'PosReg', (110, 118))	('tumor', 'Phenotype', 'HP:0002664', (270, 275))	('miR-1238', 'Gene', (218, 226))	('CSCC', 'Phenotype', 'HP:0006739', (169, 173))
61598	32911687	Up to now, over 18,000 lncRNA transcripts have been detected in the human genome, and according to their genomic position relative to the nearby protein-coding genes, they are classified into the following categories: intergenic, sense intronic, antisense, and bidirectional lncRNA.	('human', 'Species', '9606', (68, 73))	('ncRNA', 'Gene', '220202', (276, 281))	('antisense', 'Var', (246, 255))	('ncRNA', 'Gene', (24, 29))	('ncRNA', 'Gene', (276, 281))	('ncRNA', 'Gene', '220202', (24, 29))
61616	32911687	Recently, Zhang Y. and co-authors have explored the oncogenic role of MALAT1 in CSCC, demonstrating that MALAT1 knockdown strongly reduces proliferation, migration, invasiveness, and increases apoptosis.	('CSCC', 'Disease', (80, 84))	('MALAT1', 'Gene', '378938', (70, 76))	('apoptosis', 'CPA', (193, 202))	('invasiveness', 'CPA', (165, 177))	('MALAT1', 'Gene', (70, 76))	('reduces', 'NegReg', (131, 138))	('increases', 'PosReg', (183, 192))	('knockdown', 'Var', (112, 121))	('proliferation', 'CPA', (139, 152))	('MALAT1', 'Gene', '378938', (105, 111))	('CSCC', 'Phenotype', 'HP:0006739', (80, 84))	('migration', 'CPA', (154, 163))	('MALAT1', 'Gene', (105, 111))
61627	32911687	ROS especially leads to the activation of the ERK1/2 pathway, which actives the transcription factor SP3 (specificity protein 3) through direct phosphorylation.	('SP3', 'Gene', '6670', (101, 104))	('phosphorylation', 'MPA', (144, 159))	('ROS', 'Var', (0, 3))	('ROS', 'Chemical', 'MESH:D017382', (0, 3))	('specificity protein 3', 'Gene', (106, 127))	('specificity protein 3', 'Gene', '6670', (106, 127))	('ERK1/2', 'Gene', (46, 52))	('SP3', 'Gene', (101, 104))	('ERK1/2', 'Gene', '5595;5594', (46, 52))	('actives', 'MPA', (68, 75))
61632	32911687	THOR over-expression contributes to cancer progression since its silencing or depletion is well-known to induce the inhibition of cancer cell proliferation.	('silencing', 'Var', (65, 74))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('cancer', 'Disease', (130, 136))	('THOR', 'Gene', (0, 4))	('cancer', 'Disease', (36, 42))	('depletion', 'MPA', (78, 87))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('over-expression', 'PosReg', (5, 20))
61635	32911687	Mechanistically, it has been observed that THOR knockdown in CSCC cells induces the down-regulation of IGF2BP1 mRNA, which is correlated with the inhibition of the progression of cutaneous cancer.	('cutaneous cancer', 'Phenotype', 'HP:0008069', (179, 195))	('mRNA', 'MPA', (111, 115))	('CSCC', 'Phenotype', 'HP:0006739', (61, 65))	('inhibition', 'NegReg', (146, 156))	('IGF2BP1', 'Gene', '10642', (103, 110))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('down-regulation', 'NegReg', (84, 99))	('knockdown', 'Var', (48, 57))	('IGF2BP1', 'Gene', (103, 110))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('cancer', 'Disease', (189, 195))
61637	32911687	HOX antisense intergenic RNA (HOTAIR) is a lncRNA involved in different processes of normal cell development, but its aberrant over-expression can contribute to proliferation, invasion, and infiltration of malignant tumor cells.	('malignant tumor', 'Disease', (206, 221))	('over-expression', 'PosReg', (127, 142))	('infiltration', 'CPA', (190, 202))	('malignant tumor', 'Disease', 'MESH:D009369', (206, 221))	('ncRNA', 'Gene', (44, 49))	('HOTAIR', 'Gene', (30, 36))	('contribute', 'Reg', (147, 157))	('aberrant', 'Var', (118, 126))	('ncRNA', 'Gene', '220202', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('HOTAIR', 'Gene', '100124700', (30, 36))	('invasion', 'CPA', (176, 184))	('proliferation', 'CPA', (161, 174))
61647	32911687	It is well-known that in CSCC carcinogenesis, the aberrant activation of the EGFR gene leads to higher activation of the PI3K-Akt anti-apoptotic signaling pathway, which contributes to cancer progression.	('carcinogenesis', 'Disease', 'MESH:D063646', (30, 44))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('CSCC', 'Phenotype', 'HP:0006739', (25, 29))	('carcinogenesis', 'Disease', (30, 44))	('Akt', 'Gene', '207', (126, 129))	('CSCC', 'Disease', (25, 29))	('activation', 'PosReg', (59, 69))	('EGFR', 'Gene', '1956', (77, 81))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('higher activation', 'PosReg', (96, 113))	('cancer', 'Disease', (185, 191))	('contributes', 'Reg', (170, 181))	('aberrant', 'Var', (50, 58))	('EGFR', 'Gene', (77, 81))	('Akt', 'Gene', (126, 129))
61843	26919244	In univariate analyses, nuclear MYOF was associated with poor overall survival (p<0.001) and these patients had 5.5 times increased hazard of death (95% Cl 3.4-8.8).	('MYOF', 'Gene', (32, 36))	('poor', 'NegReg', (57, 61))	('patients', 'Species', '9606', (99, 107))	('MYOF', 'Gene', '26509', (32, 36))	('death', 'Disease', 'MESH:D003643', (142, 147))	('nuclear', 'Var', (24, 31))	('death', 'Disease', (142, 147))	('overall survival', 'MPA', (62, 78))
61848	26919244	Taken together, our results demonstrate for the first time that nuclear myoferlin expression independently predicts poor clinical outcome in OPSCC patients.	('OPSCC', 'Phenotype', 'HP:0012182', (141, 146))	('nuclear', 'Var', (64, 71))	('patients', 'Species', '9606', (147, 155))	('OPSCC', 'Disease', (141, 146))	('myoferlin', 'Gene', '26509', (72, 81))	('predicts', 'Reg', (107, 115))	('myoferlin', 'Gene', (72, 81))
61895	26919244	Similarly, larger proportion of patients with nuclear myoferlin expression had T3/T4 tumors (54.6% versus 29.1%; p=0.0015), had perineural invasion (40.7% versus 20.9%; p=0.008), had extracapsular spread (59.6% versus 37.6%; p=0.009), had a recurrence (50% versus 18.3%; p<0.001), and distant metastasis (45.4% versus 0.0%; p<0.001) as compared to those with non-nuclear myoferlin expression.	('distant metastasis', 'CPA', (285, 303))	('patients', 'Species', '9606', (32, 40))	('perineural invasion', 'CPA', (128, 147))	('myoferlin', 'Gene', (54, 63))	('T4 tumors', 'Disease', 'MESH:D005067', (82, 91))	('T4 tumors', 'Disease', (82, 91))	('myoferlin', 'Gene', '26509', (371, 380))	('expression', 'Var', (64, 74))	('recurrence', 'CPA', (241, 251))	('myoferlin', 'Gene', (371, 380))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('extracapsular spread', 'CPA', (183, 203))	('myoferlin', 'Gene', '26509', (54, 63))
61911	26919244	We also found that tumors with nuclear myoferlin expression had higher IL-6 (p<0.001, Figure 4D), and nanog expression (p<0.001, Figure 6B).	('tumors', 'Disease', (19, 25))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('nanog', 'Gene', '79923', (102, 107))	('IL-6', 'Gene', (71, 75))	('higher', 'PosReg', (64, 70))	('myoferlin', 'Gene', '26509', (39, 48))	('myoferlin', 'Gene', (39, 48))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('IL-6', 'Gene', '3569', (71, 75))	('nanog', 'Gene', (102, 107))	('nuclear', 'Var', (31, 38))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))
61925	26919244	It is possible that HPV-positive tumors lack the oncogenic hit(s) that upregulate myoferlin expression or HPV oncogenes (E6/E7) actively downregulate myoferlin expression.	('expression', 'MPA', (160, 170))	('upregulate', 'PosReg', (71, 81))	('HPV', 'Species', '10566', (20, 23))	('myoferlin', 'Gene', '26509', (82, 91))	('myoferlin', 'Gene', '26509', (150, 159))	('downregulate', 'NegReg', (137, 149))	('HPV', 'Species', '10566', (106, 109))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('myoferlin', 'Gene', (82, 91))	('E6/E7', 'Var', (121, 126))	('myoferlin', 'Gene', (150, 159))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('HPV-positive tumors', 'Disease', 'MESH:D030361', (20, 39))	('expression', 'MPA', (92, 102))	('HPV-positive tumors', 'Disease', (20, 39))
61936	26919244	In this study, we also show that high nanog expression is associated with poor overall survival and nanog expression is directly correlated with IL-6 and nuclear myoferlin expression.	('myoferlin', 'Gene', (162, 171))	('nanog', 'Gene', (100, 105))	('high', 'Var', (33, 37))	('IL-6', 'Gene', (145, 149))	('nanog', 'Gene', '79923', (38, 43))	('overall', 'MPA', (79, 86))	('poor', 'NegReg', (74, 78))	('IL-6', 'Gene', '3569', (145, 149))	('nanog', 'Gene', '79923', (100, 105))	('myoferlin', 'Gene', '26509', (162, 171))	('nanog', 'Gene', (38, 43))
61962	25871546	HPV-negative squamous cell carcinoma of the anal canal is unresponsive to standard treatment and frequently carries disruptive mutations in TP53 Human papillomavirus (HPV), p16 expression, and TP53 mutations are known prognostic factors in head and neck squamous cell carcinoma, but their role in squamous cell carcinoma of the anal canal (SCCAC) is less well established.	('carcinoma', 'Phenotype', 'HP:0030731', (27, 36))	('squamous cell carcinoma', 'Disease', (13, 36))	('carcinoma', 'Phenotype', 'HP:0030731', (311, 320))	('squamous cell carcinoma', 'Disease', (297, 320))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (254, 277))	('TP53', 'Gene', (140, 144))	('TP53', 'Gene', (193, 197))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (13, 36))	('mutations', 'Var', (127, 136))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (240, 277))	('carcinoma', 'Phenotype', 'HP:0030731', (268, 277))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (254, 277))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (297, 320))	('Human papillomavirus', 'Species', '10566', (145, 165))	('p16', 'Gene', (173, 176))	('TP53', 'Gene', '7157', (140, 144))	('HPV', 'Species', '10566', (167, 170))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (13, 36))	('HPV', 'Species', '10566', (0, 3))	('p16', 'Gene', '1029', (173, 176))	('TP53', 'Gene', '7157', (193, 197))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (297, 320))	('neck squamous cell carcinoma', 'Disease', (249, 277))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (249, 277))
61963	25871546	The objective of this study was to determine the prognostic significance of tumour HPV status, p16 and p53 expression, and mutations in TP53 in patients with SCCAC receiving (chemo)radiotherapy.	('p53', 'Gene', (103, 106))	('p53', 'Gene', '7157', (103, 106))	('expression', 'MPA', (107, 117))	('p16', 'Gene', '1029', (95, 98))	('tumour', 'Phenotype', 'HP:0002664', (76, 82))	('tumour HPV status', 'Disease', 'MESH:D030361', (76, 93))	('patients', 'Species', '9606', (144, 152))	('tumour HPV status', 'Disease', (76, 93))	('TP53', 'Gene', '7157', (136, 140))	('TP53', 'Gene', (136, 140))	('mutations', 'Var', (123, 132))	('p16', 'Gene', (95, 98))
61971	25871546	Disruptive mutations in TP53 were found in 80% of HPV-/p16- tumours vs 6% of HPV+/p16+ tumours (P<0.001).	('mutations', 'Var', (11, 20))	('tumours', 'Disease', (87, 94))	('tumour', 'Phenotype', 'HP:0002664', (60, 66))	('p16', 'Gene', (82, 85))	('TP53', 'Gene', (24, 28))	('tumours', 'Disease', 'MESH:D009369', (60, 67))	('tumours', 'Disease', (60, 67))	('tumours', 'Phenotype', 'HP:0002664', (60, 67))	('p16', 'Gene', (55, 58))	('tumour', 'Phenotype', 'HP:0002664', (87, 93))	('HPV', 'Species', '10566', (77, 80))	('found', 'Reg', (34, 39))	('HPV', 'Species', '10566', (50, 53))	('p16', 'Gene', '1029', (82, 85))	('tumours', 'Phenotype', 'HP:0002664', (87, 94))	('tumours', 'Disease', 'MESH:D009369', (87, 94))	('p16', 'Gene', '1029', (55, 58))	('TP53', 'Gene', '7157', (24, 28))
61982	25871546	Persisting inactivation of p53 and pRb leads to genomic instability and, upon persisting infection, to carcinogenesis.	('pRb', 'Gene', (35, 38))	('genomic instability', 'CPA', (48, 67))	('infection', 'Disease', (89, 98))	('p53', 'Gene', '7157', (27, 30))	('infection', 'Disease', 'MESH:D007239', (89, 98))	('pRb', 'Gene', '5925', (35, 38))	('inactivation', 'Var', (11, 23))	('carcinogenesis', 'Disease', 'MESH:D063646', (103, 117))	('carcinogenesis', 'Disease', (103, 117))	('leads to', 'Reg', (39, 47))	('p53', 'Gene', (27, 30))
61983	25871546	As pRb is a negative regulator of the cyclin-dependent kinase inhibitor p16, inactivation of pRb by HPV leads to marked upregulation of p16.	('HPV', 'Species', '10566', (100, 103))	('pRb', 'Gene', '5925', (93, 96))	('p16', 'Gene', '1029', (72, 75))	('pRb', 'Gene', (93, 96))	('p16', 'Gene', (136, 139))	('p16', 'Gene', '1029', (136, 139))	('p16', 'Gene', (72, 75))	('pRb', 'Gene', (3, 6))	('upregulation', 'PosReg', (120, 132))	('pRb', 'Gene', '5925', (3, 6))	('inactivation', 'Var', (77, 89))
61991	25871546	A particularly striking difference between HPV+ and HPV- HNSCC tumours are mutations in TP53 (the gene encoding p53).	('HPV- HNSCC tumours', 'Disease', (52, 70))	('HPV', 'Species', '10566', (52, 55))	('p53', 'Gene', '7157', (112, 115))	('tumour', 'Phenotype', 'HP:0002664', (63, 69))	('TP53', 'Gene', '7157', (88, 92))	('tumours', 'Phenotype', 'HP:0002664', (63, 70))	('p53', 'Gene', (112, 115))	('mutations', 'Var', (75, 84))	('HNSCC', 'Phenotype', 'HP:0012288', (57, 62))	('HPV- HNSCC tumours', 'Disease', 'MESH:D000077195', (52, 70))	('HPV', 'Species', '10566', (43, 46))	('TP53', 'Gene', (88, 92))
61992	25871546	Whereas TP53 mutations are found only sporadically in HPV+ HNSCC tumours (0-10%), they occur very frequently in HPV- tumours, with disruptive mutations present in 80-100% of cases.	('HPV+ HNSCC tumours', 'Disease', 'MESH:D000077195', (54, 72))	('HPV- tumours', 'Disease', 'MESH:D030361', (112, 124))	('tumour', 'Phenotype', 'HP:0002664', (117, 123))	('tumour', 'Phenotype', 'HP:0002664', (65, 71))	('HPV- tumours', 'Disease', (112, 124))	('HPV+ HNSCC tumours', 'Disease', (54, 72))	('tumours', 'Phenotype', 'HP:0002664', (65, 72))	('TP53', 'Gene', '7157', (8, 12))	('tumours', 'Phenotype', 'HP:0002664', (117, 124))	('TP53', 'Gene', (8, 12))	('mutations', 'Var', (13, 22))	('HNSCC', 'Phenotype', 'HP:0012288', (59, 64))
61993	25871546	TP53 mutations are of interest in particular, because they have been linked to prognosis in different types of cancer and, in addition, to resistance to radiation therapy, which is an important treatment modality for SCCAC and most other HPV-associated cancers.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('cancers', 'Phenotype', 'HP:0002664', (253, 260))	('linked', 'Reg', (69, 75))	('cancers', 'Disease', (253, 260))	('cancer', 'Disease', 'MESH:D009369', (253, 259))	('cancers', 'Disease', 'MESH:D009369', (253, 260))	('mutations', 'Var', (5, 14))	('HPV', 'Species', '10566', (238, 241))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('cancer', 'Disease', (253, 259))	('SCCAC', 'Disease', (217, 222))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('cancer', 'Phenotype', 'HP:0002664', (253, 259))
61994	25871546	To investigate the prognostic significance of HPV, p16, and alterations in p53 function in SCCAC, we determined associations with outcome of tumour HPV status, p16 expression, p53 expression, and mutations in TP53 in a cohort of 107 anal carcinoma patients treated with chemoradiotherapy or radiotherapy alone.	('HPV', 'Species', '10566', (148, 151))	('p53', 'Gene', '7157', (176, 179))	('p16', 'Gene', (51, 54))	('tumour HPV status', 'Disease', (141, 158))	('p16', 'Gene', '1029', (51, 54))	('p53', 'Gene', (176, 179))	('carcinoma', 'Phenotype', 'HP:0030731', (238, 247))	('tumour HPV status', 'Disease', 'MESH:D030361', (141, 158))	('carcinoma', 'Disease', (238, 247))	('p16', 'Gene', (160, 163))	('TP53', 'Gene', (209, 213))	('expression', 'MPA', (180, 190))	('p16', 'Gene', '1029', (160, 163))	('p53', 'Gene', '7157', (75, 78))	('patients', 'Species', '9606', (248, 256))	('mutations', 'Var', (196, 205))	('carcinoma', 'Disease', 'MESH:D002277', (238, 247))	('tumour', 'Phenotype', 'HP:0002664', (141, 147))	('HPV', 'Species', '10566', (46, 49))	('p53', 'Gene', (75, 78))	('TP53', 'Gene', '7157', (209, 213))
61997	25871546	Patients with T1-2 (T>=1 and <4 cm), N0-1, M0 disease were treated with radiotherapy alone.	('M0 disease', 'Disease', (43, 53))	('T1-2', 'Gene', (14, 18))	('M0 disease', 'Disease', 'MESH:D004194', (43, 53))	('Patients', 'Species', '9606', (0, 8))	('T1-2', 'Gene', '923;921;292', (14, 18))	('N0-1', 'Var', (37, 41))
62003	25871546	Human papillomavirus 6, 11, 40, 43, 44, 54, 71, and 74 were considered LR-HPV types, whereas HPV16, 18, 26, 31, 33, 35, 39, 45, 51, 52, 53, 56, 58, 59, 66, 68, 69, 70, 73, and 82 were considered HR-HPV types.	('HPV', 'Species', '10566', (93, 96))	('Human papillomavirus', 'Protein', (0, 20))	('HPV', 'Species', '10566', (74, 77))	('Human papillomavirus 6', 'Species', '31552', (0, 22))	('HR-HPV type', 'Disease', 'MESH:D030361', (195, 206))	('HPV', 'Species', '10566', (198, 201))	('HPV16', 'Species', '333760', (93, 98))	('HPV16', 'Var', (93, 98))	('HR-HPV type', 'Disease', (195, 206))
62014	25871546	The TP53 database of the International Agency for Research on Cancer (IARC, Lyon, France; http://p53.iarc.fr) was used to determine the functional consequences of TP53 mutations.	('p53', 'Gene', (97, 100))	('TP53', 'Gene', (4, 8))	('TP53', 'Gene', '7157', (163, 167))	('p53', 'Gene', '7157', (97, 100))	('Cancer', 'Phenotype', 'HP:0002664', (62, 68))	('TP53', 'Gene', (163, 167))	('TP53', 'Gene', '7157', (4, 8))	('mutations', 'Var', (168, 177))
62016	25871546	The primary end points of the study were LRC and OS, as a function of tumour HPV status, p16 expression, p53 expression, and TP53 mutational status.	('p16', 'Gene', (89, 92))	('OS', 'Chemical', '-', (49, 51))	('TP53', 'Gene', '7157', (125, 129))	('tumour', 'Phenotype', 'HP:0002664', (70, 76))	('TP53', 'Gene', (125, 129))	('p53', 'Gene', (105, 108))	('tumour HPV status', 'Disease', 'MESH:D030361', (70, 87))	('LRC', 'Disease', (41, 44))	('p53', 'Gene', '7157', (105, 108))	('p16', 'Gene', '1029', (89, 92))	('tumour HPV status', 'Disease', (70, 87))	('mutational status', 'Var', (130, 147))
62039	25871546	Aberrant p53 expression was more frequent in HPV-/p16- tumours (5 out of 10, 50%) than in HPV+/p16+ tumours (9 out of 93, 10%, P=0.004; Figure 1A).	('tumours', 'Disease', (55, 62))	('tumours', 'Disease', (100, 107))	('HPV', 'Species', '10566', (45, 48))	('Aberrant', 'Var', (0, 8))	('HPV', 'Species', '10566', (90, 93))	('expression', 'MPA', (13, 23))	('tumour', 'Phenotype', 'HP:0002664', (100, 106))	('p16', 'Gene', '1029', (50, 53))	('p16', 'Gene', '1029', (95, 98))	('p53', 'Gene', (9, 12))	('p53', 'Gene', '7157', (9, 12))	('tumour', 'Phenotype', 'HP:0002664', (55, 61))	('tumours', 'Phenotype', 'HP:0002664', (55, 62))	('tumours', 'Phenotype', 'HP:0002664', (100, 107))	('tumours', 'Disease', 'MESH:D009369', (100, 107))	('p16', 'Gene', (50, 53))	('p16', 'Gene', (95, 98))	('tumours', 'Disease', 'MESH:D009369', (55, 62))
62044	25871546	The distribution of disruptive TP53 mutations according to HPV/p16 status is depicted in Figure 1B, showing that mutations were far more prevalent in HPV- tumours than in HPV+ tumours.	('HPV', 'Species', '10566', (171, 174))	('HPV', 'Species', '10566', (59, 62))	('HPV- tumours', 'Disease', 'MESH:D030361', (150, 162))	('TP53', 'Gene', '7157', (31, 35))	('TP53', 'Gene', (31, 35))	('HPV+ tumours', 'Disease', 'MESH:D030361', (171, 183))	('tumour', 'Phenotype', 'HP:0002664', (176, 182))	('p16', 'Gene', (63, 66))	('tumour', 'Phenotype', 'HP:0002664', (155, 161))	('HPV- tumours', 'Disease', (150, 162))	('mutations', 'Var', (113, 122))	('tumours', 'Phenotype', 'HP:0002664', (155, 162))	('prevalent', 'Reg', (137, 146))	('HPV', 'Species', '10566', (150, 153))	('tumours', 'Phenotype', 'HP:0002664', (176, 183))	('p16', 'Gene', '1029', (63, 66))	('HPV+ tumours', 'Disease', (171, 183))
62045	25871546	Disruptive mutations were found in 1 out of 18 (6%) HPV+/p16+ tumours, 1 out of 3 (33%) HPV-/p16+, and 8 out of 10 (80%) HPV-/p16- tumours.	('tumours', 'Disease', 'MESH:D009369', (131, 138))	('mutations', 'Var', (11, 20))	('tumour', 'Phenotype', 'HP:0002664', (62, 68))	('p16', 'Gene', (57, 60))	('tumours', 'Disease', (131, 138))	('p16', 'Gene', '1029', (93, 96))	('p16', 'Gene', (126, 129))	('HPV', 'Species', '10566', (121, 124))	('HPV', 'Species', '10566', (52, 55))	('tumours', 'Phenotype', 'HP:0002664', (62, 69))	('tumour', 'Phenotype', 'HP:0002664', (131, 137))	('p16', 'Gene', (93, 96))	('HPV', 'Species', '10566', (88, 91))	('tumours', 'Disease', 'MESH:D009369', (62, 69))	('p16', 'Gene', '1029', (57, 60))	('p16', 'Gene', '1029', (126, 129))	('tumours', 'Phenotype', 'HP:0002664', (131, 138))	('tumours', 'Disease', (62, 69))
62048	25871546	Of 26 tumours that were non-aberrant on IHC, 20 (77%) did not carry a TP53 mutation.	('TP53', 'Gene', '7157', (70, 74))	('mutation', 'Var', (75, 83))	('tumour', 'Phenotype', 'HP:0002664', (6, 12))	('tumours', 'Phenotype', 'HP:0002664', (6, 13))	('TP53', 'Gene', (70, 74))	('tumours', 'Disease', 'MESH:D009369', (6, 13))	('tumours', 'Disease', (6, 13))
62049	25871546	Of 10 tumours that carried a TP53 mutation, five were aberrant on IHC (50%).	('mutation', 'Var', (34, 42))	('tumour', 'Phenotype', 'HP:0002664', (6, 12))	('tumours', 'Phenotype', 'HP:0002664', (6, 13))	('TP53', 'Gene', '7157', (29, 33))	('TP53', 'Gene', (29, 33))	('tumours', 'Disease', 'MESH:D009369', (6, 13))	('tumours', 'Disease', (6, 13))
62062	25871546	Both aberrant p53 expression and TP53 mutations were associated with inferior LRC in univariate analysis (Figure 3).	('p53', 'Gene', (14, 17))	('p53', 'Gene', '7157', (14, 17))	('TP53', 'Gene', '7157', (33, 37))	('expression', 'MPA', (18, 28))	('associated', 'Reg', (53, 63))	('TP53', 'Gene', (33, 37))	('mutations', 'Var', (38, 47))	('aberrant', 'Var', (5, 13))	('inferior LRC', 'Disease', (69, 81))
62064	25871546	Within the HPV- group, patients with aberrant p53 expression patterns tended to have inferior LRC (P=0.095) and inferior OS (P=0.108) compared with patients with non-aberrant expression (Supplementary Figure S3A and B).	('patients', 'Species', '9606', (148, 156))	('expression', 'MPA', (50, 60))	('inferior LRC', 'CPA', (85, 97))	('HPV', 'Species', '10566', (11, 14))	('S3A and B', 'Gene', '6189', (208, 217))	('OS', 'Chemical', '-', (121, 123))	('patients', 'Species', '9606', (23, 31))	('p53', 'Gene', (46, 49))	('p53', 'Gene', '7157', (46, 49))	('inferior OS', 'CPA', (112, 123))	('aberrant', 'Var', (37, 45))
62066	25871546	The single patient with a disruptive TP53 mutation in the HPV+ group achieved complete response and was disease-free at last follow-up 2.5 years after finishing treatment.	('patient', 'Species', '9606', (11, 18))	('mutation', 'Var', (42, 50))	('TP53', 'Gene', '7157', (37, 41))	('TP53', 'Gene', (37, 41))	('HPV', 'Species', '10566', (58, 61))
62072	25871546	Disruptive alterations in TP53 were frequently found in HPV-/p16- tumours (80%), compared with only sporadically in the tested HPV+/p16+ tumours (6%).	('TP53', 'Gene', (26, 30))	('alterations', 'Var', (11, 22))	('TP53', 'Gene', '7157', (26, 30))	('p16', 'Gene', '1029', (132, 135))	('p16', 'Gene', (61, 64))	('HPV', 'Species', '10566', (56, 59))	('tumours', 'Phenotype', 'HP:0002664', (137, 144))	('tumours', 'Phenotype', 'HP:0002664', (66, 73))	('found', 'Reg', (47, 52))	('tumours', 'Disease', 'MESH:D009369', (137, 144))	('tumour', 'Phenotype', 'HP:0002664', (66, 72))	('tumours', 'Disease', (137, 144))	('tumours', 'Disease', 'MESH:D009369', (66, 73))	('p16', 'Gene', '1029', (61, 64))	('p16', 'Gene', (132, 135))	('HPV', 'Species', '10566', (127, 130))	('tumours', 'Disease', (66, 73))	('tumour', 'Phenotype', 'HP:0002664', (137, 143))
62074	25871546	The distribution of HPV types, with HPV16 being the most prevalent HR-HPV type in HPV+ tumours, is in accordance with previous studies investigating the prevalence of HPV in SCCAC.	('HR-HPV type in HPV+ tumours', 'Disease', (67, 94))	('HPV', 'Species', '10566', (20, 23))	('HPV16', 'Species', '333760', (36, 41))	('HPV16', 'Var', (36, 41))	('HPV', 'Species', '10566', (70, 73))	('HPV', 'Species', '10566', (36, 39))	('tumour', 'Phenotype', 'HP:0002664', (87, 93))	('tumours', 'Phenotype', 'HP:0002664', (87, 94))	('HPV', 'Species', '10566', (82, 85))	('HR-HPV type in HPV+ tumours', 'Disease', 'MESH:D030361', (67, 94))	('HPV', 'Species', '10566', (167, 170))
62084	25871546	The mechanism of overexpression of p16 in these tumours, if truly HPV-, could be related to mutations in genes of other tumour suppressor proteins, including RB1.	('HPV', 'Species', '10566', (66, 69))	('tumours', 'Disease', (48, 55))	('p16', 'Gene', '1029', (35, 38))	('tumour', 'Phenotype', 'HP:0002664', (48, 54))	('tumour', 'Disease', 'MESH:D009369', (120, 126))	('p16', 'Gene', (35, 38))	('mutations', 'Var', (92, 101))	('tumour', 'Disease', (120, 126))	('tumour', 'Disease', 'MESH:D009369', (48, 54))	('overexpression', 'PosReg', (17, 31))	('tumour', 'Disease', (48, 54))	('tumours', 'Phenotype', 'HP:0002664', (48, 55))	('tumours', 'Disease', 'MESH:D009369', (48, 55))	('tumour', 'Phenotype', 'HP:0002664', (120, 126))
62087	25871546	We showed that disrupted p53 function, measured as disruptive TP53 mutations, was far more common in patients with HPV-/p16- tumours than in HPV+/p16+ tumours.	('p53', 'Gene', '7157', (25, 28))	('TP53', 'Gene', (62, 66))	('p16', 'Gene', (146, 149))	('p53', 'Gene', (25, 28))	('patients', 'Species', '9606', (101, 109))	('p16', 'Gene', '1029', (146, 149))	('HPV', 'Species', '10566', (115, 118))	('tumours', 'Disease', (151, 158))	('disrupted', 'NegReg', (15, 24))	('TP53', 'Gene', '7157', (62, 66))	('p16', 'Gene', (120, 123))	('tumours', 'Phenotype', 'HP:0002664', (151, 158))	('tumours', 'Disease', 'MESH:D009369', (151, 158))	('p16', 'Gene', '1029', (120, 123))	('function', 'MPA', (29, 37))	('tumour', 'Phenotype', 'HP:0002664', (151, 157))	('tumours', 'Disease', (125, 132))	('HPV', 'Species', '10566', (141, 144))	('tumour', 'Phenotype', 'HP:0002664', (125, 131))	('mutations', 'Var', (67, 76))	('tumours', 'Phenotype', 'HP:0002664', (125, 132))	('tumours', 'Disease', 'MESH:D009369', (125, 132))
62088	25871546	This inverse relationship between HPV+ status and TP53 mutations has also been demonstrated in HNSCC, and might indicate, as is thought to be the case in HNSCC, that disruption of p53 function is a key mechanism for HPV- SCCAC tumours to evolve.	('HPV', 'Species', '10566', (216, 219))	('mutations', 'Var', (55, 64))	('tumour', 'Phenotype', 'HP:0002664', (227, 233))	('p53', 'Gene', (180, 183))	('p53', 'Gene', '7157', (180, 183))	('TP53', 'Gene', '7157', (50, 54))	('HPV', 'Species', '10566', (34, 37))	('tumours', 'Phenotype', 'HP:0002664', (227, 234))	('HPV- SCCAC tumours', 'Disease', (216, 234))	('TP53', 'Gene', (50, 54))	('HNSCC', 'Disease', (95, 100))	('HNSCC', 'Phenotype', 'HP:0012288', (95, 100))	('HNSCC', 'Phenotype', 'HP:0012288', (154, 159))	('disruption', 'Var', (166, 176))	('HPV- SCCAC tumours', 'Disease', 'MESH:D030361', (216, 234))
62089	25871546	It is not surprising that mutations in TP53 are found only sporadically in HPV+ tumours, as the HPV oncoprotein E6 inhibits p53 function by targeting it for ubiquitination and degradation.	('HPV', 'Species', '10566', (96, 99))	('p53', 'Gene', (124, 127))	('degradation', 'MPA', (176, 187))	('ubiquitination', 'MPA', (157, 171))	('HPV+ tumours', 'Disease', 'MESH:D030361', (75, 87))	('p53', 'Gene', '7157', (124, 127))	('targeting', 'Reg', (140, 149))	('tumour', 'Phenotype', 'HP:0002664', (80, 86))	('mutations', 'Var', (26, 35))	('function', 'MPA', (128, 136))	('inhibits', 'NegReg', (115, 123))	('TP53', 'Gene', '7157', (39, 43))	('HPV', 'Species', '10566', (75, 78))	('tumours', 'Phenotype', 'HP:0002664', (80, 87))	('HPV+ tumours', 'Disease', (75, 87))	('TP53', 'Gene', (39, 43))
62090	25871546	An additional mutation in TP53 would, therefore, not be required for these tumours to evolve.	('TP53', 'Gene', (26, 30))	('tumours', 'Disease', 'MESH:D009369', (75, 82))	('tumours', 'Disease', (75, 82))	('mutation', 'Var', (14, 22))	('TP53', 'Gene', '7157', (26, 30))	('tumours', 'Phenotype', 'HP:0002664', (75, 82))	('tumour', 'Phenotype', 'HP:0002664', (75, 81))
62091	25871546	The apparent lower frequency of TP53 mutations in HPV-/p16+ tumours could be explained by aberrations in other tumour suppressor proteins, which could be investigated in future studies.	('tumour', 'Disease', 'MESH:D009369', (60, 66))	('tumours', 'Disease', 'MESH:D009369', (60, 67))	('tumour', 'Disease', (60, 66))	('tumours', 'Disease', (60, 67))	('TP53', 'Gene', '7157', (32, 36))	('tumour', 'Phenotype', 'HP:0002664', (111, 117))	('p16', 'Gene', (55, 58))	('mutations', 'Var', (37, 46))	('TP53', 'Gene', (32, 36))	('tumour', 'Disease', 'MESH:D009369', (111, 117))	('HPV', 'Species', '10566', (50, 53))	('tumour', 'Disease', (111, 117))	('tumour', 'Phenotype', 'HP:0002664', (60, 66))	('p16', 'Gene', '1029', (55, 58))	('tumours', 'Phenotype', 'HP:0002664', (60, 67))
62094	25871546	Our results indicate that p53 immunohistochemistry is inadequate as a surrogate measure to detect TP53 mutations in SCCAC.	('mutations', 'Var', (103, 112))	('SCCAC', 'Disease', (116, 121))	('p53', 'Gene', (26, 29))	('p53', 'Gene', '7157', (26, 29))	('TP53', 'Gene', '7157', (98, 102))	('TP53', 'Gene', (98, 102))
62095	25871546	The current concept in HNSCC is that HPV+ and HPV- tumours develop by at least two different pathways: one driven by exposure to oncoproteins expressed by HPV and the other by exposure to environmental carcinogens (such as alcohol and tobacco) without HPV involvement.	('HPV involvement', 'Disease', (252, 267))	('tobacco', 'Species', '4097', (235, 242))	('HPV- tumours', 'Disease', (46, 58))	('alcohol', 'Chemical', 'MESH:D000438', (223, 230))	('HPV- tumours', 'Disease', 'MESH:D030361', (46, 58))	('HPV', 'Species', '10566', (155, 158))	('HPV', 'Var', (155, 158))	('HPV', 'Species', '10566', (46, 49))	('tumour', 'Phenotype', 'HP:0002664', (51, 57))	('HNSCC', 'Phenotype', 'HP:0012288', (23, 28))	('tumours', 'Phenotype', 'HP:0002664', (51, 58))	('HPV involvement', 'Disease', 'MESH:D030361', (252, 267))	('HPV', 'Species', '10566', (252, 255))	('HPV', 'Species', '10566', (37, 40))	('oncoproteins', 'Protein', (129, 141))
62100	25871546	It is therefore conceivable that patients with HPV- tumours have inferior treatment response owing to a higher frequency of disrupted p53 function (via TP53 mutations).	('HPV- tumours', 'Disease', 'MESH:D030361', (47, 59))	('p53', 'Gene', '7157', (134, 137))	('patients', 'Species', '9606', (33, 41))	('tumour', 'Phenotype', 'HP:0002664', (52, 58))	('treatment response', 'CPA', (74, 92))	('TP53', 'Gene', '7157', (152, 156))	('function', 'MPA', (138, 146))	('mutations', 'Var', (157, 166))	('HPV- tumours', 'Disease', (47, 59))	('tumours', 'Phenotype', 'HP:0002664', (52, 59))	('inferior', 'NegReg', (65, 73))	('TP53', 'Gene', (152, 156))	('p53', 'Gene', (134, 137))
62102	25871546	These findings could either indicate that TP53 mutations do not have an important role in treatment resistance of HPV- tumours or that additional (genetic) alterations in the subset of HPV- tumours contribute equally to treatment resistance (i.e.	('HPV- tumours', 'Disease', (114, 126))	('TP53', 'Gene', '7157', (42, 46))	('tumour', 'Phenotype', 'HP:0002664', (119, 125))	('tumours', 'Phenotype', 'HP:0002664', (119, 126))	('TP53', 'Gene', (42, 46))	('HPV- tumours', 'Disease', 'MESH:D030361', (185, 197))	('mutations', 'Var', (47, 56))	('HPV- tumours', 'Disease', 'MESH:D030361', (114, 126))	('tumour', 'Phenotype', 'HP:0002664', (190, 196))	('treatment resistance', 'CPA', (220, 240))	('HPV- tumours', 'Disease', (185, 197))	('tumours', 'Phenotype', 'HP:0002664', (190, 197))
62103	25871546	in tumours that do not carry TP53 mutations).	('tumour', 'Phenotype', 'HP:0002664', (3, 9))	('tumours', 'Phenotype', 'HP:0002664', (3, 10))	('TP53', 'Gene', '7157', (29, 33))	('TP53', 'Gene', (29, 33))	('tumours', 'Disease', 'MESH:D009369', (3, 10))	('tumours', 'Disease', (3, 10))	('mutations', 'Var', (34, 43))
62104	25871546	We identified sporadic TP53 mutations in HPV+ tumours, as has also been demonstrated in HNSCC.	('HPV+ tumours', 'Disease', (41, 53))	('HPV+ tumours', 'Disease', 'MESH:D030361', (41, 53))	('HNSCC', 'Phenotype', 'HP:0012288', (88, 93))	('TP53', 'Gene', '7157', (23, 27))	('TP53', 'Gene', (23, 27))	('tumour', 'Phenotype', 'HP:0002664', (46, 52))	('mutations', 'Var', (28, 37))	('tumours', 'Phenotype', 'HP:0002664', (46, 53))
62107	25871546	Notwithstanding this, HPV status as a prognostic factor in SCCAC has also been recognised by others, and several studies have now shown that patients with HPV- and/or p16- disease have significantly worse outcome.	('HPV', 'Species', '10566', (155, 158))	('p16', 'Gene', (167, 170))	('SCCAC', 'Disease', (59, 64))	('HPV', 'Species', '10566', (22, 25))	('HPV-', 'Var', (155, 159))	('p16', 'Gene', '1029', (167, 170))	('patients', 'Species', '9606', (141, 149))
62108	25871546	The prognostic significance of lack of p16 expression appears to be considerable, and it is striking that OS of patients with HPV- tumours appears to be reduced despite the fact that surgical salvage treatment is generally an effective treatment for most patients with locoregional relapse.	('p16', 'Gene', (39, 42))	('reduced', 'NegReg', (153, 160))	('HPV- tumours', 'Disease', 'MESH:D030361', (126, 138))	('patients', 'Species', '9606', (112, 120))	('patients', 'Species', '9606', (255, 263))	('tumour', 'Phenotype', 'HP:0002664', (131, 137))	('p16', 'Gene', '1029', (39, 42))	('HPV- tumours', 'Disease', (126, 138))	('lack', 'Var', (31, 35))	('tumours', 'Phenotype', 'HP:0002664', (131, 138))	('OS', 'Chemical', '-', (106, 108))
62116	25871546	We show that in contrast to HPV+ tumours, HPV- tumours frequently carry TP53 mutations, suggesting that there might be large differences in the genetics of HPV+ vs HPV- tumours.	('carry', 'Reg', (66, 71))	('HPV+ tumours', 'Disease', 'MESH:D030361', (28, 40))	('HPV', 'Species', '10566', (156, 159))	('tumours', 'Phenotype', 'HP:0002664', (169, 176))	('HPV+ tumours', 'Disease', (28, 40))	('HPV', 'Species', '10566', (28, 31))	('TP53', 'Gene', '7157', (72, 76))	('tumour', 'Phenotype', 'HP:0002664', (169, 175))	('tumour', 'Phenotype', 'HP:0002664', (33, 39))	('HPV- tumours', 'Disease', (164, 176))	('tumours', 'Phenotype', 'HP:0002664', (33, 40))	('HPV', 'Species', '10566', (42, 45))	('HPV- tumours', 'Disease', 'MESH:D030361', (164, 176))	('mutations', 'Var', (77, 86))	('HPV- tumours', 'Disease', (42, 54))	('tumour', 'Phenotype', 'HP:0002664', (47, 53))	('tumours', 'Phenotype', 'HP:0002664', (47, 54))	('TP53', 'Gene', (72, 76))	('HPV- tumours', 'Disease', 'MESH:D030361', (42, 54))	('HPV', 'Species', '10566', (164, 167))
62225	31780666	Deleterious mutations in the epithelial-specific E74 Like ETS Transcription Factor 3 (ELF3) have been described as tumourigenic in many epithelial tumors; in contrast, gene amplification and oncogenic activity has also been reported in others.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumourigenic', 'CPA', (115, 127))	('tumors', 'Phenotype', 'HP:0002664', (147, 153))	('mutations', 'Var', (12, 21))	('ELF3', 'Gene', (86, 90))	('epithelial tumors', 'Disease', (136, 153))	('epithelial tumors', 'Disease', 'MESH:D002277', (136, 153))
62230	31780666	This overexpression is driven not only by a lineage-specific focal amplification event, but also via alternate DNA-level mechanisms, detected collectively in ~ 80% of LUAD and which hold prognostic value uniquely in LUAD.	('N', 'Chemical', 'MESH:D009584', (112, 113))	('LUAD', 'Disease', (167, 171))	('focal amplification event', 'Var', (61, 86))
62233	31780666	ELF3 mutations were uncommon in NSCLC, with a 1.4% mutation incidence in The Cancer Genome Atlas (TCGA) cohort (n = 408) (Supplementary Fig.	('Cancer', 'Phenotype', 'HP:0002664', (77, 83))	('mutations', 'Var', (5, 14))	('NSCLC', 'Disease', (32, 37))	('NSCLC', 'Disease', 'MESH:D002289', (32, 37))	('ELF3', 'Gene', (0, 4))
62235	31780666	Further investigations into broad copy number alterations and local promoter methylation changes that could explain additional cases of overexpression revealed disruption of the ELF3 locus in ~ 80% of LUAD (BCCA = 79%, TCGA-60 = 83%) (Fig.	('LUAD', 'Disease', (201, 205))	('disruption', 'Var', (160, 170))	('ELF3', 'Gene', (178, 182))	('TCGA-60', 'Chemical', 'MESH:C047031', (219, 226))
62236	31780666	Expression was significantly increased in tumors with genetic or epigenetic disruption compared to those without (Mann-Whitney U test p = 5.17E-07) (Fig.	('epigenetic disruption', 'Var', (65, 86))	('Expression', 'MPA', (0, 10))	('tumors', 'Disease', (42, 48))	('tumors', 'Disease', 'MESH:D009369', (42, 48))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('increased', 'PosReg', (29, 38))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('genetic', 'Var', (54, 61))
62238	31780666	Given that ERBB2 is a known oncogenic driver of LUAD, we assessed the influence of inactivating SMAD4 and activating ERBB2 mutations on ELF3 expression in tumors lacking locus disruption and find that ELF3 expression was elevated in these samples (Mann-Whitney U test p = 0.06) (Supplementary Fig.	('elevated', 'PosReg', (221, 229))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('SMAD4', 'Gene', (96, 101))	('expression', 'MPA', (206, 216))	('activating', 'PosReg', (106, 116))	('SMAD4', 'Gene', '4089', (96, 101))	('ELF3', 'Gene', (201, 205))	('tumors', 'Phenotype', 'HP:0002664', (155, 161))	('ERBB2', 'Gene', (11, 16))	('tumors', 'Disease', (155, 161))	('ERBB2', 'Gene', (117, 122))	('ERBB2', 'Gene', '2064', (11, 16))	('ERBB2', 'Gene', '2064', (117, 122))	('tumors', 'Disease', 'MESH:D009369', (155, 161))	('mutations', 'Var', (123, 132))
62242	31780666	Mutations in known LUAD drivers (KRAS, EGFR, BRAF, RIT1, ERBB2, MAP2K1, NRAS, HRAS, ERBB2 amplification, MET amplification) and tumor suppressors (TP53, KEAP1, STK11/LKB1, NF1) occurred in both tumors with ELF3 locus alterations and those without (Fig.	('NRAS', 'Gene', '4893', (72, 76))	('ERBB2', 'Gene', (57, 62))	('MAP2K1', 'Gene', '5604', (64, 70))	('STK11', 'Gene', '6794', (160, 165))	('KEAP1', 'Gene', '9817', (153, 158))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumor', 'Disease', (194, 199))	('MAP2K1', 'Gene', (64, 70))	('RIT1', 'Gene', (51, 55))	('EGFR', 'Gene', '1956', (39, 43))	('alterations', 'Var', (217, 228))	('KEAP1', 'Gene', (153, 158))	('NF1', 'Gene', '4763', (172, 175))	('TP53', 'Gene', (147, 151))	('ERBB2', 'Gene', '2064', (57, 62))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('occurred', 'Reg', (177, 185))	('BRAF', 'Gene', (45, 49))	('Mutations', 'Var', (0, 9))	('BRAF', 'Gene', '673', (45, 49))	('NF1', 'Gene', (172, 175))	('KRAS', 'Gene', '3845', (33, 37))	('tumors', 'Phenotype', 'HP:0002664', (194, 200))	('LKB1', 'Gene', '6794', (166, 170))	('ERBB2', 'Gene', (84, 89))	('NRAS', 'Gene', (72, 76))	('KRAS', 'Gene', (33, 37))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('RIT1', 'Gene', '6016', (51, 55))	('tumor', 'Disease', (128, 133))	('EGFR', 'Gene', (39, 43))	('tumors', 'Disease', (194, 200))	('TP53', 'Gene', '7157', (147, 151))	('ERBB2', 'Gene', '2064', (84, 89))	('STK11', 'Gene', (160, 165))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('HRAS', 'Gene', '3265', (78, 82))	('LKB1', 'Gene', (166, 170))	('tumors', 'Disease', 'MESH:D009369', (194, 200))	('HRAS', 'Gene', (78, 82))
62243	31780666	There was a statistical enrichment of KRAS (Fisher's exact p = 0.0011), STK11 (p = 0.0023), and KEAP1 (p = 0.0031) mutations in the ELF3-altered group, whereas MET and ERBB2 mutations and amplifications were enriched in cases without ELF3 disruption (p = 0.0009 and p = 0.0019, respectively).	('KRAS', 'Gene', '3845', (38, 42))	('mutations', 'Var', (115, 124))	('KEAP1', 'Gene', '9817', (96, 101))	('ERBB2', 'Gene', (168, 173))	('KEAP1', 'Gene', (96, 101))	('STK11', 'Gene', (72, 77))	('ERBB2', 'Gene', '2064', (168, 173))	('ELF3-altered', 'Disease', (132, 144))	('STK11', 'Gene', '6794', (72, 77))	('KRAS', 'Gene', (38, 42))
62244	31780666	This is in agreement with previous associations of KRAS mutation and chromosome 1q gain, and correlations between KRAS, STK11, and KEAP1 mutations.	('KRAS', 'Gene', '3845', (51, 55))	('STK11', 'Gene', (120, 125))	('KEAP1', 'Gene', '9817', (131, 136))	('gain', 'PosReg', (83, 87))	('KRAS', 'Gene', (114, 118))	('STK11', 'Gene', '6794', (120, 125))	('KRAS', 'Gene', '3845', (114, 118))	('KEAP1', 'Gene', (131, 136))	('mutation', 'Var', (56, 64))	('KRAS', 'Gene', (51, 55))
62247	31780666	With this preliminary observation that ELF3 knockdown reduces oncogenic phenotypes, we expanded our experiments to include four additional cell lines harboring diverse molecular drivers (A549, H1395, H1993, and H1819 (Supplementary Fig.	('H1819', 'Var', (211, 216))	('H1395', 'Chemical', 'MESH:D006859', (193, 198))	('A549', 'CellLine', 'CVCL:0023', (187, 191))	('H1819', 'CellLine', 'CVCL:1497', (211, 216))	('oncogenic phenotypes', 'MPA', (62, 82))	('ELF3', 'Gene', (39, 43))	('A549', 'Var', (187, 191))	('H1395', 'Var', (193, 198))	('knockdown', 'Var', (44, 53))	('reduces', 'NegReg', (54, 61))	('H1993', 'Var', (200, 205))
62249	31780666	To account for potential off-target effects, we validated the effect of ELF3 knockdown on cell viability using an siRNA pool (five siRNAs) on A549 cells and further tested specificity by including a cell line with low ELF3 expression (H2030).	('A549', 'CellLine', 'CVCL:0023', (142, 146))	('ELF3', 'Gene', (72, 76))	('H2030', 'CellLine', 'CVCL:1517', (235, 240))	('N', 'Chemical', 'MESH:D009584', (134, 135))	('knockdown', 'Var', (77, 86))	('N', 'Chemical', 'MESH:D009584', (117, 118))
62250	31780666	This observation was specific to LUAD cell lines with high ELF3 expression, as viability of A549 cells was significantly decreased while H2030 cells were not affected by ELF3 siRNA-mediated inhibition (Supplementary Fig.	('ELF3', 'Gene', (59, 63))	('high', 'Var', (54, 58))	('viability', 'CPA', (79, 88))	('decreased', 'NegReg', (121, 130))	('N', 'Chemical', 'MESH:D009584', (178, 179))	('expression', 'Var', (64, 74))	('A549', 'CellLine', 'CVCL:0023', (92, 96))	('H2030', 'CellLine', 'CVCL:1517', (137, 142))
62252	31780666	We stably overexpressed ELF3 in HBEC-KTs with p53 knockdown (HBEC-KT53), with oncogenic RAS expression (HBEC-KTR), and with both alterations (HBEC-KTR53), again comparing to empty vector control.	('p53', 'Gene', '7157', (46, 49))	('p53', 'Gene', (46, 49))	('knockdown', 'Var', (50, 59))	('ELF3', 'Gene', (24, 28))
62256	31780666	Although growth of polyclonal shELF3 tumors was initially slowed, it eventually reached control levels (Fig.	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('shELF3', 'Gene', (30, 36))	('slowed', 'NegReg', (58, 64))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('polyclonal', 'Var', (19, 29))	('tumors', 'Disease', (37, 43))	('growth', 'MPA', (9, 15))	('tumors', 'Disease', 'MESH:D009369', (37, 43))
62269	31780666	In contrast, ELF3 rescue in A549 shELF3 clones increased the size and number of colonies formed, and the proliferation rate of cells (Fig.	('size', 'CPA', (61, 65))	('rescue', 'Var', (18, 24))	('A549', 'CellLine', 'CVCL:0023', (28, 32))	('increased', 'PosReg', (47, 56))	('ELF3', 'Gene', (13, 17))	('proliferation rate of cells', 'CPA', (105, 132))
62276	31780666	A NSCLC-specific analysis indicated the majority (25/33) of ELF3 PPI disruptions occurred in LUAD as compared with LUSC and lung large cell carcinoma (Fig.	('lung large cell carcinoma', 'Disease', 'MESH:D018287', (124, 149))	('NSCLC', 'Disease', 'MESH:D002289', (2, 7))	('LUAD', 'Disease', (93, 97))	('large cell carcinoma', 'Phenotype', 'HP:0030360', (129, 149))	('NSCLC', 'Disease', (2, 7))	('occurred', 'Reg', (81, 89))	('ELF3 PPI', 'Gene', (60, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))	('disruptions', 'Var', (69, 80))	('lung large cell carcinoma', 'Disease', (124, 149))
62277	31780666	ELF3 PPI networks disrupted by high ELF3 expression were analyzed in LUAD as compared with non-malignant lung tissue, and LUAD dichotomized by KRAS mutation status based on the DNA-level association of ELF3 disruption in KRAS mutant LUAD.	('disruption', 'Var', (207, 217))	('mutant', 'Var', (226, 232))	('KRAS', 'Gene', (221, 225))	('KRAS', 'Gene', '3845', (221, 225))	('ELF3', 'Gene', (36, 40))	('N', 'Chemical', 'MESH:D009584', (178, 179))	('KRAS', 'Gene', (143, 147))	('KRAS', 'Gene', '3845', (143, 147))	('ELF3', 'Gene', (202, 206))
62279	31780666	Importantly, ELF3 PPI network data from KRAS mutant LUAD was compared against whole-genome expression data generated from isogenic A549 control and shELF3 clonal cell lines.	('KRAS', 'Gene', (40, 44))	('mutant', 'Var', (45, 51))	('A549', 'CellLine', 'CVCL:0023', (131, 135))	('KRAS', 'Gene', '3845', (40, 44))
62288	31780666	High ELF3 expression was associated with poor overall survival (OS) in NSCLC patients (log-rank p = 4.65E-04), an association which improved in Stage I patients (log-rank p = 2.30E-05) (Fig.	('High', 'Var', (0, 4))	('overall survival', 'MPA', (46, 62))	('expression', 'MPA', (10, 20))	('improved', 'PosReg', (132, 140))	('ELF3', 'Gene', (5, 9))	('poor', 'NegReg', (41, 45))	('patients', 'Species', '9606', (77, 85))	('NSCLC', 'Disease', (71, 76))	('patients', 'Species', '9606', (152, 160))	('NSCLC', 'Disease', 'MESH:D002289', (71, 76))
62293	31780666	Interestingly, the low mutation rate of ELF3 in lung cancer has allowed it to elude sequencing-based screens of recurrently altered oncogenes; the high frequency of alternative DNA-level disruptions in upwards of 80% of LUAD underscores the importance of interrogating multiple 'omics' levels.	('disruptions', 'Var', (187, 198))	('lung cancer', 'Disease', 'MESH:D008175', (48, 59))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('N', 'Chemical', 'MESH:D009584', (178, 179))	('lung cancer', 'Disease', (48, 59))	('lung cancer', 'Phenotype', 'HP:0100526', (48, 59))
62295	31780666	Although behavior and alteration mechanisms similar to LUAD, including gene amplification, have been observed in colorectal and breast cancer, contrasting recurrent deleterious mutations in ELF3 have been identified in biliary tract cancer, mucinous ovarian carcinoma, and cancers of the cervix, stomach, and bladder, indicating a tumor suppressive role in these cancer types.	('mucinous ovarian carcinoma', 'Phenotype', 'HP:0031494', (241, 267))	('tumor', 'Disease', 'MESH:D009369', (331, 336))	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('mucinous ovarian carcinoma', 'Disease', 'MESH:D010051', (241, 267))	('colorectal and breast cancer', 'Disease', 'MESH:D001943', (113, 141))	('mutations', 'Var', (177, 186))	('cancers', 'Phenotype', 'HP:0002664', (273, 280))	('cancer', 'Disease', 'MESH:D009369', (363, 369))	('cancers', 'Disease', (273, 280))	('stomach', 'Disease', (296, 303))	('cancer', 'Disease', (135, 141))	('cancer', 'Disease', 'MESH:D009369', (273, 279))	('tumor', 'Phenotype', 'HP:0002664', (331, 336))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('cancer', 'Disease', 'MESH:D009369', (233, 239))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (250, 267))	('biliary tract cancer', 'Disease', (219, 239))	('ELF3', 'Gene', (190, 194))	('cancer', 'Disease', (363, 369))	('mucinous ovarian carcinoma', 'Disease', (241, 267))	('identified', 'Reg', (205, 215))	('cancers', 'Disease', 'MESH:D009369', (273, 280))	('carcinoma', 'Phenotype', 'HP:0030731', (258, 267))	('cancer', 'Disease', 'MESH:D009369', (135, 141))	('cancer', 'Phenotype', 'HP:0002664', (363, 369))	('cancer', 'Disease', (273, 279))	('biliary tract cancer', 'Phenotype', 'HP:0100574', (219, 239))	('biliary tract cancer', 'Disease', 'MESH:D001661', (219, 239))	('cancer', 'Disease', (233, 239))	('tumor', 'Disease', (331, 336))	('cancer', 'Phenotype', 'HP:0002664', (273, 279))	('breast cancer', 'Phenotype', 'HP:0003002', (128, 141))	('bladder', 'Disease', (309, 316))
62299	31780666	ELF3 is highly expressed in human fetal lung tissue, and in mice Elf3 knockout induces embryonic lethality.	('human', 'Species', '9606', (28, 33))	('induces', 'PosReg', (79, 86))	('Elf3', 'Gene', (65, 69))	('embryonic lethality', 'Disease', 'MESH:D020964', (87, 106))	('embryonic lethality', 'Disease', (87, 106))	('mice', 'Species', '10090', (60, 64))	('knockout', 'Var', (70, 78))
62302	31780666	The specific relevance of ELF3 to LUAD is highlighted by its subtype-specific association with poor patient outcome; however, we caution that ELF3 alterations are enriched in KRAS, STK11, and KEAP1 mutant tumors, all of which are themselves associated with poor prognosis.	('tumors', 'Disease', 'MESH:D009369', (205, 211))	('KEAP1', 'Gene', '9817', (192, 197))	('ELF3', 'Gene', (142, 146))	('STK11', 'Gene', (181, 186))	('KEAP1', 'Gene', (192, 197))	('patient', 'Species', '9606', (100, 107))	('tumors', 'Phenotype', 'HP:0002664', (205, 211))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('STK11', 'Gene', '6794', (181, 186))	('tumors', 'Disease', (205, 211))	('KRAS', 'Gene', (175, 179))	('KRAS', 'Gene', '3845', (175, 179))	('alterations', 'Var', (147, 158))
62306	31780666	Our discovery of a region of focal amplification at the ELF3 locus, coupled with our findings that ELF3 knockdown is highly selected against in a polyclonal tumor growth model and completely abrogates tumor growth in a clonal setting highlights the importance of this oncogene.	('tumor', 'Disease', (157, 162))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('abrogates', 'NegReg', (191, 200))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('tumor', 'Disease', (201, 206))	('ELF3', 'Gene', (99, 103))	('knockdown', 'Var', (104, 113))
62307	31780666	Importantly, we further discover additional mechanisms of ELF3 overexpression including DNA copy number gain, promoter hypomethlyation, and mutations in upstream regulators in up to 80% of LUAD and across molecular subtypes.	('ELF3', 'Gene', (58, 62))	('promoter', 'MPA', (110, 118))	('gain', 'PosReg', (104, 108))	('LUAD', 'Disease', (189, 193))	('N', 'Chemical', 'MESH:D009584', (89, 90))	('mutations', 'Var', (140, 149))	('overexpression', 'PosReg', (63, 77))
62324	31780666	Thresholds for DNA copy number alterations were applied as follows: copy number loss < 1.7, copy number gain > 2.3.	('copy number', 'Var', (92, 103))	('N', 'Chemical', 'MESH:D009584', (16, 17))	('loss <', 'NegReg', (80, 86))	('copy number', 'Var', (68, 79))
62338	31780666	Human Bronchial Epithelial Cells are untransformed cells that have been immortalized by expression of cyclin-dependent kinase (Cdk) 4 and humantelomerase reverse transcriptase (hTERT) (HBEC-KT), and have been further altered to harbor p53 knockdown, oncogenic RAS expression (HBEC-KTR), and with both alterations (HBEC-KTR53).	('Human', 'Species', '9606', (0, 5))	('knockdown', 'Var', (239, 248))	('human', 'Species', '9606', (138, 143))	('hTERT', 'Gene', '7015', (177, 182))	('cyclin-dependent kinase (Cdk) 4', 'Gene', '1019', (102, 133))	('p53', 'Gene', (235, 238))	('p53', 'Gene', '7157', (235, 238))	('oncogenic', 'Protein', (250, 259))	('hTERT', 'Gene', (177, 182))
62341	31780666	Five shRNA clones were tested and the clone with the best knockdown of ELF3 transcript and protein levels in each cell line was selected for phenotypic assays.	('knockdown', 'Var', (58, 67))	('ELF3', 'Gene', (71, 75))	('N', 'Chemical', 'MESH:D009584', (8, 9))
62377	31780666	Relative human cell-specific expression of ELF3 (Hs00963882_g1 - no cross reactivity with mouse) and NOTCH3 (Hs01128537_m1 - no cross reactivity with mouse) was quantified by qRT-PCR (TaqMan:Applied Biosystems) using mouse Actb (Mm04394036_g1) and human Actb (Hs99999903_m1) as endogenous controls.	('mouse', 'Species', '10090', (217, 222))	('Hs00963882_g1', 'Var', (49, 62))	('human', 'Species', '9606', (248, 253))	('Hs99999903_m1', 'Var', (260, 273))	('mouse', 'Species', '10090', (90, 95))	('human', 'Species', '9606', (9, 14))	('Hs01128537_m1', 'Var', (109, 122))	('Mm04394036_g1', 'Var', (229, 242))	('mouse', 'Species', '10090', (150, 155))
62383	31780666	Pan-cancer: GSE19383, GSE26910, GSE3744, GSE5764, GSE20437, GSE5462, GSE6883, GSE9574, GSE9750, GSE20916, GSE8671, GSE41258, GSE5364, GSE11024, GSE14762, GSE21816, GSE7023, GSE8271, GSE6280, GSE6344, GSE781, GSE29721, GSE14520, GSE31908, GSE14407, GSE15578, GSE18520, GSE36668, GSE38666, GSE15471, GSE16515, GSE22780, GSE17951, GSE32448, GSE32982, GSE3325, GSE6956, GSE29265, GSE3467, GSE3678, GSE6004, GSE27155, GSE17025, GSE20347, GSE23400, GSE29001, GSE30784, GSE31056, GSE33426, GSE38129, GSE53757, GSE64985, GSE7305, GSE7307, GSE7803.	('GSE53757', 'Var', (493, 501))	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('GSE23400', 'Var', (433, 441))	('GSE27155', 'Var', (403, 411))	('GSE5364', 'Chemical', 'MESH:C048199', (125, 132))	('GSE38129', 'Var', (483, 491))	('GSE7803', 'Chemical', 'MESH:C043924', (531, 538))	('GSE30784', 'Var', (453, 461))	('cancer', 'Disease', 'MESH:D009369', (4, 10))	('GSE33426', 'Var', (473, 481))	('GSE6883', 'Chemical', 'MESH:C518643', (69, 76))	('GSE64985', 'Var', (503, 511))	('GSE6344', 'Chemical', 'MESH:C081303', (191, 198))	('GSE20347', 'Var', (423, 431))	('GSE17025', 'Var', (413, 421))	('GSE7307', 'Var', (522, 529))	('GSE29001', 'Var', (443, 451))	('GSE31056', 'Var', (463, 471))	('GSE6004', 'Chemical', 'MESH:C557897', (394, 401))	('GSE8671', 'Chemical', 'MESH:C043924', (106, 113))	('GSE6004', 'Var', (394, 401))	('GSE7803', 'Var', (531, 538))	('GSE7305', 'Var', (513, 520))	('cancer', 'Disease', (4, 10))
62384	31780666	Non-small cell lung cancer: GSE31210, GSE10245, GSE19188, GSE28571, GSE31908, GSE7670, GSE10072, GSE5364.	('GSE5364', 'Var', (97, 104))	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('GSE28571', 'Var', (58, 66))	('GSE5364', 'Chemical', 'MESH:C048199', (97, 104))	('GSE31908', 'Var', (68, 76))	('Non-small cell lung cancer', 'Disease', 'MESH:D002289', (0, 26))	('GSE7670', 'Var', (78, 85))	('Non-small cell lung cancer', 'Disease', (0, 26))	('Non-small cell lung cancer', 'Phenotype', 'HP:0030358', (0, 26))	('GSE31210', 'Var', (28, 36))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (4, 26))	('GSE10245', 'Var', (38, 46))	('lung cancer', 'Phenotype', 'HP:0100526', (15, 26))	('GSE10072', 'Var', (87, 95))	('GSE19188', 'Var', (48, 56))
62394	31780666	For each of the KRASmut and KRASwt groups, we calculated differential mRNA expression between ELF3high and ELF3low samples (two-tailed t test).	('KRAS', 'Gene', (28, 32))	('KRAS', 'Gene', '3845', (28, 32))	('ELF3low', 'Var', (107, 114))	('ELF3high', 'Var', (94, 102))	('KRAS', 'Gene', (16, 20))	('KRAS', 'Gene', '3845', (16, 20))	('mRNA expression', 'MPA', (70, 85))	('N', 'Chemical', 'MESH:D009584', (72, 73))
62402	31780666	Cell line experiments were performed by K.S.S.E., E.A.M., C.A., K.W.N., D.A.R., D.D.B.S., and F.J.	('N', 'Chemical', 'MESH:D009584', (68, 69))	('D.A.R.', 'Var', (72, 78))	('D.D.B.S.', 'Var', (80, 88))
62407	31780666	The gene expression profiles used to construct pan-tissue ELF3 protein-protein interaction networks are available in the GEO repository under the accession codes GSE19383, GSE26910, GSE3744, GSE5764, GSE20437, GSE5462, GSE6883, GSE9574, GSE9750, GSE20916, GSE8671, GSE41258, GSE5364, GSE11024, GSE14762, GSE21816, GSE7023, GSE8271, GSE6280, GSE6344, GSE781, GSE29721, GSE14520, GSE31908, GSE14407, GSE15578, GSE18520, GSE36668, GSE38666, GSE15471, GSE16515, GSE22780, GSE17951, GSE32448, GSE32982, GSE3325, GSE6956, GSE29265, GSE3467, GSE3678, GSE6004, GSE27155, GSE17025, GSE20347, GSE23400, GSE29001, GSE30784, GSE31056, GSE33426, GSE38129, GSE53757, GSE64985, GSE7305, GSE7307, GSE7803; gene expression profiles used to construct ELF3 protein-protein interaction networks in non-small cell lung cancer are available under the accession codes GSE31210, GSE10245, GSE19188, GSE28571, GSE31908, GSE7670, GSE10072, GSE5364 (https://www.ncbi.nlm.nih.gov/geo/).	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (778, 804))	('GSE5364', 'Var', (914, 921))	('GSE5364', 'Chemical', 'MESH:C048199', (275, 282))	('GSE6004', 'Chemical', 'MESH:C557897', (544, 551))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (782, 804))	('GSE19188', 'Var', (865, 873))	('GSE31908', 'Var', (885, 893))	('GSE7670', 'Var', (895, 902))	('GSE31210', 'Var', (845, 853))	('non-small cell lung cancer', 'Disease', (778, 804))	('GSE10245', 'Var', (855, 863))	('GSE10072', 'Var', (904, 912))	('GSE6883', 'Chemical', 'MESH:C518643', (219, 226))	('lung cancer', 'Phenotype', 'HP:0100526', (793, 804))	('GSE7803', 'Chemical', 'MESH:C043924', (681, 688))	('GSE8671', 'Chemical', 'MESH:C043924', (256, 263))	('GSE5364', 'Chemical', 'MESH:C048199', (914, 921))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (778, 804))	('GSE6344', 'Chemical', 'MESH:C081303', (341, 348))	('GSE28571', 'Var', (875, 883))	('cancer', 'Phenotype', 'HP:0002664', (798, 804))
62449	30568392	We rescored p53 expression into three groups: weak or patchy (wild type), complete loss (nonsense, frameshift, or splice-site mutation type), and diffuse and strong (missense mutation type).	('p53', 'Gene', '7157', (12, 15))	('p53', 'Gene', (12, 15))	('frameshift', 'Var', (99, 109))	('nonsense', 'Var', (89, 97))	('loss', 'NegReg', (83, 87))
62486	30568392	The 7th and 8th editions of the American Joint Committee on Cancer (AJCC) staging system include tumor location as a staging factor for T2-3N0M0 ESCC cases and T3N0M0 ESCC cases, respectively.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('Cancer', 'Phenotype', 'HP:0002664', (60, 66))	('Cancer', 'Disease', (60, 66))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('Cancer', 'Disease', 'MESH:D009369', (60, 66))	('T2-3N0M0', 'Var', (136, 144))	('tumor', 'Disease', (97, 102))	('T3N0M0', 'Var', (160, 166))
62505	30568392	We have identified certain clinicopathological features that are associated with an increased risk of tumor recurrence in pT1N0 thoracic ESCC patients after esophagectomy and thoracoabdominal two-field lymphadenectomy: (1) Patients with an upper thoracic location, ulcerative or intraluminal mass tumor type, deeper tumor invasion level, basaloid histology, angiolymphatic invasion, greater tumor thickness, greater submucosal invasion thickness, greater diameter of the largest single tongue of invasion, and/or completely negative aberrant p53 expression are at greater risk of tumor recurrence.	('intraluminal mass tumor', 'Disease', 'MESH:C536030', (279, 302))	('aberrant', 'Var', (533, 541))	('p53', 'Gene', (542, 545))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (297, 302))	('tumor', 'Disease', (391, 396))	('tumor', 'Phenotype', 'HP:0002664', (580, 585))	('tumor', 'Phenotype', 'HP:0002664', (316, 321))	('tumor', 'Disease', 'MESH:D009369', (297, 302))	('tumor', 'Disease', 'MESH:D009369', (391, 396))	('pT1', 'Gene', '58492', (122, 125))	('Patients', 'Species', '9606', (223, 231))	('tumor', 'Disease', (580, 585))	('pT1', 'Gene', (122, 125))	('intraluminal mass tumor', 'Disease', (279, 302))	('expression', 'MPA', (546, 556))	('tumor', 'Disease', 'MESH:D009369', (580, 585))	('tumor', 'Phenotype', 'HP:0002664', (297, 302))	('tumor', 'Phenotype', 'HP:0002664', (391, 396))	('tumor', 'Disease', (102, 107))	('angiolymphatic', 'Disease', (358, 372))	('negative', 'NegReg', (524, 532))	('tumor', 'Disease', (316, 321))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('p53', 'Gene', '7157', (542, 545))	('patients', 'Species', '9606', (142, 150))	('tumor', 'Disease', 'MESH:D009369', (316, 321))
62523	28031935	AKT-inhibitor MK-2206 reduced hypoxic HIF-1 signaling in most HNSCC cell lines.	('AKT', 'Gene', (0, 3))	('hypoxic HIF-1', 'Disease', (30, 43))	('MK-2206', 'Chemical', 'MESH:C548887', (14, 21))	('HNSCC', 'Phenotype', 'HP:0012288', (62, 67))	('MK-2206', 'Var', (14, 21))	('hypoxic HIF-1', 'Disease', 'MESH:D000860', (30, 43))	('AKT', 'Gene', '207', (0, 3))	('reduced', 'NegReg', (22, 29))
62530	28031935	This variation could significantly affect response to treatments targeting hypoxia or these signaling pathways.	('hypoxia', 'Disease', (75, 82))	('affect', 'Reg', (35, 41))	('hypoxia', 'Disease', 'MESH:D000860', (75, 82))	('variation', 'Var', (5, 14))
62567	28031935	To quantify the distribution of pAKT in relation to the vasculature, zones were chosen at increasing distances from the nearest vessel (0-50, 51-100, 101-150, 151-200 and 201-250 mum).	('AKT', 'Gene', (33, 36))	('AKT', 'Gene', '207', (33, 36))	('51-100', 'Var', (142, 148))
62569	28031935	Synergism between hypoxia and MK-2206 was determined by correcting the cell survival after hypoxia and MK-2206 by the effect of hypoxia alone.	('hypoxia', 'Disease', (91, 98))	('hypoxia', 'Disease', 'MESH:D000860', (91, 98))	('MK-2206', 'Chemical', 'MESH:C548887', (103, 110))	('MK-2206', 'Var', (103, 110))	('hypoxia', 'Disease', 'MESH:D000860', (18, 25))	('MK-2206', 'Chemical', 'MESH:C548887', (30, 37))	('cell survival', 'CPA', (71, 84))	('hypoxia', 'Disease', 'MESH:D000860', (128, 135))	('hypoxia', 'Disease', (128, 135))	('hypoxia', 'Disease', (18, 25))
62570	28031935	Differences between the effect of MK-2206 under normoxia and the corrected effect of MK-2206 under hypoxia (difference = supra-additive effect) were tested for significance using Mann-Whitney tests.	('MK-2206', 'Chemical', 'MESH:C548887', (34, 41))	('hypoxia', 'Disease', 'MESH:D000860', (99, 106))	('MK-2206', 'Var', (34, 41))	('hypoxia', 'Disease', (99, 106))	('MK-2206', 'Chemical', 'MESH:C548887', (85, 92))
62582	28031935	pAKT levels were decreased by MK-2206 during normoxic and hypoxic incubation in all cell lines indicating effective AKT inhibition (Supplementary Figure 1).	('decreased', 'NegReg', (17, 26))	('AKT', 'Gene', '207', (1, 4))	('AKT', 'Gene', '207', (116, 119))	('inhibition', 'NegReg', (120, 130))	('MK-2206', 'Chemical', 'MESH:C548887', (30, 37))	('AKT', 'Gene', (1, 4))	('MK-2206', 'Var', (30, 37))	('AKT', 'Gene', (116, 119))
62583	28031935	AKT inhibition decreased the hypoxic induction of GLUT-1 and/or CAIX in HNSCC lines UT-SCC15, -24A and -38.	('AKT', 'Gene', (0, 3))	('hypoxic induction', 'MPA', (29, 46))	('HNSCC', 'Phenotype', 'HP:0012288', (72, 77))	('CAIX', 'Gene', (64, 68))	('GLUT-1', 'Gene', (50, 56))	('GLUT-1', 'Gene', '6513', (50, 56))	('inhibition', 'Var', (4, 14))	('CAIX', 'Gene', '768', (64, 68))	('AKT', 'Gene', '207', (0, 3))	('decreased', 'NegReg', (15, 24))
62595	28031935	To determine whether hypoxic cells showed a higher sensitivity for MK-2206, cell survival after hypoxia and MK-2206 was corrected by the effect of hypoxia alone.	('MK-2206', 'Var', (108, 115))	('MK-2206', 'Chemical', 'MESH:C548887', (108, 115))	('hypoxia', 'Disease', (147, 154))	('hypoxia', 'Disease', 'MESH:D000860', (147, 154))	('MK-2206', 'Chemical', 'MESH:C548887', (67, 74))	('hypoxia', 'Disease', (96, 103))	('hypoxia', 'Disease', 'MESH:D000860', (96, 103))	('cell', 'CPA', (76, 80))
62597	28031935	As shown before, hypoxic cells of UT-SCC5 and UT-SCC15 were more sensitive to MK-2206 compared with normoxic cells (Figure 3A).	('MK-2206', 'Var', (78, 85))	('MK-2206', 'Chemical', 'MESH:C548887', (78, 85))	('sensitive', 'MPA', (65, 74))
62603	28031935	Although the difference was small, hypoxic H1975 cells did show enhanced sensitivity for MK-2206 compared with normoxic cells.	('sensitivity', 'MPA', (73, 84))	('MK-2206', 'Chemical', 'MESH:C548887', (89, 96))	('H1975', 'CellLine', 'CVCL:1511', (43, 48))	('MK-2206', 'Var', (89, 96))	('enhanced', 'PosReg', (64, 72))
62641	28031935	The NSCLC lines showing high sensitivity to AKT inhibition, that is, H520, HCC827 and H1975, have also the highest basal pAKT levels.	('H1975', 'Var', (86, 91))	('NSCLC', 'Disease', 'MESH:D002289', (4, 9))	('H1975', 'CellLine', 'CVCL:1511', (86, 91))	('AKT', 'Gene', '207', (44, 47))	('NSCLC', 'Phenotype', 'HP:0030358', (4, 9))	('AKT', 'Gene', '207', (122, 125))	('NSCLC', 'Disease', (4, 9))	('AKT', 'Gene', (44, 47))	('AKT', 'Gene', (122, 125))
62646	28031935	In general, NSCLC have more often activating mutations in important growth factor receptor signaling genes like EGFR and KRAS, although the percentage is lower in squamous cell NSCLC compared with adenocarcinoma NSCLC.	('NSCLC', 'Disease', 'MESH:D002289', (212, 217))	('NSCLC', 'Phenotype', 'HP:0030358', (177, 182))	('adenocarcinoma NSCLC', 'Disease', (197, 217))	('NSCLC', 'Disease', (212, 217))	('lower', 'NegReg', (154, 159))	('KRAS', 'Gene', '3845', (121, 125))	('NSCLC', 'Phenotype', 'HP:0030358', (212, 217))	('NSCLC', 'Disease', 'MESH:D002289', (12, 17))	('squamous cell NSCLC', 'Disease', (163, 182))	('EGFR', 'Gene', (112, 116))	('KRAS', 'Gene', (121, 125))	('NSCLC', 'Disease', (12, 17))	('squamous cell NSCLC', 'Disease', 'MESH:D002294', (163, 182))	('NSCLC', 'Disease', 'MESH:D002289', (177, 182))	('adenocarcinoma NSCLC', 'Disease', 'MESH:D000230', (197, 217))	('mutations', 'Var', (45, 54))	('NSCLC', 'Phenotype', 'HP:0030358', (12, 17))	('activating', 'PosReg', (34, 44))	('NSCLC', 'Disease', (177, 182))	('EGFR', 'Gene', '1956', (112, 116))	('carcinoma', 'Phenotype', 'HP:0030731', (202, 211))
62647	28031935	These activating mutations can result in 'oncogene addiction', which can make a tumor cell very sensitive to inhibition under control conditions.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('activating', 'PosReg', (6, 16))	('tumor', 'Disease', (80, 85))	("'oncogene addiction'", 'Disease', (41, 61))	('mutations', 'Var', (17, 26))	('result in', 'Reg', (31, 40))
62648	28031935	The AKT pathway is an important downstream pathway of both EGFR and KRAS and cell lines with mutations in these genes could thus also be dependent on AKT signaling.	('AKT', 'Gene', (4, 7))	('mutations', 'Var', (93, 102))	('EGFR', 'Gene', (59, 63))	('AKT', 'Gene', '207', (150, 153))	('KRAS', 'Gene', (68, 72))	('KRAS', 'Gene', '3845', (68, 72))	('AKT', 'Gene', '207', (4, 7))	('AKT', 'Gene', (150, 153))	('EGFR', 'Gene', '1956', (59, 63))
62649	28031935	We have not performed mutational analysis in our cell panel, but it is for example known that H1975 and HCC827, both very sensitive for AKT inhibition, have activating mutations in EGFR.	('EGFR', 'Gene', (181, 185))	('activating', 'PosReg', (157, 167))	('H1975', 'CellLine', 'CVCL:1511', (94, 99))	('AKT', 'Gene', '207', (136, 139))	('EGFR', 'Gene', '1956', (181, 185))	('mutations', 'Var', (168, 177))	('AKT', 'Gene', (136, 139))
62655	28031935	Our data show that high AKT expression in NSCLC, either present due to mutational changes or induced by hypoxia, is correlated with high sensitivity to AKT inhibition.	('NSCLC', 'Disease', (42, 47))	('AKT', 'Gene', (24, 27))	('AKT', 'Gene', '207', (152, 155))	('high', 'PosReg', (19, 23))	('NSCLC', 'Disease', 'MESH:D002289', (42, 47))	('expression', 'MPA', (28, 38))	('changes', 'Var', (82, 89))	('mutational', 'Var', (71, 81))	('AKT', 'Gene', (152, 155))	('hypoxia', 'Disease', (104, 111))	('hypoxia', 'Disease', 'MESH:D000860', (104, 111))	('AKT', 'Gene', '207', (24, 27))	('NSCLC', 'Phenotype', 'HP:0030358', (42, 47))
62684	25929687	Microarray analysis was used to identify changes of gene expression in response to knockdown of either WT1 or p63.	('p63', 'Gene', (110, 113))	('p63', 'Gene', '8626', (110, 113))	('knockdown', 'Var', (83, 92))
62686	25929687	We found that WT1 and p63 promoted cell proliferation, while mutant p53 (R248L) possessed the ability to suppress cell proliferation.	('R248L', 'Var', (73, 78))	('p63', 'Gene', '8626', (22, 25))	('suppress', 'NegReg', (105, 113))	('R248L', 'Mutation', 'rs11540652', (73, 78))	('promoted', 'PosReg', (26, 34))	('rat', 'Species', '10116', (47, 50))	('cell proliferation', 'CPA', (35, 53))	('p63', 'Gene', (22, 25))	('p53', 'Gene', (68, 71))	('rat', 'Species', '10116', (126, 129))	('cell proliferation', 'CPA', (114, 132))
62690	25929687	Several known WT1 and p63 target genes were affected by WT1 knockdown.	('p63', 'Gene', '8626', (22, 25))	('affected', 'Reg', (44, 52))	('p63', 'Gene', (22, 25))	('knockdown', 'Var', (60, 69))	('WT1', 'Gene', (56, 59))
62691	25929687	Protein interaction was demonstrated between WT1 and p53 but not between WT1 and p63.	('p63', 'Gene', '8626', (81, 84))	('p53', 'Var', (53, 56))	('Protein interaction', 'Interaction', (0, 19))	('p63', 'Gene', (81, 84))	('rat', 'Species', '10116', (31, 34))
62701	25929687	WT1 was previously found to interact with p53 and p63 at protein level in baby rat kidney cells and in Saos-2, an osteosarcoma cell line.	('interact', 'Interaction', (28, 36))	('p63', 'Gene', '8626', (50, 53))	('Saos-2', 'CellLine', 'CVCL:0548', (103, 109))	('osteosarcoma', 'Phenotype', 'HP:0002669', (114, 126))	('osteosarcoma', 'Disease', (114, 126))	('osteosarcoma', 'Disease', 'MESH:D012516', (114, 126))	('p63', 'Gene', (50, 53))	('rat', 'Species', '10116', (79, 82))	('p53', 'Var', (42, 45))
62707	25929687	By silencing WT1 and p63 RNA, SCCHN cell proliferation was decreased.	('silencing', 'Var', (3, 12))	('p63', 'Gene', (21, 24))	('WT1', 'Gene', (13, 16))	('decreased', 'NegReg', (59, 68))	('p63', 'Gene', '8626', (21, 24))	('rat', 'Species', '10116', (48, 51))	('SCCHN cell proliferation', 'CPA', (30, 54))
62711	25929687	To suppress expression of WT1, p63 and p53, FaDu cells were transiently transfected with siRNA of WT1 (12.5 nM/well), p63 (5 nM/well) and p53 (5 nM/well) in six well plates (3 x 105 cells/well) and 96-well plates (8 x 103 cells/well).	('p63', 'Gene', (31, 34))	('p63', 'Gene', (118, 121))	('p63', 'Gene', '8626', (31, 34))	('p53 (5 nM/well', 'Var', (138, 152))	('suppress', 'NegReg', (3, 11))	('12.5 nM/well', 'Var', (103, 115))	('p63', 'Gene', '8626', (118, 121))
62726	25929687	SKOV-3 cell line, derived from the ascitic fluid of a female with an ovarian tumor (ATCC HTB-77) with no endogenous WT1 expression and null p53 expression (p53 mutation at codon 89 and 179) was used as an extra negative control.	('mutation', 'Var', (160, 168))	('SKOV-3', 'CellLine', 'CVCL:0532', (0, 6))	('p53', 'Gene', (156, 159))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('ovarian tumor', 'Disease', (69, 82))	('ovarian tumor', 'Phenotype', 'HP:0100615', (69, 82))	('p53', 'Gene', (140, 143))	('ovarian tumor', 'Disease', 'MESH:D010051', (69, 82))
62748	25929687	Similarly, silencing p63 RNA induced a considerable decrease in cell proliferation at both time points (p < 0.05, Figure 1B).	('silencing', 'Var', (11, 20))	('p63', 'Gene', (21, 24))	('rat', 'Species', '10116', (76, 79))	('cell proliferation', 'CPA', (64, 82))	('p63', 'Gene', '8626', (21, 24))	('decrease', 'NegReg', (52, 60))
62751	25929687	The R248L mutation of p53 does not completely abolish its inhibitory effect on cell proliferation in this cell line.	('rat', 'Species', '10116', (91, 94))	('p53', 'Gene', (22, 25))	('abolish', 'NegReg', (46, 53))	('R248L', 'Var', (4, 9))	('inhibitory effect', 'MPA', (58, 75))	('cell proliferation in this cell line', 'CPA', (79, 115))	('R248L', 'Mutation', 'rs11540652', (4, 9))
62752	25929687	As shown in Figure 1C, a significant increase in cell proliferation in p53 knockdown cells was demonstrated at 48 hours after transfection compared to control cells (p < 0.05).	('rat', 'Species', '10116', (61, 64))	('cell proliferation', 'CPA', (49, 67))	('knockdown', 'Var', (75, 84))	('p53', 'Gene', (71, 74))	('increase', 'PosReg', (37, 45))	('rat', 'Species', '10116', (102, 105))
62762	25929687	An additional experiment was performed to confirm the positive correlation between WT1 and DeltaNp63 using a plasmid carrying WT1D variant into FaDu cells.	('variant', 'Var', (131, 138))	('p63', 'Gene', (97, 100))	('p63', 'Gene', '8626', (97, 100))
62765	25929687	These results indicate a possible functional link between WT1 and p63 in FaDu cells, but not a strong association between WT1 and p53 expression.	('WT1', 'Var', (58, 61))	('p63', 'Gene', '8626', (66, 69))	('p63', 'Gene', (66, 69))
62772	25929687	Genes with altered expression in response to knockdown of WT1 or p63 were detected with microarray analysis.	('p63', 'Gene', '8626', (65, 68))	('p63', 'Gene', (65, 68))	('expression', 'MPA', (19, 29))	('knockdown', 'Var', (45, 54))
62775	25929687	Ten genes involved in cell proliferation, five genes involved in cell cycle regulation and three genes associated with DNA replication were significantly altered in WT1 and p63 knockdown cells (p < 0.005, Table 1).	('cell', 'CPA', (22, 26))	('knockdown', 'Var', (177, 186))	('p63', 'Gene', (173, 176))	('rat', 'Species', '10116', (34, 37))	('altered', 'Reg', (154, 161))	('p63', 'Gene', '8626', (173, 176))
62782	25929687	However, knockdown of p63 was found to induce alterations in the transcription of 24 genes involved in apoptosis.	('p63', 'Gene', '8626', (22, 25))	('knockdown', 'Var', (9, 18))	('rat', 'Species', '10116', (50, 53))	('alterations', 'Reg', (46, 57))	('p63', 'Gene', (22, 25))	('transcription of', 'MPA', (65, 81))
62783	25929687	In addition, by using Metacore GeneGo analysis, 6 known WT1 target genes and 27 known p63 downstream target genes were found to be affected in WT1 knockdown cells (Figure 4B).	('knockdown', 'Var', (147, 156))	('p63', 'Gene', '8626', (86, 89))	('p63', 'Gene', (86, 89))	('affected', 'Reg', (131, 139))
62799	25929687	Further, in vitro experiments showed altered expression of 18 genes involved in cell proliferation, cell cycle regulation and DNA replication shared by silencing of WT1 and p63 RNA.	('silencing', 'Var', (152, 161))	('DNA replication', 'CPA', (126, 141))	('rat', 'Species', '10116', (92, 95))	('expression', 'MPA', (45, 55))	('cell', 'CPA', (100, 104))	('p63', 'Gene', (173, 176))	('altered', 'Reg', (37, 44))	('p63', 'Gene', '8626', (173, 176))
62800	25929687	Several known WT1 and p63 target genes were affected by knockdown of WT1.	('p63', 'Gene', '8626', (22, 25))	('affected', 'Reg', (44, 52))	('p63', 'Gene', (22, 25))	('WT1', 'Gene', (69, 72))	('knockdown', 'Var', (56, 65))
62803	25929687	Furthermore, increased cell proliferation induced by WT1 has been shown in several other types of cancer cells including non-small cell lung cancer and several solid cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('lung cancer', 'Phenotype', 'HP:0100526', (136, 147))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (125, 147))	('cancer', 'Disease', (166, 172))	('non-small cell lung cancer', 'Disease', (121, 147))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('increased', 'PosReg', (13, 22))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (121, 147))	('cancer', 'Disease', (98, 104))	('WT1', 'Var', (53, 56))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (121, 147))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('rat', 'Species', '10116', (35, 38))	('cell proliferation', 'CPA', (23, 41))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('cancer', 'Disease', (141, 147))
62808	25929687	However, another study has shown that the silencing of  Np63 in FaDu cells does not alter the proliferation state, as judged by Ki-67 expression and FACS analysis regarding cell cycle phase DNA content.	('silencing', 'Var', (42, 51))	('p63', 'Gene', '8626', (57, 60))	('rat', 'Species', '10116', (101, 104))	('p63', 'Gene', (57, 60))
62811	25929687	The FaDu cell line contains a point mutation of p53 at codon 248 (Arg   Leu), one of the most frequent mutation sites of the gene.	('p53', 'Gene', (48, 51))	('Arg', 'Chemical', 'MESH:D001120', (66, 69))	('Arg   Leu', 'Var', (66, 75))	('Leu', 'Chemical', 'MESH:D007930', (72, 75))
62812	25929687	Codon 248 is located in the DNA binding domain and mutations in this specific location has suggested generating a protein incapable of binding to target DNA, thereby losing its regulatory function on transcription.	('regulatory function on transcription', 'MPA', (177, 213))	('losing', 'NegReg', (166, 172))	('mutations', 'Var', (51, 60))	('rat', 'Species', '10116', (105, 108))
62814	25929687	However, we observed that p53 had an inhibitory effect on cell proliferation.	('p53', 'Var', (26, 29))	('cell proliferation', 'CPA', (58, 76))	('rat', 'Species', '10116', (70, 73))
62815	25929687	The same mutation in H322a, a non-small cell lung cancer cell line, showed that mutant p53R248L still possesses a tumor suppressor function, as demonstrated by expansion of cell proliferation due to reduction in gene expression.	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('mutant p53R248L', 'Var', (80, 95))	('expansion', 'PosReg', (160, 169))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (30, 56))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('gene expression', 'MPA', (212, 227))	('R248L', 'Mutation', 'rs11540652', (90, 95))	('tumor', 'Disease', (114, 119))	('lung cancer', 'Phenotype', 'HP:0100526', (45, 56))	('non-small cell lung cancer', 'Disease', (30, 56))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('p53R248L', 'Var', (87, 95))	('reduction', 'NegReg', (199, 208))	('rat', 'Species', '10116', (151, 154))	('rat', 'Species', '10116', (185, 188))	('cell proliferation', 'CPA', (173, 191))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (34, 56))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (30, 56))
62823	25929687	A p53 mutation at position homologues to human codon 248 in BRK cells did not abolish this interaction.	('BRK', 'Gene', (60, 63))	('BRK', 'Gene', '5753', (60, 63))	('p53', 'Gene', (2, 5))	('mutation', 'Var', (6, 14))	('human', 'Species', '9606', (41, 46))
62826	25929687	Microarray analysis showed that 18 genes involved in cell proliferation, cell cycle regulation and DNA replication were significantly altered in both WT1 and p63 knockdown cells.	('p63', 'Gene', (158, 161))	('rat', 'Species', '10116', (65, 68))	('p63', 'Gene', '8626', (158, 161))	('altered', 'Reg', (134, 141))	('cell cycle', 'CPA', (73, 83))	('cell proliferation', 'CPA', (53, 71))	('knockdown', 'Var', (162, 171))	('DNA replication', 'CPA', (99, 114))
62845	25929687	Interestingly, IL8 demonstrated decreased expression when silencing WT1, but an increased fold change when knocking down p63.	('fold change', 'MPA', (90, 101))	('IL8', 'Gene', (15, 18))	('expression', 'MPA', (42, 52))	('rat', 'Species', '10116', (26, 29))	('IL8', 'Gene', '3576', (15, 18))	('p63', 'Gene', (121, 124))	('p63', 'Gene', '8626', (121, 124))	('decreased', 'NegReg', (32, 41))	('silencing', 'Var', (58, 67))
62857	25929687	Using Metacore GeneGo software we found that expressions of ten known p63 target genes were altered in both WT1 and p63 knockdown cells.	('p63', 'Gene', (116, 119))	('expressions', 'MPA', (45, 56))	('p63', 'Gene', '8626', (116, 119))	('p63', 'Gene', (70, 73))	('knockdown', 'Var', (120, 129))	('altered', 'Reg', (92, 99))	('p63', 'Gene', '8626', (70, 73))
62876	30678455	EGFR inhibitor C225 Increases the Radio-Sensitivity of Human Breast Cancer Cells This study was undertaken to investigate the effect of C225 on the radio-sensitivity of MDA-MB-231 cells line and to disclosure underlying mechanism.	('EGFR', 'Gene', (0, 4))	('Breast Cancer', 'Disease', (61, 74))	('Cancer', 'Phenotype', 'HP:0002664', (68, 74))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (169, 179))	('Breast Cancer', 'Disease', 'MESH:D001943', (61, 74))	('Increases', 'PosReg', (20, 29))	('Human', 'Species', '9606', (55, 60))	('Breast Cancer', 'Phenotype', 'HP:0003002', (61, 74))	('C225', 'Var', (15, 19))	('EGFR', 'Gene', '1956', (0, 4))
62877	30678455	CCK8 assay was used to measure the proliferation inhibition of C225 on MDA-MB-231 cells.	('C225', 'Var', (63, 67))	('proliferation inhibition', 'CPA', (35, 59))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (71, 81))
62882	30678455	The up-regulation of the Caspase-3 expression in C225 plus radiation group revealed that C225 could increase radiation-inducing cell apoptosis.	('radiation-inducing cell apoptosis', 'CPA', (109, 142))	('Caspase-3', 'Gene', (25, 34))	('C225', 'Var', (89, 93))	('Caspase-3', 'Gene', '836', (25, 34))	('expression', 'MPA', (35, 45))	('up-regulation', 'PosReg', (4, 17))	('increase', 'PosReg', (100, 108))
62883	30678455	C225 could increase the radio-sensitivity of cells, which may be due to the anti-proliferative synergistic effect between C225 and radiation as well as the down-regulation of the PI3K/Akt signaling pathway.	('increase', 'PosReg', (11, 19))	('C225', 'Var', (122, 126))	('down-regulation', 'NegReg', (156, 171))	('C225', 'Var', (0, 4))	('Akt', 'Gene', (184, 187))	('anti-proliferative synergistic effect', 'CPA', (76, 113))	('radio-sensitivity of cells', 'CPA', (24, 50))	('Akt', 'Gene', '207', (184, 187))
62898	30678455	In the present study, we investigated the radio-sensitivity of C225 on TNBC MDA-MB-231 cells and disclosed the underlying mechanism by detecting cell proliferation, cell cycle, and apoptosis in MDA-MB-231 cells.	('detecting', 'Reg', (135, 144))	('cell cycle', 'CPA', (165, 175))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (76, 86))	('C225', 'Var', (63, 67))	('apoptosis', 'CPA', (181, 190))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (194, 204))	('cell proliferation', 'CPA', (145, 163))	('TNBC', 'Gene', (71, 75))
62899	30678455	EGFR and its downstream PI3K/Akt signaling pathway as well as apoptosis-associated genes play an important role in radiation resistance of tumors (Gupta et al., 2001), so this investigation also discussed whether C225 enhance the radio-sensitivity of MDA-MB-23l cells by blocking the PI3K/Akt signaling pathway.	('blocking', 'NegReg', (271, 279))	('EGFR', 'Gene', (0, 4))	('MDA-MB-23l', 'CellLine', 'CVCL:0062', (251, 261))	('Akt', 'Gene', (289, 292))	('C225', 'Var', (213, 217))	('Akt', 'Gene', '207', (29, 32))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('Akt', 'Gene', (29, 32))	('tumors', 'Disease', (139, 145))	('Akt', 'Gene', '207', (289, 292))	('tumors', 'Disease', 'MESH:D009369', (139, 145))	('radio-sensitivity', 'CPA', (230, 247))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('EGFR', 'Gene', '1956', (0, 4))	('enhance', 'PosReg', (218, 225))
62917	30678455	As shown in Figure 1, various concentrations of C225 inhibited the proliferation of MDA-MB-231 cells and a significant difference was found compared with control group (P<0.05).	('inhibited', 'NegReg', (53, 62))	('proliferation', 'CPA', (67, 80))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (84, 94))	('C225', 'Var', (48, 52))
62918	30678455	As shown in Figure 4, the apoptosis of MDA-MB-231cells in C225 plus radiation group was significantly higher than that in radiation group at all expose doses, and the difference between the two groups was statistically significant (P<0.05).	('apoptosis', 'CPA', (26, 35))	('higher', 'PosReg', (102, 108))	('C225 plus radiation', 'Var', (58, 77))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (39, 49))	('MDA-MB-231cells', 'Gene', (39, 54))
62919	30678455	That is to say C225 could make MDA-MB-231 cells be arrested in G0/G1 phase and slow down the cell cycle progression which was associated with the inhibition of proliferation.	('cell cycle progression', 'CPA', (93, 115))	('C225', 'Var', (15, 19))	('slow down', 'NegReg', (79, 88))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (31, 41))
62922	30678455	The results showed that the expressions of p-Akt, p-P38, and p-EGFR were significantly inhibited in C225 combined with radiation.	('EGFR', 'Gene', '1956', (63, 67))	('Akt', 'Gene', (45, 48))	('EGFR', 'Gene', (63, 67))	('C225', 'Var', (100, 104))	('P38', 'Gene', (52, 55))	('expressions', 'MPA', (28, 39))	('inhibited', 'NegReg', (87, 96))	('Akt', 'Gene', '207', (45, 48))	('P38', 'Gene', '1432', (52, 55))
62923	30678455	The results showed that the expression of Caspase-3 was significantly enhanced in C225 plus radiation group and the difference was statistically significant compared with the control group (P<0.05).	('Caspase-3', 'Gene', (42, 51))	('C225 plus radiation', 'Var', (82, 101))	('expression', 'MPA', (28, 38))	('Caspase-3', 'Gene', '836', (42, 51))	('enhanced', 'PosReg', (70, 78))
62926	30678455	C225, as a kind of EGFR inhibitors, was shown to inhibit the growth of some EGFR-expressing cell lines.	('growth', 'MPA', (61, 67))	('EGFR', 'Gene', '1956', (76, 80))	('C225', 'Var', (0, 4))	('EGFR', 'Gene', '1956', (19, 23))	('EGFR', 'Gene', (76, 80))	('EGFR', 'Gene', (19, 23))	('inhibit', 'NegReg', (49, 56))
62928	30678455	C225 in combination with EGFR not only blocked the secretion of TGF- and signal transduction but also decreased the expression of EGFR on the cell membrane surface (Liao and Carpenter, 2009).	('expression', 'MPA', (116, 126))	('EGFR', 'Gene', (25, 29))	('signal transduction', 'MPA', (73, 92))	('blocked', 'NegReg', (39, 46))	('C225', 'Var', (0, 4))	('secretion', 'MPA', (51, 60))	('TGF-', 'Protein', (64, 68))	('EGFR', 'Gene', '1956', (130, 134))	('EGFR', 'Gene', (130, 134))	('decreased', 'NegReg', (102, 111))	('EGFR', 'Gene', '1956', (25, 29))
62929	30678455	Clinically, C225 combined with radiotherapy showed a significant effect on head and neck squamous cell carcinoma and C225 combined with radiotherapy as a routine treatment on head and neck squamous cell carcinoma has been accepted by the majority of doctors (Sok et al., 2006; Pozzi et al., 2016; Suntharalingam et al., 2017 ;Weidhaas et al., 2017).	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (189, 212))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (84, 112))	('C225', 'Var', (117, 121))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (175, 212))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (89, 112))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (75, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('neck squamous cell carcinoma', 'Disease', (184, 212))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (184, 212))	('carcinoma', 'Phenotype', 'HP:0030731', (203, 212))	('neck squamous cell carcinoma', 'Disease', (84, 112))
62930	30678455	Increasing studies have shown that C225 could inhibit the proliferation of a variety of tumor cells, such as tongue cancer, colorectal cancer, and lung squamous cell carcinoma (Zhang et al., 2010; Tian et al., 2012; Wang et al., 2012).	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (147, 175))	('proliferation', 'CPA', (58, 71))	('tongue cancer', 'Disease', (109, 122))	('inhibit', 'NegReg', (46, 53))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('colorectal cancer', 'Phenotype', 'HP:0003003', (124, 141))	('tongue cancer', 'Disease', 'MESH:D014062', (109, 122))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (152, 175))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (147, 175))	('lung squamous cell carcinoma', 'Disease', (147, 175))	('carcinoma', 'Phenotype', 'HP:0030731', (166, 175))	('colorectal cancer', 'Disease', (124, 141))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('C225', 'Var', (35, 39))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('tumor', 'Disease', (88, 93))	('colorectal cancer', 'Disease', 'MESH:D015179', (124, 141))
62931	30678455	In the present study, we confirmed that C225 significantly inhibited MDA-MB-231 cell growth using CCK-8 and clonogenic assays.	('MDA-MB-231', 'CellLine', 'CVCL:0062', (69, 79))	('C225', 'Var', (40, 44))	('inhibited', 'NegReg', (59, 68))
62932	30678455	Our results on CCK-8 assay showed that the inhibition rate of MDA-MB-231 cells increased with the increase of C225 concentration, thus it can be concluded that the inhibition effect is dose-dependent (Figure 1).	('inhibition', 'NegReg', (43, 53))	('increase', 'PosReg', (98, 106))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (62, 72))	('C225', 'Var', (110, 114))
62933	30678455	Importantly, C225 in combination with radiation produced significant synergistic inhibition of MDA-MB-231 cell growth which is consistent with findings of other studies, revealing that both C225 and radiation have synergistic growth inhibition on the tumor cells (Zhang et al., 2010; Tian et al., 2012; Wang et al., 2012).	('MDA-MB-231', 'Gene', (95, 105))	('growth', 'CPA', (226, 232))	('C225', 'Var', (13, 17))	('tumor', 'Disease', (251, 256))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (95, 105))	('tumor', 'Disease', 'MESH:D009369', (251, 256))	('C225', 'Var', (190, 194))	('tumor', 'Phenotype', 'HP:0002664', (251, 256))
62935	30678455	In the present study, we confirmed that C225 could inhibit MDA-MB-231 cell growth using clonogenic assay.	('inhibit', 'NegReg', (51, 58))	('C225', 'Var', (40, 44))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (59, 69))
62936	30678455	C225 in combination with radiation produced significant synergistic inhibition of MDA-MB-231 cell growth.	('MDA-MB-231', 'CellLine', 'CVCL:0062', (82, 92))	('MDA-MB-231', 'Gene', (82, 92))	('C225', 'Var', (0, 4))	('inhibition', 'NegReg', (68, 78))
62937	30678455	The dose-survival curve of C225-treated MDA-MB-231 cells exhibited a narrow shoulder (indicating a decrease in Dq) and a greater slope rate (indicating a decrease in D0).	('slope', 'MPA', (129, 134))	('MDA-MB-231', 'Gene', (40, 50))	('narrow shoulder', 'Phenotype', 'HP:0000774', (69, 84))	('decrease', 'NegReg', (154, 162))	('decrease', 'NegReg', (99, 107))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (40, 50))	('C225-treated', 'Var', (27, 39))
62938	30678455	Through analysis of cell survival curves, we found that the Dq value of C225 combined with radiation is smaller and the curves had no apparent shoulder area, indicating that the C225 increased the sensitivity of the MDA-MB-231 cells to radiation.	('sensitivity', 'MPA', (197, 208))	('increased', 'PosReg', (183, 192))	('C225', 'Var', (178, 182))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (216, 226))
62940	30678455	The decreased SF2 value of the C225-treated MDA-MB-231 cells indicated the radio-sensitization effect of C225 on MDA-MB-231 cells.	('decreased', 'NegReg', (4, 13))	('SF2 value', 'MPA', (14, 23))	('C225-treated', 'Var', (31, 43))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (113, 123))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (44, 54))
62941	30678455	The sensitive enhancement ratio (SERD0, SERDq, and SERSF2) of 30nmol/l C225 was 1.41, 1.63, and 1.38, respectively, which suggested that C225 had radio-sensitization effect on MDA-MB-231 cells (Figure 3).	('C225', 'Var', (137, 141))	('SERD0', 'Chemical', '-', (33, 38))	('C225', 'Var', (71, 75))	('enhancement', 'PosReg', (14, 25))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (176, 186))	('SERDq', 'Chemical', '-', (40, 45))	('radio-sensitization', 'CPA', (146, 165))	('SERSF2', 'Chemical', '-', (51, 57))
62945	30678455	The mechanism of radiation sensitization of C225 on MDA-MB-231 cell could be the prevention of G1 phase conversion to S phase and slowing down the process of cell cycle, resulted in the growth rate decrease.	('decrease', 'NegReg', (198, 206))	('process', 'MPA', (147, 154))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (52, 62))	('slowing down', 'NegReg', (130, 142))	('G1 phase conversion', 'MPA', (95, 114))	('prevention', 'NegReg', (81, 91))	('radiation sensitization', 'Phenotype', 'HP:0011133', (17, 40))	('growth', 'MPA', (186, 192))	('C225', 'Var', (44, 48))
62946	30678455	In this study, the effect of C225 on the proliferation inhibition of MDA-MB-231 cells was confirmed by CCK8.	('MDA-MB-231', 'CellLine', 'CVCL:0062', (69, 79))	('proliferation inhibition', 'CPA', (41, 65))	('C225', 'Var', (29, 33))
62949	30678455	Studies have shown that activation of EGFR can inhibit apoptosis of tumor cells, reducing the radiation sensitivity (Peltola et al., 2009).	('tumor', 'Disease', (68, 73))	('reducing', 'NegReg', (81, 89))	('radiation sensitivity', 'CPA', (94, 115))	('EGFR', 'Gene', '1956', (38, 42))	('activation', 'Var', (24, 34))	('EGFR', 'Gene', (38, 42))	('inhibit', 'NegReg', (47, 54))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))
62951	30678455	Our results showed that C225 could promote the apoptosis of MDA-MB-231 cells compared to the cells in control group.	('C225', 'Var', (24, 28))	('apoptosis', 'CPA', (47, 56))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (60, 70))	('promote', 'PosReg', (35, 42))
62960	30678455	Takaoka et al., (2012) confirmed that C225 could reduce the levels of phosphorylated EGFR and Akt in oral squamous cell carcinoma NA and Ca9-22 cells.	('oral squamous cell carcinoma', 'Disease', (101, 129))	('EGFR', 'Gene', (85, 89))	('Akt', 'Gene', (94, 97))	('C225', 'Var', (38, 42))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('Ca9-22', 'CellLine', 'CVCL:1102', (137, 143))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (101, 129))	('levels', 'MPA', (60, 66))	('reduce', 'NegReg', (49, 55))	('Akt', 'Gene', '207', (94, 97))	('EGFR', 'Gene', '1956', (85, 89))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (106, 129))
62962	30678455	In this study, we evaluated EGFR signal transduction system, such as p-EGFR, p-P38 and p-AKT in MDA-MB-231 cells when C225 was combined with radiation, and the results showed that the expression of p-EGFR, p-P38 and p-AKT were significantly inhibited by C225 plus radiation (Figure 6a, Figure 6b).	('EGFR', 'Gene', '1956', (28, 32))	('P38', 'Gene', (79, 82))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (96, 106))	('EGFR', 'Gene', (28, 32))	('C225', 'Var', (254, 258))	('EGFR', 'Gene', '1956', (200, 204))	('AKT', 'Gene', '207', (89, 92))	('EGFR', 'Gene', (200, 204))	('AKT', 'Gene', '207', (218, 221))	('EGFR', 'Gene', '1956', (71, 75))	('inhibited', 'NegReg', (241, 250))	('P38', 'Gene', '1432', (79, 82))	('P38', 'Gene', (208, 211))	('expression', 'MPA', (184, 194))	('AKT', 'Gene', (89, 92))	('EGFR', 'Gene', (71, 75))	('AKT', 'Gene', (218, 221))	('P38', 'Gene', '1432', (208, 211))
62965	30678455	We found that C225 could inhibit the activation of PI3K/Akt signaling pathway, suggesting that C225 could enhance the sensitivity of TNBC cells to radiation by inhibiting EGFR signal transduction system.	('inhibiting', 'NegReg', (160, 170))	('EGFR', 'Gene', (171, 175))	('enhance', 'PosReg', (106, 113))	('C225', 'Var', (95, 99))	('EGFR', 'Gene', '1956', (171, 175))	('Akt', 'Gene', (56, 59))	('sensitivity', 'MPA', (118, 129))	('inhibit', 'NegReg', (25, 32))	('Akt', 'Gene', '207', (56, 59))
62968	30678455	In our study, C255 increased MDA-MB-231 cell apoptosis after exposure to different doses of radiation.	('C255', 'Var', (14, 18))	('increased', 'PosReg', (19, 28))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (29, 39))	('MDA-MB-231', 'Gene', (29, 39))
62969	30678455	Importantly, C255 significantly inhibited the radiation-induced EGFR-MAPK signaling pathway activation in MDA-MB-231 cells as evidenced by the reduced the phosphorylation of p38-MAPK molecules by C225.	('p38-MAPK', 'Gene', (174, 182))	('activation', 'PosReg', (92, 102))	('inhibited', 'NegReg', (32, 41))	('C225', 'Var', (196, 200))	('C255', 'Var', (13, 17))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (106, 116))	('p38-MAPK', 'Gene', '1432', (174, 182))	('phosphorylation', 'MPA', (155, 170))	('EGFR', 'Gene', '1956', (64, 68))	('EGFR', 'Gene', (64, 68))	('reduced', 'NegReg', (143, 150))
62973	30678455	Our results showed that, compared with the control group, the single C225 group, and the radiation group, the expression of Caspase-3 in C225 plus radiation group was significantly enhanced, which showed that C225 combined with radiation enhanced the cytotoxic effect of radiation on MDA-MB-231 cells and promoted the apoptosis of MDA-MB-231 cells (Figure 7a, Figure 7b).	('C225', 'Var', (209, 213))	('apoptosis', 'CPA', (318, 327))	('promoted', 'PosReg', (305, 313))	('enhanced', 'PosReg', (181, 189))	('cytotoxic effect of radiation', 'CPA', (251, 280))	('Caspase-3', 'Gene', '836', (124, 133))	('Caspase-3', 'Gene', (124, 133))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (331, 341))	('expression', 'MPA', (110, 120))	('enhanced', 'PosReg', (238, 246))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (284, 294))
62974	30678455	In summary, C225 has a significant role in the radiation sensitization, and its mechanism may be related to the inhibition of EGFR signal transduction pathway and increased apoptosis.	('apoptosis', 'CPA', (173, 182))	('EGFR', 'Gene', (126, 130))	('increased', 'PosReg', (163, 172))	('radiation sensitization', 'CPA', (47, 70))	('inhibition', 'NegReg', (112, 122))	('radiation sensitization', 'Phenotype', 'HP:0011133', (47, 70))	('C225', 'Var', (12, 16))	('EGFR', 'Gene', '1956', (126, 130))
62986	30211114	Our finding with the MCT4-/- mice suggest MCT4 is a driver of progression to oral squamous cell cancer and MCT4 inhibitors could have clinical benefits for preventing invasive HNSCC.	('MCT4', 'Gene', (107, 111))	('oral squamous cell cancer', 'Disease', 'MESH:D002294', (77, 102))	('SCC', 'Phenotype', 'HP:0002860', (178, 181))	('inhibitors', 'Var', (112, 122))	('HNSCC', 'Phenotype', 'HP:0012288', (176, 181))	('oral squamous cell cancer', 'Disease', (77, 102))	('MCT4-/-', 'Gene', '80879', (21, 28))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('MCT4-/-', 'Gene', (21, 28))	('mice', 'Species', '10090', (29, 33))	('invasive HNSCC', 'Disease', (167, 181))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (82, 102))
63003	30211114	After exposure to 4NQO, MCT4 knockout animals developed significantly fewer and less extensive invasive SCC lesions compared to wild type mice.	('knockout', 'Var', (29, 37))	('lesion', 'Disease', (108, 114))	('mice', 'Species', '10090', (138, 142))	('SCC', 'Phenotype', 'HP:0002860', (104, 107))	('4NQO', 'Chemical', 'MESH:D015112', (18, 22))	('MCT4', 'Gene', (24, 28))	('lesion', 'Disease', 'MESH:D051437', (108, 114))
63122	30211114	4NQO treatment causes mutagenesis and oxidative stress in these cells, which in turn translates in the dysregulation of key transcription factors such as NF-kB and Hif1alpha.	('Hif1alpha', 'Gene', (164, 173))	('causes', 'Reg', (15, 21))	('oxidative stress', 'Phenotype', 'HP:0025464', (38, 54))	('4NQO', 'Chemical', 'MESH:D015112', (0, 4))	('Hif1alpha', 'Gene', '15251', (164, 173))	('dysregulation', 'MPA', (103, 116))	('NF-kB', 'Gene', (154, 159))	('4NQO treatment', 'Var', (0, 14))	('mutagenesis', 'CPA', (22, 33))	('oxidative stress', 'MPA', (38, 54))
63125	30211114	The MCT4-/- mice treated with 4NQO also developed dysplastic lesions and carcinomas in situ (CIS) similarly to the wild type mice, demonstrating that MCT4 is not necessary for the induction of non-invasive OSCC.	('carcinomas in situ', 'Disease', (73, 91))	('rat', 'Species', '10116', (138, 141))	('carcinomas in situ', 'Disease', 'MESH:D002278', (73, 91))	('dysplastic lesions', 'Disease', (50, 68))	('4NQO', 'Chemical', 'MESH:D015112', (30, 34))	('MCT4-/-', 'Gene', '80879', (4, 11))	('carcinomas', 'Phenotype', 'HP:0030731', (73, 83))	('mice', 'Species', '10090', (125, 129))	('SCC', 'Phenotype', 'HP:0002860', (207, 210))	('CIS', 'Phenotype', 'HP:0030731', (93, 96))	('4NQO', 'Var', (30, 34))	('mice', 'Species', '10090', (12, 16))	('developed', 'PosReg', (40, 49))	('dysplastic lesions', 'Disease', 'MESH:D021782', (50, 68))	('MCT4-/-', 'Gene', (4, 11))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
63135	30211114	In sum, future studies will need to be conducted to determine the mechanism by which loss of MCT4 reduces tumor aggressiveness.	('loss', 'Var', (85, 89))	('MCT4', 'Gene', (93, 97))	('tumor aggressiveness', 'Disease', (106, 126))	('aggressiveness', 'Phenotype', 'HP:0000718', (112, 126))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (106, 126))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('reduces', 'NegReg', (98, 105))
63138	30211114	The data suggest that the lack of MCT4 prevents the progression of early microinvasive lesions to full invasive, arresting the tumors in a less aggressive form.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('arresting the tumors', 'Disease', (113, 133))	('lack', 'Var', (26, 30))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('arresting the tumors', 'Disease', 'MESH:D006323', (113, 133))	('prevents', 'NegReg', (39, 47))	('lesion', 'Disease', 'MESH:D051437', (87, 93))	('MCT4', 'Protein', (34, 38))	('lesion', 'Disease', (87, 93))
63140	30211114	In wild type mice expression of MCT4 facilitates lactate efflux and acidification of the microenvironment promoting invasiveness and metastasis.	('MCT4', 'Gene', (32, 36))	('mice', 'Species', '10090', (13, 17))	('acidification of the microenvironment', 'MPA', (68, 105))	('lactate efflux', 'MPA', (49, 63))	('promoting', 'PosReg', (106, 115))	('lactate', 'Chemical', 'MESH:D019344', (49, 56))	('expression', 'Var', (18, 28))	('facilitates', 'PosReg', (37, 48))
63144	30211114	In the MCT4-/- animals, the number of macrophages noted in the tumor microenvironment is lower compared to the wild type (Figure 6M) suggesting that MCT4 in either one of the compartments, or in both of them, has an effect on the macrophage population.	('tumor', 'Disease', (63, 68))	('effect', 'Reg', (216, 222))	('macrophage population', 'CPA', (230, 251))	('MCT4-/-', 'Gene', '80879', (7, 14))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('MCT4-/-', 'Gene', (7, 14))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('MCT4', 'Var', (149, 153))
63145	30211114	It has also been reported that bone marrow derived macrophages (BMDM) knock down of MCT4 reduced the production of cytokines after LPS stimulation, indicating that the F4/80 cells in the tumor microenvironment of the MCT4-/- animals may be compromised.	('knock down', 'Var', (70, 80))	('F4/80', 'Gene', (168, 173))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('MCT4', 'Gene', (84, 88))	('F4/80', 'Gene', '13733', (168, 173))	('MCT4-/-', 'Gene', '80879', (217, 224))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('LPS', 'Disease', (131, 134))	('tumor', 'Disease', (187, 192))	('LPS', 'Disease', 'MESH:C536528', (131, 134))	('reduced', 'NegReg', (89, 96))	('MCT4-/-', 'Gene', (217, 224))	('production of cytokines', 'MPA', (101, 124))
63153	30211114	Consistently, we and others have used in vitro and in vivo techniques to show that ablation of any of these proteins (MCTs or CD147) causes the degradation of the entire complex.	('degradation', 'MPA', (144, 155))	('CD147', 'Gene', (126, 131))	('MCTs', 'Chemical', '-', (118, 122))	('ablation', 'Var', (83, 91))
63157	30211114	The use of drugs targeting CD147 in cancer has been explored and the use of anti-CD147 antibodies resulted in reduced growth of OSCC xenografts.	('SCC', 'Phenotype', 'HP:0002860', (129, 132))	('reduced', 'NegReg', (110, 117))	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('cancer', 'Disease', (36, 42))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('growth', 'MPA', (118, 124))	('anti-CD147', 'Gene', (76, 86))	('anti-CD147', 'Var', (76, 86))
63158	30211114	Silencing CD147 or using drugs that target CD147 impact the expression or activity of MCT1 and MCT4, supporting the idea that targeting these transporters in patients with OSCC could slow the development and progression of the disease.	('expression', 'MPA', (60, 70))	('development', 'CPA', (192, 203))	('CD147', 'Gene', (43, 48))	('activity', 'MPA', (74, 82))	('MCT1', 'Gene', (86, 90))	('MCT4', 'Gene', (95, 99))	('CD147', 'Gene', (10, 15))	('SCC', 'Phenotype', 'HP:0002860', (173, 176))	('impact', 'Reg', (49, 55))	('slow', 'NegReg', (183, 187))	('patients', 'Species', '9606', (158, 166))	('Silencing', 'Var', (0, 9))	('OSCC', 'Disease', (172, 176))
63231	27688609	Alkabuli stated that if boundaries of the classical method were modified than we can achieve good correlation between classical method (in 10 HPF) and density method (with use of grid) and suggested modification in classical method as low (>10), moderate (50-120), and heavy (120 above) grades for eosinophils in per 10 HPF.	('50-120', 'Var', (256, 262))	('>10', 'Var', (240, 243))	('eosin', 'Chemical', 'MESH:D004801', (298, 303))	('120 above', 'Var', (276, 285))
63285	27688609	The malignant state is unleashed by defect in communication pathways, which recruit host cells to become active participants.	('participants', 'Species', '9606', (112, 124))	('defect', 'Var', (36, 42))	('communication pathways', 'Pathway', (46, 68))
63305	33707472	Applications in cancer studies show that the proportions of T regulatory cells estimated by DNA methylation have expected associations with mutation load and survival time, while the estimates from gene expression miss such associations.	('associations', 'Interaction', (122, 134))	('cancer', 'Disease', 'MESH:D009369', (16, 22))	('survival time', 'CPA', (158, 171))	('cancer', 'Disease', (16, 22))	('mutation', 'Var', (140, 148))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))
63307	33707472	This is likely because checkpoint inhibitors work by reinvigorating a pre-existing tumor immune response, which can be characterized by the cell types and the extent of immune cell infiltration in tumor samples.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('checkpoint', 'Gene', (23, 33))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('tumor', 'Disease', (83, 88))	('inhibitors', 'Var', (34, 44))	('reinvigorating', 'PosReg', (53, 67))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('tumor', 'Disease', (197, 202))
63345	33707472	This is because larger  makes it easier for EMeth to separate the aberrant CpGs from the consistent ones and thus appropriately down-weighs their contributions to the final estimates.	('aberrant', 'Var', (66, 74))	('down-weighs', 'NegReg', (128, 139))	('EMeth', 'Chemical', '-', (44, 49))
63348	33707472	We also conducted additional simulations where the proportion of aberrant CpG probes varies from 5 to 35% and reached the same conclusion that EMeth consistently outperforms all the other methods (Supplementary Table S3).	('EMeth', 'Chemical', '-', (143, 148))	('CpG', 'Gene', (74, 77))	('aberrant', 'Var', (65, 73))
63369	33707472	A tumor cell with higher mutation burden may present more mutated peptides on its cell surface, and thus has higher chance to be recognized by the immune system.	('more', 'PosReg', (53, 57))	('tumor', 'Disease', 'MESH:D009369', (2, 7))	('mutation', 'Var', (25, 33))	('higher', 'PosReg', (109, 115))	('tumor', 'Phenotype', 'HP:0002664', (2, 7))	('mutated peptides', 'MPA', (58, 74))	('tumor', 'Disease', (2, 7))
63372	33707472	We observe that CD8T cells proportions (either the ones estimated using gene expression/CIBERSORTx or DNA methylation/EMeth) are indeed higher in the hypermutated subset (Fig.	('higher', 'PosReg', (136, 142))	('hypermutated', 'Var', (150, 162))	('EMeth', 'Chemical', '-', (118, 123))	('CD8', 'Gene', (16, 19))	('CD8', 'Gene', '925', (16, 19))
63389	33707472	In fact, the Treg proportion estimates using LM22 has stronger correlation with SF11 estimates in 3 other cell types (correlation 0.74, 0.55, and 0.54 for B cells, CD4T, and monocyte, respectively) than with Treg itself (correlation 0.5).	('CD4', 'Gene', '920', (164, 167))	('Treg', 'Chemical', '-', (208, 212))	('Treg', 'Chemical', '-', (13, 17))	('correlation', 'Interaction', (63, 74))	('LM22', 'CellLine', 'CVCL:5998', (45, 49))	('LM22', 'Var', (45, 49))	('CD4', 'Gene', (164, 167))
63390	33707472	The Treg proportion estimates using either SF11 or LM22 have negative correlations with EMeth estimates (correlation -0.18 and -0.2 for SF11 and LM22 estimates, respectively, Figure S41).	('LM22', 'CellLine', 'CVCL:5998', (145, 149))	('correlations', 'Interaction', (70, 82))	('negative', 'NegReg', (61, 69))	('Treg', 'Chemical', '-', (4, 8))	('SF11', 'Var', (43, 47))	('LM22', 'Var', (51, 55))	('LM22', 'CellLine', 'CVCL:5998', (51, 55))	('EMeth', 'Chemical', '-', (88, 93))
63430	28410392	Further manipulation of the Notch1 pathway in keratinocytes impacted CYFIP1 levels and chromatin immunoprecipitation assay confirmed the direct binding of Notch1 to the CYFIP1 promoter.	('Notch1', 'Gene', (28, 34))	('Notch1', 'Gene', '4851', (28, 34))	('binding', 'Interaction', (144, 151))	('Notch1', 'Gene', (155, 161))	('CYFIP1', 'Gene', (69, 75))	('CYFIP1', 'Gene', (169, 175))	('Notch1', 'Gene', '4851', (155, 161))	('CYFIP1', 'Gene', '23191', (69, 75))	('manipulation', 'Var', (8, 20))	('CYFIP1', 'Gene', '23191', (169, 175))
63442	28410392	Its deletion in keratinocytes is sufficient to enhance susceptibility to skin cancer formation and loss of its dermal function contributes to field cancerization with development of intraepithelial and invasive SCC.	('cancer', 'Disease', (148, 154))	('enhance', 'PosReg', (47, 54))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('SCC', 'Gene', '6317', (211, 214))	('contributes', 'Reg', (127, 138))	('field', 'CPA', (142, 147))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('skin cancer', 'Phenotype', 'HP:0008069', (73, 84))	('skin cancer', 'Disease', (73, 84))	('deletion', 'Var', (4, 12))	('SCC', 'Gene', (211, 214))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('skin cancer', 'Disease', 'MESH:D012878', (73, 84))
63451	28410392	CYFIP1-mediated depletion of WAVE function reduced epithelial adhesion and led to disorganization of tissue architecture.	('disorganization', 'CPA', (82, 97))	('CYFIP1', 'Gene', (0, 6))	('depletion', 'Var', (16, 25))	('epithelial adhesion', 'CPA', (51, 70))	('CYFIP1', 'Gene', '23191', (0, 6))	('WAVE function', 'MPA', (29, 42))	('reduced', 'NegReg', (43, 50))
63463	28410392	Primary HKCs or SCC13 cells were transfected with 200 nM of stealth validated two distinct siRNAs (Invitrogen) for human CYFIP1 n 1 (HSS177241) and n 2 (HSS177242).	('HSS177241', 'Var', (133, 142))	('CYFIP1', 'Gene', (121, 127))	('SCC13', 'CellLine', 'CVCL:4029', (16, 21))	('CYFIP1', 'Gene', '23191', (121, 127))	('human', 'Species', '9606', (115, 120))	('HSS177242', 'Var', (153, 162))
63494	28410392	As shown in Fig 2C and 2D, expression of Notch1 led to an induction of CYFIP1 expression on both RNA and protein levels.	('CYFIP1', 'Gene', (71, 77))	('expression', 'MPA', (78, 88))	('Notch1', 'Gene', (41, 47))	('induction', 'Reg', (58, 67))	('Notch1', 'Gene', '4851', (41, 47))	('expression', 'Var', (27, 37))	('CYFIP1', 'Gene', '23191', (71, 77))
63515	28410392	This reduced invasive phenotype was partially rescued by inhibition of Cyfip1.	('Cyfip1', 'Gene', (71, 77))	('inhibition', 'Var', (57, 67))	('reduced', 'NegReg', (5, 12))	('Cyfip1', 'Gene', '23191', (71, 77))	('invasive phenotype', 'CPA', (13, 31))
63520	28410392	Notch activation also induces differentiation of these cells through a more indirect mechanism, involving modulation of integrin expression in the basal layer, of p63 as well as of IRF family members.	('expression', 'MPA', (129, 139))	('modulation', 'Reg', (106, 116))	('induces', 'Reg', (22, 29))	('p63', 'Gene', (163, 166))	('Notch', 'Var', (0, 5))	('p63', 'Gene', '8626', (163, 166))	('differentiation', 'CPA', (30, 45))	('integrin', 'Protein', (120, 128))
63530	28410392	Activation of Notch1 signaling, either directly by overexpression of an active Notch1 variant, or through a conditional manipulation, both increased Cyfip1 mRNA and protein expression in cells.	('Notch1', 'Gene', (79, 85))	('increased', 'PosReg', (139, 148))	('Cyfip1', 'Gene', (149, 155))	('Notch1', 'Gene', (14, 20))	('Notch1', 'Gene', '4851', (14, 20))	('Cyfip1', 'Gene', '23191', (149, 155))	('Notch1', 'Gene', '4851', (79, 85))	('variant', 'Var', (86, 93))	('overexpression', 'PosReg', (51, 65))
63550	27167065	miRNAs play a pivotal role in coding-non-coding RNA regulatory networks, and many abnormally expressed miRNAs were proven to be associated with human diseases, particularly in promoting carcinogenesis in some cancers.	('promoting', 'PosReg', (176, 185))	('human', 'Species', '9606', (144, 149))	('abnormally expressed', 'Var', (82, 102))	('cancers', 'Disease', 'MESH:D009369', (209, 216))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))	('cancers', 'Phenotype', 'HP:0002664', (209, 216))	('cancers', 'Disease', (209, 216))	('associated', 'Reg', (128, 138))	('miRNAs', 'Gene', (103, 109))	('carcinogenesis', 'Disease', 'MESH:D063646', (186, 200))	('carcinogenesis', 'Disease', (186, 200))
63569	27167065	Some miRNAs were collected to understand the isomiR expression in LUSC, including down-regulated miRNAs (miR-451 and miR-30a) and up-regulated miRNAs (miR-205, miR-210, miR-183, and miR-9).	('miR-183', 'Gene', '406959', (169, 176))	('miR-30a', 'Gene', '407029', (117, 124))	('miR-183', 'Gene', (169, 176))	('miR-210', 'Gene', (160, 167))	('down-regulated', 'NegReg', (82, 96))	('miR-451', 'Gene', '574411', (105, 112))	('miRNAs', 'MPA', (97, 103))	('miR-210', 'Gene', '406992', (160, 167))	('miR-451', 'Gene', (105, 112))	('miR-9', 'Var', (182, 187))	('miR-205', 'Gene', (151, 158))	('miR-30a', 'Gene', (117, 124))	('miR-205', 'Gene', '406988', (151, 158))	('up-regulated', 'PosReg', (130, 142))	('miRNAs', 'MPA', (143, 149))
63582	27167065	Although some miRNAs are identified as common deregulated species in gender-specific diseases, such as deregulated miR-182 and miR-183, these miRNAs always exhibit different levels of up- or down-regulated expression (S2 Table).	('miR-182', 'Gene', '406958', (115, 122))	('expression', 'MPA', (206, 216))	('miR-183', 'Gene', (127, 134))	('miR-183', 'Gene', '406959', (127, 134))	('down-regulated', 'NegReg', (191, 205))	('up-', 'PosReg', (184, 187))	('miR-182', 'Gene', (115, 122))	('deregulated', 'Var', (103, 114))
63603	32466572	Several oncogenic drivers of NSCLC, such as the epidermal growth factor receptor (EGFR) and BRAF mutations, as well as anaplastic lymphoma kinase (ALK) and ROS-1 rearrangements, have been uncovered and studied.	('mutations', 'Var', (97, 106))	('EGFR', 'Gene', (82, 86))	('BRAF', 'Gene', '673', (92, 96))	('NSCLC', 'Phenotype', 'HP:0030358', (29, 34))	('ALK', 'Gene', (147, 150))	('BRAF', 'Gene', (92, 96))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (119, 138))	('epidermal growth factor receptor', 'Gene', (48, 80))	('lymphoma', 'Phenotype', 'HP:0002665', (130, 138))	('anaplastic lymphoma', 'Disease', 'MESH:D017728', (119, 138))	('NSCLC', 'Disease', (29, 34))	('anaplastic lymphoma', 'Disease', (119, 138))	('ROS', 'Chemical', 'MESH:D017382', (156, 159))	('NSCLC', 'Disease', 'MESH:D002289', (29, 34))	('EGFR', 'Gene', '1956', (82, 86))	('epidermal growth factor receptor', 'Gene', '1956', (48, 80))	('ALK', 'Gene', '238', (147, 150))
63604	32466572	Drugs targeting these oncogenic drivers have been developed, and most of them have been approved by the US Food and Drug Administration (FDA) for the clinical treatment of advanced NSCLC patients harboring oncogenic-driven mutations.	('patients', 'Species', '9606', (187, 195))	('NSCLC', 'Disease', 'MESH:D002289', (181, 186))	('mutations', 'Var', (223, 232))	('NSCLC', 'Phenotype', 'HP:0030358', (181, 186))	('NSCLC', 'Disease', (181, 186))
63605	32466572	Currently, targeted therapies, including those based on the use of EGFR-tyrosine kinase inhibitors (TKIs), BRAF inhibitors, and ALK inhibitors, have demonstrated promising efficacy, with a 60-80% response rate and 9-30 months of progression-free survival in treating advanced NSCLC with relevant driver mutations.	('mutations', 'Var', (303, 312))	('BRAF', 'Gene', (107, 111))	('ALK', 'Gene', '238', (128, 131))	('NSCLC', 'Disease', (276, 281))	('tyrosine', 'Chemical', 'MESH:D014443', (72, 80))	('EGFR', 'Gene', (67, 71))	('NSCLC', 'Disease', 'MESH:D002289', (276, 281))	('EGFR', 'Gene', '1956', (67, 71))	('ALK', 'Gene', (128, 131))	('BRAF', 'Gene', '673', (107, 111))	('NSCLC', 'Phenotype', 'HP:0030358', (276, 281))
63616	32466572	Src is a non-receptor tyrosine kinase protein that consists of the SH1 (tyrosine kinase) SH2, SH3, and SH4 (unique) domains; the SH3-SH2 connector; the SH2-kinase linker; a C-terminal tail regulatory region; and two tyrosine sites (Tyr416 and Tyr527) (Figure 1A.).	('Tyr527', 'Var', (243, 249))	('SH4', 'CellLine', 'CVCL:1692', (103, 106))	('tyrosine', 'Chemical', 'MESH:D014443', (72, 80))	('Tyr416', 'Chemical', '-', (232, 238))	('tyrosine', 'Chemical', 'MESH:D014443', (22, 30))	('Tyr416', 'Var', (232, 238))	('tyrosine', 'Chemical', 'MESH:D014443', (216, 224))	('Tyr527', 'Chemical', '-', (243, 249))
63620	32466572	This conformation protects the catalytic pocket of Tyr 416 in the kinase domain (SH1) from inappropriate phosphorylation.	('SH1', 'Gene', (81, 84))	('Tyr 416', 'Var', (51, 58))	('Tyr', 'Chemical', 'MESH:D014443', (51, 54))	('catalytic pocket', 'MPA', (31, 47))
63621	32466572	The dephosphorylation of Ty527 causes a conformational change that unlocks the catalytic pocket of Tyr 416 and leads to subsequent activation of Src by the intramolecular autophosphorylation of Tyr416 (Figure 1B).	('activation', 'PosReg', (131, 141))	('conformational change', 'MPA', (40, 61))	('Tyr416', 'Chemical', '-', (194, 200))	('unlocks', 'PosReg', (67, 74))	('catalytic pocket of', 'MPA', (79, 98))	('Tyr416', 'Var', (194, 200))	('Tyr', 'Chemical', 'MESH:D014443', (194, 197))	('Ty527', 'Chemical', '-', (25, 30))	('Ty527', 'Var', (25, 30))	('Tyr', 'Chemical', 'MESH:D014443', (99, 102))	('dephosphorylation', 'Var', (4, 21))	('Src', 'MPA', (145, 148))
63626	32466572	EGFR kinase domain mutations, such as L858R and exon 19 deletion, are the most frequent oncogenic-driven mutations in human NSCLC (5-15% in Caucasians and 40-55% in East Asians), and EGFR-tyrosine kinase inhibitors (TKIs) have been developed as an effective therapy for advanced EGFR-mutated NSCLC.	('deletion', 'Var', (56, 64))	('EGFR', 'Gene', '1956', (279, 283))	('EGFR', 'Gene', (0, 4))	('EGFR', 'Gene', (279, 283))	('exon 19', 'Gene', (48, 55))	('NSCLC', 'Disease', (292, 297))	('EGFR', 'Gene', (183, 187))	('L858R', 'Var', (38, 43))	('EGFR', 'Gene', '1956', (183, 187))	('NSCLC', 'Disease', (124, 129))	('L858R', 'Mutation', 'rs121434568', (38, 43))	('NSCLC', 'Disease', 'MESH:D002289', (292, 297))	('NSCLC', 'Disease', 'MESH:D002289', (124, 129))	('tyrosine', 'Chemical', 'MESH:D014443', (188, 196))	('human', 'Species', '9606', (118, 123))	('NSCLC', 'Phenotype', 'HP:0030358', (292, 297))	('EGFR', 'Gene', '1956', (0, 4))	('NSCLC', 'Phenotype', 'HP:0030358', (124, 129))
63627	32466572	EGFR kinase domain mutations activate downstream signaling pathways, including the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK), phosphatidylinositol 3-kinase (PI3K)/Akt/mTOR, and interleukin 6 (IL-6)/Janus kinase (JAK)/signal transducer, and the activator of transcription 3 (STAT3) signaling pathways.	('STAT3', 'Gene', (316, 321))	('Akt', 'Gene', '207', (205, 208))	('EGFR', 'Gene', (0, 4))	('interleukin 6', 'Gene', '3569', (219, 232))	('ERK', 'Gene', (162, 165))	('Akt', 'Gene', (205, 208))	('interleukin 6', 'Gene', (219, 232))	('mutations', 'Var', (19, 28))	('phosphatidylinositol 3-kinase', 'Gene', '5293', (168, 197))	('IL-6', 'Gene', (234, 238))	('mTOR', 'Gene', (209, 213))	('STAT3', 'Gene', '6774', (316, 321))	('phosphatidylinositol 3-kinase', 'Gene', (168, 197))	('activate', 'PosReg', (29, 37))	('mTOR', 'Gene', '2475', (209, 213))	('EGFR', 'Gene', '1956', (0, 4))	('IL-6', 'Gene', '3569', (234, 238))	('ERK', 'Gene', '5594', (162, 165))
63629	32466572	A recent study found that the Src family kinase YES1 (v-YES-1 Yamaguchi sarcoma viral oncogene homolog 1) was amplified in NSCLC patients harboring EGFR mutations or echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) fusion who had acquired resistance to EGFR or ALK inhibitors.	('sarcoma', 'Phenotype', 'HP:0100242', (72, 79))	('mutations', 'Var', (153, 162))	('v-YES-1 Yamaguchi sarcoma viral oncogene homolog 1', 'Gene', (54, 104))	('EGFR', 'Gene', '1956', (293, 297))	('ALK', 'Gene', '238', (250, 253))	('lymphoma', 'Phenotype', 'HP:0002665', (233, 241))	('v-YES-1 Yamaguchi sarcoma viral oncogene homolog 1', 'Gene', '7525', (54, 104))	('ALK', 'Gene', (250, 253))	('EGFR', 'Gene', '1956', (148, 152))	('anaplastic lymphoma', 'Disease', 'MESH:D017728', (222, 241))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (222, 241))	('EML4', 'Gene', (216, 220))	('patients', 'Species', '9606', (129, 137))	('NSCLC', 'Disease', 'MESH:D002289', (123, 128))	('EGFR', 'Gene', (293, 297))	('EML4', 'Gene', '27436', (216, 220))	('ALK', 'Gene', '238', (301, 304))	('echinoderm microtubule-associated protein-like 4', 'Gene', '27436', (166, 214))	('ALK', 'Gene', (301, 304))	('NSCLC', 'Disease', (123, 128))	('anaplastic lymphoma', 'Disease', (222, 241))	('EGFR', 'Gene', (148, 152))	('NSCLC', 'Phenotype', 'HP:0030358', (123, 128))	('echinoderm microtubule-associated protein-like 4', 'Gene', (166, 214))
63630	32466572	Therefore, the amplification of the Src family kinase YES1 was identified as a mechanism for acquired resistance to EGFR and ALK inhibitors.	('amplification', 'Var', (15, 28))	('ALK', 'Gene', '238', (125, 128))	('resistance', 'MPA', (102, 112))	('EGFR', 'Gene', '1956', (116, 120))	('EGFR', 'Gene', (116, 120))	('ALK', 'Gene', (125, 128))	('Src family kinase YES1', 'Enzyme', (36, 58))
63631	32466572	In a study by Fan et al., it was demonstrated that the forced overexpression of YES1 promotes resistance to EGFR-TKIs in the human NSCLC cell line PC9, and the inhibition of Src re-enhances the cytotoxicity of EGFR-TKIs.	('resistance', 'MPA', (94, 104))	('EGFR', 'Gene', (210, 214))	('cytotoxicity', 'Disease', 'MESH:D064420', (194, 206))	('PC9', 'Gene', '255738', (147, 150))	('EGFR', 'Gene', '1956', (108, 112))	('YES1', 'Gene', (80, 84))	('promotes', 'PosReg', (85, 93))	('NSCLC', 'Disease', 'MESH:D002289', (131, 136))	('EGFR', 'Gene', '1956', (210, 214))	('inhibition', 'Var', (160, 170))	('PC9', 'Gene', (147, 150))	('NSCLC', 'Disease', (131, 136))	('human', 'Species', '9606', (125, 130))	('NSCLC', 'Phenotype', 'HP:0030358', (131, 136))	('Src', 'Protein', (174, 177))	('EGFR', 'Gene', (108, 112))	('re-enhances', 'PosReg', (178, 189))	('overexpression', 'PosReg', (62, 76))	('cytotoxicity', 'Disease', (194, 206))
63632	32466572	Two previous studies also demonstrated that inhibiting Src family kinase enhances the antitumor effect of EGFR-TKIs on EGFR-mutated NSCLC cells.	('NSCLC', 'Phenotype', 'HP:0030358', (132, 137))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('NSCLC', 'Disease', (132, 137))	('Src family kinase', 'Enzyme', (55, 72))	('EGFR', 'Gene', '1956', (119, 123))	('EGFR', 'Gene', '1956', (106, 110))	('NSCLC', 'Disease', 'MESH:D002289', (132, 137))	('EGFR', 'Gene', (106, 110))	('EGFR', 'Gene', (119, 123))	('inhibiting', 'Var', (44, 54))	('enhances', 'PosReg', (73, 81))
63642	32466572	The gene amplification of YES1 (one of the Src family kinases) has been found to partly impact the clinical prognosis of stage I or II NSCLC in previous studies.	('gene amplification', 'Var', (4, 22))	('impact', 'Reg', (88, 94))	('NSCLC', 'Disease', (135, 140))	('NSCLC', 'Disease', 'MESH:D002289', (135, 140))	('YES1', 'Gene', (26, 30))	('NSCLC', 'Phenotype', 'HP:0030358', (135, 140))
63644	32466572	suggest that molecular alterations of YES1 could be used as a prognostic biomarker and therapeutic target in human NSCLC.	('human', 'Species', '9606', (109, 114))	('NSCLC', 'Disease', (115, 120))	('molecular alterations', 'Var', (13, 34))	('NSCLC', 'Disease', 'MESH:D002289', (115, 120))	('NSCLC', 'Phenotype', 'HP:0030358', (115, 120))	('YES1', 'Gene', (38, 42))
63645	32466572	First, they showed that NSCLC patients with high YES1 expression had significantly shorter overall survival times than those with low YES1 expression.	('NSCLC', 'Disease', (24, 29))	('overall', 'CPA', (91, 98))	('high', 'Var', (44, 48))	('NSCLC', 'Disease', 'MESH:D002289', (24, 29))	('shorter', 'NegReg', (83, 90))	('patients', 'Species', '9606', (30, 38))	('NSCLC', 'Phenotype', 'HP:0030358', (24, 29))	('YES1', 'Gene', (49, 53))
63646	32466572	Second, YES1 overexpression significantly increased NSCLC cell proliferation in vitro and induced metastatic spread in preclinical mouse models.	('increased', 'PosReg', (42, 51))	('NSCLC', 'Disease', (52, 57))	('mouse', 'Species', '10090', (131, 136))	('YES1', 'Gene', (8, 12))	('NSCLC', 'Disease', 'MESH:D002289', (52, 57))	('metastatic spread', 'CPA', (98, 115))	('induced', 'Reg', (90, 97))	('NSCLC', 'Phenotype', 'HP:0030358', (52, 57))	('overexpression', 'Var', (13, 27))
63647	32466572	Third, the knockdown of the YES1 gene decreased NSCLC cell proliferation, invasion ability, and tumor growth in vivo.	('YES1', 'Gene', (28, 32))	('decreased', 'NegReg', (38, 47))	('NSCLC', 'Disease', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('NSCLC', 'Disease', 'MESH:D002289', (48, 53))	('tumor', 'Disease', (96, 101))	('NSCLC', 'Phenotype', 'HP:0030358', (48, 53))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('invasion ability', 'CPA', (74, 90))	('knockdown', 'Var', (11, 20))
63650	32466572	Furthermore, dasatinib treatment was found to significantly inhibit tumor growth in a patient-derived xenograft (PDX) model with high YES1 expression.	('tumor', 'Disease', (68, 73))	('high', 'Var', (129, 133))	('inhibit', 'NegReg', (60, 67))	('dasatinib', 'Chemical', 'MESH:D000069439', (13, 22))	('patient', 'Species', '9606', (86, 93))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('YES1', 'Gene', (134, 138))
63652	32466572	The study suggests that selected advanced NSCLC patients with high YES1 expression or genetic amplification may benefit from dasatinib treatment.	('NSCLC', 'Disease', (42, 47))	('genetic amplification', 'Var', (86, 107))	('NSCLC', 'Disease', 'MESH:D002289', (42, 47))	('expression', 'MPA', (72, 82))	('dasatinib', 'Chemical', 'MESH:D000069439', (125, 134))	('patients', 'Species', '9606', (48, 56))	('YES1', 'Gene', (67, 71))	('NSCLC', 'Phenotype', 'HP:0030358', (42, 47))	('high', 'Var', (62, 66))	('benefit', 'PosReg', (112, 119))
63654	32466572	Deregulation of the Hippo pathway and hyperactivation of YAP are frequently found in a diverse range of cancers, and the Hippo/YAP pathway has been suggested to be involved in cancer initiation and progression.	('Deregulation', 'Var', (0, 12))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('involved', 'Reg', (164, 172))	('Hippo pathway', 'Pathway', (20, 33))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('cancer', 'Disease', (176, 182))	('cancers', 'Phenotype', 'HP:0002664', (104, 111))	('YAP', 'Gene', (57, 60))	('hyperactivation', 'Var', (38, 53))	('cancer', 'Disease', (104, 110))	('cancers', 'Disease', (104, 111))	('cancers', 'Disease', 'MESH:D009369', (104, 111))
63656	32466572	Usually, activation of the Hippo pathway leads to tumor suppression, and Hippo kinase sequesters and degrades YAP in the cytoplasm.	('Hippo kinase', 'Var', (73, 85))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('YAP in the cytoplasm', 'MPA', (110, 130))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('Hippo pathway', 'Pathway', (27, 40))	('tumor', 'Disease', (50, 55))	('sequesters', 'MPA', (86, 96))	('degrades', 'NegReg', (101, 109))
63657	32466572	Conversely, when the Hippo pathway is deregulated, there is an increase in the translocation of cytoplasmic YAP into the nucleus to form complexes with transcriptional enhancer factors (TEFs; also known as TEAD).	('increase', 'PosReg', (63, 71))	('complexes', 'Interaction', (137, 146))	('TEFs', 'Disease', (186, 190))	('deregulated', 'Var', (38, 49))	('translocation', 'MPA', (79, 92))	('TEFs', 'Disease', 'MESH:C531835', (186, 190))	('Hippo pathway', 'Pathway', (21, 34))
63659	32466572	The loss of the Hippo pathway through mutation and/or the downregulation of core Hippo components has been found in various cancers and results in elevated levels of nuclear-localized YAP.	('Hippo pathway', 'Pathway', (16, 29))	('levels', 'MPA', (156, 162))	('nuclear-localized YAP', 'MPA', (166, 187))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('downregulation', 'NegReg', (58, 72))	('elevated', 'PosReg', (147, 155))	('mutation', 'Var', (38, 46))	('cancers', 'Phenotype', 'HP:0002664', (124, 131))	('loss', 'NegReg', (4, 8))	('cancers', 'Disease', (124, 131))	('cancers', 'Disease', 'MESH:D009369', (124, 131))
63665	32466572	The K-ras mutation is oncogenic and frequently occurs in NSCLC patients (15-30%), and there is still no approved effective targeted therapy for the clinical treatment of advanced NSCLC caused by K-ras mutations.	('NSCLC', 'Disease', 'MESH:D002289', (179, 184))	('occurs', 'Reg', (47, 53))	('K-ras', 'Gene', '3845', (195, 200))	('NSCLC', 'Phenotype', 'HP:0030358', (57, 62))	('mutation', 'Var', (10, 18))	('NSCLC', 'Phenotype', 'HP:0030358', (179, 184))	('patients', 'Species', '9606', (63, 71))	('K-ras', 'Gene', (195, 200))	('NSCLC', 'Disease', (57, 62))	('K-ras', 'Gene', (4, 9))	('K-ras', 'Gene', '3845', (4, 9))	('NSCLC', 'Disease', (179, 184))	('NSCLC', 'Disease', 'MESH:D002289', (57, 62))
63666	32466572	Currently, AMG 510 is the only drug with a potential antitumor effect on K-rasG12C-mutated metastatic NSCLC that has been investigated in a phase I clinical trial (NCT03600883).	('NSCLC', 'Disease', 'MESH:D002289', (102, 107))	('AMG 510', 'Chemical', '-', (11, 18))	('NSCLC', 'Disease', (102, 107))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('NSCLC', 'Phenotype', 'HP:0030358', (102, 107))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Disease', (57, 62))	('K-rasG12C', 'Chemical', '-', (73, 82))	('K-rasG12C-mutated', 'Var', (73, 90))
63668	32466572	This study demonstrated that inhibiting or knocking down K-ras has no suppression effect on the proliferation, migration, and invasive abilities of these K-ras-independent cells.	('migration', 'CPA', (111, 120))	('invasive abilities', 'CPA', (126, 144))	('K-ras', 'Gene', (154, 159))	('knocking down', 'Var', (43, 56))	('K-ras', 'Gene', (57, 62))	('inhibiting', 'Var', (29, 39))	('K-ras', 'Gene', '3845', (57, 62))	('K-ras', 'Gene', '3845', (154, 159))
63670	32466572	The YAP gene was found to be amplified in the relapsed NSCLC cells without the re-expression of K-ras, and inhibiting YAP suppressed cancer cell growth both in vitro and in vivo.	('K-ras', 'Gene', (96, 101))	('K-ras', 'Gene', '3845', (96, 101))	('YAP', 'Gene', (4, 7))	('NSCLC', 'Disease', (55, 60))	('suppressed', 'NegReg', (122, 132))	('inhibiting', 'Var', (107, 117))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('NSCLC', 'Disease', 'MESH:D002289', (55, 60))	('cancer', 'Disease', (133, 139))	('YAP', 'Gene', (118, 121))	('NSCLC', 'Phenotype', 'HP:0030358', (55, 60))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
63676	32466572	showed that, in human NSCLC cells, the inhibition of ERK1/2 decreases YAP protein expression by accelerating protein degradation.	('decreases', 'NegReg', (60, 69))	('inhibition', 'Var', (39, 49))	('NSCLC', 'Disease', 'MESH:D002289', (22, 27))	('NSCLC', 'Phenotype', 'HP:0030358', (22, 27))	('accelerating', 'PosReg', (96, 108))	('ERK1/2', 'Gene', (53, 59))	('ERK1/2', 'Gene', '5595;5594', (53, 59))	('NSCLC', 'Disease', (22, 27))	('human', 'Species', '9606', (16, 21))	('protein degradation', 'MPA', (109, 128))	('YAP protein', 'Protein', (70, 81))
63678	32466572	In addition, several studies found that the activation of YAP increases the downstream gene expression of EGFR ligands such as amphiregulin (AREG) and neuregulin 1 (NRG-1), as well as connective tissue growth factor (CTGF) and cysteine-rich angiogenic inducer 61 (CYR61), forming an autocrine loop to reinforce the MAPK signaling pathway in order to induce drug resistance and cancer metastasis.	('AREG', 'Gene', (141, 145))	('activation', 'Var', (44, 54))	('cancer', 'Phenotype', 'HP:0002664', (377, 383))	('amphiregulin', 'Gene', '374', (127, 139))	('cysteine-rich angiogenic inducer 61', 'Gene', (227, 262))	('neuregulin 1', 'Gene', (151, 163))	('NRG-1', 'Gene', '3084', (165, 170))	('MAPK signaling pathway', 'Pathway', (315, 337))	('neuregulin 1', 'Gene', '3084', (151, 163))	('EGFR', 'Gene', (106, 110))	('CTGF', 'Gene', '1490', (217, 221))	('induce', 'PosReg', (350, 356))	('drug resistance', 'CPA', (357, 372))	('connective tissue growth factor', 'Gene', '1490', (184, 215))	('connective tissue growth factor', 'Gene', (184, 215))	('cancer', 'Disease', 'MESH:D009369', (377, 383))	('NRG-1', 'Gene', (165, 170))	('YAP', 'Gene', (58, 61))	('CTGF', 'Gene', (217, 221))	('CYR61', 'Gene', '3491', (264, 269))	('AREG', 'Gene', '374', (141, 145))	('EGFR', 'Gene', '1956', (106, 110))	('amphiregulin', 'Gene', (127, 139))	('increases', 'PosReg', (62, 71))	('drug resistance', 'Phenotype', 'HP:0020174', (357, 372))	('cysteine-rich angiogenic inducer 61', 'Gene', '3491', (227, 262))	('cancer', 'Disease', (377, 383))	('CYR61', 'Gene', (264, 269))
63680	32466572	In one clinical study, the overexpression of YAP in NSCLC with a BRAF V600E mutation led to a worse initial response to BRAF and MEK inhibitors.	('V600E', 'Var', (70, 75))	('NSCLC', 'Phenotype', 'HP:0030358', (52, 57))	('NSCLC', 'Disease', (52, 57))	('BRAF', 'Gene', '673', (120, 124))	('NSCLC', 'Disease', 'MESH:D002289', (52, 57))	('BRAF', 'Gene', (120, 124))	('BRAF', 'Gene', '673', (65, 69))	('V600E', 'Mutation', 'rs113488022', (70, 75))	('overexpression', 'PosReg', (27, 41))	('BRAF', 'Gene', (65, 69))	('MEK', 'Gene', (129, 132))	('MEK', 'Gene', '5609', (129, 132))
63681	32466572	One study showed that the inhibition of YAP synergizes the cytotoxicity of BRAF and MEK inhibitors to NSCLC cells containing BRAF and K-ras mutations.	('NSCLC', 'Disease', 'MESH:D002289', (102, 107))	('cytotoxicity of BRAF', 'Disease', (59, 79))	('cytotoxicity of BRAF', 'Disease', 'MESH:D064420', (59, 79))	('BRAF', 'Gene', '673', (75, 79))	('K-ras', 'Gene', '3845', (134, 139))	('NSCLC', 'Phenotype', 'HP:0030358', (102, 107))	('K-ras', 'Gene', (134, 139))	('BRAF', 'Gene', (75, 79))	('BRAF', 'Gene', '673', (125, 129))	('mutations', 'Var', (140, 149))	('NSCLC', 'Disease', (102, 107))	('MEK', 'Gene', (84, 87))	('BRAF', 'Gene', (125, 129))	('MEK', 'Gene', '5609', (84, 87))
63682	32466572	Another study showed that the forced overexpression of YAP promotes resistance to EGFR-TKI erlotinib in the NSCLC cell line HCC827 (EGFR exon 19 deletion), and inhibiting YAP enhances the cytotoxicity of erlotinib to the NSCLC cell line H1975 (L858R + T790M mutations).	('H1975', 'CellLine', 'CVCL:1511', (237, 242))	('NSCLC', 'Disease', (221, 226))	('T790M', 'Mutation', 'rs121434569', (252, 257))	('erlotinib', 'Chemical', 'MESH:D000069347', (91, 100))	('NSCLC', 'Phenotype', 'HP:0030358', (221, 226))	('EGFR', 'Gene', (82, 86))	('EGFR', 'Gene', '1956', (132, 136))	('enhances', 'PosReg', (175, 183))	('resistance', 'MPA', (68, 78))	('promotes', 'PosReg', (59, 67))	('NSCLC', 'Disease', 'MESH:D002289', (108, 113))	('YAP', 'Gene', (171, 174))	('cytotoxicity', 'Disease', (188, 200))	('NSCLC', 'Disease', (108, 113))	('cytotoxicity', 'Disease', 'MESH:D064420', (188, 200))	('EGFR', 'Gene', '1956', (82, 86))	('inhibiting', 'NegReg', (160, 170))	('NSCLC', 'Phenotype', 'HP:0030358', (108, 113))	('L858R + T790M mutations', 'Var', (244, 267))	('erlotinib', 'Chemical', 'MESH:D000069347', (204, 213))	('EGFR', 'Gene', (132, 136))	('NSCLC', 'Disease', 'MESH:D002289', (221, 226))	('L858R', 'Mutation', 'rs121434568', (244, 249))	('HCC827', 'CellLine', 'CVCL:2063', (124, 130))
63683	32466572	One previous study also found that high tumor expression of YAP in NSCLC patients with the ALK fusion mutation was correlated with a poor response to ALK inhibitors.	('ALK', 'Gene', (91, 94))	('ALK', 'Gene', (150, 153))	('mutation', 'Var', (102, 110))	('NSCLC', 'Phenotype', 'HP:0030358', (67, 72))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('ALK', 'Gene', '238', (91, 94))	('ALK', 'Gene', '238', (150, 153))	('NSCLC', 'Disease', 'MESH:D002289', (67, 72))	('NSCLC', 'Disease', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('patients', 'Species', '9606', (73, 81))	('YAP', 'Protein', (60, 63))
63684	32466572	The same study showed that inhibition of YAP re-enhanced the anti-tumor effect of ALK inhibitors in vitro and in vivo.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Disease', (66, 71))	('re-enhanced', 'PosReg', (45, 56))	('YAP', 'Protein', (41, 44))	('ALK', 'Gene', (82, 85))	('inhibition', 'Var', (27, 37))	('ALK', 'Gene', '238', (82, 85))	('tumor', 'Disease', 'MESH:D009369', (66, 71))
63685	32466572	The role of YAP in promoting NSCLC metastasis has been investigated in vivo, and the inhibition of YAP has shown promising efficacy in suppressing NSCLC metastasis in mouse models.	('NSCLC metastasis', 'Disease', (29, 45))	('NSCLC metastasis', 'Disease', 'MESH:D009362', (29, 45))	('NSCLC', 'Phenotype', 'HP:0030358', (29, 34))	('inhibition', 'Var', (85, 95))	('NSCLC metastasis', 'Disease', (147, 163))	('NSCLC metastasis', 'Disease', 'MESH:D009362', (147, 163))	('NSCLC', 'Phenotype', 'HP:0030358', (147, 152))	('YAP', 'Gene', (99, 102))	('mouse', 'Species', '10090', (167, 172))	('suppressing', 'NegReg', (135, 146))
63686	32466572	found that the tumor suppressor gene RASSF1A inhibits YAP through the GEF-H1/RhoB pathway, and they showed that RASSF1A depletion in a mouse model enhances the metastatic potential of the NSCLC cell line H1975.	('NSCLC', 'Disease', 'MESH:D002289', (188, 193))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('inhibits', 'NegReg', (45, 53))	('H1975', 'CellLine', 'CVCL:1511', (204, 209))	('GEF-H1', 'Gene', (70, 76))	('depletion', 'Var', (120, 129))	('YAP', 'MPA', (54, 57))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('mouse', 'Species', '10090', (135, 140))	('enhances', 'PosReg', (147, 155))	('NSCLC', 'Phenotype', 'HP:0030358', (188, 193))	('tumor', 'Disease', (15, 20))	('GEF-H1', 'Gene', '16800', (70, 76))	('RhoB', 'Gene', (77, 81))	('RhoB', 'Gene', '11852', (77, 81))	('RASSF1A', 'Gene', (112, 119))	('RASSF1A', 'Gene', (37, 44))	('NSCLC', 'Disease', (188, 193))
63688	32466572	This study also demonstrated that the genetic ablation of YAP by short hairpin RNA inhibits the brain metastatic ability of H2030-BrM3 cells in vivo.	('brain metastatic ability of H2030-BrM3 cells', 'CPA', (96, 140))	('inhibits', 'NegReg', (83, 91))	('genetic ablation', 'Var', (38, 54))	('H2030-BrM3', 'CellLine', 'CVCL:1517', (124, 134))	('short hairpin RNA', 'Gene', (65, 82))
63703	32466572	Previous studies have shown that signaling pathways, including MAPK, PI3K, Wnt, TGFbeta, Notch, and Hh, directly activate YAP to form a positive loop in part and partly activate YAP by repressing Hippo kinases.	('YAP', 'Gene', (122, 125))	('Notch', 'Gene', (89, 94))	('PI3K', 'Var', (69, 73))	('Hippo kinases', 'Enzyme', (196, 209))	('TGFbeta', 'Gene', '7039', (80, 87))	('YAP', 'MPA', (178, 181))	('repressing', 'NegReg', (185, 195))	('Notch', 'Gene', '4851', (89, 94))	('activate', 'PosReg', (113, 121))	('activate', 'PosReg', (169, 177))	('TGFbeta', 'Gene', (80, 87))
63704	32466572	Loss of function or mutations in Hippo kinases, including NF2 and LATS1/2, lead to the activation of YAP, and then YAP activation positively interacts with other signaling pathways to promote cancer progression.	('interacts', 'Reg', (141, 150))	('NF2', 'Gene', (58, 61))	('activation', 'PosReg', (87, 97))	('LATS1/2', 'Gene', '9113;26524', (66, 73))	('NF2', 'Gene', '4771', (58, 61))	('LATS1/2', 'Gene', (66, 73))	('Loss of function', 'NegReg', (0, 16))	('cancer', 'Disease', (192, 198))	('cancer', 'Disease', 'MESH:D009369', (192, 198))	('YAP', 'Protein', (101, 104))	('Hippo', 'Gene', (33, 38))	('mutations', 'Var', (20, 29))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('promote', 'PosReg', (184, 191))
63706	32466572	The loss of function mutations of RASSF1A or p53, contributes to increased YAP expression in cancers.	('p53', 'Gene', (45, 48))	('cancers', 'Disease', (93, 100))	('mutations', 'Var', (21, 30))	('increased', 'PosReg', (65, 74))	('p53', 'Gene', '7157', (45, 48))	('loss of function', 'NegReg', (4, 20))	('cancers', 'Phenotype', 'HP:0002664', (93, 100))	('RASSF1A', 'Gene', (34, 41))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('cancers', 'Disease', 'MESH:D009369', (93, 100))	('YAP', 'Protein', (75, 78))
63707	32466572	Two previous studies demonstrated that YAP-induced anti-apoptosis worsens the initial treatment response to BRAF and MEK inhibitors and EGFR-TKIs in NSCLC cells with K-ras, BRAF-V600E, or EGFR mutations.	('MEK', 'Gene', '5609', (117, 120))	('mutations', 'Var', (193, 202))	('EGFR', 'Gene', '1956', (188, 192))	('NSCLC', 'Disease', 'MESH:D002289', (149, 154))	('K-ras', 'Gene', '3845', (166, 171))	('NSCLC', 'Disease', (149, 154))	('MEK', 'Gene', (117, 120))	('V600E', 'Mutation', 'rs113488022', (178, 183))	('worsens', 'NegReg', (66, 73))	('BRAF', 'Gene', '673', (108, 112))	('BRAF', 'Gene', (108, 112))	('EGFR', 'Gene', (136, 140))	('NSCLC', 'Phenotype', 'HP:0030358', (149, 154))	('BRAF', 'Gene', '673', (173, 177))	('BRAF', 'Gene', (173, 177))	('EGFR', 'Gene', (188, 192))	('K-ras', 'Gene', (166, 171))	('anti-apoptosis', 'CPA', (51, 65))	('EGFR', 'Gene', '1956', (136, 140))
63708	32466572	The two studies showed that the inhibition of YAP by either genic or pharmacological ablation restores the cytotoxicity of BRAF and MEK inhibitors and EGFR-TKIs to NSCLC cells.	('NSCLC', 'Disease', (164, 169))	('restores', 'PosReg', (94, 102))	('EGFR', 'Gene', (151, 155))	('inhibition', 'NegReg', (32, 42))	('NSCLC', 'Disease', 'MESH:D002289', (164, 169))	('cytotoxicity of BRAF', 'Disease', (107, 127))	('cytotoxicity of BRAF', 'Disease', 'MESH:D064420', (107, 127))	('MEK', 'Gene', (132, 135))	('ablation', 'Var', (85, 93))	('NSCLC', 'Phenotype', 'HP:0030358', (164, 169))	('MEK', 'Gene', '5609', (132, 135))	('EGFR', 'Gene', '1956', (151, 155))
63714	32466572	This phosphorylation of YAP increases the stabilization and nuclear translocation of YAP, which activates downstream growth factor genes to promote tissue growth and regeneration during intestinal mucosal injury.	('intestinal mucosal injury', 'Disease', (186, 211))	('increases', 'PosReg', (28, 37))	('tissue growth', 'CPA', (148, 161))	('YAP', 'Gene', (24, 27))	('regeneration', 'CPA', (166, 178))	('phosphorylation', 'Var', (5, 20))	('promote', 'PosReg', (140, 147))	('stabilization', 'MPA', (42, 55))	('intestinal mucosal injury', 'Disease', 'MESH:D007410', (186, 211))	('nuclear translocation', 'MPA', (60, 81))	('YAP', 'Gene', (85, 88))	('activates', 'PosReg', (96, 105))
63720	32466572	In addition, they found that the inhibition of Rac reduces Src and YAP expression levels and attenuates the progression of renal fibrosis in this mouse model.	('inhibition', 'Var', (33, 43))	('renal fibrosis', 'Disease', 'MESH:D005355', (123, 137))	('renal fibrosis', 'Disease', (123, 137))	('renal fibrosis', 'Phenotype', 'HP:0030760', (123, 137))	('reduces', 'NegReg', (51, 58))	('attenuates', 'NegReg', (93, 103))	('mouse', 'Species', '10090', (146, 151))	('Rac', 'Gene', '11651', (47, 50))	('Rac', 'Gene', (47, 50))
63723	32466572	The interaction of the Src kinase family and YAP is crucial for the pathological activation of cancer-associated fibroblasts, and the accumulation of nuclear YAP increases the expression of the downstream genes required for pro-tumorigenic functions.	('accumulation', 'Var', (134, 146))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('tumor', 'Disease', 'MESH:D009369', (228, 233))	('increases', 'PosReg', (162, 171))	('cancer', 'Disease', (95, 101))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('expression', 'MPA', (176, 186))	('tumor', 'Disease', (228, 233))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('YAP', 'Gene', (158, 161))
63727	32466572	The Src kinase YES1 phosphorylates YAP at the site of tyrosine 357 (Y357) to activate YAP, and Y357 phosphorylation of YAP is required for Wnt/beta-catenin signaling to maintain survival and tumorigenesis in human colorectal cancer cells.	('activate', 'PosReg', (77, 85))	('beta-catenin', 'Gene', '1499', (143, 155))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('YAP', 'Gene', (86, 89))	('colorectal cancer', 'Disease', 'MESH:D015179', (214, 231))	('tyrosine', 'Chemical', 'MESH:D014443', (54, 62))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('tumor', 'Disease', (191, 196))	('colorectal cancer', 'Phenotype', 'HP:0003003', (214, 231))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('beta-catenin', 'Gene', (143, 155))	('human', 'Species', '9606', (208, 213))	('Y357', 'Var', (95, 99))	('colorectal cancer', 'Disease', (214, 231))
63728	32466572	The Y357 phosphorylation of YAP by YES1 induces the expression of the transcriptional genes BCL2L1 and BIRC5 downstream of YAP, and the small-molecule YES1 inhibitor has been found to suppress the proliferation of beta-catenin-dependent cancers in cell lines and in vivo experiments.	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('phosphorylation', 'Var', (9, 24))	('BCL2L1', 'Gene', (92, 98))	('YES1', 'Gene', (35, 39))	('suppress', 'NegReg', (184, 192))	('Y357 phosphorylation', 'Var', (4, 24))	('expression', 'MPA', (52, 62))	('beta-catenin', 'Gene', '1499', (214, 226))	('BCL2L1', 'Gene', '598', (92, 98))	('cancers', 'Phenotype', 'HP:0002664', (237, 244))	('cancers', 'Disease', (237, 244))	('beta-catenin', 'Gene', (214, 226))	('induces', 'PosReg', (40, 47))	('cancers', 'Disease', 'MESH:D009369', (237, 244))	('proliferation', 'CPA', (197, 210))	('BIRC5', 'Gene', (103, 108))	('BIRC5', 'Gene', '332', (103, 108))
63731	32466572	Another study showed that PDGFR upregulates YAP transcriptional activity via Y357 phosphorylation mediated by Src kinases in cholangiocarcinoma.	('Src kinases', 'MPA', (110, 121))	('cholangiocarcinoma', 'Disease', (125, 143))	('upregulates', 'PosReg', (32, 43))	('PDGFR', 'Gene', (26, 31))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('PDGFR', 'Gene', '5159', (26, 31))	('YAP', 'Gene', (44, 47))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (125, 143))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (125, 143))	('Y357', 'Var', (77, 81))
63743	32466572	In a previous study conducted by Fan et al., acquired YES1 amplification was detected in five EGFR mutant NSCLC patients (three had the L858R mutation and two had the exon 19 deletion mutation) who were pre-treated with the EGFR-TKIs erlotinib or afatinib and had acquired resistance to EGFR-TKIs.	('NSCLC', 'Disease', 'MESH:D002289', (106, 111))	('L858R', 'Var', (136, 141))	('afatinib', 'Chemical', 'MESH:D000077716', (247, 255))	('EGFR', 'Gene', '1956', (94, 98))	('EGFR', 'Gene', (224, 228))	('L858R', 'Mutation', 'rs121434568', (136, 141))	('patients', 'Species', '9606', (112, 120))	('EGFR', 'Gene', (94, 98))	('YES1', 'Gene', (54, 58))	('NSCLC', 'Phenotype', 'HP:0030358', (106, 111))	('detected', 'Reg', (77, 85))	('EGFR', 'Gene', '1956', (287, 291))	('EGFR', 'Gene', (287, 291))	('mutant', 'Var', (99, 105))	('erlotinib', 'Chemical', 'MESH:D000069347', (234, 243))	('NSCLC', 'Disease', (106, 111))	('EGFR', 'Gene', '1956', (224, 228))
63744	32466572	found that EGFR mutant lung cancer cells survive initial EGFR-TKI therapy through the co-activation of STAT3 and Src-YAP signaling.	('lung cancer', 'Disease', (23, 34))	('lung cancer', 'Phenotype', 'HP:0100526', (23, 34))	('STAT3', 'Gene', (103, 108))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('EGFR', 'Gene', '1956', (11, 15))	('EGFR', 'Gene', (11, 15))	('EGFR', 'Gene', '1956', (57, 61))	('mutant', 'Var', (16, 22))	('lung cancer', 'Disease', 'MESH:D008175', (23, 34))	('STAT3', 'Gene', '6774', (103, 108))	('EGFR', 'Gene', (57, 61))	('co-activation', 'PosReg', (86, 99))	('Src-YAP signaling', 'MPA', (113, 130))
63745	32466572	In a cohort analysis of 64 EGFR mutant NSCLC patients (62 had common mutations L858R and exon 19 deletion; the other two had the uncommon mutations L861Q and G719X) treated with first-line EGFR-TKIs, patients with a high level of expression of STAT3 or YAP1 had a worse progression-free survival following EGFR-TKI therapy.	('EGFR', 'Gene', (27, 31))	('L858R', 'Var', (79, 84))	('EGFR', 'Gene', (306, 310))	('patients', 'Species', '9606', (45, 53))	('NSCLC', 'Disease', (39, 44))	('YAP1', 'Gene', '10413', (253, 257))	('STAT3', 'Gene', (244, 249))	('L861Q', 'Mutation', 'rs121913444', (148, 153))	('EGFR', 'Gene', '1956', (189, 193))	('NSCLC', 'Phenotype', 'HP:0030358', (39, 44))	('G719X', 'Mutation', 'p.G719X', (158, 163))	('L861Q', 'Var', (148, 153))	('G719X', 'Var', (158, 163))	('mutant', 'Var', (32, 38))	('STAT3', 'Gene', '6774', (244, 249))	('YAP1', 'Gene', (253, 257))	('EGFR', 'Gene', '1956', (27, 31))	('EGFR', 'Gene', '1956', (306, 310))	('L858R', 'Mutation', 'rs121434568', (79, 84))	('patients', 'Species', '9606', (200, 208))	('EGFR', 'Gene', (189, 193))	('mutations L858R', 'Var', (69, 84))	('NSCLC', 'Disease', 'MESH:D002289', (39, 44))
63747	32466572	Taken together, Src-YAP signaling appears to give primary and acquired resistance to EGFR-TKIs in NSCLC patients with sensitive EGFR mutations (L858R and exon 19 deletions).	('EGFR', 'Gene', (85, 89))	('L858R', 'Var', (144, 149))	('EGFR', 'Gene', '1956', (128, 132))	('NSCLC', 'Phenotype', 'HP:0030358', (98, 103))	('EGFR', 'Gene', (128, 132))	('L858R', 'Mutation', 'rs121434568', (144, 149))	('exon 19 deletions', 'Var', (154, 171))	('NSCLC', 'Disease', (98, 103))	('EGFR', 'Gene', '1956', (85, 89))	('patients', 'Species', '9606', (104, 112))	('NSCLC', 'Disease', 'MESH:D002289', (98, 103))
63748	32466572	The other study demonstrated that the combination of the Src family kinase inhibitor dasatinib and the MEK inhibitor trametinib decreased YAP protein expression in K-ras mutant NSCLC cells.	('dasatinib', 'Chemical', 'MESH:D000069439', (85, 94))	('NSCLC', 'Phenotype', 'HP:0030358', (177, 182))	('MEK', 'Gene', (103, 106))	('MEK', 'Gene', '5609', (103, 106))	('trametinib', 'Chemical', 'MESH:C560077', (117, 127))	('decreased', 'NegReg', (128, 137))	('NSCLC', 'Disease', (177, 182))	('mutant', 'Var', (170, 176))	('NSCLC', 'Disease', 'MESH:D002289', (177, 182))	('K-ras', 'Gene', (164, 169))	('K-ras', 'Gene', '3845', (164, 169))	('YAP protein', 'Protein', (138, 149))
63760	32466572	In a recent preclinical study, dasatinib has demonstrated to have an antitumor effect in NSCLC PDX models with high YES1 expression.	('NSCLC', 'Disease', 'MESH:D002289', (89, 94))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('NSCLC', 'Phenotype', 'HP:0030358', (89, 94))	('tumor', 'Disease', (73, 78))	('dasatinib', 'Chemical', 'MESH:D000069439', (31, 40))	('YES1', 'Gene', (116, 120))	('NSCLC', 'Disease', (89, 94))	('high', 'Var', (111, 115))
63761	32466572	The findings of this study suggested that dasatinib is a therapy that could potentially benefit selected NSCLC patients with high YES1 expression or genetic amplification.	('NSCLC', 'Disease', 'MESH:D002289', (105, 110))	('NSCLC', 'Phenotype', 'HP:0030358', (105, 110))	('genetic amplification', 'Var', (149, 170))	('dasatinib', 'Chemical', 'MESH:D000069439', (42, 51))	('YES1', 'Gene', (130, 134))	('NSCLC', 'Disease', (105, 110))	('high', 'Var', (125, 129))	('patients', 'Species', '9606', (111, 119))
63763	32466572	Therefore, the combination of dasatinib and targeted therapies in NSCLC patients with known targetable driver mutations may delay the occurrence of acquired resistance and even overcome acquired resistance in molecularly selected patients.	('acquired resistance', 'MPA', (148, 167))	('mutations', 'Var', (110, 119))	('dasatinib', 'Chemical', 'MESH:D000069439', (30, 39))	('NSCLC', 'Disease', (66, 71))	('acquired resistance', 'MPA', (186, 205))	('occurrence', 'MPA', (134, 144))	('NSCLC', 'Disease', 'MESH:D002289', (66, 71))	('patients', 'Species', '9606', (230, 238))	('delay', 'NegReg', (124, 129))	('NSCLC', 'Phenotype', 'HP:0030358', (66, 71))	('patients', 'Species', '9606', (72, 80))
63771	32466572	In BRAF mutant NSCLC, dual therapy (trametinib + dabrafenib) has a higher response rate (~60%) than single therapy with dabrafenib or vemurafenib alone (30-40% response rate).	('NSCLC', 'Disease', 'MESH:D002289', (15, 20))	('dabrafenib', 'Chemical', 'MESH:C561627', (49, 59))	('trametinib', 'Chemical', 'MESH:C560077', (36, 46))	('NSCLC', 'Phenotype', 'HP:0030358', (15, 20))	('mutant', 'Var', (8, 14))	('dabrafenib', 'Chemical', 'MESH:C561627', (120, 130))	('BRAF', 'Gene', '673', (3, 7))	('NSCLC', 'Disease', (15, 20))	('BRAF', 'Gene', (3, 7))	('vemurafenib', 'Chemical', 'MESH:D000077484', (134, 145))
63778	32466572	A recent study showed that the reactivation of YAP promotes survival and dormancy in EGFR mutant NSCLC cells, while EGFR downstream signaling is suppressed by EGFR and MEK inhibitors.	('survival', 'CPA', (60, 68))	('EGFR', 'Gene', (85, 89))	('MEK', 'Gene', (168, 171))	('MEK', 'Gene', '5609', (168, 171))	('NSCLC', 'Disease', (97, 102))	('EGFR', 'Gene', '1956', (159, 163))	('mutant', 'Var', (90, 96))	('dormancy', 'CPA', (73, 81))	('EGFR', 'Gene', (159, 163))	('promotes', 'PosReg', (51, 59))	('NSCLC', 'Disease', 'MESH:D002289', (97, 102))	('EGFR', 'Gene', '1956', (85, 89))	('EGFR', 'Gene', '1956', (116, 120))	('NSCLC', 'Phenotype', 'HP:0030358', (97, 102))	('EGFR', 'Gene', (116, 120))
63782	32466572	CDK1 has been shown to phosphorylate YAP at sites T119 and S289 during the G2/M phase of the cell cycle, promoting cell migration and invasion in cancer cells.	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('S289', 'Var', (59, 63))	('cell migration', 'CPA', (115, 129))	('CDK1', 'Gene', (0, 4))	('CDK1', 'Gene', '983', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('promoting', 'PosReg', (105, 114))
63784	32466572	Another study demonstrated that the inhibition of CDK7 attenuates the YAP protein expression level through cytoplasmic retention and degradation.	('CDK7', 'Gene', (50, 54))	('inhibition', 'Var', (36, 46))	('attenuates', 'NegReg', (55, 65))	('CDK7', 'Gene', '1022', (50, 54))	('degradation', 'MPA', (133, 144))	('cytoplasmic retention', 'CPA', (107, 128))	('YAP protein expression level', 'MPA', (70, 98))
63790	32466572	recently developed a highly selective CDK9 inhibitor, MC180295, and showed that MC180295 not only has an anticancer effect but that it is also an effective anti-PD-1 immune checkpoint inhibitor, as demonstrated through both in vitro and in vivo experiments.	('MC180295', 'Var', (80, 88))	('MC180295', 'Chemical', '-', (80, 88))	('MC180295', 'Chemical', '-', (54, 62))	('PD-1', 'Gene', (161, 165))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('PD-1', 'Gene', '5133', (161, 165))	('cancer', 'Disease', (109, 115))	('CDK9', 'Gene', (38, 42))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('CDK9', 'Gene', '1025', (38, 42))
63794	32466572	The inhibition of multiple points of the Src-YAP axis is suggested to be a potential therapeutic strategy for advanced NSCLC, based on the findings of previous studies.	('inhibition', 'Var', (4, 14))	('NSCLC', 'Disease', (119, 124))	('NSCLC', 'Phenotype', 'HP:0030358', (119, 124))	('NSCLC', 'Disease', 'MESH:D002289', (119, 124))
63849	31392181	In rest of the four cases, IHC showed positivity for CK5/6, p63, TTF-1, napsin A, and CK7 in different cell populations.	('CK7', 'Gene', '3855', (86, 89))	('TTF-1', 'Gene', (65, 70))	('CK5/6', 'Gene', '3852', (53, 58))	('p63', 'Gene', '8626', (60, 63))	('positivity', 'Var', (38, 48))	('napsin A', 'Gene', (72, 80))	('napsin A', 'Gene', '9476', (72, 80))	('CK5/6', 'Gene', (53, 58))	('TTF-1', 'Gene', '7080', (65, 70))	('CK7', 'Gene', (86, 89))	('p63', 'Gene', (60, 63))
63885	31392181	found CK5/6 positivity in 56% of adenocarcinomas, while Pelosi et al.	('adenocarcinomas', 'Disease', (33, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (38, 47))	('adenocarcinomas', 'Disease', 'MESH:D000230', (33, 48))	('CK5/6', 'Gene', '3852', (6, 11))	('positivity', 'Var', (12, 22))	('CK5/6', 'Gene', (6, 11))	('carcinomas', 'Phenotype', 'HP:0030731', (38, 48))
63893	31392181	The third case showed positivity for CK7, CK20, and CDX2 whereas being negative for TTF-1.	('CK7', 'Gene', '3855', (37, 40))	('CDX2', 'Gene', '1045', (52, 56))	('CK20', 'Gene', (42, 46))	('CK20', 'Gene', '54474', (42, 46))	('CK7', 'Gene', (37, 40))	('TTF-1', 'Gene', '7080', (84, 89))	('TTF-1', 'Gene', (84, 89))	('CDX2', 'Gene', (52, 56))	('positivity', 'Var', (22, 32))
63956	29156844	The AUCs were 0.834 (95% confidence interval (CI):0.781-0.887), 0.804 (95% CI:0.746-0.863), 0.823 (95% CI:0.767-0.879) respectively (Supplementary Figure 2).	('men', 'Species', '9606', (139, 142))	('0.804', 'Var', (64, 69))	('0.823', 'Var', (92, 97))
63958	29156844	Meanwhile, the diagnostic performance of the three-miRNA panel was also assessed in the training, testing and external validation stages separately and the AUCs were 0.969 (95% CI: 0.924-1.000; Figure 3b), 0.881 (95% CI: 0.810-0.953; Figure 3c) and 0.954 (95% CI: 0.910-0.998; Figure 3d) respectively.	('miR', 'Gene', '220972', (51, 54))	('miR', 'Gene', (51, 54))	('0.881', 'Var', (206, 211))
64001	29156844	Meanwhile, it is able to inactivate ZNRF3, leading to the activation of Wnt signaling, which promote cell proliferation and progression in lung cancer cell lines.	('lung cancer', 'Disease', (139, 150))	('lung cancer', 'Phenotype', 'HP:0100526', (139, 150))	('ZNRF3', 'Gene', '84133', (36, 41))	('promote', 'PosReg', (93, 100))	('ZNRF3', 'Gene', (36, 41))	('lung cancer', 'Disease', 'MESH:D008175', (139, 150))	('inactivate', 'Var', (25, 35))	('Wnt signaling', 'Pathway', (72, 85))	('progression', 'CPA', (124, 135))	('activation', 'PosReg', (58, 68))	('cell proliferation', 'CPA', (101, 119))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
64053	27552093	Morphologic Accuracy in Differentiating Primary Lung Adenocarcinoma From Squamous Cell Carcinoma in Cytology Specimens The National Cancer Care Network and the combined College of American Pathologists/International Association for the Study of Lung Cancer/Association for Molecular Pathology guidelines indicate that all lung adenocarcinomas (ADCs) should be tested for epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) rearrangements.	('Primary Lung Adenocarcinoma', 'Disease', 'MESH:D000077192', (40, 67))	('Cancer', 'Phenotype', 'HP:0002664', (250, 256))	('anaplastic lymphoma kinase', 'Gene', '238', (425, 451))	('anaplastic lymphoma kinase', 'Gene', (425, 451))	('Lung Cancer', 'Disease', 'MESH:D008175', (245, 256))	('Squamous Cell Carcinoma', 'Disease', 'MESH:D002294', (73, 96))	('Cancer', 'Disease', (132, 138))	('Cancer', 'Disease', (250, 256))	('epidermal growth factor receptor', 'Gene', (371, 403))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (73, 96))	('Lung Cancer', 'Phenotype', 'HP:0100526', (245, 256))	('epidermal growth factor receptor', 'Gene', '1956', (371, 403))	('Cancer', 'Phenotype', 'HP:0002664', (132, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (332, 341))	('Lung Adenocarcinoma', 'Phenotype', 'HP:0030078', (48, 67))	('rearrangements', 'Var', (458, 472))	('lymphoma', 'Phenotype', 'HP:0002665', (436, 444))	('mutations', 'Var', (411, 420))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (322, 342))	('Cancer', 'Disease', 'MESH:D009369', (132, 138))	('Primary Lung Adenocarcinoma', 'Disease', (40, 67))	('EGFR', 'Gene', (405, 409))	('Squamous Cell Carcinoma', 'Disease', (73, 96))	('Cancer', 'Disease', 'MESH:D009369', (250, 256))	('tested', 'Reg', (360, 366))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (322, 342))	('ALK', 'Gene', '238', (453, 456))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (425, 444))	('Lung Cancer', 'Disease', (245, 256))	('lung adenocarcinomas', 'Disease', (322, 342))	('Carcinoma', 'Phenotype', 'HP:0030731', (87, 96))	('ALK', 'Gene', (453, 456))	('EGFR', 'Gene', '1956', (405, 409))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))
64064	27552093	It is now known that patients with ADC, but not SqCC, may have mutations in the epidermal growth factor receptor (EGFR) and show significant tumor shrinkage on EGFR tyrosine kinase inhibitors.	('mutations', 'Var', (63, 72))	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('EGFR', 'Gene', '1956', (160, 164))	('ADC', 'Disease', (35, 38))	('tumor', 'Disease', (141, 146))	('EGFR', 'Gene', '1956', (114, 118))	('patients', 'Species', '9606', (21, 29))	('SqCC', 'Phenotype', 'HP:0002860', (48, 52))	('EGFR', 'Gene', (160, 164))	('epidermal growth factor receptor', 'Gene', (80, 112))	('EGFR', 'Gene', (114, 118))	('epidermal growth factor receptor', 'Gene', '1956', (80, 112))
64065	27552093	The National Cancer Care Network guidelines and the combined College of American Pathologists/International Association for the Study of Lung Cancer/Association for Molecular Pathology guidelines indicate that all lung ADCs, metastatic or recurrent, should be tested for the presence of the activating mutations of EGFR, as well as for ALK rearrangements.	('activating', 'PosReg', (291, 301))	('mutations', 'Var', (302, 311))	('Cancer', 'Disease', (13, 19))	('Cancer', 'Disease', 'MESH:D009369', (13, 19))	('Lung Cancer', 'Phenotype', 'HP:0100526', (137, 148))	('Cancer', 'Phenotype', 'HP:0002664', (13, 19))	('ALK', 'Gene', (336, 339))	('lung ADCs', 'Disease', (214, 223))	('Lung Cancer', 'Disease', (137, 148))	('Cancer', 'Phenotype', 'HP:0002664', (142, 148))	('Cancer', 'Disease', (142, 148))	('EGFR', 'Gene', '1956', (315, 319))	('Cancer', 'Disease', 'MESH:D009369', (142, 148))	('ALK', 'Gene', '238', (336, 339))	('Lung Cancer', 'Disease', 'MESH:D008175', (137, 148))	('EGFR', 'Gene', (315, 319))
64133	26933913	The prognostic score was calculated as follows: Prognostic-score = (-1.155xexpression level of hsa-let-7c) + (-1.063xexpression level of hsa-miR-125b-2) + (1.217xexpression level of hsa-miR-129-1) + (1.137xexpression level of hsa-miR-337) + (1.013xexpression level of hsa-miR-654) + (-1.157xexpression level of hsa-miR-99a).	('hsa-miR-654', 'Gene', (268, 279))	('hsa-miR-337', 'Gene', (226, 237))	('hsa-miR-654', 'Gene', '724024', (268, 279))	('hsa-miR-337', 'Gene', '442905', (226, 237))	('hsa-miR-129-1', 'Gene', (182, 195))	('-1.155xexpression', 'Var', (68, 85))	('hsa-miR-125b-2', 'Gene', (137, 151))	('miR-99a', 'Gene', (315, 322))	('hsa-miR-125b-2', 'Gene', '406912', (137, 151))	('hsa-let-7c', 'Gene', (95, 105))	('hsa-miR-129-1', 'Gene', '406917', (182, 195))	('hsa-let-7c', 'Gene', '406885', (95, 105))	('miR-99a', 'Gene', '407055', (315, 322))
64137	26933913	The OS rate of patients with low risk group was significantly higher than that of patients with high risk group in the all subgroup (Figure 3B/3D and Supplementary Figure S17B/D - Figure S19B/D).	('patients', 'Species', '9606', (15, 23))	('S19B', 'SUBSTITUTION', 'None', (187, 191))	('OS', 'Chemical', '-', (4, 6))	('patients', 'Species', '9606', (82, 90))	('OS rate', 'MPA', (4, 11))	('higher', 'PosReg', (62, 68))	('S17B', 'SUBSTITUTION', 'None', (171, 175))	('S19B', 'Var', (187, 191))	('S17B', 'Var', (171, 175))
64139	26933913	The numbers of the target genes of the six miRNAs were 8437, 7253, and 1119, which were predicted by three data sets using miRanda, Targetscan, and PicTar programs, respectively.	('miR', 'Gene', '220972', (43, 46))	('miR', 'Gene', (43, 46))	('miR', 'Gene', '220972', (123, 126))	('miR', 'Gene', (123, 126))	('7253', 'Var', (61, 65))	('8437', 'Var', (55, 59))
64153	26933913	The carcinogenic process of HNSCC is a multi-step process driven by a series of genetic and epigenetic alterations in tumor suppressor genes and oncogenes resulting in the progression from a normal cell to a cancer cell.	('HNSCC', 'Phenotype', 'HP:0012288', (28, 33))	('cancer', 'Disease', (208, 214))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('oncogenes', 'Gene', (145, 154))	('carcinogenic', 'Disease', 'MESH:D063646', (4, 16))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('carcinogenic', 'Disease', (4, 16))	('epigenetic alterations', 'Var', (92, 114))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('tumor', 'Disease', (118, 123))	('cancer', 'Disease', 'MESH:D009369', (208, 214))	('HNSCC', 'Disease', (28, 33))
64156	26933913	Aberrant activation of the p38 MAPK pathway may halt HNSCC cells growth and metastasis by reducing tumor-induced inflammation and angiogenesis.	('tumor', 'Disease', (99, 104))	('activation', 'PosReg', (9, 19))	('Aberrant', 'Var', (0, 8))	('inflammation', 'Disease', 'MESH:D007249', (113, 125))	('p38', 'Gene', '1432', (27, 30))	('HNSCC', 'Phenotype', 'HP:0012288', (53, 58))	('halt', 'NegReg', (48, 52))	('HNSCC', 'Disease', (53, 58))	('inflammation', 'Disease', (113, 125))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('reducing', 'NegReg', (90, 98))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('p38', 'Gene', (27, 30))
64158	26933913	SMAD4 alterations may explain the decreased tumor suppressive effect of TGF-beta signaling in HNSCC.	('alterations', 'Var', (6, 17))	('SMAD4', 'Gene', '4089', (0, 5))	('decreased', 'NegReg', (34, 43))	('HNSCC', 'Disease', (94, 99))	('HNSCC', 'Phenotype', 'HP:0012288', (94, 99))	('SMAD4', 'Gene', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumor', 'Disease', (44, 49))
64182	26933913	The target genes were selected by miRanda if the mirSVR score <= -0.1 and by Targetscan if the total context score <=-0.1.	('miR', 'Gene', (34, 37))	('<= -0.1', 'Var', (62, 69))	('miR', 'Gene', '220972', (34, 37))
64197	24314023	Furthermore, aberrant expression of miRNAs has been linked to the development and progression of cancer and has prognostic significance for several tumor types, including lung and esophageal squamous cell cancer, neuroblastoma and lymphocytic leukemia.	('cancer', 'Disease', 'MESH:D009369', (205, 211))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (191, 211))	('miR', 'Gene', (36, 39))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('cancer', 'Disease', (97, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('leukemia', 'Phenotype', 'HP:0001909', (243, 251))	('aberrant', 'Var', (13, 21))	('neuroblastoma', 'Phenotype', 'HP:0003006', (213, 226))	('cancer', 'Disease', (205, 211))	('esophageal squamous cell cancer', 'Disease', 'MESH:D002294', (180, 211))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('expression', 'MPA', (22, 32))	('cancer', 'Disease', 'MESH:D009369', (97, 103))	('lung', 'Disease', (171, 175))	('linked', 'Reg', (52, 58))	('tumor', 'Disease', (148, 153))	('neuroblastoma and lymphocytic leukemia', 'Disease', 'MESH:D009447', (213, 251))	('esophageal squamous cell cancer', 'Disease', (180, 211))	('miR', 'Gene', '220972', (36, 39))	('tumor', 'Disease', 'MESH:D009369', (148, 153))
64235	24314023	Wild type and mutant human PTTG1 3'UTR fragments (bases 655-713, NM_004219) were created by two single-strand annealing (Sangon Biotech Co., Ltd, Shanghai).	('PTTG1', 'Gene', '9232', (27, 32))	('mutant', 'Var', (14, 20))	('human', 'Species', '9606', (21, 26))	('PTTG1', 'Gene', (27, 32))
64237	24314023	For the luciferase reporter assay, EC9706 and KYSE150 cells were transiently co-transfected with the pRL-TK Renilla plasmid (Promega, Madison, WI), matched reporter vectors (wild type reporter vectors or mutant reporter vectors), and miR-655 mimics or scrambled miR-655.	('miR-655', 'Gene', '724025', (234, 241))	('EC9706', 'Var', (35, 41))	('miR-655', 'Gene', '724025', (262, 269))	('mutant', 'Var', (204, 210))	('miR-655', 'Gene', (262, 269))	('miR-655', 'Gene', (234, 241))	('EC9706', 'CellLine', 'CVCL:E307', (35, 41))	('KYSE150', 'CellLine', 'CVCL:1348', (46, 53))
64249	24314023	A log-rank test indicated that primary ESCCs with moderate to strong PTTG1 expression (>0.7770) were associated with significantly worse survival than ESCCs with weak PTTG1 expression (<0.7770) (P < 0.05).	('>0.7770', 'Var', (87, 94))	('PTTG1', 'Gene', (167, 172))	('PTTG1', 'Gene', '9232', (167, 172))	('rat', 'Species', '10116', (54, 57))	('worse', 'NegReg', (131, 136))	('PTTG1', 'Gene', '9232', (69, 74))	('survival', 'MPA', (137, 145))	('PTTG1', 'Gene', (69, 74))
64262	24314023	To verify whether PTTG1 is a direct target of miR-655, we used a Dual-Luciferase reporter system containing either the wildtype or mutant 3' UTR of PTTG1.	('mutant', 'Var', (131, 137))	('PTTG1', 'Gene', '9232', (148, 153))	('PTTG1', 'Gene', '9232', (18, 23))	('miR-655', 'Gene', '724025', (46, 53))	('PTTG1', 'Gene', (18, 23))	('PTTG1', 'Gene', (148, 153))	('miR-655', 'Gene', (46, 53))
64267	24314023	From these results we conclude that PTTG1 expression restores the anti-migration function of miR-655.	('anti-migration function', 'CPA', (66, 89))	('PTTG1', 'Gene', (36, 41))	('restores', 'PosReg', (53, 61))	('PTTG1', 'Gene', '9232', (36, 41))	('miR-655', 'Gene', '724025', (93, 100))	('rat', 'Species', '10116', (74, 77))	('miR-655', 'Gene', (93, 100))	('expression', 'Var', (42, 52))
64314	31611957	The dysregulation of PTTG1 enhances tumor cell proliferation, invasion and metastasis, and suppresses apoptosis.	('suppresses', 'NegReg', (91, 101))	('apoptosis', 'CPA', (102, 111))	('dysregulation', 'Var', (4, 17))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('PTTG1', 'Gene', '9232', (21, 26))	('PTTG1', 'Gene', (21, 26))	('enhances', 'PosReg', (27, 35))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumor', 'Disease', (36, 41))
64317	31611957	In addition, Li et al have demonstrated that knockdown of PTTG1 suppresses growth and invasion of LUAD.	('knockdown', 'Var', (45, 54))	('PTTG1', 'Gene', (58, 63))	('suppresses', 'NegReg', (64, 74))	('invasion of LUAD', 'Disease', 'MESH:C538231', (86, 102))	('PTTG1', 'Gene', '9232', (58, 63))	('LUAD', 'Phenotype', 'HP:0030078', (98, 102))	('invasion of LUAD', 'Disease', (86, 102))
64348	31611957	Patients with NSCLC with high expression of PTTG1 exhibited significantly shorter OS time compared with patients with a low expression of PTTG1 (HR, 1.66; 95% CI, 1.46-1.89; log-rank P=5.7x10-15; Fig.	('shorter', 'NegReg', (74, 81))	('NSCLC', 'Disease', (14, 19))	('PTTG1', 'Gene', (44, 49))	('NSCLC', 'Disease', 'MESH:D002289', (14, 19))	('PTTG1', 'Gene', '9232', (44, 49))	('high expression', 'Var', (25, 40))	('patients', 'Species', '9606', (104, 112))	('Patients', 'Species', '9606', (0, 8))	('PTTG1', 'Gene', (138, 143))	('NSCLC', 'Phenotype', 'HP:0030358', (14, 19))	('PTTG1', 'Gene', '9232', (138, 143))	('OS time', 'MPA', (82, 89))
64349	31611957	High expression of PTTG1 in patients with LUAD indicated a poor prognosis (HR, 2.36; 95% CI, 1.85-3.02; log-rank P=1.9x10-12; Fig.	('PTTG1', 'Gene', (19, 24))	('High', 'Var', (0, 4))	('LUAD', 'Phenotype', 'HP:0030078', (42, 46))	('LUAD', 'Disease', (42, 46))	('LUAD', 'Disease', 'MESH:C538231', (42, 46))	('patients', 'Species', '9606', (28, 36))	('PTTG1', 'Gene', '9232', (19, 24))
64350	31611957	However, in patients with LUSC, high PTTG1 expression was not associated with OS (Fig.	('high', 'Var', (32, 36))	('patients', 'Species', '9606', (12, 20))	('PTTG1', 'Gene', '9232', (37, 42))	('LUSC', 'Phenotype', 'HP:0030359', (26, 30))	('LUSC', 'Disease', 'MESH:D002294', (26, 30))	('LUSC', 'Disease', (26, 30))	('PTTG1', 'Gene', (37, 42))
64355	31611957	6A and B, high expression of PTTG3P was significantly associated with unfavorable OS for all patients with NSCLC (HR, 1.57; 95% CI, 1.38-1.78; log-rank P=2.9x10-12) and patients with LUAD (HR, 1.81; 95% CI, 1.43-2.30; log-rank P=7.1x10-7).	('PTTG3P', 'Gene', '26255', (29, 35))	('NSCLC', 'Disease', (107, 112))	('patients', 'Species', '9606', (93, 101))	('LUAD', 'Disease', (183, 187))	('patients', 'Species', '9606', (169, 177))	('LUAD', 'Disease', 'MESH:C538231', (183, 187))	('LUAD', 'Phenotype', 'HP:0030078', (183, 187))	('NSCLC', 'Disease', 'MESH:D002289', (107, 112))	('PTTG3P', 'Gene', (29, 35))	('high expression', 'Var', (10, 25))	('unfavorable', 'Disease', (70, 81))	('NSCLC', 'Phenotype', 'HP:0030358', (107, 112))	('associated with', 'Reg', (54, 69))
64379	31611957	A high expression of PTTG1 (HR, 1.39; 95% CI, 1.12-1.71; log-rank P=2.3x10-3) was significantly associated with poor OS for patients with NSCLC without invasive and/or metastatic lymph nodes (lymph node, 0).	('NSCLC', 'Disease', (138, 143))	('associated with', 'Reg', (96, 111))	('high', 'Var', (2, 6))	('NSCLC', 'Disease', 'MESH:D002289', (138, 143))	('PTTG1', 'Gene', '9232', (21, 26))	('PTTG1', 'Gene', (21, 26))	('NSCLC', 'Phenotype', 'HP:0030358', (138, 143))	('patients', 'Species', '9606', (124, 132))	('poor OS', 'Disease', (112, 119))
64382	31611957	Compared with patients with NSCLC with low expression of PTTG1, high expression of PTTG1 indicated a worse prognosis in patients with NSCLC who had never smoked (HR, 3.03; 95% CI, 1.63-5.62; log-rank P=2.2x10-4) or smoked (HR, 1.32; 95% CI, 1.07-1.62; log-rank P=8.9x10-3).	('NSCLC', 'Disease', (28, 33))	('high', 'Var', (64, 68))	('NSCLC', 'Disease', 'MESH:D002289', (134, 139))	('PTTG1', 'Gene', (57, 62))	('NSCLC', 'Disease', 'MESH:D002289', (28, 33))	('PTTG1', 'Gene', '9232', (57, 62))	('NSCLC', 'Phenotype', 'HP:0030358', (134, 139))	('PTTG1', 'Gene', '9232', (83, 88))	('patients', 'Species', '9606', (120, 128))	('PTTG1', 'Gene', (83, 88))	('NSCLC', 'Phenotype', 'HP:0030358', (28, 33))	('patients', 'Species', '9606', (14, 22))	('NSCLC', 'Disease', (134, 139))
64383	31611957	Patients with NSCLC with a high expression of PTTG2 who had smoked (HR, 1.47; 95% CI, 1.19-1.81; log-rank P=2.8x10-4) and never-smoked (HR, 2.10; 95% CI, 1.18-3.75; log-rank P=1.0x10-2) exhibited a shorter OS time compared with patients with NSCLC with low expression of PTTG2.	('NSCLC', 'Disease', (14, 19))	('PTTG2', 'Gene', '10744', (271, 276))	('PTTG2', 'Gene', '10744', (46, 51))	('NSCLC', 'Disease', 'MESH:D002289', (14, 19))	('NSCLC', 'Phenotype', 'HP:0030358', (242, 247))	('patients', 'Species', '9606', (228, 236))	('NSCLC', 'Disease', 'MESH:D002289', (242, 247))	('Patients', 'Species', '9606', (0, 8))	('high expression', 'Var', (27, 42))	('NSCLC', 'Disease', (242, 247))	('NSCLC', 'Phenotype', 'HP:0030358', (14, 19))	('PTTG2', 'Gene', (271, 276))	('PTTG2', 'Gene', (46, 51))	('shorter', 'NegReg', (198, 205))	('OS time', 'MPA', (206, 213))
64384	31611957	Additionally, high expression of PTTG3P was also significantly associated with the OS or patients who had never-smoked (HR, 3.11; 95% CI, 1.70-5.71; log-rank P=1.1x10-4) and smoked (HR, 1.41; 95% CI, 1.15-1.74; log-rank P=1.1x10-3).	('PTTG3P', 'Gene', '26255', (33, 39))	('associated', 'Reg', (63, 73))	('high', 'Var', (14, 18))	('patients', 'Species', '9606', (89, 97))	('PTTG3P', 'Gene', (33, 39))
64401	31611957	The results demonstrated that patients with NSCLC (1,924 samples) with high PTTG1, PTTG2 and PTTG3P expression exhibited a shorter OS time compared with healthy controls.	('NSCLC', 'Disease', 'MESH:D002289', (44, 49))	('shorter', 'NegReg', (123, 130))	('PTTG2', 'Gene', '10744', (83, 88))	('PTTG3P', 'Gene', '26255', (93, 99))	('high', 'Var', (71, 75))	('OS time', 'MPA', (131, 138))	('NSCLC', 'Phenotype', 'HP:0030358', (44, 49))	('PTTG3P', 'Gene', (93, 99))	('patients', 'Species', '9606', (30, 38))	('PTTG2', 'Gene', (83, 88))	('PTTG1', 'Gene', (76, 81))	('NSCLC', 'Disease', (44, 49))	('PTTG1', 'Gene', '9232', (76, 81))
64418	25537505	Fibroblast growth factor receptor 1 gene amplification is associated with poor survival in patients with resected esophageal squamous cell carcinoma To investigate the frequency and the prognostic impact of fibroblast growth factor receptor 1 (FGFR1) gene amplification in 526 curatively resected esophageal squamous cell carcinoma (ESCC).	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (125, 148))	('esophageal squamous cell carcinoma', 'Disease', (297, 331))	('fibroblast growth factor receptor 1', 'Gene', (207, 242))	('patients', 'Species', '9606', (91, 99))	('Fibroblast growth factor receptor 1', 'Gene', (0, 35))	('carcinoma', 'Phenotype', 'HP:0030731', (139, 148))	('carcinoma', 'Phenotype', 'HP:0030731', (322, 331))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (114, 148))	('FGFR1', 'Gene', (244, 249))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (308, 331))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (297, 331))	('amplification', 'Var', (41, 54))	('fibroblast growth factor receptor 1', 'Gene', '2260', (207, 242))	('FGFR1', 'Gene', '2260', (244, 249))	('Fibroblast growth factor receptor 1', 'Gene', '2260', (0, 35))	('esophageal squamous cell carcinoma', 'Disease', (114, 148))
64421	25537505	FGFR2 and FGFR3 mutations were assessed by direct sequencing in 388 cases and no mutation was detected.	('FGFR3', 'Gene', '2261', (10, 15))	('mutations', 'Var', (16, 25))	('FGFR3', 'Gene', (10, 15))	('FGFR2', 'Gene', (0, 5))	('FGFR2', 'Gene', '2263', (0, 5))
64422	25537505	High FGFR1 amplification had significantly shorter disease-free survival (34.0 vs 158.5 months P=0.019) and overall survival (52.2 vs not reached P=0.022) than low/no amplification group.	('High', 'Var', (0, 4))	('FGFR1', 'Gene', '2260', (5, 10))	('overall survival', 'CPA', (108, 124))	('disease-free survival', 'CPA', (51, 72))	('FGFR1', 'Gene', (5, 10))	('amplification', 'Var', (11, 24))	('shorter', 'NegReg', (43, 50))
64423	25537505	After adjusting for sex, smoking, stage, histology, and adjuvant treatment, high FGFR1 amplification had a greater risk of recurrence (adjusted hazard ratio [AHR], 1.6; P=0.029) and death (AHR, 1.53; P=0.050).	('FGFR1', 'Gene', (81, 86))	('recurrence', 'CPA', (123, 133))	('death', 'Disease', 'MESH:D003643', (182, 187))	('FGFR1', 'Gene', '2260', (81, 86))	('death', 'Disease', (182, 187))	('high', 'Var', (76, 80))	('amplification', 'Var', (87, 100))
64424	25537505	High FGFR1 amplification is a frequent oncogenic alteration and an independent poor prognostic factor in resected ESCC.	('ESCC', 'Disease', (114, 118))	('High', 'Var', (0, 4))	('FGFR1', 'Gene', '2260', (5, 10))	('amplification', 'Var', (11, 24))	('FGFR1', 'Gene', (5, 10))
64429	25537505	Amplification and overexpression of human epidermal growth factor receptor 2 (HER2; also known as ERBB2) was more frequent in EAC than ESCC and there was a strong concordance of HER2 status in primary and metastatic cancer.	('ERBB2', 'Gene', '2064', (98, 103))	('Amplification', 'Var', (0, 13))	('human epidermal growth factor receptor 2', 'Gene', (36, 76))	('ERBB2', 'Gene', (98, 103))	('cancer', 'Disease', 'MESH:D009369', (216, 222))	('human epidermal growth factor receptor 2', 'Gene', '2064', (36, 76))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('HER2', 'Gene', (78, 82))	('HER2', 'Gene', '2064', (78, 82))	('cancer', 'Disease', (216, 222))	('EAC', 'Disease', (126, 129))	('HER2', 'Gene', (178, 182))	('frequent', 'Reg', (114, 122))	('overexpression', 'PosReg', (18, 32))	('HER2', 'Gene', '2064', (178, 182))
64431	25537505	The therapeutic implication of HER2 protein overexpression or gene amplification has been demonstrated in the Trastuzumab for Gastric Cancer (ToGA) trial.	('HER2', 'Gene', '2064', (31, 35))	('gene amplification', 'Var', (62, 80))	('Cancer', 'Phenotype', 'HP:0002664', (134, 140))	('overexpression', 'PosReg', (44, 58))	('Gastric Cancer', 'Disease', (126, 140))	('Gastric Cancer', 'Phenotype', 'HP:0012126', (126, 140))	('Trastuzumab', 'Chemical', 'MESH:D000068878', (110, 121))	('Gastric Cancer', 'Disease', 'MESH:D013274', (126, 140))	('HER2', 'Gene', (31, 35))
64435	25537505	Among those, high copy number gains of cancer-associated genes, such as SOX2, PIK3CA, CCND1, and FGFR1, were more frequently observed in ESCC than in EAC, suggesting that genomic gain of these oncogenes may be therapeutic targets for ESCC.	('CCND1', 'Gene', (86, 91))	('FGFR1', 'Gene', '2260', (97, 102))	('PIK3CA', 'Gene', (78, 84))	('observed', 'Reg', (125, 133))	('SOX2', 'Gene', '6657', (72, 76))	('cancer', 'Disease', (39, 45))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('SOX2', 'Gene', (72, 76))	('CCND1', 'Gene', '595', (86, 91))	('ESCC', 'Disease', (137, 141))	('PIK3CA', 'Gene', '5290', (78, 84))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('high copy number gains', 'Var', (13, 35))	('FGFR1', 'Gene', (97, 102))
64436	25537505	Fibroblast growth factor receptor 1 (FGFR1) is a member of family of receptor tyrosine kinases (FGFR1-4), and its activation by amplification, mutation, or translocation leads to tumor cell proliferation and survival in many cancers.	('FGFR1', 'Gene', '2260', (37, 42))	('cancers', 'Disease', (225, 232))	('translocation', 'Var', (156, 169))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('FGFR1', 'Gene', (96, 101))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('activation', 'PosReg', (114, 124))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('Fibroblast growth factor receptor 1', 'Gene', '2260', (0, 35))	('tumor', 'Disease', (179, 184))	('FGFR1', 'Gene', (37, 42))	('cancers', 'Disease', 'MESH:D009369', (225, 232))	('Fibroblast growth factor receptor 1', 'Gene', (0, 35))	('mutation', 'Var', (143, 151))	('FGFR1', 'Gene', '2260', (96, 101))	('amplification', 'Var', (128, 141))	('leads to', 'Reg', (170, 178))	('survival', 'CPA', (208, 216))	('cancers', 'Phenotype', 'HP:0002664', (225, 232))
64437	25537505	Potentially actionable FGFR rearrangements were identified in diverse solid tumors including lung cancer, oral cancer, and breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('oral cancer', 'Disease', 'MESH:D009062', (106, 117))	('FGFR', 'Gene', (23, 27))	('solid tumors', 'Disease', 'MESH:D009369', (70, 82))	('rearrangements', 'Var', (28, 42))	('breast cancer', 'Disease', 'MESH:D001943', (123, 136))	('lung cancer', 'Disease', 'MESH:D008175', (93, 104))	('oral cancer', 'Disease', (106, 117))	('breast cancer', 'Disease', (123, 136))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('breast cancer', 'Phenotype', 'HP:0003002', (123, 136))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('solid tumors', 'Disease', (70, 82))	('lung cancer', 'Disease', (93, 104))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('lung cancer', 'Phenotype', 'HP:0100526', (93, 104))
64438	25537505	FGFR1 amplification has been frequently reported in lung squamous cell carcinoma (SqCC), small cell lung cancer, and SqCC of head and neck (SCCHN), for which smoking is a clear and dominant risk factor.	('small cell lung cancer', 'Disease', (89, 111))	('SqCC', 'Phenotype', 'HP:0002860', (82, 86))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (52, 80))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (57, 80))	('FGFR1', 'Gene', (0, 5))	('FGFR1', 'Gene', '2260', (0, 5))	('lung cancer', 'Phenotype', 'HP:0100526', (100, 111))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (52, 80))	('SqCC', 'Phenotype', 'HP:0002860', (117, 121))	('small cell lung cancer', 'Disease', 'MESH:D055752', (89, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (89, 111))	('amplification', 'Var', (6, 19))	('lung squamous cell carcinoma', 'Disease', (52, 80))	('reported', 'Reg', (40, 48))
64439	25537505	Overall, the frequency of FGFR1 amplification was reported to be 5.6%-24.8% in lung SqCC and 15%-17.4% in SCCHN, suggesting that this genetic alteration mainly target squamous cell histology.	('SCCHN', 'Disease', (106, 111))	('FGFR1', 'Gene', (26, 31))	('FGFR1', 'Gene', '2260', (26, 31))	('amplification', 'Var', (32, 45))	('lung SqCC', 'Disease', (79, 88))	('SqCC', 'Phenotype', 'HP:0002860', (84, 88))
64440	25537505	Furthermore, FGFR1 amplification has been associated with poor prognosis or unfavorable clinicopathologic parameters in lung SqCC and SCCHN.	('amplification', 'Var', (19, 32))	('FGFR1', 'Gene', (13, 18))	('lung SqCC', 'Disease', (120, 129))	('FGFR1', 'Gene', '2260', (13, 18))	('SqCC', 'Phenotype', 'HP:0002860', (125, 129))	('SCCHN', 'Disease', (134, 139))
64441	25537505	Because ESCC has risk factors in common with lung SqCC and SCCHN, we hypothesized that FGFR1 amplifications is associated with pathogenesis and poor prognosis in ESCC.	('ESCC', 'Disease', (8, 12))	('associated', 'Reg', (111, 121))	('amplifications', 'Var', (93, 107))	('FGFR1', 'Gene', (87, 92))	('FGFR1', 'Gene', '2260', (87, 92))	('ESCC', 'Disease', (162, 166))	('SqCC', 'Phenotype', 'HP:0002860', (50, 54))
64442	25537505	In this study, we sought to determine the frequency, prognostic impact and association with smoking dosage of FGFR1 amplification in surgically resected ESCC.	('ESCC', 'Disease', (153, 157))	('FGFR1', 'Gene', '2260', (110, 115))	('FGFR1', 'Gene', (110, 115))	('amplification', 'Var', (116, 129))
64443	25537505	Furthermore, we also evaluated the frequency of FGFR2 and FGFR3 mutations in ESCC.	('FGFR2', 'Gene', (48, 53))	('FGFR2', 'Gene', '2263', (48, 53))	('FGFR3', 'Gene', '2261', (58, 63))	('ESCC', 'Disease', (77, 81))	('FGFR3', 'Gene', (58, 63))	('mutations', 'Var', (64, 73))
64457	25537505	However, the incidence of high FGFR1 amplification was significantly higher in smokers than in never-smokers (P<0.001).	('high', 'Var', (26, 30))	('amplification', 'MPA', (37, 50))	('higher', 'PosReg', (69, 75))	('FGFR1', 'Gene', (31, 36))	('FGFR1', 'Gene', '2260', (31, 36))
64462	25537505	The median DFS for each of the three FGFR groups was 34.0 months in the high FGFR1 amplification, not reached (NR) in low amplification group, and 158.5 months in the no amplification group (Figure 2A).	('FGFR1', 'Gene', '2260', (77, 82))	('FGFR1', 'Gene', (77, 82))	('high', 'Var', (72, 76))
64463	25537505	By using pair-wise comparison, patients with high FGFR1 amplification showed a significantly shorter DFS than those with no amplification (34.0 vs 158.5 months in no amplification, P=0.020).	('FGFR1', 'Gene', (50, 55))	('FGFR1', 'Gene', '2260', (50, 55))	('high', 'Var', (45, 49))	('shorter', 'NegReg', (93, 100))	('patients', 'Species', '9606', (31, 39))	('DFS', 'MPA', (101, 104))	('amplification', 'Var', (56, 69))
64464	25537505	The median OS for each of the three FGFR groups was 52.2 months in the high FGFR1 amplification, 72.0 months in the low amplification, and not reached in the no amplification (Figure 2B).	('amplification', 'PosReg', (82, 95))	('OS', 'Chemical', '-', (11, 13))	('high', 'Var', (71, 75))	('FGFR1', 'Gene', (76, 81))	('FGFR1', 'Gene', '2260', (76, 81))
64465	25537505	By using pair-wise comparison, patients with high FGFR1 amplification showed a significantly shorter OS than those with no amplification (52.2 vs NR in no amplification, P=0.021).	('FGFR1', 'Gene', (50, 55))	('FGFR1', 'Gene', '2260', (50, 55))	('high', 'Var', (45, 49))	('OS', 'Chemical', '-', (101, 103))	('shorter', 'NegReg', (93, 100))	('patients', 'Species', '9606', (31, 39))	('amplification', 'Var', (56, 69))
64469	25537505	The median DFS of the high FGFR1 amplification group was significantly shorter compared with that of the low/no FGFR1 amplification group (34.0 vs 158.5 months P=0.019, Figure 3A).	('FGFR1', 'Gene', (112, 117))	('FGFR1', 'Gene', '2260', (27, 32))	('FGFR1', 'Gene', '2260', (112, 117))	('high', 'Var', (22, 26))	('DFS', 'MPA', (11, 14))	('FGFR1', 'Gene', (27, 32))	('shorter', 'NegReg', (71, 78))
64470	25537505	In addition, high FGFR1 amplification group demonstrated significantly shorter OS than low/no FGFR1 amplification group (52.2 vs NR, P=0.022, Figure 3B).	('FGFR1', 'Gene', '2260', (94, 99))	('OS', 'Chemical', '-', (79, 81))	('high', 'Var', (13, 17))	('FGFR1', 'Gene', (18, 23))	('FGFR1', 'Gene', '2260', (18, 23))	('FGFR1', 'Gene', (94, 99))	('shorter', 'NegReg', (71, 78))
64471	25537505	In Cox proportional hazard model adjusted for sex, smoking history, pathologic stage, adjuvant treatment, and histologic grade, high FGFR1 amplification was significantly associated with a shorter DFS (AHR 1.61; 95% CI, 1.05-2.46; P=0.029, Table 2).	('amplification', 'Var', (139, 152))	('FGFR1', 'Gene', (133, 138))	('FGFR1', 'Gene', '2260', (133, 138))	('shorter', 'NegReg', (189, 196))	('high', 'Var', (128, 132))	('DFS', 'MPA', (197, 200))
64475	25537505	FGFR2 and FGFR3 mutations were assessed by direct sequencing in 388 cases with FFPE tissues available and no FGFR2 or FGFR3 mutation was detected.	('FGFR3', 'Gene', (118, 123))	('FGFR3', 'Gene', '2261', (10, 15))	('mutations', 'Var', (16, 25))	('FGFR3', 'Gene', (10, 15))	('FGFR3', 'Gene', '2261', (118, 123))	('FGFR2', 'Gene', (0, 5))	('FGFR2', 'Gene', (109, 114))	('FGFR2', 'Gene', '2263', (0, 5))	('FGFR2', 'Gene', '2263', (109, 114))
64477	25537505	The incidences of high-level FGFR1 amplification in current, former and never-smokers were 19.0%, 2.5%, and 0.8%, respectively.	('amplification', 'Var', (35, 48))	('FGFR1', 'Gene', (29, 34))	('FGFR1', 'Gene', '2260', (29, 34))
64478	25537505	With increment of total cigarette smoking dosage, the incidence of high-level FGFR1 amplification was significantly increased (Figure 4B, Ptrend = 0.001).	('FGFR1', 'Gene', (78, 83))	('FGFR1', 'Gene', '2260', (78, 83))	('amplification', 'Var', (84, 97))	('increased', 'PosReg', (116, 125))	('high-level', 'Var', (67, 77))
64480	25537505	In this study, we investigated the frequency and the prognostic impact of FGFR1 amplification in resected ESCC.	('amplification', 'Var', (80, 93))	('FGFR1', 'Gene', '2260', (74, 79))	('ESCC', 'Disease', (106, 110))	('FGFR1', 'Gene', (74, 79))
64481	25537505	To our knowledge, this is the first report on the prognostic impact of FGFR1 amplification in the largest-ever cohort of resected ESCC patients from East Asian.	('patients', 'Species', '9606', (135, 143))	('FGFR1', 'Gene', (71, 76))	('ESCC', 'Disease', (130, 134))	('FGFR1', 'Gene', '2260', (71, 76))	('amplification', 'Var', (77, 90))
64482	25537505	Our study demonstrated high FGFR1 amplification is a common genetic alteration (8.6%) and an independent negative prognostic factor in resected ESCC.	('high', 'Var', (23, 27))	('FGFR1', 'Gene', (28, 33))	('ESCC', 'Disease', (144, 148))	('FGFR1', 'Gene', '2260', (28, 33))	('amplification', 'Var', (34, 47))
64483	25537505	The frequency of FGFR1 amplification has been reported to range from 6% to 9.4%.	('FGFR1', 'Gene', '2260', (17, 22))	('amplification', 'Var', (23, 36))	('FGFR1', 'Gene', (17, 22))	('to 9', 'Species', '1214577', (72, 76))
64485	25537505	A comparative genomic study revealed many focal DNA amplifications or losses such as SOX2, PIK3CA, CCND1, FGFR1, MYC, GATA4, and GATA6 in ESCC and EAC.	('PIK3CA', 'Gene', (91, 97))	('GATA6', 'Gene', '2627', (129, 134))	('GATA6', 'Gene', (129, 134))	('FGFR1', 'Gene', (106, 111))	('PIK3CA', 'Gene', '5290', (91, 97))	('GATA4', 'Gene', '2626', (118, 123))	('MYC', 'Gene', '4609', (113, 116))	('amplifications', 'Var', (52, 66))	('FGFR1', 'Gene', '2260', (106, 111))	('CCND1', 'Gene', (99, 104))	('GATA4', 'Gene', (118, 123))	('EAC', 'Disease', (147, 150))	('SOX2', 'Gene', '6657', (85, 89))	('MYC', 'Gene', (113, 116))	('ESCC', 'Disease', (138, 142))	('SOX2', 'Gene', (85, 89))	('CCND1', 'Gene', '595', (99, 104))	('losses', 'NegReg', (70, 76))
64486	25537505	Of note, FGFR1 was amplified in 21% of ESCC samples compare with 8% in EAC.	('FGFR1', 'Gene', '2260', (9, 14))	('FGFR1', 'Gene', (9, 14))	('ESCC', 'Disease', (39, 43))	('amplified', 'Var', (19, 28))
64487	25537505	Recently, FGFR1 amplification was reported to be 9.4% in the cohort with Western Europe.	('FGFR1', 'Gene', (10, 15))	('FGFR1', 'Gene', '2260', (10, 15))	('amplification', 'Var', (16, 29))
64489	25537505	Given the relatively high frequency of FGFR1 amplification, it may represent an attractive therapeutic target for ESCC.	('FGFR1', 'Gene', (39, 44))	('FGFR1', 'Gene', '2260', (39, 44))	('ESCC', 'Disease', (114, 118))	('amplification', 'Var', (45, 58))
64490	25537505	Given the histological similarity and common risk factors, it is not surprising that FGFR1 amplification has been reported in upper aerodigestive tract cancers such as lung SqCC, SCCHN, and small cell lung cancer.	('SCCHN', 'Disease', (179, 184))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('reported', 'Reg', (114, 122))	('FGFR1', 'Gene', (85, 90))	('tract cancers', 'Disease', (146, 159))	('tract cancers', 'Disease', 'MESH:D014571', (146, 159))	('amplification', 'Var', (91, 104))	('small cell lung cancer', 'Disease', 'MESH:D055752', (190, 212))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (190, 212))	('FGFR1', 'Gene', '2260', (85, 90))	('lung cancer', 'Phenotype', 'HP:0100526', (201, 212))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('small cell lung cancer', 'Disease', (190, 212))	('lung SqCC', 'Disease', (168, 177))	('SqCC', 'Phenotype', 'HP:0002860', (173, 177))	('cancers', 'Phenotype', 'HP:0002664', (152, 159))
64491	25537505	However, the prognostic significance of FGFR1 amplification in these cancers has shown controversial results.	('cancers', 'Disease', 'MESH:D009369', (69, 76))	('amplification', 'Var', (46, 59))	('FGFR1', 'Gene', (40, 45))	('FGFR1', 'Gene', '2260', (40, 45))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('cancers', 'Phenotype', 'HP:0002664', (69, 76))	('cancers', 'Disease', (69, 76))
64492	25537505	In resected lung SqCC, Kim et al reported FGFR1 amplification as negative prognostic factor, whereas Heist et al observed no significant difference in OS.	('SqCC', 'Phenotype', 'HP:0002860', (17, 21))	('OS', 'Chemical', '-', (151, 153))	('lung SqCC', 'Disease', (12, 21))	('FGFR1', 'Gene', (42, 47))	('FGFR1', 'Gene', '2260', (42, 47))	('amplification', 'Var', (48, 61))
64495	25537505	Low FGFR1 amplification occurred only in 1.1% and survival outcome of low FGFR1 amplification group was similar to no amplification group.	('low', 'Var', (70, 73))	('FGFR1', 'Gene', '2260', (74, 79))	('FGFR1', 'Gene', (4, 9))	('FGFR1', 'Gene', '2260', (4, 9))	('FGFR1', 'Gene', (74, 79))
64496	25537505	Compared with low/no amplification group, high FGFR1 amplification was significantly associated with shorter DFS regardless of sex, histology, and adjuvant therapy, implying that FGFR1 amplification as an independent negative prognostic factor in curatively resected ESCC.	('ESCC', 'Disease', (267, 271))	('FGFR1', 'Gene', (47, 52))	('DFS', 'MPA', (109, 112))	('FGFR1', 'Gene', (179, 184))	('amplification', 'Var', (53, 66))	('FGFR1', 'Gene', '2260', (47, 52))	('FGFR1', 'Gene', '2260', (179, 184))	('shorter', 'NegReg', (101, 108))	('high', 'Var', (42, 46))
64497	25537505	The identification of FGFR alteration in human cancers led to rapid development of selective FGFR inhibitor such as BGJ398 and AZD4547.	('FGFR', 'Gene', (22, 26))	('AZD4547', 'Chemical', 'MESH:C572463', (127, 134))	('human', 'Species', '9606', (41, 46))	('cancers', 'Disease', 'MESH:D009369', (47, 54))	('cancers', 'Phenotype', 'HP:0002664', (47, 54))	('cancers', 'Disease', (47, 54))	('alteration', 'Var', (27, 37))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('FGFR', 'Gene', (93, 97))	('BGJ398', 'Chemical', 'MESH:C568950', (116, 122))
64499	25537505	In another phase I study with FGFR inhibitor AZD4547, 1 partial response was also seen in lung SqCC patient with FGFR1 amplification (FGFR1/CEN8 ratio > 2.8).	('lung SqCC', 'Disease', (90, 99))	('CEN8', 'Chemical', '-', (140, 144))	('SqCC', 'Phenotype', 'HP:0002860', (95, 99))	('AZD4547', 'Chemical', 'MESH:C572463', (45, 52))	('FGFR1', 'Gene', (134, 139))	('FGFR1', 'Gene', (113, 118))	('FGFR1', 'Gene', '2260', (134, 139))	('patient', 'Species', '9606', (100, 107))	('FGFR1', 'Gene', '2260', (113, 118))	('amplification', 'Var', (119, 132))
64500	25537505	Various FGFR inhibitors are currently in clinical development for the patients with FGFR aberrations.	('patients', 'Species', '9606', (70, 78))	('FGFR', 'Gene', (8, 12))	('aberrations', 'Var', (89, 100))	('FGFR', 'Gene', (84, 88))
64501	25537505	Therefore, our study strongly suggests the therapeutic potential of FGFR inhibitor for ESCC, and future clinical trials for advanced high FGFR1 amplified ESCC are strongly warranted.	('high', 'Var', (133, 137))	('ESCC', 'Disease', (154, 158))	('FGFR1', 'Gene', (138, 143))	('ESCC', 'Disease', (87, 91))	('FGFR1', 'Gene', '2260', (138, 143))
64509	25537505	Considering clinical benefit appeared in patients with high FGFR1/CEN8 ratio in clinical trials with FGFR inhibitors, this scoring system might serve as a standardized screening tool to select patients who gain greater benefit from treatment with FGFR inhibitors.	('patients', 'Species', '9606', (193, 201))	('FGFR1', 'Gene', (60, 65))	('FGFR1', 'Gene', '2260', (60, 65))	('CEN8', 'Chemical', '-', (66, 70))	('patients', 'Species', '9606', (41, 49))	('high', 'Var', (55, 59))
64511	25537505	Accumulating evidence has shown that FGFR1 amplification correlated with smoking status in squamous cell biology.	('FGFR1', 'Gene', (37, 42))	('FGFR1', 'Gene', '2260', (37, 42))	('amplification', 'Var', (43, 56))	('correlated', 'Reg', (57, 67))	('squamous cell biology', 'Disease', (91, 112))
64512	25537505	FGFR1 amplification occurs significantly more often in the smokers of the lung SqCC, SCCHN, and small cell lung cancer.	('lung cancer', 'Phenotype', 'HP:0100526', (107, 118))	('lung SqCC', 'Disease', (74, 83))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (96, 118))	('small cell lung cancer', 'Disease', (96, 118))	('FGFR1', 'Gene', (0, 5))	('FGFR1', 'Gene', '2260', (0, 5))	('SqCC', 'Phenotype', 'HP:0002860', (79, 83))	('amplification', 'Var', (6, 19))	('often', 'Reg', (46, 51))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('SCCHN', 'Disease', (85, 90))	('small cell lung cancer', 'Disease', 'MESH:D055752', (96, 118))
64513	25537505	The proportion of FGFR1 amplification among current smokers were reported 15.8% to 28.9% in lung SqCC and 17.7% in SCCHN in a dose dependent manner.	('lung SqCC', 'Disease', (92, 101))	('SCCHN', 'Disease', (115, 120))	('FGFR1', 'Gene', (18, 23))	('SqCC', 'Phenotype', 'HP:0002860', (97, 101))	('amplification', 'Var', (24, 37))	('FGFR1', 'Gene', '2260', (18, 23))
64515	25537505	In our study, FGFR1 amplification was significantly more likely to be smokers, and 44 out of 45 high FGFR1 amplification cases were current or former smokers.	('FGFR1', 'Gene', (14, 19))	('FGFR1', 'Gene', '2260', (14, 19))	('amplification', 'Var', (20, 33))	('FGFR1', 'Gene', (101, 106))	('FGFR1', 'Gene', '2260', (101, 106))
64516	25537505	Similar to the findings in lung SqCC and SCCHN, acquisition of FGFR1 amplification in our study was also significantly increased proportional to smoking dosage.	('FGFR1', 'Gene', (63, 68))	('FGFR1', 'Gene', '2260', (63, 68))	('SqCC', 'Phenotype', 'HP:0002860', (32, 36))	('amplification', 'Var', (69, 82))	('increased', 'PosReg', (119, 128))
64517	25537505	Therefore, FGFR1 amplification may be an oncogenic driver mutation in tobacco-associated cancers of the aerodigestive tract.	('cancers', 'Phenotype', 'HP:0002664', (89, 96))	('cancers', 'Disease', 'MESH:D009369', (89, 96))	('tobacco', 'Species', '4097', (70, 77))	('cancers', 'Disease', (89, 96))	('FGFR1', 'Gene', (11, 16))	('amplification', 'Var', (17, 30))	('FGFR1', 'Gene', '2260', (11, 16))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
64518	25537505	An interesting question of the role of FGFR1 amplification on the smoking-associated carcinogenesis still remained to be solved.	('FGFR1', 'Gene', (39, 44))	('carcinogenesis', 'Disease', 'MESH:D063646', (85, 99))	('FGFR1', 'Gene', '2260', (39, 44))	('carcinogenesis', 'Disease', (85, 99))	('amplification', 'Var', (45, 58))
64520	25537505	Inhibitor-sensitive 5 mutation loci for FGFR2 and 6 mutation loci for FGFR3 were noticed in 3% of lung SqCC samples.Here, we show no FGFR2 and FGFR3 mutations in our 388 ESCC patients.	('FGFR3', 'Gene', '2261', (143, 148))	('mutations', 'Var', (149, 158))	('FGFR3', 'Gene', '2261', (70, 75))	('FGFR3', 'Gene', (143, 148))	('SqCC', 'Phenotype', 'HP:0002860', (103, 107))	('FGFR2', 'Gene', (133, 138))	('FGFR3', 'Gene', (70, 75))	('patients', 'Species', '9606', (175, 183))	('FGFR2', 'Gene', '2263', (133, 138))	('FGFR2', 'Gene', (40, 45))	('FGFR2', 'Gene', '2263', (40, 45))	('ESCC', 'Disease', (170, 174))
64523	25537505	In conclusion, we demonstrated high FGFR1 amplification is an independent poor prognostic factor in resected ESCC.	('ESCC', 'Disease', (109, 113))	('FGFR1', 'Gene', (36, 41))	('FGFR1', 'Gene', '2260', (36, 41))	('amplification', 'Var', (42, 55))	('high', 'Var', (31, 35))
64524	25537505	Patients with FGFR1 amplification were significantly more likely to be smokers and the frequency of FGFR1 amplification was also increased proportional to smoking dosage, suggesting FGFR1 amplification as an oncogenic aberration induced by smoking carcinogen.	('FGFR1', 'Gene', (14, 19))	('amplification', 'Var', (188, 201))	('FGFR1', 'Gene', (182, 187))	('smokers', 'Disease', (71, 78))	('Patients', 'Species', '9606', (0, 8))	('FGFR1', 'Gene', (100, 105))	('FGFR1', 'Gene', '2260', (14, 19))	('FGFR1', 'Gene', '2260', (182, 187))	('amplification', 'Var', (20, 33))	('FGFR1', 'Gene', '2260', (100, 105))
64525	25537505	Our finding indicates FGFR1 amplification is a promising therapeutic target in ESCC.	('FGFR1', 'Gene', '2260', (22, 27))	('ESCC', 'Disease', (79, 83))	('amplification', 'Var', (28, 41))	('FGFR1', 'Gene', (22, 27))
64540	25537505	Based on the previous study in lung SqCC, we evaluated the W290C, S320C, and K660E/K660N mutations in FGFR2, and R248C and S249C mutations in FGFR3.	('FGFR2', 'Gene', '2263', (102, 107))	('SqCC', 'Phenotype', 'HP:0002860', (36, 40))	('S249C', 'Var', (123, 128))	('S320C', 'Mutation', 'rs1057519791', (66, 71))	('S249C', 'Mutation', 'rs121913483', (123, 128))	('W290C', 'SUBSTITUTION', 'None', (59, 64))	('FGFR3', 'Gene', '2261', (142, 147))	('W290C', 'Var', (59, 64))	('K660E', 'Var', (77, 82))	('K660E', 'SUBSTITUTION', 'None', (77, 82))	('K660N', 'Mutation', 'p.K660N', (83, 88))	('FGFR2', 'Gene', (102, 107))	('FGFR3', 'Gene', (142, 147))	('R248C', 'Var', (113, 118))	('S320C', 'Var', (66, 71))	('R248C', 'Mutation', 'rs121913482', (113, 118))
64541	25537505	PCR amplification primers were designed to amplify following regions; W290C; 5'-TCCACAGTGGTCGGAGGAG-3'; 5'- AAAGTCCTCACCTTGAGAACCTTG-3', S320C; 5'-CCTGGTTGGCCGTTATATTG-3'; 5'- TGTTTTGGCAGGACAGTGAG-3', K660E/K660N; 5'- ATTCATCGAGATTTAGCAGCCAG-3'; 5'- ACATTCTGAGCCTCACCCC-3', R248C and S249C; 5'-TGGCGGTGGTGGTGAG-3'; 5'- ATTCACCTCCACGTGCTTGA-3'.	('S249C', 'Mutation', 'rs121913483', (284, 289))	('K660N', 'Mutation', 'p.K660N', (207, 212))	('S320C', 'Mutation', 'rs1057519791', (137, 142))	('R248C', 'Mutation', 'rs121913482', (274, 279))	('W290C', 'SUBSTITUTION', 'None', (70, 75))	('S320C', 'Var', (137, 142))	('K660E', 'Var', (201, 206))	('K660E', 'SUBSTITUTION', 'None', (201, 206))	('W290C', 'Var', (70, 75))	('R248C', 'Var', (274, 279))	('S249C', 'Var', (284, 289))
64543	25537505	We also assessed whether FGFR1 amplification influenced survival outcome using Kaplan-Meier curves with a log-rank test.	('influenced', 'Reg', (45, 55))	('FGFR1', 'Gene', '2260', (25, 30))	('FGFR1', 'Gene', (25, 30))	('amplification', 'Var', (31, 44))
64554	25197261	SphK1 overexpression also increased IL-6 concentration and EGF-induced STAT3 phosphorylation, exemplifying that SphK1 modulates IL-6/STAT3 signaling.	('EGF', 'Gene', '1950', (59, 62))	('IL-6', 'Gene', '3569', (128, 132))	('IL-6', 'Gene', (36, 40))	('overexpression', 'Var', (6, 20))	('IL-6', 'Gene', '3569', (36, 40))	('SphK1', 'Gene', (0, 5))	('STAT3', 'Gene', '6774', (133, 138))	('increased IL-6', 'Phenotype', 'HP:0030783', (26, 40))	('STAT3', 'Gene', '6774', (71, 76))	('STAT3', 'Gene', (133, 138))	('EGF', 'Gene', (59, 62))	('increased', 'PosReg', (26, 35))	('STAT3', 'Gene', (71, 76))	('increased IL-6 concentration', 'Phenotype', 'HP:0030783', (26, 54))	('IL-6', 'Gene', (128, 132))
64555	25197261	Notably, we show that S1P1 knockdown reduced IL-6/STAT3 signaling, representing another pathway by which SphK1/S1P regulates invasion.	('knockdown', 'Var', (27, 36))	('STAT3', 'Gene', '6774', (50, 55))	('STAT3', 'Gene', (50, 55))	('IL-6', 'Gene', (45, 49))	('S1P1', 'Gene', '1901', (22, 26))	('S1P1', 'Gene', (22, 26))	('reduced', 'NegReg', (37, 44))	('IL-6', 'Gene', '3569', (45, 49))
64561	25197261	For example, SphK1 knockdown results in lower cell proliferation and smaller HNSCC tumors, and SphK1 inhibition increases radiation sensitivity.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('SphK1', 'Gene', (95, 100))	('inhibition', 'NegReg', (101, 111))	('SphK1', 'Gene', (13, 18))	('knockdown', 'Var', (19, 28))	('HNSCC tumors', 'Disease', (77, 89))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('radiation sensitivity', 'CPA', (122, 143))	('HNSCC tumors', 'Disease', 'MESH:D000077195', (77, 89))	('smaller', 'NegReg', (69, 76))	('HNSCC', 'Phenotype', 'HP:0012288', (77, 82))	('increases', 'PosReg', (112, 121))	('cell proliferation', 'CPA', (46, 64))	('lower', 'NegReg', (40, 45))
64563	25197261	In addition, immunodeficient mice subcutaneously injected with ESCC cells overexpressing SphK1 exhibited 6-fold greater lung metastasis compared to parent cells.	('immunodeficient', 'Disease', 'MESH:D007153', (13, 28))	('immunodeficient', 'Disease', (13, 28))	('SCC', 'Gene', '6317', (64, 67))	('SphK1', 'Gene', (89, 94))	('overexpressing', 'Var', (74, 88))	('lung metastasis', 'CPA', (120, 135))	('mice', 'Species', '10090', (29, 33))	('greater', 'PosReg', (112, 119))	('SCC', 'Gene', (64, 67))
64567	25197261	Also, ESCC cells overexpressing SphK1 had greater phosphorylation of EGF, while cells transfected with siRNA against SphK1 showed reduced EGFR phosphorylation.	('SCC', 'Gene', (7, 10))	('EGF', 'Gene', '1950', (138, 141))	('phosphorylation', 'MPA', (50, 65))	('EGFR', 'Gene', '1956', (138, 142))	('greater', 'PosReg', (42, 49))	('SCC', 'Gene', '6317', (7, 10))	('EGFR', 'Gene', (138, 142))	('SphK1', 'Var', (32, 37))	('EGF', 'Gene', (138, 141))	('EGF', 'Gene', (69, 72))	('EGF', 'Gene', '1950', (69, 72))
64568	25197261	Another study showed treatment with EGFR alone increased invasion (~4x) in carcinoma of the epiglottis (PCI-37A) and inhibition of EGFR inhibited invasion by 47-fold.	('carcinoma of the epiglottis', 'Disease', 'MESH:C537690', (75, 102))	('invasion', 'CPA', (57, 65))	('inhibited', 'NegReg', (136, 145))	('EGFR', 'Gene', '1956', (36, 40))	('EGFR', 'Gene', '1956', (131, 135))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('EGFR', 'Gene', (131, 135))	('increased', 'PosReg', (47, 56))	('inhibition', 'Var', (117, 127))	('carcinoma of the epiglottis', 'Disease', (75, 102))	('EGFR', 'Gene', (36, 40))	('invasion', 'CPA', (146, 154))
64578	25197261	We confirmed that invasive cells had greater phosphorylation of AKT (ser473) and extracellular signal-related kinase (ERK) than parent cells on immunoblot analysis (Figure 1A, right), which are consistent with an invasive phenotype.	('ERK', 'Gene', '5594', (118, 121))	('extracellular signal-related kinase', 'Gene', '5594', (81, 116))	('ERK', 'Gene', (118, 121))	('AKT', 'Gene', (64, 67))	('ser473', 'Chemical', '-', (69, 75))	('AKT', 'Gene', '207', (64, 67))	('phosphorylation', 'MPA', (45, 60))	('ser473', 'Var', (69, 75))	('greater', 'PosReg', (37, 44))	('extracellular signal-related kinase', 'Gene', (81, 116))
64590	25197261	As expected, EGF-induced phosphorylation of EGFR was greater in SphK1 overexpressing cells compared to mock conditions (Figure 2A).	('EGF', 'Gene', (44, 47))	('EGF', 'Gene', (13, 16))	('phosphorylation', 'MPA', (25, 40))	('SphK1', 'Gene', (64, 69))	('EGF', 'Gene', '1950', (44, 47))	('EGFR', 'Gene', '1956', (44, 48))	('greater', 'PosReg', (53, 60))	('EGFR', 'Gene', (44, 48))	('EGF', 'Gene', '1950', (13, 16))	('overexpressing', 'Var', (70, 84))
64593	25197261	Conversely, SphK1 knockdown reduced both p-EGFR and p-ERK (Figure 2B), consistent with a previous report documenting that SphK1 knockdown reduces EGFR phosphorylation.	('SphK1', 'Gene', (12, 17))	('knockdown', 'Var', (18, 27))	('reduced', 'NegReg', (28, 35))	('p-ERK', 'Gene', '9451', (52, 57))	('EGFR', 'Gene', '1956', (146, 150))	('knockdown', 'Var', (128, 137))	('SphK1', 'Gene', (122, 127))	('p-ERK', 'Gene', (52, 57))	('reduces', 'NegReg', (138, 145))	('EGFR', 'Gene', (146, 150))	('EGFR', 'Gene', '1956', (43, 47))	('EGFR', 'Gene', (43, 47))
64594	25197261	SphK1 overexpression also increased EGF-induced p-STAT3 (Figure 2A) and this was paralleled with significantly elevated extracellular IL-6 levels as measured with an ELISA assay (P < 0.01, Figure 2C, left panel).	('elevated', 'PosReg', (111, 119))	('overexpression', 'Var', (6, 20))	('STAT3', 'Gene', '6774', (50, 55))	('SphK1', 'Gene', (0, 5))	('EGF', 'Gene', '1950', (36, 39))	('elevated extracellular IL-6', 'Phenotype', 'HP:0030783', (111, 138))	('STAT3', 'Gene', (50, 55))	('IL-6', 'Gene', (134, 138))	('increased', 'PosReg', (26, 35))	('IL-6', 'Gene', '3569', (134, 138))	('EGF', 'Gene', (36, 39))
64595	25197261	Conversely, when SphK1 was knocked down, p-STAT3 was down regulated, suggesting that SphK1 may directly regulate STAT3 (Figure 2C).	('down regulated', 'NegReg', (53, 67))	('SphK1', 'Gene', (85, 90))	('STAT3', 'Gene', '6774', (113, 118))	('STAT3', 'Gene', '6774', (43, 48))	('SphK1', 'Gene', (17, 22))	('STAT3', 'Gene', (43, 48))	('STAT3', 'Gene', (113, 118))	('regulate', 'Reg', (104, 112))	('knocked', 'Var', (27, 34))
64596	25197261	SphK1 knockdown also caused a 40% reduction in extracellular IL-6 concentrations as measured in conditioned media (P < 0.01, Figure 2C right panel).	('SphK1', 'Gene', (0, 5))	('IL-6', 'Gene', (61, 65))	('reduction', 'NegReg', (34, 43))	('IL-6', 'Gene', '3569', (61, 65))	('knockdown', 'Var', (6, 15))
64598	25197261	EGFR variant III (vIII), a constitutively active form of EGFR, has been shown to mediate HNSCC invasion and cell proliferation through increased STAT3 activation.	('EGFR', 'Gene', (0, 4))	('STAT3', 'Gene', (145, 150))	('variant III', 'Var', (5, 16))	('EGFR', 'Gene', '1956', (0, 4))	('increased', 'PosReg', (135, 144))	('EGFR', 'Gene', '1956', (57, 61))	('mediate', 'PosReg', (81, 88))	('SCC', 'Gene', (91, 94))	('cell proliferation', 'CPA', (108, 126))	('HNSCC', 'Phenotype', 'HP:0012288', (89, 94))	('EGFR', 'Gene', (57, 61))	('activation', 'PosReg', (151, 161))	('STAT3', 'Gene', '6774', (145, 150))	('SCC', 'Gene', '6317', (91, 94))
64602	25197261	S1P1 knockdown was achieved using siRNA specific to the receptor and we confirmed that S1P1 knockdown significantly reduced S1P1 mRNA levels (P < 0.0001), but did not affect other receptors, mainly S1P2 and S1P3 (Figure 3A).	('S1P1', 'Gene', (124, 128))	('S1P1', 'Gene', '1901', (0, 4))	('S1P1', 'Gene', '1901', (87, 91))	('S1P1', 'Gene', '1901', (124, 128))	('knockdown', 'Var', (92, 101))	('S1P3', 'Gene', (207, 211))	('S1P3', 'Gene', '1903', (207, 211))	('S1P2', 'Gene', (198, 202))	('reduced', 'NegReg', (116, 123))	('S1P2', 'Gene', '9294', (198, 202))	('S1P1', 'Gene', (0, 4))	('S1P1', 'Gene', (87, 91))
64605	25197261	We found that S1P1 knockdown reduced extracellular IL-6 concentrations in media conditioned by cells treated with S1P (Figure 3C).	('S1P1', 'Gene', '1901', (14, 18))	('knockdown', 'Var', (19, 28))	('reduced', 'NegReg', (29, 36))	('IL-6', 'Gene', (51, 55))	('S1P1', 'Gene', (14, 18))	('IL-6', 'Gene', '3569', (51, 55))
64606	25197261	S1P1 knockdown also reduced IL-6 induced phosphorylation of STAT3 (Figure 3D), indicating that S1P1 is required for full activation of STAT3.	('STAT3', 'Gene', '6774', (135, 140))	('S1P1', 'Gene', '1901', (0, 4))	('reduced', 'NegReg', (20, 27))	('IL-6', 'Gene', '3569', (28, 32))	('knockdown', 'Var', (5, 14))	('STAT3', 'Gene', (135, 140))	('phosphorylation', 'MPA', (41, 56))	('STAT3', 'Gene', '6774', (60, 65))	('STAT3', 'Gene', (60, 65))	('S1P1', 'Gene', (95, 99))	('IL-6', 'Gene', (28, 32))	('S1P1', 'Gene', '1901', (95, 99))	('S1P1', 'Gene', (0, 4))
64607	25197261	Here, S1P1 knockdown reduced STAT3 activation, leading to reduced extracellular IL-6 concentrations.	('reduced', 'NegReg', (21, 28))	('S1P1', 'Gene', '1901', (6, 10))	('IL-6', 'Gene', (80, 84))	('STAT3', 'Gene', '6774', (29, 34))	('IL-6', 'Gene', '3569', (80, 84))	('STAT3', 'Gene', (29, 34))	('reduced', 'NegReg', (58, 65))	('knockdown', 'Var', (11, 20))	('S1P1', 'Gene', (6, 10))
64608	25197261	This suggests that not only does IL-6 drive STAT3 activation as previously documented, but S1P1 knockdown also exerts control over STAT3 activation and affects downstream signaling to dampen IL-6 production and release.	('knockdown', 'Var', (96, 105))	('affects', 'Reg', (152, 159))	('IL-6', 'Gene', (191, 195))	('release', 'MPA', (211, 218))	('dampen', 'NegReg', (184, 190))	('STAT3', 'Gene', (131, 136))	('IL-6', 'Gene', (33, 37))	('IL-6', 'Gene', '3569', (191, 195))	('IL-6', 'Gene', '3569', (33, 37))	('STAT3', 'Gene', '6774', (44, 49))	('S1P1', 'Gene', (91, 95))	('STAT3', 'Gene', (44, 49))	('S1P1', 'Gene', '1901', (91, 95))	('downstream signaling', 'MPA', (160, 180))	('STAT3', 'Gene', '6774', (131, 136))
64609	25197261	In addition, S1P1 knockdown reduced EGF-induced phosphorylation of STAT3 (Figure 3D).	('knockdown', 'Var', (18, 27))	('reduced', 'NegReg', (28, 35))	('STAT3', 'Gene', '6774', (67, 72))	('EGF', 'Gene', '1950', (36, 39))	('STAT3', 'Gene', (67, 72))	('S1P1', 'Gene', (13, 17))	('S1P1', 'Gene', '1901', (13, 17))	('EGF', 'Gene', (36, 39))
64612	25197261	However, it appears that S1P1 knockdown has the capacity to abrogate EGF-induced ERK activation, implying S1P1 is a highly influential regulator of ERK.	('activation', 'MPA', (85, 95))	('ERK', 'Gene', '5594', (148, 151))	('ERK', 'Gene', (148, 151))	('ERK', 'Gene', '5594', (81, 84))	('abrogate', 'NegReg', (60, 68))	('ERK', 'Gene', (81, 84))	('knockdown', 'Var', (30, 39))	('EGF', 'Gene', (69, 72))	('S1P1', 'Gene', (106, 110))	('S1P1', 'Gene', '1901', (25, 29))	('S1P1', 'Gene', '1901', (106, 110))	('EGF', 'Gene', '1950', (69, 72))	('S1P1', 'Gene', (25, 29))
64613	25197261	The key finding is that S1P1 inhibition resulted in reduced invasive ability in vitro and this coincided with reduced EGF-induced STAT3 activation and IL-6 levels.	('EGF', 'Gene', (118, 121))	('reduced', 'NegReg', (110, 117))	('reduced', 'NegReg', (52, 59))	('EGF', 'Gene', '1950', (118, 121))	('S1P1', 'Gene', '1901', (24, 28))	('STAT3', 'Gene', '6774', (130, 135))	('IL-6', 'Gene', (151, 155))	('STAT3', 'Gene', (130, 135))	('IL-6', 'Gene', '3569', (151, 155))	('S1P1', 'Gene', (24, 28))	('inhibition', 'Var', (29, 39))	('invasive ability in vitro', 'CPA', (60, 85))
64615	25197261	Thus, it is expected that perturbation of S1P1 would affect invasion.	('S1P1', 'Gene', '1901', (42, 46))	('S1P1', 'Gene', (42, 46))	('invasion', 'CPA', (60, 68))	('affect', 'Reg', (53, 59))	('perturbation', 'Var', (26, 38))
64618	25197261	Notably, we observed that S1P1 knockdown reduced IL-6 and EGF-induced activation of STAT3.	('reduced', 'NegReg', (41, 48))	('IL-6', 'Gene', '3569', (49, 53))	('STAT3', 'Gene', '6774', (84, 89))	('EGF', 'Gene', (58, 61))	('STAT3', 'Gene', (84, 89))	('S1P1', 'Gene', (26, 30))	('IL-6', 'Gene', (49, 53))	('S1P1', 'Gene', '1901', (26, 30))	('activation', 'PosReg', (70, 80))	('EGF', 'Gene', '1950', (58, 61))	('knockdown', 'Var', (31, 40))
64632	25197261	SphK1 overexpression promoted increased IL-6 concentrations, and EGF-induced EGFR and STAT3 phosphorylation.	('EGF', 'Gene', '1950', (65, 68))	('EGF', 'Gene', (77, 80))	('STAT3', 'Gene', (86, 91))	('IL-6', 'Gene', (40, 44))	('overexpression', 'Var', (6, 20))	('SphK1', 'Gene', (0, 5))	('IL-6', 'Gene', '3569', (40, 44))	('increased IL-6', 'Phenotype', 'HP:0030783', (30, 44))	('EGF', 'Gene', '1950', (77, 80))	('EGFR', 'Gene', '1956', (77, 81))	('EGF', 'Gene', (65, 68))	('increased', 'PosReg', (30, 39))	('increased IL-6 concentration', 'Phenotype', 'HP:0030783', (30, 58))	('EGFR', 'Gene', (77, 81))	('STAT3', 'Gene', '6774', (86, 91))
64635	25197261	SphK1 knockdown also decreased IL-6 levels and EGFR and STAT3 activation.	('IL-6', 'Gene', (31, 35))	('IL-6', 'Gene', '3569', (31, 35))	('STAT3', 'Gene', (56, 61))	('decreased', 'NegReg', (21, 30))	('SphK1', 'Gene', (0, 5))	('decreased IL-6', 'Phenotype', 'HP:0030783', (21, 35))	('EGFR', 'Gene', '1956', (47, 51))	('knockdown', 'Var', (6, 15))	('activation', 'PosReg', (62, 72))	('EGFR', 'Gene', (47, 51))	('STAT3', 'Gene', '6774', (56, 61))
64636	25197261	Notably, SphK1 knockdown reduced STAT3 activation in the absence of stimulation, indicating SphK1 regulates STAT3 under basal conditions.	('reduced', 'NegReg', (25, 32))	('STAT3', 'Gene', '6774', (33, 38))	('STAT3', 'Gene', '6774', (108, 113))	('knockdown', 'Var', (15, 24))	('STAT3', 'Gene', (108, 113))	('STAT3', 'Gene', (33, 38))	('SphK1', 'Gene', (9, 14))
64641	25197261	The effects of LRP-1 parallel our findings and thus, we cannot rule out the possibility that perturbation of SphK1 (and associated sphingolipids) dysregulate microdomain structure and lipid rafts which fuels a cascade of events leading to invasion.	('perturbation', 'Var', (93, 105))	('SphK1', 'Gene', (109, 114))	('lipid', 'Chemical', 'MESH:D008055', (138, 143))	('LRP-1', 'Gene', (15, 20))	('lipid', 'Chemical', 'MESH:D008055', (184, 189))	('lipid rafts', 'MPA', (184, 195))	('dysregulate', 'Reg', (146, 157))	('microdomain structure', 'MPA', (158, 179))	('LRP-1', 'Gene', '4035', (15, 20))	('sphingolipids', 'Chemical', 'MESH:D013107', (131, 144))
64647	25197261	Our data indicate that knockdown of S1P1 significantly reduces IL-6/STAT3 signaling; SphK1 positively regulates EGFR and STAT3 signaling to increase invasive ability.	('EGFR', 'Gene', (112, 116))	('IL-6', 'Gene', '3569', (63, 67))	('STAT3', 'Gene', '6774', (121, 126))	('regulates', 'Reg', (102, 111))	('SphK1', 'Gene', (85, 90))	('STAT3', 'Gene', (121, 126))	('invasive ability', 'CPA', (149, 165))	('S1P1', 'Gene', (36, 40))	('knockdown', 'Var', (23, 32))	('reduces', 'NegReg', (55, 62))	('S1P1', 'Gene', '1901', (36, 40))	('STAT3', 'Gene', '6774', (68, 73))	('IL-6', 'Gene', (63, 67))	('EGFR', 'Gene', '1956', (112, 116))	('increase', 'PosReg', (140, 148))	('STAT3', 'Gene', (68, 73))
64663	25197261	Briefly, after hydration of membranes, stable SCC-25 transfectants overexpressing SphK1 were seeded (0.35 x 105 cell/well) in the presence of FBS, G418 and EGF (50 ng/ml).	('SphK1', 'Gene', (82, 87))	('FBS', 'Disease', (142, 145))	('EGF', 'Gene', '1950', (156, 159))	('FBS', 'Disease', 'MESH:D005198', (142, 145))	('G418', 'Var', (147, 151))	('SCC-25', 'CellLine', 'CVCL:1682', (46, 52))	('EGF', 'Gene', (156, 159))
64681	26208877	Cross-cancer profiling of molecular alterations within the human autophagy interaction network Aberrant activation or disruption of autophagy promotes tumorigenesis in various preclinical models of cancer, but whether the autophagy pathway is a target for recurrent molecular alteration in human cancer patient samples is unknown.	('cancer', 'Phenotype', 'HP:0002664', (296, 302))	('alterations', 'Var', (36, 47))	('rat', 'Species', '10116', (40, 43))	('cancer', 'Disease', 'MESH:D009369', (6, 12))	('patient', 'Species', '9606', (303, 310))	('disruption', 'Var', (118, 128))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('cancer', 'Disease', (198, 204))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('cancer', 'Disease', 'MESH:D009369', (296, 302))	('human', 'Species', '9606', (290, 295))	('activation', 'PosReg', (104, 114))	('autophagy', 'CPA', (132, 141))	('cancer', 'Disease', (6, 12))	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('human', 'Species', '9606', (59, 64))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('Cross-cancer', 'Disease', 'MESH:C537866', (0, 12))	('Cross-cancer', 'Disease', (0, 12))	('tumor', 'Disease', (151, 156))	('rat', 'Species', '10116', (280, 283))	('promotes', 'PosReg', (142, 150))	('cancer', 'Disease', (296, 302))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
64683	26208877	We found 3 (RB1CC1/FIP200, ULK4, WDR45/WIPI4) and one (ATG7) core autophagy genes to be under positive selection for somatic mutations in endometrial carcinoma and clear cell renal carcinoma, respectively, while 29 autophagy regulators and pathway interactors, including previously identified KEAP1, NFE2L2, and MTOR, were significantly mutated in 6 of the 11 cancer types examined.	('RB1CC1', 'Gene', '9821', (12, 18))	('cancer', 'Phenotype', 'HP:0002664', (360, 366))	('endometrial carcinoma', 'Disease', (138, 159))	('ATG7', 'Gene', '10533', (55, 59))	('MTOR', 'Gene', (312, 316))	('MTOR', 'Gene', '2475', (312, 316))	('ULK4', 'Gene', (27, 31))	('NFE2L2', 'Gene', (300, 306))	('clear cell renal carcinoma', 'Disease', (164, 190))	('cancer', 'Disease', 'MESH:D009369', (360, 366))	('carcinoma', 'Phenotype', 'HP:0030731', (150, 159))	('WDR45', 'Gene', '11152', (33, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (181, 190))	('RB1CC1', 'Gene', (12, 18))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (138, 159))	('WIPI4', 'Gene', '11152', (39, 44))	('ATG7', 'Gene', (55, 59))	('clear cell renal carcinoma', 'Disease', 'MESH:C538614', (164, 190))	('mutations', 'Var', (125, 134))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (138, 159))	('FIP200', 'Gene', (19, 25))	('mutated', 'Var', (337, 344))	('KEAP1', 'Gene', '9817', (293, 298))	('ULK4', 'Gene', '54986', (27, 31))	('WDR45', 'Gene', (33, 38))	('KEAP1', 'Gene', (293, 298))	('cancer', 'Disease', (360, 366))	('WIPI4', 'Gene', (39, 44))	('NFE2L2', 'Gene', '4780', (300, 306))	('FIP200', 'Gene', '9821', (19, 25))	('clear cell renal carcinoma', 'Phenotype', 'HP:0006770', (164, 190))	('renal carcinoma', 'Phenotype', 'HP:0005584', (175, 190))
64687	26208877	AA autophagy-associated ATG autophagy-related BRCA breast invasive carcinoma CNA copy-number alteration COAD colon adenocarcinoma F frequency FAB French-American-British FC median fold-change GBM glioblastoma multiforme HNSC head and neck squamous cell carcinoma KIRC kidney renal clear cell carcinoma LAML acute myeloid leukemia LUAD lung adenocarcinoma LUSC lung squamous cell carcinoma NMF non-negative matrix factorization OS overall survival OV ovarian serous cystadenocarcinoma PPIs protein-protein interactions READ rectum adenocarcinoma RPKM reads-per-kilobase-per-million-mapped reads SNV single nucleotide variants UCEC uterine corpus endometrial carcinoma.	('rat', 'Species', '10116', (97, 100))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (365, 388))	('breast invasive carcinoma', 'Phenotype', 'HP:0003002', (51, 76))	('COAD', 'Disease', (104, 108))	('KIRC kidney renal clear cell carcinoma', 'Phenotype', 'HP:0006770', (263, 301))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (239, 262))	('glioblastoma', 'Phenotype', 'HP:0012174', (196, 208))	('BRCA', 'Gene', (46, 50))	('breast invasive carcinoma', 'Disease', 'MESH:D018270', (51, 76))	('UCEC uterine corpus', 'Phenotype', 'HP:0000139', (625, 644))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (225, 262))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (360, 388))	('glioblastoma multiforme', 'Disease', (196, 219))	('lung squamous cell carcinoma', 'Disease', (360, 388))	('colon adenocarcinoma', 'Disease', (109, 129))	('ovarian serous cystadenocarcinoma', 'Phenotype', 'HP:0012887', (450, 483))	('carcinoma', 'Phenotype', 'HP:0030731', (253, 262))	('lung adenocarcinoma', 'Disease', (335, 354))	('rectum adenocarcinoma', 'Disease', 'MESH:D012004', (523, 544))	('leukemia', 'Phenotype', 'HP:0001909', (321, 329))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (196, 219))	('carcinoma', 'Phenotype', 'HP:0030731', (292, 301))	('LUAD', 'Phenotype', 'HP:0030078', (330, 334))	('acute myeloid leukemia', 'Disease', (307, 329))	('LUSC', 'Phenotype', 'HP:0030359', (355, 359))	('breast invasive carcinoma', 'Disease', (51, 76))	('ovarian serous cystadenocarcinoma', 'Disease', (450, 483))	('kidney renal clear cell carcinoma', 'Disease', 'MESH:C538614', (268, 301))	('BRCA', 'Phenotype', 'HP:0003002', (46, 50))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (645, 666))	('OS', 'Chemical', '-', (427, 429))	('corpus endometrial carcinoma', 'Disease', (638, 666))	('COAD', 'Disease', 'MESH:D029424', (104, 108))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (313, 329))	('corpus endometrial carcinoma', 'Disease', 'MESH:D016889', (638, 666))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (335, 354))	('OV', 'Phenotype', 'HP:0012887', (447, 449))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (335, 354))	('neck squamous cell carcinoma', 'Disease', (234, 262))	('ovarian serous cystadenocarcinoma', 'Disease', 'MESH:D018284', (450, 483))	('kidney renal clear cell carcinoma', 'Disease', (268, 301))	('single nucleotide variants', 'Var', (598, 624))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (307, 329))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (234, 262))	('BRCA', 'Gene', '672', (46, 50))	('FAB', 'Chemical', '-', (142, 145))	('colon adenocarcinoma', 'Disease', 'MESH:D003110', (109, 129))	('carcinoma', 'Phenotype', 'HP:0030731', (345, 354))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (307, 329))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('HNSC', 'Phenotype', 'HP:0012288', (220, 224))	('rectum adenocarcinoma', 'Disease', (523, 544))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (360, 388))
64690	26208877	However, defective autophagy can also promote tumorigenesis through the accumulation of genotoxic cellular waste, which facilitates the acquisition of driver mutations and chromosomal lesions that can transform precancerous cells or benefit established tumor cells.	('tumor', 'Disease', 'MESH:D009369', (46, 51))	('facilitates', 'PosReg', (120, 131))	('cancer', 'Disease', (214, 220))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Disease', 'MESH:D009369', (253, 258))	('tumor', 'Disease', (46, 51))	('tumor', 'Phenotype', 'HP:0002664', (253, 258))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('autophagy', 'CPA', (19, 28))	('defective', 'Var', (9, 18))	('promote', 'PosReg', (38, 45))	('tumor', 'Disease', (253, 258))	('cancer', 'Disease', 'MESH:D009369', (214, 220))
64695	26208877	We analyzed patterns of Darwinian selective pressure for somatic mutations identified in AA genes, examined AA gene expression changes between tumor and adjacent normal tissue samples, and identified differentially abundant autophagy pathway genes between patient groups (obtained from unsupervised clustering on AA transcript abundance) that display significant differential overall survival (OS).	('tumor', 'Disease', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('overall', 'MPA', (376, 383))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('OS', 'Chemical', '-', (394, 396))	('autophagy pathway genes', 'Gene', (224, 247))	('patient', 'Species', '9606', (256, 263))	('mutations', 'Var', (65, 74))
64696	26208877	Our catalog of DNA and RNA changes to AA genes present in cancer patient samples will both inform current investigations and stimulate further research into the consequences of altered autophagy-associated genes in human cancers.	('cancer', 'Disease', 'MESH:D009369', (221, 227))	('cancers', 'Disease', 'MESH:D009369', (221, 228))	('cancers', 'Phenotype', 'HP:0002664', (221, 228))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('cancer', 'Disease', (221, 227))	('cancers', 'Disease', (221, 228))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('patient', 'Species', '9606', (65, 72))	('changes', 'Var', (27, 34))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('cancer', 'Disease', (58, 64))	('human', 'Species', '9606', (215, 220))
64701	26208877	and identified significantly mutated AA genes in 6 out of 11 cancer types (Benjamini-Hochberg (BH) adjusted P < 0.05; Fig.	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('cancer', 'Disease', (61, 67))	('mutated', 'Var', (29, 36))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('AA genes', 'Gene', (37, 45))
64702	26208877	Core autophagy genes (i.e., genes that build autophagosomes) were not found to be significantly mutated across most cancer types; however, UCEC and KIRC had significantly mutated core genes at patient frequencies of 0.06 or less: RB1CC1/FIP200 (0.060), ULK4 (0.048), WDR45/WIPI4 (0.044) and ATG4C (0.040) in UCEC, and ATG7 (0.032) in KIRC.	('WIPI4', 'Gene', '11152', (273, 278))	('RB1CC1', 'Gene', (230, 236))	('UCEC', 'Disease', (308, 312))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('0.044', 'Var', (280, 285))	('WDR45', 'Gene', (267, 272))	('FIP200', 'Gene', '9821', (237, 243))	('ULK4', 'Gene', '54986', (253, 257))	('ATG7', 'Gene', (318, 322))	('WIPI4', 'Gene', (273, 278))	('patient', 'Species', '9606', (193, 200))	('0.040', 'Var', (298, 303))	('mutated', 'Reg', (171, 178))	('cancer', 'Disease', (116, 122))	('RB1CC1', 'Gene', '9821', (230, 236))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('0.048', 'Var', (259, 264))	('ATG4C', 'Gene', '84938', (291, 296))	('ULK4', 'Gene', (253, 257))	('ATG4C', 'Gene', (291, 296))	('WDR45', 'Gene', '11152', (267, 272))	('FIP200', 'Gene', (237, 243))	('ATG7', 'Gene', '10533', (318, 322))
64703	26208877	In addition, a single truncating hotspot mutation was identified in RB1CC1 in UCEC (R1321* [F = 0.012], where the asterisk denotes a premature stop codon and infers a truncated protein; Table S2).	('truncated', 'MPA', (167, 176))	('R1321*', 'SUBSTITUTION', 'None', (84, 90))	('RB1CC1', 'Gene', '9821', (68, 74))	('infers', 'Reg', (158, 164))	('protein', 'Protein', (177, 184))	('R1321*', 'Var', (84, 90))	('RB1CC1', 'Gene', (68, 74))
64704	26208877	Across cancers, as previously reported by TCGA, we confirmed 4 AA genes to be significantly mutated at frequencies of between 0.048 and 0.176 in 2 or more cancer types (Fig.	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('cancer', 'Disease', 'MESH:D009369', (7, 13))	('mutated', 'Var', (92, 99))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('cancers', 'Disease', 'MESH:D009369', (7, 14))	('cancers', 'Phenotype', 'HP:0002664', (7, 14))	('cancers', 'Disease', (7, 14))	('cancer', 'Disease', (7, 13))	('cancer', 'Disease', (155, 161))	('cancer', 'Disease', 'MESH:D009369', (155, 161))
64708	26208877	The highest frequency hotspots included R80* in CDKN2A (F = 0.046, HNSC), P179R in PPP2R1A (F = 0.032, UCEC), D29H/G/N/Y and R34Q/G/P in NFE2L2 (F = 0.028, LUSC), S2215Y in MTOR (F = 0.012, UCEC), and R470C in KEAP1 (F = 0.011, LUSC).	('PPP2R1A', 'Gene', (83, 90))	('KEAP1', 'Gene', '9817', (210, 215))	('KEAP1', 'Gene', (210, 215))	('S2215Y', 'Mutation', 'rs587777894', (163, 169))	('R80*', 'SUBSTITUTION', 'None', (40, 44))	('R470C', 'Mutation', 'p.R470C', (201, 206))	('HNSC', 'Phenotype', 'HP:0012288', (67, 71))	('R34Q', 'Var', (125, 129))	('CDKN2A', 'Gene', (48, 54))	('P179R', 'Var', (74, 79))	('NFE2L2', 'Gene', '4780', (137, 143))	('R34Q', 'SUBSTITUTION', 'None', (125, 129))	('LUSC', 'Phenotype', 'HP:0030359', (156, 160))	('LUSC', 'Phenotype', 'HP:0030359', (228, 232))	('R80*', 'Var', (40, 44))	('CDKN2A', 'Gene', '1029', (48, 54))	('S2215Y', 'Var', (163, 169))	('D29H', 'SUBSTITUTION', 'None', (110, 114))	('PPP2R1A', 'Gene', '5518', (83, 90))	('MTOR', 'Gene', (173, 177))	('D29H', 'Var', (110, 114))	('NFE2L2', 'Gene', (137, 143))	('MTOR', 'Gene', '2475', (173, 177))	('P179R', 'Mutation', 'rs786205228', (74, 79))	('R470C', 'Var', (201, 206))
64709	26208877	Known hotspot substitutions in or near the DLG and ETGE KEAP1-binding motifs in NFE2L2 were observed in multiple cancers (HNSC, LUSC, UCEC); similarly, convergent hotspot mutations were present in CDKN2A (W110* and E120*) in both HNSC and LUSC, which are squamous cell carcinomas of distinct tissue type that share mutational landscapes.	('LUSC', 'Phenotype', 'HP:0030359', (128, 132))	('cancers', 'Phenotype', 'HP:0002664', (113, 120))	('carcinomas', 'Disease', (269, 279))	('cancers', 'Disease', (113, 120))	('CDKN2A', 'Gene', '1029', (197, 203))	('LUSC', 'Phenotype', 'HP:0030359', (239, 243))	('W110*', 'SUBSTITUTION', 'None', (205, 210))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (255, 278))	('KEAP1', 'Gene', '9817', (56, 61))	('HNSC', 'Phenotype', 'HP:0012288', (122, 126))	('KEAP1', 'Gene', (56, 61))	('HNSC', 'Disease', (230, 234))	('squamous cell carcinoma', 'Disease', (255, 278))	('carcinoma', 'Phenotype', 'HP:0030731', (269, 278))	('carcinomas', 'Phenotype', 'HP:0030731', (269, 279))	('cancers', 'Disease', 'MESH:D009369', (113, 120))	('E120*', 'Var', (215, 220))	('carcinomas', 'Disease', 'MESH:D002277', (269, 279))	('NFE2L2', 'Gene', '4780', (80, 86))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (255, 279))	('HNSC', 'Phenotype', 'HP:0012288', (230, 234))	('CDKN2A', 'Gene', (197, 203))	('E120*', 'SUBSTITUTION', 'None', (215, 220))	('LUSC', 'Disease', (239, 243))	('NFE2L2', 'Gene', (80, 86))	('W110*', 'Var', (205, 210))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (255, 278))
64722	26208877	Only 3 differentially expressed AA genes showed a significant difference of mRNA levels (Wilcoxon rank sum test P < 0.05) in patients with focal amplifications or homozygous deletions compared to patients normal for copy-number alterations: CDK5R1 (FC = 2.45) and CDKN2A (FC = 7.48) showed recurrent (patient count > 5) amplification in BRCA, while RAB24 (FC = 1.31) showed recurrent amplification in KIRC (Table S3).	('mRNA levels', 'MPA', (76, 87))	('amplification', 'Var', (320, 333))	('CDKN2A', 'Gene', '1029', (264, 270))	('rat', 'Species', '10116', (232, 235))	('BRCA', 'Phenotype', 'HP:0003002', (337, 341))	('RAB24', 'Gene', (349, 354))	('BRCA', 'Gene', '672', (337, 341))	('patient', 'Species', '9606', (196, 203))	('patients', 'Species', '9606', (196, 204))	('CDK5R1', 'Gene', '8851', (241, 247))	('BRCA', 'Gene', (337, 341))	('CDK5R1', 'Gene', (241, 247))	('patient', 'Species', '9606', (125, 132))	('RAB24', 'Gene', '53917', (349, 354))	('CDKN2A', 'Gene', (264, 270))	('patient', 'Species', '9606', (301, 308))	('patients', 'Species', '9606', (125, 133))
64724	26208877	Table 2 summarizes AA genes that showed significant increases or decreases of mRNA in tumors that harbored alterations in known disease genes or had reported clinical phenotypes, versus patients with no such alterations or reported phenotypes (list of all tested alterations and phenotypes in Methods; Wilcoxon rank sum test P < 0.05 and FC > 1.5 (RPKM)).	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('rat', 'Species', '10116', (111, 114))	('decreases', 'NegReg', (65, 74))	('alterations', 'Var', (107, 118))	('increases', 'PosReg', (52, 61))	('mRNA', 'MPA', (78, 82))	('tumors', 'Disease', (86, 92))	('rat', 'Species', '10116', (267, 270))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('rat', 'Species', '10116', (212, 215))	('patients', 'Species', '9606', (186, 194))
64739	26208877	LAML-G3 showed the highest enrichment of patients with FAB classifications M0, M1, M2, and M3, the designation of 'favorable cytogenetic risk,' and the following molecular features: WT1 mutation, CEBPA mutation, PML-RARA fusion, chromosome translocation t(15;17), CBFB-MYH11 fusion, and loss of chromosome 7 or deletion of 7q.	('WT1', 'Gene', '7490', (182, 185))	('RARA', 'Gene', (216, 220))	('CBFB', 'Gene', '865', (264, 268))	('RARA', 'Gene', '5914', (216, 220))	('FAB', 'Chemical', '-', (55, 58))	('MYH11', 'Gene', '4629', (269, 274))	('PML', 'Gene', '5371', (212, 215))	('WT1', 'Gene', (182, 185))	('CBFB', 'Gene', (264, 268))	('deletion', 'Var', (311, 319))	('patients', 'Species', '9606', (41, 49))	('loss', 'NegReg', (287, 291))	('PML', 'Gene', (212, 215))	('CEBPA', 'Gene', (196, 201))	('MYH11', 'Gene', (269, 274))	('CEBPA', 'Gene', '1050', (196, 201))	('chromosome translocation t', 'CPA', (229, 255))
64741	26208877	Poor surviving LAML-G4 patients showed the highest enrichment for TP53 mutation, loss of chromosome 5 or deletion of 5q, and the designation of 'complex cytogenetics,' as well as increased transcript abundance for the AA modulators LAPTM4B, OPTN, and PRR5.	('LAPTM4B', 'Gene', (232, 239))	('PRR5', 'Gene', (251, 255))	('PRR5', 'Gene', '55615', (251, 255))	('TP53', 'Gene', '7157', (66, 70))	('mutation', 'Var', (71, 79))	('TP53', 'Gene', (66, 70))	('patients', 'Species', '9606', (23, 31))	('transcript abundance', 'MPA', (189, 209))	('LAPTM4B', 'Gene', '55353', (232, 239))	('OPTN', 'Gene', (241, 245))	('deletion of', 'Var', (105, 116))	('OPTN', 'Gene', '10133', (241, 245))	('increased', 'PosReg', (179, 188))	('loss', 'Var', (81, 85))
64742	26208877	LAML-G1 and -G2 showed intermediate survival compared to other groups; LAML-G2 had the highest enrichment of FAB classifications M4 and M5, designations of 'intermediate cytogenetic risk' and 'normal karyotype,' as well as enrichment for MLL-X fusion, NPM1 mutation, and CBFB-MYH11 fusions.	('CBFB', 'Gene', (271, 275))	('MYH11', 'Gene', '4629', (276, 281))	('NPM1', 'Gene', (252, 256))	('CBFB', 'Gene', '865', (271, 275))	('mutation', 'Var', (257, 265))	('MLL', 'Gene', '4297', (238, 241))	('MYH11', 'Gene', (276, 281))	('NPM1', 'Gene', '4869', (252, 256))	('MLL', 'Gene', (238, 241))	('FAB', 'Chemical', '-', (109, 112))	('fusions', 'Reg', (282, 289))
64747	26208877	Conversely, KIRC-G3, which showed increased ATG16L2 transcripts, was enriched with patients with higher tumor grade (G4), higher tumor stage (T2a, T2b), and higher stage (stage III, stage IV), and included almost all instances of BAP1 mutation (previously associated with poor OS by TCGA).	('mutation', 'Var', (235, 243))	('OS', 'Chemical', '-', (277, 279))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('BAP1', 'Gene', (230, 234))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('tumor', 'Disease', (104, 109))	('transcripts', 'MPA', (52, 63))	('ATG16L2', 'Gene', (44, 51))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('ATG16L2', 'Gene', '89849', (44, 51))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('patients', 'Species', '9606', (83, 91))	('tumor', 'Disease', (129, 134))	('increased', 'PosReg', (34, 43))	('BAP1', 'Gene', '8314', (230, 234))
64752	26208877	HPV-negative (-) patients clustered in HNSC-G2 (intermediate OS), which was enriched for CDKN2A deletions and a large proportion of TP53 mutations, and showed decreased GABARAPL1 and SQSTM1 transcripts.	('SQSTM1', 'Gene', (183, 189))	('HPV', 'Species', '10566', (0, 3))	('SQSTM1', 'Gene', '8878', (183, 189))	('TP53', 'Gene', '7157', (132, 136))	('TP53', 'Gene', (132, 136))	('HNSC', 'Phenotype', 'HP:0012288', (39, 43))	('GABARAPL1', 'Gene', (169, 178))	('mutations', 'Var', (137, 146))	('CDKN2A', 'Gene', (89, 95))	('decreased', 'NegReg', (159, 168))	('deletions', 'Var', (96, 105))	('patients', 'Species', '9606', (17, 25))	('OS', 'Chemical', '-', (61, 63))	('APL', 'Phenotype', 'HP:0004836', (174, 177))	('CDKN2A', 'Gene', '1029', (89, 95))	('GABARAPL1', 'Gene', '23710', (169, 178))
64753	26208877	The poorest OS group (HNSC-G1) contained the majority of NFE2L2/NRF2 mutations and showed striking increases of TNFSF10/TRAIL and OPTN abundance.	('mutations', 'Var', (69, 78))	('OPTN', 'Gene', '10133', (130, 134))	('NFE2L2', 'Gene', (57, 63))	('OPTN', 'Gene', (130, 134))	('TRAIL', 'Gene', (120, 125))	('NRF2', 'Gene', '4780', (64, 68))	('HNSC', 'Phenotype', 'HP:0012288', (22, 26))	('OS', 'Chemical', '-', (12, 14))	('NRF2', 'Gene', (64, 68))	('TRAIL', 'Gene', '8743', (120, 125))	('TNFSF10', 'Gene', (112, 119))	('increases', 'PosReg', (99, 108))	('NFE2L2', 'Gene', '4780', (57, 63))	('TNFSF10', 'Gene', '8743', (112, 119))
64757	26208877	In line with these ideas, our analyses revealed a diverse array of autophagy regulators and pathway interactors that were targeted for point mutation or showed differential expression in tumors, in specific disease contexts (Fig.	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('differential', 'Reg', (160, 172))	('point mutation', 'Var', (135, 149))	('autophagy', 'CPA', (67, 76))	('tumors', 'Disease', (187, 193))	('tumors', 'Disease', 'MESH:D009369', (187, 193))	('expression', 'MPA', (173, 183))	('tumors', 'Phenotype', 'HP:0002664', (187, 193))
64758	26208877	At the same time, our survey of single-nucleotide mutations targeting the autophagy pathway in 11 cancer types, coupled with our differential gene expression analysis of the pathway in matched tumor and normal samples in 4 of those cancer types, showed that the core autophagy machinery remains largely intact at the DNA level and is expressed at similar transcript levels as matched normal tissue, at least for the cancer types for which data was available from TCGA at the time of this study.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('cancer', 'Disease', 'MESH:D009369', (232, 238))	('cancer', 'Disease', (232, 238))	('cancer', 'Phenotype', 'HP:0002664', (416, 422))	('tumor', 'Disease', (193, 198))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('autophagy', 'CPA', (74, 83))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('cancer', 'Disease', (98, 104))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('cancer', 'Disease', 'MESH:D009369', (416, 422))	('single-nucleotide mutations', 'Var', (32, 59))	('cancer', 'Disease', (416, 422))
64759	26208877	Few ATG genes were found to be recurrently point-mutated (5 of 37 mammalian ATGs and paralogs), while those that were tended to be mutated at low frequency.	('ATG genes', 'Gene', (4, 13))	('mammalian', 'Species', '9606', (66, 75))	('point-mutated', 'Var', (43, 56))
64783	26208877	Deregulation of BNIP3, a hypoxia responsive gene which can induce cell death and mitophagy, is associated with aggressive disease in cancer.	('BNIP3', 'Gene', (16, 21))	('Deregulation', 'Var', (0, 12))	('BNIP3', 'Gene', '664', (16, 21))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('cancer', 'Disease', (133, 139))	('hypoxia', 'Disease', (25, 32))	('hypoxia', 'Disease', 'MESH:D000860', (25, 32))	('aggressive disease', 'Disease', 'MESH:D001523', (111, 129))	('associated with', 'Reg', (95, 110))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('aggressive disease', 'Disease', (111, 129))
64786	26208877	BNIP3's contribution to tumorigenesis has yet to be linked to its role in mitophagy; however, the fact that increased levels of BNIP3 are associated with more aggressive disease suggests that a function in tumor cell survival via autophagy or mitophagy is a more likely mechanistic scenario than a role in cell death, in contexts of BNIP3 overexpression.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('BNIP3', 'Gene', '664', (128, 133))	('mitophagy', 'CPA', (243, 252))	('BNIP3', 'Gene', '664', (333, 338))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('increased', 'PosReg', (108, 117))	('aggressive disease', 'Disease', (159, 177))	('tumor', 'Disease', (24, 29))	('BNIP3', 'Gene', (0, 5))	('levels', 'Var', (118, 124))	('aggressive disease', 'Disease', 'MESH:D001523', (159, 177))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('BNIP3', 'Gene', (128, 133))	('tumor', 'Disease', (206, 211))	('BNIP3', 'Gene', (333, 338))	('BNIP3', 'Gene', '664', (0, 5))	('associated', 'Reg', (138, 148))	('tumor', 'Disease', 'MESH:D009369', (206, 211))	('autophagy', 'CPA', (230, 239))
64787	26208877	Autophagy has documented roles in KRAS-driven lung and pancreatic cancer progression, and overactive RAS has been shown to upregulate BNIP3.	('overactive', 'Var', (90, 100))	('BNIP3', 'Gene', (134, 139))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('pancreatic cancer', 'Disease', 'MESH:D010190', (55, 72))	('pancreatic cancer', 'Disease', (55, 72))	('upregulate', 'PosReg', (123, 133))	('BNIP3', 'Gene', '664', (134, 139))	('lung', 'Disease', (46, 50))	('Autophagy', 'CPA', (0, 9))	('RAS', 'Protein', (101, 104))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (55, 72))
64789	26208877	Of 6 cancers showing significantly mutated AA genes (Fig.	('mutated', 'Var', (35, 42))	('cancers', 'Phenotype', 'HP:0002664', (5, 12))	('cancers', 'Disease', (5, 12))	('cancers', 'Disease', 'MESH:D009369', (5, 12))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))
64790	26208877	2), UCEC had the highest number of significantly mutated genes (SMGs), including nearly all significantly mutated core autophagy genes (ATG4C, ULK4, RB1CC1/FIP200), as well as a high frequency of MTOR mutation (0.105) that included previously identified hotspot mutations recently characterized as MTOR pathway activity boosters (C1483F and S2215Y).	('boosters', 'PosReg', (320, 328))	('ULK4', 'Gene', '54986', (143, 147))	('RB1CC1', 'Gene', (149, 155))	('activity', 'MPA', (311, 319))	('S2215Y', 'Var', (341, 347))	('ATG4C', 'Gene', '84938', (136, 141))	('FIP200', 'Gene', (156, 162))	('SMG', 'Gene', '23034', (64, 67))	('ATG4C', 'Gene', (136, 141))	('C1483F', 'Mutation', 'rs786205165', (330, 336))	('FIP200', 'Gene', '9821', (156, 162))	('ULK4', 'Gene', (143, 147))	('C1483F', 'Var', (330, 336))	('S2215Y', 'Mutation', 'rs587777894', (341, 347))	('MTOR', 'Gene', (196, 200))	('RB1CC1', 'Gene', '9821', (149, 155))	('MTOR', 'Gene', '2475', (196, 200))	('SMG', 'Gene', (64, 67))	('MTOR', 'Gene', (298, 302))	('MTOR', 'Gene', '2475', (298, 302))
64791	26208877	Histological UCEC subtypes include Type I endometrioid tumors that typically have better prognosis and are associated with high frequency PTEN mutation (among other lesions), while Type II serous tumors have worse prognosis and are classified by high frequency TP53 mutation.	('Type I endometrioid tumors', 'Disease', (35, 61))	('PTEN', 'Gene', (138, 142))	('better', 'PosReg', (82, 88))	('TP53', 'Gene', '7157', (261, 265))	('PTEN', 'Gene', '5728', (138, 142))	('high frequency', 'Var', (123, 137))	('Type I endometrioid tumors', 'Disease', 'MESH:D016889', (35, 61))	('Type II serous tumors', 'Disease', (181, 202))	('tumors', 'Phenotype', 'HP:0002664', (196, 202))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('mutation', 'Var', (143, 151))	('TP53', 'Gene', (261, 265))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('Type II serous tumors', 'Disease', 'MESH:D018284', (181, 202))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))
64792	26208877	Almost all AA SMGs identified in this study were found in patients with endometrioid UCEC, including 20 patients that were double-mutant for MTOR and PTEN.	('MTOR', 'Gene', (141, 145))	('double-mutant', 'Var', (123, 136))	('MTOR', 'Gene', '2475', (141, 145))	('patients', 'Species', '9606', (104, 112))	('endometrioid UCEC', 'Disease', (72, 89))	('patients', 'Species', '9606', (58, 66))	('PTEN', 'Gene', (150, 154))	('SMG', 'Gene', (14, 17))	('PTEN', 'Gene', '5728', (150, 154))	('SMG', 'Gene', '23034', (14, 17))	('found', 'Reg', (49, 54))
64794	26208877	It is noteworthy that we observed a recurrent truncating mutation (R1321*) in autophagy induction complex member RB1CC1 in 3 UCEC patients, along with a predicted damaging substitution (S93L) in 2 additional patients, suggesting autophagy induction may be compromised in these endometrioid UCEC patients.	('RB1CC1', 'Gene', (113, 119))	('endometrioid UCEC', 'Disease', (277, 294))	('patients', 'Species', '9606', (208, 216))	('RB1CC1', 'Gene', '9821', (113, 119))	('patients', 'Species', '9606', (295, 303))	('S93L', 'Mutation', 'rs757154137', (186, 190))	('patients', 'Species', '9606', (130, 138))	('R1321*', 'Var', (67, 73))	('R1321*', 'SUBSTITUTION', 'None', (67, 73))
64799	26208877	HPV positive (+) HNSC is associated with better prognosis, while TP53 mutation and CDKN2A deletion are associated with HPV-negative (-) HNSC.	('deletion', 'Var', (90, 98))	('CDKN2A', 'Gene', '1029', (83, 89))	('TP53', 'Gene', '7157', (65, 69))	('HPV', 'Species', '10566', (0, 3))	('TP53', 'Gene', (65, 69))	('HNSC', 'Phenotype', 'HP:0012288', (17, 21))	('HPV', 'Species', '10566', (119, 122))	('HNSC', 'Phenotype', 'HP:0012288', (136, 140))	('mutation', 'Var', (70, 78))	('CDKN2A', 'Gene', (83, 89))
64800	26208877	Unsupervised clustering on 211 AA gene expression levels grouped HPV+ patients with patients showing the most favorable survival and HPV- patients with TP53 and CDKN2A mutant patients (Fig.	('CDKN2A', 'Gene', '1029', (161, 167))	('patients', 'Species', '9606', (70, 78))	('mutant', 'Var', (168, 174))	('HPV', 'Species', '10566', (65, 68))	('patients', 'Species', '9606', (84, 92))	('TP53', 'Gene', '7157', (152, 156))	('patients', 'Species', '9606', (175, 183))	('TP53', 'Gene', (152, 156))	('CDKN2A', 'Gene', (161, 167))	('HPV', 'Species', '10566', (133, 136))	('patients', 'Species', '9606', (138, 146))
64801	26208877	HNSC-G1 patients showed very poor survival and included 8/14 patients with mutated NFE2L2/NRF2 (Table S1), an important transcription factor in the oxidative stress response pathway.	('NRF2', 'Gene', '4780', (90, 94))	('poor', 'NegReg', (29, 33))	('NRF2', 'Gene', (90, 94))	('patients', 'Species', '9606', (61, 69))	('mutated', 'Var', (75, 82))	('NFE2L2', 'Gene', '4780', (83, 89))	('HNSC', 'Phenotype', 'HP:0012288', (0, 4))	('oxidative stress', 'Phenotype', 'HP:0025464', (148, 164))	('NFE2L2', 'Gene', (83, 89))	('patients', 'Species', '9606', (8, 16))
64802	26208877	Activating NFE2L2 mutations have been identified in various cancers and are thought to lead to the constitutive activation of oxidative stress pathway genes that benefit tumor cell survival, including the autophagy cargo receptor SQSTM1/p62.	('p62', 'Gene', '8878', (237, 240))	('Activating', 'PosReg', (0, 10))	('p62', 'Gene', (237, 240))	('benefit', 'PosReg', (162, 169))	('tumor', 'Disease', (170, 175))	('SQSTM1', 'Gene', (230, 236))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('activation', 'PosReg', (112, 122))	('oxidative stress', 'Phenotype', 'HP:0025464', (126, 142))	('cancers', 'Disease', 'MESH:D009369', (60, 67))	('NFE2L2', 'Gene', '4780', (11, 17))	('SQSTM1', 'Gene', '8878', (230, 236))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('NFE2L2', 'Gene', (11, 17))	('oxidative stress pathway genes', 'Gene', (126, 156))	('cancers', 'Phenotype', 'HP:0002664', (60, 67))	('cancers', 'Disease', (60, 67))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('mutations', 'Var', (18, 27))
64804	26208877	Three of 4 HNSC-G2 patients mutant for NFE2L2 harbored previously characterized E79 or E82 activating changes and we found median SQSTM1/P62 mRNA levels to be higher in HNSC NFE2L2 mutants versus nonmutants (Table 2), suggesting that increased SQSTM1/p62-mediated autophagic degradation of KEAP1 could occur in NFE2L2 mutant HNSC patients with poor OS.	('KEAP1', 'Gene', (290, 295))	('NFE2L2', 'Gene', (39, 45))	('mutants', 'Var', (181, 188))	('NFE2L2', 'Gene', (174, 180))	('mutant', 'Var', (318, 324))	('P62', 'Gene', '8878', (137, 140))	('patients', 'Species', '9606', (330, 338))	('p62', 'Gene', '8878', (251, 254))	('p62', 'Gene', (251, 254))	('HNSC', 'Phenotype', 'HP:0012288', (11, 15))	('SQSTM1', 'Gene', (244, 250))	('NFE2L2', 'Gene', '4780', (311, 317))	('OS', 'Chemical', '-', (349, 351))	('HNSC', 'Phenotype', 'HP:0012288', (169, 173))	('patients', 'Species', '9606', (19, 27))	('SQSTM1', 'Gene', (130, 136))	('P62', 'Gene', (137, 140))	('NFE2L2', 'Gene', '4780', (39, 45))	('NFE2L2', 'Gene', '4780', (174, 180))	('mutant', 'Var', (28, 34))	('SQSTM1', 'Gene', '8878', (244, 250))	('NFE2L2', 'Gene', (311, 317))	('SQSTM1', 'Gene', '8878', (130, 136))	('HNSC', 'Phenotype', 'HP:0012288', (325, 329))	('KEAP1', 'Gene', '9817', (290, 295))	('autophagic degradation', 'CPA', (264, 286))	('higher', 'PosReg', (159, 165))
64808	26208877	Diagnosis and prognosis of acute myeloid leukemia (LAML) is defined by specific combinations of cytogenetic and molecular risk factors, including transcription-factor fusions and recurrent mutations that tend toward mutual exclusivity.	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (27, 49))	('leukemia', 'Phenotype', 'HP:0001909', (41, 49))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (27, 49))	('fusions', 'Var', (167, 174))	('acute myeloid leukemia', 'Disease', (27, 49))	('mutations', 'Var', (189, 198))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (33, 49))
64810	26208877	LAML-G3 patients with the most favorable OS showed enrichment for PML-RARA fusions and CEBPA mutations, alterations associated with better prognosis in LAML, whereas LAML-G4 patients with the poorest OS were enriched for TP53 mutations and monosomal (MK) and complex karyotypes (CK).	('OS', 'Chemical', '-', (41, 43))	('rat', 'Species', '10116', (108, 111))	('CEBPA', 'Gene', '1050', (87, 92))	('mutations', 'Var', (93, 102))	('OS', 'Chemical', '-', (200, 202))	('RARA', 'Gene', '5914', (70, 74))	('TP53', 'Gene', '7157', (221, 225))	('PML', 'Gene', '5371', (66, 69))	('patients', 'Species', '9606', (174, 182))	('RARA', 'Gene', (70, 74))	('TP53', 'Gene', (221, 225))	('mutations', 'Var', (226, 235))	('CEBPA', 'Gene', (87, 92))	('PML', 'Gene', (66, 69))	('monosomal', 'Var', (240, 249))	('patients', 'Species', '9606', (8, 16))
64820	26208877	High DNM1 expression is part of a gene expression signature specific to M3 patients and leukemic promyelocytes, and is also required for mitophagy in yeast, where it recruits the fission complex to degrading mitochondria.	('mitochondria', 'MPA', (208, 220))	('leukemic', 'Disease', (88, 96))	('High', 'Var', (0, 4))	('degrading', 'NegReg', (198, 207))	('patients', 'Species', '9606', (75, 83))	('yeast', 'Species', '4932', (150, 155))	('DNM1', 'Gene', (5, 9))	('leukemic', 'Disease', 'MESH:D007938', (88, 96))	('DNM1', 'Gene', '1759', (5, 9))
64825	26208877	It would be interesting to investigate whether high DNM1 expression increases mitophagy in M3 patients compared to other subtypes, and whether ATG4D, ULK1 and/or ATG13 are required for mitophagy in this context.	('increases', 'PosReg', (68, 77))	('DNM1', 'Gene', (52, 56))	('ATG13', 'Gene', (162, 167))	('mitophagy', 'CPA', (78, 87))	('patients', 'Species', '9606', (94, 102))	('ATG13', 'Gene', '9776', (162, 167))	('ATG4D', 'Gene', '84971', (143, 148))	('high', 'Var', (47, 51))	('ATG4D', 'Gene', (143, 148))	('DNM1', 'Gene', '1759', (52, 56))	('ULK1', 'Gene', (150, 154))	('ULK1', 'Gene', '8408', (150, 154))
64828	26208877	Hypoxia also plays an important role in cyst expansion in PKD through the upregulation of HIF1A in cyst epithelium; however, HIF1A has been shown to increase autophagic flux in a rat proximal tubular cell line.	('Hypoxia', 'Disease', 'MESH:D000860', (0, 7))	('Hypoxia', 'Disease', (0, 7))	('increase', 'PosReg', (149, 157))	('PKD', 'Disease', (58, 61))	('HIF1A', 'Var', (125, 130))	('PKD', 'Disease', 'MESH:C537180', (58, 61))	('upregulation', 'PosReg', (74, 86))	('autophagic flux', 'CPA', (158, 173))	('rat', 'Species', '10116', (179, 182))
64831	26208877	Loss-of-function VHL mutations in KIRC lead to HIFA stabilization and the transcriptional activation of tumor-promoting hypoxia responsive genes; however, TCGA recently found that in the absence of VHL alteration (which occurred in 20% of the TCGA KIRC cohort) other molecular alterations exist that may act to stabilize HIFA.	('VHL', 'Disease', (198, 201))	('Loss-of-function', 'NegReg', (0, 16))	('VHL', 'Disease', 'MESH:D006623', (198, 201))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('VHL', 'Disease', (17, 20))	('VHL', 'Disease', 'MESH:D006623', (17, 20))	('tumor', 'Disease', (104, 109))	('hypoxia', 'Disease', (120, 127))	('hypoxia', 'Disease', 'MESH:D000860', (120, 127))	('transcriptional', 'MPA', (74, 89))	('rat', 'Species', '10116', (281, 284))	('rat', 'Species', '10116', (206, 209))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('mutations', 'Var', (21, 30))
64834	26208877	For example, activating mutations in tyrosine kinase signaling pathway genes (e.g., EGFR, ALK, RET, ERBB2) are common in LUAD, while NFE2L2 mutations are a distinguishing feature of LUSC.	('LUSC', 'Phenotype', 'HP:0030359', (182, 186))	('RET', 'Gene', (95, 98))	('NFE2L2', 'Gene', '4780', (133, 139))	('activating', 'PosReg', (13, 23))	('ALK', 'Gene', '238', (90, 93))	('LUAD', 'Phenotype', 'HP:0030078', (121, 125))	('LUAD', 'Disease', (121, 125))	('NFE2L2', 'Gene', (133, 139))	('EGFR', 'Gene', '1956', (84, 88))	('EGFR', 'Gene', (84, 88))	('ERBB2', 'Gene', '2064', (100, 105))	('ALK', 'Gene', (90, 93))	('RET', 'Gene', '5979', (95, 98))	('ERBB2', 'Gene', (100, 105))	('mutations', 'Var', (24, 33))
64836	26208877	We stratified gene expression of all 211 AA genes in both LUAD and LUSC by known recurrent somatic disease-specific alterations, including EGFR and KRAS alterations, and did not find differences in core gene expression between altered and wild-type patients; however, LUSC patients with EGFR amplification had increased mRNA levels of NFE2L2 (median FC > 2; Table S5).	('NFE2L2', 'Gene', '4780', (335, 341))	('LUAD', 'Phenotype', 'HP:0030078', (58, 62))	('patients', 'Species', '9606', (273, 281))	('LUSC', 'Phenotype', 'HP:0030359', (268, 272))	('increased', 'PosReg', (310, 319))	('patients', 'Species', '9606', (249, 257))	('NFE2L2', 'Gene', (335, 341))	('rat', 'Species', '10116', (5, 8))	('EGFR', 'Gene', '1956', (139, 143))	('LUSC', 'Phenotype', 'HP:0030359', (67, 71))	('rat', 'Species', '10116', (157, 160))	('EGFR', 'Gene', (139, 143))	('EGFR', 'Gene', '1956', (287, 291))	('rat', 'Species', '10116', (120, 123))	('EGFR', 'Gene', (287, 291))	('amplification', 'Var', (292, 305))
64838	26208877	We confirmed that both KEAP1 and NFE2L2 are significantly mutated in TCGA lung cancer patients (Fig.	('NFE2L2', 'Gene', (33, 39))	('lung cancer', 'Disease', (74, 85))	('lung cancer', 'Phenotype', 'HP:0100526', (74, 85))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('lung cancer', 'Disease', 'MESH:D008175', (74, 85))	('KEAP1', 'Gene', '9817', (23, 28))	('mutated', 'Var', (58, 65))	('NFE2L2', 'Gene', '4780', (33, 39))	('KEAP1', 'Gene', (23, 28))	('patients', 'Species', '9606', (86, 94))
64839	26208877	KEAP1 mutations predicted to be LOF (Table S1) were found in both subtypes, while NFE2L2 mutations were found only in LUSC, as well as in HNSC and UCEC.	('NFE2L2', 'Gene', '4780', (82, 88))	('KEAP1', 'Gene', (0, 5))	('HNSC', 'Phenotype', 'HP:0012288', (138, 142))	('NFE2L2', 'Gene', (82, 88))	('LUSC', 'Phenotype', 'HP:0030359', (118, 122))	('LUSC', 'Disease', (118, 122))	('KEAP1', 'Gene', '9817', (0, 5))	('mutations', 'Var', (6, 15))
64840	26208877	Several LUSC and HNSC patients had previously characterized E79 NFE2L2 activating mutations, while activating E82 mutations were identified only in UCEC patients (Table S1).	('UCEC', 'Disease', (148, 152))	('E79', 'Var', (60, 63))	('patients', 'Species', '9606', (153, 161))	('NFE2L2', 'Gene', (64, 70))	('patients', 'Species', '9606', (22, 30))	('HNSC', 'Phenotype', 'HP:0012288', (17, 21))	('LUSC', 'Phenotype', 'HP:0030359', (8, 12))	('activating', 'PosReg', (71, 81))	('NFE2L2', 'Gene', '4780', (64, 70))
64841	26208877	SQSTM1 is a target gene for transcriptional upregulation by NFE2L2, and KEAP1 mutants in both LUAD and LUSC had significantly higher SQSTM1 mRNA levels compared to wild-type patients (Table 2; Table S5); therefore, as previously suggested, a positive-feedback loop may exist in patients with overactive NFE2L2/NRF2 (through NFE2L2 and/or KEAP1 mutation), whereby transcriptionally upregulated levels of SQSTM1 further stabilize NFE2L2 protein levels, through increased SQSTM1-mediated autophagic degradation of KEAP1.	('NFE2L2', 'Gene', (428, 434))	('KEAP1', 'Gene', (511, 516))	('higher', 'PosReg', (126, 132))	('SQSTM1', 'Gene', (469, 475))	('patients', 'Species', '9606', (278, 286))	('SQSTM1', 'Gene', (0, 6))	('autophagic degradation', 'CPA', (485, 507))	('NFE2L2', 'Gene', (324, 330))	('SQSTM1', 'Gene', (403, 409))	('NFE2L2', 'Gene', '4780', (60, 66))	('LUSC', 'Phenotype', 'HP:0030359', (103, 107))	('KEAP1', 'Gene', '9817', (72, 77))	('SQSTM1', 'Gene', (133, 139))	('KEAP1', 'Gene', (72, 77))	('SQSTM1', 'Gene', '8878', (469, 475))	('SQSTM1', 'Gene', '8878', (0, 6))	('NRF2', 'Gene', '4780', (310, 314))	('SQSTM1', 'Gene', '8878', (403, 409))	('NFE2L2', 'Gene', (60, 66))	('NFE2L2', 'Gene', '4780', (303, 309))	('LUAD', 'Phenotype', 'HP:0030078', (94, 98))	('SQSTM1', 'Gene', '8878', (133, 139))	('NFE2L2', 'Gene', '4780', (428, 434))	('increased', 'PosReg', (459, 468))	('KEAP1', 'Gene', '9817', (338, 343))	('upregulated', 'PosReg', (381, 392))	('patients', 'Species', '9606', (174, 182))	('NRF2', 'Gene', (310, 314))	('NFE2L2', 'Gene', '4780', (324, 330))	('stabilize', 'PosReg', (418, 427))	('KEAP1', 'Gene', (338, 343))	('mutants', 'Var', (78, 85))	('KEAP1', 'Gene', '9817', (511, 516))	('NFE2L2', 'Gene', (303, 309))
64844	26208877	In this study, 2 known tumor-suppressors that can also induce autophagy were mutated or had decreased mRNA in lung tumor samples compared to normal tissues, STK11/LKB1 and DRAM1, respectively, while a novel negative-regulator of both autophagy and chaperone-mediated autophagy, LRRK2, also had decreased mRNA levels in both LUAD and LUSC.	('lung tumor', 'Disease', 'MESH:D008175', (110, 120))	('LRRK2', 'Gene', (278, 283))	('tumor', 'Disease', (115, 120))	('mutated', 'Var', (77, 84))	('STK11', 'Gene', '6794', (157, 162))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('mRNA levels', 'MPA', (304, 315))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('autophagy', 'CPA', (62, 71))	('LKB1', 'Gene', (163, 167))	('LUSC', 'Phenotype', 'HP:0030359', (333, 337))	('lung tumor', 'Disease', (110, 120))	('decreased', 'NegReg', (294, 303))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('LUAD', 'Phenotype', 'HP:0030078', (324, 328))	('mRNA', 'MPA', (102, 106))	('lung tumor', 'Phenotype', 'HP:0100526', (110, 120))	('LRRK2', 'Gene', '120892', (278, 283))	('tumor', 'Disease', (23, 28))	('decreased', 'NegReg', (92, 101))	('STK11', 'Gene', (157, 162))	('DRAM1', 'Gene', (172, 177))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('DRAM1', 'Gene', '55332', (172, 177))	('LKB1', 'Gene', '6794', (163, 167))
64849	26208877	We found that stratification of expression of our gene set by the alteration status of molecular changes previously implicated in breast cancer (Table S5) revealed increased mRNA levels of ATG5 and FOXO3 in KRAS-amplified BRCA patients.	('ATG5', 'Gene', '9474', (189, 193))	('FOXO3', 'Gene', (198, 203))	('KRAS-amplified', 'Var', (207, 221))	('breast cancer', 'Disease', (130, 143))	('rat', 'Species', '10116', (70, 73))	('breast cancer', 'Phenotype', 'HP:0003002', (130, 143))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('ATG5', 'Gene', (189, 193))	('rat', 'Species', '10116', (16, 19))	('FOXO3', 'Gene', '2309', (198, 203))	('mRNA levels', 'MPA', (174, 185))	('BRCA', 'Phenotype', 'HP:0003002', (222, 226))	('BRCA', 'Gene', '672', (222, 226))	('breast cancer', 'Disease', 'MESH:D001943', (130, 143))	('patients', 'Species', '9606', (227, 235))	('BRCA', 'Gene', (222, 226))	('increased', 'PosReg', (164, 173))
64854	26208877	Further research is required to determine whether the sequence alterations and gene expression changes identified here lead to concomitant changes in protein expression and/or function, and to examine whether alterations that lead to true functional changes benefit tumor cells through modulated autophagy or through other, autophagy-independent processes.	('changes', 'Reg', (139, 146))	('alterations', 'Var', (63, 74))	('rat', 'Species', '10116', (67, 70))	('autophagy', 'CPA', (296, 305))	('changes', 'Var', (95, 102))	('benefit', 'PosReg', (258, 265))	('tumor', 'Disease', 'MESH:D009369', (266, 271))	('function', 'MPA', (176, 184))	('rat', 'Species', '10116', (213, 216))	('tumor', 'Phenotype', 'HP:0002664', (266, 271))	('tumor', 'Disease', (266, 271))	('protein expression', 'MPA', (150, 168))	('modulated', 'Reg', (286, 295))
64859	26208877	To capture cancer associated alterations targeting AA genes in the wider autophagy interaction network7(AIN), we further included non-overlapping genes from 65 bait genes used by Behrends and colleagues in their mass spectrometry-based immuno-precipitation proteomic screen that originally defined the AIN, as well as prominent autophagy regulators, adaptors and cargo receptors described in the literature (Table S1).	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('rat', 'Species', '10116', (400, 403))	('rat', 'Species', '10116', (33, 36))	('alterations', 'Var', (29, 40))	('cancer', 'Disease', 'MESH:D009369', (11, 17))	('cancer', 'Disease', (11, 17))
64863	26208877	We further split each group by its nucleotide change (A>C, A>G, A>T, C>G, C>T, G>T); stratifying mutations in this manner allows the model to consider the effect of a tumor's mutational mechanism on the background profile.	('A>T', 'Var', (64, 67))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('C>G', 'Var', (69, 72))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('C>T', 'Var', (74, 77))	('tumor', 'Disease', (167, 172))	('rat', 'Species', '10116', (87, 90))
64864	26208877	Under the assumption that synonymous mutations do not directly affect the encoded protein and thus do not confer an advantage to the gene, we use them to calculate a tumor's background mutation profile; that is, mutations appearing by chance through a tumor's mutational mechanism.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('tumor', 'Disease', 'MESH:D009369', (252, 257))	('tumor', 'Disease', (166, 171))	('mutations', 'Var', (37, 46))	('tumor', 'Phenotype', 'HP:0002664', (252, 257))	('mutations', 'Var', (212, 221))	('tumor', 'Disease', (252, 257))
64929	32317009	For all samples (public and in-house), whilst aiming at partly sidelining variable tumor fraction as a source of variability, loci (100 kb bins) were given three states to serve as model features: loss (- 1), copy neutral (0), and gain (+ 1).	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumor', 'Disease', (83, 88))	('gain', 'PosReg', (231, 235))	('loss (- 1', 'Var', (197, 206))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
64941	32317009	Here, deletions and gains are positioned in the same loci, whereas their amplitudes:a concept defined as the absolute value of a segment's log2 ratio:are mostly tumor fraction dependent.	('deletions', 'Var', (6, 15))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('tumor', 'Disease', (161, 166))	('tumor', 'Disease', 'MESH:D009369', (161, 166))
64943	32317009	Second, as SBs represent a distinct part of the total tumor, whereas LBs study all sources of cfDNA simultaneously, tumor heterogeneity introduces additional disconcordance (e.g., patient 37; at 5p and chromosome X; Additional file 4).	('disconcordance', 'MPA', (158, 172))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('chromosome X', 'Var', (202, 214))	('tumor', 'Disease', (54, 59))	('tumor', 'Disease', (116, 121))	('patient', 'Species', '9606', (180, 187))
64976	32317009	Our work further shows that LB-derived copy numbers can accurately differentiate SCLC from NSCLC, partly because SCLC ctDNA seems to be detectable with high sensitivity, and SCLCs are represented by distinct copy number profiles.	('NSCLC', 'Disease', 'MESH:D002289', (91, 96))	('copy', 'Var', (39, 43))	('NSCLC', 'Phenotype', 'HP:0030358', (91, 96))	('SCLC', 'Phenotype', 'HP:0030357', (174, 178))	('differentiate', 'Reg', (67, 80))	('SCLC', 'Gene', '7864', (113, 117))	('SCLC', 'Gene', (113, 117))	('SCLC', 'Gene', '7864', (92, 96))	('SCLC', 'Phenotype', 'HP:0030357', (113, 117))	('SCLC', 'Gene', (92, 96))	('SCLC', 'Phenotype', 'HP:0030357', (92, 96))	('NSCLC', 'Disease', (91, 96))	('SCLC', 'Gene', '7864', (81, 85))	('SCLC', 'Phenotype', 'HP:0030357', (81, 85))	('SCLC', 'Gene', (81, 85))	('SCLC', 'Gene', '7864', (174, 178))	('SCLC', 'Gene', (174, 178))
64982	32317009	Interesting in this context, small cell transformation of EGFR mutated LUAD is sometimes seen as a mechanism of resistance.	('mutated', 'Var', (63, 70))	('EGFR', 'Gene', (58, 62))	('EGFR', 'Gene', '1956', (58, 62))
65048	32218831	Tissues were then probed overnight at 4 C with appropriate primary antibodies against OPN (1:300, Abcam), AAT (1:300, Abcam) and KNG1 (1:200, Abnova).	('OPN', 'Gene', '6696', (86, 89))	('AAT', 'Gene', (106, 109))	('OPN', 'Gene', (86, 89))	('1:300', 'Var', (111, 116))	('KNG1', 'Gene', (129, 133))	('KNG1', 'Gene', '3827', (129, 133))
65078	32218831	A previous study found that aberrant ceRNA-mediated regulation of KNG1 contributed to glioblastoma-induced angiogenesis, which provided potential targets for the development of novel therapeutic strategies for glioblastoma.	('KNG1', 'Gene', (66, 70))	('KNG1', 'Gene', '3827', (66, 70))	('contributed', 'Reg', (71, 82))	('aberrant', 'Var', (28, 36))	('glioblastoma', 'Disease', (210, 222))	('glioblastoma', 'Disease', (86, 98))	('glioblastoma', 'Disease', 'MESH:D005909', (210, 222))	('glioblastoma', 'Disease', 'MESH:D005909', (86, 98))	('glioblastoma', 'Phenotype', 'HP:0012174', (210, 222))	('glioblastoma', 'Phenotype', 'HP:0012174', (86, 98))
65086	32218831	High OPN levels in plasma were associated with higher levels of hypoxia in tumors and a higher risk of recurrence in patients with early stage NSCLC.	('NSCLC', 'Disease', (143, 148))	('High', 'Var', (0, 4))	('higher', 'PosReg', (47, 53))	('NSCLC', 'Disease', 'MESH:D002289', (143, 148))	('NSCLC', 'Phenotype', 'HP:0030358', (143, 148))	('OPN', 'Gene', '6696', (5, 8))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('hypoxia in tumors', 'Disease', 'MESH:D000860', (64, 81))	('patients', 'Species', '9606', (117, 125))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('hypoxia in tumors', 'Disease', (64, 81))	('OPN', 'Gene', (5, 8))
65124	31632984	The ectopic expression for this family might promote tumor proliferation, metastasis, invasion while inhibit tumor apoptosis.	('inhibit', 'NegReg', (101, 108))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('metastasis', 'CPA', (74, 84))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('promote', 'PosReg', (45, 52))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumor', 'Disease', (53, 58))	('ectopic expression', 'Var', (4, 22))	('invasion', 'CPA', (86, 94))	('tumor', 'Disease', (109, 114))
65126	31632984	Interestingly, the ectopic expression of miR-25 might also promote invasion and migration of cancer cells through KLF4-ERK and RhoGDI1-WNT/beta-catenin signaling pathways (Wang et al.,; Ding et al.,).	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('ectopic expression', 'Var', (19, 37))	('invasion', 'CPA', (67, 75))	('migration', 'CPA', (80, 89))	('miR-25', 'Gene', '407014', (41, 47))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('beta-catenin', 'Gene', (139, 151))	('ERK', 'Gene', '5594', (119, 122))	('ERK', 'Gene', (119, 122))	('RhoGDI1', 'Gene', (127, 134))	('promote', 'PosReg', (59, 66))	('RhoGDI1', 'Gene', '396', (127, 134))	('KLF4', 'Gene', '9314', (114, 118))	('miR-25', 'Gene', (41, 47))	('KLF4', 'Gene', (114, 118))	('beta-catenin', 'Gene', '1499', (139, 151))
65133	31632984	Downregulated miR-363 could enhance the expression level of SOX4 and lead to the process of EMT and metastasis of colorectal cancer (Hu et al.,).	('metastasis of colorectal cancer', 'Disease', 'MESH:D015179', (100, 131))	('Downregulated', 'Var', (0, 13))	('metastasis of colorectal cancer', 'Disease', (100, 131))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('expression level', 'MPA', (40, 56))	('SOX4', 'Gene', (60, 64))	('colorectal cancer', 'Phenotype', 'HP:0003003', (114, 131))	('enhance', 'PosReg', (28, 35))	('miR-363', 'Gene', '574031', (14, 21))	('SOX4', 'Gene', '6659', (60, 64))	('lead to', 'Reg', (69, 76))	('EMT', 'CPA', (92, 95))	('miR-363', 'Gene', (14, 21))
65153	31632984	A vector containing the mutant 3'-UTR fragment of RGS3 was constructed as a negative control.	('mutant', 'Var', (24, 30))	('RGS3', 'Gene', (50, 54))	('RGS3', 'Gene', '5998', (50, 54))
65194	31632984	With respect to the clinical contribution of the miR-92a family to prognosis of cancer patients, the pooled HR for the high and low expression groups was 2.26 [95% CI: 1.70-3.00] indicating that groups with high expression of miR-92a family had an increased risk (2.26 times) of poor outcomes compared to groups with low expression.	('poor', 'Disease', (279, 283))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('miR', 'Gene', '220972', (226, 229))	('miR', 'Gene', (226, 229))	('miR', 'Gene', '220972', (49, 52))	('miR', 'Gene', (49, 52))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('patients', 'Species', '9606', (87, 95))	('high expression', 'Var', (207, 222))	('cancer', 'Disease', (80, 86))
65209	31632984	In addition, the abnormal expression of RGS3 might regulate the TGF-beta signaling pathway by interfering with the heteromerization of Smad protein (Xu et al.,).	('heteromerization', 'MPA', (115, 131))	('interfering', 'NegReg', (94, 105))	('TGF-beta', 'Gene', '7040', (64, 72))	('RGS3', 'Gene', '5998', (40, 44))	('regulate', 'Reg', (51, 59))	('TGF-beta', 'Gene', (64, 72))	('abnormal', 'Var', (17, 25))	('RGS3', 'Gene', (40, 44))
65230	30412141	Overexpression of TPX2 is related to poor survival rate in most solid tumors, which indicates that the expression level of TPX2 is a significant prognostic parameter and potential therapeutic target in various solid tumors.	('solid tumors', 'Disease', (64, 76))	('survival', 'MPA', (42, 50))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('poor', 'NegReg', (37, 41))	('TPX2', 'Gene', (123, 127))	('tumors', 'Phenotype', 'HP:0002664', (216, 222))	('solid tumors', 'Disease', (210, 222))	('solid tumors', 'Disease', 'MESH:D009369', (64, 76))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('Overexpression', 'Var', (0, 14))	('solid tumors', 'Disease', 'MESH:D009369', (210, 222))	('TPX2', 'Gene', (18, 22))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))
65232	30412141	Further studies indicated that TPX2 controlled MT nucleation, function, and coaction with other cell structures as an MT-associated protein (MAP), and improper expression of TPX2 lead to chromosomal instability, caused centrosome amplification, and developed aneuploidy, which highly correlated with the occurrences and developments of various tumors.	('improper expression', 'Var', (151, 170))	('caused', 'Reg', (212, 218))	('aneuploidy', 'Disease', (259, 269))	('tumor', 'Phenotype', 'HP:0002664', (344, 349))	('tumors', 'Disease', (344, 350))	('TPX2', 'Gene', (174, 178))	('lead to', 'Reg', (179, 186))	('developed', 'PosReg', (249, 258))	('chromosomal instability', 'Phenotype', 'HP:0040012', (187, 210))	('tumors', 'Phenotype', 'HP:0002664', (344, 350))	('tumors', 'Disease', 'MESH:D009369', (344, 350))	('chromosomal', 'MPA', (187, 198))	('aneuploidy', 'Disease', 'MESH:D000782', (259, 269))	('centrosome amplification', 'CPA', (219, 243))
65251	30412141	In the following analysis of subgroups classified by different cancer types, we discovered that TPX2 expression was related to the worse 3-year OS of gastric cancer (n = 2, OR = 10.63, 95% CI: 3.41-33.15, P < .0001) (Fig.	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('gastric cancer', 'Phenotype', 'HP:0012126', (150, 164))	('expression', 'Var', (101, 111))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('gastric cancer', 'Disease', (150, 164))	('cancer', 'Disease', (158, 164))	('TPX2', 'Gene', (96, 100))	('gastric cancer', 'Disease', 'MESH:D013274', (150, 164))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('cancer', 'Disease', (63, 69))
65254	30412141	Consistent with the results above, TPX2 expression was related to the worse 5-year OS of hepatocellular cancer (n = 2, OR = 4.25, 95% CI: 2.36-7.67, P < .00001) (Fig.	('TPX2', 'Gene', (35, 39))	('OS of hepatocellular cancer', 'Disease', (83, 110))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('expression', 'Var', (40, 50))	('hepatocellular cancer', 'Phenotype', 'HP:0001402', (89, 110))	('OS of hepatocellular cancer', 'Disease', 'MESH:C567932', (83, 110))
65265	30412141	For instance, Yan et al found that transfection of TPX2 siRNA decreased the viability and proliferation capacity of bladder carcinoma cell lines and TPX2-depleted tumor cells obviously grew more slowly in nude mice.	('bladder carcinoma', 'Disease', (116, 133))	('bladder carcinoma', 'Disease', 'MESH:D001749', (116, 133))	('nude mice', 'Species', '10090', (205, 214))	('decreased', 'NegReg', (62, 71))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('slowly', 'NegReg', (195, 201))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('transfection', 'Var', (35, 47))	('TPX2', 'Gene', (51, 55))	('viability', 'CPA', (76, 85))	('tumor', 'Disease', (163, 168))	('proliferation capacity', 'CPA', (90, 112))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (116, 133))	('grew', 'CPA', (185, 189))
65283	29844840	Comprehensive identification of microRNA arm selection preference in lung cancer: miR-324-5p and -3p serve oncogenic functions in lung cancer MicroRNA (miRNA/miR) dysfunction is a hallmark of lung cancer, and results in the dysregulation of tumor suppressors and oncogenes during lung cancer progression.	('lung cancer', 'Phenotype', 'HP:0100526', (130, 141))	('MicroRNA', 'MPA', (142, 150))	('dysfunction', 'Var', (163, 174))	('lung cancer', 'Disease', 'MESH:D008175', (280, 291))	('dysregulation', 'MPA', (224, 237))	('lung cancer', 'Disease', 'MESH:D008175', (192, 203))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('lung cancer', 'Phenotype', 'HP:0100526', (280, 291))	('miR-324', 'Gene', (82, 89))	('miR', 'Gene', '220972', (82, 85))	('tumor', 'Disease', (241, 246))	('oncogenes', 'Gene', (263, 272))	('lung cancer', 'Phenotype', 'HP:0100526', (192, 203))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('lung cancer', 'Disease', (69, 80))	('miR', 'Gene', '220972', (152, 155))	('tumor', 'Disease', 'MESH:D009369', (241, 246))	('lung cancer', 'Disease', (130, 141))	('hallmark of lung cancer', 'Disease', (180, 203))	('miR', 'Gene', (82, 85))	('miR', 'Gene', '220972', (158, 161))	('cancer', 'Phenotype', 'HP:0002664', (285, 291))	('miR-324', 'Gene', '442898', (82, 89))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('miR', 'Gene', (152, 155))	('lung cancer', 'Disease', (280, 291))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))	('hallmark of lung cancer', 'Disease', 'MESH:D008175', (180, 203))	('lung cancer', 'Disease', 'MESH:D008175', (69, 80))	('miR', 'Gene', (158, 161))	('lung cancer', 'Disease', 'MESH:D008175', (130, 141))	('lung cancer', 'Phenotype', 'HP:0100526', (69, 80))
65299	29844840	Transformation from a normal cell to a malignant lung cancer cell phenotype is considered to occur in a multistep manner through a series of genetic and epigenetic alterations; ultimately evolving into invasive cancer by clonal expansion.	('epigenetic alterations', 'Var', (153, 175))	('invasive cancer', 'Disease', (202, 217))	('lung cancer', 'Phenotype', 'HP:0100526', (49, 60))	('invasive cancer', 'Disease', 'MESH:D009362', (202, 217))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('malignant lung cancer', 'Disease', (39, 60))	('malignant lung cancer', 'Disease', 'MESH:D008175', (39, 60))
65300	29844840	Dysfunctional noncoding RNAs, including microRNAs (miRNAs/miRs), have been reported to be critical in carcinogenesis.	('carcinogenesis', 'Disease', 'MESH:D063646', (102, 116))	('noncoding RNAs', 'Protein', (14, 28))	('carcinogenesis', 'Disease', (102, 116))	('miR', 'Gene', '220972', (58, 61))	('miR', 'Gene', (58, 61))	('miR', 'Gene', '220972', (51, 54))	('miR', 'Gene', (51, 54))	('Dysfunctional', 'Var', (0, 13))
65303	29844840	Numerous dysregulated miRNAs have been reported in lung cancer cells, including let-7 and miR-17, -20a, -29, -107, -126, -138, and -185.	('miR-17', 'Gene', (90, 96))	('let-7', 'Var', (80, 85))	('miR', 'Gene', '220972', (22, 25))	('lung cancer', 'Disease', 'MESH:D008175', (51, 62))	('miR-17', 'Gene', '406952', (90, 96))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('lung cancer', 'Disease', (51, 62))	('lung cancer', 'Phenotype', 'HP:0100526', (51, 62))	('miR', 'Gene', '220972', (90, 93))	('miR', 'Gene', (90, 93))	('miR', 'Gene', (22, 25))
65304	29844840	Dysfunctional expression of these miRNAs serves a critical function in the co-modulation of cell cycle progression, angiogenesis, apoptosis, adhesion and motility of lung cancer cells.	('apoptosis', 'CPA', (130, 139))	('motility of lung cancer', 'Disease', 'MESH:D008175', (154, 177))	('adhesion', 'CPA', (141, 149))	('angiogenesis', 'CPA', (116, 128))	('miR', 'Gene', '220972', (34, 37))	('miR', 'Gene', (34, 37))	('cell cycle progression', 'CPA', (92, 114))	('motility of lung cancer', 'Disease', (154, 177))	('lung cancer', 'Phenotype', 'HP:0100526', (166, 177))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('Dysfunctional', 'Var', (0, 13))
65361	29844840	Following transfection, the expression of miR-324-5p and -3p significantly increased in the transfected cells compared with the scramble controls (data not shown).	('expression', 'MPA', (28, 38))	('miR-324', 'Gene', (42, 49))	('increased', 'PosReg', (75, 84))	('transfected', 'Var', (92, 103))	('miR-324', 'Gene', '442898', (42, 49))
65433	28176958	Literature search was conducted in databases such as PubMed, Embase, and Web of Science, using the following words "(microRNA-100 OR miR-100 OR mir100) AND (tumor OR neoplasm OR cancer OR carcinoma OR malignancy)."	('tumor', 'Disease', (157, 162))	('carcinoma OR malignancy', 'Disease', 'MESH:D009369', (188, 211))	('carcinoma', 'Phenotype', 'HP:0030731', (188, 197))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('mir100', 'Var', (144, 150))	('carcinoma OR malignancy', 'Disease', (188, 211))	('neoplasm', 'Disease', (166, 174))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('miR-100', 'Gene', '406892', (133, 140))	('cancer', 'Disease', (178, 184))	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('neoplasm', 'Disease', 'MESH:D009369', (166, 174))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('microRNA-100', 'Gene', '406892', (117, 129))	('miR-100', 'Gene', (133, 140))	('microRNA-100', 'Gene', (117, 129))
65445	28176958	This aberrant expression of miR-100 not only has diagnostic implications but also can predict cancer patient survival.	('predict', 'Reg', (86, 93))	('miR-100', 'Gene', (28, 35))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('miR-100', 'Gene', '406892', (28, 35))	('patient', 'Species', '9606', (101, 108))	('aberrant', 'Var', (5, 13))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
65450	28176958	A literature search was conducted in databases such as PubMed, Embase, and Web of Science, using the following words "(microRNA-100 OR miR-100 OR mir100) AND (tumor OR neoplasm OR cancer OR carcinoma OR malignancy)."	('miR-100', 'Gene', '406892', (135, 142))	('neoplasm', 'Disease', (168, 176))	('carcinoma OR malignancy', 'Disease', (190, 213))	('microRNA-100', 'Gene', '406892', (119, 131))	('carcinoma', 'Phenotype', 'HP:0030731', (190, 199))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('neoplasm', 'Disease', 'MESH:D009369', (168, 176))	('microRNA-100', 'Gene', (119, 131))	('tumor', 'Disease', (159, 164))	('miR-100', 'Gene', (135, 142))	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('carcinoma OR malignancy', 'Disease', 'MESH:D009369', (190, 213))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('cancer', 'Disease', (180, 186))	('mir100', 'Var', (146, 152))
65454	28176958	The following details of each article were recorded: publication year, first author's last name, cancer type, treatment, sample size, stage of disease, miR-100 assay, the cutoff value to discriminate high or low expression of miR-100, sample sources, follow-up time, and HR (low versus high expression).	('low', 'NegReg', (208, 211))	('miR-100', 'Gene', '406892', (152, 159))	('cancer', 'Disease', (97, 103))	('miR-100', 'Gene', (152, 159))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('miR-100', 'Gene', '406892', (226, 233))	('high', 'Var', (200, 204))	('miR-100', 'Gene', (226, 233))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
65480	28176958	Bi et al transfected U2OS cells (human osteo-sarcoma line) with a miR-100 construct or with an antisense of miR-100.	('miR-100', 'Gene', (66, 73))	('U2OS', 'CellLine', 'CVCL:0042', (21, 25))	('sarcoma', 'Phenotype', 'HP:0100242', (45, 52))	('miR-100', 'Gene', (108, 115))	('antisense', 'Var', (95, 104))	('osteo-sarcoma', 'Disease', 'MESH:D009261', (39, 52))	('human', 'Species', '9606', (33, 38))	('osteo-sarcoma', 'Phenotype', 'HP:0002669', (39, 52))	('miR-100', 'Gene', '406892', (66, 73))	('miR-100', 'Gene', '406892', (108, 115))	('osteo-sarcoma', 'Disease', (39, 52))
65532	28079142	Realistically, the role of EGFR-TKIs in NSCLC with mutated EGFR is not well known.	('EGFR', 'Gene', '1956', (27, 31))	('EGFR', 'Gene', (27, 31))	('EGFR', 'Gene', (59, 63))	('NSCLC', 'Phenotype', 'HP:0030358', (40, 45))	('NSCLC', 'Disease', (40, 45))	('EGFR', 'Gene', '1956', (59, 63))	('NSCLC', 'Disease', 'MESH:D002289', (40, 45))	('mutated', 'Var', (51, 58))
65535	28079142	Cox analysis showed that PS 0-1, recurrent disease, EGFR mutations, or EGFR-TKI treatment were associated with improved OS.	('EGFR', 'Gene', '1956', (52, 56))	('EGFR', 'Gene', (52, 56))	('improved', 'PosReg', (111, 119))	('mutations', 'Var', (57, 66))	('EGFR', 'Gene', '1956', (71, 75))	('EGFR', 'Gene', (71, 75))	('recurrent disease', 'Disease', (33, 50))
65536	28079142	In patients with EGFR-activating mutations, Cox analysis showed that patients with adenocarcinoma, recurrent disease, or EGFR-TKI treatment had significantly longer survival.	('recurrent', 'Disease', (99, 108))	('EGFR', 'Gene', '1956', (121, 125))	('longer', 'PosReg', (158, 164))	('adenocarcinoma', 'Disease', (83, 97))	('EGFR', 'Gene', (121, 125))	('mutations', 'Var', (33, 42))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('patients', 'Species', '9606', (3, 11))	('EGFR', 'Gene', '1956', (17, 21))	('adenocarcinoma', 'Disease', 'MESH:D000230', (83, 97))	('patients', 'Species', '9606', (69, 77))	('EGFR', 'Gene', (17, 21))
65537	28079142	Patients with EGFR-activating mutations who received EGFR-TKI therapy had a median OS of 24.3 months, which was significantly longer than those who had not received EGFR-TKI therapy (10.8 months).	('EGFR', 'Gene', (165, 169))	('EGFR', 'Gene', '1956', (14, 18))	('EGFR', 'Gene', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('mutations', 'Var', (30, 39))	('EGFR', 'Gene', '1956', (53, 57))	('EGFR', 'Gene', (53, 57))	('EGFR', 'Gene', '1956', (165, 169))
65538	28079142	Patients with wild-type EGFR had a median OS of 9.7 months and Cox analysis showed that PS score and disease type were independent predictors.	('EGFR', 'Gene', '1956', (24, 28))	('EGFR', 'Gene', (24, 28))	('wild-type', 'Var', (14, 23))	('Patients', 'Species', '9606', (0, 8))
65539	28079142	EGFR-TKI therapy is an independently prognostic factor for NSCLC with mutated EGFR.	('NSCLC', 'Disease', 'MESH:D002289', (59, 64))	('EGFR', 'Gene', (0, 4))	('NSCLC', 'Phenotype', 'HP:0030358', (59, 64))	('EGFR', 'Gene', '1956', (78, 82))	('EGFR', 'Gene', (78, 82))	('EGFR', 'Gene', '1956', (0, 4))	('NSCLC', 'Disease', (59, 64))	('mutated', 'Var', (70, 77))
65540	28079142	A more effective therapy is needed for patients with wild-type EGFR.	('wild-type', 'Var', (53, 62))	('EGFR', 'Gene', (63, 67))	('EGFR', 'Gene', '1956', (63, 67))	('patients', 'Species', '9606', (39, 47))
65544	28079142	The immense progress in treatment options, including the development of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs), has changed the modality of treatment for NSCLC harbouring EGFR-activating mutations.	('NSCLC', 'Disease', (189, 194))	('EGFR', 'Gene', (206, 210))	('NSCLC', 'Disease', 'MESH:D002289', (189, 194))	('epidermal growth factor receptor', 'Gene', (72, 104))	('mutations', 'Var', (222, 231))	('NSCLC', 'Phenotype', 'HP:0030358', (189, 194))	('EGFR', 'Gene', '1956', (106, 110))	('epidermal growth factor receptor', 'Gene', '1956', (72, 104))	('EGFR', 'Gene', '1956', (206, 210))	('EGFR', 'Gene', (106, 110))
65547	28079142	The frequency of EGFR mutations in lung cancer in Caucasian is 17%; in American lung adenocarcinoma populations, the frequency is 23%; and in Chinese lung adenocarcinoma patients, it is 51%.	('patients', 'Species', '9606', (170, 178))	('lung cancer', 'Disease', 'MESH:D008175', (35, 46))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (80, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (160, 169))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (150, 169))	('lung adenocarcinoma', 'Disease', (80, 99))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (80, 99))	('lung cancer', 'Disease', (35, 46))	('lung cancer', 'Phenotype', 'HP:0100526', (35, 46))	('mutations', 'Var', (22, 31))	('lung adenocarcinoma', 'Disease', (150, 169))	('EGFR', 'Gene', '1956', (17, 21))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (150, 169))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('EGFR', 'Gene', (17, 21))
65549	28079142	A series of randomized clinical trials on EGFR-TKIs for patients with EGFR-activating mutations have demonstrated that EGFR-TKIs are the most effective therapy, with distinct prolonged, progression-free survival of approximately 9.2-13.7 months.	('mutations', 'Var', (86, 95))	('patients', 'Species', '9606', (56, 64))	('EGFR', 'Gene', '1956', (42, 46))	('EGFR', 'Gene', '1956', (70, 74))	('EGFR', 'Gene', (42, 46))	('EGFR', 'Gene', (70, 74))	('EGFR', 'Gene', '1956', (119, 123))	('EGFR', 'Gene', (119, 123))
65552	28079142	also showed that EGFR-TKI therapy significantly delays disease progression in patients with EGFR mutations but has no demonstrable impact on OS; treatment with EGFR-TKIs had no impact on OS for patients with mutated-EGFR or wild-type EGFR.	('mutations', 'Var', (97, 106))	('EGFR', 'Gene', (216, 220))	('disease progression', 'CPA', (55, 74))	('patients', 'Species', '9606', (194, 202))	('EGFR', 'Gene', (234, 238))	('delays', 'NegReg', (48, 54))	('EGFR', 'Gene', '1956', (160, 164))	('patients', 'Species', '9606', (78, 86))	('EGFR', 'Gene', (160, 164))	('EGFR', 'Gene', '1956', (92, 96))	('EGFR', 'Gene', '1956', (17, 21))	('EGFR', 'Gene', (92, 96))	('EGFR', 'Gene', '1956', (216, 220))	('EGFR', 'Gene', '1956', (234, 238))	('EGFR', 'Gene', (17, 21))
65553	28079142	Compared with platinum-based chemotherapy, afatinib, a second-generation TKI, did not improve OS in an entire population with EGFR-sensitive mutations but improved OS for patients with del19 EGFR mutations.	('del19', 'Mutation', 'c.del19', (185, 190))	('mutations', 'Var', (141, 150))	('EGFR', 'Gene', (126, 130))	('improved', 'PosReg', (155, 163))	('EGFR', 'Gene', '1956', (191, 195))	('EGFR', 'Gene', (191, 195))	('del19', 'Var', (185, 190))	('patients', 'Species', '9606', (171, 179))	('afatinib', 'Chemical', 'MESH:D000077716', (43, 51))	('EGFR', 'Gene', '1956', (126, 130))	('platinum', 'Chemical', 'MESH:D010984', (14, 22))
65561	28079142	Among all 503 patients, the incidence of EGFR mutations was 36.6%; 184 patients had EGFR mutations, and 319 patients were wild type.	('EGFR', 'Gene', (41, 45))	('mutations', 'Var', (46, 55))	('EGFR', 'Gene', '1956', (41, 45))	('patients', 'Species', '9606', (71, 79))	('EGFR', 'Gene', '1956', (84, 88))	('mutations', 'Var', (89, 98))	('patients', 'Species', '9606', (108, 116))	('EGFR', 'Gene', (84, 88))	('patients', 'Species', '9606', (14, 22))
65562	28079142	Of the 184 patients with EGFR mutations, 86 patients (46.7%) had exon 19 deletions (del19), 81 patients (44.0%) had an L858R mutation at exon 21, 4 patients (2.2%) had exon 18 mutations, 5 patients (2.7%) had an L861Q mutation at exon 21, 1 patient (0.5%) had an exon 20 insertion, 2 patients (1.1%) had a T790M mutation at exon 20, and 5 patients (2.7%) had multiple mutations, of which there were 2 patients with del19 and L858R mutations, 2 with T790M and L858R mutations, and 1 with an L861Q and an L858R mutation.	('mutations', 'Var', (176, 185))	('patients', 'Species', '9606', (284, 292))	('exon', 'Var', (168, 172))	('L858R', 'Mutation', 'rs121434568', (425, 430))	('del19', 'Mutation', 'c.del19', (84, 89))	('L861Q', 'Mutation', 'rs121913444', (212, 217))	('mutations', 'Var', (431, 440))	('patients', 'Species', '9606', (189, 197))	('T790M', 'Mutation', 'rs121434569', (306, 311))	('L861Q', 'Var', (212, 217))	('patients', 'Species', '9606', (148, 156))	('L858R', 'Var', (119, 124))	('EGFR', 'Gene', (25, 29))	('patient', 'Species', '9606', (95, 102))	('L858R', 'Mutation', 'rs121434568', (503, 508))	('patients', 'Species', '9606', (44, 52))	('T790M', 'Mutation', 'rs121434569', (449, 454))	('L861Q', 'Mutation', 'rs121913444', (490, 495))	('patients', 'Species', '9606', (401, 409))	('L858R', 'Gene', (425, 430))	('patients', 'Species', '9606', (339, 347))	('patient', 'Species', '9606', (284, 291))	('L861Q', 'Var', (490, 495))	('del19', 'Mutation', 'c.del19', (415, 420))	('patient', 'Species', '9606', (339, 346))	('del19', 'Var', (415, 420))	('T790M', 'Var', (449, 454))	('patient', 'Species', '9606', (189, 196))	('mutations', 'Var', (30, 39))	('patient', 'Species', '9606', (148, 155))	('patients', 'Species', '9606', (11, 19))	('EGFR', 'Gene', '1956', (25, 29))	('L858R', 'Mutation', 'rs121434568', (459, 464))	('patient', 'Species', '9606', (44, 51))	('patients', 'Species', '9606', (95, 103))	('patient', 'Species', '9606', (401, 408))	('patient', 'Species', '9606', (241, 248))	('L858R', 'Mutation', 'rs121434568', (119, 124))	('L858R mutations', 'Var', (459, 474))	('patient', 'Species', '9606', (11, 18))	('mutation', 'Var', (125, 133))
65563	28079142	Based on histological type, 40.7% (177/435) of lung adenocarcinoma patients and 10.3% (6/58) of lung squamous cell carcinoma patients had EGFR mutations.	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (47, 66))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (96, 124))	('EGFR', 'Gene', '1956', (138, 142))	('patients', 'Species', '9606', (67, 75))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (96, 124))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (101, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (57, 66))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (47, 66))	('EGFR', 'Gene', (138, 142))	('lung squamous cell carcinoma', 'Disease', (96, 124))	('lung adenocarcinoma', 'Disease', (47, 66))	('mutations', 'Var', (143, 152))	('patients', 'Species', '9606', (125, 133))
65565	28079142	Patients with activating mutations included 86 with del19, 81 with L858R at exon 21, 4 with G719X at exon 18, 5 with L861Q at exon 21, and 3 with multiple activating mutations.	('L858R', 'Mutation', 'rs121434568', (67, 72))	('del19', 'Mutation', 'c.del19', (52, 57))	('L861Q', 'Var', (117, 122))	('G719X', 'Var', (92, 97))	('Patients', 'Species', '9606', (0, 8))	('L861Q', 'Mutation', 'rs121913444', (117, 122))	('del19', 'Var', (52, 57))	('G719X', 'Mutation', 'p.G719X', (92, 97))	('L858R', 'Var', (67, 72))
65567	28079142	Overall, 179 patients had activating EGFR mutations and 319 patients were wild type.	('activating', 'PosReg', (26, 36))	('patients', 'Species', '9606', (13, 21))	('patients', 'Species', '9606', (60, 68))	('EGFR', 'Gene', '1956', (37, 41))	('EGFR', 'Gene', (37, 41))	('mutations', 'Var', (42, 51))
65570	28079142	Of the 179 patients with EGFR-activating mutations, 146 patients (81.6%) received systemic treatment, including 65 patients (44.5%) who received EGFR-TKIs, 66 patients (45.2%) who received combined chemotherapy, 11 (7.5%) who received single-agent chemotherapy, and 4 patients (2.7%) who received chemotherapy plus anti-vascular drugs as a first-line treatment.	('mutations', 'Var', (41, 50))	('patients', 'Species', '9606', (56, 64))	('patients', 'Species', '9606', (115, 123))	('EGFR', 'Gene', (25, 29))	('EGFR', 'Gene', '1956', (145, 149))	('EGFR', 'Gene', (145, 149))	('patients', 'Species', '9606', (11, 19))	('patients', 'Species', '9606', (159, 167))	('patients', 'Species', '9606', (268, 276))	('EGFR', 'Gene', '1956', (25, 29))
65572	28079142	Of the patients with EGFR-activating mutations, 117 patients received EGFR-TKI treatment, including 65 (55.6%) who received it as a first-line treatment, 42 (35.9%) as a second-line treatment, 7 (6.0%) as a third-line treatment, 1 (0.9%) as a fourth-line treatment, and 2 (1.7%) were others.	('EGFR', 'Gene', '1956', (21, 25))	('EGFR', 'Gene', (21, 25))	('EGFR', 'Gene', '1956', (70, 74))	('mutations', 'Var', (37, 46))	('EGFR', 'Gene', (70, 74))	('patients', 'Species', '9606', (7, 15))	('patients', 'Species', '9606', (52, 60))
65573	28079142	Of the 319 patients with wild-type EGFR, 242 patients (75.9%) received first-line treatment, including 158 patients (65.3%) who received combined chemotherapy, 25 (10.3%) who received single-agent chemotherapy, 43 (17.8%) who received EGFR-TKIs, and 16 (6.6%) who received chemotherapy plus anti-vascular drugs as a first-line treatment.	('EGFR', 'Gene', '1956', (35, 39))	('EGFR', 'Gene', (35, 39))	('EGFR', 'Gene', '1956', (235, 239))	('patients', 'Species', '9606', (45, 53))	('EGFR', 'Gene', (235, 239))	('patients', 'Species', '9606', (11, 19))	('wild-type', 'Var', (25, 34))	('patients', 'Species', '9606', (107, 115))
65576	28079142	In total, 421 patients (83.7%) died (133 of 184 with EGFR mutations and 288 of 319 with wild-type EGFR), and 82 patients (16.3%) were alive at the end of the study (51 of 184 with EGFR mutations and 31 of 319 with wild-type EGFR).	('EGFR', 'Gene', (98, 102))	('mutations', 'Var', (58, 67))	('EGFR', 'Gene', (224, 228))	('EGFR', 'Gene', '1956', (180, 184))	('patients', 'Species', '9606', (112, 120))	('EGFR', 'Gene', (180, 184))	('EGFR', 'Gene', (53, 57))	('EGFR', 'Gene', '1956', (53, 57))	('EGFR', 'Gene', '1956', (98, 102))	('mutations', 'Var', (185, 194))	('patients', 'Species', '9606', (14, 22))	('EGFR', 'Gene', '1956', (224, 228))
65578	28079142	The results showed that patients with specific characteristics (female, non-smoking, PS of 0-1, adenocarcinoma, recurrent disease, EGFR mutations, receiving EGFR-TKI therapy) had a significantly longer survival than patients with opposing characteristics (male, smoker, PS >= 2, squamous cell carcinoma, locally advanced and metastatic disease, wild-type EGFR, not receiving EGFR-TKI therapy) (Table 2).	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (279, 302))	('longer', 'PosReg', (195, 201))	('EGFR', 'Gene', (131, 135))	('mutations', 'Var', (136, 145))	('EGFR', 'Gene', '1956', (157, 161))	('adenocarcinoma', 'Disease', 'MESH:D000230', (96, 110))	('EGFR', 'Gene', '1956', (355, 359))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (279, 302))	('EGFR', 'Gene', (375, 379))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('carcinoma', 'Phenotype', 'HP:0030731', (293, 302))	('squamous cell carcinoma', 'Disease', (279, 302))	('patients', 'Species', '9606', (216, 224))	('EGFR', 'Gene', '1956', (131, 135))	('EGFR', 'Gene', (157, 161))	('EGFR', 'Gene', '1956', (375, 379))	('EGFR', 'Gene', (355, 359))	('adenocarcinoma', 'Disease', (96, 110))	('patients', 'Species', '9606', (24, 32))	('survival', 'MPA', (202, 210))
65579	28079142	1b), EGFR mutations (Hazard Ratio 1.717, 95% CI 1.358 to 2.171, p < 0.001, Fig.	('mutations', 'Var', (10, 19))	('EGFR', 'Gene', '1956', (5, 9))	('EGFR', 'Gene', (5, 9))
65582	28079142	Of the 179 patients with EGFR-activating mutations, 129 (72.1%) died and 50 (27.9%) were alive at the end of the study.	('mutations', 'Var', (41, 50))	('patients', 'Species', '9606', (11, 19))	('EGFR', 'Gene', '1956', (25, 29))	('EGFR', 'Gene', (25, 29))
65590	28079142	For the 117 patients harbouring EGFR-activating mutations and who received EGFR-TKIs, their median OS was 24.3 months (95% CI 18.076 to 30.524).	('patients', 'Species', '9606', (12, 20))	('EGFR', 'Gene', '1956', (32, 36))	('EGFR', 'Gene', '1956', (75, 79))	('EGFR', 'Gene', (32, 36))	('mutations', 'Var', (48, 57))	('EGFR', 'Gene', (75, 79))
65594	28079142	Of the 319 patients with wild-type EGFR, 288 (90.3%) had died.	('patients', 'Species', '9606', (11, 19))	('wild-type', 'Var', (25, 34))	('EGFR', 'Gene', '1956', (35, 39))	('EGFR', 'Gene', (35, 39))
65598	28079142	We collected clinical data from the Beijing Chest Hospital and aimed to analyse prognostic factors for advanced NSCLC in patients with different EGFR status and identify the role of EGFR-TKIs in improving OS for patients with EGFR mutations.	('EGFR', 'Gene', '1956', (182, 186))	('EGFR', 'Gene', (182, 186))	('mutations', 'Var', (231, 240))	('EGFR', 'Gene', '1956', (145, 149))	('NSCLC', 'Phenotype', 'HP:0030358', (112, 117))	('patients', 'Species', '9606', (212, 220))	('EGFR', 'Gene', (145, 149))	('EGFR', 'Gene', '1956', (226, 230))	('NSCLC', 'Disease', (112, 117))	('patients', 'Species', '9606', (121, 129))	('NSCLC', 'Disease', 'MESH:D002289', (112, 117))	('EGFR', 'Gene', (226, 230))
65600	28079142	For patients with EGFR-activating mutations, receiving EGFR-TKI therapy resulted in a significantly longer survival than those without EGFR-TKI therapy (Hazard Ratio 2.525, 95% CI 1.748 to 3.646, p < 0.001).	('EGFR', 'Gene', '1956', (55, 59))	('survival', 'MPA', (107, 115))	('EGFR', 'Gene', '1956', (18, 22))	('EGFR', 'Gene', (55, 59))	('EGFR', 'Gene', '1956', (135, 139))	('EGFR', 'Gene', (18, 22))	('longer', 'PosReg', (100, 106))	('EGFR', 'Gene', (135, 139))	('patients', 'Species', '9606', (4, 12))	('mutations', 'Var', (34, 43))
65602	28079142	In our study, a univariate analysis showed that specific characteristics (female, non-smoking, PS 0-1, adenocarcinoma, recurrent disease, EGFR mutations, receiving EGFR-TKI therapy) predicted a better survival outcome.	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('EGFR', 'Gene', (164, 168))	('EGFR', 'Gene', '1956', (138, 142))	('recurrent disease', 'Disease', (119, 136))	('EGFR', 'Gene', '1956', (164, 168))	('adenocarcinoma', 'Disease', (103, 117))	('EGFR', 'Gene', (138, 142))	('adenocarcinoma', 'Disease', 'MESH:D000230', (103, 117))	('better', 'PosReg', (194, 200))	('mutations', 'Var', (143, 152))
65603	28079142	However, the multivariate analysis showed that a good PS score (Hazard Ratio 1.691, 95% CI 1.107 to 2.582, p = 0.015), recurrent disease (Hazard Ratio 1.524, 95% CI 1.205 to 1.927, p < 0.001), EGFR mutations (Hazard Ratio 1.717, 95% CI 1.358 to 2.171, p < 0.001), or receiving EGFR-TKI therapy (Hazard Ratio 1.445, 95% CI 1.170 to 1.786, p < 0.001) were independent factors of OS for all patients with NSCLC.	('NSCLC', 'Disease', (402, 407))	('EGFR', 'Gene', '1956', (193, 197))	('NSCLC', 'Disease', 'MESH:D002289', (402, 407))	('mutations', 'Var', (198, 207))	('EGFR', 'Gene', '1956', (277, 281))	('EGFR', 'Gene', (193, 197))	('patients', 'Species', '9606', (388, 396))	('NSCLC', 'Phenotype', 'HP:0030358', (402, 407))	('EGFR', 'Gene', (277, 281))
65604	28079142	Because several studies have demonstrated that female patients and adenocarcinoma patients have a higher frequency of EGFR mutations, EGFR status may be a valuable factor to predict survival, rather than gender or histological type.	('adenocarcinoma', 'Disease', (67, 81))	('EGFR', 'Gene', '1956', (134, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('adenocarcinoma', 'Disease', 'MESH:D000230', (67, 81))	('EGFR', 'Gene', (134, 138))	('patients', 'Species', '9606', (54, 62))	('patients', 'Species', '9606', (82, 90))	('EGFR', 'Gene', '1956', (118, 122))	('EGFR', 'Gene', (118, 122))	('mutations', 'Var', (123, 132))
65605	28079142	For all of patients harbouring EGFR-activating mutations, the median OS was 17.5 months (95% CI 15.055 to 19.945), and a Cox analysis showed that adenocarcinoma (Hazard Ratio 5.650, 95% CI 2.223 to 14.362, p < 0.001), recurrent disease (Hazard Ratio 1.976, 95% CI 1.291 to 3.025, p = 0.002), or treatment with EGFR-TKIs (Hazard Ratio 2.525, 95% CI 1.748 to 3.646, p < 0.001) were associated with improved OS.	('adenocarcinoma', 'Disease', 'MESH:D000230', (146, 160))	('EGFR', 'Gene', '1956', (31, 35))	('EGFR', 'Gene', '1956', (310, 314))	('EGFR', 'Gene', (31, 35))	('improved', 'PosReg', (396, 404))	('mutations', 'Var', (47, 56))	('carcinoma', 'Phenotype', 'HP:0030731', (151, 160))	('EGFR', 'Gene', (310, 314))	('patients', 'Species', '9606', (11, 19))	('adenocarcinoma', 'Disease', (146, 160))	('recurrent disease', 'Disease', (218, 235))
65606	28079142	For patients harbouring EGFR-activating mutations who received EGFR-TKI therapy, the OS was significantly higher than that of patients harbouring EGFR-activating mutations who did not receive EGFR-TKIs (median survival, 24.3 vs. 10.8 months, respectively; p < 0.001).	('EGFR', 'Gene', '1956', (24, 28))	('EGFR', 'Gene', '1956', (63, 67))	('EGFR', 'Gene', '1956', (146, 150))	('EGFR', 'Gene', (24, 28))	('EGFR', 'Gene', (63, 67))	('EGFR', 'Gene', (146, 150))	('higher', 'PosReg', (106, 112))	('mutations', 'Var', (40, 49))	('patients', 'Species', '9606', (126, 134))	('patients', 'Species', '9606', (4, 12))	('EGFR', 'Gene', '1956', (192, 196))	('EGFR', 'Gene', (192, 196))
65609	28079142	To analyse the prognostic factors of survival for patients harbouring activating mutations who received EGFR-TKIs, multiple factors including age, gender, smoking status, PS score, histological type, disease type, activating mutation type, and lines of treatments were enrolled for univariate and multivariate analysis, and the results showed that there was a significant difference in survival between patients with lung adenocarcinoma and patients with lung squamous cell carcinoma (24.5 months vs. 7.3 months, Hazard Ratio 11.984, 95% CI 3.873 to 37.082, p < 0.001).	('patients', 'Species', '9606', (441, 449))	('patients', 'Species', '9606', (403, 411))	('patients', 'Species', '9606', (50, 58))	('EGFR', 'Gene', (104, 108))	('carcinoma', 'Phenotype', 'HP:0030731', (427, 436))	('lung adenocarcinoma', 'Disease', (417, 436))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (417, 436))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (455, 483))	('mutations', 'Var', (81, 90))	('carcinoma', 'Phenotype', 'HP:0030731', (474, 483))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (460, 483))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (455, 483))	('lung squamous cell carcinoma', 'Disease', (455, 483))	('EGFR', 'Gene', '1956', (104, 108))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (417, 436))
65610	28079142	The prognostic role of EGFR mutations in squamous cell carcinoma had rarely been reported.	('squamous cell carcinoma', 'Disease', (41, 64))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (41, 64))	('carcinoma', 'Phenotype', 'HP:0030731', (55, 64))	('EGFR', 'Gene', '1956', (23, 27))	('EGFR', 'Gene', (23, 27))	('mutations', 'Var', (28, 37))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (41, 64))
65611	28079142	reported that, among 29 EGFR-positive patients with squamous lung cancer (which was a small sample size for the retrospective analysis), EGFR mutation-positive patients had significantly improved OS with EGFR-TKI therapy compared with those who did not receive EGFR-TKIs (18.04 months [95% CI 13.47 to 22.61] vs. 13.18 months [95% CI 5.22 to 21.13], p = 0.015).	('EGFR', 'Gene', (137, 141))	('EGFR', 'Gene', '1956', (24, 28))	('lung cancer', 'Phenotype', 'HP:0100526', (61, 72))	('patients', 'Species', '9606', (160, 168))	('EGFR', 'Gene', '1956', (261, 265))	('EGFR', 'Gene', (24, 28))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('improved', 'PosReg', (187, 195))	('EGFR', 'Gene', (261, 265))	('EGFR', 'Gene', '1956', (204, 208))	('squamous lung cancer', 'Disease', 'MESH:D008175', (52, 72))	('squamous lung cancer', 'Phenotype', 'HP:0030359', (52, 72))	('patients', 'Species', '9606', (38, 46))	('EGFR', 'Gene', '1956', (137, 141))	('EGFR', 'Gene', (204, 208))	('squamous lung cancer', 'Disease', (52, 72))	('mutation-positive', 'Var', (142, 159))
65612	28079142	Two meta-analyses showed that survival for patients with del19 was superior to patients with an L858R mutation, all of whom received EGFR-TKI therapy.	('patients', 'Species', '9606', (43, 51))	('del19', 'Var', (57, 62))	('superior', 'PosReg', (67, 75))	('L858R', 'Var', (96, 101))	('L858R', 'Mutation', 'rs121434568', (96, 101))	('EGFR', 'Gene', '1956', (133, 137))	('patients', 'Species', '9606', (79, 87))	('del19', 'Mutation', 'c.del19', (57, 62))	('EGFR', 'Gene', (133, 137))
65613	28079142	First, most importantly, the censored number was slightly higher in the del19 group, among 179 patients, there were 86 patients harbouring del19 and 81 patients harbouring an L858R mutation.	('del19', 'Var', (139, 144))	('L858R', 'Var', (175, 180))	('patients', 'Species', '9606', (95, 103))	('del19', 'Mutation', 'c.del19', (72, 77))	('patients', 'Species', '9606', (119, 127))	('L858R', 'Mutation', 'rs121434568', (175, 180))	('del19', 'Mutation', 'c.del19', (139, 144))	('del19', 'Var', (72, 77))	('patients', 'Species', '9606', (152, 160))
65617	28079142	Patients with wild-type EGFR had a poor median OS of 9.7 months (95% CI 8.506 to 10.894).	('EGFR', 'Gene', '1956', (24, 28))	('EGFR', 'Gene', (24, 28))	('wild-type', 'Var', (14, 23))	('Patients', 'Species', '9606', (0, 8))
65619	28079142	Whether in non-selected patients, or in patients with EGFR mutations or wild-type EGFR patients, OS for patients with recurrent disease was superior to patients with locally advanced or metastatic disease.	('EGFR', 'Gene', (82, 86))	('patients', 'Species', '9606', (40, 48))	('EGFR', 'Gene', (54, 58))	('EGFR', 'Gene', '1956', (54, 58))	('mutations', 'Var', (59, 68))	('patients', 'Species', '9606', (24, 32))	('EGFR', 'Gene', '1956', (82, 86))	('patients', 'Species', '9606', (87, 95))	('patients', 'Species', '9606', (104, 112))	('patients', 'Species', '9606', (152, 160))
65626	28079142	reported that patients with EGFR mutations in America had a median survival of 3.97 years.	('patients', 'Species', '9606', (14, 22))	('EGFR', 'Gene', '1956', (28, 32))	('EGFR', 'Gene', (28, 32))	('mutations', 'Var', (33, 42))
65629	28079142	In recent years, EGFR testing is standard for advanced treatment-naive patients in most cancer centres or big comprehensive hospitals in China, and more and more patients with EGFR mutations have been treated with first-line EGFR-TKI therapy.	('patients', 'Species', '9606', (162, 170))	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('patients', 'Species', '9606', (71, 79))	('EGFR', 'Gene', '1956', (176, 180))	('EGFR', 'Gene', '1956', (225, 229))	('EGFR', 'Gene', (176, 180))	('mutations', 'Var', (181, 190))	('EGFR', 'Gene', '1956', (17, 21))	('EGFR', 'Gene', (225, 229))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('EGFR', 'Gene', (17, 21))
65633	28079142	Second, the methods used to detect EGFR mutations and the treatment process were not very uniform.	('mutations', 'Var', (40, 49))	('EGFR', 'Gene', '1956', (35, 39))	('EGFR', 'Gene', (35, 39))
65635	28079142	NSCLC patients with EGFR-activating mutations who received EGFR-TKI therapy had significantly longer survival than those without EGFR-TKI therapy.	('NSCLC', 'Disease', 'MESH:D002289', (0, 5))	('EGFR', 'Gene', (20, 24))	('EGFR', 'Gene', (59, 63))	('survival', 'MPA', (101, 109))	('mutations', 'Var', (36, 45))	('EGFR', 'Gene', '1956', (20, 24))	('NSCLC', 'Phenotype', 'HP:0030358', (0, 5))	('EGFR', 'Gene', '1956', (129, 133))	('patients', 'Species', '9606', (6, 14))	('longer', 'PosReg', (94, 100))	('EGFR', 'Gene', (129, 133))	('NSCLC', 'Disease', (0, 5))	('EGFR', 'Gene', '1956', (59, 63))
65637	28079142	We aimed to conduct a retrospective analysis of OS for patients with an identified EGFR mutation status in a single cancer hospital, and we analysed the prognostic role of EGFR-TKIs in the OS of patients with different EGFR statuses.	('EGFR', 'Gene', '1956', (219, 223))	('EGFR', 'Gene', '1956', (83, 87))	('mutation', 'Var', (88, 96))	('EGFR', 'Gene', '1956', (172, 176))	('EGFR', 'Gene', (219, 223))	('cancer', 'Disease', (116, 122))	('EGFR', 'Gene', (83, 87))	('EGFR', 'Gene', (172, 176))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('patients', 'Species', '9606', (195, 203))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('patients', 'Species', '9606', (55, 63))
65643	28079142	Medical records of all patients were reviewed and clinicopathological factors, including age, gender, performance status (PS) score, smoking history, histological type, disease type, EGFR mutation type, and treatment, as well as EGFR-TKI therapy, were recorded.	('EGFR', 'Gene', '1956', (183, 187))	('mutation', 'Var', (188, 196))	('EGFR', 'Gene', (183, 187))	('patients', 'Species', '9606', (23, 31))	('EGFR', 'Gene', '1956', (229, 233))	('EGFR', 'Gene', (229, 233))
65653	25301630	There was pronounced intratumor heterogeneity in copy number alterations, translocations, and mutations associated with APOBEC cytidine deaminase activity.	('mutations', 'Var', (94, 103))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('copy number alterations', 'Var', (49, 72))	('translocations', 'Var', (74, 88))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))
65654	25301630	Despite maintained carcinogen exposure, tumors from smokers showed a relative decrease in smoking-related mutations over time, accompanied by an increase in APOBEC-associated mutations.	('decrease', 'NegReg', (78, 86))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('tumors', 'Disease', 'MESH:D009369', (40, 46))	('APOBEC-associated', 'Gene', (157, 174))	('increase', 'PosReg', (145, 153))	('mutations', 'MPA', (175, 184))	('mutations', 'Var', (106, 115))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumors', 'Disease', (40, 46))
65656	25301630	The regionally separated driver mutations, coupled with the relentless and heterogeneous nature of the genome instability processes, are likely to confound treatment success in NSCLC.	('NSCLC', 'Disease', 'MESH:D002289', (177, 182))	('mutations', 'Var', (32, 41))	('NSCLC', 'Disease', (177, 182))	('NSCLC', 'Phenotype', 'HP:0030358', (177, 182))
65661	25301630	Moreover, although both exogenous mutational processes, such as smoking, and endogenous processes, such as up-regulation of APOBEC cytidine deaminases, have been found to contribute to the large mutational burden in NSCLC, the temporal dynamics of these processes and their contribution to driver somatic aberrations over time remain unknown.	('NSCLC', 'Disease', (216, 221))	('up-regulation', 'PosReg', (107, 120))	('NSCLC', 'Disease', 'MESH:D002289', (216, 221))	('contribute', 'Reg', (171, 181))	('NSCLC', 'Phenotype', 'HP:0030358', (216, 221))	('APOBEC cytidine deaminases', 'Gene', (124, 150))	('mutational', 'Var', (195, 205))
65670	25301630	However, in L003, only a single mutation (EGFRL858R, the epidermal growth factor receptor in which Leu858 is replaced with Arg) was detected in both tumors (Fig.	('epidermal growth factor receptor', 'Gene', '1956', (57, 89))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('Leu858', 'Var', (99, 105))	('tumors', 'Disease', (149, 155))	('tumors', 'Disease', 'MESH:D009369', (149, 155))	('tumors', 'Phenotype', 'HP:0002664', (149, 155))	('EGFRL858R', 'Mutation', 'rs121434568', (42, 51))	('epidermal growth factor receptor', 'Gene', (57, 89))	('Leu858 is replaced with Arg', 'Mutation', 'rs121434568', (99, 126))
65671	25301630	Given that EGFRL858R is a highly recurrent mutation and also that no silent mutations were shared, we concluded that the tumors in L003 were of independent clonal origin, with the evolution of identical oncogenic events in parallel.	('EGFRL858R', 'Var', (11, 20))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumors', 'Disease', (121, 127))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('tumors', 'Disease', 'MESH:D009369', (121, 127))	('EGFRL858R', 'Mutation', 'rs121434568', (11, 20))
65672	25301630	To resolve the extent of genomic diversity in NSCLC and to infer the ancestral relations between tumor regions, we estimated the fraction of tumor cells within each region harboring each mutation.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('NSCLC', 'Disease', (46, 51))	('tumor', 'Disease', (141, 146))	('tumor', 'Disease', (97, 102))	('NSCLC', 'Disease', 'MESH:D002289', (46, 51))	('mutation', 'Var', (187, 195))	('NSCLC', 'Phenotype', 'HP:0030358', (46, 51))
65675	25301630	S4) and the PAX7 mutation in the lymph node of L001 (Fig.	('PAX7', 'Gene', (12, 16))	('mutation', 'Var', (17, 25))	('PAX7', 'Gene', '5081', (12, 16))
65678	25301630	Every tumor showed evidence for ubiquitous, as well as heterogeneous, driver mutations, many of which were clonally dominant in a subset of tumor regions and entirely absent in others (Fig.	('tumor', 'Disease', 'MESH:D009369', (6, 11))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('mutations', 'Var', (77, 86))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('tumor', 'Disease', (6, 11))	('tumor', 'Disease', (140, 145))
65681	25301630	These data indicate that, in NSCLC, most known driver mutations occur early in tumor evolution.	('NSCLC', 'Phenotype', 'HP:0030358', (29, 34))	('tumor', 'Disease', (79, 84))	('mutations', 'Var', (54, 63))	('NSCLC', 'Disease', (29, 34))	('NSCLC', 'Disease', 'MESH:D002289', (29, 34))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
65686	25301630	For example, in L001, a focal EGFR amplification (chr7p11.2), as well as deletions of chromosomal segments harboring CDKN2A (chr9p21.3) and PTEN (chr10q23.31), was observed in all regions, whereas, in L008, we observed heterogeneous copy number losses involving CDKN2A and PTEN.	('EGFR', 'Gene', (30, 34))	('CDKN2A', 'Gene', '1029', (262, 268))	('CDKN2A', 'Gene', '1029', (117, 123))	('PTEN', 'Gene', '5728', (273, 277))	('copy number losses', 'Var', (233, 251))	('PTEN', 'Gene', (273, 277))	('deletions', 'Var', (73, 82))	('CDKN2A', 'Gene', (117, 123))	('EGFR', 'Gene', '1956', (30, 34))	('PTEN', 'Gene', (140, 144))	('CDKN2A', 'Gene', (262, 268))	('PTEN', 'Gene', '5728', (140, 144))
65690	25301630	By contrast, for L008, 48 of the 52 identified structural variants were shared between the two tumor regions from different lobes of the lung, which suggested that the majority of these variants occurred before tumor metastasis to the other lobe (Fig.	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('variants', 'Var', (186, 194))	('tumor', 'Disease', (211, 216))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Disease', (95, 100))
65693	25301630	In three tumors (L001, L004, and L008), the genome-doubling event was shared across every tumor region; it occurred before diversification, with the majority of truncal mutations (84 to 88%) present at ploidy >=2, indicative of a large mutational burden before genome doubling.	('ploidy >=2', 'Var', (202, 212))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('present', 'Reg', (191, 198))	('tumor', 'Disease', (9, 14))	('tumors', 'Disease', (9, 15))	('tumors', 'Disease', 'MESH:D009369', (9, 15))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
65694	25301630	In one tumor, L002, the majority of heterogeneous mutations were also present at ploidy >=2, indicative of two independent genome-doubling events: one in the LUAD region and one in the LUSC region (fig.	('tumor', 'Disease', (7, 12))	('mutations', 'Var', (50, 59))	('ploidy >=2', 'Var', (81, 91))	('tumor', 'Disease', 'MESH:D009369', (7, 12))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
65696	25301630	Early (truncal) mutations likely reflect processes involved before and during tumor initiation and early development, whereas late (branched) mutations reveal mutational processes shaping the genome during tumor maintenance and progression, including those contributing to intratumor heterogeneity.	('tumor', 'Phenotype', 'HP:0002664', (278, 283))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('tumor', 'Disease', (278, 283))	('tumor', 'Disease', (206, 211))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('mutations', 'Var', (16, 25))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor initiation', 'Disease', 'MESH:D009369', (78, 94))	('tumor', 'Disease', (78, 83))	('tumor', 'Disease', 'MESH:D009369', (278, 283))	('tumor', 'Disease', 'MESH:D009369', (206, 211))	('tumor initiation', 'Disease', (78, 94))
65699	25301630	Furthermore, every tumor exhibited a statistically significant decrease in the proportion of C>A transversions in late compared with early mutations (P < 0.05) (Fig.	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('decrease', 'NegReg', (63, 71))	('tumor', 'Disease', (19, 24))	('C>A transversions', 'Var', (93, 110))
65701	25301630	To validate these observations in a larger NSCLC cohort, mutations in TCGA LUAD and LUSC samples were temporally dissected.	('TCGA', 'Gene', (70, 74))	('NSCLC', 'Phenotype', 'HP:0030358', (43, 48))	('mutations', 'Var', (57, 66))	('NSCLC', 'Disease', (43, 48))	('NSCLC', 'Disease', 'MESH:D002289', (43, 48))
65702	25301630	In the majority of M-seq tumors, the decreased proportion of C>A mutations was accompanied by an increase in C>T and C>G mutations at TpC sites, indicative of APOBEC cytidine deaminase activity.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('increase', 'PosReg', (97, 105))	('M-seq tumors', 'Disease', (19, 31))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('C>G mutations', 'Var', (117, 130))	('M-seq tumors', 'Disease', 'MESH:C566367', (19, 31))	('decreased', 'NegReg', (37, 46))
65703	25301630	Branched driver genes PIK3CA, EP300, TGFBR1, PTPRD, and AKAP9 harbored mutations in an APOBEC context, which indicated a possible functional impact of APOBEC activity on subclonal expansion.	('EP300', 'Gene', '2033', (30, 35))	('EP300', 'Gene', (30, 35))	('AKAP9', 'Gene', '10142', (56, 61))	('PIK3CA', 'Gene', '5290', (22, 28))	('TGFBR1', 'Gene', '7046', (37, 43))	('TGFBR1', 'Gene', (37, 43))	('PTPRD', 'Gene', '5789', (45, 50))	('PTPRD', 'Gene', (45, 50))	('AKAP9', 'Gene', (56, 61))	('harbored', 'Reg', (62, 70))	('mutations', 'Var', (71, 80))	('PIK3CA', 'Gene', (22, 28))
65705	25301630	However, for TCGA LUSC tumors with detectable APOBEC mutational signatures, temporal dissection of APOBEC mutations did not reveal such a clear trend (fig.	('TCGA LUSC', 'Disease', (13, 22))	('tumors', 'Disease', 'MESH:D009369', (23, 29))	('tumors', 'Disease', (23, 29))	('mutational', 'Var', (53, 63))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('APOBEC', 'Gene', (46, 52))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))
65708	25301630	In patient L002, a current smoker, tobacco carcinogens played a significant role early in tumor development, with C>A transversions representing 39% of truncal mutations (Fig.	('C>A transversions', 'Var', (114, 131))	('patient', 'Species', '9606', (3, 10))	('tumor', 'Disease', (90, 95))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tobacco', 'Species', '4097', (35, 42))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
65710	25301630	S7) and driver mutations were acquired independently in both subclones, such as a stop-gain mutation in the tumor suppressor gene FAT1 on the LUSC branch and mutations affecting TGFBR1, ZFHX4, ARHGAP35, and PTPRD in the LUAD region.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('mutation', 'Var', (92, 100))	('ARHGAP35', 'Gene', (193, 201))	('ARHGAP35', 'Gene', '2909', (193, 201))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('ZFHX4', 'Gene', (186, 191))	('tumor', 'Disease', (108, 113))	('FAT1', 'Gene', '2195', (130, 134))	('ZFHX4', 'Gene', '79776', (186, 191))	('FAT1', 'Gene', (130, 134))	('TGFBR1', 'Gene', (178, 184))	('TGFBR1', 'Gene', '7046', (178, 184))	('mutations', 'Var', (158, 167))	('PTPRD', 'Gene', '5789', (207, 212))	('PTPRD', 'Gene', (207, 212))
65711	25301630	APOBEC-associated mutations were elevated specifically in the LUAD region, which included the driver mutations in TGFBR1 and PTPRD, and the highest APOBEC3B mRNA expression was detected in this region (fig.	('TGFBR1', 'Gene', (114, 120))	('mutations', 'Var', (101, 110))	('elevated', 'PosReg', (33, 41))	('TGFBR1', 'Gene', '7046', (114, 120))	('APOBEC3B', 'Gene', '9582', (148, 156))	('mRNA expression', 'MPA', (157, 172))	('APOBEC-associated', 'Gene', (0, 17))	('PTPRD', 'Gene', '5789', (125, 130))	('PTPRD', 'Gene', (125, 130))	('APOBEC3B', 'Gene', (148, 156))	('mutations', 'Var', (18, 27))
65713	25301630	However, a tobacco smoke signature of C>A transversions was observed in more than 30% of truncal mutations both before and after doubling, and only in 21% and 9% of heterogeneous mutations in the two regions R1 and R3 from separate lobes of the lung.	('mutations', 'Var', (97, 106))	('C>A transversions', 'Var', (38, 55))	('tobacco', 'Species', '4097', (11, 18))	('truncal', 'Gene', (89, 96))
65717	25301630	In contrast to the situation in clear cell renal cell carcinoma (ccRCC), known driver mutations typically occurred early in NSCLC development, and the majority of high-confidence driver events were fully clonal.	('mutations', 'Var', (86, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (54, 63))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (32, 63))	('clear cell renal cell carcinoma', 'Disease', (32, 63))	('NSCLC', 'Disease', (124, 129))	('ccRCC', 'Phenotype', 'HP:0006770', (65, 70))	('NSCLC', 'Disease', 'MESH:D002289', (124, 129))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (32, 63))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (43, 63))	('NSCLC', 'Phenotype', 'HP:0030358', (124, 129))
65719	25301630	However, like ccRCC, all NSCLCs exhibited heterogeneous driver mutations and/or recurrent copy number aberrations and many heterogeneous mutations gave the "illusion of clonality," as they are present in all cells from certain regions but undetectable within other regions.	('mutations', 'Var', (63, 72))	('copy number', 'CPA', (90, 101))	('NSCLCs', 'Disease', 'MESH:D002289', (25, 31))	('ccRCC', 'Phenotype', 'HP:0006770', (14, 19))	('mutations', 'Var', (137, 146))	('exhibited', 'Reg', (32, 41))	('NSCLC', 'Phenotype', 'HP:0030358', (25, 30))	('NSCLCs', 'Disease', (25, 31))
65722	25301630	For instance, L008 presented with an activating BRAF (G469A) mutation in all regions and an activating PIK3CA (E542K) mutation only in region R3.	('E542K', 'Var', (111, 116))	('E542K', 'Mutation', 'rs121913273', (111, 116))	('PIK3CA', 'Gene', (103, 109))	('G469A', 'Mutation', 'rs121913355', (54, 59))	('PIK3CA', 'Gene', '5290', (103, 109))	('activating', 'PosReg', (37, 47))	('BRAF', 'Gene', '673', (48, 52))	('BRAF', 'Gene', (48, 52))
65724	25301630	Conversely, a single biopsy from any other region would suggest treatment with a BRAF inhibitor, for which the tumor cells from R3 might be resistant because of the PIK3CA mutation.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('PIK3CA', 'Gene', (165, 171))	('BRAF', 'Gene', '673', (81, 85))	('mutation', 'Var', (172, 180))	('tumor', 'Disease', (111, 116))	('BRAF', 'Gene', (81, 85))	('PIK3CA', 'Gene', '5290', (165, 171))
65734	29596469	As an example, high SOX2 expression in lung squamous cell carcinoma (SCC) is related to a favorable prognosis, while it is associated with poor outcome in lung adenocarcinoma.	('high', 'Var', (15, 19))	('lung adenocarcinoma', 'Disease', (155, 174))	('lung squamous cell carcinoma', 'Disease', (39, 67))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (39, 67))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (155, 174))	('SCC', 'Gene', (69, 72))	('expression', 'MPA', (25, 35))	('SCC', 'Phenotype', 'HP:0002860', (69, 72))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (155, 174))	('SCC', 'Gene', '6317', (69, 72))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (44, 67))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (39, 67))	('SOX2', 'Protein', (20, 24))	('carcinoma', 'Phenotype', 'HP:0030731', (165, 174))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))
65735	29596469	More recently, higher SOX2 levels and improved survival was also reported for head and neck SCC (HNSCC), and silencing of SOX2 expression in HNSCC cell lines revealed a mesenchymal-like phenotype with prominent vimentin expression.	('SCC', 'Gene', '6317', (99, 102))	('SCC', 'Gene', '6317', (92, 95))	('SCC', 'Gene', (99, 102))	('SOX2', 'Gene', (122, 126))	('SCC', 'Gene', (92, 95))	('SCC', 'Phenotype', 'HP:0002860', (143, 146))	('higher', 'PosReg', (15, 21))	('silencing', 'Var', (109, 118))	('SOX2 levels', 'MPA', (22, 33))	('improved', 'PosReg', (38, 46))	('SCC', 'Gene', '6317', (143, 146))	('survival', 'MPA', (47, 55))	('SCC', 'Phenotype', 'HP:0002860', (99, 102))	('SCC', 'Phenotype', 'HP:0002860', (92, 95))	('SCC', 'Gene', (143, 146))	('expression', 'MPA', (220, 230))	('mesenchymal-like', 'CPA', (169, 185))	('vimentin', 'Gene', '7431', (211, 219))	('vimentin', 'Gene', (211, 219))
65743	29596469	Recurrent gene amplification of the transcription factor SOX2 on human chromosome 3q is a common feature in the development of squamous cell carcinoma (SCC), but its function during carcinogenesis and prognostic value are highly context dependent.	('gene amplification', 'Var', (10, 28))	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('human', 'Species', '9606', (65, 70))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (127, 150))	('SCC', 'Gene', (152, 155))	('carcinogenesis', 'Disease', 'MESH:D063646', (182, 196))	('SOX2', 'Gene', (57, 61))	('carcinogenesis', 'Disease', (182, 196))	('SCC', 'Phenotype', 'HP:0002860', (152, 155))	('SCC', 'Gene', '6317', (152, 155))	('squamous cell carcinoma', 'Disease', (127, 150))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (127, 150))
65744	29596469	While high SOX2 expression promotes lung SCC, adeno-like carcinoma develop largely in the absence of SOX2.	('SCC', 'Gene', (41, 44))	('SOX2', 'Gene', (11, 15))	('SCC', 'Phenotype', 'HP:0002860', (41, 44))	('carcinoma', 'Disease', 'MESH:D002277', (57, 66))	('SCC', 'Gene', '6317', (41, 44))	('promotes', 'PosReg', (27, 35))	('carcinoma', 'Phenotype', 'HP:0030731', (57, 66))	('high', 'Var', (6, 10))	('carcinoma', 'Disease', (57, 66))
65746	29596469	In contrast, several studies reported a positive association between SOX2 expression and improved survival in lung SCC.	('improved', 'PosReg', (89, 97))	('survival', 'CPA', (98, 106))	('expression', 'Var', (74, 84))	('SCC', 'Gene', (115, 118))	('SCC', 'Phenotype', 'HP:0002860', (115, 118))	('SOX2', 'Protein', (69, 73))	('SCC', 'Gene', '6317', (115, 118))
65747	29596469	High SOX2 expression was also correlated with better survival in other tumor entities despite the well-established function of SOX2 in tumor-relevant processes,,.	('survival', 'CPA', (53, 61))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('High', 'Var', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('tumor', 'Disease', (135, 140))	('expression', 'MPA', (10, 20))	('SOX2', 'Gene', (5, 9))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('better', 'PosReg', (46, 52))	('tumor', 'Disease', (71, 76))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
65748	29596469	provided a possible explanation by demonstrating that silencing of SOX2 expression in head and neck squamous cell carcinoma (HNSCC) cell lines with 3q amplification induces a mesenchymal-like phenotype with increased expression of well-established mesenchymal marker genes (e.g.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (100, 123))	('SCC', 'Gene', (127, 130))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (95, 123))	('SCC', 'Phenotype', 'HP:0002860', (127, 130))	('silencing', 'Var', (54, 63))	('expression', 'MPA', (217, 227))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('SCC', 'Gene', '6317', (127, 130))	('induces', 'Reg', (165, 172))	('increased', 'PosReg', (207, 216))	('SOX2', 'Gene', (67, 71))	('neck squamous cell carcinoma', 'Disease', (95, 123))	('mesenchymal-like phenotype', 'CPA', (175, 201))
65751	29596469	However, it is worth noting that expression of epithelial markers, such as E-cadherin were not affected by SOX2 silencing in HNSCC cell lines indicating a partial but not a complete epithelial-to-mesenchymal transition.	('SCC', 'Gene', (127, 130))	('SCC', 'Phenotype', 'HP:0002860', (127, 130))	('SOX2', 'Gene', (107, 111))	('E-cadherin', 'Gene', (75, 85))	('SCC', 'Gene', '6317', (127, 130))	('E-cadherin', 'Gene', '999', (75, 85))	('silencing', 'Var', (112, 121))	('epithelial-to-mesenchymal transition', 'CPA', (182, 218))
65802	29596469	In contrast, loss of SOX2 induced more adeno-like tumors demonstrating that SOX2 acts as a determining oncogenic switch in promoting lung SCC from different cells of origin.	('promoting', 'PosReg', (123, 132))	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('SCC', 'Gene', (138, 141))	('SCC', 'Phenotype', 'HP:0002860', (138, 141))	('SCC', 'Gene', '6317', (138, 141))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('loss', 'Var', (13, 17))	('tumors', 'Disease', (50, 56))	('SOX2', 'Gene', (21, 25))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))
65803	29596469	Moreover, the univariate and multivariate analyses clearly demonstrated that SOX2 expression was a statistically significant risk factor affecting OS and DFS of patients with ACC.	('expression', 'Var', (82, 92))	('patients', 'Species', '9606', (161, 169))	('DFS', 'Disease', (154, 157))	('SOX2', 'Gene', (77, 81))
65806	29596469	In total, a reduced risk of lymph node metastasis for tumors with high SOX2 expression was reported already for esophageal and oral cancer by Chuang et al and Zullig et al,.	('tumors', 'Disease', 'MESH:D009369', (54, 60))	('reduced', 'NegReg', (12, 19))	('esophageal and oral cancer', 'Disease', 'MESH:D004938', (112, 138))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('SOX2', 'Gene', (71, 75))	('expression', 'MPA', (76, 86))	('high', 'Var', (66, 70))	('lymph node metastasis', 'CPA', (28, 49))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('tumors', 'Disease', (54, 60))
65818	29596469	could demonstrate, that exogenous SOX2 inhibits proliferation of gastric epithelial cell lines, that SOX2 plays a crucial role in gastric carcinogenesis as a tumor suppressor and that loss of SOX2 expression may cause gastric epithelial cells develop into carcinomas.	('tumor', 'Disease', (158, 163))	('SOX2', 'Gene', (192, 196))	('cause', 'Reg', (212, 217))	('proliferation', 'CPA', (48, 61))	('loss', 'Var', (184, 188))	('carcinoma', 'Phenotype', 'HP:0030731', (256, 265))	('gastric carcinogenesis', 'Disease', (130, 152))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('inhibits', 'NegReg', (39, 47))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('carcinomas', 'Disease', (256, 266))	('carcinomas', 'Disease', 'MESH:D002277', (256, 266))	('gastric', 'Disease', (218, 225))	('carcinomas', 'Phenotype', 'HP:0030731', (256, 266))	('gastric carcinogenesis', 'Disease', 'MESH:D063646', (130, 152))
65833	32429938	There was no significant difference between ARMS-PCR and immunohistochemistry in the positive rate of ALK mutation detection (P = 0.359).	('ALK', 'Gene', (102, 105))	('mutation', 'Var', (106, 114))	('ALK', 'Gene', '238', (102, 105))
65834	32429938	EGFR mutations (P = 0.02) and ALK mutations (P < 0.001) both decreased with an increasing patient age.	('ALK', 'Gene', (30, 33))	('EGFR', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))	('ALK', 'Gene', '238', (30, 33))	('patient', 'Species', '9606', (90, 97))	('decreased', 'NegReg', (61, 70))	('EGFR', 'Gene', '1956', (0, 4))
65835	32429938	Furthermore, the amount of EGFR mutations was higher in adenocarcinoma (64.1% vs 34.1%, P < 0.001) than in NSCC, favor adenocarcinoma.	('EGFR', 'Gene', '1956', (27, 31))	('EGFR', 'Gene', (27, 31))	('adenocarcinoma', 'Disease', (119, 133))	('higher', 'PosReg', (46, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('adenocarcinoma', 'Disease', 'MESH:D000230', (119, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('mutations', 'Var', (32, 41))	('adenocarcinoma', 'Disease', (56, 70))	('adenocarcinoma', 'Disease', 'MESH:D000230', (56, 70))
65836	32429938	In contrast, ALK mutations were more common in NSCC, favor adenocarcinoma (4.2% vs 8.4%, P = 0.021).	('NSCC', 'Disease', (47, 51))	('ALK', 'Gene', (13, 16))	('adenocarcinoma', 'Disease', (59, 73))	('common', 'Reg', (37, 43))	('ALK', 'Gene', '238', (13, 16))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))	('adenocarcinoma', 'Disease', 'MESH:D000230', (59, 73))	('mutations', 'Var', (17, 26))
65858	32429938	As recommended by the 2015 WHO classification schema, the following antibodies were used for IHC studies as appropriate: TTF-1, Napsin A, p40, p63, CK5/6, CD56, CgA, Syn and Ki-67.	('Syn', 'Gene', (166, 169))	('CK5/6', 'Gene', '3852', (148, 153))	('p63', 'Gene', (143, 146))	('CgA', 'Gene', '1113', (161, 164))	('Ki-67', 'Var', (174, 179))	('Syn', 'Gene', '23336', (166, 169))	('CD56', 'Gene', '4684', (155, 159))	('CK5/6', 'Gene', (148, 153))	('TTF-1', 'Gene', (121, 126))	('men', 'Species', '9606', (8, 11))	('Napsin A', 'Gene', '9476', (128, 136))	('p40', 'Gene', (138, 141))	('TTF-1', 'Gene', '7270', (121, 126))	('p63', 'Gene', '8626', (143, 146))	('CD56', 'Gene', (155, 159))	('p40', 'Gene', '3578', (138, 141))	('CgA', 'Gene', (161, 164))	('Napsin A', 'Gene', (128, 136))
65874	32429938	Amplification Refractory Mutation System PCR (ARMS-PCR) was used to identify EGFR gene mutations in 889 cases of adenocarcinoma (Table 5).	('adenocarcinoma', 'Disease', (113, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('adenocarcinoma', 'Disease', 'MESH:D000230', (113, 127))	('EGFR', 'Gene', '1956', (77, 81))	('EGFR', 'Gene', (77, 81))	('mutations', 'Var', (87, 96))
65875	32429938	Four hundred and ninety-nine cases (56.1%) were found to be mutant, 238 (26.8%) with p.L858R, 222 cases (25.0%) with exon 19 deletions, 15 (1.7%) with p.L861Q, 14 (1.6%) with exon 20 insertions, 13 (1.5%) with exon 18 mutation, 13 (1.5%) with p.T790M, and 2 (0.2%) with p.S786I.	('p.L861Q', 'Var', (151, 158))	('p.S786I', 'Var', (270, 277))	('p.L858R', 'Var', (85, 92))	('p.T790M', 'Var', (243, 250))	('exon 18', 'Var', (210, 217))	('p.L861Q', 'Mutation', 'rs121913444', (151, 158))	('p.S786I', 'Mutation', 'p.S786I', (270, 277))	('p.T790M', 'Mutation', 'rs121434569', (243, 250))	('p.L858R', 'Mutation', 'rs121434568', (85, 92))
65876	32429938	There were 18 cases of co-mutation of EGFR (Table 6), including 8 cases of p.L858R with p.T790M, 4 cases of exon 19 deletions with p.T790M, 1 case of exon 18 mutation with p.T790M, 2 cases of p.S768I with exon 18 mutations, and 3 cases of p.L861Q with exon 18 mutations,.	('EGFR', 'Gene', '1956', (38, 42))	('p.L858R', 'Var', (75, 82))	('p.T790M', 'Var', (88, 95))	('p.L861Q', 'Mutation', 'rs121913444', (239, 246))	('EGFR', 'Gene', (38, 42))	('p.S768I', 'Var', (192, 199))	('p.T790M', 'Var', (172, 179))	('p.T790M', 'Mutation', 'rs121434569', (131, 138))	('p.L861Q', 'Var', (239, 246))	('p.T790M', 'Mutation', 'rs121434569', (88, 95))	('p.S768I', 'Mutation', 'rs121913465', (192, 199))	('p.T790M', 'Var', (131, 138))	('p.L858R', 'Mutation', 'rs121434568', (75, 82))	('p.T790M', 'Mutation', 'rs121434569', (172, 179))
65877	32429938	In this study, p.T790M and p.S768I did not occur alone.	('p.S768I', 'Var', (27, 34))	('p.T790M', 'Var', (15, 22))	('p.T790M', 'Mutation', 'rs121434569', (15, 22))	('p.S768I', 'Mutation', 'rs121913465', (27, 34))
65878	32429938	We also assayed for ALK and ROS1 mutations in 211 patients with non-small cell lung cancer through ARMS-PCR.	('ALK', 'Gene', '238', (20, 23))	('patients', 'Species', '9606', (50, 58))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (64, 90))	('ROS1', 'Gene', (28, 32))	('mutations', 'Var', (33, 42))	('lung cancer', 'Phenotype', 'HP:0100526', (79, 90))	('ALK', 'Gene', (20, 23))	('non-small cell lung cancer', 'Disease', (64, 90))	('ROS1', 'Gene', '6098', (28, 32))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (68, 90))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (64, 90))
65880	32429938	There was no significant difference between ARMS-PCR and immunohistochemistry in the detection of an ALK mutation (P = 0.359).	('ALK', 'Gene', (101, 104))	('mutation', 'Var', (105, 113))	('ALK', 'Gene', '238', (101, 104))
65881	32429938	EGFR mutations were more common in females (39.7% vs 67.5%, P < 0.001) while no gender difference was noted in ALK mutations (3.7% vs 5.7%, P = 0.133).	('EGFR', 'Gene', (0, 4))	('ALK', 'Gene', '238', (111, 114))	('mutations', 'Var', (5, 14))	('EGFR', 'Gene', '1956', (0, 4))	('ALK', 'Gene', (111, 114))
65882	32429938	EGFR mutations (P = 0.02) and ALK (P < 0.001) mutations both decreased with an increasing patient age.	('ALK', 'Gene', (30, 33))	('EGFR', 'Gene', (0, 4))	('mutations', 'Var', (46, 55))	('mutations', 'Var', (5, 14))	('ALK', 'Gene', '238', (30, 33))	('patient', 'Species', '9606', (90, 97))	('decreased', 'NegReg', (61, 70))	('EGFR', 'Gene', '1956', (0, 4))
65883	32429938	In contrast, ALK mutations were more common in NSCC, favor adenocarcinoma (4.2% vs 8.4%, P = 0.021) (Table 7).	('NSCC', 'Disease', (47, 51))	('ALK', 'Gene', (13, 16))	('adenocarcinoma', 'Disease', (59, 73))	('common', 'Reg', (37, 43))	('ALK', 'Gene', '238', (13, 16))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))	('adenocarcinoma', 'Disease', 'MESH:D000230', (59, 73))	('mutations', 'Var', (17, 26))
65927	32429938	The frequency of EGFR mutation in this study was 56.1%, which was close to that of the Chinese population, 50.2%, reported by PIONEER study.	('mutation', 'Var', (22, 30))	('EGFR', 'Gene', '1956', (17, 21))	('EGFR', 'Gene', (17, 21))
65928	32429938	According to previous studies and this one, we can find that the frequency of EGFR mutation in China and other countries/regions in East Asia (approximately 30-64%) is significantly higher than that in India (22.2%) and among white people (approximately 20%).	('people', 'Species', '9606', (232, 238))	('mutation', 'Var', (83, 91))	('higher', 'PosReg', (182, 188))	('EGFR', 'Gene', '1956', (78, 82))	('EGFR', 'Gene', (78, 82))
65929	32429938	We found that the amount of EGFR mutations was significantly higher in female adenocarcinoma patients than in male, which was also supported by the data from PIONEER study.	('EGFR', 'Gene', '1956', (28, 32))	('adenocarcinoma', 'Disease', (78, 92))	('higher', 'PosReg', (61, 67))	('adenocarcinoma', 'Disease', 'MESH:D000230', (78, 92))	('EGFR', 'Gene', (28, 32))	('mutations', 'Var', (33, 42))	('patients', 'Species', '9606', (93, 101))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))
65930	32429938	It was demonstrated in our study that frequency of EGFR mutation in well-differentiated adenocarcinoma was significantly higher than that in poorly-differentiated adenocarcinoma, while PIONEER study showed that the mutational rate of EGFR was significantly higher in invasive adenocarcinoma than in bronchioloalveolar carcinoma, which is currently called pulmonary adenocarcinoma in situ.	('EGFR', 'Gene', (234, 238))	('EGFR', 'Gene', (51, 55))	('adenocarcinoma', 'Disease', 'MESH:D000230', (88, 102))	('carcinoma', 'Disease', 'MESH:D009369', (370, 379))	('carcinoma', 'Phenotype', 'HP:0030731', (318, 327))	('pulmonary adenocarcinoma', 'Disease', 'MESH:D000230', (355, 379))	('invasive adenocarcinoma', 'Disease', (267, 290))	('carcinoma', 'Disease', (318, 327))	('pulmonary adenocarcinoma', 'Phenotype', 'HP:0030078', (355, 379))	('adenocarcinoma', 'Disease', 'MESH:D000230', (365, 379))	('adenocarcinoma', 'Disease', (276, 290))	('carcinoma', 'Phenotype', 'HP:0030731', (168, 177))	('carcinoma', 'Disease', (168, 177))	('carcinoma', 'Disease', 'MESH:D009369', (281, 290))	('pulmonary adenocarcinoma', 'Disease', (355, 379))	('adenocarcinoma', 'Disease', (163, 177))	('EGFR', 'Gene', '1956', (234, 238))	('higher', 'Reg', (257, 263))	('EGFR', 'Gene', '1956', (51, 55))	('carcinoma', 'Disease', 'MESH:D009369', (318, 327))	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('adenocarcinoma', 'Disease', 'MESH:D000230', (276, 290))	('carcinoma', 'Disease', (93, 102))	('carcinoma', 'Disease', 'MESH:D009369', (168, 177))	('carcinoma', 'Phenotype', 'HP:0030731', (370, 379))	('mutation', 'Var', (56, 64))	('higher', 'PosReg', (121, 127))	('adenocarcinoma', 'Disease', (88, 102))	('adenocarcinoma', 'Disease', 'MESH:D000230', (163, 177))	('carcinoma', 'Disease', (370, 379))	('carcinoma', 'Phenotype', 'HP:0030731', (281, 290))	('adenocarcinoma', 'Disease', (365, 379))	('carcinoma', 'Disease', 'MESH:D009369', (93, 102))	('invasive adenocarcinoma', 'Disease', 'MESH:D000230', (267, 290))	('carcinoma', 'Disease', (281, 290))
65931	32429938	Therefore, it can be speculated that the amount of EGFR mutation is higher in invasive adenocarcinoma with distinct morphological differentiation, which needs to be confirmed through further research.	('invasive adenocarcinoma', 'Disease', 'MESH:D000230', (78, 101))	('EGFR', 'Gene', (51, 55))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('higher', 'Reg', (68, 74))	('mutation', 'Var', (56, 64))	('invasive adenocarcinoma', 'Disease', (78, 101))	('EGFR', 'Gene', '1956', (51, 55))
65932	32429938	The previously reported prevalence of ALK mutation was 3-7%.	('mutation', 'Var', (42, 50))	('ALK', 'Gene', '238', (38, 41))	('ALK', 'Gene', (38, 41))
65933	32429938	In this study, ALK mutation was found positive in 5.7% cases through ARMS-PCR and in 4.2% cases through IHC(D5F3), which was slightly lower than the mutational rate of 6.1% detected by Wang through IHC(D5F3).	('ALK', 'Gene', (15, 18))	('mutation', 'Var', (19, 27))	('positive', 'Reg', (38, 46))	('ALK', 'Gene', '238', (15, 18))	('ARMS-PCR', 'Disease', (69, 77))
65934	32429938	The overall frequency of ALK mutation was 4.5% in this study, which was almost consistent with previous reports.	('mutation', 'Var', (29, 37))	('ALK', 'Gene', (25, 28))	('ALK', 'Gene', '238', (25, 28))
65935	32429938	The frequency of ROS1 mutation was 0.9% in this study, which was slightly lower than that in previous reports (1.2-2.2%), probably because of the small amount of our ROS1-tested cohort.	('ROS1', 'Gene', (17, 21))	('mutation', 'Var', (22, 30))	('ROS1', 'Gene', '6098', (17, 21))	('ROS1', 'Gene', (166, 170))	('ROS1', 'Gene', '6098', (166, 170))
65937	32429938	On the basis of that, we found EGFR mutations were more common in females, younger age groups, and well-differentiated adenocarcinoma.	('common', 'Reg', (56, 62))	('EGFR', 'Gene', '1956', (31, 35))	('adenocarcinoma', 'Disease', (119, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('EGFR', 'Gene', (31, 35))	('mutations', 'Var', (36, 45))	('adenocarcinoma', 'Disease', 'MESH:D000230', (119, 133))
65938	32429938	Simultaneously, ALK mutation tended to be more common in older age groups, poorly-differentiated adenocarcinoma, and had no gender difference.	('adenocarcinoma', 'Disease', 'MESH:D000230', (97, 111))	('mutation', 'Var', (20, 28))	('ALK', 'Gene', '238', (16, 19))	('common', 'Reg', (47, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('adenocarcinoma', 'Disease', (97, 111))	('ALK', 'Gene', (16, 19))
65941	32429938	This work was supported by the National Natural Science Foundation of China (81773109), the Natural Science Foundation of Jiangsu Province (BK20151582), National key Clinical Specialty Construction Project (2014), Joint key project funded by Southeast University and Nanjing Medical University (2242019K3DN09, JX218GSP20190735) and the Fund of the priority Academic Program Development of Jiangsu Higher Education Institution (JX1023-1801).	('JX218GSP20190735', 'Var', (310, 326))	('men', 'Species', '9606', (381, 384))	('2242019K3DN09', 'Var', (295, 308))
65945	31605466	We observed that increased weight GRS was associated with increased risk of lung cancer (OR = 2.25, 95%CI: 1.81-2.78, P = 1.18 x 10-13).	('lung cancer', 'Disease', 'MESH:D008175', (76, 87))	('increased weight', 'Phenotype', 'HP:0004324', (17, 33))	('weight GRS', 'Var', (27, 37))	('lung cancer', 'Disease', (76, 87))	('lung cancer', 'Phenotype', 'HP:0100526', (76, 87))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))
65946	31605466	In different subtypes, weight GRS was significantly associated with lung adenocarcinoma risk (OR = 2.69, 95% CI: 2.11-3.42, P = 7.20 x 10-16); while lung squamous cell carcinoma showed a marginal association (OR = 1.45, 95% CI = 1.01-2.10, P = .047).	('carcinoma', 'Phenotype', 'HP:0030731', (168, 177))	('weight GRS', 'Var', (23, 33))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (149, 177))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (68, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('associated', 'Reg', (52, 62))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (149, 177))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (68, 87))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (154, 177))	('lung squamous cell carcinoma', 'Disease', (149, 177))	('lung adenocarcinoma', 'Disease', (68, 87))
65949	31605466	Those biological mechanisms changes caused by long TL may play an important role in lung carcinogenesis.	('long TL', 'Var', (46, 53))	('lung carcinogenesis', 'Disease', 'MESH:D063646', (84, 103))	('lung carcinogenesis', 'Disease', (84, 103))	('changes', 'Reg', (28, 35))
65958	31605466	Previous lung cancer MR studies also suggested increased lung cancer risk was associated with long leukocyte TL.20, 21 However, those studies were either in Western population or in East Asian never-smoking women.	('lung cancer', 'Phenotype', 'HP:0100526', (9, 20))	('long leukocyte', 'Var', (94, 108))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('women', 'Species', '9606', (207, 212))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('lung cancer', 'Disease', 'MESH:D008175', (9, 20))	('lung cancer', 'Disease', 'MESH:D008175', (57, 68))	('lung cancer', 'Disease', (9, 20))	('lung cancer', 'Disease', (57, 68))	('lung cancer', 'Phenotype', 'HP:0100526', (57, 68))
65970	31605466	The associations between nine TL-related SNPs and lung cancer risk in all participants was described in Table 1, suggesting that most of the TL-related SNPs were not in observed significant association with lung cancer, except rs2736100 and rs10936599.	('lung cancer', 'Disease', (50, 61))	('lung cancer', 'Disease', (207, 218))	('participants', 'Species', '9606', (74, 86))	('lung cancer', 'Disease', 'MESH:D008175', (207, 218))	('rs2736100', 'Var', (227, 236))	('lung cancer', 'Disease', 'MESH:D008175', (50, 61))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('rs2736100', 'Mutation', 'rs2736100', (227, 236))	('rs10936599', 'Mutation', 'rs10936599', (241, 251))	('lung cancer', 'Phenotype', 'HP:0100526', (50, 61))	('rs10936599', 'Var', (241, 251))	('lung cancer', 'Phenotype', 'HP:0100526', (207, 218))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))
65971	31605466	Meanwhile, except rs2736100 and rs11125529, the rest seven SNPs did not show significant heterogeneity between two datasets (Table S3).	('rs2736100', 'Mutation', 'rs2736100', (18, 27))	('rs2736100', 'Var', (18, 27))	('rs11125529', 'Mutation', 'rs11125529', (32, 42))	('rs11125529', 'Var', (32, 42))
65972	31605466	Associations with P < .05 were found for lung adenocarcinoma (rs10936599, rs2736100), lung squamous cell carcinoma (rs2736100, rs7675998, rs755017).	('rs755017', 'Var', (138, 146))	('rs10936599', 'Var', (62, 72))	('rs2736100', 'Mutation', 'rs2736100', (116, 125))	('rs7675998', 'Mutation', 'rs7675998', (127, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('rs10936599', 'Mutation', 'rs10936599', (62, 72))	('rs2736100', 'Mutation', 'rs2736100', (74, 83))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (86, 114))	('rs7675998', 'Var', (127, 136))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (41, 60))	('lung adenocarcinoma', 'Disease', (41, 60))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (86, 114))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (91, 114))	('lung squamous cell carcinoma', 'Disease', (86, 114))	('rs2736100', 'Var', (116, 125))	('rs755017', 'Mutation', 'rs755017', (138, 146))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (41, 60))	('rs2736100', 'Var', (74, 83))	('carcinoma', 'Phenotype', 'HP:0030731', (51, 60))
65973	31605466	Aggregate test showed one or more TL-related variants were in relation to lung cancer risk in aggregate (pooled P < 1x10-8).	('lung cancer', 'Disease', (74, 85))	('lung cancer', 'Phenotype', 'HP:0100526', (74, 85))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('variants', 'Var', (45, 53))	('TL-related', 'Gene', (34, 44))	('lung cancer', 'Disease', 'MESH:D008175', (74, 85))	('relation', 'Reg', (62, 70))
65983	31605466	We found positive slopes in all lung cancers as well as in two histology subtypes, indicating that longer TL showed a significant positive association with lung cancer risk.	('longer', 'Var', (99, 105))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('lung cancers', 'Phenotype', 'HP:0100526', (32, 44))	('cancers', 'Phenotype', 'HP:0002664', (37, 44))	('lung cancer', 'Disease', 'MESH:D008175', (156, 167))	('lung cancer', 'Disease', 'MESH:D008175', (32, 43))	('lung cancers', 'Disease', (32, 44))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('lung cancer', 'Disease', (156, 167))	('lung cancers', 'Disease', 'MESH:D008175', (32, 44))	('lung cancer', 'Phenotype', 'HP:0100526', (156, 167))	('lung cancer', 'Phenotype', 'HP:0100526', (32, 43))
65991	31605466	When testing of the pleiotropic effect for each SNP, rs2736100 in the TERT region was only one that failed in the test.	('rs2736100', 'Mutation', 'rs2736100', (53, 62))	('rs2736100', 'Var', (53, 62))	('TERT', 'Gene', (70, 74))	('TERT', 'Gene', '7015', (70, 74))
65992	31605466	SNP rs2736100 was a known lung cancer risk SNP reported in many studies across different population, and it may affect lung cancer risk through different mechanisms instead of TL.	('lung cancer', 'Disease', (119, 130))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('lung cancer', 'Phenotype', 'HP:0100526', (119, 130))	('rs2736100', 'Mutation', 'rs2736100', (4, 13))	('lung cancer', 'Disease', 'MESH:D008175', (26, 37))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('SNP rs2736100', 'Var', (0, 13))	('affect', 'Reg', (112, 118))	('lung cancer', 'Disease', 'MESH:D008175', (119, 130))	('lung cancer', 'Disease', (26, 37))	('lung cancer', 'Phenotype', 'HP:0100526', (26, 37))
65993	31605466	After excluding SNP rs2736100 (Table 2), we can still find significant associations between TL-related weight GRS and increased risk of lung adenocarcinoma (OR = 1.66, 95% CI = 1.27-2.16, P = 1.65 x 10-4) and combined lung cancer (OR = 1.45, 95% CI = 1.15-1.84, P = 1.70 x 10-3).	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('lung cancer', 'Disease', (218, 229))	('lung cancer', 'Phenotype', 'HP:0100526', (218, 229))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (136, 155))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('SNP rs2736100', 'Var', (16, 29))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (136, 155))	('rs2736100', 'Mutation', 'rs2736100', (20, 29))	('lung cancer', 'Disease', 'MESH:D008175', (218, 229))	('lung adenocarcinoma', 'Disease', (136, 155))
65996	31605466	In separate analyses for each study, we found that without rs2736100, the association between TL-related weight GRS and lung cancer risk was only significant in FLCCA data (Table S3).	('rs2736100', 'Var', (59, 68))	('lung cancer', 'Disease', (120, 131))	('lung cancer', 'Phenotype', 'HP:0100526', (120, 131))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('rs2736100', 'Mutation', 'rs2736100', (59, 68))	('lung cancer', 'Disease', 'MESH:D008175', (120, 131))
65997	31605466	When excluding pleiotropic SNP rs2736100, the TL-related variants met all MR assumptions and the association between GRS and lung cancer (including lung adenocarcinoma) remained statistically significant suggesting that TL may be a causal factor for lung cancer risk.	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (148, 167))	('TL-related', 'Gene', (46, 56))	('lung cancer', 'Phenotype', 'HP:0100526', (250, 261))	('lung cancer', 'Disease', 'MESH:D008175', (125, 136))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (148, 167))	('cancer', 'Phenotype', 'HP:0002664', (255, 261))	('variants', 'Var', (57, 65))	('lung cancer', 'Disease', 'MESH:D008175', (250, 261))	('lung adenocarcinoma', 'Disease', (148, 167))	('significant', 'Reg', (192, 203))	('rs2736100', 'Mutation', 'rs2736100', (31, 40))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (158, 167))	('lung cancer', 'Disease', (125, 136))	('lung cancer', 'Phenotype', 'HP:0100526', (125, 136))	('lung cancer', 'Disease', (250, 261))
66001	31605466	Using restricted cubic spline analysis, we observed a linear relationship between genetic predicted TL and the risk of lung cancer.	('lung cancer', 'Disease', (119, 130))	('lung cancer', 'Phenotype', 'HP:0100526', (119, 130))	('genetic predicted', 'Var', (82, 99))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('lung cancer', 'Disease', 'MESH:D008175', (119, 130))
66006	31605466	A MR analysis of TL using multi-SNP score in European population observed a significant association between long telomeres and lung adenocarcinoma (but not squamous cell carcinoma), which is accordance with our results.	('carcinoma', 'Phenotype', 'HP:0030731', (170, 179))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (127, 146))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (156, 179))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (127, 146))	('squamous cell carcinoma', 'Disease', (156, 179))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (156, 179))	('long telomeres', 'Var', (108, 122))	('lung adenocarcinoma', 'Disease', (127, 146))
66008	31605466	Contrarily, long telomeres may allow for extra cell division, which let cells have more chances to accumulate carcinogenesis somatic mutations, and finally resulted in malignant transformation.32, 33 In previous melanoma and B-cell lymphoma studies, researchers found that long TL was associated with increased cancer risk.34, 35 It is suggested that long telomeres may have a stronger effect than short telomeres in carcinogenesis, with a proposed mechanism that long telomeres may promote cell growth and proliferation, thus delaying senescence and allowing further oncogenic mutations to accumulate.	('senescence', 'CPA', (536, 546))	('carcinogenesis', 'Disease', (417, 431))	('delaying', 'NegReg', (527, 535))	('lymphoma', 'Phenotype', 'HP:0002665', (232, 240))	('promote', 'PosReg', (483, 490))	('cancer', 'Disease', (311, 317))	('cancer', 'Disease', 'MESH:D009369', (311, 317))	('cancer', 'Phenotype', 'HP:0002664', (311, 317))	('melanoma', 'Phenotype', 'HP:0002861', (212, 220))	('melanoma', 'Disease', (212, 220))	('long telomeres', 'Var', (464, 478))	('carcinogenesis', 'Disease', 'MESH:D063646', (110, 124))	('melanoma', 'Disease', 'MESH:D008545', (212, 220))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (225, 240))	('short telomeres', 'Phenotype', 'HP:0031413', (398, 413))	('cell growth', 'CPA', (491, 502))	('carcinogenesis', 'Disease', (110, 124))	('carcinogenesis', 'Disease', 'MESH:D063646', (417, 431))
66010	31605466	Together with other studies, we support that long telomeres are a risk factor of lung cancer.	('lung cancer', 'Disease', (81, 92))	('lung cancer', 'Phenotype', 'HP:0100526', (81, 92))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('long telomeres', 'Var', (45, 59))	('lung cancer', 'Disease', 'MESH:D008175', (81, 92))
66013	31605466	However, previous studies have reported that TL measured in blood and lung was correlated, supporting the assumption that our SNPs can predict TL in lung tissue.39  In conclusion, our study provides evidence for a possible causal association between telomere length and lung cancer risk in East Asian population, consistent with Western population results.	('lung cancer', 'Disease', (270, 281))	('lung cancer', 'Phenotype', 'HP:0100526', (270, 281))	('telomere length', 'Var', (250, 265))	('cancer', 'Phenotype', 'HP:0002664', (275, 281))	('lung cancer', 'Disease', 'MESH:D008175', (270, 281))
66036	30956908	By contrast, in the development of esophageal squamous cell carcinoma (ESCC), through a multi-step process of epigenetic and genetic changes, a sequence of histological changes occurs in the epithelium of the esophagus, over years of chronic irritation due to tobacco smoking.	('tobacco', 'Species', '4097', (260, 267))	('epigenetic', 'Var', (110, 120))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (35, 69))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (46, 69))	('chronic irritation', 'Disease', 'MESH:D001523', (234, 252))	('esophageal squamous cell carcinoma', 'Disease', (35, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (60, 69))	('chronic irritation', 'Disease', (234, 252))	('men', 'Species', '9606', (27, 30))
66047	30956908	Consequently, impairment of the oral cavity immune response serves to promote OC.	('oral cavity immune response', 'CPA', (32, 59))	('promote', 'PosReg', (70, 77))	('impairment', 'Var', (14, 24))	('men', 'Species', '9606', (20, 23))
66068	30956908	DNA has an elaborate repair system to eliminate DNA adducts from the genome; however, if the repair mechanism fails, due to irritant overload such as tobacco use, it can lead to mutations, which increases the risk of cancers.	('tobacco', 'Species', '4097', (150, 157))	('lead to', 'Reg', (170, 177))	('rat', 'Species', '10116', (16, 19))	('cancers', 'Phenotype', 'HP:0002664', (217, 224))	('cancers', 'Disease', 'MESH:D009369', (217, 224))	('cancers', 'Disease', (217, 224))	('mutations', 'Var', (178, 187))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))
66118	30956908	Adenocarcinoma that has spread can occur due to a mutation in the genes of Kirsten rat sarcoma viral oncogene homolog (K-RAS), epidermal growth factor receptor (EGFR), and anaplastic lymphoma kinase (ALK).	('Adenocarcinoma', 'Disease', (0, 14))	('rat', 'Species', '10116', (83, 86))	('epidermal growth factor receptor', 'Gene', (127, 159))	('EGFR', 'Gene', (161, 165))	('K-RAS', 'Gene', (119, 124))	('Adenocarcinoma', 'Disease', 'MESH:D000230', (0, 14))	('epidermal growth factor receptor', 'Gene', '24329', (127, 159))	('carcinoma', 'Phenotype', 'HP:0030731', (5, 14))	('sarcoma', 'Disease', (87, 94))	('sarcoma', 'Phenotype', 'HP:0100242', (87, 94))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (172, 191))	('anaplastic lymphoma kinase', 'Gene', (172, 198))	('sarcoma', 'Disease', 'MESH:D012509', (87, 94))	('anaplastic lymphoma kinase', 'Gene', '266802', (172, 198))	('lymphoma', 'Phenotype', 'HP:0002665', (183, 191))	('mutation', 'Var', (50, 58))
66119	30956908	Testing for these gene mutations will ultimately determine the appropriate treatment to go forward with when treating adenocarcinoma; hence, if the K-RAS mutation is present, that would indicate that the anti-EGFR treatment will not work.	('adenocarcinoma', 'Disease', 'MESH:D000230', (118, 132))	('men', 'Species', '9606', (219, 222))	('men', 'Species', '9606', (80, 83))	('mutations', 'Var', (23, 32))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('adenocarcinoma', 'Disease', (118, 132))
66160	30956908	The long-term effects of tobacco smoking have been associated with an increased TP53 gene mutation, which impairs the DNA repair mechanism, resulting in abnormal proliferation of the cell, which leads to tumor growth.	('rat', 'Species', '10116', (169, 172))	('leads', 'Reg', (195, 200))	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('increased', 'PosReg', (70, 79))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('impairs', 'NegReg', (106, 113))	('TP53', 'Gene', '7157', (80, 84))	('TP53', 'Gene', (80, 84))	('tobacco', 'Species', '4097', (25, 32))	('tumor', 'Disease', (204, 209))	('mutation', 'Var', (90, 98))
66175	30956908	PAC generally arises due to the consequence of a cancer-associated mutation that is acquired or inherited.	('mutation', 'Var', (67, 75))	('PAC', 'Phenotype', 'HP:0006699', (0, 3))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('PAC', 'Disease', (0, 3))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('cancer', 'Disease', (49, 55))
66242	30956908	The molecular alterations to these genes have been described to correlate with an altered prognosis, appearing to hold potential prognostic and therapeutic promise.	('alterations', 'Var', (14, 25))	('pear', 'Species', '23211', (103, 107))	('rat', 'Species', '10116', (18, 21))	('altered', 'Reg', (82, 89))
66257	26871600	Segmentectomy was associated with improved OS (hazard ratio = 0.626, 95% confidence interval: 0.457-0.858, P = 0.004) and LCSS (hazard ratio = 0.643, 95% CI: 0.440-0.939, P = 0.022) in invasive adenocarcinoma patients <= 65 years old.	('LCSS', 'Chemical', '-', (122, 126))	('improved', 'PosReg', (34, 42))	('invasive adenocarcinoma', 'Disease', (185, 208))	('invasive adenocarcinoma', 'Disease', 'MESH:D000230', (185, 208))	('OS', 'Chemical', '-', (43, 45))	('patients', 'Species', '9606', (209, 217))	('Segmentectomy', 'Var', (0, 13))	('carcinoma', 'Phenotype', 'HP:0030731', (199, 208))	('LCSS', 'CPA', (122, 126))
66274	26871600	Segmentectomy was associated with improved OS (HR = 0.626, 95% CI: 0.457-0.858, P = 0.004) and LCSS (HR = 0.643, 95% CI: 0.440-0.939, P = 0.022) in invasive adenocarcinoma patients <= 65 years old.	('improved', 'PosReg', (34, 42))	('LCSS', 'Chemical', '-', (95, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (162, 171))	('invasive adenocarcinoma', 'Disease', (148, 171))	('OS', 'Chemical', '-', (43, 45))	('Segmentectomy', 'Var', (0, 13))	('patients', 'Species', '9606', (172, 180))	('invasive adenocarcinoma', 'Disease', 'MESH:D000230', (148, 171))	('LCSS', 'CPA', (95, 99))
66288	26871600	We found that in <= 2 cm invasive adenocarcinoma, OS following segmentectomy was significantly better than that after wedge resection, while survival outcomes were comparable between patients receiving segmentectomy or wedge resection in invasive adenocarcinoma 2-3 cm in size, supporting the application of segmentectomy in small-sized invasive lung adenocarcinoma.	('<= 2 cm', 'Var', (17, 24))	('invasive adenocarcinoma', 'Disease', (25, 48))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (346, 365))	('invasive lung adenocarcinoma', 'Disease', (337, 365))	('invasive lung adenocarcinoma', 'Disease', 'MESH:D000077192', (337, 365))	('invasive adenocarcinoma', 'Disease', 'MESH:D000230', (25, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (252, 261))	('invasive adenocarcinoma', 'Disease', (238, 261))	('segmentectomy', 'Var', (63, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (39, 48))	('OS', 'Chemical', '-', (50, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (356, 365))	('invasive adenocarcinoma', 'Disease', 'MESH:D000230', (238, 261))	('better', 'PosReg', (95, 101))	('patients', 'Species', '9606', (183, 191))
66314	25668320	Despite the multiple head and neck tumor subsites and the variety of treatments, we found in this retrospective analysis a substantial relation of high MATH values to decreased overall survival (Cox proportional hazards analysis: hazard ratio for high/low heterogeneity, 2.2; 95% CI 1.4 to 3.3).	('high MATH values', 'Var', (147, 163))	('neck tumor', 'Disease', 'MESH:D006258', (30, 40))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('Cox', 'Gene', '1351', (195, 198))	('overall survival', 'MPA', (177, 193))	('Cox', 'Gene', (195, 198))	('head and neck tumor', 'Phenotype', 'HP:0012288', (21, 40))	('neck tumor', 'Disease', (30, 40))	('decreased', 'NegReg', (167, 176))
66323	25668320	As the mutated cell grows and divides, it accumulates additional mutations that allow it to grow even faster and eventually from a lump, or tumor (cancer).	('faster', 'PosReg', (102, 108))	('grow', 'CPA', (92, 96))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('cancer', 'Disease', (147, 153))	('mutated', 'Var', (7, 14))	('mutations', 'Var', (65, 74))	('tumor', 'Disease', (140, 145))
66324	25668320	Other mutations subsequently allow the tumor to spread around the body (metastasize) and destroy healthy tissues.	('spread', 'CPA', (48, 54))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumor', 'Disease', (39, 44))	('destroy', 'NegReg', (89, 96))	('healthy tissues', 'CPA', (97, 112))	('mutations', 'Var', (6, 15))	('allow', 'Reg', (29, 34))
66327	25668320	The gradual acquisition of mutations by tumor cells leads to the formation of subpopulations of cells, each carrying a different set of mutations.	('mutations', 'Var', (27, 36))	('tumor', 'Disease', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))
66346	25668320	Differences of a cancer cell's genome from the germ line can result from unrepaired copy-number aberrations (CNAs) (amplification or loss of chromosomes, chromosome arms, or large genome segments) or smaller somatic mutations (single-nucleotide variants or short genomic insertions or deletions) that are passed on to a cell's lineage during tumor development.	('result from', 'Reg', (61, 72))	('tumor', 'Disease', 'MESH:D009369', (342, 347))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('loss', 'NegReg', (133, 137))	('copy-number aberrations', 'CPA', (84, 107))	('cancer', 'Disease', (17, 23))	('tumor', 'Phenotype', 'HP:0002664', (342, 347))	('single-nucleotide variants', 'Var', (227, 253))	('deletions', 'Var', (285, 294))	('tumor', 'Disease', (342, 347))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
66351	25668320	Analyses of CNA patterns or somatic mutations in different portions of the same tumor, even down to individual cells, have documented the importance of intra-tumor heterogeneity in tumor biology and have supported the early hypothesis that preexisting resistant subclones may be selected by therapy, leading to treatment failure.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor', 'Disease', (158, 163))	('intra-tumor', 'Disease', 'MESH:D009369', (152, 163))	('tumor', 'Disease', (181, 186))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('mutations', 'Var', (36, 45))	('tumor', 'Disease', (80, 85))	('intra-tumor', 'Disease', (152, 163))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))
66361	25668320	Methods that combine information on somatic mutations and copy-number changes to infer the subclonal composition of tumors are still highly specialized, are computationally intensive, and typically require an underlying theoretical model or tumor-type-specific empiric examples of intra-tumor subclonal relations.	('tumors', 'Disease', (116, 122))	('intra-tumor', 'Disease', (281, 292))	('tumors', 'Disease', 'MESH:D009369', (116, 122))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))	('tumor', 'Disease', (241, 246))	('changes', 'Var', (70, 77))	('tumor', 'Disease', 'MESH:D009369', (287, 292))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('intra-tumor', 'Disease', 'MESH:D009369', (281, 292))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (287, 292))	('tumor', 'Disease', (287, 292))	('tumor', 'Disease', 'MESH:D009369', (241, 246))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))	('tumor', 'Disease', (116, 121))	('copy-number', 'Var', (58, 69))
66363	25668320	For each genomic locus having a tumor-specific mutation, WES provides the fraction of total sequenced DNA that shows the mutant allele, the mutant-allele fraction (MAF).	('tumor', 'Disease', (32, 37))	('mutation', 'Var', (47, 55))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))
66364	25668320	Typically, a locus mutated early in the clonal evolution of a tumor will be shared among later-arising subclones and have a high MAF in a bulk tumor specimen, while loci mutated later, restricted to one or a few subclones, have lower MAFs.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('tumor', 'Disease', (62, 67))	('mutated', 'Var', (19, 26))	('MAF', 'MPA', (129, 132))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
66365	25668320	Because both subclonal mutations and CNAs would be expected to lead to differences in MAF values among genomic loci, we reasoned that the width of the distribution of MAF values among tumor-specific mutated loci within an individual tumor might capture intra-tumor genetic heterogeneity arising from both mechanisms.	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('differences', 'Reg', (71, 82))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('tumor', 'Disease', (233, 238))	('tumor', 'Disease', 'MESH:D009369', (259, 264))	('intra-tumor', 'Disease', 'MESH:D009369', (253, 264))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('tumor', 'Phenotype', 'HP:0002664', (259, 264))	('tumor', 'Disease', 'MESH:D009369', (233, 238))	('tumor', 'Disease', (184, 189))	('mutations', 'Var', (23, 32))	('lead', 'Reg', (63, 67))	('tumor', 'Disease', (259, 264))	('intra-tumor', 'Disease', (253, 264))
66366	25668320	We thus proposed mutant-allele tumor heterogeneity (MATH), the width of this distribution (normalized by the median MAF value to correct for normal DNA in the tumor sample), as a simple quantitative measure of intra-tumor genetic heterogeneity.	('tumor', 'Disease', (216, 221))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('intra-tumor', 'Disease', (210, 221))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('tumor', 'Disease', (31, 36))	('tumor', 'Disease', (159, 164))	('tumor', 'Disease', 'MESH:D009369', (216, 221))	('intra-tumor', 'Disease', 'MESH:D009369', (210, 221))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('mutant-allele', 'Var', (17, 30))
66372	25668320	We examined the relation of MATH values to standard clinical variables, including HPV status, and to three molecular characteristics of HNSCC: mutation rate, TP53 mutations, and oncogenic signature.	('TP53', 'Gene', '7157', (158, 162))	('TP53', 'Gene', (158, 162))	('mutations', 'Var', (163, 172))	('HNSCC', 'Disease', (136, 141))	('HNSCC', 'Phenotype', 'HP:0012288', (136, 141))	('HPV', 'Species', '10566', (82, 85))
66380	25668320	Identification of tumor-specific mutations had already been performed at the Broad Institute of MIT and Harvard for TCGA, with the exome of tumor and matched normal DNA selected by Agilent SureSelect methods, followed by Illumina HiSeq sequencing.	('tumor', 'Disease', (18, 23))	('mutations', 'Var', (33, 42))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('tumor', 'Disease', (140, 145))
66382	25668320	For each tumor, this algorithm uses the numbers of mutant and reference reads and the quality of the reads, in both tumor and patient-matched normal DNA, to estimate the likelihood that a particular locus has a tumor-specific rather than a germ-line mutation.	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('mutant', 'Var', (51, 57))	('patient', 'Species', '9606', (126, 133))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor', 'Disease', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('tumor', 'Disease', (211, 216))	('tumor', 'Disease', (116, 121))
66383	25668320	Loci that pass the assigned threshold likelihood are deemed to have tumor-specific mutations.	('tumor', 'Disease', (68, 73))	('Loci', 'Var', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))
66384	25668320	The publicly available compilation of HNSCC mutant-allele data contained the numbers of WES reads showing the mutant allele and the number showing the reference allele at each tumor-specific mutated genomic locus for each tumor.	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('tumor', 'Disease', 'MESH:D009369', (222, 227))	('tumor', 'Disease', (176, 181))	('mutant', 'Var', (110, 116))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('tumor', 'Disease', (222, 227))	('HNSCC', 'Gene', (38, 43))	('mutant-allele', 'Var', (44, 57))	('tumor', 'Disease', 'MESH:D009369', (176, 181))	('HNSCC', 'Phenotype', 'HP:0012288', (38, 43))
66385	25668320	We calculated the MAF for each locus as the ratio of mutant reads to total reads, and tabulated all MAF values for each tumor.	('mutant reads', 'Var', (53, 65))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('tumor', 'Disease', (120, 125))
66386	25668320	In one tumor, all mutations had MAF values below that cutoff, so 305 cases remained for this study.	('mutations', 'Var', (18, 27))	('tumor', 'Disease', (7, 12))	('tumor', 'Disease', 'MESH:D009369', (7, 12))	('MAF values', 'MPA', (32, 42))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
66393	25668320	A tumor was judged to have mutant TP53 if it had any non-silent mutation in that gene.	('TP53', 'Gene', (34, 38))	('mutant', 'Var', (27, 33))	('tumor', 'Phenotype', 'HP:0002664', (2, 7))	('TP53', 'Gene', '7157', (34, 38))	('A tumor', 'Disease', (0, 7))	('A tumor', 'Disease', 'MESH:D009369', (0, 7))
66420	25668320	Patients with high- versus low-heterogeneity tumors had double the hazard of death (HR, 2.18; 95% CI, 1.44 to 3.30; p < 0.001; Fig.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('death', 'Disease', 'MESH:D003643', (77, 82))	('high-', 'Var', (14, 19))	('death', 'Disease', (77, 82))	('tumors', 'Disease', (45, 51))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('tumors', 'Disease', 'MESH:D009369', (45, 51))	('Patients', 'Species', '9606', (0, 8))
66425	25668320	Despite the strong association of HPV-positive tumors with low MATH values (Table 2), both MATH value and HPV status were significantly related to overall survival in bivariate Cox proportional hazards analysis.	('overall', 'MPA', (147, 154))	('related', 'Reg', (136, 143))	('HPV-positive tumors', 'Disease', 'MESH:D030361', (34, 53))	('HPV', 'Species', '10566', (106, 109))	('MATH values', 'MPA', (63, 74))	('HPV-positive tumors', 'Disease', (34, 53))	('Cox', 'Gene', '1351', (177, 180))	('low', 'Var', (59, 62))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('low MATH', 'Phenotype', 'HP:0001249', (59, 67))	('Cox', 'Gene', (177, 180))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))	('HPV', 'Species', '10566', (34, 37))
66430	25668320	In univariate analyses, MATH values were related to three other molecular characteristics of the tumors: the number of somatic mutations in the exome (a measure of tumor mutation rate), TP53 mutation status, and oncogenic signature class (Table 2, bottom).	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor', 'Disease', (164, 169))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('TP53', 'Gene', '7157', (186, 190))	('tumor', 'Disease', (97, 102))	('tumors', 'Disease', (97, 103))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('TP53', 'Gene', (186, 190))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('tumors', 'Disease', 'MESH:D009369', (97, 103))	('mutation', 'Var', (191, 199))
66432	25668320	Second, MATH values were significantly higher in HPV-negative tumors that harbored TP53 mutations than in HPV-positive/TP53 wild-type tumors (Table 3), and as expected, mutated TP53 was significantly related to diminished overall survival (HR, 2.61; 95% CI, 1.67 to 4.07; p < 0.001).	('diminished', 'NegReg', (211, 221))	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('higher', 'PosReg', (39, 45))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('mutations', 'Var', (88, 97))	('TP53', 'Gene', '7157', (177, 181))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('TP53', 'Gene', '7157', (119, 123))	('tumors', 'Disease', (134, 140))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('TP53', 'Gene', (83, 87))	('tumors', 'Disease', (62, 68))	('overall survival', 'MPA', (222, 238))	('HPV', 'Species', '10566', (106, 109))	('tumors', 'Disease', 'MESH:D009369', (134, 140))	('mutated', 'Var', (169, 176))	('HPV', 'Species', '10566', (49, 52))	('tumors', 'Disease', 'MESH:D009369', (62, 68))	('TP53', 'Gene', (177, 181))	('TP53', 'Gene', (119, 123))	('TP53', 'Gene', '7157', (83, 87))	('MATH values', 'MPA', (8, 19))
66433	25668320	6 (right), however, both MATH and TP53 mutation status were significantly related to survival among patients with HPV-negative tumors.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('mutation', 'Var', (39, 47))	('TP53', 'Gene', (34, 38))	('tumors', 'Disease', (127, 133))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('HPV', 'Species', '10566', (114, 117))	('tumors', 'Disease', 'MESH:D009369', (127, 133))	('patients', 'Species', '9606', (100, 108))	('related to', 'Reg', (74, 84))	('survival', 'MPA', (85, 93))	('TP53', 'Gene', '7157', (34, 38))
66434	25668320	(Only one HPV-positive tumor bore a mutation in TP53.)	('TP53', 'Gene', '7157', (48, 52))	('HPV-positive tumor', 'Disease', (10, 28))	('HPV-positive tumor', 'Disease', 'MESH:D030361', (10, 28))	('TP53', 'Gene', (48, 52))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('mutation', 'Var', (36, 44))
66435	25668320	Thus, both high MATH value and mutated TP53 were associated with survival after adjustment for their relation to each other.	('TP53', 'Gene', (39, 43))	('associated with', 'Reg', (49, 64))	('TP53', 'Gene', '7157', (39, 43))	('high MATH value', 'Var', (11, 26))	('survival', 'MPA', (65, 73))	('mutated', 'Var', (31, 38))
66437	25668320	Oncogenic signatures are genomic classifications based on over 3,000 TCGA tumors from multiple anatomic sites, with the major classes called "M" and "C." Disruptions in M-class tumors are dominated by small mutations (single nucleotide variants and small indels), versus predominant CNAs in C-class tumors.	('M-class tumors', 'Disease', 'MESH:C566367', (169, 183))	('tumor', 'Phenotype', 'HP:0002664', (299, 304))	('tumors', 'Phenotype', 'HP:0002664', (177, 183))	('A tumor', 'Disease', 'MESH:D009369', (72, 79))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumors', 'Disease', 'MESH:D009369', (177, 183))	('single nucleotide variants', 'Var', (218, 244))	('tumors', 'Disease', (299, 305))	('tumors', 'Disease', 'MESH:D009369', (299, 305))	('tumors', 'Phenotype', 'HP:0002664', (299, 305))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('tumors', 'Disease', (177, 183))	('tumors', 'Disease', 'MESH:D009369', (74, 80))	('A tumor', 'Disease', (72, 79))	('M-class tumors', 'Disease', (169, 183))	('tumors', 'Disease', (74, 80))
66442	25668320	Thus, the relation of high MATH value to increased mortality is not due to its associations with the tumor molecular characteristics of mutation rate, TP53 mutation, and oncogenic signature.	('associations', 'Interaction', (79, 91))	('TP53', 'Gene', (151, 155))	('mutation', 'Var', (136, 144))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('TP53', 'Gene', '7157', (151, 155))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
66455	25668320	In both studies, the univariate overall survival HR for high/low MATH was over 2 (previous study, 2.46; this study, 2.18), and a relation of high intra-tumor heterogeneity to decreased overall survival was seen among patients receiving chemoradiotherapy (HR in previous study, 4.1; this study, 5.2).	('overall survival', 'MPA', (185, 201))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('intra-tumor', 'Disease', (146, 157))	('high/low MATH', 'Var', (56, 69))	('low MATH', 'Phenotype', 'HP:0001249', (61, 69))	('patients', 'Species', '9606', (217, 225))	('intra-tumor', 'Disease', 'MESH:D009369', (146, 157))	('decreased', 'NegReg', (175, 184))
66462	25668320	High MATH values in tumors containing TP53 mutations suggest that deficiencies in DNA-damage and apoptotic responses may create an environment that is favorable to the generation or maintenance of intra-tumor genetic heterogeneity.	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('tumors', 'Disease', (20, 26))	('intra-tumor', 'Disease', 'MESH:D009369', (197, 208))	('apoptotic responses', 'CPA', (97, 116))	('tumors', 'Disease', 'MESH:D009369', (20, 26))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('TP53', 'Gene', (38, 42))	('mutations', 'Var', (43, 52))	('intra-tumor', 'Disease', (197, 208))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('TP53', 'Gene', '7157', (38, 42))
66465	25668320	The relation of high MATH value to LVI and nodal status suggests that intra-tumor heterogeneity may foster regional metastasis.	('regional metastasis', 'CPA', (107, 126))	('intra-tumor', 'Disease', (70, 81))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('foster', 'PosReg', (100, 106))	('intra-tumor', 'Disease', 'MESH:D009369', (70, 81))	('heterogeneity', 'Var', (82, 95))
66471	25668320	Second, the close relations among TP53 mutation status, HPV status, MATH value, and clinical characteristics mean that care must be taken in interpreting and using prognostic models in HNSCC.	('mutation', 'Var', (39, 47))	('TP53', 'Gene', (34, 38))	('HPV', 'Species', '10566', (56, 59))	('HNSCC', 'Disease', (185, 190))	('TP53', 'Gene', '7157', (34, 38))	('HNSCC', 'Phenotype', 'HP:0012288', (185, 190))
66481	25668320	The MAFs observed in a bulk tumor DNA sample are determined by several factors: the "impurity" arising from normal DNA in non-cancer cells, the cancer-cell genomic ploidy arising from large-scale gain or loss of chromosomal segments or smaller-scale CNAs, and mutations specific to genetically distinct subclones within the tumor.	('gain', 'PosReg', (196, 200))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('tumor', 'Disease', (28, 33))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('tumor', 'Disease', (324, 329))	('loss', 'NegReg', (204, 208))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('tumor', 'Phenotype', 'HP:0002664', (324, 329))	('cancer', 'Disease', (144, 150))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('mutations', 'Var', (260, 269))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('tumor', 'Disease', 'MESH:D009369', (324, 329))
66499	25668320	Unlike approaches to measuring intra-tumor heterogeneity that require pre-identification of subclone markers, detailed analysis of SNP arrays, or analysis of multiple portions down to single cells of a tumor, MATH calculations require no information beyond a list of tumor-specific mutations and their MAFs, derived directly from a patient's tumor and normal DNA.	('intra-tumor', 'Disease', (31, 42))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('tumor', 'Disease', (202, 207))	('tumor', 'Disease', 'MESH:D009369', (267, 272))	('tumor', 'Disease', 'MESH:D009369', (342, 347))	('patient', 'Species', '9606', (332, 339))	('tumor', 'Phenotype', 'HP:0002664', (267, 272))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('intra-tumor', 'Disease', 'MESH:D009369', (31, 42))	('tumor', 'Phenotype', 'HP:0002664', (342, 347))	('tumor', 'Disease', (267, 272))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('tumor', 'Disease', (342, 347))	('mutations', 'Var', (282, 291))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))
66512	32473077	Furthermore, MMP-2 production was reduced by the transfection of CD73 siRNA in fibroblasts cocultured with tumor cells.	('N', 'Chemical', 'MESH:D009584', (73, 74))	('reduced', 'NegReg', (34, 41))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('transfection', 'Var', (49, 61))	('CD73 siRNA', 'Gene', (65, 75))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('MMP-2 production', 'MPA', (13, 29))
66517	32473077	Emmprin and CD73 form a complex, and MMP-2 production from fibroblasts is reduced by knockdown of CD73 in fibroblasts cocultured with squamous cell carcinoma cells.	('CD73', 'Gene', (98, 102))	('Emmprin', 'Gene', '682', (0, 7))	('knockdown', 'Var', (85, 94))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (134, 157))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (134, 157))	('squamous cell carcinoma', 'Disease', (134, 157))	('reduced', 'NegReg', (74, 81))	('Emmprin', 'Gene', (0, 7))	('MMP-2 production', 'MPA', (37, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (148, 157))
66571	32473077	27  A431, CRL-2095, and ST353i were cultured in a growth medium consisting of DMEM supplemented with 10% FBS, streptomycin (50 mug/mL), and penicillin G (50 U/mL).	('penicillin G', 'Chemical', 'MESH:D010400', (140, 152))	('streptomycin', 'Chemical', 'MESH:D013307', (110, 122))	('CRL', 'Gene', (10, 13))	('ST353i', 'Var', (24, 30))	('A431', 'CellLine', 'CVCL:0037', (4, 8))	('CRL', 'Gene', '133396', (10, 13))	('men', 'Species', '9606', (89, 92))	('DMEM', 'Chemical', '-', (78, 82))
66576	32473077	Small interference RNA sequences were used for knockdown of CD73 or emmprin mRNA.	('knockdown', 'Var', (47, 56))	('N', 'Chemical', 'MESH:D009584', (20, 21))	('CD73', 'Gene', (60, 64))	('N', 'Chemical', 'MESH:D009584', (78, 79))
66577	32473077	Three different CD73 siRNAs (Invitrogen):NT5EHSS107326, NT5EHSS107328, and NT5EHSS181585:were tested by immunoblotting (data not shown).	('NT5EHSS107326', 'Var', (41, 54))	('N', 'Chemical', 'MESH:D009584', (75, 76))	('NT5EHSS107328', 'Var', (56, 69))	('N', 'Chemical', 'MESH:D009584', (24, 25))	('N', 'Chemical', 'MESH:D009584', (41, 42))	('N', 'Chemical', 'MESH:D009584', (56, 57))
66580	32473077	The siRNAs targeting CD73 were transfected into A431, CRL-2095, and ST353i using Oligofectamine transfection reagent in Opti-MEM (Thermo Fisher Scientific) in the absence of serum and antibiotics according to the manufacturer's instructions.	('Opti-MEM', 'Chemical', '-', (120, 128))	('Oligofectamine', 'Chemical', 'MESH:C484027', (81, 95))	('CRL', 'Gene', '133396', (54, 57))	('A431', 'CellLine', 'CVCL:0037', (48, 52))	('N', 'Chemical', 'MESH:D009584', (7, 8))	('CRL', 'Gene', (54, 57))	('CD73', 'Var', (21, 25))
66616	32473077	CD73 or emmprin expression was inhibited by the transfection of CD73 or emmprin siRNA, respectively.	('CD73', 'Gene', (64, 68))	('CD73', 'Protein', (0, 4))	('N', 'Chemical', 'MESH:D009584', (83, 84))	('emmprin', 'Gene', (8, 15))	('transfection', 'Var', (48, 60))	('inhibited', 'NegReg', (31, 40))
66619	32473077	The MMP-2 production from ST353i cells was increased in conditions of coculture with A431 or CRL-2095 cells and was inhibited by transfection of CD73 siRNA (Figure 4E,F) or emmprin siRNA (data not shown).	('N', 'Chemical', 'MESH:D009584', (153, 154))	('N', 'Chemical', 'MESH:D009584', (184, 185))	('A431', 'CellLine', 'CVCL:0037', (85, 89))	('inhibited', 'NegReg', (116, 125))	('MMP-2 production', 'MPA', (4, 20))	('CD73', 'Var', (145, 149))	('CRL', 'Gene', (93, 96))	('increased', 'PosReg', (43, 52))	('CRL', 'Gene', '133396', (93, 96))
66626	32473077	In vitro, CD73 forms a complex with emmprin and is associated with increased production of MMP-2 from fibroblasts cocultured with SCC cells.	('production of MMP-2', 'MPA', (77, 96))	('SCC', 'Gene', (130, 133))	('complex', 'Interaction', (23, 30))	('CD73', 'Var', (10, 14))	('SCC', 'Gene', '6317', (130, 133))	('increased', 'PosReg', (67, 76))	('emmprin', 'Protein', (36, 43))
66627	32473077	High emmprin expression in the tumor cells is associated with poor prognosis in SCC of the oral cavity, skin, and hypopharynx.	('SCC', 'Gene', '6317', (80, 83))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('High', 'Var', (0, 4))	('tumor', 'Disease', (31, 36))	('SCC', 'Gene', (80, 83))	('emmprin', 'Gene', (5, 12))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
66630	32473077	33  In high-grade serous ovarian cancer, high CD73 intensity of fibroblasts is associated with poor prognosis.	('serous ovarian cancer', 'Disease', (18, 39))	('high CD73', 'Var', (41, 50))	('ovarian cancer', 'Phenotype', 'HP:0100615', (25, 39))	('serous ovarian cancer', 'Disease', 'MESH:D018284', (18, 39))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))
66653	32473077	46  CD73 is also known to promote invasion and metastasis through the PI3K/Akt pathway.	('promote', 'PosReg', (26, 33))	('Akt', 'Gene', '207', (75, 78))	('Akt', 'Gene', (75, 78))	('46  CD73', 'Var', (0, 8))
66669	32047559	Next-generation sequencing was used to detect the mutation of EML4-ALK in 1505 non-small cell lung cancer patients, including 1208 tissue samples and 297 blood samples.	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (79, 105))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (83, 105))	('ALK', 'Gene', '238', (67, 70))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (79, 105))	('EML4', 'Gene', (62, 66))	('patients', 'Species', '9606', (106, 114))	('lung cancer', 'Phenotype', 'HP:0100526', (94, 105))	('non-small cell lung cancer', 'Disease', (79, 105))	('EML4', 'Gene', '27436', (62, 66))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('mutation', 'Var', (50, 58))	('ALK', 'Gene', (67, 70))
66695	32047559	NGS was used to detect EML4-ALK fusion gene mutations in tissue samples and blood samples of NSCLC patients.	('NSCLC', 'Disease', (93, 98))	('ALK', 'Gene', '238', (28, 31))	('EML4', 'Gene', '27436', (23, 27))	('NSCLC', 'Disease', 'MESH:D002289', (93, 98))	('SCLC', 'Phenotype', 'HP:0030357', (94, 98))	('patients', 'Species', '9606', (99, 107))	('ALK', 'Gene', (28, 31))	('mutations', 'Var', (44, 53))	('NSCLC', 'Phenotype', 'HP:0030358', (93, 98))	('EML4', 'Gene', (23, 27))
66716	32047559	We detected 26 fusion gene mutations of the ALK gene using this procedure.	('ALK', 'Gene', '238', (44, 47))	('ALK', 'Gene', (44, 47))	('fusion gene mutations', 'Var', (15, 36))
66717	32047559	These included 22 EML4-ALK fusion gene mutations and 4 other ALK fusion gene mutations.	('ALK', 'Gene', (23, 26))	('ALK', 'Gene', (61, 64))	('mutations', 'Var', (39, 48))	('EML4', 'Gene', (18, 22))	('ALK', 'Gene', '238', (23, 26))	('ALK', 'Gene', '238', (61, 64))	('EML4', 'Gene', '27436', (18, 22))
66718	32047559	The EML4-ALK fusion gene mutations were detected using CFX96-type fluorescent quantitative PCR from Bio-Rad company.	('ALK', 'Gene', (9, 12))	('mutations', 'Var', (25, 34))	('EML4', 'Gene', (4, 8))	('ALK', 'Gene', '238', (9, 12))	('EML4', 'Gene', '27436', (4, 8))
66741	32047559	ALK rearrangements are caused by reversal or ectopic rearrangement on chromosome 2, and the anaplastic lymphoma kinase fusion gene is the most common type.	('men', 'Species', '9606', (62, 65))	('rearrangements', 'Var', (4, 18))	('anaplastic lymphoma kinase', 'Gene', (92, 118))	('ectopic rearrangement', 'Var', (45, 66))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (92, 111))	('reversal', 'Var', (33, 41))	('ALK', 'Gene', (0, 3))	('lymphoma', 'Phenotype', 'HP:0002665', (103, 111))	('anaplastic lymphoma kinase', 'Gene', '238', (92, 118))	('men', 'Species', '9606', (13, 16))	('caused', 'Reg', (23, 29))	('ALK', 'Gene', '238', (0, 3))
66761	32047559	In addition, due to the heterogeneity of the tumor, the mutation between the metastatic tumor in the body and the tumor cells of the primary tumor may only be the same for one-third of the mutations.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumor', 'Disease', (45, 50))	('tumor', 'Disease', (141, 146))	('tumor', 'Disease', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor', 'Disease', (88, 93))	('mutations', 'Var', (189, 198))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
66832	31886099	Radiotherapy may lead to fibrosis of the lung or of the myocardium, and thus to disorders of the conduction system and also to pericarditis.	('pericarditis', 'Phenotype', 'HP:0001701', (127, 139))	('fibrosis of the lung', 'Disease', 'MESH:D005355', (25, 45))	('fibrosis of the lung', 'Phenotype', 'HP:0002206', (25, 45))	('lead to', 'Reg', (17, 24))	('Radiotherapy', 'Var', (0, 12))	('conduction system', 'MPA', (97, 114))	('disorders', 'MPA', (80, 89))	('fibrosis of the lung', 'Disease', (25, 45))	('pericarditis', 'Disease', 'MESH:D010493', (127, 139))	('pericarditis', 'Disease', (127, 139))
66851	31772670	In vitro results from cultured A549 and H1299 cells confirmed that CLEC4M could enhance cisplatin resistance, while CLEC4M knockdown led to higher sensitivity to cisplatin in these cells.	('sensitivity', 'MPA', (147, 158))	('cisplatin', 'Chemical', 'MESH:D002945', (162, 171))	('CLEC4M', 'Gene', (67, 73))	('CLEC4M', 'Gene', '10332', (67, 73))	('higher', 'PosReg', (140, 146))	('CLEC4M', 'Gene', (116, 122))	('A549', 'CellLine', 'CVCL:0023', (31, 35))	('cisplatin', 'Chemical', 'MESH:D002945', (88, 97))	('enhance', 'PosReg', (80, 87))	('CLEC4M', 'Gene', '10332', (116, 122))	('H1299', 'CellLine', 'CVCL:0060', (40, 45))	('knockdown', 'Var', (123, 132))	('cisplatin resistance', 'MPA', (88, 108))
66858	31772670	However, the development of cisplatin resistance remains one of the most challenging problems in the clinical management of patients with NSCLC; cisplatin resistance is a major cause of treatment failure.	('cisplatin', 'Var', (145, 154))	('cisplatin', 'Chemical', 'MESH:D002945', (28, 37))	('NSCLC', 'Disease', (138, 143))	('NSCLC', 'Disease', 'MESH:D002289', (138, 143))	('cisplatin', 'Chemical', 'MESH:D002945', (145, 154))	('NSCLC', 'Phenotype', 'HP:0030358', (138, 143))	('patients', 'Species', '9606', (124, 132))
66905	31772670	After stable knockdown or overexpression of CLEC4M, cells were reseeded in 6-well plates and treated with or without cisplatin (50 muM) for 24 h according to the group assignment.	('cisplatin', 'Chemical', 'MESH:D002945', (117, 126))	('overexpression', 'PosReg', (26, 40))	('muM', 'Gene', '56925', (131, 134))	('CLEC4M', 'Gene', (44, 50))	('CLEC4M', 'Gene', '10332', (44, 50))	('knockdown', 'Var', (13, 22))	('muM', 'Gene', (131, 134))
66922	31772670	In vitro results also showed that cisplatin treatment in combination with CLEC4M knockdown significantly decreased cell viability when compared with cisplatin treatment alone in both A549 (Figure 3B) and H1299 cells (Figure 3C).	('cisplatin', 'Chemical', 'MESH:D002945', (34, 43))	('H1299', 'CellLine', 'CVCL:0060', (204, 209))	('A549', 'CellLine', 'CVCL:0023', (183, 187))	('cell viability', 'CPA', (115, 129))	('cisplatin', 'Chemical', 'MESH:D002945', (149, 158))	('knockdown', 'Var', (81, 90))	('CLEC4M', 'Gene', (74, 80))	('CLEC4M', 'Gene', '10332', (74, 80))	('decreased', 'NegReg', (105, 114))
66929	31772670	As shown in Figure 4A and 4B, cisplatin promoted cell apoptosis across A549 and H1299 cells; CLEC4M knockdown significantly enhanced cisplatin-induced cell apoptosis in A549 and H1299 cells.	('knockdown', 'Var', (100, 109))	('CLEC4M', 'Gene', (93, 99))	('H1299', 'CellLine', 'CVCL:0060', (80, 85))	('4B', 'Chemical', 'MESH:D001895', (26, 28))	('CLEC4M', 'Gene', '10332', (93, 99))	('enhanced', 'PosReg', (124, 132))	('cisplatin-induced', 'MPA', (133, 150))	('cisplatin', 'Chemical', 'MESH:D002945', (133, 142))	('cell apoptosis', 'CPA', (49, 63))	('A549', 'CellLine', 'CVCL:0023', (169, 173))	('cisplatin', 'Chemical', 'MESH:D002945', (30, 39))	('H1299', 'CellLine', 'CVCL:0060', (178, 183))	('A549', 'CellLine', 'CVCL:0023', (71, 75))
66932	31772670	We found that cisplatin treatment led to a significant increase in cleaved caspase-3 expression, and CLEC4M knockdown further upregulated cisplatin-induced cleaved caspase-3 expression (Figure 4E and 4F), but CLEC4M overexpression reduced cisplatin-induced cleaved caspase-3 expression (Figure 4G and 4H).	('increase', 'PosReg', (55, 63))	('CLEC4M', 'Gene', (101, 107))	('upregulated', 'PosReg', (126, 137))	('cisplatin', 'Chemical', 'MESH:D002945', (239, 248))	('CLEC4M', 'Gene', (209, 215))	('knockdown', 'Var', (108, 117))	('4H', 'Chemical', 'MESH:D006859', (301, 303))	('cisplatin', 'Chemical', 'MESH:D002945', (14, 23))	('4F', 'Chemical', 'MESH:C006011', (200, 202))	('expression', 'MPA', (174, 184))	('caspase-3', 'Gene', '836', (164, 173))	('caspase-3', 'Gene', (164, 173))	('expression', 'MPA', (85, 95))	('caspase-3', 'Gene', '836', (75, 84))	('cisplatin', 'Chemical', 'MESH:D002945', (138, 147))	('CLEC4M', 'Gene', '10332', (101, 107))	('caspase-3', 'Gene', '836', (265, 274))	('caspase-3', 'Gene', (75, 84))	('CLEC4M', 'Gene', '10332', (209, 215))	('caspase-3', 'Gene', (265, 274))
66935	31772670	CLEC4M knockdown inhibited XPA and ERCC1 mRNA and protein expression (Figure 5A-D).	('N', 'Chemical', 'MESH:D009584', (43, 44))	('ERCC1', 'Gene', (35, 40))	('ERCC1', 'Gene', '2067', (35, 40))	('inhibited', 'NegReg', (17, 26))	('CLEC4M', 'Gene', (0, 6))	('knockdown', 'Var', (7, 16))	('XPA', 'Gene', (27, 30))	('CLEC4M', 'Gene', '10332', (0, 6))	('XPA', 'Gene', '7507', (27, 30))
66939	31772670	Upon cisplatin treatment, A549 and H1299 cells with CLEC4M knockdown showed reduced migration ability when compared with the control groups (Figure 6A and Figure 6B).	('CLEC4M', 'Gene', '10332', (52, 58))	('H1299', 'CellLine', 'CVCL:0060', (35, 40))	('reduced', 'NegReg', (76, 83))	('cisplatin', 'Chemical', 'MESH:D002945', (5, 14))	('knockdown', 'Var', (59, 68))	('CLEC4M', 'Gene', (52, 58))	('A549', 'CellLine', 'CVCL:0023', (26, 30))	('migration ability', 'CPA', (84, 101))
66945	31772670	In vitro results from A549 and H1299 cells confirmed that CLEC4M could enhance cisplatin resistance, while CLEC4M knockdown could significantly increase cisplatin sensitivity.	('CLEC4M', 'Gene', '10332', (107, 113))	('H1299', 'CellLine', 'CVCL:0060', (31, 36))	('cisplatin', 'Chemical', 'MESH:D002945', (79, 88))	('knockdown', 'Var', (114, 123))	('cisplatin', 'Chemical', 'MESH:D002945', (153, 162))	('cisplatin resistance', 'MPA', (79, 99))	('CLEC4M', 'Gene', '10332', (58, 64))	('enhance', 'PosReg', (71, 78))	('cisplatin sensitivity', 'MPA', (153, 174))	('CLEC4M', 'Gene', (58, 64))	('increase', 'PosReg', (144, 152))	('A549', 'CellLine', 'CVCL:0023', (22, 26))	('CLEC4M', 'Gene', (107, 113))
66957	31772670	These findings indicate that the poor clinical outcome of patients with higher CLEC4M expression may result from enhanced cisplatin resistance.	('patients', 'Species', '9606', (58, 66))	('cisplatin resistance', 'MPA', (122, 142))	('CLEC4M', 'Gene', '10332', (79, 85))	('cisplatin', 'Chemical', 'MESH:D002945', (122, 131))	('expression', 'MPA', (86, 96))	('higher', 'Var', (72, 78))	('enhanced', 'PosReg', (113, 121))	('CLEC4M', 'Gene', (79, 85))
66960	31772670	The results of the current study showed that cisplatin significantly induced apoptosis in both NSCLC cells A549 and H1299, while CLEC4M knockdown further enhanced cisplatin-induced apoptosis.	('NSCLC', 'Disease', 'MESH:D002289', (95, 100))	('enhanced', 'PosReg', (154, 162))	('apoptosis', 'CPA', (77, 86))	('cisplatin', 'Chemical', 'MESH:D002945', (45, 54))	('cisplatin', 'Chemical', 'MESH:D002945', (163, 172))	('A549', 'CellLine', 'CVCL:0023', (107, 111))	('knockdown', 'Var', (136, 145))	('NSCLC', 'Phenotype', 'HP:0030358', (95, 100))	('CLEC4M', 'Gene', (129, 135))	('H1299', 'CellLine', 'CVCL:0060', (116, 121))	('CLEC4M', 'Gene', '10332', (129, 135))	('NSCLC', 'Disease', (95, 100))
66970	31772670	In the early stage, clinical studies revealed that elevated DRC could enhance cisplatin resistance in NSCLC cell lines.	('DRC', 'MPA', (60, 63))	('elevated', 'Var', (51, 59))	('cisplatin resistance', 'MPA', (78, 98))	('NSCLC', 'Disease', 'MESH:D002289', (102, 107))	('enhance', 'PosReg', (70, 77))	('NSCLC', 'Phenotype', 'HP:0030358', (102, 107))	('cisplatin', 'Chemical', 'MESH:D002945', (78, 87))	('NSCLC', 'Disease', (102, 107))
66976	31772670	Our results showed that CLEC4M knockdown inhibited ERCC1 and XPA expression in both A549 and H1299 cells.	('H1299', 'CellLine', 'CVCL:0060', (93, 98))	('XPA', 'Gene', '7507', (61, 64))	('ERCC1', 'Gene', '2067', (51, 56))	('ERCC1', 'Gene', (51, 56))	('CLEC4M', 'Gene', (24, 30))	('expression', 'MPA', (65, 75))	('inhibited', 'NegReg', (41, 50))	('XPA', 'Gene', (61, 64))	('A549', 'CellLine', 'CVCL:0023', (84, 88))	('CLEC4M', 'Gene', '10332', (24, 30))	('knockdown', 'Var', (31, 40))
66986	31772670	In NSCLC patients, the serum levels of CLEC4M were higher in patients with metastasis than in those without metastasis.	('patients', 'Species', '9606', (9, 17))	('NSCLC', 'Disease', (3, 8))	('CLEC4M', 'Gene', (39, 45))	('NSCLC', 'Disease', 'MESH:D002289', (3, 8))	('patients', 'Species', '9606', (61, 69))	('CLEC4M', 'Gene', '10332', (39, 45))	('NSCLC', 'Phenotype', 'HP:0030358', (3, 8))	('higher', 'PosReg', (51, 57))	('metastasis', 'Var', (75, 85))
66989	31772670	Inhibition of CLEC4M expression significantly increased cisplatin sensitivity, suggesting potential clinical significance for targeting CLEC4M in overcoming cisplatin resistance.	('cisplatin resistance', 'MPA', (157, 177))	('CLEC4M', 'Gene', (14, 20))	('CLEC4M', 'Gene', '10332', (14, 20))	('cisplatin', 'Chemical', 'MESH:D002945', (56, 65))	('increased', 'PosReg', (46, 55))	('cisplatin sensitivity', 'MPA', (56, 77))	('CLEC4M', 'Gene', (136, 142))	('Inhibition', 'Var', (0, 10))	('CLEC4M', 'Gene', '10332', (136, 142))	('cisplatin', 'Chemical', 'MESH:D002945', (157, 166))
66998	31598171	siRNA knock down of integrin beta1 expression suppressed GLUT1 induced NSCLC cell biological behavior, as well as the phosphorylation of FAK and Src.	('GLUT1', 'Gene', (57, 62))	('knock down', 'Var', (6, 16))	('NSCLC', 'Phenotype', 'HP:0030358', (71, 76))	('GLUT1', 'Gene', '6513', (57, 62))	('FAK', 'Gene', (137, 140))	('FAK', 'Gene', '5747', (137, 140))	('integrin beta1', 'Gene', (20, 34))	('Src', 'Gene', (145, 148))	('NSCLC', 'Disease', (71, 76))	('Src', 'Gene', '6714', (145, 148))	('integrin beta1', 'Gene', '3688', (20, 34))	('phosphorylation', 'MPA', (118, 133))	('NSCLC', 'Disease', 'MESH:D002289', (71, 76))	('suppressed', 'NegReg', (46, 56))
67018	31598171	GLUT1 knockdown inhibited cell proliferation, invasion, and migration through integrin beta1/Src/FAK signaling pathways in breast cancer.	('inhibited', 'NegReg', (16, 25))	('breast cancer', 'Disease', 'MESH:D001943', (123, 136))	('GLUT1', 'Gene', (0, 5))	('integrin beta1', 'Gene', (78, 92))	('breast cancer', 'Disease', (123, 136))	('Src', 'Gene', '6714', (93, 96))	('breast cancer', 'Phenotype', 'HP:0003002', (123, 136))	('GLUT1', 'Gene', '6513', (0, 5))	('integrin beta1', 'Gene', '3688', (78, 92))	('migration', 'CPA', (60, 69))	('Src', 'Gene', (93, 96))	('knockdown', 'Var', (6, 15))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('cell proliferation', 'CPA', (26, 44))	('FAK', 'Gene', '5747', (97, 100))	('FAK', 'Gene', (97, 100))	('invasion', 'CPA', (46, 54))
67051	31598171	GLUT1 transfection had the opposite effect in LK2 cell.	('GLUT1', 'Gene', '6513', (0, 5))	('transfection', 'Var', (6, 18))	('GLUT1', 'Gene', (0, 5))
67054	31598171	The results showed that siRNA-GLUT1 inhibited cell migration in A549 cell and GLUT1 transfection had the opposite effect in LK2 cell (P<0.05, Figure 3A and 3B).	('GLUT1', 'Gene', (30, 35))	('GLUT1', 'Gene', '6513', (78, 83))	('inhibited', 'NegReg', (36, 45))	('GLUT1', 'Gene', '6513', (30, 35))	('transfection', 'Var', (84, 96))	('cell migration in A549', 'CPA', (46, 68))	('GLUT1', 'Gene', (78, 83))
67056	31598171	However, siRNA-GLUT1 or GLUT1 transfection had no effect on RhoA expression (Figure 3C and 3D).	('transfection', 'Var', (30, 42))	('RhoA', 'Gene', (60, 64))	('GLUT1', 'Gene', (24, 29))	('RhoA', 'Gene', '387', (60, 64))	('GLUT1', 'Gene', '6513', (24, 29))	('GLUT1', 'Gene', (15, 20))	('GLUT1', 'Gene', '6513', (15, 20))
67067	31598171	The apoptosis rate was markedly increased after siRNA-GLUT1 transfection in A549 cell, but significantly decreased after GLUT1 transfection in LK2 cell (P<0.05, Figure 5A and 5B).	('transfection', 'Var', (60, 72))	('GLUT1', 'Gene', (54, 59))	('GLUT1', 'Gene', '6513', (54, 59))	('GLUT1', 'Gene', (121, 126))	('increased', 'PosReg', (32, 41))	('apoptosis rate', 'CPA', (4, 18))	('GLUT1', 'Gene', '6513', (121, 126))	('decreased', 'NegReg', (105, 114))
67087	31598171	GLUT1 transfection to LK2 cell had the opposite effect.	('GLUT1', 'Gene', '6513', (0, 5))	('transfection', 'Var', (6, 18))	('GLUT1', 'Gene', (0, 5))
67113	31598171	The GLUT1 induced phosphorylation of FAK (Tyr576/577 phosphorylated) and Src (Tyr530 phosphorylated) was significantly inhibited by siRNA-integrin beta1.	('integrin beta1', 'Gene', '3688', (138, 152))	('GLUT1', 'Gene', (4, 9))	('FAK', 'Gene', (37, 40))	('FAK', 'Gene', '5747', (37, 40))	('GLUT1', 'Gene', '6513', (4, 9))	('inhibited', 'NegReg', (119, 128))	('Tyr576/577', 'Var', (42, 52))	('phosphorylation', 'MPA', (18, 33))	('Src', 'Gene', (73, 76))	('Src', 'Gene', '6714', (73, 76))	('Tyr530 phosphorylated', 'Var', (78, 99))	('integrin beta1', 'Gene', (138, 152))
67115	31598171	The genetic variation of GLUT1 could be used in predicting survival of patients with NSCLC in early stage.	('NSCLC', 'Disease', (85, 90))	('used', 'Reg', (40, 44))	('NSCLC', 'Disease', 'MESH:D002289', (85, 90))	('patients', 'Species', '9606', (71, 79))	('NSCLC', 'Phenotype', 'HP:0030358', (85, 90))	('GLUT1', 'Gene', (25, 30))	('GLUT1', 'Gene', '6513', (25, 30))	('genetic variation', 'Var', (4, 21))	('predicting', 'Reg', (48, 58))
67126	28263966	Collectively, we uncover that nickel exposure results in DNMT3b induction and MEG3 promoter hypermethylation and expression inhibition, further reduces its binding to c-Jun and in turn increasing c-Jun inhibition of PHLPP1 transcription, leading to the Akt/p70S6K/S6 axis activation, and HIF-1alpha protein translation as well as malignant transformation of human bronchial epithelial cells.	('c-Jun', 'Gene', '3725', (167, 172))	('transcription', 'MPA', (223, 236))	('c-Jun', 'Gene', (167, 172))	('Akt', 'Gene', (253, 256))	('activation', 'PosReg', (272, 282))	('binding', 'Interaction', (156, 163))	('expression', 'MPA', (113, 123))	('Akt', 'Gene', '207', (253, 256))	('HIF-1alpha', 'Gene', '3091', (288, 298))	('MEG3', 'Gene', (78, 82))	('DNMT3b', 'Gene', '1789', (57, 63))	('p70S6K', 'Gene', '6198', (257, 263))	('human', 'Species', '9606', (358, 363))	('nickel', 'Chemical', 'MESH:D009532', (30, 36))	('DNMT3b', 'Gene', (57, 63))	('inhibition', 'NegReg', (124, 134))	('induction', 'PosReg', (64, 73))	('reduces', 'NegReg', (144, 151))	('increasing', 'PosReg', (185, 195))	('c-Jun', 'Gene', '3725', (196, 201))	('HIF-1alpha', 'Gene', (288, 298))	('hypermethylation', 'Var', (92, 108))	('MEG3', 'Gene', '55384', (78, 82))	('PHLPP1', 'Gene', (216, 222))	('c-Jun', 'Gene', (196, 201))	('p70S6K', 'Gene', (257, 263))	('PHLPP1', 'Gene', '23239', (216, 222))
67138	28263966	Abnormal expression of many lncRNAs has been reported to be involved in cancer predisposition, development, and progression.	('development', 'CPA', (95, 106))	('involved', 'Reg', (60, 68))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('Abnormal', 'Var', (0, 8))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('men', 'Species', '9606', (102, 105))	('lncRNAs', 'Gene', (28, 35))	('cancer', 'Disease', (72, 78))
67172	28263966	Moreover, stable knockdown of MEG3 expression alone resulted in an increase in the basal level of HIF-1alpha protein expression, and also significantly promoted nickel-induced HIF-1alpha protein abundance (Figure 2D).	('nickel', 'Chemical', 'MESH:D009532', (161, 167))	('HIF-1alpha', 'Gene', '3091', (98, 108))	('HIF-1alpha', 'Gene', '3091', (176, 186))	('HIF-1alpha', 'Gene', (176, 186))	('MEG3', 'Gene', '55384', (30, 34))	('increase', 'PosReg', (67, 75))	('MEG3', 'Gene', (30, 34))	('HIF-1alpha', 'Gene', (98, 108))	('knockdown', 'Var', (17, 26))	('promoted', 'PosReg', (152, 160))
67187	28263966	To examine whether MEG3 was implicated in modulation of S6 phosphorylations at Ser235/236 following nickel exposure, we compared the S6 phosphorylation at Ser235/236 between Beas2B(MEG3) cells and Beas2B(Vector) cells.	('Beas2B', 'CellLine', 'CVCL:0168', (174, 180))	('MEG3', 'Gene', (19, 23))	('nickel', 'Chemical', 'MESH:D009532', (100, 106))	('MEG3', 'Gene', '55384', (19, 23))	('Ser235/236', 'Var', (155, 165))	('Ser235', 'Chemical', '-', (79, 85))	('MEG3', 'Gene', (181, 185))	('Ser235', 'Chemical', '-', (155, 161))	('Beas2B', 'CellLine', 'CVCL:0168', (197, 203))	('MEG3', 'Gene', '55384', (181, 185))	('compared', 'Reg', (120, 128))
67188	28263966	The results indicated that S6 phosphorylations at Ser235/236 was completely inhibited in Beas2B(MEG3) cells in comparison to the Beas2B(Vector) cells (Figure 3B).	('Beas2B', 'CellLine', 'CVCL:0168', (129, 135))	('Ser235/236', 'Var', (50, 60))	('Ser235', 'Chemical', '-', (50, 56))	('phosphorylations', 'MPA', (30, 46))	('MEG3', 'Gene', (96, 100))	('inhibited', 'NegReg', (76, 85))	('Beas2B', 'CellLine', 'CVCL:0168', (89, 95))	('MEG3', 'Gene', '55384', (96, 100))
67189	28263966	The findings were further validated in MEG3 knockdown transfectants, which showed an increase in S6 phosphorylation at Ser235/236 as compared with Beas2B(Nonsense) cells following nickel exposure (Figure 3C).	('Beas2B', 'CellLine', 'CVCL:0168', (147, 153))	('Ser235/236', 'Var', (119, 129))	('Ser235', 'Chemical', '-', (119, 125))	('nickel', 'Chemical', 'MESH:D009532', (180, 186))	('MEG3', 'Gene', (39, 43))	('MEG3', 'Gene', '55384', (39, 43))	('increase', 'PosReg', (85, 93))
67190	28263966	The mammalian target rapamycin (mTOR) is the upstream kinase mediating S6 phosphorylations at Ser235/236.	('mTOR', 'Gene', '2475', (32, 36))	('mTOR', 'Gene', (32, 36))	('Ser235/236', 'Var', (94, 104))	('mammalian', 'Species', '9606', (4, 13))	('Ser235', 'Chemical', '-', (94, 100))
67193	28263966	Moreover, knockdown of S6 expression by shRNA also inhibited HIF-1alpha accumulation following nickel exposure (Figure 3E), strongly supporting our notion that MEG3 inhibited HIF-1alpha translation via attenuation of the S6 phosphorylation at Ser235/236.	('HIF-1alpha', 'Gene', '3091', (61, 71))	('MEG3', 'Gene', (160, 164))	('Ser235', 'Chemical', '-', (243, 249))	('HIF-1alpha', 'Gene', '3091', (175, 185))	('MEG3', 'Gene', '55384', (160, 164))	('inhibited', 'NegReg', (165, 174))	('HIF-1alpha accumulation', 'Disease', 'MESH:C579880', (61, 84))	('attenuation', 'NegReg', (202, 213))	('HIF-1alpha', 'Gene', (61, 71))	('HIF-1alpha accumulation', 'Disease', (61, 84))	('HIF-1alpha', 'Gene', (175, 185))	('inhibited', 'NegReg', (51, 60))	('knockdown', 'Var', (10, 19))	('nickel', 'Chemical', 'MESH:D009532', (95, 101))
67196	28263966	Thus, Akt phosphorylation at Ser473 was evaluated in both MEG3 overexpressed and knockdown Beas2B cells in comparison to the corresponding vector control transfectants following nickel exposure.	('MEG3', 'Gene', '55384', (58, 62))	('nickel', 'Chemical', 'MESH:D009532', (178, 184))	('Ser473', 'Var', (29, 35))	('Ser473', 'Chemical', '-', (29, 35))	('Akt', 'Gene', (6, 9))	('Akt', 'Gene', '207', (6, 9))	('MEG3', 'Gene', (58, 62))	('Beas2B', 'CellLine', 'CVCL:0168', (91, 97))
67198	28263966	Moreover, the increase of Akt phosphorylation at Ser473 by nickel was completely abolished by ectopic overexpression of MEG3 and remarkably enhanced by knockdown of MEG3 (Figures 3B & 3C).	('knockdown', 'Var', (152, 161))	('enhanced', 'PosReg', (140, 148))	('Akt', 'Gene', '207', (26, 29))	('nickel', 'Chemical', 'MESH:D009532', (59, 65))	('MEG3', 'Gene', '55384', (165, 169))	('MEG3', 'Gene', (120, 124))	('Akt', 'Gene', (26, 29))	('MEG3', 'Gene', (165, 169))	('MEG3', 'Gene', '55384', (120, 124))	('Ser473', 'Chemical', '-', (49, 55))	('increase', 'PosReg', (14, 22))	('abolished', 'NegReg', (81, 90))
67199	28263966	To test whether Akt activation mediated S6 phosphorylation at Ser235/236 and HIF-1alpha protein translation following nickel exposure, we transiently transfected the dominant-negative mutant Akt (DN-Akt, AktT308A/S473A) into Beas2B(shMEG3) cells, and the transient transfectant Beas2B(shMEG3/DN-Akt) and its vector control transfectant Beas2B(shMEG3/Vector) were evaluated.	('Akt', 'Gene', '207', (191, 194))	('mutant', 'Var', (184, 190))	('Akt', 'Gene', '207', (295, 298))	('MEG3', 'Gene', (287, 291))	('MEG3', 'Gene', '55384', (345, 349))	('Akt', 'Gene', '207', (199, 202))	('HIF-1alpha', 'Gene', (77, 87))	('Akt', 'Gene', (204, 207))	('nickel', 'Chemical', 'MESH:D009532', (118, 124))	('Ser235', 'Chemical', '-', (62, 68))	('MEG3', 'Gene', '55384', (287, 291))	('Akt', 'Gene', '207', (204, 207))	('S473A', 'Mutation', 'p.S473A', (213, 218))	('MEG3', 'Gene', (234, 238))	('Beas2B', 'CellLine', 'CVCL:0168', (225, 231))	('MEG3', 'Gene', '55384', (234, 238))	('Beas2B', 'CellLine', 'CVCL:0168', (336, 342))	('Beas2B', 'CellLine', 'CVCL:0168', (278, 284))	('MEG3', 'Gene', (345, 349))	('HIF-1alpha', 'Gene', '3091', (77, 87))	('Akt', 'Gene', (191, 194))	('Akt', 'Gene', (16, 19))	('Akt', 'Gene', (295, 298))	('Akt', 'Gene', '207', (16, 19))	('Akt', 'Gene', (199, 202))
67200	28263966	Overexpression of DN-Akt blocked nickel-induced Akt phosphorylation at Ser473, p70S6K phosphorylation at Thr389, and S6 phosphorylation at Ser235/236, as well as HIF-1alpha protein accumulation following nickel exposure (Figure 3F).	('Akt', 'Gene', (48, 51))	('HIF-1alpha', 'Gene', (162, 172))	('HIF-1alpha', 'Gene', '3091', (162, 172))	('Akt', 'Gene', '207', (48, 51))	('Ser473', 'Chemical', '-', (71, 77))	('Thr389', 'Chemical', '-', (105, 111))	('phosphorylation', 'MPA', (86, 101))	('S6 phosphorylation', 'MPA', (117, 135))	('nickel', 'Chemical', 'MESH:D009532', (204, 210))	('Thr389', 'Var', (105, 111))	('Ser235', 'Chemical', '-', (139, 145))	('nickel', 'Chemical', 'MESH:D009532', (33, 39))	('Akt', 'Gene', '207', (21, 24))	('p70S6K', 'Gene', '6198', (79, 85))	('Akt', 'Gene', (21, 24))	('p70S6K', 'Gene', (79, 85))	('phosphorylation', 'MPA', (52, 67))
67207	28263966	Although knockdown of MEG3 also changed the protein levels of p-PTEN, p-PP2A, PP2A-B, and PHLPP2, but those change could not be reversed by overexpression of MEG3 in Beas2B(MEG3) cells (Figures 4A & 4B).	('PP2A', 'Gene', (72, 76))	('MEG3', 'Gene', '55384', (158, 162))	('knockdown', 'Var', (9, 18))	('PP2A', 'Gene', (78, 82))	('MEG3', 'Gene', (173, 177))	('PTEN', 'Gene', '5728', (64, 68))	('changed', 'Reg', (32, 39))	('MEG3', 'Gene', (22, 26))	('PP2A', 'Gene', '5524', (72, 76))	('MEG3', 'Gene', '55384', (173, 177))	('protein levels', 'MPA', (44, 58))	('PHLPP2', 'Gene', (90, 96))	('MEG3', 'Gene', (158, 162))	('PTEN', 'Gene', (64, 68))	('Beas2B', 'CellLine', 'CVCL:0168', (166, 172))	('MEG3', 'Gene', '55384', (22, 26))	('PP2A', 'Gene', '5524', (78, 82))	('PHLPP2', 'Gene', '23035', (90, 96))
67213	28263966	As shown in Figure 4E, knockdown of PHLPP1 led to marked increases in the phosphorylation of Akt at Ser473, p70S6K at Thr389 and S6 at Ser235/236, as well as induction of HIF-1alpha protein.	('phosphorylation', 'MPA', (74, 89))	('Ser473', 'Chemical', '-', (100, 106))	('Akt', 'Gene', (93, 96))	('HIF-1alpha', 'Gene', '3091', (171, 181))	('PHLPP1', 'Gene', (36, 42))	('induction', 'PosReg', (158, 167))	('knockdown', 'Var', (23, 32))	('PHLPP1', 'Gene', '23239', (36, 42))	('increases', 'PosReg', (57, 66))	('HIF-1alpha', 'Gene', (171, 181))	('p70S6K', 'Gene', '6198', (108, 114))	('Ser235', 'Chemical', '-', (135, 141))	('p70S6K', 'Gene', (108, 114))	('Akt', 'Gene', '207', (93, 96))	('Thr389', 'Chemical', '-', (118, 124))
67220	28263966	As shown in Figure 5A, overexpression of MEG3 was able to increase the basal level of phlpp1 mRNA expression and that it also brought phlpp1 mRNA in nickel-treated Beas2B(MEG3) up to the basal level observed in Beas2B(Vector) cells.	('mRNA expression', 'MPA', (93, 108))	('brought', 'PosReg', (126, 133))	('mRNA', 'MPA', (141, 145))	('increase', 'PosReg', (58, 66))	('MEG3', 'Gene', '55384', (171, 175))	('MEG3', 'Gene', '55384', (41, 45))	('Beas2B', 'CellLine', 'CVCL:0168', (164, 170))	('phlpp1', 'Gene', '23239', (134, 140))	('nickel', 'Chemical', 'MESH:D009532', (149, 155))	('phlpp1', 'Gene', (134, 140))	('MEG3', 'Gene', (171, 175))	('overexpression', 'Var', (23, 37))	('MEG3', 'Gene', (41, 45))	('phlpp1', 'Gene', '23239', (86, 92))	('Beas2B', 'CellLine', 'CVCL:0168', (211, 217))	('basal level', 'MPA', (71, 82))	('phlpp1', 'Gene', (86, 92))
67221	28263966	Consistently, knockdown of MEG3 resulted in a remarkably reducing the phlpp1 mRNA expression (Figure 5B).	('MEG3', 'Gene', '55384', (27, 31))	('phlpp1', 'Gene', '23239', (70, 76))	('MEG3', 'Gene', (27, 31))	('knockdown', 'Var', (14, 23))	('phlpp1', 'Gene', (70, 76))	('reducing', 'NegReg', (57, 65))
67232	28263966	To test this possibility, c-Jun was specifically knockdown in Beas2B(shMEG3) cells, as expected, knockdown of c-Jun promoted PHLPP1phlpp1 mRNA and protein expression (Figures 5I & 5J).	('knockdown', 'Var', (97, 106))	('Beas2B', 'CellLine', 'CVCL:0168', (62, 68))	('c-Jun', 'Gene', '3725', (26, 31))	('promoted', 'PosReg', (116, 124))	('c-Jun', 'Gene', (110, 115))	('MEG3', 'Gene', (71, 75))	('MEG3', 'Gene', '55384', (71, 75))	('PHLPP1phlpp1', 'Gene', (125, 137))	('c-Jun', 'Gene', (26, 31))	('c-Jun', 'Gene', '3725', (110, 115))
67237	28263966	It has been reported that the MEG3 promoter hypermethylation is an important mechanism associated with the loss of MEG3 expression in clinically nonfunctioning pituitary tumors.	('clinically', 'Disease', (134, 144))	('MEG3', 'Gene', (115, 119))	('expression', 'MPA', (120, 130))	('loss', 'NegReg', (107, 111))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('MEG3', 'Gene', '55384', (115, 119))	('pituitary tumors', 'Disease', 'MESH:D010911', (160, 176))	('MEG3', 'Gene', (30, 34))	('hypermethylation', 'Var', (44, 60))	('tumors', 'Phenotype', 'HP:0002664', (170, 176))	('MEG3', 'Gene', '55384', (30, 34))	('pituitary tumors', 'Disease', (160, 176))
67239	28263966	The extent of the DMR of human MEG3 was shown to span approximately 4 kb of genomic sequence that encompasses the putative promoter region and includes two consensus CTCF (CCCTC binding factor) binding sites that also exhibit differential methylation.	('methylation', 'MPA', (239, 250))	('DMR', 'Chemical', '-', (18, 21))	('CCCTC binding factor', 'Gene', (172, 192))	('MEG3', 'Gene', '55384', (31, 35))	('CCCTC binding factor', 'Gene', '10664', (172, 192))	('CTCF', 'Gene', (166, 170))	('human', 'Species', '9606', (25, 30))	('DMR', 'Var', (18, 21))	('CTCF', 'Gene', '10664', (166, 170))	('MEG3', 'Gene', (31, 35))
67240	28263966	, which have designed two independent primer sets to amplify the methylated and unmethylated DMR.	('methylated', 'Var', (65, 75))	('DMR', 'Gene', (93, 96))	('DMR', 'Chemical', '-', (93, 96))
67241	28263966	AL117190, spans ~1,700 bp, which correspond to sequences within the CpG-rich regions upstream of MEG3.	('MEG3', 'Gene', (97, 101))	('AL117190', 'Var', (0, 8))	('MEG3', 'Gene', '55384', (97, 101))
67246	28263966	These results reveal that nickel exposure led to MEG3 promoter hypermethylation contributes to HIF-1alpha protein expression in human bronchial epithelial cells.	('MEG3', 'Gene', '55384', (49, 53))	('HIF-1alpha', 'Gene', '3091', (95, 105))	('hypermethylation', 'Var', (63, 79))	('nickel', 'Chemical', 'MESH:D009532', (26, 32))	('HIF-1alpha', 'Gene', (95, 105))	('human', 'Species', '9606', (128, 133))	('expression', 'MPA', (114, 124))	('MEG3', 'Gene', (49, 53))
67252	28263966	To explore this relationship between DNMT3b and MEG3, specific sgRNA targeting DNMT3b was used to stably knockout dnmt3b in Beas2B cells.	('MEG3', 'Gene', '55384', (48, 52))	('knockout', 'Var', (105, 113))	('DNMT3b', 'Gene', '1789', (79, 85))	('dnmt3b', 'Gene', '1789', (114, 120))	('DNMT3b', 'Gene', '1789', (37, 43))	('Beas2B', 'CellLine', 'CVCL:0168', (124, 130))	('DNMT3b', 'Gene', (79, 85))	('dnmt3b', 'Gene', (114, 120))	('DNMT3b', 'Gene', (37, 43))	('MEG3', 'Gene', (48, 52))
67254	28263966	Consistently, DNMT3b knockout also abolished malignant transformation of human bronchial epithelial cells due to nickel exposure (Figures 6M& 6N).	('DNMT3b', 'Gene', '1789', (14, 20))	('abolished', 'NegReg', (35, 44))	('human', 'Species', '9606', (73, 78))	('knockout', 'Var', (21, 29))	('DNMT3b', 'Gene', (14, 20))	('nickel', 'Chemical', 'MESH:D009532', (113, 119))
67271	28263966	We showed that overexpression of MEG3 inhibited HIF-1alpha protein abundance, while knockdown of MEG3 increased HIF-1alpha protein expression by nickel exposure.	('MEG3', 'Gene', (97, 101))	('HIF-1alpha', 'Gene', (48, 58))	('HIF-1alpha', 'Gene', '3091', (112, 122))	('MEG3', 'Gene', (33, 37))	('MEG3', 'Gene', '55384', (97, 101))	('knockdown', 'Var', (84, 93))	('MEG3', 'Gene', '55384', (33, 37))	('inhibited', 'NegReg', (38, 47))	('nickel', 'Chemical', 'MESH:D009532', (145, 151))	('expression', 'MPA', (131, 141))	('HIF-1alpha', 'Gene', '3091', (48, 58))	('HIF-1alpha', 'Gene', (112, 122))	('increased', 'PosReg', (102, 111))
67274	28263966	Ribosomal protein S6 is a well-known mediator of protein translation, phosphorylation of S6 promotes the recruitment of the 40S ribosome to the mRNA and therefore has a paramount effect on protein translation.	('effect', 'Reg', (179, 185))	('promotes', 'PosReg', (92, 100))	('40S', 'Protein', (124, 127))	('protein translation', 'MPA', (189, 208))	('recruitment', 'MPA', (105, 116))	('men', 'Species', '9606', (112, 115))	('phosphorylation', 'Var', (70, 85))
67275	28263966	Our results indicated that overexpression of MEG3 inhibited nickel-induced S6 phosphorylation at Ser235/Ser236, whereas knockdown of MEG3 significantly increased S6 phosphorylation at Ser235/Ser236.	('increased S6 phosphorylation', 'Phenotype', 'HP:0003240', (152, 180))	('increased', 'PosReg', (152, 161))	('MEG3', 'Gene', (133, 137))	('S6 phosphorylation', 'MPA', (162, 180))	('knockdown', 'Var', (120, 129))	('MEG3', 'Gene', '55384', (45, 49))	('Ser236', 'Chemical', '-', (191, 197))	('MEG3', 'Gene', '55384', (133, 137))	('MEG3', 'Gene', (45, 49))	('Ser236', 'Chemical', '-', (104, 110))	('Ser235', 'Chemical', '-', (184, 190))	('nickel', 'Chemical', 'MESH:D009532', (60, 66))	('overexpression', 'PosReg', (27, 41))	('Ser235', 'Chemical', '-', (97, 103))	('inhibited', 'NegReg', (50, 59))
67276	28263966	We further found that MEG3 downregulation resulted in S6 activation, and in turn directly promoting protein translation as demonstrated by the results obtained from comparison of S6 phosphorylation at Ser235/Ser236 in Beas2B(MEG3) vs. Beas2B(Vector) and Beas2B(shMEG3) vs. Beas2B(Nonsense), and utilization of mTOR inhibitor rapamycin and the shRNA specific targeting S6.	('MEG3', 'Gene', (263, 267))	('MEG3', 'Gene', '55384', (225, 229))	('activation', 'PosReg', (57, 67))	('Ser235/Ser236', 'Var', (201, 214))	('MEG3', 'Gene', '55384', (263, 267))	('Beas2B', 'CellLine', 'CVCL:0168', (218, 224))	('Beas2B', 'CellLine', 'CVCL:0168', (273, 279))	('Beas2B', 'CellLine', 'CVCL:0168', (235, 241))	('mTOR', 'Gene', (310, 314))	('MEG3', 'Gene', (22, 26))	('promoting', 'PosReg', (90, 99))	('downregulation', 'NegReg', (27, 41))	('Ser236', 'Chemical', '-', (208, 214))	('Beas2B', 'CellLine', 'CVCL:0168', (254, 260))	('MEG3', 'Gene', (225, 229))	('mTOR', 'Gene', '2475', (310, 314))	('protein translation', 'MPA', (100, 119))	('MEG3', 'Gene', '55384', (22, 26))	('Ser235', 'Chemical', '-', (201, 207))
67277	28263966	By tracking the upstream pathways responsible for phosphorylation of S6, we defined MEG3 inhibition of Akt phosphorylation at Ser473, which is an upstream regulator directly mediating p70S6K/S6 phosphorylation and activation.	('MEG3', 'Gene', (84, 88))	('Akt', 'Gene', (103, 106))	('Akt', 'Gene', '207', (103, 106))	('Ser473', 'Chemical', '-', (126, 132))	('Ser473', 'Var', (126, 132))	('MEG3', 'Gene', '55384', (84, 88))	('inhibition', 'NegReg', (89, 99))	('p70S6K', 'Gene', (184, 190))	('phosphorylation', 'MPA', (107, 122))	('p70S6K', 'Gene', '6198', (184, 190))
67285	28263966	Silencing of genes by aberrant promoter hypermethylation is one of the mechanisms leading to tumor suppressor downregulation and cancer initiation and progression.	('aberrant', 'Var', (22, 30))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('cancer initiation', 'Disease', 'MESH:D009369', (129, 146))	('cancer initiation', 'Disease', (129, 146))	('tumor', 'Disease', (93, 98))	('Silencing', 'NegReg', (0, 9))	('promoter', 'Protein', (31, 39))	('downregulation', 'NegReg', (110, 124))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
67286	28263966	It has been reported that hypermethylation of the MEG3 regulatory region has also been associated with the loss of MEG3 expression in human tumors cell lines, such as pituitary tumors, gliomas and hepatoma.	('gliomas', 'Phenotype', 'HP:0009733', (185, 192))	('MEG3', 'Gene', '55384', (115, 119))	('hepatoma', 'Disease', (197, 205))	('MEG3', 'Gene', '55384', (50, 54))	('tumors', 'Disease', 'MESH:D009369', (177, 183))	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('expression', 'MPA', (120, 130))	('loss', 'NegReg', (107, 111))	('pituitary tumors', 'Disease', (167, 183))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('gliomas', 'Disease', (185, 192))	('human', 'Species', '9606', (134, 139))	('tumors', 'Disease', (140, 146))	('hepatoma', 'Disease', 'MESH:D006528', (197, 205))	('tumors', 'Phenotype', 'HP:0002664', (177, 183))	('gliomas', 'Disease', 'MESH:D005910', (185, 192))	('MEG3', 'Gene', (115, 119))	('tumors', 'Disease', 'MESH:D009369', (140, 146))	('MEG3', 'Gene', (50, 54))	('glioma', 'Phenotype', 'HP:0009733', (185, 191))	('hypermethylation', 'Var', (26, 42))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('pituitary tumors', 'Disease', 'MESH:D010911', (167, 183))	('tumors', 'Disease', (177, 183))
67291	28263966	Our further elucidation shows that nickel exposure upregulated DNMT3b expression, and that knockout of DNMT3b promoted MEG3 and PHLPP1 expression, accompanied by inhibition of Akt/p70/S6 pathway activation, HIF-1alpha accumulation, and malignant transformation of Beas2B cells.	('knockout', 'Var', (91, 99))	('PHLPP1', 'Gene', '23239', (128, 134))	('MEG3', 'Gene', (119, 123))	('promoted', 'PosReg', (110, 118))	('p70', 'Gene', (180, 183))	('HIF-1alpha accumulation', 'Disease', 'MESH:C579880', (207, 230))	('expression', 'MPA', (135, 145))	('MEG3', 'Gene', '55384', (119, 123))	('upregulated', 'PosReg', (51, 62))	('inhibition', 'NegReg', (162, 172))	('DNMT3b', 'Gene', '1789', (103, 109))	('malignant transformation of Beas2B cells', 'CPA', (236, 276))	('expression', 'MPA', (70, 80))	('DNMT3b', 'Gene', (103, 109))	('DNMT3b', 'Gene', '1789', (63, 69))	('PHLPP1', 'Gene', (128, 134))	('Akt', 'Gene', (176, 179))	('nickel', 'Chemical', 'MESH:D009532', (35, 41))	('HIF-1alpha accumulation', 'Disease', (207, 230))	('DNMT3b', 'Gene', (63, 69))	('Beas2B', 'CellLine', 'CVCL:0168', (264, 270))	('p70', 'Gene', '84959', (180, 183))	('activation', 'PosReg', (195, 205))	('Akt', 'Gene', '207', (176, 179))
67294	28263966	In summary, our results define a novel effect of nickel on MEG3 reduction and the upstream epigenetic regulator DNMT3b leading to this reduction, as well as the mechanisms underlying its interaction with downstream effector c-Jun, consequently resulting in attenuation of PHLPP1 expression, Akt/p70S60K/S6 activation, HIF-1alpha protein translation as well as malignant transformation of human bronchial epithelial cells.	('activation', 'PosReg', (306, 316))	('nickel', 'Chemical', 'MESH:D009532', (49, 55))	('c-Jun', 'Gene', '3725', (224, 229))	('nickel', 'Var', (49, 55))	('HIF-1alpha', 'Gene', '3091', (318, 328))	('c-Jun', 'Gene', (224, 229))	('interaction', 'Interaction', (187, 198))	('expression', 'MPA', (279, 289))	('DNMT3b', 'Gene', '1789', (112, 118))	('attenuation', 'NegReg', (257, 268))	('Akt', 'Gene', (291, 294))	('PHLPP1', 'Gene', (272, 278))	('DNMT3b', 'Gene', (112, 118))	('p70', 'Gene', '84959', (295, 298))	('human', 'Species', '9606', (388, 393))	('Akt', 'Gene', '207', (291, 294))	('HIF-1alpha', 'Gene', (318, 328))	('MEG3', 'Gene', (59, 63))	('PHLPP1', 'Gene', '23239', (272, 278))	('reduction', 'NegReg', (135, 144))	('p70', 'Gene', (295, 298))	('reduction', 'NegReg', (64, 73))	('MEG3', 'Gene', '55384', (59, 63))
67323	28222762	Our preliminary data indicates that NOS1AP isoforms differentially associate with YAP1, which, together with our previous findings, predicts that loss of YAP1 enhances cellular transformation.	('YAP1', 'Gene', (154, 158))	('YAP1', 'Gene', '10413', (154, 158))	('YAP1', 'Gene', '10413', (82, 86))	('loss', 'Var', (146, 150))	('cellular transformation', 'CPA', (168, 191))	('enhances', 'PosReg', (159, 167))	('YAP1', 'Gene', (82, 86))
67340	28222762	Deregulation of the Hippo pathway occurs in a broad range of human carcinomas, including lung, colorectal, breast, ovarian, pancreatic, gastric and liver cancers.	('lung', 'Disease', (89, 93))	('Deregulation', 'Var', (0, 12))	('cancers', 'Phenotype', 'HP:0002664', (154, 161))	('liver cancers', 'Phenotype', 'HP:0002896', (148, 161))	('carcinomas', 'Disease', 'MESH:D002277', (67, 77))	('liver cancer', 'Phenotype', 'HP:0002896', (148, 160))	('colorectal, breast, ovarian, pancreatic, gastric and liver cancers', 'Disease', 'MESH:D010190', (95, 161))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('Hippo pathway', 'Pathway', (20, 33))	('carcinomas', 'Phenotype', 'HP:0030731', (67, 77))	('carcinomas', 'Disease', (67, 77))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('human', 'Species', '9606', (61, 66))
67341	28222762	YAP deregulation has been implicated in other head and neck malignancies, and its expression has been associated with poor patient survival in esophageal cancers.	('deregulation', 'Var', (4, 16))	('YAP', 'Gene', (0, 3))	('esophageal cancers', 'Disease', (143, 161))	('associated', 'Reg', (102, 112))	('patient', 'Species', '9606', (123, 130))	('cancers', 'Phenotype', 'HP:0002664', (154, 161))	('esophageal cancers', 'Disease', 'MESH:D004938', (143, 161))	('implicated', 'Reg', (26, 36))	('neck malignancies', 'Disease', 'MESH:D009369', (55, 72))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('head and neck malignancies', 'Phenotype', 'HP:0012288', (46, 72))	('neck malignancies', 'Disease', (55, 72))
67346	28222762	P16, HPV positive OPSCC patient tissue was selected randomly from the samples in the Anatomical Pathology Department at the QEII Health Science Center.	('patient', 'Species', '9606', (24, 31))	('HPV', 'Species', '10566', (5, 8))	('HPV', 'Gene', (5, 8))	('P16', 'Var', (0, 3))	('OPSCC', 'Phenotype', 'HP:0012182', (18, 23))
67368	28222762	Here MCF7 cells were used as deregulation of either Scribble or Hippo signaling affects proliferation in these cells.	('affects', 'Reg', (80, 87))	('rat', 'Species', '10116', (95, 98))	('MCF7', 'CellLine', 'CVCL:0031', (5, 9))	('deregulation', 'Var', (29, 41))	('proliferation', 'CPA', (88, 101))
67369	28222762	MCF7 cells stably expressing YFP, YFP-NOS1APa or YFP-NOS1APc were monitored for proliferation rates in 10% serum following serum starvation.	('rat', 'Species', '10116', (94, 97))	('MCF7', 'CellLine', 'CVCL:0031', (0, 4))	('YFP', 'Var', (29, 32))	('YFP-NOS1APa', 'Var', (34, 45))	('YFP-NOS1APc', 'Var', (49, 60))	('rat', 'Species', '10116', (87, 90))
67370	28222762	Interestingly, NOS1APa and NOS1APc showed significantly lower levels of thymidine incorporation compared to YFP at 48 h (**p < 0.01) and at 72 h (***p < 0.001) in 10% serum (Fig.	('levels', 'MPA', (62, 68))	('thymidine', 'Chemical', 'MESH:D013936', (72, 81))	('NOS1APa', 'Var', (15, 22))	('lower', 'NegReg', (56, 61))	('rat', 'Species', '10116', (89, 92))	('thymidine incorporation', 'MPA', (72, 95))
67378	28222762	It is involved in coordinating numerous proteins involved in diverse biological processes that have been implicated in terminal differentiation, and deregulation of this pathway leads to cancer.	('leads to', 'Reg', (178, 186))	('cancer', 'Disease', 'MESH:D009369', (187, 193))	('cancer', 'Disease', (187, 193))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('deregulation', 'Var', (149, 161))
67392	28222762	YAP has been found to be an independent prognostic marker for overall survival in liver cancer, and Xiao et al., showed that YAP can function as a predictive marker for cervical cancer.	('cervical cancer', 'Disease', (169, 184))	('YAP', 'Var', (125, 128))	('liver cancer', 'Disease', (82, 94))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('cervical cancer', 'Disease', 'MESH:D002583', (169, 184))	('liver cancer', 'Phenotype', 'HP:0002896', (82, 94))	('liver cancer', 'Disease', 'MESH:D006528', (82, 94))
67412	33586360	The most common treatment-related adverse events of grade 3 or 4 were hypertension (17 [16%] patients), decreased appetite (6 [6%] patients), and hyponatremia (4 [4%] patients) in the anlotinib group and decreased appetite (2 [4%] patients) in the placebo group.	('patients', 'Species', '9606', (131, 139))	('hyponatremia', 'Phenotype', 'HP:0002902', (146, 158))	('appetite', 'MPA', (114, 122))	('hyponatremia', 'Disease', (146, 158))	('patients', 'Species', '9606', (231, 239))	('anlotinib', 'Chemical', 'MESH:C000625192', (184, 193))	('hyponatremia', 'Disease', 'MESH:D007010', (146, 158))	('decreased appetite', 'Phenotype', 'HP:0004396', (104, 122))	('anlotinib', 'Var', (184, 193))	('patients', 'Species', '9606', (167, 175))	('decreased', 'NegReg', (104, 113))	('decreased appetite', 'Phenotype', 'HP:0004396', (204, 222))	('hypertension', 'Disease', 'MESH:D006973', (70, 82))	('hypertension', 'Disease', (70, 82))	('patients', 'Species', '9606', (93, 101))	('hypertension', 'Phenotype', 'HP:0000822', (70, 82))
67413	33586360	Three (3%) deaths in the anlotinib group were considered as drug related, while there were no treatment-related deaths in the placebo group.	('anlotinib', 'Chemical', 'MESH:C000625192', (25, 34))	('deaths', 'Disease', 'MESH:D003643', (11, 17))	('anlotinib', 'Var', (25, 34))	('deaths', 'Disease', 'MESH:D003643', (112, 118))	('deaths', 'Disease', (112, 118))	('deaths', 'Disease', (11, 17))
67425	33586360	The Cancer Oesophagus Gefitinib (COG) trial, the first randomized phase 3 study of systemic targeted therapy in patients with advanced esophageal cancer progressing after chemotherapy, demonstrated that the overall survival did not improve by gefitinib compared to placebo.	('Gefitinib', 'Chemical', 'MESH:D000077156', (22, 31))	('gefitinib', 'Var', (243, 252))	('patients', 'Species', '9606', (112, 120))	('esophageal cancer', 'Disease', (135, 152))	('Cancer', 'Phenotype', 'HP:0002664', (4, 10))	('esophageal cancer', 'Disease', 'MESH:D004938', (135, 152))	('Cancer', 'Disease', (4, 10))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('gefitinib', 'Chemical', 'MESH:D000077156', (243, 252))	('Cancer', 'Disease', 'MESH:D009369', (4, 10))	('COG', 'Chemical', '-', (33, 36))
67426	33586360	5  More recently, three randomized phase 3 trials reported the promising efficacies of anti-PD-1 antibodies in second-line setting in patients with advanced esophageal cancer as compared with chemotherapy.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('anti-PD-1 antibodies', 'Var', (87, 107))	('esophageal cancer', 'Disease', 'MESH:D004938', (157, 174))	('antibodies', 'Var', (97, 107))	('patients', 'Species', '9606', (134, 142))	('esophageal cancer', 'Disease', (157, 174))
67429	33586360	7 ,  8  It is noteworthy that despite the longer overall survival in anti-PD-1 antibody group compared to chemotherapy group observed in these trials, only part of the patients could be benefit from the treatments.	('patients', 'Species', '9606', (168, 176))	('antibody', 'Var', (79, 87))	('longer', 'PosReg', (42, 48))	('anti-PD-1 antibody', 'Var', (69, 87))
67456	33586360	The median age of patients was 62 years in the anlotinib group and 61 years in the placebo group.	('age', 'Gene', (11, 14))	('anlotinib', 'Chemical', 'MESH:C000625192', (47, 56))	('age', 'Gene', '5973', (11, 14))	('patients', 'Species', '9606', (18, 26))	('anlotinib', 'Var', (47, 56))
67459	33586360	The proportion of patients who received previous tumor surgery was 79% in anlotinib group and 60% in placebo group.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('anlotinib', 'Chemical', 'MESH:C000625192', (74, 83))	('tumor', 'Disease', (49, 54))	('patients', 'Species', '9606', (18, 26))	('anlotinib', 'Var', (74, 83))
67465	33586360	The PFS, as assessed by investigator, was longer in patients receiving anlotinib compared to those receiving placebo (HR 0.46 [95% CI 0.32-0.66]; p < 0.001; Figure 2A).	('longer', 'PosReg', (42, 48))	('PFS', 'MPA', (4, 7))	('anlotinib', 'Chemical', 'MESH:C000625192', (71, 80))	('anlotinib', 'Var', (71, 80))	('patients', 'Species', '9606', (52, 60))
67473	33586360	The DCR was significantly higher in anlotinib group than that in placebo (70 [64%] out of 109 patients vs. 10 [18%] out of 55 patients, p < 0.001), with a higher proportion of patients achieving stable disease in the anlotinib group (62 [57%] out of 109 patients vs. eight [15%] out of 55 patients).	('patients', 'Species', '9606', (176, 184))	('patients', 'Species', '9606', (94, 102))	('higher', 'PosReg', (26, 32))	('DCR', 'Chemical', '-', (4, 7))	('anlotinib', 'Chemical', 'MESH:C000625192', (36, 45))	('patients', 'Species', '9606', (126, 134))	('anlotinib', 'Var', (36, 45))	('anlotinib', 'Chemical', 'MESH:C000625192', (217, 226))	('patients', 'Species', '9606', (254, 262))	('DCR', 'MPA', (4, 7))	('patients', 'Species', '9606', (289, 297))
67481	33586360	Grade 3 or 4 treatment-related bleeding was rare, with only two cases (2%) of hemoptysis observed in the anlotinib group and none in the placebo group.	('hemoptysis', 'Phenotype', 'HP:0002105', (78, 88))	('hemoptysis', 'Disease', (78, 88))	('bleeding', 'Disease', 'MESH:D006470', (31, 39))	('anlotinib', 'Chemical', 'MESH:C000625192', (105, 114))	('hemoptysis', 'Disease', 'MESH:D006469', (78, 88))	('bleeding', 'Disease', (31, 39))	('anlotinib', 'Var', (105, 114))
67490	33586360	Our data revealed that anlotinib might significantly prolong the PFS by 1.6 months (3.02 vs. 1.41 months) with a HR of 0.46 in patients with previously treated recurrent or metastatic ESCC.	('PFS', 'MPA', (65, 68))	('prolong', 'PosReg', (53, 60))	('anlotinib', 'Chemical', 'MESH:C000625192', (23, 32))	('patients', 'Species', '9606', (127, 135))	('anlotinib', 'Var', (23, 32))	('ESCC', 'Disease', (184, 188))
67495	33586360	6 ,  7 ,  8  The present study showed that anlotinib might lead to a median PFS of 3.0 months in patients with chemotherapy-refractory metastatic ESCC, with a clinically meaningful 1.6 months longer than that in patients given placebo.	('patients', 'Species', '9606', (212, 220))	('lead to', 'Reg', (59, 66))	('anlotinib', 'Chemical', 'MESH:C000625192', (43, 52))	('metastatic ESCC', 'Disease', (135, 150))	('PFS', 'MPA', (76, 79))	('anlotinib', 'Var', (43, 52))	('patients', 'Species', '9606', (97, 105))
67504	33586360	First of all, the ratio of patients with metastatic sites of >=2 was higher in anlotinib (85%) than that in placebo (75%).	('anlotinib', 'Var', (79, 88))	('patients', 'Species', '9606', (27, 35))	('higher', 'PosReg', (69, 75))	('anlotinib', 'Chemical', 'MESH:C000625192', (79, 88))
67509	33586360	The incidence of grade 3 or worse AEs was more frequent in the anlotinib group than that in the placebo group (39% vs. 11%).	('anlotinib', 'Var', (63, 72))	('AEs', 'Disease', (34, 37))	('anlotinib', 'Chemical', 'MESH:C000625192', (63, 72))
67546	33396515	While most patients with HPV-related OPSCC are characterized by superior locoregional control and favorable outcome in comparison to patients with HPV-negative OPSCC, morbidity and post-treatment toxicity rates are still high in both subgroups.	('HPV', 'Species', '10566', (25, 28))	('toxicity', 'Disease', 'MESH:D064420', (196, 204))	('toxicity', 'Disease', (196, 204))	('locoregional control', 'CPA', (73, 93))	('patients', 'Species', '9606', (133, 141))	('patients', 'Species', '9606', (11, 19))	('OPSCC', 'Disease', (37, 42))	('HPV-related', 'Var', (25, 36))	('HPV', 'Species', '10566', (147, 150))
67547	33396515	Recent clinical trials are investigating the blockage of e. g. LAG-3 (Trials: NCT02061761; NCT01968109, NCT03538028, NCT03625323), TIM-3 (Trials: NCT03652077) or VISTA (Trial: NCT02671955) in multiple solid cancers, including HNSCC.	('age', 'Gene', (50, 53))	('cancers', 'Disease', 'MESH:D009369', (207, 214))	('cancers', 'Phenotype', 'HP:0002664', (207, 214))	('cancers', 'Disease', (207, 214))	('age', 'Gene', '5973', (50, 53))	('NCT01968109', 'Var', (91, 102))	('NCT03538028', 'Var', (104, 115))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('LAG-3', 'Gene', (63, 68))	('HNSCC', 'Disease', (226, 231))	('NCT03625323', 'Var', (117, 128))
67555	33396515	There was a significant association between positive HPV-status and LAG-3 and TIM-3 expression on TILs (p = 0.006, p < 0.001; Table 2), but not for VISTA expression (p = 0.313; Table 2).	('LAG-3', 'Gene', (68, 73))	('HPV', 'Species', '10566', (53, 56))	('TIM-3', 'Gene', (78, 83))	('positive', 'Var', (44, 52))	('expression', 'MPA', (84, 94))
67559	33396515	In HPV-related OPSCC, double or triple expression of ICP in association with CD8+ TILs was more frequent than in HPV-negative OPSCC (Figure 2) A high number of CD8+ TILs was significantly associated with positive HPV-status (67% vs. 26%, p < 0.001; Table 2).	('CD8', 'Gene', (77, 80))	('CD8', 'Gene', '925', (160, 163))	('CD8', 'Gene', '925', (77, 80))	('HPV-related', 'Disease', (3, 14))	('ICP', 'Gene', (53, 56))	('double', 'Var', (22, 28))	('positive HPV-status', 'Disease', (204, 223))	('HPV', 'Species', '10566', (213, 216))	('HPV', 'Species', '10566', (113, 116))	('HPV', 'Species', '10566', (3, 6))	('CD8', 'Gene', (160, 163))
67570	33396515	Possible reasons for this may be the interrelationship of multiple components in the tumor immune microenvironment, as it has been reported that the co-expression of LAG-3 with other inhibitory molecules such as TIM-3 or PD-1 induces the exhaustion of immune cells, resulting in downregulated cytokine expression.	('tumor', 'Disease', (85, 90))	('induces', 'Reg', (226, 233))	('cytokine expression', 'MPA', (293, 312))	('downregulated', 'NegReg', (279, 292))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('PD-1', 'Gene', (221, 225))	('co-expression', 'Var', (149, 162))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('LAG-3', 'Gene', (166, 171))
67583	33396515	The objective response rate to combinations of LAG-3 and PD-1 blockage was 3.5-fold higher in patients with immunohistochemistry-based LAG-3 expression >=1% vs. <1%.	('LAG-3', 'Gene', (135, 140))	('age', 'Gene', '5973', (67, 70))	('patients', 'Species', '9606', (94, 102))	('>=1%', 'Var', (152, 156))	('combinations', 'Var', (31, 43))	('LAG-3', 'Gene', (47, 52))	('expression', 'MPA', (141, 151))	('age', 'Gene', (67, 70))	('PD-1', 'Gene', (57, 61))	('higher', 'PosReg', (84, 90))
67598	33396515	Significance in univariate analysis is most likely attributable to the association with positive HPV-status and a high number of CD8+ TILs as these are both factors known to have a positive effect on OS.	('CD8', 'Gene', (129, 132))	('CD8', 'Gene', '925', (129, 132))	('HPV', 'Species', '10566', (97, 100))	('HPV-status', 'Gene', (97, 107))	('positive', 'Var', (88, 96))
67629	33113895	Initially, ncRNAs were considered transcriptional "noises", but with the deepening of molecular biology research, more and more studies have clarified the important role of ncRNAs in various biological activities In addition, mutations and disorders of ncRNAs, especially long non-coding RNAs (lncRNAs), have been found to be closely related to cancer.	('disorders', 'Var', (240, 249))	('cancer', 'Phenotype', 'HP:0002664', (345, 351))	('related', 'Reg', (334, 341))	('mutations', 'Var', (226, 235))	('cancer', 'Disease', 'MESH:D009369', (345, 351))	('ncRNAs', 'Gene', (253, 259))	('cancer', 'Disease', (345, 351))
67631	33113895	Therefore, abnormally-expressed lncRNA is expected to become a novel biomarker or a new target for cancer treatment.	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('cancer', 'Disease', (99, 105))	('abnormally-expressed', 'Var', (11, 31))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('lncRNA', 'Protein', (32, 38))
67636	33113895	However, in all the studies on tumorous diseases that have been published so far, the expression level of NNT-AS1 in tumor tissues or tumor cells has been abnormal, which indicates the potential correlation between NNT-AS1 dysregulation and tumorous diseases.	('tumorous diseases', 'Disease', 'MESH:D009369', (31, 48))	('NNT-AS1', 'Gene', '100652772', (215, 222))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('tumorous diseases', 'Disease', (241, 258))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('expression level', 'MPA', (86, 102))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumor', 'Disease', (241, 246))	('NNT-AS1', 'Gene', (106, 113))	('abnormal', 'Reg', (155, 163))	('tumor', 'Disease', 'MESH:D009369', (241, 246))	('NNT-AS1', 'Gene', (215, 222))	('tumorous diseases', 'Disease', 'MESH:D009369', (241, 258))	('dysregulation', 'Var', (223, 236))	('correlation', 'Reg', (195, 206))	('tumor', 'Disease', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))	('tumorous diseases', 'Disease', (31, 48))	('tumor', 'Disease', (117, 122))	('tumor', 'Disease', (31, 36))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('NNT-AS1', 'Gene', '100652772', (106, 113))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
67653	33113895	Interestingly, it has been reported that, unlike Eralpha-receptor-negative ovarian cancer cells, treatment of Eralpha-receptor-positive ovarian cancer cells with estrogen (E2) will cause a large number of lncRNA disorders and changes in some protein levels, such as elevated TC0101441, which was found to promote the invasion and metastasis of ovarian cancer cells.	('ovarian cancer', 'Disease', 'MESH:D010051', (75, 89))	('Eralpha-receptor-positive', 'Var', (110, 135))	('metastasis of ovarian cancer', 'Disease', 'MESH:D009362', (330, 358))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('lncRNA disorders', 'MPA', (205, 221))	('cancer', 'Phenotype', 'HP:0002664', (352, 358))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('ovarian cancer', 'Disease', 'MESH:D010051', (344, 358))	('ovarian cancer', 'Disease', 'MESH:D010051', (136, 150))	('cause', 'Reg', (181, 186))	('E2', 'Chemical', 'MESH:D004958', (172, 174))	('ovarian cancer', 'Disease', (75, 89))	('ovarian cancer', 'Phenotype', 'HP:0100615', (75, 89))	('elevated TC0101441', 'Var', (266, 284))	('protein levels', 'MPA', (242, 256))	('ovarian cancer', 'Disease', (136, 150))	('changes', 'Reg', (226, 233))	('TC0101441', 'Var', (275, 284))	('ovarian cancer', 'Phenotype', 'HP:0100615', (344, 358))	('invasion', 'CPA', (317, 325))	('ovarian cancer', 'Phenotype', 'HP:0100615', (136, 150))	('metastasis of ovarian cancer', 'Disease', (330, 358))	('promote', 'PosReg', (305, 312))	('TC0101441', 'Chemical', '-', (275, 284))
67657	33113895	Therefore, the low expression of NNT-AS1 up-regulates miR-424 and E2F1, and the abnormal E2 level is likely to be correlated.	('NNT-AS1', 'Gene', (33, 40))	('E2F1', 'Gene', (66, 70))	('E2 level', 'MPA', (89, 97))	('E2', 'Chemical', 'MESH:D004958', (89, 91))	('up-regulates', 'PosReg', (41, 53))	('miR-424', 'Gene', (54, 61))	('NNT-AS1', 'Gene', '100652772', (33, 40))	('E2', 'Chemical', 'MESH:D004958', (66, 68))	('miR-424', 'Gene', '494336', (54, 61))	('E2F1', 'Gene', '1869', (66, 70))	('low expression', 'Var', (15, 29))
67661	33113895	Some studies have analyzed the diagnostic and prognostic value of abnormal expression of NNT-AS1 (Table 2).	('NNT-AS1', 'Gene', (89, 96))	('NNT-AS1', 'Gene', '100652772', (89, 96))	('abnormal', 'Var', (66, 74))
67667	33113895	Studies on NSCLC, gastric cancer, HCC, cervical cancer, and bladder cancer have shown that high-levels of NNT-AS1 were poor prognostic factors to reduce overall survival (OS).	('gastric cancer', 'Disease', (18, 32))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('bladder cancer', 'Phenotype', 'HP:0009725', (60, 74))	('cancer', 'Disease', (26, 32))	('overall survival', 'MPA', (153, 169))	('cancer', 'Disease', (48, 54))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('gastric cancer', 'Disease', 'MESH:D013274', (18, 32))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('NNT-AS1', 'Gene', (106, 113))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('NSCLC', 'Disease', 'MESH:D002289', (11, 16))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('gastric cancer', 'Phenotype', 'HP:0012126', (18, 32))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('high-levels', 'Var', (91, 102))	('reduce', 'NegReg', (146, 152))	('NSCLC', 'Disease', (11, 16))	('HCC', 'Phenotype', 'HP:0001402', (34, 37))	('bladder cancer', 'Disease', 'MESH:D001749', (60, 74))	('HCC', 'Disease', (34, 37))	('cancer', 'Disease', (68, 74))	('bladder cancer', 'Disease', (60, 74))	('NNT-AS1', 'Gene', '100652772', (106, 113))	('NSCLC', 'Phenotype', 'HP:0030358', (11, 16))
67669	33113895	found that a high level of NNT-AS1 is an independent prognostic factor leading to decreased OS in breast cancer patients.	('breast cancer', 'Disease', 'MESH:D001943', (98, 111))	('breast cancer', 'Phenotype', 'HP:0003002', (98, 111))	('breast cancer', 'Disease', (98, 111))	('NNT-AS1', 'Gene', (27, 34))	('patients', 'Species', '9606', (112, 120))	('high level', 'Var', (13, 23))	('NNT-AS1', 'Gene', '100652772', (27, 34))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('decreased', 'NegReg', (82, 91))
67681	33113895	found in GC cells that NNT-AS1 can regulate the expression of sex-determining region Y-related high-mobility-group-box transcription factor 4 (SOX4) through sponging miR-142-5p, while knockdown of NNT-AS1 will reduce beta-catenin, c-Myc, and Bcl-2 but enhance e-cadherin expression.	('beta-catenin', 'Gene', (217, 229))	('beta-catenin', 'Gene', '1499', (217, 229))	('SOX4', 'Gene', (143, 147))	('c-Myc', 'Gene', (231, 236))	('enhance', 'PosReg', (252, 259))	('c-Myc', 'Gene', '4609', (231, 236))	('miR-142', 'Gene', '406934', (166, 173))	('NNT-AS1', 'Gene', '100652772', (197, 204))	('Bcl-2', 'Gene', (242, 247))	('SOX4', 'Gene', '6659', (143, 147))	('NNT-AS1', 'Gene', '100652772', (23, 30))	('e-cadherin', 'Gene', '999', (260, 270))	('knockdown', 'Var', (184, 193))	('Bcl-2', 'Gene', '596', (242, 247))	('reduce', 'NegReg', (210, 216))	('NNT-AS1', 'Gene', (197, 204))	('e-cadherin', 'Gene', (260, 270))	('NNT-AS1', 'Gene', (23, 30))	('miR-142', 'Gene', (166, 173))
67683	33113895	The dysregulation of EMT is related to tumorigenesis and can significantly enhance the ability of cancer cells to invade and metastasize.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('EMT', 'Gene', (21, 24))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('dysregulation', 'Var', (4, 17))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('cancer', 'Disease', (98, 104))	('tumor', 'Disease', (39, 44))	('enhance', 'PosReg', (75, 82))
67694	33113895	In addition, NNT-AS1 can also increase Yes1-associated transcriptional regulator (YAP1) by sponging miR-22-3p, which in turn promotes the proliferation, migration, invasion, and EMT of NSCLC cells.	('miR-22-3p', 'Gene', (100, 109))	('miR-22-3p', 'Gene', '407008', (100, 109))	('promotes', 'PosReg', (125, 133))	('NNT-AS1', 'Gene', (13, 20))	('YAP1', 'Gene', '10413', (82, 86))	('NSCLC', 'Disease', 'MESH:D002289', (185, 190))	('proliferation', 'CPA', (138, 151))	('migration', 'CPA', (153, 162))	('sponging', 'Var', (91, 99))	('NSCLC', 'Phenotype', 'HP:0030358', (185, 190))	('invasion', 'CPA', (164, 172))	('increase', 'PosReg', (30, 38))	('NNT-AS1', 'Gene', '100652772', (13, 20))	('EMT', 'CPA', (178, 181))	('YAP1', 'Gene', (82, 86))	('NSCLC', 'Disease', (185, 190))
67706	33113895	In NSCLC, NNT-AS1 and miR-12363p competitively bind to autophagy-related gene 7 (ATG7), thereby affecting the proliferation, invasion, and metastasis of cancer cells.	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('NNT-AS1', 'Gene', '100652772', (10, 17))	('NSCLC', 'Disease', (3, 8))	('cancer', 'Disease', (153, 159))	('NSCLC', 'Disease', 'MESH:D002289', (3, 8))	('autophagy-related gene 7', 'Gene', '10533', (55, 79))	('miR-12363p', 'Chemical', '-', (22, 32))	('proliferation', 'CPA', (110, 123))	('NNT-AS1', 'Gene', (10, 17))	('affecting', 'Reg', (96, 105))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('bind', 'Interaction', (47, 51))	('autophagy-related gene 7', 'Gene', (55, 79))	('NSCLC', 'Phenotype', 'HP:0030358', (3, 8))	('ATG7', 'Gene', (81, 85))	('invasion', 'CPA', (125, 133))	('miR-12363p', 'Var', (22, 32))
67720	33113895	Further restoration experiments showed that NNT-AS1 knockdown can antagonize cisplatin resistance by adjusting the miR-186/HMGB1 axis (Figure 2B).	('NNT-AS1', 'Gene', (44, 51))	('cisplatin resistance', 'MPA', (77, 97))	('HMGB1', 'Gene', (123, 128))	('miR-186', 'Gene', '406962', (115, 122))	('miR-186', 'Gene', (115, 122))	('HMGB1', 'Gene', '3146', (123, 128))	('NNT-AS1', 'Gene', '100652772', (44, 51))	('adjusting', 'Reg', (101, 110))	('cisplatin', 'Chemical', 'MESH:D002945', (77, 86))	('knockdown', 'Var', (52, 61))	('antagonize', 'NegReg', (66, 76))
67721	33113895	Given the central position of NNT-AS1 in the ceRNA network, NNT-AS1 targeting has the potential to broaden the landscape of therapeutic interventions.	('NNT-AS1', 'Gene', (30, 37))	('targeting', 'Var', (68, 77))	('NNT-AS1', 'Gene', '100652772', (60, 67))	('NNT-AS1', 'Gene', '100652772', (30, 37))	('NNT-AS1', 'Gene', (60, 67))
67722	33113895	Taking RNA interference (RNAi) technology as an example, animal models have confirmed that siRNA-mediated lncRNA knockdown can reduce the proliferation, growth, and the metastasis of cancer cells.	('cancer', 'Disease', (183, 189))	('lncRNA', 'Protein', (106, 112))	('proliferation', 'CPA', (138, 151))	('growth', 'CPA', (153, 159))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('reduce', 'NegReg', (127, 133))	('knockdown', 'Var', (113, 122))	('cancer', 'Disease', 'MESH:D009369', (183, 189))
67724	33113895	In addition, the feasibility of antisense oligos (ASOs) targeting lncRNA in vivo has also been confirmed in different mice models of cancer.	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('antisense', 'Var', (32, 41))	('cancer', 'Disease', (133, 139))	('lncRNA', 'Protein', (66, 72))	('ASO', 'Chemical', '-', (50, 53))	('mice', 'Species', '10090', (118, 122))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
67730	33113895	Many studies have shown that NNT-AS1 dysregulation is related to tumor prognosis, especially in breast cancer and CRC, in which the abnormal expression level of NNT-AS1 is an independent prognostic marker.	('NNT-AS1', 'Gene', '100652772', (161, 168))	('dysregulation', 'Var', (37, 50))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('tumor', 'Disease', (65, 70))	('related', 'Reg', (54, 61))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('NNT-AS1', 'Gene', (161, 168))	('breast cancer', 'Disease', 'MESH:D001943', (96, 109))	('NNT-AS1', 'Gene', '100652772', (29, 36))	('CRC', 'Phenotype', 'HP:0003003', (114, 117))	('CRC', 'Disease', 'MESH:D015179', (114, 117))	('breast cancer', 'Disease', (96, 109))	('breast cancer', 'Phenotype', 'HP:0003002', (96, 109))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('NNT-AS1', 'Gene', (29, 36))	('CRC', 'Disease', (114, 117))
67731	33113895	Recent studies also revealed the involvement of NNT-AS1 in mediating cisplatin resistance and cell experiments and mouse models have confirmed that down-regulating NNT-AS1 can enhance the sensitivity to cisplatin, which provides a new idea for overcoming cisplatin resistance.	('cisplatin', 'Chemical', 'MESH:D002945', (255, 264))	('cisplatin', 'Chemical', 'MESH:D002945', (69, 78))	('NNT-AS1', 'Gene', '100652772', (48, 55))	('NNT-AS1', 'Gene', (164, 171))	('mouse', 'Species', '10090', (115, 120))	('enhance', 'PosReg', (176, 183))	('down-regulating', 'Var', (148, 163))	('NNT-AS1', 'Gene', (48, 55))	('NNT-AS1', 'Gene', '100652772', (164, 171))	('sensitivity to cisplatin', 'MPA', (188, 212))	('cisplatin', 'Chemical', 'MESH:D002945', (203, 212))
67756	32487167	circPPP1R12A-encoded protein circPPP1R12A-73aa promotes tumor growth and metastasis of colon cancer.	('metastasis of colon cancer', 'Disease', (73, 99))	('circPPP1R12A-73aa', 'Var', (29, 46))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('promotes', 'PosReg', (47, 55))	('tumor', 'Disease', (56, 61))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('metastasis of colon cancer', 'Disease', 'MESH:D015179', (73, 99))	('colon cancer', 'Phenotype', 'HP:0003003', (87, 99))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
67759	32487167	Dysregulation of PBX3 expression has been observed in many cancer types, such as prostate, gastric, cervical, and liver cancer.	('PBX3', 'Gene', '5090', (17, 21))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('prostate', 'Disease', 'MESH:D011472', (81, 89))	('liver cancer', 'Phenotype', 'HP:0002896', (114, 126))	('Dysregulation', 'Var', (0, 13))	('cervical', 'Disease', (100, 108))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('liver cancer', 'Disease', 'MESH:D006528', (114, 126))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('prostate', 'Disease', (81, 89))	('liver cancer', 'Disease', (114, 126))	('gastric', 'Disease', (91, 98))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('observed', 'Reg', (42, 50))	('PBX3', 'Gene', (17, 21))
67789	32487167	For luciferase reporter plasmids, the sequences of circCORO1C, wild type, and let-7c-5p binding site mutant PBX3 3' UTR were cloned into the psiCHECK-2 vector (Promega, Madison, WI).	('CORO1C', 'Gene', '23603', (55, 61))	('PBX3', 'Gene', (108, 112))	('PBX3', 'Gene', '5090', (108, 112))	('psiCHECK', 'Disease', 'None', (141, 149))	('mutant', 'Var', (101, 107))	('let-7c', 'Gene', (78, 84))	('psiCHECK', 'Disease', (141, 149))	('let-7c', 'Gene', '406885', (78, 84))	('CORO1C', 'Gene', (55, 61))
67793	32487167	To generate FD-LSC-1 cells with stable knockdown of circCORO1C, lentiviruses were produced in HEK293T cells by cotransfection with psh-circCORO1C and packaging plasmids GAG and VSVG.	('CORO1C', 'Gene', '23603', (139, 145))	('knockdown', 'Var', (39, 48))	('CORO1C', 'Gene', '23603', (56, 62))	('CORO1C', 'Gene', (56, 62))	('HEK293T', 'CellLine', 'CVCL:0063', (94, 101))	('CORO1C', 'Gene', (139, 145))
67819	32487167	The membranes were incubated with antibodies against PBX3 (#12571-1-AP; Proteintech, Wuhan, China), E-cadherin (#3195S; CST, Danvers, MA), N-cadherin (#13116S; CST), Vimentin (#5741S; CST), Slug (#sc-166476; Santa Cruz Biotechnology), or GAPDH (#HC301-02; TransGen Biotech) overnight at 4  C. Then membranes were washed three times with TBST followed by secondary antibody incubation for 2 h at room temperature.	('Slug', 'Gene', (190, 194))	('PBX3', 'Gene', '5090', (53, 57))	('#5741S;', 'Var', (176, 183))	('#13116S;', 'Var', (151, 159))	('Vimentin', 'Gene', (166, 174))	('E-cadherin', 'Gene', '999', (100, 110))	('Slug', 'Gene', '6591', (190, 194))	('GAPDH', 'Gene', '2597', (238, 243))	('Vimentin', 'Gene', '7431', (166, 174))	('GAPDH', 'Gene', (238, 243))	('PBX3', 'Gene', (53, 57))	('N-cadherin', 'Gene', (139, 149))	('E-cadherin', 'Gene', (100, 110))	('#12571-1-AP', 'Var', (59, 70))	('#3195S', 'Var', (112, 118))	('N-cadherin', 'Gene', '1000', (139, 149))
67850	32487167	We also tested cell viability by CCK-8 assay, and found that knockdown of circCORO1C significantly inhibited the viability of LSCC cells (Fig.	('viability', 'CPA', (113, 122))	('inhibited', 'NegReg', (99, 108))	('LSCC', 'Disease', (126, 130))	('CORO1C', 'Gene', (78, 84))	('CCK', 'Gene', '885', (33, 36))	('CCK', 'Gene', (33, 36))	('CORO1C', 'Gene', '23603', (78, 84))	('knockdown', 'Var', (61, 70))
67851	32487167	EdU staining experiments confirmed that knockdown of circCORO1C inhibited the proliferation of LSCC cells (Fig.	('CORO1C', 'Gene', (57, 63))	('inhibited', 'NegReg', (64, 73))	('knockdown', 'Var', (40, 49))	('CORO1C', 'Gene', '23603', (57, 63))	('proliferation of LSCC cells', 'CPA', (78, 105))	('EdU', 'Chemical', 'MESH:C031086', (0, 3))
67852	32487167	Colony formation experiments showed that knockdown of circCORO1C significantly inhibited the colony formation of FD-LSC-1 and TU-177 cells (Fig.	('colony formation of FD-LSC-1', 'CPA', (93, 121))	('CORO1C', 'Gene', '23603', (58, 64))	('inhibited', 'NegReg', (79, 88))	('CORO1C', 'Gene', (58, 64))	('knockdown', 'Var', (41, 50))	('TU-177', 'CellLine', 'CVCL:Z025', (126, 132))
67855	32487167	We further investigated the effect of circCORO1C on apoptosis, and found that knockdown of circCORO1C promoted apoptosis in LSCC cells (Fig.	('promoted', 'PosReg', (102, 110))	('knockdown', 'Var', (78, 87))	('CORO1C', 'Gene', (95, 101))	('CORO1C', 'Gene', '23603', (95, 101))	('CORO1C', 'Gene', (42, 48))	('CORO1C', 'Gene', '23603', (42, 48))	('apoptosis', 'CPA', (111, 120))
67865	32487167	Moreover, we constructed luciferase reporter vectors for wild-type circCORO1C and let-7c-5p binding site mutant circCORO1C and co-transfected HEK293T cells with let-7c-5p mimics or NC mimics.	('HEK293T', 'CellLine', 'CVCL:0063', (142, 149))	('let-7c', 'Gene', '406885', (82, 88))	('let-7c', 'Gene', '406885', (161, 167))	('CORO1C', 'Gene', (71, 77))	('CORO1C', 'Gene', (116, 122))	('CORO1C', 'Gene', '23603', (71, 77))	('CORO1C', 'Gene', '23603', (116, 122))	('let-7c', 'Gene', (82, 88))	('mutant', 'Var', (105, 111))	('let-7c', 'Gene', (161, 167))
67868	32487167	In addition, we found that expression of let-7c-5p in FD-LSC-1 and TU-177 cells was increased significantly after circCORO1C knockdown (Fig.	('CORO1C', 'Gene', (118, 124))	('let-7c', 'Gene', (41, 47))	('knockdown', 'Var', (125, 134))	('let-7c', 'Gene', '406885', (41, 47))	('CORO1C', 'Gene', '23603', (118, 124))	('expression', 'MPA', (27, 37))	('increased', 'PosReg', (84, 93))	('TU-177', 'CellLine', 'CVCL:Z025', (67, 73))
67885	32487167	Transwell assays showed that let-7c-5p inhibition reversed the reduction in the migration and invasion of FD-LSC-1 and TU-177 cells caused by circCORO1C knockdown (Fig.	('CORO1C', 'Gene', (146, 152))	('TU-177', 'CellLine', 'CVCL:Z025', (119, 125))	('knockdown', 'Var', (153, 162))	('let-7c', 'Gene', (29, 35))	('CORO1C', 'Gene', '23603', (146, 152))	('migration', 'CPA', (80, 89))	('invasion of FD-LSC-1', 'CPA', (94, 114))	('let-7c', 'Gene', '406885', (29, 35))	('reduction', 'NegReg', (63, 72))
67897	32487167	The wild-type and mutant reporter vectors were co-transfected with let-7c-5p mimics in cells.	('let-7c', 'Gene', (67, 73))	('let-7c', 'Gene', '406885', (67, 73))	('mutant', 'Var', (18, 24))
67906	32487167	Consistently, overexpression of PBX3 rescued the decreased colony formation ability by circCORO1C knockdown (Fig.	('CORO1C', 'Gene', (91, 97))	('knockdown', 'Var', (98, 107))	('CORO1C', 'Gene', '23603', (91, 97))	('PBX3', 'Gene', '5090', (32, 36))	('decreased', 'NegReg', (49, 58))	('colony formation ability', 'CPA', (59, 83))	('PBX3', 'Gene', (32, 36))
67907	32487167	Furthermore, Transwell assay showed that overexpression of PBX3 could reverse the decline in cell migration and invasion ability caused by circCORO1C knockdown (Fig.	('PBX3', 'Gene', '5090', (59, 63))	('PBX3', 'Gene', (59, 63))	('CORO1C', 'Gene', '23603', (143, 149))	('knockdown', 'Var', (150, 159))	('CORO1C', 'Gene', (143, 149))	('decline', 'NegReg', (82, 89))
67908	32487167	circCORO1C knockdown enhanced the expression of E-cadherin while inhibiting the expression of N-cadherin, Vimentin, and Slug (Fig.	('Vimentin', 'Gene', '7431', (106, 114))	('expression', 'MPA', (34, 44))	('Slug', 'Gene', (120, 124))	('enhanced', 'PosReg', (21, 29))	('E-cadherin', 'Gene', '999', (48, 58))	('Slug', 'Gene', '6591', (120, 124))	('N-cadherin', 'Gene', (94, 104))	('inhibiting', 'NegReg', (65, 75))	('E-cadherin', 'Gene', (48, 58))	('expression', 'MPA', (80, 90))	('CORO1C', 'Gene', '23603', (4, 10))	('Vimentin', 'Gene', (106, 114))	('CORO1C', 'Gene', (4, 10))	('knockdown', 'Var', (11, 20))	('N-cadherin', 'Gene', '1000', (94, 104))
67918	32487167	Furthermore, hematoxylin and eosin (H&E) staining showed that knockdown of circCORO1C remarkably reduced the number of lesions (Fig.	('remarkably', 'NegReg', (86, 96))	('the number of', 'MPA', (105, 118))	('hematoxylin', 'Chemical', 'MESH:D006416', (13, 24))	('eosin', 'Chemical', 'MESH:D004801', (29, 34))	('that', 'Var', (57, 61))	('CORO1C', 'Gene', (79, 85))	('CORO1C', 'Gene', '23603', (79, 85))
67921	32487167	The results revealed that knockdown of circCORO1C attenuated the mesenchymal phenotype (Fig.	('CORO1C', 'Gene', (43, 49))	('mesenchymal phenotype', 'CPA', (65, 86))	('CORO1C', 'Gene', '23603', (43, 49))	('knockdown', 'Var', (26, 35))	('attenuated', 'NegReg', (50, 60))
67936	32487167	Experimental studies further demonstrated that circHIPK3 promotes cell proliferation and invasion in nasopharyngeal carcinoma, while Hsa_circ_0005379 inhibits the cell migration, invasion, proliferation, and in vivo tumorigenesis of oral squamous cell carcinoma.	('carcinoma', 'Disease', 'MESH:D009369', (252, 261))	('cell proliferation', 'CPA', (66, 84))	('carcinoma', 'Disease', 'MESH:D009369', (116, 125))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (238, 261))	('cell migration', 'CPA', (163, 177))	('invasion', 'CPA', (179, 187))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (101, 125))	('inhibits', 'NegReg', (150, 158))	('tumor', 'Disease', (216, 221))	('proliferation', 'CPA', (189, 202))	('tumor', 'Disease', 'MESH:D009369', (216, 221))	('circHIPK3', 'Var', (47, 56))	('carcinoma', 'Phenotype', 'HP:0030731', (252, 261))	('invasion', 'CPA', (89, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('Hsa_circ_0005379', 'Var', (133, 149))	('carcinoma', 'Disease', (252, 261))	('carcinoma', 'Disease', (116, 125))	('promotes', 'PosReg', (57, 65))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (233, 261))	('oral squamous cell carcinoma', 'Disease', (233, 261))
67941	32487167	Consistent results showed that knockdown of circCORO1C inhibited cell proliferation, migration, invasion, and promoted apoptosis of LSCC, indicating that circCORO1C acts as an important oncogene to promote the malignant progression of LSCC.	('promote', 'PosReg', (198, 205))	('LSCC', 'Disease', (235, 239))	('apoptosis', 'CPA', (119, 128))	('CORO1C', 'Gene', (158, 164))	('invasion', 'CPA', (96, 104))	('CORO1C', 'Gene', (48, 54))	('CORO1C', 'Gene', '23603', (158, 164))	('cell proliferation', 'CPA', (65, 83))	('migration', 'CPA', (85, 94))	('CORO1C', 'Gene', '23603', (48, 54))	('promoted', 'PosReg', (110, 118))	('malignant progression', 'CPA', (210, 231))	('inhibited', 'NegReg', (55, 64))	('knockdown', 'Var', (31, 40))
67946	32487167	The luciferase reporter assay and AGO2 RIP experiments demonstrated that let-7c-5p bound to circCORO1C, while rescue experiments revealed that inhibition of let-7c-5p reversed the inhibitory effect of knockdown of circCORO1C on LSCC malignant phenotypes.	('LSCC', 'Disease', (228, 232))	('let-7c', 'Gene', '406885', (157, 163))	('CORO1C', 'Gene', '23603', (96, 102))	('knockdown', 'Var', (201, 210))	('CORO1C', 'Gene', (218, 224))	('let-7c', 'Gene', (73, 79))	('CORO1C', 'Gene', '23603', (218, 224))	('AGO2', 'Gene', (34, 38))	('let-7c', 'Gene', '406885', (73, 79))	('CORO1C', 'Gene', (96, 102))	('AGO2', 'Gene', '27161', (34, 38))	('let-7c', 'Gene', (157, 163))
67955	32487167	Finally, we demonstrated that knockdown of circCORO1C inhibited the growth of LSCC cell xenograft tumors through preclinical models and verified the regulatory relationship of the circCORO1C-let-7c-5p-PBX3 axis in vivo.	('inhibited', 'NegReg', (54, 63))	('LSCC', 'Disease', (78, 82))	('tumors', 'Disease', (98, 104))	('CORO1C', 'Gene', '23603', (184, 190))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('CORO1C', 'Gene', (47, 53))	('tumors', 'Disease', 'MESH:D009369', (98, 104))	('let-7c', 'Gene', (191, 197))	('PBX3', 'Gene', '5090', (201, 205))	('let-7c', 'Gene', '406885', (191, 197))	('CORO1C', 'Gene', '23603', (47, 53))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('PBX3', 'Gene', (201, 205))	('knockdown', 'Var', (30, 39))	('growth', 'CPA', (68, 74))	('CORO1C', 'Gene', (184, 190))
67983	32185135	The ligation of PD-1 and PD-L1 or PD-L2 on tumor cells or antigen-presenting cells (APCs) elicits an immunosuppressive response, which implements subsequent metabolic reprogramming in T cells, decreases effector T cells and memory T cells, and increases Treg and exhausted T cell abundance.	('PD-1', 'Var', (16, 20))	('increases', 'PosReg', (244, 253))	('PD-L2', 'Gene', (34, 39))	('elicits', 'Reg', (90, 97))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Disease', (43, 48))	('decreases', 'NegReg', (193, 202))	('ligation', 'Var', (4, 12))	('PD-L2', 'Gene', '574057', (34, 39))	('PD-L1', 'Var', (25, 30))
67985	32185135	Observe the oral cavity squamous cell carcinoma (OCSCC) as an example, the prevalence of PD-L1 positivity has been reported in 45-87% of cases, depending on the cut-off value for positivity, whether cytoplasmic staining was counted as positive, and inclusion of the proportion of HPV+ cancer cases.	('OCSCC', 'Disease', (49, 54))	('oral cavity squamous cell carcinoma', 'Disease', 'MESH:D002294', (12, 47))	('carcinoma', 'Phenotype', 'HP:0030731', (38, 47))	('cancer', 'Phenotype', 'HP:0002664', (285, 291))	('PD-L1', 'Gene', (89, 94))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (24, 47))	('HPV', 'Species', '10566', (280, 283))	('OCSCC', 'Disease', 'MESH:D002294', (49, 54))	('cancer', 'Disease', (285, 291))	('oral cavity squamous cell carcinoma', 'Disease', (12, 47))	('positivity', 'Var', (95, 105))	('cancer', 'Disease', 'MESH:D009369', (285, 291))
67993	32185135	The efficacy of anti-PD-1 and anti-PD-L1 for R/M HNSCC, regardless of its use at as salvage therapy, in the second-line, or even in the first-line while combined with platinum plus infusional 5-fluorouracil, the ORRs were fairly poor across the board.	('HNSCC', 'Disease', 'MESH:C535575', (49, 54))	('HNSCC', 'Phenotype', 'HP:0012288', (49, 54))	('HNSCC', 'Disease', (49, 54))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (192, 206))	('anti-PD-L1', 'Var', (30, 40))	('platinum', 'Chemical', 'MESH:D010984', (167, 175))	('anti-PD-1', 'Var', (16, 25))
68005	32185135	A group of investigators from Foundation Medicine Inc., Cambridge, Boston, showed that in a preclinical study focusing on endometrial carcinoma and stomach adenocarcinoma, somatic mutation of JAK1 with loss of function (meaning loss of JAK1-mediated interferon response) results in immune evasion, particularly in microsatellite instability-high (MSI-H) tumors with high total mutational burden (TMB).	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (122, 143))	('meaning loss', 'Phenotype', 'HP:0031433', (220, 232))	('endometrial carcinoma and stomach adenocarcinoma', 'Disease', 'MESH:D016889', (122, 170))	('loss of function', 'NegReg', (202, 218))	('tumor', 'Phenotype', 'HP:0002664', (354, 359))	('JAK1', 'Gene', (236, 240))	('JAK1', 'Gene', (192, 196))	('immune evasion', 'MPA', (282, 296))	('TMB', 'Chemical', '-', (396, 399))	('JAK1', 'Gene', '3716', (236, 240))	('microsatellite instability-high', 'MPA', (314, 345))	('JAK1', 'Gene', '3716', (192, 196))	('tumors', 'Phenotype', 'HP:0002664', (354, 360))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (161, 170))	('MSI-H) tumors', 'Disease', 'MESH:D053842', (347, 360))	('mutation', 'Var', (180, 188))
68009	32185135	Experiments using fecal microbiota transplantation in avatar mice demonstrate that a combination of A. muciniphila and E. hirae would increase the CCR9- or CXCR3-expressing central memory T cells in the mesenteric lymph nodes and induce dendritic cells to secrete IL-12, a Th1 cytokine essential to elicit immunogenicity during PD-1/PD-L1 blockade.	('A. muciniphila', 'Var', (100, 114))	('E. hirae', 'Species', '1354', (119, 127))	('mice', 'Species', '10090', (61, 65))	('E. hirae', 'Var', (119, 127))	('induce', 'PosReg', (230, 236))	('dendritic', 'CPA', (237, 246))	('central memory T cells', 'CPA', (173, 195))	('secrete', 'MPA', (256, 263))	('CCR9- or CXCR3-expressing', 'MPA', (147, 172))	('A. muciniphila', 'Species', '239935', (100, 114))	('increase', 'PosReg', (134, 142))
68018	32185135	Tumor cell adaption occurs through various processes, namely with modification of molecules causing immune escape via malfunction of the antigen-presenting machinery via class I HLA, reintroduction of cyclin D-CDK4 kinase heterodimers to cell cycles, enrichment of CD44+ cancer stem-like cells, JAK mutation, or development of inactivating mutation in IKZF1 gene, the master regulator of immune infiltrates recruitment.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('CD44', 'Gene', (265, 269))	('IKZF1', 'Gene', (352, 357))	('cancer', 'Phenotype', 'HP:0002664', (271, 277))	('CD44', 'Gene', '960', (265, 269))	('immune', 'MPA', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (271, 277))	('inactivating mutation', 'Var', (327, 348))	('IKZF1', 'Gene', '10320', (352, 357))	('CDK4', 'Gene', (210, 214))	('modification', 'Var', (66, 78))	('cancer', 'Disease', (271, 277))	('CDK4', 'Gene', '1019', (210, 214))
68020	32185135	SPOP mutations or copy number variation can act as a tumor suppressor or progressor depending on the different context in different cancer types.	('SPOP', 'Gene', (0, 4))	('cancer', 'Disease', (132, 138))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('mutations', 'Var', (5, 14))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('copy number variation', 'Var', (18, 39))	('tumor', 'Disease', (53, 58))	('cancer', 'Disease', 'MESH:D009369', (132, 138))
68021	32185135	In head and neck cancer, TCGA dataset, <2% of patient tumors exhibited mutated or altered SPOP, which was associated with non-significant reduction of the relative risk of relapse or disease progression (relative risk = 0.4, 95% confidence interval, 0.06-2.61) (Supplementary Table 1).	('patient', 'Species', '9606', (46, 53))	('reduction', 'NegReg', (138, 147))	('tumors', 'Disease', 'MESH:D009369', (54, 60))	('mutated', 'Var', (71, 78))	('head and neck cancer', 'Phenotype', 'HP:0012288', (3, 23))	('SPOP', 'Gene', (90, 94))	('head and neck cancer', 'Disease', 'MESH:D006258', (3, 23))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('relapse', 'CPA', (172, 179))	('exhibited', 'Reg', (61, 70))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('altered', 'Reg', (82, 89))	('tumors', 'Disease', (54, 60))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
68022	32185135	Recent research identified that cyclin D-CDK4 kinase reintroduction in CAF would destabilize PD-L1 molecules via the cullin 3-SPOP pathway.	('PD-L1', 'Protein', (93, 98))	('cullin 3', 'Gene', (117, 125))	('destabilize', 'NegReg', (81, 92))	('reintroduction', 'Var', (53, 67))	('cyclin', 'Protein', (32, 38))	('CDK4', 'Gene', (41, 45))	('cullin 3', 'Gene', '8452', (117, 125))	('CDK4', 'Gene', '1019', (41, 45))
68023	32185135	Whereas, loss of function mutations of SPOP will increase the level of PD-L1 and tumor-infiltrating lymphocytes, as observed in mouse models.	('increase', 'PosReg', (49, 57))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('mutations', 'Var', (26, 35))	('mouse', 'Species', '10090', (128, 133))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('loss of function', 'NegReg', (9, 25))	('SPOP', 'Gene', (39, 43))	('tumor', 'Disease', (81, 86))	('PD-L1', 'MPA', (71, 76))
68027	32185135	Genomic alterations of this gene could negatively affect immunogenicity and tumor response to ICB.	('ICB', 'Chemical', '-', (94, 97))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('negatively', 'NegReg', (39, 49))	('affect', 'Reg', (50, 56))	('immunogenicity', 'CPA', (57, 71))	('Genomic alterations', 'Var', (0, 19))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
68029	32185135	The HLA mutations are uncommonly found with <10% prevalence rate in HPV-negative HNSCCs, whereas, the HPV-positive tumors will have more common HLA and Beta2-microglobulin (B2M) mutations and TRAF3 loss.	('HPV', 'Species', '10566', (68, 71))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('Beta2-microglobulin', 'Gene', (152, 171))	('loss', 'NegReg', (198, 202))	('Beta2-microglobulin', 'Gene', '567', (152, 171))	('HLA', 'Disease', (144, 147))	('HPV', 'Species', '10566', (102, 105))	('tumors', 'Disease', (115, 121))	('tumors', 'Disease', 'MESH:D009369', (115, 121))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('HNSCC', 'Phenotype', 'HP:0012288', (81, 86))	('HNSCCs', 'Disease', (81, 87))	('TRAF3', 'Gene', (192, 197))	('B2M', 'Gene', (173, 176))	('mutations', 'Var', (178, 187))	('HNSCCs', 'Disease', 'MESH:C535575', (81, 87))
68030	32185135	B2M deficiency in tumor cells, which results in defective cell surface HLA Class I complex or subsequent acquired loss of B2M while under immunotherapy, has been recognized as a crucial immune escape mechanism as demonstrated in various solid tumor models.	('B2M', 'Protein', (122, 125))	('tumor', 'Disease', (18, 23))	('loss', 'NegReg', (114, 118))	('B2M', 'Gene', (0, 3))	('deficiency', 'Var', (4, 14))	('tumor', 'Disease', 'MESH:D009369', (243, 248))	('defective', 'NegReg', (48, 57))	('cell surface HLA Class I complex', 'Protein', (58, 90))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))	('tumor', 'Disease', (243, 248))
68032	32185135	T-cell functions and proliferation can be impaired through mutations in interferon-gamma-regulating genes, suppression of the Stimulator of Interferon genes (STING) pathway or result from constitutional nutritional iron deficiency states.	('result from', 'Reg', (176, 187))	('interferon-gamma', 'Gene', '3458', (72, 88))	('iron deficiency state', 'Phenotype', 'HP:0001891', (215, 236))	('T-cell functions', 'CPA', (0, 16))	('suppression', 'NegReg', (107, 118))	('interferon-gamma', 'Gene', (72, 88))	('iron deficiency', 'Disease', 'MESH:C562385', (215, 230))	('mutations', 'Var', (59, 68))	('iron deficiency', 'Disease', (215, 230))	('impaired', 'NegReg', (42, 50))
68042	32185135	The alterations of these metabolites will adversely impact anti-cancer immunity through various molecular mechanisms.	('alterations', 'Var', (4, 15))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('impact', 'Reg', (52, 58))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
68050	32185135	Current evidence suggests that one of the significant mechanisms in acquired immune escape from PD-1/PD-L1 inhibition is CD38 upregulation.	('PD-1/PD-L1', 'Gene', (96, 106))	('acquired immune escape', 'CPA', (68, 90))	('CD38', 'Gene', (121, 125))	('CD38', 'Gene', '952', (121, 125))	('inhibition', 'Var', (107, 117))	('upregulation', 'PosReg', (126, 138))
68056	32185135	These include the combined positive score (CPS) for PD-L1 protein expression, mismatch repair (MMR)-deficient status, apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like (APOBEC)-driven mutations status, the molecular exhausted immune class, molecular active immune class, the interferon-gamma signature (6-genes), the expanded immune signature (18-genes), the condition of somatic frameshift events in tumor suppressor genes, the total mutational burden (TMB), and the microenvironment infiltrating arginase 1 (Arg1)+/CD68+ macrophage-mediated immune evasion state.	('frameshift', 'Var', (395, 405))	('arginase 1', 'Gene', (513, 523))	('tumor', 'Disease', (416, 421))	('interferon-gamma', 'Gene', '3458', (290, 306))	('Arg1', 'Gene', '383', (525, 529))	('tumor', 'Phenotype', 'HP:0002664', (416, 421))	('Arg1', 'Gene', (525, 529))	('interferon-gamma', 'Gene', (290, 306))	('arginase 1', 'Gene', '383', (513, 523))	('CD68', 'Gene', (532, 536))	('CPS', 'Chemical', '-', (43, 46))	('tumor', 'Disease', 'MESH:D009369', (416, 421))	('TMB', 'Chemical', '-', (469, 472))	('CD68', 'Gene', '968', (532, 536))
68059	32185135	In various trials, CPS >= 1% predicts immunotherapy response.	('CPS >= 1%', 'Var', (19, 28))	('predicts', 'Reg', (29, 37))	('CPS', 'Chemical', '-', (19, 22))	('immunotherapy response', 'CPA', (38, 60))
68064	32185135	DNA mismatch repair (MMR) genes, hMLH1 and hMSH2, once inactivated, can accumulate thousands of mutations in simple repeats in genomic DNA and develop microsatellite instability (MSI).	('hMLH1', 'Gene', '4292', (33, 38))	('microsatellite instability', 'MPA', (151, 177))	('hMSH2', 'Gene', '4436', (43, 48))	('hMSH2', 'Gene', (43, 48))	('accumulate', 'PosReg', (72, 82))	('mutations in', 'Var', (96, 108))	('DNA', 'Gene', (135, 138))	('hMLH1', 'Gene', (33, 38))	('develop', 'PosReg', (143, 150))
68068	32185135	Generally speaking, TMB was defined as the total number of somatic, coding, base substitution, and indel mutations counted per megabase (Mb) of genome interrogated.	('TMB', 'Chemical', '-', (20, 23))	('indel mutations', 'Var', (99, 114))	('base substitution', 'Var', (76, 93))
68088	32185135	Targeted massively parallel sequencing and NanoString nCounter mRNA analysis showing the results of total mutational burden or certain immune signatures present promising tests with the potential to discriminate between immune responsive or unresponsive patients with HNSCC, thus requiring further research to confirm their utility in predictive precision immuno-oncology.	('HNSCC', 'Disease', 'MESH:C535575', (268, 273))	('HNSCC', 'Phenotype', 'HP:0012288', (268, 273))	('HNSCC', 'Disease', (268, 273))	('oncology', 'Phenotype', 'HP:0002664', (363, 371))	('mutational', 'Var', (106, 116))	('patients', 'Species', '9606', (254, 262))
68093	31666927	Covalently closed circular RNAs have recently been shown to be widespread in cancers and are proposed to be biomarkers.	('cancers', 'Disease', 'MESH:D009369', (77, 84))	('cancers', 'Phenotype', 'HP:0002664', (77, 84))	('cancers', 'Disease', (77, 84))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('cancer', 'Disease', (77, 83))	('Covalently closed circular', 'Var', (0, 26))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))
68101	31666927	However, there are ongoing clinical trials for checkpoint (anti-PD-1/PD-L1) inhibitors including Nivolumab and Pembrolizumab for different stages of ASCC (NCT02919969, NCT03233711).	('NCT03233711', 'Chemical', 'MESH:C079985', (168, 179))	('ASCC', 'Disease', (149, 153))	('NCT02919969', 'Var', (155, 166))
68117	31666927	In two systemic meta-analyses, GLUT1 expression in gallbladder cancer, pancreatic cancer, breast cancer, oral cancer, and lung cancer did correspond to higher tumor grade, lymph node metastasis and larger tumor size, which are all linked to poorer overall survival.	('higher', 'PosReg', (152, 158))	('expression', 'Var', (37, 47))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('lung cancer', 'Disease', 'MESH:D008175', (122, 133))	('pancreatic cancer', 'Disease', (71, 88))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('gallbladder cancer', 'Disease', (51, 69))	('lung cancer', 'Phenotype', 'HP:0100526', (122, 133))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('oral cancer', 'Disease', 'MESH:D009062', (105, 116))	('oral cancer', 'Disease', (105, 116))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (71, 88))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('breast cancer', 'Phenotype', 'HP:0003002', (90, 103))	('lymph node metastasis', 'CPA', (172, 193))	('lung cancer', 'Disease', (122, 133))	('breast cancer', 'Disease', 'MESH:D001943', (90, 103))	('GLUT1', 'Gene', (31, 36))	('breast cancer', 'Disease', (90, 103))	('pancreatic cancer', 'Disease', 'MESH:D010190', (71, 88))
68138	27231203	Using a newly developed approach that quantitatively predicts gene rearrangements in tumor-derived genetic material, we identified and characterized a novel oncogenic fusion involving the MER proto-oncogene tyrosine kinase (MERTK) and discovered a clinical occurrence and cell line model of the targetable FGFR3-TACC3 fusion in TNBC.	('tumor', 'Disease', (85, 90))	('TACC3', 'Gene', (312, 317))	('TNBC', 'Gene', (328, 332))	('MER proto-oncogene tyrosine kinase', 'Gene', (188, 222))	('FGFR3', 'Gene', '2261', (306, 311))	('MER proto-oncogene tyrosine kinase', 'Gene', '10461', (188, 222))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('TACC3', 'Gene', '10460', (312, 317))	('FGFR3', 'Gene', (306, 311))	('fusion', 'Var', (318, 324))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))
68139	27231203	Expanding our analysis to other malignancies, we identified a diverse array of novel and known hybrid transcripts, including rearrangements between non-coding regions and clinically relevant genes such as ALK, CSF1R, and CD274/PD-L1.	('CD274', 'Gene', (221, 226))	('malignancies', 'Disease', (32, 44))	('PD-L1', 'Gene', '29126', (227, 232))	('rearrangements', 'Var', (125, 139))	('CSF1R', 'Gene', '1436', (210, 215))	('ALK', 'Gene', '238', (205, 208))	('CD274', 'Gene', '29126', (221, 226))	('malignancies', 'Disease', 'MESH:D009369', (32, 44))	('PD-L1', 'Gene', (227, 232))	('ALK', 'Gene', (205, 208))	('CSF1R', 'Gene', (210, 215))
68144	27231203	Ongoing genomic analysis of TNBC has identified a low frequency and widely varying clonality of therapeutically actionable alterations across subtypes, including mutations in PIK3CA and BRAF, amplification of EGFR, loss of PTEN, and expression of androgen receptor (AR).	('PIK3CA', 'Gene', (175, 181))	('PTEN', 'Gene', (223, 227))	('BRAF', 'Gene', (186, 190))	('mutations', 'Var', (162, 171))	('EGFR', 'Gene', (209, 213))	('PTEN', 'Gene', '5728', (223, 227))	('EGFR', 'Gene', '1956', (209, 213))	('AR', 'Gene', '367', (266, 268))	('TNBC', 'Gene', (28, 32))	('loss', 'NegReg', (215, 219))	('PIK3CA', 'Gene', '5290', (175, 181))	('androgen receptor', 'Gene', '367', (247, 264))	('expression', 'Reg', (233, 243))	('amplification', 'Var', (192, 205))	('androgen receptor', 'Gene', (247, 264))	('BRAF', 'Gene', '673', (186, 190))
68146	27231203	A defining feature of TNBC and other clinically challenging, molecularly heterogeneous cancers such as ovarian carcinoma and lung squamous cell carcinoma is copy number alteration (CNA), which is frequently accompanied by mutation or inactivation of the p53 tumor suppressor.	('inactivation', 'NegReg', (234, 246))	('tumor', 'Disease', (258, 263))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('tumor', 'Disease', 'MESH:D009369', (258, 263))	('p53', 'Gene', '7157', (254, 257))	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (103, 120))	('cancers', 'Phenotype', 'HP:0002664', (87, 94))	('tumor', 'Phenotype', 'HP:0002664', (258, 263))	('cancers', 'Disease', (87, 94))	('ovarian carcinoma', 'Disease', (103, 120))	('p53', 'Gene', (254, 257))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (125, 153))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (130, 153))	('copy number alteration', 'Var', (157, 179))	('TNBC', 'Gene', (22, 26))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (103, 120))	('mutation', 'Var', (222, 230))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (125, 153))	('lung squamous cell carcinoma', 'Disease', (125, 153))	('cancers', 'Disease', 'MESH:D009369', (87, 94))
68155	27231203	SUM185PE cells (8000 cells/well) were reverse transfected in a 96-well format with RNAiMax (0.1 muL, Life Technologies) and siRNAs (1.25 pmole) targeting the FGFR3 exon 4/5 junction (Dharmacon D-003133-06), FGFR3 exon 11 (D-003133-05), TACC3 exon 13 (D-004155-03), TACC3 3' UTR (D-004155-04), TACC3 exon 4 (D-004155-01), or TACC3 exon 5 (D-004155-02) (siRNA #1-6, respectively).	('FGFR3', 'Gene', (207, 212))	('TACC3', 'Gene', '10460', (265, 270))	('TACC3', 'Gene', (265, 270))	('TACC3', 'Gene', '10460', (293, 298))	('FGFR3', 'Gene', (158, 163))	('D-004155-01', 'Var', (307, 318))	('TACC3', 'Gene', '10460', (324, 329))	('FGFR3', 'Gene', '2261', (207, 212))	('TACC3', 'Gene', (293, 298))	('TACC3', 'Gene', (324, 329))	('D-004155-03', 'Var', (251, 262))	('D-004155-04', 'Var', (279, 290))	('TACC3', 'Gene', '10460', (236, 241))	('D-004155-02', 'Var', (338, 349))	('FGFR3', 'Gene', '2261', (158, 163))	('D-003133-05', 'Var', (222, 233))	('TACC3', 'Gene', (236, 241))
68174	27231203	This approach allows the detection of different structural classes of rearrangements - general up- or down-regulation of a transcript might accompany promoter or untranslated region (UTR) swapping, for instance, while abrupt gain or loss of expression from one exon to the next could result from a breakpoint within the intervening DNA.	('swapping', 'Var', (188, 196))	('expression', 'MPA', (241, 251))	('down-regulation', 'NegReg', (102, 117))	('abrupt gain', 'Disease', 'MESH:D015430', (218, 229))	('up-', 'PosReg', (95, 98))	('loss', 'NegReg', (233, 237))	('abrupt gain', 'Disease', (218, 229))
68180	27231203	The algorithm also reliably identified therapeutically actionable anaplastic lymphoma kinase (ALK) fusions in lung adenocarcinoma, although DNA validation was not available in all cases due to incomplete availability of WGS data (Supplementary Fig.	('ALK', 'Gene', '238', (94, 97))	('lung adenocarcinoma', 'Disease', (110, 129))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (110, 129))	('anaplastic lymphoma kinase', 'Gene', '238', (66, 92))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (110, 129))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (66, 85))	('fusions', 'Var', (99, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('lymphoma', 'Phenotype', 'HP:0002665', (77, 85))	('ALK', 'Gene', (94, 97))	('anaplastic lymphoma kinase', 'Gene', (66, 92))
68184	27231203	In both cases, STA scores were significantly higher in the rearrangement-harboring transcripts (p < 2.2x10-6).	('higher', 'PosReg', (45, 51))	('STA', 'Chemical', '-', (15, 18))	('rearrangement-harboring', 'Var', (59, 82))	('STA scores', 'MPA', (15, 25))
68185	27231203	Due to the ability of STA to detect aberrant loss of expression in addition to gain, we hypothesized that inactivation of tumor suppressors would constitute a substantial portion of STA-predicted rearrangements.	('inactivation', 'Var', (106, 118))	('STA', 'Chemical', '-', (182, 185))	('rearrangements', 'Var', (196, 210))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('expression', 'MPA', (53, 63))	('loss', 'NegReg', (45, 49))	('tumor', 'Disease', (122, 127))	('STA', 'Chemical', '-', (22, 25))
68188	27231203	We additionally validated rearrangements with non-coding DNA in bladder and endometrial carcinoma resulting in the loss of functional domains of the PI3K negative regulator PTEN and the p300 histone acetyltransferase, respectively (Supplementary Fig.	('loss', 'NegReg', (115, 119))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (76, 97))	('functional domains', 'MPA', (123, 141))	('PTEN', 'Gene', (173, 177))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('bladder', 'Disease', (64, 71))	('PTEN', 'Gene', '5728', (173, 177))	('endometrial carcinoma', 'Disease', (76, 97))	('p300', 'Var', (186, 190))	('rearrangements', 'Var', (26, 40))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (76, 97))
68189	27231203	In a kidney chromophobe tumor, we identified a rearrangement between a non-coding portion of chromosome 5 and the gene encoding the miRNA-processing enzyme DROSHA that results in its early truncation (Supplementary Fig.	('kidney chromophobe tumor', 'Disease', 'MESH:D000238', (5, 29))	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('rearrangement', 'Var', (47, 60))	('kidney chromophobe tumor', 'Disease', (5, 29))	('truncation', 'MPA', (189, 199))	('DROSHA', 'Gene', '29102', (156, 162))	('DROSHA', 'Gene', (156, 162))
68190	27231203	Interestingly, inactivating DROSHA mutations have recently been reported in over 10% of cases of Wilms tumor, a pediatric kidney cancer.	('pediatric kidney cancer', 'Disease', 'MESH:D007680', (112, 135))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('Wilms tumor', 'Disease', (97, 108))	('Wilms tumor', 'Disease', 'MESH:D009396', (97, 108))	('DROSHA', 'Gene', '29102', (28, 34))	('inactivating', 'Var', (15, 27))	('pediatric kidney cancer', 'Disease', (112, 135))	('DROSHA', 'Gene', (28, 34))	('reported', 'Reg', (64, 72))	('kidney cancer', 'Phenotype', 'HP:0009726', (122, 135))	('Wilms tumor', 'Phenotype', 'HP:0002667', (97, 108))	('mutations', 'Var', (35, 44))
68197	27231203	To verify that the fusion protein-modulated signaling could be replicated in breast-derived, basal epithelial cells, we expressed TMEM87B-MERTK in immortalized MCF10A cells and observed similar activation of Erk and Akt after serum starvation and growth factor withdrawal (Fig.	('Akt', 'Pathway', (216, 219))	('TMEM87B-MERTK', 'Var', (130, 143))	('activation', 'PosReg', (194, 204))	('MCF10A', 'CellLine', 'CVCL:0598', (160, 166))	('Erk', 'Pathway', (208, 211))
68198	27231203	Of note, we identified an identical TMEM87B-MERTK fusion in the lung squamous cell carcinoma RNA-seq data set from TCGA, along with a BCL2L11-MERTK RNA transcript with the same breakpoint in bladder carcinoma, but WGS data were not available for DNA validation (data not shown).	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (64, 92))	('TMEM87B-MERTK', 'Gene', (36, 49))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (69, 92))	('lung squamous cell carcinoma', 'Disease', (64, 92))	('BCL2L11', 'Gene', '10018', (134, 141))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (191, 208))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (64, 92))	('BCL2L11', 'Gene', (134, 141))	('carcinoma', 'Phenotype', 'HP:0030731', (199, 208))	('bladder carcinoma', 'Disease', (191, 208))	('bladder carcinoma', 'Disease', 'MESH:D001749', (191, 208))	('fusion', 'Var', (50, 56))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))
68199	27231203	An independent RNA-seq fusion analysis of TCGA samples corroborated the TMEM87B-MERTK fusion in TNBC and identified identical rearrangements in cervical carcinoma and lung adenocarcinoma, demonstrating selection for a recurrently truncated form of MERTK in multiple cancer types.	('cancer', 'Disease', 'MESH:D009369', (266, 272))	('cancer', 'Disease', (266, 272))	('carcinoma', 'Phenotype', 'HP:0030731', (153, 162))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (167, 186))	('carcinoma', 'Phenotype', 'HP:0030731', (177, 186))	('fusion', 'Var', (86, 92))	('cancer', 'Phenotype', 'HP:0002664', (266, 272))	('TMEM87B-MERTK', 'Gene', (72, 85))	('carcinoma and lung adenocarcinoma', 'Disease', 'MESH:D000077192', (153, 186))
68200	27231203	In order to identify and evaluate an endogenous model of oncogenic gene fusions in TNBC, we expanded our analysis to RNA-seq data from 80 additional TNBC tumors and 28 TNBC cell line models.	('TNBC tumors', 'Disease', 'MESH:D009369', (149, 160))	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('TNBC', 'Disease', (83, 87))	('TNBC tumors', 'Disease', (149, 160))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('fusions', 'Var', (72, 79))
68201	27231203	In both a tumor specimen and the SUM185PE cell line, we discovered FGFR3-TACC3 fusions similar to the oncogenic rearrangements recently observed in glioblastoma and bladder carcinoma, which result in the fusion of the FGFR3 kinase domain to the coiled-coil domain of TACC3 (Fig.	('FGFR3', 'Gene', (218, 223))	('coiled-coil domain', 'MPA', (245, 263))	('glioblastoma', 'Phenotype', 'HP:0012174', (148, 160))	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('FGFR3', 'Gene', (67, 72))	('tumor', 'Disease', (10, 15))	('glioblastoma and bladder carcinoma', 'Disease', 'MESH:D005909', (148, 182))	('FGFR3', 'Gene', '2261', (67, 72))	('carcinoma', 'Phenotype', 'HP:0030731', (173, 182))	('TACC3', 'Gene', '10460', (73, 78))	('TACC3', 'Gene', '10460', (267, 272))	('FGFR3', 'Gene', '2261', (218, 223))	('TACC3', 'Gene', (73, 78))	('TACC3', 'Gene', (267, 272))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('fusions', 'Var', (79, 86))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (165, 182))	('fusion', 'Interaction', (204, 210))
68205	27231203	To verify that the viability decrease was due to the loss of fused FGFR3 rather than wild-type, we assessed two siRNAs targeting the fused portion of TACC3 (Fig.	('FGFR3', 'Gene', (67, 72))	('TACC3', 'Gene', (150, 155))	('FGFR3', 'Gene', '2261', (67, 72))	('fused', 'Var', (61, 66))	('loss', 'NegReg', (53, 57))	('viability', 'CPA', (19, 28))	('TACC3', 'Gene', '10460', (150, 155))	('decrease', 'NegReg', (29, 37))
68207	27231203	Additionally, SUM185PE cells displayed pronounced sensitivity to the FGFR inhibitor PD173074 (IC50 = 48 +- 13 nM), whereas the majority of other cell lines tested displayed micromolar or greater half-maximal inhibitory concentrations (Fig.	('PD173074', 'Chemical', 'MESH:C115711', (84, 92))	('SUM185PE', 'Var', (14, 22))	('FGFR', 'Gene', (69, 73))	('sensitivity', 'MPA', (50, 61))	('PD173074', 'Var', (84, 92))
68213	27231203	Importantly, a small portion of the retained Ig-like domain was previously demonstrated to be sufficient for the FGFR1 activation exhibited by the full-length protein, implying that the NPTN-CLUAP1 gene fusion may lead to the secretion of a paracrine FGFR1 activator.	('secretion', 'MPA', (226, 235))	('NPTN', 'Gene', '27020', (186, 190))	('lead to', 'Reg', (214, 221))	('fusion', 'Var', (203, 209))	('FGFR1', 'Gene', (113, 118))	('FGFR1', 'Gene', (251, 256))	('paracrine', 'MPA', (241, 250))	('CLUAP1', 'Gene', '23059', (191, 197))	('NPTN', 'Gene', (186, 190))	('FGFR1', 'Gene', '2260', (113, 118))	('FGFR1', 'Gene', '2260', (251, 256))	('CLUAP1', 'Gene', (191, 197))
68221	27231203	Given the ability of STA to identify novel classes of rearrangements in TNBC, we broadened our discovery efforts using 14 additional NGS datasets from TCGA.	('TNBC', 'Gene', (72, 76))	('rearrangements', 'Var', (54, 68))	('STA', 'Chemical', '-', (21, 24))
68225	27231203	Coding genes acting as the 3' transcript partner in out-of-frame fusions included a higher proportion of tumor suppressors, for example, whereas in-frame fusions and rearrangement at UTRs included more oncogenes (Supplementary Fig.	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumor', 'Disease', (105, 110))	('fusions', 'Var', (65, 72))	('out-of-frame fusions', 'Var', (52, 72))
68227	27231203	In a thyroid carcinoma sample, we identified a rearrangement between a 5' portion of the long non-coding RNA (lncRNA) MALAT1 and the recurrently fused ALK, leading to extremely high expression of a transcript retaining the ALK kinase domain (Fig.	('transcript', 'MPA', (198, 208))	('rearrangement', 'Var', (47, 60))	('expression', 'MPA', (182, 192))	('high', 'PosReg', (177, 181))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (5, 22))	('ALK', 'Gene', '238', (223, 226))	('MALAT1', 'Gene', '378938', (118, 124))	('ALK', 'Gene', (151, 154))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (5, 22))	('thyroid carcinoma', 'Disease', (5, 22))	('MALAT1', 'Gene', (118, 124))	('ALK', 'Gene', (223, 226))	('ALK', 'Gene', '238', (151, 154))	('carcinoma', 'Phenotype', 'HP:0030731', (13, 22))
68228	27231203	Of note, the MALAT1-ALK rearrangement occurs upstream of ALK exon 16 rather than the most common exon 19 and 20 breakpoints, but numerous in-frame methionines in the exon 16-19 region could allow translation initiation after the non-coding, 5' MALAT1 portion of the hybrid transcript (data not shown).	('ALK', 'Gene', '238', (20, 23))	('methionines', 'Chemical', 'MESH:D008715', (147, 158))	('MALAT1', 'Gene', (13, 19))	('MALAT1', 'Gene', '378938', (244, 250))	('ALK', 'Gene', (57, 60))	('translation initiation', 'MPA', (196, 218))	('MALAT1', 'Gene', (244, 250))	('methionines', 'Var', (147, 158))	('ALK', 'Gene', (20, 23))	('allow', 'Reg', (190, 195))	('MALAT1', 'Gene', '378938', (13, 19))	('ALK', 'Gene', '238', (57, 60))
68230	27231203	WGS analysis revealed a rearrangement between RNH1 and a DNA breakpoint upstream of the HRAS transcriptional start site.	('rearrangement', 'Var', (24, 37))	('RNH1', 'Gene', '6050', (46, 50))	('RNH1', 'Gene', (46, 50))
68235	27231203	DNA breakpoints upstream of the transcriptional start site, as seen in RNH1-HRAS, can lead to extreme overexpression that is easily detectable by STA.	('overexpression', 'MPA', (102, 116))	('RNH1', 'Gene', '6050', (71, 75))	('RNH1', 'Gene', (71, 75))	('lead to', 'Reg', (86, 93))	('DNA', 'Var', (0, 3))	('STA', 'Chemical', '-', (146, 149))
68236	27231203	In an estrogen receptor (ER)-positive breast cancer sample, the ER-responsive gene RARA displayed rearrangement with a region upstream of PRR11, leading to more than 10-fold increase of PRR11 transcript compared to the population average (Fig.	('estrogen receptor', 'Gene', (6, 23))	('RARA', 'Gene', '5914', (83, 87))	('PRR11', 'Gene', '55771', (138, 143))	('estrogen receptor', 'Gene', '2099', (6, 23))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('ER', 'Gene', '2099', (25, 27))	('breast cancer', 'Disease', 'MESH:D001943', (38, 51))	('RARA', 'Gene', (83, 87))	('PRR11', 'Gene', '55771', (186, 191))	('transcript', 'MPA', (192, 202))	('PRR11', 'Gene', (138, 143))	('breast cancer', 'Disease', (38, 51))	('breast cancer', 'Phenotype', 'HP:0003002', (38, 51))	('increase', 'PosReg', (174, 182))	('PRR11', 'Gene', (186, 191))	('ER', 'Gene', '2099', (64, 66))	('rearrangement', 'Var', (98, 111))
68237	27231203	While PRR11 is a relatively understudied cell cycle progression gene with normally periodic expression, it is overexpressed in breast and lung cancer and PRR11 knockdown inhibits cancer cell proliferation.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('PRR11', 'Gene', (6, 11))	('PRR11', 'Gene', (154, 159))	('lung cancer', 'Phenotype', 'HP:0100526', (138, 149))	('knockdown', 'Var', (160, 169))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('breast and lung cancer', 'Disease', 'MESH:D001943', (127, 149))	('overexpressed', 'PosReg', (110, 123))	('inhibits', 'NegReg', (170, 178))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('PRR11', 'Gene', '55771', (6, 11))	('PRR11', 'Gene', '55771', (154, 159))	('cancer', 'Disease', (179, 185))
68241	27231203	Additionally, a colorectal cancer sample with abnormally high expression of CD274, which encodes the T-cell suppressor PD-L1, harbors a rearrangement between the second-to-last exon of CD274 and a non-coding region of chromosome 9 (Fig.	('CD274', 'Gene', (76, 81))	('rearrangement', 'Var', (136, 149))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('CD274', 'Gene', '29126', (185, 190))	('expression', 'MPA', (62, 72))	('high', 'PosReg', (57, 61))	('PD-L1', 'Gene', (119, 124))	('colorectal cancer', 'Disease', 'MESH:D015179', (16, 33))	('CD274', 'Gene', '29126', (76, 81))	('CD274', 'Gene', (185, 190))	('PD-L1', 'Gene', '29126', (119, 124))	('colorectal cancer', 'Phenotype', 'HP:0003003', (16, 33))	('colorectal cancer', 'Disease', (16, 33))
68245	27231203	Importantly, our ability to assess rearrangements with non-coding regions led to the detection of not only inactivating truncations in tumor suppressors, but also gain-of-function events.	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('tumor', 'Disease', (135, 140))	('truncations', 'Var', (120, 131))	('gain-of-function', 'PosReg', (163, 179))	('inactivating', 'NegReg', (107, 119))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
68254	27231203	Although our analysis made use of RNA and DNA sequencing files already processed by the TCGA Research Network, a pipeline based on focused assembly of STA-predicted transcripts could increase the sensitivity, efficiency, and breadth of rearrangement detection, accelerating discovery of diagnostic and prognostic markers.	('sensitivity', 'MPA', (196, 207))	('increase', 'PosReg', (183, 191))	('accelerating', 'PosReg', (261, 273))	('STA', 'Chemical', '-', (151, 154))	('rearrangement', 'Var', (236, 249))
68264	32408477	In particular, the infiltration of immune-suppressive cells, such as regulatory T (Treg) cells and M2 macrophage, was significantly increased by NRP1 expression.	('expression', 'Var', (150, 160))	('increased', 'PosReg', (132, 141))	('infiltration of immune-suppressive cells', 'CPA', (19, 59))	('M2 macrophage', 'CPA', (99, 112))	('NRP1', 'Gene', '8829', (145, 149))	('NRP1', 'Gene', (145, 149))
68275	32408477	Depletion of NRP1 reduces cell proliferation via inhibiting the G1-S phase of cell cycle in gastric cancer cells.	('G1-S phase of cell cycle', 'CPA', (64, 88))	('NRP1', 'Gene', '8829', (13, 17))	('NRP1', 'Gene', (13, 17))	('gastric cancer', 'Disease', (92, 106))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('reduces', 'NegReg', (18, 25))	('gastric cancer', 'Disease', 'MESH:D013274', (92, 106))	('Depletion', 'Var', (0, 9))	('inhibiting', 'NegReg', (49, 59))	('gastric cancer', 'Phenotype', 'HP:0012126', (92, 106))	('cell proliferation', 'CPA', (26, 44))
68292	32408477	Interestingly, it has been reported that NRP1 expression increases infiltration of Treg cells in the TME.	('expression', 'Var', (46, 56))	('infiltration of Treg cells in the', 'CPA', (67, 100))	('NRP1', 'Gene', '8829', (41, 45))	('NRP1', 'Gene', (41, 45))	('increases', 'PosReg', (57, 66))
68329	32408477	In particular, hypomethylated NRP1 gene has a positive correlation with poor prognosis in gastric cancer.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('gastric cancer', 'Disease', 'MESH:D013274', (90, 104))	('NRP1', 'Gene', '8829', (30, 34))	('hypomethylated', 'Var', (15, 29))	('NRP1', 'Gene', (30, 34))	('gastric cancer', 'Phenotype', 'HP:0012126', (90, 104))	('gastric cancer', 'Disease', (90, 104))
68333	32408477	As shown in Figure 4a, high NRP1 expression was significantly correlated with poor prognosis in STAD.	('STAD', 'Disease', (96, 100))	('high', 'Var', (23, 27))	('NRP1', 'Gene', '8829', (28, 32))	('NRP1', 'Gene', (28, 32))	('expression', 'MPA', (33, 43))	('correlated', 'Reg', (62, 72))
68335	32408477	Survival curves of overall survival (OS), first progression (FP), and post progression survival (PPS) showed that patient survival rates were considerably decreased by NRP1 expression (Figure 4c).	('expression', 'Var', (173, 183))	('decreased', 'NegReg', (155, 164))	('NRP1', 'Gene', '8829', (168, 172))	('NRP1', 'Gene', (168, 172))	('patient', 'Species', '9606', (114, 121))
68357	32408477	These results suggest that NRP1 expression significantly affects the infiltration of Treg cells and M2 macrophages, and the infiltrated Treg cells and M2 macrophages enhance tumor progression in STAD by immune-suppressive functions, leading to the poor prognosis.	('tumor', 'Disease', (174, 179))	('expression', 'Var', (32, 42))	('affects', 'Reg', (57, 64))	('NRP1', 'Gene', '8829', (27, 31))	('NRP1', 'Gene', (27, 31))	('enhance', 'PosReg', (166, 173))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('infiltration', 'CPA', (69, 81))
68362	32408477	Therefore, to investigate whether the immune-suppressive cell-derived cytokines are also increased by NRP1 expression in STAD, we analyzed the correlation between NRP1 expression and cytokine gene markers (CSF1, TGFbeta1, IL10, EBI3) using the TIMER database (Figure 6).	('EBI3', 'Gene', (228, 232))	('EBI3', 'Gene', '10148', (228, 232))	('NRP1', 'Gene', '8829', (102, 106))	('NRP1', 'Gene', (102, 106))	('TGFbeta1', 'Gene', '7040', (212, 220))	('TGFbeta1', 'Gene', (212, 220))	('expression', 'Var', (107, 117))	('IL10', 'Gene', (222, 226))	('IL10', 'Gene', '3586', (222, 226))	('NRP1', 'Gene', '8829', (163, 167))	('NRP1', 'Gene', (163, 167))
68374	32408477	Overexpression of NRP1 is associated with poor prognosis in various cancers including prostate cancer, lung cancer, and melanoma.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('prostate cancer', 'Disease', 'MESH:D011471', (86, 101))	('lung cancer', 'Disease', 'MESH:D008175', (103, 114))	('prostate cancer', 'Phenotype', 'HP:0012125', (86, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('cancers', 'Phenotype', 'HP:0002664', (68, 75))	('cancers', 'Disease', (68, 75))	('cancers', 'Disease', 'MESH:D009369', (68, 75))	('melanoma', 'Phenotype', 'HP:0002861', (120, 128))	('melanoma', 'Disease', (120, 128))	('lung cancer', 'Disease', (103, 114))	('Overexpression', 'Var', (0, 14))	('NRP1', 'Gene', (18, 22))	('prostate cancer', 'Disease', (86, 101))	('NRP1', 'Gene', '8829', (18, 22))	('lung cancer', 'Phenotype', 'HP:0100526', (103, 114))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('melanoma', 'Disease', 'MESH:D008545', (120, 128))
68377	32408477	This study demonstrates that high expression of NRP1 correlates with poor prognosis of stomach adenocarcinoma (STAD).	('high', 'Var', (29, 33))	('stomach adenocarcinoma', 'Disease', (87, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('expression', 'MPA', (34, 44))	('stomach adenocarcinoma', 'Disease', 'MESH:D000230', (87, 109))	('NRP1', 'Gene', '8829', (48, 52))	('NRP1', 'Gene', (48, 52))
68385	32408477	Especially, abnormal methylation is frequently observed in tumors by affecting the cell division cycle, therefore it is associated with tumor malignant biological properties.	('associated', 'Reg', (120, 130))	('tumor', 'Disease', (59, 64))	('methylation', 'MPA', (21, 32))	('cell division cycle', 'CPA', (83, 102))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('affecting', 'Reg', (69, 78))	('tumors', 'Disease', (59, 65))	('tumors', 'Disease', 'MESH:D009369', (59, 65))	('abnormal', 'Var', (12, 20))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Disease', (136, 141))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
68387	32408477	In particular, NRP1 methylation, among the tumor-related genes, is found to be associated with survival of colon and liver cancers.	('NRP1', 'Gene', '8829', (15, 19))	('NRP1', 'Gene', (15, 19))	('colon and liver cancers', 'Disease', 'MESH:D006528', (107, 130))	('associated', 'Reg', (79, 89))	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('liver cancers', 'Phenotype', 'HP:0002896', (117, 130))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('cancers', 'Phenotype', 'HP:0002664', (123, 130))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('methylation', 'Var', (20, 31))	('tumor', 'Disease', (43, 48))
68390	32408477	Taken together, it suggests that the hypomethylation of NRP1 could be associated with poor prognosis of STAD.	('STAD', 'Disease', (104, 108))	('associated', 'Reg', (70, 80))	('NRP1', 'Gene', '8829', (56, 60))	('NRP1', 'Gene', (56, 60))	('hypomethylation', 'Var', (37, 52))
68397	32408477	NRP1 depletion inhibited cell proliferation and migration by inhibiting multiple receptors in which NRP1 plays a role as coreceptor.	('inhibited', 'NegReg', (15, 24))	('depletion', 'Var', (5, 14))	('inhibiting', 'NegReg', (61, 71))	('NRP1', 'Gene', '8829', (0, 4))	('NRP1', 'Gene', '8829', (100, 104))	('NRP1', 'Gene', (100, 104))	('NRP1', 'Gene', (0, 4))
68410	32408477	Therefore, this study suggests that NRP1 expression induces the production of the inhibitory cytokines IL-10, IL-35, and TGFbeta1 of the Treg cells and M2 macrophages, and the expressed cytokines serve as major signals in the immune suppression mechanism of STAD.	('production', 'MPA', (64, 74))	('TGFbeta1', 'Gene', '7040', (121, 129))	('induces', 'PosReg', (52, 59))	('expression', 'Var', (41, 51))	('inhibitory cytokines IL-10', 'MPA', (82, 108))	('TGFbeta1', 'Gene', (121, 129))	('NRP1', 'Gene', '8829', (36, 40))	('NRP1', 'Gene', (36, 40))
68413	32408477	According to a related study, the gene inhibition of CSF1 in breast cancer cells affects tumor formation in immunodeficient mice.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('breast cancer', 'Disease', (61, 74))	('breast cancer', 'Phenotype', 'HP:0003002', (61, 74))	('CSF1', 'Gene', (53, 57))	('affects', 'Reg', (81, 88))	('gene inhibition', 'Var', (34, 49))	('mice', 'Species', '10090', (124, 128))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('immunodeficient', 'Disease', 'MESH:D007153', (108, 123))	('immunodeficient', 'Disease', (108, 123))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))	('breast cancer', 'Disease', 'MESH:D001943', (61, 74))
68417	32408477	Therefore, the expression of NRP1 affects the cytokines produced by Treg cells and M2 macrophage and indicates poor prognosis for patients with STAD by the immune suppression mechanism.	('NRP1', 'Gene', '8829', (29, 33))	('NRP1', 'Gene', (29, 33))	('expression', 'Var', (15, 25))	('cytokines produced', 'MPA', (46, 64))	('patients', 'Species', '9606', (130, 138))	('affects', 'Reg', (34, 41))
68437	31401948	Taken together, our study provided the compelling evidence that miR-1254 might inhibit the progression of OSCC by partially downregulating CD36, and restoration of miR-1254 may represent an effective strategy for treating oral squamous cell carcinoma.	('inhibit', 'NegReg', (79, 86))	('carcinoma', 'Phenotype', 'HP:0030731', (241, 250))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (222, 250))	('CD36', 'Protein', (139, 143))	('progression', 'CPA', (91, 102))	('restoration', 'Var', (149, 160))	('miR-1254', 'Gene', (64, 72))	('oral squamous cell carcinoma', 'Disease', (222, 250))	('downregulating', 'NegReg', (124, 138))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (227, 250))	('miR-1254', 'Gene', (164, 172))	('miR-1254', 'Gene', '100302273', (64, 72))	('CD36', 'Species', '42374', (139, 143))	('miR-1254', 'Gene', '100302273', (164, 172))
68442	31401948	As deregulation of a single miRNA might affect hundreds or even thousands of downstream targets, accumulating evidences show that aberrant expression of miRNAs is closely associated with the development and progression of most cancers including OSCC.	('miR', 'Gene', (153, 156))	('aberrant expression', 'Var', (130, 149))	('OSCC', 'Disease', (245, 249))	('associated with', 'Reg', (171, 186))	('miR', 'Gene', '22877', (153, 156))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('affect', 'Reg', (40, 46))	('miR', 'Gene', (28, 31))	('cancers', 'Disease', 'MESH:D009369', (227, 234))	('cancers', 'Phenotype', 'HP:0002664', (227, 234))	('cancers', 'Disease', (227, 234))	('miR', 'Gene', '22877', (28, 31))
68449	31401948	Deregulated miR-1254 has been reported in various types of cancer, such as gastric cancer, breast cancer, and non-small cell lung carcinoma.	('miR-1254', 'Gene', (12, 20))	('reported', 'Reg', (30, 38))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('cancer', 'Disease', (98, 104))	('gastric cancer', 'Phenotype', 'HP:0012126', (75, 89))	('small cell lung carcinoma', 'Phenotype', 'HP:0030357', (114, 139))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('non-small cell lung carcinoma', 'Disease', 'MESH:D002289', (110, 139))	('Deregulated', 'Var', (0, 11))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('breast cancer', 'Phenotype', 'HP:0003002', (91, 104))	('gastric cancer', 'Disease', (75, 89))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('breast cancer', 'Disease', 'MESH:D001943', (91, 104))	('breast cancer', 'Disease', (91, 104))	('non-small cell lung carcinoma', 'Phenotype', 'HP:0030358', (110, 139))	('gastric cancer', 'Disease', 'MESH:D013274', (75, 89))	('miR-1254', 'Gene', '100302273', (12, 20))	('non-small cell lung carcinoma', 'Disease', (110, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', (83, 89))
68477	31401948	The miR-1254 overexpressed oral cancer cells and corresponding control cells were transfected with pMIR-CD36-3'-UTR wild-type vectors or pMIR-CD36-3'-UTR mutant vectors using Lipofectamine 2000 (Invitrogen), respectively.	('overexpressed', 'PosReg', (13, 26))	('oral cancer', 'Disease', 'MESH:D009062', (27, 38))	('CD36', 'Species', '42374', (104, 108))	("pMIR-CD36-3'-UTR", 'Var', (99, 115))	('miR-1254', 'Gene', (4, 12))	('oral cancer', 'Disease', (27, 38))	("pMIR-CD36-3'-UTR mutant", 'Var', (137, 160))	('CD36', 'Species', '42374', (142, 146))	('Lipofectamine', 'Chemical', 'MESH:C086724', (175, 188))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('miR-1254', 'Gene', '100302273', (4, 12))	('mutant', 'Var', (154, 160))
68485	31401948	Our quantitative RT-PCR results showed that the expression level of miR-1254 was significantly higher in miR-1254 mimic #1 or miR-1254 mimic #2 treated cells than the miR-1254 mimic control treated cells (***P < .001, Figure 2A).	('miR-1254', 'Gene', (105, 113))	('expression level', 'MPA', (48, 64))	('miR-1254', 'Gene', (68, 76))	('higher', 'PosReg', (95, 101))	('miR-1254', 'Gene', (167, 175))	('miR-1254', 'Gene', (126, 134))	('miR-1254', 'Gene', '100302273', (105, 113))	('miR-1254', 'Gene', '100302273', (68, 76))	('mimic #', 'Var', (114, 121))	('miR-1254', 'Gene', '100302273', (126, 134))	('miR-1254', 'Gene', '100302273', (167, 175))
68487	31401948	The cell counting assay showed that the number of cancer cells was significantly lower in miR-1254 mimics group than the control group (*P < .05, **P < .01, ***P < .001, Figure 3A).	('lower', 'NegReg', (81, 86))	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('miR-1254', 'Gene', '100302273', (90, 98))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('miR-1254', 'Gene', (90, 98))	('mimics', 'Var', (99, 105))
68492	31401948	Similarly, the MTT assay revealed that the OD values were higher in the miR-1254 inhibitor group compared to the control group (**P < .01, ***P < .001, Figure 4B).	('inhibitor', 'Var', (81, 90))	('miR-1254', 'Gene', '100302273', (72, 80))	('higher', 'PosReg', (58, 64))	('MTT', 'Chemical', 'MESH:C070243', (15, 18))	('OD values', 'MPA', (43, 52))	('miR-1254', 'Gene', (72, 80))
68493	31401948	The AlamarBlue assay showed that the relative absorbance was higher in the miR-1254 inhibitor group (***P < .001, Figure 4C).	('relative absorbance', 'MPA', (37, 56))	('higher', 'PosReg', (61, 67))	('miR-1254', 'Gene', (75, 83))	('miR-1254', 'Gene', '100302273', (75, 83))	('inhibitor', 'Var', (84, 93))
68497	31401948	In addition, for the wild-type CD36 vector, our luciferase reporter assay showed that the relative luciferase activity was lower in the miR-1254 inhibitor group than the control group (***P < .001, Figure 5D), indicating that CD36 was the direct downstream target of miR-1254.	('CD36', 'Species', '42374', (226, 230))	('miR-1254', 'Gene', (267, 275))	('activity', 'MPA', (110, 118))	('lower', 'NegReg', (123, 128))	('luciferase', 'Enzyme', (99, 109))	('CD36', 'Species', '42374', (31, 35))	('miR-1254', 'Gene', (136, 144))	('miR-1254', 'Gene', '100302273', (267, 275))	('inhibitor', 'Var', (145, 154))	('miR-1254', 'Gene', '100302273', (136, 144))
68522	31401948	Upregulation of endogenous miR-1254 by CCAR1 5'-UTR sensitized tamoxifen-resistant breast cancer cells to tamoxifen, indicating modulating the miR-1254 level might contribute the treatment of breast cancer.	('Upregulation', 'PosReg', (0, 12))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('breast cancer', 'Disease', 'MESH:D001943', (192, 205))	('tamoxifen', 'Chemical', 'MESH:D013629', (106, 115))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('modulating', 'Var', (128, 138))	('breast cancer', 'Disease', (192, 205))	('breast cancer', 'Disease', 'MESH:D001943', (83, 96))	('breast cancer', 'Phenotype', 'HP:0003002', (192, 205))	('sensitized', 'Reg', (52, 62))	('miR-1254', 'Gene', (143, 151))	('miR-1254', 'Gene', (27, 35))	('breast cancer', 'Disease', (83, 96))	('tamoxifen', 'Chemical', 'MESH:D013629', (63, 72))	('breast cancer', 'Phenotype', 'HP:0003002', (83, 96))	('miR-1254', 'Gene', '100302273', (143, 151))	('CCAR1', 'Gene', (39, 44))	('miR-1254', 'Gene', '100302273', (27, 35))
68523	31401948	Jiang et al reported that ectopic expression of miR-1254 in gastric cancer cells inhibited the proliferation, migration, and invasion in vitro and suppressed tumorigenesis in vivo, and smurf1 was the direct target of miR-1254.	('miR-1254', 'Gene', '100302273', (48, 56))	('tumor', 'Disease', (158, 163))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('miR-1254', 'Gene', '100302273', (217, 225))	('ectopic expression', 'Var', (26, 44))	('inhibited', 'NegReg', (81, 90))	('gastric cancer', 'Disease', (60, 74))	('suppressed', 'NegReg', (147, 157))	('gastric cancer', 'Phenotype', 'HP:0012126', (60, 74))	('gastric cancer', 'Disease', 'MESH:D013274', (60, 74))	('miR-1254', 'Gene', (48, 56))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('miR-1254', 'Gene', (217, 225))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('invasion', 'CPA', (125, 133))
68535	28415817	An updated meta-analysis of 23 case-control studies on the association between miR-34b/c polymorphism and cancer risk The association between in microRNA-34b/c gene rs4938723 polymorphisms and cancer risk remains inconclusive.	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('cancer', 'Disease', (193, 199))	('rs4938723', 'Mutation', 'rs4938723', (165, 174))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('microRNA-34b', 'Gene', (145, 157))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('microRNA-34b', 'Gene', '407041', (145, 157))	('cancer', 'Disease', (106, 112))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('miR-34b', 'Gene', (79, 86))	('miR-34b', 'Gene', '407041', (79, 86))	('rs4938723', 'Var', (165, 174))
68536	28415817	This meta-analysis was performed to analyze the association between microRNA-34b/c rs4938723 polymorphism and risk for cancer development.	('rs4938723', 'Var', (83, 92))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('cancer', 'Disease', (119, 125))	('rs4938723', 'Mutation', 'rs4938723', (83, 92))	('microRNA-34b', 'Gene', (68, 80))	('microRNA-34b', 'Gene', '407041', (68, 80))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
68538	28415817	Our results indicate a significant association between the rs4938723 polymorphism and cancer risk in the overdominant model (P heterogeneity = 0.018, OR = 1.093, and 95% CI = 1.015-1.177 for CT vs. CC/TT).	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('rs4938723', 'Mutation', 'rs4938723', (59, 68))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('rs4938723', 'Var', (59, 68))	('cancer', 'Disease', (86, 92))
68539	28415817	Using a stratified subgroup analysis, rs4938723 polymorphisms were associated with an increased risk for hepatocellular carcinoma, but decreased risk for colorectal, gastric, and esophageal squamous cell cancer.	('rs4938723', 'Var', (38, 47))	('colorectal', 'Disease', 'MESH:D015179', (154, 164))	('esophageal squamous cell cancer', 'Disease', (179, 210))	('rs4938723', 'Mutation', 'rs4938723', (38, 47))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (105, 129))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('gastric', 'Disease', (166, 173))	('hepatocellular carcinoma', 'Disease', (105, 129))	('colorectal', 'Disease', (154, 164))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (105, 129))	('decreased', 'NegReg', (135, 144))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (190, 210))	('increased risk for hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (86, 129))	('esophageal squamous cell cancer', 'Disease', 'MESH:D002294', (179, 210))
68540	28415817	These findings indicate that the rs4938723 gene is a susceptible locus for cancer.	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('cancer', 'Disease', (75, 81))	('rs4938723', 'Var', (33, 42))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('rs4938723', 'Mutation', 'rs4938723', (33, 42))
68544	28415817	Emerging evidence has revealed that genetic factors, such as single nucleotide polymorphisms (SNPs), influence cancer development, treatment efficacy, and survival time of cancer patients.	('influence', 'Reg', (101, 110))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('single nucleotide polymorphisms', 'Var', (61, 92))	('patients', 'Species', '9606', (179, 187))	('cancer', 'Disease', (172, 178))	('survival time', 'CPA', (155, 168))	('treatment efficacy', 'CPA', (131, 149))
68548	28415817	The miR-34b/c gene rs4938723 has been associated with hepatocellular and colorectal cancer.	('colorectal cancer', 'Disease', 'MESH:D015179', (73, 90))	('associated', 'Reg', (38, 48))	('colorectal cancer', 'Phenotype', 'HP:0003003', (73, 90))	('rs4938723', 'Var', (19, 28))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('colorectal cancer', 'Disease', (73, 90))	('miR-34b', 'Gene', (4, 11))	('miR-34b', 'Gene', '407041', (4, 11))	('hepatocellular', 'Disease', (54, 68))	('rs4938723', 'Mutation', 'rs4938723', (19, 28))
68549	28415817	However, updated, recent meta-analyses of the rs4938723 association with cancer risk have been limited.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('rs4938723', 'Var', (46, 55))	('rs4938723', 'Mutation', 'rs4938723', (46, 55))
68550	28415817	In this study, we have systematically reviewed the published data, and integrated all published studies to evaluate the association between rs4938723 polymorphism and cancer risk.	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('rs4938723', 'Mutation', 'rs4938723', (140, 149))	('cancer', 'Disease', (167, 173))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('rs4938723', 'Var', (140, 149))
68554	28415817	In the meta-analysis of the 23 eligible studies, genotype CT was significantly associated with cancer susceptibility in the overall population (overdominant model CT versus CC/TT: PH = 0.018, OR = 1.093, and 95% CI = 1.015-1.177), as shown in Table 2 and Figure 2.	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('cancer', 'Disease', (95, 101))	('associated with', 'Reg', (79, 94))	('genotype', 'Var', (49, 57))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))
68555	28415817	No association between rs4938723 polymorphism and cancer risk was observed in the allele, genotype, dominant, and recessive models.	('rs4938723', 'Mutation', 'rs4938723', (23, 32))	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('rs4938723', 'Var', (23, 32))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))
68556	28415817	For hepatocellular carcinoma, the rs4938723 polymorphism was associated with an increased cancer risk in the comparison model (allele C versus T: PH = 0.113, OR = 1.114, and 95% CI = 1.007-1.233), genotype model (CT versus TT: PH = 0.121, OR = 1.191, and 95% CI = 1.033-1.373), and overdominant model (CT vs. CC/TT: PH = 0.195, OR = 1.157, and 95% CI = 1.010-1.324).	('rs4938723', 'Var', (34, 43))	('hepatocellular carcinoma', 'Disease', (4, 28))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (19, 28))	('rs4938723', 'Mutation', 'rs4938723', (34, 43))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (4, 28))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (4, 28))
68558	28415817	The rs4938723 polymorphism decreased the risk for colorectal cancer in the genotype (CC vs. TT: PH = 0.342, OR = 0.658, and 95% CI = 0.470-0.923) and recessive models (CC vs. CT/TT: PH = 0.519, OR = 0.672, and 95% CI = 0.485-0.930).	('rs4938723', 'Var', (4, 13))	('colorectal cancer', 'Disease', 'MESH:D015179', (50, 67))	('decreased', 'NegReg', (27, 36))	('rs4938723', 'Mutation', 'rs4938723', (4, 13))	('colorectal cancer', 'Phenotype', 'HP:0003003', (50, 67))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('colorectal cancer', 'Disease', (50, 67))
68559	28415817	In addition, the rs4938723 polymorphism was negatively associated with gastric cancer risk in the comparison model of C versus T (PH = 0.843, OR = 0.758, and 95% CI = 0.643-0.893), CT versus TT (PH = 0.381, OR = 0.755, and 95% CI = 0.598-0.953), CC versus TT (PH = 0.400, OR = 0.584, and 95% CI = 0.405-0.842), CC/CT versus TT (PH = 0.664, OR = 0.715, and 95% CI = 0.574-0.892), and CC versus CT/TT (PH = 0.254, OR = 0.667, and 95% CI = 0.471-0.943).	('gastric cancer', 'Disease', (71, 85))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('gastric cancer', 'Disease', 'MESH:D013274', (71, 85))	('rs4938723', 'Mutation', 'rs4938723', (17, 26))	('gastric cancer', 'Phenotype', 'HP:0012126', (71, 85))	('negatively', 'NegReg', (44, 54))	('rs4938723', 'Var', (17, 26))
68560	28415817	The rs4938723 polymorphism showed also reverse correlation with esophageal squamous cell cancer in the comparison model of CC versus TT (PH = 0.345, OR = 0.787, and 95% CI = 0.638-0.972) and CC versus CT/TT (PH = 0.164, OR = 0.774, and 95% CI = 0.633-0.947).	('rs4938723', 'Var', (4, 13))	('esophageal squamous cell cancer', 'Disease', (64, 95))	('rs4938723', 'Mutation', 'rs4938723', (4, 13))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (75, 95))	('esophageal squamous cell cancer', 'Disease', 'MESH:D002294', (64, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
68565	28415817	The miR-34b/c gene rs4938723 polymorphism has been investigated because of its potential association with the increased risk for cancer development; however, the results remain inconclusive.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('cancer', 'Disease', (129, 135))	('rs4938723', 'Var', (19, 28))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('miR-34b', 'Gene', (4, 11))	('miR-34b', 'Gene', '407041', (4, 11))	('rs4938723', 'Mutation', 'rs4938723', (19, 28))
68566	28415817	This updated meta-analysis was performed to obtain conclusive results about the association of rs4938723 polymorphism and cancer risk.	('rs4938723', 'Mutation', 'rs4938723', (95, 104))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('association', 'Interaction', (80, 91))	('polymorphism', 'Var', (105, 117))	('rs4938723 polymorphism', 'Var', (95, 117))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))
68568	28415817	An increased risk for cancer was observed for the rs4938723 polymorphism under overdominant (CT vs. CC/TT) model.	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('cancer', 'Disease', (22, 28))	('rs4938723', 'Var', (50, 59))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('rs4938723', 'Mutation', 'rs4938723', (50, 59))
68570	28415817	Our results indicate that the rs4938723 polymorphism is a risk factor for cancer.	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('rs4938723', 'Mutation', 'rs4938723', (30, 39))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('cancer', 'Disease', (74, 80))	('risk', 'Reg', (58, 62))	('rs4938723', 'Var', (30, 39))
68571	28415817	Several meta-analyses investigated the association between miR-34b/c gene rs4938723 polymorphism and cancer risk.	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('rs4938723', 'Mutation', 'rs4938723', (74, 83))	('cancer', 'Disease', (101, 107))	('rs4938723 polymorphism', 'Var', (74, 96))	('miR-34b', 'Gene', (59, 66))	('polymorphism', 'Var', (84, 96))	('miR-34b', 'Gene', '407041', (59, 66))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('investigated', 'Reg', (22, 34))
68572	28415817	In the study conducted by Qiu et al., the meta-analysis included 11 studies, and indicated that allele C and genotype CT might be risk factors for hepatocellular cancer, and protective factors for colorectal cancer.	('allele C', 'Var', (96, 104))	('colorectal cancer', 'Disease', (197, 214))	('hepatocellular cancer', 'Disease', 'MESH:D006528', (147, 168))	('colorectal cancer', 'Disease', 'MESH:D015179', (197, 214))	('hepatocellular cancer', 'Disease', (147, 168))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('hepatocellular cancer', 'Phenotype', 'HP:0001402', (147, 168))	('colorectal cancer', 'Phenotype', 'HP:0003003', (197, 214))
68573	28415817	included 13 studies, and indicated that the rs4938723 polymorphism was associated with an increased cancer susceptibility of the Asian population.	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('rs4938723', 'Mutation', 'rs4938723', (44, 53))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('rs4938723', 'Var', (44, 53))
68574	28415817	However, the polymorphism reduced susceptibility to colorectal cancer and esophageal squamous cell cancer in Asians.	('polymorphism', 'Var', (13, 25))	('esophageal squamous cell cancer', 'Disease', (74, 105))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('colorectal cancer', 'Phenotype', 'HP:0003003', (52, 69))	('reduced', 'NegReg', (26, 33))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('colorectal cancer', 'Disease', (52, 69))	('esophageal squamous cell cancer', 'Disease', 'MESH:D002294', (74, 105))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (85, 105))	('susceptibility', 'MPA', (34, 48))	('colorectal cancer', 'Disease', 'MESH:D015179', (52, 69))
68576	28415817	Consistent with the previous meta-analyses, we observed an increased risk for cancer that was associated with the miR-34b/c gene rs4938723 polymorphism using the overdominant model.	('miR-34b', 'Gene', (114, 121))	('miR-34b', 'Gene', '407041', (114, 121))	('rs4938723', 'Mutation', 'rs4938723', (129, 138))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('rs4938723', 'Var', (129, 138))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))
68579	28415817	In the stratified analysis, the rs4938723 polymorphisms were associated with an increased risk of hepatocellular carcinoma, but with a decreased risk for colorectal, gastric, and esophageal squamous cell cancer.	('rs4938723', 'Mutation', 'rs4938723', (32, 41))	('colorectal', 'Disease', 'MESH:D015179', (154, 164))	('esophageal squamous cell cancer', 'Disease', (179, 210))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('increased risk of hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (80, 122))	('gastric', 'Disease', (166, 173))	('rs4938723', 'Var', (32, 41))	('colorectal', 'Disease', (154, 164))	('esophageal squamous cell cancer', 'Disease', 'MESH:D002294', (179, 210))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (190, 210))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (98, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('hepatocellular carcinoma', 'Disease', (98, 122))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (98, 122))
68585	28415817	In the present study, we conducted a comprehensive search of the PubMed, Embase, Web of Science, Wanfang, and CNKI databases to identify all potentially eligible studies on rs4938723 polymorphism and cancer risk.	('rs4938723', 'Mutation', 'rs4938723', (173, 182))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('polymorphism', 'Var', (183, 195))	('rs4938723 polymorphism', 'Var', (173, 195))	('cancer', 'Disease', 'MESH:D009369', (200, 206))	('cancer', 'Disease', (200, 206))
68586	28415817	The last search was updated on December 22, 2016, by using the following search terms: (pre-mir-34b/c OR pri-miR-34b/c OR mir-34b/c OR microRNA-34b/c OR rs4938723), (gene OR polymorphism OR allele OR variation), and (cancer OR carcinoma OR tumor).	('mir-34b', 'Gene', (92, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (227, 236))	('carcinoma OR tumor', 'Disease', 'MESH:D009369', (227, 245))	('miR-34b', 'Gene', (109, 116))	('carcinoma OR tumor', 'Disease', (227, 245))	('mir-34b', 'Gene', (122, 129))	('microRNA-34b', 'Gene', (135, 147))	('miR-34b', 'Gene', '407041', (109, 116))	('rs4938723', 'Var', (153, 162))	('cancer', 'Disease', (217, 223))	('cancer', 'Disease', 'MESH:D009369', (217, 223))	('microRNA-34b', 'Gene', '407041', (135, 147))	('mir-34b', 'Gene', '407041', (92, 99))	('rs4938723', 'Mutation', 'rs4938723', (153, 162))	('mir-34b', 'Gene', '407041', (122, 129))	('tumor', 'Phenotype', 'HP:0002664', (240, 245))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))
68587	28415817	All of the selected studies in our meta-analysis conformed to all of the following criteria: (1) case-control studies; (2) evaluation of rs4938723 polymorphism and cancer risk; (3) sufficient genotype frequency data for calculating the OR and 95% CI; and (4) genotype distribution of the control group that was consistent with the HWE.	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('rs4938723', 'Mutation', 'rs4938723', (137, 146))	('cancer', 'Disease', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('rs4938723', 'Var', (137, 146))
68591	28415817	The strength of the association between rs4938723 polymorphism and cancer risk was assessed by ORs and corresponding 95% CIs under five different genetic models.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('rs4938723', 'Mutation', 'rs4938723', (40, 49))	('cancer', 'Disease', (67, 73))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('rs4938723', 'Var', (40, 49))
68593	28415817	In summary, our study shows that the miR-34b/c gene rs4938723 is a susceptible locus for cancer.	('miR-34b', 'Gene', (37, 44))	('rs4938723', 'Var', (52, 61))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('miR-34b', 'Gene', '407041', (37, 44))	('rs4938723', 'Mutation', 'rs4938723', (52, 61))	('cancer', 'Disease', (89, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
68594	28415817	The rs4938723 polymorphisms are associated with an increased risk for hepatocellular carcinoma, but decreased risk for colorectal, gastric, and esophageal squamous cell cancer.	('rs4938723', 'Var', (4, 13))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (155, 175))	('colorectal', 'Disease', 'MESH:D015179', (119, 129))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (70, 94))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (70, 94))	('esophageal squamous cell cancer', 'Disease', (144, 175))	('hepatocellular carcinoma', 'Disease', (70, 94))	('rs4938723', 'Mutation', 'rs4938723', (4, 13))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('decreased', 'NegReg', (100, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('gastric', 'Disease', (131, 138))	('colorectal', 'Disease', (119, 129))	('increased risk for hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (51, 94))	('esophageal squamous cell cancer', 'Disease', 'MESH:D002294', (144, 175))
68610	31172284	In the adjuvant setting for NSCLC, reduced RDI and dose reductions have been associated with decreased survival.	('survival', 'MPA', (103, 111))	('NSCLC', 'Disease', (28, 33))	('dose reductions', 'Var', (51, 66))	('reduced', 'NegReg', (35, 42))	('NSCLC', 'Disease', 'MESH:D002289', (28, 33))	('RDI', 'MPA', (43, 46))	('decreased', 'NegReg', (93, 102))	('NSCLC', 'Phenotype', 'HP:0030358', (28, 33))
68612	31172284	A retrospective analysis of elderly patients with advanced NSCLC reported that patients who received RDI >= 80% experienced statistically higher response rates and overall survival (OS) than patients who received RDI < 80%.	('NSCLC', 'Disease', 'MESH:D002289', (59, 64))	('patients', 'Species', '9606', (191, 199))	('patients', 'Species', '9606', (36, 44))	('NSCLC', 'Phenotype', 'HP:0030358', (59, 64))	('response rates', 'CPA', (145, 159))	('patients', 'Species', '9606', (79, 87))	('NSCLC', 'Disease', (59, 64))	('higher', 'PosReg', (138, 144))	('RDI >= 80%', 'Var', (101, 111))	('overall survival', 'CPA', (164, 180))
68638	31172284	In brief, Kaplan-Meier unadjusted survival analyses and log-rank tests were performed to compare OS between patients with NSCLC who had chemotherapy dose delays >= 7 days versus < 7 days, dose reductions >= 15% versus < 15%, and RDI < 85% versus >= 85%.	('NSCLC', 'Disease', 'MESH:D002289', (122, 127))	('NSCLC', 'Phenotype', 'HP:0030358', (122, 127))	('patients', 'Species', '9606', (108, 116))	('>= 15%', 'Var', (204, 210))	('NSCLC', 'Disease', (122, 127))
68659	31172284	ECOG PS 1 versus 0 (HR, 1.364 [95% CI, 1.255-1.483]) and 2 versus 0 (HR, 1.766 [1.498-2.081]) and hemoglobin < 12 versus >= 12 g/dL (HR, 1.205 [1.111-1.308]) were significantly associated with increased risk of death, whereas adenocarcinoma versus squamous cell carcinoma tumor subgroup (HR, 0.762 [0.685-0.847]) was significantly associated with a decreased risk of death.	('tumor', 'Phenotype', 'HP:0002664', (272, 277))	('hemoglobin', 'Var', (98, 108))	('death', 'Disease', (211, 216))	('adenocarcinoma versus squamous cell carcinoma tumor', 'Disease', 'MESH:D018307', (226, 277))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (248, 271))	('death', 'Disease', 'MESH:D003643', (367, 372))	('carcinoma', 'Phenotype', 'HP:0030731', (231, 240))	('death', 'Disease', (367, 372))	('carcinoma', 'Phenotype', 'HP:0030731', (262, 271))	('death', 'Disease', 'MESH:D003643', (211, 216))
68663	31172284	RDI >=85% was significantly associated with a 17.6% decrease in risk of death (P = 0.0062).	('death', 'Disease', 'MESH:D003643', (72, 77))	('death', 'Disease', (72, 77))	('RDI >=85%', 'Var', (0, 9))	('decrease', 'NegReg', (52, 60))
68666	31172284	A recent retrospective evaluation of dose intensity for the treatment of a variety of non-metastatic cancers in the community setting (that also used the iKnowMed EHR database) found that dose delay >= 7 days, dose reduction >= 15%, and RDI < 85% were frequent, including among patients treated with myelosuppressive chemotherapy regimens for NSCLC.	('>= 15%', 'Var', (225, 231))	('NSCLC', 'Disease', 'MESH:D002289', (343, 348))	('cancers', 'Disease', 'MESH:D009369', (101, 108))	('cancers', 'Phenotype', 'HP:0002664', (101, 108))	('cancers', 'Disease', (101, 108))	('dose', 'MPA', (210, 214))	('dose', 'MPA', (188, 192))	('NSCLC', 'Phenotype', 'HP:0030358', (343, 348))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('RDI', 'MPA', (237, 240))	('patients', 'Species', '9606', (278, 286))	('NSCLC', 'Disease', (343, 348))
68673	31172284	RDI < 85% was not significantly associated with an increased risk of death in the univariable analysis; multivariable analysis suggested that RDI < 85% was significantly associated with an 18% increased risk of death.	('death', 'Disease', (211, 216))	('death', 'Disease', 'MESH:D003643', (69, 74))	('death', 'Disease', (69, 74))	('RDI < 85%', 'Var', (142, 151))	('death', 'Disease', 'MESH:D003643', (211, 216))
68679	31172284	Dose delays, dose reductions, and reduced RDI were more frequent in patients receiving treatment with carboplatin + gemcitabine or carboplatin + paclitaxel than the other chemotherapy regimens analyzed in this study.	('gemcitabine', 'Chemical', 'MESH:C056507', (116, 127))	('reduced', 'NegReg', (34, 41))	('paclitaxel', 'Chemical', 'MESH:D017239', (145, 155))	('carboplatin', 'Chemical', 'MESH:D016190', (102, 113))	('dose reductions', 'Var', (13, 28))	('patients', 'Species', '9606', (68, 76))	('carboplatin', 'Chemical', 'MESH:D016190', (131, 142))	('RDI', 'MPA', (42, 45))
68684	31172284	Our results demonstrating the relationship between RDI < 85% and an increased risk of death in the multivariable analysis are consistent with results from an earlier study that found significantly reduced OS (7 versus 10 months) in patients with advanced NSCLC who received RDI < 80% versus RDI > 80%.	('NSCLC', 'Disease', (255, 260))	('patients', 'Species', '9606', (232, 240))	('NSCLC', 'Disease', 'MESH:D002289', (255, 260))	('reduced', 'NegReg', (197, 204))	('death', 'Disease', 'MESH:D003643', (86, 91))	('RDI < 80%', 'Var', (274, 283))	('death', 'Disease', (86, 91))	('NSCLC', 'Phenotype', 'HP:0030358', (255, 260))
68685	31172284	They are also similar to those from another study in patients with advanced epithelial ovarian cancer treated with platinum-based chemotherapy in which delivered RDI < 85% was associated with significantly reduced OS compared with delivered RDI > 85%.	('advanced epithelial ovarian cancer', 'Disease', 'MESH:D010051', (67, 101))	('reduced', 'NegReg', (206, 213))	('< 85%', 'Var', (166, 171))	('patients', 'Species', '9606', (53, 61))	('platinum', 'Chemical', 'MESH:D010984', (115, 123))	('ovarian cancer', 'Phenotype', 'HP:0100615', (87, 101))	('epithelial ovarian cancer', 'Phenotype', 'HP:0025318', (76, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('advanced epithelial ovarian cancer', 'Disease', (67, 101))
68710	31413592	Diabetes and low FBG could be important predictors of death in patients with NSCLC.	('NSCLC', 'Disease', 'MESH:D002289', (77, 82))	('death', 'Disease', 'MESH:D003643', (54, 59))	('FBG', 'Gene', (17, 20))	('death', 'Disease', (54, 59))	('low', 'Var', (13, 16))	('Diabetes', 'Disease', 'MESH:D003920', (0, 8))	('patients', 'Species', '9606', (63, 71))	('NSCLC', 'Disease', (77, 82))	('Diabetes', 'Disease', (0, 8))
68748	31413592	For non-diabetic cases, FBG levels were categorized according to the following tertiles: <91 , 91-101 (reference), and >101 mg/dL.	('>101 mg/dL', 'Var', (119, 129))	('diabetic', 'Disease', 'MESH:D003920', (8, 16))	('<91', 'Var', (89, 92))	('91-101', 'Var', (95, 101))	('diabetic', 'Disease', (8, 16))
68750	31413592	The first model was adjusted for patient demographic and behavioral characteristics, including age at baseline interview (years), sex, body mass index (kg/m2), albumin (<35 g/L or >=35 g/L), family history of cancer (yes or no), patient history of chronic obstructive pulmonary disease (yes or no), smoking status (never smoker, former smoker, or current smoker), and drinking habit (yes or no).	('patient', 'Species', '9606', (33, 40))	('chronic obstructive pulmonary disease', 'Phenotype', 'HP:0006510', (248, 285))	('obstructive pulmonary disease', 'Phenotype', 'HP:0006536', (256, 285))	('cancer', 'Disease', 'MESH:D009369', (209, 215))	('chronic obstructive pulmonary disease', 'Disease', 'MESH:D029424', (248, 285))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))	('behavioral characteristics', 'Phenotype', 'HP:0000708', (57, 83))	('<35 g/L', 'Var', (169, 176))	('chronic obstructive pulmonary disease', 'Disease', (248, 285))	('cancer', 'Disease', (209, 215))	('patient', 'Species', '9606', (229, 236))
68777	31413592	In general, low FBG was significantly associated with malnutrition of patients with NSCLC and hence resulting poor survival in patients with NSCLC.	('patients', 'Species', '9606', (70, 78))	('malnutrition', 'Disease', (54, 66))	('low', 'Var', (12, 15))	('malnutrition', 'Disease', 'MESH:D044342', (54, 66))	('associated', 'Reg', (38, 48))	('survival', 'MPA', (115, 123))	('malnutrition', 'Phenotype', 'HP:0004395', (54, 66))	('NSCLC', 'Disease', (141, 146))	('NSCLC', 'Disease', (84, 89))	('patients', 'Species', '9606', (127, 135))	('NSCLC', 'Disease', 'MESH:D002289', (141, 146))	('FBG', 'Gene', (16, 19))	('poor', 'NegReg', (110, 114))	('NSCLC', 'Disease', 'MESH:D002289', (84, 89))
68780	31413592	Further studies are needed to investigate the underlying mechanisms by which low FBG levels increase mortality risk in NSCLC patients.	('NSCLC', 'Disease', 'MESH:D002289', (119, 124))	('low', 'Var', (77, 80))	('mortality', 'MPA', (101, 110))	('increase', 'PosReg', (92, 100))	('NSCLC', 'Disease', (119, 124))	('FBG', 'Gene', (81, 84))	('patients', 'Species', '9606', (125, 133))
68810	32576817	Herein, we will review the role of CSCs and how CSCs result in oral cancer relapse and metastasis after radiotherapy, as well as the potential mechanisms involved and relevant therapeutic targets.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('oral cancer', 'Disease', 'MESH:D009369', (63, 74))	('metastasis', 'CPA', (87, 97))	('result in', 'Reg', (53, 62))	('CSCs', 'Var', (48, 52))	('oral cancer', 'Disease', (63, 74))
68818	32576817	Some studies indicate that the tumorigenicity of dual-marker-positive cells in vivo is higher than that of single-marker-positive cells, as is their resistance to cancer treatment.	('tumorigenicity', 'CPA', (31, 45))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('dual-marker-positive', 'Var', (49, 69))	('cancer', 'Disease', (163, 169))	('cancer', 'Disease', 'MESH:D009369', (163, 169))	('higher', 'PosReg', (87, 93))
68836	32576817	Radiotherapy can not only cause dormant CSCs to enter the cell cycle but also induce them to develop a series of malignant phenotypes and carcinogenic metabolism.	('induce', 'Reg', (78, 84))	('cause', 'Reg', (26, 31))	('carcinogenic metabolism', 'Disease', (138, 161))	('Radiotherapy', 'Var', (0, 12))	('develop', 'PosReg', (93, 100))	('carcinogenic metabolism', 'Disease', 'MESH:D008659', (138, 161))
68839	32576817	It has been reported in breast cancer that the absolute number of CSCs is elevated after exposure to ionising radiation, which is not able to be simply explained by the preferential killing of non-tumorigenic cells by ionising radiation.	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('breast cancer', 'Disease', 'MESH:D001943', (24, 37))	('breast cancer', 'Phenotype', 'HP:0003002', (24, 37))	('elevated', 'PosReg', (74, 82))	('breast cancer', 'Disease', (24, 37))	('ionising radiation', 'Var', (101, 119))
68841	32576817	Other scholars also observed that the expression of Sox2, Oct4 and Nanog was upregulated in lymphoma cells with p53 mutations after radiation.	('lymphoma', 'Disease', (92, 100))	('Sox2', 'Gene', (52, 56))	('upregulated', 'PosReg', (77, 88))	('expression', 'MPA', (38, 48))	('Oct4', 'Gene', (58, 62))	('Nanog', 'Gene', '79923', (67, 72))	('lymphoma', 'Disease', 'MESH:D008223', (92, 100))	('lymphoma', 'Phenotype', 'HP:0002665', (92, 100))	('Nanog', 'Gene', (67, 72))	('p53', 'Gene', (112, 115))	('mutations', 'Var', (116, 125))	('p53', 'Gene', '7157', (112, 115))	('Sox2', 'Gene', '6657', (52, 56))	('Oct4', 'Gene', '5460', (58, 62))
68869	32576817	Both cancer cells and their surrounding tumour microenvironment play a crucial role in cancer progression, and CSCs initiate tumorigenesis and enhance tumour development.	('tumorigenesis', 'CPA', (125, 138))	('cancer', 'Disease', (87, 93))	('enhance', 'PosReg', (143, 150))	('cancer', 'Disease', 'MESH:D009369', (5, 11))	('tumour', 'Disease', 'MESH:D009369', (40, 46))	('tumour', 'Phenotype', 'HP:0002664', (151, 157))	('tumour', 'Disease', (40, 46))	('cancer', 'Disease', (5, 11))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('initiate', 'PosReg', (116, 124))	('CSCs', 'Var', (111, 115))	('tumour', 'Disease', 'MESH:D009369', (151, 157))	('tumour', 'Disease', (151, 157))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))	('tumour', 'Phenotype', 'HP:0002664', (40, 46))	('cancer', 'Disease', 'MESH:D009369', (87, 93))
68883	32576817	Therefore, the alteration of CSC division post-radiotherapy together with their innate strong self-renewal ability can guarantee the rapid proliferation of surviving CSCs after radiotherapy, further increasing the possibility of tumour relapse.	('self-renewal ability', 'CPA', (94, 114))	('tumour', 'Disease', 'MESH:D009369', (229, 235))	('tumour', 'Disease', (229, 235))	('increasing', 'PosReg', (199, 209))	('rapid proliferation', 'CPA', (133, 152))	('CSC division', 'CPA', (29, 41))	('tumour', 'Phenotype', 'HP:0002664', (229, 235))	('alteration', 'Var', (15, 25))
68907	32576817	In a tumour angiogenesis SCID mouse model, it was observed that specific ablation of tumour-associated endothelial cells resulted in a reduction in head and neck CSCs.	('tumour', 'Disease', 'MESH:D009369', (5, 11))	('reduction', 'NegReg', (135, 144))	('tumour', 'Disease', 'MESH:D009369', (85, 91))	('tumour', 'Disease', (85, 91))	('tumour', 'Disease', (5, 11))	('tumour angiogenesis SCID', 'Disease', (5, 29))	('tumour angiogenesis SCID', 'Disease', 'MESH:D016510', (5, 29))	('tumour', 'Phenotype', 'HP:0002664', (5, 11))	('tumour', 'Phenotype', 'HP:0002664', (85, 91))	('mouse', 'Species', '10090', (30, 35))	('ablation', 'Var', (73, 81))
68924	32576817	In addition, a large number of TAMs were found around CD44+ALDH+ cells in colon cancer and CD133+ALDH+ cells in lung cancer, which synergistically activated Sonic Hedgehog pathways in CSCs with IL-6 secretion.	('CD133', 'Gene', '8842', (91, 96))	('Sonic Hedgehog', 'Gene', (157, 171))	('colon cancer', 'Phenotype', 'HP:0003003', (74, 86))	('Sonic Hedgehog', 'Gene', '6469', (157, 171))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('lung cancer', 'Disease', (112, 123))	('lung cancer', 'Phenotype', 'HP:0100526', (112, 123))	('colon cancer', 'Disease', 'MESH:D015179', (74, 86))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('colon cancer', 'Disease', (74, 86))	('TAMs', 'Chemical', '-', (31, 35))	('lung cancer', 'Disease', 'MESH:D008175', (112, 123))	('CD44+ALDH+', 'Var', (54, 64))	('CD133', 'Gene', (91, 96))	('activated', 'PosReg', (147, 156))
68934	32576817	It is well known that the accumulation of ROS can result in DNA damage in the majority of tumour cells in response to radiotherapy.	('result in', 'Reg', (50, 59))	('ROS', 'Chemical', 'MESH:D017382', (42, 45))	('DNA damage', 'MPA', (60, 70))	('tumour', 'Phenotype', 'HP:0002664', (90, 96))	('ROS', 'Protein', (42, 45))	('tumour', 'Disease', 'MESH:D009369', (90, 96))	('accumulation', 'Var', (26, 38))	('tumour', 'Disease', (90, 96))
68935	32576817	ROS can cause structural damage when they occur within a 2-nanometre range of cellular DNA.	('cause', 'Reg', (8, 13))	('structural damage', 'CPA', (14, 31))	('ROS', 'Var', (0, 3))	('ROS', 'Chemical', 'MESH:D017382', (0, 3))
68936	32576817	Notably, the ability of ROS to result in DNA damage is attributed to the oxidative stress of irradiated cells; therefore, hypoxic cells have stronger radiation resistance than cells in a normoxic environment.	('radiation resistance', 'CPA', (150, 170))	('ROS', 'Chemical', 'MESH:D017382', (24, 27))	('hypoxic', 'Var', (122, 129))	('oxidative stress', 'Phenotype', 'HP:0025464', (73, 89))	('stronger', 'PosReg', (141, 149))	('DNA damage', 'MPA', (41, 51))
68937	32576817	Therefore, IR-induced additional ROS are less lethal to hypoxic cells and may unexpectedly promote their malignant phenotype.	('malignant phenotype', 'CPA', (105, 124))	('promote', 'PosReg', (91, 98))	('ROS', 'Var', (33, 36))	('ROS', 'Chemical', 'MESH:D017382', (33, 36))
68943	32576817	It has been reported that pancreatic cancer patients with high CD44 expression had significantly shorter overall survival than those with low CD44 expression.	('patients', 'Species', '9606', (44, 52))	('overall survival', 'MPA', (105, 121))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (26, 43))	('pancreatic cancer', 'Disease', (26, 43))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('shorter', 'NegReg', (97, 104))	('high', 'Var', (58, 62))	('CD44', 'Gene', (63, 67))	('pancreatic cancer', 'Disease', 'MESH:D010190', (26, 43))
68944	32576817	An anti-CD44 antibody could inhibit the growth and metastasis of transplanted pancreatic tumours in mice, and the anti-CD44 antibody combined with radiotherapy could reduce tumour relapse after radiotherapy.	('tumour', 'Disease', (173, 179))	('tumours', 'Phenotype', 'HP:0002664', (89, 96))	('pancreatic tumours', 'Disease', 'MESH:D010190', (78, 96))	('tumour', 'Disease', 'MESH:D009369', (173, 179))	('tumour', 'Phenotype', 'HP:0002664', (89, 95))	('mice', 'Species', '10090', (100, 104))	('tumour', 'Disease', 'MESH:D009369', (89, 95))	('tumour', 'Disease', (89, 95))	('pancreatic tumours', 'Disease', (78, 96))	('tumour', 'Phenotype', 'HP:0002664', (173, 179))	('anti-CD44', 'Var', (114, 123))	('reduce', 'NegReg', (166, 172))	('inhibit', 'NegReg', (28, 35))
68945	32576817	In preclinical trials in HNSCC patients, it has been shown that combined application of both an anti-CD44v6 monoclonal antibody and maytansinoid (DM1) in patients together with segmentation radiation could significantly improve the control of permanent local tumours.	('tumours', 'Phenotype', 'HP:0002664', (259, 266))	('DM1', 'Chemical', '-', (146, 149))	('tumours', 'Disease', 'MESH:D009369', (259, 266))	('HNSCC', 'Phenotype', 'HP:0012288', (25, 30))	('anti-CD44v6', 'Var', (96, 107))	('patients', 'Species', '9606', (154, 162))	('tumours', 'Disease', (259, 266))	('improve', 'PosReg', (220, 227))	('maytansinoid', 'Chemical', '-', (132, 144))	('tumour', 'Phenotype', 'HP:0002664', (259, 265))	('patients', 'Species', '9606', (31, 39))
68946	32576817	Additionally, in a previous clinical study of patients with refractory squamous cell carcinoma of the head and neck or oesophagus, it was observed that combined treatment with bivatuzumab, a human monoclonal antibody against CD44v6 and mertansine (DM1), led to better efficacy than monotherapy with either agent, although this clinical study was discontinued after a subject died of toxic epidermal necrolysis.	('DM1', 'Chemical', '-', (248, 251))	('patients', 'Species', '9606', (46, 54))	('bivatuzumab', 'Chemical', 'MESH:C479239', (176, 187))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (71, 94))	('refractory squamous cell carcinoma', 'Disease', (60, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('toxic epidermal necrolysis', 'Disease', (383, 409))	('human', 'Species', '9606', (191, 196))	('efficacy', 'MPA', (268, 276))	('bivatuzumab', 'Var', (176, 187))	('refractory squamous cell carcinoma', 'Disease', 'MESH:D002294', (60, 94))	('mertansine', 'Chemical', 'MESH:D008453', (236, 246))
68950	32576817	Their innate self-renewal ability is one of the most important mechanisms of CSCs causing tumour relapse after radiotherapy.	('tumour', 'Phenotype', 'HP:0002664', (90, 96))	('tumour', 'Disease', 'MESH:D009369', (90, 96))	('causing', 'Reg', (82, 89))	('CSCs', 'Var', (77, 81))	('tumour', 'Disease', (90, 96))
68953	32576817	In addition, BMI1 has been found to be highly expressed by CD133+ glioblastoma cells, which promote DNA repair by preferentially activating the DNA double-strand break (DSB) response mechanism; in addition, BMI1 deletion can seriously inhibit the DSB response, resulting in increased sensitivity to radiation, suggesting that pharmacological inhibition of BMI1 combined with radiotherapy may provide an effective means of targeting CSCs.	('glioblastoma', 'Phenotype', 'HP:0012174', (66, 78))	('DSB response', 'MPA', (247, 259))	('CD133', 'Gene', '8842', (59, 64))	('deletion', 'Var', (212, 220))	('inhibit', 'NegReg', (235, 242))	('glioblastoma', 'Disease', (66, 78))	('glioblastoma', 'Disease', 'MESH:D005909', (66, 78))	('CD133', 'Gene', (59, 64))	('sensitivity to radiation', 'MPA', (284, 308))	('increased', 'PosReg', (274, 283))	('BMI1', 'Gene', (207, 211))
68954	32576817	A similar finding of BMI1 targeting CSCs was observed in CD44+ nasopharyngeal carcinoma: when overexpressed BMI1 was knocked out in CD44+ cells, DNA damage repair was inhibited, and cell apoptosis increased after radiotherapy.	('inhibited', 'NegReg', (167, 176))	('carcinoma', 'Disease', 'MESH:D009369', (78, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('DNA damage repair', 'MPA', (145, 162))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (63, 87))	('increased', 'PosReg', (197, 206))	('cell apoptosis', 'CPA', (182, 196))	('carcinoma', 'Disease', (78, 87))	('BMI1', 'Gene', (108, 112))	('knocked out', 'Var', (117, 128))
68955	32576817	In addition, in colorectal cancer, downregulation of BMI1 inhibited the self-renewal ability of CSCs, leading to the loss of their tumorigenic potential, while the use of a small molecular inhibitor of BMI1 could cause long-term damage to colorectal xenograft tumours in mice.	('tumour', 'Phenotype', 'HP:0002664', (260, 266))	('tumorigenic potential', 'CPA', (131, 152))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('loss', 'NegReg', (117, 121))	('mice', 'Species', '10090', (271, 275))	('BMI1', 'Gene', (53, 57))	('colorectal cancer', 'Disease', 'MESH:D015179', (16, 33))	('small molecular inhibitor', 'Var', (173, 198))	('colorectal xenograft tumours', 'Disease', (239, 267))	('colorectal xenograft tumours', 'Disease', 'MESH:D015179', (239, 267))	('self-renewal ability of CSCs', 'CPA', (72, 100))	('BMI1', 'Gene', (202, 206))	('downregulation', 'NegReg', (35, 49))	('inhibited', 'NegReg', (58, 67))	('colorectal cancer', 'Phenotype', 'HP:0003003', (16, 33))	('colorectal cancer', 'Disease', (16, 33))	('tumours', 'Phenotype', 'HP:0002664', (260, 267))
68958	32576817	All these results suggest that strategies targeting CSC self-renewal, such as BMI1 inhibition, have great potential to be combined with radiotherapy in oral cancer for better prognosis.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('BMI1', 'Gene', (78, 82))	('oral cancer', 'Disease', 'MESH:D009369', (152, 163))	('inhibition', 'Var', (83, 93))	('oral cancer', 'Disease', (152, 163))
68963	32576817	Notably, metformin has been shown to inhibit EMT in a variety of tumours, correspon-dingly contributing to improving the efficiency of radiotherapy in mice xenografted with prostate cancer cells and colorectal cancer cells, as well as the radiosensitivity of breast cancer and prostate cancer patients, as observed in retrospective studies.	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('colorectal cancer', 'Disease', 'MESH:D015179', (199, 216))	('breast cancer', 'Phenotype', 'HP:0003002', (259, 272))	('improving', 'PosReg', (107, 116))	('tumours', 'Disease', (65, 72))	('EMT', 'CPA', (45, 48))	('cancer', 'Phenotype', 'HP:0002664', (286, 292))	('colorectal cancer', 'Disease', (199, 216))	('tumours', 'Phenotype', 'HP:0002664', (65, 72))	('tumours', 'Disease', 'MESH:D009369', (65, 72))	('breast cancer', 'Disease', 'MESH:D001943', (259, 272))	('metformin', 'Var', (9, 18))	('breast cancer', 'Disease', (259, 272))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('metformin', 'Chemical', 'MESH:D008687', (9, 18))	('prostate cancer', 'Disease', 'MESH:D011471', (173, 188))	('inhibit', 'NegReg', (37, 44))	('tumour', 'Phenotype', 'HP:0002664', (65, 71))	('prostate cancer', 'Phenotype', 'HP:0012125', (173, 188))	('prostate cancer', 'Disease', 'MESH:D011471', (277, 292))	('prostate cancer', 'Disease', (173, 188))	('mice', 'Species', '10090', (151, 155))	('prostate cancer', 'Phenotype', 'HP:0012125', (277, 292))	('colorectal cancer', 'Phenotype', 'HP:0003003', (199, 216))	('radiotherapy', 'CPA', (135, 147))	('prostate cancer', 'Disease', (277, 292))	('cancer', 'Phenotype', 'HP:0002664', (266, 272))	('patients', 'Species', '9606', (293, 301))
68970	32576817	Additionally, the specific ablation of tumour-related endothelial cells induced by caspase-9 leads to a reduction in CSCs in head and neck cancers, suggesting that targeted elimination of the CSC perivascular niche combined with radiotherapy may be a promising oral cancer treatment.	('CSCs', 'Disease', (117, 121))	('reduction', 'NegReg', (104, 113))	('cancers', 'Phenotype', 'HP:0002664', (139, 146))	('tumour', 'Disease', (39, 45))	('tumour', 'Phenotype', 'HP:0002664', (39, 45))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('caspase-9', 'Gene', '842', (83, 92))	('oral cancer', 'Disease', (261, 272))	('head and neck cancer', 'Phenotype', 'HP:0012288', (125, 145))	('perivascular niche', 'Phenotype', 'HP:0012520', (196, 214))	('ablation', 'Var', (27, 35))	('cancer', 'Phenotype', 'HP:0002664', (266, 272))	('head and neck cancers', 'Phenotype', 'HP:0012288', (125, 146))	('head and neck cancers', 'Disease', 'MESH:D006258', (125, 146))	('tumour', 'Disease', 'MESH:D009369', (39, 45))	('caspase-9', 'Gene', (83, 92))	('oral cancer', 'Disease', 'MESH:D009369', (261, 272))
68984	32391279	RNA sequencing data were analyzed from 8 papillary high-grade NMIUTUC specimens consisting of 4 CK14-positive and 4 CK14-negative tumors.	('tumors', 'Disease', (130, 136))	('tumors', 'Disease', 'MESH:D009369', (130, 136))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('CK14-positive', 'Var', (96, 109))
68985	32391279	Results: CK14 positivity was associated with a high TNM stage (p < 0.001) and a high World Health Organization grade (p = 0.003).	('positivity', 'Var', (14, 24))	('TNM', 'Gene', (52, 55))	('CK14', 'Gene', (9, 13))	('TNM', 'Gene', '10178', (52, 55))
68986	32391279	Survival analysis showed that CK14 positivity was significantly associated with poor progression-free survival (p = 0.015; hazard ratio [HR] = 2.990; 95% confidence interval [CI] = 1.180-7.580) and was marginally associated with poor cancer-specific survival (p = 0.052; HR = 3.77; 95% CI = 0.900-15.780).	('CK14', 'Protein', (30, 34))	('progression-free survival', 'CPA', (85, 110))	('poor', 'NegReg', (80, 84))	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('poor', 'NegReg', (229, 233))	('positivity', 'Var', (35, 45))	('cancer', 'Disease', 'MESH:D009369', (234, 240))	('rat', 'Species', '10116', (130, 133))	('cancer', 'Disease', (234, 240))
68987	32391279	Gene set enrichment analysis demonstrated that the CK14-positive tumors were associated with a basal subtype of breast cancer, squamous cell carcinoma development, p40, tumor necrosis factor alpha-nuclear factor-kappaB, and p53 pathways, and embryonic stem cells; these characteristics are reminiscent of the BASQ subtype.	('breast cancer', 'Disease', 'MESH:D001943', (112, 125))	('p53', 'Gene', '7157', (224, 227))	('breast cancer', 'Disease', (112, 125))	('tumors', 'Disease', (65, 71))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (127, 150))	('p53', 'Gene', (224, 227))	('nuclear factor-kappaB', 'Gene', '4790', (197, 218))	('p40', 'Gene', '3578', (164, 167))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('nuclear factor-kappaB', 'Gene', (197, 218))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (127, 150))	('associated', 'Reg', (77, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('p40', 'Gene', (164, 167))	('tumor necrosis', 'Disease', 'MESH:D009336', (169, 183))	('rat', 'Species', '10116', (36, 39))	('CK14-positive', 'Var', (51, 64))	('squamous cell carcinoma', 'Disease', (127, 150))	('tumor necrosis', 'Disease', (169, 183))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('breast cancer', 'Phenotype', 'HP:0003002', (112, 125))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))
68988	32391279	In addition, with a p < 0.05 and  fold change  >=2 as the cutoffs, we identified 178 differentially expressed genes when comparing CK14-positive and CK14-negative tumors.	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('tumors', 'Disease', (163, 169))	('tumors', 'Phenotype', 'HP:0002664', (163, 169))	('tumors', 'Disease', 'MESH:D009369', (163, 169))	('CK14-positive', 'Var', (131, 144))
68990	32391279	Consistent with these results, we demonstrated that the mean Ki-67 proliferative index was higher in CK14-positive tumors than it was in CK14-negative tumors (2.3 vs. 0.8%, respectively, p = 0.002).	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('higher', 'PosReg', (91, 97))	('tumors', 'Disease', (151, 157))	('tumors', 'Disease', 'MESH:D009369', (151, 157))	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('rat', 'Species', '10116', (74, 77))	('tumors', 'Disease', (115, 121))	('tumors', 'Disease', 'MESH:D009369', (115, 121))	('proliferative index', 'MPA', (67, 86))	('rat', 'Species', '10116', (41, 44))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('CK14-positive', 'Var', (101, 114))	('Ki-67', 'Gene', (61, 66))
68991	32391279	Conclusion: CK14-positive papillary NMIUTUC is an aggressive subtype with BASQ-like molecular characteristics and dynamic proliferative activity.	('rat', 'Species', '10116', (129, 132))	('CK14-positive', 'Var', (12, 25))	('papillary NMIUTUC', 'Disease', (26, 43))
69000	32391279	In line with these results when studying the urinary bladder, we previously reported that papillary non-muscle-invasive upper tract urothelial carcinoma (NMIUTUC) with luminal-like, CK5/6-negative/CK20-positive, or CD44-negative/CK20-positive, immunophenotypes had distinctly poor prognoses that were probably associated with altered cell adhesion and late cell cycle/proliferation functions.	('luminal', 'Chemical', 'MESH:D010634', (168, 175))	('CD44', 'Gene', '960', (215, 219))	('CK5/6', 'Gene', (182, 187))	('luminal-like', 'Var', (168, 180))	('CD44', 'Gene', (215, 219))	('CK20', 'Gene', '54474', (197, 201))	('CK20', 'Gene', (229, 233))	('CK20', 'Gene', '54474', (229, 233))	('CK20', 'Gene', (197, 201))	('carcinoma', 'Phenotype', 'HP:0030731', (143, 152))	('rat', 'Species', '10116', (375, 378))	('CK5/6', 'Gene', '3852', (182, 187))	('papillary non-muscle-invasive upper tract urothelial carcinoma', 'Disease', 'MESH:D012141', (90, 152))
69001	32391279	Despite these conflicting results observed regarding some of the subtype-defining markers in early urothelial carcinoma, high KRT14 levels were independently prognostic of poor survival both in NMIBC and in MIBC.	('NMIBC', 'Disease', (194, 199))	('MIBC', 'Phenotype', 'HP:0006740', (207, 211))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('poor', 'NegReg', (172, 176))	('KRT14', 'Gene', '3861', (126, 131))	('urothelial carcinoma', 'Disease', (99, 119))	('MIBC', 'Chemical', '-', (195, 199))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (99, 119))	('MIBC', 'Phenotype', 'HP:0006740', (195, 199))	('KRT14', 'Gene', (126, 131))	('high', 'Var', (121, 125))	('MIBC', 'Chemical', '-', (207, 211))
69007	32391279	In addition, CK14 was associated with a poor prognosis of other malignancies, including breast cancer, squamous cell carcinoma, and salivary gland carcinoma, because it triggers proliferation, dedifferentiation, invasion, and metastasis of these cancers.	('dedifferentiation', 'CPA', (193, 210))	('malignancies', 'Disease', 'MESH:D009369', (64, 76))	('cancers', 'Phenotype', 'HP:0002664', (246, 253))	('malignancies', 'Disease', (64, 76))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (103, 126))	('cancers', 'Disease', (246, 253))	('salivary gland carcinoma', 'Phenotype', 'HP:0100684', (132, 156))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('triggers', 'Reg', (169, 177))	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('CK14', 'Var', (13, 17))	('salivary gland carcinoma', 'Disease', (132, 156))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (103, 126))	('breast cancer', 'Phenotype', 'HP:0003002', (88, 101))	('salivary gland carcinoma', 'Disease', 'MESH:D012468', (132, 156))	('metastasis', 'CPA', (226, 236))	('carcinoma', 'Phenotype', 'HP:0030731', (147, 156))	('proliferation', 'CPA', (178, 191))	('cancers', 'Disease', 'MESH:D009369', (246, 253))	('squamous cell carcinoma', 'Disease', (103, 126))	('invasion', 'CPA', (212, 220))	('rat', 'Species', '10116', (185, 188))	('breast cancer', 'Disease', (88, 101))	('breast cancer', 'Disease', 'MESH:D001943', (88, 101))
69009	32391279	Furthermore, because of the rarity of upper tract urothelial carcinoma, which accounts for only 5-10% of the total urothelial carcinoma, CK14 expression and its clinicopathological and molecular significance in papillary NMIUTUC has not been studied.	('urothelial carcinoma', 'Disease', (115, 135))	('CK14', 'Var', (137, 141))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (50, 70))	('upper tract urothelial carcinoma', 'Disease', (38, 70))	('upper tract urothelial carcinoma', 'Disease', 'MESH:D012141', (38, 70))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (115, 135))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))
69030	32391279	CK14 positivity (IHC tumor cell score >0) and negativity (IHC tumor cell score = 0) were designated as above.	('IHC tumor', 'Disease', 'MESH:D009369', (58, 67))	('positivity', 'Var', (5, 15))	('IHC tumor', 'Disease', 'MESH:D009369', (17, 26))	('IHC tumor', 'Disease', (58, 67))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('IHC tumor', 'Disease', (17, 26))	('CK14 positivity', 'Var', (0, 15))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
69039	32391279	CK14 positivity was associated with high (>=I) TNM stage (p < 0.001) and high WHO grade (p = 0.003).	('positivity', 'Var', (5, 15))	('CK14', 'Protein', (0, 4))	('TNM', 'Gene', (47, 50))	('TNM', 'Gene', '10178', (47, 50))	('high WHO grade', 'CPA', (73, 87))
69040	32391279	In addition, CK14 positivity was related to combined CK5/6-CK20 expression (p = 0.001), where CK5/6-negative/CK20-positive expression was more prevalent in CK14-positive tumors (45.8 vs. 23.8%).	('CK20', 'Gene', (59, 63))	('CK20', 'Gene', '54474', (59, 63))	('CK5/6', 'Gene', '3852', (94, 99))	('CK5/6', 'Gene', '3852', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('CK5/6', 'Gene', (94, 99))	('tumors', 'Disease', 'MESH:D009369', (170, 176))	('CK20', 'Gene', (109, 113))	('CK5/6', 'Gene', (53, 58))	('CK20', 'Gene', '54474', (109, 113))	('tumors', 'Phenotype', 'HP:0002664', (170, 176))	('tumors', 'Disease', (170, 176))	('CK14-positive', 'Var', (156, 169))
69048	32391279	KRT14 gene was highly expressed in CK14-positive tumors compared to CK14-negative tumors (fold change = 40.2, p = 0.035).	('tumors', 'Disease', (82, 88))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('KRT14', 'Gene', '3861', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumors', 'Disease', (49, 55))	('tumors', 'Disease', 'MESH:D009369', (49, 55))	('CK14-positive', 'Var', (35, 48))	('KRT14', 'Gene', (0, 5))
69057	32391279	In agreement with the high-grade GEP cohort, cellular growth and proliferation overrepresented the biological functions associated with CK14 expression in the low-grade NMIBC cohort, as revealed by the IPA network search (Table 3, Supplementary Figure 5) and GO analysis (Figure 3B, Supplementary Table 2).	('proliferation', 'CPA', (65, 78))	('rat', 'Species', '10116', (72, 75))	('MIBC', 'Phenotype', 'HP:0006740', (170, 174))	('overrepresented', 'PosReg', (79, 94))	('CK14', 'Gene', (136, 140))	('biological', 'MPA', (99, 109))	('cellular growth', 'CPA', (45, 60))	('MIBC', 'Chemical', '-', (170, 174))	('expression', 'Var', (141, 151))
69059	32391279	CK14-positive tumors displayed a 2.3 +- 5.36% proliferative index (mean +- standard deviation), which was higher than 0.8 +- 2.06% index of CK14-negative tumors in the prognosis cohort (Mann-Whitney U, p = 0.002) (Figure 3E).	('tumors', 'Disease', (154, 160))	('tumors', 'Disease', 'MESH:D009369', (154, 160))	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('CK14-positive', 'Var', (0, 13))	('tumors', 'Disease', (14, 20))	('rat', 'Species', '10116', (53, 56))	('higher', 'PosReg', (106, 112))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('proliferative index', 'CPA', (46, 65))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
69061	32391279	We found that CK14 positivity in papillary high-grade NMIUTUC marked transcriptional characteristics reminiscent of those in BASQ-type MIBC, including signatures of basal/stem cell and squamous cell carcinoma.	('positivity', 'Var', (19, 29))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (185, 208))	('MIBC', 'Phenotype', 'HP:0006740', (135, 139))	('squamous cell carcinoma', 'Disease', (185, 208))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (185, 208))	('CK14', 'Gene', (14, 18))	('basal/stem cell', 'CPA', (165, 180))	('MIBC', 'Chemical', '-', (135, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (199, 208))
69063	32391279	IHC staining for Ki-67 verified a much higher proliferative activity in CK14-positive tumors than what was seen in CK14-negative papillary NMIUTUC.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('higher', 'PosReg', (39, 45))	('proliferative activity', 'MPA', (46, 68))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('tumors', 'Disease', (86, 92))	('rat', 'Species', '10116', (53, 56))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('CK14-positive', 'Var', (72, 85))
69070	32391279	Consistent with these reports, we showed that CK14 positivity was associated with poor PFS in papillary NMIUTUC, which was in agreement with the characteristics of CK14-positive BASQ-type MIBC.	('MIBC', 'Chemical', '-', (188, 192))	('papillary NMIUTUC', 'Disease', (94, 111))	('CK14', 'Gene', (46, 50))	('positivity', 'Var', (51, 61))	('MIBC', 'Phenotype', 'HP:0006740', (188, 192))	('poor', 'NegReg', (82, 86))	('PFS', 'MPA', (87, 90))
69071	32391279	In addition, we demonstrated that CK14-positive papillary NMIUTUC had BASQ-like genetic features that were similar to those of basal-type breast cancer and those of squamous cell carcinoma.	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (165, 188))	('squamous cell carcinoma', 'Disease', (165, 188))	('basal-type breast cancer', 'Disease', 'MESH:D001943', (127, 151))	('CK14-positive', 'Var', (34, 47))	('rat', 'Species', '10116', (23, 26))	('basal-type breast cancer', 'Disease', (127, 151))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('breast cancer', 'Phenotype', 'HP:0003002', (138, 151))	('carcinoma', 'Phenotype', 'HP:0030731', (179, 188))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (165, 188))
69072	32391279	Furthermore, CK14-positive papillary NMIUTUC shared other molecular hallmarks of BASQ-type MIBC: activated p40, c-myc, EGFR, and NF-kappaB pathways, which mediate growth and squamous differentiation of urothelial carcinoma.	('NF-kappaB', 'Gene', (129, 138))	('squamous differentiation of urothelial carcinoma', 'Disease', (174, 222))	('c-myc', 'Gene', (112, 117))	('MIBC', 'Chemical', '-', (91, 95))	('CK14-positive', 'Var', (13, 26))	('squamous differentiation of urothelial carcinoma', 'Disease', 'MESH:D002294', (174, 222))	('p40', 'Gene', (107, 110))	('EGFR', 'Gene', '1956', (119, 123))	('c-myc', 'Gene', '4609', (112, 117))	('MIBC', 'Phenotype', 'HP:0006740', (91, 95))	('p40', 'Gene', '3578', (107, 110))	('NF-kappaB', 'Gene', '4790', (129, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (213, 222))	('EGFR', 'Gene', (119, 123))	('activated', 'PosReg', (97, 106))
69074	32391279	Network and functional enrichment analyses as well as Ki-67 IHC staining demonstrated that cellular growth and proliferative functions are particularly upregulated in CK14-positive papillary NMIUTUC, in accordance with previously reported high-risk phenotypes of NMIBC and NMIUTUC.	('upregulated', 'PosReg', (152, 163))	('cellular growth', 'CPA', (91, 106))	('rat', 'Species', '10116', (118, 121))	('rat', 'Species', '10116', (80, 83))	('proliferative functions', 'CPA', (111, 134))	('MIBC', 'Chemical', '-', (264, 268))	('MIBC', 'Phenotype', 'HP:0006740', (264, 268))	('papillary', 'Var', (181, 190))	('CK14-positive papillary', 'Var', (167, 190))
69076	32391279	Dysregulation of these genes modulates proliferation, survival, migration, EMT, or metastasis of urothelial carcinoma, and other malignancies, leading to poor prognoses of these tumors.	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('rat', 'Species', '10116', (67, 70))	('rat', 'Species', '10116', (46, 49))	('malignancies', 'Disease', (129, 141))	('tumors', 'Disease', (178, 184))	('Dysregulation', 'Var', (0, 13))	('tumors', 'Disease', 'MESH:D009369', (178, 184))	('tumors', 'Phenotype', 'HP:0002664', (178, 184))	('metastasis of urothelial carcinoma', 'Disease', (83, 117))	('proliferation', 'CPA', (39, 52))	('modulates', 'Reg', (29, 38))	('EMT', 'CPA', (75, 78))	('malignancies', 'Disease', 'MESH:D009369', (129, 141))	('migration', 'CPA', (64, 73))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('metastasis of urothelial carcinoma', 'Disease', 'MESH:D009362', (83, 117))	('survival', 'CPA', (54, 62))
69080	32391279	Likewise, varied transcription activators and activation pathways (e.g., p40, c-myc, NF-kappaB, EGFR, Wnt, and mTORC1 signaling pathways) that were enriched in CK14-positive papillary NMIUTUC are linked to proliferation and/or malignant transformation of basal cells and embryonal stem cells.	('CK14-positive', 'Var', (160, 173))	('Wnt', 'Pathway', (102, 105))	('linked', 'Reg', (196, 202))	('NF-kappaB', 'Gene', '4790', (85, 94))	('malignant transformation', 'CPA', (227, 251))	('EGFR', 'Gene', '1956', (96, 100))	('EGFR', 'Gene', (96, 100))	('malignant transformation of basal cells', 'Phenotype', 'HP:0002671', (227, 266))	('NF-kappaB', 'Gene', (85, 94))	('mTORC1', 'Gene', '382056', (111, 117))	('p40', 'Gene', (73, 76))	('rat', 'Species', '10116', (213, 216))	('p40', 'Gene', '3578', (73, 76))	('c-myc', 'Gene', '4609', (78, 83))	('c-myc', 'Gene', (78, 83))	('mTORC1', 'Gene', (111, 117))
69081	32391279	For example, silencing of p40 inhibited c-myc-mediated proliferation of urothelial carcinoma, and high p63 expression was associated with poor prognosis in NMIBC.	('c-myc', 'Gene', (40, 45))	('urothelial carcinoma', 'Disease', (72, 92))	('p40', 'Gene', '3578', (26, 29))	('NMIBC', 'Disease', (156, 161))	('inhibited', 'NegReg', (30, 39))	('MIBC', 'Chemical', '-', (157, 161))	('high', 'Var', (98, 102))	('p63', 'Gene', (103, 106))	('expression', 'MPA', (107, 117))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (72, 92))	('rat', 'Species', '10116', (62, 65))	('MIBC', 'Phenotype', 'HP:0006740', (157, 161))	('p40', 'Gene', (26, 29))	('p63', 'Gene', '8626', (103, 106))	('c-myc', 'Gene', '4609', (40, 45))	('silencing', 'Var', (13, 22))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))
69087	32391279	Interestingly, poorly differentiated properties associated with CK14 positivity might be partially opposed by our finding that CK14 positivity was associated with luminal-like CK5/6-negative/CK20-positive expression in papillary NMIUTUC.	('CK5/6', 'Gene', '3852', (176, 181))	('CK5/6', 'Gene', (176, 181))	('CK20', 'Gene', (191, 195))	('luminal', 'Chemical', 'MESH:D010634', (163, 170))	('CK20', 'Gene', '54474', (191, 195))	('CK14', 'Gene', (127, 131))	('positivity', 'Var', (132, 142))
69089	32391279	Similarly, low CK5/6 and high CK20 expression profiles were associated with high-risk phenotypes of both papillary NMIUTUC and NMIBC that exhibited altered adhesion, migration, and proliferation.	('rat', 'Species', '10116', (169, 172))	('papillary NMIUTUC', 'Disease', (105, 122))	('CK20', 'Gene', '54474', (30, 34))	('CK5/6', 'Gene', '3852', (15, 20))	('low', 'NegReg', (11, 14))	('high', 'Var', (25, 29))	('CK5/6', 'Gene', (15, 20))	('NMIBC', 'Disease', (127, 132))	('rat', 'Species', '10116', (188, 191))	('MIBC', 'Chemical', '-', (128, 132))	('MIBC', 'Phenotype', 'HP:0006740', (128, 132))	('CK20', 'Gene', (30, 34))
69090	32391279	Both CK14 and CK20 were suggested to direct the aggravation of early urothelial carcinoma via the carcinoma in situ-driven pathway.	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('urothelial carcinoma via the carcinoma', 'Disease', 'MESH:D009369', (69, 107))	('CK20', 'Gene', '54474', (14, 18))	('CK20', 'Gene', (14, 18))	('urothelial carcinoma via the carcinoma', 'Disease', (69, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (98, 115))	('CK14', 'Var', (5, 9))
69100	32391279	In conclusion, CK14 positivity represents an aggressive BASQ-like subtype in papillary NMIUTUC that is enriched with brisk proliferative activity.	('papillary NMIUTUC', 'Disease', (77, 94))	('rat', 'Species', '10116', (130, 133))	('positivity', 'Var', (20, 30))	('CK14', 'Gene', (15, 19))
69101	32391279	CK14 IHC staining is a promising biomarker that can be applied in the management of non-muscle-invasive urothelial carcinoma in daily practice, with the aim of precision oncology.	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('muscle-invasive urothelial carcinoma', 'Disease', 'MESH:D009361', (88, 124))	('CK14', 'Var', (0, 4))	('muscle-invasive urothelial carcinoma', 'Disease', (88, 124))	('oncology', 'Phenotype', 'HP:0002664', (170, 178))
69108	31118072	We examined its molecular link with SRC and MEK/ERK pathways and determined the efficacy of either MEK/ERK inhibitor PD0325901 or SRC inhibitor Dasatinib on cisplatin-resistant HNSCC inhibition.	('PD0325901', 'Chemical', 'MESH:C506614', (117, 126))	('MEK', 'Gene', '5609', (99, 102))	('SRC', 'Gene', '6714', (36, 39))	('SCC', 'Gene', (179, 182))	('SRC', 'Gene', (36, 39))	('SRC', 'Gene', '6714', (130, 133))	('SCC', 'Gene', '6317', (179, 182))	('HNSCC', 'Phenotype', 'HP:0012288', (177, 182))	('SRC', 'Gene', (130, 133))	('cisplatin', 'Chemical', 'MESH:D002945', (157, 166))	('Dasatinib', 'Chemical', 'MESH:D000069439', (144, 153))	('PD0325901', 'Var', (117, 126))	('MEK', 'Gene', (44, 47))	('MEK', 'Gene', '5609', (44, 47))	('MEK', 'Gene', (99, 102))
69111	31118072	While ETS-1 knockdown inhibited cell proliferation, migration, and invasion, it could still re-sensitize cells to cisplatin treatment.	('inhibited', 'NegReg', (22, 31))	('migration', 'CPA', (52, 61))	('invasion', 'CPA', (67, 75))	('knockdown', 'Var', (12, 21))	('cisplatin', 'Chemical', 'MESH:D002945', (114, 123))	('ETS-1', 'Gene', (6, 11))	('ETS-1', 'Gene', '2113', (6, 11))	('cell proliferation', 'CPA', (32, 50))
69143	31118072	The following antibodies were purchased from Cell Signaling Technology: ETS-1 (CST-14069), phospho-ERK (CST-4370), ERK (CST-4348), phospho-SRC-Y416 (CST-2101), SRC (CST-2123), cleaved caspase-3 (CST-9664), and beta-actin (CST-4967).	('CST-9664', 'Var', (195, 203))	('SRC', 'Gene', (160, 163))	('caspase-3', 'Gene', (184, 193))	('ETS-1', 'Gene', '2113', (72, 77))	('SRC', 'Gene', (139, 142))	('CST-4348', 'Var', (120, 128))	('SRC', 'Gene', '6714', (139, 142))	('SRC', 'Gene', '6714', (160, 163))	('CST-4370', 'Var', (104, 112))	('caspase-3', 'Gene', '836', (184, 193))	('CST-4967', 'Var', (222, 230))	('beta-actin', 'Gene', '728378', (210, 220))	('beta-actin', 'Gene', (210, 220))	('ETS-1', 'Gene', (72, 77))	('CST-2101', 'Var', (149, 157))
69146	31118072	MEK inhibitor, PD0325901, and SRC inhibitors, Dasatinib and Saracatinib, were from Selleck Chemicals.	('PD0325901', 'Var', (15, 24))	('MEK', 'Gene', (0, 3))	('Dasatinib', 'Chemical', 'MESH:D000069439', (46, 55))	('SRC', 'Gene', '6714', (30, 33))	('PD0325901', 'Chemical', 'MESH:C506614', (15, 24))	('MEK', 'Gene', '5609', (0, 3))	('SRC', 'Gene', (30, 33))	('Saracatinib', 'Chemical', 'MESH:C515233', (60, 71))
69153	31118072	Briefly, cells (5 x 104 cells/mL) were seeded into 96-well plates for 24 h. The next day, the media were replaced with fresh media that contained the indicated concentrations of cisplatin, PD0325901, a combination of cisplatin and PD0325901, or vehicle control (DMSO).	('cisplatin', 'Chemical', 'MESH:D002945', (178, 187))	('PD0325901', 'Chemical', 'MESH:C506614', (231, 240))	('PD0325901', 'Var', (189, 198))	('DMSO', 'Chemical', 'MESH:D004121', (262, 266))	('PD0325901', 'Chemical', 'MESH:C506614', (189, 198))	('PD0325901', 'Var', (231, 240))	('cisplatin', 'Chemical', 'MESH:D002945', (217, 226))
69161	31118072	These data suggested that the Cal27CP and FaDu-CP cells were cisplatin-resistant (Fig.	('cisplatin-resistant', 'MPA', (61, 80))	('FaDu-CP', 'CPA', (42, 49))	('cisplatin', 'Chemical', 'MESH:D002945', (61, 70))	('Cal27CP', 'Var', (30, 37))
69167	31118072	The three cisplatin-resistant HNSCC cells, including Cal27CP, SCC25CP, and FaDu-CP, also showed much higher expression of ETS-1 compared to their parental partner cells, whereas UMSCC17B-CP showed lower ETS-1 expression in comparison to UMSCC17B cells (Fig.	('SCC', 'Gene', '6317', (239, 242))	('Cal27CP', 'Var', (53, 60))	('higher', 'PosReg', (101, 107))	('SCC', 'Gene', '6317', (180, 183))	('cisplatin', 'Chemical', 'MESH:D002945', (10, 19))	('SCC', 'Gene', '6317', (62, 65))	('SCC', 'Gene', (180, 183))	('ETS-1', 'Gene', (122, 127))	('ETS-1', 'Gene', '2113', (122, 127))	('SCC', 'Gene', (32, 35))	('SCC', 'Gene', (239, 242))	('expression', 'MPA', (108, 118))	('SCC', 'Gene', '6317', (32, 35))	('HNSCC', 'Phenotype', 'HP:0012288', (30, 35))	('ETS-1', 'Gene', (203, 208))	('ETS-1', 'Gene', '2113', (203, 208))	('SCC', 'Gene', (62, 65))
69172	31118072	A previous study by Liu, et al., showed that knockdown of ETS-1 by a siRNA against ETS-1 blocked the signaling and function of platelet-derived growth factor D-chain (PDGF-D).	('platelet-derived growth factor D', 'Gene', '80310', (127, 159))	('ETS-1', 'Gene', '2113', (83, 88))	('platelet-derived growth factor D', 'Gene', (127, 159))	('blocked', 'NegReg', (89, 96))	('PDGF-D', 'Gene', '80310', (167, 173))	('signaling', 'MPA', (101, 110))	('PDGF-D', 'Gene', (167, 173))	('ETS-1', 'Gene', (58, 63))	('function', 'MPA', (115, 123))	('ETS-1', 'Gene', (83, 88))	('ETS-1', 'Gene', '2113', (58, 63))	('knockdown', 'Var', (45, 54))
69175	31118072	The number of cells in ETS-1 knockdown samples was less than control samples three days after siRNA transfection (Fig.	('less', 'NegReg', (51, 55))	('ETS-1', 'Gene', (23, 28))	('ETS-1', 'Gene', '2113', (23, 28))	('knockdown', 'Var', (29, 38))
69177	31118072	We found that ETS-1 knockdown completely blocked colony formation of UMSCC74B cells and significantly decreased colony formation of Cal27CP SCC25CP cells (Fig.	('ETS-1', 'Gene', '2113', (14, 19))	('SCC', 'Gene', '6317', (140, 143))	('colony formation', 'CPA', (112, 128))	('SCC', 'Gene', (71, 74))	('blocked', 'NegReg', (41, 48))	('UMSCC74B', 'CellLine', 'CVCL:7780', (69, 77))	('ETS-1', 'Gene', (14, 19))	('knockdown', 'Var', (20, 29))	('colony formation', 'CPA', (49, 65))	('decreased', 'NegReg', (102, 111))	('SCC', 'Gene', '6317', (71, 74))	('SCC', 'Gene', (140, 143))
69178	31118072	In order to confirm the above results, we used another siRNA against ETS-1 (siRNA SMARTpool human ETS-1, L-003887, Dharmacon) to knock down ETS-1 in Cal27CP cells.	('ETS-1', 'Gene', '2113', (69, 74))	('ETS-1', 'Gene', (98, 103))	('ETS-1', 'Gene', (140, 145))	('ETS-1', 'Gene', '2113', (98, 103))	('knock down', 'Var', (129, 139))	('ETS-1', 'Gene', '2113', (140, 145))	('human', 'Species', '9606', (92, 97))	('ETS-1', 'Gene', (69, 74))
69182	31118072	Indeed, we found that knockdown of ETS-1 in SCC25 Cal27 cells also led to inhibition of cell growth in these cells (Additional file 1: Figure S1A and Figure S1B).	('cell growth in these cells', 'CPA', (88, 114))	('ETS-1', 'Gene', (35, 40))	('ETS-1', 'Gene', '2113', (35, 40))	('inhibition', 'NegReg', (74, 84))	('knockdown', 'Var', (22, 31))	('SCC25 Cal27', 'CellLine', 'CVCL:1107', (44, 55))
69186	31118072	Cell migration was significantly impaired upon ETS-1 knockdown (Fig.	('Cell migration', 'CPA', (0, 14))	('impaired', 'NegReg', (33, 41))	('knockdown', 'Var', (53, 62))	('ETS-1', 'Gene', (47, 52))	('ETS-1', 'Gene', '2113', (47, 52))
69187	31118072	In addition, knockdown of ETS-1 also significantly impaired Cal27CP invasion (Fig.	('Cal27CP', 'Var', (60, 67))	('ETS-1', 'Gene', (26, 31))	('ETS-1', 'Gene', '2113', (26, 31))	('impaired', 'NegReg', (51, 59))	('knockdown', 'Var', (13, 22))
69188	31118072	In line with these results, ETS-1 knockdown slowed cell migration and invasion in UMSCC74B cells (Additional file 1: Figure S2A and Figure S2B).	('slowed', 'NegReg', (44, 50))	('UMSCC74B', 'CellLine', 'CVCL:7780', (82, 90))	('cell migration', 'CPA', (51, 65))	('ETS-1', 'Gene', (28, 33))	('knockdown', 'Var', (34, 43))	('invasion', 'CPA', (70, 78))	('ETS-1', 'Gene', '2113', (28, 33))
69189	31118072	Knockdown of ETS-1 also significantly impaired cisplatin sensitive Cal27 migration and invasion (Additional file 1: Figure S3A and Figure S3B).	('cisplatin sensitive', 'MPA', (47, 66))	('Knockdown', 'Var', (0, 9))	('ETS-1', 'Gene', '2113', (13, 18))	('cisplatin', 'Chemical', 'MESH:D002945', (47, 56))	('ETS-1', 'Gene', (13, 18))	('invasion', 'CPA', (87, 95))	('impaired', 'NegReg', (38, 46))
69191	31118072	We next determined whether ETS-1 knockdown could re-sensitize cisplatin-resistant HNSCC to cisplatin treatment.	('cisplatin', 'Chemical', 'MESH:D002945', (62, 71))	('SCC', 'Gene', '6317', (84, 87))	('ETS-1', 'Gene', '2113', (27, 32))	('HNSCC', 'Phenotype', 'HP:0012288', (82, 87))	('knockdown', 'Var', (33, 42))	('cisplatin', 'Chemical', 'MESH:D002945', (91, 100))	('SCC', 'Gene', (84, 87))	('ETS-1', 'Gene', (27, 32))
69196	31118072	In the control cells treated, induction of caspase-3 cleavage did not occur, whereas in siRNA ETS-1 transfected cells, cisplatin induced caspase-3 cleavage in a dose-dependent manner (Fig.	('ETS-1', 'Gene', (94, 99))	('caspase-3', 'Gene', '836', (43, 52))	('ETS-1', 'Gene', '2113', (94, 99))	('caspase-3', 'Gene', (43, 52))	('cleavage', 'MPA', (147, 155))	('cisplatin', 'Var', (119, 128))	('caspase-3', 'Gene', (137, 146))	('caspase-3', 'Gene', '836', (137, 146))	('cisplatin', 'Chemical', 'MESH:D002945', (119, 128))
69197	31118072	MTS assay results showed that ETS-1 knockdown synergized with cisplatin to inhibit Cal27CP cell growth (Fig.	('cisplatin', 'Chemical', 'MESH:D002945', (62, 71))	('inhibit', 'NegReg', (75, 82))	('ETS-1', 'Gene', (30, 35))	('knockdown', 'Var', (36, 45))	('Cal27CP', 'Disease', (83, 90))	('ETS-1', 'Gene', '2113', (30, 35))
69199	31118072	Moreover, XTT assay data also showed that ETS-1 knockdown re-sensitized UMSCC74B cells to cisplatin treatment (Fig.	('cisplatin treatment', 'MPA', (90, 109))	('cisplatin', 'Chemical', 'MESH:D002945', (90, 99))	('UMSCC74B', 'CellLine', 'CVCL:7780', (72, 80))	('knockdown', 'Var', (48, 57))	('ETS-1', 'Gene', (42, 47))	('ETS-1', 'Gene', '2113', (42, 47))
69205	31118072	Cal27CP cells were treated with PD0325901, a MEK inhibitor, for 24 h, followed by detection of ERK and ETS-1-T38 phosphorylation.	('PD0325901', 'Var', (32, 41))	('ETS-1', 'Gene', '2113', (103, 108))	('ERK', 'MPA', (95, 98))	('MEK', 'Gene', (45, 48))	('PD0325901', 'Chemical', 'MESH:C506614', (32, 41))	('MEK', 'Gene', '5609', (45, 48))	('ETS-1', 'Gene', (103, 108))
69211	31118072	We further investigated whether inhibition of MEK/ERK pathways could re-sensitize cisplatin-resistant HNSCC to cisplatin treatment.	('inhibition', 'Var', (32, 42))	('cisplatin', 'Chemical', 'MESH:D002945', (111, 120))	('SCC', 'Gene', (104, 107))	('HNSCC', 'Phenotype', 'HP:0012288', (102, 107))	('cisplatin', 'Chemical', 'MESH:D002945', (82, 91))	('SCC', 'Gene', '6317', (104, 107))	('MEK', 'Gene', (46, 49))	('MEK', 'Gene', '5609', (46, 49))
69215	31118072	Furthermore, we demonstrated that a combination with PD0325901 did not improve the efficacy of cisplatin on the inhibition of cell proliferation by MTS assay in Cal27CP (Fig.	('PD0325901', 'Var', (53, 62))	('cell proliferation', 'CPA', (126, 144))	('inhibition', 'NegReg', (112, 122))	('PD0325901', 'Chemical', 'MESH:C506614', (53, 62))	('cisplatin', 'Chemical', 'MESH:D002945', (95, 104))
69217	31118072	Our data indicated that inhibition of MEK/ERK pathway did not re-sensitize cisplatin-resistant HNSCC to cisplatin treatment.	('cisplatin', 'Chemical', 'MESH:D002945', (104, 113))	('MEK', 'Gene', (38, 41))	('MEK', 'Gene', '5609', (38, 41))	('SCC', 'Gene', (97, 100))	('inhibition', 'Var', (24, 34))	('cisplatin', 'Chemical', 'MESH:D002945', (75, 84))	('SCC', 'Gene', '6317', (97, 100))	('HNSCC', 'Phenotype', 'HP:0012288', (95, 100))
69239	31118072	Furthermore, Dasatinib induced dramatic apoptosis while cisplatin induced apoptosis to a lesser degree, but the combination of Dasatinib and cisplatin led to significantly greater apoptosis compared to either treatment alone in Cal27CP (Fig.	('Cal27CP', 'Var', (228, 235))	('cisplatin', 'Chemical', 'MESH:D002945', (56, 65))	('greater', 'PosReg', (172, 179))	('cisplatin', 'Chemical', 'MESH:D002945', (141, 150))	('Dasatinib', 'Chemical', 'MESH:D000069439', (127, 136))	('Dasatinib', 'Chemical', 'MESH:D000069439', (13, 22))
69244	31118072	Moreover, we showed that ETS-1 knockdown led to inhibition of cell proliferation, migration, and invasion.	('ETS-1', 'Gene', '2113', (25, 30))	('cell proliferation', 'CPA', (62, 80))	('migration', 'CPA', (82, 91))	('inhibition', 'NegReg', (48, 58))	('invasion', 'CPA', (97, 105))	('ETS-1', 'Gene', (25, 30))	('knockdown', 'Var', (31, 40))
69245	31118072	In addition, ETS-1 knockdown re-sensitized cells to cisplatin treatment.	('knockdown', 'Var', (19, 28))	('cisplatin', 'Chemical', 'MESH:D002945', (52, 61))	('ETS-1', 'Gene', (13, 18))	('ETS-1', 'Gene', '2113', (13, 18))
69248	31118072	Previous studies showed that silencing ETS-1 increased cell proliferation in vitro and reduced tumor growth in vivo in some breast cancer cell lines.	('increased', 'PosReg', (45, 54))	('silencing', 'Var', (29, 38))	('ETS-1', 'Gene', (39, 44))	('reduced', 'NegReg', (87, 94))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('breast cancer', 'Disease', 'MESH:D001943', (124, 137))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('cell proliferation', 'CPA', (55, 73))	('ETS-1', 'Gene', '2113', (39, 44))	('breast cancer', 'Phenotype', 'HP:0003002', (124, 137))	('breast cancer', 'Disease', (124, 137))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Disease', (95, 100))
69249	31118072	Conversely, silencing ETS-1 suppressed cell growth of human renal carcinoma (786-0) and human glioma (U87MG) cell lines both in vitro and in vivo .	('carcinoma', 'Phenotype', 'HP:0030731', (66, 75))	('glioma', 'Disease', (94, 100))	('ETS-1', 'Gene', (22, 27))	('human renal carcinoma', 'Disease', (54, 75))	('U87MG', 'CellLine', 'CVCL:0022', (102, 107))	('renal carcinoma', 'Phenotype', 'HP:0005584', (60, 75))	('silencing', 'Var', (12, 21))	('suppressed', 'NegReg', (28, 38))	('glioma', 'Disease', 'MESH:D005910', (94, 100))	('ETS-1', 'Gene', '2113', (22, 27))	('glioma', 'Phenotype', 'HP:0009733', (94, 100))	('cell growth', 'CPA', (39, 50))	('human renal carcinoma', 'Disease', 'MESH:C538614', (54, 75))	('human', 'Species', '9606', (88, 93))	('human', 'Species', '9606', (54, 59))
69252	31118072	However, ETS-1 silencing was unable to decrease CDK2, Cyclin E, and c-Myc expression (data not shown).	('c-Myc', 'Gene', (68, 73))	('ETS-1', 'Gene', (9, 14))	('decrease', 'NegReg', (39, 47))	('CDK2', 'Gene', (48, 52))	('ETS-1', 'Gene', '2113', (9, 14))	('silencing', 'Var', (15, 24))	('c-Myc', 'Gene', '4609', (68, 73))	('Cyclin E', 'MPA', (54, 62))	('CDK2', 'Gene', '1017', (48, 52))
69259	31118072	Therefore, we did not discover what effect, if any, silencing of ETS-1 had on the expression of N-cadherin, E-cadherin, Snail, Slug, and Twist (data not shown).	('E-cadherin', 'Gene', (108, 118))	('ETS-1', 'Gene', '2113', (65, 70))	('E-cadherin', 'Gene', '999', (108, 118))	('Slug', 'Gene', '6591', (127, 131))	('Slug', 'Gene', (127, 131))	('silencing', 'Var', (52, 61))	('Snail', 'Gene', '6615', (120, 125))	('expression', 'MPA', (82, 92))	('Snail', 'Gene', (120, 125))	('N-cadherin', 'Gene', (96, 106))	('N-cadherin', 'Gene', '1000', (96, 106))	('ETS-1', 'Gene', (65, 70))
69278	31118072	To this end, a study to determine whether MEK/ERK inhibitors synergistically enhance the efficacy of other anticancer drugs on inhibition of cell proliferation in cisplatin-resistant HNSCC is forthcoming.	('inhibitors', 'Var', (50, 60))	('SCC', 'Gene', (185, 188))	('cisplatin', 'Chemical', 'MESH:D002945', (163, 172))	('HNSCC', 'Phenotype', 'HP:0012288', (183, 188))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('MEK', 'Gene', (42, 45))	('cell proliferation', 'CPA', (141, 159))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('SCC', 'Gene', '6317', (185, 188))	('MEK', 'Gene', '5609', (42, 45))	('cancer', 'Disease', (111, 117))	('enhance', 'PosReg', (77, 84))
69288	31118072	In addition, given the fact that inhibition of a single pathway by an inhibitor alone is almost impossible to completely suppress tumor growth in vitro and in vivo, we are currently performing experiments to identify crucial survival pathways that are up-regulated under SRC/ETS-1 inhibition.	('ETS-1', 'Gene', (275, 280))	('ETS-1', 'Gene', '2113', (275, 280))	('inhibition', 'Var', (281, 291))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('survival pathways', 'Pathway', (225, 242))	('SRC', 'Gene', '6714', (271, 274))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('SRC', 'Gene', (271, 274))	('up-regulated', 'PosReg', (252, 264))	('tumor', 'Disease', (130, 135))
69291	31118072	Inhibition of SRC by SRC inhibitor Dasatinib re-sensitizes cisplatin resistant head and neck squamous cell carcinoma to cisplatin treatment.	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('Dasatinib', 'Chemical', 'MESH:D000069439', (35, 44))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (88, 116))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (93, 116))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (79, 116))	('SRC', 'Gene', '6714', (21, 24))	('SRC', 'Gene', (21, 24))	('Inhibition', 'Var', (0, 10))	('SRC', 'Gene', '6714', (14, 17))	('neck squamous cell carcinoma', 'Disease', (88, 116))	('SRC', 'Gene', (14, 17))	('cisplatin', 'Chemical', 'MESH:D002945', (59, 68))	('cisplatin', 'Chemical', 'MESH:D002945', (120, 129))
69302	30275546	Patients with LUSCs tend to be smokers and have a TP53 mutation; whereas, LUAD patients have several key mutations in EGFR, KRAS, NRAS, BRAF, PIK3CA, MET, and CTNNB1 genes.	('KRAS', 'Gene', (124, 128))	('BRAF', 'Gene', '673', (136, 140))	('BRAF', 'Gene', (136, 140))	('mutations', 'Var', (105, 114))	('NRAS', 'Gene', (130, 134))	('MET', 'Gene', (150, 153))	('CTNNB1', 'Gene', '1499', (159, 165))	('Patients', 'Species', '9606', (0, 8))	('EGFR', 'Gene', '1956', (118, 122))	('TP53', 'Gene', (50, 54))	('LUSC', 'Phenotype', 'HP:0030359', (14, 18))	('PIK3CA', 'Gene', '5290', (142, 148))	('CTNNB1', 'Gene', (159, 165))	('mutation', 'Var', (55, 63))	('NRAS', 'Gene', '4893', (130, 134))	('KRAS', 'Gene', '3845', (124, 128))	('TP53', 'Gene', '7157', (50, 54))	('EGFR', 'Gene', (118, 122))	('PIK3CA', 'Gene', (142, 148))	('patients', 'Species', '9606', (79, 87))	('LUAD', 'Phenotype', 'HP:0030078', (74, 78))
69357	30275546	Consistent with previous findings, it was found that B cells and macrophages had a low correlation with intra-tumoral immune cytolytic activity, and correlations were further reduced in Subtype B than Subtype A in both LUADs and LUSCs.	('reduced', 'NegReg', (175, 182))	('intra-tumoral', 'Disease', 'MESH:D009369', (104, 117))	('LUAD', 'Phenotype', 'HP:0030078', (219, 223))	('intra-tumoral', 'Disease', (104, 117))	('Subtype B', 'Var', (186, 195))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('LUSC', 'Phenotype', 'HP:0030359', (229, 233))	('LUADs', 'Phenotype', 'HP:0030078', (219, 224))
69397	28415559	We further validated the top differentially expressed lncRNAs in three independent datasets from Gene Expression Omnibus (GEO) repository: GSE42743, GSE9844, and GSE6791.	('GSE9844', 'Chemical', '-', (149, 156))	('GSE6791', 'Var', (162, 169))	('GSE42743', 'Var', (139, 147))	('GSE6791', 'Chemical', '-', (162, 169))	('GSE9844', 'Var', (149, 156))
69402	28415559	Tobacco and alcohol consumption, as well as infection with high risk human papillomavirus (HPV), have been shown to be the main risk factors of OSCC in the U.S..	('human papillomavirus', 'Species', '10566', (69, 89))	('infection', 'Var', (44, 53))	('Tobacco', 'Species', '4097', (0, 7))	('HPV', 'Species', '10566', (91, 94))	('OSCC', 'Disease', (144, 148))	('alcohol', 'Chemical', 'MESH:D000438', (12, 19))
69412	28415559	Several such studies reported aberrantly expressed lncRNAs in oral cancers.	('cancers', 'Phenotype', 'HP:0002664', (67, 74))	('oral cancers', 'Disease', (62, 74))	('oral cancers', 'Disease', 'MESH:D009062', (62, 74))	('aberrantly', 'Var', (30, 40))	('lncRNAs', 'Protein', (51, 58))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))
69419	28415559	Some studies of head and neck cancer suggested that lncRNA, including AFAP1-AS1, AB209630, GAS5, and HOTAIR, could potentially serve as predictors of patient outcome or treatment response.	('AS1', 'Gene', '5729', (76, 79))	('AS1', 'Gene', (76, 79))	('patient', 'Species', '9606', (150, 157))	('GAS5', 'Gene', (91, 95))	('HOTAIR', 'Gene', (101, 107))	('neck cancer', 'Disease', 'MESH:D006258', (25, 36))	('AB209630', 'Var', (81, 89))	('HOTAIR', 'Gene', '100124700', (101, 107))	('AFAP1', 'Gene', (70, 75))	('head and neck cancer', 'Phenotype', 'HP:0012288', (16, 36))	('AFAP1', 'Gene', '60312', (70, 75))	('GAS5', 'Gene', '60674', (91, 95))	('neck cancer', 'Disease', (25, 36))	('men', 'Species', '9606', (174, 177))	('lncRNA', 'MPA', (52, 58))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
69448	28415559	Further, there is evidence showing that it was upregulated in oncogene-induced senescence process; and knockdown of MIR31HG induced a tumor suppressor p16INK4A dependent senescence phenotype, which might link it to HPV-related cancer carcinogenesis.	('upregulated', 'PosReg', (47, 58))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('induced', 'PosReg', (124, 131))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('cancer carcinogenesis', 'Disease', 'MESH:D063646', (227, 248))	('senescence phenotype', 'MPA', (170, 190))	('oncogene-induced senescence process', 'CPA', (62, 97))	('cancer carcinogenesis', 'Disease', (227, 248))	('MIR31HG', 'Gene', '554202', (116, 123))	('HPV', 'Species', '10566', (215, 218))	('MIR31HG', 'Gene', (116, 123))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('knockdown', 'Var', (103, 112))	('tumor', 'Disease', (134, 139))
69471	28415559	Three datasets were identified: GSE42743 with 74 oral cavity squamous cell carcinoma and 29 adjacent normal tissue; GSE9844 with 26 tongue squamous cell carcinoma and 12 matched adjacent normal tissue; and GSE6791 comprised of 28 cervical cancers, 42 head and neck cancers and 14 site-matched normal oral tissue.	('tongue squamous cell carcinoma', 'Phenotype', 'HP:0030413', (132, 162))	('head and neck cancer', 'Phenotype', 'HP:0012288', (251, 271))	('carcinoma', 'Phenotype', 'HP:0030731', (153, 162))	('GSE9844', 'Var', (116, 123))	('cancer', 'Phenotype', 'HP:0002664', (265, 271))	('neck cancers', 'Disease', (260, 272))	('cancers', 'Phenotype', 'HP:0002664', (239, 246))	('neck cancers', 'Disease', 'MESH:D006258', (260, 272))	('tongue squamous cell carcinoma', 'Disease', 'MESH:D002294', (132, 162))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (61, 84))	('cervical cancers', 'Disease', (230, 246))	('GSE42743', 'Var', (32, 40))	('cervical cancers', 'Disease', 'MESH:D002583', (230, 246))	('GSE9844', 'Chemical', '-', (116, 123))	('GSE6791', 'Var', (206, 213))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (139, 162))	('tongue squamous cell carcinoma', 'Disease', (132, 162))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (61, 84))	('GSE6791', 'Chemical', '-', (206, 213))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (139, 162))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('cancers', 'Phenotype', 'HP:0002664', (265, 272))	('head and neck cancers', 'Phenotype', 'HP:0012288', (251, 272))	('squamous cell carcinoma', 'Disease', (61, 84))
69515	32111241	Cells were also discarded if the TPM value of CD3D was < 3, TPM of CD8A < 3, or CD4 > 30 for fluorescence-activated cell sorting (FACS)-sorted CD8+ T cells and if the TPM of CD4 < 3 or CD8A > 30 for FACS-sorted CD4+ T cells.	('CD8A', 'Gene', (185, 189))	('CD3D', 'Gene', (46, 50))	('CD8', 'Gene', '925', (67, 70))	('CD8', 'Gene', (143, 146))	('CD8', 'Gene', '925', (143, 146))	('CD4 > 30', 'Var', (80, 88))	('CD8', 'Gene', (185, 188))	('CD8A', 'Gene', '925', (67, 71))	('CD8', 'Gene', '925', (185, 188))	('CD8A', 'Gene', (67, 71))	('CD8A', 'Gene', '925', (185, 189))	('CD8', 'Gene', (67, 70))	('CD3D', 'Gene', '915', (46, 50))
69581	32111241	We found that neither PDCD1-high nor PDCD1-low subset were severely biased in distribution of cells from each patient in both single-cell transcriptome datasets reanalyzed, indicating that the observed differential expression is not based on patient-specific effect (Additional file 2: Figure S2).	('ran', 'Gene', '5901', (139, 142))	('ran', 'Gene', (139, 142))	('patient', 'Species', '9606', (110, 117))	('patient', 'Species', '9606', (242, 249))	('PDCD1-high', 'Var', (22, 32))
69590	32111241	The distribution patterns of TOX-high cells and PDCD1-high cells were similar in the latent space of the tSNE plot for both melanoma and NSCLC, which were similar to the distribution patterns of IC genes (see Fig.	('melanoma', 'Disease', 'MESH:D008545', (124, 132))	('melanoma', 'Phenotype', 'HP:0002861', (124, 132))	('melanoma', 'Disease', (124, 132))	('NSCLC', 'Disease', (137, 142))	('NSCLC', 'Disease', 'MESH:D002289', (137, 142))	('PDCD1-high', 'Var', (48, 58))	('NSCLC', 'Phenotype', 'HP:0030358', (137, 142))
69613	32111241	Each population can be arranged in the following order of decreasing TOX expression: PD-1+TIM-3+ > PD-1+TIM-3- > PD-1-TIM-3- (Fig.	('PD-1+TIM-3+ > PD-1+TIM-3-', 'Var', (85, 110))	('PD-1+TIM-3-', 'Var', (99, 110))	('ran', 'Gene', (25, 28))	('ran', 'Gene', '5901', (25, 28))
69625	32111241	Interestingly, the knockdown of TOX in the TI CD8+ T cells resulted in a significant reduction of cells expressing IC molecules, such as PD-1, TIM-3, TIGIT, and CTLA-4.	('CD8', 'Gene', '925', (46, 49))	('cells expressing IC molecules', 'MPA', (98, 127))	('knockdown', 'Var', (19, 28))	('reduction', 'NegReg', (85, 94))	('CD8', 'Gene', (46, 49))
69628	32111241	Additionally, we observed that the frequency of TI CD8+ T cells that secrete effector cytokines (IFN-gamma and TNF-alpha) significantly increased upon TOX knockdown, suggesting that the anti-tumor function of TI CD8+ T cells could be restored upon TOX knockdown (Fig.	('knockdown', 'Var', (155, 164))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('TNF-alpha', 'Gene', '7124', (111, 120))	('IFN-gamma', 'Gene', (97, 106))	('CD8', 'Gene', (212, 215))	('IFN-gamma', 'Gene', '3458', (97, 106))	('TNF-alpha', 'Gene', (111, 120))	('CD8', 'Gene', (51, 54))	('CD8', 'Gene', '925', (212, 215))	('tumor', 'Disease', (191, 196))	('CD8', 'Gene', '925', (51, 54))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('increased', 'PosReg', (136, 145))
69647	32111241	In the two NSCLC cohorts, the TOX expression level in the TILs of responders was significantly lower than that in the TILs of non-responders (P = 0.016 and 0.002, two-tailed Mann-Whitney U test).	('NSCLC cohort', 'Disease', (11, 23))	('lower', 'NegReg', (95, 100))	('responders', 'Var', (66, 76))	('TOX expression level', 'MPA', (30, 50))	('NSCLC cohort', 'Disease', 'MESH:D002289', (11, 23))	('NSCLC', 'Phenotype', 'HP:0030358', (11, 16))
69666	32111241	TOX knockdown in the TI CD8+ T cells significantly downregulated the expression of IC molecules, such as PD-1 (Fig.	('expression', 'MPA', (69, 79))	('CD8', 'Gene', (24, 27))	('downregulated', 'NegReg', (51, 64))	('CD8', 'Gene', '925', (24, 27))	('knockdown', 'Var', (4, 13))	('PD-1', 'Gene', (105, 109))
69680	32111241	This study was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (2018M3C9A5064709, 2018R1A5A2025079, 2019M3A9B6065189 to IL; 2017R1A5A1014560, 2018M3A9H3024850, 2018R1A2A1A05076997, 2019M3A9B6065221 to SJH).	('2018R1A5A2025079', 'Var', (139, 155))	('2019M3A9B6065221', 'Var', (238, 254))	('2019M3A9B6065189', 'Var', (157, 173))	('2018M3A9H3024850', 'Var', (199, 215))	('2018R1A2A1A05076997', 'Var', (217, 236))	('ran', 'Gene', (77, 80))	('ran', 'Gene', '5901', (77, 80))
69690	31086813	Using hydrocarbon-stapled peptide technologies, we aim to develop potent, selective inhibitors targeting this pathway by disrupting the interaction of beta-cat with its coactivators B-cell lymphoma 9 (BCL9) and B-cell lymphoma 9-like (B9L).	('B9L', 'Gene', '80288', (235, 238))	('inhibitors', 'Var', (84, 94))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (182, 197))	('lymphoma', 'Phenotype', 'HP:0002665', (218, 226))	('B9L', 'Gene', (235, 238))	('beta-cat', 'Gene', (151, 159))	('hydrocarbon', 'Chemical', 'MESH:D006838', (6, 17))	('disrupting', 'NegReg', (121, 131))	('beta-cat', 'Gene', '12387', (151, 159))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (211, 226))	('lymphoma', 'Phenotype', 'HP:0002665', (189, 197))	('interaction', 'Interaction', (136, 147))
69691	31086813	We identified a set of peptides, including hsBCL9CT-24, that robustly inhibits the activity of beta-cat and suppresses cancer cell growth.	('activity', 'MPA', (83, 91))	('beta-cat', 'Gene', (95, 103))	('beta-cat', 'Gene', '12387', (95, 103))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('hsBCL9CT-24', 'Chemical', '-', (43, 54))	('inhibits', 'NegReg', (70, 78))	('cancer', 'Disease', (119, 125))	('hsBCL9CT-24', 'Var', (43, 54))	('suppresses', 'NegReg', (108, 118))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
69694	31086813	Given the strong correlation between Treg infiltration and APC mutation in colorectal cancers, it indicates our peptides can reactivate anti-cancer immune response suppressed by the oncogenic Wnt pathway.	('APC', 'Phenotype', 'HP:0005227', (59, 62))	('APC', 'Gene', (59, 62))	('colorectal cancers', 'Disease', (75, 93))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('mutation', 'Var', (63, 71))	('reactivate', 'MPA', (125, 135))	('cancers', 'Phenotype', 'HP:0002664', (86, 93))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('colorectal cancers', 'Disease', 'MESH:D015179', (75, 93))	('cancer', 'Disease', (141, 147))	('rat', 'Species', '10116', (48, 51))	('cancer', 'Disease', (86, 92))
69698	31086813	In many cancers, loss-of-function mutations in the APC components and gain-of-function mutations of beta-cat can enable beta-cat to escape degradation and accumulate in the nucleus, where it engages lymphoid enhancer factor/T cell factor (LEF/TCF) to induce expression of genes that promote cell survival, proliferation, and migration.	('beta-cat', 'Gene', '12387', (120, 128))	('migration', 'CPA', (325, 334))	('gain-of-function', 'PosReg', (70, 86))	('mutations', 'Var', (87, 96))	('cancers', 'Phenotype', 'HP:0002664', (8, 15))	('cancers', 'Disease', (8, 15))	('loss-of-function', 'NegReg', (17, 33))	('beta-cat', 'Gene', (120, 128))	('expression of', 'MPA', (258, 271))	('genes', 'Gene', (272, 277))	('LEF/TCF', 'Gene', (239, 246))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('LEF/TCF', 'Gene', '3172', (239, 246))	('beta-cat', 'Gene', '12387', (100, 108))	('promote', 'PosReg', (283, 290))	('APC', 'Phenotype', 'HP:0005227', (51, 54))	('proliferation', 'CPA', (306, 319))	('beta-cat', 'Gene', (100, 108))	('rat', 'Species', '10116', (313, 316))	('cancers', 'Disease', 'MESH:D009369', (8, 15))	('induce', 'PosReg', (251, 257))	('rat', 'Species', '10116', (328, 331))	('mutations', 'Var', (34, 43))	('cell survival', 'CPA', (291, 304))
69700	31086813	Aberrant activation of the Wnt pathway is associated with initiation and progression of a wide range of human epithelial malignancies.	('activation', 'PosReg', (9, 19))	('Aberrant', 'Var', (0, 8))	('associated', 'Reg', (42, 52))	('Wnt pathway', 'Pathway', (27, 38))	('human', 'Species', '9606', (104, 109))	('epithelial malignancies', 'Phenotype', 'HP:0031492', (110, 133))	('epithelial malignancies', 'Disease', (110, 133))	('epithelial malignancies', 'Disease', 'MESH:D002277', (110, 133))
69706	31086813	Loss of Wnt1 results in significant depletion of breast CSCs, thus inhibiting tumor growth and metastatic progression.	('Wnt1', 'Gene', (8, 12))	('breast CSCs', 'Protein', (49, 60))	('Wnt1', 'Gene', '22408', (8, 12))	('C', 'Chemical', 'MESH:D002244', (56, 57))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('depletion', 'MPA', (36, 45))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Disease', (78, 83))	('Loss', 'Var', (0, 4))	('inhibiting', 'NegReg', (67, 77))	('C', 'Chemical', 'MESH:D002244', (58, 59))
69715	31086813	Drug candidates in this category cannot confer inhibitory effects to cancer cells that harbor APC, Axin, or beta-cat mutations, because beta-cat activation is nearly independent of Wnt/Frizzled.	('Axin', 'Gene', '12005', (99, 103))	('mutations', 'Var', (117, 126))	('Axin', 'Gene', (99, 103))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('APC', 'Phenotype', 'HP:0005227', (94, 97))	('beta-cat', 'Gene', (136, 144))	('beta-cat', 'Gene', '12387', (136, 144))	('beta-cat', 'Gene', (108, 116))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('beta-cat', 'Gene', '12387', (108, 116))	('cancer', 'Disease', (69, 75))
69720	31086813	Thus, inhibitors of beta-cat's common binding surface have exhibited substantial adverse effects in animal studies and clinical trials, likely due to interference with off-target interactions.	('beta-cat', 'Gene', (20, 28))	('inhibitors', 'Var', (6, 16))	('beta-cat', 'Gene', '12387', (20, 28))	('interactions', 'Interaction', (179, 191))
69721	31086813	For example, disruption of the interaction between LEF/TCF and beta-cat by small molecules is known to elicit serious side effects, including severe bone marrow hypoplasia, anemia, and generalized wasting of treated mice:likely due to the presence of quinone reactive groups in compounds and interrupted homeostatic Wnt signaling in normal hematopoietic and intestinal stem cells.	('bone marrow hypoplasia', 'Disease', 'MESH:D001855', (149, 171))	('anemia', 'Disease', 'MESH:D000740', (173, 179))	('bone marrow hypoplasia', 'Phenotype', 'HP:0005528', (149, 171))	('mice', 'Species', '10090', (216, 220))	('anemia', 'Disease', (173, 179))	('interaction', 'Interaction', (31, 42))	('LEF/TCF', 'Gene', '3172', (51, 58))	('disruption', 'Var', (13, 23))	('quinone', 'Chemical', 'MESH:C004532', (251, 258))	('anemia', 'Phenotype', 'HP:0001903', (173, 179))	('beta-cat', 'Gene', (63, 71))	('bone marrow hypoplasia', 'Disease', (149, 171))	('beta-cat', 'Gene', '12387', (63, 71))	('generalized wasting', 'Phenotype', 'HP:0009055', (185, 204))	('LEF/TCF', 'Gene', (51, 58))
69729	31086813	Mechanistically, we found that hsBCL9CT-24 can modulate the tumor microenvironment (TME) by inhibiting regulatory T (Treg) cell infiltration via the transforming growth factor-beta (TGF-beta)-CCL20/CCL22 axis while promoting DC infiltration via the CCL4 axis.	('TGF-beta', 'Gene', (182, 190))	('hsBCL9CT-24', 'Var', (31, 42))	('DC infiltration', 'CPA', (225, 240))	('CCL20', 'Gene', (192, 197))	('C', 'Chemical', 'MESH:D002244', (249, 250))	('C', 'Chemical', 'MESH:D002244', (250, 251))	('CCL4', 'Gene', '20303', (249, 253))	('C', 'Chemical', 'MESH:D002244', (34, 35))	('tumor', 'Disease', (60, 65))	('CCL22', 'Gene', (198, 203))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('C', 'Chemical', 'MESH:D002244', (193, 194))	('CCL20', 'Gene', '20297', (192, 197))	('TGF-beta', 'Gene', '21803', (182, 190))	('rat', 'Species', '10116', (134, 137))	('C', 'Chemical', 'MESH:D002244', (199, 200))	('C', 'Chemical', 'MESH:D002244', (192, 193))	('C', 'Chemical', 'MESH:D002244', (198, 199))	('CCL4', 'Gene', (249, 253))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('rat', 'Species', '10116', (234, 237))	('hsBCL9CT-24', 'Chemical', '-', (31, 42))	('C', 'Chemical', 'MESH:D002244', (37, 38))	('C', 'Chemical', 'MESH:D002244', (226, 227))	('modulate', 'Reg', (47, 55))	('promoting', 'PosReg', (215, 224))	('CCL22', 'Gene', '20299', (198, 203))	('inhibiting', 'NegReg', (92, 102))
69730	31086813	These changes, in turn, increase intratumoral infiltration of cytotoxic CD8+ T cells, effector CD8+ cells, and effector CD4+ cells.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('increase', 'PosReg', (24, 32))	('rat', 'Species', '10116', (52, 55))	('CD8', 'Gene', '925', (95, 98))	('rat', 'Species', '10116', (36, 39))	('changes', 'Var', (6, 13))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('CD8', 'Gene', (72, 75))	('CD8', 'Gene', (95, 98))	('CD8', 'Gene', '925', (72, 75))
69733	31086813	To enhance in vitro potency and affinity of this peptide, we applied staple incorporation technologies and conducted lead optimization studies in three steps: (i) domain mapping of the full-length BCL9-HD2, (ii) introduction of point mutations in the active region to optimize overall peptide charge, and (iii) optimization of terminal modification and staple sites.	('peptide charge', 'MPA', (285, 299))	('enhance', 'PosReg', (3, 10))	('rat', 'Species', '10116', (83, 86))	('potency', 'MPA', (20, 27))	('BCL9-HD2', 'Gene', (197, 205))	('BCL9-HD2', 'Gene', '77578;110421', (197, 205))	('point mutations', 'Var', (228, 243))	('affinity', 'MPA', (32, 40))
69736	31086813	beta-Cat binding affinity and the competitive activity of candidate peptides bearing sequence alterations were then determined by two biochemical assays conducted under optimized conditions: homogeneous time resolved fluorescence (HTRF) binding assays and amplified luminescence proximity homogeneous assays (ALPHA) (see Methods for details).	('beta-Cat', 'Gene', '12387', (0, 8))	('alterations', 'Var', (94, 105))	('beta-Cat', 'Gene', (0, 8))	('rat', 'Species', '10116', (98, 101))	('binding', 'Interaction', (9, 16))
69745	31086813	S1E), suggesting that hsBCL9CT-24 has a greatly improved binding affinity for beta-cat over SAH-BCL9B.	('beta-cat', 'Gene', (78, 86))	('improved', 'PosReg', (48, 56))	('SAH', 'Disease', 'MESH:D013345', (92, 95))	('hsBCL9CT-24', 'Chemical', '-', (22, 33))	('SAH', 'Disease', (92, 95))	('beta-cat', 'Gene', '12387', (78, 86))	('binding affinity', 'Interaction', (57, 73))	('hsBCL9CT-24', 'Var', (22, 33))
69755	31086813	With this assay, the binding affinities of hsBCL9CT-1 to hsBCL9CT-20 were measured, and hsBCL9CT-20 displayed the strongest effect (fig.	('hsBCL9CT-20', 'Var', (88, 99))	('binding', 'Interaction', (21, 28))	('C', 'Chemical', 'MESH:D002244', (49, 50))	('C', 'Chemical', 'MESH:D002244', (94, 95))	('C', 'Chemical', 'MESH:D002244', (46, 47))	('C', 'Chemical', 'MESH:D002244', (60, 61))	('C', 'Chemical', 'MESH:D002244', (91, 92))	('C', 'Chemical', 'MESH:D002244', (63, 64))
69761	31086813	To determine whether potency of the hsBCL9CT series can be abolished by these critical amino acid mutations, we rationally designed several hsBCL9CT derivatives (hsBCL9M1 to hsBCL9M7; table S1) to incorporate point mutations and serve as negative control analogs (fig.	('C', 'Chemical', 'MESH:D002244', (42, 43))	('C', 'Chemical', 'MESH:D002244', (143, 144))	('incorporate', 'Reg', (197, 208))	('point mutations', 'Var', (209, 224))	('C', 'Chemical', 'MESH:D002244', (146, 147))	('rat', 'Species', '10116', (204, 207))	('mutations', 'Var', (98, 107))	('rat', 'Species', '10116', (112, 115))	('C', 'Chemical', 'MESH:D002244', (177, 178))	('C', 'Chemical', 'MESH:D002244', (39, 40))	('C', 'Chemical', 'MESH:D002244', (165, 166))
69762	31086813	Amino acids L366, I369, and L373 present in BCL9-HD2 were shown to drive hydrophobic interactions binding to helices 2 and 3 of the armadillo repeat 1 of beta-cat (table S1).	('drive', 'PosReg', (67, 72))	('I369', 'Var', (18, 22))	('beta-cat', 'Gene', (154, 162))	('hydrophobic interactions', 'MPA', (73, 97))	('L373', 'Var', (28, 32))	('beta-cat', 'Gene', '12387', (154, 162))	('BCL9-HD2', 'Gene', (44, 52))	('BCL9-HD2', 'Gene', '77578;110421', (44, 52))
69763	31086813	A series of mutants with single amino acid alterations for L366 (M5), I369 (M6), and L373 (M7) were found to have similar circular dichroism spectra when compared to hsBCL9CT-24 (fig.	('dichroism', 'Disease', 'None', (131, 140))	('L373', 'Var', (85, 89))	('hsBCL9CT-24', 'Chemical', '-', (166, 177))	('I369', 'Var', (70, 74))	('rat', 'Species', '10116', (47, 50))	('L366', 'Var', (59, 63))	('dichroism', 'Disease', (131, 140))
69765	31086813	However, these mutants have compromised potency in blocking the interaction between beta-cat and BCL9 when compared to wild-type hsBCL9CT-24 (fig.	('beta-cat', 'Gene', (84, 92))	('blocking', 'NegReg', (51, 59))	('beta-cat', 'Gene', '12387', (84, 92))	('BCL9', 'Gene', (97, 101))	('mutants', 'Var', (15, 22))	('hsBCL9CT-24', 'Chemical', '-', (129, 140))	('interaction', 'Interaction', (64, 75))
69768	31086813	In summary, we identified a series of hsBCL9CT peptides that exhibits robust inhibition against the interaction between beta-cat and BCL9.	('interaction', 'Interaction', (100, 111))	('beta-cat', 'Gene', (120, 128))	('peptides', 'Var', (47, 55))	('inhibition', 'NegReg', (77, 87))	('beta-cat', 'Gene', '12387', (120, 128))	('hsBCL9CT', 'Gene', (38, 46))
69770	31086813	beta-Cat transcriptional activity was then measured by LEF/TCF reporter assay in HCT116 cells (Ser45 deletion in one allele of the CTNNB1 gene), and cell viability was determined by cell viability assay in Colo320DM cells.	('deletion', 'Var', (101, 109))	('LEF/TCF', 'Gene', (55, 62))	('HCT116', 'CellLine', 'CVCL:0291', (81, 87))	('beta-Cat', 'Gene', '12387', (0, 8))	('C', 'Chemical', 'MESH:D002244', (206, 207))	('CTNNB1', 'Gene', '1499', (131, 137))	('C', 'Chemical', 'MESH:D002244', (131, 132))	('beta-Cat', 'Gene', (0, 8))	('LEF/TCF', 'Gene', '3172', (55, 62))	('C', 'Chemical', 'MESH:D002244', (5, 6))	('Ser45', 'Chemical', '-', (95, 100))	('CTNNB1', 'Gene', (131, 137))	('C', 'Chemical', 'MESH:D002244', (82, 83))	('C', 'Chemical', 'MESH:D002244', (60, 61))
69771	31086813	The HCT116 cell line was selected for its aberrant Wnt signaling activation (caused by beta-cat mutation), while the Colo320DM cell line was selected for its proliferative dependency on beta-cat and BCL9.	('C', 'Chemical', 'MESH:D002244', (117, 118))	('C', 'Chemical', 'MESH:D002244', (200, 201))	('beta-cat', 'Gene', (186, 194))	('Wnt signaling', 'MPA', (51, 64))	('mutation', 'Var', (96, 104))	('C', 'Chemical', 'MESH:D002244', (5, 6))	('HCT116', 'CellLine', 'CVCL:0291', (4, 10))	('rat', 'Species', '10116', (165, 168))	('beta-cat', 'Gene', (87, 95))	('activation', 'PosReg', (65, 75))	('beta-cat', 'Gene', '12387', (87, 95))	('beta-cat', 'Gene', '12387', (186, 194))
69772	31086813	As expected, hsBCL9CT-24 demonstrated more potent inhibition of beta-cat transcriptional activity (Fig.	('hsBCL9CT-24', 'Var', (13, 24))	('beta-cat', 'Gene', (64, 72))	('rat', 'Species', '10116', (32, 35))	('beta-cat', 'Gene', '12387', (64, 72))	('inhibition', 'NegReg', (50, 60))	('hsBCL9CT-24', 'Chemical', '-', (13, 24))
69776	31086813	Alteration of essential amino acids abolished hsBCL9CT-24's function (fig.	('essential amino acids', 'Chemical', 'MESH:D000601', (14, 35))	('hsBCL9CT-24', 'Chemical', '-', (46, 57))	('Alteration', 'Var', (0, 10))	('hsBCL9CT-24', 'Gene', (46, 57))	('rat', 'Species', '10116', (4, 7))	('abolished', 'NegReg', (36, 45))
69780	31086813	Consistent with results from LEF/TCF reporter assays, hsBCL9CT-24 proved to be more cytotoxic than the original SAH-BCL9B in Colo320DM cells (fig.	('C', 'Chemical', 'MESH:D002244', (125, 126))	('C', 'Chemical', 'MESH:D002244', (117, 118))	('SAH', 'Disease', 'MESH:D013345', (112, 115))	('LEF/TCF', 'Gene', (29, 36))	('hsBCL9CT-24', 'Chemical', '-', (54, 65))	('SAH', 'Disease', (112, 115))	('C', 'Chemical', 'MESH:D002244', (57, 58))	('cytotoxic', 'CPA', (84, 93))	('LEF/TCF', 'Gene', '3172', (29, 36))	('hsBCL9CT-24', 'Var', (54, 65))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('C', 'Chemical', 'MESH:D002244', (34, 35))	('C', 'Chemical', 'MESH:D002244', (60, 61))
69781	31086813	S3H), while mutations of key amino acids abolished the effects of hsBCL9CT-24 and hsBCL9CT-35 (fig.	('abolished', 'NegReg', (41, 50))	('mutations', 'Var', (12, 21))	('hsBCL9CT-24', 'Chemical', '-', (66, 77))	('hsBCL9CT-35', 'Var', (82, 93))
69783	31086813	In addition to Wnt pathway inhibitors, hsBCL9CT-24 demonstrated greater potency than other targeted therapeutic agents such as erlotinib (Fig.	('hsBCL9CT-24', 'Chemical', '-', (39, 50))	('rat', 'Species', '10116', (58, 61))	('potency', 'MPA', (72, 79))	('hsBCL9CT-24', 'Var', (39, 50))	('erlotinib', 'Chemical', 'MESH:D000069347', (127, 136))
69786	31086813	The growth of five Wnt/beta-cat-dependent cell lines (SW48, Colo320DM, MDA231, 4T1, and CT26) was inhibited by hsBCL9CT-24, while four Wnt/beta-cat-independent cell lines (MCF7, LS174T, HCT116D, and RKO) were not affected by hsBCL9CT-24, further indicating that the anticancer effects of hsBCL9CT-24 are mediated by blockage of the Wnt/beta-cat pathway (Fig.	('growth', 'CPA', (4, 10))	('beta-cat', 'Gene', (139, 147))	('C', 'Chemical', 'MESH:D002244', (187, 188))	('hsBCL9CT-24', 'Var', (111, 122))	('beta-cat', 'Gene', (336, 344))	('C', 'Chemical', 'MESH:D002244', (60, 61))	('CT26', 'Gene', '168400', (88, 92))	('MCF7', 'CellLine', 'CVCL:0031', (172, 176))	('inhibited', 'NegReg', (98, 107))	('hsBCL9CT-24', 'Chemical', '-', (225, 236))	('beta-cat', 'Gene', '12387', (23, 31))	('cancer', 'Disease', (270, 276))	('C', 'Chemical', 'MESH:D002244', (231, 232))	('C', 'Chemical', 'MESH:D002244', (114, 115))	('hsBCL9CT-24', 'Chemical', '-', (288, 299))	('C', 'Chemical', 'MESH:D002244', (88, 89))	('SW48', 'CellLine', 'CVCL:1724', (54, 58))	('cancer', 'Phenotype', 'HP:0002664', (270, 276))	('beta-cat', 'Gene', (23, 31))	('C', 'Chemical', 'MESH:D002244', (294, 295))	('hsBCL9CT-24', 'Var', (288, 299))	('hsBCL9CT-24', 'Chemical', '-', (111, 122))	('CT26', 'Gene', (88, 92))	('C', 'Chemical', 'MESH:D002244', (117, 118))	('beta-cat', 'Gene', '12387', (139, 147))	('MDA231', 'CellLine', 'CVCL:0062', (71, 77))	('cancer', 'Disease', 'MESH:D009369', (270, 276))	('C', 'Chemical', 'MESH:D002244', (173, 174))	('beta-cat', 'Gene', '12387', (336, 344))	('C', 'Chemical', 'MESH:D002244', (228, 229))	('HCT116', 'CellLine', 'CVCL:0291', (186, 192))	('C', 'Chemical', 'MESH:D002244', (291, 292))	('blockage', 'NegReg', (316, 324))
69792	31086813	Previous reports have described the ability of double cross-linked peptides to improve half-lives, and this phenomenon was confirmed by hsBCL9CT-35, a double cross-linked peptide that displayed a longer average half-life than hsBCL9CT-24, a single cross-linked peptide.	('improve', 'PosReg', (79, 86))	('half-lives', 'MPA', (87, 97))	('hsBCL9CT-35', 'Var', (136, 147))	('hsBCL9CT-24', 'Chemical', '-', (226, 237))
69796	31086813	Both hsBCL9CT-24 and hsBCL9CT-35 demonstrated favorable bioavailability and half-life properties, indicating the feasibility of daily dosing (fig.	('C', 'Chemical', 'MESH:D002244', (27, 28))	('hsBCL9CT-24', 'Chemical', '-', (5, 16))	('half-life', 'MPA', (76, 85))	('C', 'Chemical', 'MESH:D002244', (8, 9))	('rat', 'Species', '10116', (40, 43))	('bioavailability', 'MPA', (56, 71))	('hsBCL9CT-35', 'Var', (21, 32))	('C', 'Chemical', 'MESH:D002244', (24, 25))	('C', 'Chemical', 'MESH:D002244', (11, 12))
69799	31086813	In addition, hsBCL9CT-24 had low rates of clearance, ranging from 0.0397 to 0.0576 liter/hour per kg, and low steady-state volume of distribution (Vss), ranging from 0.0692 to 0.0946 liter/kg.	('hsBCL9CT-24', 'Var', (13, 24))	('low', 'NegReg', (29, 32))	('rat', 'Species', '10116', (33, 36))	('clearance', 'MPA', (42, 51))	('hsBCL9CT-24', 'Chemical', '-', (13, 24))
69805	31086813	Beginning on day 6, all mice treated with hsBCL9CT-24 showed a steady recovery in food consumption and body weight, suggesting an acclimation to drug treatment, and animals recovered to near-baseline levels with continued treatment by the end of the study (fig.	('mice', 'Species', '10090', (24, 28))	('hsBCL9CT-24', 'Var', (42, 53))	('recovery', 'PosReg', (70, 78))	('food consumption', 'CPA', (82, 98))	('body weight', 'CPA', (103, 114))	('hsBCL9CT-24', 'Chemical', '-', (42, 53))
69813	31086813	Repeated treatment with hsBCL9CT-35 at 30 or 40 mg/kg resulted in good tolerability and no obvious toxicological alterations in the intestine and bone marrow, consistent with our previous findings for SAH-BCL9B (fig.	('hsBCL9CT-35', 'Var', (24, 35))	('SAH', 'Disease', (201, 204))	('rat', 'Species', '10116', (117, 120))	('SAH', 'Disease', 'MESH:D013345', (201, 204))
69826	31086813	Expression of CD44 and VEGFA, two downstream targets of Wnt/beta-cat signaling with pathological significance, markedly decreased upon hsBCL9CT-24 treatment (Fig.	('decreased', 'NegReg', (120, 129))	('beta-cat', 'Gene', (60, 68))	('hsBCL9CT-24', 'Chemical', '-', (135, 146))	('Expression', 'MPA', (0, 10))	('beta-cat', 'Gene', '12387', (60, 68))	('VEGFA', 'Protein', (23, 28))	('hsBCL9CT-24', 'Var', (135, 146))	('CD44', 'Gene', (14, 18))
69828	31086813	Ten patient-derived CRC tissue samples were stained for beta-cat, BCL9, c-Myc, and CD44 (fig.	('beta-cat', 'Gene', '12387', (56, 64))	('CRC', 'Phenotype', 'HP:0003003', (20, 23))	('CD44', 'Var', (83, 87))	('C', 'Chemical', 'MESH:D002244', (20, 21))	('patient', 'Species', '9606', (4, 11))	('C', 'Chemical', 'MESH:D002244', (22, 23))	('C', 'Chemical', 'MESH:D002244', (67, 68))	('beta-cat', 'Gene', (56, 64))	('BCL9', 'Protein', (66, 70))	('C', 'Chemical', 'MESH:D002244', (83, 84))
69833	31086813	hsBCL9CT-24 significantly reduced tumor volume relative to control throughout the study period, with a TGI of 75% by day 31 (Fig.	('hsBCL9CT-24', 'Var', (0, 11))	('tumor', 'Disease', (34, 39))	('reduced', 'NegReg', (26, 33))	('hsBCL9CT-24', 'Chemical', '-', (0, 11))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
69835	31086813	Consistently, CD44 expression was reduced in tumors treated with hsBCL9CT-24 (Fig.	('C', 'Chemical', 'MESH:D002244', (14, 15))	('expression', 'MPA', (19, 29))	('reduced', 'NegReg', (34, 41))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumors', 'Disease', (45, 51))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('hsBCL9CT-24', 'Var', (65, 76))	('CD44', 'Protein', (14, 18))	('tumors', 'Disease', 'MESH:D009369', (45, 51))	('C', 'Chemical', 'MESH:D002244', (71, 72))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('C', 'Chemical', 'MESH:D002244', (68, 69))	('hsBCL9CT-24', 'Chemical', '-', (65, 76))
69837	31086813	In nude mice, hsBCL9CT-24 exhibited a comparable potency against the growth of CT26 as compared to the Colo320DM and PDX models, with a TGI of 76% upon 7-day treatment (Fig.	('C', 'Chemical', 'MESH:D002244', (17, 18))	('C', 'Chemical', 'MESH:D002244', (103, 104))	('hsBCL9CT-24', 'Var', (14, 25))	('CT26', 'Gene', '168400', (79, 83))	('CT26', 'Gene', (79, 83))	('nude mice', 'Species', '10090', (3, 12))	('C', 'Chemical', 'MESH:D002244', (20, 21))	('C', 'Chemical', 'MESH:D002244', (79, 80))	('hsBCL9CT-24', 'Chemical', '-', (14, 25))
69840	31086813	Consistently, treatment with hsBCL9CT-24 significantly prolonged the survival of animals (fig.	('C', 'Chemical', 'MESH:D002244', (35, 36))	('hsBCL9CT-24', 'Chemical', '-', (29, 40))	('survival', 'CPA', (69, 77))	('C', 'Chemical', 'MESH:D002244', (32, 33))	('hsBCL9CT-24', 'Var', (29, 40))	('prolonged', 'PosReg', (55, 64))	('C', 'Chemical', 'MESH:D002244', (0, 1))
69843	31086813	S5E), while with the same dose, hsBCL9CT-24 proved similar to oxaliplatin and much more effective than ICG-001 and erlotinib (Fig.	('erlotinib', 'Chemical', 'MESH:D000069347', (115, 124))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (62, 73))	('hsBCL9CT-24', 'Chemical', '-', (32, 43))	('effective', 'MPA', (88, 97))	('ICG', 'Chemical', 'MESH:D007208', (103, 106))	('hsBCL9CT-24', 'Var', (32, 43))
69852	31086813	These findings suggest a correlation among aberrant Wnt pathway activation, Treg cell infiltration, and CD8+ T cell inhibition in CRC.	('Treg cell infiltration', 'CPA', (76, 98))	('CRC', 'Phenotype', 'HP:0003003', (130, 133))	('C', 'Chemical', 'MESH:D002244', (104, 105))	('C', 'Chemical', 'MESH:D002244', (132, 133))	('rat', 'Species', '10116', (92, 95))	('CD8', 'Gene', (104, 107))	('C', 'Chemical', 'MESH:D002244', (130, 131))	('Wnt pathway', 'Pathway', (52, 63))	('activation', 'PosReg', (64, 74))	('CRC', 'Disease', (130, 133))	('CD8', 'Gene', '925', (104, 107))	('aberrant', 'Var', (43, 51))
69854	31086813	In human colon cancer, coexpression of the above T cell markers is the hallmark of hyper-suppressive Treg cells, which are correlated with poor prognosis of CRC patients.	('coexpression', 'Var', (23, 35))	('colon cancer', 'Disease', 'MESH:D015179', (9, 21))	('C', 'Chemical', 'MESH:D002244', (159, 160))	('human', 'Species', '9606', (3, 8))	('colon cancer', 'Disease', (9, 21))	('patients', 'Species', '9606', (161, 169))	('CRC', 'Disease', (157, 160))	('C', 'Chemical', 'MESH:D002244', (157, 158))	('correlated', 'Reg', (123, 133))	('colon cancer', 'Phenotype', 'HP:0003003', (9, 21))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('CRC', 'Phenotype', 'HP:0003003', (157, 160))
69856	31086813	To further examine these results, human CRC tumors were stratified into two categories, Treg-hi (CD4-hi, CD25-hi, and FOXP3-hi) and Treg-lo (CD4-lo, CD25-lo, and FOXP3-lo), and the same Wnt pathway genes were markedly up-regulated in the Treg-hi cohort (Fig.	('FOXP3-lo', 'Var', (162, 170))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('human', 'Species', '9606', (34, 39))	('CD25-lo', 'Var', (149, 156))	('CRC tumors', 'Disease', (40, 50))	('CRC tumors', 'Disease', 'MESH:D015179', (40, 50))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('rat', 'Species', '10116', (58, 61))	('up-regulated', 'PosReg', (218, 230))	('CRC', 'Phenotype', 'HP:0003003', (40, 43))	('Wnt pathway', 'Pathway', (186, 197))
69863	31086813	In the CT26 syngeneic CRC model, treatment of hsBCL9CT-24 led to a marked decrease of intratumoral Treg cell count in the overall CD45+ T cell populations (Fig.	('decrease', 'NegReg', (74, 82))	('C', 'Chemical', 'MESH:D002244', (7, 8))	('C', 'Chemical', 'MESH:D002244', (52, 53))	('C', 'Chemical', 'MESH:D002244', (49, 50))	('hsBCL9CT-24', 'Chemical', '-', (46, 57))	('CT26', 'Gene', '168400', (7, 11))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('CT26', 'Gene', (7, 11))	('rat', 'Species', '10116', (89, 92))	('CD45', 'Gene', '19264', (130, 134))	('hsBCL9CT-24', 'Var', (46, 57))	('C', 'Chemical', 'MESH:D002244', (22, 23))	('C', 'Chemical', 'MESH:D002244', (130, 131))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('CD45', 'Gene', (130, 134))	('CRC', 'Phenotype', 'HP:0003003', (22, 25))	('tumor', 'Disease', (91, 96))	('C', 'Chemical', 'MESH:D002244', (24, 25))
69872	31086813	Mechanistically, blockage of the Wnt pathway by hsBCL9CT-24 inhibited the expression of TGFB1 in CT26 cells, consequently leading to reduction of CCL20 and CCL22, two TGF-beta-dependent chemokines critical for Treg cell recruitment into the TME (Fig.	('Wnt pathway', 'Pathway', (33, 44))	('expression', 'MPA', (74, 84))	('CCL20', 'Gene', '20297', (146, 151))	('CCL22', 'Gene', '20299', (156, 161))	('CCL22', 'Gene', (156, 161))	('hsBCL9CT-24', 'Var', (48, 59))	('reduction', 'NegReg', (133, 142))	('TGF-beta', 'Gene', '21803', (167, 175))	('CT26', 'Gene', '168400', (97, 101))	('inhibited', 'NegReg', (60, 69))	('CCL20', 'Gene', (146, 151))	('blockage', 'NegReg', (17, 25))	('CT26', 'Gene', (97, 101))	('TGFB1', 'Gene', '21803', (88, 93))	('TGFB1', 'Gene', (88, 93))	('hsBCL9CT-24', 'Chemical', '-', (48, 59))	('TGF-beta', 'Gene', (167, 175))
69877	31086813	However, inhibition of the Wnt pathway by hsBCL9CT-24 functionally increased intratumoral infiltration of CD103+CD11c+ DCs in CT26 tumors (Fig.	('CD11c', 'Gene', (112, 117))	('CD103', 'Gene', (106, 111))	('C', 'Chemical', 'MESH:D002244', (45, 46))	('CT26', 'Gene', (126, 130))	('tumor', 'Disease', (131, 136))	('C', 'Chemical', 'MESH:D002244', (106, 107))	('tumor', 'Disease', (82, 87))	('CD11c', 'Gene', '16411', (112, 117))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('rat', 'Species', '10116', (80, 83))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('Wnt pathway', 'Pathway', (27, 38))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('increased', 'PosReg', (67, 76))	('C', 'Chemical', 'MESH:D002244', (112, 113))	('C', 'Chemical', 'MESH:D002244', (120, 121))	('hsBCL9CT-24', 'Chemical', '-', (42, 53))	('C', 'Chemical', 'MESH:D002244', (48, 49))	('CT26', 'Gene', '168400', (126, 130))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumors', 'Disease', (131, 137))	('C', 'Chemical', 'MESH:D002244', (126, 127))	('CD103', 'Gene', '16407', (106, 111))	('inhibition', 'NegReg', (9, 19))	('hsBCL9CT-24', 'Var', (42, 53))	('tumors', 'Disease', 'MESH:D009369', (131, 137))	('rat', 'Species', '10116', (96, 99))
69884	31086813	Treatment using hsBCL9CT-24 led to an over 10-fold increase in effector CD8+ cells, as indicated by expression patterns of CD44+CD62L- (Fig.	('increase', 'PosReg', (51, 59))	('hsBCL9CT-24', 'Chemical', '-', (16, 27))	('hsBCL9CT-24', 'Var', (16, 27))	('CD8', 'Gene', (72, 75))	('CD62L', 'Gene', '20343', (128, 133))	('CD62L', 'Gene', (128, 133))	('CD8', 'Gene', '925', (72, 75))
69885	31086813	Alongside elevation of CD8+ cell counts, several other anticancer immune cell populations, including effector CD4+ T cells and T helper 17 (TH17) cells, also surged upon hsBCL9CT-24 treatment (fig.	('hsBCL9CT-24', 'Chemical', '-', (170, 181))	('CD8', 'Gene', (23, 26))	('CD8', 'Gene', '925', (23, 26))	('surged', 'PosReg', (158, 164))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('hsBCL9CT-24', 'Var', (170, 181))	('elevation', 'PosReg', (10, 19))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))
69893	31086813	These results suggest that blockage of the Wnt pathway by hsBCL9CT-24 can overcome resistance to anti-PD-1 therapy by increasing active, cytotoxic Teff cell infiltration.	('rat', 'Species', '10116', (163, 166))	('hsBCL9CT-24', 'Var', (58, 69))	('increasing', 'PosReg', (118, 128))	('PD-1', 'Gene', '18566', (102, 106))	('Wnt pathway', 'Pathway', (43, 54))	('PD-1', 'Gene', (102, 106))	('hsBCL9CT-24', 'Chemical', '-', (58, 69))	('blockage', 'Var', (27, 35))
69897	31086813	In this study, we identified a set of stapled peptides that can potently inhibit beta-cat activity by specifically targeting its interaction with the coactivator BCL9.	('peptides', 'Var', (46, 54))	('beta-cat', 'Gene', (81, 89))	('beta-cat', 'Gene', '12387', (81, 89))	('targeting', 'Reg', (115, 124))	('interaction', 'Interaction', (129, 140))	('inhibit', 'NegReg', (73, 80))
69902	31086813	Consistently, genetic deletion of BCL9 and B9L in the murine gut results in no overt phenotypic consequences, indicating that blockade of BCL9 function may not be harmful to normal colon cells.	('B9L', 'Gene', '80288', (43, 46))	('BCL9', 'Gene', (34, 38))	('genetic deletion', 'Var', (14, 30))	('B9L', 'Gene', (43, 46))	('murine', 'Species', '10090', (54, 60))	('C', 'Chemical', 'MESH:D002244', (35, 36))	('C', 'Chemical', 'MESH:D002244', (139, 140))	('C', 'Chemical', 'MESH:D002244', (0, 1))
69906	31086813	Previous studies have shown that the simultaneous mutation of L156A and L159A in beta-cat disrupts only BCL9 binding, but not cadherin binding, indicating that key beta-cat/BCL9 hydrophobic residues likely do not interfere with the interaction between beta-cat and E-cadherin.	('beta-cat', 'Gene', '12387', (81, 89))	('BCL9', 'MPA', (104, 108))	('cadherin', 'Gene', (126, 134))	('cadherin', 'Gene', '12550', (126, 134))	('beta-cat', 'Gene', (81, 89))	('cadherin', 'Gene', (267, 275))	('cadherin', 'Gene', '12550', (267, 275))	('L156A', 'Var', (62, 67))	('E-cadherin', 'Gene', (265, 275))	('beta-cat', 'Gene', '12387', (252, 260))	('L159A', 'Var', (72, 77))	('interaction', 'Interaction', (232, 243))	('beta-cat', 'Gene', '12387', (164, 172))	('E-cadherin', 'Gene', '12550', (265, 275))	('beta-cat', 'Gene', (252, 260))	('beta-cat', 'Gene', (164, 172))	('L156A', 'Mutation', 'p.L156A', (62, 67))	('L159A', 'Mutation', 'p.L159A', (72, 77))	('disrupts', 'NegReg', (90, 98))
69909	31086813	While treatment of hsBCL9CT-24 caused mild loss of body weight and food intake early on, these adverse effects can be reversed in time without termination of treatment.	('hsBCL9CT-24', 'Chemical', '-', (19, 30))	('loss of body weight', 'Disease', 'MESH:D015431', (43, 62))	('hsBCL9CT-24', 'Var', (19, 30))	('loss of body weight', 'Disease', (43, 62))
69918	31086813	One of the best examples is CRC; over 90% of sporadic CRCs contain mutations in Wnt signaling, several components of which function as either tumor suppressors or oncogenes.	('C', 'Chemical', 'MESH:D002244', (28, 29))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('contain', 'Reg', (59, 66))	('C', 'Chemical', 'MESH:D002244', (56, 57))	('tumor', 'Disease', (142, 147))	('CRC', 'Phenotype', 'HP:0003003', (28, 31))	('mutations', 'Var', (67, 76))	('CRCs', 'Disease', (54, 58))	('Wnt', 'Pathway', (80, 83))	('C', 'Chemical', 'MESH:D002244', (54, 55))	('C', 'Chemical', 'MESH:D002244', (30, 31))	('CRC', 'Phenotype', 'HP:0003003', (54, 57))	('tumor', 'Disease', 'MESH:D009369', (142, 147))
69928	31086813	In this study, we found that tumor infiltration of Treg cells is significantly increased in CRC patients harboring APC mutations.	('increased', 'PosReg', (79, 88))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('C', 'Chemical', 'MESH:D002244', (117, 118))	('C', 'Chemical', 'MESH:D002244', (94, 95))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('CRC', 'Disease', (92, 95))	('tumor', 'Disease', (29, 34))	('rat', 'Species', '10116', (41, 44))	('C', 'Chemical', 'MESH:D002244', (92, 93))	('APC', 'Gene', (115, 118))	('patients', 'Species', '9606', (96, 104))	('APC', 'Phenotype', 'HP:0005227', (115, 118))	('mutations', 'Var', (119, 128))	('CRC', 'Phenotype', 'HP:0003003', (92, 95))
69930	31086813	Therefore, our findings suggest that one can effectively enhance anticancer immunity in the majority of CRC patients by blocking Wnt signaling, because over 80% of all CRC patients have APC mutations.	('CRC', 'Phenotype', 'HP:0003003', (168, 171))	('C', 'Chemical', 'MESH:D002244', (168, 169))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('enhance', 'PosReg', (57, 64))	('C', 'Chemical', 'MESH:D002244', (170, 171))	('C', 'Chemical', 'MESH:D002244', (104, 105))	('mutations', 'Var', (190, 199))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('CRC', 'Phenotype', 'HP:0003003', (104, 107))	('APC', 'Phenotype', 'HP:0005227', (186, 189))	('patients', 'Species', '9606', (172, 180))	('patients', 'Species', '9606', (108, 116))	('APC', 'Gene', (186, 189))	('C', 'Chemical', 'MESH:D002244', (106, 107))	('Wnt signaling', 'MPA', (129, 142))	('C', 'Chemical', 'MESH:D002244', (188, 189))	('cancer', 'Disease', (69, 75))	('blocking', 'NegReg', (120, 128))
69931	31086813	Using hsBCL9CT-24, we found that blockage of the oncogenic Wnt pathway can reduce Treg cell infiltration and overcome resistance to anti-PD-1 Ab in multiple cancer models.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('PD-1', 'Gene', (137, 141))	('reduce', 'NegReg', (75, 81))	('oncogenic Wnt pathway', 'Pathway', (49, 70))	('multiple cancer', 'Disease', 'MESH:D009369', (148, 163))	('rat', 'Species', '10116', (98, 101))	('blockage', 'Var', (33, 41))	('Treg cell infiltration', 'CPA', (82, 104))	('hsBCL9CT-24', 'Chemical', '-', (6, 17))	('multiple cancer', 'Disease', (148, 163))	('PD-1', 'Gene', '18566', (137, 141))
69932	31086813	The use of hsBCL9CT-24 peptide primarily reduces Treg cell infiltration without affecting Treg cell survival, making it an ideal strategy to reactivate intratumoral Teff cells and transform a "cold" immune microenvironment into a "hot" one.	('tumor', 'Disease', (157, 162))	('hsBCL9CT-24', 'Var', (11, 22))	('rat', 'Species', '10116', (131, 134))	('reduces', 'NegReg', (41, 48))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('hsBCL9CT-24 peptide', 'Chemical', '-', (11, 30))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('rat', 'Species', '10116', (155, 158))	('Treg cell infiltration', 'CPA', (49, 71))	('rat', 'Species', '10116', (65, 68))
69934	31086813	While it has been shown in melanoma that tumor-intrinsic Wnt signaling can inhibit the activation and infiltration of DCs and therefore promote immune evasion of cancer cells, we did not observe a significant correlation between DC infiltration and APC mutations in CRCs.	('C', 'Chemical', 'MESH:D002244', (251, 252))	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('promote', 'PosReg', (136, 143))	('cancer', 'Disease', (162, 168))	('C', 'Chemical', 'MESH:D002244', (266, 267))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('activation', 'MPA', (87, 97))	('CRC', 'Phenotype', 'HP:0003003', (266, 269))	('melanoma', 'Disease', 'MESH:D008545', (27, 35))	('CRCs', 'Gene', (266, 270))	('mutations', 'Var', (253, 262))	('C', 'Chemical', 'MESH:D002244', (230, 231))	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('rat', 'Species', '10116', (108, 111))	('tumor', 'Disease', (41, 46))	('inhibit', 'NegReg', (75, 82))	('infiltration', 'CPA', (102, 114))	('DCs', 'Protein', (118, 121))	('melanoma', 'Phenotype', 'HP:0002861', (27, 35))	('melanoma', 'Disease', (27, 35))	('C', 'Chemical', 'MESH:D002244', (119, 120))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('APC', 'Phenotype', 'HP:0005227', (249, 252))	('C', 'Chemical', 'MESH:D002244', (268, 269))	('APC', 'Gene', (249, 252))	('rat', 'Species', '10116', (238, 241))
69935	31086813	Despite these emerging tissue specificities, blockage of the Wnt pathway in cancer cells by hsBCL9CT-24 can simultaneously suppress Treg cell infiltration while increasing DC infiltration through different mechanisms, resulting in a marked elevation of active CD8+ T cells in colon cancer models.	('Wnt pathway', 'Pathway', (61, 72))	('colon cancer', 'Disease', (276, 288))	('hsBCL9CT-24', 'Chemical', '-', (92, 103))	('DC infiltration', 'MPA', (172, 187))	('C', 'Chemical', 'MESH:D002244', (98, 99))	('cancer', 'Disease', 'MESH:D009369', (282, 288))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('blockage', 'Var', (45, 53))	('Treg cell infiltration', 'CPA', (132, 154))	('CD8', 'Gene', '925', (260, 263))	('elevation', 'PosReg', (240, 249))	('hsBCL9CT-24', 'Var', (92, 103))	('rat', 'Species', '10116', (181, 184))	('colon cancer', 'Phenotype', 'HP:0003003', (276, 288))	('rat', 'Species', '10116', (148, 151))	('C', 'Chemical', 'MESH:D002244', (95, 96))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', (282, 288))	('CD8', 'Gene', (260, 263))	('colon cancer', 'Disease', 'MESH:D015179', (276, 288))	('cancer', 'Phenotype', 'HP:0002664', (282, 288))	('C', 'Chemical', 'MESH:D002244', (173, 174))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('increasing', 'PosReg', (161, 171))	('suppress', 'NegReg', (123, 131))	('C', 'Chemical', 'MESH:D002244', (260, 261))
70003	31086813	Cells were then stained with CD4-FITC (eBioscience, clone GK1.5), CD8a-allophycocyanin (eBioscience, clone 53-6.7), CD3-peridinin chlorophyll protein (PerCP)-Cy5.5 (BioLegend), FOXP3-allophycocyanin (eBioscience), CD25-phycoerythrin (PE) (BioLegend), CD45-PeCP.Cy5.5 (eBioscience), CD44-PE (eBioscience), CD62L-eFluor 450 (eBioscience), interferon-gamma (IFN-gamma)-PE (PeproTech), or granzyme B-eFluor 450 (eBioscience).	('C', 'Chemical', 'MESH:D002244', (251, 252))	('FITC', 'Chemical', 'MESH:D016650', (33, 37))	('granzyme B', 'Gene', (385, 395))	('CD3', 'Gene', (116, 119))	('C', 'Chemical', 'MESH:D002244', (282, 283))	('C', 'Chemical', 'MESH:D002244', (36, 37))	('GK1.5', 'Gene', '16607', (58, 63))	('C', 'Chemical', 'MESH:D002244', (305, 306))	('IFN-gamma', 'Gene', '15978', (355, 364))	('granzyme B', 'Gene', '14939', (385, 395))	('C', 'Chemical', 'MESH:D002244', (154, 155))	('C', 'Chemical', 'MESH:D002244', (66, 67))	('IFN-gamma', 'Gene', (355, 364))	('CD3', 'Gene', '12501', (116, 119))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('CD45', 'Gene', '19264', (251, 255))	('C', 'Chemical', 'MESH:D002244', (214, 215))	('CD45', 'Gene', (251, 255))	('C', 'Chemical', 'MESH:D002244', (158, 159))	('CD62L', 'Gene', (305, 310))	('CD44-PE', 'Var', (282, 289))	('C', 'Chemical', 'MESH:D002244', (261, 262))	('CD8a', 'Gene', '12525', (66, 70))	('C', 'Chemical', 'MESH:D002244', (29, 30))	('CD8a', 'Gene', (66, 70))	('C', 'Chemical', 'MESH:D002244', (116, 117))	('C', 'Chemical', 'MESH:D002244', (258, 259))	('CD62L', 'Gene', '20343', (305, 310))	('GK1.5', 'Gene', (58, 63))
70005	31086813	To identify Treg cells, the following gating strategies were used: (i) selection of live single-cell leukocytes [side scatter (SSC)-W/H low, anti-CD45+], (ii) selection of CD4+ T cells (anti-CD4+, anti-CD8-), and (iii) selection of CD25+FOXP3+ Treg cells (anti-CD25+, anti-FOXP3+).	('CD45', 'Gene', (146, 150))	('CD45', 'Gene', '19264', (146, 150))	('C', 'Chemical', 'MESH:D002244', (202, 203))	('C', 'Chemical', 'MESH:D002244', (261, 262))	('anti-FOXP3+', 'Var', (268, 279))	('C', 'Chemical', 'MESH:D002244', (146, 147))	('CD8', 'Gene', (202, 205))	('C', 'Chemical', 'MESH:D002244', (232, 233))	('rat', 'Species', '10116', (47, 50))	('CD8', 'Gene', '925', (202, 205))	('anti-CD25+', 'Var', (256, 266))	('C', 'Chemical', 'MESH:D002244', (191, 192))	('C', 'Chemical', 'MESH:D002244', (129, 130))	('anti-CD4+', 'Var', (186, 195))	('C', 'Chemical', 'MESH:D002244', (172, 173))
70006	31086813	To identify TH17 cells, the following gating strategies were used: (i) selection of live single-cell leukocytes [side scatter (SSC)-W/H low, anti-CD45+] and (ii) selection of CD194+CD196+ T cells (anti-CD194+, anti-CD196+), CD194-Brilliant Violet 421 (BioLegend), and CD196-PE (eBioscience).	('CD45', 'Gene', (146, 150))	('CD45', 'Gene', '19264', (146, 150))	('C', 'Chemical', 'MESH:D002244', (268, 269))	('C', 'Chemical', 'MESH:D002244', (224, 225))	('C', 'Chemical', 'MESH:D002244', (202, 203))	('C', 'Chemical', 'MESH:D002244', (146, 147))	('rat', 'Species', '10116', (47, 50))	('anti-CD196+', 'Var', (210, 221))	('C', 'Chemical', 'MESH:D002244', (129, 130))	('C', 'Chemical', 'MESH:D002244', (175, 176))	('C', 'Chemical', 'MESH:D002244', (215, 216))	('CD196-PE', 'Var', (268, 276))	('C', 'Chemical', 'MESH:D002244', (181, 182))	('CD194+CD196+', 'Var', (175, 187))	('CD194-Brilliant', 'Var', (224, 239))	('CD194-Brilliant Violet', 'Chemical', '-', (224, 246))
70058	31086813	COAD samples were separated into two APC mutated and nonmutated cohorts, and t test was used to evaluate CD8+ T cell and Treg cell infiltration difference between APC mutated and nonmutated samples.	('CD8', 'Gene', (105, 108))	('COAD', 'Disease', (0, 4))	('CD8', 'Gene', '925', (105, 108))	('rat', 'Species', '10116', (22, 25))	('APC', 'Phenotype', 'HP:0005227', (163, 166))	('rat', 'Species', '10116', (137, 140))	('COAD', 'Disease', 'MESH:D029424', (0, 4))	('mutated', 'Var', (167, 174))	('APC', 'Phenotype', 'HP:0005227', (37, 40))
70071	29774202	Gain- and loss-of-function experiments have shown that brachyury expression in epithelial cancer cells associates with (a) enhanced expression of mesenchymal proteins and reduction of epithelial proteins; (b) acquisition of tumor motility, invasiveness, and propensity to disseminate in vivo in xenograft models; (c) acquisition of stemness features, including a relatively quiescent state; and (d) conversion into a refractory, therapy-resistant state.	('enhanced', 'PosReg', (123, 131))	('tumor motility', 'Disease', (224, 238))	('brachyury', 'Gene', (55, 64))	('invasiveness', 'CPA', (240, 252))	('stemness', 'CPA', (332, 340))	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('acquisition', 'PosReg', (317, 328))	('reduction', 'NegReg', (171, 180))	('acquisition', 'PosReg', (209, 220))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('epithelial cancer', 'Phenotype', 'HP:0031492', (79, 96))	('epithelial proteins', 'MPA', (184, 203))	('expression', 'MPA', (132, 142))	('cancer', 'Disease', (90, 96))	('expression', 'Var', (65, 75))	('tumor motility', 'Disease', 'MESH:D015835', (224, 238))
70078	29774202	In the present study, we further investigated the mechanism involved in the immune resistance of carcinoma cells that express high levels of brachyury, and demonstrate that the loss of the cyclin-dependent kinase inhibitor 1 (p21CIP1, hereafter termed p21) is critical for the defective lysis of these cancer cells.	('lysis', 'CPA', (287, 292))	('carcinoma', 'Disease', 'MESH:D002277', (97, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('high', 'Gene', '104137', (126, 130))	('cancer', 'Phenotype', 'HP:0002664', (302, 308))	('p21CIP1', 'Gene', (226, 233))	('p21CIP1', 'Gene', '1026', (226, 233))	('carcinoma', 'Disease', (97, 106))	('loss', 'Var', (177, 181))	('cancer', 'Disease', 'MESH:D009369', (302, 308))	('cyclin-dependent kinase inhibitor 1', 'Gene', (189, 224))	('high', 'Gene', (126, 130))	('cyclin-dependent kinase inhibitor 1', 'Gene', '1026', (189, 224))	('cancer', 'Disease', (302, 308))
70080	29774202	The loss of p21 has been associated with the occurrence of epithelial-mesenchymal plasticity in cancer.	('associated', 'Reg', (25, 35))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('epithelial-mesenchymal plasticity', 'CPA', (59, 92))	('p21', 'Gene', (12, 15))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Disease', (96, 102))	('loss', 'Var', (4, 8))
70085	29774202	H460 cells were co-transfected with GeneArt Platinum Cas9 nuclease (Invitrogen) and brachyury-targeting gRNA by following the manufacturer's instructions, and subsequently grown and seeded for single cell sub-culture onto 96-well plates.	('GeneArt', 'Var', (36, 43))	('brachyury-targeting', 'Gene', (84, 103))	('H460', 'CellLine', 'CVCL:0459', (0, 4))
70090	29774202	T cells specific for the MUC1 HLA-A2 restricted peptide p93L (ALWGQDVTSV) were previously described.	('MUC1', 'Gene', (25, 29))	('MUC1', 'Gene', '4582', (25, 29))	('p93L', 'Var', (56, 60))
70104	29774202	cDNA (1-100 ng) was amplified in triplicate using Gene Expression Master Mix and the following TaqMan gene expression assays (Thermo Fisher Scientific): brachyury (Hs00610080), and GAPDH (4326317E).	('4326317E', 'Var', (188, 196))	('Hs00610080', 'Var', (164, 174))	('GAPDH', 'Gene', '2597', (181, 186))	('GAPDH', 'Gene', (181, 186))
70108	29774202	Carcinoma cell lines were treated with indicated concentrations of MK-1775 for 72 h prior to the addition of immune effector cells or a combination of cisplatin (APP Pharmaceuticals) and vinorelbine (Bedford Laboratories).	('cisplatin', 'Chemical', 'MESH:D002945', (151, 160))	('Carcinoma', 'Phenotype', 'HP:0030731', (0, 9))	('MK-1775', 'Var', (67, 74))	('MK-1775', 'Chemical', 'MESH:C549567', (67, 74))	('vinorelbine', 'Chemical', 'MESH:D000077235', (187, 198))	('Carcinoma cell lines', 'Disease', 'MESH:C538614', (0, 20))	('Carcinoma cell lines', 'Disease', (0, 20))
70112	29774202	The remaining 164 samples were ranked and subdivided into tertiles based upon the level of brachyury expression: "brachyury-high" (55 of 482), "brachyury-intermediate" (55 of 482), and "brachyury-low" (54 of 482) groups.	('high', 'Gene', (124, 128))	('brachyury-low', 'Var', (186, 199))	('high', 'Gene', '104137', (124, 128))
70118	29774202	As shown in Figure 1B (right panel), H460 cells with high levels of brachyury (Hi) were lysed less efficiently than those with undetectable brachyury (Lo).	('high', 'Gene', (53, 57))	('H460', 'CellLine', 'CVCL:0459', (37, 41))	('brachyury', 'Var', (68, 77))	('high', 'Gene', '104137', (53, 57))
70126	29774202	Using this isogenic pair of p21-low vs. p21-high cells, susceptibility to immune lysis was evaluated.	('high', 'Gene', (44, 48))	('immune lysis', 'Disease', (74, 86))	('p21-low', 'Var', (28, 35))	('high', 'Gene', '104137', (44, 48))
70128	29774202	This increased sensitivity to cell death was not restricted to immune-mediated lysis, as the H460-p21 cells were also more sensitive to killing by a combination of cisplatin and vinorelbine chemotherapy (Figure 3F) than tumor cells with low levels of p21 (H460-pCMV).	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('tumor', 'Disease', (220, 225))	('vinorelbine', 'Chemical', 'MESH:D000077235', (178, 189))	('sensitive', 'MPA', (123, 132))	('H460', 'CellLine', 'CVCL:0459', (93, 97))	('tumor', 'Disease', 'MESH:D009369', (220, 225))	('H460-p21', 'Var', (93, 101))	('H460', 'CellLine', 'CVCL:0459', (256, 260))	('cisplatin', 'Chemical', 'MESH:D002945', (164, 173))
70129	29774202	Interestingly, overexpression of p21 in these cells was associated with a reduction of vimentin expression (Figure 3A), an observation in agreement with several previous reports on the ability of p21 to inhibit the epithelial-mesenchymal switch in tumor cells.	('vimentin', 'Gene', '7431', (87, 95))	('tumor', 'Disease', (248, 253))	('overexpression', 'PosReg', (15, 29))	('vimentin', 'Gene', (87, 95))	('reduction', 'NegReg', (74, 83))	('p21', 'Var', (33, 36))	('tumor', 'Disease', 'MESH:D009369', (248, 253))	('tumor', 'Phenotype', 'HP:0002664', (248, 253))	('inhibit', 'NegReg', (203, 210))
70130	29774202	In a previous study, we demonstrated that brachyury-mediated immune resistance associates with decreased levels of the cyclin-dependent kinase 1 (CDK1) protein, and that reconstitution of CDK1 levels could restore the tumor cells' susceptibility to immune effector cells.	('decreased', 'NegReg', (95, 104))	('CDK1', 'Gene', (188, 192))	('restore', 'PosReg', (206, 213))	('brachyury-mediated', 'Var', (42, 60))	('CDK1', 'Gene', '983', (188, 192))	('tumor', 'Disease', 'MESH:D009369', (218, 223))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('tumor', 'Disease', (218, 223))	('cyclin-dependent kinase 1', 'Gene', (119, 144))	('cyclin-dependent kinase 1', 'Gene', '983', (119, 144))	('CDK1', 'Gene', (146, 150))	('CDK1', 'Gene', '983', (146, 150))
70134	29774202	Interestingly, evaluation of the stability of CDK1 in the brachyury-high H460 cells demonstrated that reconstitution of p21 in the H460-p21 cells could increase the stability of CDK1 over that observed in H460-pCMV cells (Figure 4B).	('stability', 'MPA', (165, 174))	('CDK1', 'Gene', (46, 50))	('CDK1', 'Gene', '983', (46, 50))	('increase', 'PosReg', (152, 160))	('H460', 'CellLine', 'CVCL:0459', (73, 77))	('CDK1', 'Gene', '983', (178, 182))	('high', 'Gene', (68, 72))	('CDK1', 'Gene', (178, 182))	('H460', 'CellLine', 'CVCL:0459', (205, 209))	('p21', 'Var', (120, 123))	('H460', 'CellLine', 'CVCL:0459', (131, 135))	('high', 'Gene', '104137', (68, 72))
70140	29774202	As shown in Figure 4C, WEE1 inhibition was only able to improve the sensitivity of brachyury-high/p21-low (H460-pCMV) cells in response to chemotherapy, while the same treatment had no impact on the susceptibility of H460 cells over-expressing p21 (H460-p21).	('high', 'Gene', (93, 97))	('H460', 'CellLine', 'CVCL:0459', (217, 221))	('inhibition', 'Var', (28, 38))	('high', 'Gene', '104137', (93, 97))	('WEE1', 'Gene', (23, 27))	('response to chemotherapy', 'MPA', (127, 151))	('improve', 'PosReg', (56, 63))	('H460', 'CellLine', 'CVCL:0459', (107, 111))	('H460', 'CellLine', 'CVCL:0459', (249, 253))	('sensitivity', 'MPA', (68, 79))
70141	29774202	To evaluate our results in a murine carcinoma model, the colon carcinoma cell line MC38 was stable transfected with a plasmid vector encoding the full-length brachyury protein, followed by single-cell cloning and generation of three cell lines, MC38-Lo, -Int, and -Hi, with either low, intermediate, or high levels of brachyury, respectively (Figure 5A).	('carcinoma', 'Disease', 'MESH:D002277', (63, 72))	('high', 'Gene', (303, 307))	('murine', 'Species', '10090', (29, 35))	('MC38-Lo', 'CellLine', 'CVCL:B288', (245, 252))	('colon carcinoma', 'Disease', 'MESH:D015179', (57, 72))	('carcinoma', 'Disease', (63, 72))	('brachyury protein', 'Gene', '20997', (158, 175))	('high', 'Gene', '104137', (303, 307))	('carcinoma', 'Disease', 'MESH:D002277', (36, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (36, 45))	('brachyury protein', 'Gene', (158, 175))	('colon carcinoma', 'Disease', (57, 72))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))	('MC38-Lo', 'Var', (245, 252))	('carcinoma', 'Disease', (36, 45))
70142	29774202	The sensitivity of these cells to lysis by CD8+ T cells specific for an epitope (p15E) of the endogenous retroviral env protein GP70 was evaluated.	('env', 'Gene', '30816', (116, 119))	('GP70', 'Gene', '133418', (128, 132))	('env', 'Gene', (116, 119))	('p15E', 'Var', (81, 85))	('GP70', 'Gene', (128, 132))
70143	29774202	As shown in Figure 5B (left panel), MC38 cells expressing high levels of brachyury were poorly lysed in comparison with MC38 cells expressing either low or intermediate levels of brachyury.	('brachyury', 'Var', (73, 82))	('high', 'Gene', '104137', (58, 62))	('high', 'Gene', (58, 62))	('lysed', 'CPA', (95, 100))
70152	29774202	While MC38-pCMV were highly susceptible to the effect of TRAIL and were not affected by MK-1775 treatment, MC38-pBr cells appeared resistant to the lytic activity of TRAIL and treatment with MK-1775 was able to significantly enhance their lysis in a dose-dependent way.	('high', 'Gene', '104137', (21, 25))	('MK-1775', 'Var', (191, 198))	('TRAIL', 'Gene', (57, 62))	('MK-1775', 'Chemical', 'MESH:C549567', (191, 198))	('TRAIL', 'Gene', '8743', (166, 171))	('MC38-pBr', 'Var', (107, 115))	('MK-1775', 'Chemical', 'MESH:C549567', (88, 95))	('TRAIL', 'Gene', (166, 171))	('enhance', 'PosReg', (225, 232))	('TRAIL', 'Gene', '8743', (57, 62))	('lysis', 'CPA', (239, 244))	('high', 'Gene', (21, 25))
70157	29774202	Perhaps one of the most relevant consequences of this phenotypic modulation is the resulting acquisition of tumor cell resistance to a range of cell death-inducing signals, including those initiated by chemotherapy, radiation, some small molecule-targeted therapies and, as more recently shown, resistance to immune-mediated cytotoxicity.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('cytotoxicity', 'Disease', (325, 337))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('tumor', 'Disease', (108, 113))	('cytotoxicity', 'Disease', 'MESH:D064420', (325, 337))	('small', 'Var', (232, 237))
70167	29774202	Moreover, brachyury does not reduce the expression of various components of the antigen processing and presentation machinery, including TAP1, TAP2, tapasin, LMP2, and LMP7, thus ruling out a defect in antigen presentation as the cause of reduced sensitivity to immune attack.	('expression', 'MPA', (40, 50))	('tapasin', 'Gene', (149, 156))	('tapasin', 'Gene', '6892', (149, 156))	('TAP1', 'Gene', '6890', (137, 141))	('TAP2', 'Gene', (143, 147))	('TAP2', 'Gene', '6891', (143, 147))	('LMP2', 'Gene', (158, 162))	('brachyury', 'Var', (10, 19))	('LMP2', 'Gene', '5698', (158, 162))	('LMP7', 'Gene', (168, 172))	('LMP7', 'Gene', '5696', (168, 172))	('TAP1', 'Gene', (137, 141))
70168	29774202	Rather, we showed that brachyury induced a blockade of apoptosis even in the presence of normal levels of activated caspases, which was associated with the defective phosphorylation and cleavage of the nuclear lamins following triggering.	('caspases', 'Gene', (116, 124))	('brachyury', 'Var', (23, 32))	('nuclear lamins', 'Protein', (202, 216))	('caspases', 'Gene', '841', (116, 124))	('cleavage', 'MPA', (186, 194))	('phosphorylation', 'MPA', (166, 181))	('apoptosis', 'CPA', (55, 64))	('defective', 'NegReg', (156, 165))
70171	29774202	For example, p21 has been shown to act as a major adaptor protein that assembles cyclin D1/CDK4 complexes, targeting them into the nucleus and favoring cyclin D1-associated kinase activity.	('cyclin D1', 'Gene', (152, 161))	('targeting', 'PosReg', (107, 116))	('cyclin D1', 'Gene', '595', (81, 90))	('CDK4', 'Gene', '1019', (91, 95))	('CDK4', 'Gene', (91, 95))	('p21', 'Var', (13, 16))	('favoring', 'PosReg', (143, 151))	('cyclin D1', 'Gene', (81, 90))	('cyclin D1', 'Gene', '595', (152, 161))
70172	29774202	Thus, the p21 protein could exhibit both tumor suppressor and oncogenic properties, depending on the cellular context.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Disease', (41, 46))	('oncogenic properties', 'CPA', (62, 82))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('p21', 'Var', (10, 13))
70174	29774202	As shown with other regulators of the epithelial-mesenchymal phenomenon, expression of brachyury in carcinoma cells associates with a significant reduction in cell proliferation, whereby brachyury expression inversely correlates with the expression of phosphorylated Rb, Cyclin D1, and p21.	('Cyclin D1', 'Gene', (271, 280))	('expression', 'Var', (73, 83))	('carcinoma', 'Disease', 'MESH:D002277', (100, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('carcinoma', 'Disease', (100, 109))	('cell proliferation', 'CPA', (159, 177))	('Cyclin D1', 'Gene', '595', (271, 280))	('reduction', 'NegReg', (146, 155))	('brachyury', 'Gene', (87, 96))
70177	29774202	Liu et al., for example, demonstrated that deletion of p21 in transgenic mice not only accelerates mammary oncogenesis induced by MMTV-Ras and MMTV-c-Myc but also induces the acquisition of mesenchymal and stemness features in mammary tumors, in vivo.	('acquisition', 'CPA', (175, 186))	('c-Myc', 'Gene', '4609', (148, 153))	('deletion', 'Var', (43, 51))	('p21', 'Gene', (55, 58))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('c-Myc', 'Gene', (148, 153))	('tumors', 'Phenotype', 'HP:0002664', (235, 241))	('MMTV', 'Species', '11757', (130, 134))	('induces', 'Reg', (163, 170))	('MMTV', 'Species', '11757', (143, 147))	('transgenic mice', 'Species', '10090', (62, 77))	('tumors', 'Disease', 'MESH:D009369', (235, 241))	('mammary oncogenesis', 'CPA', (99, 118))	('accelerates', 'PosReg', (87, 98))	('tumors', 'Disease', (235, 241))
70178	29774202	Similar observations with mammary carcinoma cells demonstrated that silencing of p21 and PUMA, a target of p53, leads to loss of E-cadherin and increased expression of markers of the epithelial-mesenchymal phenotypic switch.	('carcinoma', 'Phenotype', 'HP:0030731', (34, 43))	('carcinoma', 'Disease', (34, 43))	('loss', 'NegReg', (121, 125))	('p53', 'Gene', (107, 110))	('p53', 'Gene', '7157', (107, 110))	('E-cadherin', 'Gene', (129, 139))	('E-cadherin', 'Gene', '999', (129, 139))	('silencing', 'Var', (68, 77))	('carcinoma', 'Disease', 'MESH:D002277', (34, 43))	('p21', 'Gene', (81, 84))	('mammary carcinoma', 'Phenotype', 'HP:0003002', (26, 43))	('PUMA', 'Gene', (89, 93))	('increased', 'PosReg', (144, 153))	('expression', 'MPA', (154, 164))
70179	29774202	In subsequent studies, p21 has been shown to modulate the expression of various miRNAs, including miR-200 and the miR-183 cluster, which in turn regulate the expression of genes involved in the epithelial-mesenchymal switch.	('miR-200', 'Gene', (98, 105))	('miR-183', 'Gene', '406959', (114, 121))	('miR-183', 'Gene', (114, 121))	('expression', 'MPA', (158, 168))	('expression', 'MPA', (58, 68))	('p21', 'Var', (23, 26))	('modulate', 'Reg', (45, 53))	('regulate', 'Reg', (145, 153))
70180	29774202	In various model systems, silencing of p21 increased mesenchymal features, including vimentin, fibronectin, N-cadherin, Slug, and Zeb1 expression, and increased tumor cell migration and invasiveness.	('increased', 'PosReg', (151, 160))	('Slug', 'Gene', (120, 124))	('invasiveness', 'CPA', (186, 198))	('N-cadherin', 'Gene', (108, 118))	('fibronectin', 'Gene', (95, 106))	('tumor', 'Disease', (161, 166))	('N-cadherin', 'Gene', '1000', (108, 118))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('increased', 'PosReg', (43, 52))	('p21', 'Gene', (39, 42))	('Slug', 'Gene', '6591', (120, 124))	('Zeb1', 'Gene', '6935', (130, 134))	('fibronectin', 'Gene', '2335', (95, 106))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('Zeb1', 'Gene', (130, 134))	('mesenchymal features', 'CPA', (53, 73))	('silencing', 'Var', (26, 35))	('vimentin', 'Gene', '7431', (85, 93))	('vimentin', 'Gene', (85, 93))
70181	29774202	The present report demonstrates that reconstitution of p21 in brachyury-high tumor cells markedly improves tumor cell lysis mediated by antigen-specific T cells, NK and LAK cells, TRAIL, and chemotherapy.	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('brachyury-high tumor', 'Disease', (62, 82))	('TRAIL', 'Gene', '8743', (180, 185))	('improves', 'PosReg', (98, 106))	('p21', 'Gene', (55, 58))	('reconstitution', 'Var', (37, 51))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('TRAIL', 'Gene', (180, 185))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('tumor', 'Disease', (77, 82))	('brachyury-high tumor', 'Disease', 'MESH:D009369', (62, 82))
70182	29774202	In addition, reconstitution of p21 in tumor cells with high levels of brachyury is shown here to increase the stability of the CDK1 protein, leading to higher levels of CDK1 expression and the anticipated increase in tumor susceptibility to lysis.	('high', 'Gene', (55, 59))	('levels', 'MPA', (159, 165))	('increase', 'PosReg', (205, 213))	('reconstitution', 'Var', (13, 27))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (217, 222))	('brachyury', 'Gene', (70, 79))	('tumor', 'Disease', 'MESH:D009369', (217, 222))	('CDK1', 'Gene', (169, 173))	('CDK1', 'Gene', '983', (169, 173))	('expression', 'MPA', (174, 184))	('CDK1', 'Gene', '983', (127, 131))	('CDK1', 'Gene', (127, 131))	('high', 'Gene', '104137', (152, 156))	('tumor', 'Disease', (38, 43))	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('increase', 'PosReg', (97, 105))	('high', 'Gene', (152, 156))	('high', 'Gene', '104137', (55, 59))	('stability', 'MPA', (110, 119))	('tumor', 'Disease', 'MESH:D009369', (38, 43))
70183	29774202	Our observations that the loss of p21 in brachyury-high carcinoma cells drives the acquisition of resistance to cytotoxic killing are in line with the concept that loss of this protein would also promote the acquisition of a more mesenchymal and resistant tumor status.	('loss', 'Var', (164, 168))	('p21', 'Gene', (34, 37))	('promote', 'PosReg', (196, 203))	('acquisition', 'MPA', (83, 94))	('tumor', 'Disease', 'MESH:D009369', (256, 261))	('resistance to cytotoxic killing', 'MPA', (98, 129))	('brachyury-high carcinoma', 'Disease', (41, 65))	('tumor', 'Phenotype', 'HP:0002664', (256, 261))	('loss', 'Var', (26, 30))	('tumor', 'Disease', (256, 261))	('carcinoma', 'Phenotype', 'HP:0030731', (56, 65))	('brachyury-high carcinoma', 'Disease', 'MESH:D002277', (41, 65))
70185	29774202	The WEE1 kinase regulates the G2 checkpoint in response to DNA damage, where WEE1 prevents entry into mitosis by mediating the inhibitory phosphorylation of CDK1.	('regulates', 'Reg', (16, 25))	('G2 checkpoint', 'MPA', (30, 43))	('CDK1', 'Gene', (157, 161))	('inhibitory phosphorylation', 'MPA', (127, 153))	('prevents', 'NegReg', (82, 90))	('CDK1', 'Gene', '983', (157, 161))	('WEE1', 'Var', (77, 81))	('mitosis', 'Disease', (102, 109))	('mitosis', 'Disease', 'None', (102, 109))
70186	29774202	Previous studies conducted with WEE1 inhibition have shown that the effect of this inhibitor is mainly observed in the context of p53 mutant tumors, where the G1 checkpoint is lost and cells solely rely on the G2 checkpoint for cell cycle arrest following exposure to genotoxic agents.	('lost', 'NegReg', (176, 180))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumors', 'Disease', (141, 147))	('tumors', 'Disease', 'MESH:D009369', (141, 147))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (228, 245))	('p53', 'Gene', (130, 133))	('mutant', 'Var', (134, 140))	('p53', 'Gene', '7157', (130, 133))
70189	29774202	In agreement with those results, inhibition of WEE1 kinase via treatment with MK-1775 improved the lysis of brachyury-high tumor cells only in the absence of p21, while the effect was lost when p21 was forcibly overexpressed in the presence of high brachyury.	('inhibition', 'Var', (33, 43))	('lysis', 'CPA', (99, 104))	('brachyury-high tumor', 'Disease', 'MESH:D009369', (108, 128))	('brachyury-high tumor', 'Disease', (108, 128))	('high', 'Gene', '104137', (244, 248))	('MK-1775', 'Gene', (78, 85))	('improved', 'PosReg', (86, 94))	('high', 'Gene', (118, 122))	('MK-1775', 'Chemical', 'MESH:C549567', (78, 85))	('high', 'Gene', '104137', (118, 122))	('high', 'Gene', (244, 248))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
70213	24885002	mechanisms for tumor lymphangiogenesis and metastasis to the regional lymph nodes as well as HER2/neu polymorphisms.	('HER2', 'Gene', '2064', (93, 97))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('metastasis to the regional lymph nodes', 'CPA', (43, 81))	('polymorphisms', 'Var', (102, 115))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('neu', 'Gene', '2064', (98, 101))	('tumor', 'Disease', (15, 20))	('neu', 'Gene', (98, 101))	('HER2', 'Gene', (93, 97))
70268	24885002	Interestingly, there was only one reported case (6%) of SCUBE2-positivity in lymph node-positive tumors, compared with SCUBE2-positivity in 41% of lymph node-negative tumors.	('tumors', 'Disease', 'MESH:D009369', (97, 103))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('SCUBE2-positivity', 'Var', (56, 73))	('tumors', 'Disease', (97, 103))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('tumors', 'Disease', 'MESH:D009369', (167, 173))	('tumors', 'Disease', (167, 173))	('tumors', 'Phenotype', 'HP:0002664', (167, 173))
70330	24885002	The function of the STK32B gene is not known, but single nucleotide polymorphisms in the STK32B gene have been associated with oral clefts.	('oral clefts', 'Disease', 'MESH:D002972', (127, 138))	('STK32B', 'Gene', (89, 95))	('STK32B', 'Gene', (20, 26))	('associated', 'Reg', (111, 121))	('oral clefts', 'Phenotype', 'HP:0000202', (127, 138))	('STK32B', 'Gene', '55351', (20, 26))	('single nucleotide polymorphisms', 'Var', (50, 81))	('STK32B', 'Gene', '55351', (89, 95))	('oral clefts', 'Disease', (127, 138))
70332	24885002	Leovic and colleagues illustrated the clinical relevance and aberrant expression of key hedgehog signaling components in SCCs of the oral cavity and oropharynx, i.e.	('aberrant', 'Var', (61, 69))	('hedgehog', 'Gene', (88, 96))	('hedgehog', 'Gene', '6469', (88, 96))	('SCCs of', 'Disease', (121, 128))
70349	33539340	Conversely, overexpression of either IFI6 or IFI27 counteracted the inhibition of TSCC cell growth and migration induced by the overexpression of ATF3.	('expression', 'Species', '29278', (16, 26))	('expression', 'Species', '29278', (132, 142))	('IFI27', 'Var', (45, 50))	('IFI6', 'Var', (37, 41))
70372	33539340	The quantification of cells that were positive for ATF3 in their nuclei in Fig 1B and 1C are shown in Fig 1D and 1E, respectively, indicated that the percentage of cells positive for ATF3 in their nuclei was significantly higher in normal oral epithelial cells compared to tumor cells (Fig 1D and 1E).	('higher', 'PosReg', (222, 228))	('tumor', 'Disease', 'MESH:D009369', (273, 278))	('tumor', 'Phenotype', 'HP:0002664', (273, 278))	('tumor', 'Disease', (273, 278))	('ATF3', 'Var', (183, 187))
70381	33539340	The inhibition of TSCC growth and migration by disruption of ATF3 expression was found to be correlated with the increased activation of AKT and ERK signaling pathways, as shown by significant increases of pAKT and pErk, while total levels of those factors were unaffected (red arrows, Fig 2F and 2G) and the efficient deletion of ATF3 was also confirmed (Fig 2F).	('TSCC growth', 'CPA', (18, 29))	('disruption', 'Var', (47, 57))	('pErk', 'MPA', (215, 219))	('expression', 'Species', '29278', (66, 76))	('increases', 'PosReg', (193, 202))	('ATF3', 'Gene', (61, 65))	('activation', 'PosReg', (123, 133))	('ERK signaling pathways', 'Pathway', (145, 167))	('inhibition', 'NegReg', (4, 14))	('pAKT', 'MPA', (206, 210))
70385	33539340	Ectopic expression of ATF3 significantly suppressed the growth of SCC-9 cells (Fig 3A), and also inhibited their migration in Transwell assays (Fig 3B and 3C) and in wound healing migration assays (Fig 3D and 3E).	('growth', 'CPA', (56, 62))	('suppressed', 'NegReg', (41, 51))	('Ectopic expression', 'Var', (0, 18))	('expression', 'Species', '29278', (8, 18))	('ATF3', 'Gene', (22, 26))	('migration', 'CPA', (113, 122))	('inhibited', 'NegReg', (97, 106))	('wound healing migration assays', 'CPA', (166, 196))	('SCC-9', 'CellLine', 'CVCL:1685', (66, 71))
70388	33539340	In order to understand the molecular mechanism by which ATF3 negatively regulates the growth and migration of TSCC cells, we analyzed the mRNA gene expression profile of CAL 27 cells with the deletion of ATF3 using RNA-seq.	('expression', 'Species', '29278', (148, 158))	('ATF3', 'Gene', (204, 208))	('deletion', 'Var', (192, 200))
70389	33539340	Since interferons, especially the cytokine interferon alpha (IFNalpha), have been shown to mediate diverse immune responses to tumors, we further investigated the roles of IFI6 and IFI27 in ATF3 deleted and in ATF3 overexpressing TSCC cells.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('deleted', 'Var', (195, 202))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('tumors', 'Disease', (127, 133))	('ATF3', 'Gene', (190, 194))	('tumors', 'Disease', 'MESH:D009369', (127, 133))
70392	33539340	That binding could be reduced by ATF3 deletion or enhanced by ATF3 overexpression (Fig 4E and 4F), but was not detected by control non-immune IgGs (S9 Fig).	('ATF3', 'Gene', (62, 66))	('overexpression', 'PosReg', (67, 81))	('ATF3', 'Gene', (33, 37))	('deletion', 'Var', (38, 46))	('reduced', 'NegReg', (22, 29))	('enhanced', 'PosReg', (50, 58))	('expression', 'Species', '29278', (71, 81))	('binding', 'Interaction', (5, 12))
70396	33539340	We found that the overexpression of IFI6 or IFI27 together with ATF3 (ATF3+IFI6 or ATF3+IFI27) counteracted the reduced growth and migration of SCC-9 cells with only the overexpression of ATF3 (ATF3+GFP) (Fig 5C), and the high expression levels of IFI6 or IGI27 were also verified by qRT-PCR (Fig 5D).	('expression', 'Species', '29278', (174, 184))	('expression', 'Species', '29278', (227, 237))	('SCC-9', 'CellLine', 'CVCL:1685', (144, 149))	('expression', 'Species', '29278', (22, 32))	('reduced', 'NegReg', (112, 119))	('ATF3+IFI27', 'Var', (83, 93))
70397	33539340	To analyze whether ATF3 regulates TSCC migration depending on the expression of IFI6 or IFI27, in vitro wound healing assays were carried out with ATF3 deleted cells with either knockdown IFI6 or IFI27 (SG1+siIFI6 or SG1+siIFI27) (the knockdown efficiencies of IFI6 or IFI27 are shown in S10 Fig) or the overexpression of IFI6 or IFI27 in ATF highly expressing cells (ATF3+IFI6 or ATF3+IFI27).	('expression', 'Species', '29278', (308, 318))	('IFI6', 'Var', (188, 192))	('expression', 'Species', '29278', (66, 76))	('knockdown IFI6', 'Var', (178, 192))	('SG1+siIFI27', 'Var', (217, 228))
70398	33539340	We found that knockdown of either IFI6 or IFI27 inhibited the migration increased by the deletion of ATF3 (Figs 5E and S11A) and that the forced expression of IFI6 or IFI27 could rescue the migration inhibition induced by the high expression of ATF3 (Figs 5F and S11B).	('S11A', 'Var', (119, 123))	('migration inhibition', 'CPA', (190, 210))	('S11B', 'SUBSTITUTION', 'None', (263, 267))	('ATF3', 'Gene', (101, 105))	('S11A', 'SUBSTITUTION', 'None', (119, 123))	('expression', 'Species', '29278', (145, 155))	('migration increased', 'CPA', (62, 81))	('deletion', 'Var', (89, 97))	('inhibited', 'NegReg', (48, 57))	('expression', 'Species', '29278', (231, 241))	('S11B', 'Var', (263, 267))
70399	33539340	The enhancement of TSCC migration by IFI6 and by IFI27 was further confirmed using trans-well migration assays (Figs 5G and S11C).	('enhancement', 'PosReg', (4, 15))	('S11C', 'Var', (124, 128))	('IFI6', 'Var', (37, 41))	('IFI27', 'Var', (49, 54))	('S11C', 'SUBSTITUTION', 'None', (124, 128))	('TSCC migration', 'CPA', (19, 33))
70400	33539340	Importantly, the corresponding changes of AKT or ERK activity induced by the deletion or overexpression of ATF3 were counteracted by IFI6 or IFI27 expression (Fig 5H-5K).	('expression', 'Species', '29278', (147, 157))	('ATF3', 'Gene', (107, 111))	('expression', 'Species', '29278', (93, 103))	('overexpression', 'PosReg', (89, 103))	('AKT', 'CPA', (42, 45))	('deletion', 'Var', (77, 85))	('ERK', 'Pathway', (49, 52))	('activity', 'MPA', (53, 61))	('changes', 'Reg', (31, 38))
70401	33539340	To validate the biological role of ATF3 in TSCCs through IFI6 and IFI27 in vivo, we first tested whether the inhibition of ATF3 promotes tumor growth of TSCCs in mice.	('tumor', 'Disease', (137, 142))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('inhibition', 'Var', (109, 119))	('mice', 'Species', '10090', (162, 166))	('promotes', 'PosReg', (128, 136))	('ATF3', 'Gene', (123, 127))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
70402	33539340	CAL 27 cells with or without the CRISPR-Cas9 mediated deletion of ATF3 were xenografted on the dorsal skin of nu/nu mice.	('deletion', 'Var', (54, 62))	('mice', 'Species', '10090', (116, 120))	('ATF3', 'Gene', (66, 70))
70403	33539340	One month after grafting, the mice were sacrificed and the grafted tumors were collected (S12A Fig).	('S12A', 'Var', (90, 94))	('mice', 'Species', '10090', (30, 34))	('tumors', 'Disease', 'MESH:D009369', (67, 73))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('S12A', 'SUBSTITUTION', 'None', (90, 94))	('tumors', 'Disease', (67, 73))
70406	33539340	Ki-67 staining showed that there were many more Ki-67 positive cells (red arrows) in tumor tissues with the deletion of ATF3 (SG1 or SG2) (Figs 6C, 6D and S12B).	('tumor', 'Disease', (85, 90))	('Ki-67', 'Gene', (48, 53))	('S12B', 'Var', (155, 159))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('ATF3', 'Gene', (120, 124))	('S12B', 'SUBSTITUTION', 'None', (155, 159))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('deletion', 'Var', (108, 116))
70409	33539340	In contrast, ATF3 overexpressing SCC-9 cells (ATF3+GFP) generated smaller tumors than SCC-9 cells transfected with an empty vector (NEO+GFP) (Figs 6E, 6F and S13A).	('S13A', 'SUBSTITUTION', 'None', (158, 162))	('SCC-9', 'CellLine', 'CVCL:1685', (33, 38))	('smaller', 'NegReg', (66, 73))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('SCC-9', 'CellLine', 'CVCL:1685', (86, 91))	('tumors', 'Disease', (74, 80))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('S13A', 'Var', (158, 162))	('tumors', 'Disease', 'MESH:D009369', (74, 80))
70410	33539340	The effects of ATF3 overexpression on tumor growth were diminished by the overexpression of IFI6 or IFI27 (ATF3+IFI6 or ATF3+IFI27), which were further supported by staining of the cell proliferation marker Ki-67 (red arrows), which showed that the overexpression of ATF3 significantly suppressed the proliferation of tumor cells, and that suppression was blocked by the stable expression of IFI6 or IFI27 (Figs 6G, 6H and S13B).	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('expression', 'Species', '29278', (24, 34))	('expression', 'Species', '29278', (378, 388))	('tumor', 'Disease', 'MESH:D009369', (318, 323))	('S13B', 'Var', (423, 427))	('S13B', 'SUBSTITUTION', 'None', (423, 427))	('IFI27', 'Var', (400, 405))	('tumor', 'Phenotype', 'HP:0002664', (318, 323))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('suppressed', 'NegReg', (286, 296))	('diminished', 'NegReg', (56, 66))	('tumor', 'Disease', (318, 323))	('expression', 'Species', '29278', (253, 263))	('expression', 'Species', '29278', (78, 88))
70414	33539340	Taken together, these results suggest that ATF3 negatively modulates TSCC tumor growth and differentiation in vivo through the expression level of IFI6 or IFI27.	('negatively', 'NegReg', (48, 58))	('expression', 'Species', '29278', (127, 137))	('modulates', 'Reg', (59, 68))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('TSCC', 'Disease', (69, 73))	('expression', 'MPA', (127, 137))	('IFI27', 'Var', (155, 160))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('IFI6', 'Gene', (147, 151))	('ATF3', 'Gene', (43, 47))	('differentiation', 'CPA', (91, 106))	('tumor', 'Disease', (74, 79))
70417	33539340	For instance, the loss of ATF3 was found to promote prostate cancer development, but the overexpression of ATF3 enhanced the metastasis of prostate cancer.	('enhanced', 'PosReg', (112, 120))	('promote', 'PosReg', (44, 51))	('ATF3', 'Gene', (107, 111))	('loss', 'Var', (18, 22))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('expression', 'Species', '29278', (93, 103))	('overexpression', 'PosReg', (89, 103))	('prostate cancer', 'Disease', 'MESH:D011471', (52, 67))	('ATF3', 'Gene', (26, 30))	('metastasis of prostate cancer', 'Disease', (125, 154))	('prostate cancer', 'Phenotype', 'HP:0012125', (52, 67))	('prostate cancer', 'Disease', 'MESH:D011471', (139, 154))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('prostate cancer', 'Phenotype', 'HP:0012125', (139, 154))	('prostate cancer', 'Disease', (52, 67))	('metastasis of prostate cancer', 'Disease', 'MESH:D011471', (125, 154))
70424	33539340	Furthermore, suppression of TSCC growth by ATF3 was verified in an in vivo mouse model, which also showed that ATF3 could promote TSCC cell differentiation (Fig 6K-6N), agreed to GO analysis result of RNA-seq data (Fig 4A) and the induction of differentiation has been considered to be an anti-tumor function of ATF3.	('tumor', 'Disease', (294, 299))	('TSCC cell differentiation', 'CPA', (130, 155))	('promote', 'PosReg', (122, 129))	('tumor', 'Disease', 'MESH:D009369', (294, 299))	('mouse', 'Species', '10090', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (294, 299))	('ATF3', 'Var', (111, 115))
70430	33539340	However, ATF3 suppresses esophageal SCC growth by downregulating ID1 (inhibitor of DNA binding 1), blocks the metastasis of bladder cancer by regulating gelsolin-mediated remodeling of the actin cytoskeleton and inhibits the progression of hepatocellular carcinoma cells by upregulating CYR61 expression.	('hepatocellular carcinoma', 'Disease', (240, 264))	('expression', 'Species', '29278', (293, 303))	('regulating', 'Reg', (142, 152))	('inhibits', 'NegReg', (212, 220))	('carcinoma', 'Phenotype', 'HP:0030731', (255, 264))	('blocks', 'NegReg', (99, 105))	('metastasis', 'CPA', (110, 120))	('suppresses', 'NegReg', (14, 24))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (240, 264))	('downregulating', 'NegReg', (50, 64))	('CYR61', 'Protein', (287, 292))	('bladder cancer', 'Disease', 'MESH:D001749', (124, 138))	('bladder cancer', 'Disease', (124, 138))	('ATF3', 'Var', (9, 13))	('ID1', 'Gene', (65, 68))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (240, 264))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('bladder cancer', 'Phenotype', 'HP:0009725', (124, 138))	('upregulating', 'PosReg', (274, 286))	('esophageal SCC growth', 'CPA', (25, 46))	('progression', 'CPA', (225, 236))
70433	33539340	Both IFI6 and IFI27 are type I interferon alpha inducible proteins, which are encoded by genes with high expression levels in microarray analysis of OSCCs compared to normal tissues.	('expression', 'Species', '29278', (105, 115))	('OSCC', 'CellLine', 'CVCL:L894', (149, 153))	('IFI6', 'Var', (5, 9))	('IFI27', 'Gene', (14, 19))
70434	33539340	Both IFI6 and IFI27 were highly expressed in our clinical TSCC tumors, and again, that finding was supported by analysis of the TCGA database.	('IFI6', 'Var', (5, 9))	('IFI27', 'Var', (14, 19))	('TSCC', 'Disease', (58, 62))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('tumors', 'Disease', (63, 69))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
70435	33539340	Importantly, our in vitro study showed that the overexpression of IFI6 or IFI27 could counteract the inhibition of OSCC cell growth and migration induced by ATF3 overexpression and vice-versa, the knockdown of IFI6 or IFI27 blocked increased cell growth and migration with corresponding activation of the ERK/AKT pathways induced by the deletion of ATF3.	('ERK/AKT pathways', 'Pathway', (305, 321))	('cell growth', 'CPA', (242, 253))	('expression', 'Species', '29278', (52, 62))	('OSCC', 'CellLine', 'CVCL:L894', (115, 119))	('activation', 'PosReg', (287, 297))	('ATF3', 'Gene', (349, 353))	('increased', 'PosReg', (232, 241))	('expression', 'Species', '29278', (166, 176))	('deletion', 'Var', (337, 345))
70437	33539340	Both IFI6 and IFI27 are type I IFNalpha ISGs, and increasing evidence shows that IFNalpha plays dual opposing roles in cancer development based on ISGs, which determine whether it has anti- or pro-tumorigenic functions.	('IFI6', 'Var', (5, 9))	('anti-', 'CPA', (184, 189))	('IFI27', 'Var', (14, 19))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('IFNalpha', 'Gene', (81, 89))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('cancer', 'Disease', (119, 125))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('tumor', 'Disease', (197, 202))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
70438	33539340	IFI27 has been reported to be involved in different biological processes including the regulation of cellular apoptosis; modulation of the transcriptional activity of nuclear receptors NR4A1, NR4A2 and NR4A3; involvement in the ubiquitin-mediated proteasomal degradation pathway and playing antivirus functions, IFI27 has been shown to inhibit Heptatis C virus replication by through the activation of JAK/STAT signaling pathway, which has been reported to be interact with AKT and MAPK/ERK pathways and to be associated with cancer development.	('MAPK', 'Gene', (482, 486))	('cancer', 'Disease', 'MESH:D009369', (526, 532))	('AKT', 'Pathway', (474, 477))	('STAT', 'Gene', (406, 410))	('MAPK', 'Gene', '5594;26413', (482, 486))	('cancer', 'Phenotype', 'HP:0002664', (526, 532))	('interact', 'Reg', (460, 468))	('STAT', 'Gene', '20846', (406, 410))	('inhibit', 'NegReg', (336, 343))	('cancer', 'Disease', (526, 532))	('IFI27', 'Var', (312, 317))	('Heptatis C virus replication', 'MPA', (344, 372))	('associated', 'Reg', (510, 520))
70439	33539340	IFI27 has been also shown to play a tumor promoting function in multiple cancers and the knockdown of IFI27 was reported to inhibit the proliferation and invasion of TSCC cells, but the underlying molecular mechanism by which IFI27 regulates tumor cell growth and migration is still not clear.	('cancers', 'Disease', (73, 80))	('IFI27', 'Gene', (102, 107))	('migration', 'CPA', (264, 273))	('tumor', 'Disease', 'MESH:D009369', (242, 247))	('TSCC', 'Disease', (166, 170))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('tumor', 'Phenotype', 'HP:0002664', (242, 247))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('invasion', 'CPA', (154, 162))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumor', 'Disease', (242, 247))	('knockdown', 'Var', (89, 98))	('inhibit', 'NegReg', (124, 131))	('cancers', 'Disease', 'MESH:D009369', (73, 80))	('tumor', 'Disease', (36, 41))	('proliferation', 'CPA', (136, 149))
70443	33539340	Future studies will be aimed at characterizing whether IFI6 and IFI27 control the growth and migration of TSCCs through regulation of JAK/STAT, anti-apoptotic or other potential downstream signaling pathways.	('STAT', 'Gene', (138, 142))	('IFI6', 'Var', (55, 59))	('migration', 'CPA', (93, 102))	('STAT', 'Gene', '20846', (138, 142))	('anti-apoptotic', 'Pathway', (144, 158))	('control', 'Reg', (70, 77))	('growth', 'CPA', (82, 88))	('IFI27', 'Var', (64, 69))
70453	33539340	Surviving cells were analyzed by western blot analysis to validate the deletion or overexpression efficiency of the corresponding genes.	('overexpression', 'PosReg', (83, 97))	('expression', 'Species', '29278', (87, 97))	('deletion', 'Var', (71, 79))
70472	33539340	To test whether the loss of ATF3 enhances TSCC tumor growth in vivo, 8-week-old female nu/nu nude mice (Crl:NU-Foxn1nu Immunodeficient Outbred)(Beijing Vital River Laboratory Animal Technology Co., Ltd., Beijing, China) were randomly assigned to three groups: a control group (n = 6, Cal 27 cells infected with CRISPR empty vector lentivirus, V), a SG1 group (n = 6, Cal 27 cells infected with CRISPR-sgRNA1 lentivirus) and a SG2 group (n = 6, Cal 27 cells infected with CRISPR-sgRNA2 lentivirus).	('ATF3', 'Gene', (28, 32))	('Foxn1', 'Gene', (111, 116))	('loss', 'Var', (20, 24))	('infected', 'Disease', (297, 305))	('Foxn1', 'Gene', '15218', (111, 116))	('nude mice', 'Species', '10090', (93, 102))	('infected', 'Disease', 'MESH:D007239', (457, 465))	('infected', 'Disease', 'MESH:D007239', (297, 305))	('infected', 'Disease', (380, 388))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('infected', 'Disease', (457, 465))	('tumor', 'Disease', (47, 52))	('infected', 'Disease', 'MESH:D007239', (380, 388))
70479	33539340	The ATF3 levels in cytoplasms and nuclei in tumor tissues and cultured TSCCs were not biochemically tested (fractionation), the growth differences of the cultured TSCCs with and without ATF3 is marginal, the Crispr-mediated deletion of ATF3 is not confirmed by sequence analyses, etc., etc.	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('ATF3', 'Gene', (236, 240))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('deletion', 'Var', (224, 232))	('tumor', 'Disease', (44, 49))
70480	33539340	Moreover, it is unclear how ATF3 down regulates the IFI6/27, whether the IFI6/27 is dominant over the induction by the interferon produced upon white blood cell infiltration into the tumor tissues, and how IFI6/27 promotes growth, migration and invasion of TSCCs.	('growth', 'CPA', (223, 229))	('promotes', 'PosReg', (214, 222))	('invasion', 'CPA', (245, 253))	('IFI6/27', 'Var', (206, 213))	('down regulates', 'NegReg', (33, 47))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('migration', 'CPA', (231, 240))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('tumor', 'Disease', (183, 188))
70482	33539340	ATF3 represses the growth and migration of two TSCC cell lines and comprehensive gene expression analysis in one of these cell line plus/minus ATF3 gene deletion identified two targets IFI6 and IFI27.	('deletion', 'Var', (153, 161))	('expression', 'Species', '29278', (86, 96))	('represses', 'NegReg', (5, 14))
70483	33539340	According to an epistatic role for IFI6 and IFI27, their overexpression counteracted the inhibitory effects of ATF3 overexpression.	('overexpression', 'PosReg', (57, 71))	('expression', 'Species', '29278', (61, 71))	('IFI6', 'Var', (35, 39))	('IFI27', 'Var', (44, 49))	('expression', 'Species', '29278', (120, 130))
70487	33539340	In figure 2E the western blot of Cal27 cells that underwent CRISPR-mediated deletion of ATF3 (with one of the SG guides) shows a band slightly smaller than ATF3 (there are no MW to evaluate the size), but which is still recognised by ATF3 Abs.	('smaller', 'NegReg', (143, 150))	('deletion', 'Var', (76, 84))	('ATF3', 'Gene', (88, 92))	('Cal27', 'CellLine', 'CVCL:1107', (33, 38))
70504	32217756	Eleven laboratories used WES data from The Cancer Genome Atlas Multi-Center Mutation calling in Multiple Cancers (MC3) samples and calculated TMB from the subset of the exome restricted to the genes covered by their targeted panel using their own bioinformatics pipeline (panel TMB).	('Cancer', 'Disease', (43, 49))	('Cancer', 'Disease', (105, 111))	('Cancers', 'Disease', 'MESH:D009369', (105, 112))	('Cancers', 'Phenotype', 'HP:0002664', (105, 112))	('Cancer', 'Disease', 'MESH:D009369', (43, 49))	('Cancer', 'Disease', 'MESH:D009369', (105, 111))	('Cancer', 'Phenotype', 'HP:0002664', (105, 111))	('Cancer', 'Phenotype', 'HP:0002664', (43, 49))	('TMB', 'Chemical', '-', (278, 281))	('TMB', 'Chemical', '-', (142, 145))	('Mutation', 'Var', (76, 84))	('Cancers', 'Disease', (105, 112))
70518	32217756	Tumor mutational burden (TMB), which measures the number of somatic mutations per megabase (Mb) of the interrogated genomic sequence of a tumor, has been most recently identified as a biomarker of response to ICIs in several cancer types.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('cancer', 'Disease', 'MESH:D009369', (225, 231))	('tumor', 'Disease', (138, 143))	('TMB', 'Chemical', '-', (25, 28))	('cancer', 'Disease', (225, 231))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('mutations', 'Var', (68, 77))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
70519	32217756	High TMB is associated with improved outcomes in patients with melanoma treated with cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) blockade and PD-1/PD-L1 blockade across several cancer types, including melanoma, non-small-cell lung carcinoma, bladder cancer, microsatellite instability cancers and pan-tumor cohorts.	('cancer', 'Disease', 'MESH:D009369', (259, 265))	('CTLA-4', 'Gene', '1493', (130, 136))	('tumor', 'Phenotype', 'HP:0002664', (310, 315))	('small-cell lung carcinoma', 'Phenotype', 'HP:0030357', (224, 249))	('CTLA-4', 'Gene', (130, 136))	('PD-1/PD-L1 blockade', 'Disease', 'MESH:D010300', (151, 170))	('melanoma', 'Disease', 'MESH:D008545', (210, 218))	('TMB', 'Chemical', '-', (5, 8))	('melanoma', 'Phenotype', 'HP:0002861', (63, 71))	('melanoma', 'Disease', (63, 71))	('cancer', 'Disease', 'MESH:D009369', (186, 192))	('High', 'Var', (0, 4))	('cytotoxic T-lymphocyte-associated protein 4', 'Gene', '1493', (85, 128))	('non-small-cell lung carcinoma', 'Phenotype', 'HP:0030358', (220, 249))	('cancers', 'Phenotype', 'HP:0002664', (294, 301))	('PD-1/PD-L1 blockade', 'Disease', (151, 170))	('lung carcinoma', 'Disease', (235, 249))	('cancer', 'Disease', (294, 300))	('microsatellite instability cancers', 'Disease', (267, 301))	('cancer', 'Phenotype', 'HP:0002664', (294, 300))	('cancer', 'Disease', (259, 265))	('outcomes', 'MPA', (37, 45))	('microsatellite instability cancers', 'Disease', 'MESH:D053842', (267, 301))	('cytotoxic T-lymphocyte-associated protein 4', 'Gene', (85, 128))	('cancer', 'Phenotype', 'HP:0002664', (259, 265))	('tumor', 'Disease', (310, 315))	('bladder cancer', 'Disease', 'MESH:D001749', (251, 265))	('bladder cancer', 'Disease', (251, 265))	('patients', 'Species', '9606', (49, 57))	('melanoma', 'Phenotype', 'HP:0002861', (210, 218))	('melanoma', 'Disease', (210, 218))	('cancer', 'Disease', (186, 192))	('melanoma', 'Disease', 'MESH:D008545', (63, 71))	('tumor', 'Disease', 'MESH:D009369', (310, 315))	('bladder cancer', 'Phenotype', 'HP:0009725', (251, 265))	('improved', 'PosReg', (28, 36))	('cancer', 'Disease', 'MESH:D009369', (294, 300))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('lung carcinoma', 'Disease', 'MESH:D008175', (235, 249))	('carcinoma', 'Phenotype', 'HP:0030731', (240, 249))
70520	32217756	High TMB has also been associated with improved outcomes in patients treated with a combination of PD-1/PD-L1 and CTLA-4 inhibitors.	('PD-1/PD-L1', 'Disease', (99, 109))	('High', 'Var', (0, 4))	('patients', 'Species', '9606', (60, 68))	('CTLA-4', 'Gene', (114, 120))	('outcomes', 'MPA', (48, 56))	('improved', 'PosReg', (39, 47))	('TMB', 'Chemical', '-', (5, 8))	('CTLA-4', 'Gene', '1493', (114, 120))	('PD-1/PD-L1', 'Disease', 'MESH:D010300', (99, 109))
70544	32217756	The remaining cases (n=8291) were randomly assigned to training (n=4157) and validation (n=4134) datasets with similar median candidate mutations and cancer types (online supplementary figure 2).	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('cancer', 'Disease', (150, 156))	('mutations', 'Var', (136, 145))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
70565	32217756	The uniform method for analysis of WES TMB included minimum thresholds for median target coverage (median 300X as this was identified as the point where sensitivity for the lower allele frequency variants drops drastically) (see online supplementary figure 4), variant allele frequency (>=0.05), read depth (>=25) and variant count (>=3), and synonymous variants were excluded.	('TMB', 'Chemical', '-', (39, 42))	('drops', 'NegReg', (205, 210))	('variants', 'Var', (196, 204))
70575	32217756	A limitation of analyzing all cancer types together is the variable distribution of TMB across different cancer types, with some cancer types displaying large dynamic ranges of TMB values up to several hundred mutations per Mb and others with very limited distributions with very few samples reaching 20 mutations per Mb (see online supplementary figure 3).	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('mutations', 'Var', (210, 219))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', (30, 36))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('TMB', 'Chemical', '-', (177, 180))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('TMB', 'Chemical', '-', (84, 87))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
70616	32217756	This would be consistent with a recent report that found that in patients who received ICI, those who had high TMB had longer survival than those who had low TMB, but TMB-high cut-offs were cancer-type dependent.	('TMB', 'Chemical', '-', (158, 161))	('cancer', 'Disease', (190, 196))	('TMB', 'Chemical', '-', (167, 170))	('cancer', 'Disease', 'MESH:D009369', (190, 196))	('longer', 'PosReg', (119, 125))	('high', 'Var', (106, 110))	('survival', 'CPA', (126, 134))	('TMB', 'Chemical', '-', (111, 114))	('patients', 'Species', '9606', (65, 73))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))
70635	31828117	Then, the survival analysis showed that high expression of DNMT3B had a poorer overall survival in 5 cancer types.	('high expression', 'Var', (40, 55))	('poorer', 'NegReg', (72, 78))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('DNMT', 'Gene', '1786', (59, 63))	('DNMT', 'Gene', (59, 63))	('overall survival', 'MPA', (79, 95))
70636	31828117	Integrative altered methylation and expression revealed specific genes influenced by DNMT3B through DNA methylation across cancers.	('DNA', 'Var', (100, 103))	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('influenced', 'Reg', (71, 81))	('cancers', 'Disease', 'MESH:D009369', (123, 130))	('DNMT3B', 'Gene', (85, 91))	('cancers', 'Phenotype', 'HP:0002664', (123, 130))	('cancers', 'Disease', (123, 130))
70638	31828117	Our study highlights possible epigenetic disorders resulting from the deregulation of metabolic genes in pan-cancer and provides potential therapy in the clinical treatment of human cancer.	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('pan-cancer', 'Disease', (105, 115))	('deregulation', 'Var', (70, 82))	('human', 'Species', '9606', (176, 181))	('metabolic genes', 'Gene', (86, 101))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))
70641	31828117	In addition to providing energy, the research showed that disordered genes encoding metabolic enzymes may also promote tumorigenesis through other biological functions like epigenetic modification.	('epigenetic modification', 'Var', (173, 196))	('tumor', 'Disease', (119, 124))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('disordered genes', 'Var', (58, 74))	('promote', 'PosReg', (111, 118))
70642	31828117	The most studied epigenetic alterations associated with carcinogenesis were variation in DNA and histone structure through posttranslational modifications and histone variants.	('histone variants', 'Var', (159, 175))	('carcinogenesis', 'Disease', (56, 70))	('histone structure', 'Protein', (97, 114))	('variation', 'Var', (76, 85))	('carcinogenesis', 'Disease', 'MESH:D063646', (56, 70))	('posttranslational modifications', 'Var', (123, 154))	('DNA', 'Protein', (89, 92))
70644	31828117	RAS, involved in cell differentiation, proliferation, apoptosis, cellular adhesion, and migration, was hypomethylated in the promoter in hepatocellular carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (152, 161))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (137, 161))	('hypomethylated', 'Var', (103, 117))	('hepatocellular carcinoma', 'Disease', (137, 161))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (137, 161))
70645	31828117	These studies usually focused on the relationship between metabolism and epigenetics just in one type of disorder or in an isolated tumor type.	('type of disorder', 'Disease', 'MESH:D030342', (97, 113))	('type of disorder', 'Disease', (97, 113))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('epigenetics', 'Var', (73, 84))	('focused', 'Reg', (22, 29))
70674	31828117	ACLY plays a critical role in determining the histone acetylation, and ACLY knockdown leads to apoptosis and growth suppression in breast cancer cells.	('knockdown', 'Var', (76, 85))	('apoptosis', 'CPA', (95, 104))	('histone acetylation', 'MPA', (46, 65))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('breast cancer', 'Disease', 'MESH:D001943', (131, 144))	('breast cancer', 'Phenotype', 'HP:0003002', (131, 144))	('breast cancer', 'Disease', (131, 144))	('ACLY', 'Gene', (71, 75))	('growth suppression', 'CPA', (109, 127))
70680	31828117	SAM is the methyl donor, and suppression of SAM leads to decreased DNA methylation and slows the growth of pancreatic cancer cells.	('pancreatic cancer', 'Disease', (107, 124))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (107, 124))	('slows', 'NegReg', (87, 92))	('pancreatic cancer', 'Disease', 'MESH:D010190', (107, 124))	('suppression', 'Var', (29, 40))	('growth', 'CPA', (97, 103))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('decreased', 'NegReg', (57, 66))	('DNA methylation', 'MPA', (67, 82))	('SAM', 'Gene', (44, 47))
70683	31828117	DNMT1 promotes hypermethylation and downregulation of tumor suppressor gene ISL1 which increases the tumor stem cell population in breast cancer cells.	('downregulation', 'NegReg', (36, 50))	('increases', 'PosReg', (87, 96))	('ISL1', 'Gene', (76, 80))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('hypermethylation', 'Var', (15, 31))	('tumor stem cell population', 'CPA', (101, 127))	('DNMT1', 'Gene', (0, 5))	('breast cancer', 'Disease', (131, 144))	('ISL1', 'Gene', '3670', (76, 80))	('breast cancer', 'Phenotype', 'HP:0003002', (131, 144))
70684	31828117	Studies have shown that DNMT3B can induce DNA methylation in specific CpG islands in colorectal cancer and it could also induce the distinct methylation level in different regions such as CpG and non-CpG.	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('DNMT3B', 'Var', (24, 30))	('DNA methylation', 'MPA', (42, 57))	('colorectal cancer', 'Disease', (85, 102))	('induce', 'Reg', (121, 127))	('distinct methylation level', 'MPA', (132, 158))	('induce', 'PosReg', (35, 41))	('colorectal cancer', 'Disease', 'MESH:D015179', (85, 102))	('colorectal cancer', 'Phenotype', 'HP:0003003', (85, 102))
70685	31828117	ZNF154 and AQP1, whose hypermethylated patterns are biomarkers for distinguishing tumor from normal samples, are downregulated and hypermethylated in BRCA and LUAD in our study.	('BRCA', 'Phenotype', 'HP:0003002', (150, 154))	('AQP1', 'Gene', '358', (11, 15))	('ZNF154', 'Gene', (0, 6))	('downregulated', 'NegReg', (113, 126))	('LUAD', 'Phenotype', 'HP:0030078', (159, 163))	('ZNF154', 'Gene', '7710', (0, 6))	('BRCA', 'Disease', (150, 154))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('AQP1', 'Gene', (11, 15))	('hypermethylated', 'Var', (131, 146))
70686	31828117	In addition, hypermethylation and downregulation of PPP2R2B, whose mRNA expression is in a DNMT-dependent manner, were found in BRCA.	('BRCA', 'Phenotype', 'HP:0003002', (128, 132))	('PPP2R2B', 'Gene', '5521', (52, 59))	('PPP2R2B', 'Gene', (52, 59))	('downregulation', 'NegReg', (34, 48))	('BRCA', 'Disease', (128, 132))	('hypermethylation', 'Var', (13, 29))
70687	31828117	Loss of DNMT3B in the mouse model delayed the melanoma formation suggesting that other DNMTs do not adequately compensate for DNMT3B loss and suggesting nonredundant roles for DNMTs in melanoma and DNMT3B, in particular, may play specific, nonredundant roles.	('melanoma', 'Disease', 'MESH:D008545', (185, 193))	('melanoma', 'Disease', 'MESH:D008545', (46, 54))	('melanoma', 'Phenotype', 'HP:0002861', (46, 54))	('melanoma', 'Disease', (46, 54))	('delayed', 'NegReg', (34, 41))	('loss', 'NegReg', (133, 137))	('mouse', 'Species', '10090', (22, 27))	('melanoma', 'Phenotype', 'HP:0002861', (185, 193))	('Loss', 'Var', (0, 4))	('melanoma', 'Disease', (185, 193))
70690	31828117	TME modulates cancer cell metabolism and epigenetic modification contributing to tumor heterogeneity and therapeutic response through limited nutrient supply, acidic, hypoxia, and other characteristics.	('modulates', 'Reg', (4, 13))	('contributing', 'Reg', (65, 77))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('hypoxia', 'Disease', (167, 174))	('epigenetic modification', 'Var', (41, 64))	('hypoxia', 'Disease', 'MESH:D000860', (167, 174))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('limited', 'NegReg', (134, 141))
70693	30515999	FGFR1 amplification is generally considered a promising therapeutic target.	('amplification', 'Var', (6, 19))	('FGFR1', 'Gene', (0, 5))	('FGFR1', 'Gene', '2260', (0, 5))
70699	30515999	Pharmacological inhibition and siRNA knockdown of FGFR1 induced apoptosis in lung SCC cells.	('SCC', 'Gene', '6317', (82, 85))	('FGFR1', 'Gene', (50, 55))	('apoptosis', 'CPA', (64, 73))	('knockdown', 'Var', (37, 46))	('FGFR1', 'Gene', '2260', (50, 55))	('SCC', 'Gene', (82, 85))	('induced', 'Reg', (56, 63))
70706	30515999	Numerous clinical trials on FGFR1 inhibitors have been conducted recently.	('FGFR1', 'Gene', '2260', (28, 33))	('FGFR1', 'Gene', (28, 33))	('inhibitors', 'Var', (34, 44))
70714	30515999	The FGFR1 inhibitor PD173074 was provided by Sigma-Aldrich.	('FGFR1', 'Gene', (4, 9))	('PD173074', 'Var', (20, 28))	('PD173074', 'Chemical', 'MESH:C115711', (20, 28))	('FGFR1', 'Gene', '2260', (4, 9))
70715	30515999	Antibodies for various proteins were obtained from the following sources: cyclinD1, caspase-3, cleaved caspase-3,poly (ADP-ribose) polymerase (PARP), cleaved PARP, phosphop44/42 MAPK (T202/Y204), 44/42 MAPK, and phosphopFGFR1 antibodies were purchased from Cell Signaling Technology (Danvers, MA, USA), while the FGFR1 antibody was purchased from Abcam (Cambridge, MA, USA).	('PARP', 'Gene', (143, 147))	('caspase-3', 'Gene', '836', (103, 112))	('cleaved caspase-3,poly (ADP-ribose) polymerase', 'Gene', '142', (95, 141))	('caspase-3', 'Gene', (84, 93))	('PARP', 'Gene', (158, 162))	('cyclinD1', 'Gene', (74, 82))	('FGFR1', 'Gene', (313, 318))	('PARP', 'Gene', '142', (143, 147))	('FGFR1', 'Gene', (220, 225))	('caspase-3', 'Gene', '836', (84, 93))	('FGFR1', 'Gene', '2260', (313, 318))	('cyclinD1', 'Gene', '595', (74, 82))	('PARP', 'Gene', '142', (158, 162))	('T202/Y204', 'Var', (184, 193))	('FGFR1', 'Gene', '2260', (220, 225))	('caspase-3', 'Gene', (103, 112))
70750	30515999	As it has been shown that amplification of FGFR1is observed in approximately 20% of lung SCCs,7 the effect of honokiol was determined on FGFR1 in lung SCC cells after treating the H520 and SK-MES-1 cell lines with honokiol for 96 hours.	('FGFR1', 'Gene', (43, 48))	('honokiol', 'Chemical', 'MESH:C005499', (214, 222))	('SCC', 'Gene', '6317', (89, 92))	('SCC', 'Gene', '6317', (151, 154))	('FGFR1', 'Gene', '2260', (43, 48))	('amplification', 'Var', (26, 39))	('FGFR1', 'Gene', (137, 142))	('or 96', 'Gene', '138805', (224, 229))	('FGFR1', 'Gene', '2260', (137, 142))	('honokiol', 'Chemical', 'MESH:C005499', (110, 118))	('or 96', 'Gene', (224, 229))	('SK-MES-1', 'CellLine', 'CVCL:0630', (189, 197))	('SCC', 'Gene', (89, 92))	('SCC', 'Gene', (151, 154))
70759	30515999	To better understand the role of FGFR1 in honokiol-mediated cell cycle arrest and apoptosis induction, we conducted both pharmacological inhibition and siRNA knockdown of FGFR1 in lung SCC cell lines.	('SCC', 'Gene', (185, 188))	('FGFR1', 'Gene', '2260', (33, 38))	('FGFR1', 'Gene', (171, 176))	('FGFR1', 'Gene', '2260', (171, 176))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (60, 77))	('SCC', 'Gene', '6317', (185, 188))	('honokiol', 'Chemical', 'MESH:C005499', (42, 50))	('knockdown', 'Var', (158, 167))	('FGFR1', 'Gene', (33, 38))
70760	30515999	PD173074 is an ATP pocket inhibitor that shows both high affinity and selectivity for FGFR1.27 To investigate the role of the FGFR1 signaling pathway in the apoptosis-induction effect of honokiol on H520 and SK-MES-1 cells, we detected apoptosis in both cell lines after PD173074 treatment.	('detected', 'Reg', (227, 235))	('SK-MES-1', 'CellLine', 'CVCL:0630', (208, 216))	('FGFR1', 'Gene', (126, 131))	('ATP', 'Chemical', 'MESH:D000255', (15, 18))	('PD173074', 'Var', (271, 279))	('PD173074', 'Chemical', 'MESH:C115711', (0, 8))	('PD173074', 'Chemical', 'MESH:C115711', (271, 279))	('FGFR1', 'Gene', '2260', (126, 131))	('FGFR1', 'Gene', (86, 91))	('FGFR1', 'Gene', '2260', (86, 91))	('honokiol', 'Chemical', 'MESH:C005499', (187, 195))
70761	30515999	The proportion of apoptotic cells was significantly increased in the PD173074-treated groups compared to the control group, as shown in Figure 7A,B.	('PD173074', 'Chemical', 'MESH:C115711', (69, 77))	('PD173074-treated', 'Var', (69, 85))	('increased', 'PosReg', (52, 61))	('apoptotic cells', 'CPA', (18, 33))
70763	30515999	In addition, the cell cycle-related proteins cyclin D1, CDK4, and RB were inhibited by siRNA knockdown of FGFR1, while apoptosis-related proteins such as caspase-3 and PARP were activated Figure 7C,D).	('knockdown', 'Var', (93, 102))	('inhibited', 'NegReg', (74, 83))	('CDK4', 'Gene', (56, 60))	('CDK4', 'Gene', '1019', (56, 60))	('caspase-3', 'Gene', '836', (154, 163))	('FGFR1', 'Gene', (106, 111))	('FGFR1', 'Gene', '2260', (106, 111))	('PARP', 'Gene', (168, 172))	('caspase-3', 'Gene', (154, 163))	('cell cycle-related proteins', 'CPA', (17, 44))	('cyclin D1', 'Gene', '595', (45, 54))	('PARP', 'Gene', '142', (168, 172))	('cyclin D1', 'Gene', (45, 54))
70771	30515999	According to the measurements of tumor size, the treatment of mice with honokiol resulted in reduced growth of H520 xenografts compared with that in the vehicle-treated control mice Figure 9B).	('growth', 'MPA', (101, 107))	('H520 xenografts', 'CPA', (111, 126))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('mice', 'Species', '10090', (62, 66))	('reduced', 'NegReg', (93, 100))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumor', 'Disease', (33, 38))	('honokiol', 'Chemical', 'MESH:C005499', (72, 80))	('mice', 'Species', '10090', (177, 181))	('honokiol', 'Var', (72, 80))
70773	30515999	The volume of the H520 tumors was lower in mice administered honokiol than in nonhonokiol-treated control mice Figure 9C).	('mice', 'Species', '10090', (43, 47))	('mice', 'Species', '10090', (106, 110))	('H520 tumors', 'Disease', 'MESH:D009369', (18, 29))	('nonhonokiol', 'Chemical', '-', (78, 89))	('lower', 'NegReg', (34, 39))	('honokiol', 'Var', (61, 69))	('honokiol', 'Chemical', 'MESH:C005499', (61, 69))	('honokiol', 'Chemical', 'MESH:C005499', (81, 89))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('volume', 'CPA', (4, 10))	('H520 tumors', 'Disease', (18, 29))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))
70779	30515999	The present study indicated that honokiol could significantly and dose-dependently induce G0/G1 cell cycle arrest and apoptosis as well as inhibit migration in lung SCC cell lines.	('apoptosis', 'CPA', (118, 127))	('honokiol', 'Var', (33, 41))	('SCC', 'Gene', (165, 168))	('honokiol', 'Chemical', 'MESH:C005499', (33, 41))	('inhibit', 'NegReg', (139, 146))	('migration in', 'CPA', (147, 159))	('induce', 'PosReg', (83, 89))	('SCC', 'Gene', '6317', (165, 168))	('lung', 'Disease', (160, 164))	('G0/G1 cell cycle arrest', 'CPA', (90, 113))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (96, 113))
70781	30515999	Pharmacological inhibition of FGFR1 with PD173074 induced apoptosis in both SCC cell lines.	('FGFR1', 'Gene', (30, 35))	('PD173074', 'Chemical', 'MESH:C115711', (41, 49))	('SCC', 'Gene', (76, 79))	('FGFR1', 'Gene', '2260', (30, 35))	('PD173074', 'Var', (41, 49))	('apoptosis', 'CPA', (58, 67))	('SCC', 'Gene', '6317', (76, 79))
70783	30515999	The in vivo study indicated that honokiol could inhibit the growth of xenograft tumors, and this effect was associated with the inhibition of the FGF2-FGFR1 signaling pathway.	('honokiol', 'Var', (33, 41))	('inhibition', 'NegReg', (128, 138))	('honokiol', 'Chemical', 'MESH:C005499', (33, 41))	('xenograft tumors', 'Disease', 'MESH:D009369', (70, 86))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('FGFR1', 'Gene', (151, 156))	('FGFR1', 'Gene', '2260', (151, 156))	('xenograft tumors', 'Disease', (70, 86))	('inhibit', 'NegReg', (48, 55))
70789	30515999	Cell migration is an important process in tumor metastasis and progression.37 Several studies have reported that honokiol can inhibit the migration of various kinds of malignancies under different mechanisms.37, 38, 39 To investigate whether honokiol had a similar function in lung SCC, we performed a cell migration assay and found that honokiol could significantly inhibit the migration of H520 and SK-MES-1 cells, as could PD173074, which might suggest that inhibition of FGFR1 can restrict the migration of lung SCC.	('honokiol', 'Chemical', 'MESH:C005499', (242, 250))	('PD173074', 'Chemical', 'MESH:C115711', (426, 434))	('SCC', 'Gene', '6317', (282, 285))	('honokiol', 'Chemical', 'MESH:C005499', (113, 121))	('migration', 'CPA', (498, 507))	('malignancies', 'Disease', 'MESH:D009369', (168, 180))	('SCC', 'Gene', (282, 285))	('migration', 'CPA', (379, 388))	('tumor metastasis', 'Disease', 'MESH:D009362', (42, 58))	('malignancies', 'Disease', (168, 180))	('FGFR1', 'Gene', (475, 480))	('inhibition', 'Var', (461, 471))	('restrict', 'NegReg', (485, 493))	('tumor metastasis', 'Disease', (42, 58))	('SCC', 'Gene', '6317', (516, 519))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('SCC', 'Gene', (516, 519))	('inhibit', 'NegReg', (367, 374))	('honokiol', 'Chemical', 'MESH:C005499', (338, 346))	('SK-MES-1', 'CellLine', 'CVCL:0630', (401, 409))	('FGFR1', 'Gene', '2260', (475, 480))
70791	30515999	To confirm the role of the FGF2-FGFR1 autocrine loop in the antitumor function of honokiol, we used PD173074, a selective FGFR1 inhibitor, and found that it induced significant apoptosis in SCC.	('apoptosis', 'CPA', (177, 186))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('FGFR1', 'Gene', (32, 37))	('tumor', 'Disease', (64, 69))	('honokiol', 'Chemical', 'MESH:C005499', (82, 90))	('FGFR1', 'Gene', '2260', (32, 37))	('FGFR1', 'Gene', (122, 127))	('FGFR1', 'Gene', '2260', (122, 127))	('PD173074', 'Var', (100, 108))	('SCC', 'Gene', (190, 193))	('PD173074', 'Chemical', 'MESH:C115711', (100, 108))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('SCC', 'Gene', '6317', (190, 193))
70792	30515999	Using siRNA-mediated knockdown of FGFR1, we further investigated the activation of the related signaling pathway and discovered dephosphorylation of ERK, inhibition of the cyclin D1/CDK4/RB pathway and activation of the cell apoptosis pathway, which suggested that inhibition of FGFR1 might be one of the mechanisms underlying the antineoplastic function of honokiol.	('honokiol', 'Disease', (358, 366))	('FGFR1', 'Gene', (279, 284))	('inhibition', 'Var', (265, 275))	('signaling pathway', 'Pathway', (95, 112))	('knockdown', 'Var', (21, 30))	('CDK4', 'Gene', '1019', (182, 186))	('dephosphorylation', 'MPA', (128, 145))	('FGFR1', 'Gene', '2260', (34, 39))	('honokiol', 'Chemical', 'MESH:C005499', (358, 366))	('ERK', 'Gene', '5594', (149, 152))	('cell apoptosis pathway', 'Pathway', (220, 242))	('CDK4', 'Gene', (182, 186))	('inhibition', 'NegReg', (154, 164))	('FGFR1', 'Gene', '2260', (279, 284))	('cyclin D1', 'Gene', (172, 181))	('ERK', 'Gene', (149, 152))	('FGFR1', 'Gene', (34, 39))	('cyclin D1', 'Gene', '595', (172, 181))	('activation', 'PosReg', (69, 79))
70813	28465488	In addition, a recent study in NSCLC revealed that P-Thr308, but not P-Ser473, which is widely used as a marker of Akt activity, is the major regulator of Akt protein kinase activity.	('Akt', 'Gene', '207', (115, 118))	('P-Thr308', 'Var', (51, 59))	('Akt', 'Gene', (115, 118))	('NSCLC', 'Disease', (31, 36))	('Ser473', 'Chemical', '-', (71, 77))	('NSCLC', 'Disease', 'MESH:D002289', (31, 36))	('Akt', 'Gene', '207', (155, 158))	('Thr308', 'Chemical', '-', (53, 59))	('Akt', 'Gene', (155, 158))
70814	28465488	Here, we found that RACK1 was up-regulated in NSCLC, and knockdown of RACK1 inhibited cellular growth and blocked S phase entry.	('RACK1', 'Gene', (70, 75))	('S phase entry', 'CPA', (114, 127))	('RACK1', 'Gene', '10399', (20, 25))	('NSCLC', 'Disease', (46, 51))	('knockdown', 'Var', (57, 66))	('RACK1', 'Gene', '10399', (70, 75))	('blocked', 'NegReg', (106, 113))	('cellular growth', 'CPA', (86, 101))	('NSCLC', 'Disease', 'MESH:D002289', (46, 51))	('RACK1', 'Gene', (20, 25))	('up-regulated', 'PosReg', (30, 42))	('inhibited', 'NegReg', (76, 85))
70815	28465488	Furthermore, we demonstrated that the oncogenic potential of RACK1 was correlated with MCM7 function.	('RACK1', 'Gene', '10399', (61, 66))	('oncogenic potential', 'CPA', (38, 57))	('correlated', 'Reg', (71, 81))	('MCM7', 'Gene', (87, 91))	('function', 'Var', (92, 100))	('RACK1', 'Gene', (61, 66))
70818	28465488	To understand the function of RACK1 in NSCLC cells, we used siRACK1 to knock down its expression in the A549 and H460 NSCLC cell lines.	('RACK1', 'Gene', (62, 67))	('RACK1', 'Gene', '10399', (30, 35))	('NSCLC', 'Disease', 'MESH:D002289', (39, 44))	('A549', 'CellLine', 'CVCL:0023', (104, 108))	('knock', 'Var', (71, 76))	('expression', 'MPA', (86, 96))	('RACK1', 'Gene', '10399', (62, 67))	('NSCLC', 'Disease', (118, 123))	('NSCLC', 'Disease', (39, 44))	('RACK1', 'Gene', (30, 35))	('NSCLC', 'Disease', 'MESH:D002289', (118, 123))	('H460', 'CellLine', 'CVCL:0459', (113, 117))
70819	28465488	RACK1 knockdown inhibited, while RACK1 overexpression promoted, cell growth and colony formation (Figure 1A and 1B).	('promoted', 'PosReg', (54, 62))	('colony formation', 'CPA', (80, 96))	('inhibited', 'NegReg', (16, 25))	('RACK1', 'Gene', '10399', (0, 5))	('RACK1', 'Gene', (33, 38))	('cell growth', 'CPA', (64, 75))	('knockdown', 'Var', (6, 15))	('RACK1', 'Gene', '10399', (33, 38))	('RACK1', 'Gene', (0, 5))
70820	28465488	Furthermore, flow cytometry revealed that RACK1 knockdown effectively blocked entry into S-phase and reduced the percentage of cells in S-phase, suggesting that RACK1 might regulate the G1 checkpoint (Figure 1C).	('regulate', 'Reg', (173, 181))	('RACK1', 'Gene', '10399', (161, 166))	('RACK1', 'Gene', '10399', (42, 47))	('percentage of cells in S-phase', 'MPA', (113, 143))	('reduced', 'NegReg', (101, 108))	('entry into S-phase', 'MPA', (78, 96))	('knockdown', 'Var', (48, 57))	('blocked', 'NegReg', (70, 77))	('RACK1', 'Gene', (161, 166))	('RACK1', 'Gene', (42, 47))
70822	28465488	Downregulation of RACK1 decreased cyclinD1 levels, induction of the CDK inhibitor p27, dephosphorylation of Rb, and sequestration of the transcription factor E2F1, but did not alter CDK2, CDK4, or Rb expression, in G1 cells compared to negative controls (Figure 1D).	('RACK1', 'Gene', (18, 23))	('decreased', 'NegReg', (24, 33))	('p27', 'Gene', (82, 85))	('p27', 'Gene', '3429', (82, 85))	('cyclinD1', 'Gene', '595', (34, 42))	('dephosphorylation', 'MPA', (87, 104))	('CDK4', 'Gene', (188, 192))	('CDK2', 'Gene', (182, 186))	('Downregulation', 'Var', (0, 14))	('RACK1', 'Gene', '10399', (18, 23))	('CDK4', 'Gene', '1019', (188, 192))	('CDK2', 'Gene', '1017', (182, 186))	('E2F1', 'Gene', '1869', (158, 162))	('E2F1', 'Gene', (158, 162))	('induction', 'MPA', (51, 60))	('sequestration', 'MPA', (116, 129))	('cyclinD1', 'Gene', (34, 42))
70831	28465488	A log-rank test showed that NSCLC patients with high RACK1 and MCM7 levels had shorter overall survival (Figure 3B).	('NSCLC', 'Disease', (28, 33))	('MCM7', 'Gene', (63, 67))	('NSCLC', 'Disease', 'MESH:D002289', (28, 33))	('shorter', 'NegReg', (79, 86))	('RACK1', 'Gene', (53, 58))	('patients', 'Species', '9606', (34, 42))	('high', 'Var', (48, 52))	('RACK1', 'Gene', '10399', (53, 58))	('overall survival', 'MPA', (87, 103))
70844	28465488	RACK1 knockdown abolished Akt pathway-induced MCM7 phosphorylation (Figure 7A).	('Akt', 'Gene', '207', (26, 29))	('RACK1', 'Gene', '10399', (0, 5))	('Akt', 'Gene', (26, 29))	('knockdown', 'Var', (6, 15))	('RACK1', 'Gene', (0, 5))	('abolished', 'NegReg', (16, 25))
70849	28465488	Overexpression of RACK1 served as a biomarker associated with increased pathological stage, tumor size, and lymph node involvement in pulmonary adenocarcinoma in a recent study.	('increased', 'PosReg', (62, 71))	('RACK1', 'Gene', (18, 23))	('pathological stage', 'CPA', (72, 90))	('carcinoma', 'Phenotype', 'HP:0030731', (149, 158))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('pulmonary adenocarcinoma', 'Disease', 'MESH:D008175', (134, 158))	('RACK1', 'Gene', '10399', (18, 23))	('pulmonary adenocarcinoma', 'Phenotype', 'HP:0030078', (134, 158))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('Overexpression', 'Var', (0, 14))	('tumor', 'Disease', (92, 97))	('pulmonary adenocarcinoma', 'Disease', (134, 158))	('lymph node involvement', 'CPA', (108, 130))
70857	28465488	Moreover, RACK1 knockdown inhibited DNA replication and S-phase entry by increasing cell cycle arrest at the G1/S transition checkpoint.	('inhibited', 'NegReg', (26, 35))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (84, 101))	('RACK1', 'Gene', '10399', (10, 15))	('knockdown', 'Var', (16, 25))	('DNA replication', 'CPA', (36, 51))	('increasing', 'PosReg', (73, 83))	('S-phase entry', 'CPA', (56, 69))	('RACK1', 'Gene', (10, 15))
70861	28465488	found that knockdown of RACK1 suppressed Cyclin D1 and CDK6 expression, thereby dramatically increasing G0/G1 phase and reducing S phase cell populations, in glioma.	('expression', 'MPA', (60, 70))	('glioma', 'Disease', 'MESH:D005910', (158, 164))	('Cyclin D1', 'Gene', (41, 50))	('G0/G1 phase', 'CPA', (104, 115))	('glioma', 'Phenotype', 'HP:0009733', (158, 164))	('reducing', 'NegReg', (120, 128))	('suppressed', 'NegReg', (30, 40))	('S phase cell populations', 'CPA', (129, 153))	('RACK1', 'Gene', '10399', (24, 29))	('CDK6', 'Gene', (55, 59))	('glioma', 'Disease', (158, 164))	('CDK6', 'Gene', '1021', (55, 59))	('Cyclin D1', 'Gene', '595', (41, 50))	('increasing', 'PosReg', (93, 103))	('RACK1', 'Gene', (24, 29))	('knockdown', 'Var', (11, 20))
70862	28465488	reported that stable RACK1 knockdown downregulated Cyclin B1 and Cyclin D1 and promoted G1 and G2 phase arrest in oral squamous cell carcinoma.	('downregulated', 'NegReg', (37, 50))	('knockdown', 'Var', (27, 36))	('RACK1', 'Gene', (21, 26))	('Cyclin B1', 'Gene', '891', (51, 60))	('Cyclin B1', 'Gene', (51, 60))	('RACK1', 'Gene', '10399', (21, 26))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (114, 142))	('promoted', 'PosReg', (79, 87))	('Cyclin D1', 'Gene', '595', (65, 74))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (119, 142))	('Cyclin D1', 'Gene', (65, 74))	('oral squamous cell carcinoma', 'Disease', (114, 142))
70863	28465488	Interestingly, RACK1 has the opposite effect in colon cancer cells; RACK1 overexpression delays passage of HT-29 cells through G1 and mitotic checkpoints by suppressing Src-mediated Sam68 phosphorylation and maintaining the active state of CDK1-cyclinB.	('colon cancer', 'Disease', (48, 60))	('passage', 'CPA', (96, 103))	('suppressing', 'NegReg', (157, 168))	('RACK1', 'Gene', '10399', (15, 20))	('delays', 'NegReg', (89, 95))	('RACK1', 'Gene', (15, 20))	('CDK1', 'Gene', (240, 244))	('CDK1', 'Gene', '983', (240, 244))	('colon cancer', 'Phenotype', 'HP:0003003', (48, 60))	('overexpression', 'Var', (74, 88))	('phosphorylation', 'MPA', (188, 203))	('Sam68', 'Gene', '10657', (182, 187))	('Sam68', 'Gene', (182, 187))	('Src', 'Gene', (169, 172))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('colon cancer', 'Disease', 'MESH:D015179', (48, 60))	('active state', 'MPA', (224, 236))	('maintaining', 'Reg', (208, 219))	('RACK1', 'Gene', '10399', (68, 73))	('Src', 'Gene', '6714', (169, 172))	('HT-29', 'CellLine', 'CVCL:0320', (107, 112))	('RACK1', 'Gene', (68, 73))
70888	28465488	Cells were lysed in 1 mL of Buffer A (15 mM NaC2H3O2, 110 mM KC2H3O2, 2 mM MgC2H3O2, 0.5 mM EGTA, and 20 mM HEPES, pH 7.3).	('NaC2H3O2', 'Chemical', '-', (44, 52))	('NaC2H3O2', 'Var', (44, 52))	('15', 'Var', (38, 40))	('MgC2H3O2', 'Chemical', '-', (75, 83))	('EGTA', 'Chemical', 'MESH:D004533', (92, 96))	('HEPES', 'Chemical', 'MESH:D006531', (108, 113))	('KC2H3O2', 'Chemical', '-', (61, 68))
70917	28465488	The cDNA templates were as follows: RACK1 (357 bp) fragment with primers 5'-TGAGTGTGGCCTTCTCCTCT-3' (forward) and 5'-AAAGGTGTTTGCCTTCGTTG-3' (reverse); MCM7 (382 bp) fragment with primers 5'-ACCGAGACAATGACCTACGG-3' (forward) and 5'-CTAGCTGTCTGCCCCTTGTC-3' (reverse); and internal control gene beta-actin (345 bp) with primers 5'-CTCCATCCTGGCCTCGCTGT-3' (forward) and 5'-GCTGTCACCTTCACCGTTCC-3' (reverse).	('RACK1', 'Gene', '10399', (36, 41))	('beta-actin', 'Gene', '728378', (293, 303))	('beta-actin', 'Gene', (293, 303))	('345', 'Var', (305, 308))	('RACK1', 'Gene', (36, 41))
70921	33845800	Bioinformatics analysis of the expression and role of microRNA-221-3p in head and neck squamous cell carcinoma Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide, associated with a high rate of morbidity and mortality.	('neck squamous cell carcinoma', 'Disease', (82, 110))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (125, 148))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (87, 110))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('neck squamous cell carcinoma', 'Disease', (120, 148))	('mortality', 'Disease', (245, 254))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (82, 110))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (120, 148))	('Head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (111, 148))	('carcinoma', 'Phenotype', 'HP:0030731', (139, 148))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('cancer', 'Disease', (182, 188))	('microRNA-221-3p', 'Var', (54, 69))	('HNSCC', 'Phenotype', 'HP:0012288', (150, 155))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (73, 110))	('mortality', 'Disease', 'MESH:D003643', (245, 254))
70925	33845800	Overexpression of microRNA-221-3p (miR-221-3p) is significantly correlated to the onset and progression of HNSCC.	('HNSCC', 'Disease', (107, 112))	('HNSCC', 'Phenotype', 'HP:0012288', (107, 112))	('microRNA-221-3p', 'Var', (18, 33))	('miR-221-3p', 'Chemical', '-', (35, 45))	('correlated', 'Reg', (64, 74))
70926	33845800	We also conducted the meta-analysis of the cancer literature from the cancer genome atlas (TCGA) and the Gene Expression Omnibus (GEO) database to estimate the expression of miR-221-3p in HNSCC.	('miR-221-3p', 'Var', (174, 184))	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('miR-221-3p', 'Chemical', '-', (174, 184))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('cancer', 'Disease', (43, 49))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('HNSCC', 'Phenotype', 'HP:0012288', (188, 193))
70928	33845800	We observed a significantly higher expression of miR-221-3p in HNSCC compared to the normal with a summary receiver operating characteristic (sROC) of 0.86(95% Cl: 0.83,0.89).	('miR-221-3p', 'Var', (49, 59))	('expression', 'MPA', (35, 45))	('higher', 'PosReg', (28, 34))	('miR-221-3p', 'Chemical', '-', (49, 59))	('HNSCC', 'Disease', (63, 68))	('HNSCC', 'Phenotype', 'HP:0012288', (63, 68))
70929	33845800	The KEGG and GO comprehensive analysis predicted that miR-221-3p might be involved in the development of HNSCC through the following metabolic pathways, viz.	('involved', 'Reg', (74, 82))	('HNSCC', 'Phenotype', 'HP:0012288', (105, 110))	('HNSCC', 'Disease', (105, 110))	('miR-221-3p', 'Var', (54, 64))	('miR-221-3p', 'Chemical', '-', (54, 64))
70930	33845800	Drug metabolism - cytochrome P450 UGT1A7 and MAOB may be important genes for the role of miR-221-3p.	('MAOB', 'Gene', (45, 49))	('cytochrome P450', 'Gene', (18, 33))	('miR-221-3p', 'Chemical', '-', (89, 99))	('MAOB', 'Gene', '4129', (45, 49))	('UGT1A7', 'Gene', '54577', (34, 40))	('UGT1A7', 'Gene', (34, 40))	('cytochrome P450', 'Gene', '4051', (18, 33))	('miR-221-3p', 'Var', (89, 99))
70931	33845800	Based on bioinformatics analysis, our results indicate that miR-221-3p may be used as a non-invasive and hypersensitive biomarker in the diagnosis.	('miR-221-3p', 'Var', (60, 70))	('hypersensitive', 'Disease', (105, 119))	('hypersensitive', 'Disease', 'MESH:D004342', (105, 119))	('miR-221-3p', 'Chemical', '-', (60, 70))
70932	33845800	Thus, it can be concluded that miR-221-3p may be an extremely important gene locus involved in the process of the deterioration and eventual tumorigenesis of HNSCC.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('miR-221-3p', 'Var', (31, 41))	('tumor', 'Disease', (141, 146))	('miR-221-3p', 'Chemical', '-', (31, 41))	('HNSCC', 'Disease', (158, 163))	('HNSCC', 'Phenotype', 'HP:0012288', (158, 163))
70939	33845800	In normal healthy individuals, miR-221-3p is observed to play a role in the process of vascular proliferation, while the tumor promoter microRNA-221 is involved in the process of regulating apoptosis of tumor cells and is associated with a variety of cancer types, including hepatocellular cancer, cutaneous melanoma, prostate cancer, and non-small cell lung cancer.	('tumor', 'Disease', (203, 208))	('miR-221-3p', 'Var', (31, 41))	('cancer', 'Phenotype', 'HP:0002664', (359, 365))	('cancer', 'Disease', 'MESH:D009369', (251, 257))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('involved', 'Reg', (152, 160))	('associated', 'Reg', (222, 232))	('cancer', 'Disease', (327, 333))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (339, 365))	('cancer', 'Disease', 'MESH:D009369', (290, 296))	('tumor', 'Disease', (121, 126))	('melanoma', 'Phenotype', 'HP:0002861', (308, 316))	('cancer', 'Phenotype', 'HP:0002664', (327, 333))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (343, 365))	('prostate cancer', 'Disease', 'MESH:D011471', (318, 333))	('cancer', 'Disease', 'MESH:D009369', (359, 365))	('prostate cancer', 'Phenotype', 'HP:0012125', (318, 333))	('hepatocellular cancer', 'Phenotype', 'HP:0001402', (275, 296))	('tumor', 'Disease', 'MESH:D009369', (121, 126))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('prostate cancer', 'Disease', (318, 333))	('microRNA-221', 'Var', (136, 148))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (339, 365))	('cancer', 'Disease', (251, 257))	('cutaneous melanoma', 'Disease', (298, 316))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (298, 316))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (298, 316))	('cancer', 'Disease', 'MESH:D009369', (327, 333))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('cancer', 'Disease', (290, 296))	('cancer', 'Phenotype', 'HP:0002664', (290, 296))	('miR-221-3p', 'Chemical', '-', (31, 41))	('lung cancer', 'Phenotype', 'HP:0100526', (354, 365))	('non-small cell lung cancer', 'Disease', (339, 365))	('cancer', 'Disease', (359, 365))
70943	33845800	Thus, in the current study, we investigated the expression of miR-221-3p in HNSCC and attempted to explore the correlation between the two.	('HNSCC', 'Phenotype', 'HP:0012288', (76, 81))	('miR-221-3p', 'Chemical', '-', (62, 72))	('investigated', 'Reg', (31, 43))	('miR-221-3p', 'Var', (62, 72))
70950	33845800	The following keywords were used: (HNSCC OR SCC OR "squamous cell cancer" OR "squamous cell carcinoma") AND (oropharynx OR oropharyngeal OR "head and neck" OR nose OR nasopharynx OR "nasal sinus" OR "nasal cavity" OR "oral cavity" OR hypopharynx OR oral OR laryngopharynx OR larynx OR laryngopharyngeal OR laryngeal OR pharyngeal OR tongue OR tonsil OR tonsillar OR cheek OR palatal OR "paranasal sinuses" OR buccal OR lip) AND (microRNA-221-3p OR miRNA-221-3p OR "miR 221-3p" OR "miRNA 221-3p" OR miRNA221-3p OR miR221-3p).	('squamous cell cancer', 'Disease', (52, 72))	('miR 221-3p" OR "miRNA 221-3p" OR miRNA221-3p', 'Var', (465, 509))	('HNSCC', 'Phenotype', 'HP:0012288', (35, 40))	('miRNA-221-3p', 'Var', (448, 460))	('tonsil OR tonsillar OR cheek OR palatal', 'Disease', 'MESH:D014069', (343, 382))	('tonsil OR tonsillar OR cheek OR palatal', 'Disease', (343, 382))	('microRNA-221-3p', 'Var', (429, 444))	('OR cheek', 'Phenotype', 'HP:0000293', (363, 371))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (52, 72))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('HNSCC OR SCC', 'Disease', (35, 47))	('HNSCC OR SCC', 'Disease', 'MESH:D000077195', (35, 47))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (78, 101))	('squamous cell carcinoma', 'Disease', (78, 101))	('squamous cell cancer', 'Disease', 'MESH:D002294', (52, 72))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (78, 101))	('miR221-3p', 'Var', (513, 522))
70953	33845800	The inclusion criteria for the microarray datasets were as follows: (1) comprising data from HNSCC and noncancerous tissues; (2) evaluation of the association between miR-221-3p expression and clinical outcomes; and (3) availability of sufficient data to calculate the mean, SD and 95% CI.	('HNSCC', 'Disease', (93, 98))	('miR-221-3p', 'Chemical', '-', (167, 177))	('association', 'Interaction', (147, 158))	('HNSCC', 'Phenotype', 'HP:0012288', (93, 98))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('cancer', 'Disease', (106, 112))	('miR-221-3p', 'Var', (167, 177))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
70955	33845800	We use the MiRWalk 2.0 (http://zmf.umm.uniheidelberg.de/apps/zmf/mirwalk2/) and GEPIA (http://gepia.cancer-pku.cn/index.html) databases to retrieve differentially expressed genes of miR-221-3p in HNSCC.	('HNSCC', 'Phenotype', 'HP:0012288', (196, 201))	('miR-221-3p', 'Chemical', '-', (182, 192))	('miR-221-3p', 'Var', (182, 192))	('gepia.cancer-pku', 'Disease', (94, 110))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('gepia.cancer-pku', 'Disease', 'MESH:D009369', (94, 110))
70959	33845800	The standard mean difference (SMD) and 95% confidence interval were used to estimate the expression value of miR-221-3p.	('SMD', 'Disease', 'MESH:C537501', (30, 33))	('SMD', 'Disease', (30, 33))	('miR-221-3p', 'Chemical', '-', (109, 119))	('miR-221-3p', 'Var', (109, 119))
70963	33845800	The RT-qPCR data clearly showed that miR-221-3p is highly expressed in the tissues of nasopharyngeal carcinoma patients compared to the controls (p < 0.05) (Fig.1).	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (86, 110))	('carcinoma', 'Disease', (101, 110))	('miR-221-3p', 'Var', (37, 47))	('miR-221-3p', 'Chemical', '-', (37, 47))	('carcinoma', 'Disease', 'MESH:D009369', (101, 110))	('patients', 'Species', '9606', (111, 119))
70965	33845800	The meta-analysis performed on all data to explore the expression level of miR-221-3p in HNSCC indicated a high degree of heterogeneity between these studies.	('HNSCC', 'Gene', (89, 94))	('HNSCC', 'Phenotype', 'HP:0012288', (89, 94))	('miR-221-3p', 'Chemical', '-', (75, 85))	('miR-221-3p', 'Var', (75, 85))
70967	33845800	The meta-analysis data indicate that miR-221-3p expression is significantly upregulated in HNSCC, which is consistent with the results obtained by RT-qPCR.	('expression', 'MPA', (48, 58))	('miR-221-3p', 'Var', (37, 47))	('HNSCC', 'Disease', (91, 96))	('HNSCC', 'Phenotype', 'HP:0012288', (91, 96))	('upregulated', 'PosReg', (76, 87))	('miR-221-3p', 'Chemical', '-', (37, 47))
70968	33845800	In addition, miR-221-3p expression was significantly increased in HNSCC in the GSE11163, GSE103931, GSE113956, GSE31277, GSE45238, GSE82064, TCGA and PMID30928631 datasets, and the expression levels of miR-221-3p in HNSCC and normal tissues from each included dataset are shown in Fig.5.	('HNSCC', 'Disease', (66, 71))	('GSE82064', 'Var', (131, 139))	('GSE31277', 'Var', (111, 119))	('HNSCC', 'Phenotype', 'HP:0012288', (66, 71))	('miR-221-3p', 'Gene', (13, 23))	('expression', 'MPA', (24, 34))	('PMID30928631', 'Chemical', '-', (150, 162))	('miR-221-3p', 'Chemical', '-', (13, 23))	('GSE113956', 'Var', (100, 109))	('GSE11163', 'Var', (79, 87))	('miR-221-3p', 'Chemical', '-', (202, 212))	('increased', 'PosReg', (53, 62))	('GSE103931', 'Var', (89, 98))	('HNSCC', 'Phenotype', 'HP:0012288', (216, 221))	('GSE45238', 'Var', (121, 129))
70969	33845800	The random-effects model used to analyze the diagnostic value of miR-221-3p for HNSCC showed significant heterogeneity in the likelihood ratio (negative and positive) sensitivity and specificity analyses.	('HNSCC', 'Disease', (80, 85))	('miR-221-3p', 'Chemical', '-', (65, 75))	('HNSCC', 'Phenotype', 'HP:0012288', (80, 85))	('miR-221-3p', 'Var', (65, 75))
70970	33845800	The receiver operating characteristic (ROC) curve of GSE103931, GSE11163, GSE113956, GSE31277, GSE34496, GSE45238, GSE82064, TCGA and PMID30928631 is statistically significant (p < 0.05, Fig.7).	('TCGA', 'Var', (125, 129))	('PMID30928631', 'Chemical', '-', (134, 146))	('GSE45238', 'Var', (105, 113))	('GSE34496', 'Var', (95, 103))	('GSE103931', 'Var', (53, 62))	('GSE113956', 'Var', (74, 83))	('GSE31277', 'Var', (85, 93))	('PMID30928631', 'Var', (134, 146))	('GSE82064', 'Var', (115, 123))	('GSE11163', 'Var', (64, 72))
70971	33845800	Based on the HNSCC sample data extracted from the TCGA database, we analyzed 527 samples, and the results indicated the absence of any statistically significant difference between miR-221-3p expression and age, lymphatic invasion, neoplasm histologic grade and any other clinicopathological features.	('neoplasm', 'Disease', (231, 239))	('miR-221-3p', 'Var', (180, 190))	('lymphatic invasion', 'CPA', (211, 229))	('neoplasm', 'Phenotype', 'HP:0002664', (231, 239))	('miR-221-3p', 'Chemical', '-', (180, 190))	('neoplasm', 'Disease', 'MESH:D009369', (231, 239))	('HNSCC', 'Phenotype', 'HP:0012288', (13, 18))
70972	33845800	However, the results indicated statistically significant differences in the expression of miR-221-3p in different tissues, sexes, and even alcohol consumption statuses (Table 2).	('alcohol', 'Chemical', 'MESH:D000438', (139, 146))	('miR-221-3p', 'Var', (90, 100))	('miR-221-3p', 'Chemical', '-', (90, 100))	('expression', 'MPA', (76, 86))	('significant differences', 'Reg', (45, 68))
70973	33845800	These overlapped 117 genes could be considered as the target genes that miR-221-3p might play a role in HNSCC.	('role', 'Reg', (96, 100))	('HNSCC', 'Disease', (104, 109))	('miR-221-3p', 'Var', (72, 82))	('HNSCC', 'Phenotype', 'HP:0012288', (104, 109))	('miR-221-3p', 'Chemical', '-', (72, 82))	('play', 'Reg', (89, 93))
70974	33845800	KEGG enrichment analysis showed that miR-221-3p plays a significant role in HNSCC through a variety of pathways, including the drug metabolism pathways of the cytochrome P450 signaling pathway.	('cytochrome P450', 'Gene', (159, 174))	('HNSCC', 'Disease', (76, 81))	('HNSCC', 'Phenotype', 'HP:0012288', (76, 81))	('drug metabolism pathways', 'Pathway', (127, 151))	('miR-221-3p', 'Var', (37, 47))	('cytochrome P450', 'Gene', '4051', (159, 174))	('role', 'Reg', (68, 72))	('miR-221-3p', 'Chemical', '-', (37, 47))
70976	33845800	12, from which we learned that the 5 target genes (UGT1A7, CYP3A5, FMO2, MAOB and ADH1B) related to miR-221-3p were downregulated in the drug metabolism-cytochrome P450 pathway (p < 0.05).	('downregulated', 'NegReg', (116, 129))	('ADH1B', 'Gene', (82, 87))	('MAOB', 'Gene', (73, 77))	('miR-221-3p', 'Var', (100, 110))	('FMO2', 'Gene', (67, 71))	('cytochrome P450', 'Gene', (153, 168))	('ADH1B', 'Gene', '125', (82, 87))	('MAOB', 'Gene', '4129', (73, 77))	('miR-221-3p', 'Chemical', '-', (100, 110))	('CYP3A5', 'Gene', '1577', (59, 65))	('UGT1A7', 'Gene', '54577', (51, 57))	('cytochrome P450', 'Gene', '4051', (153, 168))	('CYP3A5', 'Gene', (59, 65))	('FMO2', 'Gene', '2327', (67, 71))	('UGT1A7', 'Gene', (51, 57))
70977	33845800	Spearman correlation analysis showed that GSTA1, UGT1A7 and MAOB, the target genes of the drug metabolism-cytochrome P450, were correlated with miR-221-3p in HNSCC (p < 0.05, Fig.13).	('UGT1A7', 'Gene', (49, 55))	('miR-221-3p', 'Var', (144, 154))	('correlated', 'Reg', (128, 138))	('MAOB', 'Gene', '4129', (60, 64))	('GSTA1', 'Gene', '2938', (42, 47))	('miR-221-3p', 'Chemical', '-', (144, 154))	('cytochrome P450', 'Gene', '4051', (106, 121))	('MAOB', 'Gene', (60, 64))	('UGT1A7', 'Gene', '54577', (49, 55))	('cytochrome P450', 'Gene', (106, 121))	('GSTA1', 'Gene', (42, 47))	('HNSCC', 'Phenotype', 'HP:0012288', (158, 163))
70979	33845800	For example, Liping Wang and his colleagues suggest that the inhibition of CYP3A5 in cytochrome P450 drug metabolism can drive the migration, proliferation, and invasion of HNSCC cells.	('cytochrome P450', 'Gene', '4051', (85, 100))	('HNSCC cells', 'CPA', (173, 184))	('migration', 'CPA', (131, 140))	('inhibition', 'Var', (61, 71))	('proliferation', 'CPA', (142, 155))	('invasion', 'CPA', (161, 169))	('CYP3A5', 'Gene', (75, 81))	('HNSCC', 'Phenotype', 'HP:0012288', (173, 178))	('drive', 'PosReg', (121, 126))	('cytochrome P450', 'Gene', (85, 100))	('CYP3A5', 'Gene', '1577', (75, 81))
70981	33845800	Among the target genes of miR-221-3p, MAOB and UGT1A7 are associated with the miR-221-3p and drug-cytochrome P450 signaling pathway and are downregulated in HNSCC (p < 0.05).	('MAOB', 'Gene', '4129', (38, 42))	('MAOB', 'Gene', (38, 42))	('miR-221-3p', 'Chemical', '-', (78, 88))	('UGT1A7', 'Gene', '54577', (47, 53))	('miR-221-3p', 'Gene', (26, 36))	('downregulated', 'NegReg', (140, 153))	('associated', 'Reg', (58, 68))	('cytochrome P450', 'Gene', '4051', (98, 113))	('UGT1A7', 'Gene', (47, 53))	('HNSCC', 'Disease', (157, 162))	('HNSCC', 'Phenotype', 'HP:0012288', (157, 162))	('cytochrome P450', 'Gene', (98, 113))	('miR-221-3p', 'Var', (78, 88))	('miR-221-3p', 'Chemical', '-', (26, 36))
70984	33845800	Our study suggests that miR-221-3p may play an important role as a gene that promotes the development of HNSCC by reducing the expression of the MAOB and UGT1A7 pathways in HNSCC.	('miR-221-3p', 'Var', (24, 34))	('promotes', 'PosReg', (77, 85))	('expression', 'MPA', (127, 137))	('miR-221-3p', 'Chemical', '-', (24, 34))	('UGT1A7', 'Gene', '54577', (154, 160))	('MAOB', 'Gene', (145, 149))	('HNSCC', 'Phenotype', 'HP:0012288', (173, 178))	('MAOB', 'Gene', '4129', (145, 149))	('HNSCC', 'Phenotype', 'HP:0012288', (105, 110))	('UGT1A7', 'Gene', (154, 160))	('development', 'CPA', (90, 101))	('reducing', 'NegReg', (114, 122))	('HNSCC', 'Disease', (105, 110))
70986	33845800	For example, miR-221-3p has been regarded as a tumor biomarker that can be used to assess the clinical prognosis of breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('miR-221-3p', 'Var', (13, 23))	('breast cancer', 'Disease', (116, 129))	('breast cancer', 'Phenotype', 'HP:0003002', (116, 129))	('miR-221-3p', 'Chemical', '-', (13, 23))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('breast cancer', 'Disease', 'MESH:D001943', (116, 129))	('tumor', 'Disease', (47, 52))
70987	33845800	In healthy humans, it has been shown that miR-221-3p plays a role in the process of vascular proliferation, while the tumor promoter miR-221-3p regulates the apoptosis of tumor cells.	('vascular proliferation', 'CPA', (84, 106))	('miR-221-3p', 'Chemical', '-', (133, 143))	('miR-221-3p', 'Var', (42, 52))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('miR-221-3p', 'Chemical', '-', (42, 52))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('regulates', 'Reg', (144, 153))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('apoptosis', 'CPA', (158, 167))	('tumor', 'Disease', (118, 123))	('humans', 'Species', '9606', (11, 17))	('tumor', 'Disease', (171, 176))	('miR-221-3p', 'Var', (133, 143))
70989	33845800	The biological pathways relevant to the actions of miR-221-3p will guide further understanding of the mechanisms of HNSCC.	('HNSCC', 'Phenotype', 'HP:0012288', (116, 121))	('miR-221-3p', 'Chemical', '-', (51, 61))	('miR-221-3p', 'Var', (51, 61))	('HNSCC', 'Disease', (116, 121))
70993	33845800	MAOB and UGT1A7 are potentially important targets of miR-221-3p.	('MAOB', 'Gene', '4129', (0, 4))	('UGT1A7', 'Gene', (9, 15))	('miR-221-3p', 'Var', (53, 63))	('UGT1A7', 'Gene', '54577', (9, 15))	('miR-221-3p', 'Chemical', '-', (53, 63))	('MAOB', 'Gene', (0, 4))
70994	33845800	MiR-221-3p may be used as a noninvasive and hypersensitive biomarker for the diagnosis of HNSCC and is an extremely important gene locus involved in the process of the deterioration and eventual tumorigenesis of HNSCC.	('tumor', 'Disease', (195, 200))	('HNSCC', 'Disease', (90, 95))	('HNSCC', 'Phenotype', 'HP:0012288', (90, 95))	('MiR-221-3p', 'Var', (0, 10))	('MiR-221-3p', 'Chemical', '-', (0, 10))	('hypersensitive', 'Disease', 'MESH:D004342', (44, 58))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('HNSCC', 'Phenotype', 'HP:0012288', (212, 217))	('hypersensitive', 'Disease', (44, 58))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))
70995	33845800	Finally, the biological pathways relevant to the actions of miR-221-3p will provide insights into its potential molecular mechanisms in HNSCC.	('miR-221-3p', 'Chemical', '-', (60, 70))	('HNSCC', 'Phenotype', 'HP:0012288', (136, 141))	('miR-221-3p', 'Var', (60, 70))	('HNSCC', 'Disease', (136, 141))
71030	33435562	Most of the patients with thyroid cancer received radioisotopes, while not the external beam radiation (Table 1).	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('patients', 'Species', '9606', (12, 20))	('radioisotopes', 'Var', (50, 63))	('thyroid cancer', 'Phenotype', 'HP:0002890', (26, 40))	('radioisotope', 'Chemical', 'MESH:D011868', (50, 62))	('thyroid cancer', 'Disease', (26, 40))	('thyroid cancer', 'Disease', 'MESH:D013964', (26, 40))
71033	33435562	Owing to the limitations of Fine and Gray models, the proportional sub-distribution hazard assumption in the competing risk model is often impossible to hold over a long time of follow-up, thus in some multivariable models, Cox models were utilized to calculate the effect sizes of radiotherapy vs. no radiotherapy.	('Cox', 'Gene', '1351', (224, 227))	('radiotherapy', 'Var', (282, 294))	('Cox', 'Gene', (224, 227))
71052	33435562	In the PSM-adjusted population, according to the outcomes of the survival analysis (Kaplan-Meier) considering the competing-risks in event occurrence, the results could be divided into two groups: (I) Patients receiving radiotherapy were associated with more SPMs and (II) Patients who received radiotherapy showed similar SPM incidences.	('radiotherapy', 'Var', (220, 232))	('SPMs', 'Disease', (259, 263))	('Patients', 'Species', '9606', (273, 281))	('Patients', 'Species', '9606', (201, 209))
71125	32380883	Co-targeting CCND1 and FGFR1 could provide greater clinical benefits.	('FGFR1', 'Gene', (23, 28))	('CCND1', 'Gene', '595', (13, 18))	('FGFR1', 'Gene', '2260', (23, 28))	('Co-targeting', 'Var', (0, 12))	('CCND1', 'Gene', (13, 18))
71127	32380883	Targeted drugs have been developed in lung adenocarcinoma (LADC) for patients with driven gene positive patients such as epithelial growth factor receptor (EGFR) mutation and anaplastic lymphoma kinase (ALK) or ROS proto-oncogene 1(ROS1) rearrangements to inhibit tumor progression.	('ROS1', 'Gene', (232, 236))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (38, 57))	('LADC', 'Phenotype', 'HP:0030078', (59, 63))	('rearrangements', 'Var', (238, 252))	('patients', 'Species', '9606', (69, 77))	('mutation', 'Var', (162, 170))	('ALK', 'Gene', '238', (203, 206))	('carcinoma', 'Phenotype', 'HP:0030731', (48, 57))	('si', 'Chemical', 'MESH:D012825', (97, 99))	('epithelial growth factor receptor', 'Gene', (121, 154))	('tumor', 'Disease', (264, 269))	('EGFR', 'Gene', '1956', (156, 160))	('ALK', 'Gene', (203, 206))	('tumor', 'Disease', 'MESH:D009369', (264, 269))	('anaplastic lymphoma kinase', 'Gene', '238', (175, 201))	('epithelial growth factor receptor', 'Gene', '1956', (121, 154))	('ROS1', 'Gene', '6098', (232, 236))	('anaplastic lymphoma kinase', 'Gene', (175, 201))	('si', 'Chemical', 'MESH:D012825', (277, 279))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (175, 194))	('lung adenocarcinoma', 'Disease', (38, 57))	('patients', 'Species', '9606', (104, 112))	('tumor', 'Phenotype', 'HP:0002664', (264, 269))	('inhibit', 'NegReg', (256, 263))	('EGFR', 'Gene', (156, 160))	('lymphoma', 'Phenotype', 'HP:0002665', (186, 194))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (38, 57))
71132	32380883	FGFR1 amplification is the most common type in the FGFR1 dysfunction, with 20% in LSCC, 5-7% in SCLC, and 1-3% in LADC.	('LADC', 'Disease', (114, 118))	('LSCC', 'Disease', (82, 86))	('FGFR1', 'Gene', (0, 5))	('FGFR1', 'Gene', '2260', (0, 5))	('LSCC', 'Phenotype', 'HP:0030359', (82, 86))	('common', 'Reg', (32, 38))	('FGFR1', 'Gene', (51, 56))	('LADC', 'Phenotype', 'HP:0030078', (114, 118))	('amplification', 'Var', (6, 19))	('dysfunction', 'Var', (57, 68))	('SCLC', 'Disease', (96, 100))	('SCLC', 'Disease', 'MESH:D018288', (96, 100))	('FGFR1', 'Gene', '2260', (51, 56))
71134	32380883	BGJ398 and AZD4547 are selective inhibitors of FGFR 1-3 in phase Ib clinical trials.	('AZD4547', 'Var', (11, 18))	('BGJ398', 'Chemical', 'MESH:C568950', (0, 6))	('AZD4547', 'Chemical', 'MESH:C572463', (11, 18))	('FGFR 1-3', 'Gene', (47, 55))	('FGFR 1-3', 'Gene', '2260;2263;2261', (47, 55))
71138	32380883	Notably, 1/3 of FGFR1-amplified tumors harbor amplification of CCND1 in breast cancer.	('CCND1', 'Gene', '595', (63, 68))	('FGFR1', 'Gene', '2260', (16, 21))	('amplification', 'Var', (46, 59))	('breast cancer', 'Phenotype', 'HP:0003002', (72, 85))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('breast cancer', 'Disease', 'MESH:D001943', (72, 85))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('breast cancer', 'Disease', (72, 85))	('tumors', 'Disease', (32, 38))	('CCND1', 'Gene', (63, 68))	('FGFR1', 'Gene', (16, 21))	('tumors', 'Disease', 'MESH:D009369', (32, 38))
71172	32380883	In the orthotropic lung tumor model, cell suspension of H1581(2 x 106 cells) in a total volume of 50 muL (Matrigel: PBS = 1:4) were injected directly into the left lung with insulin injection syringes (29 G*12.7 mm, BD, 328421).	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('insulin', 'Gene', (174, 181))	('PBS', 'Chemical', 'MESH:D007854', (116, 119))	('lung tumor', 'Disease', 'MESH:D008175', (19, 29))	('lung tumor', 'Disease', (19, 29))	('insulin', 'Gene', '3630', (174, 181))	('H1581', 'Var', (56, 61))	('syringes', 'Phenotype', 'HP:0003396', (192, 200))	('lung tumor', 'Phenotype', 'HP:0100526', (19, 29))	('si', 'Chemical', 'MESH:D012825', (48, 50))	('H1581', 'CellLine', 'CVCL:1479', (56, 61))
71193	32380883	Conversely, CCND1 knockdown inhibited the proliferation, as determined by CCK8 assay and colony formation assay (Figure 3(a) and (b)).	('knockdown', 'Var', (18, 27))	('proliferation', 'CPA', (42, 55))	('CCND1', 'Gene', (12, 17))	('colony formation assay', 'CPA', (89, 111))	('inhibited', 'NegReg', (28, 37))	('CCND1', 'Gene', '595', (12, 17))
71194	32380883	CCND1 knockdown inhibited the migration and invasion as determined by transwell assay (Figure 3(c)).	('inhibited', 'NegReg', (16, 25))	('CCND1', 'Gene', (0, 5))	('knockdown', 'Var', (6, 15))	('si', 'Chemical', 'MESH:D012825', (48, 50))	('CCND1', 'Gene', '595', (0, 5))
71195	32380883	CCND1 knockdown also sharply suppressed EMT process (Figure 3(d) and (e)).	('CCND1', 'Gene', (0, 5))	('EMT', 'Gene', (40, 43))	('EMT', 'Gene', '3702', (40, 43))	('knockdown', 'Var', (6, 15))	('CCND1', 'Gene', '595', (0, 5))	('suppressed', 'NegReg', (29, 39))
71202	32380883	AKT and MAPK signaling, as the most motivation of EMT being reported, were upregulated by CCND1 overexpression plasmid and downregulated by si-CCND1 (Figure 4(g)).	('AKT', 'Gene', (0, 3))	('upregulated', 'PosReg', (75, 86))	('CCND1', 'Gene', (90, 95))	('overexpression', 'Var', (96, 110))	('CCND1', 'Gene', '595', (143, 148))	('downregulated', 'NegReg', (123, 136))	('CCND1', 'Gene', '595', (90, 95))	('MAPK signaling', 'Pathway', (8, 22))	('si', 'Chemical', 'MESH:D012825', (106, 108))	('AKT', 'Gene', '207', (0, 3))	('si', 'Chemical', 'MESH:D012825', (140, 142))	('CCND1', 'Gene', (143, 148))	('si', 'Chemical', 'MESH:D012825', (13, 15))	('EMT', 'Gene', (50, 53))	('EMT', 'Gene', '3702', (50, 53))
71209	32380883	As the co-overexpression of CCND1 and FGFR1 in LSCC, we hypothesized that the co-target CCND1 and FGFR1 may provide higher efficiency.	('FGFR1', 'Gene', (98, 103))	('CCND1', 'Gene', '595', (28, 33))	('FGFR1', 'Gene', '2260', (98, 103))	('co-overexpression', 'Var', (7, 24))	('CCND1', 'Gene', (88, 93))	('LSCC', 'Phenotype', 'HP:0030359', (47, 51))	('FGFR1', 'Gene', (38, 43))	('FGFR1', 'Gene', '2260', (38, 43))	('si', 'Chemical', 'MESH:D012825', (20, 22))	('CCND1', 'Gene', '595', (88, 93))	('CCND1', 'Gene', (28, 33))	('si', 'Chemical', 'MESH:D012825', (63, 65))
71211	32380883	The IC50 for was 0.2433 muM and 11.81 muM for AZD4547 and si-CCND1, respectively.	('muM', 'Gene', '56925', (38, 41))	('muM', 'Gene', '56925', (24, 27))	('CCND1', 'Gene', (61, 66))	('muM', 'Gene', (24, 27))	('muM', 'Gene', (38, 41))	('AZD4547', 'Var', (46, 53))	('AZD4547', 'Chemical', 'MESH:C572463', (46, 53))	('CCND1', 'Gene', '595', (61, 66))	('si', 'Chemical', 'MESH:D012825', (58, 60))
71212	32380883	However, the IC50 for AZD4547 plus si-CCND1 was reduced to 0.0668 muM.	('CCND1', 'Gene', '595', (38, 43))	('AZD4547', 'Chemical', 'MESH:C572463', (22, 29))	('muM', 'Gene', '56925', (66, 69))	('muM', 'Gene', (66, 69))	('AZD4547', 'Var', (22, 29))	('CCND1', 'Gene', (38, 43))	('si', 'Chemical', 'MESH:D012825', (35, 37))
71216	32380883	To further verify the synergism in vivo, subcutaneous mouse models and orthotopic lung cancer mouse models were established using H1581 (Figure 6(b)-(e)).	('H1581', 'Var', (130, 135))	('lung cancer', 'Phenotype', 'HP:0100526', (82, 93))	('lung cancer', 'Disease', (82, 93))	('H1581', 'CellLine', 'CVCL:1479', (130, 135))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('mouse', 'Species', '10090', (94, 99))	('lung cancer', 'Disease', 'MESH:D008175', (82, 93))	('mouse', 'Species', '10090', (54, 59))	('si', 'Chemical', 'MESH:D012825', (125, 127))
71221	32380883	Meanwhile, the si-CCND1 plus AZD4547 group grew even slower than the si-CCND1 group or the AZD4547 group (p < 0.05, Figure 6(b)).	('CCND1', 'Gene', (72, 77))	('CCND1', 'Gene', '595', (18, 23))	('CCND1', 'Gene', '595', (72, 77))	('grew', 'CPA', (43, 47))	('AZD4547', 'Var', (29, 36))	('si', 'Chemical', 'MESH:D012825', (15, 17))	('AZD4547', 'Chemical', 'MESH:C572463', (91, 98))	('CCND1', 'Gene', (18, 23))	('AZD4547', 'Chemical', 'MESH:C572463', (29, 36))	('si', 'Chemical', 'MESH:D012825', (69, 71))	('slower', 'NegReg', (53, 59))
71226	32380883	In sh-CCND1 group plus AZD4547 group, FGFR1 and mesenchymal markers Snail and Vimentin were significantly suppressed, while the epithelial marker E-cadherin was highly expressed (Figure 6(d)).	('E-cadherin', 'Gene', (146, 156))	('E-cadherin', 'Gene', '999', (146, 156))	('Snail', 'Gene', '6615', (68, 73))	('Snail', 'Gene', (68, 73))	('suppressed', 'NegReg', (106, 116))	('FGFR1', 'Gene', (38, 43))	('Vimentin', 'Gene', (78, 86))	('FGFR1', 'Gene', '2260', (38, 43))	('si', 'Chemical', 'MESH:D012825', (92, 94))	('AZD4547', 'Var', (23, 30))	('CCND1', 'Gene', (6, 11))	('AZD4547', 'Chemical', 'MESH:C572463', (23, 30))	('Vimentin', 'Gene', '7431', (78, 86))	('CCND1', 'Gene', '595', (6, 11))
71228	32380883	Prior studies that have noted the importance of CCND1 and FGFR dysfunction in the initiation of cancers.	('CCND1', 'Gene', '595', (48, 53))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('initiation of cancers', 'Disease', (82, 103))	('FGFR', 'Gene', (58, 62))	('dysfunction', 'Var', (63, 74))	('initiation of cancers', 'Disease', 'MESH:D009369', (82, 103))	('cancers', 'Phenotype', 'HP:0002664', (96, 103))	('CCND1', 'Gene', (48, 53))
71237	32380883	Meanwhile, FGFR1 amplification/overexpression was reported as a mechanism of resistance to treatment with CDK4/6 inhibitors in combination with antiestrogens.	('si', 'Chemical', 'MESH:D012825', (79, 81))	('CDK4/6', 'Gene', '1019;1021', (106, 112))	('amplification/overexpression', 'PosReg', (17, 45))	('amplification/overexpression', 'Var', (17, 45))	('FGFR1', 'Gene', (11, 16))	('CDK4/6', 'Gene', (106, 112))	('si', 'Chemical', 'MESH:D012825', (41, 43))	('FGFR1', 'Gene', '2260', (11, 16))
71239	32380883	Here, we confirmed the antitumor synergism between si-CCND1 and FGFR1 inhibitor AZD4547 in vitro and in vivo.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumor', 'Disease', (27, 32))	('AZD4547', 'Var', (80, 87))	('FGFR1', 'Gene', (64, 69))	('CCND1', 'Gene', (54, 59))	('FGFR1', 'Gene', '2260', (64, 69))	('AZD4547', 'Chemical', 'MESH:C572463', (80, 87))	('CCND1', 'Gene', '595', (54, 59))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('si', 'Chemical', 'MESH:D012825', (51, 53))
71241	32380883	The mechanism of the synergistic effect remains unclear, and we found FGFR1 inhibitor AZD4547 sharply downregulated the level of CCND1.	('downregulated', 'NegReg', (102, 115))	('CCND1', 'Gene', (129, 134))	('AZD4547', 'Chemical', 'MESH:C572463', (86, 93))	('CCND1', 'Gene', '595', (129, 134))	('FGFR1', 'Gene', (70, 75))	('FGFR1', 'Gene', '2260', (70, 75))	('AZD4547', 'Var', (86, 93))
71242	32380883	The inhibitory effect of AZD4547 and si-RNA on CCND1 might be synergistic, which need further exploration.	('AZD4547', 'Var', (25, 32))	('AZD4547', 'Chemical', 'MESH:C572463', (25, 32))	('si', 'Chemical', 'MESH:D012825', (37, 39))	('inhibitory', 'NegReg', (4, 14))	('CCND1', 'Gene', (47, 52))	('CCND1', 'Gene', '595', (47, 52))	('si-RNA', 'Var', (37, 43))
71243	32380883	Despite current studies pointing to the fact that CCND1 is overexpressed and activated in a variety of cancers, few reports discuss the underlying molecular mechanisms by which CCND1 is regulated or activated in malignant tumors, especially in FGFR1 amplified lung cancer.	('cancers', 'Disease', 'MESH:D009369', (103, 110))	('malignant tumors', 'Disease', (212, 228))	('cancer', 'Phenotype', 'HP:0002664', (265, 271))	('malignant tumors', 'Disease', 'MESH:D009369', (212, 228))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('amplified', 'Var', (250, 259))	('CCND1', 'Gene', '595', (177, 182))	('CCND1', 'Gene', '595', (50, 55))	('lung cancer', 'Disease', (260, 271))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('CCND1', 'Gene', (177, 182))	('CCND1', 'Gene', (50, 55))	('FGFR1', 'Gene', (244, 249))	('cancers', 'Phenotype', 'HP:0002664', (103, 110))	('cancers', 'Disease', (103, 110))	('lung cancer', 'Disease', 'MESH:D008175', (260, 271))	('activated', 'PosReg', (199, 208))	('lung cancer', 'Phenotype', 'HP:0100526', (260, 271))	('FGFR1', 'Gene', '2260', (244, 249))	('tumors', 'Phenotype', 'HP:0002664', (222, 228))
71246	32380883	Overexpression of FGFR1 has previously been linked to shorter progress free survival (PFS) of lung cancer, and separately.	('lung cancer', 'Disease', 'MESH:D008175', (94, 105))	('FGFR1', 'Gene', (18, 23))	('progress', 'MPA', (62, 70))	('lung cancer', 'Disease', (94, 105))	('lung cancer', 'Phenotype', 'HP:0100526', (94, 105))	('Overexpression', 'Var', (0, 14))	('FGFR1', 'Gene', '2260', (18, 23))	('shorter', 'NegReg', (54, 61))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('si', 'Chemical', 'MESH:D012825', (10, 12))
71250	32380883	In addition, we found a synergistic antitumor effect between si-CCND1 and FGFR1 inhibitor AZD4547 in vitro and in vivo.	('AZD4547', 'Var', (90, 97))	('FGFR1', 'Gene', '2260', (74, 79))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('si', 'Chemical', 'MESH:D012825', (61, 63))	('AZD4547', 'Chemical', 'MESH:C572463', (90, 97))	('CCND1', 'Gene', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('FGFR1', 'Gene', (74, 79))	('CCND1', 'Gene', '595', (64, 69))
71267	31927310	By correlating TP63 isoform expression with clinical outcomes, we find that while the DNp63 isoforms correlated with improved patient prognosis, the TAp63 isoforms correlated with worse patient prognosis in bladder, breast and lung cancers.	('TP63', 'Gene', '8626', (15, 19))	('cancers', 'Phenotype', 'HP:0002664', (232, 239))	('bladder', 'Disease', (207, 214))	('breast and lung cancers', 'Disease', 'MESH:D001943', (216, 239))	('TAp63', 'Var', (149, 154))	('TP63', 'Gene', (15, 19))	('worse', 'NegReg', (180, 185))	('improved', 'PosReg', (117, 125))	('patient', 'Species', '9606', (126, 133))	('DNp63', 'Gene', (86, 91))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('patient', 'Species', '9606', (186, 193))	('lung cancers', 'Phenotype', 'HP:0100526', (227, 239))
71287	31927310	In MIBC, TP63 expression has been shown to be correlated with induction of EMT and worse patient outcomes and expression of DNp63 was shown to identify basal-subtype bladder cancers with aggressive clinical courses and poor prognosis.	('TP63', 'Gene', '8626', (9, 13))	('bladder cancers', 'Disease', (166, 181))	('patient', 'Species', '9606', (89, 96))	('TP63', 'Gene', (9, 13))	('bladder cancers', 'Disease', 'MESH:D001749', (166, 181))	('cancers', 'Phenotype', 'HP:0002664', (174, 181))	('correlated', 'Reg', (46, 56))	('expression', 'Var', (110, 120))	('MIBC', 'Disease', 'MESH:D001749', (3, 7))	('bladder cancers', 'Phenotype', 'HP:0009725', (166, 181))	('bladder cancer', 'Phenotype', 'HP:0009725', (166, 180))	('DNp63', 'Gene', (124, 129))	('EMT', 'Gene', (75, 78))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('EMT', 'Gene', '3702', (75, 78))	('MIBC', 'Disease', (3, 7))
71291	31927310	Using previously annotated, as well as, un-annotated TP63 isoforms, we show that DNp63 is the most commonly expressed isoform type in bladder cancer and most other cancer types in the TCGA and find that high expression is generally associated with improved patient outcomes.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('improved', 'PosReg', (248, 256))	('TP63', 'Gene', '8626', (53, 57))	('bladder cancer', 'Disease', 'MESH:D001749', (134, 148))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('patient', 'Species', '9606', (257, 264))	('TP63', 'Gene', (53, 57))	('cancer', 'Disease', (164, 170))	('DNp63', 'Var', (81, 86))	('bladder cancer', 'Disease', (134, 148))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('bladder cancer', 'Phenotype', 'HP:0009725', (134, 148))	('C', 'Chemical', 'MESH:D002244', (185, 186))	('cancer', 'Disease', (142, 148))
71292	31927310	Conversely, although less commonly expressed, TAp63 is associated with worse patient outcomes in bladder and other tumor types.	('TAp63', 'Var', (46, 51))	('bladder', 'Disease', (97, 104))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumor', 'Disease', (115, 120))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('patient', 'Species', '9606', (77, 84))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
71293	31927310	In bladder cancers, the favorable association of DNp63 was selectively observed in luminal tumors, whereas, the negative association of TAp63 was observed specifically in basal squamous tumor subtypes.	('squamous tumor', 'Disease', (177, 191))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('DNp63', 'Var', (49, 54))	('luminal tumors', 'Disease', 'MESH:D009369', (83, 97))	('bladder cancers', 'Disease', 'MESH:D001749', (3, 18))	('basal squamous tumor', 'Phenotype', 'HP:0002671', (171, 191))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('bladder cancer', 'Phenotype', 'HP:0009725', (3, 17))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('squamous tumor', 'Phenotype', 'HP:0002860', (177, 191))	('bladder cancers', 'Disease', (3, 18))	('luminal tumors', 'Disease', (83, 97))	('cancers', 'Phenotype', 'HP:0002664', (11, 18))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('squamous tumor', 'Disease', 'MESH:D002294', (177, 191))	('bladder cancers', 'Phenotype', 'HP:0009725', (3, 18))
71312	31927310	For example, TAp63 isoform expression was calculated by adding together all TPM values for all TP63 isoforms with a 5p trans-activation domain (TAp63alpha, TAp63alphaP, TAp63beta, TAp63gamma, TAp63delta).	('TAp63gamma', 'Var', (180, 190))	('p63alpha', 'Gene', '8626', (158, 166))	('p63alpha', 'Gene', (158, 166))	('p63alpha', 'Gene', '8626', (146, 154))	('TP63', 'Gene', '8626', (95, 99))	('p63alpha', 'Gene', (146, 154))	('TAp63delta', 'Var', (192, 202))	('TAp63beta', 'Var', (169, 178))	('TP63', 'Gene', (95, 99))
71314	31927310	Initial investigation using Cox regression showed evidence of an association with survival in BLCA, BRCA, and LUSC patient cohorts with expression of TP63, DNp63, and TAp63 isoforms.	('C', 'Chemical', 'MESH:D002244', (28, 29))	('BLCA', 'Disease', (94, 98))	('C', 'Chemical', 'MESH:D002244', (96, 97))	('BRCA', 'Gene', '672', (100, 104))	('BRCA', 'Gene', (100, 104))	('association', 'Interaction', (65, 76))	('Cox', 'Gene', '1351', (28, 31))	('TAp63', 'Var', (167, 172))	('Cox', 'Gene', (28, 31))	('TP63', 'Gene', (150, 154))	('DNp63', 'Var', (156, 161))	('TP63', 'Gene', '8626', (150, 154))	('BLCA', 'Disease', 'MESH:D001749', (94, 98))	('C', 'Chemical', 'MESH:D002244', (102, 103))	('C', 'Chemical', 'MESH:D002244', (113, 114))	('patient', 'Species', '9606', (115, 122))
71316	31927310	Genes were rank-ordered by negative log10 p-value from a Wilcoxon test to quantify differences in patient gene expression for patients with high or low TP63 isoform expression with negative fold changes represented as a negative score for ranking.	('TP63', 'Gene', (152, 156))	('TP63', 'Gene', '8626', (152, 156))	('patient', 'Species', '9606', (98, 105))	('high', 'Var', (140, 144))	('patient', 'Species', '9606', (126, 133))	('patients', 'Species', '9606', (126, 134))	('low', 'NegReg', (148, 151))
71324	31927310	Pairing of the nonprime or prime forward primer with the alpha, beta or gamma reverse primer allowed amplification of nonprime or prime alpha, beta or gamma PCR product of (567, 572 and 427 base pairs) respectively if these transcripts were present in the cDNA pools used as template.	('C', 'Chemical', 'MESH:D002244', (158, 159))	('amplification', 'MPA', (101, 114))	('567', 'Var', (173, 176))
71358	31927310	These un-annotated isoform variants are closely related to DNp63alpha and DNp63beta but harbor a 4 amino acid alternative splice junction acceptor site at the 3' end of exon 8 resulting in an alternative exon 8-9 junction (Fig.	('variants', 'Var', (27, 35))	('amino', 'Chemical', 'MESH:D000596', (99, 104))	('alternative exon 8-9 junction', 'MPA', (192, 221))	('p63alpha', 'Gene', '8626', (61, 69))	('p63alpha', 'Gene', (61, 69))
71359	31927310	This alternative exon 8-9 junction is present in TAp63alpha and DNp63delta (NM_001329148 and NM_001329149) forms, but is not present in Refgene or Encode gene definitions as a variant of DNp63alpha or DNp63beta isoforms.	('p63alpha', 'Gene', '8626', (189, 197))	('p63alpha', 'Gene', (189, 197))	('NM_001329148', 'Var', (76, 88))	('p63alpha', 'Gene', '8626', (51, 59))	('p63alpha', 'Gene', (51, 59))	('NM_001329149', 'Var', (93, 105))
71360	31927310	Here we will refer to these isoforms as DNp63alphaP (DNp63alpha prime) and DNp63betaP (DNp63beta prime).	('p63alpha', 'Gene', '8626', (42, 50))	('p63alpha', 'Gene', (42, 50))	('p63alpha', 'Gene', '8626', (55, 63))	('p63alpha', 'Gene', (55, 63))	('DNp63betaP', 'Var', (75, 85))
71361	31927310	To confirm that the DNp63alphaP and DNp63betaP isoforms were truly expressed in human bladder cancer, we designed PCR primers specific to their unique 8a-9 or 8b-9 exon junctions and the exon 12-13 junction (unique to alpha isoforms), exon 12-14 junction (beta isoforms) and for the exon 11b-14 junction (delta isoforms) (Fig.	('bladder cancer', 'Disease', (86, 100))	('bladder cancer', 'Disease', 'MESH:D001749', (86, 100))	('C', 'Chemical', 'MESH:D002244', (115, 116))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('exon 11b-14', 'Var', (283, 294))	('human', 'Species', '9606', (80, 85))	('bladder cancer', 'Phenotype', 'HP:0009725', (86, 100))	('p63alpha', 'Gene', (22, 30))	('p63alpha', 'Gene', '8626', (22, 30))
71363	31927310	PCR products for both p63alpha, p63beta and p63delta non-prime and prime isoforms were detectable in UM-UC14 and UM-UC5 but not 253J or UM-UC10 control bladder cancer cells (Fig.	('C', 'Chemical', 'MESH:D002244', (117, 118))	('bladder cancer', 'Disease', 'MESH:D001749', (152, 166))	('bladder cancer', 'Disease', (152, 166))	('p63beta', 'Var', (32, 39))	('C', 'Chemical', 'MESH:D002244', (1, 2))	('p63delta', 'Var', (44, 52))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('bladder cancer', 'Phenotype', 'HP:0009725', (152, 166))	('C', 'Chemical', 'MESH:D002244', (105, 106))	('p63alpha', 'Gene', (22, 30))	('C', 'Chemical', 'MESH:D002244', (140, 141))	('p63alpha', 'Gene', '8626', (22, 30))
71369	31927310	In bladder cancer, TP63 expression was dominated by DNp63 group isoforms (DNp63alpha, DNp63alphaP, DNp63beta, and DNp63betaP, DNp63gamma, DNp63delta, DNp63 deltaP) whereas TAp63 group isoforms (TAp63alpha, TAp63alphaP, TAp63beta, TAp63gamma and TAp63delta) were expressed in only a minority of patients (Fig.	('DNp63betaP', 'Var', (114, 124))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('TP63', 'Gene', '8626', (19, 23))	('bladder cancer', 'Phenotype', 'HP:0009725', (3, 17))	('p63alpha', 'Gene', '8626', (88, 96))	('p63alpha', 'Gene', '8626', (208, 216))	('DNp63beta', 'Var', (99, 108))	('p63alpha', 'Gene', (76, 84))	('DNp63delta', 'Var', (138, 148))	('p63alpha', 'Gene', '8626', (196, 204))	('p63alpha', 'Gene', (88, 96))	('p63alpha', 'Gene', (208, 216))	('DNp63gamma', 'Var', (126, 136))	('patients', 'Species', '9606', (294, 302))	('p63alpha', 'Gene', '8626', (76, 84))	('TP63', 'Gene', (19, 23))	('bladder cancer', 'Disease', 'MESH:D001749', (3, 17))	('bladder cancer', 'Disease', (3, 17))	('p63alpha', 'Gene', (196, 204))
71371	31927310	In all three data sets, prime versions of DNp63alpha and DNp63beta demonstrated slightly less expression than non-prime analogs, although they were among the most highly expressed transcripts.	('DNp63beta', 'Var', (57, 66))	('p63alpha', 'Gene', '8626', (44, 52))	('expression', 'MPA', (94, 104))	('p63alpha', 'Gene', (44, 52))	('less', 'NegReg', (89, 93))
71383	31927310	Diseases with the highest TP63 gene level expression had, on average, the highest amounts of DNp63alpha, DNp63alphaP, DNp63beta and DNp63betaP with lower to moderate expression of TAp63 isoforms (Fig.	('expression', 'MPA', (42, 52))	('p63alpha', 'Gene', '8626', (107, 115))	('DNp63betaP', 'Var', (132, 142))	('p63alpha', 'Gene', (107, 115))	('TP63', 'Gene', (26, 30))	('TP63', 'Gene', '8626', (26, 30))	('p63alpha', 'Gene', (95, 103))	('p63alpha', 'Gene', '8626', (95, 103))	('expression', 'MPA', (166, 176))	('DNp63beta', 'Var', (118, 127))
71397	31927310	Stratification of BLCA patients into those with TAp63 isoform expression (5%) and those without (95%) demonstrated that patients with high TAp63 or TAp63beta expressing tumors had significantly worse OS than those with low/no expression (median OS 13.4 mos.	('TAp63beta expressing', 'Var', (148, 168))	('high TAp63', 'Var', (134, 144))	('patients', 'Species', '9606', (23, 31))	('tumors', 'Disease', 'MESH:D009369', (169, 175))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('BLCA', 'Disease', 'MESH:D001749', (18, 22))	('worse', 'NegReg', (194, 199))	('patients', 'Species', '9606', (120, 128))	('tumors', 'Phenotype', 'HP:0002664', (169, 175))	('BLCA', 'Disease', (18, 22))	('tumors', 'Disease', (169, 175))
71400	31927310	Similarly, DNp63 expression was significantly associated with reduced hazard in luminal patients (HR = 0.89, CI 0.80-0.99, Cox p = 0.034), but did not show a significant association in patients with a basal squamous subtype (HR = 1.00, CI 0.91-1.10, Cox p = 0.95) (Fig.	('Cox', 'Gene', (250, 253))	('Cox', 'Gene', '1351', (123, 126))	('Cox', 'Gene', (123, 126))	('patients', 'Species', '9606', (88, 96))	('C', 'Chemical', 'MESH:D002244', (250, 251))	('C', 'Chemical', 'MESH:D002244', (236, 237))	('C', 'Chemical', 'MESH:D002244', (109, 110))	('DNp63 expression', 'Var', (11, 27))	('patients', 'Species', '9606', (185, 193))	('Cox', 'Gene', '1351', (250, 253))	('C', 'Chemical', 'MESH:D002244', (123, 124))	('reduced', 'NegReg', (62, 69))
71401	31927310	TAp63 was significantly associated with increased hazard in basal squamous subtype patients (HR = 2.35, CI 1.64-3.37, Cox p < 0.0001), but not in patients with luminal tumors.	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('luminal tumors', 'Disease', (160, 174))	('basal squamous subtype', 'Disease', (60, 82))	('C', 'Chemical', 'MESH:D002244', (118, 119))	('C', 'Chemical', 'MESH:D002244', (104, 105))	('Cox', 'Gene', '1351', (118, 121))	('luminal tumors', 'Disease', 'MESH:D009369', (160, 174))	('TAp63', 'Var', (0, 5))	('patients', 'Species', '9606', (83, 91))	('Cox', 'Gene', (118, 121))	('patients', 'Species', '9606', (146, 154))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
71402	31927310	Taken together, these results suggest that DNp63 plays a protective role in luminal bladder cancer patients whereas TAp63 is associated with poor risk in basal bladder cancers (Fig.	('bladder cancer', 'Phenotype', 'HP:0009725', (84, 98))	('luminal bladder cancer', 'Disease', (76, 98))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('basal bladder cancers', 'Disease', (154, 175))	('luminal bladder cancer', 'Disease', 'MESH:D001749', (76, 98))	('patients', 'Species', '9606', (99, 107))	('cancers', 'Phenotype', 'HP:0002664', (168, 175))	('bladder cancers', 'Phenotype', 'HP:0009725', (160, 175))	('DNp63', 'Var', (43, 48))	('TAp63', 'Var', (116, 121))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('basal bladder cancers', 'Disease', 'MESH:D001749', (154, 175))	('bladder cancer', 'Phenotype', 'HP:0009725', (160, 174))
71403	31927310	To determine if the prognostic importance of TAp63 or DNp63 was independent of other known factors associated with bladder cancer patient prognosis, we performed multivariable Cox regression to adjust for potentially relevant clinical attributes (age, gender, grade, pathologic stage).	('bladder cancer', 'Disease', (115, 129))	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('patient', 'Species', '9606', (130, 137))	('DNp63', 'Var', (54, 59))	('bladder cancer', 'Phenotype', 'HP:0009725', (115, 129))	('Cox', 'Gene', '1351', (176, 179))	('Cox', 'Gene', (176, 179))	('bladder cancer', 'Disease', 'MESH:D001749', (115, 129))
71405	31927310	Multivariable Cox regression analysis confirmed that high DNp63 expression continued to trend with increased survival when controlling for age and pathologic stage (HR 0.68, CI 0.45-1.0, Cox p = 0.062) (Fig.	('C', 'Chemical', 'MESH:D002244', (14, 15))	('expression', 'MPA', (64, 74))	('high', 'Var', (53, 57))	('DNp63', 'Gene', (58, 63))	('survival', 'MPA', (109, 117))	('C', 'Chemical', 'MESH:D002244', (187, 188))	('Cox', 'Gene', (14, 17))	('Cox', 'Gene', '1351', (14, 17))	('increased', 'PosReg', (99, 108))	('Cox', 'Gene', (187, 190))	('Cox', 'Gene', '1351', (187, 190))	('C', 'Chemical', 'MESH:D002244', (174, 175))
71406	31927310	Likewise, high TAp63 expression was significantly associated with an increased risk of death when controlling for age and pathologic stage (HR 2.7, CI 1.6-4.6, Cox p = 0.0002).	('Cox', 'Gene', (160, 163))	('C', 'Chemical', 'MESH:D002244', (148, 149))	('expression', 'MPA', (21, 31))	('death', 'Disease', 'MESH:D003643', (87, 92))	('TAp63', 'Gene', (15, 20))	('high', 'Var', (10, 14))	('C', 'Chemical', 'MESH:D002244', (160, 161))	('death', 'Disease', (87, 92))	('Cox', 'Gene', '1351', (160, 163))	('associated', 'Reg', (50, 60))
71411	31927310	Likewise, these analyses confirmed that TAp63 was associated with reduced survival for BLCA (HR 1.8, CI 1.4-2.4, Cox p = 0.0002).	('Cox', 'Gene', (113, 116))	('reduced', 'NegReg', (66, 73))	('C', 'Chemical', 'MESH:D002244', (101, 102))	('BLCA', 'Disease', 'MESH:D001749', (87, 91))	('survival', 'MPA', (74, 82))	('TAp63', 'Var', (40, 45))	('C', 'Chemical', 'MESH:D002244', (113, 114))	('BLCA', 'Disease', (87, 91))	('C', 'Chemical', 'MESH:D002244', (89, 90))	('Cox', 'Gene', '1351', (113, 116))
71413	31927310	1(b)), the isoform level DNp63 expression was associated with worse survival (HR 1.2, CI 1.1-1.4, Cox p = 0.0003) and TAp63 associated with improved survival (HR 0.70, CI 0.51-0.96, Cox p = 0.020) which was also in the opposite direction of BLCA, BRCA and LUSC.	('Cox', 'Gene', (182, 185))	('worse', 'NegReg', (62, 67))	('C', 'Chemical', 'MESH:D002244', (249, 250))	('C', 'Chemical', 'MESH:D002244', (98, 99))	('C', 'Chemical', 'MESH:D002244', (243, 244))	('BRCA', 'Gene', '672', (247, 251))	('C', 'Chemical', 'MESH:D002244', (168, 169))	('Cox', 'Gene', '1351', (98, 101))	('TAp63', 'Var', (118, 123))	('DNp63', 'Gene', (25, 30))	('BLCA', 'Disease', (241, 245))	('C', 'Chemical', 'MESH:D002244', (182, 183))	('improved', 'PosReg', (140, 148))	('BRCA', 'Gene', (247, 251))	('Cox', 'Gene', (98, 101))	('C', 'Chemical', 'MESH:D002244', (86, 87))	('Cox', 'Gene', '1351', (182, 185))	('survival', 'MPA', (149, 157))	('C', 'Chemical', 'MESH:D002244', (259, 260))	('BLCA', 'Disease', 'MESH:D001749', (241, 245))	('survival', 'MPA', (68, 76))
71416	31927310	To investigate this hypothesis, we grouped entire TCGA tumor cohorts together and plotted the average proportion of TAp63 or DNp63 over total TP63 for each population vs. TP63 HR for the entire cohort (Fig.	('TP63', 'Gene', (142, 146))	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('DNp63', 'Var', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('C', 'Chemical', 'MESH:D002244', (51, 52))	('tumor', 'Disease', (55, 60))	('TP63', 'Gene', '8626', (171, 175))	('TP63', 'Gene', (171, 175))	('TP63', 'Gene', '8626', (142, 146))
71420	31927310	These results suggest that the relative proportion of TAp63 or DNp63 vs. total TP63 associates with clinical outcome regardless of tumor type.	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumor', 'Disease', (131, 136))	('TP63', 'Gene', (79, 83))	('TAp63', 'Var', (54, 59))	('TP63', 'Gene', '8626', (79, 83))	('DNp63', 'Var', (63, 68))	('clinical outcome', 'MPA', (100, 116))
71422	31927310	had previously shown that DNp63 and TAp63 promoted transcriptional programs of prognostic significance in various tumor types including bladder cancer.	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('bladder cancer', 'Phenotype', 'HP:0009725', (136, 150))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('bladder cancer', 'Disease', 'MESH:D001749', (136, 150))	('bladder cancer', 'Disease', (136, 150))	('tumor', 'Disease', (114, 119))	('transcriptional programs', 'MPA', (51, 75))	('DNp63', 'Var', (26, 31))	('promoted', 'PosReg', (42, 50))	('TAp63', 'Gene', (36, 41))
71423	31927310	Contrasting isoform-specific associations with patient survival observed across multiple diseases lead us to investigate transcriptional signaling programs that distinguish patient populations with high levels of DNp63 or TAp63.	('patient', 'Species', '9606', (47, 54))	('TAp63', 'Gene', (222, 227))	('patient', 'Species', '9606', (173, 180))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('DNp63', 'Var', (213, 218))
71425	31927310	Patients with tumors with high levels of DNp63 enriched for gene sets related to epidermal cell differentiation, keratinization, and skin development (Fig.	('DNp63', 'Var', (41, 46))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('tumors', 'Disease', (14, 20))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('Patients', 'Species', '9606', (0, 8))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('skin development', 'CPA', (133, 149))
71440	31927310	In this context, DNp63 isoforms appear to be the predominate cancer-associated isoform.	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('cancer', 'Disease', (61, 67))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('DNp63', 'Var', (17, 22))
71446	31927310	Genome-wide association studies (GWAS) have found that bladder cancer risk is associated with a sequence variant of an enhancer specifically controlling DNp63 expression.	('associated', 'Reg', (78, 88))	('bladder cancer', 'Disease', 'MESH:D001749', (55, 69))	('sequence variant', 'Var', (96, 112))	('bladder cancer', 'Disease', (55, 69))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('bladder cancer', 'Phenotype', 'HP:0009725', (55, 69))	('expression', 'MPA', (159, 169))	('DNp63', 'Gene', (153, 158))
71447	31927310	In contrast, DNp63 in NMIBC did not correlate with tumor risk of relapse and was associated with reduced risk of invasive progression in T1 bladder tumors.	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('bladder tumor', 'Phenotype', 'HP:0009725', (140, 153))	('tumor', 'Disease', (148, 153))	('tumor', 'Disease', (51, 56))	('reduced', 'NegReg', (97, 104))	('bladder tumors', 'Disease', 'MESH:D001749', (140, 154))	('bladder tumors', 'Phenotype', 'HP:0009725', (140, 154))	('MIBC', 'Disease', (23, 27))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('MIBC', 'Disease', 'MESH:D001749', (23, 27))	('bladder tumors', 'Disease', (140, 154))	('DNp63', 'Var', (13, 18))	('invasive progression', 'CPA', (113, 133))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
71454	31927310	Finally, we hypothesize that patient prognosis may be determined by the proportion of TP63 that is expressed as DNp63 vs. TAp63.	('patient', 'Species', '9606', (29, 36))	('DNp63', 'Var', (112, 117))	('TP63', 'Gene', '8626', (86, 90))	('TP63', 'Gene', (86, 90))
71462	31927310	Although prime variant isoforms have previously been described, here we characterize two commonly expressed variants, DNp63alphaP and DNp63betaP, which are not currently part of the TP63 isoform definitions present in Refgene and Gencode.	('p63alpha', 'Gene', (120, 128))	('DNp63betaP', 'Var', (134, 144))	('TP63', 'Gene', '8626', (182, 186))	('TP63', 'Gene', (182, 186))	('p63alpha', 'Gene', '8626', (120, 128))
71488	30127882	Studies also have demonstrated that blockade of IL-6R can significantly suppress the proliferation of NSCLC cell and reduce the mRNA levels of IL-6R.	('NSCLC', 'Disease', 'MESH:D002289', (102, 107))	('IL-6R', 'Gene', '3570', (143, 148))	('suppress', 'NegReg', (72, 80))	('IL-6R', 'Gene', (48, 53))	('IL-6R', 'Gene', (143, 148))	('NSCLC', 'Phenotype', 'HP:0030358', (102, 107))	('reduce', 'NegReg', (117, 123))	('NSCLC', 'Disease', (102, 107))	('blockade', 'Var', (36, 44))	('IL-6R', 'Gene', '3570', (48, 53))
71520	30127882	The most important pathway in LUAD is cell cycle (bta04110, P=8.584E-15).	('LUAD', 'Disease', (30, 34))	('cell cycle', 'CPA', (38, 48))	('bta04110', 'Chemical', '-', (50, 58))	('bta04110', 'Var', (50, 58))	('LUAD', 'Phenotype', 'HP:0030078', (30, 34))
71521	30127882	oocyte meiosis (bta04114, P=2.573E-07), progesterone-mediated oocyte maturation (bta04914, P=3.845E-06).	('bta04914', 'Chemical', '-', (81, 89))	('progesterone-mediated oocyte maturation', 'CPA', (40, 79))	('progesterone', 'Chemical', 'MESH:D011374', (40, 52))	('bta04114', 'Var', (16, 24))	('oocyte meiosis', 'CPA', (0, 14))	('bta04114', 'Chemical', '-', (16, 24))
71522	30127882	The other two important pathways are p53 signaling pathway (bta04115, P<0.001) and HTLV-I infection (bta05166, P=0.008).	('bta05166', 'Var', (101, 109))	('HTLV-I infection', 'Disease', 'MESH:D015490', (83, 99))	('bta04115', 'Var', (60, 68))	('HTLV-I infection', 'Disease', (83, 99))	('p53 signaling pathway', 'Pathway', (37, 58))
71524	30127882	And the others are osteoclast differentiation (ptr04380, P=0.002), platelet activation (ptr04611, P=0.011), cytokine-cytokine receptor interaction (ptr04060, P=0.015) and HTLV-I infection (ptr05166, P=0.028).	('platelet activation', 'CPA', (67, 86))	('HTLV-I infection', 'Disease', 'MESH:D015490', (171, 187))	('cytokine-cytokine receptor interaction', 'MPA', (108, 146))	('ptr04060', 'Var', (148, 156))	('osteoclast differentiation', 'CPA', (19, 45))	('HTLV-I infection', 'Disease', (171, 187))	('ptr04611', 'Var', (88, 96))	('ptr04380', 'Var', (47, 55))
71565	27221039	The discovery of this novel oncogene family using distinct genetic screens provides compelling evidence that the FAM83 proteins are key oncogenic players in cancer-associated signaling when they are overexpressed or dysregulated.	('overexpressed', 'PosReg', (199, 212))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('cancer', 'Disease', (157, 163))	('proteins', 'Protein', (119, 127))	('FAM83', 'Gene', (113, 118))	('dysregulated', 'Var', (216, 228))
71567	27221039	Importantly, ablation of numerous FAM83 members results in a marked suppression of cancer-associated signaling and loss of tumorigenic potential.	('tumor', 'Disease', (123, 128))	('loss', 'NegReg', (115, 119))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('ablation', 'Var', (13, 21))	('suppression', 'NegReg', (68, 79))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('FAM83', 'Gene', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('cancer', 'Disease', (83, 89))
71584	27221039	One of the most promising potential roles for the FAM83 proteins is within the ErbB signaling network, both at the receptor level and the downstream MAPK and PI3K/AKT pathways.	('FAM83', 'Var', (50, 55))	('AKT', 'Gene', (163, 166))	('proteins', 'Protein', (56, 64))	('ErbB', 'Gene', '1956', (79, 83))	('ErbB', 'Gene', (79, 83))	('AKT', 'Gene', '207', (163, 166))
71586	27221039	Often, the aberrant activation of RTKs, such as the ErbB receptors, drives transformation by inappropriately activating the MAPK and PI3K/AKT pathways.	('ErbB', 'Gene', '1956', (52, 56))	('AKT', 'Gene', '207', (138, 141))	('AKT', 'Gene', (138, 141))	('aberrant', 'Var', (11, 19))	('activation', 'PosReg', (20, 30))	('ErbB', 'Gene', (52, 56))	('activating', 'PosReg', (109, 119))
71593	27221039	The formation of increased PIP3 activates Phosphoinositide-dependent protein kinase (PDK-1), and recruits AKT to the membrane for activation, which then phosphorylates and activates mammalian target of rapamycin(mTOR).	('activates', 'PosReg', (172, 181))	('AKT', 'Gene', (106, 109))	('mammalian target of rapamycin', 'Pathway', (182, 211))	('mammalian', 'Species', '9606', (182, 191))	('Phosphoinositide-dependent', 'Enzyme', (42, 68))	('PDK-1', 'Gene', '5163', (85, 90))	('PIP3', 'Chemical', '-', (27, 31))	('activates', 'PosReg', (32, 41))	('PDK-1', 'Gene', (85, 90))	('AKT', 'Gene', '207', (106, 109))	('rapamycin', 'Chemical', 'MESH:D020123', (202, 211))	('mTOR', 'Gene', (212, 216))	('mTOR', 'Gene', '2475', (212, 216))	('PIP3', 'Var', (27, 31))
71597	27221039	Precision therapies aimed at disrupting ErbB RTKs (erlotinib, gefitinib, cetuximab, lapatinib, trastuzumab, pertuzumab), RAS (Farnesyltransferase inhibitors and select isoform inhibitors), RAF (Vemurafenib, Dabrafenib, Trametinib, RAF265, CCT196969, CCT241161), MEK (AZD8330, Selumetinib, MEK162, PD0325901, Refametinib, Cobimetinib), or the PI3K/AKT/mTOR pathway (Everolimus, Temsirolimus, BEZ235, GDC-0980, PF-05212384, BAY80-6946, Buparlisib, GDC-0032, Perifosine, MK2206, AZD2014, MLN0128) have been developed and are currently approved for patient use or are being evaluated in a number of clinical trials.	('trastuzumab', 'Chemical', 'MESH:D000068878', (95, 106))	('PF-05212384', 'Var', (409, 420))	('MEK', 'Gene', (262, 265))	('BAY80-6946', 'Var', (422, 432))	('lapatinib', 'Chemical', 'MESH:D000077341', (84, 93))	('RAF', 'Gene', '22882', (231, 234))	('MEK1', 'Gene', '5604', (289, 293))	('MK2206', 'Var', (468, 474))	('erlotinib', 'Chemical', 'MESH:D000069347', (51, 60))	('mTOR', 'Gene', (351, 355))	('ErbB', 'Gene', (40, 44))	('gefitinib', 'Chemical', 'MESH:D000077156', (62, 71))	('AKT', 'Gene', (347, 350))	('AZD2014', 'Var', (476, 483))	('RAF', 'Gene', (231, 234))	('MEK', 'Gene', '5609', (289, 292))	('RAF', 'Gene', '22882', (189, 192))	('patient', 'Species', '9606', (545, 552))	('mTOR', 'Gene', '2475', (351, 355))	('MEK', 'Gene', (289, 292))	('MEK1', 'Gene', (289, 293))	('AKT', 'Gene', '207', (347, 350))	('MLN0128', 'Var', (485, 492))	('RAF', 'Gene', (189, 192))	('ErbB', 'Gene', '1956', (40, 44))	('MEK', 'Gene', '5609', (262, 265))
71603	27221039	The smallest FAM83 protein, FAM83A (originally named BJ-TSA-9), was first implicated as a potential cancer biomarker in 2008.	('BJ-TSA-9', 'Gene', (53, 61))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('FAM83A', 'Var', (28, 34))	('BJ-TSA-9', 'Gene', '84985', (53, 61))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))
71606	27221039	Moreover, patients who had persistent expression of FAM83A, SCCA, and LUNX in CTCs were more likely to have more advanced disease and a greater risk of recurrence.	('advanced disease', 'Disease', 'MESH:D020178', (113, 129))	('SCCA', 'Gene', (60, 64))	('FAM83A', 'Var', (52, 58))	('LUNX', 'Gene', '51297', (70, 74))	('patients', 'Species', '9606', (10, 18))	('advanced disease', 'Disease', (113, 129))	('LUNX', 'Gene', (70, 74))
71607	27221039	In addition to identifying FAM83A as a potential lung cancer biomarker, Liu et al.	('lung cancer', 'Disease', 'MESH:D008175', (49, 60))	('FAM83A', 'Var', (27, 33))	('lung cancer', 'Disease', (49, 60))	('lung cancer', 'Phenotype', 'HP:0100526', (49, 60))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
71612	27221039	Importantly, FAM83A was not identified in peripheral blood samples of normal, non-cancerous patient donors, implicating FAM83A as a diagnostic and prognostic cancer biomarker.	('FAM83A', 'Var', (120, 126))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('patient', 'Species', '9606', (92, 99))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('cancerous', 'Disease', (82, 91))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('cancer', 'Disease', (158, 164))	('cancerous', 'Disease', 'MESH:D009369', (82, 91))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
71613	27221039	In addition to the potential use of FAM83A as a biomarker, a forward genetic screen identified FAM83A as a driver of EGFR tyrosine kinase inhibitor (TKI) resistance, suggesting FAM83A plays an important role in cancer cell biology.	('FAM83A', 'Var', (95, 101))	('cancer', 'Disease', 'MESH:D009369', (211, 217))	('EGFR', 'Gene', '1956', (117, 121))	('EGFR', 'Gene', (117, 121))	('cancer', 'Disease', (211, 217))	('tyrosine kinase', 'Gene', (122, 137))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('tyrosine kinase', 'Gene', '7294', (122, 137))
71614	27221039	EGFR is frequently overexpressed, mutated, or hyperactivated by excess ligand in a wide variety of cancers, including lung, brain, head and neck, and breast, among others.	('EGFR', 'Gene', (0, 4))	('cancers', 'Disease', 'MESH:D009369', (99, 106))	('cancers', 'Phenotype', 'HP:0002664', (99, 106))	('cancers', 'Disease', (99, 106))	('hyperactivated', 'PosReg', (46, 60))	('lung', 'Disease', (118, 122))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('overexpressed', 'PosReg', (19, 32))	('breast', 'Disease', (150, 156))	('EGFR', 'Gene', '1956', (0, 4))	('mutated', 'Var', (34, 41))	('brain', 'Disease', (124, 129))
71616	27221039	When activating mutations or deletions are responsible for EGFR hyperactivation, as is often is observed in lung cancer, TKIs are often initially effective treatment options.	('activating', 'PosReg', (5, 15))	('lung cancer', 'Disease', 'MESH:D008175', (108, 119))	('EGFR', 'Gene', (59, 63))	('lung cancer', 'Disease', (108, 119))	('hyperactivation', 'PosReg', (64, 79))	('lung cancer', 'Phenotype', 'HP:0100526', (108, 119))	('deletions', 'Var', (29, 38))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('EGFR', 'Gene', '1956', (59, 63))
71622	27221039	One potential explanation is that certain EGFR mutations, which predict TKI sensitivity in lung cancer, are rare in breast cancer.	('lung cancer', 'Phenotype', 'HP:0100526', (91, 102))	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('breast cancer', 'Disease', (116, 129))	('TKI sensitivity', 'MPA', (72, 87))	('EGFR', 'Gene', '1956', (42, 46))	('breast cancer', 'Phenotype', 'HP:0003002', (116, 129))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('EGFR', 'Gene', (42, 46))	('mutations', 'Var', (47, 56))	('lung cancer', 'Disease', 'MESH:D008175', (91, 102))	('predict', 'Reg', (64, 71))	('breast cancer', 'Disease', 'MESH:D001943', (116, 129))	('lung cancer', 'Disease', (91, 102))
71623	27221039	However, even rare breast cancers harboring these specific EGFR mutations are not sensitive to TKI treatment.	('breast cancer', 'Phenotype', 'HP:0003002', (19, 32))	('cancers', 'Phenotype', 'HP:0002664', (26, 33))	('EGFR', 'Gene', (59, 63))	('breast cancers', 'Phenotype', 'HP:0003002', (19, 33))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('breast cancers', 'Disease', 'MESH:D001943', (19, 33))	('mutations', 'Var', (64, 73))	('breast cancers', 'Disease', (19, 33))	('EGFR', 'Gene', '1956', (59, 63))
71627	27221039	Additional studies confirmed FAM83A also conferred resistance to lapatinib, another EGFR TKI that also targets HER2.	('HER2', 'Gene', (111, 115))	('lapatinib', 'Chemical', 'MESH:D000077341', (65, 74))	('conferred', 'Reg', (41, 50))	('HER2', 'Gene', '2064', (111, 115))	('EGFR', 'Gene', '1956', (84, 88))	('lapatinib', 'MPA', (65, 74))	('FAM83A', 'Var', (29, 35))	('EGFR', 'Gene', (84, 88))	('resistance', 'MPA', (51, 61))
71634	27221039	Further investigation revealed a role for FAM83A downstream of EGFR in the MAPK and PI3K/AKT signaling cascades.	('EGFR', 'Gene', '1956', (63, 67))	('EGFR', 'Gene', (63, 67))	('FAM83A', 'Var', (42, 48))	('AKT', 'Gene', '207', (89, 92))	('AKT', 'Gene', (89, 92))
71635	27221039	FAM83A-overexpressing HMT3522 T4-2 cells are resistant to both EGFR and PI3K inhibitors, but not to MEK inhibitors, suggesting that FAM83A lies downstream of EGFR and PI3K, but upstream of MEK.	('EGFR', 'Gene', '1956', (63, 67))	('EGFR', 'Gene', (158, 162))	('MEK', 'Gene', (100, 103))	('MEK', 'Gene', (189, 192))	('EGFR', 'Gene', (63, 67))	('MEK', 'Gene', '5609', (100, 103))	('MEK', 'Gene', '5609', (189, 192))	('FAM83A', 'Var', (132, 138))	('HMT3522 T4-2', 'CellLine', 'CVCL:2501', (22, 34))	('EGFR', 'Gene', '1956', (158, 162))
71636	27221039	shRNA-mediated knockdown of FAM83A in HMT3522 T4-2 and MDA-MB-468 cells resulted in decreased p-ERK and p-AKT, indicating the necessity of FAM83A in the MAPK and PI3K/AKT pathways.	('AKT', 'Gene', (167, 170))	('AKT', 'Gene', (106, 109))	('HMT3522 T4-2', 'CellLine', 'CVCL:2501', (38, 50))	('FAM83A', 'Var', (28, 34))	('AKT', 'Gene', '207', (167, 170))	('AKT', 'Gene', '207', (106, 109))	('p-ERK', 'Pathway', (94, 99))	('MDA-MB-468', 'CellLine', 'CVCL:0419', (55, 65))	('decreased', 'NegReg', (84, 93))
71640	27221039	In addition to its role in TKI resistance, FAM83A may also confer resistance to trastuzumab, a monoclonal antibody used in the treatment of HER2+ breast cancer.	('breast cancer', 'Disease', 'MESH:D001943', (146, 159))	('trastuzumab', 'Chemical', 'MESH:D000068878', (80, 91))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('breast cancer', 'Disease', (146, 159))	('HER2', 'Gene', (140, 144))	('breast cancer', 'Phenotype', 'HP:0003002', (146, 159))	('resistance', 'MPA', (66, 76))	('HER2', 'Gene', '2064', (140, 144))	('FAM83A', 'Var', (43, 49))
71645	27221039	This finding is consistent with the idea that FAM83A serves as a key intermediate in ErbB-family signaling that is potentially phosphorylated by active ErbB receptors, and again hints that FAM83 phosphorylation status is an intriguing area of future study.	('ErbB', 'Gene', (152, 156))	('ErbB', 'Gene', '1956', (152, 156))	('ErbB', 'Gene', (85, 89))	('ErbB', 'Gene', '1956', (85, 89))	('FAM83A', 'Var', (46, 52))
71647	27221039	Thus, inhibition of FAM83A could re-sensitize breast cancers to multiple precision therapies, including EGFR TKIs and trastuzumab.	('breast cancers', 'Disease', 'MESH:D001943', (46, 60))	('cancers', 'Phenotype', 'HP:0002664', (53, 60))	('breast cancers', 'Disease', (46, 60))	('EGFR', 'Gene', (104, 108))	('FAM83A', 'Gene', (20, 26))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('inhibition', 'Var', (6, 16))	('re-sensitize', 'Reg', (33, 45))	('trastuzumab', 'Chemical', 'MESH:D000068878', (118, 129))	('breast cancers', 'Phenotype', 'HP:0003002', (46, 60))	('EGFR', 'Gene', '1956', (104, 108))	('breast cancer', 'Phenotype', 'HP:0003002', (46, 59))
71649	27221039	Using a Validation-Based Insertional Mutagenesis (VBIM) strategy to identify genes that promote the anchorage-independent growth of non-transformed HMEC, the Jackson laboratory found that retroviral insertion into the FAM83B gene, which elevated FAM83B expression, was sufficient to promote HMEC transformation similar to mutant RAS (Figure 2).	('FAM83B', 'Gene', (218, 224))	('FAM83B', 'Gene', (246, 252))	('expression', 'MPA', (253, 263))	('promote', 'PosReg', (283, 290))	('insertion', 'Var', (199, 208))	('FAM83B', 'Gene', '222584', (218, 224))	('FAM83B', 'Gene', '222584', (246, 252))	('elevated', 'PosReg', (237, 245))	('HMEC transformation', 'CPA', (291, 310))
71654	27221039	In addition to gene amplification and mRNA upregulation, evidence from publically available databases indicates mutations in FAM83B in 12-21% of melanomas.	('melanomas', 'Phenotype', 'HP:0002861', (145, 154))	('melanomas', 'Disease', 'MESH:D008545', (145, 154))	('mutations', 'Var', (112, 121))	('FAM83B', 'Gene', (125, 131))	('FAM83B', 'Gene', '222584', (125, 131))	('melanomas', 'Disease', (145, 154))
71668	27221039	Given that FAM83B overexpression can induce multiple EGFR signaling pathways including EGFR/PLD, MAPK, PI3K/AKT/mTOR, we hypothesized that inhibition of FAM83B might suppress multiple pathways and prevent the compensatory survival signaling.	('inhibition', 'Var', (139, 149))	('EGFR', 'Gene', '1956', (87, 91))	('MAPK', 'Pathway', (97, 101))	('prevent', 'NegReg', (197, 204))	('FAM83B', 'Gene', '222584', (11, 17))	('AKT', 'Gene', (108, 111))	('EGFR', 'Gene', '1956', (53, 57))	('FAM83B', 'Gene', '222584', (153, 159))	('mTOR', 'Gene', (112, 116))	('suppress', 'NegReg', (166, 174))	('EGFR', 'Gene', (87, 91))	('mTOR', 'Gene', '2475', (112, 116))	('induce', 'PosReg', (37, 43))	('PLD', 'Gene', '2822', (92, 95))	('PLD', 'Gene', (92, 95))	('overexpression', 'PosReg', (18, 32))	('AKT', 'Gene', '207', (108, 111))	('compensatory survival signaling', 'MPA', (209, 240))	('FAM83B', 'Gene', (11, 17))	('EGFR', 'Gene', (53, 57))	('FAM83B', 'Gene', (153, 159))
71669	27221039	Indeed, ablation of FAM83B in breast and colon cancer cells significantly suppressed tumor cell growth and in vivo tumorigenicity.	('tumor', 'Disease', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('suppressed', 'NegReg', (74, 84))	('FAM83B', 'Gene', (20, 26))	('FAM83B', 'Gene', '222584', (20, 26))	('tumor', 'Disease', (115, 120))	('colon cancer', 'Phenotype', 'HP:0003003', (41, 53))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('ablation', 'Var', (8, 16))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('breast and colon cancer', 'Disease', 'MESH:D001943', (30, 53))
71670	27221039	The growth suppression upon FAM83B ablation was coupled with decreased CRAF, PI3K, and AKT membrane localization and a subsequent suppression of activating phosphorylation of both ERK1/2 and AKT.	('suppression', 'NegReg', (11, 22))	('activating phosphorylation', 'MPA', (145, 171))	('AKT', 'Gene', '207', (191, 194))	('AKT', 'Gene', (87, 90))	('ERK1/2', 'Gene', (180, 186))	('ERK1/2', 'Gene', '5595;5594', (180, 186))	('FAM83B', 'Gene', (28, 34))	('FAM83B', 'Gene', '222584', (28, 34))	('PI3K', 'CPA', (77, 81))	('suppression', 'NegReg', (130, 141))	('AKT', 'Gene', (191, 194))	('growth', 'MPA', (4, 10))	('CRAF', 'Gene', (71, 75))	('decreased', 'NegReg', (61, 70))	('ablation', 'Var', (35, 43))	('AKT', 'Gene', '207', (87, 90))	('CRAF', 'Gene', '5894', (71, 75))
71679	27221039	The only enzymatic activity predicted in the FAM83 proteins was based on a PLD-like motif within the DUF1669, although when tested, neither FAM83A nor FAM83B possessed conventional PLD activity.	('FAM83A', 'Var', (140, 146))	('DUF1669', 'Chemical', '-', (101, 108))	('PLD', 'Gene', '2822', (181, 184))	('PLD', 'Gene', (181, 184))	('FAM83B', 'Gene', (151, 157))	('FAM83B', 'Gene', '222584', (151, 157))	('FAM83', 'Var', (45, 50))	('PLD', 'Gene', '2822', (75, 78))	('PLD', 'Gene', (75, 78))
71680	27221039	However, the DUF1669 domain in FAM83B is necessary and sufficient for EGFR and CRAF binding and FAM83B-mediated transformation.	('CRAF', 'Gene', (79, 83))	('EGFR', 'Gene', '1956', (70, 74))	('CRAF', 'Gene', '5894', (79, 83))	('FAM83B', 'Gene', '222584', (31, 37))	('FAM83B', 'Gene', '222584', (96, 102))	('binding', 'Interaction', (84, 91))	('DUF1669', 'Chemical', '-', (13, 20))	('FAM83B', 'Gene', (31, 37))	('EGFR', 'Gene', (70, 74))	('FAM83B', 'Gene', (96, 102))	('DUF1669 domain', 'Var', (13, 27))
71682	27221039	Therefore, it is conceivable that all FAM83 proteins contribute to transformation by way of the DUF1669, similar to FAM83A and FAM83B.	('DUF1669', 'Var', (96, 103))	('contribute', 'Reg', (53, 63))	('FAM83B', 'Gene', '222584', (127, 133))	('FAM83B', 'Gene', (127, 133))	('transformation', 'CPA', (67, 81))	('DUF1669', 'Chemical', '-', (96, 103))	('FAM83', 'Gene', (38, 43))
71683	27221039	Indeed, recent observations confirm that FAM83 members A-E can independently promote anchorage-independent growth, and form complexes with CRAF in mammary epithelial cells.	('FAM83 members', 'Var', (41, 54))	('promote', 'PosReg', (77, 84))	('anchorage-independent growth', 'CPA', (85, 113))	('complexes', 'Interaction', (124, 133))	('CRAF', 'Gene', (139, 143))	('CRAF', 'Gene', '5894', (139, 143))
71685	27221039	These proteins lack any significant homology beyond the DUF1669 and vary greatly in size ranging from 434-1179 amino acids (Figure 1).	('lack', 'NegReg', (15, 19))	('DUF1669', 'Var', (56, 63))	('DUF1669', 'Chemical', '-', (56, 63))	('homology', 'MPA', (36, 44))
71690	27221039	Of note, dysregulated TGF-ss and BMP signaling is associated with cancer development and recurrence.	('TGF', 'Gene', '7040', (22, 25))	('BMP', 'Gene', '649', (33, 36))	('recurrence', 'CPA', (89, 99))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('dysregulated', 'Var', (9, 21))	('TGF', 'Gene', (22, 25))	('BMP', 'Gene', (33, 36))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('associated', 'Reg', (50, 60))	('cancer', 'Disease', (66, 72))
71703	27221039	Similar to the previously identified role of FAM83A and FAM83B in resistance to EGFR TKI inhibitors, newer reports implicate FAM83H in therapeutic resistance.	('FAM83H', 'Var', (125, 131))	('therapeutic resistance', 'MPA', (135, 157))	('EGFR', 'Gene', '1956', (80, 84))	('EGFR', 'Gene', (80, 84))	('FAM83B', 'Gene', (56, 62))	('implicate', 'Reg', (115, 124))	('FAM83B', 'Gene', '222584', (56, 62))	('resistance', 'MPA', (66, 76))
71704	27221039	An insertional mutagenesis screen to find genes that confer Erlotinib resistance in pancreatic cancers identified a common integration site, LOC100128338, which shares chromosomal location with FAM83H.	('Erlotinib', 'Chemical', 'MESH:D000069347', (60, 69))	('pancreatic cancers', 'Disease', 'MESH:D010190', (84, 102))	('pancreatic cancers', 'Disease', (84, 102))	('cancers', 'Phenotype', 'HP:0002664', (95, 102))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (84, 101))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (84, 102))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('LOC100128338', 'Var', (141, 153))
71707	27221039	Unrelated to cancer, a separate series of reports have implicated mutations in FAM83H as the cause of hypocalcified Amelogenesis imperfecta (AI), a hereditary condition in which the enamel of the teeth does not mineralize to the level of normal enamel.	('mutations', 'Var', (66, 75))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('FAM83H', 'Gene', (79, 85))	('cause', 'Reg', (93, 98))	('hypocalcified Amelogenesis imperfecta', 'Disease', (102, 139))	('cancer', 'Disease', (13, 19))	('cancer', 'Disease', 'MESH:D009369', (13, 19))	('Amelogenesis imperfecta', 'Phenotype', 'HP:0000705', (116, 139))	('AI', 'Phenotype', 'HP:0000705', (141, 143))	('hypocalcified Amelogenesis imperfecta', 'Disease', 'MESH:D000567', (102, 139))
71708	27221039	A FAM83HUnexpectedly, the FAM83H knockout mouse had no tooth malformations or defects in enamel formation.	('mouse', 'Species', '10090', (42, 47))	('tooth malformations', 'Disease', 'MESH:D014071', (55, 74))	('tooth malformations', 'Phenotype', 'HP:0006482', (55, 74))	('defects', 'NegReg', (78, 85))	('tooth malformations', 'Disease', (55, 74))	('enamel formation', 'CPA', (89, 105))	('FAM83H', 'Var', (26, 32))
71709	27221039	Interestingly, of the numerous inherited FAM83H mutations noted as the cause of AI, there appears to be no increase in susceptibility to cancer.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('FAM83H', 'Gene', (41, 47))	('cause', 'Reg', (71, 76))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('cancer', 'Disease', (137, 143))	('AI', 'Phenotype', 'HP:0000705', (80, 82))	('mutations', 'Var', (48, 57))
71710	27221039	In addition interacting with casein kinases in development, FAM83H interacts with a casein-kinase isoform that has a role in colon cancer.	('colon cancer', 'Disease', 'MESH:D015179', (125, 137))	('colon cancer', 'Disease', (125, 137))	('role', 'Reg', (117, 121))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('interacts', 'Reg', (67, 76))	('colon cancer', 'Phenotype', 'HP:0003003', (125, 137))	('FAM83H', 'Var', (60, 66))
71711	27221039	A DUF1669-independent association between FAM83H, keratin 18, and casein kinase -1alpha (CK-1alpha) results in CK-1-mediated disassembly of keratin filaments and a loss of epithelial cell polarity, which may have significant implications in colon cancer invasion and metastasis.	('disassembly of', 'MPA', (125, 139))	('colon cancer', 'Disease', (241, 253))	('FAM83H', 'Var', (42, 48))	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('colon cancer', 'Disease', 'MESH:D015179', (241, 253))	('CK-1', 'Species', '2498238', (89, 93))	('keratin', 'Protein', (140, 147))	('colon cancer', 'Phenotype', 'HP:0003003', (241, 253))	('CK-1', 'Species', '2498238', (111, 115))	('loss', 'NegReg', (164, 168))	('DUF1669', 'Chemical', '-', (2, 9))
71717	27221039	Likewise, aberrant phosphorylation of signaling effectors in cancer cells often drives unchecked growth and proliferation.	('drives', 'Reg', (80, 86))	('phosphorylation', 'MPA', (19, 34))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('cancer', 'Disease', (61, 67))	('aberrant', 'Var', (10, 18))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))
71718	27221039	In addition to kinase signaling, FAM83 proteins may have additional adaptor functions in cancer cells, including nucleating and inactivating enzymes that destabilize oncogenic signaling proteins.	('destabilize', 'NegReg', (154, 165))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('cancer', 'Disease', (89, 95))	('FAM83 proteins', 'Var', (33, 47))	('oncogenic signaling proteins', 'MPA', (166, 194))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
71723	27221039	This finding brings up the interesting possibility that other FAM83 proteins may also suppress FBXW7 ubiquitin ligase activity, and potentially other ubiquitin ligases.	('FBXW7', 'Gene', '55294', (95, 100))	('suppress', 'NegReg', (86, 94))	('activity', 'MPA', (118, 126))	('FBXW7', 'Gene', (95, 100))	('FAM83', 'Var', (62, 67))
71724	27221039	In fact, FAM83 proteins contain a predicted destruction D-box motif (all FAM83 proteins) and KEN-box motif (FAM83B) for targeting by the anaphase-promoting complex (APC/C) ubiquitin ligase.	('FAM83B', 'Gene', (108, 114))	('APC', 'Disease', 'MESH:D011125', (165, 168))	('FAM83B', 'Gene', '222584', (108, 114))	('APC', 'Disease', (165, 168))	('destruction D-box motif', 'MPA', (44, 67))	('KEN-box', 'MPA', (93, 100))	('FAM83', 'Var', (9, 14))
71725	27221039	Thus, FAM83 proteins may inhibit E3 ubiquitin ligases, leading to accumulation of various downstream substrates with known roles in carcinogenesis.	('carcinogenesis', 'Disease', (132, 146))	('FAM83', 'Var', (6, 11))	('proteins', 'Protein', (12, 20))	('accumulation', 'PosReg', (66, 78))	('inhibit', 'NegReg', (25, 32))	('E3 ubiquitin ligases', 'Enzyme', (33, 53))	('carcinogenesis', 'Disease', 'MESH:D063646', (132, 146))
71731	27221039	Studies have shown FAM83 proteins interact with many key cancer-signaling proteins including EGFR (FAM83B), PI3K (FAM83A-B), AKT (FAM83B), c-RAF (FAM83A-E).	('AKT', 'Gene', '207', (125, 128))	('FAM83B', 'Gene', (99, 105))	('FAM83B', 'Gene', (130, 136))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('EGFR', 'Gene', '1956', (93, 97))	('FAM83B', 'Gene', '222584', (99, 105))	('cancer', 'Disease', (57, 63))	('AKT', 'Gene', (125, 128))	('EGFR', 'Gene', (93, 97))	('interact', 'Reg', (34, 42))	('c-RAF', 'Gene', (139, 144))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('FAM83 proteins', 'Var', (19, 33))	('FAM83B', 'Gene', '222584', (130, 136))	('c-RAF', 'Gene', '5894', (139, 144))
71736	27221039	Moreover, a mutant PI3K (p110alpha) peptide capable of disrupting p110alpha/IRS1 complexes inhibits mutant p110alpha-activity and suppresses tumorigenicity.	('p110alpha', 'Gene', (66, 75))	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('p110alpha', 'Gene', (25, 34))	('p110alpha', 'Gene', '5290', (66, 75))	('p110alpha', 'Gene', '5290', (107, 116))	('p110alpha', 'Gene', (107, 116))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('suppresses', 'NegReg', (130, 140))	('mutant', 'Var', (100, 106))	('IRS1', 'Gene', '3667', (76, 80))	('IRS1', 'Gene', (76, 80))	('tumor', 'Disease', (141, 146))	('inhibits', 'NegReg', (91, 99))	('p110alpha', 'Gene', '5290', (25, 34))
71741	27221039	Again, all FAM83 members share this domain, and studies indicate that protein interactions mediated by DUF1669 are important for driving transformation.	('DUF1669', 'Chemical', '-', (103, 110))	('DUF1669', 'Var', (103, 110))	('protein', 'Protein', (70, 77))
71742	27221039	For example, mutating K230 within the DUF1669 of FAM83B, an amino acid highly conserved among FAM83 members, weakens the FAM83B/EGFR interaction and suppresses downstream effector activation.	('K230', 'Var', (22, 26))	('K230', 'Chemical', '-', (22, 26))	('EGFR', 'Gene', '1956', (128, 132))	('EGFR', 'Gene', (128, 132))	('FAM83B', 'Gene', '222584', (121, 127))	('FAM83B', 'Gene', '222584', (49, 55))	('weakens', 'NegReg', (109, 116))	('mutating K230', 'Var', (13, 26))	('FAM83B', 'Gene', (121, 127))	('FAM83B', 'Gene', (49, 55))	('DUF1669', 'Chemical', '-', (38, 45))	('suppresses', 'NegReg', (149, 159))	('downstream effector activation', 'MPA', (160, 190))
71769	25662556	The antineoplastic activity of 1,25-(OH)2D3 was shown in-vitro and in-vivo in a wide variety of malignancies including head and neck cancer and specifically OSCC.	('malignancies', 'Disease', 'MESH:D009369', (96, 108))	('OSCC', 'Chemical', '-', (157, 161))	('neck cancer', 'Disease', 'MESH:D006258', (128, 139))	('neck cancer', 'Disease', (128, 139))	('malignancies', 'Disease', (96, 108))	('1,25-(OH)2D3', 'Chemical', 'MESH:D002117', (31, 43))	('OSCC', 'Disease', (157, 161))	('1,25-(OH)2D3', 'Var', (31, 43))	('head and neck cancer', 'Phenotype', 'HP:0012288', (119, 139))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('antineoplastic activity', 'MPA', (4, 27))
71773	25662556	Recently, we have demonstrated low VDR expression as an adverse prognostic factor for the survival of patients with OSCC.	('OSCC', 'Chemical', '-', (116, 120))	('VDR', 'Gene', '7421', (35, 38))	('patients', 'Species', '9606', (102, 110))	('OSCC', 'Disease', (116, 120))	('VDR', 'Gene', (35, 38))	('low', 'Var', (31, 34))
71816	25662556	The clonal selection model of multistep carcinogenesis describes that a random solitary cell undergoes malignant transformation, accumulates multiple mutations and subsequently acquires a survival advantage, which leads to clonal selection.	('survival advantage', 'CPA', (188, 206))	('multistep carcinogenesis', 'Disease', 'MESH:D063646', (30, 54))	('malignant transformation', 'CPA', (103, 127))	('accumulates', 'PosReg', (129, 140))	('mutations', 'Var', (150, 159))	('multistep carcinogenesis', 'Disease', (30, 54))
71827	25662556	In a Murine Model of Cutaneous Squamous Cell Carcinoma oral calcitriol supplementation enhanced Photodynamic therapy-induced tumor cell death.	('Cutaneous Squamous Cell Carcinoma oral', 'Disease', (21, 59))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('supplementation', 'Var', (71, 86))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (31, 54))	('Murine', 'Species', '10090', (5, 11))	('Cutaneous Squamous Cell Carcinoma oral', 'Disease', 'MESH:D002294', (21, 59))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('men', 'Species', '9606', (77, 80))	('tumor', 'Disease', (125, 130))	('calcitriol', 'Chemical', 'MESH:D002117', (60, 70))	('enhanced', 'PosReg', (87, 95))	('Carcinoma', 'Phenotype', 'HP:0030731', (45, 54))	('Cutaneous Squamous Cell Carcinoma', 'Phenotype', 'HP:0006739', (21, 54))
71846	25662556	strongly supports a crucial role for vitamin D signaling in oral keratinocyte pathophysiology in-vitro and in-vivo but vitamin D deficiency alone seems to be insufficient to alter oral epithelial homeostasis and provoke carcinogenesis.	('deficiency', 'Var', (129, 139))	('insufficient', 'Disease', 'MESH:D000309', (158, 170))	('alter', 'Reg', (174, 179))	('insufficient', 'Disease', (158, 170))	('vitamin D', 'Chemical', 'MESH:D014807', (37, 46))	('carcinogenesis', 'Disease', 'MESH:D063646', (220, 234))	('oral epithelial homeostasis', 'MPA', (180, 207))	('provoke', 'Reg', (212, 219))	('carcinogenesis', 'Disease', (220, 234))	('vitamin D', 'Chemical', 'MESH:D014807', (119, 128))	('vitamin', 'Gene', (119, 126))	('vitamin D deficiency', 'Phenotype', 'HP:0100512', (119, 139))
71861	31942177	Results: FAS mRNA was associated with better overall survival (OS) in breast cancer (Hazard ratio (HR): 0.59 [0.47, 0.73]; p=1.5e-06), gastric cancer (HR: 0.65 [0.54, 0.77]; p=8e-07) and non-small-cell lung cancer (NSCLC) (HR: 0.78 [0.69, 0.89]; p=0.00016), especially in lung adenocarcinoma (HR: 0.64 [0.51, 0.81], p=1.7e-04), female lung cancer (HR:0.72 [0.57, 0.9], p=0.0049) and patients who have never smoked (HR: 0.39 [0.21, 0.7], p=0.0012).	('gastric cancer', 'Disease', (135, 149))	('FAS', 'Var', (9, 12))	('lung cancer', 'Phenotype', 'HP:0100526', (202, 213))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (272, 291))	('breast cancer', 'Phenotype', 'HP:0003002', (70, 83))	('NSCLC', 'Disease', (215, 220))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (191, 213))	('lung adenocarcinoma', 'Disease', (272, 291))	('male lung cancer', 'Disease', 'MESH:D008175', (330, 346))	('gastric cancer', 'Disease', 'MESH:D013274', (135, 149))	('lung cancer', 'Phenotype', 'HP:0100526', (335, 346))	('NSCLC', 'Phenotype', 'HP:0030358', (215, 220))	('breast cancer', 'Disease', 'MESH:D001943', (70, 83))	('breast cancer', 'Disease', (70, 83))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (187, 213))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (272, 291))	('gastric cancer', 'Phenotype', 'HP:0012126', (135, 149))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('male lung cancer', 'Disease', (330, 346))	('carcinoma', 'Phenotype', 'HP:0030731', (282, 291))	('patients', 'Species', '9606', (383, 391))	('cancer', 'Phenotype', 'HP:0002664', (340, 346))	('better', 'PosReg', (38, 44))	('non-small-cell lung cancer', 'Disease', (187, 213))	('non-small-cell lung cancer', 'Disease', 'MESH:D002289', (187, 213))	('NSCLC', 'Disease', 'MESH:D002289', (215, 220))
71866	31942177	FAS mRNA expression was correlated with better OS in breast cancer, gastric cancer and lung cancer, but worse OS in pancreatic cancer and AML.	('AML', 'Phenotype', 'HP:0004808', (138, 141))	('AML', 'Disease', (138, 141))	('lung cancer', 'Disease', (87, 98))	('pancreatic cancer', 'Disease', 'MESH:D010190', (116, 133))	('gastric cancer', 'Phenotype', 'HP:0012126', (68, 82))	('breast cancer', 'Phenotype', 'HP:0003002', (53, 66))	('breast cancer', 'Disease', 'MESH:D001943', (53, 66))	('mRNA expression', 'Var', (4, 19))	('pancreatic cancer', 'Disease', (116, 133))	('breast cancer', 'Disease', (53, 66))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('lung cancer', 'Disease', 'MESH:D008175', (87, 98))	('gastric cancer', 'Disease', (68, 82))	('lung cancer', 'Phenotype', 'HP:0100526', (87, 98))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (116, 133))	('gastric cancer', 'Disease', 'MESH:D013274', (68, 82))	('FAS', 'Gene', (0, 3))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('AML', 'Disease', 'MESH:D015470', (138, 141))
71896	31942177	The results showed that FAS mRNA in AML was related with a worse OS (HR: 1.57 [1.02, 2.41], p=0.04, n=256 cases).	('AML', 'Disease', 'MESH:D015470', (36, 39))	('AML', 'Disease', (36, 39))	('FAS mRNA', 'Var', (24, 32))	('AML', 'Phenotype', 'HP:0004808', (36, 39))
71897	31942177	The pooled survival results of 12 datasets from KM-Plotter showed that FAS expression was significantly related with a better OS (HR: 0.78 [0.69, 0.89], p=1.6e-04, n=1926 cases) in NSCLC (Figure 4A).	('NSCLC', 'Disease', 'MESH:D002289', (181, 186))	('better', 'PosReg', (119, 125))	('expression', 'Var', (75, 85))	('NSCLC', 'Phenotype', 'HP:0030358', (181, 186))	('FAS', 'Protein', (71, 74))	('NSCLC', 'Disease', (181, 186))
71915	31942177	We found that FAS mRNA expression was correlated with better survival in breast cancer, gastric cancer and lung cancer, but it was associated with a worse prognosis in pancreatic cancer and AML; no relationship was found with kidney cancer, head and neck cancer, hepatic cancer, glioblastoma, colorectal cancer or ovarian cancer.	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('kidney cancer', 'Disease', (226, 239))	('pancreatic cancer', 'Disease', (168, 185))	('lung cancer', 'Disease', 'MESH:D008175', (107, 118))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('gastric cancer', 'Disease', 'MESH:D013274', (88, 102))	('colorectal cancer', 'Phenotype', 'HP:0003003', (293, 310))	('lung cancer', 'Phenotype', 'HP:0100526', (107, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('FAS', 'Gene', (14, 17))	('hepatic cancer', 'Disease', (263, 277))	('ovarian cancer', 'Disease', (314, 328))	('head and neck cancer', 'Phenotype', 'HP:0012288', (241, 261))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('glioblastoma', 'Disease', 'MESH:D005909', (279, 291))	('gastric cancer', 'Phenotype', 'HP:0012126', (88, 102))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (168, 185))	('ovarian cancer', 'Phenotype', 'HP:0100615', (314, 328))	('hepatic cancer', 'Disease', 'MESH:D009369', (263, 277))	('AML', 'Disease', 'MESH:D015470', (190, 193))	('colorectal cancer', 'Disease', 'MESH:D015179', (293, 310))	('AML', 'Disease', (190, 193))	('AML', 'Phenotype', 'HP:0004808', (190, 193))	('glioblastoma', 'Disease', (279, 291))	('hepatic cancer', 'Phenotype', 'HP:0002896', (263, 277))	('head and neck cancer', 'Disease', 'MESH:D006258', (241, 261))	('lung cancer', 'Disease', (107, 118))	('breast cancer', 'Phenotype', 'HP:0003002', (73, 86))	('kidney cancer', 'Disease', 'MESH:D007680', (226, 239))	('colorectal cancer', 'Disease', (293, 310))	('glioblastoma', 'Phenotype', 'HP:0012174', (279, 291))	('mRNA expression', 'Var', (18, 33))	('pancreatic cancer', 'Disease', 'MESH:D010190', (168, 185))	('gastric cancer', 'Disease', (88, 102))	('breast cancer', 'Disease', 'MESH:D001943', (73, 86))	('survival', 'MPA', (61, 69))	('breast cancer', 'Disease', (73, 86))	('ovarian cancer', 'Disease', 'MESH:D010051', (314, 328))	('kidney cancer', 'Phenotype', 'HP:0009726', (226, 239))	('better', 'PosReg', (54, 60))
71916	31942177	Our study found that the cases with high expression of FAS had a significant better OS and RFS in breast cancer.	('FAS', 'Gene', (55, 58))	('better', 'PosReg', (77, 83))	('high expression', 'Var', (36, 51))	('breast cancer', 'Disease', 'MESH:D001943', (98, 111))	('breast cancer', 'Phenotype', 'HP:0003002', (98, 111))	('breast cancer', 'Disease', (98, 111))	('RFS', 'CPA', (91, 94))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))
71919	31942177	FAS associated phosphatase 1 (FAP-1) can interact with the C-terminal of FAS and leave FAS in the cytoplasmic cytoskeleton.The loss of the cell membrane FAS was associated with advanced stages and lower survival rates.	('lower', 'NegReg', (197, 202))	('FAP-1', 'Gene', '5783', (30, 35))	('FAS associated phosphatase 1', 'Gene', '5783', (0, 28))	('FAS associated phosphatase 1', 'Gene', (0, 28))	('cell membrane', 'CPA', (139, 152))	('advanced stages', 'CPA', (177, 192))	('FAP-1', 'Gene', (30, 35))	('loss', 'Var', (127, 131))	('survival rates', 'CPA', (203, 217))
71921	31942177	In this study, we found that the expression of FAS was associated with better OS in lung adenocarcinoma but not in lung squamous cell carcinoma.	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (84, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('expression', 'Var', (33, 43))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (84, 103))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (115, 143))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (120, 143))	('lung adenocarcinoma', 'Disease', (84, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('FAS', 'Gene', (47, 50))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (115, 143))	('lung squamous cell carcinoma', 'Disease', (115, 143))
71931	31942177	We suggest that high expression of FAS mRNA in unselected AML patients is associated with worse OS.	('FAS mRNA', 'Protein', (35, 43))	('high', 'Var', (16, 20))	('AML', 'Disease', 'MESH:D015470', (58, 61))	('worse OS', 'Disease', (90, 98))	('AML', 'Phenotype', 'HP:0004808', (58, 61))	('patients', 'Species', '9606', (62, 70))	('AML', 'Disease', (58, 61))	('associated', 'Reg', (74, 84))
71933	31942177	The high FAS expression was accompanied by up-regulation of epithelial-mesenchymal transition genes, which were responsible for maintaining stemness and initiating metastasis.	('expression', 'MPA', (13, 23))	('FAS', 'Gene', (9, 12))	('stemness', 'Disease', (140, 148))	('stemness', 'Disease', 'MESH:D020295', (140, 148))	('up-regulation', 'PosReg', (43, 56))	('high', 'Var', (4, 8))	('epithelial-mesenchymal transition genes', 'Gene', (60, 99))
71938	31942177	The inhibition of c-Met may up-regulate the DISC and activate the FAS-associated apoptosis pathway expression.	('c-Met', 'Gene', (18, 23))	('c-Met', 'Gene', '4233', (18, 23))	('up-regulate', 'PosReg', (28, 39))	('inhibition', 'Var', (4, 14))	('FAS-associated apoptosis pathway expression', 'Pathway', (66, 109))	('DISC', 'CPA', (44, 48))	('activate', 'PosReg', (53, 61))
71941	31942177	Erlotinib is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) and has been widely used in EGFR mutant advanced NSCLC patients and advanced pancreatic cancer patients.	('tyrosine', 'Chemical', 'None', (56, 64))	('NSCLC', 'Disease', (137, 142))	('mutant', 'Var', (121, 127))	('epidermal growth factor receptor', 'Gene', '1956', (16, 48))	('Erlotinib', 'Chemical', 'MESH:C400278', (0, 9))	('pancreatic cancer', 'Disease', 'MESH:D010190', (165, 182))	('NSCLC', 'Disease', 'MESH:D002289', (137, 142))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('patients', 'Species', '9606', (143, 151))	('EGFR', 'Gene', '1956', (50, 54))	('NSCLC', 'Phenotype', 'HP:0030358', (137, 142))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (165, 182))	('epidermal growth factor receptor', 'Gene', (16, 48))	('EGFR', 'Gene', (50, 54))	('EGFR', 'Gene', '1956', (116, 120))	('EGFR', 'Gene', (116, 120))	('patients', 'Species', '9606', (183, 191))	('pancreatic cancer', 'Disease', (165, 182))
71943	31942177	The inhibition of EGFR could down-regulate the c-FLIP expression.	('EGFR', 'Gene', '1956', (18, 22))	('EGFR', 'Gene', (18, 22))	('inhibition', 'Var', (4, 14))	('c-FLIP', 'Gene', '8837', (47, 53))	('c-FLIP', 'Gene', (47, 53))	('down-regulate', 'NegReg', (29, 42))
71987	30659636	We delineated FAM83A-AS and FAM83A messenger RNA (mRNA) expression patterns in LUAD and LUSC tissues from the TCGA data portal and NSCLC tissues collected from Nanjing Drum Tower Hospital.	('LUAD', 'Phenotype', 'HP:0030078', (79, 83))	('NSCLC', 'Disease', (131, 136))	('FAM83A', 'Var', (28, 34))	('NSCLC', 'Disease', 'MESH:D002289', (131, 136))	('LUSC', 'Phenotype', 'HP:0030359', (88, 92))	('NSCLC', 'Phenotype', 'HP:0030358', (131, 136))
71988	30659636	In the matched normal control-cancer tissue pairs obtained from 10 patients with NSCLC, FAM83A mRNA expression was also significantly elevated (Figure 3C).	('mRNA expression', 'MPA', (95, 110))	('patients', 'Species', '9606', (67, 75))	('NSCLC', 'Phenotype', 'HP:0030358', (81, 86))	('cancer', 'Disease', (30, 36))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('elevated', 'PosReg', (134, 142))	('NSCLC', 'Disease', (81, 86))	('FAM83A', 'Var', (88, 94))	('NSCLC', 'Disease', 'MESH:D002289', (81, 86))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
72005	30659636	The expression level of FAM83A-AS was positively correlated with the FAM83A mRNA level in LUAD and LUSC samples from the TCGA data, which was similar to the results obtained in the matched normal control-cancer tissue pairs obtained from 10 patients with NSCLC.	('expression level', 'MPA', (4, 20))	('cancer', 'Disease', (204, 210))	('cancer', 'Disease', 'MESH:D009369', (204, 210))	('NSCLC', 'Disease', (255, 260))	('NSCLC', 'Disease', 'MESH:D002289', (255, 260))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('LUAD', 'Phenotype', 'HP:0030078', (90, 94))	('FAM83A', 'Var', (69, 75))	('LUSC', 'Phenotype', 'HP:0030359', (99, 103))	('NSCLC', 'Phenotype', 'HP:0030358', (255, 260))	('FAM83A-AS', 'Gene', (24, 33))	('patients', 'Species', '9606', (241, 249))
72009	30659636	Many studies have found that deregulated FAM38A expression contributes to cancer in several tissue types, such as lung, breast and gastric tissues.8, 9, 10, 14, 15, 16, 17 Several studies have identified FAM83A as a candidate oncogene capable of enhancing cancer cell proliferation and invasiveness through the RAS/RAF/MEK/ERK and PI3K/AKT/mTOR pathways.8, 9, 10, 14, 15, 16, 17 In our study, we found that FAM83A-AS could significantly increase the protein level of FAM38A and induce the phosphorylation of ERK, which results in the promotion of cancer cell proliferation and invasion.	('ERK', 'Gene', (323, 326))	('cancer', 'Disease', (256, 262))	('cancer', 'Disease', (74, 80))	('AKT', 'Gene', '207', (336, 339))	('invasion', 'CPA', (577, 585))	('cancer', 'Phenotype', 'HP:0002664', (256, 262))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('protein level', 'MPA', (450, 463))	('induce', 'PosReg', (478, 484))	('RAF', 'Gene', '22882', (315, 318))	('ERK', 'Gene', '5594', (508, 511))	('FAM38A', 'Gene', (41, 47))	('cancer', 'Disease', (547, 553))	('MEK', 'Gene', '5609', (319, 322))	('FAM38A', 'Gene', '9780', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (256, 262))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (547, 553))	('RAF', 'Gene', (315, 318))	('FAM38A', 'Gene', (467, 473))	('ERK', 'Gene', '5594', (323, 326))	('AKT', 'Gene', (336, 339))	('MEK', 'Gene', (319, 322))	('phosphorylation', 'MPA', (489, 504))	('mTOR', 'Gene', (340, 344))	('ERK', 'Gene', (508, 511))	('FAM83A-AS', 'Var', (407, 416))	('FAM38A', 'Gene', '9780', (467, 473))	('increase', 'PosReg', (437, 445))	('promotion', 'PosReg', (534, 543))	('mTOR', 'Gene', '2475', (340, 344))	('cancer', 'Disease', 'MESH:D009369', (547, 553))
72049	30854040	To validate the microarray data, RT-qPCR was performed to detect the expression level of certain selected differentially-expressed miRNAs, including miR-664b-5p, miR-767-5p, miR-223-3p, miR-203a and miR-375.	('miR-664b', 'Gene', (149, 157))	('miR-767-5p', 'Var', (162, 172))	('miR-223-3p', 'Var', (174, 184))	('miR-664b', 'Gene', '100847052', (149, 157))	('miR-375', 'Gene', '494324', (199, 206))	('miR-203a', 'Gene', (186, 194))	('miR-203a', 'Gene', '406986', (186, 194))	('miR-375', 'Gene', (199, 206))
72062	30854040	Similar to the current study, Li et al demonstrated that miR-203a is downregulated in ESCC samples and the transfection of miR-203a in cells mimicking esophageal cancer inhibited their proliferation and invasive capacity, indicating that miR-203a serves a tumor suppressor role.	('miR-203a', 'Gene', (123, 131))	('miR-203a', 'Gene', '406986', (57, 65))	('miR-203a', 'Gene', '406986', (123, 131))	('esophageal cancer', 'Disease', (151, 168))	('proliferation', 'CPA', (185, 198))	('esophageal cancer', 'Disease', 'MESH:D004938', (151, 168))	('tumor', 'Disease', 'MESH:D009369', (256, 261))	('miR-203a', 'Gene', '406986', (238, 246))	('downregulated', 'NegReg', (69, 82))	('transfection', 'Var', (107, 119))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('miR-203a', 'Gene', (238, 246))	('tumor', 'Phenotype', 'HP:0002664', (256, 261))	('miR-203a', 'Gene', (57, 65))	('inhibited', 'NegReg', (169, 178))	('tumor', 'Disease', (256, 261))	('ESCC', 'Disease', (86, 90))	('invasive capacity', 'CPA', (203, 220))
72069	30854040	Additionally, RT-qPCR was used to detect the expression levels of certain miRNAs, including miR-664b-5p, miR-767-5p, miR-223-3p, miR-203a and miR-375, which were identified to be differentially expressed using microarray analysis.	('miR-203a', 'Gene', (129, 137))	('miR-203a', 'Gene', '406986', (129, 137))	('miR-375', 'Gene', (142, 149))	('miR-767-5p', 'Var', (105, 115))	('expression', 'MPA', (45, 55))	('miR-664b', 'Gene', (92, 100))	('miR-223-3p', 'Var', (117, 127))	('miR-664b', 'Gene', '100847052', (92, 100))	('miR-375', 'Gene', '494324', (142, 149))
72074	30854040	According to a previous study, abnormal expression of glycolipids in tissues and organs may lead to carcinogenesis, and the abnormal metabolism of steroids is closely associated with the occurrence, metastasis and treatment of tumors.	('expression', 'MPA', (40, 50))	('abnormal', 'Var', (31, 39))	('steroids', 'Chemical', 'MESH:D013256', (147, 155))	('lead to', 'Reg', (92, 99))	('tumors', 'Disease', (227, 233))	('tumors', 'Disease', 'MESH:D009369', (227, 233))	('tumors', 'Phenotype', 'HP:0002664', (227, 233))	('abnormal metabolism', 'Phenotype', 'HP:0032245', (124, 143))	('metabolism', 'MPA', (133, 143))	('associated', 'Reg', (167, 177))	('carcinogenesis', 'CPA', (100, 114))	('glycolipid', 'Chemical', 'MESH:D006017', (54, 64))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))
72077	30854040	Therefore, the abnormal absorption of calcium ions in cells may be closely associated with tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('absorption of calcium ions', 'MPA', (24, 50))	('abnormal', 'Var', (15, 23))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('associated', 'Reg', (75, 85))	('tumor', 'Disease', (91, 96))	('calcium', 'Chemical', 'MESH:D002118', (38, 45))
72092	30854040	In conclusion, the current study performed a preliminary analysis of the biological effects of differentially expressed miRNAs in ESCC in Kazakh patients, which may be associated with the occurrence of the disease.	('patients', 'Species', '9606', (145, 153))	('associated', 'Reg', (168, 178))	('miRNAs', 'Protein', (120, 126))	('ESCC', 'Disease', (130, 134))	('differentially expressed', 'Var', (95, 119))
72103	30733838	Further, western blot analysis revealed that DIAPH1 knockdown increased the protein levels of ATR, p-p53, Bax, and cleaved caspase-3, -8, and -9.	('caspase-3', 'Protein', (123, 132))	('protein levels', 'MPA', (76, 90))	('increased', 'PosReg', (62, 71))	('cleaved', 'MPA', (115, 122))	('knockdown', 'Var', (52, 61))	('DIAPH1', 'Gene', (45, 51))	('p53', 'Gene', (101, 104))	('p53', 'Gene', '7157', (101, 104))	('Bax', 'Gene', (106, 109))	('ATR', 'Gene', '545', (94, 97))	('ATR', 'Gene', (94, 97))	('Bax', 'Gene', '581', (106, 109))
72116	30733838	It was reported that knockdown of DIAPH1 in human U87 glioblastoma cells could significantly promote cell apoptosis.	('cell apoptosis', 'CPA', (101, 115))	('DIAPH1', 'Gene', (34, 40))	('glioblastoma', 'Disease', 'MESH:D005909', (54, 66))	('human', 'Species', '9606', (44, 49))	('glioblastoma', 'Phenotype', 'HP:0012174', (54, 66))	('knockdown', 'Var', (21, 30))	('promote', 'PosReg', (93, 100))	('U87', 'CellLine', 'CVCL:0022', (50, 53))	('glioblastoma', 'Disease', (54, 66))
72139	30733838	Recombinant ribosomal protein L13A (RPL13A) was chosen as the internal control.	('L13A', 'Var', (30, 34))	('RPL13A', 'Gene', '23521', (36, 42))	('L13A', 'SUBSTITUTION', 'None', (30, 34))	('RPL13A', 'Gene', (36, 42))	('L13A', 'SUBSTITUTION', 'None', (38, 42))	('L13A', 'Var', (38, 42))
72149	30733838	9664); anti-cleaved caspase-8 (1 : 500, Santa, cat.	('caspase-8', 'Gene', '841', (20, 29))	('caspase-8', 'Gene', (20, 29))	('anti-cleaved', 'Var', (7, 19))
72150	30733838	sc-56070); anti-cleaved caspase-9 (1 : 500, Santa, cat.	('anti-cleaved', 'Var', (11, 23))	('caspase-9', 'Gene', '842', (24, 33))	('caspase-9', 'Gene', (24, 33))
72155	30733838	Second, we analyzed clinical and mRNA expression data of 500 patients with HNSCC, from TCGA, and found that in class G3, high DIAPH1 expression was significantly associated with poor OS (p = 0.002, Figure 1(b)) and that the expression of DIAPH1 was higher in tumor tissues than in adjacent normal tissues (Figure 1(c)).	('expression', 'MPA', (133, 143))	('DIAPH1', 'Gene', (126, 132))	('tumor', 'Disease', 'MESH:D009369', (259, 264))	('patients', 'Species', '9606', (61, 69))	('higher', 'PosReg', (249, 255))	('tumor', 'Phenotype', 'HP:0002664', (259, 264))	('poor OS', 'MPA', (178, 185))	('HNSCC', 'Phenotype', 'HP:0012288', (75, 80))	('expression', 'MPA', (224, 234))	('tumor', 'Disease', (259, 264))	('high', 'Var', (121, 125))	('clinical', 'Species', '191496', (20, 28))
72157	30733838	Moreover, because different types of HNSCCs, such as LSCC and hypopharyngeal squamous cell carcinoma, have distinctively different biologic behaviours, we analysed GSE65858 dataset based on different primary sites and found the trend that high DIAPH1 expression was associated with poor OS in LSCC (Figure 1(d)).	('hypopharyngeal squamous cell carcinoma', 'Disease', 'MESH:D002294', (62, 100))	('LSCC', 'Disease', (53, 57))	('high', 'Var', (239, 243))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (77, 100))	('poor OS', 'Disease', (282, 289))	('HNSCC', 'Phenotype', 'HP:0012288', (37, 42))	('DIAPH1', 'Gene', (244, 250))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('LSCC', 'Disease', (293, 297))	('hypopharyngeal squamous cell carcinoma', 'Disease', (62, 100))	('associated', 'Reg', (266, 276))
72160	30733838	RT-qPCR results suggested that DIAPH1 mRNA levels in SH1 and SH2 groups reduced more than 80% compared with that of the NC group (Figures 2(b) and 2(e)).	('reduced', 'NegReg', (72, 79))	('SH2', 'Gene', '100125854', (61, 64))	('DIAPH1 mRNA levels', 'MPA', (31, 49))	('SH2', 'Gene', (61, 64))	('SH1', 'Var', (53, 56))
72163	30733838	We used flow cytometry and costaining with PE Annexin V and/or 7-AAD to evaluate the effect of DIAPH1 knockdown on apoptosis in AMC-HN-8 and FD-LSC-1 cells (Figures 3(a) and 3(b)).	('DIAPH1', 'Gene', (95, 101))	('knockdown', 'Var', (102, 111))	('7-AAD', 'Chemical', 'MESH:C025942', (63, 68))	('Annexin V', 'Gene', '308', (46, 55))	('Annexin V', 'Gene', (46, 55))	('LSC-1', 'CellLine', 'CVCL:9U29', (144, 149))
72164	30733838	In AMC-HN-8 cells, the proportion of cells in early apoptosis (PE Annexin V positive/7-AAD negative) was significantly higher in SH1 (2.58 +- 0.10%) and SH2 (1.88 +- 0.06%) cells than in NC (1.17 +- 0.14%) cells (p < 0.01 for both comparisons, Figure 3(c)).	('Annexin V', 'Gene', '308', (66, 75))	('7-AAD', 'Chemical', 'MESH:C025942', (85, 90))	('SH2', 'Gene', '100125854', (153, 156))	('SH2', 'Gene', (153, 156))	('higher', 'PosReg', (119, 125))	('Annexin V', 'Gene', (66, 75))	('SH1', 'Var', (129, 132))
72169	30733838	We found that DIAPH1 knockdown results in an upregulation of ATR, p-p53 (Ser 15), Bax, and cleaved caspase-3, -8, and -9 protein expression (Figure 4(a)).	('cleaved', 'MPA', (91, 98))	('ATR', 'Gene', '545', (61, 64))	('Ser', 'Chemical', 'MESH:D012694', (73, 76))	('Bax', 'Gene', (82, 85))	('ATR', 'Gene', (61, 64))	('DIAPH1', 'Gene', (14, 20))	('p53', 'Gene', (68, 71))	('p53', 'Gene', '7157', (68, 71))	('upregulation', 'PosReg', (45, 57))	('knockdown', 'Var', (21, 30))	('Bax', 'Gene', '581', (82, 85))	('caspase-3', 'Protein', (99, 108))
72176	30733838	Furthermore, analysis of the correlation between DIAPH1 expression level and clinical variables showed that high DIAPH1 expression was significantly associated with increased clinical stage, which could result in a poor prognosis.	('DIAPH1', 'Gene', (113, 119))	('expression', 'MPA', (120, 130))	('clinical', 'Species', '191496', (77, 85))	('high', 'Var', (108, 112))	('clinical stage', 'CPA', (175, 189))	('clinical', 'Species', '191496', (175, 183))	('increased', 'PosReg', (165, 174))
72180	30733838	Moreover, Nox1 knockouts displayed reduced postinjury apoptosis, supporting the contention that mDia1 upregulation may reduce apoptosis.	('reduced', 'NegReg', (35, 42))	('Nox1', 'Gene', (10, 14))	('knockouts', 'Var', (15, 24))	('postinjury apoptosis', 'CPA', (43, 63))	('apoptosis', 'CPA', (126, 135))	('mDia1', 'Gene', (96, 101))	('Nox1', 'Gene', '27035', (10, 14))	('upregulation', 'PosReg', (102, 114))	('mDia1', 'Gene', '13367', (96, 101))
72183	30733838	Our flow cytometry analysis revealed that DIAPH1 could inhibit apoptosis in both AMC-HN-8 and FD-LSC-1 cells.	('DIAPH1', 'Var', (42, 48))	('inhibit', 'NegReg', (55, 62))	('apoptosis', 'CPA', (63, 72))	('LSC-1', 'CellLine', 'CVCL:9U29', (97, 102))
72184	30733838	The observed effect on apoptosis was greater in SH1 cells than in SH2 cells.	('SH2', 'Gene', (66, 69))	('SH2', 'Gene', '100125854', (66, 69))	('SH1', 'Var', (48, 51))	('apoptosis', 'CPA', (23, 32))
72187	30733838	DNA damage plays a critical role in tumor initiation and progression and severe DNA damage, such as DNA double-strand break (DSB) results in apoptosis.	('double-strand', 'Var', (104, 117))	('tumor initiation', 'Disease', 'MESH:D009369', (36, 52))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumor initiation', 'Disease', (36, 52))	('apoptosis', 'CPA', (141, 150))
72191	30733838	Here, DIAPH1 knockdown increased ATR and p-p53 protein levels in both AMC-HN-8 and FD-LSC-1 cells, implicating DIAPH1 in apoptosis.	('LSC-1', 'CellLine', 'CVCL:9U29', (86, 91))	('ATR', 'Gene', '545', (33, 36))	('ATR', 'Gene', (33, 36))	('DIAPH1', 'Gene', (6, 12))	('increased', 'PosReg', (23, 32))	('p53', 'Gene', (43, 46))	('p53', 'Gene', '7157', (43, 46))	('knockdown', 'Var', (13, 22))
72205	30733838	I3C induced p53 Ser 15 phosphorylation and the caspase-8/3 pathway.	('caspase-8/3', 'Gene', (47, 58))	('p53', 'Gene', '7157', (12, 15))	('p53', 'Gene', (12, 15))	('caspase-8/3', 'Gene', '841;836', (47, 58))	('Ser', 'Chemical', 'MESH:D012694', (16, 19))	('I3C', 'Var', (0, 3))
72207	30733838	Here, compared with NC cells, both AMC-HN-8 and FD-LSC-1 SH1 cells showed higher caspase-8/3 pathway activity, indicating that DIAPH1 knockdown activates the extrinsic apoptotic pathway mediated by ATR/p53/caspase-8/3.	('caspase-8/3', 'Gene', (81, 92))	('higher', 'PosReg', (74, 80))	('ATR', 'Gene', '545', (198, 201))	('ATR', 'Gene', (198, 201))	('DIAPH1', 'Gene', (127, 133))	('caspase-8/3', 'Gene', '841;836', (206, 217))	('LSC-1 SH1', 'CellLine', 'CVCL:9U29', (51, 60))	('activity', 'MPA', (101, 109))	('caspase-8/3', 'Gene', (206, 217))	('knockdown', 'Var', (134, 143))	('extrinsic apoptotic pathway', 'Pathway', (158, 185))	('p53', 'Gene', '7157', (202, 205))	('caspase-8/3', 'Gene', '841;836', (81, 92))	('activates', 'PosReg', (144, 153))	('p53', 'Gene', (202, 205))
72208	30733838	Therefore, our study demonstrates that DIAPH1 knockdown promotes apoptosis via the ATR/p53/caspase-3 signaling in both the intrinsic and extrinsic apoptotic pathways (Figure 4(b)).	('knockdown', 'Var', (46, 55))	('p53', 'Gene', (87, 90))	('p53', 'Gene', '7157', (87, 90))	('ATR', 'Gene', '545', (83, 86))	('apoptosis', 'CPA', (65, 74))	('promotes', 'PosReg', (56, 64))	('DIAPH1', 'Gene', (39, 45))	('ATR', 'Gene', (83, 86))
72229	33728749	7  Previous researches have demonstrated that the depleting of GSH is associated with the accumulation of ROS and the induction of ferroptosis, a new form of iron-dependent, programmed cell death, 8  which has been found involved in the development of kidney diseases, especially in KIRC.	('ferroptosis', 'Disease', (131, 142))	('kidney diseases', 'Disease', (252, 267))	('iron', 'Chemical', 'MESH:D007501', (158, 162))	('KIRC', 'Disease', (283, 287))	('ROS', 'Chemical', 'MESH:D017382', (106, 109))	('GSH', 'Chemical', 'MESH:D005978', (63, 66))	('kidney diseases', 'Disease', 'MESH:D007674', (252, 267))	('ROS', 'Protein', (106, 109))	('kidney diseases', 'Phenotype', 'HP:0000112', (252, 267))	('depleting', 'Var', (50, 59))	('accumulation', 'PosReg', (90, 102))	('GSH', 'Gene', (63, 66))	('death', 'Disease', 'MESH:D003643', (190, 195))	('death', 'Disease', (190, 195))
72269	33728749	However, by investigating the expression of CHAC1 among KIRC samples with different grades and stages, we noticed CHAC1 is up-regulated in KIRC samples with T3-T4, G3-4 and StageIII&IV when compared with the KIRC samples with T1-2, G1-2 and StageI&II respectively (Figure 1D-F).	('CHAC1', 'Gene', '79094', (114, 119))	('G3-4', 'Var', (164, 168))	('CHAC1', 'Gene', (44, 49))	('StageIII&', 'Var', (173, 182))	('CHAC1', 'Gene', '79094', (44, 49))	('T3-T4', 'Var', (157, 162))	('CHAC1', 'Gene', (114, 119))	('up-regulated', 'PosReg', (123, 135))
72339	29425237	In a univariate analysis, hypermethylation of both loci was significantly associated with the risk of death (univariate: exon 3: Hazard ratio (HR): 4.97 [1.78-16.71], p = 0.010, lincRNA C5orf66-AS1: Hazard ratio (HR): 12.23 [3.01-49.74], p<0.001).	('death', 'Disease', (102, 107))	('hypermethylation', 'Var', (26, 42))	('death', 'Disease', 'MESH:D003643', (102, 107))	('associated', 'Reg', (74, 84))
72340	29425237	PITX1 exon 3 and lincRNA C5orf66-AS1 methylation was also significantly correlated with tumor localization, T category, human papilloma virus (HPV)-negative and p16-negative tumors and tumor grade.	('papilloma', 'Phenotype', 'HP:0012740', (126, 135))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('tumor', 'Disease', (185, 190))	('PITX1', 'Gene', (0, 5))	('tumors', 'Disease', (174, 180))	('p16', 'Gene', (161, 164))	('human papilloma virus', 'Species', '10566', (120, 141))	('C5orf66-AS1', 'Gene', (25, 36))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('p16', 'Gene', '1029', (161, 164))	('PITX1', 'Gene', '5307', (0, 5))	('tumor', 'Disease', (88, 93))	('correlated', 'Reg', (72, 82))	('tumors', 'Disease', 'MESH:D009369', (174, 180))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('methylation', 'Var', (37, 48))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('tumor', 'Disease', (174, 179))	('HPV', 'Species', '10566', (143, 146))	('T category', 'Disease', (108, 118))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumors', 'Phenotype', 'HP:0002664', (174, 180))
72341	29425237	Kaplan-Meier analysis showed, that lincRNA C5orf66-AS1 hypomethylation was significantly associated with overall survival (p = 0.001) in the entire cohort as well in a subgroup of HPV-negative tumors (p = 0.003) and in patients with laryngeal tumors (p = 0.022).	('associated with', 'Reg', (89, 104))	('laryngeal tumors', 'Disease', (233, 249))	('patients', 'Species', '9606', (219, 227))	('tumors', 'Disease', (243, 249))	('C5orf66-AS1', 'Gene', (43, 54))	('tumors', 'Disease', 'MESH:D009369', (243, 249))	('laryngeal tumors', 'Disease', 'MESH:D007822', (233, 249))	('tumors', 'Phenotype', 'HP:0002664', (243, 249))	('laryngeal tumors', 'Phenotype', 'HP:0012118', (233, 249))	('overall survival', 'MPA', (105, 121))	('hypomethylation', 'Var', (55, 70))	('HPV', 'Species', '10566', (180, 183))	('tumors', 'Phenotype', 'HP:0002664', (193, 199))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('tumors', 'Disease', (193, 199))	('tumors', 'Disease', 'MESH:D009369', (193, 199))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))
72342	29425237	Methylation status of PITX1 and even more so of lincRNA C5orf66-AS1 is a promising prognostic biomarker in HNSCC, in particular for HPV-negative patients.	('HNSCC', 'Disease', (107, 112))	('patients', 'Species', '9606', (145, 153))	('Methylation status', 'Var', (0, 18))	('HPV', 'Species', '10566', (132, 135))	('PITX1', 'Gene', '5307', (22, 27))	('PITX1', 'Gene', (22, 27))
72349	29425237	These tumors exhibit a CpG island methylator phenotype (CIMP) with striking genomic stability, but are characterized by gene silencing through methylation events.	('silencing', 'NegReg', (125, 134))	('methylation', 'Var', (143, 154))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('tumors', 'Disease', (6, 12))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))
72352	29425237	A comprehensive review on molecular biomarkers in head and neck cancer is provided by Juodzbalys et al.. Aberrant DNA methylation is found frequently in cancer and the methylation status of various functional genomic loci, e.g.	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('cancer', 'Disease', (153, 159))	('cancer', 'Disease', (64, 70))	('DNA', 'Gene', (114, 117))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('head and neck cancer', 'Phenotype', 'HP:0012288', (50, 70))	('Aberrant', 'Var', (105, 113))	('neck cancer', 'Disease', 'MESH:D006258', (59, 70))	('neck cancer', 'Disease', (59, 70))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
72355	29425237	Promoter methylation of paired like homeodomain 2 (PITX2) transcription factor is a well-established and validated prognostic biomarker in various malignancies, including carcinomas of the prostate, breast, biliary tract, and lung.	('PITX2', 'Gene', '5308', (51, 56))	('carcinomas of the prostate', 'Disease', (171, 197))	('PITX2', 'Gene', (51, 56))	('malignancies', 'Disease', (147, 159))	('paired like homeodomain 2', 'Gene', '5308', (24, 49))	('carcinomas of the prostate', 'Disease', 'MESH:D011472', (171, 197))	('paired like homeodomain 2', 'Gene', (24, 49))	('biliary tract', 'Disease', (207, 220))	('Promoter methylation', 'Var', (0, 20))	('carcinoma', 'Phenotype', 'HP:0030731', (171, 180))	('carcinomas', 'Phenotype', 'HP:0030731', (171, 181))	('malignancies', 'Disease', 'MESH:D009369', (147, 159))	('lung', 'Disease', (226, 230))	('breast', 'Disease', (199, 205))
72356	29425237	Recent publications suggest a role of methylation status of PITX3 and PITX2 and adjacent long non-coding RNA (PANCR) as promising new biomarkers in HNSCC.	('PITX2', 'Gene', '5308', (70, 75))	('HNSCC', 'Disease', (148, 153))	('PANCR', 'Gene', '105377363', (110, 115))	('PITX2', 'Gene', (70, 75))	('PITX3', 'Gene', '5309', (60, 65))	('PITX3', 'Gene', (60, 65))	('PANCR', 'Gene', (110, 115))	('methylation status', 'Var', (38, 56))
72359	29425237	These data point to a role of PITX1 as potential tumor suppressor and dysregulation could influence cancer development.	('PITX1', 'Gene', (30, 35))	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('cancer', 'Disease', (100, 106))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('tumor', 'Disease', (49, 54))	('dysregulation', 'Var', (70, 83))	('PITX1', 'Gene', '5307', (30, 35))	('influence', 'Reg', (90, 99))	('cancer', 'Disease', 'MESH:D009369', (100, 106))
72362	29425237	Chromosomal rearrangements involving the PITX1 gene result in Liebenberg syndrome with partial arm-to-leg transformation.	('PITX1', 'Gene', '5307', (41, 46))	('PITX1', 'Gene', (41, 46))	('Liebenberg syndrome', 'Disease', 'MESH:C566090', (62, 81))	('partial arm-to-leg transformation', 'CPA', (87, 120))	('result in', 'Reg', (52, 61))	('Liebenberg syndrome', 'Disease', (62, 81))	('Chromosomal rearrangements', 'Var', (0, 26))
72370	29425237	Aberrant PITX1 methylation has been found in salivary gland adenoid cystic carcinoma and is associated with survival in clear cell renal cell carcinomas.	('associated with', 'Reg', (92, 107))	('methylation', 'Var', (15, 26))	('salivary gland adenoid cystic carcinoma', 'Disease', (45, 84))	('Aberrant', 'Var', (0, 8))	('PITX1', 'Gene', '5307', (9, 14))	('clear cell renal cell carcinomas', 'Phenotype', 'HP:0006770', (120, 152))	('clear cell renal cell carcinomas', 'Disease', 'MESH:C538614', (120, 152))	('carcinomas', 'Phenotype', 'HP:0030731', (142, 152))	('clear cell renal cell carcinomas', 'Disease', (120, 152))	('found', 'Reg', (36, 41))	('PITX1', 'Gene', (9, 14))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (131, 152))	('salivary gland adenoid cystic carcinoma', 'Disease', 'MESH:D003528', (45, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (142, 151))
72379	29425237	The following Illumina beads (numbered according to Fig 1) were investigated: cg00874891 (1), cg15922699 (2), cg04223420 (3), cg12673103 (4), cg18606375 (5), cg21614303 (6), cg08373003 (7), cg01966335 (8), cg24495017 (9), cg09713684(10), cg18443359 (11), cg14994060 (12), cg16258223 (13), cg11591267 (14), cg17034591 (15), cg04847174 (16), cg15528437 (17), cg03827835 (18), cg02037307 (19), cg05171952 (20), cg02213684 (21), cg02948884 (22), cg25648267 (23), cg15105206 (24), cg09839170 (25), cg01213519 (26), cg22488797 (27), cg07274716 (28), cg03347590 (29), cg23064601 (30), cg00089224 (31), cg19802165 (32), cg01830023 (33), cg24462476 (34), cg13441766 (35), cg15421305 (36), cg26509691 (37), cg00396667 (38), cg13715631 (39), cg11512280 (40), cg23341163 (41), cg11788465 (42), cg03654472 (43), cg06566775 (44), cg12622597 (45), cg22827250 (46), cg04101060 (47), cg02495310 (48), cg26972058 (49), cg08206318 (50), cg02100373 (51), cg08255782 (52), cg25330797 (53), cg12129103 (54), cg06933574 (55).	('cg00396667', 'Var', (697, 707))	('cg11788465', 'Var', (765, 775))	('cg03654472', 'Chemical', '-', (782, 792))	('cg18443359', 'Chemical', '-', (238, 248))	('cg13715631', 'Var', (714, 724))	('cg15105206', 'Chemical', '-', (459, 469))	('cg01830023', 'Chemical', '-', (612, 622))	('cg15421305', 'Var', (663, 673))	('cg13441766', 'Var', (646, 656))	('cg01830023', 'Var', (612, 622))	('cg03654472', 'Var', (782, 792))	('cg23341163', 'Var', (748, 758))	('cg26509691', 'Var', (680, 690))	('cg24462476', 'Var', (629, 639))	('cg11512280', 'Var', (731, 741))
72383	29425237	Two beads (cg18443359, cg15105206) are located within the second exon and one bead (cg03654472) targets the intron of C5orf66-AS1-201.	('cg15105206', 'Var', (23, 33))	('cg18443359', 'Chemical', '-', (11, 21))	('cg15105206', 'Chemical', '-', (23, 33))	('cg03654472', 'Chemical', '-', (84, 94))	('cg18443359', 'Var', (11, 21))	('C5orf66-AS1-201', 'Gene', (118, 133))
72385	29425237	Fifty out of 55 beads were differentially methylated between normal and tumor tissue.	('methylated', 'Var', (42, 52))	('tumor', 'Disease', (72, 77))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Disease', 'MESH:D009369', (72, 77))
72391	29425237	Methylation and expression of both PITX1 mRNA and lincRNA C5orf66-AS1 were significantly associated with tumor location, p16 expression, HPV-status and complete resection (R0) (S1 Table).	('associated', 'Reg', (89, 99))	('p16', 'Gene', '1029', (121, 124))	('PITX1', 'Gene', '5307', (35, 40))	('complete', 'Disease', (152, 160))	('Methylation', 'Var', (0, 11))	('PITX1', 'Gene', (35, 40))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('C5orf66-AS1', 'Gene', (58, 69))	('p16', 'Gene', (121, 124))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumor', 'Disease', (105, 110))	('expression', 'MPA', (16, 26))	('HPV', 'Species', '10566', (137, 140))
72395	29425237	In univariate analysis, both PITX1 exon 3 and lincRNA C5orf66-AS1 methylation was associated with an increased risk of death (hazard ratio (HR)PITX1exon3 = 1.63, 95%CI [1.12-2.38], p = 0.011; HRlncRNAC5orf66-AS1 = 1.47, 95%CI [1.16-1.86], p = 0.002).	('PITX1', 'Gene', (143, 148))	('associated', 'Reg', (82, 92))	('C5orf66-AS1', 'Gene', (54, 65))	('death', 'Disease', 'MESH:D003643', (119, 124))	('death', 'Disease', (119, 124))	('PITX1', 'Gene', '5307', (29, 34))	('methylation', 'Var', (66, 77))	('PITX1', 'Gene', (29, 34))	('PITX1', 'Gene', '5307', (143, 148))
72397	29425237	Methylation status was dichotomized in hypo- and hypermethylation using the median as cut-off for both gene loci in the entire cohort (median PITX1 exon 3 methylation: 58.0%, median C5orf66-AS1 methylation: 27.4%).	('PITX1', 'Gene', '5307', (142, 147))	('PITX1', 'Gene', (142, 147))	('methylation', 'Var', (155, 166))
72399	29425237	Kaplan-Meier curves showed a trend towards better survival in patients with high PITX1 mRNA levels and hypomethylated PITX1 exon 3 gene locus, but this result failed to be statistically significant (p = 0.21 and p = 0.12, respectively).	('mRNA levels', 'MPA', (87, 98))	('PITX1', 'Gene', '5307', (118, 123))	('patients', 'Species', '9606', (62, 70))	('PITX1', 'Gene', '5307', (81, 86))	('PITX1', 'Gene', (118, 123))	('better', 'PosReg', (43, 49))	('hypomethylated', 'Var', (103, 117))	('PITX1', 'Gene', (81, 86))	('survival', 'CPA', (50, 58))	('high', 'PosReg', (76, 80))
72400	29425237	A subgroup analysis in different tumor locations (oral cavity, larynx and oropharynx) revealed a survival benefit for patients, whose laryngeal tumors were hypomethylated at the lincRNA C5orf66-AS1 locus (p = 0.022, Fig 4).	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('benefit', 'PosReg', (106, 113))	('tumor', 'Disease', (144, 149))	('laryngeal tumors', 'Disease', (134, 150))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('laryngeal tumors', 'Disease', 'MESH:D007822', (134, 150))	('laryngeal tumors', 'Phenotype', 'HP:0012118', (134, 150))	('hypomethylated', 'Var', (156, 170))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('tumor', 'Disease', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('patients', 'Species', '9606', (118, 126))
72404	29425237	When correlating lincRNA C5orf66-AS1 hypo- and hypermethylation with p16 expression, a trend towards significance was seen in survival (p16-positive: n = 41, p = 0.086; p16-negative: n = 74, p = 0.12, Fig 5), which was supported by Kaplan-Meier curves, but ultimately failed to reach significance.	('survival', 'MPA', (126, 134))	('p16', 'Gene', '1029', (169, 172))	('p16', 'Gene', (136, 139))	('significance', 'Reg', (101, 113))	('p16', 'Gene', (69, 72))	('C5orf66-AS1', 'Gene', (25, 36))	('p16', 'Gene', (169, 172))	('hypo-', 'Var', (37, 42))	('p16', 'Gene', '1029', (136, 139))	('hypermethylation', 'Var', (47, 63))	('p16', 'Gene', '1029', (69, 72))
72406	29425237	However, additional stratification by HPV-status revealed a significantly better overall survival for patients with HPV-negative tumors and lincRNA C5orf66-AS1 hypomethylation (n = 243, p = 0.032, Fig 5).	('better', 'PosReg', (74, 80))	('HPV', 'Species', '10566', (116, 119))	('tumors', 'Disease', (129, 135))	('tumors', 'Disease', 'MESH:D009369', (129, 135))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('HPV', 'Species', '10566', (38, 41))	('patients', 'Species', '9606', (102, 110))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('overall survival', 'MPA', (81, 97))	('hypomethylation', 'Var', (160, 175))
72408	29425237	Both parameters added significant information about risk of death in univariate analysis and hyomethylation of lincRNA C5orf66-AS1 is associated with better survival, in particular in patients with negative HPV-status.	('better', 'PosReg', (150, 156))	('death', 'Disease', 'MESH:D003643', (60, 65))	('death', 'Disease', (60, 65))	('C5orf66-AS1', 'Gene', (119, 130))	('patients', 'Species', '9606', (184, 192))	('HPV', 'Species', '10566', (207, 210))	('survival', 'MPA', (157, 165))	('hyomethylation', 'Var', (93, 107))	('lincRNA C5orf66-AS1', 'Gene', (111, 130))
72413	29425237	Methylation status of lincRNA C5orf66-AS1 could emerge as a useful prognostic biomarker to identify HPV-negative patients at risk for disease recurrence and metastases, who might benefit from additional therapy like immune checkpoint inhibitors.	('C5orf66-AS1', 'Gene', (30, 41))	('metastases', 'Disease', 'MESH:D009362', (157, 167))	('HPV', 'Species', '10566', (100, 103))	('Methylation', 'Var', (0, 11))	('patients', 'Species', '9606', (113, 121))	('metastases', 'Disease', (157, 167))
72416	29425237	This confirms a more prominent role of PITX1 dysregulation in cancer development than previously thought.	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('PITX1', 'Gene', '5307', (39, 44))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('dysregulation', 'Var', (45, 58))	('PITX1', 'Gene', (39, 44))
72417	29425237	The present study indicates, that lincRNA C5orf66-AS1 might also be involved in tumorigenesis, likely by acting as (post)-transcriptional regulator of PITX1.	('PITX1', 'Gene', '5307', (151, 156))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('involved', 'Reg', (68, 76))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('C5orf66-AS1', 'Var', (42, 53))	('PITX1', 'Gene', (151, 156))	('tumor', 'Disease', (80, 85))
72418	29425237	LincRNA C5orf66-AS1 is down-regulated in esophageal squamous cell cancer and re-expression inhibits migration and invasion in vitro.	('esophageal squamous cell cancer', 'Disease', 'MESH:D002294', (41, 72))	('esophageal squamous cell cancer', 'Disease', (41, 72))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (52, 72))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('re-expression', 'Var', (77, 90))	('inhibits', 'NegReg', (91, 99))	('down-regulated', 'NegReg', (23, 37))
72422	29425237	Loss of PITX1 and lincRNA C5orf66-AS1 by aberrant epigenetic regulation might point to an overactive Ras signaling pathway, thus identifying patients who could benefit from therapy targeting this pathway, e.g.	('point to', 'Reg', (78, 86))	('epigenetic', 'MPA', (50, 60))	('Ras signaling pathway', 'Pathway', (101, 122))	('aberrant', 'Var', (41, 49))	('overactive', 'PosReg', (90, 100))	('Loss', 'NegReg', (0, 4))	('PITX1', 'Gene', '5307', (8, 13))	('PITX1', 'Gene', (8, 13))	('patients', 'Species', '9606', (141, 149))	('C5orf66-AS1', 'Gene', (26, 37))
72428	27829231	Deregulation of small non-coding RNAs at the DLK1-DIO3 imprinted locus predicts lung cancer patient outcome Deregulation of the imprinted DLK1-DIO3 locus at chromosome 14q32.1-14q32.31 has been associated with developmental and respiratory disorders, including cancer.	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('DLK1', 'Gene', '8788', (138, 142))	('Deregulation', 'Var', (108, 120))	('DIO3', 'Gene', (50, 54))	('DLK1', 'Gene', (138, 142))	('DIO3', 'Gene', '1735', (143, 147))	('lung cancer', 'Disease', 'MESH:D008175', (80, 91))	('DIO3', 'Gene', (143, 147))	('respiratory disorders', 'Disease', 'MESH:D012131', (228, 249))	('lung cancer', 'Phenotype', 'HP:0100526', (80, 91))	('cancer', 'Disease', (261, 267))	('cancer', 'Phenotype', 'HP:0002664', (261, 267))	('cancer', 'Disease', (85, 91))	('associated', 'Reg', (194, 204))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('DLK1', 'Gene', '8788', (45, 49))	('patient', 'Species', '9606', (92, 99))	('DLK1', 'Gene', (45, 49))	('respiratory disorders', 'Disease', (228, 249))	('lung cancer', 'Disease', (80, 91))	('DIO3', 'Gene', '1735', (50, 54))	('cancer', 'Disease', 'MESH:D009369', (261, 267))
72429	27829231	In lung cancer, deregulation of imprinting at DLK1-DIO3 was recently described in smokers.	('DIO3', 'Gene', '1735', (51, 55))	('lung cancer', 'Disease', (3, 14))	('lung cancer', 'Phenotype', 'HP:0100526', (3, 14))	('DIO3', 'Gene', (51, 55))	('deregulation', 'Var', (16, 28))	('DLK1', 'Gene', '8788', (46, 50))	('lung cancer', 'Disease', 'MESH:D008175', (3, 14))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('DLK1', 'Gene', (46, 50))
72435	27829231	Aberrant methylation patterns at imprinted loci resulting in expression changes of encoded transcripts are common in the pathogenesis of many diseases, including cancer.	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('common', 'Reg', (107, 113))	('cancer', 'Disease', (162, 168))	('expression changes', 'MPA', (61, 79))	('Aberrant methylation patterns', 'Var', (0, 29))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))
72436	27829231	In humans, anomalous imprinting at the DLK1-DIO3 locus at 14q32.1-14q32.31 has been associated with respiratory insufficiency and reduced thorax development, amongst many other developmentally-related disorders.	('DLK1', 'Gene', (39, 43))	('respiratory insufficiency', 'Phenotype', 'HP:0002093', (100, 125))	('anomalous imprinting', 'Var', (11, 31))	('humans', 'Species', '9606', (3, 9))	('reduced', 'NegReg', (130, 137))	('associated', 'Reg', (84, 94))	('thorax development', 'CPA', (138, 156))	('respiratory insufficiency', 'Disease', 'MESH:D012131', (100, 125))	('DIO3', 'Gene', '1735', (44, 48))	('respiratory insufficiency', 'Disease', (100, 125))	('DLK1', 'Gene', '8788', (39, 43))	('DIO3', 'Gene', (44, 48))
72442	27829231	piRNAs have highly-conserved functions across species, including epigenetic silencing of transposable elements and regulation of imprinting in mice.	('epigenetic silencing', 'Var', (65, 85))	('transposable elements', 'Gene', (89, 110))	('mice', 'Species', '10090', (143, 147))
72446	27829231	Deregulation of the DLK1-DIO3 locus has been reported to be important to lung cancer biology, but the role of piRNAs derived from this locus has not yet been described.	('lung cancer', 'Disease', 'MESH:D008175', (73, 84))	('DIO3', 'Gene', '1735', (25, 29))	('DLK1', 'Gene', '8788', (20, 24))	('Deregulation', 'Var', (0, 12))	('DLK1', 'Gene', (20, 24))	('DIO3', 'Gene', (25, 29))	('lung cancer', 'Disease', (73, 84))	('lung cancer', 'Phenotype', 'HP:0100526', (73, 84))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))
72448	27829231	Of the 138 piRNAs encoded at the DLK1-DIO3 locus, seven were expressed in LUAD, LUSC, and non-malignant lung samples in the discovery cohort (DQ596225, DQ596306, DQ596309, DQ596311, DQ596354, DQ596390, DQ596863) (Figure 1B, Figure 3).	('DIO3', 'Gene', '1735', (38, 42))	('DQ596390', 'Var', (192, 200))	('DQ596309', 'Var', (162, 170))	('LUSC', 'Phenotype', 'HP:0030359', (80, 84))	('DQ596225', 'Var', (142, 150))	('DQ596863', 'Var', (202, 210))	('DIO3', 'Gene', (38, 42))	('DLK1', 'Gene', '8788', (33, 37))	('LUAD', 'Phenotype', 'HP:0030078', (74, 78))	('DQ596306', 'Var', (152, 160))	('DQ596311', 'Var', (172, 180))	('DLK1', 'Gene', (33, 37))	('DQ596354', 'Var', (182, 190))
72449	27829231	In the discovery cohort of paired tumour and non-malignant lung tissues, four of seven somatically expressed piRNAs (DQ596225, DQ596306, DQ596309, DQ596354) were significantly overexpressed in LUAD and one piRNA (DQ596309) was overexpressed in LUSC (Figure 3).	('LUSC', 'Phenotype', 'HP:0030359', (244, 248))	('DQ596306', 'Var', (127, 135))	('tumour', 'Disease', 'MESH:D009369', (34, 40))	('DQ596225', 'Var', (117, 125))	('overexpressed', 'PosReg', (176, 189))	('LUAD', 'Phenotype', 'HP:0030078', (193, 197))	('tumour', 'Disease', (34, 40))	('DQ596309', 'Var', (137, 145))	('DQ596354', 'Var', (147, 155))	('tumour', 'Phenotype', 'HP:0002664', (34, 40))
72450	27829231	Previous work has shown that a multi-miRNA classifier (miR-370, miR-376a, and miR-411) was able to predict LUAD patient outcome (Figure 1B).	('miR-411', 'Gene', (78, 85))	('miR-370', 'Gene', (55, 62))	('patient', 'Species', '9606', (112, 119))	('LUAD', 'Phenotype', 'HP:0030078', (107, 111))	('LUAD patient outcome', 'Disease', (107, 127))	('predict', 'Reg', (99, 106))	('miR-376a', 'Var', (64, 72))	('miR-411', 'Gene', '693121', (78, 85))	('miR-370', 'Gene', '442915', (55, 62))
72457	27829231	Interestingly, while piRNA expression alone was unable to significantly predict OS in univariate or multivariate analysis, the incorporation of piRNA expression into the miRNA signature improved the stratification of patients into risk groups.	('stratification', 'MPA', (199, 213))	('incorporation', 'Var', (127, 140))	('improved', 'PosReg', (186, 194))	('patients', 'Species', '9606', (217, 225))	('piRNA', 'Gene', (144, 149))
72466	27829231	However, as was shown in LUAD, the miRNA+piRNA signature was also able to classify LUSC patients into risk groups with distinct OS outcomes in both the discovery (Figure 5B) and external datasets (Figure 7, Supplementary Figure S3).	('LUSC', 'Disease', (83, 87))	('LUSC', 'Phenotype', 'HP:0030359', (83, 87))	('patients', 'Species', '9606', (88, 96))	('miRNA+piRNA', 'Var', (35, 46))	('LUAD', 'Phenotype', 'HP:0030078', (25, 29))
72488	27829231	In addition to miRNAs previously associated with lung cancer patient outcome (miR-370, miR-376a, miR-411), Cox proportional hazard models including combinations of the seven expressed piRNAs, and combinations of the miRNAs and piRNAs were analyzed.	('lung cancer', 'Disease', 'MESH:D008175', (49, 60))	('patient', 'Species', '9606', (61, 68))	('miR-376a', 'Var', (87, 95))	('miR-411', 'Gene', '693121', (97, 104))	('miR-370', 'Gene', '442915', (78, 85))	('lung cancer', 'Disease', (49, 60))	('miR-370', 'Gene', (78, 85))	('associated', 'Reg', (33, 43))	('Cox', 'Gene', (107, 110))	('Cox', 'Gene', '1351', (107, 110))	('lung cancer', 'Phenotype', 'HP:0100526', (49, 60))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('miR-411', 'Gene', (97, 104))
72505	27729745	Although PD-L1 positivity was not found to be associated with survival of ESCC patients, we show that it may play a critical role in distant failure and progression of ESCC.	('play', 'Reg', (109, 113))	('PD-L1', 'Gene', '29126', (9, 14))	('distant failure', 'CPA', (133, 148))	('positivity', 'Var', (15, 25))	('ESCC', 'Disease', (168, 172))	('patients', 'Species', '9606', (79, 87))	('PD-L1', 'Gene', (9, 14))
72511	27729745	The PD-L1/PD-1 interaction has been found to be associated with poor prognosis and clinical outcomes in various cancers such as non-small cell lung cancer, breast cancer, gastric cancer, soft tissue sarcomas and meningioma; however, its prognostic value is still controversial.	('sarcomas', 'Phenotype', 'HP:0100242', (199, 207))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (132, 154))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('breast cancer', 'Phenotype', 'HP:0003002', (156, 169))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (128, 154))	('meningioma', 'Disease', 'MESH:D008577', (212, 222))	('cancers', 'Phenotype', 'HP:0002664', (112, 119))	('PD-1', 'Gene', (10, 14))	('gastric cancer', 'Disease', (171, 185))	('PD-1', 'Gene', '5133', (10, 14))	('interaction', 'Var', (15, 26))	('breast cancer', 'Disease', 'MESH:D001943', (156, 169))	('cancers', 'Disease', (112, 119))	('breast cancer', 'Disease', (156, 169))	('non-small cell lung cancer', 'Disease', (128, 154))	('lung cancer', 'Phenotype', 'HP:0100526', (143, 154))	('soft tissue sarcomas', 'Disease', (187, 207))	('gastric cancer', 'Disease', 'MESH:D013274', (171, 185))	('PD-L1', 'Gene', (4, 9))	('PD-L1', 'Gene', '29126', (4, 9))	('soft tissue sarcomas', 'Disease', 'MESH:D012509', (187, 207))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (187, 207))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('cancers', 'Disease', 'MESH:D009369', (112, 119))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('meningioma', 'Disease', (212, 222))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (128, 154))	('meningioma', 'Phenotype', 'HP:0002858', (212, 222))	('gastric cancer', 'Phenotype', 'HP:0012126', (171, 185))
72774	33668375	However, this was not the case for our model for which systemic thrombosis risk was not enhanced due to decreased platelet reactivity with delta-storage pool deficiency, which counteracted the pro-aggregatory characteristics of OSCC.	('thrombosis', 'Disease', 'MESH:D013927', (64, 74))	('decreased platelet', 'Phenotype', 'HP:0005537', (104, 122))	('deficiency', 'Var', (158, 168))	('SCC', 'Phenotype', 'HP:0002860', (229, 232))	('decreased', 'NegReg', (104, 113))	('thrombosis', 'Disease', (64, 74))	('decreased platelet reactivity', 'Phenotype', 'HP:0003540', (104, 133))	('platelet reactivity', 'MPA', (114, 133))
72787	33668375	Delta-storage pool deficiency is a thrombopathy defined by a reduction in granule secretion from platelets, which may be due to a quantitative defect (with a decreased number of granules per platelet) or a qualitative defect (abnormal content or abnormal mobilization of dense platelet granules).	('decreased', 'NegReg', (158, 167))	('deficiency', 'Var', (19, 29))	('thrombopathy', 'Disease', (35, 47))	('content', 'MPA', (235, 242))	('thrombopathy', 'Disease', 'None', (35, 47))	('reduction', 'NegReg', (61, 70))	('Delta-storage pool', 'MPA', (0, 18))	('mobilization', 'MPA', (255, 267))	('granule secretion from platelets', 'MPA', (74, 106))
72788	33668375	These defects lead to diminished platelet aggregation owing to the lack of a second wave of aggregation dependent on the release of dense granule content, especially ADP.	('release of dense granule content', 'MPA', (121, 153))	('diminished', 'NegReg', (22, 32))	('diminished platelet aggregation', 'Phenotype', 'HP:0003540', (22, 53))	('ADP', 'Chemical', 'MESH:D000244', (166, 169))	('ADP', 'Var', (166, 169))	('platelet aggregation', 'Disease', (33, 53))	('platelet aggregation', 'Disease', 'MESH:D001791', (33, 53))	('platelet aggregation', 'Phenotype', 'HP:0003540', (33, 53))
72790	33668375	Clinically, delta-storage pool deficiency manifests itself as hemorrhagic symptoms that are most of time moderate and often only observed following traumatism or a surgery, potentially without increasing the bleeding time.	('traumatism', 'Disease', 'MESH:D014947', (148, 158))	('traumatism', 'Disease', (148, 158))	('delta-storage pool', 'MPA', (12, 30))	('hemorrhagic', 'Disease', (62, 73))	('deficiency', 'Var', (31, 41))	('hemorrhagic symptoms', 'Phenotype', 'HP:0001892', (62, 82))	('hemorrhagic', 'Disease', 'MESH:D006470', (62, 73))	('increasing the bleeding time', 'Phenotype', 'HP:0003010', (193, 221))
72792	33668375	Delta-storage pool deficiency can also be acquired as has been observed in leukemia and myelodysplastic syndromes as well as in inflammatory diseases, such as rheumatoid arthritis, lupus erythematosus or postural orthostatic tachycardia syndrome.	('leukemia', 'Disease', 'MESH:D007938', (75, 83))	('leukemia', 'Disease', (75, 83))	('myelodysplastic syndromes', 'Disease', 'MESH:D009190', (88, 113))	('rheumatoid arthritis', 'Phenotype', 'HP:0001370', (159, 179))	('orthostatic tachycardia', 'Phenotype', 'HP:0012173', (213, 236))	('postural orthostatic tachycardia syndrome', 'Disease', 'MESH:D054972', (204, 245))	('lupus erythematosus', 'Disease', (181, 200))	('arthritis', 'Phenotype', 'HP:0001369', (170, 179))	('rheumatoid arthritis', 'Disease', (159, 179))	('lupus erythematosus', 'Disease', 'MESH:D008180', (181, 200))	('postural orthostatic tachycardia syndrome', 'Disease', (204, 245))	('lupus erythematosus', 'Phenotype', 'HP:0002725', (181, 200))	('tachycardia', 'Phenotype', 'HP:0001649', (225, 236))	('leukemia', 'Phenotype', 'HP:0001909', (75, 83))	('myelodysplastic syndromes', 'Phenotype', 'HP:0002863', (88, 113))	('deficiency', 'Var', (19, 29))	('myelodysplastic syndromes', 'Disease', (88, 113))	('rheumatoid arthritis', 'Disease', 'MESH:D001172', (159, 179))	('Delta-storage pool', 'MPA', (0, 18))
72800	33668375	Moreover, we demonstrated that a delta-storage pool deficiency in mice with tongue tumors could be responsible almost partially for the decreased platelet reactivity, which counteracted the pro-aggregatory phenotype of OSCC tumors and explains the low risk of systemic thrombosis.	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('decreased', 'NegReg', (136, 145))	('thrombosis', 'Disease', 'MESH:D013927', (269, 279))	('deficiency', 'Var', (52, 62))	('decreased platelet', 'Phenotype', 'HP:0005537', (136, 154))	('tongue tumors', 'Disease', (76, 89))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('thrombosis', 'Disease', (269, 279))	('OSCC tumors', 'Disease', 'MESH:D009369', (219, 230))	('SCC', 'Phenotype', 'HP:0002860', (220, 223))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('mice', 'Species', '10090', (66, 70))	('delta-storage pool', 'MPA', (33, 51))	('platelet reactivity', 'MPA', (146, 165))	('tumors', 'Phenotype', 'HP:0002664', (224, 230))	('tongue tumors', 'Disease', 'MESH:D014062', (76, 89))	('decreased platelet reactivity', 'Phenotype', 'HP:0003540', (136, 165))	('tongue tumor', 'Phenotype', 'HP:0100648', (76, 88))	('OSCC tumors', 'Disease', (219, 230))	('tongue tumors', 'Phenotype', 'HP:0100648', (76, 89))
72805	33738136	Accumulating studies have shown that aberrant m6A modifications have profound effects on the characteristics of tumors, which undoubtedly led to a significant breakthrough in cancer treatment.	('m6A', 'Protein', (46, 49))	('cancer', 'Disease', (175, 181))	('modifications', 'Var', (50, 63))	('tumors', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumors', 'Disease', 'MESH:D009369', (112, 118))	('effects', 'Reg', (78, 85))	('aberrant', 'Var', (37, 45))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
72820	33738136	Several studies demonstrated that m6A can affect the characteristics of cancer cells.	('affect', 'Reg', (42, 48))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('m6A', 'Var', (34, 37))	('cancer', 'Disease', (72, 78))
72822	33738136	Accordingly, the exploration of tumor characteristics that are based on m6A methylation is of great significance and may become an innovative therapeutic target in the clinic.	('m6A', 'Gene', (72, 75))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('methylation', 'Var', (76, 87))	('tumor', 'Disease', (32, 37))
72825	33738136	The m6A methylation is catalyzed by a multi-component methyltransferase complex, including methyltransferase-like 3 (METTL3), METTL14, and Wilms' tumor 1 (WT1)-associated protein (WTAP).	("Wilms' tumor", 'Phenotype', 'HP:0002667', (139, 151))	('METTL14', 'Gene', '57721', (126, 133))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('methyltransferase-like 3', 'Gene', (91, 115))	('METTL14', 'Gene', (126, 133))	("Wilms' tumor 1 (WT1)-associated protein", 'Gene', '9589', (139, 178))	('METTL3', 'Gene', '56339', (117, 123))	('WTAP', 'Gene', '9589', (180, 184))	('WTAP', 'Gene', (180, 184))	('METTL3', 'Gene', (117, 123))	('m6A', 'Var', (4, 7))	('methyltransferase-like 3', 'Gene', '56339', (91, 115))
72834	33738136	It is confirmed that NOP2/Sun RNA methyltransferase 2 (NSun2) silencing completely blocks PAR2-induced m6A methylation of pre-miR-125b2, indicating that NSun2 may regulate m6A modification in an indirect way.	('NOP2/Sun RNA methyltransferase 2', 'Gene', '54888;4839', (21, 53))	('silencing', 'Var', (62, 71))	('miR-125b2', 'Gene', '406912', (126, 135))	('NSun2', 'Gene', (55, 60))	('NSun2', 'Gene', (153, 158))	('NSun2', 'Gene', '54888', (55, 60))	('m6A methylation', 'MPA', (103, 118))	('blocks', 'NegReg', (83, 89))	('PAR2', 'Gene', '2150', (90, 94))	('PAR2', 'Gene', (90, 94))	('NSun2', 'Gene', '54888', (153, 158))	('miR-125b2', 'Gene', (126, 135))	('NOP2/Sun RNA methyltransferase 2', 'Gene', (21, 53))
72852	33738136	First, METTL3 is the main regulatory factor in the m6A-mediated apoptosis inhibition.	('METTL3', 'Gene', '56339', (7, 13))	('m6A-mediated', 'Var', (51, 63))	('METTL3', 'Gene', (7, 13))
72854	33738136	In breast cancer (BC), METTL3 silencing could dramatically trigger the apoptotic capacity of BC cells through targeting B cell lymphoma-2 (BCL-2) or hepatitis B X-interacting protein (HBXIP).	('BC', 'Phenotype', 'HP:0003002', (93, 95))	('hepatitis B', 'Disease', 'MESH:D006509', (149, 160))	('HBXIP', 'Gene', '10542', (184, 189))	('trigger', 'PosReg', (59, 66))	('METTL3', 'Gene', (23, 29))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('lymphoma', 'Phenotype', 'HP:0002665', (127, 135))	('silencing', 'Var', (30, 39))	('BC', 'Phenotype', 'HP:0003002', (18, 20))	('METTL3', 'Gene', '56339', (23, 29))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('hepatitis', 'Phenotype', 'HP:0012115', (149, 158))	('B cell lymphoma', 'Phenotype', 'HP:0012191', (120, 135))	('hepatitis B', 'Disease', (149, 160))	('apoptotic capacity', 'CPA', (71, 89))	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('breast cancer', 'Disease', (3, 16))	('targeting', 'Reg', (110, 119))	('BCL-2', 'Gene', '596', (139, 144))	('HBXIP', 'Gene', (184, 189))	('BCL-2', 'Gene', (139, 144))	('BC', 'Phenotype', 'HP:0003002', (139, 141))
72856	33738136	In acute myeloid leukemia (AML), the deficiency of METTL3 can induce apoptosis, which is caused by the increased translation of the v-myc myelocytomatosis viral oncogene homolog (c-MYC), BCL-2, and phosphatase and tensin homolog (PTEN) mRNA.	('AML', 'Phenotype', 'HP:0004808', (27, 30))	('PTEN', 'Gene', '5728', (230, 234))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (9, 25))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (3, 25))	('v-myc myelocytomatosis viral oncogene homolog', 'Gene', '4609', (132, 177))	('deficiency', 'Var', (37, 47))	('BCL-2', 'Gene', (187, 192))	('phosphatase and tensin homolog', 'Gene', '5728', (198, 228))	('induce', 'Reg', (62, 68))	('METTL3', 'Gene', (51, 57))	('apoptosis', 'Disease', (69, 78))	('acute myeloid leukemia', 'Disease', (3, 25))	('PTEN', 'Gene', (230, 234))	('leukemia', 'Phenotype', 'HP:0001909', (17, 25))	('METTL3', 'Gene', '56339', (51, 57))	('v-myc myelocytomatosis viral oncogene homolog', 'Gene', (132, 177))	('c-MYC', 'Gene', '4609', (179, 184))	('AML', 'Disease', 'MESH:D015470', (27, 30))	('BCL-2', 'Gene', '596', (187, 192))	('c-MYC', 'Gene', (179, 184))	('AML', 'Disease', (27, 30))	('BC', 'Phenotype', 'HP:0003002', (187, 189))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (3, 25))
72858	33738136	found that METTL3 knockdown correlates with apoptotic transcripts and the increased ratio of apoptotic GBM cells.	('knockdown', 'Var', (18, 27))	('METTL3', 'Gene', '56339', (11, 17))	('apoptotic transcripts', 'MPA', (44, 65))	('increased', 'PosReg', (74, 83))	('METTL3', 'Gene', (11, 17))	('ratio', 'MPA', (84, 89))
72860	33738136	In addition, METTL3 depletion suppressed the accumulation of GLI family zinc finger 1 (GLI1) and ATPase family AAA domain containing 2 (ATAD2), leading to apoptosis in prostate cancer and osteosarcoma (OS).	('ATAD2', 'Gene', '29028', (136, 141))	('osteosarcoma', 'Disease', 'MESH:D012516', (188, 200))	('GLI family zinc finger 1', 'Gene', (61, 85))	('depletion', 'Var', (20, 29))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('prostate cancer', 'Disease', 'MESH:D011471', (168, 183))	('prostate cancer', 'Phenotype', 'HP:0012125', (168, 183))	('METTL3', 'Gene', (13, 19))	('GLI1', 'Gene', (87, 91))	('prostate cancer', 'Disease', (168, 183))	('OS', 'Phenotype', 'HP:0002669', (202, 204))	('ATAD2', 'Gene', (136, 141))	('apoptosis', 'CPA', (155, 164))	('osteosarcoma', 'Phenotype', 'HP:0002669', (188, 200))	('METTL3', 'Gene', '56339', (13, 19))	('suppressed', 'NegReg', (30, 40))	('ATPase family AAA domain containing 2', 'Gene', '29028', (97, 134))	('ATPase family AAA domain containing 2', 'Gene', (97, 134))	('GLI1', 'Gene', '2735', (87, 91))	('GLI family zinc finger 1', 'Gene', '2735', (61, 85))	('osteosarcoma', 'Disease', (188, 200))
72863	33738136	In MM6 and NB4 AML cells, the apoptotic activity is enhanced following METTL14 depletion, which was associated with the regulation of MYB and MYC target mRNA in m6A-mediated manner.	('AML', 'Disease', 'MESH:D015470', (15, 18))	('MYC', 'Gene', (142, 145))	('AML', 'Disease', (15, 18))	('enhanced', 'PosReg', (52, 60))	('AML', 'Phenotype', 'HP:0004808', (15, 18))	('apoptotic activity', 'CPA', (30, 48))	('depletion', 'Var', (79, 88))	('METTL14', 'Gene', (71, 78))	('MYB', 'Gene', '4602', (134, 137))	('MYB', 'Gene', (134, 137))	('METTL14', 'Gene', '57721', (71, 78))	('MYC', 'Gene', '4609', (142, 145))
72864	33738136	also performed a preliminary study on the role of WTAP in AML and found that WTAP knockdown can promote the apoptosis of leukemia cells following etoposide treatment via the mTOR pathway.	('AML', 'Phenotype', 'HP:0004808', (58, 61))	('WTAP', 'Gene', (77, 81))	('etoposide', 'Chemical', 'MESH:D005047', (146, 155))	('mTOR', 'Gene', '2475', (174, 178))	('AML', 'Disease', 'MESH:D015470', (58, 61))	('knockdown', 'Var', (82, 91))	('promote', 'PosReg', (96, 103))	('leukemia', 'Disease', (121, 129))	('WTAP', 'Gene', '9589', (50, 54))	('leukemia', 'Disease', 'MESH:D007938', (121, 129))	('leukemia', 'Phenotype', 'HP:0001909', (121, 129))	('WTAP', 'Gene', (50, 54))	('mTOR', 'Gene', (174, 178))	('WTAP', 'Gene', '9589', (77, 81))	('apoptosis', 'CPA', (108, 117))	('AML', 'Disease', (58, 61))
72868	33738136	Low level of encoding zinc finger protein 750 (ZNF750) maintained by METTL3 upregulation in NPC and the degradation of GATA Binding Protein 3 (GATA3) modulated by KIAA1429 overexpression in HCC ultimately suppresses apoptosis.	('overexpression', 'Var', (172, 186))	('NPC', 'Phenotype', 'HP:0100630', (92, 95))	('KIAA1429', 'Gene', (163, 171))	('NPC', 'Disease', (92, 95))	('KIAA1429', 'Gene', '25962', (163, 171))	('GATA3', 'Gene', '2625', (143, 148))	('HCC', 'Phenotype', 'HP:0001402', (190, 193))	('METTL3', 'Gene', (69, 75))	('GATA3', 'Gene', (143, 148))	('GATA Binding Protein 3', 'Gene', (119, 141))	('zinc finger protein 750', 'Gene', '79755', (22, 45))	('METTL3', 'Gene', '56339', (69, 75))	('apoptosis', 'CPA', (216, 225))	('GATA Binding Protein 3', 'Gene', '2625', (119, 141))	('degradation', 'MPA', (104, 115))	('upregulation', 'PosReg', (76, 88))	('suppresses', 'NegReg', (205, 215))	('zinc finger protein 750', 'Gene', (22, 45))	('ZNF750', 'Gene', '79755', (47, 53))	('ZNF750', 'Gene', (47, 53))
72871	33738136	In addition to writers, eraser FTO could act as a tumor suppressor to accelerate cell apoptosis, while its knockdown decreases the apoptotic rate in clear cell renal cell carcinoma (ccRcc).	('knockdown', 'Var', (107, 116))	('ccRcc', 'Phenotype', 'HP:0006770', (182, 187))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (149, 180))	('clear cell renal cell carcinoma', 'Disease', (149, 180))	('decreases', 'NegReg', (117, 126))	('cell apoptosis', 'CPA', (81, 95))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (160, 180))	('accelerate', 'PosReg', (70, 80))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (149, 180))	('carcinoma', 'Phenotype', 'HP:0030731', (171, 180))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('apoptotic rate', 'MPA', (131, 145))	('tumor', 'Disease', (50, 55))
72872	33738136	Intriguingly, FTO-induced high level of m6A that affects the mRNA of the peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC-1alpha) is the critical mechanism of this process.	('PGC-1alpha', 'Gene', '10891', (142, 152))	('GC', 'Phenotype', 'HP:0012126', (143, 145))	('mRNA of the', 'MPA', (61, 72))	('m6A', 'Var', (40, 43))	('affects', 'Reg', (49, 56))	('peroxisome proliferator-activated receptor gamma coactivator 1alpha', 'Gene', '10891', (73, 140))	('PGC-1alpha', 'Gene', (142, 152))
72874	33738136	In glioma, METTL3 low expression restrains glioma cell apoptosis by upregulating HSP90, while FTO high expression inhibits apoptosis in an m6A-dependent manner as well.	('HSP90', 'Gene', (81, 86))	('upregulating', 'PosReg', (68, 80))	('glioma', 'Disease', 'MESH:D005910', (3, 9))	('glioma', 'Phenotype', 'HP:0009733', (3, 9))	('HSP90', 'Gene', '3320', (81, 86))	('METTL3', 'Gene', '56339', (11, 17))	('glioma', 'Disease', (43, 49))	('inhibits', 'NegReg', (114, 122))	('restrains', 'NegReg', (33, 42))	('METTL3', 'Gene', (11, 17))	('apoptosis', 'CPA', (123, 132))	('glioma', 'Disease', (3, 9))	('low expression', 'Var', (18, 32))	('glioma', 'Disease', 'MESH:D005910', (43, 49))	('glioma', 'Phenotype', 'HP:0009733', (43, 49))
72877	33738136	In ocular melanoma, BC, AML, and LC, the high level of m6A on anti-oncogenes mediated by low expression of FTO or ALKBH5 activates cancer apoptosis by promoting the accumulation of these genes.	('promoting', 'PosReg', (151, 160))	('ALKBH5', 'Gene', (114, 120))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('FTO', 'Gene', (107, 110))	('ALKBH5', 'Gene', '54890', (114, 120))	('ocular melanoma', 'Phenotype', 'HP:0007716', (3, 18))	('accumulation', 'MPA', (165, 177))	('AML', 'Disease', 'MESH:D015470', (24, 27))	('AML', 'Phenotype', 'HP:0004808', (24, 27))	('AML', 'Disease', (24, 27))	('ocular melanoma', 'Disease', 'MESH:D008545', (3, 18))	('low expression', 'Var', (89, 103))	('LC', 'Phenotype', 'HP:0100526', (33, 35))	('cancer', 'Disease', (131, 137))	('activates', 'PosReg', (121, 130))	('BC', 'Phenotype', 'HP:0003002', (20, 22))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('melanoma', 'Phenotype', 'HP:0002861', (10, 18))	('ocular melanoma', 'Disease', (3, 18))
72883	33738136	showed that METTL3 knockdown increases the number of autophagosomes and significantly promotes LC3-II accumulation in HCC through relinquishing the stability of forkhead box O3 (FOXO3) mRNA in a YTHDF1-dependent manner.	('METTL3', 'Gene', (12, 18))	('forkhead box O3', 'Gene', (161, 176))	('forkhead box O3', 'Gene', '2309', (161, 176))	('HCC', 'Phenotype', 'HP:0001402', (118, 121))	('knockdown', 'Var', (19, 28))	('LC', 'Phenotype', 'HP:0100526', (95, 97))	('stability', 'MPA', (148, 157))	('FOXO3', 'Gene', (178, 183))	('YTHDF1', 'Gene', '54915', (195, 201))	('YTHDF1', 'Gene', (195, 201))	('increases', 'PosReg', (29, 38))	('promotes', 'PosReg', (86, 94))	('METTL3', 'Gene', '56339', (12, 18))	('FOXO3', 'Gene', '2309', (178, 183))	('LC3-II accumulation', 'Protein', (95, 114))	('relinquishing', 'NegReg', (130, 143))
72884	33738136	found that FTO silencing inhibits the expression of LC3B II but increases the expression of the autophagy substrate p62.	('autophagy', 'CPA', (96, 105))	('expression', 'MPA', (78, 88))	('inhibits', 'NegReg', (25, 33))	('LC', 'Phenotype', 'HP:0100526', (52, 54))	('expression', 'MPA', (38, 48))	('LC3B', 'Gene', (52, 56))	('silencing', 'Var', (15, 24))	('LC3B', 'Gene', '81631', (52, 56))	('FTO', 'Gene', (11, 14))	('increases', 'PosReg', (64, 73))
72885	33738136	Mechanistically, the authors confirmed that FTO acts on three m6A sites in the 3'-UTR of unc-51-like kinase 1 (ULK1) transcripts, which regulates its protein abundance through demethylation.	('unc-51-like kinase 1', 'Gene', (89, 109))	('ULK1', 'Gene', (111, 115))	('regulates', 'Reg', (136, 145))	('ULK1', 'Gene', '8408', (111, 115))	('protein abundance', 'MPA', (150, 167))	('unc-51-like kinase 1', 'Gene', '8408', (89, 109))	('demethylation', 'Var', (176, 189))
72887	33738136	proved that FTO can promote autophagy by catalyzing m6A demethylation, but instead of ULK1, autophagy-related 5 (ATG5) and autophagy-related 7 (ATG7) are FTO direct target genes.	('autophagy', 'CPA', (28, 37))	('ULK1', 'Gene', (86, 90))	('ULK1', 'Gene', '8408', (86, 90))	('m6A', 'Var', (52, 55))	('ATG7', 'Gene', '10533', (144, 148))	('autophagy-related 7', 'Gene', (123, 142))	('autophagy-related 5', 'Gene', '9474', (92, 111))	('autophagy-related 7', 'Gene', '10533', (123, 142))	('promote', 'PosReg', (20, 27))	('autophagy-related 5', 'Gene', (92, 111))	('ATG5', 'Gene', '9474', (113, 117))	('ATG5', 'Gene', (113, 117))	('ATG7', 'Gene', (144, 148))
72901	33738136	Therefore, m6A may modulate cell metabolism under hypoxic conditions, which further leads an impact on cancer angiogenesis.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('hypoxic conditions', 'Disease', (50, 68))	('modulate', 'Reg', (19, 27))	('hypoxic conditions', 'Disease', 'MESH:D000071069', (50, 68))	('cell', 'CPA', (28, 32))	('leads', 'Reg', (84, 89))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('impact', 'Reg', (93, 99))	('m6A', 'Var', (11, 14))
72903	33738136	In HCC, the knockdown of the core writer METTL3 increases the translation of some angiogenic biomarkers, including FGF, PDGF-B, STAT3, and VEGF-A.	('FGF', 'Gene', (115, 118))	('angiogenic biomarkers', 'MPA', (82, 103))	('STAT3', 'Gene', '6774', (128, 133))	('increases', 'PosReg', (48, 57))	('METTL3', 'Gene', '56339', (41, 47))	('STAT3', 'Gene', (128, 133))	('knockdown', 'Var', (12, 21))	('METTL3', 'Gene', (41, 47))	('VEGF-A', 'Gene', '7422', (139, 145))	('translation', 'MPA', (62, 73))	('PDGF-B', 'Gene', (120, 126))	('VEGF-A', 'Gene', (139, 145))	('HCC', 'Phenotype', 'HP:0001402', (3, 6))	('PDGF-B', 'Gene', '5155', (120, 126))
72904	33738136	The increased formation of tubes by the human umbilical vein endothelial cells (HUVECs) indicates that the absence of METTL3 can stimulate angiogenesis.	('stimulate', 'PosReg', (129, 138))	('EC', 'Disease', 'MESH:D005955', (83, 85))	('angiogenesis', 'CPA', (139, 151))	('formation of tubes', 'CPA', (14, 32))	('METTL3', 'Gene', '56339', (118, 124))	('METTL3', 'Gene', (118, 124))	('increased', 'PosReg', (4, 13))	('human', 'Species', '9606', (40, 45))	('absence', 'Var', (107, 114))
72906	33738136	These results reveal that aberrant m6A may have a regulatory effect on angiogenesis in cancer; however, the specific mechanism of this event remains to be elucidated.	('cancer', 'Disease', (87, 93))	('aberrant', 'Var', (26, 34))	('angiogenesis', 'CPA', (71, 83))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('m6A', 'Protein', (35, 38))	('cancer', 'Disease', 'MESH:D009369', (87, 93))
72916	33738136	Specifically, knockdown of METTL14 constrains the recruitment and methylation of downstream SRY-related high-mobility-group box 4 (SOX4), which can be recognized by YTHDF2, thus promoting EMT through a gain in N-cadherin and vimentin expressions and a loss of E-cadherin expression.	('gain', 'PosReg', (202, 206))	('E-cadherin', 'Gene', (260, 270))	('SRY-related high-mobility-group box 4', 'Gene', (92, 129))	('METTL14', 'Gene', (27, 34))	('SOX4', 'Gene', '6659', (131, 135))	('vimentin', 'Gene', '7431', (225, 233))	('YTHDF2', 'Gene', (165, 171))	('vimentin', 'Gene', (225, 233))	('E-cadherin', 'Gene', '999', (260, 270))	('loss', 'NegReg', (252, 256))	('EMT', 'CPA', (188, 191))	('methylation', 'MPA', (66, 77))	('expression', 'MPA', (271, 281))	('N-cadherin', 'Gene', (210, 220))	('N-cadherin', 'Gene', '1000', (210, 220))	('promoting', 'PosReg', (178, 187))	('YTHDF2', 'Gene', '51441', (165, 171))	('expressions', 'MPA', (234, 245))	('recruitment', 'MPA', (50, 61))	('SRY-related high-mobility-group box 4', 'Gene', '6659', (92, 129))	('SOX4', 'Gene', (131, 135))	('METTL14', 'Gene', '57721', (27, 34))	('knockdown', 'Var', (14, 23))
72917	33738136	It is observed that METTL3 silencing elevated the expression of vimentin, beta-catenin, and N-cadherin as well as reduced E-cadherin accumulation in renal cell carcinoma (RCC) cells, while overexpression of METTL3 resulted in the opposite change of such protein levels.	('renal cell carcinoma', 'Disease', (149, 169))	('N-cadherin', 'Gene', '1000', (92, 102))	('carcinoma', 'Phenotype', 'HP:0030731', (160, 169))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (149, 169))	('elevated', 'PosReg', (37, 45))	('reduced', 'NegReg', (114, 121))	('RCC', 'Phenotype', 'HP:0005584', (171, 174))	('METTL3', 'Gene', '56339', (207, 213))	('RCC', 'Disease', (171, 174))	('expression', 'MPA', (50, 60))	('METTL3', 'Gene', (20, 26))	('E-cadherin', 'Gene', (122, 132))	('vimentin', 'Gene', '7431', (64, 72))	('E-cadherin', 'Gene', '999', (122, 132))	('N-cadherin', 'Gene', (92, 102))	('vimentin', 'Gene', (64, 72))	('RCC', 'Disease', 'MESH:C538614', (171, 174))	('METTL3', 'Gene', '56339', (20, 26))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (149, 169))	('silencing', 'Var', (27, 36))	('beta-catenin', 'Gene', (74, 86))	('METTL3', 'Gene', (207, 213))	('beta-catenin', 'Gene', '1499', (74, 86))
72923	33738136	In HCC, METTL3 mutation leads to a low level of m6A in the coding sequence (CDS) and 3'-UTRs of Snail, a key EMT translator.	('mutation', 'Var', (15, 23))	('m6A', 'MPA', (48, 51))	('Snail', 'Gene', (96, 101))	('METTL3', 'Gene', '56339', (8, 14))	('Snail', 'Gene', '6615', (96, 101))	('METTL3', 'Gene', (8, 14))	('HCC', 'Phenotype', 'HP:0001402', (3, 6))
72924	33738136	Moreover, YTHDF1 binds to m6A methylated Snail and stimulates its translation, triggering lung metastasis.	('binds', 'Interaction', (17, 22))	('m6A methylated', 'Var', (26, 40))	('triggering', 'Reg', (79, 89))	('Snail', 'Gene', (41, 46))	('Snail', 'Gene', '6615', (41, 46))	('translation', 'MPA', (66, 77))	('YTHDF1', 'Gene', '54915', (10, 16))	('YTHDF1', 'Gene', (10, 16))	('stimulates', 'PosReg', (51, 61))	('lung metastasis', 'CPA', (90, 105))
72925	33738136	Similarly, METTL3 knockdown decreases the protein levels of Snail, MMP2, MMP9, and FN1 but increases E-cadherin level, which reveals the impact of METTL3 on EMT of HCC.	('MMP2', 'Gene', (67, 71))	('increases', 'PosReg', (91, 100))	('E-cadherin', 'Gene', (101, 111))	('decreases', 'NegReg', (28, 37))	('Snail', 'Gene', (60, 65))	('E-cadherin', 'Gene', '999', (101, 111))	('HCC', 'Phenotype', 'HP:0001402', (164, 167))	('knockdown', 'Var', (18, 27))	('MMP2', 'Gene', '4313', (67, 71))	('METTL3', 'Gene', (147, 153))	('METTL3', 'Gene', (11, 17))	('FN1', 'Gene', '2335', (83, 86))	('protein levels', 'MPA', (42, 56))	('METTL3', 'Gene', '56339', (147, 153))	('METTL3', 'Gene', '56339', (11, 17))	('Snail', 'Gene', '6615', (60, 65))	('MMP9', 'Gene', (73, 77))	('MMP9', 'Gene', '4318', (73, 77))	('FN1', 'Gene', (83, 86))
72928	33738136	validated that METTL3 deficiency downregulates m6A modified Snail, thereby inhibiting EMT of NPC cells by regulating the expression of N-cadherin and E-cadherin proteins.	('METTL3', 'Gene', (15, 21))	('downregulates', 'NegReg', (33, 46))	('inhibiting', 'NegReg', (75, 85))	('Snail', 'Gene', (60, 65))	('NPC', 'Phenotype', 'HP:0100630', (93, 96))	('EMT of NPC cells', 'CPA', (86, 102))	('Snail', 'Gene', '6615', (60, 65))	('E-cadherin', 'Gene', (150, 160))	('expression', 'MPA', (121, 131))	('regulating', 'Reg', (106, 116))	('E-cadherin', 'Gene', '999', (150, 160))	('N-cadherin', 'Gene', (135, 145))	('METTL3', 'Gene', '56339', (15, 21))	('N-cadherin', 'Gene', '1000', (135, 145))	('deficiency', 'Var', (22, 32))
72929	33738136	It was reported that enhancer of zeste homolog 2 (EZH2) is relevant to tumor progression in many cancers, where EZH2 expression is elevated via METTL3-installed m6A modification, thus driving EMT in LC.	('METTL3', 'Gene', '56339', (144, 150))	('enhancer of zeste homolog 2', 'Gene', (21, 48))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('EZH2', 'Gene', '2146', (112, 116))	('cancers', 'Phenotype', 'HP:0002664', (97, 104))	('elevated', 'PosReg', (131, 139))	('cancers', 'Disease', (97, 104))	('EZH2', 'Gene', (112, 116))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('expression', 'MPA', (117, 127))	('tumor', 'Disease', (71, 76))	('enhancer of zeste homolog 2', 'Gene', '2146', (21, 48))	('LC', 'Phenotype', 'HP:0100526', (199, 201))	('cancers', 'Disease', 'MESH:D009369', (97, 104))	('driving', 'PosReg', (184, 191))	('METTL3', 'Gene', (144, 150))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('modification', 'Var', (165, 177))	('EZH2', 'Gene', '2146', (50, 54))	('EZH2', 'Gene', (50, 54))
72938	33738136	EMT capacity could be significantly disrupted by YTHDF2-mediated YAP deficiency.	('EMT capacity', 'CPA', (0, 12))	('YAP', 'Gene', (65, 68))	('disrupted', 'NegReg', (36, 45))	('YTHDF2', 'Gene', '51441', (49, 55))	('deficiency', 'Var', (69, 79))	('YTHDF2', 'Gene', (49, 55))	('YAP', 'Gene', '10413', (65, 68))
72942	33738136	In addition, YTHDF3 can be a reader of m6A-modified Zeb1 and functions as a Zeb1 mRNA stabilizer.	('YTHDF3', 'Gene', (13, 19))	('Zeb1', 'Gene', (52, 56))	('Zeb1', 'Gene', '6935', (52, 56))	('YTHDF3', 'Gene', '253943', (13, 19))	('Zeb1', 'Gene', (76, 80))	('Zeb1', 'Gene', '6935', (76, 80))	('m6A-modified', 'Var', (39, 51))
72945	33738136	Overall, m6A imposes positive and negative influences on EMT in certain cancer types, and the writers are major regulators of EMT.	('negative', 'NegReg', (34, 42))	('m6A', 'Var', (9, 12))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('EMT', 'CPA', (57, 60))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('influences', 'Reg', (43, 53))	('cancer', 'Disease', (72, 78))
72946	33738136	Inevitable therapeutic resistance has been a major obstacle in overcoming cancer owing to epigenetic alterations.	('cancer', 'Disease', (74, 80))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('epigenetic alterations', 'Var', (90, 112))
72947	33738136	Thus, we introduce the effect of abnormal m6A on chemoresistance, radioresistance, endocrine resistance, resistance to targeted therapy, and even resistance to inhibitors in cancer.	('chemoresistance', 'CPA', (49, 64))	('endocrine', 'MPA', (83, 92))	('cancer', 'Disease', (174, 180))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('radioresistance', 'CPA', (66, 81))	('abnormal', 'Var', (33, 41))	('effect', 'Reg', (23, 29))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('m6A', 'Gene', (42, 45))
72950	33738136	In leukemia, the low level of m6A that is induced by FTO-mediated demethylation promotes the expression of proliferation/survival transcripts, leading to tyrosine kinase inhibitor (TKI) resistance.	('proliferation/survival', 'CPA', (107, 129))	('leukemia', 'Phenotype', 'HP:0001909', (3, 11))	('leukemia', 'Disease', 'MESH:D007938', (3, 11))	('leukemia', 'Disease', (3, 11))	('m6A', 'Var', (30, 33))	('expression', 'MPA', (93, 103))	('leading to', 'Reg', (143, 153))	('demethylation', 'Var', (66, 79))	('promotes', 'PosReg', (80, 88))	('FTO-mediated', 'Gene', (53, 65))
72954	33738136	In NPC, m6A methylation that is activated by METTL3 and recognized by IGF2BP2 facilitates the stability of the Tripartite motif containing protein 11 (TRIM11), activates the Dvl-associating pro Tein (Daple)/beta-catenin/ABCC9 signaling pathway, and contributes to DDP resistance.	('ABCC9', 'Gene', (220, 225))	('m6A', 'Var', (8, 11))	('beta-catenin', 'Gene', (207, 219))	('beta-catenin', 'Gene', '1499', (207, 219))	('NPC', 'Phenotype', 'HP:0100630', (3, 6))	('contributes', 'Reg', (249, 260))	('METTL3', 'Gene', (45, 51))	('IGF2BP2', 'Gene', '10644', (70, 77))	('Tripartite motif containing protein 11', 'Gene', '81559', (111, 149))	('DDP', 'Chemical', 'MESH:D002945', (264, 267))	('methylation', 'Var', (12, 23))	('TRIM11', 'Gene', '81559', (151, 157))	('ABCC9', 'Gene', '10060', (220, 225))	('METTL3', 'Gene', '56339', (45, 51))	('Tripartite motif containing protein 11', 'Gene', (111, 149))	('DDP resistance', 'MPA', (264, 278))	('BC', 'Phenotype', 'HP:0003002', (221, 223))	('activates', 'PosReg', (160, 169))	('stability', 'MPA', (94, 103))	('TRIM11', 'Gene', (151, 157))	('IGF2BP2', 'Gene', (70, 77))	('facilitates', 'PosReg', (78, 89))
72962	33738136	Moreover, both erasers FTO and ALKBH5 are downregulated in resistant EOC cells, and it was shown that m6A concentration on FZD10 mRNA causes resistance to poly ADP-ribose polymerase inhibitor (PARPi) by stimulating the Wnt/beta-catenin signaling pathway.	('beta-catenin', 'Gene', (223, 235))	('FZD10', 'Gene', '11211', (123, 128))	('PARP', 'Gene', '142', (193, 197))	('causes', 'Reg', (134, 140))	('poly ADP-ribose polymerase', 'Gene', '142', (155, 181))	('EOC', 'Phenotype', 'HP:0025318', (69, 72))	('ALKBH5', 'Gene', '54890', (31, 37))	('beta-catenin', 'Gene', '1499', (223, 235))	('stimulating', 'PosReg', (203, 214))	('m6A', 'Var', (102, 105))	('PARP', 'Gene', (193, 197))	('ALKBH5', 'Gene', (31, 37))	('FZD10', 'Gene', (123, 128))	('poly ADP-ribose polymerase', 'Gene', (155, 181))	('resistance', 'MPA', (141, 151))
72963	33738136	It is worth mentioning that YTHDF1 silencing can promote the CRC sensitization to 5-Fu and L-OHP.	('silencing', 'Var', (35, 44))	('CRC', 'Phenotype', 'HP:0003003', (61, 64))	('L-OHP', 'Chemical', 'MESH:D000077150', (91, 96))	('promote', 'PosReg', (49, 56))	('YTHDF1', 'Gene', '54915', (28, 34))	('YTHDF1', 'Gene', (28, 34))	('5-Fu', 'Chemical', 'MESH:D005472', (82, 86))
72964	33738136	However, YTHDC2 knockdown induces a reduction in radioresistance by hampering the insulin-like growth factor 1 receptor (IGF1R)-AKT/S6 signaling pathway in NPC.	('insulin-like growth factor 1 receptor', 'Gene', (82, 119))	('IGF1R', 'Gene', '3480', (121, 126))	('NPC', 'Phenotype', 'HP:0100630', (156, 159))	('AKT', 'Gene', (128, 131))	('reduction', 'NegReg', (36, 45))	('knockdown', 'Var', (16, 25))	('insulin-like growth factor 1 receptor', 'Gene', '3480', (82, 119))	('YTHDC2', 'Gene', '64848', (9, 15))	('NPC', 'Disease', (156, 159))	('radioresistance', 'CPA', (49, 64))	('YTHDC2', 'Gene', (9, 15))	('hampering', 'NegReg', (68, 77))	('IGF1R', 'Gene', (121, 126))	('AKT', 'Gene', '207', (128, 131))
72972	33738136	demonstrated that N-CDPCB has a strong FTO inhibitory activity and provides an absolutely new binding site for FTO inhibitors.	('N-CDPCB', 'Var', (18, 25))	('binding site', 'Interaction', (94, 106))	('N-CDPCB', 'Chemical', '-', (18, 25))	('FTO inhibitory activity', 'MPA', (39, 62))
72974	33738136	developed new FTO inhibitors, FB23 and its derivative FB23-2, and proved that FB23-2 inhibits the proliferation and accelerates the differentiation and apoptosis of AML cells.	('AML', 'Disease', (165, 168))	('inhibits', 'NegReg', (85, 93))	('accelerates', 'PosReg', (116, 127))	('differentiation', 'CPA', (132, 147))	('FB23-2', 'Var', (78, 84))	('AML', 'Disease', 'MESH:D015470', (165, 168))	('apoptosis', 'CPA', (152, 161))	('AML', 'Phenotype', 'HP:0004808', (165, 168))	('proliferation', 'CPA', (98, 111))
72978	33738136	Furthermore, ALK-04 was identified as a specific ALKBH5 inhibitor.	('ALK-04', 'Var', (13, 19))	('ALKBH5', 'Gene', (49, 55))	('ALKBH5', 'Gene', '54890', (49, 55))
72981	33738136	METTL3 enhances the stability and expression of STAT1 mRNA via methylation modification, thus driving M1 macrophage polarization.	('expression', 'MPA', (34, 44))	('stability', 'MPA', (20, 29))	('STAT1', 'Gene', (48, 53))	('driving', 'Reg', (94, 101))	('STAT1', 'Gene', '6772', (48, 53))	('METTL3', 'Gene', '56339', (0, 6))	('methylation modification', 'Var', (63, 87))	('METTL3', 'Gene', (0, 6))	('M1 macrophage polarization', 'CPA', (102, 128))	('enhances', 'PosReg', (7, 15))
72982	33738136	FTO knockout can inhibit the polarization of M1 and M2 macrophages through accelerating the decay of STAT1 and peroxisome proliferation-activated receptor-gamma (PPAR-gamma).	('peroxisome proliferation-activated receptor-gamma', 'Gene', (111, 160))	('accelerating', 'PosReg', (75, 87))	('PPAR-gamma', 'Gene', (162, 172))	('decay', 'MPA', (92, 97))	('PPAR-gamma', 'Gene', '5468', (162, 172))	('STAT1', 'Gene', (101, 106))	('knockout', 'Var', (4, 12))	('inhibit', 'NegReg', (17, 24))	('FTO', 'Gene', (0, 3))	('polarization', 'CPA', (29, 41))	('STAT1', 'Gene', '6772', (101, 106))	('peroxisome proliferation-activated receptor-gamma', 'Gene', '5468', (111, 160))
72984	33738136	The loss of METTL3 suppresses the maturation phenotype of DC as well as decreased T cell response in vivo and in vitro.	('METTL3', 'Gene', (12, 18))	('suppresses', 'NegReg', (19, 29))	('decreased', 'NegReg', (72, 81))	('decreased T cell', 'Phenotype', 'HP:0005403', (72, 88))	('T cell response', 'CPA', (82, 97))	('maturation phenotype', 'CPA', (34, 54))	('METTL3', 'Gene', '56339', (12, 18))	('loss', 'Var', (4, 8))
72990	33738136	showed that YTHDF3 knockout increases HIV susceptibility in human CD4+ T cells.	('YTHDF3', 'Gene', '253943', (12, 18))	('CD4', 'Gene', (66, 69))	('increases', 'PosReg', (28, 37))	('knockout', 'Var', (19, 27))	('CD4', 'Gene', '920', (66, 69))	('HIV susceptibility', 'MPA', (38, 56))	('YTHDF3', 'Gene', (12, 18))	('human', 'Species', '9606', (60, 65))
72991	33738136	In regulatory T cells (Tregs), the depletion of METTL3 leads to the increase of SOCS mRNA level, consequently inhibiting the IL-2-STA T5 signaling pathway, which is essential for the function and stability of Tregs.	('SOCS', 'Gene', (80, 84))	('METTL3', 'Gene', '56339', (48, 54))	('METTL3', 'Gene', (48, 54))	('IL-2-STA T5', 'Gene', (125, 136))	('inhibiting', 'NegReg', (110, 120))	('increase', 'PosReg', (68, 76))	('IL-2-STA T5', 'Gene', '3558;6776', (125, 136))	('depletion', 'Var', (35, 44))	('SOCS', 'Gene', '1154', (80, 84))
72992	33738136	METTL14 silencing can damage IL-7-induced pro-B cell proliferation, while RNA m6A promotes pro-B cell proliferation via reader YTHDF2.	('METTL14', 'Gene', '57721', (0, 7))	('promotes', 'PosReg', (82, 90))	('METTL14', 'Gene', (0, 7))	('pro-B cell proliferation', 'CPA', (42, 66))	('YTHDF2', 'Gene', '51441', (127, 133))	('IL-7', 'Gene', '3574', (29, 33))	('silencing', 'Var', (8, 17))	('pro-B cell proliferation', 'CPA', (91, 115))	('IL-7', 'Gene', (29, 33))	('YTHDF2', 'Gene', (127, 133))	('damage', 'NegReg', (22, 28))
72993	33738136	In addition, METTL14 silencing inhibits the transformation of large-pre-B-to-small-pre-B and seriously hinders the development of early B cells.	('hinders', 'NegReg', (103, 110))	('METTL14', 'Gene', '57721', (13, 20))	('development of early B cells', 'CPA', (115, 143))	('METTL14', 'Gene', (13, 20))	('inhibits', 'NegReg', (31, 39))	('transformation', 'CPA', (44, 58))	('silencing', 'Var', (21, 30))
72998	33738136	found that demethylase FTO promotes the expression of melanoma-intrinsic programmed cell death-1 (PD-1), C-X-C chemokine receptor type 4 (CXCR4), and sex determining region Y box 10 (SOX10) via m6A modification.	('expression', 'MPA', (40, 50))	('SOX10', 'Gene', '6663', (183, 188))	('C-X-C chemokine receptor type 4', 'Gene', '7852', (105, 136))	('SOX10', 'Gene', (183, 188))	('FTO', 'Gene', (23, 26))	('melanoma', 'Disease', 'MESH:D008545', (54, 62))	('melanoma', 'Phenotype', 'HP:0002861', (54, 62))	('m6A', 'Var', (194, 197))	('melanoma', 'Disease', (54, 62))	('promotes', 'PosReg', (27, 35))	('CXCR4', 'Gene', '7852', (138, 143))	('demethylase', 'Gene', (11, 22))	('sex determining region Y box 10', 'Gene', '414903', (150, 181))	('demethylase', 'Gene', '8932', (11, 22))	('CXCR4', 'Gene', (138, 143))	('C-X-C chemokine receptor type 4', 'Gene', (105, 136))	('sex determining region Y box 10', 'Gene', (150, 181))
73006	33738136	Remarkably, YTHDF1 knockout results in a significant deceleration of melanoma growth.	('deceleration', 'NegReg', (53, 65))	('YTHDF1', 'Gene', '54915', (12, 18))	('knockout', 'Var', (19, 27))	('YTHDF1', 'Gene', (12, 18))	('melanoma growth', 'Disease', (69, 84))	('melanoma growth', 'Disease', 'MESH:D008545', (69, 84))	('melanoma', 'Phenotype', 'HP:0002861', (69, 77))
73007	33738136	Mechanistically, YTHDF1 silencing downregulates the translation of lysosomal cathepsins in DCs, thereby facilitating the cross-presentation of tumor antigens and cross-priming of CD8+ T cells.	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('lysosomal', 'Protein', (67, 76))	('tumor', 'Disease', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('CD8', 'Gene', (179, 182))	('translation', 'MPA', (52, 63))	('downregulates', 'NegReg', (34, 47))	('cross-presentation', 'MPA', (121, 139))	('YTHDF1', 'Gene', '54915', (17, 23))	('CD8', 'Gene', '925', (179, 182))	('YTHDF1', 'Gene', (17, 23))	('facilitating', 'PosReg', (104, 116))	('silencing', 'Var', (24, 33))
73009	33738136	It has been demonstrated that m6A methylation is involved in tumor characteristics, including cell death, angiogenesis, and EMT.	('methylation', 'Var', (34, 45))	('m6A', 'Protein', (30, 33))	('EMT', 'CPA', (124, 127))	('involved', 'Reg', (49, 57))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('angiogenesis', 'CPA', (106, 118))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('cell death', 'CPA', (94, 104))	('tumor', 'Disease', (61, 66))
73012	33738136	On the other hand, the role of m6A in cancer cells' therapeutic resistance lays the foundation for its use in combination therapy.	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('therapeutic resistance', 'CPA', (52, 74))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('cancer', 'Disease', (38, 44))	('m6A', 'Var', (31, 34))
73014	33738136	In addition, cancer immunotherapy, as a frontier method, is also regulated by m6A methylation, which opens up a new approach in improving immunotherapeutic effects.	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('methylation', 'Var', (82, 93))	('m6A', 'Protein', (78, 81))	('cancer', 'Disease', 'MESH:D009369', (13, 19))	('cancer', 'Disease', (13, 19))	('regulated', 'Reg', (65, 74))
73032	32411535	Large numbers of gene mutations have been reported to be served as specific biomarkers for diagnosis, treatment and prognosis for LUAD (lung adenocarcinoma), such as bevacizumab against VEGF.	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (136, 155))	('VEGF', 'Gene', (186, 190))	('bevacizumab', 'Chemical', 'MESH:D000068258', (166, 177))	('VEGF', 'Gene', '7422', (186, 190))	('mutations', 'Var', (22, 31))	('lung adenocarcinoma', 'Disease', (136, 155))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (136, 155))	('LUAD', 'Disease', (130, 134))
73084	32411535	declared that high-level KIF11 was as an independent prognostic factor in LUSC, and might be promising therapeutic option for advanced lung cancer.	('KIF11', 'Gene', (25, 30))	('LUSC', 'Phenotype', 'HP:0030359', (74, 78))	('lung cancer', 'Disease', 'MESH:D008175', (135, 146))	('high-level', 'Var', (14, 24))	('KIF11', 'Gene', '3832', (25, 30))	('LUSC', 'Disease', (74, 78))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('lung cancer', 'Disease', (135, 146))	('lung cancer', 'Phenotype', 'HP:0100526', (135, 146))
73108	32411535	demonstrated the loss of PPP2R2C was associated with cancer recurrence and a poor survival in prostate cancer.	('PPP2R2C', 'Gene', '5522', (25, 32))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('prostate cancer', 'Disease', 'MESH:D011471', (94, 109))	('poor', 'NegReg', (77, 81))	('prostate cancer', 'Disease', (94, 109))	('PPP2R2C', 'Gene', (25, 32))	('prostate cancer', 'Phenotype', 'HP:0012125', (94, 109))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('associated', 'Reg', (37, 47))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('loss', 'Var', (17, 21))
73111	32411535	MMP3 is associated with poor survival in various cancers, and its polymorphism might increase the risk of lung cancer.	('cancers', 'Phenotype', 'HP:0002664', (49, 56))	('lung cancer', 'Disease', (106, 117))	('lung cancer', 'Phenotype', 'HP:0100526', (106, 117))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('MMP3', 'Gene', (0, 4))	('polymorphism', 'Var', (66, 78))	('cancers', 'Disease', 'MESH:D009369', (49, 56))	('lung cancer', 'Disease', 'MESH:D008175', (106, 117))	('increase', 'PosReg', (85, 93))	('cancers', 'Disease', (49, 56))	('MMP3', 'Gene', '4314', (0, 4))
73116	32411535	Inhibition of SPP1 could enhance the invasion and might be a promising target for NSCLC therapy.	('invasion', 'CPA', (37, 45))	('NSCLC', 'Phenotype', 'HP:0030358', (82, 87))	('enhance', 'PosReg', (25, 32))	('SPP1', 'Gene', '6696', (14, 18))	('SPP1', 'Gene', (14, 18))	('Inhibition', 'Var', (0, 10))	('NSCLC', 'Disease', (82, 87))	('NSCLC', 'Disease', 'MESH:D002289', (82, 87))
73120	31658270	This includes tumor mutations that generate neo-antigenic epitopes that elicit cytotoxic T-cell activity and subsequent pressure to select for genetic loss of antigen presentation.	('tumor', 'Disease', (14, 19))	('cytotoxic T-cell activity', 'CPA', (79, 104))	('antigen presentation', 'MPA', (159, 179))	('elicit', 'Reg', (72, 78))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('loss', 'NegReg', (151, 155))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('mutations', 'Var', (20, 29))
73121	31658270	Most studies have focused on how tumor missense mutations can drive tumor immunity, but frameshift mutations have the potential to create far greater antigenic diversity.	('tumor', 'Disease', (68, 73))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('greater', 'PosReg', (142, 149))	('drive', 'Reg', (62, 67))	('frameshift mutations', 'Var', (88, 108))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Disease', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('antigenic diversity', 'MPA', (150, 169))	('missense mutations', 'Var', (39, 57))
73123	31658270	Here we studied how mutational changes influence global NMD and cytolytic immune responses.	('N', 'Chemical', 'MESH:D009584', (56, 57))	('influence', 'Reg', (39, 48))	('mutational changes', 'Var', (20, 38))
73127	31658270	We also observed significant co-alteration of genes in the NMD pathway, with a global increase in NMD efficiency in patients with NMD co-alterations.	('increase', 'PosReg', (86, 94))	('co-alterations', 'Var', (134, 148))	('N', 'Chemical', 'MESH:D009584', (130, 131))	('N', 'Chemical', 'MESH:D009584', (98, 99))	('patients', 'Species', '9606', (116, 124))	('N', 'Chemical', 'MESH:D009584', (59, 60))	('NMD pathway', 'Pathway', (59, 70))	('NMD efficiency', 'MPA', (98, 112))
73129	31658270	Our work suggests that beyond selecting for mutations that elicit NMD in tumor suppressors, tumor evolution may react to the selective pressure generated by inflammation to globally enhance NMD through coordinated amplification and/or mutation.	('mutation', 'Var', (235, 243))	('N', 'Chemical', 'MESH:D009584', (190, 191))	('enhance', 'PosReg', (182, 189))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('NMD', 'MPA', (190, 193))	('amplification', 'Var', (214, 227))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('inflammation', 'Disease', 'MESH:D007249', (157, 169))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Disease', (73, 78))	('mutations', 'Var', (44, 53))	('inflammation', 'Disease', (157, 169))	('tumor', 'Disease', (92, 97))	('N', 'Chemical', 'MESH:D009584', (66, 67))
73132	31658270	Then, increased killing of the tumor can lead to changes such as increased expression of PD-L1 and/or loss of function mutations in MHC Class I proteins that help a tumor evade immune surveillance.	('increased', 'PosReg', (6, 15))	('increased', 'PosReg', (65, 74))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('killing', 'CPA', (16, 23))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('tumor', 'Disease', (31, 36))	('PD-L1', 'Gene', (89, 94))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('MHC Class I', 'Gene', (132, 143))	('mutations', 'Var', (119, 128))	('PD-L1', 'Gene', '29126', (89, 94))	('proteins', 'Protein', (144, 152))	('expression', 'MPA', (75, 85))	('tumor', 'Disease', (165, 170))
73134	31658270	This presents a paradox in how frameshift mutations and NMD interact in eliciting/evading immune surveillance during the course of tumor evolution.	('eliciting/evading immune surveillance', 'MPA', (72, 109))	('frameshift mutations', 'Var', (31, 51))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('interact', 'Reg', (60, 68))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumor', 'Disease', (131, 136))	('NMD', 'Gene', (56, 59))	('N', 'Chemical', 'MESH:D009584', (56, 57))
73135	31658270	Here, we identify a new example of conditional selection, whereby tumors can coordinately mutate and/or amplify genes in the NMD pathway.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('amplify', 'MPA', (104, 111))	('NMD pathway', 'Pathway', (125, 136))	('genes', 'Gene', (112, 117))	('tumors', 'Disease', (66, 72))	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('mutate', 'Var', (90, 96))	('N', 'Chemical', 'MESH:D009584', (125, 126))
73136	31658270	We observed significant co-occurrence of mutations and copy number alterations among the NMD pathway genes.	('mutations', 'Var', (41, 50))	('copy number alterations', 'Var', (55, 78))	('N', 'Chemical', 'MESH:D009584', (89, 90))	('NMD pathway genes', 'Gene', (89, 106))
73137	31658270	The co-alterations within the NMD pathway increase the global NMD efficiency and are associated with lower cytolytic activity, and in some cases, worse overall survival.	('cytolytic activity', 'MPA', (107, 125))	('N', 'Chemical', 'MESH:D009584', (30, 31))	('lower', 'NegReg', (101, 106))	('NMD pathway', 'Pathway', (30, 41))	('co-alterations', 'Var', (4, 18))	('NMD efficiency', 'MPA', (62, 76))	('N', 'Chemical', 'MESH:D009584', (62, 63))	('increase', 'PosReg', (42, 50))
73139	31658270	Tumors with high levels of clonal neoantigens have higher levels of T-cell infiltration, and higher response rates to immunotherapies.	('higher', 'PosReg', (93, 99))	('clonal', 'Var', (27, 33))	('Tumors', 'Disease', (0, 6))	('response rates', 'CPA', (100, 114))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('T-cell infiltration', 'MPA', (68, 87))	('higher', 'PosReg', (51, 57))
73140	31658270	High levels of immune infiltration are also associated with loss of function mutations in Class I MHC proteins, suggesting that the inflammation caused by T-cell-tumor recognition can result in selective pressure to lose T-cell tumor interactions.	('T-cell-tumor', 'Disease', 'MESH:D005935', (155, 167))	('inflammation', 'Disease', 'MESH:D007249', (132, 144))	('loss of function', 'NegReg', (60, 76))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('tumor', 'Disease', 'MESH:D009369', (228, 233))	('inflammation', 'Disease', (132, 144))	('tumor', 'Disease', (162, 167))	('interactions', 'Interaction', (234, 246))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('T-cell-tumor', 'Disease', (155, 167))	('mutations', 'Var', (77, 86))	('lose', 'NegReg', (216, 220))	('tumor', 'Disease', (228, 233))	('MHC', 'Gene', (98, 101))	('tumor', 'Disease', 'MESH:D009369', (162, 167))
73148	31658270	Beyond PD-L1 positivity, other factors such as tumor mutational burden, microsatellite instability, oncogenic viruses have also been associated with therapeutic response and tumor immune infiltrates.	('tumor', 'Disease', (174, 179))	('microsatellite instability', 'Var', (72, 98))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('therapeutic response', 'CPA', (149, 169))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('PD-L1', 'Gene', (7, 12))	('tumor', 'Disease', (47, 52))	('PD-L1', 'Gene', '29126', (7, 12))	('associated', 'Reg', (133, 143))
73149	31658270	Neoantigen burden due to non-synonymous substitutions has been clearly associated with immunotherapeutic success, cytolytic activity, and overall survival.	('immunotherapeutic success', 'CPA', (87, 112))	('cytolytic activity', 'CPA', (114, 132))	('N', 'Chemical', 'MESH:D009584', (0, 1))	('Neoantigen burden', 'MPA', (0, 17))	('non-synonymous substitutions', 'Var', (25, 53))	('associated', 'Reg', (71, 81))
73150	31658270	In this randomized trial, the authors demonstrated that stage IV or recurrent NSCLC (not previously treated with chemotherapy and with a tumor PD-L1 expression level of less than 1%) who have more than 10 nonsynonymous mutations per megabase have a 42.6% progression free survival at 1 year.	('tumor', 'Disease', (137, 142))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('nonsynonymous mutations', 'Var', (205, 228))	('PD-L1', 'Gene', (143, 148))	('NSCLC', 'Disease', (78, 83))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('NSCLC', 'Disease', 'MESH:D002289', (78, 83))	('PD-L1', 'Gene', '29126', (143, 148))
73153	31658270	Recently, multiple improvements to neoantigen predictions have been made by incorporating clonality, indel mutations, and intron retention mutations into studies of immune infiltration and immune response in tumors.	('mutations', 'Var', (139, 148))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('tumors', 'Disease', (208, 214))	('tumors', 'Phenotype', 'HP:0002664', (208, 214))	('indel mutations', 'Var', (101, 116))	('tumors', 'Disease', 'MESH:D009369', (208, 214))
73156	31658270	However, the use of frameshift mutations for predictions in pan-cancer analyses raises an important question.	('frameshift mutations', 'Var', (20, 40))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
73158	31658270	Frameshift mutations cause premature termination codons (PTCs), resulting in mRNAs that are the target of nonsense-mediated decay (NMD).	('N', 'Chemical', 'MESH:D009584', (79, 80))	('premature termination codons', 'MPA', (27, 55))	('Frameshift mutations', 'Var', (0, 20))	('N', 'Chemical', 'MESH:D009584', (131, 132))	('mRNAs', 'MPA', (77, 82))
73160	31658270	This may lead to reduced NMD and result in the expression of frameshift mutations that could be presented as neoantigens.	('frameshift mutations', 'Var', (61, 81))	('N', 'Chemical', 'MESH:D009584', (25, 26))	('NMD', 'MPA', (25, 28))	('reduced', 'NegReg', (17, 24))
73161	31658270	In addition, genomic analyses of frameshift mutations and their expression suggests that NMD operates with reduced efficiency in cancer.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('N', 'Chemical', 'MESH:D009584', (89, 90))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('frameshift mutations', 'Var', (33, 53))
73162	31658270	Finally, there is also evidence in preclinical models that inhibiting nonsense mediated decay can enhance tumor immunity.	('enhance', 'PosReg', (98, 105))	('inhibiting', 'Var', (59, 69))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('nonsense mediated decay', 'Protein', (70, 93))	('tumor', 'Disease', (106, 111))
73169	31658270	Here, using this measure for immune cytolytic activity, we quantitatively examined 17 cancer indications for the contribution of mutation variant counts to observed cytolytic activity (high versus low).	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('cancer', 'Disease', (86, 92))	('variant', 'Var', (138, 145))
73172	31658270	Recent developments have suggested that frameshifts (which create very distinct neoepitopes) can improve the prediction of inflamed tumors and patient survival.	('patient', 'Species', '9606', (143, 150))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('frameshifts', 'Var', (40, 51))	('inflamed tumors', 'Disease', 'MESH:C531841', (123, 138))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('inflamed tumors', 'Disease', (123, 138))	('improve', 'PosReg', (97, 104))	('patient survival', 'CPA', (143, 159))
73180	31658270	In addition, simple metrics of mutation abundance are positively correlated with cytolytic activity while most NMD-based metrics are negatively correlated (Fig 1B, S4 Fig).	('N', 'Chemical', 'MESH:D009584', (111, 112))	('mutation', 'Var', (31, 39))	('cytolytic activity', 'MPA', (81, 99))
73187	31658270	A potential explanation for an association between the central tendency of NMD across all genes within a patient and cytolytic activity is that T-cell infiltration might exert selective pressure upon tumors to mutate or amplify genes in the NMD pathway.	('patient', 'Species', '9606', (105, 112))	('genes', 'Gene', (228, 233))	('N', 'Chemical', 'MESH:D009584', (75, 76))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('tumors', 'Phenotype', 'HP:0002664', (200, 206))	('mutate', 'Var', (210, 216))	('tumors', 'Disease', (200, 206))	('tumors', 'Disease', 'MESH:D009369', (200, 206))	('N', 'Chemical', 'MESH:D009584', (241, 242))	('amplify', 'Var', (220, 227))	('NMD pathway', 'Pathway', (241, 252))
73190	31658270	Examining all patients in the Pan-Cancer dataset, we observed amplification of NMD pathway genes (Fig 2A) that resembled a gain of function pathway such as MAPK family members more than they did tumor suppressors such as P53 and PTEN (i.e.	('P53', 'Gene', (221, 224))	('N', 'Chemical', 'MESH:D009584', (232, 233))	('tumor', 'Disease', (195, 200))	('P53', 'Gene', '7157', (221, 224))	('Cancer', 'Phenotype', 'HP:0002664', (34, 40))	('PTEN', 'Gene', (229, 233))	('N', 'Chemical', 'MESH:D009584', (79, 80))	('PTEN', 'Gene', '5728', (229, 233))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('NMD pathway genes', 'Gene', (79, 96))	('amplification', 'Var', (62, 75))	('gain', 'PosReg', (123, 127))	('patients', 'Species', '9606', (14, 22))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))
73191	31658270	Beyond amplification, while none of the individual genes in the NMD pathway are predicted to be drivers of cancer, we thought it was possible that tumor evolution might select for co-occurrence of multiple individual NMD pathway mutations.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('mutations', 'Var', (229, 238))	('N', 'Chemical', 'MESH:D009584', (64, 65))	('NMD', 'Gene', (217, 220))	('N', 'Chemical', 'MESH:D009584', (217, 218))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('cancer', 'Disease', (107, 113))
73196	31658270	Moreover, patients with NMD alterations had lower cytolytic activity (S8 Fig).	('lower', 'NegReg', (44, 49))	('alterations', 'Var', (28, 39))	('NMD', 'Gene', (24, 27))	('N', 'Chemical', 'MESH:D009584', (24, 25))	('patients', 'Species', '9606', (10, 18))	('cytolytic activity', 'MPA', (50, 68))
73204	31658270	The features that contributed toward multiple indications included counts of missense, silent, and total mutations, and several of the NMD burden metrics (mostly as measured by mean or median) (S11 Fig).	('missense', 'Var', (77, 85))	('silent', 'Var', (87, 93))	('mutations', 'Var', (105, 114))	('N', 'Chemical', 'MESH:D009584', (135, 136))
73208	31658270	With multiple hypothesis correction, we observed mutational counts or NMD burden influence survival for a subset of the cancer types (BRCA, GBM/LGG, KIPAN, OV, SKCM, and UCEC) (S2 Table).	('N', 'Chemical', 'MESH:D009584', (153, 154))	('BRCA', 'Gene', '672', (134, 138))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('mutational', 'Var', (49, 59))	('KIPAN', 'Disease', (149, 154))	('BRCA', 'Gene', (134, 138))	('SKCM', 'Disease', (160, 164))	('influence', 'Reg', (81, 90))	('survival', 'MPA', (91, 99))	('GBM/LGG', 'Disease', (140, 147))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('KIPAN', 'Chemical', 'None', (149, 154))	('SKCM', 'Disease', 'MESH:C562393', (160, 164))	('N', 'Chemical', 'MESH:D009584', (70, 71))
73210	31658270	As expected, in melanoma higher cytolytic activity was associated with a better survival outcome (hazard ratio of cyt-high vs cyt-low, 0.5; 95% CI, 0.3-0.7); p-value = 0.002) (Fig 4A).	('cyt-high', 'Var', (114, 122))	('survival', 'MPA', (80, 88))	('melanoma', 'Disease', 'MESH:D008545', (16, 24))	('melanoma', 'Phenotype', 'HP:0002861', (16, 24))	('melanoma', 'Disease', (16, 24))	('higher', 'PosReg', (25, 31))	('better', 'PosReg', (73, 79))	('cytolytic activity', 'MPA', (32, 50))
73218	31658270	Tumors with co-amplifications and mutations in the NMD pathway had increased NMD efficiencies and were less likely to have immune infiltration.	('NMD pathway', 'Gene', (51, 62))	('co-amplifications', 'Var', (12, 29))	('N', 'Chemical', 'MESH:D009584', (77, 78))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('increased', 'PosReg', (67, 76))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('NMD efficiencies', 'CPA', (77, 93))	('N', 'Chemical', 'MESH:D009584', (51, 52))	('mutations', 'Var', (34, 43))
73221	31658270	In tumor suppressors, mutations arise spontaneously, and if they occur in a region that elicits NMD, the mutation can be selected for because NMD will eliminate the mRNA of the tumor suppressor.	('mRNA of', 'MPA', (165, 172))	('mutation', 'Var', (105, 113))	('tumor', 'Disease', (3, 8))	('N', 'Chemical', 'MESH:D009584', (167, 168))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('N', 'Chemical', 'MESH:D009584', (142, 143))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('mutations', 'Var', (22, 31))	('tumor', 'Disease', 'MESH:D009369', (3, 8))	('N', 'Chemical', 'MESH:D009584', (96, 97))	('tumor', 'Disease', (177, 182))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))	('eliminate', 'NegReg', (151, 160))
73222	31658270	Clearly tumor evolution does not need to alter NMD to create loss of function in tumor suppressor proteins, it is simply selecting for mutations that happen to elicit NMD.	('loss of function', 'NegReg', (61, 77))	('N', 'Chemical', 'MESH:D009584', (47, 48))	('N', 'Chemical', 'MESH:D009584', (167, 168))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('mutations', 'Var', (135, 144))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumor', 'Disease', (8, 13))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Disease', (81, 86))
73223	31658270	However, our study suggests that at the level of a patient (and not a gene), mutations in NMD and a global increase in NMD efficiency can be selected for.	('increase', 'PosReg', (107, 115))	('N', 'Chemical', 'MESH:D009584', (119, 120))	('NMD', 'MPA', (119, 122))	('mutations', 'Var', (77, 86))	('NMD', 'Gene', (90, 93))	('patient', 'Species', '9606', (51, 58))	('N', 'Chemical', 'MESH:D009584', (90, 91))
73226	31658270	Consistent with this co-alteration, we observed that these co-occurring mutations/amplifications increased NMD efficiency in patients that had low cytolytic activity.	('increased', 'PosReg', (97, 106))	('N', 'Chemical', 'MESH:D009584', (107, 108))	('mutations/amplifications', 'Var', (72, 96))	('NMD', 'CPA', (107, 110))	('patients', 'Species', '9606', (125, 133))
73228	31658270	The association of amplifications and not deletions as well as the observed functional increase in NMD efficiency suggests that cytolytic activity is inhibited by gain of function alterations in the NMD pathway.	('increase', 'PosReg', (87, 95))	('NMD', 'CPA', (99, 102))	('inhibited', 'NegReg', (150, 159))	('alterations', 'Var', (180, 191))	('N', 'Chemical', 'MESH:D009584', (99, 100))	('NMD pathway', 'Pathway', (199, 210))	('N', 'Chemical', 'MESH:D009584', (199, 200))	('cytolytic activity', 'MPA', (128, 146))	('gain of function', 'PosReg', (163, 179))	('amplifications', 'Var', (19, 33))
73236	31658270	In addition to better understanding immunity and, potentially, the response to checkpoint therapy, the inhibition of NMD has been proposed as a therapeutic strategy in cancer.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('N', 'Chemical', 'MESH:D009584', (117, 118))	('inhibition', 'Var', (103, 113))	('cancer', 'Disease', (168, 174))	('NMD', 'Gene', (117, 120))
73237	31658270	Suppression of NMD can create a therapeutic effect through cell intrinsic (via restoring the activity of a tumor suppressor) or extrinsic mechanisms (via tumor immunity).	('NMD', 'Gene', (15, 18))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('activity', 'MPA', (93, 101))	('Suppression', 'Var', (0, 11))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('N', 'Chemical', 'MESH:D009584', (15, 16))	('restoring', 'PosReg', (79, 88))	('tumor', 'Disease', (154, 159))
73241	31658270	Thus, we suggest that indications whose cytolytic activity is particularly well explained by NMD, or patients with alterations in the NMD pathway that increase NMD efficiencies might be interesting indications to look for cell non-autonomous immune driven efficacy of future NMD inhibitors.	('patients', 'Species', '9606', (101, 109))	('N', 'Chemical', 'MESH:D009584', (160, 161))	('N', 'Chemical', 'MESH:D009584', (134, 135))	('alterations', 'Var', (115, 126))	('NMD pathway', 'Pathway', (134, 145))	('N', 'Chemical', 'MESH:D009584', (93, 94))	('N', 'Chemical', 'MESH:D009584', (275, 276))
73256	31658270	The efficiency was calculated at the gene-level, as the negative log base 2 transform of the ratio between the expression of the mutant-bearing transcript and the median mRNA expression of that transcript (calculated from samples with no mutations and copy number variations for that transcript).	('expression', 'MPA', (111, 121))	('mutant-bearing', 'Var', (129, 143))	('mRNA expression', 'MPA', (170, 185))	('N', 'Chemical', 'MESH:D009584', (172, 173))
73257	31658270	We accordingly derived NMD efficiencies for nonsense-, frameshift-, and nonsense/frameshift-bearing transcripts.	('nonsense/frameshift-bearing', 'Var', (72, 99))	('N', 'Chemical', 'MESH:D009584', (23, 24))	('frameshift-', 'Var', (55, 66))
73264	31658270	mutation, NMD burden, MSI, mutation + NMD burden, mutation + MSI, NMD burden + MSI).	('mutation +', 'Var', (27, 37))	('MSI', 'Disease', 'MESH:D053842', (61, 64))	('MSI', 'Disease', (61, 64))	('MSI', 'Disease', 'MESH:D053842', (79, 82))	('N', 'Chemical', 'MESH:D009584', (38, 39))	('MSI', 'Disease', (79, 82))	('N', 'Chemical', 'MESH:D009584', (10, 11))	('N', 'Chemical', 'MESH:D009584', (66, 67))	('MSI', 'Disease', 'MESH:D053842', (22, 25))	('MSI', 'Disease', (22, 25))
73270	31658270	Genetic alterations of NMD and their association with NMD efficiency metrics and cytolytic activity metrics were also examined, with the metrics calculated per methods described above.	('Genetic alterations', 'Var', (0, 19))	('N', 'Chemical', 'MESH:D009584', (23, 24))	('NMD', 'Gene', (23, 26))	('N', 'Chemical', 'MESH:D009584', (54, 55))	('cytolytic activity', 'MPA', (81, 99))
73289	31508508	In recent years, several successful attempts have improved classification of LUAD based on markers of overall disease aggressiveness, including mutations in oncogenes (EGFR, KRAS), proto-oncogenes (ERBB2, BRAF), and tumor suppressor genes (TP53, PTEN).	('TP53', 'Gene', '7157', (240, 244))	('EGFR', 'Gene', '1956', (168, 172))	('PTEN', 'Gene', '5728', (246, 250))	('mutations', 'Var', (144, 153))	('BRAF', 'Gene', '673', (205, 209))	('ERBB2', 'Gene', (198, 203))	('tumor', 'Disease', (216, 221))	('BRAF', 'Gene', (205, 209))	('tumor', 'Disease', 'MESH:D009369', (216, 221))	('ERBB2', 'Gene', '2064', (198, 203))	('TP53', 'Gene', (240, 244))	('EGFR', 'Gene', (168, 172))	('LUAD', 'Phenotype', 'HP:0030078', (77, 81))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('aggressiveness', 'Disease', (118, 132))	('KRAS', 'Gene', '3845', (174, 178))	('aggressiveness', 'Phenotype', 'HP:0000718', (118, 132))	('PTEN', 'Gene', (246, 250))	('aggressiveness', 'Disease', 'MESH:D001523', (118, 132))	('LUAD', 'Disease', (77, 81))	('KRAS', 'Gene', (174, 178))
73291	31508508	Recently, multiple transcriptomic and epigenomic alterations have been highlighted to play a role in primary and secondary chemoresistance across various cancer types.	('play', 'Reg', (86, 90))	('epigenomic alterations', 'Var', (38, 60))	('cancer', 'Disease', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('primary', 'CPA', (101, 108))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))
73292	31508508	For example, studies focused on transcriptomic alterations have demonstrated that: MDR1 amplification is implicated in acquired resistance to anthracyclines, vinca alkaloids, and other antineoplastic chemotherapies in breast cancer; over-expression of dihydrodiol dehydrogenase enzyme is central in resistance to cisplatin in ovarian cancer; and higher genomic instability due to p53 inactivation is essential in resistance to platinum-based chemotherapy in ovarian cancer.	('ovarian cancer', 'Disease', (458, 472))	('MDR1', 'Gene', (83, 87))	('ovarian cancer', 'Phenotype', 'HP:0100615', (458, 472))	('p53', 'Gene', '7157', (380, 383))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('ovarian cancer', 'Disease', 'MESH:D010051', (326, 340))	('anthracyclines', 'Chemical', 'MESH:D018943', (142, 156))	('over-expression', 'PosReg', (233, 248))	('cancer', 'Phenotype', 'HP:0002664', (334, 340))	('p53', 'Gene', (380, 383))	('breast cancer', 'Phenotype', 'HP:0003002', (218, 231))	('inactivation', 'Var', (384, 396))	('platinum', 'Chemical', 'MESH:D010984', (427, 435))	('ovarian cancer', 'Disease', (326, 340))	('cancer', 'Phenotype', 'HP:0002664', (466, 472))	('MDR1', 'Gene', '5243', (83, 87))	('breast cancer', 'Disease', 'MESH:D001943', (218, 231))	('ovarian cancer', 'Disease', 'MESH:D010051', (458, 472))	('ovarian cancer', 'Phenotype', 'HP:0100615', (326, 340))	('breast cancer', 'Disease', (218, 231))	('cisplatin', 'Chemical', 'MESH:D002945', (313, 322))	('alkaloids', 'Chemical', 'MESH:D000470', (164, 173))
73293	31508508	In parallel, epigenomic-centered studies have demonstrated that: genome-wide hypermethylation is implicated in resistance to antineoplastic fotemustine in melanoma; hypermethylation of DKK3 leads to docetaxel resistance in non-small cell lung cancer; and hypomethylation of MIR663A induce cyclophosphamide and docetaxel resistance in breast cancer.	('melanoma', 'Disease', 'MESH:D008545', (155, 163))	('cancer', 'Phenotype', 'HP:0002664', (243, 249))	('MIR663A', 'Gene', (274, 281))	('MIR663A', 'Gene', '724033', (274, 281))	('breast cancer', 'Disease', 'MESH:D001943', (334, 347))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (223, 249))	('breast cancer', 'Disease', (334, 347))	('docetaxel', 'Chemical', 'MESH:D000077143', (199, 208))	('cancer', 'Phenotype', 'HP:0002664', (341, 347))	('docetaxel', 'Chemical', 'MESH:D000077143', (310, 319))	('leads to', 'Reg', (190, 198))	('lung cancer', 'Phenotype', 'HP:0100526', (238, 249))	('non-small cell lung cancer', 'Disease', (223, 249))	('melanoma', 'Phenotype', 'HP:0002861', (155, 163))	('melanoma', 'Disease', (155, 163))	('hypermethylation', 'Var', (165, 181))	('breast cancer', 'Phenotype', 'HP:0003002', (334, 347))	('cyclophosphamide', 'Chemical', 'MESH:D003520', (289, 305))	('hypomethylation', 'Var', (255, 270))	('DKK3', 'Gene', (185, 189))	('docetaxel resistance', 'MPA', (199, 219))	('docetaxel resistance', 'MPA', (310, 330))	('DKK3', 'Gene', '27122', (185, 189))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (223, 249))	('induce', 'PosReg', (282, 288))	('fotemustine', 'Chemical', 'MESH:C054368', (140, 151))	('cyclophosphamide', 'MPA', (289, 305))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (227, 249))
73386	31508508	Thus, primary (i.e., before therapy administration) dysregulation in these pathways might affect drug mechanism of action and can be utilized to identify patients at risk of resistance.	('affect', 'Reg', (90, 96))	('dysregulation', 'Var', (52, 65))	('drug mechanism of action', 'MPA', (97, 121))	('patients', 'Species', '9606', (154, 162))
73456	29722145	Higher levels of chemokines MCP1/CCL2 (21.11-fold increase) and MIP-1beta/CCL4 (19.33-fold increase) were identified in LUAD than in LUSC.	('MIP-1beta/CCL4', 'Var', (64, 78))	('increase', 'PosReg', (50, 58))	('MCP1', 'Gene', (28, 32))	('LUSC', 'Phenotype', 'HP:0030359', (133, 137))	('MCP1', 'Gene', '6347', (28, 32))	('LUAD', 'Phenotype', 'HP:0030078', (120, 124))
73470	29722145	Moreover, high expression of CCL2 or CCL4 is associated with unfavorable overall survival (OS) and progression-free survival (PFS) in patients with LUAD.	('progression-free survival', 'CPA', (99, 124))	('overall', 'MPA', (73, 80))	('LUAD', 'Disease', (148, 152))	('patients', 'Species', '9606', (134, 142))	('LUAD', 'Phenotype', 'HP:0030078', (148, 152))	('CCL4', 'Gene', (37, 41))	('high', 'Var', (10, 14))	('CCL2', 'Gene', (29, 33))
73502	29722145	Signal intensity analysis showed overexpression of chemokines MCP1/CCL2 (21.11-fold increase) and MIP-1beta/CCL4 (19.33-fold increase) in LUAD compared to LUSC (Fig 2c, Table 1).	('overexpression', 'PosReg', (33, 47))	('MIP-1beta/CCL4', 'Var', (98, 112))	('LUSC', 'Phenotype', 'HP:0030359', (155, 159))	('LUAD', 'Phenotype', 'HP:0030078', (138, 142))	('MCP1', 'Gene', '6347', (62, 66))	('increase', 'PosReg', (84, 92))	('MCP1', 'Gene', (62, 66))
73503	29722145	Low expression of I-309/CCL2 (0.21-fold decrease), IP-10/CCL10 (0.20-fold decrease), and MIP-1delta/CCL15 (0.20-fold decrease) in LUAD compared to LUSC were also observed (Table 1).	('CCL15', 'Gene', '6359', (100, 105))	('decrease', 'NegReg', (40, 48))	('decrease', 'NegReg', (74, 82))	('IP-10', 'Gene', '3627', (51, 56))	('CCL15', 'Gene', (100, 105))	('LUSC', 'Phenotype', 'HP:0030359', (147, 151))	('IP-10', 'Gene', (51, 56))	('MIP-1delta', 'Gene', '6359', (89, 99))	('I-309/CCL2', 'Var', (18, 28))	('MIP-1delta', 'Gene', (89, 99))	('LUAD', 'Phenotype', 'HP:0030078', (130, 134))
73512	29722145	However, in LUAD patients, high levels of CCL2 predicted unfavorable OS (P = 6.8e-08) and PFS (P = 0.00098) (Fig 4c,d).	('CCL2', 'Gene', (42, 46))	('high', 'Var', (27, 31))	('PFS', 'MPA', (90, 93))	('patients', 'Species', '9606', (17, 25))	('LUAD', 'Phenotype', 'HP:0030078', (12, 16))	('unfavorable OS', 'MPA', (57, 71))
73534	29722145	Based on data from the TCGA database, we found that high CCL2 or CCL4 expression was significantly associated with survival in LUSC patients but predicted poor outcomes in LUAD patients.	('CCL2', 'Gene', (57, 61))	('CCL4', 'Gene', (65, 69))	('associated with', 'Reg', (99, 114))	('LUAD', 'Phenotype', 'HP:0030078', (172, 176))	('patients', 'Species', '9606', (177, 185))	('expression', 'MPA', (70, 80))	('high', 'Var', (52, 56))	('LUSC', 'Phenotype', 'HP:0030359', (127, 131))	('patients', 'Species', '9606', (132, 140))
73641	32708311	In the study on oral precancerous lesion, subepithelial CD163-positive cell count was the only significant risk factor for high-grade dysplasia.	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('subepithelial', 'Var', (42, 55))	('dysplasia', 'Disease', 'MESH:C536170', (134, 143))	('CD163', 'Gene', '9332', (56, 61))	('dysplasia', 'Disease', (134, 143))	('CD163', 'Gene', (56, 61))	('precancerous lesion', 'Disease', (21, 40))	('precancerous lesion', 'Disease', 'MESH:D011230', (21, 40))
73643	32708311	For atypical adenomatous hyperplasia, which is the pre-invasive counterpart of bronchial dysplasia for lung adenocarcinoma, it has recently been shown that tumors positive for both PD-L1 and CD8 had a larger proportion of subclonal mutations.	('bronchial dysplasia', 'Disease', (79, 98))	('CD8', 'Gene', '925', (191, 194))	('adenomatous hyperplasia', 'Disease', (13, 36))	('subclonal mutations', 'Var', (222, 241))	('lung adenocarcinoma', 'Disease', (103, 122))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (103, 122))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('PD-L1', 'Gene', (181, 186))	('adenomatous hyperplasia', 'Disease', 'MESH:D011125', (13, 36))	('tumors', 'Disease', 'MESH:D009369', (156, 162))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('bronchial dysplasia', 'Disease', 'MESH:D001982', (79, 98))	('CD8', 'Gene', (191, 194))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (103, 122))	('PD-L1', 'Gene', '29126', (181, 186))	('tumors', 'Disease', (156, 162))
73657	30596096	MiR-20a is a typical and extensively investigated example of miRNAs originating from the miR-17~92 cluster, which is located at chromosomal locus 13q31.3 and able to encode five other mature miRNAs including miR-17, miR-18a, miR-19a/b, and miR-92a.	('miR-92a', 'Var', (240, 247))	('miR-18a', 'Gene', (216, 223))	('miR-19a', 'Gene', '406979', (225, 232))	('miR-17', 'Gene', '406952', (89, 95))	('MiR-20a', 'Gene', '406982', (0, 7))	('encode', 'Reg', (166, 172))	('miR-17', 'Gene', (208, 214))	('MiR-20a', 'Gene', (0, 7))	('miR-17~92', 'Gene', '407975', (89, 98))	('miR-18a', 'Gene', '406953', (216, 223))	('miR-17~92', 'Gene', (89, 98))	('miR-19a', 'Gene', (225, 232))	('miR-17', 'Gene', '406952', (208, 214))	('miR-17', 'Gene', (89, 95))
73658	30596096	proposed that a six-miRNA plasma panel comprising miR-20a, miR-145, miR-24, miR-152, miR-25, and miR-199a was able to discriminate non-small-cell lung cancer (NSCLC) from chronic obstructive pulmonary disease (COPD) and indicate recurrence in resectable NSCLC.	('NSCLC', 'Disease', (254, 259))	('miR-25', 'Gene', '407014', (85, 91))	('miR-24', 'Var', (68, 74))	('NSCLC', 'Disease', (159, 164))	('obstructive pulmonary disease', 'Phenotype', 'HP:0006536', (179, 208))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (135, 157))	('NSCLC', 'Phenotype', 'HP:0030358', (254, 259))	('lung cancer', 'Phenotype', 'HP:0100526', (146, 157))	('NSCLC', 'Phenotype', 'HP:0030358', (159, 164))	('COPD', 'Phenotype', 'HP:0006510', (210, 214))	('COPD', 'Disease', 'MESH:D029424', (210, 214))	('COPD', 'Disease', (210, 214))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (131, 157))	('miR-20a', 'Var', (50, 57))	('miR-145', 'Gene', '406937', (59, 66))	('chronic obstructive pulmonary disease', 'Phenotype', 'HP:0006510', (171, 208))	('chronic obstructive pulmonary disease', 'Disease', 'MESH:D029424', (171, 208))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('miR-25', 'Gene', (85, 91))	('miR-145', 'Gene', (59, 66))	('miR-152', 'Gene', (76, 83))	('chronic obstructive pulmonary disease', 'Disease', (171, 208))	('NSCLC', 'Disease', 'MESH:D002289', (254, 259))	('discriminate', 'Reg', (118, 130))	('non-small-cell lung cancer', 'Disease', (131, 157))	('NSCLC', 'Disease', 'MESH:D002289', (159, 164))	('miR-152', 'Gene', '406943', (76, 83))
73666	30596096	Among those tumors, high expression of circulating miR-20a was significantly associated with unfavorable OS of cancer patients (HR = 1.71, 95% CIs: 1.43 -2.04, p < 0.01; p for heterogeneity = 0.395, I-square = 3.3%) (see Figure 2 and Table 3).	('OS of cancer', 'Disease', 'MESH:C567932', (105, 117))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('miR-20a', 'Gene', (51, 58))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('high', 'Var', (20, 24))	('OS of cancer', 'Disease', (105, 117))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('associated', 'Reg', (77, 87))
73668	30596096	MiRNA dysregulations in human cancer are mainly due to genomic changes including amplification, mutation, deletion, and disturbance of miRNA biogenesis enzymes, namely, Drosha, exportin 5, Dicer, and argonaute 2 (ARO2), and effects of these changes show cell/organ specificity.	('ARO2', 'Gene', '27161', (213, 217))	('exportin 5', 'Gene', (177, 187))	('disturbance', 'Reg', (120, 131))	('argonaute 2', 'Gene', '27161', (200, 211))	('argonaute 2', 'Gene', (200, 211))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('exportin 5', 'Gene', '57510', (177, 187))	('miRNA biogenesis enzymes', 'Gene', (135, 159))	('mutation', 'Var', (96, 104))	('amplification', 'Var', (81, 94))	('deletion', 'Var', (106, 114))	('Drosha', 'Gene', '29102', (169, 175))	('Dicer', 'Gene', '23405', (189, 194))	('ARO2', 'Gene', (213, 217))	('Dicer', 'Gene', (189, 194))	('Drosha', 'Gene', (169, 175))
73673	30596096	Circulating miR-20a could enhance tumor cell proliferation, migration, and invasion by targeting various pathways; for example, Du and his colleagues revealed that upregulated circulating miR-20a might suppress inhibitor beta of nuclear factor- (NF-) kappa B and therefore enhance activity of NF-kappa B pathway and downstream molecules such as livin and survivin.	('survivin', 'Pathway', (355, 363))	('beta of nuclear factor- (NF-) kappa B', 'Gene', '4790', (221, 258))	('enhance', 'PosReg', (273, 280))	('NF-kappa B', 'Gene', '4790', (293, 303))	('miR-20a', 'Gene', (188, 195))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('invasion', 'CPA', (75, 83))	('upregulated', 'PosReg', (164, 175))	('NF-kappa B', 'Gene', (293, 303))	('livin', 'Gene', (345, 350))	('circulating', 'Var', (176, 187))	('livin', 'Gene', '79444', (345, 350))	('tumor cell proliferation', 'CPA', (34, 58))	('activity', 'MPA', (281, 289))	('suppress', 'NegReg', (202, 210))	('enhance', 'PosReg', (26, 33))
73677	30596096	Second, some miRNAs (miR-17, miR-18a, miR-18b, miR-20b, miR-93, miR-106a, and miR-106b) are structurally homologous or expression/function-related to miR-20a; polycistronic structures of these miRNAs may allow for reciprocal interactions.	('miR-106a', 'Gene', '406899', (64, 72))	('miR-106b', 'Gene', (78, 86))	('miR-18a', 'Var', (29, 36))	('miR-93', 'Gene', '407051', (56, 62))	('miR-20b', 'Gene', '574032', (47, 54))	('miR-106a', 'Gene', (64, 72))	('miR-106b', 'Gene', '406900', (78, 86))	('miR-93', 'Gene', (56, 62))	('miR-18b', 'Gene', (38, 45))	('miR-17', 'Var', (21, 27))	('interactions', 'Interaction', (225, 237))	('miR-18b', 'Gene', '574033', (38, 45))	('miR-20b', 'Gene', (47, 54))
73712	31561282	The majority of tumours were of glottic origin, had a T2 status, did not have lymph node metastasis and were moderately differentiated.	('T2 status', 'Var', (54, 63))	('tumours', 'Disease', 'MESH:D009369', (16, 23))	('tumours', 'Disease', (16, 23))	('tumour', 'Phenotype', 'HP:0002664', (16, 22))	('tumours', 'Phenotype', 'HP:0002664', (16, 23))
73717	31561282	A significant negative association between LC and poor tumour differentiation (HR 2.18; 95% CI 1.06-4.50, P = .04), alcohol use (HR 2.94, 95% CI 1.24-6.95; P = .01) and tobacco use (HR 7.59; 95% CI 1.05-55.02, P = .045) was found.	('tumour', 'Disease', (55, 61))	('alcohol', 'Var', (116, 123))	('negative', 'NegReg', (14, 22))	('tumour', 'Phenotype', 'HP:0002664', (55, 61))	('tumour', 'Disease', 'MESH:D009369', (55, 61))	('tobacco', 'Species', '4097', (169, 176))	('alcohol', 'Chemical', 'MESH:D000431', (116, 123))	('alcohol use', 'Phenotype', 'HP:0030955', (116, 127))
73719	31561282	No associations between high Ki-67 PI and LC (HR 1.59; 95% CI 0.89-2.81; P = .11) or KI67 PI as a continuous variable and LC (HR 2.03; 95% CI 0.37-11.14; P = .42) were found (Figure S1A, Table 4).	('high Ki-67', 'Var', (24, 34))	('KI67', 'Var', (85, 89))	('KI67', 'Chemical', 'MESH:C017966', (85, 89))
73721	31561282	No associations were found between Ki-67 PI and DSS (HR 0.98; 95% CI 0.57-1.66; P = .97) or KI67 PI as a continuous variable and DSS (HR 0.62; 95% CI 0.05-8.28; P = .72) (Figure S1B, Table 5).	('DSS', 'Disease', (129, 132))	('KI67', 'Var', (92, 96))	('DSS', 'Disease', (48, 51))	('Ki-67 PI', 'Var', (35, 43))	('KI67', 'Chemical', 'MESH:C017966', (92, 96))
73729	31561282	Rademakers et al who also used DIA on whole tumour section slides do not explicitly state they adjusted scoring for non-neoplastic regions; which could have led to a lower ratio of Ki-67 positive cells.13 Also, intratumour heterogeneity may lead to lower Ki-67 PI if the incorrect region within the tumour is counted.	('Ki-67 PI', 'MPA', (255, 263))	('lower', 'NegReg', (249, 254))	('tumour', 'Disease', 'MESH:D009369', (299, 305))	('tumour', 'Disease', 'MESH:D009369', (44, 50))	('tumour', 'Phenotype', 'HP:0002664', (216, 222))	('tumour', 'Disease', (44, 50))	('tumour', 'Phenotype', 'HP:0002664', (299, 305))	('tumour', 'Phenotype', 'HP:0002664', (44, 50))	('heterogeneity', 'Var', (223, 236))	('tumour', 'Disease', 'MESH:D009369', (216, 222))	('tumour', 'Disease', (216, 222))	('tumour', 'Disease', (299, 305))
73741	30906652	Additionally, anti-sense miR-183 transfection into H1355 or H1299 tumor cells caused the upregulation of MICA/B.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('transfection', 'Var', (33, 45))	('anti-sense', 'Var', (14, 24))	('H1299 tumor', 'Disease', (60, 71))	('B', 'Chemical', 'MESH:D001895', (110, 111))	('H1355', 'CellLine', 'CVCL:1464', (51, 56))	('MICA', 'Gene', (105, 109))	('miR-183', 'Gene', '406959', (25, 32))	('MICA', 'Gene', '100507436', (105, 109))	('upregulation', 'PosReg', (89, 101))	('H1299 tumor', 'Disease', 'MESH:D009369', (60, 71))	('miR-183', 'Gene', (25, 32))
73743	30906652	Most significantly, anti-sense miR-183 transfected tumor cells became more sensitive to lysis by activated CD8+ T cells that express high levels of NKG2D.	('NKG2D', 'Gene', '22914', (148, 153))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('miR-183', 'Gene', '406959', (31, 38))	('tumor', 'Disease', (51, 56))	('NKG2D', 'Gene', (148, 153))	('sensitive to lysis', 'MPA', (75, 93))	('more', 'PosReg', (70, 74))	('CD8', 'Gene', (107, 110))	('anti-sense', 'Var', (20, 30))	('miR-183', 'Gene', (31, 38))	('CD8', 'Gene', '925', (107, 110))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
73769	30906652	In analysis of MICA/B expression in human non-small cell lung carcinoma (NSCLC) cell lines, we found low or absent levels of expression on H1155, H1355, H2170, H1299, A549 and Wi-38.	('MICA', 'Gene', (15, 19))	('H1355', 'CellLine', 'CVCL:1464', (146, 151))	('H1299', 'CellLine', 'CVCL:0060', (160, 165))	('cell lung carcinoma', 'Disease', (52, 71))	('NSCLC', 'Disease', (73, 78))	('B', 'Chemical', 'MESH:D001895', (20, 21))	('NSCLC', 'Phenotype', 'HP:0030358', (73, 78))	('A549', 'CellLine', 'CVCL:0023', (167, 171))	('cell lung carcinoma', 'Disease', 'MESH:D055752', (52, 71))	('H1299', 'Var', (160, 165))	('absent', 'NegReg', (108, 114))	('H1355', 'Var', (146, 151))	('small cell lung carcinoma', 'Phenotype', 'HP:0030357', (46, 71))	('H1155', 'Var', (139, 144))	('carcinoma', 'Phenotype', 'HP:0030731', (62, 71))	('H2170', 'Var', (153, 158))	('non-small cell lung carcinoma', 'Phenotype', 'HP:0030358', (42, 71))	('H2170', 'CellLine', 'CVCL:1535', (153, 158))	('MICA', 'Gene', '100507436', (15, 19))	('NSCLC', 'Disease', 'MESH:D002289', (73, 78))	('human', 'Species', '9606', (36, 41))
73794	30906652	We also mutated the 6-8 nucleotide seed sequence in the 3'UTR of MICA complementary to miR183, which is required for effective transcriptional repression (Figure 3(a)).	('MICA', 'Gene', (65, 69))	('MICA', 'Gene', '100507436', (65, 69))	('mutated', 'Var', (8, 15))	('miR183', 'Gene', (87, 93))	('miR183', 'Gene', '406959', (87, 93))
73795	30906652	Co-transduction of 293 cells with MICA-WT and miR-183 markedly reduced luciferase expression, as compared to MICA-WT together with scrambled control transduction, while mutant MICA-MUT, when co-expressed with miR183, resisted luciferase repression, suggesting that miR183 binding is critical for MICA gene regulation (Figure 3(b)).	('MICA', 'Gene', (296, 300))	('MICA', 'Gene', '100507436', (296, 300))	('MICA', 'Gene', '100507436', (34, 38))	('MICA', 'Gene', (176, 180))	('reduced', 'NegReg', (63, 70))	('luciferase', 'Enzyme', (71, 81))	('miR-183', 'Gene', (46, 53))	('miR183', 'Gene', (265, 271))	('expression', 'MPA', (82, 92))	('MICA', 'Gene', (109, 113))	('MICA', 'Gene', '100507436', (176, 180))	('miR-183', 'Gene', '406959', (46, 53))	('MICA', 'Gene', '100507436', (109, 113))	('miR183', 'Gene', '406959', (209, 215))	('mutant', 'Var', (169, 175))	('miR183', 'Gene', '406959', (265, 271))	('MICA', 'Gene', (34, 38))	('miR183', 'Gene', (209, 215))
73799	30906652	To accomplish this, we transfected antisense miR183 into H1355 lung tumor cells to analyze if loss of miR183 expression could increase MICA/B levels on the transfected tumor cells.	('miR183', 'Gene', '406959', (102, 108))	('MICA', 'Gene', (135, 139))	('miR183', 'Gene', '406959', (45, 51))	('B', 'Chemical', 'MESH:D001895', (140, 141))	('increase', 'PosReg', (126, 134))	('miR183', 'Gene', (102, 108))	('tumor', 'Disease', (68, 73))	('miR183', 'Gene', (45, 51))	('loss', 'Var', (94, 98))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('lung tumor', 'Disease', (63, 73))	('H1355', 'CellLine', 'CVCL:1464', (57, 62))	('tumor', 'Disease', (168, 173))	('lung tumor', 'Phenotype', 'HP:0100526', (63, 73))	('MICA', 'Gene', '100507436', (135, 139))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('lung tumor', 'Disease', 'MESH:D008175', (63, 73))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
73800	30906652	We first confirmed that antisense miR-183 transfection was successful in suppressing miR-183 expression by qPCR analysis (Figure 3(c)).	('miR-183', 'Gene', '406959', (85, 92))	('miR-183', 'Gene', (85, 92))	('antisense', 'Var', (24, 33))	('expression', 'MPA', (93, 103))	('suppressing', 'NegReg', (73, 84))	('miR-183', 'Gene', '406959', (34, 41))	('miR-183', 'Gene', (34, 41))
73805	30906652	Thus, blockade of miR-183 expression was sufficient to enhance MICA/B expression in lung tumor cells.	('miR-183', 'Gene', '406959', (18, 25))	('MICA', 'Gene', (63, 67))	('miR-183', 'Gene', (18, 25))	('lung tumor', 'Disease', (84, 94))	('MICA', 'Gene', '100507436', (63, 67))	('lung tumor', 'Disease', 'MESH:D008175', (84, 94))	('enhance', 'PosReg', (55, 62))	('blockade', 'Var', (6, 14))	('lung tumor', 'Phenotype', 'HP:0100526', (84, 94))	('B', 'Chemical', 'MESH:D001895', (68, 69))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))
73815	30906652	We first confirmed that TGFbeta mRNA was effectively knocked down by shRNA TGFbeta transfection, as compared to the scramble control (Figure 4(a)).	('TGFbeta', 'Gene', '7040', (24, 31))	('mRNA', 'MPA', (32, 36))	('knocked down', 'NegReg', (53, 65))	('TGFbeta', 'Gene', '7040', (75, 82))	('transfection', 'Var', (83, 95))	('TGFbeta', 'Gene', (24, 31))	('TGFbeta', 'Gene', (75, 82))
73817	30906652	In contrast, TGFbeta depletion led to increased MICA/B expression, with MFI rising from 659 in scramble control-shRNA transfected cells to 1077 in the shRNA TGFbeta-transfected cells (Figure (4c,d)).	('MICA', 'Gene', (48, 52))	('MICA', 'Gene', '100507436', (48, 52))	('TGFbeta', 'Gene', (13, 20))	('expression', 'MPA', (55, 65))	('TGFbeta', 'Gene', (157, 164))	('B', 'Chemical', 'MESH:D001895', (53, 54))	('depletion', 'Var', (21, 30))	('TGFbeta', 'Gene', '7040', (13, 20))	('TGFbeta', 'Gene', '7040', (157, 164))	('increased', 'PosReg', (38, 47))
73819	30906652	Depletion of TGFbeta with specific shRNA (Figure 4(e)) also caused significant depletion of miR-183 in H1299 cells (Figure 4(f)), accompanied by an upregulation of MICA/B (Figure 4(g,h)).	('H1299', 'CellLine', 'CVCL:0060', (103, 108))	('MICA', 'Gene', '100507436', (164, 168))	('upregulation', 'PosReg', (148, 160))	('B', 'Chemical', 'MESH:D001895', (169, 170))	('TGFbeta', 'Gene', (13, 20))	('miR-183', 'Gene', (92, 99))	('Depletion', 'Var', (0, 9))	('miR-183', 'Gene', '406959', (92, 99))	('TGFbeta', 'Gene', '7040', (13, 20))	('depletion', 'MPA', (79, 88))	('MICA', 'Gene', (164, 168))
73820	30906652	Since lentiviral transfection can induce a type I interferon response, we utilized a pan-Type I Interferon neutralizing antibody to ensure that our observed biologic effects were due to the silencing of TGFbeta, and not to secondary viral transfection effects or type I interferon itself.	('lentiviral', 'Var', (6, 16))	('silencing', 'NegReg', (190, 199))	('transfection', 'Var', (17, 29))	('TGFbeta', 'Gene', (203, 210))	('TGFbeta', 'Gene', '7040', (203, 210))
73821	30906652	The results were consistent with that of the original experiment, where the loss of TGFB led to increased MICA/B expression by flow cytometry the H1299 cell line(Fig.	('increased', 'PosReg', (96, 105))	('H1299', 'CellLine', 'CVCL:0060', (146, 151))	('B', 'Chemical', 'MESH:D001895', (111, 112))	('loss', 'Var', (76, 80))	('TGFB', 'Gene', '7040', (84, 88))	('MICA', 'Gene', '100507436', (106, 110))	('MICA', 'Gene', (106, 110))	('TGFB', 'Gene', (84, 88))	('B', 'Chemical', 'MESH:D001895', (87, 88))
73834	30906652	These tumor cells are Class I competent, however the T cell receptor on CD8+ T cells is not involved because H1355 tumor cells are allogeneic to the T effector cells and have no matching MHC-Class I.	('H1355', 'Var', (109, 114))	('H1355', 'CellLine', 'CVCL:1464', (109, 114))	('MHC', 'Gene', (187, 190))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumor', 'Disease', (115, 120))	('tumor', 'Disease', 'MESH:D009369', (6, 11))	('MHC', 'Gene', '3107', (187, 190))	('CD8', 'Gene', (72, 75))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('tumor', 'Disease', (6, 11))	('CD8', 'Gene', '925', (72, 75))
73835	30906652	We next transfected antisense miR-183 into H1355 tumor cells and tested their susceptibility to lysis by CD8+ T cells.	('CD8', 'Gene', (105, 108))	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('CD8', 'Gene', '925', (105, 108))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('miR-183', 'Gene', '406959', (30, 37))	('miR-183', 'Gene', (30, 37))	('tumor', 'Disease', (49, 54))	('antisense', 'Var', (20, 29))	('H1355', 'CellLine', 'CVCL:1464', (43, 48))	('tested', 'Reg', (65, 71))
73836	30906652	In 2 separate normal donors, we found that CD8+ T cells had markedly increased tumoricidal activity against H1355 mir-183 transfected tumor cells, as compared to scramble control (Figure 5(d,e)).	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('increased', 'PosReg', (69, 78))	('tumor', 'Disease', (79, 84))	('CD8', 'Gene', (43, 46))	('CD8', 'Gene', '925', (43, 46))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('H1355', 'Var', (108, 113))	('mir-183', 'Gene', (114, 121))	('H1355', 'CellLine', 'CVCL:1464', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('mir-183', 'Gene', '406959', (114, 121))	('tumor', 'Disease', (134, 139))
73840	30906652	Taken together, these results indicate that miR-183 suppression, either by means of silencing mir-183 or overexpressing MICA/B in tumor cells sensitizes them to be better recognized by T cells via the NKG2D-MICA/B pathway.	('B', 'Chemical', 'MESH:D001895', (125, 126))	('MICA', 'Gene', (207, 211))	('miR-183', 'Gene', '406959', (44, 51))	('mir-183', 'Gene', (94, 101))	('suppression', 'NegReg', (52, 63))	('miR-183', 'Gene', (44, 51))	('NKG2D', 'Gene', (201, 206))	('silencing', 'Var', (84, 93))	('MICA', 'Gene', '100507436', (207, 211))	('NKG2D', 'Gene', '22914', (201, 206))	('mir-183', 'Gene', '406959', (94, 101))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('MICA', 'Gene', (120, 124))	('tumor', 'Disease', (130, 135))	('MICA', 'Gene', '100507436', (120, 124))	('B', 'Chemical', 'MESH:D001895', (212, 213))
73846	30906652	Sequence-specific mutation of the binding site on MICA and MICB further corroborated the requirement of miR-183 in regulating MICA/B in these reporter constructs.	('miR-183', 'Gene', '406959', (104, 111))	('B', 'Chemical', 'MESH:D001895', (131, 132))	('MICA', 'Gene', (50, 54))	('MICB', 'Gene', (59, 63))	('MICA', 'Gene', '100507436', (50, 54))	('MICB', 'Gene', '4277', (59, 63))	('mutation', 'Var', (18, 26))	('MICA', 'Gene', (126, 130))	('miR-183', 'Gene', (104, 111))	('MICA', 'Gene', '100507436', (126, 130))	('B', 'Chemical', 'MESH:D001895', (62, 63))
73851	30906652	We also provide evidence of the role of TGFbeta in initiating the process, by demonstrating that anti-sense TGFbeta transfection into human lung tumor cells can downregulate miR-183 expression, with corresponding increase in MICA/B expression.	('TGFbeta', 'Gene', (40, 47))	('MICA', 'Gene', '100507436', (225, 229))	('lung tumor', 'Disease', 'MESH:D008175', (140, 150))	('TGFbeta', 'Gene', '7040', (40, 47))	('expression', 'MPA', (232, 242))	('increase', 'PosReg', (213, 221))	('miR-183', 'Gene', '406959', (174, 181))	('TGFbeta', 'Gene', (108, 115))	('human', 'Species', '9606', (134, 139))	('TGFbeta', 'Gene', '7040', (108, 115))	('expression', 'MPA', (182, 192))	('transfection', 'Var', (116, 128))	('MICA', 'Gene', (225, 229))	('miR-183', 'Gene', (174, 181))	('downregulate', 'NegReg', (161, 173))	('lung tumor', 'Disease', (140, 150))	('lung tumor', 'Phenotype', 'HP:0100526', (140, 150))	('B', 'Chemical', 'MESH:D001895', (230, 231))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('anti-sense', 'Var', (97, 107))
73852	30906652	Earlier studies have reported that MICA can be controlled by several other miRs, namely miR-10, miR-20, miR-93, miR-106, miR-373, miR-520.	('miR-373', 'Gene', (121, 128))	('MICA', 'Gene', (35, 39))	('miR-93', 'Gene', '407051', (104, 110))	('MICA', 'Gene', '100507436', (35, 39))	('miR-93', 'Gene', (104, 110))	('miR-10', 'Gene', '10288', (88, 94))	('miR-520', 'Var', (130, 137))	('miR-106', 'Gene', (112, 119))	('miR-106', 'Gene', '406899', (112, 119))	('miR-10', 'Gene', '10288', (112, 118))	('miR-520', 'Chemical', '-', (130, 137))	('miR-20', 'Gene', (96, 102))	('miR-20', 'Gene', '406982', (96, 102))	('miR-10', 'Gene', (88, 94))	('miR-373', 'Gene', '442918', (121, 128))	('miR-10', 'Gene', (112, 118))
73870	30906652	In this case, the ligation of TGFbeta transcriptionally induces miR-183 in NK cells, and it is this NK-associated miR-183 that specifically represses DAP12, a vital adaptor protein, required to anchor numerous NK activating receptors on the cell surface, including activatory Killer Immune Receptors (KIRs), NKp44, NKG2C, and NKG2E.	('miR-183', 'Gene', '406959', (114, 121))	('TGFbeta', 'Gene', (30, 37))	('miR-183', 'Gene', (114, 121))	('NKG2C', 'Gene', (315, 320))	('miR-183', 'Gene', (64, 71))	('DAP12', 'Gene', '7305', (150, 155))	('DAP12', 'Gene', (150, 155))	('miR-183', 'Gene', '406959', (64, 71))	('induces', 'Reg', (56, 63))	('NKG2E', 'Gene', (326, 331))	('NKG2E', 'Gene', '3823', (326, 331))	('TGFbeta', 'Gene', '7040', (30, 37))	('NKp44', 'Gene', '9436', (308, 313))	('ligation', 'Var', (18, 26))	('NKG2C', 'Gene', '3822', (315, 320))	('represses', 'NegReg', (140, 149))	('NKp44', 'Gene', (308, 313))
73887	30906652	Whether this TGFbeta/miR-183 network is operative in other tumor types has not yet been explored but it seems possible that it is a common strategy of most tumor cells, given the abundance of reports on TGFbeta and miR-183 co-expression in breast, colorectal, hepatic, pancreatic and prostate cancer.	('tumor', 'Disease', (59, 64))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Disease', (156, 161))	('colorectal', 'Disease', (248, 258))	('hepatic', 'Disease', (260, 267))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('TGFbeta', 'Gene', (13, 20))	('miR-183', 'Gene', '406959', (215, 222))	('TGFbeta', 'Gene', '7040', (13, 20))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('miR-183', 'Gene', (215, 222))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('miR-183', 'Gene', '406959', (21, 28))	('cancer', 'Phenotype', 'HP:0002664', (293, 299))	('TGFbeta', 'Gene', (203, 210))	('prostate cancer', 'Phenotype', 'HP:0012125', (284, 299))	('TGFbeta', 'Gene', '7040', (203, 210))	('pancreatic and prostate cancer', 'Disease', 'MESH:D010190', (269, 299))	('breast', 'Disease', (240, 246))	('co-expression', 'Var', (223, 236))	('miR-183', 'Gene', (21, 28))
73889	30906652	HBE4 human lung epithelial cells transformed with E6/E7 of the Epstein-Barr virus (American Type Culture Collection) were maintained in 10% (vol/vol) FBS Keratinocyte SFM supplemented with cholera toxin (CTX 10 ng/mL), bovine pituitary extract (50 ng/ml), and epidermal growth factor (5 ng/ml).	('FBS', 'Disease', 'MESH:D005198', (150, 153))	('bovine', 'Species', '9913', (219, 225))	('B', 'Chemical', 'MESH:D001895', (1, 2))	('B', 'Chemical', 'MESH:D001895', (71, 72))	('human', 'Species', '9606', (5, 10))	('FBS', 'Disease', (150, 153))	('E6/E7', 'Var', (50, 55))	('HBE4', 'CellLine', 'CVCL:0287', (0, 4))	('B', 'Chemical', 'MESH:D001895', (151, 152))
73894	30906652	Cells were then incubated overnight at 37oC in culture media supplemented with 10% FBS RPMI (Thermo Fisher Scientific), 1% NEAA (Corning), 1% Sodium Pyruvate (NaPyr) (Corning), 1% Pen/Strep, 1% L-glutamine (Thermo Fisher Scientific), MycoZap-PR reagent (Lonza), and IFNgamma (1000 units/ml), followed by activation with anti-CD3/anti-CD28 and expansion in recombinant human IL-2 (100 U/mL) for 6 days.	('IL-2', 'Gene', '3558', (374, 378))	('IL-2', 'Gene', (374, 378))	('Pen', 'Gene', (180, 183))	('human', 'Species', '9606', (368, 373))	('MycoZap-PR reagent (Lonza), and IFNgamma', 'Gene', '3458', (234, 274))	('FBS RPMI', 'Disease', 'MESH:D005198', (83, 91))	('Pen', 'Gene', '27344', (180, 183))	('expansion', 'Var', (343, 352))	('CD28', 'Gene', (334, 338))	('NEAA', 'Chemical', '-', (123, 127))	('CD28', 'Gene', '940', (334, 338))	('FBS RPMI', 'Disease', (83, 91))	('L-glutamine', 'Chemical', 'MESH:D005973', (194, 205))
73908	30906652	Analysis of the MICA (NM_000247) and MICB (NM_005931) 3'UTR was performed using the publically available algorithm miRANDA (microRNA.org) or TargetScan.	('NM_005931', 'Var', (43, 52))	('MICB', 'Gene', (37, 41))	('MICA', 'Gene', (16, 20))	('NM_000247', 'Var', (22, 31))	('MICA', 'Gene', '100507436', (16, 20))	('MICB', 'Gene', '4277', (37, 41))
73921	30906652	designed research; T.L., W.K., S.S.D., N.T., M.M.T., D.L.G., A.B., and W.A.	('S.S.D.', 'Var', (31, 37))	('D.L.G.', 'Var', (53, 59))	('M.M.T.', 'Var', (45, 51))	('B', 'Chemical', 'MESH:D001895', (63, 64))
74009	27056074	Cervical cancer is the fourth most common cancer among women worldwide and is induced by a persistent infection with one of the high-risk strains of the human papilloma virus (HPV), most frequently HPV16 and/or HPV18.	('cancer', 'Disease', (9, 15))	('papilloma', 'Phenotype', 'HP:0012740', (159, 168))	('HPV18', 'Var', (211, 216))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('HPV', 'Species', '10566', (211, 214))	('persistent infection', 'Phenotype', 'HP:0031035', (91, 111))	('human papilloma virus', 'Species', '10566', (153, 174))	('HPV16', 'Var', (198, 203))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('women', 'Species', '9606', (55, 60))	('infection', 'Disease', (102, 111))	('infection', 'Disease', 'MESH:D007239', (102, 111))	('HPV', 'Species', '10566', (176, 179))	('HPV16', 'Species', '333760', (198, 203))	('induced by', 'Reg', (78, 88))	('cancer', 'Disease', (42, 48))	('HPV', 'Species', '10566', (198, 201))
74040	27056074	We observed PD-L1 positivity in tumor cells, in tumor-infiltrating immune cells, and in stromal immune cells.	('tumor', 'Disease', (48, 53))	('PD-L1', 'Gene', (12, 17))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('PD-L1', 'Gene', '29126', (12, 17))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('positivity', 'Var', (18, 28))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Disease', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
74055	27056074	In the metastatic lymph nodes, PD-L1 positivity was detected in tumor cells, tumor-associated macrophages, immune cells surrounding the metastasis in peritumoral areas, immune cells in resident T-cell areas, and in germinal center histiocytes.	('tumor', 'Disease', (64, 69))	('PD-L1', 'Gene', '29126', (31, 36))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('metastasis', 'CPA', (136, 146))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('positivity', 'Var', (37, 47))	('tumor', 'Disease', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('PD-L1', 'Gene', (31, 36))	('tumor', 'Disease', (154, 159))
74064	27056074	PD-L1 positivity has been reported previously in cervical intraepithelial neoplasias and cervical carcinomas, and, recently, we have reported on the presence of PD-L1-positive immune cells in tumor-draining lymph nodes, including metastasis-free and metastatic lymph nodes.	('tumor', 'Disease', (192, 197))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('positivity', 'Var', (6, 16))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('cervical intraepithelial neoplasias and cervical carcinomas', 'Disease', 'MESH:D018290', (49, 108))	('PD-L1', 'Gene', (0, 5))	('PD-L1', 'Gene', (161, 166))	('cervical intraepithelial neoplasias', 'Phenotype', 'HP:0032242', (49, 84))	('intraepithelial neoplasias', 'Phenotype', 'HP:0032187', (58, 84))	('carcinomas', 'Phenotype', 'HP:0030731', (98, 108))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('PD-L1', 'Gene', '29126', (161, 166))	('PD-L1', 'Gene', '29126', (0, 5))	('neoplasias', 'Phenotype', 'HP:0002664', (74, 84))
74068	27056074	Apart from the tumor cells, we also observed PD-L1 positivity in immune cells present in the tumor fields and in the stromal compartment.	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('PD-L1', 'Gene', '29126', (45, 50))	('positivity', 'Var', (51, 61))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumor', 'Disease', (93, 98))	('tumor', 'Disease', (15, 20))	('PD-L1', 'Gene', (45, 50))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
74076	27056074	In accordance, we have previously shown that high IL-6 in the tumor microenvironment of cervical cancer is associated with poor patient survival.	('tumor microenvironment of cervical cancer', 'Phenotype', 'HP:0030159', (62, 103))	('IL-6', 'Gene', (50, 54))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('cervical cancer', 'Disease', (88, 103))	('cervical cancer', 'Disease', 'MESH:D002583', (88, 103))	('IL-6', 'Gene', '3569', (50, 54))	('tumor', 'Disease', (62, 67))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('high', 'Var', (45, 49))	('patient', 'Species', '9606', (128, 135))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
74086	27056074	Importantly, conjunction with infiltrating effector T cells and the release of type-1 effector cytokines might explain the observed association between marginal expression of PD-L1 and a more favorable prognosis (see Figures 3a and b).	('PD-L1', 'Gene', (175, 180))	('PD-L1', 'Gene', '29126', (175, 180))	('marginal expression', 'Var', (152, 171))
74087	27056074	Recently, we reported on a survival benefit for cervical cancer patients with high numbers of Tbet-positive T cells, indicative of high IFNgamma production.	('high', 'Var', (78, 82))	('patients', 'Species', '9606', (64, 72))	('IFNgamma', 'Gene', (136, 144))	('benefit', 'PosReg', (36, 43))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('IFNgamma', 'Gene', '3458', (136, 144))	('Tbet', 'Gene', (94, 98))	('cervical cancer', 'Disease', 'MESH:D002583', (48, 63))	('Tbet', 'Gene', '30009', (94, 98))	('cervical cancer', 'Disease', (48, 63))
74099	33654410	KDM5C Expedites Lung Cancer Growth and Metastasis Through Epigenetic Regulation of MicroRNA-133a KDM5C, a histone H3K4-specific demethylase, possess various biological functions in development of cancers.	('KDM5C', 'Gene', '8242', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('KDM5C', 'Gene', '8242', (97, 102))	('Lung Cancer', 'Phenotype', 'HP:0100526', (16, 27))	('Metastasis', 'CPA', (39, 49))	('Epigenetic', 'Var', (58, 68))	('Lung Cancer', 'Disease', (16, 27))	('cancers', 'Phenotype', 'HP:0002664', (196, 203))	('KDM5C', 'Gene', (0, 5))	('Cancer', 'Phenotype', 'HP:0002664', (21, 27))	('cancers', 'Disease', (196, 203))	('Lung Cancer', 'Disease', 'MESH:D008175', (16, 27))	('cancers', 'Disease', 'MESH:D009369', (196, 203))	('KDM5C', 'Gene', (97, 102))
74116	33654410	Moreover, miRNAs are inclined to be localized in fragile chromosomal regions which are prone to deletions, translocations and amplifications and are frequently altered in different cancers.	('translocations', 'Var', (107, 121))	('amplifications', 'Var', (126, 140))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('altered', 'Reg', (160, 167))	('deletions', 'Var', (96, 105))	('cancers', 'Disease', 'MESH:D009369', (181, 188))	('cancers', 'Phenotype', 'HP:0002664', (181, 188))	('cancers', 'Disease', (181, 188))
74121	33654410	From the perspective of molecular mechanism, lysine methylation is one of the histone posttranslational modifications that alters chromatin structure, and alterations in histone lysine methylation have been implicated in cancer formation, which is believed as a consequence of the dysregulation of histone lysine methyltransferases or the demethylases.	('lysine', 'Chemical', 'MESH:D008239', (178, 184))	('cancer', 'Disease', 'MESH:D009369', (221, 227))	('alterations', 'Var', (155, 166))	('lysine', 'Chemical', 'MESH:D008239', (306, 312))	('alters', 'Reg', (123, 129))	('implicated', 'Reg', (207, 217))	('cancer', 'Disease', (221, 227))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('histone lysine methylation', 'MPA', (170, 196))	('chromatin structure', 'MPA', (130, 149))	('lysine', 'Chemical', 'MESH:D008239', (45, 51))
74157	33654410	Lung cancer cells overexpressing miR-133a were resuspended in phosphate-buffered saline (2 x 106 cells/mL) and mixed with Matrigel (1:1).	('miR-133a', 'Var', (33, 41))	('miR-133a', 'Chemical', '-', (33, 41))	('Lung cancer', 'Phenotype', 'HP:0100526', (0, 11))	('phosphate-buffered saline', 'Chemical', '-', (62, 87))	('Lung cancer', 'Disease', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))	('Lung cancer', 'Disease', 'MESH:D008175', (0, 11))
74173	33654410	The sequences of PTBP1 3'UTR wild-type (wt) or mutant (mt) were constructed by GenScript (Nanjing, Jiangsu, China).	('PTBP1', 'Gene', '5725', (17, 22))	('PTBP1', 'Gene', (17, 22))	('mutant', 'Var', (47, 53))
74181	33654410	miR-133a was revealed as the most significantly downregulated one in lung cancer tissues (75.43 +- 5.97%) (Figure 1C).	('lung cancer', 'Disease', 'MESH:D008175', (69, 80))	('downregulated', 'NegReg', (48, 61))	('miR-133a', 'Var', (0, 8))	('miR-133a', 'Chemical', '-', (0, 8))	('lung cancer', 'Disease', (69, 80))	('lung cancer', 'Phenotype', 'HP:0100526', (69, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
74189	33654410	Significant declines were observed in cell activity of A549 and H1299 after miR-133a mimic transfection (Figure 2B).	('miR-133a', 'Chemical', '-', (76, 84))	('transfection', 'Var', (91, 103))	('cell activity', 'CPA', (38, 51))	('H1299', 'Var', (64, 69))	('declines', 'NegReg', (12, 20))	('miR-133a', 'Gene', (76, 84))
74192	33654410	Transwell experiments were then performed to assess the effect of miR-133a on the aggressiveness of lung cancer cells, and we found that A549 and H1299 cells with miR-133a mimic had a remarkable reduction in the number of cells migrated and invaded into the basolateral chamber (Figure 2D and E).	('miR-133a', 'Var', (163, 171))	('miR-133a', 'Chemical', '-', (163, 171))	('miR-133a', 'Chemical', '-', (66, 74))	('lung cancer', 'Phenotype', 'HP:0100526', (100, 111))	('aggressiveness', 'Phenotype', 'HP:0000718', (82, 96))	('aggressiveness of lung cancer', 'Disease', (82, 111))	('reduction', 'NegReg', (195, 204))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('aggressiveness of lung cancer', 'Disease', 'MESH:D008175', (82, 111))
74194	33654410	The above results tentatively suggest that miR-133a inhibits the growth and aggressiveness of lung cancer cells in vitro.	('aggressiveness of lung cancer', 'Disease', (76, 105))	('miR-133a', 'Chemical', '-', (43, 51))	('miR-133a', 'Var', (43, 51))	('aggressiveness of lung cancer', 'Disease', 'MESH:D008175', (76, 105))	('inhibits', 'NegReg', (52, 60))	('lung cancer', 'Phenotype', 'HP:0100526', (94, 105))	('aggressiveness', 'Phenotype', 'HP:0000718', (76, 90))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
74198	33654410	At day 35, the volume and weight of xenograft tumors formed by A549 cells overexpressing miR-133a decreased by 43.17 +- 5.22% and 46.17 +- 3.73%, respectively compared to those formed by cells expressing mimic NC, while the volume and weight of xenograft tumors formed by H1299 cells after overexpression of miR-133a decreased by 40.55 +- 5.04% and 39.63 +- 3.81%, respectively (Figure 3A-C).	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Phenotype', 'HP:0002664', (255, 260))	('miR-133a', 'Chemical', '-', (308, 316))	('tumors', 'Disease', (255, 261))	('tumors', 'Disease', 'MESH:D009369', (255, 261))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('tumors', 'Phenotype', 'HP:0002664', (255, 261))	('miR-133a', 'Chemical', '-', (89, 97))	('miR-133a', 'Var', (89, 97))	('tumors', 'Disease', (46, 52))	('decreased', 'NegReg', (98, 107))	('tumors', 'Disease', 'MESH:D009369', (46, 52))
74199	33654410	Furthermore, the positive rate of KI67 decreased by 55.04 +- 4.83% after overexpression of miR-133a in A549-forming xenograft tumors, while the positive rate of TUNEL increased from 5.47 +- 0.56% to 17.43 +- 1.82%.	('miR-133a', 'Chemical', '-', (91, 99))	('tumors', 'Disease', (126, 132))	('tumors', 'Disease', 'MESH:D009369', (126, 132))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('miR-133a', 'Gene', (91, 99))	('KI67', 'Var', (34, 38))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('decreased', 'NegReg', (39, 48))	('overexpression', 'PosReg', (73, 87))
74200	33654410	Consistently, the positive rate of KI67 after overexpression of miR-133a in xenograft tumors formed by H1299 decreased by 52.32 +- 5.64%, and the positive rate of TUNEL increased from 4.19 +- 0.42% to 15.37 +- 1.54% (Figure 3D and E).	('decreased', 'NegReg', (109, 118))	('KI67', 'Var', (35, 39))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('overexpression', 'PosReg', (46, 60))	('miR-133a', 'Gene', (64, 72))	('miR-133a', 'Chemical', '-', (64, 72))	('tumors', 'Disease', (86, 92))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('H1299', 'Var', (103, 108))
74209	33654410	To further clarify the targeting mechanism of miR-133a with SP1 or with PTBP1, we further analyzed the correlation between miR-133a and SP1 or PTBP1 in the TCGA-LUAD database, and we found that miR-133a had a significant correlation with PTBP1 and a poor correlation with SP1 (Figure 4F).	('miR-133a', 'Chemical', '-', (46, 54))	('miR-133a', 'Chemical', '-', (194, 202))	('PTBP1', 'Gene', (143, 148))	('PTBP1', 'Gene', '5725', (72, 77))	('miR-133a', 'Var', (194, 202))	('miR-133a', 'Chemical', '-', (123, 131))	('PTBP1', 'Gene', (72, 77))	('PTBP1', 'Gene', '5725', (238, 243))	('correlation', 'Interaction', (221, 232))	('PTBP1', 'Gene', (238, 243))	('PTBP1', 'Gene', '5725', (143, 148))	('LUAD', 'Phenotype', 'HP:0030078', (161, 165))
74225	33654410	Moreover, the promoter sequence of miR-133a exhibits significant histone methylation modifications (Figure 6C), with the most pronounced levels of histone H3 lysine 4 tri-methylation (H3K4me3) and H3K4me2 modifications.	('H3K4me2', 'Var', (197, 204))	('miR-133a', 'Gene', (35, 43))	('miR-133a', 'Chemical', '-', (35, 43))	('lysine', 'Chemical', 'MESH:D008239', (158, 164))	('histone methylation modifications', 'MPA', (65, 98))
74229	33654410	So, we speculated whether KDM5C similarly represses transcription by demethylation modification of the miR-133a promoter histone.	('represses', 'NegReg', (42, 51))	('KDM5C', 'Gene', (26, 31))	('transcription', 'MPA', (52, 65))	('KDM5C', 'Gene', '8242', (26, 31))	('demethylation', 'Var', (69, 82))	('miR-133a', 'Chemical', '-', (103, 111))
74250	33654410	Besides, miR-133a is involved in the phenotypic modulation of lung cancer cells by interacting with PTBP1.	('miR-133a', 'Var', (9, 17))	('PTBP1', 'Gene', (100, 105))	('PTBP1', 'Gene', '5725', (100, 105))	('lung cancer', 'Phenotype', 'HP:0100526', (62, 73))	('involved', 'Reg', (21, 29))	('lung cancer', 'Disease', (62, 73))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('lung cancer', 'Disease', 'MESH:D008175', (62, 73))	('interacting', 'Interaction', (83, 94))	('miR-133a', 'Chemical', '-', (9, 17))
74255	33654410	In consistence, our miRNA-based microarray on collected 37 pairs of lung cancer and adjacent tissues revealed that miR-133a was the most significantly downregulated miRNA in lung cancer.	('miR-133a', 'Chemical', '-', (115, 123))	('lung cancer', 'Disease', (68, 79))	('lung cancer', 'Disease', (174, 185))	('lung cancer', 'Phenotype', 'HP:0100526', (174, 185))	('miRNA', 'MPA', (165, 170))	('lung cancer', 'Phenotype', 'HP:0100526', (68, 79))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('downregulated', 'NegReg', (151, 164))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('lung cancer', 'Disease', 'MESH:D008175', (68, 79))	('lung cancer', 'Disease', 'MESH:D008175', (174, 185))	('miR-133a', 'Var', (115, 123))
74260	33654410	More importantly, the anti-metastatic role of miR-133a in vivo has also been highlighted in glioma and gastric cancer, which were largely consistent with our results.	('miR-133a', 'Var', (46, 54))	('miR-133a', 'Chemical', '-', (46, 54))	('gastric cancer', 'Phenotype', 'HP:0012126', (103, 117))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('glioma', 'Phenotype', 'HP:0009733', (92, 98))	('gastric cancer', 'Disease', 'MESH:D013274', (103, 117))	('glioma', 'Disease', (92, 98))	('gastric cancer', 'Disease', (103, 117))	('glioma', 'Disease', 'MESH:D005910', (92, 98))	('anti-metastatic', 'CPA', (22, 37))
74261	33654410	Integrated bioinformatics prediction and mRNA-based microarray helped us to determine that PTBP1 was both a target of miR-133a and a downregulated mRNA in lung cancer cells overexpressing miR-133a.	('miR-133a', 'Var', (118, 126))	('downregulated', 'NegReg', (133, 146))	('miR-133a', 'Var', (188, 196))	('miR-133a', 'Chemical', '-', (188, 196))	('PTBP1', 'Gene', '5725', (91, 96))	('lung cancer', 'Disease', (155, 166))	('lung cancer', 'Phenotype', 'HP:0100526', (155, 166))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('mRNA', 'MPA', (147, 151))	('PTBP1', 'Gene', (91, 96))	('miR-133a', 'Chemical', '-', (118, 126))	('lung cancer', 'Disease', 'MESH:D008175', (155, 166))
74263	33654410	For instance, PTBP1 knockdown led to constrained cell migration and invasion in addition to reduced metastasis in renal cell carcinoma.	('renal cell carcinoma', 'Disease', (114, 134))	('PTBP1', 'Gene', '5725', (14, 19))	('constrained cell migration', 'CPA', (37, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (114, 134))	('PTBP1', 'Gene', (14, 19))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (114, 134))	('invasion', 'CPA', (68, 76))	('reduced', 'NegReg', (92, 99))	('knockdown', 'Var', (20, 29))	('metastasis', 'CPA', (100, 110))
74264	33654410	Moreover, Kang et al provided evidence that miR-194 negatively regulated PTBP1 expression by binding to PTBP1 3'UTR in hepatocellular carcinoma.	('negatively regulated', 'NegReg', (52, 72))	('expression', 'MPA', (79, 89))	('PTBP1', 'Gene', '5725', (73, 78))	('PTBP1', 'Gene', '5725', (104, 109))	('binding', 'Interaction', (93, 100))	('PTBP1', 'Gene', (104, 109))	('PTBP1', 'Gene', (73, 78))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (119, 143))	('hepatocellular carcinoma', 'Disease', (119, 143))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (119, 143))	('miR-194', 'Var', (44, 51))
74268	33654410	Intriguingly, miR-133a-3p was validated to be knocked-down by DNA hypermethylation in breast cancer cells and tissue samples, which was in tight correlation with unsatisfactory prognosis of breast cancer patients.	('patients', 'Species', '9606', (204, 212))	('DNA', 'Gene', (62, 65))	('hypermethylation', 'Var', (66, 82))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('breast cancer', 'Disease', 'MESH:D001943', (86, 99))	('breast cancer', 'Phenotype', 'HP:0003002', (86, 99))	('miR-133a-3p', 'Gene', (14, 25))	('knocked-down', 'NegReg', (46, 58))	('breast cancer', 'Disease', (86, 99))	('miR-133a', 'Chemical', '-', (14, 22))	('breast cancer', 'Disease', (190, 203))	('breast cancer', 'Disease', 'MESH:D001943', (190, 203))	('breast cancer', 'Phenotype', 'HP:0003002', (190, 203))
74275	33654410	In conclusion, the findings in this investigation elucidated that miR-133a, regulated by KDM5C, played a tumor suppressor role in lung cancer through regulation of PTBP1 (Figure 9).	('PTBP1', 'Gene', (164, 169))	('lung cancer', 'Phenotype', 'HP:0100526', (130, 141))	('tumor', 'Disease', (105, 110))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('lung cancer', 'Disease', 'MESH:D008175', (130, 141))	('KDM5C', 'Gene', (89, 94))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('KDM5C', 'Gene', '8242', (89, 94))	('miR-133a', 'Var', (66, 74))	('miR-133a', 'Chemical', '-', (66, 74))	('regulation', 'Reg', (150, 160))	('lung cancer', 'Disease', (130, 141))	('PTBP1', 'Gene', '5725', (164, 169))
74276	33654410	In spite of the fact that we acknowledged that miR-133a expression was mediated by KDM5C, and that miR-133a could suppress the development and metastases of lung cancer by targeting PTBP1, there may be other upstream molecules and downstream targets of miR-133a affecting carcinogenesis of lung cancer.	('PTBP1', 'Gene', '5725', (182, 187))	('PTBP1', 'Gene', (182, 187))	('lung cancer', 'Phenotype', 'HP:0100526', (290, 301))	('metastases of lung cancer', 'Disease', (143, 168))	('suppress', 'NegReg', (114, 122))	('miR-133a', 'Chemical', '-', (253, 261))	('miR-133a', 'Chemical', '-', (47, 55))	('lung cancer', 'Phenotype', 'HP:0100526', (157, 168))	('targeting', 'Reg', (172, 181))	('carcinogenesis of lung cancer', 'Disease', 'MESH:D008175', (272, 301))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('miR-133a', 'Var', (99, 107))	('miR-133a', 'Chemical', '-', (99, 107))	('KDM5C', 'Gene', (83, 88))	('metastases of lung cancer', 'Disease', 'MESH:D008175', (143, 168))	('cancer', 'Phenotype', 'HP:0002664', (295, 301))	('KDM5C', 'Gene', '8242', (83, 88))	('carcinogenesis of lung cancer', 'Disease', (272, 301))
74278	30723589	Subjects carrying MHC variants that present fewer self-peptides should also present fewer mutated peptides, resulting in decreased immune pressure on tumor cells.	('decreased immune pressure', 'Phenotype', 'HP:0002721', (121, 146))	('self-peptides', 'MPA', (50, 63))	('mutated peptides', 'MPA', (90, 106))	('fewer', 'NegReg', (84, 89))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('decreased', 'NegReg', (121, 130))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('tumor', 'Disease', (150, 155))	('variants', 'Var', (22, 30))	('MHC', 'Gene', (18, 21))
74287	30723589	In the context of immune surveillance of cancer, it has been observed that in individuals with cancer, mutations that are poorly presented across a range of MHC occur at higher frequencies than mutations that are readily presented by many MHC, suggesting that tumor cells can exploit gaps in the self-immunopeptidome, and that individuals with smaller self-immunopeptidomes will have greater cancer risk.	('tumor', 'Disease', (260, 265))	('mutations', 'Var', (103, 112))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('cancer', 'Disease', (392, 398))	('cancer', 'Disease', 'MESH:D009369', (392, 398))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('tumor', 'Disease', 'MESH:D009369', (260, 265))	('cancer', 'Disease', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (392, 398))	('tumor', 'Phenotype', 'HP:0002664', (260, 265))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))
74291	30723589	We compared the immunogenicity of mutations found in cancer subjects to sets of matched in silico generated mutations.	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('mutations', 'Var', (34, 43))	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))
74311	30723589	We hypothesized that in TCGA, individuals with larger self-immunopeptidomes would have improved outcomes due to there being a higher probability of mutations in these tumors generating neoantigens.	('mutations', 'Var', (148, 157))	('improved', 'PosReg', (87, 95))	('tumors', 'Disease', 'MESH:D009369', (167, 173))	('TCGA', 'Disease', (24, 28))	('outcomes', 'MPA', (96, 104))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('neoantigens', 'MPA', (185, 196))	('tumors', 'Disease', (167, 173))	('generating', 'Reg', (174, 184))	('tumors', 'Phenotype', 'HP:0002664', (167, 173))
74321	30723589	Given that expressed mutations from TCGA exist within established tumors and coexist with the host immune system, neoantigens originating from these mutations were not immunogenic enough to result in tumor eradication within these subjects.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('mutations', 'Var', (149, 158))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('tumor', 'Disease', (66, 71))	('TCGA', 'Gene', (36, 40))	('tumors', 'Disease', (66, 72))	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('tumor', 'Disease', (200, 205))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('mutations', 'Var', (21, 30))
74322	30723589	To investigate this, we looked up wildtype pMHC binding scores for all expressed TCGA and in silico mutations in our predicted human immunopeptidome dataset.	('human', 'Species', '9606', (127, 132))	('TCGA', 'Gene', (81, 85))	('mutations', 'Var', (100, 109))
74323	30723589	Positions which are relatively depleted of mutations in the expressed TCGA dataset relative to the random in silico dataset may be the result of immune editing during tumor development, deleting cells which carry mutations at these positions.	('TCGA', 'Gene', (70, 74))	('deleting', 'NegReg', (186, 194))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('mutations', 'Var', (213, 222))	('tumor', 'Disease', (167, 172))
74324	30723589	It is well established that subtle changes to peptide conformation can have large effects on T cell reactivity, exposing regions of the peptide to the TCR that were previously concealed.	('TCR', 'Gene', '6962', (151, 154))	('TCR', 'Gene', (151, 154))	('T cell reactivity', 'MPA', (93, 110))	('effects', 'Reg', (82, 89))	('changes', 'Var', (35, 42))	('peptide', 'Protein', (46, 53))	('exposing', 'Reg', (112, 120))
74325	30723589	In the context of overcoming existing T cell tolerance to wildtype peptides, these data suggest that, counterintuitively, variants at anchor positions are the most immunogenic and are selected against during tumor development.	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('tumor', 'Disease', (208, 213))	('variants at', 'Var', (122, 133))	('tumor', 'Disease', 'MESH:D009369', (208, 213))
74331	30723589	By comparing observed mutations from immune-exposed TCGA tumors to in silico generated mutations, we were able to detect signals of immune-evasion within the TCGA data.	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('mutations', 'Var', (22, 31))	('immune-evasion', 'MPA', (132, 146))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('tumors', 'Disease', (57, 63))	('tumors', 'Disease', 'MESH:D009369', (57, 63))
74332	30723589	It is important to note that our in silico mutations are random and do not necessarily confer the same cancer growth advantage, or in fact any biological relevance, that is likely found in the set of TCGA mutations and thus are used as a measure of baseline pMHC generation.	('TCGA', 'Gene', (200, 204))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('mutations', 'Var', (205, 214))	('mutations', 'Var', (43, 52))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))
74334	30723589	This could be the result of immune-editing over time shaping the mutational profile of these cancer cells through accumulation of mutations that would be potentially immunogenic if expressed, but are immunologically inconsequential when present in non-expressed genes.	('cancer', 'Disease', (93, 99))	('mutations', 'Var', (130, 139))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))
74336	30723589	Given that highly immunogenic mutations could be rapidly recognized by the immune system and cancer cells containing these mutations would not survive, we assume that the mutations we see have decreased immunogenicity.	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('immunogenicity', 'MPA', (203, 217))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('mutations', 'Var', (30, 39))	('mutations', 'Var', (171, 180))	('decreased', 'NegReg', (193, 202))
74395	29780735	Previous publications have shown that CSCs can induce epithelial-mesenchymal transition (EMT) to promote tumor cell invasion and metastasis.	('induce', 'PosReg', (47, 53))	('CSCs', 'Var', (38, 42))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('epithelial-mesenchymal transition', 'CPA', (54, 87))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumor', 'Disease', (105, 110))	('promote', 'PosReg', (97, 104))
74401	29780735	indicated a positive relationship between high CD44 expression and lymph-node metastasis, Mostaan et al., and Rodrigo et al.	('CD44', 'Gene', '960', (47, 51))	('CD44', 'Gene', (47, 51))	('expression', 'MPA', (52, 62))	('high', 'Var', (42, 46))	('lymph-node metastasis', 'CPA', (67, 88))
74436	29780735	Overexpression of VE-cadherin in cancers such as melanoma and breast cancer is associated with poor prognosis.	('melanoma', 'Disease', 'MESH:D008545', (49, 57))	('VE-cadherin', 'Gene', (18, 29))	('cancers', 'Phenotype', 'HP:0002664', (33, 40))	('VE-cadherin', 'Gene', '1003', (18, 29))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('cancers', 'Disease', (33, 40))	('breast cancer', 'Disease', 'MESH:D001943', (62, 75))	('cancers', 'Disease', 'MESH:D009369', (33, 40))	('breast cancer', 'Phenotype', 'HP:0003002', (62, 75))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('breast cancer', 'Disease', (62, 75))	('Overexpression', 'Var', (0, 14))	('melanoma', 'Phenotype', 'HP:0002861', (49, 57))	('melanoma', 'Disease', (49, 57))
74455	29780735	A published study demonstrated that CD44 variant mediates disassembly of endothelial VE-cadherin junction on metastatic melanoma cells.	('CD44', 'Gene', (36, 40))	('VE-cadherin', 'Gene', (85, 96))	('melanoma', 'Phenotype', 'HP:0002861', (120, 128))	('melanoma', 'Disease', (120, 128))	('VE-cadherin', 'Gene', '1003', (85, 96))	('melanoma', 'Disease', 'MESH:D008545', (120, 128))	('variant', 'Var', (41, 48))	('CD44', 'Gene', '960', (36, 40))
74459	29780735	However, another published study on different histologic grades of OSCC indicated CD44 positivity in 80%-100% of well-differentiated cases, in 60%-85% of moderate-differentiated samples, and in 40%-62% of poor-differentiated cases.	('positivity', 'Var', (87, 97))	('CD44', 'Gene', (82, 86))	('CD44', 'Gene', '960', (82, 86))
74479	29780735	Besides, mutations due to a genetic instability and environmental factors make the solid tumors such as OSCC heterogeneous.	('solid tumors', 'Disease', 'MESH:D009369', (83, 95))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('mutations', 'Var', (9, 18))	('solid tumors', 'Disease', (83, 95))	('OSCC', 'Disease', (104, 108))	('men', 'Species', '9606', (59, 62))
74480	29780735	Heterogeneity enhances tumor formation which may prove CSC hypothesis.	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('Heterogeneity', 'Var', (0, 13))	('enhances', 'PosReg', (14, 22))	('tumor', 'Disease', (23, 28))
74547	31880186	For dual CK5/6 and TTF1 staining, positive cytoplasmic staining was considered as positive for CK5/6 expression (CK5/6(+) and TTF1(-); diagnosis of SqCC), whereas positive nuclear staining was considered as positive for TTF1 expression (CK5/6(-) and TTF1(+); diagnosis of ADC) (Table 1).	('TTF1', 'Gene', '7080', (126, 130))	('TTF1', 'Gene', (126, 130))	('TTF1', 'Gene', '7080', (220, 224))	('TTF1', 'Gene', (220, 224))	('SqCC', 'Phenotype', 'HP:0002860', (148, 152))	('TTF1', 'Gene', (19, 23))	('TTF1', 'Gene', '7080', (250, 254))	('TTF1', 'Gene', '7080', (19, 23))	('CK5/6', 'Var', (95, 100))	('TTF1', 'Gene', (250, 254))	('SqCC', 'Disease', (148, 152))
74575	31880186	p40 and CK5/6 are specific markers of lung SqCC, whereas TTF1 and napsin A are specific markers of lung ADC.	('TTF1', 'Gene', (57, 61))	('napsin A', 'Gene', (66, 74))	('p40', 'Gene', (0, 3))	('napsin A', 'Gene', '9476', (66, 74))	('p40', 'Gene', '8626', (0, 3))	('CK5/6', 'Var', (8, 13))	('lung SqCC', 'Disease', (38, 47))	('SqCC', 'Phenotype', 'HP:0002860', (43, 47))	('TTF1', 'Gene', '7080', (57, 61))
74591	32498338	KT2440, which was uniquely associated with young LUSC male patients and immune infiltration.	('LUSC', 'Phenotype', 'HP:0030359', (49, 53))	('associated', 'Reg', (27, 37))	('LUSC', 'Chemical', '-', (49, 53))	('patients', 'Species', '9606', (59, 67))	('KT2440', 'Var', (0, 6))
74671	32498338	W3110 correlate with increased patient survival, whereas the opposite abundance levels correlate with decreased patient survival.	('increased', 'PosReg', (21, 30))	('patient', 'Species', '9606', (112, 119))	('W3110', 'Var', (0, 5))	('patient survival', 'CPA', (31, 47))	('patient', 'Species', '9606', (31, 38))	('patient survival', 'CPA', (112, 128))	('decreased', 'NegReg', (102, 111))
74675	32498338	W3110 was discovered to be in common with LUAD Female and Male Age Bin 4 and uniquely associated with LUAD Male Age Bin 3 in the gender comparisons (Figure 1D).	('LUAD', 'Phenotype', 'HP:0030078', (42, 46))	('W3110', 'Var', (0, 5))	('associated', 'Reg', (86, 96))	('Bin 3', 'Gene', '55909', (116, 121))	('Bin 3', 'Gene', (116, 121))	('LUAD', 'Phenotype', 'HP:0030078', (102, 106))
74677	32498338	W3110 was also found to be uniquely associated with LUAD Female Age Bin 4 and in common between LUAD Male Age Bin 3 and 4 (Figure 1E).	('LUAD', 'Phenotype', 'HP:0030078', (96, 100))	('Bin 3 and 4', 'Gene', '55909', (110, 121))	('W3110', 'Var', (0, 5))	('LUAD Female Age Bin 4', 'Disease', (52, 73))	('LUAD', 'Phenotype', 'HP:0030078', (52, 56))	('associated', 'Reg', (36, 46))
74678	32498338	The hazard ratios for the two microbes signify that patients with high abundance of S. aureus are twice as likely to survive, whereas patients with high abundance of E. coli str.	('patients', 'Species', '9606', (134, 142))	('S. aureus', 'Species', '1280', (84, 93))	('S. aureus', 'Var', (84, 93))	('survive', 'CPA', (117, 124))	('patients', 'Species', '9606', (52, 60))
74682	32498338	The microbe P. putida KT2440 is associated uniquely with LUSC Male Age Bin 1 for both the gender and age bin comparisons.	('bin', 'Gene', '13876295', (105, 108))	('KT2440', 'Var', (22, 28))	('P. putida KT2440', 'Species', '160488', (12, 28))	('LUSC', 'Chemical', '-', (57, 61))	('Bin 1', 'Gene', (71, 76))	('Bin 1', 'Gene', '274', (71, 76))	('LUSC', 'Phenotype', 'HP:0030359', (57, 61))	('associated', 'Reg', (32, 42))	('bin', 'Gene', (105, 108))
74694	32498338	KT2440 was associated with fewer microbes, including positively correlating with CD4 T cells and dendritic cells and negatively correlating CD8 T cells and B cells.	('negatively', 'NegReg', (117, 127))	('CD8', 'Gene', (140, 143))	('CD8', 'Gene', '925', (140, 143))	('CD4', 'Gene', (81, 84))	('KT2440', 'Var', (0, 6))	('CD4', 'Gene', '920', (81, 84))
74697	32498338	K119 was found to correlate with a higher activity of effector CD8 T cells compared to naive T cells and higher activity of MCSF-activated monocytes compared to unstimulated monocytes.	('activity', 'MPA', (42, 50))	('K119', 'Var', (0, 4))	('higher', 'PosReg', (105, 111))	('MCSF', 'Gene', '1435', (124, 128))	('MCSF', 'Gene', (124, 128))	('CD8', 'Gene', (63, 66))	('CD8', 'Gene', '925', (63, 66))	('activity', 'MPA', (112, 120))	('higher', 'PosReg', (35, 41))
74699	32498338	KT2440 correlates to a higher activity of untreated epithelial cells compared to epithelial cells exposed to interferon-alpha (IFNA).	('higher', 'PosReg', (23, 29))	('IFNA', 'Gene', (127, 131))	('IFNA', 'Gene', '3440', (127, 131))	('KT2440', 'Var', (0, 6))	('activity', 'MPA', (30, 38))
74701	32498338	K119 are in common between all LUAD gender comparisons and age bin comparisons.	('bin', 'Gene', (63, 66))	('bin', 'Gene', '13876295', (63, 66))	('LUAD', 'Phenotype', 'HP:0030078', (31, 35))	('K119', 'Var', (0, 4))
74704	32498338	KT2440 is unique to LUSC Male Age Bin 1 in both the LUSC gender and age bin comparisons.	('LUSC', 'Phenotype', 'HP:0030359', (52, 56))	('LUSC', 'Chemical', '-', (20, 24))	('Bin 1', 'Gene', (34, 39))	('LUSC', 'Chemical', '-', (52, 56))	('KT2440', 'Var', (0, 6))	('Bin 1', 'Gene', '274', (34, 39))	('bin', 'Gene', (72, 75))	('bin', 'Gene', '13876295', (72, 75))	('LUSC', 'Phenotype', 'HP:0030359', (20, 24))
74708	32498338	KT2440 is only positively associated with significant cancer and immune pathways.	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('cancer', 'Disease', (54, 60))	('KT2440', 'Var', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('associated', 'Reg', (26, 36))
74712	32498338	KT2440 were correlated to at least four times as many cancer pathways than immune pathways.	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('KT2440', 'Var', (0, 6))	('cancer', 'Disease', (54, 60))
74743	32498338	W3110, which is also an LUAD-associated microbe, may function like an oncogene in that patient survival rates were significantly decreased when its abundance levels were high.	('abundance levels', 'MPA', (148, 164))	('LUAD', 'Phenotype', 'HP:0030078', (24, 28))	('W3110', 'Var', (0, 5))	('patient', 'Species', '9606', (87, 94))	('patient survival rates', 'CPA', (87, 109))	('decreased', 'NegReg', (129, 138))
74745	32498338	KT2440, which are both LUSC-associated microbes, were correlated with lower expression of various immune cell populations.	('LUSC', 'Chemical', '-', (23, 27))	('lower', 'NegReg', (70, 75))	('expression', 'MPA', (76, 86))	('LUSC', 'Phenotype', 'HP:0030359', (23, 27))	('KT2440', 'Var', (0, 6))
74755	32498338	KT2440 had all positive associations), T. chromogena exhibited the opposite proportions of positive to negative associations of immune and cancer pathways.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('T. chromogena', 'Species', '35622', (39, 52))	('immune and', 'Pathway', (128, 138))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('KT2440', 'Var', (0, 6))	('cancer', 'Disease', (139, 145))
74764	32498338	ATCC 17931, which is normally found in the oral cavity, was discovered to cause lung infections and pneumonia.	('ATCC 17931', 'Var', (0, 10))	('pneumonia', 'Disease', (100, 109))	('pneumonia', 'Disease', 'MESH:D011014', (100, 109))	('lung infections', 'Disease', 'MESH:D012141', (80, 95))	('pneumonia', 'Phenotype', 'HP:0002090', (100, 109))	('lung infections', 'Disease', (80, 95))	('cause', 'Reg', (74, 79))	('lung infections', 'Phenotype', 'HP:0006532', (80, 95))
74811	32266028	Furthermore, SOX2-OT silencing markedly promoted apoptosis and suppressed the proliferation, migration and invasion of TU-177 cells.	('TU-177', 'CellLine', 'CVCL:Z025', (119, 125))	('SOX2-OT', 'Gene', '347689', (13, 20))	('promoted', 'PosReg', (40, 48))	('suppressed', 'NegReg', (63, 73))	('SOX2-OT', 'Gene', (13, 20))	('apoptosis', 'CPA', (49, 58))	('silencing', 'Var', (21, 30))
74814	32266028	In summary, the present study reported that knockdown of SOX2-OT could suppress cell proliferation, migration and invasion, and induce apoptosis in laryngeal cancer by targeting miR-654.	('apoptosis', 'CPA', (135, 144))	('miR-654', 'Gene', '724024', (178, 185))	('SOX2-OT', 'Gene', '347689', (57, 64))	('miR-654', 'Gene', (178, 185))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('laryngeal cancer', 'Phenotype', 'HP:0012118', (148, 164))	('cancer', 'Disease', (158, 164))	('cell proliferation', 'CPA', (80, 98))	('targeting', 'Reg', (168, 177))	('SOX2-OT', 'Gene', (57, 64))	('suppress', 'NegReg', (71, 79))	('induce', 'PosReg', (128, 134))	('knockdown', 'Var', (44, 53))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
74861	32266028	1A, the levels of SOX2-OT were significantly increased in the laryngeal cell lines TU-177, AMC-HN-8 and TU686, especially in TU-177 cells, compared with the normal cell line NP69.	('SOX2-OT', 'Gene', (18, 25))	('increased', 'PosReg', (45, 54))	('TU-177', 'CellLine', 'CVCL:Z025', (125, 131))	('levels', 'MPA', (8, 14))	('TU-177', 'CellLine', 'CVCL:Z025', (83, 89))	('SOX2-OT', 'Gene', '347689', (18, 25))	('TU686', 'Var', (104, 109))
74876	32266028	To investigate whether the silencing of SOX2-OT has an effect on the apoptosis of TU-177 cells, annexin V-FITC/PI staining combined with flow cytometry was performed.	('annexin V', 'Gene', '308', (96, 105))	('silencing', 'Var', (27, 36))	('annexin V', 'Gene', (96, 105))	('SOX2-OT', 'Gene', (40, 47))	('SOX2-OT', 'Gene', '347689', (40, 47))	('TU-177', 'CellLine', 'CVCL:Z025', (82, 88))
74887	32266028	In addition, miR-654 silencing significantly reduced the expression of Bax and cleaved caspase 3 while increased Bcl-2 level compared with the shRNA-SOX2-OT-1-transfected TU-177 cells (Fig.	('expression', 'MPA', (57, 67))	('SOX2-OT', 'Gene', (149, 156))	('caspase 3', 'Gene', (87, 96))	('reduced', 'NegReg', (45, 52))	('increased', 'PosReg', (103, 112))	('caspase 3', 'Gene', '836', (87, 96))	('miR-654', 'Gene', '724024', (13, 20))	('Bax', 'Gene', (71, 74))	('miR-654', 'Gene', (13, 20))	('SOX2-OT', 'Gene', '347689', (149, 156))	('Bax', 'Gene', '581', (71, 74))	('Bcl-2', 'Gene', (113, 118))	('Bcl-2', 'Gene', '596', (113, 118))	('silencing', 'Var', (21, 30))	('cleaved', 'MPA', (79, 86))	('TU-177', 'CellLine', 'CVCL:Z025', (171, 177))
74888	32266028	The normal expression of lncRNA is necessary to maintain cell homeostasis and function, and its aberrant expression is closely associated with a variety of diseases, including cancer.	('associated', 'Reg', (127, 137))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('lncRNA', 'Protein', (25, 31))	('aberrant expression', 'Var', (96, 115))	('cancer', 'Disease', (176, 182))	('cancer', 'Disease', 'MESH:D009369', (176, 182))
74913	32266028	The expression of SOX2-OT was significantly upregulated in laryngeal cancer cell lines, and silencing of SOX2-OT markedly suppressed cell proliferation, migration and invasion, and induced apoptosis in TU-177 cells.	('SOX2-OT', 'Gene', (18, 25))	('cell proliferation', 'CPA', (133, 151))	('TU-177', 'CellLine', 'CVCL:Z025', (202, 208))	('laryngeal cancer', 'Phenotype', 'HP:0012118', (59, 75))	('suppressed', 'NegReg', (122, 132))	('upregulated', 'PosReg', (44, 55))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('migration', 'CPA', (153, 162))	('silencing', 'Var', (92, 101))	('invasion', 'CPA', (167, 175))	('SOX2-OT', 'Gene', (105, 112))	('apoptosis', 'CPA', (189, 198))	('SOX2-OT', 'Gene', '347689', (18, 25))	('induced', 'Reg', (181, 188))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('SOX2-OT', 'Gene', '347689', (105, 112))	('cancer', 'Disease', (69, 75))
74915	27095573	PIK3CA amplification is associated with poor prognosis among patients with curatively resected esophageal squamous cell carcinoma To investigate the clinicopathologic characteristics and the prognostic impact of PIK3CA gene amplification in curatively resected esophageal squamous cell carcinoma (ESCC).	('carcinoma', 'Phenotype', 'HP:0030731', (286, 295))	('esophageal squamous cell carcinoma', 'Disease', (95, 129))	('SCC', 'Gene', '6317', (298, 301))	('PIK3CA', 'Gene', (212, 218))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (261, 295))	('patients', 'Species', '9606', (61, 69))	('PIK3CA', 'Gene', (0, 6))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('PIK3CA', 'Gene', '5290', (0, 6))	('PIK3CA', 'Gene', '5290', (212, 218))	('esophageal squamous cell carcinoma', 'Disease', (261, 295))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (95, 129))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (272, 295))	('amplification', 'Var', (7, 20))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (106, 129))	('SCC', 'Gene', (298, 301))	('SCC', 'Phenotype', 'HP:0002860', (298, 301))
74918	27095573	After adjusting for gender, tumor location, pathologic stage, histologic grade and adjuvant treatment, PIK3CA amplification was significantly associated with a shorter DFS (adjusted hazard ratio [AHR] 1.53; 95% CI, 1.10-2.17; P=0.02).	('tumor', 'Disease', (28, 33))	('amplification', 'Var', (110, 123))	('PIK3CA', 'Gene', (103, 109))	('DFS', 'MPA', (168, 171))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('shorter', 'NegReg', (160, 167))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
74919	27095573	PIK3CA mutations were detected in 6 (1.5%) of 388 cases; 5 cases with exon 9 mutations in E545K while one exon 20 mutation in H1047L.	('PIK3CA', 'Gene', (0, 6))	('E545K', 'Mutation', 'rs104886003', (90, 95))	('E545K', 'Var', (90, 95))	('H1047L', 'Mutation', 'rs121913279', (126, 132))	('H1047L', 'Var', (126, 132))
74920	27095573	PIK3CA amplification is a frequent oncogenic alteration and associated with shorter survival, suggesting its role as a prognostic biomarker in resected ESCC.	('SCC', 'Gene', '6317', (153, 156))	('SCC', 'Phenotype', 'HP:0002860', (153, 156))	('survival', 'MPA', (84, 92))	('PIK3CA', 'Gene', (0, 6))	('SCC', 'Gene', (153, 156))	('shorter', 'NegReg', (76, 83))	('amplification', 'Var', (7, 20))
74933	27095573	Copy number gains of SOX2, PIK3CA, CCND1, and FGFR1 were more frequent in ESCC than in EAC, implicating these genes as therapeutic targets for ESCC.	('SCC', 'Gene', '6317', (75, 78))	('FGFR1', 'Gene', '2260', (46, 51))	('Copy number gains', 'Var', (0, 17))	('SCC', 'Gene', (144, 147))	('SCC', 'Phenotype', 'HP:0002860', (144, 147))	('PIK3CA', 'Gene', (27, 33))	('CCND1', 'Gene', '595', (35, 40))	('SCC', 'Gene', '6317', (144, 147))	('EAC', 'Phenotype', 'HP:0011459', (87, 90))	('FGFR1', 'Gene', (46, 51))	('SCC', 'Gene', (75, 78))	('SCC', 'Phenotype', 'HP:0002860', (75, 78))	('SOX2', 'Gene', (21, 25))	('SOX2', 'Gene', '6657', (21, 25))	('CCND1', 'Gene', (35, 40))
74934	27095573	Very recently, we reported that FGFR1 amplification is frequently observed and an independent prognostic factor in resected ESCC.	('FGFR1', 'Gene', (32, 37))	('FGFR1', 'Gene', '2260', (32, 37))	('SCC', 'Gene', (125, 128))	('SCC', 'Phenotype', 'HP:0002860', (125, 128))	('SCC', 'Gene', '6317', (125, 128))	('amplification', 'Var', (38, 51))
74937	27095573	Activation of the PI3K pathway occurs upon engagement with mutation or amplification of PIK3CA, the p110alpha catalytic subunit of PI3K.	('p110alpha', 'Gene', (100, 109))	('p110alpha', 'Gene', '5290', (100, 109))	('amplification', 'Var', (71, 84))	('Activation', 'PosReg', (0, 10))	('mutation', 'Var', (59, 67))	('engagement', 'Interaction', (43, 53))	('PIK3CA', 'Gene', (88, 94))	('PI3K pathway', 'Pathway', (18, 30))
74938	27095573	Amplification and mutation of PIK3CA is generally associated with increased PIK3CA expression, PI3K activation, and phosphorylation of downstream Akt, supporting the oncogenic role of PI3K aberration.	('PIK3CA', 'Gene', (30, 36))	('Amplification', 'Var', (0, 13))	('increased', 'PosReg', (66, 75))	('phosphorylation', 'MPA', (116, 131))	('Akt', 'Gene', (146, 149))	('PI3K', 'Pathway', (95, 99))	('PIK3CA', 'Gene', (76, 82))	('mutation', 'Var', (18, 26))	('expression', 'MPA', (83, 93))	('activation', 'PosReg', (100, 110))	('Akt', 'Gene', '207', (146, 149))
74939	27095573	PIK3CA gene amplification was found in 10-30% of non-small cell lung cancer, breast cancer, colon cancer and head/neck cancer.	('colon cancer', 'Disease', 'MESH:D015179', (92, 104))	('head/neck cancer', 'Phenotype', 'HP:0012288', (109, 125))	('cell lung cancer', 'Disease', 'MESH:D008175', (59, 75))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('breast cancer', 'Phenotype', 'HP:0003002', (77, 90))	('head/neck cancer', 'Disease', 'MESH:D006258', (109, 125))	('amplification', 'Var', (12, 25))	('cell lung cancer', 'Disease', (59, 75))	('colon cancer', 'Disease', (92, 104))	('head/neck cancer', 'Disease', (109, 125))	('breast cancer', 'Disease', 'MESH:D001943', (77, 90))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('breast cancer', 'Disease', (77, 90))	('lung cancer', 'Phenotype', 'HP:0100526', (64, 75))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('colon cancer', 'Phenotype', 'HP:0003003', (92, 104))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (53, 75))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (49, 75))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('found', 'Reg', (30, 35))	('PIK3CA', 'Gene', (0, 6))
74940	27095573	Activating somatic mutations (codons 542 and 545 in exon 9 and codon 1047 in exon 20) were also identified in various solid tumors.	('Activating', 'PosReg', (0, 10))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('solid tumors', 'Disease', 'MESH:D009369', (118, 130))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('solid tumors', 'Disease', (118, 130))	('codons 542', 'Var', (30, 40))	('codon 1047', 'Var', (63, 73))
74941	27095573	Despite accumulating evidence of biologic role, only a few studies have reported the frequency of PIK3CA aberration in ESCC and its prognostic role is still controversial.	('aberration', 'Var', (105, 115))	('SCC', 'Phenotype', 'HP:0002860', (120, 123))	('SCC', 'Gene', '6317', (120, 123))	('PIK3CA', 'Gene', (98, 104))	('SCC', 'Gene', (120, 123))
74942	27095573	In this study, we evaluated the frequency of PIK3CA amplification and mutation in surgically resected ESCC.	('SCC', 'Gene', (103, 106))	('PIK3CA', 'Gene', (45, 51))	('SCC', 'Phenotype', 'HP:0002860', (103, 106))	('SCC', 'Gene', '6317', (103, 106))	('mutation', 'Var', (70, 78))
74943	27095573	Furthermore, we also determined the prognostic impact of genetic aberration of PIK3CA in ESCC.	('SCC', 'Gene', (90, 93))	('SCC', 'Phenotype', 'HP:0002860', (90, 93))	('genetic aberration', 'Var', (57, 75))	('PIK3CA', 'Gene', (79, 85))	('SCC', 'Gene', '6317', (90, 93))
74953	27095573	The mean PIK3CA/CEN3 ratio was 2.3 (0.9-6.0) for the amplification group and 1.08 (0-1.9) for the no amplification group.	('CEN3', 'Gene', '1070', (16, 20))	('amplification', 'Var', (53, 66))	('CEN3', 'Gene', (16, 20))
74957	27095573	In the Cox proportional hazard model adjusted for gender, tumor location, pathologic stage, histologic grade and adjuvant treatment, PIK3CA amplification was significantly associated with a shorter DFS (adjusted hazard ration [AHR] 1.53; 95% CI, 1.10-2.17; P=0.02, Table 2).	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('DFS', 'MPA', (198, 201))	('PIK3CA', 'Gene', (133, 139))	('amplification', 'Var', (140, 153))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('shorter', 'NegReg', (190, 197))
74961	27095573	The clinicopathologic characteristics of the 6 patients with PIK3CA mutations are listed in Table 3.	('mutations', 'Var', (68, 77))	('PIK3CA', 'Gene', (61, 67))	('patients', 'Species', '9606', (47, 55))
74962	27095573	PIK3CA exon 9 mutations were identified in 5 tumors of E545K (GAG to AAG), while exon 20 mutation was identified in H1047L (CAT to CTT) (Figure 3).	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumors', 'Disease', (45, 51))	('GAG', 'Chemical', 'MESH:D006025', (62, 65))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('identified', 'Reg', (29, 39))	('PIK3CA', 'Gene', (0, 6))	('E545K', 'Mutation', 'rs104886003', (55, 60))	('tumors', 'Disease', 'MESH:D009369', (45, 51))	('E545K', 'Var', (55, 60))	('AAG', 'Gene', (69, 72))	('H1047L', 'Mutation', 'rs121913279', (116, 122))	('AAG', 'Gene', '4350', (69, 72))
74963	27095573	Of 6 PIK3CA mutants, the single case with exon 20 mutation satisfied the criteria of PIK3CA amplification with PIK3CA/CEN3 ratio of 2.5.	('PIK3CA', 'Gene', (5, 11))	('CEN3', 'Gene', (118, 122))	('CEN3', 'Gene', '1070', (118, 122))	('mutants', 'Var', (12, 19))	('PIK3CA', 'Gene', (85, 91))
74965	27095573	Furthermore, all tumors with PIK3CA mutations originated from the mid-to-lower esophageal region.	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('tumors', 'Disease', (17, 23))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('mutations', 'Var', (36, 45))	('PIK3CA', 'Gene', (29, 35))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('originated', 'Reg', (46, 56))
74966	27095573	We conducted this study to examine the frequency and prognostic impact of PIK3CA amplification among curatively resected ESCCs.	('SCC', 'Gene', (122, 125))	('SCC', 'Phenotype', 'HP:0002860', (122, 125))	('SCC', 'Gene', '6317', (122, 125))	('amplification', 'Var', (81, 94))	('PIK3CA', 'Gene', (74, 80))
74967	27095573	To our knowledge, this is the first study of PIK3CA amplification in a large cohort of East Asian ESCC patients.	('SCC', 'Gene', '6317', (99, 102))	('SCC', 'Gene', (99, 102))	('PIK3CA', 'Gene', (45, 51))	('patients', 'Species', '9606', (103, 111))	('amplification', 'Var', (52, 65))	('SCC', 'Phenotype', 'HP:0002860', (99, 102))
74968	27095573	We found that PIK3CA amplification is a common genetic event and an independent poor prognostic factor in ESCC.	('SCC', 'Gene', (107, 110))	('SCC', 'Phenotype', 'HP:0002860', (107, 110))	('PIK3CA', 'Gene', (14, 20))	('SCC', 'Gene', '6317', (107, 110))	('amplification', 'Var', (21, 34))
74971	27095573	A recent comparative genome study reported focal regions of DNA amplification or loss including SOX2, PIK3CA, CCND1, and FGFR1 are more frequent in ESCC than EAC.	('SOX2', 'Gene', (96, 100))	('CCND1', 'Gene', (110, 115))	('PIK3CA', 'Gene', (102, 108))	('SCC', 'Gene', (149, 152))	('EAC', 'Phenotype', 'HP:0011459', (158, 161))	('CCND1', 'Gene', '595', (110, 115))	('SCC', 'Phenotype', 'HP:0002860', (149, 152))	('SCC', 'Gene', '6317', (149, 152))	('DNA amplification', 'Var', (60, 77))	('FGFR1', 'Gene', (121, 126))	('loss', 'NegReg', (81, 85))	('SOX2', 'Gene', '6657', (96, 100))	('FGFR1', 'Gene', '2260', (121, 126))
74974	27095573	Activation of the PI3K pathway, generally as a result of PIK3CA amplification, has been reported in upper aerodigestive tract cancers including 12% of lung squamous cell carcinoma (SCC), 18.2% of nasopharyngeal carcinoma, 20% of oropharyngeal SCC, and 32.2% of HNSCC.	('SCC', 'Gene', '6317', (243, 246))	('SCC', 'Gene', (181, 184))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (196, 220))	('cancers', 'Disease', 'MESH:D009369', (126, 133))	('SCC', 'Gene', (243, 246))	('SCC', 'Phenotype', 'HP:0002860', (263, 266))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (151, 179))	('PIK3CA', 'Gene', (57, 63))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('SCC', 'Gene', '6317', (263, 266))	('nasopharyngeal carcinoma', 'Disease', (196, 220))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (151, 179))	('amplification', 'Var', (64, 77))	('SCC', 'Phenotype', 'HP:0002860', (181, 184))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (156, 179))	('cancers', 'Phenotype', 'HP:0002664', (126, 133))	('lung squamous cell carcinoma', 'Disease', (151, 179))	('Activation', 'PosReg', (0, 10))	('cancers', 'Disease', (126, 133))	('nasopharyngeal carcinoma', 'Disease', 'MESH:D000077274', (196, 220))	('SCC', 'Gene', (263, 266))	('PI3K pathway', 'Pathway', (18, 30))	('SCC', 'Phenotype', 'HP:0002860', (243, 246))	('carcinoma', 'Phenotype', 'HP:0030731', (170, 179))	('SCC', 'Gene', '6317', (181, 184))	('carcinoma', 'Phenotype', 'HP:0030731', (211, 220))
74975	27095573	For esophageal carcinoma, one study demonstrated 26.7% of PIK3CA gene amplification in ESCC.	('SCC', 'Gene', '6317', (88, 91))	('esophageal carcinoma', 'Disease', (4, 24))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (4, 24))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (4, 24))	('PIK3CA', 'Gene', (58, 64))	('carcinoma', 'Phenotype', 'HP:0030731', (15, 24))	('SCC', 'Gene', (88, 91))	('SCC', 'Phenotype', 'HP:0002860', (88, 91))	('amplification', 'Var', (70, 83))
74976	27095573	In nasopharyngeal carcinoma, PIK3CA amplification was strongly associated with distant metastasis, lymph node involvement, advanced tumor stage, and ultimately with reduced overall survival.	('carcinoma', 'Phenotype', 'HP:0030731', (18, 27))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (3, 27))	('nasopharyngeal carcinoma', 'Disease', (3, 27))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('associated', 'Reg', (63, 73))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('overall', 'MPA', (173, 180))	('amplification', 'Var', (36, 49))	('lymph node involvement', 'CPA', (99, 121))	('tumor', 'Disease', (132, 137))	('distant metastasis', 'CPA', (79, 97))	('PIK3CA', 'Gene', (29, 35))	('reduced', 'NegReg', (165, 172))	('nasopharyngeal carcinoma', 'Disease', 'MESH:D000077274', (3, 27))
74977	27095573	For non-lymph node metastatic HNSCC, patients with PIK3CA amplification showed earlier recurrence than those without (10% vs 31% disease free at 2 years).	('patients', 'Species', '9606', (37, 45))	('PIK3CA', 'Gene', (51, 57))	('SCC', 'Gene', (32, 35))	('SCC', 'Phenotype', 'HP:0002860', (32, 35))	('amplification', 'Var', (58, 71))	('SCC', 'Gene', '6317', (32, 35))
74978	27095573	Angulo et al reported that PIK3CA amplification was significantly more frequent in lung SCC compared with adenocarcinoma (42% vs 3%, P<0.001), however, no association was found with other clinicopathologic characteristics.	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('adenocarcinoma', 'Disease', (106, 120))	('frequent', 'Reg', (71, 79))	('PIK3CA', 'Gene', (27, 33))	('adenocarcinoma', 'Disease', 'MESH:D000230', (106, 120))	('SCC', 'Gene', (88, 91))	('amplification', 'Var', (34, 47))	('SCC', 'Phenotype', 'HP:0002860', (88, 91))	('SCC', 'Gene', '6317', (88, 91))
74980	27095573	In our study, by carefully assessing a large cohort of ESCC cases, we were able to clarify the prognostic value of PIK3CA amplification in a homogenous ESCC patients.	('SCC', 'Gene', '6317', (153, 156))	('SCC', 'Gene', (56, 59))	('SCC', 'Phenotype', 'HP:0002860', (153, 156))	('patients', 'Species', '9606', (157, 165))	('amplification', 'Var', (122, 135))	('SCC', 'Phenotype', 'HP:0002860', (56, 59))	('SCC', 'Gene', '6317', (56, 59))	('SCC', 'Gene', (153, 156))	('PIK3CA', 'Gene', (115, 121))
74981	27095573	Therefore, PIK3CA amplification was significantly associated with shorter DFS regardless of sex, histologic grade, and adjuvant therapy, implying a potential role as an independent negative prognostic factor in curatively resected ESCC.	('DFS', 'MPA', (74, 77))	('shorter', 'NegReg', (66, 73))	('PIK3CA', 'Gene', (11, 17))	('SCC', 'Gene', (232, 235))	('SCC', 'Phenotype', 'HP:0002860', (232, 235))	('amplification', 'Var', (18, 31))	('SCC', 'Gene', '6317', (232, 235))
74985	27095573	The frequency of PIK3CA mutation has been variously reported as 2.2 to 21% of ESCC cases, with controversial prognostic value.	('SCC', 'Gene', (79, 82))	('PIK3CA', 'Gene', (17, 23))	('SCC', 'Phenotype', 'HP:0002860', (79, 82))	('SCC', 'Gene', '6317', (79, 82))	('mutation', 'Var', (24, 32))
74986	27095573	Here, we report PIK3CA mutations in 1.6% of ESCCs using standard, bidirectional Sanger sequencing.	('SCC', 'Gene', (45, 48))	('SCC', 'Phenotype', 'HP:0002860', (45, 48))	('SCC', 'Gene', '6317', (45, 48))	('mutations', 'Var', (23, 32))	('PIK3CA', 'Gene', (16, 22))
74990	27095573	Cell lines with PIK3CA amplification was positively associated with BYL719 sensitivity (P=0.0037) and tumor-bearing mice with PIK3CA amplification responded to BYL719, leading to a response rate of -18% (lung cancer) and -80% (gastric cancer).	('mice', 'Species', '10090', (116, 120))	('PIK3CA', 'Gene', (126, 132))	('lung cancer', 'Disease', 'MESH:D008175', (204, 215))	('gastric cancer', 'Phenotype', 'HP:0012126', (227, 241))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))	('amplification', 'Var', (23, 36))	('associated', 'Reg', (52, 62))	('sensitivity', 'MPA', (75, 86))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('BYL719', 'MPA', (68, 74))	('PIK3CA', 'Gene', (16, 22))	('lung cancer', 'Disease', (204, 215))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('lung cancer', 'Phenotype', 'HP:0100526', (204, 215))	('gastric cancer', 'Disease', (227, 241))	('tumor', 'Disease', (102, 107))	('gastric cancer', 'Disease', 'MESH:D013274', (227, 241))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
74991	27095573	Pan-PI3K (BKM120 and GDC-0941) and alpha-selective inhibitors (BYL719 and GDC-0032) demonstrated responses and prolonged stable disease in patients with PIK3CA mutation.	('mutation', 'Var', (160, 168))	('patients', 'Species', '9606', (139, 147))	('BKM120', 'Chemical', 'MESH:C571178', (10, 16))	('GDC-0941', 'Chemical', 'MESH:C532162', (21, 29))	('PIK3CA', 'Gene', (153, 159))	('stable', 'MPA', (121, 127))	('GDC-0032', 'Chemical', 'MESH:C582924', (74, 82))
74992	27095573	In a phase I trial of GDC-0941, a heavily treated ovarian cancer patient with PIK3CA amplification achieved disease stabilization for 4 months with significant pharmacodynamic changes.	('ovarian cancer', 'Disease', 'MESH:D010051', (50, 64))	('PIK3CA', 'Gene', (78, 84))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('ovarian cancer', 'Disease', (50, 64))	('patient', 'Species', '9606', (65, 72))	('amplification', 'Var', (85, 98))	('GDC-0941', 'Chemical', 'MESH:C532162', (22, 30))	('ovarian cancer', 'Phenotype', 'HP:0100615', (50, 64))
74993	27095573	To date, clinical trials with PI3K inhibitors have been reported in un-selected patients, and current trials with PI3K inhibitors are for patients with PIK3CA gene alterations are ongoing (ClinicalTrials.gov number NCT01928459 and NCT01608022).	('PIK3CA', 'Gene', (152, 158))	('patients', 'Species', '9606', (80, 88))	('patients', 'Species', '9606', (138, 146))	('alterations', 'Var', (164, 175))
74996	27095573	In conclusion, in our large cohort study, we demonstrated that PIK3CA amplification is an independent poor prognostic factor in resected ESCC.	('SCC', 'Gene', (138, 141))	('SCC', 'Phenotype', 'HP:0002860', (138, 141))	('SCC', 'Gene', '6317', (138, 141))	('PIK3CA', 'Gene', (63, 69))	('amplification', 'Var', (70, 83))
74997	27095573	Our findings also provide strong implication that PIK3CA amplification and mutation is a promising therapeutic target in ESCC.	('SCC', 'Gene', (122, 125))	('SCC', 'Phenotype', 'HP:0002860', (122, 125))	('mutation', 'Var', (75, 83))	('SCC', 'Gene', '6317', (122, 125))	('PIK3CA', 'Gene', (50, 56))
75007	27095573	The extracted DNA was used in a PCR amplification reaction with primers were designed to amplify the following regions at codon E542, E545 and H1047; exon 9; 5';- AGAGACAATGAATTAAGGGAAAATGAC-3';; 5';- TTTAGCACTTACCTGTGACTCCA-3';, exon 20; 5';-TATTCGACAGCATGCCAATC-3';; 5';- TGTGTGGAAGATCCAATCCA-3';,.	('H1047; exon', 'Var', (143, 154))	('AAG', 'Gene', '4350', (177, 180))	('exon', 'Var', (150, 154))	('GAG', 'Chemical', 'MESH:D006025', (164, 167))	('AAG', 'Gene', (281, 284))	('AAG', 'Gene', '4350', (281, 284))	('E542', 'Var', (128, 132))	('AAG', 'Gene', (177, 180))	('E545', 'Var', (134, 138))
75056	33805318	Univariate analyses found that patients receiving 50-50.4 Gy had significantly superior overall survival (p = 0.023, Figure 1A) and disease-free survival (p = 0.047, Figure 1B) than those receiving 36 Gy.	('50-50.4 Gy', 'Var', (50, 60))	('patients', 'Species', '9606', (31, 39))	('disease-free survival', 'CPA', (132, 153))	('overall survival', 'CPA', (88, 104))	('superior', 'PosReg', (79, 87))
75069	33805318	In the study of Bedenne et al., pathological complete response was found in 25 (23%) of 110 patients with 6th AJCC T3N0-1M0 esophageal cancer receiving 30 Gy preoperative chemoradiotherapy.	('T3N0-1M0', 'Var', (115, 123))	('esophageal cancer', 'Disease', (124, 141))	('esophageal cancer', 'Disease', 'MESH:D004938', (124, 141))	('patients', 'Species', '9606', (92, 100))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))
75073	33805318	revealed that pathological complete response was found in 18 (49%) of 37 patients with 6th AJCC T1N1M0 or T2-3N0-1M0 ESCC receiving 41.4 Gy preoperative chemoradiotherapy.	('T1N1M0', 'Var', (96, 102))	('patients', 'Species', '9606', (73, 81))	('T2-3N0-1M0', 'Var', (106, 116))
75075	33805318	In the study of Tepper et al., 10 (40%) of 25 patients with 6th AJCC T1-3NxM0 esophageal cancer receiving 50.4 Gy preoperative chemoradiotherapy achieved a pathological complete response.	('patients', 'Species', '9606', (46, 54))	('T1-3NxM0', 'Var', (69, 77))	('esophageal cancer', 'Disease', (78, 95))	('esophageal cancer', 'Disease', 'MESH:D004938', (78, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
75082	33805318	found a 20% major pulmonary complication rate in patients with 6th AJCC T1-3N0-1M0 esophageal cancer receiving 35 Gy preoperative chemoradiotherapy.	('T1-3N0-1M0', 'Var', (72, 82))	('esophageal cancer', 'Disease', (83, 100))	('esophageal cancer', 'Disease', 'MESH:D004938', (83, 100))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('patients', 'Species', '9606', (49, 57))	('major', 'Disease', (12, 17))
75083	33805318	However, in patients with 6th AJCC T1N1M0 or T2-3N0-1M0 esophageal cancer receiving 41.4Gy preoperative chemoradiotherapy, Hagen et al.	('patients', 'Species', '9606', (12, 20))	('esophageal cancer', 'Disease', (56, 73))	('esophageal cancer', 'Disease', 'MESH:D004938', (56, 73))	('T1N1M0', 'Var', (35, 41))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('T2-3N0-1M0', 'Var', (45, 55))
75084	33805318	Moreover, in patients with 6th AJCC T1-3NxM0 esophageal cancer receiving 50.4 Gy preoperative chemoradiotherapy, Tepper et al.	('esophageal cancer', 'Disease', (45, 62))	('patients', 'Species', '9606', (13, 21))	('esophageal cancer', 'Disease', 'MESH:D004938', (45, 62))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('T1-3NxM0', 'Var', (36, 44))
75111	32961999	The epigenetic biomarkers, such as methylated genes could efficiently point to changes before cancers can be clinically detected and help us better understand tumorigenesis and hopefully improve cancer treatment and prevention.	('cancers', 'Disease', 'MESH:D009369', (94, 101))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('cancer', 'Disease', (195, 201))	('cancers', 'Disease', (94, 101))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('men', 'Species', '9606', (207, 210))	('tumor', 'Disease', (159, 164))	('methylated', 'Var', (35, 45))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('cancers', 'Phenotype', 'HP:0002664', (94, 101))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
75126	32961999	The heatmap representation of samples clustering for the top fifteen hypermethylated and the top fifteen hypomethylated CpG gene sites in cancer tissue compared to control healthy tissue also showed good clustering of cancer samples on one side and control samples on the other, while most of the potentially premalignant oral lesions were clustered between those two groups (Figure 3).	('cancer', 'Disease', 'MESH:D009369', (218, 224))	('cancer', 'Disease', (138, 144))	('cancer', 'Disease', (218, 224))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('oral lesions', 'Phenotype', 'HP:0100649', (322, 334))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('hypermethylated', 'Var', (69, 84))	('cancer', 'Disease', 'MESH:D009369', (138, 144))
75127	32961999	The top fifteen genes significantly hypermethylated in their promoters in cancer tissues in comparison to healthy tissues are: GPRC5D, TMPRSS11B, PIAS2, ARG1, SRPK2, AADACL2, RGPD4, SPRR3, DEGS1, TXNDC8, SH3TC1, ZPLD1, FBXO2, ATG16L1, and GRHL1 (Table 1).	('TMPRSS11B', 'Gene', (135, 144))	('hypermethylated', 'Var', (36, 51))	('ZPLD1', 'Gene', '131368', (212, 217))	('cancer', 'Disease', (74, 80))	('FBXO2', 'Gene', '26232', (219, 224))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('PIAS2', 'Gene', (146, 151))	('SRPK2', 'Gene', '6733', (159, 164))	('ARG1', 'Gene', (153, 157))	('RGPD4', 'Gene', '285190', (175, 180))	('SH3TC1', 'Gene', (204, 210))	('RGPD4', 'Gene', (175, 180))	('ATG16L1', 'Gene', '55054', (226, 233))	('GPRC5D', 'Gene', '55507', (127, 133))	('AADACL2', 'Gene', '344752', (166, 173))	('DEGS1', 'Gene', (189, 194))	('FBXO2', 'Gene', (219, 224))	('ATG16L1', 'Gene', (226, 233))	('SPRR3', 'Gene', (182, 187))	('SH3TC1', 'Gene', '54436', (204, 210))	('AADACL2', 'Gene', (166, 173))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('GRHL1', 'Gene', (239, 244))	('GPRC5D', 'Gene', (127, 133))	('ARG1', 'Gene', '383', (153, 157))	('DEGS1', 'Gene', '8560', (189, 194))	('TXNDC8', 'Gene', '255220', (196, 202))	('PIAS2', 'Gene', '9063', (146, 151))	('SRPK2', 'Gene', (159, 164))	('GRHL1', 'Gene', '29841', (239, 244))	('SPRR3', 'Gene', '6707', (182, 187))	('TXNDC8', 'Gene', (196, 202))	('ZPLD1', 'Gene', (212, 217))	('TMPRSS11B', 'Gene', '132724', (135, 144))
75131	32961999	The top fifteen genes significantly hypomethylated on different sites across the genome (5'UTR, 3'UTR, TSS1500, TSS200, 1st exon, exon body) in cancer tissues in comparison to healthy tissues are: ATXN1, PPP2R2C, CCR6, RAB37, DUSP27, ZNF521, SLC6A17, SPIN1, CXCR1, SPTBN1, NBAS, NRG3, COL5A1, CDX1, and BATF3 (Table 4).	('COL5A1', 'Gene', (285, 291))	('cancer', 'Disease', (144, 150))	('CCR6', 'Gene', (213, 217))	('PPP2R2C', 'Gene', (204, 211))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('ATXN1', 'Gene', (197, 202))	('RAB37', 'Gene', (219, 224))	('CDX1', 'Gene', (293, 297))	('SPIN1', 'Gene', (251, 256))	('NRG3', 'Gene', '10718', (279, 283))	('SLC6A17', 'Gene', '388662', (242, 249))	('DUSP27', 'Gene', (226, 232))	('CXCR1', 'Gene', (258, 263))	('BATF3', 'Gene', '55509', (303, 308))	('SPTBN1', 'Gene', (265, 271))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('hypomethylated', 'Var', (36, 50))	('BATF3', 'Gene', (303, 308))	('CXCR1', 'Gene', '3577', (258, 263))	('NBAS', 'Gene', '51594', (273, 277))	('ATXN1', 'Gene', '6310', (197, 202))	('CDX1', 'Gene', '1044', (293, 297))	('COL5A1', 'Gene', '1289', (285, 291))	('CCR6', 'Gene', '1235', (213, 217))	('ZNF521', 'Gene', (234, 240))	('SPIN1', 'Gene', '10927', (251, 256))	('SLC6A17', 'Gene', (242, 249))	('DUSP27', 'Gene', '92235', (226, 232))	('SPTBN1', 'Gene', '6711', (265, 271))	('ZNF521', 'Gene', '25925', (234, 240))	('NRG3', 'Gene', (279, 283))	('NBAS', 'Gene', (273, 277))	('PPP2R2C', 'Gene', '5522', (204, 211))	('RAB37', 'Gene', '326624', (219, 224))
75133	32961999	The top fifteen genes significantly hypomethylated in their promoters in HNSCC compared to potentially premalignant oral lesions are: ART4, EPB41L3, ESRRG, ENPP1, GNG7, PAPSS2, NGEF, HIPK4, GPR158, GSG1L, SMPD3, GDF2, RERE, CDH13, and HS3ST4 (Table 2).	('NGEF', 'Gene', (177, 181))	('GNG7', 'Gene', (163, 167))	('EPB41L3', 'Gene', (140, 147))	('SMPD3', 'Gene', '55512', (205, 210))	('ESRRG', 'Gene', (149, 154))	('CDH13', 'Gene', '1012', (224, 229))	('PAPSS2', 'Gene', (169, 175))	('GNG7', 'Gene', '2788', (163, 167))	('RERE', 'Gene', (218, 222))	('ART4', 'Gene', '420', (134, 138))	('HNSCC', 'Disease', (73, 78))	('SMPD3', 'Gene', (205, 210))	('HS3ST4', 'Gene', '9951', (235, 241))	('ENPP1', 'Gene', '5167', (156, 161))	('oral lesions', 'Phenotype', 'HP:0100649', (116, 128))	('GDF2', 'Gene', '2658', (212, 216))	('HIPK4', 'Gene', (183, 188))	('CDH13', 'Gene', (224, 229))	('GDF2', 'Gene', (212, 216))	('GSG1L', 'Gene', (198, 203))	('RERE', 'Gene', '473', (218, 222))	('HNSCC', 'Phenotype', 'HP:0012288', (73, 78))	('hypomethylated', 'Var', (36, 50))	('PAPSS2', 'Gene', '9060', (169, 175))	('GPR158', 'Gene', '57512', (190, 196))	('ENPP1', 'Gene', (156, 161))	('NGEF', 'Gene', '25791', (177, 181))	('EPB41L3', 'Gene', '23136', (140, 147))	('HS3ST4', 'Gene', (235, 241))	('HIPK4', 'Gene', '147746', (183, 188))	('ART4', 'Gene', (134, 138))	('GSG1L', 'Gene', '146395', (198, 203))	('GPR158', 'Gene', (190, 196))	('ESRRG', 'Gene', '2104', (149, 154))
75142	32961999	However, statistical significance was only reached between HNSCC and the control samples in CpG1 and CpG3 of SPRR3 gene (p = 0.01 in both cases) and CpG1 of FBXO2 gene (p = 0.01).	('CpG3', 'Var', (101, 105))	('CpG1', 'Var', (149, 153))	('CpG1', 'Var', (92, 96))	('SPRR3', 'Gene', '6707', (109, 114))	('FBXO2', 'Gene', '26232', (157, 162))	('FBXO2', 'Gene', (157, 162))	('SPRR3', 'Gene', (109, 114))	('HNSCC', 'Phenotype', 'HP:0012288', (59, 64))
75146	32961999	The ORA analysis of KEGG pathway for hypomethylated and hypermethylated gene promoters and/or CpG sites in one group of samples vs. the other group are presented in Supplementary Materials file (Figures S7 and S9, respectively).	('hypomethylated', 'Var', (37, 51))	('men', 'Species', '9606', (171, 174))	('hypermethylated', 'Var', (56, 71))	('KEGG pathway', 'Pathway', (20, 32))
75147	32961999	The GSEA analysis of GO biological processes for hypomethylated and hypermethylated gene promoters and/or CpG sites in one group of samples vs. the other group are presented in Supplementary Materials file (Figures S10 and S12, respectively).	('men', 'Species', '9606', (183, 186))	('hypermethylated', 'Var', (68, 83))	('hypomethylated', 'Var', (49, 63))	('GSEA', 'Chemical', '-', (4, 8))
75148	32961999	The GSEA analysis of KEGG pathway for hypomethylated and hypermethylated gene promoters and/or CpG sites in one group of samples vs. the other group are presented in Supplementary Materials file (Figures S11 and S13, respectively).	('men', 'Species', '9606', (172, 175))	('GSEA', 'Chemical', '-', (4, 8))	('hypermethylated', 'Var', (57, 72))	('KEGG pathway', 'Pathway', (21, 33))
75152	32961999	Out of the total of top fifteen hypermethylated gene promoters in our study, ten were found to be either under-expressed or hypermethylated in TCGA cancer cases, as expected, while one had no measurable expression and only a single CpG site in Illumina 450K DNA methylation array.	('under-expressed', 'NegReg', (105, 120))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('cancer', 'Disease', (148, 154))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('hypermethylated', 'Var', (124, 139))
75161	32961999	(2013) found, contrary to our findings, that SPRR3 hypomethylation was associated with the clinical outcome in glioblastoma multiforme patients.	('patients', 'Species', '9606', (135, 143))	('glioblastoma', 'Phenotype', 'HP:0012174', (111, 123))	('SPRR3', 'Gene', (45, 50))	('hypomethylation', 'Var', (51, 66))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (111, 134))	('SPRR3', 'Gene', '6707', (45, 50))	('glioblastoma multiforme', 'Disease', (111, 134))	('associated', 'Reg', (71, 81))
75171	32961999	The meta-analysis of the gene promoter hypermethylation in oral cancer, that included 29 studies of which 13 were about CDH1 methylation, showed a significant correlation of CDH1 hypermethylation with oral cancer risk.	('CDH1', 'Gene', (174, 178))	('oral cancer', 'Disease', (201, 212))	('CDH1', 'Gene', '999', (120, 124))	('oral cancer', 'Disease', 'MESH:D009369', (59, 70))	('CDH1', 'Gene', '999', (174, 178))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('oral cancer', 'Disease', 'MESH:D009369', (201, 212))	('oral cancer', 'Disease', (59, 70))	('CDH1', 'Gene', (120, 124))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('hypermethylation', 'Var', (179, 195))	('correlation', 'Reg', (159, 170))
75177	32961999	concluded that hypomethylation of this gene may play an important role in the recruitment or retention of CCR6+ Treg cells into the OSCC inflammatory microenvironment at the early stage of tumor progression.	('tumor', 'Disease', (189, 194))	('men', 'Species', '9606', (162, 165))	('CCR6', 'Gene', '1235', (106, 110))	('CCR6', 'Gene', (106, 110))	('men', 'Species', '9606', (85, 88))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('hypomethylation', 'Var', (15, 30))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('play', 'Reg', (48, 52))
75179	32961999	presented that the majority of hypomethylated gene sets identified across multiple cancer (breast, lung cancer, colorectal, myeloma, glioblastoma, ovarian, kidney and stomach cancer) studies were immune-related, suggesting DNA methylation-driven cancer cell invasion and tumorigenesis across various types of cancer.	('tumor', 'Phenotype', 'HP:0002664', (271, 276))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('cancer', 'Disease', (175, 181))	('glioblastoma', 'Phenotype', 'HP:0012174', (133, 145))	('cancer', 'Disease', (104, 110))	('methylation-driven', 'Var', (227, 245))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('cancer', 'Disease', (246, 252))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('colorectal, myeloma, glioblastoma, ovarian, kidney and stomach cancer', 'Disease', 'MESH:D015179', (112, 181))	('cancer', 'Disease', (309, 315))	('cancer', 'Phenotype', 'HP:0002664', (309, 315))	('tumor', 'Disease', (271, 276))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('tumor', 'Disease', 'MESH:D009369', (271, 276))	('DNA', 'Var', (223, 226))	('cancer', 'Disease', 'MESH:D009369', (246, 252))	('breast, lung cancer', 'Disease', 'MESH:D001943', (91, 110))	('stomach cancer', 'Phenotype', 'HP:0012126', (167, 181))	('cancer', 'Disease', 'MESH:D009369', (309, 315))	('cancer', 'Disease', (83, 89))	('lung cancer', 'Phenotype', 'HP:0100526', (99, 110))
75181	32961999	In summary, the majority of hypermethylated gene promoters in HNSCC in our study (10 of 15) were found to be either under-expressed or hypermethylated in TCGA cancer cases.	('cancer', 'Disease', (159, 165))	('HNSCC', 'Phenotype', 'HP:0012288', (62, 67))	('hypermethylated', 'Var', (135, 150))	('under-expressed', 'NegReg', (116, 131))	('HNSCC', 'Disease', (62, 67))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('hypermethylated', 'Var', (28, 43))
75182	32961999	Of particular interest in the HNSCC diagnostic, clinical prognosis and/or risk assessment could be the methylation of CDH1, which was also previously described as a possible biomarker for the early detection and treatment of HNSCC.	('men', 'Species', '9606', (217, 220))	('HNSCC', 'Phenotype', 'HP:0012288', (225, 230))	('CDH1', 'Gene', (118, 122))	('men', 'Species', '9606', (85, 88))	('HNSCC', 'Disease', (30, 35))	('methylation', 'Var', (103, 114))	('HNSCC', 'Phenotype', 'HP:0012288', (30, 35))	('CDH1', 'Gene', '999', (118, 122))
75184	32961999	The majority of HNSCC samples (85%) were methylated in the CDH1 gene promoter by MSP, while only 21% of healthy control samples were methylated in the same gene promoter.	('CDH1', 'Gene', '999', (59, 63))	('methylated', 'Var', (41, 51))	('HNSCC', 'Disease', (16, 21))	('HNSCC', 'Phenotype', 'HP:0012288', (16, 21))	('CDH1', 'Gene', (59, 63))
75189	32961999	Hence, we showed herein that hypermethylation on specific CpGs within the CDH1 gene could be a good biomarker of HNC and a possible option to distinguish HNSCC from potentially premalignant oral lesions and from healthy oral mucosa as well.	('CDH1', 'Gene', '999', (74, 78))	('HNC', 'Disease', 'None', (113, 116))	('HNSCC', 'Phenotype', 'HP:0012288', (154, 159))	('hypermethylation', 'Var', (29, 45))	('oral lesions', 'Phenotype', 'HP:0100649', (190, 202))	('CDH1', 'Gene', (74, 78))	('HNSCC', 'Disease', (154, 159))	('HNC', 'Disease', (113, 116))
75194	32961999	Indeed, the over-representation enrichment analysis (ORA) of GO non-redundant biological processes for differentially methylated gene promoters presented an implication of mostly immune response and cellular defense response pathways, as well as cell-cell adhesion.	('men', 'Species', '9606', (38, 41))	('cellular', 'Pathway', (199, 207))	('immune', 'CPA', (179, 185))	('over-representation', 'PosReg', (12, 31))	('differentially methylated', 'Var', (103, 128))	('cell-cell adhesion', 'CPA', (246, 264))
75209	32961999	Briefly, three sets of consensus primers for HPV detection were used: PGMY09/PGMY11, L1C1/L1C2-1/L1C2-2, and GP5+/GP6+.	('GP6', 'Gene', '51206', (114, 117))	('HPV', 'Species', '10566', (45, 48))	('GP6', 'Gene', (114, 117))	('GP5', 'Gene', (109, 112))	('PGMY09/PGMY11', 'Var', (70, 83))	('L1C1/L1C2-1/L1C2-2', 'Var', (85, 103))	('GP5', 'Gene', '2814', (109, 112))
75232	32961999	Thus, the HNSCC hypermethylated CDH1 gene, involved in cell-cell adhesion, could be considered as a good biomarker for distinguishing cancer tissues from potentially premalignant oral lesions and from healthy oral mucosa.	('HNSCC', 'Var', (10, 15))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('CDH1', 'Gene', (32, 36))	('oral lesions', 'Phenotype', 'HP:0100649', (179, 191))	('CDH1', 'Gene', '999', (32, 36))	('HNSCC', 'Phenotype', 'HP:0012288', (10, 15))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
75236	32961999	This study was supported by funds from the Croatian Science Foundation (grant code IP-2013-11-4758; Epigenetic changes in head and neck squamous cell carcinoma:Epic-HNSCC), which had no influence on the content of the manuscript.	('Epigenetic changes', 'Var', (100, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (150, 159))	('neck squamous cell carcinoma', 'Disease', (131, 159))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (136, 159))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (122, 159))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (131, 159))	('HNSCC', 'Phenotype', 'HP:0012288', (165, 170))
75238	32961999	comb.p.adj.fdr FDR adjusted combined p-value;  CpG 5'-cytosine-phosphate-guanine-3'  FDR false discovery rate  GSEA gene set enrichment analysis  HNSCC head and neck squamous cell carcinoma  HPV human papillomavirus  KEGG Kyoto encyclopedia of genes and genomes  limma linear models for microarray data  mean.mean.diff value of the mean difference across all sites in a region  miRNA micro ribonucleic acids  NA not annotated; NTA, network topology-based analysis  OLL oral lichenoid lesions  OLP oral lichen planus  OPSCC oropharyngeal squamous cell carcinoma  ORA over-representation enrichment analysis  OSCC oral squamous cell carcinoma  PCA principal component analysis  PCR polymerase chain reaction  RnBeads integrated software package for the analysis and interpretation of DNA methylation data  SNPs single nucleotide polymorphisms  TCGA The Cancer Genome Atlas  TS type-specific	('oral lichenoid lesions', 'Phenotype', 'HP:0031453', (469, 491))	('HNSCC', 'Phenotype', 'HP:0012288', (146, 151))	('men', 'Species', '9606', (131, 134))	('squamous cell carcinoma', 'Disease', (537, 560))	("5'-cytosine-phosphate-guanine-3", 'Chemical', '-', (51, 82))	('OSCC oral squamous cell carcinoma  PCA', 'Disease', (607, 645))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (166, 189))	('Cancer', 'Phenotype', 'HP:0002664', (851, 857))	('oral lichenoid lesions  OLP oral lichen planus', 'Disease', (469, 515))	('OLL', 'Phenotype', 'HP:0031453', (465, 468))	('oropharyngeal squamous cell carcinoma', 'Phenotype', 'HP:0012182', (523, 560))	('oral lichenoid lesions  OLP oral lichen planus', 'Disease', 'MESH:D017676', (469, 515))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (617, 640))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (152, 189))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (537, 560))	('GSEA', 'Chemical', '-', (111, 115))	('carcinoma', 'Phenotype', 'HP:0030731', (180, 189))	('Cancer', 'Disease', (851, 857))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (166, 189))	('carcinoma', 'Phenotype', 'HP:0030731', (631, 640))	('HNSCC head and neck squamous cell carcinoma  HPV human papillomavirus  KEGG Kyoto', 'Disease', 'MESH:D000077195', (146, 227))	('carcinoma', 'Phenotype', 'HP:0030731', (551, 560))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (617, 640))	('OSCC oral squamous cell carcinoma  PCA', 'Disease', 'MESH:D002294', (607, 645))	('men', 'Species', '9606', (592, 595))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (537, 560))	('Cancer', 'Disease', 'MESH:D009369', (851, 857))	('single nucleotide polymorphisms', 'Var', (809, 840))	('squamous cell carcinoma', 'Disease', (166, 189))	('lichenoid lesions', 'Phenotype', 'HP:0031452', (474, 491))
75242	29607329	In particular, high mRNA expression level of S100B was associated with better OS in NSCLC patients.	('high', 'Var', (15, 19))	('better OS', 'Disease', (71, 80))	('NSCLC', 'Phenotype', 'HP:0030358', (84, 89))	('mRNA expression level', 'MPA', (20, 41))	('S100B', 'Gene', '6285', (45, 50))	('NSCLC', 'Disease', (84, 89))	('OS', 'Chemical', '-', (78, 80))	('S100B', 'Gene', (45, 50))	('NSCLC', 'Disease', 'MESH:D002289', (84, 89))	('patients', 'Species', '9606', (90, 98))
75274	29607329	Only high RNA expression of S100B was linked to better prognosis (HR = 0.59, 95% CI: 0.45-0.78, and p = 0.0001).	('S100B', 'Gene', (28, 33))	('S100B', 'Gene', '6285', (28, 33))	('high', 'Var', (5, 9))
75285	29607329	Our results suggested that high mRNA expression of these members was significantly associated with worse prognosis in all NSCLC patients.	('mRNA expression', 'MPA', (32, 47))	('NSCLC', 'Disease', 'MESH:D002289', (122, 127))	('NSCLC', 'Phenotype', 'HP:0030358', (122, 127))	('high', 'Var', (27, 31))	('associated', 'Reg', (83, 93))	('patients', 'Species', '9606', (128, 136))	('NSCLC', 'Disease', (122, 127))
75291	29607329	Our data suggested that high mRNA expression of S100A2 was associated with worse OS in patients with stage I NSCLC.	('NSCLC', 'Disease', 'MESH:D002289', (109, 114))	('mRNA expression', 'MPA', (29, 44))	('associated', 'Reg', (59, 69))	('NSCLC', 'Phenotype', 'HP:0030358', (109, 114))	('S100A2', 'Gene', '6273', (48, 54))	('high', 'Var', (24, 28))	('S100A2', 'Gene', (48, 54))	('OS', 'Chemical', '-', (81, 83))	('worse OS', 'Disease', (75, 83))	('patients', 'Species', '9606', (87, 95))	('NSCLC', 'Disease', (109, 114))
75300	29607329	In this study, high mRNA expression of S100A7 was associated with worse OS in adenocarcinoma, but not in squamous cell carcinoma.	('high', 'Var', (15, 19))	('OS', 'Chemical', '-', (72, 74))	('adenocarcinoma', 'Disease', (78, 92))	('worse OS', 'Disease', (66, 74))	('S100A7', 'Gene', (39, 45))	('adenocarcinoma', 'Disease', 'MESH:D000230', (78, 92))	('S100A7', 'Gene', '6278', (39, 45))	('mRNA expression', 'MPA', (20, 35))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (105, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('squamous cell carcinoma', 'Disease', (105, 128))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (105, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))
75306	29607329	We reported a similar result, with high S100A10 expression related to poorer prognosis in NSCLC patients.	('S100A10', 'Gene', (40, 47))	('NSCLC', 'Disease', (90, 95))	('expression', 'MPA', (48, 58))	('S100A10', 'Gene', '6281', (40, 47))	('NSCLC', 'Disease', 'MESH:D002289', (90, 95))	('patients', 'Species', '9606', (96, 104))	('high', 'Var', (35, 39))	('NSCLC', 'Phenotype', 'HP:0030358', (90, 95))
75309	29607329	It was reported that the A549 and LTEP-a-2 cell lines, which have lost S100A11 expression, show a marked suppression in tumor growth, and S100A11 knockdown also significantly inhibited tumor growth in vivo.	('knockdown', 'Var', (146, 155))	('tumor', 'Disease', (185, 190))	('A549', 'CellLine', 'CVCL:0023', (25, 29))	('expression', 'MPA', (79, 89))	('a-2', 'CellLine', 'CVCL:0470', (39, 42))	('inhibited', 'NegReg', (175, 184))	('S100A11', 'Gene', '6282', (138, 145))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('suppression', 'NegReg', (105, 116))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('lost', 'NegReg', (66, 70))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('S100A11', 'Gene', (138, 145))	('S100A11', 'Gene', '6282', (71, 78))	('tumor', 'Disease', (120, 125))	('S100A11', 'Gene', (71, 78))
75311	29607329	We showed that high mRNA expression of S100A11 was associated with worse OS in NSCLC patients treated with chemotherapy and those with early-stage disease.	('high', 'Var', (15, 19))	('S100A11', 'Gene', (39, 46))	('NSCLC', 'Disease', 'MESH:D002289', (79, 84))	('OS', 'Chemical', '-', (73, 75))	('S100A11', 'Gene', '6282', (39, 46))	('associated', 'Reg', (51, 61))	('mRNA expression', 'MPA', (20, 35))	('worse OS', 'Disease', (67, 75))	('patients', 'Species', '9606', (85, 93))	('NSCLC', 'Phenotype', 'HP:0030358', (79, 84))	('NSCLC', 'Disease', (79, 84))
75323	29607329	However, contrary to our expectation, high expression of S100B in lung cancer was associated with better OS in this study.	('better OS', 'Disease', (98, 107))	('S100B', 'Gene', (57, 62))	('lung cancer', 'Disease', (66, 77))	('high expression', 'Var', (38, 53))	('lung cancer', 'Phenotype', 'HP:0100526', (66, 77))	('OS', 'Chemical', '-', (105, 107))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('S100B', 'Gene', '6285', (57, 62))	('lung cancer', 'Disease', 'MESH:D008175', (66, 77))
75389	29204340	Risk factors for cancers are, cigarette smoking (tobacco and tobacco products), exposure to cancer-causing agents in the environment (sunlight, radon gas, air pollution, and infectious agents, exposure to cancer-causing agents in the workplace, genetic factors., Reactivation of latent TB infection (LTBI) may cause TB infection.	('cancer', 'Disease', 'MESH:D009369', (205, 211))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('TB infection', 'Disease', (316, 328))	('cancers', 'Phenotype', 'HP:0002664', (17, 24))	('cancers', 'Disease', (17, 24))	('cancer', 'Disease', (17, 23))	('TB', 'Chemical', 'MESH:D013725', (316, 318))	('cause', 'Reg', (310, 315))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))	('tobacco', 'Species', '4097', (61, 68))	('men', 'Species', '9606', (128, 131))	('TB infection', 'Disease', 'MESH:D014390', (286, 298))	('cancer', 'Disease', (92, 98))	('Reactivation', 'Var', (263, 275))	('cancer', 'Disease', (205, 211))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('tobacco', 'Species', '4097', (49, 56))	('cancers', 'Disease', 'MESH:D009369', (17, 24))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('TB infection', 'Disease', 'MESH:D014390', (316, 328))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('TB infection', 'Disease', (286, 298))	('TB', 'Chemical', 'MESH:D013725', (286, 288))	('TB', 'Chemical', 'MESH:D013725', (301, 303))
75448	28594918	Previous MR analyses on lung cancer risk showed that a genetic score for increased BMI raised the risk for lung cancer, especially for squamous cell carcinoma and small cell lung cancer.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (135, 158))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (163, 185))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('lung cancer', 'Disease', 'MESH:D008175', (107, 118))	('raised', 'Reg', (87, 93))	('lung cancer', 'Disease', (24, 35))	('lung cancer', 'Phenotype', 'HP:0100526', (107, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('genetic score', 'Var', (55, 68))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (135, 158))	('increased BMI', 'Phenotype', 'HP:0031418', (73, 86))	('lung cancer', 'Disease', 'MESH:D008175', (174, 185))	('lung cancer', 'Disease', 'MESH:D008175', (24, 35))	('increased', 'PosReg', (73, 82))	('small cell lung cancer', 'Disease', 'MESH:D055752', (163, 185))	('lung cancer', 'Phenotype', 'HP:0100526', (174, 185))	('carcinoma', 'Phenotype', 'HP:0030731', (149, 158))	('BMI', 'Gene', (83, 86))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('squamous cell carcinoma', 'Disease', (135, 158))	('lung cancer', 'Phenotype', 'HP:0100526', (24, 35))	('small cell lung cancer', 'Disease', (163, 185))	('lung cancer', 'Disease', (107, 118))
75449	28594918	The goal of the current study was to use genetic variations associated with a range of metabolic factors, including obesity, body shape, dyslipidemia and hyperglycemia, to further investigate the causal relationship between these metabolic exposures and lung cancer.	('lung cancer', 'Disease', 'MESH:D008175', (254, 265))	('obesity', 'Phenotype', 'HP:0001513', (116, 123))	('dyslipidemia', 'Disease', 'MESH:D050171', (137, 149))	('hyperglycemia', 'Phenotype', 'HP:0003074', (154, 167))	('investigate', 'Reg', (180, 191))	('hyperglycemia', 'Disease', 'MESH:D006943', (154, 167))	('obesity', 'Disease', 'MESH:D009765', (116, 123))	('variations', 'Var', (49, 59))	('dyslipidemia', 'Phenotype', 'HP:0003119', (137, 149))	('lung cancer', 'Disease', (254, 265))	('obesity', 'Disease', (116, 123))	('lung cancer', 'Phenotype', 'HP:0100526', (254, 265))	('hyperglycemia', 'Disease', (154, 167))	('cancer', 'Phenotype', 'HP:0002664', (259, 265))	('dyslipidemia', 'Disease', (137, 149))	('associated', 'Reg', (60, 70))
75476	28594918	Among glucose and insulin parameters, fasting insulin was associated with an increased risk in overall lung cancer (OR [95%CI] = 1.63 [1.25-2.13] per each SD increase [44.4 pmol/l]) (Fig 1).	('lung cancer', 'Disease', 'MESH:D008175', (103, 114))	('fasting', 'Var', (38, 45))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('lung cancer', 'Disease', (103, 114))	('lung cancer', 'Phenotype', 'HP:0100526', (103, 114))	('glucose', 'Chemical', 'MESH:D005947', (6, 13))
75502	28464907	Nodal skip metastasis in thoracic esophageal squamous cell carcinoma: a cohort study Nodal skip metastasis is a prognostic factor in some sites of malignancies, but its role in esophageal cancer is still unclear.	('esophageal cancer', 'Disease', 'MESH:D004938', (177, 194))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('carcinoma', 'Phenotype', 'HP:0030731', (59, 68))	('esophageal squamous cell carcinoma', 'Disease', (34, 68))	('malignancies', 'Disease', (147, 159))	('Nodal', 'Var', (85, 90))	('esophageal cancer', 'Disease', (177, 194))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (45, 68))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (34, 68))	('malignancies', 'Disease', 'MESH:D009369', (147, 159))
75508	28464907	Adjusting for the number of lymph node metastases, patient with nodal skip metastasis had similar 5-year overall survival (14% vs. 13%, p = 0.93) and 5-year disease free survival (14% vs. 9%, p = 0.48) compared to patients with both peritumoral and distant lymph node metastases.	('lymph node metastases', 'Disease', (257, 278))	('patient', 'Species', '9606', (214, 221))	('tumor', 'Disease', (237, 242))	('patients', 'Species', '9606', (214, 222))	('nodal', 'Var', (64, 69))	('patient', 'Species', '9606', (51, 58))	('lymph node metastases', 'Disease', 'MESH:D009362', (28, 49))	('tumor', 'Disease', 'MESH:D009369', (237, 242))	('lymph node metastases', 'Disease', (28, 49))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))	('lymph node metastases', 'Disease', 'MESH:D009362', (257, 278))
75576	28464907	reported a favorable prognosis associated with the presence of NSM in a heterogeneous group of both ESCC and EAC patients.	('patients', 'Species', '9606', (113, 121))	('NSM', 'Gene', (63, 66))	('EAC', 'Gene', '1540', (109, 112))	('ESCC', 'Disease', (100, 104))	('EAC', 'Gene', (109, 112))	('presence', 'Var', (51, 59))
75584	26796520	Promoter hypermethylation is likely to silence the expression of SSTR2.	('SSTR2', 'Gene', (65, 70))	('SSTR2', 'Gene', '6752', (65, 70))	('expression', 'MPA', (51, 61))	('silence', 'NegReg', (39, 46))	('Promoter hypermethylation', 'Var', (0, 25))
75592	26796520	In conclusion, SSTR2 promoter hypermethylation might be associated with the risk and progression of LSCC in males.	('SSTR2', 'Gene', '6752', (15, 20))	('LSCC', 'Disease', (100, 104))	('associated', 'Reg', (56, 66))	('SSTR2', 'Gene', (15, 20))	('promoter hypermethylation', 'Var', (21, 46))
75599	26796520	Meanwhile, accumulating studies suggest that there are numerous aberrant epigenetic modifications in laryngeal cancer.	('laryngeal cancer', 'Disease', (101, 117))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('laryngeal cancer', 'Phenotype', 'HP:0012118', (101, 117))	('epigenetic modifications', 'Var', (73, 97))	('aberrant', 'Var', (64, 72))	('laryngeal cancer', 'Disease', 'MESH:D007822', (101, 117))
75603	26796520	Hypermethylation of SSTR1 gene along with reduced expression was found in head and neck squamous cell carcinoma, and the reversed SSTR5 methylation was shown to up-regulate SSTR5 mRNA expression in prostate cancer.	('Hypermethylation', 'Var', (0, 16))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (88, 111))	('mRNA expression', 'MPA', (179, 194))	('expression', 'MPA', (50, 60))	('reduced', 'NegReg', (42, 49))	('up-regulate', 'PosReg', (161, 172))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (74, 111))	('SSTR5', 'Gene', (173, 178))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('SSTR5', 'Gene', '6755', (173, 178))	('SSTR5', 'Gene', (130, 135))	('prostate cancer', 'Disease', 'MESH:D011471', (198, 213))	('SSTR1', 'Gene', (20, 25))	('SSTR1', 'Gene', '6751', (20, 25))	('prostate cancer', 'Phenotype', 'HP:0012125', (198, 213))	('methylation', 'Var', (136, 147))	('SSTR5', 'Gene', '6755', (130, 135))	('prostate cancer', 'Disease', (198, 213))	('neck squamous cell carcinoma', 'Disease', (83, 111))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (83, 111))
75606	26796520	However, there was a lack of association study between SSTR2 methylation and laryngeal cancer.	('methylation', 'Var', (61, 72))	('laryngeal cancer', 'Disease', 'MESH:D007822', (77, 93))	('SSTR2', 'Gene', (55, 60))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('SSTR2', 'Gene', '6752', (55, 60))	('laryngeal cancer', 'Disease', (77, 93))	('laryngeal cancer', 'Phenotype', 'HP:0012118', (77, 93))
75607	26796520	Epigenetic modifications are crucial for tumorigenesis.	('tumor', 'Disease', (41, 46))	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('Epigenetic modifications', 'Var', (0, 24))
75609	26796520	Genes with aberrant DNA methylation have been shown with great potential in the early detection and prognosis of cancers.	('cancers', 'Disease', 'MESH:D009369', (113, 120))	('cancers', 'Phenotype', 'HP:0002664', (113, 120))	('aberrant', 'Var', (11, 19))	('cancers', 'Disease', (113, 120))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
75631	26796520	Subgroup analysis by the smoking status showed that SSTR2 promoter hypermethylation was associated with the risk of laryngeal cancer in the patients with and without smoking behaviors (Figure 3a, smokers: 5.46 +- 4.94 % versus 3.88 +- 2.13 %, P = 0.013, adjusted P = 0.021; non-smokers: 7.56 +- 5.78 versus 3.87 +- 1.87, P = 0.033, adjusted P = 0.033).	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('SSTR2', 'Gene', (52, 57))	('laryngeal cancer', 'Disease', 'MESH:D007822', (116, 132))	('patients', 'Species', '9606', (140, 148))	('SSTR2', 'Gene', '6752', (52, 57))	('associated', 'Reg', (88, 98))	('laryngeal cancer', 'Disease', (116, 132))	('laryngeal cancer', 'Phenotype', 'HP:0012118', (116, 132))	('promoter hypermethylation', 'Var', (58, 83))
75632	26796520	Further subgroup analysis by age showed that the patients aged <60 years old showed a statistically higher methylation in cancer tissues than in paired non-tumor tissues, but this association could not be found in those older than 60 years old (Figure 3b, <60y: adjusted P = 0.039; 60y~: adjusted P = 0.059; 70y~: adjusted P = 0.287).	('<60y', 'Var', (256, 260))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('methylation', 'MPA', (107, 118))	('higher', 'PosReg', (100, 106))	('tumor', 'Disease', (156, 161))	('patients', 'Species', '9606', (49, 57))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))
75643	26796520	DNA hypermethylation in the promoter of tumor suppressor genes (TSGs) inhibits transcriptional initiation and results in the silencing of TSGs.	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('inhibits', 'NegReg', (70, 78))	('silencing', 'MPA', (125, 134))	('TSGs', 'Gene', (138, 142))	('transcriptional initiation', 'MPA', (79, 105))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('hypermethylation', 'Var', (4, 20))
75644	26796520	Hypermethylated promoters of tumor suppressor genes (CHD5, CHFR, PTEN, FHIT, CDKN2B, APC, DAPK1) have been shown as an important epigenetic mechanism in LSCC.	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('FHIT', 'Gene', (71, 75))	('CHD5', 'Gene', (53, 57))	('DAPK1', 'Gene', '1612', (90, 95))	('APC', 'Disease', 'MESH:D011125', (85, 88))	('CHFR', 'Gene', (59, 63))	('APC', 'Disease', (85, 88))	('Hypermethylated', 'Var', (0, 15))	('CDKN2B', 'Gene', (77, 83))	('FHIT', 'Gene', '2272', (71, 75))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('LSCC', 'Disease', (153, 157))	('CHFR', 'Gene', '55743', (59, 63))	('PTEN', 'Gene', (65, 69))	('CHD5', 'Gene', '26038', (53, 57))	('CDKN2B', 'Gene', '1030', (77, 83))	('DAPK1', 'Gene', (90, 95))	('PTEN', 'Gene', '5728', (65, 69))	('tumor', 'Disease', (29, 34))
75645	26796520	Moreover, accumulating studies have reported other aberrantly hypermethylated genes in LSCC, including CBY, IGFBP-rP1, and MYCT1.	('IGFBP-rP1', 'Gene', (108, 117))	('aberrantly', 'Var', (51, 61))	('IGFBP-rP1', 'Gene', '3490', (108, 117))	('CBY', 'Gene', (103, 106))	('CBY', 'Gene', '25776', (103, 106))	('MYCT1', 'Gene', (123, 128))	('LSCC', 'Disease', (87, 91))	('MYCT1', 'Gene', '80177', (123, 128))
75649	26796520	Besides, we found that SSTR2 promoter hypermethylation could predict a poor OS of LSCC.	('SSTR2', 'Gene', (23, 28))	('hypermethylation', 'Var', (38, 54))	('SSTR2', 'Gene', '6752', (23, 28))	('LSCC', 'Disease', (82, 86))
75657	26796520	In addition, SSTR2 deficiency may contribute to the development of tissue invasion and metastasis process.	('tissue invasion', 'CPA', (67, 82))	('deficiency', 'Var', (19, 29))	('SSTR2', 'Gene', '6752', (13, 18))	('contribute', 'Reg', (34, 44))	('metastasis process', 'CPA', (87, 105))	('SSTR2', 'Gene', (13, 18))
75659	26796520	Our breakdown analysis showed a significant association of SSTR2 methylation with LSCC risk in moderately and well differentiated LSCC patients but not in the poorly differentiated patients.	('SSTR2', 'Gene', (59, 64))	('patients', 'Species', '9606', (135, 143))	('LSCC', 'Disease', (82, 86))	('LSCC', 'Disease', (130, 134))	('SSTR2', 'Gene', '6752', (59, 64))	('patients', 'Species', '9606', (181, 189))	('methylation', 'Var', (65, 76))	('association', 'Interaction', (44, 55))
75660	26796520	Our results provided a hypothesis that the SSTR2 methylation might be involved in the metastasis and invasion of laryngeal cancer.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('SSTR2', 'Gene', '6752', (43, 48))	('laryngeal cancer', 'Disease', 'MESH:D007822', (113, 129))	('invasion', 'CPA', (101, 109))	('laryngeal cancer', 'Disease', (113, 129))	('laryngeal cancer', 'Phenotype', 'HP:0012118', (113, 129))	('involved', 'Reg', (70, 78))	('methylation', 'Var', (49, 60))	('SSTR2', 'Gene', (43, 48))	('metastasis', 'CPA', (86, 96))
75666	26796520	This study indicated that SSTR2 promoter hypermethylation was associated with the risk and progression of laryngeal cancer in males.	('SSTR2', 'Gene', '6752', (26, 31))	('promoter hypermethylation', 'Var', (32, 57))	('associated', 'Reg', (62, 72))	('laryngeal cancer', 'Disease', 'MESH:D007822', (106, 122))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('SSTR2', 'Gene', (26, 31))	('laryngeal cancer', 'Disease', (106, 122))	('laryngeal cancer', 'Phenotype', 'HP:0012118', (106, 122))
75678	25934640	In addition, the CRP/Alb ratio could identify a group of patients with mGPS score of 0 who had comparable overall survival with those with mGPS score of 1.	('mGPS score of 0', 'Var', (71, 86))	('CRP/Alb', 'Gene', (17, 24))	('patients', 'Species', '9606', (57, 65))	('CRP/Alb', 'Gene', '1401;213', (17, 24))
75706	25934640	Patients with both CRP > 10 mg/L and albumin > 35 g/L were allocated a score of 1.	('> 10 mg/L', 'Var', (23, 32))	('CRP', 'Gene', (19, 22))	('CRP', 'Gene', '1401', (19, 22))	('Patients', 'Species', '9606', (0, 8))	('albumin', 'Gene', (37, 44))	('albumin', 'Gene', '213', (37, 44))
75707	25934640	Patients with both CRP > 10 mg/L and albumin < 35 g/L were allocated a score of 2.	('> 10 mg/L', 'Var', (23, 32))	('CRP', 'Gene', (19, 22))	('CRP', 'Gene', '1401', (19, 22))	('Patients', 'Species', '9606', (0, 8))	('albumin', 'Gene', (37, 44))	('albumin', 'Gene', '213', (37, 44))
75736	25934640	Other significant prognostic indexes identified by univariate analysis included age (<=54/> 54 yr), the TNM stage (I/II/III/IV), distant metastasis (No/Yes), surgery (No/Yes), treatment purpose (Curative treatment/Palliative treatment), BMI (<=20.43/> 20.43), mGPS (0/1/2), PNI (<=49.05/> 49.05), NLR (<=1.835/> 1.835), PLR (<=163.8/> 163.8), CRP (<=10/> 10), white blood cell (WBC) (<=10/> 10), albumin (<=35/> 35).	('CRP', 'Gene', (343, 346))	('<=10/> 10', 'Var', (348, 357))	('CRP', 'Gene', '1401', (343, 346))	('mGPS (0/1/2', 'Gene', '209318;56310', (260, 271))	('albumin', 'Gene', (396, 403))	('albumin', 'Gene', '213', (396, 403))	('<=10/', 'Var', (384, 389))
75776	25934640	Several studies proved that supplement of some trophic factors, for example, omega-3 polyunsaturated fatty acids, could improve plasma fatty acid profile, CRP/Alb status, and immune function and prevent weight loss during treatment in cancer patients.	('weight loss', 'Disease', 'MESH:D015431', (203, 214))	('fatty acid', 'Chemical', 'MESH:D005227', (135, 145))	('cancer', 'Disease', (235, 241))	('improve', 'PosReg', (120, 127))	('cancer', 'Disease', 'MESH:D009369', (235, 241))	('omega-3 polyunsaturated fatty acids', 'Chemical', '-', (77, 112))	('omega-3', 'Var', (77, 84))	('fatty acid', 'Chemical', 'MESH:D005227', (101, 111))	('prevent', 'NegReg', (195, 202))	('weight loss', 'Disease', (203, 214))	('CRP/Alb', 'Gene', '1401;213', (155, 162))	('CRP/Alb', 'Gene', (155, 162))	('plasma fatty acid profile', 'MPA', (128, 153))	('weight loss', 'Phenotype', 'HP:0001824', (203, 214))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))	('immune function', 'CPA', (175, 190))	('patients', 'Species', '9606', (242, 250))
75801	25934640	Although no statistical difference of discriminatory ability was found between the CRP/Alb ratio and the mGPS, the CRP/Alb ratio could identify a group of patients with mGPS score of 0, who had comparable overall survival with those with mGPS score of 1 (P < 0.001).	('CRP/Alb', 'Gene', (115, 122))	('CRP/Alb', 'Gene', (83, 90))	('mGPS score of 0', 'Var', (169, 184))	('patients', 'Species', '9606', (155, 163))	('CRP/Alb', 'Gene', '1401;213', (83, 90))	('CRP/Alb', 'Gene', '1401;213', (115, 122))
75820	25689063	In non-small-cell lung cancer (NSCLC), our previous study showed that lesion HLA-G expression was found to be significantly associated with stage of the disease.	('lung cancer', 'Disease', 'MESH:D008175', (18, 29))	('stage', 'Disease', (140, 145))	('NSCLC', 'Disease', (31, 36))	('lesion', 'Var', (70, 76))	('NSCLC', 'Phenotype', 'HP:0030358', (31, 36))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (3, 29))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (7, 29))	('NSCLC', 'Disease', 'MESH:D002289', (31, 36))	('associated', 'Reg', (124, 134))	('lung cancer', 'Phenotype', 'HP:0100526', (18, 29))	('lung cancer', 'Disease', (18, 29))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('HLA-G', 'Gene', (77, 82))	('HLA-G', 'Gene', '3135', (77, 82))
75822	25689063	Similar findings was also observed in other malignancies such as gastric carcinomas, colorectal cancer and oesophageal squamous cell carcinoma patients that lesion HLA-G expression was strongly correlated with disease stage and poor prognosis and that HLA-G could be an independent prognostic factor.	('HLA-G', 'Gene', '3135', (164, 169))	('lesion', 'Var', (157, 163))	('correlated', 'Reg', (194, 204))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (119, 142))	('expression', 'MPA', (170, 180))	('colorectal cancer', 'Phenotype', 'HP:0003003', (85, 102))	('gastric carcinomas', 'Disease', 'MESH:D013274', (65, 83))	('gastric carcinomas', 'Disease', (65, 83))	('disease', 'Disease', (210, 217))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('carcinomas', 'Phenotype', 'HP:0030731', (73, 83))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('HLA-G', 'Gene', (252, 257))	('HLA-G', 'Gene', (164, 169))	('colorectal cancer', 'Disease', 'MESH:D015179', (85, 102))	('malignancies', 'Disease', 'MESH:D009369', (44, 56))	('malignancies', 'Disease', (44, 56))	('oesophageal squamous cell carcinoma', 'Disease', (107, 142))	('colorectal cancer', 'Disease', (85, 102))	('patients', 'Species', '9606', (143, 151))	('oesophageal squamous cell carcinoma', 'Disease', 'MESH:D002294', (107, 142))	('HLA-G', 'Gene', '3135', (252, 257))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
75870	25689063	Though the mean survival time for lesion sHLA-G-positive patients was less than that of sHLA-G-negative patients, no significance was observed between the two groups (P = 0.559, Fig.	('survival time', 'CPA', (16, 29))	('less', 'NegReg', (70, 74))	('HLA-G', 'Gene', (42, 47))	('HLA-G', 'Gene', (89, 94))	('lesion', 'Var', (34, 40))	('HLA-G', 'Gene', '3135', (42, 47))	('patients', 'Species', '9606', (57, 65))	('patients', 'Species', '9606', (104, 112))	('HLA-G', 'Gene', '3135', (89, 94))
75898	25689063	As to the lesion total HLA-G expression (with mAb 4H84), which was observed with no difference between patient with adenocarcinoma and squamous cell carcinoma, indicating that total HLA-G expression did not vary dramatically in these two histological type NSCLC patients; however, lesion total HLA-G expression was found to be significantly associated with disease clinical TNM stage and significantly associated with the poor prognosis and shorter survival time.	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (135, 158))	('NSCLC', 'Phenotype', 'HP:0030358', (256, 261))	('HLA-G', 'Gene', (23, 28))	('poor prognosis', 'CPA', (422, 436))	('lesion', 'Var', (281, 287))	('HLA-G', 'Gene', (294, 299))	('adenocarcinoma', 'Disease', (116, 130))	('HLA-G', 'Gene', (182, 187))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (135, 158))	('patient', 'Species', '9606', (103, 110))	('patient', 'Species', '9606', (262, 269))	('carcinoma', 'Phenotype', 'HP:0030731', (149, 158))	('adenocarcinoma', 'Disease', 'MESH:D000230', (116, 130))	('associated', 'Reg', (402, 412))	('squamous cell carcinoma', 'Disease', (135, 158))	('associated with', 'Reg', (341, 356))	('HLA-G', 'Gene', '3135', (23, 28))	('NSCLC', 'Disease', 'MESH:D002289', (256, 261))	('HLA-G', 'Gene', '3135', (294, 299))	('HLA-G', 'Gene', '3135', (182, 187))	('patients', 'Species', '9606', (262, 270))	('NSCLC', 'Disease', (256, 261))
75907	25689063	Patients with sHLA-G <40 ng/ml showed prolonged overall survival.	('<40 ng/ml', 'Var', (21, 30))	('overall survival', 'CPA', (48, 64))	('prolonged', 'PosReg', (38, 47))	('Patients', 'Species', '9606', (0, 8))	('HLA-G', 'Gene', (15, 20))	('HLA-G', 'Gene', '3135', (15, 20))
75911	25689063	Multiple factors influenced sHLA-G expression was observed, such as polymorphisms both in the promoter and in the 3' untranslated region that modify the affinity of gene targeted sequences for transcriptional or post-transcriptional factors, epigenetic modification, cytokines, growth factors and hormones.	('polymorphisms', 'Var', (68, 81))	('affinity', 'Interaction', (153, 161))	('HLA-G', 'Gene', (29, 34))	('HLA-G', 'Gene', '3135', (29, 34))	('epigenetic modification', 'Var', (242, 265))	('transcriptional', 'Protein', (193, 208))	('modify', 'Reg', (142, 148))
75920	33596979	Lastly, locked nucleic acid (LNA) miRs in mouse xenograft models were used to evaluate the clinical relevance of miR-34a in HNSCC tumor growth and modulation of the tumor microenvironment in vivo.	('HNSCC tumor', 'Disease', 'MESH:D000077195', (124, 135))	('mouse', 'Species', '10090', (42, 47))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('HNSCC tumor', 'Disease', (124, 135))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('miR-34a', 'Var', (113, 120))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('tumor', 'Disease', (130, 135))	('tumor', 'Disease', (165, 170))
75921	33596979	Chromosome arm 1p loss and P53 mutations are both associated with lower levels of miR-34a.	('Chromosome', 'Gene', (0, 10))	('loss', 'NegReg', (18, 22))	('mutations', 'Var', (31, 40))	('miR-34a', 'MPA', (82, 89))	('levels', 'MPA', (72, 78))	('lower', 'NegReg', (66, 71))	('P53', 'Gene', (27, 30))	('P53', 'Gene', '7157', (27, 30))
75922	33596979	In HNSCC, miR-34a acts as a tumor suppressor and physically interacts with and functionally targets the proto-oncogene MET.	('MET', 'Gene', (119, 122))	('tumor', 'Disease', (28, 33))	('miR-34a', 'Var', (10, 17))	('interacts', 'Interaction', (60, 69))	('targets', 'NegReg', (92, 99))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('MET', 'Gene', '79811', (119, 122))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
75923	33596979	Our studies found that miR-34a suppresses HNSCC carcinogenesis, at least in part, by downregulating MET, consequently inhibiting HNSCC proliferation.	('MET', 'Gene', '79811', (100, 103))	('MET', 'Gene', (100, 103))	('HNSCC proliferation', 'CPA', (129, 148))	('HNSCC carcinogenesis', 'Disease', (42, 62))	('HNSCC carcinogenesis', 'Disease', 'MESH:D000077195', (42, 62))	('downregulating', 'NegReg', (85, 99))	('miR-34a', 'Var', (23, 30))	('inhibiting', 'NegReg', (118, 128))	('suppresses', 'NegReg', (31, 41))
75924	33596979	Consistent with these findings, administration of LNA-miR-34a in an in vivo model of HNSCC leads to diminished HNSCC cell proliferation and tumor burden in vitro and in vivo, represses expression of genes involved in epithelial-mesenchymal transition, and negates the oncogenic effect of MET in mouse tumors.	('HNSCC cell proliferation', 'CPA', (111, 135))	('expression', 'MPA', (185, 195))	('tumor', 'Phenotype', 'HP:0002664', (301, 306))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('LNA-miR-34a', 'Var', (50, 61))	('tumors', 'Disease', (301, 307))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('MET', 'Gene', '79811', (288, 291))	('tumors', 'Disease', 'MESH:D009369', (301, 307))	('tumor', 'Disease', (301, 306))	('represses', 'NegReg', (175, 184))	('tumor', 'Disease', 'MESH:D009369', (301, 306))	('negates', 'NegReg', (256, 263))	('diminished', 'NegReg', (100, 110))	('cel', 'Species', '6239', (117, 120))	('MET', 'Gene', (288, 291))	('tumors', 'Phenotype', 'HP:0002664', (301, 307))	('mouse', 'Species', '10090', (295, 300))	('tumor', 'Disease', (140, 145))
75925	33596979	Consistently, LNA-miR-34a induced a decreased number of immunosuppressive PDL1-expressing tumor-associated macrophages in the tumor microenvironment.	('PDL1-expressing', 'Gene', (74, 89))	('tumor', 'Disease', (90, 95))	('LNA-miR-34a', 'Var', (14, 25))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('decreased', 'NegReg', (36, 45))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('tumor', 'Disease', (126, 131))
75926	33596979	In HNSCC patient samples, higher levels of miR-34a are significantly associated with a higher frequency of Th1 cells and CD8 naive T cells.	('Th1 cells', 'CPA', (107, 116))	('cel', 'Species', '6239', (133, 136))	('patient', 'Species', '9606', (9, 16))	('higher', 'PosReg', (26, 32))	('cel', 'Species', '6239', (111, 114))	('CD8', 'Gene', (121, 124))	('miR-34a', 'Var', (43, 50))	('CD8', 'Gene', '925', (121, 124))	('HNSCC', 'Disease', (3, 8))	('higher', 'PosReg', (87, 93))
75929	33596979	In cancer pathogenesis, miRs can exert both anti-tumorigenic and pro-tumorigenic effects by virtue of miR-specific and context-dependent mechanisms.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('miRs', 'Var', (24, 28))	('tumor', 'Disease', (69, 74))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('tumor', 'Disease', (49, 54))	('cancer', 'Disease', (3, 9))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
75939	33596979	miR-34a directly suppresses HDM4, a negative regulator of p53, forming a positive feedback loop acting on p53.	('p53', 'Gene', '7157', (106, 109))	('miR-34a', 'Var', (0, 7))	('suppresses', 'NegReg', (17, 27))	('HDM4', 'Gene', (28, 32))	('p53', 'Gene', (58, 61))	('p53', 'Gene', (106, 109))	('p53', 'Gene', '7157', (58, 61))
75940	33596979	Treatment with a miR-34a inhibitor attenuates p53-mediated apoptosis in response to genotoxic stress, whereas the ectopic expression of miR-34a causes a significant reprogramming of gene expression and induces apoptosis and cell cycle arrest.	('ectopic expression', 'Var', (114, 132))	('induces', 'Reg', (202, 209))	('p53', 'Gene', (46, 49))	('attenuates', 'NegReg', (35, 45))	('genotoxic stress', 'Disease', 'MESH:D000079225', (84, 100))	('p53', 'Gene', '7157', (46, 49))	('arrest', 'Disease', 'MESH:D006323', (235, 241))	('miR-34a', 'Gene', (136, 143))	('cel', 'Species', '6239', (224, 227))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (224, 241))	('apoptosis', 'CPA', (210, 219))	('arrest', 'Disease', (235, 241))	('reprogramming', 'CPA', (165, 178))	('genotoxic stress', 'Disease', (84, 100))
75945	33596979	Our bioinformatics and experimental analyses identified several genes, including the MET proto-oncogene, that are directly regulated by miR-34a.	('MET', 'Gene', '79811', (85, 88))	('regulated', 'Reg', (123, 132))	('MET', 'Gene', (85, 88))	('miR-34a', 'Var', (136, 143))
75950	33596979	miR-34a based therapeutics have been brought to melanoma clinical trials as a first-in-class miR therapy (https://clinicaltrials.gov/ct2/show/NCT02862145), but this has not been explored in HNSCC.	('melanoma', 'Disease', (48, 56))	('miR-34a', 'Var', (0, 7))	('melanoma', 'Disease', 'MESH:D008545', (48, 56))	('melanoma', 'Phenotype', 'HP:0002861', (48, 56))
75951	33596979	In the present study, we determined that miR-34a suppresses HNSCC growth by inducing cell cycle arrest and senescence, and we identified an anti-tumor miR-34a regulatory function in HNSCC and tumor-associated macrophages (TAMs) in vivo.	('arrest', 'Disease', 'MESH:D006323', (96, 102))	('miR-34a', 'Var', (41, 48))	('tumor', 'Disease', (192, 197))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('TAMs', 'Chemical', '-', (222, 226))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('HNSCC growth', 'CPA', (60, 72))	('arrest', 'Disease', (96, 102))	('cel', 'Species', '6239', (85, 88))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumor', 'Disease', (145, 150))	('inducing', 'Reg', (76, 84))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (85, 102))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('regulatory', 'MPA', (159, 169))	('suppresses', 'NegReg', (49, 59))	('senescence', 'CPA', (107, 117))	('miR-34a', 'Gene', (151, 158))
75953	33596979	The following data is available at gdc.cancer.gov/node/977: cancer type, p53 mutation status, chromosome arm aneuploidy status, miR-34a expression, and mRNA gene expression.	('expression', 'MPA', (136, 146))	('aneuploidy', 'Disease', 'MESH:D000782', (109, 119))	('cancer', 'Disease', (39, 45))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('p53', 'Gene', (73, 76))	('mutation', 'Var', (77, 85))	('miR-34a', 'Var', (128, 135))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('p53', 'Gene', '7157', (73, 76))	('cancer', 'Disease', (60, 66))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('aneuploidy', 'Disease', (109, 119))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
75966	33596979	Synthetic cel-miR-39, miR-34a-5p mimic, and miR-34a-3p mimic (Applied Biosystem) were serially diluted to final concentrations of 300 nM, 30 nM, 3 nM, 0.3 nM, 0.03 nM, 3 pM, 0.3 pM, 0.03 pM, 3 fM, and 0.3 fM.	('miR-39', 'Gene', '266867', (14, 20))	('miR-34a-5p', 'Chemical', '-', (22, 32))	('cel', 'Species', '6239', (10, 13))	('0.03 nM', 'Var', (159, 166))	('miR-39', 'Gene', (14, 20))	('miR-34a-3p', 'Var', (44, 54))
75967	33596979	miR-34a-5p, miR-34a-3p, and cel-miR-39 serial dilutions were reverse-transcribed and assayed using real-time PCR analysis concurrently with RNA extracted from tumor samples and normal tissue.	('miR-39', 'Gene', '266867', (32, 38))	('miR-39', 'Gene', (32, 38))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('tumor', 'Disease', (159, 164))	('cel', 'Species', '6239', (28, 31))	('miR-34a-3p', 'Var', (12, 22))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('miR-34a-5p', 'Chemical', '-', (0, 10))
75969	33596979	Standard curves for miR-34a-5p and miR-34a-3p and cel-miR-39 were included on each plate of the TaqMan microRNA assays to convert the Ct values of each sample into the corresponding number of microRNA copies.	('miR-39', 'Gene', (54, 60))	('miR-39', 'Gene', '266867', (54, 60))	('miR-34a-3p', 'Var', (35, 45))	('miR-34a-5p', 'Chemical', '-', (20, 30))	('cel', 'Species', '6239', (50, 53))
75970	33596979	The absolute quantification result of miR-34a-5p and miR-34a-3p was obtained by normalization to cel-miR-39.	('miR-39', 'Gene', '266867', (101, 107))	('miR-39', 'Gene', (101, 107))	('miR-34a-5p', 'Var', (38, 48))	('cel', 'Species', '6239', (97, 100))	('miR-34a-3p', 'Var', (53, 63))	('miR-34a-5p', 'Chemical', '-', (38, 48))
75975	33596979	Ten days post implantation of tumor cells, 24 mice were randomized to three group of control (PBS injection), LNA- miR-34a-5p or LNA-miR-34a-5p (n = 8 per group; n = 24 total).	('LNA- miR-34a-5p', 'Var', (110, 125))	('miR-34a-5p', 'Chemical', '-', (115, 125))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('LNA-miR-34a-5p', 'Var', (129, 143))	('mice', 'Species', '10090', (46, 50))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('miR-34a-5p', 'Chemical', '-', (133, 143))	('PBS', 'Chemical', 'MESH:D007854', (94, 97))	('tumor', 'Disease', (30, 35))	('cel', 'Species', '6239', (36, 39))
75984	33596979	Mutant PDL1 and MET 3'-UTRs were generated with the QuickchangeXL mutagenesis kit (Stratagene, United States) to disrupt the binding of miR-34a.	('kit', 'Gene', '3815', (78, 81))	('UTR', 'Gene', '2837', (23, 26))	('MET', 'Gene', (16, 19))	('UTR', 'Gene', (23, 26))	('miR-34a', 'Protein', (136, 143))	('binding', 'Interaction', (125, 132))	('Mutant', 'Var', (0, 6))	('PDL1', 'Gene', (7, 11))	('MET', 'Gene', '79811', (16, 19))	('disrupt', 'NegReg', (113, 120))	('kit', 'Gene', (78, 81))
75986	33596979	CAL27 cells were co-transfected with wild-type or mutant MET reporter plasmid and miR-34a-5p mimic or negative control using Lipofectamine 2000 (Invitrogen).	('MET', 'Gene', (57, 60))	('cel', 'Species', '6239', (6, 9))	('miR-34a-5p', 'Chemical', '-', (82, 92))	('mutant', 'Var', (50, 56))	('Lipofectamine 2000', 'Chemical', 'MESH:C086724', (125, 143))	('CAL27', 'CellLine', 'CVCL:1107', (0, 5))	('MET', 'Gene', '79811', (57, 60))
75987	33596979	Similar approach was taken to verify interaction of miR-34a-5p with PDL1 3'UTR in RAW macrophages.	('UTR', 'Gene', '2837', (75, 78))	('miR-34a-5p', 'Chemical', '-', (52, 62))	('PDL1', 'Gene', (68, 72))	('UTR', 'Gene', (75, 78))	('miR-34a-5p', 'Var', (52, 62))	('interaction', 'Interaction', (37, 48))
76008	33596979	TaqMan microRNA Assays (Applied Biosystems) was used for detection of miR-34a-3p and miR-34a-5p expression according to manufacturer's protocol.	('miR-34a-3p', 'Gene', (70, 80))	('miR-34a-5p', 'Chemical', '-', (85, 95))	('miR-34a-5p', 'Var', (85, 95))
76032	33596979	After washing, the eluted RNA samples were further purified with TRI reagent and subjected to TaqMan MicroRNA Assay and qRT-PCR analysis to detect miR-34a-5p and MET, respectively.	('MET', 'Gene', (162, 165))	('miR-34a-5p', 'Chemical', '-', (147, 157))	('miR-34a-5p', 'Var', (147, 157))	('MET', 'Gene', '79811', (162, 165))
76033	33596979	A flow cytometry panel consisting of Lin-1, CD45, CD11b, F4/80, and CD274 (PDL1) was used for quantification and characterization of TAMs.	('CD274', 'Var', (68, 73))	('Lin-1', 'Gene', '10421', (37, 42))	('TAMs', 'Chemical', '-', (133, 137))	('Lin-1', 'Gene', (37, 42))
76039	33596979	As miR-34a is a transcriptional target of P53, we compared miR-34 levels in cases with and without p53 mutation and found significantly lower miR-34a expression in p53 mutated cases compared to p53 wild-type (WT) cases (P < 0.001) (Fig.	('mutated', 'Var', (168, 175))	('lower', 'NegReg', (136, 141))	('miR-34', 'Gene', '407040', (3, 9))	('miR-34', 'Gene', (142, 148))	('expression', 'MPA', (150, 160))	('miR-34', 'Gene', '407040', (59, 65))	('miR-34', 'Gene', '407040', (142, 148))	('p53', 'Gene', (194, 197))	('P53', 'Gene', (42, 45))	('miR-34', 'Gene', (3, 9))	('p53', 'Gene', '7157', (194, 197))	('p53', 'Gene', '7157', (99, 102))	('p53', 'Gene', (99, 102))	('p53', 'Gene', (164, 167))	('P53', 'Gene', '7157', (42, 45))	('miR-34', 'Gene', (59, 65))	('p53', 'Gene', '7157', (164, 167))
76040	33596979	Similarly, in a squamous cell carcinomas (SCCs) and HNSCC specific analysis, we found a significantly lower expression of miR-34a in cases with p53 mutation (P < 0.001) (Fig.	('lower', 'NegReg', (102, 107))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (16, 40))	('p53', 'Gene', '7157', (144, 147))	('squamous cell carcinomas', 'Disease', (16, 40))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (16, 39))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (16, 40))	('miR-34a', 'Protein', (122, 129))	('expression', 'MPA', (108, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (30, 39))	('carcinomas', 'Phenotype', 'HP:0030731', (30, 40))	('mutation', 'Var', (148, 156))	('p53', 'Gene', (144, 147))
76041	33596979	miR-34a is located on chromosome arm 1p, and 1p deletion in non-mutated p53 cases was associated with a lower level of miR-34a in the pan-cancer analysis (P < 0.0001) (Fig.	('cancer', 'Disease', (138, 144))	('1p deletion', 'Var', (45, 56))	('p53', 'Gene', (72, 75))	('p53', 'Gene', '7157', (72, 75))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('lower', 'NegReg', (104, 109))	('miR-34a', 'Gene', (0, 7))	('cancer', 'Disease', 'MESH:D009369', (138, 144))	('miR-34a', 'MPA', (119, 126))
76046	33596979	The sequences of mature miR-34a-3p (passenger strand) and miR-34a-5p (guide stand) are reported to be conserved among species.	('miR-34a-3p', 'Gene', (24, 34))	('miR-34a-5p', 'Chemical', '-', (58, 68))	('miR-34a-5p', 'Var', (58, 68))
76048	33596979	We analyzed levels of miR-34a-3p and miR-34a-5p in our cohort of primary HNSCC tumor samples compared to the adjacent tissue (n = 42).	('miR-34a-5p', 'Var', (37, 47))	('HNSCC tumor', 'Disease', 'MESH:D000077195', (73, 84))	('miR-34a-5p', 'Chemical', '-', (37, 47))	('HNSCC tumor', 'Disease', (73, 84))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
76049	33596979	Levels of both miR-34a-5p and miR-34a-3p were decreased in tumor tissue compared to normal tissue (P < 0.05) (Fig.	('tumor', 'Disease', (59, 64))	('miR-34a-5p', 'Chemical', '-', (15, 25))	('decreased', 'NegReg', (46, 55))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('miR-34a-3p', 'Var', (30, 40))	('miR-34a-5p', 'Var', (15, 25))
76051	33596979	Moreover, levels of miR-34a-5p and miR-34a-3p were significantly lower in the circulating exosomes of patients with HNSCC compared to cancer-free patients (P < 0.05) (Fig.	('levels', 'MPA', (10, 16))	('patients', 'Species', '9606', (102, 110))	('lower', 'NegReg', (65, 70))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('miR-34a-3p', 'Var', (35, 45))	('miR-34a-5p', 'Var', (20, 30))	('HNSCC', 'Disease', (116, 121))	('miR-34a-5p', 'Chemical', '-', (20, 30))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('patients', 'Species', '9606', (146, 154))
76053	33596979	However, the miR-34a-3p copy number was overall much lower than miR-34a-5p, which could be attributed to lower stability of the passenger strand in miR biogenesis.	('lower', 'NegReg', (105, 110))	('miR-34a-3p', 'Var', (13, 23))	('stability', 'MPA', (111, 120))	('miR-34a-5p', 'Chemical', '-', (64, 74))	('lower', 'NegReg', (53, 58))
76054	33596979	As our bioinformatics prediction suggested direct targeting of MET by miR-34a-5p, we investigated MET expression in HNSCC samples.	('MET', 'Gene', '79811', (63, 66))	('MET', 'Gene', (98, 101))	('MET', 'Gene', (63, 66))	('miR-34a-5p', 'Var', (70, 80))	('MET', 'Gene', '79811', (98, 101))	('miR-34a-5p', 'Chemical', '-', (70, 80))
76057	33596979	We also found an inverse association between MET expression and miR-34a-5p in HNSCC tumors (Fig.	('HNSCC tumors', 'Disease', (78, 90))	('MET', 'Gene', '79811', (45, 48))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('inverse', 'NegReg', (17, 24))	('MET', 'Gene', (45, 48))	('miR-34a-5p', 'Var', (64, 74))	('HNSCC tumors', 'Disease', 'MESH:D000077195', (78, 90))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('miR-34a-5p', 'Chemical', '-', (64, 74))
76061	33596979	High expression of MET was associated with significantly lower survival in HNSCC cases, controlling for age, gender, race, and stage (HR: 1.65, 95% CI: 1:1-1.47), p = 0.037) (Supplementary Table 2).	('High', 'Var', (0, 4))	('MET', 'Gene', (19, 22))	('HNSCC', 'Disease', (75, 80))	('MET', 'Gene', '79811', (19, 22))	('survival', 'MPA', (63, 71))	('lower', 'NegReg', (57, 62))
76068	33596979	Overexpression of miR-34a-5p by plasmid followed by anti-Ago2 CHIP and RNA-binding protein immunoprecipitation (RIP)-qPCR on the whole cell lysate showed a complex of MET, miR-34a-5p with Ago2 in CAL27 cells.	('miR-34a-5p', 'Chemical', '-', (18, 28))	('MET', 'Gene', '79811', (167, 170))	('CAL27', 'CellLine', 'CVCL:1107', (196, 201))	('complex', 'Interaction', (156, 163))	('MET', 'Gene', (167, 170))	('cel', 'Species', '6239', (202, 205))	('RIP', 'Gene', (112, 115))	('miR-34a-5p', 'Var', (172, 182))	('miR-34a-5p', 'Chemical', '-', (172, 182))	('RIP', 'Gene', '3267', (112, 115))	('cel', 'Species', '6239', (135, 138))
76069	33596979	Luciferase assay further confirmed the direct interaction of miR-34a seed sequence with the MET 3'UTR, where a significant decrease in luciferase activity was detected when CAL27 cells were co-transfected with the WT 3'UTR of MET and not a mutated 3'UTR (Fig.	('luciferase', 'Enzyme', (135, 145))	('MET', 'Gene', '79811', (226, 229))	('MET', 'Gene', (226, 229))	('MET', 'Gene', (92, 95))	('activity', 'MPA', (146, 154))	('decrease', 'NegReg', (123, 131))	('UTR', 'Gene', (250, 253))	('CAL27', 'CellLine', 'CVCL:1107', (173, 178))	('UTR', 'Gene', '2837', (250, 253))	('UTR', 'Gene', '2837', (98, 101))	('cel', 'Species', '6239', (179, 182))	('UTR', 'Gene', '2837', (219, 222))	('UTR', 'Gene', (98, 101))	('interaction', 'Interaction', (46, 57))	('MET', 'Gene', '79811', (92, 95))	('UTR', 'Gene', (219, 222))	('miR-34a', 'Var', (61, 68))
76071	33596979	The level of miR-34a-5p was down in all the HNSCC cell lines examined compared to oral keratinocytes (P < 0.001) (Fig.	('down', 'NegReg', (28, 32))	('miR-34a-5p', 'Chemical', '-', (13, 23))	('miR-34a-5p', 'Var', (13, 23))	('cel', 'Species', '6239', (50, 53))
76085	33596979	In addition, our rescue experiment demonstrated that miR-34a-5p can reverse the anti-apoptotic effect of MET overexpression (Fig.	('miR-34a-5p', 'Var', (53, 63))	('miR-34a-5p', 'Chemical', '-', (53, 63))	('MET', 'Gene', '79811', (105, 108))	('anti-apoptotic effect', 'CPA', (80, 101))	('MET', 'Gene', (105, 108))
76089	33596979	Interestingly, the administration of miR-34a-5p led to a decreased mRNA expression of the mesenchymal marker vimentin and increased expression of epithelial marker CDH1 in CAL27 and HTB-43 (Fig.	('miR-34a-5p', 'Var', (37, 47))	('CDH1', 'Gene', '999', (164, 168))	('miR-34a-5p', 'Chemical', '-', (37, 47))	('vimentin', 'Gene', '7431', (109, 117))	('vimentin', 'Gene', (109, 117))	('mRNA expression', 'MPA', (67, 82))	('increased', 'PosReg', (122, 131))	('expression', 'MPA', (132, 142))	('CAL27', 'CellLine', 'CVCL:1107', (172, 177))	('decreased', 'NegReg', (57, 66))	('CDH1', 'Gene', (164, 168))
76090	33596979	Similarly, the administration of miR-34a-5p led to a decreased in Vimentin protein expression and an increase in CDH1 protein expression.	('miR-34a-5p', 'Var', (33, 43))	('CDH1', 'Gene', '999', (113, 117))	('miR-34a-5p', 'Chemical', '-', (33, 43))	('increase', 'PosReg', (101, 109))	('Vimentin protein', 'Protein', (66, 82))	('CDH1', 'Gene', (113, 117))	('decreased', 'NegReg', (53, 62))
76093	33596979	Tumor growth was significantly attenuated in the mice that received the LNA-miR-34a-5p mimic compared to those that received the control mimic or vehicle (Fig.	('LNA-miR-34a-5p mimic', 'Var', (72, 92))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('attenuated', 'NegReg', (31, 41))	('mice', 'Species', '10090', (49, 53))	('Tumor growth', 'CPA', (0, 12))	('miR-34a-5p', 'Chemical', '-', (76, 86))
76094	33596979	The level of miR-34a-5p was significantly increased in the tumors of mice that received LNA-miR-34a-5p (Fig.	('increased', 'PosReg', (42, 51))	('level', 'MPA', (4, 9))	('miR-34a-5p', 'Chemical', '-', (92, 102))	('LNA-miR-34a-5p', 'Var', (88, 102))	('mice', 'Species', '10090', (69, 73))	('tumors', 'Disease', 'MESH:D009369', (59, 65))	('tumors', 'Disease', (59, 65))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('miR-34a-5p', 'Chemical', '-', (13, 23))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
76097	33596979	The mesenchymal marker vimentin was significantly decreased in the treatment group, indicating suppression of EMT by miR-34a-5p (Fig.	('EMT', 'CPA', (110, 113))	('vimentin', 'Gene', '7431', (23, 31))	('decreased', 'NegReg', (50, 59))	('suppression', 'NegReg', (95, 106))	('vimentin', 'Gene', (23, 31))	('miR-34a-5p', 'Var', (117, 127))	('miR-34a-5p', 'Chemical', '-', (117, 127))
76099	33596979	PDL1 is reported to be direct target of miR-34a-5p.	('PDL1', 'Gene', (0, 4))	('miR-34a-5p', 'Chemical', '-', (40, 50))	('miR-34a-5p', 'Var', (40, 50))
76100	33596979	Consistently, a luciferase assay confirmed the direct interaction of miR-34a-5p seed sequence with the PDL1 3'UTR, where a significant decrease in luciferase activity was detected when RAW macrophages were co-transfected with the WT 3'UTR of PDL1 (Fig.	('UTR', 'Gene', '2837', (110, 113))	('UTR', 'Gene', (110, 113))	('miR-34a-5p', 'Chemical', '-', (69, 79))	('activity', 'MPA', (158, 166))	('UTR', 'Gene', '2837', (235, 238))	('UTR', 'Gene', (235, 238))	('interaction', 'Interaction', (54, 65))	('luciferase', 'Enzyme', (147, 157))	('miR-34a-5p', 'Var', (69, 79))	('decrease', 'NegReg', (135, 143))
76101	33596979	Taken together, these data support the mechanistic connection of miR-34a-5p in suppressing oncogenic MET and restoring tumor immunity through targeting PDL1.	('tumor', 'Disease', (119, 124))	('MET', 'Gene', (101, 104))	('MET', 'Gene', '79811', (101, 104))	('suppressing', 'NegReg', (79, 90))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('restoring', 'PosReg', (109, 118))	('targeting', 'Reg', (142, 151))	('miR-34a-5p', 'Var', (65, 75))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('PDL1', 'Gene', (152, 156))	('miR-34a-5p', 'Chemical', '-', (65, 75))
76107	33596979	Our analysis of TCGA data demonstrated that downregulation of miR-34a is associated with p53 mutation and chromosome arm 1p deletion in HNSCC and lung squamous cell carcinoma.	('downregulation', 'NegReg', (44, 58))	('p53', 'Gene', (89, 92))	('HNSCC', 'Disease', (136, 141))	('lung squamous cell carcinoma', 'Disease', (146, 174))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (146, 174))	('carcinoma', 'Phenotype', 'HP:0030731', (165, 174))	('p53', 'Gene', '7157', (89, 92))	('mutation', 'Var', (93, 101))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (151, 174))	('miR-34a', 'Gene', (62, 69))
76108	33596979	Additionally, higher levels of miR-34a-5p were correlated with lower levels of key transcription factors of EMT.	('miR-34a-5p', 'Chemical', '-', (31, 41))	('lower', 'NegReg', (63, 68))	('higher', 'PosReg', (14, 20))	('miR-34a-5p', 'Var', (31, 41))
76110	33596979	We found that miR-34a-5p acts as a tumor suppressor, directly represses the proto-oncogene MET, and modulates cell proliferation.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('represses', 'NegReg', (62, 71))	('miR-34a-5p', 'Chemical', '-', (14, 24))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumor', 'Disease', (35, 40))	('modulates', 'Reg', (100, 109))	('MET', 'Gene', '79811', (91, 94))	('miR-34a-5p', 'Var', (14, 24))	('cell proliferation', 'CPA', (110, 128))	('cel', 'Species', '6239', (110, 113))	('MET', 'Gene', (91, 94))
76114	33596979	Consistent with previous work, p53 mutation correlates with decreased expression of miR-34a, suggesting miR-34a as a transcriptional target of p53.	('p53', 'Gene', (31, 34))	('p53', 'Gene', '7157', (31, 34))	('decreased', 'NegReg', (60, 69))	('p53', 'Gene', '7157', (143, 146))	('miR-34a', 'Gene', (84, 91))	('expression', 'MPA', (70, 80))	('mutation', 'Var', (35, 43))	('p53', 'Gene', (143, 146))
76116	33596979	We are actively pursuing aneuploidy as a biomarker for drug response, including for miR-34a and other miRs.	('aneuploidy', 'Disease', 'MESH:D000782', (25, 35))	('miR-34a', 'Var', (84, 91))	('aneuploidy', 'Disease', (25, 35))
76117	33596979	Interestingly, the effect of copy number on miR-34a expression is masked by p53 mutation; if p53 is mutated, there is no correlation between chromosome 1p copy number and miR-34a expression.	('p53', 'Gene', (76, 79))	('p53', 'Gene', (93, 96))	('p53', 'Gene', '7157', (76, 79))	('p53', 'Gene', '7157', (93, 96))	('mutation', 'Var', (80, 88))
76118	33596979	Our mechanistic experiments showed that miR-34a directly interacts with the proto-oncogene MET and attenuates the MET signaling axis by posttranscriptional gene regulation in cancer cells.	('interacts', 'Interaction', (57, 66))	('cel', 'Species', '6239', (182, 185))	('cancer', 'Disease', (175, 181))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('MET', 'Gene', '79811', (114, 117))	('MET', 'Gene', (114, 117))	('miR-34a', 'Var', (40, 47))	('MET', 'Gene', '79811', (91, 94))	('attenuates', 'NegReg', (99, 109))	('MET', 'Gene', (91, 94))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
76119	33596979	Activating point mutations of MET and MET amplification have been reported in several cancer types, including gastric cancer, breast cancer, hepatocellular carcinoma, and non-small cell lung cancer.	('Activating', 'PosReg', (0, 10))	('MET', 'Gene', '79811', (38, 41))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (141, 165))	('breast cancer', 'Phenotype', 'HP:0003002', (126, 139))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('lung cancer', 'Phenotype', 'HP:0100526', (186, 197))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (171, 197))	('gastric cancer', 'Disease', (110, 124))	('cancer', 'Disease', (191, 197))	('hepatocellular carcinoma', 'Disease', (141, 165))	('breast cancer', 'Disease', 'MESH:D001943', (126, 139))	('breast cancer', 'Disease', (126, 139))	('point mutations', 'Var', (11, 26))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (175, 197))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('MET', 'Gene', (30, 33))	('cancer', 'Disease', (86, 92))	('cancer', 'Disease', (118, 124))	('gastric cancer', 'Disease', 'MESH:D013274', (110, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (156, 165))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (171, 197))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('MET', 'Gene', (38, 41))	('cancer', 'Disease', (133, 139))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (141, 165))	('cancer', 'Disease', 'MESH:D009369', (191, 197))	('gastric cancer', 'Phenotype', 'HP:0012126', (110, 124))	('non-small cell lung cancer', 'Disease', (171, 197))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('MET', 'Gene', '79811', (30, 33))	('cancer', 'Disease', 'MESH:D009369', (118, 124))
76126	33596979	Interestingly, MET induces MAPK re-activation in all tested HNSCC models, and blocking of MAPK with a MET inhibitor re-sensitized the HGF-stimulated tumor cells to cetuximab.	('MET', 'Gene', (102, 105))	('cel', 'Species', '6239', (155, 158))	('blocking', 'Var', (78, 86))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('HGF', 'Gene', (134, 137))	('re-activation', 'PosReg', (32, 45))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('MAPK', 'Protein', (27, 31))	('MAPK', 'Gene', (90, 94))	('HGF', 'Gene', '3082', (134, 137))	('tumor', 'Disease', (149, 154))	('MET', 'Gene', '79811', (15, 18))	('MET', 'Gene', (15, 18))	('cetuximab', 'Chemical', 'MESH:D000068818', (164, 173))	('MET', 'Gene', '79811', (102, 105))
76127	33596979	Similarly, MET knock down sensitized two cetuximab resistant non-small cell lung adenocarcinoma cell lines, LXFA 526 L and LXFA 1647 L, to EGFR inhibition.	('cetuximab', 'Chemical', 'MESH:D000068818', (41, 50))	('MET', 'Gene', '79811', (11, 14))	('cel', 'Species', '6239', (71, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('lung adenocarcinoma', 'Disease', (76, 95))	('knock down', 'Var', (15, 25))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (76, 95))	('MET', 'Gene', (11, 14))	('EGFR', 'Gene', '1956', (139, 143))	('cel', 'Species', '6239', (96, 99))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (76, 95))	('EGFR', 'Gene', (139, 143))	('sensitized', 'Reg', (26, 36))
76130	33596979	Direct interaction of mir-34a-5p with PDL1 has been reported previously.	('mir-34a-5p', 'Chemical', '-', (22, 32))	('interaction', 'Interaction', (7, 18))	('PDL1', 'Gene', (38, 42))	('mir-34a-5p', 'Var', (22, 32))
76139	33596979	In the present study, we showed that restoration of miR-34a-5p using LNA-miR34-5p could inhibit tumor growth and progression and restore anti-tumor immune function in HNSCC.	('miR-34a-5p', 'Chemical', '-', (52, 62))	('restore', 'PosReg', (129, 136))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumor', 'Disease', (142, 147))	('tumor', 'Disease', (96, 101))	('inhibit', 'NegReg', (88, 95))	('miR34', 'Gene', (73, 78))	('miR34', 'Gene', '407040', (73, 78))	('HNSCC', 'Disease', (167, 172))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('miR-34a-5p', 'Var', (52, 62))	('tumor', 'Disease', 'MESH:D009369', (142, 147))
76140	33596979	This study presents strong evidence that miR-34a-5p acts as a tumor suppressor and physically interacts with and functionally targets the proto-oncogene MET.	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', (62, 67))	('miR-34a-5p', 'Var', (41, 51))	('MET', 'Gene', '79811', (153, 156))	('miR-34a-5p', 'Chemical', '-', (41, 51))	('interacts', 'Interaction', (94, 103))	('targets', 'NegReg', (126, 133))	('MET', 'Gene', (153, 156))
76142	33596979	In particular, miR-34a-5p overexpression might be useful as adjuvant therapy or monotherapy in HNSCC.	('HNSCC', 'Disease', (95, 100))	('overexpression', 'PosReg', (26, 40))	('miR-34a-5p', 'Chemical', '-', (15, 25))	('miR-34a-5p', 'Var', (15, 25))
76158	31989769	Class I PI3Ks are divided into class IA PI3Ks that are activated by growth factor receptor tyrosine kinases, and class IB PI3Ks that are activated by G-protein-coupled receptors.5 Class IA PI3K is a heterodimer consisting of a p85 regulatory subunit and a p110 catalytic subunit.	('PI3K', 'Var', (189, 193))	('p85', 'Gene', '5296', (227, 230))	('p85', 'Gene', (227, 230))
76162	31989769	Vps34 binds to the adapter protein Vps15, which is encoded by the PIK3R4 gene.7  The role of each class of PI3K can be generally categorized into their importance in cell signaling (class I and II) or membrane trafficking (class II and III).	('PIK3R4', 'Gene', '30849', (66, 72))	('Vps15', 'Gene', (35, 40))	('Vps34', 'Gene', '5289', (0, 5))	('PI3K', 'Var', (107, 111))	('cell signaling', 'MPA', (166, 180))	('PIK3R4', 'Gene', (66, 72))	('Vps15', 'Gene', '30849', (35, 40))	('membrane trafficking', 'MPA', (201, 221))	('Vps34', 'Gene', (0, 5))
76163	31989769	A majority of the evidence for the importance of PI3K in human cancer implicates class IA PI3Ks, and specifically the p110alpha isoform.	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('p110alpha', 'Var', (118, 127))	('implicates', 'Reg', (70, 80))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('PI3Ks', 'Var', (90, 95))	('human', 'Species', '9606', (57, 62))	('cancer', 'Disease', (63, 69))
76164	31989769	The presence of PIK3CA gene mutations or amplifications has been found in a diverse range of malignancies.8 In a breast cancer mouse model, inhibition of the p110alpha isoform led to increased mammary tumorigenesis.9 Preclinical evidence has also identified a modulatory or regulatory role for other class IA isoforms such as p110beta and p110delta.9, 10 Further preclinical data suggests that there exists significant functional redundancy of class IA PI3Ks, and only a small fraction of total class I PI3K activity is required to maintain cell survival and proliferation.11 Inhibition of specific PI3K isoforms, such as p110alpha, may also lead to the upregulation of alternative bypass pathways such as the ERK pathway.	('Inhibition', 'NegReg', (576, 586))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('mouse', 'Species', '10090', (127, 132))	('breast cancer', 'Disease', 'MESH:D001943', (113, 126))	('breast cancer', 'Disease', (113, 126))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('breast cancer', 'Phenotype', 'HP:0003002', (113, 126))	('ERK pathway', 'Pathway', (710, 721))	('upregulation', 'PosReg', (654, 666))	('malignancies', 'Disease', 'MESH:D009369', (93, 105))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('tumor', 'Disease', (201, 206))	('malignancies', 'Disease', (93, 105))	('PI3K', 'Gene', (599, 603))	('alternative bypass pathways', 'Pathway', (670, 697))	('p110alpha', 'Var', (622, 631))
76172	31989769	Somatic mutations that encode for the various components of the signaling cascade and gene amplifications have been demonstrated in numerous different cancers.	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('mutations', 'Var', (8, 17))	('cancers', 'Phenotype', 'HP:0002664', (151, 158))	('cancers', 'Disease', 'MESH:D009369', (151, 158))	('demonstrated', 'Reg', (116, 128))	('cancers', 'Disease', (151, 158))
76174	31989769	Somatic mutations of PIK3CA and amplifications of PIK3CA are frequently found in patients with NSCLC.	('found', 'Reg', (72, 77))	('NSCLC', 'Disease', 'MESH:D002289', (95, 100))	('PIK3CA', 'Gene', (21, 27))	('patients', 'Species', '9606', (81, 89))	('NSCLC', 'Phenotype', 'HP:0030358', (95, 100))	('amplifications', 'Var', (32, 46))	('PIK3CA', 'Gene', (50, 56))	('NSCLC', 'Disease', (95, 100))
76175	31989769	A large study of 1144 consecutive NSCLC patients investigated tumor tissue using next generation sequencing (NGS) for PIK3CA mutations.37 Mutations were identified in 3.7% of patients, with predominance for squamous cell carcinoma (8.9%) compared with adenocarcinoma (2.9%).	('adenocarcinoma', 'Disease', (252, 266))	('NSCLC', 'Disease', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('carcinoma', 'Phenotype', 'HP:0030731', (221, 230))	('adenocarcinoma', 'Disease', 'MESH:D000230', (252, 266))	('patients', 'Species', '9606', (40, 48))	('NSCLC', 'Disease', 'MESH:D002289', (34, 39))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (207, 230))	('tumor', 'Disease', (62, 67))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (207, 230))	('NSCLC', 'Phenotype', 'HP:0030358', (34, 39))	('patients', 'Species', '9606', (175, 183))	('squamous cell carcinoma', 'Disease', (207, 230))	('PIK3CA', 'Gene', (118, 124))	('Mutations', 'Var', (138, 147))	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('carcinoma', 'Phenotype', 'HP:0030731', (257, 266))
76176	31989769	E545K exon 9 mutations (57.1%) were most common, followed by H1047R exon 20 (16.7%) and E542K exon 9 (14.3%) mutations.	('E545K', 'Mutation', 'rs104886003', (0, 5))	('E545K', 'Var', (0, 5))	('E542K', 'Var', (88, 93))	('H1047R', 'Var', (61, 67))	('E542K', 'Mutation', 'rs121913273', (88, 93))	('H1047R', 'Mutation', 'rs121913279', (61, 67))
76177	31989769	Importantly, in a significant proportion of patients (57.1%), this study found coexisting oncogenic mutations in genes encoding for EGFR, BRAF, ALK and KRAS.	('mutations', 'Var', (100, 109))	('ALK', 'Gene', '238', (144, 147))	('EGFR', 'Gene', '1956', (132, 136))	('patients', 'Species', '9606', (44, 52))	('BRAF', 'Gene', '673', (138, 142))	('KRAS', 'Gene', (152, 156))	('EGFR', 'Gene', (132, 136))	('ALK', 'Gene', (144, 147))	('KRAS', 'Gene', '3845', (152, 156))	('BRAF', 'Gene', (138, 142))
76178	31989769	Yamamoto et al.38 examined 86 NSCLC cell lines and 356 resected NSCLC tumors for PIK3CA mutations in exon 9 or 20 and PIK3CA amplification.	('NSCLC', 'Disease', 'MESH:D002289', (30, 35))	('NSCLC', 'Disease', 'MESH:D002289', (64, 69))	('PIK3CA', 'Gene', (81, 87))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('mutations in', 'Var', (88, 100))	('NSCLC', 'Phenotype', 'HP:0030358', (30, 35))	('NSCLC', 'Phenotype', 'HP:0030358', (64, 69))	('tumors', 'Disease', (70, 76))	('tumors', 'Disease', 'MESH:D009369', (70, 76))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('NSCLC', 'Disease', (30, 35))	('NSCLC', 'Disease', (64, 69))
76179	31989769	Either a mutation or amplification was detected in 12.8% of cell lines and 19.1% of tumors.	('mutation', 'Var', (9, 17))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('tumors', 'Disease', 'MESH:D009369', (84, 90))	('tumors', 'Disease', (84, 90))	('amplification', 'Var', (21, 34))
76180	31989769	In this study, PIK3CA amplifications were also more common in patients with squamous cell carcinoma (33.1%) compared with adenocarcinoma (6.2%).	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (76, 99))	('adenocarcinoma', 'Disease', (122, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('squamous cell carcinoma', 'Disease', (76, 99))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (76, 99))	('adenocarcinoma', 'Disease', 'MESH:D000230', (122, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('patients', 'Species', '9606', (62, 70))	('amplifications', 'Var', (22, 36))	('PIK3CA', 'Gene', (15, 21))	('common', 'Reg', (52, 58))
76181	31989769	The functional importance of PIK3CA mutation or amplification was confirmed with increased Akt activity, and mutations were similarly not mutually exclusive with EGFR or KRAS mutations.	('Akt', 'Gene', '207', (91, 94))	('KRAS', 'Gene', (170, 174))	('EGFR', 'Gene', '1956', (162, 166))	('Akt', 'Gene', (91, 94))	('EGFR', 'Gene', (162, 166))	('KRAS', 'Gene', '3845', (170, 174))	('PIK3CA', 'Gene', (29, 35))	('increased', 'PosReg', (81, 90))	('mutation', 'Var', (36, 44))	('amplification', 'Var', (48, 61))
76184	31989769	Another series of early stage NSCLC specimens revealed complete loss of PTEN expression in 44% of tumors, reduced level of expression in 29% and normal expression in 27%.43 This study similarly showed methylation of PTEN in 26% of tumors with loss of heterozygosity at microsatellites in chromosome 10q23 occurring in 19% of studied specimens; however, neither was a significant predictor of PTEN protein expression.	('tumors', 'Disease', (98, 104))	('PTEN', 'Gene', '5728', (72, 76))	('tumors', 'Disease', (231, 237))	('NSCLC', 'Disease', 'MESH:D002289', (30, 35))	('PTEN', 'Gene', (392, 396))	('tumors', 'Disease', 'MESH:D009369', (98, 104))	('PTEN', 'Gene', (216, 220))	('loss', 'Var', (243, 247))	('NSCLC', 'Disease', (30, 35))	('tumors', 'Disease', 'MESH:D009369', (231, 237))	('PTEN', 'Gene', '5728', (392, 396))	('NSCLC', 'Phenotype', 'HP:0030358', (30, 35))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('methylation', 'Var', (201, 212))	('PTEN', 'Gene', '5728', (216, 220))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('microsatellites', 'Var', (269, 284))	('PTEN', 'Gene', (72, 76))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('tumors', 'Phenotype', 'HP:0002664', (231, 237))
76185	31989769	A retrospective analysis of the phase III FLEX study of chemotherapy in combination with cetuximab in patients with EGFR-expressing advanced NSCLC, showed 35% with negative PTEN expression.44 The presence of PTEN expression is potentially correlated with improved survival.	('improved', 'PosReg', (255, 263))	('patients', 'Species', '9606', (102, 110))	('PTEN', 'Gene', (208, 212))	('NSCLC', 'Disease', (141, 146))	('PTEN', 'Gene', (173, 177))	('PTEN', 'Gene', '5728', (208, 212))	('PTEN', 'Gene', '5728', (173, 177))	('NSCLC', 'Disease', 'MESH:D002289', (141, 146))	('cetuximab', 'Chemical', 'MESH:D000068818', (89, 98))	('presence', 'Var', (196, 204))	('EGFR', 'Gene', '1956', (116, 120))	('NSCLC', 'Phenotype', 'HP:0030358', (141, 146))	('EGFR', 'Gene', (116, 120))
76188	31989769	Malanga et al.47 examined 105 resected NSCLC specimens, and identified a somatic mutation of the gene encoding for Akt1 through direct sequencing of PCR products.	('NSCLC', 'Phenotype', 'HP:0030358', (39, 44))	('Malanga', 'Species', '4456', (0, 7))	('mutation', 'Var', (81, 89))	('Akt1', 'Gene', (115, 119))	('NSCLC', 'Disease', (39, 44))	('NSCLC', 'Disease', 'MESH:D002289', (39, 44))	('Akt1', 'Gene', '207', (115, 119))
76189	31989769	Two squamous cell carcinoma specimens were found to contain the E17K mutation of Akt1 in exon 4.	('carcinoma', 'Phenotype', 'HP:0030731', (18, 27))	('Akt1', 'Gene', (81, 85))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (4, 27))	('squamous cell carcinoma', 'Disease', (4, 27))	('Akt1', 'Gene', '207', (81, 85))	('E17K', 'Mutation', 'rs121434592', (64, 68))	('E17K', 'Var', (64, 68))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (4, 27))
76190	31989769	Another study using a high resolution melting assay, revealed four of 219 NSCLC specimens with an Akt1 mutation.48 Of these, one contained the E17K mutations and was of squamous cell carcinoma histology.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (169, 192))	('NSCLC', 'Phenotype', 'HP:0030358', (74, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (183, 192))	('Akt1', 'Gene', '207', (98, 102))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (169, 192))	('squamous cell carcinoma', 'Disease', (169, 192))	('mutation.48', 'Var', (103, 114))	('NSCLC', 'Disease', (74, 79))	('E17K', 'Mutation', 'rs121434592', (143, 147))	('NSCLC', 'Disease', 'MESH:D002289', (74, 79))	('E17K mutations', 'Var', (143, 157))	('Akt1', 'Gene', (98, 102))	('contained', 'Reg', (129, 138))
76191	31989769	The other three tumors showed rare single nucleotide polymorphisms.	('tumors', 'Disease', (16, 22))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('single nucleotide polymorphisms', 'Var', (35, 66))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('tumors', 'Disease', 'MESH:D009369', (16, 22))
76194	31989769	The importance of mTOR in bronchial adenocarcinoma may be related to its coupling with eIF-4E which functions as an oncogene.55 The presence of mTOR activity may also be a poor prognostic factor in early stage NSCLC.	('mTOR', 'Gene', (18, 22))	('carcinoma', 'Phenotype', 'HP:0030731', (41, 50))	('mTOR', 'Gene', '2475', (18, 22))	('eIF-4E', 'Gene', '1977', (87, 93))	('bronchial adenocarcinoma', 'Disease', 'MESH:D001982', (26, 50))	('presence', 'Var', (132, 140))	('bronchial adenocarcinoma', 'Disease', (26, 50))	('NSCLC', 'Disease', (210, 215))	('activity', 'MPA', (149, 157))	('mTOR', 'Gene', (144, 148))	('NSCLC', 'Disease', 'MESH:D002289', (210, 215))	('eIF-4E', 'Gene', (87, 93))	('mTOR', 'Gene', '2475', (144, 148))	('NSCLC', 'Phenotype', 'HP:0030358', (210, 215))
76207	31989769	Alpelisib (BYL719) is a potent p110alpha inhibitor, and is currently under investigation in a phase II study of patients with advanced NSCLC and a PIK3CA mutation or amplification.67 INK1117 is another p110alpha-specific inhibitor in early phase development.68 Specific p110beta inhibitors such as GSK2636771,69 AZD818670 and SAR26030171 have also been tested in phase I trials in patients with advanced solid tumors including NSCLC.	('SAR26030171', 'Var', (326, 337))	('AZD818670', 'Chemical', '-', (312, 321))	('NSCLC', 'Phenotype', 'HP:0030358', (427, 432))	('solid tumors', 'Disease', 'MESH:D009369', (404, 416))	('SAR26030171', 'Chemical', '-', (326, 337))	('NSCLC', 'Disease', (135, 140))	('Alpelisib', 'Chemical', 'MESH:C585539', (0, 9))	('patients', 'Species', '9606', (112, 120))	('tumor', 'Phenotype', 'HP:0002664', (410, 415))	('patients', 'Species', '9606', (381, 389))	('NSCLC', 'Disease', 'MESH:D002289', (135, 140))	('GSK2636771', 'Chemical', 'MESH:C000627739', (298, 308))	('NSCLC', 'Disease', (427, 432))	('solid tumors', 'Disease', (404, 416))	('tumors', 'Phenotype', 'HP:0002664', (410, 416))	('NSCLC', 'Disease', 'MESH:D002289', (427, 432))	('NSCLC', 'Phenotype', 'HP:0030358', (135, 140))
76208	31989769	Taselisib (GDC-0032) is a PI3K inhibitor that inhibits the p110alpha, p110gamma and p110delta isoforms, but spares the p110beta isoform.	('spares', 'NegReg', (108, 114))	('p110gamma', 'Gene', '5294', (70, 79))	('GDC-0032', 'Chemical', 'MESH:C582924', (11, 19))	('inhibits', 'NegReg', (46, 54))	('p110gamma', 'Gene', (70, 79))	('Taselisib', 'Chemical', 'MESH:C582924', (0, 9))	('p110delta', 'Var', (84, 93))	('p110alpha', 'Var', (59, 68))
76209	31989769	It has been evaluated as part of the phase II LUNG-MAP study, in previously treated NSCLC patients with a PIK3CA mutation.72 This substudy was closed for futility after an interim analysis.	('NSCLC', 'Phenotype', 'HP:0030358', (84, 89))	('PIK3CA', 'Gene', (106, 112))	('NSCLC', 'Disease', (84, 89))	('NSCLC', 'Disease', 'MESH:D002289', (84, 89))	('mutation.72', 'Var', (113, 124))	('patients', 'Species', '9606', (90, 98))
76211	31989769	MK-2206 is a highly selective Akt inhibitor which was evaluated in a phase II trial, in combination with erlotinib, in NSCLC patients who had previously progressed on erlotinib therapy.73 Patients were stratified based on EGFR mutation status.	('NSCLC', 'Disease', 'MESH:D002289', (119, 124))	('MK-2206', 'Chemical', 'MESH:C548887', (0, 7))	('Akt', 'Gene', '207', (30, 33))	('NSCLC', 'Phenotype', 'HP:0030358', (119, 124))	('Patients', 'Species', '9606', (188, 196))	('erlotinib', 'Chemical', 'MESH:D000069347', (105, 114))	('erlotinib', 'Chemical', 'MESH:D000069347', (167, 176))	('Akt', 'Gene', (30, 33))	('mutation', 'Var', (227, 235))	('EGFR', 'Gene', '1956', (222, 226))	('NSCLC', 'Disease', (119, 124))	('EGFR', 'Gene', (222, 226))	('patients', 'Species', '9606', (125, 133))
76212	31989769	Median PFS was 4.4 months in EGFR mutant patients, and 4.6 months in EGFR wild-type patients.	('EGFR', 'Gene', '1956', (69, 73))	('patients', 'Species', '9606', (84, 92))	('EGFR', 'Gene', (69, 73))	('patients', 'Species', '9606', (41, 49))	('EGFR', 'Gene', '1956', (29, 33))	('EGFR', 'Gene', (29, 33))	('mutant', 'Var', (34, 40))
76215	31989769	It has been assessed in several phase I trials in previously treated advanced NSCLC, either as monotherapy88 or in combination with pemetrexed chemotherapy.89 The combination of everolimus and EGFR inhibitors has also been evaluated in phase II trials in NSCLC patients unselected for EGFR mutation status.	('pemetrexed', 'Chemical', 'MESH:D000068437', (132, 142))	('EGFR', 'Gene', '1956', (285, 289))	('NSCLC', 'Disease', (255, 260))	('mutation', 'Var', (290, 298))	('EGFR', 'Gene', (285, 289))	('NSCLC', 'Phenotype', 'HP:0030358', (78, 83))	('EGFR', 'Gene', '1956', (193, 197))	('NSCLC', 'Disease', 'MESH:D002289', (255, 260))	('EGFR', 'Gene', (193, 197))	('NSCLC', 'Disease', (78, 83))	('everolimus', 'Chemical', 'MESH:D000068338', (178, 188))	('patients', 'Species', '9606', (261, 269))	('NSCLC', 'Phenotype', 'HP:0030358', (255, 260))	('NSCLC', 'Disease', 'MESH:D002289', (78, 83))
76219	31989769	Ridaforolimus has also been investigated in KRAS mutant advanced NSCLC patients in a phase II trial versus placebo, with a two month improvement in PFS.79  Second generation inhibitors have also been developed with dual targeting of both PI3K and mTOR.	('mutant', 'Var', (49, 55))	('patients', 'Species', '9606', (71, 79))	('NSCLC', 'Disease', 'MESH:D002289', (65, 70))	('NSCLC', 'Phenotype', 'HP:0030358', (65, 70))	('KRAS', 'Gene', (44, 48))	('mTOR', 'Gene', (247, 251))	('mTOR', 'Gene', '2475', (247, 251))	('KRAS', 'Gene', '3845', (44, 48))	('NSCLC', 'Disease', (65, 70))
76222	31989769	Gedatolisib has been evaluated in a phase I trial in combination with chemotherapy (docetaxel or cisplatin) in NSCLC patients or dacomitinib in EGFR mutant NSCLC patients.91 Toxicity profiles were manageable, and ongoing phase I/II trials are underway.	('patients', 'Species', '9606', (162, 170))	('EGFR', 'Gene', (144, 148))	('dacomitinib', 'Chemical', 'MESH:C525726', (129, 140))	('NSCLC', 'Disease', (111, 116))	('NSCLC', 'Phenotype', 'HP:0030358', (156, 161))	('Toxicity', 'Disease', (174, 182))	('mutant', 'Var', (149, 155))	('cisplatin', 'Chemical', 'MESH:D002945', (97, 106))	('Toxicity', 'Disease', 'MESH:D064420', (174, 182))	('NSCLC', 'Disease', 'MESH:D002289', (111, 116))	('docetaxel', 'Chemical', 'MESH:D000077143', (84, 93))	('Gedatolisib', 'Chemical', 'MESH:C549060', (0, 11))	('NSCLC', 'Disease', (156, 161))	('patients', 'Species', '9606', (117, 125))	('EGFR', 'Gene', '1956', (144, 148))	('NSCLC', 'Phenotype', 'HP:0030358', (111, 116))	('NSCLC', 'Disease', 'MESH:D002289', (156, 161))
76232	31693903	Oropharyngeal- specific expression of E6/E7 with PIK3CAE545K in these mice promotes the development of premalignant lesions marked by immune cell infiltration, but only a subset spontaneously convert to OPSCC.	('OPSCC', 'Phenotype', 'HP:0012182', (203, 208))	('E6/E7', 'Var', (38, 43))	('PIK3CAE545K', 'Gene', (49, 60))	('development', 'CPA', (88, 99))	('promotes', 'PosReg', (75, 83))	('OPSCC', 'Disease', (203, 208))	('convert', 'Reg', (192, 199))	('mice', 'Species', '10090', (70, 74))	('premalignant lesions', 'Disease', (103, 123))
76247	31693903	Our efforts establish an autochthonous, immunocompetent HPV(+) GEMM wherein E6 and E7 expression combined with tissue-specific expression of mutant PIK3CAE545K faithfully phenocopies the histologic and molecular features in developing human HPV(+) oropharyngeal carcinoma.	('HPV', 'Species', '10566', (241, 244))	('mutant', 'Var', (141, 147))	('HPV', 'Species', '10566', (56, 59))	('carcinoma', 'Disease', (262, 271))	('PIK3CAE545K', 'Gene', (148, 159))	('human', 'Species', '9606', (235, 240))	('oropharyngeal carcinoma', 'Phenotype', 'HP:0012182', (248, 271))	('carcinoma', 'Disease', 'MESH:D002277', (262, 271))	('carcinoma', 'Phenotype', 'HP:0030731', (262, 271))
76248	31693903	Consequently, this model provides a valuable tool for studying the underlying mechanisms that HPV16-E6/E7 and mutant PIK3CA use to induce malignancy and may reveal insights that can lead to new therapies that offer similar oncologic outcomes to radiation, with less treatment morbidity.	('malignancy', 'Disease', 'MESH:D009369', (138, 148))	('mutant', 'Var', (110, 116))	('lead to', 'Reg', (182, 189))	('PIK3CA', 'Gene', (117, 123))	('malignancy', 'Disease', (138, 148))	('PIK3CA', 'Gene', '5290', (117, 123))	('induce', 'PosReg', (131, 137))	('HPV16', 'Species', '333760', (94, 99))
76251	31693903	Due to the limited number of nucleotides present between the HPV16 E6 and E7 open reading frames (ORFs), the accumulation of alternatively spliced E6*I transcripts is critical for efficient translation of E7.	('HPV16', 'Gene', (61, 66))	('E6*I', 'Var', (147, 151))	('HPV16', 'Species', '333760', (61, 66))
76254	31693903	The apparent decrease in mapped reads between nucleotides 226 and 409 suggested that E6*I, and consequently its translated product E7, is the predominant variant expressed in HPV(+) HNSCC, as reported by others.	('E6*I', 'Var', (85, 89))	('decrease', 'NegReg', (13, 21))	('HNSCC', 'Phenotype', 'HP:0012288', (182, 187))	('HPV', 'Species', '10566', (175, 178))
76255	31693903	Remarkably, E6 and the E6*I variant (i.e., E7) are expressed to near equivalent levels in HPV(+) HNSCC, whereas the alternate E6*II variant commonly expressed in HPV(+) cervical carcinoma is poorly expressed (Figure 1A; Figures S2A-S2C; Table S1).	('S2A-S2C', 'Chemical', 'MESH:D013455', (228, 235))	('carcinoma', 'Disease', (178, 187))	('HPV', 'Species', '10566', (90, 93))	('HNSCC', 'Phenotype', 'HP:0012288', (97, 102))	('HPV', 'Species', '10566', (162, 165))	('E6*II', 'Var', (126, 131))	('E6*I', 'Var', (23, 27))	('carcinoma', 'Disease', 'MESH:D002277', (178, 187))	('carcinoma', 'Phenotype', 'HP:0030731', (178, 187))
76256	31693903	To assess if variations in E6/E7 stoichiometry impact host gene expression, we analyzed mRNA expression of the 53 HPV(+) tumors by ranking the samples as a continuous variable according to the spliced/unspliced ratio and qualitatively identified two groups with a ratio cutoff at 2.0 (Figure 1B).	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('impact', 'Reg', (47, 53))	('variations', 'Var', (13, 23))	('HPV', 'Species', '10566', (114, 117))	('tumors', 'Disease', (121, 127))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('HPV', 'Gene', (114, 117))	('tumors', 'Disease', 'MESH:D009369', (121, 127))
76261	31693903	Collectively, these data indicate that the E7/E6 ratio impacts the pathobiology of HPV(+) tumors.	('E7/E6 ratio', 'Var', (43, 54))	('HPV', 'Species', '10566', (83, 86))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumors', 'Disease', (90, 96))	('tumors', 'Disease', 'MESH:D009369', (90, 96))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('impacts', 'Reg', (55, 62))
76263	31693903	However, currently available inducible HPV16 GEMMs were generated using HPV16 genomic regions that encompass the E6/E7 ORFs.	('HPV16', 'Species', '333760', (39, 44))	('HPV16', 'Gene', (72, 77))	('HPV16', 'Species', '333760', (72, 77))	('E6/E7', 'Var', (113, 118))
76271	31693903	Gross macroscopic examination revealed enlarged oral tissues with significant changes in oral volume in LH versus control littermate mice and qRT-PCR confirmed E6 and E7 expression (Figures 3B and 3C).	('enlarged', 'PosReg', (39, 47))	('mice', 'Species', '10090', (133, 137))	('oral tissues', 'CPA', (48, 60))	('changes', 'Reg', (78, 85))	('enlarged oral', 'Phenotype', 'HP:0000154', (39, 52))	('E7 expression', 'Var', (167, 180))	('oral', 'MPA', (89, 93))
76282	31693903	Compared to control littermates, KH mice displayed increased suprabasal expression of several differentiation markers, including keratins (K4 and K10) and involucrin (Ivl), in addition to the cell cycle and proliferation marker Ccne1, and DNA replication and repair markers Mcm7 and Rrm2 (Figure 4D; Figures S5B and S5C).	('DNA replication', 'CPA', (239, 254))	('suprabasal expression', 'MPA', (61, 82))	('K10', 'Gene', (146, 149))	('S5B', 'Gene', (308, 311))	('keratins', 'Protein', (129, 137))	('increased', 'PosReg', (51, 60))	('cell cycle', 'CPA', (192, 202))	('Ccne1', 'Gene', (228, 233))	('S5B', 'Gene', '66998', (308, 311))	('Rrm2', 'Gene', (283, 287))	('Ccne1', 'Gene', '12447', (228, 233))	('K10', 'Gene', '16661', (146, 149))	('mice', 'Species', '10090', (36, 40))	('K4', 'Var', (139, 141))	('Mcm7', 'Gene', (274, 278))	('Rrm2', 'Gene', '20135', (283, 287))	('Mcm7', 'Gene', '17220', (274, 278))
76287	31693903	Therefore, to assess the effects of E6:E7 expression on tumorigenesis, we administered a moderate 4NQO dose (20 microg/ml) and observed a significant decrease (p < 0.05) in oral tumor-free survival for 4NQO-treated KH animals compared to control littermates (Figure 4H).	('oral tumor', 'Phenotype', 'HP:0100649', (173, 183))	('tumor', 'Disease', (178, 183))	('4NQO-treated', 'Var', (202, 214))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('tumor', 'Disease', (56, 61))	('decrease', 'NegReg', (150, 158))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('4NQO', 'Chemical', 'MESH:C120195', (98, 102))	('4NQO', 'Chemical', 'MESH:C120195', (202, 206))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))
76299	31693903	tamoxifen delivery provides a robust and reproducible method for inducing mosaic transgene expression within lingual epithelia and supporting the utility of this methodology for modeling field cancerization.	('tamoxifen', 'Chemical', 'MESH:D013629', (0, 9))	('inducing', 'Reg', (65, 73))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('cancerization', 'Disease', (193, 206))	('cancerization', 'Disease', 'MESH:D009369', (193, 206))	('mosaic transgene expression', 'Var', (74, 101))
76311	31693903	Indeed, integrated bioinformatics analyses revealed that of the downstream pathways activated in HNSCC, PIK3CA alterations are by far among the dominant driver events, where nearly 40% of all HPV(+) HNSCC cases harbor gain-of-function PIK3CA mutations at two key hotspots within the helical domain, namely, E542K and E545K.	('gain-of-function', 'PosReg', (218, 234))	('HNSCC', 'Phenotype', 'HP:0012288', (199, 204))	('E542K', 'Var', (307, 312))	('HNSCC', 'Phenotype', 'HP:0012288', (97, 102))	('PIK3CA', 'Gene', '5290', (235, 241))	('E545K', 'Mutation', 'rs104886003', (317, 322))	('E542K', 'Mutation', 'rs121913273', (307, 312))	('PIK3CA', 'Gene', (104, 110))	('E545K', 'Var', (317, 322))	('HNSCC', 'Gene', (199, 204))	('PIK3CA', 'Gene', '5290', (104, 110))	('HPV', 'Species', '10566', (192, 195))	('PIK3CA', 'Gene', (235, 241))
76312	31693903	To recapitulate this HNSCC PIK3CA alteration, we generated a GEMM that combines Rosa26-LSL-E7iresE6 and mutant PIK3CA (Rosa26-LSL-PIK3CAE545K) under the control of KRT14-CreERtam.	('PIK3CA', 'Gene', (130, 136))	('PIK3CA', 'Gene', '5290', (130, 136))	('HNSCC', 'Phenotype', 'HP:0012288', (21, 26))	('Rosa26', 'Gene', (80, 86))	('mutant', 'Var', (104, 110))	('PIK3CA', 'Gene', (27, 33))	('PIK3CA', 'Gene', (111, 117))	('Rosa26', 'Gene', '14910', (119, 125))	('Rosa26', 'Gene', '14910', (80, 86))	('PIK3CA', 'Gene', '5290', (27, 33))	('PIK3CA', 'Gene', '5290', (111, 117))	('Rosa26', 'Gene', (119, 125))
76313	31693903	Offspring of these crosses (iKHP mice) were born with normal Mendelian distribution, but excitingly, restricting post-natal activation of these transgenes by using our i.l.	('crosses', 'Var', (19, 26))	('restricting', 'NegReg', (101, 112))	('mice', 'Species', '10090', (33, 37))
76320	31693903	Previous work demonstrated that this enhanced leukocyte infiltration is associated with PIK3CA activation and that HPV(+) HNSCCs harboring PIK3CA mutations are associated with activation of mTOR but not of AKT, suggesting that E6 and E7 expression inhibits the ability of wild-type and/or mutant PIK3CA to activate AKT.	('AKT', 'Gene', (206, 209))	('PIK3CA', 'Gene', '5290', (88, 94))	('mutant', 'Var', (289, 295))	('PIK3CA', 'Gene', (139, 145))	('HNSCC', 'Phenotype', 'HP:0012288', (122, 127))	('AKT', 'Gene', (315, 318))	('activation', 'PosReg', (176, 186))	('leukocyte infiltration', 'CPA', (46, 68))	('activate', 'PosReg', (306, 314))	('PIK3CA', 'Gene', (296, 302))	('HPV', 'Species', '10566', (115, 118))	('AKT', 'Gene', '207', (206, 209))	('PIK3CA', 'Gene', (88, 94))	('mTOR', 'Gene', (190, 194))	('activation', 'PosReg', (95, 105))	('AKT', 'Gene', '207', (315, 318))	('enhanced', 'PosReg', (37, 45))	('PIK3CA', 'Gene', '5290', (139, 145))	('enhanced leukocyte', 'Phenotype', 'HP:0001974', (37, 55))	('mutations', 'Var', (146, 155))	('mTOR', 'Gene', '2475', (190, 194))	('inhibits', 'NegReg', (248, 256))	('PIK3CA', 'Gene', '5290', (296, 302))
76322	31693903	We confirmed robust S6 phosphorylation at Ser235/236 in the iKHP oropharyngeal tumors but did not detect significant differences in AKT phosphorylation at Ser473 between control oral tissues and GEMM tumors (Figure 7D).	('AKT', 'Gene', '207', (132, 135))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('Ser235/236', 'Var', (42, 52))	('Ser', 'Chemical', 'MESH:C530429', (155, 158))	('tumors', 'Phenotype', 'HP:0002664', (200, 206))	('oropharyngeal tumors', 'Phenotype', 'HP:0100638', (65, 85))	('iKHP oropharyngeal tumors', 'Disease', 'MESH:D009959', (60, 85))	('AKT', 'Gene', (132, 135))	('iKHP oropharyngeal tumors', 'Disease', (60, 85))	('tumors', 'Disease', (79, 85))	('Ser', 'Chemical', 'MESH:C530429', (42, 45))	('tumors', 'Disease', (200, 206))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('tumors', 'Disease', 'MESH:D009369', (200, 206))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('oropharyngeal tumor', 'Phenotype', 'HP:0100638', (65, 84))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
76324	31693903	Collectively, these data indicate that mTOR activation contributes to tumor progression in our HNSCC GEMM and that mutant PIK3CA in combination with balanced expression of HPV E6 and E7 is sufficient to drive oral tumorigenesis.	('PIK3CA', 'Gene', (122, 128))	('HPV', 'Species', '10566', (172, 175))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (214, 219))	('tumor', 'Disease', (70, 75))	('mutant', 'Var', (115, 121))	('PIK3CA', 'Gene', '5290', (122, 128))	('oral tumor', 'Phenotype', 'HP:0100649', (209, 219))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('mTOR', 'Gene', (39, 43))	('drive', 'PosReg', (203, 208))	('mTOR', 'Gene', '2475', (39, 43))	('tumor', 'Disease', (214, 219))	('HNSCC', 'Phenotype', 'HP:0012288', (95, 100))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
76330	31693903	Constitutive GEMMs for in vivo study include the alphaA-HPV16-E6/E7, K14-HPV16, K14HPV16E6, and K14HPV16E7 transgenic mouse models, where HPV16 genes are expressed by the alphaA crystallin or keratin 14 (K14) promoters.	('keratin 14', 'Gene', '3861', (192, 202))	('keratin 14', 'Gene', (192, 202))	('K14HPV16E7', 'Var', (96, 106))	('HPV16', 'Species', '333760', (99, 104))	('HPV16', 'Species', '333760', (56, 61))	('HPV16', 'Gene', (138, 143))	('mouse', 'Species', '10090', (118, 123))	('HPV16', 'Species', '333760', (73, 78))	('HPV16', 'Species', '333760', (138, 143))	('HPV16', 'Species', '333760', (83, 88))	('K14-HPV16', 'Var', (69, 78))	('transgenic', 'Species', '10090', (107, 117))	('K14HPV16E6', 'Var', (80, 90))
76331	31693903	Studies using aA-HPV16-E6/E7 transgenic mice revealed that the alphaA crystallin promoter successfully directs E6/E7 expression to the mouse ocular lens, but this model is confounded by non-specific expression within cutaneous epithelia, limiting the ability to model HPV-induced oropharyngeal, cervical, or anogenital cancers.	('cervical', 'Disease', (295, 303))	('anogenital cancers', 'Disease', 'MESH:D009369', (308, 326))	('oropharyngeal', 'Disease', (280, 293))	('cancers', 'Phenotype', 'HP:0002664', (319, 326))	('HPV', 'Species', '10566', (268, 271))	('E6/E7', 'Var', (111, 116))	('transgenic mice', 'Species', '10090', (29, 44))	('mouse', 'Species', '10090', (135, 140))	('HPV16', 'Species', '333760', (17, 22))	('cancer', 'Phenotype', 'HP:0002664', (319, 325))	('anogenital cancers', 'Disease', (308, 326))	('HPV', 'Species', '10566', (17, 20))
76338	31693903	In fact, studies have identified HPV16 E7 as the dominant oncogene with respect to promoting cancer development, and repression of E7 provokes regression of high-grade cervical dysplasia and cervical tumors irrespective of E6 expression.	('cancer', 'Disease', (93, 99))	('cervical dysplasia', 'Disease', 'MESH:D002575', (168, 186))	('cervical tumors', 'Disease', (191, 206))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('HPV16', 'Species', '333760', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('cervical tumors', 'Phenotype', 'HP:0030159', (191, 206))	('tumors', 'Phenotype', 'HP:0002664', (200, 206))	('repression', 'Var', (117, 127))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('cervical dysplasia', 'Phenotype', 'HP:0032131', (168, 186))	('cervical dysplasia', 'Disease', (168, 186))	('cervical tumors', 'Disease', 'MESH:D002575', (191, 206))
76346	31693903	Two recent genomics studies reported that the alternatively spliced E6*I transcript is the dominant variant expressed in HPV(+) tumors and that full-length E6 transcripts are present at substantially lower levels.	('HPV', 'Species', '10566', (121, 124))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('E6*I', 'Var', (68, 72))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('tumors', 'Disease', (128, 134))	('tumors', 'Disease', 'MESH:D009369', (128, 134))
76357	31693903	Although previous models of oral tumorigenesis expressed CCND1, mutant Kras, Tp53, Tgfbr1, or Notch1, we specifically chose to investigate the contribution of mutant PIK3CA in promoting the development of HNSCCs given accumulating genomic sequencing evidence pointing to a potential role for PIK3CA amplification and/or mutation as a key driver event.	('Tp53', 'Gene', '7157', (77, 81))	('CCND1', 'Gene', '595', (57, 62))	('Tgfbr1', 'Gene', (83, 89))	('mutant', 'Var', (159, 165))	('CCND1', 'Gene', (57, 62))	('Kras', 'Gene', '3845', (71, 75))	('PIK3CA', 'Gene', '5290', (292, 298))	('tumor', 'Disease', (33, 38))	('mutant', 'Var', (64, 70))	('development', 'CPA', (190, 201))	('PIK3CA', 'Gene', '5290', (166, 172))	('promoting', 'PosReg', (176, 185))	('Kras', 'Gene', (71, 75))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('Notch1', 'Gene', (94, 100))	('HNSCCs', 'Disease', (205, 211))	('oral tumor', 'Phenotype', 'HP:0100649', (28, 38))	('Notch1', 'Gene', '4851', (94, 100))	('Tp53', 'Gene', (77, 81))	('Tgfbr1', 'Gene', '7046', (83, 89))	('PIK3CA', 'Gene', (292, 298))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('HNSCC', 'Phenotype', 'HP:0012288', (205, 210))	('PIK3CA', 'Gene', (166, 172))
76358	31693903	Aberrant PI3K signaling enhances tumorigenic potential by increasing cell proliferation and survival and promoting migration, invasion, metabolism, angiogenesis, as well as resistance to chemotherapy.	('survival', 'CPA', (92, 100))	('Aberrant', 'Var', (0, 8))	('migration', 'CPA', (115, 124))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('PI3K', 'Protein', (9, 13))	('increasing', 'PosReg', (58, 68))	('cell proliferation', 'CPA', (69, 87))	('invasion', 'CPA', (126, 134))	('promoting', 'PosReg', (105, 114))	('tumor', 'Disease', (33, 38))	('resistance', 'CPA', (173, 183))	('metabolism', 'CPA', (136, 146))	('enhances', 'PosReg', (24, 32))	('angiogenesis', 'CPA', (148, 160))
76359	31693903	Most gain-of-function PIK3CA mutations occur in either the kinase (H1047R) or helical domains (E542K and E545K) of p110a and create a constitutively active enzyme.	('E542K', 'Mutation', 'rs121913273', (95, 100))	('gain-of-function', 'PosReg', (5, 21))	('H1047R', 'Var', (67, 73))	('H1047R', 'SUBSTITUTION', 'None', (67, 73))	('PIK3CA', 'Gene', '5290', (22, 28))	('mutations', 'Var', (29, 38))	('E542K', 'Var', (95, 100))	('PIK3CA', 'Gene', (22, 28))	('E545K', 'Mutation', 'rs104886003', (105, 110))	('E545K', 'Var', (105, 110))
76360	31693903	But unlike breast carcinoma and HPV(:) HNSCC, nearly all HPV(+) HNSCCs selectively accumulate mutations within the helical domain, consistent with mRNA editing induced by APOBEC-mediated cytosine deaminase mutagenesis.	('breast carcinoma', 'Phenotype', 'HP:0003002', (11, 27))	('carcinoma', 'Phenotype', 'HP:0030731', (18, 27))	('mutations', 'Var', (94, 103))	('accumulate', 'PosReg', (83, 93))	('breast carcinoma', 'Disease', 'MESH:D001943', (11, 27))	('breast carcinoma', 'Disease', (11, 27))	('HPV', 'Species', '10566', (32, 35))	('HNSCC', 'Phenotype', 'HP:0012288', (64, 69))	('HNSCC', 'Phenotype', 'HP:0012288', (39, 44))	('HPV', 'Species', '10566', (57, 60))	('HPV', 'Gene', (57, 60))	('cytosine', 'Chemical', 'MESH:D003596', (187, 195))
76363	31693903	Future studies aimed at defining the genetic events that cooperate with E6/E7;PIK3CAE545K to promote invasion and migration will be important to understand the mechanisms that underlie HPV(+) cases with poor prognosis.	('promote', 'PosReg', (93, 100))	('E6/E7;PIK3CAE545K', 'Var', (72, 89))	('PIK3CAE545K', 'Var', (78, 89))	('HPV', 'Species', '10566', (185, 188))
76366	31693903	The Rosa26-LSL-E7iresE6 mice were generated by knocking-in a polycistronic cassette containing the high risk HPV16 E7 and E6 cDNAs separated by an IRES element into a Rosa26-loxP-Stop-loxP cassette, using the pBigT and pRosa26-PA vectors, as previously described.	('Rosa26', 'Gene', (4, 10))	('Rosa26', 'Gene', '14910', (167, 173))	('Rosa26', 'Gene', (220, 226))	('knocking-in', 'Var', (47, 58))	('mice', 'Species', '10090', (24, 28))	('HPV16', 'Gene', (109, 114))	('HPV16', 'Species', '333760', (109, 114))	('Rosa26', 'Gene', (167, 173))	('Rosa26', 'Gene', '14910', (4, 10))	('Rosa26', 'Gene', '14910', (220, 226))
76368	31693903	Similarly, Rosa26-LSL-GpNLuc mice were generated by knocking-in the GpNLuc LumiFluor optical reporter cDNA into a Rosa26-loxP-Stop-loxP cassette by first subcloning GpNLuc into pBigT prior to shuttling into the Rosa26-PA destination vector.	('Rosa26', 'Gene', '14910', (211, 217))	('Rosa26', 'Gene', (11, 17))	('cDNA', 'Gene', (102, 106))	('Rosa26', 'Gene', (114, 120))	('mice', 'Species', '10090', (29, 33))	('Rosa26', 'Gene', (211, 217))	('Rosa26', 'Gene', '14910', (11, 17))	('knocking-in', 'Var', (52, 63))	('Rosa26', 'Gene', '14910', (114, 120))
76374	31693903	To induce Cre-mediated transgene recombination in the tongues of iLumiFluor, iKH, or iKHP mice, tamoxifen was administered to the lingual submucosa by direct injection.	('iLumiFluor', 'Disease', (65, 75))	('mice', 'Species', '10090', (90, 94))	('iLumiFluor', 'Disease', 'None', (65, 75))	('tamoxifen', 'Chemical', 'MESH:D013629', (96, 105))	('Cre-mediated', 'Var', (10, 22))
76384	31693903	'Normal' oral keratinocyte (NOK) cell lines OKF4-TERT1, OKF4-E6/E7, OKF6-TERT1, and OKF6-E6/E7 (a gift from Jim Rheinwald and Matthew Ramsey, Harvard University, Boston, MA) and the GMSM-K (a gift from Valerie Murrah, UNC-Chapel Hill, Chapel Hill, NC) were grown in keratinocyte serum free media (KSFM) from (GIBCO, cat.	('OKF6-TERT1', 'Var', (68, 78))	('OKF6-E6/E7', 'Var', (84, 94))	('OKF4-TERT1', 'CellLine', 'CVCL:L227', (44, 54))	('OKF6-TERT1', 'CellLine', 'CVCL:L224', (68, 78))
76393	31693903	Unspliced and spliced HPV16 early gene transcripts were quantified by counting reads that included the splice junction (nt 226^409) or spanning reads (nt 226/227 and 408/409) and calculating the mean coverage for each sample.	('HPV16', 'Species', '333760', (22, 27))	('nt 226^409', 'Var', (120, 130))	('HPV16 early gene', 'Gene', (22, 38))	('nt 226/227', 'Var', (151, 161))
76394	31693903	To conditionally induce GpNLuc or E7iresE6 expression, iLumiFluor or iKH and iKHP animals were intra-lingually injected using a 27-gauge needle with 0.5mg of tamoxifen (Sigma-Aldrich, cat.	('induce', 'Reg', (17, 23))	('tamoxifen', 'Chemical', 'MESH:D013629', (158, 167))	('E7iresE6', 'Var', (34, 42))	('iLumiFluor', 'Disease', (55, 65))	('iLumiFluor', 'Disease', 'None', (55, 65))
76404	31693903	Briefly, anti-Mouse CD8a (eBioscience, cat.	('CD8a', 'Gene', (20, 24))	('eBioscience', 'Disease', (26, 37))	('CD8a', 'Gene', '925', (20, 24))	('Mouse', 'Species', '10090', (14, 19))	('anti-Mouse', 'Var', (9, 19))	('eBioscience', 'Disease', 'None', (26, 37))
76407	31693903	Alternatively, the anti-Mouse/Rat Foxp3 (eBioscience, cat.	('Rat', 'Species', '10116', (30, 33))	('eBioscience', 'Disease', (41, 52))	('Foxp3', 'Gene', (34, 39))	('eBioscience', 'Disease', 'None', (41, 52))	('anti-Mouse/Rat', 'Var', (19, 33))	('Foxp3', 'Gene', '317382', (34, 39))	('Mouse', 'Species', '10090', (24, 29))
76419	31693903	The pBigT and pRosa26-PA constructs (Addgene plasmid #21270 and #21271, respectively) were gifts from Frank Costantini, MIGR1 (Addgene plasmid #27490) was a gift from Warren Pear, and the pRetroX-Tight-MCS_PGK-GpNLuc construct (Addgene plasmid #70185) containing the LumiFluor optical reporter was previously described.	('#21271', 'Var', (64, 70))	('Pear', 'Species', '23211', (174, 178))	('Rosa26', 'Gene', (15, 21))	('Rosa26', 'Gene', '14910', (15, 21))
76428	31693903	Relative gene expression of E6, E7, E6/TP53, and E7/E2F1 targets was determined using the 2  Ct method and normalized using human and mouse RPL23.	('E2F1', 'Gene', (52, 56))	('RPL23', 'Gene', (140, 145))	('E6/TP53', 'Var', (36, 43))	('human', 'Species', '9606', (124, 129))	('E2F1', 'Gene', '1869', (52, 56))	('RPL23', 'Gene', '65019', (140, 145))	('mouse', 'Species', '10090', (134, 139))
76444	31693903	Creation of a knockin allele for balanced HPV16 E6 and E7 oncogene expression Intra-lingual tamoxifen delivery enables mosaic oropharyngeal transgene activation E6/E7 and PIK3CA activation leads to oropharyngeal squamous cell carcinoma Post-natal transgene activation maintains robust immune cell infiltration	('E6/E7', 'Var', (161, 166))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (212, 235))	('PIK3CA', 'Gene', (171, 177))	('tamoxifen', 'Chemical', 'MESH:D013629', (92, 101))	('oropharyngeal squamous cell carcinoma', 'Phenotype', 'HP:0012182', (198, 235))	('PIK3CA', 'Gene', '5290', (171, 177))	('HPV16', 'Species', '333760', (42, 47))	('carcinoma', 'Phenotype', 'HP:0030731', (226, 235))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (212, 235))	('squamous cell carcinoma', 'Disease', (212, 235))
76445	28646528	Genetic variants in microRNA-binding sites of DNA repair genes as predictors of recurrence in patients with squamous cell carcinoma of the oropharynx The incidence of squamous cell carcinoma of the oropharynx (SCCOP) continues to rise because of increasing rates of human papillomavirus (HPV) infection.	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (167, 190))	('patients', 'Species', '9606', (94, 102))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (108, 131))	('human', 'Species', '9606', (266, 271))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (108, 131))	('variants', 'Var', (8, 16))	('squamous cell carcinoma', 'Disease', (108, 131))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (167, 190))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('carcinoma', 'Phenotype', 'HP:0030731', (181, 190))	('papillomavirus (HPV) infection', 'Disease', 'MESH:D030361', (272, 302))	('squamous cell carcinoma', 'Disease', (167, 190))
76446	28646528	Inherited polymorphisms in DNA repair pathways may influence the risk of SCCOP development and the prognosis of SCCOP.	('men', 'Species', '9606', (86, 89))	('polymorphisms', 'Var', (10, 23))	('influence', 'Reg', (51, 60))	('SCCOP', 'Disease', (73, 78))	('DNA repair pathways', 'Pathway', (27, 46))
76448	28646528	In an analysis of all the patients, patients with variant genotypes of BRCA1 rs12516 and RAD51 rs7180135 had better disease-free survival (log-rank, P = 0.0002 and P = 0.0003, respectively) and lower risk of SCCOP recurrence (hazard ratio [HR], 0.5, 95% confidence interval [CI], 0.2-0.8, and HR, 0.5, 95% CI, 0.3-0.9, respectively) than patients with common homozygous genotypes of the two polymorphisms after multivariable adjustment.	('BRCA1', 'Gene', (71, 76))	('RAD51', 'Gene', '5888', (89, 94))	('disease-free survival', 'CPA', (116, 137))	('rs12516', 'Mutation', 'rs12516', (77, 84))	('patients', 'Species', '9606', (36, 44))	('rs7180135', 'Var', (95, 104))	('SCCOP recurrence', 'Disease', (208, 224))	('patients', 'Species', '9606', (26, 34))	('men', 'Species', '9606', (431, 434))	('rs12516', 'Var', (77, 84))	('better', 'PosReg', (109, 115))	('rs7180135', 'Mutation', 'rs7180135', (95, 104))	('BRCA1', 'Gene', '672', (71, 76))	('patients', 'Species', '9606', (338, 346))	('RAD51', 'Gene', (89, 94))
76449	28646528	Moreover, in tumor HPV16-positive patients, patients with variant genotypes of the same two polymorphisms also had better disease-free survival (log-rank, P = 0.004 and P = 0.003, respectively) and lower recurrence risk (HR, 0.2, 95% CI, 0.1-0.6, and HR, 0.2, 95% CI, 0.0-0.7, respectively) than patients with common homozygous genotypes of the two polymorphisms.	('recurrence', 'CPA', (204, 214))	('tumor', 'Disease', (13, 18))	('HPV16', 'Species', '333760', (19, 24))	('disease-free survival', 'CPA', (122, 143))	('patients', 'Species', '9606', (44, 52))	('better', 'PosReg', (115, 121))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('variant', 'Var', (58, 65))	('patients', 'Species', '9606', (34, 42))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('HPV16-positive', 'Gene', (19, 33))	('patients', 'Species', '9606', (296, 304))	('lower', 'NegReg', (198, 203))
76450	28646528	These findings support significant roles of BRCA1 rs12516 and RAD51 rs7180135 in modifying the risk of recurrence of SCCOP, particularly HPV16-positive SCCOP.	('BRCA1', 'Gene', (44, 49))	('RAD51', 'Gene', (62, 67))	('rs12516', 'Mutation', 'rs12516', (50, 57))	('HPV16-positive', 'Gene', (137, 151))	('RAD51', 'Gene', '5888', (62, 67))	('rs7180135', 'Var', (68, 77))	('HPV16', 'Species', '333760', (137, 142))	('rs12516', 'Var', (50, 57))	('SCCOP', 'Disease', (117, 122))	('rs7180135', 'Mutation', 'rs7180135', (68, 77))	('BRCA1', 'Gene', '672', (44, 49))
76454	28646528	Thus, genetic alterations, such as genetic polymorphisms, in DNA repair pathways may affect not only cancer risk but also the patient's response to therapy, including chemotherapy and radiotherapy, leading to differences in recurrence and survival .	('survival', 'CPA', (239, 247))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('cancer', 'Disease', (101, 107))	('differences', 'Reg', (209, 220))	('patient', 'Species', '9606', (126, 133))	('DNA repair pathways', 'Pathway', (61, 80))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('affect', 'Reg', (85, 91))	('recurrence', 'CPA', (224, 234))	('genetic alterations', 'Var', (6, 25))
76455	28646528	Studies have shown that polymorphisms in predicted miRNA-binding sites in genes implicated in DNA double strand break (DSB) repair can influence the risk of and prognosis of several types of cancer .	('influence', 'Reg', (135, 144))	('cancer', 'Disease', (191, 197))	('cancer', 'Disease', 'MESH:D009369', (191, 197))	('miRNA-binding', 'MPA', (51, 64))	('polymorphisms', 'Var', (24, 37))	('prognosis', 'CPA', (161, 170))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))
76489	28646528	Associations of SNPs in DNA DSB repair genes with SCCOP recurrence risk were estimated using hazard ratios (HRs) and 95% confidence intervals (CIs) among all patients in the study and among patients with HPV16-positive tumors.	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('DNA DSB repair genes', 'Gene', (24, 44))	('Associations', 'Interaction', (0, 12))	('HPV16-positive tumors', 'Disease', 'MESH:D009369', (204, 225))	('tumors', 'Phenotype', 'HP:0002664', (219, 225))	('SNPs', 'Var', (16, 20))	('patients', 'Species', '9606', (190, 198))	('SCCOP recurrence', 'Disease', (50, 66))	('HPV16-positive tumors', 'Disease', (204, 225))	('patients', 'Species', '9606', (158, 166))
76502	28646528	As shown in Figure 2, patients with the BRCA1 rs12516 and RAD51 rs7180135 variant genotypes had significantly better DFS than patients with the corresponding common homozygous genotypes among all SCCOP patients (log-rank, P = 0.0002 and P = 0.0003, respectively) and among SCCOP patients with HPV16-positive tumors (log-rank, P = 0.004 and P = 0.003, respectively).	('RAD51', 'Gene', (58, 63))	('rs12516', 'Mutation', 'rs12516', (46, 53))	('HPV16-positive tumors', 'Disease', 'MESH:D009369', (293, 314))	('RAD51', 'Gene', '5888', (58, 63))	('patients', 'Species', '9606', (22, 30))	('rs12516', 'Var', (46, 53))	('patients', 'Species', '9606', (202, 210))	('rs7180135', 'Var', (64, 73))	('better', 'PosReg', (110, 116))	('patients', 'Species', '9606', (279, 287))	('HPV16-positive tumors', 'Disease', (293, 314))	('patients', 'Species', '9606', (126, 134))	('rs7180135', 'Mutation', 'rs7180135', (64, 73))	('BRCA1', 'Gene', '672', (40, 45))	('DFS', 'MPA', (117, 120))	('tumor', 'Phenotype', 'HP:0002664', (308, 313))	('tumors', 'Phenotype', 'HP:0002664', (308, 314))	('BRCA1', 'Gene', (40, 45))
76503	28646528	As shown in Table 2, patients with the BRCA1 rs12516 and RAD51 rs7180135 variant genotypes had a significantly lower risk of disease recurrence than patients with the corresponding common homozygous genotypes (HR = 0.5, 95% CI 0.2-0.8, and HR = 0.5, 95% CI 0.3-0.9, respectively).	('rs12516', 'Var', (45, 52))	('patients', 'Species', '9606', (149, 157))	('disease recurrence', 'CPA', (125, 143))	('patients', 'Species', '9606', (21, 29))	('BRCA1', 'Gene', '672', (39, 44))	('lower', 'NegReg', (111, 116))	('rs7180135', 'Var', (63, 72))	('rs12516', 'Mutation', 'rs12516', (45, 52))	('RAD51', 'Gene', (57, 62))	('BRCA1', 'Gene', (39, 44))	('RAD51', 'Gene', '5888', (57, 62))	('rs7180135', 'Mutation', 'rs7180135', (63, 72))
76506	28646528	As shown in Table 3, patients with HPV16-positive SCCOP with BRCA1 rs12516 and RAD51 rs7180135 variant genotypes had a significantly lower risk of disease recurrence than patients with the corresponding common homozygous genotypes (HR = 0.2, 95% CI 0.1-0.6, and HR = 0.2, 95% CI 0.0-0.7, respectively).	('HPV16', 'Species', '333760', (35, 40))	('BRCA1', 'Gene', (61, 66))	('RAD51', 'Gene', '5888', (79, 84))	('rs12516', 'Mutation', 'rs12516', (67, 74))	('disease recurrence', 'CPA', (147, 165))	('rs12516', 'Var', (67, 74))	('rs7180135', 'Var', (85, 94))	('patients', 'Species', '9606', (171, 179))	('patients', 'Species', '9606', (21, 29))	('rs7180135', 'Mutation', 'rs7180135', (85, 94))	('BRCA1', 'Gene', '672', (61, 66))	('lower', 'NegReg', (133, 138))	('RAD51', 'Gene', (79, 84))
76507	28646528	To further characterize the potentially functional relevance of these 2 significant polymorphisms, we performed correlation analyses between tumor BRCA1 and RAD51 protein expression by IHC and genotypes of BRCA1 rs12516 and RAD51 rs7180135 polymorphisms among a subset of 64 SCCOP patients.	('expression', 'MPA', (171, 181))	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('BRCA1', 'Gene', '672', (147, 152))	('RAD51', 'Gene', (224, 229))	('BRCA1', 'Gene', '672', (206, 211))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('patients', 'Species', '9606', (281, 289))	('tumor', 'Disease', (141, 146))	('rs7180135', 'Var', (230, 239))	('BRCA1', 'Gene', (147, 152))	('BRCA1', 'Gene', (206, 211))	('RAD51', 'Gene', '5888', (224, 229))	('rs7180135', 'Mutation', 'rs7180135', (230, 239))	('rs12516', 'Mutation', 'rs12516', (212, 219))	('RAD51', 'Gene', (157, 162))	('rs12516', 'Var', (212, 219))	('RAD51', 'Gene', '5888', (157, 162))
76509	28646528	In all patients, we found that the BRCA1 rs12516 CC genotype had a significantly higher BRCA1 protein expression than BRCA1 rs12516 CT/TT variant genotypes (P = 0.036), while RAD51 rs7180135 AA genotype had a borderline significantly higher RAD51 protein expression than RAD51 rs7180135 AG/GG variant genotypes (P = 0.057) (Figure 3).	('RAD51', 'Gene', (241, 246))	('RAD51', 'Gene', '5888', (241, 246))	('RAD51', 'Gene', (175, 180))	('patients', 'Species', '9606', (7, 15))	('RAD51', 'Gene', '5888', (175, 180))	('RAD51', 'Gene', (271, 276))	('RAD51', 'Gene', '5888', (271, 276))	('BRCA1', 'Gene', '672', (35, 40))	('BRCA1', 'Gene', (35, 40))	('rs12516 CC', 'Var', (41, 51))	('BRCA1', 'Gene', '672', (88, 93))	('rs12516', 'Mutation', 'rs12516', (41, 48))	('BRCA1', 'Gene', (88, 93))	('higher', 'PosReg', (234, 240))	('expression', 'MPA', (102, 112))	('higher', 'PosReg', (81, 87))	('BRCA1', 'Gene', '672', (118, 123))	('rs7180135', 'Mutation', 'rs7180135', (277, 286))	('rs7180135', 'Mutation', 'rs7180135', (181, 190))	('BRCA1', 'Gene', (118, 123))	('rs12516', 'Mutation', 'rs12516', (124, 131))
76511	28646528	BRCA1 rs12516 CC genotype had a significantly higher BRCA1 protein expression than BRCA1 rs12516 CT/TT genotypes (P = 0.021); and RAD51 rs7180135 AA genotype had a borderline significantly higher RAD51 protein expression than RAD51 rs7180135 AG/GG genotypes (P = 0.053) (Figure 3).	('BRCA1', 'Gene', '672', (83, 88))	('BRCA1', 'Gene', (83, 88))	('higher', 'PosReg', (46, 52))	('rs12516', 'Mutation', 'rs12516', (89, 96))	('higher', 'PosReg', (189, 195))	('BRCA1', 'Gene', '672', (0, 5))	('rs7180135 AA', 'Var', (136, 148))	('BRCA1', 'Gene', (0, 5))	('rs7180135', 'Mutation', 'rs7180135', (232, 241))	('rs7180135', 'Mutation', 'rs7180135', (136, 145))	('RAD51', 'Gene', (226, 231))	('RAD51', 'Gene', '5888', (226, 231))	('RAD51', 'Gene', (196, 201))	('protein', 'Protein', (59, 66))	('RAD51', 'Gene', '5888', (196, 201))	('BRCA1', 'Gene', '672', (53, 58))	('rs12516', 'Mutation', 'rs12516', (6, 13))	('rs12516 CC', 'Var', (6, 16))	('RAD51', 'Gene', (130, 135))	('BRCA1', 'Gene', (53, 58))	('RAD51', 'Gene', '5888', (130, 135))
76512	28646528	We found that genotypic variations at BRCA1 rs12516 and RAD51 rs7180135 were significantly associated with a reduced risk of disease recurrence, particularly in patients with HPV16-positive SCCOP.	('rs12516', 'Mutation', 'rs12516', (44, 51))	('RAD51', 'Gene', (56, 61))	('BRCA1', 'Gene', (38, 43))	('RAD51', 'Gene', '5888', (56, 61))	('disease recurrence', 'CPA', (125, 143))	('HPV16', 'Species', '333760', (175, 180))	('rs12516', 'Var', (44, 51))	('patients', 'Species', '9606', (161, 169))	('reduced', 'NegReg', (109, 116))	('rs7180135', 'Var', (62, 71))	('rs7180135', 'Mutation', 'rs7180135', (62, 71))	('BRCA1', 'Gene', '672', (38, 43))
76514	28646528	Deregulation of BRCA1 reduces DNA repair capacity and increases the susceptibility of cancer cells to DNA-damaging agents, including chemotherapy and radiotherapy .	('Deregulation', 'Var', (0, 12))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('BRCA1', 'Gene', '672', (16, 21))	('increases', 'PosReg', (54, 63))	('reduces', 'NegReg', (22, 29))	('cancer', 'Disease', (86, 92))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('BRCA1', 'Gene', (16, 21))	('DNA repair capacity', 'MPA', (30, 49))	('susceptibility', 'MPA', (68, 82))
76517	28646528	Another study showed that the BRCA1 rs12516 polymorphism resulted in increased risk of early-onset and/or familial breast cancer in the Turkish population.	('BRCA1', 'Gene', (30, 35))	('rs12516', 'Mutation', 'rs12516', (36, 43))	('early-onset', 'Disease', (87, 98))	('familial breast cancer', 'Disease', 'MESH:D001943', (106, 128))	('rs12516', 'Var', (36, 43))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('BRCA1', 'Gene', '672', (30, 35))	('familial breast cancer', 'Disease', (106, 128))	('breast cancer', 'Phenotype', 'HP:0003002', (115, 128))
76518	28646528	These results indicated that this polymorphism in BRCA1 may function in the development of breast cancer .	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('breast cancer', 'Disease', (91, 104))	('BRCA1', 'Gene', (50, 55))	('polymorphism', 'Var', (34, 46))	('breast cancer', 'Phenotype', 'HP:0003002', (91, 104))	('men', 'Species', '9606', (83, 86))	('function', 'Reg', (60, 68))	('BRCA1', 'Gene', '672', (50, 55))	('breast cancer', 'Disease', 'MESH:D001943', (91, 104))
76519	28646528	In contrast, in this study, SCCOP patients with the variant genotypes of BRCA1 rs12516 had a significantly reduced risk of disease recurrence.	('rs12516', 'Var', (79, 86))	('disease recurrence', 'CPA', (123, 141))	('reduced', 'NegReg', (107, 114))	('BRCA1', 'Gene', '672', (73, 78))	('patients', 'Species', '9606', (34, 42))	('BRCA1', 'Gene', (73, 78))	('rs12516', 'Mutation', 'rs12516', (79, 86))
76520	28646528	Our finding may support that this polymorphism in the 3'UTR of BRCA1 alters the ability of miRNA to bind to the BRCA1 3' UTR and leads to loss of certain functions of BRCA1.	('ability', 'MPA', (80, 87))	('loss', 'NegReg', (138, 142))	('polymorphism', 'Var', (34, 46))	('BRCA1', 'Gene', (167, 172))	('BRCA1', 'Gene', (63, 68))	('functions', 'MPA', (154, 163))	('BRCA1', 'Gene', '672', (112, 117))	('alters', 'Reg', (69, 75))	('bind', 'Interaction', (100, 104))	('BRCA1', 'Gene', '672', (63, 68))	('BRCA1', 'Gene', (112, 117))	('BRCA1', 'Gene', '672', (167, 172))
76521	28646528	Recently, BRCA1 rs12516 has been shown to have several potential miRNAs for binding.	('BRCA1', 'Gene', '672', (10, 15))	('rs12516', 'Mutation', 'rs12516', (16, 23))	('rs12516', 'Var', (16, 23))	('BRCA1', 'Gene', (10, 15))	('binding', 'Interaction', (76, 83))
76522	28646528	Bioinformatics analysis and SNP function prediction demonstrated that the site of BRCA1 rs12516 C-to-T transition had six potential binding miRNAs: hsa-miR-188-5p, hsa-miR-502-5p, hsa-miR-557, hsa-miR-623, hsa-miR-637, and hsa-miR-639 .	('BRCA1', 'Gene', (82, 87))	('hsa-miR-623', 'Gene', (193, 204))	('hsa-miR-637', 'Gene', (206, 217))	('hsa-miR-557', 'Gene', (180, 191))	('rs12516 C-to-T', 'Var', (88, 102))	('rs12516', 'Mutation', 'rs12516', (88, 95))	('hsa-miR-639', 'Gene', (223, 234))	('miR-188', 'Gene', (152, 159))	('BRCA1', 'Gene', '672', (82, 87))	('miR-188', 'Gene', '406964', (152, 159))	('hsa-miR-639', 'Gene', '693224', (223, 234))	('hsa-miR-623', 'Gene', '693208', (193, 204))	('hsa-miR-637', 'Gene', '693222', (206, 217))	('hsa-miR-557', 'Gene', '693142', (180, 191))
76529	28646528	Overexpression of RAD51 is associated with a more aggressive cancer phenotype and treatment resistance in a variety of tumors, while downregulation of RAD51 reduces the efficiency of DNA repair and thus improves sensitivity to radiotherapy and chemotherapy .	('RAD51', 'Gene', (18, 23))	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('treatment resistance', 'CPA', (82, 102))	('RAD51', 'Gene', '5888', (18, 23))	('aggressive cancer', 'Disease', 'MESH:D009369', (50, 67))	('Overexpression', 'Var', (0, 14))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('tumors', 'Disease', (119, 125))	('downregulation', 'NegReg', (133, 147))	('aggressive cancer', 'Disease', (50, 67))	('improves', 'PosReg', (203, 211))	('DNA repair', 'MPA', (183, 193))	('RAD51', 'Gene', (151, 156))	('men', 'Species', '9606', (87, 90))	('tumors', 'Disease', 'MESH:D009369', (119, 125))	('RAD51', 'Gene', '5888', (151, 156))	('more', 'PosReg', (45, 49))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('reduces', 'NegReg', (157, 164))
76530	28646528	Our studies showed that SCCOP patients with the RAD51 rs7180135 variant genotypes had a significantly reduced risk of disease recurrence.	('rs7180135', 'Var', (54, 63))	('RAD51', 'Gene', (48, 53))	('RAD51', 'Gene', '5888', (48, 53))	('rs7180135', 'Mutation', 'rs7180135', (54, 63))	('patients', 'Species', '9606', (30, 38))	('disease recurrence', 'CPA', (118, 136))	('reduced', 'NegReg', (102, 109))
76533	28646528	This study suggested that the binding of miR-197 to RAD51 rs7180135 might alter miR-197-mRNA-binding and might predict sensitivity of tumors to radiotherapy, thus affecting outcomes in bladder cancer .	('alter', 'Reg', (74, 79))	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('miR-197', 'Gene', (80, 87))	('bladder cancer', 'Phenotype', 'HP:0009725', (185, 199))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('tumors', 'Disease', (134, 140))	('miR-197', 'Gene', '406974', (41, 48))	('affecting', 'Reg', (163, 172))	('rs7180135', 'Mutation', 'rs7180135', (58, 67))	('tumors', 'Disease', 'MESH:D009369', (134, 140))	('miR-197', 'Gene', '406974', (80, 87))	('rs7180135', 'Var', (58, 67))	('miR-197', 'Gene', (41, 48))	('RAD51', 'Gene', (52, 57))	('RAD51', 'Gene', '5888', (52, 57))	('predict', 'Reg', (111, 118))	('bladder cancer', 'Disease', 'MESH:D001749', (185, 199))	('bladder cancer', 'Disease', (185, 199))	('binding', 'Interaction', (30, 37))
76534	28646528	Several other miRNAs have previously been shown to target RAD51 and inhibit its role in homologous recombination repair, including miRNA-182, miR-155, miR-103, and miR-107 in several types of human cancer .	('miR-103', 'Var', (151, 158))	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('RAD51', 'Gene', (58, 63))	('RAD51', 'Gene', '5888', (58, 63))	('cancer', 'Disease', (198, 204))	('human', 'Species', '9606', (192, 197))	('miR-155', 'Gene', '406947', (142, 149))	('homologous recombination repair', 'MPA', (88, 119))	('inhibit', 'NegReg', (68, 75))	('miR-107', 'Gene', '406901', (164, 171))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('miR-107', 'Gene', (164, 171))	('miRNA-182', 'Gene', (131, 140))	('miR-155', 'Gene', (142, 149))	('miRNA-182', 'Gene', '406958', (131, 140))	('target', 'Reg', (51, 57))
76538	28646528	Our findings from this study showed that SCCOP patients, particularly patients with HPV16-positive SCCOP, with BRCA1 rs12516 and RAD51 rs7180135 variant genotypes had significantly better DFS and reduced risk of disease recurrence.	('patients', 'Species', '9606', (70, 78))	('rs7180135', 'Var', (135, 144))	('rs7180135', 'Mutation', 'rs7180135', (135, 144))	('rs12516', 'Var', (117, 124))	('DFS', 'MPA', (188, 191))	('SCCOP', 'Disease', (99, 104))	('better', 'PosReg', (181, 187))	('BRCA1', 'Gene', '672', (111, 116))	('patients', 'Species', '9606', (47, 55))	('RAD51', 'Gene', (129, 134))	('HPV16-positive', 'Gene', (84, 98))	('BRCA1', 'Gene', (111, 116))	('RAD51', 'Gene', '5888', (129, 134))	('rs12516', 'Mutation', 'rs12516', (117, 124))	('HPV16', 'Species', '333760', (84, 89))	('reduced', 'NegReg', (196, 203))
76542	28646528	Therefore, genetic variants of BRCA1 rs12516 and RAD51 rs7180135 may cause different expression of these two genes and lead to inter-individual differences in DNA repair capacity phenotype.	('expression', 'MPA', (85, 95))	('rs7180135', 'Mutation', 'rs7180135', (55, 64))	('RAD51', 'Gene', (49, 54))	('lead to', 'Reg', (119, 126))	('DNA repair capacity phenotype', 'MPA', (159, 188))	('differences', 'Reg', (144, 155))	('BRCA1', 'Gene', '672', (31, 36))	('RAD51', 'Gene', '5888', (49, 54))	('rs12516', 'Mutation', 'rs12516', (37, 44))	('BRCA1', 'Gene', (31, 36))	('cause', 'Reg', (69, 74))	('rs12516', 'Var', (37, 44))	('rs7180135', 'Var', (55, 64))
76543	28646528	To date, no investigations on functional relevance of BRCA1 rs12516 and RAD51 rs7180135 polymorphisms have been reported.	('rs7180135', 'Var', (78, 87))	('RAD51', 'Gene', (72, 77))	('rs12516', 'Mutation', 'rs12516', (60, 67))	('RAD51', 'Gene', '5888', (72, 77))	('rs7180135', 'Mutation', 'rs7180135', (78, 87))	('rs12516', 'Var', (60, 67))	('BRCA1', 'Gene', '672', (54, 59))	('BRCA1', 'Gene', (54, 59))
76544	28646528	In fact, in this study, we found that BRCA1 rs12516 and RAD51 rs7180135 polymorphisms significantly or borderline significantly affected expression of their protein levels in SCCOP patients, particularly HPV16-positive patients.	('patients', 'Species', '9606', (219, 227))	('expression', 'MPA', (137, 147))	('rs7180135 polymorphisms', 'Var', (62, 85))	('rs12516', 'Mutation', 'rs12516', (44, 51))	('rs7180135', 'Mutation', 'rs7180135', (62, 71))	('RAD51', 'Gene', (56, 61))	('SCCOP', 'Disease', (175, 180))	('BRCA1', 'Gene', (38, 43))	('RAD51', 'Gene', '5888', (56, 61))	('rs12516', 'Var', (44, 51))	('patients', 'Species', '9606', (181, 189))	('polymorphisms', 'Var', (72, 85))	('affected', 'Reg', (128, 136))	('protein levels', 'MPA', (157, 171))	('BRCA1', 'Gene', '672', (38, 43))	('HPV16', 'Species', '333760', (204, 209))
76545	28646528	For example, in this study, the BRCA1 rs12516 and RAD51 rs7180135 variant genotypes might have an increased miRNA-mRNA binding ability and a decreased BRCA1 and RAD51 expression.	('BRCA1', 'Gene', (32, 37))	('RAD51', 'Gene', '5888', (161, 166))	('rs7180135', 'Mutation', 'rs7180135', (56, 65))	('rs12516', 'Var', (38, 45))	('BRCA1', 'Gene', '672', (151, 156))	('decreased', 'NegReg', (141, 150))	('BRCA1', 'Gene', (151, 156))	('increased', 'PosReg', (98, 107))	('RAD51', 'Gene', (50, 55))	('BRCA1', 'Gene', '672', (32, 37))	('rs12516', 'Mutation', 'rs12516', (38, 45))	('rs7180135', 'Var', (56, 65))	('RAD51', 'Gene', '5888', (50, 55))	('miRNA-mRNA', 'MPA', (108, 118))	('RAD51', 'Gene', (161, 166))	('expression', 'MPA', (167, 177))
76548	28646528	Therefore, the altered BRCA1 and RAD51 expression caused by BRCA1 rs12516 and RAD51 rs7180135 might modify the susceptibility to radiotherapy or chemoradiotherapy.	('BRCA1', 'Gene', (60, 65))	('rs12516', 'Var', (66, 73))	('susceptibility to radiotherapy', 'Phenotype', 'HP:0011133', (111, 141))	('rs7180135', 'Var', (84, 93))	('RAD51', 'Gene', (78, 83))	('RAD51', 'Gene', (33, 38))	('rs7180135', 'Mutation', 'rs7180135', (84, 93))	('BRCA1', 'Gene', '672', (23, 28))	('altered', 'Reg', (15, 22))	('expression', 'MPA', (39, 49))	('BRCA1', 'Gene', '672', (60, 65))	('rs12516', 'Mutation', 'rs12516', (66, 73))	('RAD51', 'Gene', '5888', (33, 38))	('RAD51', 'Gene', '5888', (78, 83))	('modify', 'Reg', (100, 106))	('BRCA1', 'Gene', (23, 28))
76551	28646528	This discordance could occur between HPV status and p16 expression since some events (e.g., mutation, deletion, other epigenetic changes, etc) may impact the p16, leading to biased estimation of the associations.	('mutation', 'Var', (92, 100))	('deletion', 'Var', (102, 110))	('impact', 'Reg', (147, 153))	('p16', 'MPA', (158, 161))	('HPV', 'Species', '10566', (37, 40))	('epigenetic changes', 'Var', (118, 136))	('associations', 'Interaction', (199, 211))
76552	28646528	We found that genetic variants of BRCA1 rs12516 and RAD51 rs7180135 significantly reduced the risk of recurrence of SCCOP, particularly HPV16-positive SCCOP.	('rs7180135', 'Mutation', 'rs7180135', (58, 67))	('BRCA1', 'Gene', '672', (34, 39))	('RAD51', 'Gene', (52, 57))	('HPV16', 'Species', '333760', (136, 141))	('rs12516', 'Mutation', 'rs12516', (40, 47))	('SCCOP', 'Disease', (116, 121))	('BRCA1', 'Gene', (34, 39))	('RAD51', 'Gene', '5888', (52, 57))	('rs12516', 'Var', (40, 47))	('reduced', 'NegReg', (82, 89))	('rs7180135', 'Var', (58, 67))	('HPV16-positive SCCOP', 'Disease', (136, 156))
76554	28646528	3' -UTR 3' -untranslated region miRNA microRNA CI confidence interval HR hazard ratio SCCOP squamous cell carcinoma of the oropharynx HPV human papillomavirus SNP single-nucleotide polymorphism DSB double strand break Our study found that BRCA1 rs12516 and RAD51 rs7180135, polymorphisms in miRNA-binding sites within 3'UTRs of genes specifically involved in DNA DSB repair pathways, were significantly associated with a reduced risk of SCCOP recurrence, particularly in patients with HPV16-positive SCCOP.	('RAD51', 'Gene', (257, 262))	('RAD51', 'Gene', '5888', (257, 262))	('rs12516', 'Var', (245, 252))	('squamous cell carcinoma', 'Disease', (92, 115))	('SCCOP recurrence', 'Disease', (437, 453))	('reduced', 'NegReg', (421, 428))	('BRCA1', 'Gene', '672', (239, 244))	('BRCA1', 'Gene', (239, 244))	('papillomavirus', 'Disease', 'MESH:D030361', (144, 158))	('HPV', 'Species', '10566', (485, 488))	('rs7180135', 'Mutation', 'rs7180135', (263, 272))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (92, 115))	('HPV16', 'Species', '333760', (485, 490))	('patients', 'Species', '9606', (471, 479))	('rs12516', 'Mutation', 'rs12516', (245, 252))	('papillomavirus', 'Disease', (144, 158))	('human', 'Species', '9606', (138, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (92, 115))	('HPV', 'Species', '10566', (134, 137))
76561	28912897	For the remaining tumor types, compared with TIMT II (low PD-L1 and CD8A/CYT), TIMT I (high PD-L1 and CD8A/CYT) had a significantly higher number of mutations or neoantigens in bladder urothelial carcinoma, breast and cervical cancer, colorectal, stomach and lung adenocarcinoma, and melanoma.	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (177, 205))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (259, 278))	('CD8A', 'Gene', '925', (102, 106))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (259, 278))	('colorectal', 'Disease', 'MESH:D015179', (235, 245))	('tumor', 'Disease', (18, 23))	('melanoma', 'Phenotype', 'HP:0002861', (284, 292))	('melanoma', 'Disease', (284, 292))	('CD8A', 'Gene', '925', (68, 72))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('CD8A', 'Gene', (102, 106))	('stomach', 'Disease', (247, 254))	('higher', 'PosReg', (132, 138))	('mutations', 'Var', (149, 158))	('carcinoma', 'Phenotype', 'HP:0030731', (269, 278))	('neoantigens', 'Var', (162, 173))	('CD8A', 'Gene', (68, 72))	('carcinoma', 'Phenotype', 'HP:0030731', (196, 205))	('breast and cervical cancer', 'Disease', 'MESH:D001943', (207, 233))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('lung adenocarcinoma', 'Disease', (259, 278))	('melanoma', 'Disease', 'MESH:D008545', (284, 292))	('bladder urothelial carcinoma', 'Disease', (177, 205))	('colorectal', 'Disease', (235, 245))
76562	28912897	In contrast, TMIT I of kidney clear cell, liver hepatocellular, and thyroid carcinoma were negatively correlated with mutation burden or neoantigen numbers.	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (68, 85))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (68, 85))	('liver hepatocellular', 'Disease', 'MESH:D056486', (42, 62))	('mutation burden', 'Var', (118, 133))	('negatively', 'NegReg', (91, 101))	('TMIT', 'Chemical', '-', (13, 17))	('thyroid carcinoma', 'Disease', (68, 85))	('liver hepatocellular', 'Disease', (42, 62))
76565	28912897	Inhibition of immune checkpoint proteins, primarily CTLA-4 or PD-1/PD-L1 may reduce the ability of the tumor microenvironment to suppress host antitumor immunity.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('CTLA-4', 'Gene', (52, 58))	('reduce', 'NegReg', (77, 83))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('PD-1/PD-L1', 'Gene', (62, 72))	('tumor', 'Disease', (103, 108))	('suppress', 'NegReg', (129, 137))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('Inhibition', 'Var', (0, 10))	('CTLA-4', 'Gene', '1493', (52, 58))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
76588	28912897	As per the study by Teng and colleagues, we classified TCGA samples of each cancer type into four TMITs by merging the mRNA expression levels of PD-L1 and CD8A, or PD-L1 and CYT as follows: type I, PD-L1 high expression and CD8A/CYT high expression; type II, PD-L1 low expression and CD8A/CYT low expression; type III, PD-L1 high expression and CD8A/CYT low expression; and type IV, PD-L1 low expression and CD8A/CYT high expression.	('CD8A', 'Gene', (408, 412))	('CD8A', 'Gene', (224, 228))	('CD8A', 'Gene', '925', (155, 159))	('CD8A', 'Gene', '925', (408, 412))	('CD8A', 'Gene', (155, 159))	('CD8A', 'Gene', '925', (345, 349))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('CD8A', 'Gene', (345, 349))	('CD8A', 'Gene', '925', (284, 288))	('TMIT', 'Chemical', '-', (98, 102))	('low', 'NegReg', (389, 392))	('PD-L1', 'Var', (319, 324))	('CD8A', 'Gene', (284, 288))	('CD8A', 'Gene', '925', (224, 228))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))
76594	28912897	TMIT was classified only for those tumor types with significant differences in mutation and/or neoantigen number in both PD-L1 and CD8A/CYT RPART subgroups.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('TMIT', 'Chemical', '-', (0, 4))	('neoantigen', 'MPA', (95, 105))	('differences', 'Reg', (64, 75))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('CD8A', 'Gene', '925', (131, 135))	('tumor', 'Disease', (35, 40))	('CD8A', 'Gene', (131, 135))	('mutation', 'Var', (79, 87))
76599	28912897	The number of mutations and neoantigens were significantly positively correlated, with a strong or very strong correlation for almost all tumors (R2 > 0.6), except for the LIHC and PRAD (relatively strong), and THCA (moderate; Supplementary Figure S1).	('almost all tumors', 'Disease', (127, 144))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('mutations', 'Var', (14, 23))	('almost all tumors', 'Disease', 'MESH:D009369', (127, 144))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
76605	28912897	Besides, RPART also better distinguished the different mutation number in the PD-L1 subgroups for BLCA, BRCA, CESC, LIHC, and SKCM; in the CD8A subgroups for BLCA, KIRC, and LIHC; and in CYT subgroups for BRCA, CESC, LUAD, SKCM, and STAD (Figure 2).	('BRCA', 'Gene', '672', (104, 108))	('BLCA', 'Chemical', '-', (158, 162))	('BRCA', 'Gene', (104, 108))	('BRCA', 'Gene', '672', (205, 209))	('PD-L1', 'Gene', (78, 83))	('CD8A', 'Gene', '925', (139, 143))	('BRCA', 'Gene', (205, 209))	('CD8A', 'Gene', (139, 143))	('mutation', 'Var', (55, 63))	('CESC', 'Disease', (110, 114))	('BLCA', 'Chemical', '-', (98, 102))
76606	28912897	In summary, for both mutation and neoantigen number, KIRC differs significantly in the PD-L1 and CD8A subgroups; BLCA, BRCA, SKCM, and STAD differ significantly in the PD-L1 and CYT subgroups; and CESC and LUAD differ significantly in the PD-L1, CD8A, and CYT subgroups.	('CD8A', 'Gene', '925', (97, 101))	('CD8A', 'Gene', (97, 101))	('mutation', 'Var', (21, 29))	('PD-L1', 'Disease', (87, 92))	('BLCA', 'Chemical', '-', (113, 117))	('CD8A', 'Gene', '925', (246, 250))	('BRCA', 'Gene', '672', (119, 123))	('CD8A', 'Gene', (246, 250))	('BRCA', 'Gene', (119, 123))
76610	28912897	Based on the abovementioned results, certain tumor samples were divided into four groups of tumor microenvironments according to the RPART cut-off values of PD-L1 and CD8A/CYT expression: PD-L1+CD8A for KIRC and LIHC; PD-L1+CYT for BLCA, BRCA, SKCM, STAD, and THCA; and PD-L1+CD8A/CYT for CESC, COAD, and LUAD.	('COAD', 'Disease', (295, 299))	('PD-L1+CYT', 'Var', (218, 227))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Disease', (45, 50))	('tumor', 'Disease', (92, 97))	('CD8A', 'Gene', '925', (276, 280))	('CD8A', 'Gene', '925', (194, 198))	('CD8A', 'Gene', '925', (167, 171))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('CD8A', 'Gene', (276, 280))	('COAD', 'Disease', 'MESH:D029424', (295, 299))	('BRCA', 'Gene', (238, 242))	('CD8A', 'Gene', (194, 198))	('CD8A', 'Gene', (167, 171))	('BRCA', 'Gene', '672', (238, 242))	('BLCA', 'Chemical', '-', (232, 236))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
76615	28912897	Tumor samples with a higher mutation or neoantigen numbers than the median value also tended to have a higher proportion of TMIT I (Figures 4C-N).	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('TMIT I', 'Disease', (124, 130))	('TMIT', 'Chemical', '-', (124, 128))	('mutation', 'Var', (28, 36))	('neoantigen numbers', 'Var', (40, 58))
76640	28912897	The objective response rate was also higher in patients with PD-L1 positive status than those with negative status (53% vs. 33%).	('objective response', 'CPA', (4, 22))	('higher', 'PosReg', (37, 43))	('PD-L1', 'Gene', (61, 66))	('patients', 'Species', '9606', (47, 55))	('positive status', 'Var', (67, 82))
76644	28912897	Overall, our results are generally consistent with those observed in clinical trials evaluating checkpoint inhibitor treatment, highlighting that the combination of PD-L1 and CD8A/CYT expression may help better identify subsets of patients who will benefit from anti-PD-1/PD-L1 therapy and avoid any potential toxicities and costs.	('toxicities', 'Disease', (310, 320))	('patients', 'Species', '9606', (231, 239))	('anti-PD-1/PD-L1', 'Var', (262, 277))	('PD-L1', 'Gene', (165, 170))	('toxicities', 'Disease', 'MESH:D064420', (310, 320))	('benefit', 'PosReg', (249, 256))	('CD8A', 'Gene', '925', (175, 179))	('CD8A', 'Gene', (175, 179))
76662	33261184	Recent progress in the development of therapies targeting epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase rearrangements, and rare oncogenic drivers (such as ROS1, RET, MET, and EGFR exon 20 insertion mutations) has considerably improved the survival in a subset of patients with NSCLC.	('MET', 'Gene', '79811', (189, 192))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (99, 118))	('NSCLC', 'Disease', 'MESH:D002289', (300, 305))	('RET', 'Gene', '5979', (184, 187))	('EGFR', 'Gene', '1956', (198, 202))	('NSCLC', 'Disease', (300, 305))	('anaplastic lymphoma', 'Disease', (99, 118))	('ROS1', 'Gene', '6098', (178, 182))	('EGFR', 'Gene', '1956', (92, 96))	('insertion mutations', 'Var', (211, 230))	('NSCLC', 'Phenotype', 'HP:0030358', (300, 305))	('lymphoma', 'Phenotype', 'HP:0002665', (110, 118))	('survival', 'MPA', (262, 270))	('RET', 'Gene', (184, 187))	('epidermal growth factor receptor', 'Gene', (58, 90))	('MET', 'Gene', (189, 192))	('men', 'Species', '9606', (135, 138))	('epidermal growth factor receptor', 'Gene', '1956', (58, 90))	('men', 'Species', '9606', (30, 33))	('EGFR', 'Gene', (198, 202))	('ROS1', 'Gene', (178, 182))	('improved', 'PosReg', (249, 257))	('EGFR', 'Gene', (92, 96))	('anaplastic lymphoma', 'Disease', 'MESH:D017728', (99, 118))	('patients', 'Species', '9606', (286, 294))
76668	33261184	We also assessed PAK1 expression in association with clinicopathological parameters, including the EGFR mutation status, recurrence-free survival, and five-year survival of 201 patients with banked NSCLC tissue specimens using tissue microarray (TMA) analysis.	('EGFR', 'Gene', (99, 103))	('men', 'Species', '9606', (216, 219))	('NSCLC', 'Phenotype', 'HP:0030358', (198, 203))	('PAK1', 'Gene', '5058', (17, 21))	('PAK1', 'Gene', (17, 21))	('patients', 'Species', '9606', (177, 185))	('mutation', 'Var', (104, 112))	('NSCLC', 'Disease', (198, 203))	('EGFR', 'Gene', '1956', (99, 103))	('NSCLC', 'Disease', 'MESH:D002289', (198, 203))
76683	33261184	Mutations in the gene encoding EGFR are critical because this receptor is used as a target in lung cancer treatment.	('EGFR', 'Gene', '1956', (31, 35))	('lung cancer', 'Disease', 'MESH:D008175', (94, 105))	('men', 'Species', '9606', (111, 114))	('EGFR', 'Gene', (31, 35))	('Mutations', 'Var', (0, 9))	('lung cancer', 'Disease', (94, 105))	('lung cancer', 'Phenotype', 'HP:0100526', (94, 105))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
76684	33261184	Notably, EGFR mutations are highly prevalent among non-smoking Asian females.	('prevalent', 'Reg', (35, 44))	('EGFR', 'Gene', (9, 13))	('mutations', 'Var', (14, 23))	('EGFR', 'Gene', '1956', (9, 13))
76687	33261184	Table 2 shows the baseline characteristics depending on the PAK1 status of the patients harboring EGFR mutations.	('EGFR', 'Gene', (98, 102))	('mutations', 'Var', (103, 112))	('PAK1', 'Gene', '5058', (60, 64))	('PAK1', 'Gene', (60, 64))	('patients', 'Species', '9606', (79, 87))	('EGFR', 'Gene', '1956', (98, 102))
76712	33261184	The effect of PAK1 expression on the five-year survival of current or former smokers (defined as patients who had smoked at least 100 cigarettes in their lifetime, but had quit smoking by the time of the hospital visit) resulted in elevated chi-square scores compared to those obtained for patients who were non-smokers and showed PAK1 expression (chi2 = 8.48 vs. 19.2).	('chi-square', 'CPA', (241, 251))	('patients', 'Species', '9606', (290, 298))	('elevated', 'PosReg', (232, 240))	('expression', 'Var', (19, 29))	('PAK1', 'Gene', '5058', (14, 18))	('PAK1', 'Gene', (14, 18))	('PAK1', 'Gene', '5058', (331, 335))	('PAK1', 'Gene', (331, 335))	('patients', 'Species', '9606', (97, 105))
76718	33261184	Perhaps, the functional polymorphisms in the PAK1 gene (rs2154754) are responsible for the significant influence of smoking levels on lung cancer risk.	('lung cancer', 'Disease', (134, 145))	('lung cancer', 'Phenotype', 'HP:0100526', (134, 145))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('rs2154754', 'Mutation', 'rs2154754', (56, 65))	('PAK1', 'Gene', '5058', (45, 49))	('PAK1', 'Gene', (45, 49))	('lung cancer', 'Disease', 'MESH:D008175', (134, 145))	('rs2154754', 'Var', (56, 65))
76735	33261184	Previous studies on EGFR mutations showed that a PAK1 inhibitor, administered in combination with a selective inhibitor of protein kinase C, was effective against the acquisition of resistance induced by EGFR tyrosine kinase inhibitors.	('mutations', 'Var', (25, 34))	('EGFR', 'Gene', (20, 24))	('tyrosine kinase', 'Gene', '7294', (209, 224))	('tyrosine kinase', 'Gene', (209, 224))	('acquisition of resistance', 'MPA', (167, 192))	('EGFR', 'Gene', '1956', (204, 208))	('PAK1', 'Gene', '5058', (49, 53))	('PAK1', 'Gene', (49, 53))	('EGFR', 'Gene', (204, 208))	('EGFR', 'Gene', '1956', (20, 24))
76736	33261184	We found that the five-year mortality rates were lower in patients with PAK1-negative than in PAK1-positive EGFR mutant lung cancer.	('lung cancer', 'Disease', (120, 131))	('EGFR', 'Gene', '1956', (108, 112))	('lung cancer', 'Phenotype', 'HP:0100526', (120, 131))	('EGFR', 'Gene', (108, 112))	('mortality', 'Disease', 'MESH:D003643', (28, 37))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('PAK1', 'Gene', '5058', (94, 98))	('lower', 'NegReg', (49, 54))	('mortality', 'Disease', (28, 37))	('lung cancer', 'Disease', 'MESH:D008175', (120, 131))	('patients', 'Species', '9606', (58, 66))	('mutant', 'Var', (113, 119))	('PAK1', 'Gene', '5058', (72, 76))	('PAK1', 'Gene', (94, 98))	('PAK1', 'Gene', (72, 76))
76741	33261184	Third, patients with high PAK1 expression and EGFR mutant lung cancer showed poor prognosis and survival.	('PAK1', 'Gene', '5058', (26, 30))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('poor', 'NegReg', (77, 81))	('mutant', 'Var', (51, 57))	('lung cancer', 'Disease', (58, 69))	('PAK1', 'Gene', (26, 30))	('EGFR', 'Gene', '1956', (46, 50))	('lung cancer', 'Phenotype', 'HP:0100526', (58, 69))	('EGFR', 'Gene', (46, 50))	('patients', 'Species', '9606', (7, 15))	('lung cancer', 'Disease', 'MESH:D008175', (58, 69))
76779	32922544	Transfection with p65, p50, c-Jun, c-Fos, p85, p110, Akt, mammalian target of rapamycin (mTOR), or interleukin-6 (IL-6) siRNA markedly inhibited PM-induced MMP-2 and MMP-9 expression.	('p85', 'Gene', '5296', (42, 45))	('c-Fos', 'Gene', '2353', (35, 40))	('IL-6', 'Gene', (114, 118))	('p50', 'Gene', (23, 26))	('IL-6', 'Gene', '3569', (114, 118))	('p85', 'Gene', (42, 45))	('interleukin-6', 'Gene', (99, 112))	('p65', 'Var', (18, 21))	('p50', 'Gene', '4790', (23, 26))	('MMP-9', 'Gene', (166, 171))	('expression', 'MPA', (172, 182))	('interleukin-6', 'Gene', '3569', (99, 112))	('mammalian target of rapamycin', 'Gene', (58, 87))	('mammalian target of rapamycin', 'Gene', '2475', (58, 87))	('p110', 'Gene', '100616443', (47, 51))	('c-Fos', 'Gene', (35, 40))	('p110', 'Gene', (47, 51))	('inhibited', 'NegReg', (135, 144))
76781	32922544	Finally, we proved that transfection with Akt, p65, or c-Jun siRNA significantly inhibited PM-induced IL-6 release.	('p65', 'Var', (47, 50))	('inhibited', 'NegReg', (81, 90))	('c-Jun', 'Protein', (55, 60))	('IL-6', 'Gene', (102, 106))	('IL-6', 'Gene', '3569', (102, 106))
76812	32922544	Human scrambled, MMP-2, MMP-9, p65, p50, c-Jun, c-Fos, p85, p110, Akt, mTOR, and IL-6 siRNAs were from Sigma (St. Louis, MO).	('Human', 'Species', '9606', (0, 5))	('IL-6', 'Gene', '3569', (81, 85))	('p50', 'Gene', (36, 39))	('p85', 'Gene', '5296', (55, 58))	('p65', 'Var', (31, 34))	('p50', 'Gene', '4790', (36, 39))	('p85', 'Gene', (55, 58))	('p110', 'Gene', '100616443', (60, 64))	('IL-6', 'Gene', (81, 85))	('c-Fos', 'Gene', (48, 53))	('p110', 'Gene', (60, 64))	('c-Fos', 'Gene', '2353', (48, 53))	('c-Jun', 'MPA', (41, 46))
76844	32922544	3A, we proved that transfection with MMP-2 or MMP-9 siRNA markedly inhibited PM-induced cell migration and invasion in SCC4 cells.	('SCC4', 'Gene', '23383', (119, 123))	('MMP-9', 'Var', (46, 51))	('SCC4', 'Gene', (119, 123))	('inhibited', 'NegReg', (67, 76))
76853	32922544	4A, transfection with p65, p50, c-Jun, or c-Fos siRNA markedly reduced PM-mediated MMP-2 and MMP-9 mRNA levels in SCC4 cells.	('reduced', 'NegReg', (63, 70))	('c-Jun', 'Var', (32, 37))	('c-Fos', 'Gene', '2353', (42, 47))	('c-Fos', 'Gene', (42, 47))	('p65', 'Var', (22, 25))	('p50', 'Gene', (27, 30))	('p50', 'Gene', '4790', (27, 30))	('SCC4', 'Gene', '23383', (114, 118))	('SCC4', 'Gene', (114, 118))
76874	32922544	6C, we showed that transfection with siRNA of Akt, p65, or c-Jun significantly inhibited IL-6 secretion in response to PM.	('p65', 'Var', (51, 54))	('Akt', 'Gene', (46, 49))	('IL-6', 'Gene', (89, 93))	('inhibited', 'NegReg', (79, 88))	('c-Jun', 'Gene', (59, 64))	('IL-6', 'Gene', '3569', (89, 93))
76876	32922544	proved that Taiwanese men exposed to higher concentrations of PM2.5 have an increased risk of oral cancer.	('oral cancer', 'Disease', 'MESH:D009369', (94, 105))	('PM2.5', 'Var', (62, 67))	('men', 'Species', '9606', (22, 25))	('oral cancer', 'Disease', (94, 105))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
76885	32922544	Zhang and Li indicated that PM2.5 could induce the cell proliferation, migration, and invasion of human hepatocellular carcinoma (HCC) cell line SMMC-7721.	('PM2.5', 'Var', (28, 33))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (104, 128))	('hepatocellular carcinoma', 'Disease', (104, 128))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (104, 128))	('migration', 'CPA', (71, 80))	('cell proliferation', 'CPA', (51, 69))	('SMMC-7721', 'CellLine', 'CVCL:0534', (145, 154))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('HCC', 'Phenotype', 'HP:0001402', (130, 133))	('invasion', 'CPA', (86, 94))	('human', 'Species', '9606', (98, 103))	('induce', 'PosReg', (40, 46))
76897	32922544	On the other hand, PM2.5 has been shown to induce MMP-2 and MMP-9 expression in human keratinocytes and cause skin aging.	('expression', 'MPA', (66, 76))	('human', 'Species', '9606', (80, 85))	('cause', 'Reg', (104, 109))	('PM2.5', 'Var', (19, 24))	('induce', 'PosReg', (43, 49))	('skin', 'Disease', (110, 114))	('MMP-9', 'Gene', (60, 65))	('MMP-2', 'Gene', (50, 55))
76898	32922544	Indeed, we also found that the levels of MMP-2 and MMP-9 in oral cancer cells or breast cancer cells are higher than in human gingival fibroblasts under the stimulation of PM (Supplementary Fig.	('MMP-9', 'Var', (51, 56))	('human', 'Species', '9606', (120, 125))	('breast cancer', 'Disease', (81, 94))	('higher', 'PosReg', (105, 111))	('oral cancer', 'Disease', (60, 71))	('breast cancer', 'Phenotype', 'HP:0003002', (81, 94))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('oral cancer', 'Disease', 'MESH:D009369', (60, 71))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('men', 'Species', '9606', (182, 185))	('breast cancer', 'Disease', 'MESH:D001943', (81, 94))
76908	32922544	We proved that PM induced MMP-2 and MMP-9 expression via these signaling pathways by using siRNA of p65, c-Jun, p50, c-Fos, p85, p110, Akt, or mTOR.	('MMP-2', 'Gene', (26, 31))	('p85', 'Gene', '5296', (124, 127))	('c-Fos', 'Gene', '2353', (117, 122))	('p65', 'Var', (100, 103))	('c-Jun', 'MPA', (105, 110))	('p50', 'Gene', (112, 115))	('Akt', 'Pathway', (135, 138))	('p85', 'Gene', (124, 127))	('p110', 'Gene', '100616443', (129, 133))	('c-Fos', 'Gene', (117, 122))	('p50', 'Gene', '4790', (112, 115))	('p110', 'Gene', (129, 133))	('MMP-9', 'Gene', (36, 41))
76920	31632920	Identification of Schlafen-11 as a Target of CD47 Signaling That Regulates Sensitivity to Ionizing Radiation and Topoisomerase Inhibitors Knockdown or gene disruption of the ubiquitously expressed cell surface receptor CD47 protects non-malignant cells from genotoxic stress caused by ionizing radiation or cytotoxic chemotherapy but sensitizes tumors in an immune competent host to genotoxic stress.	('CD47', 'Gene', '961', (45, 49))	('sensitizes tumors', 'Disease', (334, 351))	('CD47', 'Gene', '961', (219, 223))	('CD47', 'Gene', (45, 49))	('tumor', 'Phenotype', 'HP:0002664', (345, 350))	('CD47', 'Gene', (219, 223))	('tumors', 'Phenotype', 'HP:0002664', (345, 351))	('sensitizes tumors', 'Disease', 'MESH:D009369', (334, 351))	('Schlafen-11', 'Chemical', 'MESH:C027406', (18, 29))	('Sensitivity to Ionizing Radiation', 'Phenotype', 'HP:0011133', (75, 108))	('gene disruption', 'Var', (151, 166))
76922	31632920	A high throughput screen of drug sensitivities indicated that CD47 expression selectively sensitizes Jurkat T cells to inhibitors of topoisomerases, which are known targets of Schlafen-11 (SLFN11).	('SLFN11', 'Gene', (189, 195))	('sensitizes', 'Reg', (90, 100))	('Schlafen-11', 'Chemical', 'MESH:C027406', (176, 187))	('topoisomerases', 'Enzyme', (133, 147))	('expression', 'Var', (67, 77))	('CD47', 'Gene', (62, 66))	('SLFN11', 'Gene', '91607', (189, 195))	('inhibitors', 'MPA', (119, 129))
76925	31632920	CD47 knockdown, gene disruption, or treatment with a CD47 function-blocking antibody decreased SLFN11 expression in Jurkat cells.	('decreased', 'NegReg', (85, 94))	('CD47', 'Gene', (0, 4))	('expression', 'MPA', (102, 112))	('knockdown', 'Var', (5, 14))	('gene disruption', 'Var', (16, 31))	('SLFN11', 'Gene', (95, 101))	('CD47', 'Gene', (53, 57))	('SLFN11', 'Gene', '91607', (95, 101))
76928	31632920	Disruption of CD47 in PC3 prostate cancer cells similarly decreased schlafen-11 expression and was associated with a CD47-dependent decrease in acetylation and increased methylation of histone H3 in the SLFN11 promoter region.	('SLFN11', 'Gene', '91607', (203, 209))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('decreased', 'NegReg', (58, 67))	('schlafen-11', 'Gene', (68, 79))	('prostate cancer', 'Disease', 'MESH:D011471', (26, 41))	('decrease', 'NegReg', (132, 140))	('prostate cancer', 'Phenotype', 'HP:0012125', (26, 41))	('Disruption', 'Var', (0, 10))	('CD47', 'Gene', (14, 18))	('prostate cancer', 'Disease', (26, 41))	('histone H3', 'Protein', (185, 195))	('schlafen-11', 'Chemical', 'MESH:C027406', (68, 79))	('CD47-dependent', 'Gene', (117, 131))	('methylation', 'MPA', (170, 181))	('expression', 'MPA', (80, 90))	('PC3', 'Gene', (22, 25))	('increased', 'PosReg', (160, 169))	('PC3', 'Gene', '3853', (22, 25))	('SLFN11', 'Gene', (203, 209))	('acetylation', 'MPA', (144, 155))
76930	31632920	Disrupting CD47 in PC3 cells increased resistance to etoposide but, in contrast to Jurkat cells, not to ionizing radiation.	('resistance to etoposide', 'MPA', (39, 62))	('PC3', 'Gene', (19, 22))	('CD47', 'Gene', (11, 15))	('etoposide', 'Chemical', 'MESH:D005047', (53, 62))	('increased', 'PosReg', (29, 38))	('Disrupting', 'Var', (0, 10))	('PC3', 'Gene', '3853', (19, 22))
76938	31632920	In vascular cells, ligation of CD47 modulates calcium, nitric oxide, cAMP, and cGMP signaling.	('calcium', 'MPA', (46, 53))	('ligation', 'Var', (19, 27))	('calcium', 'Chemical', 'MESH:D002118', (46, 53))	('cAMP', 'MPA', (69, 73))	('CD47', 'Gene', (31, 35))	('nitric oxide', 'MPA', (55, 67))	('nitric oxide', 'Chemical', 'MESH:D009569', (55, 67))	('cAMP', 'Chemical', 'MESH:D000242', (69, 73))	('cGMP signaling', 'MPA', (79, 93))	('modulates', 'Reg', (36, 45))
76940	31632920	Genetic disruption or antisense suppression of CD47 enhances cytotoxic T cell killing of target tumor cells in vitro and suppresses tumor growth in vivo when combined with local tumor irradiation or cytotoxic chemotherapy.	('tumor', 'Disease', (178, 183))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumor irradiation', 'Disease', (178, 195))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumor', 'Disease', (96, 101))	('Genetic disruption', 'Var', (0, 18))	('cytotoxic T cell killing', 'CPA', (61, 85))	('tumor', 'Disease', (132, 137))	('tumor irradiation', 'Disease', 'MESH:D012793', (178, 195))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('antisense suppression', 'Var', (22, 43))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('suppresses', 'NegReg', (121, 131))	('enhances', 'PosReg', (52, 60))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('CD47', 'Gene', (47, 51))
76941	31632920	In addition to enhancing their antitumor efficacy, blockade of CD47 signaling protects non-malignant tissues from the off-target effects of these genotoxic therapies by enhancing autophagy pathways, stem cell self-renewal, and broadly enhancing metabolic pathways to repair cell damage caused by ionizing radiation.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('CD47', 'Gene', (63, 67))	('metabolic pathways', 'CPA', (245, 263))	('autophagy pathways', 'CPA', (179, 197))	('tumor', 'Disease', (35, 40))	('blockade', 'Var', (51, 59))	('enhancing', 'PosReg', (169, 178))	('stem cell self-renewal', 'CPA', (199, 221))	('enhancing', 'PosReg', (235, 244))	('enhancing', 'PosReg', (15, 24))
76944	31632920	Loss of SLFN11 expression in cancer cells involves both hypermethylation of its promoter and epigenetic changes in histone modification.	('cancer', 'Disease', (29, 35))	('SLFN11', 'Gene', (8, 14))	('hypermethylation', 'Var', (56, 72))	('promoter', 'MPA', (80, 88))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('Loss', 'NegReg', (0, 4))	('expression', 'MPA', (15, 25))	('histone modification', 'MPA', (115, 135))	('SLFN11', 'Gene', '91607', (8, 14))	('cancer', 'Disease', 'MESH:D009369', (29, 35))
76970	31632920	PC3 cells (WT, low CD47, and CD47-null cells) were plated on 4-well ibidi chambers overnight.	('low CD47', 'Var', (15, 23))	('PC3', 'Gene', (0, 3))	('PC3', 'Gene', '3853', (0, 3))
76989	31632920	To evaluate whether CD47 also regulates the repair of genomic DNA damage caused by ionizing radiation, we assessed nuclear H2AX foci in WT and CD47- Jurkat T cells 1 h after irradiation at 10 Gy (Figure 1A).	('H2AX', 'Gene', (123, 127))	('CD47-', 'Var', (143, 148))	('H2AX', 'Gene', '3014', (123, 127))
76991	31632920	Consistent with these results, subjecting the WT T cells to 10 Gy irradiation in the presence of B6H12 resulted in accelerated but less intense H2AX foci formation that resolved by 6 h (Figure 1B).	('less', 'NegReg', (131, 135))	('accelerated', 'PosReg', (115, 126))	('B6H12', 'Var', (97, 102))	('H2AX', 'Gene', '3014', (144, 148))	('H2AX', 'Gene', (144, 148))
77003	31632920	Two independent microarray analyses of the same WT and CD47-deficient T cell lines identified 8.7- and 10-fold decreased expression of SLFN11 mRNA in the CD47-deficient Jurkat mutant (p < 0.05, Figure 4A).	('CD47-deficient', 'Var', (154, 168))	('CD47-deficient T', 'Disease', 'MESH:D001260', (55, 71))	('SLFN11', 'Gene', (135, 141))	('mutant', 'Var', (176, 182))	('decreased', 'NegReg', (111, 120))	('CD47-deficient T', 'Disease', (55, 71))	('expression', 'MPA', (121, 131))	('SLFN11', 'Gene', '91607', (135, 141))
77005	31632920	Decreased SLFN11 mRNA in the CD47- mutant was confirmed using real-time qPCR (Figure 4B).	('Decreased', 'NegReg', (0, 9))	('SLFN11', 'Gene', '91607', (10, 16))	('CD47- mutant', 'Var', (29, 41))	('SLFN11', 'Gene', (10, 16))
77009	31632920	To establish causality and exclude the potential for secondary mutations in the Jurkat somatic mutant suppressing SLFN11 expression, we examined whether acute CD47 knockdown decreases schalfen-11 expression (Figures 4A,C, Supplementary Data File 2).	('SLFN11', 'Gene', (114, 120))	('expression', 'MPA', (196, 206))	('expression', 'MPA', (121, 131))	('suppressing', 'NegReg', (102, 113))	('CD47', 'Gene', (159, 163))	('knockdown', 'Var', (164, 173))	('mutant', 'Var', (95, 101))	('SLFN11', 'Gene', '91607', (114, 120))	('schalfen-11', 'Gene', (184, 195))	('decreases', 'NegReg', (174, 183))
77010	31632920	siRNA knockdown of CD47 in the WT cells resulted in a 1.4-fold decrease in SLFN11 (p = 0.046).	('SLFN11', 'Gene', (75, 81))	('decrease', 'NegReg', (63, 71))	('knockdown', 'Var', (6, 15))	('CD47', 'Gene', (19, 23))	('SLFN11', 'Gene', '91607', (75, 81))
77011	31632920	If loss of SLFN11 contributes to the radioresistance of the CD47- cells, forced expression of SLFN11 should restore sensitivity.	('loss', 'Var', (3, 7))	('radioresistance', 'CPA', (37, 52))	('sensitivity', 'MPA', (116, 127))	('SLFN11', 'Gene', (94, 100))	('SLFN11', 'Gene', '91607', (11, 17))	('restore', 'PosReg', (108, 115))	('SLFN11', 'Gene', '91607', (94, 100))	('contributes', 'Reg', (18, 29))	('SLFN11', 'Gene', (11, 17))
77017	31632920	No inhibition of SLFN11 mRNA expression by TSP1 was observed in the CD47- mutant, indicating that the inhibitory effect of TSP1 on SLFN11 expression is CD47-dependent.	('TSP1', 'Gene', '7057', (123, 127))	('TSP1', 'Gene', (123, 127))	('SLFN11', 'Gene', (131, 137))	('SLFN11', 'Gene', '91607', (17, 23))	('SLFN11', 'Gene', '91607', (131, 137))	('TSP1', 'Gene', '7057', (43, 47))	('CD47- mutant', 'Var', (68, 80))	('mRNA expression', 'MPA', (24, 39))	('SLFN11', 'Gene', (17, 23))	('TSP1', 'Gene', (43, 47))
77019	31632920	However, some effects of B6H12 on cancer cells may be independent of inhibiting binding of CD47 ligands.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('CD47 ligands', 'Protein', (91, 103))	('B6H12', 'Var', (25, 30))	('cancer', 'Disease', (34, 40))	('inhibiting', 'NegReg', (69, 79))	('binding', 'Interaction', (80, 87))
77023	31632920	Combining B6H12 with 100 nM doxorubicin resulted in more inhibition of cell growth, consistent with an additive effect (p = 0.001, Figure 5C).	('cell growth', 'CPA', (71, 82))	('B6H12', 'Var', (10, 15))	('doxorubicin', 'Chemical', 'MESH:D004317', (28, 39))	('inhibition', 'NegReg', (57, 67))
77035	31632920	Segregating high vs. low expressing cell lines with a mean cutoff showed higher CD47 in the SLFN11 high cell lines (log ratio 0.35, p = 3.1 x 10-8).	('CD47', 'MPA', (80, 84))	('high', 'Var', (99, 103))	('SLFN11', 'Gene', (92, 98))	('SLFN11', 'Gene', '91607', (92, 98))	('higher', 'PosReg', (73, 79))
77038	31632920	CD47 was targeted using CRISPR/Cas9, and pools of mutant PC3 cells with low residual CD47 or completely lacking CD47 were isolated by fluorescence activated cell sorting.	('PC3', 'Gene', '3853', (57, 60))	('lacking', 'NegReg', (104, 111))	('mutant', 'Var', (50, 56))	('PC3', 'Gene', (57, 60))
77041	31632920	SLFN11 mRNA expression was also reduced in the CD47-null PC3 cells (Figure 7D).	('SLFN11', 'Gene', '91607', (0, 6))	('reduced', 'NegReg', (32, 39))	('PC3', 'Gene', (57, 60))	('mRNA expression', 'MPA', (7, 22))	('PC3', 'Gene', '3853', (57, 60))	('SLFN11', 'Gene', (0, 6))	('CD47-null', 'Var', (47, 56))
77042	31632920	Although loss of CD47 in Jurkat cells consistently protects these cells from ionizing radiation [present results and ], this was not the case when CD47 was disrupted in PC3 cells (Figure 7E).	('CD47', 'Gene', (17, 21))	('loss', 'Var', (9, 13))	('PC3', 'Gene', (169, 172))	('PC3', 'Gene', '3853', (169, 172))
77046	31632920	In contrast, CD47-null PC3 cells were moderately more sensitive than WT cells to entinostat and doxorubicin.	('CD47-null', 'Var', (13, 22))	('sensitive', 'MPA', (54, 63))	('PC3', 'Gene', (23, 26))	('doxorubicin', 'Chemical', 'MESH:D004317', (96, 107))	('PC3', 'Gene', '3853', (23, 26))	('entinostat', 'Chemical', 'MESH:C118739', (81, 91))
77069	31632920	In contrast, enrichment of trimethylated H3K4 and H3K27 was dose-dependent with decreasing CD47 expression (Figures 10C-F).	('decreasing', 'NegReg', (80, 90))	('H3K27', 'Var', (50, 55))	('H3K4', 'Protein', (41, 45))	('expression', 'MPA', (96, 106))	('trimethylated', 'Var', (27, 40))	('H3K4', 'Chemical', 'MESH:C024755', (41, 45))	('CD47', 'Protein', (91, 95))
77074	31632920	Loss or blockade of CD47 in non-transformed cells and tissues and in the Jurkat T cell line consistently protects cells from genotoxic and ischemic stresses.	('CD47', 'Gene', (20, 24))	('protects', 'Reg', (105, 113))	('ischemic', 'Disease', 'MESH:D007511', (139, 147))	('Loss', 'NegReg', (0, 4))	('blockade', 'Var', (8, 16))	('ischemic', 'Disease', (139, 147))
77077	31632920	Similarly, blockade of CD47 signaling that preserves non-transformed stem cells results in differentiation of breast and hepatocellular carcinoma and stem cells.	('results in', 'Reg', (80, 90))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (121, 145))	('differentiation', 'CPA', (91, 106))	('breast and hepatocellular carcinoma', 'Disease', 'MESH:D001943', (110, 145))	('CD47', 'Protein', (23, 27))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('blockade', 'Var', (11, 19))
77081	31632920	Conversely, ligation of CD47 by a CD47 antibody, which is known to confer cytoprotection in WT Jurkat cells, rapidly decreases SLFN11 expression in these cells.	('expression', 'MPA', (134, 144))	('ligation', 'Var', (12, 20))	('CD47', 'Gene', (34, 38))	('SLFN11', 'Gene', '91607', (127, 133))	('decreases', 'NegReg', (117, 126))	('CD47', 'Gene', (24, 28))	('SLFN11', 'Gene', (127, 133))
77088	31632920	In contrast, doxorubicin causes cumulative DNA damage by several mechanisms including intercalation, ROS-induced strand breaks, and inhibition of topoisomerase activity.	('inhibition', 'NegReg', (132, 142))	('ROS-induced', 'MPA', (101, 112))	('doxorubicin', 'Chemical', 'MESH:D004317', (13, 24))	('intercalation', 'MPA', (86, 99))	('topoisomerase', 'Enzyme', (146, 159))	('doxorubicin', 'Var', (13, 24))	('cumulative DNA damage', 'MPA', (32, 53))
77096	31632920	Consistent with the drug screening data, ChIP data identified CD47-dependent regulation of histone modification in the SLFN11 promoter in prostate cancer cells.	('SLFN11', 'Gene', '91607', (119, 125))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('prostate cancer', 'Disease', 'MESH:D011471', (138, 153))	('prostate cancer', 'Phenotype', 'HP:0012125', (138, 153))	('CD47-dependent', 'Var', (62, 76))	('SLFN11', 'Gene', (119, 125))	('prostate cancer', 'Disease', (138, 153))	('regulation', 'Reg', (77, 87))	('histone modification', 'MPA', (91, 111))
77097	31632920	Loss of CD47 in PC3 cells was associated with increased histone H3 K4 methylation and K27 methylation and decreased H3K18 acetylation at this locus.	('decreased', 'NegReg', (106, 115))	('PC3', 'Gene', (16, 19))	('increased', 'PosReg', (46, 55))	('PC3', 'Gene', '3853', (16, 19))	('H3K18', 'Protein', (116, 121))	('histone H3 K4', 'Protein', (56, 69))	('K27 methylation', 'MPA', (86, 101))	('H3K18', 'Chemical', 'MESH:C024755', (116, 121))	('CD47', 'Gene', (8, 12))	('Loss', 'Var', (0, 4))
77098	31632920	The observed epigenetic effects of CD47 signaling on SLFN11 could also account for the differential resistance of CD47-deficient Jurkat T cells to several HDAC inhibitors in the drug screening.	('HDAC', 'Gene', (155, 159))	('epigenetic effects', 'Var', (13, 31))	('HDAC', 'Gene', '9734', (155, 159))	('SLFN11', 'Gene', (53, 59))	('SLFN11', 'Gene', '91607', (53, 59))	('CD47-deficient', 'Gene', (114, 128))
77100	31632920	Analysis of tumor data in TCGA also implicated CD47 regulation of SLFN11 promoter methylation in a subset of cancers that includes prostate adenocarcinoma.	('SLFN11', 'Gene', (66, 72))	('promoter methylation', 'MPA', (73, 93))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('carcinoma', 'Phenotype', 'HP:0030731', (145, 154))	('cancers', 'Disease', 'MESH:D009369', (109, 116))	('cancers', 'Phenotype', 'HP:0002664', (109, 116))	('prostate adenocarcinoma', 'Disease', (131, 154))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('cancers', 'Disease', (109, 116))	('SLFN11', 'Gene', '91607', (66, 72))	('prostate adenocarcinoma', 'Disease', 'MESH:D011471', (131, 154))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('CD47', 'Var', (47, 51))	('tumor', 'Disease', (12, 17))
77124	26305218	In tumor models of NSCLC, the presence of VEGF-C and VEGFR3 leads to proliferation, invasiveness and nodal metastases.	('VEGF-C', 'Gene', (42, 48))	('tumor', 'Disease', (3, 8))	('proliferation', 'CPA', (69, 82))	('VEGFR3', 'Gene', '2324', (53, 59))	('VEGF-C', 'Gene', '7424', (42, 48))	('NSCLC', 'Disease', (19, 24))	('presence', 'Var', (30, 38))	('tumor', 'Disease', 'MESH:D009369', (3, 8))	('leads to', 'Reg', (60, 68))	('VEGFR3', 'Gene', (53, 59))	('NSCLC', 'Disease', 'MESH:D002289', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))	('invasiveness and nodal metastases', 'Disease', 'MESH:D009362', (84, 117))
77126	26305218	The inhibition of VEGFR3 in a xenograft model of NSCLC indicated that abrogation of lymphangiogenesis could prevent lymphatic metastasis.	('abrogation', 'Var', (70, 80))	('VEGFR3', 'Gene', '2324', (18, 24))	('NSCLC', 'Disease', (49, 54))	('NSCLC', 'Disease', 'MESH:D002289', (49, 54))	('lymphangiogenesis', 'CPA', (84, 101))	('prevent', 'NegReg', (108, 115))	('VEGFR3', 'Gene', (18, 24))	('lymphatic metastasis', 'CPA', (116, 136))	('inhibition', 'NegReg', (4, 14))
77181	26305218	Further, NSCLC cell-lines over-expressing the VEGF-C/VEGFR3 axis showed increased migration, and, when introduced into xenograft models, more frequently formed lung metastases, compared to NSCLC cell-lines where VEGF-C/VEGFR3 signaling had been abrogated.	('VEGF-C', 'Gene', '7424', (46, 52))	('NSCLC', 'Disease', (189, 194))	('increased', 'PosReg', (72, 81))	('more', 'PosReg', (137, 141))	('over-expressing', 'Var', (26, 41))	('NSCLC', 'Disease', 'MESH:D002289', (189, 194))	('VEGFR3', 'Gene', '2324', (53, 59))	('NSCLC', 'Disease', (9, 14))	('VEGFR3', 'Gene', (219, 225))	('metastases', 'Disease', 'MESH:D009362', (165, 175))	('migration', 'CPA', (82, 91))	('VEGF-C', 'Gene', (46, 52))	('NSCLC', 'Disease', 'MESH:D002289', (9, 14))	('VEGF-C', 'Gene', '7424', (212, 218))	('VEGFR3', 'Gene', '2324', (219, 225))	('VEGFR3', 'Gene', (53, 59))	('VEGF-C', 'Gene', (212, 218))	('metastases', 'Disease', (165, 175))
77200	26305218	Nevertheless, our meta-analysis identified high LVD-levels as a marker of poor prognosis (HR 1.84 95% CI 1.18-2.87) and LNM (HR 2.24 95% CIT 1.13-4.46) in NSCLC patients.	('LVD-levels', 'MPA', (48, 58))	('high', 'Var', (43, 47))	('NSCLC', 'Disease', (155, 160))	('patients', 'Species', '9606', (161, 169))	('NSCLC', 'Disease', 'MESH:D002289', (155, 160))	('CIT 1', 'Gene', '53844', (137, 142))	('CIT 1', 'Gene', (137, 142))
77232	32826889	Further investigation reveals that OTUD5 depletion leads to the enhanced transcriptional activity of TRIM25 and the inhibited expression of PML by altering the ubiquitination level of TRIM25.	('expression', 'Species', '29278', (126, 136))	('altering', 'Reg', (147, 155))	('expression', 'MPA', (126, 136))	('inhibited', 'NegReg', (116, 125))	('TRIM25', 'Gene', (101, 107))	('OTU', 'Phenotype', 'HP:0100615', (35, 38))	('transcriptional activity', 'MPA', (73, 97))	('depletion', 'Var', (41, 50))	('ubiquitination level', 'MPA', (160, 180))	('enhanced', 'PosReg', (64, 72))
77233	32826889	Importantly, OTUD5 knockdown accelerates tumor growth in a nude mouse model.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('accelerates', 'PosReg', (29, 40))	('tumor', 'Disease', (41, 46))	('knockdown', 'Var', (19, 28))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('OTUD5', 'Gene', (13, 18))	('OTU', 'Phenotype', 'HP:0100615', (13, 16))	('mouse', 'Species', '10090', (64, 69))
77276	32826889	Two different tumor cell lines, Huh7 and Hep3B, were then used to investigate whether the siRNA-mediated depletion of OTUD5 promoted cell proliferation.	('tumor', 'Disease', (14, 19))	('cell proliferation', 'CPA', (133, 151))	('depletion', 'Var', (105, 114))	('OTUD5', 'Gene', (118, 123))	('Hep3B', 'CellLine', 'CVCL:0326', (41, 46))	('Huh7', 'Gene', (32, 36))	('promoted', 'PosReg', (124, 132))	('OTU', 'Phenotype', 'HP:0100615', (118, 121))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('Huh7', 'Gene', '284424', (32, 36))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
77280	32826889	In order to test whether OTUD5 associates with an E3 ubiquitin ligase to regulate cell proliferation, the stable Flag-OTUD5/Hep3B cell line was established by transfecting Hep3B cells with plasmids expressing pCIN4-Flag-OTUD5.	('pCIN4-Flag-OTUD5', 'Var', (209, 225))	('OTU', 'Phenotype', 'HP:0100615', (25, 28))	('OTU', 'Phenotype', 'HP:0100615', (220, 223))	('cell proliferation', 'CPA', (82, 100))	('Hep3B', 'CellLine', 'CVCL:0326', (172, 177))	('E3 ubiquitin ligase', 'Gene', (50, 69))	('Hep3B', 'CellLine', 'CVCL:0326', (124, 129))	('OTU', 'Phenotype', 'HP:0100615', (118, 121))	('E3 ubiquitin ligase', 'Gene', '79594', (50, 69))
77283	32826889	The OTUD5 UIM domain can bind both Lys48- and Lys63-linked polyubiquitin chains.	('Lys63', 'Chemical', '-', (46, 51))	('OTU', 'Phenotype', 'HP:0100615', (4, 7))	('Lys63-linked', 'Var', (46, 58))	('Lys48', 'Chemical', '-', (35, 40))	('bind', 'Interaction', (25, 29))	('Lys48-', 'Var', (35, 41))
77285	32826889	TRIM25 has been implicated in the increased proliferation of many cancer cell types, and knockdown of TRIM25 often results in attenuated tumor growth.	('attenuated tumor', 'Disease', 'MESH:C538265', (126, 142))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('attenuated tumor', 'Disease', (126, 142))	('knockdown', 'Var', (89, 98))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('TRIM25', 'Gene', (102, 108))	('increased', 'PosReg', (34, 43))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('cancer', 'Disease', (66, 72))	('proliferation', 'CPA', (44, 57))
77288	32826889	The OTUD5 depletion-induced increase in cell proliferation was partly abrogated by TRIM25 knockdown for both the Huh7 and Hep3B cells, suggesting that the cell proliferation-promoting effects of OTUD5 knockdown were possibly mediated by TRIM25 (Fig.	('TRIM25', 'Gene', (83, 89))	('OTUD5', 'Gene', (195, 200))	('abrogated', 'NegReg', (70, 79))	('Hep3B', 'CellLine', 'CVCL:0326', (122, 127))	('OTU', 'Phenotype', 'HP:0100615', (195, 198))	('knockdown', 'Var', (90, 99))	('OTU', 'Phenotype', 'HP:0100615', (4, 7))	('Huh7', 'Gene', '284424', (113, 117))	('cell proliferation-promoting', 'CPA', (155, 183))	('Huh7', 'Gene', (113, 117))	('OTUD5', 'Gene', (4, 9))	('cell proliferation', 'CPA', (40, 58))	('increase', 'PosReg', (28, 36))
77290	32826889	Indeed, smears corresponding to ubiquitinated TRIM25 were detected with an antibody against ubiquitin, a finding that was consistent with the autoubiquitination of E3 ubiquitin ligases (Fig.	('antibody', 'Var', (75, 83))	('E3 ubiquitin ligase', 'Gene', '79594', (164, 183))	('E3 ubiquitin ligase', 'Gene', (164, 183))	('TRIM25', 'Var', (46, 52))
77296	32826889	The deubiquitination of TRIM25 was dependent on OTUD5 deubiquitinase activity and its activation by phosphorylation, as indicated by the cells coexpressing either OTUD5/C224S or OTUD5/S177A not having efficiently reduced levels of ubiquitinated TRIM25 (Fig.	('activity', 'MPA', (69, 77))	('S177A', 'Mutation', 'p.S177A', (184, 189))	('C224S', 'Mutation', 'p.C224S', (169, 174))	('OTU', 'Phenotype', 'HP:0100615', (48, 51))	('OTU', 'Phenotype', 'HP:0100615', (163, 166))	('OTUD5/S177A', 'Var', (178, 189))	('TRIM25', 'Gene', (24, 30))	('OTUD5/C224S', 'Var', (163, 174))	('deubiquitination', 'MPA', (4, 20))	('OTU', 'Phenotype', 'HP:0100615', (178, 181))
77297	32826889	Additionally, co-overexpression of OTUD5 inhibited TRIM25 ubiquitination, phenocopying the TRIM25 K117R mutant, which was missing an important TRIM25 autoubiquitination site, implying that OTUD5 played a crucial role in TRIM25 autoubiquitination (Supplementary Fig.	('ubiquitination', 'MPA', (58, 72))	('TRIM25', 'Protein', (51, 57))	('expression', 'Species', '29278', (21, 31))	('OTU', 'Phenotype', 'HP:0100615', (35, 38))	('OTU', 'Phenotype', 'HP:0100615', (189, 192))	('K117R', 'Var', (98, 103))	('TRIM25', 'Gene', (91, 97))	('inhibited', 'NegReg', (41, 50))	('K117R', 'Mutation', 'p.K117R', (98, 103))
77299	32826889	The results of the western blotting for the IPed protein showed that the OTUD5 knockdown significantly increased lys63-ubiquitination of TRIM25 (Supplementary Fig.	('increased', 'PosReg', (103, 112))	('lys63-ubiquitination', 'MPA', (113, 133))	('OTUD5', 'Gene', (73, 78))	('OTU', 'Phenotype', 'HP:0100615', (73, 76))	('lys63', 'Chemical', '-', (113, 118))	('knockdown', 'Var', (79, 88))
77311	32826889	Moreover, TRIM25 knockdown could no longer upregulated repression of BAX in PML-depleted cells (Fig.	('upregulated', 'PosReg', (43, 54))	('repression', 'MPA', (55, 65))	('BAX', 'Gene', (69, 72))	('BAX', 'Gene', '581', (69, 72))	('knockdown', 'Var', (17, 26))	('TRIM25', 'Gene', (10, 16))
77314	32826889	Notably, the knockdown of PML inhibited the cell death in TRIM25-depleted cells, in response to TSA treatment (Fig.	('cell death', 'CPA', (44, 54))	('inhibited', 'NegReg', (30, 39))	('PML', 'Gene', (26, 29))	('TSA', 'Chemical', 'MESH:C012589', (96, 99))	('knockdown', 'Var', (13, 22))
77317	32826889	In addition, the high expression of TRIM25 was correlated with poor survival outcomes for HCC patients (Fig.	('HCC', 'Phenotype', 'HP:0001402', (90, 93))	('patients', 'Species', '9606', (94, 102))	('high', 'Var', (17, 21))	('TRIM25', 'Gene', (36, 42))	('expression', 'MPA', (22, 32))	('expression', 'Species', '29278', (22, 32))	('HCC', 'Disease', (90, 93))
77320	32826889	ChIP-qPCR analysis was performed with the Huh7 and Hep3B cells transfected with plasmid expressing HA-tagged IRF-8.	('IRF-8', 'Gene', '3394', (109, 114))	('HA-tagged', 'Var', (99, 108))	('Huh7', 'Gene', (42, 46))	('IRF-8', 'Gene', (109, 114))	('Hep3B', 'CellLine', 'CVCL:0326', (51, 56))	('Huh7', 'Gene', '284424', (42, 46))
77322	32826889	The recruitment of IRF-8 to the promoter of PML was significantly increased by the depletion of TRIM25 (Fig.	('IRF-8', 'Gene', (19, 24))	('increased', 'PosReg', (66, 75))	('TRIM25', 'Gene', (96, 102))	('depletion', 'Var', (83, 92))	('recruitment', 'MPA', (4, 15))	('IRF-8', 'Gene', '3394', (19, 24))
77323	32826889	These data suggested the possibility that TRIM25 repressed PML expression, at least partly, by inhibiting the recruitment of IRF-8 to the promoter of PML.	('inhibiting', 'NegReg', (95, 105))	('recruitment', 'MPA', (110, 121))	('expression', 'Species', '29278', (63, 73))	('TRIM25', 'Var', (42, 48))	('IRF-8', 'Gene', '3394', (125, 130))	('IRF-8', 'Gene', (125, 130))	('PML', 'Gene', (59, 62))
77325	32826889	To test whether the RING domain was required for the enrichment of TRIM25 on the PML promoter, ChIP-qPCR analysis was performed with the Huh7 and Hep3B cells expressing HA-tagged TRIM25/WT or TRIM25/DeltaRING.	('Hep3B', 'CellLine', 'CVCL:0326', (146, 151))	('TRIM25/DeltaRING', 'Var', (192, 208))	('TRIM25/WT', 'Var', (179, 188))	('Huh7', 'Gene', (137, 141))	('Huh7', 'Gene', '284424', (137, 141))
77326	32826889	Consistently, the accumulation of TRIM25 K117R mutant at the PML TSS was reduced (Supplementary Fig.	('accumulation', 'MPA', (18, 30))	('reduced', 'NegReg', (73, 80))	('K117R', 'Mutation', 'p.K117R', (41, 46))	('TRIM25 K117R', 'Var', (34, 46))
77327	32826889	Expression of the TRIM25/WT but not TRIM25/DeltaRING significantly reduced the PML expression levels in the TRIM25-depleted cells (Fig.	('PML expression levels', 'MPA', (79, 100))	('reduced', 'NegReg', (67, 74))	('Expression', 'Species', '29278', (0, 10))	('expression', 'Species', '29278', (83, 93))	('TRIM25/WT', 'Var', (18, 27))
77329	32826889	The results demonstrated that the TRIM25-KR mutant inhibited cell growth, consistently, cells with increased OTUD5 expression formed fewer colonies than the control cells (Supplementary Fig.	('TRIM25-KR mutant', 'Var', (34, 50))	('cell growth', 'CPA', (61, 72))	('expression', 'Species', '29278', (115, 125))	('fewer', 'NegReg', (133, 138))	('increased', 'PosReg', (99, 108))	('colonies', 'CPA', (139, 147))	('OTUD5', 'Gene', (109, 114))	('OTU', 'Phenotype', 'HP:0100615', (109, 112))	('inhibited', 'NegReg', (51, 60))
77330	32826889	The RNA-seq analysis with OTUD5-depleted cells demonstrates that PML expression was downregulated upon OTUD5 knockdown (Supplementary Data 3-2) that OTUD5 binds to TRIM25 and functions as a TRIM25 deubiquitinase, which prompted us to assess whether OTUD5-mediated deubiquitination is involved in the regulation of TRIM25 transcriptional activity.	('downregulated', 'NegReg', (84, 97))	('OTU', 'Phenotype', 'HP:0100615', (26, 29))	('expression', 'Species', '29278', (69, 79))	('OTU', 'Phenotype', 'HP:0100615', (103, 106))	('binds', 'Interaction', (155, 160))	('OTUD5', 'Gene', (149, 154))	('OTU', 'Phenotype', 'HP:0100615', (149, 152))	('knockdown', 'Var', (109, 118))	('OTU', 'Phenotype', 'HP:0100615', (249, 252))	('TRIM25', 'Protein', (164, 170))
77338	32826889	Knocking down OTUD5 significantly inhibited the formation of PML-NBs, a finding that was consistent with the involvement of OTUD5 in the regulation of PML expression (Fig.	('Knocking down', 'Var', (0, 13))	('expression', 'Species', '29278', (155, 165))	('inhibited', 'NegReg', (34, 43))	('formation', 'MPA', (48, 57))	('OTU', 'Phenotype', 'HP:0100615', (14, 17))	('OTU', 'Phenotype', 'HP:0100615', (124, 127))	('PML-NBs', 'MPA', (61, 68))	('OTUD5', 'Gene', (14, 19))
77341	32826889	In addition, the ubiquitination level of MAVS was reduced following OTUD5 coexpression, and OTUD5 increased the protein level of SFN, demonstrating that OTUD5 was possibly involved in these signaling pathways to work with the TRIM25 E3 ubiquitin ligase in the protein complex (Supplementary Fig.	('SFN', 'Gene', (129, 132))	('OTU', 'Phenotype', 'HP:0100615', (68, 71))	('ubiquitination level', 'MPA', (17, 37))	('coexpression', 'Var', (74, 86))	('E3 ubiquitin ligase', 'Gene', '79594', (233, 252))	('OTUD5', 'Var', (92, 97))	('expression', 'Species', '29278', (76, 86))	('OTU', 'Phenotype', 'HP:0100615', (92, 95))	('increased', 'PosReg', (98, 107))	('OTUD5', 'Gene', (68, 73))	('reduced', 'NegReg', (50, 57))	('SFN', 'Gene', '25996', (129, 132))	('OTU', 'Phenotype', 'HP:0100615', (153, 156))	('protein level', 'MPA', (112, 125))	('E3 ubiquitin ligase', 'Gene', (233, 252))	('MAVS', 'Gene', (41, 45))	('MAVS', 'Gene', '57506', (41, 45))
77345	32826889	Each mouse received 106 cells of the control-infected or gene-KD Hep3B cells (OTUD5 KD, TRIM25 KD, PML KD, OTUD5/TRIM25 KD, or TRIM25/PML KD) by subcutaneous injection in both flanks.	('infected', 'Disease', 'MESH:D007239', (45, 53))	('TRIM25/PML KD', 'Var', (127, 140))	('Hep3B', 'CellLine', 'CVCL:0326', (65, 70))	('OTU', 'Phenotype', 'HP:0100615', (107, 110))	('infected', 'Disease', (45, 53))	('mouse', 'Species', '10090', (5, 10))	('TRIM25 KD', 'Var', (88, 97))	('PML KD', 'Var', (99, 105))	('OTU', 'Phenotype', 'HP:0100615', (78, 81))
77347	32826889	7a, b, the tumor spheres derived from the OTUD5-depleted cells and PML-depleted cells grew faster and had greater weight than those excised from the control cells, while TRIM25 knockdown inhibited tumor sphere formation.	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('greater', 'PosReg', (106, 113))	('grew', 'CPA', (86, 90))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('TRIM25', 'Gene', (170, 176))	('tumor', 'Disease', (11, 16))	('OTU', 'Phenotype', 'HP:0100615', (42, 45))	('knockdown', 'Var', (177, 186))	('weight', 'CPA', (114, 120))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('tumor', 'Disease', 'MESH:D009369', (11, 16))	('faster', 'PosReg', (91, 97))	('tumor', 'Disease', (197, 202))	('inhibited', 'NegReg', (187, 196))
77350	32826889	The mRNA levels of PML and BAX were downregulated upon OTUD5 knockdown (Fig.	('OTUD5', 'Gene', (55, 60))	('BAX', 'Gene', '581', (27, 30))	('OTU', 'Phenotype', 'HP:0100615', (55, 58))	('BAX', 'Gene', (27, 30))	('knockdown', 'Var', (61, 70))	('mRNA levels of PML', 'MPA', (4, 22))	('downregulated', 'NegReg', (36, 49))
77366	32826889	Two different lung tumor cell lines, H1299 and A549, were used to investigate whether siRNA-mediated depletion of OTUD5 also promoted cell proliferation.	('cell proliferation', 'CPA', (134, 152))	('lung tumor', 'Disease', 'MESH:D008175', (14, 24))	('OTUD5', 'Gene', (114, 119))	('OTU', 'Phenotype', 'HP:0100615', (114, 117))	('lung tumor', 'Phenotype', 'HP:0100526', (14, 24))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('H1299', 'CellLine', 'CVCL:0060', (37, 42))	('lung tumor', 'Disease', (14, 24))	('depletion', 'Var', (101, 110))	('promoted', 'PosReg', (125, 133))	('A549', 'CellLine', 'CVCL:0023', (47, 51))
77367	32826889	The results demonstrate that OTUD5 knockdown had a proliferation-promoting effect in both the H1299 cells and A549 cells (Fig.	('knockdown', 'Var', (35, 44))	('H1299', 'CellLine', 'CVCL:0060', (94, 99))	('A549', 'CellLine', 'CVCL:0023', (110, 114))	('OTUD5', 'Gene', (29, 34))	('OTU', 'Phenotype', 'HP:0100615', (29, 32))	('proliferation-promoting', 'CPA', (51, 74))
77380	32826889	In this study, we discovered OTUD5 function in regulating cell proliferation and suppressing tumor, as demonstrated by the increased cell proliferation after RNAi-mediated OTUD5 knockdown and by the increased tumor growth after OTUD5 knockdown in a xenograft mouse model.	('increased', 'PosReg', (123, 132))	('OTUD5', 'Gene', (172, 177))	('tumor', 'Disease', (209, 214))	('suppressing', 'NegReg', (81, 92))	('cell proliferation', 'CPA', (133, 151))	('OTU', 'Phenotype', 'HP:0100615', (172, 175))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('cell proliferation', 'CPA', (58, 76))	('tumor', 'Disease', (93, 98))	('OTUD5', 'Gene', (29, 34))	('mouse', 'Species', '10090', (259, 264))	('OTU', 'Phenotype', 'HP:0100615', (228, 231))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))	('knockdown', 'Var', (178, 187))	('tumor', 'Disease', 'MESH:D009369', (209, 214))	('OTU', 'Phenotype', 'HP:0100615', (29, 32))	('increased', 'PosReg', (199, 208))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
77381	32826889	Specifically, these unique functions of OTUD5 were mediated by TRIM25 and by the regulated PML expression through the interplay between the E3 ubiquitin ligase TRIM25 and its deubiquitinase OTUD5.	('E3 ubiquitin ligase', 'Gene', '79594', (140, 159))	('PML', 'Gene', (91, 94))	('TRIM25', 'Gene', (160, 166))	('E3 ubiquitin ligase', 'Gene', (140, 159))	('TRIM25', 'Var', (63, 69))	('OTUD5', 'Gene', (40, 45))	('mediated', 'Reg', (51, 59))	('expression', 'Species', '29278', (95, 105))	('OTU', 'Phenotype', 'HP:0100615', (190, 193))	('OTU', 'Phenotype', 'HP:0100615', (40, 43))	('interplay', 'Interaction', (118, 127))
77383	32826889	RING domain deleted and K117R mutants of TRIM25 had substantially inhibited functions, implying that OTUD5 functions by regulating the ubiquitination of TRIM25.	('K117R', 'Mutation', 'p.K117R', (24, 29))	('regulating', 'Reg', (120, 130))	('TRIM25', 'Gene', (153, 159))	('functions', 'MPA', (76, 85))	('OTU', 'Phenotype', 'HP:0100615', (101, 104))	('inhibited', 'NegReg', (66, 75))	('ubiquitination', 'MPA', (135, 149))	('TRIM25', 'Gene', (41, 47))	('K117R', 'Var', (24, 29))
77387	32826889	Consistent with these possibilities, OTUD5 cleaves the polyubiquitin chain from TRAF3, an essential type I interferon adapter protein, leading to the disassociation of the adapter protein from a downstream signaling complex and disruption of the type I interferon signaling cascade.	('cleaves', 'Var', (43, 50))	('TRAF3', 'Gene', (80, 85))	('TRAF3', 'Gene', '7187', (80, 85))	('disruption', 'Reg', (228, 238))	('type I interferon signaling cascade', 'Pathway', (246, 281))	('disassociation', 'MPA', (150, 164))	('OTU', 'Phenotype', 'HP:0100615', (37, 40))
77389	32826889	OTUD5 also modulates immune responses by deubiquitinating and stabilizing UBR5 to suppress the production of IL-17 and by selectively cleaving the polyubiquitin chains on TRAF3 to regulate IFN-I production.	('UBR5', 'Gene', '51366', (74, 78))	('cleaving', 'Reg', (134, 142))	('immune responses', 'CPA', (21, 37))	('OTU', 'Phenotype', 'HP:0100615', (0, 3))	('IFN-I production', 'MPA', (189, 205))	('TRAF3', 'Gene', '7187', (171, 176))	('modulates', 'Reg', (11, 20))	('IL-17', 'Gene', '3605', (109, 114))	('TRAF3', 'Gene', (171, 176))	('polyubiquitin', 'Protein', (147, 160))	('UBR5', 'Gene', (74, 78))	('suppress', 'NegReg', (82, 90))	('IL-17', 'Gene', (109, 114))	('regulate', 'Reg', (180, 188))	('deubiquitinating', 'Var', (41, 57))
77391	32826889	Interestingly, OTUD5 activity is dependent on its site-specific phosphorylation at a single residue, Ser177, which is both necessary and sufficient to activate the enzyme.	('Ser177', 'Var', (101, 107))	('phosphorylation', 'MPA', (64, 79))	('OTUD5', 'Gene', (15, 20))	('OTU', 'Phenotype', 'HP:0100615', (15, 18))	('Ser177', 'Chemical', '-', (101, 107))	('activity', 'MPA', (21, 29))
77392	32826889	Therefore, modulating OTUD5 phosphorylation may be a promising strategy for tumor treatment.	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('OTUD5', 'Gene', (22, 27))	('phosphorylation', 'MPA', (28, 43))	('OTU', 'Phenotype', 'HP:0100615', (22, 25))	('modulating', 'Var', (11, 21))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
77396	32826889	Defective TRIM25 activity results in broad coordinated changes affecting the expression of many metastatic effectors simultaneously.	('expression of', 'MPA', (77, 90))	('Defective', 'Var', (0, 9))	('activity', 'MPA', (17, 25))	('changes affecting', 'Reg', (55, 72))	('expression', 'Species', '29278', (77, 87))	('TRIM25', 'Gene', (10, 16))
77400	32826889	The full-length complementary DNA (cDNA) and deletion/point mutation mutants of human OTUD5 were generated by PCR and subcloned into a pCIN4-Flag or pCIN4-HA vector.	('deletion/point mutation', 'Var', (45, 68))	('OTUD5', 'Gene', (86, 91))	('OTU', 'Phenotype', 'HP:0100615', (86, 89))	('human', 'Species', '9606', (80, 85))
77407	32826889	The following primary antibodies were used at a dilution of 1:1000: anti-OTUD5 (D8Y2U, Cell Signaling Technology), anti-TRIM25 (Abcam, ab167154), anti-PML (Abcam, ab53773), anti-HA (H9658, Sigma), anti-Flag (F3165, Sigma) and anti-ubiquitin (SC-8017, Santa Cruz).	('F3165', 'Var', (208, 213))	('H9658', 'CellLine', 'CVCL:Y658', (182, 187))	('anti-PML', 'Var', (146, 154))	('OTU', 'Phenotype', 'HP:0100615', (73, 76))	('anti-TRIM25', 'Var', (115, 126))
77426	32826889	The K63-UIM and K48-UIM constructs were purified on Ni2+-NTA-agarose (Qiagen).	('K48-UIM', 'Var', (16, 23))	('Ni2+-NTA-agarose', 'Chemical', '-', (52, 68))	('K63-UIM', 'Var', (4, 11))
77446	32826889	To determine OTUD5 expression in primary liver cancer, we purchased human liver tissue microarray (#BC03119a, ALENA biotechnology, Xi'an, China and #HLivH180Su18, Shanghai Outdo Biotech Company, Shanghai, China).	('primary liver cancer', 'Disease', (33, 53))	('human', 'Species', '9606', (68, 73))	('liver cancer', 'Phenotype', 'HP:0002896', (41, 53))	('#BC03119a', 'Var', (99, 108))	('primary liver cancer', 'Disease', 'MESH:D006528', (33, 53))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('OTU', 'Phenotype', 'HP:0100615', (13, 16))	('expression', 'Species', '29278', (19, 29))
77502	32434808	Interactions linking HPV to cancer included E6-p53 and E7-Rb as well as previously unknown connections involving E7-YAP1, E2 and proteins of the WNT/beta Catenin signaling pathway, E5-p16 and E1-KEAP1 interactions.	('beta Catenin', 'Gene', (149, 161))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('KEAP1', 'Gene', (195, 200))	('HPV', 'Species', '333760', (21, 24))	('E7-Rb', 'Var', (55, 60))	('p16', 'Gene', '1029', (184, 187))	('YAP1', 'Gene', '10413', (116, 120))	('beta Catenin', 'Gene', '1499', (149, 161))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('p53', 'Gene', (47, 50))	('cancer', 'Disease', (28, 34))	('p53', 'Gene', '7157', (47, 50))	('KEAP1', 'Gene', '9817', (195, 200))	('YAP1', 'Gene', (116, 120))	('p16', 'Gene', (184, 187))
77528	32434808	Both carcinogens were powerful mutagens and induced mutation profiles in the lacI reporter gene similar to those observed in P53 gene in human HNSCC; specifically 50% of the mutations-induced by both carcinogens are G:C T:A and G:C A:T substitution and about 30% of the mutations AT base pairs and these percentages are similar to those found in the P53 gene in human HNSCC.	('C', 'Chemical', 'MESH:D002244', (371, 372))	('human', 'Species', '9606', (137, 142))	('C', 'Chemical', 'MESH:D002244', (372, 373))	('mutations-induced', 'Var', (174, 191))	('C', 'Chemical', 'MESH:D002244', (146, 147))	('G:C A:T substitution', 'Var', (228, 248))	('human', 'Species', '9606', (362, 367))	('C', 'Chemical', 'MESH:D002244', (218, 219))	('G:C T:A', 'Var', (216, 223))	('C', 'Chemical', 'MESH:D002244', (230, 231))	('C', 'Chemical', 'MESH:D002244', (147, 148))
77530	32434808	We also showed that DB[a,l]P and DB[a,l]PDE upregulated the expression of p53 and COX-2 proteins.	('expression', 'MPA', (60, 70))	('DB[a', 'Var', (33, 37))	('COX-2 proteins', 'Protein', (82, 96))	('upregulated', 'PosReg', (44, 55))	('p53', 'Gene', (74, 77))	('DB[a', 'Var', (20, 24))	('DB[a,l]P', 'Chemical', 'MESH:C041517', (33, 41))	('p53', 'Gene', '7157', (74, 77))	('DB[a,l]P', 'Chemical', 'MESH:C041517', (20, 28))
77532	32434808	In addition, we showed that hypomethylation of Fgf3 is a potential biomarker for early detection of OSCC in mice treated with DB[a,l]P. Fgf3 is among a large fibroblast growth factor superfamily genes, which are involved in numerous biological activities, including cell survival and regulation of epithelial-mesenchymal transition (EMT) pathway.	('Fgf3', 'Gene', '14174', (136, 140))	('Fgf3', 'Gene', '14174', (47, 51))	('Fgf3', 'Gene', (47, 51))	('hypomethylation', 'Var', (28, 43))	('mice', 'Species', '10090', (108, 112))	('epithelial-mesenchymal', 'Pathway', (298, 320))	('Fgf3', 'Gene', (136, 140))	('DB[a', 'Var', (126, 130))	('OSCC', 'Disease', (100, 104))	('DB[a,l]P', 'Chemical', 'MESH:C041517', (126, 134))
77539	32434808	We have generated and mechanistically characterized a genetic mouse model in which conditional loss of the tumor suppressor p120ctn in the squamous oral cavity resulted in OSCC that precisely phenocopies the histologic features of human OSCC.	('resulted in', 'Reg', (160, 171))	('loss of the tumor', 'Disease', 'MESH:D009369', (95, 112))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('mouse', 'Species', '10090', (62, 67))	('loss of the tumor', 'Disease', (95, 112))	('p120ctn', 'Var', (124, 131))	('human', 'Species', '9606', (231, 236))	('OSCC', 'Disease', (172, 176))
77542	32434808	This immune response is likely induced by NF-kappaB activation in p120ctn-null cells with commensurate cytokine secretion.	('men', 'Species', '9606', (93, 96))	('p120ctn-null', 'Var', (66, 78))	('NF-kappaB', 'Gene', '4790', (42, 51))	('NF-kappaB', 'Gene', (42, 51))	('activation', 'PosReg', (52, 62))
77547	32434808	To represent the complex environment that mimics human exposure it would be important to explore how p120ctn inactivation cooperates with other genetic and environmental factors (tobacco carcinogens) and HPV infection to induce oral cancers.	('HPV infection', 'Disease', (204, 217))	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('oral cancers', 'Disease', 'MESH:D009369', (228, 240))	('p120ctn inactivation', 'Var', (101, 121))	('human', 'Species', '9606', (49, 54))	('tobacco', 'Species', '4097', (179, 186))	('HPV infection', 'Disease', 'MESH:D030361', (204, 217))	('cancers', 'Phenotype', 'HP:0002664', (233, 240))	('oral cancers', 'Disease', (228, 240))	('induce', 'PosReg', (221, 227))
77548	32434808	An estimated 30%-40% of HNSCC have mutations in the PI3K pathway and we observed that p120ctn down regulation worked cooperatively with PIK3CA mutations to drive invasion in oral keratinocytes in vitro through increased MMP1 expression.	('PI3K pathway', 'Pathway', (52, 64))	('PIK3CA', 'Gene', (136, 142))	('drive', 'PosReg', (156, 161))	('p120ctn', 'Var', (86, 93))	('increased', 'PosReg', (210, 219))	('MMP1', 'Gene', '4312', (220, 224))	('down regulation', 'NegReg', (94, 109))	('PIK3CA', 'Gene', '5290', (136, 142))	('HNSCC', 'Gene', (24, 29))	('MMP1', 'Gene', (220, 224))	('expression', 'MPA', (225, 235))	('invasion', 'CPA', (162, 170))	('mutations', 'Var', (143, 152))	('mutations', 'Var', (35, 44))
77549	32434808	Analysis of human HNSCC confirmed that p120ctn loss and P13K pathway activation were associated with increased MMP1 expression.	('expression', 'MPA', (116, 126))	('MMP1', 'Gene', (111, 115))	('increased', 'PosReg', (101, 110))	('P13K pathway', 'Pathway', (56, 68))	('MMP1', 'Gene', '4312', (111, 115))	('human', 'Species', '9606', (12, 17))	('P13K', 'Mutation', 'p.P13K', (56, 60))	('p120ctn loss', 'Var', (39, 51))	('activation', 'PosReg', (69, 79))
77550	32434808	Thus, building on these established in vitro and in vivo models in combination with the MmuPV1 mouse model, investigations of how HPV infection may be enhanced by p120ctn loss can be conducted.	('HPV infection', 'Disease', (130, 143))	('enhanced', 'PosReg', (151, 159))	('p120ctn loss', 'Var', (163, 175))	('HPV infection', 'Disease', 'MESH:D030361', (130, 143))	('mouse', 'Species', '10090', (95, 100))
77551	32434808	In addition to establishing p120ctn's relevance in HNSCC, p120ctn has been implicated in cellular responses to tobacco carcinogens.	('p120ctn', 'Var', (28, 35))	('tobacco', 'Species', '4097', (111, 118))	('implicated', 'Reg', (75, 85))	('p120ctn', 'Var', (58, 65))
77554	32434808	It is possible that p120ctn loss may be an important event in the pathogenesis of HNSCC resulting from tobacco carcinogens.	('p120ctn', 'Var', (20, 27))	('tobacco', 'Species', '4097', (103, 110))	('HNSCC', 'Disease', (82, 87))	('loss', 'NegReg', (28, 32))
77555	32434808	It is also possible that p120ctn may be acting on pathways that are independent from tobacco carcinogens in the development of HNSCC.	('tobacco', 'Species', '4097', (85, 92))	('p120ctn', 'Var', (25, 32))	('acting', 'Reg', (40, 46))	('men', 'Species', '9606', (119, 122))	('HNSCC', 'Disease', (127, 132))
77556	32434808	Identifying which of these two relationships exist between p120ctn loss and tobacco carcinogens would be of great importance in understanding the pathobiology of HNSCC.	('tobacco', 'Species', '4097', (76, 83))	('p120ctn loss', 'Var', (59, 71))	('HNSCC', 'Disease', (162, 167))
77557	32434808	Thus, studies examining the mechanisms by which p120ctn potentiates disease development induced by tobacco carcinogens are urgently needed.	('tobacco', 'Species', '4097', (99, 106))	('potentiates', 'PosReg', (56, 67))	('p120ctn', 'Var', (48, 55))	('men', 'Species', '9606', (83, 86))	('disease development', 'CPA', (68, 87))
77558	32434808	A variety of epigenetic alterations have been described in the progression of tobacco/alcohol related OSCC.	('tobacco', 'Species', '4097', (78, 85))	('described', 'Reg', (46, 55))	('epigenetic alterations', 'Var', (13, 35))	('alcohol', 'Chemical', 'MESH:D000438', (86, 93))	('tobacco/alcohol related OSCC', 'Disease', (78, 106))
77570	32434808	Using our mouse models (DB[a,l]P, MmuPV1, p120ctn), it would be of great interest to elucidate the role of oxidants contained in whole tobacco smoke and e-cigarette aerosols in OSCC and OPSCC development.	('men', 'Species', '9606', (199, 202))	('mouse', 'Species', '10090', (10, 15))	('tobacco', 'Species', '4097', (135, 142))	('DB[a,l]P', 'Chemical', 'MESH:C041517', (24, 32))	('p120ctn', 'Var', (42, 49))	('OSCC', 'Disease', (177, 181))	('OPSCC', 'Disease', (186, 191))
77573	32434808	Alterations in the structure, diversity and function of the oral microbiome that occur in association with established risk factors (tobacco smoking, betel nut chewing, alcohol) may contribute to oral cancer development.	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('cancer', 'Disease', (201, 207))	('tobacco', 'Species', '4097', (133, 140))	('Alterations', 'Var', (0, 11))	('betel', 'Chemical', '-', (150, 155))	('contribute', 'Reg', (182, 192))	('men', 'Species', '9606', (215, 218))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('diversity', 'CPA', (30, 39))	('function', 'MPA', (44, 52))	('alcohol', 'Chemical', 'MESH:D000438', (169, 176))
77623	32434808	Among different catechins, epigallocatechins-3-gallate is the most prevalent and believed to be the major constituent that can account for cancer prevention by tea.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('epigallocatechins-3-gallate', 'Chemical', 'MESH:C045651', (27, 54))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('catechins', 'Chemical', 'MESH:D002392', (35, 44))	('cancer', 'Disease', (139, 145))	('epigallocatechins-3-gallate', 'Var', (27, 54))	('catechins', 'Chemical', 'MESH:D002392', (16, 25))
77626	32434808	Collection of oral mucosal cells is relatively simple and such cells are an excellent source of material for evaluating DNA adducts derived from structurally varied carcinogens identified in tobacco smoke and molecular alterations potentially related to cancer.	('cancer', 'Phenotype', 'HP:0002664', (254, 260))	('cancer', 'Disease', 'MESH:D009369', (254, 260))	('cancer', 'Disease', (254, 260))	('molecular alterations', 'Var', (209, 230))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('tobacco', 'Species', '4097', (191, 198))
77687	31732666	HERES, a lncRNA that regulates canonical and noncanonical Wnt signaling pathways via interaction with EZH2 Aberrant lncRNA expression is responsible for cancer progression and metastasis, positioning lncRNAs not only as biomarkers but also as promising therapeutic targets for curing cancer.	('metastasis', 'CPA', (176, 186))	('EZH2', 'Gene', (102, 106))	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('cancer', 'Disease', (153, 159))	('cancer', 'Disease', 'MESH:D009369', (284, 290))	('responsible', 'Reg', (137, 148))	('cancer', 'Disease', (284, 290))	('Aberrant', 'Var', (107, 115))	('regulates', 'Reg', (21, 30))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('cancer', 'Phenotype', 'HP:0002664', (284, 290))	('interaction', 'Interaction', (85, 96))
77689	31732666	The most upregulated lncRNA, HERES, promotes cancer progression and epigenetically regulates canonical and noncanonical Wnt signaling pathways simultaneously through interaction with EZH2.	('upregulated', 'PosReg', (9, 20))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('epigenetically', 'Var', (68, 82))	('EZH2', 'Gene', (183, 187))	('lncRNA', 'Protein', (21, 27))	('interaction', 'Interaction', (166, 177))	('regulates', 'Reg', (83, 92))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('cancer', 'Disease', (45, 51))	('promotes', 'PosReg', (36, 44))
77691	31732666	Dysregulation of these pathways often causes cancer development and progression.	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('Dysregulation', 'Var', (0, 13))	('causes', 'Reg', (38, 44))	('progression', 'CPA', (68, 79))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('cancer', 'Disease', (45, 51))
77692	31732666	Here, we describe a long noncoding RNA (lncRNA), HERES, that epigenetically regulates both canonical and noncanonical Wnt signaling pathways in esophageal squamous cell carcinoma (ESCC).	('epigenetically', 'Var', (61, 75))	('noncanonical Wnt signaling pathways', 'Pathway', (105, 140))	('esophageal squamous cell carcinoma', 'Disease', (144, 178))	('carcinoma', 'Phenotype', 'HP:0030731', (169, 178))	('regulates', 'Reg', (76, 85))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (144, 178))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (155, 178))
77703	31732666	In particular, abnormal intracellular levels of the second messenger Ca2+ promote the Wnt signaling pathway, which in turn promotes the development and progression of many types of cancers.	('development', 'CPA', (136, 147))	('promotes', 'PosReg', (123, 131))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('promote', 'PosReg', (74, 81))	('Ca2+', 'Chemical', 'MESH:D000069285', (69, 73))	('abnormal', 'Var', (15, 23))	('cancers', 'Disease', 'MESH:D009369', (181, 188))	('cancers', 'Phenotype', 'HP:0002664', (181, 188))	('Wnt signaling pathway', 'Pathway', (86, 107))	('cancers', 'Disease', (181, 188))	('progression', 'CPA', (152, 163))
77704	31732666	Controlling Wnt signaling may be a useful strategy for curing cancers caused by aberrations in such signaling.	('aberrations', 'Var', (80, 91))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('cancers', 'Phenotype', 'HP:0002664', (62, 69))	('cancers', 'Disease', 'MESH:D009369', (62, 69))	('cancers', 'Disease', (62, 69))
77705	31732666	The inhibition of either aberrant canonical or noncanonical Wnt signaling, however, has been shown to decrease progression in only a subset of cancers in a context-dependent manner.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('noncanonical', 'Protein', (47, 59))	('aberrant', 'Var', (25, 33))	('decrease', 'NegReg', (102, 110))	('cancers', 'Disease', 'MESH:D009369', (143, 150))	('cancers', 'Phenotype', 'HP:0002664', (143, 150))	('cancers', 'Disease', (143, 150))	('progression', 'CPA', (111, 122))	('inhibition', 'NegReg', (4, 14))
77706	31732666	Because aberrations in Wnt signaling pathways result from various causes, such as mutations in different Wnt signaling-related genes, ligand overexpression, and dysregulation of regulators, targeting only the canonical Wnt signaling pathway might not be a universal therapeutic approach for cancers.	('cancers', 'Phenotype', 'HP:0002664', (291, 298))	('cancers', 'Disease', (291, 298))	('cancers', 'Disease', 'MESH:D009369', (291, 298))	('mutations', 'Var', (82, 91))	('Wnt signaling-related genes', 'Gene', (105, 132))	('cancer', 'Phenotype', 'HP:0002664', (291, 297))	('Wnt signaling pathways', 'Pathway', (23, 45))
77707	31732666	Thus, the simultaneous inhibition of aberrant canonical and noncanonical Wnt signaling pathways could also benefit cancer therapy.	('cancer', 'Disease', (115, 121))	('inhibition', 'NegReg', (23, 33))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('benefit', 'PosReg', (107, 114))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('aberrant', 'Var', (37, 45))
77711	31732666	Moreover, mounting evidence indicates that aberrant lncRNA expression, by modulating cancer-related pathways, can be responsible for cancer progression.	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('lncRNA expression', 'Protein', (52, 69))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('cancer', 'Disease', (85, 91))	('cancer', 'Disease', (133, 139))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('responsible', 'Reg', (117, 128))	('modulating', 'Reg', (74, 84))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('aberrant', 'Var', (43, 51))
77714	31732666	Recently, a Chinese group performed high-throughput RNA sequencing (RNA-seq) on tissue from 15 paired ESCC patients and normal individuals and identified lncRNAs dysregulated in ESCCs.	('dysregulated', 'Var', (162, 174))	('ESCC', 'Disease', (102, 106))	('ESCCs', 'Disease', (178, 183))	('lncRNAs', 'Gene', (154, 161))	('patients', 'Species', '9606', (107, 115))
77721	31732666	Six DE lncRNAs were significantly associated with survival rates, 2 (HERES and RP11-1L12.3) of which were associated with a high hazard ratio (HHR; P  0.05) and 4 (RP11-114H23.1, RP11-114H23.2, CTD-2319I12.1, and LINC00330) of which were associated with a low hazard ratio (LHR; P  0.05).	('RP11', 'Gene', '26121', (164, 168))	('associated', 'Reg', (34, 44))	('RP11', 'Gene', '26121', (179, 183))	('CTD-2319I12.1', 'CellLine', 'CVCL:9J62', (194, 207))	('RP11', 'Gene', '26121', (79, 83))	('LINC00330', 'Gene', '144817', (213, 222))	('survival rates', 'MPA', (50, 64))	('LINC00330', 'Gene', (213, 222))	('RP11', 'Gene', (179, 183))	('CTD-2319I12.1', 'Var', (194, 207))	('RP11', 'Gene', (164, 168))	('RP11', 'Gene', (79, 83))
77730	31732666	To investigate whether HERES is involved in cancer development and progression, the effects of HERES knockdown on cell proliferation, migration, invasion, and colony formation were explored with siControl- and siHERES-treated cells.	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('HERES', 'Gene', (95, 100))	('siControl', 'Chemical', '-', (195, 204))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('knockdown', 'Var', (101, 110))
77731	31732666	Introduction of an siRNA targeting HERES (siHERES_1 or siHERES_2) to KYSE-30 and HCE-7 cells significantly reduced HERES expression (SI Appendix, Fig.	('siHERES_2', 'Var', (55, 64))	('reduced', 'NegReg', (107, 114))	('HERES expression', 'MPA', (115, 131))	('HCE-7', 'CellLine', 'CVCL:5138', (81, 86))
77732	31732666	values) were significantly reduced in both siHERES_1 and siHERES_2-treated cells compared to siControl-treated cells (Fig.	('reduced', 'NegReg', (27, 34))	('siHERES_2-treated', 'Var', (57, 74))	('siControl', 'Chemical', '-', (93, 102))	('siHERES_1', 'Var', (43, 52))
77733	31732666	Migration and invasion assays showed that both cell migration and invasion were greatly reduced in siHERES-treated cells compared to siControl-treated cells (Fig.	('reduced', 'NegReg', (88, 95))	('siHERES-treated', 'Var', (99, 114))	('cell migration', 'CPA', (47, 61))	('invasion', 'CPA', (66, 74))	('siControl', 'Chemical', '-', (133, 142))	('invasion assays', 'CPA', (14, 29))
77741	31732666	SFRP2 encodes a member of the SFRP family that modulates the Wnt signaling pathway; SFRP2 hypermethylation is known to enhance cell invasiveness in both cancers and noncancerous diseases.	('enhance', 'PosReg', (119, 126))	('cancers', 'Disease', 'MESH:D009369', (153, 160))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('Wnt signaling pathway', 'Pathway', (61, 82))	('cancers', 'Disease', (153, 160))	('hypermethylation', 'Var', (90, 106))	('noncancerous diseases', 'Disease', 'MESH:D003141', (165, 186))	('noncancerous diseases', 'Disease', (165, 186))	('cell invasiveness', 'CPA', (127, 144))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('cancers', 'Phenotype', 'HP:0002664', (153, 160))	('SFRP2', 'Gene', (84, 89))	('modulates', 'Reg', (47, 56))
77743	31732666	S7E) were down-regulated and hypermethylated in the HERES-high group, whereas EPSTI1, SLC15A3, and BST2 were up-regulated and hypomethylated in the HERES-high subgroup.	('HERES-high', 'Disease', (52, 62))	('hypermethylated', 'Var', (29, 44))	('EPSTI1', 'Gene', (78, 84))	('BST2', 'Gene', '684', (99, 103))	('down-regulated', 'NegReg', (10, 24))	('up-regulated', 'PosReg', (109, 121))	('hypomethylated', 'Var', (126, 140))	('BST2', 'Gene', (99, 103))	('SLC15A3', 'Gene', (86, 93))	('SLC15A3', 'Gene', '51296', (86, 93))	('EPSTI1', 'Gene', '94240', (78, 84))
77749	31732666	Taken together, these results suggest that HERES down-regulation in cancers perturbs and promotes canonical and noncanonical Wnt signaling pathways via epigenetic regulation, resulting in the inhibition of cancer progression.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('cancers perturbs', 'Disease', (68, 84))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('cancers perturbs', 'Disease', 'MESH:D009369', (68, 84))	('promotes', 'PosReg', (89, 97))	('cancers', 'Phenotype', 'HP:0002664', (68, 75))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('cancer', 'Disease', (68, 74))	('inhibition', 'NegReg', (192, 202))	('cancer', 'Disease', (206, 212))	('cancer', 'Disease', 'MESH:D009369', (206, 212))	('down-regulation', 'NegReg', (49, 64))	('epigenetic regulation', 'Var', (152, 173))
77763	31732666	A series of deletion mutants of human PRC2 revealed that the basic N-terminal helix of EZH2, particularly residues 32-42 in the helix, are the most critical for RNA binding through a G-rich motif.	('deletion', 'Var', (12, 20))	('PRC2', 'Gene', (38, 42))	('binding', 'Interaction', (165, 172))	('EZH2', 'Gene', (87, 91))	('human', 'Species', '9606', (32, 37))	('G-rich motif', 'Protein', (183, 195))	('RNA', 'MPA', (161, 164))
77779	30353687	Aberrant CpG-methylation affects genes expression predicting survival in lung adenocarcinoma Lung adenocarcinoma (LUAD) is a common diagnosed disease with high-mortality rate, and its prognostic implications are under discovered.	('Lung adenocarcinoma', 'Disease', (93, 112))	('Lung adenocarcinoma', 'Disease', 'MESH:D000077192', (93, 112))	('lung adenocarcinoma', 'Disease', (73, 92))	('Aberrant', 'Var', (0, 8))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (73, 92))	('genes expression', 'MPA', (33, 49))	('LUAD', 'Phenotype', 'HP:0030078', (114, 118))	('affects', 'Reg', (25, 32))	('CpG-methylation', 'Gene', (9, 24))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (73, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))
77780	30353687	DNA methylation aberrations are not only an important event for dysregulation of gene expression during tumorigenesis but also a revolution in epigenetics by identifying key prognostic biomarkers for multiple cancers.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('multiple cancers', 'Disease', (200, 216))	('tumor', 'Disease', (104, 109))	('cancers', 'Phenotype', 'HP:0002664', (209, 216))	('multiple cancers', 'Disease', 'MESH:D009369', (200, 216))	('aberrations', 'Var', (16, 27))	('methylation aberrations', 'Var', (4, 27))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
77782	30353687	Together, methylation aberrances regulate gene expression level during tumorigenesis and influence prognosis of LUAD patients.	('regulate', 'Reg', (33, 41))	('methylation aberrances', 'Var', (10, 32))	('influence', 'Reg', (89, 98))	('gene expression level', 'MPA', (42, 63))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('LUAD', 'Phenotype', 'HP:0030078', (112, 116))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('patients', 'Species', '9606', (117, 125))	('tumor', 'Disease', (71, 76))	('LUAD', 'Disease', (112, 116))
77787	30353687	DNA methylation, an important form of epigenetic modification, has significant functions on gene expression, genomic stability, and modification.6 Hypermethylation or hypomethylation of DNA was observed in variety of tumors but not in various normal tissues,7 which indicated that methylation aberration might be treated as a hallmark of a wide variety of cancers.	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('hypomethylation', 'Var', (167, 182))	('observed', 'Reg', (194, 202))	('tumors', 'Disease', (217, 223))	('tumors', 'Disease', 'MESH:D009369', (217, 223))	('tumors', 'Phenotype', 'HP:0002664', (217, 223))	('Hypermethylation', 'Var', (147, 163))	('cancers', 'Disease', 'MESH:D009369', (356, 363))	('cancers', 'Phenotype', 'HP:0002664', (356, 363))	('cancers', 'Disease', (356, 363))	('DNA', 'Gene', (186, 189))	('cancer', 'Phenotype', 'HP:0002664', (356, 362))
77790	30353687	An integrative analysis of DNA methylation and mRNA expression performed by Kim et al9 pointed out the key function of epigenetic alteration on human malignant mesothelioma cell heterogeneity.	('mesothelioma', 'Disease', 'MESH:D008654', (160, 172))	('human', 'Species', '9606', (144, 149))	('epigenetic alteration', 'Var', (119, 140))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (150, 172))	('mesothelioma', 'Disease', (160, 172))
77807	30353687	The heatmaps of all 32 genes in paired tumor and normal tissues indicated that the negative association between aberrant situation of DNA methylation and mRNA expression level (Figure 4B and C).	('mRNA expression level', 'MPA', (154, 175))	('aberrant situation', 'Var', (112, 130))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('negative', 'NegReg', (83, 91))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumor', 'Disease', (39, 44))
77813	30353687	A number of studies have shown that DNA methylation is the second "motivation" of carcinogenesis after gene mutation and has become an important marker for early tumor diagnosis.16, 17  Compared to gene mutations, abnormalities of DNA methylation are more common in tumor genomes and reversible according to various factors such as genetic background, age, environment, diet, and behavior.	('men', 'Species', '9606', (364, 367))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('carcinogenesis', 'Disease', 'MESH:D063646', (82, 96))	('tumor', 'Disease', (162, 167))	('tumor', 'Disease', 'MESH:D009369', (266, 271))	('abnormalities', 'Var', (214, 227))	('methylation', 'Gene', (235, 246))	('carcinogenesis', 'Disease', (82, 96))	('tumor', 'Phenotype', 'HP:0002664', (266, 271))	('DNA methylation', 'Gene', (231, 246))	('tumor', 'Disease', (266, 271))	('tumor', 'Disease', 'MESH:D009369', (162, 167))
77815	30353687	The occurrence of tumors is a complex process regulated by genetic, environmental, and epigenetic factors, which results in significant individual differences of cancer patients.	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('patients', 'Species', '9606', (169, 177))	('epigenetic', 'Var', (87, 97))	('cancer', 'Disease', (162, 168))	('men', 'Species', '9606', (75, 78))	('tumors', 'Disease', (18, 24))	('results in', 'Reg', (113, 123))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
77817	30353687	Toyooka et al19 found DNA methylation was ubiquitous in all stages of lung cancer development and negatively regulated the expression of oncogenes and tumor suppressor genes.	('lung cancer', 'Disease', 'MESH:D008175', (70, 81))	('methylation', 'Var', (26, 37))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('expression', 'MPA', (123, 133))	('tumor', 'Disease', (151, 156))	('regulated', 'Reg', (109, 118))	('lung cancer', 'Disease', (70, 81))	('lung cancer', 'Phenotype', 'HP:0100526', (70, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('negatively', 'NegReg', (98, 108))	('oncogenes', 'Protein', (137, 146))	('men', 'Species', '9606', (89, 92))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
77818	30353687	Therefore, the combination of aberrant DNA methylation and abnormal mRNA expression as well as cancer-associated gene expression is of great significance for selection of diagnostic and prognostic molecular marker of LUAD.	('LUAD', 'Disease', (217, 221))	('LUAD', 'Phenotype', 'HP:0030078', (217, 221))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('aberrant', 'Var', (30, 38))	('mRNA expression', 'MPA', (68, 83))	('cancer', 'Disease', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))
77819	30353687	As the results, we found 20 oncogenes and 12 tumor suppressor genes were differentially expressed caused by abnormal DNA methylation in LUAD.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('abnormal DNA methylation', 'Var', (108, 132))	('caused by', 'Reg', (98, 107))	('tumor', 'Disease', (45, 50))	('LUAD', 'Phenotype', 'HP:0030078', (136, 140))	('differentially', 'Reg', (73, 87))	('oncogenes', 'Gene', (28, 37))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
77840	30127402	Experimentally we demonstrate that non-physiological levels of BCL11A in vitro and in vivo promote squamous-like phenotypes, while its knockdown abolishes xenograft tumour formation.	('promote', 'PosReg', (91, 98))	('abolishes', 'NegReg', (145, 154))	('tumour', 'Phenotype', 'HP:0002664', (165, 171))	('knockdown', 'Var', (135, 144))	('BCL11A', 'Gene', (63, 69))	('squamous-like phenotypes', 'CPA', (99, 123))	('tumour', 'Disease', 'MESH:D009369', (165, 171))	('tumour', 'Disease', (165, 171))	('rat', 'Species', '10116', (25, 28))
77850	30127402	At the molecular level LUAD is known to harbour mutations in epidermal growth factor receptor (EGFR), V-Ki-Ras2 Kirsten Rat Sarcoma Viral Oncogene Homologue (KRAS) and Anaplastic Lymphoma Receptor Tyrosine Kinase (ALK), which are also well modelled and studied both in vitro and in vivo (for review see refs.	('Sarcoma Viral', 'Disease', (124, 137))	('epidermal growth factor receptor', 'Gene', '24329', (61, 93))	('ALK', 'Gene', (214, 217))	('epidermal growth factor receptor', 'Gene', (61, 93))	('ALK', 'Gene', '266802', (214, 217))	('Anaplastic Lymphoma Receptor Tyrosine Kinase', 'Gene', '266802', (168, 212))	('Rat', 'Species', '10116', (120, 123))	('Sarcoma', 'Phenotype', 'HP:0100242', (124, 131))	('EGFR', 'Gene', '24329', (95, 99))	('Anaplastic Lymphoma', 'Phenotype', 'HP:0012193', (168, 187))	('Anaplastic Lymphoma Receptor Tyrosine Kinase', 'Gene', (168, 212))	('Sarcoma Viral', 'Disease', 'MESH:D001102', (124, 137))	('Lymphoma', 'Phenotype', 'HP:0002665', (179, 187))	('KRAS', 'Gene', (158, 162))	('LUAD', 'Phenotype', 'HP:0030078', (23, 27))	('mutations', 'Var', (48, 57))	('KRAS', 'Gene', '24525', (158, 162))	('EGFR', 'Gene', (95, 99))
77851	30127402	On the other hand, LUSC is less studied but it is known that amplifications of Sex Determining Region Y (SRY)-Box 2 (SOX2) tend to be present in 70-80% of patients.	('SOX2', 'Gene', (117, 121))	('Sex Determining Region Y (SRY)-Box 2', 'Gene', '6657', (79, 115))	('LUSC', 'Phenotype', 'HP:0030359', (19, 23))	('patients', 'Species', '9606', (155, 163))	('amplifications', 'Var', (61, 75))
77852	30127402	We demonstrate that along with SOX2, it regulates key epigenetic factors, and that the disruption of one of these factors, SETD8 leads to selective affects in LUSC cells compared to LUAD cells.	('LUAD', 'Phenotype', 'HP:0030078', (182, 186))	('LUSC', 'Disease', (159, 163))	('LUSC', 'Phenotype', 'HP:0030359', (159, 163))	('epigenetic factors', 'MPA', (54, 72))	('rat', 'Species', '10116', (10, 13))	('SETD8', 'Gene', (123, 128))	('disruption', 'Var', (87, 97))	('affects', 'Reg', (148, 155))
77858	30127402	This observation is supported by the recent report from the TRACERx (TRAcking Cancer Evolution through therapy (Rx)) study demonstrating the amplification of BCL11A as an early event in LUSC.	('amplification', 'Var', (141, 154))	('Cancer', 'Disease', (78, 84))	('Cancer', 'Disease', 'MESH:D009369', (78, 84))	('LUSC', 'Phenotype', 'HP:0030359', (186, 190))	('Cancer', 'Phenotype', 'HP:0002664', (78, 84))	('rat', 'Species', '10116', (130, 133))	('BCL11A', 'Gene', (158, 164))
77867	30127402	Moreover, to test if the role of BCL11A is context dependant, we knocked down BCL11A in a LUAD cell line H1792 and found no change in 3D colony growth indicating specificity at the cellular level (Supplementary Fig.	('knocked', 'Var', (65, 72))	('BCL11A', 'Gene', (78, 84))	('LUAD', 'Phenotype', 'HP:0030078', (90, 94))	('H1792', 'CellLine', 'CVCL:1495', (105, 110))
77873	30127402	IHC analysis of the lungs from BCL11Aovx also indicated an increase in positivity for the proliferative marker Ki-67 (Supplementary Fig.	('positivity for the proliferative marker Ki-67', 'MPA', (71, 116))	('BCL11Aovx', 'Var', (31, 40))	('rat', 'Species', '10116', (97, 100))	('increase', 'PosReg', (59, 67))
77878	30127402	We found that in contrast to the hollow organoids normally formed by BCL11AOVX or Bcl11aCKO organoids treated with ethanol in vitro, BCs from BCL11Aovx mice treated with tamoxifen in vitro formed solid organoid structures with no hollow lumen suggesting hyper-proliferation and loss of organisation (Fig.	('organisation', 'MPA', (286, 298))	('loss', 'NegReg', (278, 282))	('Bcl11a', 'Gene', (82, 88))	('ethanol', 'Chemical', 'MESH:D000431', (115, 122))	('rat', 'Species', '10116', (267, 270))	('mice', 'Species', '10090', (152, 156))	('hyper-proliferation', 'PosReg', (254, 273))	('BCL11Aovx', 'Var', (142, 151))	('tamoxifen', 'Chemical', 'MESH:D013629', (170, 179))	('Bcl11a', 'Gene', '14025', (82, 88))
77884	30127402	To achieve this, we knocked down SOX2 (SOX2-KD) in two LUSC cell lines using two independent shRNAs (Fig.	('SOX2-KD', 'Gene', '6657', (39, 46))	('LUSC', 'Phenotype', 'HP:0030359', (55, 59))	('SOX2', 'Gene', (33, 37))	('SOX2-KD', 'Gene', (39, 46))	('knocked', 'Var', (20, 27))
77897	30127402	To understand if BCL11A regulates these genes, we sorted basal stem cells (Epcam+ve/GSIbeta4+ve) and Epcam+ve cells from trachea excised from tamoxifen-treated BCL11Aovx or WT mice (Fig.	('Epcam', 'Gene', (101, 106))	('Epcam', 'Gene', '17075', (101, 106))	('Epcam', 'Gene', (75, 80))	('mice', 'Species', '10090', (176, 180))	('tamoxifen', 'Chemical', 'MESH:D013629', (142, 151))	('BCL11Aovx', 'Var', (160, 169))	('Epcam', 'Gene', '17075', (75, 80))
77909	30127402	Once tumours reached 0.25 cm2 in size, we supplemented the mouse diet with doxycycline to induce the SETD8 KD and measured tumour growth periodically.	('tumour', 'Disease', 'MESH:D009369', (5, 11))	('tumours', 'Phenotype', 'HP:0002664', (5, 12))	('SETD8 KD', 'Var', (101, 109))	('mouse', 'Species', '10090', (59, 64))	('tumour', 'Disease', 'MESH:D009369', (123, 129))	('tumours', 'Disease', 'MESH:D009369', (5, 12))	('tumour', 'Disease', (5, 11))	('tumours', 'Disease', (5, 12))	('tumour', 'Disease', (123, 129))	('doxycycline', 'Chemical', 'MESH:D004318', (75, 86))	('tumour', 'Phenotype', 'HP:0002664', (5, 11))	('tumour', 'Phenotype', 'HP:0002664', (123, 129))
77912	30127402	13a-c) However, upon the addition of doxycycline tumours from tumours formed by the SETD8-KD cells slowed down significantly (Fig.	('tumours', 'Disease', (49, 56))	('tumours', 'Disease', (62, 69))	('tumour', 'Phenotype', 'HP:0002664', (62, 68))	('SETD8-KD', 'Var', (84, 92))	('tumour', 'Phenotype', 'HP:0002664', (49, 55))	('tumours', 'Phenotype', 'HP:0002664', (62, 69))	('tumours', 'Phenotype', 'HP:0002664', (49, 56))	('doxycycline', 'Chemical', 'MESH:D004318', (37, 48))	('tumours', 'Disease', 'MESH:D009369', (62, 69))	('tumours', 'Disease', 'MESH:D009369', (49, 56))	('slowed down', 'NegReg', (99, 110))
77913	30127402	At the end of the experiment, tumours formed by the SETD8-KD were ~50% smaller in size compared to Scram cells (Fig.	('tumours', 'Phenotype', 'HP:0002664', (30, 37))	('tumours', 'Disease', 'MESH:D009369', (30, 37))	('tumours', 'Disease', (30, 37))	('smaller', 'NegReg', (71, 78))	('tumour', 'Phenotype', 'HP:0002664', (30, 36))	('SETD8-KD', 'Var', (52, 60))
77917	30127402	To understand if SETD8 inhibition would add a clinical benefit to patients, we tested the effect of combining NSC663284 and cisplatin.	('cisplatin', 'Chemical', 'MESH:D002945', (124, 133))	('inhibition', 'Var', (23, 33))	('SETD8', 'Gene', (17, 22))	('tested', 'Reg', (79, 85))	('patients', 'Species', '9606', (66, 74))
77919	30127402	However, if we pre-treat NSCLC cell lines with NSC663284 for 48 h and then combine cisplatin with NSC663284 for a further 24 h we found that LUSC (IC50 = 4.66 muM) cells are more sensitive to cisplatin than LUAD cells (IC50 = 32.21 muM) (Fig.	('cisplatin', 'Chemical', 'MESH:D002945', (83, 92))	('muM', 'Gene', '56925', (159, 162))	('LUSC', 'Phenotype', 'HP:0030359', (141, 145))	('NSCLC', 'Disease', (25, 30))	('muM', 'Gene', '56925', (232, 235))	('NSCLC', 'Disease', 'MESH:D002289', (25, 30))	('LUAD', 'Phenotype', 'HP:0030078', (207, 211))	('muM', 'Gene', (159, 162))	('NSC663284', 'Var', (47, 56))	('SCLC', 'Phenotype', 'HP:0030357', (26, 30))	('cisplatin', 'Chemical', 'MESH:D002945', (192, 201))	('muM', 'Gene', (232, 235))	('NSCLC', 'Phenotype', 'HP:0030358', (25, 30))	('sensitive to cisplatin', 'MPA', (179, 201))
77920	30127402	It is important to note that NSC663284 has also been reported as an inhibitor of Cdc25.	('Cdc25', 'Gene', (81, 86))	('Cdc25', 'Gene', '995', (81, 86))	('inhibitor', 'MPA', (68, 77))	('NSC663284', 'Var', (29, 38))
77929	30127402	Our data suggests that disrupting the BCL11A-SOX2 transcriptional programme might provide a selective therapeutic window for LUSC patients.	('LUSC', 'Phenotype', 'HP:0030359', (125, 129))	('LUSC', 'Disease', (125, 129))	('BCL11A-SOX2 transcriptional', 'Gene', (38, 65))	('patients', 'Species', '9606', (130, 138))	('disrupting', 'Var', (23, 33))
77951	30127402	BCL11A shRNA sequences were obtained from TRC consortium (TRCN0000033449 and TRCN0000033453) and cloned into a piggyBac transposon vector (PB-H1-shRNA-GFP) as describe previously.	('TRCN0000033449', 'Disease', 'None', (58, 72))	('TRCN0000033449', 'Disease', (58, 72))	('TRCN0000033453', 'Var', (77, 91))
77954	30127402	SETD8 shRNA (TRCN0000359304 and TRCN0000359373), SKIL shRNA (TRCN0000431894 and TRCN0000424201); and TBX2 shRNA (TRCN0000232147 and TRCN0000232146) were cloned into pLKO-Tet-On vector.	('TBX2', 'Gene', '6909', (101, 105))	('TRCN0000359304', 'Var', (13, 27))	('TBX2', 'Gene', (101, 105))	('Tet', 'Chemical', 'MESH:C010349', (170, 173))	('TRCN0000431894', 'Var', (61, 75))	('SKIL', 'Gene', (49, 53))	('TRCN0000232147', 'Var', (113, 127))	('TRCN0000359373', 'Var', (32, 46))	('SKIL', 'Gene', '6498', (49, 53))
78019	33488884	Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKIs) have shown a significant therapeutic effect in advanced non-small-cell lung cancer (NSCLC) with EGFR mutations; however, many patients may develop drug resistance due to various mechanisms of resistance, such as histologic transformation.	('patients', 'Species', '9606', (205, 213))	('drug resistance', 'MPA', (226, 241))	('EGFR', 'Gene', (34, 38))	('drug resistance', 'Phenotype', 'HP:0020174', (226, 241))	('Epidermal growth factor receptor', 'Gene', (0, 32))	('non-small-cell lung cancer', 'Disease', (135, 161))	('EGFR', 'Gene', '1956', (68, 72))	('NSCLC', 'Disease', 'MESH:D002289', (163, 168))	('non-small-cell lung cancer', 'Disease', 'MESH:D002289', (135, 161))	('lung cancer', 'Phenotype', 'HP:0100526', (150, 161))	('EGFR', 'Gene', (175, 179))	('mutations', 'Var', (180, 189))	('EGFR', 'Gene', (68, 72))	('NSCLC', 'Disease', (163, 168))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (139, 161))	('EGFR', 'Gene', '1956', (34, 38))	('NSCLC', 'Phenotype', 'HP:0030358', (163, 168))	('develop', 'Reg', (218, 225))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (135, 161))	('Epidermal growth factor receptor', 'Gene', '1956', (0, 32))	('EGFR', 'Gene', '1956', (175, 179))
78039	33488884	The patient next underwent lobectomy of the left upper lung on January 20, 2020; at this stage, the pathology and immunohistochemistry suggested pleomorphic carcinoma, where the sarcomatoid component accounted for more than 80% (Figure 2(b)), and a weakly positive result for CK and CK18 and aberrant expression of vimentin, ALK, and PD-L1 (80%) (Figures 2(c) and 2(d)).	('vimentin', 'Gene', (315, 323))	('CK', 'Gene', '51727', (283, 285))	('ALK', 'Gene', (325, 328))	('pleomorphic carcinoma', 'Disease', 'MESH:D008228', (145, 166))	('CK', 'Gene', '51727', (276, 278))	('sarcomatoid component', 'Disease', (178, 199))	('PD-L1', 'Gene', '29126', (334, 339))	('CK18', 'Gene', '3875', (283, 287))	('pleomorphic carcinoma', 'Disease', (145, 166))	('sarcomatoid component', 'Disease', 'MESH:C538614', (178, 199))	('aberrant', 'Var', (292, 300))	('patient', 'Species', '9606', (4, 11))	('ALK', 'Gene', '238', (325, 328))	('carcinoma', 'Phenotype', 'HP:0030731', (157, 166))	('CK18', 'Gene', (283, 287))	('vimentin', 'Gene', '7431', (315, 323))	('PD-L1', 'Gene', (334, 339))
78041	33488884	Advanced NSCLC with EGFR or ALK mutations respond well to related TKIs; however, drug resistance can occur due to various mechanisms such as drug-resistant mutations, activation of the bypass pathways, and histologic transformation.	('EGFR', 'Gene', (20, 24))	('ALK', 'Gene', '238', (28, 31))	('mutations', 'Var', (156, 165))	('bypass pathways', 'Pathway', (185, 200))	('NSCLC', 'Disease', (9, 14))	('NSCLC', 'Disease', 'MESH:D002289', (9, 14))	('occur', 'Reg', (101, 106))	('mutations', 'Var', (32, 41))	('ALK', 'Gene', (28, 31))	('NSCLC', 'Phenotype', 'HP:0030358', (9, 14))	('drug resistance', 'Phenotype', 'HP:0020174', (81, 96))	('EGFR', 'Gene', '1956', (20, 24))	('drug', 'MPA', (81, 85))
78049	33488884	Some new studies have found that hepatocyte growth factor receptor gene (MET) mutations and high expression levels of PD-L1 are also indicators in the diagnosis and treatment of lung adenocarcinoma with sarcomatoid transformation.	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (178, 197))	('sarcomatoid transformation', 'Disease', 'MESH:C538614', (203, 229))	('PD-L1', 'Gene', (118, 123))	('MET', 'Gene', '79811', (73, 76))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (178, 197))	('mutations', 'Var', (78, 87))	('sarcomatoid transformation', 'Disease', (203, 229))	('expression levels', 'MPA', (97, 114))	('PD-L1', 'Gene', '29126', (118, 123))	('hepatocyte growth factor receptor', 'Gene', '4233', (33, 66))	('MET', 'Gene', (73, 76))	('lung adenocarcinoma', 'Disease', (178, 197))	('carcinoma', 'Phenotype', 'HP:0030731', (188, 197))	('hepatocyte growth factor receptor', 'Gene', (33, 66))
78053	33488884	reported that lung adenocarcinoma with sarcomatoid transformation may be present in a high proportion of cases with aberrant MET activation and PD-L1 expression.	('PD-L1', 'Gene', '29126', (144, 149))	('lung adenocarcinoma', 'Disease', (14, 33))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (14, 33))	('MET', 'Gene', '79811', (125, 128))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (14, 33))	('PD-L1', 'Gene', (144, 149))	('sarcomatoid transformation', 'Disease', 'MESH:C538614', (39, 65))	('MET', 'Gene', (125, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (24, 33))	('sarcomatoid transformation', 'Disease', (39, 65))	('aberrant', 'Var', (116, 124))
78079	30883339	There were increasing evidences that abnormal expression of miRNAs caused a variety of cancers, including oral cancer.	('cancers', 'Disease', (87, 94))	('oral cancer', 'Disease', 'MESH:D009062', (106, 117))	('abnormal expression', 'Var', (37, 56))	('miR', 'Gene', '220972', (60, 63))	('miR', 'Gene', (60, 63))	('oral cancer', 'Disease', (106, 117))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cancers', 'Phenotype', 'HP:0002664', (87, 94))	('caused', 'Reg', (67, 73))	('cancers', 'Disease', 'MESH:D009369', (87, 94))
78085	30883339	FBXW7 is critical for the regulation of human cell cycle, cell growth and cell differentiation, and its deletion can lead to or accelerate the proliferation of cancer cells and increase poor prognosis .	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('cancer', 'Disease', (160, 166))	('poor prognosis', 'CPA', (186, 200))	('increase', 'PosReg', (177, 185))	('FBXW7', 'Gene', (0, 5))	('accelerate', 'PosReg', (128, 138))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('lead to', 'Reg', (117, 124))	('deletion', 'Var', (104, 112))	('proliferation', 'CPA', (143, 156))	('human', 'Species', '9606', (40, 45))
78086	30883339	Previously studies have shown that the absence of FBXW7 could lead to poor prognosis for colorectal cancer, esophageal cancer and gastric cancer .	('colorectal cancer', 'Phenotype', 'HP:0003003', (89, 106))	('FBXW7', 'Gene', (50, 55))	('absence', 'Var', (39, 46))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('colorectal cancer', 'Disease', (89, 106))	('esophageal cancer', 'Disease', (108, 125))	('gastric cancer', 'Disease', (130, 144))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('gastric cancer', 'Disease', 'MESH:D013274', (130, 144))	('colorectal cancer', 'Disease', 'MESH:D015179', (89, 106))	('esophageal cancer', 'Disease', 'MESH:D004938', (108, 125))	('gastric cancer', 'Phenotype', 'HP:0012126', (130, 144))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
78098	30883339	The oral cancer cell lines were cultured in RPMI-1640 with 10% fetal bovine serum (Gibco, USA), penicillin (100 U/ml) and streptomycin (100 g/ml) (Solarbio, China), which was incubated at 37C under 5% CO atmosphere.	('100 g/ml', 'Var', (136, 144))	('oral cancer', 'Disease', 'MESH:D009062', (4, 15))	('oral cancer', 'Disease', (4, 15))	('bovine', 'Species', '9913', (69, 75))	('RPMI-1640', 'Chemical', '-', (44, 53))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('penicillin', 'Chemical', 'MESH:D010406', (96, 106))	('streptomycin', 'Chemical', 'MESH:D013307', (122, 134))	('100 U/ml', 'Var', (108, 116))
78139	30883339	5B-D shown, increasing FBXW7 could inhibit the cells proliferation and migration in OECM1 and SCC15.	('FBXW7', 'Var', (23, 28))	('SCC15', 'Gene', (94, 99))	('SCC15', 'CellLine', 'CVCL:1681', (94, 99))	('cells proliferation', 'CPA', (47, 66))	('inhibit', 'NegReg', (35, 42))
78147	30883339	Furthermore, we also provided evidences that miR-223 and FBXW7 mRNA expression were negatively correlated, and FBXW7 could reverse the promotion effect of miR-223 in OSCC cell proliferation and migration.	('miR-223', 'Gene', '407008', (155, 162))	('FBXW7', 'Gene', (57, 62))	('OSCC', 'Disease', (166, 170))	('miR-223', 'Gene', (45, 52))	('promotion', 'PosReg', (135, 144))	('miR-223', 'Gene', (155, 162))	('migration', 'CPA', (194, 203))	('mRNA expression', 'MPA', (63, 78))	('miR-223', 'Gene', '407008', (45, 52))	('FBXW7', 'Var', (111, 116))	('reverse', 'NegReg', (123, 130))
78173	28637487	Heritable constitutional mutations in the NF1 gene result in dysregulation of the RAS/MAPK pathway and are causative of NF1.	('mutations', 'Var', (25, 34))	('RAS', 'Chemical', 'MESH:D011883', (82, 85))	('NF1', 'Disease', (120, 123))	('dysregulation', 'MPA', (61, 74))	('RAS/MAPK pathway', 'Pathway', (82, 98))	('NF1', 'Gene', (42, 45))	('result in', 'Reg', (51, 60))
78177	28637487	Capitalizing upon the availability of next-generation sequencing data from cancer genomes and exomes, we review current knowledge of somatic NF1 mutations in a wide variety of tumours occurring at a number of different sites: breast, colorectum, urothelium, lung, ovary, skin, brain and neuroendocrine tissues, as well as leukaemias, in an attempt to understand their broader role and significance, and with a view ultimately to exploiting this in a diagnostic and therapeutic context.	('tumours', 'Disease', 'MESH:D009369', (176, 183))	('tumours', 'Disease', (176, 183))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('leukaemias', 'Disease', 'MESH:D007938', (322, 332))	('mutations', 'Var', (145, 154))	('ovary', 'Disease', (264, 269))	('cancer', 'Disease', (75, 81))	('ovary', 'Disease', 'MESH:D010051', (264, 269))	('tumour', 'Phenotype', 'HP:0002664', (176, 182))	('tumours', 'Phenotype', 'HP:0002664', (176, 183))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('leukaemias', 'Disease', (322, 332))	('NF1', 'Gene', (141, 144))
78178	28637487	As neurofibromin activity is a key to regulating the RAS/MAPK pathway, NF1 mutations are important in the acquisition of drug resistance, to BRAF, EGFR inhibitors, tamoxifen and retinoic acid in melanoma, lung and breast cancers and neuroblastoma.	('breast cancer', 'Phenotype', 'HP:0003002', (214, 227))	('neuroblastoma', 'Phenotype', 'HP:0003006', (233, 246))	('NF1', 'Gene', (71, 74))	('retinoic acid', 'Chemical', 'MESH:D014212', (178, 191))	('neuroblastoma', 'Disease', 'MESH:D009447', (233, 246))	('melanoma', 'Disease', 'MESH:D008545', (195, 203))	('drug resistance', 'Phenotype', 'HP:0020174', (121, 136))	('lung', 'Disease', (205, 209))	('cancers', 'Phenotype', 'HP:0002664', (221, 228))	('tamoxifen', 'Chemical', 'MESH:D013629', (164, 173))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('melanoma', 'Phenotype', 'HP:0002861', (195, 203))	('melanoma', 'Disease', (195, 203))	('breast cancers', 'Disease', 'MESH:D001943', (214, 228))	('breast cancers', 'Disease', (214, 228))	('RAS', 'Chemical', 'MESH:D011883', (53, 56))	('breast cancers', 'Phenotype', 'HP:0003002', (214, 228))	('mutations', 'Var', (75, 84))	('neuroblastoma', 'Disease', (233, 246))
78179	28637487	Other curiosities are observed, such as a high rate of somatic NF1 mutation in cutaneous melanoma, lung cancer, ovarian carcinoma and glioblastoma which are not usually associated with neurofibromatosis type 1.	('cutaneous melanoma', 'Disease', (79, 97))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (79, 97))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (79, 97))	('neurofibromatosis type 1', 'Gene', '4763', (185, 209))	('glioblastoma', 'Disease', (134, 146))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('glioblastoma', 'Phenotype', 'HP:0012174', (134, 146))	('melanoma', 'Phenotype', 'HP:0002861', (89, 97))	('NF1', 'Gene', (63, 66))	('mutation', 'Var', (67, 75))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (112, 129))	('ovarian carcinoma', 'Disease', (112, 129))	('lung cancer', 'Disease', (99, 110))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (112, 129))	('neurofibromatosis type 1', 'Gene', (185, 209))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (185, 202))	('glioblastoma', 'Disease', 'MESH:D005909', (134, 146))	('lung cancer', 'Disease', 'MESH:D008175', (99, 110))	('lung cancer', 'Phenotype', 'HP:0100526', (99, 110))
78180	28637487	Somatic NF1 mutations may be critical drivers in multiple cancers.	('NF1', 'Gene', (8, 11))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('mutations', 'Var', (12, 21))	('cancers', 'Phenotype', 'HP:0002664', (58, 65))	('cancers', 'Disease', 'MESH:D009369', (58, 65))	('cancers', 'Disease', (58, 65))
78181	28637487	The mutational landscape of somatic NF1 mutations should provide novel insights into our understanding of the pathophysiology of cancer.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('NF1', 'Gene', (36, 39))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('mutations', 'Var', (40, 49))
78182	28637487	The identification of high frequency of somatic NF1 mutations in sporadic tumours indicates that neurofibromin is likely to play a critical role in development, far beyond that evident in the tumour predisposition syndrome NF1.	('mutations', 'Var', (52, 61))	('tumour', 'Phenotype', 'HP:0002664', (192, 198))	('tumour', 'Disease', 'MESH:D009369', (74, 80))	('tumours', 'Phenotype', 'HP:0002664', (74, 81))	('sporadic tumours', 'Disease', 'MESH:D009369', (65, 81))	('tumour', 'Disease', (74, 80))	('tumour', 'Disease', 'MESH:D009369', (192, 198))	('tumour', 'Disease', (192, 198))	('tumour', 'Phenotype', 'HP:0002664', (74, 80))	('sporadic tumours', 'Disease', (65, 81))	('NF1', 'Gene', (48, 51))
78190	28637487	NF1 is a tumour suppressor gene; in order for a particular cell to become cancerous, both alleles of a tumour suppressor gene must be mutated.	('tumour', 'Disease', (9, 15))	('tumour', 'Phenotype', 'HP:0002664', (103, 109))	('cancerous', 'Disease', (74, 83))	('tumour', 'Disease', 'MESH:D009369', (103, 109))	('mutated', 'Var', (134, 141))	('tumour', 'Phenotype', 'HP:0002664', (9, 15))	('tumour', 'Disease', 'MESH:D009369', (9, 15))	('cancerous', 'Disease', 'MESH:D009369', (74, 83))	('tumour', 'Disease', (103, 109))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
78191	28637487	This concept, known as the 'two-hit' hypothesis, was first proposed by Knudson, and the majority of NF1-associated tumours exhibit biallelic inactivation of NF1.	('biallelic', 'Var', (131, 140))	('tumours', 'Disease', 'MESH:D009369', (115, 122))	('tumours', 'Disease', (115, 122))	('tumour', 'Phenotype', 'HP:0002664', (115, 121))	('NF1', 'Gene', (157, 160))	('NF1-associated', 'Gene', (100, 114))	('tumours', 'Phenotype', 'HP:0002664', (115, 122))
78199	28637487	Hence, any loss of neurofibromin functionality, due to inactivating mutations in NF1, will result in sustained intracellular levels of active RAS-GTP, resulting in prolonged activation of the RAS/RAF/MAPK signalling pathway and ultimately a loss of growth control and increased cellular proliferation.	('RAF', 'Gene', (196, 199))	('loss', 'NegReg', (241, 245))	('increased', 'PosReg', (268, 277))	('loss', 'NegReg', (11, 15))	('growth control', 'CPA', (249, 263))	('inactivating mutations', 'Var', (55, 77))	('RAS-GTP', 'Chemical', '-', (142, 149))	('NF1', 'Gene', (81, 84))	('RAS', 'Chemical', 'MESH:D011883', (192, 195))	('intracellular levels of active RAS-GTP', 'MPA', (111, 149))	('RAS', 'Chemical', 'MESH:D011883', (142, 145))	('neurofibromin', 'Protein', (19, 32))	('activation', 'PosReg', (174, 184))	('cellular proliferation', 'CPA', (278, 300))	('RAF', 'Gene', '22882', (196, 199))
78202	28637487	Indeed, the mTOR pathway is constitutively activated in neurofibromin-deficient primary cells and tumours, and is regulated by phosphorylation and inactivation of the TSC2-encoded protein tuberin by AKT, ERK and RSK.	('TSC2', 'Gene', '7249', (167, 171))	('AKT', 'Gene', (199, 202))	('RSK', 'Gene', (212, 215))	('tumours', 'Phenotype', 'HP:0002664', (98, 105))	('inactivation', 'Var', (147, 159))	('tumour', 'Phenotype', 'HP:0002664', (98, 104))	('tuberin', 'Gene', '7249', (188, 195))	('AKT', 'Gene', '207', (199, 202))	('tumours', 'Disease', 'MESH:D009369', (98, 105))	('mTOR', 'Gene', '2475', (12, 16))	('tumours', 'Disease', (98, 105))	('mTOR', 'Gene', (12, 16))	('RSK', 'Gene', '6196', (212, 215))	('tuberin', 'Gene', (188, 195))	('TSC2', 'Gene', (167, 171))
78204	28637487	Neurofibromin levels and therefore Ras signalling can also be affected by mechanisms other than NF1 mutation including ubiquitination.	('mutation', 'Var', (100, 108))	('Neurofibromin', 'Gene', '4763', (0, 13))	('affected', 'Reg', (62, 70))	('Neurofibromin', 'Gene', (0, 13))	('Ras signalling', 'MPA', (35, 49))	('NF1', 'Gene', (96, 99))	('ubiquitination', 'MPA', (119, 133))
78207	28637487	In such families, only a small proportion of the germ cells, whether sperm or ova, will carry the new NF1 mutation, but this can nevertheless result in more than one affected child being produced by clinically normal parents.	('mutation', 'Var', (106, 114))	('NF1', 'Gene', (102, 105))	('child', 'Species', '9606', (175, 180))	('result in', 'Reg', (142, 151))
78208	28637487	A major challenge for clinicians and geneticists dealing with NF1 is the successful identification and characterization of causative NF1 mutations in their patients.	('mutations', 'Var', (137, 146))	('patients', 'Species', '9606', (156, 164))	('NF1', 'Gene', (133, 136))
78209	28637487	Furthermore, some 30% of all NF1 mutations are predicted to cause aberrant splicing, and for this reason, the analysis of both RNA and DNA from patients in mutation screening protocols is clearly required.	('cause', 'Reg', (60, 65))	('NF1', 'Gene', (29, 32))	('mutations', 'Var', (33, 42))	('patients', 'Species', '9606', (144, 152))	('aberrant splicing', 'MPA', (66, 83))
78210	28637487	Whilst the majority of NF1 splicing mutations occur within consensus acceptor and donor splice site sequences, a number of missense, nonsense, and even 'silent' mutations may also result in aberrant splicing, which are often only identifiable by screening a patient's RNA.	('result in', 'Reg', (180, 189))	('nonsense', 'Var', (133, 141))	('NF1', 'Gene', (23, 26))	('mutations', 'Var', (36, 45))	('patient', 'Species', '9606', (258, 265))	('splicing', 'MPA', (199, 207))	('mutations', 'Var', (161, 170))	('missense', 'Var', (123, 131))
78211	28637487	As well as the challenges in collection and analysis of patient mRNA, a frequent issue is the difficulty in interpreting the clinical diagnostic significance of putative NF1 missense mutations, as this may require a family segregation study and/or in vitro functional analysis to determine the pathogenicity (or otherwise) of the variant in question.	('patient', 'Species', '9606', (56, 63))	('NF1', 'Gene', (170, 173))	('missense mutations', 'Var', (174, 192))
78212	28637487	Furthermore, many highly homologous NF1 pseudogene sequences are scattered throughout the human genome and can often interfere with PCR-based diagnostic tests.	('interfere', 'Reg', (117, 126))	('human', 'Species', '9606', (90, 95))	('NF1', 'Gene', (36, 39))	('pseudogene', 'Var', (40, 50))
78213	28637487	The spatial distribution of NF1 microdeletions is strongly influenced by the presence of a number of low-copy repeats (LCRs) spanning the 17q11.2 region that encompasses the NF1 gene.	('spatial', 'Gene', '219793', (4, 11))	('spatial', 'Gene', (4, 11))	('microdeletions', 'Var', (32, 46))	('NF1', 'Gene', (174, 177))	('NF1', 'Gene', (28, 31))	('influenced', 'Reg', (59, 69))
78214	28637487	Indeed, studies into NF1 microdeletions have provided a general model to understand the different mutational mechanisms underlying large genomic rearrangements associated with inherited diseases.	('inherited diseases', 'Disease', 'MESH:D030342', (176, 194))	('inherited diseases', 'Disease', (176, 194))	('NF1', 'Gene', (21, 24))	('microdeletions', 'Var', (25, 39))
78215	28637487	The NF1 mutation detection rate in classical NF1 patients can be up to 95%.	('NF1', 'Gene', (4, 7))	('patients', 'Species', '9606', (49, 57))	('mutation', 'Var', (8, 16))
78217	28637487	Mutations in multiple genes encoding the components of the RAS/MAPK pathway predispose patients to develop clinical features that overlap with those of NF1, e.g.	('Mutations', 'Var', (0, 9))	('patients', 'Species', '9606', (87, 95))	('predispose', 'Reg', (76, 86))	('RAS', 'Chemical', 'MESH:D011883', (59, 62))
78219	28637487	All cancers originate from a single cell that starts to behave abnormally due to acquired somatic mutations in its genome.	('cancers', 'Disease', 'MESH:D009369', (4, 11))	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('mutations in', 'Var', (98, 110))	('cancers', 'Phenotype', 'HP:0002664', (4, 11))	('cancers', 'Disease', (4, 11))
78220	28637487	A subset of these somatic changes, termed 'driver mutations', confer a selective growth advantage and are implicated in cancer development, whereas the remainder are considered to be 'passengers'.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('changes', 'Var', (26, 33))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('growth advantage', 'CPA', (81, 97))	('implicated', 'Reg', (106, 116))
78223	28637487	It contains data on somatic NF1 mutations in different types of tumour including melanoma (desmoplastic, skin cutaneous and uveal), breast carcinoma, neuroendocrine prostate cancer, glioblastoma, lung adenocarcinoma and squamous cell carcinoma, urothelial carcinoma, uterine carcinoma, adenoid and ovarian serous cystadenocarcinoma, paraganglioma, phaeochromocytoma, pancreatic cancer, adrenocortical carcinoma, stomach adenocarcinoma, sarcoma, oesophageal cancer, rhabdomyosarcoma and many more.	('carcinoma', 'Disease', 'MESH:D009369', (322, 331))	('carcinoma', 'Disease', 'MESH:D009369', (425, 434))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (367, 384))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (465, 481))	('sarcoma', 'Disease', 'MESH:D012509', (474, 481))	('carcinoma', 'Disease', 'MESH:D009369', (139, 148))	('sarcoma', 'Disease', (474, 481))	('cancer', 'Disease', (174, 180))	('neuroendocrine prostate cancer', 'Disease', 'MESH:D011471', (150, 180))	('uterine carcinoma', 'Phenotype', 'HP:0010784', (267, 284))	('carcinoma', 'Disease', (206, 215))	('neuroendocrine prostate cancer', 'Disease', (150, 180))	('glioblastoma', 'Disease', 'MESH:D005909', (182, 194))	('carcinoma', 'Disease', (322, 331))	('melanoma', 'Disease', 'MESH:D008545', (81, 89))	('breast carcinoma', 'Disease', 'MESH:D001943', (132, 148))	('carcinoma', 'Phenotype', 'HP:0030731', (234, 243))	('pancreatic cancer', 'Disease', (367, 384))	('NF1', 'Gene', (28, 31))	('rhabdomyosarcoma', 'Disease', (465, 481))	('carcinoma', 'Disease', (234, 243))	('cancer', 'Phenotype', 'HP:0002664', (457, 463))	('tumour', 'Disease', 'MESH:D009369', (64, 70))	('prostate cancer', 'Phenotype', 'HP:0012125', (165, 180))	('carcinoma', 'Disease', (139, 148))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (386, 410))	('paraganglioma', 'Disease', 'MESH:D010235', (333, 346))	('lung adenocarcinoma', 'Disease', (196, 215))	('stomach adenocarcinoma', 'Disease', 'MESH:D000230', (412, 434))	('breast carcinoma', 'Phenotype', 'HP:0003002', (132, 148))	('carcinoma', 'Disease', 'MESH:D009369', (401, 410))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (245, 265))	('carcinoma', 'Phenotype', 'HP:0030731', (256, 265))	('melanoma', 'Phenotype', 'HP:0002861', (81, 89))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (386, 410))	('carcinoma', 'Disease', 'MESH:D009369', (275, 284))	('carcinoma', 'Disease', (256, 265))	('phaeochromocytoma', 'Disease', 'MESH:D010673', (348, 365))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (196, 215))	('urothelial carcinoma', 'Disease', (245, 265))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('carcinoma', 'Phenotype', 'HP:0030731', (206, 215))	('ovarian serous cystadenocarcinoma', 'Phenotype', 'HP:0012887', (298, 331))	('carcinoma', 'Disease', (401, 410))	('carcinoma', 'Disease', (425, 434))	('cancer', 'Phenotype', 'HP:0002664', (378, 384))	('carcinoma', 'Disease', (275, 284))	('carcinoma', 'Phenotype', 'HP:0030731', (139, 148))	('squamous cell carcinoma', 'Disease', (220, 243))	('phaeochromocytoma', 'Disease', (348, 365))	('breast carcinoma', 'Disease', (132, 148))	('cancer', 'Disease', 'MESH:D009369', (457, 463))	('stomach adenocarcinoma', 'Disease', (412, 434))	('adrenocortical carcinoma', 'Disease', (386, 410))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (196, 215))	('mutations', 'Var', (32, 41))	('ovarian serous cystadenocarcinoma', 'Disease', (298, 331))	('carcinoma', 'Phenotype', 'HP:0030731', (275, 284))	('glioblastoma', 'Disease', (182, 194))	('tumour', 'Disease', (64, 70))	('paraganglioma', 'Disease', (333, 346))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (465, 481))	('carcinoma', 'Disease', 'MESH:D009369', (234, 243))	('cancer', 'Disease', 'MESH:D009369', (378, 384))	('melanoma', 'Disease', (81, 89))	('sarcoma', 'Phenotype', 'HP:0100242', (436, 443))	('paraganglioma', 'Phenotype', 'HP:0002668', (333, 346))	('pancreatic cancer', 'Disease', 'MESH:D010190', (367, 384))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (220, 243))	('carcinoma', 'Disease', 'MESH:D009369', (256, 265))	('sarcoma', 'Phenotype', 'HP:0100242', (474, 481))	('cancer', 'Disease', (378, 384))	('cancer', 'Disease', (457, 463))	('tumour', 'Phenotype', 'HP:0002664', (64, 70))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (220, 243))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('sarcoma', 'Disease', 'MESH:D012509', (436, 443))	('glioblastoma', 'Phenotype', 'HP:0012174', (182, 194))	('carcinoma', 'Disease', 'MESH:D009369', (206, 215))	('ovarian serous cystadenocarcinoma', 'Disease', 'MESH:D018284', (298, 331))	('sarcoma', 'Disease', (436, 443))
78224	28637487	In this review, we detail the frequency of somatic NF1 mutations in many non-NF1-associated sporadic cancers including melanoma, glioblastoma, neuroblastoma, breast cancer, ovarian serous carcinoma, paraganglioma and phaeochromocytoma, lung adenocarcinoma, lung squamous cell carcinoma, bladder, colorectal and leukaemia.	('sporadic cancers', 'Disease', 'MESH:D009369', (92, 108))	('ovarian serous carcinoma', 'Disease', (173, 197))	('paraganglioma', 'Phenotype', 'HP:0002668', (199, 212))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (257, 285))	('breast cancer', 'Phenotype', 'HP:0003002', (158, 171))	('melanoma', 'Phenotype', 'HP:0002861', (119, 127))	('lung squamous cell carcinoma', 'Disease', (257, 285))	('melanoma', 'Disease', (119, 127))	('ovarian serous carcinoma', 'Disease', 'MESH:D010051', (173, 197))	('neuroblastoma', 'Disease', (143, 156))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (236, 255))	('neuroblastoma', 'Phenotype', 'HP:0003006', (143, 156))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (262, 285))	('breast cancer', 'Disease', 'MESH:D001943', (158, 171))	('carcinoma', 'Phenotype', 'HP:0030731', (276, 285))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (236, 255))	('glioblastoma', 'Disease', 'MESH:D005909', (129, 141))	('sporadic cancers', 'Disease', (92, 108))	('breast cancer', 'Disease', (158, 171))	('neuroblastoma', 'Disease', 'MESH:D009447', (143, 156))	('carcinoma', 'Phenotype', 'HP:0030731', (246, 255))	('colorectal and leukaemia', 'Disease', 'MESH:D015179', (296, 320))	('glioblastoma', 'Disease', (129, 141))	('mutations', 'Var', (55, 64))	('glioblastoma', 'Phenotype', 'HP:0012174', (129, 141))	('melanoma', 'Disease', 'MESH:D008545', (119, 127))	('NF1', 'Gene', (51, 54))	('carcinoma', 'Phenotype', 'HP:0030731', (188, 197))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (257, 285))	('cancers', 'Phenotype', 'HP:0002664', (101, 108))	('paraganglioma and phaeochromocytoma', 'Disease', 'MESH:D010235', (199, 234))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('lung adenocarcinoma', 'Disease', (236, 255))	('bladder', 'Disease', (287, 294))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))
78225	28637487	Further, it is anticipated that with the advent of powerful sequencing technologies, combined with precise microdissection of tissue, somatic NF1 mutations will be identified in additional tumour types.	('mutations', 'Var', (146, 155))	('tumour', 'Phenotype', 'HP:0002664', (189, 195))	('tumour', 'Disease', 'MESH:D009369', (189, 195))	('tumour', 'Disease', (189, 195))	('NF1', 'Gene', (142, 145))	('identified', 'Reg', (164, 174))
78226	28637487	Elucidation of the mutational landscape of somatic NF1 mutations in a large number of sporadic tumours, their role in the initiation and progression of tumours and how they can confer resistance or sensitivity to a therapeutic intervention may provide further insight into the mechanisms underlying tumour development and ultimately aid the development and targeting of therapies.	('sporadic tumours', 'Disease', 'MESH:D009369', (86, 102))	('tumour', 'Phenotype', 'HP:0002664', (299, 305))	('tumour', 'Disease', 'MESH:D009369', (299, 305))	('tumour', 'Disease', (299, 305))	('sporadic tumours', 'Disease', (86, 102))	('tumours', 'Disease', (152, 159))	('tumours', 'Disease', (95, 102))	('tumours', 'Phenotype', 'HP:0002664', (152, 159))	('tumours', 'Phenotype', 'HP:0002664', (95, 102))	('tumours', 'Disease', 'MESH:D009369', (152, 159))	('mutations', 'Var', (55, 64))	('tumours', 'Disease', 'MESH:D009369', (95, 102))	('tumour', 'Phenotype', 'HP:0002664', (152, 158))	('NF1', 'Gene', (51, 54))	('tumour', 'Phenotype', 'HP:0002664', (95, 101))	('tumour', 'Disease', 'MESH:D009369', (152, 158))	('tumour', 'Disease', 'MESH:D009369', (95, 101))	('tumour', 'Disease', (152, 158))	('tumour', 'Disease', (95, 101))
78227	28637487	The frequency of somatic NF1 mutations in different sporadic tumour types derived from the literature is given in Table 1.	('tumour', 'Disease', 'MESH:D009369', (61, 67))	('mutations', 'Var', (29, 38))	('tumour', 'Disease', (61, 67))	('NF1', 'Gene', (25, 28))	('tumour', 'Phenotype', 'HP:0002664', (61, 67))
78233	28637487	The direct involvement of NF1 in melanoma was first reported by Andersen and colleagues in 1993 who identified a homozygous NF1 deletion in one of eight malignant melanoma cell lines which resulted in the loss of detectable NF1 mRNA and neurofibromin protein.	('NF1', 'Gene', (124, 127))	('NF1', 'Protein', (224, 227))	('melanoma', 'Disease', 'MESH:D008545', (163, 171))	('melanoma', 'Phenotype', 'HP:0002861', (163, 171))	('loss', 'NegReg', (205, 209))	('melanoma', 'Disease', (163, 171))	('melanoma', 'Disease', (33, 41))	('melanoma', 'Phenotype', 'HP:0002861', (33, 41))	('malignant melanoma', 'Phenotype', 'HP:0002861', (153, 171))	('melanoma', 'Disease', 'MESH:D008545', (33, 41))	('neurofibromin protein', 'Protein', (237, 258))	('malignant melanoma', 'Disease', 'MESH:D008545', (153, 171))	('malignant melanoma', 'Disease', (153, 171))	('deletion', 'Var', (128, 136))
78236	28637487	Many subsequent studies have identified additional somatic NF1 mutations in melanoma in 12-30% of cases.	('mutations', 'Var', (63, 72))	('melanoma', 'Disease', (76, 84))	('melanoma', 'Disease', 'MESH:D008545', (76, 84))	('NF1', 'Gene', (59, 62))	('melanoma', 'Phenotype', 'HP:0002861', (76, 84))
78237	28637487	RAS/MAPK pathway dysregulation has been identified as a key culprit in non-familial melanoma, leading to the discovery of BRAF and NRAS as the most commonly mutated genes.	('RAS', 'Chemical', 'MESH:D011883', (0, 3))	('NRAS', 'Gene', (131, 135))	('melanoma', 'Disease', 'MESH:D008545', (84, 92))	('melanoma', 'Phenotype', 'HP:0002861', (84, 92))	('melanoma', 'Disease', (84, 92))	('dysregulation', 'Var', (17, 30))	('BRAF', 'Gene', (122, 126))	('NRAS', 'Gene', '4893', (131, 135))	('RAS', 'Chemical', 'MESH:D011883', (132, 135))
78238	28637487	Indeed, BRAF mutations occur in 50-70% of all cutaneous malignant melanomas, whilst NRAS alterations only occur in 19-28% of tumours.	('melanoma', 'Phenotype', 'HP:0002861', (66, 74))	('malignant melanomas', 'Disease', 'MESH:D008545', (56, 75))	('malignant melanomas', 'Phenotype', 'HP:0002861', (56, 75))	('tumours', 'Disease', (125, 132))	('NRAS', 'Gene', (84, 88))	('BRAF', 'Gene', (8, 12))	('tumour', 'Phenotype', 'HP:0002664', (125, 131))	('malignant melanoma', 'Phenotype', 'HP:0002861', (56, 74))	('NRAS', 'Gene', '4893', (84, 88))	('malignant melanomas', 'Disease', (56, 75))	('mutations', 'Var', (13, 22))	('tumours', 'Phenotype', 'HP:0002664', (125, 132))	('melanomas', 'Phenotype', 'HP:0002861', (66, 75))	('tumours', 'Disease', 'MESH:D009369', (125, 132))
78239	28637487	In both cases, these gene lesions result in constitutive activation of the MAPK pathway and are believed to be early somatic events associated with melanoma initiation.	('melanoma initiation', 'Disease', 'MESH:D008545', (148, 167))	('melanoma', 'Phenotype', 'HP:0002861', (148, 156))	('activation', 'PosReg', (57, 67))	('melanoma initiation', 'Disease', (148, 167))	('MAPK pathway', 'Pathway', (75, 87))	('lesions', 'Var', (26, 33))
78240	28637487	The high frequency of BRAF and NRAS mutations in melanomas has recently been confirmed by high-throughput next-generation sequencing (NGS) analysis which also identified additional driver mutations, including a recurrent RAC mutation, which is the third most frequent activating mutation in sun-exposed melanomas after BRAF and NRAS mutations.	('melanoma', 'Phenotype', 'HP:0002861', (303, 311))	('melanomas', 'Phenotype', 'HP:0002861', (49, 58))	('melanomas', 'Disease', 'MESH:D008545', (49, 58))	('RAC', 'Gene', (221, 224))	('NRAS', 'Gene', '4893', (31, 35))	('melanoma', 'Phenotype', 'HP:0002861', (49, 57))	('NRAS', 'Gene', (328, 332))	('mutations', 'Var', (36, 45))	('melanomas', 'Disease', (303, 312))	('melanomas', 'Disease', (49, 58))	('melanomas', 'Phenotype', 'HP:0002861', (303, 312))	('RAC', 'Gene', '5879', (221, 224))	('NRAS', 'Gene', '4893', (328, 332))	('NRAS', 'Gene', (31, 35))	('melanomas', 'Disease', 'MESH:D008545', (303, 312))
78241	28637487	Inactivating NF1 mutations have been detected in approximately 13% of melanomas, alongside mutations in other tumour suppressor genes, including TP53, ARID2, PTEN, CDKN2A, MAP2K1 and RB1.	('RB1', 'Gene', '5925', (183, 186))	('detected', 'Reg', (37, 45))	('CDKN2A', 'Gene', '1029', (164, 170))	('PTEN', 'Gene', '5728', (158, 162))	('mutations', 'Var', (17, 26))	('melanomas', 'Phenotype', 'HP:0002861', (70, 79))	('NF1', 'Gene', (13, 16))	('Inactivating', 'Var', (0, 12))	('MAP2K1', 'Gene', '5604', (172, 178))	('melanoma', 'Phenotype', 'HP:0002861', (70, 78))	('ARID2', 'Gene', '196528', (151, 156))	('MAP2K1', 'Gene', (172, 178))	('ARID2', 'Gene', (151, 156))	('RB1', 'Gene', (183, 186))	('melanomas', 'Disease', 'MESH:D008545', (70, 79))	('tumour', 'Phenotype', 'HP:0002664', (110, 116))	('CDKN2A', 'Gene', (164, 170))	('melanomas', 'Disease', (70, 79))	('PTEN', 'Gene', (158, 162))	('tumour', 'Disease', 'MESH:D009369', (110, 116))	('tumour', 'Disease', (110, 116))
78242	28637487	The impact on NRAS is however non-uniform, with some NF1 mutant melanomas exhibiting full NRAS activation (i.e.	('NRAS', 'Gene', '4893', (14, 18))	('NRAS', 'Gene', (90, 94))	('melanomas', 'Disease', (64, 73))	('NF1', 'Gene', (53, 56))	('melanoma', 'Phenotype', 'HP:0002861', (64, 72))	('NRAS', 'Gene', '4893', (90, 94))	('melanomas', 'Phenotype', 'HP:0002861', (64, 73))	('mutant', 'Var', (57, 63))	('melanomas', 'Disease', 'MESH:D008545', (64, 73))	('NRAS', 'Gene', (14, 18))
78243	28637487	the same activation level as oncogenic NRAS mutations), whereas others exhibit only partial activation.	('mutations', 'Var', (44, 53))	('NRAS', 'Gene', '4893', (39, 43))	('NRAS', 'Gene', (39, 43))
78244	28637487	In a mouse melanoma model, NF1 mutations cooperate with BRAF mutations in the pathogenesis of melanoma by preventing oncogene-induced senescence, an indication that NF1 plays a key role in early melanoma development.	('oncogene-induced senescence', 'MPA', (117, 144))	('mutations', 'Var', (31, 40))	('melanoma', 'Disease', (195, 203))	('melanoma', 'Disease', 'MESH:D008545', (11, 19))	('BRAF', 'Gene', (56, 60))	('melanoma', 'Disease', 'MESH:D008545', (94, 102))	('melanoma', 'Phenotype', 'HP:0002861', (94, 102))	('melanoma', 'Disease', (94, 102))	('melanoma', 'Phenotype', 'HP:0002861', (11, 19))	('mutations', 'Var', (61, 70))	('melanoma', 'Phenotype', 'HP:0002861', (195, 203))	('NF1', 'Gene', (27, 30))	('mouse', 'Species', '10090', (5, 10))	('preventing', 'NegReg', (106, 116))	('melanoma', 'Disease', 'MESH:D008545', (195, 203))	('melanoma', 'Disease', (11, 19))
78246	28637487	Furthermore, they observed that resistance to the BRAF inhibitor PLX4720 was attenuated by reconstitution of NF1 in these cells.	('NF1', 'Gene', (109, 112))	('resistance', 'MPA', (32, 42))	('reconstitution', 'Var', (91, 105))	('attenuated', 'NegReg', (77, 87))	('PLX4720', 'Chemical', 'MESH:C528407', (65, 72))
78247	28637487	An RNAi screen, targeting more than 16,500 genes in a BRAF inhibitor-sensitive melanoma cell line, identified NF1 as the highest ranking protein affected by BRAF inhibition, and that, NF1 knockdown abrogated the growth inhibitory effects of BRAF inhibition.	('NF1', 'Gene', (110, 113))	('NF1', 'Gene', (184, 187))	('melanoma', 'Disease', 'MESH:D008545', (79, 87))	('abrogated', 'NegReg', (198, 207))	('knockdown', 'Var', (188, 197))	('growth inhibitory effects', 'CPA', (212, 237))	('melanoma', 'Phenotype', 'HP:0002861', (79, 87))	('melanoma', 'Disease', (79, 87))	('affected', 'Reg', (145, 153))
78248	28637487	Indeed, it was found that NF1 suppression led to a 31-fold increase in resistance to PLX4720, as well as a partial (7-fold) resistance to MEK inhibition, demonstrating that human melanoma samples with innate resistance to BRAF inhibition and sensitivity to a MEK inhibitor harboured NF1 mutations.	('melanoma', 'Phenotype', 'HP:0002861', (179, 187))	('resistance to PLX4720', 'MPA', (71, 92))	('NF1', 'Gene', (26, 29))	('NF1', 'Gene', (283, 286))	('mutations', 'Var', (287, 296))	('PLX4720', 'Chemical', 'MESH:C528407', (85, 92))	('human', 'Species', '9606', (173, 178))	('melanoma', 'Disease', 'MESH:D008545', (179, 187))	('suppression', 'NegReg', (30, 41))	('melanoma', 'Disease', (179, 187))	('increase', 'PosReg', (59, 67))
78249	28637487	Importantly, NF1 mutations have been found in melanomas that lack both BRAF and NRAS mutations, with 25-30% of such melanomas found to harbour deleterious NF1 mutations, thus implying that NF1 inactivation has conferred aberrant MAPK pathway activation in these tumours.	('melanomas', 'Disease', (116, 125))	('activation', 'PosReg', (242, 252))	('melanomas', 'Phenotype', 'HP:0002861', (46, 55))	('NRAS', 'Gene', '4893', (80, 84))	('mutations', 'Var', (17, 26))	('melanoma', 'Phenotype', 'HP:0002861', (46, 54))	('mutations', 'Var', (159, 168))	('NF1', 'Gene', (13, 16))	('BRAF', 'Gene', (71, 75))	('melanomas', 'Phenotype', 'HP:0002861', (116, 125))	('inactivation', 'Var', (193, 205))	('NF1', 'Gene', (155, 158))	('NRAS', 'Gene', (80, 84))	('tumours', 'Disease', (262, 269))	('melanomas', 'Disease', 'MESH:D008545', (46, 55))	('MAPK pathway', 'Pathway', (229, 241))	('melanoma', 'Phenotype', 'HP:0002861', (116, 124))	('melanomas', 'Disease', (46, 55))	('tumours', 'Phenotype', 'HP:0002664', (262, 269))	('tumours', 'Disease', 'MESH:D009369', (262, 269))	('tumour', 'Phenotype', 'HP:0002664', (262, 268))	('melanomas', 'Disease', 'MESH:D008545', (116, 125))
78250	28637487	BRAF/NRAS wild-type and NF1 mutant melanomas are strongly associated with UV damage, as evidenced clinically by the higher degree of solar elastosis and, at a molecular level, by a high proportion of C > T transitions at pyrimidine dimers and more frequent tandem CC>TT transitions.	('melanomas', 'Disease', 'MESH:D008545', (35, 44))	('melanomas', 'Phenotype', 'HP:0002861', (35, 44))	('mutant', 'Var', (28, 34))	('associated', 'Reg', (58, 68))	('NRAS', 'Gene', (5, 9))	('tandem', 'MPA', (257, 263))	('C > T transitions', 'Var', (200, 217))	('UV damage', 'Disease', 'MESH:C563466', (74, 83))	('NRAS', 'Gene', '4893', (5, 9))	('melanomas', 'Disease', (35, 44))	('elastosis', 'Disease', 'MESH:D005148', (139, 148))	('UV damage', 'Disease', (74, 83))	('solar', 'MPA', (133, 138))	('elastosis', 'Disease', (139, 148))	('NF1', 'Gene', (24, 27))	('melanoma', 'Phenotype', 'HP:0002861', (35, 43))	('pyrimidine', 'Chemical', 'MESH:C030986', (221, 231))
78253	28637487	Notably, almost half (26/56) of BRAF and NRAS wild-type melanomas had an NF1 mutation, most identified by loss of heterozygosity (LOH).	('NRAS', 'Gene', '4893', (41, 45))	('melanoma', 'Phenotype', 'HP:0002861', (56, 64))	('mutation', 'Var', (77, 85))	('NRAS', 'Gene', (41, 45))	('melanomas', 'Disease', (56, 65))	('NF1', 'Gene', (73, 76))	('melanomas', 'Disease', 'MESH:D008545', (56, 65))	('melanomas', 'Phenotype', 'HP:0002861', (56, 65))
78254	28637487	Furthermore, NF1 mutation-containing melanomas also harboured significantly more somatic mutations across all loci and occurred in significantly older patients, although they were associated with similar overall patient survival rates as compared to BRAF or RAS mutant or BRAF-RAS-NF1 wild-type melanoma.	('melanomas', 'Disease', (37, 46))	('RAS', 'Chemical', 'MESH:D011883', (277, 280))	('melanomas', 'Phenotype', 'HP:0002861', (37, 46))	('patient', 'Species', '9606', (212, 219))	('patient', 'Species', '9606', (151, 158))	('NF1', 'Gene', (13, 16))	('mutation-containing', 'Var', (17, 36))	('melanoma', 'Disease', (37, 45))	('patients', 'Species', '9606', (151, 159))	('melanomas', 'Disease', 'MESH:D008545', (37, 46))	('melanoma', 'Disease', (295, 303))	('melanoma', 'Disease', 'MESH:D008545', (37, 45))	('RAS', 'Chemical', 'MESH:D011883', (258, 261))	('melanoma', 'Phenotype', 'HP:0002861', (295, 303))	('melanoma', 'Disease', 'MESH:D008545', (295, 303))	('more', 'PosReg', (76, 80))	('melanoma', 'Phenotype', 'HP:0002861', (37, 45))	('somatic', 'CPA', (81, 88))
78255	28637487	In addition, all 26 NF1 mutant BRAF-RAS wild-type melanomas carried mutations in other known RASopathy genes, including RASA2, PTPN11, SOS1, RAF1 and SPRED1.	('melanomas', 'Disease', 'MESH:D008545', (50, 59))	('PTPN11', 'Gene', (127, 133))	('mutations', 'Var', (68, 77))	('melanomas', 'Disease', (50, 59))	('RAF1', 'Gene', (141, 145))	('mutant', 'Var', (24, 30))	('PTPN11', 'Gene', '5781', (127, 133))	('RAS', 'Chemical', 'MESH:D011883', (120, 123))	('RASopathy', 'Disease', 'None', (93, 102))	('SOS1', 'Gene', '6654', (135, 139))	('RASA2', 'Gene', (120, 125))	('SPRED1', 'Gene', '161742', (150, 156))	('RASopathy', 'Disease', (93, 102))	('melanomas', 'Phenotype', 'HP:0002861', (50, 59))	('RAS', 'Chemical', 'MESH:D011883', (93, 96))	('NF1', 'Gene', (20, 23))	('RAS', 'Chemical', 'MESH:D011883', (36, 39))	('SPRED1', 'Gene', (150, 156))	('SOS1', 'Gene', (135, 139))	('RASA2', 'Gene', '5922', (120, 125))	('melanoma', 'Phenotype', 'HP:0002861', (50, 58))	('carried', 'Reg', (60, 67))	('RAF1', 'Gene', '5894', (141, 145))
78256	28637487	The highest frequency of somatic NF1 mutations were found in desmoplastic melanomas (14/15).	('desmoplastic melanomas', 'Disease', 'MESH:D008545', (61, 83))	('NF1', 'Gene', (33, 36))	('melanomas', 'Phenotype', 'HP:0002861', (74, 83))	('melanoma', 'Phenotype', 'HP:0002861', (74, 82))	('mutations', 'Var', (37, 46))	('desmoplastic melanomas', 'Disease', (61, 83))
78258	28637487	The high frequency of NF1 mutations in desmoplastic melanomas appears to indicate an important role for neurofibromin in the specific biology of this type of melanoma.	('NF1', 'Gene', (22, 25))	('melanoma', 'Phenotype', 'HP:0002861', (52, 60))	('melanoma', 'Disease', (52, 60))	('melanoma', 'Disease', 'MESH:D008545', (52, 60))	('melanomas', 'Phenotype', 'HP:0002861', (52, 61))	('mutations', 'Var', (26, 35))	('desmoplastic melanomas', 'Disease', (39, 61))	('melanoma', 'Disease', 'MESH:D008545', (158, 166))	('melanoma', 'Phenotype', 'HP:0002861', (158, 166))	('melanoma', 'Disease', (158, 166))	('desmoplastic melanomas', 'Disease', 'MESH:D008545', (39, 61))
78260	28637487	mutations in CBL, ERBB2, MAP2K1, MAP3K1, BRAF, EGFR, PTPN11, MET, RAC1, SOS2, NRAS and PIK3C, which were found in 15/20 (75%), with NF1 mutations being found in 9/20 (45%).	('MAP2K1', 'Gene', (25, 31))	('MAP3K1', 'Gene', (33, 39))	('MAP3K1', 'Gene', '4214', (33, 39))	('ERBB2', 'Gene', '2064', (18, 23))	('mutations', 'Var', (0, 9))	('NRAS', 'Gene', '4893', (78, 82))	('MET', 'Gene', '79811', (61, 64))	('PTPN11', 'Gene', (53, 59))	('SOS2', 'Gene', (72, 76))	('RAC1', 'Gene', (66, 70))	('SOS2', 'Gene', '6655', (72, 76))	('PTPN11', 'Gene', '5781', (53, 59))	('RAC1', 'Gene', '5879', (66, 70))	('CBL', 'Gene', (13, 16))	('NRAS', 'Gene', (78, 82))	('EGFR', 'Gene', (47, 51))	('MET', 'Gene', (61, 64))	('CBL', 'Gene', '867', (13, 16))	('BRAF', 'Gene', (41, 45))	('ERBB2', 'Gene', (18, 23))	('MAP2K1', 'Gene', '5604', (25, 31))
78262	28637487	iris, ciliary body and choroid) is rarer than cutaneous melanoma but is nevertheless the most common primary intraocular malignancy in adults, with inactivating mutations found in approximately 60% (23/38) of uveal melanomas.	('primary intraocular malignancy', 'Disease', 'MESH:D009798', (101, 131))	('melanoma', 'Phenotype', 'HP:0002861', (215, 223))	('melanoma', 'Phenotype', 'HP:0002861', (56, 64))	('uveal melanomas', 'Disease', (209, 224))	('uveal melanomas', 'Phenotype', 'HP:0007716', (209, 224))	('melanomas', 'Phenotype', 'HP:0002861', (215, 224))	('inactivating mutations', 'Var', (148, 170))	('primary intraocular malignancy', 'Disease', (101, 131))	('uveal melanomas', 'Disease', 'MESH:C536494', (209, 224))	('cutaneous melanoma', 'Disease', (46, 64))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (46, 64))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (46, 64))
78264	28637487	In a recent study of a cohort of 75 tumours from patients with a mucosal melanoma, NF1 and RAS mutations were identified in 18.3 and 16.9% samples, respectively, whereas 8.4 and 7% of tumour samples harboured BRAF and KIT mutations.	('tumours', 'Phenotype', 'HP:0002664', (36, 43))	('tumours', 'Disease', 'MESH:D009369', (36, 43))	('mucosal melanoma', 'Disease', 'MESH:D008545', (65, 81))	('tumour', 'Phenotype', 'HP:0002664', (36, 42))	('tumour', 'Disease', 'MESH:D009369', (36, 42))	('tumour', 'Disease', (36, 42))	('mucosal melanoma', 'Disease', (65, 81))	('tumour', 'Phenotype', 'HP:0002664', (184, 190))	('RAS', 'Gene', (91, 94))	('mutations', 'Var', (95, 104))	('KIT', 'Gene', (218, 221))	('tumour', 'Disease', 'MESH:D009369', (184, 190))	('tumour', 'Disease', (184, 190))	('identified', 'Reg', (110, 120))	('patients', 'Species', '9606', (49, 57))	('NF1', 'Gene', (83, 86))	('RAS', 'Chemical', 'MESH:D011883', (91, 94))	('KIT', 'Gene', '3815', (218, 221))	('tumours', 'Disease', (36, 43))	('BRAF', 'Gene', (209, 213))	('melanoma', 'Phenotype', 'HP:0002861', (73, 81))
78269	28637487	Approximately 40% of NSCLC are ADC, and several studies have reported somatic NF1 mutations in some 7-11% of ADC.	('NSCLC', 'Disease', (21, 26))	('ADC', 'Disease', (31, 34))	('NSCLC', 'Disease', 'MESH:D002289', (21, 26))	('NF1', 'Gene', (78, 81))	('mutations', 'Var', (82, 91))
78271	28637487	A number of potential novel therapeutic targets have been identified, including the activating mutations in KRAS, BRAF, ERBB2 and PIK3CA; the translocations in RET and ROS1; and the loss of function or deletions of TP53, NF1, CDKN2A and KEAP1.	('KRAS', 'Gene', (108, 112))	('BRAF', 'Gene', (114, 118))	('ERBB2', 'Gene', (120, 125))	('ROS1', 'Gene', (168, 172))	('CDKN2A', 'Gene', (226, 232))	('RET', 'Gene', '5979', (160, 163))	('PIK3CA', 'Gene', (130, 136))	('NF1', 'Gene', (221, 224))	('ERBB2', 'Gene', '2064', (120, 125))	('deletions', 'Var', (202, 211))	('mutations', 'Var', (95, 104))	('CDKN2A', 'Gene', '1029', (226, 232))	('RET', 'Gene', (160, 163))	('KEAP1', 'Gene', '9817', (237, 242))	('loss of function', 'NegReg', (182, 198))	('translocations', 'Var', (142, 156))	('KEAP1', 'Gene', (237, 242))	('ROS1', 'Gene', '6098', (168, 172))	('TP53', 'Gene', (215, 219))	('PIK3CA', 'Gene', '5290', (130, 136))	('KRAS', 'Gene', '3845', (108, 112))
78272	28637487	In addition to NF1 being recurrently mutated in a subset of sporadic lung ADC patients, the MAPK pathway also appears to be an important regulatory pathway involved in tumorigenesis.	('NF1', 'Gene', (15, 18))	('lung ADC', 'Disease', (69, 77))	('patients', 'Species', '9606', (78, 86))	('MAPK pathway', 'Pathway', (92, 104))	('involved', 'Reg', (156, 164))	('mutated', 'Var', (37, 44))
78273	28637487	In three quarters of the samples, the group identified mutations in NF1 and other genes that activate the RTK/RAS/RAF cell signalling pathway.	('mutations', 'Var', (55, 64))	('RAF', 'Gene', '22882', (114, 117))	('RAF', 'Gene', (114, 117))	('NF1', 'Gene', (68, 71))	('RAS', 'Chemical', 'MESH:D011883', (110, 113))	('activate', 'PosReg', (93, 101))
78274	28637487	This study not only identified loss-of-function NF1 defects but also demonstrated that NF1 mutations (as well as KEAP1 and TP53 mutations) are far more frequent in the BRAF-RAS oncogene-negative subset of lung ADC.	('KEAP1', 'Gene', (113, 118))	('defects', 'Var', (52, 59))	('loss-of-function', 'NegReg', (31, 47))	('mutations', 'Var', (91, 100))	('RAS', 'Chemical', 'MESH:D011883', (173, 176))	('lung ADC', 'Disease', (205, 213))	('KEAP1', 'Gene', '9817', (113, 118))	('NF1', 'Gene', (48, 51))	('NF1', 'Gene', (87, 90))
78275	28637487	Additionally, TCGA and other groups have identified genes such as TP53, KRAS, STK11 (LKB1), EGFR and NF1 to be significantly mutated in ADC.	('NF1', 'Gene', (101, 104))	('LKB1', 'Gene', '6794', (85, 89))	('KRAS', 'Gene', (72, 76))	('TP53', 'Gene', (66, 70))	('mutated', 'Var', (125, 132))	('ADC', 'Disease', (136, 139))	('STK11', 'Gene', '6794', (78, 83))	('KRAS', 'Gene', '3845', (72, 76))	('EGFR', 'Gene', (92, 96))	('STK11', 'Gene', (78, 83))	('LKB1', 'Gene', (85, 89))
78276	28637487	By performing a genome-wide siRNA screen of both a human lung cancer cell line and a murine mutant EGFR-driven lung ADC, this revealed reduced NF1 mRNA expression in both, and furthermore, whilst the EGFR inhibitor erlotinib failed to fully inhibit RAS-ERK signalling when neurofibromin levels were reduced, treatment of neurofibromin-deficient lung cancers with MEK inhibitor restored sensitivity to erlotinib.	('neurofibromin-deficient lung cancers', 'Disease', 'MESH:D008175', (321, 357))	('lung cancer', 'Disease', 'MESH:D008175', (345, 356))	('lung cancer', 'Disease', 'MESH:D008175', (57, 68))	('human', 'Species', '9606', (51, 56))	('NF1', 'Gene', (143, 146))	('lung cancer', 'Phenotype', 'HP:0100526', (345, 356))	('cancer', 'Phenotype', 'HP:0002664', (350, 356))	('lung cancers', 'Phenotype', 'HP:0100526', (345, 357))	('lung cancer', 'Phenotype', 'HP:0100526', (57, 68))	('murine', 'Species', '10090', (85, 91))	('cancers', 'Phenotype', 'HP:0002664', (350, 357))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('neurofibromin-deficient lung cancers', 'Disease', (321, 357))	('deficient lung', 'Phenotype', 'HP:0002089', (335, 349))	('reduced', 'NegReg', (135, 142))	('erlotinib', 'Chemical', 'MESH:D000069347', (215, 224))	('mutant', 'Var', (92, 98))	('lung cancer', 'Disease', (57, 68))	('erlotinib', 'Chemical', 'MESH:D000069347', (401, 410))	('sensitivity', 'MPA', (386, 397))	('EGFR-driven', 'Gene', (99, 110))
78277	28637487	In a recent study of 591 NSCLC, 60 had NF1 mutations (10%) whilst 141 (24%) harboured KRAS mutations.	('KRAS', 'Gene', (86, 90))	('NSCLC', 'Disease', (25, 30))	('NF1', 'Gene', (39, 42))	('KRAS', 'Gene', '3845', (86, 90))	('NSCLC', 'Disease', 'MESH:D002289', (25, 30))	('mutations', 'Var', (43, 52))
78278	28637487	Approximately 25% of the NF1 mutations co-occurred with mutations in known oncogenes: BRAF, ERBB2, KRAS, HRAS and NRAS.	('ERBB2', 'Gene', '2064', (92, 97))	('ERBB2', 'Gene', (92, 97))	('NRAS', 'Gene', (114, 118))	('co-occurred', 'Reg', (39, 50))	('mutations', 'Var', (29, 38))	('HRAS', 'Gene', '3265', (105, 109))	('NRAS', 'Gene', '4893', (114, 118))	('KRAS', 'Gene', (99, 103))	('NF1', 'Gene', (25, 28))	('BRAF', 'Disease', (86, 90))	('HRAS', 'Gene', (105, 109))	('KRAS', 'Gene', '3845', (99, 103))
78279	28637487	Therapeutic strategies targeting KRAS activation, including the use of inhibitors of MAP kinase signalling, may warrant investigation in NF1 mutant tumours.	('tumours', 'Disease', 'MESH:D009369', (148, 155))	('tumours', 'Disease', (148, 155))	('mutant', 'Var', (141, 147))	('KRAS', 'Gene', (33, 37))	('NF1', 'Gene', (137, 140))	('KRAS', 'Gene', '3845', (33, 37))	('tumour', 'Phenotype', 'HP:0002664', (148, 154))	('tumours', 'Phenotype', 'HP:0002664', (148, 155))
78281	28637487	According to the TCGA, somatic NF1 changes are present in approximately 12% of squamous cell lung cancers (SqCC), of which four distinct subtypes have been identified: classical, primitive, basal and secretory expression.	('squamous cell lung cancers', 'Disease', (79, 105))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('cancers', 'Phenotype', 'HP:0002664', (98, 105))	('squamous cell lung cancers', 'Disease', 'MESH:D002294', (79, 105))	('NF1', 'Gene', (31, 34))	('lung cancer', 'Phenotype', 'HP:0100526', (93, 104))	('changes', 'Var', (35, 42))	('lung cancers', 'Phenotype', 'HP:0100526', (93, 105))
78282	28637487	The basal expression subtype was found to harbour NF1 alterations, suggesting a potential direction for the treatment of such tumours.	('tumour', 'Phenotype', 'HP:0002664', (126, 132))	('NF1', 'Gene', (50, 53))	('tumours', 'Phenotype', 'HP:0002664', (126, 133))	('tumours', 'Disease', 'MESH:D009369', (126, 133))	('alterations', 'Var', (54, 65))	('tumours', 'Disease', (126, 133))
78285	28637487	This confirms the previously reported CD74-NRG1 fusion and also suggests that the NRG1, NF1 and Hippo pathway fusions may play important roles in tumours without known driver mutations and that this prognostic factor may be associated with poor survival.	('tumours', 'Disease', 'MESH:D009369', (146, 153))	('tumours', 'Disease', (146, 153))	('NRG1', 'Gene', (43, 47))	('NF1', 'Gene', (88, 91))	('Hippo pathway', 'Gene', (96, 109))	('NRG1', 'Gene', (82, 86))	('play', 'Reg', (122, 126))	('NRG1', 'Gene', '3084', (43, 47))	('roles', 'Reg', (137, 142))	('NRG1', 'Gene', '3084', (82, 86))	('tumour', 'Phenotype', 'HP:0002664', (146, 152))	('tumours', 'Phenotype', 'HP:0002664', (146, 153))	('fusions', 'Var', (110, 117))
78287	28637487	Interestingly, both lung ADC and SqCC DNA displayed a significantly increased frequency of guanine (cytosine) to thymine (adenine) mutations, a type of mutation associated with exposure to tobacco smoke.	('adenine', 'Chemical', 'MESH:D000225', (122, 129))	('lung ADC', 'Disease', (20, 28))	('thymine', 'Chemical', 'MESH:D013941', (113, 120))	('guanine', 'Var', (91, 98))	('guanine', 'Chemical', 'MESH:D006147', (91, 98))	('cytosine', 'Chemical', 'MESH:D003596', (100, 108))	('tobacco', 'Species', '4097', (189, 196))	('increased', 'PosReg', (68, 77))
78289	28637487	Indeed, the mutational landscape of lung ADC is substantially different from that of SqCC of the lung or SCLC, with frequent receptor tyrosine kinase mutations found in lung ADC, that are rarely encountered in either SqCC or SCLC.	('SCLC', 'Gene', (225, 229))	('SCLC', 'Gene', '7864', (105, 109))	('receptor tyrosine kinase', 'Gene', (125, 149))	('SCLC', 'Gene', (105, 109))	('mutations', 'Var', (150, 159))	('receptor tyrosine kinase', 'Gene', '5979', (125, 149))	('SCLC', 'Gene', '7864', (225, 229))
78290	28637487	Mutations in TP53, KRAS, LKB1, NF1 and RBM10 are enriched in transversion-high tumours, whilst mutations in EGFR, RB1 and PIK3CA and in-frame insertions in the receptor tyrosine kinases EGFR and ERBB2 are enriched in transversion-low tumours.	('TP53', 'Gene', (13, 17))	('LKB1', 'Gene', '6794', (25, 29))	('EGFR', 'Gene', (186, 190))	('KRAS', 'Gene', '3845', (19, 23))	('tumours', 'Phenotype', 'HP:0002664', (234, 241))	('transversion-high tumours', 'Disease', 'MESH:D009369', (61, 86))	('NF1', 'Gene', (31, 34))	('PIK3CA', 'Gene', (122, 128))	('transversion-low tumours', 'Disease', 'MESH:D009800', (217, 241))	('tumour', 'Phenotype', 'HP:0002664', (234, 240))	('KRAS', 'Gene', (19, 23))	('Mutations', 'Var', (0, 9))	('mutations', 'Var', (95, 104))	('receptor tyrosine kinase', 'Gene', '5979', (160, 184))	('transversion-high tumours', 'Disease', (61, 86))	('LKB1', 'Gene', (25, 29))	('RB1', 'Gene', (114, 117))	('ERBB2', 'Gene', (195, 200))	('tumours', 'Phenotype', 'HP:0002664', (79, 86))	('receptor tyrosine kinase', 'Gene', (160, 184))	('RBM10', 'Gene', (39, 44))	('EGFR', 'Gene', (108, 112))	('PIK3CA', 'Gene', '5290', (122, 128))	('transversion-low tumours', 'Disease', (217, 241))	('ERBB2', 'Gene', '2064', (195, 200))	('tumour', 'Phenotype', 'HP:0002664', (79, 85))	('RBM10', 'Gene', '8241', (39, 44))	('RB1', 'Gene', '5925', (114, 117))
78293	28637487	At least 38 genes were significantly mutated in lung ADC and 20 genes in SqCC; however, only six genes, TP53, RB1, ARIDIA, CDKN2A, PIK3CA and NF1, were significantly mutated in both tumour types, and of these, TP53, CDKN2A and PIK3CA mutations had a significantly higher frequency in lung SqCC.	('RB1', 'Gene', (110, 113))	('lung SqCC', 'Disease', (284, 293))	('TP53', 'Gene', (104, 108))	('TP53', 'Gene', (210, 214))	('PIK3CA', 'Gene', '5290', (131, 137))	('tumour', 'Phenotype', 'HP:0002664', (182, 188))	('tumour', 'Disease', 'MESH:D009369', (182, 188))	('PIK3CA', 'Gene', (227, 233))	('RB1', 'Gene', '5925', (110, 113))	('CDKN2A', 'Gene', (123, 129))	('CDKN2A', 'Gene', (216, 222))	('PIK3CA', 'Gene', (131, 137))	('tumour', 'Disease', (182, 188))	('CDKN2A', 'Gene', '1029', (123, 129))	('PIK3CA', 'Gene', '5290', (227, 233))	('CDKN2A', 'Gene', '1029', (216, 222))	('mutations', 'Var', (234, 243))
78294	28637487	Recurrent alterations in lung SqCC were more similar to those of other squamous carcinomas than to alterations in lung ADCs, whilst the significantly mutated genes in lung ADC were most similar to those associated with glioblastoma and colorectal cancer.	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('alterations', 'Var', (10, 21))	('colorectal cancer', 'Disease', (236, 253))	('carcinomas', 'Phenotype', 'HP:0030731', (80, 90))	('squamous carcinomas', 'Disease', (71, 90))	('squamous carcinomas', 'Disease', 'MESH:D002294', (71, 90))	('colorectal cancer', 'Disease', 'MESH:D015179', (236, 253))	('glioblastoma', 'Disease', (219, 231))	('glioblastoma', 'Disease', 'MESH:D005909', (219, 231))	('lung SqCC', 'Disease', (25, 34))	('colorectal cancer', 'Phenotype', 'HP:0003003', (236, 253))	('glioblastoma', 'Phenotype', 'HP:0012174', (219, 231))
78295	28637487	Although there is a paucity of data for small cell lung cancer (SCLC), the frequency of NF1 mutations in SCLC was found to be 2.4 and 6.9% in two independent studies.	('small cell lung cancer', 'Disease', (40, 62))	('NF1', 'Gene', (88, 91))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('mutations', 'Var', (92, 101))	('small cell lung cancer', 'Disease', 'MESH:D055752', (40, 62))	('SCLC', 'Gene', '7864', (105, 109))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (40, 62))	('SCLC', 'Gene', (105, 109))	('SCLC', 'Gene', '7864', (64, 68))	('SCLC', 'Gene', (64, 68))	('lung cancer', 'Phenotype', 'HP:0100526', (51, 62))
78298	28637487	The most common non-actionable genomic alterations were found in TP53 (86% of SCLC cases), RB1 (54%) and MLL2 (17%), with NF1 mutations identified in only 3% of SCLC, consistent with the earlier studies.	('SCLC', 'Gene', '7864', (161, 165))	('RB1', 'Gene', '5925', (91, 94))	('TP53', 'Gene', (65, 69))	('MLL2', 'Gene', (105, 109))	('RB1', 'Gene', (91, 94))	('SCLC', 'Gene', '7864', (78, 82))	('NF1', 'Gene', (122, 125))	('SCLC', 'Gene', (78, 82))	('mutations', 'Var', (126, 135))	('MLL2', 'Gene', '8085', (105, 109))	('SCLC', 'Gene', (161, 165))
78300	28637487	Constitutional NF1 mutations are known to predispose individuals to myeloid malignancies such as chronic myelomonocytic leukaemia (CMML), JMML and acute myeloid leukaemia (AML).	('CMML', 'Disease', 'MESH:D054429', (131, 135))	('NF1', 'Gene', (15, 18))	('JMML', 'Disease', 'MESH:D054429', (138, 142))	('chronic myelomonocytic leukaemia', 'Disease', 'MESH:D015477', (97, 129))	('myeloid leukaemia', 'Phenotype', 'HP:0012324', (153, 170))	('acute myeloid leukaemia', 'Disease', (147, 170))	('mutations', 'Var', (19, 28))	('chronic myelomonocytic leukaemia', 'Disease', (97, 129))	('JMML', 'Disease', (138, 142))	('AML', 'Disease', 'MESH:D015470', (172, 175))	('myeloid malignancies', 'Disease', 'MESH:D009369', (68, 88))	('CMML', 'Disease', (131, 135))	('acute myeloid leukaemia', 'Disease', 'MESH:D015470', (147, 170))	('AML', 'Disease', (172, 175))	('predispose', 'Reg', (42, 52))	('myeloid malignancies', 'Disease', (68, 88))
78301	28637487	Somatic 17q11 deletions encompassing NF1 have been described in many adult myeloid malignancies.	('described', 'Reg', (51, 60))	('myeloid malignancies', 'Disease', 'MESH:D009369', (75, 95))	('NF1', 'Gene', (37, 40))	('deletions', 'Var', (14, 23))	('myeloid malignancies', 'Disease', (75, 95))
78302	28637487	More generally, the RAS signalling pathway has been found to be fundamental in the development of myeloid malignancies, with somatic activating mutations in NRAS and KRAS genes estimated to be present in 20 to 40% of diagnosed cases of AML, CMML and JMML.	('RAS', 'Chemical', 'MESH:D011883', (158, 161))	('RAS', 'Chemical', 'MESH:D011883', (167, 170))	('JMML', 'Disease', (250, 254))	('RAS', 'Chemical', 'MESH:D011883', (20, 23))	('KRAS', 'Gene', (166, 170))	('CMML', 'Disease', (241, 245))	('AML', 'Disease', (236, 239))	('NRAS', 'Gene', (157, 161))	('myeloid malignancies', 'Disease', 'MESH:D009369', (98, 118))	('JMML', 'Disease', 'MESH:D054429', (250, 254))	('KRAS', 'Gene', '3845', (166, 170))	('CMML', 'Disease', 'MESH:D054429', (241, 245))	('mutations', 'Var', (144, 153))	('myeloid malignancies', 'Disease', (98, 118))	('AML', 'Disease', 'MESH:D015470', (236, 239))	('NRAS', 'Gene', '4893', (157, 161))
78304	28637487	Whilst somatic KRAS and NRAS mutations are frequently found in AML, mutations in other RAS signalling pathway genes, including NF1, occur at lower frequencies, although the reported frequency for NF1 somatic mutations ranges quite widely from 3.5 to 23.6%.	('NRAS', 'Gene', '4893', (24, 28))	('AML', 'Disease', (63, 66))	('RAS', 'Chemical', 'MESH:D011883', (25, 28))	('KRAS', 'Gene', (15, 19))	('mutations', 'Var', (29, 38))	('NF1', 'Gene', (127, 130))	('KRAS', 'Gene', '3845', (15, 19))	('RAS', 'Chemical', 'MESH:D011883', (87, 90))	('AML', 'Disease', 'MESH:D015470', (63, 66))	('NRAS', 'Gene', (24, 28))	('RAS', 'Chemical', 'MESH:D011883', (16, 19))
78305	28637487	Parkin and colleagues identified NF1 mutations in 7% of cases with AML, with a further 12% displaying copy number alterations (CNAs) involving NF1, mainly heterozygous deletions.	('AML', 'Disease', 'MESH:D015470', (67, 70))	('copy number alterations', 'Reg', (102, 125))	('NF1', 'Gene', (33, 36))	('AML', 'Disease', (67, 70))	('mutations', 'Var', (37, 46))	('NF1', 'Gene', (143, 146))
78307	28637487	In another study of AML with CBHB-MYHII rearrangements, 16% of the samples harboured NF1 deletions.	('deletions', 'Var', (89, 98))	('NF1', 'Gene', (85, 88))	('CBHB', 'Chemical', '-', (29, 33))	('AML', 'Disease', 'MESH:D015470', (20, 23))	('AML', 'Disease', (20, 23))
78308	28637487	However, high-resolution studies have failed to provide any evidence for frequent NF1 alterations in de novo AML, although they suggested that NF1 mutations may contribute to tumour progression.	('mutations', 'Var', (147, 156))	('tumour', 'Disease', 'MESH:D009369', (175, 181))	('AML', 'Disease', 'MESH:D015470', (109, 112))	('tumour', 'Disease', (175, 181))	('contribute', 'Reg', (161, 171))	('AML', 'Disease', (109, 112))	('NF1', 'Gene', (143, 146))	('tumour', 'Phenotype', 'HP:0002664', (175, 181))	('alterations', 'Var', (86, 97))
78309	28637487	In this study, the authors screened a total of 488 previously untreated de novo AML patients for the NF1 deletion using either array comparative genomic hybridization (aCGH) or real-time quantitative PCR/fluorescence in situ hybridization approaches.	('deletion', 'Var', (105, 113))	('NF1', 'Gene', (101, 104))	('patients', 'Species', '9606', (84, 92))	('AML', 'Disease', (80, 83))	('AML', 'Disease', 'MESH:D015470', (80, 83))
78310	28637487	Using aCGH, a small ~0.3 Mbp minimally deleted region involving NF1 was defined; the overall frequency of NF1 deletion was 3.5% (17/485).	('NF1', 'Gene', (106, 109))	('Mbp', 'Gene', (25, 28))	('deletion', 'Var', (110, 118))	('Mbp', 'Gene', '4155', (25, 28))
78311	28637487	Furthermore, NF1 deletion was significantly associated with abnormal cytogenetics and a monosomal karyotype, whilst only one of five NF1-deleted patients acquired a coding mutation in the remaining allele.	('associated', 'Reg', (44, 54))	('deletion', 'Var', (17, 25))	('patients', 'Species', '9606', (145, 153))	('NF1', 'Gene', (13, 16))
78312	28637487	This study indicates that NF1 microlesions are infrequent in de novo AML and may be secondary events in leukemic progression.	('AML', 'Disease', (69, 72))	('NF1', 'Gene', (26, 29))	('leukemic', 'Disease', (104, 112))	('AML', 'Disease', 'MESH:D015470', (69, 72))	('microlesions', 'Var', (30, 42))
78313	28637487	The frequency of NF1 changes in myelodysplastic syndrome has been found to vary between 0 and 9%.	('myelodysplastic syndrome', 'Phenotype', 'HP:0002863', (32, 56))	('NF1', 'Gene', (17, 20))	('myelodysplastic syndrome', 'Disease', (32, 56))	('changes', 'Var', (21, 28))	('myelodysplastic syndrome', 'Disease', 'MESH:D009190', (32, 56))
78317	28637487	The type 1 NF1 microdeletion (1.4 Mb) was reported in 2.9% (3/103) of T-ALL patients.	('patients', 'Species', '9606', (76, 84))	('microdeletion', 'Var', (15, 28))	('NF1', 'Gene', (11, 14))
78319	28637487	In 1997, Side and colleagues reported constitutional NF1 mutations in 15% of JMML patients.	('JMML', 'Disease', (77, 81))	('patients', 'Species', '9606', (82, 90))	('NF1', 'Gene', (53, 56))	('mutations', 'Var', (57, 66))	('JMML', 'Disease', 'MESH:D054429', (77, 81))
78321	28637487	JMML was once considered a unique example of RAS-driven oncogenesis because it was thought to be initiated by mutually exclusive mutations in the RAS genes (NRAS or KRAS) or in several RAS pathway regulators (PTPN11, NF1 or CBL).	('KRAS', 'Gene', '3845', (165, 169))	('RAS-', 'Chemical', 'MESH:D011883', (45, 49))	('RAS', 'Chemical', 'MESH:D011883', (158, 161))	('PTPN11', 'Gene', (209, 215))	('mutations', 'Var', (129, 138))	('RAS', 'Chemical', 'MESH:D011883', (185, 188))	('CBL', 'Gene', (224, 227))	('CBL', 'Gene', '867', (224, 227))	('RAS', 'Chemical', 'MESH:D011883', (45, 48))	('JMML', 'Disease', (0, 4))	('NRAS', 'Gene', (157, 161))	('PTPN11', 'Gene', '5781', (209, 215))	('initiated by', 'Reg', (97, 109))	('RAS', 'Chemical', 'MESH:D011883', (146, 149))	('RAS', 'Chemical', 'MESH:D011883', (166, 169))	('JMML', 'Disease', 'MESH:D054429', (0, 4))	('KRAS', 'Gene', (165, 169))	('NRAS', 'Gene', '4893', (157, 161))
78323	28637487	In total, 85 somatically acquired genetic alterations were found in 83% (25/30) of patients in this sub-cohort.	('genetic alterations', 'Var', (34, 53))	('patients', 'Species', '9606', (83, 91))	('found', 'Reg', (59, 64))
78324	28637487	Genes containing somatic variants detected by whole-exome sequencing, or previously reported to be mutated in JMML, were then sequenced in the full cohort of 118 JMML cases.	('JMML', 'Disease', 'MESH:D054429', (162, 166))	('variants', 'Var', (25, 33))	('JMML', 'Disease', (110, 114))	('JMML', 'Disease', (162, 166))	('JMML', 'Disease', 'MESH:D054429', (110, 114))
78325	28637487	A total of 122 secondary clonal abnormalities, in addition to initiating RAS pathway mutations, were identified in 49% (58/118) of patients.	('patients', 'Species', '9606', (131, 139))	('mutations', 'Var', (85, 94))	('RAS pathway', 'Pathway', (73, 84))	('RAS', 'Chemical', 'MESH:D011883', (73, 76))
78328	28637487	Nf1/Kras double-mutant mice have been shown to develop myeloid malignancies with reduced latency and increased severity in comparison to mice with only one of the two defects because copy number variations (CNVs) in Nf1/Kras mutant mice frequently resulted in haploinsufficiency for PRC2 core subunits (SUZ12 or EZH2) or PRC2-associated factors necessary for optimal PRC2 activity (AEBP2, CDYL or JARID2).	('EZH2', 'Gene', (312, 316))	('Nf1', 'Gene', (0, 3))	('myeloid malignancies', 'Disease', (55, 75))	('CDYL', 'Gene', (389, 393))	('Kras', 'Gene', '16653', (4, 8))	('Nf1', 'Gene', '18015', (216, 219))	('mutant', 'Var', (225, 231))	('JARID2', 'Gene', (397, 403))	('CDYL', 'Gene', '12593', (389, 393))	('Nf1', 'Gene', '18015', (0, 3))	('JARID2', 'Gene', '16468', (397, 403))	('develop', 'PosReg', (47, 54))	('mice', 'Species', '10090', (137, 141))	('AEBP2', 'Gene', '11569', (382, 387))	('Kras', 'Gene', (220, 224))	('resulted in', 'Reg', (248, 259))	('EZH2', 'Gene', '14056', (312, 316))	('mice', 'Species', '10090', (232, 236))	('AEBP2', 'Gene', (382, 387))	('copy number variations', 'Var', (183, 205))	('haploinsufficiency', 'Disease', 'MESH:D058495', (260, 278))	('Nf1', 'Gene', (216, 219))	('Kras', 'Gene', (4, 8))	('Kras', 'Gene', '16653', (220, 224))	('SUZ12', 'Gene', '52615', (303, 308))	('haploinsufficiency', 'Disease', (260, 278))	('SUZ12', 'Gene', (303, 308))	('myeloid malignancies', 'Disease', 'MESH:D009369', (55, 75))	('mice', 'Species', '10090', (23, 27))
78329	28637487	In addition, haploinsufficiency for multiple genes that regulate PRC2 function can cooperate in myeloid transformation, and other mutations in JMML target a small number of pathways specifically, including components of the RAS and PRC2 networks.	('target', 'Reg', (148, 154))	('JMML', 'Disease', (143, 147))	('PRC2', 'Gene', (65, 69))	('haploinsufficiency', 'Disease', 'MESH:D058495', (13, 31))	('myeloid transformation', 'CPA', (96, 118))	('RAS', 'Chemical', 'MESH:D011883', (224, 227))	('cooperate', 'Reg', (83, 92))	('mutations', 'Var', (130, 139))	('haploinsufficiency', 'Disease', (13, 31))	('JMML', 'Disease', 'MESH:D054429', (143, 147))
78331	28637487	Loss of function of PRC2 (due to mutations in EED or SUZ12) is also found in the vast majority of sporadic, NF1-associated, and radiotherapy-associated MPNSTs (where PRC2 loss amplifies Ras-driven transcription).	('amplifies', 'PosReg', (176, 185))	('NF1-associated', 'Disease', (108, 122))	('mutations', 'Var', (33, 42))	('PRC2', 'Gene', (166, 170))	('Loss of function', 'NegReg', (0, 16))	('EED', 'Gene', '8726', (46, 49))	('SUZ12', 'Gene', (53, 58))	('SUZ12', 'Gene', '52615', (53, 58))	('loss', 'NegReg', (171, 175))	('EED', 'Gene', (46, 49))	('PRC2', 'Gene', (20, 24))
78332	28637487	In a recent study focussing on characterization of serial samples from JMML patients at diagnosis and then beyond through relapse and transformation to AML, mutations were found in NF1, NRAS, KRAS, PTPN11 or CBL in 85% of patients, as well as recurrent mutations in other genes involved in signal transduction, splicing, PRC2 and transcription.	('patients', 'Species', '9606', (76, 84))	('CBL', 'Gene', '867', (208, 211))	('JMML', 'Disease', (71, 75))	('NRAS', 'Gene', (186, 190))	('AML', 'Disease', (152, 155))	('patients', 'Species', '9606', (222, 230))	('mutations', 'Var', (253, 262))	('CBL', 'Gene', (208, 211))	('NRAS', 'Gene', '4893', (186, 190))	('mutations', 'Var', (157, 166))	('JMML', 'Disease', 'MESH:D054429', (71, 75))	('PTPN11', 'Gene', '5781', (198, 204))	('KRAS', 'Gene', (192, 196))	('NF1', 'Gene', (181, 184))	('found', 'Reg', (172, 177))	('PTPN11', 'Gene', (198, 204))	('AML', 'Disease', 'MESH:D015470', (152, 155))	('KRAS', 'Gene', '3845', (192, 196))
78335	28637487	NF1 patients have an increased risk of developing breast cancer as compared to the general population.	('NF1', 'Var', (0, 3))	('breast cancer', 'Disease', 'MESH:D001943', (50, 63))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('patients', 'Species', '9606', (4, 12))	('breast cancer', 'Disease', (50, 63))	('breast cancer', 'Phenotype', 'HP:0003002', (50, 63))
78337	28637487	A predisposition to breast cancer in NF1 patients has led researchers to postulate the potential involvement of somatic NF1 mutations in initiating and driving the malignant transformation and progression of sporadic breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('breast cancer', 'Disease', 'MESH:D001943', (217, 230))	('mutations', 'Var', (124, 133))	('breast cancer', 'Disease', 'MESH:D001943', (20, 33))	('sporadic breast cancer', 'Disease', (208, 230))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('breast cancer', 'Disease', (20, 33))	('breast cancer', 'Phenotype', 'HP:0003002', (217, 230))	('breast cancer', 'Phenotype', 'HP:0003002', (20, 33))	('NF1', 'Gene', (120, 123))	('patients', 'Species', '9606', (41, 49))	('sporadic breast cancer', 'Disease', 'MESH:D001943', (208, 230))	('predisposition', 'Reg', (2, 16))	('malignant transformation', 'CPA', (164, 188))
78340	28637487	Further analysis of the NF1 deletion-bearing tumours revealed significantly higher levels of active RAS, indicating that RAS signal transduction pathway dysregulation, through NF1 loss, may be responsible for driving malignancy in these cells.	('RAS signal', 'Pathway', (121, 131))	('NF1', 'Gene', (176, 179))	('levels', 'MPA', (83, 89))	('malignancy', 'Disease', 'MESH:D009369', (217, 227))	('malignancy', 'Disease', (217, 227))	('loss', 'NegReg', (180, 184))	('active RAS', 'MPA', (93, 103))	('RAS', 'Chemical', 'MESH:D011883', (100, 103))	('tumour', 'Phenotype', 'HP:0002664', (45, 51))	('deletion-bearing', 'Var', (28, 44))	('RAS', 'Chemical', 'MESH:D011883', (121, 124))	('tumours', 'Phenotype', 'HP:0002664', (45, 52))	('tumours', 'Disease', 'MESH:D009369', (45, 52))	('higher', 'PosReg', (76, 82))	('NF1', 'Gene', (24, 27))	('tumours', 'Disease', (45, 52))
78343	28637487	Hence, this study suggested that under-expression of NF1 and reduced neurofibromin activity may have a direct influence on malignant transformation and resistance to anti-cancer agents.	('activity', 'MPA', (83, 91))	('NF1', 'Gene', (53, 56))	('neurofibromin', 'Protein', (69, 82))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('cancer', 'Disease', (171, 177))	('malignant transformation', 'CPA', (123, 147))	('under-expression', 'Var', (33, 49))	('influence', 'Reg', (110, 119))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('resistance', 'CPA', (152, 162))	('reduced', 'NegReg', (61, 68))
78344	28637487	This is consistent with other studies and goes some way towards accounting for the presence of the somatic NF1 mutations found in sporadic breast tumours.	('mutations', 'Var', (111, 120))	('sporadic breast tumours', 'Disease', 'MESH:D001943', (130, 153))	('tumour', 'Phenotype', 'HP:0002664', (146, 152))	('tumours', 'Phenotype', 'HP:0002664', (146, 153))	('sporadic breast tumours', 'Disease', (130, 153))	('NF1', 'Gene', (107, 110))
78345	28637487	The mouse model Chaos3 is characterized by the spontaneous development of mammary tumours, due to a mutation in Mcm4 leading to chromosomal instability through disruption of the MCM2-7 complex.	('chromosomal instability', 'MPA', (128, 151))	('mouse', 'Species', '10090', (4, 9))	('MCM2-7', 'Gene', '17216;17215;17217;17218;17219;17220', (178, 184))	('Mcm4', 'Gene', (112, 116))	('tumour', 'Phenotype', 'HP:0002664', (82, 88))	('tumours', 'Phenotype', 'HP:0002664', (82, 89))	('MCM2-7', 'Gene', (178, 184))	('Mcm4', 'Gene', '17217', (112, 116))	('disruption', 'NegReg', (160, 170))	('tumours', 'Disease', 'MESH:D009369', (82, 89))	('mutation', 'Var', (100, 108))	('tumours', 'Disease', (82, 89))	('chromosomal instability', 'Phenotype', 'HP:0040012', (128, 151))	('leading to', 'Reg', (117, 127))
78346	28637487	Somatic NF1 deletions were found in almost all (59/60) of the mammary tumours studied in this mouse model, and upon subsequent examination of TCGA data, it was noted that NF1 is somatically mutated or deleted in 27.7% of human breast cancers.	('deletions', 'Var', (12, 21))	('NF1', 'Gene', (8, 11))	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('breast cancers', 'Phenotype', 'HP:0003002', (227, 241))	('tumour', 'Phenotype', 'HP:0002664', (70, 76))	('breast cancers', 'Disease', 'MESH:D001943', (227, 241))	('breast cancers', 'Disease', (227, 241))	('human', 'Species', '9606', (221, 226))	('mouse', 'Species', '10090', (94, 99))	('breast cancer', 'Phenotype', 'HP:0003002', (227, 240))	('tumours', 'Phenotype', 'HP:0002664', (70, 77))	('tumours', 'Disease', 'MESH:D009369', (70, 77))	('cancers', 'Phenotype', 'HP:0002664', (234, 241))	('found', 'Reg', (27, 32))	('tumours', 'Disease', (70, 77))
78347	28637487	Large-scale NGS to compare primary and recurrent breast cancer has found mutations in recurrent tumours which were not present in matched primary tissue.	('breast cancer', 'Phenotype', 'HP:0003002', (49, 62))	('tumours', 'Phenotype', 'HP:0002664', (96, 103))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('tumour', 'Phenotype', 'HP:0002664', (96, 102))	('breast cancer', 'Disease', 'MESH:D001943', (49, 62))	('breast cancer', 'Disease', (49, 62))	('tumours', 'Disease', 'MESH:D009369', (96, 103))	('tumours', 'Disease', (96, 103))	('mutations', 'Var', (73, 82))
78352	28637487	In contrast, genes generally mutated in breast cancers are subject to a low frequency of somatic mutations, including single nucleotide mutations and indels in driver genes.	('breast cancers', 'Disease', (40, 54))	('breast cancer', 'Phenotype', 'HP:0003002', (40, 53))	('indels', 'Var', (150, 156))	('cancers', 'Phenotype', 'HP:0002664', (47, 54))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('breast cancers', 'Phenotype', 'HP:0003002', (40, 54))	('single nucleotide mutations', 'Var', (118, 145))	('breast cancers', 'Disease', 'MESH:D001943', (40, 54))
78355	28637487	In a recent study based on 2433 molecular profiles of breast cancer, it was noted that high levels of intra-tumour heterogeneity was generally associated with a worse clinical outcome, with one exception: highly aggressive breast tumours with 11q13-14 amplification had low levels of intra-tumour heterogeneity.	('breast cancer', 'Disease', (54, 67))	('associated', 'Reg', (143, 153))	('tumour', 'Phenotype', 'HP:0002664', (230, 236))	('11q13-14 amplification', 'Var', (243, 265))	('intra-tumour', 'Disease', 'MESH:D009369', (284, 296))	('aggressive breast tumours', 'Disease', (212, 237))	('tumours', 'Phenotype', 'HP:0002664', (230, 237))	('tumour', 'Phenotype', 'HP:0002664', (108, 114))	('intra-tumour', 'Disease', (284, 296))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('intra-tumour', 'Disease', 'MESH:D009369', (102, 114))	('aggressive breast tumours', 'Disease', 'MESH:D001943', (212, 237))	('breast cancer', 'Disease', 'MESH:D001943', (54, 67))	('intra-tumour', 'Disease', (102, 114))	('breast cancer', 'Phenotype', 'HP:0003002', (54, 67))	('tumour', 'Phenotype', 'HP:0002664', (290, 296))
78356	28637487	Inactivating NF1 mutations were also found to be associated with breast cancer severity score in oestrogen receptor-negative tumours.	('breast cancer', 'Disease', 'MESH:D001943', (65, 78))	('tumours', 'Disease', (125, 132))	('tumour', 'Phenotype', 'HP:0002664', (125, 131))	('associated', 'Reg', (49, 59))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('NF1', 'Gene', (13, 16))	('breast cancer', 'Disease', (65, 78))	('Inactivating', 'Var', (0, 12))	('breast cancer', 'Phenotype', 'HP:0003002', (65, 78))	('tumours', 'Phenotype', 'HP:0002664', (125, 132))	('mutations', 'Var', (17, 26))	('tumours', 'Disease', 'MESH:D009369', (125, 132))
78357	28637487	As with melanoma and neuroblastoma, inactivation of NF1 in breast cancer is associated with resistance to drug therapy.	('NF1', 'Gene', (52, 55))	('neuroblastoma', 'Disease', (21, 34))	('melanoma', 'Disease', 'MESH:D008545', (8, 16))	('melanoma', 'Phenotype', 'HP:0002861', (8, 16))	('melanoma', 'Disease', (8, 16))	('breast cancer', 'Disease', 'MESH:D001943', (59, 72))	('neuroblastoma', 'Phenotype', 'HP:0003006', (21, 34))	('resistance', 'MPA', (92, 102))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('breast cancer', 'Disease', (59, 72))	('breast cancer', 'Phenotype', 'HP:0003002', (59, 72))	('associated', 'Reg', (76, 86))	('neuroblastoma', 'Disease', 'MESH:D009447', (21, 34))	('inactivation', 'Var', (36, 48))
78359	28637487	Silencing of NF1, amongst several other genes, has been shown to confer a tamoxifen-resistant phenotype, although it was noted that resistance- or sensitivity-specific gene expression patterns may give a better prediction of treatment outcome as compared to single genes.	('tamoxifen', 'Chemical', 'MESH:D013629', (74, 83))	('confer', 'Reg', (65, 71))	('NF1', 'Gene', (13, 16))	('tamoxifen-resistant phenotype', 'MPA', (74, 103))	('Silencing', 'Var', (0, 9))
78364	28637487	More than a third of all ovarian serous carcinomas (OSCs) harbour somatic NF1 mutations, identifying an alternative target for treatment and an additional prognostic marker.	('NF1', 'Gene', (74, 77))	('ovarian serous carcinomas', 'Disease', (25, 50))	('mutations', 'Var', (78, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (40, 49))	('carcinomas', 'Phenotype', 'HP:0030731', (40, 50))	('ovarian serous carcinomas', 'Disease', 'MESH:D010051', (25, 50))
78366	28637487	Genome-wide microarray analysis of 36 primary OSC identified homozygous NF1 deletions in two tumours.	('NF1', 'Gene', (72, 75))	('tumours', 'Disease', (93, 100))	('tumour', 'Phenotype', 'HP:0002664', (93, 99))	('tumours', 'Phenotype', 'HP:0002664', (93, 100))	('deletions', 'Var', (76, 85))	('tumours', 'Disease', 'MESH:D009369', (93, 100))
78367	28637487	This group subsequently screened 18 ovarian carcinoma-derived cell lines and 41 primary OSC for additional NF1 alterations, with 8/18 cell lines exhibiting marked reduction or no expression of NF1.	('reduction', 'NegReg', (163, 172))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (36, 53))	('alterations', 'Var', (111, 122))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (36, 53))	('ovarian carcinoma', 'Disease', (36, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (44, 53))	('NF1', 'Gene', (107, 110))
78368	28637487	Additionally, tumours and cell lines with NF1 lesions were found to lack KRAS and BRAF mutations, whilst exhibiting Ras pathway activation.	('activation', 'PosReg', (128, 138))	('NF1', 'Gene', (42, 45))	('KRAS', 'Gene', (73, 77))	('Ras pathway', 'Pathway', (116, 127))	('KRAS', 'Gene', '3845', (73, 77))	('BRAF', 'Gene', (82, 86))	('tumours', 'Phenotype', 'HP:0002664', (14, 21))	('tumour', 'Phenotype', 'HP:0002664', (14, 20))	('lack', 'NegReg', (68, 72))	('tumours', 'Disease', 'MESH:D009369', (14, 21))	('tumours', 'Disease', (14, 21))	('mutations', 'Var', (87, 96))	('lesions', 'Var', (46, 53))
78369	28637487	The Cancer Genome Atlas project analysed the expression of mRNA and microRNA, promoter methylation and DNA copy number in 489 HGOSC and performed genomic DNA analysis in 316 tumours.	('tumour', 'Phenotype', 'HP:0002664', (174, 180))	('tumours', 'Phenotype', 'HP:0002664', (174, 181))	('tumours', 'Disease', 'MESH:D009369', (174, 181))	('tumours', 'Disease', (174, 181))	('Cancer', 'Disease', (4, 10))	('mRNA', 'Var', (59, 63))	('Cancer', 'Phenotype', 'HP:0002664', (4, 10))	('promoter', 'MPA', (78, 86))	('Cancer', 'Disease', 'MESH:D009369', (4, 10))
78370	28637487	The Australian Ovarian Cancer Study (AOCS) specifically examined CNAs and reported regions of copy number loss at the NF1 locus in 34% (137/398) of ovarian cancer samples, comprising 157 serous adenocarcinomas from the TCGA cohort and a further 241 samples, of both endometrioid and serous subtypes.	('Cancer', 'Disease', (23, 29))	('Ovarian Cancer', 'Phenotype', 'HP:0100615', (15, 29))	('copy number loss', 'Var', (94, 110))	('ovarian cancer', 'Disease', (148, 162))	('Cancer', 'Disease', 'MESH:D009369', (23, 29))	('Cancer', 'Phenotype', 'HP:0002664', (23, 29))	('serous adenocarcinomas', 'Disease', (187, 209))	('ovarian cancer', 'Phenotype', 'HP:0100615', (148, 162))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('serous adenocarcinomas', 'Disease', 'MESH:D000230', (187, 209))	('carcinoma', 'Phenotype', 'HP:0030731', (199, 208))	('ovarian cancer', 'Disease', 'MESH:D010051', (148, 162))	('carcinomas', 'Phenotype', 'HP:0030731', (199, 209))	('NF1', 'Gene', (118, 121))
78374	28637487	NF1 is one of a number of known paraganglioma and phaeochromocytoma susceptibility genes, constitutional mutations in which are responsible for inherited tumour syndromes.	('tumour', 'Phenotype', 'HP:0002664', (154, 160))	('paraganglioma', 'Phenotype', 'HP:0002668', (32, 45))	('inherited tumour syndromes', 'Disease', (144, 170))	('inherited tumour syndromes', 'Disease', 'MESH:D009386', (144, 170))	('mutations', 'Var', (105, 114))	('NF1', 'Gene', (0, 3))	('paraganglioma and phaeochromocytoma', 'Disease', 'MESH:D010235', (32, 67))
78375	28637487	Somatic NF1 mutations occurred in 35/161 (21.7%) of sporadic phaeochromocytomas, with the majority exhibiting LOH and low NF1 mRNA expression, whilst somatic mutations in the susceptibility genes NF1, MAX, RET, VHL, SDHA, SDHB, SDHC, SDHD, SDHAF2, KIF1Bbeta and TMEM127 are present in 11-19% of sporadic cases.	('NF1', 'Gene', (8, 11))	('SDHA', 'Gene', (216, 220))	('SDHA', 'Gene', (240, 244))	('SDHB', 'Gene', '6390', (222, 226))	('SDHA', 'Gene', '6389', (216, 220))	('SDHC', 'Gene', (228, 232))	('SDHA', 'Gene', '6389', (240, 244))	('RET', 'Gene', '5979', (206, 209))	('TMEM127', 'Gene', (262, 269))	('VHL', 'Gene', (211, 214))	('SDHAF2', 'Gene', '54949', (240, 246))	('SDHAF2', 'Gene', (240, 246))	('sporadic phaeochromocytomas', 'Disease', (52, 79))	('LOH', 'Var', (110, 113))	('NF1', 'Gene', (196, 199))	('SDHB', 'Gene', (222, 226))	('low', 'NegReg', (118, 121))	('TMEM127', 'Gene', '55654', (262, 269))	('VHL', 'Gene', '7428', (211, 214))	('RET', 'Gene', (206, 209))	('SDHD', 'Gene', '6392', (234, 238))	('SDHC', 'Gene', '6391', (228, 232))	('mutations', 'Var', (12, 21))	('sporadic phaeochromocytomas', 'Disease', 'MESH:C538614', (52, 79))	('mRNA expression', 'MPA', (126, 141))	('occurred', 'Reg', (22, 30))	('NF1', 'Gene', (122, 125))	('SDHD', 'Gene', (234, 238))
78376	28637487	It has also been demonstrated that the majority (83%, 35/42) of sporadic phaeochromocytomas harbour a CNA in at least one of these susceptibility genes, thereby altering respective protein expression levels.	('altering', 'Reg', (161, 169))	('sporadic phaeochromocytomas', 'Disease', (64, 91))	('sporadic phaeochromocytomas', 'Disease', 'MESH:C538614', (64, 91))	('CNA', 'Var', (102, 105))	('protein expression levels', 'MPA', (181, 206))
78378	28637487	Furthermore, 10 of 11 tumours were also observed to harbour a somatic protein-truncating NF1 mutation in the second allele.	('tumours', 'Phenotype', 'HP:0002664', (22, 29))	('tumours', 'Disease', 'MESH:D009369', (22, 29))	('tumours', 'Disease', (22, 29))	('NF1', 'Gene', (89, 92))	('tumour', 'Phenotype', 'HP:0002664', (22, 28))	('mutation', 'Var', (93, 101))	('protein-truncating', 'PosReg', (70, 88))
78379	28637487	This study also identified a correlation between NF1 mutations and a biochemical phenotype: paragangliomas and phaeochromocytomas harbouring a somatic NF1 mutation were found to display higher plasma levels of normetanephrine (P = 0.005) and metanephrine (P = 0.0025), markers for catecholamine-secreting tumours.	('tumours', 'Disease', 'MESH:D009369', (305, 312))	('NF1', 'Gene', (151, 154))	('normetanephrine', 'Chemical', 'MESH:D009647', (210, 225))	('tumour', 'Phenotype', 'HP:0002664', (305, 311))	('plasma levels of normetanephrine', 'MPA', (193, 225))	('metanephrine', 'MPA', (242, 254))	('catecholamine', 'Chemical', 'MESH:D002395', (281, 294))	('higher', 'PosReg', (186, 192))	('paraganglioma', 'Phenotype', 'HP:0002668', (92, 105))	('paragangliomas', 'Phenotype', 'HP:0002668', (92, 106))	('metanephrine', 'Chemical', 'MESH:D008676', (213, 225))	('metanephrine', 'Chemical', 'MESH:D008676', (242, 254))	('mutations', 'Var', (53, 62))	('gliomas', 'Phenotype', 'HP:0009733', (99, 106))	('paragangliomas and phaeochromocytomas', 'Disease', 'MESH:D010235', (92, 129))	('tumours', 'Disease', (305, 312))	('mutation', 'Var', (155, 163))	('NF1', 'Gene', (49, 52))	('tumours', 'Phenotype', 'HP:0002664', (305, 312))
78382	28637487	Almost a quarter (25/119) of the sporadic phaeochromocytomas/paragangliomas carried an inactivating NF1 mutation, of which 21/25 were associated with the loss of the wild-type allele.	('inactivating', 'Var', (87, 99))	('phaeochromocytomas/paragangliomas', 'Disease', (42, 75))	('paragangliomas', 'Phenotype', 'HP:0002668', (61, 75))	('paraganglioma', 'Phenotype', 'HP:0002668', (61, 74))	('gliomas', 'Phenotype', 'HP:0009733', (68, 75))	('mutation', 'Var', (104, 112))	('NF1', 'Gene', (100, 103))	('phaeochromocytomas/paragangliomas', 'Disease', 'MESH:D010235', (42, 75))	('sporadic phaeochromocytomas', 'Disease', (33, 60))	('sporadic phaeochromocytomas', 'Disease', 'MESH:C538614', (33, 60))
78383	28637487	Of all the somatic mutations identified in the study, 56% were located in NF1, showing that NF1 is frequently mutated in phaeochromocytomas/paragangliomas.	('phaeochromocytomas/paragangliomas', 'Disease', 'MESH:D010235', (121, 154))	('NF1', 'Gene', (74, 77))	('mutated', 'Var', (110, 117))	('paragangliomas', 'Phenotype', 'HP:0002668', (140, 154))	('paraganglioma', 'Phenotype', 'HP:0002668', (140, 153))	('phaeochromocytomas/paragangliomas', 'Disease', (121, 154))	('mutations', 'Var', (19, 28))	('NF1', 'Gene', (92, 95))	('gliomas', 'Phenotype', 'HP:0009733', (147, 154))
78390	28637487	In this study, 4/10 neuroblastoma cell lines were observed to express either a reduced level or a complete absence of neurofibromin, with NF1 mutations being identified in two of these cell lines.	('neuroblastoma', 'Phenotype', 'HP:0003006', (20, 33))	('mutations', 'Var', (142, 151))	('neuroblastoma', 'Disease', 'MESH:D009447', (20, 33))	('neurofibromin', 'Protein', (118, 131))	('neuroblastoma', 'Disease', (20, 33))	('NF1', 'Gene', (138, 141))	('absence', 'NegReg', (107, 114))
78393	28637487	Somatic NF1 mutations in neuroblastomas have been correlated with reduced expression of neurofibromin and poor patient prognosis, whilst higher levels of expression are associated with longer progression-free survival.	('expression', 'MPA', (74, 84))	('NF1', 'Gene', (8, 11))	('reduced', 'NegReg', (66, 73))	('neuroblastomas', 'Disease', (25, 39))	('neuroblastoma', 'Phenotype', 'HP:0003006', (25, 38))	('mutations', 'Var', (12, 21))	('neurofibromin', 'Protein', (88, 101))	('patient', 'Species', '9606', (111, 118))	('neuroblastomas', 'Phenotype', 'HP:0003006', (25, 39))	('neuroblastomas', 'Disease', 'MESH:D009447', (25, 39))
78397	28637487	Loss of NF1 activates RAS-MEK signalling, which in turn represses ZNF423, a critical transcriptional coactivator of the retinoic acid receptors; neuroblastomas with low levels of both NF1 and ZNF423 have an extremely poor outcome.	('NF1', 'Gene', (8, 11))	('ZNF423', 'Gene', (66, 72))	('neuroblastomas', 'Disease', (145, 159))	('activates', 'PosReg', (12, 21))	('represses', 'NegReg', (56, 65))	('neuroblastoma', 'Phenotype', 'HP:0003006', (145, 158))	('retinoic acid', 'Chemical', 'MESH:D014212', (120, 133))	('RAS-MEK', 'MPA', (22, 29))	('ZNF423', 'Gene', '23090', (66, 72))	('ZNF423', 'Gene', '23090', (192, 198))	('neuroblastomas', 'Phenotype', 'HP:0003006', (145, 159))	('ZNF423', 'Gene', (192, 198))	('Loss', 'Var', (0, 4))	('neuroblastomas', 'Disease', 'MESH:D009447', (145, 159))
78398	28637487	However, inhibition of MEK signalling downstream of NF1 restores responsiveness to RA, suggesting a potential therapeutic strategy to overcome RA resistance in NF1-deficient neuroblastomas.	('restores', 'PosReg', (56, 64))	('responsiveness to RA', 'MPA', (65, 85))	('RA', 'Chemical', 'MESH:D014212', (143, 145))	('neuroblastoma', 'Phenotype', 'HP:0003006', (174, 187))	('NF1-deficient neuroblastomas', 'Disease', 'MESH:C537392', (160, 188))	('RA', 'Chemical', 'MESH:D014212', (83, 85))	('neuroblastomas', 'Phenotype', 'HP:0003006', (174, 188))	('MEK', 'Pathway', (23, 26))	('NF1-deficient neuroblastomas', 'Disease', (160, 188))	('inhibition', 'Var', (9, 19))
78402	28637487	Glioblastoma-associated NF1 somatic mutations are well described, with recurrent driver mutations being identified in NF1 and a number of other candidate genes (IDH1, TP53, CDK4, EGFR, PI3KR1, PIK3CA, PTEN, RB1 and CDNK2A) in GBM.	('EGFR', 'Gene', (179, 183))	('PIK3CA', 'Gene', '5290', (193, 199))	('CDK4', 'Gene', (173, 177))	('mutations', 'Var', (88, 97))	('RB1', 'Gene', '5925', (207, 210))	('NF1', 'Gene', (24, 27))	('IDH1', 'Gene', '3417', (161, 165))	('NF1', 'Gene', (118, 121))	('Glioblastoma', 'Disease', (0, 12))	('PTEN', 'Gene', (201, 205))	('CDK4', 'Gene', '1019', (173, 177))	('PIK3CA', 'Gene', (193, 199))	('PTEN', 'Gene', '5728', (201, 205))	('TP53', 'Gene', (167, 171))	('Glioblastoma', 'Disease', 'MESH:D005909', (0, 12))	('mutations', 'Var', (36, 45))	('IDH1', 'Gene', (161, 165))	('RB1', 'Gene', (207, 210))	('Glioblastoma', 'Phenotype', 'HP:0012174', (0, 12))	('CDNK2A', 'Gene', (215, 221))
78403	28637487	A TCGA analysis assessed levels of gene expression, CNAs and DNA methylation in a cohort of 206 glioblastoma tumour samples, with recurrent mutations in NF1, AKT3, PRK3R1 and PARK2 being identified, and with 14% (13/91) of samples found to contain at least one somatic NF1 mutation.	('AKT3', 'Gene', '10000', (158, 162))	('PARK2', 'Gene', (175, 180))	('NF1', 'Gene', (153, 156))	('glioblastoma tumour', 'Disease', (96, 115))	('CNAs', 'MPA', (52, 56))	('PARK2', 'Gene', '5071', (175, 180))	('glioblastoma', 'Phenotype', 'HP:0012174', (96, 108))	('mutations', 'Var', (140, 149))	('glioblastoma tumour', 'Disease', 'MESH:D005909', (96, 115))	('PRK3R1', 'Gene', (164, 170))	('AKT3', 'Gene', (158, 162))	('tumour', 'Phenotype', 'HP:0002664', (109, 115))
78405	28637487	They found that GBM with NF1 and PTEN alterations had a distinct mesenchymal-like expression profile, with 53% of mesenchymal cases having an NF1 mutation.	('mesenchymal-like', 'CPA', (65, 81))	('PTEN', 'Gene', (33, 37))	('PTEN', 'Gene', '5728', (33, 37))	('NF1', 'Gene', (25, 28))	('alterations', 'Var', (38, 49))	('mutation', 'Var', (146, 154))	('NF1', 'Gene', (142, 145))
78406	28637487	In animal models, inactivation of TP53 and PTEN may cooperate with NF1 loss in the development of glioblastoma.	('NF1', 'Gene', (67, 70))	('glioblastoma', 'Disease', (98, 110))	('glioblastoma', 'Disease', 'MESH:D005909', (98, 110))	('inactivation', 'Var', (18, 30))	('glioblastoma', 'Phenotype', 'HP:0012174', (98, 110))	('TP53', 'Protein', (34, 38))	('PTEN', 'Gene', (43, 47))	('PTEN', 'Gene', '5728', (43, 47))	('loss', 'NegReg', (71, 75))
78410	28637487	Although genetic alterations in the PI3K and RAS/MAPK pathways are common in CRC and NF1 alterations have been detected in 5-6% of cases, it remains unclear as to whether NF1 mutations in CRC are related to chemotherapeutic effect.	('PI3K', 'Pathway', (36, 40))	('RAS/MAPK pathways', 'Pathway', (45, 62))	('NF1', 'Gene', (85, 88))	('RAS', 'Chemical', 'MESH:D011883', (45, 48))	('mutations', 'Var', (175, 184))	('CRC', 'Gene', (77, 80))
78411	28637487	The best documented molecular factors involved in urothelial transitional cell carcinoma (TCC) are the RAS proto-oncogene activation and TP53 mutations.	('mutations', 'Var', (142, 151))	('urothelial transitional cell carcinoma', 'Disease', (50, 88))	('RAS', 'Chemical', 'MESH:D011883', (103, 106))	('urothelial transitional cell carcinoma', 'Disease', 'MESH:D002295', (50, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('TP53', 'Gene', (137, 141))
78412	28637487	Neurofibromin levels were also decreased in high-grade TCC, suggesting that alterations of NF1 gene expression might be involved in urinary TCC carcinogenesis.	('alterations', 'Var', (76, 87))	('involved', 'Reg', (120, 128))	('carcinogenesis', 'Disease', 'MESH:D063646', (144, 158))	('decreased', 'NegReg', (31, 40))	('carcinogenesis', 'Disease', (144, 158))	('urinary TCC', 'Disease', (132, 143))	('Neurofibromin', 'Gene', (0, 13))	('Neurofibromin', 'Gene', '4763', (0, 13))	('high-grade', 'Var', (44, 54))	('NF1 gene', 'Gene', (91, 99))	('urinary TCC', 'Phenotype', 'HP:0030409', (132, 143))
78413	28637487	Whole genomic analysis performed on 35 stage IV urothelial cancers that had relapsed and progressed after primary surgery and conventional chemotherapy revealed NF1 mutations in two cases (6%).	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('urothelial cancers', 'Disease', 'MESH:D014523', (48, 66))	('NF1', 'Gene', (161, 164))	('cancers', 'Phenotype', 'HP:0002664', (59, 66))	('mutations', 'Var', (165, 174))	('urothelial cancers', 'Disease', (48, 66))
78414	28637487	Integrated analysis of 131 urothelial carcinomas showed recurrent mutations in 32 genes, with 14% of tumours having NF1 mutations.	('mutations', 'Var', (66, 75))	('tumours', 'Disease', 'MESH:D009369', (101, 108))	('urothelial carcinomas', 'Disease', 'MESH:D014523', (27, 48))	('tumours', 'Disease', (101, 108))	('NF1', 'Gene', (116, 119))	('urothelial carcinomas', 'Disease', (27, 48))	('mutations', 'Var', (120, 129))	('tumour', 'Phenotype', 'HP:0002664', (101, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (38, 47))	('carcinomas', 'Phenotype', 'HP:0030731', (38, 48))	('tumours', 'Phenotype', 'HP:0002664', (101, 108))
78415	28637487	There are a number of other malignant tumour types that have been found to harbour NF1 alterations including neuroendocrine prostate cancer (24%), myxofibrosarcomas (10.5%) and pleomorphic liposarcomas (8%), pancreatic cancer (11%), gastric adenocarcinoma (10%) and rhabdomyosarcoma (7%).	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (266, 282))	('liposarcomas', 'Phenotype', 'HP:0012034', (189, 201))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (266, 282))	('pleomorphic liposarcomas', 'Disease', (177, 201))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (208, 225))	('carcinoma', 'Phenotype', 'HP:0030731', (246, 255))	('gastric adenocarcinoma', 'Disease', (233, 255))	('malignant tumour', 'Disease', 'MESH:D009369', (28, 44))	('myxofibrosarcomas', 'Disease', (147, 164))	('sarcoma', 'Phenotype', 'HP:0100242', (275, 282))	('pancreatic cancer', 'Disease', 'MESH:D010190', (208, 225))	('neuroendocrine prostate cancer', 'Disease', 'MESH:D011471', (109, 139))	('myxofibrosarcomas', 'Disease', 'None', (147, 164))	('sarcoma', 'Phenotype', 'HP:0100242', (156, 163))	('NF1', 'Gene', (83, 86))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('rhabdomyosarcoma', 'Disease', (266, 282))	('malignant tumour', 'Disease', (28, 44))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('alterations', 'Var', (87, 98))	('tumour', 'Phenotype', 'HP:0002664', (38, 44))	('pancreatic cancer', 'Disease', (208, 225))	('gastric adenocarcinoma', 'Disease', 'MESH:D013274', (233, 255))	('neuroendocrine prostate cancer', 'Disease', (109, 139))	('pleomorphic liposarcomas', 'Disease', 'MESH:D008080', (177, 201))	('prostate cancer', 'Phenotype', 'HP:0012125', (124, 139))	('sarcoma', 'Phenotype', 'HP:0100242', (193, 200))
78416	28637487	Somatic NF1 mutations have also been detected in 41-72% of sporadic MPNSTs, showing that NF1 inactivation plays a major role in the development of this tumour type.	('tumour', 'Disease', 'MESH:D009369', (152, 158))	('NF1', 'Gene', (8, 11))	('tumour', 'Disease', (152, 158))	('mutations', 'Var', (12, 21))	('MPNSTs', 'Disease', (68, 74))	('detected', 'Reg', (37, 45))	('tumour', 'Phenotype', 'HP:0002664', (152, 158))
78417	28637487	Neurofibromatosis type 1, caused by constitutional inactivating mutations in the tumour suppressor gene NF1, is a neurodegenerative disorder predisposing individuals to both benign and malignant tumours.	('Neurofibromatosis type 1', 'Disease', (0, 24))	('constitutional inactivating mutations', 'Var', (36, 73))	('tumour', 'Disease', 'MESH:D009369', (81, 87))	('tumour', 'Disease', 'MESH:D009369', (195, 201))	('tumour', 'Phenotype', 'HP:0002664', (81, 87))	('Neurofibromatosis', 'Phenotype', 'HP:0001067', (0, 17))	('caused by', 'Reg', (26, 35))	('tumour', 'Disease', (195, 201))	('tumour', 'Disease', (81, 87))	('tumours', 'Phenotype', 'HP:0002664', (195, 202))	('neurodegenerative disorder', 'Disease', 'MESH:D019636', (114, 140))	('malignant tumours', 'Disease', 'MESH:D009369', (185, 202))	('malignant tumours', 'Disease', (185, 202))	('neurodegenerative disorder', 'Disease', (114, 140))	('neurodegenerative disorder', 'Phenotype', 'HP:0002180', (114, 140))	('tumour', 'Phenotype', 'HP:0002664', (195, 201))	('NF1', 'Gene', (104, 107))
78419	28637487	Aberrations in neurofibromin result in the dysregulation of the RAS/MAPK pathway leading to unregulated cell growth and proliferation.	('RAS', 'Chemical', 'MESH:D011883', (64, 67))	('unregulated', 'MPA', (92, 103))	('dysregulation', 'MPA', (43, 56))	('RAS/MAPK pathway', 'Pathway', (64, 80))	('neurofibromin', 'Gene', (15, 28))	('Aberrations', 'Var', (0, 11))
78421	28637487	Mutations (chromosomal aberrations, nucleotide substitutions and epigenetic aberrations) in a subset of candidate genes are likely to confer a growth advantage resulting in the development of cancer.	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (11, 34))	('nucleotide substitutions', 'Var', (36, 60))	('cancer', 'Disease', (192, 198))	('growth advantage', 'CPA', (143, 159))	('cancer', 'Disease', 'MESH:D009369', (192, 198))	('epigenetic aberrations', 'Var', (65, 87))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))
78427	28637487	One caveat, however, is distinguishing artefactual DNA damage from the bona fide mutations that actually occurred in the tumour, given that it has been reported that mutagenic damage accounts for the majority of the erroneous identification of variants with low to moderate (1 to 5%) frequency in whole (cancer) genome sequencing studies.	('cancer', 'Disease', 'MESH:D009369', (304, 310))	('variants', 'Var', (244, 252))	('tumour', 'Phenotype', 'HP:0002664', (121, 127))	('cancer', 'Disease', (304, 310))	('tumour', 'Disease', 'MESH:D009369', (121, 127))	('tumour', 'Disease', (121, 127))	('cancer', 'Phenotype', 'HP:0002664', (304, 310))
78428	28637487	Generally, a large number of mutations occur in cancer genomes, such as somatic mutations, CNAs, methylation aberrations and histone modifications.	('methylation aberrations', 'Var', (97, 120))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('mutations', 'Var', (29, 38))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('CNAs', 'Disease', (91, 95))	('occur', 'Reg', (39, 44))	('histone', 'Protein', (125, 132))
78429	28637487	It is critical to distinguish driver mutations and driver genes (which contribute to the progression of cancer from normal to malignant states) from passenger mutations and passenger genes (which accumulate in cells but do not contribute to cancer development).	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('contribute', 'Reg', (71, 81))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('mutations', 'Var', (37, 46))	('cancer', 'Disease', (241, 247))	('cancer', 'Disease', 'MESH:D009369', (241, 247))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))
78430	28637487	A driver mutation typically confers upon a tumour only a very small growth advantage, which may be as low as a 0.4% increase in the difference between cell birth and death rates.	('mutation', 'Var', (9, 17))	('small growth', 'Phenotype', 'HP:0001510', (62, 74))	('tumour', 'Disease', (43, 49))	('growth advantage', 'CPA', (68, 84))	('death', 'Disease', 'MESH:D003643', (166, 171))	('death', 'Disease', (166, 171))	('tumour', 'Phenotype', 'HP:0002664', (43, 49))	('tumour', 'Disease', 'MESH:D009369', (43, 49))
78431	28637487	More recently, Bozic and colleagues have shown that the first, and hence most abundant, passenger mutations are influenced both by the mutation rate and by the death-birth ratio of the cancer cells.	('death', 'Disease', 'MESH:D003643', (160, 165))	('death', 'Disease', (160, 165))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('influenced', 'Reg', (112, 122))	('mutations', 'Var', (98, 107))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('cancer', 'Disease', (185, 191))
78433	28637487	This task is made all the more daunting by the possibility that drivers and passengers are not discrete entities but rather lie along a continuum which includes latent driver mutations which 'behave as passengers but coupled with other emerging mutations, drive cancer development and drug resistance'.	('cancer', 'Disease', (262, 268))	('drive', 'PosReg', (256, 261))	('cancer', 'Phenotype', 'HP:0002664', (262, 268))	('drug resistance', 'Phenotype', 'HP:0020174', (285, 300))	("drug resistance'", 'CPA', (285, 301))	('mutations', 'Var', (175, 184))	('cancer', 'Disease', 'MESH:D009369', (262, 268))
78436	28637487	Of these, approximately 90% have somatic mutations in cancer; 20% have germline mutations that predispose to cancer; and 10% harbour both somatic and germline mutations.	('mutations', 'Var', (41, 50))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('cancer', 'Disease', (109, 115))	('cancer', 'Disease', (54, 60))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
78445	28637487	Thus, sporadic tumours with NF1 mutations are mutually exclusive for mutations in MAPK kinase 1 (MAP2K1) or NRAS.	('NRAS', 'Gene', (108, 112))	('mutations', 'Var', (69, 78))	('sporadic tumours', 'Disease', 'MESH:D009369', (6, 22))	('MAP2K1', 'Gene', '5604', (97, 103))	('NRAS', 'Gene', '4893', (108, 112))	('MAP2K1', 'Gene', (97, 103))	('mutations', 'Var', (32, 41))	('tumour', 'Phenotype', 'HP:0002664', (15, 21))	('sporadic tumours', 'Disease', (6, 22))	('NF1', 'Gene', (28, 31))	('tumours', 'Phenotype', 'HP:0002664', (15, 22))
78446	28637487	Strongly activating 'canonical' mutations in oncogenes (for example G12D or G12V mutations in KRAS) can drive cancer formation on their own and are known to be epistatic in relation to other canonical mutations within the same pathway.	('cancer', 'Disease', (110, 116))	("activating 'canonical", 'PosReg', (9, 30))	('G12V', 'Mutation', 'rs121913529', (76, 80))	('KRAS', 'Gene', (94, 98))	('G12D', 'Var', (68, 72))	('G12V mutations', 'Var', (76, 90))	('G12D', 'Mutation', 'rs121913529', (68, 72))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('KRAS', 'Gene', '3845', (94, 98))	('drive', 'PosReg', (104, 109))	('cancer', 'Disease', 'MESH:D009369', (110, 116))
78447	28637487	However, whether there are, for example, 'non-canonical' mutations that weakly activate oncogenes or only partially inactivate tumour suppressor activity and yet can drive cancer formation is less clear.	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('tumour', 'Phenotype', 'HP:0002664', (127, 133))	('inactivate', 'NegReg', (116, 126))	('activate', 'PosReg', (79, 87))	('tumour', 'Disease', 'MESH:D009369', (127, 133))	('oncogenes', 'Protein', (88, 97))	('mutations', 'Var', (57, 66))	('drive', 'Reg', (166, 171))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('cancer', 'Disease', (172, 178))	('tumour', 'Disease', (127, 133))
78448	28637487	Examination of genomic data from the Cancer Cell Line Encyclopedia (CCLE) and TCGA has indicated that whilst canonical KRAS mutations do not occur with increased frequency in the context of NF1 mutations, non-canonical KRAS mutations certainly do, suggesting that such pairs of mutations might act together to confer a selective advantage in human tumours.	('tumours', 'Disease', 'MESH:D009369', (348, 355))	('KRAS', 'Gene', '3845', (219, 223))	('Cancer', 'Disease', 'MESH:D009369', (37, 43))	('tumours', 'Disease', (348, 355))	('mutations', 'Var', (194, 203))	('tumour', 'Phenotype', 'HP:0002664', (348, 354))	('Cancer', 'Phenotype', 'HP:0002664', (37, 43))	('KRAS', 'Gene', (119, 123))	('Cancer', 'Disease', (37, 43))	('KRAS', 'Gene', '3845', (119, 123))	('human', 'Species', '9606', (342, 347))	('tumours', 'Phenotype', 'HP:0002664', (348, 355))	('CCLE', 'Chemical', '-', (68, 72))	('KRAS', 'Gene', (219, 223))
78449	28637487	Activation of RAS guanine nucleotide exchange factors (RAS-GEFs) was predicted to have similar effects to neurofibromin loss and that non-canonical KRAS mutations co-occur with RAS-GEF mutations in TCGA and CCLE data.	('KRAS', 'Gene', (148, 152))	('mutations', 'Var', (153, 162))	('RAS-', 'Chemical', 'MESH:D011883', (55, 59))	('TCGA', 'Gene', (198, 202))	('KRAS', 'Gene', '3845', (148, 152))	('neurofibromin', 'MPA', (106, 119))	('RAS', 'Chemical', 'MESH:D011883', (14, 17))	('RAS', 'Chemical', 'MESH:D011883', (149, 152))	('Activation', 'PosReg', (0, 10))	('RAS-', 'Chemical', 'MESH:D011883', (177, 181))	('RAS', 'Chemical', 'MESH:D011883', (55, 58))	('CCLE', 'Chemical', '-', (207, 211))	('mutations', 'Var', (185, 194))	('loss', 'NegReg', (120, 124))	('guanine nucleotide', 'Chemical', 'MESH:D006150', (18, 36))	('RAS', 'Chemical', 'MESH:D011883', (177, 180))
78450	28637487	Furthermore, increased frequencies of mutations in both NF1 and other RAS pathway activators or effectors have been found which suggests that this principle could apply more broadly to other genes in the RAS network and possibly to other oncogenic signalling pathways.	('mutations', 'Var', (38, 47))	('RAS', 'Chemical', 'MESH:D011883', (204, 207))	('RAS', 'Chemical', 'MESH:D011883', (70, 73))	('NF1', 'Gene', (56, 59))
78451	28637487	Furthermore, on the basis of analyses of somatic co-mutation patterns in the TCGA data sets (cBio Portal for Cancer Genomics), 9.6% of melanomas with NF1 mutations also have mutations in BRAF, NRAS or RAF1.	('Cancer', 'Phenotype', 'HP:0002664', (109, 115))	('NRAS', 'Gene', (193, 197))	('Cancer', 'Disease', (109, 115))	('melanomas', 'Disease', 'MESH:D008545', (135, 144))	('NF1', 'Gene', (150, 153))	('melanoma', 'Phenotype', 'HP:0002861', (135, 143))	('Cancer', 'Disease', 'MESH:D009369', (109, 115))	('NRAS', 'Gene', '4893', (193, 197))	('melanomas', 'Phenotype', 'HP:0002861', (135, 144))	('RAF1', 'Gene', '5894', (201, 205))	('mutations', 'Var', (154, 163))	('mutations', 'Var', (174, 183))	('RAF1', 'Gene', (201, 205))	('melanomas', 'Disease', (135, 144))	('BRAF', 'Gene', (187, 191))
78452	28637487	But, whilst mutant NF1 is known to cooperate with RASopathy genes (RASA2, PTPN11, SOS1, RAF1 and SPRED1) in melanoma and although NF1 is found to be frequently mutated (25-30%) in melanomas harbouring wild-type BRAF and NRAS, it is curious that melanoma is not a tumour type associated with NF1.	('melanoma', 'Disease', 'MESH:D008545', (108, 116))	('melanoma', 'Disease', 'MESH:D008545', (180, 188))	('RASA2', 'Gene', (67, 72))	('melanomas', 'Phenotype', 'HP:0002861', (180, 189))	('NRAS', 'Gene', '4893', (220, 224))	('melanoma', 'Phenotype', 'HP:0002861', (245, 253))	('SOS1', 'Gene', (82, 86))	('melanoma', 'Disease', (245, 253))	('tumour', 'Phenotype', 'HP:0002664', (263, 269))	('SPRED1', 'Gene', '161742', (97, 103))	('melanoma', 'Phenotype', 'HP:0002861', (108, 116))	('melanoma', 'Disease', (108, 116))	('tumour', 'Disease', 'MESH:D009369', (263, 269))	('melanoma', 'Phenotype', 'HP:0002861', (180, 188))	('RASA2', 'Gene', '5922', (67, 72))	('melanoma', 'Disease', (180, 188))	('tumour', 'Disease', (263, 269))	('RAF1', 'Gene', '5894', (88, 92))	('NRAS', 'Gene', (220, 224))	('RASopathy', 'Disease', 'None', (50, 59))	('SPRED1', 'Gene', (97, 103))	('PTPN11', 'Gene', (74, 80))	('RAF1', 'Gene', (88, 92))	('RASopathy', 'Disease', (50, 59))	('NF1', 'Gene', (19, 22))	('melanomas', 'Disease', 'MESH:D008545', (180, 189))	('melanoma', 'Disease', 'MESH:D008545', (245, 253))	('mutated', 'Var', (160, 167))	('mutant', 'Var', (12, 18))	('NF1', 'Gene', (130, 133))	('SOS1', 'Gene', '6654', (82, 86))	('melanomas', 'Disease', (180, 189))	('PTPN11', 'Gene', '5781', (74, 80))
78453	28637487	The capacity of NF1 mutations to act both cooperatively and exclusively without BRAF and NRAS mutations in melanoma may be mediated through pathways other than the MAPK pathway.	('melanoma', 'Phenotype', 'HP:0002861', (107, 115))	('NF1', 'Gene', (16, 19))	('melanoma', 'Disease', (107, 115))	('NRAS', 'Gene', '4893', (89, 93))	('melanoma', 'Disease', 'MESH:D008545', (107, 115))	('NRAS', 'Gene', (89, 93))	('mutations', 'Var', (20, 29))
78454	28637487	Maertens and colleagues have identified increased activation of the PI3K/AKT/mTOR pathway in BRAF/NF1 double mutants, and a combinatorial MEK marker and mTOR inhibitor treatment has proven effective in many MEK inhibitor-resistant neoplasms.	('double mutants', 'Var', (102, 116))	('neoplasms', 'Phenotype', 'HP:0002664', (231, 240))	('AKT', 'Gene', (73, 76))	('BRAF/NF1', 'Gene', (93, 101))	('mTOR', 'Gene', (153, 157))	('mTOR', 'Gene', '2475', (153, 157))	('activation', 'PosReg', (50, 60))	('mTOR', 'Gene', '2475', (77, 81))	('neoplasms', 'Disease', 'MESH:D009369', (231, 240))	('neoplasms', 'Disease', (231, 240))	('mTOR', 'Gene', (77, 81))	('neoplasm', 'Phenotype', 'HP:0002664', (231, 239))	('AKT', 'Gene', '207', (73, 76))
78456	28637487	Moreover, whilst simultaneous inactivation of Nf1 and expression of K-RasG12D in mouse haematopoietic cells results in AML that was fatal in primary mice within 4 weeks, in ovarian serous carcinomas, cooperation between mutant TP53 and NF1 results in a poor prognosis.	('G12D', 'Mutation', 'rs121913529', (73, 77))	('Nf1', 'Gene', '18015', (46, 49))	('inactivation', 'Var', (30, 42))	('NF1', 'Gene', (236, 239))	('mutant', 'Var', (220, 226))	('ovarian serous carcinomas', 'Disease', (173, 198))	('ovarian serous carcinomas', 'Disease', 'MESH:D010051', (173, 198))	('AML', 'Disease', 'MESH:D015470', (119, 122))	('mouse', 'Species', '10090', (81, 86))	('TP53', 'Gene', (227, 231))	('mice', 'Species', '10090', (149, 153))	('Nf1', 'Gene', (46, 49))	('AML', 'Disease', (119, 122))	('K-RasG12D', 'Var', (68, 77))	('carcinoma', 'Phenotype', 'HP:0030731', (188, 197))	('carcinomas', 'Phenotype', 'HP:0030731', (188, 198))
78458	28637487	In melanomas harbouring BRAF V600E mutations, a BRAF inhibitor induces remission of the tumour; however, the same drug is ineffective in colorectal cancer cells harbouring identical mutations.	('tumour', 'Disease', 'MESH:D009369', (88, 94))	('V600E', 'Mutation', 'rs113488022', (29, 34))	('remission', 'MPA', (71, 80))	('tumour', 'Disease', (88, 94))	('colorectal cancer', 'Disease', (137, 154))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('melanomas', 'Disease', (3, 12))	('colorectal cancer', 'Disease', 'MESH:D015179', (137, 154))	('V600E', 'Var', (29, 34))	('BRAF', 'Gene', (24, 28))	('tumour', 'Phenotype', 'HP:0002664', (88, 94))	('melanoma', 'Phenotype', 'HP:0002861', (3, 11))	('melanomas', 'Phenotype', 'HP:0002861', (3, 12))	('colorectal cancer', 'Phenotype', 'HP:0003003', (137, 154))	('melanomas', 'Disease', 'MESH:D008545', (3, 12))
78461	28637487	Why, for example, are NF1 patients not predisposed to lung tumours given that at least 10% of all sporadic lung cancers have NF1 mutations?	('lung tumours', 'Disease', (54, 66))	('NF1', 'Gene', (125, 128))	('cancers', 'Phenotype', 'HP:0002664', (112, 119))	('mutations', 'Var', (129, 138))	('lung cancers', 'Disease', (107, 119))	('tumour', 'Phenotype', 'HP:0002664', (59, 65))	('lung tumours', 'Disease', 'MESH:D008175', (54, 66))	('patients', 'Species', '9606', (26, 34))	('tumours', 'Phenotype', 'HP:0002664', (59, 66))	('lung cancer', 'Phenotype', 'HP:0100526', (107, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('lung cancers', 'Disease', 'MESH:D008175', (107, 119))	('lung cancers', 'Phenotype', 'HP:0100526', (107, 119))
78462	28637487	The RAS/MAPK pathway, with an important role in cancer biology, is a prime target for anti-cancer agents; however, the presence of an NF1 mutation, resulting in reduced expression of neurofibromin, confers resistance to several therapeutic drugs.	('reduced', 'NegReg', (161, 168))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('RAS', 'Chemical', 'MESH:D011883', (4, 7))	('NF1', 'Gene', (134, 137))	('cancer', 'Disease', (48, 54))	('neurofibromin', 'Protein', (183, 196))	('presence', 'Var', (119, 127))	('expression', 'MPA', (169, 179))	('mutation', 'Var', (138, 146))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('resistance', 'MPA', (206, 216))
78463	28637487	Furthermore, NF1-associated drug resistance to RAF and EGFR inhibitors, tamoxifen and retinoic acid, has been observed in melanoma, lung cancers, breast cancers and neuroblastoma, respectively, and melanoma cells with BRAF/NF1 mutations develop resistance to BRAF inhibitors.	('RAF', 'Gene', (219, 222))	('develop', 'Reg', (237, 244))	('cancers', 'Phenotype', 'HP:0002664', (137, 144))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('tamoxifen', 'Chemical', 'MESH:D013629', (72, 81))	('drug resistance', 'MPA', (28, 43))	('observed', 'Reg', (110, 118))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('melanoma', 'Phenotype', 'HP:0002861', (198, 206))	('drug resistance', 'Phenotype', 'HP:0020174', (28, 43))	('melanoma', 'Disease', (198, 206))	('RAF', 'Gene', '22882', (260, 263))	('breast cancer', 'Phenotype', 'HP:0003002', (146, 159))	('neuroblastoma', 'Disease', (165, 178))	('breast cancers', 'Disease', 'MESH:D001943', (146, 160))	('breast cancers', 'Disease', (146, 160))	('melanoma', 'Disease', 'MESH:D008545', (122, 130))	('RAF', 'Gene', '22882', (47, 50))	('neuroblastoma', 'Phenotype', 'HP:0003006', (165, 178))	('EGFR', 'Gene', (55, 59))	('lung cancer', 'Phenotype', 'HP:0100526', (132, 143))	('breast cancers', 'Phenotype', 'HP:0003002', (146, 160))	('neuroblastoma', 'Disease', 'MESH:D009447', (165, 178))	('RAF', 'Gene', (260, 263))	('retinoic acid', 'Chemical', 'MESH:D014212', (86, 99))	('lung cancers', 'Disease', 'MESH:D008175', (132, 144))	('RAF', 'Gene', (47, 50))	('mutations', 'Var', (227, 236))	('resistance', 'MPA', (245, 255))	('RAF', 'Gene', '22882', (219, 222))	('melanoma', 'Disease', 'MESH:D008545', (198, 206))	('lung cancers', 'Disease', (132, 144))	('melanoma', 'Phenotype', 'HP:0002861', (122, 130))	('melanoma', 'Disease', (122, 130))	('cancers', 'Phenotype', 'HP:0002664', (153, 160))	('lung cancers', 'Phenotype', 'HP:0100526', (132, 144))
78464	28637487	It is not clear whether the specific nature of the mutations could have exerted an influence on the sensitivity of the drug, as complete inactivation of NF1 has been noted to confer sensitivity to rapamycin in AML.	('AML', 'Disease', (210, 213))	('sensitivity', 'MPA', (182, 193))	('mutations', 'Var', (51, 60))	('NF1', 'Gene', (153, 156))	('rapamycin', 'Chemical', 'MESH:D020123', (197, 206))	('sensitivity', 'MPA', (100, 111))	('AML', 'Disease', 'MESH:D015470', (210, 213))	('influence', 'Reg', (83, 92))	('inactivation', 'NegReg', (137, 149))
78465	28637487	Large constitutional NF1 deletions, encompassing the NF1 gene and many adjacent genes, occur in 5-10% of NF1 cases and are often associated with a more severe phenotype including learning disabilities and increased susceptibility to MPNSTs.	('associated with', 'Reg', (129, 144))	('NF1', 'Gene', (105, 108))	('MPNSTs', 'Disease', (233, 239))	('deletions', 'Var', (25, 34))	('learning disabilities', 'Disease', 'MESH:D007859', (179, 200))	('NF1', 'Gene', (21, 24))	('learning disabilities', 'Disease', (179, 200))
78466	28637487	Intriguingly, such mutations resulting in heterozygous or homozygous loss of NF1 expression are found to occur more often as sporadic events in AML and ovarian carcinoma, based on cBioPortal data.	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (152, 169))	('loss', 'NegReg', (69, 73))	('NF1', 'Gene', (77, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (160, 169))	('mutations', 'Var', (19, 28))	('AML and ovarian carcinoma', 'Disease', 'MESH:D015470', (144, 169))	('expression', 'MPA', (81, 91))
78467	28637487	An NF1 microdeletion in combination with an abnormal karyotype is an indicator of poor prognosis in AML; 7.6% of ovarian serous cystadenocarcinomas, 2.8% of lung squamous cell carcinomas, 3.3% of glioblastomas and 1.9% of phaeochromocytomas/paragangliomas harboured deletions.	('lung squamous cell carcinomas', 'Disease', 'MESH:D002294', (157, 186))	('gliomas', 'Phenotype', 'HP:0009733', (248, 255))	('carcinomas', 'Phenotype', 'HP:0030731', (176, 186))	('glioblastomas', 'Phenotype', 'HP:0012174', (196, 209))	('ovarian serous cystadenocarcinomas', 'Disease', (113, 147))	('glioblastoma', 'Phenotype', 'HP:0012174', (196, 208))	('phaeochromocytomas/paragangliomas', 'Disease', (222, 255))	('deletions', 'Var', (266, 275))	('carcinomas', 'Phenotype', 'HP:0030731', (137, 147))	('microdeletion', 'Var', (7, 20))	('lung squamous cell carcinomas', 'Disease', (157, 186))	('glioblastomas', 'Disease', (196, 209))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (157, 185))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (162, 186))	('NF1', 'Gene', (3, 6))	('glioblastomas', 'Disease', 'MESH:D005909', (196, 209))	('phaeochromocytomas/paragangliomas', 'Disease', 'MESH:D010235', (222, 255))	('AML', 'Disease', 'MESH:D015470', (100, 103))	('AML', 'Disease', (100, 103))	('ovarian serous cystadenocarcinomas', 'Disease', 'MESH:D018284', (113, 147))	('ovarian serous cystadenocarcinoma', 'Phenotype', 'HP:0012887', (113, 146))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (162, 185))	('paraganglioma', 'Phenotype', 'HP:0002668', (241, 254))	('paragangliomas', 'Phenotype', 'HP:0002668', (241, 255))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('serous cystadenocarcinomas', 'Phenotype', 'HP:0012887', (121, 147))	('carcinoma', 'Phenotype', 'HP:0030731', (176, 185))
78468	28637487	NF1 amplification, and presumably increased neurofibromin expression and hence activity, has been identified in many cancers, including breast (17%), pancreatic (21.5%), uterine endometrial (1.8%) and neuroendocrine prostate cancer (21.5%).	('expression', 'MPA', (58, 68))	('neuroendocrine prostate cancer', 'Disease', 'MESH:D011471', (201, 231))	('amplification', 'Var', (4, 17))	('NF1', 'Gene', (0, 3))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('cancers', 'Disease', 'MESH:D009369', (117, 124))	('uterine endometrial', 'Disease', (170, 189))	('activity', 'MPA', (79, 87))	('neuroendocrine prostate cancer', 'Disease', (201, 231))	('prostate cancer', 'Phenotype', 'HP:0012125', (216, 231))	('increased', 'PosReg', (34, 43))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('pancreatic', 'Disease', 'MESH:D010195', (150, 160))	('cancers', 'Phenotype', 'HP:0002664', (117, 124))	('breast', 'Disease', (136, 142))	('cancers', 'Disease', (117, 124))	('increased neurofibromin', 'Phenotype', 'HP:0001067', (34, 57))	('identified', 'Reg', (98, 108))	('pancreatic', 'Disease', (150, 160))
78469	28637487	The pathological significance of sporadic NF1 point mutations, especially putative missense mutations that have been identified in many sporadic tumours, is often unclear.	('sporadic tumours', 'Disease', 'MESH:D009369', (136, 152))	('tumours', 'Phenotype', 'HP:0002664', (145, 152))	('missense mutations', 'Var', (83, 101))	('tumour', 'Phenotype', 'HP:0002664', (145, 151))	('sporadic tumours', 'Disease', (136, 152))	('NF1', 'Gene', (42, 45))	('point mutations', 'Var', (46, 61))
78470	28637487	Constitutional NF1 missense mutations represent about 15% of all NF1 mutations, but their frequency in sporadic tumours ranges widely from 15 to 71%.	('sporadic tumours', 'Disease', (103, 119))	('mutations', 'Var', (69, 78))	('tumours', 'Phenotype', 'HP:0002664', (112, 119))	('NF1', 'Gene', (15, 18))	('sporadic tumours', 'Disease', 'MESH:D009369', (103, 119))	('NF1', 'Gene', (65, 68))	('tumour', 'Phenotype', 'HP:0002664', (112, 118))	('missense mutations', 'Var', (19, 37))
78471	28637487	For example, through analysis of missense mutations, the arginine finger loop of the neurofibromin GRD has been found to be crucial for stabilizing the transition state of the GTPase reaction, and many missense mutations in the GRD have been found to exert a significant, pathological effect on Ras activity levels.	('missense mutations', 'Var', (202, 220))	('pathological effect', 'Reg', (272, 291))	('GTP', 'Chemical', 'MESH:D006160', (176, 179))	('GRD', 'Gene', (228, 231))	('Ras activity levels', 'MPA', (295, 314))
78472	28637487	Somatic NF1 mutations are present in tumours associated with NF1 and in a range of sporadic tumours, in different cell types and at various frequencies (Table 1).	('sporadic tumours', 'Disease', (83, 99))	('NF1', 'Gene', (8, 11))	('NF1', 'Disease', (61, 64))	('tumours', 'Phenotype', 'HP:0002664', (37, 44))	('tumours', 'Phenotype', 'HP:0002664', (92, 99))	('sporadic tumours', 'Disease', 'MESH:D009369', (83, 99))	('mutations', 'Var', (12, 21))	('tumours', 'Disease', 'MESH:D009369', (92, 99))	('tumours', 'Disease', (92, 99))	('tumours', 'Disease', 'MESH:D009369', (37, 44))	('tumours', 'Disease', (37, 44))	('tumour', 'Phenotype', 'HP:0002664', (92, 98))	('tumour', 'Phenotype', 'HP:0002664', (37, 43))
78474	28637487	Whilst it is unclear whether the biallelic loss of NF1 is common or if only heterozygous mutations of NF1 contribute to tumour progression in sporadic tumours, mouse cells heterozygous for Nf1 mutations show abnormal growth and invasion.	('growth', 'CPA', (217, 223))	('sporadic tumours', 'Disease', (142, 158))	('abnormal growth', 'Phenotype', 'HP:0001507', (208, 223))	('tumour', 'Phenotype', 'HP:0002664', (151, 157))	('tumour', 'Disease', 'MESH:D009369', (120, 126))	('Nf1', 'Gene', (189, 192))	('NF1', 'Gene', (102, 105))	('sporadic tumours', 'Disease', 'MESH:D009369', (142, 158))	('tumour', 'Disease', (120, 126))	('mutations', 'Var', (193, 202))	('tumour', 'Disease', 'MESH:D009369', (151, 157))	('tumours', 'Phenotype', 'HP:0002664', (151, 158))	('Nf1', 'Gene', '18015', (189, 192))	('tumour', 'Disease', (151, 157))	('mouse', 'Species', '10090', (160, 165))	('tumour', 'Phenotype', 'HP:0002664', (120, 126))
78475	28637487	Somatic NF1 mutations may be critical drivers in multiple cancers as well as contributing to resistance to therapy.	('NF1', 'Gene', (8, 11))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('mutations', 'Var', (12, 21))	('cancers', 'Phenotype', 'HP:0002664', (58, 65))	('cancers', 'Disease', 'MESH:D009369', (58, 65))	('cancers', 'Disease', (58, 65))	('contributing', 'Reg', (77, 89))
78476	28637487	The mutational landscape of somatic NF1 mutation should provide new insights into our understanding of the pathophysiology of cancer.	('mutation', 'Var', (40, 48))	('NF1', 'Gene', (36, 39))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))
78480	28637487	The identification of somatic NF1 mutations in such a wide spectrum of tumours, including types not associated with NF1, indicates that neurofibromin is likely to play a key role in cancer, far beyond that evident in the tumour predisposition syndrome NF1.	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('tumours', 'Phenotype', 'HP:0002664', (71, 78))	('tumour', 'Disease', (221, 227))	('tumour', 'Disease', (71, 77))	('tumours', 'Disease', 'MESH:D009369', (71, 78))	('NF1', 'Gene', (30, 33))	('tumours', 'Disease', (71, 78))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('tumour', 'Phenotype', 'HP:0002664', (221, 227))	('tumour', 'Phenotype', 'HP:0002664', (71, 77))	('cancer', 'Disease', (182, 188))	('mutations', 'Var', (34, 43))	('tumour', 'Disease', 'MESH:D009369', (221, 227))	('tumour', 'Disease', 'MESH:D009369', (71, 77))
78510	28000729	PLR > 120 was only associated with advanced AJCC TNM stage (P = 0.015).	('PLR', 'Var', (0, 3))	('TNM', 'Gene', (49, 52))	('TNM', 'Gene', '10178', (49, 52))
78597	24113773	Similarly, the microdissected stroma-enriched fraction in the three independent public data sets, which were not used in construction of the gene signature was significantly decreased (ovarian cancer (GSE29156), P=2.5 x 10-5; breast cancer (GSE10797), P=1.9 x 10-7; lung cancer (GSE33363), P=5.7 x 10-7 by paired t-test; Fig.	('ovarian cancer', 'Phenotype', 'HP:0100615', (185, 199))	('decreased', 'NegReg', (174, 183))	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('breast cancer', 'Disease', (226, 239))	('cancer', 'Phenotype', 'HP:0002664', (271, 277))	('breast cancer', 'Phenotype', 'HP:0003002', (226, 239))	('ovarian cancer', 'Disease', 'MESH:D010051', (185, 199))	('lung cancer', 'Phenotype', 'HP:0100526', (266, 277))	('lung cancer', 'Disease', 'MESH:D008175', (266, 277))	('ovarian cancer', 'Disease', (185, 199))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('breast cancer', 'Disease', 'MESH:D001943', (226, 239))	('GSE10797', 'Var', (241, 249))	('GSE29156', 'Var', (201, 209))	('lung cancer', 'Disease', (266, 277))	('GSE33363', 'Var', (279, 287))
78644	24113773	We observed a reduced number of mutations per megabase in low-purity head and neck squamous cell carcinomas and clear cell renal cell carcinomas, (unpaired t-test with Benjamini-Hochberg FDR correction, adjusted P=0.055 and 0.055) but not in other tumour types, suggesting that the sequencing coverage used for TCGA samples is sufficient to comprehensively detect somatic sequence variants (Supplementary Fig.	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('carcinomas', 'Phenotype', 'HP:0030731', (134, 144))	('clear cell renal cell carcinomas', 'Phenotype', 'HP:0006770', (112, 144))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (83, 106))	('clear cell renal cell carcinomas', 'Disease', (112, 144))	('neck squamous cell carcinomas', 'Disease', 'MESH:D000077195', (78, 107))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (112, 143))	('clear cell renal cell carcinomas', 'Disease', 'MESH:C538614', (112, 144))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (83, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('mutations', 'Var', (32, 41))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (123, 144))	('carcinomas', 'Phenotype', 'HP:0030731', (97, 107))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (123, 143))	('tumour type', 'Disease', (248, 259))	('tumour', 'Phenotype', 'HP:0002664', (248, 254))	('neck squamous cell carcinomas', 'Disease', (78, 107))	('tumour type', 'Disease', 'MESH:D009369', (248, 259))
78645	24113773	Two of the ten TCGA data sets (head and neck squamous cell carcinoma, lung squamous cell carcinoma) showed a significantly decreased fraction of T>A substitutions in the low-purity group compared with the high-purity group (unpaired t-test with Benjamini-Hochberg FDR correction, adjusted P=0.015 and 0.015, respectively) (Supplementary Table S5).	('decreased', 'NegReg', (123, 132))	('substitutions', 'Var', (149, 162))	('T>A', 'Gene', (145, 148))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (70, 98))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (75, 98))	('lung squamous cell carcinoma', 'Disease', (70, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (59, 68))	('neck squamous cell carcinoma', 'Disease', (40, 68))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (45, 68))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (40, 68))
78646	24113773	The ratio of transitions and transversions was significantly associated with purity level in head and neck squamous cell carcinoma (adjusted P=0.018).	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('neck squamous cell carcinoma', 'Disease', (102, 130))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (102, 130))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (107, 130))	('transitions', 'Var', (13, 24))	('associated', 'Reg', (61, 71))
78668	24113773	The consistent reduction in T>A substitutions in some low-purity cases suggests that the tumour microenvironment can have an impact on mutational processes or alternatively that the types of mutations in the tumour can alter stromal and immune infiltrations.	('tumour', 'Phenotype', 'HP:0002664', (89, 95))	('tumour', 'Disease', (208, 214))	('tumour', 'Disease', 'MESH:D009369', (89, 95))	('reduction', 'NegReg', (15, 24))	('T>A', 'Gene', (28, 31))	('mutations', 'Var', (191, 200))	('tumour', 'Disease', (89, 95))	('mutational', 'MPA', (135, 145))	('alter', 'Reg', (219, 224))	('substitutions', 'Var', (32, 45))	('tumour', 'Phenotype', 'HP:0002664', (208, 214))	('impact', 'Reg', (125, 131))	('tumour', 'Disease', 'MESH:D009369', (208, 214))
78689	24113773	Third, we compared the tumour portion with their matched stromal part after laser-capture microdissection including ovarian cancer (GSE9890), breast cancer (GSE14548) and colorectal cancer (GSE35602) in order to evaluate the possibility that stroma-forming cells in tumour tissue differ among various tumour types.	('tumour', 'Phenotype', 'HP:0002664', (23, 29))	('tumour', 'Disease', 'MESH:D009369', (23, 29))	('breast cancer', 'Disease', 'MESH:D001943', (142, 155))	('ovarian cancer', 'Disease', (116, 130))	('tumour', 'Disease', (23, 29))	('breast cancer', 'Disease', (142, 155))	('tumour', 'Phenotype', 'HP:0002664', (266, 272))	('ovarian cancer', 'Phenotype', 'HP:0100615', (116, 130))	('colorectal cancer', 'Phenotype', 'HP:0003003', (171, 188))	('tumour', 'Disease', 'MESH:D009369', (266, 272))	('tumour type', 'Disease', 'MESH:D009369', (301, 312))	('tumour', 'Disease', (266, 272))	('GSE14548', 'Var', (157, 165))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('tumour type', 'Disease', (301, 312))	('GSE9890', 'Var', (132, 139))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('colorectal cancer', 'Disease', 'MESH:D015179', (171, 188))	('tumour', 'Phenotype', 'HP:0002664', (301, 307))	('GSE35602', 'Var', (190, 198))	('tumour', 'Disease', 'MESH:D009369', (301, 307))	('ovarian cancer', 'Disease', 'MESH:D010051', (116, 130))	('colorectal cancer', 'Disease', (171, 188))	('tumour', 'Disease', (301, 307))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('breast cancer', 'Phenotype', 'HP:0003002', (142, 155))
78713	24113773	To investigate the mutation spectrum between the two subgroups per tumour type, we selected single-nucleotide alterations and converted them into the six classes of base substitution (C>A, C>G, C>T, T>A, T>C and T>G).	('tumour', 'Phenotype', 'HP:0002664', (67, 73))	('C>A', 'Var', (184, 187))	('tumour type', 'Disease', 'MESH:D009369', (67, 78))	('T>G', 'Var', (212, 215))	('T>C and T>G', 'Var', (204, 215))	('C>G', 'Var', (189, 192))	('C>T', 'Var', (194, 197))	('T>A', 'Var', (199, 202))	('tumour type', 'Disease', (67, 78))
78725	33123467	Lastly, the abnormal expression of miR-24 was involved in the chemo- and radio- therapies of cancer patients, indicating the role of miR-24 being as a predictive biomarker to cancer treatment.	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('cancer', 'Disease', (175, 181))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('expression', 'MPA', (21, 31))	('miR-24', 'Gene', (35, 41))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('abnormal', 'Var', (12, 20))	('patients', 'Species', '9606', (100, 108))	('involved', 'Reg', (46, 54))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
78732	33123467	For example, dysregulation of miRNAs has been widely involved in the activation of oncogenes in hepatocellular carcinoma (HCC), showing the potential diagnostic and therapeutic value of miRNAs in HCC.	('miR', 'Gene', '220972', (186, 189))	('miR', 'Gene', '220972', (30, 33))	('involved', 'Reg', (53, 61))	('miR', 'Gene', (30, 33))	('hepatocellular carcinoma', 'Disease', (96, 120))	('miR', 'Gene', (186, 189))	('HCC', 'Gene', (122, 125))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (96, 120))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (96, 120))	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('HCC', 'Gene', (196, 199))	('dysregulation', 'Var', (13, 26))	('HCC', 'Phenotype', 'HP:0001402', (122, 125))	('HCC', 'Gene', '619501', (122, 125))	('HCC', 'Gene', '619501', (196, 199))	('oncogenes', 'Gene', (83, 92))	('HCC', 'Phenotype', 'HP:0001402', (196, 199))	('activation', 'PosReg', (69, 79))
78741	33123467	And ectopic miR-24 expression promoted NSCLC cell migration and invasion by targeting ZNF367.	('NSCLC', 'Phenotype', 'HP:0030358', (39, 44))	('LC', 'Phenotype', 'HP:0100526', (42, 44))	('invasion', 'CPA', (64, 72))	('promoted', 'PosReg', (30, 38))	('NSCLC', 'Disease', (39, 44))	('ectopic', 'Var', (4, 11))	('targeting', 'Reg', (76, 85))	('miR-24', 'Gene', (12, 18))	('NSCLC', 'Disease', 'MESH:D002289', (39, 44))	('ZNF367', 'Gene', '195828', (86, 92))	('ZNF367', 'Gene', (86, 92))
78745	33123467	And patients whose primary tumors expressed high levels of miR-24-3p showed a significantly lower survival rate compared to patients with low miR-24-3p levels in the TCGA (The Cancer Genome Atlas Program) cohort.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('Cancer', 'Phenotype', 'HP:0002664', (176, 182))	('miR-24-3p', 'Chemical', '-', (59, 68))	('patients', 'Species', '9606', (124, 132))	('miR-24-3p', 'Var', (59, 68))	('miR-24-3p', 'Chemical', '-', (142, 151))	('tumors', 'Disease', (27, 33))	('tumors', 'Disease', 'MESH:D009369', (27, 33))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('Cancer', 'Disease', (176, 182))	('patients', 'Species', '9606', (4, 12))	('Cancer', 'Disease', 'MESH:D009369', (176, 182))	('lower', 'NegReg', (92, 97))	('survival rate', 'CPA', (98, 111))
78746	33123467	MiR-24 was found to reduce breast cancer cell apoptosis, cleaved caspase-3 and the expression of p27.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('MiR-24', 'Var', (0, 6))	('breast cancer', 'Disease', 'MESH:D001943', (27, 40))	('caspase-3', 'Gene', '836', (65, 74))	('reduce', 'NegReg', (20, 26))	('breast cancer', 'Disease', (27, 40))	('MiR-24', 'Chemical', '-', (0, 6))	('p27', 'Gene', '3429', (97, 100))	('p27', 'Gene', (97, 100))	('breast cancer', 'Phenotype', 'HP:0003002', (27, 40))	('expression', 'MPA', (83, 93))	('caspase-3', 'Gene', (65, 74))
78749	33123467	In colorectal cancer, miR-24-1-5p could decrease cell proliferation and migration by repressing beta-catenin expression, indicating its role as a tumor suppressor in CRC.	('decrease', 'NegReg', (40, 48))	('beta-catenin', 'Gene', '1499', (96, 108))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('colorectal cancer', 'Phenotype', 'HP:0003003', (3, 20))	('miR-24-1-5p', 'Chemical', '-', (22, 33))	('miR-24-1-5p', 'Var', (22, 33))	('tumor', 'Disease', (146, 151))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('cell proliferation', 'CPA', (49, 67))	('colorectal cancer', 'Disease', (3, 20))	('CRC', 'Phenotype', 'HP:0003003', (166, 169))	('tumor', 'Disease', 'MESH:D009369', (146, 151))	('repressing', 'NegReg', (85, 95))	('colorectal cancer', 'Disease', 'MESH:D015179', (3, 20))	('beta-catenin', 'Gene', (96, 108))
78755	33123467	Several clinical evidences have supported the idea that dysregulation of miR-24 is correlated with the clinical features of human cancer.	('correlated', 'Reg', (83, 93))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('cancer', 'Disease', (130, 136))	('human', 'Species', '9606', (124, 129))	('dysregulation', 'Var', (56, 69))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('miR-24', 'Gene', (73, 79))
78767	33123467	A variety of findings have confirmed that dysregulation of miR-24 is related to the clinical performance of human cancer.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('clinical performance', 'CPA', (84, 104))	('dysregulation', 'Var', (42, 55))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('miR-24', 'Gene', (59, 65))	('human', 'Species', '9606', (108, 113))	('related', 'Reg', (69, 76))	('cancer', 'Disease', (114, 120))
78790	33123467	A study found that miR-24-3p had excellent diagnostic accuracy for oral squamous cell carcinoma [(AUC) = 0.738; P = 0.02], thus salivary exosomal miR-24-3p could be a potential novel diagnostic biomarker for OSCC.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (72, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('miR-24-3p', 'Chemical', '-', (146, 155))	('miR-24-3p', 'Chemical', '-', (19, 28))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (67, 95))	('miR-24-3p', 'Var', (19, 28))	('oral squamous cell carcinoma', 'Disease', (67, 95))
78792	33123467	Regarding the differential expression of miR-24 in human cancer, miR-24 is associated with patient survival, indicating it could be a potential prognostic biomarker in cancer.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('cancer', 'Disease', (57, 63))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('miR-24', 'Gene', (41, 47))	('human', 'Species', '9606', (51, 56))	('cancer', 'Disease', (168, 174))	('miR-24', 'Var', (65, 71))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('patient survival', 'CPA', (91, 107))	('associated', 'Reg', (75, 85))	('patient', 'Species', '9606', (91, 98))
78795	33123467	And in acute leukemia, Kaplan-Meier analysis showed that AL patients with high miR-24 expression tended to have shorter overall survival, and in the multivariate analysis stratified for known prognostic variables, miR-24 was identified as an independent prognostic marker.	('leukemia', 'Phenotype', 'HP:0001909', (13, 21))	('acute leukemia', 'Disease', 'MESH:D015470', (7, 21))	('high', 'Var', (74, 78))	('patients', 'Species', '9606', (60, 68))	('expression', 'MPA', (86, 96))	('acute leukemia', 'Phenotype', 'HP:0002488', (7, 21))	('miR-24', 'Gene', (79, 85))	('AL', 'Phenotype', 'HP:0002488', (57, 59))	('overall survival', 'MPA', (120, 136))	('shorter', 'NegReg', (112, 119))	('acute leukemia', 'Disease', (7, 21))	('AL', 'Disease', 'MESH:D009101', (57, 59))
78796	33123467	In contrast, CRC patients with low miR-24-3p level had a significantly poorer prognosis than those with high miR-24-3p level.	('CRC', 'Phenotype', 'HP:0003003', (13, 16))	('miR-24-3p', 'Chemical', '-', (35, 44))	('CRC', 'Disease', (13, 16))	('miR-24-3p level', 'Var', (35, 50))	('patients', 'Species', '9606', (17, 25))	('low', 'NegReg', (31, 34))	('miR-24-3p', 'Chemical', '-', (109, 118))
78797	33123467	And multivariate analysis revealed that miR-24-3p could be an independent prognostic indicator for OS of CRC patients.	('miR-24-3p', 'Chemical', '-', (40, 49))	('miR-24-3p', 'Var', (40, 49))	('patients', 'Species', '9606', (109, 117))	('CRC', 'Phenotype', 'HP:0003003', (105, 108))	('OS of CRC', 'Disease', (99, 108))
78799	33123467	In nasopharyngeal carcinoma, a survey proved that exosomal miR-24-3p could serve as a prognostic biomarker, due to its involvement in tumor pathogenesis by mediating T-cell inhibition.	('carcinoma', 'Phenotype', 'HP:0030731', (18, 27))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (3, 27))	('T-cell inhibition', 'CPA', (166, 183))	('miR-24-3p', 'Chemical', '-', (59, 68))	('carcinoma', 'Disease', (18, 27))	('exosomal', 'Var', (50, 58))	('involvement', 'Reg', (119, 130))	('miR-24-3p', 'Protein', (59, 68))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('carcinoma', 'Disease', 'MESH:D009369', (18, 27))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('tumor', 'Disease', (134, 139))
78807	33123467	In mesothelioma, miR-24-3p promoted tumorigenesis by inducing cancer cell growth and regulating Rho-GTP activity positively.	('miR-24-3p', 'Chemical', '-', (17, 26))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('GTP', 'Chemical', 'MESH:D006160', (100, 103))	('mesothelioma', 'Disease', (3, 15))	('regulating', 'Reg', (85, 95))	('promoted', 'PosReg', (27, 35))	('miR-24-3p', 'Var', (17, 26))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('inducing', 'PosReg', (53, 61))	('Rho-GTP activity', 'MPA', (96, 112))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('mesothelioma', 'Disease', 'MESH:D008654', (3, 15))	('tumor', 'Disease', (36, 41))
78808	33123467	In hepatocellular carcinoma, miR-24-3p increased cancer cell viability and reduced its cell apoptosis.	('carcinoma', 'Phenotype', 'HP:0030731', (18, 27))	('hepatocellular carcinoma', 'Disease', (3, 27))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('reduced', 'NegReg', (75, 82))	('cell apoptosis', 'CPA', (87, 101))	('increased', 'PosReg', (39, 48))	('miR-24-3p', 'Chemical', '-', (29, 38))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (3, 27))	('cancer', 'Disease', (49, 55))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (3, 27))	('miR-24-3p', 'Var', (29, 38))
78812	33123467	Although a previous study showed that miR-24-3p functioned as a tumor suppressor in CRC.	('tumor', 'Disease', (64, 69))	('miR-24-3p', 'Chemical', '-', (38, 47))	('CRC', 'Disease', (84, 87))	('miR-24-3p', 'Var', (38, 47))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('CRC', 'Phenotype', 'HP:0003003', (84, 87))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
78815	33123467	MiR-24-3p mediated the tumorigenesis promotion and accelerated xenografted tumor growth of breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('breast cancer', 'Disease', (91, 104))	('breast cancer', 'Phenotype', 'HP:0003002', (91, 104))	('MiR-24-3p', 'Chemical', '-', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('MiR-24-3p', 'Var', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', (23, 28))	('accelerated', 'PosReg', (51, 62))	('breast cancer', 'Disease', 'MESH:D001943', (91, 104))	('tumor', 'Disease', (75, 80))
78816	33123467	As shown in Figure 1, overexpressing miR-24-3p promoted cell proliferation and inhibited cell apoptosis in breast cancer by targeting p27Kip1.	('p27Kip1', 'Gene', (134, 141))	('promoted', 'PosReg', (47, 55))	('cell apoptosis', 'CPA', (89, 103))	('breast cancer', 'Disease', 'MESH:D001943', (107, 120))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('cell proliferation', 'CPA', (56, 74))	('inhibited', 'NegReg', (79, 88))	('breast cancer', 'Disease', (107, 120))	('breast cancer', 'Phenotype', 'HP:0003002', (107, 120))	('miR-24-3p', 'Chemical', '-', (37, 46))	('targeting', 'Reg', (124, 133))	('p27Kip1', 'Gene', '1027', (134, 141))	('miR-24-3p', 'Var', (37, 46))
78819	33123467	In bladder cancer, miR-24-3p increased cell proliferation and migration ability by targeting DEDD (Asp-Glu-Asp-Asp domain).	('Asp', 'Chemical', 'MESH:D001224', (99, 102))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('bladder cancer', 'Phenotype', 'HP:0009725', (3, 17))	('DEDD', 'Gene', (93, 97))	('Glu', 'Chemical', 'MESH:D018698', (103, 106))	('increased', 'PosReg', (29, 38))	('migration ability', 'CPA', (62, 79))	('Asp', 'Chemical', 'MESH:D001224', (107, 110))	('DEDD', 'Gene', '9191', (93, 97))	('miR-24-3p', 'Chemical', '-', (19, 28))	('bladder cancer', 'Disease', 'MESH:D001749', (3, 17))	('bladder cancer', 'Disease', (3, 17))	('cell proliferation', 'CPA', (39, 57))	('miR-24-3p', 'Var', (19, 28))	('Asp', 'Chemical', 'MESH:D001224', (111, 114))
78820	33123467	On the other hand, however, miR-24 suppresses tumorigenesis in some human cancers.	('human', 'Species', '9606', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('cancers', 'Disease', 'MESH:D009369', (74, 81))	('cancers', 'Phenotype', 'HP:0002664', (74, 81))	('tumor', 'Disease', (46, 51))	('miR-24', 'Var', (28, 34))	('cancers', 'Disease', (74, 81))	('suppresses', 'NegReg', (35, 45))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
78822	33123467	In CRC, miR-24-3p suppressed cancer cell proliferation, cell migration and invasion, functioning as a tumor suppressor.	('cancer', 'Disease', (29, 35))	('CRC', 'Phenotype', 'HP:0003003', (3, 6))	('tumor', 'Disease', (102, 107))	('invasion', 'CPA', (75, 83))	('cell migration', 'CPA', (56, 70))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('miR-24-3p', 'Chemical', '-', (8, 17))	('suppressed', 'NegReg', (18, 28))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('miR-24-3p', 'Var', (8, 17))	('cancer', 'Disease', 'MESH:D009369', (29, 35))
78823	33123467	And miR-24-1-5p decreased CRC cell proliferation, migration and survival significantly by repressing beta-catenin expression.	('survival', 'CPA', (64, 72))	('repressing', 'NegReg', (90, 100))	('beta-catenin', 'Gene', (101, 113))	('migration', 'CPA', (50, 59))	('miR-24-1-5p', 'Var', (4, 15))	('beta-catenin', 'Gene', '1499', (101, 113))	('CRC', 'Phenotype', 'HP:0003003', (26, 29))	('miR-24-1-5p', 'Chemical', '-', (4, 15))	('CRC cell proliferation', 'CPA', (26, 48))	('decreased', 'NegReg', (16, 25))
78824	33123467	Ectopic expression of miR-24 inhibited cell cycle, proliferation, migration, and clonogenic potential of prostate cancer cells, as well as inducing cell apoptosis.	('inhibited', 'NegReg', (29, 38))	('migration', 'CPA', (66, 75))	('prostate cancer', 'Disease', (105, 120))	('clonogenic potential', 'CPA', (81, 101))	('prostate cancer', 'Phenotype', 'HP:0012125', (105, 120))	('Ectopic expression', 'Var', (0, 18))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('prostate cancer', 'Disease', 'MESH:D011471', (105, 120))	('inducing', 'Reg', (139, 147))	('cell cycle', 'CPA', (39, 49))	('miR-24', 'Gene', (22, 28))	('cell apoptosis', 'CPA', (148, 162))
78825	33123467	In pancreatic ductal adenocarcinoma (PDA), miR-24-3p exerted its anti-cancer role by suppressing the expression of Laminin Subunit Beta 3 (LAMB3), an oncogene.	('LAMB3', 'Gene', '3914', (139, 144))	('LA', 'Phenotype', 'HP:0030078', (139, 141))	('Laminin Subunit Beta 3', 'Gene', (115, 137))	('suppressing', 'NegReg', (85, 96))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (3, 35))	('miR-24-3p', 'Chemical', '-', (43, 52))	('Laminin Subunit Beta 3', 'Gene', '3914', (115, 137))	('pancreatic ductal adenocarcinoma', 'Disease', (3, 35))	('LAMB3', 'Gene', (139, 144))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (3, 35))	('carcinoma', 'Phenotype', 'HP:0030731', (26, 35))	('expression', 'MPA', (101, 111))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('PDA', 'Phenotype', 'HP:0006725', (37, 40))	('miR-24-3p', 'Var', (43, 52))
78828	33123467	For example, in colorectal cancer, overexpression of miR-24-1-5p significantly repressed beta-catenin expression, and simultaneously decreased CRC cell migration.	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('miR-24-1-5p', 'Chemical', '-', (53, 64))	('beta-catenin', 'Gene', '1499', (89, 101))	('colorectal cancer', 'Disease', 'MESH:D015179', (16, 33))	('miR-24-1-5p', 'Var', (53, 64))	('colorectal cancer', 'Phenotype', 'HP:0003003', (16, 33))	('CRC cell migration', 'CPA', (143, 161))	('overexpression', 'PosReg', (35, 49))	('repressed', 'PosReg', (79, 88))	('beta-catenin', 'Gene', (89, 101))	('colorectal cancer', 'Disease', (16, 33))	('decreased', 'NegReg', (133, 142))	('CRC', 'Phenotype', 'HP:0003003', (143, 146))
78829	33123467	also confirmed that miR-24 inhibited the cell growth of both lung and colon carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('miR-24', 'Var', (20, 26))	('colon carcinoma', 'Disease', (70, 85))	('inhibited', 'NegReg', (27, 36))	('cell growth', 'CPA', (41, 52))	('colon carcinoma', 'Disease', 'MESH:D003110', (70, 85))	('lung', 'Disease', (61, 65))
78831	33123467	And In lung adenocarcinoma, miR-24-3p could suppress cell proliferation, migration, and invasion by regulating FGFR3 directly.	('migration', 'CPA', (73, 82))	('miR-24-3p', 'Chemical', '-', (28, 37))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (7, 26))	('invasion', 'CPA', (88, 96))	('FGFR3', 'Gene', '2261', (111, 116))	('miR-24-3p', 'Var', (28, 37))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (7, 26))	('suppress', 'NegReg', (44, 52))	('regulating', 'Reg', (100, 110))	('FGFR3', 'Gene', (111, 116))	('cell proliferation', 'CPA', (53, 71))	('lung adenocarcinoma', 'Disease', (7, 26))	('carcinoma', 'Phenotype', 'HP:0030731', (17, 26))
78832	33123467	In acute lymphoblastic leukemia, miR-24-3p induced cell apoptosis by regulating XIAP (X-linked inhibitor of apoptosis protein).	('acute lymphoblastic leukemia', 'Disease', (3, 31))	('X-linked inhibitor of apoptosis protein', 'Gene', '331', (86, 125))	('leukemia', 'Phenotype', 'HP:0001909', (23, 31))	('induced', 'Reg', (43, 50))	('XIAP', 'Gene', (80, 84))	('XIAP', 'Gene', '331', (80, 84))	('acute lymphoblastic leukemia', 'Disease', 'MESH:D054198', (3, 31))	('X-linked inhibitor of apoptosis protein', 'Gene', (86, 125))	('miR-24-3p', 'Chemical', '-', (33, 42))	('regulating', 'Reg', (69, 79))	('cell apoptosis', 'CPA', (51, 65))	('miR-24-3p', 'Var', (33, 42))	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (3, 31))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (9, 31))
78840	33123467	What's more, ectopic expression of miR-24 could enhance the chemosensitivity of CRC cells to 5-fluorouracil (5-FU) by targeting RNA-binding protein DND1 (dead end protein 1).	('targeting', 'Reg', (118, 127))	('chemosensitivity of CRC cells', 'CPA', (60, 89))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (93, 107))	('RNA-binding protein', 'Protein', (128, 147))	('DND1', 'Gene', (148, 152))	('miR-24', 'Gene', (35, 41))	('enhance', 'PosReg', (48, 55))	('dead end protein 1', 'Gene', (154, 172))	('DND1', 'Gene', '373863', (148, 152))	('dead end protein 1', 'Gene', '373863', (154, 172))	('CRC', 'Phenotype', 'HP:0003003', (80, 83))	('ectopic expression', 'Var', (13, 31))	('5-FU', 'Chemical', 'MESH:D005472', (109, 113))
78843	33123467	In prostate cancer, overexpression of miR-24-3p inhibited survival rate, half maximal inhibitory concentration (IC50) of paclitaxel (PTX) but increased apoptosis in prostate cancer cells after treatment of PTX, via regulating fascin1 (FSCN1).	('regulating', 'Reg', (215, 225))	('prostate cancer', 'Phenotype', 'HP:0012125', (3, 18))	('miR-24-3p', 'Chemical', '-', (38, 47))	('overexpression', 'PosReg', (20, 34))	('prostate cancer', 'Disease', (3, 18))	('FSCN1', 'Gene', (235, 240))	('paclitaxel', 'Chemical', 'MESH:D017239', (121, 131))	('miR-24-3p', 'Var', (38, 47))	('half', 'MPA', (73, 77))	('PTX', 'Chemical', 'MESH:D017239', (206, 209))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('fascin1', 'Gene', '6624', (226, 233))	('survival rate', 'CPA', (58, 71))	('PTX', 'Chemical', 'MESH:D017239', (133, 136))	('inhibited', 'NegReg', (48, 57))	('FSCN1', 'Gene', '6624', (235, 240))	('apoptosis', 'CPA', (152, 161))	('increased', 'PosReg', (142, 151))	('prostate cancer', 'Disease', 'MESH:D011471', (165, 180))	('prostate cancer', 'Phenotype', 'HP:0012125', (165, 180))	('fascin1', 'Gene', (226, 233))	('prostate cancer', 'Disease', (165, 180))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('prostate cancer', 'Disease', 'MESH:D011471', (3, 18))
78846	33123467	Interestingly, another study, published at the same year for the same cancer type, reported that miR-24-3p increased tamoxifen sensitivity by targeting Bim, leading to the induction of breast cancer cell apoptosis, acting as a tumor suppressor.	('tumor', 'Disease', (227, 232))	('cancer', 'Disease', (192, 198))	('tumor', 'Disease', 'MESH:D009369', (227, 232))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('increased', 'PosReg', (107, 116))	('tamoxifen', 'Chemical', 'MESH:D013629', (117, 126))	('cancer', 'Disease', (70, 76))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('miR-24-3p', 'Chemical', '-', (97, 106))	('breast cancer', 'Phenotype', 'HP:0003002', (185, 198))	('tamoxifen sensitivity', 'MPA', (117, 138))	('cancer', 'Disease', 'MESH:D009369', (192, 198))	('Bim', 'Gene', '10018', (152, 155))	('induction', 'Reg', (172, 181))	('breast cancer', 'Disease', 'MESH:D001943', (185, 198))	('breast cancer', 'Disease', (185, 198))	('miR-24-3p', 'Var', (97, 106))	('Bim', 'Gene', (152, 155))	('cancer', 'Disease', 'MESH:D009369', (70, 76))
78864	31548239	Conversely, we found that pharmacologic activation of PI3K signaling can repress the induction of MHCI and MHCII molecules by IFN-gamma and likewise the loss of PTEN attenuates the induction of MHCI, MHCII, and STAT1 by IFN-gamma.	('MHCII', 'Gene', (107, 112))	('MHCII', 'Gene', (200, 205))	('induction', 'MPA', (85, 94))	('repress', 'NegReg', (73, 80))	('loss', 'Var', (153, 157))	('MHCII', 'Gene', '111364', (107, 112))	('MHCI', 'Gene', (98, 102))	('MHCII', 'Gene', '111364', (200, 205))	('attenuates', 'NegReg', (166, 176))	('PTEN', 'Gene', (161, 165))	('PTEN', 'Gene', '5728', (161, 165))
78865	31548239	Consistent with these in vitro studies, we found that within human head and neck squamous cell carcinomas, intra-tumoral regions with high phospho-AKT immunohistochemical (IHC) staining had reduced MHCI IHC staining.	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (81, 105))	('intra-tumoral', 'Disease', (107, 120))	('neck squamous cell carcinomas', 'Disease', (76, 105))	('MHCI IHC staining', 'MPA', (198, 215))	('high', 'Var', (134, 138))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (67, 104))	('reduced', 'NegReg', (190, 197))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('AKT', 'Gene', '207', (147, 150))	('carcinomas', 'Phenotype', 'HP:0030731', (95, 105))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (81, 104))	('head and neck squamous cell carcinomas', 'Phenotype', 'HP:0012288', (67, 105))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('human', 'Species', '9606', (61, 66))	('intra-tumoral', 'Disease', 'MESH:D009369', (107, 120))	('neck squamous cell carcinomas', 'Disease', 'MESH:D000077195', (76, 105))	('AKT', 'Gene', (147, 150))
78872	31548239	Conversely, high MHCI and/or MHCII expression is typically associated with an improved clinical response to immunotherapy.	('high', 'Var', (12, 16))	('MHCII', 'Gene', (29, 34))	('MHCI', 'Gene', (17, 21))	('MHCII', 'Gene', '111364', (29, 34))	('improved', 'PosReg', (78, 86))	('clinical response to immunotherapy', 'CPA', (87, 121))
78886	31548239	Antibodies recognizing total STAT1, phospho-STAT1-Y701, phospho-STAT1-S727, total AKT, phospho-AKT-S473, phospho-AKT-T308, and PTEN were all purchased from Cell Signaling (Danvers, MA).	('AKT', 'Gene', '207', (95, 98))	('AKT', 'Gene', '207', (113, 116))	('phospho-STAT1-S727', 'Var', (56, 74))	('AKT', 'Gene', '207', (82, 85))	('AKT', 'Gene', (95, 98))	('AKT', 'Gene', (113, 116))	('PTEN', 'Gene', (127, 131))	('PTEN', 'Gene', '5728', (127, 131))	('AKT', 'Gene', (82, 85))
78894	31548239	Mutation, copy-number, and Z-score normalized RNAseq data for TCGA LUSC and PAAD were downloaded from cBioPortal and analyzed in R to generate violin plot distributions and compute p-values of differential HLA gene expression between cases with PTEN or PIK3CA alteration, and cases with no alterations in either gene.	('PIK3CA', 'Gene', (253, 259))	('alteration', 'Var', (260, 270))	('PIK3CA', 'Gene', '5290', (253, 259))	('PTEN', 'Gene', (245, 249))	('PTEN', 'Gene', '5728', (245, 249))	('differential HLA gene', 'Gene', (193, 214))	('expression', 'MPA', (215, 225))
78902	31548239	We found that like dactolisib, pictilisib could enhance the induction of MHCI induction by IFN-gamma (Figure 1A).	('pictilisib', 'Var', (31, 41))	('pictilisib', 'Chemical', 'MESH:C532162', (31, 41))	('induction', 'MPA', (60, 69))	('enhance', 'PosReg', (48, 55))	('MHCI induction', 'Gene', (73, 87))	('dactolisib', 'Chemical', 'MESH:C531198', (19, 29))
78903	31548239	Consistent with a prior study examining the effect of rapamycin on a murine model of head and neck squamous cell carcinoma (HNSCC), in our model, rapamycin augmented the induction of MHCI by IFN-gamma though to a lesser extent than either of the PI3K inhibitors (Figure 1A).	('rapamycin', 'Chemical', 'MESH:D020123', (54, 63))	('MHCI', 'Gene', (183, 187))	('SCC', 'Phenotype', 'HP:0002860', (126, 129))	('neck squamous cell carcinoma', 'Disease', (94, 122))	('HNSCC', 'Phenotype', 'HP:0012288', (124, 129))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (99, 122))	('augmented', 'PosReg', (156, 165))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (94, 122))	('rapamycin', 'Var', (146, 155))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (85, 122))	('rapamycin', 'Chemical', 'MESH:D020123', (146, 155))	('induction', 'MPA', (170, 179))	('murine', 'Species', '10090', (69, 75))
78909	31548239	As shown in Figure 1C, in the presence of pictilisib there were sustained increases in cell surface levels of MHCI and MHCII over the entire course of the experiment.	('pictilisib', 'Var', (42, 52))	('pictilisib', 'Chemical', 'MESH:C532162', (42, 52))	('MHCII', 'Gene', '111364', (119, 124))	('cell surface levels of', 'MPA', (87, 109))	('increases', 'PosReg', (74, 83))	('MHCII', 'Gene', (119, 124))
78910	31548239	To better define the roles of mTOR in MHCI and MHCII induction, we repeated experiments using a pan mTOR inhibitor AZD8055 and a PDK1 inhibitor BX795.	('PDK1', 'Gene', '5163', (129, 133))	('MHCII', 'Gene', '111364', (47, 52))	('PDK1', 'Gene', (129, 133))	('AZD8055', 'Chemical', 'MESH:C546624', (115, 122))	('MHCII', 'Gene', (47, 52))	('AZD8055', 'Var', (115, 122))	('BX795', 'Chemical', 'MESH:C579675', (144, 149))
78911	31548239	As shown in Figure 1D and as we observed with rapamycin, AZD8055 by itself augmented MHCI levels following IFN-gamma and did not alter the effect of pictilisib on MHCI induction.	('rapamycin', 'Chemical', 'MESH:D020123', (46, 55))	('MHCI levels', 'MPA', (85, 96))	('pictilisib', 'Chemical', 'MESH:C532162', (149, 159))	('AZD8055', 'Var', (57, 64))	('augmented', 'PosReg', (75, 84))	('AZD8055', 'Chemical', 'MESH:C546624', (57, 64))
78912	31548239	In contrast and like rapamycin, AZD8055 attenuated the impact of pictilisib on MHCII levels.	('AZD8055', 'Var', (32, 39))	('impact', 'MPA', (55, 61))	('MHCII', 'Gene', '111364', (79, 84))	('pictilisib', 'Chemical', 'MESH:C532162', (65, 75))	('rapamycin', 'Chemical', 'MESH:D020123', (21, 30))	('AZD8055', 'Chemical', 'MESH:C546624', (32, 39))	('attenuated', 'NegReg', (40, 50))	('MHCII', 'Gene', (79, 84))
78917	31548239	Pictilisib augmented the induction of MHCII in all cell lines as measured by average MFI and/or the percentage of cells expressing the MHCII gene HLA-DR (Figure 1G).	('MHCII', 'Gene', (135, 140))	('Pictilisib', 'Chemical', 'MESH:C532162', (0, 10))	('MFI', 'CPA', (85, 88))	('MHCII', 'Gene', '111364', (38, 43))	('MHCII', 'Gene', '111364', (135, 140))	('Pictilisib', 'Var', (0, 10))	('MHCII', 'Gene', (38, 43))
78921	31548239	Therefore, we tested the impact of PI3K inhibition using pictilisib on STAT1 induction by IFN-gamma and found that pictilisib increased the induction of total STAT1 by IFN-gamma with concomitant increases in phospho-STAT1-Y701 and S727 (Figure 2A and 2B).	('induction', 'MPA', (140, 149))	('pictilisib', 'Var', (115, 125))	('pictilisib', 'Chemical', 'MESH:C532162', (115, 125))	('phospho-STAT1-Y701', 'MPA', (208, 226))	('S727', 'Var', (231, 235))	('pictilisib', 'Chemical', 'MESH:C532162', (57, 67))	('increased', 'PosReg', (126, 135))	('increases', 'PosReg', (195, 204))
78926	31548239	Importantly, and in line with our data showing that pictilisib increases STAT1 induction by IFN-gamma, pictilisib treatment leads to significantly increased chromatin accessibility at regions surrounding STAT1 binding consensus sequences as revealed by ATAC-seq footprinting (Figure 3B and 3C).	('STAT1 induction', 'MPA', (73, 88))	('increases', 'PosReg', (63, 72))	('increased', 'PosReg', (147, 156))	('chromatin accessibility at regions', 'MPA', (157, 191))	('pictilisib', 'Chemical', 'MESH:C532162', (52, 62))	('pictilisib', 'Var', (103, 113))	('pictilisib', 'Chemical', 'MESH:C532162', (103, 113))
78929	31548239	SC79 binds to the pleckstrin homology domain of AKT and promotes its phosphorylation and activation by upstream kinases.	('activation', 'MPA', (89, 99))	('AKT', 'Gene', (48, 51))	('binds', 'Interaction', (5, 10))	('phosphorylation', 'MPA', (69, 84))	('promotes', 'PosReg', (56, 64))	('AKT', 'Gene', '207', (48, 51))	('SC79', 'Var', (0, 4))
78931	31548239	As expected, SC79 promoted AKT phosphorylation at serine 473 and threonine 408 (Figure 4B).	('threonine', 'Chemical', 'MESH:D013912', (65, 74))	('AKT', 'Gene', (27, 30))	('AKT', 'Gene', '207', (27, 30))	('promoted', 'PosReg', (18, 26))	('threonine 408', 'MPA', (65, 78))	('serine', 'Chemical', 'MESH:D012694', (50, 56))	('SC79', 'Var', (13, 17))
78935	31548239	As expected, the PTEN inhibitor VO-OHpic activated PI3K signaling and promoted the phosphorylation of AKT at serine 473 and threonine 308 (Figure 4D).	('serine', 'Chemical', 'MESH:D012694', (109, 115))	('PTEN', 'Gene', '5728', (17, 21))	('threonine', 'Chemical', 'MESH:D013912', (124, 133))	('PI3K signaling', 'Pathway', (51, 65))	('phosphorylation', 'MPA', (83, 98))	('threonine 308', 'MPA', (124, 137))	('AKT', 'Gene', '207', (102, 105))	('VO-OHpic', 'Var', (32, 40))	('PTEN', 'Gene', (17, 21))	('activated', 'PosReg', (41, 50))	('promoted', 'PosReg', (70, 78))	('VO-OHpic', 'Chemical', 'MESH:C000600334', (32, 40))	('AKT', 'Gene', (102, 105))
78937	31548239	To this end, we assessed how the loss of PTEN expression would influence MHCI and MHCII induction by IFN-gamma using commercially available parental HCT116 colon carcinoma cells and HCT116 cells that were rendered PTEN null by CRISPR/Cas9 gene editing.	('colon carcinoma', 'Disease', 'MESH:D003110', (156, 171))	('HCT116', 'CellLine', 'CVCL:0291', (182, 188))	('PTEN', 'Gene', (214, 218))	('MHCII', 'Gene', (82, 87))	('PTEN', 'Gene', '5728', (214, 218))	('MHCI', 'Disease', (73, 77))	('loss', 'Var', (33, 37))	('influence', 'Reg', (63, 72))	('colon carcinoma', 'Disease', (156, 171))	('PTEN', 'Gene', (41, 45))	('HCT116', 'CellLine', 'CVCL:0291', (149, 155))	('PTEN', 'Gene', '5728', (41, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (162, 171))	('MHCII', 'Gene', '111364', (82, 87))
78947	31548239	While the loss of PTEN in HCT116 cells impacted basal MHCI expression and the induction of MHCI and MHCII by IFN-gamma, the effect was most pronounced on MHCII induction and more modest on the induction of MHCI.	('loss', 'Var', (10, 14))	('PTEN', 'Gene', (18, 22))	('MHCII', 'Gene', '111364', (154, 159))	('PTEN', 'Gene', '5728', (18, 22))	('basal MHCI expression', 'MPA', (48, 69))	('MHCII', 'Gene', '111364', (100, 105))	('MHCII', 'Gene', (154, 159))	('impacted', 'Reg', (39, 47))	('MHCII', 'Gene', (100, 105))	('HCT116', 'CellLine', 'CVCL:0291', (26, 32))
78949	31548239	To determine if the loss of PTEN has MHCI gene-specific effects, we assessed the expression of HLA-A, B, and C protein separately by western blot in untreated and IFN-gamma treated HCT116 cells and those lacking PTEN.	('PTEN', 'Gene', (28, 32))	('PTEN', 'Gene', '5728', (28, 32))	('loss', 'Var', (20, 24))	('PTEN', 'Gene', '5728', (212, 216))	('HCT116', 'CellLine', 'CVCL:0291', (181, 187))	('PTEN', 'Gene', (212, 216))	('HLA-A, B, and C', 'Gene', '3105;3106;3107', (95, 110))
78950	31548239	As shown in Figure 5A and 5B, the loss of PTEN had the most marked impact on HLA-B protein expression and its induction by IFN-gamma.	('impact', 'Reg', (67, 73))	('PTEN', 'Gene', (42, 46))	('expression', 'MPA', (91, 101))	('loss', 'Var', (34, 38))	('PTEN', 'Gene', '5728', (42, 46))	('induction by', 'MPA', (110, 122))	('HLA-B', 'Gene', '3106', (77, 82))	('HLA-B', 'Gene', (77, 82))
78951	31548239	Given the increase in STAT1 protein induction that we observed in the presence of the PI3K inhibitor pictilisib, we examined how the loss of PTEN would influence STAT1phosphorylation and its induction by IFN-gamma in parental HCT116 cells and those lacking PTEN.	('STAT1 protein', 'Protein', (22, 35))	('induction', 'MPA', (191, 200))	('induction', 'MPA', (36, 45))	('PTEN', 'Gene', (141, 145))	('increase', 'PosReg', (10, 18))	('PTEN', 'Gene', '5728', (141, 145))	('HCT116', 'CellLine', 'CVCL:0291', (226, 232))	('STAT1phosphorylation', 'MPA', (162, 182))	('pictilisib', 'Chemical', 'MESH:C532162', (101, 111))	('influence', 'Reg', (152, 161))	('loss', 'Var', (133, 137))	('PTEN', 'Gene', (257, 261))	('PTEN', 'Gene', '5728', (257, 261))
78954	31548239	Interestingly, the lack of PTEN had a more prominent impact on the induction of the full length STAT1 protein (STAT1-alpha) as compared to the induction of STAT1-beta which lacks the carboxy-terminal transactivation domain of 38 amino acids.	('PTEN', 'Gene', (27, 31))	('PTEN', 'Gene', '5728', (27, 31))	('lack', 'Var', (19, 23))	('induction', 'MPA', (67, 76))
78957	31548239	With respect to MHCI genes, we found that the lack of PTEN had the largest impact on steady state mRNA levels of HLA-B, a smaller impact on HLA-A and no significant impacts on HLA-C or NLRC5 (Figure 5E).	('lack', 'Var', (46, 50))	('HLA-A', 'Gene', '3105', (140, 145))	('impact', 'Reg', (75, 81))	('NLRC5', 'Gene', '84166', (185, 190))	('HLA-A', 'Gene', (140, 145))	('HLA-C', 'Gene', (176, 181))	('PTEN', 'Gene', (54, 58))	('PTEN', 'Gene', '5728', (54, 58))	('HLA-B', 'Gene', (113, 118))	('NLRC5', 'Gene', (185, 190))	('mRNA levels', 'MPA', (98, 109))	('HLA-C', 'Gene', '3107', (176, 181))	('HLA-B', 'Gene', '3106', (113, 118))
78958	31548239	This pattern is similar to what we observed at the protein level where the loss of PTEN had the greatest impact on HLA-B expression and less of an effect on HLA-A and HLA-C.	('HLA-C', 'Gene', (167, 172))	('PTEN', 'Gene', '5728', (83, 87))	('HLA-A', 'Gene', '3105', (157, 162))	('HLA-C', 'Gene', '3107', (167, 172))	('HLA-A', 'Gene', (157, 162))	('HLA-B', 'Gene', (115, 120))	('expression', 'MPA', (121, 131))	('HLA-B', 'Gene', '3106', (115, 120))	('loss', 'Var', (75, 79))	('PTEN', 'Gene', (83, 87))
78959	31548239	The lack of PTEN also had a significant impact on the induction of STAT1 and the MHCII gene HLA-DR as well as its co-activator CIITA, which drives MHCII expression.	('induction', 'MPA', (54, 63))	('MHCII', 'Gene', '111364', (81, 86))	('impact', 'Reg', (40, 46))	('CIITA', 'Gene', (127, 132))	('CIITA', 'Gene', '4261', (127, 132))	('PTEN', 'Gene', (12, 16))	('HLA-DR', 'Gene', (92, 98))	('MHCII', 'Gene', '111364', (147, 152))	('PTEN', 'Gene', '5728', (12, 16))	('MHCII', 'Gene', (81, 86))	('lack', 'Var', (4, 8))	('STAT1', 'Gene', (67, 72))	('MHCII', 'Gene', (147, 152))
78963	31548239	However, we found no differences in MHC levels between SCCHN tumors with genetic alterations in PTEN or PIK3CA and tumors lacking alterations in these genes.	('PTEN', 'Gene', '5728', (96, 100))	('tumors', 'Disease', (61, 67))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('genetic alterations', 'Var', (73, 92))	('SCCHN tumors', 'Disease', 'MESH:D009369', (55, 67))	('SCC', 'Phenotype', 'HP:0002860', (55, 58))	('tumors', 'Disease', (115, 121))	('PIK3CA', 'Gene', (104, 110))	('SCCHN tumors', 'Disease', (55, 67))	('tumors', 'Disease', 'MESH:D009369', (115, 121))	('PIK3CA', 'Gene', '5290', (104, 110))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('MHC levels', 'MPA', (36, 46))	('PTEN', 'Gene', (96, 100))
78964	31548239	In contrast, when we extended our analysis to include other cancers, we found that in both pancreatic cancer and squamous cell carcinoma (SCC) of the lung tumors with alteration in PTEN or PIK3CA had statistically significant lower expression levels of HLA-A, B and C (Figure 5G).	('lower', 'NegReg', (226, 231))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (91, 108))	('PIK3CA', 'Gene', (189, 195))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (113, 136))	('PTEN', 'Gene', '5728', (181, 185))	('lung tumors', 'Disease', 'MESH:D008175', (150, 161))	('cancers', 'Disease', 'MESH:D009369', (60, 67))	('tumors', 'Phenotype', 'HP:0002664', (155, 161))	('lung tumors', 'Phenotype', 'HP:0100526', (150, 161))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('squamous cell carcinoma', 'Disease', (113, 136))	('pancreatic cancer', 'Disease', 'MESH:D010190', (91, 108))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('alteration', 'Var', (167, 177))	('lung tumors', 'Disease', (150, 161))	('PIK3CA', 'Gene', '5290', (189, 195))	('pancreatic cancer', 'Disease', (91, 108))	('HLA-A, B and C', 'Gene', '3105;3106;3107', (253, 267))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('cancers', 'Phenotype', 'HP:0002664', (60, 67))	('cancers', 'Disease', (60, 67))	('SCC', 'Phenotype', 'HP:0002860', (138, 141))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (113, 136))	('expression levels', 'MPA', (232, 249))	('PTEN', 'Gene', (181, 185))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
78969	31548239	Thus, intra-tumoral regions with increased PI3K signaling are associated with a decrease in MHCI protein expression.	('PI3K', 'Var', (43, 47))	('MHCI protein', 'Protein', (92, 104))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('increased', 'PosReg', (33, 42))	('intra-tumoral', 'Disease', 'MESH:D009369', (6, 19))	('decrease', 'NegReg', (80, 88))	('intra-tumoral', 'Disease', (6, 19))
78972	31548239	In these studies, murine model systems were used demonstrating that: (1) PI3K activation (through low oxygen and/or glucose) can repress STAT1 signaling and MHCI induction/expression and (2) PI3K-mediated changes in MHCI levels can functionally impact T cell infiltration into tumors and anti-tumor immunity.	('tumor', 'Disease', 'MESH:D009369', (293, 298))	('tumor', 'Phenotype', 'HP:0002664', (277, 282))	('PI3K', 'Gene', (73, 77))	('induction/expression', 'MPA', (162, 182))	('tumors', 'Disease', (277, 283))	('changes', 'Reg', (205, 212))	('oxygen', 'Chemical', 'MESH:D010100', (102, 108))	('tumor', 'Phenotype', 'HP:0002664', (293, 298))	('glucose', 'Chemical', 'MESH:D005947', (116, 123))	('repress', 'NegReg', (129, 136))	('tumors', 'Disease', 'MESH:D009369', (277, 283))	('PI3K-mediated', 'Var', (191, 204))	('tumor', 'Disease', (277, 282))	('STAT1 signaling', 'MPA', (137, 152))	('low oxygen and/or glucose', 'Phenotype', 'HP:0012418', (98, 123))	('impact', 'Reg', (245, 251))	('tumor', 'Disease', 'MESH:D009369', (277, 282))	('tumor', 'Disease', (293, 298))	('MHCI', 'Gene', (157, 161))	('murine', 'Species', '10090', (18, 24))	('tumors', 'Phenotype', 'HP:0002664', (277, 283))
78974	31548239	In contrast to the PI3K pathway, several prior studies have demonstrated that EGFR/HER activity and the activity of enzymes in the MAPK pathway (such as BRAFV600E and MEK1/2) can influence MHC expression.	('activity', 'MPA', (87, 95))	('activity', 'MPA', (104, 112))	('influence', 'Reg', (179, 188))	('MEK1/2', 'Gene', '5604;5605', (167, 173))	('BRAFV600E', 'Var', (153, 162))	('MEK1/2', 'Gene', (167, 173))	('EGFR', 'Gene', '1956', (78, 82))	('EGFR', 'Gene', (78, 82))	('expression', 'MPA', (193, 203))	('MHC', 'Gene', (189, 192))
78975	31548239	For example, expression of HER2 and BRAFV600E have been reported to downregulate MHCI levels in breast cancer and melanoma respectively and with regards to gastric cancer, an inverse correlation between MAPK activation (as measured by levels of phosphorylated extracellular signal-related kinase (ERK)) and MHCI has been reported.	('MAPK', 'Gene', (203, 207))	('ERK', 'Gene', (297, 300))	('breast cancer', 'Disease', 'MESH:D001943', (96, 109))	('breast cancer', 'Disease', (96, 109))	('BRAFV600E', 'Var', (36, 45))	('gastric cancer', 'Phenotype', 'HP:0012126', (156, 170))	('HER2', 'Gene', (27, 31))	('melanoma', 'Disease', 'MESH:D008545', (114, 122))	('activation', 'PosReg', (208, 218))	('downregulate', 'NegReg', (68, 80))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('gastric cancer', 'Disease', (156, 170))	('melanoma', 'Phenotype', 'HP:0002861', (114, 122))	('HER2', 'Gene', '2064', (27, 31))	('melanoma', 'Disease', (114, 122))	('extracellular signal-related kinase', 'Gene', (260, 295))	('ERK', 'Gene', '5594', (297, 300))	('extracellular signal-related kinase', 'Gene', '5594', (260, 295))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('MHCI levels', 'MPA', (81, 92))	('gastric cancer', 'Disease', 'MESH:D013274', (156, 170))	('breast cancer', 'Phenotype', 'HP:0003002', (96, 109))
78977	31548239	Conversely, EGFR, HER2, and MAPK inhibitors have been shown to increase levels of MHCI and/or MHCII expression.	('increase', 'PosReg', (63, 71))	('HER2', 'Gene', '2064', (18, 22))	('MHCII', 'Gene', (94, 99))	('levels', 'MPA', (72, 78))	('MAPK', 'Gene', (28, 32))	('EGFR', 'Gene', '1956', (12, 16))	('MHCII', 'Gene', '111364', (94, 99))	('MHCI', 'Gene', (82, 86))	('EGFR', 'Gene', (12, 16))	('HER2', 'Gene', (18, 22))	('inhibitors', 'Var', (33, 43))
78978	31548239	add to these studies and now demonstrate that in some contexts, PI3K signaling can also influence MHCI and/or MHCII induction.	('MHCII', 'Gene', (110, 115))	('PI3K signaling', 'Var', (64, 78))	('influence', 'Reg', (88, 97))	('MHCII', 'Gene', '111364', (110, 115))	('MHCI', 'CPA', (98, 102))
78981	31548239	For example, prior studies have shown that the loss of PTEN can alter the anti-proliferative and cytotoxic effects of IFN-gamma in lung and gastric carcinoma models.	('PTEN', 'Gene', '5728', (55, 59))	('gastric carcinoma', 'Disease', 'MESH:D013274', (140, 157))	('anti-proliferative', 'CPA', (74, 92))	('cytotoxic effects', 'CPA', (97, 114))	('alter', 'Reg', (64, 69))	('gastric carcinoma', 'Disease', (140, 157))	('lung', 'Disease', (131, 135))	('loss', 'Var', (47, 51))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (140, 157))	('carcinoma', 'Phenotype', 'HP:0030731', (148, 157))	('PTEN', 'Gene', (55, 59))
78982	31548239	Our work supports these observations and suggests that the loss of PTEN also represses the ability of IFN-gamma to induce MHCI and/or MHCII expression.	('MHCII', 'Gene', '111364', (134, 139))	('MHCII', 'Gene', (134, 139))	('PTEN', 'Gene', (67, 71))	('PTEN', 'Gene', '5728', (67, 71))	('represses', 'NegReg', (77, 86))	('loss', 'Var', (59, 63))	('ability', 'MPA', (91, 98))
78991	31548239	Thus, through their ability to alter STAT1 expression and/or phosphorylation, PI3K signaling may disrupt the cellular response to cytokines and in doing so cell-mediated anti-tumor immunity.	('tumor', 'Disease', (175, 180))	('phosphorylation', 'MPA', (61, 76))	('STAT1 expression', 'MPA', (37, 53))	('cellular response to cytokines', 'MPA', (109, 139))	('disrupt', 'NegReg', (97, 104))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('alter', 'Reg', (31, 36))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('PI3K', 'Var', (78, 82))
78995	31548239	Interestingly, the recent study by Marijt demonstrates that in B16 melanoma cells PI3K inhibitors can reverse MHCI repression by mediated in response to low oxygen and glucose.	('B16', 'CellLine', 'CVCL:N540', (63, 66))	('MHCI repression', 'Gene', (110, 125))	('oxygen', 'Chemical', 'MESH:D010100', (157, 163))	('melanoma', 'Phenotype', 'HP:0002861', (67, 75))	('response to low oxygen', 'MPA', (141, 163))	('melanoma', 'Disease', (67, 75))	('PI3K', 'Gene', (82, 86))	('melanoma', 'Disease', 'MESH:D008545', (67, 75))	('low oxygen and glucose', 'Phenotype', 'HP:0012418', (153, 175))	('glucose', 'Chemical', 'MESH:D005947', (168, 175))	('inhibitors', 'Var', (87, 97))	('reverse', 'NegReg', (102, 109))
79008	32098209	PM2.5 was positively associated with SOX2-promoter methylation (beta = 0.000216; p < 0.0001).	('SOX2', 'Gene', (37, 41))	('SOX2', 'Gene', '6657', (37, 41))	('PM2.5', 'Var', (0, 5))	('PM2', 'Chemical', '-', (0, 3))
79024	32098209	The modulation of promoter DNA methylation by PM2.5 is an essential mechanism that alters the expression of genes.	('modulation', 'Var', (4, 14))	('promoter DNA', 'MPA', (18, 30))	('alters', 'Reg', (83, 89))	('expression of', 'MPA', (94, 107))	('PM2', 'Chemical', '-', (46, 49))
79025	32098209	DNA methylation changes, alongside inflammation, apoptosis, autophagy, oxidative stress, among others, are some of the main mechanisms underlying the role of PM2.5 in lung cancer development.	('changes', 'Var', (16, 23))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('oxidative stress', 'Phenotype', 'HP:0025464', (71, 87))	('lung cancer', 'Disease', (167, 178))	('lung cancer', 'Phenotype', 'HP:0100526', (167, 178))	('methylation changes', 'Var', (4, 23))	('PM2', 'Chemical', '-', (158, 161))	('men', 'Species', '9606', (186, 189))	('DNA', 'MPA', (0, 3))	('inflammation', 'Disease', 'MESH:D007249', (35, 47))	('lung cancer', 'Disease', 'MESH:D008175', (167, 178))	('inflammation', 'Disease', (35, 47))
79041	32098209	However, PM2.5 was significantly associated with higher levels of SOX2-promoter methylation (beta = 0.000216; p < 0.0001).	('SOX2', 'Gene', '6657', (66, 70))	('SOX2', 'Gene', (66, 70))	('PM2.5', 'Var', (9, 14))	('higher', 'PosReg', (49, 55))	('PM2', 'Chemical', '-', (9, 12))
79043	32098209	After stratification by exercise habits (Table 3), PM2.5 was significantly associated with higher SOX2 methylation levels only in individuals who did regular exercise (beta = 0.0003490; p < 0.0001).	('SOX2', 'Gene', (98, 102))	('higher', 'PosReg', (91, 97))	('PM2.5', 'Var', (51, 56))	('SOX2', 'Gene', '6657', (98, 102))	('PM2', 'Chemical', '-', (51, 54))
79061	32098209	Endurance exercise was associated with the expansion of developmentally early stem cell genes including SOX2.	('men', 'Species', '9606', (63, 66))	('SOX2', 'Gene', '6657', (104, 108))	('expansion', 'Var', (43, 52))	('associated', 'Reg', (23, 33))	('SOX2', 'Gene', (104, 108))
79062	32098209	Moreover, cancer stem cell markers like SOX2 and OCT4 and related levels of microRNAs are believed to be potential biomarkers for predicting carcinogenicity resulting from exposure to PM2.5.	('OCT4', 'Gene', (49, 53))	('PM2', 'Chemical', '-', (184, 187))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('SOX2', 'Gene', (40, 44))	('SOX2', 'Gene', '6657', (40, 44))	('PM2.5', 'Var', (184, 189))	('cancer', 'Disease', 'MESH:D009369', (10, 16))	('cancer', 'Disease', (10, 16))	('OCT4', 'Gene', '5460', (49, 53))
79063	32098209	PM2.5 exposure was associated with the induction of cancer stem cell properties, marked by upregulation of mRNA levels of pluripotency-maintaining genes including SOX2 and OCT4 and subsequent increase in the risk of lung cancer.	('cancer', 'Disease', 'MESH:D009369', (221, 227))	('SOX2', 'Gene', '6657', (163, 167))	('SOX2', 'Gene', (163, 167))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('lung cancer', 'Disease', 'MESH:D008175', (216, 227))	('PM2.5', 'Var', (0, 5))	('lung cancer', 'Phenotype', 'HP:0100526', (216, 227))	('pluripotency', 'Disease', '-', (122, 134))	('pluripotency', 'Disease', (122, 134))	('OCT4', 'Gene', '5460', (172, 176))	('cancer', 'Disease', (221, 227))	('upregulation', 'PosReg', (91, 103))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('increase', 'PosReg', (192, 200))	('cancer', 'Disease', (52, 58))	('OCT4', 'Gene', (172, 176))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('lung cancer', 'Disease', (216, 227))	('PM2', 'Chemical', '-', (0, 3))
79065	32098209	SOX2 methylation is associated with several types of cancer, including small-cell lung cancer (SCLC), squamous cell carcinoma (SCC), glioblastoma, endometrial, and breast cancer.	('glioblastoma', 'Disease', (133, 145))	('squamous cell carcinoma', 'Disease', (102, 125))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('glioblastoma', 'Phenotype', 'HP:0012174', (133, 145))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (71, 93))	('SCC', 'Phenotype', 'HP:0002860', (127, 130))	('lung cancer', 'Phenotype', 'HP:0100526', (82, 93))	('breast cancer', 'Phenotype', 'HP:0003002', (164, 177))	('SCC', 'Disease', 'MESH:D002294', (127, 130))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (102, 125))	('SOX2', 'Gene', (0, 4))	('SOX2', 'Gene', '6657', (0, 4))	('cancer', 'Disease', (87, 93))	('associated', 'Reg', (20, 30))	('methylation', 'Var', (5, 16))	('cancer', 'Disease', (53, 59))	('SCC', 'Disease', (127, 130))	('breast cancer', 'Disease', 'MESH:D001943', (164, 177))	('SCLC', 'Disease', 'MESH:D055752', (95, 99))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cancer', 'Disease', (171, 177))	('breast cancer', 'Disease', (164, 177))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (102, 125))	('small-cell lung cancer', 'Disease', 'MESH:D055752', (71, 93))	('small-cell lung cancer', 'Disease', (71, 93))	('glioblastoma', 'Disease', 'MESH:D005909', (133, 145))	('SCLC', 'Disease', (95, 99))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('SCLC', 'Phenotype', 'HP:0030357', (95, 99))	('endometrial', 'Disease', (147, 158))
79067	32098209	For example, anomalous levels (either too much or too little) are believed to adversely influence cell fate decisions during the process of development in normal cells.	('anomalous levels', 'Var', (13, 29))	('men', 'Species', '9606', (147, 150))	('cell fate decisions', 'CPA', (98, 117))	('influence', 'Reg', (88, 97))
79070	32098209	In non-small cell lung cancer (NSCLC), the amplification and subsequent overexpression of the SOX2 gene were common in both squamous cell carcinomas and adenocarcinomas (with higher expressions in squamous cell carcinomas compared to adenocarcinomas).	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (197, 221))	('expressions', 'MPA', (182, 193))	('carcinoma', 'Phenotype', 'HP:0030731', (239, 248))	('carcinomas', 'Phenotype', 'HP:0030731', (138, 148))	('NSCLC', 'Disease', 'MESH:D002289', (31, 36))	('common', 'Reg', (109, 115))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (197, 221))	('non-small cell lung cancer', 'Disease', (3, 29))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (124, 148))	('adenocarcinomas', 'Disease', 'MESH:D000230', (234, 249))	('NSCLC', 'Disease', (31, 36))	('adenocarcinomas', 'Disease', (234, 249))	('amplification', 'Var', (43, 56))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (197, 220))	('adenocarcinomas', 'Disease', 'MESH:D000230', (153, 168))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (124, 148))	('lung cancer', 'Phenotype', 'HP:0100526', (18, 29))	('carcinoma', 'Phenotype', 'HP:0030731', (158, 167))	('carcinomas', 'Phenotype', 'HP:0030731', (239, 249))	('squamous cell carcinomas', 'Disease', (197, 221))	('adenocarcinomas', 'Disease', (153, 168))	('NSCLC', 'Phenotype', 'HP:0030358', (31, 36))	('carcinomas', 'Phenotype', 'HP:0030731', (158, 168))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (124, 147))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (3, 29))	('squamous cell carcinomas', 'Disease', (124, 148))	('SCLC', 'Phenotype', 'HP:0030357', (32, 36))	('overexpression', 'PosReg', (72, 86))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (7, 29))	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('SOX2', 'Gene', (94, 98))	('SOX2', 'Gene', '6657', (94, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (211, 220))	('carcinomas', 'Phenotype', 'HP:0030731', (211, 221))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (3, 29))	('squamous cell carcinomas and adenocarcinomas', 'Disease', 'MESH:D002294', (124, 168))
79071	32098209	SOX2 amplification and overexpression have also been reported as independent poor prognostic predictors of stage I lung adenocarcinoma.	('SOX2', 'Gene', '6657', (0, 4))	('overexpression', 'PosReg', (23, 37))	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('amplification', 'Var', (5, 18))	('stage I lung adenocarcinoma', 'Disease', 'MESH:D000077192', (107, 134))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (115, 134))	('SOX2', 'Gene', (0, 4))	('stage I lung adenocarcinoma', 'Disease', (107, 134))
79097	32098209	Even though the underlying mechanisms cannot be clearly stated, the findings imply that PM2.5 might influence SOX2 methylation more than exercise.	('SOX2', 'Gene', (110, 114))	('SOX2', 'Gene', '6657', (110, 114))	('PM2', 'Chemical', '-', (88, 91))	('more than exercise', 'Phenotype', 'HP:0003546', (127, 145))	('PM2.5', 'Var', (88, 93))	('influence', 'Reg', (100, 109))
79098	32098209	Since SOX2 hypermethylation is associated with cancer development, taking exercise in heavily polluted areas may not be very helpful and therefore should be minimized.	('SOX2', 'Gene', '6657', (6, 10))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('hypermethylation', 'Var', (11, 27))	('cancer', 'Disease', (47, 53))	('associated', 'Reg', (31, 41))	('men', 'Species', '9606', (61, 64))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('SOX2', 'Gene', (6, 10))
79103	31908494	Ferroptosis is involved in many diseases, including cancer, and induction of ferroptosis has shown attractive antitumour activities.	('tumour', 'Disease', (114, 120))	('induction', 'Var', (64, 73))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('tumour', 'Phenotype', 'HP:0002664', (114, 120))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('tumour', 'Disease', 'MESH:D009369', (114, 120))	('involved', 'Reg', (15, 23))
79107	31908494	Inhibition of ferroptosis has been shown to be effective in treating ischaemia/reperfusion-induced organ injury and stroke in several experimental models, and inducing ferroptosis is considered a promising method for cancer therapy.	('ferroptosis', 'CPA', (168, 179))	('stroke', 'Disease', (116, 122))	('organ injury', 'Disease', 'MESH:D019965', (99, 111))	('stroke', 'Phenotype', 'HP:0001297', (116, 122))	('inducing', 'Reg', (159, 167))	('organ injury', 'Disease', (99, 111))	('ischaemia', 'Disease', (69, 78))	('stroke', 'Disease', 'MESH:D020521', (116, 122))	('cancer', 'Disease', (217, 223))	('cancer', 'Disease', 'MESH:D009369', (217, 223))	('Inhibition', 'Var', (0, 10))	('ischaemia', 'Disease', 'MESH:D007511', (69, 78))	('ferroptosis', 'Protein', (14, 25))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))
79110	31908494	Intercellular interactions between cancer cells were shown to suppress ferroptosis by activating NF2 and regulating the Hippo signalling pathway, and blocking NF2 sensitized cancer cells to ferroptosis.	('suppress', 'NegReg', (62, 70))	('ferroptosis', 'Disease', (71, 82))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('NF2', 'Gene', (159, 162))	('blocking', 'Var', (150, 158))	('NF2', 'Gene', '4771', (97, 100))	('cancer', 'Disease', (174, 180))	('activating', 'PosReg', (86, 96))	('NF2', 'Gene', (97, 100))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('sensitized', 'Reg', (163, 173))	('NF2', 'Gene', '4771', (159, 162))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('Hippo signalling pathway', 'Pathway', (120, 144))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('cancer', 'Disease', (35, 41))
79112	31908494	Iron dependency is a characteristic of cancer cells, and its dysregulation leads to ferroptosis.	('leads to', 'Reg', (75, 83))	('Iron dependency', 'Disease', (0, 15))	('cancer', 'Disease', (39, 45))	('ferroptosis', 'Disease', (84, 95))	('dysregulation', 'Var', (61, 74))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('Iron', 'Chemical', 'MESH:D007501', (0, 4))	('Iron dependency', 'Phenotype', 'HP:0001891', (0, 15))
79117	31908494	Ferroportin upregulation inhibited ferroptosis, and silencing of ferroportin sensitized cancer cells to ferroptosis.	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('silencing', 'Var', (52, 61))	('upregulation', 'PosReg', (12, 24))	('ferroptosis', 'CPA', (35, 46))	('ferroportin', 'Gene', (65, 76))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('inhibited', 'NegReg', (25, 34))	('sensitized', 'Reg', (77, 87))
79122	31908494	In addition, knockdown of transferrin or overexpression of ferroportin-1 downregulated ROS and inhibited ferroptosis.	('inhibited', 'NegReg', (95, 104))	('ferroportin-1', 'Gene', '30061', (59, 72))	('ROS', 'Protein', (87, 90))	('transferrin', 'Gene', '7018', (26, 37))	('downregulated', 'NegReg', (73, 86))	('transferrin', 'Gene', (26, 37))	('ferroptosis', 'CPA', (105, 116))	('overexpression', 'PosReg', (41, 55))	('knockdown', 'Var', (13, 22))	('ferroportin-1', 'Gene', (59, 72))
79128	31908494	Silencing NCOA4 upregulates ferritin expression, decreases Fe2+ levels and limits erastin-induced ferroptosis.	('NCOA4', 'Gene', (10, 15))	('upregulates', 'PosReg', (16, 27))	('erastin-induced ferroptosis', 'MPA', (82, 109))	('ferritin', 'Protein', (28, 36))	('decreases', 'NegReg', (49, 58))	('Fe2+', 'Chemical', 'MESH:D007501', (59, 63))	('NCOA4', 'Gene', '8031', (10, 15))	('limits', 'NegReg', (75, 81))	('Fe2+ levels', 'MPA', (59, 70))	('expression', 'MPA', (37, 47))	('Silencing', 'Var', (0, 9))
79129	31908494	In summary, dysregulation of iron homeostasis participates in the occurrence of ferroptosis, and inducing ferroptosis by upregulating the iron level might become a new anticancer strategy.	('dysregulation', 'Var', (12, 25))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('iron', 'Chemical', 'MESH:D007501', (138, 142))	('cancer', 'Disease', (172, 178))	('inducing', 'Reg', (97, 105))	('dysregulation of iron homeostasis', 'Phenotype', 'HP:0011031', (12, 45))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('upregulating', 'PosReg', (121, 133))	('iron', 'Chemical', 'MESH:D007501', (29, 33))	('ferroptosis', 'Disease', (80, 91))	('iron level', 'MPA', (138, 148))
79132	31908494	When autophagy is activated, the cellular iron stock protein ferritin is degraded, and the cellular iron level is rapidly upregulated via ferritinophagy.	('iron', 'Chemical', 'MESH:D007501', (100, 104))	('iron', 'Chemical', 'MESH:D007501', (42, 46))	('cellular iron stock protein', 'MPA', (33, 60))	('ferritinophagy', 'Var', (138, 152))	('upregulated', 'PosReg', (122, 133))	('degraded', 'NegReg', (73, 81))	('autophagy', 'CPA', (5, 14))	('cellular iron level', 'MPA', (91, 110))
79135	31908494	Atg5 and Atg7 are key genes in the formation of the autophagosome, and knockout or knockdown of Atg5 and Atg7 reduces Fe2+ and lipid peroxidation levels by inhibiting the degradation of the iron storage protein ferritin and further inhibits erastin-induced ferroptosis.	('iron storage protein ferritin', 'MPA', (190, 219))	('Atg5', 'Gene', (0, 4))	('degradation', 'MPA', (171, 182))	('Atg5', 'Gene', (96, 100))	('Fe2+', 'Chemical', 'MESH:D007501', (118, 122))	('knockout', 'Var', (71, 79))	('Atg7', 'Gene', (9, 13))	('reduces', 'NegReg', (110, 117))	('iron', 'Chemical', 'MESH:D007501', (190, 194))	('Atg7', 'Gene', (105, 109))	('erastin-induced ferroptosis', 'CPA', (241, 268))	('Atg5', 'Gene', '9474', (96, 100))	('Atg7', 'Gene', '10533', (9, 13))	('Atg7', 'Gene', '10533', (105, 109))	('Atg5', 'Gene', '9474', (0, 4))	('inhibits', 'NegReg', (232, 240))	('knockdown', 'Var', (83, 92))	('inhibiting', 'NegReg', (156, 166))
79137	31908494	Some possible reasons are that both CQ and bafilomycin A1 are non-specific autophagy inhibitors, and they also inhibit lysosomal processes and endocytic pathways.	('inhibit', 'NegReg', (111, 118))	('bafilomycin A1', 'Chemical', 'MESH:C040929', (43, 57))	('bafilomycin A1', 'Var', (43, 57))	('lysosomal processes', 'CPA', (119, 138))	('endocytic pathways', 'CPA', (143, 161))	('CQ', 'Chemical', 'MESH:D002738', (36, 38))
79144	31908494	Inhibition of CA9 induced the ferroptosis and apoptosis of cancer cells by increasing catalytic Fe2+ in lysosomes and mitochondria and lipid peroxidation.	('apoptosis', 'CPA', (46, 55))	('lipid peroxidation', 'MPA', (135, 153))	('increasing', 'PosReg', (75, 85))	('CA9', 'Gene', (14, 17))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('CA9', 'Gene', '768', (14, 17))	('Fe2+', 'Chemical', 'MESH:D007501', (96, 100))	('Inhibition', 'Var', (0, 10))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('ferroptosis', 'CPA', (30, 41))	('cancer', 'Disease', (59, 65))	('mitochondria', 'MPA', (118, 130))
79155	31908494	CISD2 overexpression enabled resistance to sulfasalazine-induced ferroptosis, and silencing CISD2 or pioglitazone treatment sensitized resistant head and neck cancer cells to sulfasalazine-induced ferroptosis.	('cancer', 'Disease', (159, 165))	('resistance', 'MPA', (29, 39))	('CISD2', 'Gene', '493856', (92, 97))	('sulfasalazine', 'Chemical', 'MESH:D012460', (43, 56))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('sulfasalazine', 'Chemical', 'MESH:D012460', (175, 188))	('silencing', 'Var', (82, 91))	('head and neck cancer', 'Phenotype', 'HP:0012288', (145, 165))	('CISD2', 'Gene', (92, 97))	('sensitized', 'Reg', (124, 134))	('CISD2', 'Gene', '493856', (0, 5))	('pioglitazone', 'Chemical', 'MESH:C060836', (101, 113))	('CISD2', 'Gene', (0, 5))	('cancer', 'Disease', 'MESH:D009369', (159, 165))
79156	31908494	Pyrimidotriazinedione 35G8, a protein disulfide isomerase inhibitor, induced ferroptosis and autophagy by upregulating the transcription and protein expression of SLC7A11.	('SLC7A11', 'Gene', '23657', (163, 170))	('disulfide', 'Chemical', 'MESH:D004220', (38, 47))	('transcription', 'MPA', (123, 136))	('upregulating', 'PosReg', (106, 118))	('protein expression', 'MPA', (141, 159))	('autophagy', 'CPA', (93, 102))	('induced', 'PosReg', (69, 76))	('Pyrimidotriazinedione', 'Var', (0, 21))	('Pyrimidotriazinedione', 'Chemical', 'None', (0, 21))	('ferroptosis', 'CPA', (77, 88))	('SLC7A11', 'Gene', (163, 170))
79160	31908494	Importantly, mutants (C91A, S10T, E31A, L49V, C91G, H169Q, F170C and G185R) in the UCH domain of BAP1 lose the function of repressing SLC7A11 expression and the ability to inhibit anchorage-independent growth.	('L49V', 'Var', (40, 44))	('H169Q', 'Var', (52, 57))	('SLC7A11', 'Gene', (134, 141))	('SLC7A11', 'Gene', '23657', (134, 141))	('BAP1', 'Gene', (97, 101))	('S10T', 'Var', (28, 32))	('G185R', 'Var', (69, 74))	('anchorage-independent growth', 'CPA', (180, 208))	('F170C', 'Var', (59, 64))	('E31A', 'Var', (34, 38))	('G185R', 'Mutation', 'p.G185R', (69, 74))	('inhibit', 'NegReg', (172, 179))	('C91G', 'Mutation', 'rs768835477', (46, 50))	('H169Q', 'Mutation', 'p.H169Q', (52, 57))	('lose', 'NegReg', (102, 106))	('L49V', 'Mutation', 'p.L49V', (40, 44))	('expression', 'MPA', (142, 152))	('E31A', 'Mutation', 'p.E31A', (34, 38))	('F170C', 'Mutation', 'p.F170C', (59, 64))	('C91G', 'Var', (46, 50))	('BAP1', 'Gene', '8314', (97, 101))	('C91A', 'Var', (22, 26))	('S10T', 'Mutation', 'p.S10T', (28, 32))	('C91A', 'SUBSTITUTION', 'None', (22, 26))
79164	31908494	Overexpression of GPX4 confers resistance to ROS-induced cell death to tumour cells, and silencing GPX4 sensitizes tumour cells to ROS-induced cell death.	('sensitizes', 'Reg', (104, 114))	('GPX4', 'Gene', (99, 103))	('tumour', 'Disease', (71, 77))	('GPX4', 'Gene', '2879', (99, 103))	('resistance', 'CPA', (31, 41))	('tumour', 'Phenotype', 'HP:0002664', (115, 121))	('GPX4', 'Gene', (18, 22))	('GPX4', 'Gene', '2879', (18, 22))	('tumour', 'Phenotype', 'HP:0002664', (71, 77))	('tumour', 'Disease', 'MESH:D009369', (115, 121))	('silencing', 'Var', (89, 98))	('tumour', 'Disease', (115, 121))	('tumour', 'Disease', 'MESH:D009369', (71, 77))
79168	31908494	Overexpression of NRF2 renders chemosensitive NH3 cells resistant to RSL3, and silencing NRF2 has opposite effects.	('NRF2', 'Gene', '4780', (18, 22))	('NRF2', 'Gene', (89, 93))	('NRF2', 'Gene', (18, 22))	('NRF2', 'Gene', '4780', (89, 93))	('silencing', 'Var', (79, 88))
79172	31908494	Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a hereditary cancer with characteristic inactivation of the Krebs cycle enzyme fumarate hydratase (FH).	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('fumarate hydratase', 'Gene', (138, 156))	('renal cell cancer', 'Phenotype', 'HP:0005584', (30, 47))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('Hereditary leiomyomatosis and renal cell cancer', 'Disease', 'MESH:C535516', (0, 47))	('hereditary cancer', 'Disease', 'MESH:D009386', (61, 78))	('HLRCC', 'Disease', (49, 54))	('fumarate hydratase', 'Gene', '2271', (138, 156))	('HLRCC', 'Disease', 'MESH:C535516', (49, 54))	('hereditary cancer', 'Disease', (61, 78))	('inactivation', 'Var', (99, 111))	('FH', 'Gene', '2271', (158, 160))
79173	31908494	A recent study reported that a ferroptosis inducer could target and selectively kill HLRCC cells, and FH inactivation sensitized HLRCC cells to ferroptosis by promoting intracellular fumarate accumulation and further modifying the C93 succinylation of GPX4 and inhibiting its activity.	('modifying', 'Reg', (217, 226))	('C93 succinylation', 'MPA', (231, 248))	('GPX4', 'Gene', (252, 256))	('HLRCC', 'Disease', 'MESH:C535516', (129, 134))	('HLRCC', 'Disease', (85, 90))	('GPX4', 'Gene', '2879', (252, 256))	('activity', 'MPA', (276, 284))	('promoting', 'PosReg', (159, 168))	('HLRCC', 'Disease', 'MESH:C535516', (85, 90))	('fumarate', 'Chemical', 'MESH:D005650', (183, 191))	('inhibiting', 'NegReg', (261, 271))	('inactivation', 'Var', (105, 117))	('intracellular fumarate accumulation', 'MPA', (169, 204))	('FH', 'Gene', '2271', (102, 104))	('HLRCC', 'Disease', (129, 134))
79180	31908494	Meanwhile, N-terminal mutants of p53 (L25Q, F53Q, W26S and F54S) had no effect on SLC7A11 expression and ROS levels and failed to facilitate ferroptosis.	('SLC7A11', 'Gene', (82, 89))	('F53Q', 'Var', (44, 48))	('F53Q', 'Mutation', 'p.F53Q', (44, 48))	('SLC7A11', 'Gene', '23657', (82, 89))	('F54S', 'SUBSTITUTION', 'None', (59, 63))	('W26S', 'SUBSTITUTION', 'None', (50, 54))	('p53', 'Gene', (33, 36))	('W26S', 'Var', (50, 54))	('ROS levels', 'MPA', (105, 115))	('expression', 'MPA', (90, 100))	('p53', 'Gene', '7157', (33, 36))	('L25Q', 'Mutation', 'p.L25Q', (38, 42))	('F54S', 'Var', (59, 63))
79181	31908494	The P47S variant of p53 conferred human cells with resistance to RSL3-induced ferroptosis.	('p53', 'Gene', (20, 23))	('human', 'Species', '9606', (34, 39))	('p53', 'Gene', '7157', (20, 23))	('P47S', 'Var', (4, 8))	('resistance', 'CPA', (51, 61))	('P47S', 'Mutation', 'rs1800371', (4, 8))
79183	31908494	Importantly, knockout of SAT1 partially abrogates p53-mediated ferroptosis.	('knockout', 'Var', (13, 21))	('abrogates', 'NegReg', (40, 49))	('SAT1', 'Gene', '6303', (25, 29))	('p53', 'Gene', (50, 53))	('p53', 'Gene', '7157', (50, 53))	('SAT1', 'Gene', (25, 29))
79184	31908494	Compound D13, a derivative of albiziabioside A, possesses strong inhibitory activity against cancer cells, is especially efficacious against multidrug-resistant (MDR) cancer cells in vitro, and suppresses tumorigenesis without causing toxicity in normal organs in vivo.	('toxicity', 'Disease', (235, 243))	('suppresses', 'NegReg', (194, 204))	('cancer', 'Disease', (93, 99))	('inhibitory activity', 'MPA', (65, 84))	('albiziabioside A', 'Chemical', 'MESH:C000597544', (30, 46))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('cancer', 'Disease', (167, 173))	('D13', 'Var', (9, 12))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('multidrug-resistant', 'Disease', (141, 160))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('tumorigenesis', 'CPA', (205, 218))	('toxicity', 'Disease', 'MESH:D064420', (235, 243))
79189	31908494	Cystine deprivation induces ferroptosis of certain cancer cells, and stabilization of wild-type p53 attenuates ferroptosis in response to cystine deprivation via upregulation of the p53 transcriptional target p21, slowing the depletion of intracellular glutathione and reducing the accumulation of lipid ROS.	('p53', 'Gene', '7157', (96, 99))	('attenuates', 'NegReg', (100, 110))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('slowing', 'NegReg', (214, 221))	('p53', 'Gene', '7157', (182, 185))	('p53', 'Gene', (96, 99))	('Cystine', 'Chemical', 'MESH:D003553', (0, 7))	('p53', 'Gene', (182, 185))	('depletion of intracellular glutathione', 'MPA', (226, 264))	('ferroptosis of certain cancer', 'Disease', 'MESH:D009369', (28, 57))	('cystine', 'Chemical', 'MESH:D003553', (138, 145))	('induces', 'Reg', (20, 27))	('reducing', 'NegReg', (269, 277))	('p21', 'Gene', (209, 212))	('ferroptosis', 'Disease', (111, 122))	('glutathione', 'Chemical', 'MESH:D005978', (253, 264))	('p21', 'Gene', '644914', (209, 212))	('upregulation', 'PosReg', (162, 174))	('ferroptosis of certain cancer', 'Disease', (28, 57))	('accumulation of lipid ROS', 'MPA', (282, 307))	('stabilization', 'Var', (69, 82))
79190	31908494	Loss of p53 prevents nuclear accumulation of dipeptidyl peptidase-4 (DPP4) and promotes plasma membrane-associated DPP4-dependent lipid peroxidation, ultimately leading to ferroptosis.	('prevents', 'NegReg', (12, 20))	('dipeptidyl peptidase-4', 'Gene', (45, 67))	('p53', 'Gene', (8, 11))	('DPP4', 'Gene', '1803', (69, 73))	('dipeptidyl peptidase-4', 'Gene', '1803', (45, 67))	('p53', 'Gene', '7157', (8, 11))	('DPP4', 'Gene', (115, 119))	('DPP4', 'Gene', '1803', (115, 119))	('promotes', 'PosReg', (79, 87))	('DPP4', 'Gene', (69, 73))	('ferroptosis', 'Disease', (172, 183))	('leading to', 'Reg', (161, 171))	('Loss', 'Var', (0, 4))	('nuclear accumulation', 'MPA', (21, 41))
79192	31908494	miR-137 blocked the erastin- and RSL3-induced ferroptosis of human melanoma cells that harboured the BRAFV600E mutation by targeting SLC1A5, and knockdown of miR-137 enhanced the antitumour activity of erastin both in vitro and in vivo.	('miR-137', 'Gene', '406928', (158, 165))	('miR-137', 'Gene', (0, 7))	('SLC1A5', 'Gene', '6510', (133, 139))	('tumour', 'Disease', (183, 189))	('BRAFV600E', 'Mutation', 'rs113488022', (101, 110))	('miR-137', 'Gene', '406928', (0, 7))	('melanoma', 'Phenotype', 'HP:0002861', (67, 75))	('targeting', 'Reg', (123, 132))	('ferroptosis of human melanoma', 'Disease', (46, 75))	('BRAFV600E', 'Var', (101, 110))	('SLC1A5', 'Gene', (133, 139))	('ferroptosis of human melanoma', 'Disease', 'MESH:D008545', (46, 75))	('tumour', 'Disease', 'MESH:D009369', (183, 189))	('enhanced', 'PosReg', (166, 174))	('tumour', 'Phenotype', 'HP:0002664', (183, 189))	('miR-137', 'Gene', (158, 165))
79194	31908494	miR-27a regulated cisplatin resistance by directly targeting SLC7A11 in bladder cancer, and miR-27a overexpression or silencing of SLC7A11 resensitized tumour cells to cisplatin (Table 1).	('miR-27a', 'Gene', '407018', (92, 99))	('cisplatin', 'Chemical', 'MESH:D002945', (18, 27))	('cisplatin resistance', 'MPA', (18, 38))	('overexpression', 'PosReg', (100, 114))	('bladder cancer', 'Disease', 'MESH:D001749', (72, 86))	('bladder cancer', 'Disease', (72, 86))	('cisplatin', 'Chemical', 'MESH:D002945', (168, 177))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('silencing', 'Var', (118, 127))	('bladder cancer', 'Phenotype', 'HP:0009725', (72, 86))	('miR-27a', 'Gene', (92, 99))	('targeting', 'Reg', (51, 60))	('regulated', 'Reg', (8, 17))	('miR-27a', 'Gene', '407018', (0, 7))	('SLC7A11', 'Gene', (61, 68))	('SLC7A11', 'Gene', '23657', (61, 68))	('tumour', 'Phenotype', 'HP:0002664', (152, 158))	('SLC7A11', 'Gene', (131, 138))	('tumour', 'Disease', 'MESH:D009369', (152, 158))	('SLC7A11', 'Gene', '23657', (131, 138))	('tumour', 'Disease', (152, 158))	('miR-27a', 'Gene', (0, 7))
79199	31908494	NFS1 depletion suppresses the growth of metastatic and primary lung tumours by inducing ferroptosis, with no effects on the growth of mammary or subcutaneous tumours.	('suppresses', 'NegReg', (15, 25))	('tumour', 'Phenotype', 'HP:0002664', (68, 74))	('depletion', 'Var', (5, 14))	('tumour', 'Phenotype', 'HP:0002664', (158, 164))	('inducing', 'Reg', (79, 87))	('tumours', 'Phenotype', 'HP:0002664', (68, 75))	('tumours', 'Phenotype', 'HP:0002664', (158, 165))	('primary lung tumours', 'Disease', (55, 75))	('subcutaneous tumours', 'Disease', (145, 165))	('subcutaneous tumours', 'Disease', 'MESH:D013352', (145, 165))	('primary lung tumours', 'Disease', 'MESH:D008175', (55, 75))	('NFS1', 'Gene', (0, 4))	('ferroptosis', 'CPA', (88, 99))	('growth', 'CPA', (30, 36))	('NFS1', 'Gene', '9054', (0, 4))
79201	31908494	DeltaNp63alpha protected the p53-/- MEFs from erastin-induced ferroptosis, and these findings indicated that DeltaNp63alpha negatively regulated ferroptosis in a p53-independent manner.	('p53', 'Gene', (162, 165))	('negatively', 'NegReg', (124, 134))	('ferroptosis', 'CPA', (145, 156))	('DeltaNp63alpha', 'Var', (109, 123))	('p53', 'Gene', (29, 32))	('p53', 'Gene', '7157', (162, 165))	('p53', 'Gene', '7157', (29, 32))	('MEFs', 'CellLine', 'CVCL:9115', (36, 40))
79204	31908494	Silencing CDO1 inhibited erastin-induced ferroptosis in gastric cancer cells both in vitro and in vivo by increasing GSH levels, preventing ROS production, reducing lipid peroxidation and upregulating GPX4 expression.	('lipid peroxidation', 'MPA', (165, 183))	('Silencing', 'Var', (0, 9))	('gastric cancer', 'Disease', 'MESH:D013274', (56, 70))	('ROS production', 'MPA', (140, 154))	('GSH', 'Chemical', 'MESH:D005978', (117, 120))	('CDO1', 'Gene', (10, 14))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('gastric cancer', 'Phenotype', 'HP:0012126', (56, 70))	('expression', 'MPA', (206, 216))	('CDO1', 'Gene', '1036', (10, 14))	('preventing', 'NegReg', (129, 139))	('reducing', 'NegReg', (156, 164))	('erastin-induced', 'Disease', (25, 40))	('GSH levels', 'MPA', (117, 127))	('inhibited', 'NegReg', (15, 24))	('upregulating', 'PosReg', (188, 200))	('increasing', 'PosReg', (106, 116))	('GPX4', 'Gene', (201, 205))	('gastric cancer', 'Disease', (56, 70))	('GPX4', 'Gene', '2879', (201, 205))
79208	31908494	In artesunate-induced ferroptosis, GRP78 was upregulated, and silencing GRP78 sensitized pancreatic cancer cells to artesunate.	('pancreatic cancer', 'Disease', 'MESH:D010190', (89, 106))	('silencing', 'Var', (62, 71))	('sensitized', 'Reg', (78, 88))	('artesunate', 'Chemical', 'MESH:C039726', (116, 126))	('GRP78', 'Gene', (35, 40))	('GRP78', 'Gene', (72, 77))	('GRP78', 'Gene', '3309', (35, 40))	('GRP78', 'Gene', '3309', (72, 77))	('artesunate', 'Chemical', 'MESH:C039726', (3, 13))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('upregulated', 'PosReg', (45, 56))	('artesunate-induced', 'Disease', (3, 21))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (89, 106))	('pancreatic cancer', 'Disease', (89, 106))
79209	31908494	ATM was found to be an essential factor in ferroptosis, and inactivation or silencing of ATM suppressed cystine deprivation- or erastin-induced ferroptosis.	('cystine', 'Chemical', 'MESH:D003553', (104, 111))	('cystine deprivation-', 'MPA', (104, 124))	('silencing', 'Var', (76, 85))	('ATM', 'Gene', '472', (89, 92))	('ATM', 'Gene', (89, 92))	('ATM', 'Gene', (0, 3))	('ATM', 'Gene', '472', (0, 3))	('suppressed', 'NegReg', (93, 103))	('inactivation', 'Var', (60, 72))
79216	31908494	CH004, a bioactive inhibitor of human cystathionine beta-synthase (CBS), which is the key enzyme in the transsulfuration pathway for sulfur amino acids, was reported to induce the ferroptosis of HepG2 cells and inhibit tumour growth in a liver tumour xenograft mouse model.	('cystathionine beta-synthase', 'Gene', (38, 65))	('tumour', 'Phenotype', 'HP:0002664', (219, 225))	('tumour', 'Phenotype', 'HP:0002664', (244, 250))	('tumour growth', 'Disease', 'MESH:D006130', (219, 232))	('induce', 'PosReg', (169, 175))	('liver tumour', 'Disease', (238, 250))	('mouse', 'Species', '10090', (261, 266))	('CH004', 'Var', (0, 5))	('human', 'Species', '9606', (32, 37))	('tumour growth', 'Disease', (219, 232))	('CBS', 'Gene', (67, 70))	('inhibit', 'NegReg', (211, 218))	('sulfur', 'Chemical', 'MESH:D013455', (109, 115))	('sulfur', 'Chemical', 'MESH:D013455', (133, 139))	('ferroptosis', 'CPA', (180, 191))	('cystathionine beta-synthase', 'Gene', '875', (38, 65))	('HepG2', 'CellLine', 'CVCL:0027', (195, 200))	('CBS', 'Gene', '875', (67, 70))	('liver tumour', 'Disease', 'MESH:D008113', (238, 250))	('CH004', 'Chemical', 'MESH:C430545', (0, 5))	('liver tumour', 'Phenotype', 'HP:0002896', (238, 250))
79238	31908494	As SLC7A11 is the key regulator of ferroptosis, silencing SLC7A11 or inhibiting its activity can induce ferroptosis.	('silencing', 'Var', (48, 57))	('SLC7A11', 'Gene', (58, 65))	('SLC7A11', 'Gene', (3, 10))	('SLC7A11', 'Gene', '23657', (58, 65))	('SLC7A11', 'Gene', '23657', (3, 10))	('induce', 'Reg', (97, 103))	('activity', 'MPA', (84, 92))	('ferroptosis', 'Disease', (104, 115))	('inhibiting', 'NegReg', (69, 79))
79241	31908494	Importantly, high expression of SLC7A11 is significantly associated with poor prognosis in LIHC and KIRP patients (Table 2, Figure 3A and B).	('patients', 'Species', '9606', (105, 113))	('high', 'Var', (13, 17))	('SLC7A11', 'Gene', '23657', (32, 39))	('LIHC', 'Disease', (91, 95))	('LIHC', 'Disease', 'MESH:D006528', (91, 95))	('SLC7A11', 'Gene', (32, 39))	('associated', 'Reg', (57, 67))	('KIRP', 'Disease', (100, 104))
79256	31908494	5) Cancer therapy targeting ferroptosis should be further studied and validated, and inducing ferroptosis might become a promising cancer treatment method.	('cancer', 'Disease', (131, 137))	('inducing', 'Var', (85, 93))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('Cancer', 'Phenotype', 'HP:0002664', (3, 9))	('cancer', 'Disease', 'MESH:D009369', (131, 137))
79292	31612115	GSE57495 had 63 tumor tissues that were downloaded with their associated follow-up information for subsequent validation of the prognostic gene signature.	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('tumor', 'Disease', (16, 21))	('GSE57495', 'Var', (0, 8))	('tumor', 'Disease', 'MESH:D009369', (16, 21))
79312	31612115	Seven sets of DEGs (GSE71729, GSE62165, GSE62452, GSE28735, GSE15471, GSE16515, and GSE32676) comprised of 453, 2,449, 285, 395, 948, 1,238, and 472 DEGs were identified between tumor and normal tissues (Figure 2A; Supplementary Figures 1A-G).	('GSE15471', 'Var', (60, 68))	('GSE16515', 'Var', (70, 78))	('tumor', 'Disease', (178, 183))	('GSE71729', 'Var', (20, 28))	('GSE32676', 'Var', (84, 92))	('GSE62452', 'Var', (40, 48))	('GSE28735', 'Var', (50, 58))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('GSE62165', 'Var', (30, 38))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))
79352	31612115	These enriched KEGG pathways revealed that molecular alteration in the high-risk group was closely associated with the malignant properties of pancreatic cancer, especially invasion and metastasis.	('invasion', 'CPA', (173, 181))	('metastasis', 'CPA', (186, 196))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (143, 160))	('malignant properties', 'CPA', (119, 139))	('pancreatic cancer', 'Disease', (143, 160))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('pancreatic cancer', 'Disease', 'MESH:D010190', (143, 160))	('associated', 'Reg', (99, 109))	('molecular alteration', 'Var', (43, 63))
79358	31612115	The risk scores for the KRAS, TP53, and CDKN2A mutant groups were significantly higher than those for the wild type (Figures 9F-H).	('TP53', 'Gene', (30, 34))	('KRAS', 'Gene', '3845', (24, 28))	('higher', 'PosReg', (80, 86))	('CDKN2A', 'Gene', (40, 46))	('risk scores', 'MPA', (4, 15))	('CDKN2A', 'Gene', '1029', (40, 46))	('TP53', 'Gene', '7157', (30, 34))	('mutant', 'Var', (47, 53))	('KRAS', 'Gene', (24, 28))
79359	31612115	The risk score in the SMAD4 mutant group was non-significantly higher than that for the wild type (Figure 9I).	('higher', 'PosReg', (63, 69))	('mutant', 'Var', (28, 34))	('SMAD4', 'Gene', '4089', (22, 27))	('SMAD4', 'Gene', (22, 27))
79383	31612115	This group was enriched with pancreatic cancer-related oncogenic pathways and mutations and was associated with invasion, metastasis, poor survival, and significantly lower levels of CD4+ T cell infiltration.	('lower', 'NegReg', (167, 172))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (29, 46))	('invasion', 'CPA', (112, 120))	('CD4', 'Gene', (183, 186))	('CD4+ T cell infiltration', 'Phenotype', 'HP:0005407', (183, 207))	('mutations', 'Var', (78, 87))	('lower levels of CD4+ T', 'Phenotype', 'HP:0005407', (167, 189))	('pancreatic cancer', 'Disease', (29, 46))	('CD4', 'Gene', '920', (183, 186))	('pancreatic cancer', 'Disease', 'MESH:D010190', (29, 46))	('metastasis', 'CPA', (122, 132))	('oncogenic pathways', 'Pathway', (55, 73))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))
79386	31612115	MET is dysregulated in pancreatic cancer and activated by genetic mutation and gene amplification, participating in pancreatic cancer cell interactions with the tumor microenvironment.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('gene amplification', 'Var', (79, 97))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (23, 40))	('participating', 'Reg', (99, 112))	('MET', 'Gene', (0, 3))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (116, 133))	('pancreatic cancer', 'Disease', (23, 40))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('pancreatic cancer', 'Disease', 'MESH:D010190', (23, 40))	('interactions', 'Interaction', (139, 151))	('activated', 'PosReg', (45, 54))	('pancreatic cancer', 'Disease', (116, 133))	('tumor', 'Disease', (161, 166))	('genetic mutation', 'Var', (58, 74))	('pancreatic cancer', 'Disease', 'MESH:D010190', (116, 133))
79387	31612115	MET expression is closely associated with clinical stage and activates the RAS-ERK and PI3K-Akt pathways by recruiting downstream effector molecules mediating tumorigenesis, progression, metastasis, and gemcitabine chemotherapy resistance.	('ERK', 'Gene', (79, 82))	('gemcitabine', 'Chemical', 'MESH:C056507', (203, 214))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('Akt', 'Gene', '207', (92, 95))	('metastasis', 'CPA', (187, 197))	('activates', 'PosReg', (61, 70))	('tumor', 'Disease', (159, 164))	('Akt', 'Gene', (92, 95))	('recruiting', 'PosReg', (108, 118))	('ERK', 'Gene', '2048', (79, 82))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('MET', 'Var', (0, 3))
79396	31612115	KLK10 knockdown attenuated pancreatic cancer cell migration, invasion, and metastasis in vitro and in vivo.	('KLK10', 'Gene', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('attenuated pancreatic cancer', 'Disease', (16, 44))	('attenuated pancreatic cancer', 'Disease', 'MESH:D010190', (16, 44))	('invasion', 'CPA', (61, 69))	('metastasis', 'CPA', (75, 85))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (27, 44))	('knockdown', 'Var', (6, 15))	('KLK10', 'Gene', '5655', (0, 5))
79402	31612115	In contrast, COL17A1 is hypomethylated and upregulated in cervical cancer, head, neck, and lung squamous cell carcinoma, and lung adenocarcinoma.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('lung adenocarcinoma', 'Disease', (125, 144))	('upregulated', 'PosReg', (43, 54))	('cancer', 'Disease', (67, 73))	('COL17A1', 'Gene', '1308', (13, 20))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (96, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (91, 119))	('head', 'Disease', (75, 79))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (125, 144))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (91, 119))	('hypomethylated', 'Var', (24, 38))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (125, 144))	('COL17A1', 'Gene', (13, 20))	('lung squamous cell carcinoma', 'Disease', (91, 119))
79428	31612115	Anti-ITGA5B6 antibody alone or with trastuzumab halted tumor growth.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('Anti-ITGA5B6', 'Var', (0, 12))	('ITGA5B6', 'Chemical', 'MESH:C588002', (5, 12))	('tumor', 'Disease', (55, 60))	('halted', 'NegReg', (48, 54))
79431	31612115	Interruption of the circadian rhythm induces cardiovascular disease, cancers, metabolic syndromes, and aging.	('induces', 'Reg', (37, 44))	('cancers', 'Disease', 'MESH:D009369', (69, 76))	('cardiovascular disease', 'Disease', (45, 67))	('Interruption', 'Var', (0, 12))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('cardiovascular disease', 'Phenotype', 'HP:0001626', (45, 67))	('aging', 'Disease', (103, 108))	('cardiovascular disease', 'Disease', 'MESH:D002318', (45, 67))	('metabolic syndromes', 'Disease', (78, 97))	('cancers', 'Phenotype', 'HP:0002664', (69, 76))	('cancers', 'Disease', (69, 76))
79432	31612115	Variations of the genes governing the circadian pathway may be associated with cancer predisposition.	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('associated', 'Reg', (63, 73))	('Variations', 'Var', (0, 10))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))
79445	31612115	SLC25A45 mutations are associated with chronic kidney disease and preterm birth.	('kidney disease', 'Phenotype', 'HP:0000112', (47, 61))	('SLC25A45', 'Gene', '283130', (0, 8))	('chronic kidney disease', 'Disease', (39, 61))	('mutations', 'Var', (9, 18))	('preterm birth', 'Disease', (66, 79))	('preterm birth', 'Phenotype', 'HP:0001622', (66, 79))	('preterm birth', 'Disease', 'MESH:D047928', (66, 79))	('chronic kidney disease', 'Phenotype', 'HP:0012622', (39, 61))	('chronic kidney disease', 'Disease', 'MESH:D051436', (39, 61))	('associated', 'Reg', (23, 33))	('SLC25A45', 'Gene', (0, 8))
79446	31612115	The SNP of SLC25A45 was associated with the mucinous histological subtype of epithelial ovarian cancer.	('mucinous', 'Disease', (44, 52))	('SNP', 'Var', (4, 7))	('SLC25A45', 'Gene', (11, 19))	('epithelial ovarian cancer', 'Disease', 'MESH:D010051', (77, 102))	('associated', 'Reg', (24, 34))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('SLC25A45', 'Gene', '283130', (11, 19))	('epithelial ovarian cancer', 'Disease', (77, 102))	('epithelial ovarian cancer', 'Phenotype', 'HP:0025318', (77, 102))	('ovarian cancer', 'Phenotype', 'HP:0100615', (88, 102))
79521	29416792	Benchmarking was performed using 500 samples of Acute Myeloid Leukemia (AML) and normal blood sample expression data downloaded from NCBI (GSE6891, GSE2677, GSE43346, GSE63270) [HG-U133_Plus_2] Human Genome U133 Plus 2.0 Array, containing 54,675 probes.	('AML', 'Disease', 'MESH:D015470', (72, 75))	('Acute Myeloid Leukemia', 'Disease', (48, 70))	('AML', 'Phenotype', 'HP:0004808', (72, 75))	('AML', 'Disease', (72, 75))	('GSE63270', 'Var', (167, 175))	('Acute Myeloid Leukemia', 'Disease', 'MESH:D015470', (48, 70))	('Human', 'Species', '9606', (194, 199))	('Myeloid Leukemia', 'Phenotype', 'HP:0012324', (54, 70))	('Leukemia', 'Phenotype', 'HP:0001909', (62, 70))	('Acute Myeloid Leukemia', 'Phenotype', 'HP:0004808', (48, 70))
79527	29416792	Reported measures included the numbers of true positives (TP), true negatives (TN), false positives (FP), and false negatives (FN).	('false', 'Var', (110, 115))	('TP', 'Chemical', '-', (58, 60))	('false', 'Var', (84, 89))
79534	33276631	However, it is also becoming widely recognised that permanent hyper-activation of NRF2 resulting from somatic mutations in the gene that encodes NRF2, or in genes associated with its degradation, is frequently observed in certain cancers and associated with poor outcome.	('mutations', 'Var', (110, 119))	('hyper-activation', 'PosReg', (62, 78))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('NRF2', 'Gene', (145, 149))	('cancers', 'Disease', 'MESH:D009369', (230, 237))	('cancers', 'Phenotype', 'HP:0002664', (230, 237))	('cancers', 'Disease', (230, 237))	('NRF2', 'Gene', (82, 86))
79537	33276631	Moreover, we discuss how upregulation of NRF2 might aid the growth and survival of tumours, whether NRF2 upregulation in particular types of cancer is associated with mutations in specific oncogenes, and at what stage of cancer development this is likely to occur.	('NRF2', 'Gene', (41, 45))	('NRF2', 'Gene', (100, 104))	('tumours', 'Disease', (83, 90))	('cancer', 'Disease', 'MESH:D009369', (221, 227))	('upregulation', 'PosReg', (105, 117))	('cancer', 'Disease', (221, 227))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('mutations', 'Var', (167, 176))	('tumour', 'Phenotype', 'HP:0002664', (83, 89))	('men', 'Species', '9606', (235, 238))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('tumours', 'Phenotype', 'HP:0002664', (83, 90))	('growth', 'CPA', (60, 66))	('aid', 'PosReg', (52, 55))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('cancer', 'Disease', (141, 147))	('upregulation', 'PosReg', (25, 37))	('tumours', 'Disease', 'MESH:D009369', (83, 90))
79544	33276631	We similarly describe the discoveries of somatic mutations in NFE2L2 and the gene encoding the principal NRF2 repressor, Kelch-like ECH-associated protein 1 (KEAP1) along with that encoding a component of the E3 ubiquitin-ligase complex Cullin 3 (CUL3), which result in permanent activation of NRF2, and the recognition that such mutations occur frequently in many types of cancer.	('cancer', 'Phenotype', 'HP:0002664', (374, 380))	('mutations', 'Var', (49, 58))	('Cullin 3', 'Gene', (237, 245))	('activation', 'PosReg', (280, 290))	('cancer', 'Disease', (374, 380))	('Kelch-like ECH-associated protein 1', 'Gene', (121, 156))	('Cullin 3', 'Gene', '26554', (237, 245))	('NFE2L2', 'Gene', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (374, 380))	('Kelch-like ECH-associated protein 1', 'Gene', '50868', (121, 156))	('NRF2', 'Gene', (294, 298))
79545	33276631	Notably, mutations in NFE2L2, KEAP1 and CUL3 that cause persistent upregulation of NRF2 often co-exist with mutations that activate KRAS and the PI3K-PKB/Akt pathway, suggesting NRF2 supports growth of tumours in which KRAS or PKB/Akt are hyperactive.	('hyperactive', 'Disease', 'MESH:D006948', (239, 250))	('hyperactive', 'Disease', (239, 250))	('mutations', 'Var', (108, 117))	('NRF2', 'Gene', (83, 87))	('NFE2L2', 'Gene', (22, 28))	('mutations', 'Var', (9, 18))	('tumour', 'Phenotype', 'HP:0002664', (202, 208))	('tumours', 'Phenotype', 'HP:0002664', (202, 209))	('PKB', 'Gene', (150, 153))	('PKB', 'Gene', '11651', (227, 230))	('PKB', 'Gene', (227, 230))	('upregulation', 'PosReg', (67, 79))	('KRAS', 'Pathway', (132, 136))	('tumours', 'Disease', 'MESH:D009369', (202, 209))	('tumours', 'Disease', (202, 209))	('PKB', 'Gene', '11651', (150, 153))	('activate', 'PosReg', (123, 131))
79546	33276631	Besides somatic mutations, NRF2 activation in human tumours can occur by other means, such as alternative splicing that results in a NRF2 protein which lacks the KEAP1-binding domain or overexpression of other KEAP1-binding partners that compete with NRF2.	('overexpression', 'PosReg', (186, 200))	('NRF2', 'Gene', (27, 31))	('tumours', 'Disease', (52, 59))	('tumour', 'Phenotype', 'HP:0002664', (52, 58))	('activation', 'PosReg', (32, 42))	('protein', 'Protein', (138, 145))	('results in', 'Reg', (120, 130))	('human', 'Species', '9606', (46, 51))	('tumours', 'Phenotype', 'HP:0002664', (52, 59))	('lacks', 'NegReg', (152, 157))	('NRF2', 'Gene', (133, 137))	('tumours', 'Disease', 'MESH:D009369', (52, 59))	('alternative splicing', 'Var', (94, 114))
79550	33276631	Paradoxically, however, in certain types of cancer the irreversible genetic upregulation of NRF2 resulting from stochastic somatic activating mutations in NFE2L2 or inactivating mutations in the gene encoding the repressor of NRF2, Kelch-like ECH-associated protein 1 (KEAP1), or that for its E3 ligase Cullin 3 (CUL3), is associated with progression of disease once it has been initiated.	('Kelch-like ECH-associated protein 1', 'Gene', '50868', (232, 267))	('mutations', 'Var', (142, 151))	('inactivating mutations', 'Var', (165, 187))	('upregulation', 'PosReg', (76, 88))	('NFE2L2', 'Gene', (155, 161))	('cancer', 'Disease', (44, 50))	('Cullin 3', 'Gene', (303, 311))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('activating', 'PosReg', (131, 141))	('Cullin 3', 'Gene', '26554', (303, 311))	('NRF2', 'Gene', (92, 96))	('Kelch-like ECH-associated protein 1', 'Gene', (232, 267))	('NRF2', 'Gene', (226, 230))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
79576	33276631	The notion that chemoprevention extended beyond skin cancer, and could not, therefore, be simply attributed to physical shielding against absorption of the carcinogen across the skin, was revealed by several research groups, including that of Elizabeth and James Miller, who showed that administration of a low dose of various polycyclic aromatic hydrocarbons protects against liver carcinogenesis initiated by 3-methyl-4-dimethylaminoazobenzene or 2-acetylaminofluorene, results that indicated chemopreventive agents exerted systemic effects.	('3-methyl-4-dimethylaminoazobenzene', 'Var', (411, 445))	('liver carcinogenesis', 'Disease', 'MESH:D063646', (377, 397))	('3-methyl-4-dimethylaminoazobenzene', 'Chemical', 'MESH:D008749', (411, 445))	('skin cancer', 'Phenotype', 'HP:0008069', (48, 59))	('rat', 'Species', '10116', (295, 298))	('2-acetylaminofluorene', 'Chemical', 'MESH:D015073', (449, 470))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('skin cancer', 'Disease', (48, 59))	('2-acetylaminofluorene', 'MPA', (449, 470))	('liver carcinogenesis', 'Disease', (377, 397))	('polycyclic aromatic hydrocarbons', 'Chemical', 'MESH:D011084', (327, 359))	('skin cancer', 'Disease', 'MESH:D012878', (48, 59))
79585	33276631	Importantly, the increase in GST activity stimulated by BHA was shown to result from an increase in abundance in mRNA for the GST subunits, rather than merely an increase in catalytic activity, and this is true too for the increases in EPXH1, NQO1, AKRs and UGTs.	('UGT', 'Gene', (258, 261))	('catalytic', 'MPA', (174, 183))	('GST activity', 'MPA', (29, 41))	('increase', 'PosReg', (17, 25))	('abundance', 'MPA', (100, 109))	('mRNA', 'MPA', (113, 117))	('rat', 'Species', '10116', (140, 143))	('increase', 'PosReg', (88, 96))	('BHA', 'Chemical', 'MESH:D002083', (56, 59))	('BHA', 'Var', (56, 59))	('EPXH1', 'Gene', (236, 241))	('EPXH1', 'Gene', '13849', (236, 241))	('UGT', 'Gene', '22232', (258, 261))
79592	33276631	Indeed, knockout of Gsta3 renders mice sensitive to the hepatotoxic effects of the mycotoxin.	('hepatotoxic', 'Disease', 'MESH:D056486', (56, 67))	('mice', 'Species', '10090', (34, 38))	('hepatotoxic', 'Disease', (56, 67))	('Gsta3', 'Gene', '14859', (20, 25))	('sensitive to', 'MPA', (39, 51))	('knockout', 'Var', (8, 16))	('Gsta3', 'Gene', (20, 25))
79594	33276631	Following the discovery that NRF2 regulates both the basal and inducible expression of genes encoding drug-metabolising enzymes capable of detoxifying carcinogenic xenobiotics, various research groups investigated whether loss of the CNC-bZIP transcription factor might sensitise mice to tumourigenesis and diminish the effectiveness of chemopreventive agents in gastric, bladder, skin, gastrointestinal tract, oral, mammary, lung and liver cancer.	('bladder', 'Disease', (372, 379))	('liver cancer', 'Disease', (435, 447))	('diminish', 'NegReg', (307, 315))	('oral', 'Disease', (411, 415))	('mammary', 'Disease', (417, 424))	('CNC-bZIP', 'Gene', (234, 242))	('skin', 'Disease', (381, 385))	('loss', 'Var', (222, 226))	('mice', 'Species', '10090', (280, 284))	('tumour', 'Phenotype', 'HP:0002664', (288, 294))	('lung', 'Disease', (426, 430))	('effectiveness of chemopreventive agents', 'CPA', (320, 359))	('tumour', 'Disease', 'MESH:D009369', (288, 294))	('gastrointestinal tract', 'Disease', (387, 409))	('tumour', 'Disease', (288, 294))	('carcinogenic', 'Disease', (151, 163))	('liver cancer', 'Disease', 'MESH:D006528', (435, 447))	('gastric', 'Disease', (363, 370))	('carcinogenic', 'Disease', 'MESH:D063646', (151, 163))	('cancer', 'Phenotype', 'HP:0002664', (441, 447))	('liver cancer', 'Phenotype', 'HP:0002896', (435, 447))	('sensitise', 'Reg', (270, 279))
79596	33276631	Moreover, knockout of NRF2 in the rat renders them more sensitive to formation of AFB1-N7-guanine DNA adducts in the liver when exposed to the mycotoxin.	('more', 'PosReg', (51, 55))	('AFB1-N7-guanine', 'Chemical', 'MESH:C514713', (82, 97))	('knockout', 'Var', (10, 18))	('rat', 'Species', '10116', (34, 37))	('sensitive', 'MPA', (56, 65))	('NRF2', 'Gene', (22, 26))
79597	33276631	The first chemoprevention study to focus on Nrf2-ko mice revealed that whilst 48 h pre-treatment of the mutant mice with oltipraz could decrease the number of benzo[a]pyrene-initiated forestomach neoplastic lesions by approx.	('oltipraz', 'Chemical', 'MESH:C026209', (121, 129))	('forestomach neoplastic lesions', 'Disease', 'MESH:D013274', (184, 214))	('neoplastic lesions', 'Phenotype', 'HP:0002664', (196, 214))	('benzo[a]pyrene-initiated', 'MPA', (159, 183))	('forestomach neoplastic lesions', 'Disease', (184, 214))	('mutant', 'Var', (104, 110))	('decrease', 'NegReg', (136, 144))	('mice', 'Species', '10090', (52, 56))	('mice', 'Species', '10090', (111, 115))	('benzo[a]pyrene', 'Chemical', 'MESH:D001564', (159, 173))	('men', 'Species', '9606', (92, 95))
79599	33276631	Furthermore, benzo[a]pyrene produced a higher tumour burden in the forestomach of Nrf2-ko mice than in wildtype mice.	('benzo[a]pyrene', 'Var', (13, 27))	('higher', 'PosReg', (39, 45))	('benzo[a]pyrene', 'Chemical', 'MESH:D001564', (13, 27))	('tumour', 'Disease', (46, 52))	('mice', 'Species', '10090', (90, 94))	('tumour', 'Phenotype', 'HP:0002664', (46, 52))	('mice', 'Species', '10090', (112, 116))	('tumour', 'Disease', 'MESH:D009369', (46, 52))
79613	33276631	Interestingly, Nrf2-ko mice are more sensitive to 4NQO-initiated carcinogenesis than wildtype mice.	('mice', 'Species', '10090', (94, 98))	('carcinogenesis', 'Disease', 'MESH:D063646', (65, 79))	('sensitive', 'Reg', (37, 46))	('4NQO', 'Chemical', 'MESH:D015112', (50, 54))	('carcinogenesis', 'Disease', (65, 79))	('Nrf2-ko', 'Var', (15, 22))	('mice', 'Species', '10090', (23, 27))
79619	33276631	Using an ethyl carbamate-induced lung carcinogenesis model, Nrf2-ko mice have been shown to be substantially more sensitive than wildtype mice to the early stages of tumourigenesis but, surprisingly, seem to be more resistant to the later stages of lung tumourigenesis than their wildtype counterparts, suggesting that whilst Nrf2-target genes antagonise initiation of chemical carcinogenesis they facilitate the later transformation of benign adenoma to adenocarcinoma that may entail mutation of Kras.	('tumour', 'Disease', 'MESH:D009369', (166, 172))	('tumour', 'Disease', (166, 172))	('carcinogenesis', 'Disease', 'MESH:D063646', (38, 52))	('carcinogenesis', 'Disease', (378, 392))	('benign adenoma to adenocarcinoma', 'Disease', (437, 469))	('carcinoma', 'Phenotype', 'HP:0030731', (460, 469))	('lung carcinogenesis', 'Disease', (33, 52))	('benign adenoma to adenocarcinoma', 'Disease', 'MESH:D000236', (437, 469))	('mice', 'Species', '10090', (68, 72))	('carcinogenesis', 'Disease', 'MESH:D063646', (378, 392))	('mice', 'Species', '10090', (138, 142))	('tumour', 'Phenotype', 'HP:0002664', (254, 260))	('lung carcinogenesis', 'Disease', 'MESH:D063646', (33, 52))	('facilitate', 'PosReg', (398, 408))	('mutation', 'Var', (486, 494))	('tumour', 'Disease', 'MESH:D009369', (254, 260))	('tumour', 'Disease', (254, 260))	('ethyl carbamate', 'Chemical', 'MESH:D014520', (9, 24))	('Kras', 'Gene', (498, 502))	('carcinogenesis', 'Disease', (38, 52))	('tumour', 'Phenotype', 'HP:0002664', (166, 172))	('Kras', 'Gene', '16653', (498, 502))
79622	33276631	Consistent with this proposal, in KrasLSL-G12D/+ mice, which harbour oncogenic Kras, pharmacological upregulation of Nrf2 by treatment with SFN after lung tumourigenesis had been initiated has been found to result in a modest 1.35-fold increase in the number of tumours observed on the surface of the lungs, though it should be noted that this is possibly controversial as prolonged treatment with SFN has also been reported not to increase cancer in Kras-based models of lung tumourigenesis.	('tumour', 'Disease', (262, 268))	('pharmacological', 'Var', (85, 100))	('tumour', 'Phenotype', 'HP:0002664', (155, 161))	('Kras', 'Gene', (34, 38))	('tumour', 'Disease', 'MESH:D009369', (155, 161))	('men', 'Species', '9606', (130, 133))	('tumour', 'Disease', (155, 161))	('G12D', 'Mutation', 'rs121913529', (42, 46))	('KrasLSL', 'Gene', (34, 41))	('cancer', 'Disease', 'MESH:D009369', (441, 447))	('Kras', 'Gene', '16653', (34, 38))	('Kras', 'Gene', (79, 83))	('men', 'Species', '9606', (388, 391))	('Kras', 'Gene', (451, 455))	('tumours', 'Disease', (262, 269))	('upregulation', 'PosReg', (101, 113))	('tumour', 'Phenotype', 'HP:0002664', (477, 483))	('mice', 'Species', '10090', (49, 53))	('tumour', 'Disease', 'MESH:D009369', (477, 483))	('Kras', 'Gene', '16653', (79, 83))	('tumour', 'Disease', (477, 483))	('tumours', 'Phenotype', 'HP:0002664', (262, 269))	('tumours', 'Disease', 'MESH:D009369', (262, 269))	('Kras', 'Gene', '16653', (451, 455))	('SFN', 'Chemical', 'MESH:C016766', (140, 143))	('cancer', 'Disease', (441, 447))	('tumour', 'Phenotype', 'HP:0002664', (262, 268))	('cancer', 'Phenotype', 'HP:0002664', (441, 447))	('tumour', 'Disease', 'MESH:D009369', (262, 268))	('Nrf2', 'Gene', (117, 121))	('SFN', 'Chemical', 'MESH:C016766', (398, 401))	('KrasLSL', 'Gene', '16653', (34, 41))
79626	33276631	Nrf2-ko mice are substantially more sensitive to CCl4 than wildtype mice, and pharmacological or genetic activation of the CNC-bZIP transcription factor can protect against toxicity.	('mice', 'Species', '10090', (68, 72))	('sensitive', 'MPA', (36, 45))	('pharmacological', 'Var', (78, 93))	('CCl4', 'Gene', (49, 53))	('CCl4', 'Gene', '20303', (49, 53))	('CNC-bZIP', 'Gene', (123, 131))	('mice', 'Species', '10090', (8, 12))	('toxicity', 'Disease', 'MESH:D064420', (173, 181))	('toxicity', 'Disease', (173, 181))
79628	33276631	However, rather surprisingly, it has been found that in the mouse, Nrf2 upregulation resulting from somatic mutation in the Nfe2l2 gene is necessary for DEN-induced liver carcinogenesis, and thus Nrf2-ko mice are resistant to the carcinogenic effects of DEN.	('upregulation', 'PosReg', (72, 84))	('rat', 'Species', '10116', (9, 12))	('liver carcinogenesis', 'Disease', 'MESH:D063646', (165, 185))	('carcinogenic', 'Disease', 'MESH:D063646', (230, 242))	('DEN', 'Chemical', 'MESH:D004052', (254, 257))	('carcinogenic', 'Disease', (230, 242))	('Nfe2l2', 'Gene', '18024', (124, 130))	('liver carcinogenesis', 'Disease', (165, 185))	('mutation', 'Var', (108, 116))	('DEN', 'Chemical', 'MESH:D004052', (153, 156))	('mouse', 'Species', '10090', (60, 65))	('mice', 'Species', '10090', (204, 208))	('Nfe2l2', 'Gene', (124, 130))
79631	33276631	Besides these pharmacology-associated variations in the host, once initiated, the premalignant adenomas, adenocarcinomas and malignant cells will exert a wide range of host-tumour cell variations that will reflect the types of somatic mutations they have acquired during evolution of the tumour.	('tumour', 'Disease', (173, 179))	('variations', 'Var', (185, 195))	('tumour', 'Disease', 'MESH:D009369', (288, 294))	('tumour', 'Disease', 'MESH:D009369', (173, 179))	('adenomas', 'Disease', 'MESH:D000236', (95, 103))	('host-tumour', 'Disease', (168, 179))	('tumour', 'Disease', (288, 294))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('carcinomas', 'Phenotype', 'HP:0030731', (110, 120))	('tumour', 'Phenotype', 'HP:0002664', (288, 294))	('adenomas', 'Disease', (95, 103))	('tumour', 'Phenotype', 'HP:0002664', (173, 179))	('host-tumour', 'Disease', 'MESH:D009369', (168, 179))	('adenocarcinomas', 'Disease', 'MESH:D000230', (105, 120))	('adenocarcinomas', 'Disease', (105, 120))
79650	33276631	According to this proposal, it was envisioned that modification of certain Cys residues in KEAP1 would prevent it from allowing CRLKEAP1-directed ubiquitylation of NRF2.	('CRLKEAP1-directed ubiquitylation', 'MPA', (128, 160))	('Cys', 'Chemical', 'MESH:D003545', (75, 78))	('NRF2', 'Protein', (164, 168))	('modification', 'Var', (51, 63))	('prevent', 'NegReg', (103, 110))	('allowing', 'PosReg', (119, 127))
79651	33276631	Consistent with the idea that chemopreventive agents act as thiol-active reagents, Cys257, Cys273, Cys288 and Cys297 in purified recombinant mouse Keap1 were found to be modified by the inducer dexamethasone 21-mesylate.	('Cys257', 'Chemical', '-', (83, 89))	('Cys288', 'Var', (99, 105))	('Cys273', 'Chemical', '-', (91, 97))	('Keap1', 'Gene', '50868', (147, 152))	('Cys288', 'Chemical', '-', (99, 105))	('Keap1', 'Gene', (147, 152))	('thiol', 'Chemical', 'MESH:D013438', (60, 65))	('modified', 'Reg', (170, 178))	('mouse', 'Species', '10090', (141, 146))	('dexamethasone 21-mesylate', 'Chemical', 'MESH:C031710', (194, 219))	('Cys273', 'Var', (91, 97))	('Cys297', 'Var', (110, 116))	('Cys297', 'Chemical', '-', (110, 116))	('Cys257', 'Var', (83, 89))
79652	33276631	Confirmation that Cys273 and Cys288 in Keap1 are required to suppress ARE-driven luciferase activity ex vivo was obtained by ectopic expression of wildtype and mutant forms of the adaptor protein in Keap1-ko embryonic fibroblasts.	('ARE-driven', 'MPA', (70, 80))	('Keap1', 'Gene', (199, 204))	('Cys288', 'Var', (29, 35))	('Cys273', 'Var', (18, 24))	('Keap1', 'Gene', '50868', (39, 44))	('mutant', 'Var', (160, 166))	('suppress', 'NegReg', (61, 69))	('Cys273', 'Chemical', '-', (18, 24))	('activity', 'MPA', (92, 100))	('Keap1', 'Gene', (39, 44))	('Keap1', 'Gene', '50868', (199, 204))	('Cys288', 'Chemical', '-', (29, 35))
79653	33276631	Besides the requirement for Cys273 and Cys288 in KEAP1 to allow repression of NRF2, Cys151 in KEAP1 was found to be essential for the inducer SFN and the BHA metabolite tert-butyl hydroquinone (tBHQ) to block ubiquitylation of NRF2 by CUL3, and residues Cys226 and Cys613 were found to be necessary for activation of NRF2 by Cd2+, As3+, Se4+ and Zn2+ and by H2S.	('tert', 'Gene', (169, 173))	('tert', 'Gene', '21752', (169, 173))	('ubiquitylation', 'MPA', (209, 223))	('Cd2', 'Gene', '12481', (325, 328))	('quinone', 'Chemical', 'MESH:C004532', (185, 192))	('H2S', 'Chemical', 'MESH:D003903', (358, 361))	('Zn2+', 'Chemical', '-', (346, 350))	('men', 'Species', '9606', (19, 22))	('Cys288', 'Chemical', '-', (39, 45))	('block', 'NegReg', (203, 208))	('SFN', 'Chemical', 'MESH:C016766', (142, 145))	('Cd2', 'Gene', (325, 328))	('Cys226', 'Chemical', '-', (254, 260))	('Cys613', 'Var', (265, 271))	('Cys613', 'Chemical', '-', (265, 271))	('BHA', 'Chemical', 'MESH:D002083', (154, 157))	('As3+', 'Chemical', '-', (331, 335))	('Se4+', 'Chemical', '-', (337, 341))	('Cys273', 'Chemical', '-', (28, 34))	('tBHQ', 'Chemical', 'MESH:C018855', (194, 198))	('Cys151', 'Chemical', '-', (84, 90))
79654	33276631	More recently, it has been reported that Cys226, Cys613, Cys622 and Cys624 are engaged in the sensing of H2O2, through the formation of disulfide bonds between these residues.	('engaged', 'Reg', (79, 86))	('Cys624', 'Var', (68, 74))	('Cys622', 'Var', (57, 63))	('Cys622', 'Chemical', '-', (57, 63))	('H2O2', 'Gene', (105, 109))	('H2O2', 'Chemical', 'MESH:D006861', (105, 109))	('Cys613', 'Var', (49, 55))	('Cys624', 'Chemical', '-', (68, 74))	('Cys226', 'Chemical', '-', (41, 47))	('disulfide bonds', 'MPA', (136, 151))	('sensing', 'MPA', (94, 101))	('disulfide', 'Chemical', 'MESH:D004220', (136, 145))	('Cys613', 'Chemical', '-', (49, 55))	('Cys226', 'Var', (41, 47))
79655	33276631	Interestingly, there is redundancy in the system insofar as mutation of one of these four Cys residues still allows the mutant KEAP1 to sense H2O2.	('H2O2', 'Chemical', 'MESH:D006861', (142, 146))	('mutation', 'Var', (60, 68))	('sense H2O2', 'MPA', (136, 146))	('allows', 'Reg', (109, 115))	('Cys', 'Chemical', 'MESH:D003545', (90, 93))
79660	33276631	From research stimulated by an interest in chemoprevention, a picture has emerged of KEAP1 as a ubiquitin ligase substrate adaptor that allows cellular adaptation to a variety of redox stressors through complex thiol-based modifications to its various reactive Cys residues that alter its ability to repress NRF2.	('ubiquitin ligase', 'Gene', (96, 112))	('thiol', 'Chemical', 'MESH:D013438', (211, 216))	('rat', 'Species', '10116', (118, 121))	('modifications', 'Var', (223, 236))	('repress', 'NegReg', (300, 307))	('ubiquitin ligase', 'Gene', '84585', (96, 112))	('NRF2', 'Gene', (308, 312))	('Cys', 'Chemical', 'MESH:D003545', (261, 264))
79666	33276631	Shortly thereafter, it was discovered that somatic mutations in NFE2L2 commonly occur in NSCLC and oral cancer cell lines as well as various primary lung cancers and primary head and neck cancers, and that the somatic mutations resulted in amino acid substitutions at residues associated with the DLG and ETGE motifs in NRF2.	('lung cancers', 'Phenotype', 'HP:0100526', (149, 161))	('mutations', 'Var', (51, 60))	('NFE2L2', 'Gene', (64, 70))	('NSCLC', 'Phenotype', 'HP:0030358', (89, 94))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('cancer', 'Disease', (104, 110))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('occur', 'Reg', (80, 85))	('substitutions', 'Var', (251, 264))	('cancers', 'Phenotype', 'HP:0002664', (188, 195))	('head and neck cancers', 'Phenotype', 'HP:0012288', (174, 195))	('NRF2', 'Gene', (320, 324))	('lung cancer', 'Phenotype', 'HP:0100526', (149, 160))	('cancer', 'Disease', (188, 194))	('head and neck cancer', 'Phenotype', 'HP:0012288', (174, 194))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('lung cancers', 'Disease', 'MESH:D008175', (149, 161))	('NSCLC', 'Disease', 'MESH:D002289', (89, 94))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('head and neck cancers', 'Disease', 'MESH:D006258', (174, 195))	('cancers', 'Phenotype', 'HP:0002664', (154, 161))	('cancer', 'Disease', (154, 160))	('lung cancers', 'Disease', (149, 161))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('NSCLC', 'Disease', (89, 94))	('resulted in', 'Reg', (228, 239))
79667	33276631	Examination of second-generation sequencing of a large number of tumours deposited in the catalogue of somatic mutations in cancer (COSMIC) and the cancer genome atlas (TCGA) databases revealed that NFE2L2 and KEAP1 are mutated in various common cancers, including lung, head and neck, and bladder (see Table 2).	('lung', 'Disease', (265, 269))	('cancer', 'Disease', 'MESH:D009369', (124, 130))	('tumours', 'Disease', (65, 72))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('cancers', 'Phenotype', 'HP:0002664', (246, 253))	('mutated', 'Var', (220, 227))	('cancers', 'Disease', (246, 253))	('cancer', 'Disease', (246, 252))	('bladder', 'Disease', (290, 297))	('tumours', 'Phenotype', 'HP:0002664', (65, 72))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))	('tumours', 'Disease', 'MESH:D009369', (65, 72))	('tumour', 'Phenotype', 'HP:0002664', (65, 71))	('cancer', 'Disease', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (246, 252))	('cancer', 'Disease', (124, 130))	('cancers', 'Disease', 'MESH:D009369', (246, 253))	('rat', 'Species', '10116', (26, 29))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('NFE2L2', 'Gene', (199, 205))
79668	33276631	It has also been noted that intragenic deletions occur in NFE2L2 resulting in translation of NRF2 isoforms that lack amino acids that interact with KEAP1 in patients with squamous NSCLC and head and neck carcinoma.	('amino acids', 'MPA', (117, 128))	('deletions', 'Var', (39, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (204, 213))	('NRF2', 'Gene', (93, 97))	('translation', 'MPA', (78, 89))	('patients', 'Species', '9606', (157, 165))	('squamous NSCLC and head and neck carcinoma', 'Disease', 'MESH:D000077195', (171, 213))	('NFE2L2', 'Gene', (58, 64))	('NSCLC', 'Phenotype', 'HP:0030358', (180, 185))	('interact', 'Interaction', (134, 142))	('lack', 'NegReg', (112, 116))	('head and neck carcinoma', 'Phenotype', 'HP:0012288', (190, 213))
79669	33276631	Using a variety of computational bioinformatic tools NFE2L2 mutations have been considered likely to drive lung, oesophageal, cervical, bladder and uterine cancers, though this has not been formally tested.	('cancers', 'Phenotype', 'HP:0002664', (156, 163))	('NFE2L2', 'Gene', (53, 59))	('cancers', 'Disease', (156, 163))	('cervical', 'Disease', (126, 134))	('cancers', 'Disease', 'MESH:D009369', (156, 163))	('lung', 'Disease', (107, 111))	('oesophageal', 'Disease', (113, 124))	('bladder', 'Disease', (136, 143))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('uterine cancers', 'Phenotype', 'HP:0010784', (148, 163))	('mutations', 'Var', (60, 69))	('drive', 'PosReg', (101, 106))
79670	33276631	As shown in Figure 5, NRF2 can also be upregulated by oncogene-stimulated transactivation of NFE2L2, as demonstrated for Kras, Braf and Myc.	('transactivation', 'Var', (74, 89))	('rat', 'Species', '10116', (111, 114))	('Myc', 'Gene', (136, 139))	('upregulated', 'PosReg', (39, 50))	('Myc', 'Gene', '17869', (136, 139))	('Braf', 'Gene', '109880', (127, 131))	('Braf', 'Gene', (127, 131))	('Kras', 'Gene', '16653', (121, 125))	('Kras', 'Gene', (121, 125))	('NRF2', 'Gene', (22, 26))	('NFE2L2', 'Gene', (93, 99))
79680	33276631	Thus, modest permanent activation of Nrf2, as observed in the floxed Keap1FA/FA hypomorphic mouse, in which Keap1 is effectively constitutively knocked down, provides increased cytoprotection and has not been reported to result in any obvious long-term susceptibility to tumourigenesis.	('Keap1', 'Gene', '50868', (69, 74))	('Nrf2', 'Gene', (37, 41))	('tumour', 'Phenotype', 'HP:0002664', (271, 277))	('Keap1', 'Gene', '50868', (108, 113))	('Keap1', 'Gene', (69, 74))	('activation', 'PosReg', (23, 33))	('tumour', 'Disease', 'MESH:D009369', (271, 277))	('increased', 'PosReg', (167, 176))	('Keap1', 'Gene', (108, 113))	('knocked', 'Var', (144, 151))	('Keap1FA', 'Gene', '50868', (69, 76))	('tumour', 'Disease', (271, 277))	('Keap1FA', 'Gene', (69, 76))	('cytoprotection', 'CPA', (177, 191))	('mouse', 'Species', '10090', (92, 97))
79683	33276631	Furthermore, persistent hyperactivation of NRF2 in human A549 lung cancer cells results in enhancer remodelling, allowing transcriptional activation of NOTCH3 by an NRF2-CEBPB complex that strongly supports tumourigenesis, and which is not observed in normal cells under stress conditions, indicating that continual activation of NRF2 in cancer cells results in overexpression of an enlarged battery of genes that is distinct from that induced by NRF2 in normal cells.	('lung cancer', 'Disease', (62, 73))	('human', 'Species', '9606', (51, 56))	('A549', 'CellLine', 'CVCL:0023', (57, 61))	('cancer', 'Disease', 'MESH:D009369', (338, 344))	('supports', 'PosReg', (198, 206))	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('overexpression', 'PosReg', (362, 376))	('NRF2', 'Gene', (43, 47))	('lung cancer', 'Disease', 'MESH:D008175', (62, 73))	('hyperactivation', 'Var', (24, 39))	('lung cancer', 'Phenotype', 'HP:0100526', (62, 73))	('tumour', 'Phenotype', 'HP:0002664', (207, 213))	('activation', 'PosReg', (316, 326))	('tumour', 'Disease', 'MESH:D009369', (207, 213))	('cancer', 'Disease', (338, 344))	('tumour', 'Disease', (207, 213))	('NOTCH3', 'Gene', '4854', (152, 158))	('cancer', 'Disease', (67, 73))	('cancer', 'Phenotype', 'HP:0002664', (338, 344))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('NOTCH3', 'Gene', (152, 158))
79684	33276631	A number of researchers have studied the effect of expressing mutant hyperactive forms of NRF2, modelled on somatic mutants of NFE2L2 identified in clinical lung cancer samples (e.g., Nrf2E79Q and Nrf2DeltaNeh2), and none of these have provided evidence that chronic Nrf2 hyperactivity is sufficient to initiate tumourigenesis.	('mutant', 'Var', (62, 68))	('tumour', 'Phenotype', 'HP:0002664', (312, 318))	('lung cancer', 'Disease', (157, 168))	('tumour', 'Disease', 'MESH:D009369', (312, 318))	('E79Q', 'Mutation', 'rs1057519922', (188, 192))	('lung cancer', 'Phenotype', 'HP:0100526', (157, 168))	('hyperactivity', 'Phenotype', 'HP:0000752', (272, 285))	('hyperactive', 'Disease', (69, 80))	('hyperactivity', 'Disease', 'MESH:D006948', (272, 285))	('hyperactivity', 'Disease', (272, 285))	('NFE2L2', 'Gene', (127, 133))	('tumour', 'Disease', (312, 318))	('hyperactive', 'Disease', 'MESH:D006948', (69, 80))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('lung cancer', 'Disease', 'MESH:D008175', (157, 168))
79685	33276631	Thus, generation of a Nfe2l2LSL-E79Q; Krt14-Cre mouse in which Nrf2E79Q is expressed in keratin 14-positive tissues, revealed that expression of a constitutively active mutant form of the CNC-bZIP transcription factor resulted in hyperplasia of squamous cell tissue of the tongue, oesophagus and forestomach, but not squamous cell carcinoma, and that in oesophageal tissue this was associated with overexpression of well-recognised members of the ARE-gene battery, as well as genes for growth factors and related factors such as those encoding Areg, Bmp6, Epgn, Ereg, Hbegf, Myc, Vegfa and Wnt5a.	('Areg', 'Gene', (544, 548))	('mouse', 'Species', '10090', (48, 53))	('Wnt5a', 'Gene', (590, 595))	('hyperplasia of squamous', 'Disease', (230, 253))	('mutant', 'Var', (169, 175))	('Ereg', 'Gene', (562, 566))	('Epgn', 'Gene', (556, 560))	('squamous cell tissue of the tongue', 'Phenotype', 'HP:0030413', (245, 279))	('Epgn', 'Gene', '71920', (556, 560))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (317, 340))	('Ereg', 'Gene', '13874', (562, 566))	('Nrf2E79Q', 'Var', (63, 71))	('Nfe2l2', 'Gene', '18024', (22, 28))	('hyperplasia of squamous', 'Disease', 'MESH:D006965', (230, 253))	('Hbegf', 'Gene', '15200', (568, 573))	('Wnt5a', 'Gene', '22418', (590, 595))	('Bmp6', 'Gene', '12161', (550, 554))	('carcinoma', 'Phenotype', 'HP:0030731', (331, 340))	('Bmp6', 'Gene', (550, 554))	('E79Q', 'Mutation', 'rs1057519922', (67, 71))	('Nfe2l2', 'Gene', (22, 28))	('keratin 14', 'Gene', '16664', (88, 98))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (317, 340))	('Areg', 'Gene', '11839', (544, 548))	('Myc', 'Gene', (575, 578))	('Vegfa', 'Gene', '22339', (580, 585))	('rat', 'Species', '10116', (90, 93))	('E79Q', 'Mutation', 'rs1057519922', (32, 36))	('Hbegf', 'Gene', (568, 573))	('Vegfa', 'Gene', (580, 585))	('squamous cell carcinoma', 'Disease', (317, 340))	('CNC-bZIP', 'Gene', (188, 196))	('Krt14', 'Gene', (38, 43))	('keratin 14', 'Gene', (88, 98))	('rat', 'Species', '10116', (10, 13))	('Myc', 'Gene', '17869', (575, 578))	('Krt14', 'Gene', '16664', (38, 43))
79687	33276631	In a mouse model in which a constitutively active form of Nrf2 that lacks amino acids 1-88 (i.e., Nrf2DeltaNeh2, called caNrf2) was expressed from the keratin 5 promoter (with the line called K5cre-caNrf2), the mutant mice developed chloracne-like skin disease with hyperkeratosis of hair follicles in the epidermis, but not cancer.	('hyperkeratosis', 'Phenotype', 'HP:0000962', (266, 280))	('skin disease', 'Phenotype', 'HP:0000951', (248, 260))	('rat', 'Species', '10116', (153, 156))	('developed', 'Reg', (223, 232))	('cancer', 'Disease', (325, 331))	('cancer', 'Disease', 'MESH:D009369', (325, 331))	('hyperkeratosis', 'Disease', (266, 280))	('skin disease', 'Disease', (248, 260))	('rat', 'Species', '10116', (273, 276))	('skin disease', 'Disease', 'MESH:D012871', (248, 260))	('mutant', 'Var', (211, 217))	('cancer', 'Phenotype', 'HP:0002664', (325, 331))	('mouse', 'Species', '10090', (5, 10))	('mice', 'Species', '10090', (218, 222))	('hyperkeratosis', 'Disease', 'MESH:D017488', (266, 280))
79688	33276631	However, when used in skin carcinogenesis experiments, the K5cre-caNrf2 mouse was found to support survival of keratinocytes that harboured oncogenic mutations.	('men', 'Species', '9606', (48, 51))	('mouse', 'Species', '10090', (72, 77))	('support', 'PosReg', (91, 98))	('rat', 'Species', '10116', (113, 116))	('skin carcinogenesis', 'Disease', 'MESH:D063646', (22, 41))	('mutations', 'Var', (150, 159))	('skin carcinogenesis', 'Disease', (22, 41))
79690	33276631	By contrast with these findings, it has been reported that ectopic expression of caNrf2 in primary breast cancer cells had no significant effect on the rate of primary tumour formation.	('breast cancer', 'Disease', 'MESH:D001943', (99, 112))	('rat', 'Species', '10116', (152, 155))	('breast cancer', 'Disease', (99, 112))	('tumour', 'Phenotype', 'HP:0002664', (168, 174))	('tumour', 'Disease', 'MESH:D009369', (168, 174))	('breast cancer', 'Phenotype', 'HP:0003002', (99, 112))	('caNrf2', 'Gene', (81, 87))	('tumour', 'Disease', (168, 174))	('ectopic expression', 'Var', (59, 77))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
79693	33276631	This finding seems at variance with other reports that activation of NRF2 delays senescence in human fibroblasts, and may simply reflect the hyperactive nature of Nrf2DeltaNeh2 or other context-dependent factors.	('human', 'Species', '9606', (95, 100))	('hyperactive nature', 'Phenotype', 'HP:0000752', (141, 159))	('NRF2', 'Gene', (69, 73))	('activation', 'Var', (55, 65))	('senescence', 'CPA', (81, 91))	('hyperactive', 'Disease', (141, 152))	('hyperactive', 'Disease', 'MESH:D006948', (141, 152))	('delays', 'NegReg', (74, 80))
79694	33276631	Interestingly, through use of both floxed Keap1FA/FA hypomorphic mice and floxed Keap1FB/FB "normal" mice in a KrasLSL-G12D/+ mouse lung cancer model, Masi Yamamoto and colleagues showed that activation of Nrf2 in the microenvironment surrounding the tumour restricts progression of lung cancers in which Nrf2 is upregulated, and bone marrow transplantation experiments revealed that activation of the transcription factor in hematopoietic cells contributed significantly to suppression of the tumour, findings that suggest high NRF2 activity can suppress the later stages of cancer by supporting immune cell function.	('high', 'Var', (524, 528))	('cancer', 'Disease', 'MESH:D009369', (576, 582))	('tumour', 'Phenotype', 'HP:0002664', (251, 257))	('NRF2', 'Gene', (529, 533))	('lung cancers', 'Phenotype', 'HP:0100526', (283, 295))	('cancers', 'Phenotype', 'HP:0002664', (288, 295))	('cancer', 'Disease', (288, 294))	('tumour', 'Disease', 'MESH:D009369', (251, 257))	('mice', 'Species', '10090', (101, 105))	('cancer', 'Disease', (137, 143))	('tumour', 'Disease', (251, 257))	('Keap1', 'Gene', '50868', (81, 86))	('cancer', 'Phenotype', 'HP:0002664', (288, 294))	('mouse', 'Species', '10090', (126, 131))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('KrasLSL', 'Gene', '16653', (111, 118))	('G12D', 'Mutation', 'rs121913529', (119, 123))	('lung cancer', 'Disease', (132, 143))	('tumour', 'Phenotype', 'HP:0002664', (494, 500))	('suppress', 'NegReg', (547, 555))	('men', 'Species', '9606', (230, 233))	('tumour', 'Disease', 'MESH:D009369', (494, 500))	('immune cell function', 'CPA', (597, 617))	('cancer', 'Disease', 'MESH:D009369', (288, 294))	('lung cancer', 'Disease', 'MESH:D008175', (283, 294))	('cancer', 'Disease', (576, 582))	('mice', 'Species', '10090', (65, 69))	('Keap1FA', 'Gene', '50868', (42, 49))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('tumour', 'Disease', (494, 500))	('KrasLSL', 'Gene', (111, 118))	('cancer', 'Phenotype', 'HP:0002664', (576, 582))	('lung cancer', 'Phenotype', 'HP:0100526', (283, 294))	('lung cancers', 'Disease', 'MESH:D008175', (283, 295))	('men', 'Species', '9606', (364, 367))	('Keap1', 'Gene', (42, 47))	('lung cancer', 'Disease', 'MESH:D008175', (132, 143))	('activity', 'MPA', (534, 542))	('Keap1FA', 'Gene', (42, 49))	('lung cancer', 'Phenotype', 'HP:0100526', (132, 143))	('lung cancers', 'Disease', (283, 295))	('Keap1', 'Gene', (81, 86))	('Keap1', 'Gene', '50868', (42, 47))
79698	33276631	Given that hyperactivation of NRF2 is not sufficient to initiate tumourigenesis, it is necessary to establish why it is upregulated in certain types of cancer.	('NRF2', 'Gene', (30, 34))	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('upregulated', 'PosReg', (120, 131))	('tumour', 'Phenotype', 'HP:0002664', (65, 71))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('tumour', 'Disease', 'MESH:D009369', (65, 71))	('hyperactivation', 'Var', (11, 26))	('tumour', 'Disease', (65, 71))
79699	33276631	The answer appears to be that NRF2 hyperactivation contributes to tumourigenesis by ameliorating oxidative stress, supporting cell growth/proliferation by various means (e.g., increasing the PPP, serine synthesis and autophagy) and attenuating the immune system.	('hyperactivation', 'Var', (35, 50))	('NRF2', 'Gene', (30, 34))	('serine synthesis', 'MPA', (196, 212))	('oxidative stress', 'MPA', (97, 113))	('serine', 'Chemical', 'MESH:D012694', (196, 202))	('tumour', 'Phenotype', 'HP:0002664', (66, 72))	('attenuating', 'NegReg', (232, 243))	('cell growth/proliferation', 'CPA', (126, 151))	('ameliorating', 'PosReg', (84, 96))	('rat', 'Species', '10116', (145, 148))	('tumour', 'Disease', 'MESH:D009369', (66, 72))	('immune system', 'CPA', (248, 261))	('tumour', 'Disease', (66, 72))	('increasing', 'PosReg', (176, 186))	('oxidative stress', 'Phenotype', 'HP:0025464', (97, 113))	('PPP', 'MPA', (191, 194))	('supporting', 'PosReg', (115, 125))	('rat', 'Species', '10116', (90, 93))
79702	33276631	Moreover, using Alb-Cre; KrasLSL-G12D/+; p53LSL-R172H/+ mice, deletion of Keap1 has shown that upregulation of Nrf2 accelerated Kras/p53-driven cholangiocarcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (153, 162))	('Kras', 'Gene', (25, 29))	('upregulation', 'PosReg', (95, 107))	('Kras', 'Gene', (128, 132))	('p53', 'Gene', '22059', (133, 136))	('p53', 'Gene', (41, 44))	('KrasLSL', 'Gene', (25, 32))	('G12D', 'Mutation', 'rs121913529', (33, 37))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (144, 162))	('Kras', 'Gene', '16653', (25, 29))	('Kras', 'Gene', '16653', (128, 132))	('deletion', 'Var', (62, 70))	('R172H', 'Mutation', 'rs767964519', (48, 53))	('cholangiocarcinoma', 'Disease', (144, 162))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (144, 162))	('accelerated', 'PosReg', (116, 127))	('Keap1', 'Gene', (74, 79))	('p53', 'Gene', (133, 136))	('Nrf2', 'Gene', (111, 115))	('p53', 'Gene', '22059', (41, 44))	('Alb', 'Gene', '11657', (16, 19))	('Keap1', 'Gene', '50868', (74, 79))	('mice', 'Species', '10090', (56, 60))	('rat', 'Species', '10116', (122, 125))	('Alb', 'Gene', (16, 19))	('KrasLSL', 'Gene', '16653', (25, 32))
79703	33276631	Similarly, using a CRISPR-Cas9 strategy, deletion of Keap1 has been found to accelerate Kras-driven lung adenocarcinoma.	('Kras', 'Gene', (88, 92))	('lung adenocarcinoma', 'Disease', (100, 119))	('Kras', 'Gene', '16653', (88, 92))	('rat', 'Species', '10116', (83, 86))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (100, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('rat', 'Species', '10116', (33, 36))	('deletion', 'Var', (41, 49))	('Keap1', 'Gene', '50868', (53, 58))	('Keap1', 'Gene', (53, 58))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (100, 119))	('accelerate', 'PosReg', (77, 87))
79709	33276631	An example of this approach is the tamoxifen-induced conditional knockout of Slc7a11 in pancreatic ductal adenocarcinoma cells generated in KrasLSL-G12D/+; Tp53R172H/+; Pdx1FlpOtg/+; Slc7a11Fl/Fl; Rosa26CreERT2/+ mice, experiments in which knockout of Slc7a11 in the tumour resulted in ferroptotic death of the tumour cells and increased survival.	('KrasLSL', 'Gene', (140, 147))	('mice', 'Species', '10090', (213, 217))	('tumour', 'Disease', (267, 273))	('Pdx1', 'Gene', '18609', (169, 173))	('men', 'Species', '9606', (225, 228))	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('Pdx1', 'Gene', (169, 173))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (88, 120))	('survival', 'CPA', (338, 346))	('knockout', 'Var', (240, 248))	('increased', 'PosReg', (328, 337))	('tumour', 'Phenotype', 'HP:0002664', (311, 317))	('tumour', 'Disease', 'MESH:D009369', (311, 317))	('pancreatic ductal adenocarcinoma', 'Disease', (88, 120))	('tumour', 'Disease', (311, 317))	('KrasLSL', 'Gene', '16653', (140, 147))	('rat', 'Species', '10116', (131, 134))	('death of the tumour', 'Disease', 'MESH:D003643', (298, 317))	('G12D', 'Mutation', 'rs121913529', (148, 152))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (88, 120))	('Slc7a11', 'Gene', (252, 259))	('death of the tumour', 'Disease', (298, 317))	('Slc7a11', 'Gene', (77, 84))	('tamoxifen', 'Chemical', 'MESH:D013629', (35, 44))	('tumour', 'Phenotype', 'HP:0002664', (267, 273))	('tumour', 'Disease', 'MESH:D009369', (267, 273))
79712	33276631	In a model of recurrent breast cancer, tumour cells that survived oxidative stress caused by oncogene inhibition did so by NRF2-directed metabolic reprogramming that entailed overexpression of genes for oxidative PPP enzymes and TXN1, TXN2 and TXNRD1, but not those for GSH synthesis, suggesting NRF2 aids formation and growth of recurrent tumours.	('tumour', 'Phenotype', 'HP:0002664', (340, 346))	('growth', 'CPA', (320, 326))	('breast cancer', 'Disease', 'MESH:D001943', (24, 37))	('breast cancer', 'Disease', (24, 37))	('TXN1', 'Gene', (229, 233))	('tumour', 'Disease', 'MESH:D009369', (340, 346))	('tumour', 'Disease', (340, 346))	('TXN2', 'Gene', (235, 239))	('TXN2', 'Gene', '56551', (235, 239))	('TXNRD1', 'Gene', '50493', (244, 250))	('formation', 'CPA', (306, 315))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('TXNRD1', 'Gene', (244, 250))	('overexpression', 'PosReg', (175, 189))	('TXN1', 'Gene', '22166', (229, 233))	('tumours', 'Disease', (340, 347))	('tumour', 'Phenotype', 'HP:0002664', (39, 45))	('tumour', 'Disease', 'MESH:D009369', (39, 45))	('tumour', 'Disease', (39, 45))	('tumours', 'Phenotype', 'HP:0002664', (340, 347))	('inhibition', 'Var', (102, 112))	('breast cancer', 'Phenotype', 'HP:0003002', (24, 37))	('oxidative stress', 'Phenotype', 'HP:0025464', (66, 82))	('tumours', 'Disease', 'MESH:D009369', (340, 347))	('GSH', 'Chemical', 'MESH:D005978', (270, 273))
79718	33276631	Furthermore, autophagy plays a crucial role in inhibiting tumourigenesis in the liver, presumably by preventing accumulation of dysfunctional mitochondria and ameliorating oxidative stress, as evidenced by the spontaneous development of hepatic adenomas in mice with mosaic deletion of Atg5 and hepatocyte-specific deletion of Atg7.	('accumulation', 'MPA', (112, 124))	('Atg7', 'Gene', (327, 331))	('hepatic adenomas', 'Disease', 'MESH:D000236', (237, 253))	('ameliorating', 'PosReg', (159, 171))	('oxidative stress', 'MPA', (172, 188))	('dysfunctional mitochondria', 'Disease', 'MESH:C564925', (128, 154))	('mice', 'Species', '10090', (257, 261))	('dysfunctional mitochondria', 'Disease', (128, 154))	('tumour', 'Phenotype', 'HP:0002664', (58, 64))	('preventing', 'NegReg', (101, 111))	('tumour', 'Disease', 'MESH:D009369', (58, 64))	('tumour', 'Disease', (58, 64))	('rat', 'Species', '10116', (165, 168))	('autophagy', 'CPA', (13, 22))	('hepatic adenomas', 'Disease', (237, 253))	('mosaic deletion', 'Var', (267, 282))	('deletion', 'Var', (315, 323))	('men', 'Species', '9606', (229, 232))	('oxidative stress', 'Phenotype', 'HP:0025464', (172, 188))	('hepatic adenomas', 'Phenotype', 'HP:0012028', (237, 253))	('Atg5', 'Gene', '11793', (286, 290))	('inhibiting', 'NegReg', (47, 57))	('Atg5', 'Gene', (286, 290))	('Atg7', 'Gene', '74244', (327, 331))
79720	33276631	Intriguingly, inhibition of autophagy, by chloroquine treatment or knockout of ATG7, in autophagy-dependent cancer cells stimulates adaptation by NRF2-mediated induction of proteasomal subunit genes, with largest increases observed for PSMB8, PSMB9, PSMB10 and PSMC1, indicating NRF2-mediated regulatory crosstalk between the proteasome and autophagy.	('PSMB9', 'Gene', '16912', (243, 248))	('stimulates', 'PosReg', (121, 131))	('PSMC1', 'Gene', '19179', (261, 266))	('cancer', 'Disease', 'MESH:D009369', (108, 114))	('PSMB8', 'Gene', (236, 241))	('knockout', 'Var', (67, 75))	('PSMB9', 'Gene', (243, 248))	('NRF2-mediated', 'Gene', (146, 159))	('chloroquine', 'Chemical', 'MESH:D002738', (42, 53))	('autophagy', 'CPA', (28, 37))	('ATG7', 'Gene', (79, 83))	('PSMC1', 'Gene', (261, 266))	('PSMB8', 'Gene', '16913', (236, 241))	('cancer', 'Disease', (108, 114))	('PSMB10', 'Gene', (250, 256))	('PSMB10', 'Gene', '19171', (250, 256))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('ATG7', 'Gene', '74244', (79, 83))	('men', 'Species', '9606', (59, 62))
79723	33276631	In mice treated with DEN and fed a high-fat diet, hepatocyte-specific knockout of PKClambda/iota (in Alb-Cre; PrkciF/F mice) resulted in multiple hepatocellular carcinomas, some of which were aggressive, whilst similarly treated PrkciF/F mice only developed benign hepatic adenomas.	('hepatocellular carcinomas', 'Phenotype', 'HP:0001402', (146, 171))	('carcinomas', 'Phenotype', 'HP:0030731', (161, 171))	('resulted in', 'Reg', (125, 136))	('hepatic adenomas', 'Phenotype', 'HP:0012028', (265, 281))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (146, 170))	('multiple hepatocellular carcinomas', 'Disease', (137, 171))	('Alb', 'Gene', '11657', (101, 104))	('Alb', 'Gene', (101, 104))	('PKClambda', 'Gene', (82, 91))	('DEN', 'Chemical', 'MESH:D004052', (21, 24))	('benign hepatic adenomas', 'Disease', (258, 281))	('mice', 'Species', '10090', (3, 7))	('PKClambda', 'Gene', '18759', (82, 91))	('iota', 'Chemical', '-', (92, 96))	('multiple hepatocellular carcinomas', 'Disease', 'MESH:D006528', (137, 171))	('mice', 'Species', '10090', (119, 123))	('benign hepatic adenomas', 'Disease', 'MESH:C564190', (258, 281))	('carcinoma', 'Phenotype', 'HP:0030731', (161, 170))	('mice', 'Species', '10090', (238, 242))	('knockout', 'Var', (70, 78))
79724	33276631	These workers found knockout of PKClambda/iota increased autophagy and ROS levels, causing oxidative stress and, consequently, activation of Nrf2.	('oxidative stress', 'Phenotype', 'HP:0025464', (91, 107))	('PKClambda', 'Gene', (32, 41))	('iota increased', 'Phenotype', 'HP:0003261', (42, 56))	('causing', 'Reg', (83, 90))	('PKClambda', 'Gene', '18759', (32, 41))	('iota', 'Chemical', '-', (42, 46))	('oxidative stress', 'MPA', (91, 107))	('increased', 'PosReg', (47, 56))	('ROS levels', 'MPA', (71, 81))	('knockout', 'Var', (20, 28))	('autophagy', 'CPA', (57, 66))	('activation', 'PosReg', (127, 137))	('ROS', 'Chemical', 'MESH:D017382', (71, 74))	('Nrf2', 'Gene', (141, 145))
79725	33276631	They also found hepatocytes from Alb-Cre; PrkciF/F mice exhibited higher rates of proliferation than controls, and that knockdown of Nrf2 suppressed proliferation in the PKClambda/iota-knockout hepatocytes.	('PKClambda', 'Gene', '18759', (170, 179))	('rat', 'Species', '10116', (156, 159))	('mice', 'Species', '10090', (51, 55))	('Nrf2', 'Gene', (133, 137))	('Alb', 'Gene', (33, 36))	('proliferation', 'CPA', (149, 162))	('knockdown', 'Var', (120, 129))	('rates', 'MPA', (73, 78))	('rat', 'Species', '10116', (89, 92))	('iota', 'Chemical', '-', (180, 184))	('higher', 'PosReg', (66, 72))	('proliferation', 'CPA', (82, 95))	('Alb', 'Gene', '11657', (33, 36))	('suppressed', 'NegReg', (138, 148))	('PKClambda', 'Gene', (170, 179))	('rat', 'Species', '10116', (73, 76))
79728	33276631	In melanoma cells, knockout of NRF2 has been shown to decrease COX2 levels and PGE2 production, and this was associated with a large increase in expression of innate immune response genes involved in defence against viral infection, such as Rsad2, Ifih1, Ifit1 and Isg15.	('decrease', 'NegReg', (54, 62))	('viral infection', 'Disease', 'MESH:D001102', (216, 231))	('NRF2', 'Gene', (31, 35))	('expression', 'MPA', (145, 155))	('increase', 'PosReg', (133, 141))	('knockout', 'Var', (19, 27))	('Rsad2', 'Gene', '58185', (241, 246))	('Rsad2', 'Gene', (241, 246))	('melanoma', 'Disease', 'MESH:D008545', (3, 11))	('COX2', 'Gene', '19225', (63, 67))	('Isg15', 'Gene', (265, 270))	('PGE2', 'Chemical', 'MESH:D015232', (79, 83))	('PGE2 production', 'MPA', (79, 94))	('Ifih1', 'Gene', (248, 253))	('Ifit1', 'Gene', '15957', (255, 260))	('viral infection', 'Disease', (216, 231))	('Ifit1', 'Gene', (255, 260))	('Ifih1', 'Gene', '71586', (248, 253))	('COX2', 'Gene', (63, 67))	('melanoma', 'Phenotype', 'HP:0002861', (3, 11))	('melanoma', 'Disease', (3, 11))	('Isg15', 'Gene', '100038882', (265, 270))
79730	33276631	The overexpression of drug-metabolising genes caused by hyperactivation of NRF2 is likely to increase resistance to ferroptosis because AKR isoenzymes catalytically reduce lipid peroxidation products that trigger ferroptotic cell death.	('hyperactivation', 'Var', (56, 71))	('lipid', 'Chemical', 'MESH:D008055', (172, 177))	('reduce', 'NegReg', (165, 171))	('lipid peroxidation products', 'MPA', (172, 199))	('resistance', 'MPA', (102, 112))	('overexpression', 'PosReg', (4, 18))	('NRF2', 'Gene', (75, 79))
79731	33276631	Of note, AKR1C1, AKR1C2 and AKR1C3 are particularly effective at reducing 4-hydroxy-2-nonenal to 1,4-dihydroxy-2-nonene.	('4-hydroxy-2-nonenal', 'Chemical', 'MESH:C027576', (74, 93))	('AKR1C1', 'Gene', (9, 15))	('reducing', 'NegReg', (65, 73))	('1,4-dihydroxy-2-nonene', 'Chemical', 'MESH:C091765', (97, 119))	('AKR1C3', 'Var', (28, 34))	('AKR1C2', 'Var', (17, 23))	('AKR1C1', 'Gene', '83702', (9, 15))
79736	33276631	Molecular profiling of both LUAD and LUSC revealed thirty-eight genes frequently mutated in LUAD and twenty frequently mutated genes in LUSC, with six commonly mutated genes in both lung cancer subtypes: these are, TP53, RB1, ARID1A, CDKN2A, PIK3CA and NF1 (see Table 3 for the frequency of mutations in genes implicated in NRF2 activation in NSCLC).	('RB1', 'Gene', '19645', (221, 224))	('NSCLC', 'Disease', 'MESH:D002289', (343, 348))	('NF1', 'Gene', (253, 256))	('lung cancer', 'Disease', (182, 193))	('lung cancer', 'Phenotype', 'HP:0100526', (182, 193))	('ARID1A', 'Gene', (226, 232))	('RB1', 'Gene', (221, 224))	('mutated', 'Var', (81, 88))	('ARID1A', 'Gene', '93760', (226, 232))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('NSCLC', 'Phenotype', 'HP:0030358', (343, 348))	('NF1', 'Gene', '18015', (253, 256))	('CDKN2A', 'Gene', (234, 240))	('TP53', 'Gene', (215, 219))	('lung cancer', 'Disease', 'MESH:D008175', (182, 193))	('NSCLC', 'Disease', (343, 348))
79738	33276631	When pathway analysis was carried out, alterations in those linked to oxidative stress were found in 22% of tumours due to mutations in KEAP1 (mutated in 19%), CUL3 (mutated in >1%) and NFE2L2 (mutated in 3%).	('tumours', 'Disease', (108, 115))	('KEAP1', 'Gene', (136, 141))	('rat', 'Species', '10116', (43, 46))	('tumour', 'Phenotype', 'HP:0002664', (108, 114))	('alterations', 'Reg', (39, 50))	('tumours', 'Phenotype', 'HP:0002664', (108, 115))	('oxidative stress', 'Phenotype', 'HP:0025464', (70, 86))	('tumours', 'Disease', 'MESH:D009369', (108, 115))	('NFE2L2', 'Gene', (186, 192))	('mutations', 'Var', (123, 132))	('CUL3', 'Gene', (160, 164))
79740	33276631	However, they highlighted that dysregulation in oxidative stress pathways, as seen in the LUAD cases, was similarly observed in 34% of LUSC tumours, due to mutations (or copy number alterations) in KEAP1 (mutated in 12%), CUL3 (mutated in 7%) and NFE2L2 (mutated in 19%).	('tumour', 'Phenotype', 'HP:0002664', (140, 146))	('LUSC tumours', 'Disease', (135, 147))	('CUL3', 'Gene', (222, 226))	('rat', 'Species', '10116', (186, 189))	('mutations', 'Var', (156, 165))	('tumours', 'Phenotype', 'HP:0002664', (140, 147))	('NFE2L2', 'Gene', (247, 253))	('LUSC tumours', 'Disease', 'MESH:D009369', (135, 147))	('oxidative stress', 'Phenotype', 'HP:0025464', (48, 64))	('oxidative stress pathways', 'Pathway', (48, 73))	('KEAP1', 'Gene', (198, 203))
79741	33276631	Unlike mutations in NFE2L2, somatic mutations in KEAP1 were found to be distributed throughout the gene, which represents the mutational pattern associated with tumour suppressor genes.	('tumour', 'Phenotype', 'HP:0002664', (161, 167))	('tumour', 'Disease', 'MESH:D009369', (161, 167))	('mutations', 'Var', (36, 45))	('KEAP1', 'Gene', (49, 54))	('tumour', 'Disease', (161, 167))
79742	33276631	Due to their wide distribution, it is difficult to attribute a function to all the mutations in KEAP1; however, some have been studied such as the R32Q mutant, which has been shown to drive carcinogenesis.	('carcinogenesis', 'Disease', (190, 204))	('R32Q', 'Var', (147, 151))	('KEAP1', 'Gene', (96, 101))	('R32Q', 'Mutation', 'p.R32Q', (147, 151))	('carcinogenesis', 'Disease', 'MESH:D063646', (190, 204))
79743	33276631	Mutations in NFE2L2 have been demonstrated to co-occur with PIK3CA mutations and mutations in TP53.	('PIK3CA', 'Gene', (60, 66))	('rat', 'Species', '10116', (37, 40))	('NFE2L2', 'Gene', (13, 19))	('mutations', 'Var', (67, 76))	('TP53', 'Gene', (94, 98))	('Mutations', 'Var', (0, 9))	('mutations', 'Var', (81, 90))	('co-occur', 'Reg', (46, 54))
79744	33276631	Research has also revealed that several mutations in KEAP1 are G>T transversions, which are characteristic mutations associated with exposure to tobacco smoke, and may in part explain why KEAP1 mutations often co-occur with KRAS mutations, which are also associated with smoking.	('KEAP1', 'Gene', (188, 193))	('mutations', 'Var', (194, 203))	('mutations', 'Var', (40, 49))	('KRAS', 'Disease', (224, 228))	('tobacco', 'Species', '4097', (145, 152))	('KEAP1', 'Gene', (53, 58))
79745	33276631	The co-occurrence of KEAP1 and KRAS mutations suggests that KEAP1 mutations either affect NRF2 activity differently than KRAS-stimulated overexpression of NRF2, or are affecting other signalling pathways that are beneficial to the tumour.	('mutations', 'Var', (66, 75))	('tumour', 'Disease', 'MESH:D009369', (231, 237))	('affect', 'Reg', (83, 89))	('KEAP1', 'Gene', (60, 65))	('tumour', 'Disease', (231, 237))	('affecting', 'Reg', (168, 177))	('activity', 'MPA', (95, 103))	('NRF2', 'Protein', (90, 94))	('tumour', 'Phenotype', 'HP:0002664', (231, 237))	('signalling pathways', 'Pathway', (184, 203))
79748	33276631	Targeted therapies for patients with mutations in specific genes, such as EGFR and BRAF, have had very promising results in LUAD, but due to the genetic diversity between the different histotypes of NSCLC, such therapies are not applicable for LUSC.	('NSCLC', 'Disease', 'MESH:D002289', (199, 204))	('patients', 'Species', '9606', (23, 31))	('LUAD', 'Disease', (124, 128))	('mutations', 'Var', (37, 46))	('NSCLC', 'Phenotype', 'HP:0030358', (199, 204))	('EGFR', 'Gene', (74, 78))	('BRAF', 'Gene', (83, 87))	('NSCLC', 'Disease', (199, 204))
79750	33276631	Research has now shown that mutations in KEAP1 and NFE2L2 are often associated with late-stage metastatic disease, with stage-4 cancer patients showing higher NRF2 activity than stage-3 patients.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('higher', 'PosReg', (152, 158))	('patients', 'Species', '9606', (135, 143))	('associated', 'Reg', (68, 78))	('activity', 'MPA', (164, 172))	('KEAP1', 'Gene', (41, 46))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('NFE2L2', 'Gene', (51, 57))	('late-stage metastatic disease', 'Disease', (84, 113))	('mutations', 'Var', (28, 37))	('patients', 'Species', '9606', (186, 194))	('cancer', 'Disease', (128, 134))
79751	33276631	When comparing the impact of mutations in NFE2L2 or KEAP1 on expression of NRF2-target genes, mutations in NFE2L2 were found to result in overexpression of more genes compared to mutations in KEAP1, suggesting that amino acid substitutions within the transcription factor are a more robust way for the tumour to command a comprehensive oxidative stress response.	('oxidative stress', 'Phenotype', 'HP:0025464', (336, 352))	('mutations', 'Var', (94, 103))	('amino acid substitutions', 'Var', (215, 239))	('overexpression', 'PosReg', (138, 152))	('tumour', 'Phenotype', 'HP:0002664', (302, 308))	('tumour', 'Disease', 'MESH:D009369', (302, 308))	('NFE2L2', 'Gene', (107, 113))	('tumour', 'Disease', (302, 308))
79752	33276631	In view of the fact that NRF2 upregulation is not associated with cancer initiation, but with tumour progression, it would be reasonable to suggest that the mutation in KRAS, or TP53, arises as an early event that precedes mutation in KEAP1, or mutation in NFE2L2, respectively.	('tumour', 'Disease', (94, 100))	('TP53', 'Gene', (178, 182))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('KRAS', 'Gene', (169, 173))	('mutation', 'Var', (157, 165))	('tumour', 'Phenotype', 'HP:0002664', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('tumour', 'Disease', 'MESH:D009369', (94, 100))	('cancer', 'Disease', (66, 72))
79753	33276631	This has been highlighted by the findings that KRAS mutant tumours with co-occurring KEAP1 mutations are associated with later stage lung cancer.	('KEAP1', 'Gene', (85, 90))	('lung cancer', 'Disease', (133, 144))	('mutant', 'Var', (52, 58))	('lung cancer', 'Phenotype', 'HP:0100526', (133, 144))	('tumour', 'Phenotype', 'HP:0002664', (59, 65))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('tumours', 'Phenotype', 'HP:0002664', (59, 66))	('mutations', 'Var', (91, 100))	('tumours', 'Disease', 'MESH:D009369', (59, 66))	('lung cancer', 'Disease', 'MESH:D008175', (133, 144))	('associated', 'Reg', (105, 115))	('tumours', 'Disease', (59, 66))
79758	33276631	Next-generation sequencing and whole exome sequencing studies have revealed mutations in TP53 (most mutated gene in ESCC), NOTCH1, PIK3CA, TGFBR2 and NFE2L2.	('mutations', 'Var', (76, 85))	('TP53', 'Gene', (89, 93))	('revealed', 'Reg', (67, 75))	('rat', 'Species', '10116', (9, 12))	('NFE2L2', 'Gene', (150, 156))	('NOTCH1', 'Gene', '18128', (123, 129))	('TGFBR2', 'Gene', (139, 145))	('TGFBR2', 'Gene', '21813', (139, 145))	('NOTCH1', 'Gene', (123, 129))	('PIK3CA', 'Gene', (131, 137))
79759	33276631	Interestingly, unlike other cancers with high NRF2 activity, KEAP1 mutations rarely occur in ESCC.	('cancers', 'Disease', (28, 35))	('KEAP1', 'Gene', (61, 66))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('cancers', 'Disease', 'MESH:D009369', (28, 35))	('mutations', 'Var', (67, 76))	('cancers', 'Phenotype', 'HP:0002664', (28, 35))	('occur', 'Reg', (84, 89))	('ESCC', 'Disease', (93, 97))
79760	33276631	NFE2L2 mutations co-occur with mutations in TP53 and NOTCH1, but are mutually exclusive with mutations in PIK3CA.	('mutations', 'Var', (31, 40))	('NOTCH1', 'Gene', (53, 59))	('co-occur', 'Reg', (17, 25))	('NOTCH1', 'Gene', '18128', (53, 59))	('NFE2L2', 'Gene', (0, 6))	('TP53', 'Gene', (44, 48))	('mutations', 'Var', (7, 16))
79762	33276631	This high incidence in NRF2 upregulation cannot be attributed solely to mutations in NFE2L2, KEAP1 and CUL3, nor can it be attributed to mutation of oncogenic driver genes KRAS, BRAF and MYC that increase NFE2L2 expression.	('mutations', 'Var', (72, 81))	('NFE2L2', 'Gene', (205, 211))	('expression', 'MPA', (212, 222))	('MYC', 'Gene', '17869', (187, 190))	('NFE2L2', 'Gene', (85, 91))	('MYC', 'Gene', (187, 190))	('NRF2', 'Gene', (23, 27))	('upregulation', 'PosReg', (28, 40))
79764	33276631	Several miRs that exhibit altered expression in ESCC are able to regulate the activity of either NRF2 or KEAP1, and may provide an alternative route by which the expression of NRF2-target genes can be enhanced in ESCC tumours lacking NFE2L2 mutations.	('ESCC tumours', 'Disease', 'MESH:D004938', (213, 225))	('tumours', 'Phenotype', 'HP:0002664', (218, 225))	('regulate', 'Reg', (65, 73))	('expression', 'MPA', (162, 172))	('enhanced', 'PosReg', (201, 209))	('NFE2L2', 'Gene', (234, 240))	('ESCC tumours', 'Disease', (213, 225))	('activity', 'MPA', (78, 86))	('tumour', 'Phenotype', 'HP:0002664', (218, 224))	('mutations', 'Var', (241, 250))
79766	33276631	The tumour suppressor miR-153-3p directly binds to the 3' UTR of NRF2 inhibiting its expression, and miR-432-3p downregulates KEAP1 expression by directly targeting the coding region.	('expression', 'MPA', (85, 95))	('NRF2', 'Gene', (65, 69))	('tumour', 'Phenotype', 'HP:0002664', (4, 10))	('KEAP1', 'Gene', (126, 131))	('miR-432-3p', 'Var', (101, 111))	('downregulates', 'NegReg', (112, 125))	('inhibiting', 'NegReg', (70, 80))	('tumour', 'Disease', 'MESH:D009369', (4, 10))	('tumour', 'Disease', (4, 10))	('expression', 'MPA', (132, 142))
79768	33276631	The exact timing at which NRF2 activity is elevated in oesophageal carcinogenesis has not been determined but analysis of in situ ESCC tumours revealed the absence of NFE2L2 mutation, suggesting that these mutations may not be associated with the initial stages of ESCC cancer but may occur later to influence cancer progression.	('cancer', 'Disease', (310, 316))	('tumours', 'Phenotype', 'HP:0002664', (135, 142))	('mutation', 'Var', (174, 182))	('NFE2L2', 'Gene', (167, 173))	('cancer', 'Disease', (270, 276))	('cancer', 'Disease', 'MESH:D009369', (270, 276))	('tumour', 'Phenotype', 'HP:0002664', (135, 141))	('situ ESCC tumours', 'Disease', 'MESH:D004938', (125, 142))	('cancer', 'Phenotype', 'HP:0002664', (310, 316))	('cancer', 'Phenotype', 'HP:0002664', (270, 276))	('influence', 'Reg', (300, 309))	('cancer', 'Disease', 'MESH:D009369', (310, 316))	('oesophageal carcinogenesis', 'Disease', (55, 81))	('situ ESCC tumours', 'Disease', (125, 142))	('oesophageal carcinogenesis', 'Disease', 'MESH:D063646', (55, 81))
79772	33276631	Analysis of somatic mutations present in HCC revealed a high frequency of mutations in TERT (most commonly mutated gene), CTNNB1, TP53 and ARID1A.	('CTNNB1', 'Gene', (122, 128))	('TERT', 'Gene', '21752', (87, 91))	('mutations', 'Var', (74, 83))	('TERT', 'Gene', (87, 91))	('CTNNB1', 'Gene', '12387', (122, 128))	('HCC', 'Phenotype', 'HP:0001402', (41, 44))	('ARID1A', 'Gene', (139, 145))	('TP53', 'Gene', (130, 134))	('ARID1A', 'Gene', '93760', (139, 145))
79773	33276631	Mutations in NFE2L2, that specifically cluster to regions of the gene encoding amino acids in NRF2 that bind KEAP1, have been documented in early preneoplastic liver lesions and HCC tumour samples.	('tumour', 'Phenotype', 'HP:0002664', (182, 188))	('NFE2L2', 'Gene', (13, 19))	('NRF2', 'Gene', (94, 98))	('Mutations', 'Var', (0, 9))	('HCC', 'Phenotype', 'HP:0001402', (178, 181))	('HCC tumour', 'Disease', 'MESH:D006528', (178, 188))	('documented', 'Reg', (126, 136))	('liver lesions', 'Disease', 'MESH:D017093', (160, 173))	('HCC tumour', 'Disease', (178, 188))	('men', 'Species', '9606', (130, 133))	('liver lesions', 'Disease', (160, 173))
79774	33276631	KEAP1 mutations also occur in HCC tumours and when mapped, are found throughout the gene.	('KEAP1', 'Gene', (0, 5))	('tumour', 'Phenotype', 'HP:0002664', (34, 40))	('occur', 'Reg', (21, 26))	('HCC tumours', 'Disease', 'MESH:D006528', (30, 41))	('tumours', 'Phenotype', 'HP:0002664', (34, 41))	('HCC', 'Phenotype', 'HP:0001402', (30, 33))	('HCC tumours', 'Disease', (30, 41))	('mutations', 'Var', (6, 15))
79775	33276631	Interestingly, the mutational frequency in NFE2L2 and KEAP1, 3% and 5% respectively, is much lower than in some other cancer types.	('cancer', 'Disease', (118, 124))	('NFE2L2', 'Gene', (43, 49))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('mutational', 'Var', (19, 29))	('cancer', 'Disease', 'MESH:D009369', (118, 124))
79776	33276631	NFE2L2 mutations and KEAP1 mutations were found to both co-occur with mutations in TP53, CTNNB1 and ARID1A, but not with mutations in TERT.	('mutations', 'Var', (70, 79))	('CTNNB1', 'Gene', (89, 95))	('TERT', 'Gene', (134, 138))	('TP53', 'Gene', (83, 87))	('ARID1A', 'Gene', (100, 106))	('NFE2L2', 'Gene', (0, 6))	('ARID1A', 'Gene', '93760', (100, 106))	('TERT', 'Gene', '21752', (134, 138))	('CTNNB1', 'Gene', '12387', (89, 95))	('mutations', 'Var', (7, 16))
79787	33276631	The stage of cancer at which mutations in NFE2L2 and KEAP1 arise is currently unknown.	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('mutations', 'Var', (29, 38))	('arise', 'Reg', (59, 64))	('cancer', 'Disease', (13, 19))	('NFE2L2', 'Gene', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (13, 19))	('KEAP1', 'Gene', (53, 58))
79792	33276631	Whole exome sequencing of HNSCC samples has shown a high frequency of mutations in TP53, CDKN2A, FAT1 and PIK3CA.	('mutations', 'Var', (70, 79))	('FAT1', 'Gene', '14107', (97, 101))	('PIK3CA', 'Gene', (106, 112))	('FAT1', 'Gene', (97, 101))	('TP53', 'Gene', (83, 87))	('CDKN2A', 'Gene', (89, 95))	('HNSCC', 'Phenotype', 'HP:0012288', (26, 31))
79793	33276631	Mutations in NFE2L2 co-occur with mutations in all the commonly mutated genes found in HNSCC, whereas CUL3 mutations co-occur with mutations in TP53, PIK3CA and FAT1 but not CDKN2A.	('PIK3CA', 'Gene', (150, 156))	('TP53', 'Gene', (144, 148))	('HNSCC', 'Phenotype', 'HP:0012288', (87, 92))	('CUL3', 'Gene', (102, 106))	('NFE2L2', 'Gene', (13, 19))	('co-occur', 'Reg', (20, 28))	('Mutations', 'Var', (0, 9))	('FAT1', 'Gene', '14107', (161, 165))	('FAT1', 'Gene', (161, 165))	('mutations', 'Var', (34, 43))	('HNSCC', 'Disease', (87, 92))
79796	33276631	In tumours of patients that are HPV-negative, high frequencies in mutation of TP53 is observed, whereas the opposite is seen in tumours of HPV-positive patients.	('tumours', 'Disease', 'MESH:D009369', (128, 135))	('tumours', 'Disease', (128, 135))	('HPV', 'Species', '10566', (139, 142))	('tumour', 'Phenotype', 'HP:0002664', (3, 9))	('tumours', 'Phenotype', 'HP:0002664', (3, 10))	('tumour', 'Phenotype', 'HP:0002664', (128, 134))	('TP53', 'Gene', (78, 82))	('HPV', 'Species', '10566', (32, 35))	('tumours', 'Disease', 'MESH:D009369', (3, 10))	('mutation', 'Var', (66, 74))	('tumours', 'Disease', (3, 10))	('tumours', 'Phenotype', 'HP:0002664', (128, 135))	('patients', 'Species', '9606', (14, 22))	('patients', 'Species', '9606', (152, 160))
79797	33276631	As data suggest, NFE2L2 mutations tend to co-occur with TP53 mutations, this would suggest they are associated with HPV-negative tumours.	('tumour', 'Phenotype', 'HP:0002664', (129, 135))	('tumours', 'Phenotype', 'HP:0002664', (129, 136))	('HPV-negative tumours', 'Disease', (116, 136))	('mutations', 'Var', (61, 70))	('NFE2L2', 'Gene', (17, 23))	('HPV-negative tumours', 'Disease', 'MESH:D030361', (116, 136))	('TP53', 'Gene', (56, 60))	('mutations', 'Var', (24, 33))
79802	33276631	Studies into the genetics of GC have revealed a high frequency of mutations in TP53 (most commonly mutated gene), LRP1B, AIRD1A, PCLO and PIK3CA.	('mutations', 'Var', (66, 75))	('TP53', 'Gene', (79, 83))	('AIRD1A', 'Gene', (121, 127))	('GC', 'Phenotype', 'HP:0012126', (29, 31))	('PCLO', 'Gene', (129, 133))	('PCLO', 'Gene', '26875', (129, 133))	('LRP1B', 'Gene', (114, 119))	('LRP1B', 'Gene', '94217', (114, 119))
79803	33276631	Molecular profiling of stomach adenocarcinoma patient tissues has identified mutations in KEAP1, NFE2L2 and CUL3, with KEAP1 mutations being the most prevalent.	('patient', 'Species', '9606', (46, 53))	('NFE2L2', 'Gene', (97, 103))	('stomach adenocarcinoma', 'Disease', (23, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (36, 45))	('prevalent', 'Reg', (150, 159))	('mutations', 'Var', (77, 86))	('KEAP1', 'Gene', (90, 95))	('stomach adenocarcinoma', 'Disease', 'MESH:D000230', (23, 45))	('CUL3', 'Gene', (108, 112))
79805	33276631	Analyses by the Cancer Genome Atlas Research Network has revealed that GC patients with copy number amplifications in NFE2L2 often harbour mutations in TP53 and exhibit copy number amplification in PIK3CA.	('Cancer', 'Phenotype', 'HP:0002664', (16, 22))	('Cancer', 'Disease', (16, 22))	('harbour', 'Reg', (131, 138))	('mutations', 'Var', (139, 148))	('Cancer', 'Disease', 'MESH:D009369', (16, 22))	('copy number amplifications', 'Var', (88, 114))	('patients', 'Species', '9606', (74, 82))	('copy number amplification', 'MPA', (169, 194))	('PIK3CA', 'Gene', (198, 204))	('TP53', 'Protein', (152, 156))	('GC', 'Phenotype', 'HP:0012126', (71, 73))	('NFE2L2', 'Gene', (118, 124))
79806	33276631	Deletions in KEAP1 were also found in some GC patients and tended to co-occur alongside TP53 mutations.	('patients', 'Species', '9606', (46, 54))	('found', 'Reg', (29, 34))	('KEAP1', 'Gene', (13, 18))	('co-occur', 'Reg', (69, 77))	('GC', 'Phenotype', 'HP:0012126', (43, 45))	('Deletions', 'Var', (0, 9))
79811	33276631	MIBCs have a high frequency of mutations in TP53, RB1 and unstable genomes, whereas NIMBCs have mutations in FGFR3, KDM6A and stable genomes, and both groups often have CDKN2A deletions.	('KDM6A', 'Gene', (116, 121))	('CDKN2A', 'Gene', (169, 175))	('mutations', 'Var', (31, 40))	('FGFR3', 'Gene', (109, 114))	('RB1', 'Gene', '19645', (50, 53))	('MIBCs', 'Chemical', '-', (0, 5))	('deletions', 'Var', (176, 185))	('RB1', 'Gene', (50, 53))	('KDM6A', 'Gene', '22289', (116, 121))	('FGFR3', 'Gene', '14184', (109, 114))	('TP53', 'Gene', (44, 48))	('mutations', 'Var', (96, 105))
79812	33276631	Mutations in the Neh2 region of NFE2L2 have been found in MIBCs (particularly associated with patients that have a history of smoking) and are thought to increase NRF2 activity.	('activity', 'MPA', (168, 176))	('MIBCs', 'Disease', (58, 63))	('NFE2L2', 'Gene', (32, 38))	('patients', 'Species', '9606', (94, 102))	('Mutations', 'Var', (0, 9))	('MIBCs', 'Chemical', '-', (58, 63))	('increase', 'PosReg', (154, 162))	('NRF2', 'Enzyme', (163, 167))	('found', 'Reg', (49, 54))
79814	33276631	Data from the Cancer Genome Atlas Research Network has shown that TP53 is commonly mutated in MIBCs, which again supports the idea that NFE2L2 mutations may co-occur with mutations in specific driver genes.	('MIBCs', 'Chemical', '-', (94, 99))	('TP53', 'Gene', (66, 70))	('MIBCs', 'Disease', (94, 99))	('NFE2L2', 'Gene', (136, 142))	('Cancer', 'Phenotype', 'HP:0002664', (14, 20))	('Cancer', 'Disease', (14, 20))	('Cancer', 'Disease', 'MESH:D009369', (14, 20))	('mutations', 'Var', (143, 152))
79815	33276631	In the case of UBC, TP53 mutations are very prevalent in MIBCs, which is the subtype of UBC that have NFE2L2 mutations.	('mutations', 'Var', (25, 34))	('TP53', 'Gene', (20, 24))	('MIBCs', 'Chemical', '-', (57, 62))	('MIBCs', 'Disease', (57, 62))	('prevalent', 'Reg', (44, 53))
79817	33276631	The phagocytosis-related protein GULP1 is often decreased in UBC cell lines and tissues due to epigenetic alterations.	('rat', 'Species', '10116', (110, 113))	('decreased', 'NegReg', (48, 57))	('epigenetic alterations', 'Var', (95, 117))	('GULP1', 'Gene', (33, 38))	('GULP1', 'Gene', '70676', (33, 38))
79818	33276631	Silencing of GULP1 leads to increased NRF2 activity and the emergence of drug resistance.	('increased', 'PosReg', (28, 37))	('GULP1', 'Gene', (13, 18))	('GULP1', 'Gene', '70676', (13, 18))	('NRF2', 'Protein', (38, 42))	('drug resistance', 'Phenotype', 'HP:0020174', (73, 88))	('emergence', 'Reg', (60, 69))	('activity', 'MPA', (43, 51))	('Silencing', 'Var', (0, 9))	('drug resistance', 'MPA', (73, 88))
79823	33276631	By contrast, Nrf2-ko mice are more susceptible to carcinogen-induced UBC than are wildtype mice, suggesting that Nrf2 may also have an anti-cancer effect during disease initiation and expression of the Nrf2-target gene Gstp1 has been implicated in the detoxification of compounds that induced UBC.	('mice', 'Species', '10090', (91, 95))	('mice', 'Species', '10090', (21, 25))	('Gstp1', 'Gene', (219, 224))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('Gstp1', 'Gene', '14870', (219, 224))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('Nrf2', 'Var', (113, 117))	('UBC', 'Disease', (293, 296))
79826	33276631	There are several known prognostic factors associated with CRC, including the side of the colon on which the tumour is located, mutational status of driver genes (such as KRAS and BRAF), epigenetic modifications, genomic instability and DNA mismatch repair status (due to mutations in MLH1, MLH3, MSH2, MSH3, MSH6 and PSM2).	('mutations', 'Var', (272, 281))	('MSH6', 'Gene', (309, 313))	('genomic', 'MPA', (213, 220))	('tumour', 'Disease', 'MESH:D009369', (109, 115))	('tumour', 'Disease', (109, 115))	('MSH2', 'Gene', '17685', (297, 301))	('MSH3', 'Gene', '17686', (303, 307))	('CRC', 'Disease', (59, 62))	('MLH3', 'Gene', '217716', (291, 295))	('CRC', 'Phenotype', 'HP:0003003', (59, 62))	('PSM2', 'Gene', (318, 322))	('colon', 'Disease', (90, 95))	('colon', 'Disease', 'MESH:D003110', (90, 95))	('MSH3', 'Gene', (303, 307))	('MLH1', 'Gene', '17350', (285, 289))	('epigenetic', 'MPA', (187, 197))	('MSH2', 'Gene', (297, 301))	('MLH3', 'Gene', (291, 295))	('DNA mismatch repair status', 'MPA', (237, 263))	('MSH6', 'Gene', '17688', (309, 313))	('PSM2', 'Gene', '75329', (318, 322))	('MLH1', 'Gene', (285, 289))	('tumour', 'Phenotype', 'HP:0002664', (109, 115))
79827	33276631	Molecular profiling of early- and late-stage metastatic CRC has identified a high frequency of somatic mutations in APC (most mutated gene), KRAS, BRAF, TP53, PIK3CA and SMAD4.	('SMAD4', 'Gene', (170, 175))	('mutations', 'Var', (103, 112))	('KRAS', 'Gene', (141, 145))	('APC', 'Disease', 'MESH:D011125', (116, 119))	('SMAD4', 'Gene', '17128', (170, 175))	('BRAF', 'Gene', (147, 151))	('APC', 'Disease', (116, 119))	('CRC', 'Phenotype', 'HP:0003003', (56, 59))	('PIK3CA', 'Gene', (159, 165))	('TP53', 'Gene', (153, 157))
79828	33276631	Missense mutations in KEAP1 co-occur with mutations in BRAF, PIK3CA and APC but are mutually exclusive from mutations in KRAS and TP53.	('KEAP1', 'Gene', (22, 27))	('PIK3CA', 'Gene', (61, 67))	('Missense mutations', 'Var', (0, 18))	('co-occur', 'Reg', (28, 36))	('APC', 'Disease', 'MESH:D011125', (72, 75))	('mutations', 'Var', (42, 51))	('BRAF', 'Gene', (55, 59))	('APC', 'Disease', (72, 75))
79832	33276631	Conversely, demethylation of a CpG island in the promoter of NFE2L2 has been identified in CRC tumour samples.	('CRC tumour', 'Disease', 'MESH:D015179', (91, 101))	('demethylation', 'Var', (12, 25))	('NFE2L2', 'Gene', (61, 67))	('CRC', 'Phenotype', 'HP:0003003', (91, 94))	('CRC tumour', 'Disease', (91, 101))	('identified', 'Reg', (77, 87))	('tumour', 'Phenotype', 'HP:0002664', (95, 101))
79834	33276631	As KRAS and BRAF mutations are prevalent in CRC, NRF2 may frequently be upregulated by transcriptional activation of NFE2L2, as reported in mouse models of pancreatic cancer.	('mouse', 'Species', '10090', (140, 145))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (156, 173))	('BRAF', 'Gene', (12, 16))	('NRF2', 'Gene', (49, 53))	('CRC', 'Phenotype', 'HP:0003003', (44, 47))	('CRC', 'Disease', (44, 47))	('pancreatic cancer', 'Disease', (156, 173))	('pancreatic cancer', 'Disease', 'MESH:D010190', (156, 173))	('upregulated', 'PosReg', (72, 83))	('NFE2L2', 'Gene', (117, 123))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('KRAS', 'Gene', (3, 7))	('mutations', 'Var', (17, 26))
79836	33276631	APC mutations that lead to the activation of WNT signalling are one of the earliest initiation events in CRC and are associated with the generation of both the superoxide anion radical (O2 -) and H2O2.	('associated', 'Reg', (117, 127))	('CRC', 'Disease', (105, 108))	('APC', 'Disease', 'MESH:D011125', (0, 3))	('superoxide anion radical', 'MPA', (160, 184))	('superoxide anion radical', 'Chemical', '-', (160, 184))	('O2 -', 'Chemical', 'MESH:D010100', (186, 190))	('APC', 'Disease', (0, 3))	('CRC', 'Phenotype', 'HP:0003003', (105, 108))	('activation', 'PosReg', (31, 41))	('H2O2', 'Chemical', 'MESH:D006861', (196, 200))	('WNT signalling', 'MPA', (45, 59))	('rat', 'Species', '10116', (141, 144))	('mutations', 'Var', (4, 13))
79847	33276631	For example, from a large chemical screen, a class of drugs that induced oxidative stress was identified because of their selective toxicity towards KrasG12D-expressing MEFs, with lanperisone being the most potent and shown to increase ROS production and stimulate non-apoptotic death.	('increase', 'PosReg', (227, 235))	('ROS production', 'MPA', (236, 250))	('KrasG12D-expressing', 'Var', (149, 168))	('lanperisone', 'Chemical', '-', (180, 191))	('increase ROS production', 'Phenotype', 'HP:0025464', (227, 250))	('oxidative stress', 'Phenotype', 'HP:0025464', (73, 89))	('toxicity', 'Disease', 'MESH:D064420', (132, 140))	('toxicity', 'Disease', (132, 140))	('stimulate', 'PosReg', (255, 264))	('ROS', 'Chemical', 'MESH:D017382', (236, 239))	('MEFs', 'CellLine', 'CVCL:9115', (169, 173))	('non-apoptotic death', 'CPA', (265, 284))
79853	33276631	The most obvious way of treating tumours harbouring mutations in NFE2L2 or KEAP1 is with drugs that inhibit NRF2 activity, and a range of small molecules have been reported to possess this ability.	('mutations', 'Var', (52, 61))	('tumours', 'Phenotype', 'HP:0002664', (33, 40))	('tumours', 'Disease', 'MESH:D009369', (33, 40))	('tumours', 'Disease', (33, 40))	('NRF2', 'Protein', (108, 112))	('activity', 'MPA', (113, 121))	('tumour', 'Phenotype', 'HP:0002664', (33, 39))	('NFE2L2', 'Gene', (65, 71))	('inhibit', 'NegReg', (100, 107))
79857	33276631	Since upregulation of NRF2 increases NADPH levels within cells, reductive bioactivation of drugs might be considered a potentially effective strategy to treat cancer cells harbouring mutations in NFE2L2, KEAP1, or CUL3.	('cancer', 'Disease', (159, 165))	('NADPH', 'Gene', '67460', (37, 42))	('mutations', 'Var', (183, 192))	('increases', 'PosReg', (27, 36))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('NFE2L2', 'Gene', (196, 202))	('rat', 'Species', '10116', (143, 146))	('NADPH', 'Gene', (37, 42))	('upregulation', 'PosReg', (6, 18))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('NRF2', 'Gene', (22, 26))
79868	33276631	Interestingly, it has been found that 17-AAG is significantly more toxic to mouse Hepa1 cells with upregulated Nrf2, from knockout of Keap1, than those in which regulation of the transcription factor by Keap1 is intact, and this increased toxicity is dependent on the quinone moiety within the geldanamycin scaffold because HSP90 inhibitors lacking this structure were not more toxic to cells in which NRF2 is upregulated.	('Keap1', 'Gene', (134, 139))	('Hepa1', 'CellLine', 'CVCL:S550', (82, 87))	('toxicity', 'Disease', (239, 247))	('Keap1', 'Gene', '50868', (203, 208))	('Keap1', 'Gene', (203, 208))	('upregulated', 'PosReg', (99, 110))	('geldanamycin', 'Chemical', 'MESH:C001277', (294, 306))	('mouse', 'Species', '10090', (76, 81))	('HSP90', 'Gene', '104434', (324, 329))	('knockout', 'Var', (122, 130))	('HSP90', 'Gene', (324, 329))	('Keap1', 'Gene', '50868', (134, 139))	('toxicity', 'Disease', 'MESH:D064420', (239, 247))	('quinone', 'Chemical', 'MESH:C004532', (268, 275))	('Nrf2', 'Gene', (111, 115))
79878	33276631	We also recount events that led to the recognition that NRF2 is frequently upregulated in tumour cells, and describe a wide range of mechanisms that allow it to escape repression by KEAP1, with somatic mutations in NFE2L2, KEAP1 and CUL3 being the best characterized examples.	('upregulated', 'PosReg', (75, 86))	('NFE2L2', 'Gene', (215, 221))	('NRF2', 'Gene', (56, 60))	('escape repression', 'MPA', (161, 178))	('tumour', 'Phenotype', 'HP:0002664', (90, 96))	('tumour', 'Disease', 'MESH:D009369', (90, 96))	('tumour', 'Disease', (90, 96))	('mutations', 'Var', (202, 211))
79881	33276631	There are at least three reasons for this disparity: firstly, the NRF2-mediated mechanisms responsible for chemoprevention (increased detoxification) differ from those NRF2 confers during tumour progression (increased ROS scavenging, generation of NADPH, synthesis of serine and synthesis of ribonucleotides); secondly, as NRF2 can be upregulated by mechanisms other than somatic mutations in NFE2L2, KEAP1 and CUL3, the full extent to which NRF2 is constitutively activated in cancer is not known; thirdly, the demands placed on NRF2 to support growth and survival of cells harbouring mutations in genes that drive tumourigenesis are highly variable across different cancer types.	('tumour', 'Phenotype', 'HP:0002664', (188, 194))	('cancer', 'Disease', (668, 674))	('tumour', 'Disease', 'MESH:D009369', (188, 194))	('tumour', 'Disease', (188, 194))	('cancer', 'Phenotype', 'HP:0002664', (668, 674))	('serine', 'Chemical', 'MESH:D012694', (268, 274))	('tumour', 'Phenotype', 'HP:0002664', (616, 622))	('tumour', 'Disease', 'MESH:D009369', (616, 622))	('cancer', 'Disease', (478, 484))	('tumour', 'Disease', (616, 622))	('NADPH', 'Gene', (248, 253))	('cancer', 'Phenotype', 'HP:0002664', (478, 484))	('mutations', 'Var', (586, 595))	('cancer', 'Disease', 'MESH:D009369', (668, 674))	('cancer', 'Disease', 'MESH:D009369', (478, 484))	('NADPH', 'Gene', '67460', (248, 253))	('ribonucleotides', 'Chemical', 'MESH:D012265', (292, 307))	('ROS', 'Chemical', 'MESH:D017382', (218, 221))	('increased ROS scavenging', 'Phenotype', 'HP:0025464', (208, 232))	('rat', 'Species', '10116', (238, 241))
79884	33276631	For example, mutations in KEAP1 and NFE2L2 have been reported in late-stage bladder cancer and NRF2 has been reported to be upregulated in a model of post-therapy recurrence of breast cancer.	('bladder cancer', 'Disease', (76, 90))	('breast cancer', 'Disease', (177, 190))	('NFE2L2', 'Gene', (36, 42))	('KEAP1', 'Gene', (26, 31))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('upregulated', 'PosReg', (124, 135))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('bladder cancer', 'Phenotype', 'HP:0009725', (76, 90))	('reported', 'Reg', (53, 61))	('mutations', 'Var', (13, 22))	('breast cancer', 'Disease', 'MESH:D001943', (177, 190))	('NRF2', 'Gene', (95, 99))	('breast cancer', 'Phenotype', 'HP:0003002', (177, 190))	('bladder cancer', 'Disease', 'MESH:D001749', (76, 90))
79888	33276631	The functional and regulatory inter-relationships between NRF2 and other antioxidant transcription factors such as AP-1, FOXO, PGC-1alpha, NF-kappaB and TP53 during the various stages of tumourigenesis is not understood, and this issue needs to be addressed for us to appreciate fully the importance of redox signaling during the different stages of tumourigenesis; this is likely to be important in tumours with mutant TP53.	('tumours', 'Disease', (400, 407))	('NF-kappaB', 'Gene', '18033', (139, 148))	('GC', 'Phenotype', 'HP:0012126', (128, 130))	('tumour', 'Phenotype', 'HP:0002664', (187, 193))	('tumour', 'Disease', 'MESH:D009369', (187, 193))	('tumours', 'Phenotype', 'HP:0002664', (400, 407))	('tumour', 'Disease', (187, 193))	('tumours', 'Disease', 'MESH:D009369', (400, 407))	('PGC-1alpha', 'Gene', (127, 137))	('mutant', 'Var', (413, 419))	('tumour', 'Phenotype', 'HP:0002664', (400, 406))	('tumour', 'Phenotype', 'HP:0002664', (350, 356))	('tumour', 'Disease', 'MESH:D009369', (400, 406))	('tumour', 'Disease', (400, 406))	('tumour', 'Disease', 'MESH:D009369', (350, 356))	('NRF2', 'Gene', (58, 62))	('tumour', 'Disease', (350, 356))	('NF-kappaB', 'Gene', (139, 148))	('PGC-1alpha', 'Gene', '19017', (127, 137))	('TP53', 'Gene', (420, 424))
79892	33276631	Studying the impact of mutations in NFE2L2, KEAP1 and CUL3 will be made possible through the use of precise techniques such as Base Editors and Saturation Genome Editing, which can be used to generate specific point mutations.	('mutations', 'Var', (23, 32))	('NFE2L2', 'Gene', (36, 42))	('rat', 'Species', '10116', (148, 151))	('rat', 'Species', '10116', (196, 199))
79896	33276631	and Cancer Research UK (C20953/A18644, awarded to ATD-K).	('Cancer', 'Disease', 'MESH:D009369', (4, 10))	('Cancer', 'Phenotype', 'HP:0002664', (4, 10))	('Cancer', 'Disease', (4, 10))	('C20953/A18644', 'Var', (24, 37))
79903	26148869	Cancer largely results from various molecular aberrations comprising somatic mutational events such as single nucleotide mutations, copy number changes and DNA methylations.	('copy number changes', 'Var', (132, 151))	('results from', 'Reg', (15, 27))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('DNA methylations', 'Var', (156, 172))	('Cancer', 'Disease', (0, 6))	('single nucleotide mutations', 'Var', (103, 130))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))
79907	26148869	Similarly, endometrial cancers have also been classified into four categories (POLE ultramutated, microsatellite instability hypermutated, copy-number low, and serous-like) through a comprehensive, multiplatform analysis, and glioblastoma multiformae was stratified into four distinct molecular subtypes (proneural, neural, classical, and mesenchymal) based on the CpG island methylation phenotype.	('cancers', 'Phenotype', 'HP:0002664', (23, 30))	('glioblastoma', 'Disease', (226, 238))	('glioblastoma', 'Disease', 'MESH:D005909', (226, 238))	('endometrial cancers', 'Disease', 'MESH:D016889', (11, 30))	('copy-number low', 'Var', (139, 154))	('endometrial cancers', 'Disease', (11, 30))	('glioblastoma', 'Phenotype', 'HP:0012174', (226, 238))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))
79925	26148869	KIRC has been reported to have a high frequency of Von Hippel-Lindau (VHL) mutation and show distinct exclusivity from other 11 cancer types.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('mutation', 'Var', (75, 83))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('VHL', 'Disease', (70, 73))	('VHL', 'Disease', 'MESH:D006623', (70, 73))	('Von Hippel-Lindau', 'Gene', '7428', (51, 68))	('Von Hippel-Lindau', 'Gene', (51, 68))	('cancer', 'Disease', (128, 134))
79927	26148869	The similarity of these tumors has been implicated in the mutation or amplification of ERBB2-HER2.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('HER2', 'Gene', '2064', (93, 97))	('tumors', 'Disease', (24, 30))	('tumors', 'Disease', 'MESH:D009369', (24, 30))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('implicated', 'Reg', (40, 50))	('mutation', 'Var', (58, 66))	('ERBB2', 'Gene', (87, 92))	('ERBB2', 'Gene', '2064', (87, 92))	('HER2', 'Gene', (93, 97))	('amplification', 'Var', (70, 83))
79952	26148869	The relationship between mutations of VHL and KIRC has been established for decades and the association between VHL and tumor stage, tumor-cell proliferation, and patient prognosis has also been well studied.	('VHL', 'Disease', (112, 115))	('mutations', 'Var', (25, 34))	('VHL', 'Disease', 'MESH:D006623', (112, 115))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('VHL', 'Disease', 'MESH:D006623', (38, 41))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('VHL', 'Disease', (38, 41))	('patient', 'Species', '9606', (163, 170))	('tumor', 'Disease', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('tumor', 'Disease', (120, 125))
79953	26148869	Besides VHL, other genetic alterations in subgroup-5 involve the mutation of the chromatin remodeling gene PBRM1, the mutation of the histone methyltransferase gene SETD2, which has been identified as a tumor suppressor in KIRC and high methylation rate of GSTP1 (Fig.	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('tumor', 'Disease', (203, 208))	('GSTP1', 'Gene', (257, 262))	('PBRM1', 'Gene', '55193', (107, 112))	('SETD2', 'Gene', '29072', (165, 170))	('VHL', 'Disease', (8, 11))	('mutation', 'Var', (65, 73))	('PBRM1', 'Gene', (107, 112))	('SETD2', 'Gene', (165, 170))	('mutation', 'Var', (118, 126))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('histone methyltransferase', 'Gene', '56979', (134, 159))	('histone methyltransferase', 'Gene', (134, 159))	('VHL', 'Disease', 'MESH:D006623', (8, 11))	('GSTP1', 'Gene', '2950', (257, 262))
79957	26148869	Both PTEN and PIK3CA alterations were reported to have strong relationships with UCEC and COADREAD, and the loss of PTEN expression is also observed to be associated with PIK3CA mutations in metastatic colorectal cancer.	('PIK3CA', 'Gene', (171, 177))	('PTEN', 'Gene', (5, 9))	('expression', 'MPA', (121, 131))	('colorectal cancer', 'Disease', (202, 219))	('relationships', 'Reg', (62, 75))	('PIK3CA', 'Gene', (14, 20))	('PTEN', 'Gene', (116, 120))	('COADREAD', 'Disease', (90, 98))	('loss', 'Var', (108, 112))	('PTEN', 'Gene', '5728', (5, 9))	('PTEN', 'Gene', '5728', (116, 120))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('colorectal cancer', 'Phenotype', 'HP:0003003', (202, 219))	('PIK3CA', 'Gene', '5290', (171, 177))	('associated', 'Reg', (155, 165))	('PIK3CA', 'Gene', '5290', (14, 20))	('UCEC', 'Disease', (81, 85))	('mutations', 'Var', (178, 187))	('colorectal cancer', 'Disease', 'MESH:D015179', (202, 219))
79958	26148869	Altered PTEN expression was viewed as a diagnostic marker for early detection of UCEC, and is associated with favorable clinical and pathologic characteristics.	('PTEN', 'Gene', (8, 12))	('UCEC', 'Disease', (81, 85))	('Altered', 'Var', (0, 7))	('PTEN', 'Gene', '5728', (8, 12))
79959	26148869	In addition, PIK3CA mutations were reported to be present in approximately 25 % of breast cancers, particularly the estrogen receptor-positive subtypes, while they are absent in the basal-type breast cancer.	('breast cancer', 'Phenotype', 'HP:0003002', (193, 206))	('breast cancers', 'Phenotype', 'HP:0003002', (83, 97))	('basal-type breast cancer', 'Disease', 'MESH:D001943', (182, 206))	('PIK3CA', 'Gene', (13, 19))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('breast cancers', 'Disease', 'MESH:D001943', (83, 97))	('breast cancers', 'Disease', (83, 97))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('basal-type breast cancer', 'Disease', (182, 206))	('PIK3CA', 'Gene', '5290', (13, 19))	('breast cancer', 'Phenotype', 'HP:0003002', (83, 96))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('present', 'Reg', (50, 57))	('mutations', 'Var', (20, 29))
79961	26148869	The mutation of PTEN and PIK3CA together with other alterations of genes affects a common biological network, which reflects the major similarities among subgroup-1 tumors (Fig.	('common biological network', 'Pathway', (83, 108))	('tumors', 'Disease', (165, 171))	('tumors', 'Disease', 'MESH:D009369', (165, 171))	('tumors', 'Phenotype', 'HP:0002664', (165, 171))	('mutation', 'Var', (4, 12))	('PIK3CA', 'Gene', (25, 31))	('PTEN', 'Gene', (16, 20))	('PIK3CA', 'Gene', '5290', (25, 31))	('PTEN', 'Gene', '5728', (16, 20))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('affects', 'Reg', (73, 80))
79963	26148869	Finally, many subgroup-1-specific altered genes including PIK3CA show significant differential expression in subgroup-1 compared to all other patients (Fig.	('differential', 'Reg', (82, 94))	('PIK3CA', 'Gene', (58, 64))	('PIK3CA', 'Gene', '5290', (58, 64))	('patients', 'Species', '9606', (142, 150))	('subgroup-1', 'Var', (109, 119))	('expression', 'MPA', (95, 105))
79964	26148869	Subgroup-6 was mainly characterized by frequent promoter hypermethylation of MGMT and mutations of APC, KRAS, FLT3, and NPM1 (Fig.	('mutations', 'Var', (86, 95))	('APC', 'Disease', 'MESH:D011125', (99, 102))	('FLT3', 'Gene', (110, 114))	('KRAS', 'Gene', '3845', (104, 108))	('APC', 'Disease', (99, 102))	('NPM1', 'Gene', (120, 124))	('promoter hypermethylation', 'MPA', (48, 73))	('NPM1', 'Gene', '4869', (120, 124))	('MGMT', 'Gene', '4255', (77, 81))	('MGMT', 'Gene', (77, 81))	('FLT3', 'Gene', '2322', (110, 114))	('KRAS', 'Gene', (104, 108))
79968	26148869	Thus, hypermethylation of MGMT, inhibiting the expression of this gene, is of clinical interest for LAML.	('inhibiting', 'NegReg', (32, 42))	('hypermethylation', 'Var', (6, 22))	('MGMT', 'Gene', (26, 30))	('MGMT', 'Gene', '4255', (26, 30))	('expression', 'MPA', (47, 57))
79969	26148869	Moreover, the methylation of MGMT was also reported as a valuable molecular marker for the early detection of colorectal cancer.	('colorectal cancer', 'Disease', 'MESH:D015179', (110, 127))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('MGMT', 'Gene', '4255', (29, 33))	('MGMT', 'Gene', (29, 33))	('methylation', 'Var', (14, 25))	('colorectal cancer', 'Phenotype', 'HP:0003003', (110, 127))	('colorectal cancer', 'Disease', (110, 127))
79970	26148869	Therefore, the alteration of MGMT would provide potential implications for targeted and shared therapy across these two malignancies.	('implications', 'Reg', (58, 70))	('malignancies', 'Disease', 'MESH:D009369', (120, 132))	('MGMT', 'Gene', '4255', (29, 33))	('malignancies', 'Disease', (120, 132))	('MGMT', 'Gene', (29, 33))	('alteration', 'Var', (15, 25))
79973	26148869	For example, mutations of tumor suppressor gene APC were only presented in COADREAD, while mutations of FLT3 and NPM1 are exclusive to LAML.	('NPM1', 'Gene', (113, 117))	('FLT3', 'Gene', (104, 108))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('NPM1', 'Gene', '4869', (113, 117))	('APC', 'Disease', 'MESH:D011125', (48, 51))	('tumor', 'Disease', (26, 31))	('FLT3', 'Gene', '2322', (104, 108))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('mutations', 'Var', (13, 22))	('APC', 'Disease', (48, 51))
79977	26148869	This subgroup demonstrates a typical cross-cancer similarity phenomenon that subsets of samples from different tumor types are characterized by the same genomic alterations on chromosome 9.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumor', 'Disease', (111, 116))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('cross-cancer', 'Disease', (37, 49))	('cross-cancer', 'Disease', 'MESH:C537866', (37, 49))	('alterations', 'Var', (161, 172))
79978	26148869	The associations of the deletion of tumor suppressor genes CDKN2A, CDKN2B, and MTAP with the four significant enriched cancer types in this subgroup have been widely investigated and reported.	('MTAP', 'Gene', '4507', (79, 83))	('CDKN2B', 'Gene', (67, 73))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('CDKN2B', 'Gene', '1030', (67, 73))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('cancer', 'Disease', (119, 125))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('deletion', 'Var', (24, 32))	('CDKN2A', 'Gene', (59, 65))	('tumor', 'Disease', (36, 41))	('MTAP', 'Gene', (79, 83))	('associations', 'Interaction', (4, 16))	('CDKN2A', 'Gene', '1029', (59, 65))
79987	26148869	The lack of expression due to the deletion of IFNAs may be responsible for the HPV infection in carcinogenesis of these cancers; however, their relationships need to be further investigated.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('IFNA', 'Gene', '3440', (46, 50))	('HPV infection', 'Disease', 'MESH:D030361', (79, 92))	('IFNA', 'Gene', (46, 50))	('lack', 'NegReg', (4, 8))	('HPV infection', 'Disease', (79, 92))	('cancers', 'Phenotype', 'HP:0002664', (120, 127))	('cancers', 'Disease', (120, 127))	('deletion', 'Var', (34, 42))	('cancers', 'Disease', 'MESH:D009369', (120, 127))	('expression', 'MPA', (12, 22))
79990	26148869	The largest patient group, subgroup-3 enriched with BRCA-basal, UCEC-serous, and OV tumors, was characterized by multiple recurrent chromosomal gains and losses (in Additional file 1: Figure S6A).	('BRCA', 'Phenotype', 'HP:0003002', (52, 56))	('OV', 'Phenotype', 'HP:0012887', (81, 83))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('chromosomal gains', 'Var', (132, 149))	('BRCA', 'Gene', (52, 56))	('BRCA', 'Gene', '672', (52, 56))	('OV tumors', 'Disease', 'MESH:D009369', (81, 90))	('losses', 'NegReg', (154, 160))	('OV tumors', 'Disease', (81, 90))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('patient', 'Species', '9606', (12, 19))	('UCEC-serous', 'Disease', (64, 75))
79991	26148869	BRCA-basal, UCEC-serous, and OV patients in this cohort are associated with a high mutation rate of TP53 (88.4 %) (in Additional file 1: Figure S6B), which was consistent with previous observations.	('TP53', 'Gene', '7157', (100, 104))	('patients', 'Species', '9606', (32, 40))	('BRCA', 'Gene', (0, 4))	('TP53', 'Gene', (100, 104))	('mutation', 'Var', (83, 91))	('OV', 'Phenotype', 'HP:0012887', (29, 31))	('BRCA', 'Phenotype', 'HP:0003002', (0, 4))	('BRCA', 'Gene', '672', (0, 4))
79992	26148869	Amplification of 11q13 involving CCND1, ORAOV1, and ANO1 was dominated in subgroup-4, mainly consisting of luminal BRCA and HNSC (in Additional file 1: Figure S7).	('Amplification', 'Var', (0, 13))	('CCND1', 'Gene', (33, 38))	('CCND1', 'Gene', '595', (33, 38))	('OV', 'Phenotype', 'HP:0012887', (43, 45))	('BRCA', 'Phenotype', 'HP:0003002', (115, 119))	('ANO1', 'Gene', (52, 56))	('ORAOV1', 'Gene', '220064', (40, 46))	('BRCA', 'Gene', '672', (115, 119))	('ORAOV1', 'Gene', (40, 46))	('BRCA', 'Gene', (115, 119))	('ANO1', 'Gene', '55107', (52, 56))	('HNSC', 'Phenotype', 'HP:0012288', (124, 128))
79994	26148869	Amplification and overexpression of CCND1 would alter cell cycle progression and contribute to tumorigenesis.	('Amplification', 'Var', (0, 13))	('contribute', 'Reg', (81, 91))	('tumor', 'Disease', (95, 100))	('CCND1', 'Gene', (36, 41))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('alter', 'Reg', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('CCND1', 'Gene', '595', (36, 41))	('cell cycle progression', 'CPA', (54, 76))	('overexpression', 'PosReg', (18, 32))
79995	26148869	Previous studies have shown that luminal cancers harbor recurrent amplifications and overexpression of CCND1, whereas basal-like tumors harbor recurrent deletions and down-regulation of it.	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('tumors', 'Disease', (129, 135))	('tumors', 'Disease', 'MESH:D009369', (129, 135))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('overexpression', 'PosReg', (85, 99))	('CCND1', 'Gene', '595', (103, 108))	('amplifications', 'Var', (66, 80))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('down-regulation', 'NegReg', (167, 182))	('cancers', 'Phenotype', 'HP:0002664', (41, 48))	('luminal cancers', 'Disease', 'MESH:D009369', (33, 48))	('CCND1', 'Gene', (103, 108))	('deletions', 'Var', (153, 162))	('luminal cancers', 'Disease', (33, 48))
79996	26148869	Subgroup-8, mainly consisting of LUSC, HNSC, and OV tumors, was characterized by 100 % copy number gain on chromosome 3q26 involving genes PIK3CA, KCNMB3, KCNMB2, MFN1, GNB4, MECOM, ZMAT3, SOX2, and KCNJ13 (in Additional file 1: Figure S11).	('ZMAT3', 'Gene', '64393', (182, 187))	('S11', 'Gene', '6267', (236, 239))	('LUSC', 'Phenotype', 'HP:0030359', (33, 37))	('MECOM', 'Gene', (175, 180))	('OV', 'Phenotype', 'HP:0012887', (49, 51))	('KCNMB3', 'Gene', '27094', (147, 153))	('PIK3CA', 'Gene', (139, 145))	('GNB4', 'Gene', '59345', (169, 173))	('MECOM', 'Gene', '2122', (175, 180))	('gain', 'PosReg', (99, 103))	('MFN1', 'Gene', (163, 167))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('KCNJ13', 'Gene', (199, 205))	('S11', 'Gene', (236, 239))	('KCNJ13', 'Gene', '3769', (199, 205))	('KCNMB2', 'Gene', '10242', (155, 161))	('copy number', 'Var', (87, 98))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('KCNMB3', 'Gene', (147, 153))	('KCNMB2', 'Gene', (155, 161))	('GNB4', 'Gene', (169, 173))	('HNSC', 'Disease', (39, 43))	('OV tumors', 'Disease', 'MESH:D009369', (49, 58))	('MFN1', 'Gene', '55669', (163, 167))	('SOX2', 'Gene', '6657', (189, 193))	('PIK3CA', 'Gene', '5290', (139, 145))	('SOX2', 'Gene', (189, 193))	('OV tumors', 'Disease', (49, 58))	('HNSC', 'Phenotype', 'HP:0012288', (39, 43))	('LUSC', 'Disease', (33, 37))	('ZMAT3', 'Gene', (182, 187))
79997	26148869	Subgroup-9, mainly consisting of HNSC, OV, and COADREAD, was characterized by a distinct TP53 mutation rate (98.6 %, in Additional file 1: Figure S12).	('TP53', 'Gene', '7157', (89, 93))	('TP53', 'Gene', (89, 93))	('HNSC', 'Phenotype', 'HP:0012288', (33, 37))	('OV', 'Phenotype', 'HP:0012887', (39, 41))	('S12', 'Gene', (146, 149))	('S12', 'Gene', '6268', (146, 149))	('mutation', 'Var', (94, 102))
80008	26148869	Both studies reported the loss of CDKN2A in this patient cohort; however, our subgroup-7 was characterized by the copy number deletion on chromosome 9p21 with nearly 100 % frequency.	('CDKN2A', 'Gene', '1029', (34, 40))	('CDKN2A', 'Gene', (34, 40))	('patient', 'Species', '9606', (49, 56))	('copy number deletion', 'Var', (114, 134))
80012	26148869	such as the hypermethylation of MGMT and other genetic characteristics shared by subsets of LAML and UCEC in subgroup-6 and the 100 % copy number gain on chromosome 3q26 in fractional OV, LUSC, and HNSC in subgroup-8 (in Additional file 1: Figure S13).	('HNSC', 'Phenotype', 'HP:0012288', (198, 202))	('hypermethylation', 'Var', (12, 28))	('copy number', 'Var', (134, 145))	('MGMT', 'Gene', '4255', (32, 36))	('gain', 'PosReg', (146, 150))	('MGMT', 'Gene', (32, 36))	('OV', 'Phenotype', 'HP:0012887', (184, 186))	('LUSC', 'Phenotype', 'HP:0030359', (188, 192))
80023	26148869	These data contain 479 functional genetic alterations, including 116 copy number gains, 151 copy number losses, 199 recurrently mutated genes, and 13 epigenetically silenced genes recorded across 3299 tumor samples from 12 cancer types (Additional file 1: Table S1).	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('copy number gains', 'Var', (69, 86))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('copy number', 'Var', (92, 103))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('cancer', 'Disease', 'MESH:D009369', (223, 229))	('tumor', 'Disease', (201, 206))	('cancer', 'Disease', (223, 229))
80027	26148869	Briefly, the NBS applies a network propagation method to spread the influence of each mutation over its network neighborhood and produce a network-smoothed profile to reflect the effect of each genetic alteration on network module or pathway levels with a continuous value.	('NBS', 'Disease', (13, 16))	('NBS', 'Disease', 'MESH:D049932', (13, 16))	('mutation', 'Var', (86, 94))
80108	24130905	Other miRNAs downregulated markedly included miR-30b and miR-19, in both miR-19a and miR-19b forms.	('miR-19b', 'Gene', '406980', (85, 92))	('downregulated', 'NegReg', (13, 26))	('miR-19a', 'Gene', (73, 80))	('miR-19', 'Gene', (57, 63))	('miR-19b', 'Gene', (85, 92))	('miR-19a', 'Gene', '406979', (73, 80))	('miR-30b', 'Var', (45, 52))
80118	24130905	Interestingly, these results were cell line-specific: in A549 lung adenocarcinoma cells miR-205 was much less secreted and in HuH7 liver carcinoma cells miR-205 was not detected neither in cells nor in medium; while miR-30b (cell-retained in A2182) was found to be excreted both in A549 and HuH7 (data not shown).	('HuH7', 'Gene', '284424', (291, 295))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (62, 81))	('liver carcinoma', 'Phenotype', 'HP:0001402', (131, 146))	('A549', 'CellLine', 'CVCL:0023', (57, 61))	('HuH7', 'Gene', (126, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('miR-205', 'Gene', (88, 95))	('liver carcinoma', 'Disease', 'MESH:D006528', (131, 146))	('liver carcinoma', 'Disease', (131, 146))	('HuH7', 'Gene', (291, 295))	('miR-205', 'Gene', '406988', (153, 160))	('miR-30b', 'Var', (216, 223))	('HuH7', 'Gene', '284424', (126, 130))	('A549 lung adenocarcinoma', 'Disease', 'MESH:D000077192', (57, 81))	('miR-205', 'Gene', '406988', (88, 95))	('A549', 'CellLine', 'CVCL:0023', (282, 286))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('A549 lung adenocarcinoma', 'Disease', (57, 81))	('miR-205', 'Gene', (153, 160))
80147	24130905	Similarly, miR-30b is also suggested as a possible oncomiR as it was shown to be overexpressed in oral SCC and in the serum of rats bearing pancreatic ductal adenocarcinoma.	('rats', 'Species', '10116', (127, 131))	('carcinoma', 'Phenotype', 'HP:0030731', (163, 172))	('SCC', 'Gene', (103, 106))	('pancreatic ductal adenocarcinoma', 'Disease', (140, 172))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (140, 172))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (140, 172))	('SCC', 'Phenotype', 'HP:0002860', (103, 106))	('SCC', 'Gene', '6317', (103, 106))	('miR-30b', 'Var', (11, 18))	('overexpressed', 'PosReg', (81, 94))
80184	32068233	In the development of esophageal cancer, the rs11473 polymorphism of the miR-483-5p binding site plays a vital role in the 3'-UTR of the basigin gene.	('basigin', 'Gene', (137, 144))	('miR-483-5p', 'Chemical', '-', (73, 83))	('miR-483-5p', 'Gene', (73, 83))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('rs11473', 'Var', (45, 52))	('esophageal cancer', 'Disease', (22, 39))	('basigin', 'Gene', '682', (137, 144))	('esophageal cancer', 'Disease', 'MESH:D004938', (22, 39))	('rs11473', 'Mutation', 'rs11473', (45, 52))
80185	32068233	Single nucleotide polymorphisms (SNPs) in TERT may be associated with susceptibility to esophageal cancer and contribute to the development of esophageal cancer.	('contribute to', 'Reg', (110, 123))	('esophageal cancer', 'Disease', 'MESH:D004938', (88, 105))	('Single nucleotide polymorphisms', 'Var', (0, 31))	('esophageal cancer', 'Disease', 'MESH:D004938', (143, 160))	('TERT', 'Gene', '7015', (42, 46))	('TERT', 'Gene', (42, 46))	('esophageal cancer', 'Disease', (143, 160))	('esophageal cancer', 'Disease', (88, 105))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('associated', 'Reg', (54, 64))
80189	32068233	MicroRNA-506 inhibits proliferation of esophageal cancer cells by targeting CREB1.	('CREB1', 'Gene', '1385', (76, 81))	('MicroRNA-506', 'Var', (0, 12))	('CREB1', 'Gene', (76, 81))	('esophageal cancer', 'Disease', (39, 56))	('targeting', 'Reg', (66, 75))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('proliferation', 'CPA', (22, 35))	('esophageal cancer', 'Disease', 'MESH:D004938', (39, 56))	('inhibits', 'NegReg', (13, 21))
80210	32068233	We believe that the presence of these DEGs is closely related to the development of various stages of esophageal cancer.	('esophageal cancer', 'Disease', 'MESH:D004938', (102, 119))	('related', 'Reg', (54, 61))	('esophageal cancer', 'Disease', (102, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('presence', 'Var', (20, 28))
80237	32068233	Importantly, positive CPLX2 expression is associated with lymphatic invasion, pathological staging, and adverse disease-specific survival in LNET patients.	('positive', 'Var', (13, 21))	('associated', 'Reg', (42, 52))	('expression', 'MPA', (28, 38))	('pathological staging', 'CPA', (78, 98))	('CPLX2', 'Gene', (22, 27))	('CPLX2', 'Gene', '10814', (22, 27))	('patients', 'Species', '9606', (146, 154))	('lymphatic invasion', 'CPA', (58, 76))
80243	32068233	After knocking out the DPEP1 gene, cells (SW480 and HCT116) essentially increased apoptosis and attenuated cell proliferation and cell invasion.	('increased', 'PosReg', (72, 81))	('apoptosis', 'CPA', (82, 91))	('attenuated', 'NegReg', (96, 106))	('SW480', 'CellLine', 'CVCL:0546', (42, 47))	('HCT116', 'CellLine', 'CVCL:0291', (52, 58))	('cell proliferation', 'CPA', (107, 125))	('DPEP1', 'Gene', (23, 28))	('DPEP1', 'Gene', '1800', (23, 28))	('cell invasion', 'CPA', (130, 143))	('knocking out', 'Var', (6, 18))
80250	32068233	found that knockdown of ThBS4 inhibited migration and invasion of hepatocellular carcinoma cells, as well as hemangiocarcinoma-induced angiogenesis.	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('ThBS4', 'Gene', (24, 29))	('invasion', 'CPA', (54, 62))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (66, 90))	('inhibited', 'NegReg', (30, 39))	('hepatocellular carcinoma', 'Disease', (66, 90))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (66, 90))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('hemangiocarcinoma', 'Disease', (109, 126))	('ThBS4', 'Gene', '7060', (24, 29))	('hemangiocarcinoma', 'Disease', 'None', (109, 126))	('knockdown', 'Var', (11, 20))
80258	32068233	In the study of isoleucine anti-esophageal squamous cell carcinoma, it was found that iso-valine can inhibit tumor growth by activating the p53 pathway.	('esophageal squamous cell carcinoma', 'Disease', (32, 66))	('iso-valine', 'Chemical', 'MESH:C032737', (86, 96))	('inhibit', 'NegReg', (101, 108))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:C562729', (32, 66))	('activating', 'Reg', (125, 135))	('carcinoma', 'Phenotype', 'HP:0030731', (57, 66))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (43, 66))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('iso-valine', 'Var', (86, 96))	('p53', 'Gene', (140, 143))	('p53', 'Gene', '7157', (140, 143))	('tumor', 'Disease', (109, 114))
80266	32068233	Any level of distortion in these organ size regulation processes can lead to a variety of pathological conditions, of which cancer is the most terrifying.	('cancer', 'Disease', (124, 130))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('pathological', 'Disease', (90, 102))	('lead to', 'Reg', (69, 76))	('distortion', 'Var', (13, 23))	('cancer', 'Disease', 'MESH:D009369', (124, 130))
80273	32068233	Recently, some studies have shown that EGFR inhibitors may exhibit anti-tumor effects, which are associated with the continued promotion of reactive oxygen species production and induction of apoptosis.	('promotion', 'PosReg', (127, 136))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('induction', 'Reg', (179, 188))	('inhibitors', 'Var', (44, 54))	('reactive oxygen species production', 'MPA', (140, 174))	('tumor', 'Disease', (72, 77))	('apoptosis', 'CPA', (192, 201))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (140, 163))	('EGFR', 'Gene', (39, 43))	('tumor', 'Disease', 'MESH:D009369', (72, 77))
80282	32068233	found that hypermethylation of the SST promoter is common and is associated with early tumor progression in Barrett's esophagus.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('hypermethylation', 'Var', (11, 27))	('tumor', 'Disease', (87, 92))	('associated with', 'Reg', (65, 80))	('SST promoter', 'Gene', (35, 47))	("Barrett's esophagus", 'Disease', 'MESH:D001471', (108, 127))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	("Barrett's esophagus", 'Disease', (108, 127))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (108, 127))
80285	32068233	It is also possible to play an important role in the regulation of esophageal cancer by methylation modification.	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('esophageal cancer', 'Disease', (67, 84))	('esophageal cancer', 'Disease', 'MESH:D004938', (67, 84))	('methylation modification', 'Var', (88, 112))
80286	32068233	studied the effect of SH3GL2 methylation on the pathogenesis of head and neck squamous cell carcinoma, and the disorder of sh3gl2 is an independent pathway for early developmental abnormalities of the head and neck.	('SH3GL2', 'Gene', (22, 28))	('developmental abnormalities of the head', 'Disease', 'MESH:D006130', (166, 205))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('sh3gl2', 'Gene', (123, 129))	('sh3gl2', 'Gene', '6456', (123, 129))	('SH3GL2', 'Gene', '6456', (22, 28))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (78, 101))	('abnormalities of the head', 'Phenotype', 'HP:0000234', (180, 205))	('head and neck squamous cell carcinoma', 'Disease', 'MESH:C535575', (64, 101))	('disorder', 'Var', (111, 119))	('developmental abnormalities', 'Phenotype', 'HP:0001263', (166, 193))	('developmental abnormalities of the head', 'Disease', (166, 205))
80305	30569133	In the last decade, researchers have found that the changes noted in certain transcriptional regulators can significantly improve the overall survival rate of a small subset of patients with lung cancer.	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('improve', 'PosReg', (122, 129))	('lung cancer', 'Disease', 'MESH:D008175', (191, 202))	('patients', 'Species', '9606', (177, 185))	('lung cancer', 'Disease', (191, 202))	('lung cancer', 'Phenotype', 'HP:0100526', (191, 202))	('changes', 'Var', (52, 59))
80309	30569133	The dysregulated TML network motifs were associated with cancer-related functions and pathways.	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('associated', 'Reg', (41, 51))	('TML network', 'Gene', (17, 28))	('cancer', 'Disease', (57, 63))	('pathways', 'CPA', (86, 94))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('dysregulated', 'Var', (4, 16))
80322	30569133	For instance, a previous study reported that mutation of the zinc finger protein family member 718 may be a potential germline mutation of lung cancer.	('lung cancer', 'Disease', (139, 150))	('lung cancer', 'Disease', 'MESH:D008175', (139, 150))	('mutation', 'Var', (45, 53))	('lung cancer', 'Phenotype', 'HP:0100526', (139, 150))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
80323	30569133	In addition, let-7c, let-7d and let-7f were all present in dysregulated TML motifs in the present analysis, whereas it has been reported that the let-7 miRNA family suppressed NSCLC development.	('let-7c', 'Gene', '406885', (13, 19))	('let-7f', 'Var', (32, 38))	('NSCLC', 'Disease', (176, 181))	('NSCLC', 'Disease', 'MESH:D002289', (176, 181))	('suppressed', 'NegReg', (165, 175))	('let-7d', 'Gene', (21, 27))	('let-7c', 'Gene', (13, 19))	('let-7d', 'Gene', '406886', (21, 27))	('NSCLC', 'Phenotype', 'HP:0030358', (176, 181))
80328	30569133	For instance, the TF E2F1, lncRNA KB-1732A1.1 and miR-15b were identified in LUAD and LUSC.	('miR-15b', 'Gene', '406949', (50, 57))	('LUSC', 'Phenotype', 'HP:0030359', (86, 90))	('miR-15b', 'Gene', (50, 57))	('E2F1', 'Var', (21, 25))	('LUAD', 'Phenotype', 'HP:0030078', (77, 81))
80330	30569133	Recently, it was reported that mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) gene occurred in a subset of patients with lung cancer, indicating a marked response to treatment by EGFR tyrosine kinase inhibitors.	('EGFR', 'Gene', (112, 116))	('EGFR', 'Gene', '1956', (219, 223))	('mutations', 'Var', (31, 40))	('epidermal growth factor receptor', 'Gene', '1956', (78, 110))	('EGFR', 'Gene', (219, 223))	('lung cancer', 'Disease', (161, 172))	('lung cancer', 'Phenotype', 'HP:0100526', (161, 172))	('patients', 'Species', '9606', (147, 155))	('occurred', 'Reg', (123, 131))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('EGFR', 'Gene', '1956', (112, 116))	('lung cancer', 'Disease', 'MESH:D008175', (161, 172))	('epidermal growth factor receptor', 'Gene', (78, 110))
80334	30569133	Aberrant FOXM1 expression directly and constitutively activates SNAIL, thereby promoting LUAD metastasis.	('promoting', 'PosReg', (79, 88))	('FOXM1', 'Gene', (9, 14))	('Aberrant', 'Var', (0, 8))	('FOXM1', 'Gene', '2305', (9, 14))	('activates', 'PosReg', (54, 63))	('LUAD metastasis', 'CPA', (89, 104))	('SNAIL', 'Gene', (64, 69))	('SNAIL', 'Gene', '6615', (64, 69))	('LUAD', 'Phenotype', 'HP:0030078', (89, 93))
80335	30569133	Inhibition of FOXM1-SNAIL signaling may thus present an ideal target for future cancer treatment.	('cancer', 'Disease', (80, 86))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('SNAIL', 'Gene', '6615', (20, 25))	('SNAIL', 'Gene', (20, 25))	('Inhibition', 'Var', (0, 10))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('FOXM1', 'Gene', '2305', (14, 19))	('FOXM1', 'Gene', (14, 19))
80351	30569133	Gemcitabine, which is used in the treatment of NSCLC, was associated with the let-7 miRNA family, including let-7c, let-7d and let-7f.	('Gemcitabine', 'Chemical', 'MESH:C056507', (0, 11))	('let-7f', 'Var', (127, 133))	('associated', 'Reg', (58, 68))	('let-7c', 'Gene', (108, 114))	('let-7', 'Gene', (78, 83))	('let-7d', 'Gene', '406886', (116, 122))	('let-7d', 'Gene', (116, 122))	('NSCLC', 'Phenotype', 'HP:0030358', (47, 52))	('let-7c', 'Gene', '406885', (108, 114))	('NSCLC', 'Disease', (47, 52))	('NSCLC', 'Disease', 'MESH:D002289', (47, 52))
80408	28789450	3, the normalized expression of Fas and FasL mRNAs in each hyperoside group was significantly higher than that in the control group, and increased along with the increasing concentrations of hyperoside treatment.	('Fas', 'Protein', (32, 35))	('hyperoside', 'Chemical', 'MESH:C021304', (59, 69))	('FasL', 'Gene', '356', (40, 44))	('expression', 'MPA', (18, 28))	('increased', 'PosReg', (137, 146))	('hyperoside', 'Var', (59, 69))	('hyperoside', 'Chemical', 'MESH:C021304', (191, 201))	('FasL', 'Gene', (40, 44))	('higher', 'PosReg', (94, 100))
80415	28789450	The normal Fas system plays an important role in the homeostasis of organisms, maintaining a dynamic balance between apoptosis and proliferation rates, and its abnormal expression can cause immune system diseases and tumors and affects transplantation immunity.	('transplantation immunity', 'CPA', (236, 260))	('affects', 'Reg', (228, 235))	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('abnormal expression', 'Var', (160, 179))	('tumors', 'Phenotype', 'HP:0002664', (217, 223))	('cause', 'Reg', (184, 189))	('system diseases and tumors', 'Disease', 'MESH:D009423', (197, 223))
80419	28789450	Furthermore, studies have confirmed that deletion of the Fas gene reduces apoptosis rates and accelerates the proliferation of tumor cells.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('reduces', 'NegReg', (66, 73))	('tumor', 'Disease', (127, 132))	('deletion', 'Var', (41, 49))	('Fas', 'Gene', (57, 60))	('accelerates', 'PosReg', (94, 105))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('apoptosis rates', 'CPA', (74, 89))
80422	28789450	Results of MTT assays showed that hyperoside significantly inhibited the activity of the cells treated with hyperoside compared with the activity of cells in the control group.	('activity', 'MPA', (73, 81))	('inhibited', 'NegReg', (59, 68))	('MTT', 'Chemical', 'MESH:C070243', (11, 14))	('hyperoside', 'Chemical', 'MESH:C021304', (108, 118))	('hyperoside', 'Var', (108, 118))	('hyperoside', 'Chemical', 'MESH:C021304', (34, 44))
80424	28789450	Additionally, the results of RT-PCR showed the expression levels of Fas and FasL mRNAs increased with increasing hyperoside concentrations suggesting that hyperoside can upregulate the expressions of Fas and FasL and induce apoptosis.	('Fas', 'Protein', (200, 203))	('induce', 'Reg', (217, 223))	('upregulate', 'PosReg', (170, 180))	('hyperoside', 'Chemical', 'MESH:C021304', (155, 165))	('expressions', 'MPA', (185, 196))	('FasL', 'Gene', (76, 80))	('apoptosis', 'CPA', (224, 233))	('FasL', 'Gene', (208, 212))	('FasL', 'Gene', '356', (76, 80))	('hyperoside', 'Var', (155, 165))	('FasL', 'Gene', '356', (208, 212))	('hyperoside', 'Chemical', 'MESH:C021304', (113, 123))
80426	28789450	Their results support our hypothesis that hyperoside can induce apoptosis of SW579 cells by upregulating the expressions of Fas and FasL mRNAs.	('hyperoside', 'Chemical', 'MESH:C021304', (42, 52))	('apoptosis', 'CPA', (64, 73))	('FasL', 'Gene', (132, 136))	('hyperoside', 'Var', (42, 52))	('SW579', 'CellLine', 'CVCL:3603', (77, 82))	('FasL', 'Gene', '356', (132, 136))	('Fas', 'Protein', (124, 127))	('expressions', 'MPA', (109, 120))	('upregulating', 'PosReg', (92, 104))
80440	27786280	Recent studies have indicated that the abnormal expression of lncRNAs influences tumorigenesis and plays both oncogenic and tumor suppressive roles and suggested that lncRNAs could serve as diagnostic biomarkers and therapeutic targets in lung cancer.	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('lung cancer', 'Disease', (239, 250))	('lung cancer', 'Phenotype', 'HP:0100526', (239, 250))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('influences', 'Reg', (70, 80))	('expression', 'MPA', (48, 58))	('tumor', 'Disease', (124, 129))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('lung cancer', 'Disease', 'MESH:D008175', (239, 250))	('abnormal', 'Var', (39, 47))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('lncRNAs', 'Gene', (62, 69))	('tumor', 'Disease', (81, 86))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
80509	25365429	Frequent allelic loss at chromosomal locations 2q, 3p, 4q, 6p, 6q, 8p, 8q, 9p, 11q, 13q, 14q and 17q is observed in head and neck cancer patients.	('head and neck cancer', 'Phenotype', 'HP:0012288', (116, 136))	('neck cancer', 'Disease', 'MESH:D006258', (125, 136))	('neck cancer', 'Disease', (125, 136))	('patients', 'Species', '9606', (137, 145))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('allelic loss', 'Var', (9, 21))
80514	25365429	Because chromosomal deletions can affect more than one gene, in this study, we selected 10 different microsatellite markers based on their high incidence as reported in the literature, and we determined whether mutations in primary tumours match with those identified in recurrent tumours in the same patient.	('recurrent tumours', 'Disease', 'MESH:D009369', (271, 288))	('tumour', 'Phenotype', 'HP:0002664', (232, 238))	('tumours', 'Phenotype', 'HP:0002664', (281, 288))	('deletions', 'Var', (20, 29))	('primary tumours', 'Disease', (224, 239))	('primary tumours', 'Disease', 'MESH:D009369', (224, 239))	('affect', 'Reg', (34, 40))	('tumour', 'Phenotype', 'HP:0002664', (281, 287))	('recurrent tumours', 'Disease', (271, 288))	('patient', 'Species', '9606', (301, 308))	('tumours', 'Phenotype', 'HP:0002664', (232, 239))
80537	25365429	The LOH frequencies at D8s261, D9s171, D9s104, D13S317, D8S552, D9S162, P53, D3S1300, D3S1234 and D5S592 were 24.3%, 62.2%, 56.7%, 29.7%, 21.6%, 37.8%, 32.4%, 40.5%, 48.6% and 45.9%, respectively.	('P53', 'Gene', '7157', (72, 75))	('D9S162', 'Var', (64, 70))	('D13S317', 'Var', (47, 54))	('D5S592', 'Var', (98, 104))	('D9s171', 'Var', (31, 37))	('D9s104', 'Var', (39, 45))	('D3S1234', 'Var', (86, 93))	('D3S1300', 'Var', (77, 84))	('P53', 'Gene', (72, 75))	('D8s261', 'Var', (23, 29))	('D8S552', 'Var', (56, 62))
80547	25365429	Yoo suggested that chromosomal alterations may be involved in the carcinogenesis of laryngeal carcinomas.	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('carcinogenesis of laryngeal carcinomas', 'Disease', 'MESH:D063646', (66, 104))	('carcinogenesis of laryngeal carcinomas', 'Disease', (66, 104))	('laryngeal carcinoma', 'Phenotype', 'HP:0012118', (84, 103))	('laryngeal carcinomas', 'Phenotype', 'HP:0012118', (84, 104))	('carcinomas', 'Phenotype', 'HP:0030731', (94, 104))	('chromosomal alterations', 'Var', (19, 42))	('involved', 'Reg', (50, 58))
80548	25365429	LOH in cancer can occur either because of chromosomal deletions or somatic recombinations that result in uniparental disomy.	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('uniparental disomy', 'Disease', 'MESH:D024182', (105, 123))	('result in', 'Reg', (95, 104))	('cancer', 'Disease', (7, 13))	('cancer', 'Disease', 'MESH:D009369', (7, 13))	('chromosomal deletions', 'Var', (42, 63))	('uniparental disomy', 'Disease', (105, 123))
80550	25365429	Shiga observed that the functions of tumour suppressor genes differ among HNSCC patients living in various regions and that allelic loss plays a key role in the acquisition of a malignant phenotype in these tumours.	('tumours', 'Disease', 'MESH:D009369', (207, 214))	('tumour', 'Disease', (207, 213))	('patients', 'Species', '9606', (80, 88))	('tumour', 'Disease', (37, 43))	('tumours', 'Disease', (207, 214))	('allelic loss', 'Var', (124, 136))	('tumour', 'Disease', 'MESH:D009369', (37, 43))	('tumour', 'Phenotype', 'HP:0002664', (207, 213))	('tumours', 'Phenotype', 'HP:0002664', (207, 214))	('tumour', 'Phenotype', 'HP:0002664', (37, 43))	('functions', 'MPA', (24, 33))	('tumour', 'Disease', 'MESH:D009369', (207, 213))
80552	25365429	The high frequency of LOH that was observed in the head and neck tumours in this study suggests that the phenomenon of "field cancerization" first described by Slaughter in 1953 may partially result from the clonal proliferation of mucosal epithelial cells with allelic loss.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('neck tumours', 'Disease', 'MESH:D006258', (60, 72))	('result from', 'Reg', (192, 203))	('tumour', 'Phenotype', 'HP:0002664', (65, 71))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('tumours', 'Phenotype', 'HP:0002664', (65, 72))	('allelic loss', 'Var', (262, 274))	('neck tumours', 'Disease', (60, 72))
80553	25365429	Our study provides evidence that primary tumours and recurrent tumours in the same patient have identical patterns of allelic loss.	('primary tumours', 'Disease', (33, 48))	('primary tumours', 'Disease', 'MESH:D009369', (33, 48))	('tumour', 'Phenotype', 'HP:0002664', (41, 47))	('tumours', 'Phenotype', 'HP:0002664', (41, 48))	('tumour', 'Phenotype', 'HP:0002664', (63, 69))	('recurrent tumours', 'Disease', 'MESH:D009369', (53, 70))	('recurrent tumours', 'Disease', (53, 70))	('tumours', 'Phenotype', 'HP:0002664', (63, 70))	('allelic loss', 'Var', (118, 130))	('patient', 'Species', '9606', (83, 90))
80560	25365429	Zhao examined primary tumours and 182 neck lymph nodes from twenty patients using dissection of supraglottic cancer with immunohistochemical staining (i.e., anti-cytokeratin 19 and H&E staining).	('supraglottic cancer', 'Disease', 'MESH:D059525', (96, 115))	('tumours', 'Phenotype', 'HP:0002664', (22, 29))	('patients', 'Species', '9606', (67, 75))	('supraglottic cancer', 'Disease', (96, 115))	('H&E', 'Chemical', '-', (181, 184))	('primary tumours', 'Disease', 'MESH:D009369', (14, 29))	('primary tumours', 'Disease', (14, 29))	('tumour', 'Phenotype', 'HP:0002664', (22, 28))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('anti-cytokeratin', 'Var', (157, 173))
80564	25365429	Meanwhile, the presence of LOH in the primary tumour may also be predictive of lymph node metastasis and poor prognosis.	('tumour', 'Disease', (46, 52))	('LOH', 'Var', (27, 30))	('presence', 'Var', (15, 23))	('poor prognosis', 'CPA', (105, 119))	('tumour', 'Phenotype', 'HP:0002664', (46, 52))	('lymph node metastasis', 'CPA', (79, 100))	('tumour', 'Disease', 'MESH:D009369', (46, 52))
80567	25365429	We demonstrate herein that LOH in patients with laryngeal carcinoma is associated with a poor prognosis.	('LOH', 'Var', (27, 30))	('patients', 'Species', '9606', (34, 42))	('laryngeal carcinoma', 'Disease', (48, 67))	('laryngeal carcinoma', 'Disease', 'MESH:D007827', (48, 67))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))	('laryngeal carcinoma', 'Phenotype', 'HP:0012118', (48, 67))
80581	25365429	We speculate that some components of tobacco smoke continue to stimulate the body and promote the occurrence of LOH, and it has been demonstrated that a TP53 mutation is associated with a history of tobacco use.	('tobacco', 'Species', '4097', (37, 44))	('LOH', 'Disease', (112, 115))	('tobacco', 'Species', '4097', (199, 206))	('TP53', 'Gene', '7157', (153, 157))	('mutation', 'Var', (158, 166))	('stimulate', 'PosReg', (63, 72))	('promote', 'PosReg', (86, 93))	('TP53', 'Gene', (153, 157))	('associated', 'Reg', (170, 180))
80594	25013169	Network analysis of aberrantly methylated lincRNAs in cancers showed that lincRNAs with aberrant methylation patterns might be involved in cancer development and progression.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('cancers', 'Phenotype', 'HP:0002664', (54, 61))	('lincRNA', 'Chemical', '-', (42, 49))	('methylation patterns', 'Var', (97, 117))	('involved', 'Reg', (127, 135))	('cancers', 'Disease', (54, 61))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('cancers', 'Disease', 'MESH:D009369', (54, 61))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('cancer', 'Disease', (54, 60))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('lincRNA', 'Chemical', '-', (74, 81))	('cancer', 'Disease', (139, 145))
80595	25013169	The methylated and demethylated lincRNAs identified in this study provide novel insights for developing cancer biomarkers and potential therapeutic targets.	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('lincRNA', 'Chemical', '-', (32, 39))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('demethylated', 'Var', (19, 31))
80611	25013169	Some lincRNAs with aberrant methylation patterns in cancers might involve in cancer development and progression.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('cancers', 'Disease', (52, 59))	('cancers', 'Phenotype', 'HP:0002664', (52, 59))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('lincRNA', 'Chemical', '-', (5, 12))	('progression', 'CPA', (100, 111))	('involve', 'Reg', (66, 73))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('aberrant methylation patterns', 'Var', (19, 48))	('cancers', 'Disease', 'MESH:D009369', (52, 59))
80612	25013169	Early detection of hypermethylated or hypomethylated lincRNAs could serve as cancer biomarkers for diagnosis or treatment.	('lincRNAs', 'Gene', (53, 61))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('hypermethylated', 'Var', (19, 34))	('lincRNA', 'Chemical', '-', (53, 60))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('hypomethylated', 'Var', (38, 52))
80624	25013169	LincRNAs with methylated promoters in more than 20% of all tumor samples were defined as PM lincRNAs.	('tumor', 'Disease', (59, 64))	('methylated', 'Var', (14, 24))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('lincRNA', 'Chemical', '-', (92, 99))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
80641	25013169	Tumors were separated according to the median methylation of each lincRNA.	('methylation', 'Var', (46, 57))	('lincRNA', 'Chemical', '-', (66, 73))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))
80647	25013169	We identified lincRNAs with prognosis-associated (PA) methylation patterns in cancers with tumor sample size available for both clinical and methylation data >= 200 and a censoring (alive sample) rate <= 0.9; or the tumor sample size < 200 and a censoring rate <= 0.8 for an effective survival analysis (Supplementary Table S1).	('tumor', 'Disease', (216, 221))	('methylation', 'Var', (54, 65))	('lincRNA', 'Chemical', '-', (14, 21))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('cancers', 'Disease', 'MESH:D009369', (78, 85))	('cancers', 'Phenotype', 'HP:0002664', (78, 85))	('cancers', 'Disease', (78, 85))	('tumor', 'Disease', 'MESH:D009369', (216, 221))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('tumor', 'Disease', (91, 96))
80659	25013169	Compared with the other three regions, hypermethylation of promoters was more tightly linked to transcriptional silencing of lincRNAs (Supplementary Figure S4).	('transcriptional', 'MPA', (96, 111))	('linked', 'Reg', (86, 92))	('silencing', 'NegReg', (112, 121))	('lincRNA', 'Chemical', '-', (125, 132))	('hypermethylation', 'Var', (39, 55))	('lincRNAs', 'Gene', (125, 133))
80663	25013169	Since disrupting DNA methyltransferases may promote chromosome instability and tumor progression, cancer cells are usually less methylated at individual CpG dinucleotides than healthy cells.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('promote', 'PosReg', (44, 51))	('chromosome instability', 'CPA', (52, 74))	('tumor', 'Disease', (79, 84))	('disrupting', 'Var', (6, 16))	('less', 'NegReg', (123, 127))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('cancer', 'Disease', (98, 104))	('chromosome instability', 'Phenotype', 'HP:0040012', (52, 74))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
80665	25013169	In contrast, hypermethylation of lincRNAs might be involved in DNA repair, tumor cell invasion, cell cycle regulation and other events in which silencing might induce metastasis.	('lincRNAs', 'Gene', (33, 41))	('cell cycle', 'CPA', (96, 106))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('involved', 'Reg', (51, 59))	('metastasis', 'CPA', (167, 177))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('induce', 'Reg', (160, 166))	('lincRNA', 'Chemical', '-', (33, 40))	('silencing', 'Var', (144, 153))	('hypermethylation', 'Var', (13, 29))	('tumor', 'Disease', (75, 80))
80666	25013169	Aberrant promoter methylation was frequently observed in cancer samples and might have contributed to tumor progression by silencing tumor suppressor genes or activating oncogenes.	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('Aberrant', 'Var', (0, 8))	('contributed', 'Reg', (87, 98))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('cancer', 'Disease', (57, 63))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('activating', 'PosReg', (159, 169))	('promoter', 'MPA', (9, 17))	('tumor', 'Disease', (133, 138))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('silencing', 'NegReg', (123, 132))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('oncogenes', 'Gene', (170, 179))
80668	25013169	We obtained three representative cancer type-specific methylation patterns for 20 cancer types, and examples were shown in bladder urothelial cancer (BLCA), head and neck squamous cell cancer (HNSC) and LGG (Supplementary Figure S5).	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('cancer', 'Disease', (33, 39))	('cancer', 'Disease', (82, 88))	('neck squamous cell cancer', 'Disease', (166, 191))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('cancer', 'Disease', (185, 191))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('HNSC', 'Phenotype', 'HP:0012288', (193, 197))	('methylation', 'Var', (54, 65))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('bladder urothelial cancer', 'Disease', 'MESH:D001749', (123, 148))	('cancer', 'Disease', (142, 148))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('neck squamous cell cancer', 'Disease', 'MESH:D002294', (166, 191))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('head and neck squamous cell cancer', 'Phenotype', 'HP:0012288', (157, 191))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (171, 191))	('bladder urothelial cancer', 'Disease', (123, 148))	('LGG', 'Disease', (203, 206))
80689	25013169	RE insertion close to a lincRNA promoter or RE hypermethylation might interrupt the transcription factors or other regulatory elements binding to lincRNA promoters, which could contribute to lincRNAs tissue-specific expression.	('contribute', 'Reg', (177, 187))	('transcription', 'Protein', (84, 97))	('lincRNA', 'Chemical', '-', (24, 31))	('lincRNA', 'Chemical', '-', (146, 153))	('interrupt', 'NegReg', (70, 79))	('binding', 'Interaction', (135, 142))	('lincRNA', 'Chemical', '-', (191, 198))	('hypermethylation', 'Var', (47, 63))
80701	25013169	Since aberrant promoter methylation silences tumor suppressor genes and activates oncogenes, we analyzed the different methylation patterns of lincRNA promoters between tumors and corresponding normal tissue samples.	('activates', 'PosReg', (72, 81))	('lincRNA', 'Chemical', '-', (143, 150))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('oncogenes', 'Gene', (82, 91))	('aberrant', 'Var', (6, 14))	('tumor', 'Disease', (45, 50))	('tumors', 'Disease', 'MESH:D009369', (169, 175))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('promoter', 'MPA', (15, 23))	('tumors', 'Phenotype', 'HP:0002664', (169, 175))	('tumor', 'Disease', (169, 174))	('silences', 'NegReg', (36, 44))	('tumors', 'Disease', (169, 175))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
80704	25013169	The hypomethylated CM lincRNAs in BRCA or LUSC showed a more common methylation pattern in normal samples than in tumors.	('BRCA', 'Gene', '672', (34, 38))	('LUSC', 'Phenotype', 'HP:0030359', (42, 46))	('BRCA', 'Gene', (34, 38))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('methylation pattern', 'MPA', (68, 87))	('tumors', 'Disease', (114, 120))	('tumors', 'Disease', 'MESH:D009369', (114, 120))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('lincRNA', 'Chemical', '-', (22, 29))	('hypomethylated', 'Var', (4, 18))
80706	25013169	We identified the lincRNAs with subtype-specific methylation patterns in BRCA and LUSC (Figure 4E and F and Supplementary Table S6).	('methylation patterns', 'Var', (49, 69))	('BRCA', 'Gene', '672', (73, 77))	('BRCA', 'Gene', (73, 77))	('lincRNA', 'Chemical', '-', (18, 25))	('LUSC', 'Phenotype', 'HP:0030359', (82, 86))
80714	25013169	We combined the lincRNA methylation profiles with clinical annotations and identified a subset of lincRNAs with methylation values showing a trend associated with OS in BRCA, LUSC and UCEC.	('UCEC', 'Disease', (184, 188))	('associated', 'Reg', (147, 157))	('methylation', 'Var', (112, 123))	('lincRNA', 'Chemical', '-', (16, 23))	('BRCA', 'Gene', '672', (169, 173))	('LUSC', 'Phenotype', 'HP:0030359', (175, 179))	('BRCA', 'Gene', (169, 173))	('lincRNA', 'Chemical', '-', (98, 105))	('LUSC', 'Disease', (175, 179))
80718	25013169	For example, BRCA patients with lower methylation level of lincRNA XLOC_009284 had better prognosis (Figure 5A).	('methylation level', 'MPA', (38, 55))	('XLOC_009284', 'Var', (67, 78))	('lincRNA', 'Chemical', '-', (59, 66))	('BRCA', 'Gene', '672', (13, 17))	('patients', 'Species', '9606', (18, 26))	('BRCA', 'Gene', (13, 17))	('lower', 'NegReg', (32, 37))
80719	25013169	LUSC patients with relatively lower methylation level of lincRNA XLOC_009367 showed poorer prognosis (Figure 5B).	('lower', 'NegReg', (30, 35))	('patients', 'Species', '9606', (5, 13))	('LUSC', 'Phenotype', 'HP:0030359', (0, 4))	('XLOC_009367', 'Var', (65, 76))	('methylation level', 'MPA', (36, 53))	('lincRNA', 'Gene', (57, 64))	('lincRNA', 'Chemical', '-', (57, 64))
80720	25013169	For UCEC, patients with the highest methylation level of lincRNA XLOC_007617 had a better prognosis than patients with lower methylation level (Figure 5C).	('XLOC_007617', 'Var', (65, 76))	('patients', 'Species', '9606', (105, 113))	('methylation', 'MPA', (36, 47))	('UCEC', 'Disease', (4, 8))	('patients', 'Species', '9606', (10, 18))	('lincRNA', 'Gene', (57, 64))	('lincRNA', 'Chemical', '-', (57, 64))
80727	25013169	XLOC_007617 was a lincRNA that showed positive correlation between its methylation and drug-free survival in UCEC (log-rank P = 0.013; Supplementary Figure S8).	('methylation', 'Var', (71, 82))	('lincRNA', 'Chemical', '-', (18, 25))	('positive', 'PosReg', (38, 46))	('drug-free survival', 'CPA', (87, 105))	('XLOC_007617', 'Var', (0, 11))
80736	25013169	Using the AM lincRNAs between tumors and corresponding normal samples identified from 14 types of cancers with at least seven normal samples, we constructed an AM lincRNA-cancer network (AMCN; Supplementary Figure S10A).	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('tumors', 'Disease', (30, 36))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('lincRNA', 'Chemical', '-', (13, 20))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('S10A', 'SUBSTITUTION', 'None', (214, 218))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('cancers', 'Phenotype', 'HP:0002664', (98, 105))	('AMCN', 'Chemical', '-', (187, 191))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('cancer', 'Disease', (171, 177))	('lincRNA', 'Chemical', '-', (163, 170))	('cancers', 'Disease', 'MESH:D009369', (98, 105))	('cancers', 'Disease', (98, 105))	('cancer', 'Disease', (98, 104))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('S10A', 'Var', (214, 218))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))
80739	25013169	The AMCN illustrated that most lincRNAs were aberrantly methylated in a single cancer and a few lincRNAs were aberrantly methylated in multiple cancers (Supplementary Figure S10B).	('S10B', 'SUBSTITUTION', 'None', (174, 178))	('AMCN', 'Chemical', '-', (4, 8))	('lincRNA', 'Chemical', '-', (31, 38))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('lincRNA', 'Chemical', '-', (96, 103))	('multiple cancers', 'Disease', (135, 151))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('methylated', 'Var', (56, 66))	('cancer', 'Disease', (144, 150))	('S10B', 'Var', (174, 178))	('aberrantly methylated', 'Var', (45, 66))	('cancers', 'Phenotype', 'HP:0002664', (144, 151))	('multiple cancers', 'Disease', 'MESH:D009369', (135, 151))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
80740	25013169	A total of 196 lincRNAs were aberrantly methylated in more than one cancer out of all 434 AM lincRNAs in the AMCN.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('aberrantly methylated', 'Var', (29, 50))	('lincRNA', 'Chemical', '-', (93, 100))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('AMCN', 'Chemical', '-', (109, 113))	('cancer', 'Disease', (68, 74))	('lincRNA', 'Chemical', '-', (15, 22))
80742	25013169	The lincRNA XLOC_013592, located in chromosome 20, co-occurred with other AM lincRNAs in six types of cancer.	('XLOC_013592', 'Var', (12, 23))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('lincRNA', 'Chemical', '-', (4, 11))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('lincRNA', 'Chemical', '-', (77, 84))
80748	25013169	Furthermore, 191 AM lincRNAs showed consistent hypermethylated or hypomethylated status in diverse cancers.	('lincRNA', 'Chemical', '-', (20, 27))	('cancers', 'Disease', 'MESH:D009369', (99, 106))	('cancers', 'Phenotype', 'HP:0002664', (99, 106))	('hypermethylated', 'Var', (47, 62))	('cancers', 'Disease', (99, 106))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('hypomethylated', 'Var', (66, 80))
80754	25013169	In UCEC, XLOC_013045 and XLOC_013050 were found to be adjacent to zinc-finger protein genes (ZNF181, ZNF30, ZNF404, ZNF45).	('ZNF30', 'Gene', '90075', (101, 106))	('ZNF181', 'Gene', (93, 99))	('XLOC_013050', 'Var', (25, 36))	('ZNF30', 'Gene', (101, 106))	('ZNF404', 'Gene', '342908', (108, 114))	('ZNF45', 'Gene', '7596', (116, 121))	('ZNF404', 'Gene', (108, 114))	('ZNF181', 'Gene', '339318', (93, 99))	('ZNF45', 'Gene', (116, 121))	('XLOC_013045', 'Var', (9, 20))
80755	25013169	The expression level of XLOC_013350 was negatively correlated with its methylation level (Pearson's correlation coefficient, PCC = -0.63, P < 0.05) and positively correlated with the expression of ZNF404 (PCC = 0.26, P < 0.05).	('expression level', 'MPA', (4, 20))	('XLOC_013350', 'Var', (24, 35))	('PCC', 'Gene', '1421', (125, 128))	('PCC', 'Gene', '1421', (205, 208))	('correlated', 'Interaction', (163, 173))	('negatively', 'NegReg', (40, 50))	('ZNF404', 'Gene', '342908', (197, 203))	('PCC', 'Gene', (125, 128))	('methylation level', 'MPA', (71, 88))	('PCC', 'Gene', (205, 208))	('ZNF404', 'Gene', (197, 203))
80756	25013169	We also observed a positive correlation between the expression of XLOC_013045 and ZNF181 (PCC = 0.18, P < 0.05), indicating that these two lincRNAs may be involved in cell growth and apoptosis.	('ZNF181', 'Gene', (82, 88))	('ZNF181', 'Gene', '339318', (82, 88))	('PCC', 'Gene', '1421', (90, 93))	('XLOC_013045', 'Var', (66, 77))	('involved', 'Reg', (155, 163))	('cell growth', 'CPA', (167, 178))	('PCC', 'Gene', (90, 93))	('lincRNA', 'Chemical', '-', (139, 146))	('apoptosis', 'CPA', (183, 192))
80757	25013169	In PRAD, lincRNA XLOC_002726 was significantly hypermethylated in tumors and showed a negative correlation between its expression and methylation (PCC = -0.26, P < 0.05), which was a newly found susceptibility locus for prostate cancer in genome-wide association studies.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('expression', 'MPA', (119, 129))	('prostate cancer', 'Disease', 'MESH:D011471', (220, 235))	('XLOC_002726', 'Var', (17, 28))	('prostate cancer', 'Phenotype', 'HP:0012125', (220, 235))	('PCC', 'Gene', (147, 150))	('tumors', 'Disease', (66, 72))	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('lincRNA', 'Chemical', '-', (9, 16))	('negative', 'NegReg', (86, 94))	('prostate cancer', 'Disease', (220, 235))	('PRAD', 'Gene', (3, 7))	('methylation', 'MPA', (134, 145))	('PCC', 'Gene', '1421', (147, 150))
80760	25013169	Therefore, lincRNAs with aberrant methylation patterns in cancers might be involved in cancer development and progression.	('aberrant methylation patterns', 'Var', (25, 54))	('involved', 'Reg', (75, 83))	('cancer', 'Disease', (87, 93))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('lincRNA', 'Chemical', '-', (11, 18))	('cancers', 'Phenotype', 'HP:0002664', (58, 65))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cancers', 'Disease', (58, 65))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('cancers', 'Disease', 'MESH:D009369', (58, 65))	('cancer', 'Disease', (58, 64))	('cancer', 'Disease', 'MESH:D009369', (87, 93))
80761	25013169	Early detection of hypermethylation or hypomethylation of lincRNAs might serve as biomarkers for cancer diagnosis or treatment.	('cancer', 'Disease', (97, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('hypermethylation', 'Var', (19, 35))	('lincRNAs', 'Gene', (58, 66))	('hypomethylation', 'Var', (39, 54))	('lincRNA', 'Chemical', '-', (58, 65))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
80763	25013169	For example, DNA methylation disrupted a long non-coding RNA activity by affecting expression in a lethal lung developmental disorder.	('disrupted', 'NegReg', (29, 38))	('lung developmental disorder', 'Disease', 'MESH:D008171', (106, 133))	('expression in a lethal', 'MPA', (83, 105))	('methylation', 'Var', (17, 28))	('lung developmental disorder', 'Disease', (106, 133))	('affecting', 'Reg', (73, 82))	('DNA', 'Var', (13, 16))	('developmental disorder', 'Phenotype', 'HP:0001263', (111, 133))
80804	32228632	In recent years, neoadjuvant chemotherapy has become increasingly important in the treatment of ESCC; in particular, neoadjuvant chemotherapy decreases the tumor stage in patients with advanced preoperative tumor staging, regaining surgical opportunities and significantly prolonging progression-free survival and overall survival.	('decreases', 'NegReg', (142, 151))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('prolonging', 'NegReg', (273, 283))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('patients', 'Species', '9606', (171, 179))	('regaining', 'PosReg', (222, 231))	('surgical opportunities', 'CPA', (232, 254))	('overall survival', 'CPA', (314, 330))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('neoadjuvant chemotherapy', 'Var', (117, 141))	('ESCC', 'Disease', (96, 100))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumor', 'Disease', (156, 161))	('tumor', 'Disease', (207, 212))	('progression-free survival', 'CPA', (284, 309))
80835	32082486	Sphingomyelin phosphodiesterase 3 methylation and silencing in oral squamous cell carcinoma results in increased migration and invasion and altered stress response Neutral sphingomyelinase 2 (nSMase2), the product of the sphingomyelin phosphodiesterase 3 (SMPD3) gene, catalyzes the hydrolysis of sphingomyelin to ceramide.	('Neutral sphingomyelinase 2', 'Gene', (164, 190))	('Neutral sphingomyelinase 2', 'Gene', '55512', (164, 190))	('sphingomyelin phosphodiesterase 3', 'Gene', (221, 254))	('ceramide', 'Chemical', 'MESH:D002518', (314, 322))	('sphingomyelin phosphodiesterase 3', 'Gene', '55512', (221, 254))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (63, 91))	('sphingomyelin', 'Chemical', 'MESH:D013109', (172, 185))	('nSMase2', 'Gene', '55512', (192, 199))	('oral squamous cell carcinoma', 'Disease', (63, 91))	('Sphingomyelin phosphodiesterase 3', 'Gene', (0, 33))	('sphingomyelin', 'Chemical', 'MESH:D013109', (297, 310))	('methylation', 'Var', (34, 45))	('stress response', 'MPA', (148, 163))	('invasion', 'CPA', (127, 135))	('silencing', 'Var', (50, 59))	('sphingomyelin', 'Chemical', 'MESH:D013109', (221, 234))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (68, 91))	('altered', 'Reg', (140, 147))	('Sphingomyelin phosphodiesterase 3', 'Gene', '55512', (0, 33))	('increased', 'PosReg', (103, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('SMPD3', 'Gene', (256, 261))	('migration', 'CPA', (113, 122))	('nSMase2', 'Gene', (192, 199))
80844	32082486	We previously performed genome-wide DNA methylation and expression profiling of patient-matched normal, dysplasia, and carcinoma in situ (CIS) or OSCC samples obtained from the oral cavity (GEO Accession # GSE46802), with the sphingomyelin phosphodiesterase 3 (SMPD3) gene promoter identified as a site of frequent hypermethylation and silencing in dysplasia and CIS/OSCC samples as compared with normal controls.	('dysplasia', 'Disease', 'MESH:D015792', (349, 358))	('carcinoma in situ', 'Disease', 'MESH:D002278', (119, 136))	('CIS', 'Disease', 'MESH:D002278', (363, 366))	('CIS', 'Phenotype', 'HP:0030075', (138, 141))	('SMPD3', 'Gene', (261, 266))	('OSCC', 'Disease', 'MESH:D002294', (146, 150))	('CIS', 'Disease', (363, 366))	('silencing', 'NegReg', (336, 345))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('OSCC', 'Disease', 'MESH:D002294', (367, 371))	('patient', 'Species', '9606', (80, 87))	('sphingomyelin phosphodiesterase 3', 'Gene', (226, 259))	('CIS', 'Disease', 'MESH:D002278', (138, 141))	('dysplasia', 'Disease', (104, 113))	('sphingomyelin phosphodiesterase 3', 'Gene', '55512', (226, 259))	('dysplasia', 'Disease', (349, 358))	('carcinoma in situ', 'Disease', (119, 136))	('hypermethylation', 'Var', (315, 331))	('CIS', 'Disease', (138, 141))	('OSCC', 'Disease', (146, 150))	('CIS', 'Phenotype', 'HP:0030075', (363, 366))	('OSCC', 'Disease', (367, 371))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (119, 136))	('dysplasia', 'Disease', 'MESH:D015792', (104, 113))
80854	32082486	Overexpression of SMPD3 decreases the migration and invasion of OSCC cell lines and alters their response to stress in a context-dependent manner.	('response to stress', 'MPA', (97, 115))	('decreases', 'NegReg', (24, 33))	('OSCC', 'Disease', (64, 68))	('Overexpression', 'Var', (0, 14))	('SMPD3', 'Gene', (18, 23))	('alters', 'Reg', (84, 90))	('OSCC', 'Disease', 'MESH:D002294', (64, 68))	('migration', 'CPA', (38, 47))
80856	32082486	Of the seven CpG sites in the data set, we included only those five known to be located within the promoter CpG island of SMPD3 in our analysis (cg00891541, cg15201635, cg10556064, cg22116290, cg23758485) as hypermethylation of this genomic region has been linked to cancer progression through repression of tumor suppressor genes.	('cg23758485', 'Var', (193, 203))	('cancer', 'Disease', (267, 273))	('linked', 'Reg', (257, 263))	('cancer', 'Disease', 'MESH:D009369', (267, 273))	('cg10556064', 'Var', (169, 179))	('repression', 'NegReg', (294, 304))	('tumor', 'Disease', 'MESH:D009369', (308, 313))	('cancer', 'Phenotype', 'HP:0002664', (267, 273))	('tumor', 'Phenotype', 'HP:0002664', (308, 313))	('cg15201635', 'Var', (157, 167))	('hypermethylation', 'Var', (208, 224))	('tumor', 'Disease', (308, 313))	('cg22116290', 'Var', (181, 191))	('cg00891541', 'Var', (145, 155))
80858	32082486	A statistically significant difference in the distribution of beta-values was observed between normal vs. dysplasia (one-way ANOVA with Tukey's multiple comparisons test; F (2, 27) = 9.564, p = 0.007 and q (27) = 4.745, p = 0.007) and normal vs. CIS/OSCC (q (27) = 5.809, p = 0.001), but not dysplasia vs. tumor (q (27) = 1.064, p = 0.735), suggesting that SMPD3 hypermethylation occurs in the dysplasia stage and persists as cells progress towards cancer.	('CIS', 'Disease', (246, 249))	('tumor', 'Disease', (306, 311))	('dysplasia', 'Disease', (106, 115))	('dysplasia stage', 'Disease', (394, 409))	('SMPD3', 'Gene', (357, 362))	('dysplasia', 'Disease', 'MESH:D015792', (292, 301))	('dysplasia', 'Disease', (394, 403))	('tumor', 'Disease', 'MESH:D009369', (306, 311))	('cancer', 'Disease', 'MESH:D009369', (449, 455))	('dysplasia', 'Disease', 'MESH:D015792', (394, 403))	('hypermethylation', 'Var', (363, 379))	('OSCC', 'Disease', 'MESH:D002294', (250, 254))	('CIS', 'Phenotype', 'HP:0030075', (246, 249))	('tumor', 'Phenotype', 'HP:0002664', (306, 311))	('dysplasia', 'Disease', 'MESH:D015792', (106, 115))	('dysplasia stage', 'Disease', 'MESH:D007676', (394, 409))	('dysplasia', 'Disease', (292, 301))	('CIS', 'Disease', 'MESH:D002278', (246, 249))	('cancer', 'Disease', (449, 455))	('OSCC', 'Disease', (250, 254))	('cancer', 'Phenotype', 'HP:0002664', (449, 455))
80871	32082486	Other features, including tumor size, lymph node status, pathological stage, smoking and drinking history, and overall survival, did not correlate significantly with either expression or methylation.	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('methylation', 'Var', (187, 198))	('tumor', 'Disease', 'MESH:D009369', (26, 31))
80875	32082486	Taken together, our results suggest that promoter hypermethylation and silencing of SMPD3 are common events in oral tumorigenesis and that they occur early on in cancer progression (i.e., dysplasia).	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('occur', 'Reg', (144, 149))	('cancer', 'Disease', (162, 168))	('SMPD3', 'Gene', (84, 89))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('dysplasia', 'Disease', 'MESH:D015792', (188, 197))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('promoter hypermethylation', 'Var', (41, 66))	('silencing', 'MPA', (71, 80))	('dysplasia', 'Disease', (188, 197))	('tumor', 'Disease', (116, 121))
80890	32082486	We identified the promoter region of SMPD3 as a site of frequent hypermethylation in patient-derived oral tumors and further analyzed its function in oral dysplasia and tumor cell lines.	('patient', 'Species', '9606', (85, 92))	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('hypermethylation', 'Var', (65, 81))	('oral dysplasia', 'Disease', (150, 164))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('SMPD3', 'Gene', (37, 42))	('oral tumors', 'Disease', (101, 112))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('oral tumors', 'Disease', 'MESH:D009062', (101, 112))	('tumor', 'Disease', (169, 174))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('oral tumors', 'Phenotype', 'HP:0100649', (101, 112))	('oral dysplasia', 'Disease', 'MESH:D009062', (150, 164))	('tumor', 'Disease', (106, 111))
80891	32082486	Our results suggest that SMPD3 deregulation is a common event in the formation of oral tumors.	('oral tumors', 'Disease', 'MESH:D009062', (82, 93))	('SMPD3', 'Gene', (25, 30))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('deregulation', 'Var', (31, 43))	('oral tumors', 'Phenotype', 'HP:0100649', (82, 93))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('oral tumors', 'Disease', (82, 93))
80892	32082486	Indeed, hypermethylation of SMPD3 has been reported in various cancer types, including clear cell renal cell carcinoma and hepatocellular carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('clear cell renal cell carcinoma', 'Disease', (87, 118))	('hypermethylation', 'Var', (8, 24))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (87, 118))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (98, 118))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (123, 147))	('clear cell renal cell carcinoma', 'Disease', 'MESH:D002292', (87, 118))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (123, 147))	('reported', 'Reg', (43, 51))	('hepatocellular carcinoma', 'Disease', (123, 147))	('cancer', 'Disease', (63, 69))	('SMPD3', 'Gene', (28, 33))
80893	32082486	In agreement, our analysis of unpaired normal and tumor data from TCGA shows that hypermethylation of SMPD3 occurs in bladder urothelial carcinoma, breast invasive carcinoma, colon adenocarcinoma, head and neck squamous cell carcinoma, liver hepatocellular carcinoma, kidney renal papillary cell carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, thyroid carcinoma, and uterine endometrial carcinoma, but not prostate cancer (Supplementary Figure 2).	('kidney renal papillary cell carcinoma', 'Disease', (268, 305))	('lung adenocarcinoma', 'Disease', (307, 326))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (242, 266))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (389, 410))	('SMPD3', 'Gene', (102, 107))	('Supplementary Figure 2', 'Disease', 'MESH:D017034', (437, 459))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (333, 356))	('colon adenocarcinoma', 'Disease', (175, 195))	('cancer', 'Phenotype', 'HP:0002664', (429, 435))	('neck squamous cell carcinoma', 'Disease', 'MESH:C535575', (206, 234))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (328, 356))	('lung squamous cell carcinoma', 'Disease', (328, 356))	('neck squamous cell carcinoma', 'Disease', (206, 234))	('bladder urothelial carcinoma', 'Disease', (118, 146))	('Supplementary Figure 2', 'Disease', (437, 459))	('breast invasive carcinoma', 'Disease', (148, 173))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (358, 375))	('colon adenocarcinoma', 'Disease', 'MESH:D015179', (175, 195))	('liver hepatocellular carcinoma', 'Disease', 'MESH:D006528', (236, 266))	('tumor', 'Disease', (50, 55))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (307, 326))	('breast invasive carcinoma', 'Disease', 'MESH:D001943', (148, 173))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (118, 146))	('kidney renal papillary cell carcinoma', 'Disease', 'MESH:D002292', (268, 305))	('thyroid carcinoma', 'Disease', (358, 375))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (211, 234))	('renal papillary cell carcinoma', 'Phenotype', 'HP:0006766', (275, 305))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('endometrial carcinoma', 'Disease', (389, 410))	('prostate cancer', 'Disease', 'MESH:D011471', (420, 435))	('carcinoma', 'Phenotype', 'HP:0030731', (164, 173))	('occurs', 'Reg', (108, 114))	('prostate cancer', 'Phenotype', 'HP:0012125', (420, 435))	('prostate cancer', 'Disease', (420, 435))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (358, 375))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (197, 234))	('carcinoma', 'Phenotype', 'HP:0030731', (225, 234))	('carcinoma', 'Phenotype', 'HP:0030731', (186, 195))	('breast invasive carcinoma', 'Phenotype', 'HP:0003002', (148, 173))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('liver hepatocellular carcinoma', 'Disease', (236, 266))	('hypermethylation', 'Var', (82, 98))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (307, 326))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (328, 356))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (389, 410))	('carcinoma', 'Phenotype', 'HP:0030731', (257, 266))
80896	32082486	Although mutations in SMPD3 affect ~5% of acute myeloid leukemia and acute lymphocytic leukemia patients, mutations were found in only 1/279 (0.4%) tumors in the TCGA head and neck cancer dataset, with copy number variations present in only 3/279 (1%).	('mutations', 'Var', (9, 18))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (42, 64))	('leukemia', 'Phenotype', 'HP:0001909', (87, 95))	('head and neck cancer', 'Disease', 'MESH:D006258', (167, 187))	('acute lymphocytic leukemia', 'Phenotype', 'HP:0006721', (69, 95))	('leukemia', 'Phenotype', 'HP:0001909', (56, 64))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (48, 64))	('affect', 'Reg', (28, 34))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('SMPD3', 'Gene', (22, 27))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('acute myeloid leukemia', 'Disease', (42, 64))	('tumors', 'Disease', (148, 154))	('acute lymphocytic leukemia', 'Disease', (69, 95))	('patients', 'Species', '9606', (96, 104))	('head and neck cancer', 'Phenotype', 'HP:0012288', (167, 187))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('tumors', 'Disease', 'MESH:D009369', (148, 154))	('acute lymphocytic leukemia', 'Disease', 'MESH:D054198', (69, 95))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (42, 64))
80897	32082486	Thus, it appears as though hypermethylation is the primary mechanism underlying SMPD3 deregulation in OSCC and possibly other cancer types.	('OSCC', 'Disease', 'MESH:D002294', (102, 106))	('hypermethylation', 'Var', (27, 43))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('SMPD3', 'Gene', (80, 85))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('OSCC', 'Disease', (102, 106))	('deregulation', 'NegReg', (86, 98))
80899	32082486	In addition, we found that SMPD3 methylation correlates with tumor grade and lymphovascular invasion.	('methylation', 'Var', (33, 44))	('lymphovascular invasion', 'CPA', (77, 100))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('correlates', 'Reg', (45, 55))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('SMPD3', 'Gene', (27, 32))	('tumor', 'Disease', (61, 66))
80916	32082486	Second, even if nSMase2 activity is significantly increased by SMPD3 overexpression, the outcome can be modified by the expression of ceramide metabolizing enzymes, which can prevent ceramide accumulation, by the subcellular localization of ceramide production, and by the expression of other effectors, such as pro- and anti-apoptotic proteins.	('modified', 'Reg', (104, 112))	('activity', 'MPA', (24, 32))	('nSMase2', 'Gene', '55512', (16, 23))	('ceramide accumulation', 'MPA', (183, 204))	('ceramide', 'Chemical', 'MESH:D002518', (241, 249))	('nSMase2', 'Gene', (16, 23))	('increased', 'PosReg', (50, 59))	('overexpression', 'Var', (69, 83))	('prevent', 'NegReg', (175, 182))	('ceramide', 'Chemical', 'MESH:D002518', (183, 191))	('SMPD3', 'Gene', (63, 68))	('ceramide', 'Chemical', 'MESH:D002518', (134, 142))
80919	32082486	Erlotinib has been shown to increase oxidative stress in OSCC cell lines, suggesting a similar mechanism may be at play in the cell lines used here.	('oxidative stress', 'Phenotype', 'HP:0025464', (37, 53))	('Erlotinib', 'Var', (0, 9))	('oxidative stress', 'MPA', (37, 53))	('OSCC', 'Disease', (57, 61))	('OSCC', 'Disease', 'MESH:D002294', (57, 61))	('increase oxidative stress', 'Phenotype', 'HP:0025464', (28, 53))	('Erlotinib', 'Chemical', 'MESH:D000069347', (0, 9))	('increase', 'PosReg', (28, 36))
80921	32082486	In summary, we have identified the promoter region of SMPD3 as a common site of hypermethylation and downregulation in oral tumors and in oral dysplasia and cancer cell lines.	('downregulation', 'NegReg', (101, 115))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('oral tumors', 'Phenotype', 'HP:0100649', (119, 130))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('oral dysplasia', 'Disease', 'MESH:D009062', (138, 152))	('hypermethylation', 'Var', (80, 96))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('SMPD3', 'Gene', (54, 59))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('cancer', 'Disease', (157, 163))	('oral dysplasia', 'Disease', (138, 152))	('oral tumors', 'Disease', (119, 130))	('oral tumors', 'Disease', 'MESH:D009062', (119, 130))
80953	31167516	On the other hand, Fusobacterium nucleatum (F. nucleatum), one of the major periodontal pathogens, has emerged as an important factor in the colon cancer progression.	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('colon cancer', 'Disease', (141, 153))	('Fusobacterium nucleatum', 'Species', '851', (19, 42))	('colon cancer', 'Disease', 'MESH:D015179', (141, 153))	('Fusobacterium', 'Var', (19, 32))	('colon cancer', 'Phenotype', 'HP:0003003', (141, 153))	('F. nucleatum', 'Species', '851', (44, 56))
80982	31167516	The serum levels of P. gingivalis IgG were significantly higher in OSCC patients than in healthy controls (p < 0.001, multivariate analysis).	('higher', 'PosReg', (57, 63))	('P. gingivalis', 'Species', '837', (20, 33))	('P. gingivalis', 'Var', (20, 33))	('OSCC', 'Disease', (67, 71))	('serum levels', 'MPA', (4, 16))	('patients', 'Species', '9606', (72, 80))
80987	31167516	As shown in Figure 2a, the AUCs (areas under the ROC curves) were 0.708 for P. gingivalis IgG, 0.543 for F. nucleatum IgG, and 0.613 for serum IL-6, with optimal cutoff values of 1.732, 1.492, and 175.863, respectively.	('IL-6', 'Gene', (143, 147))	('IL-6', 'Gene', '3569', (143, 147))	('0.543', 'Var', (95, 100))	('P. gingivalis', 'Species', '837', (76, 89))	('0.613', 'Var', (127, 132))	('F. nucleatum', 'Species', '851', (105, 117))
80988	31167516	When the cutoff values were applied, the specificity for P. gingivalis IgG was higher (84.4%) than that for serum IL-6 (71.1%), but the sensitivity was slightly lower (53.2% vs 59.7%).	('IL-6', 'Gene', (114, 118))	('IL-6', 'Gene', '3569', (114, 118))	('specificity', 'MPA', (41, 52))	('higher', 'PosReg', (79, 85))	('P. gingivalis', 'Species', '837', (57, 70))	('P. gingivalis', 'Var', (57, 70))
81000	31167516	Our study shows that high serum levels of the inflammatory cytokine IL-6 and P. gingivalis IgG are strongly correlated with OSCC.	('correlated', 'Reg', (108, 118))	('P. gingivalis', 'Species', '837', (77, 90))	('IL-6', 'Gene', (68, 72))	('serum levels of', 'MPA', (26, 41))	('IL-6', 'Gene', '3569', (68, 72))	('OSCC', 'Disease', (124, 128))	('P. gingivalis', 'Var', (77, 90))
81004	31167516	Our previous studies demonstrated that P. gingivalis contributes to the increased aggressiveness of oral cancer by promoting epithelial-mesenchymal transition (EMT) and accelerates the invasion of cells by activating IL-8/MMPs.	('increased', 'PosReg', (72, 81))	('invasion of cells', 'CPA', (185, 202))	('aggressiveness of oral cancer', 'Disease', (82, 111))	('promoting', 'PosReg', (115, 124))	('activating', 'PosReg', (206, 216))	('aggressiveness of oral cancer', 'Disease', 'MESH:D009062', (82, 111))	('IL-8', 'Gene', '3576', (217, 221))	('aggressiveness', 'Phenotype', 'HP:0000718', (82, 96))	('epithelial-mesenchymal transition', 'CPA', (125, 158))	('IL-8', 'Gene', (217, 221))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('accelerates', 'PosReg', (169, 180))	('P. gingivalis', 'Species', '837', (39, 52))	('P. gingivalis', 'Var', (39, 52))
81005	31167516	also reported that P. gingivalis promotes the invasion of OSCC cells by activating the ERK1/2-Ets1, p38/HSP27, and PAR2/NF-kappaB pathways and by inducing pro-MMP9 expression.	('P. gingivalis', 'Species', '837', (19, 32))	('promotes', 'PosReg', (33, 41))	('p38/HSP27', 'Pathway', (100, 109))	('ERK1/2-Ets1', 'Pathway', (87, 98))	('inducing', 'PosReg', (146, 154))	('invasion of OSCC cells', 'CPA', (46, 68))	('expression', 'MPA', (164, 174))	('PAR2/NF-kappaB pathways', 'Pathway', (115, 138))	('activating', 'PosReg', (72, 82))	('P. gingivalis', 'Var', (19, 32))	('pro-MMP9', 'Protein', (155, 163))
81009	31167516	In a cohort study of pancreatic cancer, high levels of antibodies to P. gingivalis were correlated with the risk of pancreatic cancer.	('correlated with', 'Reg', (88, 103))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('P. gingivalis', 'Gene', (69, 82))	('pancreatic cancer', 'Disease', (21, 38))	('pancreatic cancer', 'Disease', 'MESH:D010190', (21, 38))	('P. gingivalis', 'Species', '837', (69, 82))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (116, 133))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('antibodies', 'Var', (55, 65))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (21, 38))	('pancreatic cancer', 'Disease', (116, 133))	('pancreatic cancer', 'Disease', 'MESH:D010190', (116, 133))
81011	31167516	This study is the first to report on the diagnostic value of P. gingivalis IgG in OSCC, and the diagnostic performance of a single IgG for OSCC in the present study was superior to that of IgG or IgA for ESCC and achieved a sensitivity of 53.2% and a specificity of 84.4%.	('OSCC', 'Disease', (82, 86))	('P. gingivalis', 'Var', (61, 74))	('P. gingivalis', 'Species', '837', (61, 74))
81016	31167516	In addition, the study that observed higher mortality for patients with orodigestive cancers with high serum P. gingivalis IgG was mostly limited to colorectal and pancreatic cancers, and only 4 cases of lip, oral, and pharyngeal cancer deaths were included in the analysis.	('cancers', 'Disease', 'MESH:D009369', (85, 92))	('colorectal and pancreatic cancers', 'Disease', 'MESH:D010190', (149, 182))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (164, 182))	('higher', 'PosReg', (37, 43))	('cancers', 'Phenotype', 'HP:0002664', (175, 182))	('cancers', 'Disease', (175, 182))	('lip', 'Disease', (204, 207))	('pharyngeal cancer', 'Phenotype', 'HP:0100638', (219, 236))	('P. gingivalis', 'Species', '837', (109, 122))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('cancers', 'Phenotype', 'HP:0002664', (85, 92))	('cancers', 'Disease', (85, 92))	('patients', 'Species', '9606', (58, 66))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('high serum P. gingivalis', 'Var', (98, 122))	('cancer deaths', 'Disease', (230, 243))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (164, 181))	('cancers', 'Disease', 'MESH:D009369', (175, 182))	('lip', 'Disease', 'MESH:D002971', (204, 207))	('cancer deaths', 'Disease', 'MESH:D003643', (230, 243))
81036	31167516	In addition, P. gingivalis IgG showed a low false negative rate and a high false positive rate, while IL-6 exhibited an inverse tendency.	('IL-6', 'Gene', (102, 106))	('P. gingivalis', 'Species', '837', (13, 26))	('IL-6', 'Gene', '3569', (102, 106))	('P. gingivalis', 'Var', (13, 26))
81066	26575422	We recently described that anchoring biotinylated Cetuximab (bCet) on the surface of AvidinOX-conjugated lung cancer cells, leads to an increase of in vitro anti-tumor activity that translates into in vivo anti-tumor efficacy of very low doses of nebulized bCet, when administered after nebulized AvidinOX.	('biotin', 'Chemical', 'MESH:D001710', (37, 43))	('lung cancer', 'Phenotype', 'HP:0100526', (105, 116))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('bCet', 'Chemical', '-', (61, 65))	('Cetuximab', 'Chemical', 'MESH:D000068818', (50, 59))	('tumor', 'Disease', (162, 167))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('lung cancer', 'Disease', 'MESH:D008175', (105, 116))	('AvidinOX', 'Chemical', '-', (297, 305))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('tumor', 'Disease', (211, 216))	('increase', 'PosReg', (136, 144))	('AvidinOX', 'Chemical', '-', (85, 93))	('anchoring', 'Var', (27, 36))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('lung cancer', 'Disease', (105, 116))	('bCet', 'Chemical', '-', (257, 261))
81073	26575422	The highest peak of the non-biotinylated Cetuximab exhibited an estimated mass of 152653 Da while the highest peak of bCet exhibited an estimated mass of 154607 Da with a mass difference of 1954 Da.	('Cetuximab', 'Chemical', 'MESH:D000068818', (41, 50))	('non-biotinylated', 'Var', (24, 40))	('biotin', 'Chemical', 'MESH:D001710', (28, 34))	('bCet', 'Chemical', '-', (118, 122))	('Cetuximab', 'Gene', (41, 50))
81075	26575422	Mass spectrometry analysis also identified preferential biotinylation sites on lysine 49, 126, 145, 188, 190 and 207 and lysine 5, 43, 75, 224, 248, 290, 319, 322, 328, 336, 362 and 416 in light and heavy antibody chains, respectively.	('lysine', 'Chemical', 'MESH:D008239', (79, 85))	('lysine', 'Chemical', 'MESH:D008239', (121, 127))	('lysine 5', 'Var', (121, 129))	('biotinylation', 'MPA', (56, 69))	('biotin', 'Chemical', 'MESH:D001710', (56, 62))	('lysine 49', 'Var', (79, 88))
81131	26575422	In the base case, addition of Cetuximab to platinum-based chemotherapy led to an increase in cost of $36,000 per person, resulting in an incremental cost effectiveness ratio (ICER) of $386,000 per quality-adjusted life-year (QALY) gained and concluding that Cetuximab could only be economically attractive if the cost of Cetuximab is substantially reduced or if future research can identify predictive markers to select patients most likely to benefit from the addition of Cetuximab to chemotherapy.	('Cetuximab', 'Chemical', 'MESH:D000068818', (258, 267))	('Cetuximab', 'Var', (30, 39))	('person', 'Species', '9606', (113, 119))	('patients', 'Species', '9606', (420, 428))	('addition', 'Var', (18, 26))	('platinum', 'Chemical', 'MESH:D010984', (43, 51))	('Cetuximab', 'Chemical', 'MESH:D000068818', (473, 482))	('Cetuximab', 'Chemical', 'MESH:D000068818', (321, 330))	('Cetuximab', 'Chemical', 'MESH:D000068818', (30, 39))	('increase', 'PosReg', (81, 89))
81191	26575422	Membranes were blocked 3 hours at room temperature with 5% non-fat dry milk in PBS, 0.05% Tween-20 (PBS-T) before overnight incubation, at 4 C, with one of the following primary antibodies: pEGFR (Tyr1068) (#2236), EGFR (#4267), pAKT (#4058), AKT (#9272) and pERK 1/2 (#9101) from Cell Signaling; pEGFR (Tyr1101) (#ab76195) from abcam.	('Cell Signaling', 'MPA', (281, 295))	('#4058', 'Var', (235, 240))	('AKT', 'Gene', (230, 233))	('AKT', 'Gene', '207', (243, 246))	('EGFR', 'Gene', '1956', (191, 195))	('EGFR', 'Gene', (191, 195))	('#9101', 'Var', (269, 274))	('EGFR', 'Gene', '1956', (215, 219))	('Tween-20', 'Chemical', 'MESH:D011136', (90, 98))	('EGFR', 'Gene', (215, 219))	('PBS', 'Chemical', 'MESH:D007854', (100, 103))	('PBS', 'Chemical', 'MESH:D007854', (79, 82))	('EGFR', 'Gene', '1956', (298, 302))	('#9272', 'Var', (248, 253))	('AKT', 'Gene', '207', (230, 233))	('AKT', 'Gene', (243, 246))	('EGFR', 'Gene', (298, 302))
81192	26575422	Immunoblotting with anti-alpha-tubulin (#T5168, Sigma Aldrich) or anti-HDAC2 (#2540, Cell Signaling) antibodies was done to confirm equal protein loading for non-nuclear/whole cell lysate and nuclear protein extracts, respectively.	('#2540', 'Var', (78, 83))	('#T5168', 'Var', (40, 46))	('HDAC2', 'Gene', (71, 76))	('HDAC2', 'Gene', '3066', (71, 76))
81195	26575422	After washing, cells were cultivated 18 hours in serum-free medium, with EGF induction the last 30 minutes (100 ng/mL).	('EGF', 'Gene', (73, 76))	('EGF', 'Gene', '1950', (73, 76))	('100 ng/mL', 'Var', (108, 117))
81204	26575422	Cleaved-caspase-3 and P21Cip1 were detected by using specific rabbit polyclonal antibodies (#9661, Cell Signaling and sc-397, Santa Cruz, respectively) and PE-conjugated goat anti-rabbit Ig as secondary antibody (#554020, BD).	('goat', 'Species', '9925', (170, 174))	('rabbit', 'Species', '9986', (180, 186))	('caspase-3', 'Gene', (8, 17))	('#554020', 'Var', (213, 220))	('rabbit', 'Species', '9986', (62, 68))	('#9661', 'Var', (92, 97))	('caspase-3', 'Gene', '836', (8, 17))	('P21Cip1', 'Gene', (22, 29))	('P21Cip1', 'Gene', '1026', (22, 29))
81244	24817012	A previous study has reported that low ERCC1 expression is associated with genomic instability and higher risk of cancer.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('associated', 'Reg', (59, 69))	('genomic instability', 'CPA', (75, 94))	('expression', 'MPA', (45, 55))	('ERCC1', 'Gene', (39, 44))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('low', 'Var', (35, 38))	('cancer', 'Disease', (114, 120))
81245	24817012	Increased genetic instability was related with increased recurrence risk and worse long-term outcome of head and neck squamous cell carcinoma (HNSCC).	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (118, 141))	('genetic instability', 'Var', (10, 29))	('neck squamous cell carcinoma', 'Disease', (113, 141))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (104, 141))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (113, 141))
81246	24817012	In fact, chemotherapeutic agents such as cisplatin, cis-dichloro-diamine-platinum (CDDP) also induce ICLs, and apparently, high immunohistochemical detection of ERCC1 might be associated with CDDP resistance.	('ERCC1', 'Gene', (161, 166))	('ICLs', 'Disease', (101, 105))	('cisplatin', 'Chemical', 'MESH:D002945', (41, 50))	('CDDP', 'Chemical', 'MESH:D002945', (83, 87))	('high', 'Var', (123, 127))	('associated', 'Reg', (176, 186))	('cis-dichloro-diamine-platinum', 'Chemical', 'MESH:D002945', (52, 81))	('induce', 'Reg', (94, 100))	('cisplatin', 'Var', (41, 50))	('CDDP', 'Chemical', 'MESH:D002945', (192, 196))	('cis-dichloro-diamine-platinum', 'Var', (52, 81))
81248	24817012	In accordance, patients with low ERCC1 expression are more likely to benefit from CDDP induction chemotherapy than patients with high ERCC1 expression.	('patients', 'Species', '9606', (115, 123))	('patients', 'Species', '9606', (15, 23))	('low', 'Var', (29, 32))	('CDDP', 'Disease', (82, 86))	('ERCC1', 'Gene', (33, 38))	('expression', 'MPA', (39, 49))	('benefit', 'Reg', (69, 76))	('CDDP', 'Chemical', 'MESH:D002945', (82, 86))
81251	24817012	recently reported that high ERCC1 expression seems to be associated with better overall survival rates in HNSCC patients submitted to adjuvant cisplatin-based chemoradiation.	('cisplatin', 'Chemical', 'MESH:D002945', (143, 152))	('expression', 'MPA', (34, 44))	('high', 'Var', (23, 27))	('overall survival', 'MPA', (80, 96))	('ERCC1', 'Gene', (28, 33))	('patients', 'Species', '9606', (112, 120))	('HNSCC', 'Disease', (106, 111))	('better', 'PosReg', (73, 79))
81252	24817012	Confirming these data, studies done in two other tobacco-related cancers, namely nonsmall cell lung cancer and pancreatic adenocarcinoma, treated by surgery alone, suggest that ERCC1 positivity may implicate a favorable prognosis.	('namely nonsmall cell lung cancer', 'Phenotype', 'HP:0030358', (74, 106))	('lung cancer', 'Phenotype', 'HP:0100526', (95, 106))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('tobacco', 'Species', '4097', (49, 56))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D010190', (111, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('positivity', 'Var', (183, 193))	('pancreatic adenocarcinoma', 'Disease', (111, 136))	('nonsmall cell lung cancer', 'Disease', (81, 106))	('cancers', 'Disease', 'MESH:D009369', (65, 72))	('ERCC1', 'Gene', (177, 182))	('nonsmall cell lung cancer', 'Disease', 'MESH:D002289', (81, 106))	('cancers', 'Phenotype', 'HP:0002664', (65, 72))	('cancers', 'Disease', (65, 72))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (111, 136))
81302	24817012	In a random sample of 18 tumor specimens, we compared the immunohistochemical reaction products to 8 F1 (ERCC1), FL-297 (ERCC1), and to the XPF antibody SPM228, the partner of ERCC1 in dimer formation.	('XPF', 'Gene', '2072', (140, 143))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumor', 'Disease', (25, 30))	('XPF', 'Gene', (140, 143))	('FL', 'Chemical', '-', (113, 115))	('FL-297', 'Var', (113, 119))	('tumor', 'Disease', 'MESH:D009369', (25, 30))
81340	24817012	These data indicate that ERCC1 is most represented in the radiosensitive G2/M phase, and CDDP, but not MMC, induces additional ERCC1 expression during treatment.	('CDDP', 'Chemical', 'MESH:D002945', (89, 93))	('expression', 'MPA', (133, 143))	('G2/M phase', 'Gene', '7916', (73, 83))	('ERCC1', 'Gene', (127, 132))	('CDDP', 'Var', (89, 93))	('MMC', 'Chemical', 'MESH:D016685', (103, 106))	('G2/M phase', 'Gene', (73, 83))
81341	24817012	suggested a novel mechanism of genetic instability in the tumor microenvironment mediated by hypoxia-induced suppression of the homologous recombination pathway in cancer cells.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('cancer', 'Disease', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('suppression', 'NegReg', (109, 120))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('hypoxia', 'Disease', 'MESH:D000860', (93, 100))	('homologous recombination pathway', 'Pathway', (128, 160))	('genetic instability', 'Var', (31, 50))	('hypoxia', 'Disease', (93, 100))
81350	24817012	Therefore, the positive clinical effect of high ERCC1 expression in HNSCC patients treated with primary combined radiochemotherapy was unlikely to be related to the chemotherapeutic part.	('expression', 'MPA', (54, 64))	('high', 'Var', (43, 47))	('ERCC1', 'Gene', (48, 53))	('patients', 'Species', '9606', (74, 82))	('HNSCC', 'Disease', (68, 73))
81359	24817012	Both CDDP and MMC treatment at IC-50 resulted in shifting cells from the less radiosensitive G1 phase to highly radiosensitive G2/M phase, and 20-33 % of cells were detected with fragmented DNA (sub-G1 phase) indicating apoptosis.	('IC-50', 'Var', (31, 36))	('CDDP', 'Chemical', 'MESH:D002945', (5, 9))	('G2/M phase', 'Gene', (127, 137))	('G2/M phase', 'Gene', '7916', (127, 137))	('MMC', 'Chemical', 'MESH:D016685', (14, 17))
81373	24817012	have recently published that patients with oropharyngeal HNSCC and high ERCC1 expression were more likely to survive and remain disease-free when compared to nonoropharyngeal squamous cell carcinoma patients with high ERCC1 expression despite treatment modality and human papillomavirus virus (HPV) status.	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (175, 198))	('papillomavirus virus', 'Disease', (272, 292))	('patients', 'Species', '9606', (29, 37))	('high', 'Var', (67, 71))	('squamous cell carcinoma', 'Disease', (175, 198))	('survive', 'CPA', (109, 116))	('HPV', 'Disease', (294, 297))	('ERCC1', 'Gene', (72, 77))	('patients', 'Species', '9606', (199, 207))	('papillomavirus virus', 'Disease', 'MESH:D030361', (272, 292))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (175, 198))	('HPV', 'Disease', 'MESH:D030361', (294, 297))	('pharyngeal squamous cell carcinoma', 'Phenotype', 'HP:0012182', (164, 198))	('carcinoma', 'Phenotype', 'HP:0030731', (189, 198))	('human', 'Species', '9606', (266, 271))
81376	33864445	Comprehensive analysis of ferritin subunits expression and positive correlations with tumor-associated macrophages and T regulatory cells infiltration in most solid tumors Ferritin is the most important iron storage form and is known to influence tumor immunity.	('tumor', 'Phenotype', 'HP:0002664', (247, 252))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('Ferritin', 'Var', (172, 180))	('iron', 'Chemical', 'MESH:D007501', (203, 207))	('tumor', 'Disease', (247, 252))	('tumor', 'Disease', (86, 91))	('tumors', 'Disease', (165, 171))	('tumors', 'Disease', 'MESH:D009369', (165, 171))	('tumors', 'Phenotype', 'HP:0002664', (165, 171))	('influence', 'Reg', (237, 246))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('tumor', 'Disease', 'MESH:D009369', (247, 252))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('tumor', 'Disease', (165, 170))
81402	33864445	The results suggested that high FTL (Figure 2B, 2C) or high FTH1 (Figure 2E-2J) mRNA levels were each related to poor OS in several cancer types.	('cancer', 'Disease', (132, 138))	('FTH1', 'Gene', (60, 64))	('mRNA levels', 'MPA', (80, 91))	('FTL', 'Gene', (32, 35))	('related', 'Reg', (102, 109))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('FTH1', 'Gene', '2495', (60, 64))	('high', 'Var', (55, 59))	('FTL', 'Gene', '2512', (32, 35))	('poor OS', 'Disease', (113, 120))	('cancer', 'Disease', 'MESH:D009369', (132, 138))
81405	33864445	FTL expression was significantly associated with PFI in four cancer types (Figure 3A): LGG (HR 1.5, 95% CI 1.26-1.78, P = 3.8 x 10-6), KIRC (HR 1.31, 95% CI 1.06-1.62, P = 1.4 x 10-2), UCEC (HR 1.21, 95% CI 1.00-1.46, P = 4.4 x 10-2), and GBM (HR 1.26, 95% CI 1.02-1.57, P = 3.3 x 10-2).	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('FTL', 'Gene', '2512', (0, 3))	('PFI', 'Disease', (49, 52))	('cancer', 'Disease', (61, 67))	('LGG', 'Disease', (87, 90))	('associated', 'Reg', (33, 43))	('expression', 'Var', (4, 14))	('UCEC', 'Disease', (185, 189))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('GBM', 'Disease', (239, 242))	('FTL', 'Gene', (0, 3))	('KIRC', 'Disease', (135, 139))
81407	33864445	As was observed for OS, poor PFI was significantly associated with high FTL (Figure 3B, 3C) or high FTH1 (Figure 3E-3J) mRNA levels in some cancers.	('FTH1', 'Gene', '2495', (100, 104))	('FTL', 'Gene', (72, 75))	('high', 'Var', (95, 99))	('cancers', 'Phenotype', 'HP:0002664', (140, 147))	('FTH1', 'Gene', (100, 104))	('FTL', 'Gene', '2512', (72, 75))	('cancers', 'Disease', (140, 147))	('cancers', 'Disease', 'MESH:D009369', (140, 147))	('mRNA levels', 'MPA', (120, 131))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('PFI', 'MPA', (29, 32))
81428	33864445	Iron is an essential element in supporting cell proliferation and often accumulates in cancer cells; however, excessive levels of Fe2+ can promote the Fenton reaction, production of reactive oxygen species, and cell death through apoptosis and ferroptosis.	('cancer', 'Disease', (87, 93))	('cell death', 'CPA', (211, 221))	('promote', 'PosReg', (139, 146))	('ferroptosis', 'CPA', (244, 255))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('apoptosis', 'CPA', (230, 239))	('Fe2+', 'Var', (130, 134))	('Fe2+', 'Chemical', '-', (130, 134))	('production of reactive oxygen species', 'MPA', (168, 205))	('Fenton reaction', 'MPA', (151, 166))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('Iron', 'Chemical', 'MESH:D007501', (0, 4))	('oxygen', 'Chemical', 'MESH:D010100', (191, 197))
81438	33864445	We found that high FTH1 expression is positively related to poor prognosis in 11 cancers, including HNSC, which is consistent with our previous study.	('HNSC', 'Disease', (100, 104))	('FTH1', 'Gene', (19, 23))	('expression', 'MPA', (24, 34))	('cancers', 'Phenotype', 'HP:0002664', (81, 88))	('cancers', 'Disease', (81, 88))	('FTH1', 'Gene', '2495', (19, 23))	('cancers', 'Disease', 'MESH:D009369', (81, 88))	('high', 'Var', (14, 18))	('HNSC', 'Phenotype', 'HP:0012288', (100, 104))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))
81443	33864445	showed that FTH1 is critical for proper functioning of the antioxidant system in ovarian cancer cells, suggesting that inhibition of FTH1 may improve cisplatin-induced cytotoxicity.	('FTH1', 'Gene', (12, 16))	('cytotoxicity', 'Disease', 'MESH:D064420', (168, 180))	('ovarian cancer', 'Phenotype', 'HP:0100615', (81, 95))	('ovarian cancer', 'Disease', 'MESH:D010051', (81, 95))	('FTH1', 'Gene', (133, 137))	('inhibition', 'Var', (119, 129))	('ovarian cancer', 'Disease', (81, 95))	('FTH1', 'Gene', '2495', (12, 16))	('FTH1', 'Gene', '2495', (133, 137))	('cytotoxicity', 'Disease', (168, 180))	('cisplatin-induced', 'MPA', (150, 167))	('improve', 'PosReg', (142, 149))	('cisplatin', 'Chemical', 'MESH:D002945', (150, 159))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
81464	33864445	However, whether FTL or FTH1 inhibition can induce M2-to-M1 repolarization will need to be investigated in future studies.	('FTH1', 'Gene', '2495', (24, 28))	('FTL', 'Gene', '2512', (17, 20))	('FTH1', 'Gene', (24, 28))	('FTL', 'Gene', (17, 20))	('M2-to-M1 repolarization', 'MPA', (51, 74))	('inhibition', 'Var', (29, 39))
81495	32377703	Methylation changes in certain tumor-associated genes have been identified in previous studies examining tumorigenesis, suggesting that they are critical risk factors of tumorigenesis and molecular markers for early diagnosis.	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('tumor', 'Disease', (31, 36))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('tumor', 'Disease', (170, 175))	('Methylation changes', 'Var', (0, 19))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumor', 'Disease', (105, 110))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
81496	32377703	Promoter methylation of PR/SET domain 5 is significantly associated with lymph node metastasis and tumor differentiation status of LSCC; therefore, this gene is a candidate target for the diagnosis, prognosis and treatment of this cancer.	('tumor', 'Disease', (99, 104))	('cancer', 'Disease', 'MESH:D009369', (231, 237))	('cancer', 'Disease', (231, 237))	('Promoter methylation', 'Var', (0, 20))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('lymph node metastasis', 'CPA', (73, 94))	('LSCC', 'Disease', (131, 135))	('associated', 'Reg', (57, 67))
81498	32377703	Tripartite motif-containing 58/cg26157385 methylation is associated with expression of 8 prognosis-associated genes in LSCC, indicating its potential regulatory role in the progression of LSCC.	('cg26157385', 'Chemical', '-', (31, 41))	('LSCC', 'Disease', (119, 123))	('Tripartite motif-containing 58', 'Gene', '25893', (0, 30))	('expression', 'MPA', (73, 83))	('methylation', 'Var', (42, 53))	('associated', 'Reg', (57, 67))	('Tripartite motif-containing 58', 'Gene', (0, 30))
81500	32377703	In addition, increasing numbers of lncRNAs with a prognostic value have been described, for example, urothelial cancer associated and long intergenic non-coding RNA-p21.	('p21', 'Gene', (165, 168))	('p21', 'Gene', '644914', (165, 168))	('long intergenic non-coding', 'Var', (134, 160))	('urothelial cancer', 'Disease', (101, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('urothelial cancer', 'Disease', 'MESH:D014523', (101, 118))
81532	32377703	The patients with low pathological T staging and those who underwent radiotherapy exhibited improved prognoses, which is consistent with the outcomes observed in clinical practice.	('prognoses', 'CPA', (101, 110))	('improved', 'PosReg', (92, 100))	('patients', 'Species', '9606', (4, 12))	('low', 'Var', (18, 21))
81544	32377703	This observation suggests that methylation status of ALDH7A1 may affect other clinical factors.	('ALDH7A1', 'Gene', (53, 60))	('methylation status', 'Var', (31, 49))	('affect', 'Reg', (65, 71))	('ALDH7A1', 'Gene', '501', (53, 60))
81547	32377703	CYTL1 has important roles in certain types of cancer and is regulated by DNA methylation in LSCC.	('LSCC', 'Disease', (92, 96))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('DNA methylation', 'Var', (73, 88))	('cancer', 'Disease', (46, 52))	('regulated', 'Reg', (60, 69))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('CYTL1', 'Gene', (0, 5))	('CYTL1', 'Gene', '54360', (0, 5))
81551	32377703	According to the present study, the CYTL1 gene was often methylated in recurring LSCC tumors, suggesting that it may be a predictive factor of LSCC recurrence.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('LSCC', 'Disease', (143, 147))	('LSCC tumors', 'Disease', 'MESH:D009369', (81, 92))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('LSCC tumors', 'Disease', (81, 92))	('CYTL1', 'Gene', '54360', (36, 41))	('CYTL1', 'Gene', (36, 41))	('methylated', 'Var', (57, 67))
81555	32377703	PDE3A expression is low in chemoresistant NSCLC cells due to DNA hypermethylation, and high PDE3A expression is associated with improved survival in patients with LUAD.	('PDE3A', 'Gene', (0, 5))	('NSCLC', 'Disease', (42, 47))	('patients', 'Species', '9606', (149, 157))	('NSCLC', 'Disease', 'MESH:D002289', (42, 47))	('expression', 'MPA', (6, 16))	('improved', 'PosReg', (128, 136))	('high', 'Var', (87, 91))	('LUAD', 'Disease', (163, 167))	('PDE3A', 'Gene', '5139', (92, 97))	('survival', 'MPA', (137, 145))	('PDE3A', 'Gene', '5139', (0, 5))	('PDE3A', 'Gene', (92, 97))	('expression', 'MPA', (98, 108))
81556	32377703	According to the results of the present study, methylated PDE3A may be associated with the prognosis of LSCC.	('methylated', 'Var', (47, 57))	('PDE3A', 'Gene', (58, 63))	('LSCC', 'Disease', (104, 108))	('PDE3A', 'Gene', '5139', (58, 63))	('associated', 'Reg', (71, 81))
81561	32377703	In lung cancer in Xuanwei, TRIP13, cAMP-responsive element-binding protein 3-like 4 and cyclin E2 exhibit concordant upregulation and frequent copy number gains, and have been proposed as potential oncogenes in the pathogenesis of lung cancer in this region.	('lung cancer', 'Disease', (231, 242))	('lung cancer', 'Phenotype', 'HP:0100526', (231, 242))	('lung cancer', 'Disease', (3, 14))	('TRIP13', 'Gene', '9319', (27, 33))	('lung cancer', 'Phenotype', 'HP:0100526', (3, 14))	('copy number', 'Var', (143, 154))	('cyclin E2', 'Gene', (88, 97))	('TRIP13', 'Gene', (27, 33))	('lung cancer', 'Disease', 'MESH:D008175', (231, 242))	('lung cancer', 'Disease', 'MESH:D008175', (3, 14))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('cAMP-responsive element-binding protein 3-like 4', 'Gene', '148327', (35, 83))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('cAMP-responsive element-binding protein 3-like 4', 'Gene', (35, 83))	('cyclin E2', 'Gene', '9134', (88, 97))	('upregulation', 'PosReg', (117, 129))
81562	32377703	In addition, silencing of TRIP13 can suppress cell growth and metastasis of hepatocellular carcinoma by activating TGF-beta1/SMAD3 signaling.	('TRIP13', 'Gene', (26, 32))	('metastasis of hepatocellular carcinoma', 'Disease', (62, 100))	('metastasis of hepatocellular carcinoma', 'Disease', 'MESH:D009362', (62, 100))	('cell growth', 'CPA', (46, 57))	('SMAD3', 'Gene', '4088', (125, 130))	('TGF-beta1', 'Gene', '7040', (115, 124))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (76, 100))	('TGF-beta1', 'Gene', (115, 124))	('suppress', 'NegReg', (37, 45))	('activating', 'PosReg', (104, 114))	('SMAD3', 'Gene', (125, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('TRIP13', 'Gene', '9319', (26, 32))	('silencing', 'Var', (13, 22))
81591	25504438	DNA methylation transcriptionally regulates the putative tumor cell growth suppressor ZNF677 in non-small cell lung cancers In our study, we investigated the role of ZNF677 in non-small cell lung cancers (NSCLC).	('ZNF677', 'Gene', (166, 172))	('non-small cell lung cancers', 'Disease', 'MESH:D002289', (176, 203))	('NSCLC', 'Disease', 'MESH:D002289', (205, 210))	('small cell lung cancers', 'Phenotype', 'HP:0030357', (100, 123))	('non-small cell lung cancers', 'Disease', 'MESH:D002289', (96, 123))	('regulates', 'Reg', (34, 43))	('NSCLC', 'Disease', (205, 210))	('lung cancer', 'Phenotype', 'HP:0100526', (191, 202))	('tumor', 'Disease', (57, 62))	('non-small cell lung cancers', 'Disease', (176, 203))	('lung cancers', 'Phenotype', 'HP:0100526', (191, 203))	('NSCLC', 'Phenotype', 'HP:0030358', (205, 210))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('methylation', 'Var', (4, 15))	('non-small cell lung cancers', 'Phenotype', 'HP:0030358', (176, 203))	('cancers', 'Phenotype', 'HP:0002664', (196, 203))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('non-small cell lung cancers', 'Disease', (96, 123))	('lung cancer', 'Phenotype', 'HP:0100526', (111, 122))	('lung cancers', 'Phenotype', 'HP:0100526', (111, 123))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('non-small cell lung cancers', 'Phenotype', 'HP:0030358', (96, 123))	('ZNF677', 'Gene', '342926', (86, 92))	('cancers', 'Phenotype', 'HP:0002664', (116, 123))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('ZNF677', 'Gene', (86, 92))	('ZNF677', 'Gene', '342926', (166, 172))	('small cell lung cancers', 'Phenotype', 'HP:0030357', (180, 203))
81593	25504438	We identified methylation as main mechanism for ZNF677 downregulation in NSCLC cells and we observed tumor-specific ZNF677 methylation in NSCLC patients (p < 0.0001).	('NSCLC', 'Disease', (138, 143))	('ZNF677', 'Gene', (116, 122))	('downregulation', 'NegReg', (55, 69))	('ZNF677', 'Gene', '342926', (48, 54))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('NSCLC', 'Disease', 'MESH:D002289', (138, 143))	('NSCLC', 'Disease', (73, 78))	('methylation', 'Var', (14, 25))	('ZNF677', 'Gene', (48, 54))	('patients', 'Species', '9606', (144, 152))	('NSCLC', 'Phenotype', 'HP:0030358', (138, 143))	('NSCLC', 'Phenotype', 'HP:0030358', (73, 78))	('ZNF677', 'Gene', '342926', (116, 122))	('NSCLC', 'Disease', 'MESH:D002289', (73, 78))	('methylation', 'MPA', (123, 134))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
81594	25504438	In the majority of TUs, ZNF677 methylation was associated with loss of ZNF677 expression.	('expression', 'MPA', (78, 88))	('ZNF677', 'Gene', '342926', (24, 30))	('ZNF677', 'Gene', (71, 77))	('TU', 'Phenotype', 'HP:0002664', (19, 21))	('ZNF677', 'Gene', (24, 30))	('TUs', 'Chemical', '-', (19, 22))	('methylation', 'Var', (31, 42))	('ZNF677', 'Gene', '342926', (71, 77))	('loss', 'NegReg', (63, 67))
81599	25504438	Gene expression in malignant tumors may be affected by genetic and epigenetic changes.	('epigenetic changes', 'Var', (67, 85))	('malignant tumors', 'Disease', (19, 35))	('affected', 'Reg', (43, 51))	('malignant tumors', 'Disease', 'MESH:D018198', (19, 35))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('genetic', 'Var', (55, 62))	('Gene expression', 'MPA', (0, 15))
81603	25504438	So far, many genes were found which are transcriptionally inactivated by methylation in NSCLCs.	('NSCLC', 'Disease', 'MESH:D002289', (88, 93))	('methylation', 'Var', (73, 84))	('NSCLC', 'Disease', (88, 93))	('NSCLC', 'Phenotype', 'HP:0030358', (88, 93))
81606	25504438	Many genes which have been identified in our study to be tumor-specifically methylated exhibited downregulated expression in TU compared to NL samples of these patients.	('patients', 'Species', '9606', (160, 168))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('expression', 'MPA', (111, 121))	('downregulated', 'NegReg', (97, 110))	('methylated', 'Var', (76, 86))	('TU', 'Phenotype', 'HP:0002664', (125, 127))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Disease', (57, 62))
81613	25504438	Overall, our results indicate that ZNF677 is frequently transcriptionally silenced by methylation in NSCLCs and they suggest that ZNF677 has tumor cell growth suppressing properties.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('ZNF677', 'Gene', (130, 136))	('ZNF677', 'Gene', '342926', (35, 41))	('NSCLC', 'Disease', (101, 106))	('tumor', 'Disease', (141, 146))	('silenced', 'NegReg', (74, 82))	('methylation', 'Var', (86, 97))	('NSCLC', 'Disease', 'MESH:D002289', (101, 106))	('ZNF677', 'Gene', '342926', (130, 136))	('ZNF677', 'Gene', (35, 41))	('NSCLC', 'Phenotype', 'HP:0030358', (101, 106))
81614	25504438	Moreover, ZNF677 methylation might be of prognostic relevance for NSCLC patients.	('NSCLC', 'Disease', (66, 71))	('ZNF677', 'Gene', '342926', (10, 16))	('methylation', 'Var', (17, 28))	('NSCLC', 'Disease', 'MESH:D002289', (66, 71))	('ZNF677', 'Gene', (10, 16))	('NSCLC', 'Phenotype', 'HP:0030358', (66, 71))	('patients', 'Species', '9606', (72, 80))
81617	25504438	A statistically significant downregulation of ZNF677 expression in TU compared to NL samples was observed in dataset E-GEOD-18842 (Bonferroni adjusted p-value = 0.00003) and similar results were seen in dataset E-GEOD-19188 (Bonferroni adjusted p-value = 0.0007).	('TU', 'Phenotype', 'HP:0002664', (67, 69))	('ZNF677', 'Gene', (46, 52))	('downregulation', 'NegReg', (28, 42))	('E-GEOD-18842', 'Var', (117, 129))	('ZNF677', 'Gene', '342926', (46, 52))	('expression', 'MPA', (53, 63))
81637	25504438	In addition, we analysed ZNF677 methylation in cell lines of other tumor entities including breast cancer (N = 5), colon cancer (N = 2), ovarian cancer (N = 2), pancreatic cancer (N = 2) and head and neck cancer (N = 2) by MS-HRM (supplementary Figure S2).	('head and neck cancer', 'Disease', 'MESH:D006258', (191, 211))	('methylation', 'Var', (32, 43))	('analysed', 'Reg', (16, 24))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (161, 178))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('tumor', 'Disease', (67, 72))	('colon cancer', 'Disease', 'MESH:D015179', (115, 127))	('breast cancer', 'Phenotype', 'HP:0003002', (92, 105))	('ovarian cancer', 'Disease', 'MESH:D010051', (137, 151))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('breast cancer', 'Disease', 'MESH:D001943', (92, 105))	('pancreatic cancer', 'Disease', 'MESH:D010190', (161, 178))	('breast cancer', 'Disease', (92, 105))	('ZNF677', 'Gene', '342926', (25, 31))	('colon cancer', 'Disease', (115, 127))	('head and neck cancer', 'Phenotype', 'HP:0012288', (191, 211))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('ZNF677', 'Gene', (25, 31))	('ovarian cancer', 'Disease', (137, 151))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('pancreatic cancer', 'Disease', (161, 178))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('ovarian cancer', 'Phenotype', 'HP:0100615', (137, 151))	('colon cancer', 'Phenotype', 'HP:0003003', (115, 127))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
81638	25504438	All these tumor cell lines except 1 breast cancer (MDA-MB-468) and 1 ovarian cancer (SCOV3) cell line were found to be ZNF677 methylated.	('ovarian cancer', 'Disease', (69, 83))	('breast cancer', 'Phenotype', 'HP:0003002', (36, 49))	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('methylated', 'Var', (126, 136))	('breast cancer', 'Disease', (36, 49))	('tumor', 'Disease', (10, 15))	('ZNF677', 'Gene', (119, 125))	('ovarian cancer', 'Phenotype', 'HP:0100615', (69, 83))	('ovarian cancer', 'Disease', 'MESH:D010051', (69, 83))	('MDA-MB-468', 'CellLine', 'CVCL:0419', (51, 61))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('ZNF677', 'Gene', '342926', (119, 125))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('breast cancer', 'Disease', 'MESH:D001943', (36, 49))
81639	25504438	By comparing methylation values of these cell lines with ZNF677 mRNA expression values from the TCGA Cancer Cell Line Encyclopedia, a strong negative correlation between ZNF677 methylation and ZNF677 expression in these cell lines was observed (R = -0.889, p < 0.0001; supplementary Figure S2).	('ZNF677', 'Gene', (170, 176))	('ZNF677', 'Gene', (57, 63))	('Cancer Cell Line Encyclopedia', 'Disease', 'MESH:C538614', (101, 130))	('negative', 'NegReg', (141, 149))	('ZNF677', 'Gene', '342926', (170, 176))	('ZNF677', 'Gene', '342926', (193, 199))	('expression', 'MPA', (200, 210))	('Cancer Cell Line Encyclopedia', 'Disease', (101, 130))	('ZNF677', 'Gene', '342926', (57, 63))	('Cancer', 'Phenotype', 'HP:0002664', (101, 107))	('methylation', 'Var', (177, 188))	('ZNF677', 'Gene', (193, 199))
81640	25504438	Overall, these results suggest that methylation of the 5  region of ZNF677 is responsible for ZNF677 silencing in many tumor cell lines of different entities including NSCLC, breast cancer, colon cancer, ovarian cancer, pancreatic cancer and head and neck cancer.	('pancreatic cancer', 'Disease', 'MESH:D010190', (220, 237))	('ovarian cancer', 'Disease', (204, 218))	('breast cancer', 'Disease', 'MESH:D001943', (175, 188))	('silencing', 'NegReg', (101, 110))	('breast cancer', 'Disease', (175, 188))	('responsible', 'Reg', (78, 89))	('colon cancer', 'Disease', (190, 202))	('head and neck cancer', 'Phenotype', 'HP:0012288', (242, 262))	('NSCLC', 'Phenotype', 'HP:0030358', (168, 173))	('ovarian cancer', 'Phenotype', 'HP:0100615', (204, 218))	('cancer', 'Phenotype', 'HP:0002664', (256, 262))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('pancreatic cancer', 'Disease', (220, 237))	('ZNF677', 'Gene', '342926', (68, 74))	('ZNF677', 'Gene', (68, 74))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('methylation', 'Var', (36, 47))	('colon cancer', 'Phenotype', 'HP:0003003', (190, 202))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('head and neck cancer', 'Disease', 'MESH:D006258', (242, 262))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (220, 237))	('ovarian cancer', 'Disease', 'MESH:D010051', (204, 218))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('tumor', 'Disease', (119, 124))	('colon cancer', 'Disease', 'MESH:D015179', (190, 202))	('breast cancer', 'Phenotype', 'HP:0003002', (175, 188))	('NSCLC', 'Disease', 'MESH:D002289', (168, 173))	('ZNF677', 'Gene', '342926', (94, 100))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('ZNF677', 'Gene', (94, 100))	('NSCLC', 'Disease', (168, 173))
81644	25504438	In addition, ROC curve analyses revealed that methylation of ZNF677 statistically significant distinguishes TU from NL samples (p = 1.1 * 10-23; area under the curve: 0.838; 95% CI: 0.792 - 0.885; Figure 3B).	('distinguishes', 'Reg', (94, 107))	('methylation', 'Var', (46, 57))	('ZNF677', 'Gene', (61, 67))	('ZNF677', 'Gene', '342926', (61, 67))	('TU', 'Phenotype', 'HP:0002664', (108, 110))
81645	25504438	For comparison of ZNF677 methylation data with clinico-pathological characteristics of the NSCLC patients, patients were grouped into "high ZNF677 TU methylation" and "low ZNF677 TU methylation" using the mean % of ZNF677 methylation in TU samples as cut-off level.	('NSCLC', 'Disease', 'MESH:D002289', (91, 96))	('ZNF677', 'Gene', '342926', (140, 146))	('methylation', 'Var', (150, 161))	('ZNF677', 'Gene', (215, 221))	('ZNF677', 'Gene', '342926', (172, 178))	('NSCLC', 'Phenotype', 'HP:0030358', (91, 96))	('ZNF677', 'Gene', (140, 146))	('low', 'NegReg', (168, 171))	('TU', 'Phenotype', 'HP:0002664', (237, 239))	('TU', 'Phenotype', 'HP:0002664', (179, 181))	('ZNF677', 'Gene', '342926', (18, 24))	('TU', 'Phenotype', 'HP:0002664', (147, 149))	('ZNF677', 'Gene', (172, 178))	('ZNF677', 'Gene', (18, 24))	('NSCLC', 'Disease', (91, 96))	('ZNF677', 'Gene', '342926', (215, 221))	('patients', 'Species', '9606', (107, 115))	('patients', 'Species', '9606', (97, 105))
81648	25504438	In addition, multivariate analyses identified ZNF677 TU methylation as independent prognostic factor for shorter OS of NSCLC patients (hazard ratio [HR] = 1.8, 95% confidence interval [CI] = 1 to 3.1, p = 0.046).	('NSCLC', 'Disease', 'MESH:D002289', (119, 124))	('TU', 'Phenotype', 'HP:0002664', (53, 55))	('ZNF677', 'Gene', (46, 52))	('TU methylation', 'Var', (53, 67))	('NSCLC', 'Phenotype', 'HP:0030358', (119, 124))	('shorter OS', 'Disease', (105, 115))	('ZNF677', 'Gene', '342926', (46, 52))	('NSCLC', 'Disease', (119, 124))	('patients', 'Species', '9606', (125, 133))
81649	25504438	No other statistically significant associations between ZNF677 methylation and clinico-pathological characteristics of the patients were observed.	('patients', 'Species', '9606', (123, 131))	('ZNF677', 'Gene', '342926', (56, 62))	('methylation', 'Var', (63, 74))	('ZNF677', 'Gene', (56, 62))
81653	25504438	Moreover, they suggest that ZNF677 methylation and ZNF677 mRNA expression might be of prognostic impact for certain NSCLC patients, however, additional studies are necessary to determine the potential clinical relevance.	('NSCLC', 'Disease', 'MESH:D002289', (116, 121))	('ZNF677', 'Gene', '342926', (28, 34))	('clinical', 'Species', '191496', (201, 209))	('NSCLC', 'Phenotype', 'HP:0030358', (116, 121))	('mRNA expression', 'MPA', (58, 73))	('ZNF677', 'Gene', (28, 34))	('ZNF677', 'Gene', '342926', (51, 57))	('patients', 'Species', '9606', (122, 130))	('methylation', 'Var', (35, 46))	('ZNF677', 'Gene', (51, 57))	('NSCLC', 'Disease', (116, 121))	('impact', 'Reg', (97, 103))
81658	25504438	In the majority of TU samples the detection of ZNF677 methylation was associated with downregulated ZNF677 protein expression.	('TU', 'Phenotype', 'HP:0002664', (19, 21))	('methylation', 'Var', (54, 65))	('ZNF677', 'Gene', (47, 53))	('ZNF677', 'Gene', '342926', (100, 106))	('protein', 'Protein', (107, 114))	('downregulated', 'NegReg', (86, 99))	('ZNF677', 'Gene', (100, 106))	('ZNF677', 'Gene', '342926', (47, 53))
81660	25504438	Thus, we compared methylation and expression data from LUAD and LUSC datasets and we found a strong negative correlation between ZNF677 methylation and ZNF677 expression in both datasets (R = -0.673 and R = -0.654, respectively; p < 0.000001, respectively; supplementary Figure S2C).	('ZNF677', 'Gene', (152, 158))	('ZNF677', 'Gene', '342926', (129, 135))	('methylation', 'Var', (136, 147))	('negative', 'NegReg', (100, 108))	('ZNF677', 'Gene', (129, 135))	('expression', 'MPA', (159, 169))	('ZNF677', 'Gene', '342926', (152, 158))
81661	25504438	Moreover, we were interested if besides methylation also mutations or copy number changes might be responsible for downregulated ZNF677 expression in NSCLC patients.	('patients', 'Species', '9606', (156, 164))	('NSCLC', 'Disease', 'MESH:D002289', (150, 155))	('ZNF677', 'Gene', '342926', (129, 135))	('expression', 'MPA', (136, 146))	('ZNF677', 'Gene', (129, 135))	('NSCLC', 'Phenotype', 'HP:0030358', (150, 155))	('downregulated', 'NegReg', (115, 128))	('mutations', 'Var', (57, 66))	('copy number changes', 'Var', (70, 89))	('NSCLC', 'Disease', (150, 155))
81662	25504438	Thus, we searched for ZNF677 mutations in LUAD and LUSC datasets.	('ZNF677', 'Gene', '342926', (22, 28))	('ZNF677', 'Gene', (22, 28))	('mutations', 'Var', (29, 38))
81663	25504438	ZNF677 mutations including 1 splice variant and 6 missense mutations (C232S, H477N, G254W, C492F, H281Y and P514T) were found only in 2% of both ADC and SCC patients and their localisation is shown in supplementary Figures S3A and S3B.	('C492F', 'Mutation', 'p.C492F', (91, 96))	('H281Y', 'Mutation', 'p.H281Y', (98, 103))	('SCC', 'Gene', '6317', (153, 156))	('C232S', 'Mutation', 'rs765013733', (70, 75))	('C232S', 'Var', (70, 75))	('C492F', 'Var', (91, 96))	('P514T', 'Mutation', 'p.P514T', (108, 113))	('G254W', 'Mutation', 'p.G254W', (84, 89))	('H477N', 'Mutation', 'p.H477N', (77, 82))	('ZNF677', 'Gene', '342926', (0, 6))	('patients', 'Species', '9606', (157, 165))	('ADC', 'Disease', (145, 148))	('H281Y', 'Var', (98, 103))	('ZNF677', 'Gene', (0, 6))	('SCC', 'Gene', (153, 156))	('G254W', 'Var', (84, 89))	('P514T', 'Var', (108, 113))	('H477N', 'Var', (77, 82))
81664	25504438	All ZNF677 mutations were mutually exclusive.	('ZNF677', 'Gene', '342926', (4, 10))	('ZNF677', 'Gene', (4, 10))	('mutations', 'Var', (11, 20))
81665	25504438	Mutations H477N and C492F were predicted to have a high functional impact (supplementary Figure S3C).	('C492F', 'Var', (20, 25))	('H477N', 'Mutation', 'p.H477N', (10, 15))	('C492F', 'Mutation', 'p.C492F', (20, 25))	('H477N', 'Var', (10, 15))
81666	25504438	In addition, we searched for ZNF677 copy number changes in LUAD and LUSC TCGA aCGH datasets of 983 NSCLC patients.	('patients', 'Species', '9606', (105, 113))	('copy number changes', 'Var', (36, 55))	('NSCLC', 'Phenotype', 'HP:0030358', (99, 104))	('NSCLC', 'Disease', 'MESH:D002289', (99, 104))	('ZNF677', 'Gene', '342926', (29, 35))	('NSCLC', 'Disease', (99, 104))	('ZNF677', 'Gene', (29, 35))
81667	25504438	A homozygous ZNF677 deletion was detected only in 1 ADC patient (supplementary Figures S3D and S3E), however, heterozygous ZNF677 deletions were found in 34% of ADC patients and in 25% of SCC patients.	('ZNF677', 'Gene', '342926', (123, 129))	('deletions', 'Var', (130, 139))	('patient', 'Species', '9606', (192, 199))	('SCC', 'Gene', '6317', (188, 191))	('ZNF677', 'Gene', '342926', (13, 19))	('ADC', 'Disease', (161, 164))	('ZNF677', 'Gene', (123, 129))	('patient', 'Species', '9606', (165, 172))	('ZNF677', 'Gene', (13, 19))	('patients', 'Species', '9606', (192, 200))	('deletion', 'Var', (20, 28))	('patients', 'Species', '9606', (165, 173))	('patient', 'Species', '9606', (56, 63))	('SCC', 'Gene', (188, 191))
81671	25504438	These results demonstrate that heterozygous ZNF677 deletions but not ZNF677 mutations occur frequently in NSCLCs indicating that ZNF677 mutations do not play a role in inactivation of ZNF677 in NSCLCs.	('NSCLC', 'Phenotype', 'HP:0030358', (194, 199))	('ZNF677', 'Gene', '342926', (129, 135))	('NSCLC', 'Disease', 'MESH:D002289', (106, 111))	('ZNF677', 'Gene', (184, 190))	('ZNF677', 'Gene', (44, 50))	('ZNF677', 'Gene', (129, 135))	('ZNF677', 'Gene', '342926', (69, 75))	('NSCLC', 'Disease', (194, 199))	('ZNF677', 'Gene', '342926', (184, 190))	('NSCLC', 'Phenotype', 'HP:0030358', (106, 111))	('deletions', 'Var', (51, 60))	('NSCLC', 'Disease', 'MESH:D002289', (194, 199))	('ZNF677', 'Gene', (69, 75))	('NSCLC', 'Disease', (106, 111))	('ZNF677', 'Gene', '342926', (44, 50))
81675	25504438	Reduced cell growth (1.4 to 3.6-fold, mean 2.7-fold) of pCMV6-ZNF677 transfected A549, NCI-H2073 and NCI-H1993 cells was confirmed using a cell viability assay (Figure 4D).	('cell growth', 'CPA', (8, 19))	('transfected', 'Var', (69, 80))	('ZNF677', 'Gene', '342926', (62, 68))	('NCI-H1993', 'CellLine', 'CVCL:1512', (101, 110))	('Reduced', 'NegReg', (0, 7))	('ZNF677', 'Gene', (62, 68))	('NCI-H2073', 'CellLine', 'CVCL:1521', (87, 96))	('A549', 'CellLine', 'CVCL:0023', (81, 85))
81678	25504438	However, we observed a reduced migration capacity of pCMV6-ZNF677 transfected cells compared to cells transfected with the empty control vector by using a scratch assay (Figure 4F).	('transfected', 'Var', (66, 77))	('migration capacity', 'CPA', (31, 49))	('ZNF677', 'Gene', '342926', (59, 65))	('ZNF677', 'Gene', (59, 65))	('reduced', 'NegReg', (23, 30))
81682	25504438	We identified 198, 71 and 83 differentially expressed genes in pCMV6-ZNF677 transfected A549, NCI-H1993 and NCI-H2073 cells compared to control cells, respectively (Figure 5B, supplementary Table S1).	('ZNF677', 'Gene', '342926', (69, 75))	('transfected', 'Var', (76, 87))	('NCI-H1993', 'CellLine', 'CVCL:1512', (94, 103))	('A549', 'CellLine', 'CVCL:0023', (88, 92))	('differentially expressed genes', 'MPA', (29, 59))	('NCI-H2073', 'CellLine', 'CVCL:1521', (108, 117))	('ZNF677', 'Gene', (69, 75))
81687	25504438	In a recent genome-wide search for CGI methylation in a large number of NSCLC patients, we identified 477 tumor-specifically methylated genes and from the majority of them regulation by methylation and/or an involvement in the pathogenesis of NSCLCs was unknown so far.	('methylated genes', 'Var', (125, 141))	('NSCLC', 'Disease', 'MESH:D002289', (243, 248))	('NSCLC', 'Disease', (72, 77))	('NSCLC', 'Disease', (243, 248))	('patients', 'Species', '9606', (78, 86))	('NSCLC', 'Disease', 'MESH:D002289', (72, 77))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('NSCLC', 'Phenotype', 'HP:0030358', (243, 248))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('NSCLC', 'Phenotype', 'HP:0030358', (72, 77))	('tumor', 'Disease', (106, 111))
81699	25504438	ZNF677 mutations were found in only 2% of the tumors using TCGA datasets.	('mutations', 'Var', (7, 16))	('ZNF677', 'Gene', '342926', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('ZNF677', 'Gene', (0, 6))	('tumors', 'Disease', (46, 52))	('tumors', 'Disease', 'MESH:D009369', (46, 52))
81700	25504438	In addition, we observed an association between ZNF677 methylation and loss of ZNF677 expression for the majority of TU samples analysed while ZNF677 not methylated TU samples mostly expressed ZNF677.	('ZNF677', 'Gene', '342926', (143, 149))	('ZNF677', 'Gene', '342926', (48, 54))	('TU', 'Phenotype', 'HP:0002664', (117, 119))	('ZNF677', 'Gene', '342926', (79, 85))	('expression', 'MPA', (86, 96))	('ZNF677', 'Gene', (48, 54))	('ZNF677', 'Gene', (143, 149))	('TU', 'Phenotype', 'HP:0002664', (165, 167))	('loss', 'NegReg', (71, 75))	('ZNF677', 'Gene', '342926', (193, 199))	('methylation', 'Var', (55, 66))	('ZNF677', 'Gene', (79, 85))	('ZNF677', 'Gene', (193, 199))
81707	25504438	These results suggest that ZNF677 methylation might be of potential prognostic relevance, however, additional studies are necessary to confirm our results.	('ZNF677', 'Gene', '342926', (27, 33))	('ZNF677', 'Gene', (27, 33))	('methylation', 'Var', (34, 45))
81710	25504438	Certain characteristics of tumor suppressor genes (TSG) include that they are often located in chromosomal regions with frequent loss of heterozygosity (LOH), that they may become inactivated by genetic or epigenetic mechanisms and that they may inhibit tumor cell growth.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumor', 'Disease', (254, 259))	('inhibit', 'NegReg', (246, 253))	('tumor', 'Disease', (27, 32))	('loss', 'NegReg', (129, 133))	('inactivated', 'NegReg', (180, 191))	('tumor', 'Disease', 'MESH:D009369', (254, 259))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (254, 259))	('epigenetic', 'Var', (206, 216))
81726	25504438	ZNF677 methylation occurs tumor-specific in NSCLC patients and might be of potential prognostic impact for these patients.	('NSCLC', 'Disease', 'MESH:D002289', (44, 49))	('patients', 'Species', '9606', (50, 58))	('ZNF677', 'Gene', '342926', (0, 6))	('patients', 'Species', '9606', (113, 121))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('NSCLC', 'Phenotype', 'HP:0030358', (44, 49))	('methylation', 'Var', (7, 18))	('ZNF677', 'Gene', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('NSCLC', 'Disease', (44, 49))
81742	25504438	ZNF677 expression was determined by RT-PCR using Taqman Gene Expression Assays (Applied Biosystems) Hs00737026_m1 (ZNF677) and Hs03929097_g1 (GAPDH).	('ZNF677', 'Gene', '342926', (0, 6))	('Hs00737026_m1', 'Var', (100, 113))	('GAPDH', 'Gene', '2597', (142, 147))	('GAPDH', 'Gene', (142, 147))	('ZNF677', 'Gene', '342926', (115, 121))	('Hs03929097_g1', 'Var', (127, 140))	('ZNF677', 'Gene', (0, 6))	('ZNF677', 'Gene', (115, 121))
81755	25504438	Membranes were blocked followed by incubation with primary antibodies anti-ZNF677 (1:100, Abcam), anti-IRF9 (1:50, Santa Cruz Biotechnology), anti-ISG15 (1:1000, Cell Signaling), anti-CSH1 (1:375, Thermo Scientific), anti-ACTB (1:200, Abcam) and anti-GAPDH (0.05mg/ml, Sigma Aldrich).	('GAPDH', 'Gene', '2597', (251, 256))	('1:200', 'Var', (228, 233))	('ISG15', 'Gene', '9636', (147, 152))	('GAPDH', 'Gene', (251, 256))	('IRF9', 'Gene', (103, 107))	('ZNF677', 'Gene', (75, 81))	('ISG15', 'Gene', (147, 152))	('CSH1', 'Gene', (184, 188))	('0.05mg/ml', 'Var', (258, 267))	('CSH1', 'Gene', '1442', (184, 188))	('ZNF677', 'Gene', '342926', (75, 81))	('IRF9', 'Gene', '10379', (103, 107))
81763	25504438	Galaxy platform and TopHat2 were used to align raw RNA-seq data (fastq files) of ZNF677 transfected NSCLC cells and of control cells to hg19.	('NSCLC', 'Disease', (100, 105))	('ZNF677', 'Gene', (81, 87))	('NSCLC', 'Disease', 'MESH:D002289', (100, 105))	('transfected', 'Var', (88, 99))	('ZNF677', 'Gene', '342926', (81, 87))	('NSCLC', 'Phenotype', 'HP:0030358', (100, 105))
81771	25548985	Total toxicity was greater in the oxaliplatin group (p=0.008), but there is no significant difference among 3/4 grade adverse events between the 2 groups (P=0.595).	('oxaliplatin', 'Var', (34, 45))	('toxicity', 'Disease', 'MESH:D064420', (6, 14))	('toxicity', 'Disease', (6, 14))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (34, 45))	('greater', 'PosReg', (19, 26))
81789	25548985	All the eligible patients were over 20 years old; Karnofsky performance status (KPS) was greater than or equal to 70; the measurable lesion was measured according to the Response Evaluation Criteria in Solid Tumors (RECIST); with adequate bone marrow function (leukocyte count >=4.0x109/L, absolute neutrophil count >=2.0x109/L, platelet count >=100x109/L, hemoglobin count >=9.5 g/dl), and adequate other organ function (serum aspartate aminotransferase, serum alanine aminotransferase, serum creatinine concentration, serum total bilirubin and the alkaline phosphatase were normal).	('serum aspartate aminotransferase', 'Phenotype', 'HP:0031956', (422, 454))	('alanine aminotransferase', 'Gene', (462, 486))	('alkaline phosphatase', 'MPA', (550, 570))	('serum aspartate aminotransferase', 'MPA', (422, 454))	('>=100x109/L', 'Var', (344, 355))	('serum total bilirubin', 'MPA', (520, 541))	('>=4.0x109/L', 'Var', (277, 288))	('alanine aminotransferase', 'Gene', '2875', (462, 486))	('serum creatinine concentration', 'MPA', (488, 518))	('Solid Tumors', 'Disease', 'MESH:D009369', (202, 214))	('Tumor', 'Phenotype', 'HP:0002664', (208, 213))	('Solid Tumors', 'Disease', (202, 214))	('patients', 'Species', '9606', (17, 25))	('bone marrow function', 'CPA', (239, 259))	('Tumors', 'Phenotype', 'HP:0002664', (208, 214))
81825	25548985	Cisplatin and docetaxel are associated with more severe leukopenia (44% vs. 14%), neutropenia (56% vs. 27%), and renal toxicity (56% vs. 11%) compared with oxaliplatin and docetaxel.	('neutropenia', 'Disease', 'MESH:D009503', (82, 93))	('docetaxel', 'Chemical', 'MESH:D000077143', (172, 181))	('docetaxel', 'Chemical', 'MESH:D000077143', (14, 23))	('leukopenia', 'Disease', 'MESH:D007970', (56, 66))	('leukopenia', 'Disease', (56, 66))	('neutropenia', 'Phenotype', 'HP:0001875', (82, 93))	('Cisplatin', 'Chemical', 'MESH:D002945', (0, 9))	('renal toxicity', 'Disease', (113, 127))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (156, 167))	('Cisplatin', 'Var', (0, 9))	('leukopenia', 'Phenotype', 'HP:0001882', (56, 66))	('neutropenia', 'Disease', (82, 93))	('renal toxicity', 'Disease', 'MESH:D007674', (113, 127))
81846	33846395	High THRalpha1 expression was associated with shorter OS.	('High', 'Var', (0, 4))	('shorter OS', 'Disease', (46, 56))	('THRalpha1', 'Chemical', '-', (5, 14))	('expression', 'MPA', (15, 25))	('THRalpha1', 'Protein', (5, 14))
81900	33846395	This finding confirmed that the poorly differentiated NSCLC cases with high THRalpha1 were originally SCC and pointed to THRalpha1 as a potentially additive diagnostic marker.	('THRalpha1', 'Chemical', '-', (121, 130))	('SCC', 'Phenotype', 'HP:0002860', (102, 105))	('high', 'Var', (71, 75))	('THRalpha1', 'Chemical', '-', (76, 85))	('NSCLC', 'Phenotype', 'HP:0030358', (54, 59))	('NSCLC', 'Disease', (54, 59))	('THRalpha1', 'Gene', (76, 85))	('NSCLC', 'Disease', 'MESH:D002289', (54, 59))
81908	33846395	The univariate regression, Table 4 indicated grade (grade III versus II: HR = 2.14, 95%, CI: 2.01-35.9, p = 0.004), TNM stage (stage III: HR = 1.83, 95%, CI: 1.34-29.2, p = 0.019), and high THRalpha1 expression (HR = 1.5, 95%, CI: 1.18-17.7, p = 0.027) were all associated with poor survival status of SCC patients.	('THRalpha1', 'Chemical', '-', (190, 199))	('THRalpha1', 'Protein', (190, 199))	('high', 'Var', (185, 189))	('SCC', 'Phenotype', 'HP:0002860', (302, 305))	('expression', 'MPA', (200, 210))	('SCC', 'Disease', (302, 305))
81933	33846395	Moreover, THRalpha1 expression was proven to influence tumor growth in their samples, which is consistent with our finding.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('expression', 'Var', (20, 30))	('tumor', 'Disease', (55, 60))	('THRalpha1', 'Gene', (10, 19))	('influence', 'Reg', (45, 54))	('THRalpha1', 'Chemical', '-', (10, 19))
81937	33846395	In our lung-SCC cases, high THRalpha1 was positively associated with T stage, N stage, metastasis and TNM stage.	('metastasis', 'CPA', (87, 97))	('THRalpha1', 'Chemical', '-', (28, 37))	('high THRalpha1', 'Var', (23, 37))	('TNM stage', 'CPA', (102, 111))	('associated', 'Reg', (53, 63))	('SCC', 'Phenotype', 'HP:0002860', (12, 15))	('T stage', 'CPA', (69, 76))	('N stage', 'CPA', (78, 85))
81938	33846395	In line with our findings, a significant association was detected between high THRalpha1 and increasing breast cancer TNM stage and T stage.	('THRalpha1', 'Chemical', '-', (79, 88))	('THRalpha1', 'Protein', (79, 88))	('high', 'Var', (74, 78))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('increasing', 'PosReg', (93, 103))	('breast cancer', 'Disease', 'MESH:D001943', (104, 117))	('breast cancer', 'Disease', (104, 117))	('breast cancer', 'Phenotype', 'HP:0003002', (104, 117))	('T stage', 'CPA', (132, 139))
81942	33846395	On the other hand, induced hypothyroidism using methimazole is associated with attenuation tumor growth and significantly reduces tumor metastasis and prolongs survival.	('survival', 'CPA', (160, 168))	('reduces', 'NegReg', (122, 129))	('hypothyroidism', 'Phenotype', 'HP:0000821', (27, 41))	('tumor metastasis', 'Disease', 'MESH:D009362', (130, 146))	('tumor metastasis', 'Disease', (130, 146))	('methimazole', 'Var', (48, 59))	('hypothyroidism', 'Disease', (27, 41))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('attenuation tumor', 'Disease', 'MESH:C538265', (79, 96))	('prolongs', 'PosReg', (151, 159))	('attenuation tumor', 'Disease', (79, 96))	('hypothyroidism', 'Disease', 'MESH:D007037', (27, 41))	('methimazole', 'Chemical', 'MESH:D008713', (48, 59))
81953	33846395	In our cases, high THRalpha1 expression was detected in most of squamous cell lung cancer cases and was associated with shorter OS and poor prognostic parameters.	('lung cancer', 'Phenotype', 'HP:0100526', (78, 89))	('squamous cell lung cancer', 'Disease', 'MESH:D002294', (64, 89))	('squamous cell lung cancer', 'Phenotype', 'HP:0030359', (64, 89))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('THRalpha1', 'Chemical', '-', (19, 28))	('high', 'Var', (14, 18))	('squamous cell lung cancer', 'Disease', (64, 89))	('expression', 'MPA', (29, 39))	('THRalpha1', 'Gene', (19, 28))
81958	26415504	AIF knockdown causes oxidation-mediated inactivation of the lipid phosphatase activity of PTEN, with ensuing activation of Akt kinase, phosphorylation of the Akt substrate GSK-3beta, and activation of beta-catenin signaling in cancer cells.	('GSK-3beta', 'Gene', '2932', (172, 181))	('activation', 'PosReg', (187, 197))	('Akt', 'Gene', '207', (158, 161))	('cancer', 'Disease', 'MESH:D009369', (227, 233))	('knockdown', 'Var', (4, 13))	('GSK-3beta', 'Gene', (172, 181))	('inactivation', 'NegReg', (40, 52))	('Akt', 'Gene', (123, 126))	('phosphorylation', 'MPA', (135, 150))	('PTEN', 'Gene', (90, 94))	('Akt', 'Gene', '207', (123, 126))	('lipid phosphatase activity', 'MPA', (60, 86))	('cancer', 'Disease', (227, 233))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('beta-catenin', 'Gene', (201, 213))	('activation', 'PosReg', (109, 119))	('beta-catenin', 'Gene', '1499', (201, 213))	('Akt', 'Gene', (158, 161))	('AIF', 'Gene', (0, 3))	('AIF', 'Gene', '9131', (0, 3))
81966	26415504	AIF contains two flavin adenine dinucleotide (FAD)-binding domains (residues 128-262 and 401-480), a putative NADH-binding domain (residues 263-400), and a C-terminal domain (residues 481-608).	('FAD', 'Chemical', 'MESH:D005182', (46, 49))	('AIF', 'Gene', '9131', (0, 3))	('NADH', 'Chemical', 'MESH:D009243', (110, 114))	('C', 'Chemical', 'MESH:D002244', (156, 157))	('flavin adenine dinucleotide', 'Chemical', 'MESH:D005182', (17, 44))	('AIF', 'Gene', (0, 3))	('residues 128-262', 'Var', (68, 84))
81972	26415504	Since PIP3 is the main cellular product of the class I phosphoinositide 3-kinases (PI3K), PTEN is capable of antagonizing PI3K activity and negatively regulates the PI3K-Akt signaling pathway.	('Akt', 'Gene', '207', (170, 173))	('PTEN', 'Var', (90, 94))	('Akt', 'Gene', (170, 173))	('PI3K', 'Pathway', (122, 126))	('PIP3', 'Chemical', '-', (6, 10))	('regulates', 'Reg', (151, 160))	('negatively', 'NegReg', (140, 150))	('activity', 'MPA', (127, 135))	('antagonizing', 'NegReg', (109, 121))
81974	26415504	Both endogenous hydrogen peroxide (H2O2) and exogenous hydrogen peroxide (H2O2) have been shown to cause oxidation of Cys124 in the catalytic center of PTEN to form a disulphide bond with Cys71, thereby leading to the reversible inactivation of PTEN phosphatase activity, followed by the increase in Akt phosphorylation.	('oxidation', 'Var', (105, 114))	('Akt', 'Gene', (300, 303))	('Cys124', 'Var', (118, 124))	('activity', 'MPA', (262, 270))	('hydrogen peroxide', 'Chemical', 'MESH:D006861', (55, 72))	('H2O2', 'Chemical', 'MESH:D006861', (35, 39))	('increase', 'PosReg', (288, 296))	('disulphide', 'Chemical', '-', (167, 177))	('PTEN phosphatase', 'Enzyme', (245, 261))	('H2O2', 'Chemical', 'MESH:D006861', (74, 78))	('hydrogen peroxide', 'Chemical', 'MESH:D006861', (16, 33))	('Cys124', 'Chemical', '-', (118, 124))	('inactivation', 'NegReg', (229, 241))	('Cys71', 'Chemical', '-', (188, 193))	('Akt', 'Gene', '207', (300, 303))
81997	26415504	Because all three short isoforms carry one FAD domain, we further detected the potential interaction of PTEN-N with FAD1 and/or FAD2 domains-deleted AIF mutants.	('FAD', 'Chemical', 'MESH:D005182', (128, 131))	('FAD2', 'Gene', (128, 132))	('interaction', 'Interaction', (89, 100))	('AIF', 'Gene', (149, 152))	('mutants', 'Var', (153, 160))	('detected', 'Reg', (66, 74))	('FAD1', 'Gene', (116, 120))	('FAD', 'Chemical', 'MESH:D005182', (43, 46))	('FAD1', 'Gene', '80308', (116, 120))	('FAD', 'Chemical', 'MESH:D005182', (116, 119))	('PTEN-N', 'Gene', (104, 110))	('domains-deleted', 'Var', (133, 148))	('AIF', 'Gene', '9131', (149, 152))
81998	26415504	The results showed that FAD1- or FAD2-deleted AIF mutant still interacted with PTEN-N, which was completely lost when both FAD1 and FAD2 were deleted (Fig 1K, right panel).	('FAD1', 'Gene', '80308', (24, 28))	('FAD', 'Chemical', 'MESH:D005182', (132, 135))	('interacted', 'Interaction', (63, 73))	('AIF', 'Gene', '9131', (46, 49))	('FAD1', 'Gene', (123, 127))	('AIF', 'Gene', (46, 49))	('FAD', 'Chemical', 'MESH:D005182', (33, 36))	('FAD', 'Chemical', 'MESH:D005182', (123, 126))	('FAD1', 'Gene', (24, 28))	('mutant', 'Var', (50, 56))	('FAD', 'Chemical', 'MESH:D005182', (24, 27))	('FAD1', 'Gene', '80308', (123, 127))
82026	26415504	It was reported that H2O2-mediated PTEN oxidation resulted in an intramolecular disulfide bond formed between Cys124 and Cys71, and mutation of either site resists oxidation by H2O2 .	('Cys71', 'Chemical', '-', (121, 126))	('resulted in', 'Reg', (50, 61))	('Cys124', 'Var', (110, 116))	('Cys71', 'Var', (121, 126))	('disulfide', 'Chemical', 'MESH:D004220', (80, 89))	('intramolecular disulfide bond formed', 'MPA', (65, 101))	('H2O2', 'Chemical', 'MESH:D006861', (177, 181))	('Cys124', 'Chemical', '-', (110, 116))	('H2O2', 'Chemical', 'MESH:D006861', (21, 25))	('mutation', 'Var', (132, 140))
82027	26415504	Hence, the recombinant PTEN was incubated with escalating concentrations of AIF with PTEN-C124S as a control, followed by probing with DCP-Bio1, a biotin-tagged probe which links covalently to oxidized cysteine and has been used to monitor oxidized proteins.	('AIF', 'Gene', '9131', (76, 79))	('biotin', 'Chemical', 'MESH:D001710', (147, 153))	('AIF', 'Gene', (76, 79))	('C124S', 'Mutation', 'p.C124S', (90, 95))	('cysteine', 'Chemical', 'MESH:D003545', (202, 210))	('PTEN-C124S', 'Var', (85, 95))	('oxidized cysteine', 'MPA', (193, 210))	('DCP-Bio1', 'Chemical', '-', (135, 143))	('links', 'Interaction', (173, 178))
82030	26415504	To address whether AIF regulates intracellular PTEN oxidation, two pairs of shRNAs (shAIF#1 and shAIF#2) specifically against AIF were used to knockdown AIF expression, together with non-specific scramble shRNA (shNC) as a negative control.	('AIF', 'Gene', (86, 89))	('AIF', 'Gene', (153, 156))	('AIF', 'Gene', '9131', (19, 22))	('AIF', 'Gene', '9131', (153, 156))	('AIF', 'Gene', '9131', (98, 101))	('AIF', 'Gene', (19, 22))	('C', 'Chemical', 'MESH:D002244', (215, 216))	('AIF', 'Gene', (98, 101))	('AIF', 'Gene', '9131', (126, 129))	('knockdown', 'Var', (143, 152))	('AIF', 'Gene', '9131', (86, 89))	('AIF', 'Gene', (126, 129))
82032	26415504	Consistent with a previous report, the mitochondrial complex I subunits NADH-ubiquinone oxidoreductase 75 kDa subunit (Ndufs1) and Ndufs3 were also decreased in SW620 cells with AIF knockdown (Fig EV2D), suggesting the effectiveness of AIF knockdown.	('Ndufs3', 'Gene', (131, 137))	('SW620', 'CellLine', 'CVCL:0547', (161, 166))	('AIF', 'Gene', '9131', (236, 239))	('mitochondrial complex I subunits NADH-ubiquinone oxidoreductase 75 kDa subunit (Ndufs1', 'Gene', '4719', (39, 125))	('decreased', 'NegReg', (148, 157))	('AIF', 'Gene', (236, 239))	('AIF', 'Gene', '9131', (178, 181))	('Ndufs3', 'Gene', '4722', (131, 137))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('knockdown', 'Var', (182, 191))	('AIF', 'Gene', (178, 181))	('EV2', 'Gene', (197, 200))	('EV2', 'Gene', '147138', (197, 200))
82033	26415504	AIF knockdown failed to affect the expression of PTEN protein (Fig 3F).	('knockdown', 'Var', (4, 13))	('AIF', 'Gene', (0, 3))	('AIF', 'Gene', '9131', (0, 3))
82035	26415504	In accordance, AIF knockdown inhibited PTEN lipid phosphatase activity in SW620 cells (Fig 3G), together with the increased phosphorylations of Akt on serine 473 (S473) and threonine 308 (T308), and of GSK-3beta, an Akt substrate (Fig 3F).	('Akt', 'Gene', (144, 147))	('inhibited', 'NegReg', (29, 38))	('phosphorylations', 'MPA', (124, 140))	('GSK-3beta', 'Gene', '2932', (202, 211))	('GSK-3beta', 'Gene', (202, 211))	('activity', 'MPA', (62, 70))	('serine', 'Chemical', 'MESH:D012694', (151, 157))	('knockdown', 'Var', (19, 28))	('PTEN lipid phosphatase', 'Enzyme', (39, 61))	('S473', 'Var', (163, 167))	('increased', 'PosReg', (114, 123))	('AIF', 'Gene', '9131', (15, 18))	('Akt', 'Gene', '207', (216, 219))	('threonine', 'Chemical', 'MESH:D013912', (173, 182))	('AIF', 'Gene', (15, 18))	('Akt', 'Gene', '207', (144, 147))	('SW620', 'CellLine', 'CVCL:0547', (74, 79))	('Akt', 'Gene', (216, 219))
82037	26415504	Notably, AIF knockdown appeared to reduce Akt-S473 and GSK-3beta phosphorylations in the PC3 cells, suggesting that additional factors impinge on the functional connections between AIF, Akt, and GSK3-3beta in the PTEN-deficient cells.	('Akt', 'Gene', (42, 45))	('AIF', 'Gene', (181, 184))	('Akt', 'Gene', '207', (186, 189))	('AIF', 'Gene', '9131', (9, 12))	('GSK-3beta', 'Gene', '2932', (55, 64))	('GSK-3beta', 'Gene', (55, 64))	('PC3', 'Gene', (89, 92))	('Akt', 'Gene', (186, 189))	('AIF', 'Gene', (9, 12))	('impinge', 'Reg', (135, 142))	('reduce', 'NegReg', (35, 41))	('Akt', 'Gene', '207', (42, 45))	('PC3', 'Gene', '10120', (89, 92))	('knockdown', 'Var', (13, 22))	('AIF', 'Gene', '9131', (181, 184))
82038	26415504	Importantly, AIF overexpression effectively reversed AIF knockdown-induced PTEN oxidation and Akt phosphorylation (Fig 3H).	('Akt', 'Gene', (94, 97))	('PTEN oxidation', 'MPA', (75, 89))	('AIF', 'Gene', '9131', (53, 56))	('AIF', 'Gene', '9131', (13, 16))	('AIF', 'Gene', (53, 56))	('knockdown-induced', 'Var', (57, 74))	('Akt', 'Gene', '207', (94, 97))	('AIF', 'Gene', (13, 16))
82039	26415504	Consistent with the previous reports, H2O2 incubation induced PTEN oxidation (Fig EV2H and I).	('H2O2', 'Var', (38, 42))	('EV2H and I', 'Gene', '79971', (82, 92))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('PTEN oxidation', 'MPA', (62, 76))	('H2O2', 'Chemical', 'MESH:D006861', (38, 42))
82040	26415504	More intriguingly, the exogenous H2O2-increased PTEN oxidation could also be significantly enhanced by AIF knockdown (Fig EV2H and I), while treatment of N-acetyl-l-cysteine (NAC), a H2O2 scavenger, not only prevented PTEN from oxidation, but also abolished the AIF knockdown-induced Akt activation (Fig 3I).	('knockdown', 'Var', (107, 116))	('AIF', 'Gene', (262, 265))	('AIF', 'Gene', '9131', (103, 106))	('Akt', 'Gene', '207', (284, 287))	('EV2H and I', 'Gene', '79971', (122, 132))	('H2O2', 'Chemical', 'MESH:D006861', (183, 187))	('NAC', 'Gene', (175, 178))	('AIF', 'Gene', (103, 106))	('NAC', 'Gene', '7504', (175, 178))	('H2O2', 'Chemical', 'MESH:D006861', (33, 37))	('Akt', 'Gene', (284, 287))	('activation', 'PosReg', (288, 298))	('enhanced', 'PosReg', (91, 99))	('AIF', 'Gene', '9131', (262, 265))	('PTEN oxidation', 'MPA', (48, 62))	('cysteine', 'Chemical', 'MESH:D003545', (165, 173))
82041	26415504	On the other hand, AIF knockdown did not increase the intracellular ROS level (Fig EV2J), precluded the possibility of increased ROS-induced PTEN oxidation in AIF knockdown cells.	('AIF', 'Gene', (159, 162))	('ROS', 'Chemical', 'MESH:D017382', (68, 71))	('increase the intracellular ROS level', 'Phenotype', 'HP:0025464', (41, 77))	('knockdown', 'Var', (23, 32))	('AIF', 'Gene', '9131', (19, 22))	('EV2', 'Gene', '147138', (83, 86))	('AIF', 'Gene', (19, 22))	('EV2', 'Gene', (83, 86))	('precluded', 'NegReg', (90, 99))	('ROS', 'Chemical', 'MESH:D017382', (129, 132))	('AIF', 'Gene', '9131', (159, 162))
82042	26415504	Of note, treatment with low concentration of H2O2 did not induce the nuclear translocation of AIF (Fig EV2K) and it also did not impact on the AIF-PTEN interaction (Fig EV2L).	('AIF', 'Gene', '9131', (94, 97))	('AIF', 'Gene', (94, 97))	('nuclear translocation', 'MPA', (69, 90))	('impact', 'Reg', (129, 135))	('interaction', 'Interaction', (152, 163))	('EV2', 'Gene', '147138', (169, 172))	('EV2', 'Gene', '147138', (103, 106))	('EV2', 'Gene', (169, 172))	('EV2', 'Gene', (103, 106))	('AIF', 'Gene', '9131', (143, 146))	('H2O2', 'Chemical', 'MESH:D006861', (45, 49))	('H2O2', 'Var', (45, 49))	('AIF', 'Gene', (143, 146))
82045	26415504	Although PTEN interacts with all these short isoforms, our results showed that, like AIF, AIFsh2 and AIFsh3 but not AIFsh could rescue AIF knockdown-induced PTEN oxidation and Akt activation (Fig 3H), further supporting that the effects of AIF on PTEN are enzymatic.	('AIF', 'Gene', '9131', (135, 138))	('AIF', 'Gene', (135, 138))	('rescue', 'PosReg', (128, 134))	('AIF', 'Gene', '9131', (85, 88))	('AIF', 'Gene', (85, 88))	('AIF', 'Gene', (101, 104))	('oxidation', 'MPA', (162, 171))	('AIF', 'Gene', '9131', (101, 104))	('AIF', 'Gene', '9131', (116, 119))	('AIF', 'Gene', (116, 119))	('AIF', 'Gene', '9131', (90, 93))	('AIF', 'Gene', (90, 93))	('PTEN', 'Protein', (157, 161))	('AIF', 'Gene', '9131', (240, 243))	('activation', 'PosReg', (180, 190))	('AIF', 'Gene', (240, 243))	('Akt', 'Gene', (176, 179))	('knockdown-induced', 'Var', (139, 156))	('Akt', 'Gene', '207', (176, 179))
82046	26415504	Although PTEN oxidation has been proved to be crucial for its activity, here we noticed that only a small fraction of PTEN was oxidized compared to total PTEN upon AIF knockdown.	('knockdown', 'Var', (168, 177))	('AIF', 'Gene', (164, 167))	('AIF', 'Gene', '9131', (164, 167))
82048	26415504	As shown in Fig EV2M, H2O2 induced a fast and transient oxidation of a small fraction of PTEN accompanied with increased Akt phosphorylation, which could be antagonized by NAC pretreatment, proposing that the oxidation of a part of PTEN can disrupt the activity of all PTEN, although its mechanisms remain to be illustrated.	('PTEN', 'Enzyme', (269, 273))	('Akt', 'Gene', (121, 124))	('increased', 'PosReg', (111, 120))	('disrupt', 'NegReg', (241, 248))	('oxidation', 'MPA', (56, 65))	('NAC', 'Gene', (172, 175))	('NAC', 'Gene', '7504', (172, 175))	('activity', 'MPA', (253, 261))	('H2O2', 'Chemical', 'MESH:D006861', (22, 26))	('H2O2', 'Var', (22, 26))	('EV2', 'Gene', '147138', (16, 19))	('Akt', 'Gene', '207', (121, 124))	('EV2', 'Gene', (16, 19))
82049	26415504	On the other hand, Cys124 is localized in the phosphatase activity center of PTEN, and the C124S mutant completely abolishes PTEN activity.	('C124S', 'Mutation', 'p.C124S', (91, 96))	('Cys124', 'Chemical', '-', (19, 25))	('Cys124', 'Var', (19, 25))	('PTEN', 'Enzyme', (125, 129))	('activity', 'MPA', (130, 138))	('abolishes', 'NegReg', (115, 124))	('C124S', 'Var', (91, 96))
82050	26415504	However, the C71S mutant still keeps the partial activity of PTEN relative to its wild-type form.	('PTEN', 'Protein', (61, 65))	('C71S', 'SUBSTITUTION', 'None', (13, 17))	('partial activity', 'MPA', (41, 57))	('C71S', 'Var', (13, 17))
82051	26415504	Here, we showed that the PTEN C71S mutant still interacted with AIF (Fig EV2N), suggesting that the cysteine is dispensable for PTEN-AIF interaction.	('interacted', 'Interaction', (48, 58))	('C71S', 'SUBSTITUTION', 'None', (30, 34))	('AIF', 'Gene', '9131', (64, 67))	('cysteine', 'Chemical', 'MESH:D003545', (100, 108))	('AIF', 'Gene', (133, 136))	('AIF', 'Gene', '9131', (133, 136))	('AIF', 'Gene', (64, 67))	('C71S', 'Var', (30, 34))	('PTEN', 'Gene', (25, 29))	('interaction', 'Interaction', (137, 148))	('EV2N', 'Chemical', '-', (73, 77))
82052	26415504	Thus, we tested whether the C71S mutant reversed AIF knockdown-enhanced oxidative inactivation of PTEN.	('AIF', 'Gene', '9131', (49, 52))	('C71S', 'Var', (28, 32))	('C71S', 'SUBSTITUTION', 'None', (28, 32))	('oxidative inactivation', 'MPA', (72, 94))	('tested', 'Reg', (9, 15))	('AIF', 'Gene', (49, 52))
82053	26415504	To this end, we introduced PTEN-WT or PTEN-C71S into PTEN-deficient PC3 cells and found that both proteins, especially PTEN-WT, inhibited Akt phosphorylation (Fig EV2O).	('Akt', 'Gene', (138, 141))	('PC3', 'Gene', (68, 71))	('Akt', 'Gene', '207', (138, 141))	('C71S', 'Var', (43, 47))	('EV2O', 'Chemical', '-', (163, 167))	('C71S', 'SUBSTITUTION', 'None', (43, 47))	('PC3', 'Gene', '10120', (68, 71))	('inhibited', 'NegReg', (128, 137))
82054	26415504	When these cells were exposed to H2O2, a small fraction of PTEN-WT but not PTEN-C71S protein was oxidized (Fig EV2O).	('oxidized', 'MPA', (97, 105))	('C71S', 'Var', (80, 84))	('H2O2', 'Chemical', 'MESH:D006861', (33, 37))	('C71S', 'SUBSTITUTION', 'None', (80, 84))	('EV2O', 'Chemical', '-', (111, 115))	('protein', 'Protein', (85, 92))
82055	26415504	Meanwhile, H2O2 counteracted the PTEN-WT but not PTEN-C71S mutant-induced inhibition of Akt phosphorylation (Fig EV2O), indicating the effectiveness of PTEN-C71S in resisting its oxidation and inactivation.	('EV2O', 'Chemical', '-', (113, 117))	('H2O2', 'Chemical', 'MESH:D006861', (11, 15))	('Akt', 'Gene', '207', (88, 91))	('C71S', 'SUBSTITUTION', 'None', (157, 161))	('mutant-induced', 'Var', (59, 73))	('inhibition', 'NegReg', (74, 84))	('C71S', 'Var', (54, 58))	('Akt', 'Gene', (88, 91))	('C71S', 'SUBSTITUTION', 'None', (54, 58))	('C71S', 'Var', (157, 161))
82056	26415504	In accordance, when PTEN-WT and PTEN-C71S were ectopically expressed in SW620 and HT29 cells with AIF knockdown, PTEN-C71S mutant but not PTEN-WT rescued AIF knockdown-induced Akt phosphorylation in these two cell lines (Fig 3J and K).	('Akt', 'Gene', (176, 179))	('C71S', 'Var', (118, 122))	('AIF', 'Gene', '9131', (98, 101))	('AIF', 'Gene', '9131', (154, 157))	('C71S', 'SUBSTITUTION', 'None', (37, 41))	('C71S', 'SUBSTITUTION', 'None', (118, 122))	('C71S', 'Var', (37, 41))	('AIF', 'Gene', (98, 101))	('AIF', 'Gene', (154, 157))	('HT29 cells', 'CellLine', 'CVCL:0320', (82, 92))	('rescued', 'PosReg', (146, 153))	('SW620', 'CellLine', 'CVCL:0547', (72, 77))	('Akt', 'Gene', '207', (176, 179))
82057	26415504	Also, the ectopically expressed PTEN-WT but not PTEN-C71S failed to inhibit Akt phosphorylation in AIF-silenced PC3 cells (Fig 3L).	('Akt', 'Gene', (76, 79))	('inhibit', 'NegReg', (68, 75))	('PC3', 'Gene', (112, 115))	('AIF', 'Gene', (99, 102))	('C71S', 'Var', (53, 57))	('AIF', 'Gene', '9131', (99, 102))	('C71S', 'SUBSTITUTION', 'None', (53, 57))	('Akt', 'Gene', '207', (76, 79))	('PC3', 'Gene', '10120', (112, 115))
82060	26415504	Indeed, there was abundant nuclear beta-catenin in AIF knockdown cells but not in shNC cells (Fig 4A and B).	('beta-catenin', 'Gene', (35, 47))	('knockdown', 'Var', (55, 64))	('AIF', 'Gene', (51, 54))	('beta-catenin', 'Gene', '1499', (35, 47))	('C', 'Chemical', 'MESH:D002244', (85, 86))	('AIF', 'Gene', '9131', (51, 54))
82062	26415504	To monitor the activation of WNT/beta-catenin signaling, shAIF#1-, shAIF#2-, and shNC-infected SW620 cells were transfected with LEF/TCF-responsive promoter Topflash luciferase (containing two sets of three copies of the LEF/TCF-binding sites) and its mutant Fopflash.	('AIF', 'Gene', (69, 72))	('AIF', 'Gene', '9131', (69, 72))	('C', 'Chemical', 'MESH:D002244', (134, 135))	('AIF', 'Gene', (59, 62))	('SW620', 'CellLine', 'CVCL:0547', (95, 100))	('Fopflash', 'Gene', (259, 267))	('LEF/TCF', 'Gene', (221, 228))	('C', 'Chemical', 'MESH:D002244', (84, 85))	('LEF/TCF', 'Gene', (129, 136))	('mutant', 'Var', (252, 258))	('C', 'Chemical', 'MESH:D002244', (226, 227))	('beta-catenin', 'Gene', (33, 45))	('LEF/TCF', 'Gene', '3172', (221, 228))	('beta-catenin', 'Gene', '1499', (33, 45))	('LEF/TCF', 'Gene', '3172', (129, 136))	('AIF', 'Gene', '9131', (59, 62))
82063	26415504	The results showed that AIF silencing significantly activated Topflash but not Fopflash (Fig 4C), indicating the activation of WNT/beta-catenin transcription in AIF knockdown cells.	('AIF', 'Gene', '9131', (24, 27))	('Topflash', 'MPA', (62, 70))	('AIF', 'Gene', (24, 27))	('beta-catenin', 'Gene', (131, 143))	('C', 'Chemical', 'MESH:D002244', (94, 95))	('silencing', 'Var', (28, 37))	('activation', 'PosReg', (113, 123))	('AIF', 'Gene', '9131', (161, 164))	('beta-catenin', 'Gene', '1499', (131, 143))	('activated', 'PosReg', (52, 61))	('AIF', 'Gene', (161, 164))
82064	26415504	Consistently, the mRNA levels of all six WNT/beta-catenin target genes tested (DKK1, LEF1, MMP7, TCF4, AXIN2, and ID2) presented the upregulated expression upon AIF knockdown in SW620 (Fig 4D) and HT29 cells (Fig EV3A).	('upregulated', 'PosReg', (133, 144))	('MMP7', 'Gene', (91, 95))	('TCF4', 'Gene', (97, 101))	('SW620', 'CellLine', 'CVCL:0547', (178, 183))	('AXIN2', 'Gene', (103, 108))	('LEF1', 'Gene', (85, 89))	('expression', 'MPA', (145, 155))	('ID2', 'Gene', '3398', (114, 117))	('C', 'Chemical', 'MESH:D002244', (98, 99))	('ID2', 'Gene', (114, 117))	('mRNA levels', 'MPA', (18, 29))	('EV3', 'Chemical', '-', (213, 216))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('beta-catenin', 'Gene', (45, 57))	('beta-catenin', 'Gene', '1499', (45, 57))	('LEF1', 'Gene', '51176', (85, 89))	('AXIN2', 'Gene', '8313', (103, 108))	('HT29 cells', 'CellLine', 'CVCL:0320', (197, 207))	('MMP7', 'Gene', '4316', (91, 95))	('AIF', 'Gene', '9131', (161, 164))	('AIF', 'Gene', (161, 164))	('TCF4', 'Gene', '6925', (97, 101))	('DKK1', 'Gene', '22943', (79, 83))	('DKK1', 'Gene', (79, 83))	('knockdown', 'Var', (165, 174))
82066	26415504	Vice versa, the overexpression of AIF downregulated these target genes (Fig 4E), and both AIF-FL and AIFsh3 rescued the AIF knockdown-induced activation of Wnt/beta-catenin transcription (Fig EV3C).	('knockdown-induced', 'Var', (124, 141))	('AIF', 'Gene', (90, 93))	('activation', 'PosReg', (142, 152))	('AIF', 'Gene', (101, 104))	('AIF', 'Gene', '9131', (101, 104))	('beta-catenin', 'Gene', (160, 172))	('downregulated', 'NegReg', (38, 51))	('AIF', 'Gene', (34, 37))	('AIF', 'Gene', '9131', (34, 37))	('AIF', 'Gene', '9131', (120, 123))	('beta-catenin', 'Gene', '1499', (160, 172))	('AIF', 'Gene', (120, 123))	('AIF', 'Gene', '9131', (90, 93))
82067	26415504	Considering previous reports showing that none of these genes are under sole control of WNT/beta-catenin signaling, we knocked down beta-catenin with a pair of shRNA specially against beta-catenin (shbeta-catenin#2) in AIF-silenced cells and found that beta-catenin knockdown almost completely blocked AIF silencing-induced expressions of all six genes (Fig EV3D), proposing the role of the activated beta-catenin in the AIF knockdown-mediated events.	('AIF', 'Gene', '9131', (302, 305))	('AIF', 'Gene', (302, 305))	('beta-catenin', 'Gene', (200, 212))	('knocked', 'Var', (119, 126))	('beta-catenin', 'Gene', (184, 196))	('expressions', 'MPA', (324, 335))	('beta-catenin', 'Gene', '1499', (200, 212))	('beta-catenin', 'Gene', '1499', (184, 196))	('EV3', 'Chemical', '-', (358, 361))	('knockdown', 'Var', (266, 275))	('beta-catenin', 'Gene', (253, 265))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('beta-catenin', 'Gene', '1499', (253, 265))	('AIF', 'Gene', '9131', (219, 222))	('AIF', 'Gene', (219, 222))	('silencing-induced', 'NegReg', (306, 323))	('beta-catenin', 'Gene', (132, 144))	('beta-catenin', 'Gene', '1499', (132, 144))	('beta-catenin', 'Gene', (92, 104))	('beta-catenin', 'Gene', '1499', (92, 104))	('beta-catenin', 'Gene', (401, 413))	('beta-catenin', 'Gene', '1499', (401, 413))	('AIF', 'Gene', '9131', (421, 424))	('blocked', 'NegReg', (294, 301))	('AIF', 'Gene', (421, 424))
82069	26415504	Thus, we conclude that AIF knockdown results in the activation of beta-catenin signaling.	('knockdown', 'Var', (27, 36))	('beta-catenin', 'Gene', (66, 78))	('beta-catenin', 'Gene', '1499', (66, 78))	('AIF', 'Gene', '9131', (23, 26))	('AIF', 'Gene', (23, 26))	('activation', 'PosReg', (52, 62))
82070	26415504	To address whether AIF regulates WNT/beta-catenin signaling through PTEN, we knocked down AIF and/or PTEN in SW620 cells (Fig 5A).	('AIF', 'Gene', (90, 93))	('SW620', 'CellLine', 'CVCL:0547', (109, 114))	('knocked', 'Var', (77, 84))	('PTEN', 'Gene', (101, 105))	('AIF', 'Gene', '9131', (19, 22))	('beta-catenin', 'Gene', (37, 49))	('AIF', 'Gene', (19, 22))	('beta-catenin', 'Gene', '1499', (37, 49))	('AIF', 'Gene', '9131', (90, 93))
82071	26415504	AIF or PTEN silencing increased, while their combined knockdown did not further enhance, expressions of WNT/beta-catenin signaling target genes (Fig 5B).	('beta-catenin', 'Gene', (108, 120))	('expressions', 'MPA', (89, 100))	('beta-catenin', 'Gene', '1499', (108, 120))	('silencing', 'Var', (12, 21))	('increased', 'PosReg', (22, 31))	('AIF', 'Gene', (0, 3))	('AIF', 'Gene', '9131', (0, 3))	('PTEN', 'Gene', (7, 11))
82072	26415504	Furthermore, LY294002, an inhibitor of the PI3K/Akt pathway, significantly antagonized AIF knockdown-induced expressions of all six WNT/beta-catenin signaling target genes tested (Fig 5C).	('beta-catenin', 'Gene', '1499', (136, 148))	('AIF', 'Gene', (87, 90))	('Akt', 'Gene', (48, 51))	('AIF', 'Gene', '9131', (87, 90))	('LY294002', 'Chemical', 'MESH:C085911', (13, 21))	('antagonized', 'NegReg', (75, 86))	('LY294002', 'Var', (13, 21))	('Akt', 'Gene', '207', (48, 51))	('beta-catenin', 'Gene', (136, 148))	('C', 'Chemical', 'MESH:D002244', (185, 186))	('expressions', 'MPA', (109, 120))
82073	26415504	Moreover, NAC treatment (Fig 5D) and overexpression of the PTEN-C71S mutant but not wild-type PTEN (Fig 5E) reversed AIF knockdown-induced expressions of WNT/beta-catenin signaling target genes.	('beta-catenin', 'Gene', (158, 170))	('AIF', 'Gene', '9131', (117, 120))	('beta-catenin', 'Gene', '1499', (158, 170))	('AIF', 'Gene', (117, 120))	('NAC', 'Gene', (10, 13))	('NAC', 'Gene', '7504', (10, 13))	('C71S', 'Var', (64, 68))	('C71S', 'SUBSTITUTION', 'None', (64, 68))	('expressions', 'MPA', (139, 150))
82074	26415504	Cumulatively, all these data propose that PTEN oxidative inactivation mediates AIF knockdown-activating WNT/beta-catenin signaling.	('beta-catenin', 'Gene', (108, 120))	('PTEN', 'Gene', (42, 46))	('AIF', 'Gene', (79, 82))	('beta-catenin', 'Gene', '1499', (108, 120))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('knockdown-activating', 'Var', (83, 103))	('AIF', 'Gene', '9131', (79, 82))
82076	26415504	Of great interest, upon AIF knockdown in SW620 cells, the mRNA and/or protein levels of the epithelial markers E-cadherin and plakoglobin dramatically decreased, and those of the mesenchymal markers fibronectin and vimentin increased (Fig 6A and B).	('AIF', 'Gene', '9131', (24, 27))	('fibronectin', 'Gene', (199, 210))	('E-cadherin', 'Gene', '999', (111, 121))	('AIF', 'Gene', (24, 27))	('vimentin', 'Gene', '7431', (215, 223))	('vimentin', 'Gene', (215, 223))	('decreased', 'NegReg', (151, 160))	('fibronectin', 'Gene', '2335', (199, 210))	('knockdown', 'Var', (28, 37))	('E-cadherin', 'Gene', (111, 121))	('increased', 'PosReg', (224, 233))	('SW620', 'CellLine', 'CVCL:0547', (41, 46))	('mRNA and/or', 'MPA', (58, 69))
82077	26415504	In line with these biochemical alterations, SW620 cells with AIF knockdown exhibited a spindle-like, fibroblastic morphology compared to the typical cobblestone-like appearance of shNC-infected cells (Fig 6C).	('SW620', 'CellLine', 'CVCL:0547', (44, 49))	('C', 'Chemical', 'MESH:D002244', (206, 207))	('C', 'Chemical', 'MESH:D002244', (183, 184))	('AIF', 'Gene', '9131', (61, 64))	('exhibited', 'Reg', (75, 84))	('knockdown', 'Var', (65, 74))	('spindle-like', 'CPA', (87, 99))	('AIF', 'Gene', (61, 64))
82079	26415504	Considering that some previous reports showed that SW620 cells have at least a partially mesenchymal character, which may be reflected in the heterogeneous appearance of these cells that present with different morphologies in culture, we also detected the potential EMT-inducing effect of AIF knockdown in two other cancer cell lines, HT29 and DU145 cells, without WNT/beta-catenin pathway activating mutations.	('AIF', 'Gene', '9131', (289, 292))	('AIF', 'Gene', (289, 292))	('DU145', 'CellLine', 'CVCL:0105', (344, 349))	('cancer', 'Phenotype', 'HP:0002664', (316, 322))	('knockdown', 'Var', (293, 302))	('beta-catenin', 'Gene', (369, 381))	('SW620', 'CellLine', 'CVCL:0547', (51, 56))	('cancer', 'Disease', 'MESH:D009369', (316, 322))	('beta-catenin', 'Gene', '1499', (369, 381))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('HT29', 'CellLine', 'CVCL:0320', (335, 339))	('cancer', 'Disease', (316, 322))	('EMT-inducing effect', 'CPA', (266, 285))
82080	26415504	The results demonstrated that, like seen in SW620 cells, AIF knockdown could also trigger these two cell lines to undergo EMT (Fig EV4A and B).	('SW620', 'CellLine', 'CVCL:0547', (44, 49))	('EV4', 'Chemical', '-', (131, 134))	('trigger', 'Reg', (82, 89))	('knockdown', 'Var', (61, 70))	('AIF', 'Gene', '9131', (57, 60))	('AIF', 'Gene', (57, 60))
82083	26415504	We also detected the expressions of the main EMT activators including ZEB1, Twist, Snail, and Slug upon AIF knockdown in SW620 cells, and results showed that among these four activators, the expression of only ZEB1, another target gene of WNT/beta-catenin signaling, was elevated by AIF knockdown (Figs 6A and B, and EV4F).	('ZEB1', 'Gene', (210, 214))	('ZEB1', 'Gene', (70, 74))	('AIF', 'Gene', (104, 107))	('EV4', 'Chemical', '-', (317, 320))	('knockdown', 'Var', (287, 296))	('ZEB1', 'Gene', '6935', (210, 214))	('AIF', 'Gene', '9131', (283, 286))	('Slug', 'Gene', '6591', (94, 98))	('AIF', 'Gene', (283, 286))	('beta-catenin', 'Gene', (243, 255))	('SW620', 'CellLine', 'CVCL:0547', (121, 126))	('elevated', 'PosReg', (271, 279))	('Slug', 'Gene', (94, 98))	('expression', 'MPA', (191, 201))	('beta-catenin', 'Gene', '1499', (243, 255))	('AIF', 'Gene', '9131', (104, 107))	('ZEB1', 'Gene', '6935', (70, 74))
82084	26415504	Of note, it appeared that the increase in ZEB1 protein was more significant than its mRNA upon AIF knockdown (Fig 6A and B).	('protein', 'Protein', (47, 54))	('AIF', 'Gene', '9131', (95, 98))	('AIF', 'Gene', (95, 98))	('knockdown', 'Var', (99, 108))	('increase', 'PosReg', (30, 38))	('ZEB1', 'Gene', (42, 46))	('ZEB1', 'Gene', '6935', (42, 46))
82086	26415504	These two shRNAs almost completely reversed the ZEB1 protein increase and EMT program upon AIF silencing (Fig 6F and G).	('ZEB1', 'Gene', '6935', (48, 52))	('EMT program', 'CPA', (74, 85))	('AIF', 'Gene', '9131', (91, 94))	('AIF', 'Gene', (91, 94))	('silencing', 'Var', (95, 104))	('increase', 'PosReg', (61, 69))	('ZEB1', 'Gene', (48, 52))
82087	26415504	The re-expression of the PTEN-C71S mutant but not PTEN-WT reversed the EMT program, including EMT marker expression (Fig 6H and I) and morphological changes (Fig 6J).	('morphological changes', 'CPA', (135, 156))	('C71S', 'SUBSTITUTION', 'None', (30, 34))	('EMT program', 'CPA', (71, 82))	('EMT marker', 'CPA', (94, 104))	('C71S', 'Var', (30, 34))
82088	26415504	Taken together, our results indicate that AIF knockdown induces EMT through WNT/beta-catenin signaling activation caused by PTEN oxidative inactivation.	('AIF', 'Gene', (42, 45))	('knockdown', 'Var', (46, 55))	('PTEN', 'MPA', (124, 128))	('induces', 'PosReg', (56, 63))	('beta-catenin', 'Gene', (80, 92))	('beta-catenin', 'Gene', '1499', (80, 92))	('activation', 'PosReg', (103, 113))	('AIF', 'Gene', '9131', (42, 45))	('EMT', 'CPA', (64, 67))
82091	26415504	Indeed, AIF knockdown cells exhibited enhanced mobility by a scratch wound-healing assay (Fig 7A) and increased invasiveness by Matrigel-coated Boyden chamber invasion assay (Fig 7B and C).	('AIF', 'Gene', '9131', (8, 11))	('AIF', 'Gene', (8, 11))	('enhanced', 'PosReg', (38, 46))	('C', 'Chemical', 'MESH:D002244', (186, 187))	('knockdown', 'Var', (12, 21))	('invasiveness', 'CPA', (112, 124))	('increased', 'PosReg', (102, 111))	('scratch wound-healing assay', 'CPA', (61, 88))	('mobility', 'CPA', (47, 55))
82101	26415504	Moreover, re-expression of PTEN-C71S mutant almost completely reversed the effect of AIF knockdown on the development of liver metastasis of splenically injected SW620 cells (Fig 7H and I), indicating that the metastasis-promoting role of AIF knockdown is mediated by PTEN oxidation.	('AIF', 'Gene', '9131', (239, 242))	('C71S', 'Var', (32, 36))	('SW620', 'CellLine', 'CVCL:0547', (162, 167))	('AIF', 'Gene', (239, 242))	('AIF', 'Gene', '9131', (85, 88))	('C71S', 'SUBSTITUTION', 'None', (32, 36))	('AIF', 'Gene', (85, 88))	('metastasis-promoting', 'CPA', (210, 230))
82102	26415504	To consolidate the role of AIF in metastasis, we also injected GFP-luciferase-labeled colon cancer HT29 cells with or without AIF knockdown into the spleen of mice (Figs 7J and EV5H).	('AIF', 'Gene', (27, 30))	('EV5H', 'Chemical', '-', (177, 181))	('colon cancer', 'Disease', (86, 98))	('colon cancer', 'Phenotype', 'HP:0003003', (86, 98))	('knockdown', 'Var', (130, 139))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('HT29 cells', 'CellLine', 'CVCL:0320', (99, 109))	('mice', 'Species', '10090', (159, 163))	('AIF', 'Gene', '9131', (126, 129))	('colon cancer', 'Disease', 'MESH:D015179', (86, 98))	('AIF', 'Gene', '9131', (27, 30))	('AIF', 'Gene', (126, 129))
82104	26415504	All these data support that knockdown of AIF expression promotes the metastasis of cancer cells.	('AIF', 'Gene', (41, 44))	('metastasis of cancer', 'Disease', (69, 89))	('metastasis of cancer', 'Disease', 'MESH:D009362', (69, 89))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('knockdown', 'Var', (28, 37))	('promotes', 'PosReg', (56, 64))	('AIF', 'Gene', '9131', (41, 44))
82125	26415504	AIF knockdown makes PTEN be oxidized, which can be rescued by re-expression of AIF or NAC treatment.	('oxidized', 'MPA', (28, 36))	('AIF', 'Gene', (79, 82))	('NAC', 'Gene', (86, 89))	('NAC', 'Gene', '7504', (86, 89))	('PTEN', 'Protein', (20, 24))	('knockdown', 'Var', (4, 13))	('AIF', 'Gene', (0, 3))	('AIF', 'Gene', '9131', (0, 3))	('AIF', 'Gene', '9131', (79, 82))
82128	26415504	Of note, only a small fraction of PTEN is oxidized compared to total PTEN upon AIF knockdown.	('knockdown', 'Var', (83, 92))	('AIF', 'Gene', (79, 82))	('AIF', 'Gene', '9131', (79, 82))
82129	26415504	The exposure to low concentrations of H2O2 also induces oxidative modification of a small fraction of PTEN accompanied with the increased Akt phosphorylation.	('H2O2', 'Var', (38, 42))	('Akt', 'Gene', (138, 141))	('increased', 'PosReg', (128, 137))	('PTEN', 'Protein', (102, 106))	('induces', 'Reg', (48, 55))	('Akt', 'Gene', '207', (138, 141))	('oxidative modification', 'MPA', (56, 78))	('H2O2', 'Chemical', 'MESH:D006861', (38, 42))
82130	26415504	The ectopically expressed PTEN-C71S mutant, whose cysteine is essential for intracellular intramolecular disulfide bond formation of PTEN oxidation, can rescue all the AIF knockdown-induced effects.	('C71S', 'Var', (31, 35))	('C71S', 'SUBSTITUTION', 'None', (31, 35))	('cysteine', 'Chemical', 'MESH:D003545', (50, 58))	('disulfide', 'Chemical', 'MESH:D004220', (105, 114))	('AIF', 'Gene', (168, 171))	('AIF', 'Gene', '9131', (168, 171))
82131	26415504	Therefore, partial modification of PTEN by oxidation contributes to the inactivation of total PTEN and thus activation of Akt.	('partial modification', 'Var', (11, 31))	('PTEN', 'Gene', (35, 39))	('inactivation', 'NegReg', (72, 84))	('Akt', 'Gene', '207', (122, 125))	('PTEN', 'Protein', (94, 98))	('Akt', 'Gene', (122, 125))	('activation', 'PosReg', (108, 118))
82135	26415504	Tumorigenesis and metastasis are caused by the dysregulation of a series of intracellular signals such as WNT signaling, which has been well established as a metastasis regulator of cancer.	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('metastasis', 'CPA', (18, 28))	('dysregulation', 'Var', (47, 60))	('caused by', 'Reg', (33, 42))	('Tumorigenesis', 'CPA', (0, 13))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('cancer', 'Disease', (182, 188))
82139	26415504	In line with this, knockdown of AIF significantly increases transcriptional activity of WNT/beta-catenin signaling and expressions of WNT/beta-catenin target genes.	('expressions', 'MPA', (119, 130))	('AIF', 'Gene', '9131', (32, 35))	('beta-catenin', 'Gene', (138, 150))	('knockdown', 'Var', (19, 28))	('AIF', 'Gene', (32, 35))	('beta-catenin', 'Gene', '1499', (138, 150))	('increases', 'PosReg', (50, 59))	('beta-catenin', 'Gene', (92, 104))	('transcriptional activity', 'MPA', (60, 84))	('beta-catenin', 'Gene', '1499', (92, 104))
82140	26415504	In particular, beta-catenin knockdown almost completely blocked AIF silencing-induced phenotype.	('AIF', 'Gene', '9131', (64, 67))	('beta-catenin', 'Gene', (15, 27))	('AIF', 'Gene', (64, 67))	('knockdown', 'Var', (28, 37))	('beta-catenin', 'Gene', '1499', (15, 27))	('blocked', 'NegReg', (56, 63))
82141	26415504	These data support the role of activated beta-catenin in AIF knockdown-induced effects.	('beta-catenin', 'Gene', (41, 53))	('beta-catenin', 'Gene', '1499', (41, 53))	('AIF', 'Gene', '9131', (57, 60))	('AIF', 'Gene', (57, 60))	('knockdown-induced', 'Var', (61, 78))
82142	26415504	Inactivation of GSK-3beta leads to the nuclear accumulation of beta-catenin, which in turn activates the WNT/beta-catenin signaling pathway and promotes the expression of a bunch of WNT/beta-catenin target genes.	('beta-catenin', 'Gene', (63, 75))	('expression', 'MPA', (157, 167))	('beta-catenin', 'Gene', '1499', (63, 75))	('beta-catenin', 'Gene', (186, 198))	('promotes', 'PosReg', (144, 152))	('beta-catenin', 'Gene', (109, 121))	('activates', 'PosReg', (91, 100))	('GSK-3beta', 'Gene', (16, 25))	('nuclear accumulation', 'MPA', (39, 59))	('beta-catenin', 'Gene', '1499', (186, 198))	('GSK-3beta', 'Gene', '2932', (16, 25))	('beta-catenin', 'Gene', '1499', (109, 121))	('Inactivation', 'Var', (0, 12))
82143	26415504	Although a previous report proposed that cross talk between the PI3K and WNT/beta-catenin pathways might be prohibited and WNT/beta-catenin-mediated transcriptional activity was not modulated by the activation of the PI3K/Akt pathway, our results showed that the oxidation-resistant mutant of PTEN, PTEN-C71S, but not wild-type PTEN, as well as PI3K/Akt inhibitor and NAC treatment, reversed AIF knockdown-induced expressions of WNT/beta-catenin signaling target genes, supporting that AIF regulates beta-catenin signaling through PTEN-PI3K/Akt pathway.	('regulates', 'Reg', (490, 499))	('Akt', 'Gene', '207', (350, 353))	('Akt', 'Gene', (222, 225))	('beta-catenin', 'Gene', (500, 512))	('NAC', 'Gene', '7504', (368, 371))	('beta-catenin', 'Gene', '1499', (500, 512))	('beta-catenin', 'Gene', (127, 139))	('beta-catenin', 'Gene', '1499', (127, 139))	('Akt', 'Gene', '207', (222, 225))	('AIF', 'Gene', '9131', (392, 395))	('AIF', 'Gene', '9131', (486, 489))	('AIF', 'Gene', (392, 395))	('Akt', 'Gene', (541, 544))	('AIF', 'Gene', (486, 489))	('C71S', 'Var', (304, 308))	('C71S', 'SUBSTITUTION', 'None', (304, 308))	('beta-catenin', 'Gene', (77, 89))	('beta-catenin', 'Gene', '1499', (77, 89))	('beta-catenin', 'Gene', (433, 445))	('Akt', 'Gene', '207', (541, 544))	('beta-catenin', 'Gene', '1499', (433, 445))	('NAC', 'Gene', (368, 371))	('Akt', 'Gene', (350, 353))
82145	26415504	Indeed, AIF silencing induces EMT and increases the in vitro mobility and invasiveness, and promotes in vivo hepatic metastasis of orthotopically implanted tumors in nude mice.	('nude mice', 'Species', '10090', (166, 175))	('AIF', 'Gene', '9131', (8, 11))	('increases', 'PosReg', (38, 47))	('promotes', 'PosReg', (92, 100))	('AIF', 'Gene', (8, 11))	('hepatic metastasis', 'Disease', (109, 127))	('silencing', 'Var', (12, 21))	('hepatic metastasis', 'Disease', 'MESH:D009362', (109, 127))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('invasiveness', 'CPA', (74, 86))	('induces', 'PosReg', (22, 29))	('EMT', 'CPA', (30, 33))	('tumors', 'Disease', 'MESH:D009369', (156, 162))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('tumors', 'Disease', (156, 162))
82148	26415504	It should be pointed out that a previous report, which showed that human colon carcinoma cell lines with AIF knockout by homologous recombination failed to form tumors in athymic mice or grow in soft agar, was completely inconsistent with our results from cancer cells with AIF knockdown.	('mice', 'Species', '10090', (179, 183))	('cancer', 'Disease', 'MESH:D009369', (256, 262))	('tumors', 'Disease', (161, 167))	('tumors', 'Phenotype', 'HP:0002664', (161, 167))	('knockout', 'Var', (109, 117))	('AIF', 'Gene', '9131', (274, 277))	('cancer', 'Disease', (256, 262))	('AIF', 'Gene', '9131', (105, 108))	('tumors', 'Disease', 'MESH:D009369', (161, 167))	('colon carcinoma', 'Disease', 'MESH:D015179', (73, 88))	('AIF', 'Gene', (274, 277))	('colon carcinoma', 'Disease', (73, 88))	('AIF', 'Gene', (105, 108))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('cancer', 'Phenotype', 'HP:0002664', (256, 262))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('human', 'Species', '9606', (67, 72))
82153	26415504	As a multifunctional protein, we proposed that its pro-survival function in cancer cells with high AIF expression contributes to tumorigenesis, and its role as antagonist of PI3K signaling in cancer cells with low AIF expression during hypoxic environment is correlated with EMT and metastasis of cancers.	('AIF', 'Gene', '9131', (214, 217))	('cancer', 'Disease', (192, 198))	('AIF', 'Gene', (214, 217))	('tumor', 'Disease', (129, 134))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('cancer', 'Disease', 'MESH:D009369', (297, 303))	('EMT', 'CPA', (275, 278))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('AIF', 'Gene', (99, 102))	('AIF', 'Gene', '9131', (99, 102))	('high', 'Var', (94, 98))	('metastasis of cancers', 'Disease', (283, 304))	('metastasis of cancers', 'Disease', 'MESH:D009362', (283, 304))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('cancer', 'Disease', 'MESH:D009369', (192, 198))	('expression', 'Var', (103, 113))	('cancer', 'Disease', (76, 82))	('pro-survival', 'PosReg', (51, 63))	('cancer', 'Disease', (297, 303))	('cancers', 'Phenotype', 'HP:0002664', (297, 304))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('cancer', 'Phenotype', 'HP:0002664', (297, 303))
82171	26415504	Plasmids expressing GST-tagged AIF and its mutants were generated by inserting correspondent CDS into pEGX-5X-1 vector.	('GST', 'Gene', (20, 23))	('AIF', 'Gene', (31, 34))	('GST', 'Gene', '373156', (20, 23))	('C', 'Chemical', 'MESH:D002244', (93, 94))	('mutants', 'Var', (43, 50))	('AIF', 'Gene', '9131', (31, 34))
82226	26415504	Recombinant full-length PTEN, AIF, and its mutants were expressed in E. coli using the SUMO-fusion expression system (Life Sensor, Tokyo, JP) and purified by nickel chelating, ion exchange, and gel filtration columns as reported.	('nickel', 'Chemical', 'MESH:D009532', (158, 164))	('AIF', 'Gene', '9131', (30, 33))	('AIF', 'Gene', (30, 33))	('mutants', 'Var', (43, 50))	('PTEN', 'Gene', (24, 28))	('E. coli', 'Species', '562', (69, 76))
82230	26415504	For endogenous PTEN phosphatase activity, SW620 cells with or without AIF knockdown were lysed in phosphatase inhibitors-free lysis buffer.	('AIF', 'Gene', (70, 73))	('AIF', 'Gene', '9131', (70, 73))	('SW620', 'CellLine', 'CVCL:0547', (42, 47))	('knockdown', 'Var', (74, 83))
82310	33160368	In univariate analysis, the MPV was significantly associated with CSS (HR 0.85, 95% CI 0.74-0.98, p = 0.025).	('associated', 'Reg', (50, 60))	('CSS', 'Disease', (66, 69))	('CSS', 'Chemical', '-', (66, 69))	('MPV', 'Var', (28, 31))
82373	30662542	Classification of TIMT based on PD-1/PD-L1 and CD8+ TIL could efficiently classify patients of different survival in ADC but not SCC, with the best overall survival achieved in TIMT3 (high CD8+ TIL and low PD-1/PD-L1), whereas TIMT2 (low CD8+ TIL and high PD-1/PD-L1) manifested the worst outcome.	('PD-1', 'Gene', (256, 260))	('SCC', 'Gene', '6317', (129, 132))	('PD-1', 'Gene', '5133', (256, 260))	('CD8', 'Gene', (47, 50))	('patients', 'Species', '9606', (83, 91))	('CD8', 'Gene', '925', (47, 50))	('CD8', 'Gene', (189, 192))	('PD-1', 'Gene', (206, 210))	('PD-1', 'Gene', '5133', (206, 210))	('CD8', 'Gene', '925', (189, 192))	('TIMT3', 'Var', (177, 182))	('PD-1', 'Gene', (32, 36))	('CD8', 'Gene', (238, 241))	('SCC', 'Gene', (129, 132))	('PD-1', 'Gene', '5133', (32, 36))	('CD8', 'Gene', '925', (238, 241))
82395	30662542	Level 3 TCGA mRNA-sequencing matrix plus clinical metadata and complete profiles of sequence-verified mutations for NSCLC were obtained with permission from the Cancer Genomics Hub (https://cghub.	('NSCLC', 'Disease', 'MESH:D002289', (116, 121))	('NSCLC', 'Phenotype', 'HP:0030358', (116, 121))	('Cancer', 'Phenotype', 'HP:0002664', (161, 167))	('Cancer', 'Disease', (161, 167))	('mutations', 'Var', (102, 111))	('Cancer', 'Disease', 'MESH:D009369', (161, 167))	('NSCLC', 'Disease', (116, 121))
82407	30662542	The statistical significance of two continuous values, such as CD8+ T cell infiltrating density, PD-1/PD-L1 mRNA expression level, the number of mutations etc.	('mutations', 'Var', (145, 154))	('PD-1', 'Gene', (97, 101))	('CD8', 'Gene', (63, 66))	('PD-1', 'Gene', '5133', (97, 101))	('CD8', 'Gene', '925', (63, 66))
82417	30662542	PD-1 mRNA expression level was higher in tumor of female gender (P<0.001), adenocarcinoma (P<0.001), tumor with mutant EGFR (P=0.007) and tumor with high mutation burden (P=0.010).	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Disease', (138, 143))	('mutant', 'Var', (112, 118))	('higher', 'PosReg', (31, 37))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('EGFR', 'Gene', (119, 123))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('adenocarcinoma', 'Disease', (75, 89))	('PD-1', 'Gene', (0, 4))	('tumor', 'Disease', (41, 46))	('PD-1', 'Gene', '5133', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('mRNA expression level', 'MPA', (5, 26))	('adenocarcinoma', 'Disease', 'MESH:D000230', (75, 89))	('tumor', 'Disease', (101, 106))	('EGFR', 'Gene', '1956', (119, 123))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
82418	30662542	While high PD-L1 mRNA expression level was associated with M0 stage (P=0.001) and squamous cell carcinoma (P=0.004).	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('squamous cell carcinoma', 'Disease', (82, 105))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (82, 105))	('high', 'Var', (6, 10))	('PD-L1', 'Gene', (11, 16))	('associated', 'Reg', (43, 53))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (82, 105))
82419	30662542	Of note, the analysis on driver mutation was performed only for adenocarcinoma, as all the mutant EGFR and 166 out of 171 mutant KRAS are of adenocarcinoma.	('EGFR', 'Gene', (98, 102))	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))	('adenocarcinoma', 'Disease', (64, 78))	('KRAS', 'Gene', (129, 133))	('adenocarcinoma', 'Disease', (141, 155))	('adenocarcinoma', 'Disease', 'MESH:D000230', (64, 78))	('KRAS', 'Gene', '3845', (129, 133))	('EGFR', 'Gene', '1956', (98, 102))	('mutant', 'Var', (91, 97))	('adenocarcinoma', 'Disease', 'MESH:D000230', (141, 155))
82427	30662542	The proportion of TMIT samples was analyzed according to histological subtypes, TNM stages, EGFR mutation status and TMB level (Fig.	('TNM', 'Gene', (80, 83))	('TMB', 'Chemical', '-', (117, 120))	('TNM', 'Gene', '10178', (80, 83))	('EGFR', 'Gene', '1956', (92, 96))	('mutation', 'Var', (97, 105))	('EGFR', 'Gene', (92, 96))
82428	30662542	The proportion of TIMT4 (high PD-L1 expression and high CD8+ TIL) is significantly lower in subgroup of TMN IV and subgroup of EGFR mutation.	('TMN IV', 'Disease', (104, 110))	('lower', 'NegReg', (83, 88))	('CD8', 'Gene', (56, 59))	('CD8', 'Gene', '925', (56, 59))	('EGFR', 'Gene', '1956', (127, 131))	('mutation', 'Var', (132, 140))	('EGFR', 'Gene', (127, 131))
82429	30662542	Among the whole cohort, the best OS was achieved in TIMT3 (low PD-L1 expression/high CD8+ TIL infiltration), and the worst was in TIMT2 (high PD-L1 expression/low CD8+ TIL infiltration) (median OS 88.0 months & 37.2 months respectively, P=0.003).	('expression/high', 'MPA', (69, 84))	('CD8', 'Gene', (85, 88))	('TIMT3', 'Gene', (52, 57))	('CD8', 'Gene', '925', (85, 88))	('high PD-L1', 'Var', (137, 147))	('low', 'Var', (59, 62))	('CD8', 'Gene', (163, 166))	('CD8', 'Gene', '925', (163, 166))
82436	30662542	Total somatic mutation number tend to be higher in tumor with high PD-L1 expression, which is even more obvious for ADC but not SCC (as shown in Fig.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('PD-L1', 'Gene', (67, 72))	('SCC', 'Gene', (128, 131))	('tumor', 'Disease', (51, 56))	('expression', 'MPA', (73, 83))	('SCC', 'Gene', '6317', (128, 131))	('higher', 'PosReg', (41, 47))	('high', 'Var', (62, 66))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
82441	30662542	The distribution of TMIT sorted by histological subtypes, TNM stages, EGFR mutation status and TMB level were shown in Fig 4B.	('TNM', 'Gene', '10178', (58, 61))	('EGFR', 'Gene', '1956', (70, 74))	('mutation', 'Var', (75, 83))	('TNM', 'Gene', (58, 61))	('EGFR', 'Gene', (70, 74))	('TMB', 'Chemical', '-', (95, 98))
82442	30662542	The proportion of TIMT4 (high PD-1 expression and high CD8+ TIL) is significantly lower in subgroup of TMN IV and subgroup of EGFR mutation.	('TMN IV', 'Disease', (103, 109))	('mutation', 'Var', (131, 139))	('PD-1', 'Gene', (30, 34))	('EGFR', 'Gene', (126, 130))	('PD-1', 'Gene', '5133', (30, 34))	('CD8', 'Gene', (55, 58))	('CD8', 'Gene', '925', (55, 58))	('EGFR', 'Gene', '1956', (126, 130))	('lower', 'NegReg', (82, 87))
82443	30662542	Similar to the results of TIMTs defined by PD-L1 and CD8+ TIL, the longest OS was achieved in TIMT3 (low PD-1 expression/high CD8+ TIL infiltration), while the shortest in TIMT2 (high PD-1 expression/low CD8+ TIL infiltration), the difference was statistically significant both for overall cohort (P=0.0043) and ADC cohort (P<0.001), but not for SCC cohort (P=0.53) (Fig.	('CD8', 'Gene', '925', (204, 207))	('CD8', 'Gene', (53, 56))	('low', 'Var', (101, 104))	('PD-1', 'Gene', '5133', (105, 109))	('CD8', 'Gene', '925', (53, 56))	('SCC', 'Gene', '6317', (346, 349))	('CD8', 'Gene', (126, 129))	('CD8', 'Gene', '925', (126, 129))	('PD-1', 'Gene', (184, 188))	('PD-1', 'Gene', '5133', (184, 188))	('PD-1', 'Gene', (105, 109))	('CD8', 'Gene', (204, 207))	('SCC', 'Gene', (346, 349))
82456	30662542	Consistent with previous finding, the best outcome was achieved in TIMT3 (low PD-1/ PD-L1 expression/high CD8+ TIL infiltration) while the worst in TIMT2 (high PD-1/ PD-L1 expression/low CD8+ TIL infiltration) (Fig.	('expression/high', 'MPA', (90, 105))	('PD-1', 'Gene', (78, 82))	('PD-1', 'Gene', '5133', (78, 82))	('low', 'NegReg', (74, 77))	('CD8', 'Gene', (106, 109))	('CD8', 'Gene', '925', (106, 109))	('CD8', 'Gene', (187, 190))	('PD-1', 'Gene', (160, 164))	('CD8', 'Gene', '925', (187, 190))	('PD-1', 'Gene', '5133', (160, 164))	('high', 'Var', (155, 159))
82476	30662542	Patients with high CD8+ TIL and high PD-1/PD-L1 expression have similar survival with patients of low CD8+ TIL, which indicates the prominent immune suppressing function of PD-1/ PD-L1 in high TIL infiltrating microenvironment.	('high', 'Var', (32, 36))	('CD8', 'Gene', (19, 22))	('CD8', 'Gene', '925', (19, 22))	('CD8', 'Gene', (102, 105))	('CD8', 'Gene', '925', (102, 105))	('immune suppressing', 'CPA', (142, 160))	('Patients', 'Species', '9606', (0, 8))	('PD-1', 'Gene', '5133', (37, 41))	('PD-1', 'Gene', (173, 177))	('PD-1', 'Gene', (37, 41))	('PD-1', 'Gene', '5133', (173, 177))	('patients', 'Species', '9606', (86, 94))
82485	30662542	Also, Mutational epitopes had been associated with higher TIL infiltration and elevation of CD8A and PD-1 gene expression, which indicates the interaction between the tumor neoantigens and immune microenvironment.	('TIL infiltration', 'CPA', (58, 74))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('expression', 'MPA', (111, 121))	('Mutational epitopes', 'Var', (6, 25))	('CD8A', 'Gene', '925', (92, 96))	('elevation', 'PosReg', (79, 88))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('PD-1', 'Gene', (101, 105))	('CD8A', 'Gene', (92, 96))	('higher', 'PosReg', (51, 57))	('PD-1', 'Gene', '5133', (101, 105))	('tumor', 'Disease', (167, 172))
82486	30662542	In our study, total somatic mutation number was slightly elevated in subgroups with high PD-1/PD-L1 expression but no significance changes in subgroups of different CD8+ TIL level.	('somatic mutation number', 'CPA', (20, 43))	('high', 'Var', (84, 88))	('PD-1', 'Gene', (89, 93))	('elevated', 'PosReg', (57, 65))	('PD-1', 'Gene', '5133', (89, 93))	('expression', 'MPA', (100, 110))	('CD8', 'Gene', (165, 168))	('CD8', 'Gene', '925', (165, 168))
82487	30662542	As not all the somatic mutations could bring about immunogenic neoantigens, further study exemplify it's the neoantigen number rather the total mutation number that positively correlated with immune cytotoxic activity and PD-1/PD-L1 expression.	('PD-1', 'Gene', '5133', (222, 226))	('expression', 'MPA', (233, 243))	('immune cytotoxic activity', 'CPA', (192, 217))	('mutations', 'Var', (23, 32))	('correlated', 'Reg', (176, 186))	('PD-1', 'Gene', (222, 226))
82492	30662542	Consistent with the previous findings, EGFR driver mutation is associated with lower PD-1 expression (P=0.007).	('PD-1', 'Gene', (85, 89))	('PD-1', 'Gene', '5133', (85, 89))	('lower', 'NegReg', (79, 84))	('expression', 'MPA', (90, 100))	('mutation', 'Var', (51, 59))	('EGFR', 'Gene', '1956', (39, 43))	('EGFR', 'Gene', (39, 43))
82493	30662542	Also, Patients with EGFR mutation tend to have lower PD-L1expression and higher CD8 + TIL infiltrating though the difference is not statistically significant.	('PD-L1expression', 'MPA', (53, 68))	('lower', 'NegReg', (47, 52))	('CD8', 'Gene', '925', (80, 83))	('EGFR', 'Gene', (20, 24))	('mutation', 'Var', (25, 33))	('Patients', 'Species', '9606', (6, 14))	('CD8', 'Gene', (80, 83))	('EGFR', 'Gene', '1956', (20, 24))	('higher', 'PosReg', (73, 79))
82494	30662542	Quite a few have found that NSCLCs harboring EGFR mutations are associated with low overall response rate to PD-1/PD-L1 inhibitors, which is partly explained by its negative association with PD-1/PD-L1 expression and uninflamed tumor microenvironment.	('low', 'NegReg', (80, 83))	('EGFR', 'Gene', (45, 49))	('mutations', 'Var', (50, 59))	('PD-1', 'Gene', '5133', (191, 195))	('tumor', 'Disease', 'MESH:D009369', (228, 233))	('NSCLCs', 'Disease', 'MESH:D002289', (28, 34))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('tumor', 'Disease', (228, 233))	('EGFR', 'Gene', '1956', (45, 49))	('PD-1', 'Gene', (191, 195))	('NSCLCs', 'Disease', (28, 34))	('NSCLC', 'Phenotype', 'HP:0030358', (28, 33))	('PD-1', 'Gene', (109, 113))	('response rate', 'MPA', (92, 105))	('PD-1', 'Gene', '5133', (109, 113))
82498	30662542	Subsequently, quite a few studies implied that KRAS mutation was associated higher PD-L1 expression.	('expression', 'MPA', (89, 99))	('KRAS', 'Gene', (47, 51))	('PD-L1', 'Gene', (83, 88))	('mutation', 'Var', (52, 60))	('KRAS', 'Gene', '3845', (47, 51))
82516	29348864	Of the tumor cell pool, beneficial mutations conferring a selective advantage on the cell may arise, followed by a successive wave of clonal expansion.	('tumor', 'Phenotype', 'HP:0002664', (7, 12))	('tumor', 'Disease', 'MESH:D009369', (7, 12))	('tumor', 'Disease', (7, 12))	('mutations', 'Var', (35, 44))
82522	29348864	WGD event was inferred to occur both before and after other copy-number alterations (CNAs) across various cancer types.	('copy-number alterations', 'Var', (60, 83))	('GD', 'Chemical', '-', (1, 3))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('cancer', 'Disease', (106, 112))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
82524	29348864	Copy number losses that occur on the background of a diploid genome before GD will result in loss of heterozygosity (LOH) whereby one of the parental alleles is lost.	('lost', 'NegReg', (161, 165))	('loss', 'NegReg', (93, 97))	('losses', 'NegReg', (12, 18))	('GD', 'Chemical', '-', (75, 77))	('heterozygosity', 'MPA', (101, 115))	('Copy number', 'Var', (0, 11))
82528	29348864	Previously, we have reported the role of APOBEC family of cytidinedeamiases in mutagenesis and identified its connection with hotspot mutations of PIK3CA in ESCC.	('connection', 'Reg', (110, 120))	('hotspot', 'PosReg', (126, 133))	('mutagenesis', 'MPA', (79, 90))	('ESCC', 'Disease', (157, 161))	('PIK3CA', 'Gene', (147, 153))	('PIK3CA', 'Gene', '5290', (147, 153))	('mutations', 'Var', (134, 143))
82529	29348864	In addition, a Japanese ESCC study displays an association of APOBEC signature with ZNF750 mutations.	('ZNF750', 'Gene', '79755', (84, 90))	('mutations', 'Var', (91, 100))	('APOBEC signature', 'Gene', (62, 78))	('ZNF750', 'Gene', (84, 90))	('association', 'Interaction', (47, 58))
82530	29348864	Assuredly, the signatures of genomic instability could be extended to genomic aberrations, for example, allelic imbalance at telomere is a marker for deficient homologous recombination repair, and it is also predictive of benefit from DNA damaging in breast and ovarian cancers.	('deficient', 'NegReg', (150, 159))	('breast and ovarian cancers', 'Disease', 'MESH:D010051', (251, 277))	('cancers', 'Phenotype', 'HP:0002664', (270, 277))	('homologous recombination repair', 'MPA', (160, 191))	('ovarian cancers', 'Phenotype', 'HP:0100615', (262, 277))	('imbalance', 'Phenotype', 'HP:0002172', (112, 121))	('cancer', 'Phenotype', 'HP:0002664', (270, 276))	('allelic imbalance at', 'Var', (104, 124))	('benefit', 'PosReg', (222, 229))
82531	29348864	In ESCC, through whole-genome analyses, we observed diverse models of genomic signatures including breakage-fusion-bridge (BFB), chromothripsis and kategsis, which frequently lead to oncogene amplifications such as CCND1 and FGFR1.	('FGFR1', 'Gene', '2260', (225, 230))	('chromothripsis', 'Disease', 'MESH:D000072837', (129, 143))	('amplifications', 'Var', (192, 206))	('kategsis', 'Disease', (148, 156))	('BFB', 'Chemical', '-', (123, 126))	('oncogene', 'MPA', (183, 191))	('CCND1', 'Gene', (215, 220))	('lead to', 'Reg', (175, 182))	('chromothripsis', 'Disease', (129, 143))	('FGFR1', 'Gene', (225, 230))	('CCND1', 'Gene', '595', (215, 220))	('breakage-fusion-bridge', 'Disease', (99, 121))
82533	29348864	Given the complexity of cancer genome that consists of genomic changes from point mutation to larger-scale copy number alteration or WGD, characterization of the potential genomic signatures and their mutational ordering may provide useful insights into the ESCC genome evolution.	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('copy number alteration', 'Var', (107, 129))	('GD', 'Chemical', '-', (134, 136))	('cancer', 'Disease', (24, 30))	('cancer', 'Disease', 'MESH:D009369', (24, 30))	('point mutation', 'Var', (76, 90))
82538	29348864	Conversely, largely copy number alterations (CNAs) were observed in almost all of esophageal carcinoma (ESCA) and frequent copy-number changes were not clustered in specific chromosome (Figure 1A).	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('observed', 'Reg', (56, 64))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (82, 102))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (82, 102))	('ESCA', 'Phenotype', 'HP:0011459', (104, 108))	('copy number alterations', 'Var', (20, 43))	('esophageal carcinoma', 'Disease', (82, 102))
82545	29348864	Specially, a non-genome doubling (NGD) ESCC-06T with poor prognosis that has much more high-level amplification peaks exhibited high intra-tumor heterogeneity.	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('intra-tumor', 'Disease', 'MESH:D009369', (133, 144))	('non-genome', 'Var', (13, 23))	('intra-tumor', 'Disease', (133, 144))	('GD', 'Chemical', '-', (35, 37))
82555	29348864	Region 9p21.3 contained three genes (CDKN2A, CDKN2B, MTAP) known to be inactivated by homozygous deletion (Figure 2C).	('CDKN2A', 'Gene', (37, 43))	('CDKN2A', 'Gene', '1029', (37, 43))	('MTAP', 'Gene', (53, 57))	('MTAP', 'Gene', '4507', (53, 57))	('CDKN2B', 'Gene', (45, 51))	('deletion', 'Var', (97, 105))	('CDKN2B', 'Gene', '1030', (45, 51))
82556	29348864	Importantly, copy-number analyses verified the deletion of CDKN2A and immunohischemistry (IHC) staining in tissue-microarray containing 36 atypical hyperplasia tissues and 72 of ESCC tumors confirmed the loss of expression of p16INK4A (Figure 2D-2F), indicating that CDKN2A depletion may be a potential biomarker for early detection of ESCC.	('CDKN2A', 'Gene', (267, 273))	('ESCC tumors', 'Disease', (178, 189))	('hyperplasia', 'Disease', (148, 159))	('ESCC', 'Disease', (336, 340))	('CDKN2A', 'Gene', '1029', (267, 273))	('expression', 'MPA', (212, 222))	('loss', 'NegReg', (204, 208))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('p16INK4A', 'Gene', (226, 234))	('hyperplasia', 'Disease', 'MESH:D006965', (148, 159))	('ESCC tumors', 'Disease', 'MESH:D004938', (178, 189))	('deletion', 'Var', (47, 55))	('tumors', 'Phenotype', 'HP:0002664', (183, 189))	('CDKN2A', 'Gene', (59, 65))	('p16INK4A', 'Gene', '1029', (226, 234))	('CDKN2A', 'Gene', '1029', (59, 65))
82558	29348864	In parallel, we verified the amplifications of these candidate genes and the over-expression of these proteins in 36 of atypical hyperplasia tissues and 72 of ESCC tumors (Figure 2D-2F).	('tumors', 'Phenotype', 'HP:0002664', (164, 170))	('over-expression', 'PosReg', (77, 92))	('ESCC tumors', 'Disease', (159, 170))	('hyperplasia', 'Disease', (129, 140))	('ESCC tumors', 'Disease', 'MESH:D004938', (159, 170))	('amplifications', 'Var', (29, 43))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('hyperplasia', 'Disease', 'MESH:D006965', (129, 140))
82567	29348864	It is particularly strong that heterozygosity of chromosome 9p and 17p was loss in 16 out of 17 GD tumors (94%) and in 11 out of 17 GD tumors (65%), as well as chromosome 5q (47%), 9q (88%), 13q (76%), 3p (82%), respectively, suggesting that deletion on chromosomes 3p, 5q, 9p, 9q, 13q and 17p occurred before GD events during the development of ESCC.	('tumors', 'Phenotype', 'HP:0002664', (99, 105))	('GD tumors', 'Disease', 'MESH:D005776', (96, 105))	('GD tumors', 'Disease', (96, 105))	('deletion', 'Var', (242, 250))	('GD', 'Chemical', '-', (132, 134))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('GD tumors', 'Disease', (132, 141))	('GD tumors', 'Disease', 'MESH:D005776', (132, 141))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('loss', 'NegReg', (75, 79))	('GD', 'Chemical', '-', (96, 98))	('GD', 'Chemical', '-', (310, 312))
82569	29348864	These results suggest that an abundance of combinations of deletions involving suppressor genes may play an important role in the tumorigenesis of ESCC.	('deletions', 'Var', (59, 68))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('ESCC', 'Disease', (147, 151))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('play', 'Reg', (100, 104))	('tumor', 'Disease', (130, 135))
82577	29348864	Of note, telomere-bounded deletion of 11q not only leads to the BFB cycles that cause high-level amplification of CCND1 but also deletion of TSGs (e.g.	('CCND1', 'Gene', (114, 119))	('deletion', 'Var', (26, 34))	('deletion', 'Var', (129, 137))	('CCND1', 'Gene', '595', (114, 119))	('leads', 'Reg', (51, 56))	('high-level amplification', 'MPA', (86, 110))	('TSGs', 'Gene', (141, 145))	('BFB', 'Chemical', '-', (64, 67))
82578	29348864	FAT3) (Supplementary Figure 4B), suggesting the dual role of telomere-bounded deletion in tumorigenesis of ESCC.	('FAT3', 'Gene', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('deletion', 'Var', (78, 86))	('FAT3', 'Gene', '120114', (0, 4))	('ESCC', 'Disease', (107, 111))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
82580	29348864	In our data, nearly all of SOX2 amplifications were TCNA, which could be further validated in a Japanese ESCC cohort.	('amplifications', 'Var', (32, 46))	('SOX2', 'Gene', (27, 31))	('SOX2', 'Gene', '6657', (27, 31))	('TCNA', 'Disease', (52, 56))
82585	29348864	First, the homozygous deletion of CDKN2A and TP53 mutations were the most common alterations in ESCC cohort regardless of GD events.	('TP53', 'Gene', (45, 49))	('mutations', 'Var', (50, 59))	('GD', 'Chemical', '-', (122, 124))	('CDKN2A', 'Gene', (34, 40))	('CDKN2A', 'Gene', '1029', (34, 40))	('ESCC', 'Disease', (96, 100))	('common', 'Reg', (74, 80))	('TP53', 'Gene', '7157', (45, 49))
82586	29348864	There were 15 ESCCs having homozygous CDKN2A (9p21.3) deletion and 5 tumors harboring NLOH or deletion of chr9p (Supplementary Figure 6A, left panel).	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('deletion', 'Var', (94, 102))	('chr9p', 'Gene', (106, 111))	('deletion', 'Var', (54, 62))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('tumors', 'Disease', (69, 75))	('CDKN2A', 'Gene', (38, 44))	('tumors', 'Disease', 'MESH:D009369', (69, 75))	('CDKN2A', 'Gene', '1029', (38, 44))	('NLOH', 'Chemical', '-', (86, 90))
82587	29348864	In the 15 tumors with TP53 mutations, 11 tumors have mutations at least two alleles, which suggest that TP53 mutation precedes its amplification (Supplementary Figure 6A, right panel).	('mutations', 'Var', (27, 36))	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('TP53', 'Gene', '7157', (104, 108))	('TP53', 'Gene', (104, 108))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('15 tumors', 'Disease', 'MESH:C567447', (7, 16))	('tumors', 'Disease', (10, 16))	('tumors', 'Disease', (41, 47))	('tumors', 'Disease', 'MESH:D009369', (41, 47))	('tumors', 'Disease', 'MESH:D009369', (10, 16))	('15 tumors', 'Disease', (7, 16))	('tumors', 'Phenotype', 'HP:0002664', (10, 16))	('TP53', 'Gene', '7157', (22, 26))	('TP53', 'Gene', (22, 26))
82588	29348864	High proportion of homozygous CDKN2A loss and TP53 mutation also support that both of them tend to occur before the amplification.	('CDKN2A', 'Gene', (30, 36))	('TP53', 'Gene', '7157', (46, 50))	('CDKN2A', 'Gene', '1029', (30, 36))	('TP53', 'Gene', (46, 50))	('mutation', 'Var', (51, 59))	('loss', 'NegReg', (37, 41))
82591	29348864	The most frequent arm of NLOH is chr17p, which account for more than half of samples (Supplementary Figure 6B), further supporting TP53 mutations is an early event in most of ESCCs.	('TP53', 'Gene', (131, 135))	('NLOH', 'Chemical', '-', (25, 29))	('mutations', 'Var', (136, 145))	('TP53', 'Gene', '7157', (131, 135))
82594	29348864	Altogether, these results implied a consensus path of ESCC evolution, beginning with the CDKN2A/TP53 mutations, followed by NLOH, and ultimately, some of them suffer GD (Figure 5B and Supplementary Figure 6D).	('mutations', 'Var', (101, 110))	('TP53', 'Gene', (96, 100))	('ESCC', 'Disease', (54, 58))	('GD', 'Chemical', '-', (166, 168))	('CDKN2A', 'Gene', (89, 95))	('CDKN2A', 'Gene', '1029', (89, 95))	('suffer', 'Reg', (159, 165))	('NLOH', 'Chemical', '-', (124, 128))	('TP53', 'Gene', '7157', (96, 100))
82595	29348864	Specially, we found the coexistence of clonal and subclonal mutations for TP53 gene in case ESCC-315T and ESCC-260T.	('TP53', 'Gene', '7157', (74, 78))	('TP53', 'Gene', (74, 78))	('ESCC-260T', 'Var', (106, 115))	('ESCC-315T', 'Var', (92, 101))
82599	29348864	Moreover, the high rate of NLOH suggests that epigenetic abnormalities of many particular genes might be involved in the development and progression of ESCC.	('NLOH', 'Chemical', '-', (27, 31))	('involved', 'Reg', (105, 113))	('epigenetic abnormalities', 'Var', (46, 70))	('ESCC', 'Disease', (152, 156))
82603	29348864	Unlike colorectal cancers in that GD is an early event, we found, in the majority of ESCC tumors, GD likely occurred as a relatively late event, after CDKN2A/TP53 mutations and NLOH, suggesting that CIN occurs before GD in ESCC evolution.	('TP53', 'Gene', (158, 162))	('colorectal cancers', 'Disease', (7, 25))	('cancers', 'Phenotype', 'HP:0002664', (18, 25))	('CIN', 'Phenotype', 'HP:0040012', (199, 202))	('ESCC tumors', 'Disease', 'MESH:D004938', (85, 96))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('CIN', 'Disease', 'MESH:D007674', (199, 202))	('TP53', 'Gene', '7157', (158, 162))	('NLOH', 'Chemical', '-', (177, 181))	('colorectal cancers', 'Disease', 'MESH:D015179', (7, 25))	('GD', 'Chemical', '-', (34, 36))	('CDKN2A', 'Gene', (151, 157))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('GD', 'Chemical', '-', (217, 219))	('ESCC tumors', 'Disease', (85, 96))	('mutations', 'Var', (163, 172))	('CIN', 'Disease', (199, 202))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('GD', 'Chemical', '-', (98, 100))	('CDKN2A', 'Gene', '1029', (151, 157))
82606	29348864	It is well known that high-level amplification is a marked feature of CIN and always accompanies with over-expression of oncogenes leading to tumor progression.	('high-level amplification', 'Var', (22, 46))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('tumor', 'Disease', (142, 147))	('CIN', 'Phenotype', 'HP:0040012', (70, 73))	('accompanies', 'Reg', (85, 96))	('CIN', 'Disease', (70, 73))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('CIN', 'Disease', 'MESH:D007674', (70, 73))
82612	29348864	We also observed copy number gain in FEN1, MTA2 and ZBTB3, suggesting that copy number gain is responsible for overexpression of these genes in at least a subset of patients with ESCC.	('FEN1', 'Gene', (37, 41))	('ZBTB3', 'Gene', (52, 57))	('MTA2', 'Gene', (43, 47))	('ZBTB3', 'Gene', '79842', (52, 57))	('ESCC', 'Disease', (179, 183))	('copy number gain', 'Var', (75, 91))	('copy number gain', 'Var', (17, 33))	('patients', 'Species', '9606', (165, 173))	('overexpression', 'PosReg', (111, 125))	('FEN1', 'Gene', '2237', (37, 41))	('MTA2', 'Gene', '9219', (43, 47))
82613	29348864	The involvement of FEN1, ZBTB3, and MTA2 in controlling genomic stability suggests that functional dysregulation of these genes through mutations would facilitate further tumor mutagenesis, raising the possibility of these oncogenes as potential therapeutic targets for ESCC patients.	('FEN1', 'Gene', (19, 23))	('MTA2', 'Gene', (36, 40))	('ESCC', 'Disease', (270, 274))	('ZBTB3', 'Gene', (25, 30))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('ZBTB3', 'Gene', '79842', (25, 30))	('FEN1', 'Gene', '2237', (19, 23))	('facilitate', 'PosReg', (152, 162))	('mutations', 'Var', (136, 145))	('MTA2', 'Gene', '9219', (36, 40))	('patients', 'Species', '9606', (275, 283))	('tumor', 'Disease', (171, 176))
82615	29348864	In their study, half of the driver mutations located on the branches of tumor phylogenetic trees targeted oncogenes, including PIK3CA, NFE2L2 and mTOR whereas the majority of truncal and clonal driver mutations occurred in tumor-suppressor genes, including TP53, KMT2D and ZNF750.	('NFE2L2', 'Gene', (135, 141))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('mTOR', 'Gene', (146, 150))	('KMT2D', 'Gene', (263, 268))	('mTOR', 'Gene', '2475', (146, 150))	('TP53', 'Gene', (257, 261))	('ZNF750', 'Gene', '79755', (273, 279))	('targeted', 'Reg', (97, 105))	('PIK3CA', 'Gene', '5290', (127, 133))	('ZNF750', 'Gene', (273, 279))	('KMT2D', 'Gene', '8085', (263, 268))	('tumor', 'Disease', (223, 228))	('tumor', 'Disease', (72, 77))	('tumor', 'Disease', 'MESH:D009369', (223, 228))	('NFE2L2', 'Gene', '4780', (135, 141))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('TP53', 'Gene', '7157', (257, 261))	('mutations', 'Var', (201, 210))	('occurred', 'Reg', (211, 219))	('PIK3CA', 'Gene', (127, 133))	('mutations', 'Var', (35, 44))
82617	29348864	Moreover, several driver mutations that were found in all tumor cells among these 21 ESCC genomes can be placed on the shared trunk of the phylogenetic tree, including mutations of TP53, CDKN2A, AJUBA, PIK3CA, NOTCH1, FBXW7, RB1, FAT1, and ZNF750.	('TP53', 'Gene', (181, 185))	('CDKN2A', 'Gene', (187, 193))	('FAT1', 'Gene', '2195', (230, 234))	('FBXW7', 'Gene', '55294', (218, 223))	('mutations', 'Var', (168, 177))	('tumor', 'Disease', (58, 63))	('CDKN2A', 'Gene', '1029', (187, 193))	('PIK3CA', 'Gene', (202, 208))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('TP53', 'Gene', '7157', (181, 185))	('RB1', 'Gene', (225, 228))	('NOTCH1', 'Gene', (210, 216))	('FAT1', 'Gene', (230, 234))	('ZNF750', 'Gene', '79755', (240, 246))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('FBXW7', 'Gene', (218, 223))	('AJUBA', 'Gene', '84962', (195, 200))	('ZNF750', 'Gene', (240, 246))	('PIK3CA', 'Gene', '5290', (202, 208))	('RB1', 'Gene', '5925', (225, 228))	('NOTCH1', 'Gene', '4851', (210, 216))	('AJUBA', 'Gene', (195, 200))
82619	29348864	For example, PIK3CA showed recurrent activating mutations suggesting that this gene may be potential therapeutic target for ESCC patients harboring PIK3CA mutation.	('PIK3CA', 'Gene', '5290', (148, 154))	('PIK3CA', 'Gene', (13, 19))	('patients', 'Species', '9606', (129, 137))	('PIK3CA', 'Gene', '5290', (13, 19))	('mutation', 'Var', (155, 163))	('PIK3CA', 'Gene', (148, 154))	('activating', 'MPA', (37, 47))	('ESCC', 'Disease', (124, 128))
82631	29348864	A modified version of a published method was used to classify the focal SCNAs with absolute copy number less than 6, via their timing relative to GD event.	('less than 6', 'Var', (104, 115))	('focal SCNAs', 'Disease', (66, 77))	('GD', 'Chemical', '-', (146, 148))
82637	29348864	Reasoning mutations that arise early in tumorigenesis or that foster rapid outgrowth would tend to be clonal whereas late-arising alterations would more often be subclonal.	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('rapid outgrowth', 'CPA', (69, 84))	('mutations', 'Var', (10, 19))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))
82645	29348864	BFB breakage-fusion-bridge CIN Chromosomal instability CNAs copy-number alterations COAD colorectal carcinoma ESCA esophageal carcinoma ESCC esophageal squamous cell carcinoma FEN1 Flap structure-specific Endonuclease 1 GD genome doubling HNSCC head and neck squamous cell carcinoma IHC immunohischemistry LOH loss of heterozygosity LIHC liver hepatocellular carcinoma NGD non-genomedoubling NLOH neutral loss of heterozygosity NMF nonnegative matrix factorization NSCLC non-small cell lung cancer PAAD pancreatic adenocarcinoma STAD stomach adenocarcinoma SCNA somatic copy number alteration SNV single-nucleotide variations TSGs tumor suppressor genes TCNAs telomere-bounded copy number alterations WGD whole genome doubling WGS whole-genome sequencing wGII genome instability index	('single-nucleotide variations', 'Var', (597, 625))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (89, 109))	('stomach adenocarcinoma', 'Disease', 'MESH:D013274', (534, 556))	('carcinoma', 'Phenotype', 'HP:0030731', (359, 368))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (141, 175))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (152, 175))	('tumor', 'Disease', 'MESH:D009369', (631, 636))	('Flap structure-specific Endonuclease 1', 'Gene', (181, 219))	('liver hepatocellular carcinoma', 'Disease', (338, 368))	('NSCLC', 'Disease', 'MESH:D002289', (465, 470))	('NLOH', 'Chemical', '-', (392, 396))	('lung cancer', 'Phenotype', 'HP:0100526', (486, 497))	('cell lung cancer', 'Disease', 'MESH:D008175', (481, 497))	('LIHC', 'Disease', 'None', (333, 337))	('BFB', 'Chemical', '-', (0, 3))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (344, 368))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (259, 282))	('COAD', 'Disease', 'MESH:D029424', (84, 88))	('TCNAs', 'Gene', (654, 659))	('carcinoma', 'Phenotype', 'HP:0030731', (166, 175))	('neck squamous cell carcinoma', 'Disease', (254, 282))	('CIN', 'Disease', (27, 30))	('NSCLC', 'Disease', (465, 470))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (254, 282))	('GD', 'Chemical', '-', (370, 372))	('tumor', 'Phenotype', 'HP:0002664', (631, 636))	('HNSCC', 'Phenotype', 'HP:0012288', (239, 244))	('cell lung cancer', 'Disease', (481, 497))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (115, 135))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('Chromosomal instability', 'Phenotype', 'HP:0040012', (31, 54))	('GD', 'Chemical', '-', (220, 222))	('NSCLC', 'Phenotype', 'HP:0030358', (465, 470))	('GD', 'Chemical', '-', (702, 704))	('cancer', 'Phenotype', 'HP:0002664', (491, 497))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (503, 528))	('stomach adenocarcinoma', 'Disease', (534, 556))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (471, 497))	('FEN1', 'Gene', '2237', (176, 180))	('liver hepatocellular carcinoma', 'Disease', 'MESH:D006528', (338, 368))	('esophageal carcinoma', 'Disease', (115, 135))	('COAD', 'Disease', (84, 88))	('PAAD', 'Phenotype', 'HP:0006725', (498, 502))	('LIHC', 'Disease', (333, 337))	('esophageal squamous cell carcinoma', 'Disease', (141, 175))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (475, 497))	('CIN', 'Phenotype', 'HP:0040012', (27, 30))	('SNV', 'Gene', (593, 596))	('Flap structure-specific Endonuclease 1', 'Gene', '2237', (181, 219))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (245, 282))	('ESCA', 'Phenotype', 'HP:0011459', (110, 114))	('carcinoma', 'Phenotype', 'HP:0030731', (273, 282))	('CIN', 'Disease', 'MESH:D007674', (27, 30))	('FEN1', 'Gene', (176, 180))	('colorectal carcinoma', 'Disease', (89, 109))	('tumor', 'Disease', (631, 636))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D010190', (503, 528))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (115, 135))	('pancreatic adenocarcinoma', 'Disease', (503, 528))
82650	27285764	Chromatin immunoprecipitation analysis showed that WHSC1L1 and H3K36me2 are enriched in the gene bodies of the cell cycle-related genes CDC6 and CDK2, implying that WHSC1L1 directly regulates the transcription of these genes.	('transcription', 'MPA', (196, 209))	('WHSC1L1', 'Gene', (51, 58))	('WHSC1L1', 'Gene', (165, 172))	('CDC6', 'Gene', '990', (136, 140))	('regulates', 'Reg', (182, 191))	('H3K36me2', 'Var', (63, 71))	('CDC6', 'Gene', (136, 140))	('WHSC1L1', 'Gene', '54904', (165, 172))	('WHSC1L1', 'Gene', '54904', (51, 58))	('CDK2', 'Gene', (145, 149))	('CDK2', 'Gene', '1017', (145, 149))
82651	27285764	According to the importance of CDC6 and CDK2 for G1 to S transition, WHSC1L1 knockdown induced strong G0/G1 arrest which was rescued by introduction of wild-type WHSC1L1 but not by that of enzyme-inactive WHSC1L1.	('WHSC1L1', 'Gene', '54904', (162, 169))	('CDC6', 'Gene', (31, 35))	('CDK2', 'Gene', '1017', (40, 44))	('WHSC1L1', 'Gene', '54904', (205, 212))	('knockdown', 'Var', (77, 86))	('WHSC1L1', 'Gene', (69, 76))	('WHSC1L1', 'Gene', (162, 169))	('WHSC1L1', 'Gene', (205, 212))	('G0/G1 arrest', 'CPA', (102, 114))	('WHSC1L1', 'Gene', '54904', (69, 76))	('CDK2', 'Gene', (40, 44))	('CDC6', 'Gene', '990', (31, 35))
82652	27285764	Our results imply that WHSC1L1 and its product H3K36me2 are essential for the transition from G1 to S phase in SCCHN cells and that WHSC1L1 could serve as a rational target for anticancer drug development for patients with head and neck cancer.	('WHSC1L1', 'Gene', (23, 30))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('H3K36me2', 'Var', (47, 55))	('WHSC1L1', 'Gene', '54904', (23, 30))	('neck cancer', 'Disease', 'MESH:D006258', (232, 243))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('head and neck cancer', 'Phenotype', 'HP:0012288', (223, 243))	('neck cancer', 'Disease', (232, 243))	('patients', 'Species', '9606', (209, 217))	('WHSC1L1', 'Gene', (132, 139))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('cancer', 'Disease', 'MESH:D009369', (237, 243))	('cancer', 'Disease', (181, 187))	('cancer', 'Disease', (237, 243))	('WHSC1L1', 'Gene', '54904', (132, 139))
82658	27285764	Specifically in SCCHN, genetic analysis of 530 tumors showed mutations, amplifications and deletions in approximately 68% of the samples.	('tumors', 'Disease', (47, 53))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('deletions', 'Var', (91, 100))	('mutations', 'Var', (61, 70))	('amplifications', 'Var', (72, 86))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('SCCHN', 'Disease', (16, 21))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))
82660	27285764	A similar frequency of genetic alterations in NSD PKMTs is also observed in lung squamous cell carcinoma, a disease with very similar genetic background as SCCHN.	('genetic', 'Var', (23, 30))	('NSD', 'Disease', (46, 49))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (76, 104))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (76, 104))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (81, 104))	('NSD', 'Disease', 'MESH:D029461', (46, 49))	('lung squamous cell carcinoma', 'Disease', (76, 104))
82661	27285764	Among these enzymes, TCGA reported a statistically significant, recurrent amplification of WHSC1L1 at chromosome 8p11.23 region in 9.3% of SCCHN tumors (Q-value=3.7e-15).	('WHSC1L1', 'Gene', '54904', (91, 98))	('amplification', 'Var', (74, 87))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('SCCHN tumors', 'Disease', 'MESH:D009369', (139, 151))	('WHSC1L1', 'Gene', (91, 98))	('SCCHN tumors', 'Disease', (139, 151))
82664	27285764	WHSC1L1, also known as Wolf-Hirschhorn syndrome candidate 1-like 1, is a nuclear protein mapped at chromosome 8p11.23 and is known to function as a chromatin modifier by modulating the expression of genes through dimethylation of lysine 36 on histone H3 (H3K36me2).	('expression', 'MPA', (185, 195))	('WHSC1L1', 'Gene', (0, 7))	('genes', 'Gene', (199, 204))	('dimethylation', 'Var', (213, 226))	('WHSC1L1', 'Gene', '54904', (0, 7))	('modulating', 'Reg', (170, 180))	('lysine', 'Chemical', 'MESH:D008239', (230, 236))	('Wolf-Hirschhorn syndrome candidate 1-like 1', 'Gene', '54904', (23, 66))	('Wolf-Hirschhorn syndrome candidate 1-like 1', 'Gene', (23, 66))
82666	27285764	There are two major WHSC1L1 isoforms, the long WHSC1L1 (1437aa) and the short WHSC1L1 (645aa), which share a common 620aa N-terminal region, while the short WHSC1L1 lacks the SET domain.	('WHSC1L1', 'Gene', (47, 54))	('WHSC1L1', 'Gene', (78, 85))	('WHSC1L1', 'Gene', (157, 164))	('WHSC1L1', 'Gene', '54904', (47, 54))	('WHSC1L1', 'Gene', (20, 27))	('WHSC1L1', 'Gene', '54904', (78, 85))	('WHSC1L1', 'Gene', '54904', (157, 164))	('1437aa', 'Var', (56, 62))	('WHSC1L1', 'Gene', '54904', (20, 27))
82668	27285764	In this study, we show that WHSC1L1 is significantly overexpressed in patients with SCCHN, its knockdown causes cell-cycle arrest and decrease in global H3K36 dimethylation levels, and that it promotes the coordinated transcription of a number of cell cycle genes, including CDK2 and CDC6, which are critical for the G1/S transition.	('patients', 'Species', '9606', (70, 78))	('global H3K36 dimethylation levels', 'MPA', (146, 179))	('CDK2', 'Gene', (275, 279))	('CDC6', 'Gene', '990', (284, 288))	('WHSC1L1', 'Gene', (28, 35))	('overexpressed', 'PosReg', (53, 66))	('cell-cycle arrest', 'CPA', (112, 129))	('decrease', 'NegReg', (134, 142))	('CDC6', 'Gene', (284, 288))	('CDK2', 'Gene', '1017', (275, 279))	('knockdown', 'Var', (95, 104))	('SCCHN', 'Disease', (84, 89))	('coordinated transcription', 'MPA', (206, 231))	('WHSC1L1', 'Gene', '54904', (28, 35))	('promotes', 'PosReg', (193, 201))	('cell cycle genes', 'Gene', (247, 263))
82679	27285764	More specifically, 81% of patients with poor differentiation grade had significantly higher WHSC1L1, compared to 31% of patients with well differentiated SCCHN (logistic regression, P=0.004).	('higher', 'PosReg', (85, 91))	('WHSC1L1', 'Gene', '54904', (92, 99))	('patients', 'Species', '9606', (26, 34))	('patients', 'Species', '9606', (120, 128))	('poor differentiation', 'Var', (40, 60))	('WHSC1L1', 'Gene', (92, 99))
82684	27285764	Western blotting analysis for WHSC1L1 was also performed in 9 SCCHN cell lines and revealed overexpression of WHSC1L1 (162kD) in 2 of 9 SCCHN cell lines (22%) (Supplementary Figure S1).	('WHSC1L1', 'Gene', '54904', (30, 37))	('overexpression', 'PosReg', (92, 106))	('WHSC1L1', 'Gene', (110, 117))	('162kD', 'Var', (119, 124))	('WHSC1L1', 'Gene', '54904', (110, 117))	('WHSC1L1', 'Gene', (30, 37))
82688	27285764	The data above support that WHSC1L1 knockdown decreases the cell proliferation and/or survival of SCCHN cells.	('cell proliferation', 'CPA', (60, 78))	('survival of SCCHN cells', 'CPA', (86, 109))	('WHSC1L1', 'Gene', (28, 35))	('knockdown', 'Var', (36, 45))	('decreases', 'NegReg', (46, 55))	('WHSC1L1', 'Gene', '54904', (28, 35))
82694	27285764	cDNA microarray analysis revealed significant downregulation of 93 genes by more than 50% in both UD-SCC-2 and YD-10B cells after knockdown of WHSC1L1 (Supplementary Table S2).	('downregulation', 'NegReg', (46, 60))	('WHSC1L1', 'Gene', (143, 150))	('SCC-2', 'Gene', (101, 106))	('WHSC1L1', 'Gene', '54904', (143, 150))	('knockdown', 'Var', (130, 139))	('SCC-2', 'Gene', '25836', (101, 106))
82712	27285764	Given the critical function of CDK2 and CDC6 in the transition from G1 to S phase of the cell division cycle, we sought to determine whether WHSC1L1 knockdown leads to arrest of the cell cycle progression from G1 to S phase.	('cell cycle progression', 'CPA', (182, 204))	('CDC6', 'Gene', '990', (40, 44))	('knockdown', 'Var', (149, 158))	('CDC6', 'Gene', (40, 44))	('WHSC1L1', 'Gene', (141, 148))	('CDK2', 'Gene', (31, 35))	('WHSC1L1', 'Gene', '54904', (141, 148))	('CDK2', 'Gene', '1017', (31, 35))
82722	27285764	In addition to SCCHN, WHSC1L1 is frequently amplified in human breast cancer cell lines and in 13% of breast cancer samples, and high WHSC1L1 mRNA levels have been associated with worse survival in breast cancer patients.	('breast cancer', 'Phenotype', 'HP:0003002', (198, 211))	('breast cancer', 'Phenotype', 'HP:0003002', (102, 115))	('breast cancer', 'Disease', 'MESH:D001943', (63, 76))	('patients', 'Species', '9606', (212, 220))	('breast cancer', 'Disease', (63, 76))	('breast cancer', 'Disease', 'MESH:D001943', (198, 211))	('breast cancer', 'Disease', 'MESH:D001943', (102, 115))	('human', 'Species', '9606', (57, 62))	('breast cancer', 'Disease', (198, 211))	('breast cancer', 'Disease', (102, 115))	('mRNA levels', 'MPA', (142, 153))	('WHSC1L1', 'Gene', '54904', (134, 141))	('associated', 'Reg', (164, 174))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('WHSC1L1', 'Gene', (134, 141))	('WHSC1L1', 'Gene', '54904', (22, 29))	('high', 'Var', (129, 133))	('breast cancer', 'Phenotype', 'HP:0003002', (63, 76))	('WHSC1L1', 'Gene', (22, 29))
82724	27285764	The TCGA database has also described frequent WHSC1L1 amplification in bladder cancer (11%) and squamous cell carcinoma of the lung (21%).	('WHSC1L1', 'Gene', '54904', (46, 53))	('squamous cell carcinoma of the lung', 'Disease', 'MESH:D002294', (96, 131))	('amplification', 'Var', (54, 67))	('bladder cancer', 'Disease', 'MESH:D001749', (71, 85))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('bladder cancer', 'Phenotype', 'HP:0009725', (71, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('carcinoma of the lung', 'Phenotype', 'HP:0100526', (110, 131))	('bladder cancer', 'Disease', (71, 85))	('squamous cell carcinoma of the lung', 'Disease', (96, 131))	('WHSC1L1', 'Gene', (46, 53))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (96, 119))	('squamous cell carcinoma of the lung', 'Phenotype', 'HP:0030359', (96, 131))
82737	27285764	Furthermore, we have shown that WHSC1L1 knockdown decreases the viability of SCCHN cells.	('WHSC1L1', 'Gene', '54904', (32, 39))	('knockdown', 'Var', (40, 49))	('viability of SCCHN cells', 'CPA', (64, 88))	('decreases', 'NegReg', (50, 59))	('WHSC1L1', 'Gene', (32, 39))
82739	27285764	In accordance with the critical roles of CDC6 and CDK2 in the cell cycle progression to the S-phase, WHSC1L1 knockdown led to marked decrease of the S phase, a phenotype which was rescued with introduction of WHSC1L1, but not with that of enzyme-inactive WHSC1L1.	('WHSC1L1', 'Gene', '54904', (101, 108))	('decrease', 'NegReg', (133, 141))	('WHSC1L1', 'Gene', (209, 216))	('WHSC1L1', 'Gene', (255, 262))	('WHSC1L1', 'Gene', '54904', (209, 216))	('S phase', 'CPA', (149, 156))	('knockdown', 'Var', (109, 118))	('CDC6', 'Gene', '990', (41, 45))	('cell', 'CPA', (62, 66))	('CDK2', 'Gene', (50, 54))	('WHSC1L1', 'Gene', '54904', (255, 262))	('CDC6', 'Gene', (41, 45))	('WHSC1L1', 'Gene', (101, 108))	('CDK2', 'Gene', '1017', (50, 54))
82742	27285764	Inhibition of CDK2 in ovarian cancer cells overexpressing cyclin E has also been shown to significantly suppress cancer cell proliferation.	('ovarian cancer', 'Disease', 'MESH:D010051', (22, 36))	('suppress', 'NegReg', (104, 112))	('CDK2', 'Gene', (14, 18))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('cancer', 'Disease', (30, 36))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('ovarian cancer', 'Disease', (22, 36))	('cancer', 'Disease', (113, 119))	('CDK2', 'Gene', '1017', (14, 18))	('ovarian cancer', 'Phenotype', 'HP:0100615', (22, 36))	('Inhibition', 'Var', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
82744	27285764	Taking the above into consideration, as well as the very low expression levels of WHSC1L1 in normal tissues, WHSC1L1 may serve as a promising candidate for drug development for patients with SCCHN as well as other cancer types characterized by WHSC1L1 amplification or overexpression.	('WHSC1L1', 'Gene', (82, 89))	('cancer', 'Disease', (214, 220))	('WHSC1L1', 'Gene', '54904', (109, 116))	('WHSC1L1', 'Gene', '54904', (82, 89))	('patients', 'Species', '9606', (177, 185))	('amplification', 'Var', (252, 265))	('cancer', 'Disease', 'MESH:D009369', (214, 220))	('WHSC1L1', 'Gene', (244, 251))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('WHSC1L1', 'Gene', (109, 116))	('WHSC1L1', 'Gene', '54904', (244, 251))	('SCCHN', 'Disease', (191, 196))	('overexpression', 'PosReg', (269, 283))
82764	27285764	MISSION_ siRNA oligonucleotide duplexes were purchased from Sigma-Aldrich for targeting the human WHSC1L1 transcripts (SASI_Hs01_00082045 and SASI_Hs01_00082044).	('SASI_Hs01_00082045', 'Var', (119, 137))	('WHSC1L1', 'Gene', '54904', (98, 105))	('SASI_Hs01_00082044', 'Var', (142, 160))	('oligonucleotide', 'Chemical', 'MESH:D009841', (15, 30))	('human', 'Species', '9606', (92, 97))	('WHSC1L1', 'Gene', (98, 105))
82778	27285764	UD-SCC2 and YD-10B cells were plated in 10cm dishes and treated with two different WHSC1L1 specific siRNAs (50nM, SASI_Hs01_00082045 and SASI_Hs01_00082044) and a negative control siRNA (siNC) for 48h.	('SASI_Hs01_00082044', 'Var', (137, 155))	('UD-SCC2', 'CellLine', 'CVCL:E325', (0, 7))	('WHSC1L1', 'Gene', (83, 90))	('SASI_Hs01_00082045', 'Var', (114, 132))	('WHSC1L1', 'Gene', '54904', (83, 90))	('50nM', 'Var', (108, 112))
82787	26799587	LncRNA TP73-AS1 knockdown inhibited BDH2 expression in EC9706 and KYSE30 cells, whereas BDH2 knockdown repressed esophageal cancer cell proliferation and induced apoptosis via the caspase-3 dependent apoptotic pathway.	('knockdown', 'Var', (93, 102))	('caspase-3', 'Gene', (180, 189))	('esophageal cancer', 'Disease', 'MESH:D004938', (113, 130))	('inhibited', 'NegReg', (26, 35))	('expression', 'MPA', (41, 51))	('induced', 'Reg', (154, 161))	('BDH2', 'Gene', (36, 40))	('BDH2', 'Gene', '56898', (36, 40))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('BDH2', 'Gene', (88, 92))	('BDH2', 'Gene', '56898', (88, 92))	('caspase-3', 'Gene', '836', (180, 189))	('EC9706', 'CellLine', 'CVCL:E307', (55, 61))	('apoptosis', 'CPA', (162, 171))	('repressed', 'NegReg', (103, 112))	('esophageal cancer', 'Disease', (113, 130))
82789	26799587	In mouse xenografts, tumor size was reduced in lncRNA TP73-ASI siRNA-transfected tumors, suggesting that downregulation of lncRNA TP73-AS1 attenuated EC proliferation in vitro and in vivo.	('EC proliferation', 'CPA', (150, 166))	('lncRNA', 'Gene', (123, 129))	('tumors', 'Disease', (81, 87))	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('mouse', 'Species', '10090', (3, 8))	('tumor', 'Disease', (21, 26))	('downregulation', 'NegReg', (105, 119))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('attenuated', 'NegReg', (139, 149))	('lncRNA', 'Var', (47, 53))	('reduced', 'NegReg', (36, 43))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('tumor', 'Disease', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
82790	26799587	In addition, BDH2 or lncRNA TP73-AS1 knockdown enhanced the chemosensitivity of esophageal cancer cells to 5-FU and cisplatin.	('enhanced', 'PosReg', (47, 55))	('lncRNA', 'Gene', (21, 27))	('esophageal cancer', 'Disease', (80, 97))	('knockdown', 'Var', (37, 46))	('5-FU', 'Chemical', 'MESH:D005472', (107, 111))	('esophageal cancer', 'Disease', 'MESH:D004938', (80, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('cisplatin', 'Chemical', 'MESH:D002945', (116, 125))	('BDH2', 'Gene', (13, 17))	('chemosensitivity', 'CPA', (60, 76))	('BDH2', 'Gene', '56898', (13, 17))
82807	26799587	LncRNA TP73-AS1 expression was generally upregulated in EC cell lines (Eca109, EC-1, EC9706, KYSE30, and KYSE150) (Figure 1F).	('EC-1', 'CellLine', 'CVCL:5V05', (79, 83))	('LncRNA TP73-AS1', 'Gene', (0, 15))	('upregulated', 'PosReg', (41, 52))	('EC9706', 'Var', (85, 91))	('KYSE150', 'Var', (105, 112))	('expression', 'MPA', (16, 26))	('EC9706', 'CellLine', 'CVCL:E307', (85, 91))
82808	26799587	Higher lncRNA TP73-AS1 levels in both EC tissues and cell lines as compared to non-cancer controls suggested that lncRNA TP73-AS1 might play an important role in EC tumorigenesis.	('lncRNA TP73-AS1 levels', 'MPA', (7, 29))	('lncRNA TP73-AS1', 'Var', (114, 129))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('play', 'Reg', (136, 140))	('Higher', 'PosReg', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('cancer', 'Disease', (83, 89))	('tumor', 'Disease', (165, 170))
82813	26799587	The results showed that the number of early and late apoptotic cells at 48-96 hours post-siRNA-transfection was significantly higher in EC9706 and KYSE30 cells (Figure 2E) compared to controls.	('EC9706', 'CellLine', 'CVCL:E307', (136, 142))	('KYSE30', 'Var', (147, 153))	('EC9706', 'Var', (136, 142))	('higher', 'PosReg', (126, 132))
82814	26799587	LncRNA TP73-AS1 knockdown also clearly induced apoptosis in EC9706 and KYSE30 cells as indicated by the Hoechst 33342 staining assay (Figure 2F).	('induced', 'Reg', (39, 46))	('apoptosis', 'CPA', (47, 56))	('Hoechst 33342', 'Chemical', 'MESH:C017807', (104, 117))	('knockdown', 'Var', (16, 25))	('EC9706', 'CellLine', 'CVCL:E307', (60, 66))
82815	26799587	To confirm the growth inhibitory effect of lncRNATP73-AS1 siRNA on EC in vivo, a xenograft tumor growth assay was performed.	('xenograft tumor', 'Disease', (81, 96))	('growth inhibitory effect', 'MPA', (15, 39))	('xenograft tumor', 'Disease', 'MESH:D009369', (81, 96))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('lncRNATP73-AS1', 'Var', (43, 57))
82816	26799587	Tumor size and luciferase signal were significantly reduced in the lncRNATP73-AS1 siRNA mice group (EC9706 and KYSE30 cells transfected with lncRNATP73-AS1 siRNA1) as compared to control mice (NC and Blank groups) at the fourth week (P<0.05, Figure 2G & 2H).	('lncRNATP73-AS1 siRNA1', 'Gene', '5729', (141, 162))	('luciferase', 'Enzyme', (15, 25))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('signal', 'MPA', (26, 32))	('reduced', 'NegReg', (52, 59))	('EC9706', 'CellLine', 'CVCL:E307', (100, 106))	('mice', 'Species', '10090', (187, 191))	('Tumor size', 'CPA', (0, 10))	('lncRNATP73-AS1 siRNA1', 'Gene', (141, 162))	('mice', 'Species', '10090', (88, 92))	('lncRNATP73-AS1 siRNA', 'Var', (67, 87))
82817	26799587	To explore the molecular mechanisms of lncRNA TP73-AS1 in tumorigenesis, mRNA microarray analysis was performed using EC9706 and KYSE30 cells transfected with lncRNATP73-AS1 siRNA or nonsense siRNA.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('lncRNATP73-AS1', 'Var', (159, 173))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('EC9706', 'CellLine', 'CVCL:E307', (118, 124))
82818	26799587	BDH2 expression was significantly decreased in EC9706 and KYSE30 cells transfected with lncRNATP73-AS1 siRNA compared to the control (P<0.05; Figure 3A).	('EC9706', 'CellLine', 'CVCL:E307', (47, 53))	('expression', 'MPA', (5, 15))	('decreased', 'NegReg', (34, 43))	('EC9706', 'Var', (47, 53))	('BDH2', 'Gene', '56898', (0, 4))	('BDH2', 'Gene', (0, 4))
82830	26799587	The number of apoptotic cells post-BDH2 siRNA transfection significantly increased in EC9706 and KYSE30 cells as compared to controls (Figure 4D).	('EC9706', 'Var', (86, 92))	('increased', 'PosReg', (73, 82))	('apoptotic cells', 'CPA', (14, 29))	('BDH2', 'Gene', (35, 39))	('BDH2', 'Gene', '56898', (35, 39))	('EC9706', 'CellLine', 'CVCL:E307', (86, 92))	('transfection', 'Var', (46, 58))
82831	26799587	These results suggest that BDH2 knockdown inhibits EC cell proliferation and induces apoptosis, which is similar to the effects of lncRNA TP73-AS1 siRNA on EC cells.	('BDH2', 'Gene', '56898', (27, 31))	('inhibits', 'NegReg', (42, 50))	('knockdown', 'Var', (32, 41))	('apoptosis', 'CPA', (85, 94))	('EC cell proliferation', 'CPA', (51, 72))	('induces', 'Reg', (77, 84))	('BDH2', 'Gene', (27, 31))
82833	26799587	We have shown that both BDH2 siRNA and lncRNATP73-AS1 siRNA induce apoptosis.	('apoptosis', 'CPA', (67, 76))	('BDH2', 'Gene', (24, 28))	('lncRNATP73-AS1', 'Var', (39, 53))	('induce', 'Reg', (60, 66))	('BDH2', 'Gene', '56898', (24, 28))
82835	26799587	BDH2 expression significantly decreased in EC9706 and KYSE30 cells after BDH2 siRNA1 or lncRNATP73-AS1 siRNA1 transfection (Figure 5A & 5B).	('BDH2', 'Gene', (73, 77))	('expression', 'MPA', (5, 15))	('lncRNATP73-AS1 siRNA1', 'Gene', (88, 109))	('BDH2', 'Gene', '56898', (73, 77))	('lncRNATP73-AS1 siRNA1', 'Gene', '5729', (88, 109))	('EC9706', 'CellLine', 'CVCL:E307', (43, 49))	('transfection', 'Var', (110, 122))	('BDH2', 'Gene', '56898', (0, 4))	('BDH2', 'Gene', (0, 4))	('decreased', 'NegReg', (30, 39))
82846	26799587	Therefore, knockdown of BDH2 or lncRNATP73-AS1 enhanced the chemosensitivity of EC cells to 5-FU and cisplatin.	('chemosensitivity', 'MPA', (60, 76))	('enhanced', 'PosReg', (47, 55))	('cisplatin', 'Chemical', 'MESH:D002945', (101, 110))	('5-FU', 'Chemical', 'MESH:D005472', (92, 96))	('lncRNATP73-AS1', 'Var', (32, 46))	('BDH2', 'Gene', '56898', (24, 28))	('knockdown', 'Var', (11, 20))	('BDH2', 'Gene', (24, 28))
82848	26799587	Western blot analysis showed that transfection increased BDH2 expression (Figure 6A).	('expression', 'MPA', (62, 72))	('BDH2', 'Gene', '56898', (57, 61))	('transfection', 'Var', (34, 46))	('increased', 'PosReg', (47, 56))	('BDH2', 'Gene', (57, 61))
82851	26799587	Apoptosis assays indicated that lncRNA TP73-AS1 knockdown increased apoptosis induced by serum starvation in EC9706 and KYSE30 cells.	('EC9706', 'CellLine', 'CVCL:E307', (109, 115))	('apoptosis', 'CPA', (68, 77))	('increased', 'PosReg', (58, 67))	('knockdown', 'Var', (48, 57))
82874	26799587	We inferred that knockdown of lncRNA TP73-AS1 or BDH2 induced cell apoptosis via a caspase-3 dependent apoptosis pathway.	('BDH2', 'Gene', (49, 53))	('caspase-3', 'Gene', '836', (83, 92))	('lncRNA TP73-AS1', 'Var', (30, 45))	('cell apoptosis', 'CPA', (62, 76))	('caspase-3', 'Gene', (83, 92))	('BDH2', 'Gene', '56898', (49, 53))
82878	26799587	We found that BDH2 or lncRNA TP73-AS1 knockdown enhanced chemosensitivity to 5-FU or cisplatin in EC cells.	('BDH2', 'Gene', (14, 18))	('5-FU', 'Chemical', 'MESH:D005472', (77, 81))	('BDH2', 'Gene', '56898', (14, 18))	('chemosensitivity to 5-FU or cisplatin', 'MPA', (57, 94))	('enhanced', 'PosReg', (48, 56))	('lncRNA', 'Gene', (22, 28))	('knockdown', 'Var', (38, 47))	('cisplatin', 'Chemical', 'MESH:D002945', (85, 94))
82889	26799587	The cell lines were cultured in RPMI-1640 medium supplemented with 10% fetal bovine serum (FBS, Gibco, Australia), 100 U/mL penicillin, and 50 mug/mL streptomycin, and were kept in incubators with humidified atmospheres of 5% CO2 and 95% air at 37 C. Recombinant lentiviral vectors carrying lncRNA TP73-AS1 siRNA1, TP73-AS1 siRNA2, BDH2 siRNA1 or BDH2 siRNA2 were constructed with standard molecular techniques.	('bovine', 'Species', '9913', (77, 83))	('BDH2', 'Gene', (347, 351))	('BDH2', 'Gene', '56898', (347, 351))	('RPMI-1640 medium', 'Chemical', '-', (32, 48))	('TP73-AS1', 'Var', (315, 323))	('FBS', 'Disease', (91, 94))	('streptomycin', 'Chemical', 'MESH:D013307', (150, 162))	('CO2', 'Chemical', '-', (226, 229))	('BDH2', 'Gene', (332, 336))	('BDH2', 'Gene', '56898', (332, 336))	('penicillin', 'Chemical', 'MESH:D010406', (124, 134))	('FBS', 'Disease', 'MESH:D005198', (91, 94))
82900	26799587	The PVDF membranes were blocked with 5% BSA in 0.05% Tween 20-TBS for 1 hour and incubated with the corresponding primary antibody diluted in blocking buffer overnight at 4 C. Dilutions for primary antibodies were as follows: anti-BDH2 (1:1,000, Santa Cruz Biotech, Dallas, TX, USA), anti-BCL-2 (1:400, Santa Cruz Biotech), anti-BAX (1:1,000, Santa Cruz Biotech), anti-cleaved-caspase-9 (1:1,000, Santa Cruz Biotech), anti-pro-caspase-9 (1:1000, Santa Cruz Biotech), and anti-cleaved caspase-3 (1:1,000, Santa Cruz Biotech).	('BAX', 'Gene', (329, 332))	('caspase-3', 'Gene', '836', (484, 493))	('PVDF', 'Chemical', 'MESH:C024865', (4, 8))	('BAX', 'Gene', '581', (329, 332))	('caspase-9', 'Gene', (427, 436))	('BDH2', 'Gene', (231, 235))	('BDH2', 'Gene', '56898', (231, 235))	('BCL-2', 'Gene', '596', (289, 294))	('caspase-9', 'Gene', '842', (377, 386))	('caspase-3', 'Gene', (484, 493))	('BCL-2', 'Gene', (289, 294))	('caspase-9', 'Gene', (377, 386))	('caspase-9', 'Gene', '842', (427, 436))	('1:400', 'Var', (296, 301))
82931	33260070	Indeed, disruption of KLK5 to SPINK5 balance through the generation of KLK5 null OSCC cells led to smaller xenografted tumors and statistically decreased proliferation rates following multiple time points of BrdU treatment in vitro.	('disruption', 'Var', (8, 18))	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('smaller', 'NegReg', (99, 106))	('decreased', 'NegReg', (144, 153))	('tumors', 'Disease', (119, 125))	('tumors', 'Disease', 'MESH:D009369', (119, 125))	('KLK5', 'Gene', (71, 75))	('BrdU', 'Chemical', 'MESH:D001973', (208, 212))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('proliferation rates', 'CPA', (154, 173))
82994	33260070	1K and 1 L; P.D.C, yellow arrowhead indicates nuclear pleomorphism while blue arrowhead indicates atypical mitosis).	('mitosis', 'Disease', (107, 114))	('mitosis', 'Disease', 'None', (107, 114))	('P.D.C', 'Var', (12, 17))	('nuclear pleomorphism', 'CPA', (46, 66))
83001	33260070	However, there is no statistical difference between LEKTI expression in W.D.C and P.D.C.	('LEKTI', 'Gene', (52, 57))	('LEKTI', 'Gene', '11005', (52, 57))	('P.D.C', 'Var', (82, 87))
83014	33260070	Because LEKTI is known to directly inhibit KLK5, we used CRISPR-Cas9 technology to knockout KLK5 and thus disturb the KLK5/LEKTI cellular balance.	('LEKTI', 'Gene', '11005', (123, 128))	('LEKTI', 'Gene', (8, 13))	('KLK5', 'Gene', (92, 96))	('LEKTI', 'Gene', (123, 128))	('LEKTI', 'Gene', '11005', (8, 13))	('disturb', 'Reg', (106, 113))	('knockout', 'Var', (83, 91))
83018	33260070	In addition, LEKTI expression does not alter following KLK5 ablation in Cal27 cell line (Clone 6, 37 KDa, Fig.	('Cal27', 'CellLine', 'CVCL:1107', (72, 77))	('ablation', 'Var', (60, 68))	('LEKTI', 'Gene', (13, 18))	('KLK5', 'Protein', (55, 59))	('LEKTI', 'Gene', '11005', (13, 18))
83024	33260070	Tumors were followed for approximately 8 weeks and the absence of KLK5 inhibited xenograft tumor growth of human OSCC cells (Fig.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('inhibited', 'NegReg', (71, 80))	('human', 'Species', '9606', (107, 112))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('KLK5', 'Protein', (66, 70))	('absence', 'Var', (55, 62))	('tumor', 'Disease', (91, 96))
83025	33260070	5P; compare black and red lines, showing KLK5 WT and KLK5 KO tumor volumes, respectively).	('KLK5 KO', 'Var', (53, 60))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Disease', (61, 66))	('tumor', 'Disease', 'MESH:D009369', (61, 66))
83032	33260070	Interestingly, different from KLK5 KO cells cultured in petri dishes, LEKTI staining was severely decreased in KLK5 KO derived tumors, yet it was still detectable (Fig.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumors', 'Disease', (127, 133))	('decreased', 'NegReg', (98, 107))	('LEKTI', 'Gene', '11005', (70, 75))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('tumors', 'Disease', 'MESH:D009369', (127, 133))	('KLK5 KO', 'Var', (111, 118))	('LEKTI', 'Gene', (70, 75))
83047	33260070	Hypothesizing that the relationship between KLK5 and LEKTI could be key to understanding the divergences in KLK5 expression levels in OSCCs, the KLK5 to LEKTI balance in an OSCC cell line expressing both KLK5 and LEKTI was disrupted by using CRISPR-Cas9 technology to knock-out KLK5 gene expression.	('LEKTI', 'Gene', (153, 158))	('LEKTI', 'Gene', (53, 58))	('LEKTI', 'Gene', '11005', (53, 58))	('LEKTI', 'Gene', '11005', (153, 158))	('LEKTI', 'Gene', (213, 218))	('knock-out', 'Var', (268, 277))	('LEKTI', 'Gene', '11005', (213, 218))	('KLK5', 'Gene', (278, 282))
83048	33260070	Of importance, KLK5 ablation alone did not modulated LEKTI expression in OSCC cell line.	('ablation', 'Var', (20, 28))	('LEKTI', 'Gene', (53, 58))	('modulated', 'Reg', (43, 52))	('LEKTI', 'Gene', '11005', (53, 58))
83051	33260070	Nonetheless, knockdown of KLK5 in PC9 lung adenocarcinoma cells also cause inhibition of cellular proliferation.	('inhibition', 'NegReg', (75, 85))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (38, 57))	('KLK5', 'Gene', (26, 30))	('PC9', 'CellLine', 'CVCL:B260', (34, 37))	('knockdown', 'Var', (13, 22))	('cellular proliferation', 'CPA', (89, 111))	('lung adenocarcinoma', 'Disease', (38, 57))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (38, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (48, 57))
83054	33260070	Taken together our data supports the relative expression of KLK5 to LEKTI as a valuable prognostic marker since the increased enzyme (KLK5) to inhibitor (LEKTI) expression in human patients and the KLK5 to LEKTI unbalance in genetically modified OSCC cell line are associated with a poor prognosis and aggravated tumor progression.	('human', 'Species', '9606', (175, 180))	('tumor', 'Phenotype', 'HP:0002664', (313, 318))	('unbalance', 'Var', (212, 221))	('tumor', 'Disease', (313, 318))	('expression', 'MPA', (161, 171))	('LEKTI', 'Gene', (154, 159))	('KLK5', 'Var', (198, 202))	('LEKTI', 'Gene', (68, 73))	('KLK5', 'Gene', (134, 138))	('patients', 'Species', '9606', (181, 189))	('LEKTI', 'Gene', (206, 211))	('increased', 'PosReg', (116, 125))	('tumor', 'Disease', 'MESH:D009369', (313, 318))	('LEKTI', 'Gene', '11005', (154, 159))	('LEKTI', 'Gene', '11005', (68, 73))	('aggravated', 'PosReg', (302, 312))	('LEKTI', 'Gene', '11005', (206, 211))
83128	33101777	Within the LUAD training cohort, upon comparing the low-ISLUAD patients with the high-ISLUAD patients, the 5-y DFS rates were 54.7% vs. 8.1%, and the 5-y OS rates were 82.4% vs. 36% (all P< .0001; Figure 2(a)).	('LUAD', 'Phenotype', 'HP:0030078', (58, 62))	('LUAD', 'Phenotype', 'HP:0030078', (11, 15))	('LUAD', 'Phenotype', 'HP:0030078', (88, 92))	('patients', 'Species', '9606', (63, 71))	('low-ISLUAD', 'Var', (52, 62))	('patients', 'Species', '9606', (93, 101))	('DFS', 'MPA', (111, 114))
83183	33101777	One prostate cancer study reported that in the tumor stroma, highly expressed CD73 was related to prolonged biochemical recurrence (BCR)-free survival.	('prolonged', 'PosReg', (98, 107))	('prostate cancer', 'Disease', 'MESH:D011471', (4, 19))	('CD73', 'Gene', (78, 82))	('tumor stroma', 'Disease', 'MESH:D009369', (47, 59))	('prostate cancer', 'Phenotype', 'HP:0012125', (4, 19))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('tumor stroma', 'Disease', (47, 59))	('prostate cancer', 'Disease', (4, 19))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('biochemical recurrence', 'CPA', (108, 130))	('highly expressed', 'Var', (61, 77))
83188	33101777	Recent literature revealed that CD39 and CD73 were new potential "immune checkpoint mediators" as the extracellular adenosine they generate could suppress the anti-tumor immune response.	('CD73', 'Var', (41, 45))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('tumor', 'Disease', (164, 169))	('suppress', 'NegReg', (146, 154))	('adenosine', 'Chemical', 'MESH:D000241', (116, 125))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('extracellular adenosine', 'MPA', (102, 125))	('CD39', 'Var', (32, 36))
83192	33101777	Several studies revealed that highly expressed Tim-3 on CD8+ T cells had a negative prognostic significance, which is consistent with our result in LUSC.	('negative', 'NegReg', (75, 83))	('LUSC', 'Phenotype', 'HP:0030359', (148, 152))	('Tim-3', 'Gene', (47, 52))	('CD8', 'Gene', (56, 59))	('highly', 'Var', (30, 36))	('CD8', 'Gene', '925', (56, 59))	('Tim-3', 'Gene', '84868', (47, 52))
83197	33101777	In addition, Rictor (an important subunit of the mTORC2 complex) has a higher rate of gene amplification in LUSC, which may promote tumor development and metastasis.	('LUSC', 'Phenotype', 'HP:0030359', (108, 112))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('gene amplification', 'Var', (86, 104))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumor', 'Disease', (132, 137))	('metastasis', 'CPA', (154, 164))	('promote', 'PosReg', (124, 131))	('Rictor', 'Gene', (13, 19))	('Rictor', 'Gene', '253260', (13, 19))
83232	31944570	Next-generation sequencing showed a tumor protein 53 (TP53) R342* (the asterix means termination codon) nonsense mutation in the lesion in the left main bronchus.	('R342*', 'SUBSTITUTION', 'None', (60, 65))	('R342*', 'Var', (60, 65))	('tumor protein 53', 'Gene', (36, 52))	('TP53', 'Gene', '7157', (54, 58))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumor protein 53', 'Gene', '7157', (36, 52))	('TP53', 'Gene', (54, 58))
83243	31944570	Although the TP53 status at initial diagnosis was unknown, the presence TP53 mutation may increase the risk of SCLC transformation.7, 9 The expression of PD-L1 changed after histologic transformation in our case.	('presence', 'Var', (63, 71))	('TP53', 'Gene', (13, 17))	('expression', 'MPA', (140, 150))	('TP53', 'Gene', '7157', (72, 76))	('SCLC', 'Gene', (111, 115))	('mutation', 'Var', (77, 85))	('PD-L1', 'Gene', (154, 159))	('changed', 'Reg', (160, 167))	('SCLC', 'Gene', '7864', (111, 115))	('SCLC', 'Phenotype', 'HP:0030357', (111, 115))	('TP53', 'Gene', (72, 76))	('PD-L1', 'Gene', '29126', (154, 159))	('TP53', 'Gene', '7157', (13, 17))
83248	31944570	Recent studies have revealed that transformation to SCLC is associated with inactivation of RB1 and TP53.9 Therefore, genetic status will help us understand how resistance and histologic transformation proceed.	('RB1', 'Gene', '5925', (92, 95))	('TP53', 'Gene', '7157', (100, 104))	('SCLC', 'Gene', '7864', (52, 56))	('SCLC', 'Phenotype', 'HP:0030357', (52, 56))	('SCLC', 'Gene', (52, 56))	('TP53', 'Gene', (100, 104))	('RB1', 'Gene', (92, 95))	('inactivation', 'Var', (76, 88))
83259	25594174	Genetic amplifications were also associated with high cytolytic activity, including immunosuppressive factors such as PDL1/2 and ALOX12B/15B.	('Genetic amplifications', 'Var', (0, 22))	('high cytolytic activity', 'MPA', (49, 72))	('ALOX12B', 'Gene', '242', (129, 136))	('PDL1/2', 'Gene', (118, 124))	('ALOX12B', 'Gene', (129, 136))	('PDL1/2', 'Gene', '29126;80380', (118, 124))
83269	25594174	Are particular recurrent mutations in tumors associated with higher cytolytic activity, reflecting mechanisms of tumor escape from cytolytic immune activities?	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('mutations', 'Var', (25, 34))	('tumor', 'Disease', (113, 118))	('tumors', 'Disease', (38, 44))	('cytolytic activity', 'MPA', (68, 86))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('tumors', 'Disease', 'MESH:D009369', (38, 44))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))
83275	25594174	Of note, CYT in colorectal tumors increased considerably given high microsatellite instability (MSI) (Data S1E).	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('MSI', 'Disease', 'None', (96, 99))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('MSI', 'Disease', (96, 99))	('colorectal tumors', 'Disease', (16, 33))	('high', 'Var', (63, 67))	('colorectal tumors', 'Disease', 'MESH:D015179', (16, 33))	('CYT', 'MPA', (9, 12))	('increased', 'PosReg', (34, 43))
83282	25594174	When we used CYT and these other metrics to identify predictors of survival (controlling for tumor histology and stage), we found that high-CYT (and other T cell markers) is associated with a modest but significant pan-cancer survival benefit (Data S1J).	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Disease', (93, 98))	('cancer', 'Disease', 'MESH:D009369', (219, 225))	('high-CYT', 'Var', (135, 143))	('cancer', 'Disease', (219, 225))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
83289	25594174	Consistent with a role for viral infection in the induction of CTLs, >2-fold increases in cytolytic activity were observed in EBV+ vs. EBV- stomach cancers and HPV+ vs. HPV- head and neck cancers, bladder cancers, uterine cancers and possibly cervical cancers (Figure 2B).	('cancers', 'Disease', 'MESH:D009369', (205, 212))	('bladder cancers', 'Disease', (197, 212))	('cancers', 'Disease', 'MESH:D009369', (252, 259))	('head and neck cancer', 'Disease', 'MESH:D006258', (174, 194))	('EBV', 'Species', '10376', (135, 138))	('cancers', 'Disease', 'MESH:D009369', (188, 195))	('cancers', 'Disease', 'MESH:D009369', (222, 229))	('EBV', 'Species', '10376', (126, 129))	('cancers', 'Disease', 'MESH:D009369', (148, 155))	('HPV', 'Species', '10566', (169, 172))	('uterine cancer', 'Phenotype', 'HP:0010784', (214, 228))	('uterine cancers', 'Phenotype', 'HP:0010784', (214, 229))	('cytolytic activity', 'MPA', (90, 108))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('EBV+ vs.', 'Var', (126, 134))	('stomach cancer', 'Phenotype', 'HP:0012126', (140, 154))	('cancers', 'Phenotype', 'HP:0002664', (205, 212))	('cancers', 'Phenotype', 'HP:0002664', (252, 259))	('cancers', 'Disease', (252, 259))	('cancers', 'Disease', (205, 212))	('neck cancers', 'Disease', (183, 195))	('cancers', 'Phenotype', 'HP:0002664', (222, 229))	('viral infection', 'Disease', (27, 42))	('cancers', 'Phenotype', 'HP:0002664', (188, 195))	('cancers', 'Disease', (188, 195))	('stomach cancers', 'Disease', 'MESH:D013274', (140, 155))	('cancers', 'Disease', (222, 229))	('head and neck cancers', 'Phenotype', 'HP:0012288', (174, 195))	('CT', 'Phenotype', 'HP:0010788', (63, 65))	('HPV', 'Species', '10566', (160, 163))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('bladder cancers', 'Phenotype', 'HP:0009725', (197, 212))	('neck cancers', 'Disease', 'MESH:D006258', (183, 195))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('head and neck cancer', 'Phenotype', 'HP:0012288', (174, 194))	('bladder cancer', 'Phenotype', 'HP:0009725', (197, 211))	('viral infection', 'Disease', 'MESH:D001102', (27, 42))	('cancers', 'Phenotype', 'HP:0002664', (148, 155))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('cervical cancers', 'Disease', (243, 259))	('cancers', 'Disease', (148, 155))	('cervical cancers', 'Disease', 'MESH:D002583', (243, 259))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('stomach cancers', 'Disease', (140, 155))	('increases', 'PosReg', (77, 86))	('HPV+', 'Var', (160, 164))	('stomach cancers', 'Phenotype', 'HP:0012126', (140, 155))	('bladder cancers', 'Disease', 'MESH:D001749', (197, 212))
83300	25594174	Melanoma mutations exhibited a likely association with CYT.	('CYT', 'Disease', (55, 58))	('association', 'Interaction', (38, 49))	('Melanoma', 'Disease', 'MESH:D008545', (0, 8))	('Melanoma', 'Phenotype', 'HP:0002861', (0, 8))	('mutations', 'Var', (9, 18))	('Melanoma', 'Disease', (0, 8))
83312	25594174	TLR7 or RAG knockouts in mice develop uncontrolled ERV expression, ERV infectivity, and ERV insertion-driven tumors yet little is known about ERV-immune and ERV-cancer interactions in humans.	('humans', 'Species', '9606', (184, 190))	('ERV expression', 'MPA', (51, 65))	('mice', 'Species', '10090', (25, 29))	('tumors', 'Disease', 'MESH:D009369', (109, 115))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('ERV-cancer', 'Disease', 'MESH:D009369', (157, 167))	('knockouts', 'Var', (12, 21))	('ERV-cancer', 'Disease', (157, 167))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('TLR7', 'Gene', (0, 4))	('interactions', 'Interaction', (168, 180))	('TLR7', 'Gene', '170743', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumors', 'Disease', (109, 115))
83323	25594174	We therefore asked whether CYT is associated with mutations in 373 'driver' genes that are frequently mutated in cancer based on analysis of TCGA exome sequencing data (q<0.1 by MutSigCV; Table S6A).	('mutations', 'Var', (50, 59))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('cancer', 'Disease', (113, 119))	('CYT', 'Disease', (27, 30))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
83325	25594174	Of the top 10 CYT-associated mutations, 8 were also associated with an independent marker of CTLs (CD8a; 10% FDR; Data S5B), demonstrating the robustness of our CYT metric.	('CTLs', 'Disease', (93, 97))	('CD8a', 'Gene', (99, 103))	('S5B', 'Gene', (119, 122))	('mutations', 'Var', (29, 38))	('associated', 'Reg', (52, 62))	('CD8a', 'Gene', '925', (99, 103))	('CT', 'Phenotype', 'HP:0010788', (93, 95))	('CYT-associated', 'Gene', (14, 28))	('S5B', 'Gene', '5711', (119, 122))
83330	25594174	The pattern of mutation was diffuse and suggested loss of function (Data S5C), a potential mechanism by which a tumor cell could evade FasL- or TRAIL-induced apoptosis.	('mutation', 'Var', (15, 23))	('tumor', 'Disease', (112, 117))	('TRAIL', 'Gene', '8743', (144, 149))	('FasL-', 'Gene', '356', (135, 140))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('loss', 'NegReg', (50, 54))	('TRAIL', 'Gene', (144, 149))	('S5C', 'Mutation', 'p.S5C', (73, 76))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('evade', 'NegReg', (129, 134))	('FasL-', 'Gene', (135, 140))
83331	25594174	Between FasL and TRAIL, FasL is most correlated with CASP8 mutations and thus more consistent with such a hypothesis (Figure 5B).	('TRAIL', 'Gene', '8743', (17, 22))	('FasL', 'Gene', (24, 28))	('FasL', 'Gene', '356', (24, 28))	('TRAIL', 'Gene', (17, 22))	('correlated', 'Interaction', (37, 47))	('FasL', 'Gene', (8, 12))	('mutations', 'Var', (59, 68))	('FasL', 'Gene', '356', (8, 12))	('CASP8', 'Gene', (53, 58))
83332	25594174	A study in mice indeed demonstrated that blockade of CASP8 results in tumor escape from CTLs, and our result indicates that this may be a common mechanism in human tumors (that may evade CTLs or NK cells).	('tumor', 'Disease', (164, 169))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('human', 'Species', '9606', (158, 163))	('CASP8', 'Protein', (53, 58))	('tumors', 'Disease', (164, 170))	('tumors', 'Disease', 'MESH:D009369', (164, 170))	('tumors', 'Phenotype', 'HP:0002664', (164, 170))	('tumor', 'Disease', (70, 75))	('CT', 'Phenotype', 'HP:0010788', (88, 90))	('CT', 'Phenotype', 'HP:0010788', (187, 189))	('blockade', 'Var', (41, 49))	('mice', 'Species', '10090', (11, 15))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
83335	25594174	PIK3CA mutations, which were often the well-known activating alterations E545K and H1047R, showed their strongest enrichment in stomach cancer, demonstrating a 20% mutation rate and a strong positive association with EBV infection (p=2.9e-10).	('EBV infection', 'Disease', (217, 230))	('mutations', 'Var', (7, 16))	('EBV infection', 'Disease', 'MESH:D020031', (217, 230))	('stomach cancer', 'Disease', 'MESH:D013274', (128, 142))	('H1047R', 'Mutation', 'rs121913279', (83, 89))	('stomach cancer', 'Phenotype', 'HP:0012126', (128, 142))	('PIK3CA', 'Gene', (0, 6))	('men', 'Species', '9606', (120, 123))	('E545K', 'Mutation', 'rs104886003', (73, 78))	('PIK3CA', 'Gene', '5290', (0, 6))	('stomach cancer', 'Disease', (128, 142))	('E545K', 'Var', (73, 78))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('H1047R', 'Var', (83, 89))
83336	25594174	As in the case of CASP8, mutations in each of these genes were more closely associated with FASL expression than TRAIL expression.	('mutations', 'Var', (25, 34))	('TRAIL', 'Gene', (113, 118))	('FASL', 'Gene', (92, 96))	('CASP8', 'Gene', (18, 23))	('associated', 'Reg', (76, 86))	('TRAIL', 'Gene', '8743', (113, 118))	('FASL', 'Gene', '356', (92, 96))
83340	25594174	The most frequent event was the same CT dinucleotide deletion observed previously in melanoma patients relapsing from T cell-based immunotherapy.	('patients', 'Species', '9606', (94, 102))	('melanoma', 'Disease', 'MESH:D008545', (85, 93))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('melanoma', 'Disease', (85, 93))	('dinucleotide deletion', 'Var', (40, 61))	('CT', 'Phenotype', 'HP:0010788', (37, 39))
83342	25594174	HLA-A and HLA-B alleles were mutated about 3 times as frequently as HLA-C alleles.	('HLA-B', 'Gene', '3106', (10, 15))	('HLA-A', 'Gene', '3105', (0, 5))	('HLA-A', 'Gene', (0, 5))	('mutated', 'Var', (29, 36))	('HLA-B', 'Gene', (10, 15))
83343	25594174	The tumor types with the highest rates of HLA mutation, stomach cancer (14%), cervical cancer (12%), and head and neck cancer (11%), were also among those with frequent viral involvement.	('tumor', 'Disease', (4, 9))	('stomach cancer', 'Phenotype', 'HP:0012126', (56, 70))	('head and neck cancer', 'Disease', 'MESH:D006258', (105, 125))	('stomach cancer', 'Disease', (56, 70))	('cervical cancer', 'Disease', 'MESH:D002583', (78, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cervical cancer', 'Disease', (78, 93))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('head and neck cancer', 'Phenotype', 'HP:0012288', (105, 125))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('men', 'Species', '9606', (182, 185))	('mutation', 'Var', (46, 54))	('HLA', 'Gene', (42, 45))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('stomach cancer', 'Disease', 'MESH:D013274', (56, 70))
83345	25594174	Given the requirement of MHC Class I and B2M in presenting tumor antigens to cytotoxic CD8 T cells, we consider the enrichment of MHC Class I and B2M mutations in high-CYT tumors as an independent and strong validation of CYT as a measure of cytolytic activity.	('tumor', 'Disease', (59, 64))	('tumor', 'Disease', (172, 177))	('B2M', 'Gene', (41, 44))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('B2M', 'Gene', '567', (146, 149))	('CD8', 'Gene', '925', (87, 90))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('men', 'Species', '9606', (122, 125))	('men', 'Species', '9606', (17, 20))	('tumors', 'Phenotype', 'HP:0002664', (172, 178))	('B2M', 'Gene', '567', (41, 44))	('mutations', 'Var', (150, 159))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('tumors', 'Disease', (172, 178))	('CD8', 'Gene', (87, 90))	('tumors', 'Disease', 'MESH:D009369', (172, 178))	('B2M', 'Gene', (146, 149))	('MHC Class I', 'Gene', (130, 141))
83346	25594174	While MHC Class II genes were not significantly mutated pan-cancer, class II gene mutations, considered collectively, were positively associated with CYT (unadj.	('associated', 'Reg', (134, 144))	('class II gene', 'Gene', (68, 81))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('CYT', 'Disease', (150, 153))	('cancer', 'Disease', (60, 66))	('mutations', 'Var', (82, 91))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
83349	25594174	We also note that mutant TP53 is negatively correlated with CYT, which may be explained either by a role for p53 in regulating immunity (e.g., loss of p53-regulated stress ligands that induce cytoxicity, or from absence of viral infection (consistent with p53 mutations being anti-correlated with viral infection in stomach (p=2.3e-5) and head and neck cancer (p=2.6e-4); Table S6D).	('viral infection', 'Disease', 'MESH:D001102', (223, 238))	('p53', 'Gene', (256, 259))	('p53', 'Gene', '7157', (151, 154))	('mutant', 'Var', (18, 24))	('head and neck cancer', 'Disease', 'MESH:D006258', (339, 359))	('negatively', 'NegReg', (33, 43))	('p53', 'Gene', '7157', (109, 112))	('viral infection', 'Disease', (297, 312))	('p53', 'Gene', (151, 154))	('cytoxicity', 'MPA', (192, 202))	('TP53', 'Gene', (25, 29))	('CYT', 'Disease', (60, 63))	('viral infection', 'Disease', 'MESH:D001102', (297, 312))	('p53', 'Gene', (109, 112))	('regulating immunity', 'MPA', (116, 135))	('loss', 'NegReg', (143, 147))	('mutations', 'Var', (260, 269))	('head and neck cancer', 'Phenotype', 'HP:0012288', (339, 359))	('viral infection', 'Disease', (223, 238))	('p53', 'Gene', '7157', (256, 259))	('TP53', 'Gene', '7157', (25, 29))	('cancer', 'Phenotype', 'HP:0002664', (353, 359))
83351	25594174	Mirroring the CYT analysis, CASP8 and MHC Class I mutations were the most enriched mutations in MSI-high tumors (p adj.	('MSI-high tumors', 'Disease', (96, 111))	('mutations', 'Var', (50, 59))	('CASP8', 'Gene', (28, 33))	('MHC Class I', 'Gene', (38, 49))	('MSI-high tumors', 'Disease', 'MESH:D009369', (96, 111))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))
83353	25594174	However, enrichment in the expression of immune-related genes were observed in tumors with mutations in some of these genes (TNFRSF14, CLEC4E, CD1D, IL32; Table S6F).	('IL32', 'Gene', (149, 153))	('CLEC4E', 'Gene', '26253', (135, 141))	('CD1D', 'Gene', (143, 147))	('TNFRSF14', 'Gene', '8764', (125, 133))	('CLEC4E', 'Gene', (135, 141))	('expression', 'MPA', (27, 37))	('men', 'Species', '9606', (15, 18))	('tumors', 'Disease', (79, 85))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('mutations', 'Var', (91, 100))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('CD1D', 'Gene', '912', (143, 147))	('TNFRSF14', 'Gene', (125, 133))	('IL32', 'Gene', '9235', (149, 153))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
83355	25594174	As with the point mutation analysis, we looked for pan-cancer CYT association with copy number alterations (CNAs) using regression and controlling for cancer subtype and background mutation rate (of amplifications and deletions).	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('copy number alterations', 'Var', (83, 106))	('cancer', 'Disease', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('cancer', 'Disease', (55, 61))
83358	25594174	First, amplification of 9p23-p24.2 (Figure 6B), a region including PDL1 (CD274) and PDL2 (PDCD1LG2),was positively associated with CYT in lung squamous cell carcinoma, head and neck cancer, cervical cancer, stomach cancer, and colorectal cancer (Figure 6E).	('CD274', 'Gene', (73, 78))	('stomach cancer', 'Disease', 'MESH:D013274', (207, 221))	('stomach cancer', 'Phenotype', 'HP:0012126', (207, 221))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (138, 166))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (143, 166))	('lung squamous cell carcinoma', 'Disease', (138, 166))	('head and neck cancer', 'Disease', 'MESH:D006258', (168, 188))	('associated with', 'Reg', (115, 130))	('p24', 'Gene', (29, 32))	('p24', 'Gene', '140767', (29, 32))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('PDL2', 'Gene', (84, 88))	('cervical cancer', 'Disease', (190, 205))	('cervical cancer', 'Disease', 'MESH:D002583', (190, 205))	('colorectal cancer', 'Phenotype', 'HP:0003003', (227, 244))	('PDCD1LG2', 'Gene', '80380', (90, 98))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('carcinoma', 'Phenotype', 'HP:0030731', (157, 166))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('PDL1', 'Gene', (67, 71))	('CD274', 'Gene', '29126', (73, 78))	('stomach cancer', 'Disease', (207, 221))	('PDL1', 'Gene', '29126', (67, 71))	('PDCD1LG2', 'Gene', (90, 98))	('colorectal cancer', 'Disease', 'MESH:D015179', (227, 244))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (138, 166))	('CYT', 'Disease', (131, 134))	('head and neck cancer', 'Phenotype', 'HP:0012288', (168, 188))	('colorectal cancer', 'Disease', (227, 244))	('amplification', 'Var', (7, 20))	('PDL2', 'Gene', '80380', (84, 88))
83360	25594174	Second, 8p11.21-8p11.23 (Data S6A) showed increased probability of amplification in low-CYT tumors (pan-cancer and breast) and is adjacent to IDO1 and IDO2, enzymes that degrade extracellular tryptophan and create a potent immunosuppressive microenvironment, which may explain the associated reduction in CYT.	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('IDO1', 'Gene', (142, 146))	('extracellular tryptophan', 'MPA', (178, 202))	('amplification', 'Var', (67, 80))	('IDO1', 'Gene', '3620', (142, 146))	('IDO2', 'Gene', '169355', (151, 155))	('low-CYT tumors', 'Disease', 'MESH:D009800', (84, 98))	('low-CYT tumors', 'Disease', (84, 98))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('men', 'Species', '9606', (253, 256))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('IDO2', 'Gene', (151, 155))	('degrade', 'NegReg', (170, 177))	('tryptophan', 'Chemical', 'MESH:D014364', (192, 202))
83363	25594174	Further supporting this model, the amplification was associated with higher necrosis in breast (p=0.002) and kidney clear cell cancer (p=0.0002), though not ovarian cancer.	('amplification', 'Var', (35, 48))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('ovarian cancer', 'Phenotype', 'HP:0100615', (157, 171))	('ovarian cancer', 'Disease', 'MESH:D010051', (157, 171))	('clear cell cancer', 'Phenotype', 'HP:0006770', (116, 133))	('necrosis', 'Disease', (76, 84))	('kidney clear cell cancer', 'Disease', (109, 133))	('breast', 'Disease', (88, 94))	('ovarian cancer', 'Disease', (157, 171))	('necrosis', 'Disease', 'MESH:D009336', (76, 84))	('kidney clear cell cancer', 'Disease', 'MESH:D008649', (109, 133))	('higher', 'PosReg', (69, 75))
83368	25594174	Our results suggest that neoantigens and viruses are likely to drive cytolytic activity, and reveal known and novel mutations that enable tumors to resist immune attack.	('cytolytic activity', 'MPA', (69, 87))	('drive', 'PosReg', (63, 68))	('tumors', 'Disease', (138, 144))	('mutations', 'Var', (116, 125))	('tumors', 'Disease', 'MESH:D009369', (138, 144))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
83375	25594174	As expected, we observed enrichment of mutations in antigen presentation machinery (thus validating our cytolytic metric), including HLA and B2M, as well as extrinsic apoptosis genes, such as CASP8, that would prevent cytolytic cells from killing tumors via FasL-Fas interactions.	('tumor', 'Phenotype', 'HP:0002664', (247, 252))	('FasL-', 'Gene', '356', (258, 263))	('tumors', 'Disease', (247, 253))	('tumors', 'Disease', 'MESH:D009369', (247, 253))	('men', 'Species', '9606', (31, 34))	('tumors', 'Phenotype', 'HP:0002664', (247, 253))	('CASP8', 'Gene', (192, 197))	('FasL-', 'Gene', (258, 263))	('mutations', 'Var', (39, 48))	('B2M', 'Gene', (141, 144))	('B2M', 'Gene', '567', (141, 144))	('prevent', 'NegReg', (210, 217))	('interactions', 'Interaction', (267, 279))
83377	25594174	Most of the identified mutations - including HLA, B2M and CASP8 - were positively correlated with CYT and are likely to represent autonomous escape mechanisms (Figure 7B).	('B2M', 'Gene', '567', (50, 53))	('CASP8', 'Gene', (58, 63))	('CYT', 'Disease', (98, 101))	('mutations', 'Var', (23, 32))	('correlated', 'Interaction', (82, 92))	('B2M', 'Gene', (50, 53))
83378	25594174	In addition, we identified a smaller number of mutations that correlated negatively with cytolytic activity - including IDO1 and IDO2, p53, and the ALOX locus - and may represent non-autonomous mechanisms of suppressing immunity (Figure 7C).	('suppressing', 'NegReg', (208, 219))	('cytolytic activity', 'MPA', (89, 107))	('IDO2', 'Gene', '169355', (129, 133))	('negatively', 'NegReg', (73, 83))	('mutations', 'Var', (47, 56))	('IDO1', 'Gene', '3620', (120, 124))	('IDO2', 'Gene', (129, 133))	('p53', 'Gene', (135, 138))	('p53', 'Gene', '7157', (135, 138))	('IDO1', 'Gene', (120, 124))
83381	25594174	If we consider positive correlation of HLA, B2M or CASP8 mutations with CYT as a 'signature' of selection pressure by the immune system, we find that colorectal, uterine, stomach, head and neck, cervical, lung squamous and breast tumors are most susceptible to immune elimination.	('B2M', 'Gene', '567', (44, 47))	('uterine', 'Disease', (162, 169))	('cervical', 'Disease', (195, 203))	('tumors', 'Phenotype', 'HP:0002664', (230, 236))	('colorectal', 'Disease', (150, 160))	('breast tumors', 'Phenotype', 'HP:0100013', (223, 236))	('mutations', 'Var', (57, 66))	('CASP8', 'Gene', (51, 56))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))	('stomach', 'Disease', (171, 178))	('lung squamous and breast tumors', 'Disease', 'MESH:D001943', (205, 236))	('B2M', 'Gene', (44, 47))
83386	25594174	To assess the utility of these markers, one would need to genotype tumors for the 35 identified genes at clonal or subclonal levels, and test if pre-treatment or post-treatment mutations predict refractoriness or relapse in response to cytolytic immunotherapy.	('tumors', 'Disease', 'MESH:D009369', (67, 73))	('mutations', 'Var', (177, 186))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('relapse', 'CPA', (213, 220))	('men', 'Species', '9606', (154, 157))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('refractoriness', 'MPA', (195, 209))	('tumors', 'Disease', (67, 73))	('men', 'Species', '9606', (172, 175))
83387	25594174	We predict that the presence of these mutations (assuming they do not lead to complete loss of susceptibility) indicates that re-activation of CD8 T cells would be therapeutically effective.	('mutations', 'Var', (38, 47))	('CD8', 'Gene', (143, 146))	('CD8', 'Gene', '925', (143, 146))
83388	25594174	In addition, we identified new candidates for therapeutic development, including the ALOX enzymes and their products, the PIK3CA protein that is enriched in activating mutations in high-CYT stomach cancers, and FASL which may be useful to upregulate in T cells to enhance the anti-tumor activity of adoptively transferred T cells.	('PIK3CA', 'Gene', (122, 128))	('FASL', 'Gene', (211, 215))	('men', 'Species', '9606', (65, 68))	('stomach cancers', 'Disease', 'MESH:D013274', (190, 205))	('stomach cancers', 'Disease', (190, 205))	('cancers', 'Phenotype', 'HP:0002664', (198, 205))	('PIK3CA', 'Gene', '5290', (122, 128))	('enhance', 'PosReg', (264, 271))	('stomach cancer', 'Phenotype', 'HP:0012126', (190, 204))	('tumor', 'Disease', 'MESH:D009369', (281, 286))	('stomach cancers', 'Phenotype', 'HP:0012126', (190, 205))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('tumor', 'Phenotype', 'HP:0002664', (281, 286))	('FASL', 'Gene', '356', (211, 215))	('tumor', 'Disease', (281, 286))	('mutations', 'Var', (168, 177))
83396	25594174	Whole exome sequencing-derived point mutation calls were accessed from TumorPortal, Synapse workspace syn1729383 (https://www.synapse.org/#!Synapse:syn1729383), TCGA Data Portal (National Institute of Health), GDAC Firehose, and the TCGA Research Network stomach adenocarcinoma publication.	('syn1729383', 'Var', (148, 158))	('stomach adenocarcinoma publication', 'Disease', (255, 289))	('stomach adenocarcinoma publication', 'Disease', 'MESH:D013274', (255, 289))	('carcinoma', 'Phenotype', 'HP:0030731', (268, 277))
83404	25594174	By comparing to matched tumor .bams, POLYSOLVER also identified HLA mutations.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('HLA', 'Disease', (64, 67))	('tumor', 'Disease', (24, 29))	('mutations', 'Var', (68, 77))	('tumor', 'Disease', 'MESH:D009369', (24, 29))
83405	25594174	Neo-epitopes were predicted for each patient by defining all novel amino acid 9mers and 10mers resulting from mutation in expressed genes (median >10 TPM in the tumor type) and determining whether the predicted binding affinity to the patient's germline HLA alleles was <500 nM using NetMHCpan (v2.4)).	('resulting from', 'Reg', (95, 109))	('patient', 'Species', '9606', (235, 242))	('patient', 'Species', '9606', (37, 44))	('mers', 'Species', '1335626', (79, 83))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('mers', 'Species', '1335626', (90, 94))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('mutation', 'Var', (110, 118))	('binding', 'Interaction', (211, 218))	('NetMHCpan', 'Chemical', '-', (284, 293))	('tumor', 'Disease', (161, 166))
83413	24603336	Unequal prognostic potentials of p53 gain-of-function mutations in human cancers associate with drug-metabolizing activity Mutation of p53 is the most common genetic change in human cancer, causing complex effects including not only loss of wild-type function but also gain of novel oncogenic functions (GOF).	('human', 'Species', '9606', (176, 181))	('p53', 'Gene', '7157', (33, 36))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('cancers', 'Disease', (73, 80))	('cancer', 'Disease', (73, 79))	('Mutation', 'Var', (123, 131))	('gain-of-function', 'PosReg', (37, 53))	('mutations', 'Var', (54, 63))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('p53', 'Gene', '7157', (135, 138))	('p53', 'Gene', (33, 36))	('cancer', 'Disease', (182, 188))	('loss', 'NegReg', (233, 237))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('p53', 'Gene', (135, 138))	('cancers', 'Disease', 'MESH:D009369', (73, 80))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('oncogenic functions', 'CPA', (283, 302))	('gain', 'PosReg', (269, 273))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('human', 'Species', '9606', (67, 72))
83414	24603336	Here we combine large-scale cancer genomic data to characterize the prognostic significance of different p53 mutations in human cancers.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('human', 'Species', '9606', (122, 127))	('cancers', 'Disease', 'MESH:D009369', (128, 135))	('cancers', 'Phenotype', 'HP:0002664', (128, 135))	('cancers', 'Disease', (128, 135))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('p53', 'Gene', (105, 108))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('mutations', 'Var', (109, 118))	('cancer', 'Disease', (28, 34))	('cancer', 'Disease', (128, 134))
83415	24603336	Unexpectedly, only mutations on the Arg248 and Arg282 positions displayed significant association with shorter patient survival, but such association was not evident for other hotspot GOF mutations.	('Arg282', 'Var', (47, 53))	('patient survival', 'CPA', (111, 127))	('Arg248', 'Var', (36, 42))	('shorter', 'NegReg', (103, 110))	('patient', 'Species', '9606', (111, 118))	('Arg248', 'Chemical', '-', (36, 42))	('Arg282', 'Chemical', '-', (47, 53))
83416	24603336	Gene set enrichment analysis on these mutations revealed higher activity of drug-metabolizing enzymes, including the CYP3A4 cytochrome P450.	('drug-metabolizing enzymes', 'Enzyme', (76, 101))	('higher', 'PosReg', (57, 63))	('CYP3A4', 'Gene', (117, 123))	('activity', 'MPA', (64, 72))	('CYP3A4', 'Gene', '1576', (117, 123))	('mutations', 'Var', (38, 47))
83417	24603336	Ectopic expression of p53 mutant R282W in H1299 and SaOS2 cells significantly upregulated CYP3A4 mRNA and protein levels, and cancer cell lines bearing mortality-associated p53 mutations display higher CYP3A4 expression and resistance to several CYP3A4-metabolized chemotherapeutic drugs.	('expression', 'MPA', (209, 219))	('CYP3A4', 'Gene', (202, 208))	('upregulated', 'PosReg', (78, 89))	('CYP3A4', 'Gene', (90, 96))	('mutations', 'Var', (177, 186))	('CYP3A4', 'Gene', '1576', (246, 252))	('higher', 'PosReg', (195, 201))	('resistance', 'CPA', (224, 234))	('cancer', 'Disease', (126, 132))	('R282W', 'Mutation', 'rs28934574', (33, 38))	('CYP3A4', 'Gene', (246, 252))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('p53', 'Gene', (173, 176))	('p53', 'Gene', (22, 25))	('mutant R282W', 'Var', (26, 38))	('H1299', 'CellLine', 'CVCL:0060', (42, 47))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('CYP3A4', 'Gene', '1576', (202, 208))	('CYP3A4', 'Gene', '1576', (90, 96))	('Ectopic expression', 'MPA', (0, 18))
83418	24603336	Our results suggest that p53 mutations have unequal GOF activities in human cancers, and future evaluation of p53 as a cancer biomarker should consider which mutation is present in the tumor, rather than having comparison between wild-type and mutant genotypes.	('p53', 'Gene', (25, 28))	('tumor', 'Disease', (185, 190))	('cancers', 'Disease', 'MESH:D009369', (76, 83))	('cancers', 'Phenotype', 'HP:0002664', (76, 83))	('cancers', 'Disease', (76, 83))	('mutations', 'Var', (29, 38))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('human', 'Species', '9606', (70, 75))	('cancer', 'Disease', (119, 125))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
83421	24603336	The vast majority (95%) of p53 mutations in human cancers are missense mutations, sitting within the DNA-binding domain (amino acids 102-292) with hot spots at codons R175, Y220, G245, R248, R249, R273 and R282 (illustrated in Figure 1b).	('human', 'Species', '9606', (44, 49))	('mutations', 'Var', (31, 40))	('R273', 'Var', (197, 201))	('cancers', 'Disease', 'MESH:D009369', (50, 57))	('cancers', 'Phenotype', 'HP:0002664', (50, 57))	('Y220', 'Var', (173, 177))	('cancers', 'Disease', (50, 57))	('R249', 'Var', (191, 195))	('R175', 'Var', (167, 171))	('R248', 'Var', (185, 189))	('G245', 'Var', (179, 183))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('R282', 'Var', (206, 210))	('p53', 'Gene', (27, 30))
83422	24603336	Mutations that occur in the p53-DNA-binding surface are defined as contact mutations (R273H and R248W), whereas mutations that cause conformational instability of the p53 protein are classified as a structural mutations (R175H, Y220C, G245S, R248Q, R249S, R282W, etc) (illustrated in Figure 1b).	('R273H', 'Var', (86, 91))	('R273H', 'Mutation', 'rs28934576', (86, 91))	('G245S', 'Mutation', 'rs28934575', (235, 240))	('R248Q', 'Mutation', 'rs11540652', (242, 247))	('R248W', 'Mutation', 'rs121912651', (96, 101))	('Y220C', 'Var', (228, 233))	('R249S', 'Mutation', 'rs28934571', (249, 254))	('R175H', 'Mutation', 'rs28934578', (221, 226))	('R175H', 'Var', (221, 226))	('R282W', 'Var', (256, 261))	('R248W', 'Var', (96, 101))	('G245S', 'Var', (235, 240))	('R249S', 'Var', (249, 254))	('R248Q', 'Var', (242, 247))	('Y220C', 'Mutation', 'rs121912666', (228, 233))	('R282W', 'Mutation', 'rs28934574', (256, 261))
83424	24603336	According to a p53-Bcl-XL complex model determined by NMR chemical shift perturbation, the p53-hotspot mutations R248W, R248Q and R282W sit in the binding surface to Bcl-XL (Figure 1c).	('R248W', 'Var', (113, 118))	('binding', 'Interaction', (147, 154))	('Bcl-XL', 'Gene', '598', (19, 25))	('Bcl-XL', 'Gene', '598', (166, 172))	('Bcl-XL', 'Gene', (166, 172))	('Bcl-XL', 'Gene', (19, 25))	('R248Q', 'Mutation', 'rs11540652', (120, 125))	('R282W', 'Var', (130, 135))	('R248W', 'Mutation', 'rs121912651', (113, 118))	('R282W', 'Mutation', 'rs28934574', (130, 135))	('p53-hotspot', 'Gene', (91, 102))	('R248Q', 'Var', (120, 125))
83425	24603336	It is currently unknown if these 'Bcl-XL contact' mutations confer any specific cancerous phenotypes.	('cancerous', 'Disease', (80, 89))	('mutations', 'Var', (50, 59))	('Bcl-XL', 'Gene', '598', (34, 40))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('Bcl-XL', 'Gene', (34, 40))	('cancerous', 'Disease', 'MESH:D009369', (80, 89))
83426	24603336	It is becoming increasingly evident that mutant p53 proteins not only lose their tumor-suppressor function but some acquire oncogenic gain-of-function (GOF).	('p53', 'Gene', (48, 51))	('mutant', 'Var', (41, 47))	('proteins', 'Protein', (52, 60))	('oncogenic', 'CPA', (124, 133))	('gain-of-function', 'PosReg', (134, 150))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Disease', (81, 86))	('lose', 'NegReg', (70, 74))
83427	24603336	The most compelling support for GOF comes from mice engineered to harbor some of the hot spot tumor-associated p53 mutations.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('mutations', 'Var', (115, 124))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('p53', 'Gene', (111, 114))	('tumor', 'Disease', (94, 99))	('mice', 'Species', '10090', (47, 51))
83428	24603336	When compared with heterozygous or null (p53+/- or p53-/-) mice, animals with one mutant allele equivalent to human R175H or R273H showed more spontaneous carcinomas, sarcomas and lymphomas.	('carcinoma', 'Phenotype', 'HP:0030731', (155, 164))	('sarcomas', 'Phenotype', 'HP:0100242', (167, 175))	('R273H', 'Mutation', 'rs28934576', (125, 130))	('mice', 'Species', '10090', (59, 63))	('R273H', 'Var', (125, 130))	('carcinomas', 'Phenotype', 'HP:0030731', (155, 165))	('carcinomas', 'Disease', (155, 165))	('carcinomas', 'Disease', 'MESH:D002277', (155, 165))	('human', 'Species', '9606', (110, 115))	('R175H', 'Mutation', 'rs28934578', (116, 121))	('lymphomas', 'Phenotype', 'HP:0002665', (180, 189))	('sarcomas and lymphomas', 'Disease', 'MESH:D012509', (167, 189))
83429	24603336	Although these mutants increased tumor metastasis, they do not shorten mouse survival time as compared with p53-null background.	('tumor metastasis', 'Disease', (33, 49))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('mutants', 'Var', (15, 22))	('increased', 'PosReg', (23, 32))	('tumor metastasis', 'Disease', 'MESH:D009362', (33, 49))	('mouse', 'Species', '10090', (71, 76))
83430	24603336	It was also found that R248Q mutation could accelerate onset of all tumor types and shorten the survival of mice, thus suggesting that hotspot mutants may confer different type and magnitude of GOF effects.	('shorten', 'NegReg', (84, 91))	('tumor', 'Disease', (68, 73))	('R248Q', 'Mutation', 'rs11540652', (23, 28))	('R248Q mutation', 'Var', (23, 37))	('mice', 'Species', '10090', (108, 112))	('survival of mice', 'CPA', (96, 112))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('accelerate', 'PosReg', (44, 54))
83431	24603336	A recent in-depth study demonstrated that R273H mutant gains new function by activation of EGFR signaling via suppressing mir-27a expression.	('expression', 'MPA', (130, 140))	('EGFR', 'Gene', (91, 95))	('mir-27a', 'Gene', (122, 129))	('mir-27a', 'Gene', '407018', (122, 129))	('activation', 'PosReg', (77, 87))	('suppressing', 'NegReg', (110, 121))	('EGFR', 'Gene', '1956', (91, 95))	('R273H', 'Var', (42, 47))	('R273H', 'Mutation', 'rs28934576', (42, 47))
83432	24603336	It is of great importance to clarify the prognostic significance of p53 mutations, as genes that display oncogenic activities may present useful information for cancer prognosis.	('mutations', 'Var', (72, 81))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('p53', 'Gene', (68, 71))	('cancer', 'Disease', (161, 167))
83433	24603336	To our knowledge, no existing empirical research addresses the effects of individual p53 mutations on human cancers.	('cancers', 'Phenotype', 'HP:0002664', (108, 115))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('mutations', 'Var', (89, 98))	('p53', 'Gene', (85, 88))	('cancers', 'Disease', 'MESH:D009369', (108, 115))	('cancers', 'Disease', (108, 115))	('human', 'Species', '9606', (102, 107))
83434	24603336	In this study, we combine large-scale cancer genomic data to characterize the effects of each hotspot p53 mutation on human cancer prognosis.	('cancer', 'Disease', (38, 44))	('cancer', 'Disease', (124, 130))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('mutation', 'Var', (106, 114))	('human', 'Species', '9606', (118, 123))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('p53', 'Gene', (102, 105))	('cancer', 'Disease', 'MESH:D009369', (124, 130))
83435	24603336	The potential pathways that may mediate drug resistance and cancer mortality were also analyzed to provide insight into the unequal mutant GOF effects in human cancers.	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('human', 'Species', '9606', (154, 159))	('cancers', 'Disease', 'MESH:D009369', (160, 167))	('cancers', 'Phenotype', 'HP:0002664', (160, 167))	('cancers', 'Disease', (160, 167))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('mutant', 'Var', (132, 138))	('cancer', 'Disease', (160, 166))	('cancer', 'Disease', (60, 66))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('drug resistance', 'Phenotype', 'HP:0020174', (40, 55))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
83436	24603336	To assess the effects of different p53 mutations in cancer outcome, we firstly performed survival analysis on the MSKCC bladder cancer data set (JCO, 2013) in combination with The Cancer Genome Atlas (TCGA) patient cohorts that had higher frequency of p53 mutation and adequate patient outcome data.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (180, 199))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('bladder cancer', 'Disease', 'MESH:D001749', (120, 134))	('mutation', 'Var', (256, 264))	('p53', 'Gene', (252, 255))	('bladder cancer', 'Disease', (120, 134))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('patient', 'Species', '9606', (278, 285))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('patient', 'Species', '9606', (207, 214))	('Cancer', 'Phenotype', 'HP:0002664', (180, 186))	('bladder cancer', 'Phenotype', 'HP:0009725', (120, 134))	('Cancer Genome Atlas', 'Disease', (180, 199))	('cancer', 'Disease', (128, 134))
83440	24603336	To analyze if mutant p53 aggregation or abolished contact with DNA is associated with patient outcome, the patients were also classified according to the type of p53 mutations.	('mutant', 'Var', (14, 20))	('associated', 'Reg', (70, 80))	('patient', 'Species', '9606', (86, 93))	('aggregation', 'Reg', (25, 36))	('patient', 'Species', '9606', (107, 114))	('patients', 'Species', '9606', (107, 115))	('p53', 'Gene', (21, 24))
83441	24603336	Kaplan-Meier survival analysis revealed that patients carrying p53 mutations on Arg248 and Arg282 residues had significantly shorter overall survival time than those carrying nonsense mutations (Figures 2a and b).	('Arg282', 'Chemical', '-', (91, 97))	('p53', 'Gene', (63, 66))	('Arg282 residues', 'Var', (91, 106))	('Arg248', 'Chemical', '-', (80, 86))	('patients', 'Species', '9606', (45, 53))	('shorter', 'NegReg', (125, 132))	('overall survival', 'MPA', (133, 149))
83442	24603336	Other frequently-occurring mutations at residues Y220, G245, R175 and R273 (Figures 2c and d) showed similar survival curves as nonsense mutations, and very few cases with the R249S mutation are available for further analysis.	('R249S', 'Mutation', 'rs28934571', (176, 181))	('R249S', 'Var', (176, 181))	('R175', 'Var', (61, 65))	('R273', 'Var', (70, 74))	('G245', 'Var', (55, 59))
83443	24603336	The frameshift, nonsense and missense mutations displayed comparable survival curves (Figure 2f), and even the comparison between wild-type and mutant p53 showed no significant difference in patient survival (Figure 2g).	('missense mutations', 'Var', (29, 47))	('nonsense', 'Var', (16, 24))	('patient', 'Species', '9606', (191, 198))	('frameshift', 'Var', (4, 14))
83444	24603336	In the multivariate (Cox regression) analysis adjusting for cancer types, mutations on R282 and R248 residues showed ~two fold higher hazard ratios than that of the nonsense mutations (Figure 3a).	('Cox', 'Gene', '1351', (21, 24))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('Cox', 'Gene', (21, 24))	('R248 residues', 'Var', (96, 109))	('cancer', 'Disease', (60, 66))	('higher', 'PosReg', (127, 133))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
83445	24603336	We tested the association between R248/R282 mutations and cancer patient survival using an independent data set extracted from published literatures (data in Supplementary Table 1), and found these mutations are indeed associated with shorter patient survival (Figure 3b).	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('patient', 'Species', '9606', (243, 250))	('shorter', 'NegReg', (235, 242))	('tested', 'Reg', (3, 9))	('R248/R282', 'Var', (34, 43))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('patient', 'Species', '9606', (65, 72))	('cancer', 'Disease', (58, 64))	('patient survival', 'CPA', (243, 259))
83447	24603336	In fact, mice carrying humanized mutation on R248 (but not R175 or R273) were also found with significantly shorter survival time, suggesting that frequently-occurring p53 mutations display unequal GOF effects in both human and mouse.	('mutations', 'Var', (172, 181))	('mutation', 'Var', (33, 41))	('mouse', 'Species', '10090', (228, 233))	('shorter', 'NegReg', (108, 115))	('R248', 'Var', (45, 49))	('human', 'Species', '9606', (218, 223))	('GOF', 'PosReg', (198, 201))	('mice', 'Species', '10090', (9, 13))	('human', 'Species', '9606', (23, 28))	('p53', 'Gene', (168, 171))
83448	24603336	Although the structural/contact classifications seem to be uncorrelated to patient survival, all the mortality-associated mutations are located in p53's binding surface to Bcl-XL (shown in Figure 1c), suggesting potential relevance of p53 mitochondrial apoptotic functions with cancer patient survival.	('cancer', 'Phenotype', 'HP:0002664', (278, 284))	('cancer', 'Disease', (278, 284))	('Bcl-XL', 'Gene', '598', (172, 178))	('cancer', 'Disease', 'MESH:D009369', (278, 284))	('patient', 'Species', '9606', (285, 292))	('mutations', 'Var', (122, 131))	('Bcl-XL', 'Gene', (172, 178))	('patient', 'Species', '9606', (75, 82))	('p53', 'Gene', (147, 150))
83450	24603336	The CRC cases contain more mortality-associated mutations (R248Q/W and R282W) and two intensively studied mutations (R175H and R273H), and thus were more suitable for further analysis.	('R273H', 'Var', (127, 132))	('R175H', 'Mutation', 'rs28934578', (117, 122))	('R248Q', 'Var', (59, 64))	('CRC', 'Phenotype', 'HP:0003003', (4, 7))	('R175H', 'Var', (117, 122))	('R282W', 'Var', (71, 76))	('R273H', 'Mutation', 'rs28934576', (127, 132))	('R248Q', 'SUBSTITUTION', 'None', (59, 64))	('R282W', 'Mutation', 'rs28934574', (71, 76))
83451	24603336	We performed Gene Set Enrichment Analysis (GSEA) to identify the specifically upregulated genes/pathways for each mutation as compared with nonsense mutations.	('mutation', 'Var', (114, 122))	('upregulated', 'PosReg', (78, 89))	('GSEA', 'Chemical', '-', (43, 47))
83452	24603336	When genes with top 1% enrichment scores were regarded as enriched genes (n=177, listed in Supplementary Table 2), R248W and R282W shared 52 commonly enriched genes.	('R282W', 'Var', (125, 130))	('R282W', 'Mutation', 'rs28934574', (125, 130))	('R248W', 'Mutation', 'rs121912651', (115, 120))	('R248W', 'Var', (115, 120))
83453	24603336	When mutations were classified according to their gene enrichment profiles, R248W and R282W fell into the same subgroup (Figure 4b).	('R282W', 'Var', (86, 91))	('R282W', 'Mutation', 'rs28934574', (86, 91))	('R248W', 'Var', (76, 81))	('R248W', 'Mutation', 'rs121912651', (76, 81))
83454	24603336	The R273H mutation shared serine-hydrolase pathway with R282W, but R175H did not show significant similarity with other mutations (Figure 4c).	('shared', 'Reg', (19, 25))	('R282W', 'Mutation', 'rs28934574', (56, 61))	('R175H', 'Mutation', 'rs28934578', (67, 72))	('R273H', 'Var', (4, 9))	('R273H', 'Mutation', 'rs28934576', (4, 9))	('R282W', 'Var', (56, 61))	('serine-hydrolase pathway', 'Pathway', (26, 50))
83457	24603336	We tested the effects of mutant p53 on CYP3A4 by ectopic expression of p53 mutants R175H, R273H and R282W in the H1299 cells (p53-null).	('R282W', 'Var', (100, 105))	('R175H', 'Mutation', 'rs28934578', (83, 88))	('CYP3A4', 'Gene', '1576', (39, 45))	('R273H', 'Var', (90, 95))	('R273H', 'Mutation', 'rs28934576', (90, 95))	('R175H', 'Var', (83, 88))	('R282W', 'Mutation', 'rs28934574', (100, 105))	('tested', 'Reg', (3, 9))	('p53', 'Gene', (71, 74))	('CYP3A4', 'Gene', (39, 45))	('H1299', 'CellLine', 'CVCL:0060', (113, 118))
83458	24603336	Immunofluorescence and Western blot studies suggested that p53 R248 and R282 mutations induced higher expression of CYP3A4 protein (Figures 5a-c, full gel image for Wb shown in Supplementary Figure 1 online).	('CYP3A4', 'Gene', '1576', (116, 122))	('R282 mutations', 'Var', (72, 86))	('expression', 'MPA', (102, 112))	('higher', 'PosReg', (95, 101))	('p53 R248', 'Var', (59, 67))	('CYP3A4', 'Gene', (116, 122))
83459	24603336	Consistently, real-time quantitative reverse transcription PCR (qRT-PCR) detected increased expression of CYP3A4 mRNA in H1299 cells expressing the mortality-associated mutants (Figure 5d).	('H1299', 'CellLine', 'CVCL:0060', (121, 126))	('CYP3A4', 'Gene', (106, 112))	('CYP3A4', 'Gene', '1576', (106, 112))	('mutants', 'Var', (169, 176))	('increased', 'PosReg', (82, 91))	('expression', 'MPA', (92, 102))
83460	24603336	When p53 mutants were expressed in another p53-null cell line SaOS2, increased CYP3A4 mRNA and protein levels were also observed for R248 and R282 mutations (Supplementary Figure S2).	('increased', 'PosReg', (69, 78))	('R248', 'Var', (133, 137))	('CYP3A4', 'Gene', (79, 85))	('p53', 'Gene', (5, 8))	('R282 mutations', 'Var', (142, 156))	('CYP3A4', 'Gene', '1576', (79, 85))
83461	24603336	Further, we tested the association between p53 mutation and CYP3A4 expression in the Cancer Cell Line Encyclopedia (CCLE) data set, which contains drug response data for 639 human cancer cell lines with known genotypes.	('CYP3A4', 'Gene', (60, 66))	('tested', 'Reg', (12, 18))	('human', 'Species', '9606', (174, 179))	('Cancer', 'Phenotype', 'HP:0002664', (85, 91))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('CYP3A4', 'Gene', '1576', (60, 66))	('mutation', 'Var', (47, 55))	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('Cancer Cell Line Encyclopedia', 'Disease', (85, 114))	('p53', 'Gene', (43, 46))	('expression', 'MPA', (67, 77))	('cancer', 'Disease', (180, 186))	('Cancer Cell Line Encyclopedia', 'Disease', 'MESH:C538614', (85, 114))	('CCLE', 'Chemical', '-', (116, 120))
83462	24603336	As expected, cancer cells bearing mortality-associated p53 mutations (R248, R282) displayed significantly higher level of CYP3A4 when compared with neutral GOF mutations (R175, R273) and nonsense LOF mutations (Figure 5e, data set in Supplementary Table 4).	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('p53', 'Gene', (55, 58))	('R282', 'Var', (76, 80))	('CYP3A4', 'Gene', '1576', (122, 128))	('cancer', 'Disease', (13, 19))	('higher', 'PosReg', (106, 112))	('cancer', 'Disease', 'MESH:D009369', (13, 19))	('R175', 'Var', (171, 175))	('CYP3A4', 'Gene', (122, 128))	('R248', 'Var', (70, 74))
83463	24603336	When the endogenous mutant p53 in SW837 (carrying p53 R248W) and HuP-T3 (p53 R282W) cells were suppressed by specific small interfering RNAs (siRNAs), the expression level of CYP3A4 also significantly decreased (Figures 5f and g).	('expression level', 'MPA', (155, 171))	('p53 R248W', 'Var', (50, 59))	('CYP3A4', 'Gene', (175, 181))	('HuP-T3', 'CellLine', 'CVCL:1299', (65, 71))	('CYP3A4', 'Gene', '1576', (175, 181))	('decreased', 'NegReg', (201, 210))	('R248W', 'Mutation', 'rs121912651', (54, 59))	('SW837', 'CellLine', 'CVCL:1729', (34, 39))	('p53 R282W', 'Var', (73, 82))	('R282W', 'Mutation', 'rs28934574', (77, 82))	('p53', 'Gene', (27, 30))
83464	24603336	These results collectively demonstrate that mutant p53 R248W and R282W could induce the expression of CYP3A4 enzyme.	('induce', 'PosReg', (77, 83))	('p53', 'Gene', (51, 54))	('CYP3A4', 'Gene', (102, 108))	('R248W', 'Mutation', 'rs121912651', (55, 60))	('R282W', 'Mutation', 'rs28934574', (65, 70))	('R248W', 'Var', (55, 60))	('CYP3A4', 'Gene', '1576', (102, 108))	('R282W', 'Var', (65, 70))	('expression', 'MPA', (88, 98))
83467	24603336	These results suggest that higher CYP3A4 level may contribute to the chemoresistance associated with p53 mortality mutations.	('chemoresistance', 'CPA', (69, 84))	('mutations', 'Var', (115, 124))	('CYP3A4', 'Gene', (34, 40))	('CYP3A4', 'Gene', '1576', (34, 40))	('p53', 'Gene', (101, 104))	('higher', 'PosReg', (27, 33))	('contribute', 'Reg', (51, 61))
83468	24603336	To test the effects of p53 GOF mutations on cell response to chemotherapy, 20muM etoposide was added to H1299 cells stably expressing p53 mutations (R175H, R273H, R248W or R282W) or the control vector.	('H1299', 'CellLine', 'CVCL:0060', (104, 109))	('R175H', 'Mutation', 'rs28934578', (149, 154))	('R282W', 'Mutation', 'rs28934574', (172, 177))	('R248W', 'Mutation', 'rs121912651', (163, 168))	('R273H', 'Var', (156, 161))	('R273H', 'Mutation', 'rs28934576', (156, 161))	('R175H', 'Var', (149, 154))	('etoposide', 'Chemical', 'MESH:D005047', (81, 90))	('R248W', 'Var', (163, 168))	('R282W', 'Var', (172, 177))	('p53', 'Gene', (134, 137))
83469	24603336	As a result, cells bearing R248W and R282W mutations showed higher viability than the control group after incubation with etoposide for 48 h (Figure 6c).	('R248W', 'Mutation', 'rs121912651', (27, 32))	('higher', 'PosReg', (60, 66))	('R282W', 'Var', (37, 42))	('R248W', 'Var', (27, 32))	('etoposide', 'Chemical', 'MESH:D005047', (122, 131))	('R282W', 'Mutation', 'rs28934574', (37, 42))	('viability', 'CPA', (67, 76))
83470	24603336	In support of these findings, cancer cells bearing mortality-associated mutations displayed increased inhibitory concentration (IC50) for etoposide, rapamycin, elesclomol, MK-2206 and NVP-BEZ235 (Figure 6d, Supplementary Table 5).	('mutations', 'Var', (72, 81))	('MK-2206', 'Chemical', 'MESH:C548887', (172, 179))	('rapamycin', 'Chemical', 'MESH:D020123', (149, 158))	('etoposide', 'Chemical', 'MESH:D005047', (138, 147))	('elesclomol', 'Chemical', 'MESH:C512195', (160, 170))	('BEZ235', 'Chemical', 'MESH:C531198', (188, 194))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('cancer', 'Disease', (30, 36))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('NVP-BEZ235', 'Var', (184, 194))	('inhibitory concentration', 'MPA', (102, 126))	('etoposide', 'MPA', (138, 147))	('increased', 'PosReg', (92, 101))	('MK-2206', 'Var', (172, 179))
83473	24603336	By characterizing the effects of hotspot p53 mutations on cancer patient survival, we present the first evidence that p53 missense mutations display different patterns and strengths of GOF activity in human cancers.	('cancer', 'Disease', 'MESH:D009369', (207, 213))	('missense mutations', 'Var', (122, 140))	('cancers', 'Disease', 'MESH:D009369', (207, 214))	('cancers', 'Phenotype', 'HP:0002664', (207, 214))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('cancers', 'Disease', (207, 214))	('p53', 'Gene', (118, 121))	('cancer', 'Disease', (207, 213))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('patient', 'Species', '9606', (65, 72))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('human', 'Species', '9606', (201, 206))	('cancer', 'Disease', (58, 64))
83474	24603336	Hotspot p53 mutations on two sites, namely R282 and R248 are associated with significantly shorter patient survival when compared with nonsense mutations.	('patient', 'Species', '9606', (99, 106))	('R248', 'Var', (52, 56))	('p53', 'Gene', (8, 11))	('R282', 'Var', (43, 47))	('patient survival', 'CPA', (99, 115))	('shorter', 'NegReg', (91, 98))
83475	24603336	Previous studies have demonstrated that mice carrying mutations equivalent to human R175H and R273H showed no difference in survival time as compared with null mutation, although a broader tumor spectrum was observed.	('tumor', 'Disease', (189, 194))	('R273H', 'Var', (94, 99))	('R273H', 'Mutation', 'rs28934576', (94, 99))	('R175H', 'Mutation', 'rs28934578', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('R175H', 'Var', (84, 89))	('survival time', 'CPA', (124, 137))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('mice', 'Species', '10090', (40, 44))	('human', 'Species', '9606', (78, 83))
83476	24603336	A recent study using humanized p53 mutant knock-in mice provided evidences that the R248Q mutation could significantly decrease survival time, but this effect was not found for G245S mutation.	('p53', 'Gene', (31, 34))	('decrease', 'NegReg', (119, 127))	('G245S', 'Mutation', 'rs28934575', (177, 182))	('mice', 'Species', '10090', (51, 55))	('human', 'Species', '9606', (21, 26))	('R248Q', 'Var', (84, 89))	('survival time', 'CPA', (128, 141))	('R248Q', 'Mutation', 'rs11540652', (84, 89))
83479	24603336	Importantly, we found that the p53 mutations on R248 and R282 could induce the expression of CYP3A4, which is one of the most important enzymes involved in the metabolism of chemotherapeutic drugs in the human body.	('p53', 'Gene', (31, 34))	('expression', 'MPA', (79, 89))	('induce', 'PosReg', (68, 74))	('CYP3A4', 'Gene', (93, 99))	('R282', 'Var', (57, 61))	('human', 'Species', '9606', (204, 209))	('CYP3A4', 'Gene', '1576', (93, 99))
83480	24603336	Consistently, cancer cells bearing p53 R248/R282 mutations displayed resistance to multiple CYP3A4-metabolized antineuplastic drugs.	('resistance', 'MPA', (69, 79))	('cancer', 'Disease', (14, 20))	('p53', 'Gene', (35, 38))	('CYP3A4', 'Gene', '1576', (92, 98))	('R248/R282', 'Var', (39, 48))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('cancer', 'Disease', 'MESH:D009369', (14, 20))	('CYP3A4', 'Gene', (92, 98))
83481	24603336	In summary, we provide the first evidence for the unequal GOF effects of p53-hotspot mutations in human cancers, and probed the potential mechanisms by which R248/R282 mutations may lead to chemoresistance and mortality.	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('chemoresistance', 'CPA', (190, 205))	('lead to', 'Reg', (182, 189))	('p53-hotspot', 'Gene', (73, 84))	('mutations', 'Var', (85, 94))	('cancers', 'Phenotype', 'HP:0002664', (104, 111))	('human', 'Species', '9606', (98, 103))	('R248/R282 mutations', 'Var', (158, 177))	('cancers', 'Disease', (104, 111))	('cancers', 'Disease', 'MESH:D009369', (104, 111))	('mortality', 'CPA', (210, 219))
83482	24603336	These findings add an important piece of evidence to GOF effects of the p53 mutant, and suggest that p53 mutations have unequal prognostic significance in human cancers.	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('mutant', 'Var', (76, 82))	('p53', 'Gene', (72, 75))	('human', 'Species', '9606', (155, 160))	('p53', 'Gene', (101, 104))	('mutations', 'Var', (105, 114))	('cancers', 'Disease', 'MESH:D009369', (161, 168))	('cancers', 'Phenotype', 'HP:0002664', (161, 168))	('cancers', 'Disease', (161, 168))
83483	24603336	All p53 mutations (R175H, R273H and R282W) were generated by site-directed mutagenesis PCR reaction using platinum PWO SuperYield DNA polymerase (Roche, Basel, Switzerland) according to the product manual.	('R282W', 'Var', (36, 41))	('R175H', 'Mutation', 'rs28934578', (19, 24))	('R273H', 'Mutation', 'rs28934576', (26, 31))	('R175H', 'Var', (19, 24))	('R273H', 'Var', (26, 31))	('p53', 'Gene', (4, 7))	('R282W', 'Mutation', 'rs28934574', (36, 41))
83487	24603336	Stable clones expressing different p53 mutations were selected with 600 mug/ml G418 for 12 weeks, and the expression of p53 was confirmed by immunofluorescence.	('G418', 'Chemical', 'MESH:C010680', (79, 83))	('p53', 'Gene', (35, 38))	('mutations', 'Var', (39, 48))
83490	24603336	The H1299 cells were plated into four-well chamber slides and transfected with different p53 mutations or the control vector.	('p53', 'Gene', (89, 92))	('mutations', 'Var', (93, 102))	('H1299', 'CellLine', 'CVCL:0060', (4, 9))
83493	24603336	Secondary antibodies (Alexa488-anti-rabbit and Alexa546-anti-mouse) were used to label CYP3A4, and p53, respectively.	('p53', 'Var', (99, 102))	('rabbit', 'Species', '9986', (36, 42))	('CYP3A4', 'Gene', (87, 93))	('mouse', 'Species', '10090', (61, 66))	('CYP3A4', 'Gene', '1576', (87, 93))	('Alexa488', 'Chemical', '-', (22, 30))	('Alexa546', 'Chemical', '-', (47, 55))
83506	24603336	The GSEA package was used to determine if the members of a given gene set were generally associated with certain p53-hotspot mutations, and was therefore performed on all genes on the HG-U133 Plus 2 chip ranked by enrichment score from most negative to most positive.	('p53-hotspot', 'Disease', (113, 124))	('associated', 'Reg', (89, 99))	('mutations', 'Var', (125, 134))	('GSEA', 'Chemical', '-', (4, 8))
83507	24603336	If a gene set had a positive enrichment score, the majority of its members had higher expression in the tumor-bearing-specified p53 missense mutation than those with nonsense mutations, and the set was termed 'enriched' in the specified hotspot mutation.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('p53', 'Gene', (128, 131))	('tumor', 'Disease', (104, 109))	('missense mutation', 'Var', (132, 149))	('expression', 'MPA', (86, 96))	('higher', 'PosReg', (79, 85))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
83508	24603336	Different p53 hot spot mutations (R175H, Y220C, G245S, R248W, R248Q, R273H and R282W) were clustered according to their enrichment scores for each gene (based on GSEA analysis).	('G245S', 'Var', (48, 53))	('R273H', 'Var', (69, 74))	('R175H', 'Var', (34, 39))	('R273H', 'Mutation', 'rs28934576', (69, 74))	('GSEA', 'Chemical', '-', (162, 166))	('R282W', 'Mutation', 'rs28934574', (79, 84))	('R248W', 'Mutation', 'rs121912651', (55, 60))	('R248Q', 'Var', (62, 67))	('Y220C', 'Mutation', 'rs121912666', (41, 46))	('R248W', 'Var', (55, 60))	('R282W', 'Var', (79, 84))	('G245S', 'Mutation', 'rs28934575', (48, 53))	('R248Q', 'Mutation', 'rs11540652', (62, 67))	('Y220C', 'Var', (41, 46))	('R175H', 'Mutation', 'rs28934578', (34, 39))	('p53', 'Gene', (10, 13))
83534	32601356	Proteins are the principal effector molecules in a cell, and their function can be influenced by posttranslational modifications such as phosphorylation, acetylation, glycosylation, or sulphation.	('p', 'Chemical', 'MESH:D010758', (137, 138))	('influenced', 'Reg', (83, 93))	('p', 'Chemical', 'MESH:D010758', (188, 189))	('p', 'Chemical', 'MESH:D010758', (17, 18))	('glycosylation', 'MPA', (167, 180))	('sulphation', 'MPA', (185, 195))	('acetylation', 'MPA', (154, 165))	('p', 'Chemical', 'MESH:D010758', (97, 98))	('p', 'Chemical', 'MESH:D010758', (141, 142))	('phosphorylation', 'Var', (137, 152))	('p', 'Chemical', 'MESH:D010758', (23, 24))	('Proteins', 'Protein', (0, 8))	('function', 'MPA', (67, 75))
83548	32601356	This ensures good quality for histological examination, but cross-links may impair the immunoreactivity of proteins by modifying their conformation and altering or masking the epitope.	('epitope', 'MPA', (176, 183))	('immunoreactivity of', 'MPA', (87, 106))	('proteins', 'Protein', (107, 115))	('p', 'Chemical', 'MESH:D010758', (107, 108))	('cross-links', 'Var', (60, 71))	('impair', 'NegReg', (76, 82))	('conformation', 'MPA', (135, 147))	('altering', 'Reg', (152, 160))	('p', 'Chemical', 'MESH:D010758', (177, 178))	('p', 'Chemical', 'MESH:D010758', (181, 182))	('modifying', 'Reg', (119, 128))	('p', 'Chemical', 'MESH:D010758', (78, 79))	('masking', 'NegReg', (164, 171))
83609	32601356	The tuning parameters were chosen between C = 10{0,1,2,3} and sigma = 0.01 x 10{-3,-2,...,3}.	('C = 10', 'Var', (42, 48))	('p', 'Chemical', 'MESH:D010758', (11, 12))	('sigma', 'Var', (62, 67))
83611	32601356	The optimal parameters were sigma = 0.0001 and C = 100.	('sigma = 0.0001', 'Var', (28, 42))	('C = 100', 'Var', (47, 54))	('p', 'Chemical', 'MESH:D010758', (5, 6))	('p', 'Chemical', 'MESH:D010758', (12, 13))
83761	32345328	TMPRSS2 deficiency affected the primary sites of infection and virus spread within the airways, which was accompanied by relatively less severe immunopathology.	('affected', 'Reg', (19, 27))	('TMPRSS2', 'Gene', (0, 7))	('infection', 'Disease', (49, 58))	('deficiency', 'Var', (8, 18))	('infection', 'Disease', 'MESH:D007239', (49, 58))	('virus spread', 'CPA', (63, 75))
83763	32345328	However, in the lung cancer samples in GSE19804, the difference in TMPRSS2 gene expression was not obvious (p-val = 2.37e- 01).	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('lung cancer', 'Disease', 'MESH:D008175', (16, 27))	('TMPRSS2', 'Gene', (67, 74))	('GSE19804', 'Var', (39, 47))	('lung cancer', 'Phenotype', 'HP:0100526', (16, 27))	('lung cancer', 'Disease', (16, 27))
83811	26020390	An elevated uptake of 18F-FDG is positively correlated with many biological processes, including glucose metabolism, hypoxia, cellular proliferation, and blood flow.	('uptake', 'MPA', (12, 18))	('18F-FDG', 'Chemical', '-', (22, 29))	('blood flow', 'CPA', (154, 164))	('18F-FDG', 'Var', (22, 29))	('correlated', 'Reg', (44, 54))	('cellular proliferation', 'CPA', (126, 148))	('glucose metabolism', 'Disease', 'MESH:D044882', (97, 115))	('elevated', 'PosReg', (3, 11))	('hypoxia', 'Disease', 'MESH:D000860', (117, 124))	('hypoxia', 'Disease', (117, 124))	('glucose metabolism', 'Disease', (97, 115))
83968	32640984	Our experiment took into account a total of six PDB structures (2MM3, 1O1U, 1O1V, 5L8I, 5L8N, 5L8O).	('1O1U', 'Var', (70, 74))	('5L8N', 'Var', (88, 92))	('5L8N', 'Chemical', '-', (88, 92))	('5L8I', 'Var', (82, 86))	('1O1V', 'Var', (76, 80))	('2MM3', 'Var', (64, 68))
83981	32640984	This protein has a single ligand active site defined by 10 amino acids: TYR14, MET18, ILE23, VAL27, TRP49, TYR53, ASN61, MET74, LEU90, ARG121.	('LEU90', 'Var', (128, 133))	('TRP49', 'Chemical', '-', (100, 105))	('ASN61', 'Chemical', '-', (114, 119))	('ARG121', 'Var', (135, 141))	('TYR14', 'Chemical', '-', (72, 77))	('ILE23', 'Chemical', '-', (86, 91))	('ARG121', 'Chemical', '-', (135, 141))	('ILE23', 'Var', (86, 91))	('ASN61', 'Var', (114, 119))	('VAL27', 'Var', (93, 98))	('TYR53', 'Var', (107, 112))	('TYR53', 'Chemical', '-', (107, 112))	('LEU90', 'Chemical', '-', (128, 133))	('TRP49', 'Var', (100, 105))	('MET18', 'Gene', '64210', (79, 84))	('VAL27', 'Chemical', '-', (93, 98))	('TYR14', 'Var', (72, 77))	('MET74', 'Var', (121, 126))	('MET18', 'Gene', (79, 84))	('MET74', 'Chemical', '-', (121, 126))
83982	32640984	1O1V amino acid - Abemaciclib atom interactions are SER54:HG, MET59:CE, ILE23:CD1, TYR53:CE2, VAL27:CG1, ILE23:CG2, LYS77:CD, GLN51:HE21, VAL27:CG2, MET74:CG, SER24:H, TYR53:CD2, TYR14:OH, VAL27:CB.	('MET', 'Chemical', 'MESH:D008715', (62, 65))	('SER54', 'Chemical', '-', (52, 57))	('CG2', 'Gene', (144, 147))	('CD', 'Chemical', 'MESH:D002104', (122, 124))	('MET', 'Chemical', 'MESH:D008715', (149, 152))	('CE2', 'Gene', '8824', (89, 92))	('CG2', 'Gene', (111, 114))	('GLN51', 'Chemical', '-', (126, 131))	('CD1', 'Gene', '911', (78, 81))	('CG2', 'Gene', '23731', (144, 147))	('MET74', 'Var', (149, 154))	('CD1', 'Gene', (78, 81))	('MET74', 'Chemical', '-', (149, 154))	('CG1', 'Gene', '54566', (100, 103))	('CG2', 'Gene', '23731', (111, 114))	('GLN51', 'Var', (126, 131))	('CG1', 'Gene', (100, 103))	('TYR53', 'Chemical', '-', (83, 88))	('TYR14', 'Chemical', '-', (179, 184))	('LYS77', 'Var', (116, 121))	('VAL27', 'Chemical', '-', (189, 194))	('SER24', 'Chemical', '-', (159, 164))	('CD', 'Chemical', 'MESH:D002104', (174, 176))	('VAL27', 'Chemical', '-', (94, 99))	('CD2', 'Gene', '914', (174, 177))	('CD2', 'Gene', (174, 177))	('HE21', 'Chemical', '-', (132, 136))	('ILE23', 'Chemical', '-', (105, 110))	('LYS77', 'Chemical', '-', (116, 121))	('CD', 'Chemical', 'MESH:D002104', (78, 80))	('VAL27', 'Chemical', '-', (138, 143))	('ILE23', 'Chemical', '-', (72, 77))	('CE2', 'Gene', (89, 92))	('TYR53', 'Chemical', '-', (168, 173))
83983	32640984	Thus, Abemaciclib interacts with TYR14, ILE23, SER24, VAL27, GLN51, TYR53, SER54, MET59, MET74, LYS77.	('MET74', 'Chemical', '-', (89, 94))	('ILE23', 'Chemical', '-', (40, 45))	('LYS77', 'Var', (96, 101))	('SER54', 'Var', (75, 80))	('SER54', 'Chemical', '-', (75, 80))	('MET59', 'Var', (82, 87))	('LYS77', 'Chemical', '-', (96, 101))	('GLN51', 'Chemical', '-', (61, 66))	('TYR14', 'Var', (33, 38))	('interacts', 'Reg', (18, 27))	('VAL27', 'Var', (54, 59))	('GLN51', 'Var', (61, 66))	('TYR53', 'Var', (68, 73))	('SER24', 'Chemical', '-', (47, 52))	('TYR53', 'Chemical', '-', (68, 73))	('MET', 'Chemical', 'MESH:D008715', (82, 85))	('MET', 'Chemical', 'MESH:D008715', (89, 92))	('VAL27', 'Chemical', '-', (54, 59))	('MET74', 'Var', (89, 94))	('SER24', 'Var', (47, 52))	('TYR14', 'Chemical', '-', (33, 38))
83984	32640984	From these amino acids, five of them are defining the active site of 1O1V: TYR14, ILE23, VAL27, TYR53, and MET74.	('TYR14', 'Var', (75, 80))	('ILE23', 'Chemical', '-', (82, 87))	('TYR53', 'Chemical', '-', (96, 101))	('ILE23', 'Var', (82, 87))	('VAL27', 'Chemical', '-', (89, 94))	('MET74', 'Chemical', '-', (107, 112))	('VAL27', 'Var', (89, 94))	('TYR14', 'Chemical', '-', (75, 80))	('MET74', 'Var', (107, 112))	('TYR53', 'Var', (96, 101))
83988	32640984	AC1 site for glycocholate ligand (CHO202) is defined by 22 amino acids: PHE2, PHE6, MET8, MET18, ALA31, ILE36, THR38, VAL40, PHE47, TRP49, GLN51, MET74, LEU90, SER101, GLU102, LEU108, VAL109, GLU110, TYR119, ARG121, and SER123.	('PHE47', 'Var', (125, 130))	('VAL40', 'Chemical', '-', (118, 123))	('SER123', 'Var', (220, 226))	('TRP49', 'Chemical', '-', (132, 137))	('SER123', 'Chemical', '-', (220, 226))	('LEU108', 'Chemical', '-', (176, 182))	('VAL109', 'Var', (184, 190))	('ILE36', 'Chemical', '-', (104, 109))	('LEU90', 'Chemical', '-', (153, 158))	('ALA31', 'Chemical', '-', (97, 102))	('LEU108', 'Var', (176, 182))	('SER101', 'Var', (160, 166))	('GLU110', 'Var', (192, 198))	('TYR119', 'Var', (200, 206))	('PHE2', 'Chemical', '-', (72, 76))	('SER101', 'Chemical', '-', (160, 166))	('MET74', 'Var', (146, 151))	('TYR119', 'Chemical', '-', (200, 206))	('GLU102', 'Chemical', '-', (168, 174))	('MET18', 'Gene', '64210', (90, 95))	('glycocholate', 'Chemical', 'MESH:D006000', (13, 25))	('THR38', 'Chemical', '-', (111, 116))	('MET74', 'Chemical', '-', (146, 151))	('GLN51', 'Chemical', '-', (139, 144))	('GLU110', 'Chemical', '-', (192, 198))	('MET18', 'Gene', (90, 95))	('TRP49', 'Var', (132, 137))	('PHE6', 'Chemical', '-', (78, 82))	('LEU90', 'Var', (153, 158))	('MET8', 'Chemical', '-', (84, 88))	('GLU102', 'Var', (168, 174))	('PHE47', 'Chemical', '-', (125, 130))	('ARG121', 'Var', (208, 214))	('GLN51', 'Var', (139, 144))	('ARG121', 'Chemical', '-', (208, 214))	('VAL109', 'Chemical', '-', (184, 190))
83989	32640984	AC2 site for glycochenodeoxycholate ligand (GCH201) is defined by 17 amino acids: LEU21, ILE23, TRP49, ASN61, PHE63, GLN72, THR73, MET74, GLY75, LYS77, PHE79, VAL83, LEU90, VAL92, TYR97, and GLN99.	('GLN99', 'Chemical', '-', (191, 196))	('VAL92', 'Chemical', '-', (173, 178))	('GLY75', 'Var', (138, 143))	('GLN72', 'Chemical', '-', (117, 122))	('LYS77', 'Chemical', '-', (145, 150))	('ASN61', 'Chemical', '-', (103, 108))	('GLY75', 'Chemical', '-', (138, 143))	('PHE63', 'Var', (110, 115))	('THR73', 'Chemical', '-', (124, 129))	('PHE79', 'Var', (152, 157))	('THR73', 'Var', (124, 129))	('LEU21', 'Var', (82, 87))	('MET74', 'Var', (131, 136))	('LEU90', 'Chemical', '-', (166, 171))	('ASN61', 'Var', (103, 108))	('TRP49', 'Chemical', '-', (96, 101))	('MET74', 'Chemical', '-', (131, 136))	('PHE63', 'Chemical', '-', (110, 115))	('GCH201', 'Chemical', '-', (44, 50))	('VAL83', 'Var', (159, 164))	('GLN99', 'Var', (191, 196))	('VAL92', 'Var', (173, 178))	('TYR97', 'Var', (180, 185))	('ILE23', 'Chemical', '-', (89, 94))	('VAL83', 'Chemical', '-', (159, 164))	('LEU21', 'Chemical', '-', (82, 87))	('GLN72', 'Var', (117, 122))	('TYR97', 'Chemical', '-', (180, 185))	('LYS77', 'Var', (145, 150))	('PHE79', 'Chemical', '-', (152, 157))	('LEU90', 'Var', (166, 171))	('glycochenodeoxycholate', 'Chemical', 'MESH:D005999', (13, 35))
83990	32640984	2MM3 amino acid - Abemaciclib atom interactions are PHE47:CZ, GLN99:HE21, MET8:CB, PHE47:CE1, GLN99:NE2, PHE2:CB, PHE47:CE2, THR38:CB, GLN51:HE21, PHE2:CD2, PHE79:CZ, LEU90:CB, GLN51:NE2, GLN99:CD, TYR97:CE2, ARG121:CD, VAL109:N, SER101:CB, TRP49:CZ3, VAL109:C, MET8:CG, SER101:HG, THR38:CG2, PHE2:C. Thus, Abemaciclib interacts with PHE2, MET8, THR38, PHE47, TRP49, GLN51, PHE79, LEU90, TYR97, GLN99, SER101, VAL109, and ARG121.	('NE2', 'Chemical', '-', (183, 186))	('PHE2', 'Chemical', '-', (105, 109))	('GLN51', 'Chemical', '-', (367, 372))	('PHE47', 'Chemical', '-', (83, 88))	('MET8', 'Chemical', '-', (74, 78))	('THR38', 'Chemical', '-', (282, 287))	('PHE47', 'Chemical', '-', (52, 57))	('ARG121', 'Chemical', '-', (422, 428))	('PHE79', 'Chemical', '-', (374, 379))	('GLN51', 'Chemical', '-', (135, 140))	('GLN99', 'Chemical', '-', (395, 400))	('PHE2', 'Chemical', '-', (334, 338))	('LEU90', 'Var', (381, 386))	('GLN99', 'Chemical', '-', (62, 67))	('GLN99', 'Chemical', '-', (94, 99))	('TRP49', 'Chemical', '-', (360, 365))	('TRP49', 'Chemical', '-', (241, 246))	('CE2', 'Gene', (120, 123))	('PHE79', 'Chemical', '-', (157, 162))	('PHE47', 'Chemical', '-', (353, 358))	('PHE47', 'Chemical', '-', (114, 119))	('CD', 'Chemical', 'MESH:D002104', (194, 196))	('GLN99', 'Chemical', '-', (188, 193))	('SER101', 'Chemical', '-', (271, 277))	('LEU90', 'Chemical', '-', (167, 172))	('NE2', 'Chemical', '-', (100, 103))	('CE1', 'Gene', (89, 92))	('MET8', 'Chemical', '-', (262, 266))	('CD', 'Chemical', 'MESH:D002104', (216, 218))	('PHE2', 'Chemical', '-', (293, 297))	('CE2', 'Gene', '8824', (120, 123))	('CZ', 'Chemical', 'MESH:C004578', (163, 165))	('CD', 'Chemical', 'MESH:D002104', (152, 154))	('VAL109', 'Chemical', '-', (252, 258))	('CE1', 'Gene', '1066', (89, 92))	('CE2', 'Gene', (204, 207))	('MET8', 'Chemical', '-', (340, 344))	('CD2', 'Gene', '914', (152, 155))	('CD2', 'Gene', (152, 155))	('CZ', 'Chemical', 'MESH:C004578', (58, 60))	('SER101', 'Chemical', '-', (230, 236))	('interacts', 'Reg', (319, 328))	('VAL109', 'Chemical', '-', (220, 226))	('CG2', 'Gene', (288, 291))	('SER101', 'Var', (402, 408))	('TYR97', 'Var', (388, 393))	('LEU90', 'Chemical', '-', (381, 386))	('TYR97', 'Chemical', '-', (198, 203))	('HE21', 'Chemical', '-', (141, 145))	('VAL109', 'Chemical', '-', (410, 416))	('ARG121', 'Chemical', '-', (209, 215))	('GLN99', 'Var', (395, 400))	('THR38', 'Chemical', '-', (125, 130))	('PHE2', 'Chemical', '-', (147, 151))	('CE2', 'Gene', '8824', (204, 207))	('HE21', 'Chemical', '-', (68, 72))	('TYR97', 'Chemical', '-', (388, 393))	('SER101', 'Chemical', '-', (402, 408))	('CZ', 'Chemical', 'MESH:C004578', (247, 249))	('GLN51', 'Chemical', '-', (177, 182))	('CG2', 'Gene', '23731', (288, 291))	('THR38', 'Chemical', '-', (346, 351))	('ARG121', 'Var', (422, 428))
83991	32640984	All these amino acids are defining both active sites for both natural ligands in 2MM3: PHE2, MET8, THR38, PHE47, GLN51, SER101, VAL109, ARG121 from AC1 active site and TRP49, PHE79, LEU90, TYR97, GLN99 from AC2 active site.	('GLN51', 'Chemical', '-', (113, 118))	('ARG121', 'Chemical', '-', (136, 142))	('TRP49', 'Var', (168, 173))	('PHE79', 'Chemical', '-', (175, 180))	('GLN99', 'Var', (196, 201))	('PHE47', 'Chemical', '-', (106, 111))	('LEU90', 'Var', (182, 187))	('GLN51', 'Var', (113, 118))	('SER101', 'Var', (120, 126))	('THR38', 'Chemical', '-', (99, 104))	('VAL109', 'Chemical', '-', (128, 134))	('SER101', 'Chemical', '-', (120, 126))	('GLN99', 'Chemical', '-', (196, 201))	('PHE47', 'Var', (106, 111))	('PHE2', 'Chemical', '-', (87, 91))	('TRP49', 'Chemical', '-', (168, 173))	('VAL109', 'Var', (128, 134))	('PHE79', 'Var', (175, 180))	('THR38', 'Var', (99, 104))	('MET8', 'Chemical', '-', (93, 97))	('TYR97', 'Var', (189, 194))	('LEU90', 'Chemical', '-', (182, 187))	('PHE2', 'Var', (87, 91))	('MET8', 'Var', (93, 97))	('TYR97', 'Chemical', '-', (189, 194))	('ARG121', 'Var', (136, 142))
83995	32640984	This protein has several active sites and only the one for P33 and PEG will be compared with the Abemaciclib interaction preference: AC5 site is defined by 11 amino acids - PHE18, TRP50, ILE72, THR74, GLY76, LEU91, TYR98, GLN100, THR101, SER102, ARG122.	('GLN100', 'Var', (222, 228))	('PEG', 'Chemical', '-', (67, 70))	('PHE18', 'Chemical', '-', (173, 178))	('SER102', 'Var', (238, 244))	('GLY76', 'Chemical', '-', (201, 206))	('TYR98', 'Chemical', '-', (215, 220))	('ILE72', 'Var', (187, 192))	('SER102', 'Chemical', '-', (238, 244))	('PHE18', 'Var', (173, 178))	('THR74', 'Chemical', '-', (194, 199))	('GLN100', 'Chemical', '-', (222, 228))	('LEU91', 'Chemical', '-', (208, 213))	('P33', 'Chemical', '-', (59, 62))	('TRP50', 'Var', (180, 185))	('GLY76', 'Var', (201, 206))	('TRP50', 'Chemical', '-', (180, 185))	('TYR98', 'Var', (215, 220))	('THR74', 'Var', (194, 199))	('THR101', 'Var', (230, 236))	('ILE72', 'Chemical', '-', (187, 192))	('LEU91', 'Var', (208, 213))	('ARG122', 'Chemical', '-', (246, 252))	('THR101', 'Chemical', '-', (230, 236))
83996	32640984	5L8N amino acid - Abemaciclib atom interactions are ALA32:CB, PHE64:CZ, MET19:CE, LEU91:CB, VAL28:CG1, PHE64:CE2, GLN100:NE2, TRP50:CE2, TRP50:CG, GLY76:CA, ILE72:CD1, TRP50:CD2, and MET75:CB.	('TRP50', 'Chemical', '-', (137, 142))	('TRP50', 'Chemical', '-', (168, 173))	('5L8N', 'Chemical', '-', (0, 4))	('VAL28', 'Chemical', '-', (92, 97))	('GLY76', 'Var', (147, 152))	('ILE72', 'Chemical', '-', (157, 162))	('MET19', 'Chemical', '-', (72, 77))	('TRP50', 'Chemical', '-', (126, 131))	('NE2', 'Chemical', '-', (121, 124))	('PHE64', 'Chemical', '-', (103, 108))	('CD1', 'Gene', '911', (163, 166))	('CE2', 'Gene', (109, 112))	('CD1', 'Gene', (163, 166))	('CE2', 'Gene', (132, 135))	('CZ', 'Chemical', 'MESH:C004578', (68, 70))	('PHE64', 'Chemical', '-', (62, 67))	('CE2', 'Gene', '8824', (109, 112))	('GLN100', 'Var', (114, 120))	('CD2', 'Gene', '914', (174, 177))	('CD2', 'Gene', (174, 177))	('CG1', 'Gene', '54566', (98, 101))	('CE2', 'Gene', '8824', (132, 135))	('ALA32', 'Chemical', '-', (52, 57))	('MET75', 'Var', (183, 188))	('GLN100', 'Chemical', '-', (114, 120))	('CG1', 'Gene', (98, 101))	('GLY76', 'Chemical', '-', (147, 152))	('MET75', 'Chemical', '-', (183, 188))	('LEU91', 'Chemical', '-', (82, 87))
83997	32640984	Thus, Abemaciclib interacts with MET19, VAL28, ALA32, TRP50, PHE64, ILE72, MET75, GLY76, LEU91, and GLN100.	('GLY76', 'Var', (82, 87))	('MET19', 'Chemical', '-', (33, 38))	('ILE72', 'Var', (68, 73))	('LEU91', 'Chemical', '-', (89, 94))	('MET19', 'Var', (33, 38))	('GLN100', 'Var', (100, 106))	('MET75', 'Var', (75, 80))	('TRP50', 'Var', (54, 59))	('ALA32', 'Chemical', '-', (47, 52))	('interacts', 'Reg', (18, 27))	('MET75', 'Chemical', '-', (75, 80))	('VAL28', 'Var', (40, 45))	('TRP50', 'Chemical', '-', (54, 59))	('GLN100', 'Chemical', '-', (100, 106))	('PHE64', 'Var', (61, 66))	('PHE64', 'Chemical', '-', (61, 66))	('LEU91', 'Var', (89, 94))	('ILE72', 'Chemical', '-', (68, 73))	('GLY76', 'Chemical', '-', (82, 87))	('VAL28', 'Chemical', '-', (40, 45))
83998	32640984	Five of these amino acids are defining AC5 active sites in 5L8N: TRP50, ILE72, GLY76, LEU91, and GLN100.	('ILE72', 'Var', (72, 77))	('TRP50', 'Chemical', '-', (65, 70))	('LEU91', 'Chemical', '-', (86, 91))	('ILE72', 'Chemical', '-', (72, 77))	('LEU91', 'Var', (86, 91))	('GLY76', 'Chemical', '-', (79, 84))	('GLN100', 'Chemical', '-', (97, 103))	('5L8N', 'Chemical', '-', (59, 63))	('GLY76', 'Var', (79, 84))	('GLN100', 'Var', (97, 103))	('TRP50', 'Var', (65, 70))
84022	32640984	Comparisons with other studies and databases, show a significant decrease in the survival of patients with a high copy number of the FABP6 gene, as seen in Fig.	('high copy number', 'Var', (109, 125))	('di', 'Disease', 'MESH:D003643', (26, 28))	('FABP6', 'Gene', (133, 138))	('survival', 'MPA', (81, 89))	('decrease', 'NegReg', (65, 73))	('patients', 'Species', '9606', (93, 101))	('FABP6', 'Gene', '2172', (133, 138))
84025	32640984	At this point, it is interesting to point out that the aberration or inhibition of this gene in tumour cells alone could theoretically provide an advantage when considering this gene as a possible therapeutic target.	('tumour', 'Phenotype', 'HP:0002664', (96, 102))	('tumour', 'Disease', 'MESH:D009369', (96, 102))	('advantage', 'PosReg', (146, 155))	('aberration', 'Var', (55, 65))	('inhibition', 'NegReg', (69, 79))	('tumour', 'Disease', (96, 102))
84027	32640984	Deregulation of these cellular pathways could provide detection of the growth and development of the tumour.	('Deregulation', 'Var', (0, 12))	('tumour', 'Disease', (101, 107))	('development', 'CPA', (82, 93))	('tumour', 'Phenotype', 'HP:0002664', (101, 107))	('tumour', 'Disease', 'MESH:D009369', (101, 107))
84038	32640984	All of the evidence indicates that inhibition of the expression of the FABP6 gene, specifically in tumour cells, would reduce the development and growth of the tumour.	('FABP6', 'Gene', '2172', (71, 76))	('tumour', 'Disease', (160, 166))	('di', 'Disease', 'MESH:D003643', (22, 24))	('tumour', 'Disease', 'MESH:D009369', (99, 105))	('tumour', 'Disease', (99, 105))	('reduce', 'NegReg', (119, 125))	('FABP6', 'Gene', (71, 76))	('inhibition', 'Var', (35, 45))	('tumour', 'Phenotype', 'HP:0002664', (160, 166))	('tumour', 'Phenotype', 'HP:0002664', (99, 105))	('tumour', 'Disease', 'MESH:D009369', (160, 166))
84152	32615948	MiR-30d-5p also participated in hypoxic-ischemic injury by mediating cell autophagy and apoptosis.	('apoptosis', 'CPA', (88, 97))	('hypoxic-ischemic injury', 'Disease', (32, 55))	('MiR-30d-5p', 'Var', (0, 10))	('mediating', 'Reg', (59, 68))	('cell autophagy', 'CPA', (69, 83))	('MiR-30d-5p', 'Chemical', '-', (0, 10))	('participated', 'Reg', (16, 28))	('hypoxic-ischemic injury', 'Disease', 'MESH:D020925', (32, 55))
84156	32615948	MiR-30d-5p targets CCNE2, while its upstream regulators are still unknown.	('CCNE2', 'Gene', (19, 24))	('MiR-30d-5p', 'Var', (0, 10))	('CCNE2', 'Gene', '9134', (19, 24))	('MiR-30d-5p', 'Chemical', '-', (0, 10))	('targets', 'Reg', (11, 18))
84166	29802697	Candidate Biomarkers for Oral Squamous Cell Carcinoma: Differential Expression of Oxidative Stress-Related Genes Alteration in the biotransformation of exogenous compounds can result in production of reactive oxygen species (ROS), which can predispose cells to malignant transformation in the head and neck.	('Alteration', 'Var', (113, 123))	('predispose', 'Reg', (241, 251))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (200, 223))	('Oxidative Stress-Related Genes', 'Gene', (82, 112))	('biotransformation of exogenous compounds', 'MPA', (131, 171))	('Oral Squamous Cell Carcinoma', 'Disease', (25, 53))	('Carcinoma', 'Phenotype', 'HP:0030731', (44, 53))	('Oral Squamous Cell Carcinoma', 'Disease', 'MESH:D002294', (25, 53))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (30, 53))	('reactive oxygen species', 'MPA', (200, 223))	('malignant transformation in the head and neck', 'Phenotype', 'HP:0012288', (261, 306))	('Oxidative Stress', 'Phenotype', 'HP:0025464', (82, 98))	('production', 'MPA', (186, 196))	('ROS', 'Chemical', 'MESH:D017382', (225, 228))	('result in', 'Reg', (176, 185))	('malignant transformation', 'CPA', (261, 285))
84189	29802697	T1N0 tumors were classified as stage I; T1N1 and T2N0-1 tumors were classified as stage II; T3N0-1 and T1-3N2 tumors were classified as stage III; and T4N0-3, T1-3N3 and T1-4N0-3M1 tumors were classified as stage IV.	('tumors', 'Disease', 'MESH:D009369', (5, 11))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('T1-3N2 tumors', 'Disease', 'MESH:D009369', (103, 116))	('tumors', 'Disease', (56, 62))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('tumors', 'Phenotype', 'HP:0002664', (181, 187))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('tumors', 'Disease', (110, 116))	('tumors', 'Phenotype', 'HP:0002664', (5, 11))	('tumors', 'Disease', (181, 187))	('tumors', 'Disease', 'MESH:D009369', (110, 116))	('T1-3N2 tumors', 'Disease', (103, 116))	('T3N0-1', 'Var', (92, 98))	('tumors', 'Disease', (5, 11))	('tumors', 'Disease', 'MESH:D009369', (181, 187))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))
84225	29802697	DUOX1 is frequently silenced by promoter hyper-methylation in lung cancer (Luxen et al., 2008).	('lung cancer', 'Phenotype', 'HP:0100526', (62, 73))	('promoter hyper-methylation', 'Var', (32, 58))	('DUOX1', 'Gene', '53905', (0, 5))	('lung cancer', 'Disease', (62, 73))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('DUOX1', 'Gene', (0, 5))	('silenced', 'NegReg', (20, 28))	('lung cancer', 'Disease', 'MESH:D008175', (62, 73))
84227	29802697	Furthermore, the high expression of DUOX1 was associated with a reduced risk of death in thyroid carcinoma (Pulcrano et al., 2007).	('death in thyroid carcinoma', 'Disease', (80, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('DUOX1', 'Gene', '53905', (36, 41))	('high expression', 'Var', (17, 32))	('death in thyroid carcinoma', 'Disease', 'MESH:D013959', (80, 106))	('reduced', 'NegReg', (64, 71))	('DUOX1', 'Gene', (36, 41))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (89, 106))
84249	29802697	Furthermore, high levels of DHCR24 were associated with tumor progression in melanomas and prostate and breast cancer, possibly due to the increase of cholesterol synthesis.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('high', 'Var', (13, 17))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('DHCR24', 'Gene', (28, 34))	('tumor', 'Disease', (56, 61))	('melanomas and prostate', 'Disease', 'MESH:D008545', (77, 99))	('breast cancer', 'Disease', 'MESH:D001943', (104, 117))	('DHCR24', 'Gene', '1718', (28, 34))	('melanomas', 'Phenotype', 'HP:0002861', (77, 86))	('cholesterol', 'Chemical', 'MESH:D002784', (151, 162))	('increase', 'PosReg', (139, 147))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('breast cancer', 'Disease', (104, 117))	('increase of cholesterol', 'Phenotype', 'HP:0003124', (139, 162))	('breast cancer', 'Phenotype', 'HP:0003002', (104, 117))	('cholesterol synthesis', 'MPA', (151, 172))	('associated', 'Reg', (40, 50))
84255	29802697	Deglutathionylation of Ras can result in activation of the MEKK (Mitogen-activated protein kinase/Extracellular signal regulated kinase kinase kinase) pathway, inhibition of Akt, and activation of apoptotic effector proteins (Allen and Mieyal, 2012).	('apoptotic effector proteins', 'Pathway', (197, 224))	('activation', 'PosReg', (183, 193))	('Akt', 'Gene', '207', (174, 177))	('inhibition', 'NegReg', (160, 170))	('MEKK', 'Gene', '4214', (59, 63))	('activation', 'PosReg', (41, 51))	('MEKK', 'Gene', (59, 63))	('Akt', 'Gene', (174, 177))	('Deglutathionylation', 'Var', (0, 19))	('Ras', 'Protein', (23, 26))
84274	27121322	A functional variant at miRNA-122 binding site in IL-1alpha 3' UTR predicts risk of recurrence in patients with oropharyngeal cancer IL-1alpha, an important regulator of immune and inflammation responses, has been implicated in cancer development and prognosis.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('cancer', 'Disease', (228, 234))	('miRNA-122', 'Gene', (24, 33))	('IL-1alpha', 'Gene', '3552', (50, 59))	('IL-1alpha', 'Gene', (50, 59))	('implicated', 'Reg', (214, 224))	('cancer', 'Disease', (126, 132))	('patients', 'Species', '9606', (98, 106))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('recurrence', 'Disease', (84, 94))	('variant', 'Var', (13, 20))	('IL-1alpha', 'Gene', (133, 142))	('miRNA-122', 'Gene', '406906', (24, 33))	('inflammation', 'Disease', 'MESH:D007249', (181, 193))	('inflammation', 'Disease', (181, 193))	('IL-1alpha', 'Gene', '3552', (133, 142))	('cancer', 'Disease', 'MESH:D009369', (228, 234))
84275	27121322	An insertion (Ins)/deletion (Del) polymorphism (IL-1alpha rs3783553) in the 3' UTR of IL-1alpha may disrupt a binding site for miRNA-122 and may affect its transcription level.	('rs3783553', 'Mutation', 'rs3783553', (58, 67))	('transcription level', 'MPA', (156, 175))	('affect', 'Reg', (145, 151))	('IL-1alpha', 'Gene', (48, 57))	('miRNA-122', 'Gene', (127, 136))	('disrupt', 'NegReg', (100, 107))	('IL-1alpha', 'Gene', (86, 95))	('rs3783553', 'Var', (58, 67))	('IL-1alpha', 'Gene', '3552', (48, 57))	('binding', 'Interaction', (110, 117))	('IL-1alpha', 'Gene', '3552', (86, 95))	('miRNA-122', 'Gene', '406906', (127, 136))
84276	27121322	Thus, this polymorphism may cause interindividual variation in immune and inflammation responses and thus may lead to different susceptibility to treatment response and prognosis of such patients.	('patients', 'Species', '9606', (187, 195))	('treatment response', 'CPA', (146, 164))	('polymorphism', 'Var', (11, 23))	('lead to different', 'Reg', (110, 127))	('cause', 'Reg', (28, 33))	('inflammation', 'Disease', 'MESH:D007249', (74, 86))	('inflammation', 'Disease', (74, 86))
84277	27121322	We evaluated the association of IL-1alpha rs3783553 polymorphism with risk of recurrence of squamous cell carcinoma of the oropharynx (SCCOP) in a cohort of 1008 patients.	('patients', 'Species', '9606', (162, 170))	('rs3783553', 'Mutation', 'rs3783553', (42, 51))	('rs3783553', 'Var', (42, 51))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (92, 115))	('IL-1alpha', 'Gene', (32, 41))	('squamous cell carcinoma', 'Disease', (92, 115))	('IL-1alpha', 'Gene', '3552', (32, 41))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (92, 115))
84279	27121322	Compared with patients with Del/Del homozygous genotype, the patients with Ins/Del+Ins/Ins variant genotypes had worse disease-free survival (log-rank P < 0.0001) and increased risk of SCCOP recurrence (HR, 2.4, 95% CI, 1.7-3.3) after multivariable adjustment.	('SCCOP recurrence', 'Disease', (185, 201))	('patients', 'Species', '9606', (61, 69))	('Ins/Del+Ins/Ins', 'Var', (75, 90))	('patients', 'Species', '9606', (14, 22))	('disease-free survival', 'CPA', (119, 140))	('worse', 'NegReg', (113, 118))
84280	27121322	Furthermore, among patients with HPV16-positive tumors, the patients with Ins/Del+Ins/Ins variant genotypes of the IL-1alpha polymorphism had worse disease-free survival (log-rank P < 0.0001) and much higher recurrence risk than those with Del/Del homozygous genotype of this polymorphism (HR, 16.3, 95% CI, 5.0-52.7).	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('recurrence', 'CPA', (208, 218))	('patients', 'Species', '9606', (19, 27))	('IL-1alpha', 'Gene', (115, 124))	('patients', 'Species', '9606', (60, 68))	('HPV16-positive tumors', 'Disease', 'MESH:D009369', (33, 54))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('worse', 'NegReg', (142, 147))	('disease-free survival', 'CPA', (148, 169))	('IL-1alpha', 'Gene', '3552', (115, 124))	('HPV16-positive tumors', 'Disease', (33, 54))	('Ins/Del+Ins/Ins', 'Var', (74, 89))	('higher', 'PosReg', (201, 207))
84281	27121322	Our findings suggest that IL-1alpha rs3783553 polymorphism may modulate the risk of SCCOP recurrence in patients, particularly for patients with HPV16-positive tumors.	('patients', 'Species', '9606', (131, 139))	('IL-1alpha', 'Gene', '3552', (26, 35))	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('HPV16-positive tumors', 'Disease', 'MESH:D009369', (145, 166))	('SCCOP recurrence', 'Disease', (84, 100))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('IL-1alpha', 'Gene', (26, 35))	('HPV16-positive tumors', 'Disease', (145, 166))	('rs3783553', 'Mutation', 'rs3783553', (36, 45))	('modulate', 'Reg', (63, 71))	('patients', 'Species', '9606', (104, 112))	('rs3783553', 'Var', (36, 45))
84292	27121322	Woodworth et al found that IL-1alpha inhibited the proliferation of normal epithelial cells cultured from human cervix tissues, while IL-1alpha significantly stimulated the proliferation of cervical cell lines immortalized by transfection with HPV16 or HPV18 DNA.	('human', 'Species', '9606', (106, 111))	('IL-1alpha', 'Gene', (27, 36))	('inhibited', 'NegReg', (37, 46))	('HPV', 'Species', '10566', (244, 247))	('proliferation', 'CPA', (51, 64))	('IL-1alpha', 'Gene', '3552', (27, 36))	('stimulated', 'PosReg', (158, 168))	('proliferation', 'CPA', (173, 186))	('HPV16', 'Species', '333760', (244, 249))	('HPV', 'Species', '10566', (253, 256))	('IL-1alpha', 'Gene', (134, 143))	('HPV18 DNA', 'Var', (253, 262))	('IL-1alpha', 'Gene', '3552', (134, 143))
84294	27121322	Given the crucial and conflicting roles of IL-1alpha in immune and inflammation regulation, its genetic variants may affect the host immune an inflammatory responses and, subsequently the sensitivity to radiotherapy and prognosis.	('host immune an inflammatory responses', 'CPA', (128, 165))	('variants', 'Var', (104, 112))	('inflammation', 'Disease', 'MESH:D007249', (67, 79))	('inflammation', 'Disease', (67, 79))	('IL-1alpha', 'Gene', (43, 52))	('IL-1alpha', 'Gene', '3552', (43, 52))	('affect', 'Reg', (117, 123))
84296	27121322	An insertion/deletion polymorphism (rs3783553, an insertion or deletion of TTCA bases) at the miRNA-122 binding site, which is located in the IL-1alpha 3' UTR, was shown to be associated with gastric, hepatocellular, nasopharyngeal, and thyroid carcinomas.	('gastric', 'Disease', (192, 199))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (237, 254))	('IL-1alpha', 'Gene', (142, 151))	('miRNA-122', 'Gene', '406906', (94, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (245, 254))	('carcinomas', 'Phenotype', 'HP:0030731', (245, 255))	('miRNA-122', 'Gene', (94, 103))	('associated', 'Reg', (176, 186))	('insertion/deletion', 'Var', (3, 21))	('IL-1alpha', 'Gene', '3552', (142, 151))	('thyroid carcinomas', 'Disease', 'MESH:D013964', (237, 255))	('rs3783553', 'Mutation', 'rs3783553', (36, 45))	('thyroid carcinomas', 'Phenotype', 'HP:0002890', (237, 255))	('thyroid carcinomas', 'Disease', (237, 255))	('hepatocellular', 'Disease', (201, 215))	('nasopharyngeal', 'Disease', (217, 231))	('rs3783553', 'Var', (36, 45))
84297	27121322	Our previous study has found that IL-1alpha 3' UTR rs3783553 polymorphism may be functional and influence susceptibility to HPV16-associated OSCC, particularly for SCCOP.	('IL-1alpha', 'Gene', (34, 43))	('rs3783553', 'Mutation', 'rs3783553', (51, 60))	('IL-1alpha', 'Gene', '3552', (34, 43))	('rs3783553', 'Var', (51, 60))	('SCCOP', 'Disease', (164, 169))	('HPV16-associated', 'Gene', (124, 140))	('HPV16', 'Species', '333760', (124, 129))	('influence', 'Reg', (96, 105))
84298	27121322	However, no larger studies have examined the associations between the IL-1alpha rs3783553 polymorphism and risk of recurrence of patients with SCCOP.	('rs3783553', 'Mutation', 'rs3783553', (80, 89))	('IL-1alpha', 'Gene', (70, 79))	('patients', 'Species', '9606', (129, 137))	('IL-1alpha', 'Gene', '3552', (70, 79))	('rs3783553', 'Var', (80, 89))
84299	27121322	Therefore, we hypothesized that the IL-1alpha rs3783553 polymorphism at miRNA-122 binding site in IL-1alpha 3' UTR is associated with risk of recurrence of SCCOP, particularly HPV16-associated SCCOP.	('miRNA-122', 'Gene', '406906', (72, 81))	('SCCOP', 'Disease', (156, 161))	('IL-1alpha', 'Gene', (36, 45))	('rs3783553', 'Mutation', 'rs3783553', (46, 55))	('miRNA-122', 'Gene', (72, 81))	('HPV16', 'Species', '333760', (176, 181))	('IL-1alpha', 'Gene', (98, 107))	('HPV16-associated SCCOP', 'Disease', (176, 198))	('rs3783553', 'Var', (46, 55))	('associated with', 'Reg', (118, 133))	('IL-1alpha', 'Gene', '3552', (36, 45))	('IL-1alpha', 'Gene', '3552', (98, 107))
84311	27121322	Table 2 shows the genotype distributions of the IL-1alpha 3' UTR rs3783553 polymorphism, 5-year actuarial recurrence rates, and results of univariate and multivariable analyses of the associations of the polymorphism with recurrence risk.	('IL-1alpha', 'Gene', (48, 57))	('IL-1alpha', 'Gene', '3552', (48, 57))	('associations', 'Interaction', (184, 196))	('rs3783553', 'Var', (65, 74))	('rs3783553', 'Mutation', 'rs3783553', (65, 74))
84312	27121322	The patients with Ins/Ins or Ins/Del genotype had a significantly worse DFS than those with in patients with Del/Del genotype (log-rank P < 0.0001) (Figure 1A).	('patients', 'Species', '9606', (95, 103))	('Ins/Ins', 'Var', (18, 25))	('worse', 'NegReg', (66, 71))	('patients', 'Species', '9606', (4, 12))	('Ins/Del', 'Var', (29, 36))	('DFS', 'MPA', (72, 75))
84313	27121322	Multivariable Cox proportional hazards regression analysis was performed to evaluate the association between the IL-1alpha 3' UTR rs3783553 polymorphism and recurrence risk in patients with SCCOP.	('patients', 'Species', '9606', (176, 184))	('IL-1alpha', 'Gene', '3552', (113, 122))	('rs3783553', 'Var', (130, 139))	('Cox', 'Gene', '1351', (14, 17))	('Cox', 'Gene', (14, 17))	('rs3783553', 'Mutation', 'rs3783553', (130, 139))	('IL-1alpha', 'Gene', (113, 122))	('SCCOP', 'Disease', (190, 195))	('association', 'Interaction', (89, 100))
84315	27121322	As shown in Table 2, compared with those with Del/Del genotype, the patients with Ins/Ins or Ins/Del genotype had a significantly increased risk of disease recurrence (HR, 2.4, 95% CI, 1.7-3.3).	('disease recurrence', 'CPA', (148, 166))	('Ins/Del', 'Var', (93, 100))	('patients', 'Species', '9606', (68, 76))	('Ins/Ins', 'Var', (82, 89))
84316	27121322	Because HPV is an important prognostic factor for SCCOP and because IL-1alpha is one of important regulators in inflammation response, we further explored the associations between IL-1alpha 3' UTR rs3783553 polymorphism and risk of recurrence of SCCOP patients with HPV16-positive tumors.	('SCCOP', 'Disease', (246, 251))	('associations', 'Interaction', (159, 171))	('tumors', 'Phenotype', 'HP:0002664', (281, 287))	('IL-1alpha', 'Gene', '3552', (68, 77))	('HPV16-positive tumors', 'Disease', 'MESH:D009369', (266, 287))	('IL-1alpha', 'Gene', (180, 189))	('HPV', 'Species', '10566', (8, 11))	('patients', 'Species', '9606', (252, 260))	('inflammation', 'Disease', 'MESH:D007249', (112, 124))	('rs3783553', 'Mutation', 'rs3783553', (197, 206))	('HPV', 'Species', '10566', (266, 269))	('inflammation', 'Disease', (112, 124))	('IL-1alpha', 'Gene', '3552', (180, 189))	('HPV16-positive tumors', 'Disease', (266, 287))	('tumor', 'Phenotype', 'HP:0002664', (281, 286))	('IL-1alpha', 'Gene', (68, 77))	('rs3783553', 'Var', (197, 206))
84317	27121322	Since we found that the patients with common homozygous Del/Del genotype of the IL-1alpha 3' UTR rs3783553 polymorphism were approximately three times as likely as patients with the corresponding Ins/Ins+Ins/Del variant genotypes to have HPV16-positive tumors (OR, 3.2, 95% CI, 1.9-5.7) (data not shown), we then performed univariate and multivariable analyses to determine the effect of IL-1alpha 3' UTR rs3783553 polymorphism on risk of recurrence among 324 SCCOP patients with HPV16-positive tumors.	('tumors', 'Phenotype', 'HP:0002664', (253, 259))	('HPV16-positive tumors', 'Disease', (480, 501))	('IL-1alpha', 'Gene', '3552', (388, 397))	('HPV16-positive tumors', 'Disease', 'MESH:D009369', (238, 259))	('Del/Del', 'Var', (56, 63))	('rs3783553', 'Mutation', 'rs3783553', (97, 106))	('IL-1alpha', 'Gene', (80, 89))	('patients', 'Species', '9606', (466, 474))	('tumor', 'Phenotype', 'HP:0002664', (495, 500))	('HPV16-positive tumors', 'Disease', 'MESH:D009369', (480, 501))	('tumors', 'Phenotype', 'HP:0002664', (495, 501))	('patients', 'Species', '9606', (24, 32))	('tumor', 'Phenotype', 'HP:0002664', (253, 258))	('IL-1alpha', 'Gene', '3552', (80, 89))	('rs3783553', 'Mutation', 'rs3783553', (405, 414))	('patients', 'Species', '9606', (164, 172))	('IL-1alpha', 'Gene', (388, 397))	('HPV16-positive tumors', 'Disease', (238, 259))
84318	27121322	As shown in Figure 1B, a significantly worse DFS was found in patients with IL-1alpha 3' UTR rs3783553 Ins/Ins+Ins/Del genotypes than in those with corresponding Del/Del genotype (log-rank P < 0.0001).	('rs3783553', 'Mutation', 'rs3783553', (93, 102))	('IL-1alpha', 'Gene', (76, 85))	('patients', 'Species', '9606', (62, 70))	('IL-1alpha', 'Gene', '3552', (76, 85))	('worse', 'NegReg', (39, 44))	('rs3783553 Ins/Ins+Ins/Del', 'Var', (93, 118))
84319	27121322	Furthermore, multivariable Cox proportional hazards regression analysis (Table 3) showed that the patients with IL-1alpha 3' UTR rs3783553 Ins/Ins+Ins/Del genotypes had an approximately 16.5-fold significantly increased risk for recurrence compared with those with the corresponding Del/Del genotype (HR, 16.3, 95% CI, 5.0-52.7).	('Cox', 'Gene', '1351', (27, 30))	('rs3783553 Ins/Ins+Ins/Del', 'Var', (129, 154))	('recurrence', 'CPA', (229, 239))	('patients', 'Species', '9606', (98, 106))	('Cox', 'Gene', (27, 30))	('rs3783553', 'Mutation', 'rs3783553', (129, 138))	('IL-1alpha', 'Gene', (112, 121))	('IL-1alpha', 'Gene', '3552', (112, 121))
84320	27121322	Additionally, we did not assess the similar associations between the IL-1alpha 3' UTR rs3783553 polymorphism and recurrence risk among the patients with HPV16-negative tumors, since we did not have enough sample size or number of outcome events in these patients for meaningful statistical analysis.	('IL-1alpha', 'Gene', (69, 78))	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('patients', 'Species', '9606', (139, 147))	('rs3783553', 'Mutation', 'rs3783553', (86, 95))	('IL-1alpha', 'Gene', '3552', (69, 78))	('tumors', 'Disease', (168, 174))	('tumors', 'Disease', 'MESH:D009369', (168, 174))	('rs3783553', 'Var', (86, 95))	('patients', 'Species', '9606', (254, 262))	('HPV16', 'Species', '333760', (153, 158))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
84321	27121322	In this cohort study of 1008 patients with incident SCCOP, we found that the IL-1alpha 3' UTR rs3783553 Ins/Ins+Ins/Del genotypes were significantly associated with an increased risk of recurrence; furthermore, we found that these Ins/Ins+Ins/Del genotypes were significantly associated with the increased risk of recurrence among SCCOP patients with HPV16-positive tumors.	('patients', 'Species', '9606', (29, 37))	('rs3783553 Ins/Ins+Ins/Del', 'Var', (94, 119))	('tumors', 'Phenotype', 'HP:0002664', (366, 372))	('rs3783553', 'Mutation', 'rs3783553', (94, 103))	('associated', 'Reg', (149, 159))	('Ins/Ins+Ins/Del', 'Var', (231, 246))	('HPV16-positive tumors', 'Disease', (351, 372))	('IL-1alpha', 'Gene', (77, 86))	('tumor', 'Phenotype', 'HP:0002664', (366, 371))	('patients', 'Species', '9606', (337, 345))	('IL-1alpha', 'Gene', '3552', (77, 86))	('recurrence', 'CPA', (186, 196))	('HPV16-positive tumors', 'Disease', 'MESH:D009369', (351, 372))
84322	27121322	These results suggest that the IL-1alpha 3' UTR rs3783553 polymorphism may predict risk of recurrence among SCCOP patients, particularly for those with HPV16-posiitve tumors.	('rs3783553', 'Mutation', 'rs3783553', (48, 57))	('IL-1alpha', 'Gene', (31, 40))	('IL-1alpha', 'Gene', '3552', (31, 40))	('rs3783553', 'Var', (48, 57))	('HPV16-posiitve tumors', 'Disease', 'MESH:D009369', (152, 173))	('HPV16-posiitve tumors', 'Disease', (152, 173))	('recurrence', 'Disease', (91, 101))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('patients', 'Species', '9606', (114, 122))	('tumors', 'Phenotype', 'HP:0002664', (167, 173))
84323	27121322	To date, this is the first epidemiological study to assess the association between the rs3783553 polymorphism and risk of recurrence of SCCOP.	('rs3783553', 'Mutation', 'rs3783553', (87, 96))	('SCCOP', 'Disease', (136, 141))	('recurrence', 'Disease', (122, 132))	('rs3783553', 'Var', (87, 96))
84324	27121322	Although we do not know how this IL-1alpha 3' UTR variant influences the recurrence risk of tumor HPV16-positive patients, it is biologically plausible that this variant may be either functional or in linkage disequilibrium with other functional variants of IL-1alpha, thereby altering the function of IL-1alpha, or with alleles at other nearby susceptibility loci.	('IL-1alpha', 'Gene', (258, 267))	('HPV16', 'Species', '333760', (98, 103))	('variant', 'Var', (50, 57))	('influences', 'Reg', (58, 68))	('IL-1alpha', 'Gene', (302, 311))	('IL-1alpha', 'Gene', '3552', (258, 267))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('patients', 'Species', '9606', (113, 121))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('IL-1alpha', 'Gene', (33, 42))	('IL-1alpha', 'Gene', '3552', (302, 311))	('IL-1alpha', 'Gene', '3552', (33, 42))	('tumor', 'Disease', (92, 97))	('altering', 'Reg', (277, 285))	('function', 'MPA', (290, 298))
84325	27121322	Such functional variants could increase or reduce IL-1alpha expression levels and thus affect the regulation of the immune and inflammation as well as inflammatory or apoptotic responses.	('inflammatory', 'CPA', (151, 163))	('reduce', 'NegReg', (43, 49))	('affect', 'Reg', (87, 93))	('IL-1alpha', 'Gene', (50, 59))	('regulation', 'MPA', (98, 108))	('inflammation', 'Disease', 'MESH:D007249', (127, 139))	('apoptotic responses', 'CPA', (167, 186))	('expression levels', 'MPA', (60, 77))	('immune', 'CPA', (116, 122))	('IL-1alpha', 'Gene', '3552', (50, 59))	('inflammation', 'Disease', (127, 139))	('variants', 'Var', (16, 24))	('increase', 'PosReg', (31, 39))
84326	27121322	For example, IL-1alpha 3' UTR rs3783553 Del/Del genotype might alter regulation in these pathways which might enable many HPV-infected cells to escape or counterattack against the immune system and might not enhance apoptotic response, leading to more likely to be HPV-positive tumors and subsequently better response to radiotherapy.	('tumor', 'Phenotype', 'HP:0002664', (278, 283))	('regulation', 'MPA', (69, 79))	('enable', 'Reg', (110, 116))	('tumors', 'Phenotype', 'HP:0002664', (278, 284))	('IL-1alpha', 'Gene', '3552', (13, 22))	('more', 'PosReg', (247, 251))	('rs3783553 Del/Del', 'Var', (30, 47))	('alter', 'Reg', (63, 68))	('escape or counterattack against the immune system', 'Phenotype', 'HP:0002721', (144, 193))	('better', 'PosReg', (302, 308))	('these pathways', 'Pathway', (83, 97))	('HPV-positive tumors', 'Disease', 'MESH:D030361', (265, 284))	('HPV-infected', 'Disease', (122, 134))	('HPV-infected', 'Disease', 'MESH:D030361', (122, 134))	('enhance', 'PosReg', (208, 215))	('rs3783553', 'Mutation', 'rs3783553', (30, 39))	('IL-1alpha', 'Gene', (13, 22))	('HPV-positive tumors', 'Disease', (265, 284))
84328	27121322	Growing evidences have suggested that the polymorphisms in the miRNA target site may influence the strength of miRNA binding, regulation of target genes and affecting the individual's cancer risk.	('cancer', 'Disease', (184, 190))	('miRNA', 'Protein', (111, 116))	('affecting', 'Reg', (157, 166))	('regulation of', 'MPA', (126, 139))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('influence', 'Reg', (85, 94))	('polymorphisms', 'Var', (42, 55))	('strength', 'Interaction', (99, 107))	('cancer', 'Disease', 'MESH:D009369', (184, 190))
84329	27121322	The rs3783553 lies within a predicted binding site (seed region) for human miR-122, which is a liver specific miRNA comprising up to 70% of all hepatic miRNA which mostly regulates lipid homeostasis.	('lipid homeostasis', 'MPA', (181, 198))	('lipid', 'Chemical', 'MESH:D008055', (181, 186))	('rs3783553', 'Var', (4, 13))	('regulates', 'Reg', (171, 180))	('binding', 'Interaction', (38, 45))	('miR-122', 'Gene', '406906', (75, 82))	('miR-122', 'Gene', (75, 82))	('human', 'Species', '9606', (69, 74))	('rs3783553', 'Mutation', 'rs3783553', (4, 13))
84331	27121322	reported the rs3783553 polymorphism affects the transcription of IL-1alpha by altering the binding strength of miRNA-122.	('IL-1alpha', 'Gene', (65, 74))	('affects', 'Reg', (36, 43))	('rs3783553', 'Var', (13, 22))	('miRNA-122', 'Gene', '406906', (111, 120))	('transcription', 'MPA', (48, 61))	('IL-1alpha', 'Gene', '3552', (65, 74))	('miRNA-122', 'Gene', (111, 120))	('binding', 'Interaction', (91, 98))	('altering', 'Reg', (78, 86))	('rs3783553', 'Mutation', 'rs3783553', (13, 22))
84332	27121322	Subsequently, this polymorphism has been identified to be associated with decreased risks for developing hepatocellular carcinoma, nasopharyngeal carcinoma, gastric cancer, papillary thyroid carcinoma, and cervical cancer.	('gastric cancer', 'Phenotype', 'HP:0012126', (157, 171))	('nasopharyngeal carcinoma', 'Disease', 'MESH:D000077274', (131, 155))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (183, 200))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('cervical cancer', 'Disease', 'MESH:D002583', (206, 221))	('cervical cancer', 'Disease', (206, 221))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (105, 129))	('carcinoma', 'Phenotype', 'HP:0030731', (191, 200))	('gastric cancer', 'Disease', (157, 171))	('papillary thyroid carcinoma', 'Phenotype', 'HP:0002895', (173, 200))	('polymorphism', 'Var', (19, 31))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (131, 155))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('papillary thyroid carcinoma', 'Disease', (173, 200))	('papillary thyroid carcinoma', 'Disease', 'MESH:D000077273', (173, 200))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (105, 129))	('gastric cancer', 'Disease', 'MESH:D013274', (157, 171))	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('nasopharyngeal carcinoma', 'Disease', (131, 155))	('hepatocellular carcinoma', 'Disease', (105, 129))	('decreased', 'NegReg', (74, 83))
84334	27121322	Since this polymorphism is within the functional region of the gene's 3'UTR of IL-1alpha, we speculated that this IL-1alpha genetic variant may have potentially functional effect on expression levels of IL-1alpha by altering the efficiency of translational initiation, leading to inter-individual differences in susceptibility to radiotherapy.	('IL-1alpha', 'Gene', (79, 88))	('variant', 'Var', (132, 139))	('altering', 'Reg', (216, 224))	('expression levels', 'MPA', (182, 199))	('IL-1alpha', 'Gene', '3552', (203, 212))	('IL-1alpha', 'Gene', (114, 123))	('IL-1alpha', 'Gene', '3552', (79, 88))	('IL-1alpha', 'Gene', '3552', (114, 123))	('susceptibility to radiotherapy', 'Phenotype', 'HP:0011133', (312, 342))	('efficiency', 'MPA', (229, 239))	('translational initiation', 'MPA', (243, 267))	('susceptibility', 'MPA', (312, 326))	('IL-1alpha', 'Gene', (203, 212))	('effect', 'Reg', (172, 178))
84335	27121322	Indeed, we previously reported that the Del/Del genotype of this polymorphism is significantly correlated with increased expression of IL-1alpha in serum.	('increased', 'PosReg', (111, 120))	('expression', 'MPA', (121, 131))	('IL-1alpha', 'Gene', (135, 144))	('Del/Del', 'Var', (40, 47))	('IL-1alpha', 'Gene', '3552', (135, 144))
84337	27121322	Since IL-1alpha plays an important role in immune and inflammatory responses, we thus further explored the roles of IL-1alpha 3' UTR rs3783553 in recurrence of SCCOP patients stratified by tumor HPV16 status.	('IL-1alpha', 'Gene', (6, 15))	('IL-1alpha', 'Gene', '3552', (116, 125))	('tumor', 'Disease', (189, 194))	('IL-1alpha', 'Gene', '3552', (6, 15))	('HPV16', 'Species', '333760', (195, 200))	('rs3783553', 'Mutation', 'rs3783553', (133, 142))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('IL-1alpha', 'Gene', (116, 125))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('patients', 'Species', '9606', (166, 174))	('rs3783553', 'Var', (133, 142))
84338	27121322	We found that the modifying effect of the IL-1alpha 3' UTR rs3783553 polymorphism on SCCOP recurrence was more pronounced in SCCOP patients with HPV16-positive tumors.	('patients', 'Species', '9606', (131, 139))	('HPV16-positive tumors', 'Disease', 'MESH:D009369', (145, 166))	('rs3783553', 'Var', (59, 68))	('IL-1alpha', 'Gene', '3552', (42, 51))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('HPV16-positive tumors', 'Disease', (145, 166))	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('SCCOP', 'Disease', (125, 130))	('SCCOP recurrence', 'Disease', (85, 101))	('rs3783553', 'Mutation', 'rs3783553', (59, 68))	('IL-1alpha', 'Gene', (42, 51))
84339	27121322	These results suggest that IL-1alpha 3' UTR rs3783553 polymorphism may modulate risk of recurrence in patients with HPV16-positive tumors.	('IL-1alpha', 'Gene', (27, 36))	('rs3783553', 'Var', (44, 53))	('HPV16-positive tumors', 'Disease', (116, 137))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('patients', 'Species', '9606', (102, 110))	('HPV16-positive tumors', 'Disease', 'MESH:D009369', (116, 137))	('IL-1alpha', 'Gene', '3552', (27, 36))	('modulate', 'Reg', (71, 79))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('rs3783553', 'Mutation', 'rs3783553', (44, 53))
84341	27121322	We expect that the IL-1alpha 3' UTR rs3783553 variant genotypes may result in decreased expression of IL-1alpha (25), which may confer protective effects against HPV infection among patients with SCOOP.	('IL-1alpha', 'Gene', '3552', (102, 111))	('HPV infection', 'Disease', 'MESH:D030361', (162, 175))	('IL-1alpha', 'Gene', (19, 28))	('rs3783553', 'Mutation', 'rs3783553', (36, 45))	('patients', 'Species', '9606', (182, 190))	('IL-1alpha', 'Gene', (102, 111))	('IL-1alpha', 'Gene', '3552', (19, 28))	('decreased', 'NegReg', (78, 87))	('expression', 'MPA', (88, 98))	('HPV infection', 'Disease', (162, 175))	('rs3783553', 'Var', (36, 45))
84342	27121322	This IL-1alpha 3' UTR rs3783553 polymorphism has been reported to affect the level of IL-1alpha.	('affect', 'Reg', (66, 72))	('IL-1alpha', 'Gene', (86, 95))	('IL-1alpha', 'Gene', '3552', (86, 95))	('IL-1alpha', 'Gene', (5, 14))	('rs3783553', 'Mutation', 'rs3783553', (22, 31))	('IL-1alpha', 'Gene', '3552', (5, 14))	('rs3783553', 'Var', (22, 31))
84347	27121322	Therefore, the IL-1alpha 3' UTR rs3783553 variant genotypes may reduce the inflammation and p53-induced apoptotic responses among patients with HPV16-positive tumors, leading to worse response to definitive radiotherapy and subsequently the increased likelihood of disease recurrence.	('rs3783553', 'Var', (32, 41))	('reduce', 'NegReg', (64, 70))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('HPV16-positive tumors', 'Disease', (144, 165))	('IL-1alpha', 'Gene', (15, 24))	('tumors', 'Phenotype', 'HP:0002664', (159, 165))	('patients', 'Species', '9606', (130, 138))	('inflammation', 'Disease', 'MESH:D007249', (75, 87))	('p53', 'Gene', (92, 95))	('inflammation', 'Disease', (75, 87))	('IL-1alpha', 'Gene', '3552', (15, 24))	('HPV16-positive tumors', 'Disease', 'MESH:D009369', (144, 165))	('rs3783553', 'Mutation', 'rs3783553', (32, 41))	('p53', 'Gene', '7157', (92, 95))
84348	27121322	Although this study reveals some significant associations between IL-1alpha 3' UTR rs3783553 polymorphism and recurrence risk of SCCOP, there are several limitations including lack of details on radiotherapy (e.g., dosage, treatment cycles, duration, etc), the limited number of outcome events in HPV16-positive, multiple ethnicities inclusion, and the relatively short follow-up time, as well as the hospital-based nature of the study.	('rs3783553', 'Mutation', 'rs3783553', (83, 92))	('SCCOP', 'Disease', (129, 134))	('IL-1alpha', 'Gene', (66, 75))	('HPV16', 'Species', '333760', (297, 302))	('polymorphism', 'Var', (93, 105))	('IL-1alpha', 'Gene', '3552', (66, 75))	('rs3783553 polymorphism', 'Var', (83, 105))
84349	27121322	In conclusion, our findings suggest that the IL-1alpha 3' UTR rs3783553 polymorphism might modulate the risk of recurrence of SCCOP, especially in patients with HPV16-positive tumors.	('rs3783553', 'Mutation', 'rs3783553', (62, 71))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('IL-1alpha', 'Gene', (45, 54))	('HPV16-positive tumors', 'Disease', (161, 182))	('IL-1alpha', 'Gene', '3552', (45, 54))	('modulate', 'Reg', (91, 99))	('rs3783553', 'Var', (62, 71))	('SCCOP', 'Disease', (126, 131))	('tumors', 'Phenotype', 'HP:0002664', (176, 182))	('patients', 'Species', '9606', (147, 155))	('HPV16-positive tumors', 'Disease', 'MESH:D009369', (161, 182))	('recurrence', 'Disease', (112, 122))
84373	27121322	Associations between IL-1alpha 3' UTR rs3783553 polymorphism and risk of recurrence were quantified by calculating hazard ratios (HRs) and their 95% CIs.	('IL-1alpha', 'Gene', (21, 30))	('rs3783553', 'Mutation', 'rs3783553', (38, 47))	('IL-1alpha', 'Gene', '3552', (21, 30))	('rs3783553', 'Var', (38, 47))
84399	27501725	Suprabasal expression of low molecular weight keratins, loss of heterozygosity of the TP53 gene, microsatellite instability, and higher chromosomal aneuploidy rates all increase the risk of malignant transformation.	('low molecular weight keratins', 'Protein', (25, 54))	('chromosomal aneuploidy', 'Disease', (136, 158))	('TP53', 'Gene', '7157', (86, 90))	('loss', 'Var', (56, 60))	('chromosomal aneuploidy', 'Disease', 'MESH:D000782', (136, 158))	('increase', 'PosReg', (169, 177))	('TP53', 'Gene', (86, 90))	('malignant transformation', 'CPA', (190, 214))	('microsatellite', 'MPA', (97, 111))
84404	27501725	Clusters of cells with cancer-associated genetic alterations such as TP53 mutations have been detected in biopsies of histologically normal mucosa of HNSCC patients, and, in particular, in those with multiple primary malignancies.	('patients', 'Species', '9606', (156, 164))	('HNSCC', 'Phenotype', 'HP:0012288', (150, 155))	('TP53', 'Gene', '7157', (69, 73))	('TP53', 'Gene', (69, 73))	('detected', 'Reg', (94, 102))	('mutations', 'Var', (74, 83))	('malignancies', 'Disease', 'MESH:D009369', (217, 229))	('cancer', 'Disease', (23, 29))	('SCC', 'Gene', (152, 155))	('cancer', 'Disease', 'MESH:D009369', (23, 29))	('SCC', 'Phenotype', 'HP:0002860', (152, 155))	('SCC', 'Gene', '6317', (152, 155))	('malignancies', 'Disease', (217, 229))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))
84408	27501725	HNSCC's mutational landscape is dominated by tumor suppressor genes with activating oncogene mutations playing an additional relevant role.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('mutations', 'Var', (93, 102))	('tumor', 'Disease', (45, 50))	('SCC', 'Gene', (2, 5))	('activating', 'PosReg', (73, 83))	('SCC', 'Phenotype', 'HP:0002860', (2, 5))	('SCC', 'Gene', '6317', (2, 5))	('HNSCC', 'Phenotype', 'HP:0012288', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
84410	27501725	Telomerase reverse transcriptase (TERT) promoter mutations resulting in increased telomerase expression have also been detected in a significant proportion of HNSCC patients.	('SCC', 'Gene', (161, 164))	('SCC', 'Phenotype', 'HP:0002860', (161, 164))	('increased', 'PosReg', (72, 81))	('mutations', 'Var', (49, 58))	('HNSCC', 'Phenotype', 'HP:0012288', (159, 164))	('TERT', 'Gene', (34, 38))	('Telomerase reverse transcriptase', 'Gene', (0, 32))	('SCC', 'Gene', '6317', (161, 164))	('Telomerase reverse transcriptase', 'Gene', '7015', (0, 32))	('TERT', 'Gene', '7015', (34, 38))	('expression', 'MPA', (93, 103))	('patients', 'Species', '9606', (165, 173))	('telomerase', 'Enzyme', (82, 92))	('detected', 'Reg', (119, 127))
84413	27501725	Most HPV-negative tumors harbor inactivating mutations in the TP53 gene.	('TP53', 'Gene', '7157', (62, 66))	('TP53', 'Gene', (62, 66))	('tumors', 'Disease', (18, 24))	('inactivating mutations', 'Var', (32, 54))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('HPV', 'Species', '10566', (5, 8))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
84417	27501725	HPV-negative HNSCC show inactivation mainly by deletion or promoter hypermethylation of the CDKN2A gene encoding p16INK4a and frequently have CCND1 amplification, which encodes cyclin D1, with both leading to a decrease in the growth-suppressive hypo-phosphorylated RB form.	('CCND1', 'Gene', (142, 147))	('RB', 'Phenotype', 'HP:0009919', (266, 268))	('CDKN2A', 'Gene', (92, 98))	('promoter', 'MPA', (59, 67))	('HPV', 'Species', '10566', (0, 3))	('p16INK4a', 'Gene', (113, 121))	('cyclin D1', 'Gene', '595', (177, 186))	('CCND1', 'Gene', '595', (142, 147))	('CDKN2A', 'Gene', '1029', (92, 98))	('HNSCC', 'Phenotype', 'HP:0012288', (13, 18))	('cyclin D1', 'Gene', (177, 186))	('deletion', 'Var', (47, 55))	('SCC', 'Gene', (15, 18))	('p16INK4a', 'Gene', '1029', (113, 121))	('growth-suppressive hypo-phosphorylated RB form', 'MPA', (227, 273))	('SCC', 'Phenotype', 'HP:0002860', (15, 18))	('SCC', 'Gene', '6317', (15, 18))	('decrease', 'NegReg', (211, 219))
84434	27501725	TRF2 depletion predominantly leads to ATM activation, whereas deprotection of 3' single-stranded overhang due to POT1 depletion activates ATR.	('TRF2', 'Gene', (0, 4))	('depletion', 'Var', (5, 14))	('ATM', 'Gene', '472', (38, 41))	('activates', 'PosReg', (128, 137))	('POT1', 'Gene', '25913', (113, 117))	('POT1', 'Gene', (113, 117))	('ATM', 'Gene', (38, 41))	('leads to', 'Reg', (29, 37))	('ATR', 'Gene', '545', (138, 141))	('ATR', 'Gene', (138, 141))	('TRF2', 'Gene', '7014', (0, 4))
84440	27501725	The consequence of telomere erosion depends, indeed, on the cellular milieu: in checkpoint-proficient cells, it leads to tumor suppression by senescence or apoptosis; while in checkpoint-compromised ones, it leads to tumor promotion by causing genetic instability (Fig.	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('tumor', 'Disease', (217, 222))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('senescence', 'CPA', (142, 152))	('tumor', 'Disease', (121, 126))	('telomere', 'Var', (19, 27))	('causing', 'Reg', (236, 243))	('genetic instability', 'MPA', (244, 263))	('tumor', 'Disease', 'MESH:D009369', (217, 222))	('apoptosis', 'CPA', (156, 165))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
84451	27501725	NF-kB can also induce TERT translocation from the cytoplasm to the nucleus.	('NF-kB', 'Var', (0, 5))	('TERT', 'Gene', (22, 26))	('TERT', 'Gene', '7015', (22, 26))	('induce', 'Reg', (15, 21))
84455	27501725	TERT promoter methylation status has unveiled a complex methylation pattern with some studies reporting hypomethylation in the CpG island in the TERT promoter region while others have described increased DNA methylation in TERT-expressing cancer cells.	('TERT', 'Gene', '7015', (223, 227))	('hypomethylation', 'Var', (104, 119))	('cancer', 'Disease', 'MESH:D009369', (239, 245))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))	('TERT', 'Gene', (223, 227))	('TERT', 'Gene', (0, 4))	('increased', 'PosReg', (194, 203))	('cancer', 'Disease', (239, 245))	('TERT', 'Gene', '7015', (0, 4))	('DNA methylation', 'MPA', (204, 219))	('TERT', 'Gene', (145, 149))	('TERT', 'Gene', '7015', (145, 149))
84466	27501725	As stated above, the abrogation of important cell cycle checkpoints, such as p53 and RB, may allow cells to bypass replicative senescence and to enter a state of crisis characterized by extremely short telomeres which may lead to BFB cycles and chromothripsis.	('BFB', 'Chemical', '-', (230, 233))	('lead to', 'Reg', (222, 229))	('RB', 'Phenotype', 'HP:0009919', (85, 87))	('p53', 'Gene', (77, 80))	('BFB cycles', 'CPA', (230, 240))	('p53', 'Gene', '7157', (77, 80))	('abrogation', 'Var', (21, 31))	('short telomeres', 'Phenotype', 'HP:0031413', (196, 211))	('chromothripsis', 'CPA', (245, 259))
84468	27501725	Supporting the theory that genetic instability in head and neck carcinogenesis can be triggered by telomere dysfunction, telomere attrition has been associated with BFB events, accumulation of centrosomes, and multipolar cell divisions in cell lines from benign and malignant head and neck tumors.	('neck carcinogenesis', 'Disease', (59, 78))	('telomere attrition', 'Var', (121, 139))	('neck tumors', 'Disease', (285, 296))	('BFB', 'Chemical', '-', (165, 168))	('triggered', 'Reg', (86, 95))	('neck carcinogenesis', 'Disease', 'MESH:D063646', (59, 78))	('associated', 'Reg', (149, 159))	('tumors', 'Phenotype', 'HP:0002664', (290, 296))	('tumor', 'Phenotype', 'HP:0002664', (290, 295))	('neck tumors', 'Disease', 'MESH:D006258', (285, 296))	('accumulation', 'PosReg', (177, 189))	('BFB', 'Gene', (165, 168))	('head and neck tumors', 'Phenotype', 'HP:0012288', (276, 296))
84471	27501725	Notably, telomere shortening has also been detected in nearby non-neoplastic esophageal epithelium from patients with invasive esophageal cancer as well as in cancer-associated normal stromal cells and pre-neoplastic lesions, respectively, from the prostate and the pancreas.	('cancer', 'Disease', (159, 165))	('telomere shortening', 'Phenotype', 'HP:0031413', (9, 28))	('cancer', 'Disease', (138, 144))	('neoplastic lesions', 'Phenotype', 'HP:0002664', (206, 224))	('invasive esophageal cancer', 'Disease', (118, 144))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('neoplastic esophageal epithelium', 'Phenotype', 'HP:0100751', (66, 98))	('telomere shortening', 'Var', (9, 28))	('detected', 'Reg', (43, 51))	('invasive esophageal cancer', 'Disease', 'MESH:D004938', (118, 144))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('patients', 'Species', '9606', (104, 112))	('cancer', 'Disease', 'MESH:D009369', (138, 144))
84472	27501725	Telomere erosion is thus emerging as a very early, common genetic event in epithelial carcinogenesis.	('epithelial carcinogenesis', 'Disease', 'MESH:D063646', (75, 100))	('Telomere erosion', 'Var', (0, 16))	('epithelial carcinogenesis', 'Disease', (75, 100))
84488	27501725	Telomerase re-activation or up-regulation can be achieved by gene amplification, promoter mutations, TERT mRNA alternative splicing, epigenetic changes, or through post-translational processing.	('TERT', 'Gene', '7015', (101, 105))	('promoter mutations', 'Var', (81, 99))	('Telomerase', 'Enzyme', (0, 10))	('epigenetic changes', 'Var', (133, 151))	('gene amplification', 'Var', (61, 79))	('TERT', 'Gene', (101, 105))	('re-activation', 'PosReg', (11, 24))	('up-regulation', 'PosReg', (28, 41))
84491	27501725	Comprehensive genomic characterization of HNSCC has frequently uncovered amplification of chromosome 5p, which encompasses TERT gene, in both HPV-positive and HPV-negative carcinomas.	('SCC', 'Gene', '6317', (44, 47))	('HNSCC', 'Phenotype', 'HP:0012288', (42, 47))	('TERT', 'Gene', (123, 127))	('HPV', 'Species', '10566', (159, 162))	('carcinomas', 'Phenotype', 'HP:0030731', (172, 182))	('carcinomas', 'Disease', (172, 182))	('carcinomas', 'Disease', 'MESH:D002277', (172, 182))	('HPV', 'Species', '10566', (142, 145))	('TERT', 'Gene', '7015', (123, 127))	('uncovered', 'Reg', (63, 72))	('SCC', 'Gene', (44, 47))	('carcinoma', 'Phenotype', 'HP:0030731', (172, 181))	('SCC', 'Phenotype', 'HP:0002860', (44, 47))	('amplification', 'Var', (73, 86))
84503	27501725	Very recently, two prevalent and mutually exclusive mutations in the promoter of TERT (228C>T and 250C>T) emerged as the most frequently observed non-coding mutations in cancer and were associated with high levels of telomerase in multiple cancer types.	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('250C>T', 'Var', (98, 104))	('cancer', 'Disease', (170, 176))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('TERT', 'Gene', (81, 85))	('TERT', 'Gene', '7015', (81, 85))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('associated', 'Reg', (186, 196))	('250C>T', 'Mutation', 'rs541791751', (98, 104))	('cancer', 'Disease', 'MESH:D009369', (240, 246))	('228C>T', 'Mutation', 'rs1055669668', (87, 93))	('cancer', 'Disease', (240, 246))	('telomerase', 'MPA', (217, 227))
84504	27501725	Notably, these mutations specifically promote TERT expression in telomerase-negative differentiated cell compartments, while their impact in telomerase-positive stem cell reservoirs appears to be neutral.	('TERT', 'Gene', (46, 50))	('TERT', 'Gene', '7015', (46, 50))	('mutations', 'Var', (15, 24))	('promote', 'PosReg', (38, 45))
84505	27501725	Thus, TERT promoter mutations uncouple cellular differentiation and telomerase silencing.	('telomerase', 'Protein', (68, 78))	('TERT', 'Gene', (6, 10))	('uncouple', 'NegReg', (30, 38))	('TERT', 'Gene', '7015', (6, 10))	('cellular differentiation', 'CPA', (39, 63))	('mutations', 'Var', (20, 29))
84506	27501725	In particular, the ETS GA-binding protein transcription factor alpha subunit selectively links the mutant form of the TERT promoter and increases TERT transcriptional activity.	('TERT', 'Gene', '7015', (118, 122))	('TERT', 'Gene', (146, 150))	('mutant', 'Var', (99, 105))	('TERT', 'Gene', '7015', (146, 150))	('increases', 'PosReg', (136, 145))	('TERT', 'Gene', (118, 122))
84510	27501725	Remarkably, 228C > T and 250C > T mutations in the TERT promoter are more frequent in laryngeal tumors in smokers compared to that in non-smokers and are independently associated with poor overall survival (OS).TERT promoter activity can be modified by a common polymorphism within the preexisting ETS2 binding site in the TERT promoter with patients with the rs2736098 variant and in particular those exposed to tobacco and alcohol having a lower risk of SCC of the oropharynx.	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('SCC', 'Gene', '6317', (456, 459))	('rs2736098', 'Mutation', 'rs2736098', (360, 369))	('laryngeal tumors', 'Disease', 'MESH:D007822', (86, 102))	('ETS2', 'Gene', (298, 302))	('TERT', 'Gene', (323, 327))	('TERT', 'Gene', (211, 215))	('TERT', 'Gene', '7015', (323, 327))	('SCC', 'Gene', (456, 459))	('TERT', 'Gene', '7015', (211, 215))	('TERT', 'Gene', (51, 55))	('laryngeal tumors', 'Phenotype', 'HP:0012118', (86, 102))	('laryngeal tumors', 'Disease', (86, 102))	('TERT', 'Gene', '7015', (51, 55))	('228C > T', 'Mutation', 'rs1055669668', (12, 20))	('alcohol', 'Chemical', 'MESH:D000438', (425, 432))	('ETS2', 'Gene', '2114', (298, 302))	('tobacco', 'Species', '4097', (413, 420))	('250C > T', 'Mutation', 'rs541791751', (25, 33))	('patients', 'Species', '9606', (342, 350))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('SCC', 'Phenotype', 'HP:0002860', (456, 459))	('rs2736098', 'Var', (360, 369))
84511	27501725	As histone deacetylase inhibitor FR901228 induces a significant increase in TERT expression in oral cancer cell lines, it is possible that the latter is epigenetically controlled in HNSCC through changes in DNA methylation or histone acetylation.	('TERT', 'Gene', '7015', (76, 80))	('FR901228', 'Var', (33, 41))	('HNSCC', 'Phenotype', 'HP:0012288', (182, 187))	('oral cancer', 'Disease', (95, 106))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('SCC', 'Gene', (184, 187))	('increase', 'PosReg', (64, 72))	('changes', 'Reg', (196, 203))	('FR901228', 'Chemical', 'MESH:C087123', (33, 41))	('TERT', 'Gene', (76, 80))	('SCC', 'Phenotype', 'HP:0002860', (184, 187))	('SCC', 'Gene', '6317', (184, 187))	('oral cancer', 'Disease', 'MESH:D009062', (95, 106))
84512	27501725	TERT regulation can also occur via post-translational protein modification.	('TERT', 'Gene', (0, 4))	('TERT', 'Gene', '7015', (0, 4))	('post-translational protein modification', 'Var', (35, 74))	('occur', 'Reg', (25, 30))
84529	27501725	The Wnt/beta-catenin pathway is a crucial regulator of the self-renewal property of normal amplifying adult stem cells, and its deregulation plays a critical role in abnormal cell proliferation and oral oncogenesis.	('abnormal cell proliferation', 'Phenotype', 'HP:0031377', (166, 193))	('beta-catenin', 'Gene', (8, 20))	('deregulation', 'Var', (128, 140))	('abnormal cell proliferation', 'CPA', (166, 193))	('beta-catenin', 'Gene', '1499', (8, 20))	('oral oncogenesis', 'CPA', (198, 214))
84537	27501725	Silencing TERT, instead, leads to the inhibition of Wnt/beta-catenin signaling and the suppression of EMT in oral cancer.	('oral cancer', 'Disease', (109, 120))	('suppression', 'NegReg', (87, 98))	('beta-catenin', 'Gene', (56, 68))	('TERT', 'Gene', (10, 14))	('beta-catenin', 'Gene', '1499', (56, 68))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('TERT', 'Gene', '7015', (10, 14))	('inhibition', 'NegReg', (38, 48))	('EMT', 'CPA', (102, 105))	('Silencing', 'Var', (0, 9))	('oral cancer', 'Disease', 'MESH:D009062', (109, 120))
84546	27501725	HPV-driven oropharyngeal SCCs show a higher propensity for lymph node metastasis with respect to their HPV-negative counterparts and are not uncommonly characterized by an atypical pattern of distant metastases.	('SCC', 'Gene', (25, 28))	('HPV', 'Species', '10566', (0, 3))	('SCC', 'Phenotype', 'HP:0002860', (25, 28))	('metastases', 'Disease', (200, 210))	('HPV', 'Species', '10566', (103, 106))	('metastases', 'Disease', 'MESH:D009362', (200, 210))	('HPV-driven', 'Var', (0, 10))	('SCC', 'Gene', '6317', (25, 28))	('lymph node metastasis', 'CPA', (59, 80))
84556	27501725	When 266 patients with oral premalignant lesions or oral SCCs were compared with 394 age- and sex-matched controls, shortened telomeres were found to be an independent risk factor in PBMCs, although the risk was considerably higher in tobacco and alcohol consumers.	('tobacco', 'Species', '4097', (235, 242))	('patients', 'Species', '9606', (9, 17))	('SCC', 'Phenotype', 'HP:0002860', (57, 60))	('SCC', 'Gene', '6317', (57, 60))	('oral premalignant lesions', 'Disease', 'MESH:D020820', (23, 48))	('PBMCs', 'Disease', (183, 188))	('alcohol', 'Chemical', 'MESH:D000438', (247, 254))	('shortened telomeres', 'Phenotype', 'HP:0031413', (116, 135))	('shortened', 'Var', (116, 125))	('SCC', 'Gene', (57, 60))	('oral premalignant lesions', 'Disease', (23, 48))
84557	27501725	Short telomeres in PBMC may constitute an additional biomarker of oral habits and thus help to identify subjects at high risk of HNSCC.	('Short telomeres', 'Phenotype', 'HP:0031413', (0, 15))	('Short telomeres', 'Var', (0, 15))	('oral habits', 'Disease', (66, 77))	('HNSCC', 'Phenotype', 'HP:0012288', (129, 134))	('SCC', 'Gene', (131, 134))	('SCC', 'Phenotype', 'HP:0002860', (131, 134))	('SCC', 'Gene', '6317', (131, 134))	('PBMC', 'Gene', (19, 23))
84558	27501725	In another study examining the association between telomere length in PBMCs and the risk of HR alpha-HPV-associated oropharyngeal SCC, the authors reported that short telomeres appeared to synergize with HPV type 16, increasing the risk of oropharyngeal SCC, particularly in the younger never smoker/drinker subgroup.	('SCC', 'Gene', (130, 133))	('SCC', 'Phenotype', 'HP:0002860', (130, 133))	('SCC', 'Gene', (254, 257))	('short telomeres', 'Var', (161, 176))	('SCC', 'Gene', '6317', (130, 133))	('SCC', 'Phenotype', 'HP:0002860', (254, 257))	('SCC', 'Gene', '6317', (254, 257))	('increasing', 'PosReg', (217, 227))	('HPV', 'Species', '10566', (204, 207))	('HPV', 'Species', '10566', (101, 104))	('short telomeres', 'Phenotype', 'HP:0031413', (161, 176))
84577	24292195	We also find new genes with recurrent amplifications (for example, DROSHA, YAP1) or homozygous deletions (for example, DDX3X) in OSCC-GB.	('DROSHA', 'Gene', (67, 73))	('amplifications', 'Var', (38, 52))	('YAP1', 'Gene', '10413', (75, 79))	('DDX3X', 'Gene', (119, 124))	('OSCC-GB', 'Chemical', '-', (129, 136))	('OSCC-GB', 'Gene', (129, 136))	('DDX3X', 'Gene', '1654', (119, 124))	('DROSHA', 'Gene', '29102', (67, 73))	('YAP1', 'Gene', (75, 79))
84580	24292195	Our work reveals molecular subtypes with distinctive mutational profiles such as patients predominantly harbouring mutations in CASP8 with or without mutations in FAT1.	('FAT1', 'Gene', '2195', (163, 167))	('mutations', 'Var', (115, 124))	('FAT1', 'Gene', (163, 167))	('patients', 'Species', '9606', (81, 89))	('CASP8', 'Gene', (128, 133))	('CASP8', 'Gene', '841', (128, 133))
84593	24292195	A recent integrative genomic analysis of OSCC additionally discovered frequent mutation of CASP8 defining a new molecular subtype, and identified four major driver pathways:mitogenic signalling, Notch, cell cycle and TP53.	('TP53', 'Gene', '7157', (217, 221))	('CASP8', 'Gene', (91, 96))	('mitogenic signalling', 'MPA', (173, 193))	('CASP8', 'Gene', '841', (91, 96))	('cell cycle', 'CPA', (202, 212))	('TP53', 'Gene', (217, 221))	('mutation', 'Var', (79, 87))
84606	24292195	Infection with HPV and Herpes Simplex Virus (HSV) was detected in 26% (all infected with high-risk subtypes; 22% with subtype 16, 2% with subtype 18 and 2% with mixed subtypes) and 2% of patients, respectively.	('subtype 16', 'Var', (118, 128))	('patients', 'Species', '9606', (187, 195))	('mixed subtypes', 'Species', '384619', (161, 175))	('detected', 'Reg', (54, 62))	('Herpes Simplex', 'Phenotype', 'HP:0012302', (23, 37))	('HPV', 'Species', '10566', (15, 18))	('HPV', 'Gene', (15, 18))	('Herpes', 'Disease', (23, 29))
84616	24292195	All TP53 mutations detected by massively parallel or Sanger sequencing were catalogued.	('mutations', 'Var', (9, 18))	('TP53', 'Gene', '7157', (4, 8))	('TP53', 'Gene', (4, 8))
84621	24292195	The mean number of variants (range: 1-39) in non-coding RNA genes per patient was 7.56+-5.99 (Supplementary Data 1 and Supplementary Table S4).	('men', 'Species', '9606', (100, 103))	('men', 'Species', '9606', (125, 128))	('patient', 'Species', '9606', (70, 77))	('RNA genes', 'Gene', (56, 65))	('variants', 'Var', (19, 27))
84623	24292195	Contrary to an earlier report on HNSCC, in the OSCC-GB patients we did not find a statistically significant difference (Z-test P-value for equality of proportions >0.05) in the proportions of different types of mutations in patients with or without HPV infection, and found that a high proportion (61%) of HPV-associated tumours carried TP53 mutations (Fig.	('HPV infection', 'Disease', (249, 262))	('TP53', 'Gene', '7157', (337, 341))	('tumours', 'Disease', 'MESH:D009369', (321, 328))	('tumours', 'Disease', (321, 328))	('HNSCC', 'Phenotype', 'HP:0012288', (33, 38))	('HPV', 'Species', '10566', (306, 309))	('TP53', 'Gene', (337, 341))	('HPV infection', 'Disease', 'MESH:D030361', (249, 262))	('OSCC-GB', 'Chemical', '-', (47, 54))	('mutations', 'Var', (342, 351))	('carried', 'Reg', (329, 336))	('patients', 'Species', '9606', (224, 232))	('patients', 'Species', '9606', (55, 63))	('tumour', 'Phenotype', 'HP:0002664', (321, 327))	('HPV', 'Species', '10566', (249, 252))	('tumours', 'Phenotype', 'HP:0002664', (321, 328))
84626	24292195	The C:G>A:T transversion, a preponderance of which is a feature of mutations induced by tobacco carcinogens, was found in high proportion (61%) in the OSCC-GB tumours; much higher than observed (15-26%) in various cancers not associated with tobacco, and also in the general population (31%) (Supplementary Fig.	('OSCC-GB tumours', 'Disease', 'MESH:D009369', (151, 166))	('C:G>A:T transversion', 'Var', (4, 24))	('cancers', 'Phenotype', 'HP:0002664', (214, 221))	('men', 'Species', '9606', (299, 302))	('tobacco', 'Species', '4097', (88, 95))	('cancers', 'Disease', (214, 221))	('cancers', 'Disease', 'MESH:D009369', (214, 221))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('tumour', 'Phenotype', 'HP:0002664', (159, 165))	('tumours', 'Phenotype', 'HP:0002664', (159, 166))	('OSCC-GB tumours', 'Disease', (151, 166))	('tobacco', 'Species', '4097', (242, 249))	('higher', 'PosReg', (173, 179))
84629	24292195	There was an over-representation of C>T and C>G mutations at 5'-TCX (Z-test P-values for equality of proportions ranged between 4.1 x 10-130 and 1.4 x 10-14), similar to findings on breast cancer and C>T somatic mutations were predominant at non-CpG sites (Fig.	('C>G mutations', 'Var', (44, 57))	('breast cancer', 'Disease', 'MESH:D001943', (182, 195))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('TCX', 'Chemical', '-', (64, 67))	('breast cancer', 'Disease', (182, 195))	('breast cancer', 'Phenotype', 'HP:0003002', (182, 195))	('C>T', 'Var', (36, 39))
84632	24292195	1), all tobacco users, who harboured large numbers of mutations (315, 391 and 939, respectively), had relatively smaller proportions of C:G>A:T transversion, compared with the C:G>G:C transversion, which was the highest proportion in all the three patients (Fig.	('C:G>A:T transversion', 'Var', (136, 156))	('patients', 'Species', '9606', (248, 256))	('smaller', 'NegReg', (113, 120))	('tobacco', 'Species', '4097', (8, 15))
84633	24292195	C>G transversion is caused by 8-oxoguanine, a DNA lesion formed by exposures to tobacco and reactive oxygen species.	('8-oxoguanine', 'Chemical', 'MESH:C024829', (30, 42))	('8-oxoguanine', 'Var', (30, 42))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (92, 115))	('caused by', 'Reg', (20, 29))	('tobacco', 'Species', '4097', (80, 87))
84634	24292195	Over activity of APOBEC family of genes has been reported to result in C>T and C>G mutations at TpCpX trinucleotides in diverse human cancers.	('result', 'Reg', (61, 67))	('cancers', 'Disease', 'MESH:D009369', (134, 141))	('C>G mutations', 'Var', (79, 92))	('cancers', 'Phenotype', 'HP:0002664', (134, 141))	('Over activity', 'PosReg', (0, 13))	('cancers', 'Disease', (134, 141))	('human', 'Species', '9606', (128, 133))	('TpCpX', 'Gene', (96, 101))	('C>T', 'Var', (71, 74))	('APOBEC family of genes', 'Gene', (17, 39))	('trinucleotides', 'Chemical', '-', (102, 116))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
84636	24292195	Among these 45 genes, those that were mutated at a significantly higher than the background rate (ascertained using data on only SNVs and indels, but not CNVs, in the gene), after appropriately adjusting for their lengths and base compositions, using the MuSiC algorithm, and independently verified by the MutSigCV algorithm, were considered as genes associated with OSCC-GB.	('higher', 'PosReg', (65, 71))	('OSCC-GB', 'Chemical', '-', (367, 374))	('mutated', 'Var', (38, 45))
84639	24292195	Mutations, many truncating, in FAT1 occurred at a higher frequency than reported earlier (12%).	('Mutations', 'Var', (0, 9))	('FAT1', 'Gene', (31, 35))	('truncating', 'Var', (16, 26))	('FAT1', 'Gene', '2195', (31, 35))
84640	24292195	Two other members of the FAT family, FAT3 and FAT4, were also mutated in 12 and 8% of OSCC-GB patients, respectively.	('OSCC-GB', 'Chemical', '-', (86, 93))	('patients', 'Species', '9606', (94, 102))	('FAT4', 'Gene', '79633', (46, 50))	('FAT4', 'Gene', (46, 50))	('FAT3', 'Gene', '120114', (37, 41))	('FAT3', 'Gene', (37, 41))	('OSCC-GB', 'Disease', (86, 93))	('mutated', 'Var', (62, 69))
84641	24292195	We have found five new genes associated with OSCC-GB:USP9X, MLL4, ARID2, UNC13C and TRPM3:that are frequently altered (10-22% of patients) at a rate significantly higher than the background rate, ascertained by GenomeMuSiC, with two of the three FDR-corrected P-values of Z-test for testing equality of proportions being <0.2 and independently verified as statistically significant (Z-test P-value for equality of proportions <0.05) by MutSigCV (Supplementary Table S5).	('OSCC-GB', 'Chemical', '-', (45, 52))	('UNC13C', 'Gene', (73, 79))	('OSCC-GB', 'Gene', (45, 52))	('MLL4', 'Gene', (60, 64))	('USP9X', 'Gene', '8239', (53, 58))	('ARID2', 'Gene', (66, 71))	('ARID2', 'Gene', '196528', (66, 71))	('altered', 'Var', (110, 117))	('patients', 'Species', '9606', (129, 137))	('TRPM3', 'Gene', '80036', (84, 89))	('UNC13C', 'Gene', '440279', (73, 79))	('higher', 'PosReg', (163, 169))	('USP9X', 'Gene', (53, 58))	('men', 'Species', '9606', (452, 455))	('MLL4', 'Gene', '8085', (60, 64))	('TRPM3', 'Gene', (84, 89))
84643	24292195	We have found copy number loss and truncating mutations in USP9X (Fig.	('USP9X', 'Gene', (59, 64))	('number loss', 'Disease', 'MESH:D016388', (19, 30))	('USP9X', 'Gene', '8239', (59, 64))	('number loss', 'Disease', (19, 30))	('truncating mutations', 'Var', (35, 55))
84645	24292195	Two chromatin remodelling genes, MLL4 and ARID2 were also significantly mutated (Fig.	('ARID2', 'Gene', (42, 47))	('mutated', 'Var', (72, 79))	('chromatin remodelling genes', 'Gene', (4, 31))	('ARID2', 'Gene', '196528', (42, 47))	('MLL4', 'Gene', '8085', (33, 37))	('MLL4', 'Gene', (33, 37))
84650	24292195	Two or more mutations in the same patient were observed (Supplementary Table S6) in: TP53 (4/31; that is, 4 patients harboured >=2 mutations in TP53 among the 31 patients who harboured mutations in this gene), FAT1 (3/20), MLL4 (2/8) and NOTCH1 (1/8).	('NOTCH1', 'Gene', (238, 244))	('patient', 'Species', '9606', (34, 41))	('patients', 'Species', '9606', (108, 116))	('NOTCH1', 'Gene', '4851', (238, 244))	('FAT1', 'Gene', (210, 214))	('TP53', 'Gene', (85, 89))	('TP53', 'Gene', '7157', (144, 148))	('harboured', 'Reg', (117, 126))	('patients', 'Species', '9606', (162, 170))	('men', 'Species', '9606', (63, 66))	('FAT1', 'Gene', '2195', (210, 214))	('patient', 'Species', '9606', (108, 115))	('TP53', 'Gene', '7157', (85, 89))	('mutations', 'Var', (131, 140))	('TP53', 'Gene', (144, 148))	('MLL4', 'Gene', '8085', (223, 227))	('mutations', 'Var', (12, 21))	('MLL4', 'Gene', (223, 227))	('mutations', 'Var', (185, 194))	('patient', 'Species', '9606', (162, 169))
84651	24292195	Observed mutations in only TP53 were clustered; the clustering was in the DNA-binding domain (Supplementary Fig.	('TP53', 'Gene', (27, 31))	('mutations', 'Var', (9, 18))	('men', 'Species', '9606', (100, 103))	('TP53', 'Gene', '7157', (27, 31))
84655	24292195	PCLO, a gene involved in calcium signalling, was mutated in 14% of OSCC-GB patients; this frequency is similar (12%) to a previous report on HNSCC, although a recent study has claimed that PCLO is not a cancer gene.	('PCLO', 'Gene', '27445', (189, 193))	('mutated', 'Var', (49, 56))	('PCLO', 'Gene', (189, 193))	('HNSCC', 'Phenotype', 'HP:0012288', (141, 146))	('OSCC-GB', 'Disease', (67, 74))	('patients', 'Species', '9606', (75, 83))	('cancer', 'Disease', (203, 209))	('OSCC-GB', 'Chemical', '-', (67, 74))	('cancer', 'Disease', 'MESH:D009369', (203, 209))	('PCLO', 'Gene', '27445', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('calcium', 'Chemical', 'MESH:D002118', (25, 32))	('PCLO', 'Gene', (0, 4))
84657	24292195	The well-known tumour suppressor, MLL2, was mutated in 10% of the OSCC-GB patients.	('OSCC-GB', 'Chemical', '-', (66, 73))	('tumour', 'Disease', 'MESH:D009369', (15, 21))	('tumour', 'Phenotype', 'HP:0002664', (15, 21))	('MLL2', 'Gene', '8085', (34, 38))	('tumour', 'Disease', (15, 21))	('patients', 'Species', '9606', (74, 82))	('mutated', 'Var', (44, 51))	('MLL2', 'Gene', (34, 38))	('OSCC-GB', 'Disease', (66, 73))
84658	24292195	There is also a long tail of mutations in known cancer genes that were mutated in <10% of OSCC-GB patients (Supplementary Fig.	('OSCC-GB', 'Disease', (90, 97))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('OSCC-GB', 'Chemical', '-', (90, 97))	('mutations', 'Var', (29, 38))	('men', 'Species', '9606', (114, 117))	('patients', 'Species', '9606', (98, 106))	('long tail', 'Phenotype', 'HP:0002831', (16, 25))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))
84659	24292195	Targeted massively parallel resequencing of the 10 significantly mutated genes (SMGs) in 60 independent OSCC-GB tumour/normal pairs showed that all the genes were mutated in 5-72% of the tumours and that FAT1 was significantly (Z-test P-value for equality of proportions=0.01) less frequently mutated (18% of patients in confirmation set versus 40% in the discovery set).	('tumours', 'Disease', 'MESH:D009369', (187, 194))	('tumour', 'Disease', (187, 193))	('tumours', 'Phenotype', 'HP:0002664', (187, 194))	('tumour', 'Disease', 'MESH:D009369', (112, 118))	('FAT1', 'Gene', '2195', (204, 208))	('mutated', 'Var', (163, 170))	('OSCC-GB', 'Chemical', '-', (104, 111))	('tumour', 'Disease', (112, 118))	('tumours', 'Disease', (187, 194))	('FAT1', 'Gene', (204, 208))	('tumour', 'Phenotype', 'HP:0002664', (187, 193))	('tumour', 'Phenotype', 'HP:0002664', (112, 118))	('patients', 'Species', '9606', (309, 317))	('tumour', 'Disease', 'MESH:D009369', (187, 193))
84660	24292195	This lower frequency was partially compensated by a higher (72 versus 62%; Z-test P-value for equality of proportions=0.28) frequency of mutated TP53.	('mutated', 'Var', (137, 144))	('TP53', 'Gene', (145, 149))	('TP53', 'Gene', '7157', (145, 149))
84661	24292195	In the discovery and confirmation sets, the frequencies with which the five new OSCC-GB genes were mutated were similar (Supplementary Table S8).	('OSCC-GB', 'Chemical', '-', (80, 87))	('OSCC-GB', 'Gene', (80, 87))	('mutated', 'Var', (99, 106))	('men', 'Species', '9606', (127, 130))
84663	24292195	CNVs were also identified in genes with recurrent mutations (SNVs and/or indels) in OSCC-GB patients.	('indels', 'Var', (73, 79))	('OSCC-GB', 'Chemical', '-', (84, 91))	('OSCC-GB', 'Disease', (84, 91))	('patients', 'Species', '9606', (92, 100))
84667	24292195	Both NOTCH1 and CDKN2A were frequently mutated in OSCC-GB.	('NOTCH1', 'Gene', '4851', (5, 11))	('CDKN2A', 'Gene', (16, 22))	('CDKN2A', 'Gene', '1029', (16, 22))	('NOTCH1', 'Gene', (5, 11))	('mutated', 'Var', (39, 46))	('OSCC-GB', 'Chemical', '-', (50, 57))
84669	24292195	Deletions in CSMD1, a putative tumour suppressor implicated in diverse cancers including HNSCC, were found in a substantial fraction (26%) of OSCC-GB patients.	('found', 'Reg', (101, 106))	('OSCC-GB', 'Disease', (142, 149))	('cancers', 'Disease', 'MESH:D009369', (71, 78))	('cancers', 'Phenotype', 'HP:0002664', (71, 78))	('cancers', 'Disease', (71, 78))	('OSCC-GB', 'Chemical', '-', (142, 149))	('tumour', 'Phenotype', 'HP:0002664', (31, 37))	('tumour', 'Disease', 'MESH:D009369', (31, 37))	('patients', 'Species', '9606', (150, 158))	('CSMD1', 'Gene', '64478', (13, 18))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('HNSCC', 'Disease', (89, 94))	('CSMD1', 'Gene', (13, 18))	('HNSCC', 'Phenotype', 'HP:0012288', (89, 94))	('tumour', 'Disease', (31, 37))	('Deletions', 'Var', (0, 9))
84670	24292195	Alterations in genes that were frequently and significantly mutated among OSCC-GB patients were considered as the drivers of pathways for initiation and progression.	('patients', 'Species', '9606', (82, 90))	('OSCC-GB', 'Gene', (74, 81))	('Alterations', 'Var', (0, 11))	('OSCC-GB', 'Chemical', '-', (74, 81))
84671	24292195	SNV and Indel data analysed with PathScan module in GenomeMuSiC identified 16 statistically significant KEGG pathways based on enrichment of mutations (Table 1).	('men', 'Species', '9606', (133, 136))	('KEGG pathways', 'Pathway', (104, 117))	('mutations', 'Var', (141, 150))
84682	24292195	In addition to CASP8, 21 (60%) of these 35 patients also possessed mutations (predominantly truncating) in FAT1 and/or NOTCH1 (Fig.	('FAT1', 'Gene', '2195', (107, 111))	('FAT1', 'Gene', (107, 111))	('patients', 'Species', '9606', (43, 51))	('NOTCH1', 'Gene', '4851', (119, 125))	('mutations', 'Var', (67, 76))	('NOTCH1', 'Gene', (119, 125))	('CASP8', 'Gene', (15, 20))	('CASP8', 'Gene', '841', (15, 20))
84683	24292195	TP53 is mutated in all of the 43 patients who belong to the second cluster (C2), predominantly with missense and in-frame indels (67.4%).	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('patients', 'Species', '9606', (33, 41))	('missense', 'Var', (100, 108))	('in-frame indels', 'Var', (113, 128))
84684	24292195	The third cluster (C3) comprising 29 patients carry alterations in a heterogeneous set of genes, although a high proportion (55%) of them carries mutations in MLL4 and USP9X.	('heterogeneous set of genes', 'MPA', (69, 95))	('mutations', 'Var', (146, 155))	('alterations', 'Reg', (52, 63))	('patients', 'Species', '9606', (37, 45))	('USP9X', 'Gene', (168, 173))	('USP9X', 'Gene', '8239', (168, 173))	('MLL4', 'Gene', '8085', (159, 163))	('MLL4', 'Gene', (159, 163))
84687	24292195	For patients belonging to the subclusters C1.2 (with mutations in CASP8, NOTCH1 and FAT1), C1.4 (with mutations in CASP8, NOTCH1 and ARID2) and C3.2 (with mutations in MLL4 and other genes), each comprising six patients (totalling 16% of all patients), the mean DFS duration was significantly longer than the overall mean (t-test P-values for equality of means were, respectively, 0.01, 0.04 and 0.03).	('CASP8', 'Gene', (66, 71))	('FAT1', 'Gene', (84, 88))	('C3.2', 'Gene', (144, 148))	('DFS', 'MPA', (262, 265))	('NOTCH1', 'Gene', '4851', (73, 79))	('patients', 'Species', '9606', (242, 250))	('patients', 'Species', '9606', (211, 219))	('ARID2', 'Gene', '196528', (133, 138))	('mutations', 'Var', (102, 111))	('patients', 'Species', '9606', (4, 12))	('C3.2', 'Gene', '51192', (144, 148))	('FAT1', 'Gene', '2195', (84, 88))	('NOTCH1', 'Gene', (122, 128))	('mutations', 'Var', (53, 62))	('ARID2', 'Gene', (133, 138))	('CASP8', 'Gene', '841', (115, 120))	('NOTCH1', 'Gene', '4851', (122, 128))	('MLL4', 'Gene', '8085', (168, 172))	('MLL4', 'Gene', (168, 172))	('CASP8', 'Gene', '841', (66, 71))	('CASP8', 'Gene', (115, 120))	('longer', 'PosReg', (293, 299))	('NOTCH1', 'Gene', (73, 79))
84693	24292195	Patients with mutations in MLL4 (n=11) had a significantly (t-test P-value for equality of means=0.047) elevated duration of DFS (20.4+-3.1 months) compared with those (n=99) who did not possess mutations (13.5+-0.9 months).	('MLL4', 'Gene', '8085', (27, 31))	('MLL4', 'Gene', (27, 31))	('Patients', 'Species', '9606', (0, 8))	('mutations', 'Var', (14, 23))	('elevated', 'PosReg', (104, 112))
84694	24292195	Patients who harboured mutations in MLL4 did not exhibit regional node involvement (8 of 11 patients) compared with the pooled set of patients (P-value of Fisher's exact two-tailed test=0.12).	('patients', 'Species', '9606', (92, 100))	('patients', 'Species', '9606', (134, 142))	('men', 'Species', '9606', (78, 81))	('mutations', 'Var', (23, 32))	('Patients', 'Species', '9606', (0, 8))	('MLL4', 'Gene', '8085', (36, 40))	('MLL4', 'Gene', (36, 40))	('regional node involvement', 'CPA', (57, 82))
84695	24292195	The high-confidence catalogue of somatic mutations created by massively parallel sequencing on two orthogonal platforms of the exomes of 50 Indian oral squamous cell carcinoma patients with involvement of only the gingivo-buccal complex has revealed many specific features that are different from earlier exome-sequencing studies on HNSCC.	('mutations', 'Var', (41, 50))	('patients', 'Species', '9606', (176, 184))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (147, 175))	('carcinoma', 'Phenotype', 'HP:0030731', (166, 175))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (152, 175))	('men', 'Species', '9606', (197, 200))	('oral squamous cell carcinoma', 'Disease', (147, 175))	('HNSCC', 'Phenotype', 'HP:0012288', (333, 338))
84697	24292195	TP53 mutations occurred on both HPV-positive and -negative backgrounds in nearly equal proportions (~65%; n=110), unlike in the anatomically less homogeneous HNSCC.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))	('HPV', 'Species', '10566', (32, 35))	('HNSCC', 'Phenotype', 'HP:0012288', (158, 163))
84700	24292195	There was also an over-representation of C>T and C>G mutations at 5'-TCX (P-values ranging from 4.1 x 10-130 to 1.4 x 10-14), similar to findings in breast cancer.	('C>T', 'Var', (41, 44))	('C>G mutations', 'Var', (49, 62))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('breast cancer', 'Disease', 'MESH:D001943', (149, 162))	('breast cancer', 'Phenotype', 'HP:0003002', (149, 162))	('TCX', 'Chemical', '-', (69, 72))	('breast cancer', 'Disease', (149, 162))
84701	24292195	Tobacco users with high numbers of mutations had a relatively smaller proportion of C:G>A:T transversion, compared with the C:G>G:C transversion.	('Tobacco', 'Species', '4097', (0, 7))	('C:G>A:T transversion', 'Var', (84, 104))	('mutations', 'Var', (35, 44))
84702	24292195	The C>G transversion is possibly caused by 8-oxoguanine lesions in the DNA formed by tobacco and reactive oxygen species and/or over activity of APOBEC family of cytidine deaminases together with uracil-DNA glycosylase that generates both C>T transition and C>G transversion at TpCpX trinuclotides.	('8-oxoguanine', 'Chemical', 'MESH:C024829', (43, 55))	('C>G transversion', 'Disease', (4, 20))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (97, 120))	('tobacco', 'Species', '4097', (85, 92))	('caused by', 'Reg', (33, 42))	('TpCpX trinuclotides', 'Chemical', '-', (278, 297))	('C>T', 'Var', (239, 242))
84703	24292195	As anatomically HNSCC is a superset of OSCC-GB, many HNSCC driver mutations were also identified and confirmed as OSCC-GB drivers.	('mutations', 'Var', (66, 75))	('HNSCC', 'Gene', (53, 58))	('OSCC-GB', 'Chemical', '-', (114, 121))	('HNSCC', 'Phenotype', 'HP:0012288', (53, 58))	('OSCC-GB', 'Chemical', '-', (39, 46))	('HNSCC', 'Phenotype', 'HP:0012288', (16, 21))
84706	24292195	Mutations in FAT1 promote aberrant Wnt activation that leads to tumorigenesis in various cancers.	('tumorigenesis', 'CPA', (64, 77))	('cancers', 'Phenotype', 'HP:0002664', (89, 96))	('Wnt activation', 'CPA', (35, 49))	('leads to', 'Reg', (55, 63))	('cancers', 'Disease', 'MESH:D009369', (89, 96))	('FAT1', 'Gene', '2195', (13, 17))	('Mutations', 'Var', (0, 9))	('cancers', 'Disease', (89, 96))	('FAT1', 'Gene', (13, 17))	('promote', 'PosReg', (18, 25))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
84707	24292195	FAT3 and FAT4 were also frequently mutated in OSCC-GB.	('mutated', 'Var', (35, 42))	('FAT3', 'Gene', (0, 4))	('FAT4', 'Gene', (9, 13))	('FAT4', 'Gene', '79633', (9, 13))	('OSCC-GB', 'Chemical', '-', (46, 53))	('OSCC-GB', 'Gene', (46, 53))	('FAT3', 'Gene', '120114', (0, 4))
84709	24292195	FAT3, whose precise function is unclear, was not reported to be frequently mutated in HNSCC, but was mutated in 12% of OSCC-GB patients.	('HNSCC', 'Disease', (86, 91))	('HNSCC', 'Phenotype', 'HP:0012288', (86, 91))	('FAT3', 'Gene', (0, 4))	('mutated', 'Var', (101, 108))	('OSCC-GB', 'Disease', (119, 126))	('patients', 'Species', '9606', (127, 135))	('OSCC-GB', 'Chemical', '-', (119, 126))	('FAT3', 'Gene', '120114', (0, 4))
84711	24292195	An additional member of the MLL family, MLL2, was also frequently mutated in 10% of OSCC-GB patients, but the estimated mutation rate in this gene was not significantly higher than the background rate.	('mutated', 'Var', (66, 73))	('MLL2', 'Gene', (40, 44))	('OSCC-GB', 'Disease', (84, 91))	('patients', 'Species', '9606', (92, 100))	('OSCC-GB', 'Chemical', '-', (84, 91))	('MLL2', 'Gene', '8085', (40, 44))
84715	24292195	Loss of USP9X therefore prevents deubiquitination of SMAD4, enhancing tumour progression.	('enhancing', 'PosReg', (60, 69))	('USP9X', 'Gene', '8239', (8, 13))	('deubiquitination', 'MPA', (33, 49))	('tumour', 'Phenotype', 'HP:0002664', (70, 76))	('SMAD4', 'Protein', (53, 58))	('prevents', 'NegReg', (24, 32))	('tumour', 'Disease', 'MESH:D009369', (70, 76))	('USP9X', 'Gene', (8, 13))	('Loss', 'Var', (0, 4))	('tumour', 'Disease', (70, 76))
84723	24292195	It is intriguing that these genes should be somatically mutated in OSCC-GB patients, although we note that a fair proportion (26%) of patients harbour germline mutations also in UNC13C, but not in TRPM3.	('UNC13C', 'Gene', '440279', (178, 184))	('TRPM3', 'Gene', (197, 202))	('mutations', 'Var', (160, 169))	('OSCC-GB', 'Disease', (67, 74))	('patients', 'Species', '9606', (75, 83))	('patients', 'Species', '9606', (134, 142))	('TRPM3', 'Gene', '80036', (197, 202))	('UNC13C', 'Gene', (178, 184))	('OSCC-GB', 'Chemical', '-', (67, 74))
84725	24292195	Investigations on possible functional impacts of the non-synonymous mutations found in the 10 genes that are frequently and significantly mutated in OSCC-GB, performed using bioinformatics tools PROVEAN and SIFT, revealed that at least 91% of the mutations are deleterious or damaging (Supplementary Table S10).	('OSCC-GB', 'Gene', (149, 156))	('men', 'Species', '9606', (292, 295))	('S10', 'Gene', '3897', (306, 309))	('OSCC-GB', 'Chemical', '-', (149, 156))	('SIFT', 'Disease', (207, 211))	('SIFT', 'Disease', 'None', (207, 211))	('S10', 'Gene', (306, 309))	('mutations', 'Var', (247, 256))	('deleterious', 'Reg', (261, 272))
84727	24292195	One subgroup harbours mutations in CASP8, with mutations in FAT1 and/or NOTCH1.	('CASP8', 'Gene', '841', (35, 40))	('FAT1', 'Gene', '2195', (60, 64))	('FAT1', 'Gene', (60, 64))	('mutations', 'Var', (47, 56))	('CASP8', 'Gene', (35, 40))	('mutations', 'Var', (22, 31))	('NOTCH1', 'Gene', '4851', (72, 78))	('NOTCH1', 'Gene', (72, 78))
84728	24292195	The subgroup with CASP8 mutations was recognized earlier.	('CASP8', 'Gene', '841', (18, 23))	('mutations', 'Var', (24, 33))	('CASP8', 'Gene', (18, 23))
84729	24292195	Another subgroup comprises patients with mutated TP53, while in patients belonging to the third subgroup predominantly MLL4 and USP9X among other genes are mutated.	('mutated', 'Var', (41, 48))	('MLL4', 'Gene', (119, 123))	('USP9X', 'Gene', '8239', (128, 133))	('TP53', 'Gene', '7157', (49, 53))	('patients', 'Species', '9606', (64, 72))	('TP53', 'Gene', (49, 53))	('patients', 'Species', '9606', (27, 35))	('USP9X', 'Gene', (128, 133))	('MLL4', 'Gene', '8085', (119, 123))
84730	24292195	Twelve percent of the patients harbour known oncogenic missense mutations in HRAS.	('HRAS', 'Gene', (77, 81))	('HRAS', 'Gene', '3265', (77, 81))	('patients', 'Species', '9606', (22, 30))	('missense mutations', 'Var', (55, 73))
84731	24292195	The HRAS mutations are known targets of therapeutic drugs of various cancers.	('cancers', 'Disease', 'MESH:D009369', (69, 76))	('cancers', 'Disease', (69, 76))	('HRAS', 'Gene', (4, 8))	('mutations', 'Var', (9, 18))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('cancers', 'Phenotype', 'HP:0002664', (69, 76))	('HRAS', 'Gene', '3265', (4, 8))
84732	24292195	Three subsets of patients:those with CASP8 and NOTCH1 mutations with additional mutations in FAT1 (C1.2) or ARID2 (C1.4) and those with mutated MLL4 (C3.2):comprising 16% of all patients have a significantly elevated (by 8 months) mean duration of disease-free survival compared with the pooled mean of all patients.	('FAT1', 'Gene', (93, 97))	('NOTCH1', 'Gene', (47, 53))	('ARID2', 'Gene', (108, 113))	('patients', 'Species', '9606', (307, 315))	('mutations', 'Var', (80, 89))	('NOTCH1', 'Gene', '4851', (47, 53))	('mutations', 'Var', (54, 63))	('patients', 'Species', '9606', (178, 186))	('C3.2', 'Gene', (150, 154))	('CASP8', 'Gene', '841', (37, 42))	('FAT1', 'Gene', '2195', (93, 97))	('elevated', 'PosReg', (208, 216))	('patients', 'Species', '9606', (17, 25))	('CASP8', 'Gene', (37, 42))	('C3.2', 'Gene', '51192', (150, 154))	('ARID2', 'Gene', '196528', (108, 113))	('MLL4', 'Gene', '8085', (144, 148))	('MLL4', 'Gene', (144, 148))	('disease-free survival', 'CPA', (248, 269))
84733	24292195	Because of limited numbers of tumours harbouring mutations in these genes (CASP8, MLL4, etc.	('tumours', 'Phenotype', 'HP:0002664', (30, 37))	('MLL4', 'Gene', (82, 86))	('CASP8', 'Gene', (75, 80))	('mutations', 'Var', (49, 58))	('tumours', 'Disease', 'MESH:D009369', (30, 37))	('tumours', 'Disease', (30, 37))	('tumour', 'Phenotype', 'HP:0002664', (30, 36))	('MLL4', 'Gene', '8085', (82, 86))	('CASP8', 'Gene', '841', (75, 80))
84740	24292195	The RNase III gene product of DROSHA, amplified in 12% of the OSCC-GB patients, is the core nuclease that initiates microRNA (miRNA) processing in the nucleus; alterations in the expression of Drosha are associated with cancer.	('patients', 'Species', '9606', (70, 78))	('Drosha', 'Gene', (193, 199))	('DROSHA', 'Gene', '29102', (30, 36))	('OSCC-GB', 'Chemical', '-', (62, 69))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('DROSHA', 'Gene', (30, 36))	('RNase III', 'Gene', '29102', (4, 13))	('RNase III', 'Gene', (4, 13))	('alterations', 'Var', (160, 171))	('Drosha', 'Gene', '29102', (193, 199))	('cancer', 'Disease', 'MESH:D009369', (220, 226))	('associated', 'Reg', (204, 214))	('cancer', 'Disease', (220, 226))
84747	24292195	The functional impacts of alterations in FGFRs 1 and 4 found in 10% of OSCC-GB patients require investigation in the context of the availability of inhibitor molecules for treatment.	('OSCC-GB', 'Disease', (71, 78))	('OSCC-GB', 'Chemical', '-', (71, 78))	('men', 'Species', '9606', (177, 180))	('alterations', 'Var', (26, 37))	('patients', 'Species', '9606', (79, 87))	('FGFRs 1', 'Gene', (41, 48))
84750	24292195	In the heterogeneous class of head and neck cancers, the mutational landscape indicates that mutations in several cancer genes are specific to driving the homogeneous subset of gingivo-buccal oral squamous cell carcinoma.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('gingivo-buccal oral squamous cell carcinoma', 'Disease', (177, 220))	('mutations', 'Var', (93, 102))	('cancers', 'Phenotype', 'HP:0002664', (44, 51))	('head and neck cancers', 'Phenotype', 'HP:0012288', (30, 51))	('gingivo-buccal oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (177, 220))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (197, 220))	('neck cancers', 'Disease', 'MESH:D006258', (39, 51))	('carcinoma', 'Phenotype', 'HP:0030731', (211, 220))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('neck cancers', 'Disease', (39, 51))	('head and neck cancer', 'Phenotype', 'HP:0012288', (30, 50))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('cancer', 'Disease', (114, 120))
84753	24292195	CNVs in genes that modulate cell cycle, apoptosis, microRNA processing, and so on, were significantly associated with gingivo-buccal oral cancer; many of these associations were not detected in earlier studies on head and neck cancer.	('associated', 'Reg', (102, 112))	('head and neck cancer', 'Phenotype', 'HP:0012288', (213, 233))	('gingivo-buccal oral cancer', 'Disease', (118, 144))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('neck cancer', 'Disease', 'MESH:D006258', (222, 233))	('CNVs', 'Var', (0, 4))	('neck cancer', 'Disease', (222, 233))	('gingivo-buccal oral cancer', 'Disease', 'MESH:D009062', (118, 144))
84756	24292195	The driver mutations in the newly identified genes associated with gingivo-buccal oral cancer require functional understanding for assessment of their translational potential.	('mutations', 'Var', (11, 20))	('gingivo-buccal oral cancer', 'Disease', (67, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('associated', 'Reg', (51, 61))	('men', 'Species', '9606', (137, 140))	('gingivo-buccal oral cancer', 'Disease', 'MESH:D009062', (67, 93))
84761	24292195	Samples with OD260/OD280 ratio>=1.8, OD260/OD230 ratio>=1.9, DNA concentration between 250 to 500 ng mul-1 and with no visible evidence of contamination with RNA or of DNA degradation were accepted for further genomic analysis, including exome capture and massively parallel DNA sequencing.	('OD260/OD230', 'Var', (37, 48))	('mul-1', 'Gene', '79594', (101, 106))	('mul-1', 'Gene', (101, 106))	('OD260/OD280 ratio', 'Var', (13, 30))
84769	24292195	Presence of HSV-1 and HSV-2 were discriminated by running a melting curve method after PCR, as HSV-2 amplicon-probe duplex has lower melting temperature (Tm) compared with the HSV-1 amplicon-probe duplex.	('HSV-1', 'Species', '10298', (176, 181))	('HSV-1 and HSV-2', 'Disease', 'MESH:C536395', (12, 27))	('melting temperature', 'MPA', (133, 152))	('HSV-2', 'Species', '10310', (22, 27))	('HSV-2', 'Species', '10310', (95, 100))	('lower', 'NegReg', (127, 132))	('HSV-1', 'Species', '10298', (12, 17))	('HSV-2', 'Var', (95, 100))
84813	24292195	Frequencies of the various nucleotide contexts in which C>X mutations were observed among OSCC-GB patients were statistically compared with the expected frequencies using a 2 x 16 contingency chi2 test.	('OSCC-GB', 'Chemical', '-', (90, 97))	('C>X mutations', 'Var', (56, 69))	('OSCC-GB', 'Disease', (90, 97))	('patients', 'Species', '9606', (98, 106))
84847	32391195	Positive Regulatory/Su(var)3-9, Enhancer-of-zeste and Trithorax Domain 2 (PRDM2) is a tumor suppressor gene (TSG) that regulates protein expression through the methylation of lysine 9 in histone H3.	('protein expression', 'MPA', (129, 147))	('histone', 'Protein', (187, 194))	('methylation of lysine 9', 'Var', (160, 183))	('tumor suppressor', 'Gene', '7248', (86, 102))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('regulates', 'Reg', (119, 128))	('PRDM2', 'Gene', '7799', (74, 79))	('lysine', 'Chemical', 'MESH:D008239', (175, 181))	('tumor suppressor', 'Gene', (86, 102))	('PRDM2', 'Gene', (74, 79))
84867	32391195	Using variants of the keywords "PRDM2" and "cancer", we performed a search from inception to July 2019 in PubMed, Cochrane Library, ProQuest, EBSCO and ScienceDirect.	('PRDM2', 'Gene', (32, 37))	('variants', 'Var', (6, 14))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('PRDM2', 'Gene', '7799', (32, 37))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
84970	32299344	FGF signaling dysregulation is associated with cancer tumorgenesis and progression.	('cancer tumorgenesis', 'Disease', 'MESH:D009369', (47, 66))	('dysregulation', 'Var', (14, 27))	('associated', 'Reg', (31, 41))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('cancer tumorgenesis', 'Disease', (47, 66))	('FGF', 'Protein', (0, 3))
84972	32299344	Altogether CNVs demonstrate the strongest impact on the multi-omics pathway score learned for FGF signaling (Table S8), and CNVs in the metalloproteinase-9 (MMP9) gene are most impactful.	('MMP9', 'Gene', '4318', (157, 161))	('CNVs', 'Var', (124, 128))	('MMP9', 'Gene', (157, 161))	('FGF', 'MPA', (94, 97))
84981	32299344	PathME cluster 3 (green PFS curve) showed the best prognosis of patients and an enrichment of somatic mutations in Isocitrate Dehydrogenase 1 (IDH1), which is a well-known positive prognostic factor in GBM.	('Isocitrate Dehydrogenase 1', 'Gene', (115, 141))	('GBM', 'Disease', (202, 205))	('patients', 'Species', '9606', (64, 72))	('Isocitrate Dehydrogenase 1', 'Gene', '3417', (115, 141))	('IDH1', 'Gene', (143, 147))	('mutations', 'Var', (102, 111))	('IDH1', 'Gene', '3417', (143, 147))
84989	32299344	The most influential data modalities on the multi-omics score for TGF-beta signaling are miRNAs and DNA methylation, and cg15001381 is the most contributing CpG.	('TGF-beta', 'Gene', (66, 74))	('cg15001381', 'Var', (121, 131))	('DNA methylation', 'MPA', (100, 115))	('TGF-beta', 'Gene', '7039', (66, 74))	('miRNAs', 'MPA', (89, 95))
84996	32299344	Moreover, SHAP values show that the Murine Double Minute 2 (MDM2) gene has a high impact on the androgen receptor activity pathway, which was found as a feature for cluster 4.	('androgen receptor', 'Gene', (96, 113))	('Murine Double Minute 2', 'Gene', (36, 58))	('Murine Double Minute 2', 'Gene', '17246', (36, 58))	('MDM2', 'Gene', (60, 64))	('gene', 'Var', (66, 70))	('impact', 'Reg', (82, 88))	('androgen receptor', 'Gene', '11835', (96, 113))
85002	32299344	Cluster 3 showed a strong enrichment of TP53 somatic mutations (p < 1E - 11), and cluster 4 of somatic mutations in Cadherin-1 (CDH1), GATA3 and Phosphatidylinositol4,5-bisphosphate 3-Kinase Catalytic subunit Alpha (PIK3CA).	('Cadherin-1', 'Gene', '999', (116, 126))	('mutations', 'Var', (103, 112))	('Phosphatidylinositol4,5-bisphosphate 3-Kinase Catalytic subunit Alpha', 'Gene', '5290', (145, 214))	('GATA3', 'Gene', (135, 140))	('CDH1', 'Gene', (128, 132))	('PIK3CA', 'Gene', (216, 222))	('CDH1', 'Gene', '999', (128, 132))	('GATA3', 'Gene', '2625', (135, 140))	('TP53', 'Gene', '7157', (40, 44))	('TP53', 'Gene', (40, 44))	('Cadherin-1', 'Gene', (116, 126))	('PIK3CA', 'Gene', '5290', (216, 222))
85010	32299344	According to SHAP a CNV in the Ribosomal Protein S6 Kinase B1 (RPS6KB1) has a high impact on the pathway score.	('pathway', 'Pathway', (97, 104))	('Ribosomal Protein S6 Kinase B1', 'Gene', (31, 61))	('CNV', 'Var', (20, 23))	('impact', 'Reg', (83, 89))	('RPS6KB1', 'Gene', (63, 70))	('Ribosomal Protein S6 Kinase B1', 'Gene', '6198', (31, 61))	('RPS6KB1', 'Gene', '6198', (63, 70))
85011	32299344	Indeed copy number alterations in this gene have been associated to prognosis of breast cancer patients.	('breast cancer', 'Disease', (81, 94))	('patients', 'Species', '9606', (95, 103))	('copy number alterations', 'Var', (7, 30))	('breast cancer', 'Phenotype', 'HP:0003002', (81, 94))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('associated', 'Reg', (54, 64))	('breast cancer', 'Disease', 'MESH:D001943', (81, 94))
85032	31360193	found that MALAT-1 was highly expressed in non-small cell lung cancer (NSCLC) with early metastasis, and high MALAT-1 expression predicted a poor prognosis of NSCLC.	('high', 'Var', (105, 109))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (43, 69))	('MALAT-1', 'Gene', (110, 117))	('NSCLC', 'Phenotype', 'HP:0030358', (71, 76))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (43, 69))	('NSCLC', 'Disease', (159, 164))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('lung cancer', 'Phenotype', 'HP:0100526', (58, 69))	('NSCLC', 'Disease', 'MESH:D002289', (159, 164))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (47, 69))	('non-small cell lung cancer', 'Disease', (43, 69))	('MALAT-1', 'Gene', '378938', (11, 18))	('MALAT-1', 'Gene', '378938', (110, 117))	('NSCLC', 'Disease', (71, 76))	('MALAT-1', 'Gene', (11, 18))	('NSCLC', 'Phenotype', 'HP:0030358', (159, 164))	('expression', 'MPA', (118, 128))	('NSCLC', 'Disease', 'MESH:D002289', (71, 76))
85036	31360193	Specifically, high UCA1 expression in bladder cancer cells increased their proliferation and resistance to therapies.	('UCA1', 'Gene', '652995', (19, 23))	('expression', 'MPA', (24, 34))	('bladder cancer', 'Phenotype', 'HP:0009725', (38, 52))	('UCA1', 'Gene', (19, 23))	('increased', 'PosReg', (59, 68))	('high', 'Var', (14, 18))	('bladder cancer', 'Disease', 'MESH:D001749', (38, 52))	('bladder cancer', 'Disease', (38, 52))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('proliferation', 'CPA', (75, 88))	('resistance to therapies', 'CPA', (93, 116))
85043	31360193	Similarly, UCA1 levels were upregulated in tongue squamous cell carcinoma, and its silencing reduced OSCC proliferation and metastasis by altering WNT/beta-catenin signaling.	('SCC', 'Phenotype', 'HP:0002860', (102, 105))	('SCC', 'Gene', '6317', (102, 105))	('tongue squamous cell carcinoma', 'Phenotype', 'HP:0030413', (43, 73))	('metastasis', 'CPA', (124, 134))	('beta-catenin', 'Gene', '1499', (151, 163))	('beta-catenin', 'Gene', (151, 163))	('reduced', 'NegReg', (93, 100))	('altering', 'Reg', (138, 146))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (50, 73))	('levels', 'MPA', (16, 22))	('tongue squamous cell carcinoma', 'Disease', (43, 73))	('UCA1', 'Gene', '652995', (11, 15))	('tongue squamous cell carcinoma', 'Disease', 'MESH:D002294', (43, 73))	('upregulated', 'PosReg', (28, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))	('SCC', 'Gene', (102, 105))	('UCA1', 'Gene', (11, 15))	('silencing', 'Var', (83, 92))
85045	31360193	In addition, lncRNA SRA variants are associated with breast cancer risk.	('breast cancer', 'Phenotype', 'HP:0003002', (53, 66))	('variants', 'Var', (24, 32))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('SRA', 'Gene', '10011', (20, 23))	('associated', 'Reg', (37, 47))	('breast cancer', 'Disease', 'MESH:D001943', (53, 66))	('SRA', 'Gene', (20, 23))	('breast cancer', 'Disease', (53, 66))
85047	31360193	Furthermore, the impact of MALAT-1 silencing on OSCC proliferation, apoptosis, colony formation capability and migration was examined in SCC4 cells.	('SCC', 'Phenotype', 'HP:0002860', (137, 140))	('SCC4', 'Gene', (137, 141))	('silencing', 'Var', (35, 44))	('SCC', 'Gene', (49, 52))	('SCC', 'Gene', '6317', (137, 140))	('SCC', 'Phenotype', 'HP:0002860', (49, 52))	('SCC', 'Gene', '6317', (49, 52))	('MALAT-1', 'Gene', '378938', (27, 34))	('SCC4', 'Gene', '23383', (137, 141))	('SCC', 'Gene', (137, 140))	('MALAT-1', 'Gene', (27, 34))
85089	31360193	After 48 h, both siRNA 6108 and 6960 significantly inhibited MALAT-1 gene expression as compared to the blank group (both p <= 0.016; Figure 2).	('expression', 'MPA', (74, 84))	('MALAT-1', 'Gene', '378938', (61, 68))	('MALAT-1', 'Gene', (61, 68))	('inhibited', 'NegReg', (51, 60))	('6960', 'Var', (32, 36))
85091	31360193	Although no differences were seen at 24 and 48 h, siRNA 6108 significantly inhibited SCC4 proliferation at 72 h as compared to the blank group (p = 0.004; Figure 3).	('SCC4', 'Gene', '23383', (85, 89))	('siRNA', 'Var', (50, 55))	('SCC4', 'Gene', (85, 89))	('inhibited', 'NegReg', (75, 84))	('SCC', 'Phenotype', 'HP:0002860', (85, 88))
85092	31360193	In addition, silencing MALAT-1 expression with either 6108 or 6960 siRNAs significantly increased the apoptosis rates of SCC4 cells as compared to the blank group (both p < 0.001; Figures 4 A and B).	('apoptosis rates', 'CPA', (102, 117))	('MALAT-1', 'Gene', '378938', (23, 30))	('6960 siRNAs', 'Var', (62, 73))	('SCC', 'Phenotype', 'HP:0002860', (121, 124))	('MALAT-1', 'Gene', (23, 30))	('increased', 'PosReg', (88, 97))	('SCC4', 'Gene', '23383', (121, 125))	('SCC4', 'Gene', (121, 125))	('6108', 'Var', (54, 58))	('silencing', 'Var', (13, 22))
85093	31360193	Thus, MALAT-1 expression alters SSC4 proliferation and apoptosis.	('expression', 'Var', (14, 24))	('SSC4 proliferation', 'CPA', (32, 50))	('alters', 'Reg', (25, 31))	('MALAT-1', 'Gene', '378938', (6, 13))	('MALAT-1', 'Gene', (6, 13))	('apoptosis', 'CPA', (55, 64))
85097	31360193	At 48 h following MALAT-1 silencing, siRNA 6108 significantly reduced cell migration as compared to the blank group (p = 0.004; Figure 6 B).	('MALAT-1', 'Gene', (18, 25))	('cell migration', 'CPA', (70, 84))	('silencing', 'Var', (26, 35))	('MALAT-1', 'Gene', '378938', (18, 25))	('reduced', 'NegReg', (62, 69))
85112	31360193	In addition to impacting cell migration, MALAT-1 silencing reduced SSC4 cell proliferation and increased their apoptosis.	('reduced', 'NegReg', (59, 66))	('silencing', 'Var', (49, 58))	('cell migration', 'CPA', (25, 39))	('SSC4 cell proliferation', 'CPA', (67, 90))	('MALAT-1', 'Gene', '378938', (41, 48))	('increased', 'PosReg', (95, 104))	('impacting', 'Reg', (15, 24))	('apoptosis', 'CPA', (111, 120))	('MALAT-1', 'Gene', (41, 48))
85126	31360193	Also, the specific regulatory mechanisms by which MALAT-1 silencing altered SCC4 cell growth and migration were not determined, and will be examined in further studies by our group.	('migration', 'CPA', (97, 106))	('MALAT-1', 'Gene', '378938', (50, 57))	('MALAT-1', 'Gene', (50, 57))	('SCC4', 'Gene', '23383', (76, 80))	('SCC', 'Phenotype', 'HP:0002860', (76, 79))	('SCC4', 'Gene', (76, 80))	('altered', 'Reg', (68, 75))	('silencing', 'Var', (58, 67))
85129	31360193	Silencing the MALAT-1 gene inhibited SCC4 cell proliferation, anchorage-independent growth and migration and promoted apoptosis.	('apoptosis', 'CPA', (118, 127))	('MALAT-1', 'Gene', (14, 21))	('SCC4', 'Gene', (37, 41))	('promoted', 'PosReg', (109, 117))	('anchorage-independent growth', 'CPA', (62, 90))	('SCC', 'Phenotype', 'HP:0002860', (37, 40))	('migration', 'CPA', (95, 104))	('MALAT-1', 'Gene', '378938', (14, 21))	('inhibited', 'NegReg', (27, 36))	('Silencing', 'Var', (0, 9))	('SCC4', 'Gene', '23383', (37, 41))
85132	31360193	In addition, studies to elucidate the mechanism through which MALAT-1 expression impacts SSC4 cell growth and migration are necessary.	('impacts', 'Reg', (81, 88))	('MALAT-1', 'Gene', '378938', (62, 69))	('SSC4', 'Disease', (89, 93))	('expression', 'Var', (70, 80))	('MALAT-1', 'Gene', (62, 69))
85250	33681225	observed that Clostridia was significant increase in the esophagus of men with PPI therapy after 8 weeks.	('men', 'Species', '9606', (70, 73))	('Clostridia', 'Disease', (14, 24))	('esophagus', 'Disease', (57, 66))	('increase', 'PosReg', (41, 49))	('PPI therapy', 'Var', (79, 90))
85357	26965579	High prevalence of TERT promoter mutations in primary squamous cell carcinoma of the urinary bladder TERT promoter mutations (TERT-mut) are detectable in the majority of urothelial carcinomas.	('TERT', 'Gene', '7015', (101, 105))	('TERT', 'Gene', (19, 23))	('carcinoma', 'Phenotype', 'HP:0030731', (181, 190))	('TERT', 'Gene', '7015', (19, 23))	('urothelial carcinomas', 'Disease', 'MESH:D014526', (170, 191))	('TERT', 'Gene', (126, 130))	('mutations', 'Var', (33, 42))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (54, 77))	('TERT', 'Gene', '7015', (126, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (68, 77))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (54, 77))	('TERT', 'Gene', (101, 105))	('carcinomas', 'Phenotype', 'HP:0030731', (181, 191))	('squamous cell carcinoma', 'Disease', (54, 77))	('urothelial carcinomas', 'Disease', (170, 191))
85365	26965579	TERT promoter mutations, commonly found in conventional urothelial carcinoma, are also highly prevalent in urinary bladder squamous cell carcinoma suggesting a common tumorigenesis and potential utility as a molecular urine-based-screening assay.	('urothelial carcinoma', 'Disease', (56, 76))	('prevalent', 'Reg', (94, 103))	('urinary bladder squamous cell carcinoma', 'Disease', (107, 146))	('TERT', 'Gene', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('TERT', 'Gene', '7015', (0, 4))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (56, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (123, 146))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('urinary bladder squamous cell carcinoma', 'Disease', 'MESH:D001749', (107, 146))	('mutations', 'Var', (14, 23))	('tumor', 'Disease', (167, 172))
85367	26965579	High rates of activating mutations in the upstream promoter of the TERT gene (TERT-mut) have been found in several solid tumor types.	('TERT', 'Gene', (78, 82))	('mutations', 'Var', (25, 34))	('TERT', 'Gene', (67, 71))	('TERT', 'Gene', '7015', (67, 71))	('TERT', 'Gene', '7015', (78, 82))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumor', 'Disease', (121, 126))	('activating', 'PosReg', (14, 24))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
85368	26965579	Mutations tend to occur in 'hot spots', particularly g.1295228C> T and g.129525OC> T. These mutations generate a CCGGAA/T or GGAA/T motif, thereby altering the binding site for Ets transcription factor, thereby increasing TERT promoter activity.	('altering', 'Reg', (147, 155))	('increasing', 'PosReg', (211, 221))	('g.129525OC> T.', 'Var', (71, 85))	('TERT', 'Gene', (222, 226))	('TERT', 'Gene', '7015', (222, 226))	('g.1295228C', 'Var', (53, 63))	('mutations', 'Var', (92, 101))	('g.1295228C> T', 'Mutation', 'g.1295228C>T', (53, 66))	('Ets', 'Protein', (177, 180))	('binding', 'Interaction', (160, 167))
85370	26965579	In the study by Kinde et al, 66% of muscle invasive and 74% of non-muscle invasive bladder lesions were shown to harbor these alterations.	('invasive bladder lesions', 'Disease', (74, 98))	('invasive bladder lesions', 'Disease', 'MESH:D001745', (74, 98))	('non-muscle invasive bladder', 'Phenotype', 'HP:0000011', (63, 90))	('muscle invasive', 'Disease', (36, 51))	('alterations', 'Var', (126, 137))	('invasive bladder', 'Phenotype', 'HP:0100645', (74, 90))
85381	26965579	Safe-SeqS amplification primers were designed to amplify segments containing the region of the TERT promoter previously shown to harbor mutations in melanomas and other tumors (Figure 1).	('melanomas', 'Disease', 'MESH:D008545', (149, 158))	('melanoma', 'Phenotype', 'HP:0002861', (149, 157))	('TERT', 'Gene', (95, 99))	('melanomas', 'Phenotype', 'HP:0002861', (149, 158))	('TERT', 'Gene', '7015', (95, 99))	('tumors', 'Disease', 'MESH:D009369', (169, 175))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('harbor', 'Reg', (129, 135))	('mutations', 'Var', (136, 145))	('men', 'Species', '9606', (60, 63))	('melanomas', 'Disease', (149, 158))	('tumors', 'Phenotype', 'HP:0002664', (169, 175))	('tumors', 'Disease', (169, 175))
85397	26965579	Of all the patients with TERT-mut, 2 (17%) were g.129525OC> T and the remaining 10 (83%) were a g.1295228C> T alteration (Table 2).	('g.1295228C> T', 'Var', (96, 109))	('g.1295228C> T', 'Mutation', 'g.1295228C>T', (96, 109))	('TERT', 'Gene', (25, 29))	('g.129525OC> T', 'Var', (48, 61))	('TERT', 'Gene', '7015', (25, 29))	('patients', 'Species', '9606', (11, 19))
85403	26965579	Subsequently, the same mutations were discovered by our group and others in numerous solid cancers, including urothelial carcinoma, gliomas and hepato-cellular carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('gliomas', 'Disease', 'MESH:D005910', (132, 139))	('cancers', 'Phenotype', 'HP:0002664', (91, 98))	('gliomas', 'Phenotype', 'HP:0009733', (132, 139))	('gliomas', 'Disease', (132, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (160, 169))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (110, 130))	('mutations', 'Var', (23, 32))	('numerous solid cancers', 'Disease', (76, 98))	('discovered', 'Reg', (38, 48))	('hepato-cellular carcinoma', 'Disease', (144, 169))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('hepato-cellular carcinoma', 'Disease', 'MESH:D020065', (144, 169))	('hepato-cellular carcinoma', 'Phenotype', 'HP:0001402', (144, 169))	('numerous solid cancers', 'Disease', 'MESH:D009369', (76, 98))	('urothelial carcinoma', 'Disease', (110, 130))
85409	26965579	All mutations were from previously published hotspots, with the majority of cases (83%) having the g.1295228C> T mutation, whereas the remainder had a g.1295250C> T mutation.	('g.1295228C> T', 'Mutation', 'g.1295228C>T', (99, 112))	('g.1295250C> T', 'Mutation', 'g.1295250C>T', (151, 164))	('g.1295250C> T', 'Var', (151, 164))	('g.1295228C> T', 'Var', (99, 112))
85420	26965579	In summary, TERT promoter mutations, commonly found in conventional urothelial carcinoma, are also highly prevalent in urinary bladder squamous cell carcinoma, suggesting a common tumorigenesis and potential utility as a molecular urine-based-screening assay.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (68, 88))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (135, 158))	('urinary bladder squamous cell carcinoma', 'Disease', (119, 158))	('TERT', 'Gene', '7015', (12, 16))	('carcinoma', 'Phenotype', 'HP:0030731', (149, 158))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('tumor', 'Disease', (180, 185))	('urinary bladder squamous cell carcinoma', 'Disease', 'MESH:D001749', (119, 158))	('mutations', 'Var', (26, 35))	('urothelial carcinoma', 'Disease', (68, 88))	('prevalent', 'Reg', (106, 115))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('TERT', 'Gene', (12, 16))
85421	32193401	Collagen type VI alpha5 gene variations may predict the risk of lung cancer development in Chinese Han population The abundant expression of collagen type VI alpha5 (COL6A5) exists in lung tissue, and its role in lung cancer is still unknown.	('lung cancer', 'Disease', (64, 75))	('lung cancer', 'Phenotype', 'HP:0100526', (64, 75))	('collagen type VI alpha5', 'Gene', (141, 164))	('lung cancer', 'Phenotype', 'HP:0100526', (213, 224))	('lung cancer', 'Disease', (213, 224))	('Collagen type VI alpha5', 'Gene', '256076', (0, 23))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('COL6A5', 'Gene', (166, 172))	('lung cancer', 'Disease', 'MESH:D008175', (64, 75))	('predict', 'Reg', (44, 51))	('lung cancer', 'Disease', 'MESH:D008175', (213, 224))	('Collagen type VI alpha5', 'Gene', (0, 23))	('collagen type VI alpha5', 'Gene', '256076', (141, 164))	('variations', 'Var', (29, 39))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('COL6A5', 'Gene', '256076', (166, 172))
85422	32193401	We performed a genetic association study with an attempt to detect the relationships between single nucleotide polymorphisms (SNPs) in COL6A5 and lung cancer predisposition in Chinese Han population.	('COL6A5', 'Gene', (135, 141))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('lung cancer', 'Disease', 'MESH:D008175', (146, 157))	('lung cancer', 'Phenotype', 'HP:0100526', (146, 157))	('single nucleotide polymorphisms', 'Var', (93, 124))	('lung cancer', 'Disease', (146, 157))	('COL6A5', 'Gene', '256076', (135, 141))
85425	32193401	COL6A5 rs13062453, rs1497305, and rs77123808 were significantly associated with the risk of lung cancer in the whole population or stratified subgroups (p < 0.05).	('lung cancer', 'Disease', (92, 103))	('associated', 'Reg', (64, 74))	('lung cancer', 'Phenotype', 'HP:0100526', (92, 103))	('rs1497305', 'Var', (19, 28))	('COL6A5', 'Gene', '256076', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('lung cancer', 'Disease', 'MESH:D008175', (92, 103))	('rs77123808', 'Mutation', 'rs77123808', (34, 44))	('rs13062453', 'Mutation', 'rs13062453', (7, 17))	('rs1497305', 'Mutation', 'rs1497305', (19, 28))	('rs77123808', 'Var', (34, 44))	('COL6A5', 'Gene', (0, 6))	('rs13062453', 'Var', (7, 17))
85426	32193401	Among them, COL6A5 rs13062453 and rs1497305 were also linked to the susceptibility of lung adenocarcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('lung adenocarcinoma', 'Disease', (86, 105))	('rs1497305', 'Mutation', 'rs1497305', (34, 43))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (86, 105))	('rs13062453', 'Mutation', 'rs13062453', (19, 29))	('COL6A5', 'Gene', (12, 18))	('rs13062453', 'Var', (19, 29))	('rs1497305', 'Var', (34, 43))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (86, 105))	('linked', 'Reg', (54, 60))	('COL6A5', 'Gene', '256076', (12, 18))
85427	32193401	Additionally, rs1497305 was found to be strongly related to the TNM staging under five genetic models (p < 0.05).	('rs1497305', 'Mutation', 'rs1497305', (14, 23))	('TNM', 'Gene', (64, 67))	('rs1497305', 'Var', (14, 23))	('related', 'Reg', (49, 56))	('TNM', 'Gene', '10178', (64, 67))
85429	32193401	COL6A5 polymorphisms rs13062453, rs1497305 and rs77123808 were associated with lung cancer risk in Chinese Han population.	('lung cancer', 'Disease', 'MESH:D008175', (79, 90))	('rs1497305', 'Var', (33, 42))	('associated', 'Reg', (63, 73))	('rs77123808', 'Mutation', 'rs77123808', (47, 57))	('COL6A5', 'Gene', '256076', (0, 6))	('lung cancer', 'Disease', (79, 90))	('lung cancer', 'Phenotype', 'HP:0100526', (79, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('rs13062453', 'Mutation', 'rs13062453', (21, 31))	('rs1497305', 'Mutation', 'rs1497305', (33, 42))	('rs77123808', 'Var', (47, 57))	('COL6A5', 'Gene', (0, 6))	('rs13062453', 'Var', (21, 31))
85443	32193401	The aberrant expression of collagen VI genes has been reported in several malignant tumors, suggesting the potential effects of collagen VI in cancer development.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('malignant tumors', 'Disease', (74, 90))	('expression', 'MPA', (13, 23))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('aberrant', 'Var', (4, 12))	('malignant tumors', 'Disease', 'MESH:D018198', (74, 90))	('collagen VI genes', 'Gene', (27, 44))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('reported', 'Reg', (54, 62))
85445	32193401	Accordingly, we hypothesized that the single nucleotide polymorphisms (SNPs) in COL6A5 might be associated with lung cancer risk, and performed a genetic association study to investigate the relationships between the COL6A5 variations and lung cancer predisposition among Chinese Han population.	('COL6A5', 'Gene', (80, 86))	('single nucleotide polymorphisms', 'Var', (38, 69))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('lung cancer', 'Disease', (239, 250))	('COL6A5', 'Gene', '256076', (217, 223))	('lung cancer', 'Disease', (112, 123))	('lung cancer', 'Phenotype', 'HP:0100526', (239, 250))	('associated', 'Reg', (96, 106))	('lung cancer', 'Phenotype', 'HP:0100526', (112, 123))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('lung cancer', 'Disease', 'MESH:D008175', (239, 250))	('lung cancer', 'Disease', 'MESH:D008175', (112, 123))	('COL6A5', 'Gene', '256076', (80, 86))	('COL6A5', 'Gene', (217, 223))
85453	32193401	Searching the 1000 Genomes website (http://www.internationalgenome.org/), we downloaded the data of COL6A5 variations in CHB (Chinese Han Beijing) and then inputted them into haploview 4.2 software.	('COL6A5', 'Gene', (100, 106))	('variations', 'Var', (107, 117))	('COL6A5', 'Gene', '256076', (100, 106))
85454	32193401	Ultimately, six COL6A5 polymorphisms, rs77123808, rs2034664, rs10212241, rs13062453, rs1497305, and rs2403340 were selected for genotyping.	('COL6A5', 'Gene', '256076', (16, 22))	('rs13062453', 'Mutation', 'rs13062453', (73, 83))	('rs1497305', 'Mutation', 'rs1497305', (85, 94))	('rs77123808', 'Var', (38, 48))	('rs2034664', 'Var', (50, 59))	('rs2403340', 'Mutation', 'rs2403340', (100, 109))	('rs10212241', 'Var', (61, 71))	('rs13062453', 'Var', (73, 83))	('rs1497305', 'Var', (85, 94))	('COL6A5', 'Gene', (16, 22))	('rs2034664', 'Mutation', 'rs2034664', (50, 59))	('rs77123808', 'Mutation', 'rs77123808', (38, 48))	('rs2403340', 'Var', (100, 109))	('rs10212241', 'Mutation', 'rs10212241', (61, 71))
85464	32193401	Subsequently, prognosis analysis indicated that patients with low expression of COL6A5 had worse overall survival (Fig.	('COL6A5', 'Gene', (80, 86))	('overall survival', 'MPA', (97, 113))	('low expression', 'Var', (62, 76))	('COL6A5', 'Gene', '256076', (80, 86))	('worse', 'NegReg', (91, 96))	('patients', 'Species', '9606', (48, 56))
85467	32193401	Specific information and minor allele frequency of the six candidate SNPs are listed in Table 2, including rs77123808 (C < A), rs2034664 (T < A), rs10212241 (T < C), rs13062453 (A < G), rs1497305 (A < G), and rs2403340 (A < G).	('rs2034664', 'Mutation', 'rs2034664', (127, 136))	('rs13062453', 'Mutation', 'rs13062453', (166, 176))	('rs77123808', 'Var', (107, 117))	('rs13062453', 'Var', (166, 176))	('rs1497305', 'Mutation', 'rs1497305', (186, 195))	('rs2403340', 'Var', (209, 218))	('rs2403340', 'Mutation', 'rs2403340', (209, 218))	('rs10212241', 'Mutation', 'rs10212241', (146, 156))	('rs1497305', 'Var', (186, 195))	('rs77123808', 'Mutation', 'rs77123808', (107, 117))
85468	32193401	All the selected variants are located in COL6A5, chromosome 3, with MAF > 0.05 in both cases and controls.	('COL6A5', 'Gene', (41, 47))	('variants', 'Var', (17, 25))	('COL6A5', 'Gene', '256076', (41, 47))
85469	32193401	From Table 2, we found that the frequency of minor allele "T" of rs10212241 (0.438 in cases and 0.438 in controls) and "A" of rs2403340 (0.175 in cases and 0.174 in controls) were similar among lung cancer patients and healthy subjects.	('lung cancer', 'Phenotype', 'HP:0100526', (194, 205))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('rs10212241', 'Mutation', 'rs10212241', (65, 75))	('lung cancer', 'Disease', 'MESH:D008175', (194, 205))	('rs2403340', 'Var', (126, 135))	('patients', 'Species', '9606', (206, 214))	('rs2403340', 'Mutation', 'rs2403340', (126, 135))	('lung cancer', 'Disease', (194, 205))
85470	32193401	Genotype distributions of the six COL6A5 variants in lung cancer cases and healthy controls are showed in Supplementary Table S1.	('variants', 'Var', (41, 49))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('COL6A5', 'Gene', '256076', (34, 40))	('lung cancer', 'Disease', 'MESH:D008175', (53, 64))	('COL6A5', 'Gene', (34, 40))	('lung cancer', 'Disease', (53, 64))	('lung cancer', 'Phenotype', 'HP:0100526', (53, 64))
85472	32193401	In control group, the HWE p value of each variant was calculated (rs77123808: 1.00. rs2034664: 0.04, rs10212241: 1.00, rs13062453: 0.15, rs1497305: 0.09, rs2403340: 0.04).	('rs10212241', 'Var', (101, 111))	('rs2034664', 'Var', (84, 93))	('rs1497305', 'Var', (137, 146))	('rs13062453', 'Mutation', 'rs13062453', (119, 129))	('rs2403340', 'Var', (154, 163))	('rs2034664', 'Mutation', 'rs2034664', (84, 93))	('rs2403340', 'Mutation', 'rs2403340', (154, 163))	('rs13062453', 'Var', (119, 129))	('rs1497305', 'Mutation', 'rs1497305', (137, 146))	('rs10212241', 'Mutation', 'rs10212241', (101, 111))	('rs77123808', 'Mutation', 'rs77123808', (66, 76))
85473	32193401	Because of the lower MAF in our population, rs2034664 and rs2403340 exhibited marginal HWE p values and were excluded from further analysis.	('rs2403340', 'Mutation', 'rs2403340', (58, 67))	('rs2034664', 'Var', (44, 53))	('rs2403340', 'Var', (58, 67))	('lower', 'NegReg', (15, 20))	('MAF', 'MPA', (21, 24))	('rs2034664', 'Mutation', 'rs2034664', (44, 53))
85474	32193401	We first investigated the relationships between rs77123808, rs10212241, rs13062453, rs1497305 and lung cancer risk in the Chinese Han population.	('rs77123808', 'Var', (48, 58))	('rs10212241', 'Mutation', 'rs10212241', (60, 70))	('rs1497305', 'Var', (84, 93))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('lung cancer', 'Disease', (98, 109))	('lung cancer', 'Phenotype', 'HP:0100526', (98, 109))	('rs10212241', 'Var', (60, 70))	('rs1497305', 'Mutation', 'rs1497305', (84, 93))	('lung cancer', 'Disease', 'MESH:D008175', (98, 109))	('rs77123808', 'Mutation', 'rs77123808', (48, 58))	('rs13062453', 'Mutation', 'rs13062453', (72, 82))	('rs13062453', 'Var', (72, 82))
85475	32193401	As presented in Table 3, the heterozygous "GA" genotype of rs13062453 was associated with an enhanced risk of lung cancer when compared with the homozygous "GG" genotype (adjusted OR = 1.33, 95% CI = 1.02-1.74, p = 0.036, power = 61.77%).	('rs13062453', 'Var', (59, 69))	('lung cancer', 'Disease', 'MESH:D008175', (110, 121))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('lung cancer', 'Disease', (110, 121))	('lung cancer', 'Phenotype', 'HP:0100526', (110, 121))	('rs13062453', 'Mutation', 'rs13062453', (59, 69))
85476	32193401	Likewise, remarkable correlation also existed between the "GA" genotype of rs1497305 and increased lung cancer susceptibility among Chinese Han individuals according to an adjusted OR of 1.37 (95% CI = 1.05-1.78, power = 69.11%) and significant p value of 0.019 (Table 3).	('increased lung cancer', 'Disease', (89, 110))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('rs1497305', 'Var', (75, 84))	('increased lung cancer', 'Disease', 'MESH:D008175', (89, 110))	('rs1497305', 'Mutation', 'rs1497305', (75, 84))	('lung cancer', 'Phenotype', 'HP:0100526', (99, 110))
85477	32193401	However, rs77123808 and rs10212241did not show any associations with lung cancer in our study cohort (p > 0.05).	('rs77123808', 'Mutation', 'rs77123808', (9, 19))	('lung cancer', 'Disease', 'MESH:D008175', (69, 80))	('rs10212241', 'Mutation', 'rs10212241', (24, 34))	('rs77123808', 'Var', (9, 19))	('rs10212241did', 'Var', (24, 37))	('lung cancer', 'Disease', (69, 80))	('lung cancer', 'Phenotype', 'HP:0100526', (69, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
85479	32193401	First, the correlations between the genetic variations and lung cancer risk were evaluated among people with different age and gender, and the significant COL6A5 variants were summarized in Table 4 (allele and genotype analysis) and Supplementary Table S3 (Genetic model analysis).	('COL6A5', 'Gene', (155, 161))	('lung cancer', 'Disease', 'MESH:D008175', (59, 70))	('people', 'Species', '9606', (97, 103))	('lung cancer', 'Disease', (59, 70))	('lung cancer', 'Phenotype', 'HP:0100526', (59, 70))	('variants', 'Var', (162, 170))	('COL6A5', 'Gene', '256076', (155, 161))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
85481	32193401	In females, rs13062453 and rs1497305 polymorphisms elevated the risk of lung cancer according to the genotype and dominant model (rs13062453: "GA" genotype adjusted OR = 1.75, 95% CI = 1.07-2.86, p = 0.027, dominant model adjusted OR = 1.68, 95% CI = 1.05-2.86, p = 0.030; rs1497305: "AA" genotype adjusted OR = 1.79, 95% CI = 1.10-2.90, p = 0.019, dominant model adjusted OR = 1.59, 95% CI = 1.01-2.52, p = 0.046), whereas rs77123808 reduced the predisposition to lung tumorigenesis ("AC" adjusted OR = 0.51, 95% CI = 0.31-0.83, p = 0.006, dominant model adjusted OR = 0.58, 95% CI = 0.37-0.92, p = 0.021).	('tumor', 'Phenotype', 'HP:0002664', (470, 475))	('rs13062453', 'Mutation', 'rs13062453', (12, 22))	('rs13062453', 'Var', (12, 22))	('rs1497305', 'Mutation', 'rs1497305', (27, 36))	('rs77123808', 'Mutation', 'rs77123808', (424, 434))	('rs77123808', 'Var', (424, 434))	('rs1497305', 'Mutation', 'rs1497305', (273, 282))	('lung tumor', 'Disease', 'MESH:D008175', (465, 475))	('lung tumor', 'Disease', (465, 475))	('rs13062453', 'Mutation', 'rs13062453', (130, 140))	('lung cancer', 'Disease', (72, 83))	('rs1497305', 'Var', (27, 36))	('lung cancer', 'Phenotype', 'HP:0100526', (72, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('reduced', 'NegReg', (435, 442))	('lung tumor', 'Phenotype', 'HP:0100526', (465, 475))	('lung cancer', 'Disease', 'MESH:D008175', (72, 83))
85482	32193401	Second, we examinated the associations of COL6A5 SNPs with two common pathological types of lung cancer, namely lung adenocarcinoma and squamous cell carcinoma.	('lung cancer', 'Disease', (92, 103))	('namely lung adenocarcinoma', 'Disease', 'MESH:D000077192', (105, 131))	('lung cancer', 'Phenotype', 'HP:0100526', (92, 103))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (112, 131))	('namely lung adenocarcinoma', 'Disease', (105, 131))	('COL6A5', 'Gene', '256076', (42, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (150, 159))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('lung cancer', 'Disease', 'MESH:D008175', (92, 103))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (136, 159))	('SNPs', 'Var', (49, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('squamous cell carcinoma', 'Disease', (136, 159))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (136, 159))	('COL6A5', 'Gene', (42, 48))	('associations', 'Interaction', (26, 38))
85483	32193401	As showed in Table 5, the "GA" genotype of rs13062453 and rs1497305 wasfound to be correlated to the increased risk of lung adenocarcinoma (rs13062453: adjusted OR = 1.46, 95% CI = 1.01-2.11, p = 0.045; rs1497305: adjusted OR = 1.76, 95% CI = 1.23-2.51, p = 0.002).	('rs1497305', 'Mutation', 'rs1497305', (203, 212))	('rs13062453', 'Mutation', 'rs13062453', (43, 53))	('rs13062453', 'Var', (43, 53))	('rs1497305', 'Mutation', 'rs1497305', (58, 67))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (119, 138))	('rs13062453', 'Mutation', 'rs13062453', (140, 150))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('rs1497305', 'Var', (203, 212))	('lung adenocarcinoma', 'Disease', (119, 138))	('rs1497305', 'Var', (58, 67))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (119, 138))
85484	32193401	Rs1497305 also showed obvious evidence in correlation to lung adenocarcinoma susceptibility in dominant model (adjusted OR = 1.51, 95% CI = 1.07-2.13, p = 0.018) and recessive model (adjusted OR = 0.45, 95% CI = 0.22-0.96, p = 0.038) (Supplementary Table S4).	('Rs1497305', 'Mutation', 'Rs1497305', (0, 9))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (57, 76))	('lung adenocarcinoma', 'Disease', (57, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('Rs1497305', 'Var', (0, 9))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (57, 76))
85486	32193401	Lastly, the contributions of COL6A5 variants on TNM staging and lymph node metastasis were demonstrated.	('contributions', 'Reg', (12, 25))	('COL6A5', 'Gene', (29, 35))	('TNM', 'Gene', '10178', (48, 51))	('lymph node metastasis', 'CPA', (64, 85))	('variants', 'Var', (36, 44))	('COL6A5', 'Gene', '256076', (29, 35))	('TNM', 'Gene', (48, 51))
85487	32193401	Notably, pronounced results of the polymorphism rs1497305 still survived in all statistical analysis for TNM staging even after adjustment, which suggested the importance of this SNP in lung cancer progression (p < 0.05, Table 6 and Supplementary Table S5).	('TNM', 'Gene', (105, 108))	('lung cancer', 'Disease', 'MESH:D008175', (186, 197))	('rs1497305', 'Mutation', 'rs1497305', (48, 57))	('TNM', 'Gene', '10178', (105, 108))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('lung cancer', 'Disease', (186, 197))	('rs1497305', 'Var', (48, 57))	('lung cancer', 'Phenotype', 'HP:0100526', (186, 197))
85488	32193401	The current study evaluated the correlations between polymorphisms in COL6A5 gene and lung cancer susceptibility among Chinese Han individuals.	('correlations', 'Interaction', (32, 44))	('lung cancer', 'Phenotype', 'HP:0100526', (86, 97))	('COL6A5', 'Gene', '256076', (70, 76))	('lung cancer', 'Disease', (86, 97))	('polymorphisms', 'Var', (53, 66))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('COL6A5', 'Gene', (70, 76))	('lung cancer', 'Disease', 'MESH:D008175', (86, 97))
85489	32193401	We found that COL6A5 rs13062453, rs1497305, and rs77123808 were associated with the risk of lung cancer in Chinese Han population.	('lung cancer', 'Disease', (92, 103))	('associated', 'Reg', (64, 74))	('rs77123808', 'Var', (48, 58))	('rs1497305', 'Var', (33, 42))	('COL6A5', 'Gene', (14, 20))	('lung cancer', 'Phenotype', 'HP:0100526', (92, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('lung cancer', 'Disease', 'MESH:D008175', (92, 103))	('COL6A5', 'Gene', '256076', (14, 20))	('rs13062453', 'Mutation', 'rs13062453', (21, 31))	('rs1497305', 'Mutation', 'rs1497305', (33, 42))	('rs77123808', 'Mutation', 'rs77123808', (48, 58))	('rs13062453', 'Var', (21, 31))
85490	32193401	Additionally, COL6A5 rs1497305 was a potential predictor for TNM staging.	('COL6A5', 'Gene', (14, 20))	('rs1497305', 'Mutation', 'rs1497305', (21, 30))	('TNM', 'Gene', (61, 64))	('rs1497305', 'Var', (21, 30))	('COL6A5', 'Gene', '256076', (14, 20))	('TNM', 'Gene', '10178', (61, 64))
85507	32193401	Eight variants located in COL6A5 gene have been demonstrated to be related to the susceptibility to atopic dermatitis among Europeans.	('related', 'Reg', (67, 74))	('variants', 'Var', (6, 14))	('susceptibility', 'Reg', (82, 96))	('COL6A5', 'Gene', (26, 32))	('dermatitis', 'Phenotype', 'HP:0011123', (107, 117))	('atopic dermatitis', 'Phenotype', 'HP:0001047', (100, 117))	('atopic dermatitis', 'Disease', 'MESH:D003876', (100, 117))	('atopic dermatitis', 'Disease', (100, 117))	('COL6A5', 'Gene', '256076', (26, 32))
85508	32193401	A longitudinal exome-wide association study performed among Japanese has showed that COL6A5 SNP rs11917356 was significantly correlated with hypertension risk through affect systolic blood pressure.	('hypertension', 'Phenotype', 'HP:0000822', (141, 153))	('rs11917356', 'Mutation', 'rs11917356', (96, 106))	('correlated', 'Reg', (125, 135))	('COL6A5', 'Gene', '256076', (85, 91))	('affect', 'Reg', (167, 173))	('COL6A5', 'Gene', (85, 91))	('hypertension', 'Disease', 'MESH:D006973', (141, 153))	('SNP', 'Var', (92, 95))	('systolic blood pressure', 'MPA', (174, 197))	('rs11917356', 'Var', (96, 106))	('hypertension', 'Disease', (141, 153))
85509	32193401	Furthermore, it has been reported that variations in COL6A5 might play causal roles for asthma together with environmental exposures.	('COL6A5', 'Gene', (53, 59))	('asthma', 'Disease', (88, 94))	('play causal roles', 'Reg', (66, 83))	('asthma', 'Disease', 'MESH:D001249', (88, 94))	('asthma', 'Phenotype', 'HP:0002099', (88, 94))	('COL6A5', 'Gene', '256076', (53, 59))	('variations', 'Var', (39, 49))
85510	32193401	But a recent study has not found any significant relationships between COL6A5 variants and asthma or chronic obstructive pulmonary disease in German.	('obstructive pulmonary disease', 'Phenotype', 'HP:0006536', (109, 138))	('COL6A5', 'Gene', (71, 77))	('chronic obstructive pulmonary disease', 'Phenotype', 'HP:0006510', (101, 138))	('chronic obstructive pulmonary disease', 'Disease', (101, 138))	('chronic obstructive pulmonary disease', 'Disease', 'MESH:D029424', (101, 138))	('asthma', 'Disease', (91, 97))	('asthma', 'Disease', 'MESH:D001249', (91, 97))	('variants', 'Var', (78, 86))	('COL6A5', 'Gene', '256076', (71, 77))	('asthma', 'Phenotype', 'HP:0002099', (91, 97))
85511	32193401	In our study, COL6A5 polymorphisms rs13062453, rs1497305, and rs77123808 were genetic polymorphic markers that confer susceptibility to lung cancer among Chinese Han individuals.	('lung cancer', 'Phenotype', 'HP:0100526', (136, 147))	('COL6A5', 'Gene', (14, 20))	('rs13062453', 'Var', (35, 45))	('rs77123808', 'Var', (62, 72))	('rs77123808', 'Mutation', 'rs77123808', (62, 72))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('rs1497305', 'Var', (47, 56))	('lung cancer', 'Disease', 'MESH:D008175', (136, 147))	('COL6A5', 'Gene', '256076', (14, 20))	('rs13062453', 'Mutation', 'rs13062453', (35, 45))	('susceptibility', 'Reg', (118, 132))	('rs1497305', 'Mutation', 'rs1497305', (47, 56))	('lung cancer', 'Disease', (136, 147))
85512	32193401	As all the significant SNPs were resided in the intron region of COL6A5 gene, which possesses regulatory functions in pre-mRNA processing, we considered that alternation at these polymorphic sites might modulate the expression efficiency of COL6A5 mRNA, contributing to the abnormal pattern of COL6A5 and thereby influencing the individual susceptibility to lung cancer.	('COL6A5', 'Gene', (241, 247))	('cancer', 'Phenotype', 'HP:0002664', (363, 369))	('lung cancer', 'Disease', 'MESH:D008175', (358, 369))	('COL6A5', 'Gene', (65, 71))	('COL6A5', 'Gene', '256076', (294, 300))	('influencing', 'Reg', (313, 324))	('contributing', 'Reg', (254, 266))	('COL6A5', 'Gene', '256076', (241, 247))	('alternation', 'Var', (158, 169))	('expression', 'MPA', (216, 226))	('modulate', 'Reg', (203, 211))	('COL6A5', 'Gene', '256076', (65, 71))	('COL6A5', 'Gene', (294, 300))	('lung cancer', 'Disease', (358, 369))	('lung cancer', 'Phenotype', 'HP:0100526', (358, 369))	('abnormal pattern', 'MPA', (274, 290))	('mRNA', 'MPA', (248, 252))
85513	32193401	Additionally, COL6A5 rs1497305 was found to be associated with TNM staging, which harbors the potential to become new target for lung cancer clinical stage evaluation in future.	('lung cancer', 'Disease', (129, 140))	('COL6A5', 'Gene', (14, 20))	('lung cancer', 'Phenotype', 'HP:0100526', (129, 140))	('TNM', 'Gene', '10178', (63, 66))	('rs1497305', 'Mutation', 'rs1497305', (21, 30))	('rs1497305', 'Var', (21, 30))	('TNM', 'Gene', (63, 66))	('COL6A5', 'Gene', '256076', (14, 20))	('lung cancer', 'Disease', 'MESH:D008175', (129, 140))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('associated', 'Reg', (47, 57))
85515	32193401	Third, the underlying mechanism of the promising SNPs and COL6A5 gene in lung cancer development is still unclear, thus suggesting the nest step for the further research.	('lung cancer', 'Disease', 'MESH:D008175', (73, 84))	('COL6A5', 'Gene', '256076', (58, 64))	('SNPs', 'Var', (49, 53))	('lung cancer', 'Disease', (73, 84))	('lung cancer', 'Phenotype', 'HP:0100526', (73, 84))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('COL6A5', 'Gene', (58, 64))
85516	32193401	In summary, this is the first research that discussed the relationships between COL6A5 polymorphisms and lung cancer risk.	('lung cancer', 'Phenotype', 'HP:0100526', (105, 116))	('COL6A5', 'Gene', (80, 86))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('lung cancer', 'Disease', 'MESH:D008175', (105, 116))	('polymorphisms', 'Var', (87, 100))	('COL6A5', 'Gene', '256076', (80, 86))	('relationships', 'Interaction', (58, 71))	('lung cancer', 'Disease', (105, 116))
85517	32193401	We uncovered significant variants that were associated with lung cancer susceptibility in Chinese Han population.	('associated', 'Reg', (44, 54))	('variants', 'Var', (25, 33))	('lung cancer', 'Disease', (60, 71))	('lung cancer', 'Phenotype', 'HP:0100526', (60, 71))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('lung cancer', 'Disease', 'MESH:D008175', (60, 71))
85621	31897183	A lentivirus vector transfection system was used to knockdown POLR1B in A549 cells.	('A549', 'CellLine', 'CVCL:0023', (72, 76))	('knockdown', 'Var', (52, 61))	('POLR1B', 'Gene', '84172', (62, 68))	('POLR1B', 'Gene', (62, 68))
85622	31897183	The Celigo Cell Counting method, MTT and colony formation assays were used to investigate the proliferation of knocking-down POLR1B in A549 cells.	('knocking-down', 'Var', (111, 124))	('MTT', 'Chemical', 'MESH:C022616', (33, 36))	('A549', 'CellLine', 'CVCL:0023', (135, 139))	('POLR1B', 'Gene', '84172', (125, 131))	('POLR1B', 'Gene', (125, 131))
85625	31897183	In addition, knocking-down the expression of POLR1B induced lung cancer cell apoptosis, visualized via flow cytometry.	('lung cancer', 'Disease', (60, 71))	('lung cancer', 'Phenotype', 'HP:0100526', (60, 71))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('lung cancer', 'Disease', 'MESH:D008175', (60, 71))	('POLR1B', 'Gene', '84172', (45, 51))	('POLR1B', 'Gene', (45, 51))	('knocking-down', 'Var', (13, 26))	('induced', 'Reg', (52, 59))
85683	31897183	Global expression of mRNAs in 3 control A549 samples and 3 POLR1B knockdown A549 samples were examined using the GeneChip PrimeView Human Gene Expression Array (Thermo Fisher Scientific, Inc.).	('A549', 'CellLine', 'CVCL:0023', (76, 80))	('A549', 'CellLine', 'CVCL:0023', (40, 44))	('POLR1B', 'Gene', (59, 65))	('Human', 'Species', '9606', (132, 137))	('POLR1B', 'Gene', '84172', (59, 65))	('knockdown', 'Var', (66, 75))
85711	31897183	Based on the aforementioned findings, demonstrating that POLR1B serves an important role in the modulation of lung cancer cell proliferation, flow cytometry was performed to analyze apoptosis in A549 cells following POLR1B knockdown.	('POLR1B', 'Gene', '84172', (57, 63))	('lung cancer', 'Disease', 'MESH:D008175', (110, 121))	('POLR1B', 'Gene', (57, 63))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('lung cancer', 'Disease', (110, 121))	('lung cancer', 'Phenotype', 'HP:0100526', (110, 121))	('POLR1B', 'Gene', '84172', (216, 222))	('knockdown', 'Var', (223, 232))	('POLR1B', 'Gene', (216, 222))	('A549', 'CellLine', 'CVCL:0023', (195, 199))
85714	31897183	4B), indicating that POLR1B depletion induces lung cancer cell apoptosis.	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('POLR1B', 'Gene', '84172', (21, 27))	('induces', 'Reg', (38, 45))	('POLR1B', 'Gene', (21, 27))	('depletion', 'Var', (28, 37))	('lung cancer', 'Disease', 'MESH:D008175', (46, 57))	('lung cancer', 'Disease', (46, 57))	('lung cancer', 'Phenotype', 'HP:0100526', (46, 57))
85716	31897183	A total of 970 genes were identified as potential targets of POLR1B, including 424 genes that were upregulated, and 546 that were downregulated following POLR1B knockdown in A549 cells (Fig.	('A549', 'CellLine', 'CVCL:0023', (174, 178))	('downregulated', 'NegReg', (130, 143))	('POLR1B', 'Gene', '84172', (61, 67))	('upregulated', 'PosReg', (99, 110))	('POLR1B', 'Gene', (61, 67))	('POLR1B', 'Gene', '84172', (154, 160))	('POLR1B', 'Gene', (154, 160))	('knockdown', 'Var', (161, 170))
85719	31897183	The top 10 upregulated and downregulated genes after POLR1B knockdown in A549 cells are listed Table I.	('POLR1B', 'Gene', (53, 59))	('A549', 'CellLine', 'CVCL:0023', (73, 77))	('upregulated', 'PosReg', (11, 22))	('downregulated', 'NegReg', (27, 40))	('knockdown', 'Var', (60, 69))	('POLR1B', 'Gene', '84172', (53, 59))
85731	31897183	In addition, small molecule inhibitors that directly target Pol I (such as CX-5461 and CX-3543) have been developed and implemented in further clinical trials for the treatment of cancer.	('Pol I', 'Gene', (60, 65))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('CX-5461', 'Var', (75, 82))	('CX-3543', 'Chemical', 'MESH:C545184', (87, 94))	('CX-3543', 'Var', (87, 94))	('Pol I', 'Gene', '11201', (60, 65))	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('cancer', 'Disease', (180, 186))
85732	31897183	Specifically, a previous study demonstrated that BMH-21, a compound that promotes proteasome-dependent destruction of the large catalytic subunit of the Pol I holocomplex (RPA194), possesses broad anti-tumorigenic activity across the NCI60 cancer cell lines, and suppresses tumor growth in vivo.	('suppresses', 'NegReg', (263, 273))	('NCI60', 'CellLine', 'CVCL:A592', (234, 239))	('RPA194', 'Gene', '25885', (172, 178))	('BMH-21', 'Var', (49, 55))	('RPA194', 'Gene', (172, 178))	('tumor', 'Disease', (202, 207))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('tumor', 'Disease', 'MESH:D009369', (274, 279))	('Pol I', 'Gene', '11201', (153, 158))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('tumor', 'Phenotype', 'HP:0002664', (274, 279))	('cancer', 'Disease', 'MESH:D009369', (240, 246))	('proteasome-dependent', 'MPA', (82, 102))	('promotes', 'PosReg', (73, 81))	('tumor', 'Disease', (274, 279))	('cancer', 'Disease', (240, 246))	('Pol I', 'Gene', (153, 158))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))
85744	31897183	Furthermore, POLR1B depletion was revealed to inhibit lung cancer cell proliferation and induce apoptosis.	('induce', 'PosReg', (89, 95))	('lung cancer', 'Disease', (54, 65))	('lung cancer', 'Phenotype', 'HP:0100526', (54, 65))	('inhibit', 'NegReg', (46, 53))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('lung cancer', 'Disease', 'MESH:D008175', (54, 65))	('POLR1B', 'Gene', '84172', (13, 19))	('POLR1B', 'Gene', (13, 19))	('apoptosis', 'CPA', (96, 105))	('depletion', 'Var', (20, 29))
85778	30473748	TP63 is a powerful diagnostic discriminant, and a cancer prognostic and predictive factor.	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('TP63', 'Var', (0, 4))	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))
85795	30473748	Overexpression of the transforming growth factor (TGF) receptor 2 gene (TGFBR2) was shown to associate with less aggressive disease courses in LUSC.	('TGFBR2', 'Gene', (72, 78))	('aggressive disease', 'Disease', 'MESH:D001523', (113, 131))	('associate with', 'Reg', (93, 107))	('aggressive disease', 'Disease', (113, 131))	('Overexpression', 'Var', (0, 14))	('LUSC', 'Disease', (143, 147))	('TGFBR2', 'Gene', '7048', (72, 78))
85819	30473748	Transcriptional network analysis showed involvement of E2F, CTGF, and PDGF in lung cancer pathogenesis.	('lung cancer', 'Disease', (78, 89))	('lung cancer', 'Phenotype', 'HP:0100526', (78, 89))	('involvement', 'Reg', (40, 51))	('E2F', 'Var', (55, 58))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('CTGF', 'Gene', '1490', (60, 64))	('lung cancer', 'Disease', 'MESH:D008175', (78, 89))	('PDGF', 'Gene', (70, 74))	('CTGF', 'Gene', (60, 64))
85821	30473748	Not surprisingly, to date, the only molecular traits that are of current use in clinical practice for prognostic and therapeutic purposes are genomic mutations of EGFR and KRAS and gene fusions of ALK.	('KRAS', 'Gene', (172, 176))	('ALK', 'Gene', (197, 200))	('KRAS', 'Gene', '3845', (172, 176))	('EGFR', 'Gene', '1956', (163, 167))	('ALK', 'Gene', '238', (197, 200))	('mutations', 'Var', (150, 159))	('EGFR', 'Gene', (163, 167))	('gene fusions', 'Var', (181, 193))
85836	30473748	Experimental evidence had previously indicated that keratin 19 (CYFRA21-1) had a negative prognostic impact on LUAD only.	('negative', 'NegReg', (81, 89))	('LUAD only', 'Disease', (111, 120))	('LUAD', 'Phenotype', 'HP:0030078', (111, 115))	('keratin 19', 'Gene', '3880', (52, 62))	('keratin 19', 'Gene', (52, 62))	('CYFRA21-1', 'Var', (64, 73))
86015	30416263	1500 data points are generated along the sine function with small noise:   where Zi ~ U[-2pi, 0] and epsiloni ~ N(0, 0.01 I10) independently for the ideal data and epsiloni ~ N(0, 10 I10) for the contaminated data.	('sin', 'Gene', (41, 44))	('sin', 'Gene', '10278', (41, 44))	('Zi ~ U[-2pi', 'Var', (81, 92))
86021	30416263	In addition, we compare kernel CO and robust kernel CO estimators using 5 kernels: linear (Poly-1), a polynomial with degree 2 (Poly-2) and polynomial with degree 3 (Poly-3), Gaussian and Laplacian on two synthetic data sets: TCSD and SFSD.	('sin', 'Gene', (67, 70))	('sin', 'Gene', '10278', (67, 70))	('Poly-3', 'Var', (166, 172))	('Poly-2', 'Var', (128, 134))
86085	29072095	After tumour transplantation in syngeneic mice, phenylboronic acid was shown to slow the growth of both tumour cell lines (4T1 and SCCVII) compared with the control.	('mice', 'Species', '10090', (42, 46))	('growth', 'MPA', (89, 95))	('phenylboronic acid', 'Chemical', 'MESH:C010686', (48, 66))	('tumour', 'Phenotype', 'HP:0002664', (6, 12))	('tumour', 'Phenotype', 'HP:0002664', (104, 110))	('phenylboronic acid', 'Var', (48, 66))	('tumour', 'Disease', 'MESH:D009369', (6, 12))	('tumour', 'Disease', 'MESH:D009369', (104, 110))	('tumour', 'Disease', (6, 12))	('tumour', 'Disease', (104, 110))	('slow', 'NegReg', (80, 84))
86165	29072095	Slight changes in pH can result in the release of the inhibitor from the active site, enabling the use of boronic acids as biological probes and in therapeutics.	('boronic acids', 'Chemical', 'MESH:D001897', (106, 119))	('release', 'MPA', (39, 46))	('result in', 'Reg', (25, 34))	('changes', 'Var', (7, 14))	('inhibitor from the active site', 'MPA', (54, 84))
86177	29072095	K2[B3O3F4OH], have been suggested for use in the prevention and/or treatment of benign or malignant changes in epidermal tissue.	('K2[B3O3F4OH]', 'Var', (0, 12))	('B3O3F4OH', 'Chemical', '-', (3, 11))	('malignant changes', 'Phenotype', 'HP:0002664', (90, 107))	('benign or', 'Disease', (80, 89))
86200	29464122	BCCs are caused by frequent exposure to ultraviolet radiation, most commonly ultraviolet spectrum B (UV-B) with a wavelength of 290-320 nm, inducing mutations in tumor suppressor genes.	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('mutations', 'Var', (149, 158))	('inducing', 'Reg', (140, 148))	('tumor', 'Disease', (162, 167))	('BCCs', 'Disease', (0, 4))	('BCC', 'Phenotype', 'HP:0002671', (0, 3))	('tumor', 'Disease', 'MESH:D009369', (162, 167))
86201	29464122	In the long run, these genetic changes can cause neoplasms.	('cause', 'Reg', (43, 48))	('neoplasm', 'Phenotype', 'HP:0002664', (49, 57))	('neoplasms', 'Disease', (49, 58))	('neoplasms', 'Disease', 'MESH:D009369', (49, 58))	('neoplasms', 'Phenotype', 'HP:0002664', (49, 58))	('genetic changes', 'Var', (23, 38))
86202	29464122	Mutations in the p53 tumor suppressor gene have been found in approximately 50% of BCC cases.	('BCC', 'Phenotype', 'HP:0002671', (83, 86))	('tumor', 'Disease', (21, 26))	('found', 'Reg', (53, 58))	('Mutations', 'Var', (0, 9))	('BCC', 'Disease', (83, 86))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('p53', 'Gene', (17, 20))	('p53', 'Gene', '7157', (17, 20))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
86252	29464122	(2011) to find the sensitivity and specificity of BerEP4 in patients of Asian origin with SCC as control also reported that BerEP4 has a sensitivity and specificity of 100%.	('BerEP4', 'Var', (124, 130))	('patients', 'Species', '9606', (60, 68))	('SCC', 'Gene', (90, 93))	('SCC', 'Phenotype', 'HP:0002860', (90, 93))	('BerEP4', 'Chemical', '-', (124, 130))	('SCC', 'Gene', '6317', (90, 93))	('BerEP4', 'Chemical', '-', (50, 56))
86262	29464122	(2013) reported that BerEP4 alone was unable to differentiate bSCC and BSC as both were stained by BerEP4, although the mean percentage of cells stained was significantly higher in BSC group compared to bSCC.	('SCC', 'Gene', (63, 66))	('SCC', 'Phenotype', 'HP:0002860', (63, 66))	('BerEP4', 'Chemical', '-', (21, 27))	('higher', 'PosReg', (171, 177))	('bSCC', 'Phenotype', 'HP:0002671', (203, 207))	('bSCC', 'Phenotype', 'HP:0002671', (62, 66))	('SCC', 'Gene', '6317', (63, 66))	('SCC', 'Gene', (204, 207))	('BerEP4', 'Var', (99, 105))	('SCC', 'Phenotype', 'HP:0002860', (204, 207))	('SCC', 'Gene', '6317', (204, 207))	('BerEP4', 'Chemical', '-', (99, 105))
86320	25724406	Tumor vascular leakiness and hypoxia were enhanced after HBOT, whereas histological characteristics, epithelial-to-mesenchymal transition markers, and metastatic incidence were not influenced.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('hypoxia', 'Disease', (29, 36))	('hypoxia', 'Disease', 'MESH:D000860', (29, 36))	('Tumor vascular leakiness', 'Disease', 'MESH:C535298', (0, 24))	('enhanced', 'PosReg', (42, 50))	('Tumor vascular leakiness', 'Disease', (0, 24))	('HBOT', 'Var', (57, 61))
86395	25724406	2d, the site of accumulation of AngioSense750 in and around the tumor is shown and coregistered with the signal of the probe MMPSense680 which indicates the tumor margins.	('tumor', 'Disease', (157, 162))	('tumor', 'Disease', (64, 69))	('AngioSense750', 'Var', (32, 45))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('accumulation', 'PosReg', (16, 28))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
86421	25724406	Also, in the irradiated groups, in which the survival period was extended by HBOT but the tumor growth rate was not affected, a trend towards increased endpoint tumor load was noticed.	('tumor', 'Disease', (161, 166))	('increased', 'PosReg', (142, 151))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('HBOT', 'Var', (77, 81))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
86428	25724406	This is the first study exploring the effects of HBOT on vascular permeability, indicating that HBOT does not lead to normalization of blood vessels and might even deteriorate tumor vascular quality.	('HBOT', 'Var', (96, 100))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('tumor', 'Disease', (176, 181))	('deteriorate', 'NegReg', (164, 175))	('tumor', 'Disease', 'MESH:D009369', (176, 181))
86432	25724406	Nevertheless, ex vivo, hypoxic regions were detected in a subset of tumors and the data suggest that irradiated tumors were more hypoxic than non-irradiated tumors and moreover, that HBOT aggravated tumor hypoxia as well.	('tumors', 'Disease', 'MESH:D009369', (68, 74))	('irradiated tumors', 'Disease', 'MESH:D012793', (101, 118))	('irradiated tumors', 'Disease', (146, 163))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('tumors', 'Disease', 'MESH:D009369', (112, 118))	('tumor hypoxia', 'Disease', 'MESH:D000860', (199, 212))	('tumors', 'Phenotype', 'HP:0002664', (157, 163))	('irradiated tumors', 'Disease', 'MESH:D012793', (146, 163))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('HBOT', 'Var', (183, 187))	('tumors', 'Disease', (157, 163))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('hypoxic', 'MPA', (129, 136))	('tumors', 'Disease', (68, 74))	('tumor hypoxia', 'Disease', (199, 212))	('tumors', 'Disease', 'MESH:D009369', (157, 163))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('irradiated tumors', 'Disease', (101, 118))	('aggravated', 'PosReg', (188, 198))	('tumors', 'Disease', (112, 118))
86457	33514401	Here, we aimed to systematically evaluate the value of B7-H3 as a target in NSCLC via T cells expressing B7-H3-specific chimeric antigen receptors (CARs) and bispecific killer cell engager (BiKE)-redirected natural killer (NK) cells.	('NSCLC', 'Disease', 'MESH:D002289', (76, 81))	('NSCLC', 'Disease', (76, 81))	('NSCLC', 'Phenotype', 'HP:0030358', (76, 81))	('B7-H3-specific', 'Var', (105, 119))
86458	33514401	We generated B7-H3 CAR and B7-H3/CD16 BiKE derived from an anti-B7-H3 antibody omburtamab that has been shown to preferentially bind tumor tissues and has been safely used in humans in early-phase clinical trials.	('bind', 'Interaction', (128, 132))	('omburtamab', 'Chemical', '-', (79, 89))	('B7-H3/CD16', 'Var', (27, 37))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('humans', 'Species', '9606', (175, 181))	('tumor', 'Disease', (133, 138))	('preferentially', 'PosReg', (113, 127))
86475	33514401	In particular, inhibiting PD-1 and its ligand PD-L1 axis has shown remarkably results in NSCLC treatment.	('NSCLC', 'Disease', 'MESH:D002289', (89, 94))	('PD-1', 'Gene', (26, 30))	('inhibiting', 'Var', (15, 25))	('NSCLC', 'Phenotype', 'HP:0030358', (89, 94))	('NSCLC', 'Disease', (89, 94))	('results', 'Reg', (78, 85))
86496	33514401	Here, we aimed to systematically evaluate the value of B7-H3 as a target in NSCLC via T cells expressing B7-H3-specific CARs and BiKE-redirected natural killer (NK) cells.	('NSCLC', 'Disease', 'MESH:D002289', (76, 81))	('NSCLC', 'Disease', (76, 81))	('NSCLC', 'Phenotype', 'HP:0030358', (76, 81))	('B7-H3-specific', 'Var', (105, 119))
86524	33514401	To generate a BiKE targeting B7-H3 and CD16, the anti-B7-H3 scFv 8H9 and anti-CD16 scFv 3G8 were linked with an additional (GGGGS)3 linker and then cloned into the pSecTag B expression vector.	('8H9', 'Chemical', '-', (65, 68))	('scFv', 'Gene', '652070', (83, 87))	('anti-CD16', 'Var', (73, 82))	('scFv', 'Gene', (83, 87))	('scFv', 'Gene', '652070', (60, 64))	('scFv', 'Gene', (60, 64))
86540	33514401	Human B7-H3 expression on cell surface of tumor cells was detected using anti-B7-H3 IgG 8H9, followed by a fluorescently-labeled anti-human Fc antibody.	('Human', 'Species', '9606', (0, 5))	('human', 'Species', '9606', (134, 139))	('tumor', 'Disease', (42, 47))	('detected', 'Reg', (58, 66))	('anti-B7-H3', 'Var', (73, 83))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('8H9', 'Chemical', '-', (88, 91))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
86564	33514401	IHC staining results showed that B7-H3 was widely expressed in all types of solid tumors with a high percentage (29/39, 74%) but was not detectable in most of the normal tissues (31/34, 91%).	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('solid tumors', 'Disease', 'MESH:D009369', (76, 88))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('solid tumors', 'Disease', (76, 88))	('B7-H3', 'Var', (33, 38))
86566	33514401	Although 8H9 did not perform adequately when used as a primary antibody to stain FFPE tumor sections, the staining of 8H9 was specific for tumor tissues but not normal tissues.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('8H9', 'Var', (118, 121))	('tumor', 'Disease', (86, 91))	('8H9', 'Chemical', '-', (9, 12))	('8H9', 'Chemical', '-', (118, 121))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
86572	33514401	High B7-H3 expression was significantly associated with poor 5-year overall survival (5yr-OS) of patients with LUAD (p = 0.0037; Additional file 1: Fig.	('poor', 'NegReg', (56, 60))	('High', 'Var', (0, 4))	('B7-H3', 'Protein', (5, 10))	('expression', 'MPA', (11, 21))	('LUAD', 'Phenotype', 'HP:0030078', (111, 115))	('overall survival', 'MPA', (68, 84))	('5yr-OS', 'Chemical', '-', (86, 92))	('patients', 'Species', '9606', (97, 105))
86583	33514401	All of B7-H3-positive tumor cell lines efficiently responded to the B7-H3 CAR.	('responded', 'MPA', (51, 60))	('B7-H3', 'Var', (68, 73))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('tumor', 'Disease', (22, 27))
86586	33514401	The percentage of tumor cells that underwent apoptosis was significantly higher in the presence of B7-H3 CAR-T cells than vehicle T cells (Fig.	('tumor', 'Disease', (18, 23))	('B7-H3 CAR-T cells', 'Var', (99, 116))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('B7-H3 CAR-T', 'CellLine', 'CVCL:4140', (99, 110))	('higher', 'PosReg', (73, 79))
86595	33514401	Overall, the B7-H3 CAR was effective to delay tumor growth in tumor-bearing mice without causing detectable organ toxicity.	('delay', 'NegReg', (40, 45))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('B7-H3 CAR', 'Var', (13, 22))	('tumor', 'Disease', (62, 67))	('tumor', 'Disease', (46, 51))	('toxicity', 'Disease', 'MESH:D064420', (114, 122))	('toxicity', 'Disease', (114, 122))	('mice', 'Species', '10090', (76, 80))	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
86597	33514401	After 24-h co-incubation of tumor cells and effector T cells at an E:T ratio of 10:1, B7-H3 CAR-T cells produced significantly higher amounts of IFN-gamma, TNF-alpha, IL-2, IL-6, IL-4 and IL-10 in the culture supernatants compared with vehicle T cells (Fig.	('TNF-alpha', 'MPA', (156, 165))	('tumor', 'Disease', (28, 33))	('B7-H3 CAR-T', 'CellLine', 'CVCL:4140', (86, 97))	('B7-H3', 'Var', (86, 91))	('higher', 'PosReg', (127, 133))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
86598	33514401	B7-H3 CAR-T cells exhibited the increased proportion of CCR7+CD62L+ cells compared with vehicle control T cells, suggesting that B7-H3 CAR-T cells differentiated into the naive and central memory T cells which are considered as favorable phenotypic characteristics to ensure persistence and antitumor effects (Fig.	('CD62L', 'Gene', (61, 66))	('B7-H3 CAR-T', 'CellLine', 'CVCL:4140', (0, 11))	('central memory T', 'Disease', (181, 197))	('tumor', 'Disease', 'MESH:D009369', (295, 300))	('central memory T', 'Disease', 'MESH:D008569', (181, 197))	('tumor', 'Phenotype', 'HP:0002664', (295, 300))	('CCR7', 'Gene', (56, 60))	('B7-H3', 'Var', (129, 134))	('CCR7', 'Gene', '12775', (56, 60))	('tumor', 'Disease', (295, 300))	('CD62L', 'Gene', '20343', (61, 66))	('B7-H3 CAR-T', 'CellLine', 'CVCL:4140', (129, 140))
86609	33514401	These data corroborate that B7-H3 redirection promotes T cell to infiltrate into tumors in a specific manner.	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('tumors', 'Disease', (81, 87))	('B7-H3 redirection', 'Var', (28, 45))	('T cell to infiltrate into', 'CPA', (55, 80))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('promotes', 'PosReg', (46, 54))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))
86610	33514401	The B7-H3/CD16 BiKE, which simultaneously targets B7-H3 and a NK cell activator CD16, was constructed by linking the anti-B7-H3 8H9 scFv and the anti-CD16 scFv with a nonimmunogenic (glycine4:serine)3 linker (Fig.	('glycine4', 'Chemical', '-', (183, 191))	('8H9', 'Chemical', '-', (128, 131))	('serine', 'Chemical', 'MESH:D012694', (192, 198))	('scFv', 'Gene', '652070', (132, 136))	('scFv', 'Gene', '652070', (155, 159))	('anti-B7-H3', 'Var', (117, 127))	('scFv', 'Gene', (132, 136))	('scFv', 'Gene', (155, 159))
86619	33514401	B7-H3/CD16 BiKE-mediated cytotoxicity was specific as the BiKE significantly potentiated cytotoxic activity against B7-H3-positive solid tumor cells, whereas no cell death was observed in a B7-H3-negative cell line Daudi (Fig.	('cytotoxicity', 'Disease', 'MESH:D064420', (25, 37))	('tumor', 'Disease', (137, 142))	('B7-H3/CD16', 'Var', (0, 10))	('potentiated', 'PosReg', (77, 88))	('cytotoxic activity', 'CPA', (89, 107))	('cytotoxicity', 'Disease', (25, 37))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
86622	33514401	As controls, the anti-B7-H3 and anti-CD16 scFv had no significant effects on the increase of cell lysis function.	('cell lysis function', 'CPA', (93, 112))	('anti-B7-H3', 'Var', (17, 27))	('scFv', 'Gene', '652070', (42, 46))	('scFv', 'Gene', (42, 46))	('anti-CD16', 'Var', (32, 41))
86644	33514401	We found that the treatment with anti-B7-H3 antibody resulted in lower levels of ROS (Fig.	('lower', 'NegReg', (65, 70))	('anti-B7-H3 antibody', 'Var', (33, 52))	('ROS', 'MPA', (81, 84))	('levels', 'MPA', (71, 77))	('ROS', 'Chemical', 'MESH:D017382', (81, 84))
86652	33514401	According to the TCGA data, the mRNA expression levels of B7-H3 were highly associated with the malignancy grade of NSCLC.	('NSCLC', 'Disease', 'MESH:D002289', (116, 121))	('mRNA expression levels', 'MPA', (32, 54))	('B7-H3', 'Var', (58, 63))	('malignancy', 'Disease', 'MESH:D009369', (96, 106))	('malignancy', 'Disease', (96, 106))	('NSCLC', 'Phenotype', 'HP:0030358', (116, 121))	('associated', 'Reg', (76, 86))	('NSCLC', 'Disease', (116, 121))
86654	33514401	B7-H3 expression may be correlated with tumor metastasis, because moderate expression of B7-H3 was also observed in paracancerous tissues, although the intensity was weaker than that in tumor tissues.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('B7-H3', 'Var', (89, 94))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('tumor', 'Disease', (186, 191))	('tumor metastasis', 'Disease', (40, 56))	('tumor', 'Disease', (40, 45))	('tumor metastasis', 'Disease', 'MESH:D009362', (40, 56))	('expression', 'MPA', (75, 85))
86660	33514401	NK dysfunctions promote metastasis in several human malignancies.	('dysfunctions', 'Var', (3, 15))	('human', 'Species', '9606', (46, 51))	('malignancies', 'Disease', 'MESH:D009369', (52, 64))	('metastasis', 'CPA', (24, 34))	('malignancies', 'Disease', (52, 64))	('promote', 'PosReg', (16, 23))
86664	33514401	In two xenografts involving A549 (high level of B7-H3) and NCI-H23 (low level of B7-H3), our results showed that BiKE was effective to suppress NSCLC growth in both models as was demonstrated with reduced tumor volume (75-80%), The in vivo activity of BiKE was not limited by B7-H3 antigen density of NCI-H23 at the low level.	('NSCLC', 'Disease', (144, 149))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('NSCLC', 'Disease', 'MESH:D002289', (144, 149))	('suppress', 'NegReg', (135, 143))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumor', 'Disease', (205, 210))	('NSCLC', 'Phenotype', 'HP:0030358', (144, 149))	('BiKE', 'Var', (113, 117))
86667	33514401	B7-H3 blockade promoted T cells differentiation into the naive and central memory T cells, reflecting the increase of T cell persistence.	('promoted', 'PosReg', (15, 23))	('T cells differentiation', 'CPA', (24, 47))	('B7-H3', 'Protein', (0, 5))	('blockade', 'Var', (6, 14))	('increase', 'PosReg', (106, 114))	('central memory T', 'Disease', (67, 83))	('T cell persistence', 'CPA', (118, 136))	('central memory T', 'Disease', 'MESH:D008569', (67, 83))
86671	33514401	Our results showed that the B7-H3 CARs are expected to have minimal off-target toxicity.	('toxicity', 'Disease', 'MESH:D064420', (79, 87))	('B7-H3 CARs', 'Var', (28, 38))	('toxicity', 'Disease', (79, 87))
86672	33514401	Because B7-H3 expression is limited in normal tissues, B7-H3 CAR T cells mainly extravasated into solid tumors but not into normal tissues.	('solid tumors', 'Disease', (98, 110))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('B7-H3', 'Var', (55, 60))	('solid tumors', 'Disease', 'MESH:D009369', (98, 110))	('extravasated', 'MPA', (80, 92))	('B7-H3 CAR T', 'CellLine', 'CVCL:4140', (55, 66))
86673	33514401	It suggests that tumor regional infiltration of B7-H3 CAR-T cells may limit systemic toxicity by reducing the cross-reactivity of CAR-T cells in other organs.	('tumor', 'Disease', (17, 22))	('toxicity', 'Disease', 'MESH:D064420', (85, 93))	('toxicity', 'Disease', (85, 93))	('B7-H3', 'Var', (48, 53))	('B7-H3 CAR-T', 'CellLine', 'CVCL:4140', (48, 59))	('limit', 'NegReg', (70, 75))	('reducing', 'NegReg', (97, 105))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('cross-reactivity', 'MPA', (110, 126))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
86675	33514401	In NSCLC patients, B7-H3 was associated with adaptive resistance to anti-PD-1 therapy.	('patients', 'Species', '9606', (9, 17))	('NSCLC', 'Disease', (3, 8))	('NSCLC', 'Disease', 'MESH:D002289', (3, 8))	('adaptive resistance', 'MPA', (45, 64))	('associated', 'Reg', (29, 39))	('NSCLC', 'Phenotype', 'HP:0030358', (3, 8))	('B7-H3', 'Var', (19, 24))
86689	33514401	Although recent studies suggested that B7-H3 modulated glucose metabolism in breast cancer and colorectal cancer, the effects of B7-H3 on aerobic glycolysis in NSCLC remain unknown.	('glucose metabolism in breast cancer', 'Disease', 'MESH:D001943', (55, 90))	('colorectal cancer', 'Phenotype', 'HP:0003003', (95, 112))	('breast cancer', 'Phenotype', 'HP:0003002', (77, 90))	('colorectal cancer', 'Disease', (95, 112))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('glucose metabolism in breast cancer', 'Disease', (55, 90))	('NSCLC', 'Phenotype', 'HP:0030358', (160, 165))	('colorectal cancer', 'Disease', 'MESH:D015179', (95, 112))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('NSCLC', 'Disease', (160, 165))	('modulated', 'Reg', (45, 54))	('B7-H3', 'Var', (39, 44))	('NSCLC', 'Disease', 'MESH:D002289', (160, 165))
86700	33514401	Therefore, further research should explore the potential of anti-B7-H3 CAR and BiKE against NSCLC in the future preclinical and clinical studies.	('NSCLC', 'Phenotype', 'HP:0030358', (92, 97))	('NSCLC', 'Disease', 'MESH:D002289', (92, 97))	('anti-B7-H3', 'Var', (60, 70))	('NSCLC', 'Disease', (92, 97))
86770	30701030	The other five patients did not undergo adjuvant therapy; the rate of no adjuvant therapy was lower in the NAIAC group than that in the PRH group (35.2% vs. 10.2%, p<0.01).	('NAIAC', 'Chemical', '-', (107, 112))	('patients', 'Species', '9606', (15, 23))	('NAIAC', 'Var', (107, 112))	('lower', 'NegReg', (94, 99))
86773	30701030	Median follow up was shorter in the NAIAC group than that in the PRH group (30 vs. 48 months, p<0.01).	('NAIAC', 'Chemical', '-', (36, 41))	('NAIAC', 'Var', (36, 41))	('shorter', 'NegReg', (21, 28))
86774	30701030	The three-year disease free survival rate was significantly higher in the NAIAC group than that in the PRH group (64% vs. 52%, p=0.02).	('disease free survival', 'CPA', (15, 36))	('NAIAC', 'Var', (74, 79))	('NAIAC', 'Chemical', '-', (74, 79))	('higher', 'PosReg', (60, 66))
86782	30701030	The NAIAC group had excellent DFS, compared with the PRH group.	('NAIAC', 'Chemical', '-', (4, 9))	('DFS', 'MPA', (30, 33))	('NAIAC', 'Var', (4, 9))
86818	30701030	In our previous report about intra-arterial chemotherapy using a 4L-DB, the platinum concentration was significantly higher in the tumors with a CR to NAIAC than those with a PR and SD (p<0.0001, CR; 11.5 +- 0.8 mug/g, PR; 7.3 +- 0.5mug/g, SD; 4.5 +- 0.1 mug/g).	('higher', 'PosReg', (117, 123))	('platinum concentration', 'MPA', (76, 98))	('platinum', 'Chemical', 'MESH:D010984', (76, 84))	('CR', 'Chemical', '-', (145, 147))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('NAIAC', 'Chemical', '-', (151, 156))	('CR to', 'Var', (145, 150))	('tumors', 'Disease', 'MESH:D009369', (131, 137))	('tumors', 'Disease', (131, 137))	('CR', 'Chemical', '-', (196, 198))	('4L-DB', 'Chemical', '-', (65, 70))
86820	30701030	Making comparison between NAC plus radical surgery and primary radiotherapy, a meta-analysis of randomized trials including 872 patients with locally advanced cervical cancer showed that NAC obtained a better DFS (HR = 0.68, 95% CI = 0.56-0.82) and OS (HR = 0.65, 95% CI = 0.53-0.80).	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('DFS', 'MPA', (209, 212))	('better', 'PosReg', (202, 208))	('NAC', 'Var', (187, 190))	('NAC', 'Chemical', '-', (187, 190))	('OS', 'Chemical', 'MESH:D009992', (249, 251))	('cervical cancer', 'Disease', 'MESH:D002583', (159, 174))	('patients', 'Species', '9606', (128, 136))	('NAC', 'Chemical', '-', (26, 29))	('cervical cancer', 'Disease', (159, 174))
86821	30701030	indicated that cisplatin-based CCRT resulted in superior DFS compared with NAC followed by radical surgery in locally advanced cervical cancer.	('cisplatin-based', 'Var', (15, 30))	('superior', 'PosReg', (48, 56))	('DFS', 'MPA', (57, 60))	('cisplatin', 'Chemical', 'MESH:D002945', (15, 24))	('cervical cancer', 'Disease', 'MESH:D002583', (127, 142))	('CR', 'Chemical', '-', (32, 34))	('cervical cancer', 'Disease', (127, 142))	('NAC', 'Chemical', '-', (75, 78))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
86831	30701030	Furthermore, NAC reduced the need for adjuvant radiotherapy and decreased the rate of distant metastasis.	('decreased', 'NegReg', (64, 73))	('NAC', 'Var', (13, 16))	('NAC', 'Chemical', '-', (13, 16))	('reduced', 'NegReg', (17, 24))	('distant metastasis', 'CPA', (86, 104))
86836	30701030	JCOG0102, which is a prospective randomized control trial for NAC in stage IB1 to IIB cervical cancer in Japan, showed that NAC had no prognostic advantage; however, it did reduce the need for adjuvant radiotherapy.	('NAC', 'Chemical', '-', (62, 65))	('reduce', 'NegReg', (173, 179))	('IIB', 'Gene', '50771', (82, 85))	('cervical cancer', 'Disease', 'MESH:D002583', (86, 101))	('IB1', 'Gene', '9479', (75, 78))	('NAC', 'Var', (124, 127))	('IIB', 'Gene', (82, 85))	('NAC', 'Chemical', '-', (124, 127))	('cervical cancer', 'Disease', (86, 101))	('IB1', 'Gene', (75, 78))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))
86837	30701030	In our study, DFS was significantly longer in those patients who received NAIAC than in those who underwent primary radical surgery.	('DFS', 'MPA', (14, 17))	('NAIAC', 'Var', (74, 79))	('longer', 'PosReg', (36, 42))	('patients', 'Species', '9606', (52, 60))	('NAIAC', 'Chemical', '-', (74, 79))
86848	30701030	Patients were eligible for inclusion in the study when they met the following criteria: (1) patients with an International Federation of Obstetricians and Gynecologists (FIGO) stage IB2, IIA2 or IIB cervical squamous cell carcinoma or adenocarcinoma who were treated by NAIAC with cisplatin and irinotecan using a 4L-DB or a radical hysterectomy with salpingo-oophorectomy as an initial treatment.	('NAIAC', 'Chemical', '-', (270, 275))	('adenocarcinoma', 'Disease', (235, 249))	('irinotecan', 'Chemical', 'MESH:D000077146', (295, 305))	('IB2', 'Gene', '23542', (182, 185))	('4L-DB', 'Chemical', '-', (314, 319))	('IIB', 'Gene', '50771', (195, 198))	('patients', 'Species', '9606', (92, 100))	('adenocarcinoma', 'Disease', 'MESH:D000230', (235, 249))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (208, 231))	('squamous cell carcinoma', 'Disease', (208, 231))	('IIA2', 'Var', (187, 191))	('Patients', 'Species', '9606', (0, 8))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (208, 231))	('IB2', 'Gene', (182, 185))	('carcinoma', 'Phenotype', 'HP:0030731', (222, 231))	('IIB', 'Gene', (195, 198))	('carcinoma', 'Phenotype', 'HP:0030731', (240, 249))	('cisplatin', 'Chemical', 'MESH:D002945', (281, 290))
86850	30701030	In contrast, PRH was performed when the patient had no seriously restricted uterus; (2) age less than 70 years; (3) a World Health Organization (WHO) performance status of 0 to 2; (4) fulfillment of pretreatment laboratory requirements, including a leukocyte count more than 3000/mm3, a platelet count more than 100 000/mm3, serum creatinine less than 1.5 mg/dl, serum bilirubin less than 1.5 mg/dl, and normal serum aspartate transaminase (AST) and serum alanine transaminase (ALT); (5) patients without any other major organ disease; and (6) the patient had sufficient clinical data regarding the oncologic outcome, including the date of recurrence.	('serum aspartate transaminase', 'MPA', (411, 439))	('patient', 'Species', '9606', (40, 47))	('serum creatinine less', 'Phenotype', 'HP:0012101', (325, 346))	('less', 'NegReg', (379, 383))	('patient', 'Species', '9606', (548, 555))	('restricted uterus', 'Phenotype', 'HP:0000013', (65, 82))	('AST', 'Gene', (441, 444))	('organ disease', 'Disease', 'MESH:D019965', (521, 534))	('patient', 'Species', '9606', (488, 495))	('serum bilirubin', 'MPA', (363, 378))	('serum alanine transaminase', 'MPA', (450, 476))	('organ disease', 'Disease', (521, 534))	('patients', 'Species', '9606', (488, 496))	('AST', 'Gene', '26503', (441, 444))	('more than 3000/mm3', 'Var', (265, 283))
86872	30053901	Using a pan-cancer cohort of 6570 tumors, we identified tumors with potentially druggable biomarkers consisting of drug-associated mutations, mRNA expression outliers, and protein/phosphoprotein expression outliers identified by DEPO.	('mutations', 'Var', (131, 140))	('tumors', 'Disease', (34, 40))	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('tumors', 'Disease', 'MESH:D009369', (34, 40))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('cancer', 'Disease', (12, 18))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('protein/phosphoprotein expression', 'MPA', (172, 205))	('tumors', 'Disease', (56, 62))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('mRNA expression', 'MPA', (142, 157))
86876	30053901	Further, our analyses showed co-occurring potentially druggable multi-omics alterations in 32% of tumors, indicating a role for individualized combinational therapy, with evidence supporting mTOR/PI3K/ESR1 co-inhibition and BRAF/AKT co-inhibition in 1.6 and 0.8% of tumors, respectively.	('alterations', 'Var', (76, 87))	('tumors', 'Disease', (98, 104))	('ESR1', 'Gene', '2099', (201, 205))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('mTOR', 'Gene', (191, 195))	('AKT', 'Gene', '207', (229, 232))	('mTOR', 'Gene', '2475', (191, 195))	('tumors', 'Disease', 'MESH:D009369', (98, 104))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('ESR1', 'Gene', (201, 205))	('tumor', 'Phenotype', 'HP:0002664', (266, 271))	('BRAF', 'Gene', (224, 228))	('AKT', 'Gene', (229, 232))	('BRAF', 'Gene', '673', (224, 228))	('tumors', 'Phenotype', 'HP:0002664', (266, 272))	('tumors', 'Disease', 'MESH:D009369', (266, 272))	('tumors', 'Disease', (266, 272))
86877	30053901	We experimentally validated a subset of putative druggable mutations in BRAF identified by a protein structure-based computational tool.	('BRAF', 'Gene', (72, 76))	('BRAF', 'Gene', '673', (72, 76))	('mutations', 'Var', (59, 68))
86886	30053901	The Cancer Genome Atlas (TCGA), the Clinical Proteomic Tumor Analysis Consortium (CPTAC), and other large-scale sequencing data sets represent an opportunity to identify "druggable" variants, i.e., variants that render a cancer type susceptible to a drug.	('cancer', 'Disease', 'MESH:D009369', (221, 227))	('cancer', 'Disease', (221, 227))	('render', 'Reg', (212, 218))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (4, 23))	('variants', 'Var', (182, 190))	('Tumor', 'Phenotype', 'HP:0002664', (55, 60))	('Cancer', 'Phenotype', 'HP:0002664', (4, 10))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('variants', 'Var', (198, 206))	('Cancer Genome Atlas', 'Disease', (4, 23))
86889	30053901	We identified tumors with drug-associated mutations and found considerable opportunity for repurposing of drugs across cancer types.	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('tumors', 'Disease', (14, 20))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('cancer', 'Disease', (119, 125))	('drug-associated', 'Reg', (26, 41))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('mutations', 'Var', (42, 51))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
86890	30053901	We used a structure-based computational tool to identify putative druggable mutations based on proximity to known druggable mutations and experimentally validated a subset of putative druggable mutations in BRAF.	('BRAF', 'Gene', (207, 211))	('BRAF', 'Gene', '673', (207, 211))	('mutations', 'Var', (76, 85))	('mutations', 'Var', (194, 203))
86898	30053901	Tumor type is included for each variant/drug entry because, with infrequent exception, a variant's effect on a tumor's response to a given drug has only been rigorously studied in one or only a few cancer type(s).	('response to a given drug', 'MPA', (119, 143))	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('cancer', 'Disease', (198, 204))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('variant', 'Var', (89, 96))	('tumor', 'Disease', (111, 116))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))
86899	30053901	For a variant/drug entry based on preclinical data, tumor type was either inferred from the xenograft or cell line, or left unspecified.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('variant/drug', 'Var', (6, 18))	('tumor', 'Disease', (52, 57))	('unspecified', 'Species', '32644', (124, 135))	('tumor', 'Disease', 'MESH:D009369', (52, 57))
86900	30053901	Copy number amplifications (CNA) and losses (CNL), high expression outliers in oncogenes, low expression outliers in tumor suppressors, and fusions that may lead to druggability are also included.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('druggability', 'MPA', (165, 177))	('losses', 'NegReg', (37, 43))	('tumor', 'Disease', (117, 122))	('lead to', 'Reg', (157, 164))	('Copy number amplifications', 'Var', (0, 26))	('oncogenes', 'Gene', (79, 88))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
86901	30053901	Effect describes whether a variant correlates with increased sensitivity of a tumor to a drug or increased resistance of a tumor to a drug.	('increased', 'PosReg', (97, 106))	('tumor', 'Disease', (123, 128))	('increased', 'PosReg', (51, 60))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('variant', 'Var', (27, 34))	('tumor', 'Disease', (78, 83))	('sensitivity', 'MPA', (61, 72))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('resistance', 'MPA', (107, 117))
86902	30053901	A given drug entry in DEPO could be associated with multiple drug families to allow for the possibility of combining therapies (e.g., dabrafenib [B-Raf inhibitor] and trametinib [MEK inhibitor] for BRAF V600E/K-mutant melanoma) and multi-targeted tyrosine kinase inhibitors (e.g., afatinib as a dual HER2 and EGFR inhibitor).	('EGFR', 'Gene', '1956', (309, 313))	('BRAF', 'Gene', '673', (198, 202))	('BRAF', 'Gene', (198, 202))	('MEK', 'Gene', '5609', (179, 182))	('dabrafenib', 'Chemical', 'MESH:C561627', (134, 144))	('melanoma', 'Disease', 'MESH:D008545', (218, 226))	('B-Raf', 'Gene', '673', (146, 151))	('V600E', 'Var', (203, 208))	('HER2', 'Gene', '2064', (300, 304))	('MEK', 'Gene', (179, 182))	('EGFR', 'Gene', (309, 313))	('tyrosine kinase', 'Gene', (247, 262))	('tyrosine kinase', 'Gene', '7294', (247, 262))	('afatinib', 'Chemical', 'MESH:D000077716', (281, 289))	('trametinib', 'Chemical', 'MESH:C560077', (167, 177))	('V600E', 'SUBSTITUTION', 'None', (203, 208))	('melanoma', 'Phenotype', 'HP:0002861', (218, 226))	('melanoma', 'Disease', (218, 226))	('B-Raf', 'Gene', (146, 151))	('HER2', 'Gene', (300, 304))
86906	30053901	Variant calls were obtained from the TCGA Genome Data Analysis Centers (GDAC), Data Coordinating Center (DCC), and previously published TCGA marker papers until the end of 2014 (https://cancergenome.nih.gov/publications).	('GDAC', 'Chemical', '-', (72, 76))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('DCC', 'Chemical', '-', (105, 108))	('cancer', 'Disease', (186, 192))	('Variant', 'Var', (0, 7))	('cancer', 'Disease', 'MESH:D009369', (186, 192))
86907	30053901	Variant calls were excluded if metastases or recurrent samples were present for samples that already had a primary tumor in the mutation annotation file (MAF).	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('metastases', 'Disease', 'MESH:D009362', (31, 41))	('tumor', 'Disease', (115, 120))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('metastases', 'Disease', (31, 41))	('Variant', 'Var', (0, 7))
86910	30053901	We identified tumors in our pan-cancer cohort that harbored one or more drug-associated SNP or indel.	('indel', 'Var', (95, 100))	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('cancer', 'Disease', (32, 38))	('tumors', 'Disease', (14, 20))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('SNP', 'Var', (88, 91))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
86911	30053901	Iterating through a mutation annotation format (MAF) file containing all variants in our pan-cancer cohort, we performed two actions for each entry in the MAF.	('cancer', 'Disease', (93, 99))	('variants', 'Var', (73, 81))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))
86912	30053901	First, we queried a hash table containing all druggable, unambiguous mutations in DEPO (e.g., BRAF V600E) and a separate hash table containing all druggable, ambiguous, single-residue mutations in DEPO (e.g., BRAF V600).	('single-residue', 'Var', (169, 183))	('mutations', 'Var', (69, 78))	('BRAF', 'Gene', (94, 98))	('V600E', 'Mutation', 'rs113488022', (99, 104))	('BRAF', 'Gene', (209, 213))	('BRAF', 'Gene', '673', (209, 213))	('DEPO', 'Gene', (197, 201))	('BRAF', 'Gene', '673', (94, 98))	('DEPO', 'Gene', (82, 86))
86913	30053901	Second, we queried several classes of mutations that occur in a specific exon or segment of a gene (EGFR exon 19 in-frame deletion).	('mutations', 'Var', (38, 47))	('EGFR', 'Gene', '1956', (100, 104))	('EGFR', 'Gene', (100, 104))
86915	30053901	In some cases, DEPO contains multiple entries per gene/mutation pair to reflect possible druggability of a gene/mutation pair in more than one tumor type, or that it may confer an effect (e.g., sensitivity or resistance) that depends on tumor type or other therapeutic context.	('resistance', 'CPA', (209, 219))	('tumor', 'Disease', (237, 242))	('tumor', 'Disease', (143, 148))	('druggability', 'MPA', (89, 101))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))	('tumor', 'Disease', 'MESH:D009369', (237, 242))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('gene/mutation', 'Var', (107, 120))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('sensitivity', 'MPA', (194, 205))
86916	30053901	For example, when visualizing "drug repurposing" across tumor types, a given mutation could be associated with > 1 "cancer-type-specific" tumor type, if a given gene/mutation pair had druggability information in DEPO in multiple tumor types at the same level of evidence.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Disease', 'MESH:D009369', (229, 234))	('tumor', 'Disease', (138, 143))	('mutation', 'Var', (77, 85))	('cancer', 'Disease', (116, 122))	('tumor', 'Disease', (56, 61))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('tumor', 'Disease', (229, 234))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('associated', 'Reg', (95, 105))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
86920	30053901	When considering potential druggable events in the cancer-type-non-specific setting, the drug with the highest level of evidence found across all tumor types was used for a specific variant (Additional file 2: Table S3).	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('tumor', 'Disease', (146, 151))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('variant', 'Var', (182, 189))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
86922	30053901	If any sensitive interaction for a variant was found regardless of the tumor type and level, it was considered a "druggable" event for these analyses.	('variant', 'Var', (35, 42))	('tumor', 'Disease', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Disease', 'MESH:D009369', (71, 76))
86923	30053901	HotSpot3D was used to spatially cluster "known" drug-associated mutations in DEPO with putative druggable mutations in our pan-cancer cohort.	('DEPO', 'Gene', (77, 81))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('mutations', 'Var', (64, 73))	('cancer', 'Disease', (127, 133))
86937	30053901	The distribution of LN(IC50) values of cell lines with DEPO mutations (both sensitive and resistant) for both the cancer-type-specific and non-specific settings were compared to a background distribution using the Mann-Whitney U test.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('DEPO', 'Gene', (55, 59))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('mutations', 'Var', (60, 69))	('cancer', 'Disease', (114, 120))
86944	30053901	Constructions expressing BRAF variants were generated from a plasmid expressing a wild-type BRAF (Addgene, #40775) with an N-terminal Flag tag using Q5 site-directed mutagenesis (New England BioLabs).	('variants', 'Var', (30, 38))	('BRAF', 'Gene', '673', (92, 96))	('BRAF', 'Gene', (92, 96))	('BRAF', 'Gene', '673', (25, 29))	('BRAF', 'Gene', (25, 29))
86945	30053901	Cells were transiently transfected with wild-type or mutant BRAF constructs using Lipofectamine 2000 reagent (Life Technologies) in six-well plates.	('BRAF', 'Gene', (60, 64))	('Lipofectamine 2000 reagent', 'Chemical', '-', (82, 108))	('BRAF', 'Gene', '673', (60, 64))	('mutant', 'Var', (53, 59))
86952	30053901	For each tumor, we mapped its "druggable" variants against one or more drugs, which were then mapped to one or more drug classes (Additional file 2: Table S8).	('tumor', 'Disease', (9, 14))	('variants', 'Var', (42, 50))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumor', 'Disease', 'MESH:D009369', (9, 14))
86953	30053901	For each variant, we used the drug that had the highest level of evidence in DEPO regardless of cancer type (Additional file 2: Table S3).	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('variant', 'Var', (9, 16))	('cancer', 'Disease', (96, 102))	('cancer', 'Disease', 'MESH:D009369', (96, 102))
86954	30053901	For the purposes of visualization, we only considered ten FDA-approved drug classes (Additional file 2: Table S9) mapping to the largest number of variants across our pan-cancer cohort (Additional file 2: Table S10).	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('variants', 'Var', (147, 155))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('cancer', 'Disease', (171, 177))
86960	30053901	Further, a substantial number (~ 25%) of sensitive variant/drug interactions are approved by the FDA for a particular cancer type or are based on late-stage clinical studies.	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('particular cancer type', 'Disease', (107, 129))	('particular cancer type', 'Disease', 'MESH:D009369', (107, 129))	('variant/drug', 'Var', (51, 63))
86961	30053901	Several genes account for a large proportion of variant/drug interactions (e.g., EGFR, KIT, ERBB2, BRCA1, PDGFRA), reflecting interest in therapeutically exploiting a relatively limited number of cancer driver genes (Fig.	('ERBB2', 'Gene', '2064', (92, 97))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('KIT', 'Gene', (87, 90))	('PDGFRA', 'Gene', '5156', (106, 112))	('ERBB2', 'Gene', (92, 97))	('BRCA1', 'Gene', (99, 104))	('variant/drug', 'Var', (48, 60))	('cancer', 'Disease', 'MESH:D009369', (196, 202))	('cancer', 'Disease', (196, 202))	('BRCA', 'Phenotype', 'HP:0003002', (99, 103))	('BRCA1', 'Gene', '672', (99, 104))	('EGFR', 'Gene', '1956', (81, 85))	('PDGFRA', 'Gene', (106, 112))	('EGFR', 'Gene', (81, 85))
86963	30053901	Our analysis reveals 2364 mutations across 2114 tumors that are associated with sensitivity to one or more drugs (mean = 1.12/tumor) (Additional file 2: Table S2).	('associated', 'Reg', (64, 74))	('tumor', 'Disease', (48, 53))	('tumors', 'Disease', (48, 54))	('tumors', 'Disease', 'MESH:D009369', (48, 54))	('sensitivity', 'MPA', (80, 91))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('mutations', 'Var', (26, 35))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('tumor', 'Disease', (126, 131))
86964	30053901	The low fraction of drug-associated mutations likely reflects the large number of passengers in cancer.	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Disease', (96, 102))	('mutations', 'Var', (36, 45))
86965	30053901	Thirty-two percent of tumors had at least one drug-associated mutation, a percentage that is consistent with the 28% of screened patients that could be matched with a targeted therapy or trial.	('patients', 'Species', '9606', (129, 137))	('tumors', 'Disease', 'MESH:D009369', (22, 28))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('mutation', 'Var', (62, 70))	('tumors', 'Phenotype', 'HP:0002664', (22, 28))	('tumors', 'Disease', (22, 28))
86967	30053901	2), that is, tumors with mutations associated with a known drug response in the cancer type with the highest level of evidence.	('mutations', 'Var', (25, 34))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Disease', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('cancer', 'Disease', (80, 86))
86968	30053901	Only 3.3% of the samples contain a druggable mutation known to be FDA approved; however, if we consider less mature evidence: clinical trials, preclinical, and case reports, we could potentially increase the percentage of tumors with drug-associated mutations to 8.2, 8.5, and 10.5%, respectively.	('tumors', 'Disease', 'MESH:D009369', (222, 228))	('drug-associated', 'Reg', (234, 249))	('mutations', 'Var', (250, 259))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('tumors', 'Phenotype', 'HP:0002664', (222, 228))	('tumors', 'Disease', (222, 228))	('increase', 'PosReg', (195, 203))
86969	30053901	Here, skin cutaneous melanoma (SKCM) is the cancer type with the largest fraction of drug-associated mutations (78%).	('mutations', 'Var', (101, 110))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (11, 29))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (6, 29))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('skin cutaneous melanoma', 'Disease', (6, 29))	('CM', 'Disease', 'MESH:D009202', (33, 35))	('melanoma', 'Phenotype', 'HP:0002861', (21, 29))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
86970	30053901	SKCM with a BRAF V600E/K mutation (40% of patients) can be treated with BRAF and MEK inhibitors based on FDA approval.	('BRAF', 'Gene', (72, 76))	('V600E', 'Var', (17, 22))	('V600E', 'SUBSTITUTION', 'None', (17, 22))	('BRAF', 'Gene', (12, 16))	('BRAF', 'Gene', '673', (12, 16))	('CM', 'Disease', 'MESH:D009202', (2, 4))	('patients', 'Species', '9606', (42, 50))	('MEK', 'Gene', (81, 84))	('BRAF', 'Gene', '673', (72, 76))	('MEK', 'Gene', '5609', (81, 84))
86971	30053901	The NRAS Q61 mutations found in 12% of SKCM patients are more challenging to treat, as is any RAS-mutant cancer due to activation of multiple signaling pathways.	('patients', 'Species', '9606', (44, 52))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('CM', 'Disease', 'MESH:D009202', (41, 43))	('activation', 'PosReg', (119, 129))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('NRAS', 'Gene', (4, 8))	('mutations', 'Var', (13, 22))	('NRAS', 'Gene', '4893', (4, 8))
86973	30053901	In colon and rectal carcinoma (COADREAD), glioblastoma multiforme (GBM), and lung adenocarcinoma (LUAD), 21, 14, and 40% of their respective tumors contain a drug-associated mutation in a cancer-type-specific setting.	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('colon and rectal carcinoma', 'Disease', 'MESH:D012004', (3, 29))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (77, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (77, 96))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumors', 'Disease', (141, 147))	('rectal carcinoma', 'Phenotype', 'HP:0100743', (13, 29))	('mutation', 'Var', (174, 182))	('tumors', 'Disease', 'MESH:D009369', (141, 147))	('glioblastoma multiforme', 'Disease', (42, 65))	('cancer', 'Disease', (188, 194))	('carcinoma', 'Phenotype', 'HP:0030731', (20, 29))	('glioblastoma', 'Phenotype', 'HP:0012174', (42, 54))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (42, 65))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('lung adenocarcinoma', 'Disease', (77, 96))	('contain', 'Reg', (148, 155))	('LUAD', 'Phenotype', 'HP:0030078', (98, 102))	('drug-associated', 'Reg', (158, 173))
86974	30053901	In COADREAD, drug-associated variants PIK3CA E542K, E545K, and H1047R are present in 2.1, 5.2, and 1.8% of tumors, respectively, and are associated with sensitivity to PI3K/AKT/mTOR pathway inhibitors in early-stage trials and aspirin in observational studies.	('H1047R', 'Mutation', 'rs121913279', (63, 69))	('AKT', 'Gene', (173, 176))	('sensitivity', 'MPA', (153, 164))	('associated with', 'Reg', (137, 152))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('mTOR', 'Gene', (177, 181))	('E542K', 'Mutation', 'rs121913273', (45, 50))	('PIK3CA', 'Gene', '5290', (38, 44))	('aspirin', 'Chemical', 'MESH:D001241', (227, 234))	('E545K', 'Mutation', 'rs104886003', (52, 57))	('E542K', 'Var', (45, 50))	('AKT', 'Gene', '207', (173, 176))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumors', 'Disease', (107, 113))	('mTOR', 'Gene', '2475', (177, 181))	('E545K', 'Var', (52, 57))	('PIK3CA', 'Gene', (38, 44))	('tumors', 'Disease', 'MESH:D009369', (107, 113))	('H1047R', 'Var', (63, 69))
86976	30053901	In GBM, the EGFR extracellular mutations (A289V, G598V, and R108K) and IDH1 mutation R132H are present in 10 and 4.5% of tumors, respectively, and are associated with drug response based on preclinical data.	('R132H', 'Mutation', 'rs121913500', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('A289V', 'Mutation', 'rs149840192', (42, 47))	('associated', 'Reg', (151, 161))	('tumors', 'Disease', (121, 127))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('G598V', 'Var', (49, 54))	('IDH1', 'Gene', (71, 75))	('R108K', 'Mutation', 'rs1057519828', (60, 65))	('EGFR', 'Gene', '1956', (12, 16))	('tumors', 'Disease', 'MESH:D009369', (121, 127))	('IDH1', 'Gene', '3417', (71, 75))	('G598V', 'Mutation', 'rs139236063', (49, 54))	('R132H', 'Var', (85, 90))	('EGFR', 'Gene', (12, 16))	('A289V', 'Var', (42, 47))	('R108K', 'Var', (60, 65))
86977	30053901	In non-small cell lung cancer, EGFR inhibitors (e.g., erlotinib) are FDA approved for tumors with activating EGFR mutations, which are present at 10 and 1% in our LUAD and lung squamous cell carcinoma (LUSC) cohorts, respectively.	('mutations', 'Var', (114, 123))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('EGFR', 'Gene', '1956', (109, 113))	('non-small cell lung cancer', 'Disease', (3, 29))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('EGFR', 'Gene', '1956', (31, 35))	('tumors', 'Disease', (86, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (191, 200))	('lung cancer', 'Phenotype', 'HP:0100526', (18, 29))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (172, 200))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (3, 29))	('erlotinib', 'Chemical', 'MESH:D000069347', (54, 63))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('EGFR', 'Gene', (109, 113))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('LUSC', 'Phenotype', 'HP:0030359', (202, 206))	('activating', 'PosReg', (98, 108))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (7, 29))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (177, 200))	('EGFR', 'Gene', (31, 35))	('lung squamous cell carcinoma', 'Disease', (172, 200))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (172, 200))	('LUAD', 'Phenotype', 'HP:0030078', (163, 167))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (3, 29))
86978	30053901	Despite the promise of targeted therapy, only 10.5% of this pan-cancer cohort contains potential drug-associated mutations in a cancer-type-specific setting.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('drug-associated', 'Reg', (97, 112))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('mutations', 'Var', (113, 122))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('cancer', 'Disease', (128, 134))
86979	30053901	With drug repurposing across cancer types, in which a drug used primarily in cancer type A with mutation X is repurposed for cancer type B with mutation X, we find that an additional 5.4% of patients may be treated with a FDA-approved drug-variant interaction (Figs.	('cancer', 'Disease', (29, 35))	('patients', 'Species', '9606', (191, 199))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('mutation', 'Var', (96, 104))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (29, 35))
86981	30053901	In this cancer-type-non-specific setting, cancer types in which at least 40% of tumors have drug-associated mutations include low-grade glioma (LGG, 76%), thyroid carcinoma (THCA, 70%), and colorectal adenocarcinoma (COADREAD, 42%).	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('THCA', 'Phenotype', 'HP:0002890', (174, 178))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumors', 'Disease', (80, 86))	('colorectal adenocarcinoma', 'Disease', (190, 215))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (155, 172))	('cancer', 'Disease', (8, 14))	('thyroid carcinoma', 'Disease', (155, 172))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('glioma', 'Disease', (136, 142))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (190, 215))	('glioma', 'Disease', 'MESH:D005910', (136, 142))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (155, 172))	('carcinoma', 'Phenotype', 'HP:0030731', (206, 215))	('glioma', 'Phenotype', 'HP:0009733', (136, 142))	('cancer', 'Disease', 'MESH:D009369', (8, 14))	('mutations', 'Var', (108, 117))	('carcinoma', 'Phenotype', 'HP:0030731', (163, 172))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('cancer', 'Disease', (42, 48))
86982	30053901	A small number of drug-associated mutations occur at high frequency in these cancer types.	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('mutations', 'Var', (34, 43))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))
86985	30053901	However, BRAF V600E also occurs at a lower frequency in HNSC, KIRP, LGG, and GBM, indicating significant repurposing potential for BRAF inhibitors (Fig.	('HNSC', 'Phenotype', 'HP:0012288', (56, 60))	('V600E', 'Var', (14, 19))	('BRAF', 'Gene', (131, 135))	('BRAF', 'Gene', (9, 13))	('V600E', 'Mutation', 'rs113488022', (14, 19))	('BRAF', 'Gene', '673', (131, 135))	('BRAF', 'Gene', '673', (9, 13))
86986	30053901	However, COADREAD has been difficult to treat due to a large presence of KRAS and BRAF mutations; EGFR inhibition as monotherapy is used for COADREAD, but only in tumors with wild-type KRAS.	('EGFR', 'Gene', (98, 102))	('KRAS', 'Gene', '3845', (185, 189))	('KRAS', 'Gene', (73, 77))	('BRAF', 'Gene', '673', (82, 86))	('KRAS', 'Gene', '3845', (73, 77))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('BRAF', 'Gene', (82, 86))	('tumors', 'Disease', (163, 169))	('tumors', 'Disease', 'MESH:D009369', (163, 169))	('tumors', 'Phenotype', 'HP:0002664', (163, 169))	('EGFR', 'Gene', '1956', (98, 102))	('mutations', 'Var', (87, 96))	('KRAS', 'Gene', (185, 189))
86990	30053901	COADREAD or other cancer types having RAS mutations, such as cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), acute myeloid leukemia (AML), stomach adenocarcinoma (STAD), and uterine corpus endometrial carcinoma (UCEC), could benefit from further exploration of combinatorial therapies targeting downstream targets of KRAS (Fig.	('corpus endometrial carcinoma', 'Disease', (207, 235))	('corpus endometrial carcinoma', 'Disease', 'MESH:D016889', (207, 235))	('carcinoma', 'Phenotype', 'HP:0030731', (177, 186))	('acute myeloid leukemia', 'Disease', (134, 156))	('cancer', 'Disease', (18, 24))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (70, 93))	('cervical squamous cell carcinoma and endocervical adenocarcinoma', 'Disease', 'MESH:D002294', (61, 125))	('RAS', 'Gene', (38, 41))	('AML', 'Disease', 'MESH:D015470', (158, 161))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('leukemia', 'Phenotype', 'HP:0001909', (148, 156))	('AML', 'Disease', (158, 161))	('stomach adenocarcinoma', 'Disease', (164, 186))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (134, 156))	('AML', 'Phenotype', 'HP:0004808', (158, 161))	('KRAS', 'Gene', '3845', (342, 346))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (134, 156))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (140, 156))	('carcinoma', 'Phenotype', 'HP:0030731', (226, 235))	('KRAS', 'Gene', (342, 346))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('cancer', 'Disease', 'MESH:D009369', (18, 24))	('stomach adenocarcinoma', 'Disease', 'MESH:D013274', (164, 186))	('mutations', 'Var', (42, 51))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (214, 235))
86993	30053901	Together, cancer-type-specific and non-specific mutational analyses identified potential therapeutic targets in 2114 tumors (32%), some of which will be considered druggable only with further clinical development and FDA approval.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('tumors', 'Disease', (117, 123))	('cancer', 'Disease', 'MESH:D009369', (10, 16))	('mutational', 'Var', (48, 58))	('cancer', 'Disease', (10, 16))
86994	30053901	We applied a structure-based clustering tool, HotSpot3D, to the pan-cancer dataset to reveal putative functional mutations (Additional file 2: Table S13).	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('mutations', 'Var', (113, 122))	('cancer', 'Disease', (68, 74))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))
86995	30053901	HotSpot3D's utility in predicting functional mutations is supported by experimental evidence using cell lines expressing one of several EGFR-mutant proteins.	('EGFR', 'Gene', '1956', (136, 140))	('mutations', 'Var', (45, 54))	('proteins', 'Protein', (148, 156))	('EGFR', 'Gene', (136, 140))
86996	30053901	Among all genes in our analysis, EGFR contains the highest number of putative sensitive mutations, with 36 mutations that clustered with 19 mutations in DEPO from seven different clusters (Fig.	('mutations', 'Var', (107, 116))	('mutations', 'Var', (88, 97))	('EGFR', 'Gene', '1956', (33, 37))	('DEPO', 'Gene', (153, 157))	('EGFR', 'Gene', (33, 37))
86998	30053901	This procedure yielded four different clusters with a "resistant" mutation in AKT1, MAP2K1, and RAC1; these four clusters contained 14 putative resistant mutations clustering with four known resistant mutations (Additional file 2: Table S13).	('AKT1', 'Gene', (78, 82))	('contained', 'Reg', (122, 131))	('MAP2K1', 'Gene', (84, 90))	('RAC1', 'Gene', '5879', (96, 100))	('AKT1', 'Gene', '207', (78, 82))	('mutation', 'Var', (66, 74))	('RAC1', 'Gene', (96, 100))	('MAP2K1', 'Gene', '5604', (84, 90))
86999	30053901	RAC1 yielded the largest cluster, with RAC1 P29S mediating resistance to BRAF inhibitors in BRAF-mutant SKCM.	('BRAF', 'Gene', '673', (73, 77))	('P29S', 'Mutation', 'rs1057519874', (44, 48))	('resistance to', 'MPA', (59, 72))	('BRAF', 'Gene', '673', (92, 96))	('CM', 'Disease', 'MESH:D009202', (106, 108))	('RAC1', 'Gene', '5879', (39, 43))	('BRAF', 'Gene', (92, 96))	('RAC1', 'Gene', (39, 43))	('RAC1', 'Gene', '5879', (0, 4))	('P29S', 'Var', (44, 48))	('BRAF', 'Gene', (73, 77))	('RAC1', 'Gene', (0, 4))	('mediating', 'Reg', (49, 58))
87000	30053901	Other mutations in this cluster that may affect binding affinity of BRAF inhibitors (or that may mediate resistance to BRAF inhibitors) are C18Y, E31D, A159V, P29L/T, and P34S.	('P29L', 'SUBSTITUTION', 'None', (159, 163))	('C18Y', 'SUBSTITUTION', 'None', (140, 144))	('BRAF', 'Gene', '673', (68, 72))	('E31D', 'Var', (146, 150))	('BRAF', 'Gene', '673', (119, 123))	('A159V', 'Mutation', 'p.A159V', (152, 157))	('BRAF', 'Gene', (68, 72))	('binding', 'Interaction', (48, 55))	('P34S', 'Var', (171, 175))	('BRAF', 'Gene', (119, 123))	('C18Y', 'Var', (140, 144))	('P34S', 'Mutation', 'p.P34S', (171, 175))	('E31D', 'Mutation', 'p.E31D', (146, 150))	('P29L', 'Var', (159, 163))	('affect', 'Reg', (41, 47))	('A159V', 'Var', (152, 157))
87001	30053901	For example, KIT has multiple clusters with known mutations; one of which has three known mutations (E490D, Y494C, S476G) in the same cluster, which are FDA approved as sensitive to combined therapy of imatinib, sunitinib, and regorafenib (KIT and angiogenesis inhibitor).	('E490D', 'Mutation', 'p.E490D', (101, 106))	('S476G', 'Var', (115, 120))	('regorafenib', 'Chemical', 'MESH:C559147', (227, 238))	('E490D', 'Var', (101, 106))	('Y494C', 'Var', (108, 113))	('sunitinib', 'Chemical', 'MESH:D000077210', (212, 221))	('Y494C', 'Mutation', 'p.Y494C', (108, 113))	('S476G', 'Mutation', 'p.S476G', (115, 120))	('imatinib', 'Chemical', 'MESH:D000068877', (202, 210))
87002	30053901	In addition, this cluster contains two other unique mutations (D439H, I438L) not in DEPO that, based on our analysis using HotSpot3D, could also affect binding affinity and potentially tumor sensitivity to KIT combined with angiogenesis inhibitors (Additional file 2: Table S13).	('tumor', 'Disease', (185, 190))	('I438L', 'Var', (70, 75))	('I438L', 'Mutation', 'p.I438L', (70, 75))	('binding affinity', 'Interaction', (152, 168))	('affect', 'Reg', (145, 151))	('D439H', 'Mutation', 'p.D439H', (63, 68))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('D439H', 'Var', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))
87003	30053901	To do this, we assessed the activity and drug sensitivity of a set of six BRAF mutations (F635I, G596D, K601E, W604L, L613F, G596R) in close spatial proximity to the well-studied V600E pathogenic mutation (Fig.	('L613F', 'Mutation', 'p.L613F', (118, 123))	('G596D', 'Mutation', 'rs397507483', (97, 102))	('W604L', 'Mutation', 'p.W604L', (111, 116))	('K601E', 'Mutation', 'rs121913364', (104, 109))	('BRAF', 'Gene', (74, 78))	('F635I', 'Mutation', 'p.F635I', (90, 95))	('BRAF', 'Gene', '673', (74, 78))	('L613F', 'Var', (118, 123))	('K601E', 'Var', (104, 109))	('G596R', 'Mutation', 'rs121913361', (125, 130))	('G596D', 'Var', (97, 102))	('G596R', 'Var', (125, 130))	('V600E', 'Mutation', 'rs113488022', (179, 184))	('F635I', 'Var', (90, 95))	('drug sensitivity', 'Phenotype', 'HP:0020174', (41, 57))	('W604L', 'Var', (111, 116))
87005	30053901	Therefore, we transfected BRAF mutations, along with wild-type BRAF and BRAF V600E, into HEK293T cells in the presence or absence of BRAF inhibitor dabrafenib, and used phosphorylation changes in MEK1/2 as an indicator of BRAF activity.	('MEK1/2', 'Gene', '5604;5605', (196, 202))	('mutations', 'Var', (31, 40))	('MEK1/2', 'Gene', (196, 202))	('BRAF', 'Gene', (72, 76))	('BRAF', 'Gene', '673', (26, 30))	('dabrafenib', 'Chemical', 'MESH:C561627', (148, 158))	('BRAF', 'Gene', '673', (133, 137))	('BRAF', 'Gene', '673', (222, 226))	('V600E', 'Mutation', 'rs113488022', (77, 82))	('BRAF', 'Gene', (26, 30))	('HEK293T', 'CellLine', 'CVCL:0063', (89, 96))	('BRAF', 'Gene', (133, 137))	('BRAF', 'Gene', (222, 226))	('BRAF', 'Gene', '673', (63, 67))	('phosphorylation', 'MPA', (169, 184))	('BRAF', 'Gene', (63, 67))	('BRAF', 'Gene', '673', (72, 76))
87006	30053901	The undetectable level of endogenous BRAF in HEK293T cells eliminates potential ambiguity in interpreting the effects of transfected BRAF mutations.	('BRAF', 'Gene', '673', (37, 41))	('BRAF', 'Gene', '673', (133, 137))	('BRAF', 'Gene', (37, 41))	('BRAF', 'Gene', (133, 137))	('HEK293T', 'CellLine', 'CVCL:0063', (45, 52))	('mutations', 'Var', (138, 147))
87007	30053901	As expected, BRAF V600E caused drastically increased phosphorylation in MEK1/2 that is reduced by dabrafenib (Fig.	('V600E', 'Var', (18, 23))	('MEK1/2', 'Gene', '5604;5605', (72, 78))	('MEK1/2', 'Gene', (72, 78))	('BRAF', 'Gene', '673', (13, 17))	('dabrafenib', 'Chemical', 'MESH:C561627', (98, 108))	('BRAF', 'Gene', (13, 17))	('increased', 'PosReg', (43, 52))	('V600E', 'Mutation', 'rs113488022', (18, 23))	('phosphorylation', 'MPA', (53, 68))
87008	30053901	Three (G596D, K601E, and W604L) out of six other transfected BRAF mutations also showed higher levels of MEK1/2 phosphorylation and sensitivity to dabrafenib than wild-type BRAF, suggesting that a high percentage of mutations identified by Hotspot3D in close spatial proximity to V600E are activated and similarly sensitive to dabrafenib.	('mutations', 'Var', (66, 75))	('K601E', 'Var', (14, 19))	('dabrafenib', 'Chemical', 'MESH:C561627', (327, 337))	('W604L', 'Var', (25, 30))	('G596D', 'Mutation', 'rs397507483', (7, 12))	('BRAF', 'Gene', '673', (173, 177))	('V600E', 'Mutation', 'rs113488022', (280, 285))	('BRAF', 'Gene', '673', (61, 65))	('BRAF', 'Gene', (173, 177))	('BRAF', 'Gene', (61, 65))	('MEK1/2', 'Gene', '5604;5605', (105, 111))	('MEK1/2', 'Gene', (105, 111))	('higher', 'PosReg', (88, 94))	('W604L', 'Mutation', 'p.W604L', (25, 30))	('G596D', 'Var', (7, 12))	('sensitivity', 'MPA', (132, 143))	('dabrafenib', 'Chemical', 'MESH:C561627', (147, 157))	('V600E', 'Var', (280, 285))	('K601E', 'Mutation', 'rs121913364', (14, 19))
87009	30053901	Notably, BRAF G596R-transfected cells appeared to have a much lower level of MEK1/2 phosphorylation when compared to those transfected with wild-type BRAF, supporting prior findings that G596R results in BRAF loss of function.	('loss of function', 'NegReg', (209, 225))	('BRAF', 'Gene', (204, 208))	('BRAF', 'Gene', (9, 13))	('BRAF', 'Gene', '673', (204, 208))	('G596R', 'Mutation', 'rs121913361', (14, 19))	('BRAF', 'Gene', (150, 154))	('lower', 'NegReg', (62, 67))	('BRAF', 'Gene', '673', (150, 154))	('MEK1/2', 'Gene', '5604;5605', (77, 83))	('G596R', 'Var', (187, 192))	('G596R', 'Mutation', 'rs121913361', (187, 192))	('MEK1/2', 'Gene', (77, 83))	('G596R-transfected', 'Var', (14, 31))	('BRAF', 'Gene', '673', (9, 13))
87011	30053901	For example, in the case of breast cancer, elevated mRNA expression and copy number amplification of ESR1 correlate with elevated protein expression of ER, as well as with sensitivity to hormonal therapy with tamoxifen.	('ESR1', 'Gene', '2099', (101, 105))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('copy number amplification', 'Var', (72, 97))	('elevated', 'PosReg', (43, 51))	('tamoxifen', 'Chemical', 'MESH:D013629', (209, 218))	('breast cancer', 'Disease', 'MESH:D001943', (28, 41))	('breast cancer', 'Phenotype', 'HP:0003002', (28, 41))	('ESR1', 'Gene', (101, 105))	('breast cancer', 'Disease', (28, 41))	('protein expression', 'MPA', (130, 148))	('mRNA expression', 'MPA', (52, 67))	('elevated', 'PosReg', (121, 129))
87017	30053901	Interestingly, tumors with "druggable" gene fusions tend to express elevated levels of the corresponding druggable gene (Additional file 2: Table S15, Additional file 3: Figure S1), suggesting that fusions may be one of several drivers of gene and protein expression.	('levels of', 'MPA', (77, 86))	('tumors', 'Disease', (15, 21))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('fusions', 'Var', (44, 51))	('elevated', 'PosReg', (68, 76))	('tumors', 'Disease', 'MESH:D009369', (15, 21))
87029	30053901	Similarly, 26 and 52% of BRCA and UCEC, respectively, show elevated activity at ESR1's p.S118 phosphosite.	('BRCA', 'Gene', (25, 29))	('ESR1', 'Gene', '2099', (80, 84))	('p.S118', 'Var', (87, 93))	('S118 phosphosite', 'Chemical', '-', (89, 105))	('activity', 'MPA', (68, 76))	('ESR1', 'Gene', (80, 84))	('elevated', 'PosReg', (59, 67))	('BRCA', 'Phenotype', 'HP:0003002', (25, 29))	('BRCA', 'Gene', '672', (25, 29))
87032	30053901	EGFR phosphosites p.Y1068 and p.Y1173 are active in GBM, head and neck squamous cell carcinoma (HNSC), KIRC, LUAD, and LUSC.	('p.Y1068', 'Var', (18, 25))	('EGFR', 'Gene', (0, 4))	('neck squamous cell carcinoma', 'Disease', (66, 94))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (71, 94))	('GBM', 'Disease', (52, 55))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (66, 94))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (57, 94))	('LUAD', 'Phenotype', 'HP:0030078', (109, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('HNSC', 'Phenotype', 'HP:0012288', (96, 100))	('LUSC', 'Phenotype', 'HP:0030359', (119, 123))	('phosphosite', 'Chemical', '-', (5, 16))	('p.Y1173', 'Var', (30, 37))	('EGFR', 'Gene', '1956', (0, 4))
87042	30053901	RAC1 P29S co-occurs with mutations in BRAF and MEK1 in four SKCM tumors (Additional file 2: Table S17, Additional file 3: Figure S3).	('mutations', 'Var', (25, 34))	('MEK1', 'Gene', '5604', (47, 51))	('SKCM tumors', 'Disease', 'MESH:D009369', (60, 71))	('MEK1', 'Gene', (47, 51))	('BRAF', 'Gene', '673', (38, 42))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('SKCM tumors', 'Disease', (60, 71))	('BRAF', 'Gene', (38, 42))	('RAC1', 'Gene', '5879', (0, 4))	('P29S', 'Var', (5, 9))	('RAC1', 'Gene', (0, 4))	('P29S', 'Mutation', 'rs1057519874', (5, 9))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
87043	30053901	RAC1 P29S renders SKCM resistant to BRAF/MEK inhibition; testing for RAC1 P29S may identify patients with BRAF V600E SKCM unlikely to benefit from BRAF/MEK inhibitor.	('CM', 'Disease', 'MESH:D009202', (20, 22))	('V600E', 'Var', (111, 116))	('P29S', 'Mutation', 'rs1057519874', (5, 9))	('patients', 'Species', '9606', (92, 100))	('RAC1', 'Gene', (0, 4))	('BRAF', 'Gene', '673', (36, 40))	('P29S', 'Mutation', 'rs1057519874', (74, 78))	('BRAF', 'Gene', (36, 40))	('MEK', 'Gene', '5609', (41, 44))	('BRAF', 'Gene', (147, 151))	('BRAF', 'Gene', '673', (147, 151))	('RAC1', 'Gene', '5879', (0, 4))	('MEK', 'Gene', '5609', (152, 155))	('V600E', 'Mutation', 'rs113488022', (111, 116))	('RAC1', 'Gene', (69, 73))	('CM', 'Disease', 'MESH:D009202', (119, 121))	('MEK', 'Gene', (41, 44))	('BRAF', 'Gene', '673', (106, 110))	('BRAF', 'Gene', (106, 110))	('MEK', 'Gene', (152, 155))	('RAC1', 'Gene', '5879', (69, 73))
87045	30053901	AKT1 E17K co-occurs with BRAF V600E in five tumors (Additional file 2: Table S17, Additional file 3: Figure S3).	('tumors', 'Disease', (44, 50))	('E17K', 'SUBSTITUTION', 'None', (5, 9))	('tumors', 'Disease', 'MESH:D009369', (44, 50))	('AKT1', 'Gene', '207', (0, 4))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('AKT1', 'Gene', (0, 4))	('V600E', 'Mutation', 'rs113488022', (30, 35))	('BRAF', 'Gene', '673', (25, 29))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('BRAF', 'Gene', (25, 29))	('E17K', 'Var', (5, 9))
87047	30053901	Transcriptomic and proteomic expression profiling reveals 48 additional tumors with BRAF V600E/K and elevated AKT (AKT1/2/3) expression at the mRNA or protein/phosphoprotein levels; these may also benefit from BRAF/AKT inhibition (Fig.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('elevated', 'PosReg', (101, 109))	('AKT', 'Gene', '207', (115, 118))	('AKT', 'Gene', (110, 113))	('AKT1/2/3', 'Gene', (115, 123))	('tumors', 'Disease', (72, 78))	('V600E', 'SUBSTITUTION', 'None', (89, 94))	('AKT', 'Gene', '207', (215, 218))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('AKT', 'Gene', '207', (110, 113))	('AKT1/2/3', 'Gene', '207;208;10000', (115, 123))	('BRAF', 'Gene', '673', (84, 88))	('BRAF', 'Gene', (84, 88))	('AKT', 'Gene', (115, 118))	('BRAF', 'Gene', (210, 214))	('BRAF', 'Gene', '673', (210, 214))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('AKT', 'Gene', (215, 218))	('V600E', 'Var', (89, 94))
87050	30053901	Additionally, 105 tumors contain activating PIK3CA mutations co-occurring with elevated mRNA or protein expression of ESR1 or PGR.	('PIK3CA', 'Gene', (44, 50))	('mutations', 'Var', (51, 60))	('PGR', 'Gene', '5241', (126, 129))	('ESR1', 'Gene', '2099', (118, 122))	('PIK3CA', 'Gene', '5290', (44, 50))	('mRNA or protein expression', 'MPA', (88, 114))	('tumors', 'Disease', (18, 24))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('elevated', 'PosReg', (79, 87))	('activating', 'PosReg', (33, 43))	('ESR1', 'Gene', (118, 122))	('PGR', 'Gene', (126, 129))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
87056	30053901	Overall, the mean LN(IC50) for cell lines that contain a sensitive mutation from DEPO was significantly lower than background LN(IC50) in both the cancer-type-specific and non-specific setting (Mann-Whitney U test, P = 1.1e-96 and P = 1.3e-109, respectively) (Fig.	('DEPO', 'Gene', (81, 85))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('mutation', 'Var', (67, 75))	('lower', 'NegReg', (104, 109))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('cancer', 'Disease', (147, 153))
87058	30053901	In both the cancer-type-specific and non-specific settings, 19 variant/drug combinations had significantly lower mean LN(IC50) than background LN(IC50) for the corresponding drug.	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('variant/drug', 'Var', (63, 75))	('cancer', 'Disease', (12, 18))	('lower', 'NegReg', (107, 112))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('combinations', 'Var', (76, 88))
87060	30053901	For example, cell lines with BRAF V600E were associated with sensitivity to BRAF inhibitors PLX4720 (1), PLX4720 (2), and dabrafenib in both the cancer-type-specific (SKCM) and non-specific settings (BRCA, COADREAD, GBM, LGG, LIHC, and THCA) (Fig.	('cancer', 'Disease', (145, 151))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('LIHC', 'Disease', 'None', (226, 230))	('THCA', 'Phenotype', 'HP:0002890', (236, 240))	('BRCA', 'Phenotype', 'HP:0003002', (200, 204))	('PLX4720', 'Var', (105, 112))	('CM', 'Disease', 'MESH:D009202', (169, 171))	('V600E', 'Mutation', 'rs113488022', (34, 39))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('BRAF', 'Gene', '673', (29, 33))	('BRAF', 'Gene', (29, 33))	('BRCA', 'Gene', '672', (200, 204))	('sensitivity', 'MPA', (61, 72))	('V600E', 'Var', (34, 39))	('BRAF', 'Gene', (76, 80))	('BRAF', 'Gene', '673', (76, 80))	('dabrafenib', 'Chemical', 'MESH:C561627', (122, 132))	('LIHC', 'Disease', (226, 230))	('BRCA', 'Gene', (200, 204))	('PLX4720', 'Gene', (92, 99))
87061	30053901	Two out of six mutations (PIK3CA H1047R and KRAS G12C) was associated with sensitivity in either the cancer-type-specific or the non-specific setting.	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('H1047R', 'Var', (33, 39))	('G12C', 'Mutation', 'rs121913530', (49, 53))	('cancer', 'Disease', (101, 107))	('PIK3CA', 'Gene', '5290', (26, 32))	('sensitivity', 'Disease', (75, 86))	('associated', 'Reg', (59, 69))	('H1047R', 'Mutation', 'rs121913279', (33, 39))	('KRAS', 'Gene', (44, 48))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('KRAS', 'Gene', '3845', (44, 48))	('PIK3CA', 'Gene', (26, 32))
87076	30053901	First, with DEPO, our analysis of druggability in a given tumor is exclusively based on mutation/drug interactions rather than gene/drug interactions, with variants including both predefined mutations (e.g., BRAF V600E) and categories of mutations (e.g., EGFR exon 19 deletions).	('EGFR', 'Gene', '1956', (255, 259))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('EGFR', 'Gene', (255, 259))	('BRAF', 'Gene', '673', (208, 212))	('BRAF', 'Gene', (208, 212))	('deletions', 'Var', (268, 277))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('V600E', 'Mutation', 'rs113488022', (213, 218))
87079	30053901	Third, it uses an analytic tool to create a set of putative druggable mutations, of which a subset occurring in BRAF were tested and validated in vitro.	('mutations', 'Var', (70, 79))	('BRAF', 'Gene', (112, 116))	('BRAF', 'Gene', '673', (112, 116))
87083	30053901	Realistically, only a fraction of the 48% of tumors with potential drug-associated omics alterations will be clinically druggable because the mere presence of a shared genetic biomarker (mutation, mRNA/protein expression outlier) does not guarantee clinical efficacy across cancer types, nor does it guarantee acceptable clinical toxicity.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('cancer', 'Disease', 'MESH:D009369', (274, 280))	('tumors', 'Disease', (45, 51))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('toxicity', 'Disease', 'MESH:D064420', (330, 338))	('toxicity', 'Disease', (330, 338))	('cancer', 'Disease', (274, 280))	('tumors', 'Disease', 'MESH:D009369', (45, 51))	('alterations', 'Var', (89, 100))	('cancer', 'Phenotype', 'HP:0002664', (274, 280))
87084	30053901	Further, we recognize that our computational survey of the landscape of potential drug-associated omics alterations may include some controversial drug/biomarker relationships (e.g., PI3K inhibitors in PIK3CA-mutant cancers), some of which have either failed clinical trials and/or are still being actively developed in clinical trials.	('alterations', 'Var', (104, 115))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('PIK3CA', 'Gene', (202, 208))	('PIK3CA', 'Gene', '5290', (202, 208))	('cancers', 'Phenotype', 'HP:0002664', (216, 223))	('cancers', 'Disease', (216, 223))	('cancers', 'Disease', 'MESH:D009369', (216, 223))
87087	30053901	Second, our analysis does not account for clonal heterogeneity, which is not unreasonable given that therapies targeting genomic alterations with high variant allele frequencies can induce substantial tumor regression.	('tumor', 'Disease', (201, 206))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('variant', 'Var', (151, 158))
87097	30053901	ACC Adrenocortical carcinoma AML/LAML Acute myeloid leukemia BLCA Bladder urothelial carcinoma BRCA Breast adenocarcinoma CESC Cervical squamous cell carcinoma and endocervical adenocarcinoma CNA Copy number amplification CNL Copy number loss CNV Copy number variation COADREAD Colon and rectal carcinoma CPTAC Clinical Proteomic Tumor Analysis Consortium DCC Data Coordinating Center DEPO Database of Evidence for Precision Oncology FBS Fetal bovine serum FDA Food and Drug Administration FFPE Formalin-fixed, paraffin-embedded GBM Glioblastoma multiforme GDAC Genome Data Analysis Centers GDSC Genomics of Drug Sensitivity in Cancer HNSC Head and neck squamous cell carcinoma IQR Interquartile range KICH Kidney chromophobe KIRC Kidney renal clear cell carcinoma KIRP Kidney renal papillary cell carcinoma LGG Low-grade glioma LIHC Liver hepatocellular carcinoma LUAD Lung adenocarcinoma LUSC Lung squamous cell carcinoma MAF Mutation annotation file NGS Next-generation sequencing NSCLC Non-small cell lung cancer OV Ovarian serous carcinoma PNNL Pacific Northwest National Laboratory PRAD Prostate adenocarcinoma RBN Replicates-based normalization RPPA Reverse phase protein array SKCM Skin cutaneous melanoma SNP Single nucleotide polymorphism STAD Stomach adenocarcinoma STR Short tandem repeat TCGA The Cancer Genome Atlas TCPA The Cancer Protein Atlas THCA Thyroid carcinoma TKI Tyrosine kinase inhibitor UCEC Uterine corpus endometrial carcinoma UCS Uterine carcinosarcoma VCF Variant call format LD designed and supervised the research.	('adenocarcinoma', 'Disease', (1262, 1276))	('Kidney renal clear cell carcinoma', 'Disease', (731, 764))	('carcinosarcoma', 'Disease', (1467, 1481))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (1310, 1329))	('adenocarcinoma', 'Disease', (1102, 1116))	('RBN', 'Chemical', '-', (1117, 1120))	('renal papillary cell carcinoma', 'Phenotype', 'HP:0006766', (777, 807))	('cancer', 'Phenotype', 'HP:0002664', (1010, 1016))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('carcinoma', 'Disease', 'MESH:D002277', (85, 94))	('DCC', 'Chemical', '-', (356, 359))	('Adrenocortical carcinoma', 'Disease', (4, 28))	('carcinoma', 'Disease', (1445, 1454))	('Acute myeloid leukemia', 'Phenotype', 'HP:0004808', (38, 60))	('squamous cell carcinoma', 'Disease', (900, 923))	('CM', 'Disease', 'MESH:D009202', (1187, 1189))	('carcinoma', 'Disease', 'MESH:D002277', (798, 807))	('adenocarcinoma', 'Disease', 'MESH:D000230', (1262, 1276))	('Cancer', 'Disease', 'MESH:D009369', (1339, 1345))	('glioma', 'Phenotype', 'HP:0009733', (822, 828))	('bovine', 'Species', '9913', (444, 450))	('Cancer', 'Phenotype', 'HP:0002664', (1310, 1316))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (44, 60))	('corpus endometrial carcinoma', 'Disease', 'MESH:D016889', (1426, 1454))	('VCF', 'Gene', '6899', (1482, 1485))	('PNNL', 'Chemical', '-', (1045, 1049))	('Breast adenocarcinoma', 'Disease', 'MESH:D000230', (100, 121))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (1195, 1213))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('Thyroid carcinoma', 'Phenotype', 'HP:0002890', (1365, 1382))	('adenocarcinoma', 'Disease', (177, 191))	('Kidney renal papillary cell carcinoma', 'Disease', (770, 807))	('Non-small cell lung cancer', 'Disease', (990, 1016))	('carcinoma', 'Disease', (85, 94))	('rectal carcinoma', 'Phenotype', 'HP:0100743', (288, 304))	('Skin cutaneous melanoma', 'Disease', (1190, 1213))	('Ovarian serous carcinoma', 'Disease', (1020, 1044))	('Kidney renal papillary cell carcinoma', 'Disease', 'MESH:D007681', (770, 807))	('urothelial carcinoma', 'Disease', (74, 94))	('FBS', 'Disease', (434, 437))	('AML', 'Phenotype', 'HP:0004808', (29, 32))	('VCF', 'Gene', (1482, 1485))	('Non-small cell lung cancer', 'Phenotype', 'HP:0030358', (990, 1016))	('Uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (1459, 1481))	('NSCLC', 'Disease', 'MESH:D002289', (984, 989))	('Cancer Protein Atlas', 'Disease', 'MESH:D009369', (1339, 1359))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (1433, 1454))	('Cancer', 'Disease', (1339, 1345))	('AML', 'Disease', 'MESH:D015470', (34, 37))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (74, 94))	('AML', 'Phenotype', 'HP:0004808', (34, 37))	('Cancer Genome Atlas', 'Disease', (1310, 1329))	('Ovarian serous carcinoma', 'Disease', 'MESH:D010051', (1020, 1044))	('THCA', 'Phenotype', 'HP:0002890', (1360, 1364))	('UCEC Uterine corpus', 'Phenotype', 'HP:0000139', (1413, 1432))	('adenocarcinoma', 'Disease', (107, 121))	('squamous cell carcinoma', 'Disease', (136, 159))	('adenocarcinoma', 'Disease', 'MESH:D000230', (1102, 1116))	('paraffin', 'Chemical', 'MESH:D010232', (511, 519))	('Non-small cell lung cancer', 'Disease', 'MESH:D002289', (990, 1016))	('Drug Sensitivity', 'Phenotype', 'HP:0020174', (608, 624))	('corpus endometrial carcinoma', 'Disease', (1426, 1454))	('KICH', 'Chemical', '-', (702, 706))	('Tumor', 'Phenotype', 'HP:0002664', (330, 335))	('Kidney chromophobe', 'Disease', 'MESH:D000238', (707, 725))	('Cancer', 'Disease', (628, 634))	('adenocarcinoma', 'Disease', (875, 889))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (649, 677))	('carcinoma', 'Disease', 'MESH:D002277', (755, 764))	('Kidney chromophobe', 'Disease', (707, 725))	('BRCA', 'Phenotype', 'HP:0003002', (95, 99))	('adenocarcinoma', 'Disease', 'MESH:D000230', (107, 121))	('Prostate adenocarcinoma', 'Disease', 'MESH:D011471', (1093, 1116))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (900, 923))	('Liver hepatocellular carcinoma', 'Disease', (834, 864))	('Liver hepatocellular carcinoma', 'Disease', 'MESH:D006528', (834, 864))	('carcinoma', 'Disease', 'MESH:D002277', (150, 159))	('Adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (4, 28))	('adenocarcinoma', 'Disease', 'MESH:D000230', (875, 889))	('Cancer', 'Disease', 'MESH:D009369', (628, 634))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (654, 677))	('Cancer', 'Phenotype', 'HP:0002664', (1339, 1345))	('endocervical adenocarcinoma', 'Disease', 'MESH:D000230', (164, 191))	('LUSC', 'Phenotype', 'HP:0030359', (890, 894))	('LIHC', 'Disease', (829, 833))	('Formalin', 'Chemical', 'MESH:D005557', (495, 503))	('adenocarcinoma', 'Disease', 'MESH:D000230', (177, 191))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (900, 923))	('carcinosarcoma', 'Disease', 'MESH:D002296', (1467, 1481))	('carcinoma', 'Disease', (19, 28))	('glioma', 'Disease', 'MESH:D005910', (822, 828))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (654, 677))	('carcinoma', 'Disease', 'MESH:D002277', (1267, 1276))	('NSCLC', 'Disease', (984, 989))	('carcinoma', 'Disease', (755, 764))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (994, 1016))	('Cancer', 'Phenotype', 'HP:0002664', (628, 634))	('carcinoma', 'Phenotype', 'HP:0030731', (150, 159))	('Stomach adenocarcinoma', 'Disease', 'MESH:D013274', (1254, 1276))	('Tyrosine kinase', 'Gene', '7294', (1387, 1402))	('NSCLC', 'Phenotype', 'HP:0030358', (984, 989))	('melanoma', 'Phenotype', 'HP:0002861', (1205, 1213))	('Breast adenocarcinoma', 'Phenotype', 'HP:0003002', (100, 121))	('carcinoma', 'Disease', 'MESH:D002277', (914, 923))	('carcinoma', 'Disease', (150, 159))	('carcinoma', 'Disease', (1373, 1382))	('carcinoma', 'Disease', 'MESH:D002277', (668, 677))	('Kidney renal clear cell carcinoma', 'Disease', 'MESH:C538614', (731, 764))	('carcinoma', 'Disease', 'MESH:D002277', (295, 304))	('HNSC', 'Phenotype', 'HP:0012288', (635, 639))	('Glioblastoma multiforme', 'Disease', (533, 556))	('Variant', 'Var', (1486, 1493))	('Cancer', 'Disease', (1310, 1316))	('Stomach adenocarcinoma', 'Disease', (1254, 1276))	('GDAC', 'Chemical', '-', (557, 561))	('lung cancer', 'Phenotype', 'HP:0100526', (1005, 1016))	('carcinoma', 'Disease', (1267, 1276))	('carcinoma', 'Disease', (1035, 1044))	('LGG Low', 'Phenotype', 'HP:0004315', (808, 815))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (136, 159))	('AML', 'Disease', (29, 32))	('carcinoma', 'Disease', (1107, 1116))	('Breast adenocarcinoma', 'Disease', (100, 121))	('carcinoma', 'Disease', 'MESH:D002277', (1373, 1382))	('carcinoma', 'Disease', 'MESH:D002277', (182, 191))	('Skin cutaneous melanoma', 'Disease', 'MESH:C562393', (1190, 1213))	('FBS', 'Disease', 'MESH:D005198', (434, 437))	('Cancer', 'Disease', 'MESH:D009369', (1310, 1316))	('carcinoma', 'Disease', (914, 923))	('glioma', 'Disease', (822, 828))	('Glioblastoma multiforme', 'Disease', 'MESH:D005909', (533, 556))	('carcinoma', 'Disease', (668, 677))	('carcinoma', 'Disease', (112, 121))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (136, 159))	('LUAD', 'Phenotype', 'HP:0030078', (865, 869))	('Acute myeloid leukemia', 'Disease', (38, 60))	('AML', 'Disease', (34, 37))	('BRCA', 'Gene', (95, 99))	('carcinoma', 'Disease', (295, 304))	('carcinoma', 'Disease', 'MESH:D002277', (1035, 1044))	('carcinoma', 'Disease', 'MESH:D002277', (19, 28))	('LIHC', 'Disease', 'None', (829, 833))	('Acute myeloid leukemia', 'Disease', 'MESH:D015470', (38, 60))	('carcinoma', 'Disease', 'MESH:D002277', (1107, 1116))	('carcinoma', 'Disease', (880, 889))	('carcinoma', 'Phenotype', 'HP:0030731', (182, 191))	('ACC', 'Phenotype', 'HP:0006744', (0, 3))	('carcinoma', 'Disease', (855, 864))	('endocervical adenocarcinoma', 'Disease', (164, 191))	('carcinoma', 'Disease', (182, 191))	('Tyrosine kinase', 'Gene', (1387, 1402))	('neck squamous cell carcinoma', 'Disease', (649, 677))	('Lung adenocarcinoma', 'Phenotype', 'HP:0030078', (870, 889))	('Adrenocortical carcinoma', 'Disease', 'MESH:D018268', (4, 28))	('carcinoma', 'Disease', 'MESH:D002277', (1445, 1454))	('carcinoma', 'Disease', 'MESH:D002277', (112, 121))	('leukemia', 'Phenotype', 'HP:0001909', (52, 60))	('Oncology', 'Phenotype', 'HP:0002664', (425, 433))	('UCS', 'Phenotype', 'HP:0002891', (1455, 1458))	('BLCA', 'Chemical', '-', (61, 65))	('AML', 'Disease', 'MESH:D015470', (29, 32))	('Glioblastoma', 'Phenotype', 'HP:0012174', (533, 545))	('Prostate adenocarcinoma', 'Disease', (1093, 1116))	('carcinoma', 'Disease', 'MESH:D002277', (880, 889))	('TCPA', 'Chemical', '-', (1330, 1334))	('carcinoma', 'Phenotype', 'HP:0030731', (19, 28))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (840, 864))	('carcinoma', 'Disease', (798, 807))	('carcinoma', 'Disease', 'MESH:D002277', (855, 864))	('Cancer Protein Atlas', 'Disease', (1339, 1359))	('BRCA', 'Gene', '672', (95, 99))
87185	28821810	In a mouse model of pancreatic cancer, CCR2 inhibitors depleted inflammatory monocytes and macrophages, which resulted in decreased tumor growth and reduced metastasis.	('decreased tumor', 'Disease', (122, 137))	('pancreatic cancer', 'Disease', 'MESH:D010190', (20, 37))	('inhibitors', 'Var', (44, 54))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('CCR2', 'Gene', (39, 43))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('reduced', 'NegReg', (149, 156))	('depleted', 'NegReg', (55, 63))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (20, 37))	('mouse', 'Species', '10090', (5, 10))	('decreased tumor', 'Disease', 'MESH:D009369', (122, 137))	('metastasis', 'CPA', (157, 167))	('pancreatic cancer', 'Disease', (20, 37))
87211	28821810	In recent years many reports, such as the discovery of cancer without driver mutations and collective metastasis etc., have challenged the traditional paradigm of tumorigenesis in which cancer cells accumulate mutations in genes that control growth, which lead to clonal expansion and metastasis at late stage while emphasizing the importance of non-cell-autonomous forces.	('metastasis', 'CPA', (285, 295))	('lead to', 'Reg', (256, 263))	('mutations', 'Var', (210, 219))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('tumor', 'Disease', (163, 168))	('clonal expansion', 'CPA', (264, 280))	('cancer', 'Disease', (55, 61))	('cancer', 'Disease', (186, 192))	('cancer', 'Disease', 'MESH:D009369', (186, 192))
87253	28423738	For example, high serum CysC level was to closely linked to poor prognosis in colorectal cancer patients and melanoma metastasis.	('high serum CysC level', 'Phenotype', 'HP:0500151', (13, 34))	('melanoma metastasis', 'Disease', 'MESH:D009362', (109, 128))	('high', 'Var', (13, 17))	('serum CysC level', 'MPA', (18, 34))	('melanoma', 'Phenotype', 'HP:0002861', (109, 117))	('colorectal cancer', 'Disease', 'MESH:D015179', (78, 95))	('linked', 'Reg', (50, 56))	('colorectal cancer', 'Phenotype', 'HP:0003003', (78, 95))	('patients', 'Species', '9606', (96, 104))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('melanoma metastasis', 'Disease', (109, 128))	('CysC', 'Chemical', '-', (24, 28))	('colorectal cancer', 'Disease', (78, 95))
87272	28423738	The results showed that the miR-338 mimic transfection sharply reduced the luciferase activity of the WT vector but could not changed that of the MUT vector (Figure 1E).	('reduced', 'NegReg', (63, 70))	('luciferase', 'Enzyme', (75, 85))	('activity', 'MPA', (86, 94))	('transfection', 'Var', (42, 54))	('miR-338', 'Gene', '442906', (28, 35))	('miR-338', 'Gene', (28, 35))
87275	28423738	The results showed that the miR-338 antagomir transfection decreased the miR-338 level by ~80% (Figure 2A) and caused a ~2-fold increase in the level of CystC (Figure 2B).	('miR-338', 'Gene', (73, 80))	('level of CystC', 'MPA', (144, 158))	('increase', 'PosReg', (128, 136))	('miR-338', 'Gene', '442906', (73, 80))	('decreased', 'NegReg', (59, 68))	('transfection', 'Var', (46, 58))	('miR-338', 'Gene', '442906', (28, 35))	('miR-338', 'Gene', (28, 35))
87278	28423738	Additionally, CCK-8 cell proliferation assay and Annexin V-FITC/PI apoptosis detection showed that silencing miR-338 significantly increased proliferation and decreased apoptosis of the primary esophageal cancer cells (Figure 2C and 2D).	('apoptosis', 'CPA', (169, 178))	('increased', 'PosReg', (131, 140))	('Annexin V', 'Gene', '308', (49, 58))	('miR-338', 'Gene', '442906', (109, 116))	('esophageal cancer', 'Disease', (194, 211))	('miR-338', 'Gene', (109, 116))	('decreased', 'NegReg', (159, 168))	('Annexin V', 'Gene', (49, 58))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('silencing', 'Var', (99, 108))	('esophageal cancer', 'Disease', 'MESH:D004938', (194, 211))
87279	28423738	In contrast to the results from the miR-338 antagomir transfection, the miR-338 mimic transfection robustly elevated the level of miR-338 and sharply reduced CystC expression (Figure 3A and 3B).	('CystC expression', 'MPA', (158, 174))	('miR-338', 'Gene', (36, 43))	('miR-338', 'Gene', '442906', (130, 137))	('miR-338', 'Gene', (130, 137))	('miR-338', 'Gene', '442906', (36, 43))	('reduced', 'NegReg', (150, 157))	('transfection', 'Var', (86, 98))	('elevated', 'PosReg', (108, 116))	('miR-338', 'Gene', '442906', (72, 79))	('miR-338', 'Gene', (72, 79))
87285	28423738	Cell proliferation and apoptosis assayes showed that Snhg1 overexpression significantly increased proliferation and decreased apoptosis of the cells, while silencing Snhg1 reduced proliferation and markedly exacerbated apoptosis of the cells (Figure 4C and 4D).	('reduced', 'NegReg', (172, 179))	('Snhg1', 'Gene', (166, 171))	('silencing', 'Var', (156, 165))	('exacerbated', 'PosReg', (207, 218))	('Snhg1', 'Gene', (53, 58))	('increased', 'PosReg', (88, 97))	('apoptosis', 'CPA', (219, 228))	('Snhg1', 'Gene', '23642', (166, 171))	('apoptosis of the cells', 'CPA', (126, 148))	('decreased', 'NegReg', (116, 125))	('Snhg1', 'Gene', '23642', (53, 58))
87286	28423738	In consistent with the results of cell proliferation and apoptosis assayes, Snhg1 overexpression increased the levels of CystC and diminished the levels of caspase-8/3, while silencing Snhg1 decreased the levels of CystC and elevated the levels of caspase-8/3 (Figure 4E).	('elevated', 'PosReg', (225, 233))	('Snhg1', 'Gene', '23642', (185, 190))	('Snhg1', 'Gene', (76, 81))	('caspase-8/3', 'Gene', '841;836', (248, 259))	('levels of CystC', 'MPA', (111, 126))	('caspase-8/3 (Figure 4E', 'Gene', '841;836', (248, 270))	('levels of CystC', 'MPA', (205, 220))	('Snhg1', 'Gene', '23642', (76, 81))	('caspase-8/3', 'Gene', (248, 259))	('diminished', 'NegReg', (131, 141))	('decreased', 'NegReg', (191, 200))	('silencing', 'Var', (175, 184))	('caspase-8/3', 'Gene', (156, 167))	('caspase-8/3', 'Gene', '841;836', (156, 167))	('Snhg1', 'Gene', (185, 190))	('overexpression increased', 'PosReg', (82, 106))
87312	28423738	However, some other studies indicated that high serum CysC level was related with poor prognosis and it could promote the progression of several cancers.	('cancers', 'Disease', (145, 152))	('high serum CysC level', 'Phenotype', 'HP:0500151', (43, 64))	('cancers', 'Phenotype', 'HP:0002664', (145, 152))	('high', 'Var', (43, 47))	('progression', 'CPA', (122, 133))	('CysC', 'Chemical', '-', (54, 58))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('promote', 'PosReg', (110, 117))	('serum CysC level', 'MPA', (48, 64))	('cancers', 'Disease', 'MESH:D009369', (145, 152))
87362	27683114	Methylation of RAD51B, XRCC3 and other homologous recombination genes is associated with expression of immune checkpoints and an inflammatory signature in squamous cell carcinoma of the head and neck, lung and cervix Immune checkpoints are emerging treatment targets, but mechanisms underlying checkpoint expression are poorly understood.	('carcinoma of the head and neck', 'Phenotype', 'HP:0012288', (169, 199))	('XRCC3', 'Gene', (23, 28))	('expression', 'MPA', (89, 99))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (155, 178))	('carcinoma', 'Phenotype', 'HP:0030731', (169, 178))	('squamous cell carcinoma', 'Disease', (155, 178))	('Methylation', 'Var', (0, 11))	('XRCC3', 'Gene', '7517', (23, 28))	('associated', 'Reg', (73, 83))	('RAD51B', 'Gene', (15, 21))	('RAD51B', 'Gene', '5890', (15, 21))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (155, 178))
87365	27683114	RAD51B methylation was identified in all cancer subtypes.	('RAD51B', 'Gene', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('methylation', 'Var', (7, 18))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('identified', 'Reg', (23, 33))
87367	27683114	Methylation of the candidate genes was also associated with expression of other checkpoints, ligands, MHC- and T-cell associated genes as well as an interferon-inflammatory immune gene signature, predictive for the efficacy of PD-1 inhibition in HNSCC.	('associated', 'Reg', (44, 54))	('expression', 'MPA', (60, 70))	('inhibition', 'NegReg', (232, 242))	('Methylation', 'Var', (0, 11))	('HNSCC', 'Phenotype', 'HP:0012288', (246, 251))	('PD-1', 'Gene', (227, 231))	('HNSCC', 'Disease', (246, 251))	('PD-1', 'Gene', '5133', (227, 231))
87368	27683114	Homologous recombination deficiency might therefore be mediated by DNA repair gene hypermethylation and linked to an immune-evasive phenotype in SCC.	('linked to', 'Reg', (104, 113))	('hypermethylation', 'Var', (83, 99))	('deficiency', 'Disease', 'MESH:D007153', (25, 35))	('SCC', 'Disease', (145, 148))	('DNA', 'Gene', (67, 70))	('mediated', 'Reg', (55, 63))	('deficiency', 'Disease', (25, 35))
87369	27683114	Among these alterations, mutations account for a significant amount of the functional changes that have been identified to drive cancer.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('mutations', 'Var', (25, 34))	('alterations', 'Var', (12, 23))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('functional', 'MPA', (75, 85))
87370	27683114	Many tumors also harbor a high mutational load with both driver and passenger mutations that accumulate through DNA damage, evolutionary selection and dysfunctional DNA repair.	('tumors', 'Disease', (5, 11))	('tumors', 'Disease', 'MESH:D009369', (5, 11))	('dysfunctional', 'Disease', (151, 164))	('dysfunctional', 'Disease', 'MESH:D006331', (151, 164))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('mutations', 'Var', (78, 87))	('tumors', 'Phenotype', 'HP:0002664', (5, 11))
87376	27683114	NCT01693783, NCT01693562 and others).	('NCT01693783', 'Var', (0, 11))	('NCT01693562', 'CellLine', 'None', (13, 24))	('NCT01693562', 'Var', (13, 24))
87382	27683114	Microsatellite instability is caused by the inactivation of DNA enzymes in the mismatch excision repair pathway (MMR).	('Microsatellite instability', 'Disease', (0, 26))	('inactivation', 'Var', (44, 56))	('Microsatellite instability', 'Disease', 'MESH:D053842', (0, 26))	('caused by', 'Reg', (30, 39))
87385	27683114	Hypermethylation of MLH1 and MSH2 genes have been implicated as a potential cause of MSI in head and neck squamous cell carcinoma.	('MSH2', 'Gene', '4436', (29, 33))	('MSI', 'Disease', (85, 88))	('Hypermethylation', 'Var', (0, 16))	('MLH1', 'Gene', '4292', (20, 24))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (92, 129))	('MLH1', 'Gene', (20, 24))	('neck squamous cell carcinoma', 'Disease', (101, 129))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('cause', 'Reg', (76, 81))	('MSI', 'Disease', 'None', (85, 88))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (101, 129))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (106, 129))	('MSH2', 'Gene', (29, 33))
87386	27683114	In ovarian cancer, alterations of homologous repair genes including BRCA1 have been associated with CD274 expression and tumor-infiltrating lymphocytes.	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('BRCA1', 'Gene', (68, 73))	('ovarian cancer', 'Phenotype', 'HP:0100615', (3, 17))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('expression', 'MPA', (106, 116))	('tumor', 'Disease', (121, 126))	('ovarian cancer', 'Disease', 'MESH:D010051', (3, 17))	('alterations', 'Var', (19, 30))	('ovarian cancer', 'Disease', (3, 17))	('associated', 'Reg', (84, 94))	('BRCA1', 'Gene', '672', (68, 73))	('CD274', 'Gene', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
87387	27683114	RAD51B and XRCC3 polymorphisms have been identified as a risk factor for prostate, ovarian, breast, head and neck and other cancer types,,.	('RAD51B', 'Gene', (0, 6))	('cancer', 'Disease', (124, 130))	('risk', 'Reg', (57, 61))	('ovarian', 'Disease', (83, 90))	('polymorphisms', 'Var', (17, 30))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('XRCC3', 'Gene', (11, 16))	('breast', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (124, 130))	('prostate', 'Disease', (73, 81))
87395	27683114	All Bonferroni corrected p-values for the candidate genes were < 0.05 with the exception of the two lung cancer candidate genes, where only one of the two correlations (RAD51B-CTLA4 and CHEK1-CD274) remained significant after correcting for multiple testing, respectively.	('lung cancer', 'Phenotype', 'HP:0100526', (100, 111))	('CHEK1', 'Gene', '1111', (186, 191))	('lung cancer', 'Disease', (100, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('CHEK1', 'Gene', (186, 191))	('lung cancer', 'Disease', 'MESH:D008175', (100, 111))	('RAD51B-CTLA4', 'Var', (169, 181))
87401	27683114	Positive correlations in all four interactions were only identified for lung, cervical and head and neck squamous cancer histologies but several cancer types showed positive correlations for either RAD51B (e.g.	('cancer', 'Disease', (145, 151))	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('neck squamous cancer', 'Disease', 'MESH:D006258', (100, 120))	('head and neck squamous cancer', 'Phenotype', 'HP:0012288', (91, 120))	('RAD51B', 'Var', (198, 204))	('squamous cancer', 'Phenotype', 'HP:0002860', (105, 120))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('correlations', 'Interaction', (174, 186))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('neck squamous cancer', 'Disease', (100, 120))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('cancer', 'Disease', (114, 120))
87407	27683114	Among the DNA-repair genes that did exhibit positive correlations in the cross-validation, MLH3 was almost uniformly hypomethylated in all three cancer types.	('cancer', 'Disease', (145, 151))	('MLH3', 'Gene', '27030', (91, 95))	('MLH3', 'Gene', (91, 95))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('hypomethylated', 'Var', (117, 131))
87411	27683114	To assess methylation differences between biologic subtypes of HNSCC, the methylation signatures of TP53 mutant and TP53 wild type HNSCC were compared and did not show relevant differences (Figure 4b).	('TP53', 'Gene', '7157', (100, 104))	('TP53', 'Gene', (116, 120))	('HNSCC', 'Phenotype', 'HP:0012288', (131, 136))	('TP53', 'Gene', (100, 104))	('TP53', 'Gene', '7157', (116, 120))	('mutant', 'Var', (105, 111))	('HNSCC', 'Phenotype', 'HP:0012288', (63, 68))
87417	27683114	Methylation of XRCC3 and RAD51B exhibited statistically significant (all Bonferroni corrected p-values <0.001, with the exception of CD276, VTCN1 and ICOSLG-RAD51B interaction), strong positive correlations with expression of inflammation associated genes in head and neck squamous cell carcinoma and also showed similar patterns in lung and cervical carcinoma (Figure 6a, 6b, 6c).	('carcinoma', 'Phenotype', 'HP:0030731', (351, 360))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (259, 296))	('carcinoma', 'Phenotype', 'HP:0030731', (287, 296))	('inflammation', 'Disease', 'MESH:D007249', (226, 238))	('lung and cervical carcinoma', 'Disease', 'MESH:D002575', (333, 360))	('VTCN1', 'Gene', (140, 145))	('RAD51B', 'Gene', (25, 31))	('XRCC3', 'Gene', (15, 20))	('Methylation', 'Var', (0, 11))	('positive', 'PosReg', (185, 193))	('inflammation', 'Disease', (226, 238))	('CD276', 'Gene', (133, 138))	('CD276', 'Gene', '80381', (133, 138))	('neck squamous cell carcinoma', 'Disease', (268, 296))	('ICOSLG', 'Gene', (150, 156))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (268, 296))	('ICOSLG', 'Gene', '23308', (150, 156))	('VTCN1', 'Gene', '79679', (140, 145))	('correlations', 'Interaction', (194, 206))	('expression', 'MPA', (212, 222))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (273, 296))
87423	27683114	Expression of the IFNG signature was not only correlated to methylation on the single gene level, but also significantly higher in patients with hypermethylation of more candidate genes in a dose-dependent manner (methylation signature) (Figure 7c).	('patients', 'Species', '9606', (131, 139))	('IFNG', 'Gene', (18, 22))	('Expression', 'MPA', (0, 10))	('methylation', 'Var', (60, 71))	('hypermethylation', 'Var', (145, 161))	('IFNG', 'Gene', '3458', (18, 22))	('higher', 'PosReg', (121, 127))
87424	27683114	We next assessed if mutations in DNA repair genes are also involved in tumor inflammation in HNSCC.	('HNSCC', 'Disease', (93, 98))	('HNSCC', 'Phenotype', 'HP:0012288', (93, 98))	('tumor inflammation', 'Disease', 'MESH:D007249', (71, 89))	('tumor inflammation', 'Disease', (71, 89))	('involved', 'Reg', (59, 67))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('DNA repair genes', 'Gene', (33, 49))	('mutations', 'Var', (20, 29))
87425	27683114	Mutations of genes involved in DNA repair pathways were present in almost 88.5% of the samples (TP53 mutations included, Supplementary Figure S10).	('Mutations', 'Var', (0, 9))	('TP53', 'Gene', '7157', (96, 100))	('TP53', 'Gene', (96, 100))
87427	27683114	In addition to the mutations of DNA repair genes, the total mutational load in HNSCC tumor samples was assessed, since a nonfunctional DNA repair mechanisms might lead to an increase in mutations and thus lead to a tumor inflammation.	('lead to', 'Reg', (205, 212))	('nonfunctional', 'Var', (121, 134))	('tumor inflammation', 'Disease', (215, 233))	('tumor inflammation', 'Disease', 'MESH:D007249', (215, 233))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('increase', 'PosReg', (174, 182))	('HNSCC tumor', 'Disease', 'MESH:D000077195', (79, 90))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('HNSCC', 'Phenotype', 'HP:0012288', (79, 84))	('HNSCC tumor', 'Disease', (79, 90))	('mutations', 'MPA', (186, 195))
87429	27683114	This report for the first time proposes a link between hypermethylation of DNA-repair genes and the expression of immune checkpoints in squamous cell carcinomas.	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (136, 160))	('squamous cell carcinomas', 'Disease', (136, 160))	('hypermethylation', 'Var', (55, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (150, 159))	('expression', 'MPA', (100, 110))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (136, 160))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (136, 159))	('carcinomas', 'Phenotype', 'HP:0030731', (150, 160))	('DNA-repair genes', 'Gene', (75, 91))
87435	27683114	The here presented results suggest that in head and neck cancer HRD might be mediated by epigenetic silencing.	('epigenetic silencing', 'Var', (89, 109))	('neck cancer HRD', 'Disease', (52, 67))	('mediated by', 'Reg', (77, 88))	('neck cancer HRD', 'Disease', 'MESH:D006258', (52, 67))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('head and neck cancer', 'Phenotype', 'HP:0012288', (43, 63))
87438	27683114	It is possibly, albeit unlikely, that hypermethylation of these genes directly leads to pathway activation and upregulation of checkpoint molecules and inflammation.	('hypermethylation', 'Var', (38, 54))	('upregulation', 'PosReg', (111, 123))	('inflammation', 'Disease', 'MESH:D007249', (152, 164))	('inflammation', 'Disease', (152, 164))	('pathway', 'Pathway', (88, 95))	('activation', 'PosReg', (96, 106))	('checkpoint', 'MPA', (127, 137))
87442	27683114	The negative correlations between methylation of some candidate genes and immune checkpoint expression in some cancer types further underline a histology-dependent effect.	('immune checkpoint expression', 'MPA', (74, 102))	('methylation', 'Var', (34, 45))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('negative', 'NegReg', (4, 12))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))
87445	27683114	Additional experiments showed that methylation of XRCC3 and RAD51B is significantly correlated to the expression of the mesenchymal marker Vimentin and reduced expression of the epithelial marker E-Cadherin (Supplementary Figure S11A, S11B).	('expression', 'MPA', (160, 170))	('S11A', 'SUBSTITUTION', 'None', (229, 233))	('XRCC3', 'Gene', (50, 55))	('expression', 'MPA', (102, 112))	('correlated', 'Reg', (84, 94))	('reduced', 'NegReg', (152, 159))	('E-Cadherin', 'Gene', (196, 206))	('RAD51B', 'Gene', (60, 66))	('Vimentin', 'Gene', (139, 147))	('methylation', 'Var', (35, 46))	('S11A', 'Var', (229, 233))	('Vimentin', 'Gene', '7431', (139, 147))	('S11B', 'SUBSTITUTION', 'None', (235, 239))	('S11B', 'Var', (235, 239))	('E-Cadherin', 'Gene', '999', (196, 206))
87449	27683114	We also did not find differences in methylation between TP53 mutant and wild-type tumors, that can also serve as a surrogate marker of HPV infection.	('tumors', 'Disease', (82, 88))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('TP53', 'Gene', '7157', (56, 60))	('HPV infection', 'Disease', 'MESH:D030361', (135, 148))	('TP53', 'Gene', (56, 60))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('mutant', 'Var', (61, 67))	('methylation', 'MPA', (36, 47))	('HPV infection', 'Disease', (135, 148))
87458	27683114	We therefore conclude that hypermethylation of homologous recombination DNA repair genes including RAD51B and XRCC3 is associated with an inflamed phenotype in squamous cell cancers of the head and neck, lung and cervix.	('associated', 'Reg', (119, 129))	('hypermethylation', 'Var', (27, 43))	('cancers of the head and neck', 'Phenotype', 'HP:0012288', (174, 202))	('cancers', 'Phenotype', 'HP:0002664', (174, 181))	('squamous cell cancers', 'Disease', (160, 181))	('squamous cell cancers', 'Phenotype', 'HP:0002860', (160, 181))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (160, 180))	('RAD51B', 'Gene', (99, 105))	('squamous cell cancers', 'Disease', 'MESH:D002294', (160, 181))	('lung', 'Disease', (204, 208))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('cervix', 'Disease', (213, 219))	('XRCC3', 'Gene', (110, 115))
87501	27330306	In all, >50% of HNSCCs harbor inactivating TP53 gene mutations and >50% demonstrate chromosomal loss at 17p - the site where the TP53 gene resides.	('mutations', 'Var', (53, 62))	('inactivating', 'NegReg', (30, 42))	('TP53', 'Gene', '7157', (129, 133))	('HNSCC', 'Phenotype', 'HP:0012288', (16, 21))	('TP53', 'Gene', '7157', (43, 47))	('TP53', 'Gene', (129, 133))	('TP53', 'Gene', (43, 47))	('loss', 'NegReg', (96, 100))
87504	27330306	The most frequently mutated component of the Rb pathway in HNSCC is the p16INK4A tumor suppressor gene.	('p16INK4A', 'Gene', '1029', (72, 80))	('mutated', 'Var', (20, 27))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('Rb', 'Phenotype', 'HP:0009919', (45, 47))	('Rb pathway', 'Pathway', (45, 55))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('p16INK4A', 'Gene', (72, 80))	('HNSCC', 'Phenotype', 'HP:0012288', (59, 64))	('tumor', 'Disease', (81, 86))	('HNSCC', 'Disease', (59, 64))
87506	27330306	Inactivation of p16INK4A can occur via promoter hypermethylation, gene mutation, or deletion, the latter being recognized genetically as a loss of heterozygosity (LOH).	('p16INK4A', 'Gene', (16, 24))	('deletion', 'Var', (84, 92))	('promoter hypermethylation', 'Var', (39, 64))	('p16INK4A', 'Gene', '1029', (16, 24))	('Inactivation', 'NegReg', (0, 12))	('gene mutation', 'Var', (66, 79))
87508	27330306	In addition to the inactivation of p16INK4A and TP53, mutations in other genes that regulate cell proliferation, including CDKN2A, PTEN, PIK3CA, and HRAS, have been implicated in HNSCC.	('PIK3CA', 'Gene', (137, 143))	('TP53', 'Gene', '7157', (48, 52))	('PTEN', 'Gene', (131, 135))	('mutations', 'Var', (54, 63))	('TP53', 'Gene', (48, 52))	('HRAS', 'Gene', '3265', (149, 153))	('PIK3CA', 'Gene', '5290', (137, 143))	('CDKN2A', 'Gene', '1029', (123, 129))	('p16INK4A', 'Gene', (35, 43))	('HRAS', 'Gene', (149, 153))	('CDKN2A', 'Gene', (123, 129))	('HNSCC', 'Disease', (179, 184))	('implicated', 'Reg', (165, 175))	('HNSCC', 'Phenotype', 'HP:0012288', (179, 184))	('p16INK4A', 'Gene', '1029', (35, 43))
87509	27330306	Whole-exome sequencing data have also shown that 30% of all HNSCC cases harbored mutations in genes that regulate squamous differentiation (eg, NOTCH1, IRF6, and TP63), implicating its dysregulation as a major driver of HNSCC carcinogenesis.	('HNSCC', 'Phenotype', 'HP:0012288', (220, 225))	('TP63', 'Gene', (162, 166))	('IRF6', 'Gene', (152, 156))	('IRF6', 'Gene', '3664', (152, 156))	('NOTCH1', 'Gene', '4851', (144, 150))	('NOTCH1', 'Gene', (144, 150))	('HNSCC carcinogenesis', 'Disease', (220, 240))	('HNSCC carcinogenesis', 'Disease', 'MESH:D000077195', (220, 240))	('HNSCC', 'Disease', (60, 65))	('HNSCC', 'Phenotype', 'HP:0012288', (60, 65))	('mutations', 'Var', (81, 90))	('harbored', 'Reg', (72, 80))	('TP63', 'Gene', '8626', (162, 166))
87511	27330306	The presence of HPV is a prognostic biomarker associated with better outcome in locally advanced oropharyngeal cancers, with a 40%-80% cure rate.	('cancers', 'Phenotype', 'HP:0002664', (111, 118))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('HPV', 'Species', '10566', (16, 19))	('oropharyngeal cancers', 'Disease', (97, 118))	('HPV', 'Gene', (16, 19))	('presence', 'Var', (4, 12))	('oropharyngeal cancers', 'Disease', 'MESH:D009959', (97, 118))
87515	27330306	Mutations in TP53 occur in 45%-70% of HNSCC.	('TP53', 'Gene', (13, 17))	('Mutations', 'Var', (0, 9))	('TP53', 'Gene', '7157', (13, 17))	('HNSCC', 'Disease', (38, 43))	('HNSCC', 'Phenotype', 'HP:0012288', (38, 43))
87517	27330306	TP53 mutations are frequently accompanied by loss of chromosome 3p and are associated with advanced clinical stage in HNSCC patients.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('HNSCC', 'Disease', (118, 123))	('mutations', 'Var', (5, 14))	('HNSCC', 'Phenotype', 'HP:0012288', (118, 123))	('chromosome 3p', 'Protein', (53, 66))	('loss', 'NegReg', (45, 49))	('associated', 'Reg', (75, 85))	('patients', 'Species', '9606', (124, 132))
87519	27330306	In HNSCC, constitutive activation of EGFR can occur via overexpression of EGFR ligands, mutation or amplification of EGFR, or by activation of other receptors or nonreceptor tyrosine kinases.	('HNSCC', 'Phenotype', 'HP:0012288', (3, 8))	('mutation', 'Var', (88, 96))	('amplification', 'Var', (100, 113))	('EGFR', 'Gene', '1956', (117, 121))	('EGFR', 'Gene', (117, 121))	('activation', 'PosReg', (129, 139))	('activation', 'PosReg', (23, 33))	('EGFR', 'Gene', '1956', (37, 41))	('EGFR', 'Gene', '1956', (74, 78))	('overexpression', 'PosReg', (56, 70))	('EGFR', 'Gene', (37, 41))	('EGFR', 'Gene', (74, 78))
87554	27330306	Pharmacological inhibition of SphK1 enzyme activity or Sphk1 gene silencing blocks tumor progression in many types of cancers.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('cancers', 'Disease', (118, 125))	('Sphk1', 'Gene', '8877', (55, 60))	('cancers', 'Disease', 'MESH:D009369', (118, 125))	('tumor', 'Disease', (83, 88))	('SphK1', 'Gene', (30, 35))	('silencing blocks', 'NegReg', (66, 82))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('activity', 'MPA', (43, 51))	('Sphk1', 'Gene', (55, 60))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('cancers', 'Phenotype', 'HP:0002664', (118, 125))	('inhibition', 'Var', (16, 26))
87558	27330306	In a chemical-induced model of tongue cancer, SphK1-knockout mice exhibited decreased tumor incidence, multiplicity, and volume when compared with wild-type mice, suggesting that SphK1 is necessary for HNSCC carcinogenesis.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('multiplicity', 'CPA', (103, 115))	('decreased tumor', 'Disease', (76, 91))	('mice', 'Species', '10090', (61, 65))	('HNSCC', 'Phenotype', 'HP:0012288', (202, 207))	('SphK1-knockout', 'Gene', (46, 60))	('mice', 'Species', '10090', (157, 161))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('HNSCC carcinogenesis', 'Disease', (202, 222))	('HNSCC carcinogenesis', 'Disease', 'MESH:D000077195', (202, 222))	('tongue cancer', 'Disease', (31, 44))	('SphK1-knockout', 'Var', (46, 60))	('tongue cancer', 'Disease', 'MESH:D014062', (31, 44))	('decreased tumor', 'Disease', 'MESH:D009369', (76, 91))
87566	27330306	LRIG1, a negative regulator of EGFR, is located at 3p14 and its copy-number loss correlates with poor clinical outcome.	('EGFR', 'Gene', '1956', (31, 35))	('EGFR', 'Gene', (31, 35))	('copy-number loss', 'Var', (64, 80))	('LRIG1', 'Gene', '26018', (0, 5))	('LRIG1', 'Gene', (0, 5))
87577	27330306	Further, SCC-15 cells transfected with SphK1-siRNA produce smaller tumors in mice compared to parent cells.	('mice', 'Species', '10090', (77, 81))	('tumors', 'Disease', 'MESH:D009369', (67, 73))	('smaller', 'NegReg', (59, 66))	('SphK1-siRNA', 'Var', (39, 50))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('SCC-15', 'CellLine', 'CVCL:1681', (9, 15))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('tumors', 'Disease', (67, 73))
87581	27330306	S1P produced in the nucleus by SphK2 inhibits HDAC1/2 activity similar to classical HDAC inhibitors, whereas reduction of nuclear S1P increases HDAC activity and concomitantly decreases histone acetylation.	('HDAC1/2', 'Gene', '3065;3066', (46, 53))	('decreases', 'NegReg', (176, 185))	('reduction', 'Var', (109, 118))	('histone acetylation', 'MPA', (186, 205))	('S1P', 'Gene', '13609', (130, 133))	('S1P', 'Gene', (0, 3))	('S1P', 'Gene', '13609', (0, 3))	('HDAC', 'Enzyme', (144, 148))	('activity', 'MPA', (54, 62))	('S1P', 'Gene', (130, 133))	('increases', 'PosReg', (134, 143))	('SphK2', 'Gene', (31, 36))	('inhibits', 'NegReg', (37, 45))	('HDAC1/2', 'Gene', (46, 53))
87582	27330306	SphK2 has shown a protective role in the development of colitis-associated cancer (CAC) in mice, whereas SphK2 deficiency exacerbates CAC.	('mice', 'Species', '10090', (91, 95))	('SphK2', 'Gene', (105, 110))	('colitis-associated cancer', 'Disease', (56, 81))	('men', 'Species', '9606', (48, 51))	('deficiency', 'Var', (111, 121))	('CAC', 'Phenotype', 'HP:0002664', (134, 137))	('CAC', 'Disease', (134, 137))	('colitis-associated cancer', 'Disease', 'MESH:D003092', (56, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('colitis', 'Phenotype', 'HP:0002583', (56, 63))	('exacerbates', 'PosReg', (122, 133))	('CAC', 'Phenotype', 'HP:0002664', (83, 86))
87587	27330306	Nonetheless, few selective inhibitors of SphK2 have shown antitumor, antiangiogenic activities in cancer cell lines as well as mouse models.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('mouse', 'Species', '10090', (127, 132))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', (62, 67))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('inhibitors', 'Var', (27, 37))	('cancer', 'Disease', (98, 104))	('SphK2', 'Gene', (41, 46))	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('antiangiogenic activities', 'CPA', (69, 94))
87601	27330306	LPP3 expression decreases the growth, survival, and tumorigenesis of ovarian cancer cells.	('ovarian cancer', 'Disease', (69, 83))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('LPP3', 'Gene', '8613', (0, 4))	('tumor', 'Disease', (52, 57))	('LPP3', 'Gene', (0, 4))	('expression', 'Var', (5, 15))	('survival', 'CPA', (38, 46))	('ovarian cancer', 'Phenotype', 'HP:0100615', (69, 83))	('ovarian cancer', 'Disease', 'MESH:D010051', (69, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('growth', 'CPA', (30, 36))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('decreases', 'NegReg', (16, 25))
87603	27330306	Further, LPP3 knockdown inhibits both glioblastoma cell proliferation in culture and tumor growth in xenograft assays by reducing beta-catenin, cyclin D1, and CD133 expression.	('tumor', 'Disease', (85, 90))	('CD133', 'Gene', (159, 164))	('CD133', 'Gene', '8842', (159, 164))	('beta-catenin', 'Gene', '1499', (130, 142))	('inhibits', 'NegReg', (24, 32))	('expression', 'MPA', (165, 175))	('glioblastoma', 'Disease', (38, 50))	('reducing', 'NegReg', (121, 129))	('cyclin D1', 'Gene', '595', (144, 153))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('LPP3', 'Gene', '8613', (9, 13))	('cyclin D1', 'Gene', (144, 153))	('knockdown', 'Var', (14, 23))	('glioblastoma', 'Disease', 'MESH:D005909', (38, 50))	('glioblastoma', 'Phenotype', 'HP:0012174', (38, 50))	('beta-catenin', 'Gene', (130, 142))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('LPP3', 'Gene', (9, 13))
87607	27330306	Indeed, HPV-positive HNSCC tumors exhibit frequent genetic alterations in PTEN.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('HNSCC', 'Phenotype', 'HP:0012288', (21, 26))	('HPV-positive HNSCC tumors', 'Disease', (8, 33))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('PTEN', 'Gene', (74, 78))	('HPV-positive HNSCC tumors', 'Disease', 'MESH:D000077195', (8, 33))	('genetic alterations', 'Var', (51, 70))
87613	27330306	Advanced lung cancer patients exhibit decreased Spns2 expression, and ectopic Spns2 expression induced apoptosis in non-small-cell lung cancer cells, whereas its knockdown enhanced cell migration.	('Spns2', 'Gene', '124976', (78, 83))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (120, 142))	('lung cancer', 'Disease', 'MESH:D008175', (131, 142))	('patients', 'Species', '9606', (21, 29))	('Spns2', 'Gene', (48, 53))	('lung cancer', 'Phenotype', 'HP:0100526', (131, 142))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (116, 142))	('Spns2', 'Gene', (78, 83))	('induced', 'Reg', (95, 102))	('lung cancer', 'Disease', 'MESH:D008175', (9, 20))	('ectopic', 'Var', (70, 77))	('lung cancer', 'Phenotype', 'HP:0100526', (9, 20))	('decreased', 'NegReg', (38, 47))	('lung cancer', 'Disease', (131, 142))	('cell migration', 'CPA', (181, 195))	('expression', 'MPA', (54, 64))	('enhanced', 'PosReg', (172, 180))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('Spns2', 'Gene', '124976', (48, 53))	('apoptosis', 'CPA', (103, 112))	('lung cancer', 'Disease', (9, 20))
87618	27330306	For example, S1PR1 and S1PR4 couple mainly to Gi, whereas S1PR2 and S1PR3 activate Gi, Gq and G12/13.	('S1PR1', 'Gene', (13, 18))	('S1PR2', 'Var', (58, 63))	('S1PR4', 'Gene', '8698', (23, 28))	('S1PR3', 'Gene', '1903', (68, 73))	('S1PR3', 'Gene', (68, 73))	('S1PR1', 'Gene', '1901', (13, 18))	('activate', 'PosReg', (74, 82))	('S1PR4', 'Gene', (23, 28))
87628	27330306	Targeted disruption of the S1PR2 in mice leads to diffuse large B-cell lymphoma formation, and mutations in S1PR2 gene has been reported in germinal center B-cell like diffuse large B-cell lymphoma.	('S1PR2', 'Gene', (27, 32))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (182, 197))	('lymphoma', 'Disease', (71, 79))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (64, 79))	('lymphoma', 'Disease', 'MESH:D008223', (71, 79))	('leads to', 'Reg', (41, 49))	('diffuse', 'Disease', (50, 57))	('S1PR2', 'Gene', (108, 113))	('reported', 'Reg', (128, 136))	('lymphoma', 'Disease', (189, 197))	('lymphoma', 'Disease', 'MESH:D008223', (189, 197))	('lymphoma', 'Phenotype', 'HP:0002665', (71, 79))	('mutations', 'Var', (95, 104))	('mice', 'Species', '10090', (36, 40))	('lymphoma', 'Phenotype', 'HP:0002665', (189, 197))
87636	27330306	Furthermore, high expression of SphK1 correlates with poor patient outcomes in many cancers, including HNSCC.	('HNSCC', 'Phenotype', 'HP:0012288', (103, 108))	('SphK1', 'Gene', (32, 37))	('HNSCC', 'Disease', (103, 108))	('high', 'Var', (13, 17))	('cancers', 'Disease', 'MESH:D009369', (84, 91))	('cancers', 'Phenotype', 'HP:0002664', (84, 91))	('patient', 'Species', '9606', (59, 66))	('cancers', 'Disease', (84, 91))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))
87637	27330306	Selective SphK1 inhibitors have been tested in cell lines and animal models of several types of cancers, eg, leukemia and glioblastoma.	('cancers', 'Phenotype', 'HP:0002664', (96, 103))	('inhibitors', 'Var', (16, 26))	('leukemia', 'Disease', 'MESH:D007938', (109, 117))	('glioblastoma', 'Disease', (122, 134))	('leukemia', 'Phenotype', 'HP:0001909', (109, 117))	('glioblastoma', 'Disease', 'MESH:D005909', (122, 134))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('SphK1', 'Gene', (10, 15))	('glioblastoma', 'Phenotype', 'HP:0012174', (122, 134))	('cancers', 'Disease', 'MESH:D009369', (96, 103))	('leukemia', 'Disease', (109, 117))	('cancers', 'Disease', (96, 103))
87640	27330306	In addition to SphK1 inhibitors, ABC294640, a SphK2 selective inhibitor, suppresses cell proliferation of a number of cancer cell lines and reduces the in vivo tumor growth of mammary adenocarcinoma xenografts.	('cancer', 'Disease', (118, 124))	('reduces', 'NegReg', (140, 147))	('ABC294640', 'Chemical', 'MESH:C548780', (33, 42))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('adenocarcinoma xenografts', 'Disease', 'MESH:D000230', (184, 209))	('carcinoma', 'Phenotype', 'HP:0030731', (189, 198))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('adenocarcinoma xenografts', 'Disease', (184, 209))	('ABC294640', 'Var', (33, 42))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('tumor', 'Disease', (160, 165))	('suppresses', 'NegReg', (73, 83))
87641	27330306	ABC294640 also exhibits synergistic effects with sorafenib, a multikinase inhibitor.	('ABC294640', 'Var', (0, 9))	('sorafenib', 'Chemical', 'MESH:D000077157', (49, 58))	('ABC294640', 'Chemical', 'MESH:C548780', (0, 9))	('synergistic effects', 'MPA', (24, 43))
87648	27330306	FTY720, a synthetic analog of sphingosine, which binds to all the S1PRs, except S1PR2, has been approved by the US Food and Drug Administration for treatment of patients with the autoimmune disease relapsing multiple sclerosis patients.	('S1P', 'Gene', '13609', (80, 83))	('multiple sclerosis', 'Disease', 'MESH:D009103', (208, 226))	('S1P', 'Gene', (80, 83))	('autoimmune disease', 'Disease', (179, 197))	('FTY720', 'Var', (0, 6))	('patients', 'Species', '9606', (227, 235))	('men', 'Species', '9606', (153, 156))	('patients', 'Species', '9606', (161, 169))	('autoimmune disease', 'Disease', 'MESH:D001327', (179, 197))	('S1P', 'Gene', '13609', (66, 69))	('autoimmune disease', 'Phenotype', 'HP:0002960', (179, 197))	('sphingosine', 'Chemical', 'MESH:D013110', (30, 41))	('S1P', 'Gene', (66, 69))	('multiple sclerosis', 'Disease', (208, 226))
87649	27330306	FTY720 inhibits tumor development and angiogenesis in mice harboring human hepatocellular, bladder, and lung cancers.	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('bladder', 'Disease', (91, 98))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('inhibits', 'NegReg', (7, 15))	('cancers', 'Phenotype', 'HP:0002664', (109, 116))	('lung cancers', 'Disease', (104, 116))	('human', 'Species', '9606', (69, 74))	('FTY720', 'Var', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('lung cancer', 'Phenotype', 'HP:0100526', (104, 115))	('lung cancers', 'Disease', 'MESH:D008175', (104, 116))	('tumor', 'Disease', (16, 21))	('men', 'Species', '9606', (29, 32))	('mice', 'Species', '10090', (54, 58))	('angiogenesis', 'CPA', (38, 50))	('hepatocellular', 'Disease', (75, 89))	('lung cancers', 'Phenotype', 'HP:0100526', (104, 116))
87656	27330306	SphK1 inhibitors in combination with conventional chemotherapy agents, such as doxorubicin and cisplatin, have been used for sensitizing squamous carcinoma cells that were either resistant to radiation, doxorubicin, or cisplatin alone.	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('squamous carcinoma', 'Disease', 'MESH:D002294', (137, 155))	('cisplatin', 'Chemical', 'MESH:D002945', (219, 228))	('squamous carcinoma', 'Disease', (137, 155))	('SphK1', 'Gene', (0, 5))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (137, 155))	('inhibitors', 'Var', (6, 16))	('doxorubicin', 'Chemical', 'MESH:D004317', (203, 214))	('doxorubicin', 'Chemical', 'MESH:D004317', (79, 90))	('cisplatin', 'Chemical', 'MESH:D002945', (95, 104))
87661	27330306	Thus, identification of potent and specific inhibitors of SK1 and selective agonist/antagonist of S1PRs combined with novel drug delivery tools may improve the prognosis of HNSCC patients.	('inhibitors', 'Var', (44, 54))	('S1P', 'Gene', '13609', (98, 101))	('HNSCC', 'Disease', (173, 178))	('HNSCC', 'Phenotype', 'HP:0012288', (173, 178))	('S1P', 'Gene', (98, 101))	('SK1', 'Gene', (58, 61))	('patients', 'Species', '9606', (179, 187))	('improve', 'PosReg', (148, 155))
87674	25003505	For example, AC frequently harbour activating mutations of the epidermal growth factor receptor gene (EGFR) or EML4-ALK rearrangements, so epidermal growth factor receptor (EGFR) inhibitors and vascular endothelial growth factor (VEGF) inhibitors are more effective in treating AC than SQCC.	('epidermal growth factor receptor', 'Gene', (63, 95))	('epidermal growth factor receptor', 'Gene', '1956', (63, 95))	('EGFR', 'Gene', '1956', (102, 106))	('ALK', 'Gene', '238', (116, 119))	('mutations', 'Var', (46, 55))	('ALK', 'Gene', (116, 119))	('EGFR', 'Gene', '1956', (173, 177))	('vascular endothelial growth factor', 'Gene', '7422', (194, 228))	('VEGF', 'Gene', '7422', (230, 234))	('SQCC', 'Phenotype', 'HP:0002860', (286, 290))	('epidermal growth factor receptor', 'Gene', (139, 171))	('VEGF', 'Gene', (230, 234))	('vascular endothelial growth factor', 'Gene', (194, 228))	('EGFR', 'Gene', (102, 106))	('epidermal growth factor receptor', 'Gene', '1956', (139, 171))	('activating', 'PosReg', (35, 45))	('EML4', 'Gene', (111, 115))	('EGFR', 'Gene', (173, 177))	('EML4', 'Gene', '27436', (111, 115))
87677	25003505	Therefore, misdiagnosis or inaccurate diagnosis of poorly differentiated non-small cell lung carcinoma by single hematoxylin-eosin (H&E) immunohistochemical method may lead to patients' insensitivity to subsequent therapies and maximization of adverse effects.	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('patients', 'Species', '9606', (176, 184))	('hematoxylin-eosin', 'Chemical', '-', (113, 130))	('non-small cell lung carcinoma', 'Phenotype', 'HP:0030358', (73, 102))	('may lead', 'Reg', (164, 172))	('small cell lung carcinoma', 'Phenotype', 'HP:0030357', (77, 102))	('cell lung carcinoma', 'Disease', 'MESH:D055752', (83, 102))	('H&E', 'Chemical', '-', (132, 135))	('cell lung carcinoma', 'Disease', (83, 102))	('misdiagnosis', 'Var', (11, 23))
87703	25003505	As a result of these limitations, several molecular diagnoses have been proposed to subclassify NSCLC in recent years, such as EGFR mutations, K-ras mutations, EML4-ALK fusions and miRNA profiling.	('ALK', 'Gene', '238', (165, 168))	('EML4', 'Gene', '27436', (160, 164))	('K-ras', 'Gene', '3845', (143, 148))	('NSCLC', 'Disease', (96, 101))	('mutations', 'Var', (149, 158))	('K-ras', 'Gene', (143, 148))	('mutations', 'Var', (132, 141))	('NSCLC', 'Disease', 'MESH:D002289', (96, 101))	('ALK', 'Gene', (165, 168))	('NSCLC', 'Phenotype', 'HP:0030358', (96, 101))	('EML4', 'Gene', (160, 164))	('EGFR', 'Gene', '1956', (127, 131))	('EGFR', 'Gene', (127, 131))
87704	25003505	EGFR mutations, K-ras mutations and EML4-ALK fusions have been shown to be primarily restricted to lung adenocarcinoma.	('EGFR', 'Gene', (0, 4))	('EML4', 'Gene', '27436', (36, 40))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (99, 118))	('mutations', 'Var', (5, 14))	('K-ras', 'Gene', (16, 21))	('ALK', 'Gene', (41, 44))	('K-ras', 'Gene', '3845', (16, 21))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('lung adenocarcinoma', 'Disease', (99, 118))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (99, 118))	('EGFR', 'Gene', '1956', (0, 4))	('EML4', 'Gene', (36, 40))	('ALK', 'Gene', '238', (41, 44))
87705	25003505	Following identification, specific therapies could then be used, such as the EGFR inhibitors Erlotinib and Gefitinib that showed the greatest benefit in EGFR mutation-positive tumors, which were predominantly adenocarcinoma.	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('adenocarcinoma', 'Disease', (209, 223))	('carcinoma', 'Phenotype', 'HP:0030731', (214, 223))	('benefit', 'PosReg', (142, 149))	('Erlotinib', 'Chemical', 'MESH:D000069347', (93, 102))	('mutation-positive', 'Var', (158, 175))	('tumors', 'Disease', (176, 182))	('EGFR', 'Gene', '1956', (153, 157))	('adenocarcinoma', 'Disease', 'MESH:D000230', (209, 223))	('EGFR', 'Gene', '1956', (77, 81))	('tumors', 'Disease', 'MESH:D009369', (176, 182))	('Gefitinib', 'Chemical', 'MESH:D000077156', (107, 116))	('tumors', 'Phenotype', 'HP:0002664', (176, 182))	('EGFR', 'Gene', (153, 157))	('EGFR', 'Gene', (77, 81))
87707	25003505	Although these molecular diagnostic markers were precise and contributed to targeted therapies, most of the studies used EGFR and K-ras mutations to classify the subtypes of lung adenocarcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (184, 193))	('EGFR', 'Gene', '1956', (121, 125))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (174, 193))	('EGFR', 'Gene', (121, 125))	('mutations', 'Var', (136, 145))	('K-ras', 'Gene', (130, 135))	('K-ras', 'Gene', '3845', (130, 135))	('lung adenocarcinoma', 'Disease', (174, 193))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (174, 193))
87708	25003505	An additional factor that must be considered is that EML4-ALK fusions were detected in only about 5% of lung adenocarcinoma, and it was mutually exclusive to other EGFR mutations and K-ras mutations.	('EML4', 'Gene', (53, 57))	('EGFR', 'Gene', (164, 168))	('EML4', 'Gene', '27436', (53, 57))	('mutations', 'Var', (169, 178))	('lung adenocarcinoma', 'Disease', (104, 123))	('K-ras', 'Gene', (183, 188))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (104, 123))	('ALK', 'Gene', (58, 61))	('K-ras', 'Gene', '3845', (183, 188))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (104, 123))	('EGFR', 'Gene', '1956', (164, 168))	('ALK', 'Gene', '238', (58, 61))
87720	33661858	Epigenetic alterations, such as DNA methylation, have been recognized to be closely associated with the tumorigenesis and progression.	('Epigenetic alterations', 'Var', (0, 22))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('DNA methylation', 'Var', (32, 47))	('tumor', 'Disease', (104, 109))	('associated', 'Reg', (84, 94))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
87722	33661858	A total of 196 DNA methylation sites exhibited a significant association with patient prognosis, and patients were further stratified into 7 prognosis subgroups based upon the consensus clustering.	('patients', 'Species', '9606', (101, 109))	('methylation', 'Var', (19, 30))	('patient', 'Species', '9606', (78, 85))	('patient', 'Disease', (78, 85))	('patient', 'Species', '9606', (101, 108))	('association', 'Interaction', (61, 72))
87724	33661858	The function enrichment analysis revealed that these 258 genes enriched in biological pathways were closely related to cancers, such as DNA methylation and demethylation, cell cycle DNA replication, regulation of signal transduction by p53 class mediator, and genetic imprinting.	('cell cycle DNA replication', 'CPA', (171, 197))	('p53', 'Gene', (236, 239))	('cancers', 'Disease', 'MESH:D009369', (119, 126))	('cancers', 'Phenotype', 'HP:0002664', (119, 126))	('cancers', 'Disease', (119, 126))	('p53', 'Gene', '7157', (236, 239))	('demethylation', 'Var', (156, 169))	('related', 'Reg', (108, 115))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
87738	33661858	Epigenetic alterations, particularly DNA methylation, have been implicated in tumor initiation and progression.	('Epigenetic alterations', 'Var', (0, 22))	('DNA methylation', 'Var', (37, 52))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('implicated', 'Reg', (64, 74))	('tumor initiation', 'Disease', 'MESH:D009369', (78, 94))	('tumor initiation', 'Disease', (78, 94))
87740	33661858	Hypermethylation of CpG islands leads to transcriptional silencing of tumor suppressor genes, while hypomethylation of CpG islands promotes transcriptional oncogenes.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('transcriptional oncogenes', 'MPA', (140, 165))	('hypomethylation', 'Var', (100, 115))	('Hypermethylation', 'Var', (0, 16))	('tumor', 'Disease', (70, 75))	('silencing', 'NegReg', (57, 66))	('transcriptional', 'MPA', (41, 56))	('promotes', 'PosReg', (131, 139))
87743	33661858	Zhang et al found that TRIM58/cg26157385 methylation site were associated with 8 prognostic genes in LUSC.	('LUSC', 'Phenotype', 'HP:0030359', (101, 105))	('associated', 'Reg', (63, 73))	('LUSC', 'Disease', (101, 105))	('methylation', 'Var', (41, 52))	('TRIM58', 'Gene', (23, 29))	('TRIM58', 'Gene', '25893', (23, 29))
87753	33661858	There were 274 matched samples between the DNA methylation profiles and the complete clinical information in patients with LUSC (Table 1).	('LUSC', 'Disease', (123, 127))	('LUSC', 'Phenotype', 'HP:0030359', (123, 127))	('methylation', 'Var', (47, 58))	('patients', 'Species', '9606', (109, 117))
87762	33661858	Finally, the KEGG results showed that these methylated genes were enriched in porphyrin and chlorophyll metabolism, steroid hormone biosynthesis, and terpenoid backbone biosynthesis signaling pathways (Figure 5D).	('methylated', 'Var', (44, 54))	('steroid', 'Chemical', 'MESH:D013256', (116, 123))	('porphyrin', 'Chemical', 'MESH:D011166', (78, 87))	('porphyrin', 'Enzyme', (78, 87))	('terpenoid', 'Chemical', 'MESH:D013729', (150, 159))	('terpenoid', 'Pathway', (150, 159))	('chlorophyll', 'Chemical', 'MESH:D002734', (92, 103))
87766	33661858	Following the multivariate analysis, we obtained 3 specific methylation sites (cg10608333, cg23179321, and cg26979339) for constructing the prediction model.	('cg26979339', 'Chemical', '-', (107, 117))	('cg23179321', 'Var', (91, 101))	('cg26979339', 'Var', (107, 117))	('cg23179321', 'Chemical', '-', (91, 101))	('cg10608333', 'Var', (79, 89))	('cg10608333', 'Chemical', '-', (79, 89))
87770	33661858	With an increased risk score of patients with LUSC, the methylation level of cg23179321 and cg10608333 was obviously increased; in contrast, the methylation level of cg26979339 was reduced.	('reduced', 'NegReg', (181, 188))	('patients', 'Species', '9606', (32, 40))	('increased', 'PosReg', (117, 126))	('methylation level', 'MPA', (145, 162))	('methylation level', 'MPA', (56, 73))	('LUSC', 'Disease', (46, 50))	('LUSC', 'Phenotype', 'HP:0030359', (46, 50))	('cg23179321', 'Var', (77, 87))	('cg26979339', 'Chemical', '-', (166, 176))	('cg10608333', 'Var', (92, 102))	('cg10608333', 'Chemical', '-', (92, 102))	('cg23179321', 'Chemical', '-', (77, 87))
87771	33661858	Epigenetic changes, particular DNA methylation, play key roles in cancer initiation and progression.	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('DNA', 'MPA', (31, 34))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('Epigenetic changes', 'Var', (0, 18))	('cancer', 'Disease', (66, 72))
87779	33661858	Hypermethylation of CpG islands can inhibit the transcription of tumor suppressor genes and hypomethylation of CpG islands can activate the oncogenes, both of which can result in tumor formation and progression.	('activate', 'PosReg', (127, 135))	('tumor', 'Disease', (65, 70))	('result in', 'Reg', (169, 178))	('Hypermethylation', 'Var', (0, 16))	('inhibit', 'NegReg', (36, 43))	('transcription', 'MPA', (48, 61))	('progression', 'CPA', (199, 210))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('oncogenes', 'Gene', (140, 149))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('hypomethylation', 'Var', (92, 107))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('tumor', 'Disease', (179, 184))
87780	33661858	We found these 196 significant methylation sites corresponded to 258 genes, such as ELOVL5 and CUL5.	('ELOVL5', 'Gene', '60481', (84, 90))	('CUL5', 'Gene', (95, 99))	('CUL5', 'Gene', '8065', (95, 99))	('methylation sites', 'Var', (31, 48))	('ELOVL5', 'Gene', (84, 90))
87781	33661858	Boot et al reported that ELOVL5 was downregulated through DNA hypermethylation in colorectal cancer, and it is involved in important cellular processes such as apoptosis, lipogenesis, and the downstream transcriptional effect of the MAPK-pathway.	('apoptosis', 'CPA', (160, 169))	('colorectal cancer', 'Disease', (82, 99))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('ELOVL5', 'Gene', (25, 31))	('MAPK-pathway', 'Pathway', (233, 245))	('colorectal cancer', 'Disease', 'MESH:D015179', (82, 99))	('involved', 'Reg', (111, 119))	('DNA hypermethylation', 'Var', (58, 78))	('ELOVL5', 'Gene', '60481', (25, 31))	('colorectal cancer', 'Phenotype', 'HP:0003003', (82, 99))	('downregulated', 'NegReg', (36, 49))
87783	33661858	The results showed that these genes were enriched in the biological processes that were correlated with lung cancer, including DNA methylation and demethylation, cell cycle DNA replication, regulation of signal transduction by p53 class mediator, and genetic imprinting.	('lung cancer', 'Disease', 'MESH:D008175', (104, 115))	('p53', 'Gene', (227, 230))	('p53', 'Gene', '7157', (227, 230))	('cell cycle', 'CPA', (162, 172))	('demethylation', 'Var', (147, 160))	('lung cancer', 'Disease', (104, 115))	('lung cancer', 'Phenotype', 'HP:0100526', (104, 115))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))
87792	33178590	A total of 10,967 tumor samples comprising 32 cancer types from The Cancer Genome Atlas (TCGA) datasets were analyzed for MET abnormal expression, mutations, and copy number variants (CNVs).	('MET', 'Gene', '79811', (122, 125))	('mutations', 'Var', (147, 156))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('tumor', 'Disease', (18, 23))	('cancer', 'Disease', (46, 52))	('MET', 'Gene', (122, 125))	('Cancer', 'Disease', 'MESH:D009369', (68, 74))	('Cancer', 'Disease', (68, 74))	('copy number variants', 'Var', (162, 182))	('Cancer', 'Phenotype', 'HP:0002664', (68, 74))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
87794	33178590	Lung adenocarcinoma (LUAD) has most targetable mutations located in the juxtamembrane domain, and both high expression and amplification of MET are significantly associated with poor prognosis.	('MET', 'Gene', '79811', (140, 143))	('LUAD', 'Phenotype', 'HP:0030078', (21, 25))	('MET', 'Gene', (140, 143))	('mutations', 'Var', (47, 56))	('associated', 'Reg', (162, 172))	('carcinoma', 'Phenotype', 'HP:0030731', (10, 19))	('Lung adenocarcinoma', 'Phenotype', 'HP:0030078', (0, 19))	('amplification', 'Var', (123, 136))	('Lung adenocarcinoma', 'Disease', (0, 19))	('Lung adenocarcinoma', 'Disease', 'MESH:D000077192', (0, 19))
87799	33178590	This study provided significant and comprehensive information regarding MET abnormal expression, alterations (mutations and CNVs), and their clinical associations among 32 cancer types and offered insights into the full MET alteration spectrum and its implications for prognosis and treatment.	('MET', 'Gene', '79811', (220, 223))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('abnormal', 'Var', (76, 84))	('MET', 'Gene', (220, 223))	('cancer', 'Disease', (172, 178))	('alterations', 'Var', (97, 108))	('MET', 'Gene', '79811', (72, 75))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('MET', 'Gene', (72, 75))	('associations', 'Interaction', (150, 162))
87802	33178590	It is frequently activated in human tumors by various mechanisms, such as mutations, amplification, and overexpression, thus leading to malignant transformation and metastasis.	('malignant transformation', 'CPA', (136, 160))	('leading to', 'Reg', (125, 135))	('metastasis', 'CPA', (165, 175))	('human', 'Species', '9606', (30, 35))	('tumors', 'Disease', 'MESH:D009369', (36, 42))	('overexpression', 'Var', (104, 118))	('mutations', 'Var', (74, 83))	('activated', 'PosReg', (17, 26))	('amplification', 'Var', (85, 98))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumors', 'Disease', (36, 42))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))
87805	33178590	Moreover, in esophageal carcinoma (ESCA) and kidney renal papillary cell carcinoma (KIRP), gene amplification with consequent protein overexpression and constitutive kinase activation of MET has been reported.	('esophageal carcinoma', 'Disease', 'MESH:D004938', (13, 33))	('protein', 'Protein', (126, 133))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (13, 33))	('overexpression', 'PosReg', (134, 148))	('renal papillary cell carcinoma', 'Phenotype', 'HP:0006766', (52, 82))	('MET', 'Gene', '79811', (187, 190))	('ESCA', 'Phenotype', 'HP:0011459', (35, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (24, 33))	('MET', 'Gene', (187, 190))	('kidney renal papillary cell carcinoma', 'Disease', (45, 82))	('gene amplification', 'Var', (91, 109))	('kidney renal papillary cell carcinoma', 'Disease', 'MESH:C538614', (45, 82))	('esophageal carcinoma', 'Disease', (13, 33))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
87808	33178590	Especially in lung cancer, inhibition of MET receptor activity has shown promising results and has become a standard therapy for patients.	('patients', 'Species', '9606', (129, 137))	('MET', 'Gene', (41, 44))	('lung cancer', 'Disease', (14, 25))	('MET', 'Gene', '79811', (41, 44))	('lung cancer', 'Phenotype', 'HP:0100526', (14, 25))	('inhibition', 'Var', (27, 37))	('activity', 'MPA', (54, 62))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('lung cancer', 'Disease', 'MESH:D008175', (14, 25))
87822	33178590	Especially, in single- and cross-cancer queries, OQL algorithm can be utilized to accurately identify copy number alterations, mutations, mRNA, and protein expression profiles.	('copy number alterations', 'Var', (102, 125))	('mRNA', 'MPA', (138, 142))	('cross-cancer', 'Disease', (27, 39))	('cross-cancer', 'Disease', 'MESH:D009369', (27, 39))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('mutations', 'Var', (127, 136))
87840	33178590	MET mutations were observed most commonly in UCEC (12.3%), SKCM (10.5%), KIRP (8.8%), bladder urothelial carcinoma (BLCA, 4.4%), COADREAD (4.4%), and LUAD (4.2%).	('KIRP', 'Disease', (73, 77))	('MET', 'Gene', '79811', (0, 3))	('bladder urothelial carcinoma', 'Disease', (86, 114))	('observed', 'Reg', (19, 27))	('COADREAD', 'Disease', (129, 137))	('MET', 'Gene', (0, 3))	('UCEC', 'Disease', (45, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('mutations', 'Var', (4, 13))	('SKCM', 'Disease', (59, 63))	('LUAD', 'Phenotype', 'HP:0030078', (150, 154))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (86, 114))
87846	33178590	The most common domains were the other domain (91 samples), Sema domain (83 samples), Pkinase-Tyr domain (69 samples), TIG domain (563-654 aa, 18 samples), TIG domain (742-815 aa, 17 samples), TIG domain (657-728 aa, 12 samples), and PSI domain (7 samples).	('Sema', 'Gene', '7869', (60, 64))	('Tyr', 'Chemical', 'MESH:D014443', (94, 97))	('657-728 aa', 'Var', (205, 215))	('Sema', 'Gene', (60, 64))
87848	33178590	Mutations in KIRP were primarily located in the Pkinase-Tyr domain, approximately three times more than the mutations located in the other domain.	('Tyr', 'Chemical', 'MESH:D014443', (56, 59))	('Mutations', 'Var', (0, 9))	('KIRP', 'Gene', (13, 17))
87849	33178590	Mutations in COADREAD and GBM were mainly located in the Sema domain (Figure 2B and Supplementary Table S3).	('located', 'Reg', (42, 49))	('GBM', 'Gene', (26, 29))	('Sema', 'Gene', (57, 61))	('Sema', 'Gene', '7869', (57, 61))	('Mutations', 'Var', (0, 9))	('COADREAD', 'Gene', (13, 21))
87852	33178590	For example, the 1,010-aa mutation was found in seven samples (six samples with X1010 splice, one with D1010fs) and occurred almost exclusively in LUAD (6/7) (Supplementary Figure S2B).	('D1010fs', 'Var', (103, 110))	('D1010fs', 'Mutation', 'p.D1010fsX', (103, 110))	('X1010 splice', 'Var', (80, 92))	('LUAD', 'Phenotype', 'HP:0030078', (147, 151))
87855	33178590	The only other tumor with mutations at this position was LGG (one sample with X1010_splice), but its role was almost unknown to this cancer.	('LGG', 'Disease', (57, 60))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('cancer', 'Disease', (133, 139))	('mutations', 'Var', (26, 35))	('tumor', 'Disease', (15, 20))	('X1010_splice', 'Var', (78, 90))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
87856	33178590	The 1,148-aa mutation in the Pkinase-Tyr domain was also observed in seven samples [six samples with R1148Q (three SKCMs, one BLCA, one BRCA, one COADREAD), one sample with R1148* (one UCEC)].	('R1148*', 'Var', (173, 179))	('observed', 'Reg', (57, 65))	('Pkinase-Tyr', 'Enzyme', (29, 40))	('R1148Q', 'Var', (101, 107))	('R1148Q', 'Mutation', 'p.R1148Q', (101, 107))	('Tyr', 'Chemical', 'MESH:D014443', (37, 40))	('R1148*', 'SUBSTITUTION', 'None', (173, 179))
87858	33178590	The most mutated positions in KIRP (17 of 25 mutations) were located at the Pkinase Tyr domain, especially at the 1,250-aa position (four samples with M1250T) and the 1,092- to 1,094-aa position (three with V1092I, three with H1094Y).	('H1094Y', 'Var', (226, 232))	('V1092I', 'Var', (207, 213))	('M1250T', 'Var', (151, 157))	('H1094Y', 'Mutation', 'p.H1094Y', (226, 232))	('Tyr', 'Chemical', 'MESH:D014443', (84, 87))	('V1092I', 'Mutation', 'p.V1092I', (207, 213))	('M1250T', 'Mutation', 'p.M1250T', (151, 157))	('mutated', 'Reg', (9, 16))
87860	33178590	The most mutated positions in UCEC (3 of 78 mutations) were located at the Pkinase-Tyr domain at the 1,186-aa position (one with L1186F, one with L1186I, one with L1186R), but its oncogenic role was considered unknown.	('L1186F', 'Mutation', 'p.L1186F', (129, 135))	('L1186F', 'Var', (129, 135))	('L1186I', 'Mutation', 'p.L1186I', (146, 152))	('Tyr', 'Chemical', 'MESH:D014443', (83, 86))	('L1186R', 'Mutation', 'p.L1186R', (163, 169))	('L1186I', 'Var', (146, 152))	('L1186R', 'Var', (163, 169))	('mutated', 'Reg', (9, 16))
87861	33178590	D1228Y/A and T222K alterations were found in UCEC (one with D1228Y, one with D1228A, one with T222K) and known to be likely oncogenic and predicted oncogenic, respectively (Supplementary Figure S2D).	('D1228Y', 'SUBSTITUTION', 'None', (60, 66))	('D1228Y', 'Var', (60, 66))	('D1228A', 'Var', (77, 83))	('T222K', 'Var', (13, 18))	('T222K', 'Mutation', 'p.T222K', (94, 99))	('D1228Y', 'Mutation', 'p.D1228Y', (0, 6))	('D1228A', 'Mutation', 'p.D1228A', (77, 83))	('D1228Y', 'SUBSTITUTION', 'None', (0, 6))	('D1228Y', 'Var', (0, 6))	('UCEC', 'Disease', (45, 49))	('D1228Y', 'Mutation', 'p.D1228Y', (60, 66))	('T222K', 'Mutation', 'p.T222K', (13, 18))
87863	33178590	Next, we analyzed the clinical targeted therapy implications of MET mutation using cBioPortal, which could provide the annotation of variants from different databases, including COSMIC, Cancer Hotspots method, CIViC, My Cancer Genome, and OncoKB.	('MET', 'Gene', (64, 67))	('CIViC', 'Disease', 'None', (210, 215))	('MET', 'Gene', '79811', (64, 67))	('Cancer', 'Phenotype', 'HP:0002664', (186, 192))	('CIViC', 'Disease', (210, 215))	('Cancer', 'Disease', (220, 226))	('Cancer', 'Disease', (186, 192))	('Cancer', 'Disease', 'MESH:D009369', (220, 226))	('Cancer', 'Disease', 'MESH:D009369', (186, 192))	('Cancer', 'Phenotype', 'HP:0002664', (220, 226))	('variants', 'Var', (133, 141))
87864	33178590	Thus, for the clinical targeted therapy implications, each MET somatic mutation could be classified into four levels as defined by OncoKB: level 2 (seven mutations), level 3B (one mutation), level 4 (13 mutations), and level NA (290 mutations) (Figure 4A and Supplementary Table S2).	('MET', 'Gene', '79811', (59, 62))	('MET', 'Gene', (59, 62))	('mutations', 'Var', (154, 163))
87871	33178590	Among the 311 samples with MET mutations mentioned above, 129 also harbored MET CNVs (108 with gain, nine with amplification, and 12 with shallow deletion).	('mutations', 'Var', (31, 40))	('MET', 'Gene', (27, 30))	('MET', 'Gene', '79811', (76, 79))	('MET', 'Gene', (76, 79))	('gain', 'PosReg', (95, 99))	('MET', 'Gene', '79811', (27, 30))
87873	33178590	As shown in Figure 5A and Figures 1A,B, KIRP harbored a very high proportion of gain and was also the cancer type with higher MET expression.	('MET', 'Gene', '79811', (126, 129))	('KIRP', 'Var', (40, 44))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('MET', 'Gene', (126, 129))	('gain', 'PosReg', (80, 84))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('cancer', 'Disease', (102, 108))
87878	33178590	MET alterations were observed most commonly in UCEC (10.21%), SKCM (10.14%), and KIRP (9.89%), in which mutations were more common.	('SKCM', 'Disease', (62, 66))	('MET', 'Gene', '79811', (0, 3))	('alterations', 'Var', (4, 15))	('MET', 'Gene', (0, 3))	('UCEC', 'Disease', (47, 51))	('KIRP', 'Disease', (81, 85))	('observed', 'Reg', (21, 29))
87879	33178590	Other cancer types with dominant MET mutations but at much lower mutation rates included LUAD (3.53%), BLCA (3.89%), COADREAD (3.2%), UCS (3.51%), and PAAD (0.54%).	('COADREAD', 'Disease', (117, 125))	('LUAD', 'Disease', (89, 93))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('UCS', 'Disease', (134, 137))	('PAAD', 'Phenotype', 'HP:0006725', (151, 155))	('PAAD', 'Disease', (151, 155))	('mutations', 'Var', (37, 46))	('cancer', 'Disease', 'MESH:D009369', (6, 12))	('BLCA', 'Disease', (103, 107))	('MET', 'Gene', '79811', (33, 36))	('cancer', 'Disease', (6, 12))	('MET', 'Gene', (33, 36))	('LUAD', 'Phenotype', 'HP:0030078', (89, 93))
87882	33178590	Approximately half of the mutations (29 of 67 mutations) in the Pkinase-Tyr domain also had MET copy gain, while nearly half of the mutations (44 of 90 mutations) in the other function-unknown domain were accompanied by amplification, gain, and shallow deletion.	('Pkinase-Tyr', 'Gene', (64, 75))	('copy', 'MPA', (96, 100))	('mutations', 'Var', (46, 55))	('MET', 'Gene', (92, 95))	('mutations', 'Var', (132, 141))	('gain', 'PosReg', (101, 105))	('amplification', 'MPA', (220, 233))	('Tyr', 'Chemical', 'MESH:D014443', (72, 75))	('mutations', 'Var', (26, 35))	('gain', 'PosReg', (235, 239))	('MET', 'Gene', '79811', (92, 95))
87889	33178590	Moreover, when the survival association analysis was performed only for MET mutation status, MET mutations were associated with poor prognosis in LUAD (Figure 7D).	('mutations', 'Var', (97, 106))	('LUAD', 'Phenotype', 'HP:0030078', (146, 150))	('MET', 'Gene', '79811', (93, 96))	('LUAD', 'Disease', (146, 150))	('MET', 'Gene', '79811', (72, 75))	('MET', 'Gene', (93, 96))	('MET', 'Gene', (72, 75))
87891	33178590	UCEC, SKCM, and KIRP had the highest MET alteration, and mutations accounted for the major proportion.	('MET', 'Gene', (37, 40))	('mutations', 'Var', (57, 66))	('MET', 'Gene', '79811', (37, 40))
87892	33178590	While mutations in UCEC and SKCM were most commonly located in the Sema domain and the other function-unknown domain, mutations in KIRP were primarily located in the Pkinase-Tyr domain, which is more important for treatment selection.	('KIRP', 'Gene', (131, 135))	('located', 'Reg', (52, 59))	('Sema', 'Gene', (67, 71))	('mutations', 'Var', (118, 127))	('Sema', 'Gene', '7869', (67, 71))	('Tyr', 'Chemical', 'MESH:D014443', (174, 177))	('mutations', 'Var', (6, 15))	('UCEC', 'Gene', (19, 23))
87894	33178590	Other cancer types, including LUAD, BLCA, COADREAD, and UCS harbored similar characteristics; all their alteration frequency was between 4 and 6%, and mutation was the primary alteration.	('LUAD', 'Disease', (30, 34))	('BLCA', 'Disease', (36, 40))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('mutation', 'Var', (151, 159))	('cancer', 'Disease', 'MESH:D009369', (6, 12))	('cancer', 'Disease', (6, 12))	('COADREAD', 'Disease', (42, 50))	('UCS', 'Disease', (56, 59))	('LUAD', 'Phenotype', 'HP:0030078', (30, 34))
87895	33178590	Mutations in LUAD are mainly X1010_splices, which are in exon 14, and mutations in this region are known for targeted therapy in clinical practice in NSCLC.	('NSCLC', 'Disease', 'MESH:D002289', (150, 155))	('LUAD', 'Gene', (13, 17))	('X1010_splices', 'Var', (29, 42))	('NSCLC', 'Disease', (150, 155))	('LUAD', 'Phenotype', 'HP:0030078', (13, 17))
87903	33178590	In addition, the prognostic role of MET in LUAD was quite clear, and both high expression and amplification of MET were significantly associated with poor prognosis.	('associated', 'Reg', (134, 144))	('MET', 'Gene', (36, 39))	('amplification', 'Var', (94, 107))	('high', 'Var', (74, 78))	('MET', 'Gene', '79811', (111, 114))	('MET', 'Gene', '79811', (36, 39))	('MET', 'Gene', (111, 114))	('LUAD', 'Phenotype', 'HP:0030078', (43, 47))
87906	33178590	Compared with other cancer types, mutations in KIRP were primarily located in the Pkinase-Tyr domain, which is known for targeted therapy with TKIs.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('Tyr', 'Chemical', 'MESH:D014443', (90, 93))	('cancer', 'Disease', 'MESH:D009369', (20, 26))	('cancer', 'Disease', (20, 26))	('mutations', 'Var', (34, 43))
87909	33178590	In addition, high expression of MET was discovered in KIRP, and most mutations in KIRP were oncogenic and likely oncogenic; however, there was no association observed between MET expression and patient prognosis in this dataset, although some reports indicated otherwise.	('MET', 'Gene', '79811', (175, 178))	('mutations', 'Var', (69, 78))	('patient', 'Species', '9606', (194, 201))	('MET', 'Gene', (175, 178))	('KIRP', 'Gene', (82, 86))	('MET', 'Gene', '79811', (32, 35))	('MET', 'Gene', (32, 35))
87910	33178590	This paradox could be due to the absence of well-known responsive mutations and the presence of alternative compensatory pathways interacting with MET pathways, such as the MAPK/ERK and PI3K/AKT pathways, which inspired further research on combinatorial therapy strategies in KIRP.	('mutations', 'Var', (66, 75))	('MET', 'Gene', '79811', (147, 150))	('AKT', 'Gene', '207', (191, 194))	('MET', 'Gene', (147, 150))	('AKT', 'Gene', (191, 194))	('ERK', 'Gene', '2048', (178, 181))	('ERK', 'Gene', (178, 181))
87912	33178590	It is well known that genomic instability and high mutation rates cause cancer to acquire numerous mutations during evolution.	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('genomic instability', 'Var', (22, 41))	('cancer', 'Disease', (72, 78))
87915	33178590	However, several recent reports have showed that passenger mutations may also have critical functional roles in driving cancer, with some authors describing them as mini drivers.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('cancer', 'Disease', (120, 126))	('mutations', 'Var', (59, 68))
87916	33178590	They found that the aggregated impact of putative passenger mutations could provide significant predictive power to distinguish cancer from non-cancer phenotypes.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('non-cancer', 'Disease', 'MESH:D009369', (140, 150))	('cancer', 'Disease', (144, 150))	('non-cancer', 'Disease', (140, 150))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('mutations', 'Var', (60, 69))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('cancer', 'Disease', (128, 134))
87917	33178590	The above content implied to us that in some types of cancers, such as UCEC, even most of these mutations belonged to the unknown class; more efforts are needed to determine the meanings of these mutations, which might be found to also have important functional roles in driving tumorigenesis.	('cancers', 'Phenotype', 'HP:0002664', (54, 61))	('tumor', 'Phenotype', 'HP:0002664', (279, 284))	('cancers', 'Disease', (54, 61))	('UCEC', 'Disease', (71, 75))	('cancers', 'Disease', 'MESH:D009369', (54, 61))	('tumor', 'Disease', (279, 284))	('mutations', 'Var', (196, 205))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('tumor', 'Disease', 'MESH:D009369', (279, 284))	('mutations', 'Var', (96, 105))
87918	33178590	In addition, several reports have showed that some gene mutations, like BRAF mutation and ERBB2 mutation, were associated with MSI status in several cancer types.	('cancer', 'Disease', (149, 155))	('MSI status', 'Disease', (127, 137))	('BRAF', 'Gene', (72, 76))	('cancer', 'Disease', 'MESH:D009369', (149, 155))	('mutation', 'Var', (77, 85))	('associated', 'Reg', (111, 121))	('mutation', 'Var', (96, 104))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('ERBB2', 'Gene', '2064', (90, 95))	('ERBB2', 'Gene', (90, 95))	('BRAF', 'Gene', '673', (72, 76))
87938	33178590	Some alterations are more involved in the development of tumors, while others participate more in targeted therapy.	('involved', 'Reg', (26, 34))	('participate', 'Reg', (78, 89))	('alterations', 'Var', (5, 16))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('tumors', 'Disease', (57, 63))	('tumors', 'Disease', 'MESH:D009369', (57, 63))
87946	30718962	The expression levels of five genetic markers were correlated with survival prognosis, and the total survival time of the patients with high expression of the genetic markers was shorter than those with low expression (P<0.001).	('shorter', 'NegReg', (179, 186))	('high expression', 'Var', (136, 151))	('expression', 'MPA', (4, 14))	('patients', 'Species', '9606', (122, 130))	('survival time', 'CPA', (101, 114))
87954	30718962	The generation and development of tumor lesions are complex processes involving several events, including abnormal expression of multiple genes that can cause abnormalities in the body, and these genes and their products interact in a way that regulates the network.	('abnormal', 'Var', (106, 114))	('tumor', 'Disease', (34, 39))	('regulates', 'Reg', (244, 253))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('interact', 'Reg', (221, 229))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
87974	30718962	Next, we used the following formula to construct a prognostic risk score model: risk score = expGene1 x betaGene1 + expGene2 x betaGene2 + expGenen x betaGenen (exp, prognostic gene expression level; beta, multivariate Cox regression model regression coefficients).	('expGene1', 'Var', (93, 101))	('Cox', 'Gene', '1351', (219, 222))	('Cox', 'Gene', (219, 222))
87993	30718962	The primers were as follows: TPBG sense, 5'-ATTGGGGATTAAGCGGTCCC-3' and anti-sense, 5'-GAACTTGGCTAACCCCCTCG-3'.	('TPBG', 'Gene', (29, 33))	('TPBG', 'Gene', '7162', (29, 33))	('anti-sense', 'Var', (72, 82))
88000	30718962	This new prognostic model formula is as follows: risk score = (0.1223xexpression value of RRM2) + (0.1780xexpression value of TPBG) + (-0.072xexpression value of CLIC3) + (0.1276xexpression value of TMPRSS4) + (-0.034xexpression value of WIF1).	('TMPRSS4', 'Gene', (199, 206))	('TPBG', 'Gene', (126, 130))	('RRM2', 'Gene', '6241', (90, 94))	('RRM2', 'Gene', (90, 94))	('0.1276xexpression', 'Var', (172, 189))	('WIF1', 'Gene', (238, 242))	('WIF1', 'Gene', '11197', (238, 242))	('TPBG', 'Gene', '7162', (126, 130))	('CLIC3', 'Gene', '9022', (162, 167))	('-0.072xexpression', 'Var', (135, 152))	('0.1223xexpression', 'Var', (63, 80))	('CLIC3', 'Gene', (162, 167))	('TMPRSS4', 'Gene', '56649', (199, 206))
88006	30718962	Multivariate analysis found that high expression of mRNA markers and clinical stage were independent prognostic factors for lung cancer patients (Table 1).	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('lung cancer', 'Disease', 'MESH:D008175', (124, 135))	('high', 'Var', (33, 37))	('mRNA', 'Protein', (52, 56))	('patients', 'Species', '9606', (136, 144))	('lung cancer', 'Disease', (124, 135))	('lung cancer', 'Phenotype', 'HP:0100526', (124, 135))
88008	30718962	A total of 1,926 patients were included in this prognostic study: 571 patients were grouped into the high TPBG expression group and the other 1,355 patients were grouped into the low TPBG expression group.	('patients', 'Species', '9606', (70, 78))	('patients', 'Species', '9606', (148, 156))	('TPBG', 'Gene', (106, 110))	('TPBG', 'Gene', '7162', (106, 110))	('TPBG', 'Gene', (183, 187))	('patients', 'Species', '9606', (17, 25))	('high', 'Var', (101, 105))	('TPBG', 'Gene', '7162', (183, 187))
88024	30718962	Previous studies showed that high expression of the RRM2 gene was associated with an increase in microvessel density in cervical cancer.	('high', 'Var', (29, 33))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('RRM2', 'Gene', '6241', (52, 56))	('RRM2', 'Gene', (52, 56))	('microvessel density', 'CPA', (97, 116))	('cervical cancer', 'Disease', (120, 135))	('cervical cancer', 'Disease', 'MESH:D002583', (120, 135))	('increase', 'PosReg', (85, 93))
88028	30718962	Silencing of the tumor suppressor gene WIF1 can promote hypermethylation, which indicates that WIF1 may be a diagnostic biomarker for colorectal cancer and breast cancer.	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('hypermethylation', 'MPA', (56, 72))	('tumor', 'Disease', (17, 22))	('colorectal cancer', 'Disease', (134, 151))	('WIF1', 'Gene', '11197', (95, 99))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('breast cancer', 'Disease', 'MESH:D001943', (156, 169))	('colorectal cancer', 'Disease', 'MESH:D015179', (134, 151))	('WIF1', 'Gene', (39, 43))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('breast cancer', 'Disease', (156, 169))	('Silencing', 'Var', (0, 9))	('breast cancer', 'Phenotype', 'HP:0003002', (156, 169))	('colorectal cancer', 'Phenotype', 'HP:0003003', (134, 151))	('WIF1', 'Gene', (95, 99))	('WIF1', 'Gene', '11197', (39, 43))
88049	29656007	We show that NSCLC tumors over-expressing miR-195 are more sensitive to MTA treatment and that induced expression of miR-195 in NSCLC tumors potentiates the anti-tumor effect of MTAs.	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('tumor', 'Disease', (162, 167))	('over-expressing', 'PosReg', (26, 41))	('NSCLC tumors', 'Disease', 'MESH:D009369', (13, 25))	('tumor', 'Disease', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('potentiates', 'PosReg', (141, 152))	('NSCLC', 'Phenotype', 'HP:0030358', (128, 133))	('miR-195', 'Var', (117, 124))	('NSCLC tumors', 'Disease', (128, 140))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('miR-195', 'Gene', (42, 49))	('sensitive', 'MPA', (59, 68))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('NSCLC', 'Phenotype', 'HP:0030358', (13, 18))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('NSCLC tumors', 'Disease', (13, 25))	('tumor', 'Disease', (134, 139))	('NSCLC tumors', 'Disease', 'MESH:D009369', (128, 140))	('tumor', 'Disease', 'MESH:D009369', (134, 139))
88050	29656007	Additionally, we demonstrate that miR-195 targets checkpoint kinase 1 (CHEK1) to regulate the response of NSCLC cells to MTAs, that over-expression of CHEK1 contributes to resistance to MTAs and that knock-down of CHEK1 synergizes with MTAs to repress cell growth.	('CHEK1', 'Gene', (71, 76))	('checkpoint kinase 1', 'Gene', '1111', (50, 69))	('NSCLC', 'Disease', 'MESH:D002289', (106, 111))	('CHEK1', 'Gene', '1111', (151, 156))	('CHEK1', 'Gene', (214, 219))	('checkpoint kinase 1', 'Gene', (50, 69))	('cell growth', 'CPA', (252, 263))	('MTAs', 'MPA', (186, 190))	('NSCLC', 'Phenotype', 'HP:0030358', (106, 111))	('over-expression', 'PosReg', (132, 147))	('CHEK1', 'Gene', (151, 156))	('CHEK1', 'Gene', '1111', (214, 219))	('CHEK1', 'Gene', '1111', (71, 76))	('knock-down', 'Var', (200, 210))	('resistance', 'MPA', (172, 182))	('NSCLC', 'Disease', (106, 111))
88058	29656007	miRNAs have been shown to regulate nearly all aspects of cancer, including the canonical hallmarks.	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('cancer', 'Disease', (57, 63))	('regulate', 'Reg', (26, 34))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('miRNAs', 'Var', (0, 6))
88067	29656007	In contrast, miR-195 has also been reported to correlate with the resistance of cervical cancer cells to temozolomide.	('correlate', 'Reg', (47, 56))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('cancer', 'Disease', (89, 95))	('miR-195', 'Var', (13, 20))	('temozolomide', 'Chemical', 'MESH:D000077204', (105, 117))	('resistance', 'MPA', (66, 76))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
88072	29656007	We found that over-expression of miR-195 sensitizes NSCLC to MTAs both in vitro and in vivo and that induced expression of miR-195 potentiates the efficacy of eribulin to repress lung tumor growth.	('lung tumor', 'Phenotype', 'HP:0100526', (179, 189))	('potentiates', 'PosReg', (131, 142))	('over-expression', 'PosReg', (14, 29))	('NSCLC', 'Disease', (52, 57))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('NSCLC', 'Disease', 'MESH:D002289', (52, 57))	('efficacy', 'MPA', (147, 155))	('miR-195', 'Gene', (33, 40))	('sensitizes', 'Reg', (41, 51))	('miR-195', 'Var', (123, 130))	('NSCLC', 'Phenotype', 'HP:0030358', (52, 57))	('repress lung tumor', 'Disease', 'MESH:D008175', (171, 189))	('repress lung tumor', 'Disease', (171, 189))
88073	29656007	Additionally, we demonstrated that knockout of miR-195 confers resistance to MTAs in NSCLC cells.	('NSCLC', 'Disease', (85, 90))	('NSCLC', 'Disease', 'MESH:D002289', (85, 90))	('NSCLC', 'Phenotype', 'HP:0030358', (85, 90))	('MTAs', 'MPA', (77, 81))	('knockout', 'Var', (35, 43))	('miR-195', 'Gene', (47, 54))	('resistance', 'MPA', (63, 73))
88098	29656007	Primers for CHEK1:  H358 and H1993 cells were transfected with miR-195 mimic (25 nM) or mock transfected.	('CHEK1', 'Gene', (12, 17))	('miR-195', 'Gene', (63, 70))	('25', 'Var', (78, 80))	('H358', 'CellLine', 'CVCL:1559', (20, 24))	('CHEK1', 'Gene', '1111', (12, 17))	('H1993', 'CellLine', 'CVCL:1512', (29, 34))
88103	29656007	Primers for CHEK1 3'UTR with deletion of the binding site of miR-195:  Cell lysates were prepared using RIPA buffer.	('CHEK1', 'Gene', (12, 17))	('deletion', 'Var', (29, 37))	('CHEK1', 'Gene', '1111', (12, 17))	('RIPA buffer', 'Chemical', '-', (104, 115))	('miR-195', 'Gene', (61, 68))
88105	29656007	Antibodies to Chk1 (A300-161A-T) and pChk1 (A304-673A-T) were purchased from Bethyl Laboratories (TX, USA).	('Chk1', 'Gene', (14, 18))	('A304-673A-T', 'Mutation', 'c.304_673A,A>T', (44, 55))	('Chk1', 'Gene', (38, 42))	('A300-161A-T', 'Var', (20, 31))	('Chk1', 'Gene', '1111', (14, 18))	('Chk1', 'Gene', '1111', (38, 42))	('A304-673A-T', 'Var', (44, 55))	('A300-161A-T', 'Mutation', 'c.300-161A,A>T', (20, 31))
88106	29656007	Antibodies to calnexin (sc-11397) and GAPDH (sc-25778) were purchased from Santa Cruz Biotechnology (TX, USA).	('GAPDH', 'Gene', '2597', (38, 43))	('GAPDH', 'Gene', (38, 43))	('calnexin', 'Gene', (14, 22))	('sc-25778', 'Var', (45, 53))	('calnexin', 'Gene', '821', (14, 22))
88119	29656007	We identified 44 miRNAs as significantly influencing both cell growth (based on average viability) and response to paclitaxel (based on average synergy) (Supplementary Table 1, Figure 1A,B).	('influencing', 'Reg', (41, 52))	('paclitaxel', 'Chemical', 'MESH:D017239', (115, 125))	('miRNAs', 'Var', (17, 23))	('cell growth', 'CPA', (58, 69))	('response to paclitaxel', 'MPA', (103, 125))
88128	29656007	Notably, in a pair of NSCLC cell lines derived from the same patient (H1993 and H2073, with the former sensitive to MTAs and the latter overexpressing MDR1 and drug resistant), we found both to be sensitive to miR-195 (Supplementary Figure 2B).	('patient', 'Species', '9606', (61, 68))	('NSCLC', 'Phenotype', 'HP:0030358', (22, 27))	('MDR1', 'Gene', (151, 155))	('sensitive', 'Reg', (103, 112))	('H1993', 'CellLine', 'CVCL:1512', (70, 75))	('overexpressing', 'PosReg', (136, 150))	('H2073', 'Var', (80, 85))	('NSCLC', 'Disease', (22, 27))	('MTAs', 'MPA', (116, 120))	('MDR1', 'Gene', '5243', (151, 155))	('H2073', 'CellLine', 'CVCL:1521', (80, 85))	('NSCLC', 'Disease', 'MESH:D002289', (22, 27))	('sensitive', 'Reg', (197, 206))
88129	29656007	Even in drug-resistant H2073 cells, miR-195 synergizes with paclitaxel to repress cell growth (Supplementary Figure 2C).	('miR-195', 'Var', (36, 43))	('paclitaxel', 'Chemical', 'MESH:D017239', (60, 70))	('cell growth', 'CPA', (82, 93))	('H2073', 'CellLine', 'CVCL:1521', (23, 28))	('repress', 'NegReg', (74, 81))
88130	29656007	To better evaluate the influence of miR-195 expression on the response of NSCLC cells to MTAs, we generated stable miR-195-overexpressing cells and found that over-expression of miR-195 sensitizes NSCLC cells to paclitaxel and eribulin (Figure 2A-C).	('sensitizes', 'Reg', (186, 196))	('NSCLC', 'Phenotype', 'HP:0030358', (74, 79))	('NSCLC', 'Phenotype', 'HP:0030358', (197, 202))	('over-expression', 'PosReg', (159, 174))	('NSCLC', 'Disease', (74, 79))	('NSCLC', 'Disease', (197, 202))	('miR-195', 'Var', (178, 185))	('NSCLC', 'Disease', 'MESH:D002289', (74, 79))	('NSCLC', 'Disease', 'MESH:D002289', (197, 202))	('paclitaxel', 'Chemical', 'MESH:D017239', (212, 222))
88131	29656007	Additionally, we knocked out miR-195 using CRISPR/Cas9 with pair of sgRNAs designed against the MIR195 locus.	('knocked', 'Var', (17, 24))	('MIR195', 'Gene', '406971', (96, 102))	('miR-195', 'Gene', (29, 36))	('MIR195', 'Gene', (96, 102))
88160	29656007	We also used two siRNAs to knock-down CHEK1.	('CHEK1', 'Gene', '1111', (38, 43))	('knock-down', 'Var', (27, 37))	('CHEK1', 'Gene', (38, 43))
88162	29656007	Intriguingly, we also found that a CHEK1 inhibitor, PF-477736, synergizes with eribulin, but not paclitaxel, in NSCLC cells (Supplementary Figure 6).	('CHEK1', 'Gene', '1111', (35, 40))	('NSCLC', 'Phenotype', 'HP:0030358', (112, 117))	('PF-477736', 'Var', (52, 61))	('paclitaxel', 'Chemical', 'MESH:D017239', (97, 107))	('CHEK1', 'Gene', (35, 40))	('NSCLC', 'Disease', (112, 117))	('NSCLC', 'Disease', 'MESH:D002289', (112, 117))
88165	29656007	We observed downregulation of CHEK1 protein or phosphorylation of CHEK1 protein by CHEK1 inhibitor PF-477736 (10 microM) in H1299 and H358 cells.	('downregulation', 'NegReg', (12, 26))	('CHEK1', 'Gene', (30, 35))	('H1299', 'CellLine', 'CVCL:0060', (124, 129))	('protein', 'Protein', (72, 79))	('CHEK1', 'Gene', '1111', (66, 71))	('phosphorylation', 'MPA', (47, 62))	('H358', 'CellLine', 'CVCL:1559', (134, 138))	('CHEK1', 'Gene', '1111', (83, 88))	('CHEK1', 'Gene', (83, 88))	('CHEK1', 'Gene', (66, 71))	('CHEK1', 'Gene', '1111', (30, 35))	('PF-477736', 'Var', (99, 108))
88167	29656007	As previously demonstrated, CHEK1 inhibitor PF-477736 represses Chk1 protein and phosphorylation of Chk1 S296 but promotes phosphorylation of Chk1 S345.	('Chk1 S', 'Gene', (142, 148))	('Chk1', 'Gene', (64, 68))	('phosphorylation', 'MPA', (123, 138))	('phosphorylation', 'MPA', (81, 96))	('CHEK1', 'Gene', '1111', (28, 33))	('Chk1', 'Gene', '1111', (142, 146))	('Chk1 S', 'Gene', '1111', (100, 106))	('Chk1', 'Gene', '1111', (64, 68))	('CHEK1', 'Gene', (28, 33))	('Chk1 S', 'Gene', '1111', (142, 148))	('represses', 'NegReg', (54, 63))	('Chk1', 'Gene', (142, 146))	('Chk1', 'Gene', (100, 104))	('promotes', 'PosReg', (114, 122))	('Chk1 S', 'Gene', (100, 106))	('Chk1', 'Gene', '1111', (100, 104))	('PF-477736', 'Var', (44, 53))
88168	29656007	This indicates that PF-477736 has different effects on different serine residues in Chk1.	('PF-477736', 'Var', (20, 29))	('Chk1', 'Gene', (84, 88))	('Chk1', 'Gene', '1111', (84, 88))	('serine', 'Chemical', 'MESH:D012694', (65, 71))	('effects', 'Reg', (44, 51))	('serine residues', 'MPA', (65, 80))
88169	29656007	Consistent with the report, our results (Figure 4B) show that PF-477736 (10 microM) represses Chk1 protein.	('PF-477736', 'Var', (62, 71))	('Chk1', 'Gene', (94, 98))	('Chk1', 'Gene', '1111', (94, 98))	('represses', 'NegReg', (84, 93))
88170	29656007	Our results also show that PF-477736 slightly represses phosphorylation of Chk1 S317 in H1299 and H358 but not in H1993 cells.	('H358', 'CellLine', 'CVCL:1559', (98, 102))	('Chk1 S', 'Gene', (75, 81))	('PF-477736', 'Var', (27, 36))	('represses', 'NegReg', (46, 55))	('H1993', 'CellLine', 'CVCL:1512', (114, 119))	('H1299', 'CellLine', 'CVCL:0060', (88, 93))	('Chk1 S', 'Gene', '1111', (75, 81))	('phosphorylation', 'MPA', (56, 71))
88175	29656007	We previously reported that high expression of miR-195 is correlated with better survival in LUAD but not in LUSC patients.	('better', 'PosReg', (74, 80))	('survival', 'CPA', (81, 89))	('LUAD', 'Disease', 'None', (93, 97))	('LUAD', 'Disease', (93, 97))	('LUAD', 'Phenotype', 'HP:0030078', (93, 97))	('LUSC', 'Phenotype', 'HP:0030359', (109, 113))	('high', 'Var', (28, 32))	('patients', 'Species', '9606', (114, 122))	('miR-195', 'Gene', (47, 54))
88176	29656007	Here, we show that high expression of CHEK1 is associated with worse overall and recurrence-free survival in LUAD patients but not in LUSC patients (Figure 5A,B).	('CHEK1', 'Gene', '1111', (38, 43))	('recurrence-free survival', 'CPA', (81, 105))	('worse', 'NegReg', (63, 68))	('high expression', 'Var', (19, 34))	('patients', 'Species', '9606', (139, 147))	('CHEK1', 'Gene', (38, 43))	('LUAD', 'Phenotype', 'HP:0030078', (109, 113))	('LUAD', 'Disease', 'None', (109, 113))	('LUAD', 'Disease', (109, 113))	('LUSC', 'Phenotype', 'HP:0030359', (134, 138))	('patients', 'Species', '9606', (114, 122))	('overall', 'CPA', (69, 76))
88177	29656007	Furthermore, LUAD patients with high ratio of miR-195 to CHEK1 is associated with better overall and recurrence-free survival in LUAD but not LUSC (Figure 5C,D).	('CHEK1', 'Gene', (57, 62))	('LUSC', 'Phenotype', 'HP:0030359', (142, 146))	('better', 'PosReg', (82, 88))	('overall', 'CPA', (89, 96))	('miR-195', 'Var', (46, 53))	('CHEK1', 'Gene', '1111', (57, 62))	('LUAD', 'Phenotype', 'HP:0030078', (129, 133))	('patients', 'Species', '9606', (18, 26))	('LUAD', 'Disease', 'None', (129, 133))	('LUAD', 'Disease', (129, 133))	('LUAD', 'Disease', (13, 17))	('LUAD', 'Disease', 'None', (13, 17))	('LUAD', 'Phenotype', 'HP:0030078', (13, 17))	('recurrence-free survival', 'CPA', (101, 125))
88178	29656007	However, CHEK1 alone might be a better prognostic marker than either miR-195 alone or the ratio of miR-195 to CHEK1 in LUAD (Figure 5).	('CHEK1', 'Gene', (110, 115))	('CHEK1', 'Gene', (9, 14))	('CHEK1', 'Gene', '1111', (9, 14))	('CHEK1', 'Gene', '1111', (110, 115))	('miR-195', 'Var', (99, 106))	('LUAD', 'Phenotype', 'HP:0030078', (119, 123))	('LUAD', 'Disease', 'None', (119, 123))	('LUAD', 'Disease', (119, 123))
88180	29656007	To identify the miRNAs that regulate both the growth of NSCLC cells and their response to MTAs, we performed a high-throughput screen and identified miR-195 as synergizing with paclitaxel to inhibit the growth of cancer cells in NSCLC.	('growth', 'CPA', (203, 209))	('miR-195', 'Var', (149, 156))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('NSCLC', 'Phenotype', 'HP:0030358', (229, 234))	('inhibit', 'NegReg', (191, 198))	('NSCLC', 'Disease', (56, 61))	('paclitaxel', 'Chemical', 'MESH:D017239', (177, 187))	('cancer', 'Disease', 'MESH:D009369', (213, 219))	('NSCLC', 'Disease', (229, 234))	('NSCLC', 'Disease', 'MESH:D002289', (56, 61))	('cancer', 'Disease', (213, 219))	('NSCLC', 'Disease', 'MESH:D002289', (229, 234))	('NSCLC', 'Phenotype', 'HP:0030358', (56, 61))
88181	29656007	We demonstrated that miR-195 synergizes with both a microtubule stabilizer (paclitaxel) and a microtubule destabilizer (eribulin) in NSCLC cells.	('paclitaxel', 'Chemical', 'MESH:D017239', (76, 86))	('NSCLC', 'Phenotype', 'HP:0030358', (133, 138))	('NSCLC', 'Disease', (133, 138))	('NSCLC', 'Disease', 'MESH:D002289', (133, 138))	('miR-195', 'Var', (21, 28))	('microtubule stabilizer', 'MPA', (52, 74))
88182	29656007	Consistently, over-expression of miR-195 sensitizes NSCLC cells to MTAs; while knockout of miR-195 contributes to resistance to MTAs.	('NSCLC', 'Disease', (52, 57))	('over-expression', 'PosReg', (14, 29))	('NSCLC', 'Disease', 'MESH:D002289', (52, 57))	('miR-195', 'Gene', (91, 98))	('miR-195', 'Gene', (33, 40))	('knockout', 'Var', (79, 87))	('sensitizes', 'Reg', (41, 51))	('NSCLC', 'Phenotype', 'HP:0030358', (52, 57))
88186	29656007	Aberrant activation of CHEK1 has been shown to promote tumorigenesis and to confer resistance to chemotherapy, therefore making it a potential target for cancer treatment.	('CHEK1', 'Gene', (23, 28))	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('Aberrant', 'Var', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('resistance to chemotherapy', 'MPA', (83, 109))	('promote', 'PosReg', (47, 54))	('cancer', 'Disease', (154, 160))	('tumor', 'Disease', (55, 60))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('CHEK1', 'Gene', '1111', (23, 28))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))
88188	29656007	Knock-down of CHEK1 by siRNA synergizes with paclitaxel and eribulin, while CHEK1 over-expression triggers resistance to paclitaxel and eribulin in NSCLC cells.	('paclitaxel', 'Chemical', 'MESH:D017239', (121, 131))	('CHEK1', 'Gene', '1111', (14, 19))	('paclitaxel', 'Chemical', 'MESH:D017239', (45, 55))	('resistance to paclitaxel', 'MPA', (107, 131))	('Knock-down', 'Var', (0, 10))	('NSCLC', 'Disease', (148, 153))	('CHEK1', 'Gene', '1111', (76, 81))	('triggers', 'Reg', (98, 106))	('NSCLC', 'Disease', 'MESH:D002289', (148, 153))	('CHEK1', 'Gene', (14, 19))	('CHEK1', 'Gene', (76, 81))	('NSCLC', 'Phenotype', 'HP:0030358', (148, 153))	('over-expression', 'PosReg', (82, 97))
88195	29112949	The aim of this study was to conduct a genome-wide analysis of gene copy number gains and corresponding gene expression levels in a clinically well annotated NSCLC patient cohort (n = 190) and their association with survival.	('NSCLC', 'Disease', (158, 163))	('NSCLC', 'Disease', 'MESH:D002289', (158, 163))	('patient', 'Species', '9606', (164, 171))	('gene copy number gains', 'Var', (63, 85))	('gene expression levels', 'MPA', (104, 126))
88197	29112949	Strong correlations were frequently based on few tumors with high copy number gains and correspondingly increased mRNA expression.	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('increased', 'PosReg', (104, 113))	('high copy number gains', 'Var', (61, 83))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('tumors', 'Disease', (49, 55))	('tumors', 'Disease', 'MESH:D009369', (49, 55))	('mRNA expression', 'MPA', (114, 129))
88202	29112949	mutations in the receptor tyrosine kinases EGFR, BRAF, or HER2, or fusion genes created by gene rearrangements involving ALK or ROS1.	('EGFR', 'Gene', (43, 47))	('ALK', 'Gene', '238', (121, 124))	('EGFR', 'Gene', '1956', (43, 47))	('ROS1', 'Gene', (128, 132))	('mutations', 'Var', (0, 9))	('BRAF', 'Gene', '673', (49, 53))	('ROS1', 'Gene', '6098', (128, 132))	('HER2', 'Gene', (58, 62))	('ALK', 'Gene', (121, 124))	('BRAF', 'Gene', (49, 53))	('HER2', 'Gene', '2064', (58, 62))
88203	29112949	Recently, amplifications of FGFR1 and MET were also identified as cancer driving mechanisms and were tested as potential therapeutic targets in clinical trials.	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('FGFR1', 'Gene', (28, 33))	('MET', 'Gene', (38, 41))	('amplifications', 'Var', (10, 24))	('FGFR1', 'Gene', '2260', (28, 33))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('cancer', 'Disease', (66, 72))
88205	29112949	A well-known example is HER2 amplification in breast and gastric cancer, which translates into higher gene and protein expression and define distinct biological subgroups in these cancers.	('cancers', 'Disease', 'MESH:D009369', (180, 187))	('amplification', 'Var', (29, 42))	('cancers', 'Phenotype', 'HP:0002664', (180, 187))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('cancers', 'Disease', (180, 187))	('higher', 'PosReg', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('gastric cancer', 'Phenotype', 'HP:0012126', (57, 71))	('HER2', 'Gene', (24, 28))	('HER2', 'Gene', '2064', (24, 28))	('breast and gastric cancer', 'Disease', 'MESH:D013274', (46, 71))
88219	29112949	Calls for normal CN, loss, gain, high gain or homozygous deletion were assigned to each of the 261801 SNPs using a two-level hierarchical mixture model which utilizes the breakpoint information from the CBS.	('gain', 'PosReg', (27, 31))	('high gain', 'PosReg', (33, 42))	('deletion', 'Var', (57, 65))	('CBS', 'Disease', 'MESH:D006712', (203, 206))	('CBS', 'Disease', (203, 206))	('loss', 'NegReg', (21, 25))
88229	29112949	To validate significant survival associations in independent patient cohorts, the R package 'meta' was applied to perform a meta-analysis of ten publicly available NSCLC data sets with Affymetrix HG U133A or Plus 2.0 array expression data and corresponding overall survival times (in total 1779 patients): GSE29013, GSE30219; GSE31210, GSE14814, GSE19188, GSE3141; Shedden et al., 2008; GSE4573, GSE50081 and GSE37745.	('GSE4573', 'Chemical', '-', (387, 394))	('NSCLC', 'Disease', (164, 169))	('GSE3141', 'Chemical', '-', (356, 363))	('GSE4573', 'Var', (387, 394))	('GSE29013', 'Var', (306, 314))	('GSE37745', 'Var', (409, 417))	('GSE31210', 'Var', (326, 334))	('NSCLC', 'Disease', 'MESH:D002289', (164, 169))	('GSE14814', 'Var', (336, 344))	('patient', 'Species', '9606', (295, 302))	('patient', 'Species', '9606', (61, 68))	('patients', 'Species', '9606', (295, 303))	('GSE19188', 'Var', (346, 354))	('GSE30219; GSE31210', 'Var', (316, 334))	('GSE3141', 'Var', (356, 363))	('GSE50081', 'Var', (396, 404))
88248	29112949	CAND1 represents an example, where high CN gain is associated with increased gene expression in adenocarcinomas but not in squamous carcinomas (Fig 4D).	('high CN', 'Var', (35, 42))	('gene expression', 'MPA', (77, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('CAND1', 'Gene', (0, 5))	('adenocarcinomas', 'Disease', 'MESH:D000230', (96, 111))	('carcinomas', 'Phenotype', 'HP:0030731', (101, 111))	('adenocarcinomas', 'Disease', (96, 111))	('CAND1', 'Gene', '55832', (0, 5))	('carcinomas', 'Phenotype', 'HP:0030731', (132, 142))	('increased', 'PosReg', (67, 76))	('squamous carcinomas', 'Disease', (123, 142))	('gain', 'PosReg', (43, 47))	('squamous carcinomas', 'Disease', 'MESH:D002294', (123, 142))
88250	29112949	RAP1B represents an example where high CN gain of both adeno- and squamous carcinomas is associated with high gene expression (Fig 4F).	('squamous carcinomas', 'Disease', 'MESH:D002294', (66, 85))	('RAP1B', 'Gene', '5908', (0, 5))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('adeno-', 'Disease', (55, 61))	('carcinomas', 'Phenotype', 'HP:0030731', (75, 85))	('high gene', 'Var', (105, 114))	('squamous carcinomas', 'Disease', (66, 85))	('RAP1B', 'Gene', (0, 5))
88256	29112949	This is in agreement with the aforementioned observation that high correlation coefficients (ECCC) are typically obtained for genes with high copy numbers in some patients and that high copy number is associated with higher ECCC (Fig 3).	('high copy number', 'Var', (181, 197))	('correlation coefficients', 'MPA', (67, 91))	('patients', 'Species', '9606', (163, 171))	('ECCC', 'MPA', (224, 228))
88259	29112949	For the highly correlating genes identified in the adenocarcinoma and squamous cell carcinoma subgroups, respectively, we identified inter alia significantly overrepresented GOs associated with DNA repair (GO:0045739, GO:0010569) and embryonal development (GO:0001824) in the adenocarcinomas, and GOs related to apoptosis (GO:0042771) in squamous cell cancer (FDR adj.	('DNA', 'MPA', (194, 197))	('carcinomas', 'Phenotype', 'HP:0030731', (281, 291))	('carcinoma', 'Phenotype', 'HP:0030731', (281, 290))	('cancer', 'Phenotype', 'HP:0002664', (352, 358))	('carcinoma', 'Phenotype', 'HP:0030731', (56, 65))	('adenocarcinoma', 'Disease', (276, 290))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (70, 93))	('overrepresented', 'PosReg', (158, 173))	('embryonal development', 'CPA', (234, 255))	('GO:0010569', 'Var', (218, 228))	('squamous cell carcinoma subgroups', 'Disease', (70, 103))	('squamous cell cancer', 'Disease', (338, 358))	('adenocarcinoma', 'Disease', 'MESH:D000230', (276, 290))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (338, 358))	('GO:0001824', 'Var', (257, 267))	('apoptosis', 'CPA', (312, 321))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('adenocarcinoma', 'Disease', (51, 65))	('squamous cell cancer', 'Disease', 'MESH:D002294', (338, 358))	('squamous cell carcinoma subgroups', 'Disease', 'MESH:D002294', (70, 103))	('GO:0045739', 'Var', (206, 216))	('adenocarcinomas', 'Disease', 'MESH:D000230', (276, 291))	('adenocarcinomas', 'Disease', (276, 291))	('adenocarcinoma', 'Disease', 'MESH:D000230', (51, 65))
88265	29112949	For adjustment, the 95% percentile of copy number and gene expression was used, since the significance of correlations (ECCC) often depends on a relatively small fraction of patients with high copy number and high expression values.	('patients', 'Species', '9606', (174, 182))	('expression', 'MPA', (214, 224))	('high copy number', 'Var', (188, 204))
88269	29112949	For 31 of the 'lung cancer genes' (86 probe sets), at least one probe set displayed a significant correlation between copy number and gene expression, and for 3 genes (11 probe sets) at least one probe set displayed a median ECCC>0.7.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('correlation', 'Interaction', (98, 109))	('gene expression', 'MPA', (134, 149))	("'lung cancer", 'Disease', (14, 26))	('copy number', 'Var', (118, 129))	('lung cancer', 'Phenotype', 'HP:0100526', (15, 26))	("'lung cancer", 'Disease', 'MESH:D008175', (14, 26))
88290	29112949	Typical examples, where high copy number gain correlates with high gene expression are MBIP, CAND1, TBL1XR1 and RABP1B.	('TBL1XR1', 'Gene', '79718', (100, 107))	('gain', 'PosReg', (41, 45))	('high gene expression', 'MPA', (62, 82))	('MBIP', 'Gene', (87, 91))	('CAND1', 'Gene', (93, 98))	('high copy number', 'Var', (24, 40))	('TBL1XR1', 'Gene', (100, 107))	('MBIP', 'Gene', '51562', (87, 91))	('RABP1B', 'Gene', (112, 118))	('CAND1', 'Gene', '55832', (93, 98))
88291	29112949	(3) Strong correlations were frequently based on only a few tumors with high copy number gain and correspondingly increased gene expression.	('gain', 'PosReg', (89, 93))	('high copy number', 'Var', (72, 88))	('increased', 'PosReg', (114, 123))	('tumors', 'Disease', 'MESH:D009369', (60, 66))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('gene expression', 'MPA', (124, 139))	('tumors', 'Disease', (60, 66))
88300	29112949	In the study of Gallegos Ruiz, 32 NSCLC cancer samples were analyzed by a gene expression microarrays and in house CGH arrays, detecting 359 transcripts, corresponding to 248 genes that were significantly affected by gene copy number changes.	('NSCLC cancer', 'Disease', 'MESH:D009369', (34, 46))	('CGH', 'Gene', (115, 118))	('Gallegos', 'Species', '558547', (16, 24))	('CGH', 'Gene', '3342', (115, 118))	('gene copy number changes', 'Var', (217, 241))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('affected', 'Reg', (205, 213))	('NSCLC cancer', 'Disease', (34, 46))
88304	29112949	To identify such genes, we applied the criteria of high correlation between copy number and gene expression (ECCC>0.7) in the Uppsala cohort, and association with survival in a meta-analysis, including data from 1,779 non-small cell lung cancer patients with an FDR adjusted p-value smaller than 0.05.	('association', 'Reg', (146, 157))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (218, 244))	('patients', 'Species', '9606', (245, 253))	('lung cancer', 'Phenotype', 'HP:0100526', (233, 244))	('non-small cell lung cancer', 'Disease', (218, 244))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (222, 244))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('copy number', 'Var', (76, 87))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (218, 244))
88307	29112949	Validation of the role of CCT2 in cell growth was provided by knocking down CCT2 using five shRNA constructs targeting CCT2.	('knocking', 'Var', (62, 70))	('CCT2', 'Gene', (26, 30))	('CCT2', 'Gene', '10576', (26, 30))	('CCT2', 'Gene', '10576', (119, 123))	('CCT2', 'Gene', (119, 123))	('CCT2', 'Gene', '10576', (76, 80))	('CCT2', 'Gene', (76, 80))
88309	29112949	In the TCGA breast cancer dataset, CCT2 amplification and/or overexpression was associated with worse outcome, in agreement with studies in gall bladder carcinoma and with our current findings in NSCLC.	('breast cancer', 'Disease', (12, 25))	('gall bladder carcinoma', 'Disease', (140, 162))	('breast cancer', 'Phenotype', 'HP:0003002', (12, 25))	('NSCLC', 'Disease', (196, 201))	('overexpression', 'PosReg', (61, 75))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (145, 162))	('carcinoma', 'Phenotype', 'HP:0030731', (153, 162))	('NSCLC', 'Disease', 'MESH:D002289', (196, 201))	('amplification', 'Var', (40, 53))	('gall bladder carcinoma', 'Disease', 'MESH:D005706', (140, 162))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('breast cancer', 'Disease', 'MESH:D001943', (12, 25))	('CCT2', 'Gene', '10576', (35, 39))	('CCT2', 'Gene', (35, 39))
88319	28656229	Co-expression of podoplanin and FGF1 was significantly associated with larger primary tumor size, advanced TNM stage and higher intratumoral MVD.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('FGF1', 'Gene', '2246', (32, 36))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumor', 'Disease', (86, 91))	('associated', 'Reg', (55, 65))	('FGF1', 'Gene', (32, 36))	('larger', 'PosReg', (71, 77))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('Co-expression', 'Var', (0, 13))	('tumor', 'Disease', (133, 138))	('higher', 'PosReg', (121, 127))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
88320	28656229	Survival analysis demonstrated that cases with podoplanin and FGF1 double-positive staining had a significantly lower survival rate compared with cases with double-negative staining.	('FGF1', 'Gene', (62, 66))	('double-positive staining', 'Var', (67, 91))	('survival rate', 'CPA', (118, 131))	('FGF1', 'Gene', '2246', (62, 66))	('lower', 'NegReg', (112, 117))
88402	28656229	The P+F+ group was significantly associated with larger primary tumor size (P=0.042) and advanced TNM stages (P=0.042) compared with the P-F- group.	('larger', 'PosReg', (49, 55))	('tumor', 'Disease', (64, 69))	('TNM stages', 'CPA', (98, 108))	('P+F+', 'Var', (4, 8))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
88406	28656229	The association between co-expression of podoplanin and FGF1, and intratumoral MVD was also investigated; intratumoral MVD (observed by CD34 staining) was demonstrated to be associated with the co-expression of podoplanin and FGF1.	('FGF1', 'Gene', '2246', (56, 60))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('associated', 'Reg', (174, 184))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('FGF1', 'Gene', (56, 60))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('CD34', 'Gene', (136, 140))	('CD34', 'Gene', '947', (136, 140))	('tumor', 'Disease', (111, 116))	('FGF1', 'Gene', '2246', (226, 230))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('co-expression', 'Var', (194, 207))	('tumor', 'Disease', (71, 76))	('FGF1', 'Gene', (226, 230))
88407	28656229	The mean MVD was 33.32+-8.01 in P+F+ specimens, 28.72+-5.93 in P+F-specimens, 29.35+-9.30 in P-F+ specimens and 26.64+-6.22 in P-F- specimens.	('men', 'Species', '9606', (42, 45))	('P+F-specimens', 'Var', (63, 76))	('men', 'Species', '9606', (72, 75))	('men', 'Species', '9606', (103, 106))	('P-F+', 'Var', (93, 97))	('men', 'Species', '9606', (137, 140))	('P+F+', 'Var', (32, 36))
88414	28656229	RT-qPCR and western blotting revealed that the expression level of FGF1 mRNA and protein were reduced in podoplanin-KD NCI-H226 cells compared with NC NCI-H226 cells (Fig.	('FGF1', 'Gene', '2246', (67, 71))	('reduced', 'NegReg', (94, 101))	('protein', 'MPA', (81, 88))	('podoplanin-KD', 'Var', (105, 118))	('expression level', 'MPA', (47, 63))	('FGF1', 'Gene', (67, 71))	('NCI-H226', 'CellLine', 'CVCL:1544', (119, 127))	('NCI-H226', 'CellLine', 'CVCL:1544', (151, 159))
88423	28656229	In addition, knockdown of podoplanin downregulated the expression of FGF1 and decreased the formation of tubular networks by HUVECs in vitro.	('downregulated', 'NegReg', (37, 50))	('FGF1', 'Gene', '2246', (69, 73))	('FGF1', 'Gene', (69, 73))	('expression', 'MPA', (55, 65))	('decreased', 'NegReg', (78, 87))	('formation of tubular networks', 'CPA', (92, 121))	('knockdown', 'Var', (13, 22))
88424	28656229	Co-expression of podoplanin and FGF1 was significantly associated with larger primary tumor size, advanced TNM stage, higher intratumoral MVD and worse overall survival.	('higher', 'PosReg', (118, 124))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('FGF1', 'Gene', '2246', (32, 36))	('tumor', 'Disease', (86, 91))	('worse', 'NegReg', (146, 151))	('associated', 'Reg', (55, 65))	('FGF1', 'Gene', (32, 36))	('larger', 'PosReg', (71, 77))	('overall survival', 'CPA', (152, 168))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('Co-expression', 'Var', (0, 13))	('tumor', 'Disease', (130, 135))
88426	28656229	Podoplanin-/- mice exhibit systemic edema due to aplasia of lymphatic vessels during fetal development and neonatal death due to respiratory failure, indicating an important role of podoplanin in normal lymphatic vessel development.	('respiratory failure', 'Phenotype', 'HP:0002878', (129, 148))	('neonatal death', 'Disease', 'MESH:D066087', (107, 121))	('respiratory failure', 'Disease', 'MESH:D012131', (129, 148))	('men', 'Species', '9606', (227, 230))	('aplasia of lymphatic vessels', 'Phenotype', 'HP:0045006', (49, 77))	('mice', 'Species', '10090', (14, 18))	('aplasia', 'Disease', (49, 56))	('edema', 'Disease', 'MESH:D004487', (36, 41))	('edema', 'Phenotype', 'HP:0000969', (36, 41))	('aplasia', 'Disease', 'MESH:C566720', (49, 56))	('neonatal death', 'Disease', (107, 121))	('respiratory failure', 'Disease', (129, 148))	('men', 'Species', '9606', (98, 101))	('Podoplanin-/-', 'Var', (0, 13))	('edema', 'Disease', (36, 41))
88444	28656229	Therefore, FGF1 may be a candidate cancer stem cell marker, and the double-positive expression of podoplanin and FGF1 may have potential as a more accurate screening method for the detection of cancer stem cells.	('double-positive', 'Var', (68, 83))	('cancer', 'Disease', (194, 200))	('FGF1', 'Gene', '2246', (113, 117))	('FGF1', 'Gene', (11, 15))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('FGF1', 'Gene', (113, 117))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('FGF1', 'Gene', '2246', (11, 15))	('cancer', 'Disease', (35, 41))	('cancer', 'Disease', 'MESH:D009369', (194, 200))
88446	28656229	According to the survival analysis performed in the present study, the overall survival was lower in patients with podoplanin-positive lung SQCC compared with patients with podoplanin-negative lung SQCC, although not to a significant extent.	('podoplanin-positive', 'Var', (115, 134))	('patients', 'Species', '9606', (101, 109))	('SQCC', 'Phenotype', 'HP:0002860', (140, 144))	('SQCC', 'Phenotype', 'HP:0002860', (198, 202))	('lung SQCC', 'Disease', (135, 144))	('patients', 'Species', '9606', (159, 167))	('lower', 'NegReg', (92, 97))
88462	26555193	SOX4 knockdown (KO) decreased cell proliferation and induced apoptosis by activating caspases-3 and -7, and poly-ADP ribose polymerase and suppressing X-linked inhibitor of apoptosis protein in HNSCC cells; it also enhanced radiation/cisplatin-induced apoptosis; and suppressed tumor cell invasion and migration.	('activating', 'PosReg', (74, 84))	('tumor', 'Phenotype', 'HP:0002664', (278, 283))	('X-linked inhibitor of apoptosis protein', 'Gene', '331', (151, 190))	('radiation/cisplatin-induced apoptosis', 'CPA', (224, 261))	('knockdown', 'Var', (5, 14))	('HNSCC', 'Phenotype', 'HP:0012288', (194, 199))	('poly-ADP ribose polymerase', 'Gene', (108, 134))	('SOX4', 'Gene', (0, 4))	('enhanced', 'PosReg', (215, 223))	('caspases-3 and -7', 'Gene', '836;840', (85, 102))	('X-linked inhibitor of apoptosis protein', 'Gene', (151, 190))	('suppressed', 'NegReg', (267, 277))	('SOX4', 'Gene', '6659', (0, 4))	('suppressing', 'NegReg', (139, 150))	('tumor', 'Disease', (278, 283))	('poly-ADP ribose polymerase', 'Gene', '142', (108, 134))	('tumor', 'Disease', 'MESH:D009369', (278, 283))	('cisplatin', 'Chemical', 'MESH:D002945', (234, 243))	('cell proliferation', 'CPA', (30, 48))	('decreased', 'NegReg', (20, 29))
88475	26555193	Reportedly, SOX4 expression results in alterations of oncogenic phenotypes, including inhibition of apoptosis, cell-cycle progression and irradiation-induced apoptosis, and promotion of epithelial to mesenchymal transition in a variety of cancer cells.	('epithelial to mesenchymal transition', 'CPA', (186, 222))	('irradiation-induced apoptosis', 'CPA', (138, 167))	('SOX4', 'Gene', (12, 16))	('SOX4', 'Gene', '6659', (12, 16))	('cancer', 'Disease', 'MESH:D009369', (239, 245))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))	('promotion', 'PosReg', (173, 182))	('cancer', 'Disease', (239, 245))	('alterations', 'Reg', (39, 50))	('cell-cycle progression', 'CPA', (111, 133))	('expression', 'Var', (17, 27))	('apoptosis', 'CPA', (100, 109))	('inhibition', 'NegReg', (86, 96))
88478	26555193	High SOX4 expression has been associated with better prognosis for patients with hepatocelluar carcinoma, medulloblastoma, and bladder cancer, but with shorter survival in prostate cancer, gastric cancer, and colon cancer.	('colon cancer', 'Phenotype', 'HP:0003003', (209, 221))	('gastric cancer', 'Disease', (189, 203))	('High', 'Var', (0, 4))	('hepatocelluar carcinoma', 'Disease', 'MESH:D002277', (81, 104))	('expression', 'MPA', (10, 20))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('hepatocelluar carcinoma', 'Disease', (81, 104))	('colon cancer', 'Disease', 'MESH:D015179', (209, 221))	('bladder cancer', 'Disease', (127, 141))	('bladder cancer', 'Disease', 'MESH:D001749', (127, 141))	('gastric cancer', 'Disease', 'MESH:D013274', (189, 203))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('patients', 'Species', '9606', (67, 75))	('SOX4', 'Gene', (5, 9))	('bladder cancer', 'Phenotype', 'HP:0009725', (127, 141))	('shorter', 'NegReg', (152, 159))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('colon cancer', 'Disease', (209, 221))	('prostate cancer', 'Disease', 'MESH:D011471', (172, 187))	('gastric cancer', 'Phenotype', 'HP:0012126', (189, 203))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('medulloblastoma', 'Disease', 'MESH:D008527', (106, 121))	('prostate cancer', 'Phenotype', 'HP:0012125', (172, 187))	('medulloblastoma', 'Phenotype', 'HP:0002885', (106, 121))	('SOX4', 'Gene', '6659', (5, 9))	('prostate cancer', 'Disease', (172, 187))	('medulloblastoma', 'Disease', (106, 121))	('better', 'PosReg', (46, 52))
88492	26555193	Specific proteins were sequentially blotted with primary antibodies: SOX4 (Catalogue# ab80261, Abcam, Cambridge, Mass, USA), cleaved caspase-3, cleaved caspase-7, cleaved poly-ADP ribose polymerase (PARP; Cell Signaling Technology, Danvers, MA, USA), X-linked inhibitor of apoptosis protein (XIAP) and polyclonal anti-GAPDH (Santa Cruz Biotechnology, CA, USA).	('poly-ADP ribose polymerase', 'Gene', '142', (171, 197))	('SOX4', 'Gene', '6659', (69, 73))	('X-linked inhibitor of apoptosis protein', 'Gene', '331', (251, 290))	('XIAP', 'Gene', (292, 296))	('XIAP', 'Gene', '331', (292, 296))	('cleaved', 'Var', (125, 132))	('PARP', 'Gene', (199, 203))	('X-linked inhibitor of apoptosis protein', 'Gene', (251, 290))	('GAPDH', 'Gene', '2597', (318, 323))	('caspase-7', 'Gene', (152, 161))	('poly-ADP ribose polymerase', 'Gene', (171, 197))	('caspase-7', 'Gene', '840', (152, 161))	('GAPDH', 'Gene', (318, 323))	('SOX4', 'Gene', (69, 73))	('PARP', 'Gene', '142', (199, 203))
88519	26555193	Final staining scores were the product of the intensity and percentage scores, with <=4 defined as low SOX4 expression and >4 defined as high SOX4 expression.	('SOX4', 'Gene', (142, 146))	('SOX4', 'Gene', '6659', (103, 107))	('SOX4', 'Gene', '6659', (142, 146))	('low', 'NegReg', (99, 102))	('expression', 'MPA', (108, 118))	('SOX4', 'Gene', (103, 107))	('<=4', 'Var', (84, 87))
88529	26555193	SOX4-KO PCI50 and SNU1041 cells displayed greater apoptotic rates than did control cells (Fig.	('apoptotic rates', 'CPA', (50, 65))	('SOX4', 'Gene', (0, 4))	('SNU1041', 'Var', (18, 25))	('SOX4', 'Gene', '6659', (0, 4))
88530	26555193	The proportion of early and late apoptotic cells induced by transfection of SOX4 siRNA was greater than that induced by transfection of negative control siRNA (9.2 % vs. 33.2 % and 7.1 % vs. 38.1 %, respectively) in PCI50 and SNU1041 cells.	('transfection', 'Var', (60, 72))	('SOX4', 'Gene', (76, 80))	('SOX4', 'Gene', '6659', (76, 80))
88542	26555193	Consistently, the SOX4-KO cells showed greater expression of cleaved caspases-3 and -7 and PARP, and less XIAP, after radiation or cisplatin treatment compared with the control cells (Fig.	('SOX4', 'Gene', '6659', (18, 22))	('PARP', 'Gene', (91, 95))	('cisplatin', 'Chemical', 'MESH:D002945', (131, 140))	('XIAP', 'Gene', '331', (106, 110))	('greater', 'PosReg', (39, 46))	('caspases-3 and -7', 'Gene', '836;840', (69, 86))	('cleaved', 'MPA', (61, 68))	('men', 'Species', '9606', (146, 149))	('PARP', 'Gene', '142', (91, 95))	('cisplatin', 'Var', (131, 140))	('XIAP', 'Gene', (106, 110))	('expression', 'MPA', (47, 57))	('SOX4', 'Gene', (18, 22))
88552	26555193	Moreover, overall survival (OS) and diease specific survival (DSS) of patients with high SOX4 expression was significantly shorter than for those with low SOX4 expression (P = 0.036 and P = 0.007, respectively; Fig.	('patients', 'Species', '9606', (70, 78))	('overall survival', 'CPA', (10, 26))	('SOX4', 'Gene', (155, 159))	('shorter', 'NegReg', (123, 130))	('high', 'Var', (84, 88))	('OS', 'Chemical', '-', (28, 30))	('SOX4', 'Gene', '6659', (155, 159))	('DSS', 'Gene', (62, 65))	('SOX4', 'Gene', (89, 93))	('DSS', 'Gene', '5376', (62, 65))	('SOX4', 'Gene', '6659', (89, 93))	('diease', 'MPA', (36, 42))	('expression', 'Var', (94, 104))
88553	26555193	In 50 patients who were treated with chemotherapy and/or radiotherapy, patients with high SOX4 expression had significantly shorter OS and DSS than those with low SOX4 expression (P = 0.007 and P = 0.003, respectively; Fig.	('SOX4', 'Gene', (90, 94))	('SOX4', 'Gene', (163, 167))	('DSS', 'Gene', (139, 142))	('SOX4', 'Gene', '6659', (90, 94))	('patients', 'Species', '9606', (71, 79))	('DSS', 'Gene', '5376', (139, 142))	('shorter', 'NegReg', (124, 131))	('OS', 'Chemical', '-', (132, 134))	('high', 'Var', (85, 89))	('SOX4', 'Gene', '6659', (163, 167))	('patients', 'Species', '9606', (6, 14))
88557	26555193	Consequently, deregulation of several SOX genes have been implicated in tumorigenesis.	('SOX', 'Gene', (38, 41))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('deregulation', 'Var', (14, 26))	('tumor', 'Disease', (72, 77))	('SOX', 'Gene', '104009', (38, 41))	('implicated', 'Reg', (58, 68))	('tumor', 'Disease', 'MESH:D009369', (72, 77))
88559	26555193	High SOX4 expression has been shown to affect tumor development or progression in gastric cancer, colon cancer, prostate cancer, breast cancer, lung cancer, and endometrial cancer.	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('colon cancer', 'Phenotype', 'HP:0003003', (98, 110))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('endometrial cancer', 'Disease', 'MESH:D016889', (161, 179))	('gastric cancer', 'Disease', 'MESH:D013274', (82, 96))	('lung cancer', 'Disease', 'MESH:D008175', (144, 155))	('endometrial cancer', 'Disease', (161, 179))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('High', 'Var', (0, 4))	('lung cancer', 'Phenotype', 'HP:0100526', (144, 155))	('colon cancer', 'Disease', 'MESH:D015179', (98, 110))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('prostate cancer', 'Disease', 'MESH:D011471', (112, 127))	('gastric cancer', 'Phenotype', 'HP:0012126', (82, 96))	('breast cancer', 'Phenotype', 'HP:0003002', (129, 142))	('prostate cancer', 'Phenotype', 'HP:0012125', (112, 127))	('SOX4', 'Gene', (5, 9))	('prostate cancer', 'Disease', (112, 127))	('tumor', 'Disease', (46, 51))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('colon cancer', 'Disease', (98, 110))	('breast cancer', 'Disease', 'MESH:D001943', (129, 142))	('tumor', 'Disease', 'MESH:D009369', (46, 51))	('breast cancer', 'Disease', (129, 142))	('progression', 'CPA', (67, 78))	('lung cancer', 'Disease', (144, 155))	('endometrial cancer', 'Phenotype', 'HP:0012114', (161, 179))	('affect', 'Reg', (39, 45))	('SOX4', 'Gene', '6659', (5, 9))	('gastric cancer', 'Disease', (82, 96))	('men', 'Species', '9606', (59, 62))
88565	26555193	In this study, knocked-down SOX4 induced apoptosis and suppressed cell proliferation, which indicates that SOX4 supresses apoptosis in HNSCC cells.	('knocked-down', 'Var', (15, 27))	('SOX4', 'Gene', '6659', (28, 32))	('SOX4', 'Gene', '6659', (107, 111))	('cell proliferation', 'CPA', (66, 84))	('HNSCC', 'Phenotype', 'HP:0012288', (135, 140))	('suppressed', 'NegReg', (55, 65))	('SOX4', 'Gene', (28, 32))	('SOX4', 'Gene', (107, 111))
88572	26555193	In the present study, knocked-down SOX4 enhanced radiation- or cisplatin-induced apoptosis in HNSCC cells, which were further supported by elevated levels of cleaved caspases-3 and -7, and PARP in SOX4-KO HNSCC cells after radiation or cisplatin treatment.	('cisplatin-induced apoptosis', 'CPA', (63, 90))	('cisplatin', 'Chemical', 'MESH:D002945', (63, 72))	('SOX4', 'Gene', (35, 39))	('elevated', 'PosReg', (139, 147))	('SOX4', 'Gene', '6659', (35, 39))	('knocked-down', 'Var', (22, 34))	('HNSCC', 'Phenotype', 'HP:0012288', (94, 99))	('cleaved', 'MPA', (158, 165))	('PARP', 'Gene', (189, 193))	('SOX4', 'Gene', (197, 201))	('caspases-3 and -7', 'Gene', '836;840', (166, 183))	('SOX4', 'Gene', '6659', (197, 201))	('HNSCC', 'Phenotype', 'HP:0012288', (205, 210))	('PARP', 'Gene', '142', (189, 193))	('cisplatin', 'Chemical', 'MESH:D002945', (236, 245))	('radiation-', 'CPA', (49, 59))	('enhanced', 'PosReg', (40, 48))	('men', 'Species', '9606', (251, 254))
88580	26555193	Our study showed that knocked-down SOX4 suppressed tumor cell invasion and migration in HNSCC cells; earlier studies showed it to significantly inhibit invasiveness and migration in prostate cancer cells.	('prostate cancer', 'Disease', 'MESH:D011471', (182, 197))	('prostate cancer', 'Phenotype', 'HP:0012125', (182, 197))	('suppressed', 'NegReg', (40, 50))	('SOX4', 'Gene', (35, 39))	('SOX4', 'Gene', '6659', (35, 39))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('knocked-down', 'Var', (22, 34))	('tumor', 'Disease', (51, 56))	('HNSCC', 'Phenotype', 'HP:0012288', (88, 93))	('prostate cancer', 'Disease', (182, 197))	('inhibit', 'NegReg', (144, 151))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
88583	26555193	In this study, we found that SOX4 expression was significantly associated with recurrence, treatment failure and shorter OS.	('men', 'Species', '9606', (96, 99))	('OS', 'Chemical', '-', (121, 123))	('treatment failure', 'CPA', (91, 108))	('SOX4', 'Gene', (29, 33))	('associated', 'Reg', (63, 73))	('SOX4', 'Gene', '6659', (29, 33))	('expression', 'Var', (34, 44))	('recurrence', 'CPA', (79, 89))	('shorter', 'Disease', (113, 120))
88585	26555193	Although several studies have associated SOX4 expression with shorter survival in prostate cancer, gastric cancer, and colon cancer, this is the first to demonstrate the correlation between SOX4 expression and treatment failure in OSCC.	('expression', 'Var', (46, 56))	('prostate cancer', 'Disease', 'MESH:D011471', (82, 97))	('gastric cancer', 'Phenotype', 'HP:0012126', (99, 113))	('SOX4', 'Gene', '6659', (41, 45))	('prostate cancer', 'Phenotype', 'HP:0012125', (82, 97))	('SOX4', 'Gene', (190, 194))	('colon cancer', 'Phenotype', 'HP:0003003', (119, 131))	('prostate cancer', 'Disease', (82, 97))	('men', 'Species', '9606', (215, 218))	('OS', 'Chemical', '-', (231, 233))	('SOX4', 'Gene', '6659', (190, 194))	('colon cancer', 'Disease', 'MESH:D015179', (119, 131))	('gastric cancer', 'Disease', (99, 113))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('shorter', 'NegReg', (62, 69))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('colon cancer', 'Disease', (119, 131))	('gastric cancer', 'Disease', 'MESH:D013274', (99, 113))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('SOX4', 'Gene', (41, 45))
88587	26555193	In particular, among patients with OSCC who received chemotherapy and/or radiotherapy, those with high SOX4 expression had significantly shorter OS.	('SOX4', 'Gene', '6659', (103, 107))	('shorter', 'NegReg', (137, 144))	('OSCC', 'Disease', (35, 39))	('OS', 'Chemical', '-', (35, 37))	('OS', 'Chemical', '-', (145, 147))	('high', 'Var', (98, 102))	('patients', 'Species', '9606', (21, 29))	('expression', 'MPA', (108, 118))	('SOX4', 'Gene', (103, 107))
88615	25478265	Immunostain was strongly positive for pankeratin and positive for CK5, CK6, and P16 (Figures 3(a) and 3(b)).	('positive', 'Reg', (25, 33))	('P16', 'Gene', '1029', (80, 83))	('pankeratin', 'Protein', (38, 48))	('CK5', 'Gene', '3852', (66, 69))	('CK5', 'Gene', (66, 69))	('CK6', 'Var', (71, 74))	('P16', 'Gene', (80, 83))
88644	25478265	P16 positivity is also seen in other primary malignancies associated with human papillomavirus infection, including squamous cell carcinomas of the oropharynx, cervix, and anus.	('carcinomas of the oropharynx', 'Phenotype', 'HP:0100638', (130, 158))	('P16', 'Gene', '1029', (0, 3))	('papillomavirus infection', 'Phenotype', 'HP:0012740', (80, 104))	('P16', 'Gene', (0, 3))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (116, 140))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (116, 139))	('primary malignancies', 'Disease', (37, 57))	('papillomavirus infection', 'Disease', (80, 104))	('anus', 'Disease', (172, 176))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (116, 140))	('positivity', 'Var', (4, 14))	('cervix', 'Disease', (160, 166))	('papillomavirus infection', 'Disease', 'MESH:D030361', (80, 104))	('squamous cell carcinomas', 'Disease', (116, 140))	('associated', 'Reg', (58, 68))	('seen', 'Reg', (23, 27))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('carcinomas', 'Phenotype', 'HP:0030731', (130, 140))	('man', 'Species', '9606', (76, 79))	('primary malignancies', 'Disease', 'MESH:D009369', (37, 57))
88645	25478265	Studies have shown that in some cases, a clone of cells in an otherwise benign epithelium may be determined as a source for metastases through microsatellite analysis before histopathology can identify definite dysplasia or malignancy.	('metastases', 'Disease', (124, 134))	('malignancy', 'Disease', 'MESH:D009369', (224, 234))	('metastases', 'Disease', 'MESH:D009362', (124, 134))	('dysplasia', 'Disease', (211, 220))	('malignancy', 'Disease', (224, 234))	('dysplasia', 'Disease', 'MESH:D004476', (211, 220))	('microsatellite', 'Var', (143, 157))
88672	31183998	Eighty-one patients who were prescribed anlotinib met the following criteria: aged 18-80 years; recurrent or advanced NSCLC (stage IIIB, IIIC, or IV [American Joint Committee on Cancer Cancer Staging Manual, 8th edition]) with failure of at least two lines of chemotherapy; EGFR-sensitive mutations for which EGFR-TKIs and at least two lines of chemotherapy had failed (treatment failure was defined as disease progression or intolerance to chemotherapy or EGFR-TKIs); an ECOG PS of 0-2; and adequate liver and kidney function.	('EGFR', 'Gene', '1956', (309, 313))	('EGFR', 'Gene', '1956', (457, 461))	('NSCLC', 'Phenotype', 'HP:0030358', (118, 123))	('mutations', 'Var', (289, 298))	('EGFR', 'Gene', (309, 313))	('EGFR', 'Gene', (457, 461))	('Cancer Cancer', 'Disease', 'MESH:D009369', (178, 191))	('Cancer', 'Phenotype', 'HP:0002664', (178, 184))	('anlotinib', 'Chemical', 'MESH:C000625192', (40, 49))	('NSCLC', 'Disease', (118, 123))	('EGFR', 'Gene', '1956', (274, 278))	('Cancer', 'Phenotype', 'HP:0002664', (185, 191))	('NSCLC', 'Disease', 'MESH:D002289', (118, 123))	('patients', 'Species', '9606', (11, 19))	('EGFR', 'Gene', (274, 278))	('Cancer Cancer', 'Disease', (178, 191))
88693	31183998	The ALTER 0303 trial showed that PFS was significantly longer in the anlotinib group than the placebo group (5.4 vs. 1.4 months; P < 0.001).	('anlotinib', 'Chemical', 'MESH:C000625192', (69, 78))	('PFS', 'MPA', (33, 36))	('anlotinib', 'Var', (69, 78))	('longer', 'PosReg', (55, 61))
88736	30777897	This included all diagnoses of the lung (ICD-10, C33-C34), bladder (C67), oesophageal squamous cell carcinoma (OSCC) (C15, morphology codes 8070-8074, 8094, 8123, 8560), laryngeal (C32) and head and neck cancers (C00-C14, C31).	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (86, 109))	('cancers', 'Phenotype', 'HP:0002664', (204, 211))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('8123', 'Var', (157, 161))	('laryngeal', 'Disease', (170, 179))	('8094', 'Var', (151, 155))	('lung', 'Disease', (35, 39))	('oesophageal squamous cell carcinoma', 'Disease', 'MESH:D002294', (74, 109))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('C15', 'Gene', (118, 121))	('C32', 'Gene', (181, 184))	('C15', 'Gene', '51316', (118, 121))	('bladder', 'Disease', (59, 66))	('head and neck cancer', 'Phenotype', 'HP:0012288', (190, 210))	('head and neck cancers', 'Disease', 'MESH:D006258', (190, 211))	('oesophageal squamous cell carcinoma', 'Disease', (74, 109))	('head and neck cancers', 'Phenotype', 'HP:0012288', (190, 211))	('C32', 'Gene', '51192', (181, 184))
88767	30777897	Over the entire length of follow-up, SIRs for second and higher order primary cancer were highest for those aged 30-49 (SIR 3.4, 95% CI 2.6 to 4.4) or 50-59 at diagnosis (SIR 2.7, 2.5 to 3.1), for women (SIR 2.0, 1.9 to 2.1) and for the most deprived patients (SIR 1.8, 1.7 to 2.0) (table 2).	('women', 'Species', '9606', (197, 202))	('50-59', 'Var', (151, 156))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('patients', 'Species', '9606', (251, 259))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))
88831	29266546	Therefore, we recently developed 2 novel mouse mAb against human PDPN (SZ163 and SZ168) and established a double-antibody sandwich ELISA, which we then used for quantitation of sPDPN in the plasma of 283 cancer patients and 99 normal controls.	('cancer', 'Disease', (204, 210))	('human', 'Species', '9606', (59, 64))	('cancer', 'Disease', 'MESH:D009369', (204, 210))	('SZ163', 'Chemical', '-', (71, 76))	('patients', 'Species', '9606', (211, 219))	('PDPN', 'Gene', (65, 69))	('mouse', 'Species', '10090', (41, 46))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('SZ168', 'Var', (81, 86))	('SZ168', 'Chemical', '-', (81, 86))	('sPDPN', 'Chemical', '-', (177, 182))
88847	29266546	The interaction with CLEC-2 was primarily observed at Glu47 and Asp48 in the platelet aggregation-stimulating (PLAG) domain (amino acids 29-54) and the alpha2-6 linked sialic acid at Thr52 of hPDPN.24 The sequence of our ploypeptide was chosen within the PLAG domain, for the purpose of developing mAb targeting the PDPN-CLEC-2 interaction with potential therapeutic application against cancer metastasis.	('CLEC-2', 'Gene', (21, 27))	('cancer metastasis', 'Disease', 'MESH:D009362', (387, 404))	('CLEC-2', 'Gene', (321, 327))	('sialic acid', 'Chemical', 'MESH:D019158', (168, 179))	('hPDPN', 'Gene', '10630', (192, 197))	('platelet aggregation', 'Disease', 'MESH:D001791', (77, 97))	('Thr52', 'Chemical', '-', (183, 188))	('hPDPN', 'Gene', (192, 197))	('interaction', 'Interaction', (4, 15))	('CLEC-2', 'Gene', '51266', (21, 27))	('Glu47', 'Chemical', '-', (54, 59))	('Glu47', 'Var', (54, 59))	('CLEC-2', 'Gene', '51266', (321, 327))	('platelet aggregation', 'Disease', (77, 97))	('cancer metastasis', 'Disease', (387, 404))	('Asp48', 'Chemical', '-', (64, 69))	('platelet aggregation', 'Phenotype', 'HP:0003540', (77, 97))	('alpha2-6', 'Gene', '3476', (152, 160))	('cancer', 'Phenotype', 'HP:0002664', (387, 393))	('alpha2-6', 'Gene', (152, 160))
88855	29266546	Cultured U87, NCI-H226 or CHO-PDPN cells were collected by trypsin-EDTA treatment and incubated with 18H5 as a positive control (Abcam, Cambridge, UK), mouse IgG as a negative control, or anti-PDPN antibodies (SZ163 and SZ168, 2 mug/tube) for 1 hour at room temperature.	('SZ163', 'Var', (210, 215))	('mouse', 'Species', '10090', (152, 157))	('NCI-H226 or CHO-PDPN', 'Disease', (14, 34))	('NCI-H226 or CHO-PDPN', 'Disease', 'None', (14, 34))	('EDTA', 'Chemical', 'MESH:D004492', (67, 71))	('U87', 'CellLine', 'CVCL:0022', (9, 12))	('SZ163', 'Chemical', '-', (210, 215))	('SZ168', 'Chemical', '-', (220, 225))
88858	29266546	After blocking with 8% skim milk in 0.1% PBST, the membrane was probed with either SZ-163 or SZ-168 (3 mug/ml in PBS + 0.1% Tween 20) for 2 hours at room temperature.	('SZ-168', 'Chemical', '-', (93, 99))	('SZ-163', 'Var', (83, 89))	('PBS', 'Chemical', 'MESH:D007854', (113, 116))	('Tween 20', 'Chemical', 'MESH:D011136', (124, 132))	('SZ-168', 'Var', (93, 99))	('PBS', 'Chemical', 'MESH:D007854', (41, 44))	('SZ-163', 'Chemical', '-', (83, 89))
88864	29266546	Furthermore, immunoblotting indicated that both SZ-163 and SZ-168 bound to the human recombinant protein PDPN-Fc (67 kDa), and to endogenous PDPN (46 or 36 kDa depending on glycosylation status) in U87 astroglioma cells, NCL-H226 lung squamous cell and CHO-PDPN cells (Figure 1B).	('SZ-163', 'Var', (48, 54))	('SZ-168', 'Chemical', '-', (59, 65))	('human', 'Species', '9606', (79, 84))	('SZ-163', 'Chemical', '-', (48, 54))	('bound', 'Interaction', (66, 71))	('astroglioma', 'Disease', 'MESH:D001254', (202, 213))	('SZ-168', 'Gene', (59, 65))	('astroglioma', 'Disease', (202, 213))	('NCL', 'Gene', '4691', (221, 224))	('CHO-PDPN', 'CellLine', 'CVCL:0213', (253, 261))	('NCL', 'Gene', (221, 224))	('U87', 'CellLine', 'CVCL:0022', (198, 201))
88865	29266546	In addition, flow cytometric analyses indicated that SZ163 and SZ168 recognized PDPN expressed on the tumor cell surface, although SZ168 appeared to have a higher affinity (Figure 1A,C).	('SZ163', 'Chemical', '-', (53, 58))	('SZ168', 'Var', (131, 136))	('SZ168', 'Chemical', '-', (131, 136))	('tumor', 'Disease', (102, 107))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('PDPN', 'Gene', (80, 84))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('SZ168', 'Chemical', '-', (63, 68))
88895	29266546	In addition, our results implied that PDPN on the surface of tumor cells can be hydrolyzed, spontaneously resulting in the release of the extracellular domain into the plasma.	('resulting in', 'Reg', (106, 118))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('PDPN', 'Var', (38, 42))	('tumor', 'Disease', (61, 66))
88902	29266546	Furthermore, the comparison of the diagnostic efficiency of sPDPN and CEA suggested that sPDPN might be a better cancer marker, with an AUC value closer to 1 and a lower cut-off value.	('sPDPN', 'Chemical', '-', (60, 65))	('CEA', 'Gene', (70, 73))	('sPDPN', 'Chemical', '-', (89, 94))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('CEA', 'Gene', '5670', (70, 73))	('sPDPN', 'Var', (89, 94))	('cancer', 'Disease', (113, 119))	('AUC', 'MPA', (136, 139))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
88908	26864211	CD44+ cells in primary human SCCHN were found to have an epithelial-to-mesenchymal (EMT) phenotype and were less immunogenic than CD44- cells when cultured with autologous CD8+ tumor-infiltrating T cells.	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('CD8', 'Gene', (172, 175))	('CD8', 'Gene', '925', (172, 175))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('human', 'Species', '9606', (23, 28))	('EMT', 'Gene', (84, 87))	('tumor', 'Disease', (177, 182))	('CD44+', 'Var', (0, 5))	('EMT', 'Gene', '3702', (84, 87))	('less', 'NegReg', (108, 112))
88909	26864211	Selective expression of the programmed death-ligand 1 (PD-L1) was observed on CD44+ cells compared to CD44- cells and was associated with constitutive phosphorylation of STAT3 on CD44+ cells.	('STAT3', 'Gene', '6774', (170, 175))	('programmed death-ligand 1', 'Gene', (28, 53))	('programmed death-ligand 1', 'Gene', '29126', (28, 53))	('STAT3', 'Gene', (170, 175))	('CD44+', 'Var', (78, 83))
88910	26864211	Importantly, inhibition of STAT3 decreased expression of PD-L1 on CD44+ cells.	('STAT3', 'Gene', (27, 32))	('inhibition', 'Var', (13, 23))	('PD-L1', 'Gene', (57, 62))	('decreased', 'NegReg', (33, 42))	('expression', 'MPA', (43, 53))	('STAT3', 'Gene', '6774', (27, 32))
88913	26864211	Our findings provide a mechanism by which long-lived CD44+ tumor-initiating cells can selectively evade host immune responses and provide rationale for targeting the PD-1 pathway in the adjuvant therapy setting of SCCHN.	('tumor', 'Disease', (59, 64))	('evade', 'NegReg', (98, 103))	('CD44+', 'Var', (53, 58))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('PD-1', 'Gene', (166, 170))	('SCCHN', 'Disease', (214, 219))	('PD-1', 'Gene', '5133', (166, 170))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
88920	26864211	Further, CD44+ cells in SCCHN can propagate in vivo tumor engraftment and give rise to CD44- cells in serial passaging of xenografts, and the idea that a "cancer stem cell" - like population is contained within the CD44+ compartment.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('CD44- cells', 'Var', (87, 98))	('tumor', 'Disease', (52, 57))	('give rise', 'Reg', (74, 83))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('propagate', 'CPA', (34, 43))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('cancer', 'Disease', (155, 161))	('cancer', 'Disease', 'MESH:D009369', (155, 161))
88929	26864211	In this study, we examined primary human SCCHN tumor samples and compared the immunogenicity of the CD44+ subset of cells with that of the CD44- counterparts.	('SCCHN tumor', 'Disease', 'MESH:D009369', (41, 52))	('SCCHN tumor', 'Disease', (41, 52))	('CD44+', 'Var', (100, 105))	('human', 'Species', '9606', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))
88949	26864211	For tumor cell profiling: Antibodies to CD44 (G44-26), CD271 (C40-1457), and p-STAT1 (pY701) (4A) were obtained from BD Pharmingen.	('tumor', 'Disease', (4, 9))	('STAT1', 'Gene', (79, 84))	('STAT1', 'Gene', '6772', (79, 84))	('CD271', 'Gene', '4804', (55, 60))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('CD44 (G44-26', 'Var', (40, 52))	('CD271', 'Gene', (55, 60))
88954	26864211	Validated Taqman Gene Expression Assays (Applied Biosystems) for HPRT1 (Hs02800695_m1), CD274 (Hs01125301_m1), IFNGR1 (Hs00988304_m1), BMI1 (Hs00180411_m1), TWIST1 (Hs01675818_s1), ZEB1 (Hs00232783_m1), ZEB2 (Hs00207691_m1), SNAI1 (Hs00195591_m1), SNAI2 (Hs00950344_m1), CDH1 (Hs01023894_m1), and CDH2 (Hs00983056_m1) were used with the Applied Biosystems 7900HT system.	('CDH2', 'Gene', (297, 301))	('SNAI1', 'Gene', (225, 230))	('Hs00950344_m1', 'Var', (255, 268))	('SNAI2', 'Gene', '6591', (248, 253))	('BMI1', 'Gene', (135, 139))	('CDH2', 'Gene', '1000', (297, 301))	('HPRT1', 'Gene', '3251', (65, 70))	('IFNGR1', 'Gene', '3459', (111, 117))	('ZEB2', 'Gene', (203, 207))	('CD274', 'Gene', '29126', (88, 93))	('IFNGR1', 'Gene', (111, 117))	('TWIST1', 'Gene', (157, 163))	('CDH1', 'Gene', '999', (271, 275))	('ZEB2', 'Gene', '9839', (203, 207))	('HPRT1', 'Gene', (65, 70))	('BMI1', 'Gene', '648', (135, 139))	('CDH1', 'Gene', (271, 275))	('TWIST1', 'Gene', '7291', (157, 163))	('SNAI2', 'Gene', (248, 253))	('CD274', 'Gene', (88, 93))	('Hs01023894_m1', 'Var', (277, 290))	('SNAI1', 'Gene', '6615', (225, 230))	('Hs00232783_m1', 'Var', (187, 200))
88960	26864211	Antibodies used were anti-PD-L1 (6E11.1.9, Genentech), anti-PD-1 (EH12.2H7, BioLegend), anti-Tim-3 (F38-2E2, BioLegend), mouse IgG2a isotype (BioLegend), and mouse IgG1 isotype (BioLegend).	('PD-1', 'Gene', '5133', (60, 64))	('mouse', 'Species', '10090', (158, 163))	('Tim-3', 'Gene', (93, 98))	('EH12.2H7', 'CellLine', 'CVCL:L804', (66, 74))	('mouse', 'Species', '10090', (121, 126))	('Tim-3', 'Gene', '84868', (93, 98))	('F38-2E2', 'Var', (100, 107))	('PD-1', 'Gene', (60, 64))
88972	26864211	We observed higher mRNA levels of EMT regulators TWIST1 and BMI1 in CD44+ cells compared to CD44- cells, as previously reported.	('EMT', 'Gene', (34, 37))	('BMI1', 'Gene', (60, 64))	('higher', 'PosReg', (12, 18))	('TWIST1', 'Gene', (49, 55))	('EMT', 'Gene', '3702', (34, 37))	('TWIST1', 'Gene', '7291', (49, 55))	('mRNA levels', 'MPA', (19, 30))	('BMI1', 'Gene', '648', (60, 64))	('CD44+', 'Var', (68, 73))
88976	26864211	Of note, following expansion, Tim-3 expression on the CD8+ TILs was significantly elevated (Fig.	('CD8', 'Gene', '925', (54, 57))	('Tim-3', 'Gene', '84868', (30, 35))	('TIL', 'Gene', '7096', (59, 62))	('expansion', 'Var', (19, 28))	('elevated', 'PosReg', (82, 90))	('TIL', 'Gene', (59, 62))	('Tim-3', 'Gene', (30, 35))	('expression', 'MPA', (36, 46))	('CD8', 'Gene', (54, 57))
88992	26864211	We observed that both CD44+PD-L1- and CD44+PD-L1+ cells formed xenograft tumors similarly over a range of cell numbers injected, while CD44- cells either did not form tumors (Fig.	('CD44+PD-L1-', 'Var', (22, 33))	('tumors', 'Disease', 'MESH:D009369', (167, 173))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('CD44+PD-L1+ cells', 'Var', (38, 55))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('tumors', 'Disease', (73, 79))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('tumors', 'Disease', 'MESH:D009369', (73, 79))	('tumors', 'Disease', (167, 173))	('tumors', 'Phenotype', 'HP:0002664', (167, 173))
89001	26864211	The increase in IFNgamma secretion by the T cells in the CD44+ co-cultures with PD-1/PD-L1 blockade was significant but did not reach the levels produced in response to CD44- cells, suggesting that additional mechanisms of immunosuppression were involved.	('blockade', 'Var', (91, 99))	('IFNgamma', 'Gene', (16, 24))	('IFNgamma', 'Gene', '3458', (16, 24))	('PD-1', 'Gene', (80, 84))	('increase', 'PosReg', (4, 12))	('PD-1', 'Gene', '5133', (80, 84))
89005	26864211	Furthermore, the purported ligand for Tim-3, galectin-9, was not detected in either the CD44+ or CD44- population (Supplementary Fig.	('Tim-3', 'Gene', (38, 43))	('galectin-9', 'Gene', '3965', (45, 55))	('Tim-3', 'Gene', '84868', (38, 43))	('galectin-9', 'Gene', (45, 55))	('CD44+', 'Var', (88, 93))	('CD44-', 'Var', (97, 102))
89006	26864211	The combination of PD-1 and Tim-3 blockade resulted in the greatest increase in IFNgamma secretion against CD44+ cells, indicating a potential for significant combined activity in the clinical setting.	('IFNgamma', 'Gene', (80, 88))	('Tim-3', 'Gene', (28, 33))	('IFNgamma', 'Gene', '3458', (80, 88))	('blockade', 'Var', (34, 42))	('Tim-3', 'Gene', '84868', (28, 33))	('increase', 'PosReg', (68, 76))	('PD-1', 'Gene', (19, 23))	('PD-1', 'Gene', '5133', (19, 23))
89007	26864211	Higher expression of CD47, a ligand that inhibits phagocytosis by macrophages, was also observed on CD44+ cells (Supplementary Fig.	('CD47', 'Gene', (21, 25))	('inhibits', 'NegReg', (41, 49))	('CD44+', 'Var', (100, 105))	('expression', 'MPA', (7, 17))	('Higher', 'PosReg', (0, 6))	('phagocytosis by macrophages', 'CPA', (50, 77))	('CD47', 'Gene', '961', (21, 25))
89011	26864211	Consistent with this possibility, we observed constitutive phosphorylation of STAT3 on CD44+ cells but not on CD44- cells isolated from SCCHN xenografts (Fig.	('CD44+', 'Var', (87, 92))	('STAT3', 'Gene', '6774', (78, 83))	('constitutive', 'MPA', (46, 58))	('STAT3', 'Gene', (78, 83))	('SCCHN', 'Disease', (136, 141))
89023	26864211	Since IFNgamma signaling also regulates MHC class I levels, we examined the expression of HLA-ABC following exposure to IFNgamma, but found no significant increase; however, the levels of HLA-ABC were very high in both CD44+ and CD44- cells and were likely at the inducible limit (Supplementary Fig.	('CD44+', 'Var', (219, 224))	('IFNgamma', 'Gene', '3458', (6, 14))	('IFNgamma', 'Gene', '3458', (120, 128))	('IFNgamma', 'Gene', (120, 128))	('IFNgamma', 'Gene', (6, 14))	('levels', 'MPA', (178, 184))	('CD44-', 'Var', (229, 234))
89029	26864211	While blockade of the PD-1:PD-L1 axis significantly increased IFNgamma production by CD8+ T cells co-cultured with the CD44+ tumor cells, there was only partial restoration of IFNgamma secretion to levels produced by CD8+ T cells co-cultured with CD44- tumor cells.	('PD-1', 'Gene', (22, 26))	('IFNgamma', 'Gene', (176, 184))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('PD-1', 'Gene', '5133', (22, 26))	('increased', 'PosReg', (52, 61))	('IFNgamma', 'Gene', '3458', (176, 184))	('CD8', 'Gene', (85, 88))	('tumor', 'Disease', 'MESH:D009369', (253, 258))	('CD8', 'Gene', '925', (85, 88))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (253, 258))	('tumor', 'Disease', (125, 130))	('blockade', 'Var', (6, 14))	('CD8', 'Gene', (217, 220))	('tumor', 'Disease', (253, 258))	('CD8', 'Gene', '925', (217, 220))	('IFNgamma', 'Gene', (62, 70))	('IFNgamma', 'Gene', '3458', (62, 70))
89031	26864211	The blockade of Tim-3 with the addition of Tim-3 antibodies to the co-cultures further augmented the production of IFNgamma by the T cells; however, this was not specific to the co-cultures with either the CD44+ or CD44- cells.	('IFNgamma', 'Gene', (115, 123))	('Tim-3', 'Gene', '84868', (43, 48))	('blockade', 'NegReg', (4, 12))	('augmented', 'PosReg', (87, 96))	('IFNgamma', 'Gene', '3458', (115, 123))	('Tim-3', 'Gene', (16, 21))	('antibodies', 'Var', (49, 59))	('Tim-3', 'Gene', (43, 48))	('Tim-3', 'Gene', '84868', (16, 21))
89049	26864211	In our studies, the enhanced response to IFNgamma by the CD44+ cells resulted in even greater expression of PD-L1 (above baseline expression) in response to IFNgamma.	('PD-L1', 'Gene', (108, 113))	('enhanced', 'PosReg', (20, 28))	('greater', 'PosReg', (86, 93))	('response', 'MPA', (29, 37))	('IFNgamma', 'Gene', (157, 165))	('IFNgamma', 'Gene', '3458', (157, 165))	('IFNgamma', 'Gene', '3458', (41, 49))	('expression', 'MPA', (94, 104))	('IFNgamma', 'Gene', (41, 49))	('CD44+', 'Var', (57, 62))
89052	26864211	CD44+ cells in SCCHN tumors have been proposed to be tumor-initiating cells or cancer stem cells due to their ability to propagate serial in vivo passage and recapitulate the morphology and phenotype of the original parental tumors after engraftment, as compared to CD44- cells.	('tumor', 'Disease', (21, 26))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Disease', (225, 230))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('SCCHN tumors', 'Disease', 'MESH:D009369', (15, 27))	('CD44+', 'Var', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (225, 230))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('cancer', 'Disease', (79, 85))	('original parental tumors', 'Disease', 'MESH:D063129', (207, 231))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))	('SCCHN tumors', 'Disease', (15, 27))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('tumors', 'Phenotype', 'HP:0002664', (225, 231))	('original parental tumors', 'Disease', (207, 231))	('tumor', 'Disease', (53, 58))	('cancer', 'Disease', 'MESH:D009369', (79, 85))
89053	26864211	Our results indicate CD44+ cells to have higher levels of ZEB1 and STAT3 phosphorylation, both of which have been shown to regulate PD-L1 expression and contribute to cancer stemness and tumorigenesis, lending credence to our hypothesis that cancer stemness could potentially be associated with PD-L1-mediated immunosuppression.	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('contribute to', 'Reg', (153, 166))	('ZEB1', 'MPA', (58, 62))	('PD-L1', 'Gene', (132, 137))	('CD44+', 'Var', (21, 26))	('cancer stemness', 'Disease', 'MESH:D009369', (167, 182))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('cancer stemness', 'Disease', 'MESH:D009369', (242, 257))	('regulate', 'Reg', (123, 131))	('cancer stemness', 'Disease', (242, 257))	('STAT3', 'Gene', '6774', (67, 72))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('tumor', 'Disease', (187, 192))	('STAT3', 'Gene', (67, 72))	('expression', 'MPA', (138, 148))	('higher', 'PosReg', (41, 47))	('cancer', 'Phenotype', 'HP:0002664', (242, 248))	('cancer stemness', 'Disease', (167, 182))
89059	26864211	In particular, it has been recently reported that T cell exclusion from the tumor microenvironment is controlled by the Wnt pathway, and therefore, patients with tumors having greater CD44+ cell proportions may tend to be non-responders to PD-1 blockade.	('patients', 'Species', '9606', (148, 156))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('Wnt', 'Pathway', (120, 123))	('PD-1', 'Gene', (240, 244))	('tumor', 'Disease', (162, 167))	('tumor', 'Disease', (76, 81))	('PD-1', 'Gene', '5133', (240, 244))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('CD44+ cell', 'Var', (184, 194))	('tumors', 'Disease', (162, 168))	('tumors', 'Disease', 'MESH:D009369', (162, 168))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))	('non-responders', 'MPA', (222, 236))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
89091	33692871	In head and neck SCC, p53 mutations acquire oncogenic functions to promote tumorigenesis and tumor progression.	('tumor', 'Disease', 'MESH:D009369', (93, 98))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('SCC', 'Phenotype', 'HP:0002860', (17, 20))	('SCC', 'Gene', '6317', (17, 20))	('p53', 'Gene', (22, 25))	('tumor', 'Disease', (93, 98))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('mutations', 'Var', (26, 35))	('p53', 'Gene', '7157', (22, 25))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', (75, 80))	('SCC', 'Gene', (17, 20))	('promote', 'PosReg', (67, 74))
89093	33692871	High Ki-67 expression is a negative prognostic marker in patients with OSCC, especially in Asian populations.	('High', 'Var', (0, 4))	('patients', 'Species', '9606', (57, 65))	('expression', 'MPA', (11, 21))	('Ki-67', 'Protein', (5, 10))	('SCC', 'Gene', (72, 75))	('SCC', 'Phenotype', 'HP:0002860', (72, 75))	('SCC', 'Gene', '6317', (72, 75))
89159	33692871	Furthermore, there were no statistical differences in the DFS (log-rank test, P=0.27 or P=0.78) and DSS (log-rank test, P=0.52 or P=0.56) between low- and high- p53 or Ki-67 expression groups, respectively (Fig.	('Ki-67', 'Gene', (168, 173))	('DFS', 'MPA', (58, 61))	('DSS', 'MPA', (100, 103))	('low-', 'Var', (146, 150))	('p53', 'Gene', (161, 164))	('p53', 'Gene', '7157', (161, 164))
89186	33692871	The inactivation and mutation of p53, which play an essential role in tumorigenesis and progression of head and neck carcinoma, are among the most frequent genetic alterations in oral squamous cell carcinoma.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (184, 207))	('inactivation', 'Var', (4, 16))	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('neck carcinoma', 'Disease', (112, 126))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (179, 207))	('neck carcinoma', 'Disease', 'MESH:D006258', (112, 126))	('tumor', 'Disease', (70, 75))	('carcinoma', 'Phenotype', 'HP:0030731', (198, 207))	('mutation', 'Var', (21, 29))	('p53', 'Gene', (33, 36))	('p53', 'Gene', '7157', (33, 36))	('oral squamous cell carcinoma', 'Disease', (179, 207))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
89191	33692871	Some studies showed a significant relationship between Ki-67 expression and overall survival, whereby, high Ki-67 expression was a marker of poor prognosis in OSCC patients.	('SCC', 'Phenotype', 'HP:0002860', (160, 163))	('Ki-67', 'Gene', (108, 113))	('SCC', 'Gene', (160, 163))	('high', 'Var', (103, 107))	('patients', 'Species', '9606', (164, 172))	('expression', 'MPA', (114, 124))	('SCC', 'Gene', '6317', (160, 163))
89192	33692871	Motta et al reported that co-expression of p53 and Ki-67 markers in SCCs of the oral cavity and tongue suggested a worse prognosis.	('SCC', 'Phenotype', 'HP:0002860', (68, 71))	('co-expression', 'Var', (26, 39))	('SCC', 'Gene', '6317', (68, 71))	('Ki-67', 'Gene', (51, 56))	('p53', 'Gene', '7157', (43, 46))	('p53', 'Gene', (43, 46))	('SCC', 'Gene', (68, 71))
89196	33692871	Meanwhile, positive vimentin expression has been associated with a higher prevalence of recurrence and shorter survival time in OSCC and has been considered a reliable predictive EMT marker for poor prognosis in OSCC.	('vimentin', 'Gene', (20, 28))	('recurrence', 'CPA', (88, 98))	('SCC', 'Gene', '6317', (129, 132))	('SCC', 'Gene', '6317', (213, 216))	('SCC', 'Phenotype', 'HP:0002860', (213, 216))	('SCC', 'Phenotype', 'HP:0002860', (129, 132))	('shorter', 'NegReg', (103, 110))	('expression', 'MPA', (29, 39))	('positive', 'Var', (11, 19))	('survival time', 'CPA', (111, 124))	('SCC', 'Gene', (129, 132))	('SCC', 'Gene', (213, 216))	('vimentin', 'Gene', '7431', (20, 28))
89213	32956555	Downregulation of m6A reader YTHDC2 promotes tumor progression and predicts poor prognosis in non-small cell lung cancer m6A modification affects the pathological progress of many diseases by affecting RNA stability and translocation.	('m6A', 'Gene', (121, 124))	('Downregulation', 'NegReg', (0, 14))	('tumor', 'Disease', (45, 50))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (98, 120))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (94, 120))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('promotes', 'PosReg', (36, 44))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('affects', 'Reg', (138, 145))	('RNA stability', 'MPA', (202, 215))	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('pathological progress', 'CPA', (150, 171))	('YTHDC2', 'Gene', '64848', (29, 35))	('lung cancer', 'Phenotype', 'HP:0100526', (109, 120))	('m6A', 'Gene', '56339', (18, 21))	('translocation', 'MPA', (220, 233))	('cancer', 'Disease', (114, 120))	('m6A', 'Gene', '56339', (121, 124))	('affecting', 'Reg', (192, 201))	('YTHDC2', 'Gene', (29, 35))	('modification', 'Var', (125, 137))	('m6A', 'Gene', (18, 21))
89224	32956555	Kaplan-Meier Plotter database analysis revealed that patients with low level of YTHDC2 had a significantly poor prognosis.	('YTHDC2', 'Gene', '64848', (80, 86))	('low level', 'Var', (67, 76))	('YTHDC2', 'Gene', (80, 86))	('patients', 'Species', '9606', (53, 61))
89236	32956555	N6-methyladenosine (m6A) modification is the most prevalent internal modification in eukaryotic mRNA.	('m6A', 'Gene', (20, 23))	('m6A', 'Gene', '56339', (20, 23))	('N6-methyladenosine', 'Chemical', 'MESH:C010223', (0, 18))	('N6-methyladenosine', 'Var', (0, 18))
89244	32956555	15  In addition, loss of YTHDC2 promoted the proliferation rate of esophageal squamous-cell carcinoma (ESCC) by affecting several cancer-related signaling pathways.	('promoted', 'PosReg', (32, 40))	('squamous-cell carcinoma', 'Disease', (78, 101))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('affecting', 'Reg', (112, 121))	('proliferation rate', 'CPA', (45, 63))	('YTHDC2', 'Gene', '64848', (25, 31))	('cancer', 'Disease', (130, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('squamous-cell carcinoma', 'Phenotype', 'HP:0002860', (78, 101))	('YTHDC2', 'Gene', (25, 31))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('squamous-cell carcinoma', 'Disease', 'MESH:D002294', (78, 101))	('loss', 'Var', (17, 21))
89256	32956555	In addition, three sets of microarray data of NSCLC tissues were downloaded from Gene Expression Omnibus (GEO) database (accession numbers: GSE63459, GSE74706 and GSE32665).	('GSE74706', 'Var', (150, 158))	('GSE63459', 'Var', (140, 148))	('GSE32665', 'Var', (163, 171))	('NSCLC', 'Disease', (46, 51))	('NSCLC', 'Disease', 'MESH:D002289', (46, 51))	('NSCLC', 'Phenotype', 'HP:0030358', (46, 51))
89279	32956555	We then also evaluated the expression of YTHDC2 by searching three GEO datasets (GSE63459, GSE74706 and GSE32665).	('GSE32665', 'Var', (104, 112))	('GSE63459', 'Var', (81, 89))	('YTHDC2', 'Gene', '64848', (41, 47))	('YTHDC2', 'Gene', (41, 47))	('GSE74706', 'Var', (91, 99))
89294	32956555	Conversely, the proliferation and migration rate of H1299 cells were drastically elevated after YTHDC2 knockdown (Fig 3d,e).	('YTHDC2', 'Gene', '64848', (96, 102))	('elevated', 'PosReg', (81, 89))	('YTHDC2', 'Gene', (96, 102))	('migration rate', 'CPA', (34, 48))	('proliferation', 'CPA', (16, 29))	('knockdown', 'Var', (103, 112))	('H1299', 'CellLine', 'CVCL:0060', (52, 57))
89309	32956555	21  Another m6A methyladenosine METTL3 (m6A writer) induced miR-143-3p has been reported to promote the brain metastasis of lung cancer via regulation of VASH1.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('lung cancer', 'Disease', 'MESH:D008175', (124, 135))	('promote', 'PosReg', (92, 99))	('m6A', 'Gene', '56339', (40, 43))	('miR-143-3p', 'Chemical', '-', (60, 70))	('brain metastasis', 'CPA', (104, 120))	('m6A', 'Gene', (12, 15))	('m6A', 'Gene', (40, 43))	('m6A', 'Gene', '56339', (12, 15))	('VASH1', 'Gene', (154, 159))	('methyladenosine', 'Chemical', '-', (16, 31))	('miR-143-3p', 'Var', (60, 70))	('lung cancer', 'Disease', (124, 135))	('METTL3', 'Gene', '56339', (32, 38))	('lung cancer', 'Phenotype', 'HP:0100526', (124, 135))	('METTL3', 'Gene', (32, 38))	('VASH1', 'Gene', '22846', (154, 159))
89332	32956555	31  Aberrant overexpression of YTHDC1 in colon adenocarcinoma has also been previously reported.	('colon adenocarcinoma', 'Disease', 'MESH:D003110', (41, 61))	('carcinoma', 'Phenotype', 'HP:0030731', (52, 61))	('YTHDC1', 'Gene', (31, 37))	('YTHDC1', 'Gene', '91746', (31, 37))	('Aberrant', 'Var', (4, 12))	('overexpression', 'PosReg', (13, 27))	('colon adenocarcinoma', 'Disease', (41, 61))
89353	31984309	Hypoxia drives transient site-specific copy alterations and increases the mutation frequency of key cancer genes.	('Hypoxia', 'Disease', 'MESH:D000860', (0, 7))	('Hypoxia', 'Disease', (0, 7))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('copy alterations', 'Var', (39, 55))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('increases', 'PosReg', (60, 69))	('mutation frequency', 'MPA', (74, 92))
89362	31984309	Hypoxia can also cause resistance to gefitinib in both EGFR mutant and wild-type non-small-cell lung cancer (NSCLC).	('EGFR', 'Gene', '1956', (55, 59))	('lung cancer', 'Disease', 'MESH:D008175', (96, 107))	('NSCLC', 'Disease', 'MESH:D002289', (109, 114))	('Hypoxia', 'Disease', 'MESH:D000860', (0, 7))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (81, 107))	('Hypoxia', 'Disease', (0, 7))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (85, 107))	('EGFR', 'Gene', (55, 59))	('cause', 'Reg', (17, 22))	('lung cancer', 'Disease', (96, 107))	('resistance', 'MPA', (23, 33))	('lung cancer', 'Phenotype', 'HP:0100526', (96, 107))	('NSCLC', 'Phenotype', 'HP:0030358', (109, 114))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('gefitinib', 'Chemical', 'MESH:C419708', (37, 46))	('mutant', 'Var', (60, 66))	('NSCLC', 'Disease', (109, 114))
89381	31984309	We further excluded kidney renal clear cell carcinoma (KIRC) and colon adenocarcinoma (COAD) samples with relatively high mutation frequency in VHL (>= 5%), which directly regulates HIF1A to induce pseudohypoxia.	('colon adenocarcinoma', 'Disease', 'MESH:D015179', (65, 85))	('kidney renal clear cell carcinoma', 'Disease', (20, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('pseudohypoxia', 'Disease', (198, 211))	('VHL', 'Disease', (144, 147))	('HIF1A', 'Gene', (182, 187))	('HIF1A', 'Gene', '3091', (182, 187))	('pseudohypoxia', 'Disease', 'None', (198, 211))	('kidney renal clear cell carcinoma', 'Disease', 'MESH:D002292', (20, 53))	('VHL', 'Disease', 'MESH:D006623', (144, 147))	('regulates', 'Reg', (172, 181))	('mutation frequency', 'Var', (122, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (44, 53))	('colon adenocarcinoma', 'Disease', (65, 85))
89454	31984309	For example, miR-375 positively correlated (drug-resistant) to A-443654 (Rs = 0.37, FDR = 9.0 x 10-4), PLX4720 (Rs = 0.39, FDR = 9.4 x 10-5) and vinblastine (Rs = 0.35, FDR = 8.5 x 10-4), and miR-200a-3p positively correlated (drug-resistant) to A-443654 (Rs = 0.35, FDR = 1.3 x 10-4), PLX4720 (Rs = 0.29, FDR = 6.1 x 10-3) and vinblastine (Rs = 0.44, FDR = 1.2 x 10-5).	('A-443654', 'Chemical', 'MESH:C504035', (246, 254))	('A-443654', 'Var', (63, 71))	('PLX4720', 'Chemical', 'MESH:C528407', (286, 293))	('miR', 'Gene', (13, 16))	('miR', 'Gene', '220972', (13, 16))	('miR', 'Gene', (192, 195))	('miR', 'Gene', '220972', (192, 195))	('PLX4720', 'Chemical', 'MESH:C528407', (103, 110))	('vinblastine', 'Chemical', 'MESH:D014747', (145, 156))	('miR-375', 'Gene', '494324', (13, 20))	('A-443654', 'Chemical', 'MESH:C504035', (63, 71))	('A-443654', 'Var', (246, 254))	('vinblastine', 'Chemical', 'MESH:D014747', (328, 339))	('miR-375', 'Gene', (13, 20))	('PLX4720', 'Var', (286, 293))
89455	31984309	For 29 genes overexpressed in hypoxia score-low samples, we also observed a similar regulatory network in that the downregulation of gene expression was consistent with hypermethylation of promoter regions and upregulation of miRNAs, and highly correlated to response to anti-cancer drugs (Supplementary Fig.	('hypoxia', 'Disease', (30, 37))	('cancer', 'Disease', (276, 282))	('gene expression', 'MPA', (133, 148))	('hypermethylation', 'Var', (169, 185))	('hypoxia', 'Disease', 'MESH:D000860', (30, 37))	('cancer', 'Disease', 'MESH:D009369', (276, 282))	('miR', 'Gene', '220972', (226, 229))	('miR', 'Gene', (226, 229))	('upregulation', 'PosReg', (210, 222))	('cancer', 'Phenotype', 'HP:0002664', (276, 282))	('downregulation', 'NegReg', (115, 129))
89458	31984309	For example, TP53 had significantly higher mutation frequency in hypoxia score-high tumors across multiple cancer types: 62.3% (137/220) and 73.5% (83/113) of samples had TP53 mutations in hypoxia score-high BCRA and LUAD, while only 8.0% (19/236) and 34.6% (44/127) of samples had TP53 mutations in hypoxia score-low BRCA and LUAD, respectively (Fig.	('TP53', 'Gene', (13, 17))	('mutations', 'Var', (176, 185))	('hypoxia score-high tumors across multiple cancer', 'Disease', 'MESH:D009369', (65, 113))	('LUAD', 'Phenotype', 'HP:0030078', (217, 221))	('LUAD', 'Phenotype', 'HP:0030078', (327, 331))	('cancer type', 'Disease', (107, 118))	('hypoxia', 'Disease', (65, 72))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('cancer type', 'Disease', 'MESH:D009369', (107, 118))	('TP53', 'Gene', (171, 175))	('LUAD', 'Disease', (217, 221))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('TP53', 'Gene', (282, 286))	('hypoxia', 'Disease', 'MESH:D000860', (65, 72))	('TP53', 'Gene', '7157', (13, 17))	('hypoxia', 'Disease', (300, 307))	('BRCA and LUAD', 'Gene', '672', (318, 331))	('hypoxia', 'Disease', 'MESH:D000860', (300, 307))	('hypoxia', 'Disease', (189, 196))	('TP53', 'Gene', '7157', (171, 175))	('TP53', 'Gene', '7157', (282, 286))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('hypoxia', 'Disease', 'MESH:D000860', (189, 196))	('hypoxia score-high tumors across multiple cancer', 'Disease', (65, 113))
89459	31984309	This is consistent with previous reports that mutations of p53 contribute to diminished oxygen consumption.	('p53', 'Gene', (59, 62))	('p53', 'Gene', '7157', (59, 62))	('mutations', 'Var', (46, 55))	('diminished', 'NegReg', (77, 87))	('oxygen', 'Chemical', 'MESH:D010100', (88, 94))	('oxygen consumption', 'MPA', (88, 106))
89460	31984309	We further observed that TP53 mutations were associated with reduced drug response to the BRAF inhibitor, AZ-628 (FDR = 5.0 x 10-4; Fig.	('BRAF', 'Gene', (90, 94))	('TP53', 'Gene', (25, 29))	('drug response to the', 'MPA', (69, 89))	('AZ-628', 'Chemical', 'MESH:C000592454', (106, 112))	('mutations', 'Var', (30, 39))	('reduced drug response', 'Phenotype', 'HP:0020173', (61, 82))	('BRAF', 'Gene', '673', (90, 94))	('TP53', 'Gene', '7157', (25, 29))	('reduced', 'NegReg', (61, 68))
89462	31984309	In contrast, IDH1 has 95.5% (63/66) mutation frequency in hypoxia score-low samples, while it only has 38.1% (32/84) in hypoxia score-high samples in LGG.	('hypoxia', 'Disease', (58, 65))	('hypoxia', 'Disease', 'MESH:D000860', (58, 65))	('hypoxia', 'Disease', 'MESH:D000860', (120, 127))	('hypoxia', 'Disease', (120, 127))	('IDH1', 'Gene', (13, 17))	('IDH1', 'Gene', '3417', (13, 17))	('mutation', 'Var', (36, 44))
89463	31984309	Mutation of IDH1 promotes the degradation of HIF1alpha, thus reducing the hypoxic effects in tumors and leading to better patient survival times (log-rank test, p = 2.6 x 10-13, Supplementary Fig.	('reducing', 'NegReg', (61, 69))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('IDH1', 'Gene', (12, 16))	('patient', 'Species', '9606', (122, 129))	('Mutation', 'Var', (0, 8))	('tumors', 'Disease', 'MESH:D009369', (93, 99))	('HIF1alpha', 'Gene', (45, 54))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('better', 'PosReg', (115, 121))	('degradation', 'MPA', (30, 41))	('IDH1', 'Gene', '3417', (12, 16))	('hypoxic', 'Disease', 'MESH:D000860', (74, 81))	('tumors', 'Disease', (93, 99))	('HIF1alpha', 'Gene', '3091', (45, 54))	('hypoxic', 'Disease', (74, 81))	('patient survival times', 'CPA', (122, 144))
89464	31984309	Hypoxia can induce transient site-specific copy number gains in tumor cells.	('gains', 'PosReg', (55, 60))	('Hypoxia', 'Disease', 'MESH:D000860', (0, 7))	('tumor', 'Disease', (64, 69))	('Hypoxia', 'Disease', (0, 7))	('copy number', 'Var', (43, 54))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
89470	31984309	Deletion of 2q37.3 (FDR = 4.2 x 10-3) occurred more frequently in hypoxia score-high samples.	('2q37.3', 'Gene', (12, 18))	('hypoxia', 'Disease', (66, 73))	('hypoxia', 'Disease', 'MESH:D000860', (66, 73))	('occurred', 'Reg', (38, 46))	('Deletion', 'Var', (0, 8))
89473	31984309	For example, 7q31.2 amplification, which harbors MET, occurred more frequently in hypoxia score-low KIRP (FDR = 5.3 x 10-3).	('7q31.2', 'Gene', (13, 19))	('hypoxia', 'Disease', (82, 89))	('hypoxia', 'Disease', 'MESH:D000860', (82, 89))	('occurred', 'Reg', (54, 62))	('amplification', 'Var', (20, 33))
89474	31984309	Deletion of 9p23, which harbors CDKN2A and CDKN2B, occurred more frequently in hypoxia score-low BRCA (FDR = 0.014).	('CDKN2A', 'Gene', (32, 38))	('CDKN2B', 'Gene', (43, 49))	('BRCA', 'Gene', '672', (97, 101))	('CDKN2B', 'Gene', '1030', (43, 49))	('CDKN2A', 'Gene', '1029', (32, 38))	('BRCA', 'Gene', (97, 101))	('hypoxia', 'Disease', (79, 86))	('hypoxia', 'Disease', 'MESH:D000860', (79, 86))	('occurred', 'Reg', (51, 59))	('Deletion', 'Var', (0, 8))
89478	31984309	For example, EGFR was biased in hypoxia score-high samples with overexpression of total proteins or phosphorylated proteins in eight cancer types (e.g., ESCA, diff = 0.54, FDR = 5.5 x 10-5; BLCA, diff = 0.42, FDR = 7.1 x 10-3), amplification in two cancer types (STAD, FDR = 0.022; LGG, FDR = 6.5 x 10-5) and hypomethylation in two cancer types (cervical squamous cell carcinoma and endocervical adenocarcinoma [CESC], diff = -0.29, FDR = 1.8 x 10-8; ESCA, diff = -0.24, FDR = 4.5 x 10-8).	('cervical squamous cell carcinoma', 'Disease', (346, 378))	('cervical squamous cell carcinoma', 'Disease', 'MESH:D002294', (346, 378))	('cancer type', 'Disease', (249, 260))	('EGFR', 'Gene', '1956', (13, 17))	('cancer', 'Phenotype', 'HP:0002664', (249, 255))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (355, 378))	('hypoxia', 'Disease', (32, 39))	('cancer type', 'Disease', 'MESH:D009369', (249, 260))	('endocervical adenocarcinoma', 'Disease', 'MESH:D000230', (383, 410))	('hypoxia', 'Disease', 'MESH:D000860', (32, 39))	('ESCA', 'Phenotype', 'HP:0011459', (153, 157))	('carcinoma', 'Phenotype', 'HP:0030731', (401, 410))	('EGFR', 'Gene', (13, 17))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('cancer', 'Phenotype', 'HP:0002664', (332, 338))	('cancer type', 'Disease', (133, 144))	('cancer type', 'Disease', (332, 343))	('carcinoma', 'Phenotype', 'HP:0030731', (369, 378))	('hypomethylation', 'Var', (309, 324))	('cancer type', 'Disease', 'MESH:D009369', (133, 144))	('cancer type', 'Disease', 'MESH:D009369', (332, 343))	('ESCA', 'Phenotype', 'HP:0011459', (451, 455))	('endocervical adenocarcinoma', 'Disease', (383, 410))
89506	31984309	These molecular alterations that are driven by the hypoxia microenvironment will likely impact a broad range of biological processes, including metabolic reprogramming, angiogenesis, apoptosis, and multiple signaling pathways.	('impact', 'Reg', (88, 94))	('angiogenesis', 'CPA', (169, 181))	('alterations', 'Var', (16, 27))	('metabolic reprogramming', 'CPA', (144, 167))	('hypoxia', 'Disease', (51, 58))	('hypoxia', 'Disease', 'MESH:D000860', (51, 58))	('apoptosis', 'CPA', (183, 192))
89532	31984309	We kept 24 cancer types with sample size >= 100, and filtered KIRC and COAD samples with relatively high mutation frequency in VHL (>= 5%) to avoid effects of pseudohypoxia in the tumors.	('mutation', 'Var', (105, 113))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('VHL', 'Disease', 'MESH:D006623', (127, 130))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('cancer type', 'Disease', (11, 22))	('VHL', 'Disease', (127, 130))	('tumors', 'Phenotype', 'HP:0002664', (180, 186))	('pseudohypoxia in the tumors', 'Disease', (159, 186))	('pseudohypoxia in the tumors', 'Disease', 'MESH:D009369', (159, 186))	('cancer type', 'Disease', 'MESH:D009369', (11, 22))
89547	31984309	A549 and H1299 were purchased from the American Type Culture Collection (ATCC) and Characterized Cell Line Core Facility (MD Anderson Cancer Center) and were cultured in DMEM supplemented with 10% FBS (Gibco) at 37  C in 5% CO2 (v/v).	('A549', 'CellLine', 'CVCL:0023', (0, 4))	('H1299', 'CellLine', 'CVCL:0060', (9, 14))	('Cancer', 'Phenotype', 'HP:0002664', (134, 140))	('MD Anderson Cancer Center', 'Disease', 'MESH:D009369', (122, 147))	('MD Anderson Cancer Center', 'Disease', (122, 147))	('CO2', 'Chemical', 'MESH:D002245', (224, 227))	('H1299', 'Var', (9, 14))
89548	31984309	AKT-inhibitor-VIII (612847-09-3) was purchased from Cayman Chemical; PHA-665752 (S1070), camptothecin (S1288) and bexarotene (S2098) were purchased from Selleckchem.	('AKT', 'Gene', (0, 3))	('camptothecin', 'Chemical', 'MESH:D002166', (89, 101))	('S2098', 'Chemical', 'MESH:C574489', (126, 131))	('S1070', 'Chemical', 'MESH:C104856', (81, 86))	('bexarotene', 'Chemical', 'MESH:C095105', (114, 124))	('S2098', 'Var', (126, 131))	('PHA-665752', 'Chemical', 'MESH:C480541', (69, 79))	('S1288', 'Chemical', 'MESH:D002117', (103, 108))	('AKT', 'Gene', '207', (0, 3))	('S1070', 'Var', (81, 86))	('S1288', 'Var', (103, 108))
89549	31984309	Plates were incubated in normoxic conditions (37 C, 5% CO2, 21% O2) or in hypoxic conditions (37 C, 5% CO2, 1% O2).	('O2', 'Chemical', 'MESH:D013481', (56, 58))	('O2', 'Chemical', 'MESH:D013481', (104, 106))	('hypoxic conditions', 'Disease', 'MESH:D009135', (74, 92))	('O2', 'Chemical', 'MESH:D013481', (111, 113))	('CO2', 'Chemical', 'MESH:D002245', (55, 58))	('O2', 'Chemical', 'MESH:D013481', (64, 66))	('CO2', 'Chemical', 'MESH:D002245', (103, 106))	('hypoxic conditions', 'Disease', (74, 92))	('37 C, 5% CO2', 'Var', (94, 106))
89560	30947633	Silencing of ENKUR in colorectal cancer cells led to enhanced cell proliferation, migration, and invasion, while the opposite effects were achieved in ENKUR-overexpressing cells.	('ENKUR', 'Gene', (13, 18))	('colorectal cancer', 'Disease', (22, 39))	('ENKUR', 'Gene', (151, 156))	('ENKUR', 'Gene', '219670', (151, 156))	('colorectal cancer', 'Disease', 'MESH:D015179', (22, 39))	('cell proliferation', 'CPA', (62, 80))	('migration', 'CPA', (82, 91))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('ENKUR', 'Gene', '219670', (13, 18))	('colorectal cancer', 'Phenotype', 'HP:0003003', (22, 39))	('Silencing', 'Var', (0, 9))	('invasion', 'CPA', (97, 105))	('enhanced', 'PosReg', (53, 61))
89577	30947633	We also investigated the effects of ENKUR overexpression and silencing on the cellular biological behavior of CRC cells and presented the first evidence of ENKUR involvement in the PI3K/Akt signaling pathway.	('involvement', 'Reg', (162, 173))	('Akt', 'Gene', '207', (186, 189))	('PI3', 'Gene', '5266', (181, 184))	('Akt', 'Gene', (186, 189))	('CRC', 'Phenotype', 'HP:0003003', (110, 113))	('ENKUR', 'Gene', '219670', (36, 41))	('ENKUR', 'Gene', '219670', (156, 161))	('silencing', 'Var', (61, 70))	('ENKUR', 'Gene', (156, 161))	('PI3', 'Gene', (181, 184))	('ENKUR', 'Gene', (36, 41))
89593	30947633	After blocking with 5% nonfat dry milk in Tris-buffered saline, the membranes were immunoblotted with the following antibodies: PI3K p85 (1:1000, #4292, Cell Signaling, Danvers, Massachusetts); phospho-PI3K p85 (Tyr458; 1:1000, #4228, Cell Signaling); Akt (1:1000, #9272, Cell Signaling); pAkt (Ser473; 1:2000, #4060, Cell Signaling); E-cadherin (1:500, #SAB4503751; Sigma Aldrich, St. Louis, Missouri); N-cadherin (1:5000, #SAB2702400; Sigma Aldrich); vimentin (1:200, #V6630; Sigma Aldrich); beta-ACTIN (1:5000, #A5441; Sigma Aldrich); and ENKUR (1:500, #SAB1103399; Sigma Aldrich).	('N-cadherin', 'Gene', '1000', (404, 414))	('Akt', 'Gene', (252, 255))	('PI3', 'Gene', '5266', (128, 131))	('PI3', 'Gene', (202, 205))	('1:5000', 'Var', (506, 512))	('Akt', 'Gene', '207', (252, 255))	('Ser473', 'Chemical', '-', (295, 301))	('Akt', 'Gene', (290, 293))	('p85', 'Gene', '5296', (207, 210))	('Tyr458', 'Chemical', '-', (212, 218))	('1:5000', 'Var', (416, 422))	('ENKUR', 'Gene', (542, 547))	('vimentin', 'Gene', '7431', (453, 461))	('PI3', 'Gene', (128, 131))	('vimentin', 'Gene', (453, 461))	('Akt', 'Gene', '207', (290, 293))	('ENKUR', 'Gene', '219670', (542, 547))	('E-cadherin', 'Gene', (335, 345))	('E-cadherin', 'Gene', '999', (335, 345))	('1:200', 'Var', (463, 468))	('p85', 'Gene', '5296', (133, 136))	('p85', 'Gene', (207, 210))	('beta-ACTIN', 'Gene', '728378', (494, 504))	('PI3', 'Gene', '5266', (202, 205))	('beta-ACTIN', 'Gene', (494, 504))	('p85', 'Gene', (133, 136))	('N-cadherin', 'Gene', (404, 414))
89624	30947633	Among the 6 cell lines, ENKUR expression was the highest in LS174T cells and the lowest in SW620 cells (Figure 3).	('SW620', 'CellLine', 'CVCL:0547', (91, 96))	('expression', 'MPA', (30, 40))	('ENKUR', 'Gene', (24, 29))	('highest', 'Reg', (49, 56))	('ENKUR', 'Gene', '219670', (24, 29))	('LS174T', 'Var', (60, 66))
89627	30947633	A considerable reduction of ENKUR expression was achieved in LS174T and SW620 cells after transduction (P < .005; Figure 4B).	('expression', 'MPA', (34, 44))	('ENKUR', 'Gene', (28, 33))	('reduction', 'NegReg', (15, 24))	('ENKUR', 'Gene', '219670', (28, 33))	('SW620', 'CellLine', 'CVCL:0547', (72, 77))	('LS174T', 'Var', (61, 67))
89628	30947633	Silencing of ENKUR in CRC cell lines provoked accelerated cell growth and stronger migratory ability.	('ENKUR', 'Gene', (13, 18))	('accelerated', 'PosReg', (46, 57))	('ENKUR', 'Gene', '219670', (13, 18))	('CRC', 'Phenotype', 'HP:0003003', (22, 25))	('migratory ability', 'CPA', (83, 100))	('cell growth', 'CPA', (58, 69))	('Silencing', 'Var', (0, 9))	('stronger', 'PosReg', (74, 82))
89639	30947633	Western blot analyses showed that silencing of ENKUR led to a remarkably decreased level of E-cadherin and increased level of N-cadherin and the intermediate filament vimentin.	('N-cadherin', 'Gene', (126, 136))	('decreased', 'NegReg', (73, 82))	('E-cadherin', 'Gene', (92, 102))	('increased', 'PosReg', (107, 116))	('E-cadherin', 'Gene', '999', (92, 102))	('N-cadherin', 'Gene', '1000', (126, 136))	('ENKUR', 'Gene', '219670', (47, 52))	('vimentin', 'Gene', '7431', (167, 175))	('vimentin', 'Gene', (167, 175))	('silencing', 'Var', (34, 43))	('ENKUR', 'Gene', (47, 52))
89641	30947633	In addition, silencing of ENKUR induced noninvasive epithelial cells to acquire a mesenchymal, spindle cell phenotype, suggestive of EMT (Figure 7B).	('acquire', 'PosReg', (72, 79))	('ENKUR', 'Gene', (26, 31))	('ENKUR', 'Gene', '219670', (26, 31))	('silencing', 'Var', (13, 22))
89656	30947633	Here, we showed that ENKUR mRNA expression and ENKUR protein level were downregulated in 6 CRC cell lines, HT29, HCT116, SW620, LS174T, RKO, and LOVO, as compared with the normal human colon mucosal epithelial cell line NCM460 (Figure 3).	('HT29', 'CellLine', 'CVCL:0320', (107, 111))	('human', 'Species', '9606', (179, 184))	('HCT116', 'CellLine', 'CVCL:0291', (113, 119))	('ENKUR', 'Gene', (21, 26))	('RKO', 'CellLine', 'CVCL:0504', (136, 139))	('ENKUR', 'Gene', '219670', (47, 52))	('LS174T', 'Var', (128, 134))	('colon mucosal epithelial', 'Disease', (185, 209))	('colon mucosal epithelial', 'Disease', 'MESH:D052016', (185, 209))	('SW620', 'CellLine', 'CVCL:0547', (121, 126))	('downregulated', 'NegReg', (72, 85))	('CRC', 'Phenotype', 'HP:0003003', (91, 94))	('ENKUR', 'Gene', '219670', (21, 26))	('SW620', 'Var', (121, 126))	('ENKUR', 'Gene', (47, 52))
89657	30947633	In addition, silencing of ENKUR promoted CRC cell proliferation, migration, and invasion, while overexpression of ENKUR led to the opposite effects (Figures 5 and 6).	('promoted', 'PosReg', (32, 40))	('migration', 'CPA', (65, 74))	('invasion', 'CPA', (80, 88))	('CRC cell proliferation', 'CPA', (41, 63))	('ENKUR', 'Gene', '219670', (114, 119))	('CRC', 'Phenotype', 'HP:0003003', (41, 44))	('ENKUR', 'Gene', (114, 119))	('ENKUR', 'Gene', '219670', (26, 31))	('ENKUR', 'Gene', (26, 31))	('silencing', 'Var', (13, 22))
89659	30947633	The pivotal role of PI3K/Akt signaling pathway in CRC has long been well established and inhibitors of PI3K/Akt signaling have been suggested as potential therapeutic agents of CRC.	('CRC', 'Disease', (177, 180))	('PI3', 'Gene', (103, 106))	('Akt', 'Gene', (108, 111))	('CRC', 'Disease', (50, 53))	('inhibitors', 'Var', (89, 99))	('PI3', 'Gene', '5266', (20, 23))	('Akt', 'Gene', '207', (25, 28))	('PI3', 'Gene', '5266', (103, 106))	('CRC', 'Phenotype', 'HP:0003003', (177, 180))	('Akt', 'Gene', '207', (108, 111))	('CRC', 'Phenotype', 'HP:0003003', (50, 53))	('Akt', 'Gene', (25, 28))	('PI3', 'Gene', (20, 23))
89660	30947633	Under normal conditions, PI3K/Akt activation is tightly controlled and dependent on extracellular and intracellular growth signals, which are the fundamental premises for proper cell function, while genetic aberrations can cause PI3K/Akt hyperactivation that ultimately leads to reduced apoptosis and enhanced cell growth.	('cell growth', 'CPA', (310, 321))	('apoptosis', 'CPA', (287, 296))	('reduced', 'NegReg', (279, 286))	('Akt', 'Gene', '207', (30, 33))	('PI3', 'Gene', (229, 232))	('hyperactivation', 'PosReg', (238, 253))	('PI3', 'Gene', '5266', (25, 28))	('Akt', 'Gene', '207', (234, 237))	('Akt', 'Gene', (30, 33))	('genetic aberrations', 'Var', (199, 218))	('PI3', 'Gene', '5266', (229, 232))	('Akt', 'Gene', (234, 237))	('PI3', 'Gene', (25, 28))	('enhanced', 'PosReg', (301, 309))
89661	30947633	Studies have shown that inactivating PI3K phosphorylation (Tyr458) reduced the expression of pAkt (Ser473), while activation of both PI3K and Akt phosphorylation contributes to cell growth and cancer metastasis.	('Akt', 'Gene', (142, 145))	('PI3', 'Gene', '5266', (37, 40))	('PI3', 'Gene', '5266', (133, 136))	('expression', 'MPA', (79, 89))	('Akt', 'Gene', (94, 97))	('cell growth', 'CPA', (177, 188))	('Tyr458', 'Var', (59, 65))	('reduced', 'NegReg', (67, 74))	('PI3', 'Gene', (37, 40))	('Ser473', 'Chemical', '-', (99, 105))	('PI3', 'Gene', (133, 136))	('cancer metastasis', 'Disease', (193, 210))	('Akt', 'Gene', '207', (94, 97))	('Akt', 'Gene', '207', (142, 145))	('Tyr458', 'Chemical', '-', (59, 65))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('cancer metastasis', 'Disease', 'MESH:D009362', (193, 210))	('inactivating', 'Var', (24, 36))
89662	30947633	In this study, we also investigated changes in the activation of PI3K/Akt signaling pathway after ENKUR overexpression or silencing.	('Akt', 'Gene', (70, 73))	('ENKUR', 'Gene', '219670', (98, 103))	('PI3', 'Gene', '5266', (65, 68))	('Akt', 'Gene', '207', (70, 73))	('silencing', 'Var', (122, 131))	('ENKUR', 'Gene', (98, 103))	('activation', 'PosReg', (51, 61))	('PI3', 'Gene', (65, 68))
89666	30947633	Our results also demonstrated that silencing of ENKUR expression in CRC cells leads to decreased level of E-cadherin and increased level of N-cadherin and vimentin accompanied with changes in cell phenotype, suggesting possible induction of EMT (Figure 7).	('N-cadherin', 'Gene', (140, 150))	('CRC', 'Phenotype', 'HP:0003003', (68, 71))	('vimentin', 'Gene', (155, 163))	('silencing', 'Var', (35, 44))	('ENKUR', 'Gene', (48, 53))	('cell', 'MPA', (192, 196))	('decreased', 'NegReg', (87, 96))	('increased', 'PosReg', (121, 130))	('N-cadherin', 'Gene', '1000', (140, 150))	('changes', 'Reg', (181, 188))	('E-cadherin', 'Gene', (106, 116))	('E-cadherin', 'Gene', '999', (106, 116))	('ENKUR', 'Gene', '219670', (48, 53))	('EMT', 'CPA', (241, 244))	('vimentin', 'Gene', '7431', (155, 163))
89667	30947633	Since the PI3K/Akt signaling pathway can affect EMT in a variety of ways to influence tumor aggressiveness, silencing of ENKUR may cause an invasion-promoting effect on CRC cells through abnormal activation of PI3K/Akt signaling.	('PI3', 'Gene', '5266', (10, 13))	('Akt', 'Gene', (15, 18))	('PI3', 'Gene', (210, 213))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (86, 106))	('Akt', 'Gene', '207', (15, 18))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('CRC', 'Disease', (169, 172))	('CRC', 'Phenotype', 'HP:0003003', (169, 172))	('PI3', 'Gene', (10, 13))	('silencing', 'Var', (108, 117))	('ENKUR', 'Gene', (121, 126))	('affect', 'Reg', (41, 47))	('influence', 'Reg', (76, 85))	('ENKUR', 'Gene', '219670', (121, 126))	('tumor aggressiveness', 'Disease', (86, 106))	('aggressiveness', 'Phenotype', 'HP:0000718', (92, 106))	('invasion-promoting effect', 'CPA', (140, 165))	('PI3', 'Gene', '5266', (210, 213))	('Akt', 'Gene', (215, 218))	('activation', 'PosReg', (196, 206))	('Akt', 'Gene', '207', (215, 218))
89675	30947633	We propose that ENKUR is downregulated in CRC and silencing of ENKUR promotes CRC cell proliferation, invasion, and migration through possible involvement in the PI3K/Akt signaling pathway.	('PI3', 'Gene', (162, 165))	('ENKUR', 'Gene', (63, 68))	('Akt', 'Gene', '207', (167, 170))	('CRC', 'Phenotype', 'HP:0003003', (42, 45))	('invasion', 'CPA', (102, 110))	('silencing', 'Var', (50, 59))	('promotes', 'PosReg', (69, 77))	('ENKUR', 'Gene', '219670', (16, 21))	('ENKUR', 'Gene', '219670', (63, 68))	('CRC', 'Disease', (78, 81))	('ENKUR', 'Gene', (16, 21))	('involvement', 'Reg', (143, 154))	('migration', 'CPA', (116, 125))	('PI3', 'Gene', '5266', (162, 165))	('Akt', 'Gene', (167, 170))	('CRC', 'Phenotype', 'HP:0003003', (78, 81))
89677	30947633	Future molecular studies of the genetic basis underlying aberrant ENKUR expression and identification of direct targets of ENKUR will help unravel the intrinsic mechanism of ENKUR-mediated carcinostatic effect and develop novel gene therapies for patients with CRC.	('ENKUR', 'Gene', (174, 179))	('ENKUR', 'Gene', '219670', (66, 71))	('ENKUR', 'Gene', (123, 128))	('CRC', 'Phenotype', 'HP:0003003', (261, 264))	('ENKUR', 'Gene', (66, 71))	('patients', 'Species', '9606', (247, 255))	('ENKUR', 'Gene', '219670', (123, 128))	('ENKUR', 'Gene', '219670', (174, 179))	('CRC', 'Disease', (261, 264))	('aberrant', 'Var', (57, 65))
89680	30405781	The objective of the present study was to evaluate aberrant expression of GSK-3beta as a potential biomarker in human breast and head and neck cancers.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('head and neck cancers', 'Phenotype', 'HP:0012288', (129, 150))	('neck cancers', 'Disease', (138, 150))	('neck cancers', 'Disease', 'MESH:D006258', (138, 150))	('aberrant expression', 'Var', (51, 70))	('GSK-3beta', 'Gene', (74, 83))	('breast', 'Disease', (118, 124))	('cancers', 'Phenotype', 'HP:0002664', (143, 150))	('head and neck cancer', 'Phenotype', 'HP:0012288', (129, 149))	('human', 'Species', '9606', (112, 117))
89685	30405781	These results support the hypothesis that aberrant nuclear GSK-3beta may represent a potential target for the clinical treatment of human breast and squamous cell carcinoma.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (149, 172))	('carcinoma', 'Phenotype', 'HP:0030731', (163, 172))	('aberrant', 'Var', (42, 50))	('human', 'Species', '9606', (132, 137))	('breast and squamous cell carcinoma', 'Disease', 'MESH:D002294', (138, 172))	('nuclear GSK-3beta', 'Protein', (51, 68))
89692	30405781	Disruption of the GSK-3beta gene in mice resulted in embryonic lethality due to hepatocyte apoptosis copying the mouse phenotype produced by a deletion of genes involved in NF-kappaB activation.	('GSK-3beta', 'Gene', (18, 27))	('hepatocyte apoptosis', 'CPA', (80, 100))	('deletion', 'Var', (143, 151))	('mice', 'Species', '10090', (36, 40))	('embryonic lethality', 'Disease', 'MESH:D020964', (53, 72))	('embryonic lethality', 'Disease', (53, 72))	('mouse', 'Species', '10090', (113, 118))	('Disruption', 'Var', (0, 10))
89695	30405781	It has been demonstrated that only the active form of GSK-3beta accumulates in the nucleus of pancreatic cancer cells and the inhibition of GSK-3beta activity depletes this nuclear pool via proteosomal degradation whereas the expression level of cytoplasmic GSK-3beta is not changed.	('proteosomal', 'MPA', (190, 201))	('inhibition', 'Var', (126, 136))	('pancreatic cancer', 'Disease', (94, 111))	('pancreatic cancer', 'Disease', 'MESH:D010190', (94, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (94, 111))	('depletes', 'NegReg', (159, 167))	('GSK-3beta', 'Gene', (140, 149))	('activity', 'MPA', (150, 158))
89697	30405781	Here, our results have identified aberrant nuclear GSK-3beta expression as a potential biomarker for breast and squamous cell carcinomas of the head and neck.	('breast and squamous cell carcinomas', 'Disease', 'MESH:D002294', (101, 136))	('aberrant', 'Var', (34, 42))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (112, 136))	('nuclear GSK-3beta', 'Protein', (43, 60))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (112, 135))	('carcinomas of the head and neck', 'Phenotype', 'HP:0012288', (126, 157))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('carcinomas', 'Phenotype', 'HP:0030731', (126, 136))
89712	30405781	Of 128 breast carcinomas analyzed, 89 (70%) showed aberrant nuclear expression of GSK-3beta (Table I, Figs.	('carcinomas', 'Phenotype', 'HP:0030731', (14, 24))	('aberrant', 'Var', (51, 59))	('nuclear expression', 'MPA', (60, 78))	('breast carcinomas', 'Disease', 'MESH:D001943', (7, 24))	('breast carcinomas', 'Disease', (7, 24))	('breast carcinoma', 'Phenotype', 'HP:0003002', (7, 23))	('GSK-3beta', 'Protein', (82, 91))	('breast carcinomas', 'Phenotype', 'HP:0003002', (7, 24))	('carcinoma', 'Phenotype', 'HP:0030731', (14, 23))
89719	30405781	Our results suggest that aberrant nuclear accumulation of GSK-3beta is a feature of breast cancer cells and therefore might serve as a potential biomarker in human breast cancer.	('breast cancer', 'Phenotype', 'HP:0003002', (84, 97))	('human', 'Species', '9606', (158, 163))	('GSK-3beta', 'Protein', (58, 67))	('aberrant', 'Var', (25, 33))	('breast cancer', 'Disease', 'MESH:D001943', (164, 177))	('breast cancer', 'Phenotype', 'HP:0003002', (164, 177))	('breast cancer', 'Disease', (164, 177))	('breast cancer', 'Disease', 'MESH:D001943', (84, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('nuclear accumulation', 'MPA', (34, 54))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('breast cancer', 'Disease', (84, 97))
89727	30405781	It also has been shown that only the active form of GSK-3beta accumulates in the nucleus of pancreatic cancer cells and the inhibition of GSK-3beta activity depletes its nuclear accumulation via proteosomal degradation.	('depletes', 'NegReg', (157, 165))	('GSK-3beta', 'Gene', (138, 147))	('nuclear accumulation', 'MPA', (170, 190))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('inhibition', 'Var', (124, 134))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (92, 109))	('proteosomal degradation', 'MPA', (195, 218))	('activity', 'MPA', (148, 156))	('pancreatic cancer', 'Disease', (92, 109))	('pancreatic cancer', 'Disease', 'MESH:D010190', (92, 109))
89743	30405781	This is the first exploratory IHC study to evaluate aberrant GSK-3beta expression in head and neck tumors.	('expression', 'MPA', (71, 81))	('neck tumors', 'Disease', (94, 105))	('head and neck tumors', 'Phenotype', 'HP:0012288', (85, 105))	('GSK-3beta', 'Gene', (61, 70))	('aberrant', 'Var', (52, 60))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('neck tumors', 'Disease', 'MESH:D006258', (94, 105))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))
89745	30405781	One of our translational goals was to evaluate aberrant GSK-3beta expression in breast and head and neck tumors as a potential biomarker for selection of cancer patients for clinical trials of GSK-3 inhibitors.	('aberrant', 'Var', (47, 55))	('head and neck tumors', 'Phenotype', 'HP:0012288', (91, 111))	('neck tumors', 'Disease', (100, 111))	('GSK-3beta', 'Gene', (56, 65))	('breast', 'Disease', (80, 86))	('cancer', 'Disease', (154, 160))	('expression', 'MPA', (66, 76))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('patients', 'Species', '9606', (161, 169))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('neck tumors', 'Disease', 'MESH:D006258', (100, 111))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))
89746	30405781	To the best of our knowledge, our study is the first to demonstrate aberrant nuclear expression of GSK-3beta as a specific marker of cancer cells in breast adenocarcinoma and malignant head and neck tumors (squamous cell and adenoid cystic carcinomas).	('breast adenocarcinoma', 'Phenotype', 'HP:0003002', (149, 170))	('tumors', 'Phenotype', 'HP:0002664', (199, 205))	('nuclear expression', 'MPA', (77, 95))	('carcinomas', 'Phenotype', 'HP:0030731', (240, 250))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (240, 249))	('cancer', 'Disease', (133, 139))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('head and neck tumors', 'Phenotype', 'HP:0012288', (185, 205))	('adenoid cystic carcinomas', 'Disease', (225, 250))	('GSK-3beta', 'Gene', (99, 108))	('carcinoma', 'Phenotype', 'HP:0030731', (161, 170))	('breast adenocarcinoma and malignant head and neck tumors', 'Disease', 'MESH:D001943', (149, 205))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('aberrant', 'Var', (68, 76))	('adenoid cystic carcinomas', 'Disease', 'MESH:D003528', (225, 250))
89755	30405781	Our results are consistent with another published study showing aberrant nuclear GSK-3beta as a specific marker of pancreatic cancer cells whereas nuclear GSK-3beta was not detectable in acinar or epithelial pancreatic cells or in PanIN (pancreatic intraepithelial neoplasia) lesions.	('epithelial pancreatic', 'Disease', 'MESH:D010195', (197, 218))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (115, 132))	('epithelial pancreatic', 'Disease', (197, 218))	('neoplasia', 'Phenotype', 'HP:0002664', (265, 274))	('pancreatic cancer', 'Disease', (115, 132))	('intraepithelial neoplasia', 'Phenotype', 'HP:0032187', (249, 274))	('pancreatic cancer', 'Disease', 'MESH:D010190', (115, 132))	('pancreatic intraepithelial neoplasia', 'Disease', 'MESH:D018290', (238, 274))	('pancreatic intraepithelial neoplasia', 'Disease', (238, 274))	('PanIN', 'Disease', (231, 236))	('aberrant', 'Var', (64, 72))	('nuclear GSK-3beta', 'Protein', (73, 90))
89757	30405781	It has been shown that only the active form of GSK-3beta accumulates in the nucleus of pancreatic cancer cells and the inhibition of GSK-3beta activity depletes its nuclear accumulation via proteosomal degradation whereas the expression level of cytoplasmic GSK-3beta is not changed.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('depletes', 'NegReg', (152, 160))	('pancreatic cancer', 'Disease', (87, 104))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (87, 104))	('pancreatic cancer', 'Disease', 'MESH:D010190', (87, 104))	('inhibition', 'Var', (119, 129))	('GSK-3beta', 'Gene', (133, 142))	('nuclear accumulation', 'MPA', (165, 185))	('activity', 'MPA', (143, 151))
89773	30210633	Also, the negative predictive value of a negative 18F-FDG PET/CT combined with normal SCC Ag and CEA levels was 100%.	('SCC Ag and CEA', 'Gene', '1048', (86, 100))	('18F-FDG', 'Chemical', 'MESH:D019788', (50, 57))	('18F-FDG', 'Var', (50, 57))	('negative', 'NegReg', (41, 49))
89797	30210633	In this study, we evaluated the clinical value of combining 18F-FDG PET/CT and routine serum tumor markers in the early detection of recurrence among follow-up patients treated for cervical squamous cell carcinoma.	('patients', 'Species', '9606', (160, 168))	('18F-FDG', 'Chemical', 'MESH:D019788', (60, 67))	('carcinoma', 'Phenotype', 'HP:0030731', (204, 213))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('cervical squamous cell carcinoma', 'Disease', (181, 213))	('tumor', 'Disease', (93, 98))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (190, 213))	('18F-FDG', 'Var', (60, 67))	('cervical squamous cell carcinoma', 'Disease', 'MESH:D002294', (181, 213))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
89812	30210633	A region was defined as malignant if the focal uptake of 18F-FDG was higher (SUVmax >=2.5) than the surrounding tissue and were not associated with physiological uptake.	('18F-FDG', 'Var', (57, 64))	('18F-FDG', 'Chemical', 'MESH:D019788', (57, 64))	('focal uptake', 'MPA', (41, 53))	('higher', 'PosReg', (69, 75))
89846	30210633	Previous studies have reported the clinical value of 18F-FDG PET and 18F-FDG PET/CT to detect recurrence in patients treated for cervical cancer.	('18F-FDG', 'Chemical', 'MESH:D019788', (53, 60))	('18F-FDG', 'Var', (69, 76))	('cervical cancer', 'Disease', (129, 144))	('cervical cancer', 'Disease', 'MESH:D002583', (129, 144))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('18F-FDG', 'Chemical', 'MESH:D019788', (69, 76))	('patients', 'Species', '9606', (108, 116))
89853	30210633	However, no such correlation was observed with CEA levels suggesting that cervical cancer recurrence with normal CEA levels would be demonstrated with 18F-FDG PET/CT or elevated CEA levels might be associated with negative 18F-FDG PET/CT.	('cervical cancer', 'Disease', (74, 89))	('cervical cancer', 'Disease', 'MESH:D002583', (74, 89))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('CEA', 'Gene', '1048', (113, 116))	('18F-FDG', 'Chemical', 'MESH:D019788', (151, 158))	('elevated CEA', 'Phenotype', 'HP:0031029', (169, 181))	('CEA', 'Gene', (113, 116))	('18F-FDG', 'Chemical', 'MESH:D019788', (223, 230))	('CEA', 'Gene', (47, 50))	('CEA', 'Gene', (178, 181))	('CEA', 'Gene', '1048', (47, 50))	('CEA', 'Gene', '1048', (178, 181))	('18F-FDG PET/CT', 'Var', (151, 165))
89857	30210633	In a comparative study between 18F-FDG PET and CT/MRI, it was reported that 18F-FDG PET was superior to CT in detecting small metastatic lymph nodes, whose principle is based on increased glycolysis levels in tumor cells.	('tumor', 'Disease', (209, 214))	('glycolysis levels', 'MPA', (188, 205))	('18F-FDG', 'Chemical', 'MESH:D019788', (31, 38))	('small metastatic lymph nodes', 'CPA', (120, 148))	('tumor', 'Disease', 'MESH:D009369', (209, 214))	('small metastatic lymph nodes', 'Phenotype', 'HP:0002732', (120, 148))	('18F-FDG PET', 'Var', (76, 87))	('18F-FDG', 'Chemical', 'MESH:D019788', (76, 83))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))	('increased', 'PosReg', (178, 187))
89865	30210633	evaluated the clinical usefulness of 18F-FDG PET/CT in the detection of early recurrence in treated cervical cancer patients with unexplained elevation of serum tumor markers and the authors reported a similar finding that 18F-FDG PET/CT combined with elevated SCC Ag levels is more accurate than 18F-FDG PET/CT combined with elevated CEA levels which is supported by no correlation between these tumor markers.	('18F-FDG', 'Chemical', 'MESH:D019788', (37, 44))	('tumor', 'Phenotype', 'HP:0002664', (397, 402))	('tumor', 'Disease', (161, 166))	('patients', 'Species', '9606', (116, 124))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('CEA', 'Gene', (335, 338))	('cervical cancer', 'Disease', (100, 115))	('cervical cancer', 'Disease', 'MESH:D002583', (100, 115))	('18F-FDG', 'Chemical', 'MESH:D019788', (223, 230))	('tumor', 'Disease', (397, 402))	('SCC', 'Gene', '6317', (261, 264))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('18F-FDG PET/CT', 'Var', (223, 237))	('tumor', 'Disease', 'MESH:D009369', (397, 402))	('SCC', 'Gene', (261, 264))	('CEA', 'Gene', '1048', (335, 338))	('elevated CEA', 'Phenotype', 'HP:0031029', (326, 338))	('18F-FDG', 'Chemical', 'MESH:D019788', (297, 304))
89882	29511369	However, cell viability and plate colony formation assays showed that both CLDN3 knockdown and overexpression did not affect SqCC cell proliferation.	('CLDN3', 'Gene', (75, 80))	('colon', 'Disease', (34, 39))	('CLDN3', 'Gene', '1365', (75, 80))	('knockdown', 'Var', (81, 90))	('colon', 'Disease', 'MESH:D015179', (34, 39))
89901	29511369	In addition, aberrant CLDN3 expression has been associated with the development and metastasis of various human cancers, but the data are controversial; for example, CLDN3 protein is overexpressed in ovarian, breast, and prostate cancers as well as in esophageal AC.	('human', 'Species', '9606', (106, 111))	('CLDN3', 'Gene', '1365', (22, 27))	('associated', 'Reg', (48, 58))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('CLDN3', 'Gene', (22, 27))	('cancers', 'Phenotype', 'HP:0002664', (112, 119))	('cancers', 'Phenotype', 'HP:0002664', (230, 237))	('prostate cancers', 'Disease', 'MESH:D011471', (221, 237))	('cancers', 'Disease', (112, 119))	('cancers', 'Disease', (230, 237))	('aberrant', 'Var', (13, 21))	('protein', 'Protein', (172, 179))	('breast', 'Disease', (209, 215))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('ovarian', 'Disease', (200, 207))	('overexpressed', 'PosReg', (183, 196))	('prostate cancer', 'Phenotype', 'HP:0012125', (221, 236))	('prostate cancers', 'Phenotype', 'HP:0012125', (221, 237))	('esophageal AC', 'Disease', (252, 265))	('prostate cancers', 'Disease', (221, 237))	('CLDN3', 'Gene', '1365', (166, 171))	('cancers', 'Disease', 'MESH:D009369', (112, 119))	('cancers', 'Disease', 'MESH:D009369', (230, 237))	('CLDN3', 'Gene', (166, 171))
89903	29511369	In lung AC, CLDN3 expression increases the malignant potential of lung AC cells, indicating that CLDN3 plays a role in epidermal growth factor receptor activation.	('malignant potential of', 'CPA', (43, 65))	('epidermal growth factor receptor', 'Gene', (119, 151))	('lung', 'Disease', (3, 7))	('CLDN3', 'Gene', '1365', (97, 102))	('CLDN3', 'Gene', '1365', (12, 17))	('epidermal growth factor receptor', 'Gene', '1956', (119, 151))	('increases', 'PosReg', (29, 38))	('CLDN3', 'Gene', (97, 102))	('expression', 'Var', (18, 28))	('CLDN3', 'Gene', (12, 17))
89934	29511369	NSCLC cells after CLDN3 cDNA or shRNA, or negative viral control infections (H520-PCDH, H520-PCDH-CLDN3, SK-MES-1-control, and SK-MES-1-shRNA) were seeded into a 6-well plate and grown overnight.	('NSCLC', 'Disease', 'MESH:D002289', (0, 5))	('CLDN3', 'Gene', '1365', (18, 23))	('SK-MES-1', 'CellLine', 'CVCL:0630', (105, 113))	('CLDN3', 'Gene', '1365', (98, 103))	('CLDN3', 'Gene', (18, 23))	('infection', 'Disease', (65, 74))	('infection', 'Disease', 'MESH:D007239', (65, 74))	('SK-MES-1', 'CellLine', 'CVCL:0630', (127, 135))	('H520-PCDH', 'Var', (77, 86))	('NSCLC', 'Disease', (0, 5))	('CLDN3', 'Gene', (98, 103))
89961	29511369	Our western blot data confirmed CLDN3 knockdown and overexpression in these two cell lines, respectively (Fig.	('CLDN3', 'Gene', (32, 37))	('overexpression', 'PosReg', (52, 66))	('knockdown', 'Var', (38, 47))	('CLDN3', 'Gene', '1365', (32, 37))
89967	29511369	In contrast, knockdown of CLDN3 expression in SK-MES-1 cells had an inverse effect on the expression of E-cadherin and Vimentin (Fig.	('CLDN3', 'Gene', (26, 31))	('SK-MES-1', 'CellLine', 'CVCL:0630', (46, 54))	('Vimentin', 'Gene', '7431', (119, 127))	('CLDN3', 'Gene', '1365', (26, 31))	('expression', 'MPA', (90, 100))	('Vimentin', 'Gene', (119, 127))	('knockdown', 'Var', (13, 22))	('E-cadherin', 'Gene', (104, 114))	('E-cadherin', 'Gene', '999', (104, 114))
89971	29511369	Our results showed that knockdown of CLDN3 expression upregulated the expression of c-Myc and cyclinD1 but downregulated the expression of beta-catenin, indicating that the Wnt/beta-catenin pathway was activated.	('upregulated', 'PosReg', (54, 65))	('beta-catenin', 'Gene', '1499', (177, 189))	('cyclinD1', 'Gene', (94, 102))	('CLDN3', 'Gene', '1365', (37, 42))	('c-Myc', 'Gene', '4609', (84, 89))	('beta-catenin', 'Gene', (139, 151))	('expression', 'MPA', (125, 135))	('expression', 'MPA', (70, 80))	('beta-catenin', 'Gene', (177, 189))	('c-Myc', 'Gene', (84, 89))	('downregulated', 'NegReg', (107, 120))	('cyclinD1', 'Gene', '595', (94, 102))	('beta-catenin', 'Gene', '1499', (139, 151))	('knockdown', 'Var', (24, 33))	('CLDN3', 'Gene', (37, 42))
89974	29511369	Together with the phenotypic data presented in the previous sections, this study demonstrated that CLDN3 was able to inactivate the Wnt/beta-catenin pathway, in turn suppressing lung SqCC cell EMT; whereas CLDN3 knockdown promoted activation of the Wnt/beta-catenin pathway proteins and enhanced lung SqCC cell EMT.	('suppressing', 'NegReg', (166, 177))	('beta-catenin', 'Gene', '1499', (136, 148))	('lung SqCC cell EMT', 'CPA', (178, 196))	('CLDN3', 'Gene', (99, 104))	('CLDN3', 'Gene', '1365', (206, 211))	('lung SqCC cell EMT', 'CPA', (296, 314))	('activation', 'PosReg', (231, 241))	('CLDN3', 'Gene', (206, 211))	('knockdown', 'Var', (212, 221))	('CLDN3', 'Gene', '1365', (99, 104))	('inactivate', 'NegReg', (117, 127))	('beta-catenin', 'Gene', (253, 265))	('beta-catenin', 'Gene', '1499', (253, 265))	('beta-catenin', 'Gene', (136, 148))	('enhanced', 'PosReg', (287, 295))
89978	29511369	Overexpression of CLDN3 inhibited H520 wound healing and the Transwell migration capacity; whereas knockdown of CLDN3 expression promoted SK-MES-1 cell wound healing and the Transwell migration capacity.	('SK-MES-1', 'CellLine', 'CVCL:0630', (138, 146))	('Transwell migration capacity', 'CPA', (174, 202))	('promoted', 'PosReg', (129, 137))	('CLDN3', 'Gene', '1365', (112, 117))	('CLDN3', 'Gene', (18, 23))	('H520 wound healing', 'CPA', (34, 52))	('inhibited', 'NegReg', (24, 33))	('knockdown', 'Var', (99, 108))	('Transwell migration capacity', 'CPA', (61, 89))	('CLDN3', 'Gene', '1365', (18, 23))	('SK-MES-1 cell wound healing', 'CPA', (138, 165))	('CLDN3', 'Gene', (112, 117))
89985	29511369	Aberrant CLDN3 expression has been associated with the development and metastasis of human cancers.	('metastasis of human cancers', 'Disease', (71, 98))	('CLDN3', 'Gene', '1365', (9, 14))	('cancers', 'Phenotype', 'HP:0002664', (91, 98))	('Aberrant', 'Var', (0, 8))	('associated', 'Reg', (35, 45))	('development', 'CPA', (55, 66))	('metastasis of human cancers', 'Disease', 'MESH:D009362', (71, 98))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('CLDN3', 'Gene', (9, 14))
89987	29511369	However, another study has reported that the CLDN expression pattern is significantly different not only between lung SqCC and lung AC but also between lung SqCC and lung AC with lepidic variants and that CLDN3 expression is higher in lung AC but not in lung SqCC.	('CLDN3', 'Gene', (205, 210))	('higher', 'PosReg', (225, 231))	('CLDN', 'Gene', (45, 49))	('lung AC', 'Disease', (235, 242))	('lung AC', 'Disease', (127, 134))	('CLDN3', 'Gene', '1365', (205, 210))	('lung SqCC', 'Disease', (113, 122))	('variants', 'Var', (187, 195))	('different', 'Reg', (86, 95))	('expression', 'MPA', (211, 221))	('expression', 'MPA', (50, 60))
89989	29511369	Indeed, our current data further support these previous studies and indicate that CLDN3 expression is organ-specific and that loss of CLDN3 expression is associated with lung SqCC development and progression.	('CLDN3', 'Gene', (82, 87))	('CLDN3', 'Gene', (134, 139))	('CLDN3', 'Gene', '1365', (82, 87))	('CLDN3', 'Gene', '1365', (134, 139))	('progression', 'CPA', (196, 207))	('loss', 'Var', (126, 130))	('associated', 'Reg', (154, 164))	('lung SqCC', 'Disease', (170, 179))
89996	29511369	Functionally, loss of CLDN3 expression downregulated the mRNA and protein levels of E-cadherin but induced the inhibitory phosphorylation of glycogen synthase kinase-3beta and activation of the beta-catenin signaling pathway, all of which are associated with tumor cell EMT.	('E-cadherin', 'Gene', (84, 94))	('CLDN3', 'Gene', (22, 27))	('loss', 'Var', (14, 18))	('glycogen synthase kinase-3beta', 'Gene', (141, 171))	('E-cadherin', 'Gene', '999', (84, 94))	('CLDN3', 'Gene', '1365', (22, 27))	('tumor', 'Disease', 'MESH:D009369', (259, 264))	('beta-catenin', 'Gene', (194, 206))	('glycogen synthase kinase-3beta', 'Gene', '2932', (141, 171))	('tumor', 'Phenotype', 'HP:0002664', (259, 264))	('inhibitory phosphorylation', 'MPA', (111, 137))	('tumor', 'Disease', (259, 264))	('induced', 'PosReg', (99, 106))	('beta-catenin', 'Gene', '1499', (194, 206))	('activation', 'PosReg', (176, 186))	('downregulated', 'NegReg', (39, 52))
90001	29511369	have shown that aberrant expression of E-cadherin and Vimentin was associated with the lymph node metastasis of 312 stage I-IIIA NSCLC patients.	('aberrant', 'Var', (16, 24))	('patients', 'Species', '9606', (135, 143))	('E-cadherin', 'Gene', (39, 49))	('E-cadherin', 'Gene', '999', (39, 49))	('expression', 'MPA', (25, 35))	('Vimentin', 'Gene', (54, 62))	('NSCLC', 'Disease', (129, 134))	('associated', 'Reg', (67, 77))	('NSCLC', 'Disease', 'MESH:D002289', (129, 134))	('Vimentin', 'Gene', '7431', (54, 62))	('lymph node metastasis', 'CPA', (87, 108))
90005	29511369	However, the migration capacity of H520 cells was restrained after upregulation of E-cadherin expression through CLDN3 overexpression, whereas the migration ability of SK-MES-1 cells was induced after downregulation of E-cadherin expression using CLDN3 shRNA transduction.	('overexpression', 'Var', (119, 133))	('E-cadherin', 'Gene', (83, 93))	('migration capacity', 'CPA', (13, 31))	('E-cadherin', 'Gene', '999', (83, 93))	('CLDN3', 'Gene', (113, 118))	('migration ability', 'CPA', (147, 164))	('CLDN3', 'Gene', (247, 252))	('upregulation', 'PosReg', (67, 79))	('E-cadherin', 'Gene', (219, 229))	('CLDN3', 'Gene', '1365', (113, 118))	('E-cadherin', 'Gene', '999', (219, 229))	('expression', 'MPA', (94, 104))	('restrained', 'NegReg', (50, 60))	('CLDN3', 'Gene', '1365', (247, 252))	('SK-MES-1', 'CellLine', 'CVCL:0630', (168, 176))
90008	29511369	Our data showed that CLDN3 expression could prevent lung SqCC H520 cells from migration and invasion as well as EMT progression by inhibition of Wnt pathway activation, whereas CLDN3 knockdown had the opposite effects on lung SqCC SK-MES-1 cells.	('CLDN3', 'Gene', (177, 182))	('prevent', 'NegReg', (44, 51))	('invasion', 'CPA', (92, 100))	('EMT progression', 'CPA', (112, 127))	('SK-MES-1', 'CellLine', 'CVCL:0630', (231, 239))	('CLDN3', 'Gene', '1365', (177, 182))	('CLDN3', 'Gene', (21, 26))	('migration', 'CPA', (78, 87))	('CLDN3', 'Gene', '1365', (21, 26))	('expression', 'Var', (27, 37))	('Wnt pathway activation', 'Pathway', (145, 167))	('inhibition', 'NegReg', (131, 141))
90025	28832500	Importantly, inhibition of the NF-kappaB signaling pathway or knockdown of NF-kappaB (p65) phenocopied the effects of miR-145-5p on the migration, invasion and EMT of ESCC cells.	('miR-145', 'Gene', (118, 125))	('p65', 'Gene', '5970', (86, 89))	('miR-145', 'Gene', '406937', (118, 125))	('ESCC', 'Disease', (167, 171))	('NF-kappaB', 'Gene', (75, 84))	('NF-kappaB', 'Gene', '4790', (31, 40))	('invasion', 'CPA', (147, 155))	('NF-kappaB', 'Gene', '4790', (75, 84))	('EMT', 'CPA', (160, 163))	('p65', 'Gene', (86, 89))	('inhibition', 'NegReg', (13, 23))	('migration', 'CPA', (136, 145))	('NF-kappaB', 'Gene', (31, 40))	('knockdown', 'Var', (62, 71))
90032	28832500	In ESCC, down-regulation of miR-145 was commonly epigenetically regulated by promoter hypermethylation.	('miR-145', 'Gene', '406937', (28, 35))	('promoter hypermethylation', 'Var', (77, 102))	('miR-145', 'Gene', (28, 35))	('down-regulation', 'NegReg', (9, 24))
90036	28832500	Importantly, knockdown of Sp1 or NF-kappaB (p65) and inhibition of the NF-kappaB signaling pathway using CAPE phenocopied the effects of miR-145-5p overexpression on the respective tumor cell phenotypes.	('tumor', 'Disease', (181, 186))	('inhibition', 'NegReg', (53, 63))	('NF-kappaB', 'Gene', (33, 42))	('p65', 'Gene', (44, 47))	('NF-kappaB', 'Gene', (71, 80))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('miR-145', 'Gene', (137, 144))	('p65', 'Gene', '5970', (44, 47))	('CAPE', 'Chemical', 'MESH:C055494', (105, 109))	('miR-145', 'Gene', '406937', (137, 144))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('Sp1', 'Gene', (26, 29))	('NF-kappaB', 'Gene', '4790', (33, 42))	('knockdown', 'Var', (13, 22))	('NF-kappaB', 'Gene', '4790', (71, 80))
90038	28832500	To study the tumorigenic roles of miR-145-5p in ESCC, we first evaluated the expression levels in four ESCC cell lines including KYSE30, KYSE180, KYSE150 and KYSE510 by real-time polymerase chain reaction (RT-PCR).	('tumor', 'Disease', (13, 18))	('KYSE150', 'Var', (146, 153))	('KYSE510', 'Var', (158, 165))	('KYSE30', 'Var', (129, 135))	('KYSE180', 'Var', (137, 144))	('KYSE510', 'CellLine', 'CVCL:1354', (158, 165))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('miR-145', 'Gene', (34, 41))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('miR-145', 'Gene', '406937', (34, 41))
90039	28832500	KYSE150 and KYSE510 exhibited lower expression levels than other two cell lines (Figure 1E).	('lower', 'NegReg', (30, 35))	('KYSE510', 'CellLine', 'CVCL:1354', (12, 19))	('KYSE510', 'Var', (12, 19))	('KYSE150', 'Var', (0, 7))	('expression levels', 'MPA', (36, 53))
90043	28832500	The results showed that miR-145-5p decreased the mRNA levels of cell cycle regulatory genes (CCNA2, CCND1 and CCNE1) in KYSE150 and KYSE510 (Figure 2D).	('CCND1', 'Gene', (100, 105))	('mRNA levels', 'MPA', (49, 60))	('KYSE510', 'CellLine', 'CVCL:1354', (132, 139))	('CCNA2', 'Gene', (93, 98))	('CCND1', 'Gene', '595', (100, 105))	('decreased', 'NegReg', (35, 44))	('CCNA2', 'Gene', '890', (93, 98))	('KYSE150', 'Var', (120, 127))	('KYSE510', 'Var', (132, 139))	('CCNE1', 'Gene', '898', (110, 115))	('miR-145', 'Gene', (24, 31))	('CCNE1', 'Gene', (110, 115))	('miR-145', 'Gene', '406937', (24, 31))
90060	28832500	Silencing of Sp1 also significantly inhibited the EMT, and down-regulated the expressions of Slug, MMP2, MMP7 and MMP13 (Figure 4G-I).	('MMP13', 'Gene', (114, 119))	('inhibited', 'NegReg', (36, 45))	('expressions', 'MPA', (78, 89))	('MMP7', 'Gene', '4316', (105, 109))	('MMP13', 'Gene', '4322', (114, 119))	('Slug', 'Gene', '6591', (93, 97))	('MMP2', 'Gene', '4313', (99, 103))	('down-regulated', 'NegReg', (59, 73))	('EMT', 'CPA', (50, 53))	('Slug', 'Gene', (93, 97))	('Sp1', 'Gene', (13, 16))	('Silencing', 'Var', (0, 9))	('MMP7', 'Gene', (105, 109))	('MMP2', 'Gene', (99, 103))
90066	28832500	Silencing of NF-kappaB (p65) also significantly reduced the mRNA levels of MMP2, MMP7 and MMP13 (Figure 6E).	('MMP2', 'Gene', (75, 79))	('MMP7', 'Gene', (81, 85))	('MMP13', 'Gene', '4322', (90, 95))	('NF-kappaB', 'Gene', '4790', (13, 22))	('reduced', 'NegReg', (48, 55))	('MMP2', 'Gene', '4313', (75, 79))	('MMP7', 'Gene', '4316', (81, 85))	('NF-kappaB', 'Gene', (13, 22))	('p65', 'Gene', (24, 27))	('Silencing', 'Var', (0, 9))	('p65', 'Gene', '5970', (24, 27))	('MMP13', 'Gene', (90, 95))
90067	28832500	All of the above suggested that inhibition of the NF-kappaB signaling pathway or knockdown of NF-kappaB (p65) phenocopied the effects of miR-145-5p on the migration, invasion and EMT of ESCC cells.	('invasion', 'CPA', (166, 174))	('migration', 'CPA', (155, 164))	('ESCC', 'Disease', (186, 190))	('p65', 'Gene', (105, 108))	('inhibition', 'NegReg', (32, 42))	('p65', 'Gene', '5970', (105, 108))	('knockdown', 'Var', (81, 90))	('miR-145', 'Gene', (137, 144))	('NF-kappaB', 'Gene', '4790', (94, 103))	('miR-145', 'Gene', '406937', (137, 144))	('EMT of', 'CPA', (179, 185))	('NF-kappaB', 'Gene', '4790', (50, 59))	('NF-kappaB', 'Gene', (94, 103))	('NF-kappaB', 'Gene', (50, 59))
90086	28832500	Inhibition of NF-kappaB signaling pathway or knockdown of NF-kappaB (p65) phenocopied the effects of miR-145-5p on the migration, invasion and EMT of ESCC cells.	('miR-145', 'Gene', (101, 108))	('Inhibition', 'NegReg', (0, 10))	('miR-145', 'Gene', '406937', (101, 108))	('NF-kappaB', 'Gene', '4790', (58, 67))	('invasion', 'CPA', (130, 138))	('NF-kappaB', 'Gene', '4790', (14, 23))	('knockdown', 'Var', (45, 54))	('ESCC', 'Disease', (150, 154))	('NF-kappaB', 'Gene', (14, 23))	('p65', 'Gene', (69, 72))	('NF-kappaB', 'Gene', (58, 67))	('EMT', 'CPA', (143, 146))	('migration', 'CPA', (119, 128))	('p65', 'Gene', '5970', (69, 72))
90092	28832500	Low expression of miR-145 is associated with poor prognosis in NSCLC, and silencing lincRNA ROR posttranscriptionally regulates the expression of p53, while silencing ROR or p53 could upregulate miR-145 levels.	('NSCLC', 'Disease', (63, 68))	('miR-145', 'Gene', (18, 25))	('ROR', 'Gene', '100885779', (167, 170))	('lincRNA ROR', 'Gene', (84, 95))	('p53', 'Gene', (146, 149))	('expression', 'MPA', (4, 14))	('NSCLC', 'Phenotype', 'HP:0030358', (63, 68))	('silencing', 'Var', (157, 166))	('Low', 'NegReg', (0, 3))	('p53', 'Gene', '7157', (174, 177))	('ROR', 'Gene', (92, 95))	('p53', 'Gene', (174, 177))	('miR-145', 'Gene', '406937', (195, 202))	('ROR', 'Gene', '100885779', (92, 95))	('silencing', 'Var', (74, 83))	('miR-145', 'Gene', (195, 202))	('upregulate', 'PosReg', (184, 194))	('miR-145', 'Gene', '406937', (18, 25))	('NSCLC', 'Disease', 'MESH:D002289', (63, 68))	('p53', 'Gene', '7157', (146, 149))	('lincRNA ROR', 'Gene', '100885779', (84, 95))	('ROR', 'Gene', (167, 170))	('expression', 'MPA', (132, 142))	('regulates', 'Reg', (118, 127))
90106	28832500	The human esophageal squamous cell carcinoma (ESCC) cell lines, including KYSE30, KYSE150, KYSE180 and KYSE510, were provided by Yutaka.	('KYSE510', 'CellLine', 'CVCL:1354', (103, 110))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (10, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (35, 44))	('human', 'Species', '9606', (4, 9))	('KYSE180', 'Var', (91, 98))	('esophageal squamous cell carcinoma', 'Disease', (10, 44))	('KYSE150', 'Var', (82, 89))	('KYSE510', 'Var', (103, 110))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (21, 44))
90125	27891193	In epithelial cancers, aberrant COL17A1 promoter methylation predicts its misexpression and increased invasion Metastasis is a leading cause of death among cancer patients.	('cancer', 'Disease', (14, 20))	('patients', 'Species', '9606', (163, 171))	('epithelial cancers', 'Disease', 'MESH:D000077216', (3, 21))	('cancer', 'Disease', (156, 162))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('death', 'Disease', 'MESH:D003643', (144, 149))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('death', 'Disease', (144, 149))	('COL17A1', 'Gene', (32, 39))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('increased', 'PosReg', (92, 101))	('epithelial cancers', 'Disease', (3, 21))	('invasion Metastasis', 'CPA', (102, 121))	('COL17A1', 'Gene', '1308', (32, 39))	('cancer', 'Disease', 'MESH:D009369', (14, 20))	('cancers', 'Phenotype', 'HP:0002664', (14, 21))	('misexpression', 'MPA', (74, 87))	('aberrant', 'Var', (23, 31))
90126	27891193	In the tumor microenvironment, altered levels of extracellular matrix proteins, such as collagens, can facilitate the first steps of cancer cell metastasis, including invasion into surrounding tissue and intravasation into the blood stream.	('facilitate', 'PosReg', (103, 113))	('altered', 'Var', (31, 38))	('invasion into surrounding', 'CPA', (167, 192))	('tumor', 'Disease', (7, 12))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('cancer', 'Disease', (133, 139))	('levels of extracellular matrix proteins', 'MPA', (39, 78))	('tumor', 'Disease', 'MESH:D009369', (7, 12))	('intravasation', 'CPA', (204, 217))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
90133	27891193	Interestingly, consistent with the opposed direction of misexpression in these cancers, the COL17A1 promoter is hypermethylated in breast cancer and hypomethylated in cervical cancer.	('COL17A1', 'Gene', '1308', (92, 99))	('cancers', 'Disease', (79, 86))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('hypomethylated in cervical cancer', 'Disease', 'MESH:D002583', (149, 182))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('hypermethylated', 'Var', (112, 127))	('COL17A1', 'Gene', (92, 99))	('breast cancer', 'Disease', 'MESH:D001943', (131, 144))	('cancers', 'Disease', 'MESH:D009369', (79, 86))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('breast cancer', 'Disease', (131, 144))	('breast cancer', 'Phenotype', 'HP:0003002', (131, 144))	('hypomethylated in cervical cancer', 'Disease', (149, 182))
90134	27891193	We also find that the COL17A1 promoter is hypomethylated in head and neck squamous cell carcinoma, lung squamous cell carcinoma, and lung adenocarcinoma, in all of which collagen XVII overexpression has previously been shown.	('COL17A1', 'Gene', '1308', (22, 29))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (104, 127))	('lung squamous cell carcinoma', 'Disease', (99, 127))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (60, 97))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (133, 152))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('neck squamous cell carcinoma', 'Disease', (69, 97))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (74, 97))	('COL17A1', 'Gene', (22, 29))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (69, 97))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (99, 127))	('lung adenocarcinoma', 'Disease', (133, 152))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (133, 152))	('carcinoma', 'Phenotype', 'HP:0030731', (143, 152))	('hypomethylated', 'Var', (42, 56))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (99, 127))
90137	27891193	This implies that aberrant epigenetic control is a key driver of COL17A1 gene misexpression and tumor cell invasion.	('COL17A1', 'Gene', (65, 72))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumor', 'Disease', (96, 101))	('aberrant epigenetic control', 'Var', (18, 45))	('COL17A1', 'Gene', '1308', (65, 72))	('misexpression', 'Var', (78, 91))	('tumor', 'Disease', 'MESH:D009369', (96, 101))
90139	27891193	Moreover, epigenetic targeting of COL17A1 could represent a novel strategy to prevent metastasis in patients.	('COL17A1', 'Gene', (34, 41))	('epigenetic targeting', 'Var', (10, 30))	('COL17A1', 'Gene', '1308', (34, 41))	('patients', 'Species', '9606', (100, 108))	('metastasis', 'CPA', (86, 96))
90146	27891193	Associations between aberrant expression of collagens and tumor progression and metastasis are well established.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('metastasis', 'CPA', (80, 90))	('Associations', 'Interaction', (0, 12))	('collagens', 'Protein', (44, 53))	('aberrant expression', 'Var', (21, 40))	('tumor', 'Disease', 'MESH:D009369', (58, 63))
90158	27891193	To identify collagens whose misexpression may contribute to breast cancer development, and in particular metastasis, we systematically evaluated expression levels of all 44 collagen genes.	('breast cancer', 'Disease', (60, 73))	('misexpression', 'Var', (28, 41))	('contribute', 'Reg', (46, 56))	('metastasis', 'CPA', (105, 115))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('breast cancer', 'Disease', 'MESH:D001943', (60, 73))	('breast cancer', 'Phenotype', 'HP:0003002', (60, 73))
90160	27891193	We more stringently tested how well the misexpression of these genes might provide independent prognostic strength by including various other clinical parameters, such as lymph node status, tumor size, and menopausal status, all of which are included in Adjuvant!	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('tested', 'Reg', (20, 26))	('menopausal status', 'Phenotype', 'HP:0008209', (206, 223))	('tumor', 'Disease', (190, 195))	('including', 'Reg', (118, 127))	('misexpression', 'Var', (40, 53))
90164	27891193	Only COL17A1 misexpression was validated, as it consistently decreased in all analyses, the latter showing a 3.70-fold decrease (p = 4.93 x 10-11, n = 3004; Fig.	('misexpression', 'Var', (13, 26))	('COL17A1', 'Gene', '1308', (5, 12))	('decrease', 'NegReg', (119, 127))	('COL17A1', 'Gene', (5, 12))	('decreased', 'NegReg', (61, 70))
90194	27891193	The observation that copy number changes do not have a major impact on COL17A1 expression levels in breast cancer suggests that additional mechanisms regulate this gene's expression.	('expression', 'MPA', (79, 89))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('COL17A1', 'Gene', (71, 78))	('breast cancer', 'Disease', 'MESH:D001943', (100, 113))	('breast cancer', 'Phenotype', 'HP:0003002', (100, 113))	('copy number changes', 'Var', (21, 40))	('breast cancer', 'Disease', (100, 113))	('COL17A1', 'Gene', '1308', (71, 78))
90199	27891193	Taken together, these analyses suggest that reduced COL17A1 expression in breast cancer is caused by hypermethylation of the COL17A1 promoter.	('expression', 'MPA', (60, 70))	('breast cancer', 'Disease', (74, 87))	('COL17A1', 'Gene', (52, 59))	('hypermethylation', 'Var', (101, 117))	('COL17A1', 'Gene', (125, 132))	('COL17A1', 'Gene', '1308', (52, 59))	('reduced', 'NegReg', (44, 51))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('COL17A1', 'Gene', '1308', (125, 132))	('breast cancer', 'Disease', 'MESH:D001943', (74, 87))	('breast cancer', 'Phenotype', 'HP:0003002', (74, 87))
90203	27891193	These data strongly suggest that increased COL17A1 expression in cervical cancer is caused by hypomethylation of the COL17A1 promoter.	('COL17A1', 'Gene', '1308', (43, 50))	('COL17A1', 'Gene', (117, 124))	('hypomethylation', 'Var', (94, 109))	('increased', 'PosReg', (33, 42))	('expression', 'MPA', (51, 61))	('COL17A1', 'Gene', '1308', (117, 124))	('COL17A1', 'Gene', (43, 50))	('cervical cancer', 'Disease', (65, 80))	('cervical cancer', 'Disease', 'MESH:D002583', (65, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
90210	27891193	This indicates that the differential COL17A1 promoter methylation dictates whether collagen XVII is under- or overexpressed in these epithelial cancers (p = 0.0313, binomial test).	('epithelial cancers', 'Disease', 'MESH:D000077216', (133, 151))	('COL17A1', 'Gene', '1308', (37, 44))	('collagen XVII', 'Disease', (83, 96))	('methylation', 'Var', (54, 65))	('overexpressed', 'PosReg', (110, 123))	('dictates', 'Reg', (66, 74))	('cancers', 'Phenotype', 'HP:0002664', (144, 151))	('epithelial cancers', 'Disease', (133, 151))	('COL17A1', 'Gene', (37, 44))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
90217	27891193	Thus, while COL17A1 misexpression is common in epithelial cancers, the absolute COL17A1 levels vary widely between and among tumors and matched normal samples of different tissue origin.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('COL17A1', 'Gene', (80, 87))	('cancers', 'Phenotype', 'HP:0002664', (58, 65))	('epithelial cancers', 'Disease', (47, 65))	('tumors', 'Disease', (125, 131))	('COL17A1', 'Gene', (12, 19))	('tumors', 'Disease', 'MESH:D009369', (125, 131))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('COL17A1', 'Gene', '1308', (12, 19))	('COL17A1', 'Gene', '1308', (80, 87))	('epithelial cancers', 'Disease', 'MESH:D000077216', (47, 65))	('misexpression', 'Var', (20, 33))
90227	27891193	It is well established that differential DNA methylation in promoter regions causes misexpression of genes in cancer.	('differential DNA methylation', 'Var', (28, 56))	('cancer', 'Disease', (110, 116))	('causes', 'Reg', (77, 83))	('misexpression of genes', 'MPA', (84, 106))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('cancer', 'Disease', 'MESH:D009369', (110, 116))
90229	27891193	However, to our knowledge, this is the first study that links the cancer type-specific, opposed direction of the misexpression of any collagen gene to cancer type-specific epigenetic alterations.	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('cancer', 'Disease', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('misexpression', 'Var', (113, 126))	('epigenetic alterations', 'Var', (172, 194))	('collagen gene', 'Gene', (134, 147))	('cancer', 'Disease', (66, 72))
90240	27891193	The underexpression in breast cancer is associated with increased invasion, while overexpression in other cancer types is also associated with increased invasion and metastasis.	('breast cancer', 'Disease', (23, 36))	('breast cancer', 'Phenotype', 'HP:0003002', (23, 36))	('increased', 'PosReg', (56, 65))	('cancer', 'Disease', (30, 36))	('breast cancer', 'Disease', 'MESH:D001943', (23, 36))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('underexpression', 'Var', (4, 19))	('cancer', 'Disease', (106, 112))	('invasion', 'CPA', (66, 74))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
90242	27891193	However, our study has significant clinical implications, as it suggests that epigenetic targeting of COL17A1 could represent a novel strategy to prevent metastasis in patients.	('epigenetic targeting', 'Var', (78, 98))	('COL17A1', 'Gene', '1308', (102, 109))	('prevent', 'PosReg', (146, 153))	('metastasis', 'CPA', (154, 164))	('patients', 'Species', '9606', (168, 176))	('COL17A1', 'Gene', (102, 109))
90270	26194878	Copy number status was correlated with human papillomavirus (HPV) status in OPSCC, with occult lymph node status in OSCC and with patient survival.	('patient', 'Species', '9606', (130, 137))	('human papillomavirus', 'Species', '10566', (39, 59))	('OPSCC', 'Phenotype', 'HP:0012182', (76, 81))	('correlated', 'Reg', (23, 33))	('OPSCC', 'Disease', (76, 81))	('Copy number', 'Var', (0, 11))	('human papillomavirus', 'Disease', (39, 59))	('HPV', 'Species', '10566', (61, 64))
90292	26194878	Constituting an important element in the causal chain to cancer initiation and progression, genetic imbalances could serve as predictive or prognostic biomarkers in the near future.	('genetic', 'Var', (92, 99))	('cancer initiation', 'Disease', 'MESH:D009369', (57, 74))	('imbalances', 'Phenotype', 'HP:0002172', (100, 110))	('cancer initiation', 'Disease', (57, 74))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))
90312	26194878	The Pearson chi-square test (or Fisher's exact when appropriate) was used to compare baseline characteristics for categorical variables and frequencies of loss, gain, or amplification for individual genes and chromosomal arms between HPV-negative and HPV-positive OPSCC and between lymph node-positive and lymph node-negative OSCC.	('OPSCC', 'Phenotype', 'HP:0012182', (264, 269))	('loss', 'NegReg', (155, 159))	('amplification', 'Var', (170, 183))	('HPV', 'Species', '10566', (234, 237))	('OPSCC', 'Disease', (264, 269))	('gain', 'PosReg', (161, 165))	('HPV', 'Species', '10566', (251, 254))
90320	26194878	All HPV-positive tumors contained HPV type 16, whereas two of 41 were co-infected with HPV 33 or HPV 52 as well.	('HPV type 16', 'Var', (34, 45))	('HPV', 'Species', '10566', (4, 7))	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('HPV', 'Species', '10566', (97, 100))	('HPV', 'Species', '10566', (87, 90))	('contained', 'Reg', (24, 33))	('HPV-positive tumors', 'Disease', 'MESH:D030361', (4, 23))	('HPV-positive tumors', 'Disease', (4, 23))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('HPV', 'Species', '10566', (34, 37))
90328	26194878	Copy number gain of EGFR and both amplification and gain of genes located at 11q13 (FADD, CTTN, CCND1, and FGF4) were significantly more frequent in HPV-negative tumors.	('FGF4', 'Gene', '2249', (107, 111))	('CTTN', 'Gene', (90, 94))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('EGFR', 'Gene', (20, 24))	('CCND1', 'Gene', '595', (96, 101))	('HPV', 'Species', '10566', (149, 152))	('gain', 'PosReg', (52, 56))	('CTTN', 'Gene', '2017', (90, 94))	('gain', 'PosReg', (12, 16))	('FGF4', 'Gene', (107, 111))	('tumors', 'Disease', (162, 168))	('FADD', 'Gene', (84, 88))	('tumors', 'Disease', 'MESH:D009369', (162, 168))	('Copy number', 'Var', (0, 11))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))	('CCND1', 'Gene', (96, 101))	('FADD', 'Gene', '8772', (84, 88))
90331	26194878	Besides these observed differences, several genes showed frequent aberrations in both HPV-positive and HPV-negative OPSCC.	('HPV', 'Species', '10566', (86, 89))	('OPSCC', 'Disease', (116, 121))	('HPV', 'Species', '10566', (103, 106))	('OPSCC', 'Phenotype', 'HP:0012182', (116, 121))	('aberrations', 'Var', (66, 77))
90333	26194878	In the whole cohort of 164 OSCCs, gain and amplification (chromosomal region 11q13, CCND1, FGF4, FADD, and CTTN) and loss (CSMD1) correlated significantly with LNMs.	('FGF4', 'Gene', (91, 95))	('CTTN', 'Gene', (107, 111))	('loss', 'NegReg', (117, 121))	('gain', 'PosReg', (34, 38))	('CCND1', 'Gene', (84, 89))	('CTTN', 'Gene', '2017', (107, 111))	('amplification', 'Var', (43, 56))	('LNMs', 'Disease', (160, 164))	('FGF4', 'Gene', '2249', (91, 95))	('FADD', 'Gene', '8772', (97, 101))	('CCND1', 'Gene', '595', (84, 89))	('FADD', 'Gene', (97, 101))	('CSMD1', 'Gene', '64478', (123, 128))	('CSMD1', 'Gene', (123, 128))
90337	26194878	In OPSCC, the baseline characteristics age, clinical nodal metastases (N1-3), clinical advanced T classification (T3-T4), and HPV negativity were significantly correlated with a decreased DFS.	('OPSCC', 'Phenotype', 'HP:0012182', (3, 8))	('decreased', 'NegReg', (178, 187))	('metastases', 'Disease', 'MESH:D009362', (59, 69))	('DFS', 'MPA', (188, 191))	('negativity', 'Var', (130, 140))	('metastases', 'Disease', (59, 69))	('HPV', 'Species', '10566', (126, 129))
90338	26194878	From the 36-gene panel, amplification of FADD and gain of wnt-induced secreted protein-1 (WISP1) correlated with a worse DFS.	('FADD', 'Gene', (41, 45))	('FADD', 'Gene', '8772', (41, 45))	('wnt-induced secreted protein-1', 'Gene', '8840', (58, 88))	('gain', 'PosReg', (50, 54))	('WISP1', 'Gene', '8840', (90, 95))	('amplification', 'Var', (24, 37))	('DFS', 'Disease', (121, 124))	('WISP1', 'Gene', (90, 95))	('wnt-induced secreted protein-1', 'Gene', (58, 88))
90340	26194878	In OSCC, both gain and amplification of chromosomal region of 11q13 and its individual genes (CCND1, FGF4, FADD, CTTN) correlated with a decreased DFS, with CCND1 gain acting as the strongest predictor (hazard ratio 2.28 with 95% CI 1.28-4.02, P = 0.004).	('CCND1', 'Gene', '595', (157, 162))	('gain', 'PosReg', (14, 18))	('CCND1', 'Gene', (94, 99))	('FGF4', 'Gene', '2249', (101, 105))	('CTTN', 'Gene', (113, 117))	('amplification', 'Var', (23, 36))	('DFS', 'MPA', (147, 150))	('CTTN', 'Gene', '2017', (113, 117))	('CCND1', 'Gene', (157, 162))	('CCND1', 'Gene', '595', (94, 99))	('FADD', 'Gene', (107, 111))	('FGF4', 'Gene', (101, 105))	('FADD', 'Gene', '8772', (107, 111))	('decreased', 'NegReg', (137, 146))	('OSCC', 'Disease', (3, 7))
90361	26194878	In this CNA, panel of 36 oncogenes and tumor suppressor genes, gain or amplification (all ratios >1.3) instead of normal copy number of 11q13 is the most accurate biomarker, with an NPV of 81% and a positive predictive value of 46%.	('gain', 'PosReg', (63, 67))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('amplification', 'Var', (71, 84))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumor', 'Disease', (39, 44))
90362	26194878	In addition, pooled results of the five studies investigating CCND1 amplification showed significant correlation (odds ratio 2.12, 95% CI 1.43-3.16, P < 0.001) with LNM.	('LNM', 'Disease', (165, 168))	('CCND1', 'Gene', '595', (62, 67))	('correlation', 'Interaction', (101, 112))	('amplification', 'Var', (68, 81))	('CCND1', 'Gene', (62, 67))
90363	26194878	However, only one study investigated the diagnostic value of CCND1 amplification in Stage I-II OSCC with an NPV of 83%, which is similar to our results.	('amplification', 'Var', (67, 80))	('CCND1', 'Gene', (61, 66))	('Stage I-II OSCC', 'Disease', (84, 99))	('CCND1', 'Gene', '595', (61, 66))
90368	26194878	Furthermore, in a subgroup of HPV-negative OPSCC 11q13 amplification or gain showed no association with outcome, altogether suggesting that 11q13 copy number gain or amplification has no prognostic value in OPSCC.	('11q13 copy number gain', 'Var', (140, 162))	('OPSCC', 'Disease', (207, 212))	('amplification', 'Var', (166, 179))	('OPSCC', 'Phenotype', 'HP:0012182', (207, 212))	('OPSCC', 'Phenotype', 'HP:0012182', (43, 48))	('HPV', 'Species', '10566', (30, 33))
90372	26194878	In esophageal squamous cell carcinoma, protein expression of WISP1 was found to be an independent prognostic factor for worse overall survival.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (14, 37))	('protein', 'Var', (39, 46))	('esophageal squamous cell carcinoma', 'Disease', (3, 37))	('WISP1', 'Gene', (61, 66))	('carcinoma', 'Phenotype', 'HP:0030731', (28, 37))	('WISP1', 'Gene', '8840', (61, 66))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (3, 37))
90378	26194878	found similar results, with nodal status and CCND1 amplification being independent predictors for survival.	('CCND1', 'Gene', (45, 50))	('CCND1', 'Gene', '595', (45, 50))	('amplification', 'Var', (51, 64))
90392	26194878	In conclusion, we have identified CNA that are associated with HPV status in OPSCC and with prognosis in OSCC.	('HPV status', 'Var', (63, 73))	('OPSCC', 'Disease', (77, 82))	('HPV', 'Species', '10566', (63, 66))	('OPSCC', 'Phenotype', 'HP:0012182', (77, 82))	('associated', 'Reg', (47, 57))
90402	33546637	Univariate Cox regression analyses showed that high preoperative DD predicted poor prognosis in patients with OSCC (HR = 2.1, P = 0.033), while FIB and PLT showed no prognostic values.	('FIB', 'Gene', (144, 147))	('high', 'Var', (47, 51))	('patients', 'Species', '9606', (96, 104))	('FIB', 'Gene', '2244', (144, 147))	('OSCC', 'Disease', (110, 114))
90437	33546637	Patients with normal preoperative DD (< 500 mug/L) had a significantly better PFS than patients with high preoperative DD (>=500 mug/L) (81.7% vs. 74.2%, P = 0.027).	('PFS', 'CPA', (78, 81))	('Patients', 'Species', '9606', (0, 8))	('< 500 mug/L', 'Var', (38, 49))	('better', 'PosReg', (71, 77))	('patients', 'Species', '9606', (87, 95))
90447	33546637	Liu Z and Liu P used 4.0 g/L as the cut-off value for FIB and 300*10^9/L for PLT, and both were significantly correlated with overall survival (P < 0.001 and P = 0.010, respectively).	('overall survival', 'CPA', (126, 142))	('FIB', 'Gene', '2244', (54, 57))	('300*10^9/L', 'Var', (62, 72))	('FIB', 'Gene', (54, 57))	('correlated with', 'Reg', (110, 125))
90449	33546637	In our study, the cut-off values of FIB and PLT were set as the mean value (3.33 g/L and 259.5*10^9/L, respectively).	('FIB', 'Gene', '2244', (36, 39))	('FIB', 'Gene', (36, 39))	('259.5*10^9/L', 'Var', (89, 101))
90482	30486632	The rate of malignant transformation is higher in non-homogenous Oral leukoplakia, lesions that demonstrate moderate to severe dysplasia and lesions on the tongue or floor of the mouth, Lesions >200 mm2, age >60 years and smokers are also more frequently associated with malignant transformation (Ho et al., 2012).	('Oral leukoplakia', 'Disease', (65, 81))	('dysplasia', 'Disease', 'MESH:D004476', (127, 136))	('malignant transformation', 'CPA', (271, 295))	('higher', 'PosReg', (40, 46))	('Oral leukoplakia', 'Disease', 'MESH:D007972', (65, 81))	('associated', 'Reg', (255, 265))	('moderate', 'Disease', (108, 116))	('Lesions >200 mm2', 'Var', (186, 202))	('malignant transformation', 'CPA', (12, 36))	('Oral leukoplakia', 'Phenotype', 'HP:0002745', (65, 81))	('floor of the mouth', 'Phenotype', 'HP:0410012', (166, 184))	('dysplasia', 'Disease', (127, 136))
90487	30486632	In oral epithelial tissues, accumulating mutations, chromosomal damage, and loss of cellular control functions, these changes are manifested as the transition from normal histology to dysplasia, to superficial cancer and invasive squamous cell carcinoma (Muller, 2018).	('mutations', 'Var', (41, 50))	('dysplasia', 'Disease', (184, 193))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('invasive squamous cell carcinoma', 'Disease', (221, 253))	('dysplasia', 'Disease', 'MESH:D004476', (184, 193))	('invasive squamous cell carcinoma', 'Disease', 'MESH:D002294', (221, 253))	('chromosomal damage', 'Var', (52, 70))	('cancer', 'Disease', 'MESH:D009369', (210, 216))	('carcinoma', 'Phenotype', 'HP:0030731', (244, 253))	('cancer', 'Disease', (210, 216))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (230, 253))
90502	30486632	The control on cell proliferation biological process is thought to be lost in cancer (Tumuluri et al., 2002), and many studies have reported that abnormal cell proliferation appears to be a precursor and may be a predictor of tumorigenesis (Gavish et al., 2016; Bacchi and Gown, 1993).	('cancer', 'Disease', (78, 84))	('abnormal', 'Var', (146, 154))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('tumor', 'Disease', 'MESH:D009369', (226, 231))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('tumor', 'Disease', (226, 231))	('abnormal cell proliferation', 'Phenotype', 'HP:0031377', (146, 173))
90540	30486632	The control on cell proliferation is thought to be impeded in cancer, and many studies have reported that abnormal cell proliferation appears to be a precursor as well as a predictor of tumorigenesis (Bacchi and Gown, 1993).	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('abnormal', 'Var', (106, 114))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('tumor', 'Disease', (186, 191))	('abnormal cell proliferation', 'Phenotype', 'HP:0031377', (106, 133))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))
90561	30486632	And we found to that cell proliferation in OSCC increasing according to histological grades by an antibody for Ki-67 protein this was in accordance with previous studies (Tumuluri et al., 2002; Dwivedi et al., 2013).	('cell proliferation', 'CPA', (21, 39))	('antibody', 'Var', (98, 106))	('increasing', 'PosReg', (48, 58))	('Ki-67', 'Chemical', '-', (111, 116))
90570	30486632	Because of expression Ki-67 protein in all proliferating cells and the prognostic value of the Ki-67 marker in many cancers, Ki-67 protein is a potential therapeutic target in cancer, and strategies that inactivate Ki-67 protein are a promising anti-proliferative approach, with potential applicability in cancer treatment (Kausch et al., 2003).	('Ki-67', 'Chemical', '-', (215, 220))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('Ki-67', 'Chemical', '-', (95, 100))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('Ki-67', 'Chemical', '-', (125, 130))	('cancer', 'Disease', 'MESH:D009369', (306, 312))	('Ki-67', 'Chemical', '-', (22, 27))	('protein', 'Protein', (221, 228))	('cancers', 'Disease', 'MESH:D009369', (116, 123))	('Ki-67', 'Gene', (215, 220))	('inactivate', 'Var', (204, 214))	('men', 'Species', '9606', (318, 321))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('cancer', 'Disease', (116, 122))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cancer', 'Disease', (306, 312))	('cancer', 'Phenotype', 'HP:0002664', (306, 312))	('cancers', 'Phenotype', 'HP:0002664', (116, 123))	('cancers', 'Disease', (116, 123))	('cancer', 'Disease', (176, 182))
90615	27409347	ING5 transfection up-regulated the expression of Cdc2, ATG13, ATG14, Beclin-1, LC-3B, AIF, cytochrome c, Akt1/2/3, ADFP, PFK-1 and PDPc, while down-regulated the expression of Bcl-2, XIAP, survivin,beta-catenin and HXK1.	('AIF', 'Gene', (86, 89))	('Akt1/2/3', 'Gene', (105, 113))	('ATG13', 'Gene', '9776', (55, 60))	('cytochrome c', 'Gene', (91, 103))	('Cdc2', 'Gene', (49, 53))	('Beclin-1', 'Gene', (69, 77))	('expression', 'MPA', (35, 45))	('XIAP', 'Gene', '331', (183, 187))	('ADFP', 'Gene', (115, 119))	('PDPc', 'Gene', '54704', (131, 135))	('down-regulated', 'NegReg', (143, 157))	('Akt1/2/3', 'Gene', '207;208;10000', (105, 113))	('beta-catenin', 'Gene', (198, 210))	('ADFP', 'Gene', '123', (115, 119))	('beta-catenin', 'Gene', '1499', (198, 210))	('ATG14', 'Gene', (62, 67))	('LC-3B', 'Gene', (79, 84))	('transfection', 'Var', (5, 17))	('XIAP', 'Gene', (183, 187))	('Bcl-2', 'Gene', (176, 181))	('ATG13', 'Gene', (55, 60))	('PDPc', 'Gene', (131, 135))	('LC-3B', 'Gene', '81631', (79, 84))	('PFK-1', 'Gene', (121, 126))	('cytochrome c', 'Gene', '54205', (91, 103))	('Cdc2', 'Gene', '983', (49, 53))	('up-regulated', 'PosReg', (18, 30))	('Bcl-2', 'Gene', '596', (176, 181))	('ATG14', 'Gene', '22863', (62, 67))	('Beclin-1', 'Gene', '8678', (69, 77))	('expression', 'MPA', (162, 172))	('PFK-1', 'Gene', '5213', (121, 126))	('AIF', 'Gene', '9131', (86, 89))
90616	27409347	ING5 transfection desensitized cells to the chemotherapy of MG132, paclitaxel, and SAHA, which paralleled with apoptotic alteration.	('MG132', 'Chemical', 'MESH:C072553', (60, 65))	('transfection', 'Var', (5, 17))	('desensitized', 'NegReg', (18, 30))	('chemotherapy', 'MPA', (44, 56))	('MG132', 'Gene', (60, 65))	('paclitaxel', 'Chemical', 'MESH:D017239', (67, 77))	('SAHA', 'Chemical', 'MESH:D000077337', (83, 87))	('ING5', 'Gene', (0, 4))
90623	27409347	Inhibitor of growth 5 (ING5) belongs to the encoding protein of Class II tumor suppressor gene (TGS) since its inactivation results from frequent genetic and epigenetic alterations.	('TGS', 'Gene', '286826', (96, 99))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('inactivation', 'MPA', (111, 123))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Disease', (73, 78))	('TGS', 'Gene', (96, 99))	('ING5', 'Gene', (23, 27))	('epigenetic alterations', 'Var', (158, 180))
90625	27409347	The latter promotes DNA replication via the interaction with mini-chromosome maintenance protein because ING5 knockdown completely abolishes DNA synthesis, and HBO1 knockdown increases S-phase cells ratio.	('knockdown', 'Var', (110, 119))	('abolishes', 'NegReg', (131, 140))	('HBO1', 'Gene', '11143', (160, 164))	('ING5', 'Gene', (105, 109))	('knockdown', 'Var', (165, 174))	('HBO1', 'Gene', (160, 164))	('S-phase cells ratio', 'CPA', (185, 204))	('promotes', 'PosReg', (11, 19))	('interaction', 'Interaction', (44, 55))	('DNA synthesis', 'MPA', (141, 154))	('increases', 'PosReg', (175, 184))
90630	27409347	The intact ING5 can inhibit proliferation and induce apoptosis in HSC-3 cells, while two truncated fragments of ING5 (aa 1-184 and 107-226) induce cellular senescence with cyclin E and CDK2 hypoexpression.	('induce', 'Reg', (140, 146))	('apoptosis', 'CPA', (53, 62))	('CDK2', 'Gene', (185, 189))	('proliferation', 'CPA', (28, 41))	('men', 'Species', '9606', (103, 106))	('cellular senescence', 'CPA', (147, 166))	('aa 1-184', 'Var', (118, 126))	('CDK2', 'Gene', '1017', (185, 189))	('induce', 'Reg', (46, 52))	('inhibit', 'NegReg', (20, 27))	('ING5', 'Gene', (112, 116))	('HSC-3', 'CellLine', 'CVCL:1288', (66, 71))
90635	27409347	ING5 deletion was found to initiate carcinogenesis of ameloblastoma and oral cancers.	('deletion', 'Var', (5, 13))	('cancers', 'Phenotype', 'HP:0002664', (77, 84))	('carcinogenesis of ameloblastoma and oral cancers', 'Disease', 'MESH:D000564', (36, 84))	('initiate', 'PosReg', (27, 35))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('ING5', 'Gene', (0, 4))
90636	27409347	Recently, down-regulated ING5 mRNA expression and the missense mutations of its LZL and NCR domains were detectable in oral squamous cell carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (119, 147))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (124, 147))	('missense mutations', 'Var', (54, 72))	('oral squamous cell carcinoma', 'Disease', (119, 147))	('ING5 mRNA', 'Protein', (25, 34))	('down-regulated', 'NegReg', (10, 24))
90646	27409347	There was a high level of apoptosis evidenced by Annexin-V (Figure 1E, p < 0.05), a high autophagy by pEGFP-tagged LC-3B transfection (Figure 1F) and a good differentiation by ALP activity (Figure 1G, p < 0.05) in ING5 transfectants, compared with the control and mock.	('ALP', 'Gene', (176, 179))	('ING5 transfectants', 'Var', (214, 232))	('Annexin-V', 'Gene', '308', (49, 58))	('apoptosis', 'CPA', (26, 35))	('LC-3B', 'Gene', (115, 120))	('ALP', 'Gene', '470', (176, 179))	('autophagy', 'CPA', (89, 98))	('LC-3B', 'Gene', '81631', (115, 120))	('transfection', 'Var', (121, 133))	('Annexin-V', 'Gene', (49, 58))
90648	27409347	Further Western-blotting showed higher expression of Cdc2, ATG13, ATG14, Beclin-1, LC-3B, AIF, cytochrome c, Akt1/2/3, ADFP, PFK-1 and PDPc in A459 and SQ-5 transfectants, but did lower expression of Bcl-2, XIAP, survivin,beta-catenin and HXK1 than the control and mock (Figure 1M).	('ATG14', 'Gene', (66, 71))	('LC-3B', 'Gene', (83, 88))	('transfectants', 'Var', (157, 170))	('higher', 'PosReg', (32, 38))	('PDPc', 'Gene', (135, 139))	('XIAP', 'Gene', '331', (207, 211))	('LC-3B', 'Gene', '81631', (83, 88))	('PFK-1', 'Gene', (125, 130))	('cytochrome c', 'Gene', '54205', (95, 107))	('ATG13', 'Gene', '9776', (59, 64))	('ATG14', 'Gene', '22863', (66, 71))	('Cdc2', 'Gene', '983', (53, 57))	('PFK-1', 'Gene', '5213', (125, 130))	('beta-catenin', 'Gene', (222, 234))	('expression', 'MPA', (39, 49))	('Beclin-1', 'Gene', '8678', (73, 81))	('AIF', 'Gene', '9131', (90, 93))	('Akt1/2/3', 'Gene', (109, 117))	('beta-catenin', 'Gene', '1499', (222, 234))	('AIF', 'Gene', (90, 93))	('ADFP', 'Gene', (119, 123))	('XIAP', 'Gene', (207, 211))	('Bcl-2', 'Gene', (200, 205))	('cytochrome c', 'Gene', (95, 107))	('ATG13', 'Gene', (59, 64))	('Beclin-1', 'Gene', (73, 81))	('Cdc2', 'Gene', (53, 57))	('ADFP', 'Gene', '123', (119, 123))	('PDPc', 'Gene', '54704', (135, 139))	('Bcl-2', 'Gene', '596', (200, 205))	('Akt1/2/3', 'Gene', '207;208;10000', (109, 117))
90650	27409347	In the nu/nu mice, ING5 suppressed the xenograft tumor growth by tumor volume and weight (Figure 3A-3E, p < 0.05), inhibited proliferation, induced apoptosis and autophagy according to immunohistochemistry and TUNEL (Figure 3F).	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('mice', 'Species', '10090', (13, 17))	('induced', 'PosReg', (140, 147))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('tumor', 'Disease', (65, 70))	('autophagy', 'CPA', (162, 171))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('proliferation', 'CPA', (125, 138))	('suppressed', 'NegReg', (24, 34))	('tumor', 'Disease', (49, 54))	('ING5', 'Var', (19, 23))	('apoptosis', 'CPA', (148, 157))	('inhibited', 'NegReg', (115, 124))	('tumor', 'Disease', 'MESH:D009369', (65, 70))
90665	27409347	Cytoplasmic translocation of ING5 had impact on the carcinogenesis of HNSCC and CRCs and cytoplasmic ING5 was positively correlated with the aggressive behaviors of CRC and gastric cancers.	('CRC', 'Phenotype', 'HP:0003003', (165, 168))	('aggressive behaviors', 'CPA', (141, 161))	('carcinogenesis', 'Disease', (52, 66))	('cytoplasmic ING5', 'Var', (89, 105))	('aggressive behaviors', 'Phenotype', 'HP:0000718', (141, 161))	('carcinogenesis', 'Disease', 'MESH:D063646', (52, 66))	('impact', 'Reg', (38, 44))	('cancers', 'Phenotype', 'HP:0002664', (181, 188))	('SCC', 'Gene', '6317', (72, 75))	('gastric cancers', 'Disease', (173, 188))	('gastric cancers', 'Phenotype', 'HP:0012126', (173, 188))	('gastric cancers', 'Disease', 'MESH:D013274', (173, 188))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('correlated with', 'Reg', (121, 136))	('SCC', 'Gene', (72, 75))	('CRCs', 'Disease', (80, 84))	('gastric cancer', 'Phenotype', 'HP:0012126', (173, 187))	('CRC', 'Phenotype', 'HP:0003003', (80, 83))	('CRC', 'Disease', (165, 168))
90668	27409347	Consistent with another report, cytoplasmic ING5 was negatively associated with lymphatic invasion of lung cancer, which might be attributable to no wide and careful application of D2-40 immunostaining in the pathological diagnosis.	('lymphatic invasion', 'CPA', (80, 98))	('lung cancer', 'Phenotype', 'HP:0100526', (102, 113))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('lung cancer', 'Disease', (102, 113))	('negatively', 'NegReg', (53, 63))	('lung cancer', 'Disease', 'MESH:D008175', (102, 113))	('cytoplasmic ING5', 'Var', (32, 48))
90673	27409347	In tumor-bearing nude mouse model, ING5 was demonstrated to suppress the tumor growth by inducing apoptosis and autophagy, and decreasing proliferative ability.	('tumor', 'Disease', (3, 8))	('proliferative ability', 'CPA', (138, 159))	('apoptosis', 'CPA', (98, 107))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('suppress', 'NegReg', (60, 68))	('ING5', 'Var', (35, 39))	('tumor', 'Disease', (73, 78))	('decreasing', 'NegReg', (127, 137))	('tumor', 'Disease', 'MESH:D009369', (3, 8))	('mouse', 'Species', '10090', (22, 27))	('autophagy', 'CPA', (112, 121))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))	('inducing', 'PosReg', (89, 97))
90674	27409347	In other words, ING5 up-regulated the apoptotic level of lung cancer cells, but had no ability to induce their apoptotic level against chemodrugs.	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('lung cancer', 'Phenotype', 'HP:0100526', (57, 68))	('lung cancer', 'Disease', 'MESH:D008175', (57, 68))	('apoptotic level', 'MPA', (38, 53))	('ING5', 'Var', (16, 20))	('lung cancer', 'Disease', (57, 68))	('up-regulated', 'PosReg', (21, 33))
90676	27409347	Reportedly, ING5 inhibited cancer aggressiveness of lung cancer via preventing epithelial to mesenchymal transition, but it was regret that the phenomenon was not observed although we utilized the same cancer cell, A549.	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('cancer', 'Disease', (57, 63))	('A549', 'CellLine', 'CVCL:0023', (215, 219))	('lung cancer', 'Phenotype', 'HP:0100526', (52, 63))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('aggressiveness', 'Phenotype', 'HP:0000718', (34, 48))	('epithelial to mesenchymal transition', 'CPA', (79, 115))	('cancer', 'Disease', 'MESH:D009369', (202, 208))	('preventing', 'NegReg', (68, 78))	('ING5', 'Var', (12, 16))	('cancer', 'Disease', 'MESH:D009369', (27, 33))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('men', 'Species', '9606', (149, 152))	('cancer aggressiveness of lung cancer', 'Disease', (27, 63))	('inhibited', 'NegReg', (17, 26))	('cancer aggressiveness of lung cancer', 'Disease', 'MESH:D008175', (27, 63))	('cancer', 'Disease', (202, 208))	('cancer', 'Disease', (27, 33))
90677	27409347	In lung cancer cells, ectopic ING5 expression caused G2 phase arrest and suppressed proliferation, while the overexpression of Cdc2 protein might be attributed to the higher proportion of cells in G2 phase.	('G2 phase arrest', 'CPA', (53, 68))	('Cdc2', 'Gene', (127, 131))	('lung cancer', 'Disease', (3, 14))	('ectopic', 'Var', (22, 29))	('lung cancer', 'Phenotype', 'HP:0100526', (3, 14))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('Cdc2', 'Gene', '983', (127, 131))	('proliferation', 'CPA', (84, 97))	('suppressed', 'NegReg', (73, 83))	('lung cancer', 'Disease', 'MESH:D008175', (3, 14))	('ING5', 'Gene', (30, 34))
90692	27409347	We for the first time reported that ING5 might induce glucose catabolism and aberrant fat deposition in lung cancer cells.	('lung cancer', 'Disease', 'MESH:D008175', (104, 115))	('induce', 'PosReg', (47, 53))	('glucose catabolism', 'Disease', 'MESH:D018149', (54, 72))	('glucose catabolism', 'Disease', (54, 72))	('lung cancer', 'Disease', (104, 115))	('lung cancer', 'Phenotype', 'HP:0100526', (104, 115))	('ING5', 'Var', (36, 40))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('aberrant', 'CPA', (77, 85))
90747	26699919	The uncontrolled cell growth of EC results from promoter methylation (Tao and Freudenheim, 2010), copy-number alteration of tumor suppressor genes and oncogenes (Zhao, et al., 2013e), and dysregulated expression of mRNA, microRNA (Banno, et al., 2013), and long noncoding RNAs (He, et al., 2014).	('promoter', 'MPA', (48, 56))	('long noncoding RNAs', 'Protein', (257, 276))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('tumor', 'Disease', (124, 129))	('mRNA', 'Protein', (215, 219))	('copy-number alteration', 'Var', (98, 120))	('microRNA', 'Protein', (221, 229))	('dysregulated', 'Var', (188, 200))	('expression', 'MPA', (201, 211))	('EC', 'Phenotype', 'HP:0012114', (32, 34))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
90781	26699919	A similar prevalence of mutations (mutation rate over 90%) can be found in 31 other cancer mutation studies from 19 cancer types.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('cancer', 'Disease', (84, 90))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('mutations', 'Var', (24, 33))
90783	26699919	Notably, those tumors adjacent to the uterus, such as bladder and colorectal cancers, have the most frequent mutational rate.	('tumors', 'Disease', (15, 21))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('cancers', 'Phenotype', 'HP:0002664', (77, 84))	('colorectal cancers', 'Disease', 'MESH:D015179', (66, 84))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('bladder', 'Disease', (54, 61))	('colorectal cancers', 'Disease', (66, 84))	('mutational', 'Var', (109, 119))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('bladder', 'Disease', 'MESH:D001745', (54, 61))	('tumors', 'Disease', 'MESH:D009369', (15, 21))
90784	26699919	This implies the adjacent tumors may have similar driver mutations in relation to the tissue of origin, an observation reported by the TCGA pan-cancer mutational analysis (Kandoth, et al., 2013).	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('cancer', 'Disease', (144, 150))	('mutations', 'Var', (57, 66))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('tumors', 'Disease', (26, 32))
90798	31074374	An integrated analysis of gene expression, DNA methylation and mutations revealed factors that regulate gene expression, including the differentially methylated sites and mutations of the lipid genes, as well as mutation and differential expression of the up-stream transcription factors for the lipid metabolism pathways.	('mutations', 'Var', (63, 72))	('regulate', 'Reg', (95, 103))	('lipid metabolism pathways', 'Pathway', (296, 321))	('lipid', 'Chemical', 'MESH:D008055', (188, 193))	('mutation', 'Var', (212, 220))	('lipid', 'Chemical', 'MESH:D008055', (296, 301))	('lipid genes', 'Gene', (188, 199))	('mutations', 'Var', (171, 180))	('up-stream', 'PosReg', (256, 265))
90805	31074374	The perturbations of lipid metabolism in cancer cells may alter cellular function dramatically.	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('lipid', 'Chemical', 'MESH:D008055', (21, 26))	('cellular function', 'MPA', (64, 81))	('lipid metabolism', 'MPA', (21, 37))	('perturbations', 'Var', (4, 17))	('alter', 'Reg', (58, 63))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (41, 47))
90810	31074374	Furthermore, increasing evidences suggest that the alterations in tumor metabolism can also contribute to the inhibition of the antitumor response.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('alterations', 'Var', (51, 62))	('inhibition', 'NegReg', (110, 120))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('tumor', 'Disease', (66, 71))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumor', 'Disease', (132, 137))	('tumor', 'Disease', 'MESH:D009369', (66, 71))
90813	31074374	A previous study demonstrated the deletion of 5-Lipoxygenase in the TME promoted lung cancer progression and metastasis through regulating T Cell recruitment.	('lung cancer', 'Disease', (81, 92))	('lung cancer', 'Phenotype', 'HP:0100526', (81, 92))	('T Cell recruitment', 'CPA', (139, 157))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('metastasis', 'CPA', (109, 119))	('deletion', 'Var', (34, 42))	('lung cancer', 'Disease', 'MESH:D008175', (81, 92))	('5-Lipoxygenase', 'Gene', (46, 60))	('regulating', 'Reg', (128, 138))	('promoted', 'PosReg', (72, 80))
90818	31074374	The integrative analysis of gene expression, mutation and DNA methylation could not only draw a landscape of the alteration of lipid metabolism pathways, but also give clues to the regulation of lipid metabolism.	('lipid metabolism', 'MPA', (127, 143))	('mutation', 'Var', (45, 53))	('lipid', 'Chemical', 'MESH:D008055', (195, 200))	('lipid', 'Chemical', 'MESH:D008055', (127, 132))
90844	31074374	We found that the alteration of the lipid metabolism pathways can affect metabolism, signaling transduction and immunity.	('affect', 'Reg', (66, 72))	('metabolism', 'CPA', (73, 83))	('signaling transduction', 'CPA', (85, 107))	('lipid metabolism pathways', 'Pathway', (36, 61))	('alteration', 'Var', (18, 28))	('immunity', 'CPA', (112, 120))	('lipid', 'Chemical', 'MESH:D008055', (36, 41))
90845	31074374	Specifically, the alteration of fatty acid degradation is also companioned with other metabolism pathways such as amino acid metabolisms and xenobiotics, as well as the cAMP signaling pathway.	('cAMP', 'Chemical', '-', (169, 173))	('fatty acid', 'Chemical', 'MESH:D005227', (32, 42))	('alteration', 'Var', (18, 28))	('fatty acid degradation', 'MPA', (32, 54))	('cAMP signaling pathway', 'Pathway', (169, 191))
90846	31074374	The alteration of arachidonic acid metabolism can not only affect other metabolism process, but also accompanied the alteration of signaling pathway such as the MAPK signaling pathway.	('affect', 'Reg', (59, 65))	('arachidonic acid', 'Chemical', 'MESH:D016718', (18, 34))	('arachidonic acid metabolism', 'MPA', (18, 45))	('metabolism process', 'MPA', (72, 90))	('accompanied', 'Reg', (101, 112))	('signaling pathway', 'Pathway', (131, 148))	('alteration', 'Var', (4, 14))	('MAPK signaling pathway', 'Pathway', (161, 183))	('alteration', 'Reg', (117, 127))
90847	31074374	The differentially expressed genes in the cholesterol metabolism pathway can also modulate multiple signaling pathways such as PI3K-Akt signaling, calcium signaling, cGMP-PKG signaling pathway etc., impling its important role in signaling modulation.	('calcium signaling', 'Pathway', (147, 164))	('cGMP-PKG signaling pathway', 'Pathway', (166, 192))	('modulate', 'Reg', (82, 90))	('calcium', 'Chemical', 'MESH:D002118', (147, 154))	('signaling pathways', 'Pathway', (100, 118))	('cholesterol', 'Chemical', 'MESH:D002784', (42, 53))	('cGMP', 'Chemical', 'MESH:D006152', (166, 170))	('cholesterol metabolism', 'Gene', (42, 64))	('differentially expressed', 'Var', (4, 28))	('PI3K-Akt signaling', 'Pathway', (127, 145))
90855	31074374	It can be observed that some of the differentially expressed lipid metabolism genes were regulated by DNA methylation.	('methylation', 'Var', (106, 117))	('regulated', 'Reg', (89, 98))	('DNA methylation', 'Var', (102, 117))	('lipid metabolism genes', 'Gene', (61, 83))	('lipid', 'Chemical', 'MESH:D008055', (61, 66))
90856	31074374	i.e., APOA1, which has anti-inflammatory and antioxidant properties, was reduced in gene expression associated with hyper-methylation of its promotor region in cholesterol metabolism pathway, which could accelerate tumor growth and metastasis primarily via modulation of innate and adaptive immune responses in tumors.	('tumors', 'Disease', (311, 317))	('tumors', 'Disease', 'MESH:D009369', (311, 317))	('tumors', 'Phenotype', 'HP:0002664', (311, 317))	('APOA1', 'Gene', (6, 11))	('gene expression', 'MPA', (84, 99))	('tumor', 'Disease', 'MESH:D009369', (215, 220))	('reduced', 'NegReg', (73, 80))	('tumor', 'Disease', 'MESH:D009369', (311, 316))	('metastasis', 'CPA', (232, 242))	('hyper-methylation', 'Var', (116, 133))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('tumor', 'Phenotype', 'HP:0002664', (311, 316))	('accelerate', 'PosReg', (204, 214))	('tumor', 'Disease', (215, 220))	('tumor', 'Disease', (311, 316))	('cholesterol', 'Chemical', 'MESH:D002784', (160, 171))
90859	31074374	Next, we identified somatic alternations that potentially regulated lipid metabolism.	('lipid metabolism', 'MPA', (68, 84))	('lipid', 'Chemical', 'MESH:D008055', (68, 73))	('alternations', 'Var', (28, 40))	('regulated', 'Reg', (58, 67))
90862	31074374	Notably, some genes with high frequency mutation also showed consistent gene differential expression patterns across pan-cancer.	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('mutation', 'Var', (40, 48))	('cancer', 'Disease', (121, 127))	('cancer', 'Disease', 'MESH:D009369', (121, 127))
90865	31074374	Candidate lipid genes with mutations in at least three tumor samples were selected, grouped by gene mutations.	('mutations', 'Var', (27, 36))	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('lipid genes', 'Gene', (10, 21))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('lipid', 'Chemical', 'MESH:D008055', (10, 15))	('tumor', 'Disease', (55, 60))
90871	31074374	The pan-cancer map of mutated transcription factors significantly associated (Wilcoxon signed-rank test) with targeted lipid genes expression is shown in Fig.	('lipid', 'Chemical', 'MESH:D008055', (119, 124))	('cancer', 'Disease', (8, 14))	('associated', 'Reg', (66, 76))	('mutated', 'Var', (22, 29))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('cancer', 'Disease', 'MESH:D009369', (8, 14))
90872	31074374	The mutations of SREBF1, SREBF2 and TP53 show significant impacts on downstream targeted lipid genes, especially in the downstream target genes in cholesterol metabolism pathway.	('SREBF2', 'Gene', (25, 31))	('lipid', 'Chemical', 'MESH:D008055', (89, 94))	('TP53', 'Gene', (36, 40))	('impacts', 'Reg', (58, 65))	('cholesterol', 'Chemical', 'MESH:D002784', (147, 158))	('lipid genes', 'Gene', (89, 100))	('cholesterol metabolism pathway', 'Pathway', (147, 177))	('mutations', 'Var', (4, 13))	('SREBF1', 'Gene', (17, 23))
90873	31074374	In addition, the mutation on SREBF1 was also associated with the expression of ACACB and SCD, which are important enzymes in fatty acid beta-oxidation and the synthesis of unsaturated fatty acids processes, respectively.	('fatty acid', 'Chemical', 'MESH:D005227', (125, 135))	('SCD', 'Disease', 'MESH:C536778', (89, 92))	('fatty acid', 'Chemical', 'MESH:D005227', (184, 194))	('SREBF1', 'Gene', (29, 35))	('SCD', 'Disease', (89, 92))	('mutation', 'Var', (17, 25))	('ACACB', 'Chemical', '-', (79, 84))	('associated', 'Reg', (45, 55))	('ACACB', 'Gene', (79, 84))	('unsaturated fatty acids', 'Chemical', 'MESH:D005231', (172, 195))
90874	31074374	In BRCA, HNSC, THCA and LUSC, TP53 mutation regulated the expression of LRP1, the up-regulation of LRP1 has been reported to be associated with the invasiveness of cancer cells by supporting ERK and inhibiting JNK signaling pathways.	('LRP1', 'Gene', (99, 103))	('TP53', 'Gene', (30, 34))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('inhibiting', 'NegReg', (199, 209))	('expression', 'MPA', (58, 68))	('JNK signaling pathways', 'Pathway', (210, 232))	('invasiveness of cancer', 'Disease', (148, 170))	('LRP1', 'Gene', (72, 76))	('regulated', 'Reg', (44, 53))	('up-regulation', 'PosReg', (82, 95))	('associated', 'Reg', (128, 138))	('invasiveness of cancer', 'Disease', 'MESH:D009362', (148, 170))	('mutation', 'Var', (35, 43))	('supporting', 'PosReg', (180, 190))	('ERK', 'Pathway', (191, 194))
90879	31074374	Similarly, the abnormal expression of SREBF2 also significantly affected the imbalance of cholesterol metabolism and arachidonic acid metabolism.	('arachidonic acid', 'Chemical', 'MESH:D016718', (117, 133))	('SREBF2', 'Gene', (38, 44))	('affected', 'Reg', (64, 72))	('arachidonic acid metabolism', 'MPA', (117, 144))	('imbalance', 'Phenotype', 'HP:0002172', (77, 86))	('cholesterol', 'Chemical', 'MESH:D002784', (90, 101))	('abnormal expression', 'Var', (15, 34))
90880	31074374	In COAD, the significant up-regulation of TBXAS1 expression is affected by hypo-methylation of the DNA promoter region and associated with mutation of the upstream transcription factor NFE2.	('up-regulation', 'PosReg', (25, 38))	('mutation', 'Var', (139, 147))	('COAD', 'Disease', (3, 7))	('expression', 'MPA', (49, 59))	('TBXAS1', 'Gene', (42, 48))	('NFE2', 'Gene', (185, 189))	('COAD', 'Disease', 'MESH:D029424', (3, 7))	('hypo-methylation', 'Var', (75, 91))
90881	31074374	In LIHC, the significant downregulation of LDLR expression may be modulated by the hyper-methylation of the DNA promoter region, the mutation of the upstream transcription factor SP3, and the down-regulation of the transcription factor EGR1.	('LDLR', 'Gene', (43, 47))	('mutation', 'Var', (133, 141))	('SP3', 'Gene', (179, 182))	('expression', 'MPA', (48, 58))	('hyper-methylation', 'MPA', (83, 100))	('LIHC', 'Disease', 'None', (3, 7))	('down-regulation', 'NegReg', (192, 207))	('EGR1', 'Gene', (236, 240))	('downregulation', 'NegReg', (25, 39))	('LIHC', 'Disease', (3, 7))
90893	31074374	3c, including ANGPTL3, PLTP and LRP2 in the cholesterol metabolism pathway, PLA2G5, CYP2B6 and GPX2 in the arachidonic acid metabolism pathway, HMGCS2 and FABP2 etc.	('arachidonic acid metabolism pathway', 'Pathway', (107, 142))	('arachidonic acid', 'Chemical', 'MESH:D016718', (107, 123))	('cholesterol', 'Chemical', 'MESH:D002784', (44, 55))	('cholesterol metabolism pathway', 'Pathway', (44, 74))	('GPX2', 'Gene', '2877', (95, 99))	('GPX2', 'Gene', (95, 99))	('HMGCS2', 'Gene', '3158', (144, 150))	('HMGCS2', 'Gene', (144, 150))	('CYP2B6', 'Var', (84, 90))
90922	31074374	Genetic depletion of the fatty acid translocase CD36 inhibits the induction of immunosuppressive function in tumor-infiltrating Myeloid-derived suppressor cells (MDSC) and results in a CD8+ T cell-dependent delay in tumor growth.	('tumor', 'Disease', (216, 221))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('depletion', 'Var', (8, 17))	('tumor', 'Disease', (109, 114))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('CD36', 'Species', '42374', (48, 52))	('tumor', 'Disease', 'MESH:D009369', (216, 221))	('induction', 'MPA', (66, 75))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('inhibits', 'NegReg', (53, 61))	('fatty acid', 'Chemical', 'MESH:D005227', (25, 35))	('CD8+ T cell-dependent delay', 'CPA', (185, 212))	('CD36', 'Gene', (48, 52))
90927	31074374	In the process of studying the mechanism of abnormal regulation of expression profile, we correlated possible causes of metabolic disorders of lipids in tumors from several aspects: somatic mutation, DNA methylation abnormality and regulation of transcription factors.	('lipids', 'Chemical', 'MESH:D008055', (143, 149))	('abnormality', 'Var', (216, 227))	('metabolic disorders', 'Disease', 'MESH:D008659', (120, 139))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('metabolic disorders', 'Disease', (120, 139))	('tumors', 'Disease', (153, 159))	('tumors', 'Phenotype', 'HP:0002664', (153, 159))	('tumors', 'Disease', 'MESH:D009369', (153, 159))
90941	31074374	For specific gene in one cancer type, hypo-methylation in the gene promoter region and over-expression, or hyper-methylated in the promoter region and down-expression were considered as positively regulations.	('down-expression', 'NegReg', (151, 166))	('hyper-methylated', 'Var', (107, 123))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('hypo-methylation', 'Var', (38, 54))	('over-expression', 'PosReg', (87, 102))	('cancer', 'Disease', 'MESH:D009369', (25, 31))	('cancer', 'Disease', (25, 31))
90942	31074374	To investigate the effect of somatic mutations on gene expression, we grouped the tumor samples according to mutations for each gene, then Wilcoxon signed-rank test was used to identify the difference of gene expression between the mutated group and the non-mutated group.	('tumor', 'Disease', (82, 87))	('mutated', 'Var', (232, 239))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumor', 'Disease', 'MESH:D009369', (82, 87))
90954	30819158	Overexpression of HOXA genes, including HOTTIP, has been associated with a more aggressive phenotype in several cancers.	('HOXA', 'Gene', '3197', (18, 22))	('cancers', 'Phenotype', 'HP:0002664', (112, 119))	('HOXA', 'Gene', (18, 22))	('cancers', 'Disease', 'MESH:D009369', (112, 119))	('HOTTIP', 'Gene', '100316868', (40, 46))	('cancers', 'Disease', (112, 119))	('Overexpression', 'Var', (0, 14))	('HOTTIP', 'Gene', (40, 46))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('associated', 'Reg', (57, 67))
90985	30819158	All patient samples were studied by Sanger sequencing for mutations in TP53 (exons 5-8) and KRAS (codon 12-13), and only adenocarcinoma patients samples were studied for EGFR mutations (exons 19-21).	('mutations', 'Var', (58, 67))	('patient', 'Species', '9606', (136, 143))	('EGFR', 'Gene', '1956', (170, 174))	('patient', 'Species', '9606', (4, 11))	('KRAS', 'Gene', (92, 96))	('adenocarcinoma', 'Disease', (121, 135))	('EGFR', 'Gene', (170, 174))	('patients', 'Species', '9606', (136, 144))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('TP53', 'Gene', '7157', (71, 75))	('KRAS', 'Gene', '3845', (92, 96))	('TP53', 'Gene', (71, 75))	('adenocarcinoma', 'Disease', 'MESH:D000230', (121, 135))
90993	30819158	TaqMan assays (Life Technologies) were used to quantify HOTTIP (Hs00955374_s1) in a 7500 Real Time PCR device (Applied Biosystems).	('HOTTIP', 'Gene', (56, 62))	('HOTTIP', 'Gene', '100316868', (56, 62))	('Hs00955374_s1', 'Var', (64, 77))
91004	30819158	Thirty-three percent of the patients harbored TP53 mutations and 20% harbored KRAS mutations.	('harbored', 'Reg', (37, 45))	('mutations', 'Var', (51, 60))	('TP53', 'Gene', '7157', (46, 50))	('KRAS', 'Gene', (78, 82))	('TP53', 'Gene', (46, 50))	('KRAS', 'Gene', '3845', (78, 82))	('patients', 'Species', '9606', (28, 36))
91005	30819158	Adenocarcinoma patients with EGFR mutations (29.8%) showed a trend towards shorter TTR (p = 0.09) and OS (p = 0.09).	('Adenocarcinoma', 'Disease', (0, 14))	('OS', 'Chemical', '-', (102, 104))	('patients', 'Species', '9606', (15, 23))	('Adenocarcinoma', 'Disease', 'MESH:D000230', (0, 14))	('carcinoma', 'Phenotype', 'HP:0030731', (5, 14))	('TTR', 'MPA', (83, 86))	('EGFR', 'Gene', '1956', (29, 33))	('EGFR', 'Gene', (29, 33))	('shorter', 'NegReg', (75, 82))	('mutations', 'Var', (34, 43))
91017	30819158	Using TCGA data and the TANRIC web tool, we found that high levels of HOTTIP were associated with shorter OS (p = 0.025) in a cohort of 91 stage I-II patients with lung adenocarcinoma (Fig.	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (164, 183))	('high levels', 'Var', (55, 66))	('HOTTIP', 'Gene', (70, 76))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (164, 183))	('HOTTIP', 'Gene', '100316868', (70, 76))	('patients', 'Species', '9606', (150, 158))	('OS', 'Chemical', '-', (106, 108))	('carcinoma', 'Phenotype', 'HP:0030731', (174, 183))	('lung adenocarcinoma', 'Disease', (164, 183))
91032	30819158	The prognostic role of HOTTIP levels has been described in several cancers and analyzed in several meta-analyses, which concluded that high HOTTIP expression in cancer patients is associated with poor clinical outcome.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('high', 'Var', (135, 139))	('cancers', 'Phenotype', 'HP:0002664', (67, 74))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('cancer', 'Disease', (67, 73))	('cancers', 'Disease', (67, 74))	('cancers', 'Disease', 'MESH:D009369', (67, 74))	('HOTTIP', 'Gene', '100316868', (23, 29))	('HOTTIP', 'Gene', '100316868', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('patients', 'Species', '9606', (168, 176))	('cancer', 'Disease', (161, 167))	('HOTTIP', 'Gene', (23, 29))	('HOTTIP', 'Gene', (140, 146))
91051	30819158	In contrast, however, an in vitro study in the A549 NSCLC cell line showed that silencing HOTTIP led to increased HOXA13 levels.	('silencing', 'Var', (80, 89))	('NSCLC', 'Disease', (52, 57))	('increased', 'PosReg', (104, 113))	('HOTTIP', 'Gene', (90, 96))	('NSCLC', 'Disease', 'MESH:D002289', (52, 57))	('A549', 'CellLine', 'CVCL:0023', (47, 51))	('HOXA13', 'Gene', (114, 120))	('HOXA13', 'Gene', '3209', (114, 120))	('NSCLC', 'Phenotype', 'HP:0030358', (52, 57))	('HOTTIP', 'Gene', '100316868', (90, 96))
91061	30819158	In line with the prognostic impact of HOTTIP levels in other cancers, high levels of HOTTIP correlated with worse TTR and worse OS in our early-stage NSCLC patients.	('patients', 'Species', '9606', (156, 164))	('NSCLC', 'Disease', 'MESH:D002289', (150, 155))	('HOTTIP', 'Gene', (38, 44))	('OS', 'Chemical', '-', (128, 130))	('high levels', 'Var', (70, 81))	('HOTTIP', 'Gene', '100316868', (85, 91))	('cancers', 'Disease', 'MESH:D009369', (61, 68))	('NSCLC', 'Phenotype', 'HP:0030358', (150, 155))	('TTR', 'MPA', (114, 117))	('cancers', 'Phenotype', 'HP:0002664', (61, 68))	('cancers', 'Disease', (61, 68))	('worse', 'NegReg', (108, 113))	('HOTTIP', 'Gene', '100316868', (38, 44))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('HOTTIP', 'Gene', (85, 91))	('NSCLC', 'Disease', (150, 155))
91099	29088890	Pregnant or lactating women were also excluded; Patients with tumors that were too large to cure radically by simple surgery and patients with large lesions that could not be repaired or affected head-and-neck function after surgery were included in the study; Patients without distant metastasis, as determined via the above imaging examinations, were included in the study; Patients without contraindications to treatment were included in the study; Patients with a pretreatment Eastern Cooperative Oncology Group performance status of 0 or 1, a life expectancy >=3 months, and adequate organ function (a leukocyte count of 4,000/mm3, a platelet count >=100,000/mm3, a hemoglobin >=9.0 g/dl, an aspartate aminotransferase (AST) <=2 times the upper limit of normal (UNL), an alanine aminotransferase (ALT) <=2 times the UNL, an alkaline phosphatase (ALP) <=2 times the UNL, a serum bilirubin <=1.5 mg/dl, and a serum creatinine <= the UNL) were included in the study.	('alkaline phosphatase', 'Gene', (829, 849))	('AST', 'Gene', (725, 728))	('<=2', 'Var', (730, 733))	('alkaline phosphatase', 'Gene', '250', (829, 849))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('serum bilirubin', 'MPA', (877, 892))	('alanine aminotransferase', 'Gene', (776, 800))	('alanine aminotransferase', 'Gene', '2875', (776, 800))	('<=1.5', 'NegReg', (893, 898))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('>=9.0', 'Var', (682, 687))	('tumors', 'Disease', (62, 68))	('aspartate aminotransferase', 'Gene', '26503', (697, 723))	('Patients', 'Species', '9606', (261, 269))	('Patients', 'Species', '9606', (48, 56))	('aspartate aminotransferase', 'Gene', (697, 723))	('ALP', 'Gene', '250', (851, 854))	('women', 'Species', '9606', (22, 27))	('patients', 'Species', '9606', (129, 137))	('tumors', 'Disease', 'MESH:D009369', (62, 68))	('Patients', 'Species', '9606', (452, 460))	('AST', 'Gene', '26503', (725, 728))	('ALP', 'Gene', (851, 854))	('Oncology', 'Phenotype', 'HP:0002664', (501, 509))	('<=2', 'NegReg', (856, 859))	('Patients', 'Species', '9606', (376, 384))
91238	25028925	Differences in miRNA Expression in Early Stage Lung Adenocarcinomas that Did and Did Not Relapse Relapse of adenocarcinoma, the most common non-small cell lung cancer (NSCLC), is a major clinical challenge to improving survival.	('Differences', 'Var', (0, 11))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (140, 166))	('Lung Adenocarcinomas', 'Phenotype', 'HP:0030078', (47, 67))	('Relapse of adenocarcinoma', 'Disease', 'None', (97, 122))	('Relapse of adenocarcinoma', 'Disease', (97, 122))	('cell lung cancer', 'Disease', 'MESH:D008175', (150, 166))	('miRNA', 'Protein', (15, 20))	('NSCLC', 'Disease', 'MESH:D002289', (168, 173))	('carcinoma', 'Phenotype', 'HP:0030731', (57, 66))	('Adenocarcinomas', 'Disease', (52, 67))	('Adenocarcinomas', 'Disease', 'MESH:D000230', (52, 67))	('lung cancer', 'Phenotype', 'HP:0100526', (155, 166))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('carcinomas', 'Phenotype', 'HP:0030731', (57, 67))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (144, 166))	('NSCLC', 'Disease', (168, 173))	('cell lung cancer', 'Disease', (150, 166))
91303	25028925	Ectopic miR-133b expression induces apoptosis, inhibits cell growth, migration, invasion, and enhances sensitivity to gefitinib in NSCLC adenocarcinoma cell lines, which may explain why we detected decreased levels in lung adenocarcinomas in our analyses.	('sensitivity to gefitinib', 'MPA', (103, 127))	('lung adenocarcinomas', 'Disease', (218, 238))	('Ectopic', 'Var', (0, 7))	('carcinoma', 'Phenotype', 'HP:0030731', (142, 151))	('migration', 'CPA', (69, 78))	('inhibits', 'NegReg', (47, 55))	('gefitinib', 'Chemical', 'MESH:D000077156', (118, 127))	('miR-133b', 'Gene', (8, 16))	('NSCLC adenocarcinoma', 'Disease', 'MESH:D000230', (131, 151))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (218, 237))	('cell growth', 'CPA', (56, 67))	('carcinoma', 'Phenotype', 'HP:0030731', (228, 237))	('apoptosis', 'CPA', (36, 45))	('induces', 'Reg', (28, 35))	('carcinomas', 'Phenotype', 'HP:0030731', (228, 238))	('NSCLC adenocarcinoma', 'Disease', (131, 151))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (218, 238))	('invasion', 'CPA', (80, 88))	('enhances', 'PosReg', (94, 102))	('miR-133b', 'Gene', '442890', (8, 16))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (218, 238))
91306	25028925	miR-96 and -183* are members of the miR-183 polycistronic family that consist of miR-96, and -182, and -183.	('miR-183', 'Gene', '406959', (36, 43))	('miR-183', 'Gene', (36, 43))	('miR-96', 'Gene', '407053', (81, 87))	('miR-96', 'Gene', (81, 87))	('miR-96', 'Gene', '407053', (0, 6))	('and -182', 'Var', (89, 97))	('miR-96', 'Gene', (0, 6))
91347	25028925	Using qRT-PCR, a significant decrease was also detected in lung adenocarcinomas in our second cohort (Fig 3A).	('qRT-PCR', 'Var', (6, 13))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (59, 79))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (59, 79))	('carcinomas', 'Phenotype', 'HP:0030731', (69, 79))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (59, 78))	('decrease', 'NegReg', (29, 37))	('lung adenocarcinomas', 'Disease', (59, 79))
91368	25028925	It was reported that miR-650 was significantly higher in NSCLC adenocarcinoma tissues than in corresponding non-tumor tissues, and high expression of miR-650 significantly associated with lymph node metastasis and poor prognosis for NSCLC adenocarcinoma patients.	('NSCLC adenocarcinoma', 'Disease', (233, 253))	('carcinoma', 'Phenotype', 'HP:0030731', (244, 253))	('tumor', 'Disease', (112, 117))	('NSCLC adenocarcinoma', 'Disease', 'MESH:D000230', (57, 77))	('NSCLC adenocarcinoma', 'Disease', 'MESH:D000230', (233, 253))	('higher', 'PosReg', (47, 53))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('associated with', 'Reg', (172, 187))	('miR-650', 'Gene', '723778', (21, 28))	('lymph node metastasis', 'CPA', (188, 209))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('miR-650', 'Gene', (150, 157))	('carcinoma', 'Phenotype', 'HP:0030731', (68, 77))	('high expression', 'Var', (131, 146))	('NSCLC adenocarcinoma', 'Disease', (57, 77))	('patients', 'Species', '9606', (254, 262))	('miR-650', 'Gene', (21, 28))	('miR-650', 'Gene', '723778', (150, 157))
91370	25028925	Dysregulation of miRNA has been demonstrated in nearly every cancer type, including lung adenocarcinoma.	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (84, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('Dysregulation', 'Var', (0, 13))	('demonstrated', 'Reg', (32, 44))	('miR', 'Gene', (17, 20))	('cancer', 'Disease', (61, 67))	('lung adenocarcinoma', 'Disease', (84, 103))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (84, 103))	('miR', 'Gene', '22877', (17, 20))
91371	25028925	Alterations in miRNA expression can be a consequence of or contribute to tumorigenesis and/or tumor progression.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('Alterations', 'Var', (0, 11))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('miR', 'Gene', '22877', (15, 18))	('tumor', 'Disease', (94, 99))	('tumor', 'Disease', (73, 78))	('contribute', 'Reg', (59, 69))	('miR', 'Gene', (15, 18))
91587	33879685	In oral squamous cell carcinoma, the abnormal expression of lncRNA is also closely related to its occurrence and progression, and may be applied as a biomarker or therapeutic target for the diagnosis and prognosis of oral squamous cell carcinoma.	('lncRNA', 'Protein', (60, 66))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (3, 31))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (8, 31))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (217, 245))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (222, 245))	('carcinoma', 'Phenotype', 'HP:0030731', (236, 245))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('oral squamous cell carcinoma', 'Disease', (3, 31))	('abnormal', 'Var', (37, 45))	('related', 'Reg', (83, 90))	('oral squamous cell carcinoma', 'Disease', (217, 245))
91659	31645882	Inhibition of JAK2 induces cytotoxicity of CD24-expressed ovarian cancer cells and increases survival of animals carrying CD24-positive tumours, supporting JAK2 as a therapeutic target for cancer cells expressing CD24.	('increases', 'PosReg', (83, 92))	('CD24', 'Gene', '100133941', (43, 47))	('CD24', 'Gene', '100133941', (122, 126))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('ovarian cancer', 'Disease', 'MESH:D010051', (58, 72))	('tumours', 'Disease', (136, 143))	('CD24', 'Gene', (213, 217))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('tumours', 'Phenotype', 'HP:0002664', (136, 143))	('cancer', 'Disease', (66, 72))	('JAK2', 'Gene', '3717', (14, 18))	('tumours', 'Disease', 'MESH:D009369', (136, 143))	('survival', 'CPA', (93, 101))	('JAK2', 'Gene', '3717', (156, 160))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('ovarian cancer', 'Disease', (58, 72))	('tumour', 'Phenotype', 'HP:0002664', (136, 142))	('ovarian cancer', 'Phenotype', 'HP:0100615', (58, 72))	('CD24', 'Gene', (43, 47))	('CD24', 'Gene', (122, 126))	('Inhibition', 'Var', (0, 10))	('CD24', 'Gene', '100133941', (213, 217))	('JAK2', 'Gene', (14, 18))	('cancer', 'Disease', (189, 195))	('JAK2', 'Gene', (156, 160))	('cytotoxicity', 'Disease', (27, 39))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('cytotoxicity', 'Disease', 'MESH:D064420', (27, 39))
91664	31645882	Experiments have shown that inhibition of cancer cells' CD44 function could reverse their malignant behaviour and sensitise them to therapy.	('CD44', 'Gene', (56, 60))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('inhibition', 'Var', (28, 38))	('reverse', 'NegReg', (76, 83))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('CD44', 'Gene', '960', (56, 60))	('malignant behaviour', 'CPA', (90, 109))
91665	31645882	For example, antibody against CD44 was able to inhibit migration of breast cancer cells and eradicate acute myeloid leukaemia stem cells.	('acute myeloid leukaemia', 'Disease', (102, 125))	('eradicate', 'NegReg', (92, 101))	('acute myeloid leukaemia', 'Phenotype', 'HP:0004808', (102, 125))	('breast cancer', 'Disease', 'MESH:D001943', (68, 81))	('myeloid leukaemia', 'Phenotype', 'HP:0012324', (108, 125))	('breast cancer', 'Phenotype', 'HP:0003002', (68, 81))	('migration', 'CPA', (55, 64))	('CD44', 'Gene', '960', (30, 34))	('breast cancer', 'Disease', (68, 81))	('inhibit', 'NegReg', (47, 54))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('CD44', 'Gene', (30, 34))	('antibody', 'Var', (13, 21))	('acute myeloid leukaemia', 'Disease', 'MESH:D015470', (102, 125))
91674	31645882	Intraperitoneal injection of anti-CD36 antibody effectively reduce tumour burden in mouse xenograft.	('anti-CD36', 'Var', (29, 38))	('reduce', 'NegReg', (60, 66))	('mouse', 'Species', '10090', (84, 89))	('tumour burden', 'Disease', (67, 80))	('tumour', 'Phenotype', 'HP:0002664', (67, 73))	('tumour burden', 'Disease', 'MESH:D009369', (67, 80))
91675	31645882	Most excitingly, in a human oral cancer model, anti-CD36 antibody treatment completely blocked the metastatic potential of CD36-positive cancer cells in mouse, reminding us of the hopeful capacity of anti-CD36 monoclonal antibody in treating malignancies like our patient's.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('cancer', 'Disease', (33, 39))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('metastatic potential', 'CPA', (99, 119))	('mouse', 'Species', '10090', (153, 158))	('oral cancer', 'Disease', 'MESH:D009062', (28, 39))	('malignancies', 'Disease', 'MESH:D009369', (242, 254))	('cancer', 'Disease', (137, 143))	('anti-CD36', 'Var', (47, 56))	('patient', 'Species', '9606', (264, 271))	('blocked', 'NegReg', (87, 94))	('oral cancer', 'Disease', (28, 39))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('human', 'Species', '9606', (22, 27))	('malignancies', 'Disease', (242, 254))
91685	30626401	We performed 181 multi-region tumor tissues sequencing and matched ctDNA sequencing from 32 operative NSCLC to compare ITH among different NSCLC subtypes, including EGFR-mutant lung adenocarcinoma (LUAD), KRAS-mutant LUAD, EGFR&KRAS-wild-type LUAD, and lung squamous cell carcinoma (LUSC), and examine potential value of ctDNA for ITH analysis.	('NSCLC', 'Disease', 'MESH:D002289', (102, 107))	('LUAD', 'Phenotype', 'HP:0030078', (217, 221))	('rat', 'Species', '10116', (95, 98))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('NSCLC', 'Disease', (102, 107))	('NSCLC', 'Phenotype', 'HP:0030358', (102, 107))	('lung adenocarcinoma', 'Disease', (177, 196))	('LUAD', 'Phenotype', 'HP:0030078', (198, 202))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('NSCLC', 'Disease', 'MESH:D002289', (139, 144))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (253, 281))	('NSCLC', 'Disease', (139, 144))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (177, 196))	('LUSC', 'Phenotype', 'HP:0030359', (283, 287))	('EGFR-mutant', 'Var', (165, 176))	('LUAD', 'Phenotype', 'HP:0030078', (243, 247))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (177, 196))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (253, 281))	('NSCLC', 'Phenotype', 'HP:0030358', (139, 144))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (258, 281))	('lung squamous cell carcinoma', 'Disease', (253, 281))	('carcinoma', 'Phenotype', 'HP:0030731', (187, 196))	('carcinoma', 'Phenotype', 'HP:0030731', (272, 281))	('tumor', 'Disease', (30, 35))
91691	30626401	Non-small cell lung cancer (NSCLC) comprises the majority of pathological types, including epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma (LUAD), kirsten rat sarcoma viral oncogene (KRAS)-mutant LUAD, EGFR&KRAS-wild-type LUAD, and lung squamous cell carcinoma (LUSC).	('LUAD', 'Phenotype', 'HP:0030078', (241, 245))	('Non-small cell lung cancer', 'Disease', 'MESH:D002289', (0, 26))	('rat', 'Species', '10116', (174, 177))	('LUAD', 'Phenotype', 'HP:0030078', (215, 219))	('epidermal growth factor receptor', 'Gene', '24329', (91, 123))	('sarcoma viral', 'Disease', 'MESH:D001102', (178, 191))	('-mutant', 'Var', (130, 137))	('lung adenocarcinoma', 'Disease', (138, 157))	('NSCLC', 'Disease', 'MESH:D002289', (28, 33))	('LUAD', 'Phenotype', 'HP:0030078', (159, 163))	('sarcoma viral', 'Disease', (178, 191))	('carcinoma', 'Phenotype', 'HP:0030731', (270, 279))	('Non-small cell lung cancer', 'Disease', (0, 26))	('epidermal growth factor receptor', 'Gene', (91, 123))	('carcinoma', 'Phenotype', 'HP:0030731', (148, 157))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (251, 279))	('NSCLC', 'Disease', (28, 33))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (138, 157))	('Non-small cell lung cancer', 'Phenotype', 'HP:0030358', (0, 26))	('NSCLC', 'Phenotype', 'HP:0030358', (28, 33))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (138, 157))	('lung cancer', 'Phenotype', 'HP:0100526', (15, 26))	('sarcoma', 'Phenotype', 'HP:0100242', (178, 185))	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (251, 279))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (256, 279))	('lung squamous cell carcinoma', 'Disease', (251, 279))	('LUSC', 'Phenotype', 'HP:0030359', (281, 285))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (4, 26))
91692	30626401	Although genetic molecular analysis is becoming more common to help clinicians select appropriate target therapies for NSCLC patients, such as EGFR-tyrosine kinase inhibitors (EGFR-TKIs) for EGFR mutant patients, intratumor heterogeneity (ITH) can still lead to therapeutic failure, drug resistance, thus leading to unfavourable prognosis.	('NSCLC', 'Disease', 'MESH:D002289', (119, 124))	('tumor', 'Disease', 'MESH:D009369', (218, 223))	('therapeutic', 'MPA', (262, 273))	('rat', 'Species', '10116', (216, 219))	('NSCLC', 'Phenotype', 'HP:0030358', (119, 124))	('EGFR', 'Gene', (191, 195))	('lead to', 'Reg', (254, 261))	('patients', 'Species', '9606', (203, 211))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('drug resistance', 'CPA', (283, 298))	('drug resistance', 'Phenotype', 'HP:0020174', (283, 298))	('tumor', 'Disease', (218, 223))	('NSCLC', 'Disease', (119, 124))	('mutant', 'Var', (196, 202))	('patients', 'Species', '9606', (125, 133))
91693	30626401	A recent study found widespread ITH for both somatic mutations and copy-number alterations in early-stage NSCLC patients, which may give useful information for evolutionary tumorigenesis.	('rat', 'Species', '10116', (83, 86))	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('NSCLC', 'Disease', 'MESH:D002289', (106, 111))	('patients', 'Species', '9606', (112, 120))	('NSCLC', 'Phenotype', 'HP:0030358', (106, 111))	('tumor', 'Disease', (173, 178))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('copy-number alterations', 'Var', (67, 90))	('NSCLC', 'Disease', (106, 111))
91699	30626401	Additionally, the cancer genome atlas (TCGA) datasets were downloaded to confirm a high correlation of mutation number between whole exome sequencing (WES) and our panel sequencing (Additional file 3: Figure S1).	('mutation', 'Var', (103, 111))	('cancer genome atlas', 'Disease', 'MESH:D009369', (18, 37))	('cancer genome atlas', 'Disease', (18, 37))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))
91701	30626401	As shown in the genetic landscape, we identified 437 somatic variations, including 421 SNVs and Indels, 13 CNVs, and 3 gene fusions in overall enrolled patients (Additional file 6: Figure S3).	('Indels', 'Var', (96, 102))	('CNVs', 'Var', (107, 111))	('SNVs', 'Var', (87, 91))	('patients', 'Species', '9606', (152, 160))
91704	30626401	EGFR-mutant LUAD had the lowest proportion of trunk mutations and the highest proportion of branch mutations, compared to KRAS-mutant LUAD and other NSCLC subtypes, in accordance with the implication of ITHi analysis.	('LUAD', 'Phenotype', 'HP:0030078', (134, 138))	('NSCLC', 'Disease', (149, 154))	('lowest', 'NegReg', (25, 31))	('LUAD', 'Phenotype', 'HP:0030078', (12, 16))	('LUAD', 'Disease', (12, 16))	('NSCLC', 'Disease', 'MESH:D002289', (149, 154))	('EGFR-mutant', 'Var', (0, 11))	('NSCLC', 'Phenotype', 'HP:0030358', (149, 154))
91706	30626401	Additionally, for driver mutations, the proportions of mutations in oncogenes and tumor suppressor genes (TSG) seemed to be similar both in the trunk (58 and 42%) and branch (49 and 51%) in general.	('mutations', 'Var', (25, 34))	('mutations', 'Var', (55, 64))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('oncogenes', 'Gene', (68, 77))	('tumor', 'Disease', (82, 87))
91707	30626401	However, oncogene mutations showed higher proportion in EGFR-mutant LUAD compared with TSG, while TSG alterations had a strong enrichment in LUSC compared with oncogene in trunk (Fig.	('LUSC', 'Disease', (141, 145))	('LUSC', 'Phenotype', 'HP:0030359', (141, 145))	('EGFR-mutant', 'Gene', (56, 67))	('LUAD', 'Phenotype', 'HP:0030078', (68, 72))	('rat', 'Species', '10116', (106, 109))	('LUAD', 'Disease', (68, 72))	('mutations', 'Var', (18, 27))
91709	30626401	A total of 146 tumor-derived mutations were detected with at least one high-quality mutant read in 29 (91%) patients.	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('mutations', 'Var', (29, 38))	('tumor', 'Disease', (15, 20))	('patients', 'Species', '9606', (108, 116))
91710	30626401	As for different NSCLC molecular subtypes, LUSC and EGFR&KRAS-wild-type LUAD had higher proportions for tumor-derived trunk mutations (81 and 53%) than those in EGFR-mutant LUAD (30%) and KRAS-mutant LUAD (22%), while the detections for tumor-derived branch mutations in ctDNA were extremely poor (from 13 to 25%) among all above NSCLC subtypes.	('NSCLC', 'Disease', (17, 22))	('tumor', 'Disease', (237, 242))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('NSCLC', 'Disease', 'MESH:D002289', (17, 22))	('LUAD', 'Phenotype', 'HP:0030078', (72, 76))	('tumor', 'Disease', (104, 109))	('NSCLC', 'Disease', (330, 335))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))	('LUAD', 'Phenotype', 'HP:0030078', (200, 204))	('NSCLC', 'Disease', 'MESH:D002289', (330, 335))	('LUAD', 'Phenotype', 'HP:0030078', (173, 177))	('LUSC', 'Phenotype', 'HP:0030359', (43, 47))	('tumor', 'Disease', 'MESH:D009369', (237, 242))	('NSCLC', 'Phenotype', 'HP:0030358', (17, 22))	('trunk', 'Var', (118, 123))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('NSCLC', 'Phenotype', 'HP:0030358', (330, 335))
91712	30626401	It is known that neoantigens arise as a consequence of tumor-specific mutations.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('mutations', 'Var', (70, 79))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Disease', (55, 60))	('neoantigens', 'MPA', (17, 28))
91716	30626401	ctDNA analysis showed only LUSC had acceptable detection of tumor-derived trunk mutations, while EGFR&KRAS-wild-type LUAD, EGFR-mutant LUAD and KRAS-mutant LUAD showed unsatisfactory detections of trunk mutations.	('mutations', 'Var', (80, 89))	('LUAD', 'Phenotype', 'HP:0030078', (117, 121))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('LUAD', 'Phenotype', 'HP:0030078', (135, 139))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('LUAD', 'Phenotype', 'HP:0030078', (156, 160))	('tumor', 'Disease', (60, 65))	('LUSC', 'Phenotype', 'HP:0030359', (27, 31))
91717	30626401	And the detections for tumor-derived branch mutations in ctDNA were extremely poor among all NSCLC subtypes.	('NSCLC', 'Disease', (93, 98))	('NSCLC', 'Disease', 'MESH:D002289', (93, 98))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('mutations', 'Var', (44, 53))	('NSCLC', 'Phenotype', 'HP:0030358', (93, 98))	('tumor', 'Disease', (23, 28))
91740	27366979	A prototypic example of racial diversity among the mutational landscape of cancer is the high prevalence of EGFR mutations among patients of Asian descent (estimated to occur in approximately 50% of the Asian population).	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('EGFR', 'Gene', '1956', (108, 112))	('patients', 'Species', '9606', (129, 137))	('EGFR', 'Gene', (108, 112))	('cancer', 'Disease', (75, 81))	('mutations', 'Var', (113, 122))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))
91741	27366979	The ability to confidently detect mutations in a particular subgroup of patients depends on the background mutational frequency (ie, noise), the mutational rate of the target of interest (ie, signal), and the absolute sample size (ie, number of tumors sequenced).	('tumors', 'Disease', 'MESH:D009369', (245, 251))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('mutations', 'Var', (34, 43))	('tumors', 'Phenotype', 'HP:0002664', (245, 251))	('tumors', 'Disease', (245, 251))	('patients', 'Species', '9606', (72, 80))
91742	27366979	TCGA project has uncovered numerous uncommon subtypes and mutations across multiple cancer types, and these results are being used to develop new therapies and ultimately improve outcomes for patients with cancer.	('mutations', 'Var', (58, 67))	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('cancer', 'Disease', (84, 90))	('patients', 'Species', '9606', (192, 200))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('cancer', 'Disease', (206, 212))	('cancer', 'Disease', 'MESH:D009369', (206, 212))
91747	27366979	With somatic mutational frequencies of 0.7 (prostate cancer) to 9.9 (lung SCC) (Table), all tumor types from white patients contained enough samples to detect a 10% mutational frequency (Figure, A).	('mutational', 'Var', (165, 175))	('patients', 'Species', '9606', (115, 123))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('prostate cancer', 'Disease', (44, 59))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('to 9', 'Species', '1214577', (61, 65))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('SCC', 'Gene', (74, 77))	('prostate cancer', 'Disease', 'MESH:D011471', (44, 59))	('tumor', 'Disease', (92, 97))	('prostate cancer', 'Phenotype', 'HP:0012125', (44, 59))	('SCC', 'Phenotype', 'HP:0002860', (74, 77))	('SCC', 'Gene', '6317', (74, 77))
91751	27366979	Interestingly, the best-known example of a targetable mutation in cancer that varies by race/ethnicity is arguably the EGFR mutation in lung adenocarcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (136, 155))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('EGFR', 'Gene', '1956', (119, 123))	('mutation', 'Var', (124, 132))	('lung adenocarcinoma', 'Disease', (136, 155))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (136, 155))	('EGFR', 'Gene', (119, 123))	('cancer', 'Disease', (66, 72))
91754	27366979	These observations are explained by the PIONEER study, a multinational epidemiologic prospective study that demonstrated that EGFR mutations are present in 51.4% of stage IIIB or IV lung adenocarcinomas among Asian patients, in contrast to approximately 20% in white and African American patients.	('patients', 'Species', '9606', (215, 223))	('mutations', 'Var', (131, 140))	('EGFR', 'Gene', (126, 130))	('IV lung adenocarcinomas', 'Disease', 'MESH:D000077192', (179, 202))	('patients', 'Species', '9606', (288, 296))	('stage IIIB', 'Disease', (165, 175))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (182, 201))	('IV lung adenocarcinomas', 'Disease', (179, 202))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (182, 202))	('carcinoma', 'Phenotype', 'HP:0030731', (192, 201))	('EGFR', 'Gene', '1956', (126, 130))
91756	27366979	Not all mutations or genomic alterations are as common as EGFR mutations in non-small-cell lung cancer.	('mutations', 'Var', (63, 72))	('EGFR', 'Gene', '1956', (58, 62))	('lung cancer', 'Phenotype', 'HP:0100526', (91, 102))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('EGFR', 'Gene', (58, 62))	('lung cancer', 'Disease', 'MESH:D008175', (91, 102))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (76, 102))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (80, 102))	('common', 'Reg', (48, 54))	('lung cancer', 'Disease', (91, 102))
91757	27366979	Another recent success in targeted therapy is targeting the relatively infrequent genomic alteration of ALK rearrangement in non- small-cell lung cancer (approximately 4% in unselected patients).	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (130, 152))	('ALK', 'Gene', '238', (104, 107))	('non- small-cell lung cancer', 'Phenotype', 'HP:0030358', (125, 152))	('lung cancer', 'Disease', (141, 152))	('lung cancer', 'Phenotype', 'HP:0100526', (141, 152))	('ALK', 'Gene', (104, 107))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('patients', 'Species', '9606', (185, 193))	('rearrangement', 'Var', (108, 121))	('lung cancer', 'Disease', 'MESH:D008175', (141, 152))
91758	27366979	Other examples from large genomic analyses of lung cancer include BRAF mutations, which in 1 study occurred in 3% (18 of 697) of patients, all of whom were from white patients.	('patients', 'Species', '9606', (129, 137))	('patients', 'Species', '9606', (167, 175))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('lung cancer', 'Disease', 'MESH:D008175', (46, 57))	('mutations', 'Var', (71, 80))	('BRAF', 'Gene', '673', (66, 70))	('BRAF', 'Gene', (66, 70))	('lung cancer', 'Disease', (46, 57))	('lung cancer', 'Phenotype', 'HP:0100526', (46, 57))
91760	27366979	As we have demonstrated, black women with breast cancer were the only subset to have ample representation of black patients to detect a less than 10% mutational frequency rate over background.	('patients', 'Species', '9606', (115, 123))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('breast cancer', 'Disease', 'MESH:D001943', (42, 55))	('mutational frequency', 'Var', (150, 170))	('breast cancer', 'Phenotype', 'HP:0003002', (42, 55))	('breast cancer', 'Disease', (42, 55))	('women', 'Species', '9606', (31, 36))
91771	30650190	Genetic Variants in RUNX3, AMD1 and MSRA in the Methionine Metabolic Pathway and Survival in Non-small Cell Lung Cancer Patients Abnormal methionine dependence in cancer cells has led to methionine restriction as a potential therapeutic strategy.	('Methionine Metabolic Pathway', 'Pathway', (48, 76))	('MSRA', 'Gene', (36, 40))	('Non-small Cell Lung Cancer', 'Disease', (93, 119))	('cancer', 'Disease', 'MESH:D009369', (163, 169))	('methionine', 'Chemical', 'MESH:D008715', (187, 197))	('AMD1', 'Gene', '262', (27, 31))	('Non-small Cell Lung Cancer', 'Disease', 'MESH:D002289', (93, 119))	('Abnormal methionine', 'Phenotype', 'HP:0010901', (129, 148))	('Cancer', 'Phenotype', 'HP:0002664', (113, 119))	('Methionine', 'Chemical', 'MESH:D008715', (48, 58))	('methionine', 'Chemical', 'MESH:D008715', (138, 148))	('RUNX3', 'Gene', (20, 25))	('Lung Cancer', 'Phenotype', 'HP:0100526', (108, 119))	('MSRA', 'Gene', '4482', (36, 40))	('small Cell Lung Cancer', 'Phenotype', 'HP:0030357', (97, 119))	('cancer', 'Disease', (163, 169))	('methionine dependence', 'MPA', (138, 159))	('AMD1', 'Gene', (27, 31))	('Non-small Cell Lung Cancer', 'Phenotype', 'HP:0030358', (93, 119))	('Variants', 'Var', (8, 16))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('RUNX3', 'Gene', '864', (20, 25))
91772	30650190	We hypothesized that genetic variants involved in methionine-metabolic genes are associated with survival in non-small cell lung cancer (NSCLC) patients.	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (109, 135))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('NSCLC', 'Disease', (137, 142))	('methionine', 'Chemical', 'MESH:D008715', (50, 60))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (109, 135))	('NSCLC', 'Disease', 'MESH:D002289', (137, 142))	('genetic variants', 'Var', (21, 37))	('NSCLC', 'Phenotype', 'HP:0030358', (137, 142))	('patients', 'Species', '9606', (144, 152))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (113, 135))	('non-small cell lung cancer', 'Disease', (109, 135))	('methionine-metabolic genes', 'Gene', (50, 76))	('lung cancer', 'Phenotype', 'HP:0100526', (124, 135))	('associated', 'Reg', (81, 91))
91773	30650190	Therefore, we investigated associations of 16,378 common single-nucleotide polymorphisms (SNPs) in 97 methionine-metabolic pathway genes with overall survival (OS) in NSCLC patients using genotyping data from two published genome-wide association study (GWAS) datasets.	('associations', 'Interaction', (27, 39))	('NSCLC', 'Disease', 'MESH:D002289', (167, 172))	('patients', 'Species', '9606', (173, 181))	('NSCLC', 'Phenotype', 'HP:0030358', (167, 172))	('investigated', 'Reg', (14, 26))	('methionine', 'Chemical', 'MESH:D008715', (102, 112))	('overall', 'MPA', (142, 149))	('methionine-metabolic pathway genes', 'Gene', (102, 136))	('single-nucleotide polymorphisms', 'Var', (57, 88))	('NSCLC', 'Disease', (167, 172))
91775	30650190	Three SNPs (RUNX3 rs7553295G>T, AMD1 rs1279590G>A and MSRA rs73534533C>A) were replicated in the validation dataset and their meta-analysis showed that adjusted hazards ratio [HR] of 0.82 [95% confidence interval (CI) =0.75-0.89] and Pmeta=2.86 x 10-6, 0.81 (0.73-0.91) and Pmeta=4.63 x 10-4, and 0.77 (0.68-0.89) and Pmeta=2.07 x 10-4, respectively).	('rs73534533C>A', 'Var', (59, 72))	('rs1279590G>A', 'DBSNP_MENTION', 'None', (37, 49))	('MSRA', 'Gene', (54, 58))	('rs1279590G>A', 'Var', (37, 49))	('AMD1', 'Gene', '262', (32, 36))	('RUNX3', 'Gene', '864', (12, 17))	('rs73534533C>A', 'DBSNP_MENTION', 'None', (59, 72))	('AMD1', 'Gene', (32, 36))	('RUNX3', 'Gene', (12, 17))	('rs7553295G>T', 'Var', (18, 30))	('MSRA', 'Gene', '4482', (54, 58))	('rs7553295G>T', 'DBSNP_MENTION', 'None', (18, 30))
91778	30650190	Taken together, these genetic variants of methionine-metabolic pathway genes may be promising predictors of survival in NSCLC patients.	('NSCLC', 'Disease', 'MESH:D002289', (120, 125))	('genetic variants', 'Var', (22, 38))	('predictors', 'Reg', (94, 104))	('methionine', 'Chemical', 'MESH:D008715', (42, 52))	('NSCLC', 'Phenotype', 'HP:0030358', (120, 125))	('patients', 'Species', '9606', (126, 134))	('NSCLC', 'Disease', (120, 125))	('methionine-metabolic pathway genes', 'Gene', (42, 76))
91783	30650190	Recently, some pathway-based hypothesis-driven studies using published genome-wide association study (GWAS) datasets have identified a number of genetic variants, i.e., single nucleotide polymorphisms (SNPs), with moderate but detectable effects on clinical outcomes of NSCLC, following by studying potential biological functions in some biological pathways, which have shed some light on prognosis prediction and possible individualized therapeutics .	('NSCLC', 'Disease', 'MESH:D002289', (270, 275))	('NSCLC', 'Phenotype', 'HP:0030358', (270, 275))	('effects', 'Reg', (238, 245))	('single nucleotide polymorphisms', 'Var', (169, 200))	('variants', 'Var', (153, 161))	('NSCLC', 'Disease', (270, 275))
91794	30650190	Previous studies have revealed that genetic variants of methionine metabolism genes, including the methionine synthase (MTR) and methionine synthase reductase (MTRR), may affect enzyme activities and thereby affect cancer risk in Turkish population and non-Hispanic whites .	('MTRR', 'Gene', (160, 164))	('methionine synthase reductase', 'Gene', '4552', (129, 158))	('methionine synthase reductase', 'Gene', (129, 158))	('MTR', 'Gene', (120, 123))	('MTRR', 'Gene', '4552', (160, 164))	('cancer', 'Disease', (215, 221))	('cancer', 'Disease', 'MESH:D009369', (215, 221))	('methionine', 'Chemical', 'MESH:D008715', (129, 139))	('affect', 'Reg', (208, 214))	('methionine', 'Chemical', 'MESH:D008715', (99, 109))	('methionine synthase', 'Gene', '4548', (99, 118))	('methionine synthase', 'Gene', '4548', (129, 148))	('enzyme activities', 'MPA', (178, 195))	('methionine', 'Chemical', 'MESH:D008715', (56, 66))	('affect', 'Reg', (171, 177))	('methionine synthase', 'Gene', (99, 118))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('variants', 'Var', (44, 52))
91795	30650190	In addition, functional SNPs in MTR, MTRR and other genes related to the methionine metabolism have also been found to be associated with lung cancer prognosis in two small studies .	('associated', 'Reg', (122, 132))	('functional SNPs', 'Var', (13, 28))	('lung cancer', 'Disease', 'MESH:D008175', (138, 149))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('MTRR', 'Gene', (37, 41))	('MTRR', 'Gene', '4552', (37, 41))	('methionine', 'Chemical', 'MESH:D008715', (73, 83))	('lung cancer', 'Disease', (138, 149))	('lung cancer', 'Phenotype', 'HP:0100526', (138, 149))	('MTR', 'Gene', (32, 35))
91796	30650190	In the present study, we used two large published GWAS datasets to determine whether common genetic variants in genes involved in the methionine metabolism pathway are associated with overall survival (OS) of NSCLC patients.	('patients', 'Species', '9606', (215, 223))	('NSCLC', 'Disease', 'MESH:D002289', (209, 214))	('methionine', 'Chemical', 'MESH:D008715', (134, 144))	('variants', 'Var', (100, 108))	('overall survival', 'MPA', (184, 200))	('associated with', 'Reg', (168, 183))	('NSCLC', 'Phenotype', 'HP:0030358', (209, 214))	('NSCLC', 'Disease', (209, 214))
91821	30650190	The Manhattan plot of associations between these variants and NSCLC OS in PLCO is shown in Supporting information Fig.	('NSCLC', 'Disease', (62, 67))	('variants', 'Var', (49, 57))	('NSCLC', 'Disease', 'MESH:D002289', (62, 67))	('NSCLC', 'Phenotype', 'HP:0030358', (62, 67))	('associations', 'Interaction', (22, 34))
91823	30650190	As shown in Table 1, three SNPs in three genes identified in the discovery phase remained statistically significant (P < 0.05): there were rs7553295 in runt-related transcription factor 3 (RUNX3), rs1279590 in S-adenosylmethionine decarboxylase 1 (AMD1) and rs73534533 in methionine sulfoxide reductase (MSRA), all of which were associated with an improved survival in both datasets.	('rs1279590', 'Var', (197, 206))	('AMD1', 'Gene', (248, 252))	('methionine sulfoxide reductase', 'Gene', '4482', (272, 302))	('RUNX3', 'Gene', (189, 194))	('rs73534533', 'DBSNP_MENTION', 'None', (258, 268))	('MSRA', 'Gene', (304, 308))	('rs7553295', 'DBSNP_MENTION', 'None', (139, 148))	('rs7553295', 'Var', (139, 148))	('improved', 'PosReg', (348, 356))	('S-adenosylmethionine decarboxylase 1', 'Gene', (210, 246))	('methionine sulfoxide reductase', 'Gene', (272, 302))	('survival', 'MPA', (357, 365))	('runt-related transcription factor 3', 'Gene', '864', (152, 187))	('rs1279590', 'DBSNP_MENTION', 'None', (197, 206))	('AMD1', 'Gene', '262', (248, 252))	('S-adenosylmethionine decarboxylase 1', 'Gene', '262', (210, 246))	('RUNX3', 'Gene', '864', (189, 194))	('runt-related transcription factor 3', 'Gene', (152, 187))	('MSRA', 'Gene', '4482', (304, 308))	('rs73534533', 'Var', (258, 268))
91824	30650190	As indicated by RegulomeDB, the scores of RUNX3 rs7553295, AMD1 rs1279590 and MSRA rs73534533 were 4, 5 and 6, respectively.	('RUNX3', 'Gene', (42, 47))	('rs73534533', 'Var', (83, 93))	('RUNX3', 'Gene', '864', (42, 47))	('rs7553295', 'Var', (48, 57))	('AMD1', 'Gene', (59, 63))	('rs1279590', 'DBSNP_MENTION', 'None', (64, 73))	('MSRA', 'Gene', (78, 82))	('rs1279590', 'Var', (64, 73))	('rs73534533', 'DBSNP_MENTION', 'None', (83, 93))	('MSRA', 'Gene', '4482', (78, 82))	('AMD1', 'Gene', '262', (59, 63))	('rs7553295', 'DBSNP_MENTION', 'None', (48, 57))
91825	30650190	Functional annotation of these SNPs in HaploReg demonstrated that RUNX3 rs7553295 overlaps with a promoter and an enhancer, potentially disrupting the motif of Zfp691 and affecting the mRNA expression; AMD1 rs1279590 overlaps with an enhancer in 18 tissues (e.g., lung, IMR90 fetal lung fibroblasts) and may disrupt three motifs, including Nanog, POU class 2 homeobox 2 (Pou2f2/Oct-2) and POU class 5 homeobox 1 (Pou5f1/Oct-4) and thus affect mRNA expression of the corresponding gene; similarly, MSRA rs73534533 may disrupt seven motifs.	('affect', 'Reg', (436, 442))	('Oct-4', 'Gene', (420, 425))	('MSRA', 'Gene', (497, 501))	('Nanog', 'Gene', '79923', (340, 345))	('Oct-2', 'Gene', (378, 383))	('Nanog', 'Gene', (340, 345))	('AMD1', 'Gene', '262', (202, 206))	('rs1279590', 'DBSNP_MENTION', 'None', (207, 216))	('affecting', 'Reg', (171, 180))	('IMR90', 'CellLine', 'CVCL:0347', (270, 275))	('RUNX3', 'Gene', '864', (66, 71))	('mRNA expression', 'MPA', (185, 200))	('Oct-2', 'Gene', '5452', (378, 383))	('Pou5f1', 'Gene', (413, 419))	('rs73534533', 'Var', (502, 512))	('Pou2f2', 'Gene', (371, 377))	('mRNA expression', 'MPA', (443, 458))	('Pou2f2', 'Gene', '5452', (371, 377))	('Pou5f1', 'Gene', '5460', (413, 419))	('Zfp691', 'Gene', '51058', (160, 166))	('MSRA', 'Gene', '4482', (497, 501))	('Zfp691', 'Gene', (160, 166))	('disrupt', 'NegReg', (517, 524))	('AMD1', 'Gene', (202, 206))	('rs7553295', 'Var', (72, 81))	('rs7553295', 'DBSNP_MENTION', 'None', (72, 81))	('RUNX3', 'Gene', (66, 71))	('Oct-4', 'Gene', '5460', (420, 425))	('rs1279590', 'Var', (207, 216))	('rs73534533', 'DBSNP_MENTION', 'None', (502, 512))
91829	30650190	In the PLCO dataset, the risk of death was significantly decreased with the increasing number of rs7553295T, rs1279590 A and rs73534533 A alleles (Ptrend <0.0001, 0.011 and 0.005, respectively).	('rs1279590', 'DBSNP_MENTION', 'None', (109, 118))	('rs73534533', 'Var', (125, 135))	('rs73534533', 'DBSNP_MENTION', 'None', (125, 135))	('rs1279590', 'Var', (109, 118))	('rs7553295T', 'Var', (97, 107))	('decreased', 'NegReg', (57, 66))
91831	30650190	In addition, regional association plots for variants in RUNX3, AMD1 and MSRA, including the 250-kb regions flanking the neighborhoods of these genes, are shown in Supporting information Fig.	('MSRA', 'Gene', (72, 76))	('AMD1', 'Gene', '262', (63, 67))	('AMD1', 'Gene', (63, 67))	('RUNX3', 'Gene', (56, 61))	('RUNX3', 'Gene', '864', (56, 61))	('MSRA', 'Gene', '4482', (72, 76))	('variants', 'Var', (44, 52))
91832	30650190	To evaluate the joint effect of the three independent SNPs on OS, the protective genotypes (i.e., RUNX3 rs7553295 GT+TT, AMD1 rs1279590 GA+AA and MSRA rs73534533 CA+AA) were combined into a genetic score as the number of protective genotypes (NPGs) (Table 3).	('rs73534533', 'Var', (151, 161))	('AMD1', 'Gene', '262', (121, 125))	('rs7553295', 'Var', (104, 113))	('rs7553295', 'DBSNP_MENTION', 'None', (104, 113))	('rs1279590', 'DBSNP_MENTION', 'None', (126, 135))	('rs73534533', 'DBSNP_MENTION', 'None', (151, 161))	('MSRA', 'Gene', '4482', (146, 150))	('AMD1', 'Gene', (121, 125))	('rs1279590', 'Var', (126, 135))	('RUNX3', 'Gene', (98, 103))	('RUNX3', 'Gene', '864', (98, 103))	('MSRA', 'Gene', (146, 150))
91840	30650190	2, rs1279590 GA+AA (or the A allele) was significantly associated with a decreased mRNA expression level of AMD1 (a trend test in a dominant model: P = 0.017) and rs73534533 CA+AA (or the A allele) was significantly associated with an increased mRNA level of MSRA (a trend test in a dominant model: P = 0.027).	('decreased', 'NegReg', (73, 82))	('MSRA', 'Gene', (259, 263))	('AMD1', 'Gene', '262', (108, 112))	('rs73534533', 'Var', (163, 173))	('AMD1', 'Gene', (108, 112))	('rs1279590', 'DBSNP_MENTION', 'None', (3, 12))	('mRNA expression level', 'MPA', (83, 104))	('increased', 'PosReg', (235, 244))	('mRNA level', 'MPA', (245, 255))	('rs73534533', 'DBSNP_MENTION', 'None', (163, 173))	('MSRA', 'Gene', '4482', (259, 263))	('rs1279590', 'Var', (3, 12))
91841	30650190	However, there was no significant association between rs7553295 GT+TT and RUNX3 mRNA expression levels (Supporting information Fig.	('rs7553295', 'DBSNP_MENTION', 'None', (54, 63))	('RUNX3', 'Gene', (74, 79))	('RUNX3', 'Gene', '864', (74, 79))	('rs7553295', 'Var', (54, 63))
91842	30650190	In Westra's 2013 study , we also found that rs7553295 GT+TT (or the T allele) and rs1279590 GA+AA (or the A allele) were associated with decreased mRNA expression levels of RUNX3 and AMD1 in the whole blood (P = 1.25 x 10-5 and 5.45 x 10-6, respectively).	('AMD1', 'Gene', '262', (183, 187))	('AMD1', 'Gene', (183, 187))	('rs1279590', 'Var', (82, 91))	('RUNX3', 'Gene', (173, 178))	('mRNA expression levels', 'MPA', (147, 169))	('rs1279590', 'DBSNP_MENTION', 'None', (82, 91))	('RUNX3', 'Gene', '864', (173, 178))	('rs7553295', 'DBSNP_MENTION', 'None', (44, 53))	('decreased', 'NegReg', (137, 146))	('rs7553295', 'Var', (44, 53))
91843	30650190	In lung normal tissues from the donors, the rs7553295 T allele (i.e., GT+TT genotypes and rs1279590 A allele (i.e., GA+AA genotypes) had a non-significant trend in correlation with decreased mRNA expression levels of RUNX3 (P = 0.140, Supporting information Fig.	('rs1279590', 'Var', (90, 99))	('RUNX3', 'Gene', (217, 222))	('mRNA expression levels', 'MPA', (191, 213))	('RUNX3', 'Gene', '864', (217, 222))	('rs1279590', 'DBSNP_MENTION', 'None', (90, 99))	('rs7553295', 'DBSNP_MENTION', 'None', (44, 53))	('rs7553295', 'Var', (44, 53))	('decreased', 'NegReg', (181, 190))
91845	30650190	4C), but this non-significant trend was not observed between the rs73534533 A allele (i.e., CA+AA genotypes) and mRNA expression levels of MSRA (P = 0.62, Supporting information Fig.	('rs73534533', 'Var', (65, 75))	('MSRA', 'Gene', (139, 143))	('mRNA expression levels', 'MPA', (113, 135))	('rs73534533', 'DBSNP_MENTION', 'None', (65, 75))	('MSRA', 'Gene', '4482', (139, 143))
91847	30650190	Only rs7553295 GT+TT (or the T allele) showed a non-significant trend in correlation with decreased mRNA expression levels of RUNX3 in all patients with NSCLC, LUSC or LUAD (P = 0.174, 0.597 and 0.197, respectively) (Supporting information Figs.	('RUNX3', 'Gene', '864', (126, 131))	('NSCLC', 'Phenotype', 'HP:0030358', (153, 158))	('patients', 'Species', '9606', (139, 147))	('rs7553295', 'DBSNP_MENTION', 'None', (5, 14))	('decreased', 'NegReg', (90, 99))	('NSCLC', 'Disease', (153, 158))	('rs7553295', 'Var', (5, 14))	('NSCLC', 'Disease', 'MESH:D002289', (153, 158))	('mRNA expression levels', 'MPA', (100, 122))	('RUNX3', 'Gene', (126, 131))
91854	30650190	These results suggested that given the low mutation rates, the functional SNPs in RUNX3, AMD1 and MSRA may play a more important role in the dysregulation of mRNA expression in tumor tissues than mutations had.	('MSRA', 'Gene', '4482', (98, 102))	('dysregulation', 'MPA', (141, 154))	('AMD1', 'Gene', (89, 93))	('SNPs', 'Var', (74, 78))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('mRNA expression', 'MPA', (158, 173))	('MSRA', 'Gene', (98, 102))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('RUNX3', 'Gene', '864', (82, 87))	('RUNX3', 'Gene', (82, 87))	('tumor', 'Disease', (177, 182))	('AMD1', 'Gene', '262', (89, 93))	('play', 'Reg', (107, 111))
91857	30650190	In the present study, we first identified rs7553295 G>T, rs1279590 C>A and rs73534533 C>A as predictors of NSCLC OS.	('NSCLC', 'Disease', (107, 112))	('rs7553295', 'Var', (42, 51))	('NSCLC', 'Disease', 'MESH:D002289', (107, 112))	('rs1279590', 'Var', (57, 66))	('rs7553295', 'DBSNP_MENTION', 'None', (42, 51))	('rs73534533', 'Var', (75, 85))	('NSCLC', 'Phenotype', 'HP:0030358', (107, 112))	('rs73534533', 'DBSNP_MENTION', 'None', (75, 85))	('rs1279590', 'DBSNP_MENTION', 'None', (57, 66))
91858	30650190	These findings suggested that genetic variants in the methionine metabolism pathway genes might have biological roles in NSCLC progression, possibly through a mechanism of modulating expression of these genes, which provides new scientific insights into metabolism-based therapeutics.	('methionine', 'Chemical', 'MESH:D008715', (54, 64))	('genetic variants', 'Var', (30, 46))	('modulating', 'Reg', (172, 182))	('NSCLC', 'Disease', (121, 126))	('methionine', 'Enzyme', (54, 64))	('NSCLC', 'Disease', 'MESH:D002289', (121, 126))	('expression', 'MPA', (183, 193))	('NSCLC', 'Phenotype', 'HP:0030358', (121, 126))
91859	30650190	In the present study, it appears that the independent effects of genetic variants in RUNX3, AMD1 and MSRA on OS and DSS in NSCLC patients can add to a much strong effect through a genetic sore, which represents the combined effects of the three genetic variants.	('RUNX3', 'Gene', (85, 90))	('RUNX3', 'Gene', '864', (85, 90))	('MSRA', 'Gene', (101, 105))	('DSS', 'Disease', (116, 119))	('NSCLC', 'Disease', (123, 128))	('patients', 'Species', '9606', (129, 137))	('NSCLC', 'Disease', 'MESH:D002289', (123, 128))	('variants', 'Var', (73, 81))	('effects', 'Reg', (54, 61))	('AMD1', 'Gene', '262', (92, 96))	('NSCLC', 'Phenotype', 'HP:0030358', (123, 128))	('genetic variants', 'Var', (65, 81))	('MSRA', 'Gene', '4482', (101, 105))	('AMD1', 'Gene', (92, 96))
91863	30650190	Due to aberrant hypermethylation of its CpG islands , RUNX3 expression has been reported to be lost in the range of 19~95% of lung cancer cell lines and tissue samples, and RUNX3 inactivation has been causally linked to the preneoplastic stage of lung adenocarcimoma .	('expression', 'MPA', (60, 70))	('lost', 'NegReg', (95, 99))	('inactivation', 'NegReg', (179, 191))	('lung cancer', 'Disease', 'MESH:D008175', (126, 137))	('linked', 'Reg', (210, 216))	('lung adenocarcimoma', 'Disease', 'MESH:D008171', (247, 266))	('RUNX3', 'Gene', '864', (54, 59))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('hypermethylation', 'Var', (16, 32))	('lung cancer', 'Disease', (126, 137))	('lung adenocarcimoma', 'Disease', (247, 266))	('RUNX3', 'Gene', (173, 178))	('RUNX3', 'Gene', '864', (173, 178))	('lung cancer', 'Phenotype', 'HP:0100526', (126, 137))	('RUNX3', 'Gene', (54, 59))	('aberrant hypermethylation', 'Var', (7, 32))
91864	30650190	In the present study, we found that rs7553295, located in the 2-kb of the 3' of RUNX3, was associated with a better survival in NSCLC patients.	('NSCLC', 'Phenotype', 'HP:0030358', (128, 133))	('patients', 'Species', '9606', (134, 142))	('RUNX3', 'Gene', (80, 85))	('NSCLC', 'Disease', (128, 133))	('rs7553295', 'DBSNP_MENTION', 'None', (36, 45))	('RUNX3', 'Gene', '864', (80, 85))	('NSCLC', 'Disease', 'MESH:D002289', (128, 133))	('rs7553295', 'Var', (36, 45))	('better', 'PosReg', (109, 115))
91868	30650190	In line with that, we found the RUNX3 rs7553295 T allele was associated with a significant decrease in mRNA expression levels of RUNX3 in whole blood.	('mRNA expression levels', 'MPA', (103, 125))	('RUNX3', 'Gene', '864', (129, 134))	('RUNX3', 'Gene', '864', (32, 37))	('RUNX3', 'Gene', (129, 134))	('RUNX3', 'Gene', (32, 37))	('rs7553295', 'DBSNP_MENTION', 'None', (38, 47))	('rs7553295', 'Var', (38, 47))	('decrease', 'NegReg', (91, 99))
91869	30650190	Therefore, rs7553295 probably affects gene expression levels by modifying the accessibility of chromatin during transcription.	('accessibility of chromatin during transcription', 'MPA', (78, 125))	('rs7553295', 'Var', (11, 20))	('affects', 'Reg', (30, 37))	('gene expression levels', 'MPA', (38, 60))	('modifying', 'Reg', (64, 73))	('rs7553295', 'DBSNP_MENTION', 'None', (11, 20))
91874	30650190	In the present study, we found that NSCLC patients with genotypes of AMD1 rs1279590 GA+AA had better survival.	('AMD1', 'Gene', '262', (69, 73))	('NSCLC', 'Phenotype', 'HP:0030358', (36, 41))	('rs1279590', 'Var', (74, 83))	('AMD1', 'Gene', (69, 73))	('better', 'PosReg', (94, 100))	('NSCLC', 'Disease', (36, 41))	('survival', 'CPA', (101, 109))	('patients', 'Species', '9606', (42, 50))	('NSCLC', 'Disease', 'MESH:D002289', (36, 41))	('rs1279590', 'DBSNP_MENTION', 'None', (74, 83))
91875	30650190	In line with that, we found the AMD1 rs1279590 A allele was associated with a significant decrease in mRNA expression levels of AMD1 in lymphobpastoid cell lines and whole blood, which supports an oncogenic effect of AMD1.	('AMD1', 'Gene', '262', (217, 221))	('mRNA expression levels', 'MPA', (102, 124))	('AMD1', 'Gene', (217, 221))	('AMD1', 'Gene', '262', (128, 132))	('AMD1', 'Gene', (128, 132))	('AMD1', 'Gene', '262', (32, 36))	('rs1279590', 'Var', (37, 46))	('AMD1', 'Gene', (32, 36))	('decrease', 'NegReg', (90, 98))	('rs1279590', 'DBSNP_MENTION', 'None', (37, 46))
91876	30650190	Meanwhile, rs1279590 might have some effects on three motifs including Nanog , Pou2f2  and Pou5f1 , which are all associated with tumorigenesis and metastasis.	('rs1279590', 'Var', (11, 20))	('Pou5f1', 'Gene', (91, 97))	('Nanog', 'Gene', '79923', (71, 76))	('metastasis', 'CPA', (148, 158))	('rs1279590', 'DBSNP_MENTION', 'None', (11, 20))	('Pou2f2', 'Gene', (79, 85))	('Pou2f2', 'Gene', '5452', (79, 85))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('associated', 'Reg', (114, 124))	('effects', 'Reg', (37, 44))	('Nanog', 'Gene', (71, 76))	('tumor', 'Disease', (130, 135))	('Pou5f1', 'Gene', '5460', (91, 97))
91877	30650190	Taken together, the evidence may possibly explain the mechanism underlying the association between rs1279590 and NSCLC OS, but further functional investigation is needed.	('rs1279590', 'DBSNP_MENTION', 'None', (99, 108))	('NSCLC', 'Phenotype', 'HP:0030358', (113, 118))	('rs1279590', 'Var', (99, 108))	('NSCLC', 'Disease', (113, 118))	('NSCLC', 'Disease', 'MESH:D002289', (113, 118))
91879	30650190	In the present study, our findings suggested that MSRA rs73534533 is associated with a better survival in NSCLC patients.	('NSCLC', 'Disease', 'MESH:D002289', (106, 111))	('MSRA', 'Gene', '4482', (50, 54))	('rs73534533', 'Var', (55, 65))	('MSRA', 'Gene', (50, 54))	('patients', 'Species', '9606', (112, 120))	('rs73534533', 'DBSNP_MENTION', 'None', (55, 65))	('NSCLC', 'Phenotype', 'HP:0030358', (106, 111))	('better', 'PosReg', (87, 93))	('NSCLC', 'Disease', (106, 111))
91880	30650190	Consistent with that, rs73534533 CA + AA genotypes were associated with a significant increase in mRNA expression levels of MSRA in lymphobplastoid cell lines.	('increase', 'PosReg', (86, 94))	('mRNA expression levels', 'MPA', (98, 120))	('rs73534533', 'Var', (22, 32))	('MSRA', 'Gene', '4482', (124, 128))	('rs73534533', 'DBSNP_MENTION', 'None', (22, 32))	('MSRA', 'Gene', (124, 128))
91883	30650190	Consistent with that, rs73534533 CA + AA genotypes are associated with a significant increase in mRNA expression levels of MSRA in lymphobplastoid cell lines, leading to suppressive genic effects on NSCLC.	('MSRA', 'Gene', '4482', (123, 127))	('suppressive', 'NegReg', (170, 181))	('NSCLC', 'Disease', 'MESH:D002289', (199, 204))	('rs73534533', 'Var', (22, 32))	('MSRA', 'Gene', (123, 127))	('NSCLC', 'Phenotype', 'HP:0030358', (199, 204))	('mRNA expression levels', 'MPA', (97, 119))	('increase', 'PosReg', (85, 93))	('rs73534533', 'DBSNP_MENTION', 'None', (22, 32))	('NSCLC', 'Disease', (199, 204))
91884	30650190	Moreover, rs73534533 might have effects on tumor progression through disruption of seven transcription regulators motifs, including homeobox protein Hox-B13, which might influence angiogenesis and epithelial cell maturation ; paired box protein Pax-4, which is correlated with cell differentiation and apoptotic process ; and THAP Domain Containing 1, which regulates endothelial cell proliferation and G1/S cell-cycle progression .	('disruption', 'NegReg', (69, 79))	('effects', 'Reg', (32, 39))	('tumor', 'Disease', (43, 48))	('THAP Domain Containing 1', 'Gene', (326, 350))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('epithelial cell maturation', 'CPA', (197, 223))	('THAP Domain Containing 1', 'Gene', '55145', (326, 350))	('rs73534533', 'Var', (10, 20))	('G1/S cell-cycle progression', 'CPA', (403, 430))	('Hox-B13', 'Gene', '10481', (149, 156))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('Pax-4', 'Gene', '5078', (245, 250))	('endothelial cell proliferation', 'CPA', (368, 398))	('influence', 'Reg', (170, 179))	('Hox-B13', 'Gene', (149, 156))	('regulates', 'Reg', (358, 367))	('angiogenesis', 'CPA', (180, 192))	('rs73534533', 'DBSNP_MENTION', 'None', (10, 20))	('Pax-4', 'Gene', (245, 250))
91891	30650190	Methionine dependence is a unique metabolic defect seen in various cancers including non-small cell lung cancer (NSCLC), and thus genetic variants involved in methionine-metabolic genes may have an impact on clinical outcomes of NSCLC.	('NSCLC', 'Phenotype', 'HP:0030358', (113, 118))	('NSCLC', 'Disease', (229, 234))	('metabolic defect', 'Disease', 'MESH:D008659', (34, 50))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('Methionine', 'Disease', (0, 10))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (85, 111))	('NSCLC', 'Phenotype', 'HP:0030358', (229, 234))	('cancers', 'Disease', 'MESH:D009369', (67, 74))	('genetic variants', 'Var', (130, 146))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (89, 111))	('impact', 'Reg', (198, 204))	('have', 'Reg', (190, 194))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (85, 111))	('Methionine', 'Chemical', 'MESH:D008715', (0, 10))	('metabolic defect', 'Disease', (34, 50))	('methionine', 'Chemical', 'MESH:D008715', (159, 169))	('NSCLC', 'Disease', 'MESH:D002289', (113, 118))	('cancers', 'Phenotype', 'HP:0002664', (67, 74))	('cancers', 'Disease', (67, 74))	('lung cancer', 'Phenotype', 'HP:0100526', (100, 111))	('non-small cell lung cancer', 'Disease', (85, 111))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('NSCLC', 'Disease', 'MESH:D002289', (229, 234))	('NSCLC', 'Disease', (113, 118))
91892	30650190	By using publically available genome-wide association study datasets, we identified RUNX3 rs7553295 T, AMD1 rs1279590 A and MSRA rs73534533 A variant genotypes that are associated with survival of NSCLC patients.	('AMD1', 'Gene', '262', (103, 107))	('rs1279590', 'Var', (108, 117))	('rs73534533', 'DBSNP_MENTION', 'None', (129, 139))	('rs7553295', 'Var', (90, 99))	('rs7553295', 'DBSNP_MENTION', 'None', (90, 99))	('NSCLC', 'Phenotype', 'HP:0030358', (197, 202))	('AMD1', 'Gene', (103, 107))	('MSRA', 'Gene', '4482', (124, 128))	('RUNX3', 'Gene', (84, 89))	('associated', 'Reg', (169, 179))	('patients', 'Species', '9606', (203, 211))	('NSCLC', 'Disease', (197, 202))	('rs73534533', 'Var', (129, 139))	('RUNX3', 'Gene', '864', (84, 89))	('rs1279590', 'DBSNP_MENTION', 'None', (108, 117))	('NSCLC', 'Disease', 'MESH:D002289', (197, 202))	('MSRA', 'Gene', (124, 128))
91893	30650190	Once validated by other investigators, these variants could possibly be used in personalized clinical management of NSCLC.	('NSCLC', 'Disease', 'MESH:D002289', (116, 121))	('men', 'Species', '9606', (108, 111))	('variants', 'Var', (45, 53))	('NSCLC', 'Phenotype', 'HP:0030358', (116, 121))	('NSCLC', 'Disease', (116, 121))
92049	26448606	Collectively, our study suggested that the disruption of miRNA positive co-expression in cancer might make contribution to cancer development.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('disruption', 'Var', (43, 53))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('cancer', 'Disease', (89, 95))	('cancer', 'Disease', (123, 129))	('miRNA positive', 'Protein', (57, 71))	('contribution', 'Reg', (107, 119))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
92076	26448606	In addition, six miRNA families, mir-8, mir-15, mir-17, mir-33, mir-146, and mir-515, were significantly enriched in the network (Table S2).	('mir-17', 'Gene', (48, 54))	('mir-146', 'Var', (64, 71))	('mir-33', 'Gene', (56, 62))	('mir-515', 'Var', (77, 84))	('mir-15', 'Var', (40, 46))	('mir-17', 'Gene', '406952', (48, 54))	('mir-33', 'Gene', '407039', (56, 62))	('mir-8', 'Var', (33, 38))
92089	26448606	Moreover, hub miRNAs were involved in more cancer types than non-hubs (Fig.	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('involved', 'Reg', (26, 34))	('cancer', 'Disease', (43, 49))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('miRNAs', 'Var', (14, 20))
92101	26448606	This result pinpoints that the miRNA CLV in the proposed network might be associated with their importance in cancer.	('miRNA', 'Var', (31, 36))	('cancer', 'Disease', (110, 116))	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))
92103	26448606	Therefore, the above network analyses further implied that the disruption of positive co-expression among miRNAs might influence cancer development.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('positive co-expression', 'MPA', (77, 99))	('influence', 'Reg', (119, 128))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('miRNAs', 'Gene', (106, 112))	('disruption', 'Var', (63, 73))
92117	26448606	Among the cancer types involved by miR-20b-5p connecting partners in the network, gastric cancer was the most frequently observed (10 partners, Fig.	('miR-20b-5p', 'Var', (35, 45))	('gastric cancer', 'Phenotype', 'HP:0012126', (82, 96))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('gastric cancer', 'Disease', 'MESH:D013274', (82, 96))	('gastric cancer', 'Disease', (82, 96))	('miR-20b-5p', 'Chemical', '-', (35, 45))	('cancer', 'Disease', 'MESH:D009369', (10, 16))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('cancer', 'Disease', (10, 16))
92118	26448606	According to our classifier, miR-20b-5p might be involved in gastric cancer.	('miR-20b-5p', 'Chemical', '-', (29, 39))	('miR-20b-5p', 'Var', (29, 39))	('gastric cancer', 'Disease', (61, 75))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('involved', 'Reg', (49, 57))	('gastric cancer', 'Disease', 'MESH:D013274', (61, 75))	('gastric cancer', 'Phenotype', 'HP:0012126', (61, 75))
92119	26448606	As expected, miR-20b-5p has also been reported to be associated with gastric cancer.	('gastric cancer', 'Disease', (69, 83))	('gastric cancer', 'Disease', 'MESH:D013274', (69, 83))	('miR-20b-5p', 'Chemical', '-', (13, 23))	('gastric cancer', 'Phenotype', 'HP:0012126', (69, 83))	('miR-20b-5p', 'Var', (13, 23))	('associated', 'Reg', (53, 63))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))
92131	26448606	More importantly, we found that genes targeted by more M1 or M2 miRNAs had a higher probability of being cancer-associated genes (Fig.	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('M2 miRNAs', 'Var', (61, 70))
92135	26448606	Dysregulation of DNA replication and/or mitosis have been known to lead to genome instability and even carcinogenesis.	('DNA replication', 'CPA', (17, 32))	('lead to', 'Reg', (67, 74))	('mitosis', 'Disease', (40, 47))	('Dysregulation', 'Var', (0, 13))	('genome instability', 'CPA', (75, 93))	('mitosis', 'Disease', 'None', (40, 47))	('carcinogenesis', 'CPA', (103, 117))
92148	26448606	Furthermore, it emphasizes that the disruption of miRNA co-expression might make contribution to cancer development.	('cancer', 'Disease', (97, 103))	('disruption', 'Var', (36, 46))	('contribution', 'Reg', (81, 93))	('miRNA', 'Protein', (50, 55))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
92155	26448606	Moreover, the results of our network analysis imply that disruption of positive co-expression among miRNAs might potentially influence cancer development.	('cancer', 'Disease', (135, 141))	('disruption', 'Var', (57, 67))	('cancer', 'Disease', 'MESH:D009369', (135, 141))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('positive', 'Protein', (71, 79))	('influence', 'Reg', (125, 134))	('miRNAs', 'Gene', (100, 106))
92164	26448606	These accession numbers are GSE32863 (lung cancer), GSE17951 (prostate cancer), GSE18520 (ovarian cancer), and GSE13861 (gastric cancer).	('lung cancer', 'Disease', (38, 49))	('GSE13861', 'Var', (111, 119))	('GSE18520', 'Var', (80, 88))	('ovarian cancer', 'Disease', 'MESH:D010051', (90, 104))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('gastric cancer', 'Phenotype', 'HP:0012126', (121, 135))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('lung cancer', 'Disease', 'MESH:D008175', (38, 49))	('GSE17951', 'Var', (52, 60))	('prostate cancer', 'Disease', 'MESH:D011471', (62, 77))	('prostate cancer', 'Phenotype', 'HP:0012125', (62, 77))	('ovarian cancer', 'Disease', (90, 104))	('lung cancer', 'Phenotype', 'HP:0100526', (38, 49))	('ovarian cancer', 'Phenotype', 'HP:0100615', (90, 104))	('prostate cancer', 'Disease', (62, 77))	('gastric cancer', 'Disease', (121, 135))	('GSE32863', 'Var', (28, 36))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('gastric cancer', 'Disease', 'MESH:D013274', (121, 135))
92331	32111101	Several studies have shown that ZnO-NPs inhibit cell growth and induce apoptosis by the production of oxidative stress in a variety of human cancer cells.	('cell growth', 'CPA', (48, 59))	('induce', 'PosReg', (64, 70))	('inhibit', 'NegReg', (40, 47))	('apoptosis', 'CPA', (71, 80))	('oxidative stress', 'Phenotype', 'HP:0025464', (102, 118))	('ZnO-NP', 'Chemical', '-', (32, 38))	('ZnO-NPs', 'Var', (32, 39))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('human', 'Species', '9606', (135, 140))	('oxidative stress', 'MPA', (102, 118))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('cancer', 'Disease', (141, 147))
92333	32111101	In this study, we found that ZnO-NPs induced growth inhibition of GSCC (Ca9-22 and OECM-1 cells), but no damage in human normal keratinocytes (HaCaT cells) and gingival fibroblasts (HGF-1 cells).	('ZnO-NP', 'Chemical', '-', (29, 35))	('GSCC', 'Phenotype', 'HP:0030413', (66, 70))	('gingival', 'Disease', 'MESH:D005891', (160, 168))	('GSCC', 'Disease', 'MESH:D002294', (66, 70))	('ZnO-NPs', 'Var', (29, 36))	('human', 'Species', '9606', (115, 120))	('growth inhibition', 'CPA', (45, 62))	('gingival', 'Disease', (160, 168))	('GSCC', 'Disease', (66, 70))
92334	32111101	ZnO-NPs caused apoptotic cell death of GSCC in a concentration-dependent manner by the quantitative assessment of oligonucleosomal DNA fragmentation.	('apoptotic cell death', 'CPA', (15, 35))	('GSCC', 'Disease', 'MESH:D002294', (39, 43))	('GSCC', 'Disease', (39, 43))	('GSCC', 'Phenotype', 'HP:0030413', (39, 43))	('ZnO-NP', 'Chemical', '-', (0, 6))	('ZnO-NPs', 'Var', (0, 7))
92335	32111101	Flow cytometric analysis of cell cycle progression revealed that sub-G1 phase accumulation was dramatically induced by ZnO-NPs.	('ZnO-NP', 'Chemical', '-', (119, 125))	('ZnO-NPs', 'Var', (119, 126))	('sub-G1 phase accumulation', 'CPA', (65, 90))	('induced', 'PosReg', (108, 115))
92336	32111101	In addition, ZnO-NPs increased the intracellular reactive oxygen species and specifically superoxide levels, and also decreased the mitochondrial membrane potential.	('increased', 'PosReg', (21, 30))	('superoxide levels', 'MPA', (90, 107))	('superoxide', 'Chemical', 'MESH:D013481', (90, 100))	('mitochondrial membrane potential', 'MPA', (132, 164))	('ZnO-NP', 'Chemical', '-', (13, 19))	('decreased', 'NegReg', (118, 127))	('intracellular reactive oxygen species', 'MPA', (35, 72))	('ZnO-NPs', 'Var', (13, 20))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (49, 72))
92340	32111101	In a corollary in vivo study, our results demonstrated that ZnO-NPs possessed an anti-cancer effect in a zebrafish xenograft model.	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('ZnO-NP', 'Chemical', '-', (60, 66))	('ZnO-NPs', 'Var', (60, 67))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('zebrafish', 'Species', '7955', (105, 114))	('cancer', 'Disease', (86, 92))
92341	32111101	Collectively, these results suggest that ZnO-NPs induce apoptosis through the mitochondrial oxidative damage and p70S6K signaling pathway in human GSCC.	('mitochondrial oxidative damage', 'MPA', (78, 108))	('GSCC', 'Phenotype', 'HP:0030413', (147, 151))	('p70S6K', 'Gene', (113, 119))	('GSCC', 'Disease', 'MESH:D002294', (147, 151))	('p70S6K', 'Gene', '6198', (113, 119))	('human', 'Species', '9606', (141, 146))	('GSCC', 'Disease', (147, 151))	('ZnO-NP', 'Chemical', '-', (41, 47))	('apoptosis', 'CPA', (56, 65))	('ZnO-NPs', 'Var', (41, 48))
92342	32111101	The present study may provide an experimental basis for ZnO-NPs to be considered as a promising novel anti-tumor agent for the treatment of gingival cancer.	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('gingival cancer', 'Disease', 'MESH:D005891', (140, 155))	('ZnO-NPs', 'Var', (56, 63))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('ZnO-NP', 'Chemical', '-', (56, 62))	('gingival cancer', 'Disease', (140, 155))
92354	32111101	The anti-cancer effects of ZnO-NPs result from the inhibition of the proliferation of cancer cells, the increase of the sensitivity for drug-resistant cancer cells, the prevention of tumor invasiveness and metastasis, as well as the restoration of cancer immunosurveillance.	('cancer', 'Disease', (9, 15))	('prevention', 'NegReg', (169, 179))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('cancer immunosurveillance', 'Disease', 'MESH:D009369', (248, 273))	('cancer', 'Disease', (248, 254))	('tumor invasiveness', 'Disease', (183, 201))	('cancer', 'Phenotype', 'HP:0002664', (248, 254))	('cancer', 'Disease', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('cancer', 'Disease', (86, 92))	('restoration', 'PosReg', (233, 244))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('drug-resistant cancer', 'Phenotype', 'HP:0020174', (136, 157))	('cancer immunosurveillance', 'Disease', (248, 273))	('cancer', 'Disease', 'MESH:D009369', (248, 254))	('ZnO-NPs', 'Var', (27, 34))	('increase', 'PosReg', (104, 112))	('inhibition', 'NegReg', (51, 61))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('ZnO-NP', 'Chemical', '-', (27, 33))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('tumor invasiveness', 'Disease', 'MESH:D009369', (183, 201))
92366	32111101	The results of quantitative analysis revealed that ZnO-NPs induced significant concentration-dependent accumulation of cell cycle at sub-G1 phase.	('cell cycle at sub-G1 phase', 'CPA', (119, 145))	('accumulation', 'PosReg', (103, 115))	('ZnO-NPs', 'Var', (51, 58))	('ZnO-NP', 'Chemical', '-', (51, 57))
92370	32111101	These results indicated that ZnO-NPs induce sub-G1 arrest of the cell cycle followed by apoptosis in human GSCC.	('apoptosis', 'CPA', (88, 97))	('ZnO-NP', 'Chemical', '-', (29, 35))	('GSCC', 'Phenotype', 'HP:0030413', (107, 111))	('ZnO-NPs', 'Var', (29, 36))	('sub-G1 arrest of the cell cycle', 'CPA', (44, 75))	('human', 'Species', '9606', (101, 106))	('GSCC', 'Disease', 'MESH:D002294', (107, 111))	('GSCC', 'Disease', (107, 111))
92371	32111101	Several studies have shown that the cytotoxicity of ZnO-NPs results from the generation of ROS.	('ZnO-NPs', 'Var', (52, 59))	('cytotoxicity', 'Disease', 'MESH:D064420', (36, 48))	('ZnO-NP', 'Chemical', '-', (52, 58))	('ROS', 'Chemical', 'MESH:D017382', (91, 94))	('ROS', 'Protein', (91, 94))	('cytotoxicity', 'Disease', (36, 48))
92375	32111101	As shown in Figure 3c, ZnO-NPs profoundly increased the content of ROS in a concentration-dependent manner after 24 h of treatment.	('increased', 'PosReg', (42, 51))	('ZnO-NP', 'Chemical', '-', (23, 29))	('ZnO-NPs', 'Var', (23, 30))	('ROS', 'Chemical', 'MESH:D017382', (67, 70))	('ROS', 'Protein', (67, 70))	('content', 'MPA', (56, 63))
92378	32111101	We further determined whether ZnO-NPs triggered apoptotic cell death through the mitochondrial pathway.	('apoptotic cell death', 'CPA', (48, 68))	('ZnO-NP', 'Chemical', '-', (30, 36))	('ZnO-NPs', 'Var', (30, 37))	('mitochondrial pathway', 'Pathway', (81, 102))
92379	32111101	The data showed that ZnO-NPs induced a significant loss of the MMP in Ca9-22 cells using an MITO-ID assay kit and JC-1 staining (Figure 4).	('MMP', 'MPA', (63, 66))	('ZnO-NP', 'Chemical', '-', (21, 27))	('ZnO-NPs', 'Var', (21, 28))	('loss', 'NegReg', (51, 55))	('MITO', 'Species', '262676', (92, 96))
92382	32111101	In addition, we found that ZnO-NPs did not affect the expression of pro-survival Bcl-2 members (Bcl-2, Bcl-xl, and Mcl-1) as well as pro-apoptosis Bcl-2 members (Bax, Bad, and Bid) in Ca9-22 cells (Figure S2).	('Bax', 'Gene', (162, 165))	('Bcl-2', 'Gene', (147, 152))	('Bcl-2', 'Gene', (96, 101))	('Bcl-2', 'Gene', '596', (147, 152))	('Bcl-2', 'Gene', '596', (96, 101))	('Bid', 'Gene', '637', (176, 179))	('Mcl-1', 'Gene', '4170', (115, 120))	('Bcl-xl', 'Gene', '598', (103, 109))	('Bcl-2', 'Gene', (81, 86))	('Bax', 'Gene', '581', (162, 165))	('Bcl-2', 'Gene', '596', (81, 86))	('Mcl-1', 'Gene', (115, 120))	('ZnO-NP', 'Chemical', '-', (27, 33))	('Bcl-xl', 'Gene', (103, 109))	('Bid', 'Gene', (176, 179))	('ZnO-NPs', 'Var', (27, 34))
92386	32111101	The results showed that ZnO-NPs did not significantly induce the activation of caspases-8, but the cleavage of caspase-9 was clearly increased after ZnO-NPs treatment (Figure 5a).	('caspases', 'Gene', '841;842', (79, 87))	('ZnO-NPs', 'Var', (149, 156))	('caspase-9', 'Gene', (111, 120))	('cleavage', 'MPA', (99, 107))	('caspases', 'Gene', (79, 87))	('ZnO-NP', 'Chemical', '-', (24, 30))	('caspase-9', 'Gene', '842', (111, 120))	('increased', 'PosReg', (133, 142))	('ZnO-NP', 'Chemical', '-', (149, 155))
92387	32111101	Meanwhile, the cleavage of caspase-3 and PARP were also profoundly activated by ZnO-NPs (Figure 5b,c).	('caspase-3', 'Gene', (27, 36))	('activated', 'PosReg', (67, 76))	('ZnO-NPs', 'Var', (80, 87))	('PARP', 'Gene', (41, 45))	('caspase-3', 'Gene', '836', (27, 36))	('PARP', 'Gene', '142', (41, 45))	('cleavage', 'MPA', (15, 23))	('ZnO-NP', 'Chemical', '-', (80, 86))
92389	32111101	Our data indicated that ZnO-NPs promoted cell apoptosis through the caspase-dependent pathway.	('promoted', 'PosReg', (32, 40))	('caspase-dependent pathway', 'Pathway', (68, 93))	('ZnO-NP', 'Chemical', '-', (24, 30))	('cell apoptosis', 'CPA', (41, 55))	('ZnO-NPs', 'Var', (24, 31))
92395	32111101	We found that ZnO-NPs significantly inhibited the phosphorylation of p70S6K, but did not abolish the phosphorylation of mTOR in both Ca9-22 and OECM-1 cells (Figure 6a,b).	('ZnO-NP', 'Chemical', '-', (14, 20))	('ZnO-NPs', 'Var', (14, 21))	('phosphorylation', 'MPA', (50, 65))	('inhibited', 'NegReg', (36, 45))	('mTOR', 'Gene', '2475', (120, 124))	('p70S6K', 'Gene', (69, 75))	('mTOR', 'Gene', (120, 124))	('p70S6K', 'Gene', '6198', (69, 75))	('phosphorylation', 'MPA', (101, 116))
92396	32111101	These findings revealed that ZnO-NPs may induce apoptotic cell death through the p70S6K signaling pathway in human GSCC.	('ZnO-NP', 'Chemical', '-', (29, 35))	('human', 'Species', '9606', (109, 114))	('p70S6K', 'Gene', (81, 87))	('GSCC', 'Disease', (115, 119))	('p70S6K', 'Gene', '6198', (81, 87))	('induce', 'PosReg', (41, 47))	('GSCC', 'Phenotype', 'HP:0030413', (115, 119))	('ZnO-NPs', 'Var', (29, 36))	('GSCC', 'Disease', 'MESH:D002294', (115, 119))	('apoptotic cell death', 'CPA', (48, 68))
92401	32111101	After quantification, the data showed that ZnO-NPs inhibited tumor growth in zebrafish inoculated with Ca9-22 cells in a dose-dependent manner (Figure 7b), thereby indicting the anti-tumor effects of ZnO-NPs in the zebrafish xenograft model.	('zebrafish', 'Species', '7955', (215, 224))	('indicting', 'NegReg', (164, 173))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('ZnO-NP', 'Chemical', '-', (43, 49))	('zebrafish', 'Species', '7955', (77, 86))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Disease', (183, 188))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('ZnO-NPs', 'Var', (43, 50))	('inhibited', 'NegReg', (51, 60))	('tumor', 'Disease', (61, 66))	('ZnO-NP', 'Chemical', '-', (200, 206))
92402	32111101	Moreover, the survival rate of zebrafish embryos was not affected by ZnO-NPs (Figure 7c), suggesting that ZnO-NPs at testing doses did not cause obvious toxicity to the zebrafish embryos.	('zebrafish', 'Species', '7955', (31, 40))	('zebrafish', 'Species', '7955', (169, 178))	('ZnO-NP', 'Chemical', '-', (106, 112))	('toxicity', 'Disease', (153, 161))	('ZnO-NPs', 'Var', (106, 113))	('toxicity', 'Disease', 'MESH:D064420', (153, 161))	('ZnO-NP', 'Chemical', '-', (69, 75))
92405	32111101	In the present study, a detailed investigation was conducted on the anti-cancer effects of ZnO-NPs in human GSCC, both in vitro and in vivo.	('cancer', 'Disease', (73, 79))	('GSCC', 'Disease', (108, 112))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('ZnO-NP', 'Chemical', '-', (91, 97))	('ZnO-NPs', 'Var', (91, 98))	('GSCC', 'Phenotype', 'HP:0030413', (108, 112))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('GSCC', 'Disease', 'MESH:D002294', (108, 112))	('human', 'Species', '9606', (102, 107))
92406	32111101	As revealed by MTT assay, the viability of Ca9-22 and OECM-1 gingival cancer cells was concentration-dependently inhibited by ZnO-NPs, but no obvious cytotoxic fashion was found in normal cells.	('viability', 'CPA', (30, 39))	('gingival cancer', 'Disease', 'MESH:D005891', (61, 76))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('inhibited', 'NegReg', (113, 122))	('ZnO-NP', 'Chemical', '-', (126, 132))	('gingival cancer', 'Disease', (61, 76))	('MTT', 'Chemical', 'MESH:C070243', (15, 18))	('ZnO-NPs', 'Var', (126, 133))
92407	32111101	In addition, ZnO-NPs dramatically caused cell cycle arrest at the sub-G1 phase.	('cell cycle arrest at the sub-G1 phase', 'CPA', (41, 78))	('ZnO-NP', 'Chemical', '-', (13, 19))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (41, 58))	('ZnO-NPs', 'Var', (13, 20))	('caused', 'Reg', (34, 40))
92408	32111101	The production of ROS and specifically superoxide was increased by ZnO-NPs, and the loss of MMP was subsequently observed in gingival cancer cells.	('ROS', 'MPA', (18, 21))	('ZnO-NP', 'Chemical', '-', (67, 73))	('superoxide', 'Chemical', 'MESH:D013481', (39, 49))	('gingival cancer', 'Disease', (125, 140))	('ZnO-NPs', 'Var', (67, 74))	('production', 'MPA', (4, 14))	('increased', 'PosReg', (54, 63))	('ROS', 'Chemical', 'MESH:D017382', (18, 21))	('superoxide', 'MPA', (39, 49))	('gingival cancer', 'Disease', 'MESH:D005891', (125, 140))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
92409	32111101	Under the quantitative assessment of oligonucleosomal DNA fragmentation, ZnO-NPs were identified as increasing cell apoptosis.	('increasing', 'PosReg', (100, 110))	('ZnO-NP', 'Chemical', '-', (73, 79))	('ZnO-NPs', 'Var', (73, 80))	('cell apoptosis', 'CPA', (111, 125))
92410	32111101	Importantly, the phosphorylation of p70S6K was downregulated, and the caspase cascade was activated by ZnO-NPs.	('activated', 'PosReg', (90, 99))	('p70S6K', 'Gene', (36, 42))	('downregulated', 'NegReg', (47, 60))	('ZnO-NPs', 'Var', (103, 110))	('p70S6K', 'Gene', '6198', (36, 42))	('phosphorylation', 'MPA', (17, 32))	('caspase cascade', 'Pathway', (70, 85))	('ZnO-NP', 'Chemical', '-', (103, 109))
92411	32111101	On the basis of the findings herein, we propose that ZnO-NPs may promote caspase-dependent apoptosis via the superoxide-induced mitochondrial dysfunction and p70S6K signaling pathway in gingival cancer cells (Figure 8).	('mitochondrial dysfunction', 'Disease', 'MESH:D028361', (128, 153))	('ZnO-NP', 'Chemical', '-', (53, 59))	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (128, 153))	('p70S6K', 'Gene', (158, 164))	('mitochondrial dysfunction', 'Disease', (128, 153))	('ZnO-NPs', 'Var', (53, 60))	('gingival cancer', 'Disease', 'MESH:D005891', (186, 201))	('p70S6K', 'Gene', '6198', (158, 164))	('gingival cancer', 'Disease', (186, 201))	('promote', 'PosReg', (65, 72))	('superoxide', 'Chemical', 'MESH:D013481', (109, 119))	('caspase-dependent', 'Pathway', (73, 90))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
92412	32111101	Notably, ZnO-NPs exerted a promising anti-tumor effect in the zebrafish xenograft model.	('ZnO-NP', 'Chemical', '-', (9, 15))	('tumor', 'Disease', (42, 47))	('zebrafish', 'Species', '7955', (62, 71))	('ZnO-NPs', 'Var', (9, 16))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
92413	32111101	This is the first demonstration that ZnO-NPs exhibit an anti-cancer property against gingival cancer in vitro and in vivo.	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('ZnO-NP', 'Chemical', '-', (37, 43))	('gingival cancer', 'Disease', 'MESH:D005891', (85, 100))	('cancer', 'Disease', (61, 67))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('ZnO-NPs', 'Var', (37, 44))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('gingival cancer', 'Disease', (85, 100))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
92414	32111101	ZnO-NPs may serve as a potential therapeutic candidate for the treatment of human oral cancer, especially GSCC.	('GSCC', 'Disease', 'MESH:D002294', (106, 110))	('oral cancer', 'Disease', (82, 93))	('GSCC', 'Phenotype', 'HP:0030413', (106, 110))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('GSCC', 'Disease', (106, 110))	('human', 'Species', '9606', (76, 81))	('ZnO-NP', 'Chemical', '-', (0, 6))	('ZnO-NPs', 'Var', (0, 7))	('oral cancer', 'Disease', 'MESH:D009062', (82, 93))
92422	32111101	In this study, our data showed that ZnO-NPs profoundly increased the content of intracellular ROS, especially superoxide anion radical, and subsequently disrupted mitochondrial function in gingival cancer cells.	('content of intracellular ROS', 'MPA', (69, 97))	('disrupted', 'NegReg', (153, 162))	('superoxide anion radical', 'MPA', (110, 134))	('gingival cancer', 'Disease', (189, 204))	('ZnO-NP', 'Chemical', '-', (36, 42))	('increased', 'PosReg', (55, 64))	('ROS', 'Chemical', 'MESH:D017382', (94, 97))	('ZnO-NPs', 'Var', (36, 43))	('gingival cancer', 'Disease', 'MESH:D005891', (189, 204))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('superoxide anion radical', 'Chemical', 'MESH:D013481', (110, 134))	('mitochondrial function', 'MPA', (163, 185))
92427	32111101	However, some contradictory reports reveal that Bax translocation without Bax/Bcl-2 ratio alteration can upregulate caspase 3 and induce apoptosis.	('induce', 'PosReg', (130, 136))	('apoptosis', 'CPA', (137, 146))	('upregulate', 'PosReg', (105, 115))	('Bax', 'Gene', (74, 77))	('translocation', 'Var', (52, 65))	('Bax', 'Gene', '581', (48, 51))	('caspase 3', 'Gene', (116, 125))	('Bcl-2', 'Gene', (78, 83))	('Bcl-2', 'Gene', '596', (78, 83))	('Bax', 'Gene', '581', (74, 77))	('Bax', 'Gene', (48, 51))	('caspase 3', 'Gene', '836', (116, 125))
92432	32111101	Here, we showed that ZnO-NPs significantly induced the cleavage of caspase-3, caspase-9, and PARP for executing cell apoptosis.	('caspase-9', 'Gene', '842', (78, 87))	('PARP', 'Gene', '142', (93, 97))	('caspase-3', 'Gene', (67, 76))	('caspase-9', 'Gene', (78, 87))	('cleavage', 'MPA', (55, 63))	('ZnO-NP', 'Chemical', '-', (21, 27))	('ZnO-NPs', 'Var', (21, 28))	('PARP', 'Gene', (93, 97))	('caspase-3', 'Gene', '836', (67, 76))
92444	32111101	In addition, the p70S6K-specific inhibitor PF-4708671 exhibits an inhibitory effect on non-small cell lung cancer in both in vitro and in vivo models.	('PF-4708671', 'Var', (43, 53))	('lung cancer', 'Phenotype', 'HP:0100526', (102, 113))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (87, 113))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('p70S6K', 'Gene', (17, 23))	('p70S6K', 'Gene', '6198', (17, 23))	('inhibitory effect', 'NegReg', (66, 83))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (91, 113))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (87, 113))	('non-small cell lung cancer', 'Disease', (87, 113))
92470	32111101	Antibodies specific for phospho-mTOR (Ser2448), mTOR, and GAPDH were purchased from Abcam (Cambridge, MA, USA).	('mTOR', 'Gene', '2475', (48, 52))	('GAPDH', 'Gene', '2597', (58, 63))	('GAPDH', 'Gene', (58, 63))	('mTOR', 'Gene', (48, 52))	('mTOR', 'Gene', '2475', (32, 36))	('mTOR', 'Gene', (32, 36))	('Ser2448', 'Var', (38, 45))	('Ser2448', 'Chemical', '-', (38, 45))
92530	31807021	The tab OncoPrint displays an overview of genetic alterations in hub genes.	('hub', 'Gene', (65, 68))	('hub', 'Gene', '1993', (65, 68))	('genetic alterations', 'Var', (42, 61))
92536	31807021	For LUSC, miR-133b expression was downregulated compared with normal tissues (0.9882589 +- 0.6567950 vs. 2.5674577 +- 0.7299547, p < 0.001 [Figure 1B and Supplement Table 1]).	('expression', 'MPA', (19, 29))	('downregulated', 'NegReg', (34, 47))	('miR-133b', 'Gene', (10, 18))	('0.9882589 +- 0.6567950', 'Var', (78, 100))	('miR-133b', 'Gene', '442890', (10, 18))
92538	31807021	The expression level of miR-133b was downregulated in NSCLC tissues compared with normal tissues (1.049451 +- 0.6949068 vs. 2.5476656 +- 0.7288576, p < 0.0001 (Figure 1C and Supplement Table 1).	('expression level', 'MPA', (4, 20))	('downregulated', 'NegReg', (37, 50))	('miR-133b', 'Gene', '442890', (24, 32))	('miR-133b', 'Gene', (24, 32))	('1.049451 +- 0.6949068', 'Var', (98, 119))	('NSCLC', 'Disease', (54, 59))	('NSCLC', 'Disease', 'MESH:D002289', (54, 59))
92545	31807021	Figure 4 and Supplement Table 2 show that the NSCLC group has significantly lower miR-133b expression levels than the normal group (0.3782883 +- 0.4082107 vs. 3.0388487 +- 0.6888178, p<0.001).	('miR-133b', 'Gene', (82, 90))	('NSCLC', 'Disease', (46, 51))	('0.3782883 +- 0.4082107', 'Var', (132, 154))	('lower', 'NegReg', (76, 81))	('NSCLC', 'Disease', 'MESH:D002289', (46, 51))	('miR-133b', 'Gene', '442890', (82, 90))
92562	31807021	The 10 hub genes were altered in NSCLC, and KIF26B, STMN1, and POSTN were altered most often in LUAD (23%, 10%, and 10%, respectively), and ITGB4 and KIF26B in LUSC (12% and 11%, respectively), including amplification and missense.	('amplification', 'Var', (204, 217))	('hub', 'Gene', '1993', (7, 10))	('ITGB4', 'Gene', (140, 145))	('STMN1', 'Gene', '3925', (52, 57))	('STMN1', 'Gene', (52, 57))	('NSCLC', 'Disease', 'MESH:D002289', (33, 38))	('POSTN', 'Gene', '10631', (63, 68))	('KIF26B', 'Gene', '55083', (44, 50))	('altered', 'Reg', (22, 29))	('KIF26B', 'Gene', '55083', (150, 156))	('KIF26B', 'Gene', (44, 50))	('KIF26B', 'Gene', (150, 156))	('altered', 'Reg', (74, 81))	('hub', 'Gene', (7, 10))	('NSCLC', 'Disease', (33, 38))	('missense', 'Var', (222, 230))	('POSTN', 'Gene', (63, 68))	('ITGB4', 'Gene', '3691', (140, 145))
92566	31807021	The tab OncoPrint displays an overview of genetic alterations in hub genes per sample.	('hub', 'Gene', (65, 68))	('hub', 'Gene', '1993', (65, 68))	('genetic alterations', 'Var', (42, 61))
92627	28748917	The deleterious effects of alcohol on the oesophageal mucosa are mediated by acetaldehyde, secondary to oxidation from the oral microbiota and salivary products, and pharmacogenetic differences in alcohol metabolism in Asian populations increase acetaldehyde exposure in this population.	('increase', 'PosReg', (237, 245))	('acetaldehyde', 'Chemical', 'MESH:D000079', (77, 89))	('acetaldehyde', 'MPA', (77, 89))	('acetaldehyde exposure', 'MPA', (246, 267))	('pharmacogenetic', 'Var', (166, 181))	('alcohol', 'Chemical', 'MESH:D000438', (27, 34))	('increase acetaldehyde exposure', 'Phenotype', 'HP:0003533', (237, 267))	('acetaldehyde', 'Chemical', 'MESH:D000079', (246, 258))	('alcohol', 'Chemical', 'MESH:D000438', (197, 204))
92632	28748917	Tylosis is an autosomal dominant disorder caused by germline mutation in RHBDF2 (encoding for iRhom2)which is associated with palmar/plantar hyperkeratosis and a 90% cumulative risk of OSCC by 70 years of age.	('Tylosis', 'Disease', 'MESH:D053546', (0, 7))	('iRhom2', 'Gene', '79651', (94, 100))	('Tylosis', 'Disease', (0, 7))	('RHBDF2', 'Gene', '79651', (73, 79))	('autosomal dominant disorder', 'Disease', (14, 41))	('palmar/plantar hyperkeratosis', 'Phenotype', 'HP:0000972', (126, 155))	('plantar hyperkeratosis', 'Phenotype', 'HP:0007556', (133, 155))	('associated', 'Reg', (110, 120))	('iRhom2', 'Gene', (94, 100))	('hyperkeratosis', 'Phenotype', 'HP:0000962', (141, 155))	('autosomal dominant disorder', 'Disease', 'MESH:D030342', (14, 41))	('caused by', 'Reg', (42, 51))	('palmar/plantar hyperkeratosis', 'Disease', 'MESH:C536306', (126, 155))	('palmar/plantar hyperkeratosis', 'Disease', (126, 155))	('RHBDF2', 'Gene', (73, 79))	('germline mutation', 'Var', (52, 69))	('OSCC', 'Disease', (185, 189))
92634	28748917	Genetic variability in detoxification processes may also modify environmental influences on OSCC susceptibility; for example functional variants in alcohol dehydrogenase IB (ADH1B) and aldehyde dehydrogenase 2 (and ALDH2) enzymes synergise with lifestyle factors to enhance OSCC risk in the Japanese population.	('variants', 'Var', (136, 144))	('ALDH2', 'Gene', (215, 220))	('modify', 'Reg', (57, 63))	('OSCC', 'Disease', (274, 278))	('aldehyde dehydrogenase 2', 'Gene', '217', (185, 209))	('ADH1B', 'Gene', (174, 179))	('ADH1B', 'Gene', '125', (174, 179))	('ALDH2', 'Gene', '217', (215, 220))	('enhance', 'PosReg', (266, 273))	('aldehyde dehydrogenase 2', 'Gene', (185, 209))	('alcohol', 'Chemical', 'MESH:D000438', (148, 155))
92636	28748917	The molecular progression from dysplasia to invasive OSCC has not been well studied, however dysregulation of TP53 and cell cycle regulators are prominent characteristics of OSCC, which may also be detected in precursor lesions.	('TP53', 'Gene', '7157', (110, 114))	('TP53', 'Gene', (110, 114))	('dysplasia', 'Disease', 'MESH:D004476', (31, 40))	('OSCC', 'Disease', (174, 178))	('dysregulation', 'Var', (93, 106))	('dysplasia', 'Disease', (31, 40))
92640	28748917	Dysregulated pathways of therapeutic interest in OSCC include cell cycle regulators, tyrosine kinase receptors, chromatin remodelling and embryonic pathways such as Hippo (via YAP1 amplification or VGLL4/ATG7 deletion).	('Hippo', 'Disease', (165, 170))	('ATG7', 'Gene', (204, 208))	('YAP1', 'Gene', (176, 180))	('VGLL4', 'Gene', (198, 203))	('deletion', 'Var', (209, 217))	('YAP1', 'Gene', '10413', (176, 180))	('VGLL4', 'Gene', '9686', (198, 203))	('ATG7', 'Gene', '10533', (204, 208))
92642	28748917	The EGFR signalling pathway was activated via mutation or amplification in 19% of tumours, and PIK3CA in 24%.	('tumour', 'Phenotype', 'HP:0002664', (82, 88))	('PIK3CA', 'Gene', (95, 101))	('tumours', 'Phenotype', 'HP:0002664', (82, 89))	('PIK3CA', 'Gene', '5290', (95, 101))	('EGFR', 'Gene', (4, 8))	('activated', 'PosReg', (32, 41))	('tumours', 'Disease', 'MESH:D009369', (82, 89))	('tumours', 'Disease', (82, 89))	('mutation', 'Var', (46, 54))	('amplification', 'Var', (58, 71))	('EGFR', 'Gene', '1956', (4, 8))
92654	28748917	Finally, the genetically determined host response to inflammation caused by germline variation in inflammation response genes such as microsomal glutathione-S-transferase 1 (MGST1) or FOXP1 may also determine individual BE and OAC risk  Typically, the oesophageal mucosa is exposed to reflux of acid and bile and is injured due to reactive oxygen species and nitric oxide production leading to DNA damage and a characteristic mutational profile of A>C transversions has been attributed to reflux-induced damage (Figure 2).	('inflammation', 'Disease', 'MESH:D007249', (53, 65))	('nitric oxide production', 'MPA', (359, 382))	('variation', 'Var', (85, 94))	('FOXP1', 'Gene', (184, 189))	('microsomal glutathione-S-transferase 1', 'Gene', (134, 172))	('inflammation', 'Disease', 'MESH:D007249', (98, 110))	('inflammation', 'Disease', (53, 65))	('reflux-induced damage', 'Disease', (489, 510))	('microsomal glutathione-S-transferase 1', 'Gene', '4257', (134, 172))	('nitric oxide', 'Chemical', 'MESH:D009569', (359, 371))	('inflammation', 'Disease', (98, 110))	('MGST1', 'Gene', '4257', (174, 179))	('reflux of acid', 'Phenotype', 'HP:0002020', (285, 299))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (331, 354))	('leading', 'Reg', (383, 390))	('FOXP1', 'Gene', '27086', (184, 189))	('DNA damage', 'MPA', (394, 404))	('MGST1', 'Gene', (174, 179))	('OAC', 'Chemical', '-', (227, 230))
92660	28748917	Dysregulation of p53 signalling plays a key role in progression of BE to invasive OAC.	('Dysregulation', 'Var', (0, 13))	('invasive OAC', 'Disease', (73, 85))	('OAC', 'Chemical', '-', (82, 85))	('p53', 'Gene', (17, 20))	('p53', 'Gene', '7157', (17, 20))
92662	28748917	A paired sequencing study of BE and OAC samples from 25 patients demonstrated that a genome doubling event in a TP53 mutant cell commonly precedes OAC development.	('patients', 'Species', '9606', (56, 64))	('precedes', 'NegReg', (138, 146))	('OAC', 'Chemical', '-', (36, 39))	('OAC', 'Disease', (147, 150))	('mutant', 'Var', (117, 123))	('OAC', 'Chemical', '-', (147, 150))	('TP53', 'Gene', '7157', (112, 116))	('genome doubling event', 'MPA', (85, 106))	('TP53', 'Gene', (112, 116))
92664	28748917	Thus, two mechanisms of OAC generation from BE are proposed, the first through the stepwise acquisition of loss of tumour suppressor genes such as CDKN2A and TP53 and also involving mutations in SMAD4 and disruption of chromatin modifying enzymes, but without an acute genome doubling event and a second mechanism involving large-scale chromosomal instability associated with aneuploidy following loss of p53 regulation.	('TP53', 'Gene', '7157', (158, 162))	('TP53', 'Gene', (158, 162))	('SMAD4', 'Gene', '4089', (195, 200))	('p53', 'Gene', '7157', (405, 408))	('disruption', 'Var', (205, 215))	('chromosomal instability', 'Phenotype', 'HP:0040012', (336, 359))	('aneuploidy', 'Disease', 'MESH:D000782', (376, 386))	('aneuploidy', 'Disease', (376, 386))	('tumour', 'Phenotype', 'HP:0002664', (115, 121))	('loss of tumour', 'Disease', (107, 121))	('loss of tumour', 'Disease', 'MESH:D009369', (107, 121))	('SMAD4', 'Gene', (195, 200))	('CDKN2A', 'Gene', (147, 153))	('OAC', 'Chemical', '-', (24, 27))	('p53', 'Gene', (405, 408))	('CDKN2A', 'Gene', '1029', (147, 153))	('mutations', 'Var', (182, 191))
92665	28748917	chromosomal crises causing chromothripsis and kategis, may also cause sudden accelerations towards invasion.	('chromosomal crises', 'Var', (0, 18))	('chromothripsis', 'Disease', (27, 41))	('chromothripsis', 'Disease', 'MESH:D000072837', (27, 41))	('kategis', 'Disease', (46, 53))	('invasion', 'CPA', (99, 107))
92666	28748917	These findings may explain the lack of copy number alterations in BE compared to invasive OAC, despite similar mutational signatures.	('copy number alterations', 'Var', (39, 62))	('invasive OAC', 'Disease', (81, 93))	('OAC', 'Chemical', '-', (90, 93))
92669	28748917	Epigenetic modification is another factor in OAC development; both BE and OAC are frequently highly methylated compared to normal oesophageal mucosa although levels are heterogeneous.	('highly', 'Reg', (93, 99))	('Epigenetic', 'Var', (0, 10))	('OAC', 'Chemical', '-', (74, 77))	('OAC', 'Chemical', '-', (45, 48))
92670	28748917	For example, hypermethylation of the promoter of CDKN2A (p16INK4a) is frequent and associated with neoplastic progression in BE, and together with loss of 9p21 loss this may lead to inactivation of CDK2NA which is a common finding in invasive OAC.	('CDKN2A', 'Gene', '1029', (49, 55))	('CDK2', 'Gene', '1017', (198, 202))	('p16INK4a', 'Gene', (57, 65))	('loss', 'NegReg', (160, 164))	('invasive OAC', 'Disease', (234, 246))	('OAC', 'Chemical', '-', (243, 246))	('neoplastic progression', 'CPA', (99, 121))	('p16INK4a', 'Gene', '1029', (57, 65))	('associated', 'Reg', (83, 93))	('CDK2', 'Gene', (198, 202))	('hypermethylation', 'Var', (13, 29))	('CDKN2A', 'Gene', (49, 55))	('inactivation', 'MPA', (182, 194))
92672	28748917	However, although point mutations are abundant in particular in tumour suppressors such as TP53, CDK2NA and ARID1A, structural alterations dominate the OAC landscape.	('TP53', 'Gene', (91, 95))	('OAC', 'Chemical', '-', (152, 155))	('tumour', 'Phenotype', 'HP:0002664', (64, 70))	('tumour', 'Disease', 'MESH:D009369', (64, 70))	('tumour', 'Disease', (64, 70))	('CDK2', 'Gene', (97, 101))	('point mutations', 'Var', (18, 33))	('ARID1A', 'Gene', '8289', (108, 114))	('ARID1A', 'Gene', (108, 114))	('TP53', 'Gene', '7157', (91, 95))	('CDK2', 'Gene', '1017', (97, 101))
92678	28748917	Following whole genome sequencing of 129 OAC as part of the International Cancer Genome Consortium, three subgroups were exemplified by either a defective homologous recombination repair, a T>G mutation pattern associated with a high mutational load, or a C>A/T mutation pattern in keeping with an aging imprint.	('high mutational load', 'MPA', (229, 249))	('Cancer', 'Phenotype', 'HP:0002664', (74, 80))	('Cancer', 'Disease', (74, 80))	('Cancer', 'Disease', 'MESH:D009369', (74, 80))	('C>A/T mutation', 'Var', (256, 270))	('OAC', 'Chemical', '-', (41, 44))	('T>G mutation', 'Var', (190, 202))	('homologous recombination repair', 'Enzyme', (155, 186))	('defective', 'NegReg', (145, 154))
92711	28748917	Aberrant P53 expression (both overexpression and loss) may be a more accurate predictor of progression than the presence of low grade dysplasia, which is prone to inter and intra-observer variability.	('P53', 'Gene', (9, 12))	('loss', 'NegReg', (49, 53))	('P53', 'Gene', '7157', (9, 12))	('Aberrant', 'Var', (0, 8))	('expression', 'MPA', (13, 23))	('overexpression', 'PosReg', (30, 44))	('dysplasia', 'Disease', (134, 143))	('dysplasia', 'Disease', 'MESH:D004476', (134, 143))
92713	28748917	Primary prevention of oesophageal cancer includes tobacco avoidance, moderation of alcohol intake (both for OSCC prevention), maintenance of a healthy weight (for OAC prevention), and increasing fresh fruit and vegetable intake with a reduction in red meat consumption.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('oesophageal cancer', 'Disease', 'MESH:D009369', (22, 40))	('moderation', 'Var', (69, 79))	('alcohol', 'Chemical', 'MESH:D000438', (83, 90))	('increasing', 'PosReg', (184, 194))	('oesophageal cancer', 'Disease', (22, 40))	('tobacco', 'Species', '4097', (50, 57))	('OAC', 'Chemical', '-', (163, 166))
92743	28748917	The risk of pulmonary complications seems to be higher following the transthoracic approach, while the longer term health-related quality of life might not differ much between these approaches.	('pulmonary complications', 'Phenotype', 'HP:0006532', (12, 35))	('pulmonary complications', 'Disease', 'MESH:D008171', (12, 35))	('pulmonary complications', 'Disease', (12, 35))	('transthoracic', 'Var', (69, 82))
92792	28748917	Based on the results of the REAL-2 trial, oxaliplatin and cisplatin are considered equivalent in efficacy, but not in toxicity profile; in REAL-2 oxaliplatin was associated with increased rates of neuropathy and diarrhoea and cisplatin with thromboembolic events and neutropenia.	('neutropenia', 'Phenotype', 'HP:0001875', (267, 278))	('cisplatin', 'Chemical', 'MESH:D002945', (58, 67))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (42, 53))	('thromboembolic', 'Disease', 'MESH:D013923', (241, 255))	('thromboembolic events', 'Phenotype', 'HP:0001907', (241, 262))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (146, 157))	('toxicity', 'Disease', 'MESH:D064420', (118, 126))	('neutropenia', 'Disease', (267, 278))	('toxicity', 'Disease', (118, 126))	('neuropathy and diarrhoea', 'Disease', 'MESH:D003967', (197, 221))	('oxaliplatin', 'Var', (146, 157))	('diarrhoea', 'Phenotype', 'HP:0002014', (212, 221))	('neuropathy', 'Phenotype', 'HP:0009830', (197, 207))	('cisplatin', 'Chemical', 'MESH:D002945', (226, 235))	('thromboembolic', 'Disease', (241, 255))	('neutropenia', 'Disease', 'MESH:D009503', (267, 278))	('increased', 'PosReg', (178, 187))
92813	28748917	Finally, oesophageal cancer is associated with a relatively high mutational load, which in other tumours is correlated with response to anti-PD-1 therapy.	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('tumours', 'Disease', (97, 104))	('mutational load', 'Var', (65, 80))	('oesophageal cancer', 'Disease', 'MESH:D009369', (9, 27))	('tumour', 'Phenotype', 'HP:0002664', (97, 103))	('oesophageal cancer', 'Disease', (9, 27))	('tumours', 'Phenotype', 'HP:0002664', (97, 104))	('tumours', 'Disease', 'MESH:D009369', (97, 104))
92891	29333007	The frequency of CD117 positivity was higher in adenocarcinoma as compared to other histological subtypes.	('CD117', 'Gene', '3815', (17, 22))	('CD117', 'Gene', (17, 22))	('adenocarcinoma', 'Disease', (48, 62))	('carcinoma', 'Phenotype', 'HP:0030731', (53, 62))	('higher', 'Reg', (38, 44))	('adenocarcinoma', 'Disease', 'MESH:D000230', (48, 62))	('positivity', 'Var', (23, 33))
92910	29333007	Most studies have reported CD117 positivity in 20% of NSCLC with a range of 7%-64%.	('CD117', 'Gene', '3815', (27, 32))	('CD117', 'Gene', (27, 32))	('positivity', 'Var', (33, 43))	('NSCLC', 'Disease', (54, 59))	('NSCLC', 'Disease', 'MESH:D002289', (54, 59))
92911	29333007	In the current study, we found CD117 positivity in 171 out of 1800 cases (9.5%).	('positivity', 'Var', (37, 47))	('CD117', 'Gene', (31, 36))	('CD117', 'Gene', '3815', (31, 36))
92919	29333007	Thus, expression of CD5 or coexpression of CD117 and CD5 in a mediastinal mass rules out squamous cell carcinoma lung.	('CD5', 'Gene', (20, 23))	('squamous cell carcinoma lung', 'Disease', (89, 117))	('CD5', 'Gene', '921', (20, 23))	('coexpression', 'Var', (27, 39))	('squamous cell carcinoma lung', 'Disease', 'MESH:D002294', (89, 117))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (89, 112))	('CD117', 'Gene', '3815', (43, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('CD5', 'Gene', (53, 56))	('CD117', 'Gene', (43, 48))	('CD5', 'Gene', '921', (53, 56))	('rules out', 'NegReg', (79, 88))
92925	27561242	Targeted therapeutic options have expanded the need for ancillary testing and in particular molecular testing, to document the presence or absence of clinically relevant genetic alterations that include: single nucleotide variants, insertion/deletions, copy number variations, and structural variants that indicate a carcinoma's susceptibility to specific drug therapies (personalized medicine).	('carcinoma', 'Disease', 'MESH:D002277', (317, 326))	('copy number variations', 'Var', (253, 275))	('single nucleotide variants', 'Var', (204, 230))	('carcinoma', 'Disease', (317, 326))	('structural variants', 'Var', (281, 300))	('insertion/deletions', 'Var', (232, 251))	('carcinoma', 'Phenotype', 'HP:0030731', (317, 326))	('indicate', 'Reg', (306, 314))
92963	27561242	Antibodies directed against rearranged ALK, ROS1, and mutated EGFR are three such markers.	('ROS1', 'Gene', (44, 48))	('EGFR', 'Gene', '1956', (62, 66))	('ALK', 'Gene', (39, 42))	('ROS1', 'Gene', '6098', (44, 48))	('EGFR', 'Gene', (62, 66))	('ALK', 'Gene', '238', (39, 42))	('mutated', 'Var', (54, 61))
92964	27561242	Antibodies directed against mutated EGFR are limited to detecting specific mutations (15 base pair deletions in exon 19 and p.L858R mutation in exon 21) and fail to detect other EGFR mutations; while the ALK antibody may have false positive and false negative results.	('ALK', 'Gene', (204, 207))	('EGFR', 'Gene', '1956', (178, 182))	('mutated', 'Var', (28, 35))	('EGFR', 'Gene', (178, 182))	('ALK', 'Gene', '238', (204, 207))	('EGFR', 'Gene', '1956', (36, 40))	('p.L858R', 'Mutation', 'rs121434568', (124, 131))	('p.L858R', 'Var', (124, 131))	('EGFR', 'Gene', (36, 40))
92966	27561242	This approach using reflex testing reduces overall cost as the percentage of pulmonary adenocarcinomas with ALK alterations is low.	('ALK', 'Gene', '238', (108, 111))	('pulmonary adenocarcinoma', 'Phenotype', 'HP:0030078', (77, 101))	('pulmonary adenocarcinomas', 'Disease', 'MESH:D008175', (77, 102))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('pulmonary adenocarcinomas', 'Disease', (77, 102))	('carcinomas', 'Phenotype', 'HP:0030731', (92, 102))	('ALK', 'Gene', (108, 111))	('alterations', 'Var', (112, 123))
92972	27561242	Antibodies raised against ROS1 protein may represent a useful screening technique for ROS1 rearrangements with subsequent reflex of positive results for FISH testing.	('ROS1', 'Gene', (26, 30))	('ROS1', 'Gene', '6098', (26, 30))	('ROS1', 'Gene', (86, 90))	('ROS1', 'Gene', '6098', (86, 90))	('rearrangements', 'Var', (91, 105))
92973	27561242	Immunocytochemical testing for mutated EGFR is not the preferred testing method for determination of tumor susceptibility to the associated tyrosine kinase inhibitors, but may be utilized in the setting of a limited volume sample when molecular testing cannot be performed.	('tyrosine kinase inhibitors', 'MPA', (140, 166))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('EGFR', 'Gene', '1956', (39, 43))	('EGFR', 'Gene', (39, 43))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('mutated', 'Var', (31, 38))
92974	27561242	Immunocytochemical testing for rearranged ALK may be used in place of FISH testing.	('rearranged', 'Var', (31, 41))	('ALK', 'Gene', (42, 45))	('ALK', 'Gene', '238', (42, 45))
93010	27561242	Moreover, cell blocks, smears, and liquid based techniques were all useful for detection of clinically important mutations in nonsmall cell lung cancer.	('lung cancer', 'Phenotype', 'HP:0100526', (140, 151))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (129, 151))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('mutations', 'Var', (113, 122))	('nonsmall cell lung cancer', 'Disease', (126, 151))	('nonsmall cell lung cancer', 'Disease', 'MESH:D002289', (126, 151))
93011	27561242	The majority of organizations and authors recommend molecular testing of pulmonary adenocarcinoma for EGFR and ALK.	('pulmonary adenocarcinoma', 'Disease', (73, 97))	('ALK', 'Gene', '238', (111, 114))	('pulmonary adenocarcinoma', 'Phenotype', 'HP:0030078', (73, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('molecular', 'Var', (52, 61))	('pulmonary adenocarcinoma', 'Disease', 'MESH:D008175', (73, 97))	('EGFR', 'Gene', '1956', (102, 106))	('EGFR', 'Gene', (102, 106))	('ALK', 'Gene', (111, 114))
93015	27561242	KRAS mutations appear to exclude mutations in EGFR and EML4-ALK and the KRAS gene product is present in the control pathway before EGFR and EML4-ALK, thus negating the impact of these latter two genes.	('EGFR', 'Gene', '1956', (46, 50))	('mutations', 'Var', (33, 42))	('EGFR', 'Gene', (131, 135))	('ALK', 'Gene', '238', (60, 63))	('ALK', 'Gene', (60, 63))	('ALK', 'Gene', '238', (145, 148))	('EML4', 'Gene', (140, 144))	('EML4', 'Gene', '27436', (140, 144))	('ALK', 'Gene', (145, 148))	('KRAS', 'Gene', '3845', (0, 4))	('KRAS', 'Gene', '3845', (72, 76))	('mutations', 'Var', (5, 14))	('EGFR', 'Gene', '1956', (131, 135))	('exclude', 'NegReg', (25, 32))	('EGFR', 'Gene', (46, 50))	('KRAS', 'Gene', (0, 4))	('KRAS', 'Gene', (72, 76))	('EML4', 'Gene', (55, 59))	('EML4', 'Gene', '27436', (55, 59))
93016	27561242	With the recent FDA approval of crizotinib for treatment of ROS1 rearranged tumors, immunocytochemical or FISH testing for ROS1 rearrangements should now be performed following negative results for EGFR and ALK testing.	('ALK', 'Gene', (207, 210))	('ROS1', 'Gene', (123, 127))	('ROS1', 'Gene', '6098', (60, 64))	('EGFR', 'Gene', (198, 202))	('crizotinib', 'Chemical', 'MESH:D000077547', (32, 42))	('ROS1', 'Gene', '6098', (123, 127))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('ALK', 'Gene', '238', (207, 210))	('EGFR', 'Gene', '1956', (198, 202))	('tumors', 'Disease', (76, 82))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('rearranged', 'Var', (65, 75))	('ROS1', 'Gene', (60, 64))
93018	27561242	Potential target genes include: fibroblast growth factor receptor 1 (FGFR1) and the related amplification in FGFR2, FGFR3, and FGFR4.	('FGFR1', 'Gene', '2260', (69, 74))	('FGFR4', 'Gene', '2264', (127, 132))	('FGFR4', 'Gene', (127, 132))	('FGFR3', 'Gene', (116, 121))	('fibroblast growth factor receptor 1', 'Gene', (32, 67))	('amplification', 'Var', (92, 105))	('FGFR1', 'Gene', (69, 74))	('fibroblast growth factor receptor 1', 'Gene', '2260', (32, 67))	('FGFR2', 'Gene', (109, 114))	('FGFR3', 'Gene', '2261', (116, 121))	('FGFR2', 'Gene', '2263', (109, 114))
93020	27561242	EGFR mutation testing should be performed at time of diagnosis for patients presenting with high stage disease (stage III and higher).	('mutation', 'Var', (5, 13))	('EGFR', 'Gene', '1956', (0, 4))	('EGFR', 'Gene', (0, 4))	('patients', 'Species', '9606', (67, 75))
93028	27561242	The testing method should be able to detect mutations in EGFR exons 18, 19, 20, and 21 as the two most commonly observed EGFR mutations in pulmonary adenocarcinomas are the p.L858R substitutions and small frame deletions in exon19.	('pulmonary adenocarcinoma', 'Phenotype', 'HP:0030078', (139, 163))	('pulmonary adenocarcinomas', 'Disease', (139, 164))	('EGFR', 'Gene', '1956', (121, 125))	('carcinomas', 'Phenotype', 'HP:0030731', (154, 164))	('EGFR', 'Gene', (121, 125))	('EGFR', 'Gene', '1956', (57, 61))	('p.L858R', 'Mutation', 'rs121434568', (173, 180))	('p.L858R', 'Var', (173, 180))	('carcinoma', 'Phenotype', 'HP:0030731', (154, 163))	('EGFR', 'Gene', (57, 61))	('pulmonary adenocarcinomas', 'Disease', 'MESH:D008175', (139, 164))	('small frame deletions', 'Var', (199, 220))
93030	27561242	KRAS mutational analysis may be helpful in therapy selection, but it should not be the sole method for EGFR therapy selection.	('EGFR', 'Gene', '1956', (103, 107))	('mutational analysis', 'Var', (5, 24))	('EGFR', 'Gene', (103, 107))	('KRAS', 'Gene', (0, 4))	('KRAS', 'Gene', '3845', (0, 4))
93031	27561242	KRAS codon 12, 13, 61, and 146 mutations can be tested for by PCR-based techniques and when present are thought to exclude mutations in EGFR and ALK rearrangements.	('mutations', 'Var', (31, 40))	('ALK', 'Gene', '238', (145, 148))	('EGFR', 'Gene', '1956', (136, 140))	('ALK', 'Gene', (145, 148))	('KRAS', 'Gene', (0, 4))	('EGFR', 'Gene', (136, 140))	('KRAS', 'Gene', '3845', (0, 4))
93032	27561242	Moreover, patients with KRAS mutations may have poor responses to both EGFR based therapy and more traditional chemotherapy justifying to some oncologists, the need for early KRAS testing.	('KRAS', 'Gene', '3845', (24, 28))	('mutations', 'Var', (29, 38))	('EGFR', 'Gene', '1956', (71, 75))	('patients', 'Species', '9606', (10, 18))	('KRAS', 'Gene', (175, 179))	('EGFR', 'Gene', (71, 75))	('KRAS', 'Gene', '3845', (175, 179))	('KRAS', 'Gene', (24, 28))
93036	27561242	ALK rearrangement testing should be performed on all high stage lung adenocarcinomas at time of diagnosis and on lower stage patients at time of recurrence or progression.	('rearrangement testing', 'Var', (4, 25))	('ALK', 'Gene', '238', (0, 3))	('lung adenocarcinomas', 'Disease', (64, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('ALK', 'Gene', (0, 3))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (64, 84))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (64, 84))	('carcinomas', 'Phenotype', 'HP:0030731', (74, 84))	('high', 'Disease', (53, 57))	('patients', 'Species', '9606', (125, 133))
93041	27561242	EGFR mutation testing should be performed at time of diagnosis for patients presenting with high stage disease.	('mutation', 'Var', (5, 13))	('EGFR', 'Gene', '1956', (0, 4))	('EGFR', 'Gene', (0, 4))	('patients', 'Species', '9606', (67, 75))
93043	27561242	Reflex testing to ALK should be performed when EGFR mutational analysis is negative.	('ALK', 'Gene', '238', (18, 21))	('mutational', 'Var', (52, 62))	('EGFR', 'Gene', '1956', (47, 51))	('ALK', 'Gene', (18, 21))	('EGFR', 'Gene', (47, 51))
93046	27561242	ROS1 rearrangements are seen in 1-2.5% of non-small cell carincoma and are mutually exclusive with other tyrosine kinase genetic abnormalities.	('carincoma', 'Disease', (57, 66))	('ROS1', 'Gene', (0, 4))	('ROS1', 'Gene', '6098', (0, 4))	('genetic abnormalities', 'Disease', 'MESH:D030342', (121, 142))	('genetic abnormalities', 'Disease', (121, 142))	('carincoma', 'Disease', 'None', (57, 66))	('rearrangements', 'Var', (5, 19))
93047	27561242	Patients with ROS1 rearrangements appear to benefit from crizotinib therapy.	('crizotinib', 'Chemical', 'MESH:D000077547', (57, 67))	('ROS1', 'Gene', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('ROS1', 'Gene', '6098', (14, 18))	('rearrangements', 'Var', (19, 33))	('benefit', 'PosReg', (44, 51))
93048	27561242	Because ROS1 rearranged pulmonary adenocarcinomas are rare, only patients lacking changes in EGFR, KRAS, and ALK should be tested for ROS1.	('EGFR', 'Gene', '1956', (93, 97))	('ALK', 'Gene', (109, 112))	('ROS1', 'Gene', (134, 138))	('pulmonary adenocarcinoma', 'Phenotype', 'HP:0030078', (24, 48))	('ROS1', 'Gene', '6098', (134, 138))	('rearranged', 'Var', (13, 23))	('EGFR', 'Gene', (93, 97))	('pulmonary adenocarcinomas', 'Disease', 'MESH:D008175', (24, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (39, 48))	('ALK', 'Gene', '238', (109, 112))	('pulmonary adenocarcinomas', 'Disease', (24, 49))	('patients', 'Species', '9606', (65, 73))	('carcinomas', 'Phenotype', 'HP:0030731', (39, 49))	('KRAS', 'Gene', (99, 103))	('ROS1', 'Gene', (8, 12))	('KRAS', 'Gene', '3845', (99, 103))	('ROS1', 'Gene', '6098', (8, 12))
93049	27561242	FISH testing for ROS1 rearrangements may be performed at the discretion of the local oncology team in high stage pulmonary adenocarcinomas who have been shown to lack molecular/genetic changes in EGFR, ALK, and KRAS.	('ROS1', 'Gene', (17, 21))	('EGFR', 'Gene', (196, 200))	('pulmonary adenocarcinoma', 'Phenotype', 'HP:0030078', (113, 137))	('ROS1', 'Gene', '6098', (17, 21))	('pulmonary adenocarcinomas', 'Disease', (113, 138))	('pulmonary adenocarcinomas', 'Disease', 'MESH:D008175', (113, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('carcinomas', 'Phenotype', 'HP:0030731', (128, 138))	('KRAS', 'Gene', (211, 215))	('EGFR', 'Gene', '1956', (196, 200))	('ALK', 'Gene', (202, 205))	('oncology', 'Phenotype', 'HP:0002664', (85, 93))	('KRAS', 'Gene', '3845', (211, 215))	('rearrangements', 'Var', (22, 36))	('ALK', 'Gene', '238', (202, 205))
93082	24356192	Thus, risk stratifications of the various subtypes required a comprehensive clinicopathologic classification system to group variants of squamous cell carcinoma based on their biologic aggressiveness or indolence.	('squamous cell carcinoma', 'Disease', (137, 160))	('aggressiveness', 'Disease', (185, 199))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (137, 160))	('variants', 'Var', (125, 133))	('aggressiveness', 'Phenotype', 'HP:0000718', (185, 199))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (137, 160))	('aggressiveness', 'Disease', 'MESH:D001523', (185, 199))	('carcinoma', 'Phenotype', 'HP:0030731', (151, 160))
93086	24356192	With the advent of microarray techniques and other high-throughput screening, gene expression profiling can help in distinguishing the variants of different subgroups among tumors with similar morphology and may be further useful for outcome analysis and risk assessment.	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('variants', 'Var', (135, 143))	('tumors', 'Disease', 'MESH:D009369', (173, 179))	('tumors', 'Disease', (173, 179))	('tumors', 'Phenotype', 'HP:0002664', (173, 179))
93140	24356192	On the basis of the mRNA levels, the performance of discrimination between tumors vs normal was highly significant with MMP1 (area under the curve = 0.94; P= 0.002), MMP10 (area under the curve = 0.90; P= 0.013) and ADAMTS1 (area under the curve = 0.74; P= 0.022).	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('ADAMTS1', 'Gene', '9510', (216, 223))	('MMP1', 'Var', (120, 124))	('MMP10', 'Gene', (166, 171))	('ADAMTS1', 'Gene', (216, 223))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumors', 'Disease', (75, 81))	('MMP10', 'Gene', '4319', (166, 171))
93183	33925205	Tumor-Infiltrating Lymphocytes in the Tumor Microenvironment of Laryngeal Squamous Cell Carcinoma: Systematic Review and Meta-Analysis The presence of tumor-infiltrating lymphocytes (TIL) in the tumor microenvironment has been demonstrated to be of prognostic value in various cancers.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumor', 'Disease', (195, 200))	('Squamous Cell Carcinoma', 'Disease', 'MESH:D002294', (74, 97))	('cancers', 'Disease', 'MESH:D009369', (277, 284))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (74, 97))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('Tumor', 'Phenotype', 'HP:0002664', (38, 43))	('cancer', 'Disease', (277, 283))	('Squamous Cell Carcinoma', 'Disease', (74, 97))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('cancer', 'Phenotype', 'HP:0002664', (277, 283))	('cancers', 'Phenotype', 'HP:0002664', (277, 284))	('cancers', 'Disease', (277, 284))	('Carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('cancer', 'Disease', 'MESH:D009369', (277, 283))	('tumor', 'Disease', (151, 156))	('presence', 'Var', (139, 147))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
93185	33925205	A meta-analysis was performed including all studies assessing the association between TIL counts in hematoxylin-eosin (HE)-stained sections, for CD8+ and/or CD3+/CD4+ TIL and overall survival (OS) or disease-free survival (DFS).	('CD8+', 'Var', (145, 149))	('eosin', 'Chemical', 'MESH:D004801', (112, 117))	('HE', 'Chemical', '-', (119, 121))	('CD3+/CD4+ TIL', 'Var', (157, 170))	('hematoxylin', 'Chemical', 'MESH:D006416', (100, 111))	('disease-free survival', 'CPA', (200, 221))	('overall survival', 'CPA', (175, 191))
93186	33925205	High stromal TIL evaluated in HE sections and intra-tumoral and stromal CD3+, CD4+ and/or CD8+ TIL might predict a better clinical outcome.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('intra-tumor', 'Disease', 'MESH:D009369', (46, 57))	('intra-tumoral', 'Disease', 'MESH:D009369', (46, 59))	('CD8+', 'Var', (90, 94))	('intra-tumoral', 'Disease', (46, 59))	('intra-tumor', 'Disease', (46, 57))	('tumoral', 'Disease', (52, 59))	('tumoral', 'Disease', 'MESH:D009369', (52, 59))	('CD4+', 'Var', (78, 82))
93224	33643901	One explanation may be that tumor cells physically absorb and neutralize ENO1 antibodies expressed and secreted on the surface to reduce circulating levels.	('reduce', 'NegReg', (130, 136))	('tumor', 'Disease', (28, 33))	('circulating levels', 'MPA', (137, 155))	('neutralize', 'Var', (62, 72))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('ENO1', 'Gene', (73, 77))	('ENO1', 'Gene', '2023', (73, 77))
93235	33643901	In this study, the cBio Cancer Genomics Portal (; accessed by April 30, 2020), which is a web tool for mutation analysis and visualization through TCGA cancer genomics profiles, was used for mutation analysis of ENO1.	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('Cancer', 'Disease', (24, 30))	('Cancer', 'Disease', 'MESH:D009369', (24, 30))	('Cancer', 'Phenotype', 'HP:0002664', (24, 30))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('ENO1', 'Gene', (212, 216))	('ENO1', 'Gene', '2023', (212, 216))	('mutation', 'Var', (191, 199))
93250	33643901	The highest ENO1 expression was found in EBV-transformed lymphocytes, whereas the lowest was observed in the left ventricle of the heart.	('ENO1', 'Gene', (12, 16))	('expression', 'MPA', (17, 27))	('ENO1', 'Gene', '2023', (12, 16))	('EBV-transformed', 'Var', (41, 56))
93257	33643901	The expression of ENO1 was significantly associated with the prognosis of eight types of cancers, including HNSC (HR = 1.32, P = 0.04), CESC (HR = 1.47, P = 0.04), BLCA (HR = 1.23, P = 0.04), LUAD (HR = 1.36, P = 0.01), SARC (HR = 1.36, P = 0.00), PAAD (HR = 1.65, P = 0.00), KICH (HR = 4.60, P = 0.00), and LIHC (HR = 1.63, P = 0.00), suggesting that high ENO1 expression might be an independent risk factor for these cancers (all HR > 1.00, P < 0.05).	('associated', 'Reg', (41, 51))	('high', 'Var', (352, 356))	('cancers', 'Phenotype', 'HP:0002664', (89, 96))	('KICH', 'Disease', (276, 280))	('cancers', 'Disease', (89, 96))	('LUAD', 'Disease', (192, 196))	('cancers', 'Disease', 'MESH:D009369', (419, 426))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('CESC', 'Disease', (136, 140))	('BLCA', 'Disease', (164, 168))	('ENO1', 'Gene', (18, 22))	('cancers', 'Disease', 'MESH:D009369', (89, 96))	('cancers', 'Phenotype', 'HP:0002664', (419, 426))	('ENO1', 'Gene', (357, 361))	('cancers', 'Disease', (419, 426))	('ENO1', 'Gene', '2023', (18, 22))	('KICH', 'Disease', 'None', (276, 280))	('HNSC', 'Disease', (108, 112))	('SARC', 'Disease', (220, 224))	('cancer', 'Phenotype', 'HP:0002664', (419, 425))	('ENO1', 'Gene', '2023', (357, 361))	('LUAD', 'Phenotype', 'HP:0030078', (192, 196))
93259	33643901	High ENO1 expression was significantly associated with worse OS in CESC (log-rank P = 0.04), BLCA (log-rank P = 0.03), KICH (log-rank P = 0.01), LIHC (log-rank P = 0.00), and SARC (log-rank P = 0.04), and worse DFS in KICH (log-rank P = 0.03) and SARC (log-rank P = 0.07).	('SARC', 'Disease', (175, 179))	('LIHC', 'Disease', (145, 149))	('KICH', 'Disease', 'None', (218, 222))	('High', 'Var', (0, 4))	('ENO1', 'Gene', '2023', (5, 9))	('expression', 'MPA', (10, 20))	('ENO1', 'Gene', (5, 9))	('CESC', 'Disease', (67, 71))	('KICH', 'Disease', 'None', (119, 123))	('KICH', 'Disease', (218, 222))	('KICH', 'Disease', (119, 123))	('BLCA', 'Disease', (93, 97))
93264	33643901	Evidently, 195 samples in the altered group and 10,772 samples in the unaltered group were included for ENO1 mutation analysis.	('ENO1', 'Gene', '2023', (104, 108))	('mutation', 'Var', (109, 117))	('ENO1', 'Gene', (104, 108))
93265	33643901	The results demonstrated that ENO1 was altered in 1.8% of all the included samples, including inframe mutation, missense mutation, truncating mutation, fusion, amplification, and deep deletion ( Figure 6 ).	('truncating', 'MPA', (131, 141))	('amplification', 'Var', (160, 173))	('ENO1', 'Gene', (30, 34))	('deep deletion', 'Var', (179, 192))	('ENO1', 'Gene', '2023', (30, 34))	('altered', 'Reg', (39, 46))	('fusion', 'Var', (152, 158))	('missense mutation', 'Var', (112, 129))
93266	33643901	Furthermore, the prognostic significance of ENO1 mutation was estimated via Kaplan-Meier method.	('ENO1', 'Gene', '2023', (44, 48))	('mutation', 'Var', (49, 57))	('ENO1', 'Gene', (44, 48))
93298	33643901	These findings are consistent with a previous study showing that high ENO1 expression is significantly correlated with DNA replication and cell cycle in hepatocellular carcinoma.	('DNA replication', 'CPA', (119, 134))	('carcinoma', 'Phenotype', 'HP:0030731', (168, 177))	('ENO1', 'Gene', (70, 74))	('ENO1', 'Gene', '2023', (70, 74))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (153, 177))	('cell cycle', 'CPA', (139, 149))	('high', 'Var', (65, 69))	('correlated', 'Reg', (103, 113))	('hepatocellular carcinoma', 'Disease', (153, 177))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (153, 177))	('expression', 'MPA', (75, 85))
93306	33643901	Furthermore, the knockdown of ENO1 has been shown to promote apoptosis and induce the arrest of cell cycle in gastric cancer cells.	('gastric cancer', 'Disease', (110, 124))	('apoptosis', 'CPA', (61, 70))	('gastric cancer', 'Disease', 'MESH:D013274', (110, 124))	('arrest', 'Disease', 'MESH:D006323', (86, 92))	('arrest', 'Disease', (86, 92))	('gastric cancer', 'Phenotype', 'HP:0012126', (110, 124))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('ENO1', 'Gene', (30, 34))	('ENO1', 'Gene', '2023', (30, 34))	('knockdown', 'Var', (17, 26))	('induce', 'Reg', (75, 81))	('promote', 'PosReg', (53, 60))
93311	33643901	Additionally, mutation of ENO1 was analysis, for it was proved that mutation could affect tumor progression; however, ENO1 mutation (1.8%) did not impact on prognosis in this study.	('affect', 'Reg', (83, 89))	('mutation', 'Var', (68, 76))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('ENO1', 'Gene', (118, 122))	('tumor', 'Disease', (90, 95))	('ENO1', 'Gene', '2023', (118, 122))	('ENO1', 'Gene', (26, 30))	('ENO1', 'Gene', '2023', (26, 30))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
93315	33643901	In consonance with our results, ENO1 expression was higher in late stages (stages III and IV), particularly that in KICH ( Figure 5E ), meanwhile, high ENO1 expression was significantly associated with worse OS in KICH ( Figure 4I ).	('worse OS', 'Disease', (202, 210))	('expression', 'MPA', (157, 167))	('ENO1', 'Gene', (152, 156))	('ENO1', 'Gene', '2023', (32, 36))	('ENO1', 'Gene', '2023', (152, 156))	('KICH', 'Disease', 'None', (214, 218))	('ENO1', 'Gene', (32, 36))	('KICH', 'Disease', 'None', (116, 120))	('high', 'Var', (147, 151))	('associated', 'Reg', (186, 196))	('higher', 'PosReg', (52, 58))	('KICH', 'Disease', (214, 218))	('expression', 'MPA', (37, 47))	('KICH', 'Disease', (116, 120))
93359	33111744	Emerging studies have suggested that the abnormal expression of lncRNAs plays critical roles in the pathogenesis of diverse types of cancer.	('abnormal', 'Var', (41, 49))	('lncRNAs', 'Protein', (64, 71))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('cancer', 'Disease', (133, 139))	('roles', 'Reg', (87, 92))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('expression', 'MPA', (50, 60))
93360	33111744	For instance, lncRNA MALAT1 (metastasis-associated lung adenocarcinoma transcript 1) overexpression inhibits the metastasis of breast cancer through regulating the pro-metastatic transcription factor TEAD.	('MALAT1', 'Gene', '378938', (21, 27))	('inhibits', 'NegReg', (100, 108))	('MALAT1', 'Gene', (21, 27))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (51, 70))	('breast cancer', 'Disease', 'MESH:D001943', (127, 140))	('breast cancer', 'Disease', (127, 140))	('overexpression', 'Var', (85, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('breast cancer', 'Phenotype', 'HP:0003002', (127, 140))	('metastasis', 'CPA', (113, 123))	('regulating', 'Reg', (149, 159))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (51, 70))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('TEAD', 'MPA', (200, 204))	('lung adenocarcinoma', 'Disease', (51, 70))
93362	33111744	Several reports suggest that the abnormal expression of LINC00355 is linked to the overall survival of cancers such as prostate cancer, colorectal cancer, and colon adenocarcinoma .	('cancers', 'Disease', 'MESH:D009369', (103, 110))	('colon adenocarcinoma', 'Disease', (159, 179))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('LINC00355', 'Gene', (56, 65))	('expression', 'MPA', (42, 52))	('colorectal cancer', 'Disease', 'MESH:D015179', (136, 153))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('colorectal cancer', 'Disease', (136, 153))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('cancers', 'Phenotype', 'HP:0002664', (103, 110))	('prostate cancer', 'Disease', 'MESH:D011471', (119, 134))	('cancers', 'Disease', (103, 110))	('prostate cancer', 'Phenotype', 'HP:0012125', (119, 134))	('colon adenocarcinoma', 'Disease', 'MESH:D003110', (159, 179))	('prostate cancer', 'Disease', (119, 134))	('LINC00355', 'Gene', '144766', (56, 65))	('colorectal cancer', 'Phenotype', 'HP:0003003', (136, 153))	('carcinoma', 'Phenotype', 'HP:0030731', (170, 179))	('linked', 'Reg', (69, 75))	('abnormal', 'Var', (33, 41))
93373	33111744	MiR-494-3p as a carcinogenic factor was upregulated in lung cancer and promoted the progression of lung cancer.	('lung cancer', 'Disease', (99, 110))	('lung cancer', 'Disease', 'MESH:D008175', (55, 66))	('promoted', 'PosReg', (71, 79))	('progression', 'CPA', (84, 95))	('MiR-494-3p', 'Chemical', '-', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('lung cancer', 'Disease', 'MESH:D008175', (99, 110))	('lung cancer', 'Disease', (55, 66))	('lung cancer', 'Phenotype', 'HP:0100526', (99, 110))	('lung cancer', 'Phenotype', 'HP:0100526', (55, 66))	('carcinogenic', 'Disease', 'MESH:D063646', (16, 28))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('MiR-494-3p', 'Var', (0, 10))	('upregulated', 'PosReg', (40, 51))	('carcinogenic', 'Disease', (16, 28))
93425	33111744	Full length LINC00355 or mutated LINC00355 was transcribed by T7 RNA polymerase (Stratagene, USA) and labeled with biotin using Biotin RNA labeling mix (Roche, Switzerland).	('Biotin', 'Chemical', 'MESH:D001710', (128, 134))	('LINC00355', 'Gene', (33, 42))	('LINC00355', 'Gene', (12, 21))	('biotin', 'Chemical', 'MESH:D001710', (115, 121))	('LINC00355', 'Gene', '144766', (12, 21))	('LINC00355', 'Gene', '144766', (33, 42))	('mutated', 'Var', (25, 32))
93438	33111744	Figure 1C shows that the overall survival rate of patients with the low LINC00355 expression was significantly higher than that with high LINC00355 expression indicating that LINC00355 expression level predicted poor prognosis of lung SCC patients.	('survival', 'CPA', (33, 41))	('LINC00355', 'Gene', (138, 147))	('LINC00355', 'Gene', (72, 81))	('patients', 'Species', '9606', (50, 58))	('LINC00355', 'Gene', '144766', (175, 184))	('LINC00355', 'Gene', '144766', (138, 147))	('patients', 'Species', '9606', (239, 247))	('LINC00355', 'Gene', '144766', (72, 81))	('low', 'Var', (68, 71))	('lung SCC', 'Disease', (230, 238))	('higher', 'PosReg', (111, 117))	('LINC00355', 'Gene', (175, 184))	('SCC', 'Phenotype', 'HP:0002860', (235, 238))
93445	33111744	LINC00355 knockdown also significantly suppressed the colony formation of NCI-H2170 cells compared to the shNC group (Figure 2C).	('LINC00355', 'Gene', '144766', (0, 9))	('colony formation', 'CPA', (54, 70))	('NCI-H2170 cells', 'CellLine', 'CVCL:1535', (74, 89))	('LINC00355', 'Gene', (0, 9))	('knockdown', 'Var', (10, 19))	('suppressed', 'NegReg', (39, 49))
93446	33111744	Moreover, the protein level of PCNA (proliferating cell nuclear antigen) was greatly down-regulated in NCI-H2170 cells by transfection of shLINC00355 compared to the shNC group (Figure 2G).	('PCNA', 'Gene', '5111', (31, 35))	('proliferating cell nuclear antigen', 'Gene', '5111', (37, 71))	('LINC00355', 'Gene', '144766', (140, 149))	('protein level', 'MPA', (14, 27))	('down-regulated', 'NegReg', (85, 99))	('transfection', 'Var', (122, 134))	('NCI-H2170 cells', 'CellLine', 'CVCL:1535', (103, 118))	('proliferating cell nuclear antigen', 'Gene', (37, 71))	('PCNA', 'Gene', (31, 35))	('LINC00355', 'Gene', (140, 149))
93449	33111744	Western blot further confirmed that knockdown of LINC00355 considerably reduced the expression level of the anti-apoptotic protein (Bcl-2) and enhanced the levels of pro-apoptotic proteins (Bax and cleaved caspase-3) in NCI-H2170 cells compared to the shNC group (Figure 2I).	('reduced', 'NegReg', (72, 79))	('levels of pro-apoptotic', 'MPA', (156, 179))	('Bax', 'Gene', (190, 193))	('enhanced', 'PosReg', (143, 151))	('NCI-H2170 cells', 'CellLine', 'CVCL:1535', (220, 235))	('LINC00355', 'Gene', (49, 58))	('caspase-3', 'Gene', '836', (206, 215))	('Bcl-2', 'Gene', (132, 137))	('knockdown', 'Var', (36, 45))	('Bcl-2', 'Gene', '596', (132, 137))	('LINC00355', 'Gene', '144766', (49, 58))	('Bax', 'Gene', '581', (190, 193))	('expression level of', 'MPA', (84, 103))	('caspase-3', 'Gene', (206, 215))
93450	33111744	Thus, LINC00355 knockdown significantly promoted the apoptosis of NCI-H2170 cells.	('LINC00355', 'Gene', (6, 15))	('apoptosis', 'CPA', (53, 62))	('NCI-H2170 cells', 'CellLine', 'CVCL:1535', (66, 81))	('promoted', 'PosReg', (40, 48))	('LINC00355', 'Gene', '144766', (6, 15))	('knockdown', 'Var', (16, 25))
93452	33111744	Compared to the control group, knockdown of LINC00355 greatly suppressed the migration of NCI-H2170 cells and decreased the number of invasive NCI-H2170 cells (Figure 2E and F).	('LINC00355', 'Gene', '144766', (44, 53))	('NCI-H2170 cells', 'CellLine', 'CVCL:1535', (143, 158))	('NCI-H2170 cells', 'CellLine', 'CVCL:1535', (90, 105))	('migration of NCI-H2170 cells', 'CPA', (77, 105))	('decreased', 'NegReg', (110, 119))	('suppressed', 'NegReg', (62, 72))	('LINC00355', 'Gene', (44, 53))	('knockdown', 'Var', (31, 40))
93453	33111744	Figure 2H shows that knockdown of LINC00355 increased the expression level of E-cadherin but decreased the level of N-cadherin compared to the shNC group.	('expression level', 'MPA', (58, 74))	('N-cadherin', 'Gene', (116, 126))	('LINC00355', 'Gene', '144766', (34, 43))	('N-cadherin', 'Gene', '1000', (116, 126))	('E-cadherin', 'Gene', (78, 88))	('decreased', 'NegReg', (93, 102))	('E-cadherin', 'Gene', '999', (78, 88))	('increased', 'PosReg', (44, 53))	('knockdown', 'Var', (21, 30))	('LINC00355', 'Gene', (34, 43))
93454	33111744	Based on the fact that low expression of E-cadherin and high level of N-cadherin can contribute to cell migration and invasion, it can be concluded that knockdown of LINC00355 inhibited the migration and invasion of NCI-H2170 cells.	('N-cadherin', 'Gene', '1000', (70, 80))	('knockdown', 'Var', (153, 162))	('invasion', 'CPA', (204, 212))	('NCI-H2170 cells', 'CellLine', 'CVCL:1535', (216, 231))	('inhibited', 'NegReg', (176, 185))	('LINC00355', 'Gene', (166, 175))	('N-cadherin', 'Gene', (70, 80))	('LINC00355', 'Gene', '144766', (166, 175))	('E-cadherin', 'Gene', (41, 51))	('E-cadherin', 'Gene', '999', (41, 51))
93455	33111744	Furthermore, compared to the shNC group, the higher fluorescence intensity in the shLINC00355 group suggested that knockdown of LINC00355 caused the excessive generation of ROS (Figure 2J).	('generation', 'MPA', (159, 169))	('ROS', 'MPA', (173, 176))	('fluorescence intensity', 'MPA', (52, 74))	('LINC00355', 'Gene', (84, 93))	('LINC00355', 'Gene', (128, 137))	('ROS', 'Chemical', 'MESH:D017382', (173, 176))	('LINC00355', 'Gene', '144766', (128, 137))	('higher', 'PosReg', (45, 51))	('LINC00355', 'Gene', '144766', (84, 93))	('knockdown', 'Var', (115, 124))
93468	33111744	After miR-466 mimic, miR-466 inhibitor, or negative control mimic (NC mimic) was transfected into NCI-H2170 cells, the level of LYAR was decreased by miR-466 mimic transfection, but increased by miR-466 inhibitor compared to the control group (Figure 4C).	('increased', 'PosReg', (182, 191))	('miR-466', 'Gene', (150, 157))	('LYAR', 'Gene', '55646', (128, 132))	('miR-466', 'Gene', '100423038', (150, 157))	('miR-466', 'Gene', (6, 13))	('LYAR', 'Gene', (128, 132))	('miR-466', 'Gene', (21, 28))	('transfection', 'Var', (164, 176))	('miR-466', 'Gene', '100423038', (21, 28))	('miR-466', 'Gene', (195, 202))	('miR-466', 'Gene', '100423038', (195, 202))	('miR-466', 'Gene', '100423038', (6, 13))	('decreased', 'NegReg', (137, 146))	('NCI-H2170 cells', 'CellLine', 'CVCL:1535', (98, 113))
93469	33111744	Compared to the control group, western blot further confirmed that miR-466 mimics decreased the protein expression of LYAR, and miR-466 inhibition caused the opposite results (Figure 4D).	('mimics', 'Var', (75, 81))	('miR-466', 'Gene', '100423038', (128, 135))	('LYAR', 'Gene', '55646', (118, 122))	('miR-466', 'Gene', '100423038', (67, 74))	('protein expression', 'MPA', (96, 114))	('LYAR', 'Gene', (118, 122))	('miR-466', 'Gene', (128, 135))	('decreased', 'NegReg', (82, 91))	('miR-466', 'Gene', (67, 74))
93473	33111744	Compared to the NC inhibitor + shNC group, knockdown of LINC00355 inhibited cell viability and colony formation (Figure 5A and B).	('LINC00355', 'Gene', (56, 65))	('colony formation', 'CPA', (95, 111))	('knockdown', 'Var', (43, 52))	('cell viability', 'CPA', (76, 90))	('LINC00355', 'Gene', '144766', (56, 65))	('inhibited', 'NegReg', (66, 75))
93475	33111744	Compared with the NC inhibitor + shNC group, the apoptotic rate of NCI-H2170 cells was decreased by shLINC00355 transfection, which was greatly reversed by co-transfection of shLINC00355 and miR-466 inhibitor (Figure 5C).	('LINC00355', 'Gene', '144766', (102, 111))	('miR-466', 'Gene', '100423038', (191, 198))	('transfection', 'Var', (112, 124))	('apoptotic rate', 'CPA', (49, 63))	('decreased', 'NegReg', (87, 96))	('LINC00355', 'Gene', (177, 186))	('NCI-H2170 cells', 'CellLine', 'CVCL:1535', (67, 82))	('LINC00355', 'Gene', (102, 111))	('LINC00355', 'Gene', '144766', (177, 186))	('miR-466', 'Gene', (191, 198))
93482	33111744	As shown in Figure 6A, the size and volume of the tumors were significantly suppressed by LINC00355 knockdown compared to the control group.	('knockdown', 'Var', (100, 109))	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('LINC00355', 'Gene', (90, 99))	('suppressed', 'NegReg', (76, 86))	('LINC00355', 'Gene', '144766', (90, 99))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('tumors', 'Disease', (50, 56))
93486	33111744	Meanwhile, LINC00355 knockdown increased the protein levels of Bax and cleaved caspase-3 and decreased the level of Bcl-2 compared to the Ad-shNC group.	('protein levels', 'MPA', (45, 59))	('increased', 'PosReg', (31, 40))	('LINC00355', 'Gene', (11, 20))	('Bax', 'Gene', '581', (63, 66))	('caspase-3', 'Gene', '836', (79, 88))	('decreased', 'NegReg', (93, 102))	('LINC00355', 'Gene', '144766', (11, 20))	('Bax', 'Gene', (63, 66))	('Bcl-2', 'Gene', (116, 121))	('caspase-3', 'Gene', (79, 88))	('knockdown', 'Var', (21, 30))	('Bcl-2', 'Gene', '596', (116, 121))
93496	33111744	These investigations indicated that LINC00355 knockdown suppressed SCC cell growth.	('LINC00355', 'Gene', '144766', (36, 45))	('knockdown', 'Var', (46, 55))	('suppressed', 'NegReg', (56, 66))	('SCC', 'Phenotype', 'HP:0002860', (67, 70))	('LINC00355', 'Gene', (36, 45))	('SCC', 'Disease', (67, 70))
93498	33111744	In this study, compared to the shNC group, the higher fluorescence intensity in the shLINC00355 group suggested that knockdown of LINC00355 caused the excessive generation of ROS.	('LINC00355', 'Gene', '144766', (130, 139))	('ROS', 'Chemical', 'MESH:D017382', (175, 178))	('LINC00355', 'Gene', (86, 95))	('higher', 'PosReg', (47, 53))	('LINC00355', 'Gene', (130, 139))	('LINC00355', 'Gene', '144766', (86, 95))	('ROS', 'MPA', (175, 178))	('knockdown', 'Var', (117, 126))	('fluorescence intensity', 'MPA', (54, 76))
93499	33111744	Thus, knockdown of LINC00355 could increase the level of ROS to influence the proliferation, apoptosis, migration, and invasion of NCI-H2170 cells.	('increase', 'PosReg', (35, 43))	('ROS', 'Chemical', 'MESH:D017382', (57, 60))	('invasion', 'CPA', (119, 127))	('migration', 'CPA', (104, 113))	('NCI-H2170 cells', 'CellLine', 'CVCL:1535', (131, 146))	('level', 'MPA', (48, 53))	('influence', 'Reg', (64, 73))	('proliferation', 'CPA', (78, 91))	('LINC00355', 'Gene', (19, 28))	('ROS', 'MPA', (57, 60))	('knockdown', 'Var', (6, 15))	('apoptosis', 'CPA', (93, 102))	('LINC00355', 'Gene', '144766', (19, 28))
93519	33111744	The results showed that miR-466 inhibitor reversed the effects of LINC00355 knockdown on lung SCC cell growth, suggesting that LINC00355 knockdown could inhibit proliferation, migration, and invasion, but promote apoptosis of lung SCC cells through regulating the miR-466/LYAR axis.	('miR-466', 'Gene', (24, 31))	('apoptosis', 'CPA', (213, 222))	('SCC', 'Phenotype', 'HP:0002860', (231, 234))	('LINC00355', 'Gene', (127, 136))	('LYAR', 'Gene', (272, 276))	('LINC00355', 'Gene', '144766', (66, 75))	('SCC', 'Phenotype', 'HP:0002860', (94, 97))	('knockdown', 'Var', (137, 146))	('miR-466', 'Gene', '100423038', (264, 271))	('promote', 'PosReg', (205, 212))	('invasion', 'CPA', (191, 199))	('LYAR', 'Gene', '55646', (272, 276))	('miR-466', 'Gene', '100423038', (24, 31))	('proliferation', 'CPA', (161, 174))	('regulating', 'Reg', (249, 259))	('inhibit', 'NegReg', (153, 160))	('LINC00355', 'Gene', (66, 75))	('LINC00355', 'Gene', '144766', (127, 136))	('migration', 'CPA', (176, 185))	('miR-466', 'Gene', (264, 271))
93623	32856476	However, the nonrandomized prospective matched-pair part of this study revealed 52 pairs of stage- and standard oncological treatment-matched NSCLC patients showing 3.08 years of mean survival time in the add-on VA (Iscador) group versus 2.60 years in the control group (no add-on VA; log-rank test: P = .05), showing a tendency toward significance for this outcome and this entity.	('patients', 'Species', '9606', (148, 156))	('age', 'Gene', '5973', (94, 97))	('add-on', 'Var', (205, 211))	('VA', 'Species', '3972', (281, 283))	('VA', 'Species', '3972', (212, 214))	('NSCLC', 'Disease', (142, 147))	('NSCLC', 'Disease', 'MESH:D002289', (142, 147))	('age', 'Gene', (94, 97))	('NSCLC', 'Phenotype', 'HP:0030358', (142, 147))
93646	32788940	MALAT1 knockdown decreased the expression of CFL1 at both the mRNA and protein levels, and affected cytoskeletal rearrangement by regulating the levels of F-actin via CFL1, leading to significantly decreased cellular migration.	('affected', 'Reg', (91, 99))	('MALAT1', 'Gene', '378938', (0, 6))	('regulating', 'Reg', (130, 140))	('CFL1', 'Gene', (45, 49))	('decreased', 'NegReg', (17, 26))	('CFL1', 'Gene', '1072', (167, 171))	('MALAT1', 'Gene', (0, 6))	('CFL1', 'Gene', '1072', (45, 49))	('levels of F-actin', 'MPA', (145, 162))	('cellular migration', 'CPA', (208, 226))	('expression', 'MPA', (31, 41))	('cytoskeletal rearrangement', 'MPA', (100, 126))	('decreased', 'NegReg', (198, 207))	('CFL1', 'Gene', (167, 171))	('knockdown', 'Var', (7, 16))
93653	32788940	lncRNA dysregulation has been associated with the occurrence and progression of malignant tumors, including lung cancer, cervical cancer and colorectal cancer, by regulating various cellular processes in tumor cells, such as proliferation, migration, differentiation, apoptosis and the cell cycle.	('differentiation', 'CPA', (251, 266))	('malignant tumors', 'Disease', 'MESH:D009369', (80, 96))	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('colorectal cancer', 'Phenotype', 'HP:0003003', (141, 158))	('lncRNA', 'Protein', (0, 6))	('cancer', 'Disease', (113, 119))	('apoptosis', 'CPA', (268, 277))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('cell cycle', 'CPA', (286, 296))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('tumor', 'Disease', (90, 95))	('lung cancer', 'Disease', (108, 119))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('regulating', 'Reg', (163, 173))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('associated', 'Reg', (30, 40))	('colorectal cancer', 'Disease', 'MESH:D015179', (141, 158))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('proliferation', 'CPA', (225, 238))	('colorectal cancer', 'Disease', (141, 158))	('migration', 'CPA', (240, 249))	('lung cancer', 'Disease', 'MESH:D008175', (108, 119))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('cancer', 'Disease', (130, 136))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('dysregulation', 'Var', (7, 20))	('tumor', 'Disease', (204, 209))	('lung cancer', 'Phenotype', 'HP:0100526', (108, 119))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('malignant tumors', 'Disease', (80, 96))
93692	32788940	Following 48 h transfection, ACHN and 786-O cells were cultured in 6-well plates until confluent.	('ACHN', 'Gene', (29, 33))	('ACHN', 'Gene', '55323', (29, 33))	('transfection', 'Var', (15, 27))
93714	32788940	MALAT1 knockdown inhibited CFL1 expression at both the mRNA and protein levels compared with respective control cells in both ACHN (Fig.	('MALAT1', 'Gene', '378938', (0, 6))	('CFL1', 'Gene', (27, 31))	('MALAT1', 'Gene', (0, 6))	('ACHN', 'Gene', '55323', (126, 130))	('CFL1', 'Gene', '1072', (27, 31))	('inhibited', 'NegReg', (17, 26))	('ACHN', 'Gene', (126, 130))	('expression', 'MPA', (32, 42))	('knockdown', 'Var', (7, 16))
93717	32788940	Knockdown of MALAT1 decreased the levels of CFL1 mRNA in both ACHN (P<0.001, Fig.	('MALAT1', 'Gene', (13, 19))	('CFL1', 'Gene', '1072', (44, 48))	('Knockdown', 'Var', (0, 9))	('decreased', 'NegReg', (20, 29))	('ACHN', 'Gene', (62, 66))	('ACHN', 'Gene', '55323', (62, 66))	('MALAT1', 'Gene', '378938', (13, 19))	('CFL1', 'Gene', (44, 48))
93721	32788940	Then, rescue experiments were performed by first knocking down MALAT1 with siRNA and then overexpressing CFL1.	('CFL1', 'Gene', '1072', (105, 109))	('MALAT1', 'Gene', '378938', (63, 69))	('knocking down', 'Var', (49, 62))	('MALAT1', 'Gene', (63, 69))	('CFL1', 'Gene', (105, 109))
93723	32788940	Western blotting showed that MALAT1 knockdown did not affect the total amount of beta-actin (Fig.	('knockdown', 'Var', (36, 45))	('MALAT1', 'Gene', '378938', (29, 35))	('MALAT1', 'Gene', (29, 35))
93724	32788940	A fluorescence staining assay was performed to measure the levels of F-actin in the cells and observed marked accumulation of F-actin near the cell membrane in MALAT1 knockdown cells as compared with the corresponding control cells (Fig.	('knockdown', 'Var', (167, 176))	('MALAT1', 'Gene', (160, 166))	('MALAT1', 'Gene', '378938', (160, 166))	('accumulation', 'PosReg', (110, 122))
93730	32788940	MALAT1 siRNA knockdown inhibited the migration and invasiveness of RCC cells compared with their corresponding control cells.	('MALAT1', 'Gene', '378938', (0, 6))	('RCC', 'Phenotype', 'HP:0005584', (67, 70))	('inhibited', 'NegReg', (23, 32))	('RCC', 'Disease', 'MESH:C538614', (67, 70))	('RCC', 'Disease', (67, 70))	('MALAT1', 'Gene', (0, 6))	('knockdown', 'Var', (13, 22))
93752	32788940	For example, MALAT1 is reported to promote EMT by sponging miR-126-5p and thereby increasing the expression of metastasis-associated molecules, such as vascular endothelial growth factor A, snail family transcriptional repressor 2 and twist family bHLH transcription factor 1 in colorectal cancer.	('MALAT1', 'Gene', (13, 19))	('colorectal cancer', 'Phenotype', 'HP:0003003', (279, 296))	('vascular endothelial growth factor A', 'Gene', '7422', (152, 188))	('snail family transcriptional repressor 2', 'Gene', (190, 230))	('miR-126-5p', 'Gene', '100302116', (59, 69))	('miR-126-5p', 'Gene', (59, 69))	('colorectal cancer', 'Disease', (279, 296))	('increasing', 'PosReg', (82, 92))	('sponging', 'Var', (50, 58))	('snail family transcriptional repressor 2', 'Gene', '6591', (190, 230))	('promote', 'PosReg', (35, 42))	('vascular endothelial growth factor A', 'Gene', (152, 188))	('EMT', 'CPA', (43, 46))	('cancer', 'Phenotype', 'HP:0002664', (290, 296))	('MALAT1', 'Gene', '378938', (13, 19))	('colorectal cancer', 'Disease', 'MESH:D015179', (279, 296))	('expression', 'MPA', (97, 107))
93756	32788940	In the present study, MALAT1 knockdown decreased CFL1 expression at both the mRNA and protein level without affecting the abundance of its pre-mRNA.	('expression', 'MPA', (54, 64))	('knockdown', 'Var', (29, 38))	('CFL1', 'Gene', (49, 53))	('MALAT1', 'Gene', '378938', (22, 28))	('CFL1', 'Gene', '1072', (49, 53))	('MALAT1', 'Gene', (22, 28))	('decreased', 'NegReg', (39, 48))
93758	32788940	In an ongoing project in the School of Basic Medical Sciences at Tianjin Medical University, it was observed that MALAT knockdown markedly affected the landscape of alternative splicing (data not shown).	('MALAT', 'Chemical', '-', (114, 119))	('knockdown', 'Var', (120, 129))	('alternative splicing', 'MPA', (165, 185))	('MALAT', 'Gene', (114, 119))	('affected', 'Reg', (139, 147))
93759	32788940	CFL1 is a critical molecule that regulates cytoskeletal dynamics by depolymerizing actin filaments, and is required for cytokinesis and cell movement, while the loss of CFL1 increases F-actin accumulation.	('increases', 'PosReg', (174, 183))	('CFL1', 'Gene', (0, 4))	('actin filaments', 'MPA', (83, 98))	('CFL1', 'Gene', '1072', (0, 4))	('CFL1', 'Gene', (169, 173))	('depolymerizing', 'NegReg', (68, 82))	('loss', 'Var', (161, 165))	('CFL1', 'Gene', '1072', (169, 173))	('F-actin accumulation', 'MPA', (184, 204))
93767	32788940	Functional and mechanistic analyses suggested that MALAT1 knockdown inhibited renal cancer cell migration by inhibiting CFL1 expression.	('renal cancer', 'Disease', 'MESH:D007680', (78, 90))	('renal cancer', 'Phenotype', 'HP:0009726', (78, 90))	('inhibiting', 'NegReg', (109, 119))	('MALAT1', 'Gene', '378938', (51, 57))	('CFL1', 'Gene', '1072', (120, 124))	('renal cancer', 'Disease', (78, 90))	('inhibited', 'NegReg', (68, 77))	('MALAT1', 'Gene', (51, 57))	('expression', 'MPA', (125, 135))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('knockdown', 'Var', (58, 67))	('CFL1', 'Gene', (120, 124))
93775	29455662	Alterations of RICTOR have been identified in a number of cancer cell types and its involvement in tumorigenesis has begun to be unraveled recently.	('tumor', 'Disease', (99, 104))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('RICTOR', 'Gene', (15, 21))	('Alterations', 'Var', (0, 11))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('identified', 'Reg', (32, 42))	('cancer', 'Disease', (58, 64))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))
93784	29455662	Genetic changes that alter the activity, abundance, cellular distribution, or regulation of RTKs are observed in a wide variety of malignancies.	('activity', 'MPA', (31, 39))	('malignancies', 'Disease', (131, 143))	('RTK', 'Gene', '5979', (92, 95))	('observed', 'Reg', (101, 109))	('Genetic changes', 'Var', (0, 15))	('RTK', 'Gene', (92, 95))	('regulation', 'MPA', (78, 88))	('malignancies', 'Disease', 'MESH:D009369', (131, 143))
93785	29455662	Gene mutations affecting EGFR members have been associated with several cancers.	('EGFR', 'Gene', (25, 29))	('associated', 'Reg', (48, 58))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('cancers', 'Disease', (72, 79))	('cancers', 'Disease', 'MESH:D009369', (72, 79))	('EGFR', 'Gene', '1956', (25, 29))	('Gene mutations', 'Var', (0, 14))
93787	29455662	Mutations affecting EGFR gene result in its overexpression in 30-50% of glioblastoma, 25-82% in colorectal cancer and 5-20% in non-small-cell lung cancer.	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('lung cancer', 'Disease', 'MESH:D008175', (142, 153))	('EGFR', 'Gene', (20, 24))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('colorectal cancer', 'Phenotype', 'HP:0003003', (96, 113))	('overexpression', 'PosReg', (44, 58))	('colorectal cancer', 'Disease', 'MESH:D015179', (96, 113))	('Mutations', 'Var', (0, 9))	('lung cancer', 'Disease', (142, 153))	('colorectal cancer', 'Disease', (96, 113))	('glioblastoma', 'Disease', (72, 84))	('glioblastoma', 'Disease', 'MESH:D005909', (72, 84))	('lung cancer', 'Phenotype', 'HP:0100526', (142, 153))	('EGFR', 'Gene', '1956', (20, 24))	('glioblastoma', 'Phenotype', 'HP:0012174', (72, 84))
93788	29455662	Mutations in the PDGFRalpha gene have been found in 5% of gastrointestinal stromal cancer (GIST) and amplifications of PDGFRalpha were reported in 5-10% of glioblastoma multiforme, in oligodendrocytoma, esophageal squamous cell carcinoma and artery intimal sarcomas.	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('found', 'Reg', (43, 48))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (214, 237))	('PDGFRalpha', 'Gene', '5156', (17, 27))	('glioblastoma', 'Phenotype', 'HP:0012174', (156, 168))	('Mutations', 'Var', (0, 9))	('sarcomas', 'Disease', 'MESH:D012509', (257, 265))	('PDGFRalpha', 'Gene', '5156', (119, 129))	('sarcomas', 'Phenotype', 'HP:0100242', (257, 265))	('glioblastoma multiforme', 'Disease', (156, 179))	('carcinoma', 'Phenotype', 'HP:0030731', (228, 237))	('sarcomas', 'Disease', (257, 265))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (156, 179))	('gastrointestinal stromal cancer', 'Disease', (58, 89))	('PDGFRalpha', 'Gene', (17, 27))	('sarcoma', 'Phenotype', 'HP:0100242', (257, 264))	('oligodendrocytoma, esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (184, 237))	('gastrointestinal stromal cancer', 'Phenotype', 'HP:0100723', (58, 89))	('gastrointestinal stromal cancer', 'Disease', 'MESH:D046152', (58, 89))	('PDGFRalpha', 'Gene', (119, 129))
93789	29455662	Mutations in KIT are mostly found in leukemia, gastrointestinal stromal tumors (GIST), testicular germ cell tumor (TGCT) and melanoma.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('melanoma', 'Disease', 'MESH:D008545', (125, 133))	('tumor', 'Disease', (108, 113))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (47, 78))	('germ cell tumor', 'Phenotype', 'HP:0100728', (98, 113))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (47, 78))	('Mutations', 'Var', (0, 9))	('leukemia', 'Phenotype', 'HP:0001909', (37, 45))	('melanoma', 'Phenotype', 'HP:0002861', (125, 133))	('melanoma', 'Disease', (125, 133))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('tumor', 'Disease', (72, 77))	('gastrointestinal stromal tumors', 'Disease', (47, 78))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('leukemia', 'Disease', 'MESH:D007938', (37, 45))	('leukemia', 'Disease', (37, 45))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('found', 'Reg', (28, 33))	('KIT', 'Gene', (13, 16))
93790	29455662	These mutations affecting RTKs result in increased cell proliferation, survival, invasion and metastasis by activating downstream pathways such as the MAPK pathway and the PI3K pathway.	('increased', 'PosReg', (41, 50))	('metastasis', 'CPA', (94, 104))	('survival', 'CPA', (71, 79))	('invasion', 'CPA', (81, 89))	('PI3', 'Gene', '5266', (172, 175))	('RTK', 'Gene', (26, 29))	('MAPK pathway', 'Pathway', (151, 163))	('cell proliferation', 'CPA', (51, 69))	('activating', 'PosReg', (108, 118))	('PI3', 'Gene', (172, 175))	('mutations', 'Var', (6, 15))	('RTK', 'Gene', '5979', (26, 29))
93795	29455662	This exchange activates RAS, allowing its interaction with a number of effectors, in particular the serine/threonine kinases of the RAF family, which activate MAP kinase kinases (MEK), which in turn activate the MAP kinases (ERK).	('exchange', 'Var', (5, 13))	('MAP kinase kinases', 'Gene', (159, 177))	('ERK', 'Gene', '5594', (225, 228))	('threonine', 'Chemical', 'MESH:D013912', (107, 116))	('activate', 'PosReg', (199, 207))	('RAS', 'Gene', (24, 27))	('interaction', 'Interaction', (42, 53))	('MEK', 'Gene', (179, 182))	('ERK', 'Gene', (225, 228))	('MAP kinase kinases', 'Gene', '5609', (159, 177))	('RAF', 'Gene', '22882', (132, 135))	('RAF', 'Gene', (132, 135))	('MEK', 'Gene', '5609', (179, 182))	('MAP kinases', 'Pathway', (212, 223))	('serine', 'Chemical', 'MESH:D012694', (100, 106))
93808	29455662	mTORC2 is the central component in the PI3K-AKT pathway, phosphorylating AKT at Ser473, causing its activation.	('mTORC2', 'Gene', '74343', (0, 6))	('Ser473', 'Chemical', '-', (80, 86))	('AKT', 'Pathway', (73, 76))	('PI3', 'Gene', '5266', (39, 42))	('PI3', 'Gene', (39, 42))	('mTORC2', 'Gene', (0, 6))	('activation', 'PosReg', (100, 110))	('phosphorylating', 'Var', (57, 72))	('Ser473', 'Var', (80, 86))
93810	29455662	RICTOR is a key component of mTORC2 and is required for mTORC2 function, shown by significant inhibition of the activation of AKT by RICTOR knockdown.	('mTORC2', 'Gene', '74343', (56, 62))	('mTORC2', 'Gene', '74343', (29, 35))	('inhibition', 'NegReg', (94, 104))	('activation', 'PosReg', (112, 122))	('RICTOR', 'Gene', (133, 139))	('AKT', 'Pathway', (126, 129))	('knockdown', 'Var', (140, 149))	('mTORC2', 'Gene', (56, 62))	('mTORC2', 'Gene', (29, 35))
93811	29455662	Therefore, as a critical regulator of the PI3K/AKT pathway, RICTOR plays an important role in tumors driven by RTK alterations.	('RTK', 'Gene', (111, 114))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('alterations', 'Var', (115, 126))	('PI3', 'Gene', '5266', (42, 45))	('tumors', 'Disease', (94, 100))	('RTK', 'Gene', '5979', (111, 114))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('PI3', 'Gene', (42, 45))
93814	29455662	This review highlights the important role played by RICTOR downstream of RTK in tumoral cells and the potential of targeted inhibition of RICTOR/mTORC2 in the treatment of tumors with alterations of RTK signaling.	('mTORC2', 'Gene', '74343', (145, 151))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('RTK', 'Gene', (73, 76))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('tumors', 'Disease', (172, 178))	('tumors', 'Disease', 'MESH:D009369', (172, 178))	('tumor', 'Disease', (172, 177))	('tumors', 'Phenotype', 'HP:0002664', (172, 178))	('RTK', 'Gene', '5979', (199, 202))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('alterations', 'Var', (184, 195))	('tumor', 'Disease', (80, 85))	('RTK', 'Gene', '5979', (73, 76))	('mTORC2', 'Gene', (145, 151))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('RTK', 'Gene', (199, 202))
93815	29455662	Several studies have demonstrated an amplification of the RICTOR gene or an overexpression of its protein in different cancer types.	('RICTOR gene', 'Gene', (58, 69))	('amplification', 'Var', (37, 50))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('cancer', 'Disease', (119, 125))	('protein', 'Protein', (98, 105))	('overexpression', 'PosReg', (76, 90))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
93817	29455662	Interestingly RTK alterations have also been identified in these tumors and analysis of the available databases through the cBioPortal for Cancer Genomics shows a tendency for co-occurrence of RICTOR and RTK alterations in these tumors (see TCGA Data Portal; (Fig.	('tumors', 'Disease', 'MESH:D009369', (229, 235))	('RTK', 'Gene', (14, 17))	('Cancer', 'Phenotype', 'HP:0002664', (139, 145))	('RTK', 'Gene', '5979', (204, 207))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('RTK', 'Gene', (204, 207))	('RTK', 'Gene', '5979', (14, 17))	('alterations', 'Var', (208, 219))	('tumors', 'Disease', (65, 71))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('Cancer', 'Disease', (139, 145))	('tumors', 'Phenotype', 'HP:0002664', (229, 235))	('Cancer', 'Disease', 'MESH:D009369', (139, 145))	('tumors', 'Disease', (229, 235))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
93818	29455662	RICTOR was identified as the most frequently amplified gene observed (~ 14% patients) in a cohort of metastatic small cell lung cancer (SCLC), where RICTOR copy number variation correlated with RICTOR protein expression in SCLC cells.	('SCLC', 'Gene', '7864', (223, 227))	('patients', 'Species', '9606', (76, 84))	('SCLC', 'Gene', (223, 227))	('RICTOR', 'Gene', (149, 155))	('lung cancer', 'Phenotype', 'HP:0100526', (123, 134))	('small cell lung cancer', 'Disease', 'MESH:D055752', (112, 134))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (112, 134))	('copy number variation', 'Var', (156, 177))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('correlated', 'Reg', (178, 188))	('SCLC', 'Gene', '7864', (136, 140))	('SCLC', 'Gene', (136, 140))	('RICTOR', 'MPA', (194, 200))	('small cell lung cancer', 'Disease', (112, 134))
93819	29455662	The overall survival in SCLC patients with RICTOR amplification was significantly decreased.	('SCLC', 'Gene', (24, 28))	('patients', 'Species', '9606', (29, 37))	('RICTOR amplification', 'Var', (43, 63))	('decreased', 'NegReg', (82, 91))	('SCLC', 'Gene', '7864', (24, 28))
93829	29455662	Quantification of RICTOR mRNA in 22 melanoma short-term cultures confirmed that RICTOR locus amplification was associated with an increase in RICTOR mRNA level.	('amplification', 'Var', (93, 106))	('melanoma', 'Phenotype', 'HP:0002861', (36, 44))	('melanoma', 'Disease', (36, 44))	('melanoma', 'Disease', 'MESH:D008545', (36, 44))	('increase', 'PosReg', (130, 138))	('RICTOR locus', 'Gene', (80, 92))	('RICTOR mRNA level', 'MPA', (142, 159))
93834	29455662	RICTOR deregulation could have important effects in tumor development either because it cooperates with altered RTKs to transform cells or as a critical regulator of a major pathway downstream of RTKs.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('cooperates', 'Reg', (88, 98))	('RTK', 'Gene', '5979', (112, 115))	('effects', 'Reg', (41, 48))	('tumor', 'Disease', (52, 57))	('deregulation', 'Var', (7, 19))	('RTK', 'Gene', '5979', (196, 199))	('RTK', 'Gene', (112, 115))	('RICTOR', 'Gene', (0, 6))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('RTK', 'Gene', (196, 199))
93838	29455662	Inhibition of mTORC1/2, by mTOR kinase inhibitors PP242 and OSI-027 or RICTOR knockdown, effectively suppressed phosphorylation of AKT (S473) and breast cancer cell proliferation and migration.	('mTOR', 'Gene', '2475', (14, 18))	('mTORC1/2', 'Gene', '74343;382056', (14, 22))	('phosphorylation', 'MPA', (112, 127))	('breast cancer', 'Disease', 'MESH:D001943', (146, 159))	('PP242', 'Var', (50, 55))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('mTORC1/2', 'Gene', (14, 22))	('mTOR', 'Gene', (14, 18))	('breast cancer', 'Disease', (146, 159))	('PP242', 'Chemical', 'MESH:C572919', (50, 55))	('OSI-027', 'Chemical', 'MESH:C568605', (60, 67))	('mTOR', 'Gene', '2475', (27, 31))	('breast cancer', 'Phenotype', 'HP:0003002', (146, 159))	('mTOR', 'Gene', (27, 31))	('suppressed', 'NegReg', (101, 111))
93841	29455662	Disruption of the mTORC2 arm of the pathway via the knockdown of RICTOR, significantly attenuated the ability of HRG to promote HER2-dependent oncogenesis.	('mTORC2', 'Gene', '74343', (18, 24))	('HRG', 'Gene', '3273', (113, 116))	('attenuated', 'NegReg', (87, 97))	('HER2-dependent', 'Protein', (128, 142))	('promote', 'PosReg', (120, 127))	('HRG', 'Gene', (113, 116))	('knockdown', 'Var', (52, 61))	('RICTOR', 'Gene', (65, 71))	('mTORC2', 'Gene', (18, 24))
93842	29455662	These results were confirmed in a HER2/Neu mouse model of breast cancer, where RICTOR ablation decreased AKT S473 phosphorylation, cellular proliferation and delayed tumor latency, burden and penetrance suggesting that RICTOR promotes the genesis of HER2-overexpressing tumors.	('ablation', 'Var', (86, 94))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('tumor', 'Phenotype', 'HP:0002664', (270, 275))	('tumors', 'Disease', (270, 276))	('promotes', 'PosReg', (226, 234))	('AKT', 'Protein', (105, 108))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('decreased', 'NegReg', (95, 104))	('cellular proliferation', 'CPA', (131, 153))	('tumors', 'Disease', 'MESH:D009369', (270, 276))	('tumor', 'Disease', (166, 171))	('breast cancer', 'Phenotype', 'HP:0003002', (58, 71))	('mouse', 'Species', '10090', (43, 48))	('tumor', 'Disease', (270, 275))	('HER2-overexpressing', 'Protein', (250, 269))	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('genesis', 'CPA', (239, 246))	('breast cancer', 'Disease', 'MESH:D001943', (58, 71))	('tumor', 'Disease', 'MESH:D009369', (270, 275))	('breast cancer', 'Disease', (58, 71))	('tumors', 'Phenotype', 'HP:0002664', (270, 276))
93844	29455662	mTORC2 inhibition may offer a promising therapeutic strategy to help eradicate HER2-amplified breast cancers, in particular in tumors which are resistant to HER2 targeted therapy or where AKT signaling is activated.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('cancers', 'Phenotype', 'HP:0002664', (101, 108))	('tumors', 'Disease', (127, 133))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('breast cancers', 'Phenotype', 'HP:0003002', (94, 108))	('tumors', 'Disease', 'MESH:D009369', (127, 133))	('eradicate', 'NegReg', (69, 78))	('HER2-amplified', 'Gene', (79, 93))	('mTORC2', 'Gene', (0, 6))	('inhibition', 'Var', (7, 17))	('breast cancers', 'Disease', 'MESH:D001943', (94, 108))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('breast cancers', 'Disease', (94, 108))	('mTORC2', 'Gene', '74343', (0, 6))	('breast cancer', 'Phenotype', 'HP:0003002', (94, 107))
93845	29455662	RICTOR amplification has been reported in lung cancer and was associated with a decrease in overall survival.	('reported', 'Reg', (30, 38))	('lung cancer', 'Disease', (42, 53))	('lung cancer', 'Phenotype', 'HP:0100526', (42, 53))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('RICTOR amplification', 'Var', (0, 20))	('overall', 'MPA', (92, 99))	('decrease', 'NegReg', (80, 88))	('lung cancer', 'Disease', 'MESH:D008175', (42, 53))
93846	29455662	RICTOR copy number variation correlated with RICTOR protein expression in SCLC cells.	('correlated', 'Reg', (29, 39))	('copy number variation', 'Var', (7, 28))	('SCLC', 'Gene', '7864', (74, 78))	('SCLC', 'Gene', (74, 78))	('RICTOR', 'MPA', (45, 51))	('RICTOR', 'Gene', (0, 6))
93847	29455662	Its oncogenic roles were suggested by decreased lung cancer cell growth both in vitro and in vivo with RICTOR ablation, and the capacity of RICTOR to transform Ba/F3-cell.	('decreased lung cancer', 'Disease', 'MESH:D008175', (38, 59))	('RICTOR', 'Gene', (103, 109))	('decreased lung cancer', 'Disease', (38, 59))	('decreased lung', 'Phenotype', 'HP:0002089', (38, 52))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('lung cancer', 'Phenotype', 'HP:0100526', (48, 59))	('ablation', 'Var', (110, 118))
93848	29455662	SCLC cell lines with various levels of RICTOR copy number (CN) gain were used to analyze its downstream effects on cell growth and migration.	('copy number', 'Var', (46, 57))	('SCLC', 'Gene', (0, 4))	('SCLC', 'Gene', '7864', (0, 4))	('RICTOR', 'Gene', (39, 45))
93849	29455662	The authors showed that SCLC cell lines with RICTOR CN gain migrated more rapidly compared to cells with no gain in RICTOR CN, associating RICTOR amplification with increased cell motility.	('SCLC', 'Gene', (24, 28))	('gain', 'PosReg', (55, 59))	('RICTOR', 'Var', (45, 51))	('migrated', 'CPA', (60, 68))	('SCLC', 'Gene', '7864', (24, 28))
93850	29455662	Lung cancer cells with RICTOR amplification showed increased sensitivity to mTORC1/2 inhibitors, whereas silencing RICTOR rendered RICTOR-amplified cells markedly more resistant to mTORC1/2 inhibitors, demonstrating that RICTOR was the target in those cells.	('mTORC1/2', 'Gene', '74343;382056', (181, 189))	('RICTOR', 'Gene', (115, 121))	('cancer', 'Disease', 'MESH:D009369', (5, 11))	('increased', 'PosReg', (51, 60))	('mTORC1/2', 'Gene', '74343;382056', (76, 84))	('cancer', 'Disease', (5, 11))	('Lung cancer', 'Phenotype', 'HP:0100526', (0, 11))	('mTORC1/2', 'Gene', (181, 189))	('mTORC1/2', 'Gene', (76, 84))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))	('silencing', 'Var', (105, 114))	('sensitivity', 'MPA', (61, 72))
93851	29455662	Interestingly in a cell line combining RICTOR and PDGFR amplification, RICTOR knockdown was associated with significantly reduced proliferation in vitro and in vivo, consistent with RICTOR's role as an oncogenic driver downstream of PDGFR.	('PDGFR', 'Gene', '5159', (233, 238))	('knockdown', 'Var', (78, 87))	('RICTOR', 'Gene', (71, 77))	('PDGFR', 'Gene', (50, 55))	('proliferation', 'CPA', (130, 143))	('PDGFR', 'Gene', '5159', (50, 55))	('PDGFR', 'Gene', (233, 238))	('reduced', 'NegReg', (122, 129))
93852	29455662	The subset of lung cancer patients with RICTOR amplification may benefit from drugs targeting mTORC1/2.	('RICTOR', 'Var', (40, 46))	('benefit', 'PosReg', (65, 72))	('mTORC1/2', 'Gene', '74343;382056', (94, 102))	('lung cancer', 'Disease', (14, 25))	('patients', 'Species', '9606', (26, 34))	('lung cancer', 'Phenotype', 'HP:0100526', (14, 25))	('lung cancer', 'Disease', 'MESH:D008175', (14, 25))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('mTORC1/2', 'Gene', (94, 102))
93858	29455662	Using a PDAC genetically engineered mouse model (GEMM), it was also shown that RICTOR deletion dramatically delayed tumor formation, whilst mice with median survival almost doubled in RICTOR-deleted mice compared with control mice.	('mouse', 'Species', '10090', (36, 41))	('mice', 'Species', '10090', (226, 230))	('mice', 'Species', '10090', (140, 144))	('mice', 'Species', '10090', (199, 203))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('delayed', 'NegReg', (108, 115))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('PDAC', 'Chemical', '-', (8, 12))	('tumor', 'Disease', (116, 121))	('RICTOR', 'Gene', (79, 85))	('deletion', 'Var', (86, 94))
93865	29455662	Selective inhibitors of TORC1/2 caused growth suppression in CRC cells in vitro and in vivo and enhanced the anticancer activities of doxorubicin in colorectal xenograft mouse models.	('TORC1', 'Gene', (24, 29))	('TORC1', 'Gene', '382056', (24, 29))	('enhanced', 'PosReg', (96, 104))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('doxorubicin', 'Chemical', 'MESH:D004317', (134, 145))	('cancer', 'Disease', (113, 119))	('mouse', 'Species', '10090', (170, 175))	('inhibitors', 'Var', (10, 20))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('growth suppression', 'CPA', (39, 57))
93874	29455662	Amplification of the gene encoding the EGFR occurs commonly in glioblastoma (GBM), the most common malignant primary brain tumor of adults.	('Amplification', 'Var', (0, 13))	('glioblastoma', 'Disease', (63, 75))	('brain tumor', 'Disease', 'MESH:D001932', (117, 128))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('brain tumor', 'Disease', (117, 128))	('glioblastoma', 'Disease', 'MESH:D005909', (63, 75))	('EGFR', 'Gene', '1956', (39, 43))	('EGFR', 'Gene', (39, 43))	('glioblastoma', 'Phenotype', 'HP:0012174', (63, 75))	('brain tumor', 'Phenotype', 'HP:0030692', (117, 128))
93878	29455662	mTORC2 inhibition reverses chemotherapy resistance in vivo.	('reverses', 'NegReg', (18, 26))	('inhibition', 'Var', (7, 17))	('mTORC2', 'Gene', (0, 6))	('mTORC2', 'Gene', '74343', (0, 6))	('chemotherapy', 'MPA', (27, 39))
93879	29455662	The co-silencing of EGFR and RICTOR in GBM cell lines resulted in reduced cell migration, and increased sensitivity to vincristine and temozolomide.	('co-silencing', 'Var', (4, 16))	('cell migration', 'CPA', (74, 88))	('RICTOR', 'Gene', (29, 35))	('reduced', 'NegReg', (66, 73))	('vincristine', 'Chemical', 'MESH:D014750', (119, 130))	('EGFR', 'Gene', (20, 24))	('increased', 'PosReg', (94, 103))	('temozolomide', 'Chemical', 'MESH:D000077204', (135, 147))	('EGFR', 'Gene', '1956', (20, 24))
93880	29455662	While the silencing of EGFR or RICTOR alone had no significant effect on xenograft tumor growth in vivo, silencing of EGFR and RICTOR simultaneously resulted in a complete eradication of tumors suggesting that the combined silencing of EGFR and RICTOR should be an effective means of treating GBM.	('silencing', 'Var', (223, 232))	('tumor', 'Disease', (83, 88))	('tumor', 'Disease', (187, 192))	('EGFR', 'Gene', '1956', (23, 27))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('eradication', 'NegReg', (172, 183))	('EGFR', 'Gene', '1956', (118, 122))	('EGFR', 'Gene', '1956', (236, 240))	('tumors', 'Phenotype', 'HP:0002664', (187, 193))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('GBM', 'Disease', (293, 296))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('tumors', 'Disease', (187, 193))	('RICTOR', 'Gene', (127, 133))	('EGFR', 'Gene', (23, 27))	('EGFR', 'Gene', (118, 122))	('tumors', 'Disease', 'MESH:D009369', (187, 193))	('silencing', 'Var', (105, 114))	('EGFR', 'Gene', (236, 240))
93888	29455662	Furthermore, RICTOR amplification defines a subset of advanced GC that displayed increased sensitivity to the dual mTORC1/2 inhibitor, AZD2014, and the dual PI3K/mTOR compound, BEZ235, whereas AKT inhibitor AZD5363 had lesser effects on RICTOR-amplified patient-derived cell growth.	('AZD5363', 'Chemical', 'MESH:C575618', (207, 214))	('mTOR', 'Gene', (162, 166))	('mTOR', 'Gene', '2475', (162, 166))	('PI3', 'Gene', '5266', (157, 160))	('mTORC1/2', 'Gene', '74343;382056', (115, 123))	('mTOR', 'Gene', '2475', (115, 119))	('mTOR', 'Gene', (115, 119))	('patient', 'Species', '9606', (254, 261))	('AZD2014', 'Var', (135, 142))	('AZD2014', 'Chemical', 'MESH:C585537', (135, 142))	('PI3', 'Gene', (157, 160))	('BEZ235', 'Chemical', 'MESH:C531198', (177, 183))	('increased', 'PosReg', (81, 90))	('mTORC1/2', 'Gene', (115, 123))	('sensitivity', 'MPA', (91, 102))
93889	29455662	RICTOR knockdown was sufficient to abrogate the inhibitory effects of AZD2014 on cell growth, consistent with the functional importance of RICTOR amplification.	('AZD2014', 'Chemical', 'MESH:C585537', (70, 77))	('AZD2014', 'Gene', (70, 77))	('cell growth', 'CPA', (81, 92))	('inhibitory effects', 'MPA', (48, 66))	('abrogate', 'NegReg', (35, 43))	('knockdown', 'Var', (7, 16))	('RICTOR', 'Gene', (0, 6))
93897	29455662	The pathological investigation showed that melanoma tissues overexpressing RICTOR are prone to form VM channels, and this formation was accompanied by AKT membrane translocation and an increase in MMP-2/9 secretion.	('RICTOR', 'Var', (75, 81))	('prone', 'Reg', (86, 91))	('increase', 'PosReg', (185, 193))	('melanoma', 'Phenotype', 'HP:0002861', (43, 51))	('melanoma', 'Disease', (43, 51))	('MMP-2/9', 'Gene', '4313;4318', (197, 204))	('MMP-2/9', 'Gene', (197, 204))	('melanoma', 'Disease', 'MESH:D008545', (43, 51))	('overexpressing', 'PosReg', (60, 74))	('AKT membrane translocation', 'MPA', (151, 177))
93898	29455662	Taken together, these studies attest that RICTOR amplification and overexpression play a role in tumor growth, at least in part via vascularization and remodeling of the tumoral stroma.	('RICTOR amplification', 'Var', (42, 62))	('tumoral stroma', 'Disease', 'MESH:D009369', (170, 184))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('remodeling', 'CPA', (152, 162))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('overexpression', 'PosReg', (67, 81))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('tumor', 'Disease', (97, 102))	('tumor', 'Disease', (170, 175))	('vascularization', 'CPA', (132, 147))	('tumoral stroma', 'Disease', (170, 184))
93903	29455662	RICTOR is frequently overexpressed in tumoral cells, often due to gene amplification.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('gene amplification', 'Var', (66, 84))	('overexpressed', 'PosReg', (21, 34))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('RICTOR', 'Gene', (0, 6))
93910	29455662	Disruption of the PRICKLE1-RICTOR interaction resulted in a strong impairment of breast cancer cell dissemination in xenograft assays.	('PRICKLE1', 'Gene', '144165', (18, 26))	('impairment of breast cancer', 'Disease', (67, 94))	('breast cancer', 'Phenotype', 'HP:0003002', (81, 94))	('impairment of breast cancer', 'Disease', 'MESH:D001943', (67, 94))	('PRICKLE1', 'Gene', (18, 26))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('interaction', 'Interaction', (34, 45))	('Disruption', 'Var', (0, 10))
93913	29455662	AKT signaling activated RAC1 through the RAC-GEF TIAM1, while PKC signaling dampened expression of the endogenous RAC1 inhibitor, RHOGDI2.	('RAC-GEF', 'Var', (41, 48))	('expression', 'MPA', (85, 95))	('RAC1', 'Gene', '5879', (114, 118))	('PKC', 'Gene', '5590', (62, 65))	('RHOGDI2', 'Gene', '397', (130, 137))	('RAC1', 'Gene', (114, 118))	('activated', 'PosReg', (14, 23))	('RAC1', 'Gene', '5879', (24, 28))	('PKC', 'Gene', (62, 65))	('dampened', 'NegReg', (76, 84))	('RAC1', 'Gene', (24, 28))	('RHOGDI2', 'Gene', (130, 137))
93923	29455662	The recent studies demonstrating that mTORC2 activity is essential for the development of a number of cancers provide a rationale for developing inhibitors specifically targeting mTORC2, which do not perturb the mTORC1-dependent negative feedback loops and have a more acceptable therapeutic window.	('mTORC1', 'Gene', '382056', (212, 218))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('mTORC2', 'Gene', (38, 44))	('cancers', 'Disease', 'MESH:D009369', (102, 109))	('mTORC1', 'Gene', (212, 218))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))	('mTORC2', 'Gene', (179, 185))	('cancers', 'Disease', (102, 109))	('inhibitors', 'Var', (145, 155))	('mTORC2', 'Gene', '74343', (179, 185))	('mTORC2', 'Gene', '74343', (38, 44))
93926	29455662	mTORC2 inhibition by RICTOR phosphorylation on Thr1135 could be used as a novel strategy for specifically inhibiting mTORC2.	('mTORC2', 'Gene', '74343', (0, 6))	('inhibiting', 'NegReg', (106, 116))	('mTORC2', 'Gene', (117, 123))	('mTORC2', 'Gene', (0, 6))	('inhibition', 'NegReg', (7, 17))	('mTORC2', 'Gene', '74343', (117, 123))	('Thr1135', 'Var', (47, 54))	('Thr1135', 'Chemical', '-', (47, 54))
93982	24814677	The 3-year RFS rate of cases with a high clusterin expression level was 28.6%, whereas that of cases with a low clusterin expression level was 45.2%.	('clusterin', 'Gene', (41, 50))	('RFS', 'Disease', (11, 14))	('expression', 'MPA', (51, 61))	('clusterin', 'Gene', (112, 121))	('clusterin', 'Gene', '1191', (112, 121))	('high', 'Var', (36, 40))	('clusterin', 'Gene', '1191', (41, 50))
93985	24814677	The 3-year RFS rate of cases with a high ZEB2 expression level was 15.6%, while that of cases with a low ZEB2 expression level was 46.3%.	('ZEB2', 'Gene', (105, 109))	('RFS', 'Disease', (11, 14))	('ZEB2', 'Gene', '9839', (41, 45))	('ZEB2', 'Gene', (41, 45))	('expression', 'MPA', (46, 56))	('high', 'Var', (36, 40))	('ZEB2', 'Gene', '9839', (105, 109))
93988	24814677	The 3-year RFS rate of cases with a high podoplanin expression level was 19.8%, while that of cases with a low podoplanin expression level was 52.6%.	('RFS', 'Disease', (11, 14))	('podoplanin', 'Gene', '10630', (41, 51))	('podoplanin', 'Gene', '10630', (111, 121))	('podoplanin', 'Gene', (111, 121))	('podoplanin', 'Gene', (41, 51))	('high', 'Var', (36, 40))
94000	24814677	We previously reported that the presence of podoplanin-positive CAFs in primary tumor is correlated with poorer prognosis in stage I SqCC, which was inconsistent with the results of our current study.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('podoplanin', 'Gene', '10630', (44, 54))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('presence', 'Var', (32, 40))	('tumor', 'Disease', (80, 85))	('podoplanin', 'Gene', (44, 54))	('poorer', 'NegReg', (105, 111))	('stage', 'Disease', (125, 130))	('SqCC', 'Phenotype', 'HP:0002860', (133, 137))
94008	24814677	Our current study showed that the presence of podoplanin-positive CAFs in metastatic lymph node tumors, but not in primary tumors, participated in recurrence, similar to the results observed for adenocarcinoma with N2 disease.	('lymph node tumors', 'Disease', (85, 102))	('podoplanin', 'Gene', '10630', (46, 56))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('adenocarcinoma', 'Disease', (195, 209))	('podoplanin', 'Gene', (46, 56))	('carcinoma', 'Phenotype', 'HP:0030731', (200, 209))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('primary tumors', 'Disease', (115, 129))	('adenocarcinoma', 'Disease', 'MESH:D000230', (195, 209))	('lymph node tumor', 'Phenotype', 'HP:0002665', (85, 101))	('participated', 'Reg', (131, 143))	('lymph node tumors', 'Disease', 'MESH:D000072717', (85, 102))	('primary tumors', 'Disease', 'MESH:D009369', (115, 129))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('presence', 'Var', (34, 42))
94022	24814677	This discrepancy may be explained by the fact that the expression of E-cadherin is regulated not only by numerous EMT-related transcription factors such as ZEB1, ZEB2, Twist, and Snail, but also by epigenetic mechanisms.	('E-cadherin', 'Gene', '999', (69, 79))	('ZEB1', 'Gene', (156, 160))	('ZEB1', 'Gene', '6935', (156, 160))	('Snail', 'Gene', (179, 184))	('epigenetic', 'Var', (198, 208))	('EMT', 'Gene', (114, 117))	('Snail', 'Gene', '6615', (179, 184))	('expression', 'MPA', (55, 65))	('EMT', 'Gene', '3702', (114, 117))	('ZEB2', 'Gene', '9839', (162, 166))	('regulated', 'Reg', (83, 92))	('E-cadherin', 'Gene', (69, 79))	('ZEB2', 'Gene', (162, 166))
94031	33057927	PET/CT scans with [18F]-FDG and [68Ga]Ga-FAPI-4 were performed for pre-operative tumor localization.	('Ga-FAPI-4', 'Chemical', '-', (38, 47))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('FDG', 'Gene', '23583', (24, 27))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('FDG', 'Gene', (24, 27))	('[68Ga]Ga-FAPI-4', 'Var', (32, 47))	('tumor', 'Disease', (81, 86))
94037	33057927	The SUVmax ratio of [68Ga]FAPI was significantly different from [18F] FDG (p = 0.03).	('SUVmax ratio', 'MPA', (4, 16))	('FDG', 'Gene', (70, 73))	('[68Ga]FAPI', 'Var', (20, 30))	('FAPI', 'Chemical', '-', (26, 30))	('different', 'Reg', (49, 58))	('FDG', 'Gene', '23583', (70, 73))
94041	33057927	Nevertheless, by offering a detection method for primary tumors with the potential of lower false positive rates and thus avoiding biopsies, patients with CUP syndrome may benefit from [68Ga]FAPI PET/CT imaging.	('benefit', 'PosReg', (172, 179))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('FAPI', 'Chemical', '-', (191, 195))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('CUP syndrome', 'Disease', (155, 167))	('tumors', 'Disease', (57, 63))	('[68Ga]', 'Var', (185, 191))	('patients', 'Species', '9606', (141, 149))	('tumors', 'Disease', 'MESH:D009369', (57, 63))
94145	33057927	After phosphorylation of FDG, tumor cells with increased anaerobic glycolysis are predominantly labeled by the intracellular accumulation of FDG tracer (metabolic trapping).	('FDG', 'Gene', (141, 144))	('anaerobic glycolysis', 'MPA', (57, 77))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('FDG', 'Gene', '23583', (25, 28))	('increased', 'PosReg', (47, 56))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('FDG', 'Gene', '23583', (141, 144))	('FDG', 'Gene', (25, 28))	('phosphorylation', 'Var', (6, 21))	('tumor', 'Disease', (30, 35))
94152	33057927	In addition, the SUVmax of the non-malignant contralateral tonsil was significantly lower for FAPI (3.55 +- 0.47) compared to FDG PET/CT imaging (8.38 +- 2.45) (p < 0.001).	('FAPI', 'Chemical', '-', (94, 98))	('FDG', 'Gene', '23583', (126, 129))	('lower', 'NegReg', (84, 89))	('FDG', 'Gene', (126, 129))	('SUVmax', 'MPA', (17, 23))	('FAPI', 'Var', (94, 98))
94168	33057927	The detection rate of lymph node metastases was 47% in FAPI PET/CT (vs. 82% in FDG PET/CT).	('FAPI PET/CT', 'Var', (55, 66))	('metastases', 'Disease', (33, 43))	('FAPI', 'Chemical', '-', (55, 59))	('metastases', 'Disease', 'MESH:D009362', (33, 43))	('FDG', 'Gene', '23583', (79, 82))	('FDG', 'Gene', (79, 82))
94181	33057927	In conclusion, the differentiation between primary tumor and surrounding or contralateral normal tonsillar tissue is improved by FAPI as compared to the standard PET radiotracer FDG.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('FAPI', 'Var', (129, 133))	('FDG', 'Gene', '23583', (178, 181))	('tumor', 'Disease', (51, 56))	('improved', 'PosReg', (117, 125))	('FDG', 'Gene', (178, 181))	('differentiation', 'MPA', (19, 34))	('FAPI', 'Chemical', '-', (129, 133))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
94195	28522860	In vivo experiment revealed that knockdown of CKAP2 inhibited C-33A cells proliferation.	('knockdown', 'Var', (33, 42))	('inhibited', 'NegReg', (52, 61))	('C-33A', 'Mutation', 'rs775538233', (62, 67))	('CKAP2', 'Gene', '26586', (46, 51))	('CKAP2', 'Gene', (46, 51))
94212	28522860	Inhibition of FAK results in the prevention of Src-mediated ERK2 and JNK activation and a reduction in MMP-2, indicating a role for Src-FAK cooperation in invasion.	('activation', 'PosReg', (73, 83))	('reduction', 'NegReg', (90, 99))	('Src', 'Gene', '6714', (132, 135))	('ERK2', 'Gene', (60, 64))	('Src', 'Gene', (47, 50))	('JNK', 'Gene', '5599', (69, 72))	('Src', 'Gene', '6714', (47, 50))	('MMP-2', 'Gene', (103, 108))	('prevention', 'NegReg', (33, 43))	('ERK2', 'Gene', '5594', (60, 64))	('Inhibition', 'Var', (0, 10))	('Src', 'Gene', (132, 135))	('FAK', 'Gene', (14, 17))	('MMP-2', 'Gene', '4313', (103, 108))	('JNK', 'Gene', (69, 72))
94215	28522860	We also showed that knockdown of CKAP2 inhibited the proliferation, migration and invasion of cervical carcinomas cells.	('cervical carcinomas', 'Disease', (94, 113))	('CKAP2', 'Gene', '26586', (33, 38))	('inhibited', 'NegReg', (39, 48))	('CKAP2', 'Gene', (33, 38))	('carcinomas', 'Phenotype', 'HP:0030731', (103, 113))	('cervical carcinomas', 'Disease', 'MESH:D002575', (94, 113))	('proliferation', 'CPA', (53, 66))	('knockdown', 'Var', (20, 29))	('migration', 'CPA', (68, 77))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))
94261	28522860	The survival time of cervical carcinoma patients showed that patients with under-expressed CKAP2 expression notably lived longer than patients with over-expressed CKAP2 expression (Fig.	('CKAP2', 'Gene', '26586', (163, 168))	('longer', 'PosReg', (122, 128))	('CKAP2', 'Gene', (163, 168))	('under-expressed', 'Var', (75, 90))	('CKAP2', 'Gene', '26586', (91, 96))	('CKAP2', 'Gene', (91, 96))	('patients', 'Species', '9606', (40, 48))	('patients', 'Species', '9606', (61, 69))	('patients', 'Species', '9606', (134, 142))	('cervical carcinoma', 'Disease', 'MESH:D002575', (21, 39))	('cervical carcinoma', 'Disease', (21, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (30, 39))
94280	28522860	These results indicate that downregualtion of CKAP2 could inhibit tumor growth in vivo.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Disease', (66, 71))	('downregualtion', 'Var', (28, 42))	('inhibit', 'NegReg', (58, 65))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('CKAP2', 'Gene', '26586', (46, 51))	('CKAP2', 'Gene', (46, 51))
94292	28522860	Moreover, PF-562271 (10 muM) or VX-11e (10 muM) treatment significantly decreased the expression level of p-ERK2, while CKAP2 overexpression increased the p-ERK2 level (Fig.	('muM', 'Gene', (43, 46))	('expression level', 'MPA', (86, 102))	('p-ERK2', 'Gene', '5594', (106, 112))	('PF-562271', 'Chemical', '-', (10, 19))	('decreased', 'NegReg', (72, 81))	('p-ERK2', 'Gene', (106, 112))	('CKAP2', 'Gene', '26586', (120, 125))	('CKAP2', 'Gene', (120, 125))	('muM', 'Gene', (24, 27))	('p-ERK2', 'Gene', '5594', (155, 161))	('PF-562271', 'Var', (10, 19))	('muM', 'Gene', '56925', (24, 27))	('muM', 'Gene', '56925', (43, 46))	('p-ERK2', 'Gene', (155, 161))	('VX-11e', 'Chemical', '-', (32, 38))
94296	28522860	These data confirm that CKAP2 functions as an oncogene by FAK and ERK2 activation in cervical carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('FAK', 'Var', (58, 61))	('cervical carcinoma', 'Disease', 'MESH:D002575', (85, 103))	('cervical carcinoma', 'Disease', (85, 103))	('ERK2', 'Gene', '5594', (66, 70))	('activation', 'PosReg', (71, 81))	('CKAP2', 'Gene', '26586', (24, 29))	('CKAP2', 'Gene', (24, 29))	('ERK2', 'Gene', (66, 70))
94311	28522860	showed that CKAP2 transfection reduced colony formation and the proportion of colon cancer cells HCT116 that was in S phase, and induced aneuploidy leading to genomic instability and tumorigenesis rather than cell death.	('CKAP2', 'Gene', (12, 17))	('reduced', 'NegReg', (31, 38))	('colon cancer', 'Phenotype', 'HP:0003003', (78, 90))	('CKAP2', 'Gene', '26586', (12, 17))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('colon cancer', 'Disease', 'MESH:D015179', (78, 90))	('aneuploidy', 'Disease', 'MESH:D000782', (137, 147))	('induced', 'Reg', (129, 136))	('colony formation', 'CPA', (39, 55))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('colon cancer', 'Disease', (78, 90))	('transfection', 'Var', (18, 30))	('genomic', 'MPA', (159, 166))	('tumor', 'Disease', (183, 188))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('aneuploidy', 'Disease', (137, 147))	('HCT116', 'CellLine', 'CVCL:0291', (97, 103))
94315	28522860	In the present study, we found that metastasis-related marker, MMP2, MMP-9 and Snail, were significantly decreased by CKAP2 knockdown, except E-cadherin.	('knockdown', 'Var', (124, 133))	('E-cadherin', 'Gene', (142, 152))	('E-cadherin', 'Gene', '999', (142, 152))	('CKAP2', 'Gene', (118, 123))	('metastasis-related', 'CPA', (36, 54))	('CKAP2', 'Gene', '26586', (118, 123))	('MMP2', 'Gene', (63, 67))	('MMP-9', 'Gene', '4318', (69, 74))	('MMP-9', 'Gene', (69, 74))	('Snail', 'Gene', '6615', (79, 84))	('Snail', 'Gene', (79, 84))	('MMP2', 'Gene', '4313', (63, 67))	('decreased', 'NegReg', (105, 114))
94319	28522860	Inhibition of FAK in MTLn3 cells results in decreased proliferation in vitro as well as decreased primary tumor growth in vivo .	('MTLn3', 'Gene', (21, 26))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Disease', (106, 111))	('Inhibition', 'Var', (0, 10))	('decreased', 'NegReg', (88, 97))	('proliferation', 'CPA', (54, 67))	('FAK', 'Gene', (14, 17))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('decreased', 'NegReg', (44, 53))
94328	28522860	Downregulating MMP-2/9 via inhibiting the activation of ERK/MAPK signaling pathways inhibited migration and invasion of colorectal cancer.	('MAPK', 'Gene', (60, 64))	('colorectal cancer', 'Disease', (120, 137))	('ERK', 'Gene', (56, 59))	('colorectal cancer', 'Phenotype', 'HP:0003003', (120, 137))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('inhibiting', 'NegReg', (27, 37))	('Downregulating', 'Var', (0, 14))	('MMP-2/9', 'Gene', '4313;4318', (15, 22))	('MMP-2/9', 'Gene', (15, 22))	('colorectal cancer', 'Disease', 'MESH:D015179', (120, 137))	('MAPK', 'Gene', '5595;5594;5595', (60, 64))	('ERK', 'Gene', '5594', (56, 59))	('inhibited', 'NegReg', (84, 93))
94342	31824199	Although rare, PSC has increased their interest among oncologist community for different reasons: a. identification of the epithelial-to-mesenchymal phenomenon as a major mechanism of secondary resistance to tyrosine kinase inhibitors; b. over-expression of PD-L1 and effective treatment with immunotherapy; c. identification of c-MET exon 14 skipping mutation representing an effective target to crizotinib and other specific inhibitors.	('c-MET', 'Gene', '4233', (329, 334))	('tyrosine', 'Chemical', 'None', (208, 216))	('skipping mutation', 'Var', (343, 360))	('PSC', 'Disease', (15, 18))	('c-MET', 'Gene', (329, 334))	('PD-L1', 'Gene', (258, 263))	('men', 'Species', '9606', (154, 157))	('men', 'Species', '9606', (283, 286))	('crizotinib', 'Chemical', 'MESH:C551994', (397, 407))	('PD-L1', 'Gene', '29126', (258, 263))	('PSC', 'Disease', 'MESH:D002292', (15, 18))
94351	31824199	Indeed, previous works have consistently evidenced the clonal origin of PSC demonstrating identical mutations of KRAS and p53 in either carcinoma and sarcoma/sarcomatous component, as also disclosed in sarcomatoid carcinoma arising in other sites.	('mutations', 'Var', (100, 109))	('sarcoma', 'Phenotype', 'HP:0100242', (202, 209))	('sarcomatoid carcinoma', 'Disease', 'MESH:D002292', (202, 223))	('carcinoma and sarcoma/sarcomatous component', 'Disease', 'MESH:D018316', (136, 179))	('PSC', 'Disease', (72, 75))	('sarcomatoid carcinoma', 'Phenotype', 'HP:0100242', (202, 223))	('carcinoma', 'Phenotype', 'HP:0030731', (214, 223))	('p53', 'Gene', '7157', (122, 125))	('sarcomatoid carcinoma', 'Disease', (202, 223))	('KRAS', 'Gene', (113, 117))	('PSC', 'Disease', 'MESH:D002292', (72, 75))	('KRAS', 'Gene', '3845', (113, 117))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('sarcoma', 'Phenotype', 'HP:0100242', (150, 157))	('sarcoma', 'Phenotype', 'HP:0100242', (158, 165))	('p53', 'Gene', (122, 125))
94352	31824199	Basically, the appearance of an additional sarcomatoid/sarcomatous component in an otherwise conventional NSCLC is due to up-regulation of the epithelial-to-mesenchymal transition (EMT) secondary to activation of genetic mechanisms generally associated with resistance to chemotherapy and tyrosine kinase inhibitors, such as KRAS mutations, c-MET gene alterations, overexpression of vimentin, ZEB1, Snail, MiR-34 coupled to down-regulation of E-cadherin and expression of epithelial markers, miR-200, mutations of EGFR (Figure 1).	('ZEB1', 'Gene', '6935', (393, 397))	('sarcomatoid/sarcomatous component', 'Disease', 'MESH:D018316', (43, 76))	('miR-200', 'Gene', (492, 499))	('EGFR', 'Gene', '1956', (514, 518))	('c-MET', 'Gene', '4233', (341, 346))	('tyrosine', 'Chemical', 'None', (289, 297))	('mutations', 'Var', (501, 510))	('c-MET', 'Gene', (341, 346))	('vimentin', 'Gene', '7431', (383, 391))	('sarcoma', 'Phenotype', 'HP:0100242', (55, 62))	('MiR-34', 'Gene', '407040', (406, 412))	('vimentin', 'Gene', (383, 391))	('Snail', 'Gene', (399, 404))	('ZEB1', 'Gene', (393, 397))	('NSCLC', 'Disease', 'MESH:D002289', (106, 111))	('EGFR', 'Gene', (514, 518))	('epithelial-to-mesenchymal transition', 'CPA', (143, 179))	('expression', 'MPA', (458, 468))	('MiR-34', 'Gene', (406, 412))	('NSCLC', 'Disease', (106, 111))	('KRAS', 'Gene', '3845', (325, 329))	('overexpression', 'PosReg', (365, 379))	('E-cadherin', 'Gene', (443, 453))	('down-regulation', 'NegReg', (424, 439))	('sarcomatoid/sarcomatous component', 'Disease', (43, 76))	('up-regulation', 'PosReg', (122, 135))	('E-cadherin', 'Gene', '999', (443, 453))	('KRAS', 'Gene', (325, 329))	('Snail', 'Gene', '6615', (399, 404))	('sarcoma', 'Phenotype', 'HP:0100242', (43, 50))
94402	31824199	34betaE12 and 5/6) are found in squamous and adenosquamous carcinoma and low-weight cytokeratins (i.e.	('adenosquamous carcinoma', 'Disease', 'MESH:D018196', (45, 68))	('squamous', 'Disease', (32, 40))	('low-weight', 'Phenotype', 'HP:0004325', (73, 83))	('carcinoma', 'Phenotype', 'HP:0030731', (59, 68))	('adenosquamous carcinoma', 'Disease', (45, 68))	('low-weight', 'Var', (73, 83))
94440	31824199	Of note, BAP-1 negativity at immunohistochemistry may be very helpful in ruling out PSC and favouring mesothelioma.	('mesothelioma', 'Disease', (102, 114))	('BAP-1', 'Gene', (9, 14))	('PSC', 'Disease', (84, 87))	('mesothelioma', 'Disease', 'MESH:D008654', (102, 114))	('PSC', 'Disease', 'MESH:D002292', (84, 87))	('negativity', 'Var', (15, 25))	('BAP-1', 'Gene', '8314', (9, 14))
94447	31824199	They reported mutations in TP53 (22.6%) KRAS (27.2%), EGFR (22.2%) and STK1 (7.4%) as the most common genetic alterations in these lesions.	('TP53', 'Gene', '7157', (27, 31))	('TP53', 'Gene', (27, 31))	('STK1', 'Gene', (71, 75))	('KRAS', 'Gene', (40, 44))	('EGFR', 'Gene', '1956', (54, 58))	('STK1', 'Gene', '2322', (71, 75))	('KRAS', 'Gene', '3845', (40, 44))	('EGFR', 'Gene', (54, 58))	('mutations', 'Var', (14, 23))
94449	31824199	In 2016, Schrock et al used a deep sequencing approach to map whole-exome mutations in a cohort of 125 PSCs.	('PSC', 'Disease', (103, 106))	('mutations', 'Var', (74, 83))	('PSC', 'Disease', 'MESH:D002292', (103, 106))
94450	31824199	While confirming that mutations in KRAS (34.4%) and TP53 (73.6%) are the most common mutations in PSCs, the results of these study refined the frequency of mutations and called into questions other relevant oncogenes that were not present in the Sequenom panel.	('PSC', 'Disease', 'MESH:D002292', (98, 101))	('KRAS', 'Gene', (35, 39))	('TP53', 'Gene', '7157', (52, 56))	('PSC', 'Disease', (98, 101))	('TP53', 'Gene', (52, 56))	('KRAS', 'Gene', '3845', (35, 39))	('mutations', 'Var', (22, 31))
94451	31824199	In particular, these authors showed that PSCs are characterized by a quite high tumor mutational burden (TMB, average of 8.1 mutations/Mb) and that both TP53 mutated tumors and KRAS mutated tumors were characterized by a higher TMB than WT samples.	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('TP53', 'Gene', '7157', (153, 157))	('tumors', 'Disease', (190, 196))	('PSC', 'Disease', (41, 44))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))	('higher', 'PosReg', (221, 227))	('KRAS', 'Gene', '3845', (177, 181))	('tumors', 'Disease', 'MESH:D009369', (190, 196))	('tumors', 'Disease', (166, 172))	('TMB', 'MPA', (228, 231))	('tumor', 'Disease', (166, 171))	('tumor', 'Disease', (80, 85))	('PSC', 'Disease', 'MESH:D002292', (41, 44))	('KRAS', 'Gene', (177, 181))	('tumor', 'Disease', (190, 195))	('TP53', 'Gene', (153, 157))	('tumors', 'Disease', 'MESH:D009369', (166, 172))	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('mutated', 'Var', (158, 165))	('tumors', 'Phenotype', 'HP:0002664', (190, 196))
94452	31824199	TP53 mutations were found in a consistent part of PSCs analyzed in this study and were reported to be widely heterogeneous as subsequentially confirmed by other reports.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('PSC', 'Disease', (50, 53))	('mutations', 'Var', (5, 14))	('found', 'Reg', (20, 25))	('PSC', 'Disease', 'MESH:D002292', (50, 53))
94453	31824199	Furthermore, the occurrence of TP53 mutations in PSCs seemed to underpin a specific genetic subtype.	('TP53', 'Gene', '7157', (31, 35))	('TP53', 'Gene', (31, 35))	('PSC', 'Disease', 'MESH:D002292', (49, 52))	('mutations', 'Var', (36, 45))	('PSC', 'Disease', (49, 52))
94454	31824199	For instance, mutation in NF1 and RB1 were reported to preferentially occur in TP53 mutated vs wild-type samples while NF2 mutations were more frequent in TP53 wild-type samples, thus hypothesizing distinct evolution pathways for PSCs with different genetic assets.	('RB1', 'Gene', (34, 37))	('TP53', 'Gene', '7157', (79, 83))	('preferentially', 'PosReg', (55, 69))	('TP53', 'Gene', (79, 83))	('NF2', 'Gene', '4771', (119, 122))	('TP53', 'Gene', '7157', (155, 159))	('RB1', 'Gene', '5925', (34, 37))	('NF1', 'Gene', (26, 29))	('PSC', 'Disease', 'MESH:D002292', (230, 233))	('TP53', 'Gene', (155, 159))	('occur', 'Reg', (70, 75))	('mutated', 'Var', (84, 91))	('mutation', 'Var', (14, 22))	('NF1', 'Gene', '4763', (26, 29))	('PSC', 'Disease', (230, 233))	('NF2', 'Gene', (119, 122))
94455	31824199	Besides TP53 and KRAS mutations, additional frequent alterations were found, including those in CDKN2B (23.2%), CDKN2A (37.6%), MET (13.6%) and NF1 (17.6%).	('CDKN2B', 'Gene', '1030', (96, 102))	('CDKN2A', 'Gene', (112, 118))	('CDKN2A', 'Gene', '1029', (112, 118))	('NF1', 'Gene', '4763', (144, 147))	('MET', 'Gene', (128, 131))	('TP53', 'Gene', '7157', (8, 12))	('KRAS', 'Gene', (17, 21))	('mutations', 'Var', (22, 31))	('TP53', 'Gene', (8, 12))	('KRAS', 'Gene', '3845', (17, 21))	('NF1', 'Gene', (144, 147))	('CDKN2B', 'Gene', (96, 102))
94456	31824199	Noticeably, mutations in EGFR (8.8%) were detected at a lower frequency than previously reported and BRAF alterations (7.3%) were limited to a reduced number of PSC samples.	('BRAF', 'Gene', (101, 105))	('EGFR', 'Gene', (25, 29))	('PSC', 'Disease', 'MESH:D002292', (161, 164))	('mutations', 'Var', (12, 21))	('PSC', 'Disease', (161, 164))	('BRAF', 'Gene', '673', (101, 105))	('EGFR', 'Gene', '1956', (25, 29))
94458	31824199	By means of whole-exome sequencing, the Authors identified mutations in the exon 14 of MET as preferentially associated with PSC.	('associated', 'Reg', (109, 119))	('PSC', 'Disease', (125, 128))	('mutations in the', 'Var', (59, 75))	('MET', 'Gene', (87, 90))	('PSC', 'Disease', 'MESH:D002292', (125, 128))
94459	31824199	MET exon 14 skipping mutations already described in other tumors including NSCLC affect either donor or acceptor splice site between exon 13 and exon 14, causing a 47 amino acid deletion in the juxta-membrane domain of the MET proteins.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumors', 'Disease', (58, 64))	('proteins', 'Protein', (227, 235))	('acceptor splice site', 'MPA', (104, 124))	('MET exon 14', 'Gene', (0, 11))	('donor', 'MPA', (95, 100))	('MET proteins', 'Protein', (223, 235))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('donor', 'Species', '9606', (95, 100))	('causing', 'Reg', (154, 161))	('deletion', 'Var', (178, 186))	('affect', 'Reg', (81, 87))	('NSCLC', 'Disease', (75, 80))	('NSCLC', 'Disease', 'MESH:D002289', (75, 80))	('mutations', 'Var', (21, 30))
94461	31824199	Loss of c-CBL binding either by point mutations in the accepting site or by exon 14 skipping, leads to MET stabilization and constitutive activation of MET-dependent signaling.	('c-CBL', 'Gene', (8, 13))	('MET stabilization', 'MPA', (103, 120))	('binding', 'Interaction', (14, 21))	('Loss', 'NegReg', (0, 4))	('constitutive', 'MPA', (125, 137))	('MET-dependent signaling', 'MPA', (152, 175))	('c-CBL', 'Gene', '867', (8, 13))	('activation', 'PosReg', (138, 148))	('point mutations', 'Var', (32, 47))
94462	31824199	As in NSCLC, in PSC MET exon 14 mutations were mutually exclusive with other oncogene mutations like KRAS, BRAF, EGFR or ALK rearrangement, but co-occurrence with PI3K mutations has been reported.	('BRAF', 'Gene', (107, 111))	('NSCLC', 'Disease', 'MESH:D002289', (6, 11))	('PSC', 'Disease', (16, 19))	('PI3', 'Gene', (163, 166))	('ALK', 'Gene', '238', (121, 124))	('KRAS', 'Gene', (101, 105))	('KRAS', 'Gene', '3845', (101, 105))	('mutations', 'Var', (32, 41))	('EGFR', 'Gene', '1956', (113, 117))	('EGFR', 'Gene', (113, 117))	('PI3', 'Gene', '5266', (163, 166))	('BRAF', 'Gene', '673', (107, 111))	('ALK', 'Gene', (121, 124))	('NSCLC', 'Disease', (6, 11))	('PSC', 'Disease', 'MESH:D002292', (16, 19))	('men', 'Species', '9606', (134, 137))
94463	31824199	Furthermore, at least in the original report, MET exon 14 mutations were exclusively found in pure PSCs or PSCs with an ADK component.	('mutations', 'Var', (58, 67))	('PSC', 'Disease', (107, 110))	('PSC', 'Disease', 'MESH:D002292', (99, 102))	('MET', 'Var', (46, 49))	('ADK', 'Gene', '132', (120, 123))	('PSC', 'Disease', (99, 102))	('found', 'Reg', (85, 90))	('PSC', 'Disease', 'MESH:D002292', (107, 110))	('ADK', 'Gene', (120, 123))
94464	31824199	Noticeably, while MET exon 14 mutations occur in about 3% of NSCLCs (according to TCGA data), up to 32% of PSCs are reported to carry this alteration.	('PSC', 'Disease', (107, 110))	('MET exon 14', 'Gene', (18, 29))	('mutations', 'Var', (30, 39))	('NSCLC', 'Disease', (61, 66))	('PSC', 'Disease', 'MESH:D002292', (107, 110))	('NSCLC', 'Disease', 'MESH:D002289', (61, 66))
94465	31824199	Indeed, according to a recent systematic meta-analysis, the incidence of MET exon 14 mutations in PSC is variable.	('PSC', 'Disease', 'MESH:D002292', (98, 101))	('MET exon 14', 'Var', (73, 84))	('PSC', 'Disease', (98, 101))
94467	31824199	Despite the different characteristics of analyzed case series, MET exon 14 mutations seem to occur particularly in PSC, ranging from 3% to 31.8%.	('PSC', 'Disease', (115, 118))	('occur', 'Reg', (93, 98))	('mutations', 'Var', (75, 84))	('PSC', 'Disease', 'MESH:D002292', (115, 118))	('MET exon', 'Var', (63, 71))
94468	31824199	The particular attention focused on MET exon 14 skipping mutations is then related to the relatively high frequency of this genetic alteration in PSC histology when compared with other conventional NSCLC, also predicting a good clinical response to MET inhibitors.	('PSC', 'Disease', (146, 149))	('predicting', 'Reg', (210, 220))	('MET inhibitors', 'MPA', (249, 263))	('skipping mutations', 'Var', (48, 66))	('NSCLC', 'Disease', (198, 203))	('MET', 'Gene', (36, 39))	('PSC', 'Disease', 'MESH:D002292', (146, 149))	('NSCLC', 'Disease', 'MESH:D002289', (198, 203))
94469	31824199	The rate of MET exon 14 mutations is significantly higher in case series including PSC without common targetable mutations in EGFR, KRAS, ALK, ROS1, and RET.	('RET', 'Gene', (153, 156))	('ROS1', 'Gene', (143, 147))	('KRAS', 'Gene', (132, 136))	('EGFR', 'Gene', (126, 130))	('ROS1', 'Gene', '6098', (143, 147))	('MET exon', 'Var', (12, 20))	('KRAS', 'Gene', '3845', (132, 136))	('ALK', 'Gene', '238', (138, 141))	('mutations', 'Var', (24, 33))	('RET', 'Gene', '5979', (153, 156))	('ALK', 'Gene', (138, 141))	('PSC', 'Disease', 'MESH:D002292', (83, 86))	('higher', 'PosReg', (51, 57))	('EGFR', 'Gene', '1956', (126, 130))	('PSC', 'Disease', (83, 86))
94484	31824199	The recent identification of MET exon 14 mutations shed new lights on the unique biology of PSCs and opened the first prospective on PSC-oriented therapy.	('mutations', 'Var', (41, 50))	('PSC', 'Disease', 'MESH:D002292', (133, 136))	('PSC', 'Disease', 'MESH:D002292', (92, 95))	('PSC', 'Disease', (92, 95))	('PSC', 'Disease', (133, 136))	('MET exon 14', 'Gene', (29, 40))
94487	31824199	For instance, EGFR actionable mutations are quite frequent in NSCLC and treatment with TKI is a first-line therapy for EGFR mutated patients.	('EGFR', 'Gene', '1956', (14, 18))	('NSCLC', 'Disease', (62, 67))	('EGFR', 'Gene', (14, 18))	('NSCLC', 'Disease', 'MESH:D002289', (62, 67))	('actionable', 'Reg', (19, 29))	('men', 'Species', '9606', (77, 80))	('mutations', 'Var', (30, 39))	('EGFR', 'Gene', '1956', (119, 123))	('patients', 'Species', '9606', (132, 140))	('EGFR', 'Gene', (119, 123))
94489	31824199	EGFR mutations in PSC is controversial (0-28% depending on series) but surely inferior to NSCLC.	('EGFR', 'Gene', (0, 4))	('NSCLC', 'Disease', (90, 95))	('mutations', 'Var', (5, 14))	('NSCLC', 'Disease', 'MESH:D002289', (90, 95))	('PSC', 'Disease', 'MESH:D002292', (18, 21))	('EGFR', 'Gene', '1956', (0, 4))	('PSC', 'Disease', (18, 21))
94490	31824199	Furthermore, according to the available information, the number of actionable EGFR mutations (p.L858R) is even lower further reducing the rationale for the employment of these drugs in this setting.	('mutations', 'Var', (83, 92))	('men', 'Species', '9606', (162, 165))	('p.L858R', 'Mutation', 'rs121434568', (94, 101))	('reducing', 'NegReg', (125, 133))	('lower', 'NegReg', (111, 116))	('EGFR', 'Gene', '1956', (78, 82))	('EGFR', 'Gene', (78, 82))
94491	31824199	Besides, the absence of evident response to EGFR inhibitors even in EGFR mutated PSCs, seems to indicate that EGFR mutations in these tumors may not be an essential driver but rather a secondary event.	('tumors', 'Disease', (134, 140))	('mutations', 'Var', (115, 124))	('mutated', 'Var', (73, 80))	('tumors', 'Disease', 'MESH:D009369', (134, 140))	('EGFR', 'Gene', '1956', (110, 114))	('EGFR', 'Gene', (110, 114))	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('PSC', 'Disease', (81, 84))	('EGFR', 'Gene', '1956', (68, 72))	('EGFR', 'Gene', '1956', (44, 48))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('EGFR', 'Gene', (44, 48))	('EGFR', 'Gene', (68, 72))	('PSC', 'Disease', 'MESH:D002292', (81, 84))
94492	31824199	KRAS mutations are among the most common alterations detected in non-squamous NSCLC.	('mutations', 'Var', (5, 14))	('NSCLC', 'Disease', (78, 83))	('KRAS', 'Gene', (0, 4))	('NSCLC', 'Disease', 'MESH:D002289', (78, 83))	('KRAS', 'Gene', '3845', (0, 4))
94494	31824199	KRAS mutations have been found significantly associated with pure sarcomatoid or with PSC with an adenocarcinoma component.	('pure sarcomatoid', 'Disease', (61, 77))	('sarcoma', 'Phenotype', 'HP:0100242', (66, 73))	('pure sarcomatoid', 'Disease', 'MESH:D002292', (61, 77))	('adenocarcinoma component', 'Disease', (98, 122))	('mutations', 'Var', (5, 14))	('associated', 'Reg', (45, 55))	('PSC', 'Disease', 'MESH:D002292', (86, 89))	('adenocarcinoma component', 'Disease', 'MESH:D000230', (98, 122))	('PSC', 'Disease', (86, 89))	('KRAS', 'Gene', (0, 4))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('KRAS', 'Gene', '3845', (0, 4))
94495	31824199	KRAS mutations are predominantly found in PSCs from smokers, and the majority of the alteration detected are transversions, the typical DNA alterations found in smokers' adenocarcinomas.	('transversions', 'Var', (109, 122))	('mutations', 'Var', (5, 14))	('PSC', 'Disease', 'MESH:D002292', (42, 45))	('adenocarcinomas', 'Disease', 'MESH:D000230', (170, 185))	('carcinoma', 'Phenotype', 'HP:0030731', (175, 184))	('carcinomas', 'Phenotype', 'HP:0030731', (175, 185))	('adenocarcinomas', 'Disease', (170, 185))	('PSC', 'Disease', (42, 45))	('KRAS', 'Gene', (0, 4))	('KRAS', 'Gene', '3845', (0, 4))
94496	31824199	Prognostic significance of KRAS mutations in PSC has been a matter of debate, in particular due to the limited number of cases in the analyzed series that precluded conclusive results.	('KRAS', 'Gene', '3845', (27, 31))	('PSC', 'Disease', 'MESH:D002292', (45, 48))	('mutations', 'Var', (32, 41))	('KRAS', 'Gene', (27, 31))	('PSC', 'Disease', (45, 48))
94497	31824199	However, we recently showed that KRAS mutations alone or in combination with TP53 mutations were associated with local metastases at recurrence and with a significantly decreased survival probability in a cohort of surgically resected PSCs.	('survival probability', 'CPA', (179, 199))	('TP53', 'Gene', '7157', (77, 81))	('KRAS', 'Gene', (33, 37))	('PSC', 'Disease', (235, 238))	('KRAS', 'Gene', '3845', (33, 37))	('metastases', 'Disease', (119, 129))	('decreased', 'NegReg', (169, 178))	('mutations', 'Var', (38, 47))	('TP53', 'Gene', (77, 81))	('PSC', 'Disease', 'MESH:D002292', (235, 238))	('metastases', 'Disease', 'MESH:D009362', (119, 129))
94498	31824199	Similarly, Mehrad and colleagues reported a significant correlation of KRAS mutations with worse patients' outcome.	('mutations', 'Var', (76, 85))	('KRAS', 'Gene', (71, 75))	('correlation', 'Interaction', (56, 67))	('KRAS', 'Gene', '3845', (71, 75))	('patients', 'Species', '9606', (97, 105))
94499	31824199	We also showed that the presence of KRAS mutations significantly correlates with increased PD-L1 expression suggesting a possible correlation, to be further investigated, between these mutations and response to immunotherapy.	('mutations', 'Var', (41, 50))	('increased PD', 'Phenotype', 'HP:0008151', (81, 93))	('PD-L1', 'Gene', (91, 96))	('KRAS', 'Gene', (36, 40))	('PD-L1', 'Gene', '29126', (91, 96))	('KRAS', 'Gene', '3845', (36, 40))	('increased', 'PosReg', (81, 90))	('expression', 'MPA', (97, 107))
94500	31824199	These results together with the recent emerging MEK inhibitors may imply a potential value of KRAS mutations as relevant predictive markers in orienting PSC tailored treatment.	('KRAS', 'Gene', (94, 98))	('PSC', 'Disease', (153, 156))	('MEK', 'Gene', (48, 51))	('KRAS', 'Gene', '3845', (94, 98))	('mutations', 'Var', (99, 108))	('MEK', 'Gene', '5609', (48, 51))	('men', 'Species', '9606', (171, 174))	('PSC', 'Disease', 'MESH:D002292', (153, 156))
94502	31824199	NSCLCs with activating alterations of MET (including MET locus amplification) have shown remarkable response to small molecules like crizotinib, cabozantinib or capmatinib that target MET activity.	('NSCLC', 'Disease', 'MESH:D002289', (0, 5))	('response', 'MPA', (100, 108))	('crizotinib', 'Chemical', 'MESH:C551994', (133, 143))	('capmatinib', 'Chemical', 'None', (161, 171))	('MET', 'MPA', (53, 56))	('cabozantinib', 'Chemical', 'MESH:C558660', (145, 157))	('MET', 'Gene', (38, 41))	('alterations', 'Var', (23, 34))	('activating', 'PosReg', (12, 22))	('NSCLC', 'Disease', (0, 5))
94503	31824199	For the same reason, the presence of MET activating mutations in PSCs would qualify a good portion of patients (about 30%) based on the reported mutations incidence for treatment with these drugs.	('patients', 'Species', '9606', (102, 110))	('PSC', 'Disease', 'MESH:D002292', (65, 68))	('men', 'Species', '9606', (174, 177))	('PSC', 'Disease', (65, 68))	('presence', 'Var', (25, 33))
94504	31824199	Preclinical evidence shows that tumor cells harboring MET ex14 mutations are responsive to MET inhibition, even if co-occurrence of PI3KCA concomitant gain of function alterations may partially reduce effectiveness of MET inhibition.	('MET ex14 mutations', 'Var', (54, 72))	('responsive to MET inhibition', 'MPA', (77, 105))	('MET inhibition', 'MPA', (218, 232))	('PI3', 'Gene', (132, 135))	('PI3', 'Gene', '5266', (132, 135))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumor', 'Disease', (32, 37))	('effectiveness', 'MPA', (201, 214))	('alterations', 'Var', (168, 179))	('reduce', 'NegReg', (194, 200))
94505	31824199	Preliminary clinical data on small series or single case confirmed that in vivo, PSC harboring MET exon 14 mutations show effective response to MET targeting drugs.	('MET targeting drugs', 'MPA', (144, 163))	('response', 'MPA', (132, 140))	('mutations', 'Var', (107, 116))	('PSC', 'Disease', (81, 84))	('PSC', 'Disease', 'MESH:D002292', (81, 84))	('MET exon 14', 'Gene', (95, 106))
94506	31824199	Even if revolutionary in the desolated PSC treatments landscape, the discovery of MET exon 14 mutations and the consequential possibility of directing patients to MET inhibitors is limited to a reduced number of patients.	('MET exon 14', 'Gene', (82, 93))	('PSC', 'Disease', 'MESH:D002292', (39, 42))	('men', 'Species', '9606', (48, 51))	('mutations', 'Var', (94, 103))	('PSC', 'Disease', (39, 42))	('patients', 'Species', '9606', (151, 159))	('patients', 'Species', '9606', (212, 220))
94516	31824199	Targetable mutations in PSC are less frequent than in NSCLC with adenocarcinoma histology.	('mutations', 'Var', (11, 20))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('PSC', 'Disease', 'MESH:D002292', (24, 27))	('adenocarcinoma', 'Disease', (65, 79))	('NSCLC', 'Disease', (54, 59))	('adenocarcinoma', 'Disease', 'MESH:D000230', (65, 79))	('NSCLC', 'Disease', 'MESH:D002289', (54, 59))	('PSC', 'Disease', (24, 27))
94517	31824199	However, Fallet et al reported uncommon/rare EGFR mutations in 22%, NRAS and PI3KCA in 5%.	('EGFR', 'Gene', (45, 49))	('PI3', 'Gene', '5266', (77, 80))	('mutations', 'Var', (50, 59))	('NRAS', 'Gene', (68, 72))	('PI3', 'Gene', (77, 80))	('NRAS', 'Gene', '4893', (68, 72))	('EGFR', 'Gene', '1956', (45, 49))
94518	31824199	Li et al performed an NGS study evidencing hot spot druggable gene alterations involving EGFR (exon 19 deletion) and EML4-ALK fusion in sporadic cases.	('EGFR', 'Gene', (89, 93))	('alterations', 'Var', (67, 78))	('ALK', 'Gene', (122, 125))	('EML4', 'Gene', (117, 121))	('EML4', 'Gene', '27436', (117, 121))	('EGFR', 'Gene', '1956', (89, 93))	('ALK', 'Gene', '238', (122, 125))
94519	31824199	Mehrad et al evidenced actionable genetic mutations in EGFR in 2 out of 23 PSCs (8.7%) and Schrock et al observed targetable genomic alteration in EGFR (8.8%), BRAF (7.2%), erb-b2 receptor tyrosine kinase 2 gene (HER2) (1.6%), and ret proto-oncogene (RET) (0.8%).	('BRAF', 'Gene', (160, 164))	('EGFR', 'Gene', '1956', (55, 59))	('BRAF', 'Gene', '673', (160, 164))	('EGFR', 'Gene', (147, 151))	('erb-b2 receptor tyrosine kinase 2', 'Gene', '2064', (173, 206))	('ret', 'Gene', (231, 234))	('ret', 'Gene', '5979', (231, 234))	('EGFR', 'Gene', (55, 59))	('erb-b2 receptor tyrosine kinase 2', 'Gene', (173, 206))	('PSC', 'Disease', (75, 78))	('PSC', 'Disease', 'MESH:D002292', (75, 78))	('RET', 'Gene', (251, 254))	('HER2', 'Gene', (213, 217))	('EGFR', 'Gene', '1956', (147, 151))	('RET', 'Gene', '5979', (251, 254))	('mutations', 'Var', (42, 51))	('HER2', 'Gene', '2064', (213, 217))
94521	31824199	Finally, Ali et al disclosed sporadic mutations in EGFR (1 case), MET (2 cases) and BRAF (1 case), KRAS (2 cases), PI3KCA (2 cases) and 1 ALK-rearranged case among 14 PSC using a combined approach with Sequenom Mass-Array and Sanger sequencing and NanoString technology.	('BRAF', 'Gene', '673', (84, 88))	('EGFR', 'Gene', (51, 55))	('PSC', 'Disease', 'MESH:D002292', (167, 170))	('ALK', 'Gene', '238', (138, 141))	('PI3', 'Gene', (115, 118))	('BRAF', 'Gene', (84, 88))	('PSC', 'Disease', (167, 170))	('ALK', 'Gene', (138, 141))	('KRAS', 'Gene', (99, 103))	('mutations', 'Var', (38, 47))	('PI3', 'Gene', '5266', (115, 118))	('KRAS', 'Gene', '3845', (99, 103))	('EGFR', 'Gene', '1956', (51, 55))
94522	31824199	By contrast, Nakagomi et al evidenced prevalent mutations in TP53 and KRAS coupled to Microsatellite instability/Mismatch repair system alteration in one case among four PSCs deeply investigated by NGS.	('PSC', 'Disease', (170, 173))	('KRAS', 'Gene', (70, 74))	('KRAS', 'Gene', '3845', (70, 74))	('Microsatellite instability', 'Disease', 'MESH:D053842', (86, 112))	('PSC', 'Disease', 'MESH:D002292', (170, 173))	('alteration', 'Reg', (136, 146))	('Microsatellite instability', 'Disease', (86, 112))	('TP53', 'Gene', (61, 65))	('TP53', 'Gene', '7157', (61, 65))	('mutations', 'Var', (48, 57))
94523	31824199	Several reasons may explain the wide range of incidence of druggable gene alterations in PSC, as follows: a) a selection bias related to the accuracy in diagnosing this unusual histology (i.e., application of morphologic criteria in biopsy versus resections, lack of specific diagnostic primary antibodies at immunohistochemistry); b) various methodologies in detecting gene alterations, including techniques with a significantly large range of sensitivity; and c) different ethnicities of the reported case series.	('PSC', 'Disease', 'MESH:D002292', (89, 92))	('PSC', 'Disease', (89, 92))	('alterations', 'Var', (74, 85))
94525	31824199	Interestingly, among acquired resistance mechanisms during treatments with tyrosine kinase inhibitors (i.e., EGFR and ALK inhibitors) or chemotherapy, histologic "change" from adenocarcinoma to small cell or squamous cell carcinomas have been well demonstrated in EGFR mutated (about 10% of cases) and ALK rearranged adenocarcinomas.	('mutated', 'Var', (269, 276))	('EGFR', 'Gene', '1956', (109, 113))	('adenocarcinoma', 'Disease', 'MESH:D000230', (317, 331))	('squamous cell carcinomas', 'Disease', (208, 232))	('EGFR', 'Gene', (264, 268))	('tyrosine', 'Chemical', 'None', (75, 83))	('carcinoma', 'Phenotype', 'HP:0030731', (222, 231))	('carcinomas', 'Phenotype', 'HP:0030731', (222, 232))	('carcinoma', 'Phenotype', 'HP:0030731', (181, 190))	('men', 'Species', '9606', (64, 67))	('carcinoma', 'Phenotype', 'HP:0030731', (322, 331))	('carcinomas', 'Phenotype', 'HP:0030731', (322, 332))	('adenocarcinoma', 'Disease', (176, 190))	('EGFR', 'Gene', (109, 113))	('ALK', 'Gene', (302, 305))	('EGFR', 'Gene', '1956', (264, 268))	('ALK', 'Gene', '238', (302, 305))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (208, 232))	('adenocarcinoma', 'Disease', (317, 331))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (208, 231))	('adenocarcinomas', 'Disease', 'MESH:D000230', (317, 332))	('ALK', 'Gene', '238', (118, 121))	('adenocarcinomas', 'Disease', (317, 332))	('adenocarcinoma', 'Disease', 'MESH:D000230', (176, 190))	('ALK', 'Gene', (118, 121))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (208, 232))
94530	31824199	Xu et al reported a case of lung adenocarcinoma resistant to EGFR TKI with concurrent acquired T790M secondary EGFR mutation and sarcomatoid spindle cell occurrence.	('sarcoma', 'Phenotype', 'HP:0100242', (129, 136))	('lung adenocarcinoma', 'Disease', (28, 47))	('sarcomatoid', 'Disease', 'MESH:D002292', (129, 140))	('EGFR', 'Gene', '1956', (111, 115))	('T790M', 'Mutation', 'rs121434569', (95, 100))	('EGFR', 'Gene', (111, 115))	('T790M', 'Var', (95, 100))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (28, 47))	('sarcomatoid', 'Disease', (129, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (38, 47))	('EGFR', 'Gene', '1956', (61, 65))	('EGFR', 'Gene', (61, 65))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (28, 47))
94531	31824199	Finally, a case of exon 21 L858R EGFR-mutated sarcomatoid carcinoma of the lung resistant to icotinib was recently reported.	('L858R', 'Var', (27, 32))	('sarcomatoid carcinoma of the lung', 'Disease', 'MESH:D002292', (46, 79))	('EGFR', 'Gene', '1956', (33, 37))	('sarcomatoid carcinoma of the lung', 'Disease', (46, 79))	('L858R', 'Mutation', 'rs121434568', (27, 32))	('icotinib', 'Chemical', 'MESH:C531470', (93, 101))	('sarcoma', 'Phenotype', 'HP:0100242', (46, 53))	('EGFR', 'Gene', (33, 37))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))	('sarcomatoid carcinoma', 'Phenotype', 'HP:0100242', (46, 67))	('carcinoma of the lung', 'Phenotype', 'HP:0100526', (58, 79))
94532	31824199	Coexistence of Nkx2-4 mutation was considered responsible of its intrinsic resistance to EGFR TKI.	('mutation', 'Var', (22, 30))	('EGFR', 'Gene', (89, 93))	('Nkx2-4', 'Gene', (15, 21))	('EGFR', 'Gene', '1956', (89, 93))	('Nkx2-4', 'Gene', '644524;4824', (15, 21))
94546	31824199	Chan et al assessed the PD-L1 expression in 713 consecutive NSCLC by four commercially available PD-L1 immunohistochemical assays (22C3, 28-8, SP142 and SP263) evidencing a high PD-L1 expression >=50% significantly associated with PSC (p < 0.001) and mutant KRAS (p = 0.005) also reporting good agreement between 22C2, 28-8 and SP263 primary antibodies.	('PD-L1', 'Gene', (97, 102))	('mutant', 'Var', (251, 257))	('PSC', 'Disease', (231, 234))	('PD-L1', 'Gene', '29126', (97, 102))	('men', 'Species', '9606', (300, 303))	('KRAS', 'Gene', '3845', (258, 262))	('PD-L1', 'Gene', '29126', (24, 29))	('PD-L1', 'Gene', (24, 29))	('NSCLC', 'Disease', 'MESH:D002289', (60, 65))	('PD-L1', 'Gene', (178, 183))	('NSCLC', 'Disease', (60, 65))	('PD-L1', 'Gene', '29126', (178, 183))	('PSC', 'Disease', 'MESH:D002292', (231, 234))	('associated', 'Reg', (215, 225))	('KRAS', 'Gene', (258, 262))
94550	31824199	Vieira et al reported high PD-L1 (clone 5H1) immunoreactivity in 40 out of 75 (53%) PSC, also confirming a significant association with the presence of KRAS mutations.	('KRAS', 'Gene', (152, 156))	('PSC', 'Disease', (84, 87))	('KRAS', 'Gene', '3845', (152, 156))	('mutations', 'Var', (157, 166))	('PD-L1', 'Gene', (27, 32))	('PSC', 'Disease', 'MESH:D002292', (84, 87))	('PD-L1', 'Gene', '29126', (27, 32))
94562	31824199	PD-L1 over-expression and MET exon 14 skipping mutation are the most important predictive biomarkers for effective targeted therapies in PSC.	('over-expression', 'PosReg', (6, 21))	('PSC', 'Disease', 'MESH:D002292', (137, 140))	('PD-L1', 'Gene', (0, 5))	('MET exon 14 skipping mutation', 'Var', (26, 55))	('PSC', 'Disease', (137, 140))	('PD-L1', 'Gene', '29126', (0, 5))
94585	31649886	It is well-known that the initiation and development of lung cancer are associated with abnormal expression of oncogenes and tumor suppressor genes.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('lung cancer', 'Phenotype', 'HP:0100526', (56, 67))	('lung cancer', 'Disease', 'MESH:D008175', (56, 67))	('men', 'Species', '9606', (48, 51))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('associated', 'Reg', (72, 82))	('tumor', 'Disease', (125, 130))	('abnormal', 'Var', (88, 96))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('nt', 'Chemical', 'MESH:D009711', (50, 52))	('lung cancer', 'Disease', (56, 67))	('expression', 'MPA', (97, 107))	('oncogenes', 'Gene', (111, 120))
94586	31649886	Numerous evidence suggested that the change in gene expression, which affects the occurrence and progression of tumors is closely related to epigenetic modification.	('epigenetic', 'Var', (141, 151))	('gene expression', 'MPA', (47, 62))	('tumors', 'Disease', (112, 118))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('affects', 'Reg', (70, 77))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumors', 'Disease', 'MESH:D009369', (112, 118))
94589	31649886	Epigenetic disruptions could promote the acquisition of a cancerous phenotype and aggressive behavior in lung cancer cells as well as primary or acquired resistance to treatment.	('lung cancer', 'Phenotype', 'HP:0100526', (105, 116))	('promote', 'PosReg', (29, 36))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('cancerous', 'Disease', 'MESH:D009369', (58, 67))	('primary or acquired resistance to treatment', 'CPA', (134, 177))	('aggressive behavior', 'Disease', (82, 101))	('nt', 'Chemical', 'MESH:D009711', (175, 177))	('men', 'Species', '9606', (173, 176))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('aggressive behavior', 'Disease', 'MESH:D001523', (82, 101))	('lung cancer', 'Disease', 'MESH:D008175', (105, 116))	('aggressive behavior', 'Phenotype', 'HP:0000718', (82, 101))	('Epigenetic disruptions', 'Var', (0, 22))	('cancerous', 'Disease', (58, 67))	('lung cancer', 'Disease', (105, 116))
94646	31649886	As shown in Figure 1A, cells formed significantly more and bigger colonies in S30 cells compared to the normal BEAS-2B cells.	('S30', 'Var', (78, 81))	('more', 'PosReg', (50, 54))	('nt', 'Chemical', 'MESH:D009711', (45, 47))
94650	31649886	Scratch wound healing assay indicated that the migratory ability was significantly increased in S30 cells compared to the normal BEAS-2B cells (Figures 2A,B).	('nt', 'Chemical', 'MESH:D009711', (78, 80))	('S30', 'Var', (96, 99))	('migratory ability', 'CPA', (47, 64))	('increased', 'PosReg', (83, 92))
94651	31649886	As shown in Figures 2C,D, further transwell migratory assay demonstrated that the migrated cells were significantly increased in S30 cells compared to the normal BEAS-2B cells.	('S30 cells', 'Var', (129, 138))	('migrated cells', 'CPA', (82, 96))	('nt', 'Chemical', 'MESH:D009711', (111, 113))	('increased', 'PosReg', (116, 125))
94661	31649886	A total of 8 miRNAs were found dysregulation in S30 cells, LUAD and LUSC samples with a similar tendency of change.	('LUAD', 'Phenotype', 'HP:0030078', (59, 63))	('LUAD', 'Disease', (59, 63))	('miR', 'Gene', '220972', (13, 16))	('LUAD', 'Disease', 'MESH:C538231', (59, 63))	('miR', 'Gene', (13, 16))	('dysregulation', 'Var', (31, 44))
94707	31649886	The datasets generated for this study can be found in the Sequence Read Archive (SRA) database (https://trace.ncbi.nlm.nih.gov/Traces/sra/) with identifier SRP182926 and SRP181756.	('SRP181756', 'Chemical', 'MESH:C426705', (170, 179))	('SRP182926', 'Var', (156, 165))	('SRP182926', 'Chemical', 'MESH:C426705', (156, 165))	('nt', 'Chemical', 'MESH:D009711', (148, 150))	('SRP181756', 'Var', (170, 179))
94784	28585123	For the group undifferentiated, large cell, anaplastic or mixed carcinoma the OR was 2.89 (95% CI 1.37-6.11, p for trend: 0.005) in the highest quartile of exposure duration.	('anaplastic', 'Var', (44, 54))	('carcinoma', 'Disease', 'MESH:D002277', (64, 73))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))	('large cell', 'Disease', (32, 42))	('carcinoma', 'Disease', (64, 73))
94790	28585123	For overall lung cancer, the adjusted OR of lung cancer was 1.49 (95% CI 1.04-2.14) in the highest quartile of cumulative exposure (1021 microg-year/m3 of EC).	('lung cancer', 'Phenotype', 'HP:0100526', (44, 55))	('lung cancer', 'Phenotype', 'HP:0100526', (12, 23))	('lung cancer', 'Disease', 'MESH:D008175', (12, 23))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('1021 microg-year/m3', 'Var', (132, 151))	('lung cancer', 'Disease', 'MESH:D008175', (44, 55))	('lung cancer', 'Disease', (12, 23))	('EC', 'Chemical', 'MESH:D002244', (155, 157))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))	('lung cancer', 'Disease', (44, 55))
94812	28585123	The group of undifferentiated, large cell, anaplastic or mixed carcinoma was associated with an increased risk.	('undifferentiated', 'Disease', (13, 29))	('carcinoma', 'Disease', (63, 72))	('anaplastic', 'Var', (43, 53))	('large cell', 'Disease', (31, 41))	('carcinoma', 'Disease', 'MESH:D002277', (63, 72))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))
94842	33707587	MicroRNA-205-5p inhibits skin cancer cell proliferation and increase drug sensitivity by targeting TNFAIP8 Tumor necrosis factor-alpha-induced protein 8 (TNFAIP8) is a member of the TIPE/TNFAIP8 family which regulates tumor growth and survival.	('skin cancer', 'Phenotype', 'HP:0008069', (25, 36))	('targeting', 'Var', (89, 98))	('Tumor necrosis factor-alpha-induced protein 8', 'Gene', (107, 152))	('tumor', 'Disease', 'MESH:D009369', (218, 223))	('skin cancer', 'Disease', (25, 36))	('Tumor', 'Phenotype', 'HP:0002664', (107, 112))	('increase', 'PosReg', (60, 68))	('Tumor necrosis factor-alpha-induced protein 8', 'Gene', '25816', (107, 152))	('TNFAIP8', 'Gene', (99, 106))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('TNFAIP8', 'Gene', (154, 161))	('skin cancer', 'Disease', 'MESH:D012878', (25, 36))	('inhibits', 'NegReg', (16, 24))	('tumor', 'Disease', (218, 223))	('drug sensitivity', 'Phenotype', 'HP:0020174', (69, 85))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('drug sensitivity', 'MPA', (69, 85))
94846	33707587	Conversely, silencing of TNFAIP8 decreased cell survival/cell migration in skin cancer cells.	('skin cancer', 'Phenotype', 'HP:0008069', (75, 86))	('skin cancer', 'Disease', 'MESH:D012878', (75, 86))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('silencing', 'Var', (12, 21))	('cell survival/cell migration in', 'CPA', (43, 74))	('decreased', 'NegReg', (33, 42))	('TNFAIP8', 'Gene', (25, 32))	('skin cancer', 'Disease', (75, 86))
94847	33707587	We also showed that miR-205-5p targets the 3'UTR of TNFAIP8 and inhibits TNFAIP8 expression.	('TNFAIP8', 'Gene', (73, 80))	('TNFAIP8', 'Gene', (52, 59))	('miR-205-5p', 'Chemical', '-', (20, 30))	('miR-205-5p', 'Var', (20, 30))	('inhibits', 'NegReg', (64, 72))	('expression', 'MPA', (81, 91))
94848	33707587	Moreover, miR-205-5p downregulates TNFAIP8 mediated cellular autophagy, increased sensitivity towards the B-RAFV600E mutant kinase inhibitor vemurafenib, and induced cell apoptosis in melanoma cells.	('B-RAF', 'Gene', '673', (106, 111))	('sensitivity', 'MPA', (82, 93))	('cellular autophagy', 'CPA', (52, 70))	('miR-205-5p', 'Var', (10, 20))	('melanoma', 'Disease', (184, 192))	('increased', 'PosReg', (72, 81))	('vemurafenib', 'Chemical', 'MESH:D000077484', (141, 152))	('melanoma', 'Disease', 'MESH:D008545', (184, 192))	('melanoma', 'Phenotype', 'HP:0002861', (184, 192))	('B-RAF', 'Gene', (106, 111))	('induced', 'Reg', (158, 165))	('downregulates', 'NegReg', (21, 34))	('miR-205-5p', 'Chemical', '-', (10, 20))	('cell apoptosis', 'CPA', (166, 180))	('TNFAIP8', 'Gene', (35, 42))
94849	33707587	Collectively our data indicate that miR-205-5p acts as a tumor suppressor in skin cancer by targeting TNFAIP8.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('targeting', 'Reg', (92, 101))	('skin cancer', 'Disease', (77, 88))	('skin cancer', 'Disease', 'MESH:D012878', (77, 88))	('miR-205-5p', 'Chemical', '-', (36, 46))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('miR-205-5p', 'Var', (36, 46))	('TNFAIP8', 'Gene', (102, 109))	('tumor', 'Disease', (57, 62))	('up', 'Gene', '7378', (64, 66))	('skin cancer', 'Phenotype', 'HP:0008069', (77, 88))
94858	33707587	Analysis of whole-genome landscapes of major melanoma subtypes has identified several key gene mutations in cutaneous melanoma, including B-RAF, CDKN2A, NRAS, in acral melanoma TP53, B-RAF, NRAS and NF1 and SF3B1 in mucosal melanoma.	('NRAS', 'Gene', '4893', (190, 194))	('acral melanoma', 'Disease', 'MESH:D008545', (162, 176))	('mucosal melanoma', 'Disease', 'MESH:D008545', (216, 232))	('TP53', 'Gene', '7157', (177, 181))	('B-RAF', 'Gene', (138, 143))	('NF1', 'Gene', (199, 202))	('melanoma', 'Phenotype', 'HP:0002861', (168, 176))	('melanoma', 'Disease', (168, 176))	('acral melanoma', 'Phenotype', 'HP:0012060', (162, 176))	('CDKN2A', 'Gene', (145, 151))	('mucosal melanoma', 'Disease', (216, 232))	('melanoma', 'Phenotype', 'HP:0002861', (118, 126))	('melanoma', 'Disease', (118, 126))	('NF1', 'Gene', '4763', (199, 202))	('NRAS', 'Gene', (153, 157))	('mutations', 'Var', (95, 104))	('B-RAF', 'Gene', '673', (183, 188))	('melanoma', 'Disease', 'MESH:D008545', (224, 232))	('melanoma', 'Disease', (45, 53))	('melanoma', 'Phenotype', 'HP:0002861', (45, 53))	('SF3B1', 'Gene', (207, 212))	('NRAS', 'Gene', (190, 194))	('CDKN2A', 'Gene', '1029', (145, 151))	('cutaneous melanoma', 'Disease', (108, 126))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (108, 126))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (108, 126))	('TP53', 'Gene', (177, 181))	('acral melanoma', 'Disease', (162, 176))	('melanoma', 'Disease', 'MESH:D008545', (168, 176))	('B-RAF', 'Gene', (183, 188))	('melanoma', 'Disease', 'MESH:D008545', (118, 126))	('B-RAF', 'Gene', '673', (138, 143))	('SF3B1', 'Gene', '23451', (207, 212))	('NRAS', 'Gene', '4893', (153, 157))	('melanoma', 'Phenotype', 'HP:0002861', (224, 232))	('melanoma', 'Disease', (224, 232))	('melanoma', 'Disease', 'MESH:D008545', (45, 53))
94859	33707587	The study further releveled that these mutations are not correlated with alternative telomere lengthening but associated with greater telomere length and also modulates the MAPK and PI3K pathway in melanomas.	('telomere length', 'MPA', (134, 149))	('melanomas', 'Disease', (198, 207))	('greater', 'PosReg', (126, 133))	('melanomas', 'Disease', 'MESH:D008545', (198, 207))	('melanoma', 'Phenotype', 'HP:0002861', (198, 206))	('melanomas', 'Phenotype', 'HP:0002861', (198, 207))	('mutations', 'Var', (39, 48))	('modulates', 'Reg', (159, 168))
94860	33707587	Moreover, during melanoma development, several somatic alterations activate the MAPK and PI3K pathway, upregulate telomerase activity, modulate chromatin landscape, override the G1/S checkpoint, the ramp-up of MAPK signaling, and disrupt the p53 pathway.	('up', 'Gene', '7378', (103, 105))	('telomerase activity', 'MPA', (114, 133))	('override', 'PosReg', (165, 173))	('alterations', 'Var', (55, 66))	('modulate', 'Reg', (135, 143))	('MAPK signaling', 'Pathway', (210, 224))	('up', 'Gene', '7378', (234, 236))	('p53', 'Gene', (242, 245))	('p53', 'Gene', '7157', (242, 245))	('up', 'Gene', '7378', (204, 206))	('melanoma', 'Phenotype', 'HP:0002861', (17, 25))	('chromatin landscape', 'MPA', (144, 163))	('melanoma', 'Disease', (17, 25))	('melanoma', 'Disease', 'MESH:D008545', (17, 25))	('G1/S checkpoint', 'MPA', (178, 193))	('PI3K pathway', 'Pathway', (89, 101))	('activate', 'PosReg', (67, 75))
94863	33707587	In melanoma, the expression of several miRNAs are upregulated, for example, miR-214, miR-30b, miR-30d, miR-506, miR-514, miR-21, miR-155, and miR-221.	('miR-514', 'Var', (112, 119))	('miR-214', 'Gene', '406996', (76, 83))	('up', 'Gene', '7378', (50, 52))	('miR-21', 'Gene', '406991', (121, 127))	('expression', 'MPA', (17, 27))	('miR-221', 'Gene', (142, 149))	('miR-21', 'Gene', (76, 82))	('miR-221', 'Gene', '407006', (142, 149))	('melanoma', 'Disease', 'MESH:D008545', (3, 11))	('miR-506', 'Gene', '574511', (103, 110))	('miR-30d', 'Gene', (94, 101))	('miR-21', 'Gene', (121, 127))	('miR-214', 'Gene', (76, 83))	('miR-155', 'Gene', (129, 136))	('miR-30d', 'Gene', '407033', (94, 101))	('miR-30b', 'Gene', '407030', (85, 92))	('miR-30b', 'Gene', (85, 92))	('miR-155', 'Gene', '406947', (129, 136))	('melanoma', 'Phenotype', 'HP:0002861', (3, 11))	('melanoma', 'Disease', (3, 11))	('miR-21', 'Gene', '406991', (76, 82))	('miR-506', 'Gene', (103, 110))
94875	33707587	Further, we demonstrated that miR-205-5p controls TNFAIP8 expression and reduces skin cancer cell survival, and increases sensitivity to the B-RAFV600E mutant kinase inhibitor vemurafenib in melanoma cells.	('skin cancer', 'Disease', (81, 92))	('skin cancer', 'Phenotype', 'HP:0008069', (81, 92))	('sensitivity', 'MPA', (122, 133))	('controls', 'Reg', (41, 49))	('melanoma', 'Disease', 'MESH:D008545', (191, 199))	('expression', 'MPA', (58, 68))	('reduces', 'NegReg', (73, 80))	('melanoma', 'Disease', (191, 199))	('TNFAIP8', 'Gene', (50, 57))	('miR-205-5p', 'Chemical', '-', (30, 40))	('skin cancer', 'Disease', 'MESH:D012878', (81, 92))	('melanoma', 'Phenotype', 'HP:0002861', (191, 199))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('B-RAF', 'Gene', '673', (141, 146))	('vemurafenib', 'Chemical', 'MESH:D000077484', (176, 187))	('miR-205-5p', 'Var', (30, 40))	('increases', 'PosReg', (112, 121))	('B-RAF', 'Gene', (141, 146))
94886	33707587	B-RAF protein is a serine-threonine kinase and mutation of B-RAFV600E increases approximately 500-fold kinase activity compared with wild-type B-RAF in 27-70% of melanoma cancer.	('kinase activity', 'MPA', (103, 118))	('melanoma', 'Phenotype', 'HP:0002861', (162, 170))	('B-RAF', 'Gene', '673', (0, 5))	('B-RAF', 'Gene', '673', (59, 64))	('B-RAF', 'Gene', '673', (143, 148))	('mutation', 'Var', (47, 55))	('B-RAF', 'Gene', (0, 5))	('increases', 'PosReg', (70, 79))	('B-RAF', 'Gene', (59, 64))	('B-RAF', 'Gene', (143, 148))	('melanoma cancer', 'Disease', 'MESH:D009369', (162, 177))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('melanoma cancer', 'Disease', (162, 177))	('serine', 'Chemical', 'MESH:D012694', (19, 25))
94887	33707587	B-RAFV600E mutant protein is constitutively active and earlier studies demonstrated that B-RAFV600E mutant dysregulates NF-kappaB/Snail/RKIP/PTEN circuit as well as activates MEK/ERK kinases that promote the epithelial to mesenchymal transition (EMT) and melanoma cell growth.	('dysregulates', 'Var', (107, 119))	('PTEN', 'Gene', (141, 145))	('MEK', 'Gene', (175, 178))	('NF-kappaB', 'Gene', (120, 129))	('activates', 'PosReg', (165, 174))	('RKIP', 'Gene', (136, 140))	('ERK', 'Gene', (179, 182))	('NF-kappaB', 'Gene', '4790', (120, 129))	('Snail', 'Gene', (130, 135))	('B-RAF', 'Gene', '673', (0, 5))	('B-RAF', 'Gene', '673', (89, 94))	('PTEN', 'Gene', '5728', (141, 145))	('RKIP', 'Gene', '5037', (136, 140))	('melanoma', 'Disease', 'MESH:D008545', (255, 263))	('B-RAF', 'Gene', (0, 5))	('B-RAF', 'Gene', (89, 94))	('promote', 'PosReg', (196, 203))	('Snail', 'Gene', '6615', (130, 135))	('MEK', 'Gene', '5609', (175, 178))	('ERK', 'Gene', '5594', (179, 182))	('melanoma', 'Phenotype', 'HP:0002861', (255, 263))	('melanoma', 'Disease', (255, 263))
94898	33707587	Interestingly, B-RAF mutant A375 and A2058 melanoma cell lines which expressed lower levels of TNFAIP8, upon a dose-dependent treatment with TNFalpha (10-50 ng/ml) induced TNFAIP8 protein expression (Fig.	('induced', 'PosReg', (164, 171))	('B-RAF', 'Gene', (15, 20))	('A2058', 'CellLine', 'CVCL:1059', (37, 42))	('mutant', 'Var', (21, 27))	('up', 'Gene', '7378', (104, 106))	('A375', 'CellLine', 'CVCL:0132', (28, 32))	('melanoma', 'Phenotype', 'HP:0002861', (43, 51))	('melanoma', 'Disease', (43, 51))	('TNFalpha', 'Gene', (141, 149))	('protein', 'Protein', (180, 187))	('melanoma', 'Disease', 'MESH:D008545', (43, 51))	('TNFAIP8', 'Gene', (172, 179))	('TNFalpha', 'Gene', '7124', (141, 149))	('B-RAF', 'Gene', '673', (15, 20))
94910	33707587	TNFAIP8 expression promoted cell colony formation in A431 cells by 3.1-fold, A375 cells by 4.2-fold, and A2058 cells by 5.1-fold compared with empty vector-transfected cells (Fig.	('A431', 'CellLine', 'CVCL:0037', (53, 57))	('promoted', 'PosReg', (19, 27))	('A2058', 'CellLine', 'CVCL:1059', (105, 110))	('cell colony formation', 'CPA', (28, 49))	('TNFAIP8', 'Gene', (0, 7))	('A375', 'CellLine', 'CVCL:0132', (77, 81))	('expression', 'Var', (8, 18))
94913	33707587	These results suggest that TNFAIP8 overexpression promotes cell growth in skin cancer cells but not in normal skin cells.	('skin cancer', 'Disease', (74, 85))	('skin cancer', 'Phenotype', 'HP:0008069', (74, 85))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('overexpression', 'Var', (35, 49))	('skin cancer', 'Disease', 'MESH:D012878', (74, 85))	('cell growth', 'CPA', (59, 70))	('promotes', 'PosReg', (50, 58))	('TNFAIP8', 'Gene', (27, 34))
94916	33707587	MTT assay demonstrated that TNFAIP8 knockdown reduced cell survival in A431 cells by 22%, in A375 cells by 55.2%, and in A2058 cells by 45.3% compared with control siRNA transfected cells (Fig.	('TNFAIP8', 'Gene', (28, 35))	('A2058', 'CellLine', 'CVCL:1059', (121, 126))	('A375', 'CellLine', 'CVCL:0132', (93, 97))	('MTT', 'Chemical', 'MESH:C070243', (0, 3))	('knockdown', 'Var', (36, 45))	('reduced', 'NegReg', (46, 53))	('cell survival', 'CPA', (54, 67))	('A431', 'CellLine', 'CVCL:0037', (71, 75))
94917	33707587	Similarly, TNFAIP8 knockdown also significantly decreased cell colony formation ability in A431 cells by 18.4%, in A375 cells by 53.2%, and in A2058 cells by 40.3% compared with control siRNA transfected cells (Fig.	('A431', 'CellLine', 'CVCL:0037', (91, 95))	('cell colony formation ability', 'CPA', (58, 87))	('knockdown', 'Var', (19, 28))	('decreased', 'NegReg', (48, 57))	('A2058', 'CellLine', 'CVCL:1059', (143, 148))	('A375', 'CellLine', 'CVCL:0132', (115, 119))	('TNFAIP8', 'Gene', (11, 18))
94919	33707587	Also, we evaluated the effect of TNFAIP8 knockdown on skin cancer cell migration using wound healing migration assay.	('skin cancer', 'Disease', (54, 65))	('skin cancer', 'Disease', 'MESH:D012878', (54, 65))	('TNFAIP8', 'Gene', (33, 40))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('skin cancer', 'Phenotype', 'HP:0008069', (54, 65))	('knockdown', 'Var', (41, 50))
94920	33707587	The wound healing migration assay revealed that TNFAIP8 knockdown significantly inhibited cell migration and wound closure in A431 (15.1%), A375 (52.5%), and A2058 (70.4%) compared with control siRNA transfected cells (Fig.	('TNFAIP8', 'Gene', (48, 55))	('A375', 'CellLine', 'CVCL:0132', (140, 144))	('A2058', 'Var', (158, 163))	('wound closure', 'CPA', (109, 122))	('A431', 'CellLine', 'CVCL:0037', (126, 130))	('cell migration', 'CPA', (90, 104))	('A2058', 'CellLine', 'CVCL:1059', (158, 163))	('inhibited', 'NegReg', (80, 89))	('knockdown', 'Var', (56, 65))
94924	33707587	In a previous study, it was reported that miR-205-5p targets the 3'-UTR of either transcription factor E2F1 or transcription factor E2F5 and suppresses the cell proliferation in melanoma cells.	('up', 'Gene', '7378', (142, 144))	('melanoma', 'Phenotype', 'HP:0002861', (178, 186))	('melanoma', 'Disease', (178, 186))	('E2F5', 'Gene', (132, 136))	('miR-205-5p', 'Chemical', '-', (42, 52))	('melanoma', 'Disease', 'MESH:D008545', (178, 186))	('miR-205-5p', 'Var', (42, 52))	('E2F1', 'Gene', '100036852', (103, 107))	('E2F1', 'Gene', (103, 107))
94926	33707587	TargetScan analysis revealed that miR-205-5p is predicted to bind with the 3' UTR of TNFAIP8 gene (61-68) (Fig.	('TNFAIP8', 'Gene', (85, 92))	('bind', 'Interaction', (61, 65))	('miR-205-5p', 'Var', (34, 44))	('miR-205-5p', 'Chemical', '-', (34, 44))
94930	33707587	A431 and A2058 cells were co-transfected with TNFAIP8-3'UTR-Luc plasmid for 18 h and then cells were transfected miR-205-5p mimic or mutant miR-205-5p mimic for 30 h and luciferase activity was determined.	('A431', 'CellLine', 'CVCL:0037', (0, 4))	('miR-205-5p', 'Chemical', '-', (140, 150))	('miR-205-5p', 'Chemical', '-', (113, 123))	("TNFAIP8-3'UTR-Luc", 'Gene', (46, 63))	('miR-205-5p', 'Var', (113, 123))	('mutant', 'Var', (133, 139))	('A2058', 'CellLine', 'CVCL:1059', (9, 14))
94931	33707587	The data showed that the miR-205-5p mimic significantly inhibited luciferase activity compared with negative control (NC) or mutant miR-205-5p mimic transfected both cell lines (Fig.	('miR-205-5p', 'Chemical', '-', (132, 142))	('mutant', 'Var', (125, 131))	('miR-205-5p', 'Chemical', '-', (25, 35))	('activity', 'MPA', (77, 85))	('inhibited', 'NegReg', (56, 65))	('luciferase', 'Enzyme', (66, 76))
94932	33707587	These results support the model where the miR-205-5p mimic binds with the TNFAIP8-3'UTR.	('binds', 'Interaction', (59, 64))	('miR-205-5p mimic', 'Var', (42, 58))	("TNFAIP8-3'UTR", 'Gene', (74, 87))	('miR-205-5p', 'Chemical', '-', (42, 52))	('up', 'Gene', '7378', (15, 17))
94933	33707587	To determine whether the miR-205-5p mimic represses the endogenous expression of TNFAIP8 mRNA and protein, we transfected normal HaCaT cells, A431 (SCC) and A2058 melanoma cells with miR-205-5p mimic or negative control (NC).	('represses', 'NegReg', (42, 51))	('melanoma', 'Disease', 'MESH:D008545', (163, 171))	('HaCaT', 'CellLine', 'CVCL:0038', (129, 134))	('miR-205-5p mimic', 'Var', (183, 199))	('melanoma', 'Disease', (163, 171))	('A2058', 'CellLine', 'CVCL:1059', (157, 162))	('endogenous', 'MPA', (56, 66))	('A431', 'CellLine', 'CVCL:0037', (142, 146))	('TNFAIP8', 'Gene', (81, 88))	('melanoma', 'Phenotype', 'HP:0002861', (163, 171))	('SCC', 'Phenotype', 'HP:0002860', (148, 151))	('miR-205-5p', 'Chemical', '-', (25, 35))	('miR-205-5p', 'Chemical', '-', (183, 193))
94936	33707587	We also performed immunocytochemistry and analyzed endogenous TNFAIP8 protein expression by immunofluorescence after delivery of Cy3 labeled miR-205-5p or Cy3 labeled NC mimic into HaCaT, A431 and A2058 cells (Fig.	('Cy3', 'Var', (155, 158))	('A2058', 'CellLine', 'CVCL:1059', (197, 202))	('Cy3', 'Chemical', '-', (129, 132))	('Cy3', 'Chemical', '-', (155, 158))	('HaCaT', 'CellLine', 'CVCL:0038', (181, 186))	('miR-205-5p', 'Chemical', '-', (141, 151))	('TNFAIP8', 'Gene', (62, 69))	('A431', 'CellLine', 'CVCL:0037', (188, 192))	('Cy3', 'Var', (129, 132))
94937	33707587	TNFAIP8 immunofluorescence data suggest that transfection of Cy3-miR-205-5p in all three cell lines decreased cytosolic TNFAIP8-associated fluorescence (merge panel) compared with Cy3-labeled-NC mimic transfected cells (Fig.	('Cy3', 'Chemical', '-', (180, 183))	('Cy3-miR-205-5p', 'Var', (61, 75))	('TNFAIP8-associated', 'Gene', (120, 138))	('cytosolic', 'MPA', (110, 119))	('Cy3', 'Chemical', '-', (61, 64))	('decreased', 'NegReg', (100, 109))	('miR-205-5p', 'Chemical', '-', (65, 75))
94938	33707587	4G) suggesting that miR-205-5p targets the TNFAIP8-3'UTR and inhibits TNFAIP8 protein expression.	("TNFAIP8-3'UTR", 'Gene', (43, 56))	('miR-205-5p', 'Chemical', '-', (20, 30))	('miR-205-5p', 'Var', (20, 30))	('TNFAIP8', 'Gene', (70, 77))	('protein', 'Protein', (78, 85))	('inhibits', 'NegReg', (61, 69))
94939	33707587	Since miR-205-5p inhibits TNFAIP8 expression and TNFAIP8 promotes cell proliferation in skin cancer cells, we further examined the role of miR-205-5p mimic in the regulation of skin cancer cell survival/cell colony formation.	('inhibits', 'NegReg', (17, 25))	('miR-205-5p', 'Chemical', '-', (139, 149))	('miR-205-5p', 'Var', (6, 16))	('skin cancer', 'Disease', (88, 99))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('expression', 'MPA', (34, 44))	('skin cancer', 'Disease', 'MESH:D012878', (177, 188))	('cell proliferation', 'CPA', (66, 84))	('skin cancer', 'Disease', 'MESH:D012878', (88, 99))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('TNFAIP8', 'Gene', (26, 33))	('TNFAIP8', 'Gene', (49, 56))	('miR-205-5p', 'Chemical', '-', (6, 16))	('skin cancer', 'Phenotype', 'HP:0008069', (177, 188))	('skin cancer', 'Phenotype', 'HP:0008069', (88, 99))	('skin cancer', 'Disease', (177, 188))	('promotes', 'PosReg', (57, 65))
94940	33707587	No significant effect on cell proliferation/survival was observed in HaCaT cells transfected of miR-205-5p or the NC mimic control, however, a significant decrease in cell proliferation was observed in A431 and A2058 cell lines (Fig.	('A431', 'CellLine', 'CVCL:0037', (202, 206))	('miR-205-5p', 'Var', (96, 106))	('A2058', 'CellLine', 'CVCL:1059', (211, 216))	('decrease', 'NegReg', (155, 163))	('HaCaT', 'CellLine', 'CVCL:0038', (69, 74))	('miR-205-5p', 'Chemical', '-', (96, 106))	('cell proliferation', 'CPA', (167, 185))
94942	33707587	Similar to the effects were seen in the cell survival assay, transfection with miR-205-5p mimic or the NC mimic control did not affect cell colony formation in HaCaT cells (Fig.	('cell colony formation', 'CPA', (135, 156))	('miR-205-5p', 'Chemical', '-', (79, 89))	('miR-205-5p mimic', 'Var', (79, 95))	('HaCaT', 'CellLine', 'CVCL:0038', (160, 165))
94943	33707587	Interestingly, cell colony formation was decreased by 32.5% in A431 cells and 38.5% in A2058 cells when cells were transfected with miR-205-5p compared with NC transfected cells (Fig.	('miR-205-5p', 'Chemical', '-', (132, 142))	('decreased', 'NegReg', (41, 50))	('miR-205-5p', 'Var', (132, 142))	('A431', 'CellLine', 'CVCL:0037', (63, 67))	('A2058', 'CellLine', 'CVCL:1059', (87, 92))	('cell colony formation', 'CPA', (15, 36))
94946	33707587	Conversely, inhibition of TNFAIP8 expression by miR-205-5p mimic decreased autophagy biomarkers LC3beta II and p62 expression in A431 and A2058 cells compared with NC mimic control transfected cells (Fig.	('LC3beta', 'Gene', (96, 103))	('expression', 'MPA', (34, 44))	('inhibition', 'NegReg', (12, 22))	('decreased', 'NegReg', (65, 74))	('TNFAIP8', 'Gene', (26, 33))	('p62', 'Gene', '23636', (111, 114))	('A2058', 'CellLine', 'CVCL:1059', (138, 143))	('expression', 'MPA', (115, 125))	('LC3beta', 'Gene', '84557', (96, 103))	('miR-205-5p', 'Chemical', '-', (48, 58))	('p62', 'Gene', (111, 114))	('autophagy', 'CPA', (75, 84))	('A431', 'CellLine', 'CVCL:0037', (129, 133))	('miR-205-5p', 'Var', (48, 58))
94948	33707587	Immunocytochemistry data showed that miR-205-5p mimic transfection significantly decreased LC3beta related puncta formation in A431 and A2058 cells as well as in HaCaT cells (Fig.	('decreased', 'NegReg', (81, 90))	('LC3beta', 'Gene', '84557', (91, 98))	('miR-205-5p', 'Chemical', '-', (37, 47))	('A2058', 'CellLine', 'CVCL:1059', (136, 141))	('LC3beta', 'Gene', (91, 98))	('HaCaT', 'CellLine', 'CVCL:0038', (162, 167))	('miR-205-5p mimic', 'Var', (37, 53))	('A431', 'CellLine', 'CVCL:0037', (127, 131))
94949	33707587	5E, upper and lower panels) suggesting that miR-205-5p inhibits cell proliferation and TNFAIP8-mediated autophagy induction in skin cancer cells.	('skin cancer', 'Phenotype', 'HP:0008069', (127, 138))	('up', 'Gene', '7378', (4, 6))	('cell proliferation', 'CPA', (64, 82))	('skin cancer', 'Disease', (127, 138))	('inhibits', 'NegReg', (55, 63))	('skin cancer', 'Disease', 'MESH:D012878', (127, 138))	('miR-205-5p', 'Chemical', '-', (44, 54))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('TNFAIP8-mediated', 'Gene', (87, 103))	('miR-205-5p', 'Var', (44, 54))
94951	33707587	We treated HaCaT and SK-MEL-2 cells which possess wild type B-RAF protein, and A375 and A2058 cells which express mutant B-RAFV600E with vemurafenib and relative drug sensitivity were analyzed by cell survival MTT assay (Fig.	('B-RAF', 'Gene', '673', (60, 65))	('A2058', 'CellLine', 'CVCL:1059', (88, 93))	('A375', 'CellLine', 'CVCL:0132', (79, 83))	('B-RAF', 'Gene', (60, 65))	('mutant', 'Var', (114, 120))	('B-RAF', 'Gene', '673', (121, 126))	('MTT', 'Chemical', 'MESH:C070243', (210, 213))	('HaCaT', 'CellLine', 'CVCL:0038', (11, 16))	('SK-MEL-2', 'CellLine', 'CVCL:0069', (21, 29))	('B-RAF', 'Gene', (121, 126))	('drug sensitivity', 'Phenotype', 'HP:0020174', (162, 178))	('vemurafenib', 'Chemical', 'MESH:D000077484', (137, 148))
94955	33707587	We transfected normal and skin cancer cells with miR-205-5p and treated with vemurafenib as indicated and relative drug sensitivity was analyzed (Fig.	('skin cancer', 'Disease', (26, 37))	('skin cancer', 'Disease', 'MESH:D012878', (26, 37))	('miR-205-5p', 'Var', (49, 59))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('miR-205-5p', 'Chemical', '-', (49, 59))	('skin cancer', 'Phenotype', 'HP:0008069', (26, 37))	('vemurafenib', 'Chemical', 'MESH:D000077484', (77, 88))	('drug sensitivity', 'Phenotype', 'HP:0020174', (115, 131))
94956	33707587	Compared with control NC mimic transfected cells, miR-205-5p transfection alone decreased cell survival in A375, and A2058 cells but not in HaCaT or SK-MEL-2 cells significantly (Fig.	('miR-205-5p transfection', 'Var', (50, 73))	('miR-205-5p', 'Chemical', '-', (50, 60))	('A2058', 'Var', (117, 122))	('transfection', 'Var', (61, 73))	('SK-MEL-2', 'CellLine', 'CVCL:0069', (149, 157))	('HaCaT', 'CellLine', 'CVCL:0038', (140, 145))	('A375', 'CellLine', 'CVCL:0132', (107, 111))	('cell survival', 'CPA', (90, 103))	('decreased', 'NegReg', (80, 89))	('A2058', 'CellLine', 'CVCL:1059', (117, 122))
94957	33707587	Transfection with miR-205-5p and treatment with vemurafenib further decreased cell survival compared with vemurafenib alone in skin cancer lines SK-MEL-2, A375, and A2058 cells (Fig.	('decreased', 'NegReg', (68, 77))	('skin cancer', 'Phenotype', 'HP:0008069', (127, 138))	('miR-205-5p', 'Var', (18, 28))	('miR-205-5p', 'Chemical', '-', (18, 28))	('SK-MEL-2', 'CellLine', 'CVCL:0069', (145, 153))	('skin cancer', 'Disease', (127, 138))	('vemurafenib', 'Chemical', 'MESH:D000077484', (48, 59))	('skin cancer', 'Disease', 'MESH:D012878', (127, 138))	('A375', 'CellLine', 'CVCL:0132', (155, 159))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('A2058', 'CellLine', 'CVCL:1059', (165, 170))	('cell survival', 'CPA', (78, 91))	('vemurafenib', 'Chemical', 'MESH:D000077484', (106, 117))
94958	33707587	Interestingly, the data also indicated that B-RAFV600E mutant cell lines A375 and A2058 showed increased sensitivity to vemurafenib treatment after transfection with miR-205-5p compared with B-RAF wild protein-expressing cell lines.	('A2058', 'CellLine', 'CVCL:1059', (82, 87))	('miR-205-5p', 'Chemical', '-', (166, 176))	('B-RAF', 'Gene', (191, 196))	('miR-205-5p', 'Var', (166, 176))	('B-RAF', 'Gene', (44, 49))	('A375', 'CellLine', 'CVCL:0132', (73, 77))	('increased', 'PosReg', (95, 104))	('B-RAF', 'Gene', '673', (44, 49))	('vemurafenib', 'Chemical', 'MESH:D000077484', (120, 131))	('B-RAF', 'Gene', '673', (191, 196))	('sensitivity', 'MPA', (105, 116))
94959	33707587	Thus, by targeting TNFAIP8, miR-205-5p could further increase drug sensitivity in the B-RAFV600E mutant melanoma cell lines (Fig.	('melanoma', 'Phenotype', 'HP:0002861', (104, 112))	('drug sensitivity', 'Phenotype', 'HP:0020174', (62, 78))	('melanoma', 'Disease', (104, 112))	('drug sensitivity', 'MPA', (62, 78))	('melanoma', 'Disease', 'MESH:D008545', (104, 112))	('TNFAIP8', 'Gene', (19, 26))	('mutant', 'Var', (97, 103))	('increase', 'PosReg', (53, 61))	('B-RAF', 'Gene', '673', (86, 91))	('miR-205-5p', 'Chemical', '-', (28, 38))	('B-RAF', 'Gene', (86, 91))	('miR-205-5p', 'Var', (28, 38))	('targeting', 'Reg', (9, 18))
94960	33707587	Moreover, transfection of miR-205-5p in A375 (B-RAFV600E mutant) cells induced the expression of cell apoptotic marker cPARP compared with NC mimic transfected cells (Fig.	('PARP', 'Gene', (120, 124))	('miR-205-5p', 'Chemical', '-', (26, 36))	('miR-205-5p', 'Var', (26, 36))	('A375', 'CellLine', 'CVCL:0132', (40, 44))	('expression', 'MPA', (83, 93))	('B-RAF', 'Gene', '673', (46, 51))	('induced', 'PosReg', (71, 78))	('B-RAF', 'Gene', (46, 51))	('PARP', 'Gene', '1302', (120, 124))
94961	33707587	Furthermore, transfection of miR-205-5p combined with vemurafenib treatment increased cPARP expression compared with NC mimic transfected and vemurafenib treated cells (Fig.	('miR-205-5p', 'Chemical', '-', (29, 39))	('PARP', 'Gene', '1302', (87, 91))	('increased', 'PosReg', (76, 85))	('miR-205-5p', 'Var', (29, 39))	('PARP', 'Gene', (87, 91))	('vemurafenib', 'Chemical', 'MESH:D000077484', (142, 153))	('vemurafenib', 'Chemical', 'MESH:D000077484', (54, 65))
94964	33707587	A higher expression of TNFAIP8, autophagy marker LB3beta II, and increased cell proliferation were observed in A375R or A2058R vemurafenib drug-resistant cells compared with parent A375 or A2058 melanoma cells (Fig.	('A2058R', 'Var', (120, 126))	('TNFAIP8', 'Gene', (23, 30))	('expression', 'MPA', (9, 19))	('autophagy', 'CPA', (32, 41))	('melanoma', 'Disease', 'MESH:D008545', (195, 203))	('A2058R', 'Mutation', 'p.A2058R', (120, 126))	('increased', 'PosReg', (65, 74))	('vemurafenib', 'Chemical', 'MESH:D000077484', (127, 138))	('A375R', 'Mutation', 'p.A375R', (111, 116))	('A2058', 'CellLine', 'CVCL:1059', (120, 125))	('A375', 'CellLine', 'CVCL:0132', (111, 115))	('melanoma', 'Phenotype', 'HP:0002861', (195, 203))	('melanoma', 'Disease', (195, 203))	('A375R', 'Var', (111, 116))	('higher', 'PosReg', (2, 8))	('A375', 'CellLine', 'CVCL:0132', (181, 185))	('A2058', 'CellLine', 'CVCL:1059', (189, 194))	('vemurafenib', 'Gene', (127, 138))	('cell proliferation', 'CPA', (75, 93))
94965	33707587	6 suggest that (A) expression of miR-205-5p in melanoma cells increases sensitivity towards vemurafenib particularly in B-RAFV600E mutant cells (B) increased expression of TNFAIP8 reduces drug-mediated cell apoptosis, and (C) increased expression of TNFAIP8 due to vemurafenib drug-resistance increases autophagy and cell proliferation.	('vemurafenib', 'Chemical', 'MESH:D000077484', (265, 276))	('TNFAIP8', 'Gene', (172, 179))	('increased', 'PosReg', (226, 235))	('drug-mediated cell apoptosis', 'CPA', (188, 216))	('B-RAF', 'Gene', '673', (120, 125))	('cell proliferation', 'CPA', (317, 335))	('TNFAIP8', 'Gene', (250, 257))	('miR-205-5p', 'Var', (33, 43))	('melanoma', 'Phenotype', 'HP:0002861', (47, 55))	('melanoma', 'Disease', (47, 55))	('B-RAF', 'Gene', (120, 125))	('expression', 'MPA', (236, 246))	('drug-resistance', 'Phenotype', 'HP:0020174', (277, 292))	('miR-205-5p', 'Chemical', '-', (33, 43))	('autophagy', 'CPA', (303, 312))	('increases', 'PosReg', (62, 71))	('mutant', 'Var', (131, 137))	('increases', 'PosReg', (293, 302))	('reduces', 'NegReg', (180, 187))	('melanoma', 'Disease', 'MESH:D008545', (47, 55))	('sensitivity towards vemurafenib', 'MPA', (72, 103))	('vemurafenib', 'Chemical', 'MESH:D000077484', (92, 103))
94966	33707587	Indeed, our data suggest that TNFAIP8 might be involved in drug resistance in melanoma cell lines by inducing autophagy as reported in prostate and liver cancer cell lines previously, whereas miR-205-5p controls TNFAIP8/autophagy axis and increased sensitivity towards skin cancer drug vemurafenib.	('TNFAIP8', 'Gene', (30, 37))	('sensitivity towards', 'MPA', (249, 268))	('liver cancer', 'Phenotype', 'HP:0002896', (148, 160))	('liver cancer', 'Disease', (148, 160))	('skin cancer', 'Disease', 'MESH:D012878', (269, 280))	('autophagy', 'CPA', (110, 119))	('drug resistance', 'Phenotype', 'HP:0020174', (59, 74))	('melanoma', 'Phenotype', 'HP:0002861', (78, 86))	('melanoma', 'Disease', (78, 86))	('miR-205-5p', 'Var', (192, 202))	('involved', 'Reg', (47, 55))	('vemurafenib', 'Chemical', 'MESH:D000077484', (286, 297))	('controls', 'NegReg', (203, 211))	('increased', 'PosReg', (239, 248))	('skin cancer', 'Disease', (269, 280))	('miR-205-5p', 'Chemical', '-', (192, 202))	('inducing', 'PosReg', (101, 109))	('melanoma', 'Disease', 'MESH:D008545', (78, 86))	('liver cancer', 'Disease', 'MESH:D006528', (148, 160))	('skin cancer', 'Phenotype', 'HP:0008069', (269, 280))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('cancer', 'Phenotype', 'HP:0002664', (274, 280))	('TNFAIP8/autophagy', 'Gene', (212, 229))
94971	33707587	Similarly, overexpression or knockdown of TNFAIP8 affected cell proliferation in skin cancer cell lines.	('TNFAIP8', 'Gene', (42, 49))	('skin cancer', 'Disease', (81, 92))	('skin cancer', 'Phenotype', 'HP:0008069', (81, 92))	('knockdown', 'Var', (29, 38))	('skin cancer', 'Disease', 'MESH:D012878', (81, 92))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('affected', 'Reg', (50, 58))
94973	33707587	Our preliminary data indicate that TNFAIP8 expression is downregulated in B-RAFV600E mutant A375, A2058 melanoma cells compared with A431, SK-MEL-2, or normal HaCaT cells which express wild-type B-RAF kinase.	('melanoma', 'Phenotype', 'HP:0002861', (104, 112))	('downregulated', 'NegReg', (57, 70))	('melanoma', 'Disease', (104, 112))	('B-RAF', 'Gene', (74, 79))	('B-RAF', 'Gene', '673', (195, 200))	('A2058', 'CellLine', 'CVCL:1059', (98, 103))	('melanoma', 'Disease', 'MESH:D008545', (104, 112))	('SK-MEL-2', 'CellLine', 'CVCL:0069', (139, 147))	('B-RAF', 'Gene', (195, 200))	('B-RAF', 'Gene', '673', (74, 79))	('mutant', 'Var', (85, 91))	('expression', 'MPA', (43, 53))	('A375', 'CellLine', 'CVCL:0132', (92, 96))	('TNFAIP8', 'Gene', (35, 42))	('A431', 'CellLine', 'CVCL:0037', (133, 137))	('HaCaT', 'CellLine', 'CVCL:0038', (159, 164))
94977	33707587	We found that melanoma cell lines show undetectable levels of miR-205-5p expression as well as higher expression of TNFAIP8 in SK-MEL-2 melanoma cells and melanoma tissue.	('melanoma', 'Disease', (14, 22))	('melanoma', 'Disease', 'MESH:D008545', (155, 163))	('miR-205-5p', 'Var', (62, 72))	('melanoma', 'Phenotype', 'HP:0002861', (155, 163))	('expression', 'MPA', (102, 112))	('higher', 'PosReg', (95, 101))	('melanoma', 'Disease', 'MESH:D008545', (136, 144))	('miR-205-5p', 'Chemical', '-', (62, 72))	('TNFAIP8', 'Gene', (116, 123))	('melanoma', 'Disease', (136, 144))	('melanoma', 'Disease', 'MESH:D008545', (14, 22))	('SK-MEL-2', 'CellLine', 'CVCL:0069', (127, 135))	('melanoma', 'Phenotype', 'HP:0002861', (136, 144))	('melanoma', 'Disease', (155, 163))	('melanoma', 'Phenotype', 'HP:0002861', (14, 22))
94978	33707587	Further, we demonstrated that miR-205-5p binds with the 3'UTR of TNFAIP8 gene and inhibits TNFAIP8 expression and TNFAIP8-mediated autophagy in skin cancer cells.	('expression', 'MPA', (99, 109))	('skin cancer', 'Disease', (144, 155))	('skin cancer', 'Phenotype', 'HP:0008069', (144, 155))	('binds', 'Interaction', (41, 46))	('TNFAIP8', 'Gene', (91, 98))	('miR-205-5p', 'Chemical', '-', (30, 40))	('skin cancer', 'Disease', 'MESH:D012878', (144, 155))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('miR-205-5p', 'Var', (30, 40))	('TNFAIP8', 'Gene', (65, 72))	('inhibits', 'NegReg', (82, 90))
94983	33707587	We also showed that inhibition on TNFAIP8 by expression of miR-205-5p drastically decreased vemurafenib-mediated cell proliferation in melanoma cell lines.	('miR-205-5p', 'Var', (59, 69))	('melanoma', 'Disease', 'MESH:D008545', (135, 143))	('melanoma', 'Phenotype', 'HP:0002861', (135, 143))	('melanoma', 'Disease', (135, 143))	('inhibition', 'NegReg', (20, 30))	('miR-205-5p', 'Chemical', '-', (59, 69))	('TNFAIP8', 'Gene', (34, 41))	('vemurafenib-mediated cell', 'MPA', (92, 117))	('decreased', 'NegReg', (82, 91))	('vemurafenib', 'Chemical', 'MESH:D000077484', (92, 103))
94989	33707587	Since disruption of the p53 pathway was reported in melanoma, and recently the role of TNFAIP8 in p53 signaling was analyzed in lung cancer cells and the study revealed that TNFAIP8 variant 2 (v2) represses tumor suppressor wild-type p53 function in lung cancer A549 cells.	('p53', 'Gene', (234, 237))	('lung cancer', 'Phenotype', 'HP:0100526', (250, 261))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('p53', 'Gene', (98, 101))	('represses', 'NegReg', (197, 206))	('function', 'MPA', (238, 246))	('cancer', 'Phenotype', 'HP:0002664', (255, 261))	('p53', 'Gene', '7157', (24, 27))	('lung cancer', 'Disease', 'MESH:D008175', (128, 139))	('up', 'Gene', '7378', (10, 12))	('melanoma', 'Disease', 'MESH:D008545', (52, 60))	('A549', 'CellLine', 'CVCL:0023', (262, 266))	('up', 'Gene', '7378', (214, 216))	('lung cancer', 'Phenotype', 'HP:0100526', (128, 139))	('variant', 'Var', (182, 189))	('lung cancer', 'Disease', (250, 261))	('p53', 'Gene', (24, 27))	('tumor', 'Disease', (207, 212))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('p53', 'Gene', '7157', (234, 237))	('melanoma', 'Phenotype', 'HP:0002861', (52, 60))	('melanoma', 'Disease', (52, 60))	('lung cancer', 'Disease', 'MESH:D008175', (250, 261))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('lung cancer', 'Disease', (128, 139))	('TNFAIP8', 'Gene', (174, 181))	('p53', 'Gene', '7157', (98, 101))
94990	33707587	Silencing of TNFAIP8 v2 induces p53-independent inhibition of DNA synthesis, widespread p53 binding, the initiation of p53-dependent cell-cycle arrest, and the sensitization of cells to doxorubicin.	('binding', 'Interaction', (92, 99))	('doxorubicin', 'Chemical', 'MESH:D004317', (186, 197))	('inhibition', 'NegReg', (48, 58))	('sensitization', 'CPA', (160, 173))	('Silencing', 'Var', (0, 9))	('p53', 'Gene', '7157', (119, 122))	('p53', 'Gene', (32, 35))	('p53', 'Gene', (88, 91))	('p53', 'Gene', '7157', (32, 35))	('p53', 'Gene', '7157', (88, 91))	('TNFAIP8 v2', 'Gene', (13, 23))	('arrest', 'Disease', 'MESH:D006323', (144, 150))	('p53', 'Gene', (119, 122))	('DNA synthesis', 'MPA', (62, 75))	('arrest', 'Disease', (144, 150))
94991	33707587	Mutant p53 (p53-K120) binds the TNFAIP8 locus at a cryptic p53 response element that is not occupied or bound by wild-type p53 and thus increases TNFAIP8 expression, which promotes lung cancer cell survival/proliferation.	('p53', 'Gene', (59, 62))	('p53', 'Gene', '7157', (7, 10))	('lung cancer', 'Disease', (181, 192))	('promotes', 'PosReg', (172, 180))	('up', 'Gene', '7378', (95, 97))	('p53', 'Gene', (7, 10))	('increases', 'PosReg', (136, 145))	('TNFAIP8', 'Gene', (146, 153))	('survival/proliferation', 'CPA', (198, 220))	('p53', 'Gene', '7157', (12, 15))	('Mutant', 'Var', (0, 6))	('p53', 'Gene', '7157', (123, 126))	('lung cancer', 'Disease', 'MESH:D008175', (181, 192))	('p53', 'Gene', '7157', (59, 62))	('TNFAIP8', 'Gene', (32, 39))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('p53', 'Gene', (12, 15))	('lung cancer', 'Phenotype', 'HP:0100526', (181, 192))	('p53', 'Gene', (123, 126))	('expression', 'MPA', (154, 164))
94995	33707587	Interestingly, we also demonstrated that the expression of miR-205-5p controls the expression of TNFAIP8 and sensitizes melanoma cells to the B-RAFV600E mutant kinase inhibitor vemurafenib.	('miR-205-5p', 'Var', (59, 69))	('TNFAIP8', 'Gene', (97, 104))	('B-RAF', 'Gene', '673', (142, 147))	('controls', 'Reg', (70, 78))	('melanoma', 'Phenotype', 'HP:0002861', (120, 128))	('melanoma', 'Disease', (120, 128))	('sensitizes', 'Reg', (109, 119))	('vemurafenib', 'Chemical', 'MESH:D000077484', (177, 188))	('expression', 'MPA', (83, 93))	('miR-205-5p', 'Chemical', '-', (59, 69))	('B-RAF', 'Gene', (142, 147))	('melanoma', 'Disease', 'MESH:D008545', (120, 128))
95011	33707587	The membranes were blocked in 1X blocking buffer (Sigma-Aldrich, St. Louis, MO) and incubated with primary antibodies overnight at 4  C. The following antibodies were obtained from Cell Signaling Technology (Danvers, MA): anti-B-RAF, anti-LC3beta I/II, anti-p62, anti-Myc tag, anti-Cleaved-PARP, anti-beta-tubulin, and anti-GAPDH.	('anti-beta-tubulin', 'Var', (296, 313))	('PARP', 'Gene', (290, 294))	('LC3beta', 'Gene', '84557', (239, 246))	('PARP', 'Gene', '1302', (290, 294))	('p62', 'Gene', '23636', (258, 261))	('B-RAF', 'Gene', '673', (227, 232))	('GAPDH', 'Gene', '2597', (324, 329))	('GAPDH', 'Gene', (324, 329))	('p62', 'Gene', (258, 261))	('Myc', 'Gene', '4609', (268, 271))	('B-RAF', 'Gene', (227, 232))	('Myc', 'Gene', (268, 271))	('LC3beta', 'Gene', (239, 246))
95033	33707587	Skin cancer A431, A375, A2058, and normal skin HaCaT cells were (1 x 105 cells/well) were grown in six plates for 18 h and cells were transiently transfected with TNFAIP8-Myc plasmid or empty-vector (EV) (2 microg/well in 6-well plates), or TNFAIP8 siRNA or control siRNA as indicated in different figures.	('Myc', 'Gene', '4609', (171, 174))	('Myc', 'Gene', (171, 174))	('HaCaT', 'CellLine', 'CVCL:0038', (47, 52))	('A375', 'CellLine', 'CVCL:0132', (18, 22))	('A2058', 'CellLine', 'CVCL:1059', (24, 29))	('Skin cancer', 'Disease', (0, 11))	('Skin cancer', 'Phenotype', 'HP:0008069', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))	('Skin cancer', 'Disease', 'MESH:D012878', (0, 11))	('A431', 'CellLine', 'CVCL:0037', (12, 16))	('TNFAIP8', 'Var', (241, 248))
95148	32113465	The typical PIOC, NOS case had many histopathological similarities to oral squamous cell carcinoma (OSCC), including the missense point mutations of TP53 Glu285Val, KDR Gln472His, and APC Pro1433Leu, which are similar to those in other cancers; however, no mutations were detected in the other patient with an atypical presentation of PIOC, NOS, which was derived from a precursor cystic lesion with similarities to both ameloblastic carcinoma and OSCC.	('APC', 'Disease', (184, 187))	('missense point mutations', 'Var', (121, 145))	('KDR', 'Gene', (165, 168))	('ameloblastic carcinoma', 'Disease', 'MESH:D009810', (421, 443))	('cystic lesion', 'Disease', 'MESH:D052177', (381, 394))	('cancers', 'Disease', 'MESH:D009369', (236, 243))	('TP53', 'Gene', (149, 153))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('squamous cell carcinoma', 'Disease', (75, 98))	('Gln472His', 'SUBSTITUTION', 'None', (169, 178))	('patient', 'Species', '9606', (294, 301))	('Glu285Val', 'Var', (154, 163))	('ameloblastic carcinoma', 'Disease', (421, 443))	('PIOC', 'Disease', (12, 16))	('KDR', 'Gene', '3791', (165, 168))	('PIOC', 'Disease', 'MESH:C564648', (12, 16))	('Glu285Val', 'SUBSTITUTION', 'None', (154, 163))	('cancers', 'Phenotype', 'HP:0002664', (236, 243))	('Pro1433Leu', 'SUBSTITUTION', 'None', (188, 198))	('carcinoma', 'Phenotype', 'HP:0030731', (434, 443))	('cancers', 'Disease', (236, 243))	('TP53', 'Gene', '7157', (149, 153))	('Pro1433Leu', 'Var', (188, 198))	('Gln472His', 'Var', (169, 178))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (75, 98))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('PIOC', 'Disease', (335, 339))	('PIOC', 'Disease', 'MESH:C564648', (335, 339))	('cystic lesion', 'Disease', (381, 394))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (75, 98))	('APC', 'Disease', 'MESH:D011125', (184, 187))
95155	32113465	Recent studies using next-generation sequencing (NGS) revealed several gene mutations in odontogenic tumors, including ameloblastoma; however, mutations in PIOC, NOS remain unclear because of the low incidence of this tumor.	('PIOC', 'Disease', (156, 160))	('mutations', 'Var', (76, 85))	('ameloblastoma', 'Disease', (119, 132))	('ameloblastoma', 'Disease', 'MESH:D000564', (119, 132))	('tumor', 'Disease', 'MESH:D009369', (218, 223))	('tumor', 'Disease', (101, 106))	('odontogenic tumors', 'Disease', 'MESH:D009808', (89, 107))	('odontogenic tumor', 'Phenotype', 'HP:0100612', (89, 106))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('PIOC', 'Disease', 'MESH:C564648', (156, 160))	('odontogenic tumors', 'Disease', (89, 107))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('tumor', 'Disease', (218, 223))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('odontogenic tumors', 'Phenotype', 'HP:0100612', (89, 107))
95184	32113465	We analyzed mutations in hotspot regions in 50 genes commonly associated with cancer by targeted NGS in specimens from these two PIOC, NOS patients.	('patients', 'Species', '9606', (139, 147))	('mutations', 'Var', (12, 21))	('PIOC', 'Disease', (129, 133))	('cancer', 'Disease', (78, 84))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('PIOC', 'Disease', 'MESH:C564648', (129, 133))
95189	32113465	In contrast, missense point mutations in TP53 Glu285Val, KDR Gln472His, and APC Pro1433Leu were noted in case 2.	('TP53', 'Gene', '7157', (41, 45))	('APC', 'Disease', 'MESH:D011125', (76, 79))	('TP53', 'Gene', (41, 45))	('Gln472His', 'SUBSTITUTION', 'None', (61, 70))	('KDR', 'Gene', '3791', (57, 60))	('Glu285Val', 'SUBSTITUTION', 'None', (46, 55))	('Gln472His', 'Var', (61, 70))	('Pro1433Leu', 'SUBSTITUTION', 'None', (80, 90))	('Glu285Val', 'Var', (46, 55))	('APC', 'Disease', (76, 79))	('Pro1433Leu', 'Var', (80, 90))	('KDR', 'Gene', (57, 60))
95190	32113465	The BRAF Val600Glu mutation was found in the patient with ameloblastoma (case 3).	('ameloblastoma', 'Disease', (58, 71))	('ameloblastoma', 'Disease', 'MESH:D000564', (58, 71))	('Val600Glu', 'SUBSTITUTION', 'None', (9, 18))	('patient', 'Species', '9606', (45, 52))	('Val600Glu', 'Var', (9, 18))	('BRAF', 'Gene', (4, 8))	('BRAF', 'Gene', '673', (4, 8))
95195	32113465	In the head and neck region, BRAF gene mutations are detected at a high frequency in ameloblastomas, and this was also confirmed not only by genetic analysis but also by immunohistochemistry using a BRAF V600E-mutant specific antibody.	('BRAF', 'Gene', '673', (29, 33))	('ameloblastomas', 'Disease', 'MESH:D000564', (85, 99))	('V600E', 'Mutation', 'rs113488022', (204, 209))	('BRAF', 'Gene', (29, 33))	('mutations', 'Var', (39, 48))	('BRAF', 'Gene', (199, 203))	('BRAF', 'Gene', '673', (199, 203))	('ameloblastomas', 'Disease', (85, 99))
95196	32113465	We recently reported that 10 out of 11 patients with calcifying cystic odontogenic tumors (calcifying odontogenic cyst) have mutations in the CTNNB1 gene, while 12 out of 14 patients with ameloblastoma have mutations in the BRAF gene.	('mutations', 'Var', (125, 134))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('CTNNB1', 'Gene', '1499', (142, 148))	('patients', 'Species', '9606', (39, 47))	('odontogenic cyst', 'Phenotype', 'HP:0100612', (102, 118))	('calcifying cystic odontogenic tumors', 'Disease', 'MESH:C537961', (53, 89))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('patients', 'Species', '9606', (174, 182))	('BRAF', 'Gene', (224, 228))	('BRAF', 'Gene', '673', (224, 228))	('odontogenic tumors', 'Phenotype', 'HP:0100612', (71, 89))	('odontogenic tumor', 'Phenotype', 'HP:0100612', (71, 88))	('CTNNB1', 'Gene', (142, 148))	('calcifying cystic odontogenic tumors', 'Disease', (53, 89))	('ameloblastoma', 'Disease', (188, 201))	('ameloblastoma', 'Disease', 'MESH:D000564', (188, 201))
95197	32113465	We also reported a patient with ghost cell odontogenic carcinoma with a mutation in the CTNNB1 gene, suggesting that CTNNB1 gene mutations are one of the common features of lesions accompanied by ghost cell keratinization.	('CTNNB1', 'Gene', '1499', (117, 123))	('patient', 'Species', '9606', (19, 26))	('odontogenic carcinoma', 'Disease', (43, 64))	('carcinoma', 'Phenotype', 'HP:0030731', (55, 64))	('mutations', 'Var', (129, 138))	('odontogenic carcinoma', 'Disease', 'MESH:D018126', (43, 64))	('CTNNB1', 'Gene', '1499', (88, 94))	('CTNNB1', 'Gene', (117, 123))	('odontogenic carcinoma', 'Phenotype', 'HP:0100612', (43, 64))	('mutation', 'Var', (72, 80))	('cell odontogenic carcinoma', 'Phenotype', 'HP:0010603', (38, 64))	('CTNNB1', 'Gene', (88, 94))
95208	32113465	Case 1 did not have any gene mutations, whereas case 2, which had features of OSCC, had mutations in the TP53, KDR, and APC genes.	('APC', 'Disease', 'MESH:D011125', (120, 123))	('mutations', 'Var', (88, 97))	('OSCC', 'Disease', (78, 82))	('KDR', 'Gene', (111, 114))	('APC', 'Disease', (120, 123))	('TP53', 'Gene', '7157', (105, 109))	('TP53', 'Gene', (105, 109))	('KDR', 'Gene', '3791', (111, 114))
95209	32113465	TP53 Glu285Val, which is located in the DNA-binding domain at codon 285 (H2 alpha-helix) of TP53, resulted in a glutamic acid to valine substitution.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('H2 alpha', 'Gene', '8337', (73, 81))	('valine', 'Chemical', 'MESH:D014633', (129, 135))	('glutamic acid', 'Chemical', 'MESH:D018698', (112, 125))	('Glu285Val', 'SUBSTITUTION', 'None', (5, 14))	('TP53', 'Gene', '7157', (92, 96))	('H2 alpha', 'Gene', (73, 81))	('TP53', 'Gene', (92, 96))	('Glu285Val', 'Var', (5, 14))
95210	32113465	reported that functional analyses of TP53 Glu285Val revealed significant defects in its ability to regulate promoter activity, suppress tumor cell growth, and trigger apoptosis, and TP53 Glu285Val efficiently functions as a dominant negative regulator that neutralizes wild-type p53 activity.	('p53', 'Gene', '7157', (279, 282))	('TP53', 'Gene', (182, 186))	('TP53', 'Gene', (37, 41))	('Glu285Val', 'Var', (187, 196))	('promoter activity', 'MPA', (108, 125))	('p53', 'Gene', (279, 282))	('Glu285Val', 'Var', (42, 51))	('Glu285Val', 'SUBSTITUTION', 'None', (187, 196))	('suppress', 'NegReg', (127, 135))	('tumor', 'Disease', (136, 141))	('TP53', 'Gene', '7157', (182, 186))	('ability', 'MPA', (88, 95))	('Glu285Val', 'SUBSTITUTION', 'None', (42, 51))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('TP53', 'Gene', '7157', (37, 41))	('trigger', 'Reg', (159, 166))	('apoptosis', 'CPA', (167, 176))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('defects', 'NegReg', (73, 80))
95211	32113465	TP53 Glu285Val was reported in a pediatric case of adrenocortical carcinoma and choroid plexus carcinoma.	('TP53', 'Gene', '7157', (0, 4))	('carcinoma', 'Phenotype', 'HP:0030731', (66, 75))	('TP53', 'Gene', (0, 4))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (51, 75))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (51, 75))	('choroid plexus carcinoma', 'Disease', (80, 104))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('Glu285Val', 'SUBSTITUTION', 'None', (5, 14))	('choroid plexus carcinoma', 'Phenotype', 'HP:0030392', (80, 104))	('adrenocortical carcinoma', 'Disease', (51, 75))	('Glu285Val', 'Var', (5, 14))	('choroid plexus carcinoma', 'Disease', 'MESH:D020288', (80, 104))
95212	32113465	There have been no reports on mutations in OSCC; however, TP53 Arg282Trp was detected in a case of OSCC that was located in the same DNA-binding domain of TP53 Glu285Val.	('TP53', 'Gene', '7157', (155, 159))	('TP53', 'Gene', '7157', (58, 62))	('TP53', 'Gene', (58, 62))	('Arg282Trp', 'Var', (63, 72))	('TP53', 'Gene', (155, 159))	('Arg282Trp', 'SUBSTITUTION', 'None', (63, 72))	('Glu285Val', 'SUBSTITUTION', 'None', (160, 169))	('detected', 'Reg', (77, 85))	('Glu285Val', 'Var', (160, 169))
95213	32113465	The KDR gene recognizes vascular endothelial growth factor receptor-2, and the KDR Gln472His mutation has been detected in lung and prostate cancers.	('Gln472His', 'Var', (83, 92))	('KDR', 'Gene', (4, 7))	('detected', 'Reg', (111, 119))	('KDR', 'Gene', (79, 82))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('vascular endothelial growth factor receptor-2', 'Gene', (24, 69))	('vascular endothelial growth factor receptor-2', 'Gene', '3791', (24, 69))	('Gln472His', 'SUBSTITUTION', 'None', (83, 92))	('KDR', 'Gene', '3791', (79, 82))	('KDR', 'Gene', '3791', (4, 7))	('cancers', 'Phenotype', 'HP:0002664', (141, 148))	('prostate cancers', 'Phenotype', 'HP:0012125', (132, 148))	('lung and prostate cancers', 'Disease', 'MESH:D011471', (123, 148))
95214	32113465	APC Pro1433Leu was also detected in renal cell carcinomas, and these results suggest that the tumor in case 2 arose from an odontogenic epithelium by mutations found in other cancers.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (36, 57))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('APC', 'Disease', 'MESH:D011125', (0, 3))	('tumor', 'Disease', (94, 99))	('Pro1433Leu', 'SUBSTITUTION', 'None', (4, 14))	('carcinoma', 'Phenotype', 'HP:0030731', (47, 56))	('renal cell carcinomas', 'Disease', (36, 57))	('APC', 'Disease', (0, 3))	('Pro1433Leu', 'Var', (4, 14))	('mutations', 'Var', (150, 159))	('cancers', 'Disease', 'MESH:D009369', (175, 182))	('cancers', 'Phenotype', 'HP:0002664', (175, 182))	('cancers', 'Disease', (175, 182))	('carcinomas', 'Phenotype', 'HP:0030731', (47, 57))	('renal cell carcinomas', 'Disease', 'MESH:D002292', (36, 57))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
95215	32113465	We previously reported that BRAF mutations were present in more than 85% of ameloblastoma cases.	('BRAF', 'Gene', '673', (28, 32))	('mutations', 'Var', (33, 42))	('ameloblastoma', 'Disease', (76, 89))	('ameloblastoma', 'Disease', 'MESH:D000564', (76, 89))	('BRAF', 'Gene', (28, 32))
95216	32113465	Although no definitive data were present, case 1 may have been a tumor other than ameloblastoma, and oncogenesis in this case may have been attributed to mutations other than those in Ion AmpliSeq Cancer Hotspot Panel v2 or to other gene alterations, such as translocations.	('Cancer', 'Phenotype', 'HP:0002664', (197, 203))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('tumor', 'Disease', (65, 70))	('translocations', 'Var', (259, 273))	('attributed', 'Reg', (140, 150))	('mutations', 'Var', (154, 163))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('ameloblastoma', 'Disease', (82, 95))	('ameloblastoma', 'Disease', 'MESH:D000564', (82, 95))
95225	31860637	Genome wide DNA methylation profiling identifies specific epigenetic features in high-risk cutaneous squamous cell carcinoma Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (135, 158))	('skin cancer', 'Phenotype', 'HP:0008069', (192, 203))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('Cutaneous squamous cell carcinoma', 'Disease', 'MESH:D002294', (125, 158))	('carcinoma', 'Phenotype', 'HP:0030731', (149, 158))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (101, 124))	('cSCC', 'Disease', (160, 164))	('skin cancer', 'Disease', (192, 203))	('cutaneous squamous cell carcinoma', 'Disease', (91, 124))	('Cutaneous squamous cell carcinoma', 'Disease', (125, 158))	('skin cancer', 'Disease', 'MESH:D012878', (192, 203))	('cSCC', 'Disease', 'MESH:D002294', (160, 164))	('epigenetic', 'Var', (58, 68))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('cutaneous squamous cell carcinoma', 'Disease', 'MESH:D002294', (91, 124))	('cutaneous squamous cell carcinoma', 'Phenotype', 'HP:0006739', (91, 124))	('cSCC', 'Phenotype', 'HP:0006739', (160, 164))
95243	31860637	However, the existence of a very high burden of mutation in cSCC, greater than in other solid tumours, makes difficult to identify the precise genetic events and number of mutations required for squamous cell carcinogenesis.	('solid tumours', 'Disease', 'MESH:D009369', (88, 101))	('cSCC', 'Phenotype', 'HP:0006739', (60, 64))	('solid tumours', 'Disease', (88, 101))	('tumour', 'Phenotype', 'HP:0002664', (94, 100))	('cSCC', 'Disease', (60, 64))	('mutation', 'Var', (48, 56))	('tumours', 'Phenotype', 'HP:0002664', (94, 101))	('squamous cell carcinogenesis', 'Disease', 'MESH:D002294', (195, 223))	('cSCC', 'Disease', 'MESH:D002294', (60, 64))	('squamous cell carcinogenesis', 'Disease', (195, 223))
95244	31860637	Alterations in the p53 gene are the most common genetic abnormalities found in AK and invasive cSCC, and deregulation of p53 pathway appears to be an early event in carcinogenesis of cSCC.	('cSCC', 'Disease', 'MESH:D002294', (95, 99))	('cSCC', 'Disease', (183, 187))	('genetic abnormalities', 'Disease', (48, 69))	('p53', 'Gene', (121, 124))	('Alterations', 'Var', (0, 11))	('p53', 'Gene', '7157', (121, 124))	('genetic abnormalities', 'Disease', 'MESH:D030342', (48, 69))	('cSCC', 'Disease', 'MESH:D002294', (183, 187))	('cSCC', 'Phenotype', 'HP:0006739', (95, 99))	('AK', 'Phenotype', 'HP:0025127', (79, 81))	('p53', 'Gene', (19, 22))	('AK', 'Disease', 'MESH:D055623', (79, 81))	('p53', 'Gene', '7157', (19, 22))	('cSCC', 'Disease', (95, 99))	('deregulation', 'Var', (105, 117))	('cSCC', 'Phenotype', 'HP:0006739', (183, 187))
95245	31860637	Other molecular alterations in the cell cycle and proliferation regulatory circuit have been identified in cSCC such as loss-of-function mutations in Notch and TFGbeta receptors, upregulated MAPK, amplification of the c-Myc locus, activating mutations of ras, aberrant activation of tyrosine kinases EGFR and Fyn, inactivation of inositol polyphosphate 5'-phosphatase, a negative regulator of PI3K/Akt signalling  as well as reduced expression of PKCdelta and p16INK4a p14ARF tumour suppressors.	('reduced', 'NegReg', (425, 432))	('tyrosine', 'Chemical', 'None', (283, 291))	('Fyn', 'Gene', '2534', (309, 312))	('TFGbeta', 'Disease', 'None', (160, 167))	('c-Myc', 'Gene', '4609', (218, 223))	('p16INK4a p14ARF tumour', 'Disease', (460, 482))	('inactivation', 'NegReg', (314, 326))	('p16INK4a p14ARF tumour', 'Disease', 'MESH:D009369', (460, 482))	('activating', 'PosReg', (231, 241))	('EGFR', 'Gene', '1956', (300, 304))	('upregulated', 'PosReg', (179, 190))	("inositol polyphosphate 5'-phosphatase", 'Enzyme', (330, 367))	('MAPK', 'Gene', (191, 195))	('inositol polyphosphate', 'Chemical', 'MESH:D011122', (330, 352))	('PKCdelta', 'Gene', '5580', (447, 455))	('PKCdelta', 'Gene', (447, 455))	('loss-of-function', 'NegReg', (120, 136))	('TFGbeta', 'Disease', (160, 167))	('Fyn', 'Gene', (309, 312))	('cSCC', 'Disease', 'MESH:D002294', (107, 111))	('tumour', 'Phenotype', 'HP:0002664', (476, 482))	('Akt', 'Gene', (398, 401))	('activation', 'PosReg', (269, 279))	('cSCC', 'Disease', (107, 111))	('expression', 'MPA', (433, 443))	('Akt', 'Gene', '207', (398, 401))	('mutations', 'Var', (242, 251))	('EGFR', 'Gene', (300, 304))	('mutations', 'Var', (137, 146))	('ras', 'Gene', (255, 258))	('c-Myc', 'Gene', (218, 223))	('cSCC', 'Phenotype', 'HP:0006739', (107, 111))
95249	31860637	In the case of cSCC, previous studies targeting specific genes have reported promoter hypermethylation associated with the disease in genes such as the cell cycle regulator CDKN2A, cadherin CDH1 and CDH13, transcription factor FOXE1, modulators of Wnt signalling SFRPs and FRZB, positive regulators of apoptosis ASC, G0S2 and DAPK1, and miRNA-204, as well as hypomethylation of the DSS1 gene.	('CDH1', 'Gene', (199, 203))	('FRZB', 'Gene', '2487', (273, 277))	('associated', 'Reg', (103, 113))	('DSS1', 'Gene', (382, 386))	('DSS1', 'Gene', '7979', (382, 386))	('CDH1', 'Gene', (190, 194))	('CDKN2A', 'Gene', '1029', (173, 179))	('FOXE1', 'Gene', '2304', (227, 232))	('cadherin', 'Gene', (181, 189))	('cSCC', 'Disease', 'MESH:D002294', (15, 19))	('DAPK1', 'Gene', '1612', (326, 331))	('miRNA-204', 'Gene', '406987', (337, 346))	('cSCC', 'Disease', (15, 19))	('hypomethylation', 'Var', (359, 374))	('G0S2', 'Gene', '50486', (317, 321))	('CDH13', 'Gene', (199, 204))	('promoter', 'MPA', (77, 85))	('cadherin', 'Gene', '999;1012', (181, 189))	('cSCC', 'Phenotype', 'HP:0006739', (15, 19))	('G0S2', 'Gene', (317, 321))	('FRZB', 'Gene', (273, 277))	('ASC', 'Gene', '29108', (312, 315))	('CDKN2A', 'Gene', (173, 179))	('DAPK1', 'Gene', (326, 331))	('CDH1', 'Gene', '999', (199, 203))	('FOXE1', 'Gene', (227, 232))	('CDH1', 'Gene', '999', (190, 194))	('ASC', 'Gene', (312, 315))	('miRNA-204', 'Gene', (337, 346))	('CDH13', 'Gene', '1012', (199, 204))
95250	31860637	However, both DNA hypermethylation and hypomethylation associated with cancer are observed throughout the genome and these alterations, in particular the loss of methylation, may have functional consequences beyond regulation of proximal genes.	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('cancer', 'Disease', (71, 77))	('methylation', 'MPA', (162, 173))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('loss', 'NegReg', (154, 158))	('hypomethylation', 'Var', (39, 54))
95253	31860637	More recently, it was reported that both AK and cSCC methylation patterns display classical features of cancer methylomes when compared to normal skin; however, no differences between AK and cSCC were detected.	('cSCC', 'Disease', (48, 52))	('cSCC', 'Disease', (191, 195))	('AK', 'Disease', 'MESH:D055623', (41, 43))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('cSCC', 'Disease', 'MESH:D002294', (48, 52))	('AK', 'Phenotype', 'HP:0025127', (41, 43))	('AK', 'Phenotype', 'HP:0025127', (184, 186))	('AK', 'Disease', 'MESH:D055623', (184, 186))	('cSCC', 'Disease', 'MESH:D002294', (191, 195))	('cSCC', 'Phenotype', 'HP:0006739', (48, 52))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('cSCC', 'Phenotype', 'HP:0006739', (191, 195))	('methylation', 'Var', (53, 64))
95255	31860637	The results allowed us to identify methylation signatures able to discriminate between progressive squamous cell carcinoma stages and to provide a prognostic prediction model for disease survival.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (99, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('methylation', 'Var', (35, 46))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (99, 122))	('squamous cell carcinoma', 'Disease', (99, 122))
95304	31860637	Regarding FGD, CpGs with gain of methylation were preferentially found in the gene body whereas CpGs with loss of methylation were enriched in the promoter regions (Fig 3C).	('CpGs', 'Chemical', 'MESH:C024660', (96, 100))	('CpGs', 'Chemical', 'MESH:C024660', (15, 19))	('methylation', 'Var', (33, 44))	('gain', 'PosReg', (25, 29))
95305	31860637	Notably, based on CpG substructure context, the distribution of CpGs with gain of methylation revealed a significant enrichment in open sea (low density CpG regions), while CpGs with loss of methylation were mainly found in CpG shores (Fig 3D).	('methylation', 'Var', (82, 93))	('CpGs', 'Chemical', 'MESH:C024660', (173, 177))	('CpGs', 'Chemical', 'MESH:C024660', (64, 68))	('gain', 'PosReg', (74, 78))
95307	31860637	Interestingly, this analysis revealed that genes with changes in CpG methylation are mainly associated with categories that are directly related to cancer, such as signal transduction and cell motility, as well as phospholipid metabolic processes.	('cancer', 'Disease', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('cell motility', 'CPA', (188, 201))	('changes', 'Var', (54, 61))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('methylation', 'Var', (69, 80))	('associated', 'Reg', (92, 102))	('CpG', 'Gene', (65, 68))
95317	31860637	cSCC is a particular type of cancer in which tumour cells accumulate a big amount of genetic alterations due to chronic exposure to sun radiation.	('cancer', 'Disease', (29, 35))	('cSCC', 'Disease', 'MESH:D002294', (0, 4))	('genetic', 'Var', (85, 92))	('tumour', 'Phenotype', 'HP:0002664', (45, 51))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('tumour', 'Disease', 'MESH:D009369', (45, 51))	('cSCC', 'Phenotype', 'HP:0006739', (0, 4))	('cancer', 'Disease', 'MESH:D009369', (29, 35))	('cSCC', 'Disease', (0, 4))	('tumour', 'Disease', (45, 51))
95318	31860637	Consistent with this, previous reports have described that aberrant DNA-methylation patterns related to cSCC, when compared to healthy skin, seems to involve vast changes encompassing a large proportion of the genome.	('DNA-methylation patterns', 'MPA', (68, 92))	('aberrant', 'Var', (59, 67))	('cSCC', 'Disease', 'MESH:D002294', (104, 108))	('cSCC', 'Phenotype', 'HP:0006739', (104, 108))	('changes', 'Reg', (163, 170))	('cSCC', 'Disease', (104, 108))
95320	31860637	This indicates that the massive epigenetic alterations associated with cSCC is not just a stationary terminal characteristic of tumour cells; rather, enormous changes are dynamically occurring along the evolution of the disease through their different stages.	('tumour', 'Disease', (128, 134))	('cSCC', 'Phenotype', 'HP:0006739', (71, 75))	('epigenetic alterations', 'Var', (32, 54))	('tumour', 'Phenotype', 'HP:0002664', (128, 134))	('cSCC', 'Disease', (71, 75))	('cSCC', 'Disease', 'MESH:D002294', (71, 75))	('tumour', 'Disease', 'MESH:D009369', (128, 134))
95331	31860637	Also, DNA methylation increases the mutation rate and tumours tend to be globally hypomethylated, which generally results in genomic instability.	('results in', 'Reg', (114, 124))	('tumours', 'Disease', 'MESH:D009369', (54, 61))	('tumours', 'Disease', (54, 61))	('mutation rate', 'MPA', (36, 49))	('genomic instability', 'MPA', (125, 144))	('increases', 'PosReg', (22, 31))	('DNA methylation', 'Var', (6, 21))	('tumours', 'Phenotype', 'HP:0002664', (54, 61))	('tumour', 'Phenotype', 'HP:0002664', (54, 60))
95332	31860637	In our analysis, CpGs with gain of methylation are preferentially found in the gene body whereas CpGs with loss of methylation were enriched in the promoter regions.	('CpGs', 'Chemical', 'MESH:C024660', (97, 101))	('gain', 'PosReg', (27, 31))	('methylation', 'Var', (35, 46))	('CpGs', 'Chemical', 'MESH:C024660', (17, 21))
95336	31860637	Interestingly, the GO analysis of the genes associated with differentially methylated CpG between low-risk and high-risk stages, indicates an enrichment of genes in categories directly involved in cancer development like signal transduction and cell motility.	('cancer', 'Disease', 'MESH:D009369', (197, 203))	('cancer', 'Disease', (197, 203))	('differentially methylated', 'Var', (60, 85))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('cell motility', 'CPA', (245, 258))	('CpG', 'Gene', (86, 89))
95338	31860637	It is important to remark that epigenetic alterations in other genes related to the Wnt-signalling pathway had been previously reported in cSCC samples, as well as genetic mutation in Notch receptors; our results support a broad extension of epigenetic alterations in the Wnt pathway and point to a combination of genetic and epigenetic alterations in the deregulation of the Notch pathway in cSCC.	('cSCC', 'Phenotype', 'HP:0006739', (139, 143))	('cSCC', 'Phenotype', 'HP:0006739', (393, 397))	('Notch pathway', 'Pathway', (376, 389))	('epigenetic alterations', 'Var', (242, 264))	('cSCC', 'Disease', (393, 397))	('cSCC', 'Disease', (139, 143))	('epigenetic alterations', 'Var', (326, 348))	('Wnt pathway', 'Pathway', (272, 283))	('cSCC', 'Disease', 'MESH:D002294', (139, 143))	('cSCC', 'Disease', 'MESH:D002294', (393, 397))
95340	31860637	They report that both AK and cSCC methylation patterns display classical features of cancer methylomes.	('cSCC', 'Phenotype', 'HP:0006739', (29, 33))	('methylation', 'Var', (34, 45))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('cSCC', 'Disease', (29, 33))	('cancer', 'Disease', (85, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('cSCC', 'Disease', 'MESH:D002294', (29, 33))	('AK', 'Disease', 'MESH:D055623', (22, 24))	('AK', 'Phenotype', 'HP:0025127', (22, 24))
95348	31860637	In this sense, we have identified a signature based on the methylation state of 32 CpGs that provides a risk-score, which is associated with the overall survival of the patients.	('CpGs', 'Chemical', 'MESH:C024660', (83, 87))	('methylation', 'Var', (59, 70))	('patients', 'Species', '9606', (169, 177))	('associated', 'Reg', (125, 135))
95350	31860637	p53 deregulation is an early event in carcinogenesis of cSCC, so it is tempting to speculate that alteration of its functional homolog p73 could be critical for bad prognosis.	('p53', 'Gene', (0, 3))	('deregulation', 'Var', (4, 16))	('p53', 'Gene', '7157', (0, 3))	('cSCC', 'Disease', (56, 60))	('p73', 'Gene', '7161', (135, 138))	('cSCC', 'Disease', 'MESH:D002294', (56, 60))	('p73', 'Gene', (135, 138))	('cSCC', 'Phenotype', 'HP:0006739', (56, 60))
95355	31860637	14 Oct 2019  PONE-D-19-25692 Genome wide DNA methylation profiling identifies specific epigenetic features in high-risk cutaneous squamous cell carcinoma.	('cutaneous squamous cell carcinoma', 'Phenotype', 'HP:0006739', (120, 153))	('epigenetic', 'Var', (87, 97))	('cutaneous squamous cell carcinoma', 'Disease', 'MESH:D002294', (120, 153))	('Oct', 'Gene', (3, 6))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (130, 153))	('cutaneous squamous cell carcinoma', 'Disease', (120, 153))	('PONE-D-19-25692', 'Chemical', 'MESH:C039200', (13, 28))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('Oct', 'Gene', '5362', (3, 6))
95359	31860637	(Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: A methylation profiling study was performed in 23 cases using the Illumina EPIC beadchip to identify the methylation changes specific to high-risk cSCC.	('cSCC', 'Disease', (237, 241))	('methylation', 'Var', (195, 206))	('cSCC', 'Disease', 'MESH:D002294', (237, 241))	('cSCC', 'Phenotype', 'HP:0006739', (237, 241))
95370	31860637	10.1371/journal.pone.0223341.r002  21 Nov 2019  RESPONSE TO REVIEWERS PONE-D-19-25692 Genome wide DNA methylation profiling identifies specific epigenetic features in high-risk cutaneous squamous cell carcinoma.	('PONE-D-19-25692', 'Chemical', 'MESH:C039200', (70, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (201, 210))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (187, 210))	('cutaneous squamous cell carcinoma', 'Disease', (177, 210))	('epigenetic features', 'Var', (144, 163))	('cutaneous squamous cell carcinoma', 'Phenotype', 'HP:0006739', (177, 210))	('cutaneous squamous cell carcinoma', 'Disease', 'MESH:D002294', (177, 210))
95384	31860637	RESPONSE TO REVIEWERS PONE-D-19-25692 Genome wide DNA methylation profiling identifies specific epigenetic features in high-risk cutaneous squamous cell carcinoma.	('cutaneous squamous cell carcinoma', 'Phenotype', 'HP:0006739', (129, 162))	('epigenetic', 'Var', (96, 106))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (139, 162))	('carcinoma', 'Phenotype', 'HP:0030731', (153, 162))	('PONE-D-19-25692', 'Chemical', 'MESH:C039200', (22, 37))	('cutaneous squamous cell carcinoma', 'Disease', (129, 162))	('cutaneous squamous cell carcinoma', 'Disease', 'MESH:D002294', (129, 162))
95388	31860637	2 Dec 2019  PONE-D-19-25692R1 Genome wide DNA  methylation profiling identifies specific epigenetic features in high-risk cutaneous squamous cell carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('cutaneous squamous cell carcinoma', 'Phenotype', 'HP:0006739', (122, 155))	('PONE-D-19-25692R1', 'Chemical', 'MESH:C039200', (12, 29))	('cutaneous squamous cell carcinoma', 'Disease', 'MESH:D002294', (122, 155))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (132, 155))	('epigenetic', 'Var', (89, 99))	('cutaneous squamous cell carcinoma', 'Disease', (122, 155))
95391	31860637	10.1371/journal.pone.0223341.r004  4 Dec 2019  RESPONSE TO REVIEWER PONE-D-19-25692 Genome wide DNA methylation profiling identifies specific epigenetic features in high-risk cutaneous squamous cell carcinoma.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (185, 208))	('cutaneous squamous cell carcinoma', 'Disease', 'MESH:D002294', (175, 208))	('epigenetic features', 'Var', (142, 161))	('cutaneous squamous cell carcinoma', 'Phenotype', 'HP:0006739', (175, 208))	('PONE-D-19-25692', 'Chemical', 'MESH:C039200', (68, 83))	('cutaneous squamous cell carcinoma', 'Disease', (175, 208))	('carcinoma', 'Phenotype', 'HP:0030731', (199, 208))
95457	30018735	Cortactin phosphorylation is a required step in invadopodia maturation; therefore we analyzed levels phosphorylation at cortactin tyrosine residue 421 (p421Y) after TNFalpha stimulation.	('TNFalpha', 'Gene', (165, 173))	('Cortactin', 'Gene', (0, 9))	('cortactin', 'Gene', (120, 129))	('TNFalpha', 'Gene', '7124', (165, 173))	('Cortactin', 'Gene', '2017', (0, 9))	('tyrosine', 'Chemical', 'MESH:D014443', (130, 138))	('cortactin', 'Gene', '2017', (120, 129))	('p421Y', 'Var', (152, 157))
95458	30018735	Our results showed a significant increase in cortactin phosphorylation after TNFalpha stimulation at the invadopodia and cell lysates (Figure 4E-4G).	('stimulation', 'Var', (86, 97))	('cortactin', 'Gene', '2017', (45, 54))	('TNFalpha', 'Gene', '7124', (77, 85))	('increase', 'PosReg', (33, 41))	('cortactin', 'Gene', (45, 54))	('TNFalpha', 'Gene', (77, 85))
95459	30018735	To further understand the role of TNFalpha in OSCC, invadopodia assays and Transwell-based invasion assays were performed using UMSCC1 cells with TNFalpha receptor (TNFR1) knockdown by siRNA.	('TNFR1', 'Gene', (165, 170))	('TNFalpha', 'Gene', (34, 42))	('UMSCC1', 'CellLine', 'CVCL:7707', (128, 134))	('TNFalpha', 'Gene', '7124', (34, 42))	('TNFalpha', 'Gene', (146, 154))	('TNFR1', 'Gene', '7132', (165, 170))	('TNFalpha', 'Gene', '7124', (146, 154))	('knockdown', 'Var', (172, 181))
95460	30018735	The results demonstrated that TNFR1 knockdown resulted in a decrease in UMSCC1 invasion and complete inhibition of TNFalpha-induced invadopodia formation (Figure 4H-4J).	('decrease', 'NegReg', (60, 68))	('UMSCC1', 'Protein', (72, 78))	('inhibition', 'NegReg', (101, 111))	('UMSCC1', 'CellLine', 'CVCL:7707', (72, 78))	('TNFalpha', 'Gene', (115, 123))	('knockdown', 'Var', (36, 45))	('TNFR1', 'Gene', '7132', (30, 35))	('TNFalpha', 'Gene', '7124', (115, 123))	('TNFR1', 'Gene', (30, 35))
95463	30018735	To determine the mechanism by which TNFalpha stimulates OSCC invadopodia formation and invasion, we utilized Transwell invasion assays in OSCC cells treated with inhibitors for EGFR (erlotinib), NFkappaB (sc-3060), Src (sc-204303) and PI3K (Lyg294).	('PI3', 'Gene', '5266', (235, 238))	('erlotinib', 'Chemical', 'MESH:D000069347', (183, 192))	('NFkappaB', 'Gene', (195, 203))	('Src', 'Gene', (215, 218))	('Lyg294', 'Chemical', '-', (241, 247))	('sc-204303', 'Var', (220, 229))	('PI3', 'Gene', (235, 238))	('TNFalpha', 'Gene', (36, 44))	('sc-3060', 'Var', (205, 212))	('NFkappaB', 'Gene', '4790', (195, 203))	('EGFR', 'Gene', '1956', (177, 181))	('invasion', 'CPA', (87, 95))	('Src', 'Gene', '6714', (215, 218))	('EGFR', 'Gene', (177, 181))	('TNFalpha', 'Gene', '7124', (36, 44))
95494	30018735	Our findings here show that TNFalpha stimulation increases IL8 and MMP9 secretion by OSCC cells, supporting our previous findings and reinforcing our sequencing results demonstrated here.	('IL8', 'Gene', '3576', (59, 62))	('TNFalpha', 'Gene', (28, 36))	('increases', 'PosReg', (49, 58))	('stimulation', 'Var', (37, 48))	('TNFalpha', 'Gene', '7124', (28, 36))	('MMP9', 'Gene', (67, 71))	('IL8', 'Gene', (59, 62))	('MMP9', 'Gene', '4318', (67, 71))
95497	30018735	To the best of our knowledge, this is the first demonstration of TNFR1 knockdown in OSCC cells leading to decrease in invadopodia formation suggesting a direct role for the TNFalpha in the activation of invadopodia and basement membrane degradation through MMP9 release.	('basement membrane degradation', 'CPA', (219, 248))	('MMP9', 'Gene', '4318', (257, 261))	('MMP9', 'Gene', (257, 261))	('TNFR1', 'Gene', (65, 70))	('invadopodia formation', 'MPA', (118, 139))	('decrease', 'NegReg', (106, 114))	('knockdown', 'Var', (71, 80))	('TNFalpha', 'Gene', (173, 181))	('invadopodia', 'CPA', (203, 214))	('TNFR1', 'Gene', '7132', (65, 70))	('TNFalpha', 'Gene', '7124', (173, 181))
95556	30018735	The samples were then blocked in 1% bovine serum albumin (BSA) and 1% FBS for 1 hour and incubated with primary antibodies cortactin (1:300) and Tks5 (1:50) or phospho-cortactin (pY421) (1:100) or TNFR1 (1:100) in 1% BSA, 1%FBS for 1 hour.	('cortactin', 'Gene', '2017', (123, 132))	('cortactin', 'Gene', '2017', (168, 177))	('Tks5', 'Gene', '9644', (145, 149))	('Tks5', 'Gene', (145, 149))	('TNFR1', 'Gene', '7132', (197, 202))	('bovine', 'Species', '9913', (36, 42))	('serum albumin', 'Gene', '213', (43, 56))	('cortactin', 'Gene', (123, 132))	('serum albumin', 'Gene', (43, 56))	('TNFR1', 'Gene', (197, 202))	('pY421) (1:100', 'Var', (179, 192))	('cortactin', 'Gene', (168, 177))
95559	30018735	For ratio imaging calculation, we have analyzed cells stained for both total cortactin (red channel) and P421Y Cortactin (Far red).	('Cortactin', 'Gene', '2017', (111, 120))	('Cortactin', 'Gene', (111, 120))	('cortactin', 'Gene', (77, 86))	('P421Y', 'Var', (105, 110))	('cortactin', 'Gene', '2017', (77, 86))	('P421Y', 'SUBSTITUTION', 'None', (105, 110))
95561	30018735	We then calculated the mean fluorescence intensity (MFI) of P421Y cortactin at the invadopodia divided by the MFI of total cortactin in the same pixel.	('cortactin', 'Gene', '2017', (123, 132))	('cortactin', 'Gene', '2017', (66, 75))	('fluorescence intensity', 'MPA', (28, 50))	('cortactin', 'Gene', (123, 132))	('P421Y', 'Var', (60, 65))	('P421Y', 'SUBSTITUTION', 'None', (60, 65))	('cortactin', 'Gene', (66, 75))
95569	30018735	Membranes were then washed three times for 10 minutes with TBS-T and incubated for 1 hour at room temperature with LI-COR secondary antibodies anti-mouse-IRDye 680RD and anti-rabbit-IRDye 800CW in 5% BSA Tris-buffered saline-Tween (TBS-T).	('TBS-T', 'Chemical', '-', (232, 237))	('anti-mouse-IRDye', 'Var', (143, 159))	('mouse', 'Species', '10090', (148, 153))	('TBS-T', 'Chemical', '-', (59, 64))	('Tris-buffered saline-Tween', 'Chemical', '-', (204, 230))	('rabbit', 'Species', '9986', (175, 181))	('anti-rabbit-IRDye 800CW', 'Var', (170, 193))
95593	29616113	Previous studies have demonstrated that miRNAs silence genes by inhibiting the synthesis of associated proteins or degrading the mRNA of target genes, and therefore serve an important role in the regulation of growth, proliferation, differentiation, apoptosis and development of cancer.	('differentiation', 'CPA', (233, 248))	('degrading', 'NegReg', (115, 124))	('growth', 'CPA', (210, 216))	('silence', 'NegReg', (47, 54))	('mRNA of target genes', 'MPA', (129, 149))	('apoptosis', 'CPA', (250, 259))	('inhibiting', 'NegReg', (64, 74))	('cancer', 'Phenotype', 'HP:0002664', (279, 285))	('miRNAs', 'Var', (40, 46))	('proliferation', 'CPA', (218, 231))	('serve', 'Reg', (165, 170))	('genes', 'Gene', (55, 60))	('cancer', 'Disease', (279, 285))	('cancer', 'Disease', 'MESH:D009369', (279, 285))	('synthesis of associated proteins', 'MPA', (79, 111))
95627	29616113	Furthermore, in LUSC patients with different tumor location and TNM stage, the AUC values were 0.574 (95% CI, 0.489-0.658; P=0.091) and 0.594 (95% CI, 0.507-0.681; P=0.028), respectively.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('TNM', 'Gene', (64, 67))	('tumor', 'Disease', (45, 50))	('patients', 'Species', '9606', (21, 29))	('TNM', 'Gene', '10178', (64, 67))	('0.594', 'Var', (136, 141))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
95689	29616113	Secondly, miRNAs regulate the function of target genes during carcinogenesis and cancer progression through different biological pathways, which form a complex regulatory network of interactions involving biological molecules.	('function', 'MPA', (30, 38))	('carcinogenesis', 'Disease', (62, 76))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('regulate', 'Reg', (17, 25))	('cancer', 'Disease', (81, 87))	('carcinogenesis', 'Disease', 'MESH:D063646', (62, 76))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('biological pathways', 'Pathway', (118, 137))	('miRNAs', 'Var', (10, 16))
95692	29616113	In addition, high expression of miR-452-5p was closely associated with the clinical parameters of LUSC, including age, cancer location and TNM stage.	('TNM', 'Gene', (139, 142))	('miR-452-5p', 'Gene', (32, 42))	('high', 'Var', (13, 17))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('associated', 'Reg', (55, 65))	('miR-452-5p', 'Gene', '100616196', (32, 42))	('cancer', 'Disease', (119, 125))	('TNM', 'Gene', '10178', (139, 142))	('clinical', 'Species', '191496', (75, 83))	('LUSC', 'Disease', (98, 102))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
95695	27264345	Copy-number variation of MCL1 predicts overall survival of non-small-cell lung cancer in a Southern Chinese population BCL2L1 and MCL1 are key anti-apoptotic genes, and critical for cancer progression.	('lung cancer', 'Disease', 'MESH:D008175', (74, 85))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (59, 85))	('lung cancer', 'Phenotype', 'HP:0100526', (74, 85))	('MCL1', 'Gene', (130, 134))	('BCL2L1', 'Gene', (119, 125))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (63, 85))	('MCL1', 'Gene', (25, 29))	('predicts', 'Reg', (30, 38))	('cancer', 'Disease', (182, 188))	('BCL2', 'Gene', '596', (119, 123))	('cancer', 'Disease', (79, 85))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('MCL1', 'Gene', '4170', (130, 134))	('MCL1', 'Gene', '4170', (25, 29))	('Copy-number variation', 'Var', (0, 21))	('lung cancer', 'Disease', (74, 85))	('BCL2', 'Gene', (119, 123))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('BCL2L1', 'Gene', '598', (119, 125))	('cancer', 'Disease', 'MESH:D009369', (79, 85))
95696	27264345	The prognostic values of BCL2L1 and MCL1 copy-number variations (CNVs) in non-small-cell lung cancer (NSCLC) remain largely unknown.	('NSCLC', 'Disease', 'MESH:D002289', (102, 107))	('MCL1', 'Gene', (36, 40))	('lung cancer', 'Phenotype', 'HP:0100526', (89, 100))	('NSCLC', 'Phenotype', 'HP:0030358', (102, 107))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('copy-number variations', 'Var', (41, 63))	('BCL2L1', 'Gene', (25, 31))	('non-small-cell lung cancer', 'Disease', (74, 100))	('NSCLC', 'Disease', (102, 107))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (74, 100))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (78, 100))
95703	27264345	Recent genomic studies revealed potential therapeutic targets for lung cancer, including ROS1 rearrangements, MET amplification, RET fusions, and activating mutations in BRAF, HER2, and KRAS in frequencies exceeding 1%5.	('HER2', 'Gene', (176, 180))	('RET', 'Gene', (129, 132))	('BRAF', 'Gene', (170, 174))	('KRAS', 'Gene', (186, 190))	('ROS1', 'Gene', (89, 93))	('HER2', 'Gene', '2064', (176, 180))	('lung cancer', 'Disease', (66, 77))	('ROS1', 'Gene', '6098', (89, 93))	('lung cancer', 'Phenotype', 'HP:0100526', (66, 77))	('rearrangements', 'Var', (94, 108))	('KRAS', 'Gene', '3845', (186, 190))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('MET amplification', 'Var', (110, 127))	('RET', 'Gene', '5979', (129, 132))	('BRAF', 'Gene', '673', (170, 174))
95707	27264345	Amplifications of 20q have been previously noted in various cancers 11, 12.	('Amplifications of', 'Var', (0, 17))	('cancers', 'Phenotype', 'HP:0002664', (60, 67))	('cancers', 'Disease', (60, 67))	('cancers', 'Disease', 'MESH:D009369', (60, 67))	('noted', 'Reg', (43, 48))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
95713	27264345	MCL1 copy number gain is a frequent event in several cancers, like mantle cell lymphoma, lung cancer, and breast cancer 18, 19.	('cancers', 'Phenotype', 'HP:0002664', (53, 60))	('breast cancer', 'Disease', (106, 119))	('lung cancer', 'Disease', (89, 100))	('breast cancer', 'Phenotype', 'HP:0003002', (106, 119))	('lung cancer', 'Phenotype', 'HP:0100526', (89, 100))	('copy number gain', 'Var', (5, 21))	('MCL1', 'Gene', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('mantle cell lymphoma', 'Disease', 'MESH:D020522', (67, 87))	('lymphoma', 'Phenotype', 'HP:0002665', (79, 87))	('mantle cell lymphoma', 'Disease', (67, 87))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('cell lymphoma', 'Phenotype', 'HP:0012191', (74, 87))	('breast cancer', 'Disease', 'MESH:D001943', (106, 119))
95721	27264345	Patients with amplifications of BCL2L1 exhibited significantly increased hazards of death, compared with those without amplifications (adjusted HR = 1.62, 95% CI = 1.10-2.40, P = 0.015, Table  2 ).	('amplifications', 'Var', (14, 28))	('Patients', 'Species', '9606', (0, 8))	('BCL2L1', 'Gene', (32, 38))
95742	33034026	Common genomic alterations included single nucleotide variants, copy number alterations and alterations in multiple signaling pathways.	('rat', 'Species', '10116', (80, 83))	('multiple signaling pathways', 'Pathway', (107, 134))	('rat', 'Species', '10116', (19, 22))	('alterations', 'Reg', (92, 103))	('single nucleotide variants', 'Var', (36, 62))	('rat', 'Species', '10116', (96, 99))	('copy number alterations', 'Var', (64, 87))
95749	33034026	In the normal esophagus of rodents and humans, NOTCH1, NOTCH2, and NOTCH3 are highly expressed whereas NOTCH4 is expressed at a minimal level.	('NOTCH3', 'Var', (67, 73))	('NOTCH4', 'Gene', '4855', (103, 109))	('humans', 'Species', '9606', (39, 45))	('NOTCH2', 'Gene', (55, 61))	('NOTCH1', 'Var', (47, 53))	('NOTCH2', 'Gene', '4853', (55, 61))	('NOTCH4', 'Gene', (103, 109))
95751	33034026	Although NOTCH1 is the major regulator of squamous differentiation among four NOTCH receptors, even in triple knockout mice (Notch1, Notch2, Notch3) the epidermis still formed almost normally except for the phenotypes of squamous hyperplasia and deficient barrier function.	('Notch1', 'Var', (125, 131))	('mice', 'Species', '10090', (119, 123))	('Notch2', 'Gene', (133, 139))	('squamous hyperplasia', 'Disease', 'MESH:D006965', (221, 241))	('barrier function', 'CPA', (256, 272))	('Notch3', 'Gene', '18131', (141, 147))	('squamous hyperplasia', 'Disease', (221, 241))	('Notch2', 'Gene', '18129', (133, 139))	('squamous hyperplasia', 'Phenotype', 'HP:0002860', (221, 241))	('Notch3', 'Gene', (141, 147))
95757	33034026	It is surprising that NOTCH1, NOTCH2, and NOTCH3 mutations occurred much more often in physiologically normal human esophageal epithelia (66.2% samples) than in ESCC (15% samples), and distribution pattern of the mutation sites was similar in normal and ESCC samples.	('SCC', 'Gene', (255, 258))	('mutations', 'Var', (49, 58))	('NOTCH2', 'Gene', '4853', (30, 36))	('NOTCH1', 'Gene', (22, 28))	('SCC', 'Gene', '6317', (255, 258))	('NOTCH3', 'Gene', (42, 48))	('SCC', 'Phenotype', 'HP:0002860', (255, 258))	('human', 'Species', '9606', (110, 115))	('SCC', 'Gene', (162, 165))	('SCC', 'Phenotype', 'HP:0002860', (162, 165))	('esophageal epithelia', 'Phenotype', 'HP:0012859', (116, 136))	('NOTCH2', 'Gene', (30, 36))	('age', 'Gene', (121, 124))	('SCC', 'Gene', '6317', (162, 165))	('age', 'Gene', '5973', (121, 124))
95758	33034026	Human subjects with ESCC risk factors (alcohol drinking, tobacco smoking, aging) were more likely to carry NOTCH mutations than those without these risk factors.	('SCC', 'Gene', (21, 24))	('Human', 'Species', '9606', (0, 5))	('NOTCH mutations', 'Var', (107, 122))	('alcohol', 'Chemical', 'MESH:D000438', (39, 46))	('tobacco', 'Species', '4097', (57, 64))	('alcohol drinking', 'Phenotype', 'HP:0030955', (39, 55))	('SCC', 'Phenotype', 'HP:0002860', (21, 24))	('SCC', 'Gene', '6317', (21, 24))	('carry', 'Reg', (101, 106))
95759	33034026	These data suggest that NOTCH mutations are not sufficient to drive carcinogenesis, and some other mutations are needed.	('carcinogenesis', 'Disease', (68, 82))	('carcinogenesis', 'Disease', 'MESH:D063646', (68, 82))	('mutations', 'Var', (30, 39))
95760	33034026	NOTCH mutations can be either driver or passenger mutations in human ESCC.	('human', 'Species', '9606', (63, 68))	('SCC', 'Gene', (70, 73))	('SCC', 'Phenotype', 'HP:0002860', (70, 73))	('NOTCH mutations', 'Var', (0, 15))	('SCC', 'Gene', '6317', (70, 73))
95761	33034026	Why normal esophageal epithelial cells are susceptible to NOTCH mutations?	('age', 'Gene', '5973', (16, 19))	('age', 'Gene', (16, 19))	('NOTCH mutations', 'Var', (58, 73))	('esophageal epithelia', 'Phenotype', 'HP:0012859', (11, 31))
95770	33034026	Moreover, inhibition of the NOTCH pathway favored goblet cell differentiation, which is diagnostic of human BE.	('BE', 'Phenotype', 'HP:0100580', (108, 110))	('favored', 'PosReg', (42, 49))	('NOTCH pathway', 'Pathway', (28, 41))	('goblet cell differentiation', 'CPA', (50, 77))	('inhibition', 'Var', (10, 20))	('human', 'Species', '9606', (102, 107))
95781	33034026	Based on the original data from two studies of 227 cases of human ESCC, NOTCH1, NOTCH2, and NOTCH3 mutations took place in 8%, 3% and 1.9% of human ESCC, respectively.	('SCC', 'Gene', (149, 152))	('NOTCH2', 'Gene', (80, 86))	('human', 'Species', '9606', (142, 147))	('SCC', 'Phenotype', 'HP:0002860', (149, 152))	('SCC', 'Gene', (67, 70))	('mutations', 'Var', (99, 108))	('SCC', 'Gene', '6317', (149, 152))	('SCC', 'Phenotype', 'HP:0002860', (67, 70))	('NOTCH2', 'Gene', '4853', (80, 86))	('SCC', 'Gene', '6317', (67, 70))	('NOTCH1', 'Gene', (72, 78))	('human', 'Species', '9606', (60, 65))	('NOTCH3', 'Gene', (92, 98))
95782	33034026	RBPJ (a key repressor of canonical NOTCH pathway) and FBXW7 (the substrate-recognition subunit of an SCF-type ubiquitin ligase complex targeting NOTCH1) were also frequently mutated.	('RBPJ', 'Gene', '3516', (0, 4))	('rat', 'Species', '10116', (70, 73))	('FBXW7', 'Gene', (54, 59))	('mutated', 'Var', (174, 181))	('FBXW7', 'Gene', '55294', (54, 59))	('RBPJ', 'Gene', (0, 4))
95783	33034026	It was interesting that NOTCH1 mutation was mutually exclusive with PIK3CA mutation.	('PIK3CA', 'Gene', '5290', (68, 74))	('mutation', 'Var', (31, 39))	('PIK3CA', 'Gene', (68, 74))	('NOTCH1', 'Gene', (24, 30))
95784	33034026	NOTCH1 mutation was associated with well-differentiated, early-stage malignancy, and less metastasis to regional lymph nodes.	('malignancy', 'Disease', 'MESH:D009369', (69, 79))	('well-differentiated', 'CPA', (36, 55))	('malignancy', 'Disease', (69, 79))	('less metastasis to regional lymph nodes', 'CPA', (85, 124))	('age', 'Gene', (65, 68))	('mutation', 'Var', (7, 15))	('NOTCH1', 'Gene', (0, 6))	('age', 'Gene', '5973', (65, 68))
95786	33034026	In contrast, patients with PIK3CA mutations had better response to chemotherapy and longer survival time than those without.	('survival', 'CPA', (91, 99))	('PIK3CA', 'Gene', '5290', (27, 33))	('patients', 'Species', '9606', (13, 21))	('better', 'PosReg', (48, 54))	('PIK3CA', 'Gene', (27, 33))	('response', 'MPA', (55, 63))	('mutations', 'Var', (34, 43))
95789	33034026	Exposure to an oro-esophageal carcinogen, 4-nitroquinoline 1-oxide (4NQO), caused loss of NOTCH1 expression in the basal cells of normal esophageal squamous epithelium, as well as Notch1 mutations.	('age', 'Gene', '5973', (142, 145))	('4NQO', 'Chemical', 'MESH:D015112', (68, 72))	('Notch1', 'Gene', (180, 186))	('mutations', 'Var', (187, 196))	('age', 'Gene', (24, 27))	('age', 'Gene', (142, 145))	('loss', 'NegReg', (82, 86))	('4-nitroquinoline 1-oxide', 'Chemical', 'MESH:D015112', (42, 66))	('NOTCH1', 'Gene', (90, 96))	('age', 'Gene', '5973', (24, 27))	('expression', 'MPA', (97, 107))
95790	33034026	Loss of Notch1 in the squamous epithelial cells caused spontaneous SCC in the skin, but not the esophagus.	('caused', 'Reg', (48, 54))	('Notch1', 'Gene', (8, 14))	('SCC', 'Gene', '6317', (67, 70))	('SCC', 'Gene', (67, 70))	('SCC', 'Phenotype', 'HP:0002860', (67, 70))	('Loss', 'Var', (0, 4))
95791	33034026	However, loss of Notch1 promoted 4NQO-induced oro-esophageal SCC.	('Notch1', 'Gene', (17, 23))	('SCC', 'Phenotype', 'HP:0002860', (61, 64))	('SCC', 'Gene', '6317', (61, 64))	('loss', 'Var', (9, 13))	('age', 'Gene', (55, 58))	('promoted', 'PosReg', (24, 32))	('4NQO', 'Chemical', 'MESH:D015112', (33, 37))	('age', 'Gene', '5973', (55, 58))	('SCC', 'Gene', (61, 64))
95792	33034026	Similarly, NOTCH inhibition in mouse esophagus increased the number and size of tumors following exposure to an esophageal carcinogen, diethylnitrosamine.	('age', 'Gene', '5973', (117, 120))	('NOTCH inhibition', 'Var', (11, 27))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('mouse', 'Species', '10090', (31, 36))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('increased', 'PosReg', (47, 56))	('diethylnitrosamine', 'Chemical', 'MESH:D004052', (135, 153))	('tumors', 'Disease', (80, 86))	('age', 'Gene', (117, 120))	('tumors', 'Disease', 'MESH:D009369', (80, 86))
95793	33034026	Using the lineage tracing technique in mice carrying a conditional dominant-negative mutant of Maml1 (a transcriptional coactivator for NOTCH), Alcolea et al found that NOTCH inhibition prevented differentiation of mutant progenitor cells and promoted differentiation of neighboring wild-type progenitor cells in mouse esophagus.	('promoted', 'PosReg', (243, 251))	('mouse', 'Species', '10090', (313, 318))	('mice', 'Species', '10090', (39, 43))	('age', 'Gene', (14, 17))	('inhibition prevented', 'NegReg', (175, 195))	('differentiation', 'CPA', (252, 267))	('age', 'Gene', '5973', (14, 17))	('mutant', 'Var', (215, 221))	('Maml1', 'Gene', (95, 100))	('mutant', 'Var', (85, 91))	('differentiation', 'CPA', (196, 211))	('NOTCH', 'Var', (169, 174))
95794	33034026	Such combined effects led to clonal expansion with mutant cells eventually replacing the entire epithelium, supporting the idea that NOTCH mutation promotes field change in the human esophageal epithelium.	('mutation', 'Var', (139, 147))	('age', 'Gene', (188, 191))	('field', 'MPA', (157, 162))	('mutant', 'Var', (51, 57))	('age', 'Gene', '5973', (188, 191))	('promotes', 'PosReg', (148, 156))	('human', 'Species', '9606', (177, 182))
95802	33034026	Both deficiency and activation of Notch1 promoted oral squamous cell carcinogenesis in a genetic model driven by HPV E6/E7 and KrasG12D.	('E6/E7', 'Var', (117, 122))	('promoted', 'PosReg', (41, 49))	('oral squamous cell carcinogenesis', 'Disease', 'MESH:D002294', (50, 83))	('activation', 'PosReg', (20, 30))	('oral squamous cell carcinogenesis', 'Disease', (50, 83))	('deficiency', 'Disease', (5, 15))	('Notch1', 'Gene', (34, 40))	('deficiency', 'Disease', 'MESH:D007153', (5, 15))
95803	33034026	Inactivation of the NOTCH pathway by a dominant-negative form of Maml1 promoted HNSCC induced by 4NQO, especially in the presence of p53 mutation or HPV16 E6/E7 oncoproteins.	('Maml1', 'Gene', (65, 70))	('HPV16', 'Gene', (149, 154))	('NOTCH pathway', 'Pathway', (20, 33))	('HPV16', 'Species', '333760', (149, 154))	('SCC', 'Gene', '6317', (82, 85))	('SCC', 'Phenotype', 'HP:0002860', (82, 85))	('mutation', 'Var', (137, 145))	('promoted', 'PosReg', (71, 79))	('p53', 'Gene', '7157', (133, 136))	('E6/E7', 'Var', (155, 160))	('4NQO', 'Chemical', 'MESH:D015112', (97, 101))	('p53', 'Gene', (133, 136))	('SCC', 'Gene', (82, 85))	('Inactivation', 'Var', (0, 12))
95826	33293583	Esophageal cancer is also among the tumor types with the highest median mutation burden, and is ranked higher than kidney, head and neck, and colorectal cancer.	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('colorectal cancer', 'Disease', 'MESH:D015179', (142, 159))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('cancer', 'Disease', (153, 159))	('colorectal cancer', 'Phenotype', 'HP:0003003', (142, 159))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('colorectal cancer', 'Disease', (142, 159))	('cancer', 'Disease', 'MESH:D009369', (11, 17))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('mutation', 'Var', (72, 80))	('cancer', 'Disease', (11, 17))	('tumor', 'Disease', (36, 41))
95846	33293583	We then analyzed "other" cluster form tumors, and found that most cells had copy number variations (CNVs), including both amplifications and deletions, suggesting that this cluster included tumor cells (Supplementary Fig.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('tumors', 'Disease', (38, 44))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('tumors', 'Disease', 'MESH:D009369', (38, 44))	('tumor', 'Disease', (190, 195))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('deletions', 'Var', (141, 150))	('copy number variations', 'Var', (76, 98))
95851	33293583	There were only minor differences between the matched adjacent and tumor tissues in three tumor-adjacent tissue pairs (S133, S134, and S150).	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('S150', 'Var', (135, 139))	('S133', 'Var', (119, 123))	('tumor', 'Disease', (67, 72))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('S134', 'Var', (125, 129))
95853	33293583	In contrast, the immune profiles of four other tumor-adjacent pairs (S135, S149, S158, S159) presented a significant shift in a PCA, in which 6-12% of total cells were T cells in tumors (Fig.	('S135', 'Var', (69, 73))	('S158, S159', 'Var', (81, 91))	('tumors', 'Disease', (179, 185))	('tumors', 'Phenotype', 'HP:0002664', (179, 185))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('PCA', 'Disease', (128, 131))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('shift', 'Reg', (117, 122))	('tumors', 'Disease', 'MESH:D009369', (179, 185))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('tumor', 'Disease', (47, 52))	('tumor', 'Disease', (179, 184))
95924	33293583	While some patients showed minimal clonal expansion (S134, S135, and S158), others were strongly dominated by a small number of T cell clones (S149 and S150).	('S135', 'Var', (59, 63))	('S134', 'Var', (53, 57))	('S150', 'Var', (152, 156))	('S149', 'Var', (143, 147))	('patients', 'Species', '9606', (11, 19))	('S158', 'Var', (69, 73))
95925	33293583	Indeed, S149 and S150 tumors showed 65% and 68% of T cells with TCRs shared by more than two cells, indicating the high clonal expansion of T cells in these tumors (Fig.	('tumors', 'Phenotype', 'HP:0002664', (22, 28))	('S150', 'Var', (17, 21))	('tumors', 'Phenotype', 'HP:0002664', (157, 163))	('expansion of T cells', 'Phenotype', 'HP:0100828', (127, 147))	('TCR', 'Gene', '6962', (64, 67))	('S149', 'Var', (8, 12))	('tumors', 'Disease', (157, 163))	('tumors', 'Disease', 'MESH:D009369', (157, 163))	('tumors', 'Disease', 'MESH:D009369', (22, 28))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('TCR', 'Gene', (64, 67))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('tumors', 'Disease', (22, 28))
95955	33293583	BHLHE40 has recently been reported to mediate tissue-specific control of macrophage self-renewal, and proliferation and we found that BHELHE40 was associated with poor prognosis of ESCC (Supplementary Fig.	('HE', 'Chemical', '-', (138, 140))	('HE', 'Chemical', '-', (135, 137))	('BHLHE40', 'Gene', (0, 7))	('BHLHE40', 'Gene', '8553', (0, 7))	('ESCC', 'Disease', (181, 185))	('HE', 'Chemical', '-', (3, 5))	('BHELHE40', 'Var', (134, 142))
96007	33293583	Pre-exhausted clusters CD8-C5-CCL5 and CD8-C6-STMN1 may serve as better targets for immunotherapies compared to the exhausted cluster (CD8-C7-TIGIT), as the latter are in a permanent and less reversible exhausted stage, making them more resistant to checkpoint inhibition due to their epigenetic changes.	('epigenetic', 'Var', (285, 295))	('TIGIT', 'Gene', (142, 147))	('CD8', 'Gene', (39, 42))	('CD8', 'Gene', (23, 26))	('CD8', 'Gene', '925', (135, 138))	('CD8', 'Gene', '925', (39, 42))	('CD8', 'Gene', '925', (23, 26))	('CCL5', 'Gene', '6352', (30, 34))	('STMN1', 'Gene', '3925', (46, 51))	('STMN1', 'Gene', (46, 51))	('CD8', 'Gene', (135, 138))	('TIGIT', 'Gene', '201633', (142, 147))	('CCL5', 'Gene', (30, 34))
96010	33293583	Our results suggested alternative pathways to re-activate anti-tumor immunity in ESCC, such as the blockade of NKG2A and CD49d alone or in combination with anti-PD1/PD-L1, which may improve the immunotherapeutic response.	('tumor', 'Disease', (63, 68))	('NKG2A', 'Gene', '3821', (111, 116))	('re-activate', 'PosReg', (46, 57))	('improve', 'PosReg', (182, 189))	('ESCC', 'Disease', (81, 85))	('CD49d', 'Gene', '3676', (121, 126))	('blockade', 'Var', (99, 107))	('NKG2A', 'Gene', (111, 116))	('PD-L1', 'Gene', (165, 170))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('CD49d', 'Gene', (121, 126))	('PD-L1', 'Gene', '29126', (165, 170))	('immunotherapeutic response', 'CPA', (194, 220))
96040	33293583	LILRB1 expression was upregulated on TAMs, disruption of either MHC class I or LILRB1 potentiated phagocytosis of tumor cells both in vitro and in vivo.	('upregulated', 'PosReg', (22, 33))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('disruption', 'Var', (43, 53))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('LILRB1', 'Gene', '10859', (0, 6))	('expression', 'MPA', (7, 17))	('MHC class I', 'Gene', (64, 75))	('tumor', 'Disease', (114, 119))	('LILRB1', 'Gene', (0, 6))	('TAMs', 'Chemical', '-', (37, 41))	('potentiated', 'PosReg', (86, 97))	('LILRB1', 'Gene', (79, 85))	('LILRB1', 'Gene', '10859', (79, 85))
96041	33293583	Investigating the mechanisms underlying this immunosuppressive MHC class I-LILRB1 signaling axis in TAMs will be useful in developing therapies to restore macrophage function, and blocking this pathway may promote antitumor immunity in ESCC.	('LILRB1', 'Gene', (75, 81))	('LILRB1', 'Gene', '10859', (75, 81))	('ESCC', 'Disease', (236, 240))	('tumor', 'Disease', 'MESH:D009369', (218, 223))	('macrophage function', 'MPA', (155, 174))	('TAMs', 'Chemical', '-', (100, 104))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('promote', 'PosReg', (206, 213))	('blocking', 'Var', (180, 188))	('tumor', 'Disease', (218, 223))
96048	33293583	Tumor and adjacent tissues were isolated by mincing the freshly obtained surgical specimens into 1-mm cubic pieces, followed by enzymatic digestion using 0.1% collagenase IV, 0.002% DNAse I, and 0.01% hyaluronidase, and were incubated on a rocker for 20-40 min at 37  C. The digested tissues were then passed through a 40 microm cell strainer and washed twice with PBS prior to surface staining.	('Tumor', 'Disease', 'MESH:D009369', (0, 5))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('PBS', 'Chemical', '-', (365, 368))	('Tumor', 'Disease', (0, 5))	('0.002', 'Var', (175, 180))
96086	33293583	The primary antibodies used were anti-human CD3 (LEICA, 1:200), anti-human CD20 (LEICA, 1:300), anti-human MPO (Long island, 1:100), anti-human CD56 (Long island, 1:400), and anti-human CD68 (Long island, 1:100).	('CD56', 'Gene', '4684', (144, 148))	('anti-human', 'Var', (175, 185))	('CD20', 'Gene', '54474', (75, 79))	('human', 'Species', '9606', (38, 43))	('CD20', 'Gene', (75, 79))	('CD68', 'Gene', (186, 190))	('anti-human', 'Var', (133, 143))	('MPO', 'Gene', (107, 110))	('anti-human', 'Var', (64, 74))	('human', 'Species', '9606', (138, 143))	('human', 'Species', '9606', (69, 74))	('CD56', 'Gene', (144, 148))	('human', 'Species', '9606', (180, 185))	('human', 'Species', '9606', (101, 106))	('CD68', 'Gene', '968', (186, 190))	('anti-human', 'Var', (96, 106))	('MPO', 'Gene', '4353', (107, 110))
96159	25114775	In disease, SOX2 alterations have been associated with developmental maladies, such as anophthalmia-esophageal-genital (AEG) syndrome, which occurs when there is a heterozygous mutation of SOX2 that leads to abnormal development of ectodermal and endodermal tissues.	('SOX2', 'Gene', (189, 193))	('anophthalmia', 'Phenotype', 'HP:0000528', (87, 99))	('anophthalmia-esophageal-genital (AEG) syndrome', 'Disease', 'MESH:C565948', (87, 133))	('SOX2', 'Gene', (12, 16))	('associated', 'Reg', (39, 49))	('alterations', 'Var', (17, 28))
96163	25114775	SOX2 amplification has previously been found in several cancer types including glioblastoma, small-cell lung cancer (SCLC) and many forms of squamous cell carcinoma (SCC).	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('SCLC', 'Phenotype', 'HP:0030357', (117, 121))	('amplification', 'Var', (5, 18))	('cancer', 'Disease', (56, 62))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (141, 164))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (93, 115))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('lung cancer', 'Phenotype', 'HP:0100526', (104, 115))	('SCC', 'Phenotype', 'HP:0002860', (166, 169))	('SOX2', 'Gene', (0, 4))	('SCLC', 'Disease', 'MESH:D018288', (117, 121))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (141, 164))	('found', 'Reg', (39, 44))	('cancer', 'Disease', (109, 115))	('glioblastoma', 'Disease', 'MESH:D005909', (79, 91))	('SCC', 'Gene', '6317', (166, 169))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('carcinoma', 'Phenotype', 'HP:0030731', (155, 164))	('squamous cell carcinoma', 'Disease', (141, 164))	('small-cell lung cancer', 'Disease', 'MESH:D055752', (93, 115))	('SCC', 'Gene', (166, 169))	('glioblastoma', 'Disease', (79, 91))	('small-cell lung cancer', 'Disease', (93, 115))	('glioblastoma', 'Phenotype', 'HP:0012174', (79, 91))	('SCLC', 'Disease', (117, 121))
96164	25114775	A summary of SOX2 amplification in various cancer types with corresponding references can be found in Table 1.	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('cancer', 'Disease', (43, 49))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('amplification', 'Var', (18, 31))	('SOX2', 'Gene', (13, 17))
96165	25114775	Justilien and colleagues revealed the co-amplification of two oncogenes, PRKCI and SOX2, is responsible for the cancer stem cell phenotype seen in lung squamous cell carcinoma (LSCC).	('PRKCI', 'Gene', '5584', (73, 78))	('SOX2', 'Gene', (83, 87))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (147, 175))	('PRKCI', 'Gene', (73, 78))	('SCC', 'Phenotype', 'HP:0002860', (178, 181))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('SCC', 'Gene', '6317', (178, 181))	('carcinoma', 'Phenotype', 'HP:0030731', (166, 175))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (152, 175))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (147, 175))	('lung squamous cell carcinoma', 'Disease', (147, 175))	('LSCC', 'Phenotype', 'HP:0030359', (177, 181))	('co-amplification', 'Var', (38, 54))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('SCC', 'Gene', (178, 181))
96166	25114775	Moreover, another study performed FISH analysis in 447 resected non-small cell lung cancer (NSCLC) tissue samples and SOX2 amplification was associated with increased gene copy number of FGFR1 and PI3KCA genes.	('FGFR1', 'Gene', (187, 192))	('FGFR1', 'Gene', '2260', (187, 192))	('cell lung cancer', 'Disease', 'MESH:D008175', (74, 90))	('NSCLC', 'Phenotype', 'HP:0030358', (92, 97))	('SCLC', 'Phenotype', 'HP:0030357', (93, 97))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (68, 90))	('lung cancer', 'Phenotype', 'HP:0100526', (79, 90))	('gene', 'MPA', (167, 171))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('increased', 'PosReg', (157, 166))	('NSCLC', 'Disease', (92, 97))	('amplification', 'Var', (123, 136))	('NSCLC', 'Disease', 'MESH:D002289', (92, 97))	('PI3KCA', 'Gene', (197, 203))	('cell lung cancer', 'Disease', (74, 90))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (64, 90))
96169	25114775	We summarized SOX2 amplification and resulting alterations in cellular functions in all cancer types in Table 1 and showed examples of SOX2's role in oncogenic signaling in Figure 2.	('cancer', 'Disease', (88, 94))	('SOX2', 'Gene', (14, 18))	('cellular functions', 'MPA', (62, 80))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('amplification', 'Var', (19, 32))	('alterations', 'Reg', (47, 58))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))
96183	25114775	Equivalently, upon silencing of SOX2 in NSCLC cell lines, apoptosis was induced.	('SCLC', 'Phenotype', 'HP:0030357', (41, 45))	('NSCLC', 'Phenotype', 'HP:0030358', (40, 45))	('silencing', 'Var', (19, 28))	('SOX2', 'Gene', (32, 36))	('induced', 'Reg', (72, 79))	('apoptosis', 'CPA', (58, 67))	('NSCLC', 'Disease', (40, 45))	('NSCLC', 'Disease', 'MESH:D002289', (40, 45))
96185	25114775	For example in melanoma, SOX2 knockdown in A2058 cells resulted in a 4.5-fold decrease in invasion in vitro and adopted this phenotype via the upregulation of matrix metalloproteinase (MMP)-3.	('matrix metalloproteinase (MMP)-3', 'Gene', '4314', (159, 191))	('A2058', 'CellLine', 'CVCL:1059', (43, 48))	('decrease', 'NegReg', (78, 86))	('melanoma', 'Phenotype', 'HP:0002861', (15, 23))	('melanoma', 'Disease', (15, 23))	('melanoma', 'Disease', 'MESH:D008545', (15, 23))	('upregulation', 'PosReg', (143, 155))	('knockdown', 'Var', (30, 39))	('SOX2', 'Gene', (25, 29))	('invasion', 'CPA', (90, 98))
96196	25114775	The reactivation of stem cell-associated markers or pluripotency factors may cause dedifferentiation and a more stem cell-like state.	('pluripotency', 'Disease', (52, 64))	('cause', 'Reg', (77, 82))	('pluripotency', 'Disease', 'None', (52, 64))	('more', 'PosReg', (107, 111))	('dedifferentiation', 'CPA', (83, 100))	('reactivation', 'Var', (4, 16))
96202	25114775	Studies in gastric cancer using siRNA-mediated SOX2 knockdown, found reduced spheroid colony formation and increased apoptosis within sphere cells, highlighting the importance of SOX2 in self-renewal capacity.	('reduced', 'NegReg', (69, 76))	('gastric cancer', 'Phenotype', 'HP:0012126', (11, 25))	('spheroid colony formation', 'CPA', (77, 102))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('apoptosis', 'CPA', (117, 126))	('gastric cancer', 'Disease', 'MESH:D013274', (11, 25))	('knockdown', 'Var', (52, 61))	('gastric cancer', 'Disease', (11, 25))
96204	25114775	Singh and colleagues showed similar results in NSCLC, when siRNA-mediated SOX2 knockdown led to a 2.5-fold reduction in sphere formation.	('NSCLC', 'Phenotype', 'HP:0030358', (47, 52))	('SCLC', 'Phenotype', 'HP:0030357', (48, 52))	('sphere formation', 'CPA', (120, 136))	('SOX2', 'Gene', (74, 78))	('NSCLC', 'Disease', (47, 52))	('knockdown', 'Var', (79, 88))	('NSCLC', 'Disease', 'MESH:D002289', (47, 52))	('reduction', 'NegReg', (107, 116))
96209	25114775	They functionally showed that the ectopic expression of SOX2 in vitro caused enhanced self-renewal capacity in melanoma cells.	('melanoma', 'Disease', 'MESH:D008545', (111, 119))	('enhanced', 'PosReg', (77, 85))	('melanoma', 'Phenotype', 'HP:0002861', (111, 119))	('melanoma', 'Disease', (111, 119))	('SOX2', 'Gene', (56, 60))	('ectopic expression', 'Var', (34, 52))
96213	25114775	The authors provide evidence that the coamplifcation of both oncogenes is required to activate the PKCi-SOX2-HHAT signaling axis which impels the stem cell phenotype.	('HHAT', 'Gene', (109, 113))	('PKCi', 'Gene', '5584', (99, 103))	('impels', 'NegReg', (135, 141))	('coamplifcation', 'Var', (38, 52))	('activate', 'PosReg', (86, 94))	('PKCi', 'Gene', (99, 103))	('HHAT', 'Gene', '55733', (109, 113))	('stem cell phenotype', 'CPA', (146, 165))
96224	25114775	Furthermore, a significant correlation between high SOX2 levels and decreasing patient survival was shown (p < 0.001).	('patient survival', 'CPA', (79, 95))	('high', 'Var', (47, 51))	('decreasing', 'NegReg', (68, 78))	('SOX2 levels', 'MPA', (52, 63))	('patient', 'Species', '9606', (79, 86))
96229	25114775	In breast cancer, silencing SOX2 not only reduced the size of the CSC population but also restored tamoxifen sensitivity, suggesting tamoxifen resistance is primarily driven by SOX2 in breast CSCs.	('reduced', 'NegReg', (42, 49))	('silencing', 'Var', (18, 27))	('tamoxifen', 'Chemical', 'MESH:D013629', (133, 142))	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('tamoxifen', 'Chemical', 'MESH:D013629', (99, 108))	('tamoxifen sensitivity', 'MPA', (99, 120))	('breast cancer', 'Disease', (3, 16))	('size', 'MPA', (54, 58))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('restored', 'PosReg', (90, 98))	('SOX2', 'Enzyme', (28, 32))
96231	25114775	When a SOX2 knockdown using shRNA was performed in HCC827 cells, decreased proliferation was observed along with increased sensitivity to erlotinib.	('SOX2', 'Gene', (7, 11))	('erlotinib', 'Chemical', 'MESH:D000069347', (138, 147))	('decreased', 'NegReg', (65, 74))	('knockdown', 'Var', (12, 21))	('HCC827', 'CellLine', 'CVCL:2063', (51, 57))	('increased', 'PosReg', (113, 122))	('proliferation', 'CPA', (75, 88))
96326	31579094	This suggests that FEZF1-AS1 dysregulation promotes the development and progression of LAD, and may therefore be used in LAD therapy.	('promotes', 'PosReg', (43, 51))	('LAD', 'Disease', (87, 90))	('LAD', 'Disease', (121, 124))	('FEZF1-AS1', 'Gene', (19, 28))	('LAD', 'Disease', 'MESH:C538231', (87, 90))	('LAD', 'Disease', 'MESH:C538231', (121, 124))	('progression', 'CPA', (72, 83))	('FEZF1-AS1', 'Gene', '154860;389549;5729', (19, 28))	('dysregulation', 'Var', (29, 42))	('development', 'CPA', (56, 67))
96346	28387300	Anit-PD-L1 is a promising treatment option in lung ASC cases in which PD-L1 upregulated and EGFR mutations are present.	('mutations', 'Var', (97, 106))	('men', 'Species', '9606', (31, 34))	('upregulated', 'PosReg', (76, 87))	('EGFR', 'Gene', (92, 96))	('lung ASC', 'Disease', (46, 54))	('PD-L1', 'Gene', (70, 75))
96353	28387300	Targeted disruption of PD-L1 function has been shown to improve outcomes in NSCLC.	('Targeted disruption', 'Var', (0, 19))	('PD-L1', 'Gene', (23, 28))	('NSCLC', 'Disease', (76, 81))	('NSCLC', 'Disease', 'MESH:D002289', (76, 81))	('improve', 'PosReg', (56, 63))
96355	28387300	And in a previous study, approximately 20% of unsorted NSCLC patients receiving anti-PD-1/PD-L1 antibodies had a meaningful response to therapy.	('NSCLC', 'Disease', (55, 60))	('patients', 'Species', '9606', (61, 69))	('NSCLC', 'Disease', 'MESH:D002289', (55, 60))	('antibodies', 'Var', (96, 106))	('anti-PD-1/PD-L1 antibodies', 'Var', (80, 106))
96357	28387300	Herein, we determined the expression pattern of PD-L1 in lung ASCs and the association between PD-L1 expression and 1) various clinicopathological characteristics and 2) alterations in major driver oncogenes including EGFR, KRAS, and ALK.	('KRAS', 'Gene', '3845', (224, 228))	('alterations', 'Var', (170, 181))	('PD-L1', 'Gene', (95, 100))	('ALK', 'Gene', (234, 237))	('ALK', 'Gene', '238', (234, 237))	('PD-L1', 'Gene', (48, 53))	('EGFR', 'Gene', (218, 222))	('KRAS', 'Gene', (224, 228))	('association', 'Interaction', (75, 86))
96358	28387300	Identification of the patients who will benefit from anti-PD1/PD-L1-targeted therapy is essential; doing so also spares those who will not benefit from unnecessary treatments and reduces the occurrence of side effects resulting from loss of PD-1/PD-L1 inhibiting function and consequent activation of the autoimmune system.	('loss', 'Var', (233, 237))	('PD-1/PD-L1', 'Gene', (241, 251))	('reduces', 'NegReg', (179, 186))	('men', 'Species', '9606', (169, 172))	('side effects', 'MPA', (205, 217))	('autoimmune system', 'Phenotype', 'HP:0002960', (305, 322))	('patients', 'Species', '9606', (22, 30))	('activation', 'PosReg', (287, 297))	('inhibiting function', 'NegReg', (252, 271))	('PD1', 'Gene', '5133', (58, 61))	('PD1', 'Gene', (58, 61))
96377	28387300	PD-L1 expression was similar in lung ASCs with EGFR mutations, KRAS mutations, or ALK rearrangements (P = 1.000, 0.544, and 0.553, respectively) (Table 5).	('mutations', 'Var', (52, 61))	('KRAS', 'Gene', '3845', (63, 67))	('ALK', 'Gene', (82, 85))	('men', 'Species', '9606', (95, 98))	('ALK', 'Gene', '238', (82, 85))	('mutations', 'Var', (68, 77))	('EGFR', 'Gene', (47, 51))	('KRAS', 'Gene', (63, 67))
96382	28387300	Hence, the expression rate of PD1/PD-L1 in a particular variant is based on a relatively small sample number in these trials, and determination of the differences (if any) between the variants requires further exploration.	('PD1', 'Gene', (30, 33))	('PD1', 'Gene', '5133', (30, 33))	('variant', 'Var', (56, 63))
96391	28387300	In our study, PD-L1 expression did not significantly correlate with most of the clinicopathological characteristics of lung ASC or with mutations in driver oncogenes such as EGFR, KRAS, and ALK.	('ALK', 'Gene', (190, 193))	('EGFR', 'Gene', (174, 178))	('lung ASC', 'Disease', (119, 127))	('KRAS', 'Gene', (180, 184))	('ALK', 'Gene', '238', (190, 193))	('KRAS', 'Gene', '3845', (180, 184))	('mutations', 'Var', (136, 145))
96393	28387300	In a previous meta-analysis positive PD-L1 expression correlated with poor prognosis in NSCLC patients, whereas there was no correlation between PD-L1 expression and clinical features (sex, histology, smoking status, tumor stage, and lymph node metastasis).	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('tumor', 'Disease', (217, 222))	('PD-L1', 'Gene', (37, 42))	('patients', 'Species', '9606', (94, 102))	('NSCLC', 'Disease', (88, 93))	('positive', 'Var', (28, 36))	('tumor', 'Disease', 'MESH:D009369', (217, 222))	('NSCLC', 'Disease', 'MESH:D002289', (88, 93))
96394	28387300	Others showed a link between activation of epidermal growth factor receptor (EGFR) signaling and upregulation of PD-L1, PD-1, and CTLA-4 in an EGFR-driven murine model of lung cancer and human NSCLC cell lines and between activating EGFR mutations and PD-L1 overexpression in tumors.	('upregulation', 'PosReg', (97, 109))	('tumor', 'Phenotype', 'HP:0002664', (276, 281))	('lung cancer', 'Phenotype', 'HP:0100526', (171, 182))	('PD-L1', 'Gene', (113, 118))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('overexpression', 'PosReg', (258, 272))	('CTLA-4', 'Gene', (130, 136))	('epidermal growth factor receptor', 'Gene', '13649', (43, 75))	('activating', 'PosReg', (222, 232))	('tumors', 'Phenotype', 'HP:0002664', (276, 282))	('EGFR', 'Gene', (233, 237))	('mutations', 'Var', (238, 247))	('tumors', 'Disease', (276, 282))	('murine', 'Species', '10090', (155, 161))	('PD-1', 'Gene', (120, 124))	('CTLA-4', 'Gene', '12477', (130, 136))	('lung cancer', 'Disease', (171, 182))	('PD-L1', 'Gene', (252, 257))	('epidermal growth factor receptor', 'Gene', (43, 75))	('tumors', 'Disease', 'MESH:D009369', (276, 282))	('NSCLC', 'Disease', 'MESH:D002289', (193, 198))	('activation', 'PosReg', (29, 39))	('human', 'Species', '9606', (187, 192))	('NSCLC', 'Disease', (193, 198))	('lung cancer', 'Disease', 'MESH:D008175', (171, 182))
96398	28387300	An ongoing clinical trial is evaluating the therapeutic effects of a combination treatment consisting of nivolumab and erlotinib (NCT01454102) in NSCLCs with EGFR mutations, which represent a minority of cases.	('EGFR', 'Gene', (158, 162))	('men', 'Species', '9606', (86, 89))	('mutations', 'Var', (163, 172))	('NSCLCs', 'Disease', (146, 152))	('nivolumab', 'Chemical', 'MESH:D000077594', (105, 114))	('erlotinib', 'Chemical', 'MESH:D000069347', (119, 128))	('NSCLCs', 'Disease', 'MESH:D002289', (146, 152))
96399	28387300	As shown here, PD-L1 expression can be detected in ASCs with EGFR mutations, and we suggest that immune checkpoint therapy combined with administration of an EGFR TKI may effectively treat these rare tumors.	('mutations', 'Var', (66, 75))	('PD-L1', 'Gene', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('tumors', 'Phenotype', 'HP:0002664', (200, 206))	('tumors', 'Disease', 'MESH:D009369', (200, 206))	('tumors', 'Disease', (200, 206))	('EGFR', 'Gene', (61, 65))
96406	28387300	Given the complexity of lung ASCs, their treatment outcomes may be improved by administration of both EGFR TKIs and anti-PD-1/PD-L1 antibodies in cases where EGFR mutations are present and PD-L1 is overexpressed.	('improved', 'PosReg', (67, 75))	('EGFR', 'Gene', (102, 106))	('mutations', 'Var', (163, 172))	('men', 'Species', '9606', (46, 49))
96482	31088500	A number of studies have suggested that PD-L1 expression correlates with an increased response to therapies in NSCLC.	('expression', 'Var', (46, 56))	('increased', 'PosReg', (76, 85))	('NSCLC', 'Disease', (111, 116))	('PD-L1', 'Gene', (40, 45))	('NSCLC', 'Disease', 'MESH:D002289', (111, 116))	('response', 'MPA', (86, 94))
96494	31088500	Patients with a prior history of malignant tumors or diagnosed with non-lung adenocarcinoma or non-lung squamous cell carcinoma, or with ALK, BRAF, ERBB2, MET, RET, or ROS1 mutations were excluded.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (104, 127))	('ROS1', 'Gene', (168, 172))	('RET', 'Gene', '5979', (160, 163))	('BRAF', 'Gene', '673', (142, 146))	('BRAF', 'Gene', (142, 146))	('non-lung adenocarcinoma or non-lung squamous cell carcinoma', 'Disease', 'MESH:D002289', (68, 127))	('Patients', 'Species', '9606', (0, 8))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('ALK', 'Gene', '238', (137, 140))	('ERBB2', 'Gene', (148, 153))	('RET', 'Gene', (160, 163))	('malignant tumors', 'Disease', 'MESH:D018198', (33, 49))	('ALK', 'Gene', (137, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('MET', 'Gene', (155, 158))	('mutations', 'Var', (173, 182))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('ERBB2', 'Gene', '2064', (148, 153))	('ROS1', 'Gene', '6098', (168, 172))	('malignant tumors', 'Disease', (33, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (72, 91))
96495	31088500	Patients with EGFR mutations received EGFR-TKIs, while the other patients (e.g.	('EGFR', 'Gene', '1956', (38, 42))	('EGFR', 'Gene', '1956', (14, 18))	('EGFR', 'Gene', (14, 18))	('EGFR', 'Gene', (38, 42))	('mutations', 'Var', (19, 28))	('Patients', 'Species', '9606', (0, 8))	('patients', 'Species', '9606', (65, 73))
96504	31088500	The TMB was defined as the number of somatic, coding, base substitutions, and indel mutations identified by NGS.	('indel mutations', 'Var', (78, 93))	('base substitutions', 'Var', (54, 72))	('TMB', 'Chemical', '-', (4, 7))
96521	31088500	Of all the EGFR mutation subjects, 33 subjects had L858R mutation and 25 subjects had exon 19 Del mutation.	('mutation', 'Var', (16, 24))	('EGFR', 'Gene', '1956', (11, 15))	('EGFR', 'Gene', (11, 15))	('L858R mutation', 'Var', (51, 65))	('L858R', 'Mutation', 'rs121434568', (51, 56))
96522	31088500	Of all the KRAS mutation subjects, there were 2 subjects with A146V mutation, 1 with A146X mutation, 1 with G12A mutation, 3 with G12C mutation, 2 with G12D mutation, 6 with G12 V mutation, 1 with G13D mutation, and 1 with Q61L mutation.	('KRAS', 'Gene', (11, 15))	('Q61L', 'Mutation', 'rs121913240', (223, 227))	('G12D', 'Var', (152, 156))	('G12D', 'Mutation', 'rs121913529', (152, 156))	('A146X mutation', 'Var', (85, 99))	('G12 V mutation', 'Var', (174, 188))	('G12A', 'Mutation', 'rs121913529', (108, 112))	('KRAS', 'Gene', '3845', (11, 15))	('A146V', 'Mutation', 'rs1057519725', (62, 67))	('G12A', 'Var', (108, 112))	('G12C mutation', 'Var', (130, 143))	('G13D', 'Mutation', 'rs112445441', (197, 201))	('G12C', 'Mutation', 'rs121913530', (130, 134))	('A146X', 'Mutation', 'p.A146X', (85, 90))	('A146V mutation', 'Var', (62, 76))	('G12 V', 'Mutation', 'rs121913529', (174, 179))
96531	31088500	For ADC subjects, the median overall survival was significantly longer in EGFR mutated group vs. wildtype group, as well as in PD-L1 (TC expression) negative group vs. positive group (P = 0.021 and < 0.0001, respectively) (Fig.	('longer', 'PosReg', (64, 70))	('TC', 'Chemical', '-', (134, 136))	('mutated', 'Var', (79, 86))	('overall survival', 'MPA', (29, 45))	('ADC', 'Var', (4, 7))	('EGFR', 'Gene', '1956', (74, 78))	('EGFR', 'Gene', (74, 78))
96532	31088500	Similar results were found in individual ADC subgroups with either mutated EGFR or wildtype (P = 0.022 and < 0.0001, respectively) (Fig.	('mutated', 'Var', (67, 74))	('EGFR', 'Gene', '1956', (75, 79))	('EGFR', 'Gene', (75, 79))	('ADC', 'Disease', (41, 44))
96547	31088500	Although no statistical significance of survival difference (all P > 0.05) was observed between Low/moderate TMB group and High TMB group, high TMB seem associate with poor prognosis in ADC but not in SQCC.	('TMB', 'Chemical', '-', (144, 147))	('TMB', 'Chemical', '-', (128, 131))	('high TMB', 'Var', (139, 147))	('ADC', 'Disease', (186, 189))	('TMB', 'Chemical', '-', (109, 112))
96566	31088500	Other studies reported lower PD-L1 positivity using antibody clone 28-8 (overall 31% in NSCLC, >=1% cutoff) and clone SP263 (overall 36.5% in NSCLC, >=1% cutoff).	('NSCLC', 'Disease', (142, 147))	('PD-L1', 'Protein', (29, 34))	('NSCLC', 'Disease', 'MESH:D002289', (142, 147))	('NSCLC', 'Disease', (88, 93))	('clone SP263', 'Var', (112, 123))	('NSCLC', 'Disease', 'MESH:D002289', (88, 93))	('lower', 'NegReg', (23, 28))
96568	31088500	This result is in agree with study reported by Chen et al.. Our study also found that patients with ADC in our cohort have a higher positivity of EGFR mutations than the Western population, suggesting it is necessary for better management of targeted therapy for Asian population.	('EGFR', 'Gene', '1956', (146, 150))	('ADC', 'Disease', (100, 103))	('positivity', 'MPA', (132, 142))	('EGFR', 'Gene', (146, 150))	('mutations', 'Var', (151, 160))	('patients', 'Species', '9606', (86, 94))
96581	31088500	An important finding presented in this study is TMB value was significantly higher in PD-L1 positive subjects than PD-L1 negative subjects, indicating an interesting association between these two biomarkers (Fig.	('positive', 'Var', (92, 100))	('TMB', 'Chemical', '-', (48, 51))	('higher', 'PosReg', (76, 82))	('PD-L1', 'Gene', (86, 91))	('TMB value', 'MPA', (48, 57))
96582	31088500	In our study, there were certain overlaps between high TMB and PD-L1 subjects in SQCC and minor overlaps between wild-type ADC and EGFR-mutant subjects (Fig.	('SQCC', 'Disease', (81, 85))	('TMB', 'Chemical', '-', (55, 58))	('EGFR', 'Gene', '1956', (131, 135))	('EGFR', 'Gene', (131, 135))	('high TMB', 'Var', (50, 58))
96585	31088500	5c & d), suggesting a complicated and indirect association with gene mutation landscape with PD-1/PD-L1 axis activation in lung cancer.	('with gene mutation', 'Var', (59, 77))	('with', 'Gene', (88, 92))	('lung cancer', 'Phenotype', 'HP:0100526', (123, 134))	('PD-1/PD-L1 axis activation in lung cancer', 'Disease', (93, 134))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('PD-1/PD-L1 axis activation in lung cancer', 'Disease', 'MESH:D010300', (93, 134))
96591	31088500	Survival analysis of ADC subjects showed remarkably longer survival in low/moderate TMB plus negative PD-L1 subgroup compared to other two subgroups (Fig.	('PD-L1', 'Gene', (102, 107))	('low/moderate', 'Var', (71, 83))	('longer', 'PosReg', (52, 58))	('survival', 'MPA', (59, 67))	('TMB', 'Chemical', '-', (84, 87))
96608	30474922	Moreover, inhibition of CD44v9 expression decreased the migration and invasiveness of esophageal squamous cell carcinoma cells.	('migration', 'CPA', (56, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('decreased', 'NegReg', (42, 51))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (97, 120))	('CD44', 'Gene', '960', (24, 28))	('expression', 'MPA', (31, 41))	('invasiveness of esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (70, 120))	('rat', 'Species', '10116', (59, 62))	('invasiveness of esophageal squamous cell carcinoma', 'Disease', (70, 120))	('inhibition', 'Var', (10, 20))	('CD44', 'Gene', (24, 28))
96645	30474922	The primary antibodies used were as follows: anti-CD44v9 (LKG-M001, 1:1000 dilution; COSMO BIO LTD), glyceraldehyde 3-phosphate dehydrogenase (GAPDH) (GTX100118, 1:1000 dilution; GeneTex Inc, Irvine, CA, USA), anti-E-cadherin (24E10, 1:1000 dilution; Cell Signaling Technology Japan, Tokyo, Japan), and anti-vimentin (D21H3, 1:1000 dilution; Cell Signaling Technology Japan).	('glyceraldehyde 3-phosphate dehydrogenase', 'Gene', '403755', (101, 141))	('CD44', 'Gene', (50, 54))	('GAPDH', 'Gene', (143, 148))	('D21H3', 'Var', (318, 323))	('glyceraldehyde 3-phosphate dehydrogenase', 'Gene', (101, 141))	('GAPDH', 'Gene', '403755', (143, 148))	('CD44', 'Gene', '960', (50, 54))
96646	30474922	At 48 hour after siCD44v9 transfection, TGF-beta treatment, or combined siCD44v9 transfection and TGF-beta treatment, TE6 cells were seeded at 5000 cells/well in 96-well plates and incubated at 37 C in an atmosphere containing 5% CO2.	('CD44', 'Gene', '960', (74, 78))	('transfection', 'Var', (26, 38))	('CD44', 'Gene', (19, 23))	('transfection', 'Var', (81, 93))	('TGF-beta', 'Gene', '7040', (40, 48))	('CD44', 'Gene', (74, 78))	('TGF-beta', 'Gene', '7040', (98, 106))	('TGF-beta', 'Gene', (40, 48))	('TE6', 'CellLine', 'CVCL:1765', (118, 121))	('CO2', 'Chemical', '-', (230, 233))	('TGF-beta', 'Gene', (98, 106))	('CD44', 'Gene', '960', (19, 23))
96663	30474922	CD44v9 expression at the TIF was significantly higher in the EMT group compared with the non-EMT group (P < 0.001) (Table S2).	('higher', 'PosReg', (47, 53))	('CD44', 'Gene', '960', (0, 4))	('expression', 'MPA', (7, 17))	('EMT', 'Var', (61, 64))	('CD44', 'Gene', (0, 4))
96711	30474922	We found that the intracellular ROS level was increased 96 hours after siCD44v9 transfection and after combined siCD44v9 transfection and TGF-beta treatment (P = 0.0051 and 0.0051, respectively).	('intracellular ROS level', 'MPA', (18, 41))	('CD44', 'Gene', (114, 118))	('increased', 'PosReg', (46, 55))	('TGF-beta', 'Gene', (138, 146))	('CD44', 'Gene', '960', (73, 77))	('ROS', 'Chemical', '-', (32, 35))	('transfection', 'Var', (80, 92))	('CD44', 'Gene', (73, 77))	('TGF-beta', 'Gene', '7040', (138, 146))	('CD44', 'Gene', '960', (114, 118))
96727	28947990	We found patients in the highest tertile of NLR (>2.40), PLR (>111.00) were at significantly higher risk of DFS and CSS (P<0.05) compared with those in the lowest tertile after multivariate analysis, whereas presenting significantly higher risk in the lowest tertile of lymphocytes (<1.60x109/L) and LMR (<3.50).	('patients', 'Species', '9606', (9, 17))	('>111.00', 'Var', (62, 69))	('LMR', 'Chemical', '-', (300, 303))	('CSS', 'Disease', (116, 119))	('DFS', 'Disease', (108, 111))	('CSS', 'Chemical', '-', (116, 119))
96763	28947990	In univariate analysis, the independent variables were age (<60 vs >=60), gender, smoking history, drinking history, tumor subsite, differentiation grade, local (T1-T2 vs T3-T4) and regional (N0 vs N+) extension as well as neutrophils, platelets, lymphocytes, monocytes, NLR, PLR and LMR categories, respectively, as defined by the tertile distribution.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('LMR', 'Chemical', '-', (284, 287))	('tumor', 'Disease', (117, 122))	('T1-T2', 'Var', (162, 167))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
96768	28947990	Additionally, Patients with LMR in the lowest tertile (<3.50) had lower DFS (HR: 1.671, 95% CI: 1.260-2.217, P<0.001) and CSS (HR: 1.975, 95% CI: 1.403-2.779, P<0.001) than those in the highest tertile (>4.80).	('CSS', 'CPA', (122, 125))	('LMR', 'Var', (28, 31))	('LMR', 'Chemical', '-', (28, 31))	('lower', 'NegReg', (66, 71))	('DFS', 'MPA', (72, 75))	('CSS', 'Chemical', '-', (122, 125))	('Patients', 'Species', '9606', (14, 22))
96807	28947990	found the pretreatment PLR (>=167.2) was significantly associated with shorter progression-free survival (PFS) in patients with nasopharyngeal carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (143, 152))	('nasopharyngeal carcinoma', 'Disease', 'MESH:D000077274', (128, 152))	('progression-free survival', 'CPA', (79, 104))	('nasopharyngeal carcinoma', 'Disease', (128, 152))	('PLR (>=167.2', 'Var', (23, 35))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (128, 152))	('shorter', 'NegReg', (71, 78))	('>=167.2', 'Var', (28, 35))	('patients', 'Species', '9606', (114, 122))
96808	28947990	found the pretreatment LMR (<3.22) was a significantly associated with shorter DFS and OS in patients with head and neck cancer.	('DFS', 'CPA', (79, 82))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('LMR', 'Chemical', '-', (23, 26))	('OS', 'Chemical', '-', (87, 89))	('head and neck cancer', 'Phenotype', 'HP:0012288', (107, 127))	('neck cancer', 'Disease', 'MESH:D006258', (116, 127))	('neck cancer', 'Disease', (116, 127))	('shorter', 'NegReg', (71, 78))	('LMR (<3.22', 'Var', (23, 33))	('patients', 'Species', '9606', (93, 101))	('head', 'Disease', (107, 111))
96904	26401130	During interphase, the Ki-67 antigen can only be detected within the cell nucleus; however, in mitosis, most of the Ki-67 is relocated to the surface of the chromosomes.	('Ki-67', 'Var', (116, 121))	('mitosis', 'Disease', 'None', (95, 102))	('mitosis', 'Disease', (95, 102))
96914	26401130	The ADC of the tumour was then calculated to quantitatively analyse the degree of diffusion, using the following formula: ADC = -ln(S/S0) / (b-b0), where S0 and S are the signal intensities, obtained at three different diffusion gradients (b = 50, b = 400 and b = 800 s/mm2).	('tumour', 'Disease', (15, 21))	('tumour', 'Phenotype', 'HP:0002664', (15, 21))	('tumour', 'Disease', 'MESH:D009369', (15, 21))	('b = 50', 'Var', (240, 246))
96942	26401130	An association between the ADC value and the Ki-67 index has been shown for various kinds of tumours, including lung cancer.	('tumours', 'Disease', (93, 100))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('lung cancer', 'Disease', (112, 123))	('lung cancer', 'Phenotype', 'HP:0100526', (112, 123))	('lung cancer', 'Disease', 'MESH:D008175', (112, 123))	('ADC', 'Var', (27, 30))	('tumour', 'Phenotype', 'HP:0002664', (93, 99))	('tumours', 'Phenotype', 'HP:0002664', (93, 100))	('tumours', 'Disease', 'MESH:D009369', (93, 100))
96958	25113306	The recognition of EGFR mutation and ALK rearrangements that occur primarily in adenocarcinomas are the primary basis for the molecular revolution that has transformed lung cancer diagnosis and treatment over the past decade, and these changes have affected recent type-specific trends.	('men', 'Species', '9606', (199, 202))	('ALK', 'Gene', (37, 40))	('lung cancer', 'Disease', (168, 179))	('rearrangements', 'Var', (41, 55))	('lung cancer', 'Phenotype', 'HP:0100526', (168, 179))	('EGFR', 'Gene', '1956', (19, 23))	('adenocarcinomas', 'Disease', 'MESH:D000230', (80, 95))	('men', 'Species', '9606', (50, 53))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('ALK', 'Gene', '238', (37, 40))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('mutation', 'Var', (24, 32))	('EGFR', 'Gene', (19, 23))	('adenocarcinomas', 'Disease', (80, 95))	('lung cancer', 'Disease', 'MESH:D008175', (168, 179))	('carcinomas', 'Phenotype', 'HP:0030731', (85, 95))
96968	25113306	The morphology codes were: squamous cell carcinoma (8051-2, 8070-6, 8078, 8083-4, 8090, 8094, 8120, 8123); small cell carcinoma (8002, 8041-5); adenocarcinoma (8015, 8050, 8140-1, 8143-5, 8147, 8190, 8201, 8211, 8250-5, 8260, 8290, 8310, 8320, 8323, 8333, 8401, 8440, 8470-1, 8480-1, 8490, 8503, 8507, 8550, 8570-2, 8574, 8576); large cell carcinoma (8012-4, 8021, 8034, 8082); other specified carcinoma (8003-4, 8022, 8030-3, 8035, 8200, 8240-1, 8243-6, 8249, 8430, 8525, 8560, 8562, 8575); and unspecified malignant neoplasms (carcinoma not otherwise specified [NOS] 8010-1, 8020, 8230; non-small cell carcinoma 8046 ; malignant neoplasm NOS 8000-1).	('malignant neoplasm', 'Disease', 'MESH:D009369', (508, 526))	('carcinoma', 'Disease', 'MESH:D002277', (118, 127))	('small cell carcinoma', 'Disease', (107, 127))	('carcinoma', 'Disease', 'MESH:D002277', (149, 158))	('malignant neoplasm', 'Disease', 'MESH:D009369', (621, 639))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (27, 50))	('non-small cell carcinoma', 'Disease', (589, 613))	('small cell carcinoma', 'Disease', 'MESH:D018288', (107, 127))	('adenocarcinoma', 'Disease', 'MESH:D000230', (144, 158))	('malignant neoplasm', 'Disease', (621, 639))	('carcinoma', 'Disease', 'MESH:D002277', (394, 403))	('unspecified', 'Species', '32644', (496, 507))	('neoplasm', 'Phenotype', 'HP:0002664', (631, 639))	('carcinoma', 'Phenotype', 'HP:0030731', (41, 50))	('squamous cell carcinoma', 'Disease', (27, 50))	('carcinoma', 'Disease', (604, 613))	('8003-4', 'Var', (405, 411))	('carcinoma', 'Disease', (41, 50))	('cell carcinoma', 'Disease', (335, 349))	('cell carcinoma', 'Disease', 'MESH:C538614', (599, 613))	('malignant neoplasms', 'Disease', 'MESH:D009369', (508, 527))	('non-small cell carcinoma', 'Disease', 'MESH:D002289', (589, 613))	('cell carcinoma', 'Disease', 'MESH:C538614', (36, 50))	('malignant neoplasms', 'Disease', (508, 527))	('neoplasm', 'Phenotype', 'HP:0002664', (518, 526))	('carcinoma', 'Phenotype', 'HP:0030731', (340, 349))	('carcinoma', 'Disease', (340, 349))	('carcinoma', 'Disease', (529, 538))	('carcinoma', 'Phenotype', 'HP:0030731', (149, 158))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('neoplasms', 'Phenotype', 'HP:0002664', (518, 527))	('carcinoma', 'Disease', (118, 127))	('carcinoma', 'Disease', (149, 158))	('cell carcinoma', 'Disease', 'MESH:C538614', (113, 127))	('carcinoma', 'Disease', 'MESH:D002277', (604, 613))	('carcinoma', 'Disease', 'MESH:D002277', (41, 50))	('small cell carcinoma', 'Disease', 'MESH:D018288', (593, 613))	('cell carcinoma', 'Disease', 'MESH:C538614', (335, 349))	('carcinoma', 'Phenotype', 'HP:0030731', (394, 403))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (27, 50))	('carcinoma', 'Disease', (394, 403))	('adenocarcinoma', 'Disease', (144, 158))	('carcinoma', 'Disease', 'MESH:D002277', (340, 349))	('8012-4', 'Var', (351, 357))	('carcinoma', 'Disease', 'MESH:D002277', (529, 538))
96969	25113306	We omitted cases specified as a non-carcinoma (8580-9999) or that appeared to be a metastasis (8005, 8095, 8124, 8130, 8146, 8160, 8170, 8231, 8247, 8263, 8312, 8340-1, 8350, 8370, 8441, 8460, 8500, 8501, 8510, 8524, 8530, 8551).	('8231', 'Var', (137, 141))	('8160', 'Var', (125, 129))	('8263', 'Var', (149, 153))	('8530', 'Var', (217, 221))	('8510', 'Var', (205, 209))	('8247', 'Var', (143, 147))	('8340-1', 'Var', (161, 167))	('8170', 'Var', (131, 135))	('8005', 'Var', (95, 99))	('non-carcinoma', 'Disease', (32, 45))	('8312', 'Var', (155, 159))	('non-carcinoma', 'Disease', 'MESH:D002289', (32, 45))	('8130', 'Var', (113, 117))	('8370', 'Var', (175, 179))	('8441', 'Var', (181, 185))	('8524', 'Var', (211, 215))	('8146', 'Var', (119, 123))	('carcinoma', 'Phenotype', 'HP:0030731', (36, 45))	('8124', 'Var', (107, 111))	('8460', 'Var', (187, 191))
96970	25113306	A code for non-small cell carcinoma (8046) was added to ICD-O-3 in 2001, which was also used for some cases diagnosed prior to 2001.	('8046', 'Var', (37, 41))	('non-small cell carcinoma', 'Disease', 'MESH:D002289', (11, 35))	('non-small cell carcinoma', 'Disease', (11, 35))	('carcinoma', 'Phenotype', 'HP:0030731', (26, 35))
97037	25113306	However, changing tobacco blends decreased nicotine but increased nitrate and N-nitrosamines, and genetic selection of tobacco plants resulted in deeper inhalation, possibly contributing to the decrease in squamous and small cell carcinomas of the central airways and increase in peripheral adenocarcinomas as smokers inhale more deeply.	('carcinomas', 'Phenotype', 'HP:0030731', (296, 306))	('tobacco', 'Species', '4097', (119, 126))	('carcinomas', 'Phenotype', 'HP:0030731', (230, 240))	('squamous and small cell carcinomas', 'Disease', 'MESH:D002294', (206, 240))	('increased', 'PosReg', (56, 65))	('nicotine', 'Chemical', 'MESH:D009538', (43, 51))	('N-nitrosamines', 'Chemical', '-', (78, 92))	('genetic selection', 'Var', (98, 115))	('nicotine', 'MPA', (43, 51))	('deeper inhalation', 'MPA', (146, 163))	('nitrate', 'Chemical', 'MESH:D009566', (66, 73))	('tobacco', 'Species', '4097', (18, 25))	('carcinoma', 'Phenotype', 'HP:0030731', (230, 239))	('decreased', 'NegReg', (33, 42))	('adenocarcinomas', 'Disease', 'MESH:D000230', (291, 306))	('adenocarcinomas', 'Disease', (291, 306))	('decrease', 'NegReg', (194, 202))	('carcinoma', 'Phenotype', 'HP:0030731', (296, 305))
97058	25113306	In the large National Lung Screening Trial of persons aged 55 to 74 years with a smoking history of at least 30 pack years who were either current smokers or former smokers who quit less than 15 years ago, lung cancer incidence increased and mortality declined among those screened with low-dose computed tomography (CT) compared to those screened only with chest radiography .	('mortality', 'CPA', (242, 251))	('declined', 'NegReg', (252, 260))	('lung cancer', 'Disease', (206, 217))	('lung cancer', 'Phenotype', 'HP:0100526', (206, 217))	('to 7', 'Species', '1214577', (62, 66))	('increased', 'PosReg', (228, 237))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('low-dose', 'Var', (287, 295))	('persons', 'Species', '9606', (46, 53))	('lung cancer', 'Disease', 'MESH:D008175', (206, 217))
97129	33947015	We confirm previous reports that patients with HPV+ disease present delayed DM failure (28 vs. 11 months (p = 0.10)) and have better OS after DM failure than those with HPV-unrelated OSCC: the two-year OS rate was 75% and 15%, respectively (p = 0.0022).	('delayed DM failure', 'Disease', (68, 86))	('delayed DM failure', 'Disease', 'MESH:D009223', (68, 86))	('better', 'PosReg', (126, 132))	('patients', 'Species', '9606', (33, 41))	('DM failure', 'Disease', 'MESH:D009223', (142, 152))	('HPV+ disease', 'Var', (47, 59))	('DM failure', 'Disease', (142, 152))	('DM failure', 'Disease', 'MESH:D009223', (76, 86))	('HPV', 'Species', '10566', (169, 172))	('HPV', 'Species', '10566', (47, 50))	('OSCC', 'Phenotype', 'HP:0012182', (183, 187))
97135	33947015	HPV-positive OPSCC has improved survival in the setting of distant metastatic presentation as compared with HPV-negative disease and shows greater responsiveness to treatment.	('HPV-negative disease', 'Disease', (108, 128))	('HPV', 'Species', '10566', (0, 3))	('HPV-negative disease', 'Disease', 'MESH:D030361', (108, 128))	('OPSCC', 'Disease', (13, 18))	('survival', 'MPA', (32, 40))	('HPV', 'Species', '10566', (108, 111))	('improved', 'PosReg', (23, 31))	('HPV-positive', 'Var', (0, 12))
97163	33663617	For example, CHD1L is a well-known activator of ARHGEF9, TCTP, SPOCK1 and NTKL and can also lead to deregulation of p53, TCTP and Nur77.	('NTKL', 'Gene', (74, 78))	('NTKL', 'Gene', '57410', (74, 78))	('TCTP', 'Gene', (57, 61))	('Nur77', 'Gene', (130, 135))	('ARHGEF9', 'Gene', (48, 55))	('ARHGEF9', 'Gene', '23229', (48, 55))	('SPOCK1', 'Gene', '6695', (63, 69))	('TCTP', 'Gene', '7178', (121, 125))	('lead to', 'Reg', (92, 99))	('TCTP', 'Gene', '7178', (57, 61))	('Nur77', 'Gene', '3164', (130, 135))	('TCTP', 'Gene', (121, 125))	('p53', 'Protein', (116, 119))	('deregulation', 'MPA', (100, 112))	('SPOCK1', 'Gene', (63, 69))	('CHD1L', 'Var', (13, 18))
97185	33663617	The HELICc is not an autonomous folding unit, but is an essential part of the helicases that utilize the energy from nucleoside triphosphate hydrolysis to provide fuel for their translocation along DNA and unwinding double-stranded DNA in the process.	('nucleoside triphosphate', 'Chemical', '-', (117, 140))	('translocation along DNA', 'MPA', (178, 201))	('unwinding', 'Var', (206, 215))
97187	33663617	SelS is a disordered protein which has a seleno sulfide bond (between Cys-174 and Sec-188) and a redox potential (- 234 mV).	('redox', 'MPA', (97, 102))	('Cys', 'Chemical', 'MESH:D003545', (70, 73))	('Sec-188', 'Var', (82, 89))	('SelS', 'Gene', (0, 4))	('seleno sulfide', 'Chemical', '-', (41, 55))	('seleno sulfide bond', 'MPA', (41, 60))	('SelS', 'Gene', '55829', (0, 4))	('Cys-174', 'Var', (70, 77))
97196	33663617	PAR is produced by PAR polymerase (PARP), and single-stranded DNA breaks (SSB) and gaps can activate PARP.	('PAR', 'Chemical', 'MESH:D011064', (35, 38))	('PARP', 'Gene', '142', (101, 105))	('PARP', 'Gene', '142', (35, 39))	('PAR', 'Chemical', 'MESH:D011064', (101, 104))	('PAR', 'Chemical', 'MESH:D011064', (19, 22))	('single-stranded DNA', 'Var', (46, 65))	('PARP', 'Gene', (101, 105))	('PAR', 'Chemical', 'MESH:D011064', (0, 3))	('PARP', 'Gene', (35, 39))	('activate', 'PosReg', (92, 100))
97201	33663617	The co-operation between CHD1L and PARP is also related to the nucleotide excision repair of UV-induced DNA damage.	('PARP', 'Gene', '142', (35, 39))	('co-operation', 'Var', (4, 16))	('CHD1L', 'Gene', (25, 30))	('PARP', 'Gene', (35, 39))	('related', 'Reg', (48, 55))
97204	33663617	Loss of ALC1 confers methyl-methanesulfonate, PARP inhibitors and formyl-dU sensitivity, which is synthetic lethal with homologous recombination deficiency (HRD).	('HRD', 'Disease', 'None', (157, 160))	('formyl-dU sensitivity', 'MPA', (66, 87))	('ALC1', 'Gene', (8, 12))	('formyl-dU', 'Chemical', '-', (66, 75))	('PARP', 'Gene', '142', (46, 50))	('deficiency', 'Disease', (145, 155))	('methyl-methanesulfonate', 'Chemical', 'MESH:D008741', (21, 44))	('deficiency', 'Disease', 'MESH:D007153', (145, 155))	('HRD', 'Disease', (157, 160))	('methyl-methanesulfonate', 'MPA', (21, 44))	('PARP', 'Gene', (46, 50))	('ALC1', 'Gene', '9557', (8, 12))	('Loss', 'Var', (0, 4))
97213	33663617	Three different heterozygous missense variants of CHD1L (variant Gly700Arg, variant Ile765Met and variant Ile827Val) were revealed by sequencing the entire coding region of the CHD1L gene in 61 CAKUT patients and exons 18, 19 and 21 in 24 CAKUT patients.	('CHD1L', 'Gene', (50, 55))	('patients', 'Species', '9606', (200, 208))	('patients', 'Species', '9606', (245, 253))	('Ile765Met', 'Mutation', 'rs148289715', (84, 93))	('Ile827Val', 'Var', (106, 115))	('Ile765Met', 'Var', (84, 93))	('Gly700Arg', 'SUBSTITUTION', 'None', (65, 74))	('Gly700Arg', 'Var', (65, 74))	('Ile827Val', 'Mutation', 'rs148434783', (106, 115))	('CHD1L', 'Gene', (177, 182))
97214	33663617	The interaction between all three CHD1L variants and PARP1 decreased compared with the wild-type CHD1L.	('interaction', 'Interaction', (4, 15))	('decreased', 'NegReg', (59, 68))	('CHD1L', 'Gene', (34, 39))	('PARP1', 'Gene', '142', (53, 58))	('PARP1', 'Gene', (53, 58))	('variants', 'Var', (40, 48))
97218	33663617	CHD1L can promote G1/S transition and DNA synthesis by upregulating cyclins, CDK2, 4 and downregulating P27, Rb and p53 in transgenic mouse models.	('CDK2', 'Gene', (77, 81))	('G1/S transition', 'CPA', (18, 33))	('P27', 'Gene', '12576', (104, 107))	('cyclins', 'Protein', (68, 75))	('upregulating', 'PosReg', (55, 67))	('P27', 'Gene', (104, 107))	('Rb', 'Gene', '19645', (109, 111))	('DNA synthesis', 'MPA', (38, 51))	('promote', 'PosReg', (10, 17))	('p53', 'Protein', (116, 119))	('CDK2', 'Gene', '12566', (77, 81))	('CHD1L', 'Var', (0, 5))	('downregulating', 'NegReg', (89, 103))	('mouse', 'Species', '10090', (134, 139))
97222	33663617	CHD1L could induce G1/S transition by the dysregulation of p53-cyclinE-CDK2 pathway in glioma.	('glioma', 'Disease', (87, 93))	('CDK2', 'Gene', '12566', (71, 75))	('dysregulation', 'Var', (42, 55))	('glioma', 'Disease', 'MESH:D005910', (87, 93))	('glioma', 'Phenotype', 'HP:0009733', (87, 93))	('induce', 'PosReg', (12, 18))	('G1/S', 'Disease', (19, 23))	('CDK2', 'Gene', (71, 75))
97224	33663617	The dysregulation of p53-cyclin D1-CDK2 pathway might be related to CHD1L-induced G1/S transition, while CHD1L might drive EMT and MET and cause metastasis of cholangiocarcinoma cells.	('carcinoma', 'Phenotype', 'HP:0030731', (168, 177))	('metastasis', 'CPA', (145, 155))	('cyclin D1', 'Gene', '595', (25, 34))	('dysregulation', 'Var', (4, 17))	('CDK2', 'Gene', '12566', (35, 39))	('MET', 'Gene', '79811', (131, 134))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (159, 177))	('cholangiocarcinoma', 'Disease', (159, 177))	('drive', 'PosReg', (117, 122))	('CDK2', 'Gene', (35, 39))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (159, 177))	('CHD1L', 'Var', (105, 110))	('MET', 'Gene', (131, 134))	('cause', 'Reg', (139, 144))	('EMT', 'CPA', (123, 126))	('cyclin D1', 'Gene', (25, 34))
97227	33663617	Taken together, inappropriate expression of CHD1L target genes and deregulation of CHD1L system may link CHD1L to tumorigenesis by several mechanisms (Fig.	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('CHD1L', 'Gene', (83, 88))	('tumor', 'Disease', (114, 119))	('link', 'Reg', (100, 104))	('deregulation', 'Var', (67, 79))	('CHD1L', 'Gene', (105, 110))
97253	33663617	ABCB1 knockdown coupled with CHD1L ectopic expression enhanced the effect of cisplatin on apoptosis of NSCLC cells.	('effect', 'MPA', (67, 73))	('ABCB1', 'Gene', (0, 5))	('cisplatin', 'MPA', (77, 86))	('NSCLC', 'Disease', (103, 108))	('NSCLC', 'Disease', 'MESH:D002289', (103, 108))	('cisplatin', 'Chemical', 'MESH:D002945', (77, 86))	('knockdown', 'Var', (6, 15))	('apoptosis', 'CPA', (90, 99))	('enhanced', 'PosReg', (54, 62))
97258	33663617	However, elevated beta-catenin expression exhibited in the CHD1L-KD group in glioma.	('elevated', 'PosReg', (9, 17))	('beta-catenin', 'Gene', (18, 30))	('beta-catenin', 'Gene', '1499', (18, 30))	('CHD1L-KD', 'Var', (59, 67))	('glioma', 'Disease', (77, 83))	('glioma', 'Disease', 'MESH:D005910', (77, 83))	('glioma', 'Phenotype', 'HP:0009733', (77, 83))
97261	33663617	Overexpression of CHD1L inhibits the expression of p53 in HCC, breast cancer and glioma, makes p53 lose its anti-cancer effect.	('glioma', 'Phenotype', 'HP:0009733', (81, 87))	('p53', 'Gene', (51, 54))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('p53', 'Var', (95, 98))	('breast cancer', 'Disease', 'MESH:D001943', (63, 76))	('inhibits', 'NegReg', (24, 32))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('glioma', 'Disease', (81, 87))	('cancer', 'Disease', (113, 119))	('breast cancer', 'Disease', (63, 76))	('breast cancer', 'Phenotype', 'HP:0003002', (63, 76))	('HCC', 'Disease', (58, 61))	('lose', 'NegReg', (99, 103))	('expression', 'MPA', (37, 47))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('glioma', 'Disease', 'MESH:D005910', (81, 87))
97262	33663617	p53 protein can upregulate p21 expression, and the latter acts as a Cdk2 inhibitor, inactivating cyclinE-CDk2 complex to control the S phase entry.	('control', 'Reg', (121, 128))	('p21', 'Gene', (27, 30))	('inactivating', 'NegReg', (84, 96))	('protein', 'Protein', (4, 11))	('p21', 'Gene', '644914', (27, 30))	('upregulate', 'PosReg', (16, 26))	('Cdk2', 'Gene', '1017', (68, 72))	('p53', 'Var', (0, 3))	('Cdk2', 'Gene', (68, 72))	('S phase entry', 'MPA', (133, 146))	('CDk2', 'Gene', (105, 109))	('CDk2', 'Gene', '1017', (105, 109))
97268	33663617	Macro domain of CHD1L acts to interact with Nur77, while the CHD1L mutants lacking residues 600-897 cannot interact with Nur77 and prevents Nur77-mediated apoptosis of hepatocellular carcinoma.	('CHD1L', 'Gene', (61, 66))	('Nur77', 'Gene', '3164', (121, 126))	('Nur77', 'Gene', (44, 49))	('Nur77', 'Gene', (140, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (183, 192))	('Nur77', 'Gene', '3164', (44, 49))	('mutants', 'Var', (67, 74))	('Nur77', 'Gene', '3164', (140, 145))	('Nur77', 'Gene', (121, 126))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (168, 192))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (168, 192))	('interact', 'Interaction', (30, 38))	('hepatocellular carcinoma', 'Disease', (168, 192))	('prevents', 'NegReg', (131, 139))
97277	33663617	Lysine methylation at a specific site on the histone H3 tails is associated with transcriptional regulation.	('transcriptional regulation', 'MPA', (81, 107))	('Lysine methylation', 'Var', (0, 18))	('associated', 'Reg', (65, 75))	('histone', 'Protein', (45, 52))	('Lysine', 'Chemical', 'MESH:D008239', (0, 6))
97286	33663617	Full length CHD1 is required in embryonic stem cell differentiation, and loss of the serine-rich region (SRR) renders CHD1 unable to support normal differentiation of ESCs into the three germ layers.	('unable', 'NegReg', (123, 129))	('CHD1', 'Gene', '1105', (12, 16))	('CHD1', 'Gene', '1105', (118, 122))	('loss', 'Var', (73, 77))	('CHD1', 'Gene', (118, 122))	('serine', 'Chemical', 'MESH:D012694', (85, 91))	('CHD1', 'Gene', (12, 16))
97287	33663617	Endothelial-specific deletion of CHD1 leads to loss of definitive hematopoietic progenitors, anemia, and lethality by embryonic day (E)15.5.	('anemia', 'Disease', (93, 99))	('CHD1', 'Gene', '1105', (33, 37))	('anemia', 'Disease', 'MESH:D000740', (93, 99))	('deletion', 'Var', (21, 29))	('loss', 'NegReg', (47, 51))	('anemia', 'Phenotype', 'HP:0001903', (93, 99))	('lethality', 'CPA', (105, 114))	('CHD1', 'Gene', (33, 37))
97288	33663617	CHD1 is the 5q21 tumor suppressor gene, and inactivation of CHD1 abolishes recruitment of androgen receptor (AR) to result in downregulation of AR-responsive genes (eg.	('CHD1', 'Gene', (60, 64))	('CHD1', 'Gene', '1105', (60, 64))	('tumor', 'Disease', (17, 22))	('downregulation', 'NegReg', (126, 140))	('androgen receptor', 'Gene', (90, 107))	('CHD1', 'Gene', (0, 4))	('recruitment', 'MPA', (75, 86))	('AR', 'Gene', '367', (109, 111))	('AR', 'Gene', '367', (144, 146))	('CHD1', 'Gene', '1105', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('androgen receptor', 'Gene', '367', (90, 107))	('abolishes', 'NegReg', (65, 74))	('inactivation', 'Var', (44, 56))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
97290	33663617	Recurrent deletion of CHD1 is a driver of prostate cancer cell invasiveness.	('CHD1', 'Gene', (22, 26))	('prostate cancer', 'Phenotype', 'HP:0012125', (42, 57))	('CHD1', 'Gene', '1105', (22, 26))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('prostate cancer', 'Disease', (42, 57))	('deletion', 'Var', (10, 18))	('prostate cancer', 'Disease', 'MESH:D011471', (42, 57))
97292	33663617	a novel CHD1-RUNX1 fusion collaborated with FLT3-ITD mutation in the development of acute myeloid leukemia.	('leukemia', 'Phenotype', 'HP:0001909', (98, 106))	('acute myeloid leukemia', 'Disease', (84, 106))	('fusion', 'Var', (19, 25))	('CHD1', 'Gene', '1105', (8, 12))	('RUNX1', 'Gene', '861', (13, 18))	('FLT3', 'Gene', '2322', (44, 48))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (84, 106))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (90, 106))	('FLT3', 'Gene', (44, 48))	('RUNX1', 'Gene', (13, 18))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (84, 106))	('CHD1', 'Gene', (8, 12))
97303	33663617	The abnormal expression of CHD1L may be prognostic factor of ACC, HNSC, KICH, KIRC, KIRP, LIHC, LUAD, MESO, SARC and THCA (Fig.	('KICH', 'Disease', 'None', (72, 76))	('ACC', 'Gene', (61, 64))	('abnormal', 'Var', (4, 12))	('LUAD', 'Disease', (96, 100))	('expression', 'MPA', (13, 23))	('HNSC', 'Disease', (66, 70))	('THCA', 'Chemical', '-', (117, 121))	('CHD1L', 'Gene', (27, 32))	('ACC', 'Gene', '31', (61, 64))	('AR', 'Gene', '367', (109, 111))	('MESO', 'Disease', (102, 106))	('KICH', 'Disease', (72, 76))
97314	33663617	reveal CHD1L manipulation impacts the single-strand DNA break repair response and potentiates PARPi-induced cancer killing through PARP2 trapping.	('single-strand DNA break repair response', 'MPA', (38, 77))	('impacts', 'Reg', (26, 33))	('PARP', 'Gene', '142', (94, 98))	('PARP', 'Gene', '142', (131, 135))	('CHD1L', 'Gene', (7, 12))	('manipulation', 'Var', (13, 25))	('cancer', 'Disease', (108, 114))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('PARP2', 'Gene', '10038', (131, 136))	('potentiates', 'PosReg', (82, 93))	('PARP', 'Gene', (94, 98))	('PARP', 'Gene', (131, 135))	('PARP2', 'Gene', (131, 136))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
97332	33280526	miR-214 was reduced in CSCC tissues and cells, and the survival of patients harboring overexpression of miR-214 was higher.	('CSCC', 'Phenotype', 'HP:0006739', (23, 27))	('patients', 'Species', '9606', (67, 75))	('higher', 'PosReg', (116, 122))	('reduced', 'NegReg', (12, 19))	('overexpression', 'PosReg', (86, 100))	('survival', 'CPA', (55, 63))	('miR-214', 'Gene', (0, 7))	('miR-214', 'Var', (104, 111))
97343	33280526	Moreover, the dysregulation of miRNAs is well-known to be participated in the progression of CSCC.	('participated', 'Reg', (58, 70))	('dysregulation', 'Var', (14, 27))	('miR', 'Gene', '220972', (31, 34))	('miR', 'Gene', (31, 34))	('CSCC', 'Phenotype', 'HP:0006739', (93, 97))	('CSCC', 'Disease', (93, 97))
97363	33280526	The significant criteria for significantly downregulated miRNAs in CSCC tissues were  Log2Foldchange  > 1.5 and p values < 0.05.	('downregulated', 'NegReg', (43, 56))	('miR', 'Gene', '220972', (57, 60))	('CSCC', 'Phenotype', 'HP:0006739', (67, 71))	('miR', 'Gene', (57, 60))	('Log2Foldchange', 'Var', (86, 100))
97390	33280526	So, we analyzed the expression of miR-214 in cancer and adjacent tissues of all patients, and observed that although there was a slight difference in the miR-214 expression among different patients, the overall expression of miR-214 in CSCC tissues was much lower than that in adjacent tissues.	('CSCC', 'Phenotype', 'HP:0006739', (236, 240))	('patients', 'Species', '9606', (80, 88))	('miR-214', 'Var', (225, 232))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('lower', 'NegReg', (258, 263))	('CSCC', 'Disease', (236, 240))	('miR-214', 'Gene', (154, 161))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('patients', 'Species', '9606', (189, 197))	('cancer', 'Disease', (45, 51))	('expression', 'MPA', (211, 221))
97392	33280526	The survival rate of patients with high miR-214 expression was higher than that those with low miR-214 expression (Figure 1C).	('survival rate', 'CPA', (4, 17))	('patients', 'Species', '9606', (21, 29))	('expression', 'Var', (48, 58))	('high miR-214 expression', 'Var', (35, 58))	('higher', 'PosReg', (63, 69))
97396	33280526	Flow cytometry showed that the number of PI-Annexin V dual positive cells was increased significantly (Figure 2C), which showed that miR-214 reduced the ability of CSCC cells proliferation and enhanced the ability of apoptosis.	('Annexin V', 'Gene', '308', (44, 53))	('Annexin V', 'Gene', (44, 53))	('reduced', 'NegReg', (141, 148))	('CSCC', 'Phenotype', 'HP:0006739', (164, 168))	('CSCC cells proliferation', 'CPA', (164, 188))	('apoptosis', 'CPA', (217, 226))	('miR-214', 'Var', (133, 140))	('enhanced', 'PosReg', (193, 201))
97404	33280526	The survival of patients with low VEGFA/Bcl2 expression was higher (Figure 3G and H), which made us wonder whether miR-214 functions in CSCC cells by targeting these 2 genes.	('Bcl2', 'Gene', '596', (40, 44))	('higher', 'PosReg', (60, 66))	('targeting', 'Reg', (150, 159))	('CSCC', 'Phenotype', 'HP:0006739', (136, 140))	('patients', 'Species', '9606', (16, 24))	('survival', 'CPA', (4, 12))	('low', 'Var', (30, 33))	('VEGFA', 'Gene', '7422', (34, 39))	('expression', 'MPA', (45, 55))	('Bcl2', 'Gene', (40, 44))	('VEGFA', 'Gene', (34, 39))
97405	33280526	Consequently, we detected changes in VEGFA and Bcl-2 expression in cells overexpressing miR-214 and found that miR-214 reduced VEGFA and Bcl-2 expression (Figure 3I).	('VEGFA', 'Gene', (127, 132))	('VEGFA', 'Gene', '7422', (37, 42))	('expression', 'MPA', (143, 153))	('miR-214', 'Var', (111, 118))	('changes', 'Reg', (26, 33))	('VEGFA', 'Gene', '7422', (127, 132))	('VEGFA', 'Gene', (37, 42))	('miR-214', 'Var', (88, 95))	('Bcl-2', 'Gene', (47, 52))	('Bcl-2', 'Gene', '596', (47, 52))	('expression', 'MPA', (53, 63))	('Bcl-2', 'Gene', (137, 142))	('reduced', 'NegReg', (119, 126))	('Bcl-2', 'Gene', '596', (137, 142))
97409	33280526	Similarly, by flow cytometry, we found that the number of cell apoptosis decreased after transfection of VEGFA/Bcl-2 and miR-214 overexpression (Figure 4D).	('miR-214', 'Gene', (121, 128))	('VEGFA', 'Gene', '7422', (105, 110))	('Bcl-2', 'Gene', (111, 116))	('decreased', 'NegReg', (73, 82))	('Bcl-2', 'Gene', '596', (111, 116))	('transfection', 'Var', (89, 101))	('overexpression', 'PosReg', (129, 143))	('VEGFA', 'Gene', (105, 110))
97412	33280526	As a result, we examined the beta-catenin and Cyclin D1 protein expression in miR-214-overexpressed cells and found that the pathway activity was decreased following miR-214 overexpression.	('Cyclin D1', 'Gene', '595', (46, 55))	('examined', 'Reg', (16, 24))	('miR-214', 'Var', (166, 173))	('Cyclin D1', 'Gene', (46, 55))	('decreased', 'NegReg', (146, 155))	('overexpression', 'PosReg', (174, 188))	('beta-catenin', 'Gene', (29, 41))	('beta-catenin', 'Gene', '1499', (29, 41))	('activity', 'MPA', (133, 141))
97413	33280526	Meanwhile, miR-214 mimic + VEGFA/Bcl-2 OE significantly increased the pathway activity in CSCC cells compared with overexpression miR-214 mimic alone, which also provides forceful evidence for miR-214 targeting VEGFA and Bcl-2 in CSCC cells (Figure 5).	('VEGFA', 'Gene', (27, 32))	('VEGFA', 'Gene', '7422', (211, 216))	('increased', 'PosReg', (56, 65))	('Bcl-2', 'Gene', (221, 226))	('miR-214', 'Var', (193, 200))	('Bcl-2', 'Gene', (33, 38))	('Bcl-2', 'Gene', '596', (221, 226))	('Bcl-2', 'Gene', '596', (33, 38))	('CSCC', 'Phenotype', 'HP:0006739', (230, 234))	('pathway activity', 'MPA', (70, 86))	('VEGFA', 'Gene', '7422', (27, 32))	('VEGFA', 'Gene', (211, 216))	('CSCC', 'Phenotype', 'HP:0006739', (90, 94))	('miR-214', 'Var', (11, 18))	('CSCC', 'Disease', (90, 94))
97415	33280526	In the current study, miR-214 expression was reduced in A431 and SCC13 cell lines, while the restoration of miR-214 suppressed the proliferation, migration and invasion, yet enhanced the apoptosis of A431 and SCC13 cells.	('enhanced', 'PosReg', (174, 182))	('expression', 'MPA', (30, 40))	('migration', 'CPA', (146, 155))	('apoptosis', 'CPA', (187, 196))	('invasion', 'CPA', (160, 168))	('suppressed', 'NegReg', (116, 126))	('restoration', 'Var', (93, 104))	('miR-214', 'Gene', (22, 29))	('proliferation', 'CPA', (131, 144))	('A431', 'CellLine', 'CVCL:0037', (200, 204))	('SCC13', 'CellLine', 'CVCL:4029', (209, 214))	('A431', 'CellLine', 'CVCL:0037', (56, 60))	('SCC13', 'CellLine', 'CVCL:4029', (65, 70))	('miR-214', 'Gene', (108, 115))
97416	33280526	Furthermore, we also discovered that VEGFA and Bcl-2 were putative targets of miR-214, which could be diminished by the upregulation of miR-214 and therefore disrupted the Wnt/beta-catenin pathway in A431 and SCC13 cells.	('VEGFA', 'Gene', '7422', (37, 42))	('beta-catenin', 'Gene', (176, 188))	('diminished', 'NegReg', (102, 112))	('miR-214', 'Gene', (78, 85))	('miR-214', 'Var', (136, 143))	('disrupted', 'NegReg', (158, 167))	('beta-catenin', 'Gene', '1499', (176, 188))	('A431', 'CellLine', 'CVCL:0037', (200, 204))	('Bcl-2', 'Gene', (47, 52))	('VEGFA', 'Gene', (37, 42))	('Bcl-2', 'Gene', '596', (47, 52))	('SCC13', 'CellLine', 'CVCL:4029', (209, 214))	('upregulation', 'PosReg', (120, 132))
97419	33280526	In line with our data, the overall survival of patients with multiple myeloma harboring high expression of miR-214 was significantly improved.	('miR-214', 'Gene', (107, 114))	('myeloma', 'Disease', 'MESH:D009101', (70, 77))	('high expression', 'Var', (88, 103))	('patients', 'Species', '9606', (47, 55))	('myeloma', 'Disease', (70, 77))	('improved', 'PosReg', (133, 141))	('multiple myeloma', 'Phenotype', 'HP:0006775', (61, 77))
97421	33280526	Consistently, miR-214-5p enhancement resulted in declines in the osteosarcoma cell proliferation, migration and invasion, and miR-214-5p inhibition contributed to the opposite trends.	('declines', 'NegReg', (49, 57))	('osteosarcoma', 'Phenotype', 'HP:0002669', (65, 77))	('osteosarcoma', 'Disease', (65, 77))	('invasion', 'CPA', (112, 120))	('osteosarcoma', 'Disease', 'MESH:D012516', (65, 77))	('miR-214-5p', 'Var', (14, 24))	('enhancement', 'PosReg', (25, 36))
97422	33280526	Meanwhile, miR-214-3p was notably decreased in colon cancer, and upregulation of miR-214-3p repressed the proliferation and migration of colon cancer cells in vivo and in vitro.	('miR-214-3p', 'Chemical', '-', (11, 21))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('colon cancer', 'Phenotype', 'HP:0003003', (47, 59))	('decreased', 'NegReg', (34, 43))	('colon cancer', 'Phenotype', 'HP:0003003', (137, 149))	('migration', 'CPA', (124, 133))	('upregulation', 'PosReg', (65, 77))	('colon cancer', 'Disease', 'MESH:D015179', (47, 59))	('colon cancer', 'Disease', 'MESH:D015179', (137, 149))	('repressed', 'NegReg', (92, 101))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('colon cancer', 'Disease', (137, 149))	('miR-214-3p', 'Chemical', '-', (81, 91))	('colon cancer', 'Disease', (47, 59))	('miR-214-3p', 'MPA', (11, 21))	('proliferation', 'CPA', (106, 119))	('miR-214-3p', 'Var', (81, 91))
97423	33280526	For exploring the mechanism through which miR-214 affects the properties of CSCC cells, we identified that VEGFA and Bcl-2 are 2 targets of miR-214 and could predict dismal survival of patients with CSCC.	('Bcl-2', 'Gene', '596', (117, 122))	('VEGFA', 'Gene', (107, 112))	('CSCC', 'Phenotype', 'HP:0006739', (199, 203))	('CSCC', 'Disease', (199, 203))	('CSCC', 'Phenotype', 'HP:0006739', (76, 80))	('miR-214', 'Var', (140, 147))	('patients', 'Species', '9606', (185, 193))	('VEGFA', 'Gene', '7422', (107, 112))	('predict', 'Reg', (158, 165))	('Bcl-2', 'Gene', (117, 122))
97426	33280526	In non-small cell lung cancer, VEGFA silencing reversed the stimulative role of circ0021205 in cell proliferative, migratory, and invasive abilities.	('lung cancer', 'Disease', 'MESH:D008175', (18, 29))	('VEGFA', 'Gene', (31, 36))	('invasive abilities', 'CPA', (130, 148))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (3, 29))	('silencing', 'Var', (37, 46))	('lung cancer', 'Phenotype', 'HP:0100526', (18, 29))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (7, 29))	('lung cancer', 'Disease', (18, 29))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('cell proliferative', 'CPA', (95, 113))	('VEGFA', 'Gene', '7422', (31, 36))
97429	33280526	On the other hand, miR-365 was found to compromised the migration and invasion, whereas enhanced apoptosis in melanoma cell lines, which was at least partially due to downregulation of the oncogene Bcl-2.	('migration', 'CPA', (56, 65))	('melanoma', 'Disease', 'MESH:D008545', (110, 118))	('miR-365', 'Chemical', '-', (19, 26))	('melanoma', 'Disease', (110, 118))	('downregulation', 'NegReg', (167, 181))	('melanoma', 'Phenotype', 'HP:0002861', (110, 118))	('miR-365', 'Var', (19, 26))	('Bcl-2', 'Gene', (198, 203))	('Bcl-2', 'Gene', '596', (198, 203))	('invasion', 'CPA', (70, 78))	('enhanced', 'PosReg', (88, 96))	('apoptosis', 'CPA', (97, 106))	('compromised', 'NegReg', (40, 51))
97432	33280526	The significance of the Wnt/beta-catenin signaling in CSCC initiation and progression has been underscored, and knockdown of beta-catenin led to a marked decline in the colony-forming activity of SCC12 cells.	('colony-forming activity of SCC12 cells', 'CPA', (169, 207))	('CSCC', 'Phenotype', 'HP:0006739', (54, 58))	('beta-catenin', 'Gene', (28, 40))	('CSCC', 'Disease', (54, 58))	('beta-catenin', 'Gene', (125, 137))	('beta-catenin', 'Gene', '1499', (28, 40))	('knockdown', 'Var', (112, 121))	('beta-catenin', 'Gene', '1499', (125, 137))	('SCC12', 'CellLine', 'CVCL:4026', (196, 201))	('decline', 'NegReg', (154, 161))
97433	33280526	circ_CHFR knockdown was observed to impede the beta-catenin expression via promoting miR-214-3p.	('beta-catenin', 'Gene', '1499', (47, 59))	('CHFR', 'Disease', (5, 9))	('impede', 'NegReg', (36, 42))	('miR-214-3p', 'MPA', (85, 95))	('CHFR', 'Disease', 'None', (5, 9))	('beta-catenin', 'Gene', (47, 59))	('miR-214-3p', 'Chemical', '-', (85, 95))	('promoting', 'PosReg', (75, 84))	('knockdown', 'Var', (10, 19))
97437	33280526	In conclusion, our study provided robust evidence that miR-214 blunted the Wnt/beta-catenin pathway by inhibiting VEGFA and Bcl-2, contributing to impeded CSCC progression (Figure 6), which offers a potent therapeutic target for CSCC.	('miR-214', 'Var', (55, 62))	('CSCC', 'Phenotype', 'HP:0006739', (229, 233))	('Bcl-2', 'Gene', (124, 129))	('VEGFA', 'Gene', (114, 119))	('Bcl-2', 'Gene', '596', (124, 129))	('beta-catenin', 'Gene', '1499', (79, 91))	('impeded', 'NegReg', (147, 154))	('inhibiting', 'NegReg', (103, 113))	('CSCC', 'Phenotype', 'HP:0006739', (155, 159))	('VEGFA', 'Gene', '7422', (114, 119))	('blunted', 'NegReg', (63, 70))	('beta-catenin', 'Gene', (79, 91))	('CSCC', 'Disease', (155, 159))
97466	31646252	At low passage (<5), CAFs were plated in 10 cm plates and grown in 5% CO2 at 37  C. Cells were lysed and RNA was isolated using a Qiagen RNeasy kit (Cat # 74104, Qiagen, Hilden, Germany), with on-column DNase-1 digestion (79254, Qiagen).	('N', 'Chemical', 'MESH:D009584', (204, 205))	('Cat # 74104', 'Var', (149, 160))	('N', 'Chemical', 'MESH:D009584', (106, 107))	('CAF', 'Chemical', 'MESH:C035000', (21, 24))	('N', 'Chemical', 'MESH:D009584', (138, 139))	('DNase-1', 'Gene', (203, 210))	('CO2', 'Chemical', 'MESH:D002245', (70, 73))	('DNase-1', 'Gene', '1773', (203, 210))
97469	31646252	Pulmonary arterial smooth muscle cells (PASMCs) were obtained from Lonza (Cat # CC-2581, Walkersville, MD) and were cultured in 5% CO2 at 37  C in low-glucose DMEM with 5% FBS, epidermal growth factor (5 ng/mL), FGF2 (5 ng/mL, Cat # 130093837, Miltenyi Biotec), insulin (same as above), and ascorbic acid (50 mug/mL).	('Cat # 130093837', 'Var', (227, 242))	('insulin', 'Gene', '3630', (262, 269))	('FGF2', 'Gene', (212, 216))	('ascorbic acid', 'Chemical', 'MESH:D001205', (291, 304))	('epidermal growth factor', 'Gene', (177, 200))	('low-glucose', 'Phenotype', 'HP:0001943', (147, 158))	('FGF2', 'Gene', '2247', (212, 216))	('CO2', 'Chemical', 'MESH:D002245', (131, 134))	('insulin', 'Gene', (262, 269))	('epidermal growth factor', 'Gene', '1950', (177, 200))	('glucose', 'Chemical', 'MESH:D005947', (151, 158))
97490	31646252	For calcium assays and wound-healing assays, we used the following GPCR agonists: Neurotensin (Cat # 1909, Tocris, Minneapolis, MN); 2-Thio-UTP (Cat # 3280, Tocris); histamine (Cat # AAJ6172703, Fischer Scientific); oxytocin (Cat # 1910, Tocris); and sulprostone (Cat # 14765, Cayman Chemical).	('Cat', 'Var', (95, 98))	('sulprostone', 'Chemical', 'MESH:C016767', (251, 262))	('GPCR', 'Gene', (67, 71))	('GPCR', 'Gene', '10663', (67, 71))	('N', 'Chemical', 'MESH:D009584', (82, 83))	('Neurotensin', 'Gene', (82, 93))	('Neurotensin', 'Gene', '4922', (82, 93))	('2-Thio-UTP', 'Chemical', 'MESH:C501084', (133, 143))	('oxytocin', 'Chemical', 'MESH:D010121', (216, 224))	('N', 'Chemical', 'MESH:D009584', (129, 130))	('histamine', 'Chemical', 'MESH:D006632', (166, 175))	('Cat # AAJ6172703', 'Var', (177, 193))	('AAJ6172703', 'Chemical', 'None', (183, 193))	('calcium', 'Chemical', 'MESH:D002118', (4, 11))
97556	31646252	Nearly, half of all identified GPCRs appears to show alternative splicing.	('N', 'Chemical', 'MESH:D009584', (0, 1))	('GPCR', 'Gene', (31, 35))	('alternative splicing', 'Var', (53, 73))	('GPCR', 'Gene', '10663', (31, 35))
97604	31646252	Other qPCR-based arrays are available that may yield comparable data but at a lower cost than TaqMan arrays, e.g., SYBR green-based arrays [e.g., Cat # 10034500 (Bio-Rad) and Cat # PAHS-071Z (Qiagen)].	('Rad', 'Gene', (166, 169))	('Rad', 'Gene', '6236', (166, 169))	('Cat # 10034500', 'Var', (146, 160))	('PAHS-071Z', 'Chemical', 'MESH:D017332', (181, 190))	('Cat # PAHS-071Z', 'Var', (175, 190))
97616	31646252	Multiple studies of "GPCRomics" combined with signaling and functional analyses have revealed novel roles for GPCRs in numerous cell types.- A growing number of studies have also begun to reveal the extent to which the presence of splice variants among GPCRs may impact their functional activity.	('impact', 'Reg', (263, 269))	('GPCR', 'Gene', '10663', (21, 25))	('GPCR', 'Gene', '10663', (110, 114))	('GPCR', 'Gene', (253, 257))	('GPCR', 'Gene', (21, 25))	('GPCR', 'Gene', (110, 114))	('splice variants', 'Var', (231, 246))	('GPCR', 'Gene', '10663', (253, 257))	('functional activity', 'MPA', (276, 295))
97617	31646252	Consequences of such alternative splicing include the presence of receptor isoforms with altered ligand binding (primarily due to changes in the N-terminus), altered downstream signaling (including "decoy" receptors that bind ligands but have no functional activity), and potential effects on receptor trafficking, internalization, and localization within specific cellular domains.	('trafficking', 'MPA', (302, 313))	('localization', 'MPA', (336, 348))	('bind', 'Interaction', (221, 225))	('changes', 'Reg', (130, 137))	('effects', 'Reg', (282, 289))	('binding', 'Interaction', (104, 111))	('N', 'Chemical', 'MESH:D009584', (145, 146))	('downstream signaling', 'MPA', (166, 186))	('ligand', 'MPA', (97, 103))	('altered', 'Reg', (158, 165))	('altered', 'Reg', (89, 96))	('internalization', 'MPA', (315, 330))	('alternative splicing', 'Var', (21, 41))
97635	31646252	These include: (a) what is the functional impact of alternative splicing of GPCRs?	('GPCR', 'Gene', (76, 80))	('alternative splicing', 'Var', (52, 72))	('GPCR', 'Gene', '10663', (76, 80))
97696	28432899	Among these miRNAs, three miRNAs expressed statistically significantly different between two groups: miRNA-136-5p was down-regulated expression in resistant group while miR-152-3p and miR-206 were up-regulated expression (P < .05, Table 2).	('miR-206', 'Gene', '406989', (184, 191))	('expression', 'MPA', (133, 143))	('up-regulated', 'PosReg', (197, 209))	('miRNA-136-5p', 'Var', (101, 113))	('miR-152', 'Gene', '406943', (169, 176))	('miR-152', 'Gene', (169, 176))	('down-regulated', 'NegReg', (118, 132))	('miR-206', 'Gene', (184, 191))
97731	28432899	In breast cancer, miR-206 expression is decreased in ERa-positive patients, restoration of miR-206 in estrogen-dependent breast cancer cells inhibits cell growth and that reduced expression levels of miR-206 is associated with breast cancer metastasis.	('restoration', 'Var', (76, 87))	('miR-206', 'Gene', '406989', (200, 207))	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('expression', 'MPA', (26, 36))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('inhibits', 'NegReg', (141, 149))	('breast cancer', 'Phenotype', 'HP:0003002', (227, 240))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('cell growth', 'CPA', (150, 161))	('miR-206', 'Gene', (91, 98))	('expression levels', 'MPA', (179, 196))	('breast cancer metastasis', 'Disease', 'MESH:D009362', (227, 251))	('miR-206', 'Gene', '406989', (91, 98))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('breast cancer', 'Disease', 'MESH:D001943', (227, 240))	('breast cancer', 'Phenotype', 'HP:0003002', (121, 134))	('associated', 'Reg', (211, 221))	('patients', 'Species', '9606', (66, 74))	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('breast cancer', 'Disease', (3, 16))	('breast cancer', 'Disease', 'MESH:D001943', (121, 134))	('breast cancer metastasis', 'Disease', (227, 251))	('breast cancer', 'Disease', (121, 134))	('miR-206', 'Gene', (18, 25))	('miR-206', 'Gene', (200, 207))	('miR-206', 'Gene', '406989', (18, 25))	('reduced', 'NegReg', (171, 178))
97817	25984601	The OEC-M1 cell line is a human oral epidermoid carcinoma generated from the primary lesion of an oral carcinoma in a Taiwanese patient, which is a p53 mutant, resistant to retinoic acid treatment, and expresses smaller sized hypophosphorylated Rb proteins compared with normal cells.	('retinoic acid', 'Chemical', 'MESH:D014212', (173, 186))	('hypophosphorylated Rb proteins', 'Disease', 'MESH:D011488', (226, 256))	('oral carcinoma', 'Disease', (98, 112))	('human', 'Species', '9606', (26, 31))	('p53', 'Gene', (148, 151))	('p53', 'Gene', '7157', (148, 151))	('oral epidermoid carcinoma', 'Disease', (32, 57))	('mutant', 'Var', (152, 158))	('hypophosphorylated Rb proteins', 'Disease', (226, 256))	('patient', 'Species', '9606', (128, 135))	('oral carcinoma', 'Disease', 'MESH:D020820', (98, 112))	('lesion of an oral', 'Phenotype', 'HP:0100649', (85, 102))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('oral epidermoid carcinoma', 'Disease', 'MESH:D002294', (32, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (48, 57))
97824	25984601	5-fluorouracil suppresses cancer cells by misincorporating fluoronucleotides into RNA and DNA as well as by inhibiting the nucleotide synthetic enzyme thymidylate synthase.	('suppresses', 'NegReg', (15, 25))	('cancer', 'Disease', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('misincorporating', 'Var', (42, 58))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (0, 14))	('thymidylate synthase', 'Gene', (151, 171))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('inhibiting', 'NegReg', (108, 118))	('fluoronucleotides', 'Chemical', '-', (59, 76))	('thymidylate synthase', 'Gene', '7298', (151, 171))
97830	25984601	Relatively high frequency of PIK3CA mutations was found in stage IV OSCC, suggesting that PI3K/Akt signaling may be involved in disease progression of OSCCs.	('Akt', 'Gene', '207', (95, 98))	('involved', 'Reg', (116, 124))	('OSCC', 'Phenotype', 'HP:0012182', (68, 72))	('stage IV OSCC', 'Disease', (59, 72))	('found', 'Reg', (50, 55))	('mutations', 'Var', (36, 45))	('Akt', 'Gene', (95, 98))	('OSCC', 'Phenotype', 'HP:0012182', (151, 155))	('PIK3CA', 'Gene', (29, 35))	('PIK3CA', 'Gene', '5290', (29, 35))
97835	25984601	Phosphorylation of Thr308 on Akt is activated by PDK1, while phosphorylation of Ser473 on Akt is activated by mTOR kinase.	('Ser473', 'Chemical', '-', (80, 86))	('mTOR', 'Gene', (110, 114))	('mTOR', 'Gene', '2475', (110, 114))	('Akt', 'Gene', (90, 93))	('Akt', 'Gene', '207', (29, 32))	('Thr308', 'Var', (19, 25))	('activated', 'PosReg', (36, 45))	('PDK1', 'Gene', '5163', (49, 53))	('Phosphorylation', 'MPA', (0, 15))	('PDK1', 'Gene', (49, 53))	('Akt', 'Gene', (29, 32))	('Akt', 'Gene', '207', (90, 93))	('Thr308', 'Chemical', '-', (19, 25))
97836	25984601	Phosphorylation of these two sites elevates activity of Akt.	('elevates', 'PosReg', (35, 43))	('Akt', 'Gene', (56, 59))	('Phosphorylation', 'Var', (0, 15))	('activity', 'MPA', (44, 52))	('Akt', 'Gene', '207', (56, 59))
97857	25984601	Dysregulation of NF-kappaB has been linked to cancer, inflammation, and autoimmune diseases.	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('Dysregulation', 'Var', (0, 13))	('cancer', 'Disease', (46, 52))	('inflammation', 'Disease', 'MESH:D007249', (54, 66))	('autoimmune diseases', 'Disease', 'MESH:D001327', (72, 91))	('autoimmune diseases', 'Disease', (72, 91))	('NF-kappaB', 'Gene', '4790', (17, 26))	('inflammation', 'Disease', (54, 66))	('NF-kappaB', 'Gene', (17, 26))	('autoimmune diseases', 'Phenotype', 'HP:0002960', (72, 91))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('linked', 'Reg', (36, 42))
97870	25984601	Treatment with CAPE decreases protein abundance of Rb, phospho-Rb Ser807/811, Skp2, and cyclin D1, but increases cell cycle inhibitor p27Kip.	('Ser807', 'Chemical', '-', (66, 72))	('decreases', 'NegReg', (20, 29))	('increases', 'PosReg', (103, 112))	('cyclin D1', 'Gene', '595', (88, 97))	('Ser807/811', 'Var', (66, 76))	('protein abundance', 'MPA', (30, 47))	('Skp2', 'Gene', '6502', (78, 82))	('cyclin D1', 'Gene', (88, 97))	('CAPE', 'Chemical', 'MESH:C055494', (15, 19))	('Rb', 'Chemical', 'MESH:D012413', (51, 53))	('Skp2', 'Gene', (78, 82))	('Rb', 'Chemical', 'MESH:D012413', (63, 65))	('cell cycle inhibitor p27Kip', 'MPA', (113, 140))
97873	25984601	As the abundance of Rb is also suppressed by CAPE treatment in TW2.6 cells, the loss of Rb function may trigger either p53-dependent or p53-independent apoptosis.	('p53', 'Gene', '7157', (136, 139))	('Rb', 'Chemical', 'MESH:D012413', (88, 90))	('p53', 'Gene', '7157', (119, 122))	('loss', 'Var', (80, 84))	('Rb', 'Chemical', 'MESH:D012413', (20, 22))	('p53', 'Gene', (119, 122))	('trigger', 'Reg', (104, 111))	('apoptosis', 'CPA', (152, 161))	('function', 'MPA', (91, 99))	('CAPE', 'Chemical', 'MESH:C055494', (45, 49))	('p53', 'Gene', (136, 139))
97891	32640423	TRIM29 overexpression and knockdown affected LSCC activity and the expression of EMT associated biomarkers.	('LSCC', 'Phenotype', 'HP:0030359', (45, 49))	('activity', 'MPA', (50, 58))	('knockdown', 'Var', (26, 35))	('TRIM29', 'Gene', '23650', (0, 6))	('expression', 'MPA', (67, 77))	('TRIM29', 'Gene', (0, 6))	('LSCC', 'CPA', (45, 49))	('affected', 'Reg', (36, 44))
97927	32640423	The results suggested that high TRIM29 expression in lung squamous cell carcinoma was significantly related to the short overall survival time (Figure 1E).	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (53, 81))	('TRIM29', 'Gene', '23650', (32, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('lung squamous cell carcinoma', 'Disease', (53, 81))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (53, 81))	('TRIM29', 'Gene', (32, 38))	('high', 'Var', (27, 31))	('related', 'Reg', (100, 107))	('expression', 'MPA', (39, 49))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (58, 81))
97929	32640423	Meanwhile, high TRIM29 expression in lung squamous cell carcinoma tissue was closely related to the poor overall survival time.	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (37, 65))	('lung squamous cell carcinoma', 'Disease', (37, 65))	('TRIM29', 'Gene', '23650', (16, 22))	('TRIM29', 'Gene', (16, 22))	('related', 'Reg', (85, 92))	('high', 'Var', (11, 15))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (37, 65))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (42, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (56, 65))	('expression', 'MPA', (23, 33))
97937	32640423	However, TRIM29 knockdown in NCL-H1915 cells could significantly reduce cell proliferation compared with those in normal HTB-182 cells on day 2, 3, 4, 5 (Figure 2B and 2C) (P<0.01).	('HTB-182', 'CellLine', 'CVCL:V059', (121, 128))	('TRIM29', 'Gene', (9, 15))	('knockdown', 'Var', (16, 25))	('cell proliferation', 'CPA', (72, 90))	('NCL-H1915', 'CellLine', 'CVCL:1505', (29, 38))	('reduce', 'NegReg', (65, 71))	('TRIM29', 'Gene', '23650', (9, 15))
97939	32640423	Meanwhile, cell proliferation-related biomarkers such as TRIM29, CyclinD1, and PCNA in TRIM29 overexpressed HTB-182 cells were higher than those in vector treated HTB-182 cells (Figure 2E).	('TRIM29', 'Gene', '23650', (57, 63))	('TRIM29', 'Gene', (87, 93))	('CyclinD1', 'Gene', '595', (65, 73))	('TRIM29', 'Gene', (57, 63))	('HTB-182', 'CellLine', 'CVCL:V059', (108, 115))	('HTB-182', 'CellLine', 'CVCL:V059', (163, 170))	('PCNA', 'Gene', (79, 83))	('higher', 'PosReg', (127, 133))	('CyclinD1', 'Gene', (65, 73))	('cell proliferation-related biomarkers', 'CPA', (11, 48))	('TRIM29', 'Gene', '23650', (87, 93))	('HTB-182', 'Var', (108, 115))	('PCNA', 'Gene', '5111', (79, 83))	('overexpressed HTB-182', 'Var', (94, 115))
97940	32640423	Furthermore, TRIM29 knockdown in NCL-H1915 cells could significantly decrease cell colony numbers compared with those in normal NCL-H1915 cells (Figure 2F) (P<0.01).	('TRIM29', 'Gene', '23650', (13, 19))	('cell colony numbers', 'CPA', (78, 97))	('NCL-H1915', 'CellLine', 'CVCL:1505', (33, 42))	('decrease', 'NegReg', (69, 77))	('TRIM29', 'Gene', (13, 19))	('NCL-H1915', 'CellLine', 'CVCL:1505', (128, 137))	('knockdown', 'Var', (20, 29))
97941	32640423	Meanwhile, western blot analysis of cell proliferation-related biomarkers showed that TRIM29 knockdown in NCL-H1915 cells was lower than those in vector treated normal NCL-H1915 cells (Figure 2G).	('knockdown', 'Var', (93, 102))	('lower', 'NegReg', (126, 131))	('NCL-H1915', 'CellLine', 'CVCL:1505', (168, 177))	('NCL-H1915', 'CellLine', 'CVCL:1505', (106, 115))	('TRIM29', 'Gene', (86, 92))	('TRIM29', 'Gene', '23650', (86, 92))
97947	32640423	Meanwhile, TRIM29 knockdown in NCL-H1915 cells could significantly reduce cell migration and invasion numbers compared with those in normal NCL-H1915 cells (Figure 2J) (P<0.01).	('reduce', 'NegReg', (67, 73))	('cell migration', 'CPA', (74, 88))	('knockdown', 'Var', (18, 27))	('NCL-H1915', 'CellLine', 'CVCL:1505', (140, 149))	('NCL-H1915', 'CellLine', 'CVCL:1505', (31, 40))	('invasion numbers', 'CPA', (93, 109))	('TRIM29', 'Gene', '23650', (11, 17))	('TRIM29', 'Gene', (11, 17))
97948	32640423	TRIM29 knockdown in NCL-H1915 cells could inhibit the protein expressions of TRIM29, N-cadherin, and Vimentin.	('N-cadherin', 'Gene', (85, 95))	('TRIM29', 'Gene', '23650', (77, 83))	('N-cadherin', 'Gene', '1000', (85, 95))	('TRIM29', 'Gene', (77, 83))	('Vimentin', 'Gene', (101, 109))	('Vimentin', 'Gene', '7431', (101, 109))	('TRIM29', 'Gene', '23650', (0, 6))	('inhibit', 'NegReg', (42, 49))	('protein expressions', 'MPA', (54, 73))	('knockdown', 'Var', (7, 16))	('TRIM29', 'Gene', (0, 6))	('NCL-H1915', 'CellLine', 'CVCL:1505', (20, 29))
97949	32640423	However, TRIM29 knockdown in NCL-H1915 cells promote the protein expressions of N-cadherin (Figure 2K).	('TRIM29', 'Gene', (9, 15))	('knockdown', 'Var', (16, 25))	('promote', 'PosReg', (45, 52))	('NCL-H1915', 'CellLine', 'CVCL:1505', (29, 38))	('TRIM29', 'Gene', '23650', (9, 15))	('N-cadherin', 'Gene', (80, 90))	('protein expressions', 'MPA', (57, 76))	('N-cadherin', 'Gene', '1000', (80, 90))
97972	32640423	In addition, we have investigated the potential relationships between TRIM29 expression and autophagy in TRIM29 knockdown NCL-H1915 cells.	('TRIM29', 'Gene', '23650', (105, 111))	('TRIM29', 'Gene', (105, 111))	('knockdown', 'Var', (112, 121))	('autophagy', 'CPA', (92, 101))	('TRIM29', 'Gene', '23650', (70, 76))	('TRIM29', 'Gene', (70, 76))	('NCL-H1915', 'CellLine', 'CVCL:1505', (122, 131))
97973	32640423	Western blot analysis of LC3-I, LC3-II, TRIM29, and p62 suggested that TRIM29 knockdown treatment could significantly inhibit LC3-II expression and p62 degradation (P<0.001) (Figure 4F-4H).	('inhibit', 'NegReg', (118, 125))	('expression', 'MPA', (133, 143))	('TRIM29', 'Gene', '23650', (71, 77))	('TRIM29', 'Gene', '23650', (40, 46))	('degradation', 'MPA', (152, 163))	('TRIM29', 'Gene', (71, 77))	('knockdown', 'Var', (78, 87))	('p62', 'Gene', '23636', (52, 55))	('TRIM29', 'Gene', (40, 46))	('p62', 'Gene', '23636', (148, 151))	('p62', 'Gene', (52, 55))	('p62', 'Gene', (148, 151))	('LC3-II', 'Protein', (126, 132))
97975	32640423	Figure 4I and 4J showed that LC3-II expression in TRIM29 knockdown NCL-H1915 cells was significantly lower than those in the normal NCL-H1915 cells.	('TRIM29', 'Gene', (50, 56))	('knockdown', 'Var', (57, 66))	('lower', 'NegReg', (101, 106))	('NCL-H1915', 'CellLine', 'CVCL:1505', (132, 141))	('LC3-II', 'Gene', (29, 35))	('NCL-H1915', 'CellLine', 'CVCL:1505', (67, 76))	('expression', 'MPA', (36, 46))	('TRIM29', 'Gene', '23650', (50, 56))
97976	32640423	It was notable that point-like aggregation of the GFP-LC3II distribution was disappeared in TRIM29 knockdown NCL-H1915 cells (Figure 4E).	('disappeared', 'NegReg', (77, 88))	('TRIM29', 'Gene', '23650', (92, 98))	('TRIM29', 'Gene', (92, 98))	('knockdown', 'Var', (99, 108))	('NCL-H1915', 'CellLine', 'CVCL:1505', (109, 118))
97978	32640423	Previous studies have shown that high expression of BECN1 in cells can induce autophagy and even autophagic cell death.	('BECN1', 'Gene', '8678', (52, 57))	('high expression', 'Var', (33, 48))	('death', 'Disease', 'MESH:D003643', (113, 118))	('death', 'Disease', (113, 118))	('autophagy', 'CPA', (78, 87))	('BECN1', 'Gene', (52, 57))	('induce', 'PosReg', (71, 77))
97983	32640423	Moreover, cell migration and invasion analysis showed that BECN1 knockdown treatment in TRIM29 overexpression HTB-182 cells could effectively reduce the number of cell migration and invasion (Figure 5E-5G).	('BECN1', 'Gene', '8678', (59, 64))	('TRIM29', 'Gene', (88, 94))	('HTB-182', 'CellLine', 'CVCL:V059', (110, 117))	('BECN1', 'Gene', (59, 64))	('invasion', 'CPA', (182, 190))	('knockdown', 'Var', (65, 74))	('reduce', 'NegReg', (142, 148))	('TRIM29', 'Gene', '23650', (88, 94))
97984	32640423	In summary, those results mentioned above suggested that knockdown BECN1 can effectively suppress metastasis-promoting phenotype caused by overexpression of TRIM29 in lung squamous cell carcinoma.	('overexpression', 'PosReg', (139, 153))	('BECN1', 'Gene', (67, 72))	('lung squamous cell carcinoma', 'Disease', (167, 195))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (167, 195))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (172, 195))	('carcinoma', 'Phenotype', 'HP:0030731', (186, 195))	('knockdown', 'Var', (57, 66))	('TRIM29', 'Gene', '23650', (157, 163))	('BECN1', 'Gene', '8678', (67, 72))	('metastasis-promoting phenotype', 'CPA', (98, 128))	('TRIM29', 'Gene', (157, 163))	('suppress', 'NegReg', (89, 97))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (167, 195))
98000	32640423	Therefore, high TRIM29 expression may be a potential molecular target for prognostic markers and NSCLC treatment.	('TRIM29', 'Gene', '23650', (16, 22))	('TRIM29', 'Gene', (16, 22))	('NSCLC', 'Disease', (97, 102))	('NSCLC', 'Disease', 'MESH:D002289', (97, 102))	('high', 'Var', (11, 15))	('expression', 'MPA', (23, 33))
98003	32640423	The results suggested that patients with high TRIM29 expression exhibited shorter overall survival tables and lower relapse-free survival rates.	('shorter', 'NegReg', (74, 81))	('TRIM29', 'Gene', '23650', (46, 52))	('TRIM29', 'Gene', (46, 52))	('relapse-free survival rates', 'CPA', (116, 143))	('high', 'Var', (41, 45))	('patients', 'Species', '9606', (27, 35))	('lower', 'NegReg', (110, 115))	('overall survival tables', 'CPA', (82, 105))
98004	32640423	Meanwhile, knocking out TRIM29 gene can inhibit the proliferation, migration, and invasion of pancreatic cancer cells in vitro.	('knocking out', 'Var', (11, 23))	('proliferation', 'CPA', (52, 65))	('inhibit', 'NegReg', (40, 47))	('TRIM29', 'Gene', '23650', (24, 30))	('invasion', 'CPA', (82, 90))	('pancreatic cancer', 'Disease', (94, 111))	('TRIM29', 'Gene', (24, 30))	('migration', 'CPA', (67, 76))	('pancreatic cancer', 'Disease', 'MESH:D010190', (94, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (94, 111))
98021	32640423	Meanwhile, BECN1 knockdown can inhibit the autophagy degradation of E-cadherin promoted by TRIM29 overexpression and cancer cell metastasis.	('TRIM29', 'Gene', '23650', (91, 97))	('BECN1', 'Gene', '8678', (11, 16))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('cancer', 'Disease', (117, 123))	('overexpression', 'PosReg', (98, 112))	('TRIM29', 'Gene', (91, 97))	('autophagy degradation', 'CPA', (43, 64))	('E-cadherin', 'Gene', (68, 78))	('E-cadherin', 'Gene', '999', (68, 78))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('knockdown', 'Var', (17, 26))	('inhibit', 'NegReg', (31, 38))	('BECN1', 'Gene', (11, 16))
98023	32640423	In summary, we demonstrated that high TRIM29 expression could be detected in lung squamous cell carcinoma, which was closely related to the OS of patients.	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('high', 'Var', (33, 37))	('TRIM29', 'Gene', '23650', (38, 44))	('expression', 'MPA', (45, 55))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (77, 105))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (82, 105))	('TRIM29', 'Gene', (38, 44))	('patients', 'Species', '9606', (146, 154))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (77, 105))	('lung squamous cell carcinoma', 'Disease', (77, 105))
98056	32640423	After being blocked for 1h at room temperature, the layer was brooded with anti-Rabbit TRIM29 (1:1000) (#5182, CST, USA), GAPDH (1:1000) (#2118, CST, USA), E-Cadherin (1:1000) (#31958, CST, USA), LC3-I (1:1000) (#4599, CST, USA), LC3-II (1:1000) (#3868, CST, USA), p62 (1:1000) (#16177, CST, USA), and BECN1(1:1000) (#14717, CST, USA) overnight.	('E-Cadherin', 'Gene', (156, 166))	('CST', 'Gene', (219, 222))	('CST', 'Gene', (145, 148))	('CST', 'Gene', '106478911', (325, 328))	('CST', 'Gene', '106478911', (287, 290))	('TRIM29', 'Gene', '23650', (87, 93))	('GAPDH', 'Gene', (122, 127))	('CST', 'Gene', '106478911', (254, 257))	('CST', 'Gene', (185, 188))	('CST', 'Gene', '106478911', (111, 114))	('CST', 'Gene', (325, 328))	('CST', 'Gene', (287, 290))	('TRIM29', 'Gene', (87, 93))	('p62', 'Gene', '23636', (265, 268))	('BECN1', 'Gene', '8678', (302, 307))	('E-Cadherin', 'Gene', '999', (156, 166))	('p62', 'Gene', (265, 268))	('CST', 'Gene', (254, 257))	('CST', 'Gene', (111, 114))	('BECN1', 'Gene', (302, 307))	('CST', 'Gene', '106478911', (219, 222))	('CST', 'Gene', '106478911', (145, 148))	('#16177', 'Var', (279, 285))	('GAPDH', 'Gene', '2597', (122, 127))	('CST', 'Gene', '106478911', (185, 188))
98068	31615536	Growing evidence demonstrates that the dysregulation of miR-29c-3p (microRNA-29c-3p) plays an important role in various tumor processes.	('dysregulation', 'Var', (39, 52))	('microRNA-29c', 'Gene', (68, 80))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('microRNA-29c', 'Gene', '407026', (68, 80))	('tumor', 'Disease', (120, 125))
98069	31615536	Our study investigates the expression of miR-29c-3p in LSCC and analyzes the correlation of its dysregulation with clinicopathologic parameters and prognosis.	('miR-29c-3p', 'Var', (41, 51))	('LSCC', 'Disease', (55, 59))	('LSCC', 'Disease', 'MESH:D002294', (55, 59))
98073	31615536	Furthermore, miR-29c expression was an independent prognostic factor for laryngeal cancer patients.	('laryngeal cancer', 'Disease', (73, 89))	('laryngeal cancer', 'Phenotype', 'HP:0012118', (73, 89))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('laryngeal cancer', 'Disease', 'MESH:D007822', (73, 89))	('miR-29c expression', 'Var', (13, 31))	('patients', 'Species', '9606', (90, 98))
98074	31615536	MiR-29c-3p has different expression levels at different stages of tumor progression, suggesting that miR-29c-3p may be a promising biomarker for evaluating the progression of LSCC and the prognosis of patients with LSCC.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('patients', 'Species', '9606', (201, 209))	('MiR-29c', 'Gene', '387224', (0, 7))	('LSCC', 'Disease', (175, 179))	('tumor', 'Disease', (66, 71))	('miR-29c-3p', 'Var', (101, 111))	('LSCC', 'Disease', 'MESH:D002294', (215, 219))	('MiR-29c', 'Gene', (0, 7))	('LSCC', 'Disease', 'MESH:D002294', (175, 179))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('LSCC', 'Disease', (215, 219))
98081	31615536	In addition, accumulating studies have proved miRs can serve as potential diagnostic biomarkers for laryngeal cancer.	('laryngeal cancer', 'Disease', (100, 116))	('laryngeal cancer', 'Phenotype', 'HP:0012118', (100, 116))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('miRs', 'Var', (46, 50))	('laryngeal cancer', 'Disease', 'MESH:D007822', (100, 116))
98086	31615536	Besides, numerous studies have showed that miR-29c can inhibit the proliferation, invasion and metastasis of tumors and promote apoptosis by regulating a variety of oncogenes, cell pathways, cell cycle and epithelial to mesenchymal transition (EMT).	('metastasis of tumors', 'Disease', (95, 115))	('miR-29c', 'Var', (43, 50))	('metastasis of tumors', 'Disease', 'MESH:D009362', (95, 115))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('promote', 'PosReg', (120, 127))	('cell pathways', 'Pathway', (176, 189))	('epithelial to mesenchymal transition', 'CPA', (206, 242))	('cell cycle', 'CPA', (191, 201))	('oncogenes', 'Protein', (165, 174))	('regulating', 'Reg', (141, 151))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('inhibit', 'NegReg', (55, 62))	('apoptosis', 'CPA', (128, 137))
98090	31615536	However, the role of miR-29c in LSCC is still unclear and lacks any relevant studies.	('LSCC', 'Disease', (32, 36))	('LSCC', 'Disease', 'MESH:D002294', (32, 36))	('miR-29c', 'Var', (21, 28))
98091	31615536	In the present study, we determined and compared the expression of miR-29c in LSCC tissues and adjacent normal laryngeal tissues.	('LSCC', 'Disease', (78, 82))	('LSCC', 'Disease', 'MESH:D002294', (78, 82))	('miR-29c', 'Var', (67, 74))
98092	31615536	Furthermore, we evaluated the relationships between miR-29c expression and the clinical parameters and the survival of LSCC patients and revealed the prognostic factors of LSCC via multivariate Cox hazard regression analysis.	('Cox', 'Gene', (194, 197))	('LSCC', 'Disease', (119, 123))	('LSCC', 'Disease', 'MESH:D002294', (119, 123))	('LSCC', 'Disease', (172, 176))	('miR-29c', 'Var', (52, 59))	('Cox', 'Gene', '1351', (194, 197))	('patients', 'Species', '9606', (124, 132))	('LSCC', 'Disease', 'MESH:D002294', (172, 176))
98103	31615536	This result indicated that miR-29c was downregulated in LSCC, suggesting that miR-29c might play an anti-oncogenic role in LSCC (Fig.	('miR-29c', 'Var', (78, 85))	('LSCC', 'Disease', (123, 127))	('LSCC', 'Disease', 'MESH:D002294', (56, 60))	('LSCC', 'Disease', 'MESH:D002294', (123, 127))	('LSCC', 'Disease', (56, 60))	('miR-29c', 'Gene', (27, 34))	('downregulated', 'NegReg', (39, 52))
98107	31615536	The expression level of miR-29c varied in patients with different tumor sites, with the highest expression of miR-29c in patients with glottic tumors, followed by glottic-type tumors, and the lowest in subglottic tumors (P < 0.05).	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('tumors', 'Phenotype', 'HP:0002664', (213, 219))	('subglottic tumors', 'Disease', 'MESH:D007829', (202, 219))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('glottic tumors', 'Disease', 'MESH:C563636', (135, 149))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('tumor', 'Disease', (66, 71))	('tumor', 'Disease', (176, 181))	('expression', 'MPA', (96, 106))	('miR-29c', 'Var', (110, 117))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('glottic tumors', 'Disease', 'MESH:C563636', (205, 219))	('tumor', 'Disease', 'MESH:D009369', (176, 181))	('glottic-type tumors', 'Disease', (163, 182))	('glottic-type tumors', 'Disease', 'MESH:C563636', (163, 182))	('tumors', 'Phenotype', 'HP:0002664', (176, 182))	('patients', 'Species', '9606', (42, 50))	('patients', 'Species', '9606', (121, 129))	('subglottic tumors', 'Phenotype', 'HP:0001607', (202, 219))	('tumor', 'Disease', (213, 218))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('tumor', 'Disease', (143, 148))	('subglottic tumors', 'Disease', (202, 219))	('tumor', 'Disease', 'MESH:D009369', (213, 218))	('glottic tumors', 'Disease', (135, 149))	('tumor', 'Disease', 'MESH:D009369', (143, 148))
98109	31615536	Furthermore, miR-29c overexpression was correlated with a lower degree of tumor differentiation and an advanced clinical stage (P < 0.01), suggesting that miR-29c might participate in the progression of the tumor.	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('lower', 'NegReg', (58, 63))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('miR-29c', 'Var', (155, 162))	('overexpression', 'PosReg', (21, 35))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('tumor', 'Disease', (74, 79))	('miR-29c', 'Gene', (13, 20))	('clinical stage', 'CPA', (112, 126))	('tumor', 'Disease', (207, 212))	('participate', 'Reg', (169, 180))
98111	31615536	This result indicated that patients with a low expression level of miR-29c had a poor prognosis.	('patients', 'Species', '9606', (27, 35))	('miR-29c', 'Var', (67, 74))	('expression level', 'MPA', (47, 63))
98112	31615536	The results of Univariate Cox hazard regression analysis showed that smoking index, tumor size, tumor site, lymph nodes metastasis, tumor differentiation, T classification and TNM stage and miR-29c expression were the factors impacting patient prognosis.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('impacting', 'Reg', (226, 235))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('miR-29c expression', 'Var', (190, 208))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumor', 'Disease', (96, 101))	('tumor', 'Disease', (84, 89))	('TNM', 'Gene', '10178', (176, 179))	('tumor', 'Disease', (132, 137))	('Cox', 'Gene', '1351', (26, 29))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('patient', 'Species', '9606', (236, 243))	('TNM', 'Gene', (176, 179))	('Cox', 'Gene', (26, 29))
98114	31615536	Our study also demonstrated that patients with a high miR-29c level had a lower death risk, implying that the miR-29c expression level was an independent prognostic factor for laryngeal cancer, in addition to differentiation, lymph node metastasis and TNM stage.	('TNM', 'Gene', (252, 255))	('patients', 'Species', '9606', (33, 41))	('laryngeal cancer', 'Disease', (176, 192))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('laryngeal cancer', 'Phenotype', 'HP:0012118', (176, 192))	('miR-29c', 'Var', (110, 117))	('TNM', 'Gene', '10178', (252, 255))	('high miR-29c', 'Var', (49, 61))	('lower', 'NegReg', (74, 79))	('laryngeal cancer', 'Disease', 'MESH:D007822', (176, 192))	('miR-29c', 'Var', (54, 61))
98119	31615536	Our study first provided evidence that miR-29c was significantly downregulated in LSCC and played a critical role in cancer occurrence, which is consistent with the study on HNSCC.	('played', 'Reg', (91, 97))	('miR-29c', 'Var', (39, 46))	('LSCC', 'Disease', (82, 86))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('role', 'Reg', (109, 113))	('downregulated', 'NegReg', (65, 78))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('LSCC', 'Disease', 'MESH:D002294', (82, 86))	('cancer', 'Disease', (117, 123))	('HNSCC', 'Phenotype', 'HP:0012288', (174, 179))
98121	31615536	It was reported that cigarettes can induce a large number of DNA mutations, leading to more DNA damage and making the risk of laryngeal cancer higher.	('laryngeal cancer', 'Phenotype', 'HP:0012118', (126, 142))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('DNA damage', 'MPA', (92, 102))	('laryngeal cancer', 'Disease', 'MESH:D007822', (126, 142))	('more', 'PosReg', (87, 91))	('laryngeal cancer', 'Disease', (126, 142))	('mutations', 'Var', (65, 74))
98122	31615536	Our results also indicated that low level expression of miR-29c correlates with smoking index>=400, which implied that miR-29c might be involved in the pathomechanism of cigarettes inducing laryngeal cancer.	('miR-29c', 'Var', (119, 126))	('laryngeal cancer', 'Disease', 'MESH:D007822', (190, 206))	('involved', 'Reg', (136, 144))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('expression', 'MPA', (42, 52))	('laryngeal cancer', 'Disease', (190, 206))	('smoking index', 'Disease', (80, 93))	('laryngeal cancer', 'Phenotype', 'HP:0012118', (190, 206))	('miR-29c', 'Gene', (56, 63))
98124	31615536	Our results demonstrated that the expression of miR-29c in tumors < 3 cm was higher than that in tumors >=3 cm, which meant that miR-29c might regulate the proliferation and apoptosis of laryngeal carcinoma cells and further affect tumor size.	('expression', 'MPA', (34, 44))	('miR-29c', 'Var', (129, 136))	('tumor', 'Disease', (59, 64))	('apoptosis', 'CPA', (174, 183))	('tumors', 'Disease', 'MESH:D009369', (59, 65))	('tumors', 'Disease', (97, 103))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('miR-29c', 'Gene', (48, 55))	('higher', 'PosReg', (77, 83))	('proliferation', 'CPA', (156, 169))	('tumor', 'Disease', (97, 102))	('tumor', 'Disease', (232, 237))	('tumors', 'Disease', 'MESH:D009369', (97, 103))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('laryngeal carcinoma', 'Disease', (187, 206))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor', 'Disease', 'MESH:D009369', (232, 237))	('carcinoma', 'Phenotype', 'HP:0030731', (197, 206))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('affect', 'Reg', (225, 231))	('laryngeal carcinoma', 'Disease', 'MESH:D007822', (187, 206))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('laryngeal carcinoma', 'Phenotype', 'HP:0012118', (187, 206))	('regulate', 'Reg', (143, 151))	('tumors', 'Disease', (59, 65))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))
98126	31615536	This may be associated with the fact that most glottic laryngeal cancer patients were diagnosed in the early stage of laryngeal cancer progression, when the expression level of miR-29c was also higher than that in advanced progression.	('glottic laryngeal cancer', 'Disease', 'MESH:D007822', (47, 71))	('higher', 'PosReg', (194, 200))	('expression', 'MPA', (157, 167))	('laryngeal cancer', 'Phenotype', 'HP:0012118', (55, 71))	('laryngeal cancer', 'Disease', (118, 134))	('laryngeal cancer', 'Phenotype', 'HP:0012118', (118, 134))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('laryngeal cancer', 'Disease', 'MESH:D007822', (118, 134))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('laryngeal cancer', 'Disease', 'MESH:D007822', (55, 71))	('miR-29c', 'Var', (177, 184))	('glottic laryngeal cancer', 'Disease', (47, 71))	('patients', 'Species', '9606', (72, 80))
98127	31615536	Therefore, miR-29c might play a significant role in regulating the progression of laryngeal cancer.	('laryngeal cancer', 'Disease', 'MESH:D007822', (82, 98))	('miR-29c', 'Var', (11, 18))	('laryngeal cancer', 'Disease', (82, 98))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('laryngeal cancer', 'Phenotype', 'HP:0012118', (82, 98))
98128	31615536	Previous studies identified that miR-29c inhibited tumor invasion and metastasis by regulating different target genes and signaling pathways, such as MMP2 and the MAPK pathway.	('MMP2', 'Gene', (150, 154))	('miR-29c', 'Var', (33, 40))	('MAPK pathway', 'Pathway', (163, 175))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('signaling pathways', 'Pathway', (122, 140))	('tumor', 'Disease', (51, 56))	('MMP2', 'Gene', '4313', (150, 154))	('inhibited', 'NegReg', (41, 50))	('regulating', 'Reg', (84, 94))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
98131	31615536	Furthermore, a low level of miR-29c correlated with LSCC clinical stages, indicating that miR-29c might participate in laryngeal cancer cell migration and invasion, and increased miR-29c expression might be a novel treatment for laryngeal carcinoma.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('laryngeal carcinoma', 'Disease', 'MESH:D007822', (229, 248))	('LSCC', 'Disease', 'MESH:D002294', (52, 56))	('laryngeal carcinoma', 'Disease', (229, 248))	('carcinoma', 'Phenotype', 'HP:0030731', (239, 248))	('laryngeal carcinoma', 'Phenotype', 'HP:0012118', (229, 248))	('miR-29c', 'Var', (179, 186))	('laryngeal cancer', 'Disease', 'MESH:D007822', (119, 135))	('laryngeal cancer', 'Phenotype', 'HP:0012118', (119, 135))	('invasion', 'CPA', (155, 163))	('LSCC', 'Disease', (52, 56))	('laryngeal cancer', 'Disease', (119, 135))	('participate', 'Reg', (104, 115))	('miR-29c', 'Gene', (90, 97))
98133	31615536	Our present study demonstrated that low expression level of miR-29c in laryngeal cancer tissues significantly correlated with shorter survival time.	('miR-29c', 'Var', (60, 67))	('low', 'NegReg', (36, 39))	('shorter', 'NegReg', (126, 133))	('expression level', 'MPA', (40, 56))	('laryngeal cancer', 'Disease', 'MESH:D007822', (71, 87))	('laryngeal cancer', 'Disease', (71, 87))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('laryngeal cancer', 'Phenotype', 'HP:0012118', (71, 87))
98134	31615536	By the multivariate Cox hazard regression analysis, we found that the miR-29c expression level was an independent prognostic positive factor for LSCC.	('LSCC', 'Disease', 'MESH:D002294', (145, 149))	('Cox', 'Gene', '1351', (20, 23))	('Cox', 'Gene', (20, 23))	('miR-29c', 'Var', (70, 77))	('LSCC', 'Disease', (145, 149))
98136	31615536	In the future, we will pay more attention to the regulated mechanism of miR-29c in laryngeal cancer cell migration and invasion and explore a novel drug treatment for laryngeal cancer patients by increasing miR-29c expression.	('laryngeal cancer', 'Disease', (83, 99))	('patients', 'Species', '9606', (184, 192))	('laryngeal cancer', 'Phenotype', 'HP:0012118', (83, 99))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('laryngeal cancer', 'Disease', 'MESH:D007822', (167, 183))	('laryngeal cancer', 'Disease', 'MESH:D007822', (83, 99))	('increasing', 'PosReg', (196, 206))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('miR-29c', 'Var', (207, 214))	('laryngeal cancer', 'Disease', (167, 183))	('miR-29c', 'Gene', (72, 79))	('laryngeal cancer', 'Phenotype', 'HP:0012118', (167, 183))	('expression', 'MPA', (215, 225))
98137	31615536	To our knowledge, the present study first reports that miR-29c-3p is downregulated in LSCC and low expression of miR-29c-3p is an independent predictor of poor prognosis for patients with LSCC.	('miR-29c-3p', 'Var', (55, 65))	('low', 'NegReg', (95, 98))	('LSCC', 'Disease', (188, 192))	('LSCC', 'Disease', 'MESH:D002294', (86, 90))	('LSCC', 'Disease', 'MESH:D002294', (188, 192))	('patients', 'Species', '9606', (174, 182))	('downregulated', 'NegReg', (69, 82))	('miR-29c-3p', 'Var', (113, 123))	('LSCC', 'Disease', (86, 90))
98138	31615536	As a tumor suppressor, miR-29c may be a useful biomarker for tumor progression, early diagnosis and prognosis assessment.	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Disease', (5, 10))	('tumor', 'Disease', (61, 66))	('miR-29c', 'Var', (23, 30))
98155	30504870	hypomethylated in one and hypermethylated in another) (Fig.1d), and which may not be identifiable by current state-of-the-art DMC calling algorithms (see later).	('hypermethylated', 'Var', (26, 41))	('hypomethylated', 'Var', (0, 14))	('DMC', 'Chemical', '-', (126, 129))
98174	30504870	In the case of blood tissue we simulated a realistic scenario, where cell-type fractions were modelled as observed in real blood EWAS but with one cell-type (CD8+ T-cells) missing from our reference: sensitivities to detect DMCTs in CD4+ T-cells were reduced at most by only 15% (Supplementary Fig.9).	('DMCTs', 'Chemical', '-', (224, 229))	('CD4', 'Gene', '920', (233, 236))	('CD8', 'Gene', (158, 161))	('DMCTs', 'Var', (224, 229))	('CD8', 'Gene', '925', (158, 161))	('sensitivities', 'MPA', (200, 213))	('CD4', 'Gene', (233, 236))
98196	30504870	We also note that CellDMC led to a larger than 4-fold reduction of DMCs compared to a method that did not adjust for cell-type fractions, and a larger than 2-fold reduction of DMCs compared to a non-interaction based model, with relatively little overlap between DMCs called by CellDMC and the standard non-interaction model (Supplementary Table 2).	('DMCs', 'Chemical', '-', (176, 180))	('CellDMC', 'Var', (18, 25))	('reduction', 'NegReg', (163, 172))	('DMCs', 'MPA', (67, 71))	('CellDMC', 'Chemical', '-', (18, 25))	('reduction', 'NegReg', (54, 63))	('CellDMC', 'Chemical', '-', (278, 285))	('DMCs', 'Chemical', '-', (263, 267))	('DMCs', 'Chemical', '-', (67, 71))	('DMCs', 'MPA', (176, 180))
98197	30504870	Thus, like the standard non-interaction based model, CellDMC is able to remove large numbers of associations caused by changes in the granulocyte/lymphocyte ratio, whilst also identifying different DMCs to those found using the standard model.	('DMCs', 'Chemical', '-', (198, 202))	('granulocyte/lymphocyte ratio', 'MPA', (134, 162))	('changes', 'Var', (119, 126))	('CellDMC', 'Chemical', '-', (53, 60))	('associations', 'Interaction', (96, 108))
98205	30504870	We had previously discovered and validated hypermethylated DMCs in endometrial cancer, mapping to the 1st exon region of the HAND2 gene, which is a main target of the progesterone receptor tumor suppressor pathway.	('tumor', 'Disease', (189, 194))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('hypermethylated', 'Var', (43, 58))	('endometrial cancer', 'Disease', (67, 85))	('HAND2', 'Gene', (125, 130))	('DMCs', 'Chemical', '-', (59, 63))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('endometrial cancer', 'Phenotype', 'HP:0012114', (67, 85))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('HAND2', 'Gene', '9464', (125, 130))	('endometrial cancer', 'Disease', 'MESH:D016889', (67, 85))
98216	30504870	Although most of the 62 gold-standard smoking-DMCs in blood were not predicted to be altered in the epithelial cells of the buccal swabs, the great majority (i.e over 90%) of DMCTs were, however, predicted to occur in the epithelial compartment, with a strong skew towards hypermethylation (Supplementary Fig.15).	('DMCTs', 'Var', (175, 180))	('DMCTs', 'Chemical', '-', (175, 180))	('DMCs', 'Chemical', '-', (46, 50))	('hypermethylation', 'MPA', (273, 289))
98219	30504870	Moreover, predicted hyper-and-hypo methylated epithelial DMCTs exhibited a highly significant trend towards positive and negative correlations between their DNAm levels and the estimated epithelial cell-type fractions, as required (Fig.5d).	('hyper-and-hypo methylated', 'Var', (20, 45))	('DNAm levels', 'MPA', (157, 168))	('DMCTs', 'Chemical', '-', (57, 62))	('negative', 'NegReg', (121, 129))	('correlations', 'Interaction', (130, 142))	('positive', 'PosReg', (108, 116))
98221	30504870	Confirming our expectation, hypermethylated and hypomethylated epithelial DMCTs exhibited increased and decreased levels of DNAm in lung cancer, respectively (Fig.5f).	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('levels', 'MPA', (114, 120))	('lung cancer', 'Disease', 'MESH:D008175', (132, 143))	('hypomethylated', 'Var', (48, 62))	('DMCTs', 'Chemical', '-', (74, 79))	('DNAm', 'MPA', (124, 128))	('decreased', 'NegReg', (104, 113))	('lung cancer', 'Disease', (132, 143))	('lung cancer', 'Phenotype', 'HP:0100526', (132, 143))	('hypermethylated', 'Var', (28, 43))
98222	30504870	Consistent with the total immune cell fraction not being altered between normal and cancer, the top ranked DMCTs specifically hypomethylated in immune cells did not exhibit decreased levels in cancer, but increased levels, probably due to shifts in the specific immune cell subtype proportions (Fig.5f) Thus, the epithelial smoking-DMCTs identified here represent epigenetic alterations occurring in the squamous cell of origin of smoking related lung cancer and therefore may mark cells that are being selected for during lung carcinogenesis.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('lung cancer', 'Phenotype', 'HP:0100526', (447, 458))	('cancer', 'Disease', (84, 90))	('cancer', 'Disease', (193, 199))	('cancer', 'Disease', (452, 458))	('lung cancer', 'Disease', (447, 458))	('cancer', 'Disease', 'MESH:D009369', (452, 458))	('lung carcinogenesis', 'Disease', (523, 542))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('lung carcinogenesis', 'Disease', 'MESH:D063646', (523, 542))	('DMCTs', 'Chemical', '-', (332, 337))	('lung cancer', 'Disease', 'MESH:D008175', (447, 458))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('cancer', 'Phenotype', 'HP:0002664', (452, 458))	('epigenetic alterations', 'Var', (364, 386))	('DMCTs', 'Chemical', '-', (107, 112))
98224	30504870	For instance, we have shown how CellDMC was able to identify validated DMCTs in a minor cell subpopulation (B-cells) within a large whole blood EWAS for Rheumatoid Arthritis, as predicted from our simulation analysis.	('Rheumatoid Arthritis', 'Disease', (153, 173))	('CellDMC', 'Chemical', '-', (32, 39))	('DMCTs', 'Chemical', '-', (71, 76))	('Arthritis', 'Phenotype', 'HP:0001369', (164, 173))	('DMCTs', 'Var', (71, 76))	('Rheumatoid Arthritis', 'Phenotype', 'HP:0001370', (153, 173))	('Rheumatoid Arthritis', 'Disease', 'MESH:D001172', (153, 173))
98226	30504870	As shown here, these alterations and not those seen in the immune cells, become aggravated in lung cancer.	('lung cancer', 'Disease', 'MESH:D008175', (94, 105))	('aggravated', 'PosReg', (80, 90))	('lung cancer', 'Disease', (94, 105))	('lung cancer', 'Phenotype', 'HP:0100526', (94, 105))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('alterations', 'Var', (21, 32))
98304	29254206	Although the exact mechanism by which c-Myc causes cellular transformation remains unclear, inhibition of c-Myc activity was shown to be of therapeutic benefit in different cancer models including KRas-driven lung cancer in mice.	('c-Myc', 'Gene', (106, 111))	('inhibition', 'Var', (92, 102))	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('c-Myc', 'Gene', (38, 43))	('KRas', 'Gene', (197, 201))	('cancer', 'Disease', (214, 220))	('mice', 'Species', '10090', (224, 228))	('cancer', 'Disease', (173, 179))	('lung cancer', 'Disease', (209, 220))	('lung cancer', 'Phenotype', 'HP:0100526', (209, 220))	('KRas', 'Gene', '16653', (197, 201))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('c-Myc', 'Gene', '4609', (106, 111))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('lung cancer', 'Disease', 'MESH:D008175', (209, 220))	('c-Myc', 'Gene', '4609', (38, 43))	('cancer', 'Disease', 'MESH:D009369', (214, 220))
98317	29254206	The thresholds for significance testing were defined as mean FC > 3, p-value in T-test < 0.05, and 100% "Increase" calls in comparative ranking analysis at least in one set of tumors for up-regulated genes, and FC < -3, p-value in T-test < 0.05, and 100% "Decrease" calls for down-regulated genes.	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('Decrease', 'NegReg', (256, 264))	('up-regulated', 'PosReg', (187, 199))	('FC < -3', 'Var', (211, 218))	('down-regulated', 'MPA', (276, 290))	('tumors', 'Disease', (176, 182))	('tumors', 'Disease', 'MESH:D009369', (176, 182))	('tumors', 'Phenotype', 'HP:0002664', (176, 182))
98381	29254206	Evidently, the murine transgenic lung cancer model recapitulates c-Myc regulation in human lung adenocarcinomas, and the observations are consistent with c-My-dependent gene regulations in transgenic tumors where high expression is associated with poorer prognosis, while the opposite is seen for down-regulated genes.	('c-Myc', 'Gene', (65, 70))	('transgenic tumors', 'Disease', 'MESH:D009369', (189, 206))	('c-Myc', 'Gene', '4609', (65, 70))	('murine', 'Species', '10090', (15, 21))	('lung cancer', 'Disease', 'MESH:D008175', (33, 44))	('expression', 'Species', '29278', (218, 228))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (91, 111))	('lung cancer', 'Phenotype', 'HP:0100526', (33, 44))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (91, 110))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('transgenic tumors', 'Disease', (189, 206))	('high expression', 'Var', (213, 228))	('lung cancer', 'Disease', (33, 44))	('tumors', 'Phenotype', 'HP:0002664', (200, 206))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (91, 111))	('human', 'Species', '9606', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('lung adenocarcinomas', 'Disease', (91, 111))	('transgenic', 'Species', '10090', (22, 32))	('carcinomas', 'Phenotype', 'HP:0030731', (101, 111))	('transgenic', 'Species', '10090', (189, 199))
98402	29254206	Importantly, independent research discovered an interaction between Spint1 and membrane-bound serine proteinases to support EMT transitions, and inhibition of Spint1 was shown to be of therapeutic benefit by increasing tumor specific immune responses.	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('Spint1', 'Gene', (68, 74))	('tumor', 'Disease', (219, 224))	('interaction', 'Interaction', (48, 59))	('support', 'PosReg', (116, 123))	('Spint1', 'Gene', (159, 165))	('EMT transitions', 'CPA', (124, 139))	('serine', 'Chemical', 'MESH:D012694', (94, 100))	('Spint1', 'Gene', '6692', (68, 74))	('tumor', 'Disease', 'MESH:D009369', (219, 224))	('inhibition', 'Var', (145, 155))	('increasing', 'PosReg', (208, 218))	('Spint1', 'Gene', '6692', (159, 165))
98410	29254206	In a recent review dysregulation of connexins in cancer have been highlighted and are currently validated for druggability.	('dysregulation', 'Var', (19, 32))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('connexins', 'Protein', (36, 45))	('cancer', 'Disease', (49, 55))
98429	29254206	Strong repression of Gadd45 was also observed in RAT-1 c-Myc over-expressing cells, and repression of these genes disrupts the growth-inhibitory signaling of TGFbeta proteins in lung tumors.	('growth-inhibitory signaling of', 'MPA', (127, 157))	('c-Myc', 'Gene', '4609', (55, 60))	('RAT', 'Species', '10116', (49, 52))	('TGFbeta proteins in lung tumors', 'Disease', (158, 189))	('c-Myc', 'Gene', (55, 60))	('repression', 'Var', (88, 98))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('Gadd45', 'Gene', '25112', (21, 27))	('Gadd45', 'Gene', (21, 27))	('tumors', 'Phenotype', 'HP:0002664', (183, 189))	('disrupts', 'NegReg', (114, 122))	('lung tumors', 'Phenotype', 'HP:0100526', (178, 189))	('TGFbeta proteins in lung tumors', 'Disease', 'MESH:D008175', (158, 189))	('lung tumor', 'Phenotype', 'HP:0100526', (178, 188))
98439	29254206	A further up-regulated component of the EGFR/Ras/Raf/Mek/Erk signaling cascade was Map2k1 (Mek), while Rassf5, the pro-apoptotic Ras effector, was repressed to attenuate Ras-mediated apoptotic signaling.	('Rassf5', 'Gene', '83593', (103, 109))	('Rassf5', 'Gene', (103, 109))	('Ras-mediated apoptotic signaling', 'MPA', (170, 202))	('attenuate', 'NegReg', (160, 169))	('Map2k1', 'Var', (83, 89))	('EGFR', 'Gene', (40, 44))	('EGFR', 'Gene', '13649', (40, 44))	('up-regulated', 'PosReg', (10, 22))
98443	29254206	Although the Ros1 protein is not expressed in normal human lung tissue, ROS1 gene fusions with oncogenic activity are reported to occur in about 1-2% of NSCLC patients and are amenable to the development of molecular targeted therapies.	('occur', 'Reg', (130, 135))	('NSCLC', 'Disease', (153, 158))	('fusions', 'Var', (82, 89))	('ROS1', 'Gene', (72, 76))	('human', 'Species', '9606', (53, 58))	('NSCLC', 'Disease', 'MESH:D002289', (153, 158))	('ROS1', 'Gene', '6098', (72, 76))	('patients', 'Species', '9606', (159, 167))
98451	29254206	Overall, modulation of Wnt signaling contributed to promotion of cell proliferation, cytoskeleton dynamics and motility of tumor cells.	('promotion', 'PosReg', (52, 61))	('Wnt signaling', 'Pathway', (23, 36))	('tumor', 'Disease', (123, 128))	('cytoskeleton dynamics', 'CPA', (85, 106))	('modulation', 'Var', (9, 19))	('cell proliferation', 'CPA', (65, 83))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
98465	29254206	This regulator of matrix metalloproteinase is involved in invasion of tumor cells and inhibition of the protein impairs breast tumorigenesis and metastasis.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('breast tumor', 'Disease', (120, 132))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('impairs', 'NegReg', (112, 119))	('tumor', 'Disease', (127, 132))	('tumor', 'Disease', (70, 75))	('breast tumor', 'Phenotype', 'HP:0100013', (120, 132))	('inhibition', 'Var', (86, 96))	('breast tumor', 'Disease', 'MESH:D001943', (120, 132))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
98470	29254206	This protein causes disorganization of basement membrane to promote progression of metastasis in a mouse prostate cancer model whereas targeted inhibition of hepsin blocks prostate cancer bone metastasis.	('promote', 'PosReg', (60, 67))	('prostate cancer', 'Disease', 'MESH:D011471', (172, 187))	('metastasis', 'CPA', (83, 93))	('mouse', 'Species', '10090', (99, 104))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('prostate cancer', 'Phenotype', 'HP:0012125', (172, 187))	('prostate cancer', 'Disease', (105, 120))	('prostate cancer', 'Phenotype', 'HP:0012125', (105, 120))	('inhibition', 'Var', (144, 154))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('disorganization', 'MPA', (20, 35))	('hepsin blocks prostate cancer bone metastasis', 'Disease', 'MESH:D009362', (158, 203))	('prostate cancer', 'Disease', 'MESH:D011471', (105, 120))	('hepsin blocks prostate cancer bone metastasis', 'Disease', (158, 203))	('disorganization of basement membrane', 'Phenotype', 'HP:0005583', (20, 56))
98484	29254206	A link of c-Myc to angiogenesis can also be inferred from studies with skin, pancreatic beta-cells and lymphoma with reversible activation of conditional c-Myc alleles inducing hyper-proliferation, dedifferentiation and angiogenesis.	('activation', 'PosReg', (128, 138))	('c-Myc', 'Gene', (154, 159))	('c-Myc', 'Gene', (10, 15))	('dedifferentiation', 'CPA', (198, 215))	('hyper-proliferation', 'CPA', (177, 196))	('inducing', 'Reg', (168, 176))	('lymphoma', 'Disease', (103, 111))	('c-Myc', 'Gene', '4609', (154, 159))	('lymphoma', 'Disease', 'MESH:D008223', (103, 111))	('angiogenesis', 'CPA', (220, 232))	('lymphoma', 'Phenotype', 'HP:0002665', (103, 111))	('alleles', 'Var', (160, 167))	('c-Myc', 'Gene', '4609', (10, 15))
98525	29254206	Seventy-five or 100 mug (50 mug in case of HEK293T over-expressing c-MYC) of total protein extracts were separated on 12.0% SDS-polyacrylamide gel and blotted onto PVDF membranes in 25 mM Tris and 190 mM glycine at 4  C for 2 h at 350 mA or using the semi-dry iBlot transfer system (InVitrogen, Life Technologies).	('SDS', 'Chemical', 'MESH:D012967', (124, 127))	('PVDF', 'Chemical', 'MESH:C024865', (164, 168))	('polyacrylamide', 'Chemical', 'MESH:C016679', (128, 142))	('c-MYC', 'Gene', '4609', (67, 72))	('HEK293T', 'CellLine', 'CVCL:0063', (43, 50))	('glycine', 'Chemical', 'MESH:D005998', (204, 211))	('c-MYC', 'Gene', (67, 72))	('HEK293T', 'Var', (43, 50))	('over-expressing', 'PosReg', (51, 66))	('Tris', 'Chemical', '-', (188, 192))
98566	28441954	In addition to drug-induced cell killing, electroporation is responsible for changes in the tumor region.	('changes', 'Reg', (77, 84))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Disease', (92, 97))	('electroporation', 'Var', (42, 57))
98650	27926487	The aberrant metabolic reprogramming, particularly an increased glycolytic metabolism, can facilitate cancer cells to undergo EMT process and acquire CSC-like properties, thus promoting tumor initiation and progression.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('promoting', 'PosReg', (176, 185))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('glycolytic metabolism', 'MPA', (64, 85))	('undergo EMT process', 'CPA', (118, 137))	('aberrant', 'Var', (4, 12))	('tumor initiation', 'Disease', 'MESH:D009369', (186, 202))	('increased', 'PosReg', (54, 63))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('facilitate', 'PosReg', (91, 101))	('tumor initiation', 'Disease', (186, 202))
98657	27926487	Importantly, we demonstrated that in vivo treatment with 2-DG significantly inhibited metastasis of tumor cells to regional lymph nodes and robustly reduced the expression of EMT- and CSC-related genes in both the in situ tumors and invaded regional lymph nodes.	('situ tumors', 'Disease', 'MESH:D002278', (217, 228))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('2-DG', 'Var', (57, 61))	('2-DG', 'Chemical', 'MESH:D003847', (57, 61))	('tumor', 'Disease', 'MESH:D009369', (222, 227))	('tumor', 'Disease', (100, 105))	('expression', 'MPA', (161, 171))	('reduced', 'NegReg', (149, 156))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('tumor', 'Disease', (222, 227))	('tumors', 'Phenotype', 'HP:0002664', (222, 228))	('situ tumors', 'Disease', (217, 228))	('inhibited', 'NegReg', (76, 85))	('tumor', 'Disease', 'MESH:D009369', (100, 105))
98676	27926487	Our results showed that the presence of 2-DG significantly prevented mesenchymal-like cell morphological changes in EGF-stimulated SCC-1 cells (Figure 3C).	('prevented', 'NegReg', (59, 68))	('2-DG', 'Var', (40, 44))	('EGF', 'Gene', (116, 119))	('mesenchymal-like cell morphological changes', 'CPA', (69, 112))	('EGF', 'Gene', '1950', (116, 119))	('2-DG', 'Chemical', 'MESH:D003847', (40, 44))
98687	27926487	As expected, EGF stimulation resulted in EGFR phosphorylation at several specific tyrosine residues (including Tyr992, 1045, 1068) and correspondingly, the activation of its downstream signaling pathways, including pAkt, pS6Kp70, and mTOR, which was completely blocked by erlotinib, a specific EGFR tyrosine kinase inhibitor (TKI) (Figure 4A).	('activation', 'PosReg', (156, 166))	('1045', 'Var', (119, 123))	('EGF', 'Gene', (294, 297))	('Tyr992', 'Var', (111, 117))	('mTOR', 'Gene', '2475', (234, 238))	('erlotinib', 'Chemical', 'MESH:D000069347', (272, 281))	('Tyr992', 'Chemical', '-', (111, 117))	('tyrosine', 'Chemical', 'MESH:D014443', (299, 307))	('EGFR', 'Gene', (41, 45))	('EGF', 'Gene', (13, 16))	('EGFR', 'Gene', (294, 298))	('EGF', 'Gene', '1950', (41, 44))	('tyrosine', 'Chemical', 'MESH:D014443', (82, 90))	('EGF', 'Gene', '1950', (294, 297))	('EGFR', 'Gene', '1956', (41, 45))	('EGF', 'Gene', (41, 44))	('EGFR', 'Gene', '1956', (294, 298))	('EGF', 'Gene', '1950', (13, 16))	('mTOR', 'Gene', (234, 238))
98691	27926487	We found that blocking EGFR, PI3K or mTOR activities with erlotinib, LY294002 or rapamycin significantly abrogated EGF-induced mesenchymal-like morphological changes and the downregulation of E-cadherin expression in SCC-1 cells, while the AKT inhibitor showed no obvious effects (Figure 4B and 4C).	('downregulation', 'NegReg', (174, 188))	('EGFR', 'Gene', '1956', (23, 27))	('LY294002', 'Chemical', 'MESH:C085911', (69, 77))	('mTOR', 'Gene', '2475', (37, 41))	('erlotinib', 'Chemical', 'MESH:D000069347', (58, 67))	('EGF', 'Gene', (23, 26))	('EGF', 'Gene', '1950', (115, 118))	('erlotinib', 'Gene', (58, 67))	('rapamycin', 'Chemical', 'MESH:D020123', (81, 90))	('E-cadherin', 'Gene', (192, 202))	('E-cadherin', 'Gene', '999', (192, 202))	('EGFR', 'Gene', (23, 27))	('EGF', 'Gene', (115, 118))	('blocking', 'NegReg', (14, 22))	('LY294002', 'Var', (69, 77))	('expression', 'MPA', (203, 213))	('EGF', 'Gene', '1950', (23, 26))	('mTOR', 'Gene', (37, 41))	('abrogated', 'NegReg', (105, 114))
98693	27926487	Functionally, we showed that blockade of EGFR/PI3K/AKT/mTOR signaling pathways significantly abrogated EGF-induced invasive abilities of SCC-1 cells (Figure 4E).	('blockade', 'Var', (29, 37))	('EGFR', 'Gene', (41, 45))	('mTOR', 'Gene', (55, 59))	('abrogated', 'NegReg', (93, 102))	('EGF', 'Gene', '1950', (103, 106))	('mTOR', 'Gene', '2475', (55, 59))	('invasive abilities of SCC-1 cells', 'CPA', (115, 148))	('EGF', 'Gene', (41, 44))	('EGF', 'Gene', (103, 106))	('EGFR', 'Gene', '1956', (41, 45))	('EGF', 'Gene', '1950', (41, 44))
98708	27926487	Following submucosal injection into the tongue of nude mice, GFP-tagged SCC-1 cells steadily formed tumors (Figure 6A; Supplementary Figure 4B), and about 20% of mice developed regional cervical LN metastasis as evidenced by the local presence of GFP-tagged SCC-1 cells (Supplementary Figure 4C, Table 1).	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('nude mice', 'Species', '10090', (50, 59))	('regional cervical LN metastasis', 'CPA', (177, 208))	('GFP-tagged', 'Var', (61, 71))	('SCC-1', 'Gene', (72, 77))	('tumors', 'Disease', (100, 106))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('mice', 'Species', '10090', (55, 59))	('mice', 'Species', '10090', (162, 166))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('developed', 'PosReg', (167, 176))
98710	27926487	However, the presence of EGF enhanced the expression of ALDH1, vimentin, and PDK1in the in situ tumors in the tongue (Figure 6A and 6D) and increased the incidence of cervical LN metastasis (70% versus 20% of the control group; p=0.038) (Fig.	('PDK1', 'Gene', '5163', (77, 81))	('cervical LN metastasis', 'CPA', (167, 189))	('PDK1', 'Gene', (77, 81))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('expression', 'MPA', (42, 52))	('situ tumors', 'Disease', 'MESH:D002278', (91, 102))	('ALDH1', 'Protein', (56, 61))	('EGF', 'Gene', '1950', (25, 28))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('EGF', 'Gene', (25, 28))	('presence', 'Var', (13, 21))	('situ tumors', 'Disease', (91, 102))	('increased', 'PosReg', (140, 149))	('enhanced', 'PosReg', (29, 37))	('vimentin', 'Protein', (63, 71))
98726	27926487	On the other hand, blocking glycolysis sensitizes non-small cell lung cancer cells with a T790M mutation to the treatment with irreversible EGFR inhibitors.	('T790M', 'Var', (90, 95))	('sensitizes', 'Reg', (39, 49))	('EGFR', 'Gene', (140, 144))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('lung cancer', 'Phenotype', 'HP:0100526', (65, 76))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (54, 76))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (50, 76))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('T790M', 'Mutation', 'rs121434569', (90, 95))	('EGFR', 'Gene', '1956', (140, 144))
98739	27926487	University of Michigan squamous cell carcinoma (UM-SCC-1), a floor-of-the mouth squamous cell carcinoma derived from tumor recurrence, was kindly provided by Professor Cun-yu Wang (University of California, Los Angeles) and cultured in RPMI-1640 supplemented with 10% fetal bovine serum (FBS), 100IU/ml penicillin, 100mug/ml streptomycin.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (80, 103))	('FBS', 'Disease', (288, 291))	('penicillin', 'Chemical', 'MESH:D010406', (303, 313))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('FBS', 'Disease', 'MESH:D005198', (288, 291))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (80, 103))	('mouth squamous cell carcinoma', 'Disease', 'MESH:D002294', (74, 103))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (23, 46))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (37, 46))	('streptomycin', 'Chemical', 'MESH:D013307', (325, 337))	('100IU/ml', 'Var', (294, 302))	('UM-SCC-1', 'CellLine', 'CVCL:7707', (48, 56))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (23, 46))	('tumor', 'Disease', (117, 122))	('mouth squamous cell carcinoma', 'Disease', (74, 103))	('RPMI-1640', 'Chemical', '-', (236, 245))	('squamous cell carcinoma', 'Disease', (23, 46))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('bovine', 'Species', '9913', (274, 280))
98741	27926487	CAL27 (ATCC  CRL-2095 ), a human tongue squamous cell carcinoma cell line, and FaDu (ATCC   HTB-43 ), a human squamous cell carcinoma cell line derived from the hypopharynx, were both obtained from ATCC and cultured in DMEM supplemented with 10% fetal bovine serum (FBS), 100IU/ml penicillin, 100mug/ml streptomycin.	('FBS', 'Disease', 'MESH:D005198', (266, 269))	('DMEM', 'Chemical', '-', (219, 223))	('human', 'Species', '9606', (27, 32))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (40, 63))	('tongue squamous cell carcinoma', 'Phenotype', 'HP:0030413', (33, 63))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (110, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (54, 63))	('human', 'Species', '9606', (104, 109))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (40, 63))	('100IU/ml', 'Var', (272, 280))	('streptomycin', 'Chemical', 'MESH:D013307', (303, 315))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (110, 133))	('tongue squamous cell carcinoma', 'Disease', 'MESH:D002294', (33, 63))	('bovine', 'Species', '9913', (252, 258))	('penicillin', 'Chemical', 'MESH:D010406', (281, 291))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('squamous cell carcinoma', 'Disease', (110, 133))	('tongue squamous cell carcinoma', 'Disease', (33, 63))	('FBS', 'Disease', (266, 269))
98743	27926487	To study downstream EGFR signaling pathway, cells were pretreated with 5muM Erlotinib (Cell Signaling Technology), an EGFR tyrosine kinase inhibitor, 50muM LY294002 (EMD Millipore), a PI3K inhibitor, or 20muM AKT inhibitor (EMD Millipore), or 2.5muM Rapamycin (EMD Millipore), an mTOR inhibitor, in serum-free RPMI for 1h followed by stimulation with EGF for 4h.	('LY294002', 'Chemical', 'MESH:C085911', (156, 164))	('EGF', 'Gene', '1950', (351, 354))	('EGFR', 'Gene', (20, 24))	('EGF', 'Gene', '1950', (118, 121))	('1h', 'Chemical', '-', (319, 321))	('mTOR', 'Gene', '2475', (280, 284))	('LY294002', 'Var', (156, 164))	('mTOR', 'Gene', (280, 284))	('EGFR', 'Gene', '1956', (118, 122))	('EGF', 'Gene', (20, 23))	('EGFR', 'Gene', (118, 122))	('tyrosine', 'Chemical', 'MESH:D014443', (123, 131))	('Erlotinib', 'Chemical', 'MESH:D000069347', (76, 85))	('EGF', 'Gene', (351, 354))	('EGF', 'Gene', '1950', (20, 23))	('EGF', 'Gene', (118, 121))	('EGFR', 'Gene', '1956', (20, 24))	('RPMI', 'Chemical', '-', (310, 314))
98770	27926487	Following transfection for 5h, the transfection medium was replaced with fresh complete medium and cells were cultured for overnight followed by stimulation with EGF (20ng/ml) for 48h.	('EGF', 'Gene', (162, 165))	('transfection', 'Var', (10, 22))	('EGF', 'Gene', '1950', (162, 165))
98802	33540574	Abnormal MYC genes lead to uncontrollable MYC expression in malignant tumors because of dysfunction and translocation among Burkitt lymphoma, cervical cancer, colon cancer, breast cancer, stomach cancer, and lung cancer, especially in the pathogenesis of B-cell lymphoma, which plays an important role.	('stomach cancer', 'Disease', (188, 202))	('cancer', 'Disease', 'MESH:D009369', (196, 202))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('colon cancer', 'Phenotype', 'HP:0003003', (159, 171))	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('dysfunction', 'MPA', (88, 99))	('breast cancer', 'Phenotype', 'HP:0003002', (173, 186))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('malignant tumors', 'Disease', (60, 76))	('malignant tumors', 'Disease', 'MESH:D009369', (60, 76))	('lung cancer', 'Disease', 'MESH:D008175', (208, 219))	('cancer', 'Disease', (151, 157))	('Burkitt lymphoma', 'Disease', (124, 140))	('cancer', 'Disease', (213, 219))	('colon cancer', 'Disease', 'MESH:D015179', (159, 171))	('stomach cancer', 'Disease', 'MESH:D013274', (188, 202))	('breast cancer', 'Disease', 'MESH:D001943', (173, 186))	('lymphoma', 'Phenotype', 'HP:0002665', (262, 270))	('stomach cancer', 'Phenotype', 'HP:0012126', (188, 202))	('cancer', 'Disease', (180, 186))	('Burkitt lymphoma', 'Disease', 'MESH:D002051', (124, 140))	('breast cancer', 'Disease', (173, 186))	('B-cell lymphoma', 'Disease', 'MESH:D016393', (255, 270))	('MYC genes', 'Gene', (9, 18))	('lead', 'Reg', (19, 23))	('lung cancer', 'Phenotype', 'HP:0100526', (208, 219))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('cancer', 'Disease', (165, 171))	('cancer', 'Disease', (196, 202))	('uncontrollable MYC expression', 'MPA', (27, 56))	('colon cancer', 'Disease', (159, 171))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (255, 270))	('lymphoma', 'Phenotype', 'HP:0002665', (132, 140))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('translocation', 'Var', (104, 117))	('cancer', 'Disease', 'MESH:D009369', (213, 219))	('Burkitt lymphoma', 'Phenotype', 'HP:0030080', (124, 140))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('lung cancer', 'Disease', (208, 219))	('B-cell lymphoma', 'Disease', (255, 270))
98806	33540574	MYC is directly linked with the PD combination of the L1 gene promoter, and the inactivation of MYC can downregulate the PD-L1 expression in mice and enhance the antitumor immune response.	('PD-L1', 'Gene', (121, 126))	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('MYC', 'Gene', (96, 99))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('expression', 'MPA', (127, 137))	('tumor', 'Disease', (166, 171))	('inactivation', 'Var', (80, 92))	('mice', 'Species', '10090', (141, 145))	('downregulate', 'NegReg', (104, 116))	('enhance', 'PosReg', (150, 157))
98815	33540574	LUAD patients (515) were divided into two groups according to the MYC expression median (MYC expression = 2541.5):namely, the low expression group (MYC expression < 2541.5, n = 257) and high expression group (MYC expression > 2541.5, n = 258).	('AD', 'Disease', (2, 4))	('MYC', 'Var', (148, 151))	('patients', 'Species', '9606', (5, 13))	('AD', 'Disease', 'MESH:D000544', (2, 4))
98833	33540574	High WT1-AS (Figure 2E) and nicotinamide phosphoribosyltransferase (NAMPT) (Figure 2F) expressions were associated with a poor prognosis in LUAD patients, and low miR-206 (Figure 2G) expression was associated with poor prognosis in patients with LUAD.	('patients', 'Species', '9606', (145, 153))	('AD', 'Disease', 'MESH:D000544', (142, 144))	('nicotinamide phosphoribosyltransferase', 'Gene', (28, 66))	('AD', 'Disease', (142, 144))	('AD', 'Disease', (248, 250))	('patients', 'Species', '9606', (232, 240))	('nicotinamide phosphoribosyltransferase', 'Gene', '10135', (28, 66))	('High WT1-AS', 'Disease', (0, 11))	('miR-206', 'Gene', (163, 170))	('NAMPT', 'Gene', '10135', (68, 73))	('High WT1-AS', 'Disease', 'MESH:D009396', (0, 11))	('AD', 'Disease', 'MESH:D000544', (248, 250))	('low', 'Var', (159, 162))	('NAMPT', 'Gene', (68, 73))	('miR-206', 'Gene', '406989', (163, 170))
98870	33540574	Our analysis showed that the highly malignant stages of LUAD correspond to higher MYC expression levels (p = 0.0276), and a high MYC expression is associated with LUAD tumor metastasis and a larger tumor diameter (p = 0.0225).	('LUAD tumor metastasis', 'Disease', (163, 184))	('tumor', 'Disease', (168, 173))	('MYC expression levels', 'MPA', (82, 103))	('associated', 'Reg', (147, 157))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('higher', 'PosReg', (75, 81))	('high MYC', 'Var', (124, 132))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('AD', 'Disease', 'MESH:D000544', (58, 60))	('AD', 'Disease', 'MESH:D000544', (165, 167))	('AD', 'Disease', (165, 167))	('tumor', 'Disease', (198, 203))	('AD', 'Disease', (58, 60))	('LUAD tumor metastasis', 'Disease', 'MESH:D009362', (163, 184))
98879	33540574	Targeting WT1-AS, miR-494-3p, and AKT may be a new option for the treatment of glioma.	('AKT', 'Gene', (34, 37))	('glioma', 'Disease', (79, 85))	('miR-494-3p', 'Var', (18, 28))	('glioma', 'Disease', 'MESH:D005910', (79, 85))	('glioma', 'Phenotype', 'HP:0009733', (79, 85))	('WT1-AS', 'Gene', '51352', (10, 16))	('AKT', 'Gene', '207', (34, 37))	('WT1-AS', 'Gene', (10, 16))
98880	33540574	Our analysis results showed that the expression level of lncRNA WT1-AS in the MYC high expression group was significantly higher than that in the MYC low expression group, showing an upregulation trend.	('upregulation', 'PosReg', (183, 195))	('higher', 'PosReg', (122, 128))	('WT1-AS', 'Gene', '51352', (64, 70))	('high expression', 'Var', (82, 97))	('WT1-AS', 'Gene', (64, 70))	('expression level', 'MPA', (37, 53))
98890	33540574	Nicotinamide phosphoribosyltransferase (NAMPT) is regarded as an important target for tumor treatment, and many studies have confirmed that NAMPT inhibitors have obvious antitumor effects.	('tumor', 'Disease', (174, 179))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('inhibitors', 'Var', (146, 156))	('Nicotinamide phosphoribosyltransferase', 'Gene', (0, 38))	('tumor', 'Disease', (86, 91))	('NAMPT', 'Gene', '10135', (40, 45))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('NAMPT', 'Gene', (140, 145))	('NAMPT', 'Gene', (40, 45))	('NAMPT', 'Gene', '10135', (140, 145))	('Nicotinamide phosphoribosyltransferase', 'Gene', '10135', (0, 38))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
98995	31615976	LncRNA HOXA-AS3 confers cisplatin resistance by interacting with HOXA3 in non-small-cell lung carcinoma cells Many studies have indicated that the aberrant expression of long noncoding RNAs (lncRNAs) is responsible for drug resistance, which represents a substantial obstacle for cancer therapy.	('drug resistance', 'Phenotype', 'HP:0020174', (219, 234))	('cancer', 'Disease', (280, 286))	('non-small-cell lung carcinoma cells', 'Disease', (74, 109))	('HOXA-AS3', 'Gene', '72628', (7, 15))	('confers', 'Reg', (16, 23))	('HOXA3', 'Gene', '15400', (65, 70))	('cancer', 'Phenotype', 'HP:0002664', (280, 286))	('cisplatin', 'Chemical', 'MESH:D002945', (24, 33))	('cisplatin resistance', 'MPA', (24, 44))	('responsible', 'Reg', (203, 214))	('HOXA3', 'Gene', (65, 70))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('cancer', 'Disease', 'MESH:D009369', (280, 286))	('small-cell lung carcinoma', 'Phenotype', 'HP:0030357', (78, 103))	('non-small-cell lung carcinoma', 'Phenotype', 'HP:0030358', (74, 103))	('aberrant', 'Var', (147, 155))	('drug resistance', 'MPA', (219, 234))	('non-small-cell lung carcinoma cells', 'Disease', 'MESH:D002289', (74, 109))	('HOXA-AS3', 'Gene', (7, 15))
98998	31615976	Tumor xenografts in nude mice were established to evaluate the antitumor effects of HOXA-AS3 knockdown in vivo.	('knockdown', 'Var', (93, 102))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumor', 'Disease', (67, 72))	('HOXA-AS3', 'Gene', (84, 92))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('nude mice', 'Species', '10090', (20, 29))
99000	31615976	We found that HOXA-AS3 levels increased with cisplatin treatment and knockdown of HOXA-AS3 enhance the efficacy of cisplatin in vitro and in vivo.	('enhance', 'PosReg', (91, 98))	('cisplatin', 'Chemical', 'MESH:D002945', (45, 54))	('cisplatin', 'Chemical', 'MESH:D002945', (115, 124))	('HOXA-AS3', 'Gene', (82, 90))	('increased', 'PosReg', (30, 39))	('efficacy', 'MPA', (103, 111))	('HOXA-AS3 levels', 'MPA', (14, 29))	('knockdown', 'Var', (69, 78))
99002	31615976	In addition, HOXA3 knockdown increased cisplatin resistance and induced epithelial-mesenchymal transition (EMT).	('cisplatin resistance', 'MPA', (39, 59))	('induced', 'Reg', (64, 71))	('knockdown', 'Var', (19, 28))	('increased', 'PosReg', (29, 38))	('epithelial-mesenchymal transition', 'CPA', (72, 105))	('cisplatin', 'Chemical', 'MESH:D002945', (39, 48))	('HOXA3', 'Gene', (13, 18))
99013	31615976	In recent years, abnormal lncRNA expression has been found in many types of tumors, playing roles in regulating cancer cell proliferation, differentiation, invasion, and metastasis.	('invasion', 'CPA', (156, 164))	('cancer', 'Disease', (112, 118))	('found', 'Reg', (53, 58))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('metastasis', 'CPA', (170, 180))	('tumors', 'Disease', (76, 82))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('differentiation', 'CPA', (139, 154))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('lncRNA expression', 'Protein', (26, 43))	('abnormal', 'Var', (17, 25))
99015	31615976	Despite recent studies showing that lncRNAs could confer chemo-resistance in cancer cells by improving DNA repair, cellular apoptosis, epithelial-mesenchymal transition (EMT), and altering drug metabolism and membrane efflux, the molecular mechanisms underlying the action of lncRNAs in these cancer cell functions remain largely elusive.	('cancer', 'Disease', (293, 299))	('improving', 'PosReg', (93, 102))	('cancer', 'Disease', 'MESH:D009369', (293, 299))	('cancer', 'Disease', (77, 83))	('lncRNAs', 'Var', (36, 43))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('DNA repair', 'MPA', (103, 113))	('altering', 'Reg', (180, 188))	('cancer', 'Phenotype', 'HP:0002664', (293, 299))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('cellular apoptosis', 'CPA', (115, 133))	('membrane efflux', 'MPA', (209, 224))	('epithelial-mesenchymal transition', 'CPA', (135, 168))	('drug metabolism', 'MPA', (189, 204))
99019	31615976	For example, long non-coding RNA NONHSAT101069 promotes epirubicin resistance through NONHSAT101069/miR-129-5p/Twist1 axis.	('epirubicin', 'Chemical', 'MESH:D015251', (56, 66))	('Twist1', 'Gene', (111, 117))	('promotes', 'PosReg', (47, 55))	('epirubicin resistance', 'MPA', (56, 77))	('NONHSAT101069', 'Var', (33, 46))	('Twist1', 'Gene', '22160', (111, 117))
99037	31615976	CCK-8 assays showed that knockdown of HOXA-AS3 resulted in a significant dose-dependent reduction in the viability of NSCLC cells in response to cisplatin treatment as compared with that in the control (Fig.	('viability', 'CPA', (105, 114))	('NSCLC', 'Phenotype', 'HP:0030358', (118, 123))	('response to cisplatin treatment', 'MPA', (133, 164))	('reduction', 'NegReg', (88, 97))	('cisplatin', 'Chemical', 'MESH:D002945', (145, 154))	('NSCLC', 'Disease', (118, 123))	('NSCLC', 'Disease', 'MESH:D002289', (118, 123))	('HOXA-AS3', 'Gene', (38, 46))	('knockdown', 'Var', (25, 34))
99038	31615976	After knockdown of HOXA-AS3, the IC50 values of cisplatin were also significantly reduced in each NSCLC cell line (Supplementary Table 1.2).	('cisplatin', 'Chemical', 'MESH:D002945', (48, 57))	('IC50 values of cisplatin', 'MPA', (33, 57))	('NSCLC', 'Phenotype', 'HP:0030358', (98, 103))	('NSCLC', 'Disease', (98, 103))	('knockdown', 'Var', (6, 15))	('reduced', 'NegReg', (82, 89))	('NSCLC', 'Disease', 'MESH:D002289', (98, 103))
99039	31615976	EDU staining assays also revealed that knockdown of HOXA-AS3 decreased NSCLC cell proliferation following cisplatin treatment for 48 h, as compared with that in the control cells (Fig.	('HOXA-AS3', 'Gene', (52, 60))	('NSCLC', 'Phenotype', 'HP:0030358', (71, 76))	('knockdown', 'Var', (39, 48))	('EDU', 'Chemical', 'None', (0, 3))	('decreased', 'NegReg', (61, 70))	('NSCLC', 'Disease', (71, 76))	('cisplatin', 'Chemical', 'MESH:D002945', (106, 115))	('NSCLC', 'Disease', 'MESH:D002289', (71, 76))
99041	31615976	Flow cytometry analysis showed that knockdown of HOXA-AS3 led to a significant increase in NSCLC cell apoptosis following cisplatin treatment (Fig.	('increase', 'PosReg', (79, 87))	('NSCLC', 'Disease', 'MESH:D002289', (91, 96))	('NSCLC', 'Phenotype', 'HP:0030358', (91, 96))	('knockdown', 'Var', (36, 45))	('cisplatin', 'Chemical', 'MESH:D002945', (122, 131))	('NSCLC', 'Disease', (91, 96))	('HOXA-AS3', 'Gene', (49, 57))
99045	31615976	Taken together, these results suggested that HOXA-AS3 mayfunction as a cis-acting RNA that needs to function at specific locations (such as on some specific chromatin regions), to confer cisplatin resistance in vitro.	('confer', 'Reg', (180, 186))	('HOXA-AS3', 'Var', (45, 53))	('cisplatin resistance', 'MPA', (187, 207))	('cisplatin', 'Chemical', 'MESH:D002945', (187, 196))
99050	31615976	The results showed that knockdown of HOXA-AS3 upregulated HOXA3 expression at both the mRNA and protein levels in all four NSCLC cell lines (Fig.	('expression', 'MPA', (64, 74))	('NSCLC', 'Disease', (123, 128))	('NSCLC', 'Disease', 'MESH:D002289', (123, 128))	('HOXA-AS3', 'Gene', (37, 45))	('NSCLC', 'Phenotype', 'HP:0030358', (123, 128))	('HOXA3', 'Gene', (58, 63))	('knockdown', 'Var', (24, 33))	('upregulated', 'PosReg', (46, 57))
99052	31615976	HOXA-AS3 knockdown decreases cisplatin resistance and increases HOXA3 expression; therefore, we investigated whether HOXA3 depletion would affect cisplatin resistance.	('affect', 'Reg', (139, 145))	('knockdown', 'Var', (9, 18))	('cisplatin', 'Chemical', 'MESH:D002945', (146, 155))	('cisplatin', 'Chemical', 'MESH:D002945', (29, 38))	('expression', 'MPA', (70, 80))	('increases', 'PosReg', (54, 63))	('decreases', 'NegReg', (19, 28))	('cisplatin resistance', 'MPA', (146, 166))	('HOXA3', 'Protein', (64, 69))	('HOXA-AS3', 'Gene', (0, 8))	('cisplatin resistance', 'MPA', (29, 49))
99053	31615976	CCK-8 assays showed that HOXA3 knockdown in NSCLC cells resulted in a significant increase in viability in response to cisplatin compared with that in the control cells (Fig.	('NSCLC', 'Disease', 'MESH:D002289', (44, 49))	('HOXA3', 'Gene', (25, 30))	('response to cisplatin', 'MPA', (107, 128))	('cisplatin', 'Chemical', 'MESH:D002945', (119, 128))	('NSCLC', 'Phenotype', 'HP:0030358', (44, 49))	('increase', 'PosReg', (82, 90))	('viability', 'CPA', (94, 103))	('NSCLC', 'Disease', (44, 49))	('knockdown', 'Var', (31, 40))
99055	31615976	EDU staining assays confirmed that knockdown of HOXA3 increased NSCLC cell viability following cisplatin treatment compared with that in the control cells (Fig.	('knockdown', 'Var', (35, 44))	('NSCLC', 'Disease', 'MESH:D002289', (64, 69))	('increased', 'PosReg', (54, 63))	('NSCLC', 'Phenotype', 'HP:0030358', (64, 69))	('EDU', 'Chemical', 'None', (0, 3))	('cisplatin', 'Chemical', 'MESH:D002945', (95, 104))	('NSCLC', 'Disease', (64, 69))	('HOXA3', 'Gene', (48, 53))
99056	31615976	Furthermore, flow cytometry showed that HOXA3 knockdown decreased apoptosis following cisplatin treatment (Fig.	('knockdown', 'Var', (46, 55))	('cisplatin', 'Chemical', 'MESH:D002945', (86, 95))	('decreased', 'NegReg', (56, 65))	('HOXA3', 'Gene', (40, 45))	('apoptosis', 'CPA', (66, 75))
99057	31615976	HOXA3 knockdown in NSCLC cell lines increased their resistance to cisplatin; therefore, we decided to investigate the underlying mechanism of this effect.	('NSCLC', 'Phenotype', 'HP:0030358', (19, 24))	('resistance to cisplatin', 'MPA', (52, 75))	('cisplatin', 'Chemical', 'MESH:D002945', (66, 75))	('increased', 'PosReg', (36, 45))	('HOXA3', 'Gene', (0, 5))	('NSCLC', 'Disease', (19, 24))	('knockdown', 'Var', (6, 15))	('NSCLC', 'Disease', 'MESH:D002289', (19, 24))
99059	31615976	In all four NSCLC cell lines, HOXA3 knockdown resulted in reduced expression of E-cadherin and increased expression of Vimentin and Twist1 (Fig.	('E-cadherin', 'Gene', (80, 90))	('E-cadherin', 'Gene', '12550', (80, 90))	('Twist1', 'Gene', '22160', (132, 138))	('NSCLC', 'Phenotype', 'HP:0030358', (12, 17))	('Twist1', 'Gene', (132, 138))	('Vimentin', 'Gene', '22352', (119, 127))	('expression', 'MPA', (66, 76))	('knockdown', 'Var', (36, 45))	('NSCLC', 'Disease', (12, 17))	('reduced', 'NegReg', (58, 65))	('HOXA3', 'Gene', (30, 35))	('Vimentin', 'Gene', (119, 127))	('NSCLC', 'Disease', 'MESH:D002289', (12, 17))	('increased', 'PosReg', (95, 104))	('expression', 'MPA', (105, 115))
99060	31615976	5i-n), indicating that HOXA3 knockdown induced EMT in the NSCLC cell lines.	('NSCLC', 'Disease', (58, 63))	('knockdown', 'Var', (29, 38))	('NSCLC', 'Disease', 'MESH:D002289', (58, 63))	('HOXA3', 'Gene', (23, 28))	('NSCLC', 'Phenotype', 'HP:0030358', (58, 63))	('induced', 'PosReg', (39, 46))
99062	31615976	CCK-8 assays showed that Twist1 knockdown enhanced cisplatin sensitivity in NSCLC cells compared with that in the controls.	('Twist1', 'Gene', (25, 31))	('cisplatin', 'Chemical', 'MESH:D002945', (51, 60))	('cisplatin sensitivity', 'MPA', (51, 72))	('NSCLC', 'Disease', (76, 81))	('enhanced', 'PosReg', (42, 50))	('knockdown', 'Var', (32, 41))	('NSCLC', 'Disease', 'MESH:D002289', (76, 81))	('Twist1', 'Gene', '22160', (25, 31))	('NSCLC', 'Phenotype', 'HP:0030358', (76, 81))
99067	31615976	As mentioned previously, CCK-8 assays showed that HOXA-AS3 knockdown in NSCLC cells resulted in a significant reduction in viability in response to cisplatin compared with that in the controls.	('reduction', 'NegReg', (110, 119))	('cisplatin', 'Chemical', 'MESH:D002945', (148, 157))	('NSCLC', 'Disease', (72, 77))	('HOXA-AS3', 'Gene', (50, 58))	('NSCLC', 'Disease', 'MESH:D002289', (72, 77))	('response to cisplatin', 'MPA', (136, 157))	('viability', 'MPA', (123, 132))	('knockdown', 'Var', (59, 68))	('NSCLC', 'Phenotype', 'HP:0030358', (72, 77))
99068	31615976	In contrast, knockdown of both HOXA-AS3 and HOXA3 restored viability to control levels in response to cisplatin (Fig.	('response to cisplatin', 'MPA', (90, 111))	('knockdown', 'Var', (13, 22))	('viability', 'MPA', (59, 68))	('cisplatin', 'Chemical', 'MESH:D002945', (102, 111))
99069	31615976	The IC50 values of cisplatin in the double-knockdown NSCLC cells were also similar to those in the control cells (Supplementary Table 1.5).	('NSCLC', 'Phenotype', 'HP:0030358', (53, 58))	('cisplatin', 'Chemical', 'MESH:D002945', (19, 28))	('double-knockdown', 'Var', (36, 52))	('NSCLC', 'Disease', (53, 58))	('NSCLC', 'Disease', 'MESH:D002289', (53, 58))
99070	31615976	Thus, HOXA3 knockdown fully reversed the increase in cisplatin resistance conferred by HOXA-AS3 knockdown.	('cisplatin resistance', 'MPA', (53, 73))	('knockdown', 'Var', (96, 105))	('HOXA-AS3', 'Gene', (87, 95))	('cisplatin', 'Chemical', 'MESH:D002945', (53, 62))	('increase', 'PosReg', (41, 49))
99076	31615976	Similarly, treatment with shCtrl, shCtrl+cisplatin, or shHOXA-AS3 resulted in increases in tumor volumes and body weight.	('shCtrl', 'Var', (26, 32))	('cisplatin', 'Chemical', 'MESH:D002945', (41, 50))	('shHOXA-AS3', 'Var', (55, 65))	('shCtrl+cisplatin', 'Var', (34, 50))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('increases', 'PosReg', (78, 87))	('tumor', 'Disease', (91, 96))	('body weight', 'CPA', (109, 120))
99078	31615976	Moreover, the tumor size and weight were markedly decreased in the shHOXA-AS3+cisplatin group compared to those in the other groups (Fig.	('tumor', 'Disease', (14, 19))	('shHOXA-AS3+cisplatin', 'Var', (67, 87))	('decreased', 'NegReg', (50, 59))	('cisplatin', 'Chemical', 'MESH:D002945', (78, 87))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
99082	31615976	The H&E assay results also indicated that the tumors treated with shHOXA-AS3+cisplatin exhibited no significant alterations in cell shape or karyopyknosis, as compared with those in the other groups (Fig.	('in cell', 'CPA', (124, 131))	('with', 'Var', (61, 65))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('cisplatin', 'Chemical', 'MESH:D002945', (77, 86))	('tumors', 'Disease', (46, 52))	('tumors', 'Disease', 'MESH:D009369', (46, 52))
99083	31615976	These results in a well-established xenograft mouse model strongly suggested that inhibition of HOXA-AS3 augments the efficacy of cisplatin to treat lung cancer.	('lung cancer', 'Disease', 'MESH:D008175', (149, 160))	('inhibition', 'Var', (82, 92))	('cisplatin', 'Chemical', 'MESH:D002945', (130, 139))	('mouse', 'Species', '10090', (46, 51))	('lung cancer', 'Phenotype', 'HP:0100526', (149, 160))	('HOXA-AS3', 'Gene', (96, 104))	('lung cancer', 'Disease', (149, 160))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('efficacy', 'MPA', (118, 126))	('augments', 'NegReg', (105, 113))
99086	31615976	The mRNA level of HOXA3 was upregulated following treatment with shHOXA-AS3+cisplatin compared with that in the cispaltin group (Fig.	('cisplatin', 'Chemical', 'MESH:D002945', (76, 85))	('mRNA level of HOXA3', 'MPA', (4, 23))	('upregulated', 'PosReg', (28, 39))	('cispaltin', 'Chemical', 'None', (112, 121))	('shHOXA-AS3+cisplatin', 'Var', (65, 85))
99087	31615976	Thus, HOXA-AS3 knockdown enhanced cisplatin efficacyand upregulated HOXA3 in vivo, confirming the in vitro results.	('cisplatin', 'Chemical', 'MESH:D002945', (34, 43))	('HOXA3', 'MPA', (68, 73))	('enhanced', 'PosReg', (25, 33))	('knockdown', 'Var', (15, 24))	('cisplatin efficacyand', 'MPA', (34, 55))	('HOXA-AS3', 'Gene', (6, 14))	('upregulated', 'PosReg', (56, 67))
99088	31615976	We then examined HOXA-AS3 expression levels and found them to be higher in the shCtrl group than in both the shHOXA-AS3 and shHOXA-AS3+cisplatin groups (Fig.	('cisplatin', 'Chemical', 'MESH:D002945', (135, 144))	('HOXA-AS3 expression levels', 'MPA', (17, 43))	('shCtrl', 'Var', (79, 85))	('higher', 'PosReg', (65, 71))
99092	31615976	Recently, many studies have indicated that the aberrant expression of lncRNAs is responsible for drug resistance, which is a substantial obstacle to effective cancer therapy.	('cancer', 'Disease', (159, 165))	('drug resistance', 'MPA', (97, 112))	('aberrant expression', 'Var', (47, 66))	('responsible', 'Reg', (81, 92))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('drug resistance', 'Phenotype', 'HP:0020174', (97, 112))	('lncRNAs', 'Gene', (70, 77))	('cancer', 'Disease', 'MESH:D009369', (159, 165))
99099	31615976	In previous studies, HOXA-AS3 was found to be upregulated in glioma tissues and cell lines, and high expression of HOXA-AS3 is associated with poor prognosis in patients with glioma.	('glioma', 'Phenotype', 'HP:0009733', (61, 67))	('associated', 'Reg', (127, 137))	('HOXA-AS3', 'Gene', (115, 123))	('glioma', 'Disease', (61, 67))	('high expression', 'Var', (96, 111))	('patients', 'Species', '9606', (161, 169))	('glioma', 'Disease', (175, 181))	('HOXA-AS3', 'Gene', (21, 29))	('glioma', 'Phenotype', 'HP:0009733', (175, 181))	('glioma', 'Disease', 'MESH:D005910', (175, 181))	('glioma', 'Disease', 'MESH:D005910', (61, 67))	('upregulated', 'PosReg', (46, 57))
99101	31615976	Studies have determined that HOXA-AS3 acts as an epigenetic switch that determines the lineage specification of mesenchymal stem cells, interacts with EZH2, and is required for H3K27me3 deposition on the key osteogenic transcription factor gene RUNX2.	('EZH2', 'Gene', '14056', (151, 155))	('H3K27me3', 'Var', (177, 185))	('EZH2', 'Gene', (151, 155))	('RUNX2', 'Gene', '12393', (245, 250))	('interacts', 'Interaction', (136, 145))	('determines', 'Reg', (72, 82))	('RUNX2', 'Gene', (245, 250))	('lineage specification of mesenchymal stem cells', 'CPA', (87, 134))
99107	31615976	In turn, a better understanding of the molecular mechanisms by which HOXA-AS3 affects drug resistance will promote the development of more effective cancer treatments.	('cancer', 'Disease', (149, 155))	('affects', 'Reg', (78, 85))	('drug resistance', 'Phenotype', 'HP:0020174', (86, 101))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('drug resistance', 'MPA', (86, 101))	('cancer', 'Disease', 'MESH:D009369', (149, 155))	('HOXA-AS3', 'Var', (69, 77))
99109	31615976	In addition, DNA hypermethylation of HOXA3 has been identified as a biomarker for lung adenocarcinoma.	('DNA hypermethylation', 'Var', (13, 33))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (82, 101))	('HOXA3', 'Protein', (37, 42))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (82, 101))	('lung adenocarcinoma', 'Disease', (82, 101))
99112	31615976	Indeed, HOXA3 knockdown significantly increased cisplatin resistance.	('cisplatin', 'Chemical', 'MESH:D002945', (48, 57))	('HOXA3', 'Gene', (8, 13))	('cisplatin resistance', 'MPA', (48, 68))	('knockdown', 'Var', (14, 23))	('increased', 'PosReg', (38, 47))
99116	31615976	In the present study, suppressing HOXA3 downregulated E-cadherin and upregulated Vimentin levels, suggesting that HOXA3 knockdown increased drug resistance in NSCLC cells by inducing EMT.	('drug resistance', 'Phenotype', 'HP:0020174', (140, 155))	('suppressing', 'NegReg', (22, 33))	('downregulated', 'NegReg', (40, 53))	('HOXA3', 'Gene', (114, 119))	('E-cadherin', 'Gene', (54, 64))	('drug resistance', 'MPA', (140, 155))	('NSCLC', 'Disease', (159, 164))	('E-cadherin', 'Gene', '12550', (54, 64))	('Vimentin', 'Gene', '22352', (81, 89))	('NSCLC', 'Disease', 'MESH:D002289', (159, 164))	('knockdown', 'Var', (120, 129))	('upregulated', 'PosReg', (69, 80))	('inducing', 'PosReg', (174, 182))	('HOXA3', 'Protein', (34, 39))	('Vimentin', 'Gene', (81, 89))	('NSCLC', 'Phenotype', 'HP:0030358', (159, 164))	('increased', 'PosReg', (130, 139))
99119	31615976	Moreover, additional studies are needed to investigate other mechanisms and signaling pathways that may be involved in the mechanism by which HOXA-AS3 confers cisplatin resistance to NSCLC cells.	('HOXA-AS3', 'Var', (142, 150))	('NSCLC', 'Phenotype', 'HP:0030358', (183, 188))	('NSCLC', 'Disease', (183, 188))	('cisplatin resistance', 'MPA', (159, 179))	('cisplatin', 'Chemical', 'MESH:D002945', (159, 168))	('NSCLC', 'Disease', 'MESH:D002289', (183, 188))
99122	31615976	Additionally, HOXA-AS3 knockdown reduced drug resistance by upregulating HOXA3 expression, which increases cisplatin resistance and induces EMT.	('drug resistance', 'Phenotype', 'HP:0020174', (41, 56))	('expression', 'MPA', (79, 89))	('cisplatin', 'Chemical', 'MESH:D002945', (107, 116))	('HOXA3', 'Gene', (73, 78))	('increases', 'PosReg', (97, 106))	('knockdown', 'Var', (23, 32))	('cisplatin resistance', 'MPA', (107, 127))	('induces', 'PosReg', (132, 139))	('drug resistance', 'MPA', (41, 56))	('reduced', 'NegReg', (33, 40))	('EMT', 'CPA', (140, 143))	('upregulating', 'PosReg', (60, 72))
99128	31615976	The membranes were then washed and blocked before incubation with the primary antibodies recognizing the following proteins: HOXA3 (SC-374237, Santa Cruz Biotechnology, Santa Cruz, CA, USA), E-cadherin (#3195, Cell Signaling Technology, Danvers, MA, USA), Vimentin (#5741, Cell Signaling Technology), Twist1 (#46702, Cell Signaling Technology) and GAPDH (#2118, Cell Signaling Technology).	('HOXA3', 'Protein', (125, 130))	('Vimentin', 'Gene', '22352', (256, 264))	('E-cadherin', 'Gene', (191, 201))	('SC-374237', 'Var', (132, 141))	('#46702', 'Var', (309, 315))	('E-cadherin', 'Gene', '12550', (191, 201))	('Twist1', 'Gene', '22160', (301, 307))	('#5741', 'Var', (266, 271))	('GAPDH', 'Gene', '14433', (348, 353))	('#2118', 'Var', (355, 360))	('Twist1', 'Gene', (301, 307))	('#3195', 'Var', (203, 208))	('Vimentin', 'Gene', (256, 264))	('GAPDH', 'Gene', (348, 353))	('SC-374237', 'Chemical', 'MESH:C049999', (132, 141))
99135	31615976	Small interfering RNAs (siRNAs) targeting HOXA-AS3 (si-HOXA-AS3-651, si-HOXA-AS3-728, si-HOXA-AS3-3507), HOXA3 (#sc-38675, Santa Cruz Biotechnology) or negative control (NC) siRNAs were transfected into NSCLC cells using Lipofectamine 3000.	('NSCLC', 'Disease', (203, 208))	('si-HOXA-AS3-651', 'Var', (52, 67))	('si-HOXA-AS3-3507', 'Var', (86, 102))	('NSCLC', 'Disease', 'MESH:D002289', (203, 208))	('si-HOXA-AS3-728', 'Var', (69, 84))	('NSCLC', 'Phenotype', 'HP:0030358', (203, 208))
99154	28938622	Profiling cancer-related gene mutations in oral squamous cell carcinoma from Japanese patients by targeted amplicon sequencing Somatic mutation analysis is a standard practice in the study of human cancers to identify mutations that cause therapeutic sensitization and resistance.	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (43, 71))	('oral squamous cell carcinoma', 'Disease', (43, 71))	('cancers', 'Disease', 'MESH:D009369', (198, 205))	('cancer', 'Disease', (10, 16))	('patients', 'Species', '9606', (86, 94))	('cancer', 'Disease', (198, 204))	('human', 'Species', '9606', (192, 197))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('therapeutic', 'MPA', (239, 250))	('carcinoma', 'Phenotype', 'HP:0030731', (62, 71))	('cancers', 'Phenotype', 'HP:0002664', (198, 205))	('cancers', 'Disease', (198, 205))	('resistance', 'CPA', (269, 279))	('mutations', 'Var', (30, 39))	('cancer', 'Disease', 'MESH:D009369', (10, 16))	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('mutations', 'Var', (218, 227))	('cause', 'Reg', (233, 238))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (48, 71))
99157	28938622	The most frequent mutations were in TP53 (61.7%), NOTCH1 (25.5%), CDKN2A (19.1%), SYNE1 (14.9%), PIK3CA (10.6%), ROS1 (10.6%), and TAF1L (10.6%).	('NOTCH1', 'Gene', '4851', (50, 56))	('ROS1', 'Gene', '6098', (113, 117))	('TP53', 'Gene', (36, 40))	('TAF1L', 'Gene', '138474', (131, 136))	('NOTCH1', 'Gene', (50, 56))	('TP53', 'Gene', '7157', (36, 40))	('CDKN2A', 'Gene', '1029', (66, 72))	('TAF1L', 'Gene', (131, 136))	('PIK3CA', 'Gene', '5290', (97, 103))	('SYNE1', 'Gene', '23345', (82, 87))	('SYNE1', 'Gene', (82, 87))	('PIK3CA', 'Gene', (97, 103))	('CDKN2A', 'Gene', (66, 72))	('ROS1', 'Gene', (113, 117))	('mutations', 'Var', (18, 27))
99158	28938622	Pathway assessment showed that the somatic aberrations within OSCC genomes are mainly involved in several important pathways, including cell cycle regulation and RTK-MAPK-PI3K.	('SCC', 'Gene', (63, 66))	('cell cycle regulation', 'CPA', (136, 157))	('SCC', 'Gene', '6317', (63, 66))	('involved', 'Reg', (86, 94))	('aberrations', 'Var', (43, 54))
99164	28938622	The poor prognosis of OSCC patients is associated with the overexpression of anti-apoptotic genes and the deregulation of p53 function, both of which may contribute to chemotherapy resistance.	('SCC', 'Gene', '6317', (23, 26))	('deregulation', 'Var', (106, 118))	('chemotherapy resistance', 'CPA', (168, 191))	('function', 'MPA', (126, 134))	('p53', 'Gene', '7157', (122, 125))	('contribute', 'Reg', (154, 164))	('patients', 'Species', '9606', (27, 35))	('overexpression', 'PosReg', (59, 73))	('SCC', 'Gene', (23, 26))	('anti-apoptotic genes', 'Gene', (77, 97))	('p53', 'Gene', (122, 125))
99166	28938622	Since unique mutations have been observed in individual human cancer samples, the identification and characterization of the molecular alterations underlying individual cancer patients are critical to developing more effective, personalized therapies.	('patients', 'Species', '9606', (176, 184))	('cancer', 'Disease', (169, 175))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('human', 'Species', '9606', (56, 61))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('mutations', 'Var', (13, 22))	('cancer', 'Disease', 'MESH:D009369', (169, 175))
99167	28938622	For example, next-generation sequencing (NGS) technologies have revolutionized cancer genomics research by providing a comprehensive method of detecting somatic cancer genome alterations, including point mutations, insertions, deletions, and copy number variations (CNVs).	('insertions', 'Var', (215, 225))	('point mutations', 'Var', (198, 213))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('copy number variations', 'Var', (242, 264))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('deletions', 'Var', (227, 236))	('cancer', 'Disease', (161, 167))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))
99170	28938622	Additional NGS-mediated discoveries included mutations in cell differentiation pathways, particularly in NOTCH and FBXW7.	('mutations', 'Var', (45, 54))	('cell differentiation', 'CPA', (58, 78))	('FBXW7', 'Gene', '55294', (115, 120))	('NOTCH', 'Gene', (105, 110))	('FBXW7', 'Gene', (115, 120))
99175	28938622	In the present study, 9 OSCC cell lines and surgically resected OSCC tissues from 47 Japanese patients were sequenced for mutations in the coding regions of 409 cancer-related genes using a semiconductor-based sequencing platform.	('9 OSCC', 'CellLine', 'CVCL:L894', (22, 28))	('SCC', 'Gene', (25, 28))	('patients', 'Species', '9606', (94, 102))	('SCC', 'Gene', (65, 68))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('SCC', 'Gene', '6317', (25, 28))	('SCC', 'Gene', '6317', (65, 68))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('mutations in', 'Var', (122, 134))	('cancer', 'Disease', (161, 167))
99177	28938622	The most common mutations in OSCCs were C>T transitions (50.2%), which is a process attributed to the normal cellular event of the deamination of 5-methylcytosine.	('SCC', 'Gene', '6317', (30, 33))	('C>T transitions', 'Var', (40, 55))	('5-methylcytosine', 'Chemical', 'MESH:D044503', (146, 162))	('SCC', 'Gene', (30, 33))
99178	28938622	C>T transitions were also the most common mutations found in HNSCC and esophageal squamous cell carcinoma (ESCC) in previous whole exome sequencing studies (Supplementary Figure 2).	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('esophageal squamous cell carcinoma', 'Disease', (71, 105))	('SCC', 'Gene', (63, 66))	('SCC', 'Gene', (108, 111))	('SCC', 'Gene', '6317', (63, 66))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (71, 105))	('SCC', 'Gene', '6317', (108, 111))	('HNSCC', 'Phenotype', 'HP:0012288', (61, 66))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (82, 105))	('C>T transitions', 'Var', (0, 15))
99179	28938622	Importantly, the second most frequent mutations in OSCC were C>A transversions.	('frequent', 'Reg', (29, 37))	('SCC', 'Gene', '6317', (52, 55))	('C>A transversions', 'Var', (61, 78))	('SCC', 'Gene', (52, 55))	('mutations', 'Var', (38, 47))
99182	28938622	TP53 mutations, which were predicted to confer loss of function, were noted in all cell lines (10 mutations), including 2 frameshifts and 6 missense, 1 nonsense, and 1 splice site mutations.	('frameshifts', 'Var', (122, 133))	('TP53', 'Gene', '7157', (0, 4))	('missense', 'Var', (140, 148))	('TP53', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))	('mutations', 'Var', (98, 107))
99185	28938622	The mutations in TP53, CDKN2A, PIK3CA, and SMAD4 detected in HSC2, HSC3, HSC4, and SCC-25 cells were consistent with the CCLE mutation data.	('HSC3', 'Gene', '150353', (67, 71))	('HSC3', 'Gene', (67, 71))	('SMAD4', 'Gene', (43, 48))	('CDKN2A', 'Gene', (23, 29))	('SCC-25', 'CellLine', 'CVCL:1682', (83, 89))	('PIK3CA', 'Gene', (31, 37))	('CCLE', 'Chemical', '-', (121, 125))	('CDKN2A', 'Gene', '1029', (23, 29))	('PIK3CA', 'Gene', '5290', (31, 37))	('mutations', 'Var', (4, 13))	('SMAD4', 'Gene', '4089', (43, 48))	('HSC2', 'CellLine', 'CVCL:1287', (61, 65))	('TP53', 'Gene', '7157', (17, 21))	('TP53', 'Gene', (17, 21))
99188	28938622	In total, we identified 357 variants (127 genes) in 47 patients with OSCC (Supplementary Table 5).	('patients', 'Species', '9606', (55, 63))	('variants', 'Var', (28, 36))	('SCC', 'Gene', (70, 73))	('SCC', 'Gene', '6317', (70, 73))
99194	28938622	Of the TP53 mutations, 22 (71.0%) were predicted to be missense mutations, 5 (16.1%) were predicted to be nonsense mutations, 2 (6.9%) were predicted to be splice site mutations, 1 (3.5%) was predicted to be a frameshift deletion, and 1 (3.5%) was predicted to be an in-frame deletion.	('mutations', 'Var', (12, 21))	('TP53', 'Gene', '7157', (7, 11))	('TP53', 'Gene', (7, 11))
99195	28938622	In addition, the majority of TP53 mutations (83.9%, 26/31) are localized in the DNA binding domain of the protein (residues 100-300, Supplementary Figure 5).	('TP53', 'Gene', '7157', (29, 33))	('TP53', 'Gene', (29, 33))	('mutations', 'Var', (34, 43))
99196	28938622	TP53 mutations were significantly correlated with a smoking habit in OSCC patients (P < 0.05).	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('smoking habit', 'Disease', (52, 65))	('patients', 'Species', '9606', (74, 82))	('SCC', 'Gene', (70, 73))	('mutations', 'Var', (5, 14))	('SCC', 'Gene', '6317', (70, 73))	('correlated', 'Reg', (34, 44))
99197	28938622	In total, 25.5% of the cases examined showed mutations in NOTCH1, which was the second most commonly mutated gene in our study, and included 10 missense mutations (9 sites), 1 frameshift insertion, and 1 splice site mutation (Supplementary Table 6).	('mutations', 'Var', (45, 54))	('frameshift', 'Var', (176, 186))	('missense mutations', 'Var', (144, 162))	('NOTCH1', 'Gene', '4851', (58, 64))	('NOTCH1', 'Gene', (58, 64))
99199	28938622	Interestingly, eight mutations (66.7%) were located in the EGF-like domains of the NOTCH1 extracellular region.	('NOTCH1', 'Gene', '4851', (83, 89))	('NOTCH1', 'Gene', (83, 89))	('mutations', 'Var', (21, 30))
99200	28938622	An amino acid sequence comparison of mutation sites among species revealed that six of the nine NOTCH1 missense mutations (G310R, D352G, R365C, T1014M, C1383Y, and Q1957P) were on highly conserved residues among vertebrate Notch1 orthologs, suggesting significant functional effects of NOTCH1 mutations in the pathogenesis of OSCC (Supplementary Figure 6).	('C1383Y', 'Var', (152, 158))	('NOTCH1', 'Gene', '4851', (96, 102))	('NOTCH1', 'Gene', '4851', (286, 292))	('T1014M', 'Var', (144, 150))	('G310R', 'Mutation', 'p.G310R', (123, 128))	('Q1957P', 'Mutation', 'rs201174576', (164, 170))	('Notch1', 'Gene', (223, 229))	('Notch1', 'Gene', '4851', (223, 229))	('Q1957P', 'Var', (164, 170))	('R365C', 'Var', (137, 142))	('SCC', 'Gene', '6317', (327, 330))	('C1383Y', 'Mutation', 'p.C1383Y', (152, 158))	('mutations', 'Var', (293, 302))	('G310R', 'Var', (123, 128))	('R365C', 'Mutation', 'rs1064795070', (137, 142))	('SCC', 'Gene', (327, 330))	('D352G', 'Mutation', 'p.D352G', (130, 135))	('D352G', 'Var', (130, 135))	('NOTCH1', 'Gene', (96, 102))	('NOTCH1', 'Gene', (286, 292))	('T1014M', 'Mutation', 'rs1393225618', (144, 150))
99201	28938622	Furthermore, four of nine NOTCH1 missense mutations (G310R, D352G, D1185N, and Q1957P) were on conserved residues among all four human Notch paralogs (Supplementary Figure 7).	('NOTCH1', 'Gene', '4851', (26, 32))	('NOTCH1', 'Gene', (26, 32))	('D352G', 'Var', (60, 65))	('G310R', 'Mutation', 'p.G310R', (53, 58))	('Q1957P', 'Mutation', 'rs201174576', (79, 85))	('Q1957P', 'Var', (79, 85))	('human', 'Species', '9606', (129, 134))	('D352G', 'Mutation', 'p.D352G', (60, 65))	('D1185N', 'Var', (67, 73))	('D1185N', 'Mutation', 'rs548083258', (67, 73))	('G310R', 'Var', (53, 58))
99202	28938622	The significance of NOTCH1 mutations has also been confirmed by the observation that the frequency of mutations in NOTCH1 is much higher than the frequency of mutations in its paralogs NOTCH2 and NOTCH4 (Supplementary Table 5).	('mutations', 'Var', (27, 36))	('NOTCH1', 'Gene', (115, 121))	('NOTCH2', 'Gene', (185, 191))	('NOTCH1', 'Gene', '4851', (20, 26))	('higher', 'Reg', (130, 136))	('NOTCH1', 'Gene', (20, 26))	('mutations', 'Var', (102, 111))	('NOTCH2', 'Gene', '4853', (185, 191))	('NOTCH4', 'Gene', (196, 202))	('NOTCH4', 'Gene', '4855', (196, 202))	('NOTCH1', 'Gene', '4851', (115, 121))
99204	28938622	All the nonsense and missense mutations in CDKN2A and missense mutations in PIK3CA are listed in the COSMIC database, suggesting the functional effects of the mutations (Supplementary Table 7).	('CDKN2A', 'Gene', (43, 49))	('missense mutations', 'Var', (54, 72))	('missense mutations', 'Var', (21, 39))	('CDKN2A', 'Gene', '1029', (43, 49))	('PIK3CA', 'Gene', (76, 82))	('PIK3CA', 'Gene', '5290', (76, 82))	('nonsense', 'Var', (8, 16))
99205	28938622	CDKN2A genes exhibited nonsense and frameshift mutations, indicating its tumor suppressor roles in OSCC.	('SCC', 'Gene', (100, 103))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('frameshift mutations', 'Var', (36, 56))	('nonsense', 'Var', (23, 31))	('SCC', 'Gene', '6317', (100, 103))	('tumor', 'Disease', (73, 78))	('CDKN2A', 'Gene', (0, 6))	('CDKN2A', 'Gene', '1029', (0, 6))
99206	28938622	Four out of five tumors with mutated PIK3CA involved the cervical lymph nodes (Supplementary Table 7), suggesting that PIK3CA mutations may be a late event in the progression of OSCC.	('involved', 'Reg', (44, 52))	('PIK3CA', 'Gene', '5290', (37, 43))	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('SCC', 'Gene', (179, 182))	('PIK3CA', 'Gene', (119, 125))	('tumors', 'Disease', (17, 23))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('PIK3CA', 'Gene', '5290', (119, 125))	('SCC', 'Gene', '6317', (179, 182))	('mutated', 'Var', (29, 36))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('PIK3CA', 'Gene', (37, 43))
99211	28938622	Cell cycle regulatory components constituted the most frequently disrupted category (87.2%, 41 of 47 cases), including mutations and CNV loss in TP53 (63.8%), CDKN2A (34.0%), and ATM (19.1%); there were also CNV gains in CCND1 (34.0%), MYC (23.4%), CCND2 (17.0%), MDM2 (14.9%), and MYCN (14.9%) and CNV losses in RB1 (27.7%) and CHEK1 (6.4%).	('MYC', 'Gene', '4609', (236, 239))	('CHEK1', 'Gene', (329, 334))	('CCND2', 'Gene', (249, 254))	('MYC', 'Gene', (282, 285))	('CCND2', 'Gene', '894', (249, 254))	('TP53', 'Gene', '7157', (145, 149))	('CNV loss', 'Disease', (133, 141))	('CNV loss', 'Disease', (299, 307))	('MYCN', 'Gene', (282, 286))	('CCND1', 'Gene', '595', (221, 226))	('CNV loss', 'Disease', 'MESH:D015431', (133, 141))	('MDM2', 'Gene', (264, 268))	('mutations', 'Var', (119, 128))	('CDKN2A', 'Gene', (159, 165))	('MYC', 'Gene', '4609', (282, 285))	('ATM', 'Gene', '472', (179, 182))	('CCND1', 'Gene', (221, 226))	('RB1', 'Gene', (313, 316))	('CNV loss', 'Disease', 'MESH:D015431', (299, 307))	('gains', 'Disease', 'MESH:D015430', (212, 217))	('TP53', 'Gene', (145, 149))	('MYC', 'Gene', (236, 239))	('MDM2', 'Gene', '4193', (264, 268))	('gains', 'Disease', (212, 217))	('CHEK1', 'Gene', '1111', (329, 334))	('CDKN2A', 'Gene', '1029', (159, 165))	('RB1', 'Gene', '5925', (313, 316))	('MYCN', 'Gene', '4613', (282, 286))	('ATM', 'Gene', (179, 182))
99214	28938622	Univariate survival analysis revealed that mutations in NOTCH1 and PIK3CA were found to be associated with worse overall survival in OSCC patients (P = 0.0054 and P = 0.0162, respectively).	('PIK3CA', 'Gene', '5290', (67, 73))	('SCC', 'Gene', '6317', (134, 137))	('worse', 'NegReg', (107, 112))	('overall survival', 'MPA', (113, 129))	('mutations', 'Var', (43, 52))	('NOTCH1', 'Gene', '4851', (56, 62))	('NOTCH1', 'Gene', (56, 62))	('PIK3CA', 'Gene', (67, 73))	('patients', 'Species', '9606', (138, 146))	('SCC', 'Gene', (134, 137))
99220	28938622	The frequency of TP53 mutations is fairly consistent with the frequency found in previous studies of OSCC (62%-73%).	('SCC', 'Gene', '6317', (102, 105))	('mutations', 'Var', (22, 31))	('SCC', 'Gene', (102, 105))	('TP53', 'Gene', '7157', (17, 21))	('TP53', 'Gene', (17, 21))
99221	28938622	Importantly, the TP53 gene was frequently mutated in early stage OSCC (stages I and II, 62.5%, 15/24 in Figure 2).	('SCC', 'Gene', (66, 69))	('mutated', 'Var', (42, 49))	('SCC', 'Gene', '6317', (66, 69))	('TP53', 'Gene', '7157', (17, 21))	('TP53', 'Gene', (17, 21))
99222	28938622	In line with our observations, previous studies have also shown that TP53 mutations occur in early stage HNSCC as well as in oral premalignant lesions, which are often identified as leukoplakia.	('leukoplakia', 'Disease', 'MESH:D007971', (182, 193))	('TP53', 'Gene', '7157', (69, 73))	('TP53', 'Gene', (69, 73))	('mutations', 'Var', (74, 83))	('SCC', 'Gene', (107, 110))	('HNSCC', 'Phenotype', 'HP:0012288', (105, 110))	('leukoplakia', 'Disease', (182, 193))	('oral premalignant lesions', 'Disease', (125, 150))	('occur', 'Reg', (84, 89))	('SCC', 'Gene', '6317', (107, 110))
99228	28938622	Tyrosine kinase inhibitors, such as erlotinib and gefitinib, are currently frontline therapeutics in EGFR mutant non-small cell lung cancer patients.	('mutant', 'Var', (106, 112))	('cell lung cancer', 'Disease', (123, 139))	('EGFR', 'Gene', '1956', (101, 105))	('EGFR', 'Gene', (101, 105))	('cell lung cancer', 'Disease', 'MESH:D008175', (123, 139))	('erlotinib', 'Chemical', 'MESH:D000069347', (36, 45))	('gefitinib', 'Chemical', 'MESH:D000077156', (50, 59))	('patients', 'Species', '9606', (140, 148))	('lung cancer', 'Phenotype', 'HP:0100526', (128, 139))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (117, 139))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (113, 139))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
99233	28938622	Importantly, Kaplan-Meier analysis showed that RTK/MAPK/PI3K pathway alteration was associated with a poorer prognosis in OSCC patients.	('SCC', 'Gene', '6317', (123, 126))	('RTK/MAPK/PI3K pathway', 'Pathway', (47, 68))	('patients', 'Species', '9606', (127, 135))	('alteration', 'Var', (69, 79))	('SCC', 'Gene', (123, 126))
99234	28938622	Notch signaling dysregulation is implicated in a number of human diseases, including cancers and developmental disorders.	('human', 'Species', '9606', (59, 64))	('implicated', 'Reg', (33, 43))	('cancers', 'Disease', 'MESH:D009369', (85, 92))	('cancers', 'Phenotype', 'HP:0002664', (85, 92))	('developmental disorders', 'Disease', (97, 120))	('cancers', 'Disease', (85, 92))	('Notch signaling', 'MPA', (0, 15))	('developmental disorders', 'Disease', 'MESH:D002658', (97, 120))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('dysregulation', 'Var', (16, 29))
99237	28938622	By contrast, loss-of-function NOTCH1 mutations are relatively common in HNSCC, lung SCC, and breast cancer.	('SCC', 'Gene', '6317', (84, 87))	('loss-of-function', 'NegReg', (13, 29))	('HNSCC', 'Phenotype', 'HP:0012288', (72, 77))	('NOTCH1', 'Gene', '4851', (30, 36))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('breast cancer', 'Disease', 'MESH:D001943', (93, 106))	('NOTCH1', 'Gene', (30, 36))	('mutations', 'Var', (37, 46))	('breast cancer', 'Disease', (93, 106))	('SCC', 'Gene', (74, 77))	('breast cancer', 'Phenotype', 'HP:0003002', (93, 106))	('SCC', 'Gene', (84, 87))	('SCC', 'Gene', '6317', (74, 77))
99239	28938622	The frequency of NOTCH1 mutations in this study (25.5%, Figure 2B) was higher than the frequency observed in the 530 HNSCC tumors of the TCGA cohort (17.8%) (http://www.cbioportal.org/study?id=hnsc_tcga#summary).	('HNSCC', 'Phenotype', 'HP:0012288', (117, 122))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('NOTCH1', 'Gene', '4851', (17, 23))	('NOTCH1', 'Gene', (17, 23))	('HNSCC tumors', 'Disease', (117, 129))	('mutations', 'Var', (24, 33))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('HNSCC tumors', 'Disease', 'MESH:D000077195', (117, 129))
99240	28938622	In addition, NOTCH1 had a significantly higher rate of mutation in Chinese OSCC patients (43.1%-48.5%), suggesting that NOTCH1 mutations may be a characteristic feature of OSCC patients of Asian descent.	('patients', 'Species', '9606', (80, 88))	('NOTCH1', 'Gene', '4851', (120, 126))	('NOTCH1', 'Gene', (120, 126))	('SCC', 'Gene', (76, 79))	('NOTCH1', 'Gene', '4851', (13, 19))	('NOTCH1', 'Gene', (13, 19))	('patients', 'Species', '9606', (177, 185))	('SCC', 'Gene', (173, 176))	('SCC', 'Gene', '6317', (76, 79))	('mutation', 'Var', (55, 63))	('mutations', 'Var', (127, 136))	('SCC', 'Gene', '6317', (173, 176))
99241	28938622	Moreover, we found that most missense mutations observed in NOTCH1 could affect highly conserved amino acids among species (Supplementary Figure 6) and were predicted to be deleterious according to the PolyPhen-2 tool, which predicts the possible impact of an amino acid substitution (Supplementary Table 6).	('NOTCH1', 'Gene', '4851', (60, 66))	('affect', 'Reg', (73, 79))	('NOTCH1', 'Gene', (60, 66))	('highly conserved amino acids among species', 'MPA', (80, 122))	('missense mutations', 'Var', (29, 47))
99242	28938622	We also found mutations in three other genes related to the Notch pathway, including FBXW7 (4 cases), NFE2L2 (2 cases), and KEAP1 (1 case) (Supplementary Table 5), implicating Notch signaling pathways in the pathogenesis of OSCC.	('SCC', 'Gene', '6317', (225, 228))	('NFE2L2', 'Gene', '4780', (102, 108))	('FBXW7', 'Gene', (85, 90))	('KEAP1', 'Gene', '9817', (124, 129))	('NFE2L2', 'Gene', (102, 108))	('SCC', 'Gene', (225, 228))	('KEAP1', 'Gene', (124, 129))	('mutations', 'Var', (14, 23))	('FBXW7', 'Gene', '55294', (85, 90))
99245	28938622	In addition to MLL2, we identified MLL mutations in two cases and MLL3 mutations in three cases (Supplementary Table 5).	('MLL2', 'Gene', (15, 19))	('MLL3', 'Gene', '58508', (66, 70))	('MLL', 'Gene', (66, 69))	('MLL', 'Gene', '4297', (35, 38))	('mutations', 'Var', (39, 48))	('MLL', 'Gene', '4297', (66, 69))	('mutations', 'Var', (71, 80))	('MLL', 'Gene', (35, 38))	('MLL3', 'Gene', (66, 70))	('MLL2', 'Gene', '8085', (15, 19))	('MLL', 'Gene', '4297', (15, 18))	('MLL', 'Gene', (15, 18))
99246	28938622	These frequent mutations in MLL family members indicate the critical roles of chromatin/histone modifiers in OSCC.	('mutations', 'Var', (15, 24))	('SCC', 'Gene', (110, 113))	('MLL', 'Gene', (28, 31))	('MLL', 'Gene', '4297', (28, 31))	('SCC', 'Gene', '6317', (110, 113))
99250	28938622	As the results, we detected recurrent mutations in the genes not covered in this study, such as CASP8, EPHA2 and FAT1 (data not shown).	('EPHA2', 'Gene', '1969', (103, 108))	('FAT1', 'Gene', '2195', (113, 117))	('FAT1', 'Gene', (113, 117))	('CASP8', 'Gene', (96, 101))	('CASP8', 'Gene', '841', (96, 101))	('EPHA2', 'Gene', (103, 108))	('mutations', 'Var', (38, 47))
99257	28938622	Somatic mutations (point mutations, insertions, and deletions) were detected using statistical approaches in tumor and normal samples from the Ion Reporter software 5.0 tumor-normal workflow (Thermo Fisher Scientific).	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('insertions', 'Var', (36, 46))	('tumor', 'Disease', (169, 174))	('deletions', 'Var', (52, 61))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumor', 'Disease', (109, 114))
99259	28938622	The SIFT, Polyphen-2, and Grantham scores were used to estimate evolutionary conservation and the effects of an amino acid substitution on the structure and function of the protein.	('amino', 'Var', (112, 117))	('SIFT', 'Disease', 'None', (4, 8))	('SIFT', 'Disease', (4, 8))
99260	28938622	Recurrent genomic regions with CNVs were identified using copy numbers greater than 3 and less than 1 for gains and losses, respectively.	('gains', 'Disease', (106, 111))	('copy numbers', 'Var', (58, 70))	('losses', 'NegReg', (116, 122))	('gains', 'Disease', 'MESH:D015430', (106, 111))
99286	28814981	Histologically normal tissue adjacent to tumors and OPML can have an aberrant methylation pattern in candidate genes, suggesting that these epigenetic modifications are early events in oral carcinogenesis.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('epigenetic modifications', 'Var', (140, 164))	('tumors', 'Disease', 'MESH:D009369', (41, 47))	('tumors', 'Disease', (41, 47))	('methylation pattern', 'MPA', (78, 97))	('oral carcinogenesis', 'Disease', (185, 204))	('oral carcinogenesis', 'Disease', 'MESH:D063646', (185, 204))
99314	28814981	Among the remaining 15 differentially methylated genes, 12 were hypermethylated (ZAP70, PAX1, KIF1A, LRRTM1, PARP15, FLI1, NTM, LINC0059, EPHX3, MIR137HG, ITGA4, MIR193), whereas three were hypomethylated (GP1BB, MIR296, TERT) in OSCC/HGSIL.	('TERT', 'Gene', '7015', (221, 225))	('MIR296', 'Gene', '407022', (213, 219))	('MIR137HG', 'Gene', '400765', (145, 153))	('NTM', 'Gene', (123, 126))	('PAX1', 'Gene', (88, 92))	('MIR193', 'Var', (162, 168))	('LINC0059', 'Var', (128, 136))	('NTM', 'Gene', '50863', (123, 126))	('GP1BB', 'Gene', (206, 211))	('SIL', 'Gene', '6491', (237, 240))	('FLI1', 'Gene', (117, 121))	('LRRTM1', 'Gene', (101, 107))	('PARP15', 'Gene', '165631', (109, 115))	('KIF1A', 'Gene', '547', (94, 99))	('GP1BB', 'Gene', '2812', (206, 211))	('hypermethylated', 'Var', (64, 79))	('ITGA4', 'Gene', '3676', (155, 160))	('FLI1', 'Gene', '2313', (117, 121))	('LRRTM1', 'Gene', '347730', (101, 107))	('ZAP70', 'Gene', (81, 86))	('SIL', 'Gene', (237, 240))	('PAX1', 'Gene', '5075', (88, 92))	('EPHX3', 'Gene', (138, 143))	('ZAP70', 'Gene', '7535', (81, 86))	('ITGA4', 'Gene', (155, 160))	('PARP15', 'Gene', (109, 115))	('MIR296', 'Gene', (213, 219))	('EPHX3', 'Gene', '79852', (138, 143))	('TERT', 'Gene', (221, 225))	('KIF1A', 'Gene', (94, 99))	('MIR137HG', 'Gene', (145, 153))
99317	28814981	ROC curve analysis applied to these scores discriminating OSCC and HGSIL from normal donors gave an area under the curve (AUC) of 0.981, identifying a threshold of 1.0615547 as the best value for sensitivity and specificity (97.1 and 100% respectively, see Fig.	('1.0615547', 'Var', (164, 173))	('SIL', 'Gene', '6491', (69, 72))	('donor', 'Species', '9606', (85, 90))	('SIL', 'Gene', (69, 72))
99340	28814981	Quantitative DNA methylation analysis of the following 13 genes: ZAP70, ITGA4, KIF1A, PARP15, EPHX3, NTM, LRRTM1, FLI1, MIR193, LINC00599, MIR296, TERT, and GP1BB, clearly discriminated OSCC and HGSIL from healthy donors or from contralateral normal mucosa from the same patients.	('NTM', 'Gene', (101, 104))	('ITGA4', 'Gene', '3676', (72, 77))	('FLI1', 'Gene', '2313', (114, 118))	('KIF1A', 'Gene', '547', (79, 84))	('NTM', 'Gene', '50863', (101, 104))	('GP1BB', 'Gene', (157, 162))	('MIR296', 'Gene', (139, 145))	('ITGA4', 'Gene', (72, 77))	('TERT', 'Gene', (147, 151))	('MIR193', 'Var', (120, 126))	('PARP15', 'Gene', '165631', (86, 92))	('TERT', 'Gene', '7015', (147, 151))	('SIL', 'Gene', '6491', (197, 200))	('discriminated', 'Reg', (172, 185))	('MIR296', 'Gene', '407022', (139, 145))	('ZAP70', 'Gene', (65, 70))	('GP1BB', 'Gene', '2812', (157, 162))	('EPHX3', 'Gene', (94, 99))	('donor', 'Species', '9606', (214, 219))	('ZAP70', 'Gene', '7535', (65, 70))	('KIF1A', 'Gene', (79, 84))	('patients', 'Species', '9606', (271, 279))	('EPHX3', 'Gene', '79852', (94, 99))	('LINC00599', 'Gene', '157627', (128, 137))	('PARP15', 'Gene', (86, 92))	('LINC00599', 'Gene', (128, 137))	('LRRTM1', 'Gene', (106, 112))	('OSCC', 'Disease', (186, 190))	('SIL', 'Gene', (197, 200))	('FLI1', 'Gene', (114, 118))	('LRRTM1', 'Gene', '347730', (106, 112))
99341	28814981	In particular, we found in OSCC and HGSIL hypermethylation of ZAP70, ITGA4, KIF1A, PARP15, EPHX3, NTM, LRRTM1, FLI1, MIR193, LINC00599, PAX1, and MIR137HG and hypomethylation of TERT, MIR296, and GP1BB at various CpGs.	('ZAP70', 'Gene', (62, 67))	('LRRTM1', 'Gene', '347730', (103, 109))	('EPHX3', 'Gene', '79852', (91, 96))	('FLI1', 'Gene', (111, 115))	('ZAP70', 'Gene', '7535', (62, 67))	('KIF1A', 'Gene', (76, 81))	('PAX1', 'Gene', (136, 140))	('ITGA4', 'Gene', '3676', (69, 74))	('PARP15', 'Gene', (83, 89))	('NTM', 'Gene', (98, 101))	('FLI1', 'Gene', '2313', (111, 115))	('MIR296', 'Gene', (184, 190))	('NTM', 'Gene', '50863', (98, 101))	('ITGA4', 'Gene', (69, 74))	('GP1BB', 'Gene', (196, 201))	('SIL', 'Gene', '6491', (38, 41))	('hypomethylation', 'Var', (159, 174))	('TERT', 'Gene', (178, 182))	('MIR296', 'Gene', '407022', (184, 190))	('TERT', 'Gene', '7015', (178, 182))	('MIR137HG', 'Gene', (146, 154))	('KIF1A', 'Gene', '547', (76, 81))	('PAX1', 'Gene', '5075', (136, 140))	('GP1BB', 'Gene', '2812', (196, 201))	('LRRTM1', 'Gene', (103, 109))	('PARP15', 'Gene', '165631', (83, 89))	('MIR137HG', 'Gene', '400765', (146, 154))	('EPHX3', 'Gene', (91, 96))	('LINC00599', 'Gene', '157627', (125, 134))	('SIL', 'Gene', (38, 41))	('LINC00599', 'Gene', (125, 134))
99342	28814981	No epigenetic changes were found in DNMT1, H19, TERC, or any global hypomethylation of repetitive LINE1.	('hypomethylation', 'Var', (68, 83))	('TERC', 'Gene', '7012', (48, 52))	('DNMT1', 'Gene', (36, 41))	('TERC', 'Gene', (48, 52))	('DNMT1', 'Gene', '1786', (36, 41))	('H19', 'Gene', (43, 46))	('H19', 'Gene', '283120', (43, 46))
99354	28814981	The behavior of a set of five genes including ZAP70, GP1BB, H19, EPHX3, and MIR193 fluctuated among the various CpGs as shown in Additional file 1.	('ZAP70', 'Gene', (46, 51))	('fluctuated', 'Reg', (83, 93))	('GP1BB', 'Gene', (53, 58))	('ZAP70', 'Gene', '7535', (46, 51))	('EPHX3', 'Gene', '79852', (65, 70))	('GP1BB', 'Gene', '2812', (53, 58))	('MIR193', 'Var', (76, 82))	('H19', 'Gene', '283120', (60, 63))	('H19', 'Gene', (60, 63))	('EPHX3', 'Gene', (65, 70))
99359	28814981	Usually, OSCC revealed a homogeneous pattern with most epialleles methylated in cis, whereas HGSIL disclosed an irregular pattern of CpG methylation as shown in Fig.	('SIL', 'Gene', '6491', (95, 98))	('methylated', 'Var', (66, 76))	('SIL', 'Gene', (95, 98))
99366	28814981	Commonly, NGS runs produce FASTQ files as output already trimmed for multiplex identifier or MID/IonXpress/Index (a short barcode sequence used to label samples/patients when multiplexing) to recognize loaded specimens.	('MID', 'Disease', 'None', (93, 96))	('MID', 'Disease', (93, 96))	('patients', 'Species', '9606', (161, 169))	('NGS', 'Var', (10, 13))
99371	28814981	By contrast, H19 showed common signs of imprinting with half of the epialleles methylated in normal donors and contralateral normal mucosa.	('H19', 'Gene', '283120', (13, 16))	('methylated', 'Var', (79, 89))	('donor', 'Species', '9606', (100, 105))	('H19', 'Gene', (13, 16))
99373	28814981	Aberrant expression of MIR296 was previously related to gastric, bladder, and lung cancer.	('lung cancer', 'Disease', (78, 89))	('Aberrant expression', 'Var', (0, 19))	('bladder', 'Disease', (65, 72))	('lung cancer', 'Phenotype', 'HP:0100526', (78, 89))	('MIR296', 'Gene', '407022', (23, 29))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('MIR296', 'Gene', (23, 29))	('gastric', 'Disease', (56, 63))	('lung cancer', 'Disease', 'MESH:D008175', (78, 89))	('related', 'Reg', (45, 52))
99375	28814981	Hypomethylation of this gene was previously reported in glioblastoma.	('glioblastoma', 'Phenotype', 'HP:0012174', (56, 68))	('Hypomethylation', 'Var', (0, 15))	('reported', 'Reg', (44, 52))	('glioblastoma', 'Disease', (56, 68))	('glioblastoma', 'Disease', 'MESH:D005909', (56, 68))
99379	28814981	Mutations of GP1BB are associated with Bernard-Soulier syndrome, an extremely rare inherited bleeding disorder.	('inherited bleeding disorder', 'Disease', 'MESH:D025861', (83, 110))	('inherited bleeding disorder', 'Disease', (83, 110))	('Mutations', 'Var', (0, 9))	('associated', 'Reg', (23, 33))	('GP1BB', 'Gene', (13, 18))	('Bernard-Soulier syndrome', 'Disease', 'MESH:D001606', (39, 63))	('GP1BB', 'Gene', '2812', (13, 18))	('Bernard-Soulier syndrome', 'Disease', (39, 63))
99381	28814981	Hypermethylation of ZAP70 gene predicted an unfavorable disease course in terms of disease progression and overall survival in chronic lymphocytic leukemia.	('ZAP70', 'Gene', '7535', (20, 25))	('leukemia', 'Phenotype', 'HP:0001909', (147, 155))	('predicted', 'Reg', (31, 40))	('Hypermethylation', 'Var', (0, 16))	('lymphocytic leukemia', 'Disease', 'MESH:D007945', (135, 155))	('lymphocytic leukemia', 'Disease', (135, 155))	('ZAP70', 'Gene', (20, 25))	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (127, 155))
99384	28814981	as related to oral cancer, FLI1 involved in Ewing sarcoma, rectal cancer, and gastric cancer, NTM in prostate, EPHX3 in salivary gland adenoid cystic carcinoma, ITGA4 in colorectal cancer ,and MIR193 in gastric cancer.	('gastric cancer', 'Phenotype', 'HP:0012126', (203, 217))	('salivary gland adenoid cystic carcinoma', 'Disease', 'MESH:D003528', (120, 159))	('rectal cancer', 'Disease', 'MESH:D012004', (59, 72))	('oral cancer', 'Disease', 'MESH:D009062', (14, 25))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('oral cancer', 'Disease', (14, 25))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('involved', 'Reg', (32, 40))	('MIR193', 'Var', (193, 199))	('Ewing sarcoma', 'Disease', (44, 57))	('EPHX3', 'Gene', (111, 116))	('rectal cancer', 'Phenotype', 'HP:0100743', (174, 187))	('colorectal cancer', 'Phenotype', 'HP:0003003', (170, 187))	('gastric cancer', 'Disease', (78, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (150, 159))	('salivary gland adenoid cystic carcinoma', 'Disease', (120, 159))	('gastric cancer', 'Disease', (203, 217))	('FLI1', 'Gene', (27, 31))	('prostate', 'Disease', (101, 109))	('EPHX3', 'Gene', '79852', (111, 116))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('rectal cancer', 'Disease', (59, 72))	('rectal cancer', 'Phenotype', 'HP:0100743', (59, 72))	('gastric cancer', 'Disease', 'MESH:D013274', (78, 92))	('gastric cancer', 'Disease', 'MESH:D013274', (203, 217))	('ITGA4', 'Gene', '3676', (161, 166))	('NTM', 'Gene', (94, 97))	('FLI1', 'Gene', '2313', (27, 31))	('rectal cancer', 'Disease', 'MESH:D012004', (174, 187))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('colorectal cancer', 'Disease', 'MESH:D015179', (170, 187))	('NTM', 'Gene', '50863', (94, 97))	('sarcoma', 'Phenotype', 'HP:0100242', (50, 57))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (44, 57))	('ITGA4', 'Gene', (161, 166))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (44, 57))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('colorectal cancer', 'Disease', (170, 187))	('gastric cancer', 'Phenotype', 'HP:0012126', (78, 92))
99388	28814981	Genetic and epigenetic changes are also detected in histopathologically clean resection fields and could cause local relapse in mucosa primarily free of cancer cells.	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('cause', 'Reg', (105, 110))	('cancer', 'Disease', (153, 159))	('Genetic', 'Var', (0, 7))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('local relapse', 'CPA', (111, 124))	('epigenetic changes', 'Var', (12, 30))
99394	28814981	In conclusion, the present study confirmed the role of epigenetic alterations and aberrant methylation DNA status in HGSIL/OSCC and also revealed an altered methylation pattern in normal mucosa distant from the OSCC area.	('epigenetic alterations', 'Var', (55, 77))	('altered', 'Reg', (149, 156))	('SIL', 'Gene', (119, 122))	('methylation pattern', 'MPA', (157, 176))	('methylation', 'MPA', (91, 102))	('SIL', 'Gene', '6491', (119, 122))	('aberrant', 'Var', (82, 90))
99398	31924844	Here, we present computational analysis of cancer drug-target interactions affected by alternative splicing.	('alternative splicing', 'Var', (87, 107))	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('cancer', 'Disease', (43, 49))	('affected', 'Reg', (75, 83))	('interactions', 'Interaction', (62, 74))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))
99406	31924844	Conversely, a disruption of such coordinated regulation is often linked to diseases, such as cancer.	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('linked', 'Reg', (65, 71))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('disruption', 'Var', (14, 24))
99413	31924844	Meanwhile, the aberrant splicing of RAC1 gene has also been linked with multiple other cancer hallmarks, including proliferation, genome instability and inflammation.	('RAC1', 'Gene', '5879', (36, 40))	('inflammation', 'Disease', 'MESH:D007249', (153, 165))	('inflammation', 'Disease', (153, 165))	('cancer hallmarks', 'Disease', (87, 103))	('RAC1', 'Gene', (36, 40))	('proliferation', 'CPA', (115, 128))	('cancer hallmarks', 'Disease', 'MESH:D009369', (87, 103))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('genome instability', 'Disease', (130, 148))	('linked', 'Reg', (60, 66))	('aberrant splicing', 'Var', (15, 32))
99414	31924844	Another aberrant splicing example responsible for sustained proliferative signaling is BRAF gene, as alternative isoforms of wild-type and V600E mutant affect its kinase domain and may confer resistance to treatment.	('V600E', 'Mutation', 'rs113488022', (139, 144))	('confer', 'Reg', (185, 191))	('kinase domain', 'MPA', (163, 176))	('affect', 'Reg', (152, 158))	('V600E', 'Var', (139, 144))	('resistance', 'MPA', (192, 202))	('BRAF', 'Gene', (87, 91))	('BRAF', 'Gene', '673', (87, 91))
99425	31924844	In this study, we focused our analysis on small molecule inhibitors, one of the two major classes of cancer drugs successfully used for targeted therapies.	('small', 'Var', (42, 47))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('cancer', 'Disease', (101, 107))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))
99429	31924844	The results indicate that majority of the cancer drug target genes undergo alternative splicing and produce multiple protein isoforms that could be functionally distinct and interact with drugs differently, which emphasizes the importance of taking isoforms and alternative splicing into consideration in drug discovery.	('alternative splicing', 'Var', (75, 95))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('interact', 'Reg', (174, 182))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('undergo', 'Reg', (67, 74))
99443	31924844	This sequence level information shows that Imatinib would potentially target all the splice-variant isoforms of BCR-ABL fusion protein, therefore, splice-variation within ABL gene does not affect the Imatinib binding to its targets.	('binding', 'Interaction', (209, 216))	('Imatinib', 'Chemical', 'MESH:C097613', (43, 51))	('BCR-ABL', 'Gene', (112, 119))	('BCR-ABL', 'Gene', '25', (112, 119))	('splice-variation', 'Var', (147, 163))	('ABL', 'Gene', '25', (116, 119))	('Imatinib', 'Chemical', 'MESH:C097613', (200, 208))	('ABL', 'Gene', '25', (171, 174))	('ABL', 'Gene', (171, 174))	('ABL', 'Gene', (116, 119))
99454	31924844	As third example, we choose PD-0325901, an oral MEK inhibitor that was discontinued for phase II clinical trial in treatment of advanced NSCLC as the efficacy was not met and the cause of lacking objective responses is not fully understood.	('NSCLC', 'Disease', (137, 142))	('PD-0325901', 'Var', (28, 38))	('NSCLC', 'Disease', 'MESH:D002289', (137, 142))	('MEK', 'Gene', (48, 51))	('NSCLC', 'Phenotype', 'HP:0030358', (137, 142))	('MEK', 'Gene', '5609', (48, 51))	('PD-0325901', 'Chemical', 'MESH:C506614', (28, 38))
99455	31924844	We investigated the target binding sites of PD-0325901 in both the isoforms of MAP2K1, MAP2K1-201/ENST00000307102 (canonical isoform), and MAP2K1-203/ENST00000566326 (alternative isoform).	('MAP2K1', 'Gene', '5604', (87, 93))	('MAP2K1', 'Gene', (79, 85))	('MAP2K1', 'Gene', (139, 145))	('MAP2K1', 'Gene', (87, 93))	('N', 'Chemical', 'MESH:D009584', (99, 100))	('PD-0325901', 'Chemical', 'MESH:C506614', (44, 54))	('N', 'Chemical', 'MESH:D009584', (151, 152))	('MAP2K1', 'Gene', '5604', (79, 85))	('MAP2K1', 'Gene', '5604', (139, 145))	('PD-0325901', 'Var', (44, 54))
99458	31924844	These results suggest that the therapeutic effects of PD-0325901 might have been significantly impacted due to the lack of partial binding site in the target region of the highly expressed alternative isoform (MAP2K1-203).	('MAP2K1', 'Gene', (210, 216))	('PD-0325901', 'Chemical', 'MESH:C506614', (54, 64))	('lack', 'NegReg', (115, 119))	('binding', 'Interaction', (131, 138))	('impacted', 'Reg', (95, 103))	('MAP2K1', 'Gene', '5604', (210, 216))	('PD-0325901', 'Var', (54, 64))
99465	31924844	In order to understand how a particular drug molecule interacts with different isoforms of a protein, we have analyzed EGFR gene with three different isoforms (Isoform-201, Isoform-206 and Isoform-207) along with reported drugs targeting them as a specific case study.	('Isoform-207', 'Var', (189, 200))	('EGFR', 'Gene', (119, 123))	('Isoform-206', 'Var', (173, 184))	('EGFR', 'Gene', '1956', (119, 123))
99478	31924844	Several studies have previously linked cancer specific aberrant splicing with drug resistance mechanisms, for example, BCR-ABL35INS protein with a truncated inactive kinase domain that Imatinib is unable to interact.	('linked cancer', 'Disease', 'MESH:D009369', (32, 45))	('BCR-ABL', 'Gene', (119, 126))	('Imatinib', 'Chemical', 'MESH:C097613', (185, 193))	('N', 'Chemical', 'MESH:D009584', (129, 130))	('BCR-ABL', 'Gene', '25', (119, 126))	('protein', 'Protein', (132, 139))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('aberrant splicing', 'Var', (55, 72))	('linked cancer', 'Disease', (32, 45))	('drug resistance', 'Phenotype', 'HP:0020174', (78, 93))
99479	31924844	Further, it was found that a subset of alternative splicing changes could affect protein domain families that were frequently mutated in tumors and potentially disrupt protein-protein interactions in cancer related pathways.	('tumors', 'Disease', (137, 143))	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('protein-protein interactions', 'MPA', (168, 196))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('protein domain families', 'Protein', (81, 104))	('alternative splicing changes', 'Var', (39, 67))	('affect', 'Reg', (74, 80))	('disrupt', 'NegReg', (160, 167))	('cancer', 'Disease', 'MESH:D009369', (200, 206))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('cancer', 'Disease', (200, 206))
99481	31924844	Imatinib family of Tyrosine Kinase Inhibitors (TKIs) were reported to inhibit not only mutant BCR-ABL fusion protein but also normal ABL protein from noncancer cells, which agrees with our prediction since the binding pocket sequences in ABL isoforms are not affected by alternative splicing.	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('cancer', 'Disease', (153, 159))	('ABL', 'Gene', (238, 241))	('ABL', 'Gene', '25', (238, 241))	('Tyrosine', 'Chemical', 'None', (19, 27))	('Imatinib', 'Chemical', 'MESH:C097613', (0, 8))	('mutant', 'Var', (87, 93))	('ABL', 'Gene', '25', (98, 101))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('BCR-ABL', 'Gene', '25', (94, 101))	('ABL', 'Gene', (133, 136))	('ABL', 'Gene', '25', (133, 136))	('inhibit', 'NegReg', (70, 77))	('ABL', 'Gene', (98, 101))	('BCR-ABL', 'Gene', (94, 101))
99483	31924844	Meanwhile, normal ABL1 protein was found to act as a tumor suppressor when co-expressed with BCR-ABL, while loss of expression of normal ABL1 results in higher aggressiveness of the disease and reduced sensitivity to Imatinib-like TKIs, although we are not sure which isoform is primarily responsible for this effect either.	('BCR-ABL', 'Gene', (93, 100))	('BCR-ABL', 'Gene', '25', (93, 100))	('higher', 'PosReg', (153, 159))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('ABL1', 'Gene', (18, 22))	('aggressiveness', 'Phenotype', 'HP:0000718', (160, 174))	('aggressiveness of the disease', 'Disease', (160, 189))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('Imatinib', 'Chemical', 'MESH:C097613', (217, 225))	('loss of expression', 'Var', (108, 126))	('reduced', 'NegReg', (194, 201))	('ABL1', 'Gene', '25', (137, 141))	('tumor', 'Disease', (53, 58))	('sensitivity to Imatinib-like TKIs', 'MPA', (202, 235))	('ABL1', 'Gene', (137, 141))	('aggressiveness of the disease', 'Disease', 'MESH:D001523', (160, 189))	('ABL1', 'Gene', '25', (18, 22))
99484	31924844	These results reinforce the fact that potentially important splicing changes in ABL isoforms can influence the therapeutic effect of Imatinib-like TKIs, which require further investigation in future studies.	('Imatinib', 'Chemical', 'MESH:C097613', (133, 141))	('splicing changes', 'Var', (60, 76))	('ABL', 'Gene', '25', (80, 83))	('therapeutic effect', 'MPA', (111, 129))	('ABL', 'Gene', (80, 83))	('influence', 'Reg', (97, 106))
99489	31924844	PD-0325901, small molecule drug which targets MAP2K1failed the phase II clinical trial due to lack of objective responses and severe side effects.	('phase II clinical trial', 'CPA', (63, 86))	('MAP2K1', 'Gene', '5604', (46, 52))	('PD-0325901', 'Var', (0, 10))	('MAP2K1', 'Gene', (46, 52))	('PD-0325901', 'Chemical', 'MESH:C506614', (0, 10))
99494	31924844	This study demonstrates how alternative splicing effects target binding residues in the target genes, both at sequence and structure level, and how varied expression of target gene isoforms in different normal tissues and cancers might lead to missed- and/or off-target effects of the drug molecule.	('missed-', 'MPA', (244, 251))	('cancers', 'Phenotype', 'HP:0002664', (222, 229))	('cancers', 'Disease', (222, 229))	('cancers', 'Disease', 'MESH:D009369', (222, 229))	('off-target', 'NegReg', (259, 269))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('alternative splicing', 'Var', (28, 48))	('effects', 'MPA', (270, 277))
99497	31635116	Herein, we focused specifically on uveal melanoma (UM) in which BAP1 mutations are associated with a metastasizing phenotype and decreased survival rates.	('uveal melanoma', 'Disease', 'MESH:C536494', (35, 49))	('mutations', 'Var', (69, 78))	('UM', 'Disease', 'MESH:C536494', (51, 53))	('uveal melanoma', 'Disease', (35, 49))	('survival rates', 'CPA', (139, 153))	('uveal melanoma', 'Phenotype', 'HP:0007716', (35, 49))	('BAP1', 'Gene', '8314', (64, 68))	('melanoma', 'Phenotype', 'HP:0002861', (41, 49))	('decreased', 'NegReg', (129, 138))	('BAP1', 'Gene', (64, 68))
99498	31635116	We identified the ubiquitin carboxyl hydrolase (UCH) domain as a major hotspot region for the pathogenic mutations with a high evolutionary action (EA) score.	('mutations', 'Var', (105, 114))	('pathogenic', 'Reg', (94, 104))	('carboxyl', 'Chemical', 'MESH:C041069', (28, 36))
99499	31635116	Computational protein interaction studies revealed that distant BAP1-associated protein complexes (FOXK2, ASXL1, BARD1, BRCA1) could be directly impacted by this mutation paradigm.	('BRCA1', 'Gene', (120, 125))	('ASXL1', 'Gene', '171023', (106, 111))	('FOXK2', 'Gene', '3607', (99, 104))	('BARD1', 'Gene', '580', (113, 118))	('impacted', 'Reg', (145, 153))	('BARD1', 'Gene', (113, 118))	('BAP1', 'Gene', '8314', (64, 68))	('ASXL1', 'Gene', (106, 111))	('FOXK2', 'Gene', (99, 104))	('mutation', 'Var', (162, 170))	('BRCA1', 'Gene', '672', (120, 125))	('BAP1', 'Gene', (64, 68))
99501	31635116	The mutations affect - independent of being somatic or germline - the binding affinity of miRNAs embedded within the BAP1 locus, thereby altering the unique regulatory network.	('unique regulatory network', 'MPA', (150, 175))	('affect', 'Reg', (14, 20))	('binding', 'Interaction', (70, 77))	('BAP1', 'Gene', '8314', (117, 121))	('BAP1', 'Gene', (117, 121))	('miRNAs', 'Protein', (90, 96))	('N', 'Chemical', 'MESH:D009584', (93, 94))	('mutations', 'Var', (4, 13))	('altering', 'Reg', (137, 145))
99505	31635116	BAP1 (BRCA1-associated protein 1) with its gene product acting as a deubiquitinating enzyme, is a critical tumor suppressor gene that is mutated in various human cancers, including metastatic uveal melanoma, pleural mesothelioma, and renal cell carcinoma.	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (208, 228))	('BRCA1-associated protein 1', 'Gene', (6, 32))	('human', 'Species', '9606', (156, 161))	('tumor', 'Disease', (107, 112))	('cancers', 'Disease', (162, 169))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('renal cell carcinoma', 'Disease', (234, 254))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (234, 254))	('BAP1', 'Gene', (0, 4))	('carcinoma', 'Phenotype', 'HP:0030731', (245, 254))	('melanoma', 'Phenotype', 'HP:0002861', (198, 206))	('uveal melanoma', 'Disease', 'MESH:C536494', (192, 206))	('cancers', 'Disease', 'MESH:D009369', (162, 169))	('uveal melanoma', 'Disease', (192, 206))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('pleural mesothelioma', 'Disease', (208, 228))	('mutated', 'Var', (137, 144))	('uveal melanoma', 'Phenotype', 'HP:0007716', (192, 206))	('BRCA1-associated protein 1', 'Gene', '8314', (6, 32))	('renal cell carcinoma', 'Disease', 'MESH:D002292', (234, 254))	('BAP1', 'Gene', '8314', (0, 4))	('cancers', 'Phenotype', 'HP:0002664', (162, 169))	('pleural mesothelioma', 'Disease', 'MESH:D008654', (208, 228))
99506	31635116	Germline BAP1 mutations define the recently identified BAP1 cancer syndrome with affected patients developing different tumor entities, such as uveal and cutaneous melanoma, malignant mesothelioma, atypical Spitz tumors and others.	('tumors', 'Phenotype', 'HP:0002664', (213, 219))	('Spitz tumors', 'Disease', 'MESH:D018332', (207, 219))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (174, 196))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('BAP1', 'Gene', (9, 13))	('uveal', 'Disease', (144, 149))	('BAP1', 'Gene', (55, 59))	('mutations', 'Var', (14, 23))	('tumor', 'Disease', (120, 125))	('malignant mesothelioma', 'Disease', (174, 196))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (174, 196))	('cancer syndrome', 'Disease', 'MESH:D009369', (60, 75))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('cutaneous melanoma', 'Disease', (154, 172))	('patients', 'Species', '9606', (90, 98))	('Spitz tumors', 'Disease', (207, 219))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (154, 172))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (154, 172))	('melanoma', 'Phenotype', 'HP:0002861', (164, 172))	('tumor', 'Disease', (213, 218))	('BAP1', 'Gene', '8314', (9, 13))	('cancer syndrome', 'Disease', (60, 75))	('tumor', 'Disease', 'MESH:D009369', (213, 218))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('BAP1', 'Gene', '8314', (55, 59))
99507	31635116	The apparent ability of BAP1 mutations, both somatic and germline variants, to cause multiple tumor types suggests that this gene has a major role in influencing cancer cell growth.	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('cancer', 'Disease', (162, 168))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('BAP1', 'Gene', (24, 28))	('mutations', 'Var', (29, 38))	('tumor', 'Disease', (94, 99))	('cause', 'Reg', (79, 84))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('BAP1', 'Gene', '8314', (24, 28))
99509	31635116	Particularly, in uveal melanoma (UM), the most frequent intraocular tumor of the eye, BAP1 mutations were identified in 84% of tumors with a metastasizing phenotype.	('identified', 'Reg', (106, 116))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('intraocular tumor', 'Disease', (56, 73))	('tumors', 'Disease', (127, 133))	('intraocular tumor', 'Disease', 'MESH:D064090', (56, 73))	('BAP1', 'Gene', '8314', (86, 90))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('melanoma', 'Phenotype', 'HP:0002861', (23, 31))	('tumors', 'Disease', 'MESH:D009369', (127, 133))	('tumor of the eye', 'Phenotype', 'HP:0100012', (68, 84))	('UM', 'Disease', 'MESH:C536494', (33, 35))	('BAP1', 'Gene', (86, 90))	('mutations', 'Var', (91, 100))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('uveal melanoma', 'Phenotype', 'HP:0007716', (17, 31))	('uveal melanoma', 'Disease', (17, 31))	('uveal melanoma', 'Disease', 'MESH:C536494', (17, 31))
99510	31635116	While a wild type BAP1 is associated with disomy of chromosome 3 (D3) and a low risk for metastasis in UM BAP1 mutations follow the appearance of monsomy of chromosome 3 (M3) and with a high probability for metastasis.	('mutations', 'Var', (111, 120))	('UM', 'Disease', 'MESH:C536494', (103, 105))	('BAP1', 'Gene', '8314', (18, 22))	('BAP1', 'Gene', (106, 110))	('BAP1', 'Gene', (18, 22))	('disomy', 'Disease', (42, 48))	('BAP1', 'Gene', '8314', (106, 110))	('disomy', 'Disease', 'MESH:D024182', (42, 48))
99511	31635116	Immunohistochemically, BAP1 mutations are characterized by absence of nuclear staining (but commonly cytoplasmic staining), while BAP1 wildtype shows a strong nuclear staining reaction in the tumor cells.	('BAP1', 'Gene', (23, 27))	('tumor', 'Disease', (192, 197))	('BAP1', 'Gene', (130, 134))	('BAP1', 'Gene', '8314', (23, 27))	('absence', 'NegReg', (59, 66))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('BAP1', 'Gene', '8314', (130, 134))	('nuclear staining', 'MPA', (70, 86))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('mutations', 'Var', (28, 37))
99514	31635116	Other genetic alterations, such as deletion/duplication of driver genes (GNAQ, GNA11, EIFAX, SF3B1, and BPA1) also act as additional contributors towards the UM specific clinical evaluations.	('GNAQ', 'Gene', '2776', (73, 77))	('BPA1', 'Gene', (104, 108))	('BPA1', 'Chemical', 'MESH:C436045', (104, 108))	('SF3B1', 'Gene', (93, 98))	('EIFAX', 'Gene', (86, 91))	('deletion/duplication', 'Var', (35, 55))	('GNA11', 'Gene', '2767', (79, 84))	('GNA11', 'Gene', (79, 84))	('GNAQ', 'Gene', (73, 77))	('UM', 'Disease', 'MESH:C536494', (158, 160))	('SF3B1', 'Gene', '23451', (93, 98))
99515	31635116	Aberrant miRNA expression was found in UM and allowed for a differentiation between high risk and low-/intermediate-risk tumors in a recent study.	('N', 'Chemical', 'MESH:D009584', (12, 13))	('miRNA', 'Protein', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('Aberrant', 'Var', (0, 8))	('tumors', 'Disease', (121, 127))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('UM', 'Disease', 'MESH:C536494', (39, 41))	('tumors', 'Disease', 'MESH:D009369', (121, 127))
99519	31635116	Although somatic mutations of the BAP1 gene are quite prevalent in UM, the impact of these mutations on the structural architecture of the BAP1 protein and its associated complexes has not been reported, yet.	('BAP1', 'Gene', (34, 38))	('BAP1', 'Gene', '8314', (139, 143))	('UM', 'Disease', 'MESH:C536494', (67, 69))	('BAP1', 'Gene', (139, 143))	('BAP1', 'Gene', '8314', (34, 38))	('mutations', 'Var', (17, 26))
99520	31635116	Herein, we have created a comprehensive map of all reported UM-associated somatic and germline missense mutations located in the BAP1 gene and have analyzed their structural and evolutionary impact.	('BAP1', 'Gene', (129, 133))	('UM', 'Disease', 'MESH:C536494', (60, 62))	('missense mutations', 'Var', (95, 113))	('BAP1', 'Gene', '8314', (129, 133))
99533	31635116	To determine the pathogenic probability of BAP1 mutations, we used the Evolutionary Action (EA) scores.	('BAP1', 'Gene', '8314', (43, 47))	('BAP1', 'Gene', (43, 47))	('mutations', 'Var', (48, 57))
99534	31635116	Usually, the loss of function mutations typically have high EA scores (e.g., >70), benign mutations have low EA scores (e.g., <30), while intermediate EA scores (~30-70) may not deactivate the protein, but rather have either detrimental or gain of function effect to the overall function.	('loss of function', 'NegReg', (13, 29))	('protein', 'Protein', (193, 200))	('detrimental', 'Disease', (225, 236))	('EA scores', 'MPA', (60, 69))	('mutations', 'Var', (30, 39))	('gain of function', 'PosReg', (240, 256))	('detrimental', 'Disease', 'MESH:D008569', (225, 236))
99535	31635116	To define the binding affinity of the miRNAs embedded in its 3' UTR towards BAP1 mutations, we implemented an RNA sequence-based statistical approach (RNA hybrid).	('N', 'Chemical', 'MESH:D009584', (152, 153))	('BAP1', 'Gene', '8314', (76, 80))	('binding', 'Interaction', (14, 21))	('BAP1', 'Gene', (76, 80))	('mutations', 'Var', (81, 90))	('N', 'Chemical', 'MESH:D009584', (41, 42))	('N', 'Chemical', 'MESH:D009584', (111, 112))
99536	31635116	Briefly, the energetically most favorable binding conformations were predicted, and minimum free energy (mfe) of the BAP1 mutants:miRNAs were calculated (units:kcal/mol).	('mutants', 'Var', (122, 129))	('BAP1', 'Gene', '8314', (117, 121))	('N', 'Chemical', 'MESH:D009584', (133, 134))	('binding', 'Interaction', (42, 49))	('BAP1', 'Gene', (117, 121))
99545	31635116	Herein, we focused on 34 BAP1 specific missense mutations which were previously shown to be associated with UM (Figure 1B).	('BAP1', 'Gene', (25, 29))	('UM', 'Disease', 'MESH:C536494', (108, 110))	('BAP1', 'Gene', '8314', (25, 29))	('associated', 'Reg', (92, 102))	('missense mutations', 'Var', (39, 57))
99546	31635116	The ubiquitin carboxyl hydrolase (UCH) domain (including the BARD1 interaction region) of the BAP1 protein emerged as a hotspot region for missense mutations.	('BAP1', 'Gene', '8314', (94, 98))	('carboxyl', 'Chemical', 'MESH:C041069', (14, 22))	('missense mutations', 'Var', (139, 157))	('BARD1', 'Gene', '580', (61, 66))	('BARD1', 'Gene', (61, 66))	('BAP1', 'Gene', (94, 98))
99547	31635116	Importantly, among the conserved UCH residues (C91, H169, and D184), two mutations (C91G, H169P) showed a high EA score.	('C91G', 'Mutation', 'c.91C>G', (84, 88))	('C91G', 'Var', (84, 88))	('H169P', 'Var', (90, 95))	('H169', 'Chemical', 'MESH:C005718', (52, 56))	('H169', 'Chemical', 'MESH:C005718', (90, 94))	('H169P', 'SUBSTITUTION', 'None', (90, 95))	('C91', 'Var', (47, 50))	('D184', 'Chemical', 'MESH:C101289', (62, 66))
99548	31635116	A comparison to 4,772 missense BAP1 variants resulting from all possible nucleotide changes, the observed BAP1 variants were significantly skewed (Kolmogorov-Smirnov p-value of 10-4) to EA scores of 80-100 predicting them to be highly pathogenic (Figure1D, Table S1).	('BAP1', 'Gene', (106, 110))	('BAP1', 'Gene', '8314', (31, 35))	('pathogenic', 'Reg', (235, 245))	('variants', 'Var', (111, 119))	('BAP1', 'Gene', (31, 35))	('BAP1', 'Gene', '8314', (106, 110))	('variants', 'Var', (36, 44))
99550	31635116	Three mutations (S63C, S98R, T117R) were found to be overlapping with these phosphorylation sites (Figure 1B, Figure S2, Table S1).	('T117R', 'Mutation', 'p.T117R', (29, 34))	('S98R', 'Mutation', 'p.S98R', (23, 27))	('S63C', 'SUBSTITUTION', 'None', (17, 21))	('S98R', 'Var', (23, 27))	('S63C', 'Var', (17, 21))	('T117R', 'Var', (29, 34))
99551	31635116	BAP1 model obtained from the ITASSER (C-score: -0.52) showed a clear structural division into ordered N and C terminal regions linked by a disordered 74 amino acid long stretch (residues 336-410) (Figure 1C).	('BAP1', 'Gene', (0, 4))	('amino', 'Chemical', 'MESH:D000596', (153, 158))	('N', 'Chemical', 'MESH:D009584', (102, 103))	('residues 336-410', 'Var', (178, 194))	('BAP1', 'Gene', '8314', (0, 4))
99560	31635116	A high percentage of the BAP1 mutations were observed in the UCH domain.	('BAP1', 'Gene', '8314', (25, 29))	('mutations', 'Var', (30, 39))	('BAP1', 'Gene', (25, 29))	('observed', 'Reg', (45, 53))
99561	31635116	A number of these mutations comprise substitutions to amino acids like glycine and proline (D68G, Q85P, C91G, L100P, H169P, L180, PE182G) that will result in disruption of the helices and exposure of the hydrophobic core to solvents, thereby leading to the unfolding of this domain.	('L180', 'Var', (124, 128))	('L100P', 'Var', (110, 115))	('PE182G', 'Chemical', 'MESH:C096583', (130, 136))	('Q85P', 'Mutation', 'p.Q85P', (98, 102))	('amino', 'Chemical', 'MESH:D000596', (54, 59))	('PE182G', 'Var', (130, 136))	('Q85P', 'Var', (98, 102))	('C91G', 'Var', (104, 108))	('glycine', 'Chemical', 'MESH:D005998', (71, 78))	('unfolding', 'MPA', (257, 266))	('proline', 'Chemical', 'MESH:C489032', (83, 90))	('H169P', 'Var', (117, 122))	('D68G', 'Mutation', 'rs1194652468', (92, 96))	('helices', 'Protein', (176, 183))	('disruption', 'NegReg', (158, 168))	('leading to', 'Reg', (242, 252))	('H169P', 'SUBSTITUTION', 'None', (117, 122))	('exposure', 'MPA', (188, 196))	('D68G', 'Var', (92, 96))	('C91G', 'Mutation', 'c.91C>G', (104, 108))	('L100P', 'Mutation', 'p.L100P', (110, 115))
99562	31635116	The mutation C91 in the UCH region is substituted to cysteines which could result in the formation of native disulfide bonds and alters the conformational landscape of the UCH domain, therefore, deleteriously affecting the enzymatic efficiency.	('enzymatic', 'MPA', (223, 232))	('formation', 'MPA', (89, 98))	('result', 'Reg', (75, 81))	('alters', 'Reg', (129, 135))	('affecting', 'Reg', (209, 218))	('cysteines', 'Chemical', 'MESH:D003545', (53, 62))	('conformational landscape', 'MPA', (140, 164))	('C91', 'Var', (13, 16))	('native disulfide bonds', 'MPA', (102, 124))	('disulfide', 'Chemical', 'MESH:D004220', (109, 118))
99563	31635116	C91 has been previously shown to ablate enzymatic activity without interfering with its interactions with BRCA1 or with FOXK1/FOXK2.	('FOXK1', 'Gene', (120, 125))	('BRCA1', 'Gene', (106, 111))	('ablate', 'NegReg', (33, 39))	('FOXK2', 'Gene', '3607', (126, 131))	('enzymatic activity', 'MPA', (40, 58))	('C91', 'Var', (0, 3))	('FOXK2', 'Gene', (126, 131))	('FOXK1', 'Gene', '221937', (120, 125))	('BRCA1', 'Gene', '672', (106, 111))	('interactions', 'Interaction', (88, 100))
99564	31635116	The three germline mutations (L100P, R146K, L180P) occurring on the UCH domain are semi-conserved in their biophysical and biochemical nature, and therefore, are expected to have less deleterious consequences on this domain.	('L100P', 'Var', (30, 35))	('R146K', 'Mutation', 'p.R146K', (37, 42))	('R146K', 'Var', (37, 42))	('L100P', 'Mutation', 'p.L100P', (30, 35))	('L180P', 'Mutation', 'p.L180P', (44, 49))	('L180P', 'Var', (44, 49))
99565	31635116	A number of mutations also involve the substitution of a hydrophobic residue to a large polar charged residue like arginine (G45R, S98R, L112R, G128R, H141R, S172R, P175R, T177R, G185R) which will disturb the closely packed hydrophobic core of the UCH domain and contribute to the unfolding of the domain structure.	('G45R', 'Var', (125, 129))	('H141R', 'Var', (151, 156))	('arginine', 'Chemical', 'MESH:D001127', (115, 123))	('disturb', 'Reg', (197, 204))	('G185R', 'Var', (179, 184))	('unfolding', 'MPA', (281, 290))	('closely packed hydrophobic core of the', 'MPA', (209, 247))	('H141R', 'Mutation', 'p.H141R', (151, 156))	('G185R', 'Mutation', 'p.G185R', (179, 184))	('G128R', 'Mutation', 'p.G128R', (144, 149))	('G128R', 'Var', (144, 149))	('S172R', 'Var', (158, 163))	('contribute', 'Reg', (263, 273))	('S172R', 'Mutation', 'p.S172R', (158, 163))	('domain structure', 'MPA', (298, 314))	('G45R', 'Mutation', 'p.G45R', (125, 129))	('P175R', 'Mutation', 'p.P175R', (165, 170))	('P175R', 'Var', (165, 170))	('L112R', 'Var', (137, 142))	('S98R', 'Mutation', 'p.S98R', (131, 135))	('T177R', 'Var', (172, 177))	('L112R', 'Mutation', 'p.L112R', (137, 142))	('T177R', 'Mutation', 'p.T177R', (172, 177))
99566	31635116	As compared to the mutations in the N-terminus, the mutations at the C-terminus (D672G, E602D) are few and occur mostly on the structurally disordered regions, and their impact most likely would be on either structural flexibility or on the interaction of BAP1 with other proteins.	('D672G', 'Var', (81, 86))	('impact', 'Reg', (170, 176))	('E602D', 'Var', (88, 93))	('structural flexibility', 'MPA', (208, 230))	('interaction', 'Interaction', (241, 252))	('N', 'Chemical', 'MESH:D009584', (36, 37))	('BAP1', 'Gene', '8314', (256, 260))	('E602D', 'Mutation', 'rs759423683', (88, 93))	('D672G', 'SUBSTITUTION', 'None', (81, 86))	('BAP1', 'Gene', (256, 260))
99567	31635116	We had earlier reported one C-terminal mutation (c.2001delG; p.[Thr668Profs*24] close to the nuclear localization signals (NLS) region and have shown the structural changes in the BAP1 protein.	('protein', 'Protein', (185, 192))	('c.2001delG', 'Mutation', 'c.2001delG', (49, 59))	('BAP1', 'Gene', '8314', (180, 184))	('N', 'Chemical', 'MESH:D009584', (123, 124))	('BAP1', 'Gene', (180, 184))	('c.2001delG;', 'Var', (49, 60))	('structural', 'MPA', (154, 164))
99568	31635116	To define the consequences of these mutations, we also generated protein models from BAP1 associated proteins and performed docking studies.	('BAP1', 'Gene', (85, 89))	('mutations', 'Var', (36, 45))	('BAP1', 'Gene', '8314', (85, 89))
99569	31635116	To begin with, the poses generated by docking the BRCA1-BARD1 heterodimeric crystal structure on the BAP1 model resulted in an interesting pattern which further implicates the disordered amino stretch between the ordered regions of BAP1 as a critical region for protein flexibility (Figure 2, Figure S1).	('BAP1', 'Gene', (232, 236))	('BRCA1', 'Gene', (50, 55))	('amino', 'Chemical', 'MESH:D000596', (187, 192))	('disordered amino stretch', 'Var', (176, 200))	('BAP1', 'Gene', '8314', (101, 105))	('implicates', 'Reg', (161, 171))	('BAP1', 'Gene', (101, 105))	('BAP1', 'Gene', '8314', (232, 236))	('BARD1', 'Gene', '580', (56, 61))	('BRCA1', 'Gene', '672', (50, 55))	('BARD1', 'Gene', (56, 61))
99576	31635116	This conformational transition could have critical implications for mutations especially at the docking interfaces of all three proteins, or even at the domain boundaries of BAP1 that could potentially hinder the complex formation (E182G, G185R, E212D, N229D, S278L, S280T, E602D).	('E212D', 'Var', (246, 251))	('E602D', 'Var', (274, 279))	('G185R', 'Var', (239, 244))	('hinder', 'NegReg', (202, 208))	('S280T', 'Var', (267, 272))	('S278L', 'Var', (260, 265))	('E182G', 'Var', (232, 237))	('N229D', 'Var', (253, 258))	('BAP1', 'Gene', (174, 178))	('S280T', 'Mutation', 'p.S280T', (267, 272))	('E182G', 'Mutation', 'rs876658395', (232, 237))	('G185R', 'Mutation', 'p.G185R', (239, 244))	('E212D', 'SUBSTITUTION', 'None', (246, 251))	('E602D', 'Mutation', 'rs759423683', (274, 279))	('S278L', 'Mutation', 'p.S278L', (260, 265))	('N229D', 'Mutation', 'p.N229D', (253, 258))	('complex formation', 'Interaction', (213, 230))	('BAP1', 'Gene', '8314', (174, 178))
99577	31635116	At the N-terminus, two mutations (E182G, G185R) showed specificity towards the BARD1 interaction site (Figure 2B).	('G185R', 'Mutation', 'p.G185R', (41, 46))	('BARD1', 'Gene', '580', (79, 84))	('E182G', 'Var', (34, 39))	('specificity', 'Reg', (55, 66))	('N', 'Chemical', 'MESH:D009584', (7, 8))	('BARD1', 'Gene', (79, 84))	('E182G', 'Mutation', 'rs876658395', (34, 39))	('G185R', 'Var', (41, 46))
99578	31635116	The C-terminus harbors very few mutations; however, three among them were located on the positions used by BAP1 to interact with other distant proteins, such as D672 (YY1), E602D (BRCA1), and S482L (FOXK2).	('S482L', 'Mutation', 'rs753329341', (192, 197))	('BAP1', 'Gene', '8314', (107, 111))	('YY1', 'Gene', '7528', (167, 170))	('BRCA1', 'Gene', '672', (180, 185))	('BAP1', 'Gene', (107, 111))	('YY1', 'Gene', (167, 170))	('E602D', 'Mutation', 'rs759423683', (173, 178))	('S482L', 'Var', (192, 197))	('BRCA1', 'Gene', (180, 185))	('D672', 'Var', (161, 165))	('FOXK2', 'Gene', '3607', (199, 204))	('FOXK2', 'Gene', (199, 204))	('interact', 'Reg', (115, 123))	('E602D', 'Var', (173, 178))
99579	31635116	A very limited number of mutations (S482L, D672G, E182G, G185R, E602D) were observed in the putative interface regions of BAP1 (Figure 2C,D, Figure S1).	('E602D', 'Mutation', 'rs759423683', (64, 69))	('D672G', 'Var', (43, 48))	('BAP1', 'Gene', (122, 126))	('E602D', 'Var', (64, 69))	('G185R', 'Var', (57, 62))	('E182G', 'Var', (50, 55))	('S482L', 'Var', (36, 41))	('E182G', 'Mutation', 'rs876658395', (50, 55))	('G185R', 'Mutation', 'p.G185R', (57, 62))	('D672G', 'SUBSTITUTION', 'None', (43, 48))	('BAP1', 'Gene', '8314', (122, 126))	('S482L', 'Mutation', 'rs753329341', (36, 41))
99580	31635116	These mutations also either act as a helix breaker or result in the changes in electrostatic polarity (except E602D).	('result', 'Reg', (54, 60))	('E602D', 'Mutation', 'rs759423683', (110, 115))	('helix', 'CPA', (37, 42))	('changes', 'Reg', (68, 75))	('electrostatic polarity', 'MPA', (79, 101))	('E602D', 'Var', (110, 115))
99582	31635116	Only one of the C-terminal BAP1 mutations lies in the BRCA1 interaction domain and might have implications in its putative interaction with BRCA1, even though the wild type and the substituted amino acid, in this case, are similar in nature.	('BRCA1', 'Gene', (140, 145))	('amino', 'Chemical', 'MESH:D000596', (193, 198))	('BAP1', 'Gene', (27, 31))	('BAP1', 'Gene', '8314', (27, 31))	('implications', 'Reg', (94, 106))	('mutations', 'Var', (32, 41))	('BRCA1', 'Gene', '672', (54, 59))	('lies', 'Reg', (42, 46))	('BRCA1', 'Gene', '672', (140, 145))	('interaction', 'Interaction', (123, 134))	('BRCA1', 'Gene', (54, 59))
99584	31635116	To determine the impact of BAP1 mutants on these miRNAs, we calculated the respective binding affinities for each variant versus individual miRNAs.	('variant', 'Var', (114, 121))	('BAP1', 'Gene', (27, 31))	('binding', 'Interaction', (86, 93))	('N', 'Chemical', 'MESH:D009584', (143, 144))	('N', 'Chemical', 'MESH:D009584', (52, 53))	('BAP1', 'Gene', '8314', (27, 31))
99586	31635116	However, D672G and E602D were found to have a higher minimum free binding energy (mfe) as compared to other mutations (Figure 3A, Table S2).	('minimum free binding energy', 'MPA', (53, 80))	('E602D', 'Var', (19, 24))	('higher', 'PosReg', (46, 52))	('D672G', 'SUBSTITUTION', 'None', (9, 14))	('E602D', 'Mutation', 'rs759423683', (19, 24))	('D672G', 'Var', (9, 14))
99587	31635116	The binding affinity of C-terminal mutations was stronger than for mutations at the N-terminus which was evident from the seven mutations (G45R, Q85P, S98R, G128R, H141R, S172R, G185R) located in the UCH domain showing a varying range of the mfe.	('G185R', 'Mutation', 'p.G185R', (178, 183))	('N', 'Chemical', 'MESH:D009584', (84, 85))	('Q85P', 'Var', (145, 149))	('G45R', 'Var', (139, 143))	('G128R', 'Var', (157, 162))	('H141R', 'Var', (164, 169))	('G185R', 'Var', (178, 183))	('stronger', 'PosReg', (49, 57))	('H141R', 'Mutation', 'p.H141R', (164, 169))	('S172R', 'Mutation', 'p.S172R', (171, 176))	('G45R', 'Mutation', 'p.G45R', (139, 143))	('S172R', 'Var', (171, 176))	('binding affinity', 'Interaction', (4, 20))	('S98R', 'Mutation', 'p.S98R', (151, 155))	('S98R', 'Var', (151, 155))	('G128R', 'Mutation', 'p.G128R', (157, 162))	('Q85P', 'Mutation', 'p.Q85P', (145, 149))
99593	31635116	Hence, one may speculate about the local impact of these mutations on the BAP1-associated miRNA network.	('BAP1', 'Gene', '8314', (74, 78))	('mutations', 'Var', (57, 66))	('BAP1', 'Gene', (74, 78))	('N', 'Chemical', 'MESH:D009584', (93, 94))
99600	31635116	By virtue of the complex regulation of the BAP1 gene and its associated proteins, it can be assumed that the specific type of genetic rearrangements (mutations, polymorphisms) in this gene will lead to disease-specific functional consequences.	('rearrangements', 'Var', (134, 148))	('genetic rearrangements', 'Var', (126, 148))	('BAP1', 'Gene', (43, 47))	('lead to', 'Reg', (194, 201))	('polymorphisms', 'Var', (161, 174))	('BAP1', 'Gene', '8314', (43, 47))
99601	31635116	Considering this, we conducted this study to determine the potential impact of UM-associated mutations in BAP1-related protein complexes.	('UM', 'Disease', 'MESH:C536494', (79, 81))	('BAP1', 'Gene', '8314', (106, 110))	('mutations', 'Var', (93, 102))	('BAP1', 'Gene', (106, 110))
99604	31635116	Interestingly, most of the mutations showed a very high evolutionary action (EA) score, which is consistent with the fact that BAP1 acts as tumor suppressor and harbors metastatic potential in combination with other factors.	('mutations', 'Var', (27, 36))	('BAP1', 'Gene', (127, 131))	('metastatic potential', 'CPA', (169, 189))	('evolutionary', 'MPA', (56, 68))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('BAP1', 'Gene', '8314', (127, 131))	('tumor', 'Disease', (140, 145))
99606	31635116	In context to the functional impact of these mutations, one study has previously described the structural destabilization of BAP1 after mutations in the catalytic domain leading to aggregation, cytoplasmic sequestration and subsequent functional loss.	('functional', 'MPA', (235, 245))	('destabilization', 'NegReg', (106, 121))	('cytoplasmic sequestration', 'MPA', (194, 219))	('BAP1', 'Gene', '8314', (125, 129))	('aggregation', 'MPA', (181, 192))	('BAP1', 'Gene', (125, 129))	('mutations in', 'Var', (136, 148))	('structural', 'MPA', (95, 105))
99611	31635116	Our structural analysis clearly showed closer interactions of neighboring residues of the S482L mutation with the forkhead-associated domain of FOXK2.	('S482L', 'Var', (90, 95))	('S482L', 'Mutation', 'rs753329341', (90, 95))	('FOXK2', 'Gene', '3607', (144, 149))	('interactions', 'Interaction', (46, 58))	('FOXK2', 'Gene', (144, 149))
99613	31635116	The potential involvement of HCF-1 is also evident from the D672G mutation, which is located in the BAP1 region essential for interactions with transcription factor YY1.	('BAP1', 'Gene', '8314', (100, 104))	('D672G', 'Var', (60, 65))	('interactions', 'Interaction', (126, 138))	('YY1', 'Gene', '7528', (165, 168))	('BAP1', 'Gene', (100, 104))	('involvement', 'Reg', (14, 25))	('HCF-1', 'Gene', '3054', (29, 34))	('YY1', 'Gene', (165, 168))	('HCF-1', 'Gene', (29, 34))	('D672G', 'SUBSTITUTION', 'None', (60, 65))
99616	31635116	In our structural analysis, the neighboring residues of mutation D672 were found to be directly involved in ASXL1-BAP1 interactions; hence, alterations in the activity of PR-DUB complex can be predicted.	('D672', 'Var', (65, 69))	('PR-DUB', 'Enzyme', (171, 177))	('activity', 'MPA', (159, 167))	('ASXL1', 'Gene', (108, 113))	('involved', 'Reg', (96, 104))	('BAP1', 'Gene', '8314', (114, 118))	('mutation D672', 'Var', (56, 69))	('alterations', 'Reg', (140, 151))	('BAP1', 'Gene', (114, 118))	('ASXL1', 'Gene', '171023', (108, 113))
99621	31635116	Since BARD1 directly interacts with BAP1, the major impact of mutations in BARD1 (E182G, G185R) as compared to BRCA1 (E602D) can be seen in the structural analysis.	('BARD1', 'Gene', '580', (75, 80))	('E182G', 'Var', (82, 87))	('BARD1', 'Gene', '580', (6, 11))	('G185R', 'Var', (89, 94))	('BRCA1', 'Gene', '672', (111, 116))	('BAP1', 'Gene', '8314', (36, 40))	('E182G', 'Mutation', 'rs876658395', (82, 87))	('BARD1', 'Gene', (75, 80))	('BARD1', 'Gene', (6, 11))	('E602D', 'Mutation', 'rs759423683', (118, 123))	('interacts', 'Interaction', (21, 30))	('BRCA1', 'Gene', (111, 116))	('BAP1', 'Gene', (36, 40))	('G185R', 'Mutation', 'p.G185R', (89, 94))	('E602D', 'Var', (118, 123))
99622	31635116	It is also noteworthy to mention that we found 15 phosphorylation sites solely in the UCH domain of BAP1 and three mutations (S63C, S98R, T117R) were found to be overlapping with these sites.	('BAP1', 'Gene', '8314', (100, 104))	('S98R', 'Mutation', 'p.S98R', (132, 136))	('S98R', 'Var', (132, 136))	('BAP1', 'Gene', (100, 104))	('T117R', 'Var', (138, 143))	('S63C', 'SUBSTITUTION', 'None', (126, 130))	('T117R', 'Mutation', 'p.T117R', (138, 143))	('phosphorylation sites', 'MPA', (50, 71))	('S63C', 'Var', (126, 130))
99623	31635116	There is concrete evidence in the literature that disruptions of phosphorylation sites are associated with cancer.	('phosphorylation sites', 'MPA', (65, 86))	('disruptions', 'Var', (50, 61))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('cancer', 'Disease', (107, 113))	('associated', 'Reg', (91, 101))
99630	31635116	Likewise, miR-200a-3p (renal carcinoma, pancreatic cancer), miR-423-5p (gastric cancer), miR-31-5p(Oral Cancer), miR-141-3p (rectal cancer) and miR-140-3p.1 (breast cancer) have also been implicated in different types of cancer.	('miR-423-5p', 'Var', (60, 70))	('cancer', 'Disease', 'MESH:D009369', (221, 227))	('renal carcinoma', 'Disease', (23, 38))	('breast cancer', 'Phenotype', 'HP:0003002', (158, 171))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('renal carcinoma', 'Phenotype', 'HP:0005584', (23, 38))	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('miR-141-3p', 'Var', (113, 123))	('pancreatic cancer', 'Disease', (40, 57))	('miR-140-3p.1', 'Var', (144, 156))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('cancer', 'Disease', (80, 86))	('gastric cancer', 'Disease', 'MESH:D013274', (72, 86))	('breast cancer', 'Disease', 'MESH:D001943', (158, 171))	('Oral Cancer', 'Disease', (99, 110))	('breast cancer', 'Disease', (158, 171))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('miR-31', 'Gene', '407035', (89, 95))	('Cancer', 'Phenotype', 'HP:0002664', (104, 110))	('rectal cancer', 'Disease', (125, 138))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('rectal cancer', 'Phenotype', 'HP:0100743', (125, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (29, 38))	('cancer', 'Disease', (221, 227))	('gastric cancer', 'Phenotype', 'HP:0012126', (72, 86))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (40, 57))	('cancer', 'Disease', (165, 171))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('Oral Cancer', 'Disease', 'MESH:D009062', (99, 110))	('cancer', 'Disease', (132, 138))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('renal carcinoma', 'Disease', 'MESH:D002292', (23, 38))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('miR-200a-3p', 'Var', (10, 21))	('rectal cancer', 'Disease', 'MESH:D012004', (125, 138))	('implicated', 'Reg', (188, 198))	('423-5p', 'Chemical', 'MESH:C072935', (64, 70))	('cancer', 'Disease', (51, 57))	('gastric cancer', 'Disease', (72, 86))	('pancreatic cancer', 'Disease', 'MESH:D010190', (40, 57))	('miR-31', 'Gene', (89, 95))
99632	31635116	This, in turn, suggests that the BAP1-miRNAs associated network (in combination with respective BAP1 mutations) might have an independent impact in UM.	('mutations', 'Var', (101, 110))	('BAP1', 'Gene', (96, 100))	('BAP1', 'Gene', '8314', (96, 100))	('BAP1', 'Gene', '8314', (33, 37))	('UM', 'Disease', 'MESH:C536494', (148, 150))	('BAP1', 'Gene', (33, 37))	('N', 'Chemical', 'MESH:D009584', (41, 42))	('impact', 'Reg', (138, 144))
99635	31635116	Considering this, we checked the BAP1 gene expression from the TCGA dataset and found that regardless of the mutation type, an alteration of the BAP1 gene expression can be used for the prognosis in 29 tumor types.	('tumor', 'Disease', (202, 207))	('BAP1', 'Gene', '8314', (33, 37))	('BAP1', 'Gene', '8314', (145, 149))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('alteration', 'Var', (127, 137))	('BAP1', 'Gene', (33, 37))	('BAP1', 'Gene', (145, 149))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))
99640	31635116	The following are available online at , Figure S1: BAP1 variants and stability of multiprotein complexes.	('variants', 'Var', (56, 64))	('BAP1', 'Gene', '8314', (51, 55))	('BAP1', 'Gene', (51, 55))
99681	26269582	Apical-basal polarity is a fundamental property of epithelial cells and organizes intracellular signaling complexes; disrupted polarity can alter cell signaling to promote cancer progression.	('disrupted', 'Var', (117, 126))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('alter', 'Reg', (140, 145))	('promote', 'PosReg', (164, 171))	('polarity', 'MPA', (127, 135))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('cancer', 'Disease', (172, 178))	('cell signaling', 'MPA', (146, 160))
99683	26269582	An oncogenic role for aPKC is supported by studies showing that knockdown or inhibition of aPKC impairs growth of human cancer cell lines or epithelial cells overexpressing H-Ras, v-Src, c-Raf, ErbB2, or PI3K.	('PI3', 'Gene', (204, 207))	('Src', 'Gene', (182, 185))	('cancer', 'Disease', (120, 126))	('human', 'Species', '9606', (114, 119))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('growth', 'CPA', (104, 110))	('inhibition', 'NegReg', (77, 87))	('Src', 'Gene', '485864', (182, 185))	('aPKC', 'Gene', (22, 26))	('H-Ras', 'Gene', '3265', (173, 178))	('aPKC', 'Gene', '47594', (22, 26))	('c-Raf', 'Gene', '5894', (187, 192))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('impairs', 'NegReg', (96, 103))	('PI3', 'Gene', '477241', (204, 207))	('ErbB2', 'Protein', (194, 199))	('aPKC', 'Gene', (91, 95))	('H-Ras', 'Gene', (173, 178))	('c-Raf', 'Gene', (187, 192))	('aPKC', 'Gene', '47594', (91, 95))	('knockdown', 'Var', (64, 73))
99689	26269582	For example, silencing aPKC in tumor cell lines with high PI3K or low PTEN suppresses growth by inducing senescence.	('PI3', 'Gene', '477241', (58, 61))	('aPKC', 'Gene', (23, 27))	('aPKC', 'Gene', '47594', (23, 27))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('inducing', 'Reg', (96, 104))	('PTEN', 'Gene', (70, 74))	('suppresses', 'NegReg', (75, 85))	('tumor', 'Disease', (31, 36))	('PTEN', 'Gene', '403832', (70, 74))	('PI3', 'Gene', (58, 61))	('growth', 'MPA', (86, 92))	('low', 'Var', (66, 69))	('senescence', 'MPA', (105, 115))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('silencing', 'Var', (13, 22))
99690	26269582	Moreover, a PI3K/PDK-1/aPKC pathway inhibits apoptosis in cancer cells through direct phosphorylation of the proapoptotic protein Bad by aPKC, and inhibiting PI3K blocks aPKC activity and Bad phosphorylation.	('PI3', 'Gene', '477241', (158, 161))	('aPKC', 'Gene', '47594', (23, 27))	('inhibiting', 'Var', (147, 157))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('aPKC', 'Gene', '47594', (137, 141))	('PI3', 'Gene', (12, 15))	('cancer', 'Disease', (58, 64))	('phosphorylation', 'MPA', (86, 101))	('inhibits', 'NegReg', (36, 44))	('activity', 'MPA', (175, 183))	('PI3', 'Gene', (158, 161))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('aPKC', 'Gene', (170, 174))	('PI3', 'Gene', '477241', (12, 15))	('apoptosis', 'CPA', (45, 54))	('aPKC', 'Gene', '47594', (170, 174))	('aPKC', 'Gene', (137, 141))	('aPKC', 'Gene', (23, 27))
99695	26269582	This polarized architecture permits the assembly of signaling networks that appropriately interpret the cellular environment, and disrupted aPKC polarity can affect key signaling mediators involved in tumor growth and invasion, including Ras, NF-kappaB, Stat3, ERK1/2, and Rac1.	('Rac1', 'Gene', '403955', (273, 277))	('ERK1/2', 'Gene', (261, 267))	('aPKC', 'Gene', (140, 144))	('Rac1', 'Gene', (273, 277))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('disrupted', 'Var', (130, 139))	('NF-kappaB', 'Protein', (243, 252))	('Ras', 'Protein', (238, 241))	('Stat3', 'Gene', '490967', (254, 259))	('aPKC', 'Gene', '47594', (140, 144))	('signaling mediators', 'MPA', (169, 188))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('affect', 'Reg', (158, 164))	('tumor', 'Disease', (201, 206))	('ERK1/2', 'Gene', '477575', (261, 267))	('Stat3', 'Gene', (254, 259))
99703	26269582	For example, Crumbs 3 can sequester Yap1, and Scrib can act as a scaffold for Mst1/2, Lats1/2, and Taz, and disruption of these polarity complexes enables nuclear translocation of Yap1/Taz and epithelial overgrowth.	('epithelial overgrowth', 'CPA', (193, 214))	('overgrowth', 'Phenotype', 'HP:0001548', (204, 214))	('Mst1/2', 'Gene', '484768', (78, 84))	('Mst1/2', 'Gene', (78, 84))	('nuclear translocation', 'MPA', (155, 176))	('Yap1/Taz', 'Protein', (180, 188))	('disruption', 'Var', (108, 118))
99707	26269582	Moreover, a high level of Yap1/Taz is associated with increased invasiveness, metastasis, cancer stem cell phenotypes, and poor patient outcomes.	('high', 'Var', (12, 16))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('increased', 'PosReg', (54, 63))	('Yap1/Taz', 'Gene', (26, 34))	('invasiveness', 'CPA', (64, 76))	('patient', 'Species', '9606', (128, 135))	('metastasis', 'CPA', (78, 88))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))
99709	26269582	Down-regulation of Mst is observed in some cancers, and deletion of both of Mst1 and Mst2 in mice causes liver and colon tumors and dysplasia in the intestine.	('colon tumors', 'Phenotype', 'HP:0100273', (115, 127))	('causes', 'Reg', (98, 104))	('cancers', 'Phenotype', 'HP:0002664', (43, 50))	('Mst', 'Gene', '269881', (76, 79))	('cancers', 'Disease', (43, 50))	('mice', 'Species', '10090', (93, 97))	('Mst', 'Gene', '269881', (19, 22))	('deletion', 'Var', (56, 64))	('Mst', 'Gene', (76, 79))	('Mst', 'Gene', (19, 22))	('Mst2', 'Gene', '56274', (85, 89))	('liver and colon tumors and dysplasia', 'Disease', 'MESH:D003110', (105, 141))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('cancers', 'Disease', 'MESH:D009369', (43, 50))	('Mst', 'Gene', '269881', (85, 88))	('Mst2', 'Gene', (85, 89))	('dysplasia in the intestine', 'Phenotype', 'HP:0002242', (132, 158))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('Mst', 'Gene', (85, 88))
99711	26269582	However, mutations of Mst and Lats kinases are rare in common cancers, indicating that additional mechanisms contribute to deactivation of the Hippo pathway.	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('mutations', 'Var', (9, 18))	('Hippo', 'Gene', (143, 148))	('Mst', 'Gene', (22, 25))	('Mst', 'Gene', '269881', (22, 25))	('Hippo', 'Gene', '37247', (143, 148))	('deactivation', 'NegReg', (123, 135))	('cancers', 'Disease', 'MESH:D009369', (62, 69))	('cancers', 'Phenotype', 'HP:0002664', (62, 69))	('cancers', 'Disease', (62, 69))
99714	26269582	To investigate the consequence of aPKC gain of function on epithelial cells, we stably expressed green fluorescent protein (GFP; control) or a constitutively active form of aPKCzeta in which Thr-410 was substituted with Glu (T410E; aPKCzeta-ca) in Madin-Darby canine kidney (MDCK) cells (Figure 1A).	('aPKC', 'Gene', '47594', (173, 177))	('aPKC', 'Gene', (34, 38))	('aPKC', 'Gene', '47594', (232, 236))	('Thr-410 was substituted with Glu', 'Mutation', 'p.T410E', (191, 223))	('aPKC', 'Gene', '47594', (34, 38))	('T410E', 'Mutation', 'p.T410E', (225, 230))	('MDCK', 'CellLine', 'CVCL:0422', (275, 279))	('canine', 'Species', '9615', (260, 266))	('Thr-410', 'Var', (191, 198))	('aPKC', 'Gene', (173, 177))	('aPKC', 'Gene', (232, 236))
99720	26269582	The time to reach half-maximal size (t1/2) was 67 +- 2 h for control and 95 +- 3 h for aPKCzeta-ca structures, and aPKCzeta-ca structures had a growth rate twice that of GFP controls at t1/2 (44 +- 4 vs. 18 +- 1 mum2/h).	('aPKCzeta-ca', 'Var', (87, 98))	('growth', 'MPA', (144, 150))	('rat', 'Species', '10116', (151, 154))	('aPKCzeta-ca', 'Var', (115, 126))
99724	26269582	Similar to MDCK cells, expression of PKCzeta-ca caused multilayered growth in 2D cultures and a sixfold increase in size of 3D cultures (Supplemental Figure S1, F-H).	('increase', 'PosReg', (104, 112))	('size', 'CPA', (116, 120))	('multilayered growth', 'CPA', (55, 74))	('expression', 'Var', (23, 33))	('MDCK', 'CellLine', 'CVCL:0422', (11, 15))	('PKC', 'Gene', (37, 40))	('PKC', 'Gene', '478686;479577;18762', (37, 40))
99726	26269582	Collectively these data demonstrate that aPKCzeta-ca induces loss of epithelial growth control in both 2D and 3D culture environments.	('loss', 'NegReg', (61, 65))	('epithelial growth control', 'CPA', (69, 94))	('rat', 'Species', '10116', (31, 34))	('aPKCzeta-ca', 'Var', (41, 52))
99728	26269582	Depletion of aPKC or other members of the Par complex (Par3 and Par6) in 3D cultures results in structures that form multiple lumens instead of a single lumen but nonetheless retain apical-basal polarity.	('aPKC', 'Gene', (13, 17))	('apical-basal', 'MPA', (182, 194))	('aPKC', 'Gene', '47594', (13, 17))	('Par3', 'Gene', '477953', (55, 59))	('Par6', 'Gene', (64, 68))	('Depletion', 'Var', (0, 9))	('results in', 'Reg', (85, 95))	('Par3', 'Gene', (55, 59))
99737	26269582	In 2D cultures, E-cadherin and ZO-1 were localized to cell membrane in both GFP control and aPKCzeta-ca MDCK cells, whereas Par6 was mislocalized in aPKCzeta-ca cells (Figure 2D and Supplemental Figure S2B).	('E-cadherin', 'Gene', (16, 26))	('ZO-1', 'Gene', '403752', (31, 35))	('MDCK', 'CellLine', 'CVCL:0422', (104, 108))	('aPKCzeta-ca', 'Var', (92, 103))	('E-cadherin', 'Gene', '442858', (16, 26))	('ZO-1', 'Gene', (31, 35))
99739	26269582	Because aPKCzeta-ca induced loss of apical-basal polarity and epithelial growth control, we asked whether aPKCzeta-ca affected Hippo/Yap1 signaling.	('apical-basal polarity', 'CPA', (36, 57))	('aPKCzeta-ca', 'Var', (8, 19))	('Hippo', 'Gene', (127, 132))	('epithelial growth control', 'CPA', (62, 87))	('affected', 'Reg', (118, 126))	('Hippo', 'Gene', '37247', (127, 132))	('loss', 'NegReg', (28, 32))
99743	26269582	Consistent with a role for aPKC in regulating Yap1 subcellular localization, we found that aPKCzeta-ca cells had reduced levels of pS127-Yap1, with no change in total Yap1 expression (Figure 3E).	('aPKC', 'Gene', (91, 95))	('levels', 'MPA', (121, 127))	('pS127-Yap1', 'Var', (131, 141))	('aPKC', 'Gene', (27, 31))	('aPKC', 'Gene', '47594', (27, 31))	('aPKC', 'Gene', '47594', (91, 95))	('reduced', 'NegReg', (113, 120))
99747	26269582	A reduction in Lats1/2 phosphorylation was also observed in NMuMG cells (Supplemental Figure S3C), indicating that aPKCzeta gain of function negatively regulates the Hippo pathway and induces accumulation of Yap1 in the nucleus of epithelial cells.	('NMuMG', 'CellLine', 'CVCL:0075', (60, 65))	('Hippo', 'Gene', '37247', (166, 171))	('negatively', 'NegReg', (141, 151))	('aPKCzeta', 'Var', (115, 123))	('Hippo', 'Gene', (166, 171))	('induces', 'Reg', (184, 191))	('gain of function', 'PosReg', (124, 140))	('regulates', 'Reg', (152, 161))	('Yap1', 'Protein', (208, 212))	('accumulation', 'PosReg', (192, 204))
99749	26269582	Of interest, it was reported that Yap1 expression induces transformation and stratification in MDCK cells grown in 2D culture, but the consequence of Yap1 expression in 3D culture is not clear.	('transformation', 'CPA', (58, 72))	('MDCK', 'CellLine', 'CVCL:0422', (95, 99))	('expression', 'Var', (39, 49))	('stratification', 'CPA', (77, 91))	('Yap1', 'Gene', (34, 38))	('rat', 'Species', '10116', (79, 82))	('induces', 'Reg', (50, 57))
99753	26269582	Moreover, Yap1 expression increased the proportion of cells expressing the proliferation marker Ki67 but had no effect on cleaved caspase 3 (Supplemental Figure S4, K-N), indicating that Yap1 affects proliferation to induce epithelial overgrowth.	('expression', 'Var', (15, 25))	('rat', 'Species', '10116', (207, 210))	('overgrowth', 'Phenotype', 'HP:0001548', (235, 245))	('affects', 'Reg', (192, 199))	('epithelial overgrowth', 'CPA', (224, 245))	('rat', 'Species', '10116', (82, 85))	('increased', 'PosReg', (26, 35))	('Yap1', 'Gene', (10, 14))
99756	26269582	However, depletion of Yap1 did reduce the formation of stratified epithelia induced by aPKCzeta-ca expression (Supplemental Figure S5, D and E).	('Yap1', 'Gene', (22, 26))	('formation of stratified epithelia', 'CPA', (42, 75))	('aPKCzeta-ca expression', 'Gene', (87, 109))	('rat', 'Species', '10116', (57, 60))	('reduce', 'NegReg', (31, 37))	('depletion', 'Var', (9, 18))
99758	26269582	In 3D cultures, expression of shYap1 significantly reduced aPKC-mediated epithelial overgrowth (Figure 4, A and B).	('aPKC', 'Gene', (59, 63))	('expression', 'Var', (16, 26))	('reduced', 'NegReg', (51, 58))	('aPKC', 'Gene', '47594', (59, 63))	('shYap1', 'Gene', (30, 36))	('overgrowth', 'Phenotype', 'HP:0001548', (84, 94))
99760	26269582	Our foregoing observations show that aPKCzeta-ca expression causes a dramatic reduction in the phosphorylation of Lats1/2 at Ser-909, whereas Mst1/2 activity is unaffected.	('Mst1/2', 'Gene', '484768', (142, 148))	('Mst1/2', 'Gene', (142, 148))	('Ser', 'Chemical', 'MESH:D012694', (125, 128))	('reduction', 'NegReg', (78, 87))	('aPKCzeta-ca expression', 'Var', (37, 59))	('phosphorylation', 'MPA', (95, 110))	('Lats1/2', 'Protein', (114, 121))
99762	26269582	This led us to hypothesize that aPKCzeta-ca uncouples Mst1/2 from Lats1/2 through a mechanism other than reduced Mst1/2 activity.	('Mst1/2', 'Gene', (54, 60))	('Mst1/2', 'Gene', (113, 119))	('aPKCzeta-ca', 'Var', (32, 43))	('Mst1/2', 'Gene', '484768', (113, 119))	('Mst1/2', 'Gene', '484768', (54, 60))
99780	26269582	If aPKC disrupts membrane localization of Mst1/2 to deregulate Yap1 localization and cell growth, then we hypothesized that restoring Mst1/2 to the plasma membrane in aPKCzeta-ca cells would restore normal Yap1 localization and block epithelial overgrowth.	('Mst1/2', 'Gene', '484768', (42, 48))	('restoring', 'Var', (124, 133))	('aPKC', 'Gene', '47594', (167, 171))	('aPKC', 'Gene', (3, 7))	('Mst1/2', 'Gene', '484768', (134, 140))	('aPKC', 'Gene', '47594', (3, 7))	('deregulate', 'Reg', (52, 62))	('Mst1/2', 'Gene', (134, 140))	('epithelial overgrowth', 'CPA', (234, 255))	('disrupts', 'NegReg', (8, 16))	('block', 'NegReg', (228, 233))	('Mst1/2', 'Gene', (42, 48))	('restore', 'PosReg', (191, 198))	('aPKC', 'Gene', (167, 171))	('Yap1 localization', 'MPA', (206, 223))	('overgrowth', 'Phenotype', 'HP:0001548', (245, 255))
99782	26269582	We observed that wild-type Mst was predominantly cytoplasmic and did not rescue aPKCzeta-ca phenotypes; however, myristoylated Mst was able to both exclude Yap1 from the nucleus and block epithelial overgrowth in 3D cultures (Figure 5, E-H, and Supplemental Figure S6H).	('Mst', 'Gene', (27, 30))	('exclude', 'NegReg', (148, 155))	('Mst', 'Gene', '269881', (27, 30))	('block', 'NegReg', (182, 187))	('epithelial overgrowth', 'CPA', (188, 209))	('overgrowth', 'Phenotype', 'HP:0001548', (199, 209))	('myristoylated', 'Var', (113, 126))	('Mst', 'Gene', (127, 130))	('Mst', 'Gene', '269881', (127, 130))	('Yap1', 'Gene', (156, 160))
99788	26269582	Knockdown of Amot produces phenotypes that resemble our observed aPKCzeta gain-of-function phenotypes in MDCK cells, including spindly shaped cells and deregulation of Yap1 localization.	('gain-of-function', 'PosReg', (74, 90))	('aPKCzeta', 'Gene', (65, 73))	('spindly shaped cells', 'CPA', (127, 147))	('Yap1', 'Protein', (168, 172))	('deregulation', 'Var', (152, 164))	('localization', 'MPA', (173, 185))	('MDCK', 'CellLine', 'CVCL:0422', (105, 109))
99790	26269582	Of importance, expression of Amot, but not AmotDeltaN, was able to restore Yap1 localization to cell junctions (Figure 6C), consistent with a role for Amot in sequestration of Yap1 at tight junctions in MDCK cells.	('expression', 'Var', (15, 25))	('rat', 'Species', '10116', (166, 169))	('Yap1', 'Gene', (75, 79))	('MDCK', 'CellLine', 'CVCL:0422', (203, 207))	('localization', 'MPA', (80, 92))	('restore', 'PosReg', (67, 74))
99793	26269582	In NMuMG cells, despite aPKCzeta-ca also reducing phosphorylated Lats1/2 and affecting Yap1 localization, Amot expression was not altered by aPKCzeta-ca expression (Supplemental Figure S3C).	('affecting', 'Reg', (77, 86))	('aPKCzeta-ca', 'Var', (24, 35))	('reducing', 'NegReg', (41, 49))	('NMuMG', 'CellLine', 'CVCL:0075', (3, 8))	('phosphorylated', 'MPA', (50, 64))	('Lats1/2', 'Protein', (65, 72))	('Yap1 localization', 'MPA', (87, 104))
99798	26269582	However, we did not observe relocalization of Mst1/2 to the plasma membrane or phosphorylation of Lats1/2 and Yap1 in aPKCzeta-ca cells when Amot expression was restored (Figure 7, A and B), indicating that disruption of Mst1/2 localization and Lats1/2 phosphorylation is upstream of Amot rather than a consequence of loss of Amot expression in these cells.	('rat', 'Species', '10116', (289, 292))	('disruption', 'Var', (207, 217))	('Mst1/2', 'Gene', (221, 227))	('Amot', 'Disease', (284, 288))	('Mst1/2', 'Gene', (46, 52))	('Mst1/2', 'Gene', '484768', (221, 227))	('Mst1/2', 'Gene', '484768', (46, 52))
99815	26269582	We demonstrate that when expressed in polarized epithelial cells, aPKCzeta-ca induces loss of apical-basal polarity, disrupted epithelial organization, and loss of epithelial contact-inhibited growth control.	('apical-basal polarity', 'CPA', (94, 115))	('loss', 'NegReg', (86, 90))	('epithelial organization', 'CPA', (127, 150))	('loss', 'NegReg', (156, 160))	('disrupted', 'NegReg', (117, 126))	('rat', 'Species', '10116', (10, 13))	('epithelial contact-inhibited growth control', 'CPA', (164, 207))	('aPKCzeta-ca', 'Var', (66, 77))
99823	26269582	Furthermore, our results are consistent with observations in Drosophila, in which expression of membrane-targeted DaPKC induced nonpolarized localization of apical proteins, and suggest that elevated aPKC expression or activity may be an important driver of polarity loss and early transformation events.	('activity', 'MPA', (219, 227))	('DaPKC', 'Gene', (114, 119))	('DaPKC', 'Gene', '47594', (114, 119))	('Drosophila', 'Species', '7227', (61, 71))	('expression', 'Var', (82, 92))	('aPKC', 'Gene', (115, 119))	('aPKC', 'Gene', (200, 204))	('aPKC', 'Gene', '47594', (200, 204))	('nonpolarized localization of apical proteins', 'MPA', (128, 172))	('aPKC', 'Gene', '47594', (115, 119))
99828	26269582	We report that in 2D cultures, aPKCzeta-ca induces cells to grow as stratified foci, consistent with loss of contact-inhibited growth.	('induces', 'Reg', (43, 50))	('aPKCzeta-ca', 'Var', (31, 42))	('rat', 'Species', '10116', (70, 73))	('cells', 'CPA', (51, 56))
99846	26269582	Of interest, although Yap1 overexpression generated enlarged 3D structures, they retained apical-basal polarity and formed multiple lumens.	('overexpression', 'Var', (27, 41))	('apical-basal polarity', 'CPA', (90, 111))	('rat', 'Species', '10116', (46, 49))	('Yap1', 'Gene', (22, 26))	('3D structures', 'CPA', (61, 74))	('enlarged', 'PosReg', (52, 60))
99852	26269582	We report that aPKC expression was associated with loss of Amot in MDCK cells, which is able to recruit Yap1 to cell junctions.	('MDCK', 'CellLine', 'CVCL:0422', (67, 71))	('aPKC', 'Gene', '47594', (15, 19))	('expression', 'Var', (20, 30))	('aPKC', 'Gene', (15, 19))	('loss', 'NegReg', (51, 55))	('Amot', 'CPA', (59, 63))
99862	26269582	Although reexpression of Amot was sufficient to restore Yap1 at tight junctions, it did not restore the plasma membrane localization of Mst1/2 or Lats1/2 phosphorylation, indicating that loss of Mst1/2 from the plasma membrane and inactivation of Lats1/2 are upstream of loss of Amot expression.	('loss', 'Var', (187, 191))	('inactivation', 'NegReg', (231, 243))	('Mst1/2', 'Gene', (195, 201))	('Mst1/2', 'Gene', (136, 142))	('Mst1/2', 'Gene', '484768', (136, 142))	('Mst1/2', 'Gene', '484768', (195, 201))	('Yap1', 'Gene', (56, 60))
99867	26269582	Loss of Amot has two major effects: it deregulates the actin cytoskeleton, causing cytoskeletal and cell shape changes, and, in parallel, it prevents Yap1 from being sequestered at junctions, resulting in nuclear accumulation of Yap1 and increased proliferation (Figure 9, A and B).	('prevents', 'NegReg', (141, 149))	('cytoskeletal', 'MPA', (83, 95))	('Amot', 'Gene', (8, 12))	('proliferation', 'CPA', (248, 261))	('nuclear accumulation', 'CPA', (205, 225))	('increased', 'PosReg', (238, 247))	('Yap1', 'Gene', (150, 154))	('deregulates', 'Reg', (39, 50))	('rat', 'Species', '10116', (255, 258))	('actin cytoskeleton', 'MPA', (55, 73))	('sequestered', 'MPA', (166, 177))	('Loss', 'Var', (0, 4))	('Yap1', 'Gene', (229, 233))
99873	26269582	To inhibit the proteosome, cells were treated for 4 h with 10 muM (final concentration) MG132 (Sigma-Aldrich).	('rat', 'Species', '10116', (80, 83))	('proteosome', 'CPA', (15, 25))	('inhibit', 'NegReg', (3, 10))	('MG132', 'Var', (88, 93))	('MG132', 'Chemical', 'MESH:C072553', (88, 93))
99898	26269582	TMAs for lung squamous cell carcinoma (LC1505) and serous ovarian adenocarcinoma (OV241) were purchased from US BioMax (Rockville, MD).	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (14, 37))	('lung squamous cell carcinoma', 'Disease', (9, 37))	('serous ovarian adenocarcinoma', 'Disease', 'MESH:D010051', (51, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('TMAs', 'Chemical', 'MESH:C071868', (0, 4))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (9, 37))	('serous ovarian adenocarcinoma', 'Disease', (51, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (28, 37))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (9, 37))	('LC1505', 'Var', (39, 45))	('ovarian adenocarcinoma', 'Phenotype', 'HP:0025318', (58, 80))
99929	28791389	Downregulation of HAX-1 was observed to significantly suppress cellular proliferation, migration and clonal.	('HAX-1', 'Gene', '10456', (18, 23))	('Downregulation', 'Var', (0, 14))	('clonal', 'CPA', (101, 107))	('suppress', 'NegReg', (54, 62))	('HAX-1', 'Gene', (18, 23))	('cellular proliferation', 'CPA', (63, 85))
99931	28791389	Furthermore, HAX-1 knockdown markedly suppressed epithelial-mesenchymal transition.	('HAX-1', 'Gene', '10456', (13, 18))	('knockdown', 'Var', (19, 28))	('epithelial-mesenchymal transition', 'CPA', (49, 82))	('HAX-1', 'Gene', (13, 18))	('suppressed', 'NegReg', (38, 48))
99936	28791389	HCLS1-associated protein X-1 (HAX-1) is a family of ubiquitously expressed proteins ranging between 26 and 35 kDa in size, which result from alternative splicing of the single HAX-1 gene.	('alternative splicing', 'Var', (141, 161))	('HAX-1', 'Gene', (30, 35))	('HAX-1', 'Gene', '10456', (176, 181))	('HCLS1-associated protein X-1', 'Gene', (0, 28))	('HCLS1-associated protein X-1', 'Gene', '10456', (0, 28))	('HAX-1', 'Gene', (176, 181))	('HAX-1', 'Gene', '10456', (30, 35))
100006	28791389	Furthermore, high HAX-1 expression in breast cancer is associated with poor prognosis.	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('HAX-1', 'Gene', '10456', (18, 23))	('expression', 'MPA', (24, 34))	('breast cancer', 'Disease', 'MESH:D001943', (38, 51))	('high', 'Var', (13, 17))	('breast cancer', 'Disease', (38, 51))	('breast cancer', 'Phenotype', 'HP:0003002', (38, 51))	('HAX-1', 'Gene', (18, 23))
100015	28791389	Furthermore, knockdown of HAX-1 may inhibit the viability, proliferative and migratory abilities of FaDu cells in vitro.	('HAX-1', 'Gene', (26, 31))	('inhibit', 'NegReg', (36, 43))	('viability', 'CPA', (48, 57))	('HAX-1', 'Gene', '10456', (26, 31))	('knockdown', 'Var', (13, 22))
100063	28251014	evaluated the clinicopathological characteristics of mixed adenosquamous carcinoma/SCC variant compared to adenocarcinoma of the gallbladder.	('adenocarcinoma of the gallbladder', 'Disease', 'MESH:D005705', (107, 140))	('SCC', 'Gene', (83, 86))	('adenocarcinoma of the gallbladder', 'Phenotype', 'HP:0100575', (107, 140))	('adenocarcinoma of the gallbladder', 'Disease', (107, 140))	('adenosquamous carcinoma', 'Disease', 'MESH:D018196', (59, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('SCC', 'Gene', '6317', (83, 86))	('SCC', 'Phenotype', 'HP:0002860', (83, 86))	('adenosquamous carcinoma', 'Disease', (59, 82))	('variant', 'Var', (87, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
100131	28146145	Notably, both the top 10 scores (P=0.0133, Student's t-test) and productive clonality (P=0.0226, Student's t-test) were significantly higher in the L-SCCA group than in the L-ADCA group (Fig.	('productive clonality', 'CPA', (65, 85))	('higher', 'PosReg', (134, 140))	('L-SCCA', 'Var', (148, 154))	('ADCA', 'Gene', (175, 179))	('ADCA', 'Gene', '5173', (175, 179))
100137	28146145	1d, right), and, similar to measures of clonality and the Top 10 Score, more likely to occur in L-SCCA than in L-ADCA (Fig.	('L-SCCA', 'Var', (96, 102))	('ADCA', 'Gene', '5173', (113, 117))	('occur', 'Reg', (87, 92))	('ADCA', 'Gene', (113, 117))
100156	28146145	Compared with normal lung tissue, NSCLC specimens displayed increased composition of 37 distinct immune cell types and subtypes, including for B cells (CD19+CD20+), T cells (CD3+), CD4+ cells and CD8+ cells.	('CD20', 'Gene', '54474', (157, 161))	('CD19', 'Gene', (152, 156))	('NSCLC', 'Disease', (34, 39))	('CD19', 'Gene', '930', (152, 156))	('CD20', 'Gene', (157, 161))	('NSCLC', 'Disease', 'MESH:D002289', (34, 39))	('CD8', 'Gene', (196, 199))	('CD4+', 'CPA', (181, 185))	('CD8', 'Gene', '925', (196, 199))	('increased', 'PosReg', (60, 69))	('CD3+', 'Var', (174, 178))	('composition', 'MPA', (70, 81))
100181	28146145	Similar to the findings with CD8+ cells, CD4+PD1+ content was significantly higher in NSCLC specimens than in matched lung tissue, and in L-SCCA compared with L-ADCA (Fig.	('NSCLC', 'Disease', (86, 91))	('CD8', 'Gene', '925', (29, 32))	('CD4+PD1+ content', 'MPA', (41, 57))	('NSCLC', 'Disease', 'MESH:D002289', (86, 91))	('ADCA', 'Gene', '5173', (161, 165))	('L-SCCA', 'Var', (138, 144))	('higher', 'PosReg', (76, 82))	('ADCA', 'Gene', (161, 165))	('CD8', 'Gene', (29, 32))
100191	28146145	However, such analytical concepts do not explain the significant reduction in macrophage content in L-SCCA compared with L-ADCA (Fig.	('ADCA', 'Gene', (123, 127))	('L-SCCA', 'Var', (100, 106))	('macrophage content', 'MPA', (78, 96))	('ADCA', 'Gene', '5173', (123, 127))	('reduction', 'NegReg', (65, 74))
100231	28146145	In addition, the presence of key driver mutations in L-ADCA (for example, KRAS, EGFR and so on) may generate unique immune responses that would define further novel subgroups.	('ADCA', 'Gene', (55, 59))	('immune responses', 'MPA', (116, 132))	('EGFR', 'Gene', '1956', (80, 84))	('EGFR', 'Gene', (80, 84))	('mutations', 'Var', (40, 49))	('KRAS', 'Gene', (74, 78))	('KRAS', 'Gene', '3845', (74, 78))	('generate', 'Reg', (100, 108))	('ADCA', 'Gene', '5173', (55, 59))
100232	28146145	Recent studies suggest that response to ICIs is associated with the development of clonal expansion within a T-cell population that likely identifies a tumour-specific mutation functioning as a neo-antigen.	('tumour', 'Disease', 'MESH:D009369', (152, 158))	('tumour', 'Phenotype', 'HP:0002664', (152, 158))	('mutation', 'Var', (168, 176))	('tumour', 'Disease', (152, 158))
100253	28146145	In addition, the presence of key driver mutations may generate polarized immune responses in L-ADCA.	('generate', 'Reg', (54, 62))	('polarized immune', 'MPA', (63, 79))	('mutations', 'Var', (40, 49))	('ADCA', 'Gene', '5173', (95, 99))	('presence', 'Var', (17, 25))	('ADCA', 'Gene', (95, 99))
100255	28146145	For example, oxaliplatin, a so-called 'immunogenic' chemotherapy, was recently combined with anti-PD1 antibodies to reduce tumour burden in a mutant Kras mouse model of lung adenocarcinoma, while anti-PD1 therapy alone was ineffective.	('mouse', 'Species', '10090', (154, 159))	('tumour burden', 'Disease', (123, 136))	('Kras', 'Gene', (149, 153))	('reduce', 'NegReg', (116, 122))	('tumour burden', 'Disease', 'MESH:D009369', (123, 136))	('lung adenocarcinoma', 'Disease', (169, 188))	('Kras', 'Gene', '3845', (149, 153))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (169, 188))	('mutant', 'Var', (142, 148))	('anti-PD1', 'Gene', (93, 101))	('tumour', 'Phenotype', 'HP:0002664', (123, 129))	('carcinoma', 'Phenotype', 'HP:0030731', (179, 188))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (13, 24))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (169, 188))
100279	28146145	Cells were stained with fluorochrome-conjugated anti-human antibodies against CD45, CD3, CD4, CD8, CD19, CD20, CD56 and gammadeltaTCR (antibody and clone details, see Supplementary Table 2) for 30 min on ice, washed and stained with fixable viability dye (FVD, eBioscience), before fixation (IC fixation buffer, eBioscience).	('CD8', 'Gene', '925', (94, 97))	('TCR', 'Gene', '6962', (130, 133))	('CD56', 'Gene', '4684', (111, 115))	('CD19', 'Gene', (99, 103))	('CD3', 'Var', (84, 87))	('CD45', 'Gene', (78, 82))	('CD8', 'Gene', (94, 97))	('CD56', 'Gene', (111, 115))	('CD19', 'Gene', '930', (99, 103))	('human', 'Species', '9606', (53, 58))	('TCR', 'Gene', (130, 133))	('CD4', 'Var', (89, 92))	('CD20', 'Gene', '54474', (105, 109))	('CD45', 'Gene', '5788', (78, 82))	('CD20', 'Gene', (105, 109))
100314	26297432	Although EGFR tyrosine kinase inhibitors are effective for NSCLC patients harboring EGFR mutations, patients invariably develop resistance to these agents.	('resistance', 'MPA', (128, 138))	('NSCLC', 'Disease', 'MESH:D002289', (59, 64))	('develop', 'Reg', (120, 127))	('EGFR', 'Gene', '1956', (84, 88))	('EGFR', 'Gene', '1956', (9, 13))	('patients', 'Species', '9606', (100, 108))	('EGFR', 'Gene', (9, 13))	('NSCLC', 'Phenotype', 'HP:0030358', (59, 64))	('mutations', 'Var', (89, 98))	('patients', 'Species', '9606', (65, 73))	('EGFR', 'Gene', (84, 88))	('NSCLC', 'Disease', (59, 64))
100315	26297432	Alterations in multiple signaling cascades have been associated with the development of resistance to EGFR inhibitors.	('resistance', 'MPA', (88, 98))	('Alterations', 'Var', (0, 11))	('associated', 'Reg', (53, 63))	('EGFR', 'Gene', '1956', (102, 106))	('EGFR', 'Gene', (102, 106))
100319	26297432	Depletion of Gli1 or inhibition of the Hedgehog signaling significantly abrogated the self-renewal of stem-like side-population cells from NSCLCs as well as vascular mimicry of such cells.	('Gli1', 'Gene', '2735', (13, 17))	('abrogated', 'NegReg', (72, 81))	('NSCLC', 'Phenotype', 'HP:0030358', (139, 144))	('vascular mimicry of', 'CPA', (157, 176))	('self-renewal of stem-like side-population cells', 'CPA', (86, 133))	('NSCLC', 'Disease', (139, 144))	('Depletion', 'Var', (0, 9))	('NSCLC', 'Disease', 'MESH:D002289', (139, 144))	('Gli1', 'Gene', (13, 17))	('Hedgehog signaling', 'Gene', (39, 57))	('inhibition', 'NegReg', (21, 31))
100321	26297432	Inhibition of Hedgehog signaling appeared to work cooperatively with EGFR inhibitors in markedly reducing the viability of NSCLC cells as well as the self-renewal of stem-like cells.	('EGFR', 'Gene', '1956', (69, 73))	('NSCLC', 'Disease', (123, 128))	('EGFR', 'Gene', (69, 73))	('NSCLC', 'Disease', 'MESH:D002289', (123, 128))	('self-renewal of stem-like cells', 'CPA', (150, 181))	('NSCLC', 'Phenotype', 'HP:0030358', (123, 128))	('reducing', 'NegReg', (97, 105))	('viability', 'CPA', (110, 119))	('Inhibition', 'Var', (0, 10))	('Hedgehog', 'Protein', (14, 22))
100322	26297432	Thus, our study demonstrates a cooperative functioning of the EGFR signaling and Hedgehog pathways in governing the stem-like functions of NSCLC cancer stem cells and presents a novel therapeutic strategy to combat NSCLC harboring EGFR mutations.	('NSCLC', 'Phenotype', 'HP:0030358', (139, 144))	('EGFR', 'Gene', '1956', (62, 66))	('stem-like functions', 'CPA', (116, 135))	('NSCLC', 'Phenotype', 'HP:0030358', (215, 220))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('EGFR', 'Gene', (62, 66))	('NSCLC', 'Disease', (139, 144))	('NSCLC cancer', 'Disease', (139, 151))	('EGFR', 'Gene', '1956', (231, 235))	('mutations', 'Var', (236, 245))	('NSCLC', 'Disease', 'MESH:D002289', (139, 144))	('NSCLC', 'Disease', (215, 220))	('EGFR', 'Gene', (231, 235))	('NSCLC cancer', 'Disease', 'MESH:D009369', (139, 151))	('NSCLC', 'Disease', 'MESH:D002289', (215, 220))
100326	26297432	NSCLC in non-smokers show predominantly mutations in EGFR; such patients respond well to EGFR inhibitors like erlotinib but eventually develop resistance and succumb to the disease.	('erlotinib', 'Chemical', 'MESH:D000069347', (110, 119))	('NSCLC', 'Disease', 'MESH:D002289', (0, 5))	('succumb', 'Reg', (158, 165))	('EGFR', 'Gene', '1956', (89, 93))	('EGFR', 'Gene', (89, 93))	('patients', 'Species', '9606', (64, 72))	('NSCLC', 'Phenotype', 'HP:0030358', (0, 5))	('mutations', 'Var', (40, 49))	('EGFR', 'Gene', '1956', (53, 57))	('resistance', 'MPA', (143, 153))	('EGFR', 'Gene', (53, 57))	('NSCLC', 'Disease', (0, 5))	('develop', 'Reg', (135, 142))
100327	26297432	Resistance to EGFR inhibitors occurs through various mechanisms, including the appearance of the T790M gatekeeper mutation, expression of c-Met gene, or activation of alternate signaling pathways.	('EGFR', 'Gene', '1956', (14, 18))	('EGFR', 'Gene', (14, 18))	('c-Met gene', 'Gene', (138, 148))	('alternate signaling pathways', 'Pathway', (167, 195))	('gatekeeper', 'Species', '111938', (103, 113))	('T790M', 'Mutation', 'rs121434569', (97, 102))	('activation', 'Reg', (153, 163))	('T790M', 'Var', (97, 102))
100330	26297432	CSCs from NSCLC cell lines, tumor samples, and mouse models have been isolated based on various markers including ALDH1, side-population phenotype, and CD133 positivity.	('NSCLC', 'Disease', (10, 15))	('positivity', 'Var', (158, 168))	('tumor', 'Disease', (28, 33))	('NSCLC', 'Disease', 'MESH:D002289', (10, 15))	('CD133', 'Gene', (152, 157))	('ALDH1', 'Gene', (114, 119))	('CD133', 'Gene', '19126', (152, 157))	('NSCLC', 'Phenotype', 'HP:0030358', (10, 15))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('mouse', 'Species', '10090', (47, 52))
100342	26297432	We have found that Sox2 levels were regulated by EGFR signaling cascades; inhibition of EGFR significantly reduced the expression of Sox2 and abrogated self-renewal of SP cells.	('EGFR', 'Gene', '1956', (49, 53))	('expression', 'MPA', (119, 129))	('abrogated', 'NegReg', (142, 151))	('inhibition', 'Var', (74, 84))	('EGFR', 'Gene', (49, 53))	('Sox2', 'Gene', '6657', (19, 23))	('reduced', 'NegReg', (107, 114))	('Sox2', 'Gene', '6657', (133, 137))	('Sox2', 'Gene', (19, 23))	('EGFR', 'Gene', '1956', (88, 92))	('Sox2', 'Gene', (133, 137))	('self-renewal of SP cells', 'CPA', (152, 176))	('EGFR', 'Gene', (88, 92))	('SP', 'Chemical', '-', (168, 170))
100348	26297432	Depletion of Gli1, the major mediator of Hh function, led to a reduction in the levels of Sox2 and significantly abrogated the self-renewal of SP cells as well as their ability to form angiogenic tubules that represent vascular mimicry.	('Gli1', 'Gene', '2735', (13, 17))	('Sox2', 'Gene', '6657', (90, 94))	('self-renewal of SP cells', 'CPA', (127, 151))	('Depletion', 'Var', (0, 9))	('Sox2', 'Gene', (90, 94))	('Gli1', 'Gene', (13, 17))	('reduction', 'NegReg', (63, 72))	('abrogated', 'NegReg', (113, 122))	('SP', 'Chemical', '-', (143, 145))
100349	26297432	Interestingly, Hh pathway inhibitors appeared to enhance the growth-suppressive properties of EGFR inhibitors and depletion of Gli1-sensitized NSCLC cells to erlotinib and gefitinib.	('Gli1', 'Gene', '2735', (127, 131))	('NSCLC', 'Disease', (143, 148))	('depletion', 'MPA', (114, 123))	('EGFR', 'Gene', '1956', (94, 98))	('gefitinib', 'Chemical', 'MESH:D000077156', (172, 181))	('inhibitors', 'Var', (26, 36))	('inhibitors', 'Var', (99, 109))	('NSCLC', 'Disease', 'MESH:D002289', (143, 148))	('enhance', 'PosReg', (49, 56))	('EGFR', 'Gene', (94, 98))	('NSCLC', 'Phenotype', 'HP:0030358', (143, 148))	('growth-suppressive properties', 'CPA', (61, 90))	('Gli1', 'Gene', (127, 131))	('erlotinib', 'Chemical', 'MESH:D000069347', (158, 167))
100352	26297432	The H1650, HCC827, and PC-9 cell lines harbor deletion DeltaE746-A750 in the exon 19 of EGFR tyrosine kinase receptor.	('DeltaE746', 'DELETION', 'None', (55, 64))	('H1650', 'CellLine', 'CVCL:1483', (4, 9))	('EGFR', 'Gene', '1956', (88, 92))	('PC-9', 'Gene', (23, 27))	('PC-9', 'Gene', '255738', (23, 27))	('DeltaE746', 'Var', (55, 64))	('EGFR', 'Gene', (88, 92))
100353	26297432	The H1975 harbors L858R mutation and additionally T790M mutation in the EGFR receptor.	('T790M', 'Mutation', 'rs121434569', (50, 55))	('EGFR', 'Gene', '1956', (72, 76))	('T790M', 'Var', (50, 55))	('EGFR', 'Gene', (72, 76))	('L858R', 'Mutation', 'rs121434568', (18, 23))	('L858R mutation', 'Var', (18, 32))	('H1975', 'Var', (4, 9))	('H1975', 'CellLine', 'CVCL:1511', (4, 9))
100357	26297432	Gefitinib (G4408), erlotinib (E-4007), and BIBW (A-8644) were purchased from LC Laboratories.	('BIBW', 'Chemical', '-', (43, 47))	('G4408', 'Chemical', '-', (11, 16))	('erlotinib', 'Chemical', 'MESH:D000069347', (19, 28))	('Gefitinib', 'Chemical', 'MESH:D000077156', (0, 9))	('G4408', 'Var', (11, 16))	('E-4007', 'Chemical', '-', (30, 36))	('E-4007', 'Var', (30, 36))
100384	26297432	FP 5'-TCCTGATTCCAGTTTGCCTC-3', RP 5'-GGGAGAGGAGGAGGGGAG-3' ChIP assays were conducted on asynchronous H1650 and H1975 as previously described using indicated antibodies.	('H1650', 'Var', (102, 107))	('H1975', 'Var', (112, 117))	('H1975', 'CellLine', 'CVCL:1511', (112, 117))	('H1650', 'CellLine', 'CVCL:1483', (102, 107))
100391	26297432	A qRT-PCR showed that the levels of Gli1 (two-fold or more) and Gli2 (1.5- to 2-fold) were significantly higher in SP cells as compared with the nonstemlike main-population cells from EGFR mutant H1650 and H1975 cell lines (Figure 1, A and B).	('H1975', 'CellLine', 'CVCL:1511', (206, 211))	('Gli2', 'Gene', (64, 68))	('higher', 'PosReg', (105, 111))	('mutant', 'Var', (189, 195))	('EGFR', 'Gene', '1956', (184, 188))	('Gli1', 'Gene', (36, 40))	('SP', 'Chemical', '-', (115, 117))	('EGFR', 'Gene', (184, 188))	('H1650', 'CellLine', 'CVCL:1483', (196, 201))	('Gli1', 'Gene', '2735', (36, 40))	('Gli2', 'Gene', '2736', (64, 68))
100394	26297432	Aldhhigh cells from H1650 and H1975 cells showed significantly higher expression of Gli1 and Gli2 in both the cell lines (Figure 1, C and D).	('H1650', 'Var', (20, 25))	('H1650', 'CellLine', 'CVCL:1483', (20, 25))	('expression', 'MPA', (70, 80))	('Gli1', 'Gene', (84, 88))	('Gli2', 'Gene', '2736', (93, 97))	('H1975', 'Var', (30, 35))	('Gli2', 'Gene', (93, 97))	('higher', 'PosReg', (63, 69))	('Gli1', 'Gene', '2735', (84, 88))	('H1975', 'CellLine', 'CVCL:1511', (30, 35))
100409	26297432	Similar Kaplan-Meier analysis also showed that Sox2 expression predicted poor prognosis in lung adenocarcinoma when overall survival was examined (P = .035; data not shown).	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (91, 110))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (91, 110))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('Sox2', 'Gene', '6657', (47, 51))	('lung adenocarcinoma', 'Disease', (91, 110))	('expression', 'Var', (52, 62))	('Sox2', 'Gene', (47, 51))	('poor', 'NegReg', (73, 77))
100412	26297432	Hence, we examined whether depletion of Gli1 affects stem-like functions of SP cells by modulating the expression of these core ES cell transcription factors.	('expression', 'MPA', (103, 113))	('SP', 'Chemical', '-', (76, 78))	('Gli1', 'Gene', (40, 44))	('stem-like functions of SP cells', 'CPA', (53, 84))	('depletion', 'Var', (27, 36))	('modulating', 'Reg', (88, 98))	('Gli1', 'Gene', '2735', (40, 44))	('affects', 'Reg', (45, 52))
100414	26297432	It was found that the levels of all three transcription factors were reduced upon Gli1 depletion; interestingly, the maximal reduction was observed for Sox2 in both the cell lines (Figure 3, A and B).	('Sox2', 'Gene', '6657', (152, 156))	('depletion', 'Var', (87, 96))	('levels', 'MPA', (22, 28))	('Sox2', 'Gene', (152, 156))	('Gli1', 'Gene', (82, 86))	('Gli1', 'Gene', '2735', (82, 86))
100416	26297432	Because depletion of Hh pathway effector Gli1 abrogated the self-renewal properties of CSCs from EGFR mutant NSCLC cell lines, we investigated if exogenous addition of SHH protein can increase their stem-like properties.	('SHH', 'Gene', (168, 171))	('mutant', 'Var', (102, 108))	('NSCLC', 'Disease', 'MESH:D002289', (109, 114))	('self-renewal properties', 'CPA', (60, 83))	('Gli1', 'Gene', '2735', (41, 45))	('EGFR', 'Gene', '1956', (97, 101))	('depletion', 'MPA', (8, 17))	('abrogated', 'NegReg', (46, 55))	('SHH', 'Gene', '6469', (168, 171))	('NSCLC', 'Phenotype', 'HP:0030358', (109, 114))	('EGFR', 'Gene', (97, 101))	('NSCLC', 'Disease', (109, 114))	('Gli1', 'Gene', (41, 45))
100420	26297432	These results confirmed that the EGFR mutant NSCLC cell lines are sensitive to Hh signaling pathway and that Sox2 may be a common target gene of the EGFR and Hh signaling pathway.	('mutant', 'Var', (38, 44))	('Hh signaling pathway', 'Pathway', (79, 99))	('NSCLC', 'Disease', (45, 50))	('Sox2', 'Gene', '6657', (109, 113))	('EGFR', 'Gene', '1956', (149, 153))	('EGFR', 'Gene', '1956', (33, 37))	('sensitive', 'Reg', (66, 75))	('NSCLC', 'Disease', 'MESH:D002289', (45, 50))	('EGFR', 'Gene', (149, 153))	('Sox2', 'Gene', (109, 113))	('EGFR', 'Gene', (33, 37))	('NSCLC', 'Phenotype', 'HP:0030358', (45, 50))
100423	26297432	ChIP assays were conducted on asynchronous H1650 and H1975 cells to assess the presence of Gli transcription factors on Sox2 proximal promoter region (- 528 to + 328) using a specific primer pair (Figure 4A).	('H1650', 'CellLine', 'CVCL:1483', (43, 48))	('H1975', 'CellLine', 'CVCL:1511', (53, 58))	('Gli', 'Gene', (91, 94))	('Sox2', 'Gene', '6657', (120, 124))	('- 528', 'Var', (151, 156))	('Sox2', 'Gene', (120, 124))	('Gli', 'Gene', '2735', (91, 94))
100428	26297432	Our earlier studies had shown that EGFR signaling induced Sox2 expression in EGFR mutant cell lines.	('Sox2', 'Gene', (58, 62))	('EGFR', 'Gene', '1956', (35, 39))	('expression', 'MPA', (63, 73))	('EGFR', 'Gene', (35, 39))	('EGFR', 'Gene', '1956', (77, 81))	('EGFR', 'Gene', (77, 81))	('Sox2', 'Gene', '6657', (58, 62))	('mutant', 'Var', (82, 88))
100433	26297432	Based on these results, we next examined if Sox2-luc could be induced by EGF or recombinant SHH or a combination of both EGF and SHH in H1650 and H1975, and whether such an induction required the presence of Gli1 or Gli2.	('H1650', 'Var', (136, 141))	('H1975', 'CellLine', 'CVCL:1511', (146, 151))	('Gli2', 'Gene', (216, 220))	('H1650', 'CellLine', 'CVCL:1483', (136, 141))	('SHH', 'Gene', '6469', (92, 95))	('Sox2', 'Gene', '6657', (44, 48))	('SHH', 'Gene', '6469', (129, 132))	('Gli1', 'Gene', (208, 212))	('Sox2', 'Gene', (44, 48))	('SHH', 'Gene', (92, 95))	('SHH', 'Gene', (129, 132))	('Gli1', 'Gene', '2735', (208, 212))	('Gli2', 'Gene', '2736', (216, 220))
100445	26297432	Western blot analysis showed that Gli1 depletion significantly reduced the EGF-mediated induction of endogenous Sox2 and Oct4 transcription factors (Figure 5, D and F); the induction of Sox2 by EGF was almost fully abolished, whereas the effect on Oct4 was less pronounced.	('Gli1', 'Gene', (34, 38))	('induction', 'MPA', (88, 97))	('Oct4', 'Gene', '5460', (121, 125))	('Sox2', 'Gene', '6657', (186, 190))	('depletion', 'Var', (39, 48))	('reduced', 'NegReg', (63, 70))	('Gli1', 'Gene', '2735', (34, 38))	('Oct4', 'Gene', (248, 252))	('Sox2', 'Gene', (186, 190))	('Oct4', 'Gene', (121, 125))	('Sox2', 'Gene', '6657', (112, 116))	('Oct4', 'Gene', '5460', (248, 252))	('endogenous', 'MPA', (101, 111))	('Sox2', 'Gene', (112, 116))
100455	26297432	As shown in Figure 6, A and B, 10 muM of GDC-0449 or 5 muM of BMS-833923 reduced the viability of cells only marginally, as seen by MTT assays.	('muM', 'Gene', '56925', (34, 37))	('muM', 'Gene', '56925', (55, 58))	('muM', 'Gene', (34, 37))	('reduced', 'NegReg', (73, 80))	('GDC-0449', 'Chemical', 'MESH:C538724', (41, 49))	('MTT', 'Chemical', '-', (132, 135))	('muM', 'Gene', (55, 58))	('GDC-0449', 'Var', (41, 49))	('BMS-833923', 'Gene', (62, 72))
100457	26297432	Because depletion of Gli1 abrogated self-renewal of CSCs, we next examined whether Hh inhibitors could affect the self-renewal of SP cells from the EGFR mutant cell lines H1650, PC-9, and H1975.	('H1650', 'CellLine', 'CVCL:1483', (171, 176))	('PC-9', 'Gene', (178, 182))	('Gli1', 'Gene', '2735', (21, 25))	('PC-9', 'Gene', '255738', (178, 182))	('EGFR', 'Gene', '1956', (148, 152))	('depletion', 'MPA', (8, 17))	('EGFR', 'Gene', (148, 152))	('mutant', 'Var', (153, 159))	('abrogated', 'NegReg', (26, 35))	('SP', 'Chemical', '-', (130, 132))	('self-renewal', 'CPA', (114, 126))	('self-renewal of CSCs', 'CPA', (36, 56))	('Gli1', 'Gene', (21, 25))	('H1975', 'CellLine', 'CVCL:1511', (188, 193))	('affect', 'Reg', (103, 109))
100458	26297432	The two cell lines H1650 and PC-9 harbor deletion in Exon 19 DeltaE746-A750 in the EGFR tyrosine kinase receptor.	('EGFR', 'Gene', '1956', (83, 87))	('DeltaE746', 'Var', (61, 70))	('H1650', 'CellLine', 'CVCL:1483', (19, 24))	('DeltaE746', 'DELETION', 'None', (61, 70))	('EGFR', 'Gene', (83, 87))	('PC-9', 'Gene', (29, 33))	('deletion', 'Var', (41, 49))	('PC-9', 'Gene', '255738', (29, 33))
100459	26297432	The H1975 cell line harbor L858R mutation as well as the secondary T790M gatekeeper mutation in the EGFR receptor, which makes it more resistant to tyrosine kinase inhibitor (TKI) therapies.	('gatekeeper', 'Species', '111938', (73, 83))	('EGFR', 'Gene', '1956', (100, 104))	('T790M', 'Mutation', 'rs121434569', (67, 72))	('EGFR', 'Gene', (100, 104))	('T790M', 'Var', (67, 72))	('L858R mutation', 'Var', (27, 41))	('resistant', 'MPA', (135, 144))	('L858R', 'Mutation', 'rs121434568', (27, 32))	('H1975', 'CellLine', 'CVCL:1511', (4, 9))
100464	26297432	Because the above results suggested that Hh pathway might be contributing to survival and self-renewal functions mediated by EGFR signaling, we next examined whether depletion of Gli1 could sensitize the EGFR mutant NSCLC cells to EGFR inhibitors.	('NSCLC', 'Disease', (216, 221))	('sensitize', 'Reg', (190, 199))	('Gli1', 'Gene', '2735', (179, 183))	('NSCLC', 'Disease', 'MESH:D002289', (216, 221))	('EGFR', 'Gene', '1956', (125, 129))	('NSCLC', 'Phenotype', 'HP:0030358', (216, 221))	('EGFR', 'Gene', '1956', (231, 235))	('EGFR', 'Gene', (125, 129))	('EGFR', 'Gene', '1956', (204, 208))	('self-renewal', 'CPA', (90, 102))	('EGFR', 'Gene', (231, 235))	('Gli1', 'Gene', (179, 183))	('mutant', 'Var', (209, 215))	('EGFR', 'Gene', (204, 208))
100467	26297432	It was found that depleting Gli1 could enhance the sensitivity of both the cell lines to EGFR inhibitors (Figure 6, F and G).	('EGFR', 'Gene', (89, 93))	('Gli1', 'Gene', (28, 32))	('Gli1', 'Gene', '2735', (28, 32))	('depleting', 'Var', (18, 27))	('sensitivity', 'MPA', (51, 62))	('enhance', 'PosReg', (39, 46))	('EGFR', 'Gene', '1956', (89, 93))
100471	26297432	To further investigate the mechanisms by which Hh and EGFR inhibition abrogates the self-renewal of NSCLC CSCs, we examined how the inhibitors alone, or in combination, affected the expression of stem cell transcription factors.	('abrogates', 'NegReg', (70, 79))	('affected', 'Reg', (169, 177))	('expression', 'MPA', (182, 192))	('NSCLC', 'Disease', (100, 105))	('NSCLC', 'Disease', 'MESH:D002289', (100, 105))	('EGFR', 'Gene', '1956', (54, 58))	('inhibition', 'Var', (59, 69))	('NSCLC', 'Phenotype', 'HP:0030358', (100, 105))	('EGFR', 'Gene', (54, 58))	('self-renewal of', 'CPA', (84, 99))
100473	26297432	BMS-833923 could reduce the levels of both Gli1 and Sox2 and in combination with EGFR inhibitors could almost completely eliminate the expression of Sox2 (Figure 7A).	('eliminate', 'NegReg', (121, 130))	('levels', 'MPA', (28, 34))	('Sox2', 'Gene', (52, 56))	('Sox2', 'Gene', '6657', (149, 153))	('reduce', 'NegReg', (17, 23))	('BMS-833923', 'Var', (0, 10))	('Sox2', 'Gene', (149, 153))	('Gli1', 'Gene', '2735', (43, 47))	('expression', 'MPA', (135, 145))	('Gli1', 'Gene', (43, 47))	('Sox2', 'Gene', '6657', (52, 56))	('EGFR', 'Gene', '1956', (81, 85))	('EGFR', 'Gene', (81, 85))
100474	26297432	Similar results were obtained in H1975 cells, which are less sensitive to gefitinib and erlotinib (Figure 7B); the combination of BMS-833923 with EGFR inhibitors could significantly reduce the levels of Sox2 in these cells as well (Figure 7B).	('EGFR', 'Gene', '1956', (146, 150))	('combination', 'Interaction', (115, 126))	('Sox2', 'Gene', (203, 207))	('BMS-833923', 'Var', (130, 140))	('erlotinib', 'Chemical', 'MESH:D000069347', (88, 97))	('H1975', 'CellLine', 'CVCL:1511', (33, 38))	('EGFR', 'Gene', (146, 150))	('reduce', 'NegReg', (182, 188))	('Sox2', 'Gene', '6657', (203, 207))	('gefitinib', 'Chemical', 'MESH:D000077156', (74, 83))
100478	26297432	Western blot experiments clearly indicated that there was increased expression of Gli1 protein in drug-resistant cells compared with parental cells (Figure 7, E and F).	('drug-resistant', 'Var', (98, 112))	('increased', 'PosReg', (58, 67))	('expression', 'MPA', (68, 78))	('protein', 'Protein', (87, 94))	('Gli1', 'Gene', (82, 86))	('Gli1', 'Gene', '2735', (82, 86))
100484	26297432	In the past decade, the novel agents that have been used to target the genetic alterations of NSCLC were found to be effective in early stages of the disease, but the tumors recur by developing alternate survival pathways.	('NSCLC', 'Phenotype', 'HP:0030358', (94, 99))	('survival pathways', 'CPA', (204, 221))	('tumors', 'Disease', 'MESH:D009369', (167, 173))	('genetic alterations', 'Var', (71, 90))	('NSCLC', 'Disease', (94, 99))	('NSCLC', 'Disease', 'MESH:D002289', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('tumors', 'Disease', (167, 173))	('tumors', 'Phenotype', 'HP:0002664', (167, 173))
100486	26297432	The biopsies from NSCLC patients who acquire resistance show that, in addition to the original activating EGFR mutation, other mutations arose like EGFR T790M mutation that interferes with the binding of the drugs like gefitinib or erlotinib to the receptor, amplification of MET tyrosine kinase receptor driving cell growth.	('T790M', 'Mutation', 'rs121434569', (153, 158))	('gefitinib', 'Chemical', 'MESH:D000077156', (219, 228))	('T790M', 'Var', (153, 158))	('MET tyrosine kinase receptor', 'MPA', (276, 304))	('NSCLC', 'Disease', (18, 23))	('EGFR', 'Gene', '1956', (148, 152))	('EGFR', 'Gene', (148, 152))	('erlotinib', 'Chemical', 'MESH:D000069347', (232, 241))	('NSCLC', 'Disease', 'MESH:D002289', (18, 23))	('patients', 'Species', '9606', (24, 32))	('interferes', 'NegReg', (173, 183))	('NSCLC', 'Phenotype', 'HP:0030358', (18, 23))	('binding', 'Interaction', (193, 200))	('EGFR', 'Gene', '1956', (106, 110))	('mutation', 'Var', (111, 119))	('EGFR', 'Gene', (106, 110))
100488	26297432	A small population with acquired resistance to EGFR inhibitors displays mutation in B-Raf gene (G469A ad V600E).	('B-Raf', 'Gene', (84, 89))	('G469A ad V600E', 'Var', (96, 110))	('B-Raf', 'Gene', '673', (84, 89))	('V600E', 'Mutation', 'rs113488022', (105, 110))	('EGFR', 'Gene', '1956', (47, 51))	('EGFR', 'Gene', (47, 51))	('G469A', 'Mutation', 'rs121913355', (96, 101))
100498	26297432	It has been found that Hh pathway plays a crucial role in tumorigenesis when reactivated in adult mammalian tissues due to mutations or other mechanisms.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('mammalian', 'Species', '9606', (98, 107))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('mutations', 'Var', (123, 132))	('Hh pathway', 'Pathway', (23, 33))
100499	26297432	In this context, the results presented here show that high Gli1 expression predicts poor survival for lung adenocarcinoma patients, supporting the hypothesis that this pathway contributes to the genesis and drug resistance of this disease.	('Gli1', 'Gene', (59, 63))	('Gli1', 'Gene', '2735', (59, 63))	('high', 'Var', (54, 58))	('poor', 'NegReg', (84, 88))	('patients', 'Species', '9606', (122, 130))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (102, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('drug resistance', 'Phenotype', 'HP:0020174', (207, 222))	('lung adenocarcinoma', 'Disease', (102, 121))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (102, 121))
100501	26297432	Similar to Gli1, high Sox2 expression correlates with poor prognosis of lung adenocarcinoma patients and is known to play a clear role in stemness of lung adenocarcinoma as well as squamous carcinoma cells.	('squamous carcinoma', 'Disease', 'MESH:D002294', (181, 199))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (150, 169))	('carcinoma', 'Phenotype', 'HP:0030731', (160, 169))	('expression', 'MPA', (27, 37))	('Gli1', 'Gene', '2735', (11, 15))	('carcinoma', 'Phenotype', 'HP:0030731', (190, 199))	('patients', 'Species', '9606', (92, 100))	('Sox2', 'Gene', (22, 26))	('lung adenocarcinoma', 'Disease', (72, 91))	('Gli1', 'Gene', (11, 15))	('squamous carcinoma', 'Disease', (181, 199))	('stemness of lung adenocarcinoma', 'Disease', (138, 169))	('stemness of lung adenocarcinoma', 'Disease', 'MESH:D000077192', (138, 169))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (72, 91))	('high', 'Var', (17, 21))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (181, 199))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('Sox2', 'Gene', '6657', (22, 26))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (72, 91))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (150, 169))
100514	26297432	Our results show that combining these inhibitors or depletion of Gli1 decreases their viability as well as self-renewal.	('Gli1', 'Gene', (65, 69))	('decreases', 'NegReg', (70, 79))	('Gli1', 'Gene', '2735', (65, 69))	('viability', 'CPA', (86, 95))	('depletion', 'Var', (52, 61))	('self-renewal', 'CPA', (107, 119))
100515	26297432	This is especially relevant in the case of H1975 cells, which harbor a T790M gatekeeper mutation and are generally refractory to EGFR inhibitors.	('T790M', 'Mutation', 'rs121434569', (71, 76))	('gatekeeper', 'Species', '111938', (77, 87))	('T790M', 'Var', (71, 76))	('EGFR', 'Gene', '1956', (129, 133))	('H1975', 'CellLine', 'CVCL:1511', (43, 48))	('EGFR', 'Gene', (129, 133))
100516	26297432	Thus, targeting Hh pathway along with EGFR signaling could be a viable strategy to combat NSCLC, especially those that harbor EGFR mutations.	('EGFR', 'Gene', '1956', (38, 42))	('mutations', 'Var', (131, 140))	('EGFR', 'Gene', (126, 130))	('EGFR', 'Gene', (38, 42))	('NSCLC', 'Disease', (90, 95))	('NSCLC', 'Disease', 'MESH:D002289', (90, 95))	('NSCLC', 'Phenotype', 'HP:0030358', (90, 95))	('EGFR', 'Gene', '1956', (126, 130))
100521	28170390	However, most approaches for identifying cancer mutations focus on either the entire-gene or single amino-acid level.	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('mutations', 'Var', (48, 57))	('cancer', 'Disease', (41, 47))
100526	28170390	Identifying driver mutations in cancer has been a major challenge in cancer research, with the ultimate goal of understanding the detailed molecular origins of cancer and providing genetically personalized treatments.	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('cancer', 'Disease', (160, 166))	('cancer', 'Disease', (32, 38))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('mutations', 'Var', (19, 28))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Disease', (69, 75))
100527	28170390	For decades, the cancer research community has known that mutations in certain genes:such as tumor suppressors like P53:can drive cancer.	('mutations', 'Var', (58, 67))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('P53', 'Gene', (116, 119))	('cancer', 'Disease', (130, 136))	('tumor', 'Disease', (93, 98))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('cancer', 'Disease', (17, 23))	('P53', 'Gene', '7157', (116, 119))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('drive', 'Reg', (124, 129))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
100528	28170390	In some cases it is also clear that mutations within cancer genes are localized in a single amino:such as the V600E mutation in BRAF.	('V600E', 'Mutation', 'rs113488022', (110, 115))	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('V600E', 'Var', (110, 115))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('BRAF', 'Gene', '673', (128, 132))	('BRAF', 'Gene', (128, 132))
100531	28170390	This is a PLOS Computational Biology Methods paper Somatic mutations are amongst the most frequent genomic aberrations associated with cancer.	('Somatic mutations', 'Var', (51, 68))	('cancer', 'Disease', (135, 141))	('cancer', 'Disease', 'MESH:D009369', (135, 141))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))
100533	28170390	To date, millions of distinct somatic mutations have been observed in human cancers through genome wide characterization projects such as The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC).	('cancers', 'Disease', 'MESH:D009369', (76, 83))	('Cancer', 'Disease', 'MESH:D009369', (187, 193))	('cancers', 'Phenotype', 'HP:0002664', (76, 83))	('cancers', 'Disease', (76, 83))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('human', 'Species', '9606', (70, 75))	('Cancer', 'Phenotype', 'HP:0002664', (142, 148))	('Cancer', 'Disease', (142, 148))	('mutations', 'Var', (38, 47))	('Cancer Genome Atlas', 'Disease', (142, 161))	('Cancer', 'Disease', 'MESH:D009369', (142, 148))	('Cancer', 'Phenotype', 'HP:0002664', (187, 193))	('Cancer', 'Disease', (187, 193))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (142, 161))
100534	28170390	Computational methods are particularly well suited for the assessment of somatic mutations at this scale in order to identify those with cancer-associated functional consequences.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('cancer', 'Disease', (137, 143))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('mutations', 'Var', (81, 90))
100536	28170390	In addition, methods including PolyPhen, SIFT, and CADD utilize prior knowledge such as conservation and machine learning based on disease associated variants to predict functional mutation impact.	('SIFT', 'Disease', (41, 45))	('SIFT', 'Disease', 'None', (41, 45))	('variants', 'Var', (150, 158))
100537	28170390	Yet other methods including OncodriveCLUST and CLUMPS, iPAC, and graphPAC take a parameterized, data-driven approach to predict cancer-associated mutations based on spatial clustering of linear sequence, three-dimensional protein structure, and graphical representations thereof.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('mutations', 'Var', (146, 155))	('cancer', 'Disease', (128, 134))
100538	28170390	Importantly, functional mutations that occur within the coding sequence and are known to be associated with cancer do not occur at random positions.	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('mutations', 'Var', (24, 33))	('associated', 'Reg', (92, 102))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
100539	28170390	On the contrary, hotspots or clusters are frequently observed as recurrent missense mutations across a significant fraction of cancer samples.	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('missense mutations', 'Var', (75, 93))	('cancer', 'Disease', (127, 133))
100540	28170390	These sets of mutations are typically attributed to alterations in function at specific sites of the protein that give rise to a variety of cancer phenotypes.	('alterations', 'Reg', (52, 63))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('give rise to', 'Reg', (114, 126))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('mutations', 'Var', (14, 23))	('function', 'MPA', (67, 75))
100541	28170390	Oftentimes, these mutation clusters can be readily interpreted in the context of their protein structure and function; for example, mutations in the GTP binding pocket of KRAS that modulates intrinsic GTPase activity, lead to constitutive activation of KRAS and persistent stimulation of downstream signaling pathways.	('stimulation', 'PosReg', (273, 284))	('downstream signaling pathways', 'Pathway', (288, 317))	('mutations', 'Var', (132, 141))	('GTP', 'Chemical', 'MESH:D006160', (149, 152))	('GTP', 'Chemical', 'MESH:D006160', (201, 204))	('activation', 'PosReg', (239, 249))	('KRAS', 'Gene', (253, 257))	('KRAS', 'Gene', (171, 175))	('KRAS', 'Gene', '3845', (253, 257))	('KRAS', 'Gene', '3845', (171, 175))
100542	28170390	Such mutation clusters need not be located within structural protein domains; for example, N-terminal mutations of beta-catenin (CTNNB1) affect protein phosphorylation sites and thereby abrogate ubiquitin-mediated proteasomal degradation.	('protein phosphorylation sites', 'MPA', (144, 173))	('abrogate', 'NegReg', (186, 194))	('CTNNB1', 'Gene', (129, 135))	('beta-catenin', 'Gene', (115, 127))	('ubiquitin-mediated proteasomal degradation', 'MPA', (195, 237))	('mutations', 'Var', (102, 111))	('CTNNB1', 'Gene', '1499', (129, 135))	('beta-catenin', 'Gene', '1499', (115, 127))	('affect', 'Reg', (137, 143))
100543	28170390	These mutations then result in beta-catenin accumulating in the nucleus and continuously driving transcription of its target genes.	('beta-catenin', 'Gene', (31, 43))	('beta-catenin', 'Gene', '1499', (31, 43))	('transcription', 'MPA', (97, 110))	('accumulating', 'PosReg', (44, 56))	('driving', 'Reg', (89, 96))	('result in', 'Reg', (21, 30))	('mutations', 'Var', (6, 15))
100544	28170390	While these examples highlight readily identifiable and interpretable focal mutation clusters that lead to cancer-associated effects on protein function, such mutation consequences need not be restricted to dense clusters at just a few amino acid positions in the protein sequence.	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('protein function', 'MPA', (136, 152))	('effects', 'MPA', (125, 132))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('mutation', 'Var', (76, 84))	('cancer', 'Disease', (107, 113))
100545	28170390	For example, tumor protein p53 (TP53) contains a combination of mutations that are recurrently located at specific amino acids that bind directly to DNA (e.g., R248Q, R273C) as well as more broadly distributed sets of mutations throughout the core DNA binding domain of TP53 that disrupt the folding and stability of the protein.	('tumor', 'Disease', (13, 18))	('R273C', 'Mutation', 'rs121913343', (167, 172))	('p53', 'Gene', '7157', (27, 30))	('R248Q', 'Mutation', 'rs11540652', (160, 165))	('folding', 'MPA', (292, 299))	('TP53', 'Gene', '7157', (32, 36))	('TP53', 'Gene', '7157', (270, 274))	('R273C', 'Var', (167, 172))	('TP53', 'Gene', (270, 274))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('TP53', 'Gene', (32, 36))	('stability of the', 'MPA', (304, 320))	('disrupt', 'NegReg', (280, 287))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('R248Q', 'Var', (160, 165))	('p53', 'Gene', (27, 30))
100546	28170390	Additionally, sets of mutations do not only affect individual regions or domains of proteins; rather, functional mutations are observed in distinct clusters within different regions or domains of individual proteins (e.g., PIK3CA), indicating the possibility for differential functional consequences of such mutation clusters.	('PIK3CA', 'Gene', (223, 229))	('mutations', 'Var', (113, 122))	('PIK3CA', 'Gene', '5290', (223, 229))	('mutations', 'Var', (22, 31))
100553	28170390	A cluster is assigned as positive (1) to a tumor sample if that sample contains at least one non-synonymous mutation within the cluster and negative (0) otherwise.	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Disease', (43, 48))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('non-synonymous mutation', 'Var', (93, 116))
100558	28170390	We assigned clusters to specific tumor samples if there was at least one non-synonymous mutation in a sample at an amino acid position within a cluster.	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('non-synonymous mutation', 'Var', (73, 96))	('tumor', 'Disease', (33, 38))
100562	28170390	On the high end, lung squamous cell carcinoma and uterine carcinosarcoma have over 80% of their non-synonymous mutations in clusters.	('carcinosarcoma', 'Disease', 'MESH:D002296', (58, 72))	('non-synonymous mutations', 'Var', (96, 120))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (17, 45))	('lung squamous cell carcinoma', 'Disease', (17, 45))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (50, 72))	('carcinosarcoma', 'Disease', (58, 72))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (22, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (36, 45))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (17, 45))
100563	28170390	On the low end, acute myeloid leukemia and thyroid carcinoma have 23% and 34% of their non-synonymous mutations in clusters, respectively.	('myeloid leukemia', 'Phenotype', 'HP:0012324', (22, 38))	('leukemia', 'Phenotype', 'HP:0001909', (30, 38))	('acute myeloid leukemia', 'Disease', (16, 38))	('non-synonymous mutations', 'Var', (87, 111))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (43, 60))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (16, 38))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (43, 60))	('thyroid carcinoma', 'Disease', (43, 60))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (16, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (51, 60))
100568	28170390	We found 426 mutational clusters enriched for a specific tumor type at a false discovery rate of 1% and 996 at a false discovery rate of 10%.	('tumor', 'Disease', (57, 62))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('mutational', 'Var', (13, 23))
100570	28170390	The statistical associations were carried out on binary vectors that indicate whether a sample in a specific tumor type had a mutation in a specific cluster (1) or not (0).	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('mutation', 'Var', (126, 134))	('tumor', 'Disease', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))
100571	28170390	This methodology was chosen because, in general, gene expression from a particular pathway is not universally upregulated or downregulated due to cancer mutations.	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('mutations', 'Var', (153, 162))	('upregulated', 'PosReg', (110, 121))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('downregulated', 'NegReg', (125, 138))
100579	28170390	Note that associations were not computed if fewer than 5 samples in a given gene and tumor type had non-synonymous mutations outside of all clusters.	('non-synonymous mutations', 'Var', (100, 124))	('tumor', 'Disease', (85, 90))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))
100581	28170390	Significant results for PFAM domains can be found in and T6C in S1 Tables (global) and T7C in S1 Tables (pathway).	('T6C', 'Var', (57, 60))	('PFAM', 'Protein', (24, 28))	('T7C', 'Var', (87, 90))	('T6C', 'Mutation', 'rs754763517', (57, 60))	('T7C', 'Mutation', 'rs768725324', (87, 90))
100585	28170390	Here, we highlight several well-known and novel clusters in the cancer literature recovered by M2C: Two of PIK3CA's eleven mutation clusters are associated with global changes of gene expression in breast invasive carcinoma: amino acid positions 539-547 and 1043-1049.	('carcinoma', 'Phenotype', 'HP:0030731', (214, 223))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('associated', 'Reg', (145, 155))	('amino acid positions 539-547', 'Var', (225, 253))	('gene expression', 'MPA', (179, 194))	('1043-1049', 'Var', (258, 267))	('PIK3CA', 'Gene', (107, 113))	('changes', 'Reg', (168, 175))	('breast invasive carcinoma', 'Disease', 'MESH:D018270', (198, 223))	('breast invasive carcinoma', 'Disease', (198, 223))	('PIK3CA', 'Gene', '5290', (107, 113))	('breast invasive carcinoma', 'Phenotype', 'HP:0003002', (198, 223))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
100586	28170390	We note that the first clusters are significantly enriched for mutations in the following tumor types: breast invasive carcinoma, head and neck squamous cell carcinoma, uterine corpus endometrial carcinoma, cervical squamous cell carcinoma and endocervical adenocarcinoma (FDR < 1%).	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (139, 167))	('breast invasive carcinoma', 'Disease', (103, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (230, 239))	('carcinoma', 'Phenotype', 'HP:0030731', (262, 271))	('mutations', 'Var', (63, 72))	('tumor', 'Disease', (90, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (158, 167))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('breast invasive carcinoma', 'Phenotype', 'HP:0003002', (103, 128))	('squamous cell carcinoma and endocervical adenocarcinoma', 'Disease', 'MESH:D002294', (216, 271))	('carcinoma', 'Phenotype', 'HP:0030731', (196, 205))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (184, 205))	('breast invasive carcinoma', 'Disease', 'MESH:D018270', (103, 128))	('corpus endometrial carcinoma', 'Disease', (177, 205))	('corpus endometrial carcinoma', 'Disease', 'MESH:D016889', (177, 205))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('neck squamous cell carcinoma', 'Disease', (139, 167))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (144, 167))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (216, 239))
100587	28170390	The second cluster is significantly enriched for mutations in breast invasive carcinoma and uterine corpus endometrial carcinoma (FDR < 1%).	('corpus endometrial carcinoma', 'Disease', (100, 128))	('corpus endometrial carcinoma', 'Disease', 'MESH:D016889', (100, 128))	('breast invasive carcinoma', 'Disease', 'MESH:D018270', (62, 87))	('mutations', 'Var', (49, 58))	('breast invasive carcinoma', 'Phenotype', 'HP:0003002', (62, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('breast invasive carcinoma', 'Disease', (62, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (107, 128))
100592	28170390	The cluster is also enriched for mutations in lung adenocarcinoma (FDR < 5%), as well as in uterine corpus endometrial carcinoma (FDR < 1%).	('corpus endometrial carcinoma', 'Disease', (100, 128))	('corpus endometrial carcinoma', 'Disease', 'MESH:D016889', (100, 128))	('lung adenocarcinoma', 'Disease', (46, 65))	('mutations', 'Var', (33, 42))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (46, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (107, 128))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (46, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (56, 65))
100597	28170390	Different GATA3 mutations have been associated with Luminal A and B subtypes of breast cancer and changes in survival prognoses.	('GATA3', 'Gene', '2625', (10, 15))	('changes', 'Reg', (98, 105))	('associated', 'Reg', (36, 46))	('GATA3', 'Gene', (10, 15))	('mutations', 'Var', (16, 25))	('breast cancer', 'Disease', 'MESH:D001943', (80, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('breast cancer', 'Disease', (80, 93))	('breast cancer', 'Phenotype', 'HP:0003002', (80, 93))	('survival prognoses', 'CPA', (109, 127))	('Luminal A', 'Disease', (52, 61))
100598	28170390	We note that all three of these clusters are enriched for mutations in breast invasive carcinoma (FDR<1%).	('mutations', 'Var', (58, 67))	('breast invasive carcinoma', 'Disease', 'MESH:D018270', (71, 96))	('breast invasive carcinoma', 'Phenotype', 'HP:0003002', (71, 96))	('breast invasive carcinoma', 'Disease', (71, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))
100605	28170390	Previously single nucleotide mutations in ZBTB20 have been associated with gastric cancer.	('ZBTB20', 'Gene', (42, 48))	('gastric cancer', 'Disease', (75, 89))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('gastric cancer', 'Disease', 'MESH:D013274', (75, 89))	('associated', 'Reg', (59, 69))	('single nucleotide mutations', 'Var', (11, 38))	('gastric cancer', 'Phenotype', 'HP:0012126', (75, 89))	('ZBTB20', 'Gene', '26137', (42, 48))
100607	28170390	We note that this cluster is enriched in gastric cancer along with two other clusters in ZBTB20, 190-248 and 345-504 (FDR < 1%).	('ZBTB20', 'Gene', (89, 95))	('gastric cancer', 'Phenotype', 'HP:0012126', (41, 55))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('345-504', 'Var', (109, 116))	('ZBTB20', 'Gene', '26137', (89, 95))	('190-248', 'Var', (97, 104))	('gastric cancer', 'Disease', (41, 55))	('gastric cancer', 'Disease', 'MESH:D013274', (41, 55))
100608	28170390	The 190-248 cluster is also enriched for mutations in low grade glioma (FDR < 10%).	('mutations', 'Var', (41, 50))	('glioma', 'Phenotype', 'HP:0009733', (64, 70))	('glioma', 'Disease', (64, 70))	('glioma', 'Disease', 'MESH:D005910', (64, 70))
100612	28170390	This cluster is enriched for mutations in uterine corpus endometrial carcinoma and uterine carcinosarcoma (FDR < 1%).	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (57, 78))	('carcinosarcoma', 'Disease', (91, 105))	('mutations', 'Var', (29, 38))	('corpus endometrial carcinoma', 'Disease', 'MESH:D016889', (50, 78))	('corpus endometrial carcinoma', 'Disease', (50, 78))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (83, 105))	('carcinosarcoma', 'Disease', 'MESH:D002296', (91, 105))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))
100613	28170390	Additionally, the 237-275 in PPP2R1A is enriched for mutations in lung squamous cell carcinoma and gastric cancer (FDR<10%).	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (66, 94))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (71, 94))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (66, 94))	('lung squamous cell carcinoma', 'Disease', (66, 94))	('gastric cancer', 'Disease', (99, 113))	('mutations', 'Var', (53, 62))	('237-275', 'Var', (18, 25))	('gastric cancer', 'Disease', 'MESH:D013274', (99, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('PPP2R1A', 'Gene', '5518', (29, 36))	('PPP2R1A', 'Gene', (29, 36))	('gastric cancer', 'Phenotype', 'HP:0012126', (99, 113))
100614	28170390	The 391-490 cluster is enriched for mutations in uterine corpus endometrial carcinoma (FDR <1%).	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (64, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('mutations', 'Var', (36, 45))	('corpus endometrial carcinoma', 'Disease', (57, 85))	('corpus endometrial carcinoma', 'Disease', 'MESH:D016889', (57, 85))
100622	28170390	Similarly, in thyroid carcinoma the 600-601 mutation cluster has 235 non-synonymous mutations and is more significantly associated to global changes in gene expression (P<10-82) than any-non-synonymous mutation which has 237 total non-synonymous mutations (P<10-80).	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (14, 31))	('associated', 'Reg', (120, 130))	('thyroid carcinoma', 'Disease', (14, 31))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('600-601 mutation', 'Var', (36, 52))	('changes', 'Reg', (141, 148))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (14, 31))	('non-synonymous mutations', 'MPA', (69, 93))	('gene expression', 'MPA', (152, 167))
100630	28170390	Mutations in this cluster are likely to affect this binding and thereby the regulation of Beta-catenin.	('regulation', 'MPA', (76, 86))	('Beta-catenin', 'Gene', '1499', (90, 102))	('binding', 'Interaction', (52, 59))	('Mutations', 'Var', (0, 9))	('affect', 'Reg', (40, 46))	('Beta-catenin', 'Gene', (90, 102))
100633	28170390	One example is the 248-254 cluster in FGFR3 in bladder urothelial carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (66, 75))	('FGFR3', 'Gene', '2261', (38, 43))	('248-254 cluster', 'Var', (19, 34))	('FGFR3', 'Gene', (38, 43))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (47, 75))	('bladder urothelial carcinoma', 'Disease', (47, 75))
100634	28170390	Point mutations in this region have been previously implicated in low grade glioma tumors.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('glioma tumors', 'Disease', (76, 89))	('glioma tumors', 'Disease', 'MESH:D005910', (76, 89))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('glioma', 'Phenotype', 'HP:0009733', (76, 82))	('Point mutations', 'Var', (0, 15))	('implicated', 'Reg', (52, 62))
100637	28170390	This cluster is also enriched for mutations in both bladder cancer (FDR < 1%) and lung squamous cell carcinoma (FDR < 10%).	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (87, 110))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (82, 110))	('lung squamous cell carcinoma', 'Disease', (82, 110))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('bladder cancer', 'Phenotype', 'HP:0009725', (52, 66))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (82, 110))	('bladder cancer', 'Disease', 'MESH:D001749', (52, 66))	('bladder cancer', 'Disease', (52, 66))	('mutations', 'Var', (34, 43))
100639	28170390	We note that this cluster is enriched for mutations in gastric cancer (FDR < 1%) and the 456-522 cluster is enriched in lung adenocarcinoma (FDR < 5%).	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (120, 139))	('gastric cancer', 'Disease', (55, 69))	('gastric cancer', 'Disease', 'MESH:D013274', (55, 69))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (120, 139))	('gastric cancer', 'Phenotype', 'HP:0012126', (55, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('mutations', 'Var', (42, 51))	('lung adenocarcinoma', 'Disease', (120, 139))
100644	28170390	FUBP1 has two clusters each with predominantly nonsense mutations with differential pathway association in lower grade glioma.	('glioma', 'Disease', 'MESH:D005910', (119, 125))	('glioma', 'Phenotype', 'HP:0009733', (119, 125))	('FUBP1', 'Gene', (0, 5))	('glioma', 'Disease', (119, 125))	('nonsense mutations', 'Var', (47, 65))	('FUBP1', 'Gene', '8880', (0, 5))
100649	28170390	Specifically, there are 10 drug associations with the BRAF mutation cluster 600-601, 6 with NRAS mutation cluster at amino acid 61 and 4 with KRAS mutation cluster 12-13.	('KRAS', 'Gene', (142, 146))	('BRAF', 'Gene', (54, 58))	('NRAS', 'Gene', (92, 96))	('BRAF', 'Gene', '673', (54, 58))	('KRAS', 'Gene', '3845', (142, 146))	('NRAS', 'Gene', '4893', (92, 96))	('mutation cluster 600-601', 'Var', (59, 83))
100652	28170390	First, we observed that cell lines with mutations in the cluster 116-146 in PTEN strongly responded to mTOR inhibitor Temsirolimus, whereas mutations across the entire gene showed only a small indication of drug sensitivity (Fig 6A).	('mTOR', 'Gene', (103, 107))	('drug sensitivity', 'Phenotype', 'HP:0020174', (207, 223))	('PTEN', 'Gene', (76, 80))	('mutations in', 'Var', (40, 52))	('PTEN', 'Gene', '5728', (76, 80))	('mTOR', 'Gene', '2475', (103, 107))
100653	28170390	Second, we observed that cell lines with mutations in the cluster 1043-1049 in PIK3CA showed a stronger response to a PI3K beta inhibitor than other mutation clusters or the any non-synonymous mutation feature (Fig 6B).	('stronger', 'PosReg', (95, 103))	('PI3K beta', 'Gene', (118, 127))	('PI3K beta', 'Gene', '5291', (118, 127))	('PIK3CA', 'Gene', (79, 85))	('mutations in', 'Var', (41, 53))	('PIK3CA', 'Gene', '5290', (79, 85))
100654	28170390	This corresponds with our observation that in breast cancer this same mutation cluster is very strongly associated with global changes in gene expression compared to other clusters in PIK3CA.	('PIK3CA', 'Gene', '5290', (184, 190))	('changes', 'Reg', (127, 134))	('associated', 'Reg', (104, 114))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('breast cancer', 'Disease', 'MESH:D001943', (46, 59))	('PIK3CA', 'Gene', (184, 190))	('breast cancer', 'Phenotype', 'HP:0003002', (46, 59))	('mutation', 'Var', (70, 78))	('gene expression', 'MPA', (138, 153))	('breast cancer', 'Disease', (46, 59))
100655	28170390	These results provide additional support for the idea that it is important to consider mutations in a specific region of a cancer gene, and not merely a single amino acid alteration or a mutation anywhere in the entire gene.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('cancer', 'Disease', (123, 129))	('mutations', 'Var', (87, 96))	('cancer', 'Disease', 'MESH:D009369', (123, 129))
100658	28170390	We show that many of the clusters found by M2C are representative of functional regions of proteins where mutations have a larger effect in terms of influencing the hallmarks of cancer.	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('M2C', 'Gene', (43, 46))	('influencing', 'Reg', (149, 160))	('cancer', 'Disease', (178, 184))	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('mutations', 'Var', (106, 115))
100661	28170390	Furthermore, we have shown that certain genes contain multiple clusters that may have different functional consequences, suggesting that different mutations in these genes may play different roles in cancer onset and progression based upon the location of the mutation.	('mutations', 'Var', (147, 156))	('play', 'Reg', (176, 180))	('roles', 'Reg', (191, 196))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('cancer', 'Disease', 'MESH:D009369', (200, 206))	('cancer', 'Disease', (200, 206))
100662	28170390	Finally, we investigated whether mutation clusters are associated with drug response data in cancer cell lines and found many mutation clusters which are associated with differential drug sensitivity.	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('drug sensitivity', 'Phenotype', 'HP:0020174', (183, 199))	('mutation', 'Var', (126, 134))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('associated', 'Reg', (154, 164))
100663	28170390	These genes were further filtered to ensure that there are in total at least 15 mutations in each gene across all 23 cancer types considered.	('cancer', 'Disease', (117, 123))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('mutations', 'Var', (80, 89))
100666	28170390	First, M2C converts TCGA mutation calls in amino acid space from all 23 cancers into multiple continuous probability density functions (Fig 7A and section C step 1 in S1 Text).	('M2C', 'Var', (7, 10))	('cancers', 'Disease', (72, 79))	('mutation', 'Var', (25, 33))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('TCGA', 'Gene', (20, 24))	('cancers', 'Disease', 'MESH:D009369', (72, 79))
100667	28170390	The score, Sc, of cluster c, is given by the log of the ratio of the emission probability of the mutations in the cluster with the emission probability of the same mutations based upon the null hypothesis of a uniform mutation distribution across the cluster,  M is the set of all N pan-cancer mutations in cluster c. G(x; muc, sigmac) is the normalized Gaussian distribution with mean muc and standard deviation sigmac representing the unweighted component of the mixture model corresponding to cluster c. Finally U = L-1 is the emission probability of single mutation by a uniform distribution over the gene containing the clusters of length L (in amino acids).	('cancer', 'Disease', (287, 293))	('cancer', 'Disease', 'MESH:D009369', (287, 293))	('L-1', 'Gene', '3897', (519, 522))	('L-1', 'Gene', (519, 522))	('cancer', 'Phenotype', 'HP:0002664', (287, 293))	('mutations', 'Var', (294, 303))
100668	28170390	To determine whether specific cancer types are enriched for specific mutation clusters, we used Fisher's exact test to calculate an enrichment P-value.	('mutation', 'Var', (69, 77))	('cancer', 'Disease', (30, 36))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
100671	28170390	A binary feature matrix represents which tumor samples contain mutations in which clusters.	('mutations', 'Var', (63, 72))	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('tumor', 'Disease', (41, 46))
100672	28170390	A tumor sample is said to be positive (1) for a given cluster if it contains a non-synonymous or nonsense mutation within the cluster (see boxes B and C of Fig 7 for an illustration).	('aid', 'Gene', (19, 22))	('tumor', 'Disease', 'MESH:D009369', (2, 7))	('tumor', 'Phenotype', 'HP:0002664', (2, 7))	('aid', 'Gene', '57379', (19, 22))	('tumor', 'Disease', (2, 7))	('nonsense mutation', 'Var', (97, 114))	('non-synonymous', 'Var', (79, 93))
100694	30239818	Desmoglein 3 (DSG3) is highly expressed in lung squamous cell carcinoma, while it is well-known that anti-DSG3 antibodies cause pemphigus vulgaris, an autoimmune disease.	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (43, 71))	('lung squamous cell carcinoma', 'Disease', (43, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (62, 71))	('cause', 'Reg', (122, 127))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (43, 71))	('autoimmune disease', 'Disease', (151, 169))	('DSG3', 'Gene', (14, 18))	('autoimmune disease', 'Phenotype', 'HP:0002960', (151, 169))	('anti-DSG3 antibodies', 'Var', (101, 121))	('antibodies', 'Var', (111, 121))	('Desmoglein 3', 'Gene', '13512', (0, 12))	('pemphigus vulgaris', 'Disease', (128, 146))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (48, 71))	('autoimmune disease', 'Disease', 'MESH:D001327', (151, 169))	('Desmoglein 3', 'Gene', (0, 12))
100696	30239818	Pathogenic anti-DSG3 antibodies induce skin blisters by inhibiting the cell-cell interaction in a Ca2+-dependent manner.	('blister', 'Phenotype', 'HP:0008066;HP:0200037', (44, 51))	('blisters', 'Phenotype', 'HP:0008066;HP:0200037', (44, 52))	('anti-DSG3 antibodies', 'Var', (11, 31))	('cell-cell interaction', 'CPA', (71, 92))	('antibodies', 'Var', (21, 31))	('inhibiting', 'NegReg', (56, 66))	('skin blisters', 'Disease', (39, 52))	('induce', 'Reg', (32, 38))	('Ca2+', 'Chemical', 'MESH:D000069285', (98, 102))	('skin blisters', 'Phenotype', 'HP:0008066', (39, 52))
100697	30239818	We screened anti-DSG3 antibodies that bind DGS3 independent of Ca2+ and have high antibody-dependent cell cytotoxicity (ADCC) activity against DSG3-expressing cells.	('antibodies', 'Var', (22, 32))	('Ca2+', 'Chemical', 'MESH:D000069285', (63, 67))	('cytotoxicity', 'Disease', (106, 118))	('anti-DSG3', 'Gene', (12, 21))	('cytotoxicity', 'Disease', 'MESH:D064420', (106, 118))
100707	30239818	Here we show that we have obtained an anti-mouse DSG3 monoclonal antibody (mAb) with therapeutic potential and have evaluated whether its pathogenic activity had been successfully separated from its anticancer activity.	('anti-mouse', 'Var', (38, 48))	('DSG3', 'Gene', (49, 53))	('cancer', 'Disease', (203, 209))	('cancer', 'Disease', 'MESH:D009369', (203, 209))	('mouse', 'Species', '10090', (43, 48))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))
100764	30239818	Anti-human DSG3 mAbs DF029, DF129, DF131, DF132, DF138, DF187 and DF269 were biotinylated.	('biotin', 'Chemical', 'MESH:D001710', (77, 83))	('DF269', 'Chemical', '-', (66, 71))	('DF187', 'Var', (56, 61))	('DF029', 'Chemical', '-', (21, 26))	('DF132', 'Chemical', '-', (42, 47))	('DF187', 'Chemical', '-', (56, 61))	('DF138', 'Chemical', '-', (49, 54))	('DF131', 'Chemical', '-', (35, 40))	('DF138', 'Var', (49, 54))	('DF269', 'Var', (66, 71))	('human', 'Species', '9606', (5, 10))	('DF132', 'Var', (42, 47))	('DF129', 'Chemical', '-', (28, 33))	('DF029', 'Var', (21, 26))	('DF129', 'Var', (28, 33))
100775	30239818	Defucosylated antibody 18-1m or DF366m was expressed in GFT (-/-) CHO cells with disrupted GFT alleles of GFT gene and designated as df-18-1m or df-DF366m.	('df-DF366', 'Chemical', '-', (145, 153))	('DF366', 'Chemical', '-', (148, 153))	('DF366m', 'Var', (32, 38))	('CHO', 'CellLine', 'CVCL:0213', (66, 69))	('GFT', 'Gene', (106, 109))	('DF366', 'Chemical', '-', (32, 37))
100791	30239818	Each group consisted of 10 mice, and 18-1m, df-18-1m (10 mg/kg) or vehicle (PBS) was administered intravenously on days 1, 8 and 15.	('df-18-1m', 'Var', (44, 52))	('mice', 'Species', '10090', (27, 31))	('PBS', 'Disease', (76, 79))	('PBS', 'Disease', 'MESH:D011535', (76, 79))
100796	30239818	Four SCID mice per group (SCC-15) were dosed intraperitoneally with 10 mg/kg of mAb (df-DF366m) or vehicle (PBS) once a week for 5 weeks.	('SCID', 'Disease', 'MESH:D053632', (5, 9))	('PBS', 'Disease', (108, 111))	('PBS', 'Disease', 'MESH:D011535', (108, 111))	('SCID', 'Disease', (5, 9))	('mice', 'Species', '10090', (10, 14))	('df-DF366', 'Chemical', '-', (85, 93))	('SCC-15', 'Gene', (26, 32))	('SCC', 'Phenotype', 'HP:0002860', (26, 29))	('SCC-15', 'Gene', '100034867', (26, 32))	('df-DF366m', 'Var', (85, 94))
100815	30239818	18-1 and AK23 were genetically engineered into mouse IgG2a-type chimeric antibodies 18-1m and AK23m, and were subjected to the assay.	('IgG2a', 'Gene', (53, 58))	('AK23m', 'Var', (94, 99))	('mouse', 'Species', '10090', (47, 52))	('IgG2a', 'Gene', '668478', (53, 58))
100818	30239818	After administering 18-1m or df-18-1m once a week for 3 weeks to LC12-inoculated mice, the body weight of antibody-administered mice was slightly lower compared with that of vehicle-administered mice at the end of the study.	('mice', 'Species', '10090', (195, 199))	('mice', 'Species', '10090', (81, 85))	('df-18-1m', 'Var', (29, 37))	('mice', 'Species', '10090', (128, 132))	('lower', 'NegReg', (146, 151))	('body weight', 'CPA', (91, 102))
100821	30239818	Suppression of tumour growth was marked in the df-18-1 group compared with the 18-1m group.	('tumour growth', 'Disease', (15, 28))	('df-18-1', 'Var', (47, 54))	('Suppression', 'NegReg', (0, 11))	('tumour', 'Phenotype', 'HP:0002664', (15, 21))	('tumour growth', 'Disease', 'MESH:D006130', (15, 28))
100823	30239818	Histopathologically, single-cell necrosis of tumour cells and inflammatory cell infiltration were observed in palpable tumours of the 18-1m group.	('tumour', 'Phenotype', 'HP:0002664', (119, 125))	('necrosis of tumour', 'Disease', 'MESH:D009336', (33, 51))	('tumours', 'Phenotype', 'HP:0002664', (119, 126))	('inflammatory cell infiltration', 'CPA', (62, 92))	('tumours', 'Disease', 'MESH:D009369', (119, 126))	('tumour', 'Phenotype', 'HP:0002664', (45, 51))	('tumours', 'Disease', (119, 126))	('18-1m', 'Var', (134, 139))	('necrosis of tumour', 'Disease', (33, 51))
100824	30239818	Similar changes were observed in the palpable tumours of the df-18-1m group (Fig.	('tumours', 'Disease', 'MESH:D009369', (46, 53))	('tumours', 'Disease', (46, 53))	('df-18-1m', 'Var', (61, 69))	('tumour', 'Phenotype', 'HP:0002664', (46, 52))	('tumours', 'Phenotype', 'HP:0002664', (46, 53))
100833	30239818	As expected, the binding regions of the two clones with the strongest ADCC, DF366 and DF378, were located between aa 491 and 615.	('DF366', 'Var', (76, 81))	('DF378', 'Var', (86, 91))	('DF378', 'Chemical', '-', (86, 91))	('DF366', 'Chemical', '-', (76, 81))
100834	30239818	From these results, DF366 was selected as the clone with strongest ADCC activity and converted to a mouse IgG2a subclass (designated as DF366m) to evaluate cell-cell dissociation activity in human keratinocyte sheets.	('IgG2a', 'Gene', (106, 111))	('DF366', 'Chemical', '-', (20, 25))	('ADCC activity', 'MPA', (67, 80))	('strongest', 'PosReg', (57, 66))	('mouse', 'Species', '10090', (100, 105))	('IgG2a', 'Gene', '668478', (106, 111))	('human', 'Species', '9606', (191, 196))	('DF366', 'Var', (20, 25))	('DF366', 'Chemical', '-', (136, 141))
100836	30239818	ADCC activity of DF366m was compared with a defucosylated antibody (df-DF366m) with mFcgammaRIIIa-NK92 as the effector cells.	('DF366', 'Chemical', '-', (17, 22))	('df-DF366', 'Chemical', '-', (68, 76))	('activity', 'MPA', (5, 13))	('FcgammaRIIIa', 'Gene', '2214', (85, 97))	('DF366m', 'Var', (17, 23))	('DF366', 'Chemical', '-', (71, 76))	('FcgammaRIIIa', 'Gene', (85, 97))
100837	30239818	The anti-tumour effect of ADCC-enhanced df-DF366m was evaluated in an in vitro ADCC assay with human SCC cell lines HARA, A431 or SCC-15.	('SCC', 'Gene', (130, 133))	('tumour', 'Disease', (9, 15))	('human', 'Species', '9606', (95, 100))	('SCC', 'Phenotype', 'HP:0002860', (130, 133))	('df-DF366', 'Chemical', '-', (40, 48))	('SCC', 'Gene', '6317', (130, 133))	('SCC', 'Gene', '6317', (101, 104))	('SCC-15', 'Gene', '100034867', (130, 136))	('SCC', 'Gene', (101, 104))	('SCC', 'Phenotype', 'HP:0002860', (101, 104))	('SCC-15', 'Gene', (130, 136))	('tumour', 'Phenotype', 'HP:0002664', (9, 15))	('tumour', 'Disease', 'MESH:D009369', (9, 15))	('df-DF366m', 'Var', (40, 49))	('A431', 'CellLine', 'CVCL:0037', (122, 126))
100838	30239818	The results showed that both DF366 and df-DF366m have ADCC activity against human SCC cell lines (Fig.	('SCC', 'Phenotype', 'HP:0002860', (82, 85))	('SCC', 'Gene', '6317', (82, 85))	('ADCC activity', 'MPA', (54, 67))	('DF366', 'Chemical', '-', (42, 47))	('df-DF366', 'Chemical', '-', (39, 47))	('human', 'Species', '9606', (76, 81))	('DF366', 'Var', (29, 34))	('DF366', 'Chemical', '-', (29, 34))	('SCC', 'Gene', (82, 85))	('df-DF366m', 'Var', (39, 48))
100839	30239818	df-DF366m showed strong ADCC activity even at concentrations that were several score times lower than DF366m.	('ADCC', 'Enzyme', (24, 28))	('df-DF366m', 'Var', (0, 9))	('DF366', 'Chemical', '-', (3, 8))	('activity', 'MPA', (29, 37))	('df-DF366', 'Chemical', '-', (0, 8))	('DF366', 'Chemical', '-', (102, 107))
100840	30239818	Next, the anti-tumour effect of df-DF366m was investigated in vivo using xenograft models of HARA, A431 and SCC-15.	('df-DF366', 'Chemical', '-', (32, 40))	('A431', 'CellLine', 'CVCL:0037', (99, 103))	('tumour', 'Disease', 'MESH:D009369', (15, 21))	('tumour', 'Disease', (15, 21))	('SCC-15', 'Gene', (108, 114))	('SCC', 'Phenotype', 'HP:0002860', (108, 111))	('SCC-15', 'Gene', '100034867', (108, 114))	('df-DF366m', 'Var', (32, 41))	('tumour', 'Phenotype', 'HP:0002664', (15, 21))
100841	30239818	In all models, efficacy of df-DF366m was significantly enhanced (Fig.	('enhanced', 'PosReg', (55, 63))	('df-DF366m', 'Var', (27, 36))	('df-DF366', 'Chemical', '-', (27, 35))
100845	30239818	On the other hand, DSG3 is also expressed in normal squamous epithelium, and autoantibodies against DSG3 cause PV, an autoimmune disease that includes severe skin lesions, such as blistering.	('blister', 'Phenotype', 'HP:0008066;HP:0200037', (180, 187))	('blistering', 'Phenotype', 'HP:0008066;HP:0200037', (180, 190))	('cause', 'Reg', (105, 110))	('autoimmune disease', 'Disease', 'MESH:D001327', (118, 136))	('autoimmune disease', 'Phenotype', 'HP:0002960', (118, 136))	('DSG3', 'Gene', (100, 104))	('autoantibodies', 'Var', (77, 91))	('skin lesions', 'Disease', 'MESH:D012871', (158, 170))	('skin lesions', 'Disease', (158, 170))	('blistering', 'Disease', (180, 190))	('autoimmune disease', 'Disease', (118, 136))
100846	30239818	have also shown that anti-DSG3 mAbs induced PV blisters in a passive transfer assay with neonatal mouse.	('induced', 'Reg', (36, 43))	('anti-DSG3 mAbs', 'Var', (21, 35))	('PV blisters', 'CPA', (44, 55))	('blister', 'Phenotype', 'HP:0008066;HP:0200037', (47, 54))	('blisters', 'Phenotype', 'HP:0008066;HP:0200037', (47, 55))	('PV blisters', 'Phenotype', 'HP:0008066', (44, 55))	('mouse', 'Species', '10090', (98, 103))
100851	30239818	It has been reported that in the pemphigus pathogenesis the neutralizing activity of patient pathogenic autoantibodies causes a disruption of the DSG3-DSG3 adhesive interaction, and that subsequently destroys the epithelial cell structure.	('patient', 'Species', '9606', (85, 92))	('disruption', 'Reg', (128, 138))	('adhesive interaction', 'Interaction', (156, 176))	('epithelial cell structure', 'CPA', (213, 238))	('destroys', 'NegReg', (200, 208))	('pemphigus', 'Disease', (33, 42))	('DSG3-DSG3', 'Gene', (146, 155))	('neutralizing activity', 'Var', (60, 81))
100858	30239818	We investigated the binding region of these clones by domain-swapped mutant analysis, and found that the mouse clone 18-1 binds to a region in the cadherin domains not EC1, while DF366 recognizes the membrane-proximal region (data not shown).	('DF366', 'Chemical', '-', (179, 184))	('binds', 'Interaction', (122, 127))	('mouse', 'Species', '10090', (105, 110))	('DF366', 'Var', (179, 184))
100868	30239818	From these results we judged that the defucosylated antibody improved anti-tumour activity, while the enhanced ADCC activity was not associated with enhanced toxicity.	('improved', 'PosReg', (61, 69))	('tumour', 'Disease', 'MESH:D009369', (75, 81))	('enhanced', 'PosReg', (102, 110))	('toxicity', 'Disease', 'MESH:D064420', (158, 166))	('tumour', 'Disease', (75, 81))	('toxicity', 'Disease', (158, 166))	('defucosylated', 'Var', (38, 51))	('activity', 'MPA', (116, 124))	('ADCC', 'CPA', (111, 115))	('tumour', 'Phenotype', 'HP:0002664', (75, 81))
100871	30239818	Defucosylated anti-human DSG3 antibody showed anti-tumour activity against three differential SCC cell lines in xenograft models.	('SCC', 'Gene', (94, 97))	('Defucosylated', 'Var', (0, 13))	('DSG3', 'Gene', (25, 29))	('tumour', 'Phenotype', 'HP:0002664', (51, 57))	('SCC', 'Phenotype', 'HP:0002860', (94, 97))	('SCC', 'Gene', '6317', (94, 97))	('tumour', 'Disease', 'MESH:D009369', (51, 57))	('human', 'Species', '9606', (19, 24))	('tumour', 'Disease', (51, 57))
100881	25432788	Overexpression of epidermal growth factor receptor (EGFR), an ErbB family member, is associated with poor prognosis in HNSCC.	('EGFR', 'Gene', '1956', (52, 56))	('EGFR', 'Gene', (52, 56))	('epidermal growth factor receptor', 'Gene', '1956', (18, 50))	('epidermal growth factor receptor', 'Gene', (18, 50))	('Overexpression', 'Var', (0, 14))	('HNSCC', 'Phenotype', 'HP:0012288', (119, 124))	('ErbB', 'Gene', (62, 66))	('HNSCC', 'Disease', (119, 124))	('ErbB', 'Gene', '1956', (62, 66))
100911	25432788	Epidermal growth factor receptor (EGFR; ErbB1) is expressed in over 90% of HNSCCs, with high levels of EGFR protein expression being associated with decreased survival, resistance to radiotherapy, locoregional treatment failure and high rates of distant metastases.	('EGFR', 'Gene', '1956', (103, 107))	('metastases', 'Disease', 'MESH:D009362', (254, 264))	('EGFR', 'Gene', (34, 38))	('ErbB1', 'Gene', '1956', (40, 45))	('EGFR', 'Gene', (103, 107))	('Epidermal growth factor receptor', 'Gene', (0, 32))	('survival', 'CPA', (159, 167))	('locoregional treatment failure', 'CPA', (197, 227))	('HNSCC', 'Phenotype', 'HP:0012288', (75, 80))	('ErbB1', 'Gene', (40, 45))	('metastases', 'Disease', (254, 264))	('decreased', 'NegReg', (149, 158))	('resistance to radiotherapy', 'CPA', (169, 195))	('Epidermal growth factor receptor', 'Gene', '1956', (0, 32))	('high levels', 'Var', (88, 99))	('EGFR', 'Gene', '1956', (34, 38))
100912	25432788	A 2011 study showed that patients with HNSCC and high EGFR protein expression display inferior 5-year overall survival rates, compared with patients with HNSCC and low EGFR protein expression (P = 0.029).	('EGFR', 'Gene', '1956', (168, 172))	('EGFR', 'Gene', (168, 172))	('HNSCC', 'Disease', (39, 44))	('EGFR', 'Gene', '1956', (54, 58))	('patients', 'Species', '9606', (25, 33))	('overall survival rates', 'CPA', (102, 124))	('high', 'Var', (49, 53))	('patients', 'Species', '9606', (140, 148))	('HNSCC', 'Phenotype', 'HP:0012288', (39, 44))	('inferior', 'NegReg', (86, 94))	('EGFR', 'Gene', (54, 58))	('HNSCC', 'Phenotype', 'HP:0012288', (154, 159))
100930	25432788	Afatinib is approved in the major ICH (International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use) regions of the USA, EU and Japan for the treatment of patients with non-small cell lung cancer harbouring distinct EGFR activating mutations.	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (226, 252))	('ICH', 'Disease', (34, 37))	('mutations', 'Var', (289, 298))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (226, 252))	('activating', 'PosReg', (278, 288))	('lung cancer', 'Phenotype', 'HP:0100526', (241, 252))	('Human', 'Species', '9606', (147, 152))	('patients', 'Species', '9606', (212, 220))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (230, 252))	('ICH', 'Disease', 'MESH:D002543', (34, 37))	('non-small cell lung cancer', 'Disease', (226, 252))	('EGFR', 'Gene', '1956', (273, 277))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))	('Afatinib', 'Chemical', 'MESH:D000077716', (0, 8))	('EGFR', 'Gene', (273, 277))
100932	25432788	Approval was based on findings from the pivotal phase III LUX-Lung 3 study, which demonstrated a median progression-free survival of 11.1 months in patients treated with afatinib versus 6.9 months in patients treated with chemotherapy (P < 0.001) in the first-line EGFR mutation-positive setting.	('patients', 'Species', '9606', (148, 156))	('patients', 'Species', '9606', (200, 208))	('afatinib', 'Var', (170, 178))	('EGFR', 'Gene', '1956', (265, 269))	('EGFR', 'Gene', (265, 269))	('afatinib', 'Chemical', 'MESH:D000077716', (170, 178))
100937	25432788	In stage 2 of the study, after crossover had occurred, the disease control rate (including complete response, partial response and stable disease) was 33% in afatinib-treated patients versus 19% in cetuximab-treated patients.	('afatinib', 'Chemical', 'MESH:D000077716', (158, 166))	('partial', 'Disease', (110, 117))	('disease control', 'CPA', (59, 74))	('complete', 'Disease', (91, 99))	('patients', 'Species', '9606', (216, 224))	('cetuximab', 'Chemical', 'MESH:D000068818', (198, 207))	('patients', 'Species', '9606', (175, 183))	('stable', 'Disease', (131, 137))	('afatinib-treated', 'Var', (158, 174))
100940	25432788	Gastrointestinal and dermatological side effects are common in patients receiving EGFR tyrosine kinase inhibitors, and have a large impact on patients' quality of life.	('EGFR', 'Gene', (82, 86))	('tyrosine', 'Var', (87, 95))	('dermatological', 'Disease', (21, 35))	('patients', 'Species', '9606', (63, 71))	('Gastrointestinal', 'Disease', (0, 16))	('EGFR', 'Gene', '1956', (82, 86))	('patients', 'Species', '9606', (142, 150))	('impact', 'Reg', (132, 138))
100951	25432788	The hypothesis being tested is that prolonged, irreversible, small-molecule inhibitor-mediated ErbB family blockade will improve disease-free survival outcomes.	('small-molecule', 'Var', (61, 75))	('ErbB', 'Gene', '1956', (95, 99))	('disease-free survival outcomes', 'CPA', (129, 159))	('ErbB', 'Gene', (95, 99))	('improve', 'PosReg', (121, 128))
100967	25432788	The main exclusion criteria are prior treatment with EGFR-targeted small molecules, EGFR-targeted antibodies or any investigational agents for HNSCC, patients with a smoking history of <=10 pack-years and with primary tumour site of base of tongue or tonsil, and primary cancer of nasopharynx, sinuses or salivary glands.	('primary tumour', 'Disease', (210, 224))	('primary tumour', 'Disease', 'MESH:D009369', (210, 224))	('cancer', 'Phenotype', 'HP:0002664', (271, 277))	('EGFR', 'Gene', '1956', (84, 88))	('small molecules', 'Var', (67, 82))	('patients', 'Species', '9606', (150, 158))	('cancer of nasopharynx', 'Phenotype', 'HP:0100630', (271, 292))	('cancer', 'Disease', 'MESH:D009369', (271, 277))	('EGFR', 'Gene', '1956', (53, 57))	('EGFR', 'Gene', (53, 57))	('EGFR', 'Gene', (84, 88))	('tumour', 'Phenotype', 'HP:0002664', (218, 224))	('cancer', 'Disease', (271, 277))	('HNSCC', 'Phenotype', 'HP:0012288', (143, 148))
100978	25432788	Exploratory biomarkers to be assessed are p16 status, ErbB ligands, ErbB receptor expression, EGFR mutational or activation status and ErbB downstream signalling markers.	('p16', 'Gene', '1029', (42, 45))	('ErbB', 'Gene', (135, 139))	('ErbB', 'Gene', '1956', (135, 139))	('EGFR', 'Gene', '1956', (94, 98))	('ErbB', 'Gene', (54, 58))	('ErbB', 'Gene', '1956', (54, 58))	('ErbB', 'Gene', '1956', (68, 72))	('ErbB', 'Gene', (68, 72))	('EGFR', 'Gene', (94, 98))	('p16', 'Gene', (42, 45))	('mutational', 'Var', (99, 109))
101047	29937423	In other words, patients with high level expression of kininogen-1 tend to have a shorter overall survival and recurrence-free survival.	('overall survival', 'CPA', (90, 106))	('kininogen-1', 'Gene', '3827', (55, 66))	('patients', 'Species', '9606', (16, 24))	('high level expression', 'Var', (30, 51))	('recurrence-free survival', 'CPA', (111, 135))	('kininogen-1', 'Gene', (55, 66))	('shorter', 'NegReg', (82, 89))
101050	29937423	Various factors such as genetic mutations and polymorphisms are associated with oral malignancies.	('associated', 'Reg', (64, 74))	('oral malignancies', 'Disease', (80, 97))	('genetic mutations', 'Var', (24, 41))	('oral malignancies', 'Disease', 'MESH:D020820', (80, 97))	('polymorphisms', 'Var', (46, 59))
101052	29937423	However, angiotensinogen gene polymorphism is associated with increased risk of oral cancer (Vairaktaris et al., 2008).	('oral cancer', 'Disease', 'MESH:D009062', (80, 91))	('angiotensinogen', 'Gene', '183', (9, 24))	('angiotensinogen', 'Gene', (9, 24))	('oral cancer', 'Disease', (80, 91))	('polymorphism', 'Var', (30, 42))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
101084	29937423	Some investigations have shown that inhibition of fibronectin cleavage could be of significant benefit for the management of oral diseases, including periodontal disease and oral cancer (Stanley et al., 2008).	('oral diseases', 'Disease', (125, 138))	('fibronectin', 'Gene', '2335', (50, 61))	('oral cancer', 'Disease', (174, 185))	('inhibition', 'Var', (36, 46))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('periodontal disease', 'Phenotype', 'HP:0000704', (150, 169))	('fibronectin', 'Gene', (50, 61))	('oral diseases', 'Disease', 'MESH:D020820', (125, 138))	('periodontal disease', 'Disease', (150, 169))	('periodontal disease', 'Disease', 'MESH:D010510', (150, 169))	('oral cancer', 'Disease', 'MESH:D009062', (174, 185))
101086	29937423	mutations and abnormal expression of proteins) but also on extrinsic factors (such as the ECM composition), which can help understand the failure of some tumor therapies and development of new anti-tumorigenic approaches (de Oliveira Ramos et al., 2016).	('tumor', 'Disease', (154, 159))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('proteins', 'Protein', (37, 45))	('mutations', 'Var', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('tumor', 'Disease', (198, 203))	('expression', 'MPA', (23, 33))
101091	29937423	Therefore, manipulation of this protein may be helpful in predicting the treatment of oral cancer.	('oral cancer', 'Disease', (86, 97))	('oral cancer', 'Disease', 'MESH:D009062', (86, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('manipulation', 'Var', (11, 23))
101129	28472344	National Institutes of Health (NIH) [K01LM012426, P20GM103534, P30CA023108, U19CA148127 and U01CA196386].	('U01', 'CellLine', 'CVCL:2220', (92, 95))	('LM012426', 'CellLine', 'CVCL:5998', (40, 48))	('P30CA023108', 'Var', (63, 74))	('U19CA148127', 'Var', (76, 87))	('U01CA196386]', 'Var', (92, 104))	('P20GM103534', 'Var', (50, 61))
101153	28361224	An increase in the burden of nonsynonymous mutations in tumors has been associated with improvements in objective response and long-lasting clinical benefit as well as progression-free survival (PFS).	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('nonsynonymous mutations', 'Var', (29, 52))	('improvements', 'PosReg', (88, 100))	('tumors', 'Disease', (56, 62))	('objective response', 'CPA', (104, 122))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('progression-free', 'CPA', (168, 184))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('clinical benefit', 'CPA', (140, 156))
101198	28361224	Progressively growing tumors contain mutant tumor antigen-specific T cells.	('tumors', 'Phenotype', 'HP:0002664', (22, 28))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('tumors', 'Disease', 'MESH:D009369', (22, 28))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('mutant', 'Var', (37, 43))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumor', 'Disease', (22, 27))	('tumors', 'Disease', (22, 28))	('tumor', 'Disease', (44, 49))
101199	28361224	These are reactivated after treatment with anti-PD-1 and/or anti-CTLA-4, and although they show some overlap, their transcriptional profiles are mostly treatment-specific, giving them the ability to mediate tumor rejection.	('anti-CTLA-4', 'Var', (60, 71))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('mediate', 'Reg', (199, 206))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('tumor', 'Disease', (207, 212))	('anti-PD-1', 'Var', (43, 52))
101200	28361224	Tumor-specific mutant antigens are thus not only major targets in checkpoint blockade therapy but can be further used in the development of personalized and cancer-specific vaccines as well as in the investigation of the mechanisms underlying the various checkpoint blockade treatments.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('cancer', 'Disease', (157, 163))	('mutant', 'Var', (15, 21))
101218	28361224	Nevertheless, most of these clinical responses were associated with both on- and off-target toxicity, and death from complications has occurred in some patients receiving gene-modified T cells.	('patients', 'Species', '9606', (152, 160))	('toxicity', 'Disease', 'MESH:D064420', (92, 100))	('toxicity', 'Disease', (92, 100))	('gene-modified', 'Var', (171, 184))
101223	28361224	A phase I study of T cells engineered to recognize the NY-ESO-1 marker (TBI-1301) in patients with solid tumors, including ESCC (NCT02366546).	('NY-ESO-1', 'Gene', '246100', (55, 63))	('NCT02366546', 'Var', (129, 140))	('NY-ESO-1', 'Gene', (55, 63))	('TBI-1301', 'Gene', (72, 80))	('SCC', 'Gene', (124, 127))	('solid tumors', 'Disease', 'MESH:D009369', (99, 111))	('patients', 'Species', '9606', (85, 93))	('SCC', 'Phenotype', 'HP:0002860', (124, 127))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('SCC', 'Gene', '6317', (124, 127))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('solid tumors', 'Disease', (99, 111))
101247	28361224	These promising results have led to a number of phase I trials currently testing combination treatment with an anti-CTLA-4 and an anti-PD-1/PD-L1 antibody.	('testing', 'Reg', (73, 80))	('anti-CTLA-4', 'Gene', (111, 122))	('combination', 'Interaction', (81, 92))	('PD-L1', 'Gene', (140, 145))	('PD-L1', 'Gene', '29126', (140, 145))	('anti-CTLA-4', 'Var', (111, 122))
101357	27755795	Because the biopsied specimen was positive for an epidermal growth factor receptor (EGFR) gene mutation, we commenced gefitinib administration.	('epidermal growth factor receptor', 'Gene', '1956', (50, 82))	('positive', 'Reg', (34, 42))	('EGFR', 'Gene', '1956', (84, 88))	('gefitinib', 'Chemical', 'MESH:D000077156', (118, 127))	('epidermal growth factor receptor', 'Gene', (50, 82))	('EGFR', 'Gene', (84, 88))	('mutation', 'Var', (95, 103))
101359	27755795	Therefore, tyrosine kinase inhibitors should be used for cases that present EGFR activating mutations independently from the presence of skin and soft tissue metastases.	('EGFR', 'Gene', '1956', (76, 80))	('mutations', 'Var', (92, 101))	('metastases', 'Disease', (158, 168))	('EGFR', 'Gene', (76, 80))	('activating', 'PosReg', (81, 91))	('metastases', 'Disease', 'MESH:D009362', (158, 168))
101370	27755795	However, the pathological examination revealed a mutation (point mutation in exon 21 L858R) in the epidermal growth factor receptor (EGFR) gene.	('L858R', 'Var', (85, 90))	('epidermal growth factor receptor', 'Gene', '1956', (99, 131))	('L858R', 'Mutation', 'rs121434568', (85, 90))	('EGFR', 'Gene', '1956', (133, 137))	('revealed', 'Reg', (38, 46))	('epidermal growth factor receptor', 'Gene', (99, 131))	('EGFR', 'Gene', (133, 137))
101377	27755795	EGFR is activated in many malignancies, including lung cancer, and gefitinib inhibits the proliferation of cancerous cells through the inhibition of EGFR tyrosine kinase.4 Gefitinib has been reported to significantly extend the progression-free survival period compared with conventional chemotherapy.5, 6, 7, 8 Although EGFR tyrosine kinase inhibitors, including gefitinib, have been effectively used for the treatment of lung cancer with EGFR mutations, most patients become drug resistant within a few years.	('EGFR', 'Gene', (440, 444))	('lung cancer', 'Disease', 'MESH:D008175', (50, 61))	('lung cancer', 'Phenotype', 'HP:0100526', (50, 61))	('lung cancer', 'Disease', 'MESH:D008175', (423, 434))	('gefitinib', 'Chemical', 'MESH:D000077156', (364, 373))	('cancerous', 'Disease', (107, 116))	('EGFR', 'Gene', (321, 325))	('malignancies', 'Disease', 'MESH:D009369', (26, 38))	('EGFR', 'Gene', '1956', (149, 153))	('malignancies', 'Disease', (26, 38))	('cancer', 'Phenotype', 'HP:0002664', (428, 434))	('mutations', 'Var', (445, 454))	('lung cancer', 'Phenotype', 'HP:0100526', (423, 434))	('EGFR', 'Gene', '1956', (440, 444))	('EGFR', 'Gene', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('gefitinib', 'Chemical', 'MESH:D000077156', (67, 76))	('EGFR', 'Gene', '1956', (321, 325))	('lung cancer', 'Disease', (50, 61))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('cancerous', 'Disease', 'MESH:D009369', (107, 116))	('Gefitinib', 'Chemical', 'MESH:D000077156', (172, 181))	('lung cancer', 'Disease', (423, 434))	('EGFR', 'Gene', (149, 153))	('EGFR', 'Gene', '1956', (0, 4))	('patients', 'Species', '9606', (461, 469))
101379	27755795	The percentage of cancers positive for EGFR gene mutations varies depending on factors such as histological type, race, and gender, with about 30% of lung adenocarcinomas in Japanese positive for EGFR gene mutations.	('EGFR', 'Gene', (196, 200))	('cancers', 'Disease', (18, 25))	('cancers', 'Phenotype', 'HP:0002664', (18, 25))	('mutations', 'Var', (49, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (160, 169))	('lung adenocarcinomas', 'Disease', (150, 170))	('EGFR', 'Gene', '1956', (196, 200))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('positive', 'Reg', (183, 191))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (150, 170))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (150, 170))	('EGFR', 'Gene', '1956', (39, 43))	('EGFR', 'Gene', (39, 43))	('cancers', 'Disease', 'MESH:D009369', (18, 25))
101388	27755795	We advocate that molecular-targeted drugs be actively used for the management of skin-exposed tumors with EGFR gene mutations.	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('mutations', 'Var', (116, 125))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('tumors', 'Disease', (94, 100))	('EGFR', 'Gene', '1956', (106, 110))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('EGFR', 'Gene', (106, 110))
101395	33375169	The differences in prognoses or progression patterns between T4b non-N4 and non-T4b N4 esophageal squamous cell carcinoma post chemoradiotherapy (CRT) is unclear.	('N', 'Chemical', 'MESH:D009584', (84, 85))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (87, 121))	('non-T4b N4', 'Var', (76, 86))	('esophageal squamous cell carcinoma', 'Disease', (87, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (98, 121))	('T4b non-N4', 'Var', (61, 71))	('N', 'Chemical', 'MESH:D009584', (69, 70))
101403	33375169	We found no significant differences in prognoses or progression patterns among patients with T4b non-N4, non-T4b N4, and T4b N4 esophageal squamous cell carcinoma.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (139, 162))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (128, 162))	('N', 'Chemical', 'MESH:D009584', (113, 114))	('T4b N4', 'Var', (121, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (153, 162))	('T4b non-N4', 'Var', (93, 103))	('patients', 'Species', '9606', (79, 87))	('N', 'Chemical', 'MESH:D009584', (125, 126))	('non-T4b N4', 'Var', (105, 115))	('N', 'Chemical', 'MESH:D009584', (101, 102))	('esophageal squamous cell carcinoma', 'Disease', (128, 162))
101417	33375169	The T/N factor groups were T4bN0-3 (28 patients, 42.4%), T1-4aN4 (24 patients, 36.4%), and T4bN4 (14 patients, 21.2%).	('patients', 'Species', '9606', (101, 109))	('T4bN4', 'Var', (91, 96))	('patients', 'Species', '9606', (39, 47))	('T1-4aN4', 'Var', (57, 64))	('N', 'Chemical', 'MESH:D009584', (30, 31))	('N', 'Chemical', 'MESH:D009584', (6, 7))	('N', 'Chemical', 'MESH:D009584', (62, 63))	('T4bN0-3', 'Var', (27, 34))	('patients', 'Species', '9606', (69, 77))	('N', 'Chemical', 'MESH:D009584', (94, 95))
101428	33375169	In the T1-4aN4 group, progression or recurrence occurred inside the irradiated area with/without out-of-field recurrence (eight patients, 33%), outside the irradiated area with/without in-field recurrence (14 patients, 58%), and in both areas (four patients, 17%).	('recurrence', 'CPA', (37, 47))	('progression', 'CPA', (22, 33))	('N', 'Chemical', 'MESH:D009584', (12, 13))	('patients', 'Species', '9606', (249, 257))	('T1-4aN4', 'Var', (7, 14))	('patients', 'Species', '9606', (209, 217))	('patients', 'Species', '9606', (128, 136))
101429	33375169	In the T4bN4 group, progression or recurrence occurred inside the irradiated area with/without out-of-field recurrence (six patients, 43%) and outside the irradiated area with/without in-field recurrence (six patients, 43%).	('T4bN4', 'Var', (7, 12))	('N', 'Chemical', 'MESH:D009584', (10, 11))	('patients', 'Species', '9606', (209, 217))	('progression', 'CPA', (20, 31))	('recurrence', 'CPA', (35, 45))	('patients', 'Species', '9606', (124, 132))
101441	33375169	However, we did not manage to detect differences among the T4bN0-3, T1-4aN4, and T4bN4 groups in terms of their progression pattern, PFS, and OS.	('N', 'Chemical', 'MESH:D009584', (84, 85))	('N', 'Chemical', 'MESH:D009584', (73, 74))	('T4bN4', 'Var', (81, 86))	('T4bN0-3', 'Var', (59, 66))	('N', 'Chemical', 'MESH:D009584', (62, 63))
101445	33375169	While stage IVa esophageal cancer includes locally advanced T4b; lymph node spread tendency N4; and T4bnon-N4, non-T4b N4, and T4b N4 disease, to our knowledge, no previous studies have examined their differences in outcomes or progression patterns.	('T4bnon-N4', 'Var', (100, 109))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('N', 'Chemical', 'MESH:D009584', (92, 93))	('N', 'Chemical', 'MESH:D009584', (119, 120))	('stage IVa esophageal cancer', 'Disease', (6, 33))	('N', 'Chemical', 'MESH:D009584', (107, 108))	('N', 'Chemical', 'MESH:D009584', (131, 132))	('lymph', 'Disease', (65, 70))	('stage IVa esophageal cancer', 'Disease', 'MESH:D004938', (6, 33))
101446	33375169	Our results indicated that the T4bN0-3, T1-4aN4, and T4bN4 groups had similar outcomes in terms of progression pattern, PFS, and OS.	('T1-4aN4', 'Var', (40, 47))	('PFS', 'CPA', (120, 123))	('N', 'Chemical', 'MESH:D009584', (34, 35))	('T4bN0-3', 'Var', (31, 38))	('N', 'Chemical', 'MESH:D009584', (56, 57))	('N', 'Chemical', 'MESH:D009584', (45, 46))	('T4bN4', 'Var', (53, 58))
101449	33375169	Thus, stage IVa esophageal cancer with either T4b or N4 requires both sufficient radiotherapy as local treatment and chemotherapy as a systemic treatment because progression can occur in and out of the irradiated field, regardless of T/N factors.	('N', 'Chemical', 'MESH:D009584', (53, 54))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('N', 'Chemical', 'MESH:D009584', (236, 237))	('men', 'Species', '9606', (149, 152))	('men', 'Species', '9606', (108, 111))	('stage IVa esophageal cancer', 'Disease', (6, 33))	('T4b', 'Var', (46, 49))	('stage IVa esophageal cancer', 'Disease', 'MESH:D004938', (6, 33))
101466	33375169	Although ENI may reduce regional nodal failure, these recent studies suggest that prophylactically expanding the irradiation field may not be prudent to reduce toxicities, especially hematological, and complete planned definitive CRT.	('toxicities', 'Disease', 'MESH:D064420', (160, 170))	('reduce', 'NegReg', (17, 23))	('regional nodal failure', 'Disease', 'MESH:D006333', (24, 46))	('regional nodal failure', 'Disease', (24, 46))	('ENI', 'Chemical', '-', (9, 12))	('toxicities', 'Disease', (160, 170))	('ENI', 'Var', (9, 12))
101467	33375169	However, this study did not manage to detect differences among the T4bN0-3, T1-4aN4, and T4bN4 groups in terms of their progression pattern, PFS, and OS.	('T4bN0-3', 'Var', (67, 74))	('N', 'Chemical', 'MESH:D009584', (81, 82))	('N', 'Chemical', 'MESH:D009584', (92, 93))	('T4bN4', 'Var', (89, 94))	('N', 'Chemical', 'MESH:D009584', (70, 71))
101510	32520206	We found that miR-424-5p expression in NPC tissues is downregulated and negatively correlated with lymph node metastasis and clinical staging.	('miR-424-5p', 'Var', (14, 24))	('correlated', 'Reg', (83, 93))	('negatively', 'NegReg', (72, 82))	('clinical staging', 'CPA', (125, 141))	('NPC', 'Phenotype', 'HP:0100630', (39, 42))	('NPC', 'Gene', '4864', (39, 42))	('NPC', 'Gene', (39, 42))	('lymph node metastasis', 'CPA', (99, 120))	('downregulated', 'NegReg', (54, 67))
101511	32520206	Expression of miR-424-5p in NPC cells was also downregulated, and transfection with miR-424-5p mimics inhibited proliferation, migration, and invasion of NPC-1 cells.	('NPC', 'Phenotype', 'HP:0100630', (28, 31))	('downregulated', 'NegReg', (47, 60))	('miR-424-5p', 'Var', (84, 94))	('inhibited', 'NegReg', (102, 111))	('Expression', 'MPA', (0, 10))	('NPC', 'Gene', '4864', (28, 31))	('NPC', 'Phenotype', 'HP:0100630', (154, 157))	('NPC', 'Gene', (154, 157))	('NPC', 'Gene', '4864', (154, 157))	('proliferation', 'CPA', (112, 125))	('invasion', 'CPA', (142, 150))	('migration', 'CPA', (127, 136))	('NPC', 'Gene', (28, 31))
101512	32520206	Bioinformatics identified the AKT3 gene as a potential target of miR-424-5p and dual luciferase assays confirmed this finding.	('AKT3', 'Gene', '10000', (30, 34))	('miR-424-5p', 'Var', (65, 75))	('AKT3', 'Gene', (30, 34))
101513	32520206	Upregulation of AKT3 expression rescued the inhibitory effect of miR-424-5p on the proliferation, migration, and invasion.	('Upregulation', 'PosReg', (0, 12))	('AKT3', 'Gene', '10000', (16, 20))	('proliferation', 'CPA', (83, 96))	('invasion', 'CPA', (113, 121))	('inhibitory effect', 'MPA', (44, 61))	('migration', 'CPA', (98, 107))	('AKT3', 'Gene', (16, 20))	('miR-424-5p', 'Var', (65, 75))
101514	32520206	Our results suggest that miR-424-5p inhibited the proliferation, migration, and invasion of NPC cells by decreasing AKT3 expression.	('migration', 'CPA', (65, 74))	('inhibited', 'NegReg', (36, 45))	('decreasing', 'NegReg', (105, 115))	('expression', 'MPA', (121, 131))	('NPC', 'Gene', (92, 95))	('NPC', 'Phenotype', 'HP:0100630', (92, 95))	('AKT3', 'Gene', (116, 120))	('miR-424-5p', 'Var', (25, 35))	('AKT3', 'Gene', '10000', (116, 120))	('NPC', 'Gene', '4864', (92, 95))
101528	32520206	Furthermore, aberrant expression of these oncogenic and tumor suppressive miRNA molecules has been identified in multiple cancers, leading to changes in cell proliferation, invasion, and metastasis.	('miR', 'Gene', (74, 77))	('invasion', 'CPA', (173, 181))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('miR', 'Gene', '220972', (74, 77))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('tumor', 'Disease', (56, 61))	('metastasis', 'CPA', (187, 197))	('cell proliferation', 'CPA', (153, 171))	('cancers', 'Disease', 'MESH:D009369', (122, 129))	('cancers', 'Phenotype', 'HP:0002664', (122, 129))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('cancers', 'Disease', (122, 129))	('changes', 'Reg', (142, 149))	('aberrant', 'Var', (13, 21))
101532	32520206	Abnormal expression of miR-424-5p has been detected in many tumor tissues.	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('miR-424-5p', 'Var', (23, 33))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('detected', 'Reg', (43, 51))	('tumor', 'Disease', (60, 65))
101534	32520206	Currently, the expression and function of miR-424-5p in NPC are still unclear.	('NPC', 'Gene', '4864', (56, 59))	('miR-424-5p', 'Var', (42, 52))	('NPC', 'Phenotype', 'HP:0100630', (56, 59))	('NPC', 'Gene', (56, 59))
101535	32520206	In the present study, we evaluated the expression and potential function of miR-424-5p in NPC.	('NPC', 'Gene', (90, 93))	('miR-424-5p', 'Var', (76, 86))	('NPC', 'Gene', '4864', (90, 93))	('NPC', 'Phenotype', 'HP:0100630', (90, 93))
101577	32520206	Based on the bioinformatics results, wild-type (WT) and mutant seed regions of miR-424-5p in the 3'-UTR of AKT3 gene were chemically synthesized in vitro.	('AKT3', 'Gene', (107, 111))	('mutant', 'Var', (56, 62))	('AKT3', 'Gene', '10000', (107, 111))
101578	32520206	Plasmids (0.5 mug) with WT or mutant 3'-UTR sequences were co-transfected with agomiR-negative control (NC) or agomiR-424-5p (100 nM; Sangon Biotech, China) into 293T cells.	('miR', 'Gene', '220972', (82, 85))	('miR', 'Gene', (82, 85))	('293T', 'CellLine', 'CVCL:0063', (162, 166))	('miR', 'Gene', '220972', (114, 117))	('miR', 'Gene', (114, 117))	('mutant', 'Var', (30, 36))	("3'-UTR", 'Gene', (37, 43))
101579	32520206	The relative expression of miR-424-5p in NPC tissues (0.25+-0.05) was significantly lower than that in the control group (P<0.05) (Figure 1A).	('NPC', 'Gene', '4864', (41, 44))	('expression', 'MPA', (13, 23))	('lower', 'NegReg', (84, 89))	('miR-424-5p', 'Var', (27, 37))	('NPC', 'Phenotype', 'HP:0100630', (41, 44))	('NPC', 'Gene', (41, 44))
101580	32520206	In addition, the relative expression of miR-424-5p in NPC tissues from patients with lymph node metastasis (0.48+-0.05; N1 group) was significantly lower than that from patients without lymph node metastasis (N0 group; P<0.05) (Figure 1B).	('expression', 'MPA', (26, 36))	('patients', 'Species', '9606', (169, 177))	('patients', 'Species', '9606', (71, 79))	('NPC', 'Gene', (54, 57))	('miR-424-5p', 'Var', (40, 50))	('lower', 'NegReg', (148, 153))	('NPC', 'Phenotype', 'HP:0100630', (54, 57))	('NPC', 'Gene', '4864', (54, 57))
101581	32520206	The relative expression of miR-424-5p in NPC tissues at TNM stage II or at stages III and IV was significantly lower than that in NPC tissues at stage I (P<0.05) (Figure 1C).	('NPC', 'Gene', '4864', (41, 44))	('NPC', 'Gene', '4864', (130, 133))	('expression', 'MPA', (13, 23))	('TNM', 'Gene', '10178', (56, 59))	('lower', 'NegReg', (111, 116))	('NPC', 'Gene', (130, 133))	('miR-424-5p', 'Var', (27, 37))	('NPC', 'Phenotype', 'HP:0100630', (130, 133))	('NPC', 'Phenotype', 'HP:0100630', (41, 44))	('NPC', 'Gene', (41, 44))	('TNM', 'Gene', (56, 59))
101583	32520206	These results suggested that the expression of miR-424-5p was reduced in NPC tissues and correlated with the occurrence and development of NPC.	('NPC', 'Phenotype', 'HP:0100630', (73, 76))	('NPC', 'Gene', (73, 76))	('NPC', 'Gene', '4864', (139, 142))	('miR-424-5p', 'Var', (47, 57))	('NPC', 'Gene', '4864', (73, 76))	('NPC', 'Phenotype', 'HP:0100630', (139, 142))	('NPC', 'Gene', (139, 142))	('expression', 'MPA', (33, 43))	('correlated', 'Reg', (89, 99))	('reduced', 'NegReg', (62, 69))
101585	32520206	qRT-PCR showed that the expression of miR-425-5p in NPC-1 cells was significantly lower than that in NP69 cells (P<0.05) (Figure 2D).	('NPC', 'Phenotype', 'HP:0100630', (52, 55))	('expression', 'MPA', (24, 34))	('NP69', 'CellLine', 'CVCL:F755', (101, 105))	('miR-425-5p', 'Var', (38, 48))	('lower', 'NegReg', (82, 87))
101591	32520206	Among all the potential target genes of miR-424-5p, AKT3 participated in the regulation of proliferation, apoptosis, and migration of cells and was involved in signaling pathways that were closely related to the occurrence and development of tumors, such as MAPK and ErRb signaling pathways (data not shown).	('related', 'Reg', (197, 204))	('AKT3', 'Gene', (52, 56))	('tumors', 'Disease', 'MESH:D009369', (242, 248))	('participated', 'Reg', (57, 69))	('ErRb', 'Gene', '2103', (267, 271))	('involved in', 'Reg', (148, 159))	('AKT3', 'Gene', '10000', (52, 56))	('tumors', 'Disease', (242, 248))	('apoptosis', 'CPA', (106, 115))	('tumors', 'Phenotype', 'HP:0002664', (242, 248))	('migration of cells', 'CPA', (121, 139))	('miR-424-5p', 'Var', (40, 50))	('tumor', 'Phenotype', 'HP:0002664', (242, 247))	('regulation', 'MPA', (77, 87))	('proliferation', 'CPA', (91, 104))	('ErRb', 'Gene', (267, 271))	('signaling pathways', 'Pathway', (160, 178))	('MAPK', 'Pathway', (258, 262))
101592	32520206	To determine whether miR-424-5p targets the 3'-UTR of AKT3 mRNA, dual luciferase reporter assay was performed.	('AKT3', 'Gene', '10000', (54, 58))	('miR-424-5p', 'Var', (21, 31))	('AKT3', 'Gene', (54, 58))
101593	32520206	The luciferase activity of cells co-transfected with agomiR-424-5p and the pMIR-REPORT-WT luciferase reporter plasmids, containing the wild-type 3'-UTR of AKT3 mRNA, was significantly lower than that in the negative control group (P<0.05).	('AKT3', 'Gene', (155, 159))	('agomiR-424-5p', 'Var', (53, 66))	('AKT3', 'Gene', '10000', (155, 159))	('activity', 'MPA', (15, 23))	('lower', 'NegReg', (184, 189))	('luciferase', 'Enzyme', (4, 14))
101599	32520206	These results suggested that AKT3 rescued the inhibitory effect of miR-424-5p on the proliferation, migration, and invasion of NPC-1 cells.	('inhibitory effect', 'MPA', (46, 63))	('migration', 'CPA', (100, 109))	('miR-424-5p', 'Var', (67, 77))	('AKT3', 'Gene', (29, 33))	('AKT3', 'Gene', '10000', (29, 33))	('NPC', 'Phenotype', 'HP:0100630', (127, 130))	('proliferation', 'CPA', (85, 98))	('invasion', 'CPA', (115, 123))
101607	32520206	Several studies have shown that the expression and biological functions of miR-424-5p vary across different tumors.	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('miR-424-5p', 'Var', (75, 85))	('tumors', 'Disease', (108, 114))	('tumors', 'Disease', 'MESH:D009369', (108, 114))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))
101608	32520206	For example, the expression of miR-424-5p is reduced in liver cancer, gastric cancer, and osteosarcoma tissues, and miR-424-5p inhibits the proliferation and metastasis of these tumor cells.	('inhibits', 'NegReg', (127, 135))	('osteosarcoma', 'Phenotype', 'HP:0002669', (90, 102))	('gastric cancer', 'Disease', (70, 84))	('tumor', 'Disease', (178, 183))	('expression', 'MPA', (17, 27))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('miR-424-5p', 'Gene', (31, 41))	('gastric cancer', 'Disease', 'MESH:D013274', (70, 84))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('osteosarcoma', 'Disease', (90, 102))	('miR-424-5p', 'Var', (116, 126))	('liver cancer', 'Disease', 'MESH:D006528', (56, 68))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('osteosarcoma', 'Disease', 'MESH:D012516', (90, 102))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('reduced', 'NegReg', (45, 52))	('gastric cancer', 'Phenotype', 'HP:0012126', (70, 84))	('liver cancer', 'Phenotype', 'HP:0002896', (56, 68))	('liver cancer', 'Disease', (56, 68))
101609	32520206	In contrast, expression of miR-424-5p is increased in squamous cell carcinoma of the esophagus, breast cancer, and pancreatic cancer, and it promotes the occurrence and development of these tumors.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (115, 132))	('carcinoma of the esophagus', 'Phenotype', 'HP:0011459', (68, 94))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('breast cancer', 'Disease', 'MESH:D001943', (96, 109))	('breast cancer', 'Disease', (96, 109))	('tumors', 'Disease', (190, 196))	('squamous cell carcinoma', 'Disease', (54, 77))	('promotes', 'PosReg', (141, 149))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('pancreatic cancer', 'Disease', 'MESH:D010190', (115, 132))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (54, 77))	('breast cancer', 'Phenotype', 'HP:0003002', (96, 109))	('tumors', 'Disease', 'MESH:D009369', (190, 196))	('tumors', 'Phenotype', 'HP:0002664', (190, 196))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('pancreatic cancer', 'Disease', (115, 132))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (54, 77))	('increased', 'PosReg', (41, 50))	('expression', 'MPA', (13, 23))	('carcinoma', 'Phenotype', 'HP:0030731', (68, 77))	('miR-424-5p', 'Var', (27, 37))	('development', 'CPA', (169, 180))
101610	32520206	In the present study, we showed that miR-424-5p expression was significantly reduced in NPC tissues and negatively correlated with lymph node metastasis and TNM staging.	('lymph node metastasis', 'CPA', (131, 152))	('correlated', 'Reg', (115, 125))	('negatively', 'NegReg', (104, 114))	('miR-424-5p', 'Var', (37, 47))	('TNM', 'Gene', (157, 160))	('NPC', 'Gene', (88, 91))	('NPC', 'Phenotype', 'HP:0100630', (88, 91))	('reduced', 'NegReg', (77, 84))	('NPC', 'Gene', '4864', (88, 91))	('TNM', 'Gene', '10178', (157, 160))
101611	32520206	Moreover, we isolated primary NPC cells with low expression of miR-425-5p, particularly NPC-1 cells.	('NPC', 'Phenotype', 'HP:0100630', (30, 33))	('NPC', 'Gene', (88, 91))	('NPC', 'Gene', (30, 33))	('NPC', 'Phenotype', 'HP:0100630', (88, 91))	('NPC', 'Gene', '4864', (88, 91))	('miR-425-5p', 'Var', (63, 73))	('NPC', 'Gene', '4864', (30, 33))
101612	32520206	In vitro functional analyses showed that upregulation of miR-424-5p expression inhibits the proliferation, migration, and invasion of NPC-1 cells, suggesting that miR-424-5p has oncogenic function and that reduced expression of miR-424-5p in NPC may be related to the occurrence and development of NPC.	('migration', 'CPA', (107, 116))	('miR-424-5p', 'Var', (163, 173))	('NPC', 'Phenotype', 'HP:0100630', (242, 245))	('miR-424-5p', 'Gene', (57, 67))	('inhibits', 'NegReg', (79, 87))	('NPC', 'Gene', '4864', (134, 137))	('NPC', 'Gene', (242, 245))	('invasion', 'CPA', (122, 130))	('oncogenic function', 'CPA', (178, 196))	('NPC', 'Gene', '4864', (242, 245))	('NPC', 'Gene', (298, 301))	('NPC', 'Phenotype', 'HP:0100630', (298, 301))	('NPC', 'Phenotype', 'HP:0100630', (134, 137))	('NPC', 'Gene', (134, 137))	('proliferation', 'CPA', (92, 105))	('upregulation', 'PosReg', (41, 53))	('NPC', 'Gene', '4864', (298, 301))
101614	32520206	reported that miR-424-5p regulates the Notch signaling pathway by targeting KDM5B and has tumor suppressor functions in cervical cancer.	('miR-424-5p', 'Var', (14, 24))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('Notch signaling pathway', 'Pathway', (39, 62))	('KDM5B', 'Gene', (76, 81))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('regulates', 'Reg', (25, 34))	('targeting', 'Reg', (66, 75))	('KDM5B', 'Gene', '10765', (76, 81))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
101615	32520206	showed that miR-424-5p regulates the TGF-beta signaling pathway by targeting Smad3 and promotes the proliferation of gastric cancer cells.	('TGF-beta', 'Gene', '7039', (37, 45))	('regulates', 'Reg', (23, 32))	('targeting', 'Reg', (67, 76))	('gastric cancer', 'Phenotype', 'HP:0012126', (117, 131))	('miR-424-5p', 'Var', (12, 22))	('Smad3', 'Gene', (77, 82))	('proliferation', 'CPA', (100, 113))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('TGF-beta', 'Gene', (37, 45))	('gastric cancer', 'Disease', (117, 131))	('promotes', 'PosReg', (87, 95))	('gastric cancer', 'Disease', 'MESH:D013274', (117, 131))	('Smad3', 'Gene', '4088', (77, 82))
101616	32520206	Our bioinformatics results revealed the AKT3 gene as a potential target of miR-424-5p.	('AKT3', 'Gene', '10000', (40, 44))	('miR-424-5p', 'Var', (75, 85))	('AKT3', 'Gene', (40, 44))
101618	32520206	Our qRT-PCR and western blotting data demonstrated that miR-424-5p downregulated the expression of AKT3 mRNA and protein.	('AKT3', 'Gene', '10000', (99, 103))	('expression', 'MPA', (85, 95))	('miR-424-5p', 'Var', (56, 66))	('AKT3', 'Gene', (99, 103))	('downregulated', 'NegReg', (67, 80))
101621	32520206	For example, AKT3 can make 40-60% non-hereditary melanoma cells survive, and inhibition of AKT3 activity promotes the death of these cells.	('promotes', 'PosReg', (105, 113))	('activity', 'MPA', (96, 104))	('melanoma', 'Disease', 'MESH:D008545', (49, 57))	('inhibition', 'Var', (77, 87))	('AKT3', 'Gene', '10000', (13, 17))	('AKT3', 'Gene', (91, 95))	('AKT3', 'Gene', (13, 17))	('AKT3', 'Gene', '10000', (91, 95))	('melanoma', 'Phenotype', 'HP:0002861', (49, 57))	('death', 'Disease', 'MESH:D003643', (118, 123))	('melanoma', 'Disease', (49, 57))	('death', 'Disease', (118, 123))
101623	32520206	The present study showed that elevation of AKT3 expression reversed the inhibitory effect of miR-424-5p on NPC cells and promoted the proliferation, migration, and invasion of NPC cells.	('miR-424-5p', 'Var', (93, 103))	('NPC', 'Phenotype', 'HP:0100630', (107, 110))	('NPC', 'Gene', (176, 179))	('NPC', 'Gene', (107, 110))	('migration', 'CPA', (149, 158))	('NPC', 'Phenotype', 'HP:0100630', (176, 179))	('expression', 'MPA', (48, 58))	('NPC', 'Gene', '4864', (107, 110))	('proliferation', 'CPA', (134, 147))	('elevation', 'PosReg', (30, 39))	('NPC', 'Gene', '4864', (176, 179))	('AKT3', 'Gene', (43, 47))	('invasion', 'CPA', (164, 172))	('AKT3', 'Gene', '10000', (43, 47))	('promoted', 'PosReg', (121, 129))
101626	32520206	In conclusion, the present study demonstrated that miR-424-5p inhibited the proliferation, migration, and invasion of NPC cells by targeting AKT3 expression.	('miR-424-5p', 'Var', (51, 61))	('migration', 'CPA', (91, 100))	('NPC', 'Gene', (118, 121))	('AKT3', 'Gene', (141, 145))	('NPC', 'Phenotype', 'HP:0100630', (118, 121))	('AKT3', 'Gene', '10000', (141, 145))	('NPC', 'Gene', '4864', (118, 121))	('proliferation', 'CPA', (76, 89))	('invasion', 'CPA', (106, 114))	('inhibited', 'NegReg', (62, 71))	('targeting', 'Reg', (131, 140))	('expression', 'MPA', (146, 156))
101628	32066500	The pan-cancer landscape of prognostic germline variants in 10,582 patients While clinical factors such as age, grade, stage, and histological subtype provide physicians with information about patient prognosis, genomic data can further improve these predictions.	('cancer', 'Disease', (8, 14))	('variants', 'Var', (48, 56))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('patient', 'Species', '9606', (193, 200))	('patient', 'Species', '9606', (67, 74))	('cancer', 'Disease', 'MESH:D009369', (8, 14))
101629	32066500	Previous studies have shown that germline variants in known cancer driver genes are predictive of patient outcome, but no study has systematically analyzed multiple cancers in an unbiased way to identify genetic loci that can improve patient outcome predictions made using clinical factors.	('patient', 'Species', '9606', (98, 105))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('cancer', 'Disease', (60, 66))	('patient', 'Species', '9606', (234, 241))	('cancer', 'Disease', (165, 171))	('germline variants', 'Var', (33, 50))	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('cancers', 'Disease', 'MESH:D009369', (165, 172))	('cancers', 'Phenotype', 'HP:0002664', (165, 172))	('cancers', 'Disease', (165, 172))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
101630	32066500	We analyzed sequencing data from the over 10,000 cancer patients available through The Cancer Genome Atlas to identify germline variants associated with patient outcome using multivariate Cox regression models.	('patients', 'Species', '9606', (56, 64))	('C', 'Chemical', '-', (87, 88))	('Cancer', 'Phenotype', 'HP:0002664', (87, 93))	('Cox', 'Gene', (188, 191))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('variants', 'Var', (128, 136))	('patient', 'Species', '9606', (153, 160))	('patient', 'Species', '9606', (56, 63))	('cancer', 'Disease', (49, 55))	('Cox', 'Gene', '1351', (188, 191))	('C', 'Chemical', '-', (188, 189))
101631	32066500	We identified 79 prognostic germline variants in individual cancers and 112 prognostic germline variants in groups of cancers.	('cancers', 'Disease', (118, 125))	('cancers', 'Disease', 'MESH:D009369', (118, 125))	('cancers', 'Phenotype', 'HP:0002664', (60, 67))	('cancers', 'Disease', (60, 67))	('cancers', 'Disease', 'MESH:D009369', (60, 67))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('variants', 'Var', (37, 45))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('cancers', 'Phenotype', 'HP:0002664', (118, 125))
101632	32066500	The germline variants identified in individual cancers provide additional predictive power about patient outcomes beyond clinical information currently in use and may therefore augment clinical decisions based on expected tumor aggressiveness.	('variants', 'Var', (13, 21))	('aggressiveness', 'Phenotype', 'HP:0000718', (228, 242))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (222, 242))	('cancers', 'Disease', 'MESH:D009369', (47, 54))	('cancers', 'Phenotype', 'HP:0002664', (47, 54))	('cancers', 'Disease', (47, 54))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('patient', 'Species', '9606', (97, 104))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('augment', 'NegReg', (177, 184))	('tumor aggressiveness', 'Disease', (222, 242))
101633	32066500	Molecularly, at least 12 of the germline variants are likely associated with patient outcome through perturbation of protein structure and at least five through association with gene expression differences.	('perturbation', 'Reg', (101, 113))	('variants', 'Var', (41, 49))	('association', 'Interaction', (161, 172))	('patient', 'Disease', (77, 84))	('associated', 'Reg', (61, 71))	('patient', 'Species', '9606', (77, 84))	('protein structure', 'MPA', (117, 134))
101634	32066500	Almost half of these germline variants are in previously reported tumor suppressors, oncogenes or cancer driver genes with the other half pointing to genomic loci that should be further investigated for their roles in cancers.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('variants', 'Var', (30, 38))	('cancer', 'Disease', 'MESH:D009369', (218, 224))	('tumor', 'Disease', (66, 71))	('cancer', 'Disease', (218, 224))	('cancers', 'Disease', 'MESH:D009369', (218, 225))	('cancers', 'Phenotype', 'HP:0002664', (218, 225))	('cancers', 'Disease', (218, 225))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('cancer', 'Disease', (98, 104))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('tumor', 'Disease', 'MESH:D009369', (66, 71))
101635	32066500	Germline variants are predictive of outcome in cancer patients and specific germline variants can improve patient outcome predictions beyond predictions made using clinical factors alone.	('patient', 'Species', '9606', (54, 61))	('improve', 'PosReg', (98, 105))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('variants', 'Var', (85, 93))	('patients', 'Species', '9606', (54, 62))	('patient', 'Species', '9606', (106, 113))	('cancer', 'Disease', (47, 53))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))
101636	32066500	The germline variants also implicate new means by which known oncogenes, tumor suppressor genes, and driver genes are perturbed in cancer and suggest roles in cancer for other genes that have not been extensively studied in oncology.	('cancer', 'Disease', (159, 165))	('cancer', 'Disease', (131, 137))	('variants', 'Var', (13, 21))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('roles', 'Reg', (150, 155))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('oncology', 'Phenotype', 'HP:0002664', (224, 232))	('perturbed', 'NegReg', (118, 127))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('tumor', 'Disease', (73, 78))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('cancer', 'Disease', 'MESH:D009369', (131, 137))
101637	32066500	Further studies in other cancer cohorts are necessary to confirm that germline variation is associated with outcome in cancer patients as this is a proof-of-principle study.	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('cancer', 'Disease', (119, 125))	('germline variation', 'Var', (70, 88))	('cancer', 'Disease', 'MESH:D009369', (25, 31))	('patients', 'Species', '9606', (126, 134))	('cancer', 'Disease', (25, 31))	('associated', 'Reg', (92, 102))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
101640	32066500	While much effort has been directed towards characterizing somatic mutations in cancer, recent studies suggest that germline variants also have significant clinical utility.	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancer', 'Disease', (80, 86))	('variants', 'Var', (125, 133))
101641	32066500	In line with the heritability of some cancers, several germline variants predict a patient's risk for developing cancer and are useful for individualizing cancer screening guidelines.	('predict', 'Reg', (73, 80))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('cancers', 'Phenotype', 'HP:0002664', (38, 45))	('cancer', 'Disease', (113, 119))	('cancers', 'Disease', (38, 45))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('patient', 'Species', '9606', (83, 90))	('cancer', 'Disease', (38, 44))	('cancers', 'Disease', 'MESH:D009369', (38, 45))	('variants', 'Var', (64, 72))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('cancer', 'Disease', (155, 161))	('cancer', 'Disease', 'MESH:D009369', (155, 161))
101642	32066500	Germline variation can affect drug sensitivity, predict drug toxicity, and could help select therapy to minimize side-effects.	('predict', 'Reg', (48, 55))	('Germline variation', 'Var', (0, 18))	('affect', 'Reg', (23, 29))	('drug sensitivity', 'Phenotype', 'HP:0020174', (30, 46))	('drug sensitivity', 'MPA', (30, 46))	('drug toxicity', 'Disease', (56, 69))	('drug toxicity', 'Disease', 'MESH:D064420', (56, 69))
101643	32066500	Some germline variants increase patient risk for specific somatic aberrations, suggesting that germline variation may impact disease course.	('variants', 'Var', (14, 22))	('patient', 'Species', '9606', (32, 39))	('impact', 'Reg', (118, 124))	('disease course', 'CPA', (125, 139))
101644	32066500	We hypothesized that the effects of germline variants on cancer progression may be strong enough to identify associations with patient outcome.	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('patient', 'Species', '9606', (127, 134))	('cancer', 'Disease', (57, 63))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('associations', 'Interaction', (109, 121))	('germline variants', 'Var', (36, 53))
101645	32066500	Previous studies tested for an association between patient outcome and a small number of germline variants in genes well-characterized in a given cancer.	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('tested', 'Reg', (17, 23))	('patient', 'Species', '9606', (51, 58))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('germline variants', 'Var', (89, 106))
101646	32066500	We published an unbiased method of testing for an association between a large number of germline variants and patient outcome in patients with lower-grade gliomas.	('gliomas', 'Phenotype', 'HP:0009733', (155, 162))	('patients', 'Species', '9606', (129, 137))	('variants', 'Var', (97, 105))	('glioma', 'Phenotype', 'HP:0009733', (155, 161))	('patient', 'Species', '9606', (110, 117))	('gliomas', 'Disease', (155, 162))	('gliomas', 'Disease', 'MESH:D005910', (155, 162))	('patient', 'Species', '9606', (129, 136))
101648	32066500	These germline variants significantly improve predictions of patient outcome compared to clinical variables alone, identify biological mechanisms by which germline variants affect patient outcomes, and identify genes and pathways that impact cancer biology and therapy.	('patient', 'Species', '9606', (61, 68))	('cancer', 'Disease', (242, 248))	('cancer', 'Disease', 'MESH:D009369', (242, 248))	('variants', 'Var', (164, 172))	('impact', 'Reg', (235, 241))	('affect', 'Reg', (173, 179))	('improve', 'PosReg', (38, 45))	('cancer', 'Phenotype', 'HP:0002664', (242, 248))	('variants', 'Var', (15, 23))	('patient', 'Species', '9606', (180, 187))
101650	32066500	We determined the germline variant statuses of 10,582 cancer patients by variant calling the patients' whole-exome sequenced normal samples (WXS normal), whole-exome sequenced tumor samples (WXS tumor), and RNA sequenced tumor samples (RNA tumor) available on Cancer Genomics Cloud using VarDict (mapping quality > 30, base quality > 25, variant reads > 2, minimum allele frequency > 5%, no duplicate reads) and determined the sequencing depth at each position using samtools (mapping quality > 30).	('tumor', 'Disease', (195, 200))	('WXS', 'Chemical', '-', (141, 144))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('patients', 'Species', '9606', (93, 101))	('variant', 'Var', (73, 80))	('tumor', 'Disease', (240, 245))	('tumor', 'Disease', (176, 181))	('patients', 'Species', '9606', (61, 69))	('tumor', 'Disease', 'MESH:D009369', (240, 245))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('tumor', 'Disease', 'MESH:D009369', (176, 181))	('tumor', 'Disease', (221, 226))	('cancer', 'Disease', (54, 60))	('variant reads', 'Var', (338, 351))	('C', 'Chemical', '-', (276, 277))	('C', 'Chemical', '-', (260, 261))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('tumor', 'Phenotype', 'HP:0002664', (240, 245))	('tumor', 'Disease', 'MESH:D009369', (221, 226))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('Cancer', 'Phenotype', 'HP:0002664', (260, 266))	('WXS', 'Chemical', '-', (191, 194))
101652	32066500	We only included variants with an allele frequency of greater than 5% in the non-Finnish European population of gnomAD, variants found in more than 14 patients in a given cancer, and variants whose calls were greater than 90% concordant with each other in a given cancer in our final analysis.	('variants', 'Var', (120, 128))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('cancer', 'Phenotype', 'HP:0002664', (264, 270))	('AD', 'Disease', 'MESH:D000544', (116, 118))	('AD', 'Disease', (116, 118))	('cancer', 'Disease', (171, 177))	('patients', 'Species', '9606', (151, 159))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('cancer', 'Disease', (264, 270))	('cancer', 'Disease', 'MESH:D009369', (264, 270))
101655	32066500	We labeled variant calls as concordant for a given variant if they gave the exact same variant call (homozygous for the reference allele, heterozygous, or homozygous for the alternate allele) in the WXS normal, WXS tumor, and RNA tumor samples.	('tumor', 'Disease', (230, 235))	('WXS', 'Chemical', '-', (199, 202))	('tumor', 'Disease', 'MESH:D009369', (215, 220))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('tumor', 'Disease', 'MESH:D009369', (230, 235))	('WXS', 'Chemical', '-', (211, 214))	('variant', 'Var', (51, 58))	('tumor', 'Disease', (215, 220))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))
101662	32066500	Where we did not control for patient race composition in cancers where patient race composition was not identified as a significant predictor of patient outcome by Lasso-regularized Cox regression, we later retested the set of prognostic germline variants by adding back patient race composition as a covariate into our Cox regression models.	('patient', 'Species', '9606', (29, 36))	('variants', 'Var', (247, 255))	('Cox', 'Gene', '1351', (182, 185))	('Cox', 'Gene', (182, 185))	('cancers', 'Phenotype', 'HP:0002664', (57, 64))	('patient', 'Species', '9606', (271, 278))	('Cox', 'Gene', '1351', (320, 323))	('cancers', 'Disease', (57, 64))	('patient', 'Species', '9606', (145, 152))	('cancers', 'Disease', 'MESH:D009369', (57, 64))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('Cox', 'Gene', (320, 323))	('patient', 'Species', '9606', (71, 78))
101663	32066500	As expected, because patient race composition was not a significant predictor of patient outcome in these cancers, we still found all of our originally identified prognostic germline variants to be statistically significant predictors of patient outcome.	('patient', 'Species', '9606', (81, 88))	('patient', 'Species', '9606', (21, 28))	('variants', 'Var', (183, 191))	('cancers', 'Phenotype', 'HP:0002664', (106, 113))	('cancers', 'Disease', (106, 113))	('cancers', 'Disease', 'MESH:D009369', (106, 113))	('patient', 'Species', '9606', (238, 245))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
101667	32066500	The most natural way for treatment differences to account for the observation that germline variation is associated with patient outcome is due to socioeconomic differences associated with patient race or unconscious or conscious biases in treatment selection based on patient race.	('germline variation', 'Var', (83, 101))	('patient', 'Species', '9606', (189, 196))	('patient', 'Species', '9606', (269, 276))	('associated', 'Reg', (105, 115))	('patient', 'Species', '9606', (121, 128))
101673	32066500	In all analyses, we tested variants for an association with outcome using a Cox regression model, controlling for the covariates that we identified previously for each cancer using Lasso regularization.	('variants', 'Var', (27, 35))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('tested', 'Reg', (20, 26))	('Cox', 'Gene', '1351', (76, 79))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('cancer', 'Disease', (168, 174))	('Cox', 'Gene', (76, 79))
101675	32066500	In analysis 1, we tested variants for an association with patient outcome in individual cancers, setting an adjusted p value threshold (FDR) less than 0.10.	('variants', 'Var', (25, 33))	('patient', 'Species', '9606', (58, 65))	('cancers', 'Disease', 'MESH:D009369', (88, 95))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('cancers', 'Disease', (88, 95))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('tested', 'Reg', (18, 24))
101676	32066500	In the second analysis, we filtered our results from analysis 1 to identify germline variants that were recurrently associated (p < 0.05) with favorable (hazard ratio (HR) < 1) or poor (HR > 1) outcome relative to the reference allele in seven or more cancers, such that the most recurrent prognostic variants would be reported.	('poor', 'NegReg', (180, 184))	('cancers', 'Phenotype', 'HP:0002664', (252, 259))	('variants', 'Var', (85, 93))	('cancers', 'Disease', (252, 259))	('cancers', 'Disease', 'MESH:D009369', (252, 259))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))
101683	32066500	Analyses 4-6 were quite similar to analyses 1 through 3, except that we restricted our analysis to only germline variants that caused significant amino acid changes with a Combined Annotation Dependent Depletion (CADD) score greater than 25.	('C', 'Chemical', '-', (213, 214))	('C', 'Chemical', '-', (172, 173))	('variants', 'Var', (113, 121))	('amino acid changes', 'MPA', (146, 164))
101684	32066500	In analysis 4, we tested variants with CADD score > 25 in individual cancers for an association with patient outcome (FDR < 0.10).	('association', 'Interaction', (84, 95))	('cancers', 'Disease', 'MESH:D009369', (69, 76))	('variants', 'Var', (25, 33))	('CADD score', 'Gene', (39, 49))	('cancers', 'Disease', (69, 76))	('cancers', 'Phenotype', 'HP:0002664', (69, 76))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('patient', 'Species', '9606', (101, 108))	('tested', 'Reg', (18, 24))
101685	32066500	In analysis 5, we filtered the results from analysis 4 to identify germline variants with CADD score > 25 that were recurrently associated (p < 0.05) with favorable (HR < 1) or poor (HR > 1) prognosis in five or more patients.	('poor', 'NegReg', (177, 181))	('variants', 'Var', (76, 84))	('associated', 'Reg', (128, 138))	('CADD score >', 'Gene', (90, 102))	('patients', 'Species', '9606', (217, 225))
101687	32066500	Identifying germline variants associated with patient outcome in cancer X  Identifying germline variants associated with patient outcome in cancer Y  Identifying germline variants associated with patient outcome when the patients with cancer X and the patients with cancer Y are pooled together  The Cox regression models that we fit for individual cancers controlled for the covariates that we found to be prognostic in those cancers (Additional file 1: Table S1).	('patients', 'Species', '9606', (221, 229))	('cancers', 'Disease', 'MESH:D009369', (427, 434))	('cancer', 'Disease', 'MESH:D009369', (427, 433))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('Cox', 'Gene', '1351', (300, 303))	('patient', 'Species', '9606', (121, 128))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (266, 272))	('variants', 'Var', (96, 104))	('cancer', 'Disease', 'MESH:D009369', (235, 241))	('patients', 'Species', '9606', (252, 260))	('associated', 'Reg', (180, 190))	('cancers', 'Phenotype', 'HP:0002664', (349, 356))	('cancer', 'Disease', (349, 355))	('cancers', 'Disease', (349, 356))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('Cox', 'Gene', (300, 303))	('patient', 'Species', '9606', (221, 228))	('patient', 'Species', '9606', (46, 53))	('patient', 'Species', '9606', (252, 259))	('cancers', 'Phenotype', 'HP:0002664', (427, 434))	('cancer', 'Phenotype', 'HP:0002664', (349, 355))	('cancer', 'Disease', (427, 433))	('cancers', 'Disease', (427, 434))	('patient', 'Species', '9606', (196, 203))	('cancer', 'Disease', (140, 146))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('variants', 'Var', (21, 29))	('cancer', 'Disease', (235, 241))	('cancer', 'Disease', (266, 272))	('cancer', 'Disease', 'MESH:D009369', (349, 355))	('cancers', 'Disease', 'MESH:D009369', (349, 356))	('cancer', 'Phenotype', 'HP:0002664', (266, 272))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))	('variants', 'Var', (171, 179))
101691	32066500	Then we would fit two Cox regression models to identify prognostic germline variants in individual cancers and a third Cox regression model to identify germline variants prognostic in the pooled cohort, as illustrated below.	('Cox', 'Gene', '1351', (119, 122))	('Cox', 'Gene', (119, 122))	('cancers', 'Disease', 'MESH:D009369', (99, 106))	('cancers', 'Phenotype', 'HP:0002664', (99, 106))	('cancers', 'Disease', (99, 106))	('variants', 'Var', (76, 84))	('Cox', 'Gene', '1351', (22, 25))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('Cox', 'Gene', (22, 25))
101696	32066500	We tested whether germline variants associated with patient outcome (p < 0.05) in three of more cancers were typically recurrently associated with increased risk of poor outcome or recurrently associated with decreased risk of poor outcome more often than would be expected by random chance and if the hazard ratios estimated for these prognostic germline variants in different cancers were correlated with each other.	('variants', 'Var', (27, 35))	('cancers', 'Phenotype', 'HP:0002664', (96, 103))	('cancer', 'Phenotype', 'HP:0002664', (378, 384))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('tested', 'Reg', (3, 9))	('cancers', 'Phenotype', 'HP:0002664', (378, 385))	('patient', 'Species', '9606', (52, 59))	('cancers', 'Disease', 'MESH:D009369', (96, 103))	('cancers', 'Disease', 'MESH:D009369', (378, 385))	('associated', 'Reg', (36, 46))	('cancers', 'Disease', (96, 103))	('cancers', 'Disease', (378, 385))	('decreased', 'NegReg', (209, 218))
101698	32066500	While theoretically the expected value would be 0.5 for a random germline variant, we empirically estimated the expected value by the following calculation:  In this set of prognostic variants, there were more variants associated with poor patient outcome (HR < 1) than favorable patient outcome (HR > 1), resulting in the expected index being 0.589.	('patient', 'Species', '9606', (280, 287))	('associated with', 'Reg', (219, 234))	('variants', 'Var', (210, 218))	('poor patient outcome', 'CPA', (235, 255))	('patient', 'Species', '9606', (240, 247))	('variants', 'Var', (184, 192))
101700	32066500	We identified the set of variants associated with favorable (HR < 1) outcome and poor (HR > 1) outcome in three or more cancers.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('variants', 'Var', (25, 33))	('cancers', 'Phenotype', 'HP:0002664', (120, 127))	('cancers', 'Disease', (120, 127))	('cancers', 'Disease', 'MESH:D009369', (120, 127))
101704	32066500	For example, suppose a variant was found to be prognostic in both group 20 (KICH, KIRP) and group 19 (KICH, KIRC, KIRP).	('C', 'Chemical', '-', (111, 112))	('variant', 'Var', (23, 30))	('C', 'Chemical', '-', (104, 105))	('KICH', 'Disease', 'None', (102, 106))	('KICH', 'Disease', (76, 80))	('C', 'Chemical', '-', (78, 79))	('KICH', 'Disease', (102, 106))	('KICH', 'Disease', 'None', (76, 80))
101709	32066500	Because most of the prognostic variants in individual cancers were associated with increased risk for poor outcome, we limited this analysis to only variants associated with increased risk for poor outcome and excluded variants associated with favorable outcome.	('cancers', 'Phenotype', 'HP:0002664', (54, 61))	('variants', 'Var', (31, 39))	('cancers', 'Disease', (54, 61))	('cancers', 'Disease', 'MESH:D009369', (54, 61))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
101711	32066500	Patients homozygous for the reference allele of both prognostic germline variants Patients heterozygous for one of the two prognostic germline variants and homozygous for the reference allele of the other prognostic germline variant Patients heterozygous for both of the prognostic germline variants Having setup the conditions for this test, we created three groups for each pair of prognostic germline variants associated with poor patient outcome:  We then tested for differences in patient outcome between groups (2) and (1) and groups (3) and (1).	('patient', 'Species', '9606', (486, 493))	('Patients', 'Species', '9606', (82, 90))	('Patients', 'Species', '9606', (0, 8))	('Patients', 'Species', '9606', (233, 241))	('tested', 'Reg', (460, 466))	('patient', 'Species', '9606', (434, 441))	('variants', 'Var', (143, 151))
101714	32066500	For each prognostic germline variant, we tested whether the variant associated with increased risk of poor outcome was associated with an increased incidence of somatic mutations in each of the driver genes being considered for that cancer in patients with the allele associated with increased risk of poor outcome compared to patients with the protective allele using one-sided Fisher's exact test.	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('patients', 'Species', '9606', (243, 251))	('variant', 'Var', (60, 67))	('cancer', 'Disease', (233, 239))	('cancer', 'Disease', 'MESH:D009369', (233, 239))	('tested', 'Reg', (41, 47))	('patients', 'Species', '9606', (327, 335))
101716	32066500	While we had identified germline variants associated with outcome controlling for clinical covariates, we aimed to determine whether these variants significantly improved patient outcome predictions beyond predictions made using the clinical model alone, particularly in cancers in which the prediction by the clinical model was already quite accurate.	('patient', 'Species', '9606', (171, 178))	('cancer', 'Phenotype', 'HP:0002664', (271, 277))	('improved', 'PosReg', (162, 170))	('patient outcome', 'MPA', (171, 186))	('variants', 'Var', (139, 147))	('cancers', 'Disease', 'MESH:D009369', (271, 278))	('cancers', 'Phenotype', 'HP:0002664', (271, 278))	('cancers', 'Disease', (271, 278))	('variants', 'Var', (33, 41))
101717	32066500	We generated receiver operator characteristic (ROC) curves from the tenth percentile of patient death or patient progression to the ninetieth percentile of patient death or patient progression for each variant in R (https://cran.r-project.org/web/packages/survivalROC/survivalROC.pdf, https://cran.r-project.org/web/packages/timeROC/timeROC.pdf).	('C', 'Chemical', '-', (278, 279))	('patient', 'Species', '9606', (105, 112))	('patient', 'Species', '9606', (88, 95))	('C', 'Chemical', '-', (49, 50))	('C', 'Chemical', '-', (331, 332))	('patient', 'Species', '9606', (173, 180))	('death', 'Disease', 'MESH:D003643', (164, 169))	('death', 'Disease', (164, 169))	('death', 'Disease', 'MESH:D003643', (96, 101))	('C', 'Chemical', '-', (266, 267))	('death', 'Disease', (96, 101))	('variant', 'Var', (202, 209))	('C', 'Chemical', '-', (339, 340))	('patient', 'Species', '9606', (156, 163))
101719	32066500	While our Cox regression analysis identified variants that were significantly associated with patient outcome, these variants may not necessarily substantially improve clinical outcome predictions in cancers in which the clinical variables are already very good at predicting outcome.	('associated', 'Reg', (78, 88))	('cancers', 'Disease', 'MESH:D009369', (200, 207))	('cancers', 'Phenotype', 'HP:0002664', (200, 207))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('variants', 'Var', (45, 53))	('cancers', 'Disease', (200, 207))	('Cox', 'Gene', (10, 13))	('Cox', 'Gene', '1351', (10, 13))	('patient', 'Species', '9606', (94, 101))
101720	32066500	Having generated a list of genes that the germline variants are associated with from biomaRt, we first specifically searched the literature to see if these genes had a function in cancer that had been characterized and that fit a category described by Weinberg and Hanahan.	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('variants', 'Var', (51, 59))	('cancer', 'Disease', (180, 186))	('cancer', 'Disease', 'MESH:D009369', (180, 186))
101724	32066500	Finally, to understand in general whether or not these genes are being actively studied by the field, we categorized these genes based on whether or not the literature suggested that the genes are being studied in a cancer in which the germline variant was found to be prognostic, studied in any cancer, or studied in any human disease.	('germline', 'Var', (236, 244))	('cancer', 'Phenotype', 'HP:0002664', (296, 302))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('cancer', 'Disease', 'MESH:D009369', (296, 302))	('cancer', 'Disease', (216, 222))	('cancer', 'Disease', 'MESH:D009369', (216, 222))	('human', 'Species', '9606', (322, 327))	('cancer', 'Disease', (296, 302))
101726	32066500	We determined the domain in which these germline variants cause their amino acid changes using the National Center for Biotechnology Information databases (https://www.ncbi.nlm.nih.gov/) and the Ensembl and Uniprot databases.	('C', 'Chemical', '-', (108, 109))	('amino acid changes', 'MPA', (70, 88))	('variants', 'Var', (49, 57))
101727	32066500	For each germline variant, we separated patients based on whether or not they had at least one non-reference allele and then determined whether or not there was a statistically significant difference between the mean expression of the gene associated with the variant between the two groups using a Wilcoxon rank sum test.	('patients', 'Species', '9606', (40, 48))	('expression', 'MPA', (217, 227))	('variant', 'Var', (260, 267))
101731	32066500	We found the germline variant rs1800932 in MSH6 to be associated with favorable patient outcome and increased MSH6 expression.	('MSH6', 'Gene', '2956', (43, 47))	('increased', 'PosReg', (100, 109))	('MSH6', 'Gene', '2956', (110, 114))	('MSH6', 'Gene', (43, 47))	('expression', 'MPA', (115, 125))	('rs1800932', 'Mutation', 'rs1800932', (30, 39))	('patient', 'Species', '9606', (80, 87))	('rs1800932', 'Var', (30, 39))	('MSH6', 'Gene', (110, 114))
101732	32066500	Because a previous analysis found that MSH6 knockdown resulted in increased temozolomide resistance, we tested whether MSH6 expression was correlated with temozolomide sensitivity in cancer cell lines.	('cancer', 'Disease', (183, 189))	('increased', 'PosReg', (66, 75))	('MSH6', 'Gene', '2956', (119, 123))	('temozolomide', 'Chemical', 'MESH:D000077204', (155, 167))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('MSH6', 'Gene', (119, 123))	('temozolomide', 'Chemical', 'MESH:D000077204', (76, 88))	('MSH6', 'Gene', (39, 43))	('knockdown', 'Var', (44, 53))	('temozolomide resistance', 'MPA', (76, 99))	('tested', 'Reg', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (183, 189))	('MSH6', 'Gene', '2956', (39, 43))
101737	32066500	To identify prognostic germline variants that provide additional outcome information not already captured by clinical variables, we created clinical models predictive of patient outcome for each cancer using the clinical information previously collected by the TCGA research network along with the components of calculated race from The Cancer Genome Ancestry Atlas.	('C', 'Chemical', '-', (337, 338))	('C', 'Chemical', '-', (262, 263))	('cancer', 'Disease', (195, 201))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('variants', 'Var', (32, 40))	('Cancer', 'Phenotype', 'HP:0002664', (337, 343))	('patient', 'Species', '9606', (170, 177))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
101739	32066500	The first three analyses identified germline variants associated with prognosis in (1) individual cancers, (2) multiple cancers giving roughly equal weight to each cancer, and (3) cancers grouped by organ system, histological, or molecular classifications (Fig.	('cancers', 'Phenotype', 'HP:0002664', (98, 105))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('cancer', 'Disease', (98, 104))	('cancers', 'Disease', (98, 105))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('cancers', 'Disease', 'MESH:D009369', (180, 187))	('cancers', 'Phenotype', 'HP:0002664', (120, 127))	('cancers', 'Disease', (120, 127))	('germline variants', 'Var', (36, 53))	('cancer', 'Disease', (180, 186))	('prognosis', 'Disease', (70, 79))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('cancers', 'Disease', 'MESH:D009369', (98, 105))	('cancer', 'Disease', (164, 170))	('associated with', 'Reg', (54, 69))	('cancers', 'Phenotype', 'HP:0002664', (180, 187))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('cancers', 'Disease', (180, 187))	('cancers', 'Disease', 'MESH:D009369', (120, 127))	('cancer', 'Disease', 'MESH:D009369', (180, 186))
101740	32066500	Analysis 1 tested 519,139 variants for associations with patient outcome in individual cancers and identified 70 unique prognostic variants (Fig.	('cancers', 'Disease', (87, 94))	('patient', 'Species', '9606', (57, 64))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cancers', 'Phenotype', 'HP:0002664', (87, 94))	('variants', 'Var', (131, 139))	('associations', 'Interaction', (39, 51))	('cancers', 'Disease', 'MESH:D009369', (87, 94))	('variants', 'Var', (26, 34))
101741	32066500	While analysis 2 identified hundreds of variants recurrently predictive of outcome in > 4 cancers, we will only discuss the 5 variants that were predictive in seven or more cancers (Fig.	('cancers', 'Disease', (90, 97))	('cancers', 'Disease', 'MESH:D009369', (173, 180))	('variants', 'Var', (126, 134))	('cancers', 'Disease', (173, 180))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('variants', 'Var', (40, 48))	('cancers', 'Phenotype', 'HP:0002664', (173, 180))	('cancers', 'Disease', 'MESH:D009369', (90, 97))
101746	32066500	Analyses 4-6 repeated analyses 1-3 but limited these analyses to variants within the top 0.3% of deleterious mutants across the human genome with CADD > 25 (Fig.	('CADD > 25', 'Gene', (146, 155))	('variants', 'Var', (65, 73))	('human', 'Species', '9606', (128, 133))	('mutants', 'Var', (109, 116))
101747	32066500	Of the 16 variants that were recurrently predictive of patient outcomes in four or more cancers (analysis 5), we will discuss the one variant that was predictive in five cancers (Fig.	('cancers', 'Phenotype', 'HP:0002664', (170, 177))	('cancers', 'Disease', (170, 177))	('variants', 'Var', (10, 18))	('cancers', 'Disease', 'MESH:D009369', (170, 177))	('cancers', 'Disease', 'MESH:D009369', (88, 95))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('cancers', 'Disease', (88, 95))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('patient', 'Species', '9606', (55, 62))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))
101748	32066500	Analysis 6 tested 903 unique variants for an association with outcome in the patient groups used in analysis 3 and described in Fig.	('variants', 'Var', (29, 37))	('patient', 'Species', '9606', (77, 84))	('association', 'Interaction', (45, 56))
101752	32066500	We also found that some of the prognostic germline variants were associated with an increased risk of somatic mutations in cancer driver genes.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('germline variants', 'Var', (42, 59))	('cancer', 'Disease', (123, 129))	('cancer', 'Disease', 'MESH:D009369', (123, 129))
101754	32066500	The effect sizes of prognostic germline variants from analysis 1 were large enough to hypothesize that germline variants identified in individual cancers could improve clinical outcome models in current use.	('clinical outcome models', 'MPA', (168, 191))	('cancers', 'Disease', (146, 153))	('cancers', 'Disease', 'MESH:D009369', (146, 153))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('variants', 'Var', (40, 48))	('cancers', 'Phenotype', 'HP:0002664', (146, 153))	('variants', 'Var', (112, 120))	('improve', 'PosReg', (160, 167))
101762	32066500	There is a consistent, statistically significant (p < 0.05) increase in AUC when the clinical model is enhanced by germline variant information (C + GV) compared to the clinical model alone (C) for 63 of the predictive germline variants out of 70 tested (Additional file 3: Table S4).	('AUC', 'MPA', (72, 75))	('C', 'Chemical', '-', (145, 146))	('C', 'Chemical', '-', (191, 192))	('C', 'Chemical', '-', (74, 75))	('increase', 'PosReg', (60, 68))	('enhanced', 'PosReg', (103, 111))	('C + GV', 'Chemical', '-', (145, 151))	('variants', 'Var', (228, 236))
101764	32066500	In total, 90 of the 193 genes in the proximity of one of the prognostic germline variants have been functionally implicated in nine of the 12 hallmarks of cancer (Fig.	('hallmarks of cancer', 'Disease', (142, 161))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('implicated', 'Reg', (113, 123))	('hallmarks of cancer', 'Disease', 'MESH:D009369', (142, 161))	('variants', 'Var', (81, 89))
101765	32066500	Roughly 50% of the predictive variants are found in or near genes that possibly have tumor suppressor or oncogenic activity (Fig.	('tumor', 'Disease', (85, 90))	('variants', 'Var', (30, 38))	('oncogenic activity', 'CPA', (105, 123))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))
101766	32066500	About 25% of the predictive genes were previously studied in the cancer in which the germline variant was found to be prognostic, about half were previously studied in at least one cancer, and roughly two thirds were studied in at least one human disease (Fig.	('variant', 'Var', (94, 101))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('human', 'Species', '9606', (241, 246))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('cancer', 'Disease', (181, 187))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))
101767	32066500	Prognostic variants were identified in or near MSH6, POLQ, ARID5B, and IDH2, which are previously reported cancer driver genes (Fig.	('MSH6', 'Gene', '2956', (47, 51))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('variants', 'Var', (11, 19))	('IDH2', 'Gene', (71, 75))	('IDH2', 'Gene', '3418', (71, 75))	('MSH6', 'Gene', (47, 51))	('POLQ', 'Gene', (53, 57))	('ARID5B', 'Gene', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('POLQ', 'Gene', '10721', (53, 57))	('ARID5B', 'Gene', '84159', (59, 65))	('cancer', 'Disease', (107, 113))
101769	32066500	Some of the prognostic variants are linked with diseases that occur in the tissue giving rise to the tumor, suggesting the variant has an important function in that tissue (Fig.	('variants', 'Var', (23, 31))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
101772	32066500	rs1800932 predicts favorable patient outcome in gliomas (LGG and GBM).	('patient', 'Species', '9606', (29, 36))	('gliomas', 'Disease', 'MESH:D005910', (48, 55))	('gliomas', 'Phenotype', 'HP:0009733', (48, 55))	('glioma', 'Phenotype', 'HP:0009733', (48, 54))	('rs1800932', 'Mutation', 'rs1800932', (0, 9))	('rs1800932', 'Var', (0, 9))	('gliomas', 'Disease', (48, 55))
101774	32066500	We found MSH6 expression to be correlated with elevated temozolomide sensitivity in cancer cell lines (Spearman's rho = 0.165, p = 5.01E-7).	('expression', 'Var', (14, 24))	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('temozolomide sensitivity', 'MPA', (56, 80))	('cancer', 'Disease', (84, 90))	('MSH6', 'Gene', (9, 13))	('elevated', 'PosReg', (47, 55))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('temozolomide', 'Chemical', 'MESH:D000077204', (56, 68))	('MSH6', 'Gene', '2956', (9, 13))
101776	32066500	MSH6 knockdown increases temozolomide resistance and somatic mutations in MSH6 are associated with temozolomide resistance in gliomas.	('glioma', 'Phenotype', 'HP:0009733', (126, 132))	('temozolomide resistance', 'MPA', (99, 122))	('knockdown', 'Var', (5, 14))	('MSH6', 'Gene', '2956', (74, 78))	('MSH6', 'Gene', '2956', (0, 4))	('temozolomide', 'Chemical', 'MESH:D000077204', (25, 37))	('mutations', 'Var', (61, 70))	('temozolomide resistance', 'MPA', (25, 48))	('associated', 'Reg', (83, 93))	('MSH6', 'Gene', (74, 78))	('increases', 'PosReg', (15, 24))	('gliomas', 'Disease', 'MESH:D005910', (126, 133))	('gliomas', 'Phenotype', 'HP:0009733', (126, 133))	('gliomas', 'Disease', (126, 133))	('MSH6', 'Gene', (0, 4))	('temozolomide', 'Chemical', 'MESH:D000077204', (99, 111))
101777	32066500	Taken together, this suggests that rs1800932 is an eQTL for increased expression of MSH6 in gliomas, which may increase sensitivity to temozolomide, the primary chemotherapeutic agent for gliomas.	('MSH6', 'Gene', '2956', (84, 88))	('increase', 'PosReg', (111, 119))	('glioma', 'Phenotype', 'HP:0009733', (188, 194))	('rs1800932', 'Var', (35, 44))	('sensitivity to temozolomide', 'MPA', (120, 147))	('MSH6', 'Gene', (84, 88))	('gliomas', 'Disease', (92, 99))	('expression', 'MPA', (70, 80))	('gliomas', 'Disease', 'MESH:D005910', (188, 195))	('gliomas', 'Disease', (188, 195))	('gliomas', 'Disease', 'MESH:D005910', (92, 99))	('temozolomide', 'Chemical', 'MESH:D000077204', (135, 147))	('gliomas', 'Phenotype', 'HP:0009733', (92, 99))	('gliomas', 'Phenotype', 'HP:0009733', (188, 195))	('glioma', 'Phenotype', 'HP:0009733', (92, 98))	('increased', 'PosReg', (60, 69))	('rs1800932', 'Mutation', 'rs1800932', (35, 44))
101778	32066500	rs55796947 in MAP2K3/MKK3 predicts favorable prognosis in KIRC.	('MKK3', 'Gene', '5606', (21, 25))	('MAP2K3', 'Gene', '5606', (14, 20))	('MKK3', 'Gene', (21, 25))	('rs55796947', 'Var', (0, 10))	('KIRC', 'Disease', (58, 62))	('C', 'Chemical', '-', (61, 62))	('MAP2K3', 'Gene', (14, 20))	('rs55796947', 'Mutation', 'rs55796947', (0, 10))
101781	32066500	Indeed, tumors in patients with this variant upregulate genes involved with apoptosis (p < 0.001, Fig.	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('variant', 'Var', (37, 44))	('tumors', 'Disease', (8, 14))	('tumors', 'Disease', 'MESH:D009369', (8, 14))	('patients', 'Species', '9606', (18, 26))	('tumors', 'Phenotype', 'HP:0002664', (8, 14))	('genes', 'Gene', (56, 61))	('upregulate', 'PosReg', (45, 55))
101782	32066500	This germline variant likely truncates the kinase domain of MAP2K3, resulting in cell cycle arrest, apoptosis, and favorable patient outcome.	('MAP2K3', 'Gene', (60, 66))	('truncates', 'NegReg', (29, 38))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (81, 98))	('kinase domain', 'MPA', (43, 56))	('patient', 'Species', '9606', (125, 132))	('MAP2K3', 'Gene', '5606', (60, 66))	('variant', 'Var', (14, 21))	('apoptosis', 'CPA', (100, 109))	('cell cycle arrest', 'CPA', (81, 98))
101783	32066500	rs77903511 predicts poor patient outcome in UVM (Fig.	('rs77903511', 'Var', (0, 10))	('patient', 'Species', '9606', (25, 32))	('rs77903511', 'Mutation', 'rs77903511', (0, 10))	('UVM', 'Disease', (44, 47))
101786	32066500	Consistent with a role of BIRC5 in apoptosis inhibition, BIRC5 expression is associated with poor patient outcome (Fig.	('patient', 'Species', '9606', (98, 105))	('C', 'Chemical', '-', (29, 30))	('BIRC5', 'Gene', '332', (26, 31))	('BIRC5', 'Gene', '332', (57, 62))	('BIRC5', 'Gene', (26, 31))	('BIRC5', 'Gene', (57, 62))	('C', 'Chemical', '-', (60, 61))	('C', 'Chemical', '-', (0, 1))	('expression', 'Var', (63, 73))
101787	32066500	This variant, therefore, may be associated with poor outcome because of an increase of the apoptosis inhibitor BIRC5.	('BIRC5', 'Gene', (111, 116))	('BIRC5', 'Gene', '332', (111, 116))	('variant', 'Var', (5, 12))	('increase', 'PosReg', (75, 83))
101788	32066500	This study shows, as a general principle, that germline variants are associated with cancer patient outcome.	('patient', 'Species', '9606', (92, 99))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('cancer', 'Disease', (85, 91))	('associated with', 'Reg', (69, 84))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('germline variants', 'Var', (47, 64))
101789	32066500	The prognostic germline variants enhanced patient outcome predictions compared to models based on currently collected clinical data.	('patient', 'Species', '9606', (42, 49))	('patient', 'MPA', (42, 49))	('enhanced', 'PosReg', (33, 41))	('variants', 'Var', (24, 32))
101793	32066500	The power calculations and the identification of additional prognostic germline variants by grouping similar cancers suggest that more prognostic germline variants will likely emerge as more tumors are sequenced and will further support the notion that germline variation is associated with patient outcome across cancers.	('tumors', 'Phenotype', 'HP:0002664', (191, 197))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('cancers', 'Disease', 'MESH:D009369', (314, 321))	('variants', 'Var', (155, 163))	('patient', 'Species', '9606', (291, 298))	('cancers', 'Disease', 'MESH:D009369', (109, 116))	('cancers', 'Phenotype', 'HP:0002664', (109, 116))	('cancers', 'Disease', (314, 321))	('associated', 'Reg', (275, 285))	('cancers', 'Disease', (109, 116))	('tumors', 'Disease', 'MESH:D009369', (191, 197))	('cancer', 'Phenotype', 'HP:0002664', (314, 320))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('tumors', 'Disease', (191, 197))	('cancers', 'Phenotype', 'HP:0002664', (314, 321))
101796	32066500	It is reassuring that a significant fraction of prognostic germline variants are found in or near possible tumor suppressor genes, oncogenes, or known cancer driver genes.	('germline variants', 'Var', (59, 76))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('cancer', 'Disease', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('tumor', 'Disease', 'MESH:D009369', (107, 112))
101797	32066500	The variants in cancer driver genes, MSH6, POLQ, ARID5B, and IDH2, warrant further study to determine the mechanism by which these variant affect cancer progression.	('MSH6', 'Gene', '2956', (37, 41))	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('affect', 'Reg', (139, 145))	('variants', 'Var', (4, 12))	('cancer', 'Disease', 'MESH:D009369', (16, 22))	('cancer', 'Disease', (16, 22))	('IDH2', 'Gene', (61, 65))	('MSH6', 'Gene', (37, 41))	('IDH2', 'Gene', '3418', (61, 65))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('ARID5B', 'Gene', '84159', (49, 55))	('POLQ', 'Gene', (43, 47))	('ARID5B', 'Gene', (49, 55))	('POLQ', 'Gene', '10721', (43, 47))
101798	32066500	A handful of the prognostic germline variants have been associated with human disease, some in the same tissue and others in unrelated tissues, suggesting that these pathologies may stem from shared molecular phenomena (Additional file 5: Table S6).	('variants', 'Var', (37, 45))	('human disease', 'Disease', (72, 85))	('human', 'Species', '9606', (72, 77))	('associated', 'Reg', (56, 66))
101799	32066500	There are many possibilities by which the variants that do not cause amino acid changes could affect cancer biology.	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('cancer', 'Disease', (101, 107))	('variants', 'Var', (42, 50))	('affect', 'Reg', (94, 100))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))
101800	32066500	Some of the variants may also be acting as eQTLs in non-tumor cells, such as immune system cells or cells of the vasculature.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('variants', 'Var', (12, 20))	('tumor', 'Disease', (56, 61))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
101801	32066500	The already high involvement of tumor suppressor genes, oncogenes, and driver genes among the prognostic germline variants is promising for future study.	('variants', 'Var', (114, 122))	('tumor', 'Disease', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumor', 'Disease', 'MESH:D009369', (32, 37))
101805	32066500	We identified prognostic germline variants across individual cancers and group of cancers and find that these germline variants provide additional predictive power about patient outcomes beyond the information that can be gathered from clinical factors alone.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('variants', 'Var', (34, 42))	('cancers', 'Phenotype', 'HP:0002664', (82, 89))	('cancers', 'Disease', 'MESH:D009369', (61, 68))	('cancers', 'Phenotype', 'HP:0002664', (61, 68))	('cancers', 'Disease', (82, 89))	('cancers', 'Disease', 'MESH:D009369', (82, 89))	('cancers', 'Disease', (61, 68))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('patient', 'Species', '9606', (170, 177))
101806	32066500	Mechanistically, 12 of the germline variants seem to be associated with patient outcome through perturbation of protein structure and at least five through association with gene expression differences, though the molecular functions of most of the germline variants are currently unknown.	('gene', 'MPA', (173, 177))	('associated', 'Reg', (56, 66))	('perturbation', 'NegReg', (96, 108))	('patient', 'Species', '9606', (72, 79))	('protein structure', 'MPA', (112, 129))	('variants', 'Var', (36, 44))	('association', 'Interaction', (156, 167))
101807	32066500	About half of the germline variants are in previously reported tumor suppressor genes, oncogenes, or driver genes with the other half implicating loci that deserve further investigation in oncology.	('tumor', 'Disease', (63, 68))	('variants', 'Var', (27, 35))	('oncology', 'Phenotype', 'HP:0002664', (189, 197))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
101853	27761967	The median mitotic index values and the percentage of necrosis, budding cells, and stromal reaction were all significantly less in ILT and LN-Mic than PT and LN-Mac (P < 0.001).	('budding cells', 'CPA', (64, 77))	('ILT', 'Disease', (131, 134))	('less', 'NegReg', (123, 127))	('mitotic index values', 'CPA', (11, 31))	('stromal reaction', 'CPA', (83, 99))	('necrosis', 'Disease', (54, 62))	('LN-Mic', 'Var', (139, 145))	('necrosis', 'Disease', 'MESH:D009336', (54, 62))
101897	31322243	In conclusion, the results of the present study suggest that miR-543 acts as a tumor promoter and serves a vital role in OSCC proliferation and invasion.	('OSCC', 'Disease', (121, 125))	('tumor', 'Disease', (79, 84))	('invasion', 'CPA', (144, 152))	('rat', 'Species', '10116', (133, 136))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('miR-543', 'Var', (61, 68))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
101907	31322243	The abnormal expression of miRNAs, when comparing normal and cancerous tissues, is closely associated with biological processes in tumors, including the cell cycle, proliferation, differentiation, growth and apoptosis.	('apoptosis', 'CPA', (208, 217))	('abnormal', 'Var', (4, 12))	('expression', 'MPA', (13, 23))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('miR', 'Gene', '220972', (27, 30))	('miR', 'Gene', (27, 30))	('cancerous', 'Disease', 'MESH:D009369', (61, 70))	('cancerous', 'Disease', (61, 70))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('cell cycle', 'CPA', (153, 163))	('differentiation', 'CPA', (180, 195))	('rat', 'Species', '10116', (172, 175))	('tumors', 'Disease', (131, 137))	('tumors', 'Disease', 'MESH:D009369', (131, 137))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('growth', 'CPA', (197, 203))	('proliferation', 'CPA', (165, 178))	('associated', 'Reg', (91, 101))
101914	31322243	Early studies have reported that the abnormal expression of CYP3A5 may be associated with the progression of HCC and may serve as a target for the treatment of hepatitis C-associated HCC as well as a marker.	('HCC', 'Gene', (109, 112))	('HCC', 'Gene', '619501', (183, 186))	('hepatitis C', 'Species', '11103', (160, 171))	('HCC', 'Gene', '619501', (109, 112))	('hepatitis', 'Phenotype', 'HP:0012115', (160, 169))	('HCC', 'Gene', (183, 186))	('CYP3A5', 'Gene', (60, 66))	('abnormal', 'Var', (37, 45))	('expression', 'MPA', (46, 56))	('associated', 'Reg', (74, 84))	('CYP3A5', 'Gene', '1577', (60, 66))
101961	31322243	First, we analyzed the expression level of miR-543 and CYP3A5 in 20 pairs of OSCC tissues by linear regression.	('CYP3A5', 'Gene', (55, 61))	('CYP3A5', 'Gene', '1577', (55, 61))	('miR-543', 'Var', (43, 50))
101984	31322243	5A), while the apoptotic rate was increased in the miR-543 inhibitor groups (Fig.	('miR-543', 'Gene', (51, 58))	('inhibitor', 'Var', (59, 68))	('apoptotic rate', 'CPA', (15, 29))	('rat', 'Species', '10116', (25, 28))	('increased', 'PosReg', (34, 43))
101994	31322243	The overexpression of miR-543 significantly reduced the luciferase activity of WT CYP3A5 3'UTR, while the MUT CYP3A5 3'UTR induced virtually no change (Fig.	('CYP3A5', 'Gene', '1577', (82, 88))	('CYP3A5', 'Gene', (110, 116))	('luciferase', 'Enzyme', (56, 66))	('activity', 'MPA', (67, 75))	('miR-543', 'Var', (22, 29))	('CYP3A5', 'Gene', '1577', (110, 116))	('reduced', 'NegReg', (44, 51))	('CYP3A5', 'Gene', (82, 88))
101995	31322243	Therefore, it was confirmed that CYP3A5 directly binds with miR-543, and that CYP3A5 acts as a downstream target gene of miR-543 in order to exert its influence on OSCC.	('CYP3A5', 'Gene', '1577', (78, 84))	('CYP3A5', 'Gene', (33, 39))	('miR-543', 'Var', (121, 128))	('binds', 'Interaction', (49, 54))	('CYP3A5', 'Gene', (78, 84))	('miR-543', 'Gene', (60, 67))	('influence', 'Reg', (151, 160))	('OSCC', 'Disease', (164, 168))	('CYP3A5', 'Gene', '1577', (33, 39))
101998	31322243	By contrast, the mRNA and protein expression of CYP3A5 was upregulated following miR-543 knockdown (Fig.	('CYP3A5', 'Gene', '1577', (48, 54))	('upregulated', 'PosReg', (59, 70))	('miR-543', 'Gene', (81, 88))	('knockdown', 'Var', (89, 98))	('CYP3A5', 'Gene', (48, 54))
102026	31322243	Kaplan-Meier Plot analysis demonstrated that patients with higher levels of miR-543 had significantly poorer survival than patients with lower miR-543 expression levels (Fig.	('poorer', 'NegReg', (102, 108))	('patients', 'Species', '9606', (123, 131))	('miR-543', 'Var', (76, 83))	('patients', 'Species', '9606', (45, 53))	('rat', 'Species', '10116', (34, 37))	('survival', 'CPA', (109, 117))
102027	31322243	These results indicated that miR-543 may be closely associated with the prognosis of patients.	('patients', 'Species', '9606', (85, 93))	('associated', 'Reg', (52, 62))	('miR-543', 'Var', (29, 36))
102032	31322243	It has also been demonstrated that aberrantly expressed miRNAs can regulate OSCC progression and that miRNAs may become targets for future therapy.	('OSCC', 'Disease', (76, 80))	('regulate', 'Reg', (67, 75))	('miR', 'Gene', '220972', (102, 105))	('miR', 'Gene', (102, 105))	('miR', 'Gene', '220972', (56, 59))	('miR', 'Gene', (56, 59))	('aberrantly expressed', 'Var', (35, 55))	('rat', 'Species', '10116', (24, 27))
102035	31322243	In previous research, it was demonstrated that miR-543 suppressed breast cancer cell proliferation, cell cycle and induced apoptosis by the extracellular signal-regulated kinase-2 (ERK2)/mitogen-activated protein kinase (MAPK) signaling pathway, and the phosphorylation of downstream factors including RSK2 and MSK1 was impeded.	('RSK2', 'Gene', '6197', (302, 306))	('miR-543', 'Var', (47, 54))	('extracellular signal-regulated kinase-2', 'Gene', (140, 179))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('phosphorylation', 'MPA', (254, 269))	('suppressed', 'NegReg', (55, 65))	('rat', 'Species', '10116', (36, 39))	('rat', 'Species', '10116', (92, 95))	('apoptosis', 'CPA', (123, 132))	('RSK2', 'Gene', (302, 306))	('breast cancer', 'Phenotype', 'HP:0003002', (66, 79))	('ERK2', 'Gene', '5594', (181, 185))	('MSK1', 'Gene', (311, 315))	('extracellular signal-regulated kinase-2', 'Gene', '5594', (140, 179))	('cell cycle', 'CPA', (100, 110))	('ERK2', 'Gene', (181, 185))	('induced', 'PosReg', (115, 122))	('breast cancer', 'Disease', 'MESH:D001943', (66, 79))	('breast cancer', 'Disease', (66, 79))	('MSK1', 'Gene', '9252', (311, 315))
102036	31322243	However, the present study did not further verify whether miR-543 affects OSCC through the ERK2/MAPK signaling pathway, which will be a direction for subsequent research.	('ERK2', 'Gene', (91, 95))	('OSCC', 'Disease', (74, 78))	('affects', 'Reg', (66, 73))	('ERK2', 'Gene', '5594', (91, 95))	('miR-543', 'Var', (58, 65))
102037	31322243	In addition, miR-543 exhibited a similar decrease in colorectal cancer and inhibited the growth, invasion and metastasis of colon cancer by targeting kirsten rat sarcoma viral oncogene homolog, metastasis-associated 1 and high mobility group AT-hook 2 genes.	('metastasis of colon cancer', 'Disease', (110, 136))	('sarcoma viral oncogene homolog, metastasis-associated 1 and high mobility group AT-hook 2', 'Gene', '84017', (162, 251))	('decrease', 'NegReg', (41, 49))	('inhibited', 'NegReg', (75, 84))	('targeting', 'Reg', (140, 149))	('metastasis of colon cancer', 'Disease', 'MESH:D009362', (110, 136))	('colorectal cancer', 'Disease', 'MESH:D015179', (53, 70))	('sarcoma', 'Phenotype', 'HP:0100242', (162, 169))	('rat', 'Species', '10116', (158, 161))	('colon cancer', 'Phenotype', 'HP:0003003', (124, 136))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('colorectal cancer', 'Phenotype', 'HP:0003003', (53, 70))	('growth', 'CPA', (89, 95))	('invasion', 'CPA', (97, 105))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('miR-543', 'Var', (13, 20))	('colorectal cancer', 'Disease', (53, 70))
102040	31322243	In gastric cancer and osteosarcoma, miR-543 was observed to be overexpressed and to serve as an oncogene to promote cancer cell proliferation and glycolysis.	('osteosarcoma', 'Disease', (22, 34))	('osteosarcoma', 'Disease', 'MESH:D012516', (22, 34))	('sarcoma', 'Phenotype', 'HP:0100242', (27, 34))	('gastric cancer', 'Phenotype', 'HP:0012126', (3, 17))	('rat', 'Species', '10116', (135, 138))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('gastric cancer', 'Disease', (3, 17))	('miR-543', 'Var', (36, 43))	('glycolysis', 'CPA', (146, 156))	('cancer', 'Disease', 'MESH:D009369', (11, 17))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('promote', 'PosReg', (108, 115))	('cancer', 'Disease', (11, 17))	('gastric cancer', 'Disease', 'MESH:D013274', (3, 17))	('osteosarcoma', 'Phenotype', 'HP:0002669', (22, 34))
102045	31322243	By contrast, inhibition of miR-543 suppressed the proliferation, invasion, migration and cell cycle progression of OSCC, while the levels of cell apoptosis were elevated.	('inhibition', 'Var', (13, 23))	('proliferation', 'CPA', (50, 63))	('rat', 'Species', '10116', (78, 81))	('suppressed', 'NegReg', (35, 45))	('elevated', 'PosReg', (161, 169))	('rat', 'Species', '10116', (57, 60))	('invasion', 'CPA', (65, 73))	('migration', 'CPA', (75, 84))	('miR-543', 'Gene', (27, 34))	('cell cycle progression', 'CPA', (89, 111))
102047	31322243	In the present study, CYP3A5 was identified as a direct target of miR-543.	('CYP3A5', 'Gene', '1577', (22, 28))	('miR-543', 'Var', (66, 73))	('CYP3A5', 'Gene', (22, 28))
102048	31322243	The supporting results were as follows: i) A complementary sequence of miR-543 was identified by site prediction in the 3'UTR of CYP3A5 mRNA; ii) the expression levels of miR-543 and CYP3A5 were negatively correlated in OSCC; and iii) the overexpression of miR-543 resulted in a significant decrease in CYP3A5 at the mRNA and protein levels, whereas the inhibition of miR-543 resulted in the opposite outcome.	('miR-543', 'Var', (257, 264))	('CYP3A5', 'Gene', '1577', (129, 135))	('CYP3A5', 'Gene', (183, 189))	('CYP3A5', 'Gene', (303, 309))	('decrease', 'NegReg', (291, 299))	('overexpression', 'PosReg', (239, 253))	('CYP3A5', 'Gene', (129, 135))	('CYP3A5', 'Gene', '1577', (303, 309))	('CYP3A5', 'Gene', '1577', (183, 189))
102049	31322243	The overexpression of miR-543 inhibited CYP3A5 3'UTR luciferase reporter activity and this effect was attenuated via mutations in the miR-543 seed binding site.	('mutations', 'Var', (117, 126))	('attenuated', 'NegReg', (102, 112))	('inhibited', 'NegReg', (30, 39))	('CYP3A5', 'Gene', (40, 46))	('miR-543', 'Gene', (22, 29))	('miR-543', 'Gene', (134, 141))	('overexpression', 'PosReg', (4, 18))	('CYP3A5', 'Gene', '1577', (40, 46))
102050	31322243	These results indicated that miR-543 may function as a tumor oncogene in OSCC mediated by the inhibition of CYP3A5 expression.	('CYP3A5', 'Gene', (108, 114))	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('inhibition', 'NegReg', (94, 104))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Disease', (55, 60))	('CYP3A5', 'Gene', '1577', (108, 114))	('miR-543', 'Var', (29, 36))	('OSCC', 'Disease', (73, 77))
102051	31322243	CYP3A5 is one of the major members of the cytochrome P450 CYP3A subfamily, and has been the focus of many previous studies investigating the associations with drug metabolism, CYP3A5 polymorphism and cancer risk.	('CYP3A', 'Gene', '1576', (176, 181))	('CYP3A5', 'Gene', (176, 182))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('CYP3A', 'Gene', (0, 5))	('associations', 'Interaction', (141, 153))	('polymorphism', 'Var', (183, 195))	('CYP3A', 'Gene', '1576', (0, 5))	('CYP3A5', 'Gene', '1577', (0, 6))	('CYP3A', 'Gene', (58, 63))	('CYP3A5', 'Gene', '1577', (176, 182))	('cancer', 'Disease', 'MESH:D009369', (200, 206))	('CYP3A', 'Gene', (176, 181))	('CYP3A5', 'Gene', (0, 6))	('cancer', 'Disease', (200, 206))	('CYP3A', 'Gene', '1576', (58, 63))
102058	31322243	In conclusion, the present study highlights the important role of miR-543 in promoting the cell proliferation, invasion and migration of OSCC cells by repressing of the expression of CYP3A5.	('rat', 'Species', '10116', (103, 106))	('CYP3A5', 'Gene', (183, 189))	('migration', 'CPA', (124, 133))	('rat', 'Species', '10116', (127, 130))	('repressing', 'NegReg', (151, 161))	('promoting', 'PosReg', (77, 86))	('CYP3A5', 'Gene', '1577', (183, 189))	('invasion', 'CPA', (111, 119))	('cell proliferation', 'CPA', (91, 109))	('miR-543', 'Var', (66, 73))
102096	30604926	To further investigate whether Type I collagen could be derived from cancer cells in addition to fibroblasts, we conducted Western blotting to detect the potential expression of Type I collagen in four kinds of lung cancer cell lines, including squamous carcinoma and adenocarcinoma (SCC35, SCC37, SCC210011, and AD212102).	('lung cancer', 'Phenotype', 'HP:0100526', (211, 222))	('squamous carcinoma and adenocarcinoma', 'Disease', 'MESH:D002294', (245, 282))	('AD212102', 'Var', (313, 321))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('SCC35', 'Var', (284, 289))	('carcinoma', 'Phenotype', 'HP:0030731', (254, 263))	('lung cancer', 'Disease', 'MESH:D008175', (211, 222))	('carcinoma', 'Phenotype', 'HP:0030731', (273, 282))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (245, 263))	('cancer', 'Disease', (216, 222))	('cancer', 'Disease', 'MESH:D009369', (216, 222))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Disease', (69, 75))	('lung cancer', 'Disease', (211, 222))
102110	30604926	The results of wounding healing assay demonstrated that inhibition of Type I collagen in A549 cells promoted the invasive ability of cancer cells (Fig 4a,b).	('A549', 'CellLine', 'CVCL:0023', (89, 93))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('Type I collagen', 'Protein', (70, 85))	('promoted', 'PosReg', (100, 108))	('cancer', 'Disease', (133, 139))	('inhibition', 'Var', (56, 66))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
102111	30604926	Fewer clones formed from cancer cells in the group treated with procollagen C-proteinase than in the control group (Fig 4c).	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('Fewer', 'NegReg', (0, 5))	('procollagen C-proteinase', 'Var', (64, 88))	('cancer', 'Disease', 'MESH:D009369', (25, 31))	('cancer', 'Disease', (25, 31))
102173	29426835	High ALDH1A3 expression has been reported as a poor prognostic marker for breast cancer and cholangiocarcinoma.	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (92, 110))	('breast cancer', 'Disease', (74, 87))	('breast cancer', 'Phenotype', 'HP:0003002', (74, 87))	('High', 'Var', (0, 4))	('ALDH1A3', 'Gene', (5, 12))	('expression', 'MPA', (13, 23))	('ALDH1A3', 'Gene', '220', (5, 12))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('cholangiocarcinoma', 'Disease', (92, 110))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('breast cancer', 'Disease', 'MESH:D001943', (74, 87))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (92, 110))
102187	29426835	In addition, tumor vs. normal microarray profiles for HNSC (GSE6631) and BRCA (GSE25291) have also been downloaded and analyzed.	('tumor', 'Disease', (13, 18))	('BRCA', 'Phenotype', 'HP:0003002', (73, 77))	('BRCA', 'Gene', '672', (73, 77))	('GSE6631', 'Var', (60, 67))	('BRCA', 'Gene', (73, 77))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('GSE6631', 'Chemical', '-', (60, 67))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('GSE25291', 'Var', (79, 87))
102201	29426835	The analysis showed that ALDH2 high expressed patients (N = 142) had significantly better survival than ALDH2 low expressed patients (N = 141) (HR = 1.59, CI = 1.1-2.29, p-value = 0.014) (Fig.	('patients', 'Species', '9606', (46, 54))	('ALDH2', 'Gene', '217', (25, 30))	('ALDH2', 'Gene', '217', (104, 109))	('better', 'PosReg', (83, 89))	('high expressed', 'Var', (31, 45))	('survival', 'CPA', (90, 98))	('ALDH2', 'Gene', (25, 30))	('ALDH2', 'Gene', (104, 109))	('patients', 'Species', '9606', (124, 132))
102202	29426835	Since the ALDH2 rs671 SNP is specifically common in the Asian and Taiwanese populations, we performed genotyping for HNSC patient samples and also compared the RNA expression between the tumor and normal tissues.	('rs671', 'Mutation', 'rs671', (16, 21))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('patient', 'Species', '9606', (122, 129))	('ALDH2', 'Gene', '217', (10, 15))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('ALDH2', 'Gene', (10, 15))	('tumor', 'Disease', (187, 192))	('rs671 SNP', 'Var', (16, 25))
102203	29426835	Interestingly, comparisons of ALDH2 genotype and expression levels in samples derived from our VGHTPE cohort resulted in the identification of a similar trend of lower ALDH2 expression in tumor samples both in the ALDH2 rs671 GG wild type allele and in the GA heterozygous allele when compared to normal tissues (Fig.	('tumor', 'Disease', (188, 193))	('ALDH2', 'Gene', (214, 219))	('expression', 'MPA', (174, 184))	('rs671 GG', 'Var', (220, 228))	('ALDH2', 'Gene', '217', (168, 173))	('ALDH2', 'Gene', (30, 35))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('rs671', 'Mutation', 'rs671', (220, 225))	('lower', 'NegReg', (162, 167))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('ALDH2', 'Gene', (168, 173))	('ALDH2', 'Gene', '217', (214, 219))	('ALDH2', 'Gene', '217', (30, 35))
102218	29426835	For the proof of concept, we used the ALDH2 agonist, Alda-1, which can specifically enhance enzymatic activity both in ALDH2 wild type and mutant form to treat cancer cells and observe the responsive phenotypes.	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('ALDH2', 'Gene', '217', (119, 124))	('Alda-1', 'Chemical', '-', (53, 59))	('cancer', 'Disease', (160, 166))	('ALDH2', 'Gene', '217', (38, 43))	('mutant', 'Var', (139, 145))	('ALDH2', 'Gene', (38, 43))	('ALDH2', 'Gene', (119, 124))	('enzymatic activity', 'MPA', (92, 110))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('enhance', 'PosReg', (84, 91))
102220	29426835	On the contrary, using siRNA to knockdown ALDH2 in MDA-MB-468 also increased migration (Supplemental Fig.	('ALDH2', 'Gene', '217', (42, 47))	('knockdown', 'Var', (32, 41))	('migration', 'CPA', (77, 86))	('increased', 'PosReg', (67, 76))	('ALDH2', 'Gene', (42, 47))	('MDA-MB-468', 'CellLine', 'CVCL:0419', (51, 61))
102223	29426835	The East Asian-specific ALDH2 rs671 SNP has raised attention and has been demonstrated to be a strong genetic factor for increased cancer risk, especially in patients with high alcohol intake.	('cancer', 'Disease', (131, 137))	('rs671 SNP', 'Var', (30, 39))	('rs671', 'Mutation', 'rs671', (30, 35))	('ALDH2', 'Gene', '217', (24, 29))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('ALDH2', 'Gene', (24, 29))	('patients', 'Species', '9606', (158, 166))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('alcohol', 'Chemical', 'MESH:D000438', (177, 184))
102224	29426835	ALDH2 rs671 is a SNP resulting in a K487E mutation.	('rs671', 'Var', (6, 11))	('K487E', 'Mutation', 'p.K487E', (36, 41))	('K487E', 'Var', (36, 41))	('rs671', 'Mutation', 'rs671', (6, 11))	('ALDH2', 'Gene', (0, 5))	('ALDH2', 'Gene', '217', (0, 5))
102225	29426835	This single amino acid mutation causes a severe functional deficiency of the ALDH2 enzymatic activity which then leads to acetaldehyde accumulation, even after intake of a single alcoholic beverage and is believed to be the underlying cause of increased cancer risks for HNSC and ESSC.	('cancer', 'Phenotype', 'HP:0002664', (254, 260))	('HNSC', 'Disease', (271, 275))	('acetaldehyde accumulation', 'Phenotype', 'HP:0003533', (122, 147))	('ALDH2', 'Gene', (77, 82))	('acetaldehyde', 'Chemical', 'MESH:D000079', (122, 134))	('ESSC', 'Disease', (280, 284))	('alcohol', 'Chemical', 'MESH:D000438', (179, 186))	('single amino acid mutation', 'Var', (5, 31))	('cancer', 'Disease', 'MESH:D009369', (254, 260))	('cancer', 'Disease', (254, 260))	('ALDH2', 'Gene', '217', (77, 82))	('functional deficiency', 'Disease', (48, 69))	('functional deficiency', 'Disease', 'OMIM:608852', (48, 69))	('acetaldehyde accumulation', 'MPA', (122, 147))	('leads to', 'Reg', (113, 121))
102226	29426835	In the current study, because the TCGA cohort represents data for mostly non-Asian subjects, the effects of the ALDH2 rs671 SNP on the DE for ALDH2 could only be analyzed from our own VGHTPE cohort.	('ALDH2', 'Gene', (112, 117))	('ALDH2', 'Gene', '217', (142, 147))	('rs671', 'Var', (118, 123))	('ALDH2', 'Gene', (142, 147))	('ALDH2', 'Gene', '217', (112, 117))	('rs671', 'Mutation', 'rs671', (118, 123))
102227	29426835	The results showed similar downregulation of ALDH2 in tumors with the ALDH2 GG wild type allele and the rs671 GA heterozygous allele, suggesting that this may be a general regulation independent from the ALDH2 SNP.	('ALDH2', 'Gene', (204, 209))	('tumors', 'Disease', 'MESH:D009369', (54, 60))	('ALDH2', 'Gene', '217', (70, 75))	('ALDH2', 'Gene', '217', (45, 50))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('rs671 GA', 'Var', (104, 112))	('ALDH2', 'Gene', '217', (204, 209))	('rs671', 'Mutation', 'rs671', (104, 109))	('downregulation', 'NegReg', (27, 41))	('tumors', 'Disease', (54, 60))	('ALDH2', 'Gene', (70, 75))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('ALDH2', 'Gene', (45, 50))
102239	29426835	For the high prevalence of the ALDH2 rs671 SNP, ALDH2 downregulation not only increases cancer risk but also influences cancer prognosis.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('downregulation', 'NegReg', (54, 68))	('ALDH2', 'Gene', '217', (48, 53))	('cancer', 'Disease', (120, 126))	('ALDH2', 'Gene', '217', (31, 36))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('rs671 SNP', 'Var', (37, 46))	('ALDH2', 'Gene', (48, 53))	('rs671', 'Mutation', 'rs671', (37, 42))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('increases', 'PosReg', (78, 87))	('ALDH2', 'Gene', (31, 36))	('influences', 'Reg', (109, 119))
102252	29426835	Genotyping of ALDH2*2 (rs671) was performed by Sequenom MassARRAY technology with iPLEX gold chemistry (Sequenom, San Diego, CA, USA).	('ALDH2', 'Gene', (14, 19))	('ALDH2', 'Gene', '217', (14, 19))	('rs671', 'Var', (23, 28))	('rs671', 'Mutation', 'rs671', (23, 28))
102284	28440022	FGF9, belonging to the FGF family, its aberrant expression has been identified in diverse tumors, such as breast, prostate, endometrioid, and lung cancers, indicating its tumor biomarker role in various cancers 12, 13, 14, 15.	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('tumors', 'Disease', 'MESH:D009369', (90, 96))	('FGF9', 'Gene', (0, 4))	('tumor', 'Disease', (90, 95))	('FGF9', 'Gene', '2254', (0, 4))	('cancers', 'Disease', 'MESH:D009369', (147, 154))	('lung cancers', 'Disease', 'MESH:D008175', (142, 154))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('cancers', 'Disease', 'MESH:D009369', (203, 210))	('aberrant', 'Var', (39, 47))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('lung cancers', 'Disease', (142, 154))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('lung cancer', 'Phenotype', 'HP:0100526', (142, 153))	('prostate', 'Disease', (114, 122))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('lung cancers', 'Phenotype', 'HP:0100526', (142, 154))	('breast', 'Disease', (106, 112))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumors', 'Disease', (90, 96))	('cancers', 'Phenotype', 'HP:0002664', (147, 154))	('cancers', 'Disease', (147, 154))	('tumor', 'Disease', (171, 176))	('cancers', 'Phenotype', 'HP:0002664', (203, 210))	('identified', 'Reg', (68, 78))	('endometrioid', 'Disease', (124, 136))	('cancers', 'Disease', (203, 210))
102285	28440022	indicated that FGF9 was upregulated in patients with lung adenocarcinoma, and that aberrant FGF9 expression might inhibit the progression of lung adenocarcinoma 16.	('FGF9', 'Gene', '2254', (92, 96))	('lung adenocarcinoma', 'Disease', (141, 160))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (53, 72))	('inhibit', 'NegReg', (114, 121))	('patients', 'Species', '9606', (39, 47))	('lung adenocarcinoma', 'Disease', (53, 72))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (141, 160))	('aberrant', 'Var', (83, 91))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (53, 72))	('FGF9', 'Gene', (15, 19))	('progression', 'CPA', (126, 137))	('FGF9', 'Gene', (92, 96))	('upregulated', 'PosReg', (24, 35))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (141, 160))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))	('FGF9', 'Gene', '2254', (15, 19))	('expression', 'MPA', (97, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (151, 160))
102310	28440022	A wild-type or mutated FGF9 3'-UTR segment was inserted between the XhoI and PmeI restriction sites of the pMiRGLO vector (Sangon Co., LTD, ShangHai, China).	('FGF9', 'Gene', '2254', (23, 27))	('MiR', 'Gene', (108, 111))	('MiR', 'Gene', '220972', (108, 111))	('mutated', 'Var', (15, 22))	('FGF9', 'Gene', (23, 27))
102333	28440022	To confirm that miR-372-3p could directly target FGF9 3'UTR, mutated FGF9 3'UTR (sequence showing in Fig.	('FGF9', 'Gene', (49, 53))	('FGF9', 'Gene', (69, 73))	('miR-372', 'Gene', '442917', (16, 23))	('FGF9', 'Gene', '2254', (49, 53))	('FGF9', 'Gene', '2254', (69, 73))	('mutated', 'Var', (61, 68))	('miR-372', 'Gene', (16, 23))
102344	28440022	We transfected NCI-H520 cells with miR-372-3p inhibitors or FGF9 cDNAs to see whether miR-372-3p and FGF9 deregulation could affect NCI-H520 cell mitosis.	('affect', 'Reg', (125, 131))	('NCI-H520 cell mitosis', 'Disease', 'MESH:C538614', (132, 153))	('miR-372', 'Gene', (35, 42))	('FGF9', 'Gene', (101, 105))	('miR-372', 'Gene', (86, 93))	('NCI-H520', 'CellLine', 'CVCL:1566', (132, 140))	('NCI-H520 cell mitosis', 'Disease', (132, 153))	('NCI-H520', 'CellLine', 'CVCL:1566', (15, 23))	('FGF9', 'Gene', '2254', (101, 105))	('FGF9', 'Gene', (60, 64))	('miR-372', 'Gene', '442917', (35, 42))	('miR-372', 'Gene', '442917', (86, 93))	('FGF9', 'Gene', '2254', (60, 64))	('deregulation', 'Var', (106, 118))
102349	28440022	Meanwhile, exogenous FGF9 also substantially inhibited the LSCC cell mobility (P < 0.05).	('FGF9', 'Gene', '2254', (21, 25))	('LSCC cell mobility', 'CPA', (59, 77))	('LSCC', 'Phenotype', 'HP:0030359', (59, 63))	('inhibited', 'NegReg', (45, 54))	('FGF9', 'Gene', (21, 25))	('exogenous', 'Var', (11, 20))
102393	28416958	The expression of B-cell lymphoma (Bcl)-xL, an oncoprotein involved in lung SCC tumorigenesis, is known to correlate with apoptosis; furthermore, deactivation of the tumorigenic mammalian target of rapamycin (mTOR) signaling pathway, which plays a key role in regulating cellular proliferation, survival, and angiogenesis, also affects apoptosis in lung cancers.	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('B-cell lymphoma (Bcl)-xL', 'Gene', '598', (18, 42))	('lymphoma', 'Phenotype', 'HP:0002665', (25, 33))	('SCC', 'Gene', '6317', (76, 79))	('mTOR', 'Gene', (209, 213))	('lung cancers', 'Disease', 'MESH:D008175', (349, 361))	('Bcl', 'Phenotype', 'HP:0012191', (35, 38))	('SCC', 'Gene', (76, 79))	('lung cancers', 'Disease', (349, 361))	('mTOR', 'Gene', '2475', (209, 213))	('lung cancer', 'Phenotype', 'HP:0100526', (349, 360))	('apoptosis', 'CPA', (336, 345))	('affects', 'Reg', (328, 335))	('lung cancers', 'Phenotype', 'HP:0100526', (349, 361))	('tumor', 'Disease', (166, 171))	('tumor', 'Disease', (80, 85))	('mammalian target of rapamycin', 'Gene', '2475', (178, 207))	('cancers', 'Phenotype', 'HP:0002664', (354, 361))	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('deactivation', 'Var', (146, 158))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (18, 33))	('cancer', 'Phenotype', 'HP:0002664', (354, 360))	('mammalian target of rapamycin', 'Gene', (178, 207))	('SCC', 'Phenotype', 'HP:0002860', (76, 79))	('B-cell lymphoma (Bcl)-xL', 'Gene', (18, 42))
102408	28416958	Sections were then immersed in a H2O2-phosphate-buffered saline solution prior to overnight incubation with primary anti-pS6 (1:400, Cell Signaling Technology, Danvers, MA, USA) or Bcl-xL antibodies (1:600, Cell Signaling Technology).	('Bcl-xL', 'Gene', '598', (181, 187))	('Bcl', 'Phenotype', 'HP:0012191', (181, 184))	('phosphate-buffered saline', 'Chemical', '-', (38, 63))	('pS6', 'Gene', (121, 124))	('H2O2', 'Chemical', 'MESH:D006861', (33, 37))	('Bcl-xL', 'Gene', (181, 187))	('1:400', 'Var', (126, 131))	('pS6', 'Gene', '338413', (121, 124))
102429	28416958	For these reasons, keratinization within tumors is considered a marker of well-differentiated SCC of the head and neck, as well as of the lungs.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('SCC', 'Gene', (94, 97))	('tumors', 'Disease', (41, 47))	('tumors', 'Disease', 'MESH:D009369', (41, 47))	('SCC', 'Phenotype', 'HP:0002860', (94, 97))	('SCC', 'Gene', '6317', (94, 97))	('keratinization', 'Var', (19, 33))
102430	28416958	Studies on head and neck SCC showed an association between the keratinizing subtype and a poorer OS (compared with the nonkeratinizing subtype).	('SCC', 'Gene', (25, 28))	('SCC', 'Phenotype', 'HP:0002860', (25, 28))	('keratinizing', 'Var', (63, 75))	('SCC', 'Gene', '6317', (25, 28))	('OS', 'Chemical', '-', (97, 99))	('poorer OS', 'Disease', (90, 99))
102431	28416958	Although the underlying mechanism remains unclear, some researchers have indicated that keratinization is associated with poor prognosis in human papillomavirus-negative head and neck SCC.	('human papillomavirus', 'Species', '10566', (140, 160))	('SCC', 'Gene', (184, 187))	('SCC', 'Phenotype', 'HP:0002860', (184, 187))	('SCC', 'Gene', '6317', (184, 187))	('keratinization', 'Var', (88, 102))
102436	28416958	Furthermore, among cases of nonkeratinizing lung SCC, the differentiated subtype correlated significantly with higher IKKalpha expression relative to the undifferentiated subtype; in other words, keratinization of lung SCC might correlate with a poor OS, regardless of the differentiation status.	('IKKalpha', 'Gene', (118, 126))	('OS', 'Chemical', '-', (251, 253))	('keratinization', 'Var', (196, 210))	('expression', 'MPA', (127, 137))	('SCC', 'Gene', (219, 222))	('SCC', 'Gene', (49, 52))	('SCC', 'Phenotype', 'HP:0002860', (49, 52))	('SCC', 'Phenotype', 'HP:0002860', (219, 222))	('SCC', 'Gene', '6317', (219, 222))	('SCC', 'Gene', '6317', (49, 52))	('higher', 'PosReg', (111, 117))	('poor OS', 'Disease', (246, 253))	('IKKalpha', 'Gene', '1147', (118, 126))
102444	28416958	Herein, we demonstrated the association of keratinization of lung SCC with a poor clinical outcome, in comparison with the nonkeratinization subtype.	('SCC', 'Gene', (66, 69))	('SCC', 'Phenotype', 'HP:0002860', (66, 69))	('SCC', 'Gene', '6317', (66, 69))	('keratinization', 'Var', (43, 57))	('association', 'Reg', (28, 39))
102513	32757307	Furthermore, in the irradiated part of the oesophagus, (deep) ulceration, scarring and atrophy of the subepithelial layers of the oesophagus in several instances resulted in a more superficial location of these layers than expected.	('atrophy', 'Disease', (87, 94))	('scarring', 'Phenotype', 'HP:0100699', (74, 82))	('scarring', 'Var', (74, 82))	('resulted in', 'Reg', (162, 173))	('atrophy', 'Disease', 'MESH:D001284', (87, 94))
102567	33099569	To confirm the expression profiles of ITGA3, ITGA5, and ITGA6 in HNSC, 6 microarray series, GSE2379, GSE6631, GSE29330, GSE53819, GSE58911, and GSE107591, containing tumor and nontumor samples were collected from the Gene Expression Omnibus (GEO) database.	('GSE58911', 'Var', (130, 138))	('ITGA3', 'Gene', (38, 43))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('GSE6631', 'Chemical', '-', (101, 108))	('ITGA6', 'Gene', '3655', (56, 61))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('HNSC', 'Phenotype', 'HP:0012288', (65, 69))	('ITGA5', 'Gene', (45, 50))	('GSE6631', 'Var', (101, 108))	('ITGA3', 'Gene', '3675', (38, 43))	('GSE53819', 'Var', (120, 128))	('GSE2379', 'Chemical', '-', (92, 99))	('tumor', 'Disease', (166, 171))	('ITGA5', 'Gene', '3678', (45, 50))	('GSE107591', 'Var', (144, 153))	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('GSE2379', 'Var', (92, 99))	('GSE29330', 'Var', (110, 118))	('ITGA6', 'Gene', (56, 61))	('tumor', 'Disease', (179, 184))
102575	33099569	METASCAPE was applied for pathway and process enrichment analysis of ITGA3, ITGA5, and ITGA6 and adjacent genes significantly related to ITGA3, ITGA5, and ITGA6 alterations.	('ITGA3', 'Gene', (69, 74))	('ITGA5', 'Gene', '3678', (144, 149))	('ITGA5', 'Gene', (76, 81))	('ITGA3', 'Gene', (137, 142))	('ITGA6', 'Gene', '3655', (87, 92))	('ITGA3', 'Gene', '3675', (137, 142))	('related', 'Reg', (126, 133))	('ITGA3', 'Gene', '3675', (69, 74))	('ITGA6', 'Gene', (87, 92))	('ITGA5', 'Gene', '3678', (76, 81))	('ITGA5', 'Gene', (144, 149))	('ITGA6', 'Gene', '3655', (155, 160))	('ITGA6', 'Gene', (155, 160))	('alterations', 'Var', (161, 172))
102597	33099569	The GSE2379, GSE6631, GSE29330, GSE53819, GSE58911, and GSE107591 results showed substantial upregulation in tumor tissues compared with normal tissues (all P<0.05, Figures 3, 4).	('upregulation', 'PosReg', (93, 105))	('GSE6631', 'Chemical', '-', (13, 20))	('GSE58911', 'Var', (42, 50))	('GSE2379', 'Chemical', '-', (4, 11))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('GSE6631', 'Var', (13, 20))	('GSE2379', 'Var', (4, 11))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('GSE107591', 'Var', (56, 65))	('GSE29330', 'Var', (22, 30))	('GSE53819', 'Var', (32, 40))	('tumor', 'Disease', (109, 114))
102613	33099569	ITGA5 levels also had a statistically significant correlation with arm-level deletion in CD8+ T cells (P=6.52e-05), neutrophils (P=0.003) and dendritic cells (P=0.017), and arm-level gain in B cells (P=0.012).	('ITGA5', 'Gene', '3678', (0, 5))	('CD8', 'Gene', (89, 92))	('CD8', 'Gene', '925', (89, 92))	('deletion', 'Var', (77, 85))	('ITGA5', 'Gene', (0, 5))
102614	33099569	Moreover, ITGA6 expression correlated significantly with arm-level gain in CD8+ T cells (P=5.19e-13), CD4+ T cells (P<0.001), B cells (P=6.89e-05), macrophages (P=0.001), neutrophils (P=1.47e-11), and dendritic cells (P=8.26e-06) (Figure 9).	('expression', 'Var', (16, 26))	('CD8', 'Gene', '925', (75, 78))	('ITGA6', 'Gene', '3655', (10, 15))	('ITGA6', 'Gene', (10, 15))	('arm-level', 'MPA', (57, 66))	('gain', 'PosReg', (67, 71))	('CD8', 'Gene', (75, 78))	('CD4', 'Gene', (102, 105))	('CD4', 'Gene', '920', (102, 105))
102645	33099569	ITGA6 is overexpressed in multiple tumors, promoting tumorigenesis and metastasis, and expression of ITGA6 is strongly related to the occurrence of intravesical recurrence.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('expression', 'Var', (87, 97))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('ITGA6', 'Gene', '3655', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('ITGA6', 'Gene', (0, 5))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('tumor', 'Disease', (35, 40))	('metastasis', 'CPA', (71, 81))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('intravesical recurrence', 'Disease', (148, 171))	('tumors', 'Disease', (35, 41))	('tumors', 'Disease', 'MESH:D009369', (35, 41))	('promoting', 'PosReg', (43, 52))	('ITGA6', 'Gene', '3655', (101, 106))	('tumor', 'Disease', (53, 58))	('ITGA6', 'Gene', (101, 106))	('related to', 'Reg', (119, 129))
102656	31921636	A Strong Decrease in TIMP3 Expression Mediated by the Presence of miR-17 and 20a Enables Extracellular Matrix Remodeling in the NSCLC Lesion Surroundings Background: Lung cancer is one of the most common causes of death worldwide with a relatively high fatality rate and a mean 5-years survival of about 18%.	('miR-17', 'Gene', (66, 72))	('Lung cancer', 'Disease', 'MESH:D008175', (166, 177))	('Expression', 'MPA', (27, 37))	('NSCLC', 'Disease', (128, 133))	('miR-17', 'Gene', '406952', (66, 72))	('Presence', 'Var', (54, 62))	('NSCLC', 'Disease', 'MESH:D002289', (128, 133))	('Decrease', 'NegReg', (9, 17))	('TIMP3', 'Gene', '7078', (21, 26))	('Lung cancer', 'Phenotype', 'HP:0100526', (166, 177))	('TIMP3', 'Gene', (21, 26))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('Lung cancer', 'Disease', (166, 177))
102741	31921636	The type of surgery did not affect the expression of postoperative miRs (p = 0.202 for miR-17 and p = 0.202 for miR-20a, Kruskal-Wallis test).	('miR-20a', 'Gene', (112, 119))	('miR-20a', 'Gene', '406982', (112, 119))	('miR-17', 'Gene', (87, 93))	('miR', 'Gene', '220972', (112, 115))	('miR', 'Gene', (112, 115))	('p = 0.202', 'Var', (98, 107))	('miR-17', 'Gene', '406952', (87, 93))	('miR', 'Gene', '220972', (87, 90))	('miR', 'Gene', (87, 90))	('miR', 'Gene', '220972', (67, 70))	('miR', 'Gene', (67, 70))
102767	31921636	On the other hand, the observed in the present study, silencing of the metalloproteinase inhibitor TIMP3 suggests that the proteins taking part in ECM remodeling can display intensified activity.	('silencing', 'Var', (54, 63))	('activity', 'MPA', (186, 194))	('TIMP3', 'Gene', '7078', (99, 104))	('TIMP3', 'Gene', (99, 104))	('proteins', 'Protein', (123, 131))
102775	31921636	It was earlier demonstrated that molecular changes like microsatellite instability (MSI) or suppressor gene hypermethylation could occur in histologically-normal epithelia or macroscopically-unchanged tissue adjacent to the resected tumors in smoking patients with primary lung cancer.	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('lung cancer', 'Phenotype', 'HP:0100526', (273, 284))	('suppressor gene', 'Gene', (92, 107))	('cancer', 'Phenotype', 'HP:0002664', (278, 284))	('tumors', 'Disease', (233, 239))	('tumors', 'Disease', 'MESH:D009369', (233, 239))	('hypermethylation', 'Var', (108, 124))	('microsatellite instability', 'MPA', (56, 82))	('tumors', 'Phenotype', 'HP:0002664', (233, 239))	('primary lung cancer', 'Disease', (265, 284))	('patients', 'Species', '9606', (251, 259))	('primary lung cancer', 'Disease', 'MESH:D008175', (265, 284))
102782	31921636	The lack of the MMP2 expression differences among tissues, together with the observed TIMP3/MMP2 ratio distortion in NLNT (strongly decreased TIMP3 expression in comparison to MMP2, compared to the data from RNAseq studies), indicate that ECM remodeling may be observed some distance from the lesion center.	('TIMP3', 'Gene', '7078', (86, 91))	('TIMP3', 'Gene', '7078', (142, 147))	('MMP2', 'Gene', '4313', (176, 180))	('distortion', 'Var', (103, 113))	('MMP2', 'Gene', '4313', (92, 96))	('TIMP3', 'Gene', (86, 91))	('MMP2', 'Gene', '4313', (16, 20))	('MMP2', 'Gene', (176, 180))	('decreased', 'NegReg', (132, 141))	('expression', 'MPA', (148, 158))	('MMP2', 'Gene', (16, 20))	('MMP2', 'Gene', (92, 96))	('TIMP3', 'Gene', (142, 147))
102818	31921636	The observed in our study negative correlation of TIMP3 with miR-20a expression (both preoperative and postoperative miR20a in SCC subtype, post miR20a in the entire study cohort), can be explained as epigenetic silencing of the genes controlling the ECM remodeling.	('miR-20a', 'Gene', (61, 68))	('miR20a', 'Gene', (145, 151))	('negative', 'NegReg', (26, 34))	('SCC', 'Disease', (127, 130))	('miR-20a', 'Gene', '406982', (61, 68))	('miR20a', 'Gene', '406982', (117, 123))	('TIMP3', 'Gene', '7078', (50, 55))	('expression', 'MPA', (69, 79))	('epigenetic silencing', 'Var', (201, 221))	('TIMP3', 'Gene', (50, 55))	('miR20a', 'Gene', '406982', (145, 151))	('SCC', 'Disease', 'MESH:D002294', (127, 130))	('miR20a', 'Gene', (117, 123))
102843	29763624	The Cancer Genome Atlas (TCGA) for lung SCC revealed frequent mutations in receptor tyrosine kinases (RTKs), AKT and PI3K that converge to activate the mechanistic target of rapamycin (mTOR) signaling pathway.	('RTKs', 'Gene', (102, 106))	('SCC', 'Gene', '6317', (40, 43))	('mechanistic target of rapamycin', 'Gene', '2475', (152, 183))	('mechanistic target of rapamycin', 'Gene', (152, 183))	('AKT', 'Pathway', (109, 112))	('Cancer', 'Phenotype', 'HP:0002664', (4, 10))	('PI3K', 'Gene', (117, 121))	('Cancer Genome Atlas', 'Disease', (4, 23))	('SCC', 'Gene', (40, 43))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (4, 23))	('mutations', 'Var', (62, 71))	('activate', 'PosReg', (139, 147))
102844	29763624	Importantly, the PI3K-AKT-mTOR signaling axis is a druggable pathway as evidenced by multiple early phase clinical trials which have begun assessing targeted therapies against PI3K, AKT and mTOR in lung cancer (NCT01493843, NCT01248247, NCT01058707).	('lung cancer', 'Disease', (198, 209))	('lung cancer', 'Phenotype', 'HP:0100526', (198, 209))	('NCT01493843', 'Var', (211, 222))	('mTOR', 'Gene', (190, 194))	('AKT', 'Pathway', (182, 185))	('PI3K', 'Var', (176, 180))	('lung cancer', 'Disease', 'MESH:D008175', (198, 209))	('NCT01248247', 'Var', (224, 235))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))
102846	29763624	Agreeing with clinical results, we have demonstrated that chronic inhibition with the catalytic mTOR kinase inhibitor MLN128 effectively inhibited mTOR and suppressed glucose metabolism in both ADC and SCC tumor subtypes but failed to restrict tumor growth in lung SCC.	('SCC tumor', 'Disease', 'MESH:D009369', (202, 211))	('MLN128', 'Var', (118, 124))	('SCC', 'Gene', '6317', (202, 205))	('SCC', 'Gene', '6317', (265, 268))	('tumor', 'Phenotype', 'HP:0002664', (244, 249))	('SCC', 'Gene', (202, 205))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('SCC', 'Gene', (265, 268))	('inhibited', 'NegReg', (137, 146))	('MLN128', 'Chemical', '-', (118, 124))	('suppressed glucose metabolism', 'Phenotype', 'HP:0040270', (156, 185))	('ADC', 'Disease', (194, 197))	('suppressed', 'NegReg', (156, 166))	('mTOR', 'MPA', (147, 151))	('tumor', 'Disease', (244, 249))	('tumor', 'Disease', (206, 211))	('glucose metabolism', 'MPA', (167, 185))	('SCC tumor', 'Disease', (202, 211))	('glucose', 'Chemical', 'MESH:D005947', (167, 174))	('tumor', 'Disease', 'MESH:D009369', (244, 249))	('tumor', 'Disease', 'MESH:D009369', (206, 211))
102847	29763624	These results suggested that lung SCC may utilize alternate nutrients such as amino acids to circumvent MLN128-mediated suppression of glycolysis.	('SCC', 'Gene', (34, 37))	('SCC', 'Gene', '6317', (34, 37))	('MLN128-mediated', 'Var', (104, 119))	('glycolysis', 'MPA', (135, 145))	('MLN128', 'Chemical', '-', (104, 110))
102851	29763624	Additionally, in vivo profiling of lung tumors in a KrasG12D;Trp53-/- (KP) mutant mouse model of NSCLC demonstrated these tumors were dependent on glycolysis for tumor cell survival but not glutamine.	('tumors', 'Disease', 'MESH:D009369', (122, 128))	('tumor', 'Disease', (162, 167))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('lung tumors', 'Disease', (35, 46))	('tumor', 'Disease', (122, 127))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('tumors', 'Disease', (40, 46))	('Trp53', 'Gene', '22059', (61, 66))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('Trp53', 'Gene', (61, 66))	('tumors', 'Phenotype', 'HP:0002664', (122, 128))	('tumors', 'Disease', 'MESH:D009369', (40, 46))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('glutamine', 'Chemical', 'MESH:D005973', (190, 199))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('NSCLC', 'Disease', 'MESH:D002289', (97, 102))	('tumor', 'Disease', (40, 45))	('mouse', 'Species', '10090', (82, 87))	('tumors', 'Disease', (122, 128))	('NSCLC', 'Disease', (97, 102))	('lung tumors', 'Disease', 'MESH:D008175', (35, 46))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('mutant', 'Var', (75, 81))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('lung tumors', 'Phenotype', 'HP:0100526', (35, 46))
102861	29763624	We took advantage of 18F-FDG PET and computed tomography (CT) imaging and quantified uptake of 18F-FDG between SCC and ADC tumors in KL mice.	('18F-FDG', 'Chemical', 'MESH:D019788', (95, 102))	('mice', 'Species', '10090', (136, 140))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('PET', 'Gene', (29, 32))	('18F-FDG', 'Chemical', 'MESH:D019788', (21, 28))	('SCC', 'Gene', (111, 114))	('ADC tumors', 'Disease', (119, 129))	('ADC tumors', 'Disease', 'MESH:D009369', (119, 129))	('18F-FDG', 'Var', (95, 102))	('SCC', 'Gene', '6317', (111, 114))	('PET', 'Gene', '22095', (29, 32))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
102864	29763624	We previously showed that chronic treatment of KL mice with the catalytic mTOR kinase inhibitor MLN128 significantly reduced the total number of lesions.	('MLN128', 'Chemical', '-', (96, 102))	('reduced', 'NegReg', (117, 124))	('MLN128', 'Var', (96, 102))	('mice', 'Species', '10090', (50, 54))
102865	29763624	However, we found that in every mouse treated with MLN128 there were large SCC tumors that escaped treatment despite reduced mTOR signaling.	('mTOR signaling', 'MPA', (125, 139))	('reduced', 'NegReg', (117, 124))	('MLN128', 'Var', (51, 57))	('SCC tumors', 'Disease', 'MESH:D009369', (75, 85))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('mouse', 'Species', '10090', (32, 37))	('SCC tumors', 'Disease', (75, 85))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('MLN128', 'Chemical', '-', (51, 57))
102867	29763624	Mice were 18F-FDG PET imaged following 8 weeks of daily treatment with vehicle or MLN128.	('18F-FDG', 'Chemical', 'MESH:D019788', (10, 17))	('PET', 'Gene', '22095', (18, 21))	('MLN128', 'Chemical', '-', (82, 88))	('Mice', 'Species', '10090', (0, 4))	('PET', 'Gene', (18, 21))	('MLN128', 'Var', (82, 88))
102868	29763624	We again saw that SCC consistently escaped MLN128 treatment and that the 18F-FDG signal was significantly reduced in MLN128 treated SCC tumors as compared to vehicle treated ones (Figures 1H and 1I).	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('MLN128', 'Chemical', '-', (117, 123))	('SCC', 'Gene', (18, 21))	('MLN128 treated', 'Var', (117, 131))	('SCC tumors', 'Disease', 'MESH:D009369', (132, 142))	('SCC', 'Gene', (132, 135))	('MLN128', 'Chemical', '-', (43, 49))	('SCC tumors', 'Disease', (132, 142))	('SCC', 'Gene', '6317', (18, 21))	('18F-FDG', 'Chemical', 'MESH:D019788', (73, 80))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('SCC', 'Gene', '6317', (132, 135))	('reduced', 'NegReg', (106, 113))	('18F-FDG signal', 'MPA', (73, 87))
102869	29763624	While MLN128 induced a metabolic response in SCC tumors and effectively inhibited mTORC1 signaling as shown by reduced phosphorylation of the mTORC1 substrate 4EBP1 (p4EBP1), treatment failed to reduce the Ki67 index (Figures 1J and 1K).	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('4EBP1', 'Gene', '1978', (167, 172))	('Ki67', 'Gene', (206, 210))	('MLN128', 'Var', (6, 12))	('4EBP1', 'Gene', '1978', (159, 164))	('SCC tumors', 'Disease', (45, 55))	('phosphorylation', 'MPA', (119, 134))	('mTORC1', 'Gene', (82, 88))	('MLN128', 'Chemical', '-', (6, 12))	('SCC tumors', 'Disease', 'MESH:D009369', (45, 55))	('Ki67', 'Gene', '17345', (206, 210))	('mTORC1', 'Gene', '382056', (82, 88))	('reduced', 'NegReg', (111, 118))	('metabolic', 'MPA', (23, 32))	('inhibited', 'NegReg', (72, 81))	('4EBP1', 'Gene', (167, 172))	('mTORC1', 'Gene', (142, 148))	('4EBP1', 'Gene', (159, 164))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('mTORC1', 'Gene', '382056', (142, 148))
102870	29763624	Gene set enrichment analysis (GSEA) performed on vehicle and MLN128 treated KL SCC tumors confirmed a decrease in expression of core genes involved in glycolysis, the pentose phosphate pathway and the mTOR pathway (Figures 1L and S1B).	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('SCC tumors', 'Disease', (79, 89))	('pentose phosphate pathway', 'Pathway', (167, 192))	('mTOR pathway', 'Pathway', (201, 213))	('decrease', 'NegReg', (102, 110))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('MLN128', 'Chemical', '-', (61, 67))	('expression', 'MPA', (114, 124))	('pentose phosphate', 'Chemical', 'MESH:D010428', (167, 184))	('GSEA', 'Chemical', '-', (30, 34))	('MLN128 treated', 'Var', (61, 75))	('SCC tumors', 'Disease', 'MESH:D009369', (79, 89))
102871	29763624	Together, our data suggests that hypermetabolic SCC tumors can maintain high proliferation rates despite chronic suppression of glycolysis with MLN128.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('glycolysis', 'MPA', (128, 138))	('hypermetabolic SCC tumors', 'Disease', 'MESH:C565498', (33, 58))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('hypermetabolic SCC tumors', 'Disease', (33, 58))	('MLN128', 'Chemical', '-', (144, 150))	('suppression', 'NegReg', (113, 124))	('MLN128', 'Var', (144, 150))
102876	29763624	We conducted serial PET imaging of KL mice with 18F-FDG and 11C-Gln within the same week as previously described (Figure S2).	('PET', 'Gene', '22095', (20, 23))	('11C-Gln', 'Var', (60, 67))	('11C-Gln', 'Chemical', '-', (60, 67))	('18F-FDG', 'Var', (48, 55))	('mice', 'Species', '10090', (38, 42))	('18F-FDG', 'Chemical', 'MESH:D019788', (48, 55))	('PET', 'Gene', (20, 23))
102877	29763624	In agreement with previous data, SCC tumors were highly avid for 18F-FDG (Figure 2A).	('18F-FDG', 'Var', (65, 72))	('SCC tumors', 'Disease', 'MESH:D009369', (33, 43))	('18F-FDG', 'Chemical', 'MESH:D019788', (65, 72))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('SCC tumors', 'Disease', (33, 43))	('tumors', 'Phenotype', 'HP:0002664', (37, 43))
102878	29763624	We imaged the same mouse with 11C-Gln and identified this same tumor was positive for 11C-Gln (Figure 2A).	('tumor', 'Disease', (63, 68))	('11C-Gln', 'Var', (86, 93))	('11C-Gln', 'Chemical', '-', (30, 37))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('mouse', 'Species', '10090', (19, 24))	('11C-Gln', 'Chemical', '-', (86, 93))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
102884	29763624	The ADC (T1) showed lower avidity for both 18F-FDG and 11C-Gln as compared to the SCC (T2).	('lower', 'NegReg', (20, 25))	('SCC', 'Gene', '6317', (82, 85))	('18F-FDG', 'Chemical', 'MESH:D019788', (43, 50))	('avidity', 'MPA', (26, 33))	('18F-FDG', 'Var', (43, 50))	('SCC', 'Gene', (82, 85))	('11C-Gln', 'Var', (55, 62))	('11C-Gln', 'Chemical', '-', (55, 62))
102887	29763624	Having established that lung SCC tumors have high influx of glutamine, we explored the possibility that glutamine supports biomass generation when glycolysis is inhibited by MLN128.	('biomass generation', 'MPA', (123, 141))	('glutamine', 'Chemical', 'MESH:D005973', (104, 113))	('high influx of glutamine', 'Phenotype', 'HP:0003217', (45, 69))	('inhibited', 'NegReg', (161, 170))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('lung SCC tumors', 'Disease', (24, 39))	('glycolysis', 'MPA', (147, 157))	('MLN128', 'Chemical', '-', (174, 180))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('MLN128', 'Var', (174, 180))	('lung SCC tumors', 'Disease', 'MESH:D008175', (24, 39))	('influx of glutamine', 'MPA', (50, 69))	('glutamine', 'Chemical', 'MESH:D005973', (60, 69))
102888	29763624	We next measured glucose and glutamine consumption in cell culture media in the RH2 human SCC line following treated with MLN128.	('RH2', 'Gene', '6005', (80, 83))	('RH2', 'Gene', (80, 83))	('glutamine', 'Chemical', 'MESH:D005973', (29, 38))	('SCC', 'Gene', '6317', (90, 93))	('SCC', 'Gene', (90, 93))	('MLN128', 'Chemical', '-', (122, 128))	('MLN128', 'Var', (122, 128))	('human', 'Species', '9606', (84, 89))	('glucose', 'Chemical', 'MESH:D005947', (17, 24))
102889	29763624	We demonstrated that both MLN128 and the allosteric mTORC1 inhibitor rapamycin suppressed glucose uptake while concomitantly inducing an increase in glutamine uptake in vitro (Figures 3A and S3A).	('glutamine uptake', 'MPA', (149, 165))	('glutamine', 'Chemical', 'MESH:D005973', (149, 158))	('mTORC1', 'Gene', '382056', (52, 58))	('suppressed', 'NegReg', (79, 89))	('MLN128', 'Chemical', '-', (26, 32))	('inducing', 'Reg', (125, 133))	('MLN128', 'Var', (26, 32))	('increase', 'PosReg', (137, 145))	('mTORC1', 'Gene', (52, 58))	('rapamycin', 'Chemical', 'MESH:D020123', (69, 78))	('glucose uptake', 'MPA', (90, 104))	('glucose', 'Chemical', 'MESH:D005947', (90, 97))
102891	29763624	Treatment of RH2 xenografts with MLN128 outlined in Figure 3C induced an identical metabolic response as seen in SCC tumors from KL mice.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('RH2', 'Gene', '6005', (13, 16))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('RH2', 'Gene', (13, 16))	('MLN128', 'Chemical', '-', (33, 39))	('SCC tumors', 'Disease', 'MESH:D009369', (113, 123))	('mice', 'Species', '10090', (132, 136))	('MLN128 outlined', 'Var', (33, 48))	('SCC tumors', 'Disease', (113, 123))	('metabolic response', 'MPA', (83, 101))
102892	29763624	MLN128 significantly suppressed 18F-FDG uptake in RH2 tumors (Figures 3D and S3B) and inhibited mTORC1 signaling as measured by p4EBP1 staining (Figures 3E and 3F), but it failed to reduce tumor growth or tumor cell proliferation as measured by Ki67 staining (Figures 3E-3G).	('MLN128', 'Var', (0, 6))	('RH2', 'Gene', '6005', (50, 53))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('MLN128', 'Chemical', '-', (0, 6))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('Ki67', 'Gene', (245, 249))	('4EBP1', 'Gene', (129, 134))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('18F-FDG', 'Chemical', 'MESH:D019788', (32, 39))	('mTORC1', 'Gene', (96, 102))	('18F-FDG uptake', 'MPA', (32, 46))	('tumors', 'Disease', (54, 60))	('suppressed', 'NegReg', (21, 31))	('mTORC1', 'Gene', '382056', (96, 102))	('Ki67', 'Gene', '17345', (245, 249))	('tumors', 'Disease', 'MESH:D009369', (54, 60))	('tumor', 'Disease', (189, 194))	('RH2', 'Gene', (50, 53))	('4EBP1', 'Gene', '1978', (129, 134))	('tumor', 'Disease', (205, 210))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('inhibited', 'NegReg', (86, 95))	('tumor', 'Disease', (54, 59))
102896	29763624	Plasma glucose enrichment reached 63% (+- 9.7%) in mice infused with 13C6-Glucose for 120 min (Figure S3C).	('Plasma glucose enrichment', 'MPA', (0, 25))	('mice', 'Species', '10090', (51, 55))	('13C6-Glucose', 'Var', (69, 81))	('glucose', 'Chemical', 'MESH:D005947', (7, 14))	('13C6-Glucose', 'Chemical', '-', (69, 81))
102897	29763624	We detected significantly lower levels of lactate (M3 labeled) derived from 13C6-glucose in MLN128 treated mice compared with vehicle treated mice (Figure 3J).	('MLN128', 'Chemical', '-', (92, 98))	('levels', 'MPA', (32, 38))	('mice', 'Species', '10090', (142, 146))	('mice', 'Species', '10090', (107, 111))	('13C6-glucose', 'Chemical', '-', (76, 88))	('MLN128 treated', 'Var', (92, 106))	('lactate', 'Chemical', 'MESH:D019344', (42, 49))	('lower', 'NegReg', (26, 31))
102898	29763624	We also detected significantly lower levels of citrate (M2 labeled) and aspartate (M3 labeled) derived from 13C6-Glucose in MLN128 group, suggesting that contribution of glucose to TCA cycle was lowered by MLN128 (Figures 3K and 3L).	('MLN128', 'Var', (206, 212))	('MLN128', 'Chemical', '-', (124, 130))	('lower levels of citrate', 'Phenotype', 'HP:0012405', (31, 54))	('aspartate', 'MPA', (72, 81))	('MLN128', 'Var', (124, 130))	('TCA cycle', 'Enzyme', (181, 190))	('glucose', 'Chemical', 'MESH:D005947', (170, 177))	('levels', 'MPA', (37, 43))	('lowered', 'NegReg', (195, 202))	('lower', 'NegReg', (31, 36))	('TCA', 'Chemical', 'MESH:D014238', (181, 184))	('13C6-Glucose', 'Chemical', '-', (108, 120))	('aspartate', 'Chemical', 'MESH:D001224', (72, 81))	('citrate', 'Chemical', 'MESH:D019343', (47, 54))	('MLN128', 'Chemical', '-', (206, 212))	('citrate', 'MPA', (47, 54))
102899	29763624	The reduced glucose metabolism in MLN128 treated tumors is not due to differential glucose uptake as both unlabeled (M0) and fully labeled (M6) glucose were present at similar levels in vehicle and MLN128 treated tumors (Figure S3D).	('glucose', 'Chemical', 'MESH:D005947', (83, 90))	('MLN128 treated', 'Var', (34, 48))	('tumors', 'Disease', (213, 219))	('reduced', 'NegReg', (4, 11))	('tumors', 'Disease', 'MESH:D009369', (213, 219))	('MLN128', 'Chemical', '-', (198, 204))	('tumors', 'Phenotype', 'HP:0002664', (213, 219))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('glucose', 'Chemical', 'MESH:D005947', (12, 19))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('glucose metabolism', 'MPA', (12, 30))	('MLN128', 'Chemical', '-', (34, 40))	('tumors', 'Disease', (49, 55))	('tumors', 'Disease', 'MESH:D009369', (49, 55))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('glucose', 'Chemical', 'MESH:D005947', (144, 151))	('reduced glucose metabolism', 'Phenotype', 'HP:0040270', (4, 30))
102900	29763624	We also did not detect a decrease in ATP or AMP levels in MLN128 treated tumors (Figure S3E).	('ATP', 'Chemical', 'MESH:D000255', (37, 40))	('MLN128 treated', 'Var', (58, 72))	('ATP', 'MPA', (37, 40))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('AMP', 'Chemical', 'MESH:D000249', (44, 47))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('AMP levels', 'MPA', (44, 54))	('tumors', 'Disease', (73, 79))	('MLN128', 'Chemical', '-', (58, 64))	('tumors', 'Disease', 'MESH:D009369', (73, 79))
102903	29763624	We detected significantly higher uptake of fully labeled (M5) glutamine in tumors in the MLN128 treated group compared to the vehicle group, (Figure 3O and S3F) suggesting that glutamine uptake is enhanced when glycolysis is restricted.	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('MLN128 treated', 'Var', (89, 103))	('higher', 'PosReg', (26, 32))	('glutamine uptake', 'MPA', (177, 193))	('uptake', 'MPA', (33, 39))	('glutamine', 'Chemical', 'MESH:D005973', (177, 186))	('MLN128', 'Chemical', '-', (89, 95))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('enhanced', 'PosReg', (197, 205))	('tumors', 'Disease', (75, 81))	('glutamine', 'Chemical', 'MESH:D005973', (62, 71))
102904	29763624	We also detected significantly higher levels of fully labeled (M5) glutamate derived from 13C5-glutamine in MLN128 treated tumors (Figure 3P and S3F).	('MLN128', 'Chemical', '-', (108, 114))	('tumors', 'Disease', (123, 129))	('tumors', 'Disease', 'MESH:D009369', (123, 129))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('MLN128 treated', 'Var', (108, 122))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('13C5-glutamine', 'Chemical', '-', (90, 104))	('higher', 'PosReg', (31, 37))	('glutamate', 'Chemical', 'MESH:D018698', (67, 76))	('levels', 'MPA', (38, 44))
102906	29763624	We detected a four-fold increase in levels of labeled aspartate (M4) derived from 13C5-glutamine in MLN128 treated tumors compared to vehicle treated tumors (Figure 3Q and S3F), suggesting that glutamine undergoes oxidative decarboxylation and is used to replenish TCA cycle intermediates depleted by treatment with MLN128 and subsequent reduced glycolysis.	('tumors', 'Phenotype', 'HP:0002664', (150, 156))	('increase', 'PosReg', (24, 32))	('MLN128', 'Var', (316, 322))	('glutamine', 'Chemical', 'MESH:D005973', (194, 203))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('MLN128', 'Chemical', '-', (316, 322))	('tumors', 'Disease', (150, 156))	('MLN128', 'Var', (100, 106))	('glycolysis', 'MPA', (346, 356))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('TCA', 'Chemical', 'MESH:D014238', (265, 268))	('glutamine', 'Chemical', 'MESH:D005973', (87, 96))	('MLN128', 'Chemical', '-', (100, 106))	('aspartate', 'Chemical', 'MESH:D001224', (54, 63))	('tumors', 'Disease', 'MESH:D009369', (150, 156))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('oxidative decarboxylation', 'MPA', (214, 239))	('tumors', 'Disease', (115, 121))	('reduced', 'NegReg', (338, 345))	('13C5-glutamine', 'Chemical', '-', (82, 96))	('tumors', 'Disease', 'MESH:D009369', (115, 121))
102907	29763624	Overall, our data describes a metabolic reliance of lung SCC on both glucose and glutamine in vivo that enables tumors to rapidly adapt to MLN128-mediated suppression of glycolysis.	('tumors', 'Disease', 'MESH:D009369', (112, 118))	('glucose', 'Chemical', 'MESH:D005947', (69, 76))	('MLN128', 'Chemical', '-', (139, 145))	('suppression', 'NegReg', (155, 166))	('SCC', 'Gene', '6317', (57, 60))	('glycolysis', 'MPA', (170, 180))	('MLN128-mediated', 'Var', (139, 154))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('glutamine', 'Chemical', 'MESH:D005973', (81, 90))	('SCC', 'Gene', (57, 60))	('tumors', 'Disease', (112, 118))
102908	29763624	We next sought to identify the molecular mechanism(s) regulating metabolic adaptation in lung SCC that enabled them to escape MLN128 treatment.	('SCC', 'Gene', (94, 97))	('MLN128', 'Chemical', '-', (126, 132))	('SCC', 'Gene', '6317', (94, 97))	('MLN128', 'Var', (126, 132))
102910	29763624	We previously found that SCC tumors from KL mice that escaped MLN128 treatment had increased levels of phospho-AKT Thr308 (pAKTT308) as well as increased levels of the phosphorylated form of its downstream substrate glycogen synthase kinase 3 (GSK3alpha/beta), a regulator of cell growth and proliferation, which AKT phosphorylates at Ser21/Ser9 (pGSK3alpha/betaS21/9).	('MLN128', 'Var', (62, 68))	('Ser9', 'Chemical', '-', (341, 345))	('GSK3alpha/beta', 'Gene', (348, 362))	('Thr308', 'Chemical', '-', (115, 121))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('MLN128', 'Chemical', '-', (62, 68))	('mice', 'Species', '10090', (44, 48))	('GSK3alpha/beta', 'Gene', (244, 258))	('increased', 'PosReg', (83, 92))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('GSK3alpha/beta', 'Gene', '2931', (348, 362))	('Ser21', 'Chemical', '-', (335, 340))	('levels', 'MPA', (93, 99))	('GSK3alpha/beta', 'Gene', '2931', (244, 258))	('levels', 'MPA', (154, 160))	('increased', 'PosReg', (144, 153))	('SCC tumors', 'Disease', (25, 35))	('pGSK3alpha', 'Chemical', '-', (347, 357))	('SCC tumors', 'Disease', 'MESH:D009369', (25, 35))	('betaS21', 'Chemical', '-', (358, 365))
102911	29763624	Inhibition of AKT had additive effects when combined with mTOR inhibitors MLN128 or rapamycin in vitro.	('rapamycin', 'Chemical', 'MESH:D020123', (84, 93))	('Inhibition', 'NegReg', (0, 10))	('MLN128', 'Chemical', '-', (74, 80))	('MLN128', 'Var', (74, 80))	('AKT', 'Pathway', (14, 17))
102916	29763624	These studies suggest that GSK3alpha/beta may serve as a key node that upregulates GLS expression and glutamine metabolism following mTOR inhibition.	('GLS', 'Gene', (83, 86))	('upregulates', 'PosReg', (71, 82))	('expression', 'MPA', (87, 97))	('GSK3alpha/beta', 'Gene', '2931', (27, 41))	('glutamine metabolism', 'MPA', (102, 122))	('glutamine', 'Chemical', 'MESH:D005973', (102, 111))	('inhibition', 'Var', (138, 148))	('GLS', 'Gene', '2744', (83, 86))	('GSK3alpha/beta', 'Gene', (27, 41))
102917	29763624	The model in Figure 4A proposes that inhibition of AKT should prevent GSK3alpha/beta mediated upregulation of GLS in the presence of MLN128.	('GSK3alpha/beta', 'Gene', (70, 84))	('AKT', 'Protein', (51, 54))	('GLS', 'Gene', (110, 113))	('upregulation', 'PosReg', (94, 106))	('prevent', 'NegReg', (62, 69))	('MLN128', 'Chemical', '-', (133, 139))	('GSK3alpha/beta', 'Gene', '2931', (70, 84))	('MLN128', 'Var', (133, 139))	('GLS', 'Gene', '2744', (110, 113))
102918	29763624	Interestingly, we found that nanomolar doses of the pan AKT inhibitor MK2206 induced cMYC expression (Figure S4A), agreeing with a recent study that showed Lapatinib mediated AKT inhibition resulted in cMYC upregulation in breast cancer cells.	('upregulation', 'PosReg', (207, 219))	('induced', 'Reg', (77, 84))	('cMYC', 'Gene', '4609', (202, 206))	('cMYC', 'Gene', '4609', (85, 89))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('breast cancer', 'Disease', 'MESH:D001943', (223, 236))	('MK2206', 'Chemical', 'MESH:C548887', (70, 76))	('Lapatinib', 'Chemical', 'MESH:D000077341', (156, 165))	('cMYC', 'Gene', (85, 89))	('breast cancer', 'Disease', (223, 236))	('inhibition', 'NegReg', (179, 189))	('breast cancer', 'Phenotype', 'HP:0003002', (223, 236))	('MK2206', 'Var', (70, 76))	('cMYC', 'Gene', (202, 206))
102919	29763624	The combination of low dose MLN128 and MK2206 failed to fully suppress upregulation of GLS (Figure S4A) suggesting that MLN128+MK2206 may not be an effective treatment combination for lung SCC.	('GLS', 'Gene', (87, 90))	('MK2206', 'Chemical', 'MESH:C548887', (127, 133))	('SCC', 'Gene', (189, 192))	('SCC', 'Gene', '6317', (189, 192))	('MLN128+MK2206', 'Var', (120, 133))	('MLN128', 'Chemical', '-', (120, 126))	('MLN128', 'Chemical', '-', (28, 34))	('MK2206', 'Chemical', 'MESH:C548887', (39, 45))	('GLS', 'Gene', '2744', (87, 90))
102920	29763624	This prompted us to identify druggable targets downstream of GSK3alpha/beta that would overcome resistance to MLN128.	('GSK3alpha/beta', 'Gene', '2931', (61, 75))	('MLN128', 'Var', (110, 116))	('GSK3alpha/beta', 'Gene', (61, 75))	('MLN128', 'Chemical', '-', (110, 116))
102921	29763624	Examination of GSK3alpha/beta signaling in lung SCC tumor lysates isolated from KL mice showed increased phosphorylation of AKTT308 and GSK3alpha/betaS21/9 in MLN128 treated tumors as compared to vehicle (Figure 4B).	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('phosphorylation', 'MPA', (105, 120))	('MLN128', 'Chemical', '-', (159, 165))	('tumors', 'Disease', (174, 180))	('tumors', 'Disease', 'MESH:D009369', (174, 180))	('lung SCC tumor', 'Disease', 'MESH:D008175', (43, 57))	('GSK3alpha/beta', 'Gene', (15, 29))	('lung SCC tumor', 'Disease', (43, 57))	('mice', 'Species', '10090', (83, 87))	('MLN128 treated', 'Var', (159, 173))	('AKTT308', 'Gene', (124, 131))	('GSK3alpha/beta', 'Gene', (136, 150))	('GSK3alpha/beta', 'Gene', '2931', (15, 29))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('increased', 'PosReg', (95, 104))	('betaS21', 'Chemical', '-', (146, 153))	('tumors', 'Phenotype', 'HP:0002664', (174, 180))	('GSK3alpha/beta', 'Gene', '2931', (136, 150))
102923	29763624	We identified that MLN128 treated SCCs had higher levels of nuclear localized cMYC and cJUN as well as the KGA isoform of GLS (Figures 4B, and S4C).	('KGA', 'Gene', '2744', (107, 110))	('cMYC', 'Gene', '4609', (78, 82))	('SCC', 'Gene', (34, 37))	('higher', 'PosReg', (43, 49))	('SCC', 'Gene', '6317', (34, 37))	('MLN128', 'Chemical', '-', (19, 25))	('GLS', 'Gene', '2744', (122, 125))	('cMYC', 'Gene', (78, 82))	('MLN128 treated', 'Var', (19, 33))	('cJUN', 'MPA', (87, 91))	('GLS', 'Gene', (122, 125))	('KGA', 'Gene', (107, 110))
102926	29763624	Both mTORC1 substrates pS6K and p4EBP1 were reduced in MLN128 treated tumors confirming mTORC1 was sufficiently inhibited in these tumors (Figure 4B).	('4EBP1', 'Gene', '1978', (33, 38))	('mTORC1', 'Gene', (5, 11))	('MLN128 treated', 'Var', (55, 69))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('mTORC1', 'Gene', '382056', (5, 11))	('MLN128', 'Chemical', '-', (55, 61))	('mTORC1', 'Gene', (88, 94))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('tumors', 'Disease', (70, 76))	('mTORC1', 'Gene', '382056', (88, 94))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('pS6K', 'Gene', '6198', (23, 27))	('tumors', 'Disease', 'MESH:D009369', (70, 76))	('4EBP1', 'Gene', (33, 38))	('tumors', 'Disease', (131, 137))	('pS6K', 'Gene', (23, 27))	('reduced', 'NegReg', (44, 51))	('tumors', 'Disease', 'MESH:D009369', (131, 137))
102927	29763624	We next measured response to MLN128 in human lung SCC and large cell carcinoma (LCC) lines RH2 and H460, respectively.	('RH2', 'Gene', '6005', (91, 94))	('SCC', 'Gene', '6317', (50, 53))	('RH2', 'Gene', (91, 94))	('large cell carcinoma', 'Phenotype', 'HP:0030360', (58, 78))	('MLN128', 'Chemical', '-', (29, 35))	('MLN128', 'Var', (29, 35))	('cell carcinoma', 'Disease', (64, 78))	('SCC', 'Gene', (50, 53))	('cell carcinoma', 'Disease', 'MESH:C538614', (64, 78))	('human', 'Species', '9606', (39, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))
102928	29763624	Nanomolar doses of MLN128 inhibited mTORC1 as shown by reduced p4EBP1 (Figure 4C).	('inhibited', 'NegReg', (26, 35))	('reduced', 'NegReg', (55, 62))	('mTORC1', 'Gene', (36, 42))	('MLN128', 'Chemical', '-', (19, 25))	('MLN128', 'Var', (19, 25))	('4EBP1', 'Gene', '1978', (64, 69))	('4EBP1', 'Gene', (64, 69))	('mTORC1', 'Gene', '382056', (36, 42))
102929	29763624	Both cell lines showed an increase in pAKTT308, pGSK3alpha/betaS21/9 and cMYC in response to MLN128 treatment (Figure 4C).	('cMYC', 'Gene', (73, 77))	('GSK3alpha/beta', 'Gene', (49, 63))	('MLN128', 'Chemical', '-', (93, 99))	('MLN128 treatment', 'Var', (93, 109))	('pGSK3alpha', 'Chemical', '-', (48, 58))	('GSK3alpha/beta', 'Gene', '2931', (49, 63))	('cMYC', 'Gene', '4609', (73, 77))	('betaS21', 'Chemical', '-', (59, 66))	('pAKTT308', 'CPA', (38, 46))	('increase', 'PosReg', (26, 34))
102931	29763624	The differential response to MLN128 between RH2 and H460 predicts that in vivo H460 tumor xenografts may be responsive to MLN128 while RH2 tumors are expected to be refractory to MLN128.	('RH2', 'Gene', '6005', (44, 47))	('RH2', 'Gene', (135, 138))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('RH2', 'Gene', (44, 47))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('MLN128', 'Chemical', '-', (29, 35))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('responsive to', 'MPA', (108, 121))	('tumor', 'Disease', (139, 144))	('tumor', 'Disease', (84, 89))	('MLN128', 'Var', (122, 128))	('RH2', 'Gene', '6005', (135, 138))	('MLN128', 'Chemical', '-', (122, 128))	('tumors', 'Disease', (139, 145))	('tumors', 'Disease', 'MESH:D009369', (139, 145))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('MLN128', 'Chemical', '-', (179, 185))
102932	29763624	Additionally, we examined lung ADC cell lines to determine if the molecular response to MLN128 was unique to SCC tumors or conserved across both tumor histologies.	('tumor', 'Disease', (113, 118))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('MLN128', 'Chemical', '-', (88, 94))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('MLN128', 'Var', (88, 94))	('tumor', 'Disease', (145, 150))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('SCC tumors', 'Disease', 'MESH:D009369', (109, 119))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('SCC tumors', 'Disease', (109, 119))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
102933	29763624	Nanomolar doses of MLN128 inhibited mTORC1 in lung ADC cell lines A549 and H838 as measured by reduced levels of p4EBP1 (Figure 4C).	('4EBP1', 'Gene', '1978', (114, 119))	('inhibited', 'NegReg', (26, 35))	('A549', 'CellLine', 'CVCL:0023', (66, 70))	('mTORC1', 'Gene', (36, 42))	('4EBP1', 'Gene', (114, 119))	('MLN128', 'Chemical', '-', (19, 25))	('MLN128', 'Var', (19, 25))	('reduced', 'NegReg', (95, 102))	('mTORC1', 'Gene', '382056', (36, 42))	('levels', 'MPA', (103, 109))
102935	29763624	While A549 cells showed a modest increase in pAKTT308 levels following MLN128 treatment, both ADC lines showed no change in pGSK3alpha/betaS21/9, cMYC or cJUN levels (Figure 4C).	('betaS21', 'Chemical', '-', (135, 142))	('pAKTT308 levels', 'MPA', (45, 60))	('GSK3alpha/beta', 'Gene', (125, 139))	('cJUN levels', 'MPA', (154, 165))	('A549', 'CellLine', 'CVCL:0023', (6, 10))	('cMYC', 'Gene', (146, 150))	('MLN128', 'Chemical', '-', (71, 77))	('increase', 'PosReg', (33, 41))	('pGSK3alpha', 'Chemical', '-', (124, 134))	('cMYC', 'Gene', '4609', (146, 150))	('GSK3alpha/beta', 'Gene', '2931', (125, 139))	('MLN128 treatment', 'Var', (71, 87))
102936	29763624	Furthermore, MLN128 induced a reduction in GLS in both ADC cell lines opposite that which was observed in SCC cells.	('SCC', 'Gene', '6317', (106, 109))	('GLS', 'Gene', '2744', (43, 46))	('GLS', 'Gene', (43, 46))	('reduction', 'NegReg', (30, 39))	('MLN128', 'Chemical', '-', (13, 19))	('MLN128', 'Var', (13, 19))	('SCC', 'Gene', (106, 109))
102938	29763624	We treated RH2 and H460 cell lines with increasing doses of the GSK3alpha/beta inhibitor (GSK3i) CHIR99021 and evaluated levels of GLS, cMYC and cJUN.	('GLS', 'Gene', '2744', (131, 134))	('GLS', 'Gene', (131, 134))	('cJUN', 'MPA', (145, 149))	('GSK3alpha/beta', 'Gene', '2931', (64, 78))	('cMYC', 'Gene', '4609', (136, 140))	('CHIR99021', 'Var', (97, 106))	('RH2', 'Gene', '6005', (11, 14))	('RH2', 'Gene', (11, 14))	('cMYC', 'Gene', (136, 140))	('GSK3alpha/beta', 'Gene', (64, 78))
102939	29763624	GSK3i induced a dose dependent increase in the protein levels of GLS, cMYC and cJUN (Figure 4D) in both cell lines.	('cMYC', 'Gene', (70, 74))	('GSK3i', 'Var', (0, 5))	('protein levels', 'MPA', (47, 61))	('GLS', 'Gene', '2744', (65, 68))	('cMYC', 'Gene', '4609', (70, 74))	('GLS', 'Gene', (65, 68))	('increase', 'PosReg', (31, 39))
102942	29763624	We next performed siRNA-mediated knockdown of cMYC or cJUN in RH2 and H460 cells in the presence of GSK3i and measured GLS protein levels.	('measured', 'Reg', (110, 118))	('cJUN', 'Gene', (54, 58))	('knockdown', 'Var', (33, 42))	('RH2', 'Gene', '6005', (62, 65))	('GLS', 'Gene', '2744', (119, 122))	('RH2', 'Gene', (62, 65))	('GLS', 'Gene', (119, 122))	('cMYC', 'Gene', (46, 50))	('cMYC', 'Gene', '4609', (46, 50))
102943	29763624	We showed that following cJUN knockdown, both RH2 and H460 cells are unable to upregulate GLS in the presence of GSK3i thus demonstrating a reliance on cJUN (Figure 4E bottom panel red box).	('GLS', 'Gene', (90, 93))	('RH2', 'Gene', (46, 49))	('red box', 'Species', '1226038', (181, 188))	('upregulate', 'PosReg', (79, 89))	('cJUN', 'Gene', (25, 29))	('knockdown', 'Var', (30, 39))	('GLS', 'Gene', '2744', (90, 93))	('RH2', 'Gene', '6005', (46, 49))
102944	29763624	In contrast, cMYC knockdown did not hinder GLS upregulation in RH2 cells while H460 cells were unable to upregulate GLS following cMYC knockdown (Figure 4E top panel blue box).	('knockdown', 'Var', (135, 144))	('cMYC', 'Gene', '4609', (130, 134))	('GLS', 'Gene', '2744', (43, 46))	('cMYC', 'Gene', '4609', (13, 17))	('GLS', 'Gene', (43, 46))	('GLS', 'Gene', '2744', (116, 119))	('cMYC', 'Gene', (13, 17))	('RH2', 'Gene', '6005', (63, 66))	('GLS', 'Gene', (116, 119))	('RH2', 'Gene', (63, 66))	('cMYC', 'Gene', (130, 134))
102947	29763624	In addition, inhibition of the Jun N-terminal Kinase (JNK) using the JNK inhibitor JNK-IN-8 reduced phosphorylation of cJUN at Ser73 and cooperated with MLN128 to reduce cell viability in lung SCC cell lines (Figures S4G-J).	('MLN128', 'Chemical', '-', (153, 159))	('cJUN', 'Protein', (119, 123))	('Ser73', 'Chemical', '-', (127, 132))	('Jun N-terminal Kinase', 'Gene', '5599', (31, 52))	('MLN128', 'Var', (153, 159))	('phosphorylation', 'MPA', (100, 115))	('cell viability', 'CPA', (170, 184))	('SCC', 'Gene', (193, 196))	('reduced', 'NegReg', (92, 99))	('inhibition', 'NegReg', (13, 23))	('SCC', 'Gene', '6317', (193, 196))	('Jun N-terminal Kinase', 'Gene', (31, 52))	('reduce', 'NegReg', (163, 169))
102953	29763624	HKII is a MYC target gene that is suppressed by MLN128 resulting in reduced 18F-FDG signal in MLN128 treated tumors.	('MLN128', 'Var', (48, 54))	('tumors', 'Disease', 'MESH:D009369', (109, 115))	('MLN128', 'Chemical', '-', (94, 100))	('MYC', 'Gene', (10, 13))	('HKII', 'Gene', '3099', (0, 4))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('MLN128', 'Var', (94, 100))	('MYC', 'Gene', '4609', (10, 13))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('MLN128', 'Chemical', '-', (48, 54))	('reduced', 'NegReg', (68, 75))	('HKII', 'Gene', (0, 4))	('18F-FDG', 'Chemical', 'MESH:D019788', (76, 83))	('tumors', 'Disease', (109, 115))	('18F-FDG signal', 'MPA', (76, 90))
102957	29763624	Our data in Figure 4 showed that inactivation of GSK3alpha/beta confers resistance to MLN128 through upregulation of GLS.	('GSK3alpha/beta', 'Gene', (49, 63))	('MLN128', 'Var', (86, 92))	('upregulation', 'PosReg', (101, 113))	('GSK3alpha/beta', 'Gene', '2931', (49, 63))	('GLS', 'Gene', '2744', (117, 120))	('inactivation', 'Var', (33, 45))	('MLN128', 'Chemical', '-', (86, 92))	('GLS', 'Gene', (117, 120))
102958	29763624	The data also suggest that the phosphorylation state of GSK3alpha/betaS21/9 is predictive of differentiating responders and non-responders to single therapy MLN128.	('GSK3alpha/beta', 'Gene', (56, 70))	('GSK3alpha/beta', 'Gene', '2931', (56, 70))	('phosphorylation', 'MPA', (31, 46))	('betaS21', 'Chemical', '-', (66, 73))	('MLN128', 'Chemical', '-', (157, 163))	('MLN128', 'Var', (157, 163))
102959	29763624	To test this we implanted mice with human lung SCC/LCC tumor lines RH2, H1703, H460 and H2170 and began daily treatment with vehicle or MLN128 when tumors reached a volume of 50 mm3-150 mm3.	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('lung SCC/LCC tumor', 'Disease', (42, 60))	('MLN128', 'Chemical', '-', (136, 142))	('H1703', 'CellLine', 'CVCL:1490', (72, 77))	('mice', 'Species', '10090', (26, 30))	('tumors', 'Disease', 'MESH:D009369', (148, 154))	('tumors', 'Disease', (148, 154))	('lung SCC/LCC tumor', 'Disease', 'MESH:D006528', (42, 60))	('MLN128', 'Var', (136, 142))	('human', 'Species', '9606', (36, 41))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('RH2', 'Gene', '6005', (67, 70))	('RH2', 'Gene', (67, 70))
102960	29763624	We identified that RH2 and H1703 tumor xenografts were unresponsive to single therapy MLN128 while H460 and H2170 tumors showed significant response to MLN128 (Figures 5A-5D).	('RH2', 'Gene', '6005', (19, 22))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('RH2', 'Gene', (19, 22))	('MLN128', 'Var', (86, 92))	('MLN128', 'Chemical', '-', (152, 158))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('H1703', 'CellLine', 'CVCL:1490', (27, 32))	('tumor', 'Disease', (114, 119))	('MLN128', 'Var', (152, 158))	('tumors', 'Disease', (114, 120))	('tumor', 'Disease', (33, 38))	('tumors', 'Disease', 'MESH:D009369', (114, 120))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('MLN128', 'Chemical', '-', (86, 92))
102961	29763624	We classified these tumors as non-responders (RH2, H1703) and responders (H460, H2170).	('RH2', 'Gene', (46, 49))	('tumors', 'Disease', (20, 26))	('tumors', 'Disease', 'MESH:D009369', (20, 26))	('RH2', 'Gene', '6005', (46, 49))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('H1703', 'CellLine', 'CVCL:1490', (51, 56))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('H460', 'Var', (74, 78))	('H2170', 'Var', (80, 85))
102964	29763624	While cJUN and p-cJUNS73 expression consistently delineated MLN128 responders from non-responders, cMYC staining was variable in both responders and non-responders (Figure S5A and S5B).	('MLN128 responders', 'Var', (60, 77))	('cMYC', 'Gene', '4609', (99, 103))	('MLN128', 'Chemical', '-', (60, 66))	('S5B', 'Gene', '5711', (180, 183))	('p-cJUNS73', 'Var', (15, 24))	('cMYC', 'Gene', (99, 103))	('S5B', 'Gene', (180, 183))
102966	29763624	We next sought to test whether pGSK3alpha/betaS21/9 was a predictive marker of MLN128 response in human PDXs of lung SCC.	('MLN128 response', 'Var', (79, 94))	('SCC', 'Gene', (117, 120))	('pGSK3alpha', 'Chemical', '-', (31, 41))	('GSK3alpha/beta', 'Gene', (32, 46))	('betaS21', 'Chemical', '-', (42, 49))	('SCC', 'Gene', '6317', (117, 120))	('human', 'Species', '9606', (98, 103))	('GSK3alpha/beta', 'Gene', '2931', (32, 46))	('MLN128', 'Chemical', '-', (79, 85))
102967	29763624	Before treating PDXs with MLN128, we functionally characterized metabolism and protein biomarkers in lung SCC PDXs to confirm these tumors retained a hypermetabolic and glycolytic phenotype similar to the patients' primary tumors (Figure S5C-S5E).	('primary tumors', 'Disease', 'MESH:D009369', (215, 229))	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('patients', 'Species', '9606', (205, 213))	('SCC', 'Gene', '6317', (106, 109))	('tumors', 'Disease', (223, 229))	('tumors', 'Disease', 'MESH:D009369', (223, 229))	('tumors', 'Phenotype', 'HP:0002664', (223, 229))	('MLN128', 'Chemical', '-', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('glycolytic', 'MPA', (169, 179))	('MLN128', 'Var', (26, 32))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('tumors', 'Disease', (132, 138))	('S5E', 'Mutation', 'p.S5E', (242, 245))	('primary tumors', 'Disease', (215, 229))	('tumors', 'Disease', 'MESH:D009369', (132, 138))	('SCC', 'Gene', (106, 109))
102968	29763624	18F-FDG PET imaging confirmed that PDX005 and PDX007 retained a hypermetabolic, 18F-FDG avid and glycolytic tumor phenotype (Figure S5D and S5E), which was identical to the patient's primary tumor phenotype (comparing Figures S5C to S5D).	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('PDX005', 'Var', (35, 41))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('glycolytic tumor', 'Disease', 'MESH:D009369', (97, 113))	('S5E', 'Mutation', 'p.S5E', (140, 143))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('18F-FDG', 'Chemical', 'MESH:D019788', (0, 7))	('hypermetabolic', 'MPA', (64, 78))	('tumor', 'Disease', (108, 113))	('PDX007', 'Gene', (46, 52))	('PET', 'Gene', '22095', (8, 11))	('tumor', 'Disease', (191, 196))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('patient', 'Species', '9606', (173, 180))	('PET', 'Gene', (8, 11))	('glycolytic tumor', 'Disease', (97, 113))	('18F-FDG', 'Chemical', 'MESH:D019788', (80, 87))
102969	29763624	Importantly, PDXs had high activation of the mTOR pathway as indicated by positive staining for p4EBP1 (Figure S5F), thus making these PDXs logical candidates for MLN128 therapy.	('MLN128', 'Chemical', '-', (163, 169))	('4EBP1', 'Gene', '1978', (97, 102))	('MLN128', 'Var', (163, 169))	('4EBP1', 'Gene', (97, 102))	('mTOR pathway', 'Pathway', (45, 57))	('activation', 'PosReg', (27, 37))
102973	29763624	We identified differential pGSK3alpha/betaS21/9 staining between PDXs, with PDX007 having a stronger pGSK3alpha/betaS21/9 staining signal compared to PDX005 (Figure 5I).	('stronger', 'PosReg', (92, 100))	('GSK3alpha/beta', 'Gene', '2931', (102, 116))	('betaS21', 'Chemical', '-', (112, 119))	('GSK3alpha/beta', 'Gene', '2931', (28, 42))	('pGSK3alpha', 'Chemical', '-', (101, 111))	('pGSK3alpha', 'Chemical', '-', (27, 37))	('GSK3alpha/beta', 'Gene', (102, 116))	('betaS21', 'Chemical', '-', (38, 45))	('GSK3alpha/beta', 'Gene', (28, 42))	('PDX007', 'Var', (76, 82))
102974	29763624	In addition, we identified that PDX007 had a modest increase in cJUN, p-cJUNS73 and cMYC staining compared to PDX005 (Figures 5I and S5G).	('p-cJUNS73', 'MPA', (70, 79))	('cJUN', 'MPA', (64, 68))	('increase', 'PosReg', (52, 60))	('PDX007', 'Var', (32, 38))	('cMYC', 'Gene', (84, 88))	('cMYC', 'Gene', '4609', (84, 88))
102975	29763624	Together, our data supports pGSK3alpha/betaS21/9 as a predictive biomarker that correlates with response to treatment with MLN128.	('betaS21', 'Chemical', '-', (39, 46))	('pGSK3alpha', 'Chemical', '-', (28, 38))	('GSK3alpha/beta', 'Gene', (29, 43))	('MLN128', 'Chemical', '-', (123, 129))	('GSK3alpha/beta', 'Gene', '2931', (29, 43))	('MLN128', 'Var', (123, 129))
102977	29763624	We examined whether combining MLN128 with GLS inhibitor CB-839 would result in an improved therapy response in lung SCC.	('SCC', 'Gene', (116, 119))	('CB-839', 'Gene', (56, 62))	('SCC', 'Gene', '6317', (116, 119))	('MLN128', 'Chemical', '-', (30, 36))	('CB-839', 'Chemical', 'MESH:C000593334', (56, 62))	('therapy response', 'CPA', (91, 107))	('MLN128', 'Var', (30, 36))	('GLS', 'Gene', '2744', (42, 45))	('improved', 'PosReg', (82, 90))	('GLS', 'Gene', (42, 45))
102978	29763624	We first tested combinatorial MLN128 and CB-839 treatment in a panel of 9 human lung SCC cell lines.	('CB-839', 'Gene', (41, 47))	('SCC', 'Gene', '6317', (85, 88))	('CB-839', 'Chemical', 'MESH:C000593334', (41, 47))	('MLN128', 'Chemical', '-', (30, 36))	('human', 'Species', '9606', (74, 79))	('MLN128', 'Var', (30, 36))	('SCC', 'Gene', (85, 88))
102979	29763624	Single and combinatorial treatment with MLN128 or CB-839 significantly reduced cell viability compared to vehicle, and combinatorial MLN128+CB-839 treatment further reduced viability compared single therapy MLN128 and CB-839 (Figure 6A).	('CB-839', 'Chemical', 'MESH:C000593334', (140, 146))	('MLN128', 'Chemical', '-', (207, 213))	('cell viability', 'CPA', (79, 93))	('CB-839', 'Chemical', 'MESH:C000593334', (218, 224))	('MLN128', 'Chemical', '-', (40, 46))	('CB-839', 'Gene', (50, 56))	('MLN128+CB-839', 'Var', (133, 146))	('reduced', 'NegReg', (71, 78))	('MLN128', 'Chemical', '-', (133, 139))	('MLN128', 'Var', (40, 46))	('viability', 'CPA', (173, 182))	('CB-839', 'Chemical', 'MESH:C000593334', (50, 56))	('reduced', 'NegReg', (165, 172))	('MLN128+CB-839', 'Gene', (133, 146))
102982	29763624	Single therapy MLN128 and CB-839 treatments showed no reduction in tumor volume compared to the vehicle group, however, combinatorial MLN128+CB-839 treatment significantly slowed tumor growth (Figure 6B) and significantly reduced tumor cell proliferation measured by Ki67 (Figure 6C).	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('MLN128', 'Chemical', '-', (134, 140))	('tumor', 'Disease', (67, 72))	('CB-839', 'Chemical', 'MESH:C000593334', (26, 32))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('MLN128', 'Chemical', '-', (15, 21))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('tumor', 'Disease', (230, 235))	('MLN128+CB-839', 'Gene', (134, 147))	('Ki67', 'Gene', (267, 271))	('CB-839', 'Chemical', 'MESH:C000593334', (141, 147))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Disease', 'MESH:D009369', (230, 235))	('MLN128+CB-839', 'Var', (134, 147))	('reduced', 'NegReg', (222, 229))	('slowed', 'NegReg', (172, 178))	('Ki67', 'Gene', '17345', (267, 271))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))	('tumor', 'Disease', (179, 184))
102983	29763624	As expected, MLN128 effectively inhibited mTORC1 as measured by reduced p4EBP1 (Figure 6C).	('4EBP1', 'Gene', '1978', (73, 78))	('inhibited', 'NegReg', (32, 41))	('mTORC1', 'Gene', '382056', (42, 48))	('4EBP1', 'Gene', (73, 78))	('mTORC1', 'Gene', (42, 48))	('MLN128', 'Chemical', '-', (13, 19))	('reduced', 'NegReg', (64, 71))	('MLN128', 'Var', (13, 19))
102984	29763624	In both PDXs CB-839 treatment alone had no effect on tumor growth and MLN128 alone slowed tumor growth only in PDX005 but not PDX007 as shown in Figure 4.	('MLN128 alone', 'Var', (70, 82))	('PDX005', 'Var', (111, 117))	('CB-839', 'Chemical', 'MESH:C000593334', (13, 19))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('tumor', 'Disease', (53, 58))	('slowed', 'NegReg', (83, 89))	('MLN128', 'Chemical', '-', (70, 76))
102985	29763624	In both PDXs the combination of MLN128 and CB-839 significantly reduced tumor growth (Figures 6D and 6E).	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Disease', (72, 77))	('MLN128', 'Chemical', '-', (32, 38))	('MLN128', 'Var', (32, 38))	('CB-839', 'Gene', (43, 49))	('reduced', 'NegReg', (64, 71))	('CB-839', 'Chemical', 'MESH:C000593334', (43, 49))	('tumor', 'Disease', 'MESH:D009369', (72, 77))
102990	29763624	We identified significant tumor cell death in mice treated with second line CB-839 compared to those receiving only MLN128, with a nearly 3 fold increase in tumor necrosis in tumors receiving CB-839 (Figures 6G and 6H).	('tumor necrosis in tumors', 'Disease', (157, 181))	('tumors', 'Phenotype', 'HP:0002664', (175, 181))	('CB-839', 'Var', (76, 82))	('tumor necrosis in tumors', 'Disease', 'MESH:D009369', (157, 181))	('tumor cell death', 'Disease', 'MESH:D003643', (26, 42))	('CB-839', 'Chemical', 'MESH:C000593334', (192, 198))	('increase', 'PosReg', (145, 153))	('tumor cell death', 'Disease', (26, 42))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('MLN128', 'Chemical', '-', (116, 122))	('CB-839', 'Chemical', 'MESH:C000593334', (76, 82))	('mice', 'Species', '10090', (46, 50))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('CB-839', 'Var', (192, 198))
102992	29763624	Identical to KL GEMMs, we discovered that second line CB-839 treatment cooperated with MLN128 to significantly reduce tumor growth (Figure 6J).	('MLN128', 'Chemical', '-', (87, 93))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('MLN128', 'Var', (87, 93))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('CB-839', 'Gene', (54, 60))	('tumor', 'Disease', (118, 123))	('reduce', 'NegReg', (111, 117))	('CB-839', 'Chemical', 'MESH:C000593334', (54, 60))
102993	29763624	Collectively, these results demonstrate that CB-839 overcame acquired metabolic resistance to MLN128.	('MLN128', 'Chemical', '-', (94, 100))	('CB-839', 'Gene', (45, 51))	('CB-839', 'Chemical', 'MESH:C000593334', (45, 51))	('MLN128', 'Var', (94, 100))	('overcame', 'PosReg', (52, 60))
102994	29763624	CB-839 was highly effective when used as either a first or second line therapy with MLN128 to significantly reduce growth of human lung SCC.	('SCC', 'Gene', (136, 139))	('MLN128', 'Chemical', '-', (84, 90))	('CB-839', 'Chemical', 'MESH:C000593334', (0, 6))	('SCC', 'Gene', '6317', (136, 139))	('MLN128', 'Var', (84, 90))	('human', 'Species', '9606', (125, 130))	('reduce growth', 'Phenotype', 'HP:0001510', (108, 121))	('reduce', 'NegReg', (108, 114))	('growth', 'MPA', (115, 121))
102995	29763624	Due to the lack of defined genetic mutations in the human lung SCC that are predictive of therapeutic response to targeted therapies, we reasoned that stratification of human lung SCCs by metabolic phenotypes represents a means to identify patients who would respond to therapies targeting metabolism.	('SCC', 'Gene', (63, 66))	('human', 'Species', '9606', (52, 57))	('SCC', 'Gene', (180, 183))	('SCC', 'Gene', '6317', (63, 66))	('human', 'Species', '9606', (169, 174))	('patients', 'Species', '9606', (240, 248))	('SCC', 'Gene', '6317', (180, 183))	('mutations', 'Var', (35, 44))
102996	29763624	We identified five proteins whose expression was consistently amplified in 18F-FDG and 11C-Glutamine positive SCC lung tumors.	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('11C-Glutamine', 'Chemical', '-', (87, 100))	('lung tumors', 'Phenotype', 'HP:0100526', (114, 125))	('expression', 'MPA', (34, 44))	('SCC lung tumors', 'Disease', 'MESH:D008175', (110, 125))	('Glutamine positive', 'Phenotype', 'HP:0003217', (91, 109))	('SCC lung tumors', 'Disease', (110, 125))	('amplified', 'PosReg', (62, 71))	('11C-Glutamine', 'Var', (87, 100))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('18F-FDG', 'Chemical', 'MESH:D019788', (75, 82))
102997	29763624	These proteins include the glucose and glutamine transporters GLUT1 and SLC1A5, the mTORC1 substrate p4EBP1 as well as pGSK3alpha/betaS21/S9 and p-cJUNS73 and represent the core components of what we defined as a metabolic signature in lung SCC based on the data from this study.	('SLC1A5', 'Gene', (72, 78))	('SCC', 'Gene', (241, 244))	('GSK3alpha/beta', 'Gene', '2931', (120, 134))	('betaS21', 'Chemical', '-', (130, 137))	('mTORC1', 'Gene', (84, 90))	('pGSK3alpha', 'Chemical', '-', (119, 129))	('SCC', 'Gene', '6317', (241, 244))	('glutamine', 'Chemical', 'MESH:D005973', (39, 48))	('p-cJUNS73', 'Var', (145, 154))	('GSK3alpha/beta', 'Gene', (120, 134))	('4EBP1', 'Gene', '1978', (102, 107))	('mTORC1', 'Gene', '382056', (84, 90))	('4EBP1', 'Gene', (102, 107))	('glucose', 'Chemical', 'MESH:D005947', (27, 34))
103007	29763624	We then tested MLN128+CB-839 in mouse xenografts implanted with the HNSCC tumor line Tu686 and a PDX implanted with an OS pulmonary metastasis (OSPM).	('tested', 'Reg', (8, 14))	('OS pulmonary metastasis', 'Disease', (119, 142))	('MLN128+CB-839', 'Var', (15, 28))	('HNSCC tumor', 'Disease', 'MESH:D000077195', (68, 79))	('MLN128', 'Chemical', '-', (15, 21))	('OS pulmonary metastasis', 'Disease', 'MESH:C567932', (119, 142))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('HNSCC tumor', 'Disease', (68, 79))	('mouse', 'Species', '10090', (32, 37))	('MLN128+CB-839', 'Gene', (15, 28))	('CB-839', 'Chemical', 'MESH:C000593334', (22, 28))
103008	29763624	Both the HNSCC xenografts and OS PDXs significantly responded to the combination of MLN128+CB-839 (Figures S7C and S7D).	('CB-839', 'Chemical', 'MESH:C000593334', (91, 97))	('SCC', 'Gene', (11, 14))	('MLN128', 'Chemical', '-', (84, 90))	('responded', 'Reg', (52, 61))	('SCC', 'Gene', '6317', (11, 14))	('MLN128+CB-839', 'Var', (84, 97))	('MLN128+CB-839', 'Gene', (84, 97))
103009	29763624	Tumors from Tu686 xenografts and PDX004-OS were positive for GLUT1, SLC1A5, p4EBP1, pGSK3alpha/betaS21/9 and nuclear p-cJUNS73 staining (Figure S7E).	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('GSK3alpha/beta', 'Gene', '2931', (85, 99))	('betaS21', 'Chemical', '-', (95, 102))	('4EBP1', 'Gene', (77, 82))	('Tu686', 'Var', (12, 17))	('GLUT1', 'Protein', (61, 66))	('positive', 'Reg', (48, 56))	('4EBP1', 'Gene', '1978', (77, 82))	('nuclear p-cJUNS73 staining', 'Protein', (109, 135))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('pGSK3alpha', 'Chemical', '-', (84, 94))	('SLC1A5', 'Gene', (68, 74))	('GSK3alpha/beta', 'Gene', (85, 99))
103011	29763624	These results demonstrate that HNSCC and OS share a similar metabolic signature with that of lung SCC tumors and are responsive to MLN128+CB-839 treatment.	('SCC', 'Gene', '6317', (33, 36))	('MLN128', 'Chemical', '-', (131, 137))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('MLN128+CB-839', 'Var', (131, 144))	('SCC', 'Gene', '6317', (98, 101))	('CB-839', 'Chemical', 'MESH:C000593334', (138, 144))	('lung SCC tumors', 'Disease', (93, 108))	('SCC', 'Gene', (33, 36))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('lung SCC tumors', 'Disease', 'MESH:D008175', (93, 108))	('SCC', 'Gene', (98, 101))
103012	29763624	Lastly, we show that patients with low activity of GSK3alpha/beta and high p-cJUNS73 protein expression levels had significantly reduced progression free survival (PFS) or overall survival, respectively (Figures 7E and 7F).	('progression free survival', 'CPA', (137, 162))	('GSK3alpha/beta', 'Gene', (51, 65))	('overall survival', 'CPA', (172, 188))	('high p-cJUNS73', 'Var', (70, 84))	('GSK3alpha/beta', 'Gene', '2931', (51, 65))	('patients', 'Species', '9606', (21, 29))	('reduced', 'NegReg', (129, 136))	('low activity', 'Var', (35, 47))
103013	29763624	Interestingly, TCGA data suggests that lung SCC patients with high expression of SLC1A5 had significantly worse PFS and overall survival compared with patients with low expression of SLC1A5 (Figure S7F).	('SCC', 'Gene', '6317', (44, 47))	('worse', 'NegReg', (106, 111))	('PFS', 'MPA', (112, 115))	('SLC1A5', 'Gene', (81, 87))	('patients', 'Species', '9606', (151, 159))	('high expression', 'Var', (62, 77))	('SCC', 'Gene', (44, 47))	('overall survival', 'CPA', (120, 136))	('patients', 'Species', '9606', (48, 56))
103016	29763624	In addition, pGSK3alpha/betaS21/9 and p-cJUNS73 may have utility as functional biomarkers that can be used to stratify patients for metabolic therapies.	('p-cJUNS73', 'Var', (38, 47))	('GSK3alpha/beta', 'Gene', (14, 28))	('pGSK3alpha', 'Chemical', '-', (13, 23))	('patients', 'Species', '9606', (119, 127))	('GSK3alpha/beta', 'Gene', '2931', (14, 28))	('betaS21', 'Chemical', '-', (24, 31))
103020	29763624	Importantly, we discovered that the phosphorylation state of GSK3alpha/beta serves as a predictive biomarker of response or resistance to MLN128.	('MLN128', 'Chemical', '-', (138, 144))	('MLN128', 'Var', (138, 144))	('GSK3alpha/beta', 'Gene', '2931', (61, 75))	('GSK3alpha/beta', 'Gene', (61, 75))
103021	29763624	We confirmed that CB-839 together with MLN128 was highly effective in reducing tumor growth in a series of lung SCC models that included: human cell lines, mouse xenografts, GEMMs and PDXs.	('CB-839', 'Gene', (18, 24))	('tumor', 'Disease', (79, 84))	('SCC', 'Gene', '6317', (112, 115))	('MLN128', 'Chemical', '-', (39, 45))	('human', 'Species', '9606', (138, 143))	('MLN128', 'Var', (39, 45))	('CB-839', 'Chemical', 'MESH:C000593334', (18, 24))	('reducing', 'NegReg', (70, 78))	('mouse', 'Species', '10090', (156, 161))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('SCC', 'Gene', (112, 115))
103022	29763624	Lastly, we decoded a metabolic signature within hypermetabolic human lung SCC, HNSCC and OS defined by positive staining for GLUT1, SLC1A5, p4EBP1, pGSK3alpha/betaS21/9 and nuclear p-cJUNS73 that were responsive to combined MLN128 and CB-839 treatment.	('metabolic', 'MPA', (21, 30))	('SCC', 'Gene', '6317', (81, 84))	('MLN128', 'Var', (224, 230))	('SLC1A5', 'Gene', (132, 138))	('SCC', 'Gene', '6317', (74, 77))	('4EBP1', 'Gene', '1978', (141, 146))	('human', 'Species', '9606', (63, 68))	('4EBP1', 'Gene', (141, 146))	('GSK3alpha/beta', 'Gene', (149, 163))	('SCC', 'Gene', (74, 77))	('GSK3alpha/beta', 'Gene', '2931', (149, 163))	('SCC', 'Gene', (81, 84))	('MLN128', 'Chemical', '-', (224, 230))	('betaS21', 'Chemical', '-', (159, 166))	('pGSK3alpha', 'Chemical', '-', (148, 158))	('CB-839', 'Chemical', 'MESH:C000593334', (235, 241))
103026	29763624	MLN128 potently inhibited mTORC1 as well as glucose metabolism in lung SCC yet tumors continued to grow.	('MLN128', 'Var', (0, 6))	('inhibited', 'NegReg', (16, 25))	('glucose metabolism in lung SCC yet tumors', 'Disease', (44, 85))	('mTORC1', 'Gene', (26, 32))	('glucose metabolism in lung SCC yet tumors', 'Disease', 'MESH:D044882', (44, 85))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('mTORC1', 'Gene', '382056', (26, 32))	('MLN128', 'Chemical', '-', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
103027	29763624	We hypothesized that lung SCCs escaped mTOR inhibition not because the drug failed to reach its target but rather because tumors upregulated alternative nutrient sources that enabled escape of MLN128 treatment.	('tumors', 'Phenotype', 'HP:0002664', (122, 128))	('tumors', 'Disease', (122, 128))	('tumors', 'Disease', 'MESH:D009369', (122, 128))	('SCC', 'Gene', '6317', (26, 29))	('MLN128', 'Chemical', '-', (193, 199))	('upregulated', 'PosReg', (129, 140))	('MLN128 treatment', 'Var', (193, 209))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('SCC', 'Gene', (26, 29))
103029	29763624	Serial PET imaging of KL GEMMs with 11C-Gln and 18F-FDG identified high influx of both glutamine and glucose that was consistently elevated and associated with intense protein staining for GLUT1 and SLC1A5 transporters consistent with previously published studies.	('elevated', 'PosReg', (131, 139))	('influx of', 'MPA', (72, 81))	('11C-Gln', 'Var', (36, 43))	('18F-FDG', 'Var', (48, 55))	('PET', 'Gene', '22095', (7, 10))	('glucose', 'Chemical', 'MESH:D005947', (101, 108))	('11C-Gln', 'Chemical', '-', (36, 43))	('PET', 'Gene', (7, 10))	('18F-FDG', 'Chemical', 'MESH:D019788', (48, 55))	('glutamine', 'Chemical', 'MESH:D005973', (87, 96))
103030	29763624	Following up on PET imaging, we performed in vivo metabolic tracing of lung SCC tumors that successfully defined a metabolic route by which lung SCC tumors adapt to MLN128 through upregulation of glutamine.	('lung SCC tumors', 'Disease', (140, 155))	('MLN128', 'Var', (165, 171))	('PET', 'Gene', (16, 19))	('lung SCC tumors', 'Disease', 'MESH:D008175', (71, 86))	('lung SCC tumors', 'Disease', 'MESH:D008175', (140, 155))	('upregulation', 'PosReg', (180, 192))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('glutamine', 'MPA', (196, 205))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('tumors', 'Phenotype', 'HP:0002664', (149, 155))	('PET', 'Gene', '22095', (16, 19))	('MLN128', 'Chemical', '-', (165, 171))	('lung SCC tumors', 'Disease', (71, 86))	('glutamine', 'Chemical', 'MESH:D005973', (196, 205))
103035	29763624	Both, pGSK3alpha/betaS21/9 and p-cJUNS73 have potential to be developed as surrogate biomarkers of response or resistance to MLN128 treatment.	('p-cJUNS73', 'Var', (31, 40))	('GSK3alpha/beta', 'Gene', '2931', (7, 21))	('betaS21', 'Chemical', '-', (17, 24))	('pGSK3alpha', 'Chemical', '-', (6, 16))	('MLN128', 'Chemical', '-', (125, 131))	('GSK3alpha/beta', 'Gene', (7, 21))
103036	29763624	We show that tumors with low levels of pGSK3alpha/betaS21/9 and p-cJUNS73 were sensitive to MLN128 as a single therapy while tumors with high levels of pGSK3alpha/betaS21/9 and p-cJUNS73 were refractory to MLN128.	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('MLN128', 'Var', (92, 98))	('MLN128', 'Chemical', '-', (206, 212))	('GSK3alpha/beta', 'Gene', '2931', (40, 54))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('MLN128', 'Chemical', '-', (92, 98))	('tumors', 'Disease', (125, 131))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('betaS21', 'Chemical', '-', (163, 170))	('tumors', 'Disease', (13, 19))	('GSK3alpha/beta', 'Gene', (153, 167))	('tumors', 'Disease', 'MESH:D009369', (125, 131))	('pGSK3alpha', 'Chemical', '-', (152, 162))	('pGSK3alpha', 'Chemical', '-', (39, 49))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('betaS21', 'Chemical', '-', (50, 57))	('GSK3alpha/beta', 'Gene', (40, 54))	('GSK3alpha/beta', 'Gene', '2931', (153, 167))
103037	29763624	If we extrapolate our results to clinical applications then patients with low phosphorylation of GSK3alpha/betaS21/9 and cJUNS73 represent a patient population who may be responsive to single agent MLN128 while those with tumor(s) having elevated levels of pGSK3alpha/betaS21/9 and p-cJUNS73 would require MLN128 in combination with CB-839.	('MLN128', 'Chemical', '-', (198, 204))	('low', 'NegReg', (74, 77))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('GSK3alpha/beta', 'Gene', '2931', (97, 111))	('GSK3alpha/beta', 'Gene', (258, 272))	('MLN128', 'Var', (306, 312))	('pGSK3alpha', 'Chemical', '-', (257, 267))	('patients', 'Species', '9606', (60, 68))	('patient', 'Species', '9606', (141, 148))	('betaS21', 'Chemical', '-', (268, 275))	('MLN128', 'Chemical', '-', (306, 312))	('phosphorylation', 'MPA', (78, 93))	('CB-839', 'Chemical', 'MESH:C000593334', (333, 339))	('GSK3alpha/beta', 'Gene', '2931', (258, 272))	('tumor', 'Disease', (222, 227))	('betaS21', 'Chemical', '-', (107, 114))	('patient', 'Species', '9606', (60, 67))	('tumor', 'Disease', 'MESH:D009369', (222, 227))	('GSK3alpha/beta', 'Gene', (97, 111))	('MLN128', 'Var', (198, 204))
103039	29763624	The combination of MLN128 and CB-839 was highly effective in halting growth of aggressive lung SCC tumors.	('CB-839', 'Chemical', 'MESH:C000593334', (30, 36))	('halting', 'NegReg', (61, 68))	('halting growth', 'Phenotype', 'HP:0001510', (61, 75))	('MLN128', 'Chemical', '-', (19, 25))	('MLN128', 'Var', (19, 25))	('CB-839', 'Gene', (30, 36))	('aggressive lung SCC tumors', 'Disease', 'MESH:D008175', (79, 105))	('growth', 'MPA', (69, 75))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('aggressive lung SCC tumors', 'Disease', (79, 105))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))
103040	29763624	Therefore, we tested single dose delivery of MLN128 followed by second line delivery of CB-839 after tumors became non-responsive to MLN128.	('MLN128', 'Var', (45, 51))	('CB-839', 'Chemical', 'MESH:C000593334', (88, 94))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('CB-839', 'Gene', (88, 94))	('MLN128', 'Chemical', '-', (133, 139))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('MLN128', 'Chemical', '-', (45, 51))	('tumors', 'Disease', (101, 107))	('tumors', 'Disease', 'MESH:D009369', (101, 107))
103042	29763624	In a clinical setting, biomarkers will be needed to identify metabolically active tumors that will be responsive to MLN128 and CB-839 treatment.	('CB-839', 'Gene', (127, 133))	('tumors', 'Disease', (82, 88))	('CB-839', 'Chemical', 'MESH:C000593334', (127, 133))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('MLN128', 'Chemical', '-', (116, 122))	('MLN128', 'Var', (116, 122))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))
103043	29763624	Our discovery of a conserved metabolic signature in lung SCC, HNSCC and OS suggest that hypermetabolic, 18F-FDG avid tumors may be responsive to combinatorial treatment with MLN128 and CB-839.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('SCC', 'Gene', '6317', (57, 60))	('CB-839', 'Var', (185, 191))	('SCC', 'Gene', '6317', (64, 67))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('CB-839', 'Chemical', 'MESH:C000593334', (185, 191))	('tumors', 'Disease', (117, 123))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('MLN128', 'Chemical', '-', (174, 180))	('18F-FDG', 'Chemical', 'MESH:D019788', (104, 111))	('MLN128', 'Var', (174, 180))	('SCC', 'Gene', (57, 60))	('SCC', 'Gene', (64, 67))
103044	29763624	In addition to NSCLC, high 18F-FDG uptake correlates with significantly worse survival in number of cancers, including HNSCC and OS.	('cancers', 'Phenotype', 'HP:0002664', (100, 107))	('high', 'Var', (22, 26))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('SCC', 'Gene', (121, 124))	('worse', 'NegReg', (72, 77))	('18F-FDG', 'Chemical', 'MESH:D019788', (27, 34))	('NSCLC', 'Disease', (15, 20))	('18F-FDG', 'Protein', (27, 34))	('SCC', 'Gene', '6317', (121, 124))	('NSCLC', 'Disease', 'MESH:D002289', (15, 20))	('cancers', 'Disease', 'MESH:D009369', (100, 107))	('cancers', 'Disease', (100, 107))
103047	29763624	While genetically disparate in their mutation spectrums, lung SCC, HNSCC and OS all shared a conserved metabolic signature and showed significant response to MLN128 and CB-839 treatment.	('response', 'MPA', (146, 154))	('SCC', 'Gene', (69, 72))	('SCC', 'Gene', '6317', (62, 65))	('conserved metabolic signature', 'MPA', (93, 122))	('SCC', 'Gene', '6317', (69, 72))	('MLN128', 'Chemical', '-', (158, 164))	('MLN128', 'Var', (158, 164))	('CB-839', 'Chemical', 'MESH:C000593334', (169, 175))	('SCC', 'Gene', (62, 65))
103049	29763624	Targeted therapies such as MLN128 and CB-839 have an important role in oncology but only when used in the correct context and combination.	('CB-839', 'Gene', (38, 44))	('CB-839', 'Chemical', 'MESH:C000593334', (38, 44))	('oncology', 'Disease', (71, 79))	('oncology', 'Phenotype', 'HP:0002664', (71, 79))	('MLN128', 'Chemical', '-', (27, 33))	('MLN128', 'Var', (27, 33))
103050	29763624	Importantly, combinatorial use of MLN128 and CB-839 may provide a much needed therapeutic benefit for lung SCC, HNSCC and OS patients who are frequently refractory to conventional therapies.	('CB-839', 'Gene', (45, 51))	('CB-839', 'Chemical', 'MESH:C000593334', (45, 51))	('SCC', 'Gene', (114, 117))	('SCC', 'Gene', (107, 110))	('MLN128', 'Chemical', '-', (34, 40))	('SCC', 'Gene', '6317', (114, 117))	('SCC', 'Gene', '6317', (107, 110))	('MLN128', 'Var', (34, 40))	('patients', 'Species', '9606', (125, 133))
103057	29763624	All patients provided written informed consent for use of samples in research under protocols approved by Institutional Review Boards at University of California, Los Angeles IRB # 10-001096 (for SCC), IRB #10-001857 (for OS) and at Long Beach Memorial Hospital IRB #208-13 (for SCC).	('SCC', 'Gene', (196, 199))	('SCC', 'Gene', (279, 282))	('SCC', 'Gene', '6317', (196, 199))	('IRB #10-001857', 'Var', (202, 216))	('SCC', 'Gene', '6317', (279, 282))	('IRB # 10-001096', 'Var', (175, 190))	('patients', 'Species', '9606', (4, 12))
103071	29763624	For treatment study with MLN128, following intranasal administration of Adenoviral Cre, KL mice were randomly sorted into two groups following imaging with bioluminescence: vehicle and MLN128.	('MLN128', 'Var', (25, 31))	('MLN128', 'Chemical', '-', (185, 191))	('mice', 'Species', '10090', (91, 95))	('MLN128', 'Var', (185, 191))	('MLN128', 'Chemical', '-', (25, 31))
103076	29763624	Four weeks after tumor induction, mice started receiving daily treatment of MLN128.	('MLN128', 'Var', (76, 82))	('mice', 'Species', '10090', (34, 38))	('tumor', 'Disease', (17, 22))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('MLN128', 'Chemical', '-', (76, 82))
103077	29763624	After 8 weeks of daily 1 mg/kg MLN128 treatment, mice were randomly selected to receive either 1 mg/kg MLN128 (i.p., q.d.)	('MLN128', 'Var', (103, 109))	('MLN128', 'Var', (31, 37))	('mice', 'Species', '10090', (49, 53))	('MLN128', 'Chemical', '-', (103, 109))	('MLN128', 'Chemical', '-', (31, 37))
103084	29763624	), 1 mg/kg MLN128 + 200 mg/kg CB-839.	('CB-839', 'Chemical', 'MESH:C000593334', (30, 36))	('MLN128', 'Chemical', '-', (11, 17))	('CB-839', 'Gene', (30, 36))	('MLN128 + 200 mg/kg', 'Var', (11, 29))
103089	29763624	Once tumors reached ~75 mm3 mice were randomly assigned to one of four treatment groups: Vehicle, 1 mg/kg MLN128 (i.p., q.d.	('tumors', 'Disease', (5, 11))	('tumors', 'Disease', 'MESH:D009369', (5, 11))	('mice', 'Species', '10090', (28, 32))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('MLN128', 'Chemical', '-', (106, 112))	('MLN128', 'Var', (106, 112))	('tumors', 'Phenotype', 'HP:0002664', (5, 11))
103090	29763624	For the second line therapy study with CB-839 using PDX005, when tumors reached ~75 mm3 mice were randomly assigned to either Vehicle or 1 mg/kg MLN128 (i.p., q.d.)	('MLN128', 'Chemical', '-', (145, 151))	('MLN128', 'Var', (145, 151))	('tumors', 'Disease', (65, 71))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('mice', 'Species', '10090', (88, 92))	('CB-839', 'Chemical', 'MESH:C000593334', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
103113	29763624	Cells were seeded into 6 cm plates overnight and were subsequently treated with DMSO (Vehicle), MLN128, Rapamycin or CHIR99021 in fresh DMEM medium for 72 hr.	('MLN128', 'Chemical', '-', (96, 102))	('MLN128', 'Var', (96, 102))	('CHIR99021', 'Var', (117, 126))	('DMEM medium', 'Chemical', '-', (136, 147))	('Rapamycin', 'Chemical', 'MESH:D020123', (104, 113))	('DMSO', 'Chemical', 'MESH:D004121', (80, 84))
103115	29763624	For in vitro studies MLN128 (Active Biochem), Rapamycin (LC laboratories), CHIR99021 (Cayman Chemical), and JNK-IN-8 (Fisher Scientific) were dissolved in DMSO.	('MLN128', 'Chemical', '-', (21, 27))	('Rapamycin', 'Chemical', 'MESH:D020123', (46, 55))	('CHIR99021', 'Var', (75, 84))	('DMSO', 'Chemical', 'MESH:D004121', (155, 159))	('MLN128', 'Var', (21, 27))
103150	30651778	Recently, an increasing number of studies have indicated that the altered expression of claudin (CLDN) tight junction (TJ) proteins has an essential role in the tumorigenesis and progression of various human cancer types by affecting the structure and function of TJs and associated cellular signaling pathways.	('function', 'MPA', (252, 260))	('altered', 'Var', (66, 73))	('cancer', 'Disease', (208, 214))	('TJs', 'Protein', (264, 267))	('human', 'Species', '9606', (202, 207))	('affecting', 'Reg', (224, 233))	('CLDN', 'Gene', (97, 101))	('TJ', 'Gene', (119, 121))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('cellular signaling pathways', 'Pathway', (283, 310))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('structure', 'MPA', (238, 247))	('tumor', 'Disease', (161, 166))	('cancer', 'Disease', 'MESH:D009369', (208, 214))
103153	30651778	In addition, high-level cytoplasmic CLDN3 expression was revealed to be an independent predictor of poor survival in triple-negative breast cancer.	('high-level', 'Var', (13, 23))	('CLDN3', 'Gene', (36, 41))	('breast cancer', 'Disease', (133, 146))	('breast cancer', 'Phenotype', 'HP:0003002', (133, 146))	('CLDN3', 'Gene', '1365', (36, 41))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('breast cancer', 'Disease', 'MESH:D001943', (133, 146))
103154	30651778	Furthermore, CLDN4 has been reported to be overexpressed in advanced ovarian cancer (OC), and Kaplan-Meier survival analysis and Log-Rank testing suggested that high expression of CLDN4 may have prognostic value in OC.	('ovarian cancer', 'Disease', (69, 83))	('CLDN4', 'Gene', '1364', (13, 18))	('OC', 'Phenotype', 'HP:0100615', (215, 217))	('OC', 'Phenotype', 'HP:0100615', (85, 87))	('high expression', 'Var', (161, 176))	('CLDN4', 'Gene', '1364', (180, 185))	('ovarian cancer', 'Phenotype', 'HP:0100615', (69, 83))	('CLDN4', 'Gene', (13, 18))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('ovarian cancer', 'Disease', 'MESH:D010051', (69, 83))	('overexpressed', 'PosReg', (43, 56))	('CLDN4', 'Gene', (180, 185))
103155	30651778	These observations indicate that alterations in the expression of CLDNs may be associated with tumorigenesis and cancer progression in various human carcinomas.	('associated', 'Reg', (79, 89))	('human', 'Species', '9606', (143, 148))	('carcinoma', 'Phenotype', 'HP:0030731', (149, 158))	('CLDNs', 'Gene', (66, 71))	('carcinomas', 'Phenotype', 'HP:0030731', (149, 159))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('carcinomas', 'Disease', (149, 159))	('carcinomas', 'Disease', 'MESH:D002277', (149, 159))	('expression', 'MPA', (52, 62))	('cancer', 'Disease', (113, 119))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('alterations', 'Var', (33, 44))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('tumor', 'Disease', (95, 100))
103157	30651778	Previous genetic and pharmacological assays confirmed that the expression of CLDN3 was downregulated in colon cancer, and that loss of CLDN3 induced Wnt/beta-catenin activation and thus promoted colon cancer.	('colon cancer', 'Disease', (104, 116))	('CLDN3', 'Gene', (77, 82))	('CLDN3', 'Gene', '1365', (77, 82))	('colon cancer', 'Phenotype', 'HP:0003003', (195, 207))	('expression', 'MPA', (63, 73))	('beta-catenin', 'Gene', (153, 165))	('CLDN3', 'Gene', (135, 140))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('downregulated', 'NegReg', (87, 100))	('colon cancer', 'Disease', 'MESH:D015179', (195, 207))	('colon cancer', 'Disease', 'MESH:D015179', (104, 116))	('colon cancer', 'Phenotype', 'HP:0003003', (104, 116))	('colon cancer', 'Disease', (195, 207))	('loss', 'Var', (127, 131))	('beta-catenin', 'Gene', '1499', (153, 165))	('promoted', 'PosReg', (186, 194))	('CLDN3', 'Gene', '1365', (135, 140))
103229	30651778	The results suggested that CLDN12 expression levels in the CLDN12 overexpressed group were markedly increased compared with the empty vector group, and that CLDN12 was primarily localized on cell membranes.	('CLDN12', 'Gene', (157, 163))	('increased', 'PosReg', (100, 109))	('CLDN12', 'Gene', (27, 33))	('CLDN12', 'Gene', (59, 65))	('overexpressed', 'Var', (66, 79))	('CLDN12', 'Gene', '9069', (157, 163))	('CLDN12', 'Gene', '9069', (27, 33))	('CLDN12', 'Gene', '9069', (59, 65))	('expression levels', 'MPA', (34, 51))
103243	30651778	Following the knockdown of Tyk2, the phosphorylation levels of Stat1 were significantly downregulated in the BEAS-2B cell line overexpressing CLDN12 (P<0.01; Fig.	('Stat1', 'Gene', (63, 68))	('BEAS-2B', 'CellLine', 'CVCL:0168', (109, 116))	('phosphorylation levels', 'MPA', (37, 59))	('Tyk2', 'Gene', '7297', (27, 31))	('CLDN12', 'Gene', (142, 148))	('Stat1', 'Gene', '6772', (63, 68))	('knockdown', 'Var', (14, 23))	('Tyk2', 'Gene', (27, 31))	('CLDN12', 'Gene', '9069', (142, 148))	('downregulated', 'NegReg', (88, 101))
103248	30651778	Certain reports have indicated CLDN to function as a tumor suppressor gene, where loss of CLDN contributed to enhanced tumorigenic properties of tumor cells.	('tumor', 'Disease', (119, 124))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('CLDN', 'Gene', (90, 94))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('enhanced', 'PosReg', (110, 118))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Disease', (145, 150))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('tumor', 'Disease', (53, 58))	('loss', 'Var', (82, 86))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))
103282	27811377	In both populations, patients with low IL-1beta level had better prognosis than high IL-1beta level (P < 0.001 and P = 0.010, respectively).	('IL-1beta', 'Gene', (39, 47))	('IL-1beta', 'Gene', '3553', (39, 47))	('IL-1beta', 'Gene', (85, 93))	('patients', 'Species', '9606', (21, 29))	('IL-1beta', 'Gene', '3553', (85, 93))	('low', 'Var', (35, 38))
103305	27811377	Moreover, in both LUAD and LUSC, low IL-1beta cases had better prognosis that high IL-1beta ones.	('LUAD', 'Disease', (18, 22))	('IL-1beta', 'Gene', (37, 45))	('IL-1beta', 'Gene', '3553', (37, 45))	('LUAD', 'Phenotype', 'HP:0030078', (18, 22))	('LUAD', 'Disease', 'None', (18, 22))	('low', 'Var', (33, 36))	('IL-1beta', 'Gene', '3553', (83, 91))	('IL-1beta', 'Gene', (83, 91))	('LUSC', 'Phenotype', 'HP:0030359', (27, 31))
103316	27811377	The IL-1beta level was defined as "high" and "low" using median (28.3992 pg/mL and 43.5495 pg/mL in LUAD and LUSC, respectively) as threshold.	('LUAD', 'Disease', (100, 104))	('LUAD', 'Phenotype', 'HP:0030078', (100, 104))	('LUAD', 'Disease', 'None', (100, 104))	('IL-1beta', 'Gene', (4, 12))	('LUSC', 'Phenotype', 'HP:0030359', (109, 113))	('IL-1beta', 'Gene', '3553', (4, 12))	('28.3992 pg/mL', 'Var', (65, 78))
103320	27811377	In both LUAD (Figure 2A) and LUSC (Figure 2B) populations, patients with low IL-1beta level showed better prognosis than those with high IL-1beta level (P < 0.001 and P = 0.010, respectively).	('better', 'PosReg', (99, 105))	('IL-1beta', 'Gene', (137, 145))	('IL-1beta', 'Gene', (77, 85))	('LUSC', 'Phenotype', 'HP:0030359', (29, 33))	('IL-1beta', 'Gene', '3553', (137, 145))	('IL-1beta', 'Gene', '3553', (77, 85))	('LUAD', 'Phenotype', 'HP:0030078', (8, 12))	('LUAD', 'Disease', 'None', (8, 12))	('patients', 'Species', '9606', (59, 67))	('LUAD', 'Disease', (8, 12))	('low', 'Var', (73, 76))
103321	27811377	In LUAD population, patients with high TNF-alpha level exhibited better prognosis than those with low TNF-alpha level (P = 0.017).	('TNF-alpha', 'Gene', (102, 111))	('LUAD', 'Disease', 'None', (3, 7))	('LUAD', 'Disease', (3, 7))	('LUAD', 'Phenotype', 'HP:0030078', (3, 7))	('high', 'Var', (34, 38))	('better', 'PosReg', (65, 71))	('patients', 'Species', '9606', (20, 28))	('TNF-alpha', 'Gene', '7124', (39, 48))	('TNF-alpha', 'Gene', '7124', (102, 111))	('TNF-alpha', 'Gene', (39, 48))
103334	27811377	The combination of IL-1beta exposure and miR-144-3p silencing promoted proliferation more significantly than mono-treatment (P < 0.0001, Figure 6B).	('silencing', 'Var', (52, 61))	('IL-1beta', 'Gene', (19, 27))	('IL-1beta', 'Gene', '3553', (19, 27))	('miR-144', 'Gene', (41, 48))	('miR-144', 'Gene', '406936', (41, 48))	('proliferation', 'CPA', (71, 84))	('promoted', 'PosReg', (62, 70))
103344	27811377	A few studies have approved that Celecoxib can promote epithelial-mesenchymal transition (EMT) of cancer cells, leading to increased metastatic risk.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('increased', 'PosReg', (123, 132))	('Celecoxib', 'Chemical', 'MESH:D000068579', (33, 42))	('Celecoxib', 'Var', (33, 42))	('promote', 'PosReg', (47, 54))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('epithelial-mesenchymal transition', 'CPA', (55, 88))	('metastatic risk', 'CPA', (133, 148))	('cancer', 'Disease', (98, 104))
103385	27811377	Cells were collected at 0, 24, 48 and 72 h after IL-1beta exposure and miR-144-3p mimics/antagomir transfection.	('transfection', 'Var', (99, 111))	('miR-144', 'Gene', '406936', (71, 78))	('IL-1beta', 'Gene', '3553', (49, 57))	('miR-144', 'Gene', (71, 78))	('IL-1beta', 'Gene', (49, 57))
103429	33499345	From previous reports, we predicted that patients with a good prognosis might contain a stronger clonal expansion of TIL, which might play an important role in improving the prognosis after definitive CRT.	('improving', 'PosReg', (160, 169))	('patients', 'Species', '9606', (41, 49))	('clonal expansion', 'Var', (97, 113))	('TIL', 'Gene', (117, 120))	('stronger', 'PosReg', (88, 96))
103460	33499345	We predicted that not only the clonal expansion of TIL but, also, PD-L1 suppression, which is likely upregulated during chemotherapy and chemoradiation therapy, should play an important role in improving the prognosis.	('PD-L1 suppression', 'Disease', 'MESH:D010300', (66, 83))	('clonal', 'Var', (31, 37))	('upregulated', 'PosReg', (101, 112))	('PD-L1 suppression', 'Disease', (66, 83))
103464	31537801	DNA methylation loss promotes immune evasion of tumours with high mutation and copy number load Mitotic cell division increases tumour mutation burden and copy number load, predictive markers of the clinical benefit of immunotherapy.	('immune evasion', 'MPA', (30, 44))	('tumours', 'Disease', (48, 55))	('tumour', 'Phenotype', 'HP:0002664', (48, 54))	('DNA', 'Gene', (0, 3))	('copy number load', 'Var', (79, 95))	('copy', 'MPA', (155, 159))	('promotes', 'PosReg', (21, 29))	('Mitotic cell division increases tumour', 'Disease', (96, 134))	('Mitotic cell division increases tumour', 'Disease', 'MESH:C536987', (96, 134))	('loss', 'NegReg', (16, 20))	('tumour', 'Phenotype', 'HP:0002664', (128, 134))	('tumours', 'Phenotype', 'HP:0002664', (48, 55))	('high mutation', 'Var', (61, 74))	('tumours', 'Disease', 'MESH:D009369', (48, 55))
103467	31537801	Methylome data of our cohort (n = 60) and a published cohort (n = 81) in lung cancer and a melanoma cohort (n = 40) consistently demonstrated that genomic methylation alterations counteract the contribution of high mutation burden and increase immunotherapeutic resistance.	('lung cancer', 'Disease', 'MESH:D008175', (73, 84))	('melanoma', 'Phenotype', 'HP:0002861', (91, 99))	('melanoma cohort', 'Disease', 'MESH:D008545', (91, 106))	('melanoma cohort', 'Disease', (91, 106))	('increase', 'PosReg', (235, 243))	('lung cancer', 'Disease', (73, 84))	('lung cancer', 'Phenotype', 'HP:0100526', (73, 84))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('alterations', 'Var', (167, 178))	('methylation alterations', 'Var', (155, 178))
103468	31537801	We also found that genomic hypomethylation correlates with the immune escape signatures of aneuploid tumours.	('aneuploid tumours', 'Disease', (91, 108))	('immune escape signatures', 'CPA', (63, 87))	('hypomethylation', 'Var', (27, 42))	('tumour', 'Phenotype', 'HP:0002664', (101, 107))	('tumours', 'Phenotype', 'HP:0002664', (101, 108))	('aneuploid tumours', 'Disease', 'MESH:D000782', (91, 108))
103469	31537801	Demethylation of the genome is found in cancer.	('Demethylation', 'Var', (0, 13))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('cancer', 'Disease', (40, 46))
103476	31537801	Therefore, tumours with high mutation load are more likely to respond to anti-immunosuppressive strategies based on checkpoint blockade.	('high mutation load', 'Var', (24, 42))	('more', 'PosReg', (47, 51))	('tumour', 'Phenotype', 'HP:0002664', (11, 17))	('tumours', 'Phenotype', 'HP:0002664', (11, 18))	('tumours', 'Disease', 'MESH:D009369', (11, 18))	('tumours', 'Disease', (11, 18))	('respond', 'MPA', (62, 69))
103482	31537801	Global demethylation in cancer promotes chromosomal instability, particularly involving large-scale alterations leading to aneuploidy.	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('promotes', 'PosReg', (31, 39))	('chromosomal instability', 'MPA', (40, 63))	('aneuploidy', 'Disease', 'MESH:D000782', (123, 133))	('cancer', 'Disease', (24, 30))	('cancer', 'Disease', 'MESH:D009369', (24, 30))	('Global demethylation', 'Var', (0, 20))	('aneuploidy', 'Disease', (123, 133))	('chromosomal instability', 'Phenotype', 'HP:0040012', (40, 63))
103487	31537801	Our pan-cancer analyses of TCGA data demonstrated that markers of cell proliferation tightly correlate with mutation burden and aneuploidy across cancer types and among samples within each cancer type (Supplementary Fig.	('aneuploidy across cancer', 'Disease', 'MESH:D009369', (128, 152))	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('cancer', 'Disease', (8, 14))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('aneuploidy across cancer', 'Disease', (128, 152))	('mutation burden', 'Var', (108, 123))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('correlate', 'Reg', (93, 102))	('cancer', 'Disease', 'MESH:D009369', (8, 14))	('cancer', 'Disease', (189, 195))
103489	31537801	However, immune cell markers are expected to correlate with mutation burden and also are known to be associated with aneuploidy.	('mutation', 'Var', (60, 68))	('aneuploidy', 'Disease', 'MESH:D000782', (117, 127))	('associated', 'Reg', (101, 111))	('correlate', 'Reg', (45, 54))	('aneuploidy', 'Disease', (117, 127))
103490	31537801	To disentangle this intercorrelation, we performed multiple regression of the expression level of each gene on sample-level features, namely, global L1 methylation, mutation burden, aneuploidy, tumour purity, age, and tumour stage.	('tumour', 'Phenotype', 'HP:0002664', (218, 224))	('mutation burden', 'Var', (165, 180))	('tumour', 'Disease', (194, 200))	('tumour', 'Disease', (218, 224))	('aneuploidy', 'Disease', 'MESH:D000782', (182, 192))	('tumour purity', 'Disease', (194, 207))	('global L1', 'Protein', (142, 151))	('tumour', 'Phenotype', 'HP:0002664', (194, 200))	('tumour', 'Disease', 'MESH:D009369', (218, 224))	('tumour', 'Disease', 'MESH:D009369', (194, 200))	('aneuploidy', 'Disease', (182, 192))	('tumour purity', 'Disease', 'MESH:D009369', (194, 207))
103496	31537801	Because methylation loss occurs primarily in late-replicating regions, we examined whether the transcriptional activity of late-replicated genes are affected in the tumours that underwent global demethylation.	('tumour', 'Phenotype', 'HP:0002664', (165, 171))	('methylation', 'MPA', (8, 19))	('transcriptional', 'MPA', (95, 110))	('tumours', 'Phenotype', 'HP:0002664', (165, 172))	('tumours', 'Disease', 'MESH:D009369', (165, 172))	('loss', 'NegReg', (20, 24))	('affected', 'Reg', (149, 157))	('global', 'Var', (188, 194))	('tumours', 'Disease', (165, 172))
103502	31537801	In contrast to our data from tumour-intrinsic demethylation, treatment of methylation inhibitors was shown to induce double-stranded RNAs (dsRNAs) derived from endogenous retroviruses (ERVs) and LINEs, resulting in the activation of the IFN-alpha/beta response in cancer.	('tumour-intrinsic demethylation', 'Disease', 'MESH:C563242', (29, 59))	('cancer', 'Phenotype', 'HP:0002664', (264, 270))	('methylation', 'Gene', (74, 85))	('double-stranded RNAs', 'MPA', (117, 137))	('activation', 'PosReg', (219, 229))	('tumour-intrinsic demethylation', 'Disease', (29, 59))	('induce', 'PosReg', (110, 116))	('tumour', 'Phenotype', 'HP:0002664', (29, 35))	('IFN-alpha', 'Gene', '3439', (237, 246))	('IFN-alpha', 'Gene', (237, 246))	('inhibitors', 'Var', (86, 96))	('cancer', 'Disease', (264, 270))	('cancer', 'Disease', 'MESH:D009369', (264, 270))
103503	31537801	Without the silencing of the IFN-alpha/beta pathway, genomic demethylation would cause the antiviral response and facilitate antitumour immune reaction as demonstrated with demethylating agents.	('tumour', 'Phenotype', 'HP:0002664', (129, 135))	('IFN-alpha', 'Gene', '3439', (29, 38))	('IFN-alpha', 'Gene', (29, 38))	('demethylation', 'Var', (61, 74))	('tumour', 'Disease', 'MESH:D009369', (129, 135))	('cause', 'PosReg', (81, 86))	('facilitate', 'PosReg', (114, 124))	('tumour', 'Disease', (129, 135))	('antiviral response', 'CPA', (91, 109))
103505	31537801	5), implying that IFN-alpha/beta silencing overrides the immune-stimulatory effects of ERV/L1 expression by genomic demethylation.	('silencing', 'NegReg', (33, 42))	('demethylation', 'Var', (116, 129))	('ERV/L1', 'Gene', (87, 93))	('immune-stimulatory effects', 'MPA', (57, 83))	('IFN-alpha', 'Gene', '3439', (18, 27))	('IFN-alpha', 'Gene', (18, 27))	('overrides', 'PosReg', (43, 52))
103509	31537801	A recent study showed PMD demethylation is a common feature of diverse cancer type.	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('PMD', 'Disease', 'MESH:D020371', (22, 25))	('cancer', 'Disease', (71, 77))	('demethylation', 'Var', (26, 39))	('PMD', 'Disease', (22, 25))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))
103512	31537801	Similarly, genes in PMDs in various types of cancers are largely silenced by the formation of repressive chromatin structures or via CGI hypermethylation.	('silenced', 'NegReg', (65, 73))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('PMDs', 'Disease', 'None', (20, 24))	('cancers', 'Disease', 'MESH:D009369', (45, 52))	('cancers', 'Phenotype', 'HP:0002664', (45, 52))	('hypermethylation', 'Var', (137, 153))	('cancers', 'Disease', (45, 52))	('PMDs', 'Disease', (20, 24))
103521	31537801	Hypermethylated CGIs are most abundant within 150 kb of PMD boundaries.	('PMD', 'Disease', 'MESH:D020371', (56, 59))	('Hypermethylated', 'Var', (0, 15))	('PMD', 'Disease', (56, 59))
103523	31537801	To test whether global methylation alterations affect the clinical benefit of immunotherapy, we generated methylome and exome data for 60 samples in an anti-PD-1/PD-L1 cohort in lung cancer collected from Samsung Medical Center (SMC) (Supplementary Table 3).	('alterations', 'Var', (35, 46))	('lung cancer', 'Disease', (178, 189))	('PD-1', 'Gene', '5133', (157, 161))	('lung cancer', 'Phenotype', 'HP:0100526', (178, 189))	('PD-L1', 'Gene', '29126', (162, 167))	('PD-1', 'Gene', (157, 161))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('affect', 'Reg', (47, 53))	('lung cancer', 'Disease', 'MESH:D008175', (178, 189))	('PD-L1', 'Gene', (162, 167))
103527	31537801	In agreement with our pan-cancer molecular data analyses, the global low methylation samples showed high mutation burden and aneuploidy as well as CGI hypermethylation in the short PMDs (Fig.	('CGI', 'MPA', (147, 150))	('mutation', 'Var', (105, 113))	('short PMDs', 'Disease', (175, 185))	('aneuploidy', 'Disease', (125, 135))	('cancer', 'Disease', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('short PMDs', 'Disease', 'MESH:C537327', (175, 185))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('aneuploidy', 'Disease', 'MESH:D000782', (125, 135))	('hypermethylation', 'Var', (151, 167))
103535	31537801	Taken together, both low methylation and high aneuploidy are expected to decrease tumour immunity and undermine the clinical benefit of immunotherapy.	('tumour', 'Phenotype', 'HP:0002664', (82, 88))	('undermine', 'NegReg', (102, 111))	('low methylation', 'Var', (21, 36))	('tumour', 'Disease', 'MESH:D009369', (82, 88))	('aneuploidy', 'Disease', (46, 56))	('tumour', 'Disease', (82, 88))	('methylation', 'Var', (25, 36))	('decrease', 'NegReg', (73, 81))	('aneuploidy', 'Disease', 'MESH:D000782', (46, 56))
103542	31537801	Global demethylation in cancer promotes chromosomal instability.	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('promotes', 'PosReg', (31, 39))	('chromosomal instability', 'MPA', (40, 63))	('cancer', 'Disease', (24, 30))	('cancer', 'Disease', 'MESH:D009369', (24, 30))	('Global demethylation', 'Var', (0, 20))	('chromosomal instability', 'Phenotype', 'HP:0040012', (40, 63))
103543	31537801	DNA hypomethylation-related instability is mainly of chromosomal nature and involves large-scale alterations leading to aneuploidy rather than widespread amplifications or deletions.	('aneuploidy', 'Disease', 'MESH:D000782', (120, 130))	('aneuploidy', 'Disease', (120, 130))	('alterations', 'Var', (97, 108))	('leading to', 'Reg', (109, 119))
103544	31537801	As in ICF syndrome (for immunodeficiency, centromere instability, and facial anomalies), failure of methylation maintenance in pericentromeric sequences can cause erroneous chromosomal segregation in cancer.	('immunodeficiency', 'Phenotype', 'HP:0002721', (24, 40))	('cause', 'Reg', (157, 162))	('erroneous', 'Var', (163, 172))	('failure', 'Var', (89, 96))	('immunodeficiency', 'Disease', (24, 40))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('ICF syndrome', 'Disease', (6, 18))	('ICF syndrome', 'Disease', 'MESH:D061325', (6, 18))	('facial anomalies', 'Phenotype', 'HP:0000271', (70, 86))	('facial anomalies', 'Disease', (70, 86))	('cancer', 'Disease', 'MESH:D009369', (200, 206))	('facial anomalies', 'Disease', 'MESH:D005148', (70, 86))	('cancer', 'Disease', (200, 206))	('immunodeficiency', 'Disease', 'MESH:D007153', (24, 40))
103548	31537801	Indeed, a recent molecular mechanism study contradicted the previous report by suggesting that aneuploid cells generate pro-inflammatory signals for their own elimination by the immune system as a means for cancer cell immunosurveillance.	('cancer', 'Disease', 'MESH:D009369', (207, 213))	('cancer', 'Disease', (207, 213))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('pro-inflammatory signals', 'MPA', (120, 144))	('aneuploid cells', 'Var', (95, 110))
103549	31537801	In this work, we propose that DNA methylation aberration is an important determinant of the tumour response to host immune activity, and can provide a mechanism by which rapidly dividing and highly mutated tumours escape immune reaction and resist immunotherapy.	('tumour', 'Disease', 'MESH:D009369', (92, 98))	('tumour', 'Phenotype', 'HP:0002664', (92, 98))	('tumour', 'Disease', (92, 98))	('immune reaction', 'CPA', (221, 236))	('tumour', 'Phenotype', 'HP:0002664', (206, 212))	('tumour', 'Disease', 'MESH:D009369', (206, 212))	('tumours', 'Phenotype', 'HP:0002664', (206, 213))	('escape', 'PosReg', (214, 220))	('tumours', 'Disease', 'MESH:D009369', (206, 213))	('aberration', 'Var', (46, 56))	('highly mutated', 'Var', (191, 205))	('tumour', 'Disease', (206, 212))	('tumours', 'Disease', (206, 213))	('resist immunotherapy', 'CPA', (241, 261))
103551	31537801	In any case, our results suggest that mitotic cell division causes genetic and epigenetic alterations that exert opposing effects on tumour immunity by increasing neoantigens and inhibiting immune gene expression, respectively.	('neoantigens', 'MPA', (163, 174))	('increasing', 'PosReg', (152, 162))	('tumour', 'Phenotype', 'HP:0002664', (133, 139))	('inhibiting', 'NegReg', (179, 189))	('tumour', 'Disease', 'MESH:D009369', (133, 139))	('immune gene expression', 'MPA', (190, 212))	('tumour', 'Disease', (133, 139))	('epigenetic alterations', 'Var', (79, 101))
103552	31537801	Our data show that the particular association of chromosomal copy number changes with low antitumour immune activity can be explained by global methylation loss.	('tumour', 'Disease', (94, 100))	('chromosomal copy number changes', 'Var', (49, 80))	('loss', 'NegReg', (156, 160))	('tumour', 'Phenotype', 'HP:0002664', (94, 100))	('low', 'NegReg', (86, 89))	('methylation', 'MPA', (144, 155))	('tumour', 'Disease', 'MESH:D009369', (94, 100))
103554	31537801	The repression signatures for IFN-alpha/beta signaling draw particular attention, given that this pathway is supposed to stimulate immune responses against dsRNAs induced by genomic demethylation.	('genomic', 'Var', (174, 181))	('IFN-alpha', 'Gene', (30, 39))	('demethylation', 'Var', (182, 195))	('IFN-alpha', 'Gene', '3439', (30, 39))	('stimulate', 'PosReg', (121, 130))	('immune', 'MPA', (131, 137))
103556	31537801	According to our results, tumours with global methylation loss tend to resist immunotherapy alone and may particularly benefit from this combined treatment approach.	('methylation', 'Var', (46, 57))	('loss', 'NegReg', (58, 62))	('tumours', 'Disease', 'MESH:D009369', (26, 33))	('tumours', 'Disease', (26, 33))	('resist immunotherapy alone', 'CPA', (71, 97))	('benefit', 'PosReg', (119, 126))	('tumour', 'Phenotype', 'HP:0002664', (26, 32))	('tumours', 'Phenotype', 'HP:0002664', (26, 33))
103560	31537801	Specifically, it needs to be tested whether methylation inhibitors or other epigenetic modulators are capable of restoring the IFN-alpha/beta response and other immunomodulatory pathways by diminishing CGI methylation or loosening heterochromatin structure in these intrinsically demethylated tumours.	('loosening', 'NegReg', (221, 230))	('heterochromatin structure', 'MPA', (231, 256))	('methylation', 'Var', (44, 55))	('demethylated tumours', 'Disease', (280, 300))	('diminishing', 'NegReg', (190, 201))	('IFN-alpha', 'Gene', '3439', (127, 136))	('tumour', 'Phenotype', 'HP:0002664', (293, 299))	('IFN-alpha', 'Gene', (127, 136))	('tumours', 'Phenotype', 'HP:0002664', (293, 300))	('restoring', 'PosReg', (113, 122))	('CGI methylation', 'MPA', (202, 217))	('demethylated tumours', 'Disease', 'MESH:D009369', (280, 300))
103603	31537801	We used Strelka2 to call somatic variants and selected single nucleotide variants (SNVs) and indels covered by at least ten and five reads in tumour, respectively.	('tumour', 'Disease', (142, 148))	('tumour', 'Disease', 'MESH:D009369', (142, 148))	('tumour', 'Phenotype', 'HP:0002664', (142, 148))	('single nucleotide variants', 'Var', (55, 81))
103605	31537801	Specifically, we applied the defined threshold of +- 0.2 (average value of LUAD and LUSC) on the segment log2 ratio (tumour versus normal) to detect amplifications/deletions affecting at least 10% of a chromosome arm or 5% of a chromosome.	('tumour', 'Phenotype', 'HP:0002664', (117, 123))	('affecting', 'Reg', (174, 183))	('tumour', 'Disease', 'MESH:D009369', (117, 123))	('amplifications/deletions', 'Var', (149, 173))	('tumour', 'Disease', (117, 123))
103620	31537801	The methylation chip and RNA-seq data for the samples of our lung cancer cohort are available at Gene Expression Omnibus under GSE119144 and GSE135222, respectively.	('lung cancer', 'Disease', (61, 72))	('lung cancer', 'Phenotype', 'HP:0100526', (61, 72))	('GSE135222', 'Var', (141, 150))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('lung cancer', 'Disease', 'MESH:D008175', (61, 72))
103691	30119639	We used the following primary antibodies: anti-NFKB-p65 (1:2000; Abcam #ab16502), anti-NFKB-p65 (phospho-Ser536) [93H1] (1:1000; Cell Signaling Technology #3033), anti-IKKa [Y463] (1:5000; Abcam #ab32041), anti-IKKa (phospho-Ser32/36) [5A5] (1:1000; Cell Signaling Technology #9246), anti-p44/4S2 MAPK [137F5] (1:2000; Cell Signaling Technology #4695), anti-p44/42 MAPK (phospho-Thr202/Tyr204) [E10] (1:2000; Cell Signaling Technology #9106), anti-LC3B (1 mg/mL; Abcam #ab48394), EGFR (#4267, CST), pEGFR (#2234, CST) and beta-actin (#A5316, Sigma).	('#2234', 'Var', (506, 511))	('p65', 'Gene', (92, 95))	('IKKa', 'Gene', '1147', (168, 172))	('#4267', 'Var', (486, 491))	('CST', 'Gene', '106478911', (493, 496))	('p65', 'Gene', (52, 55))	('EGFR', 'Gene', (480, 484))	('p44', 'Gene', (289, 292))	('IKKa', 'Gene', (168, 172))	('LC3B', 'Gene', (448, 452))	('p44', 'Gene', '10561', (289, 292))	('LC3B', 'Gene', '81631', (448, 452))	('p65', 'Gene', '5970', (92, 95))	('beta-actin', 'Gene', '728378', (522, 532))	('p44', 'Gene', (358, 361))	('CST', 'Gene', (493, 496))	('EGFR', 'Gene', (500, 504))	('CST', 'Gene', '106478911', (513, 516))	('IKKa', 'Gene', '1147', (211, 215))	('p44', 'Gene', '10561', (358, 361))	('p65', 'Gene', '5970', (52, 55))	('IKKa', 'Gene', (211, 215))	('EGFR', 'Gene', '1956', (480, 484))	('Ser536', 'Chemical', '-', (105, 111))	('CST', 'Gene', (513, 516))	('EGFR', 'Gene', '1956', (500, 504))	('beta-actin', 'Gene', (522, 532))
103696	30119639	Gene expression analysis was performed using TaqMan probes from Life Technologies: Hs00906696_m1 FAM (PDZK1IP) and Hs99999905_m1 FAM (GAPDH).	('GAPDH', 'Gene', (134, 139))	('PDZK1', 'Gene', (102, 107))	('Hs99999905_m1 FAM', 'Var', (115, 132))	('Hs00906696_m1 FAM', 'Var', (83, 100))	('GAPDH', 'Gene', '2597', (134, 139))	('PDZK1', 'Gene', '5174', (102, 107))
103717	30119639	Overall, taken together, the data suggest that high MAP17 levels showed worse prognosis than did patients with tumours with low MAP17 levels, and this is independent of histology and stage and radiation treatment.	('tumours', 'Disease', 'MESH:D009369', (111, 118))	('MAP17', 'Gene', (52, 57))	('tumours', 'Disease', (111, 118))	('high', 'Var', (47, 51))	('tumour', 'Phenotype', 'HP:0002664', (111, 117))	('MAP17', 'Gene', (128, 133))	('patients', 'Species', '9606', (97, 105))	('MAP17', 'Gene', '10158', (52, 57))	('tumours', 'Phenotype', 'HP:0002664', (111, 118))	('MAP17', 'Gene', '10158', (128, 133))
103722	30119639	We observed a clear trend showing that cell lines with high MAP17 expression were more sensitive to cisplatin (p = 0.18) and a statistically significant association of higher MAP17 levels and carboplatin sensitivity (p = 0.01, Fig.	('sensitive to cisplatin', 'MPA', (87, 109))	('cisplatin', 'Chemical', 'MESH:D002945', (100, 109))	('carboplatin', 'Chemical', 'MESH:D016190', (192, 203))	('more', 'PosReg', (82, 86))	('MAP17', 'Gene', '10158', (60, 65))	('MAP17', 'Gene', '10158', (175, 180))	('carboplatin sensitivity', 'MPA', (192, 215))	('higher', 'PosReg', (168, 174))	('MAP17', 'Gene', (60, 65))	('high', 'Var', (55, 59))	('MAP17', 'Gene', (175, 180))
103724	30119639	We found the same trend in the database, suggesting that adenocarcinoma cell lines with high MAP17 expression are more sensitive to this compound (p = 0.09, Fig.	('expression', 'MPA', (99, 109))	('MAP17', 'Gene', (93, 98))	('high', 'Var', (88, 92))	('adenocarcinoma', 'Disease', 'MESH:D000230', (57, 71))	('sensitive', 'MPA', (119, 128))	('MAP17', 'Gene', '10158', (93, 98))	('adenocarcinoma', 'Disease', (57, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (62, 71))
103730	30119639	We observed that the two models exhibiting low MAP17expression, TP40 and TP60, were insensitive to carboplatin treatment, while those models with the highest MAP17 expression, TP57 and TP79, were sensitive to the drug, with tumour growth inhibition (TGI) percentages of 49.5% and 66.4%, respectively (Fig.	('tumour', 'Disease', (224, 230))	('MAP17', 'Gene', '10158', (47, 52))	('tumour', 'Phenotype', 'HP:0002664', (224, 230))	('MAP17', 'Gene', '10158', (158, 163))	('TP40', 'Gene', '924', (64, 68))	('TP60', 'Var', (73, 77))	('MAP17', 'Gene', (47, 52))	('tumour', 'Disease', 'MESH:D009369', (224, 230))	('TP40', 'Gene', (64, 68))	('MAP17', 'Gene', (158, 163))	('carboplatin', 'Chemical', 'MESH:D016190', (99, 110))
103732	30119639	We found that patients with high MAP17expression exhibited higher overall survival when analysing cisplatin/carboplatin-, cisplatin- and carboplatin-treated subsets (p = 0.002, p = 0.015 and p = 0.051, respectively, Fig.	('overall survival', 'MPA', (66, 82))	('carboplatin', 'Chemical', 'MESH:D016190', (137, 148))	('cisplatin', 'Chemical', 'MESH:D002945', (122, 131))	('MAP17', 'Gene', (33, 38))	('higher', 'PosReg', (59, 65))	('carboplatin', 'Chemical', 'MESH:D016190', (108, 119))	('cisplatin', 'Chemical', 'MESH:D002945', (98, 107))	('high', 'Var', (28, 32))	('patients', 'Species', '9606', (14, 22))	('MAP17', 'Gene', '10158', (33, 38))
103733	30119639	As EGFR inhibitors have been associated with ROS induction, similar to platinum-based compounds, we assessed the predictive potential of MAP17expression for erlotinib sensitivity in vitro.	('EGFR', 'Gene', '1956', (3, 7))	('EGFR', 'Gene', (3, 7))	('ROS', 'Chemical', 'MESH:D017382', (45, 48))	('erlotinib', 'Chemical', 'MESH:D000069347', (157, 166))	('MAP17', 'Gene', '10158', (137, 142))	('platinum', 'Chemical', 'MESH:D010984', (71, 79))	('associated', 'Reg', (29, 39))	('MAP17', 'Gene', (137, 142))	('ROS', 'Disease', (45, 48))	('inhibitors', 'Var', (8, 18))
103735	30119639	We found that cell lines with the highest MAP17 expression showed increased erlotinib sensitivity compared to that of the other the cell lines (p = 0.01, Fig.	('MAP17', 'Gene', (42, 47))	('erlotinib', 'Chemical', 'MESH:D000069347', (76, 85))	('increased', 'PosReg', (66, 75))	('erlotinib sensitivity', 'MPA', (76, 97))	('MAP17', 'Gene', '10158', (42, 47))	('expression', 'Var', (48, 58))
103738	30119639	We found that high MAP17 expression correlated with increased sensitivity to six different EGFR inhibitors: pelitinib (p = 0.16), afatinib (p = 0.02), cetuximab (p = 0.08), lapatinib (p = 0.32), erlotinib (p < 0.01) and gefitinib (p < 0.01) (Fig.	('gefitinib', 'Chemical', 'MESH:D000077156', (220, 229))	('EGFR', 'Gene', (91, 95))	('increased', 'PosReg', (52, 61))	('cetuximab', 'Chemical', 'MESH:D000068818', (151, 160))	('sensitivity', 'MPA', (62, 73))	('expression', 'MPA', (25, 35))	('MAP17', 'Gene', (19, 24))	('high', 'Var', (14, 18))	('afatinib', 'Chemical', 'MESH:D000077716', (130, 138))	('lapatinib', 'Chemical', 'MESH:D000077341', (173, 182))	('pelitinib', 'Chemical', 'MESH:C413879', (108, 117))	('erlotinib', 'Chemical', 'MESH:D000069347', (195, 204))	('EGFR', 'Gene', '1956', (91, 95))	('MAP17', 'Gene', '10158', (19, 24))
103741	30119639	Two PDX models with expression of high levels of wild-type EGFR, TP57 and TP126 were selected for these experiments.	('EGFR', 'Gene', '1956', (59, 63))	('TP126', 'Var', (74, 79))	('EGFR', 'Gene', (59, 63))
103742	30119639	We observed that the model with low MAP17 expression (TP126) showed no sensitivity to erlotinib treatment, while the model with high MAP17 levels exhibited sensitivity to this EGFR TKI, with a TGI rate of 67% (p = 0.048, Fig.	('MAP17', 'Gene', '10158', (133, 138))	('MAP17', 'Gene', '10158', (36, 41))	('erlotinib', 'Chemical', 'MESH:D000069347', (86, 95))	('EGFR', 'Gene', '1956', (176, 180))	('MAP17', 'Gene', (133, 138))	('MAP17', 'Gene', (36, 41))	('EGFR', 'Gene', (176, 180))	('sensitivity', 'Reg', (156, 167))	('sensitivity', 'MPA', (71, 82))	('TP126', 'Var', (54, 59))
103747	30119639	Despite our promising findings with platinum-based therapies and EGFR inhibitors, there is still a high percentage of patients who may not respond to these therapies, highlighting the necessity for novel therapies in lung cancer.	('EGFR', 'Gene', '1956', (65, 69))	('lung cancer', 'Disease', (217, 228))	('EGFR', 'Gene', (65, 69))	('lung cancer', 'Phenotype', 'HP:0100526', (217, 228))	('platinum', 'Chemical', 'MESH:D010984', (36, 44))	('inhibitors', 'Var', (70, 80))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('lung cancer', 'Disease', 'MESH:D008175', (217, 228))	('patients', 'Species', '9606', (118, 126))
103751	30119639	To confirm these results, we studied the sensitivity to bortezomib and to another proteasome inhibitor, MG132, in adenocarcinoma cell lines from the GDSC database, and we found that high MAP17 expression correlated with higher sensitivity to both proteasome inhibitors (p = 0.031 and p = 0.078, respectively, Fig.	('MAP17', 'Gene', '10158', (187, 192))	('adenocarcinoma', 'Disease', 'MESH:D000230', (114, 128))	('sensitivity to', 'MPA', (227, 241))	('MAP17', 'Gene', (187, 192))	('bortezomib', 'Chemical', 'MESH:D000069286', (56, 66))	('high', 'Var', (182, 186))	('MG132', 'Chemical', 'MESH:C072553', (104, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('higher', 'PosReg', (220, 226))	('adenocarcinoma', 'Disease', (114, 128))
103753	30119639	To assess the efficacy of bortezomib in vivo, we selected three lung adenocarcinoma PDXs with differential MAP17 expression levels (TP40, TP57 and TP60, Fig.	('MAP17', 'Gene', (107, 112))	('TP40', 'Gene', '924', (132, 136))	('TP40', 'Gene', (132, 136))	('TP60', 'Var', (147, 151))	('bortezomib', 'Chemical', 'MESH:D000069286', (26, 36))	('lung adenocarcinoma PDXs', 'Disease', 'MESH:D000077192', (64, 88))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (64, 83))	('lung adenocarcinoma PDXs', 'Disease', (64, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('MAP17', 'Gene', '10158', (107, 112))	('TP57', 'Var', (138, 142))
103766	30119639	We have shown that MAP17 expression is induced in lung tumourigenesis, particularly in adenocarcinomas, mainly by demethylation, and that it correlates with higher tumour stage.	('tumour', 'Disease', (55, 61))	('demethylation', 'Var', (114, 127))	('tumour', 'Phenotype', 'HP:0002664', (164, 170))	('lung tumour', 'Phenotype', 'HP:0100526', (50, 61))	('induced', 'Reg', (39, 46))	('expression', 'MPA', (25, 35))	('MAP17', 'Gene', (19, 24))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('lung tumour', 'Disease', (50, 61))	('tumour', 'Disease', 'MESH:D009369', (164, 170))	('tumour', 'Phenotype', 'HP:0002664', (55, 61))	('adenocarcinomas', 'Disease', 'MESH:D000230', (87, 102))	('carcinomas', 'Phenotype', 'HP:0030731', (92, 102))	('adenocarcinomas', 'Disease', (87, 102))	('tumour', 'Disease', (164, 170))	('tumour', 'Disease', 'MESH:D009369', (55, 61))	('lung tumour', 'Disease', 'MESH:D008175', (50, 61))	('MAP17', 'Gene', '10158', (19, 24))
103770	30119639	Furthermore, we provide evidence that this upregulation may be a consequence of MAP17 promoter and gene demethylation.	('MAP17', 'Gene', (80, 85))	('upregulation', 'PosReg', (43, 55))	('demethylation', 'Var', (104, 117))	('MAP17', 'Gene', '10158', (80, 85))
103776	30119639	Correlating with this hypothesis, high MAP17 expression is associated with increased survival in patients treated with cisplatin in several tumour settings.	('tumour', 'Phenotype', 'HP:0002664', (140, 146))	('tumour', 'Disease', 'MESH:D009369', (140, 146))	('MAP17', 'Gene', (39, 44))	('tumour', 'Disease', (140, 146))	('high', 'Var', (34, 38))	('expression', 'MPA', (45, 55))	('patients', 'Species', '9606', (97, 105))	('survival', 'MPA', (85, 93))	('increased', 'PosReg', (75, 84))	('cisplatin', 'Chemical', 'MESH:D002945', (119, 128))	('MAP17', 'Gene', '10158', (39, 44))
103780	30119639	We found that high MAP17 expression correlates with increased sensitivity to a variety of EGFR inhibitors in vitro and with increased sensitivity to erlotinib in lung adenocarcinoma PDX models with high EGFR activation.	('sensitivity', 'MPA', (134, 145))	('EGFR', 'Gene', '1956', (203, 207))	('increased', 'PosReg', (52, 61))	('erlotinib', 'Chemical', 'MESH:D000069347', (149, 158))	('sensitivity', 'MPA', (62, 73))	('expression', 'MPA', (25, 35))	('MAP17', 'Gene', (19, 24))	('lung adenocarcinoma', 'Disease', (162, 181))	('increased', 'PosReg', (124, 133))	('EGFR', 'Gene', (203, 207))	('EGFR', 'Gene', '1956', (90, 94))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (162, 181))	('high', 'Var', (14, 18))	('EGFR', 'Gene', (90, 94))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (162, 181))	('carcinoma', 'Phenotype', 'HP:0030731', (172, 181))	('MAP17', 'Gene', '10158', (19, 24))
103793	30119639	In fact, analysis of multiple myeloma patients also suggests that high levels of MAP17 are indicative of a better response.	('multiple myeloma', 'Disease', 'MESH:D009101', (21, 37))	('multiple myeloma', 'Disease', (21, 37))	('MAP17', 'Gene', '10158', (81, 86))	('high levels', 'Var', (66, 77))	('MAP17', 'Gene', (81, 86))	('patients', 'Species', '9606', (38, 46))	('multiple myeloma', 'Phenotype', 'HP:0006775', (21, 37))
103799	30119639	Therefore, the presence of MAP17 renders tumour cells unable to exploit these cytoprotective effects.	('tumour', 'Phenotype', 'HP:0002664', (41, 47))	('presence', 'Var', (15, 23))	('tumour', 'Disease', 'MESH:D009369', (41, 47))	('MAP17', 'Gene', '10158', (27, 32))	('tumour', 'Disease', (41, 47))	('MAP17', 'Gene', (27, 32))
103802	30119639	Ultimately, high levels of MAP17 could be of prognostic value for predicting treatment response in patients with diseases clinically treated with bortezomib.	('high', 'Var', (12, 16))	('MAP17', 'Gene', '10158', (27, 32))	('patients', 'Species', '9606', (99, 107))	('bortezomib', 'Chemical', 'MESH:D000069286', (146, 156))	('clinical', 'Species', '191496', (122, 130))	('MAP17', 'Gene', (27, 32))
103852	26869135	The clinical care signature is analogous to a gene expression signature: just as the combined gene expression alteration of a tumor may be associated with the tumor's overall behavior, a small group of process-related care practices may also be associated with the overall quality of care.	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('tumor', 'Disease', (159, 164))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('associated', 'Reg', (245, 255))	('associated', 'Reg', (139, 149))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('combined gene expression', 'MPA', (85, 109))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('alteration', 'Var', (110, 120))	('tumor', 'Disease', (126, 131))
103869	26869135	Compliance with the clinical care signature was associated with significantly improved OS, DSS, and DFS on univariable analysis (log-rank test, P < .05 for each) (Figure 1).	('OS', 'Chemical', '-', (87, 89))	('DFS', 'MPA', (100, 103))	('Compliance', 'Var', (0, 10))	('improved', 'PosReg', (78, 86))	('DSS', 'Chemical', '-', (91, 94))	('DSS', 'Disease', (91, 94))
103870	26869135	Compliance with the clinical care signature remained associated with improved OS, DSS, and DFS on multivariable analysis (Figure 2).	('DSS', 'Chemical', '-', (82, 85))	('DSS', 'Disease', (82, 85))	('improved', 'PosReg', (69, 77))	('Compliance', 'Var', (0, 10))	('OS', 'Chemical', '-', (78, 80))	('DFS', 'Disease', (91, 94))
103930	26482899	Both DFS and OS of patients in the NLR <= 2.17 group were significantly longer than for patients in the NLR > 2.17 group.	('DFS', 'MPA', (5, 8))	('patients', 'Species', '9606', (19, 27))	('patients', 'Species', '9606', (88, 96))	('NLR <= 2.17', 'Var', (35, 46))	('longer', 'PosReg', (72, 78))	('OS', 'Chemical', '-', (13, 15))
103957	32962182	Depletion of AKT expression and activation, and related signaling cascades by its inhibitors, decreases the growth of skin cancer and metastasis.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('expression', 'MPA', (17, 27))	('growth of', 'CPA', (108, 117))	('decreases', 'NegReg', (94, 103))	('Depletion', 'Var', (0, 9))	('skin cancer', 'Phenotype', 'HP:0008069', (118, 129))	('AKT', 'Protein', (13, 16))	('skin cancer', 'Disease', (118, 129))	('skin cancer', 'Disease', 'MESH:D012878', (118, 129))
103967	32962182	Generally, the human skin is affected by solar UV (100-400 nm) radiation composed of UVA (315-400 nm, ~95%) and UVB (280-315 nm, ~5%) rays triggering skin inflammation, carcinogenesis and cancer development.	('skin inflammation', 'Disease', 'MESH:D007249', (150, 167))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('carcinogenesis', 'Disease', (169, 183))	('human', 'Species', '9606', (15, 20))	('UVB', 'Chemical', '-', (112, 115))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('cancer', 'Disease', (188, 194))	('skin inflammation', 'Disease', (150, 167))	('carcinogenesis', 'Disease', 'MESH:D063646', (169, 183))	('triggering', 'Reg', (139, 149))	('280-315', 'Var', (117, 124))	('skin inflammation', 'Phenotype', 'HP:0011123', (150, 167))
103968	32962182	Genetic mutation of p53, BRAF, RAS, CDKN2A and PTEN, and abnormal expression/activation of T-LAK cell-originated protein kinase (TOPK), mitogen-activated protein kinase kinase (MEK), 90 kDa ribosomal S6 kinase (RSK) and AKT in melanoma and NMSC induce cancer cell signal transduction thereby promoting skin carcinogenesis and cancer cell proliferation, migration and invasion.	('p53', 'Gene', (20, 23))	('CDKN2A', 'Gene', (36, 42))	('promoting', 'PosReg', (292, 301))	('RAS', 'Gene', (31, 34))	('cancer', 'Disease', 'MESH:D009369', (252, 258))	('T-LAK cell-originated protein kinase', 'Gene', '52033', (91, 127))	('p53', 'Gene', '22060', (20, 23))	('melanoma', 'Disease', 'MESH:D008545', (227, 235))	('mitogen-activated protein kinase kinase', 'Gene', (136, 175))	('ribosomal S6 kinase', 'Gene', (190, 209))	('TOPK', 'Gene', (129, 133))	('MEK', 'Gene', '17242', (177, 180))	('PTEN', 'Gene', '19211', (47, 51))	('cancer', 'Disease', (326, 332))	('mutation', 'Var', (8, 16))	('cancer', 'Phenotype', 'HP:0002664', (326, 332))	('cancer', 'Disease', (252, 258))	('ribosomal S6 kinase', 'Gene', '20111', (190, 209))	('BRAF', 'Gene', '109880', (25, 29))	('expression/activation', 'PosReg', (66, 87))	('TOPK', 'Gene', '52033', (129, 133))	('MEK', 'Gene', (177, 180))	('RSK', 'Gene', '20111', (211, 214))	('RSK', 'Gene', (211, 214))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('melanoma', 'Phenotype', 'HP:0002861', (227, 235))	('melanoma', 'Disease', (227, 235))	('skin carcinogenesis', 'Disease', 'MESH:D063646', (302, 321))	('skin carcinogenesis', 'Disease', (302, 321))	('cancer', 'Disease', 'MESH:D009369', (326, 332))	('mitogen-activated protein kinase kinase', 'Gene', '17242', (136, 175))	('PTEN', 'Gene', (47, 51))	('BRAF', 'Gene', (25, 29))	('T-LAK cell-originated protein kinase', 'Gene', (91, 127))	('CDKN2A', 'Gene', '12578', (36, 42))
103969	32962182	Solar UV triggers PTEN mutations.	('mutations', 'Var', (23, 32))	('PTEN', 'Gene', (18, 22))	('PTEN', 'Gene', '19211', (18, 22))
103975	32962182	Vemurafenib is a competitive inhibitor of BRAF kinase activity, and especially inhibits melanoma with a V600 mutation.	('melanoma', 'Phenotype', 'HP:0002861', (88, 96))	('inhibits', 'NegReg', (79, 87))	('V600 mutation', 'Var', (104, 117))	('melanoma', 'Disease', (88, 96))	('melanoma', 'Disease', 'MESH:D008545', (88, 96))	('Vemurafenib', 'Chemical', 'MESH:D000077484', (0, 11))	('BRAF', 'Gene', '109880', (42, 46))	('BRAF', 'Gene', (42, 46))
103984	32962182	Together with downstream target protein mTOR, the activated AKT1 induces highly metastatic melanomas involving lung (67%) and brain (17%) in BRAFV600E/Cdkn2aNull mice.	('melanomas', 'Disease', (91, 100))	('melanoma', 'Phenotype', 'HP:0002861', (91, 99))	('BRAFV600E', 'Mutation', 'rs113488022', (141, 150))	('mTOR', 'Gene', (40, 44))	('induces', 'Reg', (65, 72))	('melanomas', 'Phenotype', 'HP:0002861', (91, 100))	('mice', 'Species', '10090', (162, 166))	('AKT1', 'Gene', '11651', (60, 64))	('activated', 'Var', (50, 59))	('mTOR', 'Gene', '56717', (40, 44))	('melanomas', 'Disease', 'MESH:D008545', (91, 100))	('AKT1', 'Gene', (60, 64))
103998	32962182	C15H24O2-(3s-(3a,3aa,5a,6a,8ab))-octahydro-3-methyl-8-methylene-5-(1-methylethyl)-6h-3a,6-epoxyazulen-6-ol, is a polyphenol compound derived from Curcuma Wenyujin (ethanol fraction), with pharmacological anticancer activities in liver, lung and gastric cancer.	('liver', 'Disease', (229, 234))	('gastric cancer', 'Disease', (245, 259))	('cancer', 'Disease', (208, 214))	('gastric cancer', 'Disease', 'MESH:D013274', (245, 259))	('C15H24O2-', 'Var', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (253, 259))	('cancer', 'Disease', 'MESH:D009369', (253, 259))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('gastric cancer', 'Phenotype', 'HP:0012126', (245, 259))	('cancer', 'Disease', (253, 259))	('cancer', 'Disease', 'MESH:D009369', (208, 214))	('ethanol', 'Chemical', 'MESH:D000431', (164, 171))	('Curcuma Wenyujin', 'Species', '136221', (146, 162))	('lung', 'Disease', (236, 240))	('polyphenol', 'Chemical', 'MESH:D059808', (113, 123))
104002	32962182	Treatment with polyphyllin I at 1.5, 3.0 and 6.0 mg/L concentrations suppressed A375 melanoma cell progression by reducing cell proliferation, migration and invasion, and the induction of G1 cell cycle accumulation, apoptosis and autophagy at 48 h. Polyphyllin I-induced apoptosis and autophagy was mediated via the downregulation of pPI3K, pAKT and pmTOR expression.	('expression', 'MPA', (356, 366))	('mTOR', 'Gene', (351, 355))	('polyphyllin I', 'Chemical', 'MESH:C556217', (15, 28))	('Polyphyllin I', 'Chemical', 'MESH:C556217', (249, 262))	('mTOR', 'Gene', '56717', (351, 355))	('autophagy', 'CPA', (285, 294))	('A375', 'CellLine', 'CVCL:0132', (80, 84))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('pPI3K', 'Gene', (334, 339))	('melanoma', 'Disease', (85, 93))	('Polyphyllin', 'Var', (249, 260))	('apoptosis', 'CPA', (271, 280))	('melanoma', 'Disease', 'MESH:D008545', (85, 93))	('downregulation', 'NegReg', (316, 330))	('pAKT', 'Gene', (341, 345))
104005	32962182	The levels of proliferation marker, Ki-67 and apoptosis feature, TUNEL-positive cells, were inhibited and increased in polyphyllin I-treated tissues compared with vehicle-treated controls, respectively.	('apoptosis', 'CPA', (46, 55))	('polyphyllin', 'Var', (119, 130))	('inhibited', 'NegReg', (92, 101))	('Ki-67', 'Gene', '17345', (36, 41))	('levels of', 'MPA', (4, 13))	('Ki-67', 'Gene', (36, 41))	('polyphyllin I', 'Chemical', 'MESH:C556217', (119, 132))	('increased', 'PosReg', (106, 115))
104013	32962182	retarded the tumor growth and weight, and inhibited the expression of MMP-2 and MMP-9, and pPI3K and pAKT1.	('tumor', 'Disease', (13, 18))	('pPI3K', 'Var', (91, 96))	('AKT1', 'Gene', (102, 106))	('MMP-9', 'Gene', '17395', (80, 85))	('MMP-9', 'Gene', (80, 85))	('expression', 'MPA', (56, 66))	('inhibited', 'NegReg', (42, 51))	('MMP-2', 'Gene', (70, 75))	('MMP-2', 'Gene', '17390', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('AKT1', 'Gene', '11651', (102, 106))	('retarded', 'NegReg', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
104018	32962182	The results were confirmed by treatment of cells with chloroquine, an autophagy inhibitor and a LY294002, PI3K/AKT inhibitor.	('autophagy inhibitor', 'CPA', (70, 89))	('chloroquine', 'Chemical', 'MESH:D002738', (54, 65))	('LY294002', 'Chemical', 'MESH:C085911', (96, 104))	('LY294002', 'Var', (96, 104))
104029	32962182	Moreover, pPI3K, pAKT and pmTOR expression were decreased by alpha-mangostin administration in mouse tissues of DMBA/TPA-induced skin carcinogenesis.	('mTOR', 'Gene', '56717', (27, 31))	('skin carcinogenesis', 'Disease', (129, 148))	('DMBA', 'Chemical', '-', (112, 116))	('pPI3K', 'Var', (10, 15))	('decreased', 'NegReg', (48, 57))	('TPA', 'Chemical', 'MESH:D013755', (117, 120))	('skin carcinogenesis', 'Disease', 'MESH:D063646', (129, 148))	('pAKT', 'MPA', (17, 21))	('alpha-mangostin', 'Chemical', 'MESH:C021053', (61, 76))	('mTOR', 'Gene', (27, 31))	('mouse', 'Species', '10090', (95, 100))
104033	32962182	Silibinin (50 and 100 muM) and DHS (50 and 100 muM) also inhibited signaling pathways including pEGFR, pERK1/2, pAKT and pSTAT3 expression in ASZ cells at 72 h, thereby abrogating NF-kappaB and AP-1 activities.	('abrogating', 'NegReg', (169, 179))	('inhibited', 'NegReg', (57, 66))	('EGFR', 'Gene', '1956', (97, 101))	('NF-kappaB', 'Enzyme', (180, 189))	('pERK1/2', 'Gene', (103, 110))	('Silibinin', 'Chemical', 'MESH:D000077385', (0, 9))	('AP-1', 'Enzyme', (194, 198))	('50', 'Var', (11, 13))	('EGFR', 'Gene', (97, 101))	('pSTAT3', 'Gene', (121, 127))	('signaling pathways', 'Pathway', (67, 85))	('50', 'Var', (36, 38))	('activities', 'MPA', (199, 209))
104034	32962182	Based on the results of ASZ cells in a mouse allograft model, the oral administration of silibinin (200 mg/kg) and DHS (200 mg/kg) significantly reduced the tumor weight.	('tumor', 'Disease', (157, 162))	('reduced', 'NegReg', (145, 152))	('silibinin', 'Chemical', 'MESH:D000077385', (89, 98))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('mouse', 'Species', '10090', (39, 44))	('200 mg/kg', 'Var', (100, 109))
104063	32139907	Consistent with this, we observe an enrichment for WGD in tumor types with extensive loss of heterozygosity (LOH), including lung and triple negative breast cancers, and we find evidence for negative selection against homozygous loss of essential genes prior to, but not after, WGD.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('tumor', 'Disease', (58, 63))	('breast cancers', 'Disease', 'MESH:D001943', (150, 164))	('breast cancers', 'Disease', (150, 164))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('homozygous', 'Var', (218, 228))	('lung', 'Disease', (125, 129))	('cancers', 'Phenotype', 'HP:0002664', (157, 164))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('loss', 'NegReg', (85, 89))	('breast cancers', 'Phenotype', 'HP:0003002', (150, 164))
104064	32139907	Finally, we demonstrate that LOH and temporal dissection of mutations can be exploited to identify novel tumor suppressor genes and to obtain a deeper characterization of known cancer genes.	('cancer', 'Disease', (177, 183))	('cancer', 'Disease', 'MESH:D009369', (177, 183))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('mutations', 'Var', (60, 69))	('tumor', 'Disease', (105, 110))
104065	32139907	Whole genome doubling (WGD), involving the duplication of a complete set of chromosomes, is a common feature of cancer genomes.	('duplication', 'Var', (43, 54))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('Whole genome doubling', 'Disease', (0, 21))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))
104079	32139907	We noted a lower proportion of the genome subject to LOH in non-WGD tumors compared to their genome doubled counterparts (Figure 1a-c), but as expected, by virtue of the additional genome copies, on average only 1.32% of the genome was haploid in WGD tumors, compared to 9.55% in nWGD cases (Figure 1a,b).	('haploid', 'Var', (236, 243))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('tumors', 'Phenotype', 'HP:0002664', (251, 257))	('WGD tumors', 'Disease', 'MESH:D009369', (64, 74))	('WGD tumors', 'Disease', 'MESH:D009369', (247, 257))	('WGD tumors', 'Disease', (64, 74))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('WGD tumors', 'Disease', (247, 257))	('tumor', 'Phenotype', 'HP:0002664', (251, 256))
104080	32139907	Additionally, we observed a significant positive correlation between the amount of haploid LOH in non-WGD tumors and the frequency of WGD events across tumor types (Figure 1d).	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('WGD tumors', 'Disease', 'MESH:D009369', (102, 112))	('WGD tumors', 'Disease', (102, 112))	('haploid', 'Var', (83, 90))	('WGD events across tumor', 'Disease', (134, 157))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('WGD events across tumor', 'Disease', 'MESH:D009369', (134, 157))
104083	32139907	In our model, alterations in cancer genes is associated with a fitness gain (sd) while passenger alterations in haploid regions are associated with a weak fitness cost (sp), reducing the birth rate.	('alterations', 'Var', (14, 25))	('fitness cost', 'Disease', (155, 167))	('fitness gain', 'Disease', (63, 75))	('cancer', 'Disease', (29, 35))	('reducing', 'NegReg', (174, 182))	('birth rate', 'CPA', (187, 197))	('fitness gain', 'Disease', 'MESH:D015430', (63, 75))	('fitness cost', 'Disease', 'MESH:D012640', (155, 167))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('cancer', 'Disease', 'MESH:D009369', (29, 35))
104085	32139907	To explore WGD we simulated the evolution of cancer populations (starting with a 1,000 cells), and varied the fitness costs of passenger alterations (sp  {0-0.01}, where 0.01 represents a 1% increase in waiting time to birth) and WGD (sWGD  {0-1.5}) (Supplementary Table 1).	('0.01', 'Var', (170, 174))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('fitness costs', 'Disease', 'MESH:D012640', (110, 123))	('waiting time to birth', 'Phenotype', 'HP:0001622', (203, 224))	('cancer', 'Disease', (45, 51))	('fitness costs', 'Disease', (110, 123))
104096	32139907	Conversely, alterations with a substantial fitness cost (sp >0.01) were associated with strong negative selection.	('alterations', 'Var', (12, 23))	('fitness cost', 'Disease', (43, 55))	('fitness cost', 'Disease', 'MESH:D012640', (43, 55))
104100	32139907	Applying temporal dissection of mutations to tumors exhibiting WGD in TRACERx and TCGA datasets suggests that the majority of detectable clonal mutations in NSCLC accumulate prior to WGD (Figure 3c).	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumors', 'Disease', (45, 51))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('tumors', 'Disease', 'MESH:D009369', (45, 51))	('NSCLC', 'Disease', (157, 162))	('mutations', 'Var', (144, 153))	('NSCLC', 'Disease', 'MESH:D002289', (157, 162))
104103	32139907	These data suggest homozygous disruption to essential genes in regions of LOH in diploid genomes resulting in disruption of both alleles, leads to a detectable fitness impairment; indeed, on average, approximately half of clones harboring early truncating mutations in regions of LOH are predicted to be lost due to purifying selection.	('disruption', 'Var', (30, 40))	('mutations', 'Var', (256, 265))	('fitness impairment', 'Disease', 'MESH:D004827', (160, 178))	('fitness impairment', 'Disease', (160, 178))	('early truncating', 'NegReg', (239, 255))
104104	32139907	However, due to the limited number of point mutations in essential genes, we can estimate that on average only one clone harboring a nonsense mutation in an essential gene is eliminated per tumor prior to WGD during its evolution.	('tumor', 'Disease', (190, 195))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('nonsense mutation', 'Var', (133, 150))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))
104106	32139907	In order to assess the effect of using different essential gene lists, in addition to the essential genes from(Figure 4a), we took advantage of CRISPR screens and calculated the dNdS ratio for pre-WGD mutations in LOH in NSCLC specific essential genes.	('NSCLC', 'Disease', 'MESH:D002289', (221, 226))	('NSCLC', 'Disease', (221, 226))	('LOH', 'Gene', (214, 217))	('mutations', 'Var', (201, 210))
104107	32139907	For TCGA-LUAD we noted that while negative selection was observed prior to doubling in all cases, for genes derived from, a weak signal of negative selection was observed for post WGD mutations, potentially due to some genes acting in a haploinsufficient manner.	('mutations', 'Var', (184, 193))	('TCGA-LUAD', 'Gene', (4, 13))	('haploinsufficient', 'Disease', 'MESH:D058495', (237, 254))	('haploinsufficient', 'Disease', (237, 254))
104108	32139907	However, given that these mutations are relatively rare events during cancer evolution (up<0.0001), these data, together with the simulations, suggest WGD cannot be selected solely to buffer against nonsense mutations in essential genes.	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('mutations', 'Var', (26, 35))	('nonsense', 'Var', (199, 207))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))
104109	32139907	Homozygous deletions are rare in NSCLC genomes, consistent with complete loss of gene function generally having a negative effect on cell fitness.	('loss', 'NegReg', (73, 77))	('fitness', 'Disease', 'MESH:D012640', (138, 145))	('negative', 'NegReg', (114, 122))	('deletions', 'Var', (11, 20))	('NSCLC', 'Disease', (33, 38))	('NSCLC', 'Disease', 'MESH:D002289', (33, 38))	('fitness', 'Disease', (138, 145))
104111	32139907	We simulated copy number losses randomly (at the chromosome arm level) in WGD tumors, fixing the number of chromosome arms in pre-WGD LOH based on the observed data.	('WGD tumors', 'Disease', 'MESH:D009369', (74, 84))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('copy', 'Var', (13, 17))	('WGD tumors', 'Disease', (74, 84))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('losses', 'NegReg', (25, 31))
104116	32139907	Significant signatures of purifying selection in pre-WGD truncating mutations in LOH in essential genes (but not after WGD) were observed in skin cutaneous melanoma (SKCM), which is characterized by high mutation rates and high LOH (Supplementary Figure 6).	('melanoma', 'Phenotype', 'HP:0002861', (156, 164))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (141, 164))	('truncating mutations', 'Var', (57, 77))	('LOH in essential genes', 'Gene', (81, 103))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (146, 164))	('skin cutaneous melanoma', 'Disease', (141, 164))
104120	32139907	These data may reflect strong selection for inactivation of both copies of tumor suppressor genes through LOH and mutation, prior to WGD.	('LOH', 'Var', (106, 109))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('mutation', 'Var', (114, 122))	('inactivation', 'Var', (44, 56))	('tumor', 'Disease', (75, 80))
104126	32139907	Other genes that were only identified as significant when looking at mutations in regions of LOH were NOTCH1 and SMAD4 in LUSC (Figure 5b and Supplementary Figure 3).	('SMAD4', 'Gene', '4089', (113, 118))	('mutations', 'Var', (69, 78))	('NOTCH1', 'Gene', '4851', (102, 108))	('SMAD4', 'Gene', (113, 118))	('NOTCH1', 'Gene', (102, 108))
104127	32139907	On the other hand, CUL3 (Cullin-3), which plays an important role in the ubiquitin-proteasome system, showed high signatures of selection in genomic regions not subject to LOH, possibly reflecting haploinsufficient activity in cancer, and, conceivably, the requirement for an intact wild-type allele.	('CUL3', 'Gene', (19, 23))	('haploinsufficient activity', 'Disease', (197, 223))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('cancer', 'Disease', 'MESH:D009369', (227, 233))	('haploinsufficient activity', 'Disease', 'MESH:D058495', (197, 223))	('Cullin-3', 'Gene', (25, 33))	('cancer', 'Disease', (227, 233))	('Cullin-3', 'Gene', '8452', (25, 33))	('CUL3', 'Gene', '8452', (19, 23))	('selection', 'Var', (128, 137))
104133	32139907	We detected six potential cancer genes when looking at LOH mutations that were not significant when assessing all mutations together.	('cancer', 'Disease', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('mutations', 'Var', (59, 68))
104139	32139907	Focussing on genomic segments exhibiting LOH, we demonstrate that truncating mutations in essential genes occurring before WGD in a haploid context are subject to negative selection in lung cancer evolution.	('lung cancer', 'Disease', 'MESH:D008175', (185, 196))	('lung cancer', 'Disease', (185, 196))	('lung cancer', 'Phenotype', 'HP:0100526', (185, 196))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('truncating mutations', 'Var', (66, 86))	('negative', 'NegReg', (163, 171))
104140	32139907	Analogous to haploid asexual and non-recombining populations in nature, cancer cells will accumulate these alterations irreversibly, in a ratchet-like process.	('alterations', 'Var', (107, 118))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('cancer', 'Disease', (72, 78))
104141	32139907	Thus, in cancers with a high rate of deleterious alteration acquisition (reflecting both point mutations and SCNA losses) and high levels of LOH, and in the absence of other compensating mechanisms, this may lead to the attrition of subclones.	('cancers', 'Disease', 'MESH:D009369', (9, 16))	('cancers', 'Phenotype', 'HP:0002664', (9, 16))	('cancers', 'Disease', (9, 16))	('lead to', 'Reg', (208, 215))	('point mutations', 'Var', (89, 104))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('alteration', 'Var', (49, 59))	('attrition', 'MPA', (220, 229))
104143	32139907	Thus, regardless of the underlying reason for why WGD occurs, by duplicating haploid genomic segments (which hence become diploid), WGD may attenuate cancer cell attrition through disruption of the genome.	('WGD', 'Var', (132, 135))	('duplicating', 'Var', (65, 76))	('attenuate', 'NegReg', (140, 149))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('cancer', 'Disease', (150, 156))	('disruption', 'Var', (180, 190))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
104148	32139907	Further experimental work is required to explore the fitness consequences of WGD and to obtain a detailed understanding how different types of alterations, including nonsense and SCNA may negatively impact upon the fitness of cancer cells and how this changes during the disease course.	('nonsense', 'Var', (166, 174))	('fitness of cancer', 'Disease', 'MESH:D009369', (215, 232))	('fitness', 'Disease', (53, 60))	('SCNA', 'Var', (179, 183))	('fitness', 'Disease', (215, 222))	('fitness', 'Disease', 'MESH:D012640', (53, 60))	('impact', 'Reg', (199, 205))	('fitness', 'Disease', 'MESH:D012640', (215, 222))	('fitness of cancer', 'Disease', (215, 232))	('negatively', 'NegReg', (188, 198))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
104149	32139907	Indeed, previous work has suggested a triploid karyotype represents an optimal fitness state for cancer cells.	('cancer', 'Disease', (97, 103))	('fitness', 'Disease', 'MESH:D012640', (79, 86))	('triploid karyotype', 'Var', (38, 56))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('fitness', 'Disease', (79, 86))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
104153	32139907	Conceivably, a similar framework could be applied to identify cancer genes subject to either mutation and methylation.	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('methylation', 'Var', (106, 117))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('mutation', 'Var', (93, 101))
104161	32139907	We performed simulations to model the viability of a cancerous cell over time and illustrate the potential of increasing DNA copies via genome duplication in the mitigation of damaging effects of mutations using an adapted version of the cancer evolution model developed by McFarland et al..	('cancer', 'Disease', (238, 244))	('cancer', 'Disease', 'MESH:D009369', (238, 244))	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('cancerous', 'Disease', 'MESH:D009369', (53, 62))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('cancerous', 'Disease', (53, 62))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('increasing', 'PosReg', (110, 120))	('mutations', 'Var', (196, 205))
104163	32139907	The viability of the population of cells varies by a function of the mutations that the cell has accumulated over time, which exert deleterious or beneficial effects on cell fitness to varying degrees, depending on the type of genes where they are accumulated.	('mutations', 'Var', (69, 78))	('fitness', 'Disease', (174, 181))	('fitness', 'Disease', 'MESH:D012640', (174, 181))	('beneficial effects', 'PosReg', (147, 165))
104164	32139907	Passenger alterations in regions of haploid LOH decrease the fitness by increasing the time to the next birth.	('haploid LOH decrease the fitness', 'Disease', (36, 68))	('alterations', 'Var', (10, 21))	('haploid LOH decrease the fitness', 'Disease', 'MESH:D012640', (36, 68))	('time to the next birth', 'CPA', (87, 109))	('increasing', 'PosReg', (72, 82))
104176	32139907	Additionally, we calculated dNdS values for early mutations in LOH in essential genes inferred by NSCLC CRISPR analyses (Achilles) available at the DepMap portal https://depmap.org/portal/.	('mutations', 'Var', (50, 59))	('NSCLC', 'Disease', 'MESH:D002289', (98, 103))	('NSCLC', 'Disease', (98, 103))
104177	32139907	Genes were ranked by the average gene-knockout effect (a measurement of the consequences of gene deletion on cell viability) across 283 samples annotated as lung cancer for the primary disease and took lists of top genes of different lengths ranging from 500 to 7,000.	('lung cancer', 'Disease', (157, 168))	('lung cancer', 'Phenotype', 'HP:0100526', (157, 168))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('primary disease', 'Disease', (177, 192))	('lung cancer', 'Disease', 'MESH:D008175', (157, 168))	('primary disease', 'Disease', 'MESH:D003141', (177, 192))	('deletion', 'Var', (97, 105))
104182	32139907	In order to demonstrate that we can accurately quantify which mutations and copy number losses occur pre and post the WGD event we used mutation and copy number data from 2 diploid and 4 tetraploid subclones derived from diploid human colon carcinoma HCT-116 cells, isolated at different passages (4 and 50 passages).	('colon carcinoma', 'Disease', (235, 250))	('carcinoma', 'Phenotype', 'HP:0030731', (241, 250))	('losses', 'NegReg', (88, 94))	('colon carcinoma', 'Disease', 'MESH:D003110', (235, 250))	('HCT-116', 'CellLine', 'CVCL:0291', (251, 258))	('human', 'Species', '9606', (229, 234))	('mutations', 'Var', (62, 71))
104196	32016472	Higher methylation levels of cg24063645 were associated with shorter overall survival time of patients with LUSC.	('overall survival', 'MPA', (69, 85))	('shorter', 'NegReg', (61, 68))	('LUSC', 'Phenotype', 'HP:0030359', (108, 112))	('patients', 'Species', '9606', (94, 102))	('cg24063645', 'Var', (29, 39))	('methylation levels', 'MPA', (7, 25))
104210	32016472	In terms of esophageal squamous cell carcinoma, Chen et al reported that ADARB1 induces apoptosis and suppresses tumor growth by editing insulin-like growth factor binding protein 7 mRNA.	('ADARB1', 'Gene', '104', (73, 79))	('tumor', 'Disease', (113, 118))	('apoptosis', 'CPA', (88, 97))	('insulin-like growth factor binding protein 7', 'Gene', '3490', (137, 181))	('ADARB1', 'Gene', (73, 79))	('editing', 'Var', (129, 136))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:C562729', (12, 46))	('carcinoma', 'Phenotype', 'HP:0030731', (37, 46))	('suppresses', 'NegReg', (102, 112))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (23, 46))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('insulin-like growth factor binding protein 7', 'Gene', (137, 181))	('esophageal squamous cell carcinoma', 'Disease', (12, 46))
104215	32016472	The expression and methylation status of ADARB1 were significantly associated with clinical characteristics and prognosis.	('methylation status', 'Var', (19, 37))	('expression', 'MPA', (4, 14))	('associated', 'Reg', (67, 77))	('ADARB1', 'Gene', '104', (41, 47))	('ADARB1', 'Gene', (41, 47))
104229	32016472	The MethSurv tool was used to analyze the association between ADARB1 methylation and LUSC prognosis by using the mean value to dichotomize methylation profiles of patients.	('patients', 'Species', '9606', (163, 171))	('LUSC prognosis', 'Disease', (85, 99))	('association', 'Interaction', (42, 53))	('methylation', 'Var', (69, 80))	('ADARB1', 'Gene', '104', (62, 68))	('LUSC', 'Phenotype', 'HP:0030359', (85, 89))	('ADARB1', 'Gene', (62, 68))
104254	32016472	The highest methylation value of cg24063645 in ADARB1 was identified using the Wanderer and MethSurv databases (P=3.60x10-19; Fig.	('Wanderer', 'Species', '320184', (79, 87))	('ADARB1', 'Gene', '104', (47, 53))	('cg24063645', 'Var', (33, 43))	('ADARB1', 'Gene', (47, 53))	('methylation', 'MPA', (12, 23))
104256	32016472	The methylation of cg24063645 of ADARB1 was significantly associated with the Karnofsky score of patients with LUSC (P=0.025; Table III).	('ADARB1', 'Gene', '104', (33, 39))	('associated', 'Reg', (58, 68))	('Karnofsky score', 'Disease', (78, 93))	('ADARB1', 'Gene', (33, 39))	('LUSC', 'Phenotype', 'HP:0030359', (111, 115))	('methylation', 'Var', (4, 15))	('cg24063645', 'Var', (19, 29))	('patients', 'Species', '9606', (97, 105))
104257	32016472	Moreover, higher methylation levels of cg24063645 of ADARB1 were associated with shorter OS of patients with LUSC (P=0.044; Fig.	('ADARB1', 'Gene', '104', (53, 59))	('patients', 'Species', '9606', (95, 103))	('ADARB1', 'Gene', (53, 59))	('methylation levels', 'MPA', (17, 35))	('cg24063645', 'Var', (39, 49))	('LUSC', 'Phenotype', 'HP:0030359', (109, 113))	('higher', 'PosReg', (10, 16))	('shorter', 'NegReg', (81, 88))
104265	32016472	Firstly, 14,102 genes co-expressed with ADARB1 in LUSC were identified using the cBioPortal database, and a volcano plot was generated to display the association between groups with altered and unaltered ADARB1 expression (Fig.	('ADARB1', 'Gene', '104', (204, 210))	('altered', 'Var', (182, 189))	('ADARB1', 'Gene', (204, 210))	('LUSC', 'Phenotype', 'HP:0030359', (50, 54))	('ADARB1', 'Gene', (40, 46))	('ADARB1', 'Gene', '104', (40, 46))
104276	32016472	In addition, the global methylation levels of ADARB1 were upregulated in LUSC and a higher methylation value of cg24063645 was related to a shorter OS in patients with LUSC.	('LUSC', 'Phenotype', 'HP:0030359', (168, 172))	('ADARB1', 'Gene', (46, 52))	('LUSC', 'Disease', (73, 77))	('ADARB1', 'Gene', '104', (46, 52))	('upregulated', 'PosReg', (58, 69))	('global methylation levels', 'MPA', (17, 42))	('patients', 'Species', '9606', (154, 162))	('cg24063645', 'Var', (112, 122))	('methylation', 'MPA', (91, 102))	('higher', 'PosReg', (84, 90))	('LUSC', 'Phenotype', 'HP:0030359', (73, 77))
104277	32016472	A-to-I RNA editing is a post-transcriptional modification mediated by the ADAR family, which is comprised of three members, ADAR1, ADARB1 and ADAR3.	('ADARB1', 'Gene', (131, 137))	('ADAR', 'Gene', '103', (142, 146))	('ADAR3', 'Gene', '105', (142, 147))	('ADAR', 'Gene', '103', (124, 128))	('ADAR', 'Gene', '103', (131, 135))	('ADAR', 'Gene', (124, 128))	('A-to-I RNA', 'Var', (0, 10))	('ADAR', 'Gene', '103', (74, 78))	('ADAR', 'Gene', (142, 146))	('ADAR1', 'Gene', (124, 129))	('ADAR3', 'Gene', (142, 147))	('ADAR', 'Gene', (131, 135))	('ADAR1', 'Gene', '103', (124, 129))	('ADAR', 'Gene', (74, 78))	('ADARB1', 'Gene', '104', (131, 137))
104285	32016472	In addition, Galeano et al reported that ADARB1 could inhibit glioblastoma growth by the regulation of the cell division cycle 14B/S-phase kinase associated protein 2/p21/p27 axis; therefore, ADARB1 or its substrates represented suitable targets for the treatment of glioblastoma.	('p21', 'Gene', '644914', (167, 170))	('glioblastoma', 'Disease', (267, 279))	('p27', 'Gene', '3429', (171, 174))	('glioblastoma', 'Phenotype', 'HP:0012174', (62, 74))	('inhibit', 'NegReg', (54, 61))	('p27', 'Gene', (171, 174))	('glioblastoma', 'Disease', 'MESH:D005909', (62, 74))	('glioblastoma', 'Disease', 'MESH:D005909', (267, 279))	('14B/S', 'Var', (127, 132))	('glioblastoma', 'Phenotype', 'HP:0012174', (267, 279))	('glioblastoma', 'Disease', (62, 74))	('ADARB1', 'Gene', (192, 198))	('ADARB1', 'Gene', '104', (41, 47))	('14B/S', 'SUBSTITUTION', 'None', (127, 132))	('ADARB1', 'Gene', '104', (192, 198))	('ADARB1', 'Gene', (41, 47))	('p21', 'Gene', (167, 170))
104287	32016472	Furthermore, the hypermethylation of ADARB1 was related to the poor prognosis of patients with LUSC.	('ADARB1', 'Gene', (37, 43))	('LUSC', 'Phenotype', 'HP:0030359', (95, 99))	('ADARB1', 'Gene', '104', (37, 43))	('patients', 'Species', '9606', (81, 89))	('LUSC', 'Disease', (95, 99))	('hypermethylation', 'Var', (17, 33))	('related', 'Reg', (48, 55))
104298	32016472	A previous study indicated that, following phosphorylation on a regulatory tyrosine, EGFR can be activated in a ligand-dependent or -independent manner to induce tumor progression.	('EGFR', 'Gene', (85, 89))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('tumor', 'Disease', (162, 167))	('tyrosine', 'Chemical', 'None', (75, 83))	('phosphorylation on', 'Var', (43, 61))	('induce', 'PosReg', (155, 161))	('EGFR', 'Gene', '1956', (85, 89))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('activated', 'PosReg', (97, 106))
104300	32016472	Moreover, the combination of aberrantly expressed EGFR and transforming growth factor (TGF)-alpha secretion by NSCLC cells can form a TGF-alpha-EGFR autocrine ring, which promotes tumor development.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('EGFR', 'Gene', (144, 148))	('promotes', 'PosReg', (171, 179))	('aberrantly expressed', 'Var', (29, 49))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('NSCLC', 'Disease', (111, 116))	('TGF-alpha', 'Gene', (134, 143))	('tumor', 'Disease', (180, 185))	('EGFR', 'Gene', '1956', (50, 54))	('NSCLC', 'Disease', 'MESH:D002289', (111, 116))	('EGFR', 'Gene', (50, 54))	('EGFR', 'Gene', '1956', (144, 148))	('NSCLC', 'Phenotype', 'HP:0030358', (111, 116))	('TGF)-alpha', 'Gene', '7039', (87, 97))	('TGF-alpha', 'Gene', '7039', (134, 143))
104330	29486777	Then, we identified and compared regulatory variants associated with the three subtypes of lung cancer, as well as their target genes.	('lung cancer', 'Phenotype', 'HP:0100526', (91, 102))	('subtypes of lung cancer', 'Disease', 'MESH:D008175', (79, 102))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('subtypes of lung cancer', 'Disease', (79, 102))	('variants', 'Var', (44, 52))
104346	29486777	investigated how genetic variation affects gene expression levels in human lung tissues.	('human', 'Species', '9606', (69, 74))	('genetic variation', 'Var', (17, 34))	('affects', 'Reg', (35, 42))	('gene expression levels', 'MPA', (43, 65))
104364	29486777	This one SNP was rs578776, on chromosome 15 in the 3' untranslated region of CHRNA3, in the chr.15q25 locus known to be associated with different histology subtypes of lung cancer.	('associated', 'Reg', (120, 130))	('rs578776', 'Var', (17, 25))	('CHRNA3', 'Gene', (77, 83))	('lung cancer', 'Phenotype', 'HP:0100526', (168, 179))	('subtypes of lung cancer', 'Disease', 'MESH:D008175', (156, 179))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('subtypes of lung cancer', 'Disease', (156, 179))	('CHRNA3', 'Gene', '1136', (77, 83))	('rs578776', 'Mutation', 'rs578776', (17, 25))
104366	29486777	After we removed duplicated SNPs within each subtype, we found 8295 SNPs associated with LUAD, 8734 with LUSC, and 8361 with SCLC, among which 167 SNPs overlapped between all three subtypes (Additional file 1: Figure S2B).	('LUAD', 'Disease', (89, 93))	('SNPs', 'Var', (68, 72))	('SCLC', 'Gene', (125, 129))	('SCLC', 'Gene', '7864', (125, 129))	('SCLC', 'Phenotype', 'HP:0030357', (125, 129))	('associated', 'Reg', (73, 83))	('LUSC', 'Phenotype', 'HP:0030359', (105, 109))	('LUSC', 'Disease', (105, 109))	('LUAD', 'Phenotype', 'HP:0030078', (89, 93))
104400	29486777	It is also possible that somatic mutations can act in concert with expression-altering SNPs in driving the tumor and would not have the same effect on growth advantage in the absence of the SNP.	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('driving', 'CPA', (95, 102))	('mutations', 'Var', (33, 42))	('tumor', 'Disease', 'MESH:D009369', (107, 112))
104401	29486777	Additionally, a specific understanding of the regulatory roles that common genetic variants play in the development of lung cancer subtypes is an important research question because the majority of common variants that increase cancer risk are located within non-coding regions and most likely act as regulators of gene expression.	('lung cancer', 'Disease', (119, 130))	('increase cancer', 'Disease', (219, 234))	('lung cancer', 'Phenotype', 'HP:0100526', (119, 130))	('men', 'Species', '9606', (111, 114))	('increase cancer', 'Disease', 'MESH:D009369', (219, 234))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('variants', 'Var', (205, 213))	('lung cancer', 'Disease', 'MESH:D008175', (119, 130))
104404	29486777	We used marginally significant GWAS results (p < 1 x 10- 3) to search for regulatory roles for common variants associated with LUAD, LUSC, and SCLC.	('variants', 'Var', (102, 110))	('SCLC', 'Gene', '7864', (143, 147))	('LUSC', 'Disease', (133, 137))	('SCLC', 'Gene', (143, 147))	('LUSC', 'Phenotype', 'HP:0030359', (133, 137))	('LUAD', 'Disease', (127, 131))	('LUAD', 'Phenotype', 'HP:0030078', (127, 131))	('SCLC', 'Phenotype', 'HP:0030357', (143, 147))
104429	29486777	In summary, we used common genetic variants found in three lung cancer subtypes to interrogate the similarity between them at four biological levels (SNP, gene, regulatory, and pathway levels).	('lung cancer', 'Disease', 'MESH:D008175', (59, 70))	('variants', 'Var', (35, 43))	('lung cancer', 'Disease', (59, 70))	('lung cancer', 'Phenotype', 'HP:0100526', (59, 70))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
104433	29486777	eQTL Expression quantitative trait loci FANTOM Functional Annotation of the Mammalian Genome GTEx Genotype-Tissue Expression project GWAS Genome-wide association study IM-PET Integrated Methods for Predicting Enhancer Targets KEGG Kyoto Encyclopedia of Genes and Genomes LD Linkage disequilibrium LUAD Lung adenocarcinoma LUSC Lung squamous cell carcinoma NCBI National Center for Biotechnology Information NSCLC Non-small cell lung cancer PCA Principal component analysis SCLC Small cell lung cancer SNP Single-nucleotide polymorphism TCGA The Cancer Genome Atlas TDO, PJ, and ZZ contributed to the conception and design of the study.	('squamous cell carcinoma', 'Disease', (332, 355))	('Small cell lung cancer', 'Disease', (478, 500))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (417, 439))	('NSCLC', 'Phenotype', 'HP:0030358', (407, 412))	('SCLC', 'Phenotype', 'HP:0030357', (473, 477))	('cancer', 'Phenotype', 'HP:0002664', (494, 500))	('Non-small cell lung cancer', 'Disease', 'MESH:D002289', (413, 439))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (545, 564))	('SCLC', 'Gene', (473, 477))	('Small cell lung cancer', 'Disease', 'MESH:D055752', (478, 500))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (332, 355))	('SCLC', 'Gene', '7864', (473, 477))	('adenocarcinoma', 'Disease', (307, 321))	('Cancer Genome Atlas', 'Disease', (545, 564))	('GTEx', 'Chemical', '-', (93, 97))	('Non-small cell lung cancer', 'Disease', (413, 439))	('SCLC', 'Phenotype', 'HP:0030357', (408, 412))	('LUSC', 'Phenotype', 'HP:0030359', (322, 326))	('carcinoma', 'Phenotype', 'HP:0030731', (346, 355))	('NSCLC', 'Disease', 'MESH:D002289', (407, 412))	('SCLC', 'Gene', (408, 412))	('adenocarcinoma', 'Disease', 'MESH:D000230', (307, 321))	('lung cancer', 'Phenotype', 'HP:0100526', (428, 439))	('TDO', 'Gene', (565, 568))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (332, 355))	('SCLC', 'Gene', '7864', (408, 412))	('Single-nucleotide polymorphism', 'Var', (505, 535))	('TDO', 'Gene', '6999', (565, 568))	('Small cell lung cancer', 'Phenotype', 'HP:0030357', (478, 500))	('Non-small cell lung cancer', 'Phenotype', 'HP:0030358', (413, 439))	('cancer', 'Phenotype', 'HP:0002664', (433, 439))	('Cancer', 'Phenotype', 'HP:0002664', (545, 551))	('Mammalian', 'Species', '9606', (76, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (312, 321))	('LUAD', 'Phenotype', 'HP:0030078', (297, 301))	('NSCLC', 'Disease', (407, 412))	('Lung adenocarcinoma', 'Phenotype', 'HP:0030078', (302, 321))	('lung cancer', 'Phenotype', 'HP:0100526', (489, 500))
104443	26373952	Although many molecular genetic studies have implicated certain genetic mutations in non-small cell lung cancer (NSCLC), including mutations in the EGFR, PIK3CA, BRAF, KRAS, and ALK genes, only a few studies have focused on the genetic events associated with salivary gland-type lung carcinomas.	('NSCLC', 'Phenotype', 'HP:0030358', (113, 118))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('ALK', 'Gene', '238', (178, 181))	('mutations', 'Var', (72, 81))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (85, 111))	('PIK3CA', 'Gene', (154, 160))	('EGFR', 'Gene', '1956', (148, 152))	('ALK', 'Gene', (178, 181))	('carcinoma', 'Phenotype', 'HP:0030731', (284, 293))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (89, 111))	('KRAS', 'Gene', '3845', (168, 172))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (85, 111))	('salivary gland-type lung carcinomas', 'Disease', 'MESH:D012468', (259, 294))	('carcinomas', 'Phenotype', 'HP:0030731', (284, 294))	('BRAF', 'Gene', '673', (162, 166))	('KRAS', 'Gene', (168, 172))	('NSCLC', 'Disease', 'MESH:D002289', (113, 118))	('BRAF', 'Gene', (162, 166))	('mutations', 'Var', (131, 140))	('salivary gland-type lung carcinomas', 'Disease', (259, 294))	('EGFR', 'Gene', (148, 152))	('lung cancer', 'Phenotype', 'HP:0100526', (100, 111))	('PIK3CA', 'Gene', '5290', (154, 160))	('non-small cell lung cancer', 'Disease', (85, 111))	('NSCLC', 'Disease', (113, 118))
104445	26373952	Gene alterations in KIT, EGFR, BRAF, HRAS, KRAS, NRAS, PIK3CA, PDGFRA, and PTEN have been reported in adenoid cystic carcinoma (ACC), but the results are inconsistent among different studies.	('PDGFRA', 'Gene', (63, 69))	('PDGFRA', 'Gene', '5156', (63, 69))	('adenoid cystic carcinoma', 'Disease', (102, 126))	('HRAS', 'Gene', '3265', (37, 41))	('alterations', 'Var', (5, 16))	('NRAS', 'Gene', (49, 53))	('KRAS', 'Gene', '3845', (43, 47))	('KIT', 'Gene', (20, 23))	('HRAS', 'Gene', (37, 41))	('EGFR', 'Gene', (25, 29))	('reported', 'Reg', (90, 98))	('KRAS', 'Gene', (43, 47))	('PTEN', 'Gene', (75, 79))	('BRAF', 'Gene', '673', (31, 35))	('PIK3CA', 'Gene', '5290', (55, 61))	('BRAF', 'Gene', (31, 35))	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('PTEN', 'Gene', '5728', (75, 79))	('EGFR', 'Gene', '1956', (25, 29))	('adenoid cystic carcinoma', 'Disease', 'MESH:D003528', (102, 126))	('NRAS', 'Gene', '4893', (49, 53))	('PIK3CA', 'Gene', (55, 61))
104454	26373952	Libraries were prepared using the Ion AmpliSeq Library Kit 2.0 (Life Technologies, USA) and the Lung Cancer Mutation Panel (ACCB Biotech, China), which is designed to detect mutations within 16 exons of seven lung cancer driver genes (EGFR, KRAS, BRAF, ALK, PIK3CA, PDGFRA, and DDR2) (Table 1).	('ALK', 'Gene', (253, 256))	('lung cancer', 'Phenotype', 'HP:0100526', (209, 220))	('PIK3CA', 'Gene', (258, 264))	('DDR2', 'Gene', '4921', (278, 282))	('KRAS', 'Gene', '3845', (241, 245))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('EGFR', 'Gene', '1956', (235, 239))	('PDGFRA', 'Gene', (266, 272))	('mutations', 'Var', (174, 183))	('PDGFRA', 'Gene', '5156', (266, 272))	('Lung Cancer', 'Disease', (96, 107))	('DDR2', 'Gene', (278, 282))	('KRAS', 'Gene', (241, 245))	('lung cancer', 'Disease', (209, 220))	('PIK3CA', 'Gene', '5290', (258, 264))	('BRAF', 'Gene', '673', (247, 251))	('Lung Cancer', 'Disease', 'MESH:D008175', (96, 107))	('BRAF', 'Gene', (247, 251))	('ALK', 'Gene', '238', (253, 256))	('EGFR', 'Gene', (235, 239))	('lung cancer', 'Disease', 'MESH:D008175', (209, 220))	('Lung Cancer', 'Phenotype', 'HP:0100526', (96, 107))	('Cancer', 'Phenotype', 'HP:0002664', (101, 107))
104458	26373952	Mutations within 16 exons of the seven lung cancer driver genes were also screened by PCR-based bidirectional direct Sanger sequencing using primers.	('lung cancer', 'Phenotype', 'HP:0100526', (39, 50))	('lung cancer', 'Disease', (39, 50))	('lung cancer', 'Disease', 'MESH:D008175', (39, 50))	('Mutations', 'Var', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
104470	26373952	Recently, important advances have been made in ACC; a signature t(6;9)(q22-23; p23-24) chromosomal translocation resulting in a MYB-NFIB fusion gene was identified, and the fusion oncoprotein activates the transcription of MYB targets that are important for oncogenic transformation.	('q22-23', 'Var', (71, 77))	('NFIB', 'Gene', (132, 136))	('MYB', 'Gene', (128, 131))	('MYB', 'Gene', (223, 226))	('NFIB', 'Gene', '4781', (132, 136))	('transcription', 'MPA', (206, 219))	('activates', 'PosReg', (192, 201))	('MYB', 'Gene', '4602', (128, 131))	('MYB', 'Gene', '4602', (223, 226))
104473	26373952	Genetic alterations associated with the development of NSCLC have been extensively characterized.	('Genetic alterations', 'Var', (0, 19))	('NSCLC', 'Disease', (55, 60))	('NSCLC', 'Disease', 'MESH:D002289', (55, 60))	('men', 'Species', '9606', (47, 50))	('NSCLC', 'Phenotype', 'HP:0030358', (55, 60))
104475	26373952	Activating mutations in EGFR identify those NSCLC patients with an improved clinical response to tyrosine kinase inhibitor (TKI) therapy, but it remains unknown whether patients with PACC harbour EGFR mutations and can thus benefit from TKI therapy.	('tyrosine kinase', 'Gene', (97, 112))	('EGFR', 'Gene', (196, 200))	('mutations', 'Var', (11, 20))	('NSCLC', 'Disease', 'MESH:D002289', (44, 49))	('patients', 'Species', '9606', (169, 177))	('EGFR', 'Gene', '1956', (24, 28))	('patients', 'Species', '9606', (50, 58))	('EGFR', 'Gene', (24, 28))	('tyrosine kinase', 'Gene', '7294', (97, 112))	('EGFR', 'Gene', '1956', (196, 200))	('NSCLC', 'Phenotype', 'HP:0030358', (44, 49))	('benefit', 'Reg', (224, 231))	('NSCLC', 'Disease', (44, 49))
104476	26373952	EGFR mutations have been reported in pulmonary and salivary mucoepidermoid carcinoma, but they are rare in ACC of the salivary gland, and no EGFR mutations were detected in PACC in a previous study.	('reported', 'Reg', (25, 33))	('EGFR', 'Gene', (0, 4))	('pulmonary', 'Disease', (37, 46))	('EGFR', 'Gene', '1956', (141, 145))	('salivary mucoepidermoid carcinoma', 'Disease', 'MESH:D018277', (51, 84))	('mutations', 'Var', (5, 14))	('EGFR', 'Gene', (141, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('EGFR', 'Gene', '1956', (0, 4))	('salivary mucoepidermoid carcinoma', 'Disease', (51, 84))
104478	26373952	A few studies have identified alterations in KRAS in ACC, and KRAS alterations were reported to be more common than other gene alterations, with the exception of MYB, in a recent study; however, KRAS mutations were absent in other studies that involved whole exome sequencing of ACC and next-generation sequencing.	('KRAS', 'Gene', '3845', (45, 49))	('KRAS', 'Gene', (62, 66))	('MYB', 'Gene', '4602', (162, 165))	('KRAS', 'Gene', '3845', (62, 66))	('MYB', 'Gene', (162, 165))	('alterations', 'Var', (30, 41))	('KRAS', 'Gene', (195, 199))	('KRAS', 'Gene', (45, 49))	('KRAS', 'Gene', '3845', (195, 199))
104480	26373952	Genetic alterations in PIK3CA and BRAF have been detected in ACC at a lower frequency than KRAS, and a study suggested that the PI3K/AKT pathway may be responsible for the unusually aggressive course of ACC.	('Genetic alterations', 'Var', (0, 19))	('PIK3CA', 'Gene', (23, 29))	('KRAS', 'Gene', '3845', (91, 95))	('AKT', 'Gene', '207', (133, 136))	('KRAS', 'Gene', (91, 95))	('PIK3CA', 'Gene', '5290', (23, 29))	('BRAF', 'Gene', '673', (34, 38))	('AKT', 'Gene', (133, 136))	('BRAF', 'Gene', (34, 38))	('ACC', 'Disease', (203, 206))
104482	26373952	ALK gene alterations mainly occur in lung adenocarcinoma and are associated with gene rearrangements.	('occur', 'Reg', (28, 33))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (37, 56))	('alterations', 'Var', (9, 20))	('carcinoma', 'Phenotype', 'HP:0030731', (47, 56))	('lung adenocarcinoma', 'Disease', (37, 56))	('ALK', 'Gene', (0, 3))	('men', 'Species', '9606', (95, 98))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (37, 56))	('ALK', 'Gene', '238', (0, 3))
104483	26373952	ALK inhibitors exhibit marked anti-tumour activity against lung cancers with ALK rearrangements.	('rearrangements', 'Var', (81, 95))	('lung cancers', 'Disease', (59, 71))	('ALK', 'Gene', (77, 80))	('men', 'Species', '9606', (90, 93))	('ALK', 'Gene', '238', (0, 3))	('cancers', 'Phenotype', 'HP:0002664', (64, 71))	('tumour', 'Phenotype', 'HP:0002664', (35, 41))	('ALK', 'Gene', '238', (77, 80))	('lung cancer', 'Phenotype', 'HP:0100526', (59, 70))	('ALK', 'Gene', (0, 3))	('tumour', 'Disease', 'MESH:D009369', (35, 41))	('lung cancers', 'Disease', 'MESH:D008175', (59, 71))	('lung cancers', 'Phenotype', 'HP:0100526', (59, 71))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('tumour', 'Disease', (35, 41))
104484	26373952	However, emerging genomic data are revealing common ALK point mutations in various cancer types other than lung cancer, and several recent studies have demonstrated that ALK point mutations, independent of ALK gene rearrangements, can be oncogenic.	('cancer', 'Disease', (112, 118))	('lung cancer', 'Disease', 'MESH:D008175', (107, 118))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('lung cancer', 'Phenotype', 'HP:0100526', (107, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('men', 'Species', '9606', (224, 227))	('ALK', 'Gene', '238', (52, 55))	('ALK', 'Gene', '238', (170, 173))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('ALK', 'Gene', (52, 55))	('ALK', 'Gene', (170, 173))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('oncogenic', 'CPA', (238, 247))	('lung cancer', 'Disease', (107, 118))	('ALK', 'Gene', '238', (206, 209))	('point mutations', 'Var', (174, 189))	('ALK', 'Gene', (206, 209))	('point mutations', 'Var', (56, 71))	('cancer', 'Disease', (83, 89))
104485	26373952	Genetic alterations of DDR2 and PDGFRA are associated with the development of LSCC.	('Genetic alterations', 'Var', (0, 19))	('LSCC', 'Disease', (78, 82))	('associated with', 'Reg', (43, 58))	('DDR2', 'Gene', '4921', (23, 27))	('LSCC', 'Phenotype', 'HP:0030359', (78, 82))	('men', 'Species', '9606', (70, 73))	('DDR2', 'Gene', (23, 27))	('PDGFRA', 'Gene', (32, 38))	('PDGFRA', 'Gene', '5156', (32, 38))
104486	26373952	Recently, DDR2 mutations were reported in approximately 4 % of LSCC cases, and some of these mutations induced oncogenic transformation.	('reported', 'Reg', (30, 38))	('mutations', 'Var', (93, 102))	('mutations', 'Var', (15, 24))	('DDR2', 'Gene', '4921', (10, 14))	('LSCC', 'Disease', (63, 67))	('oncogenic transformation', 'CPA', (111, 135))	('LSCC', 'Phenotype', 'HP:0030359', (63, 67))	('induced', 'Reg', (103, 110))	('DDR2', 'Gene', (10, 14))
104487	26373952	DDR2 mutations are associated with increased sensitivity to dasatinib, and the clinical activity of dasatinib in lung cancer is being evaluated in numerous clinical trials.	('increased', 'PosReg', (35, 44))	('lung cancer', 'Disease', (113, 124))	('dasatinib', 'Chemical', 'MESH:D000069439', (60, 69))	('lung cancer', 'Phenotype', 'HP:0100526', (113, 124))	('DDR2', 'Gene', '4921', (0, 4))	('mutations', 'Var', (5, 14))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('dasatinib', 'Chemical', 'MESH:D000069439', (100, 109))	('sensitivity to dasatinib', 'MPA', (45, 69))	('lung cancer', 'Disease', 'MESH:D008175', (113, 124))	('DDR2', 'Gene', (0, 4))
104570	33336030	Clinical significance and potential mechanisms of miR-223-3p and miR-204-5p in squamous cell carcinoma of head and neck: a study based on TCGA and GEO To explore the clinical significance and mechanisms of altered miRNAs in squamous cell carcinoma of head and neck (SCCHN) and provide references for SCCHN diagnosis and prognosis.	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (79, 102))	('carcinoma of head and neck', 'Phenotype', 'HP:0012288', (238, 264))	('squamous cell carcinoma of head', 'Disease', (79, 110))	('squamous cell carcinoma of head', 'Disease', (224, 255))	('carcinoma', 'Phenotype', 'HP:0030731', (238, 247))	('carcinoma of head and neck', 'Phenotype', 'HP:0012288', (93, 119))	('squamous cell carcinoma of head', 'Disease', 'MESH:D002294', (79, 110))	('squamous cell carcinoma of head', 'Disease', 'MESH:D002294', (224, 255))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (224, 247))	('miR-204-5p', 'Var', (65, 75))
104573	33336030	Epithelial-mesenchymal transition (EMT) related biological process and energy metabolism controlling related AMPK signaling pathway might mediate the roles of miR-223-3p and miR-204-5p, respectively.	('miR-223', 'Gene', '407008', (159, 166))	('AMPK', 'Gene', '5562', (109, 113))	('AMPK', 'Gene', (109, 113))	('Epithelial-mesenchymal transition', 'CPA', (0, 33))	('miR-223', 'Gene', (159, 166))	('miR-204-5p', 'Chemical', '-', (174, 184))	('miR-204-5p', 'Var', (174, 184))
104574	33336030	With diagnostic and prognostic values, miR-223-3p and miR-204-5p may be involved in the progression of SCCHN through EMT-related biological process and energy balance related AMPK signaling pathway, respectively.	('SCCHN', 'Disease', (103, 108))	('AMPK', 'Gene', '5562', (175, 179))	('miR-223', 'Gene', '407008', (39, 46))	('AMPK', 'Gene', (175, 179))	('miR-204-5p', 'Chemical', '-', (54, 64))	('miR-204-5p', 'Var', (54, 64))	('involved', 'Reg', (72, 80))	('miR-223', 'Gene', (39, 46))
104579	33336030	Moreover, the abnormally expressed miRNAs influence the cellular resistance against the radiotherapy or chemotherapy through PI3K-Akt signaling pathway, miR-936/GPR78 or miR-372-ZBTB7A-TRAIL-R2 pathway in SCCHN.	('miR-936', 'Gene', (153, 160))	('miR-372', 'Gene', '442917', (170, 177))	('ZBTB7A', 'Gene', (178, 184))	('ZBTB7A', 'Gene', '51341', (178, 184))	('Akt', 'Gene', '207', (130, 133))	('TRAIL-R2', 'Gene', (185, 193))	('abnormally expressed', 'Var', (14, 34))	('influence', 'Reg', (42, 51))	('miRNAs', 'Protein', (35, 41))	('GPR78', 'Gene', (161, 166))	('SCCHN', 'Disease', (205, 210))	('Akt', 'Gene', (130, 133))	('GPR78', 'Gene', '27201', (161, 166))	('miR-936', 'Gene', '100126326', (153, 160))	('miR-372', 'Gene', (170, 177))	('TRAIL-R2', 'Gene', '8795', (185, 193))
104584	33336030	Further detailed analyses indicated that miR-223-3p and miR-204-5p, with potential diagnostic and prognostic values, might involve in the occurrence and development of SCCHN through the mediation of EMT-related biological process and energy metabolism controlling related AMPK signaling pathway.	('SCCHN', 'Disease', (168, 173))	('miR-223', 'Gene', (41, 48))	('mediation', 'Reg', (186, 195))	('involve', 'Reg', (123, 130))	('AMPK', 'Gene', '5562', (272, 276))	('miR-223', 'Gene', '407008', (41, 48))	('miR-204-5p', 'Chemical', '-', (56, 66))	('AMPK', 'Gene', (272, 276))	('miR-204-5p', 'Var', (56, 66))
104591	33336030	For verification, the miRNA expression levels of GSE124566 in SCCHN, a different miRNA expression profile, were acquired from TCGA, which consists of 524 cancerous tissues and 45 normal tissues of SCCHN and includes 2,242 miRNAs (Query strategy: Project Id IS TCGA-HNSC AND Access IS open AND Data Category IN (clinical transcriptome profiling) AND Data Format IS txt AND Data Type IS miRNA Expression Quantification).	('cancerous', 'Disease', (154, 163))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('cancerous', 'Disease', 'MESH:D009369', (154, 163))	('GSE124566', 'Var', (49, 58))
104593	33336030	Nevertheless, miR-142-5p, miR-23b-5p, and miR-4647 showed no significant difference in the expression trend between cancerous and normal tissues.	('cancerous', 'Disease', 'MESH:D009369', (116, 125))	('-5p', 'Chemical', '-', (21, 24))	('miR-4647', 'Gene', (42, 50))	('miR-142-5p', 'Var', (14, 24))	('miR-23b-5p', 'Var', (26, 36))	('cancerous', 'Disease', (116, 125))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('-5p', 'Chemical', '-', (33, 36))	('miR-4647', 'Gene', '100616124', (42, 50))
104594	33336030	Even miR-513c-5p and miR-3654 showed an opposite expression tendency to GSE124566.	('miR-513c-5p', 'Var', (5, 16))	('miR-3654', 'Gene', (21, 29))	('miR-3654', 'Gene', '100500804', (21, 29))
104595	33336030	However, merely miR-223-3p and miR-142-3p showed significant differences with lower p-values (p < 0.05) (Figure 4).	('miR-142-3p', 'Var', (31, 41))	('miR-223', 'Gene', '407008', (16, 23))	('miR-142-3p', 'Chemical', '-', (31, 41))	('miR-223', 'Gene', (16, 23))	('p-values', 'MPA', (84, 92))	('lower', 'NegReg', (78, 83))
104596	33336030	Inconsistently, for an overexpressed miR-142-3p in cancerous tissues, it seems to present that patients with high expression levels of miR-142-3p may have a long survival period.	('miR-142-3p', 'Var', (135, 145))	('patients', 'Species', '9606', (95, 103))	('miR-142-3p', 'Chemical', '-', (135, 145))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('miR-142-3p', 'Chemical', '-', (37, 47))	('cancerous', 'Disease', 'MESH:D009369', (51, 60))	('expression', 'MPA', (114, 124))	('cancerous', 'Disease', (51, 60))
104598	33336030	Through a receiver operating characteristic (ROC) curve analyzing the diagnostic values of 12 validated DEMs, the results presented that five out of 12 miRNAs may have potential diagnostic values with high area under ROC curves (AUC) (AUC >= 0.85, p < 0.05), including miR-503-5p, miR-424-5p, miR-21-5p, miR-204-5p, and miR-375-3p (Figure 5).	('miR-21-5p', 'Var', (293, 302))	('miR-503-5p', 'Var', (269, 279))	('miR-375-3p', 'Var', (320, 330))	('miR-424-5p', 'Var', (281, 291))	('miR-204-5p', 'Chemical', '-', (304, 314))	('-375-3p', 'Chemical', '-', (323, 330))	('miR-204-5p', 'Var', (304, 314))	('miR-503-5p', 'Chemical', '-', (269, 279))
104599	33336030	For exploring the associations between the miRNA expression levels and clinical features, the expression levels of miRNAs (miR-223-3p, miR-503-5p, miR-424-5p, miR-21-5p, miR-204-5p, and miR-375-3p) in different groups with distinct clinical features were compared and analyzed.	('miR-21-5p', 'Var', (159, 168))	('miR-223', 'Gene', (123, 130))	('miR-503-5p', 'Var', (135, 145))	('miR-204-5p', 'Chemical', '-', (170, 180))	('-375-3p', 'Chemical', '-', (189, 196))	('miR-223', 'Gene', '407008', (123, 130))	('miR-503-5p', 'Chemical', '-', (135, 145))	('miR-424-5p', 'Var', (147, 157))
104604	33336030	Followed, the target mRNAs of miR-223-3p and miR-204-5p were predicted by TargetScanHuman 7.2, miRDB, and miRWalk separately.	('miR-204-5p', 'Chemical', '-', (45, 55))	('miR-223', 'Gene', '407008', (30, 37))	('miR-223', 'Gene', (30, 37))	('miR-204-5p', 'Var', (45, 55))
104606	33336030	Afterwards, functional enrichment analyses of intersection mRNAs showed that miR-223-3p or miR-204-5p may be involved in multiple biological processes, molecular functions, and signaling pathways, respectively.	('miR-204-5p', 'Chemical', '-', (91, 101))	('miR-223', 'Gene', '407008', (77, 84))	('miR-204-5p', 'Var', (91, 101))	('miR-223', 'Gene', (77, 84))	('involved', 'Reg', (109, 117))
104607	33336030	Analyses illustrated that miR-223-3p may participate in multiple biological processes (GO: 0001837 ~ epithelial-to-mesenchymal transition and GO: 0030177 ~ positive regulation of Wnt signaling pathway) and molecular functions (GO: 0046322 ~ SMAD binding and GO: 0008134 ~ transcription factor binding), which indicated that miR-223-3p may be involved in the regulation of EMT.	('Wnt signaling pathway', 'Pathway', (179, 200))	('miR-223', 'Gene', '407008', (26, 33))	('epithelial-to-mesenchymal transition', 'CPA', (101, 137))	('miR-223', 'Gene', (324, 331))	('binding', 'Interaction', (293, 300))	('GO: 0046322 ~', 'Var', (227, 240))	('miR-223', 'Gene', (26, 33))	('GO: 0001837 ~', 'Var', (87, 100))	('participate', 'Reg', (41, 52))	('GO: 0030177 ~', 'Var', (142, 155))	('miR-223', 'Gene', '407008', (324, 331))	('GO: 0008134 ~', 'Var', (258, 271))
104608	33336030	Analyses also illustrated that miR-223-3p and miR-204-5p may be involved in the process of energy anabolism and catabolism mediated by the same signaling pathway (hsa04152: AMPK signaling pathway).	('energy anabolism', 'MPA', (91, 107))	('involved', 'Reg', (64, 72))	('AMPK', 'Gene', '5562', (173, 177))	('miR-204-5p', 'Chemical', '-', (46, 56))	('miR-223', 'Gene', (31, 38))	('AMPK', 'Gene', (173, 177))	('miR-204-5p', 'Var', (46, 56))	('catabolism', 'MPA', (112, 122))	('miR-223', 'Gene', '407008', (31, 38))
104612	33336030	Of the 18 miRNAs, 12 miRNA expression trends were verified by TCGA, including the downregulated miR-204-5p in cancerous tissues, a proved tumor suppressor by the original research study.	('miR-204-5p', 'Var', (96, 106))	('downregulated', 'NegReg', (82, 95))	('tumor', 'Disease', (138, 143))	('cancerous', 'Disease', (110, 119))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('cancerous', 'Disease', 'MESH:D009369', (110, 119))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('miR-204-5p', 'Chemical', '-', (96, 106))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
104614	33336030	In addition, the survival analyses also suggested that the patients with high expression levels of miR-142-3p presented significantly long survival times.	('survival times', 'CPA', (139, 153))	('long', 'PosReg', (134, 138))	('miR-142-3p', 'Var', (99, 109))	('patients', 'Species', '9606', (59, 67))	('miR-142-3p', 'Chemical', '-', (99, 109))	('high expression levels', 'Var', (73, 95))
104615	33336030	This phenomenon seems to embody a protective effect of miR-142-3p on SCCHN patients, but this effect is contrary to the overexpression of miR-142-3p in cancerous tissues.	('cancerous', 'Disease', (152, 161))	('miR-142-3p', 'Var', (55, 65))	('miR-142-3p', 'Chemical', '-', (55, 65))	('miR-142-3p', 'Chemical', '-', (138, 148))	('SCCHN', 'Disease', (69, 74))	('cancerous', 'Disease', 'MESH:D009369', (152, 161))	('patients', 'Species', '9606', (75, 83))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))
104616	33336030	This result needs a thorough study to explore the definite role of miR-142-3p in SCCHN.	('miR-142-3p', 'Var', (67, 77))	('SCCHN', 'Disease', (81, 86))	('miR-142-3p', 'Chemical', '-', (67, 77))
104618	33336030	In view of this, the present study distinguished five miRNAs with possible diagnostic values, which consisted of miR-503-5p, miR-424-5p, miR-21-5p, miR-204-5p, and miR-375-3p.	('-375-3p', 'Chemical', '-', (167, 174))	('miR-375-3p', 'Var', (164, 174))	('miR-204-5p', 'Chemical', '-', (148, 158))	('miR-204-5p', 'Var', (148, 158))	('miR-503-5p', 'Chemical', '-', (113, 123))	('miR-21-5p', 'Var', (137, 146))	('miR-503-5p', 'Var', (113, 123))	('miR-424-5p', 'Var', (125, 135))
104620	33336030	Of the above-mentioned six miRNAs with prognostic or diagnostic values, miR-223-3p and miR-204-5p presented significant distinct expression levels in different clinical stages or tissue differentiation, respectively.	('miR-204-5p', 'Chemical', '-', (87, 97))	('miR-204-5p', 'Var', (87, 97))	('miR-223', 'Gene', (72, 79))	('miR-223', 'Gene', '407008', (72, 79))	('expression levels', 'MPA', (129, 146))
104621	33336030	Notably, for miR-204-5p, the original study indicated that the patients with high expression levels of miR-204-5p showed higher clinical stages and positive neck lymph node metastasis.	('expression', 'MPA', (82, 92))	('high', 'Var', (77, 81))	('miR-204-5p', 'Chemical', '-', (13, 23))	('patients', 'Species', '9606', (63, 71))	('miR-204-5p', 'Chemical', '-', (103, 113))	('higher', 'PosReg', (121, 127))	('clinical stages', 'CPA', (128, 143))	('miR-204-5p', 'Var', (103, 113))
104624	33336030	However, the prognostic value of miR-204-5p and its correlation with clinical features suggested that miR-204-5p may be an effective tumor marker or target for diagnostic and prognostic evaluation or therapy, which has been elaborated and confirmed in the original research study.	('miR-204-5p', 'Chemical', '-', (33, 43))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('miR-204-5p', 'Chemical', '-', (102, 112))	('miR-204-5p', 'Var', (102, 112))	('tumor', 'Disease', (133, 138))
104625	33336030	The present analyses also indicated that the miR-503-5p expression levels were related to smoking history, an agreed risk factor for the occurrence and development of SCCHN.	('miR-503-5p expression', 'Var', (45, 66))	('SCCHN', 'Disease', (167, 172))	('smoking', 'Disease', (90, 97))	('miR-503-5p', 'Chemical', '-', (45, 55))	('related', 'Reg', (79, 86))
104626	33336030	This finding suggested that miR-503-5p may play an unknown role in the effect of tobacco on SCCHN.	('miR-503-5p', 'Var', (28, 38))	('SCCHN', 'Disease', (92, 97))	('tobacco', 'Species', '4097', (81, 88))	('miR-503-5p', 'Chemical', '-', (28, 38))
104627	33336030	In general, miRNAs exert diverse regulatory roles through target differential mRNAs, same for miR-223-3p and miR-204-5p.	('miR-204-5p', 'Chemical', '-', (109, 119))	('miR-223', 'Gene', (94, 101))	('miR-204-5p', 'Var', (109, 119))	('mRNAs', 'MPA', (78, 83))	('miR-223', 'Gene', '407008', (94, 101))
104628	33336030	Considering the potential clinical significance of miR-223-3p and miR-204-5p, it is necessary and worthy to define the possible targets for providing reference for the followed study.	('miR-223', 'Gene', '407008', (51, 58))	('miR-204-5p', 'Var', (66, 76))	('miR-223', 'Gene', (51, 58))	('miR-204-5p', 'Chemical', '-', (66, 76))
104629	33336030	Therefore, TargetScanHuman 7.2, miRDB, and miRWalk jointly predicted the targets of miR-223-3p and miR-204-5p, respectively.	('miR-223', 'Gene', '407008', (84, 91))	('miR-204-5p', 'Chemical', '-', (99, 109))	('miR-204-5p', 'Var', (99, 109))	('miRWalk jointly', 'Disease', 'None', (43, 58))	('miR-223', 'Gene', (84, 91))	('miRWalk jointly', 'Disease', (43, 58))
104632	33336030	Analyses also suggested that miR-223-3p and miR-204-5p may affect the energy balance of SCCHN through AMPK signaling pathway, a proved regulatory signaling pathway for the energy metabolism of tumors.	('affect', 'Reg', (59, 65))	('miR-223', 'Gene', '407008', (29, 36))	('miR-204-5p', 'Chemical', '-', (44, 54))	('SCCHN', 'Disease', (88, 93))	('AMPK', 'Gene', '5562', (102, 106))	('AMPK', 'Gene', (102, 106))	('miR-204-5p', 'Var', (44, 54))	('tumors', 'Phenotype', 'HP:0002664', (193, 199))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('tumors', 'Disease', (193, 199))	('tumors', 'Disease', 'MESH:D009369', (193, 199))	('miR-223', 'Gene', (29, 36))	('energy balance', 'MPA', (70, 84))
104634	33336030	The present study screened out the altered 18 miRNAs in SCCHN through a series of analyses and identified the six miRNAs (miR-223-3p, miR-503-5p, miR-424-5p, miR-21-5p, miR-204-5p, and miR-375-3p) with significant prognostic or diagnostic values.	('miR-223', 'Gene', (122, 129))	('miR-375-3p', 'Var', (185, 195))	('miR-204-5p', 'Chemical', '-', (169, 179))	('miR-204-5p', 'Var', (169, 179))	('miR-424-5p', 'Var', (146, 156))	('miR-503-5p', 'Chemical', '-', (134, 144))	('miR-21-5p', 'Var', (158, 167))	('miR-223', 'Gene', '407008', (122, 129))	('miR-503-5p', 'Var', (134, 144))	('-375-3p', 'Chemical', '-', (188, 195))
104636	33336030	Meanwhile, miR-223-3p and miR-204-5p may also involve in the regulation of cancer energy metabolism through AMPK signaling pathway.	('AMPK', 'Gene', '5562', (108, 112))	('involve', 'Reg', (46, 53))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('miR-223', 'Gene', (11, 18))	('cancer', 'Disease', (75, 81))	('regulation', 'MPA', (61, 71))	('miR-204-5p', 'Chemical', '-', (26, 36))	('miR-204-5p', 'Var', (26, 36))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('miR-223', 'Gene', '407008', (11, 18))	('AMPK', 'Gene', (108, 112))
104652	33243967	Previously, through in vitro assays, we found that Apatinib can induce apoptosis and cell cycle arrest in esophageal cancer cells Kyse-150; moreover, Apatinib increased the radiosensitivity of these cells and showed a synergistic effect when combined with X-ray radiation.	('arrest', 'Disease', 'MESH:D006323', (96, 102))	('esophageal cancer', 'Disease', 'MESH:D004938', (106, 123))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('apoptosis', 'CPA', (71, 80))	('arrest', 'Disease', (96, 102))	('Apatinib', 'Chemical', 'MESH:C553458', (150, 158))	('radiosensitivity', 'CPA', (173, 189))	('increased', 'PosReg', (159, 168))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (85, 102))	('Apatinib', 'Chemical', 'MESH:C553458', (51, 59))	('Apatinib', 'Var', (150, 158))	('esophageal cancer', 'Disease', (106, 123))
104688	33243967	The RTOG85-01 trial showed that in patients with T1-3N0-1M0 esophageal cancer, the 5-year survival rate of cisplatin/5-fluorouracil chemotherapy plus 50.4 Gy radiotherapy was significantly higher than 64 Gy radiotherapy alone.	('cisplatin', 'Chemical', 'MESH:D002945', (107, 116))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (117, 131))	('esophageal cancer', 'Disease', (60, 77))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('higher', 'PosReg', (189, 195))	('patients', 'Species', '9606', (35, 43))	('esophageal cancer', 'Disease', 'MESH:D004938', (60, 77))	('T1-3N0-1M0', 'Var', (49, 59))
104694	33243967	Studies have shown that patients with esophageal cancer with a high expression of VEGF had 1.82 times higher risk of death, indicating that anti-VEGF therapy may improve the efficacy and prognosis of esophageal cancer.	('esophageal cancer', 'Disease', (38, 55))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('VEGF', 'Gene', (145, 149))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('esophageal cancer', 'Disease', 'MESH:D004938', (38, 55))	('patients', 'Species', '9606', (24, 32))	('VEGF', 'Gene', (82, 86))	('esophageal cancer', 'Disease', (200, 217))	('high expression', 'Var', (63, 78))	('death', 'Disease', (117, 122))	('improve', 'PosReg', (162, 169))	('VEGF', 'Gene', '7422', (145, 149))	('esophageal cancer', 'Disease', 'MESH:D004938', (200, 217))	('death', 'Disease', 'MESH:D003643', (117, 122))	('VEGF', 'Gene', '7422', (82, 86))
104733	31131258	Since then, multiple studies have reported dysregulation of beta-defensins in cancers from diverse anatomical locations within the human body; e.g., oral cavity, esophagus, skin, kidney, prostate, thyroid, liver, lung, colon, vulva, and cervix (Table 1).	('colon', 'Disease', (219, 224))	('cancers', 'Disease', 'MESH:D009369', (78, 85))	('liver', 'Disease', (206, 211))	('beta-defensins', 'Protein', (60, 74))	('dysregulation', 'Var', (43, 56))	('vulva', 'Disease', (226, 231))	('thyroid', 'Disease', (197, 204))	('prostate', 'Disease', (187, 195))	('lung', 'Disease', (213, 217))	('skin', 'Disease', (173, 177))	('oral cavity', 'Disease', (149, 160))	('cancers', 'Phenotype', 'HP:0002664', (78, 85))	('cancers', 'Disease', (78, 85))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('cervix', 'Disease', (237, 243))	('esophagus', 'Disease', (162, 171))	('human', 'Species', '9606', (131, 136))	('kidney', 'Disease', (179, 185))	('colon', 'Disease', 'MESH:D015179', (219, 224))
104805	31131258	Therefore, as we concluded for hBD-1 and-2, dysregulation of hBD-3 in cancer tissue appears to be associated with the type of cancer being studied and its location.	('hBD-3', 'Gene', (61, 66))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('dysregulation', 'Var', (44, 57))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('hBD-1 and-2', 'Gene', (31, 42))	('hBD-1 and-2', 'Gene', '1672;1673', (31, 42))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('associated', 'Reg', (98, 108))	('hBD-3', 'Gene', '55894', (61, 66))
104813	31131258	Induction of hBD-1 by ectopic expression of DEFB1 cDNA in prostate cancer cell lines PC3 and DU145 also resulted in decreased cell growth and viability.	('prostate cancer', 'Disease', 'MESH:D011471', (58, 73))	('hBD-1', 'Gene', (13, 18))	('PC3', 'CellLine', 'CVCL:0035', (85, 88))	('prostate cancer', 'Phenotype', 'HP:0012125', (58, 73))	('DEFB1', 'Gene', '1672', (44, 49))	('ectopic expression', 'Var', (22, 40))	('hBD-1', 'Gene', '1672', (13, 18))	('prostate cancer', 'Disease', (58, 73))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('DEFB1', 'Gene', (44, 49))	('DU145', 'CellLine', 'CVCL:0105', (93, 98))	('cell growth', 'CPA', (126, 137))	('decreased', 'NegReg', (116, 125))
104819	31131258	Increased expression of hBD-2 generated by gene transfection inhibits the proliferation and invasion of the OSCC cell line (SAS), possibly via G1/S arrest and pRB gene expression, indicating that hBD-2 may act as a tumor suppressor.	('gene transfection', 'Var', (43, 60))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('S arrest', 'Disease', 'MESH:D006323', (146, 154))	('hBD-2', 'Gene', (24, 29))	('expression', 'MPA', (10, 20))	('hBD-2', 'Gene', '1673', (24, 29))	('inhibits', 'NegReg', (61, 69))	('SCC', 'Phenotype', 'HP:0002860', (109, 112))	('Increased', 'PosReg', (0, 9))	('proliferation', 'CPA', (74, 87))	('tumor', 'Disease', (215, 220))	('pRB', 'Gene', '5925', (159, 162))	('SCC', 'Gene', '6317', (109, 112))	('hBD-2', 'Gene', (196, 201))	('tumor', 'Disease', 'MESH:D009369', (215, 220))	('pRB', 'Gene', (159, 162))	('S arrest', 'Disease', (146, 154))	('hBD-2', 'Gene', '1673', (196, 201))	('SCC', 'Gene', (109, 112))
104822	31131258	Thus, in cancers where hBD-2 under-expression has been reported, it inhibits migration and proliferation of cell lines emanating from those cancers, while in cancers where it is overexpressed it promotes respective cancer cell growth.	('cancer', 'Disease', (9, 15))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('cancers', 'Phenotype', 'HP:0002664', (9, 16))	('cancer', 'Disease', (215, 221))	('cancers', 'Disease', (9, 16))	('cancers', 'Phenotype', 'HP:0002664', (158, 165))	('promotes', 'PosReg', (195, 203))	('cancer', 'Disease', (158, 164))	('cancers', 'Disease', (158, 165))	('hBD-2', 'Gene', (23, 28))	('cancers', 'Disease', 'MESH:D009369', (140, 147))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('inhibits', 'NegReg', (68, 76))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('hBD-2', 'Gene', '1673', (23, 28))	('cancer', 'Disease', (140, 146))	('under-expression', 'Var', (29, 45))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('cancers', 'Disease', 'MESH:D009369', (9, 16))	('cancer', 'Disease', 'MESH:D009369', (215, 221))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('cancers', 'Phenotype', 'HP:0002664', (140, 147))	('cancers', 'Disease', 'MESH:D009369', (158, 165))	('cancers', 'Disease', (140, 147))
104824	31131258	In vitro observations have also reported that exogenous hBD-3 promotes directed chemotaxis of myeloid cells via the chemotaxis receptor CCR2.	('CCR2', 'Gene', '729230', (136, 140))	('exogenous', 'Var', (46, 55))	('CCR2', 'Gene', (136, 140))	('hBD-3', 'Gene', (56, 61))	('hBD-3', 'Gene', '55894', (56, 61))	('promotes', 'PosReg', (62, 70))	('directed chemotaxis of myeloid cells', 'CPA', (71, 107))
104891	27880943	We show that TP53 is the most frequently mutated gene in a number of cancers, and its mutations appear to be early events in cancer initiation.	('cancers', 'Disease', 'MESH:D009369', (69, 76))	('mutations', 'Var', (86, 95))	('TP53', 'Gene', (13, 17))	('cancer initiation', 'Disease', (125, 142))	('cancers', 'Phenotype', 'HP:0002664', (69, 76))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('cancer initiation', 'Disease', 'MESH:D009369', (125, 142))	('TP53', 'Gene', '7157', (13, 17))	('cancers', 'Disease', (69, 76))
104894	27880943	This study shows that while TP53-truncating mutations often result in decreased TP53 expression, other non-truncating TP53 mutations result in increased TP53 expression in some cancers.	('expression', 'MPA', (85, 95))	('increased', 'PosReg', (143, 152))	('TP53', 'Gene', '7157', (28, 32))	('cancers', 'Disease', 'MESH:D009369', (177, 184))	('cancers', 'Phenotype', 'HP:0002664', (177, 184))	('expression', 'MPA', (158, 168))	('cancers', 'Disease', (177, 184))	('TP53', 'Gene', (28, 32))	('decreased', 'NegReg', (70, 79))	('TP53', 'Gene', '7157', (153, 157))	('TP53', 'Gene', (80, 84))	('TP53', 'Gene', '7157', (80, 84))	('TP53', 'Gene', '7157', (118, 122))	('TP53', 'Gene', (118, 122))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('TP53', 'Gene', (153, 157))	('mutations', 'Var', (123, 132))
104895	27880943	Survival analyses in a number of cancers show that patients with TP53 mutations are more likely to have worse prognoses than TP53-wildtype patients, and that elevated TP53 expression often leads to poor clinical outcomes.	('mutations', 'Var', (70, 79))	('TP53', 'Gene', '7157', (65, 69))	('TP53', 'Gene', (65, 69))	('leads to', 'Reg', (189, 197))	('patients', 'Species', '9606', (139, 147))	('TP53', 'Gene', '7157', (125, 129))	('cancers', 'Phenotype', 'HP:0002664', (33, 40))	('cancers', 'Disease', (33, 40))	('cancers', 'Disease', 'MESH:D009369', (33, 40))	('expression', 'MPA', (172, 182))	('TP53', 'Gene', (125, 129))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('poor clinical outcomes', 'MPA', (198, 220))	('patients', 'Species', '9606', (51, 59))	('TP53', 'Gene', '7157', (167, 171))	('elevated', 'PosReg', (158, 166))	('TP53', 'Gene', (167, 171))
104898	27880943	TP53 mutations and dysfunction occur in more than half of all human cancer cases, and are independent markers of poor prognoses in some cancers.	('TP53', 'Gene', '7157', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('TP53', 'Gene', (0, 4))	('cancers', 'Phenotype', 'HP:0002664', (136, 143))	('human', 'Species', '9606', (62, 67))	('cancers', 'Disease', (136, 143))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('cancers', 'Disease', 'MESH:D009369', (136, 143))	('mutations', 'Var', (5, 14))	('occur', 'Reg', (31, 36))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('cancer', 'Disease', (136, 142))	('cancer', 'Disease', (68, 74))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
104899	27880943	In addition to mutations in TP53 itself, mutations in p53 pathway genes are significantly enriched in cancer.	('mutations', 'Var', (41, 50))	('TP53', 'Gene', '7157', (28, 32))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('TP53', 'Gene', (28, 32))	('p53', 'Gene', (54, 57))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('p53', 'Gene', '7157', (54, 57))	('enriched', 'Reg', (90, 98))
104906	27880943	Some therapeutic strategies have been proposed to treat TP53-mutated cancers, such as restoring wild-type activity to; promoting the degradation of; or targeting pathways regulated by mutant p53.	('cancers', 'Disease', 'MESH:D009369', (69, 76))	('degradation of', 'MPA', (133, 147))	('wild-type', 'MPA', (96, 105))	('mutant', 'Var', (184, 190))	('TP53', 'Gene', '7157', (56, 60))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('p53', 'Gene', (191, 194))	('TP53', 'Gene', (56, 60))	('p53', 'Gene', '7157', (191, 194))	('targeting', 'Reg', (152, 161))	('pathways', 'Pathway', (162, 170))	('cancers', 'Phenotype', 'HP:0002664', (69, 76))	('promoting', 'PosReg', (119, 128))	('cancers', 'Disease', (69, 76))
104908	27880943	Thus, the targeted disruption of a gene that is SL for TP53 should selectively kill cancer cells with somatic mutations in TP53, but spare normal TP53-wildtype cells.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('TP53', 'Gene', '7157', (146, 150))	('mutations', 'Var', (110, 119))	('disruption', 'Var', (19, 29))	('kill', 'NegReg', (79, 83))	('cancer', 'Disease', (84, 90))	('TP53', 'Gene', (55, 59))	('TP53', 'Gene', '7157', (55, 59))	('TP53', 'Gene', (146, 150))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('TP53', 'Gene', '7157', (123, 127))	('TP53', 'Gene', (123, 127))
104911	27880943	We analyzed TP53 mutation and gene expression data to identify potential nodes in TP53 interaction networks, and performed survival analyses based on TP53 mutations and expression profiles across the 33 cancer types, respectively.	('TP53', 'Gene', (82, 86))	('TP53', 'Gene', (150, 154))	('mutations', 'Var', (155, 164))	('TP53', 'Gene', '7157', (12, 16))	('cancer', 'Disease', (203, 209))	('cancer', 'Disease', 'MESH:D009369', (203, 209))	('TP53', 'Gene', '7157', (82, 86))	('TP53', 'Gene', (12, 16))	('TP53', 'Gene', '7157', (150, 154))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))
104914	27880943	Almost one-third of cancer types have a TP53 mutation rate greater than 50%, and more than one-half have a rate greater than 30%.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('cancer', 'Disease', 'MESH:D009369', (20, 26))	('TP53', 'Gene', '7157', (40, 44))	('mutation', 'Var', (45, 53))	('TP53', 'Gene', (40, 44))	('cancer', 'Disease', (20, 26))
104915	27880943	The two cancer types with the highest TP53 mutation rates affect women: uterine carcino-sarcoma (UCS) (91.2%) and ovarian serous cystadeno-carcinoma (OV) (83%).	('ovarian serous cystadeno-carcinoma', 'Phenotype', 'HP:0012887', (114, 148))	('ovarian serous cystadeno-carcinoma', 'Disease', (114, 148))	('cancer', 'Disease', (8, 14))	('uterine carcino-sarcoma', 'Phenotype', 'HP:0002891', (72, 95))	('mutation', 'Var', (43, 51))	('TP53', 'Gene', (38, 42))	('carcino-sarcoma', 'Disease', 'MESH:D012509', (80, 95))	('ovarian serous cystadeno-carcinoma', 'Disease', 'MESH:D010051', (114, 148))	('carcinoma', 'Phenotype', 'HP:0030731', (139, 148))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('carcino-sarcoma', 'Disease', (80, 95))	('women', 'Species', '9606', (65, 70))	('sarcoma', 'Phenotype', 'HP:0100242', (88, 95))	('cancer', 'Disease', 'MESH:D009369', (8, 14))	('TP53', 'Gene', '7157', (38, 42))
104916	27880943	The other eight cancer types with a TP53 mutation rate that exceeds 50% include four gastro-intestinal cancers: esophageal carcinoma (ESCA), rectal adeno-carcinoma (READ), pancreatic adeno-carcinoma (PAAD) and colon adeno-carcinoma (COAD); two lung cancers: lung squamous-cell carcinoma (LUSC) and lung adeno-carcinoma (LUAD); and head-and-neck squamous-cell carcinoma (HNSC) and brain lower-grade glioma (LGG).	('COAD', 'Disease', (233, 237))	('gastro-intestinal cancers', 'Disease', 'MESH:D007414', (85, 110))	('cancers', 'Phenotype', 'HP:0002664', (249, 256))	('colon adeno-carcinoma', 'Disease', (210, 231))	('cancer', 'Disease', (249, 255))	('TP53', 'Gene', (36, 40))	('cancer', 'Disease', (103, 109))	('cancer', 'Phenotype', 'HP:0002664', (249, 255))	('lung adeno-carcinoma', 'Disease', (298, 318))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (112, 132))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('lung squamous-cell carcinoma', 'Phenotype', 'HP:0030359', (258, 286))	('lung adeno-carcinoma', 'Phenotype', 'HP:0030078', (298, 318))	('cancer', 'Disease', (16, 22))	('gastro-intestinal cancers', 'Disease', (85, 110))	('carcinoma', 'Phenotype', 'HP:0030731', (277, 286))	('carcinoma', 'Phenotype', 'HP:0030731', (222, 231))	('mutation', 'Var', (41, 49))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('cancers', 'Phenotype', 'HP:0002664', (103, 110))	('glioma', 'Disease', (398, 404))	('carcinoma', 'Phenotype', 'HP:0030731', (189, 198))	('glioma', 'Disease', 'MESH:D005910', (398, 404))	('colon adeno-carcinoma', 'Disease', 'MESH:D015179', (210, 231))	('cancer', 'Disease', 'MESH:D009369', (249, 255))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('TP53', 'Gene', '7157', (36, 40))	('lung squamous-cell carcinoma', 'Disease', 'MESH:D002294', (258, 286))	('lung adeno-carcinoma', 'Disease', 'MESH:D008175', (298, 318))	('lung cancers', 'Disease', 'MESH:D008175', (244, 256))	('COAD', 'Disease', 'MESH:D029424', (233, 237))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('squamous-cell carcinoma', 'Phenotype', 'HP:0002860', (263, 286))	('squamous-cell carcinoma (HNSC)', 'Disease', 'MESH:D002294', (345, 375))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (112, 132))	('lung cancers', 'Disease', (244, 256))	('cancer', 'Disease', 'MESH:D009369', (16, 22))	('glioma', 'Phenotype', 'HP:0009733', (398, 404))	('squamous-cell carcinoma', 'Phenotype', 'HP:0002860', (345, 368))	('adeno-carcinoma (READ), pancreatic adeno-carcinoma', 'Disease', 'MESH:C562463', (148, 198))	('lung cancer', 'Phenotype', 'HP:0100526', (244, 255))	('pancreatic adeno-carcinoma', 'Phenotype', 'HP:0006725', (172, 198))	('lung cancers', 'Phenotype', 'HP:0100526', (244, 256))	('lung squamous-cell carcinoma', 'Disease', (258, 286))	('carcinoma', 'Phenotype', 'HP:0030731', (154, 163))	('esophageal carcinoma', 'Disease', (112, 132))
104918	27880943	We found that TP53 has the highest mutation rate in six cancer types: UCS, OV, ESCA, LUSC, HNSC and sarcoma (SARC), and the second-highest mutation rate in seven other cancer types: READ, LUAD, LGG, bladder urothelial carcinoma (BLCA), stomach adeno-carcinoma (STAD), liver hepato-cellular carcinoma (LIHC), and breast-invasive carcinoma (BRCA).	('TP53', 'Gene', (14, 18))	('breast-invasive carcinoma (BRCA)', 'Gene', '672', (312, 344))	('cancer', 'Disease', (168, 174))	('mutation', 'Var', (35, 43))	('cancer', 'Disease', (56, 62))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('bladder urothelial carcinoma', 'Disease', (199, 227))	('ESCA', 'Disease', (79, 83))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('LUSC', 'Disease', (85, 89))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (199, 227))	('TP53', 'Gene', '7157', (14, 18))	('sarcoma', 'Phenotype', 'HP:0100242', (100, 107))	('stomach adeno-carcinoma (STAD), liver hepato-cellular carcinoma', 'Disease', 'MESH:D006528', (236, 299))	('breast-invasive carcinoma (BRCA', 'Gene', (312, 343))	('hepato-cellular carcinoma', 'Phenotype', 'HP:0001402', (274, 299))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('LUAD', 'Disease', (188, 192))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('UCS', 'Disease', (70, 73))	('READ', 'Disease', (182, 186))	('HNSC and sarcoma', 'Disease', 'MESH:D012509', (91, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (218, 227))	('carcinoma', 'Phenotype', 'HP:0030731', (250, 259))	('carcinoma', 'Phenotype', 'HP:0030731', (328, 337))	('LGG', 'Disease', (194, 197))	('carcinoma', 'Phenotype', 'HP:0030731', (290, 299))
104923	27880943	Surprisingly, there are marked differences in the TP53 mutation rates in cancers from the same organ but different cell types, e.g., in KIRP, KIRC, and kidney chromophobe (KICH), with rates of 2.5%, 2.4% and 33.3%, respectively.	('cancers', 'Disease', (73, 80))	('KICH', 'Disease', (172, 176))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('TP53', 'Gene', '7157', (50, 54))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('kidney chromophobe', 'Disease', (152, 170))	('TP53', 'Gene', (50, 54))	('mutation', 'Var', (55, 63))	('KICH', 'Disease', 'None', (172, 176))	('cancers', 'Disease', 'MESH:D009369', (73, 80))	('kidney chromophobe', 'Disease', 'MESH:D000238', (152, 170))
104924	27880943	TP53 mutations are comprised of eight classes: missense, nonsense, frame-shift deletion, frame-shift insertion, in-frame deletion, in-frame insertion, silent and splice-site.	('missense', 'Var', (47, 55))	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('frame-shift insertion', 'Var', (89, 110))	('frame-shift deletion', 'Var', (67, 87))	('nonsense', 'Var', (57, 65))	('mutations', 'Var', (5, 14))	('in-frame insertion', 'Var', (131, 149))	('in-frame deletion', 'Var', (112, 129))	('silent', 'Var', (151, 157))
104925	27880943	Figure 1 summarizes the proportion of each class of TP53 mutations in all 33 TCGA cancer types.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('TP53', 'Gene', '7157', (52, 56))	('TP53', 'Gene', (52, 56))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('cancer', 'Disease', (82, 88))	('mutations', 'Var', (57, 66))
104926	27880943	The most frequent classes of TP53 mutations are missense (62%), nonsense (14%) and frame-shift deletions (9%).	('frame-shift deletions', 'Var', (83, 104))	('missense', 'Var', (48, 56))	('nonsense', 'Var', (64, 72))	('TP53', 'Gene', '7157', (29, 33))	('TP53', 'Gene', (29, 33))
104927	27880943	The proportions of each class of mutations in all of the TP53 mutations in each cancer type are listed in Supplementary Table S2.	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('TP53', 'Gene', '7157', (57, 61))	('TP53', 'Gene', (57, 61))	('mutations', 'Var', (62, 71))	('cancer', 'Disease', (80, 86))
104928	27880943	In general, nonsense mutations, frame-shift deletions, frame-shift insertions and splice-site mutations are all highly deleterious, and 34.5% of all TP53 mutations fall into one of these classes.	('frame-shift deletions', 'Var', (32, 53))	('TP53', 'Gene', '7157', (149, 153))	('fall', 'Phenotype', 'HP:0002527', (164, 168))	('nonsense mutations', 'Var', (12, 30))	('TP53', 'Gene', (149, 153))	('mutations', 'Var', (154, 163))	('frame-shift', 'Var', (55, 66))
104929	27880943	In contrast, in-frame deletions, in-frame insertions, and silent mutations have comparatively much less deleterious effects, but only 3.5% of all TP53 mutations fall into one of these mutation classes.	('TP53', 'Gene', '7157', (146, 150))	('in-frame insertions', 'Var', (33, 52))	('fall', 'Phenotype', 'HP:0002527', (161, 165))	('TP53', 'Gene', (146, 150))	('mutations', 'Var', (151, 160))
104930	27880943	Since most TP53 missense mutations are deleterious, we can conclude that deleterious or altered-function mutations predominate among TP53 mutations discovered in cancers.	('cancers', 'Disease', 'MESH:D009369', (162, 169))	('missense mutations', 'Var', (16, 34))	('cancers', 'Disease', (162, 169))	('TP53', 'Gene', '7157', (11, 15))	('cancers', 'Phenotype', 'HP:0002664', (162, 169))	('TP53', 'Gene', (11, 15))	('mutations', 'Var', (105, 114))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('TP53', 'Gene', '7157', (133, 137))	('altered-function', 'Reg', (88, 104))	('TP53', 'Gene', (133, 137))
104933	27880943	Once mutations compromise p53's transcriptional repression function, genes that are usually repressed by it should have elevated expression in TP53-mutated cancers compared to TP53-wildtype cancers or normal tissue.	('cancers', 'Disease', 'MESH:D009369', (190, 197))	('TP53', 'Gene', '7157', (176, 180))	('p53', 'Gene', (26, 29))	('TP53', 'Gene', '7157', (143, 147))	('compromise', 'NegReg', (15, 25))	('TP53-wildtype cancers', 'Disease', (176, 197))	('expression', 'MPA', (129, 139))	('cancers', 'Disease', 'MESH:D009369', (156, 163))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('cancers', 'Phenotype', 'HP:0002664', (190, 197))	('cancers', 'Disease', (190, 197))	('mutations', 'Var', (5, 14))	('TP53', 'Gene', (176, 180))	('elevated', 'PosReg', (120, 128))	('TP53', 'Gene', (143, 147))	('cancers', 'Phenotype', 'HP:0002664', (156, 163))	('TP53-wildtype cancers', 'Disease', 'MESH:D009369', (176, 197))	('cancers', 'Disease', (156, 163))	('transcriptional repression function', 'MPA', (32, 67))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('p53', 'Gene', '7157', (26, 29))
104934	27880943	We identified genes potentially repressed by p53 by comparing gene expression levels in cancers with non-silent (functionally significant) TP53 mutations compared to TP53-wildtype cancers in the TCGA datasets.	('p53', 'Gene', (45, 48))	('p53', 'Gene', '7157', (45, 48))	('TP53-wildtype cancers', 'Disease', (166, 187))	('cancers', 'Disease', 'MESH:D009369', (180, 187))	('cancers', 'Phenotype', 'HP:0002664', (180, 187))	('TP53-wildtype cancers', 'Disease', 'MESH:D009369', (166, 187))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('cancers', 'Disease', (180, 187))	('cancers', 'Disease', 'MESH:D009369', (88, 95))	('TP53', 'Gene', '7157', (166, 170))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('TP53', 'Gene', '7157', (139, 143))	('cancers', 'Disease', (88, 95))	('TP53', 'Gene', (139, 143))	('TP53', 'Gene', (166, 170))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('gene expression levels', 'MPA', (62, 84))	('mutations', 'Var', (144, 153))
104949	27880943	The products of these eight genes are of particular interest as targets for the development of small-molecule kinase inhibitors, a strategy adopted by several cancer therapies.	('cancer', 'Disease', (159, 165))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('small-molecule', 'Var', (95, 109))
104953	27880943	Using the PANTHER Classification System, we categorized the 120 TP53-MW genes into eight molecular function classes: binding (GO:0005488), catalytic activity (GO:0003824), channel regulator activity (GO:0016247), enzyme regulator activity (GO:0030234), nucleic acid binding transcription factor activity (GO:0001071), receptor activity (GO:0004872), structural molecule activity (GO:0005198), and transporter activity (GO:0005215).	('catalytic activity', 'MPA', (139, 157))	('GO:0003824', 'Var', (159, 169))	('GO:0001071', 'Var', (305, 315))	('receptor activity', 'MPA', (318, 335))	('transporter activity', 'MPA', (397, 417))	('GO:0005488', 'Var', (126, 136))	('binding', 'Interaction', (117, 124))	('GO:0004872', 'Var', (337, 347))	('nucleic', 'MPA', (253, 260))	('enzyme regulator activity', 'MPA', (213, 238))	('TP53', 'Gene', '7157', (64, 68))	('GO:0005198', 'Var', (380, 390))	('structural molecule activity', 'MPA', (350, 378))	('TP53', 'Gene', (64, 68))	('GO:0030234', 'Var', (240, 250))	('channel regulator activity', 'MPA', (172, 198))	('GO:0016247', 'Var', (200, 210))
104969	27880943	Our results indicate that p53 may in turn inhibit TTK by a negative feedback loop, since TP53 mutations seem to cause the elevated expression of TTK.	('negative feedback loop', 'MPA', (59, 81))	('TP53', 'Gene', '7157', (89, 93))	('TP53', 'Gene', (89, 93))	('TTK', 'Gene', (145, 148))	('mutations', 'Var', (94, 103))	('p53', 'Gene', (26, 29))	('TTK', 'Gene', (50, 53))	('expression', 'MPA', (131, 141))	('TTK', 'Gene', '7272', (145, 148))	('elevated', 'PosReg', (122, 130))	('p53', 'Gene', '7157', (26, 29))	('inhibit', 'NegReg', (42, 49))	('TTK', 'Gene', '7272', (50, 53))
104972	27880943	We are interested in these genes because the mechanism underlying the elevated expression of TP53-MSN genes could be specifically related to TP53 mutations.	('elevated', 'PosReg', (70, 78))	('mutations', 'Var', (146, 155))	('expression', 'MPA', (79, 89))	('TP53', 'Gene', '7157', (93, 97))	('TP53', 'Gene', '7157', (141, 145))	('TP53', 'Gene', (93, 97))	('TP53', 'Gene', (141, 145))	('MSN', 'Gene', '4478', (98, 101))	('MSN', 'Gene', (98, 101))
104977	27880943	In addition, our results suggest that TP53 may also inhibit other TP53-MSN genes, and that TP53 mutations may contribute to their elevated expression in a number of different cancer types.	('TP53', 'Gene', (91, 95))	('inhibit', 'NegReg', (52, 59))	('TP53', 'Gene', '7157', (66, 70))	('MSN', 'Gene', '4478', (71, 74))	('TP53', 'Gene', (38, 42))	('TP53', 'Gene', (66, 70))	('MSN', 'Gene', (71, 74))	('cancer', 'Disease', (175, 181))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('elevated', 'PosReg', (130, 138))	('expression', 'MPA', (139, 149))	('TP53', 'Gene', '7157', (91, 95))	('mutations', 'Var', (96, 105))	('TP53', 'Gene', '7157', (38, 42))
104978	27880943	We compared the TP53 mutation rates among different clinical phenotypes of cancer patients including gender, race, tumor stage, size or direct extent of the primary tumor (T), lymph nodes (N), and metastasis (M) in 18 cancer types: ACC, BLCA, BRCA, CESC, CHOL, COAD, DLBC, ESCA, GBM, HNSC, KICH, KIRC, KIRP, LAML, LGG, LIHC, LUAD, and LUSC (Supplementary Table S11).	('KICH', 'Disease', 'None', (290, 294))	('tumor', 'Disease', (115, 120))	('CHOL', 'Disease', (255, 259))	('BRCA', 'Gene', '672', (243, 247))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('COAD', 'Disease', 'MESH:D029424', (261, 265))	('cancer', 'Disease', 'MESH:D009369', (218, 224))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('TP53', 'Gene', '7157', (16, 20))	('KICH', 'Disease', (290, 294))	('BRCA', 'Gene', (243, 247))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('patients', 'Species', '9606', (82, 90))	('COAD', 'Disease', (261, 265))	('tumor', 'Disease', (165, 170))	('CHOL', 'Disease', 'None', (255, 259))	('cancer', 'Disease', (218, 224))	('cancer', 'Disease', (75, 81))	('mutation', 'Var', (21, 29))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('TP53', 'Gene', (16, 20))
104980	27880943	In DLBC the TP53 mutation rate is lower in male than female subjects (unadjusted P-value = 0.05, odds ratio = 0), while in LIHC the rate is higher in male than female subjects (unadjusted P-value = 0.0007, odds ratio = 2.4).	('TP53', 'Gene', '7157', (12, 16))	('TP53', 'Gene', (12, 16))	('lower', 'NegReg', (34, 39))	('mutation', 'Var', (17, 25))
104982	27880943	For the race phenotype, only HNSC shows a significantly higher TP53 mutation rate in African-American than in White-American subjects (unadjusted P-value = 0.03, odds ratio = 2.48).	('higher', 'PosReg', (56, 62))	('TP53', 'Gene', (63, 67))	('mutation', 'Var', (68, 76))	('TP53', 'Gene', '7157', (63, 67))
104983	27880943	We did not find significant differences in the TP53 mutation rates among different stages, T, N, or M status of tumor except that ACC shows a significantly higher TP53 mutation rate in large-size cancers (T3, T4) than small-size cancers (T1, T2) (unadjusted P-value = 0.04, odds ratio = 3.42).	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('higher', 'PosReg', (156, 162))	('cancers', 'Disease', 'MESH:D009369', (196, 203))	('cancers', 'Disease', 'MESH:D009369', (229, 236))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('TP53', 'Gene', '7157', (163, 167))	('cancers', 'Phenotype', 'HP:0002664', (229, 236))	('cancers', 'Disease', (229, 236))	('cancers', 'Phenotype', 'HP:0002664', (196, 203))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('TP53', 'Gene', (163, 167))	('cancers', 'Disease', (196, 203))	('mutation', 'Var', (168, 176))	('TP53', 'Gene', '7157', (47, 51))	('tumor', 'Disease', (112, 117))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('TP53', 'Gene', (47, 51))
104984	27880943	Since the phenotypes tumor stage, T, N, and M reflect the development or progress status of tumors, our results indicate that TP53 mutations are probably early events in tumorigenesis and drive its progression.	('mutations', 'Var', (131, 140))	('tumors', 'Disease', 'MESH:D009369', (92, 98))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('TP53', 'Gene', (126, 130))	('tumor', 'Disease', (21, 26))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Disease', (170, 175))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('tumor', 'Disease', (92, 97))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('tumors', 'Disease', (92, 98))	('TP53', 'Gene', '7157', (126, 130))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
104986	27880943	Kaplan-Meier survival curves (Figure 6) show that patients with TP53 mutations have significantly worse OS prognoses compared with those without TP53 mutations in seven cancer types: ACC, COAD, HNSC, KIRC, LAML, LUAD, and PAAD; however, they have better OS prognoses in GBM (log-rank test, unadjusted P-value < 0.05).	('COAD', 'Disease', (188, 192))	('mutations', 'Var', (69, 78))	('cancer', 'Disease', (169, 175))	('patients', 'Species', '9606', (50, 58))	('COAD', 'Disease', 'MESH:D029424', (188, 192))	('TP53', 'Gene', '7157', (145, 149))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('TP53', 'Gene', (145, 149))	('GBM', 'Disease', (270, 273))	('TP53', 'Gene', '7157', (64, 68))	('TP53', 'Gene', (64, 68))	('cancer', 'Disease', 'MESH:D009369', (169, 175))
104988	27880943	Kaplan-Meier survival curves (Figure 6) show that patients with TP53 mutations have significantly worse DFS prognoses compared with those without TP53 mutations in three cancer types: ACC, PAAD, and UCEC (log-rank test, unadjusted P-value < 0.05).	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('mutations', 'Var', (69, 78))	('TP53', 'Gene', '7157', (146, 150))	('cancer', 'Disease', (170, 176))	('patients', 'Species', '9606', (50, 58))	('ACC', 'Disease', (184, 187))	('TP53', 'Gene', (146, 150))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('PAAD', 'Disease', (189, 193))	('DFS', 'MPA', (104, 107))	('TP53', 'Gene', '7157', (64, 68))	('TP53', 'Gene', (64, 68))	('worse', 'NegReg', (98, 103))
104989	27880943	These results confirm that TP53 mutations lead to poor clinical outcomes in a number of cancers.	('TP53', 'Gene', '7157', (27, 31))	('TP53', 'Gene', (27, 31))	('cancers', 'Disease', 'MESH:D009369', (88, 95))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('cancers', 'Disease', (88, 95))	('mutations', 'Var', (32, 41))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))
105001	27880943	It makes sense that some TP53 mutations compromise p53 tumor suppressor function by reducing TP53 expression.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('p53', 'Gene', (51, 54))	('p53', 'Gene', '7157', (51, 54))	('TP53', 'Gene', (25, 29))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('compromise', 'NegReg', (40, 50))	('TP53', 'Gene', '7157', (93, 97))	('TP53', 'Gene', (93, 97))	('tumor', 'Disease', (55, 60))	('TP53', 'Gene', '7157', (25, 29))	('mutations', 'Var', (30, 39))	('reducing', 'NegReg', (84, 92))	('expression', 'MPA', (98, 108))
105003	27880943	The explanation for these results could be that some TP53 mutations result in overexpression of mutant forms of TP53 while other mutations simply inactivate TP53.	('TP53', 'Gene', (157, 161))	('mutations', 'Var', (58, 67))	('mutant', 'Var', (96, 102))	('TP53', 'Gene', '7157', (157, 161))	('result in', 'Reg', (68, 77))	('overexpression', 'MPA', (78, 92))	('TP53', 'Gene', '7157', (53, 57))	('TP53', 'Gene', '7157', (112, 116))	('TP53', 'Gene', (53, 57))	('TP53', 'Gene', (112, 116))
105007	27880943	We then divided TP53 mutations into truncating and non-truncating classes to observe their respective effects on TP53 expression.	('TP53', 'Gene', '7157', (113, 117))	('TP53', 'Gene', '7157', (16, 20))	('TP53', 'Gene', (113, 117))	('TP53', 'Gene', (16, 20))	('mutations', 'Var', (21, 30))
105012	27880943	In contrast, TP53 non-truncating mutations may result in increased TP53 expression.	('TP53', 'Gene', (13, 17))	('expression', 'MPA', (72, 82))	('non-truncating mutations', 'Var', (18, 42))	('TP53', 'Gene', '7157', (67, 71))	('increased', 'PosReg', (57, 66))	('TP53', 'Gene', (67, 71))	('TP53', 'Gene', '7157', (13, 17))
105047	27880943	We found that BI-2536, GW843682X, Epothilone B, Afatinib and Gefitinib have significantly lower IC50 values in TP53-mutated cancer cell lines than in TP53-wildtype cancer cell lines (P-value < 0.05, FDR < 0.2, Supplementary Table S21).	('TP53', 'Gene', (150, 154))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (124, 130))	('TP53', 'Gene', '7157', (111, 115))	('Epothilone B', 'Chemical', 'MESH:C093788', (34, 46))	('lower', 'NegReg', (90, 95))	('Afatinib', 'Chemical', 'MESH:D000077716', (48, 56))	('TP53', 'Gene', '7157', (150, 154))	('GW843682X', 'Var', (23, 32))	('GW843682X', 'Chemical', 'MESH:C524135', (23, 32))	('IC50 values', 'MPA', (96, 107))	('BI-2536', 'Var', (14, 21))	('cancer', 'Disease', (164, 170))	('BI-2536', 'Chemical', 'MESH:C518477', (14, 21))	('cancer', 'Disease', (124, 130))	('Gefitinib', 'Chemical', 'MESH:D000077156', (61, 70))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('TP53', 'Gene', (111, 115))
105052	27880943	In our study we performed extensive analyses of TP53 mutation, gene expression, and clinical data from 33 TCGA cancer type-specific datasets.	('TP53', 'Gene', '7157', (48, 52))	('mutation', 'Var', (53, 61))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('TP53', 'Gene', (48, 52))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))
105053	27880943	We identified potential TP53 interaction networks, the association between patient survival and TP53 mutation or gene expression status, and potential druggable SL partners of TP53.	('TP53', 'Gene', (96, 100))	('TP53', 'Gene', (24, 28))	('TP53', 'Gene', '7157', (176, 180))	('association', 'Interaction', (55, 66))	('TP53', 'Gene', (176, 180))	('interaction', 'Interaction', (29, 40))	('mutation', 'Var', (101, 109))	('patient', 'Species', '9606', (75, 82))	('TP53', 'Gene', '7157', (96, 100))	('TP53', 'Gene', '7157', (24, 28))
105055	27880943	This indicates that TP53-truncating mutations reduce TP53 expression but some non-truncating mutations are capable of increasing it.	('reduce', 'NegReg', (46, 52))	('TP53', 'Gene', (20, 24))	('expression', 'MPA', (58, 68))	('mutations', 'Var', (36, 45))	('TP53', 'Gene', '7157', (53, 57))	('TP53', 'Gene', '7157', (20, 24))	('TP53', 'Gene', (53, 57))
105056	27880943	However, we did not find significant survival time (OS or DFS) differences between TP53-truncated and TP53-mutated but TP53-non-truncated classes of cancer patients, indicating that both types of TP53 mutations are equally deleterious and lead to poor clinical outcomes.	('TP53', 'Gene', (196, 200))	('patients', 'Species', '9606', (156, 164))	('TP53', 'Gene', (102, 106))	('cancer', 'Disease', (149, 155))	('mutations', 'Var', (201, 210))	('TP53', 'Gene', '7157', (83, 87))	('TP53', 'Gene', (83, 87))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('TP53', 'Gene', '7157', (196, 200))	('TP53', 'Gene', '7157', (102, 106))	('TP53', 'Gene', '7157', (119, 123))	('TP53', 'Gene', (119, 123))	('cancer', 'Disease', 'MESH:D009369', (149, 155))
105077	27880943	We performed survival analyses of TCGA patients based on TP53 mutation data and TP53 gene expression data, respectively.	('patients', 'Species', '9606', (39, 47))	('TCGA', 'Disease', (34, 38))	('TP53', 'Gene', '7157', (80, 84))	('TP53', 'Gene', (80, 84))	('mutation', 'Var', (62, 70))	('TP53', 'Gene', '7157', (57, 61))	('TP53', 'Gene', (57, 61))
105087	31640185	Exploiting ING2 Epigenetic Modulation as a Therapeutic Opportunity for Non-Small Cell Lung Cancer Non-small cell lung cancer (NSCLC) has been the leading cause of cancer-related death worldwide, over the last few decades.	('NSCLC', 'Disease', 'MESH:D002289', (126, 131))	('Cancer', 'Phenotype', 'HP:0002664', (91, 97))	('Non-small cell lung cancer', 'Disease', (98, 124))	('Non-Small Cell Lung Cancer', 'Disease', 'MESH:D002289', (71, 97))	('Lung Cancer', 'Phenotype', 'HP:0100526', (86, 97))	('cancer', 'Disease', 'MESH:D009369', (163, 169))	('NSCLC', 'Disease', (126, 131))	('lung cancer', 'Phenotype', 'HP:0100526', (113, 124))	('death', 'Disease', 'MESH:D003643', (178, 183))	('NSCLC', 'Phenotype', 'HP:0030358', (126, 131))	('Non-Small Cell Lung Cancer', 'Disease', (71, 97))	('cancer', 'Disease', (118, 124))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (102, 124))	('Small Cell Lung Cancer', 'Phenotype', 'HP:0030357', (75, 97))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('Non-Small Cell Lung Cancer', 'Phenotype', 'HP:0030358', (71, 97))	('ING2', 'Gene', (11, 15))	('cancer', 'Disease', (163, 169))	('Non-small cell lung cancer', 'Disease', 'MESH:D002289', (98, 124))	('death', 'Disease', (178, 183))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('Epigenetic Modulation', 'Var', (16, 37))	('ING2', 'Gene', '3622', (11, 15))	('cancer', 'Disease', 'MESH:D009369', (118, 124))
105096	31640185	In addition, as part of the p53 pathway, ING2 is involved in diverse cellular processes that are recognized as hallmarks of cancer and its deletion in mice led to spontaneous soft tissue sarcomas formation.	('deletion', 'Var', (139, 147))	('mice', 'Species', '10090', (151, 155))	('hallmarks of cancer', 'Disease', (111, 130))	('sarcomas', 'Disease', 'MESH:D012509', (187, 195))	('ING2', 'Gene', (41, 45))	('involved', 'Reg', (49, 57))	('sarcomas', 'Phenotype', 'HP:0100242', (187, 195))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('led to', 'Reg', (156, 162))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (175, 194))	('sarcoma', 'Phenotype', 'HP:0100242', (187, 194))	('sarcomas', 'Disease', (187, 195))	('hallmarks of cancer', 'Disease', 'MESH:D009369', (111, 130))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (175, 195))
105101	31640185	ING genes are made up of multiple exons, resulting in numerous transcribed variants, thanks to alternative mRNA splicing.	('transcribed', 'MPA', (63, 74))	('variants', 'Var', (75, 83))	('N', 'Chemical', 'MESH:D009584', (1, 2))	('N', 'Chemical', 'MESH:D009584', (109, 110))
105108	31640185	The biological roles of ING2 are related to its various domains (Figure 1, panel A) and more particularly, to its plant homeodomain (PHD), which is characterized by a Cys4-His-Cys3 zinc-binding motif that allows ING2 stabilization at active chromatin, through the binding to H3K4me3.	('H3K4me3', 'Chemical', 'MESH:C024755', (275, 282))	('H3K4me3', 'Protein', (275, 282))	('Cys4-His', 'SUBSTITUTION', 'None', (167, 175))	('ING2', 'Gene', (212, 216))	('ING2', 'Gene', (24, 28))	('Cys4-His', 'Var', (167, 175))	('binding', 'Interaction', (264, 271))
105118	31640185	Of note, it has been shown that the sumoylation of ING2 at Lysine 195 enhances ING2 association with the mSin3A/HDAC complex.	('association', 'Interaction', (84, 95))	('mSin3A', 'Gene', (105, 111))	('sumoylation', 'Var', (36, 47))	('ING2', 'Gene', (79, 83))	('mSin3A', 'Gene', '20466', (105, 111))	('Lysine', 'Chemical', 'MESH:C114808', (59, 65))	('Lysine 195', 'Var', (59, 69))	('enhances', 'PosReg', (70, 78))
105123	31640185	Of note, ING1 and ING2 are mutually exclusive in the mSin3A/HDAC complex and the binding affinity for H3K4me3 is greater for ING2 compared to the one of ING1.	('mSin3A', 'Gene', '20466', (53, 59))	('H3K4me3', 'Var', (102, 109))	('ING2', 'Var', (125, 129))	('binding affinity', 'Interaction', (81, 97))	('mSin3A', 'Gene', (53, 59))	('greater', 'PosReg', (113, 120))	('H3K4me3', 'Chemical', 'MESH:C024755', (102, 109))
105124	31640185	Furthermore, the expression of ING2 results in p53 acetylation at Lysine 382 through the histone acetyltransferase p300.	('p53 acetylation at Lysine 382', 'MPA', (47, 76))	('p300', 'Gene', '2033', (115, 119))	('results in', 'Reg', (36, 46))	('ING2', 'Gene', (31, 35))	('expression', 'Var', (17, 27))	('Lysine', 'Chemical', 'MESH:C114808', (66, 72))	('p300', 'Gene', (115, 119))	('histone acetyltransferase', 'Enzyme', (89, 114))
105126	31640185	Moreover, a study conducted on ING2 knockout mice indicates that ING2 deficiency spontaneously increases soft tissue sarcoma formation.	('mice', 'Species', '10090', (45, 49))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (105, 124))	('increases soft tissue sarcoma', 'Disease', (95, 124))	('sarcoma', 'Phenotype', 'HP:0100242', (117, 124))	('ING2', 'Gene', (65, 69))	('increases soft tissue sarcoma', 'Disease', 'MESH:D012509', (95, 124))	('deficiency', 'Var', (70, 80))
105127	31640185	All of these facts highlight ING2 as a tumor suppressor gene, playing a critical role against tumor development and cancer, notably through the regulation of mSin3A/HDAC-mediated epigenetic functions.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('mSin3A', 'Gene', (158, 164))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('tumor', 'Disease', (94, 99))	('mSin3A', 'Gene', '20466', (158, 164))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('epigenetic', 'Var', (179, 189))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('tumor', 'Disease', (39, 44))	('ING2', 'Gene', (29, 33))
105133	31640185	Nevertheless, some authors found that miR-153-3p represses ING2 expression in ALL cells by binding to the 3'-UTR site, and that miR-153-3p is downregulated in ALL cells, leading to ING2 overexpression.	('overexpression', 'PosReg', (186, 200))	('miR-153-3p', 'Var', (128, 138))	('expression', 'MPA', (64, 74))	('ING2', 'Gene', (181, 185))	('ING2', 'Gene', (59, 63))	('ALL', 'Phenotype', 'HP:0006721', (78, 81))	('N', 'Chemical', 'MESH:D009584', (60, 61))	('represses', 'NegReg', (49, 58))	('N', 'Chemical', 'MESH:D009584', (0, 1))	('N', 'Chemical', 'MESH:D009584', (182, 183))	('downregulated', 'NegReg', (142, 155))	('ALL', 'Phenotype', 'HP:0006721', (159, 162))	('binding', 'Interaction', (91, 98))	('miR-153-3p', 'Var', (38, 48))
105142	31640185	Moreover, LOH of the 4q35.1 region in HNSCC was correlated with tumor stage and disease-free survival but not with node status or overall survival, whereas no correlation has been found in hepatocellular carcinoma.	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (189, 213))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (189, 213))	('tumor', 'Disease', (64, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (204, 213))	('hepatocellular carcinoma', 'Disease', (189, 213))	('N', 'Chemical', 'MESH:D009584', (39, 40))	('LOH', 'Var', (10, 13))	('HNSCC', 'Gene', (38, 43))	('disease-free survival', 'CPA', (80, 101))	('correlated', 'Reg', (48, 58))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('HNSCC', 'Phenotype', 'HP:0012288', (38, 43))
105143	31640185	Additionally, deletion of the chromosomic region 4q34-35.2 containing the ING2 gene has also been reported in uterine leiomyosarcoma (3/6), and hypermethylation of the seven CpG sites in multiple intronic regions of the ING2 gene has been shown in patients with esophageal squamous cell carcinoma.	('hypermethylation', 'Var', (144, 160))	('leiomyosarcoma', 'Disease', (118, 132))	('uterine leiomyosarcoma', 'Phenotype', 'HP:0002891', (110, 132))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (118, 132))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (118, 132))	('esophageal squamous cell carcinoma', 'Disease', (262, 296))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:C562729', (262, 296))	('carcinoma', 'Phenotype', 'HP:0030731', (287, 296))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (273, 296))	('sarcoma', 'Phenotype', 'HP:0100242', (125, 132))	('deletion', 'Var', (14, 22))	('patients', 'Species', '9606', (248, 256))	('ING2', 'Gene', (74, 78))	('reported', 'Reg', (98, 106))
105145	31640185	To explore further ING2 status in cancer, we used The Cancer Genome Atlas database to analyze alterations of the ING2 gene and the members of the mSin3A/HDAC complex.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('alterations', 'Var', (94, 105))	('Cancer', 'Phenotype', 'HP:0002664', (54, 60))	('mSin3A', 'Gene', '20466', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('ING2 gene', 'Gene', (113, 122))	('cancer', 'Disease', (34, 40))	('mSin3A', 'Gene', (146, 152))
105146	31640185	This analysis revealed that 221 out of 9,892 (2.23%) human cancer samples included in the TCGA Pancancer study presented an alteration of ING2 gene and 161 of these 221 (73%) alterations were deletions.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('alteration', 'Reg', (124, 134))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('ING2', 'Gene', (138, 142))	('deletions', 'Var', (192, 201))	('cancer', 'Disease', (98, 104))	('human', 'Species', '9606', (53, 58))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))
105148	31640185	Interestingly, one of the tumor types with the most frequent alteration in ING2 was the lung squamous cell carcinoma, comprising 5.54% of the tumors involved (Figure 2, panel A).	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('lung squamous cell carcinoma', 'Disease', (88, 116))	('ING2', 'Gene', (75, 79))	('alteration', 'Var', (61, 71))	('tumor', 'Disease', (142, 147))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (93, 116))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (88, 116))	('tumors', 'Disease', (142, 148))	('tumors', 'Disease', 'MESH:D009369', (142, 148))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (88, 116))
105163	31640185	Therefore, it is still unclear if the deletion of ING2 alone or the whole chromosomic region is implicated in promoting tumorigenesis.	('promoting', 'PosReg', (110, 119))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('deletion', 'Var', (38, 46))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('ING2', 'Gene', (50, 54))	('tumor', 'Disease', (120, 125))
105164	31640185	Concerning ING2 mutations, only silent ones have been found in NSCLC.	('NSCLC', 'Disease', (63, 68))	('NSCLC', 'Disease', 'MESH:D002289', (63, 68))	('mutations', 'Var', (16, 25))	('ING2', 'Gene', (11, 15))	('NSCLC', 'Phenotype', 'HP:0030358', (63, 68))
105165	31640185	As an example, a study reported a substitution (C to T) in exon 1 at codon 13 in 6 out of 31 lung cancer (without any change of the encoded amino acid (Alanine)) was likely to be a polymorphism (Table 1).	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('lung cancer', 'Disease', 'MESH:D008175', (93, 104))	('C to T', 'Var', (48, 54))	('Alanine', 'Chemical', 'MESH:D000409', (152, 159))	('lung cancer', 'Disease', (93, 104))	('lung cancer', 'Phenotype', 'HP:0100526', (93, 104))
105167	31640185	Moreover, the ING2 gene deep deletion was the most frequent alteration with 17 out of 408 (3.54%) NSCLC and was found to be higher in squamous cell carcinoma than in adenocarcinoma (6.18% and 2.61%, respectively).	('higher', 'Reg', (124, 130))	('squamous cell carcinoma than in adenocarcinoma', 'Disease', 'MESH:D002294', (134, 180))	('NSCLC', 'Phenotype', 'HP:0030358', (98, 103))	('squamous cell carcinoma than in adenocarcinoma', 'Disease', (134, 180))	('carcinoma', 'Phenotype', 'HP:0030731', (171, 180))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (134, 157))	('NSCLC', 'Disease', (98, 103))	('deep deletion', 'Var', (24, 37))	('ING2 gene', 'Gene', (14, 23))	('NSCLC', 'Disease', 'MESH:D002289', (98, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (148, 157))
105168	31640185	Only one missense mutation (E204Q) of ING2 of unknown significance was reported out of the 408 NSCLC samples.	('NSCLC', 'Disease', 'MESH:D002289', (95, 100))	('E204Q', 'Var', (28, 33))	('ING2', 'Gene', (38, 42))	('E204Q', 'Mutation', 'p.E204Q', (28, 33))	('NSCLC', 'Phenotype', 'HP:0030358', (95, 100))	('NSCLC', 'Disease', (95, 100))
105170	31640185	Notably, we found that patients presenting an alteration in at least one member of the mSin3A/HDAC complex had a higher probability of prolonged overall survival, in comparison with patients without any alteration of the complex in lung squamous cell carcinoma (p = 0.0451) (data not shown).	('alteration', 'Var', (46, 56))	('mSin3A', 'Gene', '20466', (87, 93))	('patients', 'Species', '9606', (23, 31))	('overall survival', 'MPA', (145, 161))	('N', 'Chemical', 'MESH:D009584', (0, 1))	('mSin3A', 'Gene', (87, 93))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (232, 260))	('prolonged', 'PosReg', (135, 144))	('patients', 'Species', '9606', (182, 190))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (237, 260))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (232, 260))	('lung squamous cell carcinoma', 'Disease', (232, 260))	('carcinoma', 'Phenotype', 'HP:0030731', (251, 260))
105172	31640185	ING2 gene alterations in NSCLC are predominantly deletion, but still remain a rare event (less than 3%).	('alterations', 'Var', (10, 21))	('NSCLC', 'Disease', (25, 30))	('ING2', 'Gene', (0, 4))	('NSCLC', 'Disease', 'MESH:D002289', (25, 30))	('deletion', 'Var', (49, 57))	('NSCLC', 'Phenotype', 'HP:0030358', (25, 30))
105186	31640185	However, the relative high frequencies of genomic alteration concerning at least one member of the mSin3A/HDAC complex in NSCLC TCGA samples, notably gene amplification (23.6% of adenocarcinoma and 17.53% of squamous cell carcinoma) (Figure 2, Panel B), clearly pledges for a "gain-of-function" phenotype predisposing tumors cells to a selective advantage.	('mSin3A', 'Gene', (99, 105))	('NSCLC', 'Disease', 'MESH:D002289', (122, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (184, 193))	('adenocarcinoma', 'Disease', (179, 193))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (208, 231))	('adenocarcinoma', 'Disease', 'MESH:D000230', (179, 193))	('mSin3A', 'Gene', '20466', (99, 105))	('NSCLC', 'Phenotype', 'HP:0030358', (122, 127))	('squamous cell carcinoma', 'Disease', (208, 231))	('carcinoma', 'Phenotype', 'HP:0030731', (222, 231))	('tumor', 'Phenotype', 'HP:0002664', (318, 323))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (208, 231))	('tumors', 'Disease', (318, 324))	('tumors', 'Disease', 'MESH:D009369', (318, 324))	('tumors', 'Phenotype', 'HP:0002664', (318, 324))	('NSCLC', 'Disease', (122, 127))	('gene amplification', 'Var', (150, 168))
105187	31640185	Additionally, small molecule inhibitors targeting Paired Amphipathic Helix 2 (PAH2) domain of mSin3A was shown to induce transcriptional reprogramming, impairment of clonogenic abilities, inhibition of proliferation, and metastasis in triple negative breast cancer models.	('proliferation', 'CPA', (202, 215))	('inhibitors', 'Var', (29, 39))	('mSin3A', 'Gene', '20466', (94, 100))	('impairment of clonogenic abilities', 'Disease', 'OMIM:313000', (152, 186))	('cancer', 'Phenotype', 'HP:0002664', (258, 264))	('breast cancer', 'Disease', 'MESH:D001943', (251, 264))	('metastasis', 'CPA', (221, 231))	('impairment of clonogenic abilities', 'Disease', (152, 186))	('breast cancer', 'Disease', (251, 264))	('inhibition', 'NegReg', (188, 198))	('induce', 'PosReg', (114, 120))	('transcriptional reprogramming', 'CPA', (121, 150))	('mSin3A', 'Gene', (94, 100))	('breast cancer', 'Phenotype', 'HP:0003002', (251, 264))
105192	31640185	However, some could argue that many non-epigenetic functions of ING2 favor its tumor suppressive activity (DNA repair, DNA replication, cell cycle progression, etc.)	('DNA replication', 'CPA', (119, 134))	('ING2', 'Gene', (64, 68))	('non-epigenetic functions', 'Var', (36, 60))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('tumor', 'Disease', (79, 84))	('N', 'Chemical', 'MESH:D009584', (108, 109))	('N', 'Chemical', 'MESH:D009584', (120, 121))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('N', 'Chemical', 'MESH:D009584', (65, 66))	('cell cycle progression', 'CPA', (136, 158))	('favor', 'PosReg', (69, 74))
105198	31640185	Consequently, authors hypothesized that ING2 disruption lead to the induction of p21 transcription, as it was observed, upon HDACi treatment.	('induction', 'MPA', (68, 77))	('ING2', 'Gene', (40, 44))	('disruption', 'Var', (45, 55))	('p21', 'Gene', (81, 84))	('p21', 'Gene', '644914', (81, 84))
105201	31640185	Notably, as already mentioned above, ING2 sumoylation on Lysine 195 has been described to enhance its interaction with mSin3A.	('Lysine', 'Chemical', 'MESH:C114808', (57, 63))	('mSin3A', 'Gene', (119, 125))	('ING2', 'Gene', (37, 41))	('sumoylation on Lysine 195', 'Var', (42, 67))	('enhance', 'PosReg', (90, 97))	('N', 'Chemical', 'MESH:D009584', (0, 1))	('mSin3A', 'Gene', '20466', (119, 125))	('N', 'Chemical', 'MESH:D009584', (38, 39))	('interaction', 'Interaction', (102, 113))
105212	31640185	Of note, studies claiming to inactivate mSin3A as a therapeutic target in leukemia are limited to the use of non-selective HDAC inhibitors that do not target mSin3A directly.	('mSin3A', 'Gene', (40, 46))	('leukemia', 'Phenotype', 'HP:0001909', (74, 82))	('mSin3A', 'Gene', (158, 164))	('mSin3A', 'Gene', '20466', (40, 46))	('mSin3A', 'Gene', '20466', (158, 164))	('inactivate', 'Var', (29, 39))	('leukemia', 'Disease', (74, 82))	('leukemia', 'Disease', 'MESH:D007938', (74, 82))
105219	31640185	Interestingly, genomic alterations of mSin3A/HDAC members occur frequently in NSCLC, mainly through gene amplification.	('mSin3A', 'Gene', (38, 44))	('gene amplification', 'Var', (100, 118))	('NSCLC', 'Phenotype', 'HP:0030358', (78, 83))	('mSin3A', 'Gene', '20466', (38, 44))	('NSCLC', 'Disease', (78, 83))	('NSCLC', 'Disease', 'MESH:D002289', (78, 83))
105282	27663899	Role of KEAP1/NRF2 and TP53 mutations in lung squamous cell carcinoma development and radiotherapy response prediction Lung squamous cell carcinomas (LSCC) pathogenesis remains incompletely understood and biomarkers predicting treatment response remain lacking.	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (41, 69))	('NRF2', 'Gene', (14, 18))	('carcinomas', 'Phenotype', 'HP:0030731', (138, 148))	('men', 'Species', '9606', (232, 235))	('TP53', 'Gene', '22059', (23, 27))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (124, 148))	('Lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (119, 147))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (46, 69))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (41, 69))	('lung squamous cell carcinoma', 'Disease', (41, 69))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (124, 148))	('NRF2', 'Gene', '18024', (14, 18))	('KEAP1', 'Gene', (8, 13))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (124, 147))	('men', 'Species', '9606', (77, 80))	('squamous cell carcinomas', 'Disease', (124, 148))	('mutations', 'Var', (28, 37))	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('carcinoma', 'Phenotype', 'HP:0030731', (60, 69))	('TP53', 'Gene', (23, 27))	('KEAP1', 'Gene', '50868', (8, 13))
105284	27663899	Deletion of Trp53 and Keap1 in ABSCs, but not more differentiated tracheal cells, produced tumors recapitulating histological and molecular features of human LSCCs, indicating that they represent the likely cell of origin in this model.	('tumors', 'Disease', (91, 97))	('tumors', 'Disease', 'MESH:D009369', (91, 97))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('human', 'Species', '9606', (152, 157))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('Trp53', 'Gene', (12, 17))	('Deletion', 'Var', (0, 8))
105285	27663899	Deletion of Keap1 promoted tumor aggressiveness, metastasis, and resistance to oxidative stress and radiotherapy (RT).	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('metastasis', 'CPA', (49, 59))	('tumor aggressiveness', 'Disease', (27, 47))	('aggressiveness', 'Phenotype', 'HP:0000718', (33, 47))	('oxidative stress', 'Phenotype', 'HP:0025464', (79, 95))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (27, 47))	('promoted', 'PosReg', (18, 26))	('resistance to oxidative stress', 'MPA', (65, 95))	('Keap1', 'Gene', (12, 17))	('Deletion', 'Var', (0, 8))
105286	27663899	KEAP1/NRF2 mutation status predicted risk of local recurrence after RT in non-small lung cancer (NSCLC) patients and could be non-invasively identified in circulating tumor DNA.	('non-small lung cancer', 'Phenotype', 'HP:0030358', (74, 95))	('mutation', 'Var', (11, 19))	('KEAP1/NRF2', 'Gene', (0, 10))	('lung cancer', 'Phenotype', 'HP:0100526', (84, 95))	('NSCLC', 'Disease', (97, 102))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('small lung', 'Phenotype', 'HP:0002089', (78, 88))	('NSCLC', 'Disease', 'MESH:D002289', (97, 102))	('non-small lung cancer', 'Disease', 'MESH:D002289', (74, 95))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('non-small lung cancer', 'Disease', (74, 95))	('local recurrence', 'MPA', (45, 61))	('patients', 'Species', '9606', (104, 112))	('tumor', 'Disease', (167, 172))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
105287	27663899	Thus, KEAP1/NRF2 mutations could serve as predictive biomarkers for personalization of therapeutic strategies for NSCLCs.	('KEAP1/NRF2', 'Gene', (6, 16))	('rat', 'Species', '10116', (101, 104))	('NSCLC', 'Disease', (114, 119))	('NSCLC', 'Disease', 'MESH:D002289', (114, 119))	('mutations', 'Var', (17, 26))
105291	27663899	Recently, several LSCC mouse models have been reported, involving inactivation of IKKalpha, Lkb1, and Pten, or activation of Sox2.	('activation', 'PosReg', (111, 121))	('Lkb1', 'Gene', (92, 96))	('Pten', 'Gene', (102, 106))	('IKKalpha', 'Gene', (82, 90))	('Sox2', 'Gene', (125, 129))	('Pten', 'Gene', '19211', (102, 106))	('IKKalpha', 'Gene', '12675', (82, 90))	('inactivation', 'Var', (66, 78))	('LSCC', 'Disease', (18, 22))	('mouse', 'Species', '10090', (23, 28))
105294	27663899	In addition to mutations affecting several other pathways, KEAP1/NRF2 pathway mutations were found in over one third of LSCC patients.	('KEAP1/NRF2', 'Gene', (59, 69))	('LSCC', 'Disease', (120, 124))	('mutations', 'Var', (78, 87))	('found', 'Reg', (93, 98))	('patients', 'Species', '9606', (125, 133))
105300	27663899	Importantly, although a number of groups have examined the effects of KEAP1 and NRF2 on treatment resistance in lung cancer cell lines, no studies have done so in genetically engineered mouse models and no studies have demonstrated a clinical association between mutations in KEAP1/NRF2 and response to radiotherapy in lung cancer patients.	('lung cancer', 'Disease', (319, 330))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('lung cancer', 'Phenotype', 'HP:0100526', (319, 330))	('men', 'Species', '9606', (93, 96))	('lung cancer', 'Disease', (112, 123))	('lung cancer', 'Phenotype', 'HP:0100526', (112, 123))	('mutations', 'Var', (263, 272))	('cancer', 'Phenotype', 'HP:0002664', (324, 330))	('KEAP1/NRF2', 'Gene', (276, 286))	('mouse', 'Species', '10090', (186, 191))	('lung cancer', 'Disease', 'MESH:D008175', (112, 123))	('lung cancer', 'Disease', 'MESH:D008175', (319, 330))	('rat', 'Species', '10116', (226, 229))	('patients', 'Species', '9606', (331, 339))
105302	27663899	Furthermore, deletion of Trp53 with or without Keap1 in tracheal cells leads to the formation of lung cancer with features of SCC, while the same deletions in peripheral lung cells leads to adenocarcinoma formation.	('adenocarcinoma', 'Disease', 'MESH:D000230', (190, 204))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('lung cancer', 'Disease', 'MESH:D008175', (97, 108))	('Trp53', 'Gene', (25, 30))	('deletion', 'Var', (13, 21))	('adenocarcinoma', 'Disease', (190, 204))	('carcinoma', 'Phenotype', 'HP:0030731', (195, 204))	('lung cancer', 'Disease', (97, 108))	('lung cancer', 'Phenotype', 'HP:0100526', (97, 108))	('leads to', 'Reg', (71, 79))
105304	27663899	Also, constitutive Nrf2 activation and ROS suppression by Keap1 deletion promoted tumor aggressiveness, metastasis, and resistance to oxidative stress and radiotherapy (RT).	('ROS', 'Chemical', 'MESH:D017382', (39, 42))	('ROS', 'Protein', (39, 42))	('Nrf2', 'Gene', (19, 23))	('Keap1', 'Gene', (58, 63))	('aggressiveness', 'Phenotype', 'HP:0000718', (88, 102))	('metastasis', 'CPA', (104, 114))	('oxidative stress', 'Phenotype', 'HP:0025464', (134, 150))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (82, 102))	('deletion', 'Var', (64, 72))	('resistance to oxidative stress', 'MPA', (120, 150))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('suppression', 'NegReg', (43, 54))	('activation', 'PosReg', (24, 34))	('promoted', 'PosReg', (73, 81))	('tumor aggressiveness', 'Disease', (82, 102))	('Nrf2', 'Gene', '18024', (19, 23))
105306	27663899	Consistently, KEAP1/NRF2 mutation status in NSCLC patients was predictive of local recurrence after RT in human patients and these mutations could be non-invasively identified in circulating tumor DNA.	('NSCLC', 'Disease', 'MESH:D002289', (44, 49))	('human', 'Species', '9606', (106, 111))	('KEAP1/NRF2', 'Gene', (14, 24))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('patients', 'Species', '9606', (50, 58))	('mutation', 'Var', (25, 33))	('patients', 'Species', '9606', (112, 120))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('tumor', 'Disease', (191, 196))	('local', 'Disease', (77, 82))	('NSCLC', 'Disease', (44, 49))
105312	27663899	Consistently, upon the single cell sorting, Keap1-/- basal cells from tamoxifen injected Krt5CreERT2;Keap1f/f;R26tdTomato mice formed ~70% more tracheospheres than WT basal cells from tamoxifen injected Krt5CreERT2;R26tdTomato mice (Supplementary Fig.	('mice', 'Species', '10090', (122, 126))	('tracheospheres', 'CPA', (144, 158))	('Keap1f/f;R26tdTomato', 'Var', (101, 121))	('Krt5', 'Gene', (89, 93))	('mice', 'Species', '10090', (227, 231))	('Krt5', 'Gene', (203, 207))	('Krt5', 'Gene', '110308', (203, 207))	('Krt5', 'Gene', '110308', (89, 93))	('men', 'Species', '9606', (239, 242))	('tamoxifen', 'Chemical', 'MESH:D013629', (184, 193))	('tamoxifen', 'Chemical', 'MESH:D013629', (70, 79))	('more', 'PosReg', (139, 143))
105313	27663899	Furthermore, tracheospheres derived from Keap1-/-;Trp53-/- cells displayed aberrant morphologic features manifesting as solid spheres devoid of a central acellular lumen, while tracheospheres derived from WT, Keap1-/-, and Keap1f/f;Trp53f/f cells displayed the expected cystic shape.	('men', 'Species', '9606', (166, 169))	('Keap1-/-', 'Var', (41, 49))	('Trp53-/-', 'Gene', (50, 58))	('cystic shape', 'CPA', (270, 282))
105315	27663899	These data indicate that combined deletion of Keap1 and Trp53 leads to greater enhancement of ABSC self-renewal than deletion of either gene alone, as well as deregulated expansion of ABSCs.	('enhancement', 'PosReg', (79, 90))	('men', 'Species', '9606', (86, 89))	('Trp53', 'Gene', (56, 61))	('Keap1', 'Gene', (46, 51))	('ABSC self-renewal', 'CPA', (94, 111))	('deletion', 'Var', (34, 42))	('expansion', 'CPA', (171, 180))
105320	27663899	At 9 dpi, however, tdTomato+ cells expressing either KRT5 or ACT were observed, indicating that transduced basal cells had generated luminal cells (Fig.	('KRT5', 'Gene', (53, 57))	('ACT', 'Gene', (61, 64))	('transduced', 'Var', (96, 106))	('luminal cells', 'MPA', (133, 146))	('rat', 'Species', '10116', (127, 130))
105321	27663899	We employed this approach to test if the ratio of basal and luminal tracheal epithelial cells was altered by deletion of Keap1 or Trp53.	('deletion', 'Var', (109, 117))	('Keap1', 'Gene', (121, 126))	('rat', 'Species', '10116', (41, 44))	('altered', 'Reg', (98, 105))	('Trp53', 'Gene', (130, 135))
105323	27663899	Deletion of either Keap1 or Trp53 increased the basal-to-luminal ratio about ~2.5-fold compared to WT or non-recombined Keap1f/f or Trp53f/f cells (Fig.	('Trp53', 'Gene', (28, 33))	('Deletion', 'Var', (0, 8))	('basal-to-luminal ratio', 'MPA', (48, 70))	('increased', 'PosReg', (34, 43))	('rat', 'Species', '10116', (65, 68))
105324	27663899	In addition, FACS-sorted Keap1-/- tdTomato+ cells formed ~3 fold more tracheospheres than WT tdTomato+ cells (Supplementary Fig.	('FACS', 'Gene', (13, 17))	('tracheospheres', 'CPA', (70, 84))	('more', 'PosReg', (65, 69))	('Keap1-/-', 'Var', (25, 33))	('FACS', 'Gene', '14081', (13, 17))	('men', 'Species', '9606', (116, 119))
105326	27663899	However, as previously observed with Trp53f/f mice treated with endotracheal Ad-Cre without SO2 injury, Trp53f/f;R26tdTomato or Keap1f/f;Trp53f/f;R26tdTomato mice developed SFTPC+NKX2-1+KRT5-adenocarcinomas in the lung periphery that necessitated euthanasia, regardless of SO2 injury (Fig.	('NKX2-1', 'Gene', (179, 185))	('carcinomas', 'Phenotype', 'HP:0030731', (196, 206))	('mice', 'Species', '10090', (158, 162))	('KRT5-adenocarcinomas', 'Disease', (186, 206))	('regardless of SO2 injury', 'Disease', 'MESH:D058186', (259, 283))	('SO2', 'Chemical', 'MESH:D013458', (273, 276))	('regardless of SO2 injury', 'Disease', (259, 283))	('mice', 'Species', '10090', (46, 50))	('Trp53f/f;R26tdTomato', 'Var', (104, 124))	('NKX2-1', 'Gene', '21869', (179, 185))	('carcinoma', 'Phenotype', 'HP:0030731', (196, 205))	('developed', 'Reg', (163, 172))	('SO2', 'Chemical', 'MESH:D013458', (92, 95))	('KRT5-adenocarcinomas', 'Disease', 'MESH:D000230', (186, 206))
105334	27663899	Thus, deletion of Trp53 with or without Keap1 in peripheral lung cells leads to lung adenocarcinoma and not squamous cell carcinoma.	('Trp53', 'Gene', (18, 23))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (108, 131))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('lung adenocarcinoma', 'Disease', (80, 99))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (80, 99))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (108, 131))	('squamous cell carcinoma', 'Disease', (108, 131))	('deletion', 'Var', (6, 14))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (80, 99))	('leads to', 'Reg', (71, 79))
105339	27663899	Within 2-4 months, tumors appeared in >80% of animals transplanted with either Trp53-/- or Keap1-/-;Trp53-/- cells, but never from WT or Keap1-/- cells (Fig.	('tumors', 'Disease', (19, 25))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('Trp53-/- cells', 'Var', (100, 114))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('Trp53-/-', 'Var', (79, 87))
105343	27663899	Consistent with their poorly differentiated histologic appearance, both P-LSCC and K/P-LSCC showed high tumor initiating cell frequency of ~1/10 in in vivo limiting dilution analyses (Supplementary Table S1).	('P-LSCC', 'Var', (72, 78))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumor', 'Disease', (104, 109))	('men', 'Species', '9606', (190, 193))	('K/P-LSCC', 'Var', (83, 91))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
105348	27663899	Additionally, compared to WT lung tissue, Krt5, Krt14, and p63 mRNAs were significantly more highly expressed in K/P-LSCCs while Sftpc expression was negligible (Supplementary Fig.	('more highly expressed', 'PosReg', (88, 109))	('Sftpc', 'Gene', '20389', (129, 134))	('K/P-LSCCs', 'Var', (113, 122))	('p63', 'Gene', '22061', (59, 62))	('Krt14', 'Gene', '16664', (48, 53))	('p63', 'Gene', (59, 62))	('Krt5', 'Gene', (42, 46))	('Krt5', 'Gene', '110308', (42, 46))	('Krt14', 'Gene', (48, 53))	('Sftpc', 'Gene', (129, 134))	('men', 'Species', '9606', (168, 171))
105351	27663899	Thus, while deletion of Trp53 with or without deletion of Keap1 in peripheral lung cells leads to formation of tumors closely resembling human LUAD, the same genetic alterations in bulk tracheal epithelial cells lead to formation of tumors closely resembling human LSCC (Fig.	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('deletion', 'Var', (12, 20))	('human', 'Species', '9606', (137, 142))	('Trp53', 'Gene', (24, 29))	('tumors', 'Disease', (233, 239))	('tumors', 'Disease', 'MESH:D009369', (233, 239))	('leads to', 'Reg', (89, 97))	('tumors', 'Phenotype', 'HP:0002664', (233, 239))	('rat', 'Species', '10116', (170, 173))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumors', 'Disease', (111, 117))	('tumors', 'Disease', 'MESH:D009369', (111, 117))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('lead to', 'Reg', (212, 219))	('human', 'Species', '9606', (259, 264))
105360	27663899	Similarly, in vivo tumor growth studies revealed that K/P-LSCCs grew significantly more rapidly than P-LSCCs when equal numbers of tumor cells were implanted subcutaneously (Fig.	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('tumor', 'Disease', (131, 136))	('grew', 'CPA', (64, 68))	('tumor', 'Disease', (19, 24))	('rapidly', 'PosReg', (88, 95))	('K/P-LSCCs', 'Var', (54, 63))
105361	27663899	In addition, K/P-LSCC cells displayed significantly higher migratory potential in vitro (Fig.	('rat', 'Species', '10116', (62, 65))	('migratory potential', 'CPA', (59, 78))	('higher', 'PosReg', (52, 58))	('K/P-LSCC', 'Var', (13, 21))
105367	27663899	In agreement with these gene expression changes, intracellular ROS levels were significantly lower in K/P-LSCC cells than P-LSCC cells (Fig.	('ROS', 'Chemical', 'MESH:D017382', (63, 66))	('men', 'Species', '9606', (8, 11))	('K/P-LSCC', 'Var', (102, 110))	('lower', 'NegReg', (93, 98))	('intracellular ROS levels', 'MPA', (49, 73))
105369	27663899	While Nrf2 target genes were upregulated by Keap1 loss, NFkB target genes were not differentially enriched in either of K/P-LSCC or P-LSCC cells (Fig 5E).	('upregulated', 'PosReg', (29, 40))	('Nrf2', 'Gene', '18024', (6, 10))	('K/P-LSCC', 'Var', (120, 128))	('Nrf2', 'Gene', (6, 10))	('Keap1', 'Gene', (44, 49))
105371	27663899	Furthermore, Nrf2 silencing in K/P-LSCC cells decreased cell proliferation in vitro and tumor growth in vivo to similar levels seen in P-LSCC cells (Fig.	('silencing', 'Var', (18, 27))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('Nrf2', 'Gene', (13, 17))	('rat', 'Species', '10116', (68, 71))	('cell proliferation', 'CPA', (56, 74))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('decreased', 'NegReg', (46, 55))	('tumor', 'Disease', (88, 93))	('Nrf2', 'Gene', '18024', (13, 17))
105375	27663899	These data indicate that loss of Keap1 in LSCCs leads to increased cell proliferation, invasion, and expression of Nrf2 target genes and suggest that Nrf2 activation and subsequent ROS decrease is the main mechanistic mediator of phenotypes observed upon Keap1 loss.	('Nrf2', 'Gene', (115, 119))	('cell proliferation', 'CPA', (67, 85))	('loss', 'NegReg', (261, 265))	('loss', 'Var', (25, 29))	('Nrf2', 'Gene', '18024', (150, 154))	('ROS', 'Chemical', 'MESH:D017382', (181, 184))	('decrease', 'NegReg', (185, 193))	('Nrf2', 'Gene', (150, 154))	('ROS', 'MPA', (181, 184))	('expression', 'MPA', (101, 111))	('increased', 'PosReg', (57, 66))	('invasion', 'CPA', (87, 95))	('rat', 'Species', '10116', (79, 82))	('Keap1', 'Gene', (33, 38))	('Nrf2', 'Gene', '18024', (115, 119))	('activation', 'PosReg', (155, 165))
105377	27663899	Consistent with baseline differences in ROS, treatment with the ROS inhibitor N-Acetylcysteine (NAC) increased tumorsphere formation in P-LSCC but not in K/P-LSCC cells (Fig.	('ROS', 'Chemical', 'MESH:D017382', (64, 67))	('increased', 'PosReg', (101, 110))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumors', 'Disease', (111, 117))	('tumors', 'Disease', 'MESH:D009369', (111, 117))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('men', 'Species', '9606', (50, 53))	('NAC', 'Chemical', 'MESH:D000111', (96, 99))	('P-LSCC', 'Var', (136, 142))	('N-Acetylcysteine', 'Chemical', 'MESH:D000111', (78, 94))	('ROS', 'Chemical', 'MESH:D017382', (40, 43))
105379	27663899	Next, we asked whether treatment with NAC could mimic the pro-metastatic effects of Keap1 deletion.	('deletion', 'Var', (90, 98))	('NAC', 'Chemical', 'MESH:D000111', (38, 41))	('Keap1', 'Gene', (84, 89))	('men', 'Species', '9606', (28, 31))
105382	27663899	Thus, effects of Keap1 deletion on cell proliferation, clonogenicity, and metastasis can be mimicked by reduction of cellular ROS.	('effects', 'Reg', (6, 13))	('reduction', 'NegReg', (104, 113))	('deletion', 'Var', (23, 31))	('Keap1', 'Gene', (17, 22))	('ROS', 'Chemical', 'MESH:D017382', (126, 129))	('metastasis', 'CPA', (74, 84))	('cell proliferation', 'CPA', (35, 53))	('clonogenicity', 'CPA', (55, 68))	('rat', 'Species', '10116', (47, 50))	('cellular', 'MPA', (117, 125))
105384	27663899	Congruent with this hypothesis, we found that K/P-LSCC cells were significantly more resistant to H2O2 treatment than P-LSCC cells (Fig.	('K/P-LSCC', 'Var', (46, 54))	('men', 'Species', '9606', (108, 111))	('H2O2', 'Chemical', 'MESH:D006861', (98, 102))	('resistant', 'MPA', (85, 94))
105386	27663899	Since the main mechanism of ionizing radiation (IR)-induced cell killing involves DNA damage caused by ROS induction, we next explored the effect of Keap1 deletion on LSCC radiosensitivity.	('ROS', 'Chemical', 'MESH:D017382', (103, 106))	('DNA damage', 'MPA', (82, 92))	('deletion', 'Var', (155, 163))	('Keap1', 'Gene', (149, 154))	('ROS', 'Gene', (103, 106))	('cell killing', 'CPA', (60, 72))
105387	27663899	In agreement with our findings of enhanced ability to survive ROS stress, K/P-LSCC cells were significantly more radioresistant than P-LSCC cells in tumorsphere clonogenic assays (Fig.	('K/P-LSCC', 'Var', (74, 82))	('ROS', 'Chemical', 'MESH:D017382', (62, 65))	('men', 'Species', '9606', (8, 11))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('radioresistant', 'CPA', (113, 127))	('tumors', 'Disease', (149, 155))	('tumors', 'Disease', 'MESH:D009369', (149, 155))	('tumors', 'Phenotype', 'HP:0002664', (149, 155))	('more', 'PosReg', (108, 112))
105389	27663899	Furthermore, IR-induced phosphorylated histone 2AX (gamma-H2AX) nuclear foci were significantly fewer in K/P-LSCC cells than in P-LSCC cells, indicating that K/P-LSCC cells develop less DNA double strand breaks after IR (Supplementary Fig.	('K/P-LSCC', 'Var', (105, 113))	('fewer', 'NegReg', (96, 101))	('men', 'Species', '9606', (227, 230))	('gamma-H2AX', 'Gene', '15270', (52, 62))	('less', 'NegReg', (181, 185))	('DNA double strand breaks', 'MPA', (186, 210))	('gamma-H2AX', 'Gene', (52, 62))
105395	27663899	Finally, we sought to identify a potential strategy for overcoming Keap1-mediated radioresistance.	('Keap1-mediated', 'Var', (67, 81))	('radioresistance', 'CPA', (82, 97))	('rat', 'Species', '10116', (45, 48))
105396	27663899	One of the genes most highly overexpressed by K/P-LSCCs compared to P-LSCCs was Slc7a11 (>15 fold, Supplementary Fig.	('Slc7a11', 'Gene', (80, 87))	('Slc7a11', 'Gene', '26570', (80, 87))	('men', 'Species', '9606', (105, 108))	('overexpressed', 'PosReg', (29, 42))	('K/P-LSCCs', 'Var', (46, 55))
105402	27663899	Based on the findings that both K/P-LSCCs and K/P-LUADs are more radioresistant to IR than P-LSCCs and P-LUAD respectively, we hypothesized that KEAP1/NRF2 mutations lead to increased rates of local recurrence in patients with localized NSCLCs treated with RT.	('NSCLC', 'Disease', (237, 242))	('P-LUADs', 'Disease', (48, 55))	('KEAP1/NRF2', 'Gene', (145, 155))	('local recurrence', 'MPA', (193, 209))	('mutations', 'Var', (156, 165))	('rat', 'Species', '10116', (184, 187))	('NSCLC', 'Disease', 'MESH:D002289', (237, 242))	('P-LUADs', 'Disease', 'MESH:C000656865', (48, 55))	('P-LUAD', 'Disease', (48, 54))	('patients', 'Species', '9606', (213, 221))	('P-LUAD', 'Disease', 'MESH:C000656865', (48, 54))	('P-LUAD', 'Disease', (103, 109))	('P-LUAD', 'Disease', 'MESH:C000656865', (103, 109))
105403	27663899	We therefore genotyped a cohort of 42 tumors from patients with Stage I-III NSCLC treated with RT, with or without concurrent chemotherapy and identified 9 patients with mutations in NRF2 or KEAP1 (Fig.	('patients', 'Species', '9606', (156, 164))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumors', 'Disease', (38, 44))	('NRF2', 'Gene', (183, 187))	('patients', 'Species', '9606', (50, 58))	('mutations', 'Var', (170, 179))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('NSCLC', 'Disease', (76, 81))	('tumors', 'Disease', 'MESH:D009369', (38, 44))	('NSCLC', 'Disease', 'MESH:D002289', (76, 81))	('KEAP1', 'Gene', (191, 196))
105405	27663899	All seven KEAP1 mutations are predicted to be deleterious to protein structure/function and six are located in the Kelch repeat domain that mediates interaction with NRF2 (Supplementary Table S3).	('protein', 'MPA', (61, 68))	('KEAP1', 'Gene', (10, 15))	('interaction', 'Interaction', (149, 160))	('mutations', 'Var', (16, 25))	('NRF2', 'Protein', (166, 170))	('mediates', 'Reg', (140, 148))	('men', 'Species', '9606', (178, 181))
105406	27663899	Strikingly, the cumulative incidence of local failure at 30 months was 70% in patients whose tumors carried mutations in KEAP1/NRF2 and 18% in patients with wild type tumors (P<0.003; Fig.	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('mutations', 'Var', (108, 117))	('tumors', 'Disease', 'MESH:D009369', (167, 173))	('type tumors', 'Disease', 'MESH:D009369', (162, 173))	('local failure', 'Disease', (40, 53))	('tumors', 'Disease', 'MESH:D009369', (93, 99))	('patients', 'Species', '9606', (78, 86))	('type tumors', 'Disease', (162, 173))	('patients', 'Species', '9606', (143, 151))	('local failure', 'Disease', 'MESH:D012594', (40, 53))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('tumors', 'Disease', (93, 99))	('tumors', 'Disease', (167, 173))	('tumors', 'Phenotype', 'HP:0002664', (167, 173))	('KEAP1/NRF2', 'Gene', (121, 131))
105407	27663899	Additionally, out of 12 total patients who developed local recurrence, 6 had tumors with KEAP1/NRF2 mutations, implicating the pathway in half of RT failures in our cohort.	('tumors', 'Disease', (77, 83))	('mutations', 'Var', (100, 109))	('tumors', 'Disease', 'MESH:D009369', (77, 83))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('patients', 'Species', '9606', (30, 38))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('KEAP1/NRF2', 'Gene', (89, 99))
105408	27663899	Restricting analysis to patients with Stage II-III NSCLC also revealed significantly higher rates of local failure in patients with KEAP1 or NRF2 mutations (P <0.04; Fig.	('local failure', 'Disease', 'MESH:D012594', (101, 114))	('mutations', 'Var', (146, 155))	('NSCLC', 'Disease', (51, 56))	('NRF2', 'Gene', (141, 145))	('rat', 'Species', '10116', (92, 95))	('NSCLC', 'Disease', 'MESH:D002289', (51, 56))	('patients', 'Species', '9606', (24, 32))	('patients', 'Species', '9606', (118, 126))	('KEAP1', 'Gene', (132, 137))	('local failure', 'Disease', (101, 114))
105409	27663899	Of note, mutations in TP53, which were found in 19 patients, were not associated with risk of local recurrence (Supplementary Fig.	('mutations', 'Var', (9, 18))	('men', 'Species', '9606', (118, 121))	('patients', 'Species', '9606', (51, 59))	('local recurrence', 'CPA', (94, 110))	('TP53', 'Gene', (22, 26))
105411	27663899	To facilitate such analyses, our group developed an ultra-sensitive approach for detection of mutant circulating tumor DNA (ctDNA) called CAPP-Seq, which we have recently optimized for non-invasive mutation detection.	('tumor', 'Disease', (113, 118))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('mutant', 'Var', (94, 100))
105412	27663899	We were able to obtain pre-treatment plasma for 7 of the patients in our initial cohort and found that CAPP-Seq analysis correctly identified KEAP1 mutation status in all of them (Fig.	('mutation', 'Var', (148, 156))	('KEAP1', 'Gene', (142, 147))	('patients', 'Species', '9606', (57, 65))	('men', 'Species', '9606', (32, 35))
105413	27663899	Furthermore, in one patient for whom we analyzed serial plasma samples, the KEAP1 mutation as well as other co-occurring mutations tracked with treatment response (Fig.	('mutation', 'Var', (82, 90))	('patient', 'Species', '9606', (20, 27))	('men', 'Species', '9606', (149, 152))	('KEAP1', 'Gene', (76, 81))
105415	27663899	We applied CAPP-Seq to non-invasively genotype each patient's tumor using the pre-RT plasma sample and identified 5 patients with KEAP1 mutations (Supplementary Table S4).	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('KEAP1', 'Gene', (130, 135))	('patient', 'Species', '9606', (116, 123))	('patients', 'Species', '9606', (116, 124))	('tumor', 'Disease', (62, 67))	('men', 'Species', '9606', (153, 156))	('mutations', 'Var', (136, 145))	('patient', 'Species', '9606', (52, 59))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
105416	27663899	As in our initial cohort, the cumulative incidence of local recurrence was significantly higher in patients with KEAP1 mutations (p=0.02) (Fig.	('KEAP1', 'Gene', (113, 118))	('patients', 'Species', '9606', (99, 107))	('higher', 'PosReg', (89, 95))	('mutations', 'Var', (119, 128))	('local recurrence', 'CPA', (54, 70))
105417	27663899	Taken together, these results suggest that KEAP1/NRF2 mutation status is a predictor of local recurrence after RT in NSCLC patients.	('mutation', 'Var', (54, 62))	('NSCLC', 'Disease', (117, 122))	('KEAP1/NRF2', 'Gene', (43, 53))	('patients', 'Species', '9606', (123, 131))	('NSCLC', 'Disease', 'MESH:D002289', (117, 122))	('local recurrence', 'CPA', (88, 104))
105418	27663899	In this study, we demonstrate that deletion of Keap1 or Trp53 in murine ABSCs promotes their self-renewal, leading to expansion of mutant stem cell clones.	('Keap1', 'Gene', (47, 52))	('promotes', 'PosReg', (78, 86))	('Trp53', 'Gene', (56, 61))	('mutant', 'Var', (131, 137))	('expansion', 'PosReg', (118, 127))	('deletion', 'Var', (35, 43))	('rat', 'Species', '10116', (25, 28))	('self-renewal', 'CPA', (93, 105))	('murine', 'Species', '10090', (65, 71))
105420	27663899	Finally, we show for the first time that KEAP1/NRF2 mutations strongly predict clinical resistance to RT in NSCLC patients.	('mutations', 'Var', (52, 61))	('KEAP1/NRF2', 'Gene', (41, 51))	('NSCLC', 'Disease', (108, 113))	('predict', 'Reg', (71, 78))	('NSCLC', 'Disease', 'MESH:D002289', (108, 113))	('clinical resistance to RT', 'MPA', (79, 104))	('patients', 'Species', '9606', (114, 122))
105428	27663899	We found that the type of lung cancer formed by deletion of Trp53 is dependent on the normal cell type that is targeted.	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('type of lung cancer', 'Disease', 'MESH:D008175', (18, 37))	('deletion', 'Var', (48, 56))	('Trp53', 'Gene', (60, 65))	('type of lung cancer', 'Disease', (18, 37))	('lung cancer', 'Phenotype', 'HP:0100526', (26, 37))
105429	27663899	Specifically, inactivation of Trp53 by Ad-Cre inhalation, which leads to recombination in peripheral lung cells but not in the central airway, led to SFTPC+TTF-1+KRT5- LUAD formation.	('Trp53', 'Protein', (30, 35))	('TTF-1', 'Gene', (156, 161))	('TTF-1', 'Gene', '22130', (156, 161))	('inactivation', 'Var', (14, 26))
105430	27663899	However, when we specifically induced deletion of Trp53 with or without Keap1 in tracheal epithelial cells, LSCCs were generated.	('Trp53', 'Gene', (50, 55))	('rat', 'Species', '10116', (123, 126))	('deletion', 'Var', (38, 46))
105440	27663899	provided data indicating that IKKalpha inactivation in Krt5 expressing lung cells, but not other types of lung cells, lead to LSCC formation, consistent with our findings of ABSCs as the cell of origin in our LSCC models.	('lead to', 'Reg', (118, 125))	('LSCC formation', 'Disease', (126, 140))	('Krt5', 'Gene', '110308', (55, 59))	('IKKalpha', 'Gene', '12675', (30, 38))	('Krt5', 'Gene', (55, 59))	('IKKalpha', 'Gene', (30, 38))	('inactivation', 'Var', (39, 51))
105441	27663899	Separately, in an Lkb1;Pten deletion-based LSCC model, SPC-Cre and CCSP-Cre failed to produce tumors, while endotracheal Ad-Cre administration led to only LSCC formation.	('SPC', 'Gene', '20693', (55, 58))	('SPC', 'Gene', (55, 58))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('Pten', 'Gene', (23, 27))	('Pten', 'Gene', '19211', (23, 27))	('tumors', 'Disease', (94, 100))	('deletion-based', 'Var', (28, 42))	('rat', 'Species', '10116', (136, 139))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('rat', 'Species', '10116', (4, 7))	('CCSP', 'Gene', '22287', (67, 71))	('CCSP', 'Gene', (67, 71))
105444	27663899	Rather, a complex interplay between the cell of origin and the driver mutation appears to determine the type of lung cancer that develops.	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('type of lung cancer', 'Disease', 'MESH:D008175', (104, 123))	('lung cancer', 'Phenotype', 'HP:0100526', (112, 123))	('determine', 'Reg', (90, 99))	('mutation', 'Var', (70, 78))	('type of lung cancer', 'Disease', (104, 123))
105447	27663899	Specifically, Krt5CrePR-mediated Kras activation or Pten deletion resulted in mixed LSCC and LUAD tumors, although as the authors point out, this may have been due to leakiness of the promoter that was used.	('LUAD tumors', 'Disease', 'MESH:D009369', (93, 104))	('leakiness', 'Disease', 'MESH:C535298', (167, 176))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('leakiness', 'Disease', (167, 176))	('LUAD tumors', 'Disease', (93, 104))	('deletion', 'Var', (57, 65))	('Krt5', 'Gene', (14, 18))	('mixed LSCC', 'Disease', (78, 88))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('resulted in', 'Reg', (66, 77))	('Krt5', 'Gene', '110308', (14, 18))	('Pten', 'Gene', (52, 56))	('Pten', 'Gene', '19211', (52, 56))
105448	27663899	Thus, it appears that the cell of origin may dictate the lung cancer subtype that forms for certain mutations such as Trp53 but not for others such as Kras and Sox2.	('mutations', 'Var', (100, 109))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('lung cancer', 'Disease', 'MESH:D008175', (57, 68))	('Trp53', 'Gene', (118, 123))	('dictate', 'Reg', (45, 52))	('lung cancer', 'Disease', (57, 68))	('lung cancer', 'Phenotype', 'HP:0100526', (57, 68))
105450	27663899	Conversely, driver mutations that are predominantly observed in human LSCC, such as Sox2 and Lkb1, appear to be able to induce LSCC even in bronchiolar club cells or alveolar type II cells while mutations that are predominantly observed in human LUADs such as Kras, appear to be able to drive LUAD formation in murine ABSCs.	('induce', 'Reg', (120, 126))	('human', 'Species', '9606', (64, 69))	('LSCC', 'Disease', (127, 131))	('human', 'Species', '9606', (240, 245))	('murine', 'Species', '10090', (311, 317))	('mutations', 'Var', (19, 28))	('club', 'Phenotype', 'HP:0001217', (152, 156))	('alveolar type II', 'Disease', (166, 182))	('alveolar type II', 'Disease', 'MESH:D002282', (166, 182))	('Lkb1', 'Gene', (93, 97))
105452	27663899	Significantly, the impact of Trp53 loss on ABSC self-renewal and the fact that loss of both Trp53 and Keap1 leads to increased self-renewal compared to loss of either gene alone have not been previously demonstrated and is of clinical relevance, since TP53 is mutated in over 80% of human LSCCs harboring KEAP1 mutations.	('KEAP1', 'Gene', (305, 310))	('rat', 'Species', '10116', (210, 213))	('self-renewal', 'CPA', (127, 139))	('increased', 'PosReg', (117, 126))	('loss', 'NegReg', (35, 39))	('mutations', 'Var', (311, 320))	('Trp53', 'Gene', (29, 34))	('human', 'Species', '9606', (283, 288))	('Trp53', 'Gene', (92, 97))	('TP53', 'Gene', (252, 256))
105453	27663899	recently also reported a role for ROS regulation in ABSC homeostasis that was mediated through increased Notch pathway signaling and reflected by gene expression changes of Notch pathway components upon Nrf2 modulation.	('Nrf2', 'Gene', '18024', (203, 207))	('ROS', 'Chemical', 'MESH:D017382', (34, 37))	('ROS', 'Protein', (34, 37))	('modulation', 'Var', (208, 218))	('Notch', 'Gene', '18128', (173, 178))	('Nrf2', 'Gene', (203, 207))	('Notch', 'Gene', '18128', (105, 110))	('Notch', 'Gene', (173, 178))	('increased', 'PosReg', (95, 104))	('Notch', 'Gene', (105, 110))	('changes', 'Reg', (162, 169))	('ABSC homeostasis', 'Disease', (52, 68))
105454	27663899	We did not observe any differences in expression of the same genes by Keap1 deletion, suggesting that this Notch-based mechanism does not play a major role in mediating the effects of Nrf2 activation in our LSCC models.	('deletion', 'Var', (76, 84))	('Notch', 'Gene', '18128', (107, 112))	('Notch', 'Gene', (107, 112))	('Keap1', 'Gene', (70, 75))	('Nrf2', 'Gene', '18024', (184, 188))	('LSCC', 'Disease', (207, 211))	('Nrf2', 'Gene', (184, 188))
105455	27663899	Indeed, evidence consistent with such clonal expansion of mutant ABSCs has been demonstrated in humans.	('mutant', 'Var', (58, 64))	('humans', 'Species', '9606', (96, 102))	('ABSCs', 'Gene', (65, 70))	('rat', 'Species', '10116', (87, 90))
105456	27663899	Specifically, it has been shown that pre-invasive lesions consisting of keratin 14 expressing basal cells that contain TP53 mutations can expand through large portions of the bronchial tree, including spreading from one side to the other.	('keratin 14', 'Gene', '16664', (72, 82))	('TP53', 'Gene', (119, 123))	('mutations', 'Var', (124, 133))	('keratin 14', 'Gene', (72, 82))
105457	27663899	Although the mutation status of KEAP1 has not been examined in these studies, we speculate that a premalignant clone containing a TP53 mutation would gain significant additional fitness if it acquired mutations in KEAP1, mediated by the increased proliferation, migration, and resistance to oxidative stress that we observed in our model.	('migration', 'CPA', (262, 271))	('increased', 'PosReg', (237, 246))	('mutations', 'Var', (201, 210))	('TP53', 'Gene', (130, 134))	('oxidative stress', 'Phenotype', 'HP:0025464', (291, 307))	('fitness', 'CPA', (178, 185))	('rat', 'Species', '10116', (254, 257))	('mutation', 'Var', (135, 143))	('gain', 'PosReg', (150, 154))	('rat', 'Species', '10116', (265, 268))
105458	27663899	From a clinical standpoint, our finding of most immediate potential impact is the observation that KEAP1/NRF2 mutation status predicts the rate of local failure after radiotherapy in NSCLC patients.	('rat', 'Species', '10116', (139, 142))	('NSCLC', 'Disease', (183, 188))	('local failure', 'Disease', (147, 160))	('NSCLC', 'Disease', 'MESH:D002289', (183, 188))	('local failure', 'Disease', 'MESH:D012594', (147, 160))	('mutation', 'Var', (110, 118))	('predicts', 'Reg', (126, 134))	('patients', 'Species', '9606', (189, 197))	('KEAP1/NRF2', 'Gene', (99, 109))
105459	27663899	Since radiotherapy kills cells by induction of ROS that lead to DNA double strand breaks, KEAP1/NRF2 mutant tumors are likely resistant to RT due to enhanced expression of ROS scavengers and detoxification pathways.	('lead to', 'Reg', (56, 63))	('KEAP1/NRF2', 'Gene', (90, 100))	('ROS', 'Chemical', 'MESH:D017382', (172, 175))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('expression', 'MPA', (158, 168))	('mutant', 'Var', (101, 107))	('tumors', 'Disease', (108, 114))	('enhanced', 'PosReg', (149, 157))	('tumors', 'Disease', 'MESH:D009369', (108, 114))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('DNA double strand breaks', 'MPA', (64, 88))	('ROS', 'Chemical', 'MESH:D017382', (47, 50))
105460	27663899	However, we cannot rule out that additional somatic or epigenetic alterations that we did not interrogate may play a role in the higher incidence of local recurrence in KEAP1/NRF2 mutant tumors.	('rat', 'Species', '10116', (70, 73))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('local', 'CPA', (149, 154))	('mutant', 'Var', (180, 186))	('KEAP1/NRF2', 'Gene', (169, 179))	('tumors', 'Disease', (187, 193))	('tumors', 'Disease', 'MESH:D009369', (187, 193))	('tumors', 'Phenotype', 'HP:0002664', (187, 193))
105462	27663899	We hypothesize that these conflicting results likely relate to statistical power, differences in clinical covariates among the different cohorts, and the potential impact of additional somatic or epigenetic modifiers of tumor aggressiveness whose prevalence may differ between studies.	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('tumor aggressiveness', 'Disease', (220, 240))	('aggressiveness', 'Phenotype', 'HP:0000718', (226, 240))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (220, 240))	('epigenetic modifiers', 'Var', (196, 216))	('relate', 'Reg', (53, 59))
105463	27663899	All of the KEAP1 mutations we identified in human patients were somatic and appeared to be heterozygous.	('human', 'Species', '9606', (44, 49))	('mutations', 'Var', (17, 26))	('KEAP1', 'Gene', (11, 16))	('patients', 'Species', '9606', (50, 58))
105464	27663899	Separately, epigenetic modifications of KEAP1 promoter associated with loss of expression have been reported in a variety of malignancies, including lung cancer.	('lung cancer', 'Disease', 'MESH:D008175', (149, 160))	('reported', 'Reg', (100, 108))	('expression', 'MPA', (79, 89))	('KEAP1 promoter', 'Gene', (40, 54))	('lung cancer', 'Phenotype', 'HP:0100526', (149, 160))	('malignancies', 'Disease', 'MESH:D009369', (125, 137))	('rat', 'Species', '10116', (4, 7))	('loss of', 'NegReg', (71, 78))	('lung cancer', 'Disease', (149, 160))	('epigenetic modifications', 'Var', (12, 36))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('malignancies', 'Disease', (125, 137))
105465	27663899	Our observation of KEAP1/NRF2 mutations in the plasma of NSCLC patients being treated with RT suggests that non-invasive mutation assessment using ctDNA could be a valuable approach for facilitating personalized management of NSCLC patients who have limited tissue samples available for molecular analysis.	('NSCLC', 'Disease', 'MESH:D002289', (226, 231))	('patients', 'Species', '9606', (232, 240))	('mutations', 'Var', (30, 39))	('KEAP1/NRF2', 'Gene', (19, 29))	('patients', 'Species', '9606', (63, 71))	('NSCLC', 'Disease', (57, 62))	('men', 'Species', '9606', (218, 221))	('men', 'Species', '9606', (136, 139))	('NSCLC', 'Disease', (226, 231))	('NSCLC', 'Disease', 'MESH:D002289', (57, 62))
105466	27663899	Given the high rate of local failure we observed in patients with KEAP1/NRF2 mutations, mutation testing for these genes in tumor or plasma could potentially be used to personalize treatment strategies for NSCLC patients.	('KEAP1/NRF2', 'Gene', (66, 76))	('local failure', 'Disease', (23, 36))	('rat', 'Species', '10116', (193, 196))	('rat', 'Species', '10116', (15, 18))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('NSCLC', 'Disease', (206, 211))	('tumor', 'Disease', (124, 129))	('patients', 'Species', '9606', (212, 220))	('NSCLC', 'Disease', 'MESH:D002289', (206, 211))	('men', 'Species', '9606', (186, 189))	('local failure', 'Disease', 'MESH:D012594', (23, 36))	('mutations', 'Var', (77, 86))	('patients', 'Species', '9606', (52, 60))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
105468	27663899	We speculate that KEAP1/NRF2 mutation status could potentially be used to select the best choice of local therapy for such patients or to identify patients who might benefit from radiation dose escalation.	('patients', 'Species', '9606', (123, 131))	('mutation', 'Var', (29, 37))	('patients', 'Species', '9606', (147, 155))	('KEAP1/NRF2', 'Gene', (18, 28))
105469	27663899	Furthermore, inhibition of critical NRF2 targets, such system xc-, may allow targeted radiosensitization in patients with KEAP1/NRF2 mutations.	('patients', 'Species', '9606', (108, 116))	('mutations', 'Var', (133, 142))	('KEAP1/NRF2', 'Gene', (122, 132))
105470	27663899	Prospective studies to validate the association of KEAP1/NRF2 mutations with radioresistance and to test personalized treatment approaches will be of course be critical.	('radioresistance', 'CPA', (77, 92))	('men', 'Species', '9606', (123, 126))	('KEAP1/NRF2', 'Gene', (51, 61))	('mutations', 'Var', (62, 71))
105471	27663899	Lastly, since KEAP1/NRF2 mutations are found in many other cancer types, we hypothesize that they may contribute to radioresistance in a substantial fraction of cancer patients.	('mutations', 'Var', (25, 34))	('KEAP1/NRF2', 'Gene', (14, 24))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('radioresistance', 'CPA', (116, 131))	('found', 'Reg', (39, 44))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('contribute', 'Reg', (102, 112))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('patients', 'Species', '9606', (168, 176))	('cancer', 'Disease', (161, 167))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))
105519	27663899	When matched germline was available, variants at >=2.5% were called and when only tumor DNA was available variants at >=5% were called.	('variants', 'Var', (37, 45))	('tumor', 'Disease', (82, 87))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))
105520	27663899	Non-invasive genotyping was performed to call nonsynonymous SNVs and indels in KEAP1, NRF2, and TP53 that were present in pre-treatment plasma but not matched germline DNA obtained from plasma-depleted whole blood.	('TP53', 'Gene', (96, 100))	('KEAP1', 'Gene', (79, 84))	('men', 'Species', '9606', (131, 134))	('NRF2', 'Gene', (86, 90))	('SNVs', 'Var', (60, 64))	('indels', 'Var', (69, 75))
105522	27663899	The global amount of circulating tumor DNA in each sample was calculated using single nucleotide variants and indel reporters detected in the tumor biopsy.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('tumor', 'Disease', (142, 147))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumor', 'Disease', (33, 38))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('single nucleotide variants', 'Var', (79, 105))
105531	27663899	KEAP1/NRF2 mutations increase radioresistance and predict local tumor recurrence in radiotherapy patients.	('mutations', 'Var', (11, 20))	('KEAP1/NRF2', 'Gene', (0, 10))	('tumor', 'Disease', (64, 69))	('radioresistance', 'CPA', (30, 45))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('increase', 'PosReg', (21, 29))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('patients', 'Species', '9606', (97, 105))
105532	27663899	Our findings are of potential clinical relevance and could lead to personalized treatment strategies for tumors with KEAP1/NRF2 mutations.	('tumors', 'Disease', (105, 111))	('tumors', 'Disease', 'MESH:D009369', (105, 111))	('KEAP1/NRF2', 'Gene', (117, 127))	('mutations', 'Var', (128, 137))	('lead', 'Reg', (59, 63))	('rat', 'Species', '10116', (92, 95))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('men', 'Species', '9606', (85, 88))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))
105537	25644553	A 37-year-old Japanese man was diagnosed with T4b (descending aorta) N2M0, Stage IIIC middle thoracic esophageal squamous cell carcinoma.	('man', 'Species', '9606', (23, 26))	('thoracic esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (93, 136))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (113, 136))	('descending aorta', 'Phenotype', 'HP:0025495', (51, 67))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('T4b', 'Var', (46, 49))	('thoracic esophageal squamous cell carcinoma', 'Disease', (93, 136))
105558	25644553	Based on these results, this patient was diagnosed with T4b (descending aorta) N2M0, Stage IIIC middle thoracic esophageal squamous cell carcinoma.	('patient', 'Species', '9606', (29, 36))	('descending aorta', 'Phenotype', 'HP:0025495', (61, 77))	('thoracic esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (103, 146))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (123, 146))	('T4b', 'Var', (56, 59))	('thoracic esophageal squamous cell carcinoma', 'Disease', (103, 146))
105596	31096734	Fibroblast Growth Factor Receptor 1 (FGFR1) Amplification Detected by Droplet Digital Polymerase Chain Reaction (ddPCR) Is a Prognostic Factor in Colorectal Cancers The purpose of this study was to reveal the clinicopathological characteristics and prognostic implications associated with fibroblast growth factor receptor 1 (FGFR1) amplification in colorectal cancers (CRCs).	('FGFR1', 'Gene', (326, 331))	('FGFR1', 'Gene', '2260', (37, 42))	('Droplet Digital', 'Disease', 'MESH:D058066', (70, 85))	('colorectal cancers', 'Disease', 'MESH:D015179', (350, 368))	('CRCs', 'Disease', (370, 374))	('Cancers', 'Phenotype', 'HP:0002664', (157, 164))	('Colorectal Cancers', 'Disease', 'MESH:D015179', (146, 164))	('Fibroblast Growth Factor Receptor 1', 'Gene', '2260', (0, 35))	('FGFR1', 'Gene', (37, 42))	('FGFR1', 'Gene', '2260', (326, 331))	('fibroblast growth factor receptor 1', 'Gene', '2260', (289, 324))	('CRCs', 'Disease', 'MESH:D015179', (370, 374))	('Colorectal Cancers', 'Disease', (146, 164))	('fibroblast growth factor receptor 1', 'Gene', (289, 324))	('colorectal cancers', 'Disease', (350, 368))	('Droplet Digital', 'Disease', (70, 85))	('cancer', 'Phenotype', 'HP:0002664', (361, 367))	('Cancer', 'Phenotype', 'HP:0002664', (157, 163))	('amplification', 'Var', (333, 346))	('Fibroblast Growth Factor Receptor 1', 'Gene', (0, 35))	('cancers', 'Phenotype', 'HP:0002664', (361, 368))
105599	31096734	FGFR1 amplification was found in 10 of the 384 CRCs (2.6%) in the SNUH2007 dataset, and in 28 of the 380 CRCs (7.4%) in the SNUH Folfox dataset.	('CRCs', 'Disease', 'MESH:D015179', (105, 109))	('CRCs', 'Disease', 'MESH:D015179', (47, 51))	('FGFR1', 'Gene', (0, 5))	('CRCs', 'Disease', (105, 109))	('amplification', 'Var', (6, 19))	('CRCs', 'Disease', (47, 51))
105600	31096734	High FGFR1 expression was associated with female sex and KRAS mutation.	('High', 'Var', (0, 4))	('expression', 'MPA', (11, 21))	('female sex', 'Disease', (42, 52))	('KRAS', 'Gene', (57, 61))	('KRAS', 'Gene', '3845', (57, 61))	('associated', 'Reg', (26, 36))	('FGFR1', 'Gene', (5, 10))
105601	31096734	At the molecular level, FGFR1 amplification was mutually exclusive with BRAF mutation, microsatellite instability, and MLH1 methylation, in both SNUH2007 and SNUH Folfox datasets.	('microsatellite instability', 'MPA', (87, 113))	('BRAF', 'Gene', (72, 76))	('MLH1', 'Gene', '4292', (119, 123))	('MLH1', 'Gene', (119, 123))	('mutation', 'Var', (77, 85))	('FGFR1', 'Gene', (24, 29))	('methylation', 'Var', (124, 135))	('BRAF', 'Gene', '673', (72, 76))
105602	31096734	Within the SNUH2007 dataset, CRC patients with high FGFR1 expression had an inferior progression-free survival compared with those with low FGFR1 expression.	('progression-free survival', 'CPA', (85, 110))	('patients', 'Species', '9606', (33, 41))	('high', 'Var', (47, 51))	('FGFR1', 'Gene', (52, 57))	('inferior', 'NegReg', (76, 84))
105607	31096734	Although alternative carcinogenic pathways, such as microsatellite instability (MSI) and CpG island methylator phenotype (CIMP), have been described, the vast majority of CRCs (approximately 70%) exhibit chromosomal instability (CIN), which is characterized by the accumulation of somatic mutations and copy number alterations (CNAs).	('CRCs', 'Disease', (171, 175))	('carcinogenic', 'Disease', 'MESH:D063646', (21, 33))	('CRCs', 'Disease', 'MESH:D015179', (171, 175))	('carcinogenic', 'Disease', (21, 33))	('copy number alterations', 'Var', (303, 326))	('chromosomal instability', 'Phenotype', 'HP:0040012', (204, 227))	('chromosomal instability', 'Disease', (204, 227))	('exhibit', 'Reg', (196, 203))
105609	31096734	However, several genomic regions show significant focal amplification or deletion of CRCs.	('deletion', 'Var', (73, 81))	('CRCs', 'Disease', (85, 89))	('CRCs', 'Disease', 'MESH:D015179', (85, 89))
105614	31096734	Amplification of the FGFR1 gene is reported in estrogen receptor (ER)-positive breast cancers, lung cancers, esophageal cancers, and bladder cancers.	('esophageal cancers', 'Disease', 'MESH:D004938', (109, 127))	('bladder cancers', 'Disease', 'MESH:D001749', (133, 148))	('reported', 'Reg', (35, 43))	('bladder cancers', 'Disease', (133, 148))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('lung cancers', 'Disease', 'MESH:D008175', (95, 107))	('cancers', 'Phenotype', 'HP:0002664', (120, 127))	('cancers', 'Phenotype', 'HP:0002664', (86, 93))	('lung cancers', 'Disease', (95, 107))	('cancers', 'Phenotype', 'HP:0002664', (141, 148))	('estrogen receptor', 'Gene', '2099', (47, 64))	('lung cancer', 'Phenotype', 'HP:0100526', (95, 106))	('lung cancers', 'Phenotype', 'HP:0100526', (95, 107))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('breast cancers', 'Disease', 'MESH:D001943', (79, 93))	('breast cancers', 'Disease', (79, 93))	('FGFR1', 'Gene', (21, 26))	('cancers', 'Phenotype', 'HP:0002664', (100, 107))	('bladder cancers', 'Phenotype', 'HP:0009725', (133, 148))	('esophageal cancers', 'Disease', (109, 127))	('breast cancers', 'Phenotype', 'HP:0003002', (79, 93))	('Amplification', 'Var', (0, 13))	('ER', 'Gene', '2099', (66, 68))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('breast cancer', 'Phenotype', 'HP:0003002', (79, 92))	('estrogen receptor', 'Gene', (47, 64))
105615	31096734	Recently, FGFR1 amplification has been suggested to be associated with poor prognosis in various types of cancers, including squamous cell carcinoma of the lung and esophagus, and ERpositive breast cancers.	('squamous cell carcinoma of the lung', 'Phenotype', 'HP:0030359', (125, 160))	('cancers', 'Phenotype', 'HP:0002664', (106, 113))	('cancers', 'Disease', 'MESH:D009369', (198, 205))	('cancers', 'Disease', (106, 113))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (125, 148))	('ERpositive breast cancers', 'Disease', 'MESH:D001943', (180, 205))	('associated', 'Reg', (55, 65))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('esophagus', 'Disease', (165, 174))	('cancers', 'Phenotype', 'HP:0002664', (198, 205))	('cancers', 'Disease', (198, 205))	('cancers', 'Disease', 'MESH:D009369', (106, 113))	('squamous cell carcinoma of the lung', 'Disease', (125, 160))	('squamous cell carcinoma of the lung', 'Disease', 'MESH:D002294', (125, 160))	('carcinoma', 'Phenotype', 'HP:0030731', (139, 148))	('carcinoma of the lung', 'Phenotype', 'HP:0100526', (139, 160))	('amplification', 'Var', (16, 29))	('FGFR1', 'Gene', (10, 15))	('ERpositive breast cancers', 'Disease', (180, 205))	('breast cancers', 'Phenotype', 'HP:0003002', (191, 205))	('breast cancer', 'Phenotype', 'HP:0003002', (191, 204))
105618	31096734	FGFR1 amplification is found in 2% to 5% of CRCs.	('amplification', 'Var', (6, 19))	('CRCs', 'Disease', (44, 48))	('CRCs', 'Disease', 'MESH:D015179', (44, 48))	('FGFR1', 'Gene', (0, 5))
105619	31096734	However, the clinicopathologic characteristics and prognostic implications associated with FGFR1 amplification in CRCs are not well established because of the scarcity of this alteration.	('CRCs', 'Disease', (114, 118))	('amplification', 'Var', (97, 110))	('FGFR1', 'Gene', (91, 96))	('CRCs', 'Disease', 'MESH:D015179', (114, 118))
105620	31096734	In this study, we evaluated the FGFR1 copy number in CRCs using ddPCR and evaluated its association with clinicopathologic characteristics and prognostic implications.	('FGFR1', 'Gene', (32, 37))	('CRCs', 'Disease', 'MESH:D015179', (53, 57))	('copy number', 'Var', (38, 49))	('CRCs', 'Disease', (53, 57))	('association', 'Interaction', (88, 99))
105636	31096734	The microsatellite status of each tumor was determined by the evaluation of five microsatellite markers: D2S123, D5S346, D17S250, BAT25, and BAT26.	('D17S250', 'Var', (121, 128))	('tumor', 'Disease', (34, 39))	('D2S123', 'Var', (105, 111))	('BAT25', 'Var', (130, 135))	('D5S346', 'Var', (113, 119))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('BAT26', 'Gene', (141, 146))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
105638	31096734	Five CRC cell lines, with FGFR1 amplification (SNU-C1), high FGFR1 expression (SNU-283, SW620 and HCT116), and no FGFR1 amplification and low FGFR1 expression (SNU-81) were grown for 72 hours in RPMI-1640 or Dulbecco's modified Eagle's medium containing 10% fetal bovine serum, at 37& under a humidified 5% CO2 atmosphere.	('SW620', 'CellLine', 'CVCL:0547', (88, 93))	('FGFR1', 'Gene', (61, 66))	('FGFR1', 'Gene', (26, 31))	('HCT116', 'CellLine', 'CVCL:0291', (98, 104))	('amplification', 'Var', (32, 45))	('CO2', 'Chemical', 'MESH:D002245', (307, 310))	('expression', 'MPA', (67, 77))
105639	31096734	The effect of FGFR inhibitor, PD173074, on cell proliferation was determined using the WST-1 assay in SNU-C1, and 3-(4,5-dimethylthiazol-2-yl)-2-5-diphenyltetrazolium bromide (MTT) cell viability assay in the other cell lines.	('PD173074', 'Var', (30, 38))	('MTT', 'Chemical', 'MESH:C022616', (176, 179))	('PD173074', 'Chemical', 'MESH:C115711', (30, 38))	('FGFR', 'Gene', (14, 18))	('3-(4,5-dimethylthiazol-2-yl)-2-5-diphenyltetrazolium bromide', 'Chemical', 'MESH:C022616', (114, 174))	('cell proliferation', 'CPA', (43, 61))
105656	31096734	Based on a cut-off value of 3.3, 10 patients (2.6%) showed FGFR1 amplification.	('amplification', 'Var', (65, 78))	('patients', 'Species', '9606', (36, 44))	('FGFR1', 'Gene', (59, 64))
105662	31096734	There was no significant correlation between FGFR1 copy number and FGFR1 expression in either the SNUH2007 dataset (p for ANOVA=0.789) or the SNUH Folfox dataset (p for ANOVA=0.889) (S4A and S4B Fig.).	('FGFR1', 'Gene', (67, 72))	('S4A', 'Chemical', 'MESH:D013455', (183, 186))	('expression', 'MPA', (73, 83))	('copy', 'Var', (51, 55))	('FGFR1', 'Gene', (45, 50))
105667	31096734	In DNA methylation analysis, TCGA COADREAD dataset showed a hypomethylation of CpGs located in the gene body which correspond to AKAP12, GEM, and NOTCH4 (cg09846917, cg22885-024, and cg26793289, respectively) in cases with FGFR1 amplification compared with cases without FGFR1 amplification.	('hypomethylation', 'MPA', (60, 75))	('COAD', 'Disease', (34, 38))	('COAD', 'Disease', 'MESH:D012004', (34, 38))	('NOTCH4', 'Gene', (146, 152))	('NOTCH4', 'Gene', '4855', (146, 152))	('cg26793289', 'Var', (183, 193))	('AKAP12', 'Gene', (129, 135))	('FGFR1', 'Gene', (223, 228))	('cg09846917', 'Var', (154, 164))	('AKAP12', 'Gene', '9590', (129, 135))	('cg22885-024', 'Var', (166, 177))	('CpGs', 'Chemical', 'MESH:C024660', (79, 83))
105668	31096734	However, the corresponding CpGs were not hypo-methylated in FGFR1 amplified cases compared with non- amplified FGFR1 in the TCGA BRCA dataset and TCGA LUSC dataset.	('LUSC', 'Disease', (151, 155))	('BRCA', 'Disease', (129, 133))	('amplified', 'Var', (66, 75))	('FGFR1', 'Gene', (60, 65))	('BRCA', 'Disease', 'MESH:D001943', (129, 133))	('CpGs', 'Chemical', 'MESH:C024660', (27, 31))	('LUSC', 'Disease', 'MESH:D002294', (151, 155))
105669	31096734	To demonstrate the clinicopathological characteristics of CRCs with FGFR1 amplification or high FGFR1 expression in an unbiased manner, we performed exploratory analysis for the SNUH2007 dataset, which consisted of consecutively resected primary CRCs (Table 1).	('amplification', 'Var', (74, 87))	('expression', 'MPA', (102, 112))	('FGFR1', 'Gene', (68, 73))	('CRCs', 'Disease', 'MESH:D015179', (246, 250))	('CRCs', 'Disease', (58, 62))	('FGFR1', 'Gene', (96, 101))	('CRCs', 'Disease', 'MESH:D015179', (58, 62))	('CRCs', 'Disease', (246, 250))
105670	31096734	In the SNUH2007 dataset, CRCs with FGFR1 amplification were marginally associated with a lower age of onset (p=0.048).	('lower', 'NegReg', (89, 94))	('CRCs', 'Disease', (25, 29))	('age of', 'MPA', (95, 101))	('CRCs', 'Disease', 'MESH:D015179', (25, 29))	('amplification', 'Var', (41, 54))	('FGFR1', 'Gene', (35, 40))
105671	31096734	CRCs with high FGFR1 expression were more frequent in female patients (p=0.004), and patients with a KRAS mutation (p=0.030), compared with CRCs with low FGFR1 expression.	('CRCs', 'Disease', (140, 144))	('CRCs', 'Disease', (0, 4))	('KRAS', 'Gene', (101, 105))	('mutation', 'Var', (106, 114))	('CRCs', 'Disease', 'MESH:D015179', (140, 144))	('expression', 'MPA', (21, 31))	('KRAS', 'Gene', '3845', (101, 105))	('patients', 'Species', '9606', (85, 93))	('patients', 'Species', '9606', (61, 69))	('CRCs', 'Disease', 'MESH:D015179', (0, 4))	('high', 'Var', (10, 14))	('FGFR1', 'Gene', (15, 20))
105672	31096734	At the molecular level, FGFR1 amplification was mutually exclusive with BRAF mutation, MSI-high, MLH1 methylation, and CIMPP2 (Fig.	('BRAF', 'Gene', (72, 76))	('mutation', 'Var', (77, 85))	('FGFR1', 'Gene', (24, 29))	('MLH1', 'Gene', '4292', (97, 101))	('MLH1', 'Gene', (97, 101))	('BRAF', 'Gene', '673', (72, 76))
105674	31096734	The clinicopathological characteristics of CRCs with FGFR1 amplification or high FGFR1 expression in the SNUH Folfox dataset are summarized in S6 Table.	('FGFR1', 'Gene', (53, 58))	('FGFR1', 'Gene', (81, 86))	('CRCs', 'Disease', 'MESH:D015179', (43, 47))	('expression', 'MPA', (87, 97))	('amplification', 'Var', (59, 72))	('high', 'Var', (76, 80))	('CRCs', 'Disease', (43, 47))
105675	31096734	Univariate survival analysis revealed that in SNUH2007 dataset, FGFR1 amplification and high FGFR1 expression were associated with inferior 5-year PFS (p=0.008 for FGFR1 amplification and p=0.031 for high FGFR1 expression) compared with CRCs with no FGFR1 amplification and low FGFR1 expression, respectively (Fig.	('inferior', 'NegReg', (131, 139))	('high', 'Var', (88, 92))	('PFS', 'MPA', (147, 150))	('CRCs', 'Disease', (237, 241))	('FGFR1', 'Gene', (64, 69))	('FGFR1', 'Gene', (93, 98))	('CRCs', 'Disease', 'MESH:D015179', (237, 241))	('amplification', 'Var', (70, 83))
105676	31096734	The univariate survival analysis revealed that patients with FGFR1 amplification exhibited marginally worse 5-year DFS compared with those without amplification (p=0.030) (Fig.	('worse', 'NegReg', (102, 107))	('FGFR1', 'Gene', (61, 66))	('amplification', 'Var', (67, 80))	('patients', 'Species', '9606', (47, 55))	('DFS', 'MPA', (115, 118))
105677	31096734	However, there was no significant difference in the 5-year DFS between CRC patients with high vs. low FGFR1 expression (p=0.404) (S7B Fig.).	('high', 'Var', (89, 93))	('FGFR1', 'Gene', (102, 107))	('patients', 'Species', '9606', (75, 83))
105678	31096734	Multivariate survival analysis established, FGFR1 amplification as a prognostic marker for poor 5-year DFS, independent of KRAS mutations, lymphovascular invasion, and gross appearance (hazard ratio, 2.22; 95% confidence interval, 1.04 to 4.77; p=0.040) (Table 2).	('KRAS', 'Gene', '3845', (123, 127))	('amplification', 'Var', (50, 63))	('FGFR1', 'Gene', (44, 49))	('KRAS', 'Gene', (123, 127))
105679	31096734	In the TCGA COADREAD dataset, patients with FGFR1 amplification showed a tendency of poor overall survival, although this was not statistically significant (p=0.300) (Fig.	('amplification', 'Var', (50, 63))	('FGFR1', 'Gene', (44, 49))	('overall', 'MPA', (90, 97))	('poor', 'NegReg', (85, 89))	('patients', 'Species', '9606', (30, 38))	('COAD', 'Disease', (12, 16))	('COAD', 'Disease', 'MESH:D012004', (12, 16))
105681	31096734	To investigate whether FGFR1 amplification or high FGFR1 expression is a predictive marker for anti-FGFR drug sensitivity, we performed a cell proliferation assay using the FGFR1 inhibitor PD173074, in CRC cell lines with FGFR1 amplification (SNU-C1), high FGFR1 expression (SNU-283, SW620, and HCT116), and one cell line with no FGFR1 amplification and low FGFR1 expression (SNU-81).	('HCT116', 'CellLine', 'CVCL:0291', (295, 301))	('SW620', 'CellLine', 'CVCL:0547', (284, 289))	('drug sensitivity', 'Phenotype', 'HP:0020174', (105, 121))	('FGFR1', 'Gene', (257, 262))	('PD173074', 'Var', (189, 197))	('FGFR1 amplification', 'Var', (222, 241))	('PD173074', 'Chemical', 'MESH:C115711', (189, 197))	('expression', 'MPA', (263, 273))
105682	31096734	In the cell proliferation assays, cell lines with FGFR1 high-expression (SNU-283, SW620, and HCT116) showed a lower IC50 for PD173074 compared with FGFR1 amplified cell line (SNUC1) (Fig.	('high-expression', 'PosReg', (56, 71))	('SW620', 'CellLine', 'CVCL:0547', (82, 87))	('FGFR1', 'Gene', (50, 55))	('PD173074', 'Chemical', 'MESH:C115711', (125, 133))	('SNUC1', 'CellLine', 'CVCL:1708', (175, 180))	('lower', 'NegReg', (110, 115))	('HCT116', 'CellLine', 'CVCL:0291', (93, 99))	('PD173074', 'Var', (125, 133))	('IC50', 'MPA', (116, 120))
105687	31096734	Little is known about the clinicopathological characteristics of CRCs with FGFR1 gene amplification or FGFR1 highexpression.	('CRCs', 'Disease', (65, 69))	('CRCs', 'Disease', 'MESH:D015179', (65, 69))	('gene amplification', 'Var', (81, 99))	('FGFR1', 'Gene', (75, 80))
105688	31096734	In the present study, CRCs with FGFR1 amplification were marginally associated with a younger age at diagnosis in the SNUH2007 dataset.	('amplification', 'Var', (38, 51))	('CRCs', 'Disease', 'MESH:D015179', (22, 26))	('FGFR1', 'Gene', (32, 37))	('CRCs', 'Disease', (22, 26))
105690	31096734	Molecular analysis revealed that FGFR1 amplification was mutually exclusive with BRAF mutation, MSI-high, MLH1 methylation, and CIMP-P2, in both SNUH2007 and SNUH Folfox datasets.	('MLH1', 'Gene', '4292', (106, 110))	('MLH1', 'Gene', (106, 110))	('BRAF', 'Gene', '673', (81, 85))	('BRAF', 'Gene', (81, 85))	('mutation', 'Var', (86, 94))	('FGFR1', 'Gene', (33, 38))
105693	31096734	Unlike breast cancers or squamous cell carcinoma of the lung, which show a positive correlation between FGFR1 amplification and FGFR1 mRNA expression, FGFR1 amplification was not associated with FGFR1 mRNA or FGFR1 protein overexpression in CRCs.	('breast cancers', 'Phenotype', 'HP:0003002', (7, 21))	('breast cancer', 'Phenotype', 'HP:0003002', (7, 20))	('protein', 'Protein', (215, 222))	('FGFR1', 'Gene', (128, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (39, 48))	('carcinoma of the lung', 'Phenotype', 'HP:0100526', (39, 60))	('FGFR1', 'Gene', (151, 156))	('squamous cell carcinoma of the lung', 'Disease', (25, 60))	('squamous cell carcinoma of the lung', 'Disease', 'MESH:D002294', (25, 60))	('CRCs', 'Disease', (241, 245))	('mRNA expression', 'MPA', (134, 149))	('FGFR1', 'Gene', (195, 200))	('overexpression', 'PosReg', (223, 237))	('cancers', 'Phenotype', 'HP:0002664', (14, 21))	('squamous cell carcinoma of the lung', 'Phenotype', 'HP:0030359', (25, 60))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('FGFR1', 'Gene', (209, 214))	('breast cancers', 'Disease', 'MESH:D001943', (7, 21))	('breast cancers', 'Disease', (7, 21))	('amplification', 'Var', (157, 170))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (25, 48))	('CRCs', 'Disease', 'MESH:D015179', (241, 245))
105695	31096734	In the TCGA BRCA and LUSC datasets, the methylation of these CpG sites was not different between the cases with amplified vs. non-amplified FGFR1.	('BRCA', 'Disease', (12, 16))	('LUSC', 'Disease', (21, 25))	('FGFR1', 'Gene', (140, 145))	('BRCA', 'Disease', 'MESH:D001943', (12, 16))	('amplified', 'Var', (112, 121))	('LUSC', 'Disease', 'MESH:D002294', (21, 25))
105696	31096734	Even though the exact relationship of these genes with FGFR1 is not well known, reduced expression of these genes could be a clue to the absence of positive correlation between FGFR1 amplification and FGFR1 mRNA or FGFR1 protein expression in CRCs, because gene body methylation is associated with reduced expression of corresponding genes.	('FGFR1', 'Gene', (215, 220))	('FGFR1', 'Gene', (201, 206))	('methylation', 'Var', (267, 278))	('FGFR1', 'Gene', (177, 182))	('CRCs', 'Disease', 'MESH:D015179', (243, 247))	('expression', 'MPA', (88, 98))	('expression', 'MPA', (306, 316))	('reduced', 'NegReg', (298, 305))	('CRCs', 'Disease', (243, 247))
105700	31096734	Moreover, there was no significant difference in the TNM stage between CRCs with high vs. low FGFR1 expression in the SNUH2007 dataset.	('CRCs', 'Disease', 'MESH:D015179', (71, 75))	('TNM', 'Gene', (53, 56))	('high', 'Var', (81, 85))	('TNM', 'Gene', '10178', (53, 56))	('FGFR1', 'Gene', (94, 99))	('CRCs', 'Disease', (71, 75))
105701	31096734	The prognostic value of FGFR1 amplification in CRCs was not well documented due to its low prevalence.	('FGFR1', 'Gene', (24, 29))	('CRCs', 'Disease', (47, 51))	('CRCs', 'Disease', 'MESH:D015179', (47, 51))	('amplification', 'Var', (30, 43))
105702	31096734	In the present study, CRCs with FGFR1 amplification was associated with a poor 5-year PFS in consecutively resected CRC datasets.	('FGFR1', 'Gene', (32, 37))	('CRCs', 'Disease', 'MESH:D015179', (22, 26))	('PFS', 'MPA', (86, 89))	('amplification', 'Var', (38, 51))	('CRCs', 'Disease', (22, 26))
105703	31096734	In the TCGA COADREAD dataset, FGFR1 amplification showed a tendency of poor overall survival.	('FGFR1', 'Gene', (30, 35))	('poor', 'NegReg', (71, 75))	('amplification', 'Var', (36, 49))	('COAD', 'Disease', (12, 16))	('COAD', 'Disease', 'MESH:D012004', (12, 16))
105704	31096734	Moreover, FGFR1 amplification was an independent marker of poor 5-year DFS in patients treated with the Folfox regimen, which is a standard adjuvant combination chemotherapy for high-risk stage II or stage III CRCs.	('DFS', 'MPA', (71, 74))	('CRCs', 'Disease', (210, 214))	('patients', 'Species', '9606', (78, 86))	('amplification', 'Var', (16, 29))	('FGFR1', 'Gene', (10, 15))	('poor', 'NegReg', (59, 63))	('CRCs', 'Disease', 'MESH:D015179', (210, 214))
105708	31096734	showed that a selective FGFR inhibitor, PD173074, inhibited the growth and induced apoptosis in lung cancer cells with FGFR1 amp-lification.	('induced', 'Reg', (75, 82))	('lung cancer', 'Disease', 'MESH:D008175', (96, 107))	('PD173074', 'Chemical', 'MESH:C115711', (40, 48))	('lung cancer', 'Disease', (96, 107))	('lung cancer', 'Phenotype', 'HP:0100526', (96, 107))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('apoptosis', 'CPA', (83, 92))	('growth', 'CPA', (64, 70))	('inhibited', 'NegReg', (50, 59))	('PD173074', 'Var', (40, 48))
105709	31096734	However, in our present study, the lowest IC50 for PD173074 was observed in the HCT116 cell line, which exhi-bits high FGFR1 expression.	('FGFR1', 'Gene', (119, 124))	('expression', 'MPA', (125, 135))	('PD173074', 'Var', (51, 59))	('HCT116', 'CellLine', 'CVCL:0291', (80, 86))	('PD173074', 'Chemical', 'MESH:C115711', (51, 59))
105710	31096734	Furthermore, BGJ398 and AZD4547 are known to have a strong anti-proliferative effect in CRC cell lines with high FGFR1 expression.	('AZD4547', 'Var', (24, 31))	('AZD4547', 'Chemical', 'MESH:C572463', (24, 31))	('FGFR1', 'Gene', (113, 118))	('anti-proliferative effect', 'CPA', (59, 84))	('high', 'Var', (108, 112))	('BGJ398', 'Var', (13, 19))	('BGJ398', 'Chemical', 'MESH:C568950', (13, 19))
105711	31096734	Second, even though poor clinical outcomes for FGFR1 amplified CRCs were consistently found in each dataset, the validation of the prognostic value of FGFR1 amplification is still limited, due to the different clinical settings of each dataset.	('amplified', 'Var', (53, 62))	('CRCs', 'Disease', (63, 67))	('FGFR1', 'Gene', (47, 52))	('CRCs', 'Disease', 'MESH:D015179', (63, 67))
105712	31096734	In conclusion, FGFR1 amplification could be a prognostic indicator of poor clinical outcome in CRCs.	('CRCs', 'Disease', (95, 99))	('amplification', 'Var', (21, 34))	('FGFR1', 'Gene', (15, 20))	('CRCs', 'Disease', 'MESH:D015179', (95, 99))
105741	30817620	T1bN0M0, stage IA for gastric cancer and T1bN0M0, stage IB for esophageal cancer were observed.	('esophageal cancer', 'Disease', (63, 80))	('esophageal cancer', 'Disease', 'MESH:D004938', (63, 80))	('T1bN0M0', 'Var', (0, 7))	('gastric cancer', 'Disease', (22, 36))	('T1bN0M0', 'Var', (41, 48))	('gastric cancer', 'Disease', 'MESH:D013274', (22, 36))	('gastric cancer', 'Phenotype', 'HP:0012126', (22, 36))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
105748	30817620	T3N0M0, stage IIA for esophageal cancer and T1bN0M0, stage IA for gastric cancer were observed.	('gastric cancer', 'Phenotype', 'HP:0012126', (66, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('T1bN0M0', 'Var', (44, 51))	('esophageal cancer', 'Disease', (22, 39))	('gastric cancer', 'Disease', (66, 80))	('esophageal cancer', 'Disease', 'MESH:D004938', (22, 39))	('gastric cancer', 'Disease', 'MESH:D013274', (66, 80))
105771	31311932	Here, the authors provide a mutational landscape for this cancer, showing a low burden of somatic mutations and high prevalence of copy number variations.	('cancer', 'Disease', (58, 64))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('copy number variations', 'Var', (131, 153))	('cancer', 'Disease', 'MESH:D009369', (58, 64))
105777	31311932	Driver mutations such as epidermal growth factor receptor (EGFR) mutation and anaplastic lymphoma kinase (ALK) rearrangement are rarely detected in pulmonary LELC.	('ALK', 'Gene', '238', (106, 109))	('pulmonary LELC', 'Disease', (148, 162))	('EGFR', 'Gene', (59, 63))	('epidermal growth factor receptor', 'Gene', (25, 57))	('anaplastic lymphoma kinase', 'Gene', (78, 104))	('ALK', 'Gene', (106, 109))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (78, 97))	('rearrangement', 'Var', (111, 124))	('lymphoma', 'Phenotype', 'HP:0002665', (89, 97))	('epidermal growth factor receptor', 'Gene', '1956', (25, 57))	('mutation', 'Var', (65, 73))	('anaplastic lymphoma kinase', 'Gene', '238', (78, 104))	('EGFR', 'Gene', '1956', (59, 63))
105791	31311932	Signature 2 was characterized primarily by C > T and C > G mutations at TpCpN trinucleotides and was attributed to the overactivity of the AID/APOBEC family of cytidine deaminases.	('trinucleotides', 'Chemical', '-', (78, 92))	('C > T', 'Var', (43, 48))	('C > G mutations', 'Var', (53, 68))	('overactivity', 'PosReg', (119, 131))	('TpCpN', 'Gene', (72, 77))	('AID', 'Disease', 'None', (139, 142))	('AID', 'Disease', (139, 142))
105798	31311932	Although TP53 mutation was the most frequent in our cohort and twice the frequency of previously reported in pulmonary LELC, it is infrequent as compared to that of other primary lung cancers (Supplementary Fig.	('cancers', 'Phenotype', 'HP:0002664', (184, 191))	('frequent', 'Reg', (36, 44))	('primary lung cancers', 'Disease', 'MESH:D008175', (171, 191))	('lung cancer', 'Phenotype', 'HP:0100526', (179, 190))	('pulmonary LELC', 'Disease', (109, 123))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('primary lung cancers', 'Disease', (171, 191))	('TP53', 'Gene', '7157', (9, 13))	('TP53', 'Gene', (9, 13))	('mutation', 'Var', (14, 22))	('lung cancers', 'Phenotype', 'HP:0100526', (179, 191))
105799	31311932	Nevertheless, all the TP53 mutations were located at the structural domains and 93% (13/14) of these mutations were in the DNA-binding domain (Supplementary Fig.	('mutations', 'Var', (27, 36))	('mutations', 'Var', (101, 110))	('TP53', 'Gene', (22, 26))	('TP53', 'Gene', '7157', (22, 26))
105802	31311932	The dysregulation of these laminin subunit genes has been widely reported to promote tumor invasion and metastasis in different cancers.	('tumor', 'Disease', (85, 90))	('cancers', 'Disease', 'MESH:D009369', (128, 135))	('promote', 'PosReg', (77, 84))	('cancers', 'Phenotype', 'HP:0002664', (128, 135))	('cancers', 'Disease', (128, 135))	('metastasis', 'CPA', (104, 114))	('dysregulation', 'Var', (4, 17))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))
105808	31311932	In addition, copy number gain of the whole chromosome 12 was observed in 48% (22/46) of patients, leading to amplification of 34 cancer related genes annotated in the Catalogue of Somatic Mutations in Cancer (COSMIC) database and signaling pathways including MAPK (q = 0.001), JAK/STAT (q = 0.014), and cell cycle (q = 0.032) (Supplementary Data 8).	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('Cancer', 'Phenotype', 'HP:0002664', (201, 207))	('patients', 'Species', '9606', (88, 96))	('signaling pathways', 'Pathway', (230, 248))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('cell cycle', 'CPA', (303, 313))	('copy number gain', 'Var', (13, 29))	('MAPK', 'Gene', (259, 263))	('amplification', 'PosReg', (109, 122))
105809	31311932	The predominant event was amplification in 11q13.3, which contained the CCND1 gene.	('CCND1', 'Gene', (72, 77))	('CCND1', 'Gene', '595', (72, 77))	('amplification', 'Var', (26, 39))
105810	31311932	Amplification of CCND1 may drive cell cycle progression and contribute to tumorigenesis.	('Amplification', 'Var', (0, 13))	('CCND1', 'Gene', '595', (17, 22))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('contribute', 'Reg', (60, 70))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('drive', 'PosReg', (27, 32))	('cell cycle progression', 'CPA', (33, 55))	('tumor', 'Disease', (74, 79))	('CCND1', 'Gene', (17, 22))
105812	31311932	Amplification of CD274 was associated with elevated programmed cell death ligand-1 (PD-L1) expression in EBV-associated gastric cancer.	('expression', 'MPA', (91, 101))	('Amplification', 'Var', (0, 13))	('PD-L1', 'Gene', (84, 89))	('CD274', 'Gene', '29126', (17, 22))	('gastric cancer', 'Disease', (120, 134))	('elevated', 'PosReg', (43, 51))	('EBV', 'Species', '10376', (105, 108))	('gastric cancer', 'Disease', 'MESH:D013274', (120, 134))	('PD-L1', 'Gene', '29126', (84, 89))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('gastric cancer', 'Phenotype', 'HP:0012126', (120, 134))	('CD274', 'Gene', (17, 22))
105814	31311932	The amplification of CD274 identified herein may provide an alternative mechanism of the overexpression of PD-L1 in pulmonary LELC and the rationale for immunotherapy.	('PD-L1', 'Gene', '29126', (107, 112))	('CD274', 'Gene', '29126', (21, 26))	('overexpression', 'PosReg', (89, 103))	('pulmonary LELC', 'Disease', (116, 130))	('amplification', 'Var', (4, 17))	('PD-L1', 'Gene', (107, 112))	('CD274', 'Gene', (21, 26))
105816	31311932	Frequent deletion of 9p21.3 was observed in a variety of cancers including NPC and lung cancer.	('lung cancer', 'Disease', 'MESH:D008175', (83, 94))	('9p21.3', 'Gene', (21, 27))	('observed', 'Reg', (32, 40))	('deletion', 'Var', (9, 17))	('cancers', 'Phenotype', 'HP:0002664', (57, 64))	('NPC', 'Gene', (75, 78))	('cancers', 'Disease', (57, 64))	('cancers', 'Disease', 'MESH:D009369', (57, 64))	('lung cancer', 'Disease', (83, 94))	('lung cancer', 'Phenotype', 'HP:0100526', (83, 94))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('NPC', 'Gene', '4864', (75, 78))
105818	31311932	Patients with 9p21.3 focal deletion were significantly associated with poor survival (Fig.	('poor', 'NegReg', (71, 75))	('focal deletion', 'Var', (21, 35))	('Patients', 'Species', '9606', (0, 8))
105819	31311932	In addition to the focal deletion region, nearby regions within 9p21.3 also showed high frequency of deletion involving two tumor suppressors (CDKN2A, CDKN2B), MTAP and a cluster of type I IFN genes (Supplementary Data 10, Fig.	('CDKN2B', 'Gene', '1030', (151, 157))	('deletion', 'Var', (101, 109))	('MTAP', 'Gene', (160, 164))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('tumor', 'Disease', (124, 129))	('MTAP', 'Gene', '4507', (160, 164))	('CDKN2A', 'Gene', (143, 149))	('CDKN2B', 'Gene', (151, 157))	('CDKN2A', 'Gene', '1029', (143, 149))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
105822	31311932	Interestingly, we found that tumors with 9p21.3 deletion had lower level of CD8 + tumor infiltration lymphocytes (TILs) than those without 9p21.3 deletion, with marginal significance (Student's t-test, P = 0.05; Supplementary Fig.	('lower', 'NegReg', (61, 66))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('9p21.3', 'Gene', (41, 47))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumor', 'Disease', (29, 34))	('tumors', 'Disease', 'MESH:D009369', (29, 35))	('CD8', 'Gene', '925', (76, 79))	('CD8', 'Gene', (76, 79))	('tumors', 'Disease', (29, 35))	('tumor', 'Disease', (82, 87))	('level', 'MPA', (67, 72))	('deletion', 'Var', (48, 56))
105824	31311932	Integrated analysis of mutational profiles revealed core signaling pathways implicated in discrete functional categories, including cell cycle, JAK/STAT and NF-kappaB (Fig.	('cell cycle', 'Disease', (132, 142))	('NF-kappaB', 'Gene', '4790', (157, 166))	('JAK/STAT', 'Disease', (144, 152))	('NF-kappaB', 'Gene', (157, 166))	('mutational', 'Var', (23, 33))
105825	31311932	Cell cycle pathway was altered primarily by mutation or deletion of TP53, amplification of MDM2 and CCND1, and deletion of CDKN2A/B and RB1, revealing frequent defects in the G1/S transition control (Fig.	('deletion', 'Var', (56, 64))	('CCND1', 'Gene', (100, 105))	('mutation', 'Var', (44, 52))	('RB1', 'Gene', '5925', (136, 139))	('defects', 'NegReg', (160, 167))	('MDM2', 'Gene', '4193', (91, 95))	('CCND1', 'Gene', '595', (100, 105))	('MDM2', 'Gene', (91, 95))	('CDKN2A/B', 'Gene', (123, 131))	('G1/S transition control', 'MPA', (175, 198))	('CDKN2A/B', 'Gene', '1029;1030', (123, 131))	('altered', 'Reg', (23, 30))	('TP53', 'Gene', '7157', (68, 72))	('RB1', 'Gene', (136, 139))	('TP53', 'Gene', (68, 72))	('Cell cycle pathway', 'Pathway', (0, 18))	('deletion', 'Var', (111, 119))
105826	31311932	JAK/STAT pathway was frequently dysregulated, largely owing to deletion of CISH (in 95% of the patients), followed by mutation or deletion of PTPRD, and mutation or amplification of JAK2 (Fig.	('patients', 'Species', '9606', (95, 103))	('CISH', 'Gene', '1154', (75, 79))	('JAK2', 'Gene', '3717', (182, 186))	('deletion', 'Var', (130, 138))	('JAK/STAT pathway', 'Pathway', (0, 16))	('mutation', 'Var', (118, 126))	('PTPRD', 'Gene', (142, 147))	('deletion', 'Var', (63, 71))	('PTPRD', 'Gene', '5789', (142, 147))	('CISH', 'Gene', (75, 79))	('dysregulated', 'Reg', (32, 44))	('JAK2', 'Gene', (182, 186))	('mutation', 'Var', (153, 161))
105830	31311932	NF-kappaB pathway aberration was implicated in 18% of patients by somatic mutations and 93% of patients by SCNAs (Fig.	('implicated', 'Reg', (33, 43))	('NF-kappaB', 'Gene', '4790', (0, 9))	('patients', 'Species', '9606', (95, 103))	('patients', 'Species', '9606', (54, 62))	('NF-kappaB', 'Gene', (0, 9))	('aberration', 'Var', (18, 28))
105831	31311932	Negative regulators of NF-kappaB pathway including TRAF3, CYLD, NFKBIA, and NLRC5 were frequently deleted in pulmonary LELC.	('TRAF3', 'Gene', (51, 56))	('NLRC5', 'Gene', (76, 81))	('NF-kappaB', 'Gene', (23, 32))	('TRAF3', 'Gene', '7187', (51, 56))	('pulmonary LELC', 'Disease', (109, 123))	('CYLD', 'Gene', '1540', (58, 62))	('CYLD', 'Gene', (58, 62))	('NFKBIA', 'Gene', (64, 70))	('NLRC5', 'Gene', '84166', (76, 81))	('NFKBIA', 'Gene', '4792', (64, 70))	('NF-kappaB', 'Gene', '4790', (23, 32))	('deleted', 'Var', (98, 105))
105833	31311932	Defects in TRAF3/CYLD have been implicated in the activation of NF-kappaB signaling in HPV-positive head and neck squamous cell carcinoma (HNSCC) and EBV-positive NPC, suggesting that TRAF3 and CYLD genetic alterations may also participate in EBV-mediated tumorigenesis in pulmonary LELC.	('CYLD', 'Gene', (194, 198))	('CYLD', 'Gene', (17, 21))	('TRAF3', 'Gene', (11, 16))	('CYLD', 'Gene', '1540', (194, 198))	('TRAF3', 'Gene', (184, 189))	('CYLD', 'Gene', '1540', (17, 21))	('NPC', 'Gene', (163, 166))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('pulmonary LELC', 'Disease', (273, 287))	('HPV', 'Disease', 'MESH:D030361', (87, 90))	('activation', 'PosReg', (50, 60))	('EBV', 'Species', '10376', (243, 246))	('NF-kappaB', 'Gene', (64, 73))	('neck squamous cell carcinoma', 'Disease', (109, 137))	('tumor', 'Disease', (256, 261))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (109, 137))	('NF-kappaB', 'Gene', '4790', (64, 73))	('participate', 'Reg', (228, 239))	('Defects', 'Var', (0, 7))	('NPC', 'Gene', '4864', (163, 166))	('tumor', 'Disease', 'MESH:D009369', (256, 261))	('TRAF3', 'Gene', '7187', (11, 16))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (114, 137))	('EBV', 'Species', '10376', (150, 153))	('TRAF3', 'Gene', '7187', (184, 189))	('tumor', 'Phenotype', 'HP:0002664', (256, 261))	('HPV', 'Disease', (87, 90))
105834	31311932	In addition to deletion of negative regulators, somatic mutations or amplification of multiple components of the canonical NF-kappaB pathway were also identified, including FADD, TRAF2, TRAF6, and CARD11.	('NF-kappaB', 'Gene', '4790', (123, 132))	('deletion', 'Var', (15, 23))	('TRAF2', 'Gene', '7186', (179, 184))	('TRAF6', 'Gene', (186, 191))	('CARD11', 'Gene', '84433', (197, 203))	('CARD11', 'Gene', (197, 203))	('TRAF6', 'Gene', '7189', (186, 191))	('NF-kappaB', 'Gene', (123, 132))	('TRAF2', 'Gene', (179, 184))	('amplification', 'Var', (69, 82))	('FADD', 'Gene', (173, 177))	('FADD', 'Gene', '8772', (173, 177))
105846	31311932	However, there were no significant associations between PD-L1 overexpression and number of signature 2 mutations, percentage of EBV type 1 reads, somatic mutation burden or the three core signaling pathways (Supplementary Fig.	('EBV', 'Species', '10376', (128, 131))	('mutations', 'Var', (103, 112))	('PD-L1', 'Gene', '29126', (56, 61))	('PD-L1', 'Gene', (56, 61))
105847	31311932	Also, no significant correlation was observed between CD8 + TILs and number of signature 2 mutations, percentage of EBV type 1 reads, somatic mutation burden or the three core signaling pathways (Supplementary Fig.	('CD8', 'Gene', '925', (54, 57))	('EBV', 'Species', '10376', (116, 119))	('mutations', 'Var', (91, 100))	('CD8', 'Gene', (54, 57))
105850	31311932	In our pulmonary LELC cohort, TRAF3 mutation was identified in five cases (Fig.	('identified', 'Reg', (49, 59))	('TRAF3', 'Gene', (30, 35))	('pulmonary LELC', 'Disease', (7, 21))	('TRAF3', 'Gene', '7187', (30, 35))	('mutation', 'Var', (36, 44))
105851	31311932	Furthermore, TRAF3 deletion was ubiquitously observed in pulmonary LELC (80%) (Fig.	('pulmonary LELC', 'Disease', (57, 71))	('deletion', 'Var', (19, 27))	('TRAF3', 'Gene', (13, 18))	('observed', 'Reg', (45, 53))	('TRAF3', 'Gene', '7187', (13, 18))
105852	31311932	Given the frequent TRAF3 aberrations in pulmonary LELC, we further examined its biological function in BEAS-2B cells.	('aberrations', 'Var', (25, 36))	('TRAF3', 'Gene', (19, 24))	('pulmonary LELC', 'Disease', (40, 54))	('TRAF3', 'Gene', '7187', (19, 24))	('BEAS-2B', 'CellLine', 'CVCL:0168', (103, 110))
105857	31311932	All lung cancer subtypes except pulmonary LELC were characterized by frequent C:G > A:T transversions of tobacco smoking fingerprint.	('tobacco', 'Species', '4097', (105, 112))	('pulmonary LELC', 'Disease', (32, 46))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('lung cancer', 'Disease', (4, 15))	('lung cancer', 'Phenotype', 'HP:0100526', (4, 15))	('C:G > A:T transversions', 'Var', (78, 101))	('lung cancer', 'Disease', 'MESH:D008175', (4, 15))
105861	31311932	LUAD, LUSC, and SCLC showed apparent amplifications of 1q, 5p, 8q and deletion of 8p, which were absent in pulmonary LELC.	('deletion', 'Var', (70, 78))	('SCLC', 'Disease', 'MESH:D018288', (16, 20))	('SCLC', 'Disease', (16, 20))
105862	31311932	Notably, NKTCL showed less SCNAs than pulmonary LELC and NPC did and had an evident higher propensity for deletion of 6q, consistent with previous studies.	('less', 'NegReg', (22, 26))	('deletion', 'Var', (106, 114))	('NPC', 'Gene', (57, 60))	('NPC', 'Gene', '4864', (57, 60))	('SCNAs', 'MPA', (27, 32))
105863	31311932	Both pulmonary LELC and NPC showed amplification of the whole chromosome 12 and deletion of 3p (contained BAP1), 13q (RB1), 14q (TRAF3), and 16q (CYLD).	('NPC', 'Gene', (24, 27))	('deletion', 'Var', (80, 88))	('BAP1', 'Gene', (106, 110))	('TRAF3', 'Gene', (129, 134))	('NPC', 'Gene', '4864', (24, 27))	('pulmonary LELC', 'Disease', (5, 19))	('RB1', 'Gene', (118, 121))	('CYLD', 'Gene', (146, 150))	('BAP1', 'Gene', '8314', (106, 110))	('RB1', 'Gene', '5925', (118, 121))	('CYLD', 'Gene', '1540', (146, 150))	('TRAF3', 'Gene', '7187', (129, 134))
105870	31311932	In multivariate analysis controlling for potential confounding factors including age, gender, performance status, stage, and number of metastatic organs, gemcitabine plus cisplatin remained significantly associated with improved progression-free survival (Cox proportional-hazards regression, P = 0.024) and overall response (Cox proportional-hazards regression, P = 0.001) compared with pemetrexed plus cisplatin (Supplementary Data 13).	('improved', 'PosReg', (220, 228))	('Cox', 'Gene', '1351', (326, 329))	('Cox', 'Gene', (256, 259))	('Cox', 'Gene', (326, 329))	('pemetrexed', 'Chemical', 'MESH:D000068437', (388, 398))	('cisplatin', 'Chemical', 'MESH:D002945', (404, 413))	('overall response', 'CPA', (308, 324))	('progression-free survival', 'CPA', (229, 254))	('gemcitabine', 'Var', (154, 165))	('Cox', 'Gene', '1351', (256, 259))	('cisplatin', 'Chemical', 'MESH:D002945', (171, 180))	('gemcitabine', 'Chemical', 'MESH:C056507', (154, 165))
105875	31311932	Given the rarity of somatic driver mutations in pulmonary LELC and the fact that this disease is closely related to EBV infection, the underlying mechanism of tumorigenesis is of special interest.	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('tumor', 'Disease', (159, 164))	('pulmonary LELC', 'Disease', (48, 62))	('EBV infection', 'Disease', (116, 129))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('EBV infection', 'Disease', 'MESH:D020031', (116, 129))	('mutations', 'Var', (35, 44))
105877	31311932	Besides, we identified widespread signature 2 mutations, which are attributed to the overactivity of AID/APOBEC family of cytidine deaminases that participate in the antiviral innate immune response partially through inducing transcription of type I interferons, as well as modification of viral genome.	('inducing', 'PosReg', (217, 225))	('mutations', 'Var', (46, 55))	('AID', 'Disease', 'None', (101, 104))	('AID', 'Disease', (101, 104))	('overactivity', 'PosReg', (85, 97))	('participate', 'Reg', (147, 158))	('transcription', 'MPA', (226, 239))	('modification', 'Reg', (274, 286))
105881	31311932	Collectively, the APOBEC family gene signature, dysregulated NF-kappaB pathway and loss of type I IFN genes are likely responsible for the EBV-induced carcinogenesis of pulmonary LELC and might facilitate development of novel therapeutic strategies.	('dysregulated', 'Var', (48, 60))	('carcinogenesis of pulmonary LELC', 'Disease', (151, 183))	('NF-kappaB', 'Gene', (61, 70))	('responsible', 'Reg', (119, 130))	('EBV', 'Species', '10376', (139, 142))	('APOBEC family gene', 'Gene', (18, 36))	('carcinogenesis of pulmonary LELC', 'Disease', 'MESH:D063646', (151, 183))	('loss', 'NegReg', (83, 87))	('NF-kappaB', 'Gene', '4790', (61, 70))
105882	31311932	We also found that TRAF3 was ubiquitously altered in pulmonary LELC, including 5% of simple somatic mutation and 80% of deletion.	('TRAF3', 'Gene', (19, 24))	('altered', 'Reg', (42, 49))	('pulmonary LELC', 'Disease', (53, 67))	('deletion', 'Var', (120, 128))	('TRAF3', 'Gene', '7187', (19, 24))	('simple somatic mutation', 'Var', (85, 108))
105906	31311932	For somatic InDels, mutations were further removed if the supporting reads from both tumor and normal samples was <5, median/mad of InDel offsets from the starts or ends of the reads >=5 bp, average mapping qualities of the reads supported reference and InDel in tumor samples was <=20, or in simple repeat regions.	('tumor', 'Disease', (85, 90))	('tumor', 'Disease', 'MESH:D009369', (263, 268))	('tumor', 'Phenotype', 'HP:0002664', (263, 268))	('offsets', 'NegReg', (138, 145))	('tumor', 'Disease', (263, 268))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('mutations', 'Var', (20, 29))
105910	31311932	Genes frequently mutated in NPC, NKTCL, LUAD (TCGA), LUSC (TCGA), and SCLC.	('SCLC', 'Disease', 'MESH:D018288', (70, 74))	('mutated', 'Var', (17, 24))	('NPC', 'Gene', '4864', (28, 31))	('LUAD', 'Disease', (40, 44))	('LUSC', 'Disease', (53, 57))	('SCLC', 'Disease', (70, 74))	('NPC', 'Gene', (28, 31))
105913	31311932	Thus, we have three categories of unique genes included in the 114 gene panel: cancer associated genes frequently mutated in pulmonary LELC or other related cancers, and NF-kB pathway genes.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('NF-kB pathway', 'Gene', (170, 183))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('mutated', 'Var', (114, 121))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('cancers', 'Disease', 'MESH:D009369', (157, 164))	('cancers', 'Phenotype', 'HP:0002664', (157, 164))	('cancer', 'Disease', (157, 163))	('cancers', 'Disease', (157, 164))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('pulmonary LELC', 'Disease', (125, 139))
105927	31311932	Total somatic mutation rate for each cancer type was calculated with the non-silent mutations and tested by Student's t-test.	('cancer', 'Disease', (37, 43))	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('non-silent', 'Var', (73, 83))
105936	31311932	According to the report by Yvonne Y. Li et al., the LMP1 expression was categorized into absence/low (score 0-100) and high (score 101-300).	('LMP1', 'Gene', (52, 56))	('score 101-300', 'Var', (125, 138))	('LMP1', 'Gene', '9260', (52, 56))	('score 0-100', 'Var', (102, 113))	('absence/low', 'NegReg', (89, 100))
105942	31311932	Recombinant lentivirus expressing either vector (GV248) or GV248 subcloned with TRAF3 siRNA was constructed by GENE Corporation (Shanghai, China).	('GV248', 'Var', (59, 64))	('TRAF3', 'Gene', (80, 85))	('TRAF3', 'Gene', '7187', (80, 85))
105952	31311932	The antibodies specific for TRAF3 (Cat#: 4729, 1:1000 dilution), P100 (Cat#, 4882, 1:1000 dilution), P52 (Cat#, 4882, 1:1000 dilution), IKbetaalpha (Cat#, 2859, 1:1000 dilution), and beta-actin (Cat#, 4970, 1:1000 dilution) were purchased from Cell Signaling Technologies, USA.	('beta-actin', 'Gene', (183, 193))	('beta-actin', 'Gene', '728378', (183, 193))	('TRAF3', 'Gene', '7187', (28, 33))	('Cat#', 'Var', (71, 75))	('Cat#', 'Var', (195, 199))	('Cat#', 'Var', (106, 110))	('P52', 'Gene', '4791', (101, 104))	('P52', 'Gene', (101, 104))	('TRAF3', 'Gene', (28, 33))	('Cat#: 4729', 'Var', (35, 45))	('Cat#', 'Var', (149, 153))
105961	28412093	Cancers with SIR >1.0 had higher risk for NSCLC than expected.	('NSCLC', 'Disease', (42, 47))	('Cancers', 'Disease', (0, 7))	('NSCLC', 'Disease', 'MESH:D002289', (42, 47))	('Cancers', 'Phenotype', 'HP:0002664', (0, 7))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancers', 'Disease', 'MESH:D009369', (0, 7))	('NSCLC', 'Phenotype', 'HP:0030358', (42, 47))	('SIR >1.0', 'Var', (13, 21))
105982	28412093	One study using a Markov model has suggested that lung cancer screening in Hodgkin's lymphoma survivors may benefit survival, increase quality of life, and be cost-effective.	('lung cancer', 'Disease', (50, 61))	("Hodgkin's lymphoma", 'Disease', 'MESH:D006689', (75, 93))	('survival', 'CPA', (116, 124))	('quality of life', 'CPA', (135, 150))	("Hodgkin's lymphoma", 'Disease', (75, 93))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('lung cancer', 'Disease', 'MESH:D008175', (50, 61))	('benefit', 'PosReg', (108, 115))	('lymphoma', 'Phenotype', 'HP:0002665', (85, 93))	('screening', 'Var', (62, 71))	("Hodgkin's lymphoma", 'Phenotype', 'HP:0012189', (75, 93))	('increase', 'PosReg', (126, 134))	('lung cancer', 'Phenotype', 'HP:0100526', (50, 61))
106093	24603603	Although data are heterogeneous, overexpression is often associated with an aggressive tumor phenotype and a poor clinical prognosis.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('associated', 'Reg', (57, 67))	('aggressive tumor', 'Disease', 'MESH:D001523', (76, 92))	('overexpression', 'Var', (33, 47))	('aggressive tumor', 'Disease', (76, 92))
106097	24603603	Blocking of the EGFR also affects the cell cycle by inducing upregulation of the cell cycle inhibitor p27Kip1.	('cell cycle', 'CPA', (38, 48))	('p27Kip1', 'Gene', '1027', (102, 109))	('affects', 'Reg', (26, 33))	('Blocking', 'Var', (0, 8))	('p27Kip1', 'Gene', (102, 109))	('inducing', 'Reg', (52, 60))	('upregulation', 'PosReg', (61, 73))	('cell cycle', 'CPA', (81, 91))	('EGFR', 'Gene', (16, 20))
106102	24603603	Further, potential reasons for cetuximab resistance include the most frequently detected EGFR mutation class III variant (EGFRvIII), or mutation of the EGFR tyrosine kinase domain, or mutation of the oncogene KRAS, BRAF or NRAS that can activate the EGFR even during EGFR inhibition.	('NRAS', 'Gene', '4893', (223, 227))	('EGFR', 'Gene', (89, 93))	('BRAF', 'Gene', (215, 219))	('mutation', 'Var', (136, 144))	('activate', 'PosReg', (237, 245))	('variant', 'Var', (113, 120))	('KRAS', 'Gene', '3845', (209, 213))	('EGFR', 'Gene', (152, 156))	('BRAF', 'Gene', '673', (215, 219))	('KRAS', 'Gene', (209, 213))	('NRAS', 'Gene', (223, 227))	('mutation', 'Var', (94, 102))	('mutation', 'Var', (184, 192))
106135	24603603	In result the combination of 131I-cetuximab with external radiation inhibited cell proliferation in vitro.	('cell proliferation in vitro', 'CPA', (78, 105))	('inhibited', 'NegReg', (68, 77))	('131I-cetuximab', 'Var', (29, 43))	('131I-cetuximab', 'Chemical', '-', (29, 43))	('combination', 'Interaction', (14, 25))
106136	24603603	177Lu is the more favorable therapeutic radionuclide for treatment of small tumors due to its low energy and tissue penetration of about 1.5 mm.	('177Lu', 'Var', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('small tumors', 'Disease', (70, 82))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('small tumors', 'Disease', 'MESH:D058405', (70, 82))
106137	24603603	The chemistry of 177Lu resembles the metallic radionuclide 90Y forming also stable complexes with DOTA and cysteine-based DTPA.	('cysteine-based DTPA', 'Chemical', '-', (107, 126))	('complexes', 'Interaction', (83, 92))	('177Lu', 'Var', (17, 22))
106143	24603603	But still, the tumor uptake of 64Cu-DOTA-cetuximab is relatively high.	('64Cu-DOTA-cetuximab', 'Var', (31, 50))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('64Cu-DOTA-cetuximab', 'Chemical', 'MESH:C532429', (31, 50))	('tumor uptake', 'CPA', (15, 27))
106144	24603603	Overall, the liver uptake of 90Y-DOTA- and 64Cu-DOTA cetuximab in rats appears to be proportionally lower as compared to mice.	('64Cu-DOTA', 'Var', (43, 52))	('liver uptake', 'MPA', (13, 25))	('lower', 'NegReg', (100, 105))	('cetuximab', 'Gene', (53, 62))	('90Y-DOTA-', 'Var', (29, 38))	('90Y-DOTA', 'Chemical', '-', (29, 37))
106147	24603603	In a first clinical imaging study in patients with lung squamous cell carcinoma 111In-DTPA-MAb225, the murine forerunner of cetuximab, also showed a high liver accumulation.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (56, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('high liver', 'Phenotype', 'HP:0002240', (149, 159))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (51, 79))	('lung squamous cell carcinoma', 'Disease', (51, 79))	('111In-DTPA-MAb225', 'Var', (80, 97))	('liver accumulation', 'MPA', (154, 172))
106149	24603603	Besides, a malfunction of lymphatic vessels in tumor tissue impairs the clearance of macromolecules and lipids, so that they remain in the tumor interstitium for longer time.	('impairs', 'NegReg', (60, 67))	('lipids', 'Chemical', 'MESH:D008055', (104, 110))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('malfunction', 'Var', (11, 22))
106171	31802910	Cancer susceptibility 9 (CASC9) was first defined upregulated lncRNA in esophageal squamous cell carcinoma (ESCC) by RNA sequencing, and knockdown of CASC9 significantly suppressed cell migration and invasion in ESCC cells.	('suppressed', 'NegReg', (170, 180))	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('CASC9', 'Gene', '101805492', (25, 30))	('lncRNA', 'Protein', (62, 68))	('CASC9', 'Gene', '101805492', (150, 155))	('knockdown', 'Var', (137, 146))	('esophageal squamous cell carcinoma', 'Disease', (72, 106))	('Cancer susceptibility 9', 'Gene', '101805492', (0, 23))	('ESCC', 'Disease', 'MESH:C562729', (212, 216))	('invasion', 'CPA', (200, 208))	('upregulated', 'PosReg', (50, 61))	('CASC9', 'Gene', (25, 30))	('ESCC', 'Disease', 'MESH:C562729', (108, 112))	('Cancer susceptibility 9', 'Gene', (0, 23))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('CASC9', 'Gene', (150, 155))	('cell migration', 'CPA', (181, 195))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (83, 106))	('ESCC', 'Disease', (212, 216))	('ESCC', 'Disease', (108, 112))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:C562729', (72, 106))
106197	31802910	2.5x104 cells were seeded per upper chambers in serum-free 1640 (for 95D and A549 cells) or F-12K (for HFL-1 cells) whereas the lower chambers were loaded with the same 1640 or F-12K medium containing 5% FBS.	('HFL-1', 'Gene', '3078', (103, 108))	('HFL-1', 'Gene', (103, 108))	('A549', 'CellLine', 'CVCL:0023', (77, 81))	('F-12K', 'Var', (92, 97))
106211	31802910	Also, compared with that in human normal lung epithelial HFL-1 cells, CASC9 expression was obviously increased in lung cancer cell lines, in which 95D and A549 exhibited higher CASC9 levels (Figure 1D).	('higher', 'PosReg', (170, 176))	('lung cancer', 'Disease', 'MESH:D008175', (114, 125))	('increased', 'PosReg', (101, 110))	('CASC9', 'Gene', (70, 75))	('human', 'Species', '9606', (28, 33))	('CASC9', 'Gene', '101805492', (70, 75))	('A549', 'CellLine', 'CVCL:0023', (155, 159))	('CASC9', 'Gene', (177, 182))	('HFL-1', 'Gene', (57, 62))	('lung cancer', 'Disease', (114, 125))	('expression', 'MPA', (76, 86))	('CASC9', 'Gene', '101805492', (177, 182))	('HFL-1', 'Gene', '3078', (57, 62))	('A549', 'Var', (155, 159))	('lung cancer', 'Phenotype', 'HP:0100526', (114, 125))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
106215	31802910	Then CCK-8 assay was used to measure cell proliferation alteration by CASC9 knockdown.	('CASC9', 'Gene', (70, 75))	('CASC9', 'Gene', '101805492', (70, 75))	('cell proliferation', 'CPA', (37, 55))	('knockdown', 'Var', (76, 85))
106216	31802910	As shown in Figure 2B, knockdown of CASC9 significantly inhibited cell proliferation in the two lung cancer cell lines.	('lung cancer', 'Disease', 'MESH:D008175', (96, 107))	('knockdown', 'Var', (23, 32))	('lung cancer', 'Disease', (96, 107))	('cell proliferation in the two', 'CPA', (66, 95))	('lung cancer', 'Phenotype', 'HP:0100526', (96, 107))	('CASC9', 'Gene', (36, 41))	('CASC9', 'Gene', '101805492', (36, 41))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('inhibited', 'NegReg', (56, 65))
106217	31802910	Colony formation assay also revealed that CASC9 knockdown resulted in growth inhibition in 95D cells (Figure 2C), indicating that CASC9 itself promotes lung cancer cell proliferation.	('CASC9', 'Gene', (42, 47))	('CASC9', 'Gene', '101805492', (42, 47))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('lung cancer', 'Disease', 'MESH:D008175', (152, 163))	('promotes', 'PosReg', (143, 151))	('CASC9', 'Gene', '101805492', (130, 135))	('lung cancer', 'Phenotype', 'HP:0100526', (152, 163))	('CASC9', 'Gene', (130, 135))	('growth', 'MPA', (70, 76))	('lung cancer', 'Disease', (152, 163))	('knockdown', 'Var', (48, 57))
106219	31802910	To test this, wound healing assay was performed to evaluate cell migration ability upon CASC9 knockdown.	('cell migration', 'CPA', (60, 74))	('knockdown', 'Var', (94, 103))	('CASC9', 'Gene', (88, 93))	('CASC9', 'Gene', '101805492', (88, 93))
106220	31802910	The results showed that CASC9 knockdown significantly inhibited cell migration in 95D and A549 cells (Figure 3A).	('inhibited', 'NegReg', (54, 63))	('CASC9', 'Gene', '101805492', (24, 29))	('A549', 'CellLine', 'CVCL:0023', (90, 94))	('knockdown', 'Var', (30, 39))	('cell migration in 95D', 'CPA', (64, 85))	('CASC9', 'Gene', (24, 29))
106223	31802910	As we demonstrated that knockdown of CASC9 significantly inhibited cell migration and invasion in lung cancer cells, we suspected that CASC9 could promote EMT procedure in lung cancer.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('lung cancer', 'Disease', (98, 109))	('inhibited', 'NegReg', (57, 66))	('CASC9', 'Gene', (135, 140))	('promote', 'PosReg', (147, 154))	('lung cancer', 'Disease', (172, 183))	('CASC9', 'Gene', '101805492', (135, 140))	('lung cancer', 'Phenotype', 'HP:0100526', (98, 109))	('CASC9', 'Gene', (37, 42))	('EMT procedure', 'CPA', (155, 168))	('CASC9', 'Gene', '101805492', (37, 42))	('lung cancer', 'Phenotype', 'HP:0100526', (172, 183))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('lung cancer', 'Disease', 'MESH:D008175', (98, 109))	('knockdown', 'Var', (24, 33))	('lung cancer', 'Disease', 'MESH:D008175', (172, 183))
106225	31802910	Western blot showed that knockdown of CASC9 significantly increased the protein level of E-cadherin and decreased the protein levels of N-cadherin, Vimentin and beta-catenin (Figure 3C), indicating that knockdown of CASC9 inhibit EMT.	('beta-catenin', 'Gene', '1499', (161, 173))	('protein level', 'MPA', (72, 85))	('knockdown', 'Var', (203, 212))	('CASC9', 'Gene', '101805492', (38, 43))	('CASC9', 'Gene', (216, 221))	('decreased', 'NegReg', (104, 113))	('inhibit', 'NegReg', (222, 229))	('Vimentin', 'Gene', '7431', (148, 156))	('N-cadherin', 'Gene', (136, 146))	('increased', 'PosReg', (58, 67))	('Vimentin', 'Gene', (148, 156))	('N-cadherin', 'Gene', '1000', (136, 146))	('E-cadherin', 'Gene', (89, 99))	('E-cadherin', 'Gene', '999', (89, 99))	('CASC9', 'Gene', '101805492', (216, 221))	('knockdown', 'Var', (25, 34))	('CASC9', 'Gene', (38, 43))	('beta-catenin', 'Gene', (161, 173))	('EMT', 'CPA', (230, 233))
106233	31802910	In addition, CASC9 knockdown also led to decreased expression of GLUT1 and VEGF, the two well-known direct targets of HIF-1alpha (Figure 4C).	('VEGF', 'Gene', '7422', (75, 79))	('knockdown', 'Var', (19, 28))	('decreased', 'NegReg', (41, 50))	('GLUT1', 'Gene', (65, 70))	('CASC9', 'Gene', '101805492', (13, 18))	('HIF-1alpha', 'Gene', (118, 128))	('GLUT1', 'Gene', '6513', (65, 70))	('expression', 'MPA', (51, 61))	('VEGF', 'Gene', (75, 79))	('CASC9', 'Gene', (13, 18))	('HIF-1alpha', 'Gene', '3091', (118, 128))
106236	31802910	MG132 treatment could nearly recover the protein level of HIF-1alpha protein to the extent of the control group (Figure 4E).	('MG132', 'Var', (0, 5))	('recover', 'PosReg', (29, 36))	('HIF-1alpha', 'Gene', '3091', (58, 68))	('protein level', 'MPA', (41, 54))	('HIF-1alpha', 'Gene', (58, 68))
106240	31802910	Then we questioned whether HIF-1alpha restoration could rescue the observed proliferation and metastasis defects caused by CASC9 knockdown.	('CASC9', 'Gene', (123, 128))	('CASC9', 'Gene', '101805492', (123, 128))	('HIF-1alpha', 'Gene', (27, 37))	('metastasis defects', 'Disease', 'MESH:D009362', (94, 112))	('knockdown', 'Var', (129, 138))	('proliferation', 'CPA', (76, 89))	('metastasis defects', 'Disease', (94, 112))	('HIF-1alpha', 'Gene', '3091', (27, 37))
106258	31802910	Then loss-of-function assays were performed to knockdown CASC9 and measure the cell proliferation, migration, invasion and EMT activities in 95D and A549 lung cancer cells.	('lung cancer', 'Disease', (154, 165))	('EMT activities', 'CPA', (123, 137))	('CASC9', 'Gene', '101805492', (57, 62))	('lung cancer', 'Phenotype', 'HP:0100526', (154, 165))	('cell proliferation', 'CPA', (79, 97))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('knockdown', 'Var', (47, 56))	('lung cancer', 'Disease', 'MESH:D008175', (154, 165))	('A549', 'CellLine', 'CVCL:0023', (149, 153))	('migration', 'CPA', (99, 108))	('CASC9', 'Gene', (57, 62))	('invasion', 'CPA', (110, 118))	('loss-of-function', 'NegReg', (5, 21))
106260	31802910	Functionally, knockdown of CASC9 in two lung cancer cell lines, 95D and A549 cell lines, who contained relatively higher level of endogenous CASC9, significantly inhibited cell proliferation, migration, invasion and EMT, suggesting that CASC9 itself could promote cell proliferation and metastasis in lung cancer cells.	('promote', 'PosReg', (256, 263))	('cell proliferation', 'CPA', (264, 282))	('inhibited', 'NegReg', (162, 171))	('metastasis in lung cancer', 'Disease', 'MESH:D008175', (287, 312))	('CASC9', 'Gene', '101805492', (237, 242))	('CASC9', 'Gene', (27, 32))	('CASC9', 'Gene', '101805492', (141, 146))	('lung cancer', 'Disease', 'MESH:D008175', (301, 312))	('lung cancer', 'Disease', 'MESH:D008175', (40, 51))	('A549', 'CellLine', 'CVCL:0023', (72, 76))	('lung cancer', 'Phenotype', 'HP:0100526', (301, 312))	('lung cancer', 'Phenotype', 'HP:0100526', (40, 51))	('metastasis in lung cancer', 'Disease', (287, 312))	('EMT', 'CPA', (216, 219))	('CASC9', 'Gene', (237, 242))	('CASC9', 'Gene', '101805492', (27, 32))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('CASC9', 'Gene', (141, 146))	('cell proliferation', 'CPA', (172, 190))	('cancer', 'Phenotype', 'HP:0002664', (306, 312))	('knockdown', 'Var', (14, 23))	('lung cancer', 'Disease', (40, 51))
106264	31802910	Consistent with the results in the previous literature, our results showed that knockdown of CASC9 significantly increased the protein level of E-cadherin and decreased the protein levels of N-cadherin, Vimentin and beta-catenin, indicating that CASC9 truly promoted EMT procedure.	('beta-catenin', 'Gene', (216, 228))	('knockdown', 'Var', (80, 89))	('CASC9', 'Gene', (93, 98))	('CASC9', 'Gene', '101805492', (93, 98))	('N-cadherin', 'Gene', '1000', (191, 201))	('beta-catenin', 'Gene', '1499', (216, 228))	('Vimentin', 'Gene', '7431', (203, 211))	('CASC9', 'Gene', (246, 251))	('CASC9', 'Gene', '101805492', (246, 251))	('E-cadherin', 'Gene', (144, 154))	('decreased', 'NegReg', (159, 168))	('promoted', 'PosReg', (258, 266))	('increased', 'PosReg', (113, 122))	('E-cadherin', 'Gene', '999', (144, 154))	('EMT procedure', 'CPA', (267, 280))	('N-cadherin', 'Gene', (191, 201))	('Vimentin', 'Gene', (203, 211))
106277	31802910	Here, we found that knockdown of CASC9 decreased the mRNA and protein mRNA levels of HIF-1alpha.	('CASC9', 'Gene', (33, 38))	('HIF-1alpha', 'Gene', '3091', (85, 95))	('CASC9', 'Gene', '101805492', (33, 38))	('HIF-1alpha', 'Gene', (85, 95))	('knockdown', 'Var', (20, 29))	('decreased', 'NegReg', (39, 48))
106294	31624596	Computed tomography (CT) scan found a T3N1M0 p16-negative poorly differentiated papillary squamous cell carcinoma.	('p16', 'Gene', '1029', (45, 48))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (90, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('p16', 'Gene', (45, 48))	('papillary squamous cell carcinoma', 'Disease', 'MESH:D002294', (80, 113))	('papillary squamous cell carcinoma', 'Disease', (80, 113))	('T3N1M0', 'Var', (38, 44))
106301	31624596	Several weeks to months after each endoscopic cryoablation, recurrent tracheal squamous cell carcinomas were identified, but CT imaging of the neck and chest showed no other area of cancer involvement.	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (79, 102))	('tracheal squamous cell carcinomas', 'Disease', (70, 103))	('cryoablation', 'Var', (46, 58))	('tracheal squamous cell carcinomas', 'Disease', 'MESH:D002294', (70, 103))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('carcinomas', 'Phenotype', 'HP:0030731', (93, 103))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (79, 103))	('cancer', 'Disease', (182, 188))
106343	31333777	Polymorphisms and expression of ERCC1 commonly predicted the occurrence and prognosis of lung cancer.	('lung cancer', 'Disease', (89, 100))	('lung cancer', 'Phenotype', 'HP:0100526', (89, 100))	('Polymorphisms', 'Var', (0, 13))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('ERCC1', 'Gene', (32, 37))	('lung cancer', 'Disease', 'MESH:D008175', (89, 100))	('predicted', 'Reg', (47, 56))	('ERCC1', 'Gene', '2067', (32, 37))
106346	31333777	Firstly, the qRT-PCR data showed that AC138128.1 expression was much lower in lung cancer comparing with its para-cancer tissues, which further analyzed by ROC curve.	('lung cancer', 'Disease', (78, 89))	('AC138128.1', 'Var', (38, 48))	('lung cancer', 'Phenotype', 'HP:0100526', (78, 89))	('para-cancer', 'Disease', 'MESH:D009369', (109, 120))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('lower', 'NegReg', (69, 74))	('expression', 'MPA', (49, 59))	('para-cancer', 'Disease', (109, 120))	('lung cancer', 'Disease', 'MESH:D008175', (78, 89))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('AC138128', 'Chemical', '-', (38, 46))
106348	31333777	Then AC138128.1 expression was found to have an increasing trend in a dose or time-dependent manner after cisplatin treatment.	('AC138128', 'Chemical', '-', (5, 13))	('cisplatin', 'Chemical', 'MESH:D002945', (106, 115))	('expression', 'MPA', (16, 26))	('AC138128.1', 'Var', (5, 15))
106350	31333777	Interestingly a positive relationship between AC138128.1 and ERCC1 expression was only found in cancer tissues, which reminded AC138128.1 may be involved in the regulation of ERCC1.	('ERCC1', 'Gene', (175, 180))	('ERCC1', 'Gene', '2067', (61, 66))	('AC138128.1', 'Var', (127, 137))	('ERCC1', 'Gene', '2067', (175, 180))	('AC138128', 'Chemical', '-', (46, 54))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('involved', 'Reg', (145, 153))	('AC138128', 'Chemical', '-', (127, 135))	('expression', 'MPA', (67, 77))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('ERCC1', 'Gene', (61, 66))	('cancer', 'Disease', (96, 102))
106351	31333777	Therefore, as a preliminary exploration of the lncRNA originated from ERCC1, the present study suggested AC138128.1 is of potential value in predicting platinum analogue benefit in lung cancer.	('ERCC1', 'Gene', (70, 75))	('platinum', 'Chemical', 'MESH:D010984', (152, 160))	('AC138128', 'Chemical', '-', (105, 113))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('lung cancer', 'Disease', (181, 192))	('ERCC1', 'Gene', '2067', (70, 75))	('lung cancer', 'Phenotype', 'HP:0100526', (181, 192))	('AC138128.1', 'Var', (105, 115))	('lung cancer', 'Disease', 'MESH:D008175', (181, 192))
106357	31333777	Excision repair cross-complementing rodent repair deficiency, complementation group 1 (ERCC1), an endonuclease as a key member of the nucleotide excision repair (NER) pathway, is vital to the repair of DNA damage, particularly DNA adducts or double-stranded breaks.	('double-stranded breaks', 'Var', (242, 264))	('DNA adducts', 'Var', (227, 238))	('ERCC1', 'Gene', (87, 92))	('ERCC1', 'Gene', '2067', (87, 92))
106359	31333777	Our previous study showed that a polymorphism site in the 3' untranslated region (UTR) of ERCC1 was associated with BPDE-DNA (7,8-dihydroxybenzo(a)pyrene-9,10-oxide) adduct levels, an indicator closely related to tumorigenesis.	('tumor', 'Disease', (213, 218))	('associated', 'Reg', (100, 110))	('BPDE-DNA', 'Chemical', 'MESH:C043931', (116, 124))	('polymorphism site in', 'Var', (33, 53))	('ERCC1', 'Gene', (90, 95))	('ERCC1', 'Gene', '2067', (90, 95))	('tumor', 'Disease', 'MESH:D009369', (213, 218))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('7,8-dihydroxybenzo(a)pyrene-9,10-oxide', 'Chemical', '-', (126, 164))
106367	31333777	Moreover, it has been reported that AC138128.1 is down-regulated in gastric cancer and liver cancer.	('gastric cancer', 'Phenotype', 'HP:0012126', (68, 82))	('AC138128', 'Chemical', '-', (36, 44))	('liver cancer', 'Phenotype', 'HP:0002896', (87, 99))	('liver cancer', 'Disease', 'MESH:D006528', (87, 99))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('AC138128.1', 'Var', (36, 46))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('gastric cancer', 'Disease', (68, 82))	('liver cancer', 'Disease', (87, 99))	('gastric cancer', 'Disease', 'MESH:D013274', (68, 82))	('down-regulated', 'NegReg', (50, 64))
106368	31333777	However, whether AC138128.1 is associated with the risk or prognosis of lung cancer is unknown.	('AC138128.1', 'Var', (17, 27))	('associated', 'Reg', (31, 41))	('AC138128', 'Chemical', '-', (17, 25))	('lung cancer', 'Disease', (72, 83))	('lung cancer', 'Phenotype', 'HP:0100526', (72, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('lung cancer', 'Disease', 'MESH:D008175', (72, 83))
106369	31333777	In order to clarify the implication of lncRNA AC138128.1as a possible biomarker in lung cancer, we first detected the expression of lncRNA AC138128.1 in the cancer and its para-cancer tissues.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('cancer', 'Disease', (177, 183))	('cancer', 'Disease', (88, 94))	('lung cancer', 'Disease', 'MESH:D008175', (83, 94))	('cancer', 'Disease', 'MESH:D009369', (177, 183))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('AC138128', 'Chemical', '-', (46, 54))	('AC138128', 'Chemical', '-', (139, 147))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('para-cancer', 'Disease', 'MESH:D009369', (172, 183))	('lung cancer', 'Disease', (83, 94))	('lung cancer', 'Phenotype', 'HP:0100526', (83, 94))	('cancer', 'Disease', (157, 163))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('lncRNA AC138128.1', 'Var', (132, 149))	('para-cancer', 'Disease', (172, 183))
106401	31333777	The upstream and downstream 100k nts of ERCC1 gene is from 45876341 to 46078414 in chromosome 19 (GRCh37).	('ERCC1', 'Gene', (40, 45))	('ERCC1', 'Gene', '2067', (40, 45))	('46078414', 'Var', (71, 79))
106424	31333777	In 64 pairs of tissues, AC138128.1 is significantly downregulated in cancer tissues (Figure 4A).	('AC138128.1', 'Var', (24, 34))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('downregulated', 'NegReg', (52, 65))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('AC138128', 'Chemical', '-', (24, 32))	('cancer', 'Disease', (69, 75))
106427	31333777	The area under the ROC curve is 0.852 (P < 0.001 95%CI: 0.787 - 0.918) (Figure 5), which reminds that AC138128.1 can be of value to distinguish the lung cancer and para-cancer tissue.	('lung cancer', 'Disease', 'MESH:D008175', (148, 159))	('para-cancer', 'Disease', 'MESH:D009369', (164, 175))	('AC138128', 'Chemical', '-', (102, 110))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('lung cancer', 'Disease', (148, 159))	('para-cancer', 'Disease', (164, 175))	('lung cancer', 'Phenotype', 'HP:0100526', (148, 159))	('AC138128.1', 'Var', (102, 112))
106430	31333777	We found that the expression of AC138128.1 is much lower in the A549 and LK2 cell lines compared with 16HBE (both P < 0.05), as shown in Figure 6, which is consistent with the result of cancer tissue.	('AC138128', 'Chemical', '-', (32, 40))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('lower', 'NegReg', (51, 56))	('AC138128.1', 'Var', (32, 42))	('expression', 'MPA', (18, 28))	('LK2', 'CellLine', 'CVCL:1377', (73, 76))	('A549', 'CellLine', 'CVCL:0023', (64, 68))	('cancer', 'Disease', (186, 192))	('cancer', 'Disease', 'MESH:D009369', (186, 192))
106435	31333777	The range of AC138128.1 expression (1x103) in cancer is 0.031-20.977 (median, 1.133) and the IC50 is 5.985-680.388 mug/mL (median, 42.14 mug/mL).	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('cancer', 'Disease', (46, 52))	('AC138128', 'Chemical', '-', (13, 21))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('AC138128.1', 'Var', (13, 23))
106436	31333777	In para-cancer tissues, AC138128.1 expression (1x103) ranges from 0.001 to 989.62 (median, 81.023) and the IC50 ranges from 13.002 to 6780.1 mug/mL (media, 254.98 mug/mL).	('AC138128.1', 'Var', (24, 34))	('para-cancer', 'Disease', 'MESH:D009369', (3, 14))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('para-cancer', 'Disease', (3, 14))	('AC138128', 'Chemical', '-', (24, 32))
106437	31333777	The results indicate that AC138128.1 expression has a negative relationship with the sensitivity of cisplatin in cancer tissue (rs = 0.493, P = 0.027) while no similar significance is found in its para-cancer tissue (rs = -0.179, P = 0.450).	('AC138128.1 expression', 'Var', (26, 47))	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('cisplatin', 'Chemical', 'MESH:D002945', (100, 109))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('para-cancer', 'Disease', (197, 208))	('cancer', 'Disease', (113, 119))	('cancer', 'Disease', 'MESH:D009369', (202, 208))	('AC138128', 'Chemical', '-', (26, 34))	('cancer', 'Disease', (202, 208))	('sensitivity of cisplatin', 'MPA', (85, 109))	('para-cancer', 'Disease', 'MESH:D009369', (197, 208))	('negative', 'NegReg', (54, 62))
106446	31333777	Because AC138128.1 is an intronic lncRNA mostly present in the nucleus, it may be involved in the transcriptional regulation of its neighboring genes.	('AC138128.1', 'Var', (8, 18))	('AC138128', 'Chemical', '-', (8, 16))	('involved', 'Reg', (82, 90))
106448	31333777	In cancer tissues, AC138128.1 and ERCC1 show a strong correlation (r = 0.46, P < 0.05).	('ERCC1', 'Gene', (34, 39))	('ERCC1', 'Gene', '2067', (34, 39))	('AC138128', 'Chemical', '-', (19, 27))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('cancer', 'Disease', (3, 9))	('AC138128.1', 'Var', (19, 29))	('correlation', 'Interaction', (54, 65))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
106460	31333777	The previous study also found that the efficiency of repairing DNA adduct was affected by a polymorphism located in ERCC1 3'UTR and ERCC1 was mainly regulated by the post-transcriptional regulation of miRNA.	('regulated', 'Reg', (149, 158))	('affected', 'Reg', (78, 86))	('polymorphism', 'Var', (92, 104))	('ERCC1', 'Gene', '2067', (132, 137))	('ERCC1', 'Gene', (132, 137))	('ERCC1', 'Gene', '2067', (116, 121))	('ERCC1', 'Gene', (116, 121))
106463	31333777	However, whether AC138128.1 is associated with lung cancer is still uncertain; we attempted to design a study to clarify the linkage.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('lung cancer', 'Disease', (47, 58))	('lung cancer', 'Phenotype', 'HP:0100526', (47, 58))	('associated', 'Reg', (31, 41))	('AC138128', 'Chemical', '-', (17, 25))	('lung cancer', 'Disease', 'MESH:D008175', (47, 58))	('AC138128.1', 'Var', (17, 27))
106465	31333777	Interestingly, the ROC curve supports the value of the lncRNA AC138128.1 to distinguish AC138128.1 expression in cancer and para-cancer tissues (area under the curve > 0.8), which further confirmed its lower expression in lung cancer tissues.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('lung cancer', 'Disease', (222, 233))	('para-cancer', 'Disease', (124, 135))	('lung cancer', 'Phenotype', 'HP:0100526', (222, 233))	('AC138128', 'Chemical', '-', (88, 96))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('AC138128.1', 'Var', (88, 98))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', (113, 119))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (227, 233))	('para-cancer', 'Disease', 'MESH:D009369', (124, 135))	('cancer', 'Disease', (227, 233))	('lung cancer', 'Disease', 'MESH:D008175', (222, 233))	('AC138128', 'Chemical', '-', (62, 70))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
106469	31333777	Due to AC138128.1 located in in the genome of ERCC1 genes, we wonder if AC138128.1 plays an important role in DNA damage caused by genotoxic substances such as cisplatin, like the ERCC1 gene.	('AC138128.1', 'Var', (7, 17))	('AC138128', 'Chemical', '-', (72, 80))	('ERCC1', 'Gene', (180, 185))	('ERCC1', 'Gene', '2067', (46, 51))	('ERCC1', 'Gene', (46, 51))	('ERCC1', 'Gene', '2067', (180, 185))	('cisplatin', 'Chemical', 'MESH:D002945', (160, 169))	('AC138128', 'Chemical', '-', (7, 15))
106471	31333777	As we expected, the expression of AC138128.1 increased in both time-dependent and dose-dependent manners, which reminded AC138128.1 was sensitive to genotoxic agents as cisplatin.	('AC138128', 'Chemical', '-', (121, 129))	('expression', 'MPA', (20, 30))	('AC138128.1', 'Var', (121, 131))	('cisplatin', 'Chemical', 'MESH:D002945', (169, 178))	('AC138128.1', 'Gene', (34, 44))	('AC138128', 'Chemical', '-', (34, 42))
106477	31333777	Additionally, AC138128.1 is an intronic lncRNA and may function in cis, meaning that it may regulate its adjacent genes.	('regulate', 'Reg', (92, 100))	('AC138128.1', 'Var', (14, 24))	('AC138128', 'Chemical', '-', (14, 22))
106483	31333777	In conclusion, our present data showed that AC138128.1, an intronic lncRNA originated from ERCC1, may cooperate with ERCC1 and have a unique function, and become a potential biomarker to predict platinum treatment of lung cancer.	('platinum', 'Chemical', 'MESH:D010984', (195, 203))	('lung cancer', 'Disease', 'MESH:D008175', (217, 228))	('lung cancer', 'Disease', (217, 228))	('ERCC1', 'Gene', (117, 122))	('lung cancer', 'Phenotype', 'HP:0100526', (217, 228))	('AC138128', 'Chemical', '-', (44, 52))	('ERCC1', 'Gene', '2067', (117, 122))	('cooperate', 'Interaction', (102, 111))	('AC138128.1', 'Var', (44, 54))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('ERCC1', 'Gene', (91, 96))	('ERCC1', 'Gene', '2067', (91, 96))
106486	31564804	FAT1 was frequently mutated in ESCC and was deleted in multiple cancers.	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('cancers', 'Disease', 'MESH:D009369', (64, 71))	('cancers', 'Phenotype', 'HP:0002664', (64, 71))	('cancers', 'Disease', (64, 71))	('ESCC', 'Disease', (31, 35))	('FAT1', 'Gene', (0, 4))	('mutated', 'Var', (20, 27))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
106489	31564804	Several large-scale analyses demonstrated that some genes and pathways, such as TP53, RB1, CDKN2A, PIK3CA, Notch and FAT atypical cadherin 1 (FAT1), may contribute to ESCC tumorigenesis.Among these aberrant genes, the "sleeping giant" FAT1 is inactivated by a two-hit model in ESCC tumors, where somatic mutations are often accompanied by the loss of heterozygosity or homozygous deletion, showing an anti-tumor activity.	('RB1', 'Gene', (86, 89))	('ESCC tumors', 'Disease', (277, 288))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('tumor', 'Phenotype', 'HP:0002664', (282, 287))	('CDKN2A', 'Gene', (91, 97))	('PIK3CA', 'Gene', '5290', (99, 105))	('tumors', 'Phenotype', 'HP:0002664', (282, 288))	('RB1', 'Gene', '5925', (86, 89))	('TP53', 'Gene', '7157', (80, 84))	('tumor', 'Phenotype', 'HP:0002664', (406, 411))	('TP53', 'Gene', (80, 84))	('CDKN2A', 'Gene', '1029', (91, 97))	('anti-tumor activity', 'MPA', (401, 420))	('homozygous deletion', 'Var', (369, 388))	('PIK3CA', 'Gene', (99, 105))
106491	31564804	The inactivation of FAT1 via somatic mutations or deletions is also observed in multiple human cancers to promote Wnt/beta-catenin signaling and tumorigenesis.	('tumorigenesis', 'CPA', (145, 158))	('human', 'Species', '9606', (89, 94))	('inactivation', 'Var', (4, 16))	('cancers', 'Phenotype', 'HP:0002664', (95, 102))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('promote', 'PosReg', (106, 113))	('Wnt/beta-catenin signaling', 'MPA', (114, 140))	('FAT1', 'Gene', (20, 24))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('deletions', 'Var', (50, 59))
106494	31564804	All siRNAs (25-mer duplex Stealth siRNAs) were obtained from Invitrogen, and the sequence information is as follows: siFAT1: HSS103568 and HSS176716 and siE2F1: HSS103016 and HSS103017.	('HSS103016', 'Var', (161, 170))	('HSS103568', 'Chemical', 'None', (125, 134))	('HSS176716', 'Chemical', 'None', (139, 148))	('HSS103016', 'Chemical', 'None', (161, 170))	('HSS103017', 'Chemical', 'MESH:C097589', (175, 184))	('HSS103017', 'Var', (175, 184))	('HSS176716', 'Var', (139, 148))	('HSS103568', 'Var', (125, 134))
106503	31564804	As expected, FAT1 knockdown induced the mRNA levels of MAP3K8, MAP2K2 and MAP2K6 and decreased the mRNA level of MAPK inactivator DUSP6 (Figure 5C).	('MAP2K2', 'Gene', '5605', (63, 69))	('knockdown', 'Var', (18, 27))	('decreased', 'NegReg', (85, 94))	('MAP3K8', 'Gene', '1326', (55, 61))	('MAP2K2', 'Gene', (63, 69))	('induced', 'PosReg', (28, 35))	('MAP3K8', 'Gene', (55, 61))	('mRNA levels', 'MPA', (40, 51))	('FAT1', 'Gene', (13, 17))	('MAP2K6', 'Gene', (74, 80))	('MAP2K6', 'Gene', '5608', (74, 80))	('DUSP6', 'Gene', (130, 135))	('DUSP6', 'Gene', '1848', (130, 135))
106504	31564804	Meanwhile, FAT1 knockdown enhanced the mRNA levels of L1CAM and CDH5, which are involved in the cell adhesion process (Figure 5D).	('enhanced', 'PosReg', (26, 34))	('FAT1', 'Gene', (11, 15))	('CDH5', 'Gene', (64, 68))	('CDH5', 'Gene', '1003', (64, 68))	('L1CAM', 'Gene', (54, 59))	('knockdown', 'Var', (16, 25))	('mRNA levels', 'MPA', (39, 50))	('L1CAM', 'Gene', '3897', (54, 59))
106509	31564804	On the other hand, the GO functional analysis and RT-qPCR also revealed that loss of FAT1 subsequently upregulated the expression of genes that participate in the cell adhesion process, including L1CAM and CHD5, which may play roles in the progression or metastasis of multiple cancers and correlate with poor outcomes.	('metastasis of multiple cancers', 'Disease', 'MESH:D009362', (255, 285))	('CHD5', 'Gene', (206, 210))	('expression', 'MPA', (119, 129))	('metastasis of multiple cancers', 'Disease', (255, 285))	('loss', 'Var', (77, 81))	('cancer', 'Phenotype', 'HP:0002664', (278, 284))	('L1CAM', 'Gene', (196, 201))	('cancers', 'Phenotype', 'HP:0002664', (278, 285))	('FAT1', 'Gene', (85, 89))	('upregulated', 'PosReg', (103, 114))	('CHD5', 'Gene', '26038', (206, 210))
106522	30627543	Table 1 listed mostly frequent DEMs and DEGs across 11 types of cancer, including genes like ADGRB3, ASF1B, CDKN2A, CDT1, DPT, E2F1, E2F7, MYBL2, TCEAL2 and miRNAs like miR-183, miR-96, miR-1, miR-1258, miR-133a, miR-135b, miR-144, miR-182, miR-195, miR-21.	('E2F7', 'Gene', (133, 137))	('miR-183', 'Gene', '406959', (169, 176))	('DPT', 'Gene', (122, 125))	('ASF1B', 'Gene', '55723', (101, 106))	('miR-195', 'Gene', '406971', (241, 248))	('miR-21', 'Gene', '406991', (250, 256))	('CDT1', 'Gene', '81620', (116, 120))	('MYBL2', 'Gene', '4605', (139, 144))	('miR-135b', 'Gene', (213, 221))	('miR-133a', 'Var', (203, 211))	('miR-1258', 'Gene', (193, 201))	('E2F1', 'Gene', (127, 131))	('CDT1', 'Gene', (116, 120))	('miR-96', 'Gene', '407053', (178, 184))	('CDKN2A', 'Gene', '1029', (108, 114))	('miR-183', 'Gene', (169, 176))	('miR-195', 'Gene', (241, 248))	('TCEAL2', 'Gene', '140597', (146, 152))	('E2F1', 'Gene', '1869', (127, 131))	('ADGRB3', 'Gene', (93, 99))	('miR-144', 'Gene', '406936', (223, 230))	('miR-21', 'Gene', (250, 256))	('E2F7', 'Gene', '144455', (133, 137))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('TCEAL2', 'Gene', (146, 152))	('DPT', 'Gene', '1805', (122, 125))	('miR-1', 'Var', (186, 191))	('miR-1258', 'Gene', '100302172', (193, 201))	('ADGRB3', 'Gene', '577', (93, 99))	('miR-144', 'Gene', (223, 230))	('miR-182', 'Var', (232, 239))	('MYBL2', 'Gene', (139, 144))	('ASF1B', 'Gene', (101, 106))	('miR-96', 'Gene', (178, 184))	('CDKN2A', 'Gene', (108, 114))	('miR-135b', 'Gene', '442891', (213, 221))
106523	30627543	For example, MYBL2 which was targeted by miR-143-3p could regulate breast cancer cell proliferation and apoptosis; CDT1 was a critical regulator for normal genome replication, knockdown of TGFBR3 in T24 cells could result in decreased cell growth, motility and invasion, and miRNAs like miR-182, miR-183, miR-21, miR-195 and miR-96 were all associated with tumorigenesis.	('motility', 'CPA', (248, 256))	('associated', 'Reg', (341, 351))	('tumorigenesis', 'CPA', (357, 370))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('miR-182', 'Var', (287, 294))	('tumor', 'Phenotype', 'HP:0002664', (357, 362))	('miR-183', 'Var', (296, 303))	('miR-96', 'Var', (325, 331))	('CDT1', 'Gene', (115, 119))	('TGFBR3', 'Gene', '7049', (189, 195))	('miR-21', 'Var', (305, 311))	('knockdown', 'Var', (176, 185))	('miR-195', 'Var', (313, 320))	('breast cancer', 'Phenotype', 'HP:0003002', (67, 80))	('TGFBR3', 'Gene', (189, 195))	('invasion', 'CPA', (261, 269))	('breast cancer', 'Disease', 'MESH:D001943', (67, 80))	('breast cancer', 'Disease', (67, 80))	('cell growth', 'CPA', (235, 246))	('decreased', 'NegReg', (225, 234))
106527	30627543	Thus, dysregulated miRNA-target gene pairs involved in these genes like miR-21/GNE, miR-369/TRIM2, and miR-203a/PDE7A might promote the migration of cancer cells.	('miR-369', 'Gene', '442914', (84, 91))	('miR-21/GNE', 'Var', (72, 82))	('miR-369', 'Gene', (84, 91))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('migration of cancer cells', 'CPA', (136, 161))	('miR-203a', 'Gene', (103, 111))	('miR-203a', 'Gene', '406986', (103, 111))	('promote', 'PosReg', (124, 131))
106529	30627543	These included known cancer-related pathways, such as Pathways in cancer (p = 3.78E-07, Bonferroni correction, BLCA), cell cycle pathway (p = 1.20E-05, Bonferroni correction, BRCA), p53 signaling pathway (p = 8.83E-06, Bonferroni correction, HNSC), and AMPK signaling pathway (p = 3.60E-04, Bonferroni correction, KIRC).	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('AMPK signaling pathway', 'Pathway', (253, 275))	('p53', 'Gene', (182, 185))	('cell cycle pathway', 'Pathway', (118, 136))	('p53', 'Gene', '7157', (182, 185))	('Bonferroni correction', 'Var', (152, 173))
106540	29953591	Our data indicates that RUMI modulates Notch activity in NSCLC cells, and that its silencing dramatically decreases cell proliferation, migration and survival.	('cell proliferation', 'CPA', (116, 134))	('NSCLC', 'Disease', 'MESH:D002289', (57, 62))	('RUMI', 'Gene', (24, 28))	('Notch', 'Gene', '31293', (39, 44))	('survival', 'CPA', (150, 158))	('RUMI', 'Gene', '56983', (24, 28))	('NSCLC', 'Phenotype', 'HP:0030358', (57, 62))	('modulates', 'Reg', (29, 38))	('Notch', 'Gene', (39, 44))	('NSCLC', 'Disease', (57, 62))	('decreases', 'NegReg', (106, 115))	('silencing', 'Var', (83, 92))
106543	29953591	Notwithstanding the enormous progress made in the dissection of the signaling pathways and networks governing lung development and carcinogenesis, and the substantial advances in the identification of lung cancer driver mutations, the precise molecular and cellular mechanisms triggering lung cancer initiation and formation are not yet clearly understood.	('carcinogenesis', 'Disease', (131, 145))	('lung cancer', 'Phenotype', 'HP:0100526', (288, 299))	('lung cancer', 'Disease', 'MESH:D008175', (201, 212))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('lung cancer', 'Disease', 'MESH:D008175', (288, 299))	('lung cancer initiation', 'Disease', (288, 310))	('carcinogenesis', 'Disease', 'MESH:D063646', (131, 145))	('cancer', 'Phenotype', 'HP:0002664', (293, 299))	('lung cancer', 'Phenotype', 'HP:0100526', (201, 212))	('lung cancer', 'Disease', (201, 212))	('mutations', 'Var', (220, 229))	('lung cancer initiation', 'Disease', 'MESH:D008175', (288, 310))
106554	29953591	Strikingly, Rumi is also required for ligand-independent S2 cleavage activation of Notch, and its inactivation is capable of suppressing both hyperactive, ligand-independent Notch signaling activity and Notch activity-driven neoplastic cell growth.	('inactivation', 'Var', (98, 110))	('Notch', 'Gene', (174, 179))	('Notch', 'Gene', (83, 88))	('Notch', 'Gene', (203, 208))	('Notch', 'Gene', '31293', (174, 179))	('hyperactive', 'Disease', 'MESH:D006948', (142, 153))	('Notch', 'Gene', '31293', (83, 88))	('hyperactive', 'Disease', (142, 153))	('Notch', 'Gene', '31293', (203, 208))	('suppressing', 'NegReg', (125, 136))
106570	29953591	Non-target control MISSION shRNA (SHC002) and the two independent and non-overlapping MISSION shRNAs directed against two distinct regions of the coding sequence of human RUMI mRNA (shRNA1, TRCN0000155317; shRNA2, TRCN0000151420) were from SIGMA.	('RUMI', 'Gene', '56983', (171, 175))	('RUMI', 'Gene', (171, 175))	('TRCN0000151420', 'Var', (214, 228))	('human', 'Species', '9606', (165, 170))
106581	29953591	As tumor stage is a well-known prognostic factor, Kaplan-Meier (KM) plot of OS in the validation set based on protein expression high/low status was stratified on tumor stage.	('tumor', 'Disease', (3, 8))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('high/low', 'Var', (129, 137))	('protein', 'Protein', (110, 117))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('tumor', 'Disease', (163, 168))	('tumor', 'Disease', 'MESH:D009369', (3, 8))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))
106583	29953591	Validated Taqman hydrolysis assays were obtained from Life Technologies and included primers/probe sets for RUMI (Hs00220308_m1), HEY1 (Hs01114113_m1), HES2 (Hs00219505_m1) and 18S rRNA (4319413E).	('Hs00219505_m1', 'Var', (158, 171))	('RUMI', 'Gene', '56983', (108, 112))	('RUMI', 'Gene', (108, 112))	('Hs01114113_m1', 'Var', (136, 149))	('4319413E', 'Var', (187, 195))	('HEY1', 'Gene', '23462', (130, 134))	('HES2', 'Gene', '54626', (152, 156))	('HES2', 'Gene', (152, 156))	('Hs00220308_m1', 'Var', (114, 127))	('HEY1', 'Gene', (130, 134))
106595	29953591	Notably, through this colocalization experiment, it was evident that Rumi is not exclusively expressed in alveolar type II cells since there were also cells in the alveolar parenchyma that scored positive for Rumi but not for SP-C (Fig.	('SP-C', 'Gene', '6440', (226, 230))	('positive', 'Reg', (196, 204))	('SP-C', 'Gene', (226, 230))	('alveolar parenchyma', 'Disease', 'MESH:D002282', (164, 183))	('alveolar parenchyma', 'Disease', (164, 183))	('Rumi', 'Var', (209, 213))
106600	29953591	Accordingly, our inquiries in biorepository databases of genomic alterations in human cancers indicated that the frequency of RUMI amplifications is markedly high in NSCLC, including, in particular, the Squamous Cell Carcinoma subtype (Fig.	('RUMI', 'Gene', (126, 130))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (203, 226))	('RUMI', 'Gene', '56983', (126, 130))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('Carcinoma', 'Phenotype', 'HP:0030731', (217, 226))	('NSCLC', 'Disease', (166, 171))	('Squamous Cell Carcinoma', 'Disease', 'MESH:D002294', (203, 226))	('amplifications', 'Var', (131, 145))	('human', 'Species', '9606', (80, 85))	('NSCLC', 'Disease', 'MESH:D002289', (166, 171))	('cancers', 'Phenotype', 'HP:0002664', (86, 93))	('high', 'Reg', (158, 162))	('NSCLC', 'Phenotype', 'HP:0030358', (166, 171))	('cancers', 'Disease', 'MESH:D009369', (86, 93))	('Squamous Cell Carcinoma', 'Disease', (203, 226))	('cancers', 'Disease', (86, 93))
106609	29953591	As can be seen in the table inscribed in Figure 3C, patients with high levels of RUMI expression in the KTMA cohort had worse OS prognosis, with a statistically significant increase in the hazard ratio (HR) value (HR=1.81, 95% CI (1.08 to 3.01), P=0.023).	('RUMI', 'Gene', (81, 85))	('high levels', 'Var', (66, 77))	('increase', 'PosReg', (173, 181))	('patients', 'Species', '9606', (52, 60))	('RUMI', 'Gene', '56983', (81, 85))
106610	29953591	Critically, these results were further validated in the YTMA cohort, where patients with high RUMI expression also show worse OS prognosis (HR=2.89, 95% CI (1.17 to 7.16), P=0.022).	('patients', 'Species', '9606', (75, 83))	('RUMI', 'Gene', '56983', (94, 98))	('to 7', 'Species', '1214577', (162, 166))	('high', 'Var', (89, 93))	('RUMI', 'Gene', (94, 98))
106611	29953591	Importantly, we found no association between the high/low status of RUMI and known prognostic factors (Fig.	('high/low', 'Var', (49, 57))	('RUMI', 'Gene', '56983', (68, 72))	('RUMI', 'Gene', (68, 72))
106617	29953591	Furthermore, our multivariable Cox analysis for TTP in KTMA indicates that patients with high levels of RUMI expression have a highly significant increased HR of 2.32 (95% CI (1.48 to 4.27), P=0.008) compared to patients with low levels of RUMI.	('RUMI', 'Gene', (240, 244))	('RUMI', 'Gene', '56983', (240, 244))	('RUMI', 'Gene', '56983', (104, 108))	('RUMI', 'Gene', (104, 108))	('increased', 'PosReg', (146, 155))	('patients', 'Species', '9606', (75, 83))	('patients', 'Species', '9606', (212, 220))	('high levels', 'Var', (89, 100))
106624	29953591	As expected, RUMI knockdown in A549 cells resulted in a highly significant decrease in transcript levels of Notch effectors HEY1 (61.3% by shRNA1 and 70.7% by shRNA2), and HES2 (60.2% by shRNA1 and 53.9% by shRNA2), thus indicating that RUMI silencing downregulates Notch signaling activity in these cells (Fig.	('knockdown', 'Var', (18, 27))	('Notch', 'Gene', (266, 271))	('transcript levels', 'MPA', (87, 104))	('downregulates', 'NegReg', (252, 265))	('decrease', 'NegReg', (75, 83))	('RUMI', 'Gene', (237, 241))	('HEY1', 'Gene', (124, 128))	('silencing', 'Var', (242, 251))	('RUMI', 'Gene', '56983', (237, 241))	('HEY1', 'Gene', '23462', (124, 128))	('A549', 'CellLine', 'CVCL:0023', (31, 35))	('Notch', 'Gene', '31293', (266, 271))	('Notch', 'Gene', (108, 113))	('HES2', 'Gene', '54626', (172, 176))	('HES2', 'Gene', (172, 176))	('RUMI', 'Gene', '56983', (13, 17))	('Notch', 'Gene', '31293', (108, 113))	('RUMI', 'Gene', (13, 17))
106626	29953591	In conclusion, these results indicate that RUMI silencing could effectively inhibit Notch signaling activity in NSCLC cell lines.	('silencing', 'Var', (48, 57))	('Notch', 'Gene', '31293', (84, 89))	('inhibit', 'NegReg', (76, 83))	('NSCLC', 'Phenotype', 'HP:0030358', (112, 117))	('NSCLC', 'Disease', (112, 117))	('Notch', 'Gene', (84, 89))	('RUMI', 'Gene', '56983', (43, 47))	('RUMI', 'Gene', (43, 47))	('NSCLC', 'Disease', 'MESH:D002289', (112, 117))
106627	29953591	Having demonstrated Notch signaling inhibition through RUMI silencing, we next explored the effects of RUMI knockdown on cell function in NSCLC cell lines.	('RUMI', 'Gene', (55, 59))	('Notch', 'Gene', (20, 25))	('NSCLC', 'Disease', (138, 143))	('RUMI', 'Gene', (103, 107))	('RUMI', 'Gene', '56983', (55, 59))	('RUMI', 'Gene', '56983', (103, 107))	('inhibition', 'NegReg', (36, 46))	('NSCLC', 'Disease', 'MESH:D002289', (138, 143))	('Notch', 'Gene', '31293', (20, 25))	('silencing', 'Var', (60, 69))	('NSCLC', 'Phenotype', 'HP:0030358', (138, 143))
106628	29953591	Our data on crystal violet assays indicate that RUMI silencing dramatically affects cell proliferation of A549 cells (Fig.	('RUMI', 'Gene', (48, 52))	('RUMI', 'Gene', '56983', (48, 52))	('silencing', 'Var', (53, 62))	('cell proliferation', 'CPA', (84, 102))	('A549', 'CellLine', 'CVCL:0023', (106, 110))	('affects', 'Reg', (76, 83))
106631	29953591	The results of our DAPI and DAPI/EdU incorporation experiments clearly show that RUMI knockdown causes a severe S-phase arrest in A549 cells (Fig.	('RUMI', 'Gene', (81, 85))	('knockdown', 'Var', (86, 95))	('S-phase arrest', 'CPA', (112, 126))	('A549', 'CellLine', 'CVCL:0023', (130, 134))	('RUMI', 'Gene', '56983', (81, 85))
106632	29953591	S4A, B), with a highly statistically significant increase in the fraction of cells actively incorporating EdU into their DNA, from 28.1% in Non-target control cells to 39.7% and 48.2% in RUMI-silenced cells with shRNA1 and shRNA2, respectively (Fig.	('shRNA2', 'Var', (223, 229))	('increase', 'PosReg', (49, 57))	('shRNA1', 'Var', (212, 218))	('RUMI', 'Gene', (187, 191))	('RUMI', 'Gene', '56983', (187, 191))
106634	29953591	5E, F), which, similarly to what was shown for A549 cells, show a statistically significant increase in the proportion of total S-phase arrested cells (46.4% in shRNA1 and 42.3% in shRNA2 compared to 40.1% in Non-target shRNA) (Fig.	('S-phase arrested', 'MPA', (128, 144))	('increase', 'PosReg', (92, 100))	('shRNA1', 'Var', (161, 167))	('A549', 'CellLine', 'CVCL:0023', (47, 51))
106635	29953591	Interestingly, in H23 cells, a further marked aneuploid genomic instability was also observed upon RUMI knockdown (modeled as aneuploid, An1, in Fig.	('H23', 'CellLine', 'CVCL:1547', (18, 21))	('RUMI', 'Gene', '56983', (99, 103))	('RUMI', 'Gene', (99, 103))	('knockdown', 'Var', (104, 113))
106639	29953591	Interestingly, our Annexin-V/propidium iodide assays showed that RUMI silencing did not result in increased numbers of cells undergoing early apoptosis (Fig.	('RUMI', 'Gene', '56983', (65, 69))	('Annexin-V', 'Gene', (19, 28))	('silencing', 'Var', (70, 79))	('RUMI', 'Gene', (65, 69))	('propidium iodide', 'Chemical', 'MESH:D011419', (29, 45))	('Annexin-V', 'Gene', '308', (19, 28))
106642	29953591	Our data in these studies manifestly show that RUMI silencing results in a marked impairment on cell migration in both H23 and A549 cells (Fig.	('silencing', 'Var', (52, 61))	('cell migration in', 'CPA', (96, 113))	('H23', 'CellLine', 'CVCL:1547', (119, 122))	('RUMI', 'Gene', (47, 51))	('A549', 'CellLine', 'CVCL:0023', (127, 131))	('RUMI', 'Gene', '56983', (47, 51))	('impairment', 'NegReg', (82, 92))
106644	29953591	Similarly, our data on A549 cells, indicates that a statistically significant difference in the wound healing capacity is exhibited in RUMI knockdown cells (42% in shRNA1 and 46% in shRNA2) compared to Non-target control cells (78%) (Fig.	('wound healing capacity', 'CPA', (96, 118))	('RUMI', 'Gene', (135, 139))	('RUMI', 'Gene', '56983', (135, 139))	('knockdown', 'Var', (140, 149))	('A549', 'CellLine', 'CVCL:0023', (23, 27))
106647	29953591	Targeted inactivation of either Rbpjk or Jagged1 in the pulmonary epithelium results in alveolarization and septation defects, and Notch2 is required for alveolar type II cell proliferation and maturation.	('Rbpjk', 'Gene', (32, 37))	('alveolar type II cell proliferation', 'Disease', (154, 189))	('Rbpjk', 'Gene', '3516', (32, 37))	('Notch2', 'Gene', '4853', (131, 137))	('Jagged1', 'Gene', (41, 48))	('results in', 'Reg', (77, 87))	('Jagged1', 'Gene', '182', (41, 48))	('septation defects', 'CPA', (108, 125))	('Notch2', 'Gene', (131, 137))	('inactivation', 'Var', (9, 21))	('alveolar type II cell proliferation', 'Disease', 'MESH:D002282', (154, 189))	('septation defects', 'Phenotype', 'HP:0001671', (108, 125))	('alveolarization', 'CPA', (88, 103))
106648	29953591	Moreover, Shh-Cre-directed deletion of Notch regulator Pofut1 (protein O-fucosyltransferase 1) causes a marked decrease in type II cell proliferation and failure in alveolarization accompanied by emphysematous enlargement of the distal airspaces.	('Pofut1', 'Gene', (55, 61))	('Notch', 'Gene', '31293', (39, 44))	('Pofut1', 'Gene', '23509', (55, 61))	('Shh', 'Gene', '6469', (10, 13))	('emphysematous enlargement', 'Disease', 'MESH:D041882', (196, 221))	('emphysematous enlargement', 'Phenotype', 'HP:0002097', (196, 221))	('alveolarization', 'CPA', (165, 180))	('emphysematous enlargement', 'Disease', (196, 221))	('deletion', 'Var', (27, 35))	('failure', 'NegReg', (154, 161))	('type II cell proliferation', 'CPA', (123, 149))	('protein O-fucosyltransferase 1', 'Gene', (63, 93))	('Notch', 'Gene', (39, 44))	('decrease', 'NegReg', (111, 119))	('Shh', 'Gene', (10, 13))	('protein O-fucosyltransferase 1', 'Gene', '23509', (63, 93))
106652	29953591	Of importance, it is shown that Notch1 over-activation in SP-C-expressing cells results in mucous metaplasia and reduction of ciliated cells, and that Notch signaling abrogation disrupts Club cell fate specification, causing an imbalance towards the generation of ciliated cells.	('causing', 'Reg', (217, 224))	('Notch', 'Gene', '31293', (151, 156))	('disrupts', 'NegReg', (178, 186))	('Notch', 'Gene', '31293', (32, 37))	('imbalance towards', 'MPA', (228, 245))	('abrogation', 'Var', (167, 177))	('Notch', 'Gene', (151, 156))	('SP-C', 'Gene', '6440', (58, 62))	('imbalance', 'Phenotype', 'HP:0002172', (228, 237))	('reduction', 'NegReg', (113, 122))	('SP-C', 'Gene', (58, 62))	('Club', 'Phenotype', 'HP:0001217', (187, 191))	('Notch1', 'Gene', (32, 38))	('Notch1', 'Gene', '4851', (32, 38))	('Notch', 'Gene', (32, 37))	('ciliated cells', 'CPA', (126, 140))	('Club cell fate specification', 'CPA', (187, 215))	('over-activation', 'PosReg', (39, 54))
106653	29953591	While our studies in this subject are limited and cannot provide an assessment of Rumi's function on type II cells or Club cells, our data from gene silencing experiments in A549 and H23 lung cancer cells showing a requirement for RUMI in Notch activity and cell proliferation and survival, could certainly support the notion that RUMI could be exerting a functional role in these cell populations.	('A549', 'CellLine', 'CVCL:0023', (174, 178))	('H23', 'CellLine', 'CVCL:1547', (183, 186))	('Notch', 'Gene', '31293', (239, 244))	('lung cancer', 'Phenotype', 'HP:0100526', (187, 198))	('lung cancer', 'Disease', 'MESH:D008175', (187, 198))	('gene', 'Var', (144, 148))	('RUMI', 'Gene', (331, 335))	('RUMI', 'Gene', '56983', (331, 335))	('RUMI', 'Gene', (231, 235))	('RUMI', 'Gene', '56983', (231, 235))	('Club', 'Phenotype', 'HP:0001217', (118, 122))	('lung cancer', 'Disease', (187, 198))	('Notch', 'Gene', (239, 244))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))
106656	29953591	Remarkably, activating mutations in Notch1 heterodimerization and PEST domains have been found in 10% NSCLCs, and elevated Notch3 expression has been shown to occur in 30-40% of primary lung tumors.	('Notch3', 'Gene', '4854', (123, 129))	('expression', 'MPA', (130, 140))	('tumors', 'Phenotype', 'HP:0002664', (191, 197))	('lung tumors', 'Phenotype', 'HP:0100526', (186, 197))	('heterodimerization', 'MPA', (43, 61))	('NSCLCs', 'Disease', 'MESH:D002289', (102, 108))	('Notch3', 'Gene', (123, 129))	('NSCLC', 'Phenotype', 'HP:0030358', (102, 107))	('primary lung tumors', 'Disease', (178, 197))	('mutations', 'Var', (23, 32))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('PEST domains', 'MPA', (66, 78))	('Notch1', 'Gene', (36, 42))	('NSCLCs', 'Disease', (102, 108))	('primary lung tumors', 'Disease', 'MESH:D008175', (178, 197))	('activating', 'PosReg', (12, 22))	('elevated', 'PosReg', (114, 122))	('Notch1', 'Gene', '4851', (36, 42))
106665	29953591	Moreover, it is known that Notch3 blockade impairs the self-renewal capacity of CD24+ITGB4+Notchhi NSCLC tumor-initiating cells, and that Notch activity is required for Kras-induced adenocarcinoma development.	('self-renewal capacity', 'CPA', (55, 76))	('CD24', 'Gene', (80, 84))	('Kras', 'Gene', '3845', (169, 173))	('Notch', 'Gene', (138, 143))	('adenocarcinoma', 'Disease', (182, 196))	('NSCLC tumor', 'Disease', (99, 110))	('Kras', 'Gene', (169, 173))	('Notch', 'Gene', (91, 96))	('blockade', 'Var', (34, 42))	('Notch', 'Gene', (27, 32))	('NSCLC tumor', 'Disease', 'MESH:D009369', (99, 110))	('adenocarcinoma', 'Disease', 'MESH:D000230', (182, 196))	('CD24', 'Gene', '100133941', (80, 84))	('ITGB4', 'Gene', '3691', (85, 90))	('impairs', 'NegReg', (43, 50))	('Notch3', 'Gene', '4854', (27, 33))	('Notch3', 'Gene', (27, 33))	('Notch', 'Gene', '31293', (138, 143))	('ITGB4', 'Gene', (85, 90))	('Notch', 'Gene', '31293', (91, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (187, 196))	('NSCLC', 'Phenotype', 'HP:0030358', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('Notch', 'Gene', '31293', (27, 32))
106666	29953591	Strikingly, inactivation of presenilins 1 and 2, disruption of the canonical Notch activation-mediator Rbpjk, or pharmacological inhibition of the gamma-secretase complex, all exert a suppressive effect on Kras-driven lung adenocarcinoma development.	('Notch', 'Gene', (77, 82))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (218, 237))	('suppressive', 'NegReg', (184, 195))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (218, 237))	('Notch', 'Gene', '31293', (77, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (228, 237))	('lung adenocarcinoma', 'Disease', (218, 237))	('Rbpjk', 'Gene', (103, 108))	('presenilins 1 and 2', 'Gene', '5663;5664', (28, 47))	('Kras', 'Gene', (206, 210))	('Rbpjk', 'Gene', '3516', (103, 108))	('inactivation', 'Var', (12, 24))	('disruption', 'Var', (49, 59))	('Kras', 'Gene', '3845', (206, 210))
106671	29953591	Furthermore, Rumi inactivation has been shown to be effective in suppressing both oncogenic NotchDeltaLNR hyperactivity and Notch activity-driven neoplastic cell growth, which, in the context of NSCLC is of particular importance, especially considering that many NSCLCs are driven by ligand-independent Notch activity.	('neoplastic cell growth', 'CPA', (146, 168))	('NSCLC', 'Phenotype', 'HP:0030358', (263, 268))	('NSCLCs', 'Disease', (263, 269))	('Notch', 'Gene', (124, 129))	('NotchDeltaLNR hyperactivity', 'Disease', 'MESH:D006948', (92, 119))	('NSCLC', 'Disease', 'MESH:D002289', (195, 200))	('Notch', 'Gene', '31293', (303, 308))	('hyperactivity', 'Phenotype', 'HP:0000752', (106, 119))	('NSCLCs', 'Disease', 'MESH:D002289', (263, 269))	('NSCLC', 'Disease', (195, 200))	('inactivation', 'Var', (18, 30))	('Notch', 'Gene', '31293', (92, 97))	('NSCLC', 'Phenotype', 'HP:0030358', (195, 200))	('Notch', 'Gene', (303, 308))	('NSCLC', 'Disease', 'MESH:D002289', (263, 268))	('suppressing', 'NegReg', (65, 76))	('Rumi', 'Gene', (13, 17))	('Notch', 'Gene', '31293', (124, 129))	('NotchDeltaLNR hyperactivity', 'Disease', (92, 119))	('NSCLC', 'Disease', (263, 268))	('Notch', 'Gene', (92, 97))
106730	29085482	Studies have shown that multiple genes in this region were associated with the occurrence and development of a variety of clinical diseases, and the functional abnormalities of the genes can led to the occurrence of tumors.	('tumors', 'Disease', (216, 222))	('genes', 'Var', (181, 186))	('led to', 'Reg', (191, 197))	('associated', 'Reg', (59, 69))	('tumors', 'Disease', 'MESH:D009369', (216, 222))	('tumors', 'Phenotype', 'HP:0002664', (216, 222))	('development', 'CPA', (94, 105))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))
106737	29085482	Related studies also showed that the presence of STK33 protein in colon cancer, lung cancer, breast cancer, pancreatic cancer and other tumor cells is closely related to occurrence of mutations in KRAS gene.	('STK33', 'Gene', (49, 54))	('mutations', 'Var', (184, 193))	('KRAS', 'Gene', (197, 201))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (108, 125))	('breast cancer', 'Phenotype', 'HP:0003002', (93, 106))	('colon cancer', 'Phenotype', 'HP:0003003', (66, 78))	('lung cancer', 'Disease', 'MESH:D008175', (80, 91))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('protein', 'Protein', (55, 62))	('breast cancer', 'Disease', 'MESH:D001943', (93, 106))	('pancreatic cancer', 'Disease', 'MESH:D010190', (108, 125))	('breast cancer', 'Disease', (93, 106))	('lung cancer', 'Phenotype', 'HP:0100526', (80, 91))	('colon cancer', 'Disease', 'MESH:D015179', (66, 78))	('tumor', 'Disease', (136, 141))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('pancreatic cancer', 'Disease', (108, 125))	('presence', 'Reg', (37, 45))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('related', 'Reg', (159, 166))	('colon cancer', 'Disease', (66, 78))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('lung cancer', 'Disease', (80, 91))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('KRAS', 'Gene', '3845', (197, 201))	('STK33', 'Gene', '65975', (49, 54))
106814	28984210	Figure 4c shows the percentage of samples with mutations of the 32 TargetCancer genes, their function classification, and number of targeting drugs.	('Cancer', 'Disease', (73, 79))	('Cancer', 'Disease', 'MESH:D009369', (73, 79))	('Cancer', 'Phenotype', 'HP:0002664', (73, 79))	('mutations', 'Var', (47, 56))
106815	28984210	Indeed, for the 32 Target Cancer genes, there was a significant correlation between the percentages of samples with mutations and numbers of targeted drugs (Pearson's correlation: r = 0.40, P = 0.0230).	('Cancer', 'Phenotype', 'HP:0002664', (26, 32))	('mutations', 'Var', (116, 125))	('Cancer', 'Disease', 'MESH:D009369', (26, 32))	('Cancer', 'Disease', (26, 32))
106817	28984210	Its mutations significantly occur in the brain cancer GBM (27.1%), lung cancer (13.5%), COAD/READ (5.8%), HNSC (6.2%).	('GBM', 'Phenotype', 'HP:0012174', (54, 57))	('occur', 'Reg', (28, 33))	('brain cancer', 'Disease', 'MESH:D001932', (41, 53))	('COAD', 'Disease', 'MESH:D029424', (88, 92))	('lung cancer', 'Disease', 'MESH:D008175', (67, 78))	('HNSC', 'Disease', (106, 110))	('lung cancer', 'Phenotype', 'HP:0100526', (67, 78))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('brain cancer', 'Phenotype', 'HP:0030692', (41, 53))	('HNSC', 'Phenotype', 'HP:0012288', (106, 110))	('READ', 'Disease', 'None', (93, 97))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('mutations', 'Var', (4, 13))	('brain cancer', 'Disease', (41, 53))	('COAD', 'Disease', (88, 92))	('lung cancer', 'Disease', (67, 78))	('READ', 'Disease', (93, 97))
106860	32346412	Comparison of the characteristics of uncommon epidermal growth factor receptor (EGFR) mutations and EGFR-tyrosine kinase inhibitor treatment in patients with non-small cell lung cancer from different ethnic groups Patients with epidermal growth factor receptor (EGFR)-sensitive mutations generally have a significantly higher objective response rate (ORR) and longer progression-free survival (PFS) after EGFR-tyrosine kinase inhibitor (TKI) treatment.	('EGFR', 'Gene', '1956', (262, 266))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (158, 184))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (162, 184))	('EGFR', 'Gene', '1956', (80, 84))	('epidermal growth factor receptor', 'Gene', (228, 260))	('epidermal growth factor receptor', 'Gene', (46, 78))	('lung cancer', 'Disease', (173, 184))	('epidermal growth factor receptor', 'Gene', '1956', (228, 260))	('mutations', 'Var', (278, 287))	('EGFR', 'Gene', '1956', (100, 104))	('epidermal growth factor receptor', 'Gene', '1956', (46, 78))	('longer', 'PosReg', (360, 366))	('men', 'Species', '9606', (447, 450))	('objective', 'MPA', (326, 335))	('men', 'Species', '9606', (136, 139))	('progression-free survival', 'CPA', (367, 392))	('mutations', 'Var', (86, 95))	('EGFR', 'Gene', (405, 409))	('lung cancer', 'Disease', 'MESH:D008175', (173, 184))	('Patients', 'Species', '9606', (214, 222))	('EGFR', 'Gene', (262, 266))	('EGFR', 'Gene', (80, 84))	('lung cancer', 'Phenotype', 'HP:0100526', (173, 184))	('EGFR', 'Gene', (100, 104))	('higher', 'PosReg', (319, 325))	('patients', 'Species', '9606', (144, 152))	('EGFR', 'Gene', '1956', (405, 409))
106861	32346412	However, the efficacy of EGFR-TKIs in the case of uncommon EGFR mutations has remained elusive.	('EGFR', 'Gene', (25, 29))	('EGFR', 'Gene', (59, 63))	('mutations', 'Var', (64, 73))	('EGFR', 'Gene', '1956', (25, 29))	('EGFR', 'Gene', '1956', (59, 63))
106862	32346412	In the present study, the characteristics of uncommon EGFR mutations and EGFR-TKI treatments were compared in patients with non-small cell lung cancer (NSCLC) from different ethnic groups.	('lung cancer', 'Phenotype', 'HP:0100526', (139, 150))	('non-small cell lung cancer', 'Disease', (124, 150))	('EGFR', 'Gene', '1956', (73, 77))	('men', 'Species', '9606', (87, 90))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (128, 150))	('patients', 'Species', '9606', (110, 118))	('NSCLC', 'Disease', (152, 157))	('EGFR', 'Gene', (73, 77))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (124, 150))	('EGFR', 'Gene', '1956', (54, 58))	('NSCLC', 'Disease', 'MESH:D002289', (152, 157))	('mutations', 'Var', (59, 68))	('EGFR', 'Gene', (54, 58))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (124, 150))
106864	32346412	The Amplification Refractory Mutation System was adopted to determine EGFR gene expression, compare the ethnic differences in EGFR mutations between Xinjiang Uygur and Han people, analyze the distribution of uncommon mutation types and evaluate the link between clinicopathological features associated with uncommon mutations and the efficacy of EGFR-TKI treatment.	('EGFR', 'Gene', (346, 350))	('men', 'Species', '9606', (360, 363))	('mutations', 'Var', (131, 140))	('EGFR', 'Gene', (126, 130))	('EGFR', 'Gene', '1956', (70, 74))	('EGFR', 'Gene', (70, 74))	('EGFR', 'Gene', '1956', (346, 350))	('EGFR', 'Gene', '1956', (126, 130))	('people', 'Species', '9606', (172, 178))
106865	32346412	There were significant differences in EGFR mutations in lung adenocarcinoma and lung squamous cell carcinoma between patients from the Xinjiang Uygur group and the Han group (P<0.001).	('EGFR', 'Gene', '1956', (38, 42))	('carcinoma', 'Phenotype', 'HP:0030731', (66, 75))	('EGFR', 'Gene', (38, 42))	('lung adenocarcinoma', 'Disease', (56, 75))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (56, 75))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (80, 108))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (85, 108))	('mutations', 'Var', (43, 52))	('patients', 'Species', '9606', (117, 125))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (80, 108))	('lung squamous cell carcinoma', 'Disease', (80, 108))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (56, 75))
106866	32346412	The differences in the uncommon EGFR mutations were significant in patients with lung adenocarcinoma (P<0.05).	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (81, 100))	('patients', 'Species', '9606', (67, 75))	('EGFR', 'Gene', '1956', (32, 36))	('lung adenocarcinoma', 'Disease', (81, 100))	('mutations', 'Var', (37, 46))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (81, 100))	('EGFR', 'Gene', (32, 36))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))
106868	32346412	Of the uncommon mutations, the most common single mutations were L861Q, G719X and 20ins mutations; the most common double mutation was the S768I and 20ins mutation.	('20ins mutations', 'Var', (82, 97))	('L861Q', 'Var', (65, 70))	('S768I', 'Mutation', 'rs121913465', (139, 144))	('20ins', 'Mutation', 'c.20ins', (149, 154))	('G719X', 'Mutation', 'p.G719X', (72, 77))	('L861Q', 'Mutation', 'rs121913444', (65, 70))	('20ins', 'Mutation', 'c.20ins', (82, 87))	('G719X', 'Var', (72, 77))	('S768I', 'Var', (139, 144))
106869	32346412	The incidence rate of EGFR gene mutations was significantly higher in Han people from Xinjiang than in Uygur people.	('higher', 'PosReg', (60, 66))	('mutations', 'Var', (32, 41))	('people', 'Species', '9606', (109, 115))	('EGFR', 'Gene', '1956', (22, 26))	('people', 'Species', '9606', (74, 80))	('EGFR', 'Gene', (22, 26))
106870	32346412	There were marked differences between individuals regarding the efficacy of EGFR-TKI treatment and the survival time of patients with uncommon EGFR mutations, second-line EGFR-TKIs had a lower ORR and DCR while had a longer mPFS.	('EGFR', 'Gene', (171, 175))	('EGFR', 'Gene', (143, 147))	('mutations', 'Var', (148, 157))	('EGFR', 'Gene', '1956', (171, 175))	('DCR', 'MPA', (201, 204))	('men', 'Species', '9606', (90, 93))	('EGFR', 'Gene', '1956', (76, 80))	('EGFR', 'Gene', (76, 80))	('patients', 'Species', '9606', (120, 128))	('lower', 'NegReg', (187, 192))	('EGFR', 'Gene', '1956', (143, 147))
106873	32346412	Overexpression of EGFR is linked to the migration and invasion of tumor cells and patient prognosis.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('EGFR', 'Gene', '1956', (18, 22))	('patient', 'Species', '9606', (82, 89))	('tumor', 'Disease', (66, 71))	('EGFR', 'Gene', (18, 22))	('linked', 'Reg', (26, 32))	('Overexpression', 'Var', (0, 14))	('migration', 'CPA', (40, 49))	('tumor', 'Disease', 'MESH:D009369', (66, 71))
106876	32346412	Previous studies have indicated that EGFR mutations are highly associated with ethnicity, gender, adenocarcinoma and smoking status.	('adenocarcinoma', 'Disease', (98, 112))	('adenocarcinoma', 'Disease', 'MESH:D000230', (98, 112))	('associated', 'Reg', (63, 73))	('EGFR', 'Gene', '1956', (37, 41))	('EGFR', 'Gene', (37, 41))	('mutations', 'Var', (42, 51))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))
106877	32346412	With the application of sequencing and PCR technology, EGFR mutations have become the major predictors of the effectiveness of EGFR-tyrosine kinase inhibitor (TKI) targeted therapy.	('EGFR', 'Gene', '1956', (55, 59))	('EGFR', 'Gene', (55, 59))	('mutations', 'Var', (60, 69))	('EGFR', 'Gene', '1956', (127, 131))	('EGFR', 'Gene', (127, 131))
106879	32346412	EGFR mutations mainly exist in exons 18-21, among which exon 19 deletion mutation, exon 21 L858R point mutation and exon 20 T790M mutation are the most common types, which account for 50-90% of the overall EGFR mutations and are referred to as classical mutations; other sensitive mutations, referred to as uncommon mutations in clinical practice, include G719X in exon18, L861Q and G719C in exon 21.	('L861Q', 'Var', (373, 378))	('EGFR', 'Gene', (0, 4))	('EGFR', 'Gene', (206, 210))	('L858R', 'Mutation', 'rs121434568', (91, 96))	('G719C', 'Mutation', 'rs28929495', (383, 388))	('G719C', 'Var', (383, 388))	('G719X', 'Mutation', 'p.G719X', (356, 361))	('EGFR', 'Gene', '1956', (206, 210))	('G719X', 'Var', (356, 361))	('L861Q', 'Mutation', 'rs121913444', (373, 378))	('EGFR', 'Gene', '1956', (0, 4))	('T790M', 'Mutation', 'rs121434569', (124, 129))
106881	32346412	Previous studies have suggested that for EGFR-TKI treatment, NSCLC patients with uncommon mutations are less responsive than those with common mutations, as indicated by their shorter PFS and lower ORR after EGFR-TKI treatment.	('ORR', 'MPA', (198, 201))	('EGFR', 'Gene', (41, 45))	('mutations', 'Var', (90, 99))	('men', 'Species', '9606', (55, 58))	('patients', 'Species', '9606', (67, 75))	('lower', 'NegReg', (192, 197))	('EGFR', 'Gene', '1956', (208, 212))	('shorter', 'NegReg', (176, 183))	('NSCLC', 'Disease', (61, 66))	('EGFR', 'Gene', (208, 212))	('men', 'Species', '9606', (222, 225))	('EGFR', 'Gene', '1956', (41, 45))	('NSCLC', 'Disease', 'MESH:D002289', (61, 66))	('PFS', 'MPA', (184, 187))
106883	32346412	The frequency of EGFR mutation in NSCLC has been documented to differ across ethnic groups and the occurrence was observed to be markedly higher in East-Asian trials compared with that in European studies.	('mutation', 'Var', (22, 30))	('NSCLC', 'Disease', (34, 39))	('NSCLC', 'Disease', 'MESH:D002289', (34, 39))	('EGFR', 'Gene', '1956', (17, 21))	('men', 'Species', '9606', (53, 56))	('higher', 'PosReg', (138, 144))	('EGFR', 'Gene', (17, 21))
106887	32346412	A total of 2,984 patients who were hospitalized at the Affiliated Tumor Hospital of Xinjiang Medical University (Urumqi, China) between February 2012 and February 2017 and had been pathologically confirmed as having NSCLC were enrolled in the present study, among whom 29 patients with uncommon mutations were screened out after the ADx-ARMS test for EGFR gene mutations.	('NSCLC', 'Disease', (216, 221))	('mutations', 'Var', (361, 370))	('NSCLC', 'Disease', 'MESH:D002289', (216, 221))	('EGFR', 'Gene', '1956', (351, 355))	('EGFR', 'Gene', (351, 355))	('Tumor', 'Phenotype', 'HP:0002664', (66, 71))	('patients', 'Species', '9606', (17, 25))	('patients', 'Species', '9606', (272, 280))
106890	32346412	The exclusion criteria were as follows: i) Patients with known drug-resistant EGFR mutations; ii) patients who had received no EGFR-TKI treatment or had not been treated with EGFR-TKI as required; iii) patients who stopped the medication or reduced the dose due to adverse reactions; iv) patients who died from diseases not associated with the disease studied (e.g.	('mutations', 'Var', (83, 92))	('men', 'Species', '9606', (141, 144))	('EGFR', 'Gene', (175, 179))	('patients', 'Species', '9606', (288, 296))	('patients', 'Species', '9606', (98, 106))	('Patients', 'Species', '9606', (43, 51))	('patients', 'Species', '9606', (202, 210))	('EGFR', 'Gene', '1956', (78, 82))	('EGFR', 'Gene', (78, 82))	('EGFR', 'Gene', '1956', (127, 131))	('EGFR', 'Gene', '1956', (175, 179))	('EGFR', 'Gene', (127, 131))
106893	32346412	In order to explore whether uncommon EGFR mutations were associated with specific metastases, patients with uncommon mutations were examined for organ and lymph node metastasis.	('patients', 'Species', '9606', (94, 102))	('EGFR', 'Gene', '1956', (37, 41))	('metastases', 'Disease', (82, 92))	('EGFR', 'Gene', (37, 41))	('mutations', 'Var', (42, 51))	('metastases', 'Disease', 'MESH:D009362', (82, 92))	('associated', 'Reg', (57, 67))
106903	32346412	The chi2 test was used to analyze the differences in the uncommon EGFR mutations between Uygur and Han people.	('people', 'Species', '9606', (103, 109))	('EGFR', 'Gene', (66, 70))	('mutations', 'Var', (71, 80))	('EGFR', 'Gene', '1956', (66, 70))
106907	32346412	There were significant differences in EGFR mutations between Xinjiang Uygur and Han people (P<0.001): Uygur and Han people with adenocarcinoma had an EGFR mutation rate of 10.79 and 72.22%, respectively, and those with squamous cell carcinoma had an EGFR mutation rate of 3.26 and 10.13%, respectively.	('EGFR', 'Gene', '1956', (38, 42))	('squamous cell carcinoma', 'Disease', (219, 242))	('EGFR', 'Gene', (150, 154))	('adenocarcinoma', 'Disease', 'MESH:D000230', (128, 142))	('EGFR', 'Gene', (38, 42))	('people', 'Species', '9606', (84, 90))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('people', 'Species', '9606', (116, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (233, 242))	('EGFR', 'Gene', '1956', (250, 254))	('mutation', 'Var', (155, 163))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (219, 242))	('adenocarcinoma', 'Disease', (128, 142))	('EGFR', 'Gene', '1956', (150, 154))	('EGFR', 'Gene', (250, 254))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (219, 242))
106908	32346412	The differences in uncommon EGFR mutations were significant between Uygur and Han people with lung adenocarcinoma (P<0.05), but not significant between those with lung squamous cell carcinoma.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (168, 191))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (94, 113))	('EGFR', 'Gene', '1956', (28, 32))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (163, 191))	('lung adenocarcinoma', 'Disease', (94, 113))	('EGFR', 'Gene', (28, 32))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (94, 113))	('mutations', 'Var', (33, 42))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (163, 191))	('lung squamous cell carcinoma', 'Disease', (163, 191))	('carcinoma', 'Phenotype', 'HP:0030731', (182, 191))	('people', 'Species', '9606', (82, 88))
106909	32346412	Uygur and Han people with lung adenocarcinoma had an uncommon EGFR mutation rate of 0.25 and 1.96%, respectively, and those with lung squamous cell carcinoma had an uncommon EGFR mutation rate of 0 and 0.26%, respectively.	('EGFR', 'Gene', (174, 178))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (129, 157))	('lung squamous cell carcinoma', 'Disease', (129, 157))	('EGFR', 'Gene', '1956', (62, 66))	('mutation', 'Var', (67, 75))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (26, 45))	('people', 'Species', '9606', (14, 20))	('EGFR', 'Gene', (62, 66))	('carcinoma', 'Phenotype', 'HP:0030731', (36, 45))	('lung adenocarcinoma', 'Disease', (26, 45))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (134, 157))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (26, 45))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (129, 157))	('carcinoma', 'Phenotype', 'HP:0030731', (148, 157))	('EGFR', 'Gene', '1956', (174, 178))
106910	32346412	The differences in the EGFR gene mutations between Xinjiang Uygur and Han people are presented in Table I.	('EGFR', 'Gene', '1956', (23, 27))	('EGFR', 'Gene', (23, 27))	('mutations', 'Var', (33, 42))	('people', 'Species', '9606', (74, 80))
106920	32346412	The mPFS of all patients with uncommon mutations who received EGFR-TKIs ranged from 5.5 to 2.7 months (first-line, second-line and third-line EGFR-TKIs was 5.5, 4.0 and 2.7 months, respectively), with no significant differences observed (Fig.	('EGFR', 'Gene', '1956', (62, 66))	('EGFR', 'Gene', '1956', (142, 146))	('EGFR', 'Gene', (142, 146))	('patients', 'Species', '9606', (16, 24))	('EGFR', 'Gene', (62, 66))	('mutations', 'Var', (39, 48))
106925	32346412	Studies on treatments targeting EGFR have opened up novel avenues for the treatment of lung malignancies, but sensitivity to treatment is significantly associated with EGFR mutation types.	('men', 'Species', '9606', (79, 82))	('lung malignancies', 'Phenotype', 'HP:0100526', (87, 104))	('EGFR', 'Gene', '1956', (168, 172))	('EGFR', 'Gene', (168, 172))	('EGFR', 'Gene', '1956', (32, 36))	('men', 'Species', '9606', (16, 19))	('lung malignancies', 'Disease', 'MESH:D008175', (87, 104))	('EGFR', 'Gene', (32, 36))	('lung malignancies', 'Disease', (87, 104))	('associated', 'Reg', (152, 162))	('men', 'Species', '9606', (130, 133))	('mutation', 'Var', (173, 181))
106926	32346412	Exon 19 deletion and exon 21 L858R mutation are the most common types, which account for almost 90% of all EGFR mutations in lung cancer.	('lung cancer', 'Disease', 'MESH:D008175', (125, 136))	('EGFR', 'Gene', '1956', (107, 111))	('EGFR', 'Gene', (107, 111))	('mutations', 'Var', (112, 121))	('L858R', 'Var', (29, 34))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('lung cancer', 'Disease', (125, 136))	('lung cancer', 'Phenotype', 'HP:0100526', (125, 136))	('L858R', 'Mutation', 'rs121434568', (29, 34))
106928	32346412	Certain studies have indicated that the proportion of patients with uncommon mutations receiving first-line EGFR-TKIs is up to 85.7%, and that proportion is higher for patients with uncommon mutations combined with 19-DEL and L858R complex mutations.	('19-DEL', 'Var', (215, 221))	('EGFR', 'Gene', '1956', (108, 112))	('patients', 'Species', '9606', (54, 62))	('EGFR', 'Gene', (108, 112))	('L858R', 'Mutation', 'rs121434568', (226, 231))	('mutations', 'Var', (77, 86))	('patients', 'Species', '9606', (168, 176))	('L858R', 'Var', (226, 231))
106930	32346412	In the present study, 2,984 patients of Uygur and Han ethnicities with stage IIIB/IV NSCLC in Xinjiang were retrospectively analyzed and the results indicated that Uygur and Han people exhibited significant differences in EGFR mutations in adenocarcinoma and squamous cell carcinoma.	('NSCLC', 'Disease', (85, 90))	('people', 'Species', '9606', (178, 184))	('adenocarcinoma and squamous cell carcinoma', 'Disease', 'MESH:D002294', (240, 282))	('NSCLC', 'Disease', 'MESH:D002289', (85, 90))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (259, 282))	('carcinoma', 'Phenotype', 'HP:0030731', (245, 254))	('carcinoma', 'Phenotype', 'HP:0030731', (273, 282))	('EGFR', 'Gene', '1956', (222, 226))	('patients', 'Species', '9606', (28, 36))	('EGFR', 'Gene', (222, 226))	('mutations', 'Var', (227, 236))
106931	32346412	A meta-analysis by Wang and Wang suggested that the overall EGFR mutation rate of Chinese patients was 37.5% and Wu et al reported that 37.9% of Chinese NSCLS patients had EGFR mutations.	('EGFR', 'Gene', '1956', (172, 176))	('NSCLS', 'Disease', 'None', (153, 158))	('EGFR', 'Gene', (172, 176))	('mutations', 'Var', (177, 186))	('EGFR', 'Gene', '1956', (60, 64))	('mutation', 'Var', (65, 73))	('patients', 'Species', '9606', (159, 167))	('patients', 'Species', '9606', (90, 98))	('EGFR', 'Gene', (60, 64))	('NSCLS', 'Disease', (153, 158))
106932	32346412	However, the EGFR mutation rate of Han people in the present study was 72.22%, which was higher than that in other studies.	('EGFR', 'Gene', '1956', (13, 17))	('people', 'Species', '9606', (39, 45))	('EGFR', 'Gene', (13, 17))	('mutation', 'Var', (18, 26))
106933	32346412	The differences in the uncommon EGFR mutations were significant between Uygur and Han people with lung adenocarcinoma, but not significant between the two ethnic groups with lung squamous cell carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (174, 202))	('lung squamous cell carcinoma', 'Disease', (174, 202))	('people', 'Species', '9606', (86, 92))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (98, 117))	('EGFR', 'Gene', '1956', (32, 36))	('carcinoma', 'Phenotype', 'HP:0030731', (193, 202))	('mutations', 'Var', (37, 46))	('EGFR', 'Gene', (32, 36))	('lung adenocarcinoma', 'Disease', (98, 117))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (174, 202))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (98, 117))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (179, 202))
106934	32346412	A total of 2,984 patients with EGFR mutations were enrolled, among whom 29 harbored uncommon mutations.	('EGFR', 'Gene', '1956', (31, 35))	('EGFR', 'Gene', (31, 35))	('patients', 'Species', '9606', (17, 25))	('mutations', 'Var', (36, 45))
106935	32346412	It was indicated that the proportion of patients harboring uncommon EGFR mutations was not significantly different across different genders and smoking statuses, which was similar to the results obtained by Sonobe et al.	('patients', 'Species', '9606', (40, 48))	('EGFR', 'Gene', '1956', (68, 72))	('EGFR', 'Gene', (68, 72))	('mutations', 'Var', (73, 82))
106936	32346412	The most common lymph node metastasis sites in patients with uncommon mutations were hilar lymph node, supraclavicular/subclavian lymph node, cervical lymph node and mediastinal lymph node, and the most common distant metastatic organs were the lung, bone, brain, liver and adrenal gland.	('lymph node metastasis sites', 'CPA', (16, 43))	('mutations', 'Var', (70, 79))	('patients', 'Species', '9606', (47, 55))
106937	32346412	Comparison of the efficacy of EGFR-TKIs in patients with uncommon EGFR mutations revealed that patients on treatment with first-line EGFR-TKIs had an ORR of 43.75%, a DCR of 50% and mPFS of 5.5 months; the ORR and PFS of patients on treatment with first-line EGFR-TKIs were inferior to those in patients with classical mutations, and were also inferior to the previous research of certain patients with uncommon mutations, but were superior to those with wild-type EGFRs.	('patients', 'Species', '9606', (221, 229))	('EGFR', 'Gene', (30, 34))	('men', 'Species', '9606', (238, 241))	('patients', 'Species', '9606', (95, 103))	('EGFR', 'Gene', (66, 70))	('patients', 'Species', '9606', (43, 51))	('EGFR', 'Gene', '1956', (66, 70))	('patients', 'Species', '9606', (295, 303))	('EGFR', 'Gene', '1956', (259, 263))	('EGFR', 'Gene', '1956', (465, 469))	('mutations', 'Var', (71, 80))	('EGFR', 'Gene', '1956', (133, 137))	('patients', 'Species', '9606', (389, 397))	('EGFR', 'Gene', (259, 263))	('men', 'Species', '9606', (112, 115))	('EGFR', 'Gene', '1956', (30, 34))	('EGFR', 'Gene', (465, 469))	('EGFR', 'Gene', (133, 137))
106944	32346412	Previous studies have suggested that the affinity for ATP of the G719 mutant is between that of wild-type EGFR and L858R.	('ATP', 'Chemical', 'MESH:D000255', (54, 57))	('affinity', 'MPA', (41, 49))	('G719', 'Var', (65, 69))	('EGFR', 'Gene', '1956', (106, 110))	('L858R', 'Mutation', 'rs121434568', (115, 120))	('EGFR', 'Gene', (106, 110))
106945	32346412	According to one study, patients with G791X single mutations had an ORR of 36.8%, but it has also been reported that patients with G719 mutations, whether single or double, had an ORR of 53.3% and mPFS of 8.1 months.	('G791X single', 'Var', (38, 50))	('patients', 'Species', '9606', (24, 32))	('G719 mutations', 'Var', (131, 145))	('patients', 'Species', '9606', (117, 125))	('G791X', 'Mutation', 'p.G791X', (38, 43))
106948	32346412	It may be suggested that certain patients with compound mutations harbored drug-resistant mutations whose affinity for ATP was lower than that of G719 single mutations and the possibility of bypass interference cannot be excluded.	('ATP', 'Chemical', 'MESH:D000255', (119, 122))	('patients', 'Species', '9606', (33, 41))	('lower', 'NegReg', (127, 132))	('affinity for ATP', 'MPA', (106, 122))	('compound mutations', 'Var', (47, 65))	('harbored', 'Reg', (66, 74))	('drug-resistant', 'MPA', (75, 89))
106949	32346412	L861Q, as a mutation at position 861 on exon 20 of the EGFR, was another common mutation site in the present study.	('EGFR', 'Gene', '1956', (55, 59))	('EGFR', 'Gene', (55, 59))	('L861Q', 'Mutation', 'rs121913444', (0, 5))	('L861Q', 'Var', (0, 5))
106951	32346412	A previous study reported that L861Q accounted for 2% of EGFR mutations; Yoshida et al indicated that patients with L861Q mutation were resistant to first-line EGFR-TKIs, but certain other studies suggested that certain EGFR-TKIs were effective for the treatment of L816Q mutation with the efficacy being inferior to that for L858R and G719 mutations.	('L816Q', 'Var', (266, 271))	('men', 'Species', '9606', (258, 261))	('L858R', 'Mutation', 'rs121434568', (326, 331))	('EGFR', 'Gene', (220, 224))	('patients', 'Species', '9606', (102, 110))	('L816Q', 'Mutation', 'rs121913444', (266, 271))	('EGFR', 'Gene', '1956', (160, 164))	('L861Q', 'Mutation', 'rs121913444', (116, 121))	('EGFR', 'Gene', '1956', (57, 61))	('EGFR', 'Gene', (160, 164))	('L861Q', 'Mutation', 'rs121913444', (31, 36))	('EGFR', 'Gene', (57, 61))	('EGFR', 'Gene', '1956', (220, 224))
106952	32346412	In the NEJ002 study, the efficacy of gefitinib was retrospectively analyzed in 7 patients with uncommon G719X mutations and 3 patients with uncommon L8861Q.	('G719X', 'Var', (104, 109))	('L8861Q', 'Var', (149, 155))	('patients', 'Species', '9606', (81, 89))	('L8861Q', 'SUBSTITUTION', 'None', (149, 155))	('G719X', 'Mutation', 'p.G719X', (104, 109))	('patients', 'Species', '9606', (126, 134))	('gefitinib', 'Chemical', 'MESH:D000077156', (37, 46))
106953	32346412	It was indicated that the median OS of the patients with uncommon sensitive mutations in the gefitinib group was significantly shorter than that in the classical sensitive mutation group, while the median OS was not significantly different between patients with uncommon sensitive mutations and those with common sensitive mutations in the chemotherapy group.	('shorter', 'NegReg', (127, 134))	('mutations', 'Var', (76, 85))	('patients', 'Species', '9606', (43, 51))	('gefitinib', 'Chemical', 'MESH:D000077156', (93, 102))	('patients', 'Species', '9606', (248, 256))
106954	32346412	In the present study, the ORR was 40% and the mPFS was 6.2 months in 5 patients with L861Q treated with first-line EGFR-TKIs.	('L861Q', 'Var', (85, 90))	('patients', 'Species', '9606', (71, 79))	('EGFR', 'Gene', '1956', (115, 119))	('L861Q', 'Mutation', 'rs121913444', (85, 90))	('EGFR', 'Gene', (115, 119))
106955	32346412	However, it should be noted that cohort size (n=2,984) of the present study was relatively small, which may have affected the uncommon EGRF mutation rate between Uygur and Han people.	('people', 'Species', '9606', (176, 182))	('affected', 'Reg', (113, 121))	('mutation', 'Var', (140, 148))	('EGRF', 'Gene', (135, 139))
106956	32346412	The number of patients with uncommon EGFR mutations among the Uygur people was too small, so large samples should be carried out in the future to further verify the results of the present study.	('EGFR', 'Gene', '1956', (37, 41))	('EGFR', 'Gene', (37, 41))	('mutations', 'Var', (42, 51))	('people', 'Species', '9606', (68, 74))	('patients', 'Species', '9606', (14, 22))
106957	32346412	In conclusion, the incidence of EGFR gene mutations is significantly higher in Han people who live in Xinjiang than in Uygur people.	('people', 'Species', '9606', (83, 89))	('people', 'Species', '9606', (125, 131))	('EGFR', 'Gene', '1956', (32, 36))	('higher', 'PosReg', (69, 75))	('EGFR', 'Gene', (32, 36))	('mutations', 'Var', (42, 51))
106958	32346412	The uncommon EGFR mutations may be divided into different subtypes, which may result in different outcomes and survival time of patients on treatment with EGFR-TKIs.	('men', 'Species', '9606', (145, 148))	('EGFR', 'Gene', '1956', (155, 159))	('result in', 'Reg', (78, 87))	('EGFR', 'Gene', (155, 159))	('patients', 'Species', '9606', (128, 136))	('EGFR', 'Gene', '1956', (13, 17))	('EGFR', 'Gene', (13, 17))	('mutations', 'Var', (18, 27))
106960	32346412	In general, patients with uncommon EGFR mutations have a lower ORR and shorter PFS than those with classical mutations, but certain patients with uncommon EGFR mutations have a higher ORR and longer PFS than patients with wild-type mutations.	('patients', 'Species', '9606', (12, 20))	('ORR', 'MPA', (184, 187))	('patients', 'Species', '9606', (208, 216))	('EGFR', 'Gene', '1956', (155, 159))	('PFS', 'MPA', (79, 82))	('PFS', 'MPA', (199, 202))	('EGFR', 'Gene', '1956', (35, 39))	('EGFR', 'Gene', (35, 39))	('ORR', 'MPA', (63, 66))	('EGFR', 'Gene', (155, 159))	('mutations', 'Var', (40, 49))	('shorter', 'NegReg', (71, 78))	('patients', 'Species', '9606', (132, 140))	('lower', 'NegReg', (57, 62))
106978	29288495	The goal of this massive project was to comprehensively characterize multiple molecular aspects of 33 selected cancer types (Table 1; Figure 1), including DNA sequence (all exomes and low-pass genomes for a subset), copy number and methylation, mRNA and microRNA (miRNA) expression, and the expression of selected proteins.	('expression', 'MPA', (291, 301))	('methylation', 'Var', (232, 243))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('copy number', 'Var', (216, 227))	('proteins', 'Protein', (314, 322))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))
106999	29288495	At the genomic level, malignancies appear to be divided into two broad categories reflecting divergent oncogenic processes: copy number-driven and mutation-driven.	('malignancies', 'Disease', (22, 34))	('copy number-driven', 'Var', (124, 142))	('malignancies', 'Disease', 'MESH:D009369', (22, 34))
107000	29288495	Malignancies in the PanCancer12 analysis with high levels of somatic copy number alterations were associated with early TP53 mutations, reflecting the importance of TP53 in regulating genomic stability, and included ovarian carcinoma, squamous cell carcinoma, breast invasive ductal carcinoma, uterine serous carcinoma, uterine carcinosarcoma, and pleomorphic adult sarcomas.	('sarcomas', 'Phenotype', 'HP:0100242', (366, 374))	('Cancer', 'Disease', (23, 29))	('TP53', 'Gene', (165, 169))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (216, 233))	('Malignancies', 'Disease', (0, 12))	('ovarian carcinoma', 'Disease', (216, 233))	('squamous cell carcinoma', 'Disease', (235, 258))	('TP53', 'Gene', '7157', (120, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (309, 318))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (276, 292))	('carcinosarcoma', 'Disease', (328, 342))	('Cancer', 'Disease', 'MESH:D009369', (23, 29))	('carcinosarcoma', 'Disease', 'MESH:D002296', (328, 342))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (216, 233))	('TP53', 'Gene', '7157', (165, 169))	('mutations', 'Var', (125, 134))	('serous carcinoma', 'Disease', (302, 318))	('carcinoma', 'Phenotype', 'HP:0030731', (283, 292))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (235, 258))	('pleomorphic adult sarcomas', 'Disease', (348, 374))	('TP53', 'Gene', (120, 124))	('pleomorphic adult sarcomas', 'Disease', 'MESH:D008228', (348, 374))	('serous carcinoma', 'Disease', 'MESH:D018284', (302, 318))	('breast invasive ductal carcinoma', 'Disease', (260, 292))	('Malignancies', 'Disease', 'MESH:D009369', (0, 12))	('breast invasive ductal carcinoma', 'Disease', 'MESH:D018270', (260, 292))	('carcinoma', 'Phenotype', 'HP:0030731', (249, 258))	('sarcoma', 'Phenotype', 'HP:0100242', (335, 342))	('Cancer', 'Phenotype', 'HP:0002664', (23, 29))	('sarcoma', 'Phenotype', 'HP:0100242', (366, 373))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (235, 258))	('carcinoma', 'Phenotype', 'HP:0030731', (224, 233))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (320, 342))
107003	29288495	Common somatic copy number alterations across malignancies include amplification of regions containing oncogenes [CCND1, CCNE1, MYC, epidermal growth factor receptor (EGFR), ERBB2, MCL1, and MDM2], or genes involved in telomere maintenance, histone modification, or chromatin remodelling (TERC, RMRP, WHSC1L1, BRD4, KAT6A, KAT6B, NSD1, and PHF1), emphasizing the importance of epigenetic factors in tumourigenesis.	('copy', 'Var', (15, 19))	('PHF1', 'Gene', (340, 344))	('NSD1', 'Gene', (330, 334))	('MCL1', 'Gene', '4170', (181, 185))	('CCND1', 'Gene', '595', (114, 119))	('epidermal growth factor receptor', 'Gene', (133, 165))	('alterations', 'Var', (27, 38))	('KAT6A', 'Gene', (316, 321))	('CCND1', 'Gene', (114, 119))	('MYC', 'Gene', (128, 131))	('PHF1', 'Gene', '5252', (340, 344))	('epidermal growth factor receptor', 'Gene', '1956', (133, 165))	('ERBB2', 'Gene', (174, 179))	('malignancies', 'Disease', 'MESH:D009369', (46, 58))	('tumour', 'Phenotype', 'HP:0002664', (399, 405))	('NSD1', 'Gene', '64324', (330, 334))	('malignancies', 'Disease', (46, 58))	('BRD4', 'Gene', (310, 314))	('EGFR', 'Gene', (167, 171))	('MDM2', 'Gene', (191, 195))	('tumour', 'Disease', 'MESH:D009369', (399, 405))	('tumour', 'Disease', (399, 405))	('WHSC1L1', 'Gene', '54904', (301, 308))	('RMRP', 'Gene', (295, 299))	('ERBB2', 'Gene', '2064', (174, 179))	('KAT6B', 'Gene', (323, 328))	('CCNE1', 'Gene', (121, 126))	('WHSC1L1', 'Gene', (301, 308))	('MDM2', 'Gene', '4193', (191, 195))	('MYC', 'Gene', '4609', (128, 131))	('KAT6B', 'Gene', '23522', (323, 328))	('KAT6A', 'Gene', '7994', (316, 321))	('MCL1', 'Gene', (181, 185))	('BRD4', 'Gene', '23476', (310, 314))	('RMRP', 'Gene', '6023', (295, 299))	('CCNE1', 'Gene', '898', (121, 126))	('EGFR', 'Gene', '1956', (167, 171))
107004	29288495	Likewise, recurrent hotspot mutations in the chromatin modifier genes ARID1 and CTCF are frequent across multiple cancer lineages.	('multiple cancer', 'Disease', (105, 120))	('multiple cancer', 'Disease', 'MESH:D009369', (105, 120))	('CTCF', 'Gene', (80, 84))	('hotspot', 'PosReg', (20, 27))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('ARID1', 'Gene', (70, 75))	('CTCF', 'Gene', '10664', (80, 84))	('mutations', 'Var', (28, 37))
107006	29288495	For instance, in the multiplatform analysis, squamous cell carcinomas from the lung and head and neck clustered together with a subset of bladder carcinomas into a molecular subtype characterized by TP53 alterations, amplification of TP63, and high expression of immune-related and proliferation genes.	('carcinomas', 'Phenotype', 'HP:0030731', (59, 69))	('carcinomas', 'Phenotype', 'HP:0030731', (146, 156))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (45, 69))	('TP53', 'Gene', '7157', (199, 203))	('expression', 'MPA', (249, 259))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (45, 69))	('bladder carcinomas', 'Phenotype', 'HP:0002862', (138, 156))	('bladder carcinomas', 'Disease', 'MESH:D001749', (138, 156))	('amplification', 'Var', (217, 230))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (45, 68))	('bladder carcinomas', 'Disease', (138, 156))	('squamous cell carcinomas', 'Disease', (45, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (59, 68))	('TP63', 'Gene', (234, 238))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (138, 155))	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('TP53', 'Gene', (199, 203))	('alterations', 'Var', (204, 215))	('TP63', 'Gene', '8626', (234, 238))	('immune-related', 'Gene', (263, 277))
107011	29288495	The main distinction within colorectal carcinoma is the increased frequency of hypermethylated and hypermutated DNA mismatch repair-deficient (resulting in microsatellite instability) and DNA polymerase-epsilon-deficient carcinomas in the right colon; otherwise, non-hypermutated carcinomas showed identical genomic, epigenomic and transcriptomic alterations, independently of rectal or colon origin.	('carcinoma', 'Phenotype', 'HP:0030731', (221, 230))	('carcinoma', 'Phenotype', 'HP:0030731', (280, 289))	('hypermethylated', 'Var', (79, 94))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (28, 48))	('epsilon-deficient carcinomas', 'Disease', 'MESH:D001321', (203, 231))	('carcinomas', 'Disease', 'MESH:D002277', (221, 231))	('carcinoma', 'Phenotype', 'HP:0030731', (39, 48))	('DNA mismatch', 'Gene', (112, 124))	('carcinomas', 'Phenotype', 'HP:0030731', (221, 231))	('carcinomas', 'Phenotype', 'HP:0030731', (280, 290))	('carcinomas', 'Disease', (221, 231))	('carcinomas', 'Disease', (280, 290))	('carcinomas', 'Disease', 'MESH:D002277', (280, 290))	('colorectal carcinoma', 'Disease', (28, 48))	('epsilon-deficient carcinomas', 'Disease', (203, 231))
107012	29288495	Interestingly, microsatellite-unstable colon cancers do show different histological features from microsatellite-stable cases.	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('microsatellite-unstable', 'Var', (15, 38))	('colon cancers', 'Disease', (39, 52))	('cancers', 'Phenotype', 'HP:0002664', (45, 52))	('colon cancers', 'Phenotype', 'HP:0003003', (39, 52))	('colon cancers', 'Disease', 'MESH:D015179', (39, 52))
107015	29288495	Indeed, the effort has identified numerous mutations that are present across disparate tumour types.	('mutations', 'Var', (43, 52))	('tumour', 'Disease', (87, 93))	('tumour', 'Phenotype', 'HP:0002664', (87, 93))	('tumour', 'Disease', 'MESH:D009369', (87, 93))
107016	29288495	Some of these alterations represent potentially attractive therapeutic targets, such as mutant BRAF, EGFR, or ARID1A.	('EGFR', 'Gene', '1956', (101, 105))	('BRAF', 'Gene', '673', (95, 99))	('EGFR', 'Gene', (101, 105))	('BRAF', 'Gene', (95, 99))	('mutant', 'Var', (88, 94))	('ARID1A', 'Gene', '8289', (110, 116))	('ARID1A', 'Gene', (110, 116))
107017	29288495	BRAF mutations have been found in multiple cancer types, including melanoma, thyroid carcinoma, and colorectal adenocarcinoma, as well as in a subset of pancreatic and lung adenocarcinomas.	('multiple cancer', 'Disease', (34, 49))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (77, 94))	('BRAF', 'Gene', '673', (0, 4))	('thyroid carcinoma', 'Disease', (77, 94))	('BRAF', 'Gene', (0, 4))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (168, 188))	('colorectal adenocarcinoma', 'Disease', (100, 125))	('melanoma', 'Disease', 'MESH:D008545', (67, 75))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (77, 94))	('found', 'Reg', (25, 30))	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (100, 125))	('mutations', 'Var', (5, 14))	('multiple cancer', 'Disease', 'MESH:D009369', (34, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('pancreatic and lung adenocarcinomas', 'Disease', 'MESH:D000077192', (153, 188))	('melanoma', 'Phenotype', 'HP:0002861', (67, 75))	('melanoma', 'Disease', (67, 75))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (168, 187))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (178, 187))	('carcinomas', 'Phenotype', 'HP:0030731', (178, 188))
107018	29288495	The dramatic response of melanoma positive for BRAF p.V600E mutations to BRAF inhibitors such as vemurafenib or dabrafenib suggested that other malignancies harbouring the identical alteration might also respond.	('BRAF', 'Gene', (73, 77))	('BRAF', 'Gene', '673', (73, 77))	('p.V600E', 'Var', (52, 59))	('malignancies', 'Disease', 'MESH:D009369', (144, 156))	('BRAF', 'Gene', (47, 51))	('dabrafenib', 'Chemical', 'MESH:C561627', (112, 122))	('BRAF', 'Gene', '673', (47, 51))	('vemurafenib', 'Chemical', 'MESH:D000077484', (97, 108))	('malignancies', 'Disease', (144, 156))	('melanoma', 'Disease', 'MESH:D008545', (25, 33))	('melanoma', 'Phenotype', 'HP:0002861', (25, 33))	('melanoma', 'Disease', (25, 33))	('p.V600E', 'Mutation', 'rs113488022', (52, 59))
107019	29288495	Whereas BRAF inhibitors show promise in BRAF-mutated papillary thyroid carcinoma, patients with colorectal carcinomas with BRAF mutations (representing 10% of all colorectal adenocarcinoma) have shorter survival, and are less responsive to conventional chemotherapy than patients with other colorectal carcinomas.	('survival', 'MPA', (203, 211))	('BRAF', 'Gene', '673', (40, 44))	('BRAF', 'Gene', (40, 44))	('carcinomas', 'Phenotype', 'HP:0030731', (302, 312))	('BRAF', 'Gene', '673', (8, 12))	('carcinoma', 'Phenotype', 'HP:0030731', (302, 311))	('mutations', 'Var', (128, 137))	('shorter', 'NegReg', (195, 202))	('BRAF', 'Gene', (8, 12))	('colorectal carcinomas', 'Disease', (291, 312))	('colorectal carcinomas', 'Disease', 'MESH:D015179', (291, 312))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('papillary thyroid carcinoma', 'Phenotype', 'HP:0002895', (53, 80))	('papillary thyroid carcinoma', 'Disease', (53, 80))	('patients', 'Species', '9606', (82, 90))	('BRAF', 'Gene', (123, 127))	('BRAF', 'Gene', '673', (123, 127))	('papillary thyroid carcinoma', 'Disease', 'MESH:D000077273', (53, 80))	('colorectal carcinomas', 'Disease', (96, 117))	('colorectal carcinomas', 'Disease', 'MESH:D015179', (96, 117))	('colorectal adenocarcinoma', 'Disease', (163, 188))	('patients', 'Species', '9606', (271, 279))	('carcinoma', 'Phenotype', 'HP:0030731', (179, 188))	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (63, 80))	('carcinomas', 'Phenotype', 'HP:0030731', (107, 117))	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (163, 188))
107020	29288495	In contrast to melanoma, which shows initial response rates of up to 80% prior to the development of resistance, colorectal adenocarcinomas with the identical BRAF p.V600E mutation respond to vemurafenib as a sole agent in <5% of cases.	('vemurafenib', 'Chemical', 'MESH:D000077484', (192, 203))	('BRAF', 'Gene', (159, 163))	('melanoma', 'Phenotype', 'HP:0002861', (15, 23))	('melanoma', 'Disease', (15, 23))	('colorectal adenocarcinomas', 'Disease', 'MESH:D015179', (113, 139))	('p.V600E', 'Mutation', 'rs113488022', (164, 171))	('melanoma', 'Disease', 'MESH:D008545', (15, 23))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('p.V600E', 'Var', (164, 171))	('colorectal adenocarcinomas', 'Disease', (113, 139))	('carcinomas', 'Phenotype', 'HP:0030731', (129, 139))	('BRAF', 'Gene', '673', (159, 163))
107039	29288495	oestrogen receptor (ER), progesterone receptor (PR), HER2, and Ki67], although these have been somewhat slow to achieve widespread use.	('progesterone receptor', 'Gene', (25, 46))	('progesterone receptor', 'Gene', '5241', (25, 46))	('oestrogen', 'Protein', (0, 9))	('HER2', 'Gene', (53, 57))	('Ki67', 'Var', (63, 67))	('HER2', 'Gene', '2064', (53, 57))	('PR', 'Gene', '5241', (48, 50))
107049	29288495	Nuclear pleomorphism has long been appreciated as a prognostic indicator in many cancers, and is routinely evaluated as part of the grading of sarcoma, breast carcinoma, and other malignancies.	('sarcoma', 'Phenotype', 'HP:0100242', (143, 150))	('carcinoma', 'Phenotype', 'HP:0030731', (159, 168))	('breast carcinoma', 'Phenotype', 'HP:0003002', (152, 168))	('cancers', 'Phenotype', 'HP:0002664', (81, 88))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('cancers', 'Disease', (81, 88))	('cancers', 'Disease', 'MESH:D009369', (81, 88))	('sarcoma', 'Disease', 'MESH:D012509', (143, 150))	('Nuclear pleomorphism', 'Var', (0, 20))	('malignancies', 'Disease', 'MESH:D009369', (180, 192))	('breast carcinoma', 'Disease', (152, 168))	('malignancies', 'Disease', (180, 192))	('sarcoma', 'Disease', (143, 150))	('breast carcinoma', 'Disease', 'MESH:D001943', (152, 168))
107142	29956810	The patients were principally divided into 3 groups on the basis of BMI: Underweight (<18.5 kg/m2), normal (>=18.5 to <25.0 kg/m2) and high (>=25.0 kg/m2).	('>=18.5 to <25.0', 'Var', (108, 123))	('<18.5 kg/m2', 'Var', (86, 97))	('patients', 'Species', '9606', (4, 12))
107143	29956810	The high group included two sub-groups: Overweight (>=25 to <30 kg/m2) and obese (>=30 kg/m2).	('obese', 'Disease', 'MESH:D009765', (75, 80))	('Overweight', 'Phenotype', 'HP:0025502', (40, 50))	('>=30 kg/m2', 'Var', (82, 92))	('obese', 'Disease', (75, 80))	('>=25', 'Var', (52, 56))
107181	29956810	The result suggested that high BMI (>=25) was a high risk factor for cancer in the gallbladder, rectum, kidney and uterus.	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('high', 'Var', (26, 30))	('cancer', 'Disease', (69, 75))
107220	29956810	We identified a positive correlation between a high BMI and the corresponding two/five-year survival rate in cancer samples (r=0.53, Spearman correlation coefficient, Figs.	('BMI', 'MPA', (52, 55))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('high', 'Var', (47, 51))	('cancer', 'Disease', (109, 115))	('two/five-year survival rate', 'CPA', (78, 105))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))
107234	29956810	For example, high levels of testosterone, and estrogen and progesterone are risk factors for prostate cancer and breast cancer, respectively.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('prostate cancer', 'Disease', (93, 108))	('breast cancer', 'Disease', 'MESH:D001943', (113, 126))	('risk factors', 'Reg', (76, 88))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('breast cancer', 'Disease', (113, 126))	('high', 'Var', (13, 17))	('breast cancer', 'Phenotype', 'HP:0003002', (113, 126))	('testosterone', 'Chemical', 'MESH:D013739', (28, 40))	('prostate cancer', 'Disease', 'MESH:D011471', (93, 108))	('prostate cancer', 'Phenotype', 'HP:0012125', (93, 108))
107244	29956810	Patients with a low BMI (<18.5) had a reduced incidence for all 38 types of cancer.	('low BMI', 'Phenotype', 'HP:0045082', (16, 23))	('reduced', 'NegReg', (38, 45))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('Patients', 'Species', '9606', (0, 8))	('<18.5', 'Var', (25, 30))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))
107296	33891617	In renal cell carcinoma, small cell lung cancer and melanoma, the microbiota can alter the response to immunotherapy via antibodies targeting programmed cell death protein-1 (PD-1) or its ligand (PDL-1).	('small cell lung cancer', 'Disease', (25, 47))	('PDL-1', 'Gene', '29126', (196, 201))	('renal cell carcinoma', 'Disease', (3, 23))	('antibodies', 'Var', (121, 131))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (3, 23))	('programmed cell death protein-1', 'Gene', '5133', (142, 173))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('melanoma', 'Disease', 'MESH:D008545', (52, 60))	('alter', 'Reg', (81, 86))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (25, 47))	('carcinoma', 'Phenotype', 'HP:0030731', (14, 23))	('PD-1', 'Gene', (175, 179))	('PD-1', 'Gene', '5133', (175, 179))	('programmed cell death protein-1', 'Gene', (142, 173))	('PDL-1', 'Gene', (196, 201))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (3, 23))	('melanoma', 'Phenotype', 'HP:0002861', (52, 60))	('melanoma', 'Disease', (52, 60))	('small cell lung cancer', 'Disease', 'MESH:D055752', (25, 47))	('lung cancer', 'Phenotype', 'HP:0100526', (36, 47))	('response to immunotherapy', 'MPA', (91, 116))
107422	31183356	Significant benefits of osimertinib in treating acquired resistance to first-generation EGFR-TKIs in lung squamous cell cancer: A case report Lung squamous cell cancer (LSCC) rarely harbors epidermal growth factor receptor (EGFR) mutations, even much rarer for acquired T790M mutation.	('squamous cell cancer', 'Phenotype', 'HP:0002860', (106, 126))	('LSCC', 'Phenotype', 'HP:0030359', (169, 173))	('mutations', 'Var', (230, 239))	('squamous cell cancer', 'Disease', 'MESH:D002294', (106, 126))	('epidermal growth factor receptor', 'Gene', (190, 222))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('EGFR', 'Gene', (224, 228))	('epidermal growth factor receptor', 'Gene', '1956', (190, 222))	('lung squamous cell cancer', 'Phenotype', 'HP:0030359', (101, 126))	('EGFR', 'Gene', (88, 92))	('osimertinib', 'Chemical', 'MESH:C000603933', (24, 35))	('Lung squamous cell cancer', 'Phenotype', 'HP:0030359', (142, 167))	('squamous cell cancer', 'Disease', (147, 167))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (147, 167))	('EGFR', 'Gene', '1956', (224, 228))	('T790M', 'Mutation', 'rs121434569', (270, 275))	('lung squamous cell cancer', 'Disease', 'MESH:D002294', (101, 126))	('EGFR', 'Gene', '1956', (88, 92))	('squamous cell cancer', 'Disease', 'MESH:D002294', (147, 167))	('lung squamous cell cancer', 'Disease', (101, 126))
107423	31183356	Although clinical trials of AURA series illustrated that non-small cell lung cancer (NSCLC) with EGFR T790M mutation can benefit from osimertinib, only five LSCC patients were enrolled in total; moreover, the efficacy for LSCC was not shown in the results.	('NSCLC', 'Disease', (85, 90))	('patients', 'Species', '9606', (162, 170))	('cell lung cancer', 'Disease', 'MESH:D008175', (67, 83))	('osimertinib', 'Chemical', 'MESH:C000603933', (134, 145))	('NSCLC', 'Disease', 'MESH:D002289', (85, 90))	('EGFR', 'Gene', '1956', (97, 101))	('LSCC', 'Phenotype', 'HP:0030359', (222, 226))	('T790M', 'Mutation', 'rs121434569', (102, 107))	('NSCLC', 'Phenotype', 'HP:0030358', (85, 90))	('LSCC', 'Phenotype', 'HP:0030359', (157, 161))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (61, 83))	('benefit', 'PosReg', (121, 128))	('EGFR', 'Gene', (97, 101))	('T790M', 'Var', (102, 107))	('lung cancer', 'Phenotype', 'HP:0100526', (72, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('cell lung cancer', 'Disease', (67, 83))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (57, 83))
107425	31183356	We report an LSCC case with T790M-related acquired resistance after treatments with first-generation EGFR-tyrosine kinase inhibitors (EGFR-TKIs) and benefited from osimertinib significantly.	('osimertinib', 'Chemical', 'MESH:C000603933', (164, 175))	('EGFR', 'Gene', (134, 138))	('LSCC', 'Disease', (13, 17))	('T790M-related', 'Var', (28, 41))	('EGFR', 'Gene', '1956', (101, 105))	('EGFR', 'Gene', (101, 105))	('LSCC', 'Phenotype', 'HP:0030359', (13, 17))	('T790M', 'Mutation', 'rs121434569', (28, 33))	('acquired resistance', 'MPA', (42, 61))	('EGFR', 'Gene', '1956', (134, 138))
107428	31183356	Molecular testing of EGFR by amplification refractory mutation system-polymerase chain reaction detected the exon 19-deletion without T790M mutation.	('exon 19-deletion', 'Var', (109, 125))	('EGFR', 'Gene', (21, 25))	('T790M', 'Mutation', 'rs121434569', (134, 139))	('EGFR', 'Gene', '1956', (21, 25))
107430	31183356	Then the frozen re-biopsy tissue was tested by next-generation sequencing (NGS), which detected an EGFR T790M mutation.	('EGFR', 'Gene', '1956', (99, 103))	('EGFR', 'Gene', (99, 103))	('T790M', 'Var', (104, 109))	('T790M', 'Mutation', 'rs121434569', (104, 109))
107434	31183356	Our findings highlight that EGFR T790M mutation may also be an important acquired drug resistance mechanism for LSCC and offer direct evidence of the efficacy of osimertinib in LSCC with T790M mutation.	('T790M', 'Mutation', 'rs121434569', (33, 38))	('T790M', 'Mutation', 'rs121434569', (187, 192))	('LSCC', 'Disease', (112, 116))	('EGFR', 'Gene', '1956', (28, 32))	('drug resistance', 'Phenotype', 'HP:0020174', (82, 97))	('LSCC', 'Phenotype', 'HP:0030359', (177, 181))	('LSCC', 'Phenotype', 'HP:0030359', (112, 116))	('T790M', 'Var', (33, 38))	('EGFR', 'Gene', (28, 32))	('osimertinib', 'Chemical', 'MESH:C000603933', (162, 173))	('T790M mutation', 'Var', (187, 201))
107435	31183356	NGS and better preservation conditions may contribute to higher sensitivity of EGFR T790M detection.	('sensitivity', 'MPA', (64, 75))	('T790M', 'Mutation', 'rs121434569', (84, 89))	('EGFR', 'Gene', '1956', (79, 83))	('T790M', 'Var', (84, 89))	('EGFR', 'Gene', (79, 83))	('higher', 'PosReg', (57, 63))
107436	31183356	Core tip: This is a case report of T790M-related acquired drug resistant lung squamous cell cancer (LSCC) patient with good response to osimertinib, which indicated that T790M is also an important mechanism for acquired resistance in LSCC.	('T790M', 'Mutation', 'rs121434569', (170, 175))	('lung squamous cell cancer', 'Disease', 'MESH:D002294', (73, 98))	('T790M', 'Var', (170, 175))	('lung squamous cell cancer', 'Phenotype', 'HP:0030359', (73, 98))	('patient', 'Species', '9606', (106, 113))	('LSCC', 'Phenotype', 'HP:0030359', (234, 238))	('T790M-related', 'Var', (35, 48))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (78, 98))	('lung squamous cell cancer', 'Disease', (73, 98))	('LSCC', 'Phenotype', 'HP:0030359', (100, 104))	('T790M', 'Mutation', 'rs121434569', (35, 40))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('osimertinib', 'Chemical', 'MESH:C000603933', (136, 147))
107437	31183356	In this case, the secondary T790M mutation of epidermal growth factor receptor (EGFR) was detected by next-generation sequencing (NGS) for frozen tissue but not detected by amplification refractory mutation system-polymerase chain reaction for formalin-fixed and paraffin-embedded sample, which suggests that NGS and better preservation conditions may contribute to higher sensitivity of EGFR T790M detection.	('T790M', 'Mutation', 'rs121434569', (393, 398))	('epidermal growth factor receptor', 'Gene', '1956', (46, 78))	('T790M', 'Var', (393, 398))	('EGFR', 'Gene', (388, 392))	('EGFR', 'Gene', '1956', (80, 84))	('EGFR', 'Gene', (80, 84))	('paraffin', 'Chemical', 'MESH:D010232', (263, 271))	('epidermal growth factor receptor', 'Gene', (46, 78))	('T790M', 'Mutation', 'rs121434569', (28, 33))	('T790M', 'Var', (28, 33))	('formalin', 'Chemical', 'MESH:D005557', (244, 252))	('EGFR', 'Gene', '1956', (388, 392))
107439	31183356	Epidermal growth factor receptor (EGFR) is the most important driver gene in lung adenocarcinoma; therefore, LSCC rarely harbours EGFR mutations.	('LSCC', 'Phenotype', 'HP:0030359', (109, 113))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (77, 96))	('EGFR', 'Gene', (34, 38))	('Epidermal growth factor receptor', 'Gene', (0, 32))	('mutations', 'Var', (135, 144))	('lung adenocarcinoma', 'Disease', (77, 96))	('Epidermal growth factor receptor', 'Gene', '1956', (0, 32))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (77, 96))	('EGFR', 'Gene', '1956', (130, 134))	('EGFR', 'Gene', (130, 134))	('EGFR', 'Gene', '1956', (34, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))
107443	31183356	Osimertinib, an oral, potent, irreversible EGFR-TKI, has been reported to be highly effective in patients with EGFR T790M mutation-positive non-small-cell lung cancer (NSCLC) in previous three clinical trials of the AURA series.	('cell lung cancer', 'Disease', 'MESH:D008175', (150, 166))	('EGFR', 'Gene', '1956', (111, 115))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (144, 166))	('NSCLC', 'Disease', 'MESH:D002289', (168, 173))	('T790M', 'Mutation', 'rs121434569', (116, 121))	('cell lung cancer', 'Disease', (150, 166))	('Osimertinib', 'Chemical', 'MESH:C000603933', (0, 11))	('EGFR', 'Gene', (111, 115))	('T790M', 'Var', (116, 121))	('patients', 'Species', '9606', (97, 105))	('EGFR', 'Gene', '1956', (43, 47))	('lung cancer', 'Phenotype', 'HP:0100526', (155, 166))	('NSCLC', 'Phenotype', 'HP:0030358', (168, 173))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (140, 166))	('EGFR', 'Gene', (43, 47))	('NSCLC', 'Disease', (168, 173))	('effective', 'PosReg', (84, 93))
107445	31183356	T790M-positive LSCC is rarely reported.	('T790M-positive', 'Var', (0, 14))	('T790M', 'Mutation', 'rs121434569', (0, 5))	('LSCC', 'Disease', (15, 19))	('LSCC', 'Phenotype', 'HP:0030359', (15, 19))
107447	31183356	Although one patient with a T790M mutation was administered with another third-generation EGFR-TKI, rociletinib, this was an LSCC transformation from adenocarcinoma, rather than acquired resistance to first-generation TKIs.	('carcinoma', 'Phenotype', 'HP:0030731', (155, 164))	('adenocarcinoma', 'Disease', (150, 164))	('patient', 'Species', '9606', (13, 20))	('adenocarcinoma', 'Disease', 'MESH:D000230', (150, 164))	('EGFR', 'Gene', '1956', (90, 94))	('rociletinib', 'Chemical', 'MESH:C000589977', (100, 111))	('EGFR', 'Gene', (90, 94))	('T790M', 'Mutation', 'rs121434569', (28, 33))	('T790M', 'Var', (28, 33))	('LSCC', 'Phenotype', 'HP:0030359', (125, 129))
107449	31183356	More clinical evidence is needed for the management of LSCC with T790M after treatment with first-generation EGFR-TKIs.	('man', 'Species', '9606', (41, 44))	('T790M', 'Mutation', 'rs121434569', (65, 70))	('EGFR', 'Gene', '1956', (109, 113))	('LSCC', 'Disease', (55, 59))	('T790M', 'Var', (65, 70))	('LSCC', 'Phenotype', 'HP:0030359', (55, 59))	('EGFR', 'Gene', (109, 113))
107450	31183356	Here, we report an LSCC patient with T790M-related acquired drug resistance after treatments with first-generation EGFR-TKIs who benefited from the third-generation EGFR-TKI osimertinib.	('EGFR', 'Gene', (165, 169))	('osimertinib', 'Chemical', 'MESH:C000603933', (174, 185))	('T790M', 'Mutation', 'rs121434569', (37, 42))	('LSCC', 'Phenotype', 'HP:0030359', (19, 23))	('acquired drug resistance', 'MPA', (51, 75))	('EGFR', 'Gene', '1956', (115, 119))	('patient', 'Species', '9606', (24, 31))	('EGFR', 'Gene', (115, 119))	('T790M-related', 'Var', (37, 50))	('drug resistance', 'Phenotype', 'HP:0020174', (60, 75))	('EGFR', 'Gene', '1956', (165, 169))
107456	31183356	Magnetic resonance imaging showed abnormal long T1 and T2 signals at the right femoral neck and ischium and radionuclide bone imaging revealed increased bone uptake on TC-99m (Figure 1C-E).	('TC-99m', 'Var', (168, 174))	('increased', 'PosReg', (143, 152))	('TC-99', 'Chemical', '-', (168, 173))	('bone uptake', 'CPA', (153, 164))
107458	31183356	We also tested for EGFR mutations by amplification refractory mutation system-polymerase chain reaction (ARMS-PCR; AmoyDx, Xiamen, China) using a small biopsy specimen.	('tested', 'Reg', (8, 14))	('mutations', 'Var', (24, 33))	('EGFR', 'Gene', '1956', (19, 23))	('EGFR', 'Gene', (19, 23))
107468	31183356	Pathological testing showed identical LSCC (Figure 3), and molecular testing of EGFR by ARMS-PCR quantified the exon 19 deletion without the T790M mutation, which remained unchanged from the baseline status (Figure 4A).	('exon 19 deletion', 'Var', (112, 128))	('EGFR', 'Gene', '1956', (80, 84))	('EGFR', 'Gene', (80, 84))	('LSCC', 'Phenotype', 'HP:0030359', (38, 42))	('T790M', 'Mutation', 'rs121434569', (141, 146))
107472	31183356	Then, the frozen tissue was subjected to molecular testing by next-generation sequencing (NGS; NextSeq, Illumina), which confirmed the presence of an EGFR T790M mutation (allele frequency of 9.2%) in addition to the baseline exon 19 deletion mutation with an allele frequency of 70.2% (Figure 4B).	('T790M', 'Mutation', 'rs121434569', (155, 160))	('EGFR', 'Gene', '1956', (150, 154))	('T790M', 'Var', (155, 160))	('EGFR', 'Gene', (150, 154))
107477	31183356	LSCC harbouring activating EGFR mutations are rare and even rarer for the coexistence of T790M mutations.	('EGFR', 'Gene', '1956', (27, 31))	('EGFR', 'Gene', (27, 31))	('T790M', 'Mutation', 'rs121434569', (89, 94))	('LSCC', 'Phenotype', 'HP:0030359', (0, 4))	('mutations', 'Var', (32, 41))	('T790M', 'Var', (89, 94))	('activating', 'PosReg', (16, 26))
107478	31183356	This is a rare case of LSCC with coexistence of the EGFR exon 19 deletion and T790M mutation.	('LSCC', 'Disease', (23, 27))	('LSCC', 'Phenotype', 'HP:0030359', (23, 27))	('EGFR', 'Gene', '1956', (52, 56))	('T790M', 'Mutation', 'rs121434569', (78, 83))	('EGFR', 'Gene', (52, 56))	('T790M', 'Var', (78, 83))	('deletion', 'Var', (65, 73))
107480	31183356	LSCC rarely harbours EGFR mutations, not to mention an acquired T790M mutation.	('EGFR', 'Gene', '1956', (21, 25))	('EGFR', 'Gene', (21, 25))	('T790M', 'Mutation', 'rs121434569', (64, 69))	('LSCC', 'Phenotype', 'HP:0030359', (0, 4))	('mutations', 'Var', (26, 35))
107486	31183356	However, this patient had an LSCC transformation derived from adenocarcinoma with de novo T790M detected at baseline.	('LSCC transformation', 'Disease', (29, 48))	('T790M', 'Var', (90, 95))	('adenocarcinoma', 'Disease', (62, 76))	('patient', 'Species', '9606', (14, 21))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('adenocarcinoma', 'Disease', 'MESH:D000230', (62, 76))	('T790M', 'Mutation', 'rs121434569', (90, 95))	('LSCC', 'Phenotype', 'HP:0030359', (29, 33))
107488	31183356	As far as we are aware, this is the first reported T790M-related acquired resistant LSCC case with response to osimertinib, which serves as direct evidence of the effectiveness of osimertinib in LSCC.	('LSCC', 'Phenotype', 'HP:0030359', (84, 88))	('acquired resistant LSCC', 'Disease', (65, 88))	('T790M-related', 'Var', (51, 64))	('osimertinib', 'Chemical', 'MESH:C000603933', (111, 122))	('LSCC', 'Phenotype', 'HP:0030359', (195, 199))	('osimertinib', 'Chemical', 'MESH:C000603933', (180, 191))	('T790M', 'Mutation', 'rs121434569', (51, 56))
107489	31183356	In this case of LSCC, we observed a secondary T790M mutation of EGFR, contributing to the acquired resistance to first-generation EGFR inhibitors.	('LSCC', 'Disease', (16, 20))	('T790M', 'Var', (46, 51))	('LSCC', 'Phenotype', 'HP:0030359', (16, 20))	('resistance', 'MPA', (99, 109))	('EGFR', 'Gene', '1956', (64, 68))	('EGFR', 'Gene', (64, 68))	('EGFR', 'Gene', '1956', (130, 134))	('EGFR', 'Gene', (130, 134))	('T790M', 'Mutation', 'rs121434569', (46, 51))
107490	31183356	This means that T790M is also an important mechanism for acquired resistance in LSCC.	('T790M', 'Mutation', 'rs121434569', (16, 21))	('T790M', 'Var', (16, 21))	('acquired', 'MPA', (57, 65))	('LSCC', 'Disease', (80, 84))	('LSCC', 'Phenotype', 'HP:0030359', (80, 84))
107492	31183356	Both of the results supported an identical diagnosis of LSCC with an EGFR exon 19 deletion mutation (Figure 3).	('EGFR', 'Gene', '1956', (69, 73))	('EGFR', 'Gene', (69, 73))	('LSCC', 'Disease', (56, 60))	('deletion mutation', 'Var', (82, 99))	('LSCC', 'Phenotype', 'HP:0030359', (56, 60))
107498	31183356	In this case, the second biopsy specimen was analysed for EGFR mutation by ARMS-PCR and NGS separately; however, the EGFR T790M mutation was only detected by NGS, which was attributed to the higher sensitivity of NGS and lower degradation rate of DNA stored in liquid nitrogen.	('EGFR', 'Gene', '1956', (58, 62))	('EGFR', 'Gene', '1956', (117, 121))	('EGFR', 'Gene', (58, 62))	('EGFR', 'Gene', (117, 121))	('T790M', 'Mutation', 'rs121434569', (122, 127))	('T790M', 'Var', (122, 127))	('nitrogen', 'Chemical', 'MESH:D009584', (268, 276))
107499	31183356	We foresee that NGS will play a more important role in EGFR T790M detection in the future.	('T790M', 'Var', (60, 65))	('EGFR', 'Gene', '1956', (55, 59))	('EGFR', 'Gene', (55, 59))	('T790M', 'Mutation', 'rs121434569', (60, 65))
107500	31183356	In summary, our findings highlighted that EGFR T790M is also an important mechanism of acquired resistance for LSCC and offered direct evidence of the effectiveness of osimertinib in LSCC patients with the T790M mutation.	('T790M', 'Var', (206, 211))	('EGFR', 'Gene', '1956', (42, 46))	('T790M', 'Mutation', 'rs121434569', (47, 52))	('osimertinib', 'Chemical', 'MESH:C000603933', (168, 179))	('EGFR', 'Gene', (42, 46))	('T790M', 'Var', (47, 52))	('patients', 'Species', '9606', (188, 196))	('LSCC', 'Disease', (183, 187))	('LSCC', 'Disease', (111, 115))	('T790M', 'Mutation', 'rs121434569', (206, 211))	('LSCC', 'Phenotype', 'HP:0030359', (183, 187))	('LSCC', 'Phenotype', 'HP:0030359', (111, 115))
107501	31183356	Novel detection methods, such as NGS and better preservation conditions, hold promise for the more sensitive detection of the EGFR T790M mutation.	('T790M', 'Var', (131, 136))	('T790M', 'Mutation', 'rs121434569', (131, 136))	('EGFR', 'Gene', '1956', (126, 130))	('EGFR', 'Gene', (126, 130))
107503	25891159	The present study aimed to investigate whether inhibition of autophagy may decrease overall tumor resistance to radiation.	('decrease', 'NegReg', (75, 83))	('inhibition', 'Var', (47, 57))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Disease', (92, 97))	('autophagy', 'CPA', (61, 70))
107507	25891159	Inhibition of autophagy was shown to significantly increase the radiosensitivity of the tumors in vitro and in vivo.	('increase', 'PosReg', (51, 59))	('autophagy', 'CPA', (14, 23))	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('Inhibition', 'Var', (0, 10))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('tumors', 'Disease', (88, 94))
107508	25891159	The enhancement ratio of sensitization in EC9706 cells was 1.76 when the cells were treated with 10 mM 3-MA, alongside ionizing radiation.	('sensitization', 'MPA', (25, 38))	('enhancement', 'PosReg', (4, 15))	('EC9706', 'CellLine', 'CVCL:E307', (42, 48))	('3-MA', 'Chemical', 'MESH:C025946', (103, 107))	('EC9706', 'Var', (42, 48))
107511	25891159	The present study demonstrated in vitro and in vivo that radiation-induced autophagy has a protective effect against cell death, and inhibition of autophagy is able to enhance the radiosensitivity of esophageal squamous cell carcinoma.	('enhance', 'PosReg', (168, 175))	('autophagy', 'CPA', (147, 156))	('carcinoma', 'Phenotype', 'HP:0030731', (225, 234))	('inhibition', 'Var', (133, 143))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (211, 234))	('radiosensitivity', 'CPA', (180, 196))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (200, 234))	('cell death', 'CPA', (117, 127))	('protective effect', 'CPA', (91, 108))	('esophageal squamous cell carcinoma', 'Disease', (200, 234))
107522	25891159	Previous studies have demonstrated that autophagy inhibits angiogenesis, whereas other studies have suggested that autophagy promotes cancer, and inhibition of autophagy prevents angiogenesis.	('autophagy', 'CPA', (115, 124))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('angiogenesis', 'CPA', (179, 191))	('autophagy', 'CPA', (40, 49))	('angiogenesis', 'CPA', (59, 71))	('inhibits', 'NegReg', (50, 58))	('promotes', 'PosReg', (125, 133))	('inhibition', 'Var', (146, 156))	('prevents', 'NegReg', (170, 178))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
107524	25891159	A preliminary study demonstrated that inhibition of autophagy enhanced the cytotoxicity of radiotherapy in the TE-1 esophageal cancer cell line.	('esophageal cancer', 'Disease', 'MESH:D004938', (116, 133))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('autophagy', 'CPA', (52, 61))	('cytotoxicity', 'Disease', (75, 87))	('enhanced', 'PosReg', (62, 70))	('inhibition', 'Var', (38, 48))	('cytotoxicity', 'Disease', 'MESH:D064420', (75, 87))	('esophageal cancer', 'Disease', (116, 133))
107526	25891159	The present study provided proof that the inhibition of autophagy may improve the outcomes of radiation therapy of human esophageal squamous cell carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (121, 155))	('autophagy', 'CPA', (56, 65))	('outcomes', 'MPA', (82, 90))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (132, 155))	('inhibition', 'Var', (42, 52))	('improve', 'PosReg', (70, 77))	('human', 'Species', '9606', (115, 120))	('esophageal squamous cell carcinoma', 'Disease', (121, 155))
107534	25891159	sc-1836), anti-cleaved caspase-3 (cat.	('caspase-3', 'Gene', (23, 32))	('caspase-3', 'Gene', '836', (23, 32))	('anti-cleaved', 'Var', (10, 22))
107535	25891159	sc-22171-R), anti-cleaved caspase-9 (cat.	('anti-cleaved', 'Var', (13, 25))	('caspase-9', 'Gene', '842', (26, 35))	('caspase-9', 'Gene', (26, 35))
107536	25891159	sc-56073), anti-cleaved poly(ADP ribose) polymerase (PARP; cat.	('PARP', 'Gene', (53, 57))	('poly(ADP ribose) polymerase', 'Gene', (24, 51))	('poly(ADP ribose) polymerase', 'Gene', '142', (24, 51))	('PARP', 'Gene', '142', (53, 57))	('anti-cleaved', 'Var', (11, 23))
107554	25891159	The membranes were then blocked with 5% skimmed milk (Cusabio Biotech Co., Ltd.) for 1 h and incubated overnight at 4 C with the following primary antibodies: anti-LC3-I/II (diluted 1:2,000), anti-beclin-1 (diluted 1:800), anti-VEGF (diluted 1:400), anti-caspase-3 (diluted 1:400), anti-caspase-9 (diluted 1:500), anti-PARP (diluted 1:400), anti-PCNA (diluted 1:1,000), anti-Ki-67 (diluted 1:800), anti-Bax (diluted 1:1,000) and anti-Bcl-2 (diluted 1:1,000).	('Bcl-2', 'Gene', (434, 439))	('caspase-3', 'Gene', '836', (255, 264))	('VEGF', 'Gene', (228, 232))	('PCNA', 'Gene', '5111', (346, 350))	('caspase-3', 'Gene', (255, 264))	('LC3-I', 'Gene', '84557', (164, 169))	('Bcl-2', 'Gene', '596', (434, 439))	('LC3-I', 'Gene', (164, 169))	('beclin-1', 'Gene', '8678', (197, 205))	('Bax', 'Gene', (403, 406))	('caspase-9', 'Gene', '842', (287, 296))	('diluted', 'Var', (382, 389))	('Bax', 'Gene', '581', (403, 406))	('beclin-1', 'Gene', (197, 205))	('PARP', 'Gene', '142', (319, 323))	('PCNA', 'Gene', (346, 350))	('caspase-9', 'Gene', (287, 296))	('PARP', 'Gene', (319, 323))	('VEGF', 'Gene', '7422', (228, 232))
107589	25891159	In the presence of 3-MA, there was an increase in the number of EC9706 cells in G2/M phase by 65.7% and 218.0% following treatment with 5.0 and 10 mM of 3-MA, respectively.	('EC9706', 'CellLine', 'CVCL:E307', (64, 70))	('increase', 'PosReg', (38, 46))	('3-MA', 'Chemical', 'MESH:C025946', (153, 157))	('EC9706', 'Var', (64, 70))	('3-MA', 'Chemical', 'MESH:C025946', (19, 23))
107596	25891159	These results indicated that radiation-induced autophagy has a protective role in tumor cells against apoptosis, and inhibition of autophagy subsequently enhances the rate of apoptosis in the cells.	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('autophagy', 'CPA', (131, 140))	('enhances', 'PosReg', (154, 162))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('inhibition', 'Var', (117, 127))	('tumor', 'Disease', (82, 87))
107599	25891159	The protein expression levels of VEGF were reduced in EC9706 cells treated with 3-MA, as compared with those in the untreated cells.	('VEGF', 'Gene', (33, 37))	('3-MA', 'Chemical', 'MESH:C025946', (80, 84))	('EC9706', 'Var', (54, 60))	('protein expression levels', 'MPA', (4, 29))	('reduced', 'NegReg', (43, 50))	('VEGF', 'Gene', '7422', (33, 37))	('EC9706', 'CellLine', 'CVCL:E307', (54, 60))
107602	25891159	The response of the EC9706 xenografts to radiation plus 3-MA was significantly enhanced, as compared with the that of the untreated, 3-MA alone and radiation alone groups (P<0.01, Fig.	('EC9706', 'CellLine', 'CVCL:E307', (20, 26))	('3-MA', 'Chemical', 'MESH:C025946', (56, 60))	('enhanced', 'PosReg', (79, 87))	('EC9706', 'Var', (20, 26))	('response', 'MPA', (4, 12))	('3-MA', 'Chemical', 'MESH:C025946', (133, 137))
107622	25891159	Inhibition of autophagy induction using small interfering (si)RNA targeted to beclin-1 and ATG7 significantly enhanced the effects of chemotherapeutic drugs, and reduced the recovery of drug-treated cells.	('autophagy', 'CPA', (14, 23))	('ATG7', 'Gene', '10533', (91, 95))	('small interfering', 'Var', (40, 57))	('beclin-1', 'Gene', '8678', (78, 86))	('reduced', 'NegReg', (162, 169))	('recovery of drug-treated cells', 'MPA', (174, 204))	('enhanced', 'PosReg', (110, 118))	('ATG7', 'Gene', (91, 95))	('effects of chemotherapeutic drugs', 'MPA', (123, 156))	('beclin-1', 'Gene', (78, 86))
107623	25891159	Autophagy is frequently observed in cancer cells following exposure to ionizing radiation, and inhibition of autophagy has been shown to precipitate radiation-induced cell death.	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('inhibition', 'Var', (95, 105))	('cancer', 'Disease', (36, 42))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('Autophagy', 'CPA', (0, 9))	('autophagy', 'CPA', (109, 118))
107640	25891159	Furthermore, cellular proliferation was evaluated by measuring the expression levels of PCNA and Ki-67; decreased protein expression levels of PCNA and Ki-67 were most significant in the radiation plus 3-MA-treated tumor samples.	('PCNA', 'Gene', (88, 92))	('3-MA', 'Chemical', 'MESH:C025946', (202, 206))	('protein expression levels', 'MPA', (114, 139))	('PCNA', 'Gene', (143, 147))	('tumor', 'Disease', 'MESH:D009369', (215, 220))	('PCNA', 'Gene', '5111', (88, 92))	('Ki-67', 'Var', (152, 157))	('decreased', 'NegReg', (104, 113))	('PCNA', 'Gene', '5111', (143, 147))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('tumor', 'Disease', (215, 220))
107646	25891159	Autophagy inhibition has garnered attention as a novel anti-cancer therapeutic strategy, and inhibitors of autophagy have been reported to act as potent anti-cancer drugs and to sensitize cancer cells to anti-cancer therapy.	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('inhibition', 'NegReg', (10, 20))	('autophagy', 'CPA', (107, 116))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('cancer', 'Disease', 'MESH:D009369', (209, 215))	('cancer', 'Disease', (60, 66))	('cancer', 'Disease', (158, 164))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('cancer', 'Disease', (209, 215))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('cancer', 'Disease', (188, 194))	('Autophagy', 'CPA', (0, 9))	('inhibitors', 'Var', (93, 103))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
107647	25891159	The present study demonstrated that inhibition of autophagy was able to markedly enhance the anti-cancer effects of radiotherapy by promoting apoptotic cell death and downregulating angiogenesis.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('inhibition', 'Var', (36, 46))	('autophagy', 'CPA', (50, 59))	('promoting', 'PosReg', (132, 141))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('angiogenesis', 'CPA', (182, 194))	('cancer', 'Disease', (98, 104))	('downregulating', 'NegReg', (167, 181))	('apoptotic cell death', 'CPA', (142, 162))	('enhance', 'PosReg', (81, 88))
107650	25484917	We identify novel mutation hotspots such as K36M in histone H3.1, and uncover a general trend in which transcriptional profiles and somatic mutations in tumor samples favor increased transcriptionally repressive histone methylation, and defective chromatin remodeling.	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('K36M', 'Var', (44, 48))	('H3.1', 'Gene', '8352', (60, 64))	('K36M', 'Mutation', 'p.K36M', (44, 48))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('defective', 'NegReg', (237, 246))	('chromatin remodeling', 'CPA', (247, 267))	('increased', 'PosReg', (173, 182))	('H3.1', 'Gene', (60, 64))	('transcriptionally repressive histone methylation', 'MPA', (183, 231))
107652	25484917	Epigenetic control of gene expression dictates cell fate in health and disease, and dysregulation of epigenetic signals is associated with cancer.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('dysregulation', 'Var', (84, 97))	('associated', 'Reg', (123, 133))	('dictates', 'Reg', (38, 46))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('Epigenetic', 'Var', (0, 10))	('cell fate', 'CPA', (47, 56))	('cancer', 'Disease', (139, 145))
107653	25484917	Two observations support pharmacological targeting of the 'cancer epigenome': (1) some cancer-associated epigenetic aberrations drive cancer initiation or progression; and (2) unlike genetic information, epigenetic states are reversible.	('cancer', 'Disease', (87, 93))	("'cancer", 'Disease', 'MESH:D009369', (58, 65))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('epigenetic aberrations', 'Var', (105, 127))	('cancer initiation', 'Disease', 'MESH:D009369', (134, 151))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	("'cancer", 'Disease', (58, 65))	('progression', 'CPA', (155, 166))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('cancer initiation', 'Disease', (134, 151))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('cancer', 'Disease', (59, 65))	('drive', 'Reg', (128, 133))
107655	25484917	Cancer associated overexpression, mutation, or aberrant recruitment of chromatin factors (defined here as proteins that participate in the chemical modification of DNA, histones, or control nucleosome occupancy), represent emerging opportunities for cancer therapy.	('aberrant', 'Var', (47, 55))	('cancer', 'Disease', 'MESH:D009369', (250, 256))	('recruitment', 'MPA', (56, 67))	('cancer', 'Disease', (250, 256))	('mutation', 'Var', (34, 42))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))	('overexpression', 'PosReg', (18, 32))
107656	25484917	For instance, inhibitors of EZH2 - a histone 3 lysine 27 (H3K27) methyltransferase that is overexpressed in a number of solid tumors and is the site of recurrent gain-of-function mutations in lymphoma - are raising considerable interest as potential anti-cancer agents, and have recently advanced to the clinic.	('solid tumors', 'Disease', 'MESH:D009369', (120, 132))	('cancer', 'Phenotype', 'HP:0002664', (255, 261))	('H3K27', 'Gene', '126961', (58, 63))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('solid tumors', 'Disease', (120, 132))	('lymphoma', 'Disease', 'MESH:D008223', (192, 200))	('cancer', 'Disease', 'MESH:D009369', (255, 261))	('EZH2', 'Gene', '2146', (28, 32))	('lymphoma', 'Phenotype', 'HP:0002665', (192, 200))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('EZH2', 'Gene', (28, 32))	('lysine', 'Chemical', 'MESH:D008239', (47, 53))	('cancer', 'Disease', (255, 261))	('mutations', 'Var', (179, 188))	('inhibitors', 'Var', (14, 24))	('gain-of-function', 'PosReg', (162, 178))	('H3K27', 'Gene', (58, 63))	('lymphoma', 'Disease', (192, 200))
107657	25484917	Chromosomal aberrations and altered expression of chromatin factors that are recurrent in specific cancer types have been reported in the literature, some extensively, and recently reviewed.	('Chromosomal aberrations', 'Var', (0, 23))	('altered', 'Reg', (28, 35))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('Chromosomal aberrations', 'Phenotype', 'HP:0040012', (0, 23))	('cancer', 'Disease', (99, 105))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('expression', 'MPA', (36, 46))
107662	25484917	This systematic and integrated approach identifies many oncogenic aberrations already recorded in the literature, but also uncovers novel alterations recurrently affecting chromatin factors in specific cancer types.	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('alterations', 'Var', (138, 149))	('cancer', 'Disease', 'MESH:D009369', (202, 208))	('affecting', 'Reg', (162, 171))	('cancer', 'Disease', (202, 208))	('chromatin factors', 'MPA', (172, 189))
107663	25484917	Overall our results provide novel insight into the cancer epigenome revealing a tendency toward alterations predicted to result in greater transcriptional repression, decreased transcriptional activation and reduced chromatin remodeling.	('chromatin remodeling', 'MPA', (216, 236))	('alterations', 'Var', (96, 107))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('transcriptional activation', 'MPA', (177, 203))	('reduced', 'NegReg', (208, 215))	('greater', 'PosReg', (131, 138))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('transcriptional repression', 'MPA', (139, 165))	('decreased', 'NegReg', (167, 176))
107672	25484917	As shown in Additional file 2: Figure S1 and Table 1, our analysis retrieved a number of known cancer-associated aberrations in chromatin factors.	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('cancer', 'Disease', (95, 101))	('chromatin factors', 'Protein', (128, 145))	('aberrations', 'Var', (113, 124))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))
107675	25484917	Other examples include recurrent mutations of the chromatin remodeling protein ATRX in lower grade glioblastoma (40% of patient), or DNMT3A and TET2 in acute myeloid leukemia (25% and 8.6% of patients, respectively), mutations of the H3K4 methyltransferase MLL3 in 7.7% of breast cancer patients, or mutations of the bromodomain containing protein PBRM1 in 28.5% of kidney renal clear cell carcinoma.	('patient', 'Species', '9606', (192, 199))	('carcinoma', 'Phenotype', 'HP:0030731', (390, 399))	('acute myeloid leukemia', 'Disease', (152, 174))	('glioblastoma', 'Disease', 'MESH:D005909', (99, 111))	('DNMT3A', 'Gene', (133, 139))	('mutations', 'Var', (33, 42))	('TET2', 'Gene', '54790', (144, 148))	('leukemia', 'Phenotype', 'HP:0001909', (166, 174))	('cancer', 'Phenotype', 'HP:0002664', (280, 286))	('kidney renal clear cell carcinoma', 'Disease', 'MESH:C538614', (366, 399))	('MLL3', 'Gene', '58508', (257, 261))	('glioblastoma', 'Disease', (99, 111))	('patient', 'Species', '9606', (287, 294))	('glioblastoma', 'Phenotype', 'HP:0012174', (99, 111))	('patient', 'Species', '9606', (120, 127))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (158, 174))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (152, 174))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (152, 174))	('kidney renal clear cell carcinoma', 'Disease', (366, 399))	('PBRM1', 'Gene', '55193', (348, 353))	('breast cancer', 'Phenotype', 'HP:0003002', (273, 286))	('mutations', 'Var', (300, 309))	('patients', 'Species', '9606', (192, 200))	('DNMT3A', 'Gene', '1788', (133, 139))	('MLL3', 'Gene', (257, 261))	('breast cancer', 'Disease', 'MESH:D001943', (273, 286))	('TET2', 'Gene', (144, 148))	('breast cancer', 'Disease', (273, 286))	('PBRM1', 'Gene', (348, 353))	('H3', 'Gene', '126961', (234, 236))	('patients', 'Species', '9606', (287, 295))	('ATRX', 'Gene', (79, 83))	('ATRX', 'Gene', '546', (79, 83))	('mutations', 'Var', (217, 226))
107679	25484917	Another PMT, MLL2, and the HAT EP300 are found mutated in 18% and 7.8% of head and neck tumors, respectively (Table 1).	('head and neck tumors', 'Phenotype', 'HP:0012288', (74, 94))	('neck tumors', 'Disease', (83, 94))	('MLL2', 'Gene', '9757', (13, 17))	('EP300', 'Gene', '2033', (31, 36))	('MLL2', 'Gene', (13, 17))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('EP300', 'Gene', (31, 36))	('mutated', 'Var', (47, 54))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('neck tumors', 'Disease', 'MESH:D006258', (83, 94))
107685	25484917	Again, the rationale here may be that since chromatin factors control the transcriptional profile of the cancer genome, mutations affecting a single chromatin factor may have a strong impact on the expression of a combination of genes involved in cell fate, survival, or DNA damage response.	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('transcriptional', 'MPA', (74, 89))	('mutations', 'Var', (120, 129))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('expression', 'MPA', (198, 208))	('impact', 'Reg', (184, 190))
107691	25484917	It has been proposed that site-specific missense mutations that recur across a sizable cohort of cancer patients are indicative of an oncogenic role for the targeted gene, while genes that are frequently mutated at random positions are more likely to act as tumor suppressors.	('missense mutations', 'Var', (40, 58))	('tumor', 'Phenotype', 'HP:0002664', (258, 263))	('cancer', 'Disease', (97, 103))	('tumor', 'Disease', (258, 263))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('tumor', 'Disease', 'MESH:D009369', (258, 263))	('patients', 'Species', '9606', (104, 112))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
107692	25484917	For instance, we did not have access to lymphoma data, and failed to retrieve known Y641 mutants that increase the trimethylase activity of EZH2 in this cancer type.	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('lymphoma', 'Disease', 'MESH:D008223', (40, 48))	('cancer', 'Disease', (153, 159))	('EZH2', 'Gene', '2146', (140, 144))	('lymphoma', 'Phenotype', 'HP:0002665', (40, 48))	('EZH2', 'Gene', (140, 144))	('trimethylase activity', 'MPA', (115, 136))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('increase', 'PosReg', (102, 110))	('Y641', 'Var', (84, 88))	('lymphoma', 'Disease', (40, 48))
107695	25484917	For instance, genes coding for the histone variant H3.1, are mutated in 17 out of 270 head and neck squamous cell carcinoma samples (HNSC), and four of these mutations replace a lysine with methionine at position 36 (twice in HIST1H3C, once in HIST1H3E and once in HIST1H3I) suggesting that H3K36M is an oncogenic mutation that drives tumor initiation or progression in a fraction of HNSC patients.	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (86, 123))	('mutations replace', 'Var', (158, 175))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('replace', 'Var', (168, 175))	('HIST1H3C', 'Gene', '8352', (226, 234))	('tumor', 'Phenotype', 'HP:0002664', (335, 340))	('neck squamous cell carcinoma', 'Disease', (95, 123))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (95, 123))	('H3.1', 'Gene', '8352', (51, 55))	('HIST1H3C', 'Gene', (226, 234))	('tumor initiation', 'Disease', 'MESH:D009369', (335, 351))	('tumor initiation', 'Disease', (335, 351))	('HIST1H3E', 'Gene', (244, 252))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (100, 123))	('HIST1H3E', 'Gene', '8353', (244, 252))	('HIST1H3I', 'Gene', (265, 273))	('patients', 'Species', '9606', (389, 397))	('H3.1', 'Gene', (51, 55))	('H3K36M', 'Var', (291, 297))	('HIST1H3I', 'Gene', '8354', (265, 273))	('lysine with methionine at position 36', 'Mutation', 'p.K36M', (178, 215))	('head', 'Disease', (86, 90))
107700	25484917	We also found a H3K36M mutation in a colorectal cancer sample, suggesting that this mechanism may extend to other cancer types.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('colorectal cancer', 'Disease', (37, 54))	('found', 'Reg', (8, 13))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('colorectal cancer', 'Disease', 'MESH:D015179', (37, 54))	('H3K36M', 'Var', (16, 22))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('colorectal cancer', 'Phenotype', 'HP:0003003', (37, 54))	('cancer', 'Disease', (114, 120))
107701	25484917	Though statistically significant, we note that the H3K36M mutation rate of 24% out of the 6.2% HNSC samples carrying a mutation at H3.1 remains low.	('mutation', 'Var', (119, 127))	('H3.1', 'Gene', (131, 135))	('H3.1', 'Gene', '8352', (131, 135))	('H3K36M', 'Gene', (51, 57))
107702	25484917	As a comparison, over 40% of cutaneous melanoma samples carry a mutation in BRAF, 90% of which are at the hotspot V600E.	('BRAF', 'Gene', (76, 80))	('BRAF', 'Gene', '673', (76, 80))	('mutation', 'Var', (64, 72))	('melanoma', 'Phenotype', 'HP:0002861', (39, 47))	('cutaneous melanoma', 'Disease', (29, 47))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (29, 47))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (29, 47))	('V600E', 'Mutation', 'rs113488022', (114, 119))
107703	25484917	Another histone, H2B is mutated in seven out of 377 glioblastoma multiform patients, resulting in a G53D mutant in three cases (in HIST1H2BE, HIST1H2BL and HIST1H2BF) (Figure 2A,B).	('H2B', 'Gene', (147, 150))	('H2B', 'Gene', '8349', (136, 139))	('glioblastoma', 'Disease', 'MESH:D005909', (52, 64))	('HIST1H2BF', 'Gene', '8343', (156, 165))	('H2B', 'Gene', (161, 164))	('H2B', 'Gene', (17, 20))	('HIST1H2BL', 'Gene', '8340', (142, 151))	('glioblastoma', 'Disease', (52, 64))	('glioblastoma', 'Phenotype', 'HP:0012174', (52, 64))	('H2B', 'Gene', (136, 139))	('HIST1H2BL', 'Gene', (142, 151))	('patients', 'Species', '9606', (75, 83))	('H2B', 'Gene', '8349', (147, 150))	('HIST1H2BE', 'Gene', (131, 140))	('G53D', 'Mutation', 'p.G53D', (100, 104))	('G53D', 'Var', (100, 104))	('HIST1H2BF', 'Gene', (156, 165))	('H2B', 'Gene', '8349', (161, 164))	('H2B', 'Gene', '8349', (17, 20))	('HIST1H2BE', 'Gene', '8344', (131, 140))
107704	25484917	This mutation places an acidic residue in the minor groove of the DNA wrapped around the histone octamer (Additional file 4: Figure S3), which should destabilize nucleosomal H2B, and possibly nucleosome fluctuation or chromatin architecture.	('nucleosomal', 'MPA', (162, 173))	('destabilize', 'NegReg', (150, 161))	('H2B', 'Gene', '8349', (174, 177))	('mutation', 'Var', (5, 13))	('H2B', 'Gene', (174, 177))
107706	25484917	We find that WHSC1, an H3K36 di-methylase that harbors two PWWP domains, is mutated in eight HNSC samples.	('WHSC1', 'Gene', (13, 18))	('mutated', 'Var', (76, 83))	('H3', 'Gene', '126961', (23, 25))	('WHSC1', 'Gene', '7468', (13, 18))
107707	25484917	In four cases, this produces a frameshift insertion at position G944 of the C-terminal PWWP domain (Figure 2B).	('frameshift', 'Var', (31, 41))	('G944 of the C', 'Mutation', 'rs775942317', (64, 77))	('produces', 'Reg', (20, 28))
107708	25484917	This results in deletion of the C-terminal helix of the WHSC1 PWWP domain, expected to cap the methyl-lysine binding aromatic cage, and may also cause truncation of the methyltransferase domain of WHSC1, located on a downstream exon.	('methyl-lysine binding aromatic cage', 'MPA', (95, 130))	('WHSC1', 'Gene', '7468', (56, 61))	('cap', 'PosReg', (87, 90))	('deletion', 'Var', (16, 24))	('methyltransferase', 'Enzyme', (169, 186))	('WHSC1', 'Gene', (56, 61))	('results in', 'Reg', (5, 15))	('WHSC1', 'Gene', '7468', (197, 202))	('truncation', 'MPA', (151, 161))	('cause', 'Reg', (145, 150))	('methyl-lysine', 'Chemical', '-', (95, 108))	('WHSC1', 'Gene', (197, 202))
107710	25484917	We find that the H3K36M mutation and WHSC1 frameshifts are mutually exclusive in HNSC tumor samples.	('HNSC tumor', 'Disease', 'MESH:D009369', (81, 91))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('HNSC tumor', 'Disease', (81, 91))	('H3K36M mutation', 'Var', (17, 32))	('WHSC1', 'Gene', '7468', (37, 42))	('frameshifts', 'Var', (43, 54))	('WHSC1', 'Gene', (37, 42))
107711	25484917	Both aberrations are expected to affect H3K36me2 signaling and may represent alternate pathways to the same molecular endpoint.	('affect', 'Reg', (33, 39))	('aberrations', 'Var', (5, 16))	('H3', 'Gene', '126961', (40, 42))
107712	25484917	While mutation hotspots are expected to reveal oncogenes, tumor suppressors are generally targeted by mutations that are more distributed over the gene in cancer.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('targeted', 'Reg', (90, 98))	('mutations', 'Var', (102, 111))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('cancer', 'Disease', (155, 161))	('cancer', 'Disease', 'MESH:D009369', (155, 161))
107716	25484917	In total, six of the most mutated genes in various cancer types methylate H3K4 or H3K36 (Additional file 2: Figure S1A, Table 1).	('H3', 'Gene', '126961', (82, 84))	('H3', 'Gene', '126961', (74, 76))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('methylate', 'Var', (64, 73))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))
107720	25484917	Importantly, we observe that D328 makes critical electrostatic interactions with both H3K4 and H3K9 in the DPF3 complex, and is conserved in MLL3 (corresponding residue: D400 - Figure 2C - Bottom).	('H3', 'Gene', '126961', (95, 97))	('MLL3', 'Gene', '58508', (141, 145))	('D328', 'Chemical', '-', (29, 33))	('electrostatic interactions', 'MPA', (49, 75))	('D328', 'Var', (29, 33))	('H3', 'Gene', '126961', (86, 88))	('DPF3', 'Gene', (107, 111))	('MLL3', 'Gene', (141, 145))	('DPF3', 'Gene', '8110', (107, 111))
107721	25484917	Intriguingly, D400N is one of the three mutations affecting the triple PHD finger of MLL3 in colorectal cancer, and, based on these structural observations, should significantly affect histone binding.	('D400N', 'Mutation', 'p.D400N', (14, 19))	('histone', 'MPA', (185, 192))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('colorectal cancer', 'Phenotype', 'HP:0003003', (93, 110))	('MLL3', 'Gene', (85, 89))	('colorectal cancer', 'Disease', (93, 110))	('D400N', 'Var', (14, 19))	('MLL3', 'Gene', '58508', (85, 89))	('colorectal cancer', 'Disease', 'MESH:D015179', (93, 110))	('affect', 'Reg', (178, 184))
107724	25484917	The C347G mutation will irremediably affect the structure of this domain, expected to participate in substrate binding.	('structure', 'MPA', (48, 57))	('affect', 'Reg', (37, 43))	('C347G', 'Var', (4, 9))	('participate', 'Reg', (86, 97))	('C347G', 'Mutation', 'rs754368331', (4, 9))
107725	25484917	Somatic mutations affecting MLL3 in colorectal cancer seem therefore to target with high precision residues involved in recruiting the enzyme to appropriately marked loci.	('MLL3', 'Gene', '58508', (28, 32))	('colorectal cancer', 'Disease', (36, 53))	('mutations', 'Var', (8, 17))	('colorectal cancer', 'Disease', 'MESH:D015179', (36, 53))	('MLL3', 'Gene', (28, 32))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('colorectal cancer', 'Phenotype', 'HP:0003003', (36, 53))
107726	25484917	Selective targeting of H3K4 and H3K36 methylation by oncogenic mutations was also observed in other studies that are not yet available from TCGA; for instance, mutations in SETD2 and genes affecting H3K36 methylation are recurrent in high-grade gliomas.	('H3', 'Gene', '126961', (23, 25))	('recurrent', 'Reg', (221, 230))	('mutations', 'Var', (160, 169))	('SETD2', 'Gene', (173, 178))	('gliomas', 'Disease', (245, 252))	('H3', 'Gene', '126961', (199, 201))	('gliomas', 'Disease', 'MESH:D005910', (245, 252))	('gliomas', 'Phenotype', 'HP:0009733', (245, 252))	('glioma', 'Phenotype', 'HP:0009733', (245, 251))	('H3', 'Gene', '126961', (32, 34))	('SETD2', 'Gene', '29072', (173, 178))
107727	25484917	Together, these results show that H3K36 and H3K4 mediated signaling is highly targeted in cancer via hotspot mutations of oncogenes and random mutation of tumor suppressors.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('H3', 'Gene', '126961', (44, 46))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('H3', 'Gene', '126961', (34, 36))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('tumor', 'Disease', (155, 160))	('oncogenes', 'Gene', (122, 131))	('mutations', 'Var', (109, 118))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))
107728	25484917	To identify cancer-associated chromatin factor alterations that are either synergistic or redundant, we searched for co-occurring and mutually exclusive mutation patterns, respectively (Additional file 5: Table S2).	('cancer', 'Disease', (12, 18))	('alterations', 'Var', (47, 58))	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))
107729	25484917	We find that mutations are co-occurring in ATRX, TP53, and IDH1, and that these are mutually exlusive with mutations in PTEN and EGFR in glioblatoma multiform (GBM) and lower grade glioma (LGG) (Figure 3; Additional file 5: Table S2).	('IDH1', 'Gene', '3417', (59, 63))	('mutations', 'Var', (107, 116))	('TP53', 'Gene', '7157', (49, 53))	('glioma', 'Phenotype', 'HP:0009733', (181, 187))	('TP53', 'Gene', (49, 53))	('mutations', 'Var', (13, 22))	('ATRX', 'Gene', '546', (43, 47))	('glioma', 'Disease', 'MESH:D005910', (181, 187))	('glioblatoma multiform', 'Disease', (137, 158))	('EGFR', 'Gene', '1956', (129, 133))	('PTEN', 'Gene', (120, 124))	('glioblatoma multiform', 'Disease', 'MESH:D004892', (137, 158))	('PTEN', 'Gene', '5728', (120, 124))	('IDH1', 'Gene', (59, 63))	('EGFR', 'Gene', (129, 133))	('glioma', 'Disease', (181, 187))	('ATRX', 'Gene', (43, 47))
107730	25484917	For example, TP53 is mutated in 50% of all LGG samples, but in 95% of the 80 ATRX-mutated samples.	('TP53', 'Gene', (13, 17))	('ATRX', 'Gene', '546', (77, 81))	('TP53', 'Gene', '7157', (13, 17))	('LGG', 'Disease', (43, 46))	('mutated', 'Var', (21, 28))	('ATRX', 'Gene', (77, 81))
107732	25484917	Interestingly, it was found that mutations in IDH1, ATRX, or TP53 were recurrent only in glioma-CpG island methylator phenotype-positive tumors (a phenotype probably attributable to the competitive inhibition of TET demethylases, following accumulation of 2-hydroxyglutarate caused by IDH1 mutation), while mutations in EGFR and PTEN were only observed in other tumor subtypes, which is in agreement with the pattern that we observe.	('tumors', 'Disease', (137, 143))	('mutation', 'Var', (290, 298))	('mutations', 'Var', (33, 42))	('tumor', 'Disease', (362, 367))	('IDH1', 'Gene', (285, 289))	('TP53', 'Gene', (61, 65))	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('IDH1', 'Gene', (46, 50))	('tumor', 'Disease', 'MESH:D009369', (362, 367))	('EGFR', 'Gene', (320, 324))	('ATRX', 'Gene', (52, 56))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (256, 274))	('PTEN', 'Gene', (329, 333))	('glioma', 'Disease', (89, 95))	('ATRX', 'Gene', '546', (52, 56))	('IDH1', 'Gene', '3417', (285, 289))	('tumor', 'Disease', (137, 142))	('glioma', 'Disease', 'MESH:D005910', (89, 95))	('IDH1', 'Gene', '3417', (46, 50))	('tumor', 'Phenotype', 'HP:0002664', (362, 367))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('PTEN', 'Gene', '5728', (329, 333))	('TP53', 'Gene', '7157', (61, 65))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('glioma', 'Phenotype', 'HP:0009733', (89, 95))	('EGFR', 'Gene', '1956', (320, 324))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
107733	25484917	An important mutation that is missed in our exome-centric analysis is an upregulating mutation in the promoter of the telomerase reverse transcriptase (TERT), observed in 58% to 84% of primary glioblastomas, suggesting that telomere lengthening plays an important role in tumor growth.	('tumor', 'Phenotype', 'HP:0002664', (272, 277))	('TERT', 'Gene', '7015', (152, 156))	('glioblastomas', 'Disease', 'MESH:D005909', (193, 206))	('tumor', 'Disease', (272, 277))	('telomerase reverse transcriptase', 'Gene', (118, 150))	('glioblastoma', 'Phenotype', 'HP:0012174', (193, 205))	('glioblastomas', 'Disease', (193, 206))	('telomerase reverse transcriptase', 'Gene', '7015', (118, 150))	('tumor', 'Disease', 'MESH:D009369', (272, 277))	('upregulating', 'PosReg', (73, 85))	('mutation', 'Var', (86, 94))	('TERT', 'Gene', (152, 156))	('glioblastomas', 'Phenotype', 'HP:0012174', (193, 206))
107734	25484917	Interestingly, ATRX is required for accumulation at telomeres, and ATRX mutations promote telomere lengthening and cellular proliferation.	('ATRX', 'Gene', (67, 71))	('mutations', 'Var', (72, 81))	('ATRX', 'Gene', '546', (15, 19))	('cellular proliferation', 'CPA', (115, 137))	('ATRX', 'Gene', '546', (67, 71))	('promote', 'PosReg', (82, 89))	('telomere lengthening', 'CPA', (90, 110))	('ATRX', 'Gene', (15, 19))
107735	25484917	Similarly TP53 deficiency favors telomere lengthening.	('telomere lengthening', 'CPA', (33, 53))	('TP53', 'Gene', (10, 14))	('favors', 'PosReg', (26, 32))	('deficiency', 'Var', (15, 25))	('TP53', 'Gene', '7157', (10, 14))
107736	25484917	This suggests complementary pressures towards an oncogenic pathway depending on telomere lengthening by mutations co-occurring at ATRX, TP53 and (hypothetically) IDH1 in adult brain tumors where the PTEN/EGFR surface signaling axis is not altered.	('PTEN', 'Gene', '5728', (199, 203))	('brain tumors', 'Disease', (176, 188))	('telomere', 'MPA', (80, 88))	('mutations', 'Var', (104, 113))	('ATRX', 'Gene', (130, 134))	('brain tumors', 'Disease', 'MESH:D001932', (176, 188))	('IDH1', 'Gene', '3417', (162, 166))	('tumors', 'Phenotype', 'HP:0002664', (182, 188))	('brain tumors', 'Phenotype', 'HP:0030692', (176, 188))	('TP53', 'Gene', '7157', (136, 140))	('ATRX', 'Gene', '546', (130, 134))	('EGFR', 'Gene', '1956', (204, 208))	('oncogenic pathway', 'Pathway', (49, 66))	('EGFR', 'Gene', (204, 208))	('TP53', 'Gene', (136, 140))	('PTEN', 'Gene', (199, 203))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))	('IDH1', 'Gene', (162, 166))
107737	25484917	Other intriguing observations include a mutual exclusion in lower grade glioma between ATRX and CIC, a transcriptional repressor that may play a role in development of the central nervous system, and mutual exclusion in uterine corpus endometrial carcinoma between mutations at TP53 and SWI/SNF remodeling complex protein ARID1A (Additional file 5: Table S2).	('glioma', 'Disease', (72, 78))	('mutations', 'Var', (265, 274))	('TP53', 'Gene', '7157', (278, 282))	('TP53', 'Gene', (278, 282))	('ARID1A', 'Gene', (322, 328))	('ATRX', 'Gene', '546', (87, 91))	('glioma', 'Phenotype', 'HP:0009733', (72, 78))	('ATRX', 'Gene', (87, 91))	('glioma', 'Disease', 'MESH:D005910', (72, 78))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (235, 256))	('CIC', 'Gene', '23152', (96, 99))	('ARID1A', 'Gene', '8289', (322, 328))	('endometrial carcinoma', 'Disease', (235, 256))	('carcinoma', 'Phenotype', 'HP:0030731', (247, 256))	('SWI/SNF', 'Gene', (287, 294))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (235, 256))	('CIC', 'Gene', (96, 99))
107739	25484917	We find that some of the changes observed in the cancer epigenome can be associated with a hyperproliferative phenotype, a hallmark of cancer.	('hallmark of cancer', 'Disease', 'MESH:D009369', (123, 141))	('cancer', 'Disease', (135, 141))	('cancer', 'Disease', 'MESH:D009369', (135, 141))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('associated', 'Reg', (73, 83))	('hyperproliferative phenotype', 'Disease', (91, 119))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('changes', 'Var', (25, 32))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('hallmark of cancer', 'Disease', (123, 141))	('cancer', 'Disease', (49, 55))
107742	25484917	We also find that the only two proteins known to act as direct links between histone methylation and the DNA replication machinery, ORC1 (that binds to H4K20me3 and recruits the origin of replication complex at replication origins) and UHRF1 (that binds H3K9me3 and recruits DNMT1 to hemi-methylated cytosines), are among the five most frequently overexpressed chromatin factors across all cancer types studied (Additional file 2: Figure S1B).	('DNMT1', 'Gene', (275, 280))	('ORC1', 'Gene', '4998', (132, 136))	('UHRF1', 'Gene', (236, 241))	('cancer', 'Disease', 'MESH:D009369', (390, 396))	('DNMT1', 'Gene', '1786', (275, 280))	('UHRF1', 'Gene', '29128', (236, 241))	('cancer', 'Disease', (390, 396))	('H3', 'Gene', '126961', (254, 256))	('ORC1', 'Gene', (132, 136))	('recruits', 'PosReg', (165, 173))	('cancer', 'Phenotype', 'HP:0002664', (390, 396))	('H4K20me3', 'Var', (152, 160))
107743	25484917	Another histone chaperone that is significantly overexpressed - actually the most frequently overexpressed chromatin factor in cancer - is HJURP, a chaperone of the histone H3 variant CENP-A, which facilitates aneuploidy and genome instability, another hallmark of cancer (Additional file 2: Figure S1B; Table 1).	('CENP-A', 'Gene', '1058', (184, 190))	('aneuploidy', 'Disease', (210, 220))	('variant', 'Var', (176, 183))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('cancer', 'Disease', 'MESH:D009369', (265, 271))	('genome instability', 'CPA', (225, 243))	('CENP-A', 'Gene', (184, 190))	('hallmark of cancer', 'Disease', 'MESH:D009369', (253, 271))	('HJURP', 'Gene', '55355', (139, 144))	('hallmark of cancer', 'Disease', (253, 271))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('aneuploidy', 'Disease', 'MESH:D000782', (210, 220))	('HJURP', 'Gene', (139, 144))	('cancer', 'Phenotype', 'HP:0002664', (265, 271))	('cancer', 'Disease', (127, 133))	('cancer', 'Disease', (265, 271))	('H3', 'Gene', '126961', (173, 175))	('facilitates', 'PosReg', (198, 209))
107752	25484917	Additionally, ATRX is responsible for the incorporation H3.3 at telomeres, and its mutation can cause alternative telomere lengthening, associated with increased genomic instability.	('increased', 'PosReg', (152, 161))	('ATRX', 'Gene', (14, 18))	('H3', 'Gene', '126961', (56, 58))	('cause', 'Reg', (96, 101))	('mutation', 'Var', (83, 91))	('genomic', 'MPA', (162, 169))	('ATRX', 'Gene', '546', (14, 18))	('alternative telomere lengthening', 'MPA', (102, 134))
107753	25484917	These observations strongly suggest that genetic or transcriptional aberrations targeting chromatin factors in cancer favor replication and contribute to genome instability.	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('contribute', 'Reg', (140, 150))	('favor', 'PosReg', (118, 123))	('chromatin factors', 'Protein', (90, 107))	('replication', 'CPA', (124, 135))	('aberrations', 'Var', (68, 79))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('genome instability', 'MPA', (154, 172))
107755	25484917	Cancer genomes generally have large numbers of 'passenger' mutations and a small number of driver genetic events.	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('mutations', 'Var', (59, 68))	("'passenger'", 'PosReg', (47, 58))
107757	25484917	To identify candidate drivers affecting epigenetic mechanisms, we looked for correlations between copy number gains and overexpression of chromatin factors in cancer samples compared with matched normal samples.	('cancer', 'Disease', (159, 165))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('copy number', 'Var', (98, 109))
107760	25484917	Amplification of the SETDB1 gene in lung cancer was recently shown to contribute to lung tumorigenesis, and shRNA-mediated depletion of SETDB1 in amplified cells reduced tumor growth in a mouse xenograft model.	('SETDB1', 'Gene', (136, 142))	('lung cancer', 'Disease', (36, 47))	('mouse', 'Species', '10090', (188, 193))	('Amplification', 'Var', (0, 13))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('reduced', 'NegReg', (162, 169))	('SETDB1', 'Gene', (21, 27))	('lung cancer', 'Disease', 'MESH:D008175', (36, 47))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('tumor', 'Disease', (170, 175))	('depletion', 'Var', (123, 132))	('contribute', 'Reg', (70, 80))	('lung cancer', 'Phenotype', 'HP:0100526', (36, 47))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
107764	25484917	Interestingly, knockdown of WHSC1L1 results in profound loss of growth survival of 8p11-12 amplified breast cancer cells, but not control MCF10A cells.	('MCF10A', 'CellLine', 'CVCL:0598', (138, 144))	('loss', 'NegReg', (56, 60))	('knockdown', 'Var', (15, 24))	('WHSC1L1', 'Gene', (28, 35))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('breast cancer', 'Disease', 'MESH:D001943', (101, 114))	('WHSC1L1', 'Gene', '54904', (28, 35))	('growth survival', 'CPA', (64, 79))	('breast cancer', 'Disease', (101, 114))	('breast cancer', 'Phenotype', 'HP:0003002', (101, 114))
107765	25484917	These results suggest that amplification of WHSC1L1 drives cancer in a subset of breast cancer patients.	('cancer', 'Disease', (88, 94))	('WHSC1L1', 'Gene', '54904', (44, 51))	('breast cancer', 'Disease', (81, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('patients', 'Species', '9606', (95, 103))	('breast cancer', 'Phenotype', 'HP:0003002', (81, 94))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('drives', 'Reg', (52, 58))	('amplification', 'Var', (27, 40))	('WHSC1L1', 'Gene', (44, 51))	('breast cancer', 'Disease', 'MESH:D001943', (81, 94))
107772	25484917	Together, these results show that overall copy number variation do not appear to drive transcriptional de-regulation of most chromatin factors and are therefore likely to be passenger events in cancer.	('cancer', 'Disease', (194, 200))	('transcriptional', 'MPA', (87, 102))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('copy number variation', 'Var', (42, 63))	('cancer', 'Disease', 'MESH:D009369', (194, 200))
107777	25484917	Specific combinations of post-translational modifications of DNA and histones at distinct genomic elements control chromatin compaction, nucleosome occupancy, and gene activation status: histone acetylation and H3K4 di- or tri-methylation at promoters, H3K4 mono-methylation at enhancers and tri-methylation of H3K36 as well as DNA methylation in gene bodies are associated with transcriptionally active genes.	('associated', 'Reg', (363, 373))	('H3', 'Gene', '126961', (311, 313))	('H3', 'Gene', '126961', (253, 255))	('tri-methylation', 'Var', (292, 307))	('H3', 'Gene', '126961', (211, 213))
107778	25484917	Promoters tri-methylated at H3K4 and H3K27 are thought to be in a state that is transcriptionally repressed, but 'poised' for rapid activation upon demethylation of H3K37.	('H3', 'Gene', '126961', (165, 167))	('H3K27', 'Gene', '126961', (37, 42))	('H3K27', 'Gene', (37, 42))	('H3', 'Gene', '126961', (28, 30))	('H3', 'Gene', '126961', (37, 39))	('tri-methylated', 'Var', (10, 24))
107779	25484917	Finally, tri-methylated H3K9 and methylated DNA at enhancers, or a combination of these two marks with trimethylated H3K27 at promoters, is associated with gene silencing (Figure 6A,B).	('H3K27', 'Gene', (117, 122))	('H3K27', 'Gene', '126961', (117, 122))	('gene', 'MPA', (156, 160))	('H3', 'Gene', '126961', (117, 119))	('H3', 'Gene', '126961', (24, 26))	('methylated', 'Var', (33, 43))
107780	25484917	Intriguingly, we find that enzymes that deposit histone marks associated with gene activation, such as the H3K4 trimethylases MLL1-4 and SETD1A/B, or the H3K36 trimethylase SETD2 are more often repressed and mutated in cancer (Figure 6C).	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('SETD2', 'Gene', (173, 178))	('MLL1', 'Gene', '4297', (126, 130))	('H3', 'Gene', '126961', (154, 156))	('SETD1A/B', 'Gene', (137, 145))	('SETD1A/B', 'Gene', '9739', (137, 145))	('cancer', 'Disease', 'MESH:D009369', (219, 225))	('H3', 'Gene', '126961', (107, 109))	('mutated', 'Var', (208, 215))	('cancer', 'Disease', (219, 225))	('MLL1', 'Gene', (126, 130))	('repressed', 'MPA', (194, 203))	('SETD2', 'Gene', '29072', (173, 178))
107788	25484917	Some of the emerging epigenetic drugs, such as bromodomain, protein methyltransferase, or IDH1 inhibitors, are targeting patient group with clear oncogenic chromosomal aberrations such as gene fusions at BRD4 and MLL1, or mutations at IDH1.	('IDH1', 'Gene', (90, 94))	('chromosomal aberrations', 'Disease', (156, 179))	('BRD4', 'Gene', (204, 208))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (156, 179))	('chromosomal aberrations', 'Disease', 'MESH:D002869', (156, 179))	('IDH1', 'Gene', (235, 239))	('MLL1', 'Gene', '4297', (213, 217))	('IDH1', 'Gene', '3417', (90, 94))	('IDH1', 'Gene', '3417', (235, 239))	('chromosomal aberration', 'Phenotype', 'HP:0040012', (156, 178))	('mutations', 'Var', (222, 231))	('BRD4', 'Gene', '23476', (204, 208))	('patient', 'Species', '9606', (121, 128))	('MLL1', 'Gene', (213, 217))
107789	25484917	Translocations are not included in our analysis, but IDH1 mutations are high on our chromatin factor mutation landscape (Additional file 2: Figure S1A).	('mutations', 'Var', (58, 67))	('IDH1', 'Gene', '3417', (53, 57))	('IDH1', 'Gene', (53, 57))
107790	25484917	Other peaks, such as ATRX mutations in lower grade glioma or ARID1A mutations in endometrial cancer and stomach adenocarcinoma may represent other points of entry for therapeutic intervention.	('stomach adenocarcinoma', 'Disease', (104, 126))	('endometrial cancer', 'Phenotype', 'HP:0012114', (81, 99))	('glioma', 'Disease', (51, 57))	('ARID1A', 'Gene', (61, 67))	('endometrial cancer', 'Disease', 'MESH:D016889', (81, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('ATRX', 'Gene', (21, 25))	('glioma', 'Disease', 'MESH:D005910', (51, 57))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('glioma', 'Phenotype', 'HP:0009733', (51, 57))	('mutations', 'Var', (26, 35))	('ATRX', 'Gene', '546', (21, 25))	('endometrial cancer', 'Disease', (81, 99))	('mutations', 'Var', (68, 77))	('stomach adenocarcinoma', 'Disease', 'MESH:D013274', (104, 126))	('ARID1A', 'Gene', '8289', (61, 67))
107795	25484917	It has been proposed that most epigenetic-associated mutations are observed in hematological, in pediatric, or in rare and aggressive variants of solid tumors.	('solid tumors', 'Disease', 'MESH:D009369', (146, 158))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('observed', 'Reg', (67, 75))	('mutations', 'Var', (53, 62))	('hematological', 'Disease', (79, 92))	('solid tumors', 'Disease', (146, 158))	('tumors', 'Phenotype', 'HP:0002664', (152, 158))	('epigenetic-associated mutations', 'Var', (31, 62))
107811	25484917	This is in agreement with previous work showing that some cancer types are particularly enriched in false mutation calling.	('false mutation calling', 'Var', (100, 122))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('cancer', 'Disease', (58, 64))
107818	25484917	GISTIC values are used to evaluate copy number variations relative to the reference genome (hg18 for COAD/READ, LAML and OV; hg19 for all other cancer types).	('COAD', 'Disease', 'MESH:D029424', (101, 105))	('AML', 'Disease', 'MESH:D015470', (113, 116))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('cancer', 'Disease', (144, 150))	('COAD', 'Disease', (101, 105))	('AML', 'Phenotype', 'HP:0004808', (113, 116))	('AML', 'Disease', (113, 116))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('copy number variations', 'Var', (35, 57))
107823	25484917	Mutation hotspots were defined as aminoacids affected by a minimum of three mutations representing at least 20% of non-silent mutations for that gene in a given cancer type.	('cancer', 'Disease', (161, 167))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('mutations', 'Var', (76, 85))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))
107842	25109877	For example, patterns of copy number change varied across tissue types, and subtyping of the tumors based on copy number alterations revealed a significant correlation with tissue (p < 6x10-6, Chi-square test).	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumors', 'Disease', 'MESH:D009369', (93, 99))	('copy', 'Var', (25, 29))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('tumors', 'Disease', (93, 99))
107850	25109877	Of the 11 COCA-integrated subtypes, five show simple, near one-to-one relationships with tissue site of origin: C5-KIRC, C6-UCEC, C9-OV, C10-GBM and C13-LAML (Figure 1A).	('AML', 'Disease', 'MESH:D015470', (154, 157))	('C5-KIRC', 'Var', (112, 119))	('COCA', 'Species', '289672', (10, 14))	('AML', 'Disease', (154, 157))	('C9-OV', 'Var', (130, 135))	('C10-GBM', 'Var', (137, 144))
107855	25109877	That difficulty poses an important clinical challenge since histology is used to guide the selection of chemotherapy and to select patients for further mutational analysis (e.g., EGFR mutation and ALK fusion testing in non-squamous NSCLC).	('EGFR', 'Gene', (179, 183))	('patients', 'Species', '9606', (131, 139))	('ALK', 'Gene', (197, 200))	('NSCLC', 'Disease', (232, 237))	('ALK', 'Gene', '238', (197, 200))	('NSCLC', 'Disease', 'MESH:D002289', (232, 237))	('EGFR', 'Gene', '1956', (179, 183))	('mutation', 'Var', (184, 192))
107879	25109877	We next identified the major genomic determinants of the COCA subtypes, including somatic mutations and DNA copy number changes.	('COCA', 'Species', '289672', (57, 61))	('mutations', 'Var', (90, 99))	('COCA', 'Disease', (57, 61))
107883	25109877	KEAP1 and STK11 are preferentially mutated in C1-LUAD-enriched tumors, whereas CDKN2A, NOTCH1, MLL2 and NFE2L2, among others, are preferentially mutated in C2-Squamous-like (Figure 2A).	('mutated', 'Var', (35, 42))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('STK11', 'Gene', (10, 15))	('C1-LUAD-enriched tumors', 'Disease', 'MESH:C565170', (46, 69))	('C2-Squamous-like', 'Disease', (156, 172))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('C1-LUAD-enriched tumors', 'Disease', (46, 69))	('CDKN2A', 'Gene', (79, 85))
107886	25109877	A protein-protein interaction network analysis of mutations associated with the COCA subtypes obtained using a new version of the HotNet algorithm provides an overview of the genomic determinants of the COCA subtypes (Figure S4E).	('mutations', 'Var', (50, 59))	('COCA', 'Species', '289672', (203, 207))	('COCA', 'Species', '289672', (80, 84))	('COCA', 'Disease', (203, 207))
107887	25109877	The C9-OV, C4-BRCA/Basal and C1-LUAD-enriched subtypes showed the most marked genomic instability, as assessed by average number of copy number segments per subtype (Figure 2C), whereas AML and UCEC showed the least.	('AML', 'Disease', 'MESH:D015470', (186, 189))	('C4-BRCA/Basal', 'Var', (11, 24))	('AML', 'Disease', (186, 189))	('genomic instability', 'CPA', (78, 97))	('C9-OV', 'Var', (4, 9))
107888	25109877	Numerous COCA subtype-associated alterations implicated specific regions, arm-level copy number changes (Figure S4A) and/or focal regions of copy number alteration (Figure S4B).	('COCA', 'Species', '289672', (9, 13))	('alterations', 'Var', (33, 44))	('COCA', 'Disease', (9, 13))
107889	25109877	Of note were a number of previously described tissue type-specific and subtype-specific alterations, including Chr7 gain and Chr10 loss in GBM, 3p loss and 5q gain in kidney, 4q and 5q loss in Breast Basal-like cancers and 3p loss and 3q gain in Lung Squamous tumors.	('kidney', 'Disease', (167, 173))	('Chr10', 'Gene', (125, 130))	('loss', 'NegReg', (147, 151))	('loss', 'NegReg', (226, 230))	('4q and', 'Var', (175, 181))	('tumors', 'Phenotype', 'HP:0002664', (260, 266))	('Basal-like cancers', 'Phenotype', 'HP:0002671', (200, 218))	('loss', 'NegReg', (131, 135))	('tumor', 'Phenotype', 'HP:0002664', (260, 265))	('loss', 'NegReg', (185, 189))	('Chr7', 'Gene', (111, 115))	('gain in Lung Squamous tumors', 'Disease', 'MESH:D015430', (238, 266))	('gain in Lung Squamous tumors', 'Disease', (238, 266))	('gain', 'PosReg', (159, 163))	('Breast Basal-like cancers', 'Disease', 'MESH:D001943', (193, 218))	('cancers', 'Phenotype', 'HP:0002664', (211, 218))	('Breast Basal-like cancers', 'Disease', (193, 218))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('gain', 'PosReg', (116, 120))
107896	25109877	Intriguingly, GP7, along with fatty acid oxidation (GP10), tumor suppressing miRNA targets (GP3) and the PTEN/MTOR signaling program, were found to be significantly associated with patient outcome in kidney cancer using a Cox proportional hazards survival analysis (Figure S5D; Table S4F).	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Disease', (59, 64))	('MTOR', 'Gene', '2475', (110, 114))	('patient', 'Species', '9606', (181, 188))	('PTEN', 'Gene', (105, 109))	('PTEN', 'Gene', '5728', (105, 109))	('associated with', 'Reg', (165, 180))	('GP7', 'Var', (14, 17))	('kidney cancer', 'Disease', 'MESH:D007680', (200, 213))	('kidney cancer', 'Phenotype', 'HP:0009726', (200, 213))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('fatty acid', 'Chemical', 'MESH:D005227', (30, 40))	('kidney cancer', 'Disease', (200, 213))	('MTOR', 'Gene', (110, 114))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
107910	25109877	The identified discriminating features of the COCA subtypes confirm several expectations: 1) C3-BRCA/Luminal was defined by protein and gene signatures for ER and GATA3 determined by the Elastic Net model as well as by PIK3CA-related signaling revealed by copy number variation-based and mutation-based GSEA, 2) C5-KIRC was defined by multiple features of hypoxia found by mutation- and mRNA-Seq-based GSEA as well as predictive Elastic Net features, and 3) C7-COAD/READ was in part defined by APC mutations.	('C7-COAD/READ', 'Disease', 'MESH:C566443', (458, 470))	('mutations', 'Var', (498, 507))	('C7-COAD/READ', 'Disease', (458, 470))	('APC', 'Disease', 'MESH:D011125', (494, 497))	('APC', 'Disease', (494, 497))	('hypoxia', 'Disease', 'MESH:D000860', (356, 363))	('mutation-', 'Var', (373, 382))	('hypoxia', 'Disease', (356, 363))	('COCA', 'Species', '289672', (46, 50))
107914	25109877	TP53 mutation is frequent (72%), followed by a dramatic drop-off in mutation frequency to MLL2 (20%), PIK3CA (19%), CDKN2A (18%), NOTCH1 (16%), NFE2L2 (10%) and MALAT1 (6%), the only other genes mutated at >=10% frequency (Table S2A).	('MLL2', 'Gene', (90, 94))	('mutation frequency', 'MPA', (68, 86))	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('PIK3CA', 'Gene', (102, 108))	('CDKN2A', 'Gene', (116, 122))	('NOTCH1', 'Gene', (130, 136))	('MALAT1', 'Gene', (161, 167))	('NFE2L2', 'Gene', (144, 150))	('mutation', 'Var', (5, 13))	('drop-off', 'NegReg', (56, 64))
107915	25109877	Of potential interest in the C2-Squamous-like group, tumors without TP53 mutations show a higher density of PIK3CA mutations (Figure 1), consistent with recent evidence linking PI3K activation and wild-type TP53 inactivation in HNSC.	('mutations', 'Var', (115, 124))	('TP53', 'Gene', '7157', (207, 211))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('TP53', 'Gene', (207, 211))	('PIK3CA', 'Gene', (108, 114))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('TP53', 'Gene', '7157', (68, 72))	('TP53', 'Gene', (68, 72))	('tumors', 'Disease', (53, 59))	('mutations', 'Var', (73, 82))
107916	25109877	Putative driver analysis identified several genes (PIK3CA, MLL3 and KEAP1) frequently mutated in the C2-Squamous-like group but also in other COCA subtypes (Figure 4B).	('mutated', 'Var', (86, 93))	('KEAP1', 'Gene', (68, 73))	('C2-Squamous-like', 'Disease', (101, 117))	('MLL3', 'Gene', (59, 63))	('PIK3CA', 'Gene', (51, 57))	('COCA', 'Species', '289672', (142, 146))	('COCA', 'Disease', (142, 146))
107917	25109877	Putative driver analysis also revealed a number of genes with higher mutation frequencies in the C2-Squamous-like subtype than in any other subtype: TP53, SYNE1, MLL2, CDKN2A, NOTCH1, NFE2L2 and EP300, among others (Figure 4C; Figure S7A).	('MLL2', 'Gene', (162, 166))	('C2-Squamous-like subtype', 'Disease', (97, 121))	('TP53', 'Gene', '7157', (149, 153))	('mutation', 'Var', (69, 77))	('higher', 'PosReg', (62, 68))	('CDKN2A', 'Gene', (168, 174))	('TP53', 'Gene', (149, 153))	('EP300', 'Var', (195, 200))	('NFE2L2', 'Gene', (184, 190))	('NOTCH1', 'Gene', (176, 182))
107921	25109877	The C9-OV (94%), C4-BRCA/Basal (80%) and C2-Squamous-like (72%) subtypes have the highest frequencies of TP53 mutation.	('TP53', 'Gene', '7157', (105, 109))	('mutation', 'Var', (110, 118))	('TP53', 'Gene', (105, 109))
107924	25109877	All six of those subtypes show TP53 mutation and large-scale copy number changes.	('TP53', 'Gene', '7157', (31, 35))	('copy', 'MPA', (61, 65))	('TP53', 'Gene', (31, 35))	('mutation', 'Var', (36, 44))
107928	25109877	In addition, both subtypes show up-regulation of the proliferation/DNA synthesis gene program (GP1), as well as signatures of TP53 mutation, MYC targets/TERT, VEGF signaling and activation of the PD1 and CTLA4 immune co-stimulatory pathways (Table S4A, Figure 3).	('CTLA4 immune co-stimulatory pathways', 'Pathway', (204, 240))	('TP53', 'Gene', (126, 130))	('MYC targets/TERT', 'MPA', (141, 157))	('activation', 'PosReg', (178, 188))	('up-regulation', 'PosReg', (32, 45))	('GP1', 'Gene', (95, 98))	('TP53', 'Gene', '7157', (126, 130))	('mutation', 'Var', (131, 139))
107934	25109877	High TP53 mutation rates characterize several tumor types including those represented by the COCA subtypes C4-BRCA/Basal, C9-OV, and C2-Squamous-like (Table S2A).	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('C9-OV', 'Disease', (122, 127))	('tumor', 'Disease', (46, 51))	('mutation', 'Var', (10, 18))	('C4-BRCA/Basal', 'Disease', (107, 120))	('COCA', 'Species', '289672', (93, 97))	('TP53', 'Gene', '7157', (5, 9))	('TP53', 'Gene', (5, 9))	('C2-Squamous-like', 'Disease', (133, 149))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
107937	25109877	Second, the copy number data when aligned with TP53 missense and truncating mutations, reveals more loss of heterozygosity (LOH) in the C9-OV and C4-BRCA/Basal than in the C2-Squamous-like samples.	('C9-OV', 'Disease', (136, 141))	('C4-BRCA/Basal', 'Var', (146, 159))	('heterozygosity', 'MPA', (108, 122))	('TP53', 'Gene', '7157', (47, 51))	('TP53', 'Gene', (47, 51))	('loss', 'NegReg', (100, 104))
107938	25109877	The apparent higher TP53-pathway activity in C2-Squamous-like tumors may be related to the expression of isoforms of related family members TP63 and/or TP73 (Figure 5B), which may compensate for TP53 mutation in the C2-Squamous-like tumors as revealed by PARADIGM-Shift analysis (Figure 5C), and as supported by functional experimental data in HNSC lines and tumors.	('C2-Squamous-like tumors', 'Disease', 'OMIM:217000', (216, 239))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('activity', 'MPA', (33, 41))	('TP53', 'Gene', (195, 199))	('TP53', 'Gene', (20, 24))	('TP73', 'Var', (152, 156))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('higher', 'PosReg', (13, 19))	('C2-Squamous-like tumors', 'Disease', (216, 239))	('mutation', 'Var', (200, 208))	('Squamous-like tumors', 'Phenotype', 'HP:0002860', (48, 68))	('C2-Squamous-like tumors', 'Disease', 'OMIM:217000', (45, 68))	('tumors', 'Phenotype', 'HP:0002664', (233, 239))	('tumors', 'Phenotype', 'HP:0002664', (359, 365))	('HNSC lines and tumors', 'Disease', 'MESH:D009369', (344, 365))	('TP63', 'Var', (140, 144))	('TP53', 'Gene', '7157', (195, 199))	('TP53', 'Gene', '7157', (20, 24))	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('tumor', 'Phenotype', 'HP:0002664', (359, 364))	('RA', 'Disease', 'MESH:D001172', (257, 259))	('C2-Squamous-like tumors', 'Disease', (45, 68))	('Squamous-like tumors', 'Phenotype', 'HP:0002860', (219, 239))
107939	25109877	Third, the transcriptional targets of TP53 shared with TP63/73 appear to be more highly expressed in the C2-Squamous-like subtype than in the C9-OV or C4-BRCA/Basal subtype (Figure S7D).	('highly expressed', 'PosReg', (81, 97))	('TP53', 'Gene', (38, 42))	('C2-Squamous-like', 'Disease', (105, 121))	('TP63/73', 'Var', (55, 62))	('TP53', 'Gene', '7157', (38, 42))
107944	25109877	These studies show the potential for p63/73 compensatory function for mutated or suppressed p53 in HNSCC and breast cancer, which has potential implications for targeted and standard therapy across these malignancies.	('malignancies', 'Disease', (204, 216))	('suppressed', 'NegReg', (81, 91))	('HNSCC', 'Disease', 'MESH:D000077195', (99, 104))	('breast cancer', 'Disease', (109, 122))	('breast cancer', 'Phenotype', 'HP:0003002', (109, 122))	('breast cancer', 'Disease', 'MESH:D001943', (109, 122))	('p53', 'Gene', (92, 95))	('malignancies', 'Disease', 'MESH:D009369', (204, 216))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('HNSCC', 'Disease', (99, 104))	('mutated', 'Var', (70, 77))	('p63/73', 'Var', (37, 43))
107953	25109877	There are significant differences in copy number (Figure S4A), protein expression (Figure 6B), mutations (Figure 6C), gene programs (Figure 6D) and PARADIGM pathway networks (Figure 6E; Figure S8A).	('copy', 'Var', (37, 41))	('gene programs', 'CPA', (118, 131))	('protein', 'Protein', (63, 70))	('RA', 'Disease', 'MESH:D001172', (150, 152))	('mutations', 'Var', (95, 104))
107954	25109877	There is also a significant difference in 3p arm-level events; the C2-Squamous-like subset shows the characteristic squamous-like pattern of 3p loss, whereas the C8-BLCA subtype does not (Figure 2B).	('squamous-like pattern', 'Phenotype', 'HP:0002860', (116, 137))	('C8-BLCA', 'Chemical', '-', (162, 169))	('loss', 'NegReg', (144, 148))	('C2-Squamous-like', 'Var', (67, 83))
107956	25109877	Conversely, markers of epithelial-to-mesenchymal transition (EMT) such as low E-cadherin, high fibronectin, and high N-cadherin expression are apparent in the C2-Squamous-like bladder cancers (Figure 6B).	('cancers', 'Phenotype', 'HP:0002664', (184, 191))	('C2-Squamous-like bladder cancers', 'Disease', (159, 191))	('low', 'NegReg', (74, 77))	('C2-Squamous-like bladder cancers', 'Disease', 'OMIM:217000', (159, 191))	('high', 'Var', (112, 116))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('bladder cancer', 'Phenotype', 'HP:0009725', (176, 190))	('epithelial-to-mesenchymal transition', 'CPA', (23, 59))	('bladder cancers', 'Phenotype', 'HP:0009725', (176, 191))	('N-cadherin', 'Protein', (117, 127))	('E-cadherin', 'Protein', (78, 88))	('expression', 'MPA', (128, 138))	('high', 'Var', (90, 94))
107961	25109877	With respect to its therapeutic relevance, this proportion of potentially misclassified tumors is comparable to the rate of EGFR mutations in unselected non-small cell lung cancers and ERBB2 amplifications among all breast cancers.	('small cell lung cancers', 'Phenotype', 'HP:0030357', (157, 180))	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('EGFR', 'Gene', '1956', (124, 128))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('cancers', 'Phenotype', 'HP:0002664', (223, 230))	('cancers', 'Phenotype', 'HP:0002664', (173, 180))	('breast cancer', 'Phenotype', 'HP:0003002', (216, 229))	('breast cancers', 'Disease', 'MESH:D001943', (216, 230))	('breast cancers', 'Disease', (216, 230))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('non-small cell lung cancers', 'Phenotype', 'HP:0030358', (153, 180))	('cell lung cancers', 'Disease', 'MESH:D008175', (163, 180))	('lung cancers', 'Phenotype', 'HP:0100526', (168, 180))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('cell lung cancers', 'Disease', (163, 180))	('breast cancers', 'Phenotype', 'HP:0003002', (216, 230))	('mutations', 'Var', (129, 138))	('ERBB2', 'Gene', (185, 190))	('EGFR', 'Gene', (124, 128))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumors', 'Disease', (88, 94))
107970	25109877	oral cavity, lungs, and bladder); and malignancies from this cellular subtype possess a characteristic set of dysregulated genomic features, including SOX2 and DeltaNp63 high expression (by 3q26-29 amplification) with TP53 mutation.	('malignancies', 'Disease', 'MESH:D009369', (38, 50))	('TP53', 'Gene', '7157', (218, 222))	('mutation', 'Var', (223, 231))	('malignancies', 'Disease', (38, 50))	('TP53', 'Gene', (218, 222))
107973	25109877	While all three COCA subtypes exhibit comparably high TP53 mutation frequencies and expression of the GP17_Basal signaling gene program, the C2-Squamous-like cancers are distinguished from all others by their significantly higher TP63 and TP73 expression, both short (DeltaNp63, DeltaNp73) and long (TAp63, TAp73) isoforms, which may partially compensate TP53 mutation in this COCA subtype.	('COCA', 'Species', '289672', (16, 20))	('C2-Squamous-like cancers', 'Disease', 'OMIM:217000', (141, 165))	('COCA', 'Species', '289672', (377, 381))	('TP53', 'Gene', '7157', (355, 359))	('C2-Squamous-like cancers', 'Disease', (141, 165))	('TP53', 'Gene', (355, 359))	('cancers', 'Phenotype', 'HP:0002664', (158, 165))	('TP73', 'Protein', (239, 243))	('TP53', 'Gene', '7157', (54, 58))	('TP63', 'Protein', (230, 234))	('mutation', 'Var', (59, 67))	('DeltaNp73', 'Var', (279, 288))	('expression', 'MPA', (244, 254))	('higher', 'PosReg', (223, 229))	('TP53', 'Gene', (54, 58))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
108106	33119806	Preoperative diagnoses were M, less, Type 0-IIc, ycT1a, ycN0, ycM0 ycStage I and L, Gre, Type 0-IIa, ycT1a, ycN0, ycM0, ycStage I according to the Japanese Classification of Gastric Carcinoma 15th edition.	('Gastric Carcinoma', 'Disease', (174, 191))	('Carcinoma', 'Phenotype', 'HP:0030731', (182, 191))	('ycT1a', 'Var', (101, 106))	('ycStage I', 'Var', (120, 129))	('Gastric Carcinoma', 'Disease', 'MESH:D013274', (174, 191))	('ycM0', 'Var', (114, 118))	('ycM0 ycStage I', 'Var', (62, 76))	('ycN0', 'Var', (108, 112))	('ycN0', 'Var', (56, 60))	('Gastric Carcinoma', 'Phenotype', 'HP:0012126', (174, 191))
108114	33119806	reported a patient with gastric adenocarcinoma (cT1bN0M0 Stage IA) and lung adenocarcinoma (cT1aN3M1a Stage IV) who had achieved a good response for 3 months with nivolumab.	('cT1bN0M0', 'Var', (48, 56))	('cT1aN3M1a', 'Var', (92, 101))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (71, 90))	('carcinoma', 'Phenotype', 'HP:0030731', (37, 46))	('lung adenocarcinoma', 'Disease', (71, 90))	('gastric adenocarcinoma', 'Disease', 'MESH:D013274', (24, 46))	('patient', 'Species', '9606', (11, 18))	('gastric adenocarcinoma', 'Disease', (24, 46))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (71, 90))	('nivolumab', 'Chemical', 'MESH:D000077594', (163, 172))
108115	33119806	of gastric adenocarcinoma (cT1bN0M0 Stage IA) and lung squamous cell carcinoma (cT4N3M1a Stage IVa), showing that each cancer had ameliorated and that the effect of nivolumab was maintained over 96 weeks.	('lung squamous cell carcinoma', 'Disease', (50, 78))	('ameliorated', 'PosReg', (130, 141))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (55, 78))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('gastric adenocarcinoma', 'Disease', 'MESH:D013274', (3, 25))	('gastric adenocarcinoma', 'Disease', (3, 25))	('nivolumab', 'Chemical', 'MESH:D000077594', (165, 174))	('carcinoma', 'Phenotype', 'HP:0030731', (16, 25))	('cancer', 'Disease', (119, 125))	('cT1bN0M0', 'Var', (27, 35))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (50, 78))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
108164	31819525	However, miR-301-3p and miR-132 enhanced the cell proliferation and tumor growth of LSCC.	('miR-301-3p', 'Var', (9, 19))	('tumor', 'Disease', (68, 73))	('miR-132', 'Gene', (24, 31))	('cell proliferation', 'CPA', (45, 63))	('LSCC', 'Disease', 'MESH:D002294', (84, 88))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('miR-132', 'Gene', '406921', (24, 31))	('enhanced', 'PosReg', (32, 40))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('LSCC', 'Disease', (84, 88))
108171	31819525	In this study, we evaluated the expression of miRNA 424-5p in LSCC tissues by qPCR and analyzed the association of miR-424-5p level and clinical features of LSCC.	('LSCC', 'Disease', 'MESH:D002294', (62, 66))	('LSCC', 'Disease', (157, 161))	('miRNA', 'Var', (46, 51))	('miR-424', 'Gene', (115, 122))	('LSCC', 'Disease', (62, 66))	('LSCC', 'Disease', 'MESH:D002294', (157, 161))	('miR-424', 'Gene', '494336', (115, 122))
108199	31819525	The mutant CADM1 3'UTR luciferase reporter was produced by overlapping extension PCR.	('CADM1', 'Gene', (11, 16))	('mutant', 'Var', (4, 10))	('CADM1', 'Gene', '23705', (11, 16))
108201	31819525	Briefly, cells were seeded in 24-well plates and co-transfected with NC or miR-424-5p mimics and WT or mutant CADM1 3' UTR reporter plasmid (0.1 mug/well).	('mutant', 'Var', (103, 109))	('miR-424', 'Gene', (75, 82))	('CADM1', 'Gene', (110, 115))	('CADM1', 'Gene', '23705', (110, 115))	('miR-424', 'Gene', '494336', (75, 82))
108237	31819525	The number of cells in the S and G2 phases was significantly increased after transfection with miR-424-5p mimics than the NC mimics, and the number of cells in the G1 phase was decreased (Figure 5A and B).	('miR-424', 'Gene', '494336', (95, 102))	('transfection', 'Var', (77, 89))	('increased', 'PosReg', (61, 70))	('miR-424', 'Gene', (95, 102))	('decreased', 'NegReg', (177, 186))
108253	31819525	However, Wei et al reported that miR-424-5p was upregulated in gastric cancer tissues, and restoration of miR-424-5p could promote the proliferation of gastric cancer cells.	('miR-424', 'Gene', '494336', (33, 40))	('gastric cancer', 'Disease', (63, 77))	('gastric cancer', 'Disease', 'MESH:D013274', (152, 166))	('gastric cancer', 'Disease', 'MESH:D013274', (63, 77))	('gastric cancer', 'Disease', (152, 166))	('miR-424', 'Gene', '494336', (106, 113))	('promote', 'PosReg', (123, 130))	('gastric cancer', 'Phenotype', 'HP:0012126', (63, 77))	('proliferation', 'CPA', (135, 148))	('miR-424', 'Gene', (33, 40))	('restoration', 'Var', (91, 102))	('gastric cancer', 'Phenotype', 'HP:0012126', (152, 166))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('upregulated', 'PosReg', (48, 59))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('miR-424', 'Gene', (106, 113))
108256	31819525	By contrast, upregulation of miR-424-5p in cancers involves more complex transcriptional and post-transcriptional mechanisms, such as dysregulated upstream transcription factors and long non-coding RNA.	('long non-coding RNA', 'Var', (182, 201))	('cancers', 'Phenotype', 'HP:0002664', (43, 50))	('cancers', 'Disease', (43, 50))	('cancers', 'Disease', 'MESH:D009369', (43, 50))	('upregulation', 'PosReg', (13, 25))	('miR-424', 'Gene', (29, 36))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('dysregulated', 'Var', (134, 146))	('miR-424', 'Gene', '494336', (29, 36))
108259	31819525	Clinical features associated with miRNAs play important regulatory roles in cancer progression, including miR-145-5p, miR-195 and miR-106b-5p.	('miR-145', 'Gene', '406937', (106, 113))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('miR-145', 'Gene', (106, 113))	('miR-195', 'Gene', (118, 125))	('miR-195', 'Gene', '406971', (118, 125))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('cancer', 'Disease', (76, 82))	('miR-106b-5p', 'Var', (130, 141))
108268	31819525	Furthermore, restoration of miR-424-5p expression enhanced the migration, invasion, and adhesion of LSCC cells.	('invasion', 'CPA', (74, 82))	('miR-424', 'Gene', (28, 35))	('LSCC', 'Disease', (100, 104))	('miR-424', 'Gene', '494336', (28, 35))	('adhesion', 'CPA', (88, 96))	('enhanced', 'PosReg', (50, 58))	('restoration', 'Var', (13, 24))	('migration', 'CPA', (63, 72))	('LSCC', 'Disease', 'MESH:D002294', (100, 104))
108331	28293540	When compared to those with low levels of intake, subjects in the highest intake level of beta-carotene, alpha-carotene, beta-cryptoxanthin, lycopene, and vitamin C had a statistically significant lower risk of lung cancer.	('beta-cryptoxanthin', 'Var', (121, 139))	('lower', 'NegReg', (197, 202))	('lung cancer', 'Phenotype', 'HP:0100526', (211, 222))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('vitamin C', 'Chemical', 'MESH:D001205', (155, 164))	('alpha-carotene', 'Chemical', 'MESH:C041635', (105, 119))	('lung cancer', 'Disease', 'MESH:D008175', (211, 222))	('lycopene', 'Chemical', 'MESH:D000077276', (141, 149))	('beta-cryptoxanthin', 'Chemical', 'MESH:D000072743', (121, 139))	('beta-carotene', 'Chemical', 'MESH:D019207', (90, 103))	('lung cancer', 'Disease', (211, 222))
108342	28293540	Among women in the intermediate smoking intensity category, intakes in the third tertile of beta-carotene and second tertiles of beta-cryptoxanthin, lycopene, and vitamin C were associated with a lower lung cancer risk, while both medium and high intakes of vitamin C showed an inverse relationship in heavy smoking women.	('vitamin C', 'Chemical', 'MESH:D001205', (258, 267))	('lung cancer', 'Disease', 'MESH:D008175', (202, 213))	('beta-carotene', 'Chemical', 'MESH:D019207', (92, 105))	('lung cancer', 'Disease', (202, 213))	('lower', 'NegReg', (196, 201))	('lung cancer', 'Phenotype', 'HP:0100526', (202, 213))	('beta-cryptoxanthin', 'Chemical', 'MESH:D000072743', (129, 147))	('vitamin C', 'Chemical', 'MESH:D001205', (163, 172))	('women', 'Species', '9606', (6, 11))	('high intakes of vitamin C', 'Phenotype', 'HP:0100510', (242, 267))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('beta-cryptoxanthin', 'Var', (129, 147))	('lycopene', 'Chemical', 'MESH:D000077276', (149, 157))	('women', 'Species', '9606', (316, 321))
108349	28293540	High intakes of beta-carotene, beta-cryptoxanthin, lutein/zeaxanthin, lycopene, and vitamin C were similarly associated with statistically non-significant increases in risk of large cell carcinoma, although it should be noted that these results were based on relatively few cases.	('carcinoma', 'Phenotype', 'HP:0030731', (187, 196))	('large cell carcinoma', 'Phenotype', 'HP:0030360', (176, 196))	('lutein', 'Chemical', 'MESH:D014975', (51, 57))	('beta-carotene', 'Chemical', 'MESH:D019207', (16, 29))	('lycopene', 'Chemical', 'MESH:D000077276', (70, 78))	('vitamin C', 'Chemical', 'MESH:D001205', (84, 93))	('zeaxanthin', 'Chemical', 'MESH:D065146', (58, 68))	('beta-cryptoxanthin', 'Chemical', 'MESH:D000072743', (31, 49))	('large cell carcinoma', 'Disease', (176, 196))	('beta-cryptoxanthin', 'Var', (31, 49))	('large cell carcinoma', 'Disease', 'MESH:D018287', (176, 196))
108353	28293540	In our study, high dietary intakes of beta-carotene, alpha-carotene, beta-cryptoxanthin, lycopene, and vitamin C were associated with a decreased risk of lung cancer in main effects analyses.	('lung cancer', 'Disease', (154, 165))	('beta-cryptoxanthin', 'Var', (69, 87))	('lung cancer', 'Phenotype', 'HP:0100526', (154, 165))	('vitamin C', 'Chemical', 'MESH:D001205', (103, 112))	('lycopene', 'Chemical', 'MESH:D000077276', (89, 97))	('alpha-carotene', 'Chemical', 'MESH:C041635', (53, 67))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('lung cancer', 'Disease', 'MESH:D008175', (154, 165))	('beta-carotene', 'Chemical', 'MESH:D019207', (38, 51))	('decreased', 'NegReg', (136, 145))	('beta-cryptoxanthin', 'Chemical', 'MESH:D000072743', (69, 87))
108357	28293540	We also found an inverse association between high intakes of vitamin C and lung cancer risk, a finding in line with two studies but at odds with another.	('lung cancer', 'Disease', (75, 86))	('lung cancer', 'Phenotype', 'HP:0100526', (75, 86))	('high intakes of vitamin C', 'Phenotype', 'HP:0100510', (45, 70))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('inverse', 'NegReg', (17, 24))	('high intakes', 'Var', (45, 57))	('lung cancer', 'Disease', 'MESH:D008175', (75, 86))	('vitamin C', 'Chemical', 'MESH:D001205', (61, 70))
108366	28293540	Our findings for beta-carotene are at odds with those from the CARET and the ATBC randomized controlled trials in which beta-carotene supplementation in smokers was associated with an increase in lung cancer incidence.	('men', 'Species', '9606', (140, 143))	('supplementation', 'Var', (134, 149))	('increase in lung cancer', 'Disease', (184, 207))	('lung cancer', 'Phenotype', 'HP:0100526', (196, 207))	('ATBC', 'Chemical', '-', (77, 81))	('beta-carotene', 'Chemical', 'MESH:D019207', (120, 133))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('beta-carotene', 'Chemical', 'MESH:D019207', (17, 30))	('beta-carotene', 'Protein', (120, 133))	('increase in lung cancer', 'Disease', 'MESH:D008175', (184, 207))
108369	28293540	We also found that women whose cumulative smoking history ranged from 1 to 850 cigarette-years benefited from intakes in the third tertile level of beta-carotene and in the second tertile level of beta-cryptoxanthin, lycopene, and vitamin C, findings not reported before.	('beta-cryptoxanthin', 'Chemical', 'MESH:D000072743', (197, 215))	('women', 'Species', '9606', (19, 24))	('benefited', 'PosReg', (95, 104))	('lycopene', 'Chemical', 'MESH:D000077276', (217, 225))	('vitamin C', 'Chemical', 'MESH:D001205', (231, 240))	('intakes', 'Var', (110, 117))	('beta-carotene', 'Chemical', 'MESH:D019207', (148, 161))
108377	28293540	beta-carotene, beta-cryptoxanthin, lutein, zeaxanthin, and lycopene may also inhibit cancerous cell proliferation and contribute to cell-to-cell communication.	('contribute', 'Reg', (118, 128))	('beta-cryptoxanthin', 'Chemical', 'MESH:D000072743', (15, 33))	('lycopene', 'Var', (59, 67))	('cell-to-cell communication', 'CPA', (132, 158))	('inhibit', 'NegReg', (77, 84))	('zeaxanthin', 'Chemical', 'MESH:D065146', (43, 53))	('lycopene', 'Chemical', 'MESH:D000077276', (59, 67))	('lutein', 'Chemical', 'MESH:D014975', (35, 41))	('cancerous', 'Disease', (85, 94))	('beta-carotene', 'Chemical', 'MESH:D019207', (0, 13))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('cancerous', 'Disease', 'MESH:D009369', (85, 94))
108459	27749580	The complexity of genetic alterations in lung SCC limits the application of molecular-targeted therapies.	('genetic alterations', 'Var', (18, 37))	('limits', 'NegReg', (50, 56))	('SCC', 'Gene', (46, 49))	('SCC', 'Phenotype', 'HP:0002860', (46, 49))	('SCC', 'Gene', '6317', (46, 49))
108496	27462454	Abrogating this negative regulation on DNMT3A or overexpression of DNMT3A leads to increased DNA methylation and impaired tumor growth.	('DNMT3A', 'Gene', (67, 73))	('increased', 'PosReg', (83, 92))	('impaired tumor growth', 'Disease', (113, 134))	('Abrogating', 'Var', (0, 10))	('impaired tumor growth', 'Disease', 'MESH:D006130', (113, 134))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('DNA methylation', 'MPA', (93, 108))
108497	27462454	We propose a working model that UHRF1/2 safeguards the fidelity of DNA methylation and suggests that UHRF1/2 overexpression is likely a causal factor for widespread DNA hypomethylation in cancer via suppressing DNMT3A.	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('DNMT3A', 'Gene', (211, 217))	('UHRF1/2', 'Gene', '18140;109113', (32, 39))	('UHRF1/2', 'Gene', '18140;109113', (101, 108))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('suppressing', 'NegReg', (199, 210))	('UHRF1/2', 'Gene', (101, 108))	('UHRF1/2', 'Gene', (32, 39))	('hypomethylation', 'Var', (169, 184))	('cancer', 'Disease', (188, 194))
108498	27462454	In mammals, DNA methylation at cytosine-C5 in the context of CpG dinucleotides is a key epigenetic modification required for embryonic development, transcriptional regulation, heterochromatin formation, X-inactivation, imprinting and genome stability.	('DNA', 'Var', (12, 15))	('methylation', 'Var', (16, 27))	('dinucleotides', 'Chemical', 'MESH:D015226', (65, 78))
108501	27462454	Interestingly, although the mammalian genome also encodes a highly similar protein named UHRF2 (also known as NIRF), UHRF2 is neither required for DNA maintenance methylation nor able to substitute for UHRF1 in DNA maintenance methylation.	('UHRF2', 'Var', (117, 122))	('NIRF', 'Gene', '115426', (110, 114))	('NIRF', 'Gene', (110, 114))	('mammalian', 'Species', '9606', (28, 37))
108502	27462454	The most common epigenetic alteration in cancer is global DNA hypomethylation.	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('global DNA hypomethylation', 'Var', (51, 77))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('cancer', 'Disease', (41, 47))
108504	27462454	DNA hypomethylation can be a causal factor for tumorigenesis, as demonstrated by studies of DNMT-deficient mice.	('hypomethylation', 'Var', (4, 19))	('DNMT', 'Gene', (92, 96))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('causal', 'Reg', (29, 35))	('mice', 'Species', '10090', (107, 111))	('DNMT', 'Gene', '13433', (92, 96))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor', 'Disease', (47, 52))
108506	27462454	Furthermore, recurrent somatic DNMT3A mutations have been identified in acute myeloid leukemia and other hematological malignancies, indicating that impaired activity of DNMT3A is a causal factor of tumorigenesis.	('tumor', 'Disease', (199, 204))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (72, 94))	('hematological malignancies', 'Disease', 'MESH:D019337', (105, 131))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (78, 94))	('hematological malignancies', 'Phenotype', 'HP:0004377', (105, 131))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('leukemia', 'Phenotype', 'HP:0001909', (86, 94))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (72, 94))	('DNMT3A', 'Gene', (31, 37))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('mutations', 'Var', (38, 47))	('acute myeloid leukemia', 'Disease', (72, 94))	('hematological malignancies', 'Disease', (105, 131))	('identified', 'Reg', (58, 68))
108507	27462454	However, DNMT3B appears to function as an oncogene, as its deletion and overexpression have been shown to suppress and promote lung cancer, respectively.	('DNMT3B', 'Gene', (9, 15))	('lung cancer', 'Disease', (127, 138))	('lung cancer', 'Phenotype', 'HP:0100526', (127, 138))	('promote', 'PosReg', (119, 126))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('suppress', 'NegReg', (106, 114))	('lung cancer', 'Disease', 'MESH:D008175', (127, 138))	('deletion', 'Var', (59, 67))	('overexpression', 'PosReg', (72, 86))
108510	27462454	We present evidence that UHRF1/2 overexpression is likely a common mechanism for suppressing DNMT3A activity and consequently widespread DNA hypomethylation in cancers.	('suppressing', 'NegReg', (81, 92))	('cancers', 'Disease', 'MESH:D009369', (160, 167))	('UHRF1/2', 'Gene', (25, 32))	('cancers', 'Phenotype', 'HP:0002664', (160, 167))	('cancers', 'Disease', (160, 167))	('overexpression', 'Var', (33, 47))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('DNMT3A', 'Enzyme', (93, 99))	('activity', 'MPA', (100, 108))	('UHRF1/2', 'Gene', '18140;109113', (25, 32))
108512	27462454	To examine if UHRF2 plays a role in DNA methylation, we knocked down UHRF2 in the human lung cancer cell line A549 using shRNA and examined the DNA methylation status by immunofluorescent staining using an anti-5-meC antibody.	('lung cancer', 'Disease', (88, 99))	('UHRF2', 'Gene', (69, 74))	('A549', 'CellLine', 'CVCL:0023', (110, 114))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('lung cancer', 'Disease', 'MESH:D008175', (88, 99))	('knocked', 'Var', (56, 63))	('human', 'Species', '9606', (82, 87))	('lung cancer', 'Phenotype', 'HP:0100526', (88, 99))
108524	27462454	In addition, we knocked down Uhrf2 in Uhrf1-/- ES cells using two different siRNAs and examined the effect on DNA methylation by bisulfite sequencing and immunofluorecent staining.	('knocked', 'Var', (16, 23))	('bisulfite', 'Chemical', 'MESH:C042345', (129, 138))	('Uhrf2', 'Gene', '109113', (29, 34))	('Uhrf1', 'Gene', (38, 43))	('Uhrf1', 'Gene', '18140', (38, 43))	('Uhrf2', 'Gene', (29, 34))
108525	27462454	Bisulfite sequencing analysis demonstrated that knockdown of Uhrf2 by siRNA resulted in increased methylation of the repetitive sequences IAP (from 10.1 to 49%) (Figure 2b).	('Uhrf2', 'Gene', (61, 66))	('IAP', 'Gene', (138, 141))	('IAP', 'Gene', '15601', (138, 141))	('Uhrf2', 'Gene', '109113', (61, 66))	('increased', 'PosReg', (88, 97))	('Bisulfite', 'Chemical', 'MESH:C042345', (0, 9))	('methylation', 'MPA', (98, 109))	('knockdown', 'Var', (48, 57))
108532	27462454	Similarly, immunofluorescent analysis of 5-meC showed that knockdown of Uhrf2 by siRNA against Uhrf2 led to increased DNA methylation in Dnmt1-/- ES cells, but not in Dnmt3ab-/- ES cells (Supplementary Figure S3).	('Uhrf2', 'Gene', (95, 100))	('increased', 'PosReg', (108, 117))	('Dnmt1', 'Gene', '13433', (137, 142))	('Uhrf2', 'Gene', (72, 77))	('Uhrf2', 'Gene', '109113', (95, 100))	('Dnmt1', 'Gene', (137, 142))	('knockdown', 'Var', (59, 68))	('DNA methylation', 'MPA', (118, 133))	('Dnmt3a', 'Gene', '13435', (167, 173))	('Dnmt3a', 'Gene', (167, 173))	('Uhrf2', 'Gene', '109113', (72, 77))
108535	27462454	The knockdown of Uhrf2 mRNA was verified by RT-PCR analysis (Figure 2g).	('Uhrf2', 'Gene', '109113', (17, 22))	('knockdown', 'Var', (4, 13))	('Uhrf2', 'Gene', (17, 22))
108538	27462454	We knocked down Uhrf2 in mouse P19 cells using lentiviruses encoding control or shRNAs against Uhrf1 or Uhrf2 and subsequently examined the levels of proteins and mRNAs of Dnmt3a and Dnmt3b by western blot and RT-PCR analysis, respectively.	('Uhrf1', 'Gene', (95, 100))	('Uhrf2', 'Gene', '109113', (104, 109))	('Uhrf1', 'Gene', '18140', (95, 100))	('Dnmt3a', 'Gene', '13435', (172, 178))	('Dnmt3a', 'Gene', (172, 178))	('examined', 'Reg', (127, 135))	('Uhrf2', 'Gene', '109113', (16, 21))	('mouse', 'Species', '10090', (25, 30))	('Dnmt3b', 'Gene', '13436', (183, 189))	('knocked', 'Var', (3, 10))	('Uhrf2', 'Gene', (104, 109))	('Dnmt3b', 'Gene', (183, 189))	('P19', 'Gene', (31, 34))	('P19', 'Gene', '12581', (31, 34))	('Uhrf2', 'Gene', (16, 21))
108539	27462454	We observed that knockdown of Uhrf2 in P19 cells led to substantially increased proteins of Dnmt3a but not Dnmt3b (Figure 3a).	('Uhrf2', 'Gene', (30, 35))	('increased', 'PosReg', (70, 79))	('Dnmt3b', 'Gene', '13436', (107, 113))	('P19', 'Gene', (39, 42))	('Dnmt3b', 'Gene', (107, 113))	('Dnmt3a', 'Gene', (92, 98))	('P19', 'Gene', '12581', (39, 42))	('proteins', 'MPA', (80, 88))	('Uhrf2', 'Gene', '109113', (30, 35))	('knockdown', 'Var', (17, 26))	('Dnmt3a', 'Gene', '13435', (92, 98))
108541	27462454	By the same approach, we observed that knockdown of Uhrf2 in NIH3T3 cells led to increased Dnmt3a but not Dnmt3b at the level of proteins (Figure 3a) but not mRNA (data not shown).	('NIH3T3', 'CellLine', 'CVCL:0594', (61, 67))	('Dnmt3a', 'Gene', '13435', (91, 97))	('Dnmt3b', 'Gene', (106, 112))	('knockdown', 'Var', (39, 48))	('Uhrf2', 'Gene', (52, 57))	('increased', 'PosReg', (81, 90))	('Dnmt3a', 'Gene', (91, 97))	('Uhrf2', 'Gene', '109113', (52, 57))	('Dnmt3b', 'Gene', '13436', (106, 112))
108543	27462454	Initially attempted as controls, we also knocked down Uhrf1 in P19 cells with shRNAs.	('Uhrf1', 'Gene', (54, 59))	('Uhrf1', 'Gene', '18140', (54, 59))	('knocked down', 'Var', (41, 53))	('P19', 'Gene', (63, 66))	('P19', 'Gene', '12581', (63, 66))
108544	27462454	We were surprised to observe that this also led to a substantial increase of Dnmt3a proteins (Figure 3a), despite the observed opposite effect on DNA methylation upon knockdown of Uhrf1 and Uhrf2 (Figure 1).	('increase', 'PosReg', (65, 73))	('Dnmt3a', 'Gene', '13435', (77, 83))	('Uhrf2', 'Gene', '109113', (190, 195))	('DNA methylation', 'MPA', (146, 161))	('knockdown', 'Var', (167, 176))	('Uhrf1', 'Gene', (180, 185))	('Uhrf1', 'Gene', '18140', (180, 185))	('Uhrf2', 'Gene', (190, 195))	('Dnmt3a', 'Gene', (77, 83))
108545	27462454	The specific knockdown of Uhrf2 or Uhrf1 by their respective shRNAs was confirmed by western blot analysis (Figure 3a).	('Uhrf2', 'Gene', (26, 31))	('Uhrf2', 'Gene', '109113', (26, 31))	('Uhrf1', 'Gene', (35, 40))	('Uhrf1', 'Gene', '18140', (35, 40))	('knockdown', 'Var', (13, 22))
108546	27462454	Again RT-PCR analysis showed that knockdown of Uhrf1 had no effect on the levels of mRNAs of Dnmt3b or Dnmt3a in P19 cells (Figure 3b).	('Uhrf1', 'Gene', (47, 52))	('Uhrf1', 'Gene', '18140', (47, 52))	('P19', 'Gene', (113, 116))	('Dnmt3a', 'Gene', (103, 109))	('P19', 'Gene', '12581', (113, 116))	('Dnmt3b', 'Gene', '13436', (93, 99))	('knockdown', 'Var', (34, 43))	('Dnmt3a', 'Gene', '13435', (103, 109))	('mRNAs', 'MPA', (84, 89))	('levels', 'MPA', (74, 80))	('Dnmt3b', 'Gene', (93, 99))
108547	27462454	Similarly, knockdown of Uhrf1 in NIH3T3 cells led to increased levels of Dnmt3a but not Dnmt1 and Dnmt3b proteins (Figure 3a).	('Dnmt3b', 'Gene', (98, 104))	('Dnmt1', 'Gene', (88, 93))	('Uhrf1', 'Gene', (24, 29))	('Uhrf1', 'Gene', '18140', (24, 29))	('Dnmt1', 'Gene', '13433', (88, 93))	('Dnmt3a', 'Gene', (73, 79))	('increased', 'PosReg', (53, 62))	('NIH3T3', 'CellLine', 'CVCL:0594', (33, 39))	('Dnmt3a', 'Gene', '13435', (73, 79))	('knockdown', 'Var', (11, 20))	('Dnmt3b', 'Gene', '13436', (98, 104))
108550	27462454	Similarly, knockdown of either Uhrf1 or Uhrf2 in mouse R1 ES cells or primary MEFs resulted in increased Dnmt3a proteins (Supplementary Figure S4).	('Uhrf2', 'Gene', (40, 45))	('Dnmt3a', 'Gene', '13435', (105, 111))	('MEFs', 'CellLine', 'CVCL:9115', (78, 82))	('Uhrf1', 'Gene', (31, 36))	('Uhrf2', 'Gene', '109113', (40, 45))	('mouse', 'Species', '10090', (49, 54))	('Uhrf1', 'Gene', '18140', (31, 36))	('increased', 'PosReg', (95, 104))	('Dnmt3a', 'Gene', (105, 111))	('knockdown', 'Var', (11, 20))
108552	27462454	To determine whether UHRF2 and UHRF1 also negatively regulate DNMT3A in human cancer cell lines, we knocked down UHRF2 or UHRF1 in cervical cancer HeLa and colorectal cancer HCT116 cells by lentiviral-mediated shRNA infection.	('cancer', 'Disease', (167, 173))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('colorectal cancer', 'Phenotype', 'HP:0003003', (156, 173))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('human', 'Species', '9606', (72, 77))	('knocked', 'Var', (100, 107))	('colorectal cancer', 'Disease', 'MESH:D015179', (156, 173))	('HCT116', 'CellLine', 'CVCL:0291', (174, 180))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('UHRF1', 'Gene', (122, 127))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', (140, 146))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('colorectal cancer', 'Disease', (156, 173))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('UHRF2', 'Gene', (113, 118))	('cervical cancer HeLa', 'Disease', 'MESH:D002583', (131, 151))	('cervical cancer HeLa', 'Disease', (131, 151))
108553	27462454	Furthermore, while knockdown of either UHRF1 or UHRF2 led to increased DNMT3A, a more pronounced increase of DNMT3A was observed when both UHRF1 and UHRF2 were knocked down in the MDA-231 breast cancer cell line (Figure 3f), indicating that UHRF1 and UHRF2 cooperatively regulate DNMT3A.	('UHRF1', 'Gene', (139, 144))	('increase', 'PosReg', (97, 105))	('UHRF1', 'Gene', (39, 44))	('UHRF2', 'Gene', (48, 53))	('breast cancer', 'Disease', 'MESH:D001943', (188, 201))	('breast cancer', 'Phenotype', 'HP:0003002', (188, 201))	('breast cancer', 'Disease', (188, 201))	('knockdown', 'Var', (19, 28))	('MDA-231', 'CellLine', 'CVCL:0062', (180, 187))	('DNMT3A', 'MPA', (71, 77))	('UHRF2', 'Gene', (149, 154))	('increased', 'PosReg', (61, 70))	('knocked down', 'Var', (160, 172))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
108556	27462454	Results in Figure 4a showed that expression of Flag-UHRF2 substantially reduced the levels of Dnmt3a but did not affect the levels of Dnmt3b (Figure 4a).	('reduced', 'NegReg', (72, 79))	('Dnmt3b', 'Gene', (134, 140))	('expression', 'Var', (33, 43))	('levels', 'MPA', (84, 90))	('Dnmt3a', 'Gene', (94, 100))	('Flag-UHRF2', 'Gene', (47, 57))	('Dnmt3a', 'Gene', '13435', (94, 100))	('Dnmt3b', 'Gene', '13436', (134, 140))
108558	27462454	Similarly, we found that expression of Flag-UHRF1 also resulted in reduced Dnmt3a but not Dnmt3b in R1 ES cells, and this effect was blocked by the addition of MG132 (Figure 4b).	('Flag-UHRF1', 'Gene', (39, 49))	('MG132', 'Chemical', 'MESH:C072553', (160, 165))	('Dnmt3b', 'Gene', '13436', (90, 96))	('reduced', 'NegReg', (67, 74))	('Dnmt3b', 'Gene', (90, 96))	('expression', 'Var', (25, 35))	('Dnmt3a', 'Gene', '13435', (75, 81))	('Dnmt3a', 'Gene', (75, 81))
108560	27462454	In further support for a role of the UHRF1/2 E3 ubiquitin ligase in DNMT3A degradation, a UHRF1 mutant impaired in E3 ligase activity due to change of three cysteine residues in RING domain to alanine (3C/3A) was unable to induce DNMT3A degradation in R1 ES cells (Supplementary Figure S5A).	('ubiquitin ligase', 'Gene', '84585', (48, 64))	('mutant', 'Var', (96, 102))	('ubiquitin ligase', 'Gene', (48, 64))	('UHRF1/2 E', 'Gene', (37, 46))	('activity', 'MPA', (125, 133))	('E3 ligase', 'Enzyme', (115, 124))	('UHRF1', 'Gene', (90, 95))	('change', 'Reg', (141, 147))	('alanine', 'Chemical', 'MESH:D000409', (193, 200))	('UHRF1/2 E', 'Gene', '18140', (37, 46))	('cysteine', 'Chemical', 'MESH:D003545', (157, 165))	('impaired', 'NegReg', (103, 111))
108562	27462454	Using a panel of deletion mutants, we also examined the potential roles of other UHRF2 structural domains in targeting Dnmt3a degradation.	('Dnmt3a', 'Gene', '13435', (119, 125))	('examined', 'Reg', (43, 51))	('Dnmt3a', 'Gene', (119, 125))	('deletion', 'Var', (17, 25))	('UHRF2', 'Gene', (81, 86))
108563	27462454	The results in Figure 4c showed that the deletion of either PHD or TUDOR domain from UHRF2 had no effect, whereas deletion of either the UBL or SRA domain impaired the ability of UHRF2 to induce Dnmt3a degradation (Figure 4c).	('PHD', 'Disease', (60, 63))	('deletion', 'Var', (114, 122))	('induce', 'Reg', (188, 194))	('Dnmt3a', 'Gene', '13435', (195, 201))	('deletion', 'Var', (41, 49))	('ability', 'MPA', (168, 175))	('PHD', 'Disease', 'MESH:D011547', (60, 63))	('impaired', 'NegReg', (155, 163))	('Dnmt3a', 'Gene', (195, 201))	('UHRF2', 'Gene', (85, 90))
108565	27462454	However, deletion of SRA did not significantly affect the UHRF2-DNMT3A interaction (Supplementary Figure S5B).	('S5B', 'Gene', (105, 108))	('S5B', 'Gene', '66998', (105, 108))	('deletion', 'Var', (9, 17))	('interaction', 'Interaction', (71, 82))	('SRA', 'Gene', (21, 24))
108567	27462454	Consistent with this idea, we found that the UHRF1 SRA mutants with impaired hemi-mCpG binding activity were unable to induce Dnmt3a degradation, whereas a mutant with impaired H3K9me2/3-binding activity maintained the DNMT3A degradation activity (Supplementary Figure S5C).	('Dnmt3a', 'Gene', '13435', (126, 132))	('mutants', 'Var', (55, 62))	('UHRF1 SRA', 'Gene', (45, 54))	('DNMT3A degradation activity', 'MPA', (219, 246))	('unable', 'NegReg', (109, 115))	('Dnmt3a', 'Gene', (126, 132))
108569	27462454	To this end, we first tested the ability of UHRF1 and UHRF2 as well as their deletion of RING mutants to promote ubiquitination of endogenous DNMT3A in 293T cells.	('deletion', 'Var', (77, 85))	('293T', 'CellLine', 'CVCL:0063', (152, 156))	('promote', 'PosReg', (105, 112))	('ubiquitination', 'MPA', (113, 127))
108570	27462454	Consistent with the above data that both the UBL and SRA domains were required for UHRF2-induced DNMT3A degradation, the UBL and SRA deletion mutants also failed to promote the ubiquitination of endogenous DNMT3A in 293T cells (Figure 4e).	('293T', 'CellLine', 'CVCL:0063', (216, 220))	('failed', 'NegReg', (155, 161))	('UBL', 'Gene', (121, 124))	('deletion mutants', 'Var', (133, 149))	('SRA', 'Gene', (129, 132))	('promote', 'PosReg', (165, 172))	('ubiquitination', 'MPA', (177, 191))
108571	27462454	Furthermore, the ability of UHRF1 to catalyze DNMT3A2 ubiquitination was dependent on its E3 ligase activity, because recombinant UHRF1 H741A, a mutant that was impaired in E3 ligase activity in cellular based assay, failed to catalyze DNMT3A2 ubiquitination in our in vitro assay (Figure 4g).	('H741A', 'Var', (136, 141))	('H741A', 'Mutation', 'p.H741A', (136, 141))	('UHRF1', 'Gene', (130, 135))
108576	27462454	In support of this idea, knockdown of either Uhrf2 or Uhrf1 in Dnmt1-/- ES cells resulted in increased levels of Dnmt3a, but simultaneous knockdown of both Uhrf1 and Uhrf2 led to a more pronounced increase of Dnmt3a proteins (Figure 5b), indicating that Uhrf1 and Uhrf2 cooperatively target Dnmt3a for degradation.	('Uhrf2', 'Gene', '109113', (45, 50))	('Uhrf1', 'Gene', (54, 59))	('increase', 'PosReg', (197, 205))	('increased', 'PosReg', (93, 102))	('Uhrf2', 'Gene', (45, 50))	('Uhrf2', 'Gene', '109113', (264, 269))	('Uhrf1', 'Gene', (156, 161))	('Dnmt1', 'Gene', '13433', (63, 68))	('Dnmt3a', 'Gene', '13435', (291, 297))	('knockdown', 'Var', (138, 147))	('Dnmt3a', 'Gene', (209, 215))	('Uhrf1', 'Gene', '18140', (54, 59))	('Uhrf2', 'Gene', (264, 269))	('Dnmt3a', 'Gene', (113, 119))	('Dnmt3a', 'Gene', '13435', (209, 215))	('Uhrf1', 'Gene', '18140', (156, 161))	('Uhrf2', 'Gene', '109113', (166, 171))	('Uhrf1', 'Gene', (254, 259))	('Uhrf2', 'Gene', (166, 171))	('knockdown', 'Var', (25, 34))	('Dnmt3a', 'Gene', '13435', (113, 119))	('Uhrf1', 'Gene', '18140', (254, 259))	('Dnmt1', 'Gene', (63, 68))	('Dnmt3a', 'Gene', (291, 297))
108578	27462454	We found that knockdown of Dnmt3a in R1 ES cells was sufficient to downregulate the global DNA methylation in R1 ES cells, whereas ectopic expression of DNMT3A in primary MEF cells was sufficient to upregulate the global DNA methylation in transfected MEF cells as shown by immunofluorescent staining assay (Supplementary Figure S9).	('MEF', 'Disease', (252, 255))	('Dnmt3a', 'Gene', (27, 33))	('downregulate', 'NegReg', (67, 79))	('Dnmt3a', 'Gene', '13435', (27, 33))	('MEF', 'Disease', 'None', (252, 255))	('global DNA methylation', 'MPA', (84, 106))	('knockdown', 'Var', (14, 23))	('MEF', 'Disease', (171, 174))	('MEF', 'Disease', 'None', (171, 174))
108580	27462454	Global DNA hypomethylation is a common epigenetic alteration of cancers.	('Global DNA hypomethylation', 'Var', (0, 26))	('cancers', 'Phenotype', 'HP:0002664', (64, 71))	('cancers', 'Disease', 'MESH:D009369', (64, 71))	('cancers', 'Disease', (64, 71))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
108581	27462454	Furthermore, highly recurrent somatic DNMT3A mutations have been identified in several types of leukemia and are associated with poor prognosis of the diseases, suggesting a causal link between loss of DNMT3A function and tumorigenesis.	('mutations', 'Var', (45, 54))	('tumor', 'Disease', 'MESH:D009369', (222, 227))	('identified', 'Reg', (65, 75))	('leukemia', 'Disease', (96, 104))	('leukemia', 'Phenotype', 'HP:0001909', (96, 104))	('leukemia', 'Disease', 'MESH:D007938', (96, 104))	('DNMT3A', 'Gene', (38, 44))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('tumor', 'Disease', (222, 227))	('associated', 'Reg', (113, 123))
108596	27462454	Furthermore, as shown in Figure 6b, knockdown of UHRF2 led to a substantial increase of DNMT3A in A549 cells, whereas the increase of DNMT3A upon knockdown of UHRF2 was more subtle in CRL5803, CRL5810, PC-9 and HTB177 cell lines.	('A549', 'CellLine', 'CVCL:0023', (98, 102))	('increase', 'PosReg', (76, 84))	('DNMT3A', 'MPA', (88, 94))	('UHRF2', 'Gene', (49, 54))	('UHRF2', 'Gene', (159, 164))	('knockdown', 'Var', (36, 45))	('PC-9', 'Gene', (202, 206))	('PC-9', 'Gene', '255738', (202, 206))	('HTB177', 'CellLine', 'CVCL:F127', (211, 217))
108597	27462454	On the other hand, knockdown of UHRF1 led to increased DNMT3A (2- to 4-fold) not only in A549 cells, but also in all other four cell lines.	('DNMT3A', 'MPA', (55, 61))	('A549', 'CellLine', 'CVCL:0023', (89, 93))	('UHRF1', 'Gene', (32, 37))	('increased', 'PosReg', (45, 54))	('knockdown', 'Var', (19, 28))
108603	27462454	We verified by immunofluorescent staining that transfection of A549 cells with two different shUHRF2 plasmids all led to substantially increased levels of DNMT3A proteins (Supplementary Figure S11A) and increased levels of DNA methylation (Supplementary Figure S11B).	('shUHRF2', 'Gene', (93, 100))	('transfection', 'Var', (47, 59))	('A549', 'CellLine', 'CVCL:0023', (63, 67))	('S11B', 'SUBSTITUTION', 'None', (261, 265))	('S11B', 'Var', (261, 265))	('increased', 'PosReg', (135, 144))	('DNA methylation', 'MPA', (223, 238))	('S11A', 'Var', (193, 197))	('DNMT3A proteins', 'Protein', (155, 170))	('levels', 'MPA', (213, 219))	('S11A', 'SUBSTITUTION', 'None', (193, 197))	('increased', 'PosReg', (203, 212))
108611	27462454	We noticed that shUHRF2 A549 cells exhibited a reduced growth rate compared with the shVector control A549 cells (Figure 6e).	('A549', 'CellLine', 'CVCL:0023', (24, 28))	('reduced growth rate', 'Phenotype', 'HP:0001510', (47, 66))	('A549', 'CellLine', 'CVCL:0023', (102, 106))	('shUHRF2', 'Var', (16, 23))	('reduced', 'NegReg', (47, 54))	('growth rate', 'MPA', (55, 66))
108613	27462454	When the same amounts of cells (5 millions) were injected subcutaneously into the back of nude mice, the shUHRF2-expressing A549 cells gave rise to tumors that were substantially smaller in volume than the control shRNA-expressing A549 cells (Figure 6f and g).	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('smaller', 'NegReg', (179, 186))	('A549', 'CellLine', 'CVCL:0023', (124, 128))	('shUHRF2-expressing', 'Gene', (105, 123))	('A549', 'Var', (124, 128))	('tumors', 'Disease', 'MESH:D009369', (148, 154))	('tumors', 'Disease', (148, 154))	('A549', 'CellLine', 'CVCL:0023', (231, 235))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('nude mice', 'Species', '10090', (90, 99))
108614	27462454	By weight the tumors derived from the shUHRF2-expressing A549 cells were in average six to seven times smaller than those from the control shRNA-expressing A549 cells (Figure 6h).	('A549', 'Var', (57, 61))	('shUHRF2-expressing A549', 'Var', (38, 61))	('tumors', 'Disease', (14, 20))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('smaller', 'NegReg', (103, 110))	('A549', 'CellLine', 'CVCL:0023', (156, 160))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('A549', 'CellLine', 'CVCL:0023', (57, 61))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
108616	27462454	To investigate if the increased level of DNMT3A proteins in the shUHRF2-expressing A549 cells is responsible for reduced tumor growth, we established A549 cell lines that stably expressed either the wild-type DNMT3A or its R882C mutant, which has an impaired enzymatic activity.	('A549', 'CellLine', 'CVCL:0023', (150, 154))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('A549', 'CellLine', 'CVCL:0023', (83, 87))	('shUHRF2-expressing', 'Gene', (64, 82))	('DNMT3A', 'Gene', (209, 215))	('tumor', 'Disease', (121, 126))	('R882C', 'Var', (223, 228))	('R882C', 'Mutation', 'rs377577594', (223, 228))	('reduced', 'NegReg', (113, 120))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
108617	27462454	The expression of DNMT3A or R882C mutant was confirmed by western blot analysis (Figure 7a) and the levels are comparable with the level of DNMT3A observed in shUHRF2-expressing A549 cells (Supplementary Figure S11C).	('A549', 'CellLine', 'CVCL:0023', (178, 182))	('S11C', 'Var', (211, 215))	('R882C', 'Var', (28, 33))	('R882C', 'Mutation', 'rs377577594', (28, 33))	('S11C', 'SUBSTITUTION', 'None', (211, 215))
108618	27462454	HPLC analysis of total 5-meC revealed an approximately 40% (from ~3 to 4.2%) increase in DNA methylation in the DNMT3A but not in R882C mutant-expressing cells (Figure 7b).	('R882C', 'Mutation', 'rs377577594', (130, 135))	('DNA methylation', 'MPA', (89, 104))	('DNMT3A', 'Var', (112, 118))	('increase', 'PosReg', (77, 85))
108620	27462454	As shown in Figure 7c, DNMT3A expression resulted in global increase of DNA methylation, generating substantially more hypermethylated (48 666) than hypomethylated (1 210) regions (Supplementary Figure S12A and B).	('DNMT3A expression', 'Var', (23, 40))	('S12A', 'SUBSTITUTION', 'None', (202, 206))	('expression', 'Var', (30, 40))	('S12A', 'Var', (202, 206))	('increase', 'PosReg', (60, 68))	('DNA methylation', 'MPA', (72, 87))	('more', 'PosReg', (114, 118))
108623	27462454	To test how ectopic DNMT3A expression affected tumor growth, the control, DNMT3A and R882C mutant-expressing A549 cells were injected subcutaneously into nude mice and tumor growth was analyzed as above.	('tumor', 'Disease', (168, 173))	('affected', 'Reg', (38, 46))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('nude mice', 'Species', '10090', (154, 163))	('R882C', 'Var', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('R882C', 'Mutation', 'rs377577594', (85, 90))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('A549', 'CellLine', 'CVCL:0023', (109, 113))	('tumor', 'Disease', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
108624	27462454	As shown in Figure 7e and f, the tumors from the DNMT3A-expressing A549 cells were substantially smaller in both volume and weight than those from the control A549 cells, whereas the tumors from R882C mutant-expressing cells were similar to those from the control A549 cells.	('A549', 'Var', (67, 71))	('DNMT3A-expressing A549', 'Var', (49, 71))	('tumors', 'Disease', 'MESH:D009369', (183, 189))	('A549', 'CellLine', 'CVCL:0023', (264, 268))	('A549', 'CellLine', 'CVCL:0023', (67, 71))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('A549', 'CellLine', 'CVCL:0023', (159, 163))	('tumors', 'Phenotype', 'HP:0002664', (183, 189))	('tumors', 'Disease', 'MESH:D009369', (33, 39))	('R882C', 'Var', (195, 200))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('smaller', 'NegReg', (97, 104))	('R882C', 'Mutation', 'rs377577594', (195, 200))	('tumors', 'Disease', (183, 189))	('tumors', 'Disease', (33, 39))
108625	27462454	Immunohistochemistry staining confirmed the sustained expression of both wild type and mutant DNMT3A in the recovered tumors (Figure 7g).	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('mutant', 'Var', (87, 93))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('tumors', 'Disease', (118, 124))	('DNMT3A', 'Gene', (94, 100))	('tumors', 'Disease', 'MESH:D009369', (118, 124))
108631	27462454	However, we found that knockdown of Uhrf2 resulted in a comparable increased level of DNA methylation in the wild type and Tet1-/- MEF cells (Supplementary Figure S13), which argues against the possibility that UHRF2 negatively regulates DNA methylation through TET1-mediated demethylation.	('regulates', 'Reg', (228, 237))	('TET1', 'Gene', '52463', (262, 266))	('Uhrf2', 'Gene', (36, 41))	('Tet1', 'Gene', '52463', (123, 127))	('MEF', 'Disease', (131, 134))	('knockdown', 'Var', (23, 32))	('MEF', 'Disease', 'None', (131, 134))	('Uhrf2', 'Gene', '109113', (36, 41))	('increased', 'PosReg', (67, 76))	('Tet1', 'Gene', (123, 127))	('DNA methylation', 'MPA', (86, 101))	('DNA methylation', 'MPA', (238, 253))	('negatively', 'NegReg', (217, 227))	('TET1', 'Gene', (262, 266))
108637	27462454	According to this model, abrogation of this negative regulation on DNMT3A would lead to increased DNA methylation, as shown by knockdown of UHRF2 in NIH3T3, MEF and many other cell lines and by knockdown of Uhrf1 in Dnmt1-/- ES cells in our study.	('MEF', 'Disease', 'None', (157, 160))	('DNA methylation', 'MPA', (98, 113))	('NIH3T3', 'CellLine', 'CVCL:0594', (149, 155))	('increased', 'PosReg', (88, 97))	('Dnmt1', 'Gene', (216, 221))	('Dnmt1', 'Gene', '13433', (216, 221))	('MEF', 'Disease', (157, 160))	('knockdown', 'Var', (127, 136))	('Uhrf1', 'Gene', (207, 212))	('UHRF2', 'Gene', (140, 145))	('Uhrf1', 'Gene', '18140', (207, 212))
108640	27462454	DNA hypomethylation at a genome-wide scale or more prevalently in repetitive sequences is one of the most recognized and common epigenetic changes in cancer.	('cancer', 'Disease', (150, 156))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('DNA hypomethylation', 'Var', (0, 19))
108641	27462454	Animal studies have shown that DNA hypomethylation as a consequence of Dnmt deficiencies promotes tumorigenesis in a tissue-dependent manner.	('Dnmt', 'Gene', (71, 75))	('promotes', 'PosReg', (89, 97))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('hypomethylation', 'Var', (35, 50))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('deficiencies', 'Var', (76, 88))	('tumor', 'Disease', (98, 103))	('Dnmt', 'Gene', '13433', (71, 75))
108656	27462454	Thus, the destabilization and mis-targeting reported in their study may operate under excessive UHRF1 overexpression, as they suggested, whereas the negative regulation of DNMT3A by UHRF1/2 reported in our study occurs in both regular and cancer cells.	('UHRF1/2', 'Gene', (182, 189))	('mis-targeting', 'Var', (30, 43))	('overexpression', 'PosReg', (102, 116))	('cancer', 'Disease', 'MESH:D009369', (239, 245))	('cancer', 'Disease', (239, 245))	('UHRF1', 'Gene', (96, 101))	('UHRF1/2', 'Gene', '18140;109113', (182, 189))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))
108657	27462454	Our study also supports a causal link between DNA hypomethylation and tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('hypomethylation', 'Var', (50, 65))	('tumor', 'Disease', (70, 75))	('DNA', 'Gene', (46, 49))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
108660	27462454	Note that we could not directly evaluate the scope of DNA hypomethylation induced by overexpressed UHRF1 in cancer cells, because UHRF1 is also required for DNA maintenance methylation by DNMT1 and knockdown of UHRF1 compromises DNA methylation by DNMT1.	('UHRF1', 'Gene', (211, 216))	('knockdown', 'Var', (198, 207))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('compromises', 'NegReg', (217, 228))	('DNA methylation', 'MPA', (229, 244))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
108661	27462454	Importantly, knockdown of UHRF2 in A549 cells led to increased global DNA methylation as well as methylation in LINE1, demonstrating that downregulation of DNMT3A by UHRF2 is causally linked to DNA hypomethylation phenotype in A549 cells.	('DNMT3A', 'Enzyme', (156, 162))	('A549', 'CellLine', 'CVCL:0023', (227, 231))	('UHRF2', 'Gene', (166, 171))	('downregulation', 'NegReg', (138, 152))	('methylation', 'MPA', (97, 108))	('A549', 'CellLine', 'CVCL:0023', (35, 39))	('global DNA methylation', 'MPA', (63, 85))	('increased', 'PosReg', (53, 62))	('knockdown', 'Var', (13, 22))	('UHRF2', 'Gene', (26, 31))
108662	27462454	Furthermore, as knockdown of UHRF2 in A549 cells led to reduced cell proliferation and impaired tumor growth (Figure 6), our data support a positive link between DNA hypomethylation and tumor growth.	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('A549', 'CellLine', 'CVCL:0023', (38, 42))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('cell proliferation', 'CPA', (64, 82))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('reduced', 'NegReg', (56, 63))	('tumor', 'Disease', (96, 101))	('knockdown', 'Var', (16, 25))	('tumor', 'Disease', (186, 191))	('UHRF2', 'Gene', (29, 34))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('impaired tumor growth', 'Disease', (87, 108))	('impaired tumor growth', 'Disease', 'MESH:D006130', (87, 108))
108663	27462454	In further support of this conclusion, we demonstrated that overexpression of wild type but not enzymatic activity-deficient DNMT3A mutant phenocopied the impaired tumor growth result observed for UHRF2 knockdown A549 cells (Figure 7e and f).	('impaired tumor growth', 'Disease', (155, 176))	('A549', 'CellLine', 'CVCL:0023', (213, 217))	('overexpression', 'PosReg', (60, 74))	('mutant', 'Var', (132, 138))	('DNMT3A', 'Gene', (125, 131))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('impaired tumor growth', 'Disease', 'MESH:D006130', (155, 176))
108664	27462454	Thus, knockdown of UHRF2 or overexpression of DNMT3A all led to increased global DNA methylation and methylation in repetitive sequences, reduced cell proliferation and reduced tumor growth, thus supporting that overexpression of UHRF1/2 is a mechanism driving DNA hypomethylation in cancer and that DNA hypomethylation promotes tumorigenesis.	('DNMT3A', 'Gene', (46, 52))	('reduced', 'NegReg', (138, 145))	('cancer', 'Disease', 'MESH:D009369', (284, 290))	('reduced', 'NegReg', (169, 176))	('global DNA methylation', 'MPA', (74, 96))	('cell proliferation', 'CPA', (146, 164))	('tumor', 'Disease', (329, 334))	('tumor', 'Disease', 'MESH:D009369', (329, 334))	('UHRF2', 'Gene', (19, 24))	('tumor', 'Disease', (177, 182))	('UHRF1/2', 'Gene', '18140;109113', (230, 237))	('cancer', 'Disease', (284, 290))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('promotes', 'PosReg', (320, 328))	('tumor', 'Phenotype', 'HP:0002664', (329, 334))	('cancer', 'Phenotype', 'HP:0002664', (284, 290))	('UHRF1/2', 'Gene', (230, 237))	('methylation in repetitive sequences', 'MPA', (101, 136))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('knockdown', 'Var', (6, 15))	('increased', 'PosReg', (64, 73))
108665	27462454	Somatic recurrent DNMT3A mutations have been identified in multiple types of human hematological malignancies, thus linking loss of DNMT3A enzymatic function directly with tumorigenesis.	('hematological malignancies', 'Phenotype', 'HP:0004377', (83, 109))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('mutations', 'Var', (25, 34))	('loss', 'Var', (124, 128))	('tumor', 'Disease', (172, 177))	('hematological malignancies', 'Disease', (83, 109))	('hematological malignancies', 'Disease', 'MESH:D019337', (83, 109))	('DNMT3A', 'Gene', (18, 24))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('DNMT3A', 'Gene', (132, 138))	('human', 'Species', '9606', (77, 82))
108671	27462454	The shRNA sequences were as follows: shUhrf1A sense CCAGTTAACCAGGCATCTA, antisense TAGATGCCTGGTTAACTGG; shUhrf1B sense GATTGTTAACATATTGCAA, antisense TTGCAATATGTTAACAATC; shUhrf2A sense GGACTAATGGAAATGTAAA, antisense TTTACATTTCCATTAGTCC; shUhrf2B sense GAATGATGCTCAGGTTAAA, antisense TTTAACCTGAGCATCATTC; shUHRF1A sense AGGTGGTCATGCTCAACTA, antisense TAGTTGAGCATGACCACCT; shUHRF2B sense GGTGGAATTCATGGTCGAA, antisense TTCGACCATGAATTCCACC.	('Uhrf1', 'Gene', (106, 111))	('shUHRF2B', 'Var', (372, 380))	('Uhrf1', 'Gene', '18140', (106, 111))	('Uhrf2', 'Gene', '109113', (173, 178))	('Uhrf2', 'Gene', '109113', (240, 245))	('Uhrf2', 'Gene', (240, 245))	('Uhrf2', 'Gene', (173, 178))	('Uhrf1', 'Gene', (39, 44))	('Uhrf1', 'Gene', '18140', (39, 44))
108680	27462454	For detecting endogenous DNMT3A ubiquitination in 293T cells, UHRF1 or UHRF2 and their mutants were co-transfected with 6xHis-Ub into 293T cells.	('293T', 'CellLine', 'CVCL:0063', (134, 138))	('6xHis-Ub', 'Chemical', '-', (120, 128))	('mutants', 'Var', (87, 94))	('DNMT3A', 'Gene', (25, 31))	('ubiquitination', 'MPA', (32, 46))	('293T', 'CellLine', 'CVCL:0063', (50, 54))	('UHRF2', 'Gene', (71, 76))
108689	27462454	The groups of 4-week-old male nude mice (n=7) were each injected subcutaneously with 5 million cells of control A549 or A549 cells expressing either shUHRF2 or the wild type or R882C mutant DNMT3A as indicated.	('A549', 'CellLine', 'CVCL:0023', (112, 116))	('R882C', 'Mutation', 'rs377577594', (177, 182))	('R882C', 'Var', (177, 182))	('shUHRF2', 'Var', (149, 156))	('nude mice', 'Species', '10090', (30, 39))	('DNMT3A', 'Gene', (190, 196))	('A549', 'CellLine', 'CVCL:0023', (120, 124))
108701	32864805	We found higher rates of grade 2 vomiting and grade 2 and 3 anemia and thrombocytopenia in the double-agent group, which could be possible because cisplatin is highly likely to cause vomiting.	('thrombocytopenia', 'Disease', (71, 87))	('vomiting', 'Disease', (33, 41))	('vomiting', 'Disease', 'MESH:D014839', (33, 41))	('cisplatin', 'Chemical', 'MESH:D002945', (147, 156))	('2 vomiting', 'Phenotype', 'HP:0002572', (31, 41))	('anemia', 'Disease', 'MESH:D000740', (60, 66))	('anemia', 'Disease', (60, 66))	('anemia', 'Phenotype', 'HP:0001903', (60, 66))	('thrombocytopenia', 'Disease', 'MESH:D013921', (71, 87))	('grade', 'Disease', (46, 51))	('vomiting', 'Disease', 'MESH:D014839', (183, 191))	('cisplatin', 'Var', (147, 156))	('vomiting', 'Phenotype', 'HP:0002013', (183, 191))	('thrombocytopenia', 'Phenotype', 'HP:0001873', (71, 87))	('vomiting', 'Phenotype', 'HP:0002013', (33, 41))	('vomiting', 'Disease', (183, 191))	('higher', 'PosReg', (9, 15))
108728	32864805	Furthermore, previous retrospective studies showed that single-drug concurrent chemoradiotherapy has lower hematotoxicity than a double-agent regimen concurrent chemoradiotherapy in patients with esophageal cancer [20, 21].	('cancer', 'Disease', 'MESH:D009369', (207, 213))	('hematotoxicity', 'Disease', 'MESH:D006402', (107, 121))	('cancer', 'Disease', (207, 213))	('single-drug', 'Var', (56, 67))	('hematotoxicity', 'Disease', (107, 121))	('lower', 'NegReg', (101, 106))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('patients', 'Species', '9606', (182, 190))
108744	33428597	In recent years, with the deepening of tumor research, it is recognized that the expression of oncogene depends not only on the gene itself, but also on epigenetic modification without changing the gene sequence.	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('epigenetic modification', 'Var', (153, 176))	('tumor', 'Disease', (39, 44))	('expression', 'MPA', (81, 91))
108747	33428597	The level of M6A is dynamically regulated by a methyltransferase (encoder), a binding protein (reader), and a demethylase (decoder), so, it is a dynamic and reversible process.	('binding', 'Interaction', (78, 85))	('M6A', 'Chemical', '-', (13, 16))	('methyltransferase', 'Enzyme', (47, 64))	('M6A', 'Var', (13, 16))
108748	33428597	Related studies have shown that changes in M6A regulatory genes could promote the progression of breast cancer, liver cancer, and hematological malignant tumors by inducing the formation of cancer stem cells and their abnormal differentiation.	('progression', 'CPA', (82, 93))	('hematological malignant tumors', 'Disease', (130, 160))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', (190, 196))	('M6A', 'Chemical', '-', (43, 46))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('promote', 'PosReg', (70, 77))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('liver cancer', 'Disease', 'MESH:D006528', (112, 124))	('cancer', 'Disease', (118, 124))	('M6A regulatory genes', 'Gene', (43, 63))	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('breast cancer', 'Phenotype', 'HP:0003002', (97, 110))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('liver cancer', 'Phenotype', 'HP:0002896', (112, 124))	('changes', 'Var', (32, 39))	('liver cancer', 'Disease', (112, 124))	('cancer', 'Disease', 'MESH:D009369', (190, 196))	('inducing', 'Reg', (164, 172))	('breast cancer', 'Disease', 'MESH:D001943', (97, 110))	('breast cancer', 'Disease', (97, 110))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('hematological malignant tumors', 'Disease', 'MESH:D019337', (130, 160))
108750	33428597	Through the description of the genetic variation of M6A regulatory factor in lung adenocarcinoma, it was found that FTO and YTHDF3 mutations were related to the decrease of overall survival rate.	('overall survival rate', 'CPA', (173, 194))	('mutations', 'Var', (131, 140))	('FTO', 'Gene', '79068', (116, 119))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (77, 96))	('decrease', 'NegReg', (161, 169))	('lung adenocarcinoma', 'Disease', (77, 96))	('FTO', 'Gene', (116, 119))	('YTHDF3', 'Gene', (124, 130))	('M6A', 'Chemical', '-', (52, 55))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (77, 96))	('YTHDF3', 'Gene', '253943', (124, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))
108751	33428597	A series of studies have shown that once the components involved in the regulation of M6A modification have been lost or abnormal, it would lead to abnormal physiological functions such as cell differentiation, and gene expression would be abnormally activated or inhibited.	('lost', 'NegReg', (113, 117))	('cell differentiation', 'CPA', (189, 209))	('modification', 'Var', (90, 102))	('abnormal physiological functions', 'MPA', (148, 180))	('lead to', 'Reg', (140, 147))	('abnormal', 'Var', (121, 129))	('M6A', 'Chemical', '-', (86, 89))	('M6A', 'Gene', (86, 89))	('inhibited', 'NegReg', (264, 273))	('activated', 'PosReg', (251, 260))	('gene expression', 'MPA', (215, 230))
108753	33428597	Various types of genomic changes, including CNV, played an important role in promoting the occurrence and development of cancer, and were also key factors leading to genetic and epigenetic abnormalities.	('leading', 'Reg', (155, 162))	('epigenetic abnormalities', 'Disease', 'MESH:D018376', (178, 202))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('development', 'CPA', (106, 117))	('promoting', 'PosReg', (77, 86))	('epigenetic abnormalities', 'Disease', (178, 202))	('genetic', 'Var', (166, 173))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('CNV', 'Disease', (44, 47))	('cancer', 'Disease', (121, 127))
108755	33428597	CNV, the amplification or deletion of DNA caused by genomic instability, can be used as an important therapeutic target, as it is related to drug resistance and tumor biology in many cancers, such as breast cancer and non-small cell lung cancer (NSCLC).	('lung cancer', 'Phenotype', 'HP:0100526', (233, 244))	('non-small cell lung cancer', 'Disease', (218, 244))	('deletion', 'Var', (26, 34))	('NSCLC', 'Disease', (246, 251))	('tumor', 'Disease', (161, 166))	('cancers', 'Phenotype', 'HP:0002664', (183, 190))	('cancers', 'Disease', (183, 190))	('NSCLC', 'Phenotype', 'HP:0030358', (246, 251))	('related', 'Reg', (130, 137))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (218, 244))	('amplification', 'Var', (9, 22))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (222, 244))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('breast cancer', 'Phenotype', 'HP:0003002', (200, 213))	('cancers', 'Disease', 'MESH:D009369', (183, 190))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (218, 244))	('DNA', 'Gene', (38, 41))	('breast cancer', 'Disease', 'MESH:D001943', (200, 213))	('drug resistance', 'Phenotype', 'HP:0020174', (141, 156))	('breast cancer', 'Disease', (200, 213))	('NSCLC', 'Disease', 'MESH:D002289', (246, 251))
108759	33428597	obtained a four-gene signature that significantly stratified the overall survival rate for LUAD through the analysis of EGFR wild type and EGFR mutation subgroups of LUAD.	('EGFR', 'Gene', '1956', (139, 143))	('mutation', 'Var', (144, 152))	('stratified', 'Reg', (50, 60))	('LUAD', 'Phenotype', 'HP:0030078', (166, 170))	('EGFR', 'Gene', '1956', (120, 124))	('EGFR', 'Gene', (139, 143))	('LUAD', 'Disease', (91, 95))	('LUAD', 'Phenotype', 'HP:0030078', (91, 95))	('EGFR', 'Gene', (120, 124))
108779	33428597	Although great progress has been made in neoadjuvant radiotherapy, chemotherapy, molecular targeted therapy and immunotherapy methods, and greatly increase clinical expectations for the successful treatment of malignant diseases, local recurrence and distant metastasis caused by tumor heterogeneity and drug resistance are still threatening the lives of patients, resulting in a low long-term survival rate.	('patients', 'Species', '9606', (355, 363))	('low', 'NegReg', (380, 383))	('drug resistance', 'Var', (304, 319))	('local recurrence', 'CPA', (230, 246))	('tumor', 'Disease', 'MESH:D009369', (280, 285))	('tumor', 'Phenotype', 'HP:0002664', (280, 285))	('tumor', 'Disease', (280, 285))	('malignant diseases', 'Disease', 'MESH:D009369', (210, 228))	('drug resistance', 'Phenotype', 'HP:0020174', (304, 319))	('distant metastasis', 'CPA', (251, 269))	('malignant diseases', 'Disease', (210, 228))
108781	33428597	Cancer is a complex genetic and epigenetic disease, which involves mutations and dysregulation of oncogenes and tumor suppressor genes.	('dysregulation', 'Var', (81, 94))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('oncogenes', 'Gene', (98, 107))	('mutations', 'Var', (67, 76))	('Cancer', 'Disease', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('tumor', 'Disease', (112, 117))
108782	33428597	Among them, epigenetic modifications can participate in the occurrence and progression of tumors by inhibiting the expression of tumor suppressor genes and enhancing that of oncogenes.	('participate', 'Reg', (41, 52))	('tumor', 'Disease', (129, 134))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('tumor', 'Disease', (90, 95))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('oncogenes', 'MPA', (174, 183))	('inhibiting', 'NegReg', (100, 110))	('tumors', 'Disease', (90, 96))	('tumors', 'Disease', 'MESH:D009369', (90, 96))	('expression', 'MPA', (115, 125))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('epigenetic modifications', 'Var', (12, 36))	('enhancing', 'PosReg', (156, 165))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
108785	33428597	For example, Xinyao Lin et al found that M6A could regulate the progression of epithelial-mesenchymal transformation in vitro and in vivo and the M6A modification of mRNAs increases in cancer cells were an important step in cancer cell metastasis.	('progression', 'CPA', (64, 75))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('M6A', 'Chemical', '-', (41, 44))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('M6A', 'Var', (146, 149))	('regulate', 'Reg', (51, 59))	('epithelial-mesenchymal transformation', 'CPA', (79, 116))	('cancer', 'Disease', 'MESH:D009369', (224, 230))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('M6A', 'Chemical', '-', (146, 149))	('cancer', 'Disease', (185, 191))	('cancer', 'Disease', (224, 230))
108789	33428597	In different types of cancer, M6A regulatory factors have been shown to undergo a wide range of genetic changes, including mutations and CNVs.	('M6A', 'Chemical', '-', (30, 33))	('mutations', 'Var', (123, 132))	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('cancer', 'Disease', (22, 28))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('M6A regulatory factors', 'Gene', (30, 52))
108797	33428597	YTHDF1 can recognize and bind the M6A methylation of mRNA, thus inhibiting the translation of mRNA.	('inhibiting', 'NegReg', (64, 74))	('M6A methylation', 'Var', (34, 49))	('M6A', 'Chemical', '-', (34, 37))	('mRNA', 'Protein', (53, 57))	('translation', 'MPA', (79, 90))	('bind', 'Interaction', (25, 29))	('YTHDF1', 'Gene', (0, 6))
108798	33428597	It was found that the tumor size of YTHDF1 knockout mice is much smaller than that of wild type, and the immunoreactivity of M6A knockout mice was stronger than that of wild type, indicating that YTHDF1 can be used as an important target of immunotherapy against clinical tumors.	('tumor', 'Phenotype', 'HP:0002664', (272, 277))	('tumors', 'Disease', (272, 278))	('tumors', 'Phenotype', 'HP:0002664', (272, 278))	('tumor', 'Disease', (272, 277))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('YTHDF1', 'Gene', (36, 42))	('knockout', 'Var', (43, 51))	('mice', 'Species', '10090', (138, 142))	('smaller', 'NegReg', (65, 72))	('stronger', 'PosReg', (147, 155))	('mice', 'Species', '10090', (52, 56))	('tumors', 'Disease', 'MESH:D009369', (272, 278))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('tumor', 'Disease', 'MESH:D009369', (272, 277))	('tumor', 'Disease', (22, 27))	('M6A', 'Chemical', '-', (125, 128))
108799	33428597	In addition, Shi Y et al observed that high expression of YTHDF1 was associated with better clinical outcomes, and its depletion lead to cancer cells becoming resistant to cisplatin therapy.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('lead to', 'Reg', (129, 136))	('cisplatin', 'Chemical', 'MESH:D002945', (172, 181))	('high expression', 'Var', (39, 54))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('cancer', 'Disease', (137, 143))	('YTHDF1', 'Gene', (58, 64))	('depletion', 'MPA', (119, 128))
108804	33428597	The study found that the OS and progression-free survival of colorectal cancer patients with high expression of M6A regulatory factor METTL3 were shorter on average.	('colorectal cancer', 'Disease', (61, 78))	('METTL3', 'Gene', (134, 140))	('M6A', 'Chemical', '-', (112, 115))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('shorter', 'NegReg', (146, 153))	('colorectal cancer', 'Disease', 'MESH:D015179', (61, 78))	('patients', 'Species', '9606', (79, 87))	('progression-free survival', 'CPA', (32, 57))	('high expression', 'Var', (93, 108))	('colorectal cancer', 'Phenotype', 'HP:0003003', (61, 78))	('METTL3', 'Gene', '56339', (134, 140))
108808	33428597	Studies have shown that FTO can activate the migration of LUAD cells through M6A demethylation and promote the progression of LUAD.	('LUAD', 'Phenotype', 'HP:0030078', (126, 130))	('M6A', 'Chemical', '-', (77, 80))	('LUAD', 'Phenotype', 'HP:0030078', (58, 62))	('LUAD', 'Disease', (126, 130))	('migration', 'CPA', (45, 54))	('demethylation', 'Var', (81, 94))	('promote', 'PosReg', (99, 106))	('FTO', 'Gene', '79068', (24, 27))	('M6A', 'Protein', (77, 80))	('activate', 'PosReg', (32, 40))	('FTO', 'Gene', (24, 27))	('progression', 'CPA', (111, 122))
108813	33428597	Further analysis showed a correlation between the copy numbers of HNRNPC, YTHDF1, HNRNPA2B1, METTL3, FTO and the corresponding gene expression, that is, with an increase in copy number, the expression of these genes increased.	('FTO', 'Gene', (101, 104))	('METTL3', 'Gene', (93, 99))	('YTHDF1', 'Gene', (74, 80))	('METTL3', 'Gene', '56339', (93, 99))	('HNRNPA2B1', 'Gene', '3181', (82, 91))	('increase', 'PosReg', (161, 169))	('FTO', 'Gene', '79068', (101, 104))	('HNRNPA2B1', 'Gene', (82, 91))	('expression', 'MPA', (190, 200))	('expression', 'MPA', (132, 142))	('HNRNPC', 'Gene', '3183', (66, 72))	('HNRNPC', 'Gene', (66, 72))	('increased', 'PosReg', (216, 225))	('copy number', 'Var', (173, 184))
108818	33428597	In addition, we observed the correlation between the CNVs of five M6A-related genes in the risk scoring system and the corresponding gene expression.	('M6A', 'Chemical', '-', (66, 69))	('expression', 'MPA', (138, 148))	('CNVs', 'Var', (53, 57))	('M6A-related genes', 'Gene', (66, 83))
108874	33634093	Animal studies indicate that sex steroid hormones (estrogen and endogenous progesterone) are capable of inducing cancer in in vitro and in vivo experiments associated with HPV E2, E6, and E7 proteins (reviewed by Hellberg,).	('inducing', 'PosReg', (104, 112))	('HPV E2', 'Var', (172, 178))	('HPV', 'Species', '10566', (172, 175))	('E7', 'Chemical', '-', (188, 190))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('cancer', 'Disease', (113, 119))	('progesterone', 'Chemical', 'MESH:D011374', (75, 87))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('steroid', 'Chemical', 'MESH:D013256', (33, 40))
108879	33634093	In cultures derived from a transfection of 4 different HPV-immortalized keratinocyte cell lines (CX18-1, CX16-5, CX16-2) engineered with HSV-2 DNA, the transfection with HSV-2 DNA was capable of inducing the tumorigenic conversion of the HPV-immortalized human genital epithelial cells (Paolo et al.,).	('tumor', 'Disease', 'MESH:D009369', (208, 213))	('HPV', 'Species', '10566', (55, 58))	('human', 'Species', '9606', (255, 260))	('rat', 'Species', '10116', (74, 77))	('HPV', 'Species', '10566', (238, 241))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('HSV-2', 'Species', '10310', (137, 142))	('tumor', 'Disease', (208, 213))	('HSV-2', 'Species', '10310', (170, 175))	('transfection', 'Var', (152, 164))	('inducing', 'PosReg', (195, 203))
108893	33634093	The mutagenesis of critical positions at the E6-p53 interface disrupts p53 degradation (Martinez-Zapien et al.,).	('p53', 'Gene', (48, 51))	('mutagenesis', 'Var', (4, 15))	('p53', 'Gene', '7157', (48, 51))	('disrupts', 'NegReg', (62, 70))	('p53', 'Gene', (71, 74))	('p53', 'Gene', '7157', (71, 74))
108909	33634093	Consequently, the p53 levels are low and cyclin-dependent kinases (CDKs) are active, stimulating the cell cycle progression in an uncontrolled way and causing the accumulation of genetic mutations (reviewed by Estevao et al.,).	('stimulating', 'PosReg', (85, 96))	('p53', 'Gene', (18, 21))	('causing', 'Reg', (151, 158))	('p53', 'Gene', '7157', (18, 21))	('CDKs', 'Gene', '1017', (67, 71))	('cell cycle progression', 'CPA', (101, 123))	('accumulation', 'PosReg', (163, 175))	('genetic mutations', 'Var', (179, 196))	('cyclin-dependent', 'Enzyme', (41, 57))	('CDKs', 'Gene', (67, 71))
108913	33634093	pRb degradation, not solely binding, is important for the E7-induced inactivation of pRb (Gonzalez et al.,).	('E7', 'Chemical', '-', (58, 60))	('inactivation', 'NegReg', (69, 81))	('E7-induced', 'Var', (58, 68))	('pRb', 'Gene', '5925', (85, 88))	('pRb', 'Gene', (85, 88))	('pRb', 'Gene', '5925', (0, 3))	('pRb', 'Gene', (0, 3))
108921	33634093	The association of E7 and HDAC1/2 does not result in the inhibition of HDAC activity but does play a role in HPV E7-associated transcriptional regulation.	('HDAC1', 'Gene', (26, 31))	('HPV', 'Disease', (109, 112))	('association', 'Interaction', (4, 15))	('role', 'Reg', (101, 105))	('HPV', 'Species', '10566', (109, 112))	('transcriptional regulation', 'MPA', (127, 153))	('HDAC1', 'Gene', '3065', (26, 31))	('E7', 'Chemical', '-', (19, 21))	('E7-associated', 'Var', (113, 126))	('HDAC', 'Gene', (26, 30))	('HDAC', 'Gene', (71, 75))	('HDAC', 'Gene', '9734', (26, 30))	('E7', 'Chemical', '-', (113, 115))	('HDAC', 'Gene', '9734', (71, 75))	('play', 'Reg', (94, 98))
108929	33634093	The association of E7 and HDAC1/2 plays a role in HPV E7-associated transcriptional regulation suppression of interferon response factor 1 (IRF1) and blockage of HIF-1alpha (hypoxia-inducible factor-1), triggering pro-angiogenic factors by HPVE7 (reviewed by Gupta and Mania-Pramanik,).	('IRF1', 'Gene', '3659', (140, 144))	('HDAC1', 'Gene', '3065', (26, 31))	('suppression', 'NegReg', (95, 106))	('pro-angiogenic factors', 'MPA', (214, 236))	('blockage', 'Var', (150, 158))	('Mania', 'Phenotype', 'HP:0100754', (269, 274))	('HIF-1alpha', 'Gene', (162, 172))	('hypoxia', 'Disease', (174, 181))	('HPV', 'Species', '10566', (50, 53))	('E7', 'Chemical', '-', (54, 56))	('HPV', 'Species', '10566', (240, 243))	('triggering', 'PosReg', (203, 213))	('hypoxia', 'Disease', 'MESH:D000860', (174, 181))	('HPV E7-associated', 'Gene', (50, 67))	('E7', 'Chemical', '-', (243, 245))	('HDAC1', 'Gene', (26, 31))	('IRF1', 'Gene', (140, 144))	('transcriptional regulation', 'MPA', (68, 94))	('E7', 'Chemical', '-', (19, 21))	('Mani', 'Species', '156483', (269, 273))	('HIF-1alpha', 'Gene', '3091', (162, 172))
108944	33634093	So far, a precocious relationship between histone-rich domains in lysine, histone modification, and RNA synthesis has been found (Allfrey et al.,).	('RNA synthesis', 'MPA', (100, 113))	('histone-rich', 'Var', (42, 54))	('lysine', 'Chemical', 'MESH:D008239', (66, 72))	('histone', 'MPA', (74, 81))
108945	33634093	Afterward, the histones could be further modified by the attachment of acetyl, methyl, or phosphoryl groups in the preformed lysine peptide chains.	('acetyl', 'Protein', (71, 77))	('acetyl', 'Chemical', '-', (71, 77))	('histones', 'Protein', (15, 23))	('phosphoryl', 'Var', (90, 100))	('lysine', 'Chemical', 'MESH:D008239', (125, 131))	('modified', 'Reg', (41, 49))	('attachment', 'Interaction', (57, 67))
108971	33634093	Due to the overexpression of HDAC in many types of cancer, including cervical cancer, it is known that HDAC inhibitors act by reducing tumor development, being used alone or in combination with other drugs.	('HDAC', 'Gene', '9734', (103, 107))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('reducing', 'NegReg', (126, 134))	('cancer', 'Disease', (78, 84))	('tumor', 'Disease', (135, 140))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('HDAC', 'Gene', (29, 33))	('tumor', 'Disease', 'MESH:D009369', (135, 140))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('HDAC', 'Gene', '9734', (29, 33))	('overexpression', 'PosReg', (11, 25))	('cervical cancer', 'Disease', 'MESH:D002583', (69, 84))	('inhibitors', 'Var', (108, 118))	('cancer', 'Disease', (51, 57))	('cervical cancer', 'Disease', (69, 84))	('HDAC', 'Gene', (103, 107))
108988	33634093	Aberrant expression among distinct HDAC is related to different types of cancer.	('cancer', 'Disease', (73, 79))	('Aberrant expression', 'Var', (0, 19))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('HDAC', 'Gene', (35, 39))	('related', 'Reg', (43, 50))	('HDAC', 'Gene', '9734', (35, 39))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))
108996	33634093	After knockdown of HDAC8 using siRNA experiments, an interference in the cell cycle was observed, as well as an alteration in cellular migration and morphology, which pointed out that HDAC8i could be a useful target in cervical cancer cells (Vanaja et al.,).	('cellular migration', 'CPA', (126, 144))	('rat', 'Species', '10116', (138, 141))	('HDAC8', 'Gene', '55869', (19, 24))	('interference', 'Reg', (53, 65))	('HDAC8', 'Gene', (184, 189))	('cervical cancer', 'Disease', (219, 234))	('HDAC8', 'Gene', (19, 24))	('cervical cancer', 'Disease', 'MESH:D002583', (219, 234))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('alteration', 'Reg', (112, 122))	('cell cycle', 'CPA', (73, 83))	('rat', 'Species', '10116', (116, 119))	('knockdown', 'Var', (6, 15))	('HDAC8', 'Gene', '55869', (184, 189))
109010	33634093	A mutant HDAC10 without histone deacetylation effect did not exhibit any suppressive effect on MMP2 and MMP9 genes.	('HDAC10', 'Gene', '83933', (9, 15))	('HDAC10', 'Gene', (9, 15))	('MMP2', 'Gene', (95, 99))	('MMP9', 'Gene', (104, 108))	('MMP9', 'Gene', '4318', (104, 108))	('MMP2', 'Gene', '4313', (95, 99))	('acetyl', 'Chemical', '-', (34, 40))	('mutant', 'Var', (2, 8))
109017	33634093	The study also shows that the knockdown of HDAC2 in cells causes an increase in apoptosis (possibly through an upregulation of p21Cip1/WAF1, but independent of p53), which is confirmed in the results of Zhu et al., where they demonstrate that HDAC2 overexpression works as a protection for cells against apoptosis, which can be important to facilitate the development of tumors.	('WAF1', 'Gene', (135, 139))	('HDAC2', 'Gene', (43, 48))	('HDAC2', 'Gene', '3066', (43, 48))	('HDAC2', 'Gene', '3066', (243, 248))	('tumors', 'Disease', (371, 377))	('p21Cip1', 'Gene', '1026', (127, 134))	('tumors', 'Disease', 'MESH:D009369', (371, 377))	('tumors', 'Phenotype', 'HP:0002664', (371, 377))	('HDAC2', 'Gene', (243, 248))	('p53', 'Gene', (160, 163))	('p53', 'Gene', '7157', (160, 163))	('WAF1', 'Gene', '1026', (135, 139))	('increase', 'PosReg', (68, 76))	('rat', 'Species', '10116', (233, 236))	('knockdown', 'Var', (30, 39))	('apoptosis', 'CPA', (80, 89))	('tumor', 'Phenotype', 'HP:0002664', (371, 376))	('p21Cip1', 'Gene', (127, 134))
109039	33634093	In HeLa cells, vorinostat also induces apoptosis through a series of mechanism including mitochondrial membrane potential, caspase activation, and PARP cleavage.	('activation', 'PosReg', (131, 141))	('apoptosis', 'CPA', (39, 48))	('PARP', 'Gene', (147, 151))	('induces', 'Reg', (31, 38))	('vorinostat', 'Var', (15, 25))	('vorinostat', 'Chemical', 'MESH:D000077337', (15, 25))	('caspase', 'CPA', (123, 130))	('HeLa', 'CellLine', 'CVCL:0030', (3, 7))	('PARP', 'Gene', '142', (147, 151))	('mitochondrial membrane potential', 'CPA', (89, 121))
109050	33634093	Enzymatic assays with different HDAC isoforms were also evaluated and shown for belinostat values of IC50 of 34 nM (HDAC1), 353 nM (HDAC8), 9850 nM (HDAC4), 27 nM (HDAC6), and 25000 nM (HDAC11) (Li et al.,).	('belinostat', 'Chemical', 'MESH:C487081', (80, 90))	('HDAC6', 'Gene', '10013', (164, 169))	('HDAC', 'Gene', (186, 190))	('HDAC', 'Gene', '9734', (32, 36))	('HDAC8', 'Gene', '55869', (132, 137))	('HDAC11', 'Gene', (186, 192))	('HDAC1', 'Gene', (116, 121))	('HDAC', 'Gene', (32, 36))	('HDAC4', 'Gene', '9759', (149, 154))	('HDAC8', 'Gene', (132, 137))	('HDAC1', 'Gene', (186, 191))	('9850 nM', 'Var', (140, 147))	('HDAC4', 'Gene', (149, 154))	('HDAC6', 'Gene', (164, 169))	('HDAC', 'Gene', '9734', (132, 136))	('HDAC', 'Gene', '9734', (149, 153))	('HDAC1', 'Gene', '3065', (116, 121))	('HDAC', 'Gene', '9734', (116, 120))	('353 nM', 'Var', (124, 130))	('HDAC', 'Gene', '9734', (164, 168))	('HDAC', 'Gene', (132, 136))	('HDAC', 'Gene', (149, 153))	('HDAC1', 'Gene', '3065', (186, 191))	('HDAC', 'Gene', '9734', (186, 190))	('HDAC11', 'Gene', '79885', (186, 192))	('HDAC', 'Gene', (116, 120))	('HDAC', 'Gene', (164, 168))
109051	33634093	In fact, HDAC1 seems to be one of the main targets of belinostat since HeLa cell knockdown for HDAC1 decreases its sensitivity to belinostat (Dejligbjerg et al.,).	('HDAC1', 'Gene', '3065', (9, 14))	('decreases', 'NegReg', (101, 110))	('HDAC1', 'Gene', (95, 100))	('HeLa', 'CellLine', 'CVCL:0030', (71, 75))	('belinostat', 'Chemical', 'MESH:C487081', (54, 64))	('knockdown', 'Var', (81, 90))	('belinostat', 'Chemical', 'MESH:C487081', (130, 140))	('HDAC1', 'Gene', '3065', (95, 100))	('HDAC1', 'Gene', (9, 14))	('sensitivity to belinostat', 'MPA', (115, 140))
109057	33634093	Using recombinant enzymes, it was found that panobinostat has a role as pan-inhibitor, being more potent than vorinostat and belinostat.	('belinostat', 'Chemical', 'MESH:C487081', (125, 135))	('potent', 'MPA', (98, 104))	('vorinostat', 'Chemical', 'MESH:D000077337', (110, 120))	('panobinostat', 'Var', (45, 57))	('panobinostat', 'Chemical', 'MESH:D000077767', (45, 57))
109061	33634093	In cervical cancer cells, it was found that panobinostat increases histone H3 acetylation and diminishes the cellular viability in a dose- and time-dependent manner.	('cellular viability', 'CPA', (109, 127))	('panobinostat', 'Var', (44, 56))	('acetyl', 'Chemical', '-', (78, 84))	('cervical cancer', 'Disease', 'MESH:D002583', (3, 18))	('diminishes', 'NegReg', (94, 104))	('cervical cancer', 'Disease', (3, 18))	('histone', 'MPA', (67, 74))	('panobinostat', 'Chemical', 'MESH:D000077767', (44, 56))	('increases', 'PosReg', (57, 66))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))
109072	33634093	The synergism between HDACi and topoisomerase inhibitors can be explained based on HDACi's effect, which after hyperacetylation keeps the chromatin structure opened, allowing easy access to DNA by damaging agents (Nolan et al.,).	('HDAC', 'Gene', (83, 87))	('acetyl', 'Chemical', '-', (116, 122))	('HDAC', 'Gene', '9734', (83, 87))	('hyperacetylation', 'Var', (111, 127))	('HDAC', 'Gene', (22, 26))	('chromatin', 'MPA', (138, 147))	('HDAC', 'Gene', '9734', (22, 26))
109075	33634093	Acetylation of p53 results in the transcriptional activation of target genes, such as the pro-apoptotic Bad protein (Lee et al.,).	('Acetylation', 'Var', (0, 11))	('activation', 'PosReg', (50, 60))	('p53', 'Gene', '7157', (15, 18))	('p53', 'Gene', (15, 18))	('transcriptional', 'MPA', (34, 49))
109090	33634093	In vivo, the combination of vorinostat and bortezomib improves even more the specificity of the immune system against the tumor, making cancerous cells more susceptible to antigen-specific CD8+ T cells than those treated with isolated drugs (Huang et al.,).	('cancerous', 'Disease', 'MESH:D009369', (136, 145))	('vorinostat', 'Chemical', 'MESH:D000077337', (28, 38))	('improves', 'PosReg', (54, 62))	('susceptible', 'MPA', (157, 168))	('bortezomib', 'Gene', (43, 53))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('cancerous', 'Disease', (136, 145))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('bortezomib', 'Chemical', 'MESH:D000069286', (43, 53))	('combination', 'Var', (13, 24))	('tumor', 'Disease', (122, 127))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('specificity', 'MPA', (77, 88))
109187	31842910	The optimal cutoff values of lung V5, V20, V30 and MLD were set at 44% (AUC [area under the curve] = 0.593), 24% (AUC = 0.607), 14.2% (AUC = 0.622) and 1226 cGy (AUC = 0.626).	('V30', 'Var', (43, 46))	('MLD', 'Disease', 'MESH:D007966', (51, 54))	('MLD', 'Disease', (51, 54))	('1226 cGy', 'Var', (152, 160))
109188	31842910	The grade >= 2 RP rate was only 9.4% for the low-risk group (Lung V5 <= 44%, V20 <= 24%, V30 <= 14.2%, and MLD <= 1226 cGy) in patients received gemcitabine induction chemotherapy.	('MLD', 'Disease', (107, 110))	('V30 <=', 'Var', (89, 95))	('gemcitabine', 'Chemical', 'MESH:C056507', (145, 156))	('patients', 'Species', '9606', (127, 135))	('V20 <= 24%', 'Var', (77, 87))	('MLD', 'Disease', 'MESH:D007966', (107, 110))
109202	31842910	Dosimetric parameters, including mean lung dose (MLD), V5, V20, V30, are still the best predictors of RP at present.	('V30', 'Var', (64, 67))	('V20', 'Var', (59, 62))	('MLD', 'Disease', 'MESH:D007966', (49, 52))	('MLD', 'Disease', (49, 52))
109203	31842910	To reduce the risk of RP, the National Comprehensive Cancer Network (NCCN) guidelines limit the dose-volume parameters of lungs as follows: MLD <= 20 Gy, V20 <= 35% and V5 <= 65%.	('Cancer', 'Disease', 'MESH:D009369', (53, 59))	('Cancer', 'Phenotype', 'HP:0002664', (53, 59))	('V5 <= 65', 'Var', (169, 177))	('V20 <= 35%', 'Var', (154, 164))	('MLD', 'Disease', 'MESH:D007966', (140, 143))	('MLD', 'Disease', (140, 143))	('Cancer', 'Disease', (53, 59))
109244	31842910	The AUCs for lung V5, V20, V30, and MLD are all statistically significant (P<0.05).	('V20', 'Var', (22, 25))	('V30', 'Var', (27, 30))	('MLD', 'Disease', 'MESH:D007966', (36, 39))	('MLD', 'Disease', (36, 39))
109245	31842910	After calculation the highest Youden index, the optimal cutoff values of lung V5, V20, V30 and MLD were set at 44% (AUC = 0.593), 24% (AUC = 0.607), 14.2% (AUC = 0.622) and 1226 cGy (AUC = 0.626).	('MLD', 'Disease', 'MESH:D007966', (95, 98))	('MLD', 'Disease', (95, 98))	('1226 cGy', 'Var', (173, 181))
109249	31842910	Lung V5, V20, V30, and MLD were all associated with increased risk of grade >= 2 RP in univariate analysis (Table 2).	('grade >= 2 RP', 'Disease', (70, 83))	('V30', 'Var', (14, 17))	('MLD', 'Disease', 'MESH:D007966', (23, 26))	('V20', 'Var', (9, 12))	('MLD', 'Disease', (23, 26))
109287	31842910	Numerous studies demonstrated that dose-volume parameters, such as lung V5, V10, V20, V30, V50, and MLD, could efficiently predict the occurrence of RP.	('V30', 'Var', (86, 89))	('V50', 'Var', (91, 94))	('V20', 'Var', (81, 84))	('MLD', 'Disease', 'MESH:D007966', (100, 103))	('MLD', 'Disease', (100, 103))
109288	31842910	In our study, all dosimetric parameters considered in the study (lung V5, V20, V30, and MLD) correlated significantly with RP in all patients and in the subgroup of patients who received gemcitabine induction chemotherapy.	('correlated', 'Reg', (93, 103))	('V30', 'Var', (79, 82))	('MLD', 'Disease', 'MESH:D007966', (88, 91))	('MLD', 'Disease', (88, 91))	('patients', 'Species', '9606', (133, 141))	('patients', 'Species', '9606', (165, 173))	('gemcitabine', 'Chemical', 'MESH:C056507', (187, 198))
109289	31842910	study showed that V30 >= 18% was one of the best predictors of severe acute RP among patients treated with definitive external beam radiotherapy.	('patients', 'Species', '9606', (85, 93))	('severe acute RP', 'Disease', (63, 78))	('V30 >= 18%', 'Var', (18, 28))
109296	31842910	Lung V5, V20, V30, and MLD were all associated with increased risk of grade >= 2 RP in patients received gemcitabine induction chemotherapy followed by radiotherapy.	('grade >= 2 RP', 'Disease', (70, 83))	('V30', 'Var', (14, 17))	('MLD', 'Disease', 'MESH:D007966', (23, 26))	('V20', 'Var', (9, 12))	('MLD', 'Disease', (23, 26))	('gemcitabine', 'Chemical', 'MESH:C056507', (105, 116))	('patients', 'Species', '9606', (87, 95))
109297	31842910	The grade >= 2 RP rate was only 9.4% for the low-risk group (Lung V5 <= 44%, V20 <= 24%, V30 <= 14.2%, and MLD <= 1226 cGy).	('MLD', 'Disease', 'MESH:D007966', (107, 110))	('MLD', 'Disease', (107, 110))	('V20 <= 24%', 'Var', (77, 87))	('V30 <=', 'Var', (89, 95))
109394	33925297	Inhibition of MYC and NF-kappaB signaling using KJ-Pyr-9, dexamethasone, and pyrrolidinedithiocarbamate resulted in significant reductions in cell survival for SCC- and AC-derived cells.	('KJ-Pyr-9', 'Var', (48, 56))	('reductions', 'NegReg', (128, 138))	('cell survival', 'CPA', (142, 155))	('Inhibition', 'NegReg', (0, 10))	('MYC', 'Gene', (14, 17))	('pyrrolidinedithiocarbamate', 'Chemical', 'MESH:C020972', (77, 103))	('NF-kappaB', 'Gene', (22, 31))	('dexamethasone', 'Chemical', 'MESH:D003907', (58, 71))	('pyrrolidinedithiocarbamate', 'Var', (77, 103))	('MYC', 'Gene', '4609', (14, 17))	('KJ-Pyr-9', 'Chemical', 'MESH:C000593138', (48, 56))	('SCC', 'Phenotype', 'HP:0002860', (160, 163))	('NF-kappaB', 'Gene', '4790', (22, 31))
109406	33925297	Within a recent pan-cancer study, Schaub and coworkers identified MYC family members amplified in up to 33% of all lung adenocarcinomas.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('carcinomas', 'Phenotype', 'HP:0030731', (125, 135))	('MYC', 'Gene', (66, 69))	('lung adenocarcinomas', 'Disease', (115, 135))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (115, 135))	('cancer', 'Disease', 'MESH:D009369', (20, 26))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (115, 135))	('cancer', 'Disease', (20, 26))	('MYC', 'Gene', '4609', (66, 69))	('amplified', 'Var', (85, 94))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (115, 134))
109418	33925297	Notably, exposure of AC- and SCC-derived CSCs to the small molecule KJ-Pyr-9, which inhibits the protein-protein interaction of MYC/N-myc proto-oncogene (NMYC) with Myc-associated factor X (MAX), resulted in the strongest decrease in cell survival.	('cell survival', 'CPA', (234, 247))	('decrease', 'NegReg', (222, 230))	('Myc-associated factor X', 'Gene', '4149', (165, 188))	('NMYC', 'Gene', (154, 158))	('MAX', 'Gene', '4149', (190, 193))	('KJ-Pyr-9', 'Var', (68, 76))	('N-myc proto-oncogene', 'Gene', (132, 152))	('MYC', 'Gene', '4609', (155, 158))	('MYC', 'Gene', (128, 131))	('KJ-Pyr-9', 'Chemical', 'MESH:C000593138', (68, 76))	('Myc-associated factor X', 'Gene', (165, 188))	('inhibits', 'NegReg', (84, 92))	('NMYC', 'Gene', '4613', (154, 158))	('protein-protein interaction', 'MPA', (97, 124))	('MAX', 'Gene', (190, 193))	('SCC', 'Phenotype', 'HP:0002860', (29, 32))	('MYC', 'Gene', '4609', (128, 131))	('MYC', 'Gene', (155, 158))	('N-myc proto-oncogene', 'Gene', '4613', (132, 152))
109472	33925297	To analyze the influence of the proto-oncogenes MYC and NMYC as well as transcription factor NF-kB, we treated cells with MYC/NMYC inhibitor KJ-Pyr-9 (Merck) and/or dexamethasone (Dexa; Sigma Aldrich), lenalidomide (Sigma Aldrich), and PDTC (Sigma Aldrich).	('Aldrich', 'Disease', 'MESH:D014923', (248, 255))	('NF-kB', 'Gene', '309165', (93, 98))	('KJ-Pyr-9', 'Var', (141, 149))	('Aldrich', 'Disease', (222, 229))	('MYC', 'Gene', (122, 125))	('KJ-Pyr-9', 'Chemical', 'MESH:C000593138', (141, 149))	('PDTC', 'Chemical', 'MESH:C020972', (236, 240))	('dexamethasone', 'Chemical', 'MESH:D003907', (165, 178))	('Aldrich', 'Disease', 'MESH:D014923', (222, 229))	('MYC', 'Gene', (57, 60))	('lenalidomide', 'Chemical', 'MESH:D000077269', (202, 214))	('MYC', 'Gene', (127, 130))	('NMYC', 'Gene', (56, 60))	('MYC', 'Gene', (48, 51))	('Aldrich', 'Disease', (192, 199))	('MYC', 'Gene', '4609', (122, 125))	('NMYC', 'Gene', (126, 130))	('Aldrich', 'Disease', (248, 255))	('NF-kB', 'Gene', (93, 98))	('NMYC', 'Gene', '4613', (56, 60))	('MYC', 'Gene', '4609', (57, 60))	('MYC', 'Gene', '4609', (127, 130))	('Merck', 'Chemical', '-', (151, 156))	('Aldrich', 'Disease', 'MESH:D014923', (192, 199))	('Dexa', 'Chemical', 'MESH:D003907', (180, 184))	('MYC', 'Gene', '4609', (48, 51))	('NMYC', 'Gene', '4613', (126, 130))
109482	33925297	Analysis of clinically relevant mutations of donors of BKZ-7, -8, and -9, which were inoperable, revealed an epidermal growth factor receptor (EGFR) mutation for the tumor tissue of the donor of BKZ-7, with no mutation for KRAS proto-oncogene (KRAS), B-Raf proto-oncogene (BRAF), or serine/threonine kinase 11 (STK11).	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('BKZ-', 'Chemical', '-', (195, 199))	('epidermal growth factor receptor', 'Gene', (109, 141))	('serine/threonine kinase 11', 'Gene', '6794', (283, 309))	('epidermal growth factor receptor', 'Gene', '1956', (109, 141))	('mutations', 'Var', (32, 41))	('B-Raf proto-oncogene', 'Gene', '673', (251, 271))	('EGFR', 'Gene', (143, 147))	('STK11', 'Gene', (311, 316))	('serine/threonine kinase 11', 'Gene', (283, 309))	('KRAS', 'Gene', '3845', (223, 227))	('BKZ-', 'Chemical', '-', (55, 59))	('tumor', 'Disease', (166, 171))	('B-Raf proto-oncogene', 'Gene', (251, 271))	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('KRAS', 'Gene', (223, 227))	('KRAS', 'Gene', '3845', (244, 248))	('BRAF', 'Gene', '673', (273, 277))	('BRAF', 'Gene', (273, 277))	('STK11', 'Gene', '6794', (311, 316))	('EGFR', 'Gene', '1956', (143, 147))	('mutation', 'Var', (149, 157))	('KRAS', 'Gene', (244, 248))
109483	33925297	Donor of BKZ-8 did not reveal any therapeutic relevant mutation, while the tumor material of BKZ-9 donor showed mutations in the KRAS gene and in STK11 (Table S2).	('BKZ-9', 'Chemical', '-', (93, 98))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('KRAS', 'Gene', (129, 133))	('mutations', 'Var', (112, 121))	('BKZ-8', 'Chemical', '-', (9, 14))	('KRAS', 'Gene', '3845', (129, 133))	('STK11', 'Gene', (146, 151))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', (75, 80))	('STK11', 'Gene', '6794', (146, 151))
109518	33925297	On the basis of the consistent expression of MYC and NMYC in all NSCLC-derived cells, we examined the influence of the small molecule KJ-Pyr-9, an inhibitor of the protein-protein interaction of MYC/NMYC with MAX.	('MYC', 'Gene', (195, 198))	('MYC', 'Gene', '4609', (54, 57))	('KJ-Pyr-9', 'Chemical', 'MESH:C000593138', (134, 142))	('NMYC', 'Gene', '4613', (53, 57))	('MYC', 'Gene', '4609', (45, 48))	('MYC', 'Gene', (200, 203))	('NMYC', 'Gene', (199, 203))	('MYC', 'Gene', '4609', (195, 198))	('MAX', 'Gene', '4149', (209, 212))	('SCLC', 'Phenotype', 'HP:0030357', (66, 70))	('NSCLC', 'Disease', 'MESH:D002289', (65, 70))	('MYC', 'Gene', (54, 57))	('NSCLC', 'Disease', (65, 70))	('MYC', 'Gene', '4609', (200, 203))	('NMYC', 'Gene', '4613', (199, 203))	('MYC', 'Gene', (45, 48))	('NMYC', 'Gene', (53, 57))	('NSCLC', 'Phenotype', 'HP:0030358', (65, 70))	('KJ-Pyr-9', 'Var', (134, 142))	('MAX', 'Gene', (209, 212))
109521	33925297	Treatment with 10 microM KJ-Pyr-9 led to a significant decrease of the survival rates of BKZ-4 with 72.42% (+-8.43), BKZ-5 with 80.01% (+-1.4), and BKZ-6 with 70.23% (+-4.62).	('BKZ-4', 'Chemical', '-', (89, 94))	('survival rates', 'CPA', (71, 85))	('decrease', 'NegReg', (55, 63))	('KJ-Pyr-9', 'Chemical', 'MESH:C000593138', (25, 33))	('BKZ-6', 'Chemical', '-', (148, 153))	('BKZ-5', 'Chemical', '-', (117, 122))	('KJ-Pyr-9', 'Var', (25, 33))
109522	33925297	Nevertheless, especially the treatment with 20 microM KJ-Pyr-9 showed a potential therapeutically relevant effect on survival of BKZ-4, -5, and -6, as survival rates were impaired to 4.92% (+-0.16), 3.58% (+-0.32), and 3.09% (+-0.19), respectively (Figure 5A-C).	('KJ-Pyr-9', 'Chemical', 'MESH:C000593138', (54, 62))	('KJ-Pyr-9', 'Var', (54, 62))	('impaired', 'NegReg', (171, 179))	('survival', 'CPA', (117, 125))	('BKZ-4', 'Chemical', '-', (129, 134))	('survival rates', 'CPA', (151, 165))
109526	33925297	Nevertheless, for AC-derived cells, only concentrations greater than 10 microM KJ-Pyr-9 revealed a significant effect on cell survival compared to control.	('cell survival', 'CPA', (121, 134))	('KJ-Pyr-9', 'Chemical', 'MESH:C000593138', (79, 87))	('KJ-Pyr-9', 'Var', (79, 87))	('effect', 'Reg', (111, 117))
109527	33925297	Again, usage of 20 microM KJ-Pyr-9 reduced cell survival significantly for BKZ-7 to 5.98% (+-0.93), BKZ-8 to 2.02% (+-0.33), and BKZ-9 to 3.36% (+-0.28) (Figure 5D-F).	('BKZ-', 'Chemical', '-', (75, 79))	('BKZ-', 'Chemical', '-', (100, 104))	('reduced', 'NegReg', (35, 42))	('BKZ-8', 'Chemical', '-', (100, 105))	('BKZ-9', 'Chemical', '-', (129, 134))	('KJ-Pyr-9', 'Chemical', 'MESH:C000593138', (26, 34))	('KJ-Pyr-9', 'Var', (26, 34))	('cell survival', 'CPA', (43, 56))	('BKZ-', 'Chemical', '-', (129, 133))
109529	33925297	However, only application of 20 microM KJ-Pyr-9 impaired cell survival in a highly significant way, with final survival of only 3.79% (+-0.65) (Figure 5H).	('impaired', 'NegReg', (48, 56))	('KJ-Pyr-9', 'Chemical', 'MESH:C000593138', (39, 47))	('KJ-Pyr-9', 'Var', (39, 47))	('cell survival', 'CPA', (57, 70))
109531	33925297	Investigation of the influence of KJ-Pyr-9 on LXF-289 cells revealed significant reductions in cell survival after exposure to 10 microM KJ-Pyr-9 with 69.78% (+-3.62) and 20 microM KJ-Pyr-9 with 9.877 (+-4.94) survival left (Figure 5I).	('reductions', 'NegReg', (81, 91))	('KJ-Pyr-9', 'Chemical', 'MESH:C000593138', (137, 145))	('KJ-Pyr-9', 'Chemical', 'MESH:C000593138', (34, 42))	('KJ-Pyr-9', 'Var', (137, 145))	('LXF-289', 'CellLine', 'CVCL:1394', (46, 53))	('KJ-Pyr-9', 'Chemical', 'MESH:C000593138', (181, 189))	('cell survival', 'CPA', (95, 108))
109532	33925297	Interestingly, 24 h treatment of NSCLC-derived cell populations with 10 or 20 microM KJ-Pyr-9 led to heterogeneous nuclear localization of MYC for SCC- and AC-derived cell populations (Supplementary Figure S11).	('NSCLC', 'Phenotype', 'HP:0030358', (33, 38))	('SCLC', 'Phenotype', 'HP:0030357', (34, 38))	('SCC', 'Phenotype', 'HP:0002860', (147, 150))	('heterogeneous nuclear localization', 'MPA', (101, 135))	('MYC', 'Gene', '4609', (139, 142))	('MYC', 'Gene', (139, 142))	('NSCLC', 'Disease', (33, 38))	('KJ-Pyr-9', 'Chemical', 'MESH:C000593138', (85, 93))	('KJ-Pyr-9', 'Var', (85, 93))	('NSCLC', 'Disease', 'MESH:D002289', (33, 38))
109533	33925297	Analysis of potential target genes of MYC involved in the KJ-Pyr-9-induced survival decrease revealed a decrease of cyclin D1 (CCND1) after 24 h treatment with 20 microM KJ-Pyr-9 for BKZ-6 and BKZ-8 as representative cell populations for squamous cell carcinoma- and adenocarcinoma-derived LCSC-like cells.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (238, 261))	('MYC', 'Gene', '4609', (38, 41))	('BKZ-6', 'Chemical', '-', (183, 188))	('decrease', 'NegReg', (84, 92))	('adenocarcinoma', 'Disease', (267, 281))	('KJ-Pyr-9', 'Var', (170, 178))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (238, 261))	('CCND1', 'Gene', '595', (127, 132))	('adenocarcinoma', 'Disease', 'MESH:D000230', (267, 281))	('KJ-Pyr-9', 'Chemical', 'MESH:C000593138', (170, 178))	('carcinoma', 'Phenotype', 'HP:0030731', (252, 261))	('squamous cell carcinoma', 'Disease', (238, 261))	('decrease', 'NegReg', (104, 112))	('cyclin D1', 'Gene', (116, 125))	('CCND1', 'Gene', (127, 132))	('BKZ-8', 'Chemical', '-', (193, 198))	('KJ-Pyr-9', 'Chemical', 'MESH:C000593138', (58, 66))	('MYC', 'Gene', (38, 41))	('cyclin D1', 'Gene', '595', (116, 125))	('carcinoma', 'Phenotype', 'HP:0030731', (272, 281))
109534	33925297	Additionally, BKZ-8 exhibited significantly reduced mRNA expression levels of ribosomal protein lateral stalk subunit P1 (RPLP1) and ribosomal protein L28 (RPL28), both involved in ribosomal biosynthesis.	('RPLP1', 'Gene', '6176', (122, 127))	('ribosomal protein lateral stalk subunit P1', 'Gene', '6176', (78, 120))	('RPL28', 'Gene', (156, 161))	('RPLP1', 'Gene', (122, 127))	('RPL28', 'Gene', '6158', (156, 161))	('BKZ-8', 'Chemical', '-', (14, 19))	('ribosomal protein lateral stalk subunit P1', 'Gene', (78, 120))	('ribosomal protein L28', 'Gene', (133, 154))	('ribosomal protein L28', 'Gene', '6158', (133, 154))	('reduced', 'NegReg', (44, 51))	('mRNA expression levels', 'MPA', (52, 74))	('BKZ-8', 'Var', (14, 19))
109535	33925297	Not regulated in LCSC-like cells but regulated in the lung adenocarcinoma cell line LXF-289 were lactate dehydrogenase A (LDHA) and MYC mRNA expressions, as LDHA was significantly reduced and MYC significantly increased after KJ-Pyr-9 application (Figure 6).	('LDHA', 'Gene', '3939', (157, 161))	('LXF-289', 'CellLine', 'CVCL:1394', (84, 91))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (54, 73))	('MYC', 'Gene', (192, 195))	('KJ-Pyr-9', 'Var', (226, 234))	('MYC', 'Gene', '4609', (132, 135))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (54, 73))	('lactate dehydrogenase A', 'Gene', '3939', (97, 120))	('KJ-Pyr-9', 'Chemical', 'MESH:C000593138', (226, 234))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))	('LDHA', 'Gene', (157, 161))	('LDHA', 'Gene', '3939', (122, 126))	('increased', 'PosReg', (210, 219))	('lactate dehydrogenase A', 'Gene', (97, 120))	('MYC', 'Gene', '4609', (192, 195))	('reduced', 'NegReg', (180, 187))	('MYC', 'Gene', (132, 135))	('lung adenocarcinoma', 'Disease', (54, 73))	('LDHA', 'Gene', (122, 126))
109537	33925297	Additional analysis of the number of senescent cells after treatment with 20 microM KJ-Pyr-9 for 24 h led to a significant increase in SCC-derived senescent cells, but not in AC-derived senescent cells (Supplementary Figure S13).	('SCC-derived', 'Disease', (135, 146))	('KJ-Pyr-9', 'Chemical', 'MESH:C000593138', (84, 92))	('KJ-Pyr-9', 'Var', (84, 92))	('increase', 'PosReg', (123, 131))	('SCC', 'Phenotype', 'HP:0002860', (135, 138))
109540	33925297	Here, treatment with dexamethasone (300 microM) and PDTC (100 microM) led to significant reductions of SCC- and AC-derived cell survival (Figure 7A,B).	('reductions', 'NegReg', (89, 99))	('SCC', 'Phenotype', 'HP:0002860', (103, 106))	('dexamethasone', 'Chemical', 'MESH:D003907', (21, 34))	('PDTC', 'Chemical', 'MESH:C020972', (52, 56))	('100', 'Var', (58, 61))
109546	33925297	Interestingly, nuclear RelA localization was only slightly affected by PDTC-treatment for 24 h, although a tendency showing a decrease in the ratio of nuclear RelA to total RelA was observable after exposure of LCSC-like cells to PDTC compared to control (Supplementary Figure S15).	('RelA', 'Gene', (173, 177))	('RelA', 'Gene', (23, 27))	('PDTC', 'Var', (230, 234))	('PDTC', 'Chemical', 'MESH:C020972', (71, 75))	('RelA', 'Gene', '5970', (173, 177))	('RelA', 'Gene', '5970', (159, 163))	('PDTC', 'Chemical', 'MESH:C020972', (230, 234))	('decrease', 'NegReg', (126, 134))	('ratio', 'MPA', (142, 147))	('RelA', 'Gene', '5970', (23, 27))	('RelA', 'Gene', (159, 163))
109549	33925297	Accordingly, combined MYC/NMYC and NF-kappaB inhibition using 10 microM KJ-Pyr-9 with dexamethasone and/or PDTC did not result in synergistic reductions in survival of NSCLC-derived LCSC-like cells.	('inhibition', 'NegReg', (45, 55))	('MYC', 'Gene', '4609', (22, 25))	('reductions', 'NegReg', (142, 152))	('KJ-Pyr-9', 'Chemical', 'MESH:C000593138', (72, 80))	('KJ-Pyr-9', 'Var', (72, 80))	('NMYC', 'Gene', '4613', (26, 30))	('NSCLC', 'Disease', 'MESH:D002289', (168, 173))	('NMYC', 'Gene', (26, 30))	('NF-kappaB', 'Gene', '4790', (35, 44))	('NSCLC', 'Phenotype', 'HP:0030358', (168, 173))	('SCLC', 'Phenotype', 'HP:0030357', (169, 173))	('MYC', 'Gene', (22, 25))	('dexamethasone', 'Chemical', 'MESH:D003907', (86, 99))	('MYC', 'Gene', '4609', (27, 30))	('PDTC', 'Chemical', 'MESH:C020972', (107, 111))	('NF-kappaB', 'Gene', (35, 44))	('NSCLC', 'Disease', (168, 173))	('MYC', 'Gene', (27, 30))
109551	33925297	The use of TNF-alpha, KJ-Pyr-9, dexamethasone, and PDTC in parallel did not impair NSCLC-derived LCSC-like cell survival synergistically (Figure 7A,B).	('TNF-alpha', 'Gene', '7124', (11, 20))	('NSCLC', 'Disease', (83, 88))	('KJ-Pyr-9', 'Chemical', 'MESH:C000593138', (22, 30))	('impair', 'NegReg', (76, 82))	('NSCLC', 'Disease', 'MESH:D002289', (83, 88))	('TNF-alpha', 'Gene', (11, 20))	('PDTC', 'Chemical', 'MESH:C020972', (51, 55))	('KJ-Pyr-9', 'Var', (22, 30))	('NSCLC', 'Phenotype', 'HP:0030358', (83, 88))	('SCLC', 'Phenotype', 'HP:0030357', (84, 88))	('dexamethasone', 'Chemical', 'MESH:D003907', (32, 45))
109552	33925297	In summary, the inhibition of MYC/NMYC signaling using KJ-Pyr-9 as well as the inhibition of NF-kappaB signaling utilizing dexamethasone or PDTC significantly reduced survival of SCC- and AC-derived LCSC-like cells with no synergistic effects (Table 2).	('NMYC', 'Gene', '4613', (34, 38))	('MYC', 'Gene', (35, 38))	('SCC', 'Phenotype', 'HP:0002860', (179, 182))	('MYC', 'Gene', '4609', (30, 33))	('survival', 'CPA', (167, 175))	('inhibition', 'NegReg', (16, 26))	('reduced', 'NegReg', (159, 166))	('dexamethasone', 'Chemical', 'MESH:D003907', (123, 136))	('PDTC', 'Chemical', 'MESH:C020972', (140, 144))	('NF-kappaB', 'Gene', '4790', (93, 102))	('NMYC', 'Gene', (34, 38))	('MYC', 'Gene', '4609', (35, 38))	('MYC', 'Gene', (30, 33))	('NF-kappaB', 'Gene', (93, 102))	('KJ-Pyr-9', 'Chemical', 'MESH:C000593138', (55, 63))	('KJ-Pyr-9', 'Var', (55, 63))
109553	33925297	Usage of low doses of the MYC signaling inhibitor KJ-Pyr-9 led to a significant depletion in survival of SCC- as well as AC-derived LCSC-like cells, representing the impairment of protein-protein interaction of MYC/NMYC, with MAX as a promising target in treating NCSLC, particularly by engaging MYC high-expressing LCSC.	('MYC', 'Gene', '4609', (211, 214))	('NCSLC', 'Disease', (264, 269))	('MYC', 'Gene', (296, 299))	('MAX', 'Gene', (226, 229))	('MYC', 'Gene', (216, 219))	('MYC', 'Gene', '4609', (26, 29))	('MAX', 'Gene', '4149', (226, 229))	('NMYC', 'Gene', (215, 219))	('KJ-Pyr-9', 'Chemical', 'MESH:C000593138', (50, 58))	('KJ-Pyr-9', 'Var', (50, 58))	('NMYC', 'Gene', '4613', (215, 219))	('survival', 'CPA', (93, 101))	('MYC', 'Gene', (211, 214))	('MYC', 'Gene', '4609', (216, 219))	('MYC', 'Gene', '4609', (296, 299))	('SCC', 'Phenotype', 'HP:0002860', (105, 108))	('MYC', 'Gene', (26, 29))	('depletion', 'NegReg', (80, 89))
109563	33925297	Regarding NSCLC, a knockdown of Nestin protein using short hairpin RNA not only decreased proliferation but also affected migration, invasion, and sphere formation of AC-derived cells.	('NSCLC', 'Disease', (10, 15))	('affected', 'Reg', (113, 121))	('Nestin', 'Gene', '10763', (32, 38))	('NSCLC', 'Disease', 'MESH:D002289', (10, 15))	('invasion', 'CPA', (133, 141))	('proliferation', 'CPA', (90, 103))	('knockdown', 'Var', (19, 28))	('SCLC', 'Phenotype', 'HP:0030357', (11, 15))	('Nestin', 'Gene', (32, 38))	('sphere formation of', 'CPA', (147, 166))	('short', 'Gene', (53, 58))	('decreased', 'NegReg', (80, 89))	('NSCLC', 'Phenotype', 'HP:0030358', (10, 15))	('migration', 'CPA', (122, 131))
109564	33925297	This stands in accordance with Liu and coworkers, who indicated that a CRISPR/Cas9-mediated knockout of Nestin led to reduced proliferation, invasion, and colony formation of H1299 and A549 cell lines.	('invasion', 'CPA', (141, 149))	('proliferation', 'CPA', (126, 139))	('Nestin', 'Gene', (104, 110))	('knockout', 'Var', (92, 100))	('A549', 'CellLine', 'CVCL:0023', (185, 189))	('reduced', 'NegReg', (118, 125))	('H1299', 'CellLine', 'CVCL:0060', (175, 180))	('Nestin', 'Gene', '10763', (104, 110))	('colony formation', 'CPA', (155, 171))
109571	33925297	While KJ-Pyr-9 is a small molecule with highest activity in MYC inhibition, it is interesting to note that recent efforts in drug development led to new derivates with similar activity but higher solubility and better stability.	('MYC', 'Gene', '4609', (60, 63))	('solubility', 'MPA', (196, 206))	('MYC', 'Gene', (60, 63))	('KJ-Pyr-9', 'Chemical', 'MESH:C000593138', (6, 14))	('KJ-Pyr-9', 'Var', (6, 14))
109575	33925297	Notably, inhibition of MYC by application of 20 microM small molecule KJ-Pyr-9 resulted in strong inhibition of cell survival in LCSC-like cells, while concentration of up to 10 muM KJ-Pyr-9 led to a slight yet significant decrease in survival.	('inhibition', 'NegReg', (9, 19))	('KJ-Pyr-9', 'Chemical', 'MESH:C000593138', (70, 78))	('KJ-Pyr-9', 'Var', (70, 78))	('MYC', 'Gene', '4609', (23, 26))	('inhibition', 'NegReg', (98, 108))	('cell survival in LCSC-like cells', 'CPA', (112, 144))	('MYC', 'Gene', (23, 26))	('KJ-Pyr-9', 'Chemical', 'MESH:C000593138', (182, 190))
109578	33925297	On the contrary, KJ-Pyr-9 was described to have no effect on MYC-MAX in an SPR assay up to 10 muM, with the reason for this discrepancy being unclear.	('MAX', 'Gene', (65, 68))	('MAX', 'Gene', '4149', (65, 68))	('MYC', 'Gene', '4609', (61, 64))	('KJ-Pyr-9', 'Chemical', 'MESH:C000593138', (17, 25))	('SPR assay up to 10 muM', 'MPA', (75, 97))	('MYC', 'Gene', (61, 64))	('KJ-Pyr-9', 'Var', (17, 25))
109580	33925297	Nevertheless, MYC and NMYC expression of LXF-289 were principally lower in comparison to BKZ populations, except for BKZ-4 for MYC protein.	('BKZ', 'Chemical', '-', (117, 120))	('LXF-289', 'CellLine', 'CVCL:1394', (41, 48))	('MYC', 'Gene', (14, 17))	('BKZ-4 for MYC', 'Gene', (117, 130))	('NMYC', 'Gene', (22, 26))	('LXF-289', 'Var', (41, 48))	('lower', 'NegReg', (66, 71))	('MYC', 'Gene', '4609', (23, 26))	('MYC', 'Gene', '4609', (127, 130))	('MYC', 'Gene', (23, 26))	('MYC', 'Gene', '4609', (14, 17))	('BKZ', 'Chemical', '-', (89, 92))	('BKZ-4 for MYC', 'Gene', '4609', (117, 130))	('NMYC', 'Gene', '4613', (22, 26))	('MYC', 'Gene', (127, 130))
109582	33925297	To gain first insights into the working mechanism of KJ-Pyr-9-induced survival decrease in MYC expressing lung cancer cells, we tested for alterations in mRNA levels of several known MYC target genes, such as CCND1, CCND3, and MYC itself.	('tested', 'Reg', (128, 134))	('MYC', 'Gene', (227, 230))	('CCND1', 'Gene', (209, 214))	('CCND3', 'Gene', (216, 221))	('lung cancer', 'Disease', 'MESH:D008175', (106, 117))	('MYC', 'Gene', '4609', (91, 94))	('lung cancer', 'Phenotype', 'HP:0100526', (106, 117))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('MYC', 'Gene', (183, 186))	('KJ-Pyr-9', 'Chemical', 'MESH:C000593138', (53, 61))	('survival', 'CPA', (70, 78))	('MYC', 'Gene', '4609', (227, 230))	('CCND3', 'Gene', '896', (216, 221))	('alterations', 'Reg', (139, 150))	('KJ-Pyr-9-induced', 'Var', (53, 69))	('MYC', 'Gene', '4609', (183, 186))	('lung cancer', 'Disease', (106, 117))	('decrease', 'NegReg', (79, 87))	('MYC', 'Gene', (91, 94))	('mRNA levels', 'MPA', (154, 165))	('CCND1', 'Gene', '595', (209, 214))
109585	33925297	Quantification revealed significant reductions in CCND1 mRNA levels for the representative LCSC-like cell populations BKZ-6 and BKZ-8 after KJ-Pyr-9 application, possibly explaining the survival-decreasing effects.	('reductions', 'NegReg', (36, 46))	('CCND1', 'Gene', (50, 55))	('KJ-Pyr-9', 'Chemical', 'MESH:C000593138', (140, 148))	('CCND1', 'Gene', '595', (50, 55))	('BKZ-8', 'Chemical', '-', (128, 133))	('KJ-Pyr-9', 'Var', (140, 148))	('BKZ-6', 'Chemical', '-', (118, 123))
109591	33925297	Thus, downregulation of LDHA may be one cause for KJ-Pyr-9-mediated decrease in cell survival of LXF-289.	('LDHA', 'Gene', (24, 28))	('LDHA', 'Gene', '3939', (24, 28))	('decrease', 'NegReg', (68, 76))	('cell survival', 'CPA', (80, 93))	('KJ-Pyr-9', 'Chemical', 'MESH:C000593138', (50, 58))	('downregulation', 'NegReg', (6, 20))	('LXF-289', 'CellLine', 'CVCL:1394', (97, 104))	('KJ-Pyr-9-mediated', 'Var', (50, 67))
109593	33925297	Further, the in 1995 established lung adenocarcinoma-derived cell line LXF-289 showed atypical effects upon MYC inhibition, as mRNA levels of the transcript were increased by KJ-Pyr-9 treatment.	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (33, 52))	('increased', 'PosReg', (162, 171))	('mRNA levels of the transcript', 'MPA', (127, 156))	('MYC', 'Gene', (108, 111))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (33, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (43, 52))	('KJ-Pyr-9', 'Chemical', 'MESH:C000593138', (175, 183))	('lung adenocarcinoma', 'Disease', (33, 52))	('LXF-289', 'CellLine', 'CVCL:1394', (71, 78))	('KJ-Pyr-9', 'Var', (175, 183))	('MYC', 'Gene', '4609', (108, 111))
109609	33925297	Inhibitors of pro-inflammatory signaling such as dexamethasone, lenalidomide, or PDTC are known to influence the production of cytokines and growth factors, which in turn enhances the immune response against tumor cells and inhibits tumor angiogenesis.	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('inhibits', 'NegReg', (224, 232))	('production of cytokines', 'MPA', (113, 136))	('tumor', 'Disease', (233, 238))	('PDTC', 'Chemical', 'MESH:C020972', (81, 85))	('tumor', 'Disease', 'MESH:D009369', (208, 213))	('influence', 'Reg', (99, 108))	('Inhibitors', 'Var', (0, 10))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('enhances', 'PosReg', (171, 179))	('dexamethasone', 'Chemical', 'MESH:D003907', (49, 62))	('tumor', 'Disease', (208, 213))	('lenalidomide', 'Chemical', 'MESH:D000077269', (64, 76))	('tumor', 'Disease', 'MESH:D009369', (233, 238))	('PDTC', 'Gene', (81, 85))
109618	33925297	Next to dexamethasone, PDTC is commonly known to inhibit the IkBalpha degradation and p65 nuclear import, and was likewise shown to reduce survival of NSCLC-derived LCSC-like cells in the present study.	('p65', 'Gene', '5970', (86, 89))	('degradation', 'MPA', (70, 81))	('NSCLC', 'Disease', (151, 156))	('PDTC', 'Chemical', 'MESH:C020972', (23, 27))	('NSCLC', 'Disease', 'MESH:D002289', (151, 156))	('SCLC', 'Phenotype', 'HP:0030357', (152, 156))	('IkBalpha', 'Protein', (61, 69))	('survival', 'CPA', (139, 147))	('dexamethasone', 'Chemical', 'MESH:D003907', (8, 21))	('p65', 'Gene', (86, 89))	('NSCLC', 'Phenotype', 'HP:0030358', (151, 156))	('PDTC', 'Var', (23, 27))	('inhibit', 'NegReg', (49, 56))	('reduce', 'NegReg', (132, 138))
109620	33925297	In this study, PDTC treatment was more effective in decreasing cell survival of SCC-derived LCSC-like cells in comparison to high doses of dexamethasone.	('cell survival of', 'CPA', (63, 79))	('PDTC', 'Var', (15, 19))	('SCC', 'Phenotype', 'HP:0002860', (80, 83))	('decreasing', 'NegReg', (52, 62))	('dexamethasone', 'Chemical', 'MESH:D003907', (139, 152))	('PDTC', 'Chemical', 'MESH:C020972', (15, 19))
109621	33925297	Two of three parental tissues of AC-derived LCSC-like cells revealed clinically relevant mutations, one for EGFR and one for KRAS and STK11, possibly explaining the observed reduction in sensitivity for PDTC.	('STK11', 'Gene', (134, 139))	('KRAS', 'Gene', (125, 129))	('EGFR', 'Gene', '1956', (108, 112))	('EGFR', 'Gene', (108, 112))	('KRAS', 'Gene', '3845', (125, 129))	('PDTC', 'Chemical', 'MESH:C020972', (203, 207))	('STK11', 'Gene', '6794', (134, 139))	('mutations', 'Var', (89, 98))
109622	33925297	Generally, co-treatment with PDTC and dexamethasone, and especially application of KJ-Pyr-9 seem to be more effective in targeting NSCLC-derived LCSC-like cells in comparison to various standard chemotherapeutics such as cisplatin, docetaxel, pemetrexed, paclitaxel or vinorelbine as investigated by Herreros-Pomares and colleagues.	('paclitaxel', 'Chemical', 'MESH:D017239', (255, 265))	('pemetrexed', 'Chemical', 'MESH:D000068437', (243, 253))	('vinorelbine', 'Chemical', 'MESH:D000077235', (269, 280))	('cisplatin', 'Chemical', 'MESH:D002945', (221, 230))	('NSCLC', 'Disease', (131, 136))	('SCLC', 'Phenotype', 'HP:0030357', (132, 136))	('dexamethasone', 'Chemical', 'MESH:D003907', (38, 51))	('NSCLC', 'Disease', 'MESH:D002289', (131, 136))	('KJ-Pyr-9', 'Chemical', 'MESH:C000593138', (83, 91))	('docetaxel', 'Chemical', 'MESH:D000077143', (232, 241))	('NSCLC', 'Phenotype', 'HP:0030358', (131, 136))	('PDTC', 'Chemical', 'MESH:C020972', (29, 33))	('KJ-Pyr-9', 'Var', (83, 91))
109629	33925297	Still, direct inhibition of MYC/NMYC using low doses of KJ-Pyr-9 was shown to be more effective than PDTC-treatment for both SCC- and AC-derived LCSC-like cells.	('KJ-Pyr-9', 'Chemical', 'MESH:C000593138', (56, 64))	('NMYC', 'Gene', (32, 36))	('KJ-Pyr-9', 'Var', (56, 64))	('MYC', 'Gene', (28, 31))	('MYC', 'Gene', '4609', (33, 36))	('SCC', 'Phenotype', 'HP:0002860', (125, 128))	('NMYC', 'Gene', '4613', (32, 36))	('MYC', 'Gene', '4609', (28, 31))	('PDTC', 'Chemical', 'MESH:C020972', (101, 105))	('MYC', 'Gene', (33, 36))	('inhibition', 'NegReg', (14, 24))
109634	33925297	Application of inhibitors of NF-kappaB and MYC signaling led to significant reductions in survival of both AC- and SCC-derived cells.	('reductions', 'NegReg', (76, 86))	('NF-kappaB', 'Gene', (29, 38))	('NF-kappaB', 'Gene', '4790', (29, 38))	('MYC', 'Gene', '4609', (43, 46))	('SCC', 'Phenotype', 'HP:0002860', (115, 118))	('MYC', 'Gene', (43, 46))	('survival', 'CPA', (90, 98))	('inhibitors', 'Var', (15, 25))
109635	33925297	Nevertheless, inhibition of MYC/NMYC using KJ-Pyr-9 was observed to impair LCSC-like cells most effectively, suggesting MYC signaling as a possible object for targeting LCSC.	('MYC', 'Gene', (120, 123))	('NMYC', 'Gene', (32, 36))	('impair', 'NegReg', (68, 74))	('MYC', 'Gene', (28, 31))	('MYC', 'Gene', '4609', (33, 36))	('KJ-Pyr-9', 'Chemical', 'MESH:C000593138', (43, 51))	('KJ-Pyr-9', 'Var', (43, 51))	('MYC', 'Gene', '4609', (120, 123))	('LCSC-like cells', 'CPA', (75, 90))	('NMYC', 'Gene', '4613', (32, 36))	('MYC', 'Gene', '4609', (28, 31))	('MYC', 'Gene', (33, 36))
109648	33925297	Treatment of non-small cell lung cancer-derived cell populations with KJ-Pyr-9 led to heterogeneous nuclear localization of myc proto-oncogene (MYC).	('KJ-Pyr-9', 'Chemical', 'MESH:C000593138', (70, 78))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (13, 39))	('heterogeneous nuclear localization', 'MPA', (86, 120))	('MYC', 'Gene', (144, 147))	('lung cancer', 'Disease', 'MESH:D008175', (28, 39))	('myc', 'Gene', (124, 127))	('KJ-Pyr-9', 'Var', (70, 78))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('lung cancer', 'Disease', (28, 39))	('MYC', 'Gene', '4609', (144, 147))	('lung cancer', 'Phenotype', 'HP:0100526', (28, 39))	('myc', 'Gene', '4609', (124, 127))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (17, 39))
109663	33430230	Ca2+ signalling may serve as a novel hallmark of cancer due to the versatility of Ca2+ signals in cells, which suggests that the modulation of specific upstream/downstream targets may be a therapeutic approach to treat cancer, particularly in patients with metastatic cancers.	('cancer', 'Disease', (268, 274))	('cancers', 'Disease', (268, 275))	('cancers', 'Disease', 'MESH:D009369', (268, 275))	('Ca2+', 'Chemical', 'MESH:D000069285', (82, 86))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('Ca2+', 'Chemical', 'MESH:D000069285', (0, 4))	('patients', 'Species', '9606', (243, 251))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('hallmark of cancer', 'Disease', (37, 55))	('cancer', 'Phenotype', 'HP:0002664', (268, 274))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('cancer', 'Disease', 'MESH:D009369', (219, 225))	('hallmark of cancer', 'Disease', 'MESH:D009369', (37, 55))	('cancer', 'Disease', (219, 225))	('modulation', 'Var', (129, 139))	('cancer', 'Disease', 'MESH:D009369', (268, 274))	('cancers', 'Phenotype', 'HP:0002664', (268, 275))	('cancer', 'Disease', (49, 55))
109670	33430230	Importantly, dysregulation of spatiotemporal Ca2+ homeostasis at both intracellular and extracellular levels, in terms of spatiotemporal oscillations or waves, alters cellular physiological processes at the local level leading to metastatic cancer globally (shown in Figure 1).	('Ca2+', 'Chemical', 'MESH:D000069285', (45, 49))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('dysregulation', 'Var', (13, 26))	('cellular physiological processes', 'MPA', (167, 199))	('leading to', 'Reg', (219, 229))	('cancer', 'Disease', (241, 247))	('cancer', 'Disease', 'MESH:D009369', (241, 247))	('alters', 'Reg', (160, 166))
109682	33430230	(2006) found that high SERCA2 expression was correlated with lymph node metastasis, advanced stages of tumourigenesis, and significantly shorter survival compared to low SERCA2 expression in patients with colorectal cancer.	('expression', 'MPA', (30, 40))	('shorter', 'NegReg', (137, 144))	('colorectal cancer', 'Disease', 'MESH:D015179', (205, 222))	('patients', 'Species', '9606', (191, 199))	('survival', 'MPA', (145, 153))	('SERCA2', 'Gene', '488', (23, 29))	('SERCA2', 'Gene', (170, 176))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('tumour', 'Phenotype', 'HP:0002664', (103, 109))	('lymph node metastasis', 'CPA', (61, 82))	('colorectal cancer', 'Phenotype', 'HP:0003003', (205, 222))	('tumour', 'Disease', 'MESH:D009369', (103, 109))	('SERCA2', 'Gene', (23, 29))	('SERCA2', 'Gene', '488', (170, 176))	('high', 'Var', (18, 22))	('colorectal cancer', 'Disease', (205, 222))	('tumour', 'Disease', (103, 109))
109683	33430230	Unlike earlier findings, high SERCA3 expression was significantly associated with longer survival, negatively correlated tumour node metastasis (TNM) staging and distant metastases, but not with lymph node metastasis in patients with gastric carcinomas.	('SERCA3', 'Gene', (30, 36))	('longer', 'PosReg', (82, 88))	('tumour node metastasis', 'Disease', (121, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (242, 251))	('tumour node metastasis', 'Disease', 'MESH:D009362', (121, 143))	('tumour', 'Phenotype', 'HP:0002664', (121, 127))	('metastases', 'Disease', (170, 180))	('high', 'Var', (25, 29))	('gastric carcinomas', 'Disease', (234, 252))	('patients', 'Species', '9606', (220, 228))	('gastric carcinomas', 'Disease', 'MESH:D013274', (234, 252))	('metastases', 'Disease', 'MESH:D009362', (170, 180))	('carcinomas', 'Phenotype', 'HP:0030731', (242, 252))	('expression', 'MPA', (37, 47))	('negatively', 'NegReg', (99, 109))	('SERCA3', 'Gene', '489', (30, 36))
109689	33430230	They have shown that TRAM2 knockdown eliminated metastatic traits:including cell invasion and transendothelial migration in oral squamous cell carcinoma (OSCC) cells:by modulating the expression of matrix metalloproteinases.	('knockdown', 'Var', (27, 36))	('metastatic traits', 'CPA', (48, 65))	('matrix metalloproteinases', 'Protein', (198, 223))	('cell invasion', 'CPA', (76, 89))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (124, 152))	('transendothelial migration', 'CPA', (94, 120))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (129, 152))	('TRAM2', 'Gene', '9697', (21, 26))	('eliminated', 'NegReg', (37, 47))	('modulating', 'Reg', (169, 179))	('expression', 'MPA', (184, 194))	('carcinoma', 'Phenotype', 'HP:0030731', (143, 152))	('oral squamous cell carcinoma', 'Disease', (124, 152))	('TRAM2', 'Gene', (21, 26))
109690	33430230	Their study found that Ca2+ permeability via translocon mediates cancer progression.	('translocon', 'Var', (45, 55))	('mediates', 'Reg', (56, 64))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('Ca2+', 'Chemical', 'MESH:D000069285', (23, 27))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('Ca2+ permeability', 'MPA', (23, 40))
109695	33430230	They discovered genetic mutations in IP3R3 in metastatic or recurrent HNSCC cancers, but not in the primary tumour.	('tumour', 'Disease', (108, 114))	('HNSCC cancers', 'Disease', 'MESH:D000077195', (70, 83))	('IP3R3', 'Gene', '3710', (37, 42))	('cancers', 'Phenotype', 'HP:0002664', (76, 83))	('IP3R3', 'Gene', (37, 42))	('metastatic', 'Disease', (46, 56))	('genetic mutations', 'Var', (16, 33))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('tumour', 'Phenotype', 'HP:0002664', (108, 114))	('HNSCC cancers', 'Disease', (70, 83))	('tumour', 'Disease', 'MESH:D009369', (108, 114))
109709	33430230	Notably, the inhibition of TPC2 function using siRNA or inhibitors in an in vivo mouse mammary cancer model has been shown to significantly reduce the formation of lung metastasis.	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('reduce', 'NegReg', (140, 146))	('TPC2', 'Gene', '219931', (27, 31))	('cancer', 'Disease', (95, 101))	('inhibitors', 'Var', (56, 66))	('TPC2', 'Gene', (27, 31))	('inhibition', 'NegReg', (13, 23))	('mouse', 'Species', '10090', (81, 86))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('formation of lung metastasis', 'CPA', (151, 179))
109713	33430230	TRPML1 knockdown conducted with siRNA in HepG2 cells (an in vitro human hepatocellular liver carcinoma model) impaired invasion and attenuated cell migration compared to WT HepG2 cells.	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('TRPML1', 'Gene', (0, 6))	('impaired', 'NegReg', (110, 118))	('hepatocellular liver carcinoma', 'Disease', (72, 102))	('HepG2', 'CellLine', 'CVCL:0027', (41, 46))	('hepatocellular liver carcinoma', 'Disease', 'MESH:D006528', (72, 102))	('cell migration', 'CPA', (143, 157))	('invasion', 'CPA', (119, 127))	('hepatocellular liver', 'Phenotype', 'HP:0001404', (72, 92))	('HepG2', 'CellLine', 'CVCL:0027', (173, 178))	('human', 'Species', '9606', (66, 71))	('attenuated', 'NegReg', (132, 142))	('hepatocellular liver carcinoma', 'Phenotype', 'HP:0001402', (72, 102))	('knockdown', 'Var', (7, 16))
109714	33430230	Additionally, this study identified for the first time the mechanism of action of tetrabromobisphenol A (TBBPA), a toxin that has been linked to hepatic cancer invasion and migration, finding that TBBPA evoked endolysosomal Ca2+ signals upon binding to TRPML1.	('Ca2+', 'Chemical', 'MESH:D000069285', (224, 228))	('tetrabromobisphenol A', 'Chemical', 'MESH:C020806', (82, 103))	('hepatic cancer', 'Phenotype', 'HP:0002896', (145, 159))	('evoked endolysosomal Ca2+ signals', 'MPA', (203, 236))	('TBBPA', 'Var', (197, 202))	('linked', 'Reg', (135, 141))	('migration', 'CPA', (173, 182))	('binding', 'Interaction', (242, 249))	('TRPML1', 'Gene', (253, 259))	('TBBPA', 'Chemical', 'MESH:C020806', (105, 110))	('TBBPA', 'Chemical', 'MESH:C020806', (197, 202))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('hepatic cancer', 'Disease', (145, 159))	('hepatic cancer', 'Disease', 'MESH:D008113', (145, 159))
109715	33430230	An increased expression of transient receptor potential mucolipin1 (TRPML1) was also detected in advanced stages (III-IV) compared to early stages (I-II) of tumourigenesis in patients with non-small-cell lung cancer (NSCLC); TRPML1 silencing or inhibition in vitro impaired pathophysiological processes related to metastatic NSCLC cancer, indicating that enhanced expression of mucolipin 1 was involved in cancer progression and metastasis by promoting cell invasion, proliferation and migration in NSCLC.	('NSCLC', 'Disease', 'MESH:D002289', (325, 330))	('proliferation', 'CPA', (468, 481))	('tumour', 'Phenotype', 'HP:0002664', (157, 163))	('tumour', 'Disease', 'MESH:D009369', (157, 163))	('TRPML1', 'Gene', (225, 231))	('NSCLC cancer', 'Disease', (325, 337))	('NSCLC', 'Disease', 'MESH:D002289', (499, 504))	('tumour', 'Disease', (157, 163))	('NSCLC', 'Disease', (325, 330))	('transient receptor potential mucolipin1', 'Gene', (27, 66))	('cancer', 'Disease', 'MESH:D009369', (331, 337))	('NSCLC', 'Disease', (499, 504))	('cancer', 'Disease', (406, 412))	('cancer', 'Disease', 'MESH:D009369', (209, 215))	('NSCLC', 'Phenotype', 'HP:0030358', (325, 330))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))	('cancer', 'Phenotype', 'HP:0002664', (406, 412))	('transient receptor potential mucolipin1', 'Gene', '57192', (27, 66))	('NSCLC', 'Phenotype', 'HP:0030358', (499, 504))	('TRPML1', 'Gene', (68, 74))	('non-small-cell lung cancer', 'Disease', (189, 215))	('NSCLC', 'Disease', 'MESH:D002289', (217, 222))	('expression', 'MPA', (364, 374))	('cell invasion', 'CPA', (453, 466))	('non-small-cell lung cancer', 'Disease', 'MESH:D002289', (189, 215))	('mucolipin 1', 'Gene', (378, 389))	('enhanced', 'PosReg', (355, 363))	('NSCLC cancer', 'Disease', 'MESH:D009369', (325, 337))	('lung cancer', 'Phenotype', 'HP:0100526', (204, 215))	('mucolipin 1', 'Gene', '57192', (378, 389))	('NSCLC', 'Disease', (217, 222))	('cancer', 'Disease', (331, 337))	('cancer', 'Disease', 'MESH:D009369', (406, 412))	('patients', 'Species', '9606', (175, 183))	('cancer', 'Disease', (209, 215))	('NSCLC', 'Phenotype', 'HP:0030358', (217, 222))	('silencing', 'Var', (232, 241))	('migration', 'CPA', (486, 495))	('cancer', 'Phenotype', 'HP:0002664', (331, 337))	('promoting', 'PosReg', (443, 452))
109743	33430230	The CaSR suppresses cell proliferation and induces terminal differentiation in parathyroid and colon tumors, as shown by recent studies which provided abundant evidence that overexpressing the CaSR suppressed the proliferation of colorectal cancer cell both in vivo and in vitro, while inversely, it acts as an oncogene in prostate, testicular, ovarian, and breast cancer, especially bone metastasis in breast and prostate cancer.	('CaSR', 'Gene', (193, 197))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('breast cancer', 'Disease', 'MESH:D001943', (358, 371))	('colorectal cancer', 'Disease', 'MESH:D015179', (230, 247))	('breast cancer', 'Disease', (358, 371))	('suppressed', 'NegReg', (198, 208))	('suppresses', 'NegReg', (9, 19))	('proliferation', 'CPA', (213, 226))	('colorectal cancer', 'Disease', (230, 247))	('cancer', 'Phenotype', 'HP:0002664', (423, 429))	('cancer', 'Phenotype', 'HP:0002664', (365, 371))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('colon tumors', 'Phenotype', 'HP:0100273', (95, 107))	('ovarian', 'Disease', (345, 352))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('prostate cancer', 'Phenotype', 'HP:0012125', (414, 429))	('prostate', 'Disease', (323, 331))	('parathyroid and colon tumors', 'Disease', 'MESH:D003110', (79, 107))	('CaSR', 'Gene', '846', (4, 8))	('testicular', 'Disease', (333, 343))	('bone metastasis in breast and prostate cancer', 'Disease', 'MESH:D001943', (384, 429))	('colorectal cancer', 'Phenotype', 'HP:0003003', (230, 247))	('induces', 'Reg', (43, 50))	('CaSR', 'Gene', '846', (193, 197))	('cell proliferation', 'CPA', (20, 38))	('ovarian', 'Disease', 'MESH:D010049', (345, 352))	('overexpressing', 'Var', (174, 188))	('CaSR', 'Gene', (4, 8))	('terminal differentiation', 'CPA', (51, 75))	('breast cancer', 'Phenotype', 'HP:0003002', (358, 371))
109756	33430230	reported that genetic downregulation of ORAI1 or pharmacological inhibition of SOCE using SKF96365 improves 5-FU-induced autophagy and cell death in HepG2 cells (an in vitro model of hepatocarcinoma).	('5-FU-induced', 'MPA', (108, 120))	('downregulation', 'NegReg', (22, 36))	('hepatocarcinoma', 'Disease', (183, 198))	('HepG2', 'CellLine', 'CVCL:0027', (149, 154))	('ORAI1', 'Gene', '84876', (40, 45))	('ORAI1', 'Gene', (40, 45))	('SKF96365', 'Var', (90, 98))	('5-FU', 'Chemical', 'MESH:D005472', (108, 112))	('improves', 'PosReg', (99, 107))	('cell death', 'CPA', (135, 145))	('SKF96365', 'Chemical', 'MESH:C063159', (90, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (189, 198))	('hepatocarcinoma', 'Disease', 'None', (183, 198))
109765	33430230	STIM1 also affects invasion and migration of gastric cancer cells, possibly through an unknown pathway independent of the MEK/ERK signaling, as reported by Xu et al.. Alterations of Ca2+ homeostasis via transient receptor potential (TRP) channels were implicated in several processes attributed to cancer metastasis, practically cell proliferation and migration, which are two of cancer's hallmarks.	('Alterations', 'Var', (167, 178))	('Ca2+ homeostasis', 'MPA', (182, 198))	('gastric cancer', 'Phenotype', 'HP:0012126', (45, 59))	('cell proliferation', 'CPA', (329, 347))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('TRP', 'Gene', (233, 236))	('cancer metastasis', 'Disease', 'MESH:D009362', (298, 315))	('cancer', 'Disease', 'MESH:D009369', (298, 304))	('cancer', 'Disease', (380, 386))	('gastric cancer', 'Disease', (45, 59))	('cancer', 'Phenotype', 'HP:0002664', (380, 386))	('cancer', 'Disease', (53, 59))	('MEK', 'Gene', '5609', (122, 125))	('ERK', 'Gene', '5594', (126, 129))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('gastric cancer', 'Disease', 'MESH:D013274', (45, 59))	('MEK', 'Gene', (122, 125))	('implicated', 'Reg', (252, 262))	('cancer', 'Disease', 'MESH:D009369', (380, 386))	('Ca2+', 'Chemical', 'MESH:D000069285', (182, 186))	('migration', 'CPA', (352, 361))	('cancer', 'Disease', (298, 304))	('TRP', 'Chemical', '-', (233, 236))	('cancer metastasis', 'Disease', (298, 315))	('ERK', 'Gene', (126, 129))	('cancer', 'Phenotype', 'HP:0002664', (298, 304))
109777	33430230	The availability of a TRPM8 antagonist (PF-05105679), which has been tested in humans (phase 1 trial, NCT01393652), raises a translational question regarding the possibility of modulating TRPM8 as a therapeutic approach and giving it as adjuvant therapy for patients with metastatic cancer after adequate data for its safety and tolerability (I.e.	('cancer', 'Disease', 'MESH:D009369', (283, 289))	('cancer', 'Disease', (283, 289))	('TRPM8', 'Gene', '79054', (22, 27))	('modulating', 'Var', (177, 187))	('TRPM8', 'Gene', (22, 27))	('TRPM8', 'Gene', '79054', (188, 193))	('cancer', 'Phenotype', 'HP:0002664', (283, 289))	('patients', 'Species', '9606', (258, 266))	('TRPM8', 'Gene', (188, 193))	('humans', 'Species', '9606', (79, 85))
109794	33430230	Knocked down or pharmacologically inhibited T-type calcium channels showed reduced migration and invasion of BRAFV600E cells, which provides evidence that T-type calcium channels play a role in melanoma metastasis.	('Knocked down', 'Var', (0, 12))	('calcium', 'Chemical', 'MESH:D002118', (162, 169))	('melanoma metastasis', 'Disease', 'MESH:D009362', (194, 213))	('melanoma', 'Phenotype', 'HP:0002861', (194, 202))	('inhibited', 'NegReg', (34, 43))	('reduced', 'NegReg', (75, 82))	('T-type calcium', 'Gene', (44, 58))	('melanoma metastasis', 'Disease', (194, 213))	('BRAFV600E', 'Mutation', 'rs113488022', (109, 118))	('invasion', 'CPA', (97, 105))	('calcium', 'Chemical', 'MESH:D002118', (51, 58))	('migration', 'CPA', (83, 92))
109805	33430230	They also deciphered the underlying molecular mechanism of epigenetic activation for calpain-2-evoked cancer metastasis via the nuclear factor- kappaB (NF-kappaB)/ DNA (cytosine-5)-methyltransferase 1(DNMT1) signalling pathway.	('cancer metastasis', 'Disease', 'MESH:D009362', (102, 119))	('calpain-2', 'Gene', (85, 94))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('calpain-2', 'Gene', '824', (85, 94))	('DNMT1', 'Gene', (201, 206))	('NF-kappaB', 'Gene', '4790', (152, 161))	('DNMT1', 'Gene', '1786', (201, 206))	('DNA (cytosine-5)-methyltransferase 1', 'Gene', '1786', (164, 200))	('cancer metastasis', 'Disease', (102, 119))	('activation', 'PosReg', (70, 80))	('NF-kappaB', 'Gene', (152, 161))	('epigenetic', 'Var', (59, 69))
109815	33430230	Pharmacological modulation of CaM by KN93, a specific inhibitor, in HCT116 cells (an in vitro model of human colon cancer) was found to drastically decrease colon cancer cell invasion and migration via ERK1/2 or p38 signalling.	('decrease colon cancer', 'Disease', (148, 169))	('ERK1/2', 'Gene', (202, 208))	('ERK1/2', 'Gene', '5595;5594', (202, 208))	('HCT116', 'CellLine', 'CVCL:0291', (68, 74))	('colon cancer', 'Disease', (109, 121))	('KN93', 'Chemical', 'MESH:C072105', (37, 41))	('human', 'Species', '9606', (103, 108))	('decrease colon', 'Phenotype', 'HP:0005210', (148, 162))	('p38', 'Gene', '5594', (212, 215))	('migration', 'CPA', (188, 197))	('colon cancer', 'Phenotype', 'HP:0003003', (109, 121))	('decrease colon cancer', 'Disease', 'MESH:D015179', (148, 169))	('colon cancer', 'Phenotype', 'HP:0003003', (157, 169))	('CaM', 'Gene', '801', (30, 33))	('invasion', 'CPA', (175, 183))	('modulation', 'Var', (16, 26))	('CaM', 'Gene', (30, 33))	('colon cancer', 'Disease', 'MESH:D015179', (109, 121))	('KN93', 'Var', (37, 41))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('colon cancer', 'Disease', 'MESH:D015179', (157, 169))	('p38', 'Gene', (212, 215))
109824	33430230	Overexpression of LAMP2 has been associated with worse OS in oesophageal squamous cell carcinoma patients.	('oesophageal squamous cell carcinoma', 'Disease', 'MESH:D002294', (61, 96))	('LAMP2', 'Gene', '3920', (18, 23))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (73, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))	('Overexpression', 'Var', (0, 14))	('oesophageal squamous cell carcinoma', 'Disease', (61, 96))	('LAMP2', 'Gene', (18, 23))	('patients', 'Species', '9606', (97, 105))
109827	33430230	In addition, the authors showed that the number of lung metastases were attenuated after LAMP3 knockdown in an in vivo mouse model used for investigating LAMP3-mediated ESCC cell metastasis.	('mouse', 'Species', '10090', (119, 124))	('lung metastases', 'Disease', (51, 66))	('lung metastases', 'Disease', 'MESH:D009362', (51, 66))	('attenuated', 'NegReg', (72, 82))	('knockdown', 'Var', (95, 104))	('LAMP3', 'Gene', (89, 94))
109835	33430230	This strategy is currently under investigation in phase 2 clinical trials (such as NCT01941901, NCT04259658, and NCT03628417), mainly in skin cancers in the metastatic state, in which it is administered intratumourally.	('NCT04259658', 'Var', (96, 107))	('skin cancers', 'Phenotype', 'HP:0008069', (137, 149))	('tumour', 'Disease', (208, 214))	('skin cancers', 'Disease', (137, 149))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('cancers', 'Phenotype', 'HP:0002664', (142, 149))	('skin cancers', 'Disease', 'MESH:D012878', (137, 149))	('NCT01941901', 'Var', (83, 94))	('NCT03628417', 'Var', (113, 124))	('tumour', 'Phenotype', 'HP:0002664', (208, 214))	('tumour', 'Disease', 'MESH:D009369', (208, 214))
109838	33430230	Mipsagargin has moved into phase 2, and its investigation has been completed in various cancer subtypes including hepatocellular carcinoma (NCT01777594), glioblastoma (NCT02067156), clear cell renal cell carcinoma (NCT02607553), and prostatic neoplasms (NCT02381236).	('cancer', 'Disease', (88, 94))	('neoplasms', 'Phenotype', 'HP:0002664', (243, 252))	('prostatic neoplasms', 'Disease', 'MESH:D011471', (233, 252))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (182, 213))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('NCT02381236', 'Var', (254, 265))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (114, 138))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (193, 213))	('prostatic neoplasms', 'Phenotype', 'HP:0100787', (233, 252))	('prostatic neoplasms', 'Disease', (233, 252))	('glioblastoma', 'Disease', 'MESH:D005909', (154, 166))	('NCT01777594', 'Var', (140, 151))	('Mipsagargin', 'Chemical', '-', (0, 11))	('clear cell renal cell carcinoma', 'Disease', (182, 213))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (204, 213))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (114, 138))	('glioblastoma', 'Disease', (154, 166))	('glioblastoma', 'Phenotype', 'HP:0012174', (154, 166))	('NCT02067156', 'Var', (168, 179))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (182, 213))	('hepatocellular carcinoma', 'Disease', (114, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('NCT02607553', 'Var', (215, 226))
109842	33430230	Several studies have detected dysregulated expression of intracellular or extracellular calcium channels or proteins related to Ca2+ signalling-triggered metastasis at the mRNA or protein levels in various cancer subtypes (see Table 1).	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('proteins', 'Protein', (108, 116))	('Ca2+', 'Chemical', 'MESH:D000069285', (128, 132))	('calcium', 'Chemical', 'MESH:D002118', (88, 95))	('cancer', 'Disease', 'MESH:D009369', (206, 212))	('dysregulated', 'Var', (30, 42))	('cancer', 'Disease', (206, 212))	('expression', 'MPA', (43, 53))
109852	31857991	PD-L1 contributes to failed antitumor immunity; thereby, blockade of PD-L1 with monoclonal antibody enhances the immune response.	('PD-L1', 'Gene', '29126', (69, 74))	('blockade', 'Var', (57, 65))	('immune response', 'CPA', (113, 128))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('PD-L1', 'Gene', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('enhances', 'PosReg', (100, 108))	('tumor', 'Disease', (32, 37))	('PD-L1', 'Gene', '29126', (0, 5))	('PD-L1', 'Gene', (69, 74))
109871	31857991	When the p53 gene is mutated, the mutant p53 protein loses its cancer inhibition function and promotes the transformation of normal cells to malignant cells.	('p53', 'Gene', '7157', (41, 44))	('transformation', 'CPA', (107, 121))	('protein', 'Protein', (45, 52))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('p53', 'Gene', (9, 12))	('p53', 'Gene', '7157', (9, 12))	('mutant', 'Var', (34, 40))	('loses', 'NegReg', (53, 58))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('promotes', 'PosReg', (94, 102))	('cancer', 'Disease', (63, 69))	('p53', 'Gene', (41, 44))
109872	31857991	Mutant p53 is present in almost all types of human malignant tumor.	('malignant tumor', 'Disease', (51, 66))	('malignant tumor', 'Disease', 'MESH:D009369', (51, 66))	('p53', 'Gene', '7157', (7, 10))	('human', 'Species', '9606', (45, 50))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('Mutant', 'Var', (0, 6))	('p53', 'Gene', (7, 10))
109873	31857991	Also, mutant p53 is closely correlated with oral squamous cell carcinoma.	('mutant', 'Var', (6, 12))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (49, 72))	('p53', 'Gene', (13, 16))	('oral squamous cell carcinoma', 'Disease', (44, 72))	('p53', 'Gene', '7157', (13, 16))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (44, 72))	('correlated', 'Reg', (28, 38))
109885	31857991	The following commercial antibodies were purchased: PD-L1 (1:1, rabbit monoclonal, 790-4905; Ventana Medical Systems, Inc.; Roche, USA), p53 (1:100, mouse monoclonal, M7001; Dako Denmark, Glostrup, Denmark) and CK17 (1:50, mouse monoclonal, M7046; Dako Denmark, Glostrup, Denmark).	('PD-L1', 'Gene', '29126', (52, 57))	('M7001', 'Var', (167, 172))	('p53', 'Gene', '7157', (137, 140))	('PD-L1', 'Gene', (52, 57))	('M7046', 'Var', (241, 246))	('p53', 'Gene', (137, 140))	('CK17', 'Gene', '3872', (211, 215))	('CK17', 'Gene', (211, 215))
109902	31857991	OSCC patients with high PD-L1 expression had poor clinical outcome and might require PD-L1-targeted immunotherapy to improve their prognosis.	('expression', 'MPA', (30, 40))	('high', 'Var', (19, 23))	('patients', 'Species', '9606', (5, 13))	('PD-L1', 'Gene', (85, 90))	('PD-L1', 'Gene', (24, 29))	('PD-L1', 'Gene', '29126', (85, 90))	('OSCC', 'Disease', (0, 4))	('PD-L1', 'Gene', '29126', (24, 29))
109903	31857991	Mutant p53 is present in almost all types of human tumor and is closely correlated with the development of OSCC.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor', 'Disease', (51, 56))	('p53', 'Gene', '7157', (7, 10))	('human', 'Species', '9606', (45, 50))	('correlated with', 'Reg', (72, 87))	('Mutant', 'Var', (0, 6))	('p53', 'Gene', (7, 10))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
109904	31857991	Mutated p53 loses its ability to suppress the function of oncogenes.	('oncogenes', 'Protein', (58, 67))	('p53', 'Gene', (8, 11))	('p53', 'Gene', '7157', (8, 11))	('loses', 'NegReg', (12, 17))	('suppress', 'NegReg', (33, 41))	('function', 'MPA', (46, 54))	('Mutated', 'Var', (0, 7))
109905	31857991	Furthermore, mutant p53 may function as an oncogene to stimulate cell division and promote the growth of tumor cells..	('mutant', 'Var', (13, 19))	('p53', 'Gene', (20, 23))	('p53', 'Gene', '7157', (20, 23))	('cell division', 'CPA', (65, 78))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('promote', 'PosReg', (83, 90))	('tumor', 'Disease', (105, 110))	('stimulate', 'PosReg', (55, 64))
109907	31857991	Regarding tumor cells, the expression of PD-L1 and p53 is positively correlated, because wild-type p53 is rapidly degraded (~0.5h); however, as the resolution time of variant p53 protein is delayed (>2h) and the protein is accumulated in the nucleus, the variant p53 protein is identified as overexpression.	('p53', 'Gene', (51, 54))	('p53', 'Gene', '7157', (263, 266))	('accumulated', 'PosReg', (223, 234))	('variant', 'Var', (255, 262))	('PD-L1', 'Gene', (41, 46))	('p53', 'Gene', '7157', (175, 178))	('PD-L1', 'Gene', '29126', (41, 46))	('tumor', 'Disease', (10, 15))	('variant', 'Var', (167, 174))	('p53', 'Gene', (263, 266))	('p53', 'Gene', (175, 178))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('protein', 'Protein', (212, 219))	('p53', 'Gene', '7157', (99, 102))	('protein', 'Protein', (267, 274))	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('p53', 'Gene', '7157', (51, 54))	('protein', 'Protein', (179, 186))	('p53', 'Gene', (99, 102))
109908	31857991	Although wild-type p53 inhibits the expression of PD-L1 directly, when variant p53 which has lost a function is accumulated, PD-L1 is overexpressed.	('p53', 'Gene', (79, 82))	('p53', 'Gene', '7157', (79, 82))	('variant', 'Var', (71, 78))	('PD-L1', 'Gene', '29126', (125, 130))	('PD-L1', 'Gene', (50, 55))	('p53', 'Gene', (19, 22))	('p53', 'Gene', '7157', (19, 22))	('PD-L1', 'Gene', '29126', (50, 55))	('inhibits', 'NegReg', (23, 31))	('PD-L1', 'Gene', (125, 130))	('expression', 'MPA', (36, 46))
109931	31744230	However, unlike p53, the p63alpha variant presents a protein-protein interaction domain of unknown function, the sterile alpha motif (SAM), and the transactivation inhibitory domain (TID), which is involved in transcriptional inhibition of the TAp63 isoform (Figure 1a).	('p63alpha', 'Gene', '8626', (25, 33))	('p63', 'Gene', (25, 28))	('p53', 'Gene', (16, 19))	('p63', 'Gene', '8626', (25, 28))	('protein-protein interaction domain', 'MPA', (53, 87))	('p53', 'Gene', '7157', (16, 19))	('variant', 'Var', (34, 41))	('p63', 'Gene', (246, 249))	('p63', 'Gene', '8626', (246, 249))	('p63alpha', 'Gene', (25, 33))
109965	31744230	The oncogenic properties of DeltaNp63 were established in in vivo experiments that showed overexpression of DeltaNp63 enhances mutant Ras-driven tumourigenesis of undifferentiated cSCC.	('enhances', 'PosReg', (118, 126))	('mutant', 'Var', (127, 133))	('tumour', 'Disease', (145, 151))	('men', 'Species', '9606', (72, 75))	('SCC', 'Phenotype', 'HP:0002860', (181, 184))	('DeltaNp63', 'Gene', (108, 117))	('SCC', 'Disease', (181, 184))	('tumour', 'Phenotype', 'HP:0002664', (145, 151))	('tumour', 'Disease', 'MESH:D009369', (145, 151))	('SCC', 'Disease', 'MESH:D002294', (181, 184))
109967	31744230	A well-known inhibitor of p53, iASPP, was shown to regulate p63 expression via repression of miR-574 and miR-720 in the normal epidermis.	('expression', 'MPA', (64, 74))	('miR-720', 'Var', (105, 112))	('p63', 'Gene', '8626', (60, 63))	('iASPP', 'Gene', '10848', (31, 36))	('miR-574', 'Gene', (93, 100))	('p53', 'Gene', (26, 29))	('repression', 'NegReg', (79, 89))	('regulate', 'Reg', (51, 59))	('p53', 'Gene', '7157', (26, 29))	('iASPP', 'Gene', (31, 36))	('miR-574', 'Gene', '693159', (93, 100))	('p63', 'Gene', (60, 63))
109970	31744230	Indeed, Rho-dependent phosphorylation of NUP62 leads to nuclear translocation of p63 and permits its oncogenic activity.	('leads to', 'Reg', (47, 55))	('p63', 'Gene', '8626', (81, 84))	('NUP62', 'Gene', '23636', (41, 46))	('oncogenic activity', 'CPA', (101, 119))	('phosphorylation', 'Var', (22, 37))	('nuclear translocation', 'MPA', (56, 77))	('permits', 'PosReg', (89, 96))	('NUP62', 'Gene', (41, 46))	('p63', 'Gene', (81, 84))
110031	31744230	Furthermore, unexpected evidence recently emerged of a high incidence of mutation in the TP63 gene in melanoma samples (14.7% of samples).	('melanoma', 'Phenotype', 'HP:0002861', (102, 110))	('melanoma', 'Disease', (102, 110))	('melanoma', 'Disease', 'MESH:D008545', (102, 110))	('TP63', 'Gene', '8626', (89, 93))	('TP63', 'Gene', (89, 93))	('mutation', 'Var', (73, 81))
110032	31744230	In contrast to the cancer, mutations within the TP63 gene are common in epidermal dysplasia.	('mutations', 'Var', (27, 36))	('cancer', 'Disease', 'MESH:D009369', (19, 25))	('epidermal dysplasia', 'Disease', (72, 91))	('cancer', 'Disease', (19, 25))	('epidermal dysplasia', 'Disease', 'MESH:D004814', (72, 91))	('TP63', 'Gene', '8626', (48, 52))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('TP63', 'Gene', (48, 52))	('common', 'Reg', (62, 68))
110033	31744230	Therefore, the possible impact of TP63 mutation of melanomagenesis remains elusive.	('mutation', 'Var', (39, 47))	('TP63', 'Gene', (34, 38))	('TP63', 'Gene', '8626', (34, 38))	('melanoma', 'Phenotype', 'HP:0002861', (51, 59))	('melanoma', 'Disease', (51, 59))	('melanoma', 'Disease', 'MESH:D008545', (51, 59))
110079	31744230	One possible explanation might be that tumour cells express not only DeltaN but also TA isoforms of p63 that are recognised by 4A4 but not p40.	('N', 'Chemical', 'MESH:D009584', (74, 75))	('p63', 'Gene', (100, 103))	('p40', 'Gene', '8626', (139, 142))	('tumour', 'Disease', (39, 45))	('DeltaN', 'Var', (69, 75))	('p63', 'Gene', '8626', (100, 103))	('tumour', 'Phenotype', 'HP:0002664', (39, 45))	('tumour', 'Disease', 'MESH:D009369', (39, 45))	('p40', 'Gene', (139, 142))
110088	31744230	The high specificity and sensitivity of MMp40 BC28 was confirmed in multiple types of cancer such as lung, prostate, breast, and skin cancer.	('skin cancer', 'Phenotype', 'HP:0008069', (129, 140))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('skin cancer', 'Disease', (129, 140))	('breast', 'Disease', (117, 123))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('skin cancer', 'Disease', 'MESH:D012878', (129, 140))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('lung', 'Disease', (101, 105))	('MMp40 BC28', 'Var', (40, 50))	('prostate', 'Disease', (107, 115))	('cancer', 'Disease', (86, 92))
110103	31744230	conducted the literature search, wrote the manuscript, and prepared figures, F.N., M.A.-P., C.M.P., and G.M.	('M.A.-P.', 'Var', (83, 90))	('N', 'Chemical', 'MESH:D009584', (79, 80))	('search', 'Disease', (25, 31))	('C.M.P.', 'Var', (92, 98))	('search', 'Disease', 'None', (25, 31))
110115	27350753	The diagnostic cutoff levels of Cyfra21-1, SCCAg, ferritin, and CEA were 2.17, 0.72, 109.95, and 1.99 ng/mL, respectively.	('Cyfra21-1', 'Var', (32, 41))	('CEA', 'Gene', '1084', (64, 67))	('CEA', 'Gene', (64, 67))
110117	27350753	Meanwhile, Cyfra21-1 had better early diagnostic value for patients with OSCC/OPSCC.	('Cyfra21-1', 'Var', (11, 20))	('patients', 'Species', '9606', (59, 67))	('OSCC/OPSCC', 'Disease', (73, 83))
110126	27350753	Since the levels of the serum TMs are different among different malignant tumors, six kinds of serum TMs which were commonly used in clinics at present, including Cyfra21-1, SCCAg, ferritin, CEA, carbohydrate antigen 19-9 (CA19-9), and AFP were selected for this study.	('AFP', 'Gene', (236, 239))	('malignant tumors', 'Disease', (64, 80))	('Cyfra21-1', 'Var', (163, 172))	('AFP', 'Gene', '174', (236, 239))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('CEA', 'Gene', (191, 194))	('malignant tumors', 'Disease', 'MESH:D018198', (64, 80))	('CEA', 'Gene', '1084', (191, 194))	('carbohydrate', 'Chemical', 'MESH:D002241', (196, 208))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))
110148	27350753	The results demonstrated that the specificity of Cyfra21-1 was the highest, significantly higher than that of SCCAg, ferritin, and CEA (P<0.05).	('specificity', 'MPA', (34, 45))	('CEA', 'Gene', (131, 134))	('CEA', 'Gene', '1084', (131, 134))	('higher', 'PosReg', (90, 96))	('Cyfra21-1', 'Var', (49, 58))
110160	27350753	In the study, the specificity of Cyfra21-1 was the highest (81.03%), the sensitivity was 60.36% and showed no significant difference compared to CEA.	('CEA', 'Gene', '1084', (145, 148))	('CEA', 'Gene', (145, 148))	('Cyfra21-1', 'Var', (33, 42))
110161	27350753	Therefore, the diagnostic values of Cyfra21-1 and SCCAg were superior to those of other TMs for patients with OSCC/OPSCC.	('OSCC/OPSCC', 'Disease', (110, 120))	('Cyfra21-1', 'Var', (36, 45))	('SCCAg', 'Gene', (50, 55))	('patients', 'Species', '9606', (96, 104))
110162	27350753	Cyfra21-1 is a soluble fragment of cytokeratin19 (CK19).	('cytokeratin19', 'Gene', (35, 48))	('CK19', 'Gene', (50, 54))	('CK19', 'Gene', '3880', (50, 54))	('Cyfra21-1', 'Var', (0, 9))	('cytokeratin19', 'Gene', '3880', (35, 48))
110168	27350753	The result showed that the level of serum Cyfra21-1 in patients with early OSCC/OPSCC was significantly higher than that of benign tumor group and healthy control group, suggesting that Cyfra21-1 had better clinical value in the screening and diagnosis of patients with early OSCC/OPSCC.	('early OSCC/OPSCC', 'Disease', (270, 286))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('patients', 'Species', '9606', (256, 264))	('level', 'MPA', (27, 32))	('early OSCC/OPSCC', 'Disease', (69, 85))	('patients', 'Species', '9606', (55, 63))	('higher', 'PosReg', (104, 110))	('Cyfra21-1', 'Var', (186, 195))	('benign tumor', 'Disease', (124, 136))	('benign tumor', 'Disease', 'MESH:D009369', (124, 136))
110174	24565165	Genes associated with genotype-specific DNA methylation in squamous cell carcinoma as candidate drug targets Aberrant DNA methylation is often associated with cancers.	('cancers', 'Disease', (159, 166))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (59, 82))	('associated', 'Reg', (143, 153))	('squamous cell carcinoma', 'Disease', (59, 82))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (59, 82))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('DNA', 'Gene', (118, 121))	('cancers', 'Phenotype', 'HP:0002664', (159, 166))	('Aberrant', 'Var', (109, 117))	('cancers', 'Disease', 'MESH:D009369', (159, 166))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
110176	24565165	Thus, the selection of genes with genotype-specific aberrant DNA methylation in cancers is potentially important for tailor-made medicine.	('cancers', 'Disease', 'MESH:D009369', (80, 87))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancers', 'Disease', (80, 87))	('aberrant', 'Var', (52, 60))	('cancers', 'Phenotype', 'HP:0002664', (80, 87))
110184	24565165	For example, the promoters of the PAK3, NISCH, KIF1A, and OGDHL genes are specifically methylated in several cancers, including breast, esophagus, lung, pancreas, colon, prostate, gastric, cervix, thyroid, kidney, head and neck, ovary, and bladder cancers.	('cervix', 'Disease', (189, 195))	('cancers', 'Disease', 'MESH:D009369', (109, 116))	('pancreas', 'Disease', 'MESH:D010190', (153, 161))	('colon', 'Disease', 'MESH:D015179', (163, 168))	('NISCH', 'Gene', '11188', (40, 45))	('esophagus', 'Disease', (136, 145))	('colon', 'Disease', (163, 168))	('cancers', 'Phenotype', 'HP:0002664', (248, 255))	('cancers', 'Disease', (248, 255))	('bladder cancers', 'Phenotype', 'HP:0009725', (240, 255))	('cancer', 'Phenotype', 'HP:0002664', (248, 254))	('kidney', 'Disease', (206, 212))	('KIF1A', 'Gene', '547', (47, 52))	('methylated', 'Var', (87, 97))	('thyroid', 'Disease', (197, 204))	('ovary', 'Disease', (229, 234))	('PAK3', 'Gene', (34, 38))	('ovary', 'Disease', 'MESH:D010051', (229, 234))	('cancers', 'Phenotype', 'HP:0002664', (109, 116))	('bladder cancers', 'Disease', 'MESH:D001749', (240, 255))	('cancers', 'Disease', (109, 116))	('OGDHL', 'Gene', (58, 63))	('OGDHL', 'Gene', '55753', (58, 63))	('NISCH', 'Gene', (40, 45))	('PAK3', 'Gene', '5063', (34, 38))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('bladder cancers', 'Disease', (240, 255))	('prostate', 'Disease', (170, 178))	('pancreas', 'Disease', (153, 161))	('lung', 'Disease', (147, 151))	('KIF1A', 'Gene', (47, 52))	('cancers', 'Disease', 'MESH:D009369', (248, 255))	('breast', 'Disease', (128, 134))	('gastric', 'Disease', (180, 187))
110185	24565165	Because genes with methylated promoters are believed to be suppressive, genes with tumor-specific hypermethylated promoters were assumed to be tumor suppressors.	('methylated', 'Var', (19, 29))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumor', 'Disease', (143, 148))	('tumor', 'Disease', (83, 88))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
110186	24565165	Similarly, genes with tumor-specific hypomethylated promoters were supposed to be oncogenic (i.e., expressed in tumors) and potential oncogene targets.	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('hypomethylated', 'Var', (37, 51))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('tumor', 'Disease', (22, 27))	('tumor', 'Disease', (112, 117))	('tumors', 'Disease', 'MESH:D009369', (112, 118))	('tumors', 'Disease', (112, 118))
110190	24565165	Currently, there are no established mechanisms that can relate gene mutations to cancer formation.	('mutations', 'Var', (68, 77))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('cancer', 'Disease', (81, 87))	('cancer', 'Disease', 'MESH:D009369', (81, 87))
110191	24565165	For example, a cancer-specific single nucleotide polymorphism (SNP) is often associated with specific cancers, but this SNP is located in an intron of the gene.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('cancer', 'Disease', (15, 21))	('cancer', 'Disease', 'MESH:D009369', (15, 21))	('cancer', 'Disease', (102, 108))	('single nucleotide polymorphism', 'Var', (31, 61))	('cancers', 'Disease', 'MESH:D009369', (102, 109))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))	('cancers', 'Disease', (102, 109))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('associated', 'Reg', (77, 87))
110198	24565165	found that genotypic variants at position 2q33 on the human chromosome were related to risk of ESCC.	('human', 'Species', '9606', (54, 59))	('ESCC', 'Disease', (95, 99))	('related', 'Reg', (76, 83))	('genotypic variants', 'Var', (11, 29))
110199	24565165	found that phosphoinositide-3-kinase and BRAF mutations were associated with metastatic ESCC and Wang et al.	('phosphoinositide-3-kinase', 'MPA', (11, 36))	('mutations', 'Var', (46, 55))	('BRAF', 'Gene', '673', (41, 45))	('metastatic ESCC', 'Disease', (77, 92))	('BRAF', 'Gene', (41, 45))	('associated', 'Reg', (61, 71))	('Wang et al', 'Disease', (97, 107))
110200	24565165	found that ESCC was related to polymorphisms in ALDH2 and ADH1B in Chinese females.	('ALDH2', 'Gene', '217', (48, 53))	('polymorphisms', 'Var', (31, 44))	('ADH1B', 'Gene', (58, 63))	('ALDH2', 'Gene', (48, 53))	('ESCC', 'Disease', (11, 15))	('ADH1B', 'Gene', '125', (58, 63))
110210	24565165	Ideally, to be sure that a particular genotype-specific DNA methylation could cause the tumor, the following conditions should be satisfied: 1.	('cause', 'Reg', (78, 83))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('DNA methylation', 'Var', (56, 71))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor', 'Disease', (88, 93))
110211	24565165	The genotype is specifically demethylated/methylated in the tumor tissue compared with other genotypes (strength of aberrant DNA methylation).	('demethylated/methylated', 'MPA', (29, 52))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('demethylated/methylated', 'Var', (29, 52))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Disease', (60, 65))
110212	24565165	The genotype is abundant in the tumor tissue (abundance of aberrant DNA methylation).	('aberrant', 'Var', (59, 67))	('tumor', 'Disease', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumor', 'Disease', 'MESH:D009369', (32, 37))
110244	24565165	The only exceptions were SNP_A-4242077 (associated with PIWIL1), SNP_A-4288260 (associated with PIGO), and SNP_A-1988914(associated with TARBP1).	('PIGO', 'Gene', (96, 100))	('PIGO', 'Gene', '84720', (96, 100))	('PIWIL1', 'Gene', '9271', (56, 62))	('TARBP1', 'Gene', (137, 143))	('SNP_A-4242077', 'Var', (25, 38))	('PIWIL1', 'Gene', (56, 62))	('TARBP1', 'Gene', '6894', (137, 143))	('SNP_A-4288260', 'Var', (65, 78))	('SNP_A-1988914', 'Var', (107, 120))
110246	24565165	This finding indicates that we have correctly selected mutation that may cause cancer formation.	('cause', 'Reg', (73, 78))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('mutation', 'Var', (55, 63))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))
110310	24465512	Aberrant cell proliferation is a hallmark of cancer and increased expression of cell cycle genes is found in multiple tumor types, including those not causally associated with smoking such as breast and prostate cancer.	('Aberrant', 'Var', (0, 8))	('increased', 'PosReg', (56, 65))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('prostate cancer', 'Phenotype', 'HP:0012125', (203, 218))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('cell cycle genes', 'Gene', (80, 96))	('breast and prostate cancer', 'Disease', 'MESH:D011471', (192, 218))	('expression', 'MPA', (66, 76))	('hallmark of cancer', 'Disease', (33, 51))	('multiple tumor', 'Disease', (109, 123))	('multiple tumor', 'Disease', 'MESH:D009369', (109, 123))	('hallmark of cancer', 'Disease', 'MESH:D009369', (33, 51))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))
110323	30863760	Inhibition of epidermal growth factor receptor signaling has been shown to be a critical component of therapeutic option.	('epidermal growth factor receptor', 'Gene', '1956', (14, 46))	('epidermal growth factor receptor', 'Gene', (14, 46))	('Inhibition', 'Var', (0, 10))
110335	30863760	The severity of these adverse effects has been shown to be predictors of treatment response from inhibitors of epidermal growth factor receptor.	('epidermal growth factor receptor', 'Gene', (111, 143))	('epidermal growth factor receptor', 'Gene', '1956', (111, 143))	('inhibitors', 'Var', (97, 107))
110340	30863760	Overexpression of EGFR and its ligand have been reported in 80% to 90% of SCCHN tumors compared with levels in normal mucosa of patients without cancer.	('cancer', 'Disease', (145, 151))	('EGFR', 'Gene', '1956', (18, 22))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('SCCHN tumors', 'Disease', (74, 86))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('SCCHN tumors', 'Disease', 'MESH:D009369', (74, 86))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('EGFR', 'Gene', (18, 22))	('Overexpression', 'Var', (0, 14))	('patients', 'Species', '9606', (128, 136))	('cancer', 'Disease', 'MESH:D009369', (145, 151))
110378	30863760	Many factors may affect severity of skin rash including genetic variations in EGFR and metabolism of EGFR TKI.	('metabolism', 'MPA', (87, 97))	('EGFR', 'Gene', '1956', (101, 105))	('EGFR', 'Gene', (101, 105))	('skin rash', 'Phenotype', 'HP:0000988', (36, 45))	('rash', 'Phenotype', 'HP:0000988', (41, 45))	('EGFR', 'Gene', '1956', (78, 82))	('EGFR', 'Gene', (78, 82))	('affect', 'Reg', (17, 23))	('skin rash', 'Disease', 'MESH:D005076', (36, 45))	('skin rash', 'Disease', (36, 45))	('genetic variations', 'Var', (56, 74))
110381	30863760	However, the incidence of this type of EGFR mutations is low and fails to predict sensitivity to EGFR TKIs in SCCHN.	('EGFR', 'Gene', '1956', (97, 101))	('SCCHN', 'Disease', (110, 115))	('EGFR', 'Gene', (97, 101))	('mutations', 'Var', (44, 53))	('EGFR', 'Gene', '1956', (39, 43))	('EGFR', 'Gene', (39, 43))
110385	30863760	Whole exome sequencing of the pretreatment tumor revealed a MAPK1 E322K somatic mutation, which was further implicated in mediating erlotinib sensitivity.	('MAPK1', 'Gene', (60, 65))	('E322K', 'Mutation', 'rs1057519911', (66, 71))	('erlotinib', 'Chemical', 'MESH:D000069347', (132, 141))	('E322K', 'Var', (66, 71))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('MAPK1', 'Gene', '5594', (60, 65))	('tumor', 'Disease', (43, 48))
110386	30863760	This response to erlotinib occurred in the context of an activating somatic MAPK1 E322K mutation, which led to increased EGFR ligand production and EGFR activation in preclinical studies.	('increased', 'PosReg', (111, 120))	('EGFR', 'Gene', '1956', (121, 125))	('activation', 'PosReg', (153, 163))	('MAPK1', 'Gene', '5594', (76, 81))	('EGFR', 'Gene', '1956', (148, 152))	('EGFR', 'Gene', (148, 152))	('EGFR', 'Gene', (121, 125))	('E322K', 'Var', (82, 87))	('MAPK1', 'Gene', (76, 81))	('E322K', 'Mutation', 'rs1057519911', (82, 87))	('erlotinib', 'Chemical', 'MESH:D000069347', (17, 26))	('activating', 'PosReg', (57, 67))
110389	30863760	Patient's tumor was subsequently biopsied and found to have amplification of fibroblast growth factor genes by next-generation sequencing.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('amplification', 'Var', (60, 73))	('tumor', 'Disease', (10, 15))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('Patient', 'Species', '9606', (0, 7))	('fibroblast growth factor genes', 'Gene', (77, 107))
110408	30486628	A meta analysis suggested that a higher intake of carotenoids (beta-carotene, alpha- carotene, lycopene, beta-cryptoxanthin, lutein, and zeaxanthin) is associated with lower risk of esophageal cancer (Xiao-Xiao et al., 2013).	('lycopene', 'Chemical', 'MESH:D000077276', (95, 103))	('esophageal cancer', 'Disease', (182, 199))	('lower', 'NegReg', (168, 173))	('beta-cryptoxanthin', 'Chemical', 'MESH:D000072743', (105, 123))	('esophageal cancer', 'Disease', 'MESH:D004938', (182, 199))	('beta-cryptoxanthin', 'Var', (105, 123))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('carotenoids', 'Chemical', 'MESH:D002338', (50, 61))	('beta-carotene', 'Chemical', 'MESH:D019207', (63, 76))	('alpha- carotene', 'Chemical', 'MESH:C041635', (78, 93))
110434	30486628	A significant reduction in DNA synthesis was observed with 5 microM alpha-carotene, beta-carotene, or alpha- plus beta-carotene (P<0.05).	('beta-carotene', 'Chemical', 'MESH:D019207', (114, 127))	('beta-carotene', 'Chemical', 'MESH:D019207', (84, 97))	('DNA synthesis', 'MPA', (27, 40))	('alpha-carotene', 'Chemical', 'MESH:C041635', (68, 82))	('alpha- plus beta-carotene', 'Var', (102, 127))	('reduction', 'NegReg', (14, 23))	('alpha- plus beta-carotene', 'Chemical', '-', (102, 127))
110439	30486628	A significant decrease in HESC cell DNA synthesis was observed with a low concentration of 5microM alpha-carotene (P = 0.024) and 10microM beta-carotene (P = 0.007).	('beta-carotene', 'Chemical', 'MESH:D019207', (139, 152))	('HESC cell DNA synthesis', 'MPA', (26, 49))	('alpha-carotene', 'Chemical', 'MESH:C041635', (99, 113))	('decrease', 'NegReg', (14, 22))	('HESC', 'CellLine', 'CVCL:C777', (26, 30))	('10microM', 'Var', (130, 138))
110460	30486628	Considering the significant inhibition of cellular proliferation of human esophageal cancer cells by a-carotene at a lower concentration, additional studies are needed to elucidate the role of alpha-carotenoids as prophylactic as well as therapeutic agents in esophageal carcinogenesis in human trials and animal studies.	('esophageal carcinogenesis', 'Disease', (260, 285))	('human', 'Species', '9606', (68, 73))	('a-carotene', 'Chemical', '-', (101, 111))	('a-carotene', 'Var', (101, 111))	('esophageal cancer', 'Disease', (74, 91))	('human', 'Species', '9606', (289, 294))	('cellular proliferation', 'CPA', (42, 64))	('alpha-carotenoids', 'Chemical', '-', (193, 210))	('inhibition', 'NegReg', (28, 38))	('esophageal cancer', 'Disease', 'MESH:D004938', (74, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (260, 285))
110492	30177858	There are several oral agents available for patients who harbor specific mutations, but little is known about mutations and affected pathways in HIV-infected patients with lung cancer.	('patients', 'Species', '9606', (44, 52))	('HIV-infected', 'Disease', 'MESH:D015658', (145, 157))	('lung cancer', 'Disease', (172, 183))	('lung cancer', 'Phenotype', 'HP:0100526', (172, 183))	('HIV-infected', 'Disease', (145, 157))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('patients', 'Species', '9606', (158, 166))	('mutations', 'Var', (73, 82))	('lung cancer', 'Disease', 'MESH:D008175', (172, 183))
110514	30177858	Our analysis results suggest that alterations in these 10 candidate genes interact in at least a subset of tumors.	('interact', 'Reg', (74, 82))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumors', 'Disease', (107, 113))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('tumors', 'Disease', 'MESH:D009369', (107, 113))	('alterations', 'Var', (34, 45))
110529	30177858	To better distinguish the cancer tissue from the surrounding tissue, we finally stained with p63 and TTF-1 as lung cancer cell specific markers and found that all the two SCC cases showed strong positive staining for p63 (Fig.	('p63', 'Var', (217, 220))	('SCC', 'Gene', (171, 174))	('cancer', 'Disease', (115, 121))	('lung cancer', 'Disease', 'MESH:D008175', (110, 121))	('cancer', 'Disease', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('SCC', 'Gene', '6317', (171, 174))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('lung cancer', 'Disease', (110, 121))	('lung cancer', 'Phenotype', 'HP:0100526', (110, 121))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (115, 121))
110545	30177858	These results implied that TNM was not only a major prognostic factor in the general population but also in HIV and might yield a survival benefit, although our study population was small.	('survival benefit', 'CPA', (130, 146))	('HIV', 'Disease', (108, 111))	('TNM', 'Var', (27, 30))	('HIV', 'Disease', 'MESH:D015658', (108, 111))
110564	30177858	SYNPO2 (synaptopodin-2) is a repressor of tumor cell invasion, being predominant in prostate acinar epithelial and basal cells, and induces formation of complex stress fiber networks in the cell body.	('tumor', 'Disease', (42, 47))	('SYNPO2', 'Var', (0, 6))	('induces', 'Reg', (132, 139))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('stress fiber networks', 'CPA', (161, 182))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
110586	30177858	This was followed by a PBS wash and incubation with Anti-TFAP2A (Abcam, ab108311), Anti-TTF-1 (Dako Corporation, CA), Anti-p63 (Novocastra Laboratories Ltd, UK), or Anti-SIX1 (Cell Signaling Technology, #16960, Danvers, MA) antibodies for IHC analysis.	('SIX1', 'Gene', '6495', (170, 174))	('Anti-TFAP2A', 'Var', (52, 63))	('PBS', 'Chemical', 'MESH:D007854', (23, 26))	('Anti-p63', 'Var', (118, 126))	('Anti-TTF-1', 'Var', (83, 93))	('SIX1', 'Gene', (170, 174))
110588	30177858	SIX1, TTF-1, p63 and TFAP2A proteins appeared as brownish granules after staining.	('proteins', 'Protein', (28, 36))	('TFAP2A', 'Gene', (21, 27))	('SIX1', 'Gene', (0, 4))	('SIX1', 'Gene', '6495', (0, 4))	('p63', 'Var', (13, 16))	('TTF-1', 'Gene', (6, 11))
110591	30177858	planned overall concepts and designed experiments; L.W., Z.C., Z.P., Z.L., X.Z., D.Y., Q.X.	('Z.P.', 'Var', (63, 67))	('Z.C.', 'Var', (57, 61))	('D.Y.', 'Var', (81, 85))	('X.Z.', 'Var', (75, 79))	('men', 'Species', '9606', (44, 47))	('Z.L.', 'Var', (69, 73))
110592	30177858	performed experiments; Z.Z., Y.F., Y.S., W.C., X.Y.Z., J.X.	('men', 'Species', '9606', (16, 19))	('W.C.', 'Var', (41, 45))	('X.Y.Z.', 'Var', (47, 53))
110595	28722656	Because of this enhanced propensity to accumulate DNA damage, tumor cells rely on homologous recombination repair as a means of protection from the lethal effect of both spontaneous and therapy-induced double-strand breaks (DSBs) in DNA.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('double-strand breaks', 'Var', (202, 222))	('tumor', 'Disease', (62, 67))	('DSBs', 'Chemical', '-', (224, 228))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
110596	28722656	Thus, modulation of DNA repair pathways have important consequences for genomic instability within tumor cell biology and viability maintenance under high genotoxic stress.	('modulation', 'Var', (6, 16))	('genomic instability within tumor', 'Disease', 'MESH:D001929', (72, 104))	('genomic instability within tumor', 'Disease', (72, 104))	('consequences', 'Reg', (55, 67))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))
110607	28722656	Therefore, although carcinogens undoubtedly increase cancer risk, other factors such as variation in the DDR likely alter susceptibility to and prognosis in disease.	('alter', 'Reg', (116, 121))	('carcinogens undoubtedly increase cancer', 'Disease', (20, 59))	('susceptibility', 'MPA', (122, 136))	('carcinogens undoubtedly increase cancer', 'Disease', 'MESH:D009369', (20, 59))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('variation', 'Var', (88, 97))	('DDR', 'Gene', (105, 108))
110611	28722656	For instance, mutations in tumor suppressor and DNA damage response genes BRCA1/2 leaves the cellular protein depleted or inactive and increases one's risk of breast and ovarian cancer.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('cellular protein depleted', 'MPA', (93, 118))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('tumor', 'Disease', (27, 32))	('breast and ovarian cancer', 'Disease', 'MESH:D010051', (159, 184))	('increases', 'PosReg', (135, 144))	('BRCA1/2', 'Gene', (74, 81))	('ovarian cancer', 'Phenotype', 'HP:0100615', (170, 184))	('BRCA1/2', 'Gene', '672;675', (74, 81))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('inactive', 'MPA', (122, 130))	('mutations', 'Var', (14, 23))
110613	28722656	While it makes sense that an alteration in the DDR would elicit a higher predisposition to develop cancer, conversely looking at the DDR as an actual pro-oncogenic mechanism is not as straight forward.	('elicit', 'Reg', (57, 63))	('DDR', 'Gene', (47, 50))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('cancer', 'Disease', (99, 105))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('alteration', 'Var', (29, 39))
110619	28722656	Unrepaired or incorrectly repaired DSBs can result in cell death, senescence, or chromosomal aberrations such translocations, deletions and insertions which may induce a loss of heterozygosity.	('insertions', 'Var', (140, 150))	('cell death', 'CPA', (54, 64))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (81, 104))	('DSBs', 'Chemical', '-', (35, 39))	('deletions', 'Var', (126, 135))	('chromosomal aberrations', 'CPA', (81, 104))	('result in', 'Reg', (44, 53))	('translocations', 'CPA', (110, 124))	('senescence', 'CPA', (66, 76))
110623	28722656	The RAD52 epistasis genes (RAD50, RAD51, RAD52, RAD54, RAD55, RAD57, RAD59, MRE11, and XRS2) are mainly RAD genes involved in recombinational repair of DSBs.	('RAD52', 'Gene', (41, 46))	('RAD55', 'Var', (55, 60))	('MRE11', 'Gene', '4361', (76, 81))	('DSBs', 'Chemical', '-', (152, 156))	('RAD50', 'Gene', (27, 32))	('RAD50', 'Gene', '10111', (27, 32))	('RAD54', 'Gene', (48, 53))	('MRE11', 'Gene', (76, 81))	('RAD54', 'Gene', '8438', (48, 53))	('RAD57', 'Var', (62, 67))	('RAD52', 'Gene', (4, 9))	('RAD59', 'Var', (69, 74))	('RAD51', 'Var', (34, 39))
110630	28722656	These include both novel characterizations of genes found to be involved in tumorigenesis, as well as genetic mutations in oncogenes and tumor suppressors that effect tumor growth.	('tumor', 'Disease', (137, 142))	('mutations', 'Var', (110, 119))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('effect', 'Reg', (160, 166))	('oncogenes', 'Gene', (123, 132))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('tumor', 'Disease', (167, 172))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
110632	28722656	Recent evidence has begun to show that genetic variants also play a role in cancer progression and prognosis in patients.	('genetic variants', 'Var', (39, 55))	('prognosis', 'CPA', (99, 108))	('patients', 'Species', '9606', (112, 120))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('play', 'Reg', (61, 65))	('role', 'Reg', (68, 72))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))
110634	28722656	This preliminary study designated variation in RAD52 as a risk factor for squamous cell lung cancer by comparing 5,355 European ever-smoker lung cancer patients with 4,344 smoking control subjects.	('squamous cell lung cancer', 'Disease', 'MESH:D002294', (74, 99))	('lung cancer', 'Disease', (140, 151))	('lung cancer', 'Phenotype', 'HP:0100526', (140, 151))	('squamous cell lung cancer', 'Phenotype', 'HP:0030359', (74, 99))	('variation', 'Var', (34, 43))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('lung cancer', 'Disease', 'MESH:D008175', (88, 99))	('RAD52', 'Gene', (47, 52))	('lung cancer', 'Disease', 'MESH:D008175', (140, 151))	('squamous cell lung cancer', 'Disease', (74, 99))	('risk', 'Reg', (58, 62))	('patients', 'Species', '9606', (152, 160))	('lung cancer', 'Phenotype', 'HP:0100526', (88, 99))
110636	28722656	The Pardini group demonstrated the role of single nucleotide polymorphisms (SNPs) residing in miRNA target sites of DSB repair genes and their association with colorectal cancer (CRC) risk and clinical outcome.	('association', 'Interaction', (143, 154))	('CRC', 'Phenotype', 'HP:0003003', (179, 182))	('colorectal cancer', 'Disease', 'MESH:D015179', (160, 177))	('colorectal cancer', 'Phenotype', 'HP:0003003', (160, 177))	('DSB repair', 'Gene', (116, 126))	('single nucleotide polymorphisms', 'Var', (43, 74))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('colorectal cancer', 'Disease', (160, 177))
110642	28722656	Alterations in DNA repair is also at the forefront of cervical cancer, especially in overcoming therapeutic resistance.	('cervical cancer', 'Disease', (54, 69))	('cervical cancer', 'Disease', 'MESH:D002583', (54, 69))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('Alterations', 'Var', (0, 11))	('DNA', 'Gene', (15, 18))
110648	28722656	Thus, in correlating variants in DDR genes with protein expression and subsequent survival rates, variants in DDR genes such as RAD52 may be able to predict prognosis in cervical cancer patients.	('variants', 'Var', (21, 29))	('cervical cancer', 'Disease', (170, 185))	('predict', 'Reg', (149, 156))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('patients', 'Species', '9606', (186, 194))	('RAD52', 'Gene', (128, 133))	('cervical cancer', 'Disease', 'MESH:D002583', (170, 185))	('variants', 'Var', (98, 106))
110650	28722656	Subsequently, we showed that amplification of the genomic region 12p13.33, which contains RAD52, was associated with the development of LUSC and that somatic overexpression of RAD52 was significant in LUSC tumors from our own patient cohort.	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('amplification', 'Var', (29, 42))	('RAD52', 'Gene', (90, 95))	('tumors', 'Phenotype', 'HP:0002664', (206, 212))	('patient', 'Species', '9606', (226, 233))	('LUSC', 'Disease', (201, 205))	('tumors', 'Disease', (206, 212))	('tumors', 'Disease', 'MESH:D009369', (206, 212))	('development', 'CPA', (121, 132))	('associated with', 'Reg', (101, 116))	('LUSC', 'Disease', (136, 140))
110653	28722656	This data aligns with that of others in connecting variation in RAD52 expression to the survival of tumor cells from numerous organ sites.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Disease', (100, 105))	('variation', 'Var', (51, 60))	('RAD52', 'Gene', (64, 69))	('tumor', 'Disease', 'MESH:D009369', (100, 105))
110655	28722656	Although RAD52 functions in a similar manner to the BRCA2 tumor suppressor, repairing DNA damage in order to stabilize cell homeostasis and viability, expression of RAD52 has recently been linked to several different forms of tumorigenesis (Table 1).	('BRCA2', 'Gene', (52, 57))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('BRCA2', 'Gene', '675', (52, 57))	('tumor', 'Disease', 'MESH:D009369', (226, 231))	('expression', 'Var', (151, 161))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('RAD52', 'Gene', (165, 170))	('linked to', 'Reg', (189, 198))	('tumor', 'Disease', (226, 231))
110659	28722656	Surprisingly, Rad52 was found to be upregulated in 10-week-old TGFalpha/c-myc and c-myc transgenic livers, respectively, compared with wildtype controls.	('upregulated', 'PosReg', (36, 47))	('transgenic', 'Var', (88, 98))	('Rad52', 'Gene', (14, 19))	('c-myc', 'Gene', '4609', (72, 77))	('c-myc', 'Gene', (72, 77))	('c-myc', 'Gene', '4609', (82, 87))	('c-myc', 'Gene', (82, 87))
110662	28722656	Cancer predisposition caused by A-T likely results from the loss of ATM kinase activity and excessive homologous recombination, leading to tumors with aberrant levels of DNA amplifications, deletions, and translocations.	('activity', 'MPA', (79, 87))	('A-T', 'Disease', 'MESH:D001260', (32, 35))	('translocations', 'Var', (205, 219))	('loss', 'NegReg', (60, 64))	('Cancer', 'Disease', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('ATM kinase', 'Enzyme', (68, 78))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('tumors', 'Disease', (139, 145))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('tumors', 'Disease', 'MESH:D009369', (139, 145))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('deletions', 'Var', (190, 199))	('A-T', 'Disease', (32, 35))
110663	28722656	This group found that knockout of the Rad52 gene in an in vivo ATM-/- mouse model led to not only an increased latency period to develop T-cell lymphoma, but also an increased lifespan and decreased overall tumor incidence in Rad52 knockout mice compared to Rad52 wildtype.	('lifespan', 'CPA', (176, 184))	('decreased', 'NegReg', (189, 198))	('increased', 'PosReg', (101, 110))	('knockout', 'Var', (232, 240))	('increased', 'PosReg', (166, 175))	('mouse', 'Species', '10090', (70, 75))	('mice', 'Species', '10090', (241, 245))	('knockout', 'Var', (22, 30))	('T-cell lymphoma', 'Disease', 'MESH:D016399', (137, 152))	('Rad52', 'Gene', (38, 43))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('T-cell lymphoma', 'Disease', (137, 152))	('T-cell lymphoma', 'Phenotype', 'HP:0012190', (137, 152))	('cell lymphoma', 'Phenotype', 'HP:0012191', (139, 152))	('lymphoma', 'Phenotype', 'HP:0002665', (144, 152))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('tumor', 'Disease', (207, 212))
110664	28722656	This newfound ability to decrease tumorigenesis and increase survival by depletion of Rad52 in a tumorigenic environment was hypothesized to stem from a reduction in excessive intrachromosomal recombination found in the absence of ATM.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor', 'Disease', (34, 39))	('reduction', 'NegReg', (153, 162))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('survival', 'CPA', (61, 69))	('increase', 'PosReg', (52, 60))	('decrease', 'NegReg', (25, 33))	('tumor', 'Disease', (97, 102))	('Rad52', 'Gene', (86, 91))	('depletion', 'Var', (73, 82))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
110668	28722656	Consequently, hindering the binding capability of RAD52 prohibited the proliferative and clonogenic potential of CML-CP leukemia stem and progenitor cells due to the cells' oncogenic addiction to Rad52 DNA repair.	('leukemia', 'Phenotype', 'HP:0001909', (120, 128))	('hindering', 'Var', (14, 23))	('binding', 'Interaction', (28, 35))	('prohibited', 'NegReg', (56, 66))	('CML-CP leukemia', 'Disease', 'MESH:D015464', (113, 128))	('CML-CP leukemia', 'Disease', (113, 128))
110670	28722656	Concomitantly, unpublished data from our group suggests Rad52-/- mice are more resistant to squamous cell lung carcinoma compared to wildtype.	('resistant', 'CPA', (79, 88))	('squamous cell lung carcinoma', 'Phenotype', 'HP:0030359', (92, 120))	('squamous cell lung carcinoma', 'Disease', (92, 120))	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('mice', 'Species', '10090', (65, 69))	('Rad52-/-', 'Var', (56, 64))	('squamous cell lung carcinoma', 'Disease', 'MESH:D002294', (92, 120))
110673	28722656	Our novel observations suggest that knockout of the Rad52 gene in an in vivo mouse model of carcinogenesis decreases murine lung hyper-plasia, in situ carcinoma and lung SCC.	('knockout', 'Var', (36, 44))	('carcinogenesis decreases murine lung hyper-plasia', 'Disease', 'MESH:D063646', (92, 141))	('SCC', 'Gene', (170, 173))	('mouse', 'Species', '10090', (77, 82))	('carcinogenesis decreases murine lung hyper-plasia', 'Disease', (92, 141))	('Rad52', 'Gene', (52, 57))	('situ carcinoma', 'Disease', 'MESH:D002278', (146, 160))	('SCC', 'Gene', '6317', (170, 173))	('situ carcinoma', 'Disease', (146, 160))	('carcinoma', 'Phenotype', 'HP:0030731', (151, 160))
110674	28722656	Cancer is the result of uncontrolled cell proliferation, generally due to unresolved DNA mutations which allow for the cell cycle to bypass any warnings or red flags that would normally cause the replication process to halt.	('flags', 'Species', '34205', (160, 165))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('mutations', 'Var', (89, 98))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('DNA', 'Gene', (85, 88))
110682	28722656	Thus, the manipulation of DNA repair pathways in cancer may play a key role in promoting tumori-genesis and progression by maintaining genomic stability within tumor cells and actually enhancing their survival.	('promoting', 'PosReg', (79, 88))	('cancer', 'Disease', (49, 55))	('enhancing', 'PosReg', (185, 194))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('genomic stability', 'CPA', (135, 152))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('tumor', 'Disease', (89, 94))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('maintaining', 'PosReg', (123, 134))	('manipulation', 'Var', (10, 22))	('survival', 'CPA', (201, 209))	('progression', 'CPA', (108, 119))	('tumor', 'Disease', (160, 165))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('DNA', 'Gene', (26, 29))
110683	28722656	Emerging data suggests that inhibition of DNA repair may be inducing cell death through both apoptotic, as well as necrotic means.	('necrotic', 'Disease', 'MESH:D009336', (115, 123))	('inhibition', 'Var', (28, 38))	('necrotic', 'Disease', (115, 123))	('apoptotic', 'CPA', (93, 102))	('cell death', 'CPA', (69, 79))	('inducing', 'Reg', (60, 68))	('DNA repair', 'Protein', (42, 52))
110687	28722656	Along these lines, our own unpublished data shows that depletion of RAD52 in human squamous cell lung carcinoma cell lines enhances phenotypes associated with decreased tumorigenesis and increased cell death.	('cell death', 'CPA', (197, 207))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('depletion', 'Var', (55, 64))	('enhances', 'PosReg', (123, 131))	('squamous cell lung carcinoma', 'Phenotype', 'HP:0030359', (83, 111))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('squamous cell lung carcinoma', 'Disease', 'MESH:D002294', (83, 111))	('decreased', 'NegReg', (159, 168))	('increased', 'PosReg', (187, 196))	('squamous cell lung carcinoma', 'Disease', (83, 111))	('tumor', 'Disease', (169, 174))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('RAD52', 'Gene', (68, 73))	('human', 'Species', '9606', (77, 82))
110689	28722656	Such functional studies continue to support genetic findings by revealing that loss of RAD52 may induce DNA damage and genomic instability within squamous lung tumor cells beyond a threshold of viability.	('DNA damage', 'MPA', (104, 114))	('RAD52', 'Gene', (87, 92))	('loss', 'Var', (79, 83))	('genomic instability within squamous lung tumor', 'Disease', (119, 165))	('lung tumor', 'Phenotype', 'HP:0100526', (155, 165))	('squamous lung tumor', 'Phenotype', 'HP:0030359', (146, 165))	('induce', 'Reg', (97, 103))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('genomic instability within squamous lung tumor', 'Disease', 'MESH:D001929', (119, 165))
110692	28722656	In accordance, several groups have begun identifying and optimizing small molecule inhibitors against proteins which are believed to enhance tumorigenesis, such as RAD52, to better treat lung cancers and other diseases.	('enhance', 'PosReg', (133, 140))	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('lung cancers', 'Phenotype', 'HP:0100526', (187, 199))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('lung cancers', 'Disease', (187, 199))	('cancers', 'Phenotype', 'HP:0002664', (192, 199))	('tumor', 'Disease', (141, 146))	('lung cancers', 'Disease', 'MESH:D008175', (187, 199))	('small molecule inhibitors', 'Var', (68, 93))	('proteins', 'Protein', (102, 110))	('lung cancer', 'Phenotype', 'HP:0100526', (187, 198))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('inhibitors', 'Var', (83, 93))
110693	28722656	Targeting Rad52 has been shown to eliminate cancer stem and progenitor cells, induce high levels of spon-taneous DNA damage and decrease tumorigenesis without detectable effects on normal cells and tissues.	('induce', 'Reg', (78, 84))	('tumor', 'Disease', (137, 142))	('spon-taneous DNA damage', 'MPA', (100, 123))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('Rad52', 'Gene', (10, 15))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('eliminate', 'NegReg', (34, 43))	('decrease', 'NegReg', (128, 136))	('Targeting', 'Var', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
110695	28722656	In the context of cancer, synthetic lethality results when a genetic mutation in a single gene leaves the cell viable, but simultaneous mutations in two genes leads to cell death.	('leaves', 'NegReg', (95, 101))	('cell', 'CPA', (168, 172))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('genetic mutation', 'Var', (61, 77))	('mutations', 'Var', (136, 145))	('cancer', 'Disease', (18, 24))	('cancer', 'Disease', 'MESH:D009369', (18, 24))
110696	28722656	So, targeting a gene that is synthetic lethal to a cancer-relevant mutation should kill only cancer cells and spare normal cells.	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('mutation', 'Var', (67, 75))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))
110698	28722656	Functional results using these inhibitors demonstrated that inhibiting RAD52, in a model of hereditary breast and ovarian cancer, works to suppress growth of BRCA1- and BRCA2-deficient cells, impeding tumorigenesis.	('BRCA2', 'Gene', (169, 174))	('BRCA1', 'Gene', (158, 163))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('suppress', 'NegReg', (139, 147))	('RAD52', 'Gene', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('BRCA2', 'Gene', '675', (169, 174))	('ovarian cancer', 'Phenotype', 'HP:0100615', (114, 128))	('impeding', 'NegReg', (192, 200))	('hereditary breast and ovarian cancer', 'Disease', 'MESH:D061325', (92, 128))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('tumor', 'Disease', (201, 206))	('inhibiting', 'Var', (60, 70))	('BRCA1', 'Gene', '672', (158, 163))	('growth', 'MPA', (148, 154))
110712	28722656	Thus, through either peptide aptamers, small molecule inhibitors, or chemotherapeutic histone deactylase inhibitors, RAD52 inhibition can be used as a prototype for development of novel therapies against hereditary cancers with defective BRCA proteins or can be applied against sporadic cancers in which BRCA1 or BRCA2 are either mutated or downregulated due to mechanisms such as constitutive promoter methylation.	('mutated', 'Var', (330, 337))	('hereditary cancers', 'Disease', (204, 222))	('defective BRCA proteins', 'Disease', 'MESH:D011488', (228, 251))	('cancers', 'Disease', 'MESH:D009369', (215, 222))	('BRCA2', 'Gene', '675', (313, 318))	('cancers', 'Phenotype', 'HP:0002664', (215, 222))	('cancers', 'Disease', (215, 222))	('BRCA1', 'Gene', (304, 309))	('cancers', 'Disease', 'MESH:D009369', (287, 294))	('cancers', 'Phenotype', 'HP:0002664', (287, 294))	('hereditary cancers', 'Disease', 'MESH:D009369', (204, 222))	('cancers', 'Disease', (287, 294))	('BRCA1', 'Gene', '672', (304, 309))	('downregulated', 'NegReg', (341, 354))	('cancer', 'Phenotype', 'HP:0002664', (287, 293))	('defective BRCA proteins', 'Disease', (228, 251))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('BRCA2', 'Gene', (313, 318))
110718	28722656	Furthermore, unlike previous data showing that knockout models of Rad51 are lethal to normal cells both in vivo and in vitro, this precise method solely effects tumor cells and does not cause damage to normal cells because recombinational repair is mostly active in S-phase of the cell cycle where DNA is being replicated at a high rate in ultra-proliferative tumor cells.	('Rad51', 'Gene', (66, 71))	('Rad51', 'Gene', '5888', (66, 71))	('tumor', 'Disease', (360, 365))	('effects', 'Reg', (153, 160))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('recombinational', 'Var', (223, 238))	('tumor', 'Disease', 'MESH:D009369', (360, 365))	('tumor', 'Disease', (161, 166))	('tumor', 'Phenotype', 'HP:0002664', (360, 365))
110720	28722656	Recent advances in genome analysis have identified a number of genetic alterations in cancer that could be therapeutically exploited or used as predictive bio markers for guiding treatment decisions, customizing therapy, and eventually improving patient outcome.	('patient', 'Species', '9606', (246, 253))	('genetic alterations', 'Var', (63, 82))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('cancer', 'Disease', (86, 92))
110722	28722656	Inhibiting DDR pathways that tumor cells have come to rely on for sustaining viability may work to combat the cancer by amplifying both endogenous and drug-induced DNA damage, thus, triggering cell death in tumor cells while sparing normal cells that do not rely on these pathways to maintain their integrity.	('cell death', 'CPA', (193, 203))	('cancer', 'Disease', (110, 116))	('Inhibiting', 'Var', (0, 10))	('DDR pathways', 'Pathway', (11, 23))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('DNA', 'MPA', (164, 167))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('triggering', 'Reg', (182, 192))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('tumor', 'Disease', (29, 34))	('tumor', 'Disease', (207, 212))	('cancer', 'Disease', 'MESH:D009369', (110, 116))
110724	28722656	Finally, beyond the scope of induced synthetic lethality in BRCA deficient cells, this Rad52-targeted phenotype may also be proven relevant by genetic and epigenetic deficiencies found in other genes, lending to the importance of prototypic Rad52 inhibitors currently in the pipeline.	('Rad52-targeted', 'Gene', (87, 101))	('deficiencies', 'Var', (166, 178))	('BRCA', 'Gene', (60, 64))	('BRCA', 'Gene', '672', (60, 64))
110726	28722656	As shown in Figure 1, loss of Rad52 increases genomic instability beyond a manageable threshold and consents the damaged cells to death before they are able to become tumor cells.	('genomic instability', 'MPA', (46, 65))	('Rad52', 'Gene', (30, 35))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('increases', 'PosReg', (36, 45))	('loss', 'Var', (22, 26))	('tumor', 'Disease', (167, 172))
110776	33982791	In our study, it was revealed that neferine inhibited the growth and induced the apoptosis of HNSCC cells both in vitro and in vivo.	('neferine', 'Var', (35, 43))	('inhibited', 'NegReg', (44, 53))	('apoptosis', 'CPA', (81, 90))	('neferine', 'Chemical', 'MESH:C057222', (35, 43))	('induced', 'Reg', (69, 76))	('growth', 'CPA', (58, 64))
110777	33982791	Furthermore, the results revealed that neferine activated the ASK1/JNK pathway by increasing reactive oxygen species production, resulting in the subsequent induction of apoptosis and the regulation of canonical autophagy in HNSCC cells.	('regulation', 'Reg', (188, 198))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (93, 116))	('JNK', 'Gene', (67, 70))	('neferine', 'Chemical', 'MESH:C057222', (39, 47))	('canonical autophagy', 'CPA', (202, 221))	('ASK1', 'Gene', '4217', (62, 66))	('ASK1', 'Gene', (62, 66))	('reactive oxygen species production', 'MPA', (93, 127))	('increasing', 'PosReg', (82, 92))	('JNK', 'Gene', '5599', (67, 70))	('neferine', 'Var', (39, 47))	('increasing reactive oxygen species production', 'Phenotype', 'HP:0025464', (82, 127))	('induction', 'Reg', (157, 166))	('activated', 'PosReg', (48, 57))	('apoptosis', 'CPA', (170, 179))
110790	33982791	Furthermore, recent research suggests that neferine induces autophagy and inhibits ovarian cancer cell angiogenesis.	('ovarian cancer', 'Phenotype', 'HP:0100615', (83, 97))	('inhibits ovarian cancer', 'Disease', (74, 97))	('neferine', 'Chemical', 'MESH:C057222', (43, 51))	('induces', 'PosReg', (52, 59))	('inhibits ovarian cancer', 'Disease', 'MESH:C565433', (74, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('neferine', 'Var', (43, 51))	('autophagy', 'CPA', (60, 69))
110824	33982791	The primary antibodies were as follows: Anti-cleaved caspase-3 (product no.	('Anti-cleaved', 'Var', (40, 52))	('caspase-3', 'Gene', (53, 62))	('caspase-3', 'Gene', '836', (53, 62))
110825	33982791	sc-7272; Santa Cruz Biotechnology, Inc.), anti-cleaved caspase-9 (cat.	('caspase-9', 'Gene', '842', (55, 64))	('anti-cleaved', 'Var', (42, 54))	('caspase-9', 'Gene', (55, 64))
110826	33982791	10380-1-AP), anti-cleaved PARP1 (cat.	('PARP1', 'Gene', (26, 31))	('anti-cleaved', 'Var', (13, 25))	('PARP1', 'Gene', '142', (26, 31))
110836	33982791	E2888; Sigma Aldrich; Merck KGaA), 6 h; chloroquine (MCE) 10 microM, 24 h].	('E2888', 'Var', (0, 5))	('Aldrich', 'Disease', (13, 20))	('Aldrich', 'Disease', 'MESH:D014923', (13, 20))	('chloroquine', 'Chemical', 'MESH:D002738', (40, 51))	('MCE', 'Chemical', '-', (53, 56))
110851	33982791	9664; 1:1,000; Cell Signaling Technology, Inc.); anti-cleaved PARP1 (cat.	('PARP1', 'Gene', (62, 67))	('PARP1', 'Gene', '142', (62, 67))	('anti-cleaved', 'Var', (49, 61))
110865	33982791	The results revealed that neferine increased apoptosis from 7.51% (0 microM) to 11.81% (5 microM), 27.90% (10 microM), 49.10% (15 microM), and 64.70% (20 microM) in HN6 cells (Fig.	('apoptosis', 'CPA', (45, 54))	('neferine', 'Chemical', 'MESH:C057222', (26, 34))	('HN6', 'CellLine', 'CVCL:5516', (165, 168))	('neferine', 'Var', (26, 34))
110897	33982791	However, chloroquine further amplified neferine-induced cell cytotoxicity (Fig.	('cell cytotoxicity', 'Disease', 'MESH:D064420', (56, 73))	('cell cytotoxicity', 'Disease', (56, 73))	('neferine', 'Chemical', 'MESH:C057222', (39, 47))	('amplified', 'PosReg', (29, 38))	('neferine-induced', 'Var', (39, 55))	('chloroquine', 'Chemical', 'MESH:D002738', (9, 20))
110906	33982791	Flow cytometric analysis revealed that p62 knockdown alleviated the neferine-induced apoptosis (from 43.3 to 29.7%) in CAL27 cells (Fig.	('alleviated', 'NegReg', (53, 63))	('neferine', 'Chemical', 'MESH:C057222', (68, 76))	('knockdown', 'Var', (43, 52))	('apoptosis', 'CPA', (85, 94))	('CAL27', 'CellLine', 'CVCL:1107', (119, 124))	('p62', 'Gene', '8878', (39, 42))	('p62', 'Gene', (39, 42))
110910	33982791	The tumor volumes following treatment with neferine were significantly smaller than that of the control.	('tumor', 'Disease', (4, 9))	('neferine', 'Chemical', 'MESH:C057222', (43, 51))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('neferine', 'Var', (43, 51))	('smaller', 'NegReg', (71, 78))
110911	33982791	The growth rate of tumors treated with neferine was also slower than that of the control (Fig.	('tumors', 'Disease', (19, 25))	('slower', 'NegReg', (57, 63))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('neferine', 'Chemical', 'MESH:C057222', (39, 47))	('growth rate', 'CPA', (4, 15))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('neferine', 'Var', (39, 47))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))
110914	33982791	In addition, neferine increased the expression of cleaved caspase-3 and cleaved PARP1 in the nucleus, indicating that neferine induced the apoptosis of xenograft tumors.	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('cleaved', 'Var', (72, 79))	('expression', 'MPA', (36, 46))	('caspase-3', 'Gene', '836', (58, 67))	('cleaved', 'MPA', (50, 57))	('PARP1', 'Gene', '142', (80, 85))	('neferine', 'Chemical', 'MESH:C057222', (13, 21))	('PARP1', 'Gene', (80, 85))	('increased', 'PosReg', (22, 31))	('tumors', 'Disease', (162, 168))	('tumors', 'Disease', 'MESH:D009369', (162, 168))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))	('caspase-3', 'Gene', (58, 67))	('apoptosis', 'CPA', (139, 148))	('neferine', 'Chemical', 'MESH:C057222', (118, 126))
110915	33982791	In accordance with the in vitro results, neferine also increased the level of LC3-II and p62, indicating that neferine induced autophagosome generation and inhibited autophagy influx in vivo.	('p62', 'Gene', '8878', (89, 92))	('LC3-II', 'Chemical', '-', (78, 84))	('autophagy influx', 'CPA', (166, 182))	('induced', 'Reg', (119, 126))	('autophagosome generation', 'CPA', (127, 151))	('neferine', 'Var', (110, 118))	('increased', 'PosReg', (55, 64))	('level', 'MPA', (69, 74))	('neferine', 'Chemical', 'MESH:C057222', (41, 49))	('neferine', 'Chemical', 'MESH:C057222', (110, 118))	('LC3-II', 'Protein', (78, 84))	('p62', 'Gene', (89, 92))	('inhibited', 'NegReg', (156, 165))
110924	33982791	Neferine was also revealed to suppress the healing and migration of HNSCC cells, further highlighting its potential anticancer properties, which were verified in an in vivo murine xenograft model.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('murine', 'Species', '10090', (173, 179))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('Neferine', 'Chemical', 'MESH:C057222', (0, 8))	('Neferine', 'Var', (0, 8))	('suppress', 'NegReg', (30, 38))
110938	33982791	It was revealed that neferine induced autophagosome generation, while also inhibiting autophagic flux at the autophagosome degradation step as evidenced by the increased conversion of LC3-I to LC3-II and the accumulation of p62.	('inhibiting', 'NegReg', (75, 85))	('increased', 'PosReg', (160, 169))	('conversion', 'MPA', (170, 180))	('p62', 'Gene', '8878', (224, 227))	('p62', 'Gene', (224, 227))	('LC3', 'Gene', '84557', (193, 196))	('autophagosome generation', 'CPA', (38, 62))	('LC3', 'Gene', (193, 196))	('neferine', 'Chemical', 'MESH:C057222', (21, 29))	('LC3', 'Gene', '84557', (184, 187))	('LC3-II', 'Chemical', '-', (193, 199))	('LC3', 'Gene', (184, 187))	('accumulation', 'PosReg', (208, 220))	('neferine', 'Var', (21, 29))
111010	33114328	In human pancreatic ductal adenocarcinoma (PDAC) tumors and in transgenic mice engineered to carry KRas and p53 mutations under the control of the pancreatic specific Cre promoter (KPC), different subpopulations of CAFs were identified based on their expression of meflin, a glycosylphosphatidylinositol-anchored protein expressed by MSCs that maintains their undifferentiated state.	('CAF', 'Gene', (215, 218))	('meflin', 'Gene', (265, 271))	('p53', 'Gene', (108, 111))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('human', 'Species', '9606', (3, 8))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (9, 41))	('glycosylphosphatidylinositol-anchored', 'Disease', (275, 312))	('CAF', 'Gene', '8850', (215, 218))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('carcinoma', 'Phenotype', 'HP:0030731', (32, 41))	('KRas', 'Gene', (99, 103))	('mutations', 'Var', (112, 121))	('p53', 'Gene', '22060', (108, 111))	('glycosylphosphatidylinositol-anchored', 'Disease', 'MESH:C537277', (275, 312))	('KRas', 'Gene', '16653', (99, 103))	('transgenic mice', 'Species', '10090', (63, 78))	('pancreatic ductal adenocarcinoma (PDAC) tumors', 'Disease', 'MESH:C537768', (9, 55))
111038	33114328	Furthermore, CD10+GPR77+ CAFs promote successful engraftment of PDXs, and targeting these CAFs with a neutralizing anti-GPR77 antibody abolishes tumor formation and restores tumor chemosensitivity via the production of IL-6 and IL-8.	('targeting', 'Var', (74, 83))	('D', 'Chemical', 'MESH:D003903', (14, 15))	('production of IL-6', 'MPA', (205, 223))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('GPR77', 'Gene', '27202', (18, 23))	('CAF', 'Gene', '8850', (90, 93))	('tumor', 'Disease', (145, 150))	('GPR77', 'Gene', '27202', (120, 125))	('CAF', 'Gene', (90, 93))	('CAF', 'Gene', '8850', (25, 28))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('CAF', 'Gene', (25, 28))	('CD10', 'Gene', '4311', (13, 17))	('GPR77', 'Gene', (18, 23))	('tumor', 'Disease', (174, 179))	('D', 'Chemical', 'MESH:D003903', (65, 66))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('engraftment', 'CPA', (49, 60))	('GPR77', 'Gene', (120, 125))	('CD10', 'Gene', (13, 17))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('restores', 'PosReg', (165, 173))	('abolishes', 'NegReg', (135, 144))
111055	33114328	When EVs are captured by tumor cells, miRNAs can promote resistance to cisplatin by downregulating cyclin-dependent kinase inhibitor (CDKN)1A and ferroptosis, a newly described programmed cell death mechanism characterized by the accumulation of lipid peroxides and a lack of cellular anti-oxidant response.	('ferroptosis', 'Gene', (146, 157))	('accumulation', 'PosReg', (230, 242))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumor', 'Disease', (25, 30))	('CDKN)1A', 'Gene', '1026', (134, 141))	('lipid peroxides', 'Chemical', 'MESH:D008054', (246, 261))	('resistance to cisplatin', 'MPA', (57, 80))	('downregulating', 'NegReg', (84, 98))	('cyclin-dependent', 'MPA', (99, 115))	('lipid peroxides', 'MPA', (246, 261))	('promote', 'PosReg', (49, 56))	('miRNAs', 'Var', (38, 44))	('cisplatin', 'Chemical', 'MESH:D002945', (71, 80))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('oxidant response', 'Phenotype', 'HP:0025464', (290, 306))
111074	33114328	In mouse models of PDAC, the population of CAFs expressing alpha-SMA exhibit increased activation of Shh signaling that inhibits the production of VEGF, CXCL-12 and IL-8, which affects tumor growth, angiogenesis and immunosuppression.	('inhibits', 'NegReg', (120, 128))	('affects', 'Reg', (177, 184))	('activation', 'PosReg', (87, 97))	('PDAC', 'Disease', (19, 23))	('tumor', 'Disease', (185, 190))	('D', 'Chemical', 'MESH:D003903', (20, 21))	('mouse', 'Species', '10090', (3, 8))	('CAF', 'Gene', (43, 46))	('alpha-SMA', 'Var', (59, 68))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('CAF', 'Gene', '8850', (43, 46))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('Shh signaling', 'Pathway', (101, 114))	('production of VEGF', 'MPA', (133, 151))
111104	33114328	In bladder and breast cancers, high expression of MFAP5 in CAFs correlated with high-grade malignancy, presence of metastasis and unfavorable clinical outcome.	('cancers', 'Phenotype', 'HP:0002664', (22, 29))	('correlated', 'Reg', (64, 74))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('breast cancers', 'Phenotype', 'HP:0003002', (15, 29))	('MFAP5', 'Gene', (50, 55))	('CAF', 'Gene', (59, 62))	('malignancy', 'Disease', 'MESH:D009369', (91, 101))	('breast cancer', 'Phenotype', 'HP:0003002', (15, 28))	('bladder', 'Disease', (3, 10))	('high', 'Var', (31, 35))	('breast cancers', 'Disease', 'MESH:D001943', (15, 29))	('malignancy', 'Disease', (91, 101))	('breast cancers', 'Disease', (15, 29))	('expression', 'MPA', (36, 46))	('CAF', 'Gene', '8850', (59, 62))
111105	33114328	In murine models of ovarian and PDAC cancers, inhibition of MFAP5 with monoclonal antibodies is associated with a decrease in the number of CAFs and microvessels, but also with increased sensitivity to paclitaxel.	('ovarian and PDAC cancers', 'Disease', 'MESH:C537768', (20, 44))	('paclitaxel', 'Chemical', 'MESH:D017239', (202, 212))	('inhibition', 'Var', (46, 56))	('cancers', 'Phenotype', 'HP:0002664', (37, 44))	('CAF', 'Gene', (140, 143))	('increased', 'PosReg', (177, 186))	('murine', 'Species', '10090', (3, 9))	('MFAP5', 'Gene', (60, 65))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('CAF', 'Gene', '8850', (140, 143))	('decrease', 'NegReg', (114, 122))	('sensitivity to paclitaxel', 'MPA', (187, 212))
111121	33114328	When tested in Phase I clinical trials in non-small cell lung carcinoma (NCT00243204, NCT02209727), melanoma (NCT00083252) and pancreatic carcinoma (NCT00116389), sibrotuzumab, a monoclonal antibody against alphaFAP, and PT-100, a small molecule peptidyl peptidase inhibitor, have shown feasibility in the absence of severe toxicity, but their efficacy in Phase II trials has been limited.	('non-small cell lung carcinoma', 'Disease', 'MESH:D002289', (42, 71))	('pancreatic carcinoma', 'Disease', 'MESH:D010190', (127, 147))	('NCT00116389', 'Var', (149, 160))	('NCT02209727', 'Var', (86, 97))	('NCT00243204', 'Var', (73, 84))	('melanoma', 'Phenotype', 'HP:0002861', (100, 108))	('toxicity', 'Disease', 'MESH:D064420', (324, 332))	('pancreatic carcinoma', 'Disease', (127, 147))	('NCT00083252', 'Var', (110, 121))	('small cell lung carcinoma', 'Phenotype', 'HP:0030357', (46, 71))	('sibrotuzumab', 'Disease', (163, 175))	('melanoma', 'Disease', (100, 108))	('carcinoma', 'Phenotype', 'HP:0030731', (62, 71))	('sibrotuzumab', 'Disease', 'None', (163, 175))	('non-small cell lung carcinoma', 'Phenotype', 'HP:0030358', (42, 71))	('non-small cell lung carcinoma', 'Disease', (42, 71))	('toxicity', 'Disease', (324, 332))	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('melanoma', 'Disease', 'MESH:D008545', (100, 108))
111122	33114328	TRC-105, a monoclonal antibody against endoglin (CD105) present on the surface of ECs, CAFs and MSCs, enhances immunotherapy with NK cells in xenotransplanted human neuroblastoma tumors.	('CD10', 'Gene', '4311', (49, 53))	('CAF', 'Gene', '8850', (87, 90))	('immunotherapy with', 'CPA', (111, 129))	('neuroblastoma tumors', 'Disease', 'MESH:D009447', (165, 185))	('endoglin', 'Gene', (39, 47))	('TRC-105', 'Var', (0, 7))	('tumors', 'Phenotype', 'HP:0002664', (179, 185))	('enhances', 'PosReg', (102, 110))	('neuroblastoma tumors', 'Disease', (165, 185))	('human', 'Species', '9606', (159, 164))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('neuroblastoma', 'Phenotype', 'HP:0003006', (165, 178))	('CAF', 'Gene', (87, 90))	('endoglin', 'Gene', '2022', (39, 47))	('CD10', 'Gene', (49, 53))
111127	33114328	Evidence that CAF activation involves regulatory miRNAs such as miR-221-5p, miR-145 and miR-Let-7 and epigenetic mechanisms such as DNA methylation and histone acetylation suggests other strategies to reverse CAF activation.	('histone acetylation', 'MPA', (152, 171))	('miR-145', 'Gene', (76, 83))	('CAF', 'Gene', (209, 212))	('miR-145', 'Gene', '406937', (76, 83))	('miR-Let-7', 'Var', (88, 97))	('miR-221', 'Gene', '407006', (64, 71))	('D', 'Chemical', 'MESH:D003903', (132, 133))	('CAF', 'Gene', '8850', (209, 212))	('CAF', 'Gene', (14, 17))	('miR-221', 'Gene', (64, 71))	('CAF', 'Gene', '8850', (14, 17))
111128	33114328	One such strategy tested in breast, prostate and OSCC cancer xenograft models is to re-induce the expression of miRNAs (miR-145, miR-15, miR-16, Let-7b) that prevent CAF activation.	('Let-7b', 'Gene', '406884', (145, 151))	('miR-16', 'Gene', '51573', (137, 143))	('CAF', 'Gene', '8850', (166, 169))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('miR-15', 'Var', (129, 135))	('cancer', 'Disease', (54, 60))	('miR-145', 'Gene', (120, 127))	('Let-7b', 'Gene', (145, 151))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('miR-145', 'Gene', '406937', (120, 127))	('CAF', 'Gene', (166, 169))	('miR-16', 'Gene', (137, 143))
111135	33114328	Ruxolitinib improves survival for patients with metastatic pancreatic cancer, whereas in lung cancer, combining ruxolitinib with other drugs does not improve efficiency over administering ruxolitinib alone (NCT01423604, NCT02145637, NCT02155465).	('NCT01423604', 'Var', (207, 218))	('pancreatic cancer', 'Disease', 'MESH:D010190', (59, 76))	('ruxolitinib', 'Chemical', 'MESH:C540383', (112, 123))	('Ruxolitinib', 'Chemical', 'MESH:C540383', (0, 11))	('pancreatic cancer', 'Disease', (59, 76))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('lung cancer', 'Disease', (89, 100))	('lung cancer', 'Phenotype', 'HP:0100526', (89, 100))	('NCT02145637', 'Var', (220, 231))	('ruxolitinib', 'Chemical', 'MESH:C540383', (188, 199))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('patients', 'Species', '9606', (34, 42))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (59, 76))	('survival', 'MPA', (21, 29))	('lung cancer', 'Disease', 'MESH:D008175', (89, 100))	('improves', 'PosReg', (12, 20))	('NCT02155465', 'Var', (233, 244))
111136	33114328	Based on data demonstrating a difference in the dependence of CAFs on BCL-2 vs. MCL-1 for survival, studies have shown that CAFs in human breast cancer are sensitive to inhibitors targeting MCL-1 (A-1210477 and S63845) but not to those targeting BCL-2/BCL-XL (ABT-737 and navitoclax).	('CAF', 'Gene', '8850', (124, 127))	('MCL-1', 'Gene', '4170', (80, 85))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('MCL-1', 'Gene', '4170', (190, 195))	('A-1210477', 'Var', (197, 206))	('CAF', 'Gene', (124, 127))	('S63845', 'Var', (211, 217))	('MCL-1', 'Gene', (80, 85))	('MCL-1', 'Gene', (190, 195))	('breast cancer', 'Phenotype', 'HP:0003002', (138, 151))	('BCL-2', 'Gene', '596', (246, 251))	('BCL-XL', 'Gene', (252, 258))	('BCL-2', 'Gene', (246, 251))	('BCL-2', 'Gene', '596', (70, 75))	('breast cancer', 'Disease', 'MESH:D001943', (138, 151))	('breast cancer', 'Disease', (138, 151))	('BCL-2', 'Gene', (70, 75))	('CAF', 'Gene', '8850', (62, 65))	('BCL-XL', 'Gene', '598', (252, 258))	('CAF', 'Gene', (62, 65))	('human', 'Species', '9606', (132, 137))
111146	33114328	A recent Phase III clinical trial tested nab-paclitaxel in combination with atezolizumab, a monoclonal antibody against PD-L1, in unresectable and metastatic triple-negative breast cancer (NCT02425891) and metastatic lung cancer (NCT02367781), showing an increase in PFS and OS.	('breast cancer', 'Disease', 'MESH:D001943', (174, 187))	('paclitaxel', 'Chemical', 'MESH:D017239', (45, 55))	('lung cancer', 'Disease', (217, 228))	('breast cancer', 'Disease', (174, 187))	('lung cancer', 'Phenotype', 'HP:0100526', (217, 228))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('atezolizumab', 'Chemical', 'MESH:C000594389', (76, 88))	('breast cancer', 'Phenotype', 'HP:0003002', (174, 187))	('PFS', 'Disease', (267, 270))	('NCT02425891', 'Var', (189, 200))	('PD-L1', 'Gene', (120, 125))	('nab', 'Chemical', '-', (41, 44))	('PD-L1', 'Gene', '29126', (120, 125))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('lung cancer', 'Disease', 'MESH:D008175', (217, 228))	('NCT02367781', 'Var', (230, 241))	('increase', 'PosReg', (255, 263))
111157	33114328	Other clinical trials testing galunisertib in combination with capecitabine, an anti-metabolite drug, in colorectal cancer (NCT04031872), or with enzalutamide, an androgen receptor inhibitor, in metastatic prostate cancer (NCT02452008) are ongoing.	('prostate cancer', 'Disease', 'MESH:D011471', (206, 221))	('colorectal cancer', 'Disease', 'MESH:D015179', (105, 122))	('capecitabine', 'Chemical', 'MESH:D000069287', (63, 75))	('androgen receptor', 'Gene', (163, 180))	('enzalutamide', 'Chemical', 'MESH:C540278', (146, 158))	('prostate cancer', 'Phenotype', 'HP:0012125', (206, 221))	('NCT04031872', 'Var', (124, 135))	('colorectal cancer', 'Phenotype', 'HP:0003003', (105, 122))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('androgen receptor', 'Gene', '367', (163, 180))	('prostate cancer', 'Disease', (206, 221))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('galunisertib', 'Chemical', 'MESH:C557799', (30, 42))	('colorectal cancer', 'Disease', (105, 122))
111183	32111983	In this study, we characterized and confirmed that FGF19 serves as an oncogenic driver in LSQ development and progression, and reported that the amplification and high expression of FGF19 in LSQ was significantly associated with poor overall and progression-free survival.	('associated', 'Reg', (213, 223))	('amplification', 'Var', (145, 158))	('LSQ', 'Chemical', '-', (191, 194))	('poor', 'NegReg', (229, 233))	('FGF19', 'Gene', (182, 187))	('LSQ', 'Phenotype', 'HP:0030359', (90, 93))	('LSQ', 'Disease', (90, 93))	('LSQ', 'Phenotype', 'HP:0030359', (191, 194))	('overall', 'CPA', (234, 241))	('progression-free survival', 'CPA', (246, 271))	('LSQ', 'Chemical', '-', (90, 93))	('high', 'PosReg', (163, 167))
111194	32111983	Recently, targeted therapies against specific genes including EGFR, ALK, ROS1, and BRAF have markedly improved the outcome for adenocarcinoma patients.	('EGFR', 'Gene', '1956', (62, 66))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('ALK', 'Gene', (68, 71))	('targeted', 'Var', (10, 18))	('adenocarcinoma', 'Disease', (127, 141))	('EGFR', 'Gene', (62, 66))	('ROS1', 'Gene', (73, 77))	('ROS1', 'Gene', '6098', (73, 77))	('ALK', 'Gene', '238', (68, 71))	('adenocarcinoma', 'Disease', 'MESH:D000230', (127, 141))	('BRAF', 'Gene', '673', (83, 87))	('patients', 'Species', '9606', (142, 150))	('BRAF', 'Gene', (83, 87))	('improved', 'PosReg', (102, 110))
111195	32111983	However, only a small proportion of LSQ harbor these driver gene mutations.	('LSQ', 'Phenotype', 'HP:0030359', (36, 39))	('LSQ', 'Disease', (36, 39))	('mutations', 'Var', (65, 74))	('LSQ', 'Chemical', '-', (36, 39))
111200	32111983	In patients with hepatocellular carcinoma, high amplification of FGF19 promotes progression and epithelial-mesenchymal transition (EMT) by modulating the GSK3beta/beta-catenin or STAT3 pathway.	('STAT3', 'Gene', (179, 184))	('hepatocellular carcinoma', 'Disease', (17, 41))	('promotes', 'PosReg', (71, 79))	('beta-catenin', 'Gene', (163, 175))	('epithelial-mesenchymal transition', 'CPA', (96, 129))	('FGF19', 'Gene', (65, 70))	('carcinoma', 'Phenotype', 'HP:0030731', (32, 41))	('modulating', 'Reg', (139, 149))	('beta-catenin', 'Gene', '1499', (163, 175))	('STAT3', 'Gene', '6774', (179, 184))	('GSK3beta', 'Gene', (154, 162))	('patients', 'Species', '9606', (3, 11))	('GSK3beta', 'Gene', '2931', (154, 162))	('progression', 'CPA', (80, 91))	('high amplification', 'Var', (43, 61))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (17, 41))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (17, 41))
111204	32111983	FGFR4, the direct receptor of FGF19 and predominately expressed in liver tissues, was reported to be highly expressed in oral and oropharyngeal squamous cell carcinoma with a frequent Gly388Arg SNP.	('Gly388Arg', 'Var', (184, 193))	('FGF19', 'Gene', (30, 35))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (144, 167))	('Gly388Arg', 'SUBSTITUTION', 'None', (184, 193))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (144, 167))	('oropharyngeal squamous cell carcinoma', 'Phenotype', 'HP:0012182', (130, 167))	('carcinoma', 'Phenotype', 'HP:0030731', (158, 167))	('FGFR4', 'Gene', '2264', (0, 5))	('FGFR4', 'Gene', (0, 5))	('squamous cell carcinoma', 'Disease', (144, 167))
111206	32111983	Mutated FGFR4 was found to induce local growth and enhance metastasis in these cancers.	('local growth', 'CPA', (34, 46))	('metastasis', 'CPA', (59, 69))	('cancers', 'Disease', (79, 86))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('enhance', 'PosReg', (51, 58))	('induce', 'PosReg', (27, 33))	('FGFR4', 'Gene', '2264', (8, 13))	('FGFR4', 'Gene', (8, 13))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('Mutated', 'Var', (0, 7))	('cancers', 'Disease', 'MESH:D009369', (79, 86))
111207	32111983	In breast cancer, FGFR4 resist cancer cell apoptosis by phosphorylating MST1.	('FGFR4', 'Gene', '2264', (18, 23))	('FGFR4', 'Gene', (18, 23))	('phosphorylating', 'Var', (56, 71))	('MST1', 'Gene', '4485', (72, 76))	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('breast cancer', 'Disease', (3, 16))	('MST1', 'Gene', (72, 76))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('cancer', 'Disease', 'MESH:D009369', (10, 16))	('cancer', 'Disease', (31, 37))	('cancer', 'Disease', (10, 16))
111213	32111983	AZD2014, a small molecular drug currently in phase II clinical trials, could block signals from both mTORC1 and mTORC2 complexes in ER + breast cancer.	('breast cancer', 'Disease', 'MESH:D001943', (137, 150))	('breast cancer', 'Phenotype', 'HP:0003002', (137, 150))	('breast cancer', 'Disease', (137, 150))	('mTORC2', 'Gene', (112, 118))	('mTORC1', 'Gene', (101, 107))	('AZD2014', 'Chemical', 'MESH:C585537', (0, 7))	('mTORC2', 'Gene', '74343', (112, 118))	('signals', 'MPA', (83, 90))	('mTORC1', 'Gene', '382056', (101, 107))	('block', 'NegReg', (77, 82))	('AZD2014', 'Var', (0, 7))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
111217	32111983	Inhibitors targeting FGF19/FGFR4 axis or the mTOR kinase are effective therapeutics to suppress LSQ.	('suppress', 'NegReg', (87, 95))	('FGFR4', 'Gene', '2264', (27, 32))	('FGFR4', 'Gene', (27, 32))	('LSQ', 'Phenotype', 'HP:0030359', (96, 99))	('LSQ', 'Disease', (96, 99))	('Inhibitors', 'Var', (0, 10))	('LSQ', 'Chemical', '-', (96, 99))	('mTOR', 'Gene', '2475', (45, 49))	('mTOR', 'Gene', (45, 49))
111236	32111983	Decreased expression of FGF19 was found in the co-treatment group, as compared with those with TG or TM single drug treatment (Fig.	('TG', 'Chemical', 'MESH:D019284', (95, 97))	('Decreased', 'NegReg', (0, 9))	('FGF19', 'Gene', (24, 29))	('expression', 'MPA', (10, 20))	('co-treatment', 'Var', (47, 59))	('TM', 'Chemical', 'MESH:D014415', (101, 103))
111254	32111983	Using a subcutaneous model, a marked increase in tumor size was observed in mice receiving FGF19-OE lentivirus compared with those receiving the control lentivirus in SK-MES-1 cells (Fig.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor', 'Disease', (49, 54))	('mice', 'Species', '10090', (76, 80))	('FGF19-OE', 'Var', (91, 99))	('increase', 'PosReg', (37, 45))	('SK-MES-1', 'CellLine', 'CVCL:0630', (167, 175))
111255	32111983	This effect was also accompanied by higher PCNA expression, higher serum FGF19 levels, increased tumor volume and decreased body weight in the FGF19-OE group vs. control group (Fig.	('increased', 'PosReg', (87, 96))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('higher', 'PosReg', (36, 42))	('serum FGF19 levels', 'MPA', (67, 85))	('higher', 'PosReg', (60, 66))	('PCNA', 'Gene', (43, 47))	('decreased body weight', 'Phenotype', 'HP:0004325', (114, 135))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumor', 'Disease', (97, 102))	('PCNA', 'Gene', '5111', (43, 47))	('decreased', 'NegReg', (114, 123))	('body weight', 'CPA', (124, 135))	('FGF19-OE', 'Var', (143, 151))
111256	32111983	IHC results revealed that the levels of Ki-67 were significantly increased in the mice injected with FGF19-OE cells compared with the mice receiving the vehicle control cells (FGF19-EV) (Fig.	('mice', 'Species', '10090', (82, 86))	('increased', 'PosReg', (65, 74))	('mice', 'Species', '10090', (134, 138))	('FGF19-OE cells', 'Var', (101, 115))	('Ki-67', 'Gene', '17345', (40, 45))	('levels', 'MPA', (30, 36))	('Ki-67', 'Gene', (40, 45))
111257	32111983	We further performed Oil red O staining of tumors from these two groups and observed that intracellular lipid content in FGF19-OE groups was reduced (Fig.	('FGF19-OE', 'Var', (121, 129))	('reduced', 'NegReg', (141, 148))	('intracellular lipid content', 'MPA', (90, 117))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumors', 'Disease', (43, 49))	('Oil red O', 'Chemical', 'MESH:C011049', (21, 30))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('tumors', 'Disease', 'MESH:D009369', (43, 49))
111263	32111983	To verify the role of FGF19 in a physiologically more relevant tumor background, we developed an orthotopic mouse model to closely recapitulate the clinical features of human lung cancer by using SK-MES-1 cells that were stably infected with FGF19-OE lentivirus or control lentivirus FGF19-EV (n = 10 per group).	('tumor', 'Disease', (63, 68))	('infected', 'Disease', (228, 236))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('lung cancer', 'Disease', (175, 186))	('FGF19-OE', 'Var', (242, 250))	('lung cancer', 'Phenotype', 'HP:0100526', (175, 186))	('mouse', 'Species', '10090', (108, 113))	('human', 'Species', '9606', (169, 174))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('SK-MES-1', 'CellLine', 'CVCL:0630', (196, 204))	('lung cancer', 'Disease', 'MESH:D008175', (175, 186))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('infected', 'Disease', 'MESH:D007239', (228, 236))
111265	32111983	IHC analysis of Ki-67 expression revealed that a remarkable increase of proliferation in tumor and lung of the FGF19-OE groups (Fig.	('FGF19-OE', 'Var', (111, 119))	('Ki-67', 'Gene', '17345', (16, 21))	('proliferation', 'CPA', (72, 85))	('increase', 'PosReg', (60, 68))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('Ki-67', 'Gene', (16, 21))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
111274	32111983	5c), and immunofluorescence Ki-67 signals were significantly reduced by either FGF19 or FGFR4 knockdown (Fig.	('Ki-67', 'Gene', (28, 33))	('knockdown', 'Var', (94, 103))	('FGF19', 'Gene', (79, 84))	('FGFR4', 'Gene', (88, 93))	('FGFR4', 'Gene', '2264', (88, 93))	('Ki-67', 'Gene', '17345', (28, 33))	('reduced', 'NegReg', (61, 68))
111275	32111983	Direct FGFR4 siRNA transfection effectively decreased FGFR4 protein levels, accompanied by a significant reduction of PCNA level (Fig.	('FGFR4', 'Gene', '2264', (7, 12))	('transfection', 'Var', (19, 31))	('FGFR4', 'Gene', (7, 12))	('PCNA', 'Gene', '5111', (118, 122))	('reduction', 'NegReg', (105, 114))	('FGFR4', 'Gene', '2264', (54, 59))	('FGFR4', 'Gene', (54, 59))	('decreased', 'NegReg', (44, 53))	('PCNA', 'Gene', (118, 122))
111277	32111983	Accordingly, by FGF19 siRNA transfection, H520 cells showed a significant reduction of PCNA level (Supplementary Fig.	('reduction', 'NegReg', (74, 83))	('transfection', 'Var', (28, 40))	('PCNA', 'Gene', (87, 91))	('FGF19', 'Gene', (16, 21))	('PCNA', 'Gene', '5111', (87, 91))
111278	32111983	To further evaluate the function of FGFR4 in FGF19 signaling, we treated H520 and HCC15 cells with the FGFR4-specific inhibitor BLU9931 and observed that BLU9931 induced G1 to S phase arrest (Fig.	('FGFR4', 'Gene', '2264', (36, 41))	('FGFR4', 'Gene', '2264', (103, 108))	('arrest', 'Disease', 'MESH:D006323', (184, 190))	('FGFR4', 'Gene', (103, 108))	('BLU9931', 'Chemical', 'MESH:C000625545', (154, 161))	('BLU9931', 'Var', (154, 161))	('arrest', 'Disease', (184, 190))	('HCC15', 'CellLine', 'CVCL:2057', (82, 87))	('BLU9931', 'Chemical', 'MESH:C000625545', (128, 135))	('FGFR4', 'Gene', (36, 41))	('induced', 'Reg', (162, 169))
111281	32111983	Moreover, either FGF19 siRNA or FGFR4 siRNA transfection in H520 cells enhanced the sensitivity to Taxol or cisplatin (Supplementary Fig.	('enhanced', 'PosReg', (71, 79))	('FGF19', 'Var', (17, 22))	('transfection', 'Var', (44, 56))	('cisplatin', 'Chemical', 'MESH:D002945', (108, 117))	('Taxol', 'Chemical', 'MESH:D017239', (99, 104))	('FGFR4', 'Gene', '2264', (32, 37))	('FGFR4', 'Gene', (32, 37))	('sensitivity to Taxol', 'MPA', (84, 104))
111284	32111983	Collectively, these findings demonstrated that loss of either FGF19 or FGFR4 could impair the malignant phenotypes of LSQ cells.	('malignant phenotypes of', 'CPA', (94, 117))	('LSQ', 'Chemical', '-', (118, 121))	('impair', 'NegReg', (83, 89))	('FGF19', 'Gene', (62, 67))	('FGFR4', 'Gene', '2264', (71, 76))	('loss', 'Var', (47, 51))	('FGFR4', 'Gene', (71, 76))	('LSQ', 'Disease', (118, 121))	('LSQ', 'Phenotype', 'HP:0030359', (118, 121))
111287	32111983	2h, mTOR signaling was enriched in FGF19 up genes, thus we selected AZD2014, an ATP-competitive inhibitor of mTOR, to perform in vivo experiments.	('AZD2014', 'Chemical', 'MESH:C585537', (68, 75))	('ATP', 'Chemical', 'MESH:D000255', (80, 83))	('mTOR', 'Gene', '2475', (109, 113))	('mTOR', 'Gene', (109, 113))	('AZD2014', 'Var', (68, 75))	('mTOR', 'Gene', (4, 8))	('mTOR', 'Gene', '2475', (4, 8))	('FGF19 up', 'Gene', (35, 43))
111288	32111983	In vitro, AZD2014 significantly inhibited AKT-p70S6K-S6 pathway in SK-MES-1 cells (Fig.	('p70S6K', 'Gene', (46, 52))	('p70S6K', 'Gene', '6198', (46, 52))	('AZD2014', 'Chemical', 'MESH:C585537', (10, 17))	('inhibited', 'NegReg', (32, 41))	('AZD2014', 'Var', (10, 17))	('SK-MES-1', 'CellLine', 'CVCL:0630', (67, 75))
111293	32111983	In this model, a marked reduction in tumor growth was observed in mice treated with AZD2014 (Fig.	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('mice', 'Species', '10090', (66, 70))	('AZD2014', 'Var', (84, 91))	('AZD2014', 'Chemical', 'MESH:C585537', (84, 91))	('tumor', 'Disease', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('reduction', 'NegReg', (24, 33))
111298	32111983	In conclusion, AZD2014 could effectively suppress the growth of FGF19- overexpressing LSQ cells in vivo.	('growth', 'MPA', (54, 60))	('LSQ', 'Phenotype', 'HP:0030359', (86, 89))	('AZD2014', 'Var', (15, 22))	('AZD2014', 'Chemical', 'MESH:C585537', (15, 22))	('suppress', 'NegReg', (41, 49))	('LSQ', 'Chemical', '-', (86, 89))	('FGF19-', 'Gene', (64, 70))
111305	32111983	In addition to the downregulation of FGF19 to demonstrate the anti-cancer effect that was also shown in other cancer models, herein we demonstrated for the first time that overexpressing FGF19 promoted tumor cell proliferation and metastasis in vivo in LSQ.	('LSQ', 'Disease', (253, 256))	('promoted', 'PosReg', (193, 201))	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('cancer', 'Disease', (110, 116))	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('cancer', 'Disease', (67, 73))	('tumor', 'Disease', (202, 207))	('LSQ', 'Chemical', '-', (253, 256))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('metastasis', 'CPA', (231, 241))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('overexpressing', 'Var', (172, 186))	('FGF19', 'Gene', (187, 192))	('LSQ', 'Phenotype', 'HP:0030359', (253, 256))
111306	32111983	Moreover, knockdown of FGFR4 was also effective to suppress the growth and migration of LSQ cells.	('suppress', 'NegReg', (51, 59))	('LSQ', 'Chemical', '-', (88, 91))	('FGFR4', 'Gene', '2264', (23, 28))	('FGFR4', 'Gene', (23, 28))	('knockdown', 'Var', (10, 19))	('LSQ', 'Phenotype', 'HP:0030359', (88, 91))
111311	32111983	For LSQ cells with basal FGF19 levels, downregulating FGF19 combined with mTOR inhibitor AZD2014 showed no significant difference from downregulating FGF19 alone groups in the effective tumor inhibition in vivo.	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('FGF19', 'Gene', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('LSQ', 'Phenotype', 'HP:0030359', (4, 7))	('downregulating', 'Var', (39, 53))	('mTOR', 'Gene', (74, 78))	('tumor', 'Disease', (186, 191))	('mTOR', 'Gene', '2475', (74, 78))	('AZD2014', 'Chemical', 'MESH:C585537', (89, 96))	('LSQ', 'Chemical', '-', (4, 7))
111312	32111983	In this scenario, knockdown FGF19 is potent enough to suppress the growth of LSQ cells since mTOR is a direct downstream effector of the FGF19 signal.	('knockdown', 'Var', (18, 27))	('mTOR', 'Gene', (93, 97))	('FGF19', 'Gene', (28, 33))	('mTOR', 'Gene', '2475', (93, 97))	('LSQ', 'Chemical', '-', (77, 80))	('suppress', 'NegReg', (54, 62))	('growth of LSQ cells', 'CPA', (67, 86))	('LSQ', 'Phenotype', 'HP:0030359', (77, 80))
111322	32111983	Thus, high expression of FGF19 may serve as a novel diagnostic index for screening LSQ, although a larger sample size is needed in future studies.	('LSQ', 'Chemical', '-', (83, 86))	('LSQ', 'Disease', (83, 86))	('FGF19', 'Gene', (25, 30))	('high', 'Var', (6, 10))	('LSQ', 'Phenotype', 'HP:0030359', (83, 86))
111325	32111983	Further, inhibition of the mTOR pathway performed a good outcome in FGF19-driven LSQ.	('FGF19-driven', 'Reg', (68, 80))	('LSQ', 'Chemical', '-', (81, 84))	('mTOR', 'Gene', (27, 31))	('FGF19-driven', 'Gene', (68, 80))	('LSQ', 'Phenotype', 'HP:0030359', (81, 84))	('LSQ', 'Disease', (81, 84))	('inhibition', 'Var', (9, 19))	('mTOR', 'Gene', '2475', (27, 31))
111336	32111983	Tubulin (#ab179513), Ki-67 (#ab92742) and FRS2 (#ab10425) antibodies were purchased from Abcam and other antibodies were obtained from Cell Signaling Technology.	('Ki-67', 'Gene', (21, 26))	('#ab10425', 'Var', (48, 56))	('FRS2', 'Gene', (42, 46))	('FRS2', 'Gene', '10818', (42, 46))	('#ab179513', 'Var', (9, 18))	('#ab92742', 'Var', (28, 36))	('Ki-67', 'Gene', '17345', (21, 26))
111343	32111983	Cells were infected with either FGF19-OE or FGF19-EV lentiviruses, cultured in media containing G418 for two weeks and stained to determine the number of colonies.	('infected', 'Disease', 'MESH:D007239', (11, 19))	('G418', 'Chemical', 'MESH:C010680', (96, 100))	('FGF19-OE', 'Var', (32, 40))	('FGF19-EV', 'Gene', (44, 52))	('infected', 'Disease', (11, 19))
111391	31842516	As expected, point mutations in RAS are not common in breast and prostate cancer.	('breast and prostate cancer', 'Disease', 'MESH:D001943', (54, 80))	('point mutations', 'Var', (13, 28))	('prostate cancer', 'Phenotype', 'HP:0012125', (65, 80))	('RAS', 'Gene', (32, 35))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
111392	31842516	Interestingly, genetic alterations in HDAC4 are more frequent in uterine and stomach cancers, with a conspicuous incidence of truncations and point mutations of still unknown impact on the activities of this deacetylase (Figure 1).	('activities', 'MPA', (189, 199))	('frequent', 'Reg', (53, 61))	('stomach cancers', 'Disease', 'MESH:D013274', (77, 92))	('stomach cancers', 'Disease', (77, 92))	('truncations', 'MPA', (126, 137))	('cancers', 'Phenotype', 'HP:0002664', (85, 92))	('genetic alterations', 'Var', (15, 34))	('point mutations', 'Var', (142, 157))	('HDAC4', 'Gene', '9759', (38, 43))	('uterine', 'Disease', (65, 72))	('HDAC4', 'Gene', (38, 43))	('stomach cancers', 'Phenotype', 'HP:0012126', (77, 92))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
111396	31842516	To prove the above enounced concept, we interrogated the gene expression profiles of BJ-hTERT/ST/LT/MYC, BJ-hTERT/ST/LT/HRASG12V, and BJ-hTERT/ST/LT/HDAC4-S246A, S467A, S632A, relatively to the isogenic pre-transformed control cells, expressing the SV40 LT and ST or the entire early region.	('S246A', 'Mutation', 'p.S246A', (155, 160))	('HDAC4', 'Gene', (149, 154))	('MYC', 'Gene', (100, 103))	('HDAC4', 'Gene', '9759', (149, 154))	('BJ-hTERT', 'CellLine', 'CVCL:6573', (134, 142))	('BJ-hTERT', 'CellLine', 'CVCL:6573', (85, 93))	('S632A', 'Var', (169, 174))	('S632A', 'SUBSTITUTION', 'None', (169, 174))	('MYC', 'Gene', '4609', (100, 103))	('BJ-hTERT', 'CellLine', 'CVCL:6573', (105, 113))	('S467A', 'Var', (162, 167))	('S467A', 'SUBSTITUTION', 'None', (162, 167))
111428	31842516	Finally, SRPX (sushi repeat containing protein X-linked), known also as ETX1 or DRS, was initially isolated as deleted in patients with X-linked retinitis pigmentosa, as well as downregulated by v-src.	('X-linked retinitis pigmentosa', 'Disease', (136, 165))	('retinitis', 'Phenotype', 'HP:0032118', (145, 154))	('retinitis pigmentosa', 'Phenotype', 'HP:0000510', (145, 165))	('ETX1', 'Gene', '8406', (72, 76))	('sushi repeat containing protein X-linked', 'Gene', '8406', (15, 55))	('SRPX', 'Gene', (9, 13))	('downregulated', 'NegReg', (178, 191))	('DRS', 'Gene', '8406', (80, 83))	('deleted', 'Var', (111, 118))	('patients', 'Species', '9606', (122, 130))	('SRPX', 'Gene', '8406', (9, 13))	('DRS', 'Gene', (80, 83))	('ETX1', 'Gene', (72, 76))	('sushi repeat containing protein X-linked', 'Gene', (15, 55))	('X-linked retinitis pigmentosa', 'Disease', 'MESH:D012174', (136, 165))
111437	31842516	In fact in ACC, which is a rare, aggressive malignancy, G0S2 hypermethylation is a hallmark of rapidly recurrent or fatal disease, amenable to targeted assessment using routine molecular diagnostics.	('aggressive malignancy', 'Disease', 'MESH:D001523', (33, 54))	('ACC', 'Disease', 'MESH:D018268', (11, 14))	('hypermethylation', 'Var', (61, 77))	('G0S2', 'Gene', (56, 60))	('aggressive malignancy', 'Disease', (33, 54))	('ACC', 'Disease', (11, 14))
111438	31842516	Very low levels of G0S2 mRNA expression characterize tumors with G0S2 hypermethylation.	('hypermethylation', 'Var', (70, 86))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('mRNA expression', 'MPA', (24, 39))	('G0S2', 'Gene', (65, 69))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('tumors', 'Disease', (53, 59))	('G0S2', 'Protein', (19, 23))
111473	31842516	G0S2 is abundantly expressed in adipose tissue and G0S2 transgenic mice experience difficulties in shifting from carbohydrate to FA oxidation during fasting.	('transgenic mice', 'Species', '10090', (56, 71))	('shifting from carbohydrate to FA oxidation', 'MPA', (99, 141))	('G0S2', 'Gene', (51, 55))	('carbohydrate', 'Chemical', 'MESH:D002241', (113, 125))	('transgenic', 'Var', (56, 66))
111481	31842516	The recent discovery that the targeting of MYC through an epigenetic therapy provides an important advantage for an efficient immunotherapy could represent an important clinical perspective of all these studies.	('MYC', 'Gene', (43, 46))	('MYC', 'Gene', '4609', (43, 46))	('epigenetic therapy', 'Var', (58, 76))	('advantage', 'PosReg', (99, 108))
111492	31842516	In each dataset, the transformation model represented by pre-transformed BJ cells expressing RAS G12V (GSE17941) or MYC (GSE72530) or HDAC4 (GSE120040) was compared to the pre-transformation model which is represented by BJ fibroblasts expressing hTERT, LT, and ST SV40 genes.	('G12V', 'Mutation', 'rs104894230', (97, 101))	('BJ', 'CellLine', 'CVCL:6573', (73, 75))	('BJ', 'CellLine', 'CVCL:6573', (221, 223))	('hTERT', 'Gene', (247, 252))	('MYC', 'Gene', '4609', (116, 119))	('HDAC4', 'Gene', '9759', (134, 139))	('GSE120040', 'Var', (141, 150))	('HDAC4', 'Gene', (134, 139))	('hTERT', 'Gene', '7015', (247, 252))	('GSE17941', 'Var', (103, 111))	('GSE72530', 'Var', (121, 129))	('MYC', 'Gene', (116, 119))
111503	31842516	To evaluate the contribution/disturbance of the inflammatory infiltrate to the prediction of survival based on the transformation signatures, patients were divided into four groups accordingly to the expression levels of genes belonging to the MCPcounter signatures and to the transformation signatures: High-high (high levels of both), high-low (high MCP/low transformation), low-low (low levels of both), or low-high (low MCP-high transformation).	('MCP', 'Gene', (352, 355))	('MCP', 'Gene', (424, 427))	('MCP', 'Gene', '822', (244, 247))	('low-high', 'Var', (410, 418))	('MCP', 'Gene', '822', (352, 355))	('MCP', 'Gene', '822', (424, 427))	('patients', 'Species', '9606', (142, 150))	('MCP', 'Gene', (244, 247))	('low MCP', 'Phenotype', 'HP:0025066', (420, 427))
111518	28592260	Genetic aberrations in glioblastoma including EGFR, PDGFRA, PIK3CA, PTEN, TP53 and CDKN2A/B etc., drive the dysfunction of signaling pathways such as PI3K/Akt/mTOR, p53 and RB1 pathways, and open up possible therapies for GBM by targeting these pathways with selective inhibitors.	('drive', 'PosReg', (98, 103))	('RB1', 'Gene', (173, 176))	('EGFR', 'Gene', '1956', (46, 50))	('aberrations', 'Var', (8, 19))	('glioblastoma', 'Phenotype', 'HP:0012174', (23, 35))	('PTEN', 'Gene', (68, 72))	('CDKN2A/B', 'Gene', '1029;1030', (83, 91))	('PDGFRA', 'Gene', (52, 58))	('PI3', 'Gene', '5266', (150, 153))	('PIK3CA', 'Gene', (60, 66))	('PDGFRA', 'Gene', '5156', (52, 58))	('PTEN', 'Gene', '5728', (68, 72))	('RB1', 'Gene', '5925', (173, 176))	('TP53', 'Gene', (74, 78))	('p53', 'Gene', '7157', (165, 168))	('rat', 'Species', '10116', (12, 15))	('mTOR', 'Gene', (159, 163))	('PI3', 'Gene', (150, 153))	('dysfunction', 'MPA', (108, 119))	('EGFR', 'Gene', (46, 50))	('p53', 'Gene', (165, 168))	('glioblastoma', 'Disease', 'MESH:D005909', (23, 35))	('CDKN2A/B', 'Gene', (83, 91))	('signaling pathways', 'Pathway', (123, 141))	('mTOR', 'Gene', '2475', (159, 163))	('TP53', 'Gene', '7157', (74, 78))	('glioblastoma', 'Disease', (23, 35))
111524	28592260	Its variant III mutation (EGFRvIII), characterized by an in-frame deletion in exons 2-7, is common (25%-50%) in GBM and produces a truncated EGFR protein without the extracellular ligand-binding domain, leading to its ligand-independent constitutive activation.	('EGFR', 'Gene', (26, 30))	('EGFR', 'Gene', '1956', (141, 145))	('EGFR', 'Gene', (141, 145))	('protein', 'Protein', (146, 153))	('truncated', 'MPA', (131, 140))	('EGFR', 'Gene', '1956', (26, 30))	('ligand-independent constitutive activation', 'MPA', (218, 260))	('deletion', 'Var', (66, 74))
111530	28592260	Akt at Thr308 and Ser473 residues are then phosphorylated by phosphoinositide-dependent kinase -1 (PDK-1) and mammalian target of rapamycin complex 2 (mTORC2), respectively, leading to its complete activation.	('phosphoinositide-dependent kinase -1', 'Gene', '5163', (61, 97))	('Ser473', 'Chemical', '-', (18, 24))	('PDK-1', 'Gene', '5163', (99, 104))	('activation', 'PosReg', (198, 208))	('Thr308', 'Chemical', '-', (7, 13))	('phosphoinositide-dependent kinase -1', 'Gene', (61, 97))	('PDK-1', 'Gene', (99, 104))	('Akt', 'Protein', (0, 3))	('mTORC2', 'Gene', (151, 157))	('mammalian target of rapamycin', 'Gene', '2475', (110, 139))	('mammalian target of rapamycin', 'Gene', (110, 139))	('Ser473 residues', 'Var', (18, 33))	('mTORC2', 'Gene', '74343', (151, 157))	('Thr308', 'Var', (7, 13))
111531	28592260	PTEN (phosphatase and tensin homolog deleted on chromosome 10) and PHLPP (PH domain and leucine rich repeat protein phosphatase) are two tumor suppressors, the former transforms PIP3 to PIP2 and blocks the recruitment of Akt to the plasma membrane, while the latter dephosphorylates Ser473 in Akt and subsequently suppresses Akt activation.	('recruitment', 'MPA', (206, 217))	('blocks', 'NegReg', (195, 201))	('PIP3', 'Chemical', '-', (178, 182))	('PIP3 to PIP2', 'MPA', (178, 190))	('Ser473', 'MPA', (283, 289))	('leucine rich repeat protein', 'Gene', (88, 115))	('leucine rich repeat protein', 'Gene', '60506', (88, 115))	('tumor', 'Disease', (137, 142))	('dephosphorylates', 'Var', (266, 282))	('PIP2', 'Chemical', 'MESH:D019269', (186, 190))	('Akt', 'Pathway', (325, 328))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('PTEN', 'Gene', (0, 4))	('Ser473', 'Chemical', '-', (283, 289))	('Akt', 'Pathway', (293, 296))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('PHLPP', 'Gene', '23239', (67, 72))	('Akt', 'Pathway', (221, 224))	('PHLPP', 'Gene', (67, 72))	('transforms', 'Reg', (167, 177))	('suppresses', 'NegReg', (314, 324))	('PTEN', 'Gene', '5728', (0, 4))
111535	28592260	Inhibition of PI3K alone or in combination with other molecules may result in GBM cell death and retarded tumor progression.	('retarded tumor', 'Disease', 'MESH:D009369', (97, 111))	('death', 'Disease', 'MESH:D003643', (87, 92))	('result in', 'Reg', (68, 77))	('PI3', 'Gene', '5266', (14, 17))	('Inhibition', 'Var', (0, 10))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('death', 'Disease', (87, 92))	('retarded tumor', 'Disease', (97, 111))	('PI3', 'Gene', (14, 17))
111538	28592260	Class IA PI3K is composed of a heterodimer consisting of a 110 kDa catalytic subunit (p110alpha, p110beta and p110delta) and an 85 kDa regulatory subunit.	('p110beta', 'Gene', (97, 105))	('p110alpha', 'Var', (86, 95))	('PI3', 'Gene', (9, 12))	('p110delta', 'Var', (110, 119))	('PI3', 'Gene', '5266', (9, 12))	('p110beta', 'Gene', '5291', (97, 105))
111540	28592260	The p110alpha and p110beta isoforms are ubiquitously expressed, whereas p110delta and p110gamma are primarily expressed in leukocytes.	('p110gamma', 'Gene', '5294', (86, 95))	('p110delta', 'Var', (72, 81))	('p110gamma', 'Gene', (86, 95))	('p110beta', 'Gene', '5291', (18, 26))	('p110alpha', 'Var', (4, 13))	('p110beta', 'Gene', (18, 26))
111541	28592260	The p110alpha, p110beta and p110delta isoforms exhibit distinct roles in different pathological processes in cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('p110beta', 'Gene', (15, 23))	('p110delta', 'Var', (28, 37))	('cancer', 'Disease', (109, 115))	('p110alpha', 'Var', (4, 13))	('p110beta', 'Gene', '5291', (15, 23))
111543	28592260	Compared to PTEN or EGFR mutations, mutations of PIK3CA (encodes p110alpha) in 10 of 20 exons are less frequent but very important in GBM, ranging from 4% to 27%.	('EGFR', 'Gene', (20, 24))	('mutations', 'Var', (36, 45))	('PTEN', 'Gene', (12, 16))	('PTEN', 'Gene', '5728', (12, 16))	('PIK3CA', 'Gene', (49, 55))	('EGFR', 'Gene', '1956', (20, 24))
111544	28592260	Whole genome sequencing of TCGA GBM samples shows that 18.3% of GBM exhibit PIK3CA and PIK3R1 mutations, which are mutually exclusive of PTEN mutation or deletion.	('mutations', 'Var', (94, 103))	('PIK3CA', 'Gene', (76, 82))	('PIK3R1', 'Gene', '5295', (87, 93))	('PTEN', 'Gene', (137, 141))	('PIK3R1', 'Gene', (87, 93))	('PTEN', 'Gene', '5728', (137, 141))
111545	28592260	The majority of PIK3CA mutants (including the hot-spot mutations in exon 9 and 20) show gain of PI3K function and promote the recruitment of p110alpha to membrane phospholipids, leading to the constitutive activation of p110alpha and Akt.	('PI3', 'Gene', (96, 99))	('p110alpha', 'Protein', (141, 150))	('phospholipids', 'Chemical', 'MESH:D010743', (163, 176))	('PI3', 'Gene', '5266', (96, 99))	('PIK3CA', 'Gene', (16, 22))	('p110alpha', 'Pathway', (220, 229))	('gain', 'PosReg', (88, 92))	('recruitment', 'MPA', (126, 137))	('mutants', 'Var', (23, 30))	('activation', 'PosReg', (206, 216))	('function', 'MPA', (101, 109))	('Akt', 'Pathway', (234, 237))	('promote', 'PosReg', (114, 121))
111546	28592260	Accumulating studies demonstrate that p110alpha plays a critical role in tumorigenesis and progress of GBM.	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('GBM', 'Disease', (103, 106))	('tumor', 'Disease', (73, 78))	('p110alpha', 'Var', (38, 47))	('rat', 'Species', '10116', (28, 31))
111548	28592260	In addition, GBM cell growth, survival and migration are effectively suppressed in vitro by the p110alpha isoform-selective inhibitors A66 or PIK-75.	('PIK-75', 'Gene', (142, 148))	('rat', 'Species', '10116', (46, 49))	('A66', 'Gene', (135, 138))	('suppressed', 'NegReg', (69, 79))	('GBM cell growth', 'CPA', (13, 28))	('p110alpha', 'Var', (96, 105))
111553	28592260	However, PIK3CB knockdown barely suppresses GBM cell migration.	('suppresses', 'NegReg', (33, 43))	('rat', 'Species', '10116', (56, 59))	('knockdown', 'Var', (16, 25))	('GBM cell migration', 'CPA', (44, 62))	('PIK3CB', 'Gene', (9, 15))	('PIK3CB', 'Gene', '5291', (9, 15))
111557	28592260	Due to the high expression level in leukocytes, the p110delta and p110gamma subunits are promising therapeutic targets for hematologic malignancies including leukemia, lymphoma and multiple myeloma.	('multiple myeloma', 'Phenotype', 'HP:0006775', (181, 197))	('p110gamma', 'Gene', '5294', (66, 75))	('multiple myeloma', 'Disease', (181, 197))	('leukemia', 'Disease', (158, 166))	('leukemia', 'Phenotype', 'HP:0001909', (158, 166))	('leukemia', 'Disease', 'MESH:D007938', (158, 166))	('lymphoma', 'Disease', (168, 176))	('p110delta', 'Var', (52, 61))	('lymphoma', 'Disease', 'MESH:D008223', (168, 176))	('lymphoma', 'Phenotype', 'HP:0002665', (168, 176))	('hematologic malignancies', 'Disease', 'MESH:D019337', (123, 147))	('p110gamma', 'Gene', (66, 75))	('multiple myeloma', 'Disease', 'MESH:D009101', (181, 197))	('hematologic malignancies', 'Disease', (123, 147))
111558	28592260	Recently, overexpression of p110delta is also observed in solid tumors such as GBM, neuroblastoma, breast and prostate cancers, indicating that inhibition of p110delta may also be an attractive option for GBM treatment.	('GBM', 'Disease', (79, 82))	('p110delta', 'Var', (158, 167))	('neuroblastoma', 'Disease', 'MESH:D009447', (84, 97))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('solid tumors', 'Disease', (58, 70))	('p110delta', 'Var', (28, 37))	('neuroblastoma', 'Disease', (84, 97))	('breast and prostate cancers', 'Disease', 'MESH:D011471', (99, 126))	('cancers', 'Phenotype', 'HP:0002664', (119, 126))	('prostate cancer', 'Phenotype', 'HP:0012125', (110, 125))	('neuroblastoma', 'Phenotype', 'HP:0003006', (84, 97))	('prostate cancers', 'Phenotype', 'HP:0012125', (110, 126))	('overexpression', 'PosReg', (10, 24))	('solid tumors', 'Disease', 'MESH:D009369', (58, 70))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
111559	28592260	Our previous study shows that p110delta is overexpressed in 50% of high grade glioma cell lines (6 of 12), and knockdown of p110delta inhibits migration and invasion of GBM cells by decreasing focal adhesion kinase (FAK) expression.	('inhibits', 'NegReg', (134, 142))	('focal adhesion kinase', 'Gene', (193, 214))	('glioma', 'Phenotype', 'HP:0009733', (78, 84))	('rat', 'Species', '10116', (146, 149))	('FAK', 'Gene', '5747', (216, 219))	('decreasing', 'NegReg', (182, 192))	('focal adhesion kinase', 'Gene', '5747', (193, 214))	('p110delta', 'Var', (124, 133))	('FAK', 'Gene', (216, 219))	('glioma', 'Disease', (78, 84))	('expression', 'MPA', (221, 231))	('glioma', 'Disease', 'MESH:D005910', (78, 84))
111560	28592260	However, inhibition of p110delta by its selective inhibitor CAL-101 moderately impairs GBM cell proliferation and migration, but it doesn't significantly suppress tumor growth in GBM xenograft mouse model.	('inhibition', 'NegReg', (9, 19))	('rat', 'Species', '10116', (72, 75))	('rat', 'Species', '10116', (103, 106))	('rat', 'Species', '10116', (117, 120))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('CAL-101', 'Chemical', 'MESH:C552946', (60, 67))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('mouse', 'Species', '10090', (193, 198))	('tumor', 'Disease', (163, 168))	('impairs', 'NegReg', (79, 86))	('p110delta', 'Var', (23, 32))	('CAL-101', 'Gene', (60, 67))
111568	28592260	However, only a handful of them such as BKM120, XL147 and XL765 have successfully entered into clinical trials for GBM treatment.	('BKM120', 'Chemical', 'MESH:C571178', (40, 46))	('GBM', 'Disease', (115, 118))	('XL147', 'Chemical', 'MESH:C581157', (48, 53))	('BKM120', 'Var', (40, 46))	('XL765', 'Var', (58, 63))
111570	28592260	The first generation of pan-PI3K inhibitors wortmannin and LY294002, that target all class IA p110 isoforms, are of limited use clinically due to their poor pharmaceutical properties (insolubility and short half-life), off-target effects and unacceptable toxicities in animal studies.	('LY294002', 'Var', (59, 67))	('toxicities', 'Disease', (255, 265))	('wortmannin', 'Chemical', 'MESH:D000077191', (44, 54))	('p110', 'Gene', '100616443', (94, 98))	('toxicities', 'Disease', 'MESH:D064420', (255, 265))	('p110', 'Gene', (94, 98))	('PI3', 'Gene', '5266', (28, 31))	('LY294002', 'Chemical', 'MESH:C085911', (59, 67))	('PI3', 'Gene', (28, 31))	('rat', 'Species', '10116', (14, 17))
111571	28592260	A new generation of pan-PI3K inhibitors with improved safety, efficacy and pharmacokinetics such as BKM120, XL147, PX-866, GDC-0941 and GDC-0032 have been developed and have entered into clinical trials (Table 3).	('PI3', 'Gene', (24, 27))	('PX-866', 'Chemical', 'MESH:C496788', (115, 121))	('BKM120', 'Var', (100, 106))	('GDC-0032', 'Chemical', 'MESH:C582924', (136, 144))	('PX-866', 'Var', (115, 121))	('GDC-0941', 'Var', (123, 131))	('PI3', 'Gene', '5266', (24, 27))	('GDC-0941', 'Chemical', 'MESH:C532162', (123, 131))	('BKM120', 'Chemical', 'MESH:C571178', (100, 106))	('rat', 'Species', '10116', (10, 13))	('XL147', 'Chemical', 'MESH:C581157', (108, 113))
111576	28592260	Furthermore, preclinical studies show that BKM120 impedes intracerebral U-87 MG GBM cell xenograft growth and prolongs survival of animals harboring xenograft, without obvious adverse effects.	('BKM120', 'Chemical', 'MESH:C571178', (43, 49))	('survival', 'CPA', (119, 127))	('impedes', 'NegReg', (50, 57))	('prolongs', 'PosReg', (110, 118))	('BKM120', 'Var', (43, 49))	('intracerebral U-87 MG GBM cell xenograft growth', 'CPA', (58, 105))
111577	28592260	Currently, BKM120 is the most frequently-used PI3K inhibitor in the clinical trials for GBM treatment, since it is well-tolerated and permeable to the blood-brain barrier (BBB).	('rat', 'Species', '10116', (124, 127))	('BKM120', 'Var', (11, 17))	('PI3', 'Gene', (46, 49))	('BKM120', 'Chemical', 'MESH:C571178', (11, 17))	('GBM', 'Disease', (88, 91))	('PI3', 'Gene', '5266', (46, 49))
111578	28592260	In a phase II study of BKM120 in recurrent GBM, patients with radiologic progression and activation of PI3K/Akt pathway including PIK3CA mutations, PTEN loss and increased phosphorylation of Akt were recruited (NCT01339052).	('PIK3CA', 'Gene', (130, 136))	('PTEN', 'Gene', (148, 152))	('PI3', 'Gene', (103, 106))	('PTEN', 'Gene', '5728', (148, 152))	('BKM120', 'Chemical', 'MESH:C571178', (23, 29))	('increased', 'PosReg', (162, 171))	('loss', 'NegReg', (153, 157))	('phosphorylation', 'MPA', (172, 187))	('mutations', 'Var', (137, 146))	('Akt', 'Pathway', (191, 194))	('PI3', 'Gene', '5266', (103, 106))	('patients', 'Species', '9606', (48, 56))
111580	28592260	Paradoxically, patients harboring PTEN loss and/or PIK3CA mutations were not sensitive to BKM120 treatment even though it inhibits Akt phosphorylation.	('mutations', 'Var', (58, 67))	('patients', 'Species', '9606', (15, 23))	('inhibits', 'NegReg', (122, 130))	('PIK3CA', 'Gene', (51, 57))	('Akt', 'Pathway', (131, 134))	('BKM120', 'Chemical', 'MESH:C571178', (90, 96))	('PTEN', 'Gene', (34, 38))	('PTEN', 'Gene', '5728', (34, 38))
111587	28592260	In a phase Ib dose escalation study, BKM120 was combined with LDE225, a Smoothened (Smo) antagonist, in the patients with advanced solid tumors including recurrent GBM (NCT01576666).	('GBM', 'Disease', (164, 167))	('Smo', 'Gene', (72, 75))	('solid tumors', 'Disease', 'MESH:D009369', (131, 143))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('NCT01576666', 'Var', (169, 180))	('recurrent', 'Disease', (154, 163))	('Smo', 'Gene', (84, 87))	('Smo', 'Gene', '6608', (84, 87))	('Smoothened', 'Gene', (72, 82))	('Smo', 'Gene', '6608', (72, 75))	('LDE225', 'Chemical', 'MESH:C561435', (62, 68))	('BKM120', 'Var', (37, 43))	('Smoothened', 'Gene', '6608', (72, 82))	('patients', 'Species', '9606', (108, 116))	('solid tumors', 'Disease', (131, 143))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('BKM120', 'Chemical', 'MESH:C571178', (37, 43))
111588	28592260	Combination of BKM120 and Capmatinib (INC280), a c-Met inhibitor, is investigated in a phase Ib/II clinical trials to assess its safety, dose and anti-tumor activity in patients with recurrent GBM with PTEN loss or MET alteration (NCT01870726).	('Capmatinib', 'Chemical', 'MESH:C000613976', (26, 36))	('patients', 'Species', '9606', (169, 177))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('loss', 'NegReg', (207, 211))	('c-Met', 'Gene', (49, 54))	('MET alteration', 'Var', (215, 229))	('c-Met', 'Gene', '4233', (49, 54))	('tumor', 'Disease', (151, 156))	('GBM', 'Disease', (193, 196))	('BKM120', 'Var', (15, 21))	('PTEN', 'Gene', (202, 206))	('PTEN', 'Gene', '5728', (202, 206))	('rat', 'Species', '10116', (223, 226))	('tumor', 'Disease', 'MESH:D009369', (151, 156))	('BKM120', 'Chemical', 'MESH:C571178', (15, 21))
111590	28592260	Last but not least, a multi-center phase Ib/II study in patients with recurrent GBM is ongoing to determine the maximum tolerated dose (MTD) and therapeutic effect of BKM120 combined with carboplatin or lomustine (NCT01934361).	('rat', 'Species', '10116', (124, 127))	('patients', 'Species', '9606', (56, 64))	('BKM120', 'Chemical', 'MESH:C571178', (167, 173))	('carboplatin', 'Chemical', 'MESH:D016190', (188, 199))	('NCT01934361', 'Var', (214, 225))	('lomustine', 'Chemical', 'MESH:D008130', (203, 212))	('BKM120', 'Var', (167, 173))	('GBM', 'Disease', (80, 83))
111591	28592260	Pilaralisib (XL147, SAR245408) is an orally bioavailable and reversible pan-class IA PI3K inhibitor against p110alpha/delta/gamma with IC50 of approximate 30 nM, but less potent upon p110beta.	('PI3', 'Gene', '5266', (85, 88))	('p110beta', 'Gene', (183, 191))	('Pilaralisib', 'Chemical', 'MESH:C581157', (0, 11))	('XL147', 'Chemical', 'MESH:C581157', (13, 18))	('PI3', 'Gene', (85, 88))	('p110alpha/delta/gamma', 'Var', (108, 129))	('p110beta', 'Gene', '5291', (183, 191))	('SAR245408', 'Chemical', 'MESH:C581157', (20, 29))
111593	28592260	XL147 could induce an upregulation of HER3 expression and phosphorylation in HER2-overexpressing breast cancer cells, and it synergizes with trastuzumab or lapatinib to suppress xenograft growth.	('HER3', 'Gene', '2065', (38, 42))	('XL147', 'Var', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('phosphorylation', 'MPA', (58, 73))	('trastuzumab', 'Chemical', 'MESH:D000068878', (141, 152))	('suppress', 'NegReg', (169, 177))	('HER2', 'Gene', (77, 81))	('XL147', 'Chemical', 'MESH:C581157', (0, 5))	('lapatinib', 'Chemical', 'MESH:D000077341', (156, 165))	('HER2', 'Gene', '2064', (77, 81))	('breast cancer', 'Disease', 'MESH:D001943', (97, 110))	('breast cancer', 'Phenotype', 'HP:0003002', (97, 110))	('upregulation', 'PosReg', (22, 34))	('expression', 'MPA', (43, 53))	('xenograft growth', 'CPA', (178, 194))	('HER3', 'Gene', (38, 42))	('breast cancer', 'Disease', (97, 110))
111596	28592260	Three cohorts of 21 patients were treated with different doses of XL147 and XL765 for >10 days, respectively.	('XL765', 'Var', (76, 81))	('patients', 'Species', '9606', (20, 28))	('XL147', 'Chemical', 'MESH:C581157', (66, 71))	('XL147', 'Var', (66, 71))
111597	28592260	The mean tumor to plasma ratios of XL147 and XL765 were from 0.27 to 0.40, and treatment of these two drugs led to reduced S6 K1 phosphorylation and Ki67 expression, suggesting that they possess a moderate BBB-penetration capacity and a potential to inhibit GBM growth.	('XL765', 'Var', (45, 50))	('Ki67', 'Gene', (149, 153))	('rat', 'Species', '10116', (201, 204))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('inhibit', 'NegReg', (250, 257))	('BBB-penetration capacity', 'CPA', (206, 230))	('reduced', 'NegReg', (115, 122))	('S6 K1', 'Protein', (123, 128))	('rat', 'Species', '10116', (215, 218))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('GBM growth', 'CPA', (258, 268))	('tumor', 'Disease', (9, 14))	('rat', 'Species', '10116', (25, 28))	('XL147', 'Chemical', 'MESH:C581157', (35, 40))	('expression', 'MPA', (154, 164))
111601	28592260	In 13 human cancer cell line-derived xenografts, tumors with PTEN loss or PIK3CA mutations are sensitive to PX-866, whereas those harboring RAS-activating mutation show resistance, suggesting that RAS mutation may be an important prognostic predictor of PX-866 for cancer treatment.	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('cancer', 'Phenotype', 'HP:0002664', (265, 271))	('tumors', 'Disease', (49, 55))	('PTEN', 'Gene', (61, 65))	('mutations', 'Var', (81, 90))	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('sensitive', 'MPA', (95, 104))	('tumors', 'Disease', 'MESH:D009369', (49, 55))	('PTEN', 'Gene', '5728', (61, 65))	('cancer', 'Disease', 'MESH:D009369', (265, 271))	('PX-866', 'Chemical', 'MESH:C496788', (108, 114))	('PIK3CA', 'Gene', (74, 80))	('human', 'Species', '9606', (6, 11))	('loss', 'NegReg', (66, 70))	('cancer', 'Disease', (12, 18))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('PX-866', 'Chemical', 'MESH:C496788', (254, 260))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('cancer', 'Disease', (265, 271))
111603	28592260	PX-866 reduced GBM cell number in G1 phase via suppressing cyclin D1 expression and Rb1 activation, and induced autophagy through promoting the conversion of LC3-I to LC3-II.	('reduced', 'NegReg', (7, 14))	('PX-866', 'Chemical', 'MESH:C496788', (0, 6))	('GBM cell number in G1 phase', 'CPA', (15, 42))	('Rb1', 'Gene', '5925', (84, 87))	('PX-866', 'Var', (0, 6))	('suppressing', 'NegReg', (47, 58))	('Rb1', 'Gene', (84, 87))	('expression', 'MPA', (69, 79))	('cyclin D1', 'Gene', '595', (59, 68))	('conversion', 'MPA', (144, 154))	('promoting', 'PosReg', (130, 139))	('activation', 'MPA', (88, 98))	('induced', 'Reg', (104, 111))	('cyclin D1', 'Gene', (59, 68))	('autophagy', 'CPA', (112, 121))
111606	28592260	Furthermore, combination of PX-866 and the dinuclear platinum compound BBR3610 displayed synergistic effects on reduction of GBM cell migration and extension of GBM xenograft mice survival.	('mice', 'Species', '10090', (175, 179))	('GBM xenograft mice survival', 'CPA', (161, 188))	('BBR3610', 'Gene', (71, 78))	('PX-866', 'Chemical', 'MESH:C496788', (28, 34))	('PX-866', 'Var', (28, 34))	('reduction', 'NegReg', (112, 121))	('rat', 'Species', '10116', (137, 140))	('platinum', 'Chemical', 'MESH:D010984', (53, 61))	('BBR3610', 'Chemical', 'MESH:C523470', (71, 78))	('extension', 'PosReg', (148, 157))	('GBM cell migration', 'CPA', (125, 143))
111607	28592260	As an orally bioavailable pan-PI3K inhibitor, PX-866 has entered into clinical trials for many cancers including ovarian, colorectal, prostate, head and neck (H&N) cancers, melanoma, NSCLC and GBM.	('NSCLC', 'Disease', (183, 188))	('melanoma', 'Disease', 'MESH:D008545', (173, 181))	('cancers', 'Disease', 'MESH:D009369', (164, 171))	('PX-866', 'Var', (46, 52))	('entered', 'Reg', (57, 64))	('and', 'Disease', (189, 192))	('NSCLC', 'Phenotype', 'HP:0030358', (183, 188))	('PX-866', 'Chemical', 'MESH:C496788', (46, 52))	('colorectal', 'Disease', 'MESH:D015179', (122, 132))	('cancers', 'Phenotype', 'HP:0002664', (95, 102))	('cancers', 'Disease', (95, 102))	('prostate', 'Disease', (134, 142))	('ovarian', 'Disease', (113, 120))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('PI3', 'Gene', '5266', (30, 33))	('H&N', 'Chemical', '-', (159, 162))	('melanoma', 'Phenotype', 'HP:0002861', (173, 181))	('melanoma', 'Disease', (173, 181))	('cancers', 'Phenotype', 'HP:0002664', (164, 171))	('cancers', 'Disease', (164, 171))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('PI3', 'Gene', (30, 33))	('colorectal', 'Disease', (122, 132))	('cancers', 'Disease', 'MESH:D009369', (95, 102))	('NSCLC', 'Disease', 'MESH:D002289', (183, 188))
111612	28592260	It is noteworthy that there was no significant association between clinical outcome and mutations of PTEN, PIK3CA, PIK3R1, or EGFRvIII.	('EGFR', 'Gene', (126, 130))	('PTEN', 'Gene', (101, 105))	('mutations', 'Var', (88, 97))	('PTEN', 'Gene', '5728', (101, 105))	('PIK3R1', 'Gene', (115, 121))	('PIK3CA', 'Gene', (107, 113))	('PIK3R1', 'Gene', '5295', (115, 121))	('EGFR', 'Gene', '1956', (126, 130))
111615	28592260	Furthermore, the oral bioavailability of GDC-0941 is up to 78% and it shows sustained and remarkable inhibition of Akt phosphorylation and tumor growth (98% inhibition) in subcutaneous U-87 MG xenograft mice.	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('inhibition', 'NegReg', (101, 111))	('mice', 'Species', '10090', (203, 207))	('Akt', 'Pathway', (115, 118))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('GDC-0941', 'Chemical', 'MESH:C532162', (41, 49))	('GDC-0941', 'Var', (41, 49))
111616	28592260	Combination of GDC-0941 and a Bcl-2 family inhibitor ATB-263 displayed synergistic effects on loss of mitochondrial membrane potential, induction of GBM cell apoptosis and suppressing sphere formation in GBM stem-like cells, via decreasing Akt phosphorylation and Mcl-1 expression.	('GBM cell apoptosis', 'CPA', (149, 167))	('sphere formation', 'CPA', (184, 200))	('Akt', 'Pathway', (240, 243))	('Mcl-1', 'Gene', '4170', (264, 269))	('decreasing', 'NegReg', (229, 239))	('loss', 'NegReg', (94, 98))	('ATB-263', 'Gene', (53, 60))	('GDC-0941', 'Var', (15, 23))	('GDC-0941', 'Chemical', 'MESH:C532162', (15, 23))	('suppressing', 'NegReg', (172, 183))	('ATB-263', 'Chemical', '-', (53, 60))	('Mcl-1', 'Gene', (264, 269))	('Bcl-2', 'Gene', (30, 35))	('Bcl-2', 'Gene', '596', (30, 35))	('mitochondrial membrane potential', 'MPA', (102, 134))	('expression', 'MPA', (270, 280))
111617	28592260	In addition, GDC-0941 also synergizes with a natural compound B10, a glycosylated derivative of betulinic acid, to inhibit GBM cell viability, enhance lysosomal compartments and induce lysosomal membrane permeabilization through increasing TFEB and LAMP1 expression.	('lysosomal compartments', 'MPA', (151, 173))	('enhance', 'PosReg', (143, 150))	('LAMP1', 'Gene', (249, 254))	('inhibit', 'NegReg', (115, 122))	('increasing', 'PosReg', (229, 239))	('induce', 'Reg', (178, 184))	('expression', 'MPA', (255, 265))	('GBM cell viability', 'CPA', (123, 141))	('TFEB', 'Gene', '7942', (240, 244))	('GDC-0941', 'Chemical', 'MESH:C532162', (13, 21))	('GDC-0941', 'Var', (13, 21))	('TFEB', 'Gene', (240, 244))	('lysosomal membrane permeabilization', 'MPA', (185, 220))	('LAMP1', 'Gene', '3916', (249, 254))	('betulinic acid', 'Chemical', 'MESH:C002070', (96, 110))
111622	28592260	An in-vivo study also shows that combination of GDC-0941, irinotecan, sunitinib and temozolomide doesn't significantly prolong the survival of mice with GBM xenograft, possibly due to the poor BBB permeability of GDC-0941.	('GDC-0941', 'Chemical', 'MESH:C532162', (48, 56))	('sunitinib', 'Chemical', 'MESH:D000077210', (70, 79))	('irinotecan', 'Chemical', 'MESH:D000077146', (58, 68))	('prolong', 'PosReg', (119, 126))	('survival', 'CPA', (131, 139))	('temozolomide', 'Chemical', 'MESH:D000077204', (84, 96))	('GDC-0941', 'Chemical', 'MESH:C532162', (213, 221))	('GDC-0941', 'Var', (48, 56))	('mice', 'Species', '10090', (143, 147))
111625	28592260	Both ZSTK474 and AMG 511 could suppress the proliferation of GBM cell lines and subcutaneous U-87 MG xenograft growth.	('AMG', 'Gene', '265', (17, 20))	('ZSTK474', 'Chemical', 'MESH:C510150', (5, 12))	('proliferation of GBM cell lines', 'CPA', (44, 75))	('subcutaneous U-87 MG xenograft growth', 'CPA', (80, 117))	('ZSTK474', 'Var', (5, 12))	('suppress', 'NegReg', (31, 39))	('AMG', 'Gene', (17, 20))	('rat', 'Species', '10116', (51, 54))
111626	28592260	GDC-0032 exhibits potent anti-proliferative and anti-tumor activities in head and neck squamous cell carcinoma and uterine serous carcinomas cell lines and xenografts with PIK3CA mutations or amplifications.	('neck squamous cell carcinoma', 'Disease', (82, 110))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (87, 110))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (82, 110))	('serous carcinomas', 'Disease', 'MESH:D018284', (123, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('GDC-0032', 'Chemical', 'MESH:C582924', (0, 8))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('serous carcinomas', 'Disease', (123, 140))	('rat', 'Species', '10116', (37, 40))	('PIK3CA', 'Gene', (172, 178))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('carcinomas', 'Phenotype', 'HP:0030731', (130, 140))	('anti-proliferative', 'CPA', (25, 43))	('GDC-0032', 'Gene', (0, 8))	('tumor', 'Disease', (53, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('mutations', 'Var', (179, 188))
111627	28592260	BAY 80-6946, a more potent inhibitor against p110alpha and p110delta, impedes cell proliferation and induces apoptosis in human breast, endometrial and hematologic cancer cell lines with PIK3CA mutations and/or HER2 overexpression.	('human', 'Species', '9606', (122, 127))	('rat', 'Species', '10116', (90, 93))	('p110alpha', 'Var', (45, 54))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('p110delta', 'Var', (59, 68))	('HER2', 'Gene', (211, 215))	('apoptosis', 'CPA', (109, 118))	('BAY 80-6946', 'Chemical', 'MESH:C000589253', (0, 11))	('mutations', 'Var', (194, 203))	('HER2', 'Gene', '2064', (211, 215))	('impedes', 'NegReg', (70, 77))	('hematologic cancer', 'Phenotype', 'HP:0004377', (152, 170))	('PIK3CA', 'Gene', (187, 193))	('overexpression', 'PosReg', (216, 230))	('induces', 'Reg', (101, 108))	('endometrial and hematologic cancer', 'Disease', 'MESH:D016889', (136, 170))	('cell proliferation', 'CPA', (78, 96))
111632	28592260	Inhibition of p110alpha by PIK-75 or A66 is sufficient to suppress GBM cell viability, migration and invasion, whereas inhibition of p110beta by TGX-221 only blocks cell migration, and inhibition of p110delta by IC87114 or CAL-101 moderately impedes cell proliferation and migration.	('cell migration', 'CPA', (165, 179))	('p110beta', 'Gene', '5291', (133, 141))	('IC87114', 'Chemical', 'MESH:C477872', (212, 219))	('rat', 'Species', '10116', (262, 265))	('suppress', 'NegReg', (58, 66))	('p110alpha', 'Var', (14, 23))	('rat', 'Species', '10116', (276, 279))	('rat', 'Species', '10116', (173, 176))	('A66', 'Var', (37, 40))	('TGX-221', 'Chemical', 'MESH:C504718', (145, 152))	('rat', 'Species', '10116', (235, 238))	('CAL-101', 'Chemical', 'MESH:C552946', (223, 230))	('rat', 'Species', '10116', (90, 93))	('GBM cell viability', 'CPA', (67, 85))	('blocks', 'NegReg', (158, 164))	('cell proliferation', 'CPA', (250, 268))	('p110beta', 'Gene', (133, 141))	('impedes', 'NegReg', (242, 249))	('PIK-75', 'Gene', (27, 33))	('invasion', 'CPA', (101, 109))
111633	28592260	Since PIK3CA mutations and PTEN loss/mutation are frequently found in GBM, isoform-selective PI3K inhibitors, especially against p110alpha and p110beta, may have potentials for the treatment of GBM bearing these genetic mutations.	('PI3', 'Gene', (93, 96))	('p110beta', 'Gene', (143, 151))	('loss/mutation', 'NegReg', (32, 45))	('p110beta', 'Gene', '5291', (143, 151))	('PIK3CA', 'Gene', (6, 12))	('GBM', 'Disease', (194, 197))	('p110alpha', 'Var', (129, 138))	('PI3', 'Gene', '5266', (93, 96))	('PTEN', 'Gene', (27, 31))	('mutations', 'Var', (13, 22))	('PTEN', 'Gene', '5728', (27, 31))
111634	28592260	Currently, several novel isoform-selective PI3K inhibitors including BYL719, MLN1117, CAL-101, GSK2636771 and CH5132799 have entered phase I/II clinical trials in patients with solid tumors and hematologic malignancies.	('BYL719', 'Var', (69, 75))	('PI3', 'Gene', '5266', (43, 46))	('patients', 'Species', '9606', (163, 171))	('hematologic malignancies', 'Disease', 'MESH:D019337', (194, 218))	('solid tumors', 'Disease', (177, 189))	('CAL-101', 'Var', (86, 93))	('solid tumors', 'Disease', 'MESH:D009369', (177, 189))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('GSK2636771', 'Chemical', 'MESH:C000627739', (95, 105))	('PI3', 'Gene', (43, 46))	('tumors', 'Phenotype', 'HP:0002664', (183, 189))	('hematologic malignancies', 'Disease', (194, 218))	('MLN1117', 'Var', (77, 84))	('CH5132799', 'Chemical', 'MESH:C559137', (110, 119))	('CAL-101', 'Chemical', 'MESH:C552946', (86, 93))	('GSK2636771', 'Var', (95, 105))	('CH5132799', 'Var', (110, 119))
111639	28592260	Cancer cells carrying PIK3CA mutations are more sensitive to BYL719, while tumors bearing PIK3CA amplifications or PTEN mutations only respond moderately.	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('PTEN', 'Gene', (115, 119))	('mutations', 'Var', (29, 38))	('PTEN', 'Gene', '5728', (115, 119))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('tumors', 'Disease', (75, 81))	('sensitive', 'MPA', (48, 57))	('rat', 'Species', '10116', (147, 150))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('PIK3CA', 'Gene', (22, 28))
111640	28592260	Thus, it suggests that PIK3CA alteration may be a positive prognostic predictor for the clinical use of p110alpha-selective inhibitors.	('PIK3CA', 'Gene', (23, 29))	('p110alpha-selective', 'Var', (104, 123))	('alteration', 'Var', (30, 40))	('rat', 'Species', '10116', (34, 37))
111642	28592260	Another p110alpha-selective inhibitor MLN1117, and a p110alpha/gamma inhibitor CH5132799 are also in phase I/II trials for advanced solid malignancies treatment.	('malignancies', 'Disease', 'MESH:D009369', (138, 150))	('CH5132799', 'Chemical', 'MESH:C559137', (79, 88))	('malignancies', 'Disease', (138, 150))	('MLN1117', 'Var', (38, 45))
111643	28592260	The selective p110beta inhibitor GSK2636771 has entered into phase I/II trials for the treatment of advance solid tumors bearing PTEN loss or mutation (NCT01458067).	('p110beta', 'Gene', (14, 22))	('advance solid tumors bearing PTEN loss', 'Disease', 'MESH:D006223', (100, 138))	('GSK2636771', 'Chemical', 'MESH:C000627739', (33, 43))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('p110beta', 'Gene', '5291', (14, 22))	('mutation', 'Var', (142, 150))	('advance solid tumors bearing PTEN loss', 'Disease', (100, 138))
111644	28592260	Due to the high expression levels of p110delta and p110gamma in leukocytes, the p110delta inhibitors CAL-101 and AMG319, as well as the p110delta/gamma inhibitor INK1197 are currently in phase I/II clinical trials for patients with hematologic malignancies including leukemia, lymphoma and myeloma.	('leukemia', 'Phenotype', 'HP:0001909', (267, 275))	('lymphoma', 'Disease', (277, 285))	('CAL-101', 'Chemical', 'MESH:C552946', (101, 108))	('leukemia', 'Disease', 'MESH:D007938', (267, 275))	('AMG319', 'Chemical', 'MESH:C000597234', (113, 119))	('patients', 'Species', '9606', (218, 226))	('p110gamma', 'Gene', '5294', (51, 60))	('myeloma', 'Disease', (290, 297))	('lymphoma', 'Disease', 'MESH:D008223', (277, 285))	('hematologic malignancies', 'Disease', 'MESH:D019337', (232, 256))	('p110delta', 'Var', (80, 89))	('lymphoma', 'Phenotype', 'HP:0002665', (277, 285))	('p110gamma', 'Gene', (51, 60))	('expression levels', 'MPA', (16, 33))	('hematologic malignancies', 'Disease', (232, 256))	('p110delta', 'Var', (37, 46))	('myeloma', 'Disease', 'MESH:D009101', (290, 297))	('leukemia', 'Disease', (267, 275))
111650	28592260	Therefore, dual PI3K/mTOR inhibitors such as NVP-BEZ235, XL765, GDC-0084 and PQR309 are produced and currently tested in clinical trials (Table 3).	('NVP-BEZ235', 'Var', (45, 55))	('PI3', 'Gene', (16, 19))	('PQR309', 'Var', (77, 83))	('PQR309', 'Chemical', '-', (77, 83))	('GDC-0084', 'Chemical', '-', (64, 72))	('mTOR', 'Gene', (21, 25))	('mTOR', 'Gene', '2475', (21, 25))	('PI3', 'Gene', '5266', (16, 19))
111653	28592260	Furthermore, NVP-BEZ235 alone or in combination of MEK1/2 inhibitors UO126 or SL327 promotes cell differentiation to neuronal and glial lineages and suppresses the tumorigenic potential of GBM stem-like cells (GSLCs).	('tumor', 'Disease', (164, 169))	('UO126', 'Chemical', 'MESH:C113580', (69, 74))	('NVP-BEZ235', 'Var', (13, 23))	('SL327', 'Gene', (78, 83))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('UO126', 'Var', (69, 74))	('suppresses', 'NegReg', (149, 159))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('promotes', 'PosReg', (84, 92))
111654	28592260	These findings indicate that NVP-BEZ235 plus temozolomide, radiotherapy or other inhibitors may be possible strategies for GBM treatment.	('rat', 'Species', '10116', (110, 113))	('GBM', 'Disease', (123, 126))	('temozolomide', 'Chemical', 'MESH:D000077204', (45, 57))	('NVP-BEZ235', 'Var', (29, 39))
111656	28592260	In a phase I dose-escalation study of patients with advanced solid tumors, NVP-BEZ235 was generally well-tolerated with mild dose-limiting toxicities (DLTs) including mucositis, hyperglycemia, dehydration, fatigue and thrombocytopenia.	('hyperglycemia', 'Phenotype', 'HP:0003074', (178, 191))	('fatigue', 'Disease', (206, 213))	('fatigue', 'Phenotype', 'HP:0012378', (206, 213))	('toxicities', 'Disease', (139, 149))	('thrombocytopenia', 'Disease', 'MESH:D013921', (218, 234))	('thrombocytopenia', 'Phenotype', 'HP:0001873', (218, 234))	('patients', 'Species', '9606', (38, 46))	('solid tumors', 'Disease', (61, 73))	('dehydration', 'Disease', (193, 204))	('rat', 'Species', '10116', (109, 112))	('rat', 'Species', '10116', (198, 201))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('hyperglycemia', 'Disease', (178, 191))	('fatigue', 'Disease', 'MESH:D005221', (206, 213))	('hyperglycemia', 'Disease', 'MESH:D006943', (178, 191))	('solid tumors', 'Disease', 'MESH:D009369', (61, 73))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('mucositis', 'Disease', 'MESH:D052016', (167, 176))	('thrombocytopenia', 'Disease', (218, 234))	('NVP-BEZ235', 'Var', (75, 85))	('mucositis', 'Disease', (167, 176))	('toxicities', 'Disease', 'MESH:D064420', (139, 149))	('dehydration', 'Phenotype', 'HP:0001944', (193, 204))	('dehydration', 'Disease', 'MESH:D003681', (193, 204))
111659	28592260	Voxtalisib (XL765, SAR245409) is also a potent ATP-competitive, orally bioavailable, BBB-permeable PI3K/mTOR inhibitor with high inhibition on p110gamma and an additional inhibition against DNA protein kinase.	('mTOR', 'Gene', (104, 108))	('mTOR', 'Gene', '2475', (104, 108))	('PI3', 'Gene', '5266', (99, 102))	('ATP', 'Chemical', 'MESH:D000255', (47, 50))	('p110gamma', 'Gene', '5294', (143, 152))	('XL765', 'Var', (12, 17))	('p110gamma', 'Gene', (143, 152))	('SAR245409', 'Var', (19, 28))	('DNA protein kinase', 'Enzyme', (190, 208))	('PI3', 'Gene', (99, 102))	('inhibition', 'NegReg', (129, 139))	('Voxtalisib', 'Chemical', 'MESH:C576808', (0, 10))
111660	28592260	It exhibits robust anti-proliferative activity in a panel of GBM cell lines including U-87 MG, U-251 MG and U-373 MG via decreased phosphorylation of Akt, GSK3beta and p70S6 K, reduced expression of cyclin D, and G1-cycle arrest.	('expression', 'MPA', (185, 195))	('GSK3beta', 'Gene', '2932', (155, 163))	('phosphorylation', 'MPA', (131, 146))	('reduced', 'NegReg', (177, 184))	('U-373 MG', 'Var', (108, 116))	('decreased', 'NegReg', (121, 130))	('U-251 MG', 'Var', (95, 103))	('arrest', 'Disease', 'MESH:D006323', (222, 228))	('rat', 'Species', '10116', (31, 34))	('p70S6 K', 'Var', (168, 175))	('cyclin D', 'Protein', (199, 207))	('Akt', 'Pathway', (150, 153))	('arrest', 'Disease', (222, 228))	('anti-proliferative activity', 'MPA', (19, 46))	('GSK3beta', 'Gene', (155, 163))
111662	28592260	Furthermore, XL765 alone or in combination of temozolomide markedly suppresses growth of subcutaneous or intracranial GBM xenograft, and prolongs survival of tumor-bearing nude mice, indicating its potent anti-GBM activity and BBB penetration capacity.	('tumor', 'Disease', (158, 163))	('rat', 'Species', '10116', (236, 239))	('suppresses', 'NegReg', (68, 78))	('anti-GBM activity', 'CPA', (205, 222))	('prolongs', 'PosReg', (137, 145))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('XL765', 'Var', (13, 18))	('temozolomide', 'Chemical', 'MESH:D000077204', (46, 58))	('survival', 'CPA', (146, 154))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('nude mice', 'Species', '10090', (172, 181))
111671	28592260	PQR309 is a novel, ATP-competitive, BBB-penetrating pan-PI3K/mTOR inhibitor with potent inhibitory effects on Akt and ribosomal protein S6 phosphorylation.	('PI3', 'Gene', (56, 59))	('ATP', 'Chemical', 'MESH:D000255', (19, 22))	('PQR309', 'Chemical', '-', (0, 6))	('Akt', 'Pathway', (110, 113))	('mTOR', 'Gene', (61, 65))	('PI3', 'Gene', '5266', (56, 59))	('mTOR', 'Gene', '2475', (61, 65))	('inhibitory', 'NegReg', (88, 98))	('PQR309', 'Var', (0, 6))	('rat', 'Species', '10116', (45, 48))	('ribosomal protein S6 phosphorylation', 'MPA', (118, 154))
111672	28592260	In a PC-3 prostate tumor xenograft model, PQR309 has been shown to be oral bioavailable, and it effectively inhibits PI3K/Akt signaling and reduces tumor growth.	('PQR309', 'Chemical', '-', (42, 48))	('PI3', 'Gene', (117, 120))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('reduces', 'NegReg', (140, 147))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('a PC-3', 'CellLine', 'CVCL:0035', (3, 9))	('prostate tumor', 'Disease', 'MESH:D011471', (10, 24))	('tumor', 'Disease', (148, 153))	('inhibits', 'NegReg', (108, 116))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('PI3', 'Gene', '5266', (117, 120))	('tumor', 'Disease', (19, 24))	('prostate tumor', 'Disease', (10, 24))	('prostate tumor', 'Phenotype', 'HP:0100787', (10, 24))	('PQR309', 'Var', (42, 48))
111674	28592260	Concentration-dependent hyperglycemia has been confirmed as a mechanism-based toxicity of PQR309 (NCT01940133, NCT02483858).	('hyperglycemia', 'Phenotype', 'HP:0003074', (24, 37))	('NCT02483858', 'Var', (111, 122))	('toxicity', 'Disease', 'MESH:D064420', (78, 86))	('toxicity', 'Disease', (78, 86))	('PQR309', 'Chemical', '-', (90, 96))	('hyperglycemia', 'Disease', 'MESH:D006943', (24, 37))	('PQR309', 'Gene', (90, 96))	('rat', 'Species', '10116', (7, 10))	('hyperglycemia', 'Disease', (24, 37))	('NCT01940133', 'Var', (98, 109))
111676	28592260	Other novel dual PI3K/mTOR inhibitors including NVP-BGT226, GSK2126458, GSK1059615, GDC-0980, VS-5584, PF-04691502 and PKI-587 have entered phase I/II clinical trials for advanced solid tumors.	('GSK2126458', 'Var', (60, 70))	('VS-5584', 'Var', (94, 101))	('GDC-0980', 'Var', (84, 92))	('PF-04691502', 'Var', (103, 114))	('solid tumors', 'Disease', 'MESH:D009369', (180, 192))	('solid tumors', 'Disease', (180, 192))	('GSK1059615', 'Chemical', '-', (72, 82))	('NVP', 'Chemical', 'MESH:D019829', (48, 51))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('GDC-0980', 'Chemical', 'MESH:C569670', (84, 92))	('PI3', 'Gene', '5266', (17, 20))	('tumors', 'Phenotype', 'HP:0002664', (186, 192))	('GSK1059615', 'Var', (72, 82))	('mTOR', 'Gene', '2475', (22, 26))	('GSK2126458', 'Chemical', 'MESH:C561454', (60, 70))	('NVP-BGT226', 'Gene', (48, 58))	('PI3', 'Gene', (17, 20))	('mTOR', 'Gene', (22, 26))
111678	28592260	Considering that inhibition of PI3K isoforms might lead to compensatory activation of other signaling pathways, or the feedback, and subsequent compromise of the inhibitory effects, GBM patients may benefit from combination treatment strategies by dual inhibition of PI3K and other molecules.	('activation', 'PosReg', (72, 82))	('PI3', 'Gene', '5266', (267, 270))	('rat', 'Species', '10116', (236, 239))	('PI3', 'Gene', '5266', (31, 34))	('inhibition', 'Var', (17, 27))	('PI3', 'Gene', (267, 270))	('GBM', 'Disease', (182, 185))	('PI3', 'Gene', (31, 34))	('patients', 'Species', '9606', (186, 194))
111680	28592260	It is noteworthy that, PIK3CA and EGFRvIII mutations often lead to PI3K activation independent of RTKs such as EGFR, HER2, PDGFR, VEGFR and c-Met, suggesting that inhibition of RTKs alone is not sufficient to obstruct PI3K/Akt signaling.	('HER2', 'Gene', (117, 121))	('PI3', 'Gene', '5266', (218, 221))	('PIK3CA', 'Gene', (23, 29))	('EGFR', 'Gene', '1956', (111, 115))	('PI3', 'Gene', (67, 70))	('EGFR', 'Gene', (131, 135))	('c-Met', 'Gene', (140, 145))	('EGFR', 'Gene', (34, 38))	('PI3', 'Gene', (218, 221))	('lead to', 'Reg', (59, 66))	('VEGFR', 'Gene', '3791', (130, 135))	('activation', 'PosReg', (72, 82))	('HER2', 'Gene', '2064', (117, 121))	('VEGFR', 'Gene', (130, 135))	('EGFR', 'Gene', '1956', (131, 135))	('EGFR', 'Gene', (111, 115))	('PI3', 'Gene', '5266', (67, 70))	('c-Met', 'Gene', '4233', (140, 145))	('EGFR', 'Gene', '1956', (34, 38))	('mutations', 'Var', (43, 52))	('PDGFR', 'Gene', (123, 128))	('PDGFR', 'Gene', '5159', (123, 128))
111681	28592260	Evidence shows that overall alteration (including amplification, mutation, rearrangement and altered splicing) of EGFR in TCGA GBM samples is up to 57.4%.	('rat', 'Species', '10116', (32, 35))	('altered', 'Reg', (93, 100))	('EGFR', 'Gene', '1956', (114, 118))	('mutation', 'Var', (65, 73))	('EGFR', 'Gene', (114, 118))	('amplification', 'MPA', (50, 63))	('splicing', 'MPA', (101, 109))	('rearrangement', 'Var', (75, 88))	('alteration', 'Reg', (28, 38))
111684	28592260	Compared with single inhibitor alone, combination of a dual PI3K/mTOR inhibitor PF-05212384 and a pan-ERBB inhibitor PF-00299804 (dacomitinib) induces more apoptosis of GBM cells harboring both EGFR amplification and PI3K activation.	('mTOR', 'Gene', (65, 69))	('dacomitinib', 'Chemical', 'MESH:C525726', (130, 141))	('PI3', 'Gene', (217, 220))	('mTOR', 'Gene', '2475', (65, 69))	('PI3', 'Gene', '5266', (60, 63))	('induces', 'Reg', (143, 150))	('ERBB', 'Gene', (102, 106))	('PI3', 'Gene', (60, 63))	('combination', 'Interaction', (38, 49))	('PF-00299804', 'Chemical', 'MESH:C525726', (117, 128))	('PF-05212384', 'Chemical', 'MESH:C549060', (80, 91))	('PI3', 'Gene', '5266', (217, 220))	('EGFR', 'Gene', '1956', (194, 198))	('EGFR', 'Gene', (194, 198))	('ERBB', 'Gene', '1956', (102, 106))	('amplification', 'Var', (199, 212))	('apoptosis', 'CPA', (156, 165))
111689	28592260	With respect to GBM patients, a phase Ib/II study of BKM120 plus a c-Met inhibitor INC280 in patients with recurrent GBM bearing PTEN loss or MET alteration is still ongoing (NCT01870726).	('MET alteration', 'Var', (142, 156))	('PTEN', 'Gene', (129, 133))	('rat', 'Species', '10116', (150, 153))	('c-Met', 'Gene', (67, 72))	('PTEN', 'Gene', '5728', (129, 133))	('patients', 'Species', '9606', (20, 28))	('loss', 'NegReg', (134, 138))	('c-Met', 'Gene', '4233', (67, 72))	('patients', 'Species', '9606', (93, 101))	('BKM120', 'Chemical', 'MESH:C571178', (53, 59))
111692	28592260	Therefore, combination therapies targeting PI3K/Akt and MAPK pathways may have synergism in cancers harboring RAS mutations.	('PI3', 'Gene', '5266', (43, 46))	('cancers', 'Phenotype', 'HP:0002664', (92, 99))	('mutations', 'Var', (114, 123))	('RAS', 'Gene', (110, 113))	('cancers', 'Disease', 'MESH:D009369', (92, 99))	('PI3', 'Gene', (43, 46))	('cancers', 'Disease', (92, 99))	('MAPK pathways', 'Pathway', (56, 69))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
111693	28592260	Evidence shows that mice with K-RAS mutated lung cancer well respond to the combination of NVP-BEZ235 and a MEK inhibitor ARRY-142886, rather than NVP-BEZ235 alone.	('lung cancer', 'Phenotype', 'HP:0100526', (44, 55))	('K-RAS', 'Gene', '16653', (30, 35))	('respond', 'Reg', (61, 68))	('rat', 'Species', '10116', (135, 138))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('mice', 'Species', '10090', (20, 24))	('mutated', 'Var', (36, 43))	('lung cancer', 'Disease', 'MESH:D008175', (44, 55))	('combination', 'Interaction', (76, 87))	('K-RAS', 'Gene', (30, 35))	('lung cancer', 'Disease', (44, 55))
111694	28592260	Moreover, combination of BKM120 and MEK inhibitors exhibits decreased glioblastoma cell viability and prolonged survival of mice with intracranial xenograft, through downregulating the phosphorylation of ERK, Akt and p70S6 K. Combination of NVP-BEZ235 and MEK1/2 inhibitors UO126 or SL327 displays synergistic inhibitory effect on self-renewal and tumorigenic capacities of GBM stem-like cells (GSLCs), and prolongs the survival of mice with GSLC xenograft.	('glioblastoma', 'Phenotype', 'HP:0012174', (70, 82))	('prolongs', 'NegReg', (407, 415))	('survival', 'CPA', (420, 428))	('mice', 'Species', '10090', (432, 436))	('UO126', 'Var', (274, 279))	('UO126', 'Chemical', 'MESH:C113580', (274, 279))	('tumor', 'Disease', 'MESH:D009369', (348, 353))	('mice', 'Species', '10090', (124, 128))	('tumor', 'Phenotype', 'HP:0002664', (348, 353))	('NVP-BEZ235', 'Gene', (241, 251))	('glioblastoma cell viability', 'Disease', (70, 97))	('BKM120', 'Chemical', 'MESH:C571178', (25, 31))	('SL327', 'Gene', (283, 288))	('tumor', 'Disease', (348, 353))	('self-renewal', 'CPA', (331, 343))	('glioblastoma cell viability', 'Disease', 'MESH:D005909', (70, 97))
111697	28592260	A phase I trial shows that patients with advanced solid tumors receiving combination therapies targeting PI3K/Akt and Ras/Raf/MEK/ERK pathways have better prognosis in response to PTEN deletions and KRAS/BRAF mutations.	('KRAS', 'Gene', '3845', (199, 203))	('Raf', 'Gene', '22882', (122, 125))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('BRAF', 'Gene', (204, 208))	('solid tumors', 'Disease', 'MESH:D009369', (50, 62))	('PTEN', 'Gene', (180, 184))	('PI3', 'Gene', (105, 108))	('deletions', 'Var', (185, 194))	('Raf', 'Gene', (122, 125))	('PTEN', 'Gene', '5728', (180, 184))	('patients', 'Species', '9606', (27, 35))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('mutations', 'Var', (209, 218))	('better', 'PosReg', (148, 154))	('solid tumors', 'Disease', (50, 62))	('PI3', 'Gene', '5266', (105, 108))	('KRAS', 'Gene', (199, 203))	('BRAF', 'Gene', '673', (204, 208))
111701	28592260	Growth factor-induced activation of Hh signaling positively correlates with Akt phosphorylation level in esophageal cancer and breast cancer, while inhibition of PI3K activity decreases Smo and Gli1 expression, suggesting that Hh signaling activation may be partially activated through PI3K/Akt signaling.	('inhibition', 'Var', (148, 158))	('breast cancer', 'Phenotype', 'HP:0003002', (127, 140))	('esophageal cancer', 'Disease', 'MESH:D004938', (105, 122))	('PI3', 'Gene', (162, 165))	('expression', 'MPA', (199, 209))	('breast cancer', 'Disease', 'MESH:D001943', (127, 140))	('breast cancer', 'Disease', (127, 140))	('Gli1', 'Gene', (194, 198))	('esophageal cancer', 'Disease', (105, 122))	('PI3', 'Gene', '5266', (286, 289))	('Akt phosphorylation level', 'MPA', (76, 101))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('decreases', 'NegReg', (176, 185))	('Smo', 'Gene', '6608', (186, 189))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('PI3', 'Gene', (286, 289))	('Smo', 'Gene', (186, 189))	('Gli1', 'Gene', '2735', (194, 198))	('activation', 'PosReg', (22, 32))	('PI3', 'Gene', '5266', (162, 165))
111702	28592260	In addition, loss of PTEN confers medulloblastoma cells resistance to Hh pathway inhibitor GDC-0449.	('medulloblastoma', 'Disease', 'MESH:D008527', (34, 49))	('medulloblastoma', 'Phenotype', 'HP:0002885', (34, 49))	('PTEN', 'Gene', '5728', (21, 25))	('resistance to', 'MPA', (56, 69))	('medulloblastoma', 'Disease', (34, 49))	('PTEN', 'Gene', (21, 25))	('loss', 'Var', (13, 17))	('GDC-0449', 'Chemical', 'MESH:C538724', (91, 99))
111704	28592260	Evidence shows that combination of BKM120 and a Smo inhibitor LDE225 significantly reduces tumor growth and increases apoptosis in intracranial GBM xenografts.	('apoptosis', 'CPA', (118, 127))	('BKM120', 'Var', (35, 41))	('increases', 'PosReg', (108, 117))	('Smo', 'Gene', '6608', (48, 51))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('reduces', 'NegReg', (83, 90))	('LDE225', 'Chemical', 'MESH:C561435', (62, 68))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('BKM120', 'Chemical', 'MESH:C571178', (35, 41))	('tumor', 'Disease', (91, 96))	('Smo', 'Gene', (48, 51))
111706	28592260	In addition, combination of NVP-BEZ235 and LDE225 also shows synergistic inhibitory effects on self-renewal capacity of pancreatic cancer stem cells (CSCs) and their growth in nude mice.	('NVP-BEZ235', 'Var', (28, 38))	('pancreatic cancer', 'Disease', 'MESH:D010190', (120, 137))	('LDE225', 'Gene', (43, 49))	('LDE225', 'Chemical', 'MESH:C561435', (43, 49))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (120, 137))	('inhibitory', 'NegReg', (73, 83))	('self-renewal capacity', 'CPA', (95, 116))	('nude mice', 'Species', '10090', (176, 185))	('pancreatic cancer', 'Disease', (120, 137))	('combination', 'Var', (13, 24))
111710	28592260	Firstly, blockade of a single pathway generally gives rise to the compensatory activation of other pathways to relieve the inhibitory effects and maintain tumor cell survival.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('tumor', 'Disease', (155, 160))	('inhibitory effects', 'MPA', (123, 141))	('maintain', 'PosReg', (146, 154))	('blockade', 'Var', (9, 17))
111715	28592260	The majority of PI3K inhibitors in the clinical studies exhibit adverse effects including fatigue, hyperglycemia, nausea, vomiting and increased ALT/AST.	('hyperglycemia', 'Phenotype', 'HP:0003074', (99, 112))	('fatigue', 'Disease', 'MESH:D005221', (90, 97))	('AST', 'Gene', '26503', (149, 152))	('nausea', 'Disease', (114, 120))	('PI3', 'Gene', '5266', (16, 19))	('hyperglycemia', 'Disease', (99, 112))	('nausea', 'Disease', 'MESH:D009325', (114, 120))	('PI3', 'Gene', (16, 19))	('hyperglycemia', 'Disease', 'MESH:D006943', (99, 112))	('AST', 'Gene', (149, 152))	('fatigue', 'Disease', (90, 97))	('inhibitors', 'Var', (21, 31))	('fatigue', 'Phenotype', 'HP:0012378', (90, 97))	('vomiting', 'Disease', 'MESH:D014839', (122, 130))	('increased ALT', 'Phenotype', 'HP:0031964', (135, 148))	('vomiting', 'Phenotype', 'HP:0002013', (122, 130))	('increased', 'PosReg', (135, 144))	('nausea', 'Phenotype', 'HP:0002018', (114, 120))	('vomiting', 'Disease', (122, 130))
111720	28592260	Although the latter shows less off-target effects and toxicities, their clinical efficacy and application are largely limited by various genetic alterations such as PIK3CA, RAS and PTEN mutations, seen in patients.	('rat', 'Species', '10116', (149, 152))	('toxicities', 'Disease', 'MESH:D064420', (54, 64))	('patients', 'Species', '9606', (205, 213))	('mutations', 'Var', (186, 195))	('PIK3CA', 'Gene', (165, 171))	('RAS', 'Gene', (173, 176))	('toxicities', 'Disease', (54, 64))	('PTEN', 'Gene', (181, 185))	('PTEN', 'Gene', '5728', (181, 185))
111721	28592260	In order to maximize the applications of these specific inhibitors, future therapeutic strategies should include the molecular pathological diagnosis of GBM patients like PIK3CA, RAS mutations and PTEN loss/mutation prior to drug administration.	('loss/mutation', 'Var', (202, 215))	('PIK3CA', 'Gene', (171, 177))	('mutations', 'Var', (183, 192))	('RAS', 'Gene', (179, 182))	('patients', 'Species', '9606', (157, 165))	('rat', 'Species', '10116', (89, 92))	('PTEN', 'Gene', (197, 201))	('GBM', 'Disease', (153, 156))	('PTEN', 'Gene', '5728', (197, 201))	('rat', 'Species', '10116', (238, 241))
111723	28592260	Recently, the p110delta inhibitor CAL-101 has been approved by FDA for certain types of lymphoma, offering hopes of PI3K inhibitors for cancer treatment.	('lymphoma', 'Phenotype', 'HP:0002665', (88, 96))	('PI3', 'Gene', '5266', (116, 119))	('p110delta', 'Var', (14, 23))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('CAL-101', 'Gene', (34, 41))	('cancer', 'Disease', (136, 142))	('PI3', 'Gene', (116, 119))	('CAL-101', 'Chemical', 'MESH:C552946', (34, 41))	('lymphoma', 'Disease', (88, 96))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('lymphoma', 'Disease', 'MESH:D008223', (88, 96))
111725	28592260	The future strategies to promote the potential of PI3K inhibitors for GBM treatment need to focus upon: identifying genetic alternations such as PI3KCA mutations, PTEN mutations/loss and RAS mutations prior to the treatment regime; rational combinations with other molecules' inhibitors or other therapies, on the basis of understanding of the crosstalks between PI3K and other signaling molecules/pathways; employing a BBB-permeable drug delivering system specifically targeting GBM cells to decrease toxicities on normal cells.	('PI3', 'Gene', '5266', (363, 366))	('PI3', 'Gene', (145, 148))	('rat', 'Species', '10116', (232, 235))	('mutations', 'Var', (152, 161))	('mutations/loss', 'NegReg', (168, 182))	('PTEN', 'Gene', (163, 167))	('toxicities', 'Disease', (502, 512))	('mutations', 'Var', (191, 200))	('PTEN', 'Gene', '5728', (163, 167))	('PI3', 'Gene', (50, 53))	('PI3', 'Gene', (363, 366))	('PI3', 'Gene', '5266', (145, 148))	('rat', 'Species', '10116', (13, 16))	('toxicities', 'Disease', 'MESH:D064420', (502, 512))	('mutations/loss', 'Var', (168, 182))	('PI3', 'Gene', '5266', (50, 53))
111735	28261346	Patients with lower GOLPH3L expression level, poorer tumor differentiation, shorter NACT treatment intervals and smaller tumor sizes were more likely to achieve a pCR after NACT.	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('lower', 'NegReg', (14, 19))	('GOLPH3L expression level', 'MPA', (20, 44))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Disease', (121, 126))	('poorer', 'Var', (46, 52))	('pCR', 'Disease', (163, 166))	('Patients', 'Species', '9606', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('NACT', 'Chemical', '-', (173, 177))	('NACT', 'Chemical', '-', (84, 88))	('tumor', 'Disease', (53, 58))	('achieve', 'PosReg', (153, 160))	('lower GOLPH3L expression level', 'Phenotype', 'HP:0031037', (14, 44))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
111805	28261346	Patients with low levels of GOLPH3L expression, poorer tumor differentiation, shorter NACT treatment intervals and smaller tumor sizes were more likely to achieve a pCR after NACT (P=0.032, 0.045, 0.041, 0.005, respectively, Table 2).	('poorer', 'Var', (48, 54))	('pCR', 'Disease', (165, 168))	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Disease', (123, 128))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('NACT', 'Chemical', '-', (86, 90))	('NACT', 'Chemical', '-', (175, 179))	('tumor', 'Disease', (55, 60))	('achieve', 'PosReg', (155, 162))	('Patients', 'Species', '9606', (0, 8))	('low levels of GOLPH3L', 'Phenotype', 'HP:0031037', (14, 35))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('low', 'Var', (14, 17))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('GOLPH3L', 'Protein', (28, 35))
111816	28261346	Compared with the negative control and blank groups, the proportion of GOLPH3L-silenced SiHa and HeLa cells in the G1 phase of the cell cycle significantly increased, indicating that silencing GOLPH3L expression induced cell cycle arrest at the G1 phase (P<0.05) (Fig.	('silencing', 'Var', (183, 192))	('GOLPH3L', 'Gene', (193, 200))	('increased', 'PosReg', (156, 165))	('SiHa', 'CellLine', 'CVCL:0032', (88, 92))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (220, 237))	('cell cycle arrest at the G1 phase', 'CPA', (220, 253))	('HeLa', 'CellLine', 'CVCL:0030', (97, 101))
111822	28261346	siRNA-mediated gene silencing of GOLPH3L significantly enhanced cell growth inhibition, apoptosis, cell cycle arrest, and cisplatin sensitivity.	('apoptosis', 'CPA', (88, 97))	('cell cycle arrest', 'CPA', (99, 116))	('cell growth inhibition', 'CPA', (64, 86))	('enhanced', 'PosReg', (55, 63))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (99, 116))	('cisplatin sensitivity', 'CPA', (122, 143))	('GOLPH3L', 'Gene', (33, 40))	('cisplatin', 'Chemical', 'MESH:D002945', (122, 131))	('gene silencing', 'Var', (15, 29))
111827	28261346	GOLPH3 plays an important role in the DNA damage response mediated by novel Golgi-associated pathway, and GOLPH3 overexpression confers resistance to DNA damaging agents, suggesting that GOLPH3 functions as an oncogene by mediating chemotherapy resistance.	('GOLPH3', 'Gene', '64083', (187, 193))	('GOLPH3', 'Gene', (0, 6))	('GOLPH3', 'Gene', (106, 112))	('Golgi-associated pathway', 'Pathway', (76, 100))	('mediating', 'Reg', (222, 231))	('GOLPH3', 'Gene', '64083', (106, 112))	('GOLPH3', 'Gene', (187, 193))	('GOLPH3', 'Gene', '64083', (0, 6))	('chemotherapy resistance', 'CPA', (232, 255))	('overexpression', 'Var', (113, 127))
111836	28261346	In addition to the increased proportion of cells arrested in the G0/G1 phase of the cell cycle, the phospho-antibody array identified several key cell cycle-associated proteins, including CHK1, CHK2 and CDC2, which exhibited differential phosphorylation patterns in cells expressing GOLPH3L siRNA (Table 4).	('CHK2', 'Gene', (194, 198))	('CHK1', 'Gene', (188, 192))	('CDC2', 'Gene', (203, 207))	('GOLPH3L siRNA', 'Var', (283, 296))	('CDC2', 'Gene', '983', (203, 207))	('CHK1', 'Gene', '1111', (188, 192))	('CHK2', 'Gene', '11200', (194, 198))
111837	28261346	CHK1 and CHK2 are key mediators of cell cycle regulation, and the phosphorylation of CHK1 and CHK2 can activate the G1/S and G2/M checkpoints in cells with unrepaired DNA damage or can activate apoptosis.	('apoptosis', 'CPA', (194, 203))	('CHK1', 'Gene', (85, 89))	('G1/S', 'CPA', (116, 120))	('activate', 'PosReg', (185, 193))	('CHK2', 'Gene', '11200', (94, 98))	('G2/M checkpoints', 'CPA', (125, 141))	('CHK1', 'Gene', (0, 4))	('CHK2', 'Gene', '11200', (9, 13))	('activate', 'PosReg', (103, 111))	('CHK1', 'Gene', '1111', (85, 89))	('CHK1', 'Gene', '1111', (0, 4))	('CHK2', 'Gene', (94, 98))	('CHK2', 'Gene', (9, 13))	('phosphorylation', 'Var', (66, 81))
111839	28261346	CDC2 is the primary kinase regulating the M phase of the cell cycle, and the phosphorylation of CDC2 at tyrosine-15 inhibits CDC2 activity, thereby arresting cell cycle progression in the G2 phase.	('tyrosine', 'Chemical', 'MESH:D014443', (104, 112))	('arresting', 'NegReg', (148, 157))	('cell cycle progression', 'CPA', (158, 180))	('CDC2', 'Gene', '983', (0, 4))	('CDC2', 'Gene', (0, 4))	('phosphorylation', 'Var', (77, 92))	('CDC2', 'Gene', '983', (96, 100))	('CDC2', 'Gene', (96, 100))	('CDC2', 'Gene', (125, 129))	('CDC2', 'Gene', '983', (125, 129))	('activity', 'MPA', (130, 138))	('inhibits', 'NegReg', (116, 124))
111840	28261346	In addition, GOLPH3L silencing increased the sensitivity of cervical cancer cells to chemotherapy.	('increased', 'PosReg', (31, 40))	('sensitivity', 'MPA', (45, 56))	('cervical cancer', 'Disease', (60, 75))	('cervical cancer', 'Disease', 'MESH:D002583', (60, 75))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('GOLPH3L', 'Gene', (13, 20))	('silencing', 'Var', (21, 30))
111841	28261346	Additionally, the phospho-antibody array revealed that Caspase-9 is activated upon GOLPH3L silencing, consistent with the increase in apoptosis rates demonstrated by flow cytometry analysis.	('GOLPH3L', 'Gene', (83, 90))	('activated', 'PosReg', (68, 77))	('Caspase-9', 'Gene', '842', (55, 64))	('silencing', 'Var', (91, 100))	('Caspase-9', 'Gene', (55, 64))
111855	28261346	GOLPH3L silencing reduces cell viability and increases the response of cervical cancer cells to cisplatin.	('cisplatin', 'Chemical', 'MESH:D002945', (96, 105))	('increases', 'PosReg', (45, 54))	('cervical cancer', 'Disease', (71, 86))	('cervical cancer', 'Disease', 'MESH:D002583', (71, 86))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('reduces', 'NegReg', (18, 25))	('silencing', 'Var', (8, 17))	('cell viability', 'CPA', (26, 40))	('response', 'MPA', (59, 67))	('GOLPH3L', 'Gene', (0, 7))
111859	28261346	We also demonstrated that GOLPH3L silencing is associated with a reduction in cell viability, induction of cell cycle arrest, and increased apoptosis rates and cisplatin sensitivity.	('silencing', 'Var', (34, 43))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (107, 124))	('cell cycle arrest', 'CPA', (107, 124))	('cisplatin sensitivity', 'CPA', (160, 181))	('cisplatin', 'Chemical', 'MESH:D002945', (160, 169))	('GOLPH3L', 'Gene', (26, 33))	('increased', 'PosReg', (130, 139))	('apoptosis rates', 'CPA', (140, 155))	('reduction', 'NegReg', (65, 74))	('cell viability', 'CPA', (78, 92))
111869	32185172	Multiple lines of evidence suggest that numerous risk elements, containing genetic and environmental factors, account for cancer initiation and development, among which the involvement of mis-regulation of non-coding RNAs (ncRNAs) in cancer has aroused extensive attention during the past few decades.	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('mis-regulation', 'Var', (188, 202))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('cancer initiation', 'Disease', 'MESH:D009369', (122, 139))	('cancer', 'Disease', 'MESH:D009369', (234, 240))	('ncRNA', 'Gene', (223, 228))	('cancer initiation', 'Disease', (122, 139))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('cancer', 'Disease', (234, 240))	('account', 'Reg', (110, 117))	('ncRNA', 'Gene', '220202', (223, 228))
111879	32185172	lncRNAs are divided into several categories according to genomic organization and relation to coding genes, such as long intergenic non-coding RNAs, antisense RNAs, sense overlapping RNAs, sense intronic RNAs, enhancer RNAs as well as pseudogene-expressed lncRNAs.	('ncRNA', 'Gene', '220202', (257, 262))	('sense overlapping RNAs', 'Var', (165, 187))	('antisense', 'Var', (149, 158))	('ncRNA', 'Gene', '220202', (1, 6))	('sense intronic RNAs', 'Var', (189, 208))	('ncRNA', 'Gene', (257, 262))	('ncRNA', 'Gene', (1, 6))
111884	32185172	Dysregulation of lncRNAs, pseudogenes and circRNAs leads to alteration of abundance of miRNAs, thus affecting their inhibition of downstream target expression.	('Dysregulation', 'Var', (0, 13))	('abundance', 'MPA', (74, 83))	('alteration', 'Reg', (60, 70))	('downstream target expression', 'MPA', (130, 158))	('affecting', 'Reg', (100, 109))	('ncRNA', 'Gene', (18, 23))	('miRNAs', 'Protein', (87, 93))	('ncRNA', 'Gene', '220202', (18, 23))	('inhibition', 'MPA', (116, 126))
111886	32185172	Based on ceRNA mechanism, researchers and scholars have discovered a variety of potential cancer-associated pseudogenes using in silico analysis.	('pseudogenes', 'Var', (108, 119))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))
111891	32185172	Dysregulation of pseudogenes and their transcripts has been implicated into initiation and/or progression of human disorders, including cancer.	('human', 'Species', '9606', (109, 114))	('Dysregulation', 'Var', (0, 13))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('implicated', 'Reg', (60, 70))	('cancer', 'Disease', (136, 142))	('pseudogenes', 'Protein', (17, 28))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
111892	32185172	Among pseudogene-derived lncRNAs, some act as tumor promotors, facilitating cancer development, whereas the other function as tumor suppressors, inhibiting cancer progression.	('tumor', 'Disease', 'MESH:D009369', (46, 51))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('cancer', 'Disease', (156, 162))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('ncRNA', 'Gene', (26, 31))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumor', 'Disease', (46, 51))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('ncRNA', 'Gene', '220202', (26, 31))	('inhibiting', 'NegReg', (145, 155))	('facilitating', 'PosReg', (63, 75))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('cancer', 'Disease', (76, 82))	('pseudogene-derived', 'Var', (6, 24))	('tumor', 'Disease', (126, 131))
111906	32185172	Dysregulation of pseudogenes and their transcripts accounts for the development of chemo-resistance and radio-resistance of HCC which greatly reduces the efficacy of chemotherapy and radiotherapy.	('HCC', 'Phenotype', 'HP:0001402', (124, 127))	('Dysregulation', 'Var', (0, 13))	('reduces', 'NegReg', (142, 149))	('HCC', 'Disease', 'MESH:D006528', (124, 127))	('pseudogenes', 'Protein', (17, 28))	('HCC', 'Disease', (124, 127))
111907	32185172	For example, suggested that PDIAP3 caused doxorubicin resistance of HCC by targeting miR-125/124-TRAF6/NF-KB signaling; found that knockdown of SUMO1P3 markedly enhanced radio-sensitivity in HCC.	('HCC', 'Disease', 'MESH:D006528', (191, 194))	('enhanced', 'PosReg', (161, 169))	('HCC', 'Disease', (191, 194))	('knockdown', 'Var', (131, 140))	('SUMO1P3', 'Gene', '474338', (144, 151))	('doxorubicin', 'MPA', (42, 53))	('HCC', 'Phenotype', 'HP:0001402', (191, 194))	('TRAF6', 'Gene', (97, 102))	('HCC', 'Disease', 'MESH:D006528', (68, 71))	('TRAF6', 'Gene', '7189', (97, 102))	('HCC', 'Disease', (68, 71))	('SUMO1P3', 'Gene', (144, 151))	('doxorubicin', 'Chemical', 'MESH:D004317', (42, 53))	('HCC', 'Phenotype', 'HP:0001402', (68, 71))	('radio-sensitivity', 'MPA', (170, 187))
111917	32185172	NANOGP8 expression was significantly elevated in gastric cancer and knockdown of NANOGP8 resulted in decreased proliferation and promoted apoptosis of gastric cancer cells.	('promoted', 'PosReg', (129, 137))	('NANOGP8', 'Gene', '388112', (0, 7))	('gastric cancer', 'Phenotype', 'HP:0012126', (49, 63))	('elevated', 'PosReg', (37, 45))	('gastric cancer', 'Disease', 'MESH:D013274', (151, 165))	('gastric cancer', 'Phenotype', 'HP:0012126', (151, 165))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('decreased', 'NegReg', (101, 110))	('knockdown', 'Var', (68, 77))	('apoptosis', 'CPA', (138, 147))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('expression', 'MPA', (8, 18))	('NANOGP8', 'Gene', (81, 88))	('gastric cancer', 'Disease', (151, 165))	('gastric cancer', 'Disease', (49, 63))	('NANOGP8', 'Gene', '388112', (81, 88))	('NANOGP8', 'Gene', (0, 7))	('gastric cancer', 'Disease', 'MESH:D013274', (49, 63))
111920	32185172	Overexpression of DUXAP8 promoted cell proliferation and migration of gastric cancer by epigenetically inhibiting PLEKHO1 expression.	('gastric cancer', 'Disease', 'MESH:D013274', (70, 84))	('expression', 'MPA', (122, 132))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('PLEKHO1', 'Gene', '51177', (114, 121))	('cell proliferation', 'CPA', (34, 52))	('gastric cancer', 'Disease', (70, 84))	('gastric cancer', 'Phenotype', 'HP:0012126', (70, 84))	('DUXAP8', 'Gene', (18, 24))	('migration', 'CPA', (57, 66))	('DUXAP8', 'Gene', '503637', (18, 24))	('promoted', 'PosReg', (25, 33))	('PLEKHO1', 'Gene', (114, 121))	('epigenetically', 'Var', (88, 102))
111925	32185172	High expression PTTG3P linked to large tumor size, increased tumor invasiveness and served as an unfavorable prognostic biomarker.	('High expression', 'Var', (0, 15))	('increased', 'PosReg', (51, 60))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('PTTG3P', 'Gene', '26255', (16, 22))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumor invasiveness', 'Disease', (61, 79))	('tumor invasiveness', 'Disease', 'MESH:D009361', (61, 79))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Disease', (39, 44))	('PTTG3P', 'Gene', (16, 22))	('tumor', 'Disease', (61, 66))
111926	32185172	Besides, the abilities of gastric cancer proliferation and invasion were enhanced after ectopic expression of PTTG3P.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('ectopic expression', 'Var', (88, 106))	('PTTG3P', 'Gene', '26255', (110, 116))	('gastric cancer proliferation', 'Disease', (26, 54))	('gastric cancer proliferation', 'Disease', 'MESH:D013274', (26, 54))	('PTTG3P', 'Gene', (110, 116))	('enhanced', 'PosReg', (73, 81))	('invasion', 'CPA', (59, 67))	('gastric cancer', 'Phenotype', 'HP:0012126', (26, 40))
111931	32185172	High SUMO1P3 level was reported to be associated with advanced histological stages, metastasis, angiogenesis and poor prognosis of colon cancer patients.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('colon cancer', 'Disease', 'MESH:D015179', (131, 143))	('associated', 'Reg', (38, 48))	('High', 'Var', (0, 4))	('SUMO1P3', 'Gene', (5, 12))	('colon cancer', 'Disease', (131, 143))	('metastasis', 'CPA', (84, 94))	('patients', 'Species', '9606', (144, 152))	('angiogenesis', 'CPA', (96, 108))	('colon cancer', 'Phenotype', 'HP:0003003', (131, 143))	('SUMO1P3', 'Gene', '474338', (5, 12))
111932	32185172	Inhibition of SUMO1P3 repressed proliferation, migration, invasion and pro-angiogenesis of colon cancer cells in vitro, and reduced growth, liver metastasis and vascularization of colon cancer in vivo by decreasing cyclin D1, vimentin and VEGFA but increasing E-cadherin expression.	('vimentin', 'Gene', (226, 234))	('colon cancer', 'Disease', 'MESH:D015179', (91, 103))	('E-cadherin', 'Gene', (260, 270))	('VEGFA', 'Gene', (239, 244))	('migration', 'CPA', (47, 56))	('E-cadherin', 'Gene', '999', (260, 270))	('vascularization', 'CPA', (161, 176))	('colon cancer', 'Disease', (180, 192))	('liver metastasis', 'Disease', (140, 156))	('expression', 'MPA', (271, 281))	('colon cancer', 'Disease', (91, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('cyclin D1', 'Gene', (215, 224))	('invasion', 'CPA', (58, 66))	('SUMO1P3', 'Gene', (14, 21))	('VEGFA', 'Gene', '7422', (239, 244))	('SUMO1P3', 'Gene', '474338', (14, 21))	('cyclin D1', 'Gene', '595', (215, 224))	('Inhibition', 'Var', (0, 10))	('colon cancer', 'Phenotype', 'HP:0003003', (180, 192))	('colon cancer', 'Phenotype', 'HP:0003003', (91, 103))	('pro-angiogenesis', 'CPA', (71, 87))	('reduced', 'NegReg', (124, 131))	('increasing', 'PosReg', (249, 259))	('liver metastasis', 'Disease', 'MESH:D009362', (140, 156))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('growth', 'CPA', (132, 138))	('vimentin', 'Gene', '7431', (226, 234))	('decreasing', 'NegReg', (204, 214))	('colon cancer', 'Disease', 'MESH:D015179', (180, 192))
111935	32185172	The authors also indicated that silencing expression of TPTE2P1 resulted in cell cycle arrest at S phase and caused cell apoptosis in colorectal cancer.	('cell cycle arrest at S phase', 'CPA', (76, 104))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (76, 93))	('colorectal cancer', 'Disease', (134, 151))	('cell apoptosis', 'CPA', (116, 130))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('silencing', 'Var', (32, 41))	('TPTE2P1', 'Gene', (56, 63))	('caused', 'Reg', (109, 115))	('colorectal cancer', 'Disease', 'MESH:D015179', (134, 151))	('TPTE2P1', 'Gene', '646405', (56, 63))	('colorectal cancer', 'Phenotype', 'HP:0003003', (134, 151))
111937	32185172	DUXAP8 was remarkably overexpressed in colorectal cancer and DUXAP8 knockdown led to inhibited proliferation, migration and invasion and enhanced apoptosis.	('enhanced', 'PosReg', (137, 145))	('DUXAP8', 'Gene', (0, 6))	('inhibited', 'NegReg', (85, 94))	('DUXAP8', 'Gene', '503637', (0, 6))	('colorectal cancer', 'Disease', 'MESH:D015179', (39, 56))	('knockdown', 'Var', (68, 77))	('colorectal cancer', 'Phenotype', 'HP:0003003', (39, 56))	('DUXAP8', 'Gene', (61, 67))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('invasion', 'CPA', (124, 132))	('apoptosis', 'CPA', (146, 155))	('DUXAP8', 'Gene', '503637', (61, 67))	('colorectal cancer', 'Disease', (39, 56))
111939	32185172	DUXAP10 promoted cell proliferation and cell cycle progression and blocked cell apoptosis by epigenetically silencing expression of p21 and PTEN.	('blocked', 'NegReg', (67, 74))	('cell apoptosis', 'CPA', (75, 89))	('cell proliferation', 'CPA', (17, 35))	('p21', 'Gene', '1026', (132, 135))	('DUXAP10', 'Gene', (0, 7))	('p21', 'Gene', (132, 135))	('epigenetically silencing', 'Var', (93, 117))	('DUXAP10', 'Gene', '503639', (0, 7))	('cell cycle progression', 'CPA', (40, 62))	('PTEN', 'Gene', (140, 144))	('promoted', 'PosReg', (8, 16))	('PTEN', 'Gene', '5728', (140, 144))
111943	32185172	reported that DUXAP8, upregulated in non-small cell lung cancer and an unfavorable prognostic biomarker, significantly facilitated cell growth, migration and invasion, and impaired apoptosis both in vitro and in vivo by epigenetically silencing EGR1 and RHOB.	('upregulated', 'PosReg', (22, 33))	('cell growth', 'CPA', (131, 142))	('epigenetically silencing', 'Var', (220, 244))	('EGR1', 'Gene', (245, 249))	('apoptosis', 'CPA', (181, 190))	('lung cancer', 'Phenotype', 'HP:0100526', (52, 63))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('EGR1', 'Gene', '1958', (245, 249))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (37, 63))	('impaired', 'NegReg', (172, 180))	('DUXAP8', 'Gene', (14, 20))	('DUXAP8', 'Gene', '503637', (14, 20))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (41, 63))	('RHOB', 'Gene', '388', (254, 258))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (37, 63))	('RHOB', 'Gene', (254, 258))	('facilitated', 'PosReg', (119, 130))	('non-small cell lung cancer', 'Disease', (37, 63))	('invasion', 'CPA', (158, 166))	('migration', 'CPA', (144, 153))
111945	32185172	Functional and mechanistic experiments suggested that DUXAP10 exerted oncogenic roles in non-small cell lung cancer by binding to LSD1 and epigenetic silencing expression of LATS2 and RRAD.	('small cell lung cancer', 'Phenotype', 'HP:0030357', (93, 115))	('DUXAP10', 'Gene', (54, 61))	('RRAD', 'Gene', (184, 188))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('RRAD', 'Gene', '6236', (184, 188))	('DUXAP10', 'Gene', '503639', (54, 61))	('LATS2', 'Gene', (174, 179))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (89, 115))	('LATS2', 'Gene', '26524', (174, 179))	('LSD1', 'Gene', '23028', (130, 134))	('lung cancer', 'Phenotype', 'HP:0100526', (104, 115))	('non-small cell lung cancer', 'Disease', (89, 115))	('epigenetic silencing', 'Var', (139, 159))	('LSD1', 'Gene', (130, 134))	('binding', 'Interaction', (119, 126))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (89, 115))
111952	32185172	also experimentally confirmed that knockdown of OGFRP1 suppressed the malignant behaviors of endometrial cancer, including suppressed cell viability, enhanced cell apoptosis and inhibited cell migration and invasion.	('knockdown', 'Var', (35, 44))	('OGFRP1', 'Gene', (48, 54))	('enhanced', 'PosReg', (150, 158))	('suppressed', 'NegReg', (123, 133))	('malignant behaviors of endometrial cancer', 'Disease', (70, 111))	('cell viability', 'CPA', (134, 148))	('endometrial cancer', 'Phenotype', 'HP:0012114', (93, 111))	('inhibited', 'NegReg', (178, 187))	('OGFRP1', 'Gene', '388906', (48, 54))	('suppressed', 'NegReg', (55, 65))	('malignant behaviors of endometrial cancer', 'Disease', 'MESH:D016889', (70, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('cell apoptosis', 'CPA', (159, 173))
111957	32185172	demonstrated that FTH1P3 was notably upregulated in esophageal squamous cell carcinoma and knockdown of FTH1P3 significantly inhibited proliferation, migration and invasion of esophageal squamous cell carcinoma cells by regulating SP1/NF-kB signaling.	('proliferation', 'CPA', (135, 148))	('invasion', 'CPA', (164, 172))	('esophageal squamous cell carcinoma', 'Disease', (176, 210))	('migration', 'CPA', (150, 159))	('upregulated', 'PosReg', (37, 48))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (63, 86))	('knockdown', 'Var', (91, 100))	('regulating', 'Reg', (220, 230))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:C562729', (52, 86))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (187, 210))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:C562729', (176, 210))	('SP1/NF-kB signaling', 'MPA', (231, 250))	('FTH1P3', 'Gene', (104, 110))	('FTH1P3', 'Gene', (18, 24))	('carcinoma', 'Phenotype', 'HP:0030731', (201, 210))	('FTH1P3', 'Gene', '2498', (104, 110))	('FTH1P3', 'Gene', '2498', (18, 24))	('esophageal squamous cell carcinoma', 'Disease', (52, 86))	('inhibited', 'NegReg', (125, 134))
111959	32185172	They also showed that DUXAP10 was positively correlated with poor prognosis and epigenetically silenced p21 by recruiting EZH2 to the promoter of p21, thereby promoting cell proliferation and metastasis.	('EZH2', 'Gene', (122, 126))	('EZH2', 'Gene', '2146', (122, 126))	('p21', 'Gene', '1026', (104, 107))	('p21', 'Gene', '1026', (146, 149))	('promoting', 'PosReg', (159, 168))	('p21', 'Gene', (104, 107))	('p21', 'Gene', (146, 149))	('DUXAP10', 'Gene', '503639', (22, 29))	('recruiting', 'PosReg', (111, 121))	('cell proliferation', 'CPA', (169, 187))	('metastasis', 'CPA', (192, 202))	('epigenetically silenced', 'Var', (80, 103))	('DUXAP10', 'Gene', (22, 29))
111967	32185172	By epigenetically silencing CDKN1A an KLF2, DUXAP8, upregulated in pancreatic cancer, promoted growth of pancreatic cancer.	('KLF2', 'Gene', (38, 42))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (105, 122))	('growth', 'MPA', (95, 101))	('epigenetically silencing', 'Var', (3, 27))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (67, 84))	('DUXAP8', 'Gene', '503637', (44, 50))	('pancreatic cancer', 'Disease', (105, 122))	('CDKN1A', 'Gene', (28, 34))	('DUXAP8', 'Gene', (44, 50))	('pancreatic cancer', 'Disease', 'MESH:D010190', (105, 122))	('pancreatic cancer', 'Disease', 'MESH:D010190', (67, 84))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('pancreatic cancer', 'Disease', (67, 84))	('CDKN1A', 'Gene', '1026', (28, 34))	('upregulated', 'PosReg', (52, 63))	('promoted', 'PosReg', (86, 94))	('KLF2', 'Gene', '10365', (38, 42))
111969	32185172	They also confirmed that knockdown of DUXAP10 could result in inhibited proliferation, migration, invasion and enhanced apoptosis in renal cell carcinoma through interacting with RNA-binding proteins, EZH2 and LSD1.	('migration', 'CPA', (87, 96))	('proliferation', 'CPA', (72, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('invasion', 'CPA', (98, 106))	('enhanced', 'PosReg', (111, 119))	('LSD1', 'Gene', (210, 214))	('LSD1', 'Gene', '23028', (210, 214))	('RNA-binding proteins', 'Protein', (179, 199))	('renal cell carcinoma', 'Disease', 'MESH:D002292', (133, 153))	('DUXAP10', 'Gene', '503639', (38, 45))	('knockdown', 'Var', (25, 34))	('renal cell carcinoma', 'Disease', (133, 153))	('apoptosis', 'CPA', (120, 129))	('DUXAP10', 'Gene', (38, 45))	('EZH2', 'Gene', '2146', (201, 205))	('inhibited', 'NegReg', (62, 71))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (133, 153))	('EZH2', 'Gene', (201, 205))	('interacting', 'Interaction', (162, 173))
111972	32185172	Furthermore, after knockdown of SUMO1P3, bladder cancer exhibited cell proliferation and migration inhibition and apoptosis induction.	('SUMO1P3', 'Gene', (32, 39))	('knockdown', 'Var', (19, 28))	('cell proliferation', 'CPA', (66, 84))	('migration inhibition', 'CPA', (89, 109))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('bladder cancer', 'Phenotype', 'HP:0009725', (41, 55))	('SUMO1P3', 'Gene', '474338', (32, 39))	('apoptosis induction', 'CPA', (114, 133))	('bladder cancer', 'Disease', 'MESH:D001749', (41, 55))	('bladder cancer', 'Disease', (41, 55))
111978	32185172	Two pseudogene-derived lncRNAs, TPTE2P1 and Loc344887, have been documented to play oncogenic roles in development of gallbladder cancer.	('TPTE2P1', 'Gene', '646405', (32, 39))	('bladder cancer', 'Phenotype', 'HP:0009725', (122, 136))	('gallbladder cancer', 'Disease', (118, 136))	('gallbladder cancer', 'Disease', 'MESH:D005706', (118, 136))	('ncRNA', 'Gene', (24, 29))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('Loc344887', 'Var', (44, 53))	('TPTE2P1', 'Gene', (32, 39))	('ncRNA', 'Gene', '220202', (24, 29))	('play', 'Reg', (79, 83))
111979	32185172	Depletion of TPTE2P1 significantly blocked epithelial-mesenchymal transition, migration and invasion of gallbladder cancer.	('epithelial-mesenchymal transition', 'CPA', (43, 76))	('TPTE2P1', 'Gene', (13, 20))	('invasion of gallbladder cancer', 'Disease', 'MESH:D005706', (92, 122))	('Depletion', 'Var', (0, 9))	('bladder cancer', 'Phenotype', 'HP:0009725', (108, 122))	('TPTE2P1', 'Gene', '646405', (13, 20))	('migration', 'CPA', (78, 87))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('blocked', 'NegReg', (35, 42))	('invasion of gallbladder cancer', 'Disease', (92, 122))
111980	32185172	Loc344887 was elevated in gallbladder cancer, was positively associated with larger tumor size, and facilitated cell proliferation, cell cycle progression, migration and invasion.	('cell proliferation', 'CPA', (112, 130))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('bladder cancer', 'Phenotype', 'HP:0009725', (30, 44))	('migration', 'CPA', (156, 165))	('tumor', 'Disease', (84, 89))	('gallbladder cancer', 'Disease', (26, 44))	('gallbladder cancer', 'Disease', 'MESH:D005706', (26, 44))	('cell cycle progression', 'CPA', (132, 154))	('facilitated', 'PosReg', (100, 111))	('associated', 'Reg', (61, 71))	('invasion', 'CPA', (170, 178))	('Loc344887', 'Var', (0, 9))	('elevated', 'Reg', (14, 22))
111982	32185172	confirmed FTH1P3 was significantly upregulated in laryngeal squamous cell cancer and positively linked to the poor differentiation, high T classification, positive lymph node metastasis and advanced clinical stage.	('poor differentiation', 'CPA', (110, 130))	('FTH1P3', 'Gene', '2498', (10, 16))	('linked', 'Reg', (96, 102))	('laryngeal squamous cell cancer', 'Disease', 'MESH:D018307', (50, 80))	('positive lymph node metastasis', 'CPA', (155, 185))	('laryngeal squamous cell cancer', 'Disease', (50, 80))	('upregulated', 'PosReg', (35, 46))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (60, 80))	('high', 'Var', (132, 136))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('FTH1P3', 'Gene', (10, 16))
112000	32185172	Apart from PTENP1, some pseudogene-derived lncRNAs were also demonstrated to be downregulated in gastric cancer and play tumor suppressive roles in gastric cancer progression.	('gastric cancer', 'Disease', (97, 111))	('gastric cancer', 'Disease', (148, 162))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('gastric cancer', 'Disease', 'MESH:D013274', (97, 111))	('gastric cancer', 'Disease', 'MESH:D013274', (148, 162))	('ncRNA', 'Gene', (44, 49))	('tumor', 'Disease', (121, 126))	('gastric cancer', 'Phenotype', 'HP:0012126', (97, 111))	('tumor', 'Disease', 'MESH:D009369', (121, 126))	('gastric cancer', 'Phenotype', 'HP:0012126', (148, 162))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('downregulated', 'NegReg', (80, 93))	('PTENP1', 'Gene', (11, 17))	('ncRNA', 'Gene', '220202', (44, 49))	('PTENP1', 'Gene', '11191', (11, 17))	('pseudogene-derived', 'Var', (24, 42))
112011	32185172	The investigation performed by the group of Johnson G demonstrated that silencing of NMRAL2P could protect against sulforaphane-mediated inhibition of cell growth, colony formation and migration in colon cancer.	('sulforaphane-mediated inhibition', 'MPA', (115, 147))	('silencing', 'Var', (72, 81))	('colon cancer', 'Phenotype', 'HP:0003003', (198, 210))	('colon cancer', 'Disease', 'MESH:D015179', (198, 210))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('NMRAL2P', 'Gene', (85, 92))	('sulforaphane', 'Chemical', 'MESH:C016766', (115, 127))	('colon cancer', 'Disease', (198, 210))	('NMRAL2P', 'Gene', '344887', (85, 92))	('colony formation', 'CPA', (164, 180))	('cell growth', 'CPA', (151, 162))	('migration', 'CPA', (185, 194))
112021	32185172	Subsequently, they also validated that HERC2P2 overexpression attenuated migration and colony formation abilities of glioma in vitro and inhibited glioma xenograft growth in vivo.	('glioma', 'Disease', (117, 123))	('attenuated', 'NegReg', (62, 72))	('inhibited', 'NegReg', (137, 146))	('glioma', 'Disease', 'MESH:D005910', (147, 153))	('glioma', 'Disease', 'MESH:D005910', (117, 123))	('glioma', 'Phenotype', 'HP:0009733', (147, 153))	('glioma', 'Phenotype', 'HP:0009733', (117, 123))	('HERC2P2', 'Gene', (39, 46))	('HERC2P2', 'Gene', '400322', (39, 46))	('glioma', 'Disease', (147, 153))	('overexpression', 'Var', (47, 61))
112032	32185172	Over the past decades, pseudogenes have been documented to play crucial roles in diverse cancer types in DNA, RNA and protein levels.	('DNA', 'MPA', (105, 108))	('pseudogenes', 'Var', (23, 34))	('protein levels', 'MPA', (118, 132))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('cancer', 'Disease', (89, 95))	('roles', 'Reg', (72, 77))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
112045	32185172	also suggested a FTH1 gene: pseudogene: microRNA modulated tumorigenesis in prostate cancer.	('modulated', 'Reg', (49, 58))	('tumor', 'Disease', (59, 64))	('microRNA', 'Var', (40, 48))	('prostate cancer', 'Disease', 'MESH:D011471', (76, 91))	('prostate cancer', 'Phenotype', 'HP:0012125', (76, 91))	('FTH1', 'Gene', (17, 21))	('FTH1', 'Gene', '2495', (17, 21))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('prostate cancer', 'Disease', (76, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
112048	32185172	confirmed that FLT1P1 antisense transcript suppressed VEGFA by interaction with miR-520a and inhibited tumor cell proliferation and xenograft tumor growth.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('VEGFA', 'Gene', '7422', (54, 59))	('tumor', 'Disease', (103, 108))	('tumor', 'Disease', (142, 147))	('interaction', 'Interaction', (63, 74))	('miR-520a', 'Gene', (80, 88))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('antisense', 'Var', (22, 31))	('miR-520a', 'Gene', '574467', (80, 88))	('FLT1P1', 'Gene', (15, 21))	('VEGFA', 'Gene', (54, 59))	('FLT1P1', 'Gene', '391533', (15, 21))	('inhibited', 'NegReg', (93, 102))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('suppressed', 'NegReg', (43, 53))
112054	32185172	for the first time, reported HMGA1 pseudogenes as candidate proto-oncogenic ceRNAs, including HMGA1P6 and HMGA1P7.	('HMGA1', 'Gene', (29, 34))	('HMGA1', 'Gene', '3159', (29, 34))	('HMGA1P7', 'Gene', (106, 113))	('HMGA1', 'Gene', (106, 111))	('HMGA1P6', 'Gene', '100130029', (94, 101))	('HMGA1P6', 'Gene', (94, 101))	('HMGA1P7', 'Gene', '387065', (106, 113))	('HMGA1', 'Gene', '3159', (106, 111))	('pseudogenes', 'Var', (35, 46))	('HMGA1', 'Gene', (94, 99))	('HMGA1', 'Gene', '3159', (94, 99))
112055	32185172	HMGA1P7 was found to increase H19 and lgf2 expression by acting as decoy for miR-15, miR-16, miR-214, and miR-761.	('miR-16', 'Gene', '51573', (85, 91))	('miR-214', 'Gene', (93, 100))	('HMGA1P7', 'Gene', '387065', (0, 7))	('miR-15', 'Var', (77, 83))	('HMGA1P7', 'Gene', (0, 7))	('miR-214', 'Gene', '406996', (93, 100))	('lgf2', 'Gene', (38, 42))	('expression', 'MPA', (43, 53))	('increase', 'PosReg', (21, 29))	('miR-16', 'Gene', (85, 91))	('miR-761', 'Gene', '100313892', (106, 113))	('H19', 'Gene', '283120', (30, 33))	('H19', 'Gene', (30, 33))	('miR-761', 'Gene', (106, 113))
112059	32185172	OCT4-pg5 also upregulated OCT4 by sponging miR-145 and thus facilitated cell proliferation of endometrial carcinoma.	('sponging', 'Var', (34, 42))	('OCT4-pg5', 'Gene', (0, 8))	('OCT4-pg5', 'Gene', '100009667', (0, 8))	('facilitated', 'PosReg', (60, 71))	('miR-145', 'Gene', (43, 50))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (94, 115))	('OCT4', 'Gene', '5460', (26, 30))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('cell proliferation', 'CPA', (72, 90))	('miR-145', 'Gene', '406937', (43, 50))	('upregulated', 'PosReg', (14, 25))	('endometrial carcinoma', 'Disease', (94, 115))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (94, 115))	('OCT4', 'Gene', (26, 30))	('OCT4', 'Gene', '5460', (0, 4))	('OCT4', 'Gene', (0, 4))
112061	32185172	suggested that PTTG3P expression positively associated with PTTG1 expression and may function by sponging miR-129-5p, miR-383-5p, and miR-376c-3p.	('associated', 'Reg', (44, 54))	('miR-376c-3p', 'Var', (134, 145))	('PTTG1', 'Gene', (60, 65))	('miR-383', 'Gene', '494332', (118, 125))	('PTTG1', 'Gene', '9232', (60, 65))	('expression', 'MPA', (66, 76))	('miR-129-5p', 'Gene', '100302178', (106, 116))	('PTTG3P', 'Gene', '26255', (15, 21))	('miR-383', 'Gene', (118, 125))	('miR-129-5p', 'Gene', (106, 116))	('PTTG3P', 'Gene', (15, 21))
112066	32185172	What's more, TUSC2P promotes those functions by binding miR-17, miR-93, miR-299-3p, miR-520a, miR-608, and miR-661 according to the research conducted by.	('miR-93', 'Gene', (64, 70))	('miR-661', 'Gene', (107, 114))	('miR-17', 'Gene', (56, 62))	('promotes', 'PosReg', (20, 28))	('miR-17', 'Gene', '406952', (56, 62))	('miR-661', 'Gene', '724031', (107, 114))	('binding', 'Interaction', (48, 55))	('miR-520a', 'Gene', (84, 92))	('miR-608', 'Gene', (94, 101))	('TUSC2P', 'Gene', (13, 19))	('miR-608', 'Gene', '693193', (94, 101))	('miR-520a', 'Gene', '574467', (84, 92))	('TUSC2P', 'Gene', '359794', (13, 19))	('miR-93', 'Gene', '407051', (64, 70))	('miR-299-3p', 'Var', (72, 82))
112067	32185172	ASS1P3, a pseudogene of ASS1, promoted cell proliferation by functioning as a miRNA decoy for miR-34a-5p in renal cell carcinoma reported by the team of.	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (108, 128))	('ASS1', 'Gene', '445', (0, 4))	('ASS1', 'Gene', (24, 28))	('ASS1P3', 'Gene', '158452', (0, 6))	('ASS1', 'Gene', '445', (24, 28))	('promoted', 'PosReg', (30, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('cell proliferation', 'CPA', (39, 57))	('ASS1P3', 'Gene', (0, 6))	('miR-34a-5p', 'Var', (94, 104))	('renal cell carcinoma', 'Disease', 'MESH:D002292', (108, 128))	('ASS1', 'Gene', (0, 4))	('renal cell carcinoma', 'Disease', (108, 128))
112069	32185172	CYP2A7P was discovered to affect expression of its cognate gene CYP2A6 by functioning as a decoy for miR-126 in human liver.	('CYP2A6', 'Gene', '1548', (64, 70))	('affect', 'Reg', (26, 32))	('CYP2A6', 'Gene', (64, 70))	('miR-126', 'Gene', '406913', (101, 108))	('expression', 'MPA', (33, 43))	('human', 'Species', '9606', (112, 117))	('miR-126', 'Gene', (101, 108))	('CYP2A7P', 'Var', (0, 7))
112072	32185172	By luciferase reporter assay, the authors confirmed that FOXO3P exerted its roles through sponging several miRNAs, including miR-22, miR-136*, miR-138, miR-149*, miR-433, miR-762, miR-3614-5p, and miR-3622b-5p.	('miR-149', 'Gene', '406941', (152, 159))	('miR-136', 'Gene', '406927', (133, 140))	('miR-22', 'Gene', '407004', (125, 131))	('FOXO3', 'Gene', (57, 62))	('miR-3614', 'Gene', '100500827', (180, 188))	('miR-22', 'Gene', (125, 131))	('sponging', 'Reg', (90, 98))	('miR-138', 'Var', (143, 150))	('miR-3622b-5p', 'Var', (197, 209))	('miR-433', 'Gene', (162, 169))	('FOXO3', 'Gene', '2309', (57, 62))	('miR-433', 'Gene', '574034', (162, 169))	('miR-762', 'Gene', (171, 178))	('miR-762', 'Gene', '100313837', (171, 178))	('miR-149', 'Gene', (152, 159))	('miR-3614', 'Gene', (180, 188))	('miR-136', 'Gene', (133, 140))
112073	32185172	GBA encodes lysosomal glucocerebrosidase and its mutations are associated with Parkinson's disease.	('glucocerebrosidase', 'Disease', 'MESH:D005776', (22, 40))	("Parkinson's disease", 'Disease', 'MESH:D010300', (79, 98))	('mutations', 'Var', (49, 58))	('GBA', 'Gene', '2629', (0, 3))	('associated', 'Reg', (63, 73))	('GBA', 'Gene', (0, 3))	('glucocerebrosidase', 'Disease', (22, 40))	("Parkinson's disease", 'Disease', (79, 98))
112088	32185172	Furthermore, seven miRNAs binding with RP11-564D11.3 were predicted, including miR-200b-3p, miR-200a-3p, miR-429, miR-101-3p, miR-9-5p, miR-200c-3p, and miR-141-3p.	('miR-429', 'Gene', (105, 112))	('miR-141-3p', 'Var', (153, 163))	('miR-9-5p', 'Gene', (126, 134))	('miR-9-5p', 'Gene', '407052', (126, 134))	('miR-101-3p', 'Var', (114, 124))	('RP11', 'Gene', (39, 43))	('miR-200b-3p', 'Var', (79, 90))	('RP11', 'Gene', '26121', (39, 43))	('binding', 'Interaction', (26, 33))	('miR-200c-3p', 'Var', (136, 147))	('miR-200a-3p', 'Var', (92, 103))	('miR-429', 'Gene', '554210', (105, 112))
112108	32185172	Expression and/or function dysregulation of these RNA transcripts account for the occurrence of multiple human disorders, containing cancer.	('occurrence', 'Reg', (82, 92))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('function', 'MPA', (18, 26))	('cancer', 'Disease', (133, 139))	('dysregulation', 'Var', (27, 40))	('account', 'Reg', (66, 73))	('human', 'Species', '9606', (105, 110))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
112119	32185172	Of course, the current findings about roles and mechanisms of known pseudogene-derived lncRNAs need to be further precisely validated by basic lab experiments and large clinical trials.	('ncRNA', 'Gene', (88, 93))	('pseudogene-derived', 'Var', (68, 86))	('ncRNA', 'Gene', '220202', (88, 93))
112146	33373169	16  Other studies have been carried out to examine the proliferation, overexpression or mutation of TFAP4 in specific types of cancer, but those studies had low sample sizes and diverse methods.	('mutation', 'Var', (88, 96))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('overexpression', 'PosReg', (70, 84))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('cancer', 'Disease', (127, 133))	('TFAP4', 'Gene', (100, 105))	('TFAP4', 'Gene', '7023', (100, 105))
112172	33373169	TMB measures the mutation number in a specific cancer genome.	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('TMB', 'Chemical', '-', (0, 3))	('cancer', 'Disease', (47, 53))	('mutation', 'Var', (17, 25))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))
112191	33373169	In the OS analysis, Cox regression identified that high TFAP4 expression was a risk factor for ACC (P = .049), KIRC (P < .001), KIRP (P < .001), SKCM (P = .026) and LIHC (P < .001); however, it appeared to be a protective factor in UVM (P = .009), READ (P = .012), STAD (P = .046) and LGG (P = .008), as shown in Figure 3A and Table 1.	('TFAP4', 'Gene', '7023', (56, 61))	('SKCM', 'Disease', (145, 149))	('LGG', 'Disease', (285, 288))	('STAD', 'Disease', (265, 269))	('ACC', 'Disease', (95, 98))	('high', 'Var', (51, 55))	('UVM', 'Disease', (232, 235))	('TFAP4', 'Gene', (56, 61))
112192	33373169	KM analysis showed that patients with higher TFAP4 levels had a shorter OS compared with patients with lower TFAP4 levels in KIRC (P = .010), KIRP (P < .001), LIHC (P = .050) and UCEC (P = .015), whereas those with increased TFAP4 levels showed a superior OS to those with decreased TFAP4 levels in READ (P = .045), THYM (P = .038) and UVM (P = .004), as seen in Figure 3B-H. Cox regression analysis of DSS identified that high TFAP4 expression was a risk factor in KIRC (P < .001), LIHC (P = .019), KIRP (P < .001), SKCM (P = .019) and THCA (P = .014).	('KIRC', 'Disease', (466, 470))	('SKCM', 'Disease', (517, 521))	('DSS', 'Chemical', '-', (403, 406))	('high', 'Var', (423, 427))	('THCA', 'Chemical', '-', (537, 541))	('TFAP4', 'Gene', (428, 433))	('TFAP4', 'Gene', '7023', (428, 433))	('TFAP4', 'Gene', (283, 288))	('TFAP4', 'Gene', (109, 114))	('TFAP4', 'Gene', '7023', (283, 288))	('LIHC', 'Disease', (483, 487))	('TFAP4', 'Gene', '7023', (109, 114))	('TFAP4', 'Gene', (45, 50))	('TFAP4', 'Gene', (225, 230))	('TFAP4', 'Gene', '7023', (45, 50))	('TFAP4', 'Gene', '7023', (225, 230))	('lower TFAP4 levels', 'Phenotype', 'HP:0040209', (103, 121))	('KIRP', 'Disease', (500, 504))	('patients', 'Species', '9606', (89, 97))	('patients', 'Species', '9606', (24, 32))	('THCA', 'Disease', (537, 541))
112194	33373169	Patients with increased TFAP4 levels showed superior DSS to those with decreased TFAP4 levels in BRCA (P = .046) and UVM (P < .001), as seen in Figure 4B-G. Cox regression analysis of PFI identified high TFAP4 expression as a risk factor in ACC (P = .010), KIRP (P = .032), KIRC (P < .001), PRAD (P = .001), LIHC (P < .001), THCA (P = .004) and UCEC (P = .008), while it was a protective factor in GBM (P = .004), LGG (P < .001) and LUSC (P = .017) (Figure 5A).	('PRAD', 'Disease', (291, 295))	('KIRC', 'Disease', (274, 278))	('TFAP4', 'Gene', (81, 86))	('high', 'Var', (199, 203))	('LGG', 'Disease', (414, 417))	('TFAP4', 'Gene', (24, 29))	('TFAP4', 'Gene', '7023', (81, 86))	('THCA', 'Chemical', '-', (325, 329))	('TFAP4', 'Gene', '7023', (24, 29))	('Patients', 'Species', '9606', (0, 8))	('KIRP', 'Disease', (257, 261))	('decreased TFAP4 levels in BRCA', 'Phenotype', 'HP:0040209', (71, 101))	('TFAP4', 'Gene', (204, 209))	('DSS', 'Chemical', '-', (53, 56))	('UCEC', 'Disease', (345, 349))	('TFAP4', 'Gene', '7023', (204, 209))	('LIHC', 'Disease', (308, 312))	('THCA', 'Disease', (325, 329))	('ACC', 'Disease', (241, 244))
112222	33373169	We also found that most cancer types had a higher number of TFAP4 alternations, and that abnormal TFAP4 expression served as a prognostic factor in some types of cancer, based on both Cox and KM survival analyses.	('alternations', 'Var', (66, 78))	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('abnormal', 'Var', (89, 97))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('cancer', 'Disease', (162, 168))	('TFAP4', 'Gene', (98, 103))	('TFAP4', 'Gene', (60, 65))	('TFAP4', 'Gene', '7023', (98, 103))	('cancer', 'Disease', (24, 30))	('cancer', 'Disease', 'MESH:D009369', (24, 30))	('TFAP4', 'Gene', '7023', (60, 65))	('expression', 'MPA', (104, 114))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))
112244	33373169	32  Specific gene mutations may predict patient prognosis and treatment response.	('patient', 'Species', '9606', (40, 47))	('predict', 'Reg', (32, 39))	('mutations', 'Var', (18, 27))
112282	31952975	Therefore, advanced cutaneous squamous cell carcinoma is a life-threatening condition for patients who are treated with cytotoxic chemotherapy or EGFR inhibitors, and it is associated with substantial morbidity, impact on quality of life, and health-care burden.	('EGFR', 'Gene', '1956', (146, 150))	('cutaneous squamous cell carcinoma', 'Disease', 'MESH:D002294', (20, 53))	('cutaneous squamous cell carcinoma', 'Phenotype', 'HP:0006739', (20, 53))	('EGFR', 'Gene', (146, 150))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (30, 53))	('inhibitors', 'Var', (151, 161))	('carcinoma', 'Phenotype', 'HP:0030731', (44, 53))	('patients', 'Species', '9606', (90, 98))	('cutaneous squamous cell carcinoma', 'Disease', (20, 53))
112284	31952975	Because of ultraviolet-mediated mutagenesis, the median tumour mutational burden of cutaneous squamous cell carcinoma is approximately 45 mutations per megabase, three times higher than that of skin melanoma.	('cutaneous squamous cell carcinoma', 'Disease', 'MESH:D002294', (84, 117))	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (94, 117))	('tumour', 'Phenotype', 'HP:0002664', (56, 62))	('cutaneous squamous cell carcinoma', 'Disease', (84, 117))	('skin melanoma', 'Disease', 'MESH:D008545', (194, 207))	('tumour', 'Disease', 'MESH:D009369', (56, 62))	('cutaneous squamous cell carcinoma', 'Phenotype', 'HP:0006739', (84, 117))	('melanoma', 'Phenotype', 'HP:0002861', (199, 207))	('skin melanoma', 'Disease', (194, 207))	('tumour', 'Disease', (56, 62))	('mutations', 'Var', (138, 147))
112285	31952975	High tumour mutational burden has been associated with efficacy of programmed cell death 1 (PD-1) checkpoint inhibition in various advanced solid tumour types.	('PD-1', 'Gene', (92, 96))	('tumour', 'Disease', 'MESH:D009369', (5, 11))	('High tumour', 'Disease', 'MESH:D009369', (0, 11))	('tumour', 'Disease', (146, 152))	('PD-1', 'Gene', '5133', (92, 96))	('tumour', 'Disease', (5, 11))	('mutational', 'Var', (12, 22))	('tumour', 'Phenotype', 'HP:0002664', (146, 152))	('programmed cell death 1', 'Gene', '5133', (67, 90))	('programmed cell death 1', 'Gene', (67, 90))	('High tumour', 'Disease', (0, 11))	('tumour', 'Phenotype', 'HP:0002664', (5, 11))	('tumour', 'Disease', 'MESH:D009369', (146, 152))
112293	31952975	Acceptable reasons for surgery to be considered inappropriate were cutaneous squamous cell carcinoma with substantial local invasion that precluded complete resection; cutaneous squamous cell carcinoma that was technically amenable to surgery, but clinically inappropriate because of the lesion being in an anatomically challenging location for which surgery might result in severe disfigurement or dysfunction; cutaneous squamous cell carcinoma that was technically amenable to surgery, but clinically inappropriate because of the lesion being in the same location after two or more surgical procedures and with curative resection deemed unlikely; or other conditions deemed contraindicating for surgery.	('dysfunction', 'Disease', (399, 410))	('cutaneous squamous cell carcinoma', 'Phenotype', 'HP:0006739', (412, 445))	('cutaneous squamous cell carcinoma', 'Phenotype', 'HP:0006739', (168, 201))	('cutaneous squamous cell carcinoma', 'Disease', (67, 100))	('result', 'Reg', (365, 371))	('carcinoma', 'Phenotype', 'HP:0030731', (192, 201))	('cutaneous squamous cell carcinoma', 'Disease', 'MESH:D002294', (67, 100))	('surgery', 'Var', (351, 358))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (77, 100))	('cutaneous squamous cell carcinoma', 'Disease', (412, 445))	('carcinoma', 'Phenotype', 'HP:0030731', (436, 445))	('cutaneous squamous cell carcinoma', 'Disease', (168, 201))	('cutaneous squamous cell carcinoma', 'Disease', 'MESH:D002294', (412, 445))	('cutaneous squamous cell carcinoma', 'Disease', 'MESH:D002294', (168, 201))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (178, 201))	('cutaneous squamous cell carcinoma', 'Phenotype', 'HP:0006739', (67, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (422, 445))	('severe disfigurement', 'Disease', (375, 395))
112316	31952975	Tumour mutational burden was estimated in the DNA samples extracted from the formalin-fixed paraffin embedded tumour biopsies with the analytically validated TruSight Oncology 500 (Illumina, San Diego, CA, USA) to detect single nucleotide variants, insertions and deletions, copy number alterations in 500 genes, and a selected set of gene rearrangements.	('insertions', 'Var', (249, 259))	('500', 'Gene', (302, 305))	('single nucleotide variants', 'Var', (221, 247))	('copy number alterations', 'Var', (275, 298))	('formalin', 'Chemical', 'MESH:D005557', (77, 85))	('Oncology', 'Phenotype', 'HP:0002664', (167, 175))	('deletions', 'Var', (264, 273))	('tumour', 'Phenotype', 'HP:0002664', (110, 116))	('paraffin', 'Chemical', 'MESH:D010232', (92, 100))	('Tumour', 'Phenotype', 'HP:0002664', (0, 6))	('tumour', 'Disease', 'MESH:D009369', (110, 116))	('tumour', 'Disease', (110, 116))
112361	31952975	Median tumour mutational burden was 74 (IQR 46-100) mutations per megabase among 21 responders and 29 (4-59) mutations per megabase among 29 non-responders (as per independent central review for both groups) (figure 3).	('mutations', 'Var', (52, 61))	('tumour', 'Phenotype', 'HP:0002664', (7, 13))	('tumour', 'Disease', 'MESH:D009369', (7, 13))	('tumour', 'Disease', (7, 13))
112362	31952975	Among 29 patients who achieved durable disease control, median tumour mutational burden was 65 (IQR 19-100) mutations per megabase and among 21 patients who did not, it was 31 (7-56) mutations per megabase, as per independent central review for both groups (figure 3).	('patients', 'Species', '9606', (9, 17))	('mutations', 'Var', (108, 117))	('tumour', 'Phenotype', 'HP:0002664', (63, 69))	('patients', 'Species', '9606', (144, 152))	('tumour', 'Disease', 'MESH:D009369', (63, 69))	('tumour', 'Disease', (63, 69))
112367	31952975	Six (8%) of the 78 patients discontinued treatment because of the following treatment-related adverse events: grade 4 pneumonia and grade 4 pneumonitis in one patient; grade 3 hepatitis, grade 3 increased alanine aminotransferase, grade 3 elevated aspartate aminotransferase, and grade 3 increased alkaline phosphatase in the second patient; and the following in each of the remaining four patients: grade 4 pneumonitis, grade 3 proctitis, grade 3 encephalitis, and grade 1 arthralgia.	('pneumonitis', 'Disease', 'MESH:D011014', (140, 151))	('patient', 'Species', '9606', (19, 26))	('alanine aminotransferase', 'Gene', '2875', (205, 229))	('hepatitis', 'Phenotype', 'HP:0012115', (176, 185))	('increased alkaline phosphatase', 'Phenotype', 'HP:0003155', (288, 318))	('pneumonia', 'Disease', (118, 127))	('pneumonitis', 'Disease', (140, 151))	('arthralgia', 'Phenotype', 'HP:0002829', (474, 484))	('hepatitis', 'Disease', 'MESH:D056486', (176, 185))	('patient', 'Species', '9606', (159, 166))	('increased', 'PosReg', (195, 204))	('arthralgia', 'Disease', 'MESH:D018771', (474, 484))	('patient', 'Species', '9606', (390, 397))	('pneumonitis', 'Disease', 'MESH:D011014', (408, 419))	('patient', 'Species', '9606', (333, 340))	('arthralgia', 'Disease', (474, 484))	('hepatitis', 'Disease', (176, 185))	('pneumonitis', 'Disease', (408, 419))	('encephalitis', 'Disease', (448, 460))	('alkaline phosphatase', 'MPA', (298, 318))	('patients', 'Species', '9606', (19, 27))	('elevated', 'PosReg', (239, 247))	('elevated aspartate aminotransferase', 'Phenotype', 'HP:0031956', (239, 274))	('grade', 'Disease', (440, 445))	('encephalitis', 'Disease', 'MESH:D004660', (448, 460))	('increased', 'PosReg', (288, 297))	('aspartate aminotransferase', 'MPA', (248, 274))	('pneumonia', 'Phenotype', 'HP:0002090', (118, 127))	('encephalitis', 'Phenotype', 'HP:0002383', (448, 460))	('grade', 'Var', (187, 192))	('patients', 'Species', '9606', (390, 398))	('pneumonia', 'Disease', 'MESH:D011014', (118, 127))	('increased alanine aminotransferase', 'Phenotype', 'HP:0031964', (195, 229))	('increased alanine', 'Phenotype', 'HP:0003348', (195, 212))	('alanine aminotransferase', 'Gene', (205, 229))	('grade', 'Disease', (421, 426))	('elevated aspartate', 'Phenotype', 'HP:0500159', (239, 257))
112389	31952975	Recent findings suggest that the characteristics of the mutations (eg, insertions and deletions vs substitutions) are an important determinant of the association between tumour mutational burden and responsiveness.	('tumour', 'Disease', (170, 176))	('deletions', 'Var', (86, 95))	('tumour', 'Phenotype', 'HP:0002664', (170, 176))	('insertions', 'Var', (71, 81))	('tumour', 'Disease', 'MESH:D009369', (170, 176))
112425	33127882	We found that mMFI2 promoted the expression of EMT's common marker N-cadherin by downregulating the transcription factor KLI4, which in turn promoted tumor metastasis; sMFI2 could promote the metastasis of autologous tumor cells in an autocrine manner but the mechanism is different from that of mMFI2.	('mMFI2', 'Gene', '30060', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('N-cadherin', 'Gene', (67, 77))	('N-cadherin', 'Gene', '1000', (67, 77))	('tumor', 'Disease', (217, 222))	('tumor', 'Disease', 'MESH:D009369', (217, 222))	('promoted', 'PosReg', (141, 149))	('tumor metastasis', 'Disease', 'MESH:D009362', (150, 166))	('mMFI2', 'Gene', (296, 301))	('sMFI2', 'Var', (168, 173))	('mMFI2', 'Gene', '30060', (296, 301))	('promote', 'PosReg', (180, 187))	('tumor', 'Disease', (150, 155))	('downregulating', 'NegReg', (81, 95))	('EMT', 'Gene', (47, 50))	('tumor metastasis', 'Disease', (150, 166))	('EMT', 'Gene', '3702', (47, 50))	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('sMFI2', 'Chemical', '-', (168, 173))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('mMFI2', 'Gene', (14, 19))
112426	33127882	In addition, sMFI2 was proved could inhibit the migration of vascular endothelial cells and subsequently enhance angiogenic responses in a paracrine manner.	('sMFI2', 'Var', (13, 18))	('sMFI2', 'Chemical', '-', (13, 18))	('inhibit', 'NegReg', (36, 43))	('migration of vascular endothelial cells', 'CPA', (48, 87))	('enhance', 'PosReg', (105, 112))	('angiogenic responses', 'CPA', (113, 133))
112434	33127882	Currently, a variety of cancer-related cell surface protein disorders including changes in expression levels or protein variants have been widely reported.	('changes', 'Reg', (80, 87))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('variants', 'Var', (120, 128))	('protein', 'MPA', (112, 119))	('cancer', 'Disease', (24, 30))	('cancer', 'Disease', 'MESH:D009369', (24, 30))	('expression levels', 'MPA', (91, 108))
112452	33127882	Compared with normal cells, expression of MFI2 was high in H226, intermediate in A549, but clearly low in H1299 and H460 (Fig.	('low', 'NegReg', (99, 102))	('H460', 'Chemical', '-', (116, 120))	('expression', 'MPA', (28, 38))	('MFI2', 'Gene', (42, 46))	('H226', 'Var', (59, 63))	('high', 'PosReg', (51, 55))
112458	33127882	2I-M) and knockdown of mMFI2 significantly inhibited migration and invasion of A549 and H226 cell lines (Fig.	('inhibited', 'NegReg', (43, 52))	('mMFI2', 'Gene', (23, 28))	('knockdown', 'Var', (10, 19))	('mMFI2', 'Gene', '30060', (23, 28))
112460	33127882	In order to explain this phenomenon, we screened a protein chip containing 35 apoptosis-related key proteins in mMFI2 overexpressing and non-overexpressing cell lines.	('mMFI2', 'Gene', (112, 117))	('overexpressing', 'Var', (118, 132))	('mMFI2', 'Gene', '30060', (112, 117))
112465	33127882	In order to prove the regulatory effect of mMFI2 on N-cadherin, we deliberately knocked down N-cadherin to observe whether the biological function of mMFI2 changed.	('knocked', 'Var', (80, 87))	('mMFI2', 'Gene', '30060', (43, 48))	('mMFI2', 'Gene', '30060', (150, 155))	('N-cadherin', 'Gene', (52, 62))	('N-cadherin', 'Gene', (93, 103))	('mMFI2', 'Gene', (43, 48))	('mMFI2', 'Gene', (150, 155))	('N-cadherin', 'Gene', '1000', (52, 62))	('N-cadherin', 'Gene', '1000', (93, 103))
112466	33127882	3G and H. We found that the increased cell migration and invasion capacity by mMFI2 was attenuated by knockdown of N-cadherin expression (Fig.	('increased', 'PosReg', (28, 37))	('cell migration', 'CPA', (38, 52))	('mMFI2', 'Gene', '30060', (78, 83))	('knockdown', 'Var', (102, 111))	('mMFI2', 'Gene', (78, 83))	('N-cadherin', 'Gene', (115, 125))	('attenuated', 'NegReg', (88, 98))	('N-cadherin', 'Gene', '1000', (115, 125))	('invasion capacity', 'CPA', (57, 74))
112475	33127882	To verify the ability of mMFI2 to promote metastasis in vivo, A549 cells with knockdown or overexpression of MFI2, and control cells were injected into the blood of NOD/SCID mice by tail vein in an amount of 2 x 106/mouse.	('SCID', 'Disease', 'MESH:D053632', (169, 173))	('mouse', 'Species', '10090', (216, 221))	('SCID', 'Disease', (169, 173))	('mMFI2', 'Gene', (25, 30))	('overexpression', 'PosReg', (91, 105))	('mice', 'Species', '10090', (174, 178))	('mMFI2', 'Gene', '30060', (25, 30))	('knockdown', 'Var', (78, 87))	('metastasis', 'CPA', (42, 52))	('MFI2', 'Gene', (109, 113))
112477	33127882	The mouse overexpressing mMFI2 had more lung metastases than the control group, but the mouse with mMFI2 knockdown showed a significant decrease in metastatic nodules relative to the control group (Fig.	('mouse', 'Species', '10090', (4, 9))	('mMFI2', 'Gene', (25, 30))	('metastases', 'Disease', 'MESH:D009362', (45, 55))	('decrease', 'NegReg', (136, 144))	('knockdown', 'Var', (105, 114))	('mMFI2', 'Gene', '30060', (99, 104))	('metastatic nodules', 'CPA', (148, 166))	('mouse', 'Species', '10090', (88, 93))	('mMFI2', 'Gene', '30060', (25, 30))	('mMFI2', 'Gene', (99, 104))	('metastases', 'Disease', (45, 55))
112481	33127882	Then we explored whether sMFI2 could promote tumor cell metastasis like mMFI2, as they might only differ in structure by a GPI-anchored protein.	('mMFI2', 'Gene', (72, 77))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('promote', 'PosReg', (37, 44))	('sMFI2', 'Var', (25, 30))	('tumor', 'Disease', (45, 50))	('GPI-anchored', 'Disease', (123, 135))	('sMFI2', 'Chemical', '-', (25, 30))	('GPI-anchored', 'Disease', 'MESH:C537277', (123, 135))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('mMFI2', 'Gene', '30060', (72, 77))
112491	33127882	The above experiments demonstrated that sMFI2 could promote the metastasis of autologous cells in the same way as mMFI2 in an autocrine manner, but the mechanism of promoting metastasis was different from mMFI2.	('sMFI2', 'Var', (40, 45))	('sMFI2', 'Chemical', '-', (40, 45))	('mMFI2', 'Gene', (114, 119))	('metastasis of autologous cells', 'CPA', (64, 94))	('mMFI2', 'Gene', '30060', (205, 210))	('mMFI2', 'Gene', (205, 210))	('promote', 'PosReg', (52, 59))	('mMFI2', 'Gene', '30060', (114, 119))
112499	33127882	5F and G) The results also showed that HUVEC cells treated with recombinant sMFI2 did not show reduced angiogenic capacity after siRNA knockdown of MMRN2 expression (Fig.	('MMRN2', 'Gene', (148, 153))	('knockdown', 'Var', (135, 144))	('angiogenic capacity', 'CPA', (103, 122))	('MMRN2', 'Gene', '79812', (148, 153))	('sMFI2', 'Chemical', '-', (76, 81))
112503	33127882	We found that when HUVEC was treated with sMFI2, the expression of MMP9 was decreased while the expression of MMRN2 was increased (Fig.	('MMRN2', 'Gene', (110, 115))	('sMFI2', 'Var', (42, 47))	('MMP9', 'Gene', '4318', (67, 71))	('sMFI2', 'Chemical', '-', (42, 47))	('expression', 'MPA', (96, 106))	('decreased', 'NegReg', (76, 85))	('MMP9', 'Gene', (67, 71))	('MMRN2', 'Gene', '79812', (110, 115))	('expression', 'MPA', (53, 63))	('increased', 'PosReg', (120, 129))
112510	33127882	According to reports in the literature, sMFI2 has a strong ability to cross the blood-brain barrier, and may affect the integrity of the connection between cells.	('integrity of the connection between cells', 'CPA', (120, 161))	('sMFI2', 'Var', (40, 45))	('affect', 'Reg', (109, 115))	('sMFI2', 'Chemical', '-', (40, 45))
112511	33127882	We hypothesized that since sMFI2 inhibits endothelial cell migration and angiogenesis, it might also affect the connections between endothelial cells leading to changes in vascular permeability and further inhibit tumor metastasis.	('tumor metastasis', 'Disease', (214, 230))	('connections', 'Interaction', (112, 123))	('sMFI2', 'Var', (27, 32))	('endothelial cell migration', 'CPA', (42, 68))	('affect', 'Reg', (101, 107))	('changes', 'Reg', (161, 168))	('sMFI2', 'Chemical', '-', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('inhibit', 'NegReg', (206, 213))	('inhibits', 'NegReg', (33, 41))	('vascular permeability', 'MPA', (172, 193))	('angiogenesis', 'CPA', (73, 85))	('tumor metastasis', 'Disease', 'MESH:D009362', (214, 230))
112513	33127882	The expression of ZO-1, P120, and N-cadherin, which are common intracellular connections increased to some extent after co-culture, indicating that the intercellular connections were not destroyed (Fig.	('N-cadherin', 'Gene', (34, 44))	('ZO-1', 'Gene', '7082', (18, 22))	('expression', 'MPA', (4, 14))	('N-cadherin', 'Gene', '1000', (34, 44))	('ZO-1', 'Gene', (18, 22))	('increased', 'PosReg', (89, 98))	('P120', 'Var', (24, 28))
112516	33127882	The above test indicated that although sMFI2 could inhibit angiogenesis, it did not affect vascular permeability, and there was little transfer of tumor cells across blood vessels.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('angiogenesis', 'CPA', (59, 71))	('sMFI2', 'Var', (39, 44))	('inhibit', 'NegReg', (51, 58))	('sMFI2', 'Chemical', '-', (39, 44))
112527	33127882	To validate this phenomenon, we separately extracted the cytoplasmic components of mMFI2 overexpressing and non-overexpressing cell line A549, and then evaluated the cytosolic mMFI2 content by western blot.	('mMFI2', 'Gene', (83, 88))	('mMFI2', 'Gene', (176, 181))	('overexpressing', 'Var', (89, 103))	('mMFI2', 'Gene', '30060', (83, 88))	('mMFI2', 'Gene', '30060', (176, 181))
112541	33127882	Among 506 patients with lung adenocarcinoma, high expression of MFI2 resulted in lower overall survival (p value = 0.034) (Fig.	('lung adenocarcinoma', 'Disease', (24, 43))	('MFI2', 'Gene', (64, 68))	('lower', 'NegReg', (81, 86))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (24, 43))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (24, 43))	('high expression', 'Var', (45, 60))	('patients', 'Species', '9606', (10, 18))	('carcinoma', 'Phenotype', 'HP:0030731', (34, 43))	('overall survival', 'MPA', (87, 103))
112575	33127882	In other words, whether the content of extracellular secretory MFI2 protein could be affected by both sMFI2 and mMFI2?	('sMFI2', 'Var', (102, 107))	('mMFI2', 'Gene', '30060', (112, 117))	('sMFI2', 'Chemical', '-', (102, 107))	('content of extracellular secretory MFI2 protein', 'MPA', (28, 75))	('affected', 'Reg', (85, 93))	('mMFI2', 'Gene', (112, 117))
112589	31691525	Circulating plasma lncRNAs as novel markers of EGFR mutation status and monitors of epidermal growth factor receptor-tyrosine kinase inhibitor therapy Epidermal growth factor receptor (EGFR) gene mutations predict tumor response to EGFR tyrosine kinase inhibitors (EGFR-TKIs) in non-small cell lung cancer (NSCLC).	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (279, 305))	('EGFR', 'Gene', '1956', (47, 51))	('EGFR', 'Gene', (185, 189))	('Epidermal growth factor receptor', 'Gene', (151, 183))	('EGFR', 'Gene', (265, 269))	('NSCLC', 'Disease', 'MESH:D002289', (307, 312))	('epidermal growth factor receptor', 'Gene', (84, 116))	('EGFR', 'Gene', (232, 236))	('non-small cell lung cancer', 'Disease', (279, 305))	('lung cancer', 'Phenotype', 'HP:0100526', (294, 305))	('epidermal growth factor receptor', 'Gene', '1956', (84, 116))	('NSCLC', 'Disease', (307, 312))	('tumor', 'Disease', (214, 219))	('predict', 'Reg', (206, 213))	('NSCLC', 'Phenotype', 'HP:0030358', (307, 312))	('EGFR', 'Gene', (47, 51))	('mutations', 'Var', (196, 205))	('EGFR', 'Gene', '1956', (185, 189))	('tumor', 'Disease', 'MESH:D009369', (214, 219))	('EGFR', 'Gene', '1956', (265, 269))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (283, 305))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (279, 305))	('cancer', 'Phenotype', 'HP:0002664', (299, 305))	('Epidermal growth factor receptor', 'Gene', '1956', (151, 183))	('tyrosine', 'Chemical', 'None', (237, 245))	('EGFR', 'Gene', '1956', (232, 236))	('tyrosine', 'Chemical', 'None', (117, 125))
112590	31691525	However, even patients with EGFR-sensitive mutations in NSCLC have limited efficacy with EGFR-TKI.	('EGFR', 'Gene', '1956', (28, 32))	('EGFR', 'Gene', (89, 93))	('NSCLC', 'Disease', (56, 61))	('EGFR', 'Gene', (28, 32))	('NSCLC', 'Disease', 'MESH:D002289', (56, 61))	('mutations', 'Var', (43, 52))	('patients', 'Species', '9606', (14, 22))	('EGFR', 'Gene', '1956', (89, 93))	('NSCLC', 'Phenotype', 'HP:0030358', (56, 61))
112592	31691525	This study aimed to explore the correlation between lncRNA in NSCLC patients with EGFR mutation status and EGFR-TKI efficacy.	('EGFR', 'Gene', (82, 86))	('NSCLC', 'Disease', (62, 67))	('mutation status', 'Var', (87, 102))	('EGFR', 'Gene', '1956', (107, 111))	('NSCLC', 'Disease', 'MESH:D002289', (62, 67))	('EGFR', 'Gene', (107, 111))	('patients', 'Species', '9606', (68, 76))	('NSCLC', 'Phenotype', 'HP:0030358', (62, 67))	('EGFR', 'Gene', '1956', (82, 86))
112593	31691525	The amplification-refractory mutation system method was used to test the EGFR mutation status in tumor tissues and pleural effusions of NSCLC patients.	('NSCLC', 'Disease', 'MESH:D002289', (136, 141))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('EGFR', 'Gene', '1956', (73, 77))	('mutation', 'Var', (78, 86))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('EGFR', 'Gene', (73, 77))	('NSCLC', 'Phenotype', 'HP:0030358', (136, 141))	('tumor', 'Disease', (97, 102))	('pleural effusion', 'Phenotype', 'HP:0002202', (115, 131))	('pleural effusions', 'Phenotype', 'HP:0002202', (115, 132))	('pleural effusions', 'Disease', (115, 132))	('patients', 'Species', '9606', (142, 150))	('NSCLC', 'Disease', (136, 141))	('pleural effusions', 'Disease', 'MESH:D010996', (115, 132))	('test', 'Reg', (64, 68))
112596	31691525	Five lncRNAs significantly associated with EGFR mutation status were screened by FC value and GO analysis, and then evaluated by real-time quantitative polymerase chain reaction in NSCLC patients' pleural effusions.	('patients', 'Species', '9606', (187, 195))	('NSCLC', 'Disease', 'MESH:D002289', (181, 186))	('pleural effusions', 'Disease', 'MESH:D010996', (197, 214))	('pleural effusions', 'Phenotype', 'HP:0002202', (197, 214))	('associated', 'Reg', (27, 37))	('NSCLC', 'Phenotype', 'HP:0030358', (181, 186))	('EGFR', 'Gene', '1956', (43, 47))	('mutation', 'Var', (48, 56))	('pleural effusion', 'Phenotype', 'HP:0002202', (197, 213))	('EGFR', 'Gene', (43, 47))	('NSCLC', 'Disease', (181, 186))	('pleural effusions', 'Disease', (197, 214))
112598	31691525	There were 61 significant differences in lncRNA between EGFR mutation-positive and wild-type patients.	('patients', 'Species', '9606', (93, 101))	('mutation-positive', 'Var', (61, 78))	('EGFR', 'Gene', '1956', (56, 60))	('EGFR', 'Gene', (56, 60))	('lncRNA', 'MPA', (41, 47))
112599	31691525	Among them, SCARNA7, MALAT1, NONHSAT017369, NONHSAT051892, and FTH1P2 were significantly associated with EGFR mutation status.	('MALAT1', 'Gene', '378938', (21, 27))	('associated', 'Reg', (89, 99))	('mutation status', 'Var', (110, 125))	('MALAT1', 'Gene', (21, 27))	('NONHSAT017369', 'Chemical', 'None', (29, 42))	('FTH1P2', 'Gene', '2497', (63, 69))	('NONHSAT017369', 'Var', (29, 42))	('EGFR', 'Gene', '1956', (105, 109))	('FTH1P2', 'Gene', (63, 69))	('NONHSAT051892', 'Var', (44, 57))	('EGFR', 'Gene', (105, 109))	('SCARNA7', 'Gene', (12, 19))	('NONHSAT051892', 'Chemical', 'None', (44, 57))	('SCARNA7', 'Gene', '677767', (12, 19))
112600	31691525	SCARNA7, MALAT1, and NONHSAT017369 showed consistent results with plasma in pleural effusions compared to EGFR wild-type, all upregulated in the EGFR mutation group.	('NONHSAT017369', 'Var', (21, 34))	('EGFR', 'Gene', '1956', (145, 149))	('mutation', 'Var', (150, 158))	('MALAT1', 'Gene', '378938', (9, 15))	('SCARNA7', 'Gene', (0, 7))	('SCARNA7', 'Gene', '677767', (0, 7))	('upregulated', 'PosReg', (126, 137))	('EGFR', 'Gene', (145, 149))	('pleural effusion', 'Phenotype', 'HP:0002202', (76, 92))	('MALAT1', 'Gene', (9, 15))	('pleural effusions', 'Disease', (76, 93))	('pleural effusions', 'Disease', 'MESH:D010996', (76, 93))	('EGFR', 'Gene', '1956', (106, 110))	('pleural effusions', 'Phenotype', 'HP:0002202', (76, 93))	('NONHSAT017369', 'Chemical', 'None', (21, 34))	('EGFR', 'Gene', (106, 110))
112601	31691525	This study shows that lncRNAs can be used not only as potential biomarkers for predicting the mutation status of EGFR and the efficacy of EGFR-TKI, but also for monitoring the efficacy of EGFR-TKI.	('EGFR', 'Gene', '1956', (138, 142))	('EGFR', 'Gene', (138, 142))	('EGFR', 'Gene', '1956', (188, 192))	('EGFR', 'Gene', '1956', (113, 117))	('EGFR', 'Gene', (113, 117))	('EGFR', 'Gene', (188, 192))	('mutation', 'Var', (94, 102))
112603	31691525	According to the National Comprehensive Cancer Network (NCCN) guidelines, patients with EGFR-mutant disease (mainly the EGFR exon 19 deletion and p.L858R point mutation) are advised to undergo EGFR-tyrosine kinase inhibitor (TKI) therapy as first-line treatment.4 It is therefore important to identify the tumor genotype after histopathological determination.	('tyrosine', 'Chemical', 'None', (198, 206))	('tumor', 'Disease', 'MESH:D009369', (306, 311))	('Cancer', 'Phenotype', 'HP:0002664', (40, 46))	('Cancer', 'Disease', (40, 46))	('tumor', 'Phenotype', 'HP:0002664', (306, 311))	('deletion', 'Var', (133, 141))	('EGFR', 'Gene', '1956', (193, 197))	('Cancer', 'Disease', 'MESH:D009369', (40, 46))	('patients', 'Species', '9606', (74, 82))	('tumor', 'Disease', (306, 311))	('p.L858R', 'Mutation', 'rs121434568', (146, 153))	('EGFR', 'Gene', '1956', (88, 92))	('EGFR', 'Gene', (193, 197))	('EGFR', 'Gene', '1956', (120, 124))	('EGFR', 'Gene', (88, 92))	('EGFR', 'Gene', (120, 124))
112606	31691525	Moreover, rebiopsy during EGFR-TKI therapy in order to continuously monitor EGFR mutation status and analyze EGFR-TKI resistance remains a major challenge.	('EGFR', 'Gene', (26, 30))	('EGFR', 'Gene', '1956', (76, 80))	('mutation', 'Var', (81, 89))	('EGFR', 'Gene', '1956', (109, 113))	('EGFR', 'Gene', (76, 80))	('EGFR', 'Gene', '1956', (26, 30))	('EGFR', 'Gene', (109, 113))
112610	31691525	Therefore, it is necessary to define a group of noninvasive, convenient, economical markers as a supplement for predicting EGFR mutation status and monitoring the efficacy of EGFR-TKI therapy in patients with NSCLC.	('EGFR', 'Gene', (123, 127))	('NSCLC', 'Disease', 'MESH:D002289', (209, 214))	('EGFR', 'Gene', (175, 179))	('NSCLC', 'Phenotype', 'HP:0030358', (209, 214))	('patients', 'Species', '9606', (195, 203))	('EGFR', 'Gene', '1956', (123, 127))	('mutation', 'Var', (128, 136))	('EGFR', 'Gene', '1956', (175, 179))	('NSCLC', 'Disease', (209, 214))
112612	31691525	With the continuous understanding of lncRNA, it is believed that the differential expression and mutation of lncRNA play an important role in the malignant proliferation of tumors.	('malignant proliferation', 'CPA', (146, 169))	('mutation', 'Var', (97, 105))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumors', 'Disease', 'MESH:D009369', (173, 179))	('tumors', 'Disease', (173, 179))	('tumors', 'Phenotype', 'HP:0002664', (173, 179))	('lncRNA', 'Gene', (109, 115))
112614	31691525	However, the association between circulating plasma lncRNAs and EGFR mutation status and the role of lncRNAs in monitoring the efficacy of EGFR-TKI therapy have yet to be systematically studied.	('EGFR', 'Gene', '1956', (139, 143))	('mutation', 'Var', (69, 77))	('EGFR', 'Gene', (139, 143))	('EGFR', 'Gene', '1956', (64, 68))	('EGFR', 'Gene', (64, 68))
112615	31691525	Our objective was to identify a group of circulating plasma lncRNAs that can predict EGFR mutation status and explore the potential of this group of lncRNAs to monitor the efficacy of EGFR-TKI therapy.	('EGFR', 'Gene', (85, 89))	('EGFR', 'Gene', '1956', (184, 188))	('EGFR', 'Gene', (184, 188))	('predict', 'Reg', (77, 84))	('EGFR', 'Gene', '1956', (85, 89))	('mutation', 'Var', (90, 98))
112618	31691525	A number of studies have shown that pleural effusions are more sensitive to detecting EGFR mutation status than blood samples.	('pleural effusions', 'Disease', (36, 53))	('pleural effusions', 'Disease', 'MESH:D010996', (36, 53))	('EGFR', 'Gene', '1956', (86, 90))	('mutation status', 'Var', (91, 106))	('pleural effusions', 'Phenotype', 'HP:0002202', (36, 53))	('EGFR', 'Gene', (86, 90))	('pleural effusion', 'Phenotype', 'HP:0002202', (36, 52))
112619	31691525	To improve the specificity and sensitivity of this study, we used Clariom D Human Chip technology to detect pleural effusions with different EGFR mutation status.	('pleural effusions', 'Disease', 'MESH:D010996', (108, 125))	('pleural effusions', 'Phenotype', 'HP:0002202', (108, 125))	('EGFR', 'Gene', '1956', (141, 145))	('mutation status', 'Var', (146, 161))	('EGFR', 'Gene', (141, 145))	('pleural effusion', 'Phenotype', 'HP:0002202', (108, 124))	('Human', 'Species', '9606', (76, 81))	('pleural effusions', 'Disease', (108, 125))
112626	31691525	Blood samples were dynamically collected from 36 of the 72 patients with EGFR mutations at one, three, and five months of EGFR-TKI treatment.	('EGFR', 'Gene', '1956', (73, 77))	('EGFR', 'Gene', (73, 77))	('mutations', 'Var', (78, 87))	('patients', 'Species', '9606', (59, 67))	('EGFR', 'Gene', '1956', (122, 126))	('EGFR', 'Gene', (122, 126))
112636	31691525	According to the inclusion criteria, we selected 77 patients with EGFR mutation status confirmed in the tumor tissue by histological examination from 218 patients with NSCLC with pleural effusion, and those diagnosed with tumor cells in pleural effusion for the study (35 EGFR mutants, 42 EGFR wild-type).	('pleural effusion', 'Disease', (237, 253))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('pleural effusion', 'Phenotype', 'HP:0002202', (179, 195))	('EGFR', 'Gene', (289, 293))	('NSCLC', 'Phenotype', 'HP:0030358', (168, 173))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('pleural effusion', 'Disease', 'MESH:D010996', (237, 253))	('EGFR', 'Gene', (66, 70))	('EGFR', 'Gene', (272, 276))	('patients', 'Species', '9606', (52, 60))	('EGFR', 'Gene', '1956', (289, 293))	('pleural effusion', 'Disease', (179, 195))	('pleural effusion', 'Phenotype', 'HP:0002202', (237, 253))	('tumor', 'Disease', (104, 109))	('patients', 'Species', '9606', (154, 162))	('tumor', 'Disease', (222, 227))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('pleural effusion', 'Disease', 'MESH:D010996', (179, 195))	('EGFR', 'Gene', '1956', (272, 276))	('tumor', 'Disease', 'MESH:D009369', (222, 227))	('EGFR', 'Gene', '1956', (66, 70))	('NSCLC', 'Disease', 'MESH:D002289', (168, 173))	('mutants', 'Var', (277, 284))	('NSCLC', 'Disease', (168, 173))
112640	31691525	Of the 72 patients with advanced NSCLC EGFR mutations, 68 received a first-generation EGFR-TKI treatment.	('NSCLC', 'Phenotype', 'HP:0030358', (33, 38))	('EGFR', 'Gene', '1956', (86, 90))	('EGFR', 'Gene', (86, 90))	('mutations', 'Var', (44, 53))	('NSCLC', 'Disease', (33, 38))	('EGFR', 'Gene', '1956', (39, 43))	('patients', 'Species', '9606', (10, 18))	('EGFR', 'Gene', (39, 43))	('NSCLC', 'Disease', 'MESH:D002289', (33, 38))
112646	31691525	Among the five lncRNAs, SCARNA7, MALAT1, NONHSAT017369, and NONHSAT051892 were significantly upregulated and FTH1P2 was significantly downregulated in EGFR-mutant patients.	('patients', 'Species', '9606', (163, 171))	('MALAT1', 'Gene', (33, 39))	('downregulated', 'NegReg', (134, 147))	('EGFR', 'Gene', (151, 155))	('NONHSAT051892', 'Var', (60, 73))	('NONHSAT017369', 'Chemical', 'None', (41, 54))	('MALAT1', 'Gene', '378938', (33, 39))	('SCARNA7', 'Gene', '677767', (24, 31))	('FTH1P2', 'Gene', '2497', (109, 115))	('upregulated', 'PosReg', (93, 104))	('SCARNA7', 'Gene', (24, 31))	('NONHSAT017369', 'Var', (41, 54))	('NONHSAT051892', 'Chemical', 'None', (60, 73))	('EGFR', 'Gene', '1956', (151, 155))	('FTH1P2', 'Gene', (109, 115))
112650	31691525	The expression levels of both NONHSAT051892 and FTH1P2 were not significantly different between the EGFR-mutant and wild-type groups.	('EGFR', 'Gene', '1956', (100, 104))	('NONHSAT051892', 'Chemical', 'None', (30, 43))	('FTH1P2', 'Gene', '2497', (48, 54))	('EGFR', 'Gene', (100, 104))	('FTH1P2', 'Gene', (48, 54))	('NONHSAT051892', 'Var', (30, 43))
112651	31691525	Therefore, SCARNA7, MALAT1, and NONHSAT017369 were selected for further study.	('MALAT1', 'Gene', (20, 26))	('SCARNA7', 'Gene', '677767', (11, 18))	('NONHSAT017369', 'Chemical', 'None', (32, 45))	('NONHSAT017369', 'Var', (32, 45))	('SCARNA7', 'Gene', (11, 18))	('MALAT1', 'Gene', '378938', (20, 26))
112653	31691525	We observed the same trend as we did in the pleural effusions, namely, significant upregulation of SCARNA7, MALAT1, and NONHSAT017369 in the EGFR-mutant group compared to the EGFR wild-type group (P < 0.05; Fig 2).	('upregulation', 'PosReg', (83, 95))	('EGFR', 'Gene', (175, 179))	('pleural effusions', 'Disease', (44, 61))	('EGFR', 'Gene', '1956', (141, 145))	('MALAT1', 'Gene', '378938', (108, 114))	('SCARNA7', 'Gene', '677767', (99, 106))	('SCARNA7', 'Gene', (99, 106))	('pleural effusions', 'Disease', 'MESH:D010996', (44, 61))	('pleural effusions', 'Phenotype', 'HP:0002202', (44, 61))	('EGFR', 'Gene', (141, 145))	('MALAT1', 'Gene', (108, 114))	('NONHSAT017369', 'Chemical', 'None', (120, 133))	('EGFR', 'Gene', '1956', (175, 179))	('pleural effusion', 'Phenotype', 'HP:0002202', (44, 60))	('NONHSAT017369', 'Var', (120, 133))
112654	31691525	Further analysis of patients harboring EGFR exon 19 deletions and p.L858R point mutations revealed that MALAT1 was upregulated in the EGFR exon 19 deletion group compared to the EGFR p.L858R point mutation group (P < 0.05; Fig 2); no statistically significant differences were observed in the expression of the remaining two lncRNAs by EGFR mutation.	('EGFR', 'Gene', '1956', (178, 182))	('EGFR', 'Gene', (336, 340))	('MALAT1', 'Gene', '378938', (104, 110))	('EGFR', 'Gene', (134, 138))	('p.L858R', 'Mutation', 'rs121434568', (66, 73))	('EGFR', 'Gene', (178, 182))	('MALAT1', 'Gene', (104, 110))	('deletion', 'Var', (147, 155))	('p.L858R', 'Mutation', 'rs121434568', (183, 190))	('patients', 'Species', '9606', (20, 28))	('deletions', 'Var', (52, 61))	('EGFR', 'Gene', '1956', (39, 43))	('EGFR', 'Gene', (39, 43))	('EGFR', 'Gene', '1956', (336, 340))	('EGFR', 'Gene', '1956', (134, 138))	('upregulated', 'PosReg', (115, 126))
112655	31691525	The potential of circulating plasma SCARNA7, MALAT1, and NONHSAT017369 as diagnostic markers for EGFR mutation status in NSCLC patients was evaluated using ROC curve analysis.	('SCARNA7', 'Gene', '677767', (36, 43))	('SCARNA7', 'Gene', (36, 43))	('mutation', 'Var', (102, 110))	('EGFR', 'Gene', '1956', (97, 101))	('NONHSAT017369', 'Chemical', 'None', (57, 70))	('NSCLC', 'Disease', (121, 126))	('MALAT1', 'Gene', (45, 51))	('EGFR', 'Gene', (97, 101))	('patients', 'Species', '9606', (127, 135))	('NONHSAT017369', 'Var', (57, 70))	('NSCLC', 'Disease', 'MESH:D002289', (121, 126))	('MALAT1', 'Gene', '378938', (45, 51))	('NSCLC', 'Phenotype', 'HP:0030358', (121, 126))
112657	31691525	No significant differences were found between the EGFR exon 19 deletion group and the EGFR p.L858R point mutation group.	('EGFR', 'Gene', '1956', (86, 90))	('EGFR', 'Gene', '1956', (50, 54))	('EGFR', 'Gene', (86, 90))	('deletion', 'Var', (63, 71))	('EGFR', 'Gene', (50, 54))	('p.L858R', 'Mutation', 'rs121434568', (91, 98))
112659	31691525	MALAT1 was significantly upregulated in the EGFR exon 19 deletion group compared to the EGFR p.L858R point mutation group, with a ROC-AUC of 0.74 (95% CI: 0.64-0.85), sensitivity of 70.0%, and specificity of 69.0% (Fig 3c).	('MALAT1', 'Gene', '378938', (0, 6))	('deletion', 'Var', (57, 65))	('MALAT1', 'Gene', (0, 6))	('exon 19 deletion', 'Var', (49, 65))	('upregulated', 'PosReg', (25, 36))	('p.L858R', 'Mutation', 'rs121434568', (93, 100))	('EGFR', 'Gene', '1956', (88, 92))	('EGFR', 'Gene', '1956', (44, 48))	('EGFR', 'Gene', (44, 48))	('EGFR', 'Gene', (88, 92))
112660	31691525	NONHSAT017369 could only distinguish between the EGFR-mutant group and the EGFR wild-type group.	('EGFR', 'Gene', '1956', (49, 53))	('EGFR', 'Gene', (49, 53))	('NONHSAT017369', 'Chemical', 'None', (0, 13))	('EGFR', 'Gene', '1956', (75, 79))	('NONHSAT017369', 'Var', (0, 13))	('EGFR', 'Gene', (75, 79))
112661	31691525	To further evaluate the diagnostic potential of the combinations of SCARNA7, MALAT1, and NONHSAT017369, a logistic regression analysis was conducted to combine the ROC curve analyses of these three lncRNAs.	('SCARNA7', 'Gene', (68, 75))	('SCARNA7', 'Gene', '677767', (68, 75))	('NONHSAT017369', 'Chemical', 'None', (89, 102))	('MALAT1', 'Gene', '378938', (77, 83))	('NONHSAT017369', 'Var', (89, 102))	('MALAT1', 'Gene', (77, 83))
112666	31691525	Kaplan-Meier analysis was performed for progression-free survival (PFS) based on clinicopathological factors, as well as the initial (before EGFR-TKI) plasma levels of SCARNA7, MALAT1, and NONHSAT017369.	('NONHSAT017369', 'Var', (189, 202))	('EGFR', 'Gene', '1956', (141, 145))	('MALAT1', 'Gene', '378938', (177, 183))	('EGFR', 'Gene', (141, 145))	('SCARNA7', 'Gene', (168, 175))	('SCARNA7', 'Gene', '677767', (168, 175))	('MALAT1', 'Gene', (177, 183))	('NONHSAT017369', 'Chemical', 'None', (189, 202))
112670	31691525	The initial expression of SCARNA7 and NONHSAT017369 had no significant correlation with PFS (P = 0.67 and P = 0.855, respectively).	('NONHSAT017369', 'Var', (38, 51))	('SCARNA7', 'Gene', (26, 33))	('SCARNA7', 'Gene', '677767', (26, 33))	('PFS', 'Disease', (88, 91))	('NONHSAT017369', 'Chemical', 'None', (38, 51))
112672	31691525	In patients with high and low expression of MALAT1, the median PFS were 11.6 and 8.2 months, respectively (hazard ratio: 0.431; 95% CI: 0.236-0.787).	('low', 'NegReg', (26, 29))	('high', 'Var', (17, 21))	('patients', 'Species', '9606', (3, 11))	('MALAT1', 'Gene', '378938', (44, 50))	('MALAT1', 'Gene', (44, 50))
112674	31691525	To determine whether the plasma levels of SCARNA7, MALAT1, and NONHSAT017369 had predictive value for the efficacy of EGFR-TKI therapy, qRT-PCR was used to compare the plasma levels of the three lncRNAs in 36 patients before and after EGFR-TKI treatment.	('NONHSAT017369', 'Var', (63, 76))	('MALAT1', 'Gene', '378938', (51, 57))	('MALAT1', 'Gene', (51, 57))	('EGFR', 'Gene', '1956', (118, 122))	('patients', 'Species', '9606', (209, 217))	('EGFR', 'Gene', (235, 239))	('EGFR', 'Gene', (118, 122))	('SCARNA7', 'Gene', (42, 49))	('EGFR', 'Gene', '1956', (235, 239))	('SCARNA7', 'Gene', '677767', (42, 49))	('NONHSAT017369', 'Chemical', 'None', (63, 76))
112679	31691525	There was no statistically significant difference in the plasma levels of NONHSAT017369 after EGFR-TKI treatment (P > 0.05).	('EGFR', 'Gene', (94, 98))	('NONHSAT017369', 'Chemical', 'None', (74, 87))	('NONHSAT017369', 'Var', (74, 87))	('EGFR', 'Gene', '1956', (94, 98))
112681	31691525	The assessment of the EGFR gene mutation status in lung cancer tissues has important predictive value for the efficacy of EGFR-TKI.	('lung cancer', 'Disease', 'MESH:D008175', (51, 62))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('lung cancer', 'Disease', (51, 62))	('mutation', 'Var', (32, 40))	('lung cancer', 'Phenotype', 'HP:0100526', (51, 62))	('EGFR', 'Gene', '1956', (22, 26))	('EGFR', 'Gene', '1956', (122, 126))	('EGFR', 'Gene', (122, 126))	('EGFR', 'Gene', (22, 26))
112683	31691525	Although clinically circulating ctDNA detection of EGFR mutation status has been recommended by the NCCN and Chinese Society of Clinical Oncology (CSCO) guidelines as complementary means to obtain tumor tissue.	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('EGFR', 'Gene', (51, 55))	('Oncology', 'Phenotype', 'HP:0002664', (137, 145))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('mutation', 'Var', (56, 64))	('tumor', 'Disease', (197, 202))	('EGFR', 'Gene', '1956', (51, 55))
112691	31691525	Finally, five lncRNAs were found to play a key role in EGFR 19 exon mutation.20 However, few studies have focused on the expression of lncRNA in blood samples associated with EGFR mutation status in patients with advanced NSCLC.	('EGFR', 'Gene', '1956', (55, 59))	('EGFR', 'Gene', (175, 179))	('NSCLC', 'Phenotype', 'HP:0030358', (222, 227))	('EGFR', 'Gene', (55, 59))	('NSCLC', 'Disease', (222, 227))	('patients', 'Species', '9606', (199, 207))	('NSCLC', 'Disease', 'MESH:D002289', (222, 227))	('EGFR', 'Gene', '1956', (175, 179))	('mutation', 'Var', (180, 188))
112692	31691525	In this study, we systematically evaluated the ability of circulating lncRNAs as potential markers for predicting EGFR mutation status, EGFR-TKI efficacy, and monitoring the efficacy of EGFR-TKI in patients with EGFR-positive NSCLC.	('mutation', 'Var', (119, 127))	('NSCLC', 'Disease', 'MESH:D002289', (226, 231))	('patients', 'Species', '9606', (198, 206))	('EGFR', 'Gene', '1956', (186, 190))	('NSCLC', 'Disease', (226, 231))	('EGFR', 'Gene', (186, 190))	('EGFR', 'Gene', '1956', (114, 118))	('EGFR', 'Gene', '1956', (212, 216))	('NSCLC', 'Phenotype', 'HP:0030358', (226, 231))	('EGFR', 'Gene', (114, 118))	('EGFR', 'Gene', '1956', (136, 140))	('EGFR', 'Gene', (136, 140))	('EGFR', 'Gene', (212, 216))
112694	31691525	In recent years, several studies have shown that the specificity and sensitivity of pleural effusion detection of ctDNA EGFR mutation status are close to, or even higher than, that of tumor tissue.	('mutation status', 'Var', (125, 140))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('pleural effusion', 'Phenotype', 'HP:0002202', (84, 100))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('tumor', 'Disease', (184, 189))	('pleural effusion', 'Disease', (84, 100))	('EGFR', 'Gene', '1956', (120, 124))	('pleural effusion', 'Disease', 'MESH:D010996', (84, 100))	('higher', 'PosReg', (163, 169))	('specificity', 'MPA', (53, 64))	('EGFR', 'Gene', (120, 124))
112695	31691525	used pleural effusion supernatants from 50 patients with lung adenocarcinoma to test for EGFR mutation status.	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (57, 76))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (57, 76))	('EGFR', 'Gene', (89, 93))	('patients', 'Species', '9606', (43, 51))	('lung adenocarcinoma', 'Disease', (57, 76))	('test', 'Reg', (80, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('pleural effusion', 'Disease', 'MESH:D010996', (5, 21))	('pleural effusion', 'Phenotype', 'HP:0002202', (5, 21))	('pleural effusion', 'Disease', (5, 21))	('EGFR', 'Gene', '1956', (89, 93))	('mutation', 'Var', (94, 102))
112696	31691525	That study found that the results of pleural effusion were 100% matched with tumor tissue, and three patients with positive EGFR mutations were found among 19 EGFR wild-type patients.	('pleural effusion', 'Phenotype', 'HP:0002202', (37, 53))	('patients', 'Species', '9606', (101, 109))	('EGFR', 'Gene', '1956', (124, 128))	('EGFR', 'Gene', '1956', (159, 163))	('mutations', 'Var', (129, 138))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('EGFR', 'Gene', (124, 128))	('patients', 'Species', '9606', (174, 182))	('EGFR', 'Gene', (159, 163))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('pleural effusion', 'Disease', 'MESH:D010996', (37, 53))	('tumor', 'Disease', (77, 82))	('pleural effusion', 'Disease', (37, 53))
112699	31691525	Therefore, the identification of potential markers delineating EGFR mutant subtypes (mainly the EGFR exon 19 deletion and p.L858R point mutation) is also crucial in clinical studies.	('EGFR', 'Gene', '1956', (63, 67))	('p.L858R point', 'Var', (122, 135))	('p.L858R', 'Mutation', 'rs121434568', (122, 129))	('EGFR', 'Gene', (96, 100))	('EGFR', 'Gene', (63, 67))	('EGFR', 'Gene', '1956', (96, 100))
112702	31691525	In addition, because EGFR exon 19 deletion has a better therapeutic response to EGFR-TKI than EGFR21 p.L858R point mutation, further analysis of EGFR mutant subtypes shows that plasma MALAT1 is significantly associated with it.	('EGFR', 'Gene', '1956', (21, 25))	('EGFR', 'Gene', (21, 25))	('MALAT1', 'Gene', '378938', (184, 190))	('EGFR', 'Gene', '1956', (94, 98))	('EGFR', 'Gene', '1956', (145, 149))	('EGFR', 'Gene', '1956', (80, 84))	('EGFR', 'Gene', (94, 98))	('EGFR', 'Gene', (80, 84))	('EGFR', 'Gene', (145, 149))	('MALAT1', 'Gene', (184, 190))	('associated', 'Reg', (208, 218))	('deletion', 'Var', (34, 42))	('p.L858R', 'Mutation', 'rs121434568', (101, 108))	('therapeutic response', 'MPA', (56, 76))
112712	31691525	To date, no report has described the correlation between SCARNA7 and NONHSAT017369 and lung cancer or EGFR signaling.	('NONHSAT017369', 'Var', (69, 82))	('lung cancer', 'Disease', 'MESH:D008175', (87, 98))	('SCARNA7', 'Gene', (57, 64))	('SCARNA7', 'Gene', '677767', (57, 64))	('lung cancer', 'Disease', (87, 98))	('lung cancer', 'Phenotype', 'HP:0100526', (87, 98))	('NONHSAT017369', 'Chemical', 'None', (69, 82))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('EGFR', 'Gene', '1956', (102, 106))	('EGFR', 'Gene', (102, 106))
112714	31691525	There are few reports on NONHSAT017369, and regulatory network analysis found that NONHSAT017369 can be targeted to IL6R.	('NONHSAT017369', 'Chemical', 'None', (25, 38))	('NONHSAT017369', 'Var', (83, 96))	('IL6R', 'Gene', (116, 120))	('IL6R', 'Gene', '3570', (116, 120))	('NONHSAT017369', 'Chemical', 'None', (83, 96))
112715	31691525	IL6R is involved in the JAK-signal transducer and activator of transcription (STAT) signaling pathway, which is commonly known as the signaling pathway downstream of EGFR.25, 26 Therefore, NONHSAT017369 may affect EGFR status through STAT activation.	('STAT', 'MPA', (234, 238))	('NONHSAT017369', 'Var', (189, 202))	('IL6R', 'Gene', (0, 4))	('EGFR', 'Gene', '1956', (166, 170))	('affect', 'Reg', (207, 213))	('EGFR', 'Gene', (166, 170))	('EGFR', 'Gene', '1956', (214, 218))	('activation', 'PosReg', (239, 249))	('EGFR', 'Gene', (214, 218))	('IL6R', 'Gene', '3570', (0, 4))	('NONHSAT017369', 'Chemical', 'None', (189, 202))
112725	31691525	In conclusion, this exploratory study established a group of plasma lncRNAs for predicting EGFR mutation status, and this model could serve as a new noninvasive biomarker for the diagnosis of EGFR-mutant patients with NSCLC and an important indicator for predicting the efficacy of EGFR-TKI therapy.	('NSCLC', 'Disease', 'MESH:D002289', (218, 223))	('patients', 'Species', '9606', (204, 212))	('EGFR', 'Gene', (91, 95))	('EGFR', 'Gene', '1956', (282, 286))	('NSCLC', 'Phenotype', 'HP:0030358', (218, 223))	('EGFR', 'Gene', (282, 286))	('mutation', 'Var', (96, 104))	('NSCLC', 'Disease', (218, 223))	('EGFR', 'Gene', '1956', (91, 95))	('EGFR', 'Gene', '1956', (192, 196))	('EGFR', 'Gene', (192, 196))
112734	31617686	Among 10 highly-expressed risk lincRNAs, a small panel of LINC00487, LINC01927, and C10orf143 (LINC00959) could effectively predict malignancies in paired samples (AUC = 0.7274, 95%CI = (0.6264, 0.8285)).	('LINC00959', 'Gene', '387723', (95, 104))	('C10orf143', 'Var', (84, 93))	('predict', 'Reg', (124, 131))	('LINC00487', 'Gene', '400941', (58, 67))	('LINC01927', 'Chemical', '-', (69, 78))	('ncRNA', 'Gene', '54719', (33, 38))	('malignancies', 'Disease', 'MESH:D009369', (132, 144))	('LINC00959', 'Gene', (95, 104))	('malignancies', 'Disease', (132, 144))	('LINC00487', 'Gene', (58, 67))	('ncRNA', 'Gene', (33, 38))
112736	31617686	Additionally, three highly-expressed risk lincRNAs, LINC01031, LINC01088, and LINC01931, were significantly associated with poor prognosis in PT samples, suggesting potential targets for anti-LSqCC treatment.	('LINC01931', 'Var', (78, 87))	('LINC01088', 'Gene', '100505875', (63, 72))	('LSqCC', 'Phenotype', 'HP:0030359', (192, 197))	('ncRNA', 'Gene', (44, 49))	('LINC01931', 'Chemical', '-', (78, 87))	('LINC01088', 'Gene', (63, 72))	('LINC01031', 'Gene', '101929184', (52, 61))	('ncRNA', 'Gene', '54719', (44, 49))	('LINC01031', 'Gene', (52, 61))
112739	31617686	The combination of LINC00487, LINC01927, LINC00959, LINC02315, LINC00491, and LINC01697 could effectively predict malignancies in both paired samples (AUC=0.8030) and nonpaired samples (AUC=0.7481).	('LINC01697', 'Chemical', '-', (78, 87))	('LINC00491', 'Gene', (63, 72))	('LINC01927', 'Chemical', '-', (30, 39))	('LINC00487', 'Gene', (19, 28))	('LINC01697', 'Var', (78, 87))	('LINC00959', 'Gene', '387723', (41, 50))	('malignancies', 'Disease', 'MESH:D009369', (114, 126))	('LINC01927', 'Var', (30, 39))	('LINC00491', 'Gene', '285708', (63, 72))	('LINC00487', 'Gene', '400941', (19, 28))	('LINC02315', 'Var', (52, 61))	('malignancies', 'Disease', (114, 126))	('predict', 'Reg', (106, 113))	('LINC00959', 'Gene', (41, 50))
112740	31617686	Additionally, high levels of risky lincRNAs, LINC01031, LINC01088, and LINC01931, in PT samples were significantly associated with poor prognosis, suggesting potential targets for anti-LSqCC treatment.	('LINC01931', 'Var', (71, 80))	('ncRNA', 'Gene', (37, 42))	('LSqCC', 'Phenotype', 'HP:0030359', (185, 190))	('poor prognosis', 'CPA', (131, 145))	('LINC01088', 'Gene', '100505875', (56, 65))	('LINC01931', 'Chemical', '-', (71, 80))	('associated', 'Reg', (115, 125))	('ncRNA', 'Gene', '54719', (37, 42))	('LINC01088', 'Gene', (56, 65))	('LINC01031', 'Gene', '101929184', (45, 54))	('LINC01031', 'Gene', (45, 54))
112747	31617686	In lung adenocarcinoma, patients with EGFR mutations could obtain survival benefits from EGFR inhibitors (Takano et al., 2008), especially for "never smokers" (Sun et al., 2010).	('EGFR', 'Gene', '1956', (38, 42))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (3, 22))	('EGFR', 'Gene', (89, 93))	('EGFR', 'Gene', (38, 42))	('survival benefits', 'CPA', (66, 83))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (3, 22))	('inhibitors', 'NegReg', (94, 104))	('mutations', 'Var', (43, 52))	('patients', 'Species', '9606', (24, 32))	('carcinoma', 'Phenotype', 'HP:0030731', (13, 22))	('EGFR', 'Gene', '1956', (89, 93))	('lung adenocarcinoma', 'Disease', (3, 22))
112794	31617686	These validated risk lincRNAs were LINC00487, LINC01927, C10orf143 (LINC00959), LINC01031, LINC01088, LINC01352, LINC01504, LINC01931, LINC01985, and LINC02395.	('LINC00487', 'Gene', (35, 44))	('ncRNA', 'Gene', (23, 28))	('LINC01031', 'Gene', (80, 89))	('LINC00959', 'Gene', '387723', (68, 77))	('C10orf143', 'Var', (57, 66))	('LINC01931', 'Chemical', '-', (124, 133))	('LINC01504', 'Gene', '100507540', (113, 122))	('LINC00487', 'Gene', '400941', (35, 44))	('LINC01088', 'Gene', (91, 100))	('LINC01352', 'Gene', (102, 111))	('LINC01504', 'Gene', (113, 122))	('LINC01352', 'Gene', '101929730', (102, 111))	('ncRNA', 'Gene', '54719', (23, 28))	('LINC01927', 'Chemical', '-', (46, 55))	('LINC00959', 'Gene', (68, 77))	('LINC01031', 'Gene', '101929184', (80, 89))	('LINC01088', 'Gene', '100505875', (91, 100))
112796	31617686	These validated protective factors were LINC00307, LINC00491, LINC01063, LINC01385, LINC01448, LINC01524, LINC01697, LINC01719, and LINC02026.	('LINC00307', 'Gene', (40, 49))	('LINC01063', 'Gene', (62, 71))	('LINC01448', 'Gene', '101928795', (84, 93))	('LINC01697', 'Chemical', '-', (106, 115))	('LINC00491', 'Gene', (51, 60))	('LINC01385', 'Gene', '106144542', (73, 82))	('LINC01524', 'Gene', '101927700', (95, 104))	('LINC01063', 'Gene', '101929769', (62, 71))	('LINC02026', 'Var', (132, 141))	('LINC01719', 'Var', (117, 126))	('LINC01385', 'Gene', (73, 82))	('LINC01697', 'Var', (106, 115))	('LINC00307', 'Gene', '266919', (40, 49))	('LINC01448', 'Gene', (84, 93))	('LINC00491', 'Gene', '285708', (51, 60))	('LINC01524', 'Gene', (95, 104))
112799	31617686	The top three risk lincRNAs with the biggest area under ROC curve (AUC) values were selected out and integrated into a small joint panel A (LINC00487 + LINC01927 + C10orf143 (LINC00959)).	('LINC00959', 'Gene', '387723', (175, 184))	('ncRNA', 'Gene', '54719', (21, 26))	('LINC00487', 'Gene', '400941', (140, 149))	('C10orf143', 'Var', (164, 173))	('LINC01927', 'Chemical', '-', (152, 161))	('LINC00487', 'Gene', (140, 149))	('LINC00959', 'Gene', (175, 184))	('ncRNA', 'Gene', (21, 26))
112800	31617686	The top three protective lincRNAs with the biggest AUC values were selected out and integrated into a small joint panel B (LINC02315 + LINC00491 + LINC01697).	('LINC00491', 'Gene', '285708', (135, 144))	('ncRNA', 'Gene', '54719', (27, 32))	('LINC00491', 'Gene', (135, 144))	('LINC01697', 'Chemical', '-', (147, 156))	('LINC02315 +', 'Var', (123, 134))	('ncRNA', 'Gene', (27, 32))
112802	31617686	The gene expression level (FPKM) of LINC02315, LINC00491, and LINC01697 in independent PT samples (blue) and SN tissue samples (yellow) were shown in Figure 2c.	('LINC00491', 'Gene', '285708', (47, 56))	('LINC01697', 'Chemical', '-', (62, 71))	('LINC02315', 'Gene', (36, 45))	('LINC00491', 'Gene', (47, 56))	('LINC01697', 'Var', (62, 71))
112803	31617686	Boxplots in Figure 2d showed the gene expression level (FPKM) of LINC00487, LINC01927, and C10orf143 (LINC00959) in independent PT samples (red) and SN tissue samples (yellow).	('LINC01927', 'Gene', (76, 85))	('C10orf143', 'Var', (91, 100))	('LINC00487', 'Gene', '400941', (65, 74))	('LINC00959', 'Gene', (102, 111))	('LINC01927', 'Chemical', '-', (76, 85))	('gene expression level', 'MPA', (33, 54))	('LINC00487', 'Gene', (65, 74))	('LINC00959', 'Gene', '387723', (102, 111))
112809	31617686	Figure 2e showed LINC01697 as a significant negative indicator of advance stage (logOR (95% CI) <0).	('LINC01697', 'Chemical', '-', (17, 26))	('negative', 'NegReg', (44, 52))	('LINC01697', 'Var', (17, 26))	('advance stage', 'CPA', (66, 79))
112810	31617686	When evaluating the lincRNAs profile, we found that except above 20 risk/ protective lincRNA candidates, other 12 lincRNAs were significantly risk factor for advanced stages (logOR (95% CI) >0); LINC01697 and other 23 lincRNAs were significantly protective factors for advanced stages (logOR (95% CI) <0) (Figure S2).	('advanced', 'Disease', (269, 277))	('LINC01697', 'Chemical', '-', (195, 204))	('ncRNA', 'Gene', '54719', (220, 225))	('ncRNA', 'Gene', (22, 27))	('ncRNA', 'Gene', '54719', (87, 92))	('risk factor', 'Reg', (142, 153))	('ncRNA', 'Gene', (116, 121))	('LINC01697', 'Var', (195, 204))	('ncRNA', 'Gene', '54719', (22, 27))	('ncRNA', 'Gene', (220, 225))	('ncRNA', 'Gene', (87, 92))	('ncRNA', 'Gene', '54719', (116, 121))	('advanced', 'Disease', (158, 166))
112815	31617686	Among ten risk lincRNA candidates, we luckily obtained three lincRNAs (LINC01031, LINC01088, and LINC01931) that were also significant risk factor for poor survival (HR (95%CI) >1, Table 3).	('ncRNA', 'Gene', '54719', (63, 68))	('LINC01088', 'Gene', (82, 91))	('LINC01031', 'Gene', '101929184', (71, 80))	('poor survival', 'CPA', (151, 164))	('LINC01031', 'Gene', (71, 80))	('ncRNA', 'Gene', (63, 68))	('ncRNA', 'Gene', (17, 22))	('LINC01931', 'Var', (97, 106))	('LINC01088', 'Gene', '100505875', (82, 91))	('ncRNA', 'Gene', '54719', (17, 22))	('LINC01931', 'Chemical', '-', (97, 106))
112818	31617686	The 1-year, 5-year, and 10-year survival rate of LINC01524 low-level subgroup were 0.7489, 0.5194, and 0.2897, respectively, which were not significantly higher than the 1-year, 5-year, and 10-year survival rate of 0.6750, 0.4589, and 0.2252, respectively, in LINC01524 high-level subgroup (Logrank p-value = .1134, Wilcoxon p-value = .2085, Table S5A).	('LINC01524', 'Gene', (49, 58))	('LINC01524', 'Gene', '101927700', (260, 269))	('0.2897', 'Var', (103, 109))	('LINC01524', 'Gene', '101927700', (49, 58))	('LINC01524', 'Gene', (260, 269))
112819	31617686	KM curves and lifetest confirmed a significant poorer OS for patients with high level of LINC01031 (Logrank p = .0244, Figure 3b), LINC01088 (Logrank p = .0379, Figure 3c), and LINC01931 (Logrank p = .0204, Figure 3d) respectively.	('LINC01931', 'Var', (177, 186))	('LINC01931', 'Chemical', '-', (177, 186))	('LINC01031', 'Gene', '101929184', (89, 98))	('patients', 'Species', '9606', (61, 69))	('LINC01088', 'Gene', '100505875', (131, 140))	('LINC01031', 'Gene', (89, 98))	('LINC01088', 'Gene', (131, 140))
112820	31617686	The 1-year, 5-year, and 10-year survival rate of LINC01031 low-level subgroup were 0.7056, 0.4890, and 0.2495, respectively, which were significantly higher than the 1-year, 5-year, and 10-year survival rate of 0.5892, 0.0.3549, and 0, respectively, in LINC01031 high-level subgroup (Logrank p-value = .0244, Wilcoxon p-value = .0073, Table S5B).	('LINC01031', 'Gene', (49, 58))	('LINC01031', 'Gene', '101929184', (253, 262))	('higher', 'PosReg', (150, 156))	('0.4890', 'Var', (91, 97))	('0.2495', 'Var', (103, 109))	('LINC01031', 'Gene', (253, 262))	('LINC01031', 'Gene', '101929184', (49, 58))	('0.7056', 'Var', (83, 89))
112821	31617686	The 1-year, 5-year, and 10-year survival rate of LINC01088 low-level subgroup were 0.7268, 0.5003, and 0.3248, respectively, which were significantly higher than the 1-year, 5-year, and 10-year survival rate of 0.	('0.5003', 'Var', (91, 97))	('LINC01088', 'Gene', (49, 58))	('higher', 'PosReg', (150, 156))	('LINC01088', 'Gene', '100505875', (49, 58))	('0.3248', 'Var', (103, 109))
112822	31617686	6,503, 0.4413, and 0.0984, respectively, in LINC01088 high-level subgroup (Logrank p-value = .0379, Wilcoxon p-value = .0857, Table S5C).	('0.4413', 'Var', (7, 13))	('LINC01088', 'Gene', '100505875', (44, 53))	('0.0984', 'Var', (19, 25))	('LINC01088', 'Gene', (44, 53))
112823	31617686	The 1-year, 5-year, and 10-year survival rate of LINC01931 low-level subgroup were 0.7189, 0.5080, and 0.2755, respectively, which were significantly higher than the 1-year, 5-year, and 10-year survival rate of 0.6319, 0.3955, and 0, respectively, in LINC01931 high-level subgroup (Logrank p-value = .0204, Wilcoxon p-value = .0693, Table S5D).	('LINC01931', 'Gene', (49, 58))	('0.7189', 'Var', (83, 89))	('LINC01931', 'Chemical', '-', (49, 58))	('higher', 'PosReg', (150, 156))	('0.5080', 'Var', (91, 97))	('0.2755', 'Var', (103, 109))	('LINC01931', 'Chemical', '-', (251, 260))
112835	31617686	In gastric cancer, the knockdown of lncRNA GHET1 by shRNA could suppress tumor proliferation, invasion, migration, and enhance apoptosis (Huang, Liao, Zhu, Liu, & Cai, 2017).	('enhance', 'PosReg', (119, 126))	('invasion', 'CPA', (94, 102))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('gastric cancer', 'Phenotype', 'HP:0012126', (3, 17))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('migration', 'CPA', (104, 113))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('suppress', 'NegReg', (64, 72))	('lncRNA GHET1', 'Gene', (36, 48))	('knockdown', 'Var', (23, 32))	('apoptosis', 'CPA', (127, 136))	('tumor', 'Disease', (73, 78))	('gastric cancer', 'Disease', (3, 17))	('lncRNA GHET1', 'Gene', '102723099', (36, 48))	('gastric cancer', 'Disease', 'MESH:D013274', (3, 17))
112836	31617686	In cancer cells, LncRNA HOTAIR (HOX transcript antisense RNA) modulates cancer epigenome and facilitates metastasis (Gupta et al., 2010); silencing HOTAIR is viable to suppress cancer cells (Li et al., 2013).	('HOX transcript antisense RNA', 'Gene', '100124700', (32, 60))	('cancer', 'Disease', (177, 183))	('HOTAIR', 'Gene', (148, 154))	('facilitates', 'PosReg', (93, 104))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('HOX transcript antisense RNA', 'Gene', (32, 60))	('HOTAIR', 'Gene', '100124700', (24, 30))	('cancer', 'Disease', (72, 78))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('modulates', 'Reg', (62, 71))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('HOTAIR', 'Gene', (24, 30))	('ncRNA', 'Gene', (18, 23))	('ncRNA', 'Gene', '54719', (18, 23))	('silencing', 'Var', (138, 147))	('cancer', 'Disease', 'MESH:D009369', (177, 183))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('HOTAIR', 'Gene', '100124700', (148, 154))	('metastasis', 'CPA', (105, 115))	('cancer', 'Disease', (3, 9))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
112838	31617686	The knockdown of BCYRN1 by siRNA could suppress cell proliferation in a broad spectrum of tumors (Booy et al., 2017).	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('cell proliferation', 'CPA', (48, 66))	('tumors', 'Disease', (90, 96))	('tumors', 'Disease', 'MESH:D009369', (90, 96))	('suppress', 'NegReg', (39, 47))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('BCYRN1', 'Gene', (17, 23))	('BCYRN1', 'Gene', '618', (17, 23))	('knockdown', 'Var', (4, 13))
112839	31617686	In this study, high levels of LINC01031, LINC01088, and LINC01931 were not only valuable in tumor diagnosis, but also predicted a poor survival in LSqCC patients.	('LSqCC', 'Disease', (147, 152))	('patients', 'Species', '9606', (153, 161))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('LINC01931', 'Chemical', '-', (56, 65))	('tumor', 'Disease', (92, 97))	('LINC01088', 'Gene', '100505875', (41, 50))	('LSqCC', 'Phenotype', 'HP:0030359', (147, 152))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('LINC01931', 'Var', (56, 65))	('poor', 'NegReg', (130, 134))	('predicted', 'Reg', (118, 127))	('LINC01031', 'Gene', '101929184', (30, 39))	('LINC01031', 'Gene', (30, 39))	('LINC01088', 'Gene', (41, 50))
112840	31617686	Since lincRNAs always co-express with their neighboring genes and regulate the transcription of these gene (Cabili et al., 2011), so LINC01031, LINC01088, and LINC01931 might promote LSqCC through their neighboring genes.	('LINC01931', 'Chemical', '-', (159, 168))	('ncRNA', 'Gene', (8, 13))	('LINC01031', 'Gene', '101929184', (133, 142))	('LINC01088', 'Gene', (144, 153))	('transcription', 'MPA', (79, 92))	('LINC01031', 'Gene', (133, 142))	('promote', 'PosReg', (175, 182))	('ncRNA', 'Gene', '54719', (8, 13))	('LSqCC', 'Disease', (183, 188))	('LSqCC', 'Phenotype', 'HP:0030359', (183, 188))	('LINC01931', 'Var', (159, 168))	('LINC01088', 'Gene', '100505875', (144, 153))
112847	31617686	LINC01031, LINC01088, and LINC01931 might be the promising treatment targets for LSqCC patients.	('LSqCC', 'Phenotype', 'HP:0030359', (81, 86))	('LINC01931', 'Var', (26, 35))	('LINC01088', 'Gene', '100505875', (11, 20))	('LINC01031', 'Gene', '101929184', (0, 9))	('LINC01931', 'Chemical', '-', (26, 35))	('LINC01031', 'Gene', (0, 9))	('LSqCC', 'Disease', (81, 86))	('LINC01088', 'Gene', (11, 20))	('patients', 'Species', '9606', (87, 95))
112850	31617686	In LSqCC patients, high levels of LINC01031, LINC01088, and LINC01931 were significantly associated with poor prognosis, suggesting potential targets for anti-LSqCC treatment.	('associated', 'Reg', (89, 99))	('LSqCC', 'Disease', (3, 8))	('patients', 'Species', '9606', (9, 17))	('LINC01931', 'Var', (60, 69))	('LINC01088', 'Gene', '100505875', (45, 54))	('LSqCC', 'Phenotype', 'HP:0030359', (3, 8))	('LINC01931', 'Chemical', '-', (60, 69))	('LINC01031', 'Gene', '101929184', (34, 43))	('LINC01088', 'Gene', (45, 54))	('LSqCC', 'Phenotype', 'HP:0030359', (159, 164))	('LINC01031', 'Gene', (34, 43))
112862	30845770	We present an overview of all connexins but particularly focus on four isoforms implicated in lung cancer: Cx26, Cx30.3, Cx32 and Cx43.	('Cx32', 'Var', (121, 125))	('connexin', 'Gene', '100128922', (30, 38))	('connexin', 'Gene', (30, 38))	('lung cancer', 'Disease', 'MESH:D008175', (94, 105))	('Cx43', 'Var', (130, 134))	('lung cancer', 'Disease', (94, 105))	('Cx30.3', 'Var', (113, 119))	('lung cancer', 'Phenotype', 'HP:0100526', (94, 105))	('Cx26', 'Var', (107, 111))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
112880	30845770	Cx26 and Cx43 have been detected in human epithelial cells of the respiratory airways, whereas a variety of additional connexins has been detected in murine models, including Cx32, Cx37 and Cx46.	('Cx37', 'Gene', '14612', (181, 185))	('rat', 'Species', '10116', (71, 74))	('Cx37', 'Gene', (181, 185))	('Cx43', 'Gene', (9, 13))	('murine', 'Species', '10090', (150, 156))	('Cx46', 'Gene', '14611', (190, 194))	('Cx32', 'Var', (175, 179))	('Cx46', 'Gene', (190, 194))	('connexin', 'Gene', '100128922', (119, 127))	('human', 'Species', '9606', (36, 41))	('connexin', 'Gene', (119, 127))
112893	30845770	In A549 LUAD cells, Cx32 increases vinorelbine-induced cytotoxicity by reducing the expression of the multidrug resistance-1 (MDR-1) gene.	('Cx32', 'Var', (20, 24))	('reducing', 'NegReg', (71, 79))	('A549', 'CellLine', 'CVCL:0023', (3, 7))	('multidrug resistance-1', 'Gene', '5243', (102, 124))	('vinorelbine', 'Chemical', 'MESH:D000077235', (35, 46))	('vinorelbine-induced', 'MPA', (35, 54))	('increases', 'PosReg', (25, 34))	('MDR-1', 'Gene', (126, 131))	('cytotoxicity', 'Disease', (55, 67))	('LUAD', 'Phenotype', 'HP:0030078', (8, 12))	('multidrug resistance-1', 'Gene', (102, 124))	('expression', 'MPA', (84, 94))	('cytotoxicity', 'Disease', 'MESH:D064420', (55, 67))	('MDR-1', 'Gene', '5243', (126, 131))
112902	30845770	Various studies have suggested promotor methylation regulate connexin expression in cancer.	('methylation', 'Var', (40, 51))	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('connexin', 'Gene', (61, 69))	('cancer', 'Disease', (84, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('connexin', 'Gene', '100128922', (61, 69))
112903	30845770	Decreased expression of Cx43 at the mRNA and protein levels due to promoter methylation has been shown to occur during NSCLC tumour progression.	('promoter methylation', 'Var', (67, 87))	('Decreased', 'NegReg', (0, 9))	('tumour', 'Phenotype', 'HP:0002664', (125, 131))	('NSCLC tumour', 'Disease', 'MESH:D009369', (119, 131))	('expression', 'MPA', (10, 20))	('NSCLC', 'Phenotype', 'HP:0030358', (119, 124))	('Cx43', 'Gene', (24, 28))	('NSCLC tumour', 'Disease', (119, 131))
112904	30845770	Hypermethylation of the GJA1 (Cx43) promoter has been significantly associated with heavy smoking, poorly differentiated NSCLC and low expression of Cx43.	('heavy smoking', 'Disease', (84, 97))	('associated', 'Reg', (68, 78))	('Hypermethylation', 'Var', (0, 16))	('GJA1', 'Gene', (24, 28))	('NSCLC', 'Disease', (121, 126))	('GJA1', 'Gene', '2697', (24, 28))	('NSCLC', 'Disease', 'MESH:D002289', (121, 126))	('expression', 'MPA', (135, 145))	('NSCLC', 'Phenotype', 'HP:0030358', (121, 126))	('low', 'NegReg', (131, 134))	('Cx43', 'Protein', (149, 153))
112905	30845770	There is also strong evidence that promoter methylation can cause decreased Cx26 expression in lung tumours.	('promoter methylation', 'Var', (35, 55))	('lung tumours', 'Disease', (95, 107))	('lung tumour', 'Phenotype', 'HP:0100526', (95, 106))	('decreased', 'NegReg', (66, 75))	('tumour', 'Phenotype', 'HP:0002664', (100, 106))	('lung tumours', 'Disease', 'MESH:D008175', (95, 107))	('tumours', 'Phenotype', 'HP:0002664', (100, 107))	('Cx26 expression', 'MPA', (76, 91))
112906	30845770	Cx32 has been positively correlated with the degree of tumour differentiation and survival rates of NSCLC patients.	('tumour', 'Disease', (55, 61))	('survival', 'CPA', (82, 90))	('rat', 'Species', '10116', (91, 94))	('NSCLC', 'Disease', (100, 105))	('NSCLC', 'Disease', 'MESH:D002289', (100, 105))	('tumour', 'Phenotype', 'HP:0002664', (55, 61))	('tumour', 'Disease', 'MESH:D009369', (55, 61))	('patients', 'Species', '9606', (106, 114))	('Cx32', 'Var', (0, 4))	('NSCLC', 'Phenotype', 'HP:0030358', (100, 105))
112911	30845770	For example, Cx43 reverses cisplatin resistance in A549 LUAD cells by inhibiting EMT.	('cisplatin', 'Chemical', 'MESH:D002945', (27, 36))	('reverses', 'NegReg', (18, 26))	('Cx43', 'Var', (13, 17))	('A549', 'CellLine', 'CVCL:0023', (51, 55))	('cisplatin resistance', 'MPA', (27, 47))	('LUAD', 'Phenotype', 'HP:0030078', (56, 60))	('inhibiting', 'NegReg', (70, 80))	('EMT', 'CPA', (81, 84))
112912	30845770	In contrast, Cx26 (in a GJIC-independent manner) induces EMT via the PI3K-AKT signalling pathway and confers resistance to the EGFR inhibitor gefitinib in HCC827 and PC9 LUAD cells.	('Cx26', 'Var', (13, 17))	('induces', 'PosReg', (49, 56))	('gefitinib', 'Chemical', 'MESH:D000077156', (142, 151))	('PI3K-AKT signalling pathway', 'Pathway', (69, 96))	('LUAD', 'Phenotype', 'HP:0030078', (170, 174))	('resistance', 'MPA', (109, 119))	('EMT', 'CPA', (57, 60))	('PC9 LUAD', 'CellLine', 'CVCL:B260', (166, 174))	('EGFR', 'Gene', '1956', (127, 131))	('EGFR', 'Gene', (127, 131))
112913	30845770	Other studies have implicated Cx43 in this process through enhanced attachment of lung tumour cells to the endothelium that facilitates extravasation, a critical feature for efficient metastasis.	('lung tumour', 'Disease', 'MESH:D008175', (82, 93))	('attachment', 'CPA', (68, 78))	('extravasation', 'MPA', (136, 149))	('Cx43', 'Var', (30, 34))	('enhanced', 'PosReg', (59, 67))	('facilitates', 'PosReg', (124, 135))	('lung tumour', 'Phenotype', 'HP:0100526', (82, 93))	('tumour', 'Phenotype', 'HP:0002664', (87, 93))	('lung tumour', 'Disease', (82, 93))
112914	30845770	Recently, a clear pro-tumorigenic role for Cx43 in lung cancer and metastasis to the brain was demonstrated.	('lung cancer', 'Disease', 'MESH:D008175', (51, 62))	('pro-tumorigenic', 'MPA', (18, 33))	('Cx43', 'Var', (43, 47))	('metastasis to the brain', 'CPA', (67, 90))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('lung cancer', 'Disease', (51, 62))	('lung cancer', 'Phenotype', 'HP:0100526', (51, 62))	('rat', 'Species', '10116', (102, 105))
112917	30845770	More recently, Cx30.3 was shown to be overexpressed in lung tumours and to be associated with poor prognosis and recurrence.	('associated', 'Reg', (78, 88))	('lung tumours', 'Disease', 'MESH:D008175', (55, 67))	('overexpressed', 'PosReg', (38, 51))	('Cx30.3', 'Var', (15, 21))	('lung tumours', 'Disease', (55, 67))	('lung tumour', 'Phenotype', 'HP:0100526', (55, 66))	('tumour', 'Phenotype', 'HP:0002664', (60, 66))	('tumours', 'Phenotype', 'HP:0002664', (60, 67))
112918	30845770	Functionally, Cx30.3 appears to activate the c-Src proto-oncogene to induce a number of cellular traits associated with malignancy.	('Cx30.3', 'Var', (14, 20))	('c-Src', 'Gene', '6714', (45, 50))	('malignancy', 'Disease', (120, 130))	('induce', 'PosReg', (69, 75))	('malignancy', 'Disease', 'MESH:D009369', (120, 130))	('cellular', 'MPA', (88, 96))	('c-Src', 'Gene', (45, 50))
112939	30845770	We focused on four connexin genes:Cx26, Cx30.3, Cx32 and Cx43:thought to play a role in lung cancer based on previous research (including mouse models).	('lung cancer', 'Disease', (88, 99))	('Cx43', 'Var', (57, 61))	('mouse', 'Species', '10090', (138, 143))	('lung cancer', 'Phenotype', 'HP:0100526', (88, 99))	('Cx30.3', 'Var', (40, 46))	('Cx26', 'Var', (34, 38))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('lung cancer', 'Disease', 'MESH:D008175', (88, 99))	('connexin', 'Gene', '100128922', (19, 27))	('connexin', 'Gene', (19, 27))	('Cx32', 'Var', (48, 52))
112943	30845770	Cx26 and Cx30.3 have been suggested to be pro-tumorigenic in the lung, and the in silico data supported this notion based on the idea that overexpression may drive tumour progression.	('Cx30.3', 'Var', (9, 15))	('tumour', 'Phenotype', 'HP:0002664', (164, 170))	('Cx26', 'Var', (0, 4))	('tumour', 'Disease', 'MESH:D009369', (164, 170))	('drive', 'PosReg', (158, 163))	('tumour', 'Disease', (164, 170))	('pro-tumorigenic', 'MPA', (42, 57))
112950	30845770	As seen in Figure 2, methylation-specific changes were connexin and tumour subtype-specific.	('tumour', 'Phenotype', 'HP:0002664', (68, 74))	('methylation-specific', 'Var', (21, 41))	('connexin', 'Gene', '100128922', (55, 63))	('connexin', 'Gene', (55, 63))	('tumour subtype', 'Disease', 'MESH:C535673', (68, 82))	('changes', 'Reg', (42, 49))	('tumour subtype', 'Disease', (68, 82))
112952	30845770	Overall, however, GJB2 seemed to be hypomethylated (a state considered to occur with a Beta value in the range around or below 0.25-0.30), which favours trancription.	('GJB2', 'Gene', (18, 22))	('hypomethylated', 'Var', (36, 50))	('GJB2', 'Gene', '2706', (18, 22))
112960	30845770	Indeed, although there were no major overall changes in the methylation status of GJB2 (encoding Cx26; Figure 2a), a noticeable demethylation was seen in probe cg24425972 in LUSC (Figure 2a,b) compared with normal tissues, which correlates well with the observed significant upregulation of the mRNA expression-based Illumina HiSeq RNA-seq (Figure 2b, see also Figure 1a).	('demethylation', 'MPA', (128, 141))	('cg24425972', 'Var', (160, 170))	('GJB2', 'Gene', '2706', (82, 86))	('LUSC', 'Phenotype', 'HP:0030359', (174, 178))	('upregulation', 'PosReg', (275, 287))	('GJB2', 'Gene', (82, 86))
112963	30845770	Indeed, among only 30 genes identified, methylation of GJB2 (encoding Cx26) was associated with tumour stage in LUAD (Kruskal-Wallis p-value = 0.0001923, Q value = 0.119).	('GJB2', 'Gene', '2706', (55, 59))	('methylation', 'Var', (40, 51))	('tumour', 'Disease', (96, 102))	('GJB2', 'Gene', (55, 59))	('tumour', 'Phenotype', 'HP:0002664', (96, 102))	('tumour', 'Disease', 'MESH:D009369', (96, 102))	('associated', 'Reg', (80, 90))	('LUAD', 'Phenotype', 'HP:0030078', (112, 116))	('LUAD', 'Disease', (112, 116))
112970	30845770	We paid particular attention to connexin genes known to play a role in lung cancer, namely, Cx26, Cx30.3, Cx32 and Cx43.	('lung cancer', 'Phenotype', 'HP:0100526', (71, 82))	('lung cancer', 'Disease', 'MESH:D008175', (71, 82))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('Cx30.3', 'Var', (98, 104))	('Cx32', 'Var', (106, 110))	('connexin', 'Gene', '100128922', (32, 40))	('connexin', 'Gene', (32, 40))	('lung cancer', 'Disease', (71, 82))	('Cx43', 'Var', (115, 119))	('Cx26', 'Var', (92, 96))
112973	30845770	On the other hand, high Cx32 expression predicted better survival in overal NSCLC and LUAD patients, whereas LUSC patients had a tendency to perform worse if grouped in the cohort with high Cx32 expression (Figure 3b).	('high', 'Var', (19, 23))	('patients', 'Species', '9606', (91, 99))	('Cx32', 'Protein', (24, 28))	('NSCLC', 'Disease', (76, 81))	('LUAD', 'Phenotype', 'HP:0030078', (86, 90))	('LUAD', 'Disease', (86, 90))	('survival', 'MPA', (57, 65))	('NSCLC', 'Disease', 'MESH:D002289', (76, 81))	('LUSC', 'Phenotype', 'HP:0030359', (109, 113))	('overal', 'Disease', (69, 75))	('expression', 'MPA', (29, 39))	('better', 'PosReg', (50, 56))	('NSCLC', 'Phenotype', 'HP:0030358', (76, 81))	('patients', 'Species', '9606', (114, 122))
112974	30845770	The recent findings that Cx30.3 is linked to tumour progression are strongly supported by our in silico analysis, which predicted significantly worse survival in the NSCLC group and the LUAD subtype (Figure 3c).	('NSCLC', 'Phenotype', 'HP:0030358', (166, 171))	('worse', 'NegReg', (144, 149))	('tumour', 'Phenotype', 'HP:0002664', (45, 51))	('NSCLC', 'Disease', (166, 171))	('tumour', 'Disease', 'MESH:D009369', (45, 51))	('LUAD', 'Phenotype', 'HP:0030078', (186, 190))	('NSCLC', 'Disease', 'MESH:D002289', (166, 171))	('survival', 'MPA', (150, 158))	('Cx30.3', 'Var', (25, 31))	('tumour', 'Disease', (45, 51))
112976	30845770	Cx26 predicts a poor outcome for NSCLC in general, and a significantly worse prognosis in the LUAD subgroup (HR = 2.12), where patients with high Cx26 expression are predicted to live an average of 56 months less than those with low Cx26 expression (80 months vs. 136 months).	('NSCLC', 'Phenotype', 'HP:0030358', (33, 38))	('less', 'NegReg', (208, 212))	('NSCLC', 'Disease', 'MESH:D002289', (33, 38))	('Cx26', 'Var', (0, 4))	('Cx26', 'Gene', (146, 150))	('patients', 'Species', '9606', (127, 135))	('LUAD', 'Phenotype', 'HP:0030078', (94, 98))	('NSCLC', 'Disease', (33, 38))	('high', 'Var', (141, 145))
112988	30845770	Cx43 is implicated in lung cancer but substantial evidence also indicates that Cx43, in a highly context-dependent manner, can act as both a tumour supressor and tumour promoter.	('lung cancer', 'Disease', (22, 33))	('tumour', 'Disease', (162, 168))	('lung cancer', 'Phenotype', 'HP:0100526', (22, 33))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('tumour', 'Phenotype', 'HP:0002664', (141, 147))	('lung cancer', 'Disease', 'MESH:D008175', (22, 33))	('Cx43', 'Var', (79, 83))	('tumour', 'Phenotype', 'HP:0002664', (162, 168))	('tumour', 'Disease', 'MESH:D009369', (141, 147))	('tumour', 'Disease', (141, 147))	('tumour', 'Disease', 'MESH:D009369', (162, 168))
112990	30845770	Cx43 is the most widely expressed connexin in lung epithelia, and several studies indicate dysregulation at multiple levels: transcription (including methylation), translation (including internal translation of truncated isoforms) and post-translational modifications (notably phosphorylation).	('connexin', 'Gene', '100128922', (34, 42))	('methylation', 'Var', (150, 161))	('connexin', 'Gene', (34, 42))	('lung epithelia', 'Disease', (46, 60))	('lung epithelia', 'Disease', 'MESH:D008171', (46, 60))	('translation', 'MPA', (164, 175))
112991	30845770	These alterations may affect Cx43 expression levels, function and subcellular localization.	('alterations', 'Var', (6, 17))	('Cx43 expression levels', 'MPA', (29, 51))	('subcellular localization', 'MPA', (66, 90))	('affect', 'Reg', (22, 28))	('rat', 'Species', '10116', (10, 13))	('function', 'MPA', (53, 61))
113004	30845770	We could not correlate the presence of nuclear Cx43 with a specific tumour subtype or stage (i.e., we detected nuclear Cx43 in both low grade and high grade tumours, as well as in various LUAD subtypes such as acinar, papillary, micropapillary and solid).	('tumour', 'Phenotype', 'HP:0002664', (68, 74))	('acinar', 'Disease', (210, 216))	('tumour', 'Phenotype', 'HP:0002664', (157, 163))	('tumours', 'Phenotype', 'HP:0002664', (157, 164))	('tumours', 'Disease', 'MESH:D009369', (157, 164))	('papillary', 'Disease', (218, 227))	('tumour subtype', 'Disease', 'MESH:C535673', (68, 82))	('micropapillary', 'Disease', (229, 243))	('nuclear Cx43', 'Var', (111, 123))	('detected', 'Reg', (102, 110))	('tumours', 'Disease', (157, 164))	('LUAD', 'Phenotype', 'HP:0030078', (188, 192))	('tumour subtype', 'Disease', (68, 82))
113007	30845770	Our Kaplan-Meier survival curve analysis (Figure 6a) indicated that nuclear Cx43 was significantly associated with poor OS in NSCLC (p = 0.014).	('NSCLC', 'Disease', 'MESH:D002289', (126, 131))	('poor', 'Disease', (115, 119))	('NSCLC', 'Phenotype', 'HP:0030358', (126, 131))	('NSCLC', 'Disease', (126, 131))	('nuclear Cx43', 'Var', (68, 80))
113010	30845770	When including patients that scored positive for either CM Cx43 IHC or nuclear Cx43, no significance was observed in NSCLC, LUSC or LUAD (Supplementary Figure S4g-i).	('LUSC', 'Phenotype', 'HP:0030359', (124, 128))	('NSCLC', 'Disease', (117, 122))	('patients', 'Species', '9606', (15, 23))	('LUSC', 'Disease', (124, 128))	('LUAD', 'Phenotype', 'HP:0030078', (132, 136))	('LUAD', 'Disease', (132, 136))	('NSCLC', 'Disease', 'MESH:D002289', (117, 122))	('NSCLC', 'Phenotype', 'HP:0030358', (117, 122))	('CM Cx43 IHC', 'Var', (56, 67))	('nuclear Cx43', 'Var', (71, 83))
113011	30845770	However, patients classified into a single group positive for either nuclear Cx43 staining or moderate to strong CM staining, showed significant association for poor prognosis in NSCLC (p = 0.008) and LUAD (p = 0.005) (Supplementary Figure S4j-l).	('moderate', 'Var', (94, 102))	('patients', 'Species', '9606', (9, 17))	('NSCLC', 'Disease', 'MESH:D002289', (179, 184))	('nuclear Cx43 staining', 'Var', (69, 90))	('LUAD', 'Phenotype', 'HP:0030078', (201, 205))	('LUAD', 'Disease', (201, 205))	('poor', 'NegReg', (161, 165))	('rat', 'Species', '10116', (98, 101))	('NSCLC', 'Phenotype', 'HP:0030358', (179, 184))	('NSCLC', 'Disease', (179, 184))
113025	30845770	The direct correlation between methylation status and transcription in cancer seems to be restricted to a subset of genes in a tissue-specific manner, and the exact underlying mechanism remains elusive.	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('cancer', 'Disease', (71, 77))	('methylation', 'Var', (31, 42))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('transcription', 'MPA', (54, 67))
113039	30845770	It is also noteworthy that we observed nuclear Cx43 in non-tumoural cells (e.g., endothelial cells, chondrocytes and immune cells) in those tumours displaying nuclear Cx43.	('tumour', 'Phenotype', 'HP:0002664', (140, 146))	('nuclear Cx43', 'Var', (159, 171))	('tumours', 'Phenotype', 'HP:0002664', (140, 147))	('tumour', 'Disease', 'MESH:D009369', (140, 146))	('tumour', 'Phenotype', 'HP:0002664', (59, 65))	('tumour', 'Disease', (140, 146))	('nuclear Cx43', 'MPA', (39, 51))	('tumours', 'Disease', 'MESH:D009369', (140, 147))	('tumours', 'Disease', (140, 147))	('tumour', 'Disease', (59, 65))	('tumour', 'Disease', 'MESH:D009369', (59, 65))
113044	30845770	Nuclear Cx43 has additionally been detected in some tumours, notably in glioma and colon cancers, although these studies did not report an association with overall survival.	('glioma', 'Disease', (72, 78))	('colon cancers', 'Phenotype', 'HP:0003003', (83, 96))	('detected', 'Reg', (35, 43))	('tumours', 'Disease', (52, 59))	('cancers', 'Phenotype', 'HP:0002664', (89, 96))	('colon cancers', 'Disease', 'MESH:D015179', (83, 96))	('tumour', 'Phenotype', 'HP:0002664', (52, 58))	('glioma', 'Phenotype', 'HP:0009733', (72, 78))	('glioma', 'Disease', 'MESH:D005910', (72, 78))	('tumours', 'Phenotype', 'HP:0002664', (52, 59))	('Nuclear Cx43', 'Var', (0, 12))	('colon cancers', 'Disease', (83, 96))	('tumours', 'Disease', 'MESH:D009369', (52, 59))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
113077	30845770	It also proposes that modulation of Cx43 trafficking may be a useful therapeutic strategy.	('Cx43', 'Protein', (36, 40))	('rat', 'Species', '10116', (83, 86))	('modulation', 'Var', (22, 32))
113083	29212036	DeltaNp63 Inhibits Oxidative Stress-Induced Cell Death Including Ferroptosis and Cooperates with the BCL-2 Family to Promote Clonogenic Survival The BCL-2 family proteins are central regulators of apoptosis.	('Stress-Induced Cell Death', 'Disease', 'MESH:D004194', (29, 54))	('Clonogenic Survival', 'CPA', (125, 144))	('Promote', 'PosReg', (117, 124))	('Stress-Induced Cell Death', 'Disease', (29, 54))	('BCL-2', 'Gene', (101, 106))	('Ferroptosis', 'CPA', (65, 76))	('DeltaNp63', 'Var', (0, 9))	('BCL-2', 'Gene', '596', (101, 106))	('Oxidative Stress', 'Phenotype', 'HP:0025464', (19, 35))	('BCL-2', 'Gene', '596', (149, 154))	('Inhibits', 'NegReg', (10, 18))	('DeltaNp63', 'Chemical', '-', (0, 9))	('BCL-2', 'Gene', (149, 154))
113085	29212036	Here, we show that DeltaNp63alpha overexpression protects cells from oxidative stress induced by oxidants, DNA damage, anoikis, or ferroptosis-inducing agents.	('DeltaNp63alpha', 'Var', (19, 33))	('DeltaNp63alpha', 'Chemical', '-', (19, 33))	('oxidative stress', 'MPA', (69, 85))	('oxidative stress', 'Phenotype', 'HP:0025464', (69, 85))
113088	29212036	Analysis of The Cancer Genome Atlas (TCGA) lung squamous cell carcinoma dataset reveals that TP63 amplification/overexpression upregulates the glutathione metabolism pathway in primary human tumors.	('tumors', 'Phenotype', 'HP:0002664', (191, 197))	('glutathione', 'Chemical', 'MESH:D005978', (143, 154))	('TP63', 'Gene', (93, 97))	('human', 'Species', '9606', (185, 190))	('Cancer', 'Phenotype', 'HP:0002664', (16, 22))	('amplification/overexpression upregulates', 'PosReg', (98, 138))	('amplification/overexpression', 'Var', (98, 126))	('tumors', 'Disease', 'MESH:D009369', (191, 197))	('glutathione metabolism pathway', 'Pathway', (143, 173))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('tumors', 'Disease', (191, 197))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (43, 71))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (48, 71))	('TP63', 'Gene', '8626', (93, 97))	('Cancer Genome Atlas (TCGA) lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (16, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (62, 71))
113089	29212036	Strikingly, overexpression of DeltaNp63alpha promotes clonogenic survival of p53-/-Bax-/-Bak-/- cells against DNA damage.	('DeltaNp63alpha', 'Chemical', '-', (30, 44))	('DeltaNp63alpha', 'Var', (30, 44))	('p53', 'Gene', (77, 80))	('promotes', 'PosReg', (45, 53))	('p53', 'Gene', '7157', (77, 80))	('clonogenic survival', 'CPA', (54, 73))
113092	29212036	DeltaNp63alpha alleviates oxidative stress and cooperates with BCL-2 family to promote both long-term cellular wellbeing and cancer metastasis.	('long-term cellular wellbeing', 'CPA', (92, 120))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('cancer metastasis', 'Disease', (125, 142))	('oxidative stress', 'MPA', (26, 42))	('DeltaNp63alpha', 'Chemical', '-', (0, 14))	('promote', 'PosReg', (79, 86))	('DeltaNp63alpha', 'Var', (0, 14))	('cancer metastasis', 'Disease', 'MESH:D009362', (125, 142))	('oxidative stress', 'Phenotype', 'HP:0025464', (26, 42))	('alleviates', 'NegReg', (15, 25))
113093	29212036	Proper execution of cell death ensures normal biological processes, and its deregulation causes human diseases, ranging from cancer to neurodegenerative disorders.	('causes', 'Reg', (89, 95))	('human', 'Species', '9606', (96, 101))	('neurodegenerative disorders', 'Disease', 'MESH:D019636', (135, 162))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('neurodegenerative disorders', 'Phenotype', 'HP:0002180', (135, 162))	('neurodegenerative disorders', 'Disease', (135, 162))	('deregulation', 'Var', (76, 88))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))
113101	29212036	Notably, DNA alkylation induces PARP-dependent necrotic death whereas double-strand DNA breaks induce PARP-independent necrotic death in DKO cells.	('necrotic death', 'Disease', 'MESH:D003643', (47, 61))	('necrotic death', 'Disease', 'MESH:D003643', (119, 133))	('double-strand', 'Var', (70, 83))	('PARP', 'Gene', (102, 106))	('PARP', 'Gene', '142', (32, 36))	('necrotic death', 'Disease', (47, 61))	('necrotic death', 'Disease', (119, 133))	('DNA alkylation', 'Var', (9, 23))	('PARP', 'Gene', '142', (102, 106))	('PARP', 'Gene', (32, 36))
113107	29212036	The importance of ROS in regulating cell death is further exemplified by the recent characterization of ferroptosis, an iron-dependent, oxidative form of PND that is triggered by the depletion of intracellular glutathione or inhibition of GPX4, leading to accumulation of lipid hydroperoxides.	('GPX4', 'Gene', (239, 243))	('GPX4', 'Gene', '2879', (239, 243))	('depletion', 'MPA', (183, 192))	('accumulation', 'PosReg', (256, 268))	('lipid hydroperoxides', 'MPA', (272, 292))	('lipid hydroperoxides', 'Chemical', 'MESH:D008054', (272, 292))	('glutathione', 'Chemical', 'MESH:D005978', (210, 221))	('ROS', 'Chemical', 'MESH:D017382', (18, 21))	('ferroptosis', 'Disease', (104, 115))	('iron', 'Chemical', 'MESH:D007501', (120, 124))	('inhibition', 'Var', (225, 235))
113111	29212036	Here, we demonstrate that long-term clonogenic survival of apoptosis-defective cells in response to DNA damage or loss of matrix attachment could be achieved through overexpression of the putative oncogene DeltaNp63alpha, the major isoform of p63.	('DeltaNp63alpha', 'Chemical', '-', (206, 220))	('DeltaNp63alpha', 'Var', (206, 220))	('loss', 'NegReg', (114, 118))	('overexpression', 'PosReg', (166, 180))
113112	29212036	DeltaNp63alpha increases cellular resistance against oxidative stress and ferroptosis by regulating the synthesis, utilization, and regeneration of glutathione, a central component of the cellular antioxidant defense system.	('oxidative stress', 'Phenotype', 'HP:0025464', (53, 69))	('cellular resistance against oxidative stress', 'MPA', (25, 69))	('regulating', 'Reg', (89, 99))	('regeneration', 'MPA', (132, 144))	('synthesis', 'MPA', (104, 113))	('DeltaNp63alpha', 'Chemical', '-', (0, 14))	('increases', 'PosReg', (15, 24))	('DeltaNp63alpha', 'Var', (0, 14))	('glutathione', 'Chemical', 'MESH:D005978', (148, 159))	('utilization', 'MPA', (115, 126))
113113	29212036	The regulation of the glutathione metabolic pathway by DeltaNp63alpha was further demonstrated in human squamous cell lung cancer in which TP63 is frequently amplified.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('squamous cell lung cancer', 'Disease', (104, 129))	('glutathione metabolic pathway', 'Pathway', (22, 51))	('DeltaNp63alpha', 'Chemical', '-', (55, 69))	('TP63', 'Gene', (139, 143))	('TP63', 'Gene', '8626', (139, 143))	('squamous cell lung cancer', 'Disease', 'MESH:D002294', (104, 129))	('squamous cell lung cancer', 'Phenotype', 'HP:0030359', (104, 129))	('lung cancer', 'Phenotype', 'HP:0100526', (118, 129))	('glutathione', 'Chemical', 'MESH:D005978', (22, 33))	('human', 'Species', '9606', (98, 103))	('DeltaNp63alpha', 'Var', (55, 69))
113114	29212036	Amplification of TP63 appears to serve as a mechanism by which squamous cell lung cancer evades oxidative stress and promotes tumorigenesis.	('lung cancer', 'Phenotype', 'HP:0100526', (77, 88))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('Amplification', 'Var', (0, 13))	('squamous cell lung cancer', 'Disease', (63, 88))	('oxidative stress', 'Phenotype', 'HP:0025464', (96, 112))	('TP63', 'Gene', '8626', (17, 21))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('evades oxidative stress', 'MPA', (89, 112))	('squamous cell lung cancer', 'Phenotype', 'HP:0030359', (63, 88))	('TP63', 'Gene', (17, 21))	('squamous cell lung cancer', 'Disease', 'MESH:D002294', (63, 88))	('promotes', 'PosReg', (117, 125))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumor', 'Disease', (126, 131))
113120	29212036	Overexpression of DeltaNp63alpha also reduced etoposide-induced lipid peroxidation (Figure 1B).	('DeltaNp63alpha', 'Chemical', '-', (18, 32))	('DeltaNp63alpha', 'Var', (18, 32))	('etoposide-induced lipid peroxidation', 'MPA', (46, 82))	('lipid', 'Chemical', 'MESH:D008055', (64, 69))	('reduced', 'NegReg', (38, 45))	('etoposide', 'Chemical', 'MESH:D005047', (46, 55))
113122	29212036	Furthermore, overexpression of either DeltaNp63alpha or p53 DN provided only a short-term survival advantage against etoposide (Figure 1C), whereas co-expression of both DeltaNp63alpha and p53 DN enhanced clonogenic survival of DKO cells (Figure 1D).	('etoposide', 'Chemical', 'MESH:D005047', (117, 126))	('enhanced', 'PosReg', (196, 204))	('DeltaNp63alpha', 'Var', (170, 184))	('p53', 'Gene', '7157', (189, 192))	('p53', 'Gene', (56, 59))	('p53', 'Gene', '7157', (56, 59))	('DeltaNp63alpha', 'Chemical', '-', (170, 184))	('clonogenic survival', 'CPA', (205, 224))	('DeltaNp63alpha', 'Chemical', '-', (38, 52))	('DeltaNp63alpha', 'Var', (38, 52))	('p53', 'Gene', (189, 192))
113123	29212036	Of note, we have previously shown that transformation of MEFs by SV40 genome does not inactivate p53.	('MEFs', 'CellLine', 'CVCL:9115', (57, 61))	('p53', 'Gene', (97, 100))	('p53', 'Gene', '7157', (97, 100))	('SV40 genome', 'Var', (65, 76))
113124	29212036	To evaluate whether DeltaNp63alpha regulates ROS independently of p53, p53-/-Bax-/-Bak-/- triple-knockout (TKO) MEFs were generated.	('p53', 'Gene', '7157', (66, 69))	('ROS', 'Chemical', 'MESH:D017382', (45, 48))	('MEFs', 'CellLine', 'CVCL:9115', (112, 116))	('p53', 'Gene', (71, 74))	('p53', 'Gene', '7157', (71, 74))	('DeltaNp63alpha', 'Chemical', '-', (20, 34))	('DeltaNp63alpha', 'Var', (20, 34))	('ROS', 'MPA', (45, 48))	('p53', 'Gene', (66, 69))
113126	29212036	Importantly, overexpression of DeltaNp63alpha protected TKO from etoposide-induced ROS accumulation and cell death (Figures 1E, 1F, and S2).	('DeltaNp63alpha', 'Var', (31, 45))	('DeltaNp63alpha', 'Chemical', '-', (31, 45))	('ROS', 'Chemical', 'MESH:D017382', (83, 86))	('etoposide-induced ROS accumulation', 'MPA', (65, 99))	('cell death', 'CPA', (104, 114))	('etoposide', 'Chemical', 'MESH:D005047', (65, 74))
113127	29212036	Furthermore, inhibition of oxidative stress by DeltaNp63alpha conferred clonogenic survival of TKO cells against DNA damage (Figure 1G).	('clonogenic survival', 'CPA', (72, 91))	('DeltaNp63alpha', 'Chemical', '-', (47, 61))	('DeltaNp63alpha', 'Var', (47, 61))	('oxidative stress', 'Phenotype', 'HP:0025464', (27, 43))	('inhibition', 'NegReg', (13, 23))	('conferred', 'PosReg', (62, 71))	('oxidative stress', 'MPA', (27, 43))
113128	29212036	Because BCL-XL amplification/overexpression and p53 mutations can co-occur in human cancers, we next examined whether DeltaNp63alpha can inhibit etoposide-induced death in BCL-XL-overexpressing p53-deficient MEFs that resemble p53-/-Bax-/-Bak-/- TKO MEFs.	('p53', 'Gene', (227, 230))	('p53', 'Gene', (194, 197))	('BCL-XL', 'Gene', (8, 14))	('DeltaNp63alpha', 'Var', (118, 132))	('DeltaNp63alpha', 'Chemical', '-', (118, 132))	('cancers', 'Disease', 'MESH:D009369', (84, 91))	('p53', 'Gene', '7157', (48, 51))	('human', 'Species', '9606', (78, 83))	('p53', 'Gene', (48, 51))	('BCL-XL', 'Gene', '598', (8, 14))	('BCL-XL', 'Gene', (172, 178))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('etoposide-induced death', 'MPA', (145, 168))	('mutations', 'Var', (52, 61))	('MEFs', 'CellLine', 'CVCL:9115', (250, 254))	('etoposide', 'Chemical', 'MESH:D005047', (145, 154))	('cancers', 'Phenotype', 'HP:0002664', (84, 91))	('p53', 'Gene', '7157', (227, 230))	('cancers', 'Disease', (84, 91))	('p53', 'Gene', '7157', (194, 197))	('inhibit', 'NegReg', (137, 144))	('BCL-XL', 'Gene', '598', (172, 178))	('MEFs', 'CellLine', 'CVCL:9115', (208, 212))
113129	29212036	Indeed, overexpression of both BCL-XL and DeltaNp63alpha but not alone completely blocked etoposide-induced death of p53-/- MEFs (Figure 1H).	('p53', 'Gene', (117, 120))	('p53', 'Gene', '7157', (117, 120))	('etoposide', 'Chemical', 'MESH:D005047', (90, 99))	('BCL-XL', 'Gene', (31, 37))	('blocked', 'NegReg', (82, 89))	('BCL-XL', 'Gene', '598', (31, 37))	('DeltaNp63alpha', 'Chemical', '-', (42, 56))	('DeltaNp63alpha', 'Var', (42, 56))	('MEFs', 'CellLine', 'CVCL:9115', (124, 128))	('etoposide-induced death', 'MPA', (90, 113))
113132	29212036	Of note, MEFs only express TAp63 but not DeltaNp63 as determined by qRT-PCR (Figure S3).	('express', 'Reg', (19, 26))	('MEFs', 'CellLine', 'CVCL:9115', (9, 13))	('DeltaNp63', 'Chemical', '-', (41, 50))	('TAp63', 'Chemical', '-', (27, 32))	('TAp63', 'Var', (27, 32))
113137	29212036	Moreover, expression of a human EEC syndrome (ectrodactyly, ectodermal dysplasia, and cleft lip/palate)-derived R244H DeltaNp63alpha mutant that loses DNA binding activity failed to protect DKO cells from DNA damage-induce cell death (Figure 1J).	('R244H', 'Var', (112, 117))	('ectrodactyly', 'Phenotype', 'HP:0100257', (46, 58))	('cleft lip', 'Phenotype', 'HP:0410030', (86, 95))	('DeltaNp63alpha', 'Chemical', '-', (118, 132))	('ectodermal dysplasia', 'Disease', 'MESH:D004476', (60, 80))	('R244H', 'Mutation', 'rs371409680', (112, 117))	('ectodermal dysplasia', 'Disease', (60, 80))	('DeltaNp63alpha', 'Gene', (118, 132))	('cleft lip/palate', 'Phenotype', 'HP:0000202', (86, 102))	('EEC syndrome', 'Disease', 'MESH:C536189', (32, 44))	('cleft lip/palate', 'Disease', (86, 102))	('ectodermal dysplasia', 'Phenotype', 'HP:0000968', (60, 80))	('EEC syndrome', 'Disease', (32, 44))	('human', 'Species', '9606', (26, 31))	('cleft lip/palate', 'Disease', 'MESH:D002971', (86, 102))
113139	29212036	We envisioned that if DeltaNp63alpha prevents DNA damage-induced oxidative stress by increasing antioxidant capacity, DeltaNp63alpha could protect cells against exogenous oxidants.	('DeltaNp63alpha', 'Var', (118, 132))	('DeltaNp63alpha', 'Chemical', '-', (118, 132))	('increasing', 'PosReg', (85, 95))	('DeltaNp63alpha', 'Chemical', '-', (22, 36))	('DeltaNp63alpha', 'Var', (22, 36))	('DNA damage-induced oxidative stress', 'MPA', (46, 81))	('oxidative stress', 'Phenotype', 'HP:0025464', (65, 81))	('antioxidant capacity', 'MPA', (96, 116))
113140	29212036	Indeed, overexpression of DeltaNp63alpha protected wild-type (WT) MEFs from thiol oxidant diamide and lipid oxidant tert-butyl hydroperoxide (TBH) (Figure 2A).	('diamide', 'Chemical', 'MESH:D003958', (90, 97))	('lipid', 'Chemical', 'MESH:D008055', (102, 107))	('thiol oxidant diamide', 'MPA', (76, 97))	('tert-butyl hydroperoxide', 'Chemical', 'MESH:D020122', (116, 140))	('DeltaNp63alpha', 'Chemical', '-', (26, 40))	('DeltaNp63alpha', 'Var', (26, 40))	('TBH', 'Chemical', 'MESH:D020122', (142, 145))	('MEFs', 'CellLine', 'CVCL:9115', (66, 70))	('thiol', 'Chemical', 'MESH:D013438', (76, 81))
113141	29212036	Given that glutathione is the major antioxidant produced by the cell and plays a central role in regulating the intracellular redox state, one testable thesis is that DeltaNp63alpha mitigates oxidative stress through transcriptional regulation of glutathione metabolism genes.	('glutathione', 'Chemical', 'MESH:D005978', (247, 258))	('mitigates oxidative stress', 'MPA', (182, 208))	('oxidative stress', 'Phenotype', 'HP:0025464', (192, 208))	('DeltaNp63alpha', 'Chemical', '-', (167, 181))	('DeltaNp63alpha', 'Var', (167, 181))	('glutathione', 'Chemical', 'MESH:D005978', (11, 22))	('glutathione metabolism genes', 'Gene', (247, 275))	('transcriptional', 'MPA', (217, 232))
113148	29212036	qRT-PCR confirmed that GCLC (the catalytic subunit of GCL), GSS, IDH2, and GPX2 were upregulated by DeltaNp63alpha (Figure 2C).	('DeltaNp63alpha', 'Var', (100, 114))	('IDH2', 'Gene', '3418', (65, 69))	('upregulated', 'PosReg', (85, 96))	('GCLC', 'Gene', '2729', (23, 27))	('GCL', 'Gene', (23, 26))	('GCL', 'Gene', (54, 57))	('GCLC', 'Gene', (23, 27))	('GSS', 'Gene', '2937', (60, 63))	('GSS', 'Gene', (60, 63))	('GPX2', 'Gene', (75, 79))	('GCL', 'Gene', '2729', (23, 26))	('IDH2', 'Gene', (65, 69))	('GCL', 'Gene', '2729', (54, 57))	('DeltaNp63alpha', 'Chemical', '-', (100, 114))
113150	29212036	Indeed, overexpression of DeltaNp63alpha significantly increased the GSH/GSSG ratio in cells both before and after etoposide treatment (Figure 2D).	('overexpression', 'PosReg', (8, 22))	('etoposide', 'Chemical', 'MESH:D005047', (115, 124))	('GSH/GSSG ratio', 'MPA', (69, 83))	('GSH', 'Chemical', '-', (69, 72))	('GSSG', 'Chemical', 'MESH:D019803', (73, 77))	('increased', 'PosReg', (55, 64))	('DeltaNp63alpha', 'Chemical', '-', (26, 40))	('DeltaNp63alpha', 'Var', (26, 40))
113153	29212036	The protective effect of DeltaNp63alpha was also mitigated by the GCLC inhibitor buthionine sulfoximine (BSO) (Figure S4).	('BSO', 'Chemical', 'MESH:D019328', (105, 108))	('buthionine sulfoximine', 'Chemical', 'MESH:D019328', (81, 103))	('DeltaNp63alpha', 'Chemical', '-', (25, 39))	('DeltaNp63alpha', 'Var', (25, 39))	('GCLC', 'Gene', (66, 70))	('GCLC', 'Gene', '2729', (66, 70))
113154	29212036	Of note, knockdown of these genes also enhanced etoposide-induced cell death in control DKO cells, but to a lesser degree (Figures 2E-2H), supporting the involvement of oxidative stress in this form of cell death.	('etoposide', 'Chemical', 'MESH:D005047', (48, 57))	('knockdown', 'Var', (9, 18))	('etoposide-induced', 'MPA', (48, 65))	('oxidative stress', 'Phenotype', 'HP:0025464', (169, 185))	('enhanced', 'PosReg', (39, 47))
113155	29212036	Collectively, our data show that DeltaNp63alpha orchestrates a tightly coupled glutathione metabolic circuit to alleviate oxidative stress (Figure 2B), protecting apoptosis-defective cells from ROS-mediated necrotic cell death.	('DeltaNp63alpha', 'Chemical', '-', (33, 47))	('DeltaNp63alpha', 'Var', (33, 47))	('oxidative stress', 'Phenotype', 'HP:0025464', (122, 138))	('alleviate', 'PosReg', (112, 121))	('glutathione', 'Chemical', 'MESH:D005978', (79, 90))	('necrotic cell death', 'Disease', 'MESH:D003643', (207, 226))	('ROS', 'Chemical', 'MESH:D017382', (194, 197))	('oxidative stress', 'MPA', (122, 138))	('necrotic cell death', 'Disease', (207, 226))
113156	29212036	As the DNA binding activity is required for DeltaNp63alpha to alleviate oxidative stress, we searched for the p63 response element in glutathione metabolism genes.	('alleviate oxidative stress', 'MPA', (62, 88))	('glutathione', 'Chemical', 'MESH:D005978', (134, 145))	('DeltaNp63alpha', 'Chemical', '-', (44, 58))	('DeltaNp63alpha', 'Var', (44, 58))	('oxidative stress', 'Phenotype', 'HP:0025464', (72, 88))
113157	29212036	Potential p63 binding sites were identified in the intron 1 of GCLC and GPX2.	('GPX2', 'Gene', (72, 76))	('binding', 'Interaction', (14, 21))	('GCLC', 'Gene', '2729', (63, 67))	('GCLC', 'Gene', (63, 67))	('p63', 'Var', (10, 13))
113160	29212036	These results highlight the importance of DeltaNp63alpha in orchestrating a tightly coupled glutathione metabolic circuit in maintaining redox homeostasis.	('glutathione', 'Chemical', 'MESH:D005978', (92, 103))	('DeltaNp63alpha', 'Chemical', '-', (42, 56))	('maintaining redox homeostasis', 'MPA', (125, 154))	('DeltaNp63alpha', 'Var', (42, 56))
113163	29212036	Consequently, the protective effect of DeltaNp63alpha against DNA damage-induced necrotic death was not affected by NRF2 loss (Figure 3E).	('necrotic death', 'Disease', 'MESH:D003643', (81, 95))	('DeltaNp63alpha', 'Chemical', '-', (39, 53))	('DeltaNp63alpha', 'Var', (39, 53))	('loss', 'NegReg', (121, 125))	('NRF2', 'Gene', '4780', (116, 120))	('necrotic death', 'Disease', (81, 95))	('NRF2', 'Gene', (116, 120))
113164	29212036	Furthermore, the DNA-binding incompetent R244H mutant of DeltaNp63alpha failed to upregulate GCLC (Figure 3F).	('GCLC', 'Gene', (93, 97))	('DeltaNp63alpha', 'Chemical', '-', (57, 71))	('upregulate', 'PosReg', (82, 92))	('R244H', 'Var', (41, 46))	('DeltaNp63alpha', 'Gene', (57, 71))	('GCLC', 'Gene', '2729', (93, 97))	('R244H', 'Mutation', 'rs371409680', (41, 46))
113165	29212036	In summary, these data not only illustrate an NRF2-independent regulation of GCLC by DeltaNp63alpha but also indicate that DeltaNp63alpha is a central regulator of glutathione biogenesis.	('NRF2', 'Gene', '4780', (46, 50))	('GCLC', 'Gene', '2729', (77, 81))	('GCLC', 'Gene', (77, 81))	('DeltaNp63alpha', 'Chemical', '-', (85, 99))	('DeltaNp63alpha', 'Var', (85, 99))	('NRF2', 'Gene', (46, 50))	('DeltaNp63alpha', 'Chemical', '-', (123, 137))	('regulation', 'MPA', (63, 73))	('glutathione', 'Chemical', 'MESH:D005978', (164, 175))
113168	29212036	Knockdown of DeltaNp63alpha using miR30-based shRNA or siRNA specific for DeltaNp63 also increased ROS (Figure S5).	('DeltaNp63', 'Chemical', '-', (13, 22))	('DeltaNp63', 'Var', (74, 83))	('ROS', 'MPA', (99, 102))	('DeltaNp63', 'Chemical', '-', (74, 83))	('DeltaNp63alpha', 'Chemical', '-', (13, 27))	('increased', 'PosReg', (89, 98))	('ROS', 'Chemical', 'MESH:D017382', (99, 102))	('DeltaNp63alpha', 'Gene', (13, 27))
113170	29212036	Knockdown of DeltaNp63alpha increased ROS whereas knockdown of TAp63 increased DeltaNp63 expression and slightly reduced ROS (Figure S5).	('increased', 'PosReg', (28, 37))	('DeltaNp63', 'Chemical', '-', (13, 22))	('ROS', 'MPA', (121, 124))	('expression', 'MPA', (89, 99))	('increased', 'PosReg', (69, 78))	('DeltaNp63', 'Gene', (79, 88))	('DeltaNp63', 'Chemical', '-', (79, 88))	('ROS', 'Chemical', 'MESH:D017382', (38, 41))	('TAp63', 'Chemical', '-', (63, 68))	('ROS', 'Chemical', 'MESH:D017382', (121, 124))	('DeltaNp63alpha', 'Chemical', '-', (13, 27))	('DeltaNp63alpha', 'Var', (13, 27))	('reduced', 'NegReg', (113, 120))	('ROS', 'MPA', (38, 41))
113171	29212036	Together, these results support that DeltaNp63 suppresses ROS accumulation.	('ROS', 'Chemical', 'MESH:D017382', (58, 61))	('suppresses', 'NegReg', (47, 57))	('DeltaNp63', 'Var', (37, 46))	('ROS accumulation', 'MPA', (58, 74))	('DeltaNp63', 'Chemical', '-', (37, 46))
113172	29212036	Importantly, qRT-PCR showed that DeltaNp63alpha knockdown downregulated GCLC, GSS, IDH2, and GPX2 (Figure 4C):the same set of genes that was upregulated by DeltaNp63alpha (Figure 2C).	('DeltaNp63alpha knockdown', 'Var', (33, 57))	('GCLC', 'Gene', '2729', (72, 76))	('IDH2', 'Gene', '3418', (83, 87))	('GPX2', 'Gene', (93, 97))	('DeltaNp63alpha', 'Chemical', '-', (33, 47))	('DeltaNp63alpha', 'Var', (156, 170))	('DeltaNp63alpha', 'Chemical', '-', (156, 170))	('GSS', 'Gene', '2937', (78, 81))	('downregulated', 'NegReg', (58, 71))	('GSS', 'Gene', (78, 81))	('upregulated', 'PosReg', (141, 152))	('IDH2', 'Gene', (83, 87))	('GCLC', 'Gene', (72, 76))	('knockdown', 'Var', (48, 57))
113174	29212036	Consistent with downregulation of glutathione metabolism genes by DeltaNp63alpha knockdown, the GSH/GSSG ratio was reduced in cells deficient for DeltaNp63alpha (Figure 4D), indicating a more oxidized redox state.	('GSH', 'Chemical', '-', (96, 99))	('glutathione', 'Chemical', 'MESH:D005978', (34, 45))	('DeltaNp63alpha', 'Chemical', '-', (146, 160))	('downregulation', 'NegReg', (16, 30))	('DeltaNp63alpha', 'Gene', (66, 80))	('GSSG', 'Chemical', 'MESH:D019803', (100, 104))	('reduced', 'NegReg', (115, 122))	('oxidized redox', 'MPA', (192, 206))	('knockdown', 'Var', (81, 90))	('glutathione', 'MPA', (34, 45))	('more', 'PosReg', (187, 191))	('GSH/GSSG ratio', 'MPA', (96, 110))	('downregulation of glutathione metabolism', 'Phenotype', 'HP:0003343', (16, 56))	('DeltaNp63alpha', 'Chemical', '-', (66, 80))
113175	29212036	Consequently, DeltaNp63alpha knockdown enhanced diamide-induced cell death, which was blocked by NAC (Figure 4E).	('knockdown', 'Var', (29, 38))	('DeltaNp63alpha', 'Gene', (14, 28))	('diamide-induced', 'Disease', (48, 63))	('diamide', 'Chemical', 'MESH:D003958', (48, 55))	('NAC', 'Gene', (97, 100))	('NAC', 'Gene', '7504', (97, 100))	('DeltaNp63alpha', 'Chemical', '-', (14, 28))	('enhanced', 'PosReg', (39, 47))
113176	29212036	Furthermore, DeltaNp63alpha knockdown slightly increased baseline cell death over time and sensitized cells to chemotherapeutic agent-induced cell death (Figure S5).	('DeltaNp63alpha', 'Protein', (13, 27))	('increased', 'PosReg', (47, 56))	('DeltaNp63alpha', 'Chemical', '-', (13, 27))	('knockdown', 'Var', (28, 37))	('sensitized', 'Reg', (91, 101))	('baseline', 'MPA', (57, 65))
113178	29212036	Given that DeltaNp63alpha orchestrates glutathione homeostasis and glutathione depletion induces ferroptosis, we envisioned that DeltaNp63alpha might inhibit ferroptosis.	('glutathione', 'Chemical', 'MESH:D005978', (39, 50))	('glutathione depletion', 'MPA', (67, 88))	('induces', 'Reg', (89, 96))	('inhibit', 'NegReg', (150, 157))	('DeltaNp63alpha', 'Chemical', '-', (11, 25))	('DeltaNp63alpha', 'Chemical', '-', (129, 143))	('glutathione', 'Chemical', 'MESH:D005978', (67, 78))	('DeltaNp63alpha', 'Var', (129, 143))	('ferroptosis', 'CPA', (158, 169))	('DeltaNp63alpha', 'Var', (11, 25))	('glutathione homeostasis', 'MPA', (39, 62))	('ferroptosis', 'Disease', (97, 108))
113180	29212036	Consistent with the published results, p53 deficiency protected MEFs from ferroptosis induced by erastin but only at early time point (Figures 5A and 5B).	('ferroptosis', 'Disease', (74, 85))	('MEFs', 'CellLine', 'CVCL:9115', (64, 68))	('erastin', 'Chemical', 'MESH:C477224', (97, 104))	('p53', 'Gene', '7157', (39, 42))	('p53', 'Gene', (39, 42))	('deficiency', 'Var', (43, 53))
113181	29212036	Overexpression of DeltaNp63alpha protected both WT and p53-/- MEFs from erastin-induced death, suggesting that the anti-ferroptotic activity of DeltaNp63alpha is independent of p53.	('DeltaNp63alpha', 'Chemical', '-', (18, 32))	('erastin', 'Chemical', 'MESH:C477224', (72, 79))	('p53', 'Gene', (55, 58))	('p53', 'Gene', '7157', (55, 58))	('anti-ferroptotic activity', 'MPA', (115, 140))	('p53', 'Gene', (177, 180))	('p53', 'Gene', '7157', (177, 180))	('DeltaNp63alpha', 'Chemical', '-', (144, 158))	('DeltaNp63alpha', 'Var', (144, 158))	('MEFs', 'CellLine', 'CVCL:9115', (62, 66))
113183	29212036	Although the effect of DeltaNp63alpha on glutathione homeostasis is probably sufficient to inhibit ferroptosis, DeltaNp63alpha may also regulate the expression of Slc7a11 directly or indirectly through p53.	('Slc7a11', 'Gene', (163, 170))	('DeltaNp63alpha', 'Chemical', '-', (112, 126))	('DeltaNp63alpha', 'Chemical', '-', (23, 37))	('inhibit', 'NegReg', (91, 98))	('DeltaNp63alpha', 'Var', (112, 126))	('glutathione', 'Chemical', 'MESH:D005978', (41, 52))	('glutathione homeostasis', 'MPA', (41, 64))	('regulate', 'Reg', (136, 144))	('expression', 'MPA', (149, 159))	('p53', 'Gene', '7157', (202, 205))	('ferroptosis', 'CPA', (99, 110))	('Slc7a11', 'Gene', '23657', (163, 170))	('p53', 'Gene', (202, 205))
113184	29212036	Interestingly, DeltaNp63alpha upregulated Slc7a11 expression in p53-/- but not in WT MEFs where p53 suppressed Slc7a11 expression (Figure 5D), suggesting that DeltaNp63alpha is unable to abrogate p53-mediated transcriptional repression of Slc7a11.	('DeltaNp63alpha', 'Var', (15, 29))	('p53', 'Gene', '7157', (96, 99))	('upregulated', 'PosReg', (30, 41))	('DeltaNp63alpha', 'Chemical', '-', (15, 29))	('Slc7a11', 'Gene', '23657', (42, 49))	('p53', 'Gene', '7157', (64, 67))	('expression', 'MPA', (50, 60))	('p53', 'Gene', (96, 99))	('Slc7a11', 'Gene', '23657', (239, 246))	('p53', 'Gene', (64, 67))	('Slc7a11', 'Gene', '23657', (111, 118))	('p53', 'Gene', '7157', (196, 199))	('Slc7a11', 'Gene', (42, 49))	('expression', 'MPA', (119, 129))	('MEFs', 'CellLine', 'CVCL:9115', (85, 89))	('Slc7a11', 'Gene', (239, 246))	('suppressed', 'NegReg', (100, 110))	('p53', 'Gene', (196, 199))	('Slc7a11', 'Gene', (111, 118))	('DeltaNp63alpha', 'Chemical', '-', (159, 173))
113185	29212036	Together, these findings suggest that the protective effect of DeltaNp63alpha against ferroptosis is probably due to its transcriptional control of glutathione metabolism genes in WT MEFs whereas its regulation of Slc7a11 further contributes to its anti-ferroptotic activity in p53-deficient MEFs.	('transcriptional', 'MPA', (121, 136))	('p53', 'Gene', (278, 281))	('p53', 'Gene', '7157', (278, 281))	('Slc7a11', 'Gene', '23657', (214, 221))	('Slc7a11', 'Gene', (214, 221))	('MEFs', 'CellLine', 'CVCL:9115', (292, 296))	('ferroptosis', 'Disease', (86, 97))	('glutathione', 'Chemical', 'MESH:D005978', (148, 159))	('MEFs', 'CellLine', 'CVCL:9115', (183, 187))	('anti-ferroptotic activity', 'CPA', (249, 274))	('DeltaNp63alpha', 'Chemical', '-', (63, 77))	('DeltaNp63alpha', 'Var', (63, 77))
113187	29212036	DeltaNp63alpha knockdown enhanced ferroptosis and downregulated SLC7A11 expression in ME-180 (Figures 5E-5G), which is consistent with our gain-of-function studies in MEFs.	('SLC7A11', 'Gene', (64, 71))	('enhanced', 'PosReg', (25, 33))	('knockdown', 'Var', (15, 24))	('MEFs', 'CellLine', 'CVCL:9115', (167, 171))	('SLC7A11', 'Gene', '23657', (64, 71))	('expression', 'MPA', (72, 82))	('DeltaNp63alpha', 'Chemical', '-', (0, 14))	('downregulated', 'NegReg', (50, 63))	('DeltaNp63alpha', 'Gene', (0, 14))	('ferroptosis', 'CPA', (34, 45))
113188	29212036	In contrast, TAp63 knockdown in ME-180 neither reduced SLC7A11 expression nor enhanced ferroptosis (Figure S5).	('knockdown', 'Var', (19, 28))	('expression', 'MPA', (63, 73))	('ferroptosis', 'CPA', (87, 98))	('ME-180', 'Gene', (32, 38))	('SLC7A11', 'Gene', (55, 62))	('TAp63', 'Chemical', '-', (13, 18))	('SLC7A11', 'Gene', '23657', (55, 62))	('reduced', 'NegReg', (47, 54))	('enhanced', 'PosReg', (78, 86))
113189	29212036	Overall, our data suggest that DeltaNp63alpha can inhibit ferroptosis independently of p53.	('p53', 'Gene', (87, 90))	('p53', 'Gene', '7157', (87, 90))	('inhibit', 'NegReg', (50, 57))	('DeltaNp63alpha', 'Chemical', '-', (31, 45))	('DeltaNp63alpha', 'Var', (31, 45))	('ferroptosis', 'CPA', (58, 69))
113190	29212036	The observation that antioxidant and anti-apoptotic BCL-2 work in concert to promote long-term clonogenic survival against matrix detachment prompted us to investigate whether DeltaNp63alpha can mitigate oxidative stress associated with anoikis and whether DeltaNp63alpha can cooperate with BCL-2 to prevent the luminal clearance of acini in 3D culture of MCF-10A.	('oxidative stress', 'MPA', (204, 220))	('luminal clearance', 'CPA', (312, 329))	('DeltaNp63alpha', 'Chemical', '-', (176, 190))	('DeltaNp63alpha', 'Chemical', '-', (257, 271))	('DeltaNp63alpha', 'Var', (176, 190))	('mitigate', 'NegReg', (195, 203))	('oxidative stress', 'Phenotype', 'HP:0025464', (204, 220))	('MCF-10A', 'CellLine', 'CVCL:0598', (356, 363))
113191	29212036	Interestingly, loss of matrix attachment led to downregulation of DeltaNp63alpha in both MCF-10A and ME-180 where DeltaNp63alpha knockdown induced oxidative stress (Figures 6A and 4B).	('matrix', 'Protein', (23, 29))	('induced', 'Reg', (139, 146))	('DeltaNp63alpha', 'Gene', (66, 80))	('DeltaNp63alpha', 'Chemical', '-', (114, 128))	('knockdown', 'Var', (129, 138))	('loss', 'NegReg', (15, 19))	('oxidative stress', 'Phenotype', 'HP:0025464', (147, 163))	('downregulation', 'NegReg', (48, 62))	('DeltaNp63alpha knockdown', 'Var', (114, 138))	('oxidative stress', 'MPA', (147, 163))	('MCF-10A', 'CellLine', 'CVCL:0598', (89, 96))	('DeltaNp63alpha', 'Chemical', '-', (66, 80))
113192	29212036	Notably, overexpression of DeltaNp63alpha but not BCL-2 prevented matrix detachment-induced ROS accumulation in MCF-10A even though DeltaNp63alpha provided less protection against cell death than BCL-2 (Figures 6B and 6C).	('ROS', 'Chemical', 'MESH:D017382', (92, 95))	('DeltaNp63alpha', 'Chemical', '-', (132, 146))	('DeltaNp63alpha', 'Var', (132, 146))	('matrix detachment-induced ROS accumulation', 'MPA', (66, 108))	('MCF-10A', 'CellLine', 'CVCL:0598', (112, 119))	('DeltaNp63alpha', 'Chemical', '-', (27, 41))	('MCF-10A', 'Gene', (112, 119))
113194	29212036	Overexpression of either BCL-2 or DeltaNp63alpha only weakly inhibited luminal clearance whereas co-expression of BCL-2 and DeltaNp63alpha markedly blocked luminal clearance (Figures 6D and 6E).	('luminal clearance', 'MPA', (71, 88))	('DeltaNp63alpha', 'Chemical', '-', (124, 138))	('inhibited', 'NegReg', (61, 70))	('DeltaNp63alpha', 'Chemical', '-', (34, 48))	('DeltaNp63alpha', 'Var', (34, 48))	('luminal clearance', 'MPA', (156, 173))	('DeltaNp63alpha', 'Var', (124, 138))	('blocked', 'NegReg', (148, 155))
113195	29212036	Luminal clearance of MCF-10A acini was evident within two weeks after seeding, whereas co-expression of BCL-2 and DeltaNp63alpha potently blocked luminal clearance for up to a month (Figures 6D and 6E).	('MCF-10A', 'CellLine', 'CVCL:0598', (21, 28))	('DeltaNp63alpha', 'Chemical', '-', (114, 128))	('MCF-10A', 'Var', (21, 28))	('DeltaNp63alpha', 'Gene', (114, 128))	('luminal clearance', 'MPA', (146, 163))	('blocked', 'NegReg', (138, 145))	('Luminal clearance', 'CPA', (0, 17))
113196	29212036	Importantly, overexpression of DeltaNp63alpha but not BCL-2 suppressed ROS accumulation in the matrix-deprived luminal cells at early time points before these cells were eliminated (Figure 6F).	('suppressed', 'NegReg', (60, 70))	('ROS', 'Chemical', 'MESH:D017382', (71, 74))	('DeltaNp63alpha', 'Chemical', '-', (31, 45))	('DeltaNp63alpha', 'Var', (31, 45))	('ROS accumulation', 'MPA', (71, 87))
113197	29212036	Both TAp63 and DeltaNp63 have been shown to regulate the expression of adhesion molecules and adenovirus-mediated knockdown of p63 was reported to induce anoikis.	('expression', 'MPA', (57, 67))	('regulate', 'Reg', (44, 52))	('p63', 'Gene', (127, 130))	('induce', 'Reg', (147, 153))	('TAp63', 'Chemical', '-', (5, 10))	('knockdown', 'Var', (114, 123))	('DeltaNp63', 'Chemical', '-', (15, 24))	('DeltaNp63', 'Gene', (15, 24))	('adhesion molecules', 'Protein', (71, 89))	('anoikis', 'CPA', (154, 161))
113198	29212036	Notably, only DeltaNp63 but not TAp63 is capable of regulating oxidative stress (Figures 1I and S5).	('DeltaNp63', 'Chemical', '-', (14, 23))	('TAp63', 'Chemical', '-', (32, 37))	('oxidative stress', 'Phenotype', 'HP:0025464', (63, 79))	('DeltaNp63', 'Var', (14, 23))	('oxidative stress', 'MPA', (63, 79))
113200	29212036	As resistance to anoikis has been proposed to promote cancer metastasis and oxidative stress has been shown to limit cancer metastasis, we next examined whether overexpression of DeltaNp63alpha and/or BCL-2 promotes lung metastasis of a triple-negative breast cancer cell line MDA-MB-231 that is transduced with luciferase for bioluminescence imaging.	('cancer metastasis', 'Disease', 'MESH:D009362', (54, 71))	('breast cancer', 'Phenotype', 'HP:0003002', (253, 266))	('BCL-2', 'Gene', (201, 206))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('cancer metastasis', 'Disease', (117, 134))	('cancer', 'Phenotype', 'HP:0002664', (260, 266))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (277, 287))	('oxidative stress', 'Phenotype', 'HP:0025464', (76, 92))	('DeltaNp63alpha', 'Var', (179, 193))	('lung metastasis', 'CPA', (216, 231))	('cancer metastasis', 'Disease', 'MESH:D009362', (117, 134))	('DeltaNp63alpha', 'Chemical', '-', (179, 193))	('cancer metastasis', 'Disease', (54, 71))	('breast cancer', 'Disease', 'MESH:D001943', (253, 266))	('promotes', 'PosReg', (207, 215))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('breast cancer', 'Disease', (253, 266))
113201	29212036	Tail vein injection of DeltaNp63alpha overexpressing, luciferase-transduced MDA-MB-231 cells into immunodeficient mice resulted in lung metastases in 2 out of 5 mice whereas GFP-expressing control cells failed to metastasize to lung (Figures 6G and 6H).	('lung metastases', 'Disease', (131, 146))	('mice', 'Species', '10090', (161, 165))	('lung metastases', 'Disease', 'MESH:D009362', (131, 146))	('DeltaNp63alpha', 'Chemical', '-', (23, 37))	('immunodeficient', 'Disease', 'MESH:D007153', (98, 113))	('DeltaNp63alpha', 'Var', (23, 37))	('immunodeficient', 'Disease', (98, 113))	('resulted in', 'Reg', (119, 130))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (76, 86))	('mice', 'Species', '10090', (114, 118))
113203	29212036	Although overexpression of BCL-2 alone did not increase lung metastasis, co-expression of BCL-2 and DeltaNp63alpha further increased lung metastases and 4 out of 5 mice following injection developed lung metastases (Figures 6G and 6H).	('increased', 'PosReg', (123, 132))	('lung metastases', 'Disease', 'MESH:D009362', (199, 214))	('DeltaNp63alpha', 'Gene', (100, 114))	('increase lung metastasis', 'Disease', (47, 71))	('mice', 'Species', '10090', (164, 168))	('co-expression', 'Var', (73, 86))	('lung metastases', 'Disease', (133, 148))	('lung metastases', 'Disease', 'MESH:D009362', (133, 148))	('BCL-2', 'Gene', (90, 95))	('DeltaNp63alpha', 'Chemical', '-', (100, 114))	('increase lung metastasis', 'Disease', 'MESH:D009362', (47, 71))	('lung metastases', 'Disease', (199, 214))
113205	29212036	In contrast to the tumor suppressor function of p53, DeltaNp63alpha has been implicated as an oncogene and is frequently amplified and/or overexpressed in human squamous cell carcinoma of the lung and of the head and neck.	('p53', 'Gene', (48, 51))	('squamous cell carcinoma of the lung', 'Disease', 'MESH:D002294', (161, 196))	('DeltaNp63alpha', 'Var', (53, 67))	('overexpressed', 'PosReg', (138, 151))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('p53', 'Gene', '7157', (48, 51))	('human', 'Species', '9606', (155, 160))	('DeltaNp63alpha', 'Chemical', '-', (53, 67))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (161, 184))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('tumor', 'Disease', (19, 24))	('carcinoma', 'Phenotype', 'HP:0030731', (175, 184))	('squamous cell carcinoma of the lung', 'Disease', (161, 196))	('carcinoma of the lung', 'Phenotype', 'HP:0100526', (175, 196))
113206	29212036	As cancers often have an increased demand for antioxidant capacity compared to normal tissues likely due to inherent metabolic derangements that increase ROS production, DeltaNp63alpha might promote tumorigenesis by reducing oxidative stress.	('reducing', 'NegReg', (216, 224))	('metabolic derangements', 'Phenotype', 'HP:0001939', (117, 139))	('increase ROS production', 'Phenotype', 'HP:0025464', (145, 168))	('demand for antioxidant capacity', 'MPA', (35, 66))	('promote', 'PosReg', (191, 198))	('oxidative stress', 'MPA', (225, 241))	('cancers', 'Disease', 'MESH:D009369', (3, 10))	('DeltaNp63alpha', 'Chemical', '-', (170, 184))	('tumor', 'Disease', (199, 204))	('DeltaNp63alpha', 'Var', (170, 184))	('ROS production', 'MPA', (154, 168))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('ROS', 'Chemical', 'MESH:D017382', (154, 157))	('oxidative stress', 'Phenotype', 'HP:0025464', (225, 241))	('increase', 'PosReg', (145, 153))	('cancers', 'Phenotype', 'HP:0002664', (3, 10))	('cancers', 'Disease', (3, 10))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
113207	29212036	To explore this possibility, we analyzed The Cancer Genome Atlas (TCGA) lung squamous cell carcinoma dataset to determine whether amplification/overexpression of p63 upregulates the glutathione metabolism pathway in primary human tumors.	('amplification/overexpression', 'Var', (130, 158))	('upregulates', 'PosReg', (166, 177))	('glutathione', 'Chemical', 'MESH:D005978', (182, 193))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (77, 100))	('tumors', 'Disease', (230, 236))	('tumors', 'Disease', 'MESH:D009369', (230, 236))	('tumors', 'Phenotype', 'HP:0002664', (230, 236))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (72, 100))	('Cancer', 'Phenotype', 'HP:0002664', (45, 51))	('human', 'Species', '9606', (224, 229))	('glutathione metabolism pathway', 'Pathway', (182, 212))	('Cancer Genome Atlas (TCGA) lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (45, 100))	('p63', 'Gene', (162, 165))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))
113209	29212036	We further interrogated the database using Gene Set Enrichment Analysis (GSEA) and found that tumor samples harboring TP63 amplification and overexpressing DeltaNp63 had significant enrichment of glutathione metabolic pathway genes when compared to diploid tumor samples (Figures 7A and 7B).	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('glutathione', 'Chemical', 'MESH:D005978', (196, 207))	('TP63', 'Gene', '8626', (118, 122))	('diploid tumor', 'Disease', (249, 262))	('tumor', 'Disease', (257, 262))	('glutathione metabolic pathway', 'Pathway', (196, 225))	('overexpressing', 'PosReg', (141, 155))	('GSEA', 'Chemical', '-', (73, 77))	('TP63', 'Gene', (118, 122))	('DeltaNp63', 'Chemical', '-', (156, 165))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Disease', (94, 99))	('DeltaNp63', 'Gene', (156, 165))	('diploid tumor', 'Disease', 'MESH:C548012', (249, 262))	('tumor', 'Disease', 'MESH:D009369', (257, 262))	('amplification', 'Var', (123, 136))	('tumor', 'Phenotype', 'HP:0002664', (257, 262))
113212	29212036	We next examined whether DeltaNp63alpha promotes anchorage-independent growth by inhibiting oxidative stress.	('oxidative stress', 'Phenotype', 'HP:0025464', (92, 108))	('inhibiting', 'NegReg', (81, 91))	('oxidative stress', 'MPA', (92, 108))	('anchorage-independent growth', 'CPA', (49, 77))	('DeltaNp63alpha', 'Chemical', '-', (25, 39))	('DeltaNp63alpha', 'Var', (25, 39))	('promotes', 'PosReg', (40, 48))
113214	29212036	In contrast, DeltaNp63alpha knockdown in a squamous cell lung cancer cell line HCC95 that highly expresses DeltaNp63alpha led to increased ROS accumulation and reduced soft agar colony formation (Figures 7G and 7H).	('increased ROS accumulation', 'Phenotype', 'HP:0025464', (129, 155))	('squamous cell lung cancer', 'Phenotype', 'HP:0030359', (43, 68))	('squamous cell lung cancer', 'Disease', 'MESH:D002294', (43, 68))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('increased', 'PosReg', (129, 138))	('reduced', 'NegReg', (160, 167))	('DeltaNp63alpha', 'Var', (107, 121))	('squamous cell lung cancer', 'Disease', (43, 68))	('ROS accumulation', 'MPA', (139, 155))	('HCC95', 'CellLine', 'CVCL:5137', (79, 84))	('DeltaNp63alpha', 'Chemical', '-', (13, 27))	('ROS', 'Chemical', 'MESH:D017382', (139, 142))	('agar', 'Chemical', 'MESH:D000362', (173, 177))	('DeltaNp63alpha', 'Chemical', '-', (107, 121))	('soft agar colony formation', 'CPA', (168, 194))	('lung cancer', 'Phenotype', 'HP:0100526', (57, 68))
113215	29212036	Because genomic amplification on chromosome 3q26.33 harbors an oncogene SOX2 in additional to TP63, we envisioned that SOX2 and DeltaNp63alpha might cooperate to promote oncogenesis.	('TP63', 'Gene', (94, 98))	('DeltaNp63alpha', 'Chemical', '-', (128, 142))	('SOX2', 'Gene', '6657', (72, 76))	('SOX2', 'Gene', (72, 76))	('SOX2', 'Gene', (119, 123))	('genomic amplification', 'Var', (8, 29))	('SOX2', 'Gene', '6657', (119, 123))	('promote', 'PosReg', (162, 169))	('oncogenesis', 'CPA', (170, 181))	('TP63', 'Gene', '8626', (94, 98))
113217	29212036	Significantly, SOX2 and DeltaNp63alpha synergized to transform normal human bronchial epithelial cells BEAS-2B (Fig.	('epithelia', 'Disease', (86, 95))	('transform', 'Reg', (53, 62))	('SOX2', 'Gene', '6657', (15, 19))	('human', 'Species', '9606', (70, 75))	('SOX2', 'Gene', (15, 19))	('BEAS-2B', 'CellLine', 'CVCL:0168', (103, 110))	('DeltaNp63alpha', 'Chemical', '-', (24, 38))	('DeltaNp63alpha', 'Var', (24, 38))	('epithelia', 'Disease', 'None', (86, 95))
113218	29212036	Collectively, these data support a notion that amplification of TP63 may be a strategy by which squamous cell lung cancer evades oxidative stress and thereby promotes tumorigenesis.	('squamous cell lung cancer', 'Disease', (96, 121))	('oxidative stress', 'Phenotype', 'HP:0025464', (129, 145))	('TP63', 'Gene', '8626', (64, 68))	('squamous cell lung cancer', 'Disease', 'MESH:D002294', (96, 121))	('evades', 'NegReg', (122, 128))	('oxidative stress', 'MPA', (129, 145))	('promotes', 'PosReg', (158, 166))	('amplification', 'Var', (47, 60))	('TP63', 'Gene', (64, 68))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('lung cancer', 'Phenotype', 'HP:0100526', (110, 121))	('squamous cell lung cancer', 'Phenotype', 'HP:0030359', (96, 121))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('tumor', 'Disease', (167, 172))
113219	29212036	Here, we report that DeltaNp63alpha prevents oxidative stress and cooperates with apoptotic inhibition to promote long-term cellular survival against DNA damage and extracellular matrix detachment, highlighting the quintessence of suppressing oxidative stress in promoting long-term survival (Figure S7).	('oxidative stress', 'Phenotype', 'HP:0025464', (243, 259))	('promote', 'PosReg', (106, 113))	('oxidative stress', 'Phenotype', 'HP:0025464', (45, 61))	('DeltaNp63alpha', 'Chemical', '-', (21, 35))	('DeltaNp63alpha', 'Var', (21, 35))	('oxidative stress', 'MPA', (45, 61))
113224	29212036	We and others have previously shown that cells incompetent of undergoing apoptosis still succumb to oxidative stress upon DNA damage or loss of matrix attachment and display morphological features of necrosis.	('damage', 'Var', (126, 132))	('succumb', 'Reg', (89, 96))	('oxidative stress', 'Phenotype', 'HP:0025464', (100, 116))	('matrix attachment', 'Protein', (144, 161))	('necrosis', 'Disease', (200, 208))	('loss', 'NegReg', (136, 140))	('necrosis', 'Disease', 'MESH:D009336', (200, 208))	('oxidative stress', 'MPA', (100, 116))
113226	29212036	In fact, DeltaNp63alpha guards against oxidative stress triggered by a wide array of death stimuli in several different cell lines, including intrinsic apoptotic signals, thiol or lipid oxidants, and ferroptosis-inducing agents.	('DeltaNp63alpha', 'Var', (9, 23))	('oxidative stress', 'Phenotype', 'HP:0025464', (39, 55))	('DeltaNp63alpha', 'Chemical', '-', (9, 23))	('thiol', 'Chemical', 'MESH:D013438', (171, 176))	('lipid', 'Chemical', 'MESH:D008055', (180, 185))	('oxidative stress', 'MPA', (39, 55))
113230	29212036	In fact, DeltaNp63alpha is important in maintaining the stem cell populations of stratified epithelia.	('stem cell populations', 'CPA', (56, 77))	('DeltaNp63alpha', 'Var', (9, 23))	('DeltaNp63alpha', 'Chemical', '-', (9, 23))	('epithelia', 'Disease', 'None', (92, 101))	('epithelia', 'Disease', (92, 101))
113231	29212036	In addition to sustaining the proliferative capacity of epithelial stem cells as previously proposed, our data implicate that DeltaNp63alpha may also promote stem cell survival through its antioxidant function.	('antioxidant function', 'MPA', (189, 209))	('promote', 'PosReg', (150, 157))	('DeltaNp63alpha', 'Chemical', '-', (126, 140))	('DeltaNp63alpha', 'Var', (126, 140))	('stem cell survival', 'CPA', (158, 176))	('epithelia', 'Disease', 'None', (56, 65))	('proliferative', 'CPA', (30, 43))	('epithelia', 'Disease', (56, 65))
113232	29212036	Intriguingly, p63+/- mice have a shortened life span and display features of accelerated aging, and p63-deficient cells exhibit heightened cellular senescence, all of which could be caused by oxidative damage and may be linked to oxidative stress resulting from the loss of DeltaNp63alpha.	('p63+/-', 'Var', (14, 20))	('mice', 'Species', '10090', (21, 25))	('DeltaNp63alpha', 'Protein', (274, 288))	('oxidative stress', 'Phenotype', 'HP:0025464', (230, 246))	('DeltaNp63alpha', 'Chemical', '-', (274, 288))	('heightened', 'PosReg', (128, 138))	('loss', 'Var', (266, 270))	('cellular senescence', 'CPA', (139, 158))	('shortened', 'NegReg', (33, 42))	('caused by', 'Reg', (182, 191))	('p63-deficient', 'Var', (100, 113))
113234	29212036	To evade apoptotic checkpoints, cancer cells often overexpress anti-apoptotic BCL-2 family proteins through chromosome translocation involving BCL-2 or amplification of BCL-XL and MCL-1.	('amplification', 'Var', (152, 165))	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('BCL-XL', 'Gene', '598', (169, 175))	('MCL-1', 'Gene', (180, 185))	('BCL-2 family proteins', 'Protein', (78, 99))	('cancer', 'Disease', (32, 38))	('MCL-1', 'Gene', '4170', (180, 185))	('overexpress', 'PosReg', (51, 62))	('chromosome translocation', 'Var', (108, 132))	('anti-apoptotic', 'Gene', (63, 77))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('BCL-XL', 'Gene', (169, 175))
113235	29212036	Likewise, amplification of TP63 can be a strategy for cancer cells to evade oxidative stress-induced cell death.	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('cancer', 'Disease', (54, 60))	('TP63', 'Gene', '8626', (27, 31))	('amplification', 'Var', (10, 23))	('oxidative stress', 'Phenotype', 'HP:0025464', (76, 92))	('TP63', 'Gene', (27, 31))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
113236	29212036	The importance of antioxidant defense in tumorigenesis is also supported by the discovery of frequent loss-of-function mutations of KEAP1 and gain-of-function mutations of NRF2 in human cancers.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('loss-of-function', 'NegReg', (102, 118))	('cancers', 'Disease', 'MESH:D009369', (186, 193))	('cancers', 'Phenotype', 'HP:0002664', (186, 193))	('tumor', 'Disease', (41, 46))	('NRF2', 'Gene', (172, 176))	('mutations', 'Var', (159, 168))	('cancers', 'Disease', (186, 193))	('human', 'Species', '9606', (180, 185))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('NRF2', 'Gene', '4780', (172, 176))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('KEAP1', 'Gene', '9817', (132, 137))	('gain-of-function', 'PosReg', (142, 158))	('mutations', 'Var', (119, 128))	('KEAP1', 'Gene', (132, 137))
113238	29212036	Here, we showed that DeltaNp63alpha could regulate GCLC, the rate-limiting GSH biosynthetic enzyme, through an NRF2-independent manner, supporting a central role of DeltaNp63alpha in glutathione biogenesis.	('NRF2', 'Gene', '4780', (111, 115))	('NRF2', 'Gene', (111, 115))	('GSH', 'Chemical', '-', (75, 78))	('GCLC', 'Gene', (51, 55))	('GCLC', 'Gene', '2729', (51, 55))	('DeltaNp63alpha', 'Chemical', '-', (21, 35))	('DeltaNp63alpha', 'Var', (21, 35))	('glutathione', 'Chemical', 'MESH:D005978', (183, 194))	('DeltaNp63alpha', 'Chemical', '-', (165, 179))	('regulate', 'Reg', (42, 50))
113239	29212036	In addition, we showed that DeltaNp63alpha could inhibit ferroptosis independently of p53.	('p53', 'Gene', '7157', (86, 89))	('ferroptosis', 'CPA', (57, 68))	('DeltaNp63alpha', 'Var', (28, 42))	('DeltaNp63alpha', 'Chemical', '-', (28, 42))	('inhibit', 'NegReg', (49, 56))	('p53', 'Gene', (86, 89))
113240	29212036	Given the recent discovery of ferroptosis regulation as one of the tumor suppressor mechanisms of p53, suppression of ferroptosis by DeltaNp63alpha may contribute to its oncogenic properties.	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('suppression', 'NegReg', (103, 114))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('DeltaNp63alpha', 'Chemical', '-', (133, 147))	('DeltaNp63alpha', 'Var', (133, 147))	('p53', 'Gene', '7157', (98, 101))	('p53', 'Gene', (98, 101))	('tumor', 'Disease', (67, 72))	('ferroptosis', 'MPA', (30, 41))
113241	29212036	Our study highlights the importance of evading two cell death mechanisms in tumorigenesis, which may provide a selection pressure for genetic/epigenetic alterations with oncogenic advantages.	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('genetic/epigenetic alterations', 'Var', (134, 164))
113262	29212036	Antibodies used are listed as follows: anti-FLAG (M2, Sigma), anti-p53 (FL393, Santa Cruz Biotechnology), anti-p63 (4A4, Santa Cruz Biotechnology), anti-GCLC (HPA036359, Sigma), anti-IDH2 (ab55271, Abcam), anti-RIP1 (610458, BD Biosciences), and anti-beta-Actin (A1978, Sigma).	('beta-Actin', 'Gene', (251, 261))	('IDH2', 'Gene', '3418', (183, 187))	('GCLC', 'Gene', (153, 157))	('beta-Actin', 'Gene', '728378', (251, 261))	('GCLC', 'Gene', '2729', (153, 157))	('RIP1', 'Gene', (211, 215))	('p53', 'Gene', (67, 70))	('p53', 'Gene', '7157', (67, 70))	('RIP1', 'Gene', '8737', (211, 215))	('ab55271', 'Var', (189, 196))	('IDH2', 'Gene', (183, 187))	('HPA036359', 'Var', (159, 168))
113271	29212036	We first identified tumor samples with diploid (N = 25) and amplified TP63 (inferred gain of >=2 copies, N = 91).	('TP63', 'Gene', (70, 74))	('TP63', 'Gene', '8626', (70, 74))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('amplified', 'Var', (60, 69))	('tumor', 'Disease', (20, 25))
113279	29212036	DeltaNp63alpha is a key cellular guardian against oxidative stress including ferroptosis DeltaNp63alpha inhibits oxidative stress through regulation of glutathione metabolism DeltaNp63alpha cooperates with the BCL-2 family to promote long term clonogenic survival TP63 amplification upregulates glutathione metabolism to promote tumorigenesis	('promote', 'PosReg', (321, 328))	('amplification', 'Var', (269, 282))	('glutathione', 'Chemical', 'MESH:D005978', (295, 306))	('upregulates', 'PosReg', (283, 294))	('promote', 'PosReg', (226, 233))	('tumor', 'Disease', 'MESH:D009369', (329, 334))	('DeltaNp63alpha', 'Chemical', '-', (175, 189))	('DeltaNp63alpha', 'Chemical', '-', (89, 103))	('DeltaNp63alpha', 'Chemical', '-', (0, 14))	('glutathione metabolism', 'MPA', (295, 317))	('oxidative stress', 'Phenotype', 'HP:0025464', (113, 129))	('glutathione', 'Chemical', 'MESH:D005978', (152, 163))	('tumor', 'Phenotype', 'HP:0002664', (329, 334))	('TP63', 'Gene', '8626', (264, 268))	('oxidative stress', 'Phenotype', 'HP:0025464', (50, 66))	('tumor', 'Disease', (329, 334))	('TP63', 'Gene', (264, 268))
113358	29137247	We extracted patients with oral tongue squamous cell carcinoma (International Classification of Diseases for Oncology, Third Edition [ICD-O-3], code C01.9, C02.0, C02.1, C02.2, C02.3, C02.4, C02.8, C02.9) for our study.	('Oncology', 'Phenotype', 'HP:0002664', (109, 117))	('oral tongue squamous cell carcinoma', 'Disease', 'MESH:D002294', (27, 62))	('tongue squamous cell carcinoma', 'Phenotype', 'HP:0030413', (32, 62))	('C02.9', 'CellLine', 'CVCL:AX53', (198, 203))	('patients', 'Species', '9606', (13, 21))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (39, 62))	('C02.4', 'Var', (184, 189))	('C02.0', 'Var', (156, 161))	('carcinoma', 'Phenotype', 'HP:0030731', (53, 62))	('C02.3', 'Var', (177, 182))	('C02.2', 'Var', (170, 175))	('oral tongue squamous cell carcinoma', 'Disease', (27, 62))	('C01.9', 'CellLine', 'CVCL:E303', (149, 154))	('C02.1', 'Var', (163, 168))
113359	29137247	Patients were included when meeting the following criteria: (1) patients were aged 18 years or older at diagnosis; (2) oral tongue carcinoma was diagnosed between 2004 and 2013; (3) histological types were limited to squamous cell carcinoma (code 8050, 8051, 8052, 8070, 8071, 8072, 8073, 8074, 8075, 8076, 8081, 8082, 8083 and 8084).	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (217, 240))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('patients', 'Species', '9606', (64, 72))	('tongue carcinoma', 'Phenotype', 'HP:0030415', (124, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (231, 240))	('8072', 'Var', (277, 281))	('8071', 'Var', (271, 275))	('tongue carcinoma', 'Disease', (124, 140))	('8081', 'Var', (307, 311))	('Patients', 'Species', '9606', (0, 8))	('tongue carcinoma', 'Disease', 'MESH:D014062', (124, 140))	('8070', 'Var', (265, 269))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (217, 240))	('8074', 'Var', (289, 293))	('8073', 'Var', (283, 287))	('8075', 'Var', (295, 299))	('squamous cell carcinoma', 'Disease', (217, 240))	('8052', 'Var', (259, 263))
113367	33448640	Generally, the significant association between cg05293407TRIM27 and survival only remained in NSCLC patients having medium-to-high pack-year of smoking.	('cg05293407TRIM27', 'Chemical', '-', (47, 63))	('NSCLC', 'Phenotype', 'HP:0030358', (94, 99))	('cg05293407TRIM27', 'Var', (47, 63))	('NSCLC', 'Disease', (94, 99))	('patients', 'Species', '9606', (100, 108))	('NSCLC', 'Disease', 'MESH:D002289', (94, 99))
113372	33448640	The methylation of the CpG probe cg05293407TRIM27 was significantly associated with overall survival in patients with LUSC (HR = 1.65, 95% CI: 1.30-2.09, P = 4.52 x 10-5), but not in patients with LUAD (HR = 1.08, 95% CI: 0.87-1.33, P = 0.493).	('cg05293407TRIM27', 'Var', (33, 49))	('associated with', 'Reg', (68, 83))	('LUSC', 'Phenotype', 'HP:0030359', (118, 122))	('methylation', 'Var', (4, 15))	('overall survival', 'MPA', (84, 100))	('LUSC', 'Disease', (118, 122))	('LUAD', 'Phenotype', 'HP:0030078', (197, 201))	('cg05293407TRIM27', 'Chemical', '-', (33, 49))	('patients', 'Species', '9606', (104, 112))	('patients', 'Species', '9606', (183, 191))
113373	33448640	As incidence of LUSC is associated with higher smoking intensity compared to LUAD, we investigated whether smoking intensity impacted on the prognostic effect of cg05293407TRIM27 methylation in NSCLC.	('NSCLC', 'Phenotype', 'HP:0030358', (194, 199))	('NSCLC', 'Disease', (194, 199))	('NSCLC', 'Disease', 'MESH:D002289', (194, 199))	('LUSC', 'Disease', (16, 20))	('cg05293407TRIM27', 'Var', (162, 178))	('cg05293407TRIM27', 'Chemical', '-', (162, 178))	('LUAD', 'Phenotype', 'HP:0030078', (77, 81))	('LUSC', 'Phenotype', 'HP:0030359', (16, 20))
113375	33448640	cg05293407TRIM27 was significantly associated with overall survival only in NSCLC patients with medium-high pack-year of smoking (HR = 1.58, 95% CI: 1.26-1.96, P = 5.25 x 10-5).	('cg05293407TRIM27', 'Var', (0, 16))	('patients', 'Species', '9606', (82, 90))	('cg05293407TRIM27', 'Chemical', '-', (0, 16))	('NSCLC', 'Disease', (76, 81))	('associated', 'Reg', (35, 45))	('NSCLC', 'Disease', 'MESH:D002289', (76, 81))	('NSCLC', 'Phenotype', 'HP:0030358', (76, 81))	('overall survival', 'MPA', (51, 67))
113376	33448640	We conclude that cg05293407TRIM27 methylation is a potential predictor of LUSC prognosis, and smoking intensity may impact on its prognostic value across the various types of NSCLC.	('NSCLC', 'Disease', 'MESH:D002289', (175, 180))	('impact', 'Reg', (116, 122))	('cg05293407TRIM27 methylation', 'Var', (17, 45))	('cg05293407TRIM27', 'Chemical', '-', (17, 33))	('NSCLC', 'Phenotype', 'HP:0030358', (175, 180))	('LUSC', 'Phenotype', 'HP:0030359', (74, 78))	('LUSC', 'Disease', (74, 78))	('NSCLC', 'Disease', (175, 180))
113384	33448640	RET rearrangements were implicated in NSCLC [13].	('NSCLC', 'Disease', (38, 43))	('RET', 'Gene', '5979', (0, 3))	('NSCLC', 'Disease', 'MESH:D002289', (38, 43))	('rearrangements', 'Var', (4, 18))	('RET', 'Gene', (0, 3))	('NSCLC', 'Phenotype', 'HP:0030358', (38, 43))	('implicated', 'Reg', (24, 34))	('men', 'Species', '9606', (13, 16))
113386	33448640	Also, aberrant DNA methylation of TRIM27 was identified affecting lung function in monozygotic twins [26].	('TRIM27', 'Gene', (34, 40))	('affecting lung function', 'Phenotype', 'HP:0005952', (56, 79))	('affecting', 'Reg', (56, 65))	('TRIM27', 'Gene', '5987', (34, 40))	('aberrant DNA methylation', 'Var', (6, 30))	('lung', 'MPA', (66, 70))
113388	33448640	Furthermore, DNA methylation changes have been linked to various environmental exposures (e.g., cigarette smoking) and may explain part of the association between smoking and cancer recurrence and mortality [15, 27, 28].	('changes', 'Var', (29, 36))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('explain', 'Reg', (123, 130))	('cancer', 'Disease', (175, 181))	('methylation changes', 'Var', (17, 36))	('mortality', 'Disease', (197, 206))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('men', 'Species', '9606', (72, 75))	('linked', 'Reg', (47, 53))	('mortality', 'Disease', 'MESH:D003643', (197, 206))	('DNA', 'Gene', (13, 16))
113413	33448640	We observed a significant heterogeneous effect of cg05293407TRIM27 across histology, but the distributions of cg05293407TRIM27 methylation in LUAD and LUSC patients were comparable.	('patients', 'Species', '9606', (156, 164))	('cg05293407TRIM27', 'Chemical', '-', (50, 66))	('LUAD', 'Phenotype', 'HP:0030078', (142, 146))	('cg05293407TRIM27', 'Var', (110, 126))	('cg05293407TRIM27', 'Chemical', '-', (110, 126))	('LUSC', 'Phenotype', 'HP:0030359', (151, 155))	('cg05293407TRIM27', 'Var', (50, 66))
113421	33448640	One probe, cg05293407TRIM27, was significantly associated with LUSC survival in both discovery (HR = 2.10, 95% CI: 1.41-3.12, P = 2.70 x 10-4, FDR-q = 0.026) and validation phases (HR = 1.49, 95% CI: 1.07-2.07, P = 0.018) and showed robust association in combined data (HR = 1.65, 95% CI: 1.30-2.09, P = 4.52 x 10-5) (Tables S4 and S5).	('LUSC', 'Phenotype', 'HP:0030359', (63, 67))	('cg05293407TRIM27', 'Var', (11, 27))	('cg05293407TRIM27', 'Chemical', '-', (11, 27))	('associated', 'Reg', (47, 57))	('LUSC survival', 'CPA', (63, 76))
113423	33448640	However, the effect of cg05293407TRIM27 on LUAD survival was not significant (HR = 1.08, 95% CI: 0.87-1.33, P = 0.493) (Fig.	('cg05293407TRIM27', 'Chemical', '-', (23, 39))	('LUAD', 'Phenotype', 'HP:0030078', (43, 47))	('cg05293407TRIM27', 'Var', (23, 39))	('LUAD survival', 'CPA', (43, 56))
113424	33448640	3A), indicating a significant heterogeneous effect of cg05293407TRIM27 across NSCLC histology (P = 8.66 x 10-3).	('NSCLC', 'Phenotype', 'HP:0030358', (78, 83))	('cg05293407TRIM27', 'Var', (54, 70))	('NSCLC', 'Disease', (78, 83))	('NSCLC', 'Disease', 'MESH:D002289', (78, 83))	('cg05293407TRIM27', 'Chemical', '-', (54, 70))
113427	33448640	However, distribution of cg05293407TRIM27 methylation in LUAD and LUSC patients was similar (Fig.	('LUSC', 'Phenotype', 'HP:0030359', (66, 70))	('cg05293407TRIM27', 'Chemical', '-', (25, 41))	('patients', 'Species', '9606', (71, 79))	('cg05293407TRIM27 methylation', 'Var', (25, 53))	('LUAD', 'Phenotype', 'HP:0030078', (57, 61))	('LUAD', 'Disease', (57, 61))
113429	33448640	Therefore, we assumed that there might exist a methylation-smoking interaction accounting for the heterogeneous effect of cg05293407TRIM27 on NSCLC survival across histology.	('cg05293407TRIM27', 'Chemical', '-', (122, 138))	('cg05293407TRIM27', 'Var', (122, 138))	('NSCLC', 'Disease', (142, 147))	('NSCLC', 'Disease', 'MESH:D002289', (142, 147))	('NSCLC', 'Phenotype', 'HP:0030358', (142, 147))
113432	33448640	We identified a significant interaction between cg05293407TRIM27 and pack-year of smoking in all NSCLC patients (HRinteraction = 1.01, 95% CI: 1.00-1.02, P = 0.034).	('NSCLC', 'Disease', (97, 102))	('cg05293407TRIM27', 'Chemical', '-', (48, 64))	('NSCLC', 'Disease', 'MESH:D002289', (97, 102))	('cg05293407TRIM27', 'Var', (48, 64))	('patients', 'Species', '9606', (103, 111))	('NSCLC', 'Phenotype', 'HP:0030358', (97, 102))
113434	33448640	Therefore, pack-year of smoking was a modifier of the association between cg05293407TRIM27 and NSCLC survival.	('NSCLC', 'Disease', 'MESH:D002289', (95, 100))	('cg05293407TRIM27', 'Var', (74, 90))	('NSCLC', 'Phenotype', 'HP:0030358', (95, 100))	('association', 'Interaction', (54, 65))	('NSCLC', 'Disease', (95, 100))	('cg05293407TRIM27', 'Chemical', '-', (74, 90))
113435	33448640	We also evaluated joint effect of cg05293407TRIM27 methylation level and pack-year of smoking on NSCLC survival (Table 2).	('NSCLC', 'Disease', (97, 102))	('cg05293407TRIM27', 'Chemical', '-', (34, 50))	('cg05293407TRIM27', 'Var', (34, 50))	('NSCLC', 'Disease', 'MESH:D002289', (97, 102))	('NSCLC', 'Phenotype', 'HP:0030358', (97, 102))
113436	33448640	Patients were categorized into three groups (high, medium and low) by tertiles of cg05293407TRIM27 methylation level (1.33% and 1.78%) and were also categorized into three groups (high, medium and low) by cut-off values of pack-year of smoking (39 and 54).	('Patients', 'Species', '9606', (0, 8))	('methylation level', 'MPA', (99, 116))	('cg05293407TRIM27', 'Var', (82, 98))	('cg05293407TRIM27', 'Chemical', '-', (82, 98))
113440	33448640	In the combined dataset, the main effect of high pack-year of smoking was HR = 1.12 (95% CI: 0.84-1.49; P = 0.438), and the main effect of high methylation of cg05293407TRIM27 was HR = 1.10 (95% CI: 0.83-1.45; P = 0.502).	('high methylation', 'Var', (139, 155))	('cg05293407TRIM27', 'Var', (159, 175))	('cg05293407TRIM27', 'Chemical', '-', (159, 175))
113441	33448640	However, the joint effect was HR = 2.00 (95% CI: 1.43-2.79; P = 5.00 x 10-5), which was greater than the product of the two individual risk effects (1.2320 = 1.12 x 1.10), indicating a synergistic interaction between high methylation of cg05293407TRIM27 and high pack-year of smoking (HRinteraction = 1.62; 95% CI: 1.04-2.53; P = 3.21 x 10-2).	('cg05293407TRIM27', 'Var', (237, 253))	('high methylation', 'Var', (217, 233))	('cg05293407TRIM27', 'Chemical', '-', (237, 253))
113442	33448640	To illustrate the modification effect by pack-year of smoking, effect of cg05293407TRIM27 on NSCLC survival was evaluated in patients with low, medium and high levels of pack-year of smoking.	('NSCLC', 'Disease', (93, 98))	('NSCLC', 'Disease', 'MESH:D002289', (93, 98))	('cg05293407TRIM27', 'Chemical', '-', (73, 89))	('cg05293407TRIM27', 'Var', (73, 89))	('NSCLC', 'Phenotype', 'HP:0030358', (93, 98))	('patients', 'Species', '9606', (125, 133))
113444	33448640	For LUAD patients with a high level of pack-year of smoking, high methylation of cg05293407TRIM27 had significantly worse survival (HRHigh vs Low = 1.88, 95% CI: 1.07-3.32, P = 0.029) (Fig.	('worse', 'NegReg', (116, 121))	('patients', 'Species', '9606', (9, 17))	('LUAD', 'Phenotype', 'HP:0030078', (4, 8))	('methylation', 'MPA', (66, 77))	('cg05293407TRIM27', 'Var', (81, 97))	('high', 'Var', (61, 65))	('cg05293407TRIM27', 'Chemical', '-', (81, 97))	('survival', 'MPA', (122, 130))
113446	33448640	Our results indicated that cg05293407TRIM27 influenced NSCLC survival actually regardless of histology, but only among these patients exposed to relatively heavy smoking.	('NSCLC', 'Disease', (55, 60))	('cg05293407TRIM27', 'Chemical', '-', (27, 43))	('cg05293407TRIM27', 'Var', (27, 43))	('influenced', 'Reg', (44, 54))	('NSCLC', 'Disease', 'MESH:D002289', (55, 60))	('NSCLC', 'Phenotype', 'HP:0030358', (55, 60))	('patients', 'Species', '9606', (125, 133))
113451	33448640	7), suggesting that methylation of cg05293407TRIM27 upregulated TRIM27 expression.	('TRIM27', 'Gene', '5987', (45, 51))	('expression', 'MPA', (71, 81))	('TRIM27', 'Gene', (64, 70))	('TRIM27', 'Gene', (45, 51))	('cg05293407TRIM27', 'Chemical', '-', (35, 51))	('methylation', 'Var', (20, 31))	('TRIM27', 'Gene', '5987', (64, 70))	('upregulated', 'PosReg', (52, 63))
113453	33448640	However, genome-wide methylation-transcription analysis showed that expression of 29 genes was associated with cg05293407TRIM27 (Table S7 and Fig.	('associated', 'Reg', (95, 105))	('cg05293407TRIM27', 'Var', (111, 127))	('cg05293407TRIM27', 'Chemical', '-', (111, 127))	('expression', 'MPA', (68, 78))
113458	33448640	For example, both mutated genes and recurrent somatic copy number alterations are largely distinct between the two NSCLC types [41].	('NSCLC', 'Disease', 'MESH:D002289', (115, 120))	('NSCLC', 'Disease', (115, 120))	('NSCLC', 'Phenotype', 'HP:0030358', (115, 120))	('mutated', 'Var', (18, 25))
113459	33448640	We only observed one probe, cg05293407TRIM27, exclusively associated with early-stage LUSC prognosis in stratified analysis by histology, whereas no promising CpG probes were observed for LUAD, possibly due to underlying epigenetic heterogeneity between LUAD and LUSC.	('LUAD', 'Phenotype', 'HP:0030078', (254, 258))	('associated with', 'Reg', (58, 73))	('LUSC', 'Phenotype', 'HP:0030359', (86, 90))	('cg05293407TRIM27', 'Chemical', '-', (28, 44))	('cg05293407TRIM27', 'Var', (28, 44))	('LUSC', 'Phenotype', 'HP:0030359', (263, 267))	('early-stage LUSC prognosis', 'Disease', (74, 100))	('LUAD', 'Phenotype', 'HP:0030078', (188, 192))
113460	33448640	In addition, a methylation-smoking interaction may potentially provide interpretation of the heterogeneous effect of cg05293407TRIM27.	('cg05293407TRIM27', 'Chemical', '-', (117, 133))	('cg05293407TRIM27', 'Var', (117, 133))	('methylation-smoking', 'Var', (15, 34))
113461	33448640	The tumour-specific shift to transcriptional repression is associated with DNA methylation at TSSs in multiple tumour types [42].	('transcriptional repression', 'MPA', (29, 55))	('tumour', 'Phenotype', 'HP:0002664', (4, 10))	('tumour', 'Phenotype', 'HP:0002664', (111, 117))	('DNA methylation', 'Var', (75, 90))	('tumour', 'Disease', 'MESH:D009369', (4, 10))	('tumour', 'Disease', 'MESH:D009369', (111, 117))	('tumour', 'Disease', (4, 10))	('tumour', 'Disease', (111, 117))
113462	33448640	In our study, DNA methylation at cg05293407 in the 200 kb TSS region of TRIM27 upregulated gene expression in tumour tissues, which was consistent with previous reports [45, 46].	('gene expression', 'MPA', (91, 106))	('TRIM27', 'Gene', '5987', (72, 78))	('tumour', 'Disease', 'MESH:D009369', (110, 116))	('TRIM27', 'Gene', (72, 78))	('tumour', 'Phenotype', 'HP:0002664', (110, 116))	('methylation', 'Var', (18, 29))	('upregulated', 'PosReg', (79, 90))	('cg05293407', 'Var', (33, 43))	('tumour', 'Disease', (110, 116))
113464	33448640	In LUSC patients, the methylation level of cg05293407TRIM27 ranged from 0.62% to 4.09% and its median value was 1.48%, indicating a narrow range and low average level.	('cg05293407TRIM27', 'Chemical', '-', (43, 59))	('cg05293407TRIM27', 'Var', (43, 59))	('methylation level', 'MPA', (22, 39))	('LUSC', 'Phenotype', 'HP:0030359', (3, 7))	('patients', 'Species', '9606', (8, 16))
113466	33448640	Meanwhile, plenty of studies have revealed that aberrant DNA methylations of these hypo-methylated CpG probes were also involved in diseases (e.g., female panic disorder risk associated cg07308824HECA and paediatric medulloblastoma prognosis associated cg02257300ERCC2) [48, 49].	('paediatric medulloblastoma', 'Phenotype', 'HP:0007129', (205, 231))	('panic disorder', 'Disease', 'MESH:D016584', (155, 169))	('panic disorder', 'Disease', (155, 169))	('involved', 'Reg', (120, 128))	('ERCC2', 'Gene', '2068', (263, 268))	('medulloblastoma', 'Disease', 'MESH:D008527', (216, 231))	('panic disorder', 'Phenotype', 'HP:0025269', (155, 169))	('medulloblastoma', 'Phenotype', 'HP:0002885', (216, 231))	('aberrant', 'Var', (48, 56))	('cg07308824HECA', 'Var', (186, 200))	('CpG', 'Gene', (99, 102))	('ERCC2', 'Gene', (263, 268))	('medulloblastoma', 'Disease', (216, 231))
113472	33448640	Combined with our results, these data suggested that high methylation of cg05293407TRIM27 might promote TRIM27 expression, further leading to STAT3 activation and poor prognosis (Fig.	('leading to', 'Reg', (131, 141))	('TRIM27', 'Gene', '5987', (104, 110))	('TRIM27', 'Gene', '5987', (83, 89))	('STAT3', 'Gene', (142, 147))	('high methylation', 'Var', (53, 69))	('activation', 'PosReg', (148, 158))	('TRIM27', 'Gene', (104, 110))	('TRIM27', 'Gene', (83, 89))	('promote', 'PosReg', (96, 103))	('expression', 'MPA', (111, 121))	('cg05293407TRIM27', 'Chemical', '-', (73, 89))	('STAT3', 'Gene', '6774', (142, 147))
113473	33448640	Smoking is associated with several genetic alterations in NSCLC [53] and has been well-established as a relevant factor of lung cancer risk as well as prognosis [15].	('genetic alterations', 'Var', (35, 54))	('NSCLC', 'Disease', (58, 63))	('associated', 'Reg', (11, 21))	('lung cancer', 'Disease', (123, 134))	('NSCLC', 'Disease', 'MESH:D002289', (58, 63))	('lung cancer', 'Phenotype', 'HP:0100526', (123, 134))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('lung cancer', 'Disease', 'MESH:D008175', (123, 134))	('NSCLC', 'Phenotype', 'HP:0030358', (58, 63))
113482	33448640	In terms of the cg05293407TRIM27 and smoking interaction, high methylation was associated with poor prognosis in NSCLC patients with medium-high pack-year of smoking rather than low pack-year of smoking, possibly because high activation of STAT3 and low expression of PTEN may only occur in patients with medium-high methylation of cg05293407TRIM27.	('STAT3', 'Gene', (240, 245))	('PTEN', 'Gene', (268, 272))	('cg05293407TRIM27', 'Chemical', '-', (332, 348))	('PTEN', 'Gene', '5728', (268, 272))	('methylation', 'MPA', (63, 74))	('cg05293407TRIM27', 'Var', (332, 348))	('patients', 'Species', '9606', (119, 127))	('STAT3', 'Gene', '6774', (240, 245))	('NSCLC', 'Phenotype', 'HP:0030358', (113, 118))	('patients', 'Species', '9606', (291, 299))	('NSCLC', 'Disease', (113, 118))	('cg05293407TRIM27', 'Chemical', '-', (16, 32))	('NSCLC', 'Disease', 'MESH:D002289', (113, 118))
113483	33448640	We observed three genes associated with cg05293407TRIM27: GJC3, NAALAD2 and USP26.	('GJC3', 'Gene', '349149', (58, 62))	('USP26', 'Gene', (76, 81))	('GJC3', 'Gene', (58, 62))	('NAALAD2', 'Gene', '10003', (64, 71))	('USP26', 'Gene', '83844', (76, 81))	('cg05293407TRIM27', 'Chemical', '-', (40, 56))	('NAALAD2', 'Gene', (64, 71))	('cg05293407TRIM27', 'Var', (40, 56))
113485	33448640	Further, patients with low GJC3 expression had a better prognosis in our study.	('patients', 'Species', '9606', (9, 17))	('low', 'Var', (23, 26))	('expression', 'MPA', (32, 42))	('GJC3', 'Gene', '349149', (27, 31))	('GJC3', 'Gene', (27, 31))
113494	33448640	First, though three genes associated with cg05293407TRIM27 further affected lung cancer prognosis in our study, there was no explicit evidence of their mechanisms.	('lung cancer', 'Disease', 'MESH:D008175', (76, 87))	('affected', 'Reg', (67, 75))	('cg05293407TRIM27', 'Chemical', '-', (42, 58))	('lung cancer', 'Disease', (76, 87))	('lung cancer', 'Phenotype', 'HP:0100526', (76, 87))	('cg05293407TRIM27', 'Var', (42, 58))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))
113495	33448640	Anyway, the association between cg05293407TRIM27 and prognosis remained significant in TCGA, indicating our results were conservative and roust.	('cg05293407TRIM27', 'Chemical', '-', (32, 48))	('TCGA', 'Disease', (87, 91))	('cg05293407TRIM27', 'Var', (32, 48))
113498	33448640	In summary, our study identified cg05293407TRIM27 as a potential biomarker for LUSC prognosis and laid out a case that the methylation-smoking interaction may account for heterogeneous effects of cg05293407TRIM27 across histology.	('LUSC', 'Phenotype', 'HP:0030359', (79, 83))	('cg05293407TRIM27', 'Var', (33, 49))	('LUSC', 'Disease', (79, 83))	('cg05293407TRIM27', 'Var', (196, 212))	('cg05293407TRIM27', 'Chemical', '-', (196, 212))	('cg05293407TRIM27', 'Chemical', '-', (33, 49))
113615	25889238	Phimosis is considered an important risk factor for the development of penile cancer and is found in approximately 25% to 75% of patients with this cancer in the largest series.	('Phimosis', 'Var', (0, 8))	('cancer', 'Disease', (148, 154))	('men', 'Species', '9606', (63, 66))	('to 7', 'Species', '1214577', (119, 123))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('patients', 'Species', '9606', (129, 137))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('penile cancer', 'Disease', (71, 84))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('penile cancer', 'Disease', 'MESH:D004414', (71, 84))	('Phimosis', 'Phenotype', 'HP:0001741', (0, 8))
113627	25889238	The mechanism by which HPV leads to malignant transformation is likely mediated through two viral genes, E6 and E7, which are actively transcribed in HPV-infected cells.	('malignant transformation', 'CPA', (36, 60))	('HPV-infected', 'Disease', 'MESH:D030361', (150, 162))	('HPV', 'Species', '10566', (150, 153))	('HPV-infected', 'Disease', (150, 162))	('HPV', 'Species', '10566', (23, 26))	('HPV', 'Var', (23, 26))
113710	32206121	Results: We provided evidence showing that PAQR4 is increased in NSCLC cancer cell lines (A549, H1299, H1650, H1975, H358, GLC-82 and SPC-A1), and identified many mutations in PAQR4 in non-small cell lung cancer (NSCLC) tissues.	('cancer', 'Disease', 'MESH:D009369', (205, 211))	('NSCLC', 'Disease', 'MESH:D002289', (213, 218))	('SPC-A1', 'Gene', (134, 140))	('SPC-A1', 'Gene', '27032', (134, 140))	('lung cancer', 'Phenotype', 'HP:0100526', (200, 211))	('non-small cell lung cancer', 'Disease', (185, 211))	('H358', 'CellLine', 'CVCL:1559;-0.030168853306138242', (117, 121))	('NSCLC', 'Disease', (213, 218))	('increased', 'PosReg', (52, 61))	('cancer', 'Disease', (71, 77))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (185, 211))	('cancer', 'Disease', (205, 211))	('NSCLC', 'Disease', 'MESH:D002289', (65, 70))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (189, 211))	('NSCLC', 'Disease', (65, 70))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('mutations', 'Var', (163, 172))	('PAQR4', 'Gene', (43, 48))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (185, 211))	('GLC', 'Chemical', 'MESH:D005947', (123, 126))	('PAQR4', 'Gene', (176, 181))	('H1975', 'CellLine', 'CVCL:1511;-0.011510194290142526', (110, 115))
113712	32206121	Conclusion: Our results suggest that PAQR4 depletion enhances the sensitivity of cancerous cell to chemotherapy both in vitro and xenograft tumor formation in vivo, by promoting Nrf2 protein degradation through a Keap1-mediated ubiquitination process.	('PAQR4', 'Gene', (37, 42))	('promoting', 'PosReg', (168, 177))	('Keap1', 'Gene', '9817', (213, 218))	('Keap1', 'Gene', (213, 218))	('Nrf2', 'Gene', '4780', (178, 182))	('depletion', 'Var', (43, 52))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('enhances', 'PosReg', (53, 61))	('protein', 'Protein', (183, 190))	('cancer', 'Disease', (81, 87))	('Nrf2', 'Gene', (178, 182))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('tumor', 'Disease', (140, 145))
113719	32206121	Clinical trials with tyrosine kinase inhibitors (TKIs) targeted to mutant EGFR or ALK-fusion proteins, show a significant increase of the 5-year survival rate of NSCLC.	('ALK', 'Gene', (82, 85))	('NSCLC', 'Disease', (162, 167))	('NSCLC', 'Disease', 'MESH:D002289', (162, 167))	('EGFR', 'Gene', '1956', (74, 78))	('ALK', 'Gene', '238', (82, 85))	('mutant', 'Var', (67, 73))	('EGFR', 'Gene', (74, 78))	('increase', 'PosReg', (122, 130))
113730	32206121	Moreover, many Keap1 mutations or loss of heterozygosity in the Keap1 locus has been identified in lung cancer.	('Keap1', 'Gene', (64, 69))	('lung cancer', 'Disease', (99, 110))	('loss of', 'NegReg', (34, 41))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('lung cancer', 'Disease', 'MESH:D008175', (99, 110))	('lung cancer', 'Phenotype', 'HP:0100526', (99, 110))	('Keap1', 'Gene', '9817', (15, 20))	('Keap1', 'Gene', (15, 20))	('Keap1', 'Gene', '9817', (64, 69))	('identified', 'Reg', (85, 95))	('mutations', 'Var', (21, 30))
113746	32206121	Next, we found that PAQR4 high expression correlates with a worse overall survival rate, using a Kaplan Meier plotter containing the affymetrix gene expression dataset for lung cancer (Figure 1C) .	('high expression', 'Var', (26, 41))	('PAQR4', 'Gene', (20, 25))	('lung cancer', 'Disease', (172, 183))	('lung cancer', 'Phenotype', 'HP:0100526', (172, 183))	('overall survival rate', 'MPA', (66, 87))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('lung cancer', 'Disease', 'MESH:D008175', (172, 183))	('worse', 'NegReg', (60, 65))
113749	32206121	Due to the higher expression of PAQR4 in NSCLC cancerous cell lines we hypothesized that PAQR4 might also be frequently mutated in NSCLC.	('PAQR4', 'Gene', (32, 37))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('NSCLC', 'Disease', (41, 46))	('NSCLC', 'Disease', (131, 136))	('PAQR4', 'Gene', (89, 94))	('cancer', 'Disease', (47, 53))	('NSCLC', 'Disease', 'MESH:D002289', (41, 46))	('NSCLC', 'Disease', 'MESH:D002289', (131, 136))	('expression', 'MPA', (18, 28))	('higher', 'PosReg', (11, 17))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('mutated', 'Var', (120, 127))
113750	32206121	Indeed, we identified many PAQR4 mutants in NSCLC by applying the cBioPortal web resource  (Figure 1D; Table 3-4), suggesting that PAQR4 plays potential important role in lung homeostasis.	('NSCLC', 'Disease', 'MESH:D002289', (44, 49))	('NSCLC', 'Disease', (44, 49))	('mutants', 'Var', (33, 40))	('PAQR4', 'Gene', (27, 32))
113752	32206121	As expected, stable knockdown of PAQR4 inhibited SPC-A1 and GLC-82 cell proliferation and colony formation in vitro, and this effect could be rescued by PAQR4 overexpression (Figure 1H-J and Figure S1D, E, I, J).	('overexpression', 'PosReg', (159, 173))	('inhibited', 'NegReg', (39, 48))	('SPC-A1', 'Gene', (49, 55))	('SPC-A1', 'Gene', '27032', (49, 55))	('GLC', 'Chemical', 'MESH:D005947', (60, 63))	('knockdown', 'Var', (20, 29))	('colony formation', 'CPA', (90, 106))	('PAQR4', 'Gene', (33, 38))	('PAQR4', 'Gene', (153, 158))
113753	32206121	Indeed, we observed that PAQR4 knockdown significantly decreased the ratio of BrdU-positive cells in SPC-A1 and GLC-82 (Figure 1K-L and Figure S1F-G).	('SPC-A1', 'Gene', (101, 107))	('SPC-A1', 'Gene', '27032', (101, 107))	('decreased', 'NegReg', (55, 64))	('GLC', 'Chemical', 'MESH:D005947', (112, 115))	('PAQR4', 'Gene', (25, 30))	('knockdown', 'Var', (31, 40))	('BrdU', 'Chemical', 'MESH:D001973', (78, 82))
113755	32206121	However, we analyzed the cell cycle transition by flow cytometry, and did not find significant cell cycle modulation after PAQR4 knockdown, or change in CDK2 and CDK4 protein stabilities (Figure S1H, K), suggesting a cellular context dependent role for PAQR4.	('CDK4', 'Gene', '1019', (162, 166))	('knockdown', 'Var', (129, 138))	('PAQR4', 'Gene', (123, 128))	('stabilities', 'MPA', (175, 186))	('CDK2', 'Gene', (153, 157))	('cell cycle', 'CPA', (95, 105))	('CDK4', 'Gene', (162, 166))	('CDK2', 'Gene', '1017', (153, 157))
113757	32206121	In vitro, we also found that PAQR4 is upregulated in cisplatin-resistant A549 (A549/DDP) and SPC-A1 (SPC-A1/DDP) cell lines, whereas knockdown of PAQR4 in both cells inhibited cellular viability (Figure 2G-J and Figure S2G-J).	('PAQR4', 'Gene', (29, 34))	('SPC-A1', 'Gene', (93, 99))	('SPC-A1', 'Gene', '27032', (93, 99))	('SPC-A1', 'Gene', (101, 107))	('SPC-A1', 'Gene', '27032', (101, 107))	('upregulated', 'PosReg', (38, 49))	('SPC-A1/DDP', 'Gene', (101, 111))	('knockdown', 'Var', (133, 142))	('DDP', 'Gene', '1678', (84, 87))	('cisplatin', 'Chemical', 'MESH:D002945', (53, 62))	('cellular viability', 'CPA', (176, 194))	('DDP', 'Gene', (108, 111))	('DDP', 'Gene', '1678', (108, 111))	('inhibited', 'NegReg', (166, 175))	('SPC-A1/DDP', 'Gene', '27032;1678', (101, 111))	('DDP', 'Gene', (84, 87))
113761	32206121	As expected, tumor formation, tumor weights and volumes in PAQR4 knockdown groups were dramatically decreased over the control group (Figure 3A-C and Figure S3A-D).	('tumor', 'Disease', (13, 18))	('PAQR4', 'Gene', (59, 64))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('decreased', 'NegReg', (100, 109))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('knockdown', 'Var', (65, 74))	('tumor', 'Disease', (30, 35))	('volumes', 'CPA', (48, 55))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
113767	32206121	As expected, Nrf2 protein levels were strongly reduced in PAQR4 knockdown cells, which could be reversed by proteasome inhibitor MG132 treatment, whereas the mRNA transcripts of Nrf2 were not regulated by PAQR4 (Figure 4A-B and Figure S4B, D, E), suggesting that PAQR4 inhibits Nrf2 expression at posttranslational level in a ubiquitination-proteasome dependent manner.	('protein levels', 'MPA', (18, 32))	('Nrf2', 'Gene', '4780', (178, 182))	('Nrf2', 'Gene', (13, 17))	('Nrf2', 'Gene', '4780', (278, 282))	('PAQR4 knockdown', 'Var', (58, 73))	('Nrf2', 'Gene', (178, 182))	('inhibits', 'NegReg', (269, 277))	('Nrf2', 'Gene', (278, 282))	('knockdown', 'Var', (64, 73))	('MG132', 'Chemical', 'MESH:C072553', (129, 134))	('Nrf2', 'Gene', '4780', (13, 17))	('expression', 'MPA', (283, 293))	('reduced', 'NegReg', (47, 54))
113770	32206121	In addition, the increased cellular apoptosis in PAQR4 knockdown cells could be rescued by Nrf2 overexpression (Figure S4H-J).	('knockdown', 'Var', (55, 64))	('Nrf2', 'Gene', (91, 95))	('cellular apoptosis', 'CPA', (27, 45))	('PAQR4', 'Gene', (49, 54))	('overexpression', 'PosReg', (96, 110))	('Nrf2', 'Gene', '4780', (91, 95))
113775	32206121	Thus, we performed co-immunoprecipitation (co-IP) with cell lysates from Myc-Nrf2 and HA-Keap1 transiently overexpressed HEK-293T, and recapitulated the reciprocal interaction between Nrf2 and Keap1 as documented before (Figure S5D).	('Keap1', 'Gene', (89, 94))	('HEK-293T', 'Var', (121, 129))	('Nrf2', 'Gene', (77, 81))	('Nrf2', 'Gene', '4780', (77, 81))	('Myc', 'Gene', '4609', (73, 76))	('Nrf2', 'Gene', '4780', (184, 188))	('Myc', 'Gene', (73, 76))	('Keap1', 'Gene', '9817', (193, 198))	('Keap1', 'Gene', (193, 198))	('Nrf2', 'Gene', (184, 188))	('Keap1', 'Gene', '9817', (89, 94))
113777	32206121	Consistently, we generated and purified the GST-PAQR4 fusion proteins and performed GST pulldown assays, to confirm that GST-PAQR4 binds to the endogenous Nrf2 and Keap1 proteins (Figure 5E).	('Keap1', 'Gene', '9817', (164, 169))	('Keap1', 'Gene', (164, 169))	('binds', 'Interaction', (131, 136))	('Nrf2', 'Gene', '4780', (155, 159))	('Nrf2', 'Gene', (155, 159))	('GST-PAQR4', 'Var', (121, 130))
113778	32206121	Importantly, the physical interaction between Nrf2 and Keap1 was reduced when PAQR4 was co-expressed in HEK-293T (Figure 5F), suggesting that PAQR4 antagonizes with Keap1 to keep Nrf2 from protein degradation using the ubiquitination-proteasome signaling pathway.	('Nrf2', 'Gene', '4780', (179, 183))	('Nrf2', 'Gene', (46, 50))	('Keap1', 'Gene', (165, 170))	('Keap1', 'Gene', '9817', (165, 170))	('protein degradation', 'MPA', (189, 208))	('Nrf2', 'Gene', (179, 183))	('Keap1', 'Gene', '9817', (55, 60))	('Keap1', 'Gene', (55, 60))	('keep', 'PosReg', (174, 178))	('Nrf2', 'Gene', '4780', (46, 50))	('PAQR4', 'Var', (142, 147))
113780	32206121	Remarkable advances in the development of predictive biomarkers and specific targeted small molecule inhibitors have led to improvements in some NSCLC patients' survival rates and quality of life.	('improvements', 'PosReg', (124, 136))	('quality of life', 'CPA', (180, 195))	('small', 'Var', (86, 91))	('NSCLC', 'Disease', (145, 150))	('patients', 'Species', '9606', (151, 159))	('NSCLC', 'Disease', 'MESH:D002289', (145, 150))
113786	32206121	Furthermore, PAQR4 knockdown promotes the sensitivity of cancerous cell to DDP/ Paclitaxel treatment through decreasing Nrf2 protein levels.	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('decreasing', 'NegReg', (109, 119))	('knockdown', 'Var', (19, 28))	('cancer', 'Disease', (57, 63))	('Nrf2', 'Gene', (120, 124))	('DDP', 'Gene', '1678', (75, 78))	('sensitivity', 'MPA', (42, 53))	('PAQR4', 'Gene', (13, 18))	('Nrf2', 'Gene', '4780', (120, 124))	('Paclitaxel', 'Chemical', 'MESH:D017239', (80, 90))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('DDP', 'Gene', (75, 78))	('promotes', 'PosReg', (29, 37))
113791	32206121	Recent findings showed that PAQR4 promotes cell proliferation and metastasis through CDK4-pRB-E2F1 in NSCLC, although we also observed that PAQR4 regulates NSCLC cancerous cell proliferation, we concluded that PAQR4 knockdown inhibits cell proliferation by inducing cellular apoptosis instead of regulating CDK4 protein stabilities.	('NSCLC', 'Disease', 'MESH:D002289', (102, 107))	('cell proliferation', 'CPA', (235, 253))	('cellular apoptosis', 'CPA', (266, 284))	('cancer', 'Disease', (162, 168))	('CDK4', 'Gene', (85, 89))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('NSCLC', 'Disease', (102, 107))	('CDK4', 'Gene', '1019', (307, 311))	('knockdown', 'Var', (216, 225))	('CDK4', 'Gene', '1019', (85, 89))	('NSCLC', 'Disease', 'MESH:D002289', (156, 161))	('inhibits', 'NegReg', (226, 234))	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('pRB', 'Gene', '5925', (90, 93))	('E2F1', 'Gene', (94, 98))	('PAQR4', 'Gene', (28, 33))	('pRB', 'Gene', (90, 93))	('NSCLC', 'Disease', (156, 161))	('metastasis', 'CPA', (66, 76))	('E2F1', 'Gene', '1869', (94, 98))	('inducing', 'Reg', (257, 265))	('PAQR4', 'Gene', (210, 215))	('cell proliferation', 'CPA', (43, 61))	('CDK4', 'Gene', (307, 311))
113798	32206121	A549, H1299, H1975, H1650 were purchased from Cobioer, China with STR document, BEAS-2B, A549, H1650, H1975, H358, GLC-82 and SPC-A1 cells were cultured in RPMI1640 medium (Corning) supplemented with 10% fetal bovine serum (FBS) and 1% penicillin/streptomycin.	('penicillin', 'Chemical', 'MESH:D010406', (236, 246))	('GLC', 'Chemical', 'MESH:D005947', (115, 118))	('H1975', 'CellLine', 'CVCL:1511;-0.011510194290142526', (102, 107))	('H1299', 'Var', (6, 11))	('bovine', 'Species', '9913', (210, 216))	('H1975', 'Var', (13, 18))	('SPC-A1', 'Gene', (126, 132))	('H358', 'CellLine', 'CVCL:1559;-0.030168853306138242', (109, 113))	('RPMI1640', 'Chemical', '-', (156, 164))	('H1975', 'CellLine', 'CVCL:1511;-0.011510194290142526', (13, 18))	('SPC-A1', 'Gene', '27032', (126, 132))	('streptomycin', 'Chemical', 'MESH:D013307', (247, 259))	('H1975', 'Var', (102, 107))	('H1650', 'Var', (95, 100))
113809	32206121	Male nude mice aged 5 weeks were randomly divided into different groups, and were then injected with 2 independent PAQR4 knockdown cell lines or scramble control shRNA cells, (1x106 cells/ subcutaneously).	('knockdown', 'Var', (121, 130))	('PAQR4', 'Gene', (115, 120))	('nude mice', 'Species', '10090', (5, 14))
113819	27864908	E2F transcription factor 2 variants as predictive biomarkers for recurrence risk in patients with squamous cell carcinoma of the oropharynx Because E2F transcription factor 2 (E2F2) promoter polymorphisms have been implicated in carcinogenesis and prognosis, we investigated associations between genetic variants in five E2F2 promoter polymorphisms and recurrence risk of squamous cell carcinoma of the oropharynx (SCCOP) in 1,008 patients.	('E2F transcription factor 2', 'Gene', '1870', (148, 174))	('carcinogenesis', 'Disease', (229, 243))	('investigated', 'Reg', (262, 274))	('E2F2', 'Gene', (321, 325))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('E2F transcription factor 2', 'Gene', (0, 26))	('variants', 'Var', (304, 312))	('E2F2', 'Gene', '1870', (321, 325))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (98, 121))	('carcinogenesis', 'Disease', 'MESH:D063646', (229, 243))	('E2F2', 'Gene', (176, 180))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (372, 395))	('patients', 'Species', '9606', (84, 92))	('E2F2', 'Gene', '1870', (176, 180))	('squamous cell carcinoma', 'Disease', (98, 121))	('E2F transcription factor 2', 'Gene', (148, 174))	('patients', 'Species', '9606', (431, 439))	('carcinoma', 'Phenotype', 'HP:0030731', (386, 395))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (372, 395))	('E2F transcription factor 2', 'Gene', '1870', (0, 26))	('associations', 'Interaction', (275, 287))	('squamous cell carcinoma', 'Disease', (372, 395))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (98, 121))
113823	27864908	Our findings suggest that E2F2 polymorphisms may individually or jointly modify SCCOP recurrence risk, particularly for SCCOP patients with HPV16-positive tumors.	('modify', 'Reg', (73, 79))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('HPV16-positive tumors', 'Disease', (140, 161))	('tumors', 'Phenotype', 'HP:0002664', (155, 161))	('SCCOP recurrence', 'Disease', (80, 96))	('E2F2', 'Gene', (26, 30))	('polymorphisms', 'Var', (31, 44))	('HPV16-positive tumors', 'Disease', 'MESH:D009369', (140, 161))	('patients', 'Species', '9606', (126, 134))	('E2F2', 'Gene', '1870', (26, 30))
113825	27864908	Thus, understanding the effect of genetic variations on disease-free and overall survival may improve clinical and therapeutic decision-making and thereby improve patient survival and quality of life.	('patient survival', 'CPA', (163, 179))	('improve', 'PosReg', (155, 162))	('improve', 'PosReg', (94, 101))	('patient', 'Species', '9606', (163, 170))	('clinical', 'CPA', (102, 110))	('genetic variations', 'Var', (34, 52))
113831	27864908	Because many important checkpoints and regulatory pathways control the cell cycle and ensure the fidelity of DNA replication and chromosome segregation, dysregulation of the cell cycle may lead to carcinogenesis.	('dysregulation', 'Var', (153, 166))	('carcinogenesis', 'Disease', (197, 211))	('dysregulation of the cell cycle', 'Phenotype', 'HP:0011018', (153, 184))	('chromosome segregation', 'CPA', (129, 151))	('lead to', 'Reg', (189, 196))	('carcinogenesis', 'Disease', 'MESH:D063646', (197, 211))
113832	27864908	Outcomes vary widely among patients, indicating that genetic alterations may affect these genes' expression and SCCOP prognosis.	('affect', 'Reg', (77, 83))	('patients', 'Species', '9606', (27, 35))	('genetic alterations', 'Var', (53, 72))	('expression', 'MPA', (97, 107))
113833	27864908	Genetic variants or polymorphisms in the promoter of E2F2 affect the expression of E2F2; such alterations of expression may also affect cell-cycle control and response to radiotherapy, thus leading to susceptibility to SCCOP recurrence.	('SCCOP recurrence', 'Disease', (219, 235))	('response to radiotherapy', 'CPA', (159, 183))	('expression', 'MPA', (109, 119))	('alterations', 'Var', (94, 105))	('E2F2', 'Gene', '1870', (83, 87))	('E2F2', 'Gene', (53, 57))	('variants', 'Var', (8, 16))	('expression', 'MPA', (69, 79))	('leading to susceptibility', 'Reg', (190, 215))	('affect', 'Reg', (129, 135))	('cell-cycle control', 'CPA', (136, 154))	('E2F2', 'Gene', (83, 87))	('E2F2', 'Gene', '1870', (53, 57))	('affect', 'Reg', (58, 64))
113836	27864908	Given the important roles of E2F2 in cell-cycle regulation and the interaction between E2F2 and HPV, we hypothesized that E2F2 promoter polymorphisms may affect E2F2 expression and cause interindividual variations in responses to radiotherapy, leading to different risk of SCCOP recurrence.	('E2F2', 'Gene', '1870', (122, 126))	('E2F2', 'Gene', '1870', (161, 165))	('HPV', 'Species', '10566', (96, 99))	('E2F2', 'Gene', (29, 33))	('E2F2', 'Gene', '1870', (29, 33))	('cause', 'Reg', (181, 186))	('E2F2', 'Gene', '1870', (87, 91))	('polymorphisms', 'Var', (136, 149))	('SCCOP recurrence', 'Disease', (273, 289))	('E2F2', 'Gene', (122, 126))	('affect', 'Reg', (154, 160))	('E2F2', 'Gene', (161, 165))	('responses to radiotherapy', 'MPA', (217, 242))	('expression', 'MPA', (166, 176))	('E2F2', 'Gene', (87, 91))
113837	27864908	In the current study, we assessed the associations of common and variant genotypes of five E2F2 promoter polymorphisms, both individually and jointly, with the risk of SCOPP recurrence in a cohort of 1,008 patients with SCCOP and the subgroup of patients with HPV16(+) SCCOP (n=324).	('SCOPP recurrence', 'Disease', (168, 184))	('associations', 'Interaction', (38, 50))	('patients', 'Species', '9606', (246, 254))	('HPV16', 'Species', '333760', (260, 265))	('E2F2', 'Gene', (91, 95))	('patients', 'Species', '9606', (206, 214))	('variant', 'Var', (65, 72))	('E2F2', 'Gene', '1870', (91, 95))
113864	27864908	Associations of E2F2 polymorphisms with risk of SCCOP recurrence were estimated using hazard ratios (HRs) and 95% confidence intervals (CIs) among both the whole patients and patients with HPV16(+) tumors, while in this study we did not include similar analyses for patients with HPV16(-) tumors owing to the relatively small sample size and the rarity of SCCOP recurrence in this subgroup.	('patients', 'Species', '9606', (162, 170))	('patients', 'Species', '9606', (266, 274))	('Associations', 'Interaction', (0, 12))	('SCCOP recurrence', 'Disease', (48, 64))	('HPV16', 'Species', '333760', (280, 285))	('tumor', 'Phenotype', 'HP:0002664', (289, 294))	('E2F2', 'Gene', (16, 20))	('tumors', 'Phenotype', 'HP:0002664', (289, 295))	('HPV16', 'Species', '333760', (189, 194))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('patients', 'Species', '9606', (175, 183))	('tumors', 'Disease', (289, 295))	('polymorphisms', 'Var', (21, 34))	('tumors', 'Disease', (198, 204))	('tumors', 'Disease', 'MESH:D009369', (198, 204))	('tumors', 'Disease', 'MESH:D009369', (289, 295))	('E2F2', 'Gene', '1870', (16, 20))	('tumors', 'Phenotype', 'HP:0002664', (198, 204))
113872	27864908	We performed a multivariable Cox proportional hazards regression analysis to assess the associations of genotypes of the five single nucleotide polymorphisms with recurrence risk in patients with SCCOP.	('recurrence', 'Disease', (163, 173))	('patients', 'Species', '9606', (182, 190))	('SCCOP', 'Disease', (196, 201))	('associations', 'Interaction', (88, 100))	('single nucleotide', 'Var', (126, 143))
113890	27864908	Furthermore, we found that patients with more than 1 risk genotype among the five E2F2 polymorphisms had higher risk of SCCOP recurrence, especially in patients with HPV16(+) SCCOP tumors.	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('tumors', 'Disease', (181, 187))	('tumors', 'Disease', 'MESH:D009369', (181, 187))	('tumors', 'Phenotype', 'HP:0002664', (181, 187))	('E2F2', 'Gene', (82, 86))	('patients', 'Species', '9606', (27, 35))	('SCCOP recurrence', 'Disease', (120, 136))	('HPV16', 'Species', '333760', (166, 171))	('HPV16(+', 'Var', (166, 173))	('patients', 'Species', '9606', (152, 160))	('E2F2', 'Gene', '1870', (82, 86))
113891	27864908	These findings suggest that certain E2F2 polymorphisms may individually or jointly predict risk of SCCOP recurrence, particularly in patients with HPV16(+) tumors.	('predict', 'Reg', (83, 90))	('E2F2', 'Gene', (36, 40))	('polymorphisms', 'Var', (41, 54))	('patients', 'Species', '9606', (133, 141))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('SCCOP recurrence', 'Disease', (99, 115))	('HPV16', 'Gene', (147, 152))	('HPV16', 'Species', '333760', (147, 152))	('E2F2', 'Gene', '1870', (36, 40))	('tumors', 'Disease', 'MESH:D009369', (156, 162))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('tumors', 'Disease', (156, 162))
113892	27864908	Although the exact mechanism by which these E2F2 promoter variants modify cancer recurrence remains unknown, it is likely that these variants could alter expression of E2F2 and thus might affect susceptibility of response to radiotherapy, leading to different clinical outcomes.	('response to radiotherapy', 'CPA', (213, 237))	('modify', 'Reg', (67, 73))	('variants', 'Var', (58, 66))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('E2F2', 'Gene', '1870', (168, 172))	('leading to', 'Reg', (239, 249))	('E2F2', 'Gene', (44, 48))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('cancer', 'Disease', (74, 80))	('E2F2', 'Gene', (168, 172))	('alter', 'Reg', (148, 153))	('E2F2', 'Gene', '1870', (44, 48))	('variants', 'Var', (133, 141))	('affect', 'Reg', (188, 194))	('expression', 'MPA', (154, 164))
113893	27864908	Therefore, E2F2 variants could be potential predictive biomarkers for SCCOP recurrence and could help identify patients for individualized therapies.	('E2F2', 'Gene', '1870', (11, 15))	('SCCOP', 'Disease', (70, 75))	('E2F2', 'Gene', (11, 15))	('variants', 'Var', (16, 24))	('patients', 'Species', '9606', (111, 119))
113895	27864908	Thus, it is biologically plausible that E2F2 promoter polymorphisms might affect E2F2 protein expression, which, in turn, could affect p16 expression level, thereby influencing cancer prognosis.	('polymorphisms', 'Var', (54, 67))	('E2F2', 'Gene', '1870', (81, 85))	('E2F2', 'Gene', (40, 44))	('cancer', 'Disease', (177, 183))	('affect', 'Reg', (128, 134))	('cancer', 'Disease', 'MESH:D009369', (177, 183))	('protein', 'Protein', (86, 93))	('influencing', 'Reg', (165, 176))	('p16', 'Gene', '1029', (135, 138))	('E2F2', 'Gene', '1870', (40, 44))	('E2F2', 'Gene', (81, 85))	('expression level', 'MPA', (139, 155))	('expression', 'MPA', (94, 104))	('affect', 'Reg', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('p16', 'Gene', (135, 138))
113897	27864908	Since E2F2 regulates expression of p16 through Rb- mediated pathways and these E2F2 polymorphisms are within the functional regions of the E2F2's promoter, it is likely that these E2F2 polymorphisms may have potentially functional effect on expression levels of p16, thus leading to better survival.	('E2F2', 'Gene', (139, 143))	('p16', 'Gene', (35, 38))	('E2F2', 'Gene', '1870', (139, 143))	('p16', 'Gene', '1029', (35, 38))	('Rb', 'Chemical', 'MESH:D012413', (47, 49))	('regulates', 'Reg', (11, 20))	('E2F2', 'Gene', (79, 83))	('Rb- mediated pathways', 'Pathway', (47, 68))	('E2F2', 'Gene', '1870', (79, 83))	('p16', 'Gene', (262, 265))	('E2F2', 'Gene', (6, 10))	('E2F2', 'Gene', (180, 184))	('polymorphisms', 'Var', (84, 97))	('p16', 'Gene', '1029', (262, 265))	('E2F2', 'Gene', '1870', (6, 10))	('expression levels', 'MPA', (241, 258))	('expression', 'MPA', (21, 31))	('E2F2', 'Gene', '1870', (180, 184))	('effect', 'Reg', (231, 237))	('leading to', 'Reg', (272, 282))	('better', 'PosReg', (283, 289))
113898	27864908	In fact, in this study, we found that E2F2-rs2742976 polymorphism significantly affected expression of E2F2 in SCCOP patients, particularly HPV16-positive patients but not in HPV16-negative cases in SCCOP tumor specimens.	('expression', 'MPA', (89, 99))	('E2F2', 'Gene', '1870', (38, 42))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('E2F2', 'Gene', '1870', (103, 107))	('HPV16', 'Species', '333760', (140, 145))	('HPV16', 'Species', '333760', (175, 180))	('patients', 'Species', '9606', (117, 125))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumor', 'Disease', (205, 210))	('polymorphism', 'Var', (53, 65))	('rs2742976', 'Mutation', 'rs2742976', (43, 52))	('patients', 'Species', '9606', (155, 163))	('E2F2', 'Gene', (38, 42))	('SCCOP', 'Disease', (111, 116))	('E2F2', 'Gene', (103, 107))	('affected', 'Reg', (80, 88))
113902	27864908	Several studies have shown the associations of E2F2 promoter polymorphisms with risk of various types of human cancer, but no studies have investigated the modifying effect of E2F2 polymorphisms on SCCOP recurrence risk, especially for HPV-associated SCCOP.	('SCCOP', 'Disease', (198, 203))	('E2F2', 'Gene', (176, 180))	('associations', 'Interaction', (31, 43))	('polymorphisms', 'Var', (61, 74))	('human', 'Species', '9606', (105, 110))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('HPV-associated SCCOP', 'Disease', (236, 256))	('E2F2', 'Gene', (47, 51))	('E2F2', 'Gene', '1870', (176, 180))	('HPV', 'Species', '10566', (236, 239))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('E2F2', 'Gene', '1870', (47, 51))
113905	27864908	did not find a main effect of E2F2 variants or other variant genotypes on risk of squamous cell carcinoma of the head and neck, and Justenhoven et al.	('E2F2', 'Gene', '1870', (30, 34))	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('squamous cell carcinoma', 'Disease', (82, 105))	('variants', 'Var', (35, 43))	('E2F2', 'Gene', (30, 34))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (82, 105))	('carcinoma of the head and neck', 'Phenotype', 'HP:0012288', (96, 126))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (82, 105))
113906	27864908	found that the E2F2_-5368_A>G (rs760607) promoter polymorphism was not significantly associated with risk of breast cancer.	('E2F2', 'Gene', (15, 19))	('breast cancer', 'Disease', (109, 122))	('rs760607', 'Var', (31, 39))	('breast cancer', 'Phenotype', 'HP:0003002', (109, 122))	('-5368_A>G', 'Mutation', 'rs760607', (20, 29))	('rs760607', 'Mutation', 'rs760607', (31, 39))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('E2F2', 'Gene', '1870', (15, 19))	('associated', 'Reg', (85, 95))	('breast cancer', 'Disease', 'MESH:D001943', (109, 122))
113908	27864908	The inconsistent results regarding the associations of E2F2 promoter polymorphisms with cancer risk and prognosis suggest that these effects might also depend on other factors, such as cancer type, genetic background, environmental factors, sample size, disease stage, treatment, adequacy of adjustment for other confounding factors, and different study populations.	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('E2F2', 'Gene', '1870', (55, 59))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('polymorphisms', 'Var', (69, 82))	('associations', 'Interaction', (39, 51))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('E2F2', 'Gene', (55, 59))	('cancer', 'Disease', (185, 191))	('depend', 'Reg', (152, 158))
113909	27864908	The retinoblastoma-E2F pathway and other molecular pathways involved in cell-cycle control, DNA repair, and apoptosis and/or interactions between functional genetic variants and therapeutic agents may also cause interindividual differences in prognosis.	('retinoblastoma', 'Disease', 'MESH:D012175', (4, 18))	('retinoblastoma', 'Disease', (4, 18))	('variants', 'Var', (165, 173))	('interactions', 'Interaction', (125, 137))	('cause', 'Reg', (206, 211))	('retinoblastoma', 'Phenotype', 'HP:0009919', (4, 18))
113910	27864908	Tumor HPV status also significantly affected risk of SCCOP recurrence: patients with HPV16(+) SCCOP had a better prognosis than those with HPV(-) SCCOP.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('SCCOP', 'Var', (94, 99))	('HPV', 'Species', '10566', (6, 9))	('patients', 'Species', '9606', (71, 79))	('HPV16', 'Species', '333760', (85, 90))	('HPV', 'Species', '10566', (139, 142))	('HPV16(+) SCCOP', 'Var', (85, 99))	('HPV', 'Species', '10566', (85, 88))
113911	27864908	Patients with HPV(+) SCCOP, who have few somatic mutations, appear to have a better response to radiotherapy than those with HPV(-) SCCOP, whose disease is mainly driven by smoking and who have common somatic mutations, such as those in p53.	('HPV(+', 'Var', (14, 19))	('better', 'PosReg', (77, 83))	('p53', 'Gene', '7157', (237, 240))	('HPV', 'Species', '10566', (14, 17))	('HPV', 'Species', '10566', (125, 128))	('Patients', 'Species', '9606', (0, 8))	('p53', 'Gene', (237, 240))
113915	27864908	Although the molecular mechanisms underlying these findings in patients with HPV16(+) SCCOP remain incompletely understood, the variant genotypes of these two polymorphisms may affect DNA repair capacity or apoptosis through controlling the cell cycle.	('variant', 'Var', (128, 135))	('controlling', 'Reg', (225, 236))	('apoptosis', 'CPA', (207, 216))	('HPV16', 'Gene', (77, 82))	('HPV16', 'Species', '333760', (77, 82))	('cell cycle', 'CPA', (241, 251))	('affect', 'Reg', (177, 183))	('patients', 'Species', '9606', (63, 71))	('DNA repair', 'MPA', (184, 194))
113917	27864908	Thus, E2F2 variants may affect susceptibility to radiotherapy and lead to different recurrence outcomes.	('E2F2', 'Gene', '1870', (6, 10))	('variants', 'Var', (11, 19))	('susceptibility', 'MPA', (31, 45))	('lead to', 'Reg', (66, 73))	('E2F2', 'Gene', (6, 10))	('affect', 'Reg', (24, 30))	('susceptibility to radiotherapy', 'Phenotype', 'HP:0011133', (31, 61))
113922	27864908	Taken together, our findings suggest that the E2F2 promoter variants might individually or in combination modulate the risk of SCCOP recurrence, especially in patients with HPV16(+) tumors who have received definitive radiotherapy.	('E2F2', 'Gene', (46, 50))	('HPV16', 'Gene', (173, 178))	('tumors', 'Phenotype', 'HP:0002664', (182, 188))	('patients', 'Species', '9606', (159, 167))	('tumors', 'Disease', (182, 188))	('tumors', 'Disease', 'MESH:D009369', (182, 188))	('E2F2', 'Gene', '1870', (46, 50))	('modulate', 'Reg', (106, 114))	('variants', 'Var', (60, 68))	('SCCOP recurrence', 'Disease', (127, 143))	('HPV16', 'Species', '333760', (173, 178))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
113924	27864908	E2F2 promoter variants individually or jointly modify the risk of SCCOP recurrence, and may be a predictive biomarker for recurrence risk of SCCOP, particularly in HPV-positive SCCOP patients.	('E2F2', 'Gene', '1870', (0, 4))	('SCCOP recurrence', 'Disease', (66, 82))	('variants', 'Var', (14, 22))	('modify', 'Reg', (47, 53))	('E2F2', 'Gene', (0, 4))	('SCCOP', 'Disease', (141, 146))	('HPV', 'Species', '10566', (164, 167))	('patients', 'Species', '9606', (183, 191))
113932	29088286	ECT2 mutation was observed in 5% of LUAD and in 51% of LUSC cases.	('LUSC', 'Phenotype', 'HP:0030359', (55, 59))	('ECT2', 'Gene', (0, 4))	('LUAD', 'Disease', (36, 40))	('LUAD', 'Phenotype', 'HP:0030078', (36, 40))	('observed', 'Reg', (18, 26))	('mutation', 'Var', (5, 13))	('ECT2', 'Gene', '1894', (0, 4))
113934	29088286	High ECT2 expression was associated with unfavorable overall survival (OS) (p<0.0001) and recurrence-free survival (RFS) (p = 0.001) in LUAD patients.	('High', 'Var', (0, 4))	('ECT2', 'Gene', '1894', (5, 9))	('overall survival', 'CPA', (53, 69))	('recurrence-free survival', 'CPA', (90, 114))	('LUAD', 'Disease', (136, 140))	('ECT2', 'Gene', (5, 9))	('patients', 'Species', '9606', (141, 149))	('LUAD', 'Phenotype', 'HP:0030078', (136, 140))
113936	29088286	The following univariate and multivariate analysis showed that the high ECT2 expression was an independent prognostic factor for poor OS (HR: 2.039, 95%CI: 1.457-2.852, p<0.001) and RFS (HR: 1.715, 95%CI: 1.210-2.432, p = 0.002) in LUAD patients, but not in LUSC patients.	('expression', 'MPA', (77, 87))	('LUSC', 'Phenotype', 'HP:0030359', (258, 262))	('high', 'Var', (67, 71))	('RFS', 'Disease', (182, 185))	('patients', 'Species', '9606', (263, 271))	('ECT2', 'Gene', '1894', (72, 76))	('ECT2', 'Gene', (72, 76))	('LUAD', 'Disease', (232, 236))	('poor OS', 'Disease', (129, 136))	('patients', 'Species', '9606', (237, 245))	('LUAD', 'Phenotype', 'HP:0030078', (232, 236))
113963	29088286	Then, we tried to investigate the underlying mechanisms of dysregulated ECT2 expression in LUSC and LUAD.	('dysregulated', 'Var', (59, 71))	('LUAD', 'Phenotype', 'HP:0030078', (100, 104))	('ECT2', 'Gene', '1894', (72, 76))	('LUSC', 'Phenotype', 'HP:0030359', (91, 95))	('ECT2', 'Gene', (72, 76))
113965	29088286	ECT2 mutation was observed in 5% of LUAD and in 51% of LUSC cases (Fig 3B).	('LUSC', 'Phenotype', 'HP:0030359', (55, 59))	('ECT2', 'Gene', (0, 4))	('LUAD', 'Disease', (36, 40))	('LUAD', 'Phenotype', 'HP:0030078', (36, 40))	('observed', 'Reg', (18, 26))	('mutation', 'Var', (5, 13))	('ECT2', 'Gene', '1894', (0, 4))
113966	29088286	Amplification was the predominant type of alteration and was associated with increased ECT2 mRNA expression in both LUAD and LUSC (Fig 3C and 3D).	('Amplification', 'Var', (0, 13))	('LUSC', 'Phenotype', 'HP:0030359', (125, 129))	('ECT2', 'Gene', '1894', (87, 91))	('ECT2', 'Gene', (87, 91))	('increased', 'PosReg', (77, 86))	('LUAD', 'Phenotype', 'HP:0030078', (116, 120))
113972	29088286	Besides, the high ECT2 expression group also had a significantly higher ratio of death (136/318, 42.8% vs. 47/184, 25.5%, p<0.0001) compared with the low ECT2 expression group (Table 1).	('death', 'Disease', 'MESH:D003643', (81, 86))	('ECT2', 'Gene', '1894', (154, 158))	('high', 'Var', (13, 17))	('death', 'Disease', (81, 86))	('ECT2', 'Gene', '1894', (18, 22))	('ECT2', 'Gene', (154, 158))	('ECT2', 'Gene', (18, 22))
113975	29088286	High ECT2 expression was associated with significantly worse OS (p<0.0001) and RFS (p = 0.001) in patients with LUAD (Fig 5C and 5D).	('RFS', 'MPA', (79, 82))	('High', 'Var', (0, 4))	('expression', 'MPA', (10, 20))	('patients', 'Species', '9606', (98, 106))	('ECT2', 'Gene', '1894', (5, 9))	('LUAD', 'Phenotype', 'HP:0030078', (112, 116))	('ECT2', 'Gene', (5, 9))	('LUAD', 'Disease', (112, 116))
113977	29088286	By performing univariate analysis, we found that advanced stage (III/IV) and high ECT2 expression were associated with significantly shorter OS and RFS in LUAD patients (Table 3).	('shorter', 'NegReg', (133, 140))	('patients', 'Species', '9606', (160, 168))	('ECT2', 'Gene', (82, 86))	('RFS', 'MPA', (148, 151))	('high', 'Var', (77, 81))	('LUAD', 'Phenotype', 'HP:0030078', (155, 159))	('expression', 'MPA', (87, 97))	('ECT2', 'Gene', '1894', (82, 86))
113978	29088286	Following multivariate analysis confirmed that the high ECT2 expression was an independent prognostic factor for poor OS (HR: 2.039, 95%CI: 1.457-2.852, p<0.001) and RFS (HR: 1.715, 95%CI: 1.210-2.432, p = 0.002) in LUAD patients (Table 3).	('LUAD', 'Disease', (216, 220))	('patients', 'Species', '9606', (221, 229))	('ECT2', 'Gene', '1894', (56, 60))	('high', 'Var', (51, 55))	('RFS', 'Disease', (166, 169))	('ECT2', 'Gene', (56, 60))	('poor OS', 'Disease', (113, 120))	('LUAD', 'Phenotype', 'HP:0030078', (216, 220))
113989	29088286	In addition, we also observed that some CpG loci of ECT2 gene had higher levels of methylation in LUAD than in LUSC, suggesting that epigenetic alteration is also an important mechanism of dysregulated ECT2 in NSCLC.	('dysregulated', 'Var', (189, 201))	('methylation', 'MPA', (83, 94))	('ECT2', 'Gene', (202, 206))	('levels', 'MPA', (73, 79))	('ECT2', 'Gene', '1894', (52, 56))	('LUSC', 'Phenotype', 'HP:0030359', (111, 115))	('NSCLC', 'Disease', (210, 215))	('epigenetic alteration', 'Var', (133, 154))	('NSCLC', 'Disease', 'MESH:D002289', (210, 215))	('ECT2', 'Gene', (52, 56))	('higher', 'PosReg', (66, 72))	('LUAD', 'Phenotype', 'HP:0030078', (98, 102))	('ECT2', 'Gene', '1894', (202, 206))	('NSCLC', 'Phenotype', 'HP:0030358', (210, 215))
113992	29088286	In patients with colorectal cancer, high expression level of ECT2 was significantly associated with tumor size, serum CEA levels and TNM stage.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('colorectal cancer', 'Phenotype', 'HP:0003003', (17, 34))	('ECT2', 'Gene', (61, 65))	('CEA', 'Gene', (118, 121))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('TNM', 'Gene', (133, 136))	('tumor', 'Disease', (100, 105))	('CEA', 'Gene', '1084', (118, 121))	('colorectal cancer', 'Disease', 'MESH:D015179', (17, 34))	('colorectal cancer', 'Disease', (17, 34))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('patients', 'Species', '9606', (3, 11))	('associated', 'Reg', (84, 94))	('TNM', 'Gene', '10178', (133, 136))	('high', 'Var', (36, 40))	('ECT2', 'Gene', '1894', (61, 65))
113993	29088286	Kaplan-Meier survival analysis indicated that patients with high ECT2 expression had a remarkably shorter OS.	('patients', 'Species', '9606', (46, 54))	('ECT2', 'Gene', '1894', (65, 69))	('high', 'Var', (60, 64))	('ECT2', 'Gene', (65, 69))	('shorter', 'NegReg', (98, 105))
113995	29088286	One study based on patients with LUAD indicated that high ECT2 expression was associated with unfavorable disease-free survival and overall survival.	('ECT2', 'Gene', '1894', (58, 62))	('high', 'Var', (53, 57))	('disease-free survival', 'CPA', (106, 127))	('patients', 'Species', '9606', (19, 27))	('overall survival', 'CPA', (132, 148))	('ECT2', 'Gene', (58, 62))	('LUAD', 'Phenotype', 'HP:0030078', (33, 37))
113997	29088286	In this study, based on large datasets in TCGA, we found that although ECT2 amplification is common in LUSC, its mutation had no influence on survival outcomes.	('ECT2', 'Gene', (71, 75))	('ECT2', 'Gene', '1894', (71, 75))	('LUSC', 'Phenotype', 'HP:0030359', (103, 107))	('amplification', 'Var', (76, 89))
113998	29088286	Nevertheless, although ECT2 amplification was less frequent in LUAD, its mutation was associated with significantly worse disease-free survival.	('worse', 'NegReg', (116, 121))	('ECT2', 'Gene', '1894', (23, 27))	('disease-free survival', 'CPA', (122, 143))	('LUAD', 'Phenotype', 'HP:0030078', (63, 67))	('LUAD', 'Disease', (63, 67))	('mutation', 'Var', (73, 81))	('ECT2', 'Gene', (23, 27))
114001	29088286	In addition, our univariate and multivariate analysis showed that high ECT2 expression was an independent prognostic factor for poor OS (HR: 2.039, 95%CI: 1.457-2.852, p<0.001) and RFS (HR: 1.715, 95%CI: 1.210-2.432, p = 0.002) in LUAD patients, but not in LUSC patients.	('ECT2', 'Gene', (71, 75))	('RFS', 'Disease', (181, 184))	('patients', 'Species', '9606', (236, 244))	('poor OS', 'Disease', (128, 135))	('LUAD', 'Phenotype', 'HP:0030078', (231, 235))	('expression', 'MPA', (76, 86))	('ECT2', 'Gene', '1894', (71, 75))	('high', 'Var', (66, 70))	('LUAD', 'Disease', (231, 235))	('LUSC', 'Phenotype', 'HP:0030359', (257, 261))	('patients', 'Species', '9606', (262, 270))
114006	29088286	The following KEGG pathway analysis of the enrichment of ECT2 co-expressed genes showed that Cell cycle, p53 signaling pathway, DNA replication, Mismatch repair, Homologous recombination and Fanconi anemia pathway are common in LUSC and LUAD.	('ECT2', 'Gene', (57, 61))	('anemia', 'Phenotype', 'HP:0001903', (199, 205))	('Cell', 'Pathway', (93, 97))	('Fanconi anemia', 'Phenotype', 'HP:0001994', (191, 205))	('LUAD', 'Phenotype', 'HP:0030078', (237, 241))	('Mismatch', 'Var', (145, 153))	('LUAD', 'Disease', (237, 241))	('Fanconi anemia', 'Disease', (191, 205))	('LUSC', 'Disease', (228, 232))	('p53', 'Gene', (105, 108))	('p53', 'Gene', '7157', (105, 108))	('LUSC', 'Phenotype', 'HP:0030359', (228, 232))	('DNA replication', 'Gene', (128, 143))	('ECT2', 'Gene', '1894', (57, 61))	('Fanconi anemia', 'Disease', 'MESH:D005199', (191, 205))
114009	29088286	Both genetic and epigenetic alterations contributed to dysregulated ECT2 in NSCLC.	('ECT2', 'Gene', (68, 72))	('dysregulated', 'Var', (55, 67))	('NSCLC', 'Disease', (76, 81))	('contributed', 'Reg', (40, 51))	('NSCLC', 'Disease', 'MESH:D002289', (76, 81))	('ECT2', 'Gene', '1894', (68, 72))	('epigenetic alterations', 'Var', (17, 39))	('NSCLC', 'Phenotype', 'HP:0030358', (76, 81))
114010	29088286	High ECT2 expression was an independent prognostic factor for poor OS and RFS in LUAD patients, but not in LUSC patients.	('LUAD', 'Phenotype', 'HP:0030078', (81, 85))	('RFS', 'Disease', (74, 77))	('High', 'Var', (0, 4))	('poor OS', 'Disease', (62, 69))	('LUSC', 'Phenotype', 'HP:0030359', (107, 111))	('expression', 'MPA', (10, 20))	('patients', 'Species', '9606', (112, 120))	('ECT2', 'Gene', '1894', (5, 9))	('ECT2', 'Gene', (5, 9))	('patients', 'Species', '9606', (86, 94))
114020	33477374	Significant infratentorial clusters were associated with young age, male sex, lung neuroendocrine and squamous cell carcinomas, high expression of Ki-67 of primaries and BMs, and patients with poorer prognosis.	('expression', 'MPA', (133, 143))	('squamous cell carcinomas', 'Disease', (102, 126))	('Ki-67', 'Gene', (147, 152))	('carcinomas', 'Phenotype', 'HP:0030731', (116, 126))	('Ki-67', 'Chemical', '-', (147, 152))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (102, 126))	('age', 'Gene', (63, 66))	('patients', 'Species', '9606', (179, 187))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('high', 'Var', (128, 132))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (102, 125))	('age', 'Gene', '5973', (63, 66))	('lung neuroendocrine', 'Disease', 'MESH:D018358', (78, 97))	('lung neuroendocrine', 'Disease', (78, 97))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (102, 126))
114056	33477374	BMs with Ki-67 >= the median (45%) showed significant localization in the left cerebellum (Figure 4F).	('localization', 'MPA', (54, 66))	('Ki-67 >=', 'Var', (9, 17))	('Ki-67', 'Chemical', '-', (9, 14))
114157	32533054	Since immunosuppression from abnormalities of the TME critically interrupts immunotherapeutic approaches, understanding the TME and characterizing novel immune subtypes have been extensively researched to predict immunotherapy responses and enhance antitumor activity by targeting TME-induced ICI resistance.	('tumor', 'Disease', 'MESH:D009369', (253, 258))	('abnormalities', 'Var', (29, 42))	('enhance', 'PosReg', (241, 248))	('tumor', 'Phenotype', 'HP:0002664', (253, 258))	('immunotherapeutic approaches', 'CPA', (76, 104))	('targeting', 'Reg', (271, 280))	('tumor', 'Disease', (253, 258))	('interrupts', 'NegReg', (65, 75))
114205	32533054	We identified significantly amplified or deleted loci and genes within both subtypes across 7 cancers except few subtypes (Supplementary Table 3 and 4, respectively), and recurrent amplifications and deletions at several loci with immune checkpoint genes were found in KIRP, PAAD, PCPG, SARC and SKCM (Supplementary Fig.	('cancers', 'Disease', 'MESH:D009369', (94, 101))	('SKCM', 'Disease', (296, 300))	('PCPG', 'Disease', (281, 285))	('KIRP', 'Disease', (269, 273))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('PAAD', 'Disease', (275, 279))	('deletions', 'Var', (200, 209))	('cancers', 'Phenotype', 'HP:0002664', (94, 101))	('SARC', 'Disease', (287, 291))	('cancers', 'Disease', (94, 101))
114229	32533054	At gene levels, recurrent amplifications and deletions at immune checkpoint genes were found in several subtypes of cancers but not in TME-dependent manner.	('deletions', 'Var', (45, 54))	('cancers', 'Disease', 'MESH:D009369', (116, 123))	('cancers', 'Phenotype', 'HP:0002664', (116, 123))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('immune checkpoint genes', 'Gene', (58, 81))	('cancers', 'Disease', (116, 123))	('found', 'Reg', (87, 92))	('amplifications', 'Var', (26, 40))
114248	32533054	GISTIC analysis was conducted to find recurrent amplification and deletion in the subtypes of 7 cancer types.	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Disease', (96, 102))	('deletion', 'Var', (66, 74))	('amplification', 'Var', (48, 61))
114308	27574101	Amplifications of epidermal growth factor receptor (EGFR) and c-MYC have been identified in AK and cuSCC.	('identified', 'Reg', (78, 88))	('c-MYC', 'Gene', (62, 67))	('EGFR', 'Gene', '1956', (52, 56))	('EGFR', 'Gene', (52, 56))	('epidermal growth factor receptor', 'Gene', '1956', (18, 50))	('epidermal growth factor receptor', 'Gene', (18, 50))	('SCC', 'Gene', (101, 104))	('Amplifications', 'Var', (0, 14))	('c-MYC', 'Gene', '4609', (62, 67))	('SCC', 'Gene', '6317', (101, 104))
114321	27574101	mutations in similar proportions to those in human cuSCC, along with copy number variations that map to ones reported in human cuSCC (chromosomes 3p, 11p and 9q) (refs) Serial Analysis of Gene Expression (SAGE) mRNA gene expression data from this model, comparing UVR-induced cuSCC to NS epidermis, shows substantially similar patterns of changes to our human data including overexpression of matrix metalloproteinases and hyperproliferative keratins.	('SCC', 'Gene', '6317', (53, 56))	('SCC', 'Gene', '6317', (129, 132))	('NS epidermis', 'Disease', (285, 297))	('SCC', 'Gene', (278, 281))	('human', 'Species', '9606', (354, 359))	('changes', 'Reg', (339, 346))	('hyperproliferative', 'CPA', (423, 441))	('human', 'Species', '9606', (45, 50))	('human', 'Species', '9606', (121, 126))	('matrix', 'Protein', (393, 399))	('SCC', 'Gene', '6317', (278, 281))	('mutations', 'Var', (0, 9))	('NS epidermis', 'Disease', 'MESH:D009404', (285, 297))	('SCC', 'Gene', (53, 56))	('SCC', 'Gene', (129, 132))	('overexpression', 'PosReg', (375, 389))
114327	27574101	The mutational load varied widely across our cohort of well-differentiated primary cuSCC, averaging 2,927 somatic variants (range 385-9,156) or 45.7 variants per Mb (Fig.	('variants', 'Var', (114, 122))	('SCC', 'Gene', (85, 88))	('SCC', 'Gene', '6317', (85, 88))
114330	27574101	Hi-depth targeted sequencing of 74 genes has demonstrated an estimated five mutations per Mb in chronically UVR-exposed eyelid skin, with a strong preponderance of NOTCH1-3, TP53 and FGFR3 mutations suggesting positive selection for these mutations.	('eyelid skin', 'Phenotype', 'HP:0010750', (120, 131))	('NOTCH1-3', 'Gene', (164, 172))	('TP53', 'Gene', (174, 178))	('NOTCH1-3', 'Gene', '4851;4853;4854', (164, 172))	('FGFR3', 'Gene', '2261', (183, 188))	('mutations', 'Var', (189, 198))	('FGFR3', 'Gene', (183, 188))
114333	27574101	The proportion of dinucleotide variants that are CC TT is 90% for both AK and cuSCC and 84% for NS (Supplementary Fig.	('SCC', 'Gene', '6317', (80, 83))	('dinucleotide', 'Chemical', 'MESH:D015226', (18, 30))	('dinucleotide variants', 'Var', (18, 39))	('SCC', 'Gene', (80, 83))	('men', 'Species', '9606', (106, 109))
114336	27574101	AK and cuSCC are clearly driven by UVR exposure, with substantial enrichment for the classic UVB C T transition signature at dipyrimidines in a manner that correlated with increasing mutational load (Fig.	('men', 'Species', '9606', (72, 75))	('mutational', 'Var', (183, 193))	('increasing', 'PosReg', (172, 182))	('SCC', 'Gene', (9, 12))	('dipyrimidines', 'Chemical', '-', (125, 138))	('SCC', 'Gene', '6317', (9, 12))
114338	27574101	To identify significantly mutated genes (SMG), we identified those that were recurrently mutated in at least seven pairings and that were either previously implicated in cuSCC or have COSMIC frequencies over 400 (Fig.	('SCC', 'Gene', (172, 175))	('SCC', 'Gene', '6317', (172, 175))	('mutated', 'Var', (89, 96))
114341	27574101	2c), most prominently, TP53, NOTCH1-2, FAT1 and MLL2.	('MLL2', 'Gene', (48, 52))	('FAT1', 'Gene', '2195', (39, 43))	('FAT1', 'Gene', (39, 43))	('MLL2', 'Gene', '9757', (48, 52))	('TP53', 'Var', (23, 27))	('NOTCH1-2', 'Gene', (29, 37))	('NOTCH1-2', 'Gene', '4851;4853', (29, 37))
114342	27574101	We also identified a rare KNSTRN missense mutation (resulting in p.P28S) in only two pairings (one cuSCC, AK), which appears to be within the same functional domain as a previously reported hotspot p.S25F (ref.).	('p.P28S', 'Var', (65, 71))	('KNSTRN', 'Gene', '90417', (26, 32))	('KNSTRN', 'Gene', (26, 32))	('SCC', 'Gene', (101, 104))	('p.S25F', 'Mutation', 'p.S25F', (198, 204))	('p.P28S', 'Mutation', 'p.P28S', (65, 71))	('SCC', 'Gene', '6317', (101, 104))
114344	27574101	Of note, the NS sample (patient 1) with high variant allele frequencies, has evidence for three TP53 mutations (Fig.	('mutations', 'Var', (101, 110))	('patient', 'Species', '9606', (24, 31))	('TP53', 'Gene', (96, 100))
114349	27574101	The most significant degree of site-specific mutational overlap occurred between two cuSCCs from patient 4 (Table 2), which were in close physical proximity (Fig.	('patient', 'Species', '9606', (97, 104))	('SCC', 'Gene', (87, 90))	('mutational overlap', 'Var', (45, 63))	('SCC', 'Gene', '6317', (87, 90))
114351	27574101	When viewed within patients, functionally significant genes were mutated in multiple samples, including TP53 (four patients), FAT1 (three patients) and MLL3 (three patients) (Supplementary Fig.	('MLL3', 'Gene', (152, 156))	('patients', 'Species', '9606', (115, 123))	('patients', 'Species', '9606', (19, 27))	('TP53', 'Gene', (104, 108))	('MLL3', 'Gene', '58508', (152, 156))	('FAT1', 'Gene', '2195', (126, 130))	('FAT1', 'Gene', (126, 130))	('patients', 'Species', '9606', (164, 172))	('patients', 'Species', '9606', (138, 146))	('men', 'Species', '9606', (181, 184))	('mutated', 'Var', (65, 72))
114353	27574101	Overlaps in AK-cuSCC were the most common even among these genes, suggesting that they are specifically targeted in the development of cuSCC.	('SCC', 'Gene', '6317', (17, 20))	('SCC', 'Gene', '6317', (137, 140))	('Overlaps', 'Var', (0, 8))	('men', 'Species', '9606', (127, 130))	('SCC', 'Gene', (17, 20))	('SCC', 'Gene', (137, 140))
114355	27574101	The two cuSCCs from patient 4, which shared the greatest overlap (195), shared a TP53W23X mutant (Fig.	('SCC', 'Gene', (10, 13))	('SCC', 'Gene', '6317', (10, 13))	('TP53W23X', 'Var', (81, 89))	('patient', 'Species', '9606', (20, 27))
114356	27574101	Among all the human tumour samples sequenced, only amino acid R248, which is a mutational hotspot in cuSCC, was multiply altered within two patients (patients 1 and 4).	('human', 'Species', '9606', (14, 19))	('SCC', 'Gene', (103, 106))	('tumour', 'Disease', 'MESH:D009369', (20, 26))	('tumour', 'Disease', (20, 26))	('altered', 'Reg', (121, 128))	('patients', 'Species', '9606', (150, 158))	('SCC', 'Gene', '6317', (103, 106))	('patients', 'Species', '9606', (140, 148))	('amino acid R248', 'Var', (51, 66))	('tumour', 'Phenotype', 'HP:0002664', (20, 26))
114357	27574101	These findings are consistent with the concept that mutations that inactivate tumour suppressor genes are often distributed across the entire coding region and that there has not been a strongly dominant oncogenic mutation identified in cuSCC.	('mutations', 'Var', (52, 61))	('inactivate', 'NegReg', (67, 77))	('SCC', 'Gene', '6317', (239, 242))	('tumour', 'Disease', 'MESH:D009369', (78, 84))	('tumour', 'Disease', (78, 84))	('SCC', 'Gene', (239, 242))	('tumour', 'Phenotype', 'HP:0002664', (78, 84))
114370	27574101	Using TRANSFAC-based motif analysis, we identified significantly overrepresented motifs and their associated transcription factors for all pairwise comparisons in both human and mice.	('overrepresented', 'PosReg', (65, 80))	('mice', 'Species', '10090', (178, 182))	('human', 'Species', '9606', (168, 173))	('motifs', 'Var', (81, 87))
114396	27574101	Following cross-species overlap of mouse and human data, this model also clearly demonstrated that the majority of changes occur in the earliest transition from NS to AK/PAP versus the subsequent transition to cuSCC (Fig.	('SCC', 'Gene', (212, 215))	('SCC', 'Gene', '6317', (212, 215))	('mouse', 'Species', '10090', (35, 40))	('human', 'Species', '9606', (45, 50))	('changes', 'Var', (115, 122))
114427	27574101	TP53 mutations occur at over 70% frequency in all SCCs; NOTCH family genes are mutated in over 70% of cuSCC, 10-20% of HNSCC, 13% of LUSC and 10% of oesophageal SCC (ESCA SCC); and SOX2 amplification is a common lineage-specific driver of SCC.	('SCC', 'Gene', (171, 174))	('SCC', 'Gene', '6317', (239, 242))	('SCC', 'Gene', '6317', (50, 53))	('SCC', 'Gene', (161, 164))	('TP53', 'Gene', (0, 4))	('mutated', 'Var', (79, 86))	('SCC', 'Gene', '6317', (104, 107))	('SCC', 'Gene', '6317', (171, 174))	('SCC', 'Gene', (104, 107))	('SCC', 'Gene', (121, 124))	('mutations', 'Var', (5, 14))	('SCC', 'Gene', '6317', (161, 164))	('SCC', 'Gene', (239, 242))	('SCC', 'Gene', (50, 53))	('SOX2', 'Gene', '6657', (181, 185))	('SOX2', 'Gene', (181, 185))	('SCC', 'Gene', '6317', (121, 124))
114433	27574101	Given that HNSCC is consistently the most closely related tumour to cuSCC, we asked whether cuSCC-derived signatures from our cohort of well-differentiated tumours could also be used to predict outcomes in carcinogen-driven (non-HPV) HNSCCs, which have TP53 mutations and high mutational loads.	('tumours', 'Disease', 'MESH:D009369', (156, 163))	('SCC', 'Gene', (70, 73))	('tumour', 'Phenotype', 'HP:0002664', (156, 162))	('tumour', 'Disease', 'MESH:D009369', (156, 162))	('tumour', 'Disease', (156, 162))	('tumour', 'Phenotype', 'HP:0002664', (58, 64))	('tumour', 'Disease', 'MESH:D009369', (58, 64))	('tumour', 'Disease', (58, 64))	('SCC', 'Gene', '6317', (94, 97))	('mutations', 'Var', (258, 267))	('SCC', 'Gene', '6317', (236, 239))	('SCC', 'Gene', '6317', (13, 16))	('tumours', 'Disease', (156, 163))	('SCC', 'Gene', (94, 97))	('HPV', 'Species', '10566', (229, 232))	('SCC', 'Gene', '6317', (70, 73))	('SCC', 'Gene', (236, 239))	('SCC', 'Gene', (13, 16))	('tumours', 'Phenotype', 'HP:0002664', (156, 163))	('TP53', 'Gene', (253, 257))
114436	27574101	8b:bottom right), showing that these microRNA target genes likely regulate not only important processes in cuSCC development but also drivers of disease outcome in HNSCC.	('SCC', 'Gene', '6317', (109, 112))	('genes', 'Var', (53, 58))	('SCC', 'Gene', '6317', (166, 169))	('SCC', 'Gene', (166, 169))	('SCC', 'Gene', (109, 112))	('regulate', 'Reg', (66, 74))	('men', 'Species', '9606', (120, 123))
114440	27574101	Importantly, high mutational loads have recently been described in chronically UVR-exposed blepharoplasty samples, and, for the first time, we show the large degree of mosaicism present across the entire exome in non-lesional UVR-exposed peri-tumoural skin, with quantitatively similar mutational loads (Fig.	('tumour', 'Phenotype', 'HP:0002664', (243, 249))	('mosaicism', 'Var', (168, 177))	('tumoural skin', 'Phenotype', 'HP:0008069', (243, 256))	('tumoural skin', 'Disease', 'MESH:D012878', (243, 256))	('tumoural skin', 'Disease', (243, 256))
114441	27574101	The SMGs identified, including TP53, NOTCH1-2, FAT1 and MLL2 are ones likely to be important in cuSCC pathogenesis (Fig.	('NOTCH1-2', 'Gene', '4851;4853', (37, 45))	('TP53', 'Var', (31, 35))	('MLL2', 'Gene', (56, 60))	('SCC', 'Gene', '6317', (98, 101))	('FAT1', 'Gene', '2195', (47, 51))	('FAT1', 'Gene', (47, 51))	('MLL2', 'Gene', '9757', (56, 60))	('NOTCH1-2', 'Gene', (37, 45))	('SCC', 'Gene', (98, 101))
114443	27574101	Our findings are consistent with the notion that tumour suppressor genes, which represent the largest class of cancer genes known to be recurrently targeted in cuSCC, can often be inactivated by mutational insults spread across their entire coding regions.	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('tumour', 'Phenotype', 'HP:0002664', (49, 55))	('SCC', 'Gene', (162, 165))	('mutational insults', 'Var', (195, 213))	('inactivated', 'NegReg', (180, 191))	('tumour', 'Disease', 'MESH:D009369', (49, 55))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('SCC', 'Gene', '6317', (162, 165))	('tumour', 'Disease', (49, 55))
114445	27574101	The subsequent expansion in overall mutational load, which occurs in progression to AK and cuSCC correlates with a significant enrichment for UVB-signature mutations (Fig.	('expansion', 'Var', (15, 24))	('UVB-signature', 'Gene', (142, 155))	('mutations', 'Var', (156, 165))	('SCC', 'Gene', (93, 96))	('men', 'Species', '9606', (133, 136))	('SCC', 'Gene', '6317', (93, 96))	('mutational load', 'MPA', (36, 51))
114447	27574101	It is possible that initiated clones persist longer than normal keratinocytes, thereby enabling expansion or accumulation of further UVB-mediated DNA damage, a notion consistent with the early appearance of TP53 mutations (Figs 2c and 3b), and dramatically illustrated in the NS sample from patient 1 (Figs 2a,b and 3b).	('TP53', 'Gene', (207, 211))	('mutations', 'Var', (212, 221))	('patient', 'Species', '9606', (291, 298))
114451	27574101	8a) at the mutational and transcriptional levels, and include deregulation of key pathways such as those driven by altered RB1, TP53 and TP63 function.	('RB1', 'Gene', '5925', (123, 126))	('TP53', 'Gene', (128, 132))	('altered', 'Var', (115, 122))	('TP63', 'Gene', (137, 141))	('key pathways', 'Pathway', (78, 90))	('TP63', 'Gene', '8626', (137, 141))	('RB1', 'Gene', (123, 126))	('deregulation', 'Reg', (62, 74))
114465	27574101	Other mouse models of cuSCC have also been extensively studied, most prominently the DMBA/TPA model; in this model, tumorigenesis is overwhelmingly driven by HrasQ61 mutations which are rarely found in UVR-driven human cuSCC and in the UVR-driven Hairless mouse model (Supplementary Data 1).	('men', 'Species', '9606', (275, 278))	('Hairless', 'Gene', (247, 255))	('human', 'Species', '9606', (213, 218))	('mutations', 'Var', (166, 175))	('HrasQ61', 'Gene', (158, 165))	('driven', 'Reg', (148, 154))	('SCC', 'Gene', (24, 27))	('tumorigenesis', 'CPA', (116, 129))	('DMBA', 'Chemical', 'MESH:C082386', (85, 89))	('SCC', 'Gene', '6317', (24, 27))	('SCC', 'Gene', (221, 224))	('TPA', 'Chemical', '-', (90, 93))	('Hairless', 'Gene', '15460', (247, 255))	('SCC', 'Gene', '6317', (221, 224))	('mouse', 'Species', '10090', (256, 261))	('mouse', 'Species', '10090', (6, 11))
114469	27574101	Furthermore, early cuSCC signatures were able to predict survival in TP53-mutant (non-HPV) HNSCC (Fig.	('SCC', 'Gene', (21, 24))	('HPV', 'Species', '10566', (86, 89))	('SCC', 'Gene', '6317', (21, 24))	('SCC', 'Gene', (93, 96))	('TP53-mutant', 'Var', (69, 80))	('SCC', 'Gene', '6317', (93, 96))	('predict', 'Reg', (49, 56))
114497	27574101	TRANSFAC-based analysis (http://www.gene-regulation.com/index2.html) was performed by first identifying significantly overrepresented motifs and their associated transcription factors for all pairwise comparisons in both human and mice.	('human', 'Species', '9606', (221, 226))	('motifs', 'Var', (134, 140))	('mice', 'Species', '10090', (231, 235))	('overrepresented', 'PosReg', (118, 133))
114513	27574101	Commercially available Taqman (Life Technologies) probes were acquired for human miR-21 (000397), miR-31 (002279), PTPN14 (Hs00193643_m1), FAM134B (Hs00375273_m1), HMG2A (Hs00171569_m1), TIMP3 (Hs00165949_m1) and ARHGAP24 (Hs01097580_m1) and used in qRT-PCR based quantitation of expression in these tissues, as benchmarked to RNU6B (001093, microRNA) and 18S rRNA (Hs99999901, mRNA).	('miR-31', 'Gene', (98, 104))	('TIMP3', 'Gene', (187, 192))	('TIMP3', 'Gene', '7078', (187, 192))	('HMG2A', 'Gene', '3149', (164, 169))	('HMG2A', 'Gene', (164, 169))	('001093', 'Var', (334, 340))	('ARHGAP24', 'Gene', '83478', (213, 221))	('PTPN14', 'Gene', (115, 121))	('002279', 'Var', (106, 112))	('miR-31', 'Gene', '407035', (98, 104))	('miR-21', 'Gene', '406991', (81, 87))	('FAM134B', 'Gene', '54463', (139, 146))	('Hs01097580_m1', 'Var', (223, 236))	('Hs99999901', 'Var', (366, 376))	('Hs00375273_m1', 'Var', (148, 161))	('Hs00193643_m1', 'Var', (123, 136))	('Hs00171569_m1', 'Var', (171, 184))	('FAM134B', 'Gene', (139, 146))	('RNU6B', 'Gene', (327, 332))	('Hs00165949_m1', 'Var', (194, 207))	('miR-21', 'Gene', (81, 87))	('ARHGAP24', 'Gene', (213, 221))	('RNU6B', 'Gene', '26826', (327, 332))	('PTPN14', 'Gene', '5784', (115, 121))	('human', 'Species', '9606', (75, 80))
114519	27574101	We evaluated the survival prognostic power of cuSCC progression-associated gene signature using human specimen cohorts from the Cancer Genome Atlas (TCGA) (https://tcga-data.nci.nih.gov/tcga/), specifically HNSCC which are TP53-mutant.	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (128, 147))	('TP53-mutant', 'Var', (223, 234))	('SCC', 'Gene', '6317', (209, 212))	('men', 'Species', '9606', (107, 110))	('human', 'Species', '9606', (96, 101))	('SCC', 'Gene', (48, 51))	('SCC', 'Gene', '6317', (48, 51))	('Cancer Genome Atlas', 'Disease', (128, 147))	('Cancer', 'Phenotype', 'HP:0002664', (128, 134))	('SCC', 'Gene', (209, 212))
114529	32882793	To investigate the role of Sestrin2 expression in lung cancer cells, we knocked down Sestrin2 in A549, a non-small cell lung cancer cell line; this resulted in reduced cell proliferation, migration, sphere formation, and drug resistance, suggesting that Sestrin2 is closely related to lung cancer progression.	('lung cancer', 'Disease', (120, 131))	('lung cancer', 'Disease', 'MESH:D008175', (50, 61))	('A549', 'CellLine', 'CVCL:0023', (97, 101))	('lung cancer', 'Disease', (285, 296))	('lung cancer', 'Phenotype', 'HP:0100526', (50, 61))	('cell proliferation', 'CPA', (168, 186))	('reduced', 'NegReg', (160, 167))	('drug resistance', 'CPA', (221, 236))	('lung cancer', 'Disease', 'MESH:D008175', (120, 131))	('migration', 'CPA', (188, 197))	('lung cancer', 'Disease', 'MESH:D008175', (285, 296))	('lung cancer', 'Phenotype', 'HP:0100526', (120, 131))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('lung cancer', 'Phenotype', 'HP:0100526', (285, 296))	('Sestrin2', 'Gene', (85, 93))	('sphere formation', 'CPA', (199, 215))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (105, 131))	('lung cancer', 'Disease', (50, 61))	('drug resistance', 'Phenotype', 'HP:0020174', (221, 236))	('knocked', 'Var', (72, 79))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (109, 131))	('cancer', 'Phenotype', 'HP:0002664', (290, 296))
114543	32882793	A recent study revealed that Sestrin1 and Sestrin2 activate Nrf2 and subsequently increase Srx, which is important for oxidative metabolism.	('Sestrin1', 'Gene', '27244', (29, 37))	('Nrf2', 'Gene', (60, 64))	('activate', 'PosReg', (51, 59))	('Srx', 'Gene', '140809', (91, 94))	('Sestrin2', 'Var', (42, 50))	('Sestrin1', 'Gene', (29, 37))	('Srx', 'Gene', (91, 94))	('increase', 'PosReg', (82, 90))	('Nrf2', 'Gene', '4780', (60, 64))
114548	32882793	In the presence of leucine, Sestrin2 detaches from GATOR2 and consequently activates mTORC1.	('mTORC1', 'Gene', '382056', (85, 91))	('leucine', 'Var', (19, 26))	('mTORC1', 'Gene', (85, 91))	('activates', 'PosReg', (75, 84))	('detaches', 'NegReg', (37, 45))	('leucine', 'Chemical', 'MESH:D007930', (19, 26))	('Sestrin2', 'Gene', (28, 36))
114553	32882793	Sestrin2 knockdown accelerates colorectal carcinogenesis.	('knockdown', 'Var', (9, 18))	('accelerates', 'PosReg', (19, 30))	('Sestrin2', 'Gene', (0, 8))	('colorectal carcinogenesis', 'Disease', (31, 56))	('colorectal carcinogenesis', 'Disease', 'MESH:D015179', (31, 56))
114596	32882793	RT-PCR revealed that the expression of EMT markers (Vimentin, Snail, ZEB1) was significantly reduced in Sestrin2 knockdown cells compared to that in scramble cells.	('Sestrin2', 'Gene', (104, 112))	('Vimentin', 'Gene', (52, 60))	('expression', 'MPA', (25, 35))	('reduced', 'NegReg', (93, 100))	('Vimentin', 'Gene', '7431', (52, 60))	('knockdown', 'Var', (113, 122))	('Snail', 'Gene', (62, 67))	('Snail', 'Gene', '6615', (62, 67))	('ZEB1', 'Gene', (69, 73))	('ZEB1', 'Gene', '6935', (69, 73))
114601	32882793	The size of the spheres formed by the Sestrin2 knockdown A549 cells was smaller than that formed by scramble A549 cells.	('smaller', 'NegReg', (72, 79))	('knockdown', 'Var', (47, 56))	('A549', 'CellLine', 'CVCL:0023', (109, 113))	('Sestrin2', 'Gene', (38, 46))	('A549', 'CellLine', 'CVCL:0023', (57, 61))
114602	32882793	This result showed that Sestrin2 knockdown reduced lung cancer stemness.	('knockdown', 'Var', (33, 42))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('lung cancer', 'Phenotype', 'HP:0100526', (51, 62))	('reduced', 'NegReg', (43, 50))	('lung cancer stemness', 'Disease', (51, 71))	('Sestrin2', 'Gene', (24, 32))	('lung cancer stemness', 'Disease', 'MESH:D008175', (51, 71))
114604	32882793	Expression of the drug resistance marker genes was decreased in Sestrin2 knockdown A549 cells compared to that in cells with scramble (Figure 2C).	('A549', 'CellLine', 'CVCL:0023', (83, 87))	('decreased', 'NegReg', (51, 60))	('drug resistance', 'Phenotype', 'HP:0020174', (18, 33))	('Sestrin2', 'Gene', (64, 72))	('Expression of', 'MPA', (0, 13))	('knockdown', 'Var', (73, 82))
114606	32882793	The survival rate of Sestrin2 knockdown cells was significantly decreased compared to that of scramble cells regardless of anticancer drug treatment.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('survival rate', 'CPA', (4, 17))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('Sestrin2', 'Gene', (21, 29))	('knockdown', 'Var', (30, 39))	('cancer', 'Disease', (127, 133))	('decreased', 'NegReg', (64, 73))
114608	32882793	The reduced recovery rate of Sestrin2 knockdown cells in doxorubicin treatment suggests that cells became more sensitive to doxorubicin treatment.	('reduced', 'NegReg', (4, 11))	('Sestrin2', 'Gene', (29, 37))	('recovery rate', 'MPA', (12, 25))	('doxorubicin', 'Chemical', 'MESH:D004317', (124, 135))	('knockdown', 'Var', (38, 47))	('doxorubicin', 'Chemical', 'MESH:D004317', (57, 68))
114612	32882793	Because Sestrin2 activates the NRF2 pathway in cancer cells, the effect of Sestrin2 knockdown on NRF2 and oxidative status of A549 cells was investigated.	('A549', 'CellLine', 'CVCL:0023', (126, 130))	('NRF2', 'Gene', '4780', (97, 101))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('NRF2', 'Gene', (31, 35))	('knockdown', 'Var', (84, 93))	('cancer', 'Disease', (47, 53))	('NRF2', 'Gene', (97, 101))	('Sestrin2', 'Gene', (75, 83))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('activates', 'PosReg', (17, 26))	('NRF2', 'Gene', '4780', (31, 35))
114613	32882793	For ROS measurement by DCFDA assay, Sestrin2 knockdown cells without GFP expression were generated, and the knockdown of Sestrin2 and downregulation of NRF2 and heme oxygenase (HO-1) were confirmed in A549 cells (Figure 3A).	('Sestrin2', 'Gene', (121, 129))	('knockdown', 'Var', (108, 117))	('NRF2', 'Gene', '4780', (152, 156))	('downregulation', 'NegReg', (134, 148))	('ROS', 'Chemical', 'MESH:D017382', (4, 7))	('DCFDA', 'Chemical', 'MESH:C110400', (23, 28))	('A549', 'CellLine', 'CVCL:0023', (201, 205))	('NRF2', 'Gene', (152, 156))	('HO-1', 'Gene', (177, 181))	('HO-1', 'Gene', '3162', (177, 181))
114614	32882793	Reduced expression of NRF2 and HO-1 were also observed in Sestrin2 knockdown A549 cells with the shRNA vectors used in Figure 1 and Figure 2 (Supplementary Figure S3).	('HO-1', 'Gene', (31, 35))	('knockdown', 'Var', (67, 76))	('Reduced', 'NegReg', (0, 7))	('HO-1', 'Gene', '3162', (31, 35))	('NRF2', 'Gene', '4780', (22, 26))	('A549', 'CellLine', 'CVCL:0023', (77, 81))	('NRF2', 'Gene', (22, 26))	('expression', 'MPA', (8, 18))	('Sestrin2', 'Gene', (58, 66))
114616	32882793	In the Sestrin2 knockdown cells, ROS levels were significantly increased by nearly threefold (Figure 3B).	('Sestrin2', 'Gene', (7, 15))	('increased', 'PosReg', (63, 72))	('knockdown', 'Var', (16, 25))	('ROS levels', 'MPA', (33, 43))	('ROS', 'Chemical', 'MESH:D017382', (33, 36))
114623	32882793	The lung tumor was strongly stained by Sestrin2 antibody HPA018191 (patient ID = 3391), while pneumocytes of the normal lung were stained less strongly (patient ID = 2268).	('patient', 'Species', '9606', (68, 75))	('HPA018191', 'Var', (57, 66))	('lung tumor', 'Phenotype', 'HP:0100526', (4, 14))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('patient', 'Species', '9606', (153, 160))	('lung tumor', 'Disease', (4, 14))	('lung tumor', 'Disease', 'MESH:D008175', (4, 14))
114627	32882793	The survival rate of the lung cancer patient group with high Sestrin2 expression was lower than that in the patient group with low Sestrin2 expression in the GSE3141 dataset (p-value: 0.0037) and in the GSE11117 (p-value: 0.023) (Figure 4D).	('survival rate', 'CPA', (4, 17))	('lower', 'NegReg', (85, 90))	('patient', 'Species', '9606', (37, 44))	('lung cancer', 'Disease', (25, 36))	('lung cancer', 'Phenotype', 'HP:0100526', (25, 36))	('Sestrin2', 'Gene', (61, 69))	('GSE3141', 'Chemical', '-', (158, 165))	('patient', 'Species', '9606', (108, 115))	('expression', 'Var', (70, 80))	('lung cancer', 'Disease', 'MESH:D008175', (25, 36))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('high', 'Var', (56, 60))
114628	32882793	However, Sestrin2 expression is positively correlated with patient overall survival in the GSE13213.	('Sestrin2', 'Gene', (9, 17))	('patient', 'Species', '9606', (59, 66))	('correlated', 'Reg', (43, 53))	('GSE13213', 'Var', (91, 99))	('expression', 'MPA', (18, 28))
114629	32882793	In KM plotter analysis, the lung squamous carcinoma patient group with higher Sestrin2 expression had worse overall survival than the patient group with lower Sestrin2 expression in the RNAseq dataset (p-value: 0.042) and in the Affymetrix Genechip dataset with probe 223195_s_at (p-value: 0.023) (Figure 4D).	('higher', 'PosReg', (71, 77))	('worse', 'NegReg', (102, 107))	('expression', 'Var', (87, 97))	('lung squamous carcinoma', 'Disease', (28, 51))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (33, 51))	('overall survival', 'CPA', (108, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (42, 51))	('Sestrin2', 'Gene', (78, 86))	('lung squamous carcinoma', 'Disease', 'MESH:D002294', (28, 51))	('patient', 'Species', '9606', (52, 59))	('lung squamous carcinoma', 'Phenotype', 'HP:0030359', (28, 51))	('patient', 'Species', '9606', (134, 141))
114632	32882793	The mutations of Sestrin2 in lung cancer patients were analyzed across 4510 samples from 4154 patients in 16 studies.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('patients', 'Species', '9606', (94, 102))	('lung cancer', 'Disease', 'MESH:D008175', (29, 40))	('patients', 'Species', '9606', (41, 49))	('Sestrin2', 'Gene', (17, 25))	('mutations', 'Var', (4, 13))	('lung cancer', 'Disease', (29, 40))	('lung cancer', 'Phenotype', 'HP:0100526', (29, 40))
114633	32882793	Mutation occurred in 2.19% of the samples, and deep deletion occurred in 0.55% of the samples, resulting in gene alteration in 2.73% of the lung adenocarcinoma Broad dataset (Figure 5B,C).	('2.19', 'Gene', '60343', (21, 25))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (140, 159))	('Mutation', 'Var', (0, 8))	('carcinoma', 'Phenotype', 'HP:0030731', (150, 159))	('lung adenocarcinoma', 'Disease', (140, 159))	('deep deletion', 'Var', (47, 60))	('2.19', 'Gene', (21, 25))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (140, 159))	('gene', 'MPA', (108, 112))
114634	32882793	Expression of Sestrin2 increased the following in order: deep deletion (DD), shallow deletion (SD), diploid (D), gain (G), and amplification (A) in lung adenocarcinoma and lung squamous cell carcinoma.	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (148, 167))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (172, 200))	('Expression', 'MPA', (0, 10))	('lung adenocarcinoma', 'Disease', (148, 167))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (172, 200))	('lung squamous cell carcinoma', 'Disease', (172, 200))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (148, 167))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (177, 200))	('carcinoma', 'Phenotype', 'HP:0030731', (191, 200))	('deep deletion', 'Var', (57, 70))	('gain', 'PosReg', (113, 117))	('increased', 'PosReg', (23, 32))	('shallow', 'MPA', (77, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (158, 167))	('amplification', 'Var', (127, 140))	('Sestrin2', 'Gene', (14, 22))	('diploid', 'Var', (100, 107))
114644	32882793	In this paper, we investigated the effect of Sestrin2 knockdown in A549, a non-small cell lung cancer cell line, and analyzed the prognostic value of Sestrin2 expression in human lung cancer by employing various bioinformatic tools on various lung cancer datasets.	('lung cancer', 'Disease', 'MESH:D008175', (90, 101))	('lung cancer', 'Disease', (243, 254))	('lung cancer', 'Phenotype', 'HP:0100526', (243, 254))	('knockdown', 'Var', (54, 63))	('lung cancer', 'Disease', (179, 190))	('lung cancer', 'Phenotype', 'HP:0100526', (179, 190))	('cancer', 'Phenotype', 'HP:0002664', (248, 254))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('lung cancer', 'Disease', (90, 101))	('lung cancer', 'Phenotype', 'HP:0100526', (90, 101))	('lung cancer', 'Disease', 'MESH:D008175', (243, 254))	('human', 'Species', '9606', (173, 178))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (75, 101))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (79, 101))	('A549', 'CellLine', 'CVCL:0023', (67, 71))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('lung cancer', 'Disease', 'MESH:D008175', (179, 190))
114645	32882793	In the A549 lung cancer cell line, Sestrin2 knockdown led to downregulation of cancer properties, confirming the oncogenic function of Sestrin2.	('downregulation', 'NegReg', (61, 75))	('Sestrin2', 'Gene', (35, 43))	('lung cancer', 'Disease', 'MESH:D008175', (12, 23))	('A549', 'CellLine', 'CVCL:0023', (7, 11))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('cancer', 'Disease', (17, 23))	('lung cancer', 'Disease', (12, 23))	('knockdown', 'Var', (44, 53))	('lung cancer', 'Phenotype', 'HP:0100526', (12, 23))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
114646	32882793	Our data showed that Sestrin2 knockdown resulted in reduced tumor cell proliferation and migration (Figure 1).	('reduced', 'NegReg', (52, 59))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('Sestrin2', 'Gene', (21, 29))	('knockdown', 'Var', (30, 39))	('tumor', 'Disease', (60, 65))
114647	32882793	Moreover, in the sphere-forming assay, the size of sphere was significantly decreased upon Sestrin2 knockdown in A549 cells (Figure 2).	('knockdown', 'Var', (100, 109))	('sphere-forming assay', 'CPA', (17, 37))	('Sestrin2', 'Gene', (91, 99))	('size of sphere', 'CPA', (43, 57))	('decreased', 'NegReg', (76, 85))	('A549', 'CellLine', 'CVCL:0023', (113, 117))
114650	32882793	However, Sestrin2 knockdown has also been reported to promote proliferation of cancer cells, inhibit apoptosis of cells, and enhance migration in the wound healing assay, which is in complete contrast to our results.	('inhibit', 'NegReg', (93, 100))	('knockdown', 'Var', (18, 27))	('promote', 'PosReg', (54, 61))	('Sestrin2', 'Gene', (9, 17))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('proliferation', 'CPA', (62, 75))	('enhance', 'PosReg', (125, 132))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('migration in the wound healing assay', 'CPA', (133, 169))	('apoptosis of cells', 'CPA', (101, 119))
114652	32882793	Sestrin2 was proposed to regulate AMPK/mTORC pathway activation and tumor cell growth in colorectal cancer, and Sestrin2 knockdown accelerated colorectal carcinogenesis.	('tumor', 'Disease', (68, 73))	('knockdown', 'Var', (121, 130))	('colorectal cancer', 'Phenotype', 'HP:0003003', (89, 106))	('accelerated', 'PosReg', (131, 142))	('AMPK', 'Gene', '5563', (34, 38))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('colorectal cancer', 'Disease', (89, 106))	('colorectal carcinogenesis', 'Disease', (143, 168))	('mTOR', 'Gene', (39, 43))	('Sestrin2', 'Gene', (112, 120))	('AMPK', 'Gene', (34, 38))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('colorectal carcinogenesis', 'Disease', 'MESH:D015179', (143, 168))	('colorectal cancer', 'Disease', 'MESH:D015179', (89, 106))	('mTOR', 'Gene', '2475', (39, 43))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))
114659	32882793	Sestrin2 knockdown increased the intracellular ROS concentration in A549 cells with reduced expression of antioxidant genes nrf-2 and HO-1 (Figure 3).	('nrf-2', 'Gene', '4780', (124, 129))	('HO-1', 'Gene', '3162', (134, 138))	('Sestrin2', 'Gene', (0, 8))	('knockdown', 'Var', (9, 18))	('intracellular ROS concentration', 'MPA', (33, 64))	('nrf-2', 'Gene', (124, 129))	('reduced', 'NegReg', (84, 91))	('increased', 'PosReg', (19, 28))	('HO-1', 'Gene', (134, 138))	('A549', 'CellLine', 'CVCL:0023', (68, 72))	('expression', 'MPA', (92, 102))	('ROS', 'Chemical', 'MESH:D017382', (47, 50))
114663	32882793	Sensitization to doxorubicin and cisplatin in Sestrin2 knockdown cell was not apparently detectable because impaired proliferation of Sestrin2 knockdown cells already reduced the recovered number of cells in no treatment control cells.	('proliferation', 'CPA', (117, 130))	('doxorubicin', 'Chemical', 'MESH:D004317', (17, 28))	('cisplatin', 'Chemical', 'MESH:D002945', (33, 42))	('Sestrin2', 'Gene', (134, 142))	('knockdown', 'Var', (143, 152))	('reduced', 'NegReg', (167, 174))	('impaired', 'NegReg', (108, 116))
114664	32882793	However, the reduction in the rate of survival in Sestrin2 knockdown A549 cells in the doxorubicin-treated group is larger than that of no treatment control, suggesting sensitization to doxorubicin treatment in Sestrin2 knockdown cells (Figure 2D).	('doxorubicin', 'Chemical', 'MESH:D004317', (186, 197))	('A549', 'CellLine', 'CVCL:0023', (69, 73))	('Sestrin2', 'Gene', (50, 58))	('knockdown', 'Var', (59, 68))	('reduction', 'NegReg', (13, 22))	('doxorubicin', 'Chemical', 'MESH:D004317', (87, 98))
114671	32882793	In the tumorigenesis processes, somatic loss-of-function or gain-of-function alterations in specific genes could have carcinogenic effects.	('gain-of-function', 'PosReg', (60, 76))	('tumor', 'Disease', (7, 12))	('alterations', 'Var', (77, 88))	('loss-of-function', 'NegReg', (40, 56))	('carcinogenic', 'Disease', 'MESH:D063646', (118, 130))	('tumor', 'Disease', 'MESH:D009369', (7, 12))	('carcinogenic', 'Disease', (118, 130))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
114672	32882793	This result implies that augmented Sestrin2 expression could be caused by the copy number alteration in lung cancer cells.	('lung cancer', 'Disease', 'MESH:D008175', (104, 115))	('expression', 'MPA', (44, 54))	('augmented', 'PosReg', (25, 34))	('lung cancer', 'Disease', (104, 115))	('lung cancer', 'Phenotype', 'HP:0100526', (104, 115))	('copy number alteration', 'Var', (78, 100))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('Sestrin2', 'Gene', (35, 43))
114674	32882793	The most highly ranked term in GO molecular function, N6-methyladenosine-containing RNA binding, may also be involved in transcriptional control; N6-methyladenosine is the most frequent mRNA modification significantly affecting gene expression and splicing.	('N6-methyladenosine', 'Var', (146, 164))	('N6-methyladenosine', 'Chemical', 'MESH:C010223', (54, 72))	('splicing', 'MPA', (248, 256))	('N6-methyladenosine', 'Chemical', 'MESH:C010223', (146, 164))	('gene expression', 'MPA', (228, 243))	('affecting', 'Reg', (218, 227))
114679	32882793	In conclusion, Sestrin2 knockdown in lung cancer cells suppressed cancer cell properties, including proliferation, migration, stemness, and drug resistance.	('drug resistance', 'CPA', (140, 155))	('drug resistance', 'Phenotype', 'HP:0020174', (140, 155))	('lung cancer', 'Disease', (37, 48))	('lung cancer', 'Phenotype', 'HP:0100526', (37, 48))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('migration', 'CPA', (115, 124))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('stemness', 'CPA', (126, 134))	('Sestrin2', 'Gene', (15, 23))	('proliferation', 'CPA', (100, 113))	('cancer', 'Disease', (42, 48))	('suppressed', 'NegReg', (55, 65))	('lung cancer', 'Disease', 'MESH:D008175', (37, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('knockdown', 'Var', (24, 33))	('cancer', 'Disease', (66, 72))
114688	32392248	Applying the method to lung cancer cohorts, we observed that deregulated genes in tumors exhibit a cancer-type-specific commitment towards up- or down-regulation.	('up-', 'PosReg', (139, 142))	('lung cancer', 'Disease', (23, 34))	('down-regulation', 'NegReg', (146, 161))	('lung cancer', 'Phenotype', 'HP:0100526', (23, 34))	('tumors', 'Disease', (82, 88))	('deregulated', 'Var', (61, 72))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('cancer', 'Disease', (99, 105))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('lung cancer', 'Disease', 'MESH:D008175', (23, 34))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('cancer', 'Disease', (28, 34))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
114723	32392248	Using the maximal value of informedness (TPR-FPR) as a summary statistic of the ROC curve, we observed that the method reached an optimal prediction efficiency for l~10-100.	('l~10-100', 'Var', (164, 172))	('TPR', 'Gene', (41, 44))	('FPR', 'Gene', '2357', (45, 48))	('TPR', 'Gene', '7175', (41, 44))	('FPR', 'Gene', (45, 48))
114742	32392248	To illustrate such differential behaviors, we specifically depicted genes belonging to two known pathways involved in cancer progression: the squamous differentiation, that often display somatic alterations in SQCC cancers, and the receptor tyrosine kinase (RTK)/RAS/RAF pathway, frequently mutated in ADC cancers (Fig 4B and 4C).	('cancers', 'Phenotype', 'HP:0002664', (306, 313))	('cancers', 'Disease', (306, 313))	('RTK', 'Gene', '5979', (258, 261))	('SQCC cancers', 'Disease', (210, 222))	('cancer', 'Disease', 'MESH:D009369', (306, 312))	('cancer', 'Disease', (215, 221))	('cancers', 'Phenotype', 'HP:0002664', (215, 222))	('cancers', 'Disease', (215, 222))	('SQCC cancers', 'Disease', 'MESH:D009369', (210, 222))	('alterations', 'Reg', (195, 206))	('mutated', 'Var', (291, 298))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('receptor tyrosine kinase', 'Gene', '5979', (232, 256))	('cancer', 'Disease', (118, 124))	('cancers', 'Disease', 'MESH:D009369', (306, 313))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('receptor tyrosine kinase', 'Gene', (232, 256))	('cancer', 'Disease', (306, 312))	('cancer', 'Disease', 'MESH:D009369', (215, 221))	('cancers', 'Disease', 'MESH:D009369', (215, 222))	('cancer', 'Phenotype', 'HP:0002664', (306, 312))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('RTK', 'Gene', (258, 261))
114748	32392248	Taken together, these results suggest that personalized analysis of both genetic mutations and gene expression variations are required for a full understanding of regulation pathways involved in tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('tumor', 'Disease', (195, 200))	('variations', 'Var', (111, 121))
114749	32392248	Recurrent gene deregulations are considered as characteristic features of cancer initiation and progression.	('gene deregulations', 'Var', (10, 28))	('cancer initiation', 'Disease', 'MESH:D009369', (74, 91))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('cancer initiation', 'Disease', (74, 91))
114796	32392248	Applying DESeq2, one of the most common DE analysis software, to the ADC and SQCC TCGA cohorts, highlighted similarities and differences for the genes with specific deregulation patterns identified by PenDA (super-conserved, super-up-regulated, super-down-regulated) (S10A and S10B Fig).	('PenDA', 'Chemical', '-', (201, 206))	('S10B', 'Var', (277, 281))	('S10A', 'Var', (268, 272))	('deregulation', 'MPA', (165, 177))	('S10B', 'SUBSTITUTION', 'None', (277, 281))	('S10A', 'SUBSTITUTION', 'None', (268, 272))
114806	32392248	Overall survival of ADC patients could be significantly discriminated using the synergic effect of GINS deregulation (Fig 8B), however, no significant effect of GINS deregulation could be identified using single gene Cox regression models (Fig 8C).	('GINS', 'MPA', (99, 103))	('ADC', 'Disease', (20, 23))	('patients', 'Species', '9606', (24, 32))	('deregulation', 'Var', (104, 116))
114815	32392248	If Eq (1) is satisfied then g is considered as down-regulated or up-regulated if  Ld + Hd < L  or  Lu + Hu < H  respectively.	('up-regulated', 'PosReg', (65, 77))	('Lu + Hu < H', 'Var', (99, 110))	('down-regulated', 'NegReg', (47, 61))	('Hd', 'Disease', 'None', (87, 89))
114816	32392248	Then, a gene g in tumor sample T with an expression E(g,T) was considered as differentially expressed in that sample if E(g,T)<pl/f (down-regulation) or E(g,T)>pu*f (up-regulation), with f>=1 a user-defined factor allowing to expand the window of normal expression.	('E(g,T)<pl/f', 'Var', (120, 131))	('tumor', 'Disease', (18, 23))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('E(g,T)>pu*f', 'Var', (153, 164))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
114820	32392248	From the 5% and 95% percentiles of Deltan(k), noted p5(k) and p95(k) respectively, we isolated the subset  of values in Deltac(k) that are smaller than p5(k) or greater than p95(k).	('p95', 'Gene', '4683', (62, 65))	('p95', 'Gene', '4683', (174, 177))	('p5(k', 'Var', (52, 56))	('p95', 'Gene', (174, 177))	('p5(k', 'Var', (152, 156))	('p95', 'Gene', (62, 65))
114824	32392248	The choice of the percentiles (5%, 95%) impacts on the ROC curves while PenDA still remains the best investigated methods in the low FPR range (S11B Fig).	('PenDA', 'Chemical', '-', (72, 77))	('impacts', 'Reg', (40, 47))	('S11B', 'SUBSTITUTION', 'None', (144, 148))	('S11B', 'Var', (144, 148))	('ROC curves', 'MPA', (55, 65))	('FPR', 'Gene', (133, 136))	('FPR', 'Gene', '2357', (133, 136))
114843	32392248	Performing DESeq2 with or without its internal normalization routine may impact the ROC analysis in particular if data are not standardized (S11C Fig).	('impact', 'Reg', (73, 79))	('DESeq2', 'Var', (11, 17))	('S11C', 'Var', (141, 145))	('ROC analysis', 'MPA', (84, 96))	('S11C', 'SUBSTITUTION', 'None', (141, 145))
114929	30542452	Wild-type (WT) and mutant seeding regions of miR-455-5p in the 3'-UTR of Rab31 were chemically synthesized, following which SpeI and HindIII restriction sites were added and cloned into pMIR-REPORT luciferase reporter plasmids (0.5 microg; Thermo Fisher Scientific, Inc.) with WT or mutant 3'-UTR DNA sequences.	('miR-455', 'Gene', (45, 52))	('miR-455', 'Gene', '619556', (45, 52))	('5p', 'Chemical', '-', (53, 55))	('WT', 'Disease', 'MESH:C536751', (277, 279))	('mutant', 'Var', (283, 289))	('mutant', 'Var', (19, 25))	('Rab31', 'Gene', '11031', (73, 78))	('WT', 'Disease', 'MESH:C536751', (11, 13))	('Rab31', 'Gene', (73, 78))
114934	30542452	miR-455-5p was also significantly downregulated in ESCC tissues from patients with poor differentiation compared with tissues from patients with high or moderate differentiation (P<0.05; Fig.	('patients', 'Species', '9606', (131, 139))	('5p', 'Chemical', '-', (8, 10))	('miR-455', 'Gene', (0, 7))	('downregulated', 'NegReg', (34, 47))	('miR-455', 'Gene', '619556', (0, 7))	('poor differentiation', 'Var', (83, 103))	('ESCC', 'Disease', (51, 55))	('patients', 'Species', '9606', (69, 77))
114951	30542452	5C), whereas Rab31 downregulation induced by miR-455-5p overexpression reduced migration and invasion compared with the miR-NC group (P<0.05; Fig.	('Rab31', 'Gene', '11031', (13, 18))	('miR-455', 'Gene', (45, 52))	('miR', 'Gene', '220972', (120, 123))	('overexpression', 'Var', (56, 70))	('miR', 'Gene', (120, 123))	('miR-455', 'Gene', '619556', (45, 52))	('Rab31', 'Gene', (13, 18))	('5p', 'Chemical', '-', (53, 55))	('miR', 'Gene', '220972', (45, 48))	('miR', 'Gene', (45, 48))	('reduced', 'NegReg', (71, 78))	('downregulation', 'NegReg', (19, 33))
114958	30542452	It is associated with gene mutation, abnormal expression, epigenetic inheritance and tumor stem cells.	('tumor', 'Disease', (85, 90))	('abnormal expression', 'Var', (37, 56))	('associated', 'Reg', (6, 16))	('gene mutation', 'Var', (22, 35))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('epigenetic inheritance', 'Var', (58, 80))
114993	26378045	In vitro, ectopic NBAT1 inhibits migration and invasion of breast cancer cells.	('breast cancer', 'Disease', 'MESH:D001943', (59, 72))	('inhibits', 'NegReg', (24, 32))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('breast cancer', 'Disease', (59, 72))	('NBAT1', 'Gene', '729177', (18, 23))	('invasion', 'CPA', (47, 55))	('breast cancer', 'Phenotype', 'HP:0003002', (59, 72))	('ectopic', 'Var', (10, 17))	('NBAT1', 'Gene', (18, 23))
114996	26378045	Taken together, our study demonstrates that long noncoding RNA NBAT1 is a potential breast cancer prognostic marker, as well as a potential therapeutic target to inhibit breast cancer metastasis.	('NBAT1', 'Gene', (63, 68))	('breast cancer', 'Phenotype', 'HP:0003002', (84, 97))	('inhibit', 'NegReg', (162, 169))	('long noncoding RNA', 'Var', (44, 62))	('NBAT1', 'Gene', '729177', (63, 68))	('breast cancer metastasis', 'Disease', 'MESH:D009362', (170, 194))	('breast cancer', 'Disease', 'MESH:D001943', (170, 183))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('breast cancer', 'Disease', 'MESH:D001943', (84, 97))	('breast cancer', 'Phenotype', 'HP:0003002', (170, 183))	('breast cancer metastasis', 'Disease', (170, 194))	('breast cancer', 'Disease', (84, 97))
115008	26378045	Loss of NBAT1 contributes to the aggressiveness of neuroblastoma by promoting proliferation and by impairment of differentiation of neuronal precursors.	('aggressiveness', 'Phenotype', 'HP:0000718', (33, 47))	('promoting', 'PosReg', (68, 77))	('aggressiveness of neuroblastoma', 'Disease', 'MESH:D009447', (33, 64))	('NBAT1', 'Gene', (8, 13))	('neuroblastoma', 'Phenotype', 'HP:0003006', (51, 64))	('proliferation', 'CPA', (78, 91))	('aggressiveness of neuroblastoma', 'Disease', (33, 64))	('differentiation', 'CPA', (113, 128))	('impairment', 'NegReg', (99, 109))	('Loss', 'Var', (0, 4))	('NBAT1', 'Gene', '729177', (8, 13))
115025	26378045	The cells with higher migration potentials (MDA-MB-231, MDA-MB-436 and BT-549) expressed significantly lower NBAT1 compared to cells with lower migration potentials (MCF7, T-470, ZR-75-1, BT-474, SK-BR-3 and MDA-MB-453) (Figure 2a).	('NBAT1', 'Gene', '729177', (109, 114))	('higher', 'PosReg', (15, 21))	('MDA-MB-436', 'Var', (56, 66))	('T-470', 'CellLine', 'CVCL:M921', (172, 177))	('MCF7', 'CellLine', 'CVCL:0031', (166, 170))	('lower', 'NegReg', (103, 108))	('BT-549', 'Var', (71, 77))	('SK-BR-3', 'CellLine', 'CVCL:0033', (196, 203))	('NBAT1', 'Gene', (109, 114))	('MDA-MB-453', 'CellLine', 'CVCL:0418', (208, 218))	('BT-549', 'CellLine', 'CVCL:1092', (71, 77))	('MDA-MB-436', 'CellLine', 'CVCL:0623', (56, 66))	('migration potentials', 'CPA', (22, 42))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (44, 54))
115029	26378045	Wound healing and transwell assays suggested that exogenous NBAT1 suppressed both migration and invasion of MDA-MB-231 cells (Figure 2c-2g).	('NBAT1', 'Gene', '729177', (60, 65))	('exogenous', 'Var', (50, 59))	('migration', 'CPA', (82, 91))	('invasion', 'CPA', (96, 104))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (108, 118))	('suppressed', 'NegReg', (66, 76))	('NBAT1', 'Gene', (60, 65))
115030	26378045	On other hand, silencing NBAT1 by siRNAs in MCF7 cells significantly reduced NBAT1 expression levels (Figure 3a), which was accompanied by significantly increased migration and invasion of MCF7 cells (Figure 3b-3f).	('MCF7', 'CellLine', 'CVCL:0031', (189, 193))	('NBAT1', 'Gene', '729177', (77, 82))	('invasion', 'CPA', (177, 185))	('reduced', 'NegReg', (69, 76))	('expression levels', 'MPA', (83, 100))	('NBAT1', 'Gene', (25, 30))	('migration', 'CPA', (163, 172))	('increased', 'PosReg', (153, 162))	('NBAT1', 'Gene', '729177', (25, 30))	('silencing', 'Var', (15, 24))	('NBAT1', 'Gene', (77, 82))	('MCF7', 'CellLine', 'CVCL:0031', (44, 48))
115041	26378045	And knock-down of NBAT1-upregulated DKK1 has partially reversed the effects of NBAT1-regulated cellular invasion (Figure 5c, 5d).	('DKK1', 'Gene', '22943', (36, 40))	('cellular invasion', 'CPA', (95, 112))	('NBAT1', 'Gene', '729177', (79, 84))	('NBAT1', 'Gene', '729177', (18, 23))	('knock-down', 'Var', (4, 14))	('DKK1', 'Gene', (36, 40))	('NBAT1', 'Gene', (79, 84))	('NBAT1', 'Gene', (18, 23))
115047	26378045	In agreement with the previous result, silencing NBAT1 with siRNAs in MCF7 down-regulated DKK1 in both mRNA and protein levels.	('NBAT1', 'Gene', (49, 54))	('MCF7', 'CellLine', 'CVCL:0031', (70, 74))	('DKK1', 'Gene', '22943', (90, 94))	('NBAT1', 'Gene', '729177', (49, 54))	('silencing', 'Var', (39, 48))	('DKK1', 'Gene', (90, 94))	('down-regulated', 'NegReg', (75, 89))	('MCF7', 'Gene', (70, 74))
115057	26378045	EZH2 regulates invasion of breast cancer mainly through mediating transcriptional silencing of the tumor suppressor genes, including E-cadherin by regulating histone modifications in the promoters of these target genes, including H3K27me3.	('regulates', 'Reg', (5, 14))	('tumor', 'Disease', (99, 104))	('transcriptional', 'MPA', (66, 81))	('invasion', 'Disease', (15, 23))	('EZH2', 'Gene', '2146', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('breast cancer', 'Disease', 'MESH:D001943', (27, 40))	('EZH2', 'Gene', (0, 4))	('E-cadherin', 'Gene', (133, 143))	('regulating', 'Reg', (147, 157))	('breast cancer', 'Disease', (27, 40))	('H3K27me3', 'Var', (230, 238))	('breast cancer', 'Phenotype', 'HP:0003002', (27, 40))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('E-cadherin', 'Gene', '999', (133, 143))	('histone modifications', 'MPA', (158, 179))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))
115062	26378045	Over-expression NBAT1 could down-regulate H3K27me3 level of DKK1 and significantly increase the expression of DKK1, while the effects of NBAT1 over-expression on invasion was partially reversed by concomitant DKK1 knockdown, suggesting that the effect of NBAT1 on cell migration and invasion is mediated, at least in part, through DKK1.	('invasion', 'CPA', (283, 291))	('Over-expression', 'Var', (0, 15))	('DKK1', 'Gene', '22943', (331, 335))	('DKK1', 'Gene', (331, 335))	('NBAT1', 'Gene', (137, 142))	('H3K27me3 level', 'MPA', (42, 56))	('DKK1', 'Gene', (60, 64))	('NBAT1', 'Gene', (255, 260))	('DKK1', 'Gene', '22943', (60, 64))	('cell migration', 'CPA', (264, 278))	('expression', 'MPA', (96, 106))	('down-regulate', 'NegReg', (28, 41))	('NBAT1', 'Gene', (16, 21))	('increase', 'PosReg', (83, 91))	('DKK1', 'Gene', (209, 213))	('NBAT1', 'Gene', '729177', (137, 142))	('DKK1', 'Gene', '22943', (209, 213))	('NBAT1', 'Gene', '729177', (255, 260))	('NBAT1', 'Gene', '729177', (16, 21))	('DKK1', 'Gene', '22943', (110, 114))	('DKK1', 'Gene', (110, 114))
115091	26378045	Protein extracts were resolved in 10% SDS-polyacrylamide gel electrophoresis, transferred to polyvinylidene difluoride membranes and probed with antibodies against EZH2 (1:500, sc-166609, Santa Cruz), DKK1 (1:500, sc-374574, Santa Cruz) and beta-actin (1:1,000, 5125, CST).	('sc-166609', 'Var', (177, 186))	('EZH2', 'Gene', '2146', (164, 168))	('EZH2', 'Gene', (164, 168))	('1:500', 'Var', (170, 175))	('polyvinylidene difluoride', 'Chemical', 'MESH:C024865', (93, 118))	('DKK1', 'Gene', (201, 205))	('SDS', 'Chemical', 'MESH:D012967', (38, 41))	('polyacrylamide', 'Chemical', 'MESH:C016679', (42, 56))	('1:500', 'Var', (207, 212))	('DKK1', 'Gene', '22943', (201, 205))
115101	29444745	MicroRNA-598 Inhibits Cell Proliferation and Invasion of Glioblastoma by Directly Targeting Metastasis Associated in Colon Cancer-1 (MACC1) The dysregulation of microRNA (miRNA) expression is closely related with tumorigenesis and tumor development in glioblastoma (GBM).	('glioblastoma', 'Disease', 'MESH:D005909', (252, 264))	('Cancer', 'Phenotype', 'HP:0002664', (123, 129))	('Metastasis Associated in Colon Cancer-1', 'Gene', (92, 131))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('Targeting', 'NegReg', (82, 91))	('Cell Proliferation', 'CPA', (22, 40))	('MACC1', 'Gene', '346389', (133, 138))	('Glioblastoma', 'Disease', (57, 69))	('GBM', 'Phenotype', 'HP:0012174', (266, 269))	('Metastasis Associated in Colon Cancer-1', 'Gene', '346389', (92, 131))	('glioblastoma', 'Disease', (252, 264))	('MicroRNA-598', 'Gene', (0, 12))	('glioblastoma', 'Phenotype', 'HP:0012174', (252, 264))	('tumor', 'Disease', (231, 236))	('tumor', 'Disease', 'MESH:D009369', (231, 236))	('dysregulation', 'Var', (144, 157))	('Inhibits', 'NegReg', (13, 21))	('microRNA', 'Protein', (161, 169))	('tumor', 'Disease', (213, 218))	('MACC1', 'Gene', (133, 138))	('related', 'Reg', (200, 207))	('Colon Cancer', 'Phenotype', 'HP:0003003', (117, 129))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('Glioblastoma', 'Disease', 'MESH:D005909', (57, 69))	('tumor', 'Disease', 'MESH:D009369', (213, 218))	('Glioblastoma', 'Phenotype', 'HP:0012174', (57, 69))	('MicroRNA-598', 'Gene', '693183', (0, 12))
115104	29444745	Moreover, we validated that metastasis associated in colon cancer-1 (MACC1) is a novel target of miR-598 in GBM.	('miR-598', 'Var', (97, 104))	('metastasis associated in colon cancer-1', 'Gene', '346389', (28, 67))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('MACC1', 'Gene', (69, 74))	('MACC1', 'Gene', '346389', (69, 74))	('miR-598', 'Chemical', '-', (97, 104))	('GBM', 'Phenotype', 'HP:0012174', (108, 111))	('metastasis associated in colon cancer-1', 'Gene', (28, 67))	('colon cancer', 'Phenotype', 'HP:0003003', (53, 65))
115107	29444745	Our results provided compelling evidence that miR-598 serves tumor-suppressive roles in GBM and that its antioncogenic effects are mediated chiefly through the direct suppression of MACC1 expression and regulation of the Met/AKT signaling pathway.	('GBM', 'Phenotype', 'HP:0012174', (88, 91))	('AKT', 'Gene', '207', (225, 228))	('expression', 'MPA', (188, 198))	('Met', 'Gene', '79811', (221, 224))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('Met', 'Gene', (221, 224))	('miR-598', 'Var', (46, 53))	('AKT', 'Gene', (225, 228))	('MACC1', 'Gene', (182, 187))	('MACC1', 'Gene', '346389', (182, 187))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('GBM', 'Disease', (88, 91))	('miR-598', 'Chemical', '-', (46, 53))	('suppression', 'NegReg', (167, 178))	('tumor', 'Disease', (61, 66))
115116	29444745	In recent years, emerging evidence has shown that the dysregulation of miRNAs is a common characteristic of human malignancies, including GBM.	('miRNAs', 'Protein', (71, 77))	('GBM', 'Disease', (138, 141))	('malignancies', 'Disease', 'MESH:D009369', (114, 126))	('human', 'Species', '9606', (108, 113))	('GBM', 'Phenotype', 'HP:0012174', (138, 141))	('malignancies', 'Disease', (114, 126))	('dysregulation', 'Var', (54, 67))
115145	29444745	The 3'-UTRs of human MACC1 gene containing the wild-type or mutant binding sequences for miR-598 were amplified by GenePharma and inserted into pGL3 vectors (Promega Corp., Madison, WI, USA).	('miR-598', 'Chemical', '-', (89, 96))	('pGL3', 'Gene', '6391', (144, 148))	('MACC1', 'Gene', (21, 26))	('MACC1', 'Gene', '346389', (21, 26))	('miR-598', 'Gene', (89, 96))	('human', 'Species', '9606', (15, 20))	('mutant', 'Var', (60, 66))	('pGL3', 'Gene', (144, 148))
115149	29444745	Primary antibodies were purchased from Cell Signaling Technology, Inc. (Danvers, MA, USA) and included rabbit anti-human monoclonal MACC1 (#86290; 1:1,000 dilution) and rabbit anti-human GAPDH monoclonal (#5174; 1:1,000 dilution) antibodies.	('human', 'Species', '9606', (181, 186))	('#5174;', 'Var', (205, 211))	('human', 'Species', '9606', (115, 120))	('GAPDH', 'Gene', '2597', (187, 192))	('GAPDH', 'Gene', (187, 192))	('MACC1', 'Gene', (132, 137))	('MACC1', 'Gene', '346389', (132, 137))
115160	29444745	Additionally, we performed Matrigel invasion assay to examine the invasion ability of U87 and U251 cells transfected with miR-598 mimics or miR-NC.	('U251', 'CellLine', 'CVCL:0021', (94, 98))	('miR-NC', 'Var', (140, 146))	('miR-598', 'Chemical', '-', (122, 129))	('miR-598', 'Gene', (122, 129))
115166	29444745	Therefore, we conducted the dual-luciferase reporter assay to determine if the 3'-UTR of MACC1 is a direct target of miR-598.	('MACC1', 'Gene', (89, 94))	('miR-598', 'Chemical', '-', (117, 124))	('miR-598', 'Var', (117, 124))	('MACC1', 'Gene', '346389', (89, 94))
115167	29444745	The results showed that compared with introducing miR-NC, introducing miR-598 mimic to U87 and U251 cells with the wild-type reporter plasmid significantly inhibited luciferase activities (p < 0.05).	('U251', 'CellLine', 'CVCL:0021', (95, 99))	('luciferase', 'Enzyme', (166, 176))	('miR-598', 'Chemical', '-', (70, 77))	('miR-598 mimic', 'Var', (70, 83))	('activities', 'MPA', (177, 187))	('inhibited', 'NegReg', (156, 165))
115168	29444745	However, the luciferase activities of the mutant reporter plasmid were unaffected in U87 and U251 cells cotransfected with miR-598 mimics (Fig.	('miR-598', 'Chemical', '-', (123, 130))	('mutant', 'Var', (42, 48))	('U251', 'CellLine', 'CVCL:0021', (93, 97))	('luciferase', 'Enzyme', (13, 23))
115180	29444745	4C) of U87 and U251cells induced by miR-598 overexpression.	('miR-598', 'Gene', (36, 43))	('overexpression', 'PosReg', (44, 58))	('U251cells', 'Var', (15, 24))	('U251', 'CellLine', 'CVCL:0021', (15, 19))	('miR-598', 'Chemical', '-', (36, 43))
115181	29444745	These results demonstrated that miR-598 exerts tumor-suppressive roles in GBM, at least in part, by downregulating MACC1 expression.	('GBM', 'Phenotype', 'HP:0012174', (74, 77))	('downregulating', 'NegReg', (100, 114))	('miR-598', 'Var', (32, 39))	('expression', 'MPA', (121, 131))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('MACC1', 'Gene', '346389', (115, 120))	('GBM', 'Disease', (74, 77))	('miR-598', 'Chemical', '-', (32, 39))	('MACC1', 'Gene', (115, 120))	('tumor', 'Disease', (47, 52))
115184	29444745	U87 and U251 cells were transfected with miR-598 mimic or miR-NC.	('U251', 'CellLine', 'CVCL:0021', (8, 12))	('miR-NC', 'Var', (58, 64))	('miR-598 mimic', 'Var', (41, 54))	('miR-598', 'Chemical', '-', (41, 48))
115186	29444745	The results showed that the ectopic expression of miR-598 decreased Met and p-AKT expression without altering total AKT expression in U87 and U251 cells (p < 0.05) (Fig.	('decreased', 'NegReg', (58, 67))	('ectopic expression', 'MPA', (28, 46))	('miR-598', 'Var', (50, 57))	('U251', 'CellLine', 'CVCL:0021', (142, 146))	('AKT', 'Gene', '207', (78, 81))	('AKT', 'Gene', '207', (116, 119))	('Met', 'Gene', (68, 71))	('AKT', 'Gene', (78, 81))	('miR-598', 'Chemical', '-', (50, 57))	('AKT', 'Gene', (116, 119))	('Met', 'Gene', '79811', (68, 71))
115187	29444745	These results suggested that miR-598 inhibits the Met/AKT pathway activation in GBM.	('GBM', 'Phenotype', 'HP:0012174', (80, 83))	('AKT', 'Gene', '207', (54, 57))	('miR-598', 'Var', (29, 36))	('Met', 'Gene', '79811', (50, 53))	('Met', 'Gene', (50, 53))	('AKT', 'Gene', (54, 57))	('inhibits', 'NegReg', (37, 45))	('miR-598', 'Chemical', '-', (29, 36))	('activation', 'PosReg', (66, 76))
115188	29444745	A growing body of evidence has demonstrated that miRNAs act as oncogenes or tumor suppressor genes in GBM by regulating their target genes; thus, the dysregulation of miRNA expression is closely related with tumorigenesis and tumor development in GBM.	('dysregulation', 'Var', (150, 163))	('tumor', 'Disease', 'MESH:D009369', (208, 213))	('GBM', 'Phenotype', 'HP:0012174', (102, 105))	('GBM', 'Phenotype', 'HP:0012174', (247, 250))	('tumor', 'Disease', (76, 81))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('tumor', 'Disease', 'MESH:D009369', (226, 231))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('miRNA', 'Protein', (167, 172))	('tumor', 'Disease', (208, 213))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('related', 'Reg', (195, 202))	('tumor', 'Disease', (226, 231))
115192	29444745	Additionally, MACC1 was confirmed as a novel direct target of miR-598 in GBM.	('miR-598', 'Chemical', '-', (62, 69))	('MACC1', 'Gene', '346389', (14, 19))	('MACC1', 'Gene', (14, 19))	('GBM', 'Phenotype', 'HP:0012174', (73, 76))	('miR-598', 'Var', (62, 69))
115193	29444745	Restored MACC1 expression partially abolished the tumor-suppressive effects of miR-598 in GBM.	('miR-598', 'Var', (79, 86))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('miR-598', 'Chemical', '-', (79, 86))	('MACC1', 'Gene', '346389', (9, 14))	('GBM', 'Phenotype', 'HP:0012174', (90, 93))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('MACC1', 'Gene', (9, 14))	('tumor', 'Disease', (50, 55))	('abolished', 'NegReg', (36, 45))
115195	29444745	Overall, miR-598 may act as a tumor suppressor in GBM by directly targeting MACC1 and suppressing the Met/AKT signaling pathway.	('AKT', 'Gene', (106, 109))	('miR-598', 'Var', (9, 16))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('GBM', 'Disease', (50, 53))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('suppressing', 'NegReg', (86, 97))	('targeting', 'Reg', (66, 75))	('MACC1', 'Gene', '346389', (76, 81))	('Met', 'Gene', (102, 105))	('MACC1', 'Gene', (76, 81))	('AKT', 'Gene', '207', (106, 109))	('miR-598', 'Chemical', '-', (9, 16))	('tumor', 'Disease', (30, 35))	('Met', 'Gene', '79811', (102, 105))	('GBM', 'Phenotype', 'HP:0012174', (50, 53))
115197	29444745	For example, a previous study showed that miR-598 was overexpressed in bile duct cancer and that the expression level of miR-598 could serve as prognostic and predictive markers for survival of patients with bile duct cancer.	('bile duct cancer', 'Disease', 'MESH:D001650', (208, 224))	('patients', 'Species', '9606', (194, 202))	('bile duct cancer', 'Disease', 'MESH:D001650', (71, 87))	('miR-598', 'Chemical', '-', (42, 49))	('miR-598', 'Var', (121, 128))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('bile duct cancer', 'Phenotype', 'HP:0030153', (208, 224))	('bile duct cancer', 'Phenotype', 'HP:0030153', (71, 87))	('miR-598', 'Chemical', '-', (121, 128))	('overexpressed', 'PosReg', (54, 67))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('bile duct cancer', 'Disease', (208, 224))	('expression', 'MPA', (101, 111))	('bile duct cancer', 'Disease', (71, 87))	('miR-598', 'Gene', (42, 49))
115198	29444745	found that miR-598 was significantly underexpressed in colorectal cancer tissues and cell lines.	('miR-598', 'Var', (11, 18))	('colorectal cancer', 'Disease', 'MESH:D015179', (55, 72))	('miR-598', 'Chemical', '-', (11, 18))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('colorectal cancer', 'Phenotype', 'HP:0003003', (55, 72))	('underexpressed', 'NegReg', (37, 51))	('colorectal cancer', 'Disease', (55, 72))
115200	29444745	also found that miR-598 was underexpressed in osteosarcoma tissues and cell lines, as well as plasmids.	('miR-598', 'Var', (16, 23))	('osteosarcoma', 'Disease', (46, 58))	('miR-598', 'Chemical', '-', (16, 23))	('osteosarcoma', 'Phenotype', 'HP:0002669', (46, 58))	('osteosarcoma', 'Disease', 'MESH:D012516', (46, 58))
115207	29444745	The aberrant expression of MACC1 was closely correlated with the clinicopathological characteristics and prognosis of patients with different malignancies.	('malignancies', 'Disease', 'MESH:D009369', (142, 154))	('MACC1', 'Gene', (27, 32))	('aberrant expression', 'Var', (4, 23))	('MACC1', 'Gene', '346389', (27, 32))	('malignancies', 'Disease', (142, 154))	('patients', 'Species', '9606', (118, 126))	('correlated', 'Reg', (45, 55))
115209	29444745	High MACC1 expression levels were associated with the low overall survival rate of patients with lung squamous cell carcinoma.	('MACC1', 'Gene', '346389', (5, 10))	('overall survival', 'MPA', (58, 74))	('low', 'NegReg', (54, 57))	('High', 'Var', (0, 4))	('expression levels', 'MPA', (11, 28))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('patients', 'Species', '9606', (83, 91))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (97, 125))	('lung squamous cell carcinoma', 'Disease', (97, 125))	('MACC1', 'Gene', (5, 10))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (102, 125))
115211	29444745	MACC1 deregulation had crucial roles in the biological behaviors, including proliferation, cell cycle, apoptosis, migration, invasion, epithelial-mesenchymal transition, autophagy, angiogenesis, and chemoresistance, of various malignancies.	('chemoresistance', 'CPA', (199, 214))	('deregulation', 'Var', (6, 18))	('MACC1', 'Gene', '346389', (0, 5))	('MACC1', 'Gene', (0, 5))	('malignancies', 'Disease', 'MESH:D009369', (227, 239))	('migration', 'CPA', (114, 123))	('autophagy', 'CPA', (170, 179))	('proliferation', 'CPA', (76, 89))	('malignancies', 'Disease', (227, 239))	('apoptosis', 'CPA', (103, 112))	('angiogenesis', 'CPA', (181, 193))	('roles', 'Reg', (31, 36))	('epithelial-mesenchymal transition', 'CPA', (135, 168))	('cell cycle', 'CPA', (91, 101))	('invasion', 'CPA', (125, 133))
115214	29444745	GBM patients with high MACC1 expression had poorer prognosis than those with low MACC1 expression.	('MACC1', 'Gene', '346389', (81, 86))	('expression', 'Var', (29, 39))	('MACC1', 'Gene', (81, 86))	('GBM', 'Phenotype', 'HP:0012174', (0, 3))	('high', 'Var', (18, 22))	('patients', 'Species', '9606', (4, 12))	('MACC1', 'Gene', '346389', (23, 28))	('MACC1', 'Gene', (23, 28))
115216	29444745	In GBM, inhibiting MACC1 expression restricted cell proliferation, migration, and invasion, as well as promoted apoptosis and increased chemosensitivity.	('MACC1', 'Gene', '346389', (19, 24))	('apoptosis', 'CPA', (112, 121))	('expression', 'MPA', (25, 35))	('invasion', 'CPA', (82, 90))	('GBM', 'Phenotype', 'HP:0012174', (3, 6))	('restricted', 'NegReg', (36, 46))	('inhibiting', 'Var', (8, 18))	('chemosensitivity', 'CPA', (136, 152))	('migration', 'CPA', (67, 76))	('promoted', 'PosReg', (103, 111))	('increased', 'PosReg', (126, 135))	('MACC1', 'Gene', (19, 24))	('cell proliferation', 'CPA', (47, 65))
115217	29444745	Hence, targeting MACC1 may be an effective method for GBM treatment.	('MACC1', 'Gene', (17, 22))	('GBM', 'Phenotype', 'HP:0012174', (54, 57))	('targeting', 'Var', (7, 16))	('MACC1', 'Gene', '346389', (17, 22))
115384	30405048	The recombinant virus TB40/EmCherry-UL99eGFP (UL99eGFP) was generated by tagging the C-terminus of the UL99 open reading frame (ORF) with enhanced green fluorescent protein (eGFP) with the forward (FOR) and reverse (REV) primers listed in Table 1 using standard galK recombineering protocols, described in detail previously (e.g., Refs.).	('UL99', 'Gene', (36, 40))	('UL99', 'Gene', '3077533', (103, 107))	('galK', 'Gene', (262, 266))	('UL99', 'Gene', '3077533', (46, 50))	('UL99', 'Gene', (103, 107))	('UL99', 'Gene', '3077533', (36, 40))	('galK', 'Gene', '2584', (262, 266))	('tagging', 'Var', (73, 80))	('UL99', 'Gene', (46, 50))
115427	30405048	Ganciclovir resistance is attributed to mutations within the HCMV-encoded kinase, UL97, underscoring the need for novel therapies to suppress HCMV lytic replication.	('UL97', 'Gene', '3077517', (82, 86))	('attributed', 'Reg', (26, 36))	('HCMV', 'Species', '10359', (142, 146))	('mutations', 'Var', (40, 49))	('Ganciclovir', 'Chemical', 'MESH:D015774', (0, 11))	('UL97', 'Gene', (82, 86))	('HCMV', 'Species', '10359', (61, 65))
115440	30405048	We collected total RNA at the indicated time points and assessed two representative genes from each class of lytic gene transcription: UL123 and UL122 (IE), UL44 and UL54 (E), and UL32 and UL99 (L).	('UL32', 'Var', (180, 184))	('UL44', 'Var', (157, 161))	('UL54', 'Gene', '3077501', (166, 170))	('UL54', 'Gene', (166, 170))	('UL99', 'Gene', '3077533', (189, 193))	('UL99', 'Gene', (189, 193))	('UL123', 'Var', (135, 140))	('UL122', 'Var', (145, 150))
115448	30405048	However, IE2-60, an IE2 protein isoform that accumulates at late times of infection, displayed a significant reduction in protein expression in deguelin-treated cells compared to those that received vehicle treatment (Figure 6).	('reduction', 'NegReg', (109, 118))	('IE2-60', 'Var', (9, 15))	('infection', 'Disease', 'MESH:D007239', (74, 83))	('infection', 'Disease', (74, 83))	('deguelin', 'Chemical', 'MESH:C107676', (144, 152))	('protein expression', 'MPA', (122, 140))
115469	30405048	For example, HCMV activates both the PI3K and mammalian target of rapamycin (mTOR) complex 1 (mTORC1) pathways, both of which are inhibited by deguelin.	('mammalian target of rapamycin', 'Gene', '2475', (46, 75))	('PI3K', 'Pathway', (37, 41))	('mTORC1', 'Gene', (94, 100))	('mTOR', 'Gene', (94, 98))	('mTOR', 'Gene', '2475', (94, 98))	('mTOR', 'Gene', '2475', (77, 81))	('mTOR', 'Gene', (77, 81))	('mTORC1', 'Gene', '382056', (94, 100))	('deguelin', 'Chemical', 'MESH:C107676', (143, 151))	('HCMV', 'Var', (13, 17))	('HCMV', 'Species', '10359', (13, 17))	('activates', 'PosReg', (18, 27))	('mammalian target of rapamycin', 'Gene', (46, 75))
115581	28619685	HPV-positive OPSCC also exhibits marked sensitivity to treatment and a significantly better prognosis than HPV-negative HNSCC, observations which have led to the establishment of a staging system specific to this entity and shifts in treatment paradigms.	('HPV', 'Species', '10566', (0, 3))	('OPSCC', 'Disease', (13, 18))	('better', 'Reg', (85, 91))	('HPV', 'Species', '10566', (107, 110))	('OPSCC', 'Phenotype', 'HP:0012182', (13, 18))	('HNSCC', 'Phenotype', 'HP:0012288', (120, 125))	('HPV-positive', 'Var', (0, 12))
115612	28619685	Degradation of Rb also releases CDKN2A gene expression, which codes for the tumor suppressors p14ARF, as well as p16INK4A, a surrogate marker of HPV-driven OPSCC.	('expression', 'MPA', (44, 54))	('Degradation', 'Var', (0, 11))	('p16INK4A', 'Gene', (113, 121))	('CDKN2A', 'Gene', (32, 38))	('Rb', 'Phenotype', 'HP:0009919', (15, 17))	('p14ARF', 'Gene', '1029', (94, 100))	('HPV', 'Species', '10566', (145, 148))	('tumor', 'Disease', (76, 81))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('CDKN2A', 'Gene', '1029', (32, 38))	('p16INK4A', 'Gene', '1029', (113, 121))	('OPSCC', 'Phenotype', 'HP:0012182', (156, 161))	('p14ARF', 'Gene', (94, 100))	('releases', 'PosReg', (23, 31))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
115616	28619685	Analysis of 279 HNSCC, of which 36 were HPV-positive, identified recurring activating mutations in PIK3CA in HPV-positive HNSCC.	('mutations', 'Var', (86, 95))	('PIK3CA', 'Gene', '5290', (99, 105))	('HNSCC', 'Phenotype', 'HP:0012288', (16, 21))	('HPV', 'Species', '10566', (40, 43))	('HPV', 'Species', '10566', (109, 112))	('HNSCC', 'Phenotype', 'HP:0012288', (122, 127))	('activating', 'PosReg', (75, 85))	('PIK3CA', 'Gene', (99, 105))
115620	28619685	Amplification of the E2F1 was another important HPV-specific finding.	('HPV', 'Species', '10566', (48, 51))	('Amplification', 'Var', (0, 13))	('E2F1', 'Gene', (21, 25))
115622	28619685	Overexpression of E2F1 leads to dysregulation of this cell cycle checkpoint, pushing the cell toward carcinogenesis.	('E2F1', 'Gene', (18, 22))	('pushing', 'PosReg', (77, 84))	('carcinogenesis', 'Disease', (101, 115))	('dysregulation', 'MPA', (32, 45))	('Overexpression', 'Var', (0, 14))	('carcinogenesis', 'Disease', 'MESH:D063646', (101, 115))
115624	28619685	TCGA found the inactivation of TRAF3, found in 22% of HPV-positive tumors, to be another mutation typical of HPV-positive HNSCC.	('HPV-positive tumors', 'Disease', 'MESH:D030361', (54, 73))	('TRAF3', 'Gene', '7187', (31, 36))	('HPV-positive tumors', 'Disease', (54, 73))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('HPV', 'Species', '10566', (54, 57))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('HPV', 'Species', '10566', (109, 112))	('HNSCC', 'Phenotype', 'HP:0012288', (122, 127))	('inactivation', 'Var', (15, 27))	('TRAF3', 'Gene', (31, 36))
115627	28619685	Inactivating mutations in TRAF3, thus, promote molecular pathways known to plays significant roles in carcinogenesis.	('molecular pathways', 'Pathway', (47, 65))	('carcinogenesis', 'Disease', 'MESH:D063646', (102, 116))	('promote', 'PosReg', (39, 46))	('carcinogenesis', 'Disease', (102, 116))	('TRAF3', 'Gene', (26, 31))	('Inactivating mutations', 'Var', (0, 22))	('TRAF3', 'Gene', '7187', (26, 31))
115628	28619685	Indeed, studies beyond TCGA have identified mutations in TRAF3 and CYLD, another regulator of NF-kappaB, as defining features of a subset of HPV-positive HNSCC.	('CYLD', 'Gene', (67, 71))	('CYLD', 'Gene', '1540', (67, 71))	('HPV', 'Species', '10566', (141, 144))	('TRAF3', 'Gene', (57, 62))	('NF-kappaB', 'Gene', '4790', (94, 103))	('mutations', 'Var', (44, 53))	('TRAF3', 'Gene', '7187', (57, 62))	('HNSCC', 'Phenotype', 'HP:0012288', (154, 159))	('NF-kappaB', 'Gene', (94, 103))
115631	28619685	Evidence of amplification of this gene provides a mechanism for conversion of squamous cells to cancer stem cells, a concept that has been supported by other studies.	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('amplification', 'Var', (12, 25))	('cancer', 'Disease', (96, 102))	('cancer', 'Disease', 'MESH:D009369', (96, 102))
115634	28619685	HPV-positive HNSCC display enrichment of cytosine-to-thymidine (C to T) mutations at TpC sites, which are thought to result from dysregulation of APOBEC.	('mutations', 'Var', (72, 81))	('HPV', 'Species', '10566', (0, 3))	('result', 'Reg', (117, 123))	('cytosine', 'Chemical', 'MESH:D003596', (41, 49))	('thymidine', 'Chemical', 'MESH:D013936', (53, 62))	('HNSCC', 'Phenotype', 'HP:0012288', (13, 18))
115635	28619685	APOBEC comprises a family cytosine deaminases that play key roles in viral immunity by mutating viral DNA and restricting viral replication.	('viral replication', 'CPA', (122, 139))	('restricting', 'NegReg', (110, 121))	('mutating', 'Var', (87, 95))	('cytosine', 'Chemical', 'MESH:D003596', (26, 34))	('viral', 'Protein', (96, 101))	('APOBEC', 'Gene', (0, 6))
115636	28619685	However, high levels of APOBEC activity has been observed in several virally-induced cancers to also induce mutation of the host genome, and patterns of APOBEC-related mutagenesis with cytosine deaminase hyperactivity is a common event in virally transformed cancers.	('hyperactivity', 'Disease', (204, 217))	('hyperactivity', 'Phenotype', 'HP:0000752', (204, 217))	('cancers', 'Disease', 'MESH:D009369', (259, 266))	('cancers', 'Phenotype', 'HP:0002664', (259, 266))	('cancers', 'Disease', 'MESH:D009369', (85, 92))	('cancers', 'Disease', (259, 266))	('cancers', 'Phenotype', 'HP:0002664', (85, 92))	('cancers', 'Disease', (85, 92))	('hyperactivity', 'Disease', 'MESH:D006948', (204, 217))	('cancer', 'Phenotype', 'HP:0002664', (259, 265))	('cytosine', 'Chemical', 'MESH:D003596', (185, 193))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('induce', 'Reg', (101, 107))	('mutation', 'Var', (108, 116))	('mutagenesis', 'Var', (168, 179))	('APOBEC-related', 'Gene', (153, 167))
115637	28619685	HPV-related dysfunction of the APOBEC family proteins in HPV-positive HNSCC likely causes non-synonymous mutations within isolated hot-spots.	('HPV', 'Species', '10566', (0, 3))	('HNSCC', 'Phenotype', 'HP:0012288', (70, 75))	('dysfunction', 'Var', (12, 23))	('APOBEC family proteins', 'Protein', (31, 53))	('HPV', 'Species', '10566', (57, 60))
115638	28619685	Thus, the prototypical gene mutated by APOBEC dysregulation in HPV-positive HNSCC is PIK3CA, in which C to T mutations at two hotspots cause recurring E542K and E545K amino acid substitutions that cause gain of function mutations and result in PIK3CA kinase activation.	('E545K', 'Mutation', 'rs104886003', (161, 166))	('E545K', 'Var', (161, 166))	('HPV', 'Species', '10566', (63, 66))	('HNSCC', 'Phenotype', 'HP:0012288', (76, 81))	('C to T', 'Gene', (102, 108))	('PIK3CA', 'Gene', '5290', (85, 91))	('E542K', 'Mutation', 'rs121913273', (151, 156))	('PIK3CA', 'Gene', (244, 250))	('gain of function', 'PosReg', (203, 219))	('PIK3CA', 'Gene', '5290', (244, 250))	('activation', 'PosReg', (258, 268))	('E542K', 'Var', (151, 156))	('PIK3CA', 'Gene', (85, 91))
115639	28619685	The insertion of HPV genomic DNA into the host cellular genome, termed viral integration, is not considered a part of the natural life cycle of HPV; however, it may contribute to HPV-related carcinogenesis.	('HPV', 'Gene', (17, 20))	('HPV', 'Species', '10566', (144, 147))	('carcinogenesis', 'Disease', (191, 205))	('HPV', 'Species', '10566', (179, 182))	('insertion', 'Var', (4, 13))	('HPV-related', 'Disease', (179, 190))	('contribute', 'Reg', (165, 175))	('carcinogenesis', 'Disease', 'MESH:D063646', (191, 205))	('HPV', 'Species', '10566', (17, 20))
115640	28619685	Viral DNA integration into human genome more often occurs with oncogenic HPV types, and is frequently found in HPV-positive OPSCC.	('Viral DNA integration', 'Var', (0, 21))	('HPV', 'Species', '10566', (73, 76))	('human', 'Species', '9606', (27, 32))	('OPSCC', 'Phenotype', 'HP:0012182', (124, 129))	('HPV', 'Species', '10566', (111, 114))	('occurs', 'Reg', (51, 57))
115645	28619685	Recent data correlate HPV16 integration sites in cervical cancer with super-enhancer domains of open chromatin, enriched by H3K27Ac, MED1 (RNA polymerase II [PolII] transcription subunit), and BRD4 proteins.	('HPV16', 'Species', '333760', (22, 27))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('integration sites', 'Var', (28, 45))	('HPV16', 'Gene', (22, 27))	('MED1', 'Protein', (133, 137))	('H3K27Ac', 'Var', (124, 131))	('BRD4', 'Gene', '23476', (193, 197))	('cervical cancer', 'Disease', 'MESH:D002583', (49, 64))	('cervical cancer', 'Disease', (49, 64))	('BRD4', 'Gene', (193, 197))
115651	28619685	Twenty-nine of 75 tumor samples (39%) were found to amplify HPV16-human mRNA fusion products, evidence consistent with viral integration.	('HPV16', 'Species', '333760', (60, 65))	('tumor', 'Disease', (18, 23))	('human', 'Species', '9606', (66, 71))	('HPV16-human mRNA fusion products', 'Protein', (60, 92))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('amplify', 'Var', (52, 59))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
115653	28619685	This data suggested that HPV16 integration had no impact on HPV-dysregulated human transcripts and or the expression of key viral oncogenes.	('integration', 'Var', (31, 42))	('HPV', 'Species', '10566', (25, 28))	('expression', 'MPA', (106, 116))	('HPV', 'Species', '10566', (60, 63))	('HPV16', 'Species', '333760', (25, 30))	('HPV16', 'Gene', (25, 30))	('HPV-dysregulated human transcripts', 'MPA', (60, 94))	('human', 'Species', '9606', (77, 82))
115658	28619685	Higher detail insertion-site analysis identified several putative mechanisms demonstrating that non-random HPV integration may confer a selective advantage to tumor cells and promote tumor progression.	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('non-random', 'Var', (96, 106))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('HPV', 'Species', '10566', (107, 110))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('HPV', 'Gene', (107, 110))	('tumor', 'Disease', (159, 164))	('promote', 'PosReg', (175, 182))	('advantage', 'PosReg', (146, 155))	('tumor', 'Disease', (183, 188))	('tumor', 'Disease', 'MESH:D009369', (159, 164))
115662	28619685	RAD51B is an essential component of DNA double-strand break repair machinery and, consistent with its role as a tumor suppressor gene, loss-of function RAD51B mutations have been reported in cancer.	('RAD51B', 'Gene', (0, 6))	('cancer', 'Disease', (191, 197))	('cancer', 'Disease', 'MESH:D009369', (191, 197))	('mutations', 'Var', (159, 168))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('RAD51B', 'Gene', (152, 158))	('loss-of function', 'NegReg', (135, 151))	('RAD51B', 'Gene', '5890', (152, 158))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('tumor', 'Disease', (112, 117))	('RAD51B', 'Gene', '5890', (0, 6))
115663	28619685	Monoallelic HPV integration was detected in ETS2, another tumor suppressor, resulting in significant reductions in the expression of exons 7 and 8.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('expression', 'MPA', (119, 129))	('tumor', 'Disease', (58, 63))	('reductions', 'NegReg', (101, 111))	('ETS2', 'Gene', (44, 48))	('integration', 'Var', (16, 27))	('HPV', 'Species', '10566', (12, 15))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('ETS2', 'Gene', '2114', (44, 48))	('exons', 'Protein', (133, 138))
115664	28619685	This suggests alternative splicing pattern potentially may lead to biallelic loss of ETS2 function by a dominant negative effect.	('lead to', 'Reg', (59, 66))	('function', 'MPA', (90, 98))	('ETS2', 'Gene', (85, 89))	('loss', 'NegReg', (77, 81))	('alternative splicing pattern', 'Var', (14, 42))	('ETS2', 'Gene', '2114', (85, 89))
115666	28619685	Alternative PDL1 transcripts have been associated with poor prognosis renal cell carcinoma.	('associated with', 'Reg', (39, 54))	('renal cell carcinoma', 'Disease', (70, 90))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (70, 90))	('transcripts', 'Var', (17, 28))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (70, 90))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('PDL1', 'Gene', '29126', (12, 16))	('PDL1', 'Gene', (12, 16))
115671	28619685	Although preliminary, these findings set forth putative mechanisms by which HPV integration may promote tumor progression.	('integration', 'Var', (80, 91))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumor', 'Disease', (104, 109))	('HPV', 'Species', '10566', (76, 79))	('promote', 'PosReg', (96, 103))	('HPV', 'Gene', (76, 79))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
115674	28619685	This line of study was pioneered by Seiwert et al, who found that HPV-positive tumors showed a distinct genetic profile with unique mutations in DDX3X, CYLD, and FGFR, as well as enrichment for PI3K pathway alterations and rarer KRAS mutations common for HPV-negative HNSCC tissues.	('DDX3X', 'Gene', (145, 150))	('HPV', 'Species', '10566', (255, 258))	('HPV', 'Species', '10566', (66, 69))	('HNSCC', 'Phenotype', 'HP:0012288', (268, 273))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('alterations', 'Reg', (207, 218))	('mutations', 'Var', (132, 141))	('PI3K pathway', 'Pathway', (194, 206))	('KRAS', 'Gene', (229, 233))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('HPV-positive tumors', 'Disease', 'MESH:D030361', (66, 85))	('FGFR', 'Gene', (162, 166))	('CYLD', 'Gene', (152, 156))	('HPV-positive tumors', 'Disease', (66, 85))	('CYLD', 'Gene', '1540', (152, 156))
115675	28619685	As an opposite, the mutational profile in HPV-negative HNSCC included enrichment for mutations in TP53, CDKN2A, MLL2, CUL3, NSD1, and PIK3CA genes, and copy-number increases in EGFR, CCND1, and FGFR1.	('CDKN2A', 'Gene', '1029', (104, 110))	('PIK3CA', 'Gene', (134, 140))	('CUL3', 'Gene', (118, 122))	('CCND1', 'Gene', (183, 188))	('increases', 'PosReg', (164, 173))	('HPV', 'Species', '10566', (42, 45))	('HNSCC', 'Phenotype', 'HP:0012288', (55, 60))	('NSD1', 'Gene', (124, 128))	('PIK3CA', 'Gene', '5290', (134, 140))	('mutations', 'Var', (85, 94))	('EGFR', 'Gene', '1956', (177, 181))	('MLL2', 'Gene', (112, 116))	('TP53', 'Gene', '7157', (98, 102))	('copy-number', 'CPA', (152, 163))	('CDKN2A', 'Gene', (104, 110))	('EGFR', 'Gene', (177, 181))	('FGFR1', 'Gene', (194, 199))	('TP53', 'Gene', (98, 102))
115677	28619685	These DNA-repair genes mutations occurred in HPV-positive tumors in non-/light smokers.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('DNA-repair genes', 'Gene', (6, 22))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('occurred', 'Reg', (33, 41))	('mutations', 'Var', (23, 32))	('HPV-positive tumors', 'Disease', 'MESH:D030361', (45, 64))	('HPV-positive tumors', 'Disease', (45, 64))
115678	28619685	Considering a recent report that RAD51B, a BRCA2 cofactor, was a potential integration target for HPV16 leading to loss of its DNA-repair function, may indicate that the role of DNA repair gene disruption in HPV-positive HNSCC carcinogenesis warrants further investigation.	('HPV16', 'Species', '333760', (98, 103))	('loss', 'NegReg', (115, 119))	('RAD51B', 'Gene', '5890', (33, 39))	('HPV-positive HNSCC carcinogenesis', 'Disease', 'MESH:D000077195', (208, 241))	('HNSCC', 'Phenotype', 'HP:0012288', (221, 226))	('HPV16', 'Gene', (98, 103))	('RAD51B', 'Gene', (33, 39))	('DNA-repair function', 'MPA', (127, 146))	('HPV-positive HNSCC carcinogenesis', 'Disease', (208, 241))	('disruption', 'Var', (194, 204))
115689	28619685	Pollock et al published a paper in 2015 which reported that expression of total HER2, total HER3, HER2:HER3 heterodimers, and the HER3:PI3K complex were significantly elevated in HPV-positive HNSCC.	('HNSCC', 'Phenotype', 'HP:0012288', (192, 197))	('expression', 'MPA', (60, 70))	('HER2', 'Gene', '2064', (80, 84))	('HER2', 'Gene', (80, 84))	('HPV', 'Species', '10566', (179, 182))	('elevated', 'PosReg', (167, 175))	('HER3', 'Protein', (92, 96))	('HER2', 'Gene', (98, 102))	('Pollock', 'Species', '8060', (0, 7))	('heterodimers', 'Protein', (108, 120))	('HER2', 'Gene', '2064', (98, 102))	('HPV-positive', 'Var', (179, 191))
115695	28619685	This study proposed a novel mechanism by which HPV can promote tumor growth through the mTOR/AKT/PI3K pathway.	('tumor', 'Disease', (63, 68))	('HPV', 'Var', (47, 50))	('mTOR', 'Gene', (88, 92))	('mTOR', 'Gene', '2475', (88, 92))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('promote', 'PosReg', (55, 62))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('HPV', 'Species', '10566', (47, 50))
115701	28619685	KTN3379 was shown to be effective in growth inhibition in 4 out of 4 HPV-positive HNSCC cell lines, versus 2 out of 5 HPV- lines.	('growth inhibition', 'CPA', (37, 54))	('HPV', 'Species', '10566', (69, 72))	('HPV', 'Species', '10566', (118, 121))	('KTN3379', 'Var', (0, 7))	('HNSCC', 'Phenotype', 'HP:0012288', (82, 87))
115702	28619685	KTN3379 inhibited phosphorylation of HER3 in all HNSCC cell lines regardless of HPV status, but analysis of downstream PI3K signaling revealed that phospho-AKT and phospho-RPS6 were more significantly inhibited in three HPV-positive cell lines versus three HPV-negative cell lines.	('inhibited', 'NegReg', (8, 17))	('HPV', 'Species', '10566', (220, 223))	('HNSCC', 'Phenotype', 'HP:0012288', (49, 54))	('HER3', 'Protein', (37, 41))	('KTN3379', 'Var', (0, 7))	('HPV', 'Species', '10566', (80, 83))	('phosphorylation', 'MPA', (18, 33))	('phospho-RPS6', 'Enzyme', (164, 176))	('phospho-AKT', 'Enzyme', (148, 159))	('inhibited', 'NegReg', (201, 210))	('HPV', 'Species', '10566', (257, 260))
115708	28619685	The drive to understand the molecular underpinnings of HPV-positive HNSCC and, based on that knowledge, to develop biomarkers predictive of prognosis and treatment has now progressed to include epigenetic changes.	('HPV', 'Species', '10566', (55, 58))	('HNSCC', 'Disease', (68, 73))	('HNSCC', 'Phenotype', 'HP:0012288', (68, 73))	('epigenetic changes', 'Var', (194, 212))
115709	28619685	DNA methylation, the addition of a methyl group to a DNA molecule, especially the C5 position of cytosine, is the most common form of epigenetic modification.	('DNA', 'Disease', (0, 3))	('cytosine', 'Chemical', 'MESH:D003596', (97, 105))	('methylation', 'Var', (4, 15))
115711	28619685	One such exploration was conducted by Kostareli at al, found a negative correlation between gene promoter hypermethylation and gene transcript levels in ALDH1A2lo, OSR2lo, GATA4hi, GRIA4hi, and IRX4hi in HPV-related tumors.	('tumors', 'Disease', (216, 222))	('negative', 'NegReg', (63, 71))	('IRX4hi', 'Var', (194, 200))	('tumors', 'Disease', 'MESH:D009369', (216, 222))	('tumors', 'Phenotype', 'HP:0002664', (216, 222))	('HPV', 'Species', '10566', (204, 207))	('gene transcript levels', 'MPA', (127, 149))	('gene promoter hypermethylation', 'MPA', (92, 122))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('ALDH1A2lo', 'Gene', (153, 162))
115718	28619685	Similar to Sartor et al, the independent group of Lleras et al reported a greater level of differential DNA methylation in HPV-positive OPSCC cases compared to HPV-negative cases, and identified that this increase was due in large part to hypermethylation of CpG islands in HPV-positive cases.	('OPSCC', 'Disease', (136, 141))	('HPV', 'Species', '10566', (274, 277))	('differential DNA methylation', 'MPA', (91, 119))	('hypermethylation', 'Var', (239, 255))	('HPV', 'Species', '10566', (160, 163))	('HPV', 'Species', '10566', (123, 126))	('OPSCC', 'Phenotype', 'HP:0012182', (136, 141))
115723	28619685	A possible explanation for this discrepancy may be found in study design: Sartor et al excluded samples containing less than 40% tumor from subsequent analysis for nodal metastasis signature and HPV status, while Lleras et al included such samples in the initial identification of hyper- and hypo-methylated CpG loci.	('HPV', 'Species', '10566', (195, 198))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('CpG', 'Gene', (308, 311))	('hypo-methylated', 'Var', (292, 307))	('tumor', 'Disease', (129, 134))
115724	28619685	The enhancers may drive transcriptional dysregulation responsible for the development and progression of HPV-positive HNSCC at a genome-wide scale.. HPV-E6/E7 proteins were also found to interact with p300 and MYC, main constituents of enhancer regions.	('proteins', 'Protein', (159, 167))	('HPV', 'Species', '10566', (149, 152))	('interact', 'Interaction', (187, 195))	('HNSCC', 'Phenotype', 'HP:0012288', (118, 123))	('HPV-E6/E7', 'Gene', (149, 158))	('HPV', 'Species', '10566', (105, 108))	('p300', 'Var', (201, 205))
115726	28619685	Indeed, the leading HNSCC oncoproteins NF-kappaB and STAT, were also found to participate in enhancer formation during Epstein Barr Virus-caused carcinogenesis In addition, since E6/E7 lack enzymatic activities and don't directly bind to DNA they exert their functions by binding with a vast number of cellular proteins.	('NF-kappaB', 'Gene', '4790', (39, 48))	('E6/E7', 'Var', (179, 184))	('NF-kappaB', 'Gene', (39, 48))	('lack', 'NegReg', (185, 189))	('binding', 'Interaction', (272, 279))	('enzymatic', 'MPA', (190, 199))	('carcinogenesis', 'Disease', 'MESH:D063646', (145, 159))	('bind', 'Interaction', (230, 234))	('carcinogenesis', 'Disease', (145, 159))	('HNSCC', 'Phenotype', 'HP:0012288', (20, 25))	('Epstein Barr Virus', 'Species', '10376', (119, 137))
115727	28619685	Published data suggest that direct or indirect targets of HPV E6/E7 affect the chromatin landscape of cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('HPV', 'Gene', (58, 61))	('E6/E7', 'Var', (62, 67))	('chromatin landscape', 'MPA', (79, 98))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('HPV', 'Species', '10566', (58, 61))	('affect', 'Reg', (68, 74))
115730	28619685	Additionally, binding and inactivation of E2F6, Rb, and p130 by HPV E7 induces acetylation of H3K9 and methylation of H3K4, both of which are marks of open chromatin and active transcription.	('HPV E7', 'Gene', (64, 70))	('p130', 'Gene', '5934', (56, 60))	('binding', 'Interaction', (14, 21))	('methylation', 'MPA', (103, 114))	('p130', 'Gene', (56, 60))	('Rb', 'Phenotype', 'HP:0009919', (48, 50))	('acetylation', 'MPA', (79, 90))	('H3K9', 'Protein', (94, 98))	('induces', 'Reg', (71, 78))	('E2F6', 'Var', (42, 46))	('H3K4', 'Protein', (118, 122))	('HPV', 'Species', '10566', (64, 67))	('inactivation', 'NegReg', (26, 38))
115733	28619685	The current literature suggests that viral oncoproteins lead to significant epigenetic cascades and that aberrant chromatin structure plays an important role in the integration of HPV into the host genome.	('epigenetic cascades', 'MPA', (76, 95))	('aberrant', 'Var', (105, 113))	('HPV', 'Species', '10566', (180, 183))	('lead to', 'Reg', (56, 63))
115785	32992452	During the implementation of the murine model of skin irradiated with UV-B light, UV-B radiation was found to cause skin lesions in SKH-1 mice; an erythematous lesion and a lesion related to the development of neoplasic lesion (squamous cell carcinoma) which coincides with Makinen and Stenback and Cano et al., who reported that excessive exposure to UV-B is carcinogenic and that epidermal and dermal lesions are easier to be induced by UV-B radiation in SKH-1 mice.	('murine', 'Species', '10090', (33, 39))	('neoplasic lesion', 'Disease', (210, 226))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (228, 251))	('carcinoma', 'Phenotype', 'HP:0030731', (242, 251))	('mice', 'Species', '10090', (463, 467))	('erythema', 'Phenotype', 'HP:0010783', (147, 155))	('mice', 'Species', '10090', (138, 142))	('neoplasic lesion', 'Phenotype', 'HP:0002664', (210, 226))	('carcinogenic', 'Disease', 'MESH:D063646', (360, 372))	('UV-B', 'Var', (82, 86))	('squamous cell carcinoma', 'Disease', (228, 251))	('erythematous lesion', 'Disease', (147, 166))	('skin lesions', 'Disease', (116, 128))	('carcinogenic', 'Disease', (360, 372))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (228, 251))	('erythematous lesion', 'Disease', 'MESH:D004893', (147, 166))	('skin lesions', 'Disease', 'MESH:D012871', (116, 128))	('neoplasic lesion', 'Disease', 'MESH:D001768', (210, 226))
115861	32638704	In addition, ectopic expression of TNNC1 inhibited colony formation of multiple LUAD cell lines and induced DNA damage, cell cycle arrest and ultimately apoptosis.	('DNA damage', 'MPA', (108, 118))	('colony formation of multiple LUAD cell lines', 'CPA', (51, 95))	('TNNC1', 'Gene', (35, 40))	('arrest', 'Disease', 'MESH:D006323', (131, 137))	('LUAD', 'Phenotype', 'HP:0030078', (80, 84))	('arrest', 'Disease', (131, 137))	('induced', 'Reg', (100, 107))	('inhibited', 'NegReg', (41, 50))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (120, 137))	('ectopic expression', 'Var', (13, 31))	('apoptosis', 'CPA', (153, 162))
115862	32638704	We further examined potential correlations between expression levels of TNNC1 and various clinical parameters and found that low-level expression is significantly associated with invasiveness of the tumor.	('TNNC1', 'Gene', (72, 77))	('low-level', 'Var', (125, 134))	('invasiveness of the tumor', 'Disease', (179, 204))	('associated with', 'Reg', (163, 178))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('invasiveness of the tumor', 'Disease', 'MESH:D009361', (179, 204))
115925	32638704	Next, we utilized the well-established soft agar assay using NIH3T3 cells to test if TNNC1 can inhibit anchorage independent growth induced by the oncogenic KRAS mutant.	('inhibit', 'NegReg', (95, 102))	('mutant', 'Var', (162, 168))	('anchorage independent growth', 'CPA', (103, 131))	('TNNC1', 'Gene', (85, 90))	('KRAS', 'Gene', (157, 161))	('NIH3T3', 'CellLine', 'CVCL:0594', (61, 67))	('agar', 'Chemical', 'MESH:D000362', (44, 48))
115926	32638704	Retroviruses expressing TNNC1 and KRASG12D were generated and used to infect NIH3T3 cells which were subsequently seeded and cultured in soft agar.	('KRASG12D', 'Var', (34, 42))	('agar', 'Chemical', 'MESH:D000362', (142, 146))	('TNNC1', 'Gene', (24, 29))	('infect', 'Reg', (70, 76))	('NIH3T3', 'CellLine', 'CVCL:0594', (77, 83))	('G12D', 'Mutation', 'rs121913529', (38, 42))
115932	32638704	Both OS and recurrence-free survival showed that high expression of TNNC1 was associated with better survival although the OS did not have the statistical significance of P value < 0.05 most likely due to the limited number of patients (Figs.	('survival', 'MPA', (101, 109))	('high expression', 'Var', (49, 64))	('better', 'PosReg', (94, 100))	('TNNC1', 'Gene', (68, 73))	('patients', 'Species', '9606', (227, 235))
115936	32638704	Indeed, in 4 days after ectopic expression of TNNC1, significant increases in Annexin V and PI positive cells were seen from both A549 and H2009 cells (Fig.	('TNNC1', 'Gene', (46, 51))	('increases', 'PosReg', (65, 74))	('H2009', 'CellLine', 'CVCL:1514', (139, 144))	('Annexin V', 'Gene', '308', (78, 87))	('PI positive cells', 'CPA', (92, 109))	('ectopic expression', 'Var', (24, 42))	('A549', 'CellLine', 'CVCL:0023', (130, 134))	('Annexin V', 'Gene', (78, 87))
115939	32638704	Interestingly, in 2 days after viral transduction, A549 cells showed a significant decrease in the fraction of cells in the S phase and a corresponding increase in the fraction of cells in G1 phase (Fig.	('transduction', 'Var', (37, 49))	('decrease', 'NegReg', (83, 91))	('increase', 'PosReg', (152, 160))	('A549', 'CellLine', 'CVCL:0023', (51, 55))
115958	32638704	While ectopic expression of TNNC1 had little effect on the behavior of A549 cells (data not shown), knockdown of TNNC1 by specific siRNAs promoted invasive activity of the cells over 2 fold (Fig.	('knockdown', 'Var', (100, 109))	('promoted', 'PosReg', (138, 146))	('TNNC1', 'Gene', (113, 118))	('invasive activity of the cells', 'CPA', (147, 177))	('A549', 'CellLine', 'CVCL:0023', (71, 75))
115971	32638704	Given that mutations in EGFR, KRAS and BRAF collectively account for up to 40% of the LUAD, finding targets or regulators of this pathway seems to be of particular importance.	('EGFR', 'Gene', '1956', (24, 28))	('mutations', 'Var', (11, 20))	('BRAF', 'Gene', '673', (39, 43))	('EGFR', 'Gene', (24, 28))	('BRAF', 'Gene', (39, 43))	('LUAD', 'Phenotype', 'HP:0030078', (86, 90))	('LUAD', 'Disease', (86, 90))	('account for', 'Reg', (57, 68))	('KRAS', 'Gene', (30, 34))
115983	29996471	Mechanistic studies revealed that knockdown of NGAL increased oral cancer cell proliferation, survival, and migration; it also induced resistance against cisplatin.	('cisplatin', 'Chemical', 'MESH:D002945', (154, 163))	('migration', 'CPA', (108, 117))	('increased', 'PosReg', (52, 61))	('oral cancer', 'Disease', 'MESH:D009062', (62, 73))	('oral cancer', 'Disease', (62, 73))	('induced', 'Reg', (127, 134))	('knockdown', 'Var', (34, 43))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('NGAL', 'Gene', (47, 51))	('resistance against cisplatin', 'MPA', (135, 163))	('survival', 'CPA', (94, 102))	('NGAL', 'Gene', '3934', (47, 51))
115984	29996471	Silencing of NGAL activated mammalian target of rapamycin (mTOR)signaling and reduced autophagy by the liver kinase B1 (LKB1)-activated protein kinase (AMPK)-p53-Redd1 signaling axis.	('p53', 'Gene', '7157', (158, 161))	('mTOR', 'Gene', '2475', (59, 63))	('Silencing', 'Var', (0, 9))	('liver kinase B1', 'Gene', '6794', (103, 118))	('NGAL', 'Gene', (13, 17))	('liver kinase B1', 'Gene', (103, 118))	('LKB1', 'Gene', '6794', (120, 124))	('autophagy', 'CPA', (86, 95))	('Redd1', 'Gene', '54541', (162, 167))	('mammalian target of rapamycin', 'Gene', '2475', (28, 57))	('p53', 'Gene', (158, 161))	('activated', 'PosReg', (18, 27))	('AMPK', 'Gene', (152, 156))	('NGAL', 'Gene', '3934', (13, 17))	('AMPK', 'Gene', '5564', (152, 156))	('mammalian target of rapamycin', 'Gene', (28, 57))	('reduced', 'NegReg', (78, 85))	('LKB1', 'Gene', (120, 124))	('Redd1', 'Gene', (162, 167))	('mTOR', 'Gene', (59, 63))
115985	29996471	Moreover, cyclin-D1, Bcl-2, and matrix metalloproteinase-9 (MMP-9) were upregulated, and caspase-9 was downregulated, suggesting that silencing of NGAL increases oral cancer cell proliferation, survival, and migration.	('cyclin-D1', 'Gene', (10, 19))	('cyclin-D1', 'Gene', '595', (10, 19))	('silencing', 'Var', (134, 143))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('matrix metalloproteinase-9', 'Gene', (32, 58))	('Bcl-2', 'Gene', (21, 26))	('downregulated', 'NegReg', (103, 116))	('MMP-9', 'Gene', '4318', (60, 65))	('MMP-9', 'Gene', (60, 65))	('NGAL', 'Gene', (147, 151))	('Bcl-2', 'Gene', '596', (21, 26))	('increases oral cancer', 'Disease', (152, 173))	('caspase-9', 'Gene', '842', (89, 98))	('matrix metalloproteinase-9', 'Gene', '4318', (32, 58))	('upregulated', 'PosReg', (72, 83))	('survival', 'CPA', (194, 202))	('NGAL', 'Gene', '3934', (147, 151))	('caspase-9', 'Gene', (89, 98))	('migration', 'CPA', (208, 217))	('increases oral cancer', 'Disease', 'MESH:D009062', (152, 173))
115997	29996471	Likewise, silencing of NGAL reduces migration and invasion via the downregulation of vimentin, MMP-2, and MMP-9 and increases the expression of E-cadherin.	('MMP-9', 'Gene', (106, 111))	('NGAL', 'Gene', '3934', (23, 27))	('expression', 'MPA', (130, 140))	('downregulation', 'NegReg', (67, 81))	('MMP-2', 'Gene', (95, 100))	('reduces', 'NegReg', (28, 35))	('MMP-2', 'Gene', '4313', (95, 100))	('migration', 'CPA', (36, 45))	('E-cadherin', 'Gene', (144, 154))	('E-cadherin', 'Gene', '999', (144, 154))	('vimentin', 'Gene', '7431', (85, 93))	('MMP-9', 'Gene', '4318', (106, 111))	('NGAL', 'Gene', (23, 27))	('increases', 'PosReg', (116, 125))	('vimentin', 'Gene', (85, 93))	('silencing', 'Var', (10, 19))
116010	29996471	The percentage of cells positive for NGAL were graded by the following protocol: grade 0 intensity (<10% positive cells); grade 1+ intensity (10-25% positive cells), grade 2+ intensity (25-50%), grade 3 intensity (50-75% positive cells), and grade 4 intensity (75-100% positive cells).	('10-25', 'Var', (142, 147))	('NGAL', 'Gene', (37, 41))	('25-50%', 'Var', (186, 192))	('NGAL', 'Gene', '3934', (37, 41))
116074	29996471	Therefore, we sought to study the effect of silencing of NGAL on the proliferation and survival of oral cancer cells.	('oral cancer', 'Disease', (99, 110))	('NGAL', 'Gene', '3934', (57, 61))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('oral cancer', 'Disease', 'MESH:D009062', (99, 110))	('silencing', 'Var', (44, 53))	('NGAL', 'Gene', (57, 61))
116076	29996471	We carried out an MTT assay and observed that knockdown of NGAL increased cell viability in a time-dependent manner (Figure 3B).	('NGAL', 'Gene', '3934', (59, 63))	('MTT', 'Chemical', '-', (18, 21))	('knockdown', 'Var', (46, 55))	('increased', 'PosReg', (64, 73))	('cell viability', 'CPA', (74, 88))	('NGAL', 'Gene', (59, 63))
116077	29996471	To confirm that knockdown of NGAL increases cell viability, we studied its effect on different phases of the cell cycle.	('knockdown', 'Var', (16, 25))	('NGAL', 'Gene', (29, 33))	('NGAL', 'Gene', '3934', (29, 33))	('cell viability', 'CPA', (44, 58))	('increases', 'PosReg', (34, 43))
116078	29996471	We found that silencing of NGAL led to an increase in the number of cells in S-phase and reduced the number of cells in G2/M phase in comparison to control shRNA (Figure 3C).	('silencing', 'Var', (14, 23))	('NGAL', 'Gene', (27, 31))	('NGAL', 'Gene', '3934', (27, 31))	('reduced', 'NegReg', (89, 96))	('increase', 'PosReg', (42, 50))
116079	29996471	The increase in number of cells in S-phase suggests that NGAL knockdown allows cancer cells to proliferate uninterruptedly and pass through the G2/M check point.	('NGAL', 'Gene', '3934', (57, 61))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('NGAL', 'Gene', (57, 61))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('knockdown', 'Var', (62, 71))
116081	29996471	We also assessed if knockdown of NGAL increases oral cancer cell survival by using a clonogenicity assay (Figure 3D).	('increases oral cancer', 'Disease', 'MESH:D009062', (38, 59))	('knockdown', 'Var', (20, 29))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('NGAL', 'Gene', '3934', (33, 37))	('NGAL', 'Gene', (33, 37))	('increases oral cancer', 'Disease', (38, 59))
116083	29996471	Our IHC results advocate that downregulation of NGAL is strongly associated with metastases; accordingly, we hypothesized that knockdown of NGAL may induce invasion and migration of oral cancer cells.	('NGAL', 'Gene', (140, 144))	('invasion', 'CPA', (156, 164))	('NGAL', 'Gene', (48, 52))	('NGAL', 'Gene', '3934', (140, 144))	('downregulation', 'NegReg', (30, 44))	('NGAL', 'Gene', '3934', (48, 52))	('metastases', 'Disease', (81, 91))	('induce', 'PosReg', (149, 155))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('metastases', 'Disease', 'MESH:D009362', (81, 91))	('knockdown', 'Var', (127, 136))	('migration of oral cancer', 'Disease', (169, 193))	('migration of oral cancer', 'Disease', 'MESH:D009062', (169, 193))
116093	29996471	We observed that knockdown of NGAL activated S6 (serine 235/236) (Figure 5A,B).	('serine', 'Chemical', 'MESH:D012694', (49, 55))	('NGAL', 'Gene', '3934', (30, 34))	('NGAL', 'Gene', (30, 34))	('knockdown', 'Var', (17, 26))
116097	29996471	Thus, knockdown of NGAL activates mTOR signalling via the AMPK-LKB pathway.	('AMPK', 'Gene', '5564', (58, 62))	('knockdown', 'Var', (6, 15))	('NGAL', 'Gene', '3934', (19, 23))	('NGAL', 'Gene', (19, 23))	('activates', 'PosReg', (24, 33))	('mTOR', 'Gene', '2475', (34, 38))	('AMPK', 'Gene', (58, 62))	('mTOR', 'Gene', (34, 38))
116104	29996471	Therefore, silencing of NGAL increases survival, proliferation, invasion, and migration of oral cancer cells via the LKB1-AMPK-p53-Redd1-mTOR axis (Figure 5C,D).	('NGAL', 'Gene', (24, 28))	('proliferation', 'CPA', (49, 62))	('LKB1', 'Gene', (117, 121))	('mTOR', 'Gene', (137, 141))	('p53', 'Gene', '7157', (127, 130))	('survival', 'CPA', (39, 47))	('NGAL', 'Gene', '3934', (24, 28))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('migration of oral cancer', 'Disease', (78, 102))	('migration of oral cancer', 'Disease', 'MESH:D009062', (78, 102))	('AMPK', 'Gene', (122, 126))	('Redd1', 'Gene', '54541', (131, 136))	('AMPK', 'Gene', '5564', (122, 126))	('mTOR', 'Gene', '2475', (137, 141))	('p53', 'Gene', (127, 130))	('invasion', 'CPA', (64, 72))	('LKB1', 'Gene', '6794', (117, 121))	('silencing', 'Var', (11, 20))	('Redd1', 'Gene', (131, 136))	('increases', 'PosReg', (29, 38))
116105	29996471	We observed that knockdown of NGAL upregulated cyclin D1, Bcl-2, and MMP-9 as well as downregulated caspase-9, confirming the same (Figure 5A,B).	('Bcl-2', 'Gene', '596', (58, 63))	('NGAL', 'Gene', '3934', (30, 34))	('caspase-9', 'Gene', (100, 109))	('MMP-9', 'Gene', '4318', (69, 74))	('MMP-9', 'Gene', (69, 74))	('cyclin D1', 'Gene', '595', (47, 56))	('downregulated', 'NegReg', (86, 99))	('cyclin D1', 'Gene', (47, 56))	('upregulated', 'PosReg', (35, 46))	('caspase-9', 'Gene', '842', (100, 109))	('knockdown', 'Var', (17, 26))	('NGAL', 'Gene', (30, 34))	('Bcl-2', 'Gene', (58, 63))
116106	29996471	In addition to the significant role of mTOR in cancer progression, activation of mTOR downregulates autophagy.	('mTOR', 'Gene', '2475', (81, 85))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('cancer', 'Disease', (47, 53))	('autophagy', 'CPA', (100, 109))	('mTOR', 'Gene', (39, 43))	('mTOR', 'Gene', '2475', (39, 43))	('activation', 'Var', (67, 77))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('mTOR', 'Gene', (81, 85))	('downregulates', 'NegReg', (86, 99))
116111	29996471	We observed that knockdown of NGAL selectively induced resistance against cisplatin, while both control shRNA and shNGAL cells were sensitive to 5-FU (Figure 6A,B).	('hNGAL', 'Gene', (115, 120))	('5-FU', 'Chemical', '-', (145, 149))	('NGAL', 'Gene', '3934', (116, 120))	('NGAL', 'Gene', '3934', (30, 34))	('hNGAL', 'Gene', '3934', (115, 120))	('resistance against cisplatin', 'MPA', (55, 83))	('induced', 'Reg', (47, 54))	('cisplatin', 'Chemical', 'MESH:D002945', (74, 83))	('knockdown', 'Var', (17, 26))	('NGAL', 'Gene', (116, 120))	('NGAL', 'Gene', (30, 34))
116124	29996471	Upon activation, NNK and NNN induce mutations in tumour suppressor genes and oncogenes; they form DNA adducts that result in tumour initiation.	('NNK', 'Gene', (17, 20))	('NNN', 'Gene', (25, 28))	('tumour initiation', 'Disease', 'MESH:D009369', (125, 142))	('oncogenes', 'Gene', (77, 86))	('tumour', 'Phenotype', 'HP:0002664', (125, 131))	('NNK', 'Chemical', 'MESH:C016583', (17, 20))	('mutations', 'Var', (36, 45))	('tumour', 'Phenotype', 'HP:0002664', (49, 55))	('tumour', 'Disease', 'MESH:D009369', (49, 55))	('tumour initiation', 'Disease', (125, 142))	('tumour', 'Disease', 'MESH:D009369', (125, 131))	('tumour', 'Disease', (125, 131))	('NNN', 'Chemical', 'MESH:C008655', (25, 28))	('result in', 'Reg', (115, 124))	('tumour', 'Disease', (49, 55))
116130	29996471	Recently, Lin et al., 2016 reported that knockdown of NGAL increased in vitro cell motility and in vivo metastases.	('metastases', 'Disease', (104, 114))	('metastases', 'Disease', 'MESH:D009362', (104, 114))	('increased', 'PosReg', (59, 68))	('NGAL', 'Gene', (54, 58))	('NGAL', 'Gene', '3934', (54, 58))	('knockdown', 'Var', (41, 50))
116131	29996471	However, this is the first study that has shown that knockdown of NGAL increases in vitro cell viability and survival in oral cancer.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('NGAL', 'Gene', (66, 70))	('knockdown', 'Var', (53, 62))	('oral cancer', 'Disease', 'MESH:D009062', (121, 132))	('NGAL', 'Gene', '3934', (66, 70))	('increases', 'PosReg', (71, 80))	('oral cancer', 'Disease', (121, 132))	('survival', 'CPA', (109, 117))
116132	29996471	Similar to our findings, a recent study in colorectal cancer showed that knockdown of NGAL increased cell proliferation, survival and induced EMT.	('colorectal cancer', 'Disease', (43, 60))	('EMT', 'CPA', (142, 145))	('NGAL', 'Gene', (86, 90))	('NGAL', 'Gene', '3934', (86, 90))	('colorectal cancer', 'Disease', 'MESH:D015179', (43, 60))	('survival', 'CPA', (121, 129))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('increased', 'PosReg', (91, 100))	('colorectal cancer', 'Phenotype', 'HP:0003003', (43, 60))	('cell proliferation', 'CPA', (101, 119))	('induced', 'PosReg', (134, 141))	('knockdown', 'Var', (73, 82))
116133	29996471	Our study shows that knockdown of NGAL activated mTOR signalling and reduced autophagy via the LKB1-AMPK-p53-Redd1 signalling axis.	('mTOR', 'Gene', (49, 53))	('LKB1', 'Gene', (95, 99))	('mTOR', 'Gene', '2475', (49, 53))	('NGAL', 'Gene', '3934', (34, 38))	('activated', 'PosReg', (39, 48))	('NGAL', 'Gene', (34, 38))	('reduced', 'NegReg', (69, 76))	('LKB1', 'Gene', '6794', (95, 99))	('Redd1', 'Gene', '54541', (109, 114))	('p53', 'Gene', (105, 108))	('Redd1', 'Gene', (109, 114))	('p53', 'Gene', '7157', (105, 108))	('AMPK', 'Gene', (100, 104))	('autophagy', 'CPA', (77, 86))	('AMPK', 'Gene', '5564', (100, 104))	('knockdown', 'Var', (21, 30))
116134	29996471	Aberrant activation of mTOR is seen in OSCC and is associated with poor prognosis.	('activation', 'PosReg', (9, 19))	('Aberrant', 'Var', (0, 8))	('OSCC', 'Disease', (39, 43))	('mTOR', 'Gene', (23, 27))	('mTOR', 'Gene', '2475', (23, 27))
116135	29996471	Phosphorylated S6, the downstream target of mTOR, was found to be upregulated in epithelial dysplasia and OSCC; it also can serve as a potent diagnostic biomarker for oral cancer.	('Phosphorylated', 'Var', (0, 14))	('oral cancer', 'Disease', 'MESH:D009062', (167, 178))	('epithelial dysplasia', 'Disease', 'MESH:C567703', (81, 101))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('oral cancer', 'Disease', (167, 178))	('upregulated', 'PosReg', (66, 77))	('mTOR', 'Gene', (44, 48))	('epithelial dysplasia', 'Disease', (81, 101))	('mTOR', 'Gene', '2475', (44, 48))	('OSCC', 'Disease', (106, 110))
116140	29996471	A similar mechanism was observed in our study, indicating that silencing of NGAL mediates autophagy via Redd1.	('Redd1', 'Gene', (104, 109))	('autophagy', 'CPA', (90, 99))	('NGAL', 'Gene', (76, 80))	('Redd1', 'Gene', '54541', (104, 109))	('NGAL', 'Gene', '3934', (76, 80))	('mediates', 'Reg', (81, 89))	('silencing', 'Var', (63, 72))
116144	29996471	Moreover, in cells lacking p53, ectopic expression of p53 induced the endogenous activity of Redd1; additionally, the promoter region of Redd1 comprises of p53 binding sites, indicating that Redd1 is a direct transcriptional target of p53.	('induced', 'PosReg', (58, 65))	('Redd1', 'Gene', (93, 98))	('Redd1', 'Gene', '54541', (137, 142))	('p53', 'Gene', '7157', (27, 30))	('ectopic expression', 'Var', (32, 50))	('Redd1', 'Gene', '54541', (93, 98))	('p53', 'Gene', (156, 159))	('Redd1', 'Gene', (191, 196))	('p53', 'Gene', (54, 57))	('p53', 'Gene', '7157', (156, 159))	('endogenous activity', 'MPA', (70, 89))	('p53', 'Gene', (235, 238))	('p53', 'Gene', '7157', (54, 57))	('Redd1', 'Gene', (137, 142))	('p53', 'Gene', '7157', (235, 238))	('Redd1', 'Gene', '54541', (191, 196))	('p53', 'Gene', (27, 30))
116145	29996471	Thus, our study demonstrates that knockdown of NGAL activates the mTOR pathway via the LKB1-AMPK-p53-Redd1 signalling axis.	('mTOR', 'Gene', (66, 70))	('mTOR', 'Gene', '2475', (66, 70))	('p53', 'Gene', (97, 100))	('Redd1', 'Gene', (101, 106))	('LKB1', 'Gene', (87, 91))	('AMPK', 'Gene', (92, 96))	('p53', 'Gene', '7157', (97, 100))	('AMPK', 'Gene', '5564', (92, 96))	('LKB1', 'Gene', '6794', (87, 91))	('Redd1', 'Gene', '54541', (101, 106))	('NGAL', 'Gene', (47, 51))	('knockdown', 'Var', (34, 43))	('NGAL', 'Gene', '3934', (47, 51))	('activates', 'PosReg', (52, 61))
116147	29996471	In addition to promoting mTOR signalling, knockdown of NGAL decreased autophagy.	('decreased', 'NegReg', (60, 69))	('autophagy', 'CPA', (70, 79))	('NGAL', 'Gene', (55, 59))	('promoting', 'PosReg', (15, 24))	('NGAL', 'Gene', '3934', (55, 59))	('mTOR', 'Gene', '2475', (25, 29))	('knockdown', 'Var', (42, 51))	('mTOR', 'Gene', (25, 29))
116151	29996471	Thus, our study clearly demonstrates that knockdown of NGAL increases oral cancer cell proliferation, survival, invasion, and migration by upregulating mTOR signalling and suppressing autophagy.	('survival', 'CPA', (102, 110))	('mTOR', 'Gene', (152, 156))	('increases oral cancer', 'Disease', 'MESH:D009062', (60, 81))	('invasion', 'CPA', (112, 120))	('NGAL', 'Gene', (55, 59))	('increases oral cancer', 'Disease', (60, 81))	('autophagy', 'CPA', (184, 193))	('suppressing', 'NegReg', (172, 183))	('mTOR', 'Gene', '2475', (152, 156))	('NGAL', 'Gene', '3934', (55, 59))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('upregulating', 'PosReg', (139, 151))	('migration', 'CPA', (126, 135))	('knockdown', 'Var', (42, 51))
116154	29996471	Mechanistic studies revealed that knockdown of NGAL augmented cell survival, invasion, and migration by activating the mTOR pathway and also downregulated autophagy via the LKB1-AMPK-p53-Redd1 signalling axis (Figure 7).	('p53', 'Gene', '7157', (183, 186))	('invasion', 'CPA', (77, 85))	('activating', 'PosReg', (104, 114))	('NGAL', 'Gene', (47, 51))	('LKB1', 'Gene', (173, 177))	('p53', 'Gene', (183, 186))	('mTOR', 'Gene', (119, 123))	('Redd1', 'Gene', '54541', (187, 192))	('knockdown', 'Var', (34, 43))	('AMPK', 'Gene', '5564', (178, 182))	('AMPK', 'Gene', (178, 182))	('NGAL', 'Gene', '3934', (47, 51))	('autophagy', 'CPA', (155, 164))	('downregulated', 'NegReg', (141, 154))	('migration', 'CPA', (91, 100))	('mTOR', 'Gene', '2475', (119, 123))	('LKB1', 'Gene', '6794', (173, 177))	('cell survival', 'CPA', (62, 75))	('augmented', 'PosReg', (52, 61))	('Redd1', 'Gene', (187, 192))
116167	32991419	On univariate analyzes, treatment package time >=118 days, sake index >=60, Brinkman index >=450, maximum standardized uptake value >=42.45, and the presence of synchronous cancer were significantly associated with shorter oropharyngeal squamous cell carcinoma-specific survival.	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (237, 260))	('squamous cell carcinoma', 'Disease', (237, 260))	('>=60', 'Var', (70, 74))	('synchronous cancer', 'Disease', 'MESH:D009369', (161, 179))	('oropharyngeal squamous cell carcinoma', 'Phenotype', 'HP:0012182', (223, 260))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('>=118', 'Var', (47, 52))	('shorter', 'NegReg', (215, 222))	('synchronous cancer', 'Disease', (161, 179))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (237, 260))	('carcinoma', 'Phenotype', 'HP:0030731', (251, 260))
116203	32991419	Using Cox proportional hazards model, multivariate survival analyses for OPSCC-specific survival, OS, LRRFS, and DMFS were performed, with adjustments for TPT (<118/>=118 days), synchronous cancer (absent/present), sake index (<60/>=60), Brinkman index (<450/>=450), and SUVmax (<42.45/>=42.45).	('TPT', 'Chemical', '-', (155, 158))	('synchronous cancer', 'Disease', 'MESH:D009369', (178, 196))	('<450/>=450', 'Var', (254, 264))	('synchronous cancer', 'Disease', (178, 196))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('<60/>=60', 'Var', (227, 235))
116209	32991419	The results showed that a shorter OPSCC-specific survival was significantly associated with sake index >=60 (P = .01), Brinkman index >=450 (P < .01), SUVmax >=42.45 (P = .03), TPT >=118 (P < .01), and the presence of synchronous cancer (P < .01).	('TPT', 'Chemical', '-', (177, 180))	('synchronous cancer', 'Disease', (218, 236))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('OPSCC-specific survival', 'CPA', (34, 57))	('SUVmax >=42.45', 'Var', (151, 165))	('shorter', 'NegReg', (26, 33))	('synchronous cancer', 'Disease', 'MESH:D009369', (218, 236))	('TPT >=118', 'Var', (177, 186))
116211	32991419	Compared with patients who had TPT <118 (n = 40), those who had TPT >=118 (n = 9) had significantly higher sake index (P < .01) and Brinkman index (P = .01) and received more frequent adjuvant treatment (P < .01) and surgery as the initial treatment (P < .01).	('sake index', 'MPA', (107, 117))	('Brinkman index', 'MPA', (132, 146))	('TPT >=118', 'Var', (64, 73))	('TPT', 'Chemical', '-', (64, 67))	('higher', 'PosReg', (100, 106))	('adjuvant treatment', 'CPA', (184, 202))	('patients', 'Species', '9606', (14, 22))	('TPT', 'Chemical', '-', (31, 34))
116212	32991419	On log-rank test, patients with TPT >=118 had significantly shorter OS (P = .01) and DMFS (P < .01) compared with those in patients with TPT <118.	('TPT', 'Chemical', '-', (32, 35))	('patients', 'Species', '9606', (123, 131))	('DMFS', 'CPA', (85, 89))	('patients', 'Species', '9606', (18, 26))	('TPT', 'Chemical', '-', (137, 140))	('shorter', 'NegReg', (60, 67))	('TPT >=118', 'Var', (32, 41))
116213	32991419	However, there was no significant difference in the LRRFS (P = .19) between TPT >=118 and TPT <118.	('LRRFS', 'MPA', (52, 57))	('TPT', 'Chemical', '-', (76, 79))	('TPT', 'Chemical', '-', (90, 93))	('TPT >=118', 'Var', (76, 85))	('TPT <118', 'Var', (90, 98))
116219	32991419	In the log-rank test, patients with Brinkman index of >=450 were significantly associated with shorter OPSCC-specific survival than those with Brinkman index of <450 (Fig.	('Brinkman index of >=450', 'Var', (36, 59))	('patients', 'Species', '9606', (22, 30))	('shorter', 'NegReg', (95, 102))	('OPSCC-specific', 'Disease', (103, 117))
116230	32991419	Likewise, the present study showed a significant association between prolonged TPT and a high Brinkman index.	('TPT', 'Disease', (79, 82))	('prolonged', 'Var', (69, 78))	('TPT', 'Chemical', '-', (79, 82))
116253	32602212	circ_0007385 expression was higher in NSCLC tissues and cell lines, and was associated with poor overall survival.	('NSCLC', 'Disease', (38, 43))	('circ_0007385', 'Var', (0, 12))	('NSCLC', 'Disease', 'MESH:D002289', (38, 43))	('expression', 'MPA', (13, 23))	('poor', 'NegReg', (92, 96))	('overall', 'MPA', (97, 104))	('associated', 'Reg', (76, 86))	('higher', 'PosReg', (28, 34))	('circ_0007385', 'Chemical', '-', (0, 12))
116254	32602212	Silencing circ_0007385 could suppress cell proliferation, migration and invasion in A549 and H1975 cells, as well as cisplatin (DDP) resistance.	('circ_0007385', 'Chemical', '-', (10, 22))	('cell proliferation', 'CPA', (38, 56))	('H1975', 'CellLine', 'CVCL:1511', (93, 98))	('circ_0007385', 'Var', (10, 22))	('cisplatin', 'Chemical', 'MESH:D002945', (117, 126))	('suppress', 'NegReg', (29, 37))	('DDP', 'Chemical', '-', (128, 131))	('Silencing circ_0007385', 'Var', (0, 22))	('cisplatin', 'MPA', (117, 126))	('A549', 'CellLine', 'CVCL:0023', (84, 88))	('invasion', 'CPA', (72, 80))	('migration', 'CPA', (58, 67))
116256	32602212	Molecularly, there was a direct interaction between miR-519d-3p and either circ_0007385 or HMGB1; expression of miR-519d-3p was downregulated in NSCLC tumors in a circ_0007385-correlated manner, and circ_0007385 could indirectly regulate HMGB1 via miR-519d-3p.	('miR-519d', 'Gene', (52, 60))	('circ_0007385', 'Var', (199, 211))	('circ_0007385', 'Chemical', '-', (163, 175))	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('miR-519d', 'Gene', '574480', (248, 256))	('miR-519d', 'Gene', (248, 256))	('-519d-3p', 'Chemical', '-', (115, 123))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('miR-519d', 'Gene', '574480', (112, 120))	('miR-519d', 'Gene', (112, 120))	('NSCLC tumors', 'Disease', (145, 157))	('circ_0007385', 'Chemical', '-', (75, 87))	('downregulated', 'NegReg', (128, 141))	('-519d-3p', 'Chemical', '-', (55, 63))	('NSCLC tumors', 'Disease', 'MESH:D009369', (145, 157))	('circ_0007385', 'Chemical', '-', (199, 211))	('-519d-3p', 'Chemical', '-', (251, 259))	('miR-519d', 'Gene', '574480', (52, 60))	('HMGB1', 'Gene', (238, 243))	('regulate', 'Reg', (229, 237))	('expression', 'MPA', (98, 108))
116257	32602212	Functionally, both inhibiting miR-519d-3p and restoring HMGB1 could overturn the suppressive effect of circ_0007385 knockdown on cell proliferation, migration, invasion, and DDP resistance.	('cell proliferation', 'CPA', (129, 147))	('inhibiting', 'NegReg', (19, 29))	('-519d-3p', 'Chemical', '-', (33, 41))	('circ_0007385', 'Chemical', '-', (103, 115))	('invasion', 'CPA', (160, 168))	('migration', 'CPA', (149, 158))	('restoring', 'PosReg', (46, 55))	('HMGB1', 'Gene', (56, 61))	('miR-519d', 'Gene', (30, 38))	('knockdown', 'Var', (116, 125))	('miR-519d', 'Gene', '574480', (30, 38))	('overturn', 'NegReg', (68, 76))	('DDP', 'Chemical', '-', (174, 177))	('DDP resistance', 'CPA', (174, 188))
116258	32602212	Collectively, circ_0007385 deletion could function anti-tumor role in NSCLC by suppressing malignant behaviors and DDP resistance in vitro and in vivo via circ_0007385/miR-519d-3p/HMGB1 axis.	('circ_0007385', 'Chemical', '-', (155, 167))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('circ_0007385', 'Chemical', '-', (14, 26))	('NSCLC', 'Disease', (70, 75))	('tumor', 'Disease', (56, 61))	('-519d-3p', 'Chemical', '-', (171, 179))	('DDP', 'Chemical', '-', (115, 118))	('DDP', 'MPA', (115, 118))	('suppressing', 'NegReg', (79, 90))	('miR-519d', 'Gene', '574480', (168, 176))	('NSCLC', 'Disease', 'MESH:D002289', (70, 75))	('malignant behaviors', 'Disease', 'MESH:D009369', (91, 110))	('malignant behaviors', 'Disease', (91, 110))	('miR-519d', 'Gene', (168, 176))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('circ_0007385 deletion', 'Var', (14, 35))
116260	32602212	circ_0007385 was upregulated in NSCLC tissues and cells, and was associated with poor overall survival.	('circ_0007385', 'Var', (0, 12))	('upregulated', 'PosReg', (17, 28))	('poor', 'NegReg', (81, 85))	('associated', 'Reg', (65, 75))	('NSCLC', 'Disease', (32, 37))	('NSCLC', 'Disease', 'MESH:D002289', (32, 37))	('circ_0007385', 'Chemical', '-', (0, 12))
116261	32602212	Silenced circ_0007385 suppressed NSCLC cell proliferation, migration, invasion, and DDP resistance in vitro, and tumor growth in vivo.	('tumor', 'Disease', (113, 118))	('suppressed', 'NegReg', (22, 32))	('circ_0007385', 'Chemical', '-', (9, 21))	('circ_0007385', 'Var', (9, 21))	('DDP resistance', 'CPA', (84, 98))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('NSCLC', 'Disease', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('migration', 'CPA', (59, 68))	('NSCLC', 'Disease', 'MESH:D002289', (33, 38))	('DDP', 'Chemical', '-', (84, 87))	('invasion', 'CPA', (70, 78))
116276	32602212	The hsa_circ_0007385 (circ_0007385) is derived from host gene MEMO1, and has been declared to be upregulated in NSCLC tissues and cells.	('MEMO1', 'Gene', '51072', (62, 67))	('NSCLC', 'Disease', (112, 117))	('circ_0007385', 'Chemical', '-', (8, 20))	('MEMO1', 'Gene', (62, 67))	('circ_0007385', 'Chemical', '-', (22, 34))	('circ_0007385', 'Var', (22, 34))	('upregulated', 'PosReg', (97, 108))	('NSCLC', 'Disease', 'MESH:D002289', (112, 117))
116277	32602212	19  In this study, we intended to determine the role of circ_0007385 in malignant behaviors and DDP resistance of NSCLC cells.	('circ_0007385', 'Chemical', '-', (56, 68))	('DDP', 'Chemical', '-', (96, 99))	('malignant behaviors', 'Disease', (72, 91))	('NSCLC', 'Disease', (114, 119))	('circ_0007385', 'Var', (56, 68))	('NSCLC', 'Disease', 'MESH:D002289', (114, 119))	('malignant behaviors', 'Disease', 'MESH:D009369', (72, 91))
116278	32602212	Furthermore, the cross-talk among circ_0007385, miR-519d-3p and high-mobility group box 1 (HMGB1) was revealed.	('circ_0007385', 'Var', (34, 46))	('high-mobility group box 1', 'Gene', (64, 89))	('high-mobility group box 1', 'Gene', '3146', (64, 89))	('-519d-3p', 'Chemical', '-', (51, 59))	('cross-talk', 'Reg', (17, 27))	('miR-519d', 'Gene', '574480', (48, 56))	('miR-519d', 'Gene', (48, 56))	('circ_0007385', 'Chemical', '-', (34, 46))
116301	32602212	After blocking in 5% skin milk, the membranes were incubated in primary antibodies from Proteintech (Deansgate, Manchester, UK) including anti-HMGB1 (10829-1-AP, 1: 2000), antiproliferating cell nuclear antigen (PCNA; 10 205-2-AP, 1: 10000), anti-E-cadherin (E-cad; 20 874-1-AP, 1: 50000), anti-N-cadherin (N-cad; 22 018-1-AP, 1: 10000), and anti-GAPDH (10494-1-AP, 1: 40000) at 4 C for overnight, and in secondary antibody anti-rabbit IgG-HRP (sc-2357, 1: 5000) from Santa Cruz (Shanghai, China) at room temperature for 2 hours.	('N-cad', 'Gene', (307, 312))	('N-cad', 'Gene', '1000', (307, 312))	('N-cadherin', 'Gene', '1000', (295, 305))	('GAPDH', 'Gene', '2597', (347, 352))	('E-cad', 'Gene', (259, 264))	('GAPDH', 'Gene', (347, 352))	('PCNA', 'Gene', (212, 216))	('E-cad', 'Gene', '999', (247, 252))	('N-cad', 'Gene', '1000', (295, 300))	('N-cad', 'Gene', (295, 300))	('E-cadherin', 'Gene', (247, 257))	('10494-1-AP', 'Var', (354, 364))	('PCNA', 'Gene', '5111', (212, 216))	('E-cad', 'Gene', '999', (259, 264))	('E-cad', 'Gene', (247, 252))	('E-cadherin', 'Gene', '999', (247, 257))	('N-cadherin', 'Gene', (295, 305))
116307	32602212	Then, the putative binding sites of miR-519d-3p in circ_0007385 and HMGB1 3'UTR were mutated, and their mutated-type (MUT) vectors (circ_0007385 MUT and HMGB1 3'UTR MUT) were similarly constructed.	('circ_0007385', 'Chemical', '-', (51, 63))	('miR-519d', 'Gene', (36, 44))	('circ_0007385', 'Chemical', '-', (132, 144))	('HMGB1', 'Gene', (68, 73))	('-519d-3p', 'Chemical', '-', (39, 47))	('mutated', 'Var', (85, 92))	('miR-519d', 'Gene', '574480', (36, 44))
116308	32602212	A549 and H1975 cells were passaged in a 24-well plate at a density of 5 x 104 cells/well, and cotransfected with miR-519d-3p/NC mimic (10 muM) and either circ_0007385 WT/MUT (300 ng) or HMGB1 3'UTR WT/MUT (300 ng) using Lipofectamine 3000 reagent (Invitrogen) according to the manufacturer's instruction.	('circ_0007385', 'Chemical', '-', (154, 166))	('Lipofectamine 3000', 'Chemical', '-', (220, 238))	('circ_0007385', 'Var', (154, 166))	('A549', 'CellLine', 'CVCL:0023', (0, 4))	('miR-519d', 'Gene', '574480', (113, 121))	('-519d-3p', 'Chemical', '-', (116, 124))	('H1975', 'CellLine', 'CVCL:1511', (9, 14))	('miR-519d', 'Gene', (113, 121))	('HMGB1', 'Gene', (186, 191))
116315	32602212	The expression of circ_0007385 in tissues was detected using RT-qPCR, and circ_0007385 level was higher in NSCLC tumors (Fig 1a), and was even higher in advanced tumors (III + IV stages; n = 43) (Fig 1b).	('circ_0007385', 'Chemical', '-', (18, 30))	('higher', 'PosReg', (97, 103))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('tumors', 'Disease', (113, 119))	('NSCLC tumors', 'Disease', (107, 119))	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('higher', 'PosReg', (143, 149))	('circ_0007385', 'Chemical', '-', (74, 86))	('tumors', 'Disease', (162, 168))	('tumors', 'Disease', 'MESH:D009369', (162, 168))	('circ_0007385', 'Var', (74, 86))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('NSCLC tumors', 'Disease', 'MESH:D009369', (107, 119))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
116316	32602212	Moreover, the five-year overall survival of these NSCLC patients was about 18% in the circ_0007385 high expression group (>=mean, n = 39; Fig 1c), and about 39% in the circ_0007385 low expression group (<mean, n = 36; Fig 1c).	('circ_0007385', 'Chemical', '-', (168, 180))	('patients', 'Species', '9606', (56, 64))	('circ_0007385', 'Chemical', '-', (86, 98))	('NSCLC', 'Disease', (50, 55))	('circ_0007385 high', 'Var', (86, 103))	('NSCLC', 'Disease', 'MESH:D002289', (50, 55))
116317	32602212	Expression of circ_0007385 in human NSCLC cell lines was also detected, and RT-qPCR data showed an overall upregulation of circ_0007385 in A549, HCC827, H1975, and H2342 cells versus 16HBE (Fig 1d).	('upregulation', 'PosReg', (107, 119))	('human', 'Species', '9606', (30, 35))	('circ_0007385', 'Chemical', '-', (14, 26))	('H1975', 'CellLine', 'CVCL:1511', (153, 158))	('A549', 'CellLine', 'CVCL:0023', (139, 143))	('NSCLC', 'Disease', (36, 41))	('HCC827', 'CellLine', 'CVCL:2063', (145, 151))	('circ_0007385', 'Chemical', '-', (123, 135))	('NSCLC', 'Disease', 'MESH:D002289', (36, 41))	('circ_0007385', 'Var', (123, 135))
116318	32602212	These results indicated that circ_0007385 was deregulated in NSCLC tissues and cells, suggesting a potential biological role of circ_0007385 in malignant progression of NSCLC cells.	('circ_0007385', 'Chemical', '-', (128, 140))	('NSCLC', 'Disease', (169, 174))	('circ_0007385', 'Var', (128, 140))	('circ_0007385', 'Chemical', '-', (29, 41))	('NSCLC', 'Disease', 'MESH:D002289', (169, 174))	('NSCLC', 'Disease', (61, 66))	('NSCLC', 'Disease', 'MESH:D002289', (61, 66))	('circ_0007385', 'Gene', (29, 41))
116320	32602212	As shown in Fig 2a, circ_0007385 level was significantly lowered in A549 and H1975 cells with sh-circ transfection.	('lowered', 'NegReg', (57, 64))	('sh-circ transfection', 'Var', (94, 114))	('H1975', 'CellLine', 'CVCL:1511', (77, 82))	('A549', 'CellLine', 'CVCL:0023', (68, 72))	('circ_0007385 level', 'MPA', (20, 38))	('circ_0007385', 'Chemical', '-', (20, 32))
116322	32602212	CCK-8 assay displayed a decrease of cell viability in circ_0007385-downregulated cells, compared to sh-NC-transfected cells (Fig 2b and c).	('circ_0007385-downregulated', 'Var', (54, 80))	('circ_0007385', 'Chemical', '-', (54, 66))	('decrease', 'NegReg', (24, 32))	('cell viability', 'CPA', (36, 50))	('CCK-', 'Chemical', '-', (0, 4))
116323	32602212	In addition, western blotting result showed an increase of E-cad, and a decrease of PCNA and N-cad in response to sh-circ transfection in A549 and H1975 cells (Fig 2f).	('H1975', 'CellLine', 'CVCL:1511', (147, 152))	('PCNA', 'Gene', (84, 88))	('A549', 'CellLine', 'CVCL:0023', (138, 142))	('N-cad', 'Gene', '1000', (93, 98))	('E-cad', 'Gene', '999', (59, 64))	('sh-circ transfection', 'Var', (114, 134))	('PCNA', 'Gene', '5111', (84, 88))	('E-cad', 'Gene', (59, 64))	('increase', 'PosReg', (47, 55))	('decrease', 'NegReg', (72, 80))	('N-cad', 'Gene', (93, 98))
116324	32602212	These data together demonstrated that circ_0007385 knockdown could depress cell proliferation, migration and invasion in NSCLC cells in vitro.	('circ_0007385', 'Chemical', '-', (38, 50))	('circ_0007385 knockdown', 'Var', (38, 60))	('invasion', 'CPA', (109, 117))	('NSCLC', 'Disease', (121, 126))	('depress', 'NegReg', (67, 74))	('cell proliferation', 'CPA', (75, 93))	('NSCLC', 'Disease', 'MESH:D002289', (121, 126))	('migration', 'CPA', (95, 104))	('knockdown', 'Var', (51, 60))
116326	32602212	With treatment of 2.5, 5, 10, 20, 40, and 80 muM of DDP, cell viability inhibition was observed in transfected A549 and H1975 cells; moreover, IC50 of DDP was reduced by sh-circ transfection from 10.39 to 5.92 muM in A549 cells, and from 13.69 to 7.77 muM in H1975 cells (Fig 3a and b).	('DDP', 'Chemical', '-', (151, 154))	('A549', 'CellLine', 'CVCL:0023', (217, 221))	('reduced', 'NegReg', (159, 166))	('H1975', 'CellLine', 'CVCL:1511', (259, 264))	('A549', 'CellLine', 'CVCL:0023', (111, 115))	('DDP', 'Chemical', '-', (52, 55))	('cell viability', 'CPA', (57, 71))	('sh-circ transfection', 'Var', (170, 190))	('IC50', 'MPA', (143, 147))	('H1975', 'CellLine', 'CVCL:1511', (120, 125))	('DDP', 'Var', (151, 154))
116327	32602212	Moreover, circ_0007385 deletion enhanced apoptosis rate (Fig 3c and d) and caspase-3 activity (Fig 3e and f) in A549 and H1975 cells with 5 muM of DDP treatment.	('A549', 'CellLine', 'CVCL:0023', (112, 116))	('caspase-3', 'Gene', '836', (75, 84))	('circ_0007385', 'Chemical', '-', (10, 22))	('DDP', 'Chemical', '-', (147, 150))	('H1975', 'CellLine', 'CVCL:1511', (121, 126))	('caspase-3', 'Gene', (75, 84))	('enhanced', 'PosReg', (32, 40))	('activity', 'MPA', (85, 93))	('apoptosis rate', 'CPA', (41, 55))	('circ_0007385 deletion', 'Var', (10, 31))
116328	32602212	These data suggested a suppression of circ_0007385 knockdown on DDP resistance in NSCLC cells in vitro.	('circ_0007385', 'Chemical', '-', (38, 50))	('DDP', 'Chemical', '-', (64, 67))	('NSCLC', 'Disease', 'MESH:D002289', (82, 87))	('circ_0007385', 'Gene', (38, 50))	('suppression', 'NegReg', (23, 34))	('DDP resistance in', 'MPA', (64, 81))	('NSCLC', 'Disease', (82, 87))	('knockdown', 'Var', (51, 60))
116334	32602212	Thereby, we speculated that circ_0007385 modulate the malignant progression of NSCLC cells by directly regulating miR-519d-3p expression.	('malignant progression', 'CPA', (54, 75))	('NSCLC', 'Disease', 'MESH:D002289', (79, 84))	('circ_0007385', 'Var', (28, 40))	('regulating', 'Reg', (103, 113))	('miR-519d', 'Gene', '574480', (114, 122))	('-519d-3p', 'Chemical', '-', (117, 125))	('modulate', 'Reg', (41, 49))	('miR-519d', 'Gene', (114, 122))	('NSCLC', 'Disease', (79, 84))	('circ_0007385', 'Chemical', '-', (28, 40))
116335	32602212	The anti-miR-519d-3p was used to delete miR-519d-3p expression in A549 and H1975 cells, and RT-qPCR further validated this silencing efficiency (Fig 5a).	('miR-519d', 'Gene', (9, 17))	('miR-519d', 'Gene', (40, 48))	('miR-519d', 'Gene', '574480', (40, 48))	('-519d-3p', 'Chemical', '-', (43, 51))	('A549', 'CellLine', 'CVCL:0023', (66, 70))	('delete', 'Var', (33, 39))	('H1975', 'CellLine', 'CVCL:1511', (75, 80))	('miR-519d', 'Gene', '574480', (9, 17))	('-519d-3p', 'Chemical', '-', (12, 20))
116336	32602212	Cell proliferation was inhibited by circ_0007385 downregulation in A549 and H1975 cells, which was abolished by the presence of anti-miR-519d-3p, as described by improved cell viability (Fig 5b and c) and PCNA expression (Fig 5f).	('PCNA', 'Gene', '5111', (205, 209))	('inhibited', 'NegReg', (23, 32))	('PCNA', 'Gene', (205, 209))	('miR-519d', 'Gene', '574480', (133, 141))	('H1975', 'CellLine', 'CVCL:1511', (76, 81))	('improved', 'PosReg', (162, 170))	('miR-519d', 'Gene', (133, 141))	('-519d-3p', 'Chemical', '-', (136, 144))	('circ_0007385', 'Chemical', '-', (36, 48))	('circ_0007385', 'Var', (36, 48))	('downregulation', 'NegReg', (49, 63))	('A549', 'CellLine', 'CVCL:0023', (67, 71))	('cell viability', 'CPA', (171, 185))	('Cell proliferation', 'CPA', (0, 18))
116337	32602212	Cell migration and invasion were also restrained by circ_0007385 silencing, and then rescued by anti-miR-519d-3p transfection, as evidenced by higher numbers of transwell migratory and invasive cells (Fig 5d and e), increased N-cad expression, and decreased E-cad level (Fig 5f).	('Cell migration', 'CPA', (0, 14))	('miR-519d', 'Gene', (101, 109))	('invasion', 'CPA', (19, 27))	('E-cad', 'Gene', '999', (258, 263))	('circ_0007385', 'Chemical', '-', (52, 64))	('circ_0007385 silencing', 'Var', (52, 74))	('N-cad', 'Gene', (226, 231))	('decreased', 'NegReg', (248, 257))	('N-cad', 'Gene', '1000', (226, 231))	('higher', 'PosReg', (143, 149))	('E-cad', 'Gene', (258, 263))	('expression', 'MPA', (232, 242))	('restrained', 'NegReg', (38, 48))	('increased', 'PosReg', (216, 225))	('miR-519d', 'Gene', '574480', (101, 109))	('-519d-3p', 'Chemical', '-', (104, 112))
116338	32602212	On the contrary, the promotion of circ_0007385 knockdown on DDP sensitivity was abrogated by the deletion of miR-519d-3p, as depicted by elevated IC50 (Fig 5g), and descended apoptosis rate (Fig 5h) and caspase-3 activity (Fig 5i and j).	('promotion', 'PosReg', (21, 30))	('activity', 'MPA', (213, 221))	('miR-519d', 'Gene', '574480', (109, 117))	('abrogated', 'NegReg', (80, 89))	('IC50', 'MPA', (146, 150))	('caspase-3', 'Gene', '836', (203, 212))	('miR-519d', 'Gene', (109, 117))	('DDP', 'Disease', (60, 63))	('-519d-3p', 'Chemical', '-', (112, 120))	('apoptosis rate', 'CPA', (175, 189))	('elevated', 'PosReg', (137, 145))	('descended', 'PosReg', (165, 174))	('DDP', 'Chemical', '-', (60, 63))	('caspase-3', 'Gene', (203, 212))	('deletion', 'Var', (97, 105))	('circ_0007385', 'Chemical', '-', (34, 46))
116339	32602212	Collectively, these outcomes showed that miR-519d-3p inhibition could overturn the suppressive effect of circ_0007385 knockdown on cell proliferation, migration, invasion, and DDP resistance in A549 and H1975 cells, suggesting the role of circ_0007385 in the malignant progression of NSCLC cells by sponging miR-519d-3p.	('-519d-3p', 'Chemical', '-', (44, 52))	('knockdown', 'Var', (118, 127))	('miR-519d', 'Gene', '574480', (41, 49))	('miR-519d', 'Gene', (41, 49))	('NSCLC', 'Disease', 'MESH:D002289', (284, 289))	('invasion', 'CPA', (162, 170))	('migration', 'CPA', (151, 160))	('H1975', 'CellLine', 'CVCL:1511', (203, 208))	('overturn', 'NegReg', (70, 78))	('DDP resistance', 'CPA', (176, 190))	('circ_0007385', 'Chemical', '-', (105, 117))	('NSCLC', 'Disease', (284, 289))	('miR-519d', 'Gene', '574480', (308, 316))	('miR-519d', 'Gene', (308, 316))	('DDP', 'Chemical', '-', (176, 179))	('-519d-3p', 'Chemical', '-', (311, 319))	('circ_0007385', 'Chemical', '-', (239, 251))	('cell proliferation', 'CPA', (131, 149))	('A549', 'CellLine', 'CVCL:0023', (194, 198))
116345	32602212	These data suggested that circ_0007385 could affect HMGB1 via sponging miR-519d-3p in NSCLC cells.	('affect', 'Reg', (45, 51))	('miR-519d', 'Gene', '574480', (71, 79))	('-519d-3p', 'Chemical', '-', (74, 82))	('NSCLC', 'Disease', (86, 91))	('miR-519d', 'Gene', (71, 79))	('NSCLC', 'Disease', 'MESH:D002289', (86, 91))	('HMGB1', 'Gene', (52, 57))	('circ_0007385', 'Chemical', '-', (26, 38))	('circ_0007385', 'Var', (26, 38))
116348	32602212	In addition, the suppression of circ_0007385 knockdown on DDP resistance was also counteracted with the administration of HMGB1 overexpression vector, as manifested by recovered IC50 (Fig 7g), and declined apoptosis rate (Fig 7h) and caspase-3 activity (Fig 7i and j).	('recovered', 'PosReg', (168, 177))	('caspase-3', 'Gene', '836', (234, 243))	('activity', 'MPA', (244, 252))	('IC50', 'MPA', (178, 182))	('declined', 'NegReg', (197, 205))	('DDP', 'Chemical', '-', (58, 61))	('circ_0007385', 'Chemical', '-', (32, 44))	('circ_0007385', 'Var', (32, 44))	('DDP resistance', 'MPA', (58, 72))	('apoptosis rate', 'CPA', (206, 220))	('caspase-3', 'Gene', (234, 243))	('suppression', 'NegReg', (17, 28))	('knockdown', 'Var', (45, 54))
116349	32602212	These results suggested that circ_0007385 silencing suppressed malignant behaviors and DDP resistance of NSCLC cells in vitro by downregulating HMGB1 via miR-519d-3p.	('NSCLC', 'Disease', 'MESH:D002289', (105, 110))	('silencing', 'Var', (42, 51))	('DDP resistance', 'CPA', (87, 101))	('malignant behaviors', 'Disease', 'MESH:D009369', (63, 82))	('malignant behaviors', 'Disease', (63, 82))	('miR-519d', 'Gene', '574480', (154, 162))	('HMGB1', 'Gene', (144, 149))	('-519d-3p', 'Chemical', '-', (157, 165))	('circ_0007385', 'Chemical', '-', (29, 41))	('DDP', 'Chemical', '-', (87, 90))	('miR-519d', 'Gene', (154, 162))	('suppressed', 'NegReg', (52, 62))	('NSCLC', 'Disease', (105, 110))	('downregulating', 'NegReg', (129, 143))
116351	32602212	Tumor growth of A549 cells in mice was dramatically retarded in the sh-circ group compared with the sh-NC group, as indicated by decreased tumor volume (Fig 8a) and tumor weight (Fig 8b).	('decreased tumor', 'Disease', 'MESH:D002303', (129, 144))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('mice', 'Species', '10090', (30, 34))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('retarded', 'NegReg', (52, 60))	('A549', 'CellLine', 'CVCL:0023', (16, 20))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('decreased tumor', 'Disease', (129, 144))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('sh-circ', 'Var', (68, 75))	('Tumor growth', 'CPA', (0, 12))	('tumor', 'Disease', (165, 170))
116352	32602212	Molecularly, sh-circ transfection led to circ_0007385 knockdown in the tissues from neoplasm (Fig 8c), accompanied with miR-519d-3p upregulation (Fig 8d) and HMGB1 protein downregulation (Fig 8e).	('protein', 'Protein', (164, 171))	('HMGB1', 'Gene', (158, 163))	('knockdown', 'Var', (54, 63))	('upregulation', 'PosReg', (132, 144))	('-519d-3p', 'Chemical', '-', (123, 131))	('circ_0007385', 'Gene', (41, 53))	('neoplasm', 'Disease', (84, 92))	('downregulation', 'NegReg', (172, 186))	('miR-519d', 'Gene', (120, 128))	('miR-519d', 'Gene', '574480', (120, 128))	('neoplasm', 'Phenotype', 'HP:0002664', (84, 92))	('neoplasm', 'Disease', 'MESH:D009369', (84, 92))	('circ_0007385', 'Chemical', '-', (41, 53))
116353	32602212	These data demonstrated that circ_0007385 knockdown retarded tumor growth of NSCLC cells in vivo partially through synergistically regulating miR-519d-3p and HMGB1.	('NSCLC', 'Disease', 'MESH:D002289', (77, 82))	('HMGB1', 'Gene', (158, 163))	('retarded tumor', 'Disease', 'MESH:D009369', (52, 66))	('-519d-3p', 'Chemical', '-', (145, 153))	('retarded tumor', 'Disease', (52, 66))	('circ_0007385', 'Chemical', '-', (29, 41))	('miR-519d', 'Gene', '574480', (142, 150))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('circ_0007385', 'Var', (29, 41))	('NSCLC', 'Disease', (77, 82))	('regulating', 'Reg', (131, 141))	('miR-519d', 'Gene', (142, 150))
116358	32602212	19 ,  26  Moreover, RNA sequencing analyses profiled circRNA expression patterns in 10 pairs of LUAD and lung squamous cell carcinoma (LUSC), two subtypes of NSCLC, and two circRNAs (hsa_circ_0001073 and hsa_circ_0001495) have been proposed to distinguish LUAD and LUSC.	('NSCLC', 'Disease', (158, 163))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (110, 133))	('LUAD', 'Disease', (96, 100))	('NSCLC', 'Disease', 'MESH:D002289', (158, 163))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('hsa_circ_0001073', 'Var', (183, 199))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (105, 133))	('LUAD', 'Disease', (256, 260))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (105, 133))	('lung squamous cell carcinoma', 'Disease', (105, 133))
116359	32602212	27  Functionally, multiple oncogenic circRNAs, such as circRNA ARHGAP10, circNT5E, and circ-ZKSCAN1, have been certified to contribute to NSCLC cell proliferation and metastasis in vitro and in vivo; 26 ,  28 ,  29  DDP resistance in NSCLC cells has also been declared to be affected by several circRNAs, including circ-SMARCA5, circ_0076305 and circ_0001946.	('ZKSCAN1', 'Gene', '7586', (92, 99))	('circ_0076305', 'Var', (329, 341))	('NSCLC', 'Disease', (234, 239))	('DDP', 'Chemical', '-', (216, 219))	('NSCLC', 'Disease', (138, 143))	('NSCLC', 'Disease', 'MESH:D002289', (234, 239))	('SMARCA5', 'Gene', '8467', (320, 327))	('NSCLC', 'Disease', 'MESH:D002289', (138, 143))	('ARHGAP10', 'Gene', '79658', (63, 71))	('metastasis', 'CPA', (167, 177))	('circ_0001946', 'Var', (346, 358))	('ARHGAP10', 'Gene', (63, 71))	('SMARCA5', 'Gene', (320, 327))	('ZKSCAN1', 'Gene', (92, 99))
116360	32602212	30 ,  31 ,  32   According to the findings of Jiang et al., 19  circ_0007385 might function as an oncogene in NSCLC carcinogenesis, and miR-181 was a target of circ_0007385.	('NSCLC carcinogenesis', 'Disease', (110, 130))	('NSCLC carcinogenesis', 'Disease', 'MESH:D063646', (110, 130))	('circ_0007385', 'Chemical', '-', (160, 172))	('circ_0007385', 'Chemical', '-', (64, 76))	('circ_0007385', 'Var', (64, 76))
116361	32602212	Here, we reported the upregulation of circ_0007385 in NSCLC tissues and cell lines, and discovered a suppressive effect of circ_0007385 deletion on cell proliferation, migration and invasion in A549 and H1975 cells, and tumor growth in vivo.	('H1975', 'CellLine', 'CVCL:1511', (203, 208))	('migration', 'CPA', (168, 177))	('circ_0007385', 'Chemical', '-', (38, 50))	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('suppressive', 'NegReg', (101, 112))	('circ_0007385', 'Gene', (123, 135))	('tumor', 'Disease', (220, 225))	('deletion', 'Var', (136, 144))	('cell proliferation', 'CPA', (148, 166))	('A549', 'CellLine', 'CVCL:0023', (194, 198))	('upregulation', 'PosReg', (22, 34))	('NSCLC', 'Disease', (54, 59))	('circ_0007385', 'Chemical', '-', (123, 135))	('tumor', 'Disease', 'MESH:D009369', (220, 225))	('invasion', 'CPA', (182, 190))	('NSCLC', 'Disease', 'MESH:D002289', (54, 59))
116364	32602212	Furthermore, we noticed that circ_0007385 knockdown suppressed DDP resistance of NSCLC cells in vitro, as evidenced by the lowered IC50 of DDP, and elevated DDP-induced apoptosis rate and caspase-3 activity in A549 and H1975 cells.	('elevated', 'PosReg', (148, 156))	('caspase-3', 'Gene', '836', (188, 197))	('DDP', 'Chemical', '-', (157, 160))	('A549', 'CellLine', 'CVCL:0023', (210, 214))	('lowered', 'NegReg', (123, 130))	('IC50', 'MPA', (131, 135))	('circ_0007385', 'Chemical', '-', (29, 41))	('DDP', 'Chemical', '-', (63, 66))	('caspase-3', 'Gene', (188, 197))	('activity', 'MPA', (198, 206))	('suppressed', 'NegReg', (52, 62))	('NSCLC', 'Disease', (81, 86))	('circ_0007385', 'Var', (29, 41))	('DDP-induced', 'MPA', (157, 168))	('DDP', 'Chemical', '-', (139, 142))	('NSCLC', 'Disease', 'MESH:D002289', (81, 86))	('DDP resistance', 'MPA', (63, 77))	('H1975', 'CellLine', 'CVCL:1511', (219, 224))
116365	32602212	Clinically, we discovered that low expression of circ_0007385 might predict a relative better overall survival in NSCLC patients, hinting a potential biomarker of circ_0007385 for the prognosis of NSCLC tumors.	('better', 'PosReg', (87, 93))	('circ_0007385', 'Chemical', '-', (49, 61))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('circ_0007385', 'Var', (49, 61))	('NSCLC tumors', 'Disease', 'MESH:D009369', (197, 209))	('overall survival', 'MPA', (94, 110))	('NSCLC tumors', 'Disease', (197, 209))	('circ_0007385', 'Chemical', '-', (163, 175))	('tumors', 'Phenotype', 'HP:0002664', (203, 209))	('expression', 'MPA', (35, 45))	('NSCLC', 'Disease', (114, 119))	('NSCLC', 'Disease', (197, 202))	('NSCLC', 'Disease', 'MESH:D002289', (114, 119))	('patients', 'Species', '9606', (120, 128))	('low', 'NegReg', (31, 34))	('NSCLC', 'Disease', 'MESH:D002289', (197, 202))
116366	32602212	Therefore, we established a circ_0007385/miR-519d-3p/HMGB1 pathway underlying the oncogenic role of circ_0007385 in NSCLC.	('NSCLC', 'Disease', 'MESH:D002289', (116, 121))	('-519d-3p', 'Chemical', '-', (44, 52))	('circ_0007385', 'Var', (100, 112))	('miR-519d', 'Gene', '574480', (41, 49))	('miR-519d', 'Gene', (41, 49))	('NSCLC', 'Disease', (116, 121))	('circ_0007385', 'Chemical', '-', (100, 112))	('circ_0007385', 'Chemical', '-', (28, 40))
116374	32602212	More importantly, we validated circ_0007385 as a novel ceRNA for miR-519d-3p, and HMGB1 as a new downstream target of miR-519d-3p.	('miR-519d', 'Gene', (118, 126))	('circ_0007385', 'Var', (31, 43))	('-519d-3p', 'Chemical', '-', (68, 76))	('-519d-3p', 'Chemical', '-', (121, 129))	('miR-519d', 'Gene', '574480', (65, 73))	('miR-519d', 'Gene', '574480', (118, 126))	('miR-519d', 'Gene', (65, 73))	('HMGB1', 'Gene', (82, 87))	('circ_0007385', 'Chemical', '-', (31, 43))
116378	32602212	Functionally and mechanically, HMGB1 has been previously described to be a downstream target of miRNAs in NSCLC cell proliferation, migration and invasion, such as miR-520a-3p, miR-449a and miR-200c.	('miR-520a-3p', 'Var', (164, 175))	('NSCLC', 'Disease', 'MESH:D002289', (106, 111))	('miR-449a', 'Gene', '554213', (177, 185))	('miR-200c', 'Gene', (190, 198))	('miR-200c', 'Gene', '406985', (190, 198))	('migration', 'CPA', (132, 141))	('HMGB1', 'Gene', (31, 36))	('miR-449a', 'Gene', (177, 185))	('NSCLC', 'Disease', (106, 111))	('invasion', 'CPA', (146, 154))
116386	32602212	In conclusion, this study demonstrated that circ_0007385 was upregulated in NSCLC tissues and cells, and its high expression could predict a shorter five-year overall survival.	('upregulated', 'PosReg', (61, 72))	('NSCLC', 'Disease', (76, 81))	('shorter', 'NegReg', (141, 148))	('circ_0007385', 'Chemical', '-', (44, 56))	('NSCLC', 'Disease', 'MESH:D002289', (76, 81))	('circ_0007385', 'Var', (44, 56))
116387	32602212	The silencing of circ_0007385 could suppress cell proliferation, migration, invasion, and DDP resistance in NSCLC cells in vitro through regulating miR-519d-3p/HMGB1 axis, accompanied with tumor growth inhibition in vivo.	('migration', 'CPA', (65, 74))	('tumor', 'Disease', (189, 194))	('miR-519d', 'Gene', (148, 156))	('circ_0007385', 'Gene', (17, 29))	('DDP resistance', 'CPA', (90, 104))	('suppress', 'NegReg', (36, 44))	('cell proliferation', 'CPA', (45, 63))	('NSCLC', 'Disease', (108, 113))	('regulating', 'Reg', (137, 147))	('miR-519d', 'Gene', '574480', (148, 156))	('DDP', 'Chemical', '-', (90, 93))	('-519d-3p', 'Chemical', '-', (151, 159))	('NSCLC', 'Disease', 'MESH:D002289', (108, 113))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('circ_0007385', 'Chemical', '-', (17, 29))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('silencing', 'Var', (4, 13))	('invasion', 'CPA', (76, 84))
116395	32110039	EFEMP2 overexpression significantly inhibited the invasion of lung cancer cells, hampered the process of EMT, and decreased the expression and activity of MMP2 and MMP9, while EFEMP2 knockdown remarkably enhanced the invasion of lung cancer cells, promoted EMT, and increased the expression and activity of MMP2 and MMP9.	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('invasion of lung cancer', 'Disease', 'MESH:D008175', (217, 240))	('MMP2', 'Gene', (155, 159))	('process of EMT', 'CPA', (94, 108))	('decreased', 'NegReg', (114, 123))	('activity', 'MPA', (295, 303))	('activity', 'MPA', (143, 151))	('MMP2', 'Gene', '4313', (307, 311))	('expression', 'MPA', (280, 290))	('hampered', 'NegReg', (81, 89))	('invasion of lung cancer', 'Disease', 'MESH:D008175', (50, 73))	('inhibited', 'NegReg', (36, 45))	('EFEMP2', 'Gene', (176, 182))	('MMP9', 'Gene', (316, 320))	('MMP9', 'Gene', '4318', (316, 320))	('invasion of lung cancer', 'Disease', (217, 240))	('increased', 'PosReg', (266, 275))	('expression', 'MPA', (128, 138))	('MMP2', 'Gene', '4313', (155, 159))	('MMP9', 'Gene', (164, 168))	('EMT', 'CPA', (257, 260))	('MMP9', 'Gene', '4318', (164, 168))	('lung cancer', 'Phenotype', 'HP:0100526', (62, 73))	('invasion of lung cancer', 'Disease', (50, 73))	('enhanced', 'PosReg', (204, 212))	('lung cancer', 'Phenotype', 'HP:0100526', (229, 240))	('knockdown', 'Var', (183, 192))	('MMP2', 'Gene', (307, 311))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('promoted', 'PosReg', (248, 256))
116412	32110039	EFEMP2 is a 443 amino acid secretory protein and contains of a N-terminal modified cbEGF module, five consecutive cbEGF modules and the FC domain.	('EFEMP2', 'Gene', (0, 6))	('modified', 'Var', (74, 82))	('EGF', 'Gene', (85, 88))	('EGF', 'Gene', '1950', (85, 88))	('EGF', 'Gene', (116, 119))	('EGF', 'Gene', '1950', (116, 119))
116413	32110039	Defects of EFEMP2 in patients have been linked to many diseases, such as autosomal recessive cutis laxa syndrome, aneurysms and tortuosity of the large arteries, developmental emphysema, diaphragmatic and inguinal hernia, joint laxity and cancer.	('tortuosity of the large arteries', 'Disease', (128, 160))	('joint laxity', 'Disease', (222, 234))	('patients', 'Species', '9606', (21, 29))	('developmental emphysema', 'Disease', 'MESH:D004646', (162, 185))	('inguinal hernia', 'Disease', 'MESH:D006552', (205, 220))	('EFEMP2', 'Gene', (11, 17))	('joint laxity', 'Disease', 'MESH:C535884', (222, 234))	('cancer', 'Disease', (239, 245))	('diaphragmatic', 'Disease', (187, 200))	('inguinal hernia', 'Phenotype', 'HP:0000023', (205, 220))	('hernia', 'Phenotype', 'HP:0100790', (214, 220))	('linked', 'Reg', (40, 46))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))	('developmental emphysema', 'Disease', (162, 185))	('aneurysms', 'Disease', 'MESH:D000783', (114, 123))	('Defects', 'Var', (0, 7))	('aneurysms', 'Disease', (114, 123))	('aneurysms', 'Phenotype', 'HP:0002617', (114, 123))	('autosomal recessive cutis laxa syndrome', 'Disease', 'MESH:C536225', (73, 112))	('autosomal recessive cutis laxa syndrome', 'Disease', (73, 112))	('joint laxity', 'Phenotype', 'HP:0001388', (222, 234))	('emphysema', 'Phenotype', 'HP:0002097', (176, 185))	('cancer', 'Disease', 'MESH:D009369', (239, 245))	('cutis laxa', 'Phenotype', 'HP:0000973', (93, 103))	('inguinal hernia', 'Disease', (205, 220))
116415	32110039	High expression of EFEMP2 was associated with tumor progress and poor prognosis in cervical carcinoma, ovarian carcinoma, glioblastoma and osteosarcoma.	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('cervical carcinoma', 'Disease', (83, 101))	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('High', 'Var', (0, 4))	('glioblastoma', 'Disease', 'MESH:D005909', (122, 134))	('EFEMP2', 'Gene', (19, 25))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (103, 120))	('osteosarcoma', 'Disease', (139, 151))	('osteosarcoma', 'Disease', 'MESH:D012516', (139, 151))	('associated', 'Reg', (30, 40))	('ovarian carcinoma', 'Disease', (103, 120))	('glioblastoma', 'Disease', (122, 134))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('tumor', 'Disease', (46, 51))	('glioblastoma', 'Phenotype', 'HP:0012174', (122, 134))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (103, 120))	('tumor', 'Disease', 'MESH:D009369', (46, 51))	('osteosarcoma', 'Phenotype', 'HP:0002669', (139, 151))	('cervical carcinoma', 'Disease', 'MESH:D002583', (83, 101))
116422	32110039	A549, H460, H1299, H1650 (human lung cancer cell lines), and BEAS-2B (normal lung epithelial cell line) were obtained from the Cell Resource Center of Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences.	('H1299', 'Var', (12, 17))	('H1650', 'CellLine', 'CVCL:1483', (19, 24))	('A549', 'CellLine', 'CVCL:0023', (0, 4))	('H460', 'CellLine', 'CVCL:0459', (6, 10))	('BEAS-2B', 'CellLine', 'CVCL:0168', (61, 68))	('human', 'Species', '9606', (26, 31))	('H1299', 'CellLine', 'CVCL:0060', (12, 17))	('lung cancer', 'Disease', 'MESH:D008175', (32, 43))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('lung cancer', 'Disease', (32, 43))	('lung cancer', 'Phenotype', 'HP:0100526', (32, 43))
116478	32110039	In one word, the prognosis of patients with high expression of EFEMP2 was significantly better than that with low expression of EFEMP2 (HR=0.77 (0.68-0.88), logrank P=5.7e-05).	('high expression', 'Var', (44, 59))	('EFEMP2', 'Gene', (63, 69))	('patients', 'Species', '9606', (30, 38))	('prognosis', 'CPA', (17, 26))	('better', 'PosReg', (88, 94))
116484	32110039	Next, by RT-qPCR (Figure 3C) and Western blotting (Figure 3D), we confirmed that the expression of EFEMP2 was remarkably down-regulated in BEAS-2B cells transfected with EFEMP2 shRNA, and there was no significant difference between the negative control shRNA transfected cells and the uninfected cells.	('expression', 'MPA', (85, 95))	('BEAS-2B', 'CellLine', 'CVCL:0168', (139, 146))	('EFEMP2', 'Var', (170, 176))	('down-regulated', 'NegReg', (121, 135))	('EFEMP2', 'Gene', (99, 105))
116485	32110039	For overexpression experiment, we also affirmed the successful and effective transfection in the lung cancer cell lines H1299 and H1650, with more than 80% GFP positive cells (Figure 4A and B) and up-regulation of EFEMP2 expression in EFEMP2 cDNA transfected cells at mRNA (Figure 4C and E) and protein (Figure 4D and F) levels.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('transfection', 'Var', (77, 89))	('H1650', 'CellLine', 'CVCL:1483', (130, 135))	('lung cancer', 'Disease', 'MESH:D008175', (97, 108))	('EFEMP2', 'Gene', (214, 220))	('expression', 'MPA', (221, 231))	('H1299', 'CellLine', 'CVCL:0060', (120, 125))	('up-regulation', 'PosReg', (197, 210))	('lung cancer', 'Disease', (97, 108))	('lung cancer', 'Phenotype', 'HP:0100526', (97, 108))
116497	32110039	The tumors formed by EFEMP2 shRNA-transfected BEAS-2B cells grew faster than that formed by the negative control cells, whereas the EFENP2 cDNA transfected group showed a clear delay in both tumor size and growth rate in vivo (Figure 7A).	('tumor', 'Disease', (4, 9))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('faster', 'PosReg', (65, 71))	('tumors', 'Disease', (4, 10))	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('growth rate', 'CPA', (206, 217))	('grew', 'CPA', (60, 64))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('tumor', 'Disease', (191, 196))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('EFEMP2', 'Var', (21, 27))	('BEAS-2B', 'CellLine', 'CVCL:0168', (46, 53))	('delay', 'NegReg', (177, 182))
116498	32110039	the subcutaneous tumors formed by EFEMP2 shRNA-transfected BEAS-2B cells were larger than that formed by the negative control cells, in contrast, the average subcutaneous tumor size in the EFENP2 cDNA transfected group was significantly smaller than that in the negative control group (Figure 7B).	('EFEMP2 shRNA-transfected', 'Var', (34, 58))	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('tumor', 'Disease', (17, 22))	('smaller', 'NegReg', (237, 244))	('tumors', 'Disease', (17, 23))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('BEAS-2B', 'CellLine', 'CVCL:0168', (59, 66))	('subcutaneous tumor', 'Phenotype', 'HP:0001482', (4, 22))	('EFENP2', 'Var', (189, 195))	('subcutaneous tumor', 'Phenotype', 'HP:0001482', (158, 176))	('subcutaneous tumors', 'Phenotype', 'HP:0001482', (4, 23))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', (171, 176))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
116499	32110039	Collectively, EFEMP2 knockdown could promote tumor formation and growth in the nude mice, whereas EFEMP2 up-regulation could inhibit tumor growth in vivo.	('inhibit', 'NegReg', (125, 132))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('promote', 'PosReg', (37, 44))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('growth', 'CPA', (65, 71))	('tumor', 'Disease', (45, 50))	('EFEMP2', 'Gene', (14, 20))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('up-regulation', 'PosReg', (105, 118))	('tumor', 'Disease', (133, 138))	('nude mice', 'Species', '10090', (79, 88))	('knockdown', 'Var', (21, 30))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('EFEMP2', 'Gene', (98, 104))
116503	32110039	MMPs can almost degrade various protein components in ECM, destroy the histological barrier of tumor cell invasion, and play a key role in tumor invasion and metastasis.	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('MMPs', 'Var', (0, 4))	('play', 'Reg', (120, 124))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('protein', 'Protein', (32, 39))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('metastasis', 'CPA', (158, 168))	('degrade', 'NegReg', (16, 23))	('tumor', 'Disease', (95, 100))	('destroy', 'NegReg', (59, 66))
116504	32110039	By RT-qPCR and MMP zymography assay, we found that the mRNA expression of MMP2 and MMP9 was significantly increased in EFEMP2 shRNA-transfected BEAS-2B cells (Figure 8B), and their activities were significantly higher in the EFEMP2 shRNA-transfected group than in the negative control group (Figure 8C).	('activities', 'MPA', (181, 191))	('MMP9', 'Gene', '4318', (83, 87))	('MMP9', 'Gene', (83, 87))	('higher', 'PosReg', (211, 217))	('MMP2', 'Gene', '4313', (74, 78))	('BEAS-2B', 'CellLine', 'CVCL:0168', (144, 151))	('mRNA expression', 'MPA', (55, 70))	('EFEMP2 shRNA-transfected', 'Var', (119, 143))	('MMP2', 'Gene', (74, 78))	('increased', 'PosReg', (106, 115))
116505	32110039	In summary, EFEMP2 knockdown could promote EMT and enhance the expression and activity of MMP2 and MMP9.	('knockdown', 'Var', (19, 28))	('enhance', 'PosReg', (51, 58))	('expression', 'MPA', (63, 73))	('MMP2', 'Gene', (90, 94))	('EFEMP2', 'Gene', (12, 18))	('promote', 'PosReg', (35, 42))	('EMT', 'CPA', (43, 46))	('activity', 'MPA', (78, 86))	('MMP2', 'Gene', '4313', (90, 94))	('MMP9', 'Gene', '4318', (99, 103))	('MMP9', 'Gene', (99, 103))
116511	32110039	EFEMP2 could hamper the process of EMT and reduce the activity of MMPs, and decelerate the proliferation and invasion capacity of lung cancer cells.	('lung cancer', 'Phenotype', 'HP:0100526', (130, 141))	('process of EMT', 'CPA', (24, 38))	('reduce', 'NegReg', (43, 49))	('decelerate', 'NegReg', (76, 86))	('MMPs', 'Protein', (66, 70))	('lung cancer', 'Disease', 'MESH:D008175', (130, 141))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('activity', 'MPA', (54, 62))	('EFEMP2', 'Var', (0, 6))	('invasion capacity', 'CPA', (109, 126))	('hamper', 'NegReg', (13, 19))	('lung cancer', 'Disease', (130, 141))
116512	32110039	The IHC results of lung tissues showed that the high expression rate of EFEMP2 in normal lung tissues was higher than that in lung cancer tissues, and EFEMP2 was highly expressed in well-differentiated carcinoma in contrast with poorly differentiated carcinoma.	('carcinoma', 'Disease', (202, 211))	('EFEMP2', 'Gene', (72, 78))	('expression rate', 'MPA', (53, 68))	('carcinoma', 'Disease', 'MESH:D002277', (202, 211))	('carcinoma', 'Disease', (251, 260))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('lung cancer', 'Disease', (126, 137))	('lung cancer', 'Phenotype', 'HP:0100526', (126, 137))	('carcinoma', 'Phenotype', 'HP:0030731', (202, 211))	('EFEMP2', 'Var', (151, 157))	('lung cancer', 'Disease', 'MESH:D008175', (126, 137))	('carcinoma', 'Disease', 'MESH:D002277', (251, 260))	('carcinoma', 'Phenotype', 'HP:0030731', (251, 260))
116513	32110039	The high expression of EFEMP2 was negatively associated with poor clinical pathological characteristics and prognosis of lung cancer.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('lung cancer', 'Disease', 'MESH:D008175', (121, 132))	('negatively', 'NegReg', (34, 44))	('lung cancer', 'Disease', (121, 132))	('lung cancer', 'Phenotype', 'HP:0100526', (121, 132))	('high', 'Var', (4, 8))	('EFEMP2', 'Gene', (23, 29))
116518	32110039	In 1999, EFEMP2 was first identified as a partner of mutant p53 interaction, also called MBP1 (Mutant p53-Binding Protein 1), and was considered as a candidate oncogene.	('MBP1', 'Gene', (89, 93))	('MBP1', 'Gene', '30008', (89, 93))	('Mutant p53-Binding Protein 1', 'Gene', '30008', (95, 123))	('p53', 'Gene', '7157', (102, 105))	('p53', 'Gene', (60, 63))	('mutant', 'Var', (53, 59))	('p53', 'Gene', (102, 105))	('Mutant p53-Binding Protein 1', 'Gene', (95, 123))	('interaction', 'Interaction', (64, 75))	('p53', 'Gene', '7157', (60, 63))
116524	32110039	In gliomas, EFEMP2 had the carcinogenic potential and its knockdown inhibited the growth and metastasis of cancer cells, high expression of EFEMP2 was related to the poor prognosis of glioblastoma.	('carcinogenic', 'Disease', (27, 39))	('EFEMP2', 'Gene', (12, 18))	('gliomas', 'Disease', (3, 10))	('metastasis of cancer', 'Disease', (93, 113))	('carcinogenic', 'Disease', 'MESH:D063646', (27, 39))	('inhibited', 'NegReg', (68, 77))	('gliomas', 'Disease', 'MESH:D005910', (3, 10))	('knockdown', 'Var', (58, 67))	('glioblastoma', 'Disease', 'MESH:D005909', (184, 196))	('expression', 'MPA', (126, 136))	('metastasis of cancer', 'Disease', 'MESH:D009362', (93, 113))	('glioma', 'Phenotype', 'HP:0009733', (3, 9))	('gliomas', 'Phenotype', 'HP:0009733', (3, 10))	('glioblastoma', 'Disease', (184, 196))	('glioblastoma', 'Phenotype', 'HP:0012174', (184, 196))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('related', 'Reg', (151, 158))	('EFEMP2', 'Gene', (140, 146))	('high', 'Var', (121, 125))
116532	32110039	Whether the high or low expression of EFEMP2 can promote tumorigenesis depends on the type of cancer, and the complexity might originate from the specific microenvironment of each human cancer.	('type of cancer', 'Disease', 'MESH:D009369', (86, 100))	('cancer', 'Disease', 'MESH:D009369', (186, 192))	('EFEMP2', 'Gene', (38, 44))	('high', 'Var', (12, 16))	('expression', 'MPA', (24, 34))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('human', 'Species', '9606', (180, 185))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('low', 'NegReg', (20, 23))	('type of cancer', 'Disease', (86, 100))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('cancer', 'Disease', (94, 100))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('promote', 'PosReg', (49, 56))	('tumor', 'Disease', (57, 62))	('cancer', 'Disease', (186, 192))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
116535	32110039	In human osteosarcoma, EFEMP2 knockdown could suppress the invasion and metastasis of osteosarcoma cells by inhibiting EMT, meanwhile EFEMP2 up-regulation could enhance the invasion and metastasis of osteosarcoma cells by inducing EMT, which suggested that EFEMP2 promoted the process of EMT in osteosarcoma cells.	('human', 'Species', '9606', (3, 8))	('osteosarcoma', 'Disease', (86, 98))	('osteosarcoma', 'Phenotype', 'HP:0002669', (9, 21))	('inhibiting', 'NegReg', (108, 118))	('knockdown', 'Var', (30, 39))	('osteosarcoma', 'Disease', 'MESH:D012516', (86, 98))	('osteosarcoma', 'Phenotype', 'HP:0002669', (200, 212))	('osteosarcoma', 'Phenotype', 'HP:0002669', (295, 307))	('up-regulation', 'PosReg', (141, 154))	('suppress', 'NegReg', (46, 54))	('osteosarcoma', 'Phenotype', 'HP:0002669', (86, 98))	('osteosarcoma', 'Disease', (200, 212))	('osteosarcoma', 'Disease', (9, 21))	('osteosarcoma', 'Disease', 'MESH:D012516', (9, 21))	('inducing', 'PosReg', (222, 230))	('EFEMP2', 'Gene', (134, 140))	('osteosarcoma', 'Disease', 'MESH:D012516', (200, 212))	('osteosarcoma', 'Disease', (295, 307))	('enhance', 'PosReg', (161, 168))	('osteosarcoma', 'Disease', 'MESH:D012516', (295, 307))	('EMT', 'CPA', (231, 234))	('EMT', 'CPA', (119, 122))	('EFEMP2', 'Gene', (23, 29))
116544	32110039	In glioma, the silence of EFEMP2 expression in two glioma cell lines remarkably inhibited cell proliferation, induced cell apoptosis and significantly inhibited the invasive ability of both glioma cells, accompanied by the down-regulation of MMP-2 and MMP-9, which suggested that EFEMP2 could promote the invasion of glioma cells by regulating MMP-2 and MMP-9.	('cell proliferation', 'CPA', (90, 108))	('glioma', 'Phenotype', 'HP:0009733', (317, 323))	('glioma', 'Disease', (3, 9))	('MMP-9', 'Gene', '4318', (252, 257))	('MMP-9', 'Gene', (252, 257))	('glioma', 'Disease', (51, 57))	('glioma', 'Disease', 'MESH:D005910', (3, 9))	('MMP-2', 'Gene', '4313', (242, 247))	('invasion', 'CPA', (305, 313))	('glioma', 'Disease', 'MESH:D005910', (51, 57))	('MMP-9', 'Gene', '4318', (354, 359))	('MMP-9', 'Gene', (354, 359))	('EFEMP2', 'Gene', (26, 32))	('induced', 'Reg', (110, 117))	('promote', 'PosReg', (293, 300))	('MMP-2', 'Gene', '4313', (344, 349))	('glioma', 'Phenotype', 'HP:0009733', (3, 9))	('glioma', 'Disease', (190, 196))	('glioma', 'Phenotype', 'HP:0009733', (51, 57))	('glioma', 'Disease', 'MESH:D005910', (190, 196))	('inhibited', 'NegReg', (80, 89))	('MMP-2', 'Gene', (242, 247))	('cell apoptosis', 'CPA', (118, 132))	('glioma', 'Disease', (317, 323))	('glioma', 'Disease', 'MESH:D005910', (317, 323))	('inhibited', 'NegReg', (151, 160))	('MMP-2', 'Gene', (344, 349))	('invasive ability', 'CPA', (165, 181))	('silence', 'Var', (15, 22))	('glioma', 'Phenotype', 'HP:0009733', (190, 196))	('down-regulation', 'NegReg', (223, 238))
116545	32110039	Our data indicated that EFEMP2 overexpression notably inhibited the invasion of lung cancer cells and decreased the expression and activity of MMP2 and MMP9, while EFEMP2 knockdown remarkably promoted the invasion of lung normal epithelial cells and enhanced the expression and activity of MMP2 and MMP9.	('invasion of lung cancer', 'Disease', 'MESH:D008175', (68, 91))	('knockdown', 'Var', (171, 180))	('expression', 'MPA', (263, 273))	('MMP9', 'Gene', (299, 303))	('activity', 'MPA', (278, 286))	('MMP2', 'Gene', '4313', (290, 294))	('MMP9', 'Gene', '4318', (299, 303))	('invasion of lung cancer', 'Disease', (68, 91))	('lung cancer', 'Phenotype', 'HP:0100526', (80, 91))	('EFEMP2', 'Gene', (24, 30))	('decreased', 'NegReg', (102, 111))	('MMP2', 'Gene', (143, 147))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('invasion', 'CPA', (205, 213))	('inhibited', 'NegReg', (54, 63))	('expression', 'MPA', (116, 126))	('promoted', 'PosReg', (192, 200))	('activity', 'MPA', (131, 139))	('MMP9', 'Gene', (152, 156))	('MMP2', 'Gene', '4313', (143, 147))	('EFEMP2', 'Gene', (164, 170))	('MMP9', 'Gene', '4318', (152, 156))	('MMP2', 'Gene', (290, 294))	('overexpression', 'PosReg', (31, 45))	('enhanced', 'PosReg', (250, 258))
116557	31248101	ERBB2 Regulates MED24 during Cancer Progression in Mice with Pten and Smad4 Deletion in the Pulmonary Epithelium ERBB2 is an oncogenic driver with frequent gene mutations and amplification in human lung tumors and is an attractive target for lung cancer therapy.	('MED24', 'Gene', '23989', (16, 21))	('Deletion', 'Var', (76, 84))	('Smad4', 'Gene', (70, 75))	('ERBB2', 'Gene', (113, 118))	('ERBB2', 'Gene', (0, 5))	('Pten', 'Gene', (61, 65))	('Pten', 'Gene', '19211', (61, 65))	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('ERBB2', 'Gene', '13866', (0, 5))	('human', 'Species', '9606', (192, 197))	('tumors', 'Phenotype', 'HP:0002664', (203, 209))	('ERBB2', 'Gene', '13866', (113, 118))	('lung tumor', 'Phenotype', 'HP:0100526', (198, 208))	('lung tumors', 'Disease', 'MESH:D008175', (198, 209))	('lung cancer', 'Disease', (242, 253))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('lung tumors', 'Phenotype', 'HP:0100526', (198, 209))	('Regulates', 'Reg', (6, 15))	('Smad4', 'Gene', '17128', (70, 75))	('Mice', 'Species', '10090', (51, 55))	('Cancer', 'Phenotype', 'HP:0002664', (29, 35))	('MED24', 'Gene', (16, 21))	('lung tumors', 'Disease', (198, 209))	('lung cancer', 'Disease', 'MESH:D008175', (242, 253))	('lung cancer', 'Phenotype', 'HP:0100526', (242, 253))
116559	31248101	Here, we generated genetic mouse models to show that Erbb2 loss inhibited lung tumor development induced by deletion of Pten and Smad4.	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('Erbb2', 'Gene', (53, 58))	('mouse', 'Species', '10090', (27, 32))	('lung tumor', 'Disease', (74, 84))	('Pten', 'Gene', (120, 124))	('lung tumor', 'Disease', 'MESH:D008175', (74, 84))	('lung tumor', 'Phenotype', 'HP:0100526', (74, 84))	('Pten', 'Gene', '19211', (120, 124))	('Smad4', 'Gene', (129, 134))	('Erbb2', 'Gene', '13866', (53, 58))	('Smad4', 'Gene', '17128', (129, 134))	('loss inhibited', 'NegReg', (59, 73))	('deletion', 'Var', (108, 116))
116560	31248101	Transcriptome analysis showed that Erbb2 loss suppressed the significant changes of most of the induced genes by ablation of Pten and Smad4.	('Smad4', 'Gene', '17128', (134, 139))	('Pten', 'Gene', (125, 129))	('ablation', 'Var', (113, 121))	('Erbb2', 'Gene', '13866', (35, 40))	('Smad4', 'Gene', (134, 139))	('Erbb2', 'Gene', (35, 40))	('loss suppressed', 'NegReg', (41, 56))	('Pten', 'Gene', '19211', (125, 129))
116574	31248101	Meanwhile, additional studies have shown that ERBB2 is a critical driver gene in human lung cancer and is frequently altered in the development of lung cancer by gene mutations and amplification.	('gene mutations', 'Var', (162, 176))	('altered', 'Reg', (117, 124))	('lung cancer', 'Disease', 'MESH:D008175', (87, 98))	('lung cancer', 'Disease', (147, 158))	('lung cancer', 'Phenotype', 'HP:0100526', (87, 98))	('lung cancer', 'Phenotype', 'HP:0100526', (147, 158))	('lung cancer', 'Disease', (87, 98))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('amplification', 'Var', (181, 194))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('human', 'Species', '9606', (81, 86))	('ERBB2', 'Gene', (46, 51))	('lung cancer', 'Disease', 'MESH:D008175', (147, 158))
116579	31248101	Overexpression of wild-type human ERBB2 in mouse lungs was shown to cause the development of adenocarcinoma.	('adenocarcinoma', 'Disease', 'MESH:D000230', (93, 107))	('human', 'Species', '9606', (28, 33))	('cause', 'Reg', (68, 73))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('ERBB2', 'Gene', (34, 39))	('adenocarcinoma', 'Disease', (93, 107))	('Overexpression', 'Var', (0, 14))	('mouse', 'Species', '10090', (43, 48))
116580	31248101	Overexpression of the most common human ERBB2 mutant (ERBB2YVMA) in mice was shown to drive the development of lung adenosquamous tumors.	('mice', 'Species', '10090', (68, 72))	('human', 'Species', '9606', (34, 39))	('lung adenosquamous tumors', 'Disease', 'MESH:D018196', (111, 136))	('mutant', 'Var', (46, 52))	('development', 'CPA', (96, 107))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('drive', 'PosReg', (86, 91))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('lung adenosquamous tumors', 'Disease', (111, 136))
116583	31248101	In this study, we investigated the physiological significance of ERBB2 activation in this model by ablating Erbb2 in the lungs of mice with Pten and Smad4 deletion.	('ablating', 'NegReg', (99, 107))	('mice', 'Species', '10090', (130, 134))	('Erbb2', 'Gene', '13866', (108, 113))	('Pten', 'Gene', (140, 144))	('Smad4', 'Gene', (149, 154))	('Pten', 'Gene', '19211', (140, 144))	('deletion', 'Var', (155, 163))	('Smad4', 'Gene', '17128', (149, 154))	('Erbb2', 'Gene', (108, 113))
116584	31248101	The impact of Erbb2 ablation on lung tumor development in the Pten-/-/Smad4-/- model demonstrated that the Erbb2 gene was required for lung tumor development.	('lung tumor', 'Disease', (135, 145))	('Erbb2', 'Gene', '13866', (14, 19))	('lung tumor', 'Disease', 'MESH:D008175', (135, 145))	('lung tumor', 'Disease', (32, 42))	('Smad4', 'Gene', (70, 75))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('lung tumor', 'Disease', 'MESH:D008175', (32, 42))	('Smad4', 'Gene', '17128', (70, 75))	('Erbb2', 'Gene', '13866', (107, 112))	('Erbb2', 'Gene', (14, 19))	('lung tumor', 'Phenotype', 'HP:0100526', (135, 145))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('lung tumor', 'Phenotype', 'HP:0100526', (32, 42))	('Pten', 'Gene', (62, 66))	('ablation', 'Var', (20, 28))	('Erbb2', 'Gene', (107, 112))	('Pten', 'Gene', '19211', (62, 66))
116592	31248101	A 50 nM siRNA smart pool from Dharmacon was used as the final concentration to knockdown MED24 or non-targeting genome sites using Lipofectamine RNAiMAX Reagent (Cat.	('knockdown', 'Var', (79, 88))	('MED24', 'Gene', (89, 94))	('Lipofectamine', 'Chemical', 'MESH:C086724', (131, 144))
116611	31248101	Consequently, 377 patients were qualified for the Kaplan-Meier survival analysis; 20 of them were considered to be in the MED24 high expression group while the rest were in the MED24 low expression group.	('MED24', 'Gene', (122, 127))	('high expression', 'Var', (128, 143))	('patients', 'Species', '9606', (18, 26))
116615	31248101	Here, we generated Ptend/dSmad4d/dErbb2d/d (CCSPiCrePtend/dSmad4d/dErbb2d/d) mice to examine whether Erbb2 ablation inhibited lung tumor development induced by deletion of Pten and Smad4.	('Erbb2', 'Gene', '13866', (34, 39))	('deletion', 'Var', (160, 168))	('inhibited', 'NegReg', (116, 125))	('Pten', 'Gene', (52, 56))	('Pten', 'Gene', (172, 176))	('Pten', 'Gene', '19211', (52, 56))	('Pten', 'Gene', '19211', (172, 176))	('ablation', 'Var', (107, 115))	('mice', 'Species', '10090', (77, 81))	('Smad4', 'Gene', (59, 64))	('Erbb2', 'Gene', (67, 72))	('Smad4', 'Gene', '17128', (26, 31))	('Pten', 'Gene', (19, 23))	('Pten', 'Gene', '19211', (19, 23))	('Erbb2', 'Gene', (34, 39))	('lung tumor', 'Disease', (126, 136))	('lung tumor', 'Phenotype', 'HP:0100526', (126, 136))	('Smad4', 'Gene', '17128', (181, 186))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('Erbb2', 'Gene', '13866', (101, 106))	('Smad4', 'Gene', (26, 31))	('Smad4', 'Gene', '17128', (59, 64))	('lung tumor', 'Disease', 'MESH:D008175', (126, 136))	('Erbb2', 'Gene', '13866', (67, 72))	('Smad4', 'Gene', (181, 186))	('Erbb2', 'Gene', (101, 106))
116621	31248101	Taken together, genetic ablation of Erbb2 in mouse lungs prevents malignant lung tumor development caused by deletion of Pten and Smad4.	('Pten', 'Gene', '19211', (121, 125))	('Smad4', 'Gene', '17128', (130, 135))	('deletion', 'Var', (109, 117))	('prevents', 'NegReg', (57, 65))	('lung tumor', 'Phenotype', 'HP:0100526', (76, 86))	('Erbb2', 'Gene', (36, 41))	('mouse', 'Species', '10090', (45, 50))	('lung tumor', 'Disease', (76, 86))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('Smad4', 'Gene', (130, 135))	('lung tumor', 'Disease', 'MESH:D008175', (76, 86))	('Erbb2', 'Gene', '13866', (36, 41))	('Pten', 'Gene', (121, 125))
116628	31248101	Ingenuity Pathway Analysis (IPA) of these genes impacted by Erbb2 ablation in the cancer model (Table S4) showed that they are significantly related to cancer, cellular movement, cell death, and survival (Figure 2C).	('cellular movement', 'CPA', (160, 177))	('ablation', 'Var', (66, 74))	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('cell death', 'CPA', (179, 189))	('survival', 'CPA', (195, 203))	('Erbb2', 'Gene', (60, 65))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('Erbb2', 'Gene', '13866', (60, 65))	('related', 'Reg', (141, 148))
116630	31248101	These results, at a molecular level, show that Erbb2 loss suppressed the transcriptome profile changes induced by deletion of Pten and Smad4.	('Erbb2', 'Gene', (47, 52))	('loss suppressed', 'NegReg', (53, 68))	('Smad4', 'Gene', (135, 140))	('Pten', 'Gene', (126, 130))	('transcriptome profile changes', 'MPA', (73, 102))	('Pten', 'Gene', '19211', (126, 130))	('Smad4', 'Gene', '17128', (135, 140))	('Erbb2', 'Gene', '13866', (47, 52))	('deletion', 'Var', (114, 122))
116636	31248101	Meanwhile, 3808 genes had a positive correlation with ERBB2 in human lung SCC with the same cutoff of the p-value (Table S7).	('human', 'Species', '9606', (63, 68))	('ERBB2', 'Gene', (54, 59))	('SCC', 'Gene', (74, 77))	('SCC', 'Phenotype', 'HP:0002860', (74, 77))	('SCC', 'Gene', '6317', (74, 77))	('3808', 'Var', (11, 15))
116652	31248101	FAM83E had a positive correlation with ERBB2 in mouse and human lung tumors and also was overexpressed in mouse lung tumors (Figure 3A).	('mouse', 'Species', '10090', (48, 53))	('human', 'Species', '9606', (58, 63))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('lung tumor', 'Phenotype', 'HP:0100526', (112, 122))	('correlation', 'Interaction', (22, 33))	('lung tumors', 'Disease', 'MESH:D008175', (64, 75))	('lung tumors', 'Disease', 'MESH:D008175', (112, 123))	('ERBB2', 'Gene', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('lung tumors', 'Phenotype', 'HP:0100526', (64, 75))	('lung tumors', 'Phenotype', 'HP:0100526', (112, 123))	('overexpressed', 'PosReg', (89, 102))	('lung tumor', 'Phenotype', 'HP:0100526', (64, 74))	('lung tumors', 'Disease', (64, 75))	('lung tumors', 'Disease', (112, 123))	('mouse', 'Species', '10090', (106, 111))	('FAM83E', 'Var', (0, 6))
116654	31248101	Of note, FAM83E promoted human mammary epithelial cell (HMEC) transformation and was recently identified as an oncogene.	('promoted', 'PosReg', (16, 24))	('FAM83E', 'Var', (9, 15))	('human', 'Species', '9606', (25, 30))
116657	31248101	Meanwhile, there was an increase of Erbb2 and Med24 mRNA expression after deletion of Pten and Smad4 in comparison to the wild-type group (Figure 4A,B).	('increase', 'PosReg', (24, 32))	('Pten', 'Gene', (86, 90))	('Med24', 'Gene', (46, 51))	('Pten', 'Gene', '19211', (86, 90))	('Med24', 'Gene', '23989', (46, 51))	('Smad4', 'Gene', '17128', (95, 100))	('Erbb2', 'Gene', (36, 41))	('deletion', 'Var', (74, 82))	('Smad4', 'Gene', (95, 100))	('Erbb2', 'Gene', '13866', (36, 41))
116664	31248101	In line with these oncogenic characteristics of MED24 in human lung cancer cells, we found that NSCLC patients with MED24 high expression had a lower survival rate (Figure 5G and Figure S4).	('survival rate', 'CPA', (150, 163))	('MED24', 'Gene', (116, 121))	('lung cancer', 'Disease', 'MESH:D008175', (63, 74))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('NSCLC', 'Disease', (96, 101))	('lower', 'NegReg', (144, 149))	('patients', 'Species', '9606', (102, 110))	('NSCLC', 'Disease', 'MESH:D002289', (96, 101))	('high expression', 'Var', (122, 137))	('lung cancer', 'Disease', (63, 74))	('lung cancer', 'Phenotype', 'HP:0100526', (63, 74))	('NSCLC', 'Phenotype', 'HP:0030358', (96, 101))	('human', 'Species', '9606', (57, 62))
116665	31248101	Using mouse models, we demonstrated that Erbb2 deficiency prevented lung tumor development induced by deletion of Pten and Smad4 by de-dysregulation of these cancer-related genes.	('lung tumor', 'Phenotype', 'HP:0100526', (68, 78))	('Smad4', 'Gene', '17128', (123, 128))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('mouse', 'Species', '10090', (6, 11))	('Erbb2', 'Gene', '13866', (41, 46))	('deletion', 'Var', (102, 110))	('cancer', 'Disease', (158, 164))	('lung tumor', 'Disease', 'MESH:D008175', (68, 78))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('deficiency', 'Disease', 'MESH:D007153', (47, 57))	('Pten', 'Gene', (114, 118))	('Smad4', 'Gene', (123, 128))	('Pten', 'Gene', '19211', (114, 118))	('deficiency', 'Disease', (47, 57))	('Erbb2', 'Gene', (41, 46))	('prevented', 'NegReg', (58, 67))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('de-dysregulation', 'NegReg', (132, 148))	('lung tumor', 'Disease', (68, 78))
116673	31248101	We not only identified that MED24 is a conserved downstream gene of ERBB2 in mouse and human lung tumors but also showed that its knockdown attenuates cell growth of lung cancer cells.	('attenuates', 'NegReg', (140, 150))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('cell growth of', 'CPA', (151, 165))	('lung tumors', 'Phenotype', 'HP:0100526', (93, 104))	('human', 'Species', '9606', (87, 92))	('lung cancer', 'Disease', 'MESH:D008175', (166, 177))	('MED24', 'Gene', (28, 33))	('lung tumors', 'Disease', 'MESH:D008175', (93, 104))	('knockdown', 'Var', (130, 139))	('ERBB2', 'Gene', (68, 73))	('lung tumor', 'Phenotype', 'HP:0100526', (93, 103))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('lung cancer', 'Disease', (166, 177))	('lung cancer', 'Phenotype', 'HP:0100526', (166, 177))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('mouse', 'Species', '10090', (77, 82))	('lung tumors', 'Disease', (93, 104))
116684	31248101	Clinically, MED24 expression is associated with a poor survival rate of NSCLC patients, suggesting MED24 as a potential target for lung cancer patients, especially those with ERBB2 alterations.	('MED24', 'Gene', (12, 17))	('NSCLC', 'Disease', (72, 77))	('lung cancer', 'Disease', 'MESH:D008175', (131, 142))	('patients', 'Species', '9606', (78, 86))	('NSCLC', 'Disease', 'MESH:D002289', (72, 77))	('patients', 'Species', '9606', (143, 151))	('lung cancer', 'Disease', (131, 142))	('NSCLC', 'Phenotype', 'HP:0030358', (72, 77))	('lung cancer', 'Phenotype', 'HP:0100526', (131, 142))	('expression', 'Var', (18, 28))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('survival', 'MPA', (55, 63))
116717	27512210	Postoperative histopathology reported well differentiated squamous cell carcinoma of size 1 cm x 0.8 cm x 0.7 cm with the involvement of overlying skin and 5 out of 36 lymph nodes dissected were positive - pT4aN2bMx stage IVA.	('positive - pT4aN2bMx', 'Var', (195, 215))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (58, 81))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('squamous cell carcinoma', 'Disease', (58, 81))	('well', 'Disease', (38, 42))	('IVA', 'Disease', 'MESH:C538167', (222, 225))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (58, 81))	('IVA', 'Disease', (222, 225))
116744	32751080	Moreover, oxidative stress has been suggested to cause cancer-specific gene mutations in the cell cycle, apoptosis, and various processes of the regeneration cycle, which may lead to liver damage.	('mutations', 'Var', (76, 85))	('apoptosis', 'CPA', (105, 114))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('oxidative stress', 'Phenotype', 'HP:0025464', (10, 26))	('lead to', 'Reg', (175, 182))	('cell cycle', 'CPA', (93, 103))	('rat', 'Species', '10116', (151, 154))	('liver damage', 'Disease', 'MESH:D056486', (183, 195))	('cause', 'Reg', (49, 54))	('liver damage', 'Disease', (183, 195))	('cancer', 'Disease', (55, 61))
116745	32751080	NF-E2-related factor 2 (NRF2) transcription factor is activated by oxidative stress, and recent studies have suggested that the aberrant activation of NRF2 triggers hepatomegaly and HCC development, however, this factor also acts to protect the liver from oxidative stress.	('triggers', 'Reg', (156, 164))	('NF-E2-related factor 2', 'Gene', '4780', (0, 22))	('HCC development', 'CPA', (182, 197))	('hepatomegaly', 'Phenotype', 'HP:0002240', (165, 177))	('aberrant', 'Var', (128, 136))	('HCC', 'Phenotype', 'HP:0001402', (182, 185))	('activation', 'PosReg', (137, 147))	('NF-E2-related factor 2', 'Gene', (0, 22))	('hepatomegaly', 'Disease', 'MESH:D006529', (165, 177))	('hepatomegaly', 'Disease', (165, 177))	('oxidative stress', 'Phenotype', 'HP:0025464', (256, 272))	('oxidative stress', 'Phenotype', 'HP:0025464', (67, 83))	('NRF2', 'Gene', (151, 155))
116750	32751080	Oxidative stress also induces mitochondrial dysfunction, accelerates telomere shortening, causes DNA damage, and is associated with mutations of apoptosis-specific genes in HCC.	('accelerates', 'PosReg', (57, 68))	('apoptosis-specific genes', 'Gene', (145, 169))	('mitochondrial dysfunction', 'Disease', (30, 55))	('HCC', 'Phenotype', 'HP:0001402', (173, 176))	('DNA damage', 'MPA', (97, 107))	('mutations', 'Var', (132, 141))	('Oxidative stress', 'Phenotype', 'HP:0025464', (0, 16))	('causes', 'Reg', (90, 96))	('HCC', 'Gene', (173, 176))	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (30, 55))	('telomere shortening', 'Phenotype', 'HP:0031413', (69, 88))	('rat', 'Species', '10116', (63, 66))	('mitochondrial dysfunction', 'Disease', 'MESH:D028361', (30, 55))	('telomere', 'MPA', (69, 77))	('induces', 'Reg', (22, 29))	('associated', 'Reg', (116, 126))
116755	32751080	In contrast, HepG2 HCC cells exposed to cadmium telluride quantum dots-induced oxidative stress exhibit decreased levels of Glutathione-SH and Bcl2 and increased expression of NRF2 together with apoptosis induction due to the activation of the MAPK-JNK pathway.	('Glutathione', 'Chemical', 'MESH:D005978', (124, 135))	('oxidative', 'MPA', (79, 88))	('apoptosis', 'CPA', (195, 204))	('increased', 'PosReg', (152, 161))	('Bcl2', 'Gene', '596', (143, 147))	('decreased', 'NegReg', (104, 113))	('JNK', 'Gene', (249, 252))	('HepG2 HCC', 'CellLine', 'CVCL:0027', (13, 22))	('NRF2', 'Gene', (176, 180))	('expression', 'MPA', (162, 172))	('HCC', 'Phenotype', 'HP:0001402', (19, 22))	('cadmium', 'Var', (40, 47))	('levels of Glutathione-SH', 'MPA', (114, 138))	('cadmium telluride', 'Chemical', 'MESH:C028337', (40, 57))	('decreased levels of Glutathione-SH', 'Phenotype', 'HP:0003343', (104, 138))	('oxidative stress', 'Phenotype', 'HP:0025464', (79, 95))	('JNK', 'Gene', '5599', (249, 252))	('Bcl2', 'Gene', (143, 147))
116764	32751080	It has been reported that one single-point mutation, a proline substitution for serine 383 (S383P) in KEAP1, significantly reduces the ability of the Kelch domain to bind with the Neh2 domain of NRF2.	('S383P', 'Var', (92, 97))	('NRF2', 'Protein', (195, 199))	('KEAP1', 'Gene', (102, 107))	('ability', 'MPA', (135, 142))	('bind', 'Interaction', (166, 170))	('S383P', 'Mutation', 'rs186171287', (92, 97))	('proline substitution for serine 383', 'Mutation', 'rs186171287', (55, 90))	('reduces', 'NegReg', (123, 130))
116765	32751080	Moreover, KEAP1 substitution mutations of cysteine residues Cys273S/A and Cys288S/A do not affect the ability of KEAP1 to interact with NRF2, but they impair the KEAP1-mediated degradation of NRF2.	('interact', 'Interaction', (122, 130))	('KEAP1-mediated', 'Enzyme', (162, 176))	('cysteine', 'Chemical', 'MESH:D003545', (42, 50))	('NRF2', 'Protein', (192, 196))	('Cys288S/A', 'Var', (74, 83))	('impair', 'NegReg', (151, 157))	('Cys288S', 'Chemical', '-', (74, 81))	('Cys273S/A', 'Mutation', 'p.C273S,A', (60, 69))	('Cys273S/A', 'Var', (60, 69))
116766	32751080	Notably, many studies have revealed that the loss of interaction between NRF2 and KEAP1 causes tumor development in multiple cancer types.	('KEAP1', 'Gene', (82, 87))	('NRF2', 'Gene', (73, 77))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('loss', 'Var', (45, 49))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('interaction', 'Interaction', (53, 64))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('causes', 'Reg', (88, 94))	('tumor', 'Disease', (95, 100))
116767	32751080	Furthermore, it has been reported that the deletion of Exon2 in NRF2, which reduces interaction with KEAP1, causes tumor development in lung and liver cancer.	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('liver cancer', 'Disease', (145, 157))	('tumor', 'Disease', (115, 120))	('liver cancer', 'Phenotype', 'HP:0002896', (145, 157))	('liver cancer', 'Disease', 'MESH:D006528', (145, 157))	('NRF2', 'Gene', (64, 68))	('deletion of Exon2', 'Var', (43, 60))	('causes', 'Reg', (108, 114))	('lung', 'Disease', (136, 140))	('interaction', 'Interaction', (84, 95))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
116768	32751080	Together, a tightly regulated balance of NRF2 and KEAP1 interaction is essential to protect cells or tissues from oxidative stress, and the failure of that mechanism (e.g., mutations of critical amino acids) triggers cancer development.	('mutations of', 'Var', (173, 185))	('triggers', 'Reg', (208, 216))	('cancer', 'Disease', (217, 223))	('cancer', 'Disease', 'MESH:D009369', (217, 223))	('oxidative stress', 'Phenotype', 'HP:0025464', (114, 130))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))
116769	32751080	The International Cancer Genome Consortium (ICGC; ) has identified somatic mutations in the NRF2 gene of human lung, liver, breast, head, and neck cancer patients.	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('neck cancer', 'Disease', 'MESH:D006258', (142, 153))	('neck cancer', 'Disease', (142, 153))	('breast', 'Disease', (124, 130))	('patients', 'Species', '9606', (154, 162))	('lung', 'Disease', (111, 115))	('Cancer', 'Phenotype', 'HP:0002664', (18, 24))	('neck cancer', 'Phenotype', 'HP:0012288', (142, 153))	('liver', 'Disease', (117, 122))	('mutations', 'Var', (75, 84))	('NRF2', 'Gene', (92, 96))	('human', 'Species', '9606', (105, 110))	('Cancer', 'Disease', 'MESH:D009369', (18, 24))	('Cancer', 'Disease', (18, 24))	('head', 'Disease', (132, 136))
116770	32751080	Notably, these mutations were mostly located within the DLG and ETGE motifs, which provides NRF2 with gain-of-function activity in different cancer types.	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('gain-of-function', 'PosReg', (102, 118))	('mutations', 'Var', (15, 24))	('NRF2', 'Gene', (92, 96))	('activity', 'MPA', (119, 127))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('cancer', 'Disease', (141, 147))
116771	32751080	Comprehensive genomic analyses have identified somatic mutations in the NRF2 and KEAP1 genes in various types of cancer.	('KEAP1', 'Gene', (81, 86))	('mutations', 'Var', (55, 64))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('NRF2', 'Gene', (72, 76))	('cancer', 'Disease', (113, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
116772	32751080	Interestingly, mutations in KEAP1 and NRF2 are mutually exclusive and rarely occurred in the same cancer cell.	('NRF2', 'Gene', (38, 42))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('mutations', 'Var', (15, 24))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('KEAP1', 'Gene', (28, 33))	('cancer', 'Disease', (98, 104))
116774	32751080	Somatic NRF2 and KEAP1 mutations were most often found in lung squamous cell carcinoma, esophageal carcinoma, uterine corpus endometrial carcinoma, lung adenocarcinoma, head and neck cancers, and HCC; the overlapping somatic NRF2 or KEAP1 mutations are associated with a sustained NRF2 activation phenotype.	('neck cancer', 'Phenotype', 'HP:0012288', (178, 189))	('lung adenocarcinoma', 'Disease', (148, 167))	('KEAP1', 'Gene', (233, 238))	('lung squamous cell carcinoma', 'Disease', (58, 86))	('mutations', 'Var', (239, 248))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (58, 86))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (125, 146))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (88, 108))	('neck cancers', 'Disease', (178, 190))	('cancers', 'Phenotype', 'HP:0002664', (183, 190))	('head and neck cancers', 'Phenotype', 'HP:0012288', (169, 190))	('neck cancers', 'Disease', 'MESH:D006258', (178, 190))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (63, 86))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (125, 146))	('KEAP1', 'Gene', (17, 22))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (148, 167))	('HCC', 'Disease', (196, 199))	('mutations', 'Var', (23, 32))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('NRF2', 'Gene', (225, 229))	('carcinoma', 'Phenotype', 'HP:0030731', (158, 167))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (148, 167))	('HCC', 'Phenotype', 'HP:0001402', (196, 199))	('found', 'Reg', (49, 54))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (88, 108))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (58, 86))	('endometrial carcinoma', 'Disease', (125, 146))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('NRF2', 'Gene', (8, 12))	('esophageal carcinoma', 'Disease', (88, 108))
116775	32751080	In 995 lung cancer cases, 423 cases were estimated to have constitutive NRF2 activation, and 165 cases harbored either NRF2 or KEAP1 mutations with higher expression of NRF2 target genes, including Aldo-Keto Reductase Family 1 Member B10 (AKR1B10), Aldo-Keto Reductase Family 1 Member B15 (AKR1B15), Glutathione Peroxidase 2 (GPX2), Thioredoxin Reductase 1 (TXNRD1), Glutamate-Cysteine Ligase Modifier Subunit (GCLM), and Glutamate-Cysteine Ligase Catalytic Subunit Glutamate-Cysteine Ligase Catalytic Subunit (GCLC).	('Thioredoxin Reductase 1', 'Gene', '7296', (333, 356))	('lung cancer', 'Disease', (7, 18))	('TXNRD1', 'Gene', (358, 364))	('Aldo-Keto Reductase Family 1 Member B15', 'Gene', '441282', (249, 288))	('GPX2', 'Gene', (326, 330))	('Glutamate-Cysteine Ligase Modifier Subunit', 'Gene', (367, 409))	('GCLC', 'Gene', (511, 515))	('mutations', 'Var', (133, 142))	('AKR1B10', 'Gene', '57016', (239, 246))	('Aldo-Keto Reductase Family 1 Member B15', 'Gene', (249, 288))	('AKR1B15', 'Gene', '441282', (290, 297))	('lung cancer', 'Disease', 'MESH:D008175', (7, 18))	('higher', 'PosReg', (148, 154))	('Glutathione Peroxidase 2', 'Gene', '2877', (300, 324))	('Glutamate-Cysteine Ligase Modifier Subunit', 'Gene', '2730', (367, 409))	('lung cancer', 'Phenotype', 'HP:0100526', (7, 18))	('TXNRD1', 'Gene', '7296', (358, 364))	('GCLM', 'Gene', (411, 415))	('Aldo-Keto Reductase Family 1 Member B10', 'Gene', '57016', (198, 237))	('NRF2', 'Gene', (169, 173))	('AKR1B10', 'Gene', (239, 246))	('NRF2', 'Gene', (119, 123))	('Aldo-Keto Reductase Family 1 Member B10', 'Gene', (198, 237))	('activation', 'PosReg', (77, 87))	('GPX2', 'Gene', '2877', (326, 330))	('expression', 'MPA', (155, 165))	('Glutathione Peroxidase 2', 'Gene', (300, 324))	('NRF2', 'Gene', (72, 76))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('GCLM', 'Gene', '2730', (411, 415))	('Thioredoxin Reductase 1', 'Gene', (333, 356))	('AKR1B15', 'Gene', (290, 297))
116776	32751080	In an experimental rat model of hepatocarcinogenesis, it was found that the NRF2 gene was frequently mutated or activated during the early stage of the tumorigenic process.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('hepatocarcinogenesis', 'Disease', 'MESH:D063646', (32, 52))	('mutated', 'Var', (101, 108))	('activated', 'PosReg', (112, 121))	('tumor', 'Disease', (152, 157))	('rat', 'Species', '10116', (19, 22))	('NRF2 gene', 'Gene', (76, 85))	('hepatocarcinogenesis', 'Disease', (32, 52))
116778	32751080	In Lung Squamous Cell Carcinoma (LSCC) mice models developed by KEAP1 deletion, the persistent activation of NRF2 has been suggested to contribute to increased tumor formation, metastasis, and resistance to oxidative stress and irradiation.	('deletion', 'Var', (70, 78))	('LSCC', 'Phenotype', 'HP:0030359', (33, 37))	('Carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('Lung Squamous Cell Carcinoma', 'Disease', (3, 31))	('oxidative stress', 'Phenotype', 'HP:0025464', (207, 223))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('activation', 'PosReg', (95, 105))	('Lung Squamous Cell Carcinoma', 'Disease', 'MESH:D002294', (3, 31))	('metastasis', 'CPA', (177, 187))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (8, 31))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('NRF2', 'Gene', (109, 113))	('increased', 'PosReg', (150, 159))	('resistance', 'CPA', (193, 203))	('tumor', 'Disease', (160, 165))	('Lung Squamous Cell Carcinoma', 'Phenotype', 'HP:0030359', (3, 31))	('mice', 'Species', '10090', (39, 43))
116780	32751080	A recent CRISPR/Cas9 genome-wide screening study demonstrated that KEAP1 depletion causes aberrant NRF2 transcriptional activity as well as high chemoresistance.	('KEAP1', 'Gene', (67, 72))	('NRF2', 'Protein', (99, 103))	('rat', 'Species', '10116', (56, 59))	('transcriptional activity', 'MPA', (104, 128))	('depletion', 'Var', (73, 82))
116782	32751080	NRF2 DLG and ETGE mutations that demonstrate a loss of interaction with KEAP1, are localized to the nucleus and exert sustained target gene activation.	('NRF2', 'Gene', (0, 4))	('rat', 'Species', '10116', (40, 43))	('interaction', 'Interaction', (55, 66))	('activation', 'PosReg', (140, 150))	('ETGE', 'Gene', (13, 17))	('mutations', 'Var', (18, 27))
116783	32751080	In fact, NRF2 mutations occur frequently in the DLG or ETGE motifs and activate Nqo1, Gclc, and Gsta4 pathways.	('activate', 'PosReg', (71, 79))	('Gclc', 'Gene', '2729', (86, 90))	('Nqo1', 'Gene', (80, 84))	('NRF2', 'Gene', (9, 13))	('Nqo1', 'Gene', '1728', (80, 84))	('Gsta4', 'Gene', '2941', (96, 101))	('mutations', 'Var', (14, 23))	('Gsta4', 'Gene', (96, 101))	('Gclc', 'Gene', (86, 90))
116784	32751080	Mutation in the DLG motif of NRF2 induces ARE-regulated PPP enzyme transcription, which is required for cell growth and proliferation.	('ARE-regulated', 'MPA', (42, 55))	('induces', 'Reg', (34, 41))	('Mutation', 'Var', (0, 8))	('PPP', 'Gene', (56, 59))	('NRF2', 'Gene', (29, 33))	('rat', 'Species', '10116', (127, 130))	('transcription', 'MPA', (67, 80))
116786	32751080	Moreover, methylation of the KEAP1 promoter has been reported to induce cancer development and chemo- and radio- resistance in multiple cancer types.	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('cancer', 'Disease', (136, 142))	('induce', 'PosReg', (65, 71))	('methylation', 'Var', (10, 21))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('KEAP1', 'Gene', (29, 34))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('cancer', 'Disease', (72, 78))
116787	32751080	It has been determined that the most frequent somatic mutations found in HCC are telomerase reverse transcriptase (TERT) promoter mutations, identified in premalignant lesions in cirrhosis.	('TERT', 'Gene', '7015', (115, 119))	('HCC', 'Phenotype', 'HP:0001402', (73, 76))	('cirrhosis', 'Phenotype', 'HP:0001394', (179, 188))	('cirrhosis', 'Disease', 'MESH:D005355', (179, 188))	('telomerase reverse transcriptase', 'Gene', (81, 113))	('mutations', 'Var', (130, 139))	('telomerase reverse transcriptase', 'Gene', '7015', (81, 113))	('cirrhosis', 'Disease', (179, 188))	('TERT', 'Gene', (115, 119))
116789	32751080	TERT promoter mutations are associated with increased telomerase activity, which displays enhanced NRF2 expression and inhibited glycogen accumulation.	('NRF2', 'Gene', (99, 103))	('telomerase', 'Enzyme', (54, 64))	('inhibited', 'NegReg', (119, 128))	('TERT', 'Gene', (0, 4))	('glycogen accumulation', 'MPA', (129, 150))	('expression', 'MPA', (104, 114))	('enhanced', 'PosReg', (90, 98))	('TERT', 'Gene', '7015', (0, 4))	('increased', 'PosReg', (44, 53))	('glycogen', 'Chemical', 'MESH:D006003', (129, 137))	('mutations', 'Var', (14, 23))
116790	32751080	As such, it appears there are many possible pathways to trigger liver cancer via aberrant NRF2 transcriptional activity, and further phenotypic validation of the roles of these pathways in liver cancer development merits investigation.	('liver cancer', 'Disease', (64, 76))	('aberrant', 'Var', (81, 89))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('liver cancer', 'Phenotype', 'HP:0002896', (189, 201))	('liver cancer', 'Disease', 'MESH:D006528', (189, 201))	('NRF2', 'Gene', (90, 94))	('liver cancer', 'Disease', (189, 201))	('liver cancer', 'Phenotype', 'HP:0002896', (64, 76))	('liver cancer', 'Disease', 'MESH:D006528', (64, 76))	('transcriptional activity', 'MPA', (95, 119))	('trigger', 'Reg', (56, 63))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
116791	32751080	As summarized in Table 2, it has been suggested that excessive NRF2 transcriptional activity promotes the development of liver cancer by regulating the expression of various genes.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('NRF2', 'Gene', (63, 67))	('excessive', 'Var', (53, 62))	('regulating', 'Reg', (137, 147))	('liver cancer', 'Phenotype', 'HP:0002896', (121, 133))	('liver cancer', 'Disease', 'MESH:D006528', (121, 133))	('liver cancer', 'Disease', (121, 133))	('promotes', 'PosReg', (93, 101))	('expression of various genes', 'MPA', (152, 179))	('transcriptional activity', 'MPA', (68, 92))
116806	32751080	In HepG2 cells, a significant decrease in cell proliferation and upregulation of proapoptotic genes BAX and Caspase 3 were observed when PRDX1 was silenced, suggesting the prosurvival and tumorigenic roles of PRDX1.	('PRDX1', 'Gene', (209, 214))	('tumor', 'Disease', (188, 193))	('silenced', 'Var', (147, 155))	('PRDX1', 'Gene', (137, 142))	('decrease', 'NegReg', (30, 38))	('rat', 'Species', '10116', (54, 57))	('cell proliferation', 'CPA', (42, 60))	('BAX', 'Gene', (100, 103))	('PRDX1', 'Gene', '5052', (209, 214))	('PRDX1', 'Gene', '5052', (137, 142))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('BAX', 'Gene', '581', (100, 103))	('HepG2', 'CellLine', 'CVCL:0027', (3, 8))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('upregulation', 'PosReg', (65, 77))	('Caspase 3', 'Gene', (108, 117))	('Caspase 3', 'Gene', '836', (108, 117))
116812	32751080	Genetic knockdown (KD) of either NRF2 or MTHFD1L or inhibition of the folate cycle through antifolate drug can inhibit liver cancer cell proliferation by increasing oxidative stress, altering the metabolic program, and sensitizing HCC cells to sorafenib treatment.	('sorafenib', 'Chemical', 'MESH:D000077157', (244, 253))	('HCC', 'Phenotype', 'HP:0001402', (231, 234))	('rat', 'Species', '10116', (144, 147))	('inhibit', 'NegReg', (111, 118))	('oxidative stress', 'Phenotype', 'HP:0025464', (165, 181))	('MTHFD1L', 'Gene', (41, 48))	('liver cancer', 'Disease', 'MESH:D006528', (119, 131))	('inhibition', 'NegReg', (52, 62))	('metabolic program', 'MPA', (196, 213))	('increasing', 'PosReg', (154, 164))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('sensitizing', 'Reg', (219, 230))	('NRF2', 'Gene', (33, 37))	('altering', 'Reg', (183, 191))	('liver cancer', 'Phenotype', 'HP:0002896', (119, 131))	('folate', 'Chemical', 'MESH:D005492', (95, 101))	('MTHFD1L', 'Gene', '25902', (41, 48))	('liver cancer', 'Disease', (119, 131))	('knockdown', 'Var', (8, 17))	('folate', 'Chemical', 'MESH:D005492', (70, 76))	('oxidative stress', 'MPA', (165, 181))
116813	32751080	In cancer cells, the aberrant activation of NRF2 helps their metabolic adaptations through regulating the key genes involved in glucose metabolism pathways.	('glucose metabolism', 'Disease', (128, 146))	('regulating', 'Reg', (91, 101))	('aberrant', 'Var', (21, 29))	('activation', 'PosReg', (30, 40))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('glucose metabolism', 'Disease', 'MESH:D044882', (128, 146))	('cancer', 'Disease', (3, 9))	('NRF2', 'Gene', (44, 48))	('helps', 'PosReg', (49, 54))	('metabolic adaptations', 'CPA', (61, 82))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
116815	32751080	The miR-1 and miR-206 regulate their target genes of the PPP (pentose phosphate pathway) (Glucose-6-phosphate dehydrogenase (G6PD), Phosphogluconate Dehydrogenase (PGD), Transketolase (TKT), and Transaldolase 1 (TALDO1)), suggesting that suppression of these miRNAs expression caused by NRF2 aberrant activation may enhance tumor development through glucose metabolism deficiency.	('pentose phosphate', 'Chemical', 'MESH:D010428', (62, 79))	('suppression', 'NegReg', (238, 249))	('enhance', 'PosReg', (316, 323))	('G6PD', 'Gene', '2539', (125, 129))	('Glucose-6-phosphate dehydrogenase', 'Gene', '2539', (90, 123))	('miR-1', 'Gene', '83856', (4, 9))	('glucose metabolism deficiency', 'Disease', (350, 379))	('Phosphogluconate Dehydrogenase', 'Gene', (132, 162))	('Phosphogluconate Dehydrogenase', 'Gene', '5226', (132, 162))	('Glucose-6-phosphate dehydrogenase', 'Gene', (90, 123))	('tumor', 'Phenotype', 'HP:0002664', (324, 329))	('miR-206', 'Gene', (14, 21))	('TALDO1', 'Gene', (212, 218))	('G6PD', 'Gene', (125, 129))	('miR-1', 'Gene', (4, 9))	('miR-206', 'Gene', '406989', (14, 21))	('TALDO1', 'Gene', '6888', (212, 218))	('aberrant', 'Var', (292, 300))	('activation', 'PosReg', (301, 311))	('Transketolase', 'Gene', '7086', (170, 183))	('glucose metabolism deficiency', 'Disease', 'MESH:D044882', (350, 379))	('NRF2', 'Gene', (287, 291))	('TKT', 'Gene', '7086', (185, 188))	('Transketolase', 'Gene', (170, 183))	('TKT', 'Gene', (185, 188))	('PGD', 'Gene', (164, 167))	('tumor', 'Disease', (324, 329))	('Transaldolase 1', 'Gene', (195, 210))	('Transaldolase 1', 'Gene', '6888', (195, 210))	('PGD', 'Gene', '5226', (164, 167))	('tumor', 'Disease', 'MESH:D009369', (324, 329))
116827	32751080	In leptin-deficient mice, constitutive activation of NRF2 via KEAP1-KD established insulin resistance, inhibited the accumulation of lipids in adipose tissue, and subsequently increased hepatic steatosis..	('accumulation of lipids in adipose tissue', 'Phenotype', 'HP:0009058', (117, 157))	('hepatic steatosis', 'Phenotype', 'HP:0001397', (186, 203))	('activation', 'PosReg', (39, 49))	('increased', 'PosReg', (176, 185))	('accumulation of lipids in adipose tissue', 'MPA', (117, 157))	('KEAP1-KD', 'Var', (62, 70))	('mice', 'Species', '10090', (20, 24))	('hepatic steatosis', 'Disease', (186, 203))	('hepatic steatosis', 'Disease', 'MESH:D005234', (186, 203))	('steatosis', 'Phenotype', 'HP:0001397', (194, 203))	('inhibited', 'NegReg', (103, 112))	('leptin', 'Gene', '16846', (3, 9))	('leptin', 'Gene', (3, 9))	('NRF2', 'Gene', (53, 57))	('insulin resistance', 'Phenotype', 'HP:0000855', (83, 101))	('insulin', 'Gene', (83, 90))	('insulin', 'Gene', '3630', (83, 90))	('lipids', 'Chemical', 'MESH:D008055', (133, 139))
116840	32751080	Since NRF2 is widely known to be a potent protector in anti-oxidative response, a question arises as to how NRF2 DLG and ETGE mutations lead to increased malignancy of HCC and trigger its resistance to chemotherapy.	('increased', 'PosReg', (144, 153))	('NRF2', 'Gene', (108, 112))	('HCC', 'Disease', (168, 171))	('malignancy', 'Disease', (154, 164))	('HCC', 'Phenotype', 'HP:0001402', (168, 171))	('resistance to', 'CPA', (188, 201))	('mutations', 'Var', (126, 135))	('malignancy', 'Disease', 'MESH:D009369', (154, 164))	('trigger', 'Reg', (176, 183))
116843	32751080	Interestingly, oncogenic gene mutations such as K-RasG12D, B-RafV619E enhanced transcription of NRF2 with elevated NRF2 target gene expression and lowered intracellular ROS.	('NRF2', 'Gene', (96, 100))	('intracellular ROS', 'MPA', (155, 172))	('transcription', 'MPA', (79, 92))	('lowered', 'NegReg', (147, 154))	('ROS', 'Chemical', 'MESH:D017382', (169, 172))	('enhanced', 'PosReg', (70, 78))	('mutations', 'Var', (30, 39))	('elevated', 'PosReg', (106, 114))	('expression', 'MPA', (132, 142))
116844	32751080	Therefore, it is assumed that aberrant transcriptional activity induced by high expression or mutation of NRF2 may lead to malignancy in combination with other factors (for example, mutation of oncogene leads cells to early cancer state or abnormality of metabolic state changes in cellular environment).	('malignancy', 'Disease', (123, 133))	('aberrant', 'Var', (30, 38))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('mutation', 'Var', (94, 102))	('high', 'PosReg', (75, 79))	('transcriptional activity', 'MPA', (39, 63))	('malignancy', 'Disease', 'MESH:D009369', (123, 133))	('mutation', 'Var', (182, 190))	('cancer', 'Disease', 'MESH:D009369', (224, 230))	('iron', 'Chemical', 'MESH:D007501', (294, 298))	('cancer', 'Disease', (224, 230))	('NRF2', 'Gene', (106, 110))	('lead to', 'Reg', (115, 122))
116846	32751080	Interestingly, it has been shown that elevated p62 levels aberrantly activate NRF2 transcriptional activity, which induces HCC pathogenesis by accelerating the survival of HCC-initiating cells.	('survival', 'CPA', (160, 168))	('rat', 'Species', '10116', (149, 152))	('p62', 'Var', (47, 50))	('activate', 'PosReg', (69, 77))	('accelerating', 'PosReg', (143, 155))	('transcriptional activity', 'MPA', (83, 107))	('HCC', 'Disease', (123, 126))	('HCC', 'Phenotype', 'HP:0001402', (123, 126))	('NRF2', 'Gene', (78, 82))	('HCC', 'Phenotype', 'HP:0001402', (172, 175))	('induces', 'Reg', (115, 122))
116847	32751080	p62, which is encoded by Sequestosome-1 (SQSTM1), is an autophagy adaptor.	('Sequestosome-1', 'Gene', (25, 39))	('Sequestosome-1', 'Gene', '8878', (25, 39))	('p62', 'Var', (0, 3))	('SQSTM1', 'Gene', (41, 47))	('SQSTM1', 'Gene', '8878', (41, 47))
116848	32751080	Atg7 deletion mice develop hepatocellular adenoma accompanied by aberrant accumulation of p62 followed by NRF2 activation.	('activation', 'PosReg', (111, 121))	('deletion', 'Var', (5, 13))	('p62', 'MPA', (90, 93))	('mice', 'Species', '10090', (14, 18))	('hepatocellular adenoma', 'Phenotype', 'HP:0012028', (27, 49))	('adenoma', 'Disease', 'MESH:D000236', (42, 49))	('adenoma', 'Disease', (42, 49))	('develop', 'PosReg', (19, 26))	('accumulation', 'PosReg', (74, 86))	('Atg7', 'Gene', (0, 4))
116849	32751080	Furthermore, high levels of p62 expression activates NRF2 and mTORC1 in HCC.	('HCC', 'Disease', (72, 75))	('HCC', 'Phenotype', 'HP:0001402', (72, 75))	('mTORC1', 'Gene', '382056', (62, 68))	('activates', 'PosReg', (43, 52))	('p62', 'Var', (28, 31))	('mTORC1', 'Gene', (62, 68))	('NRF2', 'Gene', (53, 57))
116851	32751080	Moreover, a xenograft experiment using a nude mouse demonstrated that the tumor formation capacity of mutant Huh-1 cells (p62 KO and S349A) is reduced as compared to the wild-type.	('mutant', 'Var', (102, 108))	('Huh-1', 'Gene', (109, 114))	('S349A', 'Mutation', 'p.S349A', (133, 138))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('mouse', 'Species', '10090', (46, 51))	('tumor', 'Disease', (74, 79))	('rat', 'Species', '10116', (59, 62))	('S349A', 'Var', (133, 138))	('Huh-1', 'Gene', '25932', (109, 114))	('reduced', 'NegReg', (143, 150))
116854	32751080	These findings clearly demonstrate that sustained activation of NRF2 by p62 activation is responsible for HCC pathology, suggesting that NRF2 and KEAP1 mutations, as well as aberrant p62 activation enhance the growth of HCC cells through metabolic dysregulation.	('growth', 'CPA', (210, 216))	('aberrant', 'Var', (174, 182))	('mutations', 'Var', (152, 161))	('rat', 'Species', '10116', (30, 33))	('activation enhance', 'PosReg', (187, 205))	('HCC', 'Disease', (220, 223))	('HCC', 'Disease', (106, 109))	('p62', 'Gene', (183, 186))	('KEAP1', 'Gene', (146, 151))	('HCC', 'Phenotype', 'HP:0001402', (220, 223))	('HCC', 'Phenotype', 'HP:0001402', (106, 109))	('NRF2', 'Gene', (137, 141))
116865	32751080	Likewise, liver-specific inactivation of the Nrf1 gene in adult mice has been reported to trigger NASH, suggesting that the proper activity of NRF1 and NRF3 blocks carcinogenesis, including liver cancer.	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('inactivation', 'Var', (25, 37))	('NRF1', 'Gene', (143, 147))	('NRF3', 'Gene', (152, 156))	('carcinogenesis', 'Disease', 'MESH:D063646', (164, 178))	('Nrf1', 'Gene', '18181', (45, 49))	('NASH', 'Disease', (98, 102))	('carcinogenesis', 'Disease', (164, 178))	('liver cancer', 'Phenotype', 'HP:0002896', (190, 202))	('liver cancer', 'Disease', 'MESH:D006528', (190, 202))	('liver cancer', 'Disease', (190, 202))	('mice', 'Species', '10090', (64, 68))	('Nrf1', 'Gene', (45, 49))
116867	32751080	In a diseased microenvironment, when NRF2 over-activation is induced through mutation, epigenetic changes, competition or other constitutive changes, and cellular responses are variable.	('over-activation', 'PosReg', (42, 57))	('mutation', 'Var', (77, 85))	('induced', 'Reg', (61, 68))	('epigenetic changes', 'Var', (87, 105))	('NRF2', 'Gene', (37, 41))	('iron', 'Chemical', 'MESH:D007501', (22, 26))
116869	32751080	Further studies are needed to clarify the underlying mechanisms and investigate the role of NRF2 mutations in the development of liver cancer.	('mutations', 'Var', (97, 106))	('liver cancer', 'Disease', (129, 141))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('NRF2', 'Gene', (92, 96))	('liver cancer', 'Phenotype', 'HP:0002896', (129, 141))	('liver cancer', 'Disease', 'MESH:D006528', (129, 141))
116876	32578582	We screened 146 upregulated DEGs and 431 downregulated DEGs with the criteria of  logFC  >1 and P<0.05, and the GO analysis indicated that DEGs were implicated in mitotic nuclear division (biological process, BP), the nucleus (cellular component, CC), and protein binding (molecular function, MF) and were associated with multiple KEGG pathways, such as the p53 signaling pathway in cancer.	('upregulated', 'PosReg', (16, 27))	('cancer', 'Disease', (383, 389))	('p53', 'Gene', (358, 361))	('DEGs', 'Var', (139, 143))	('cancer', 'Disease', 'MESH:D009369', (383, 389))	('p53', 'Gene', '7157', (358, 361))	('associated with', 'Reg', (306, 321))	('mitotic nuclear division', 'CPA', (163, 187))	('cancer', 'Phenotype', 'HP:0002664', (383, 389))	('protein', 'Protein', (256, 263))
116896	32578582	The common intersection of identified uDEGs and dDEGs from GSE75037, GSE85716, and GSE118370 was separately acquired using Venny diagram plotter (http://bioinfogp.cnb.csic.es/tools/venny/index.html).	('uDEGs', 'Chemical', '-', (38, 43))	('GSE75037', 'Var', (59, 67))	('dDEGs', 'Chemical', '-', (48, 53))	('GSE118370', 'Var', (83, 92))
116921	32578582	To better define hub genes in LUAD, 3 conditions were set for hub genes: 1) the degree score of DEGs tested by cytohHubba was in the top 15; 2) DEGs were in the 3 modules obtained by MCODE; and 3) DEGs were associated with the survival rate of the patients in the survival curve (Figure 3A-3H).	('hub', 'Gene', '1993', (62, 65))	('DEGs', 'Var', (197, 201))	('hub', 'Gene', '1993', (17, 20))	('hub', 'Gene', (17, 20))	('hub', 'Gene', (62, 65))	('associated', 'Reg', (207, 217))	('patients', 'Species', '9606', (248, 256))
116944	32578582	Decreased expression of secreted phosphoprotein 1 (SPP1), associated with EGFR mutation, is interconnected with the improvement of the overall survival rate and recurrence-free survival rate of LUAD.	('secreted phosphoprotein 1', 'Gene', '6696', (24, 49))	('Decreased', 'NegReg', (0, 9))	('expression', 'MPA', (10, 20))	('secreted phosphoprotein 1', 'Gene', (24, 49))	('recurrence-free survival', 'CPA', (161, 185))	('SPP1', 'Gene', '6696', (51, 55))	('SPP1', 'Gene', (51, 55))	('LUAD', 'Disease', (194, 198))	('mutation', 'Var', (79, 87))	('improvement', 'PosReg', (116, 127))	('EGFR', 'Gene', (74, 78))
116953	32578582	The high expression rate of CHEK1 in breast cancer was found to be 61%, and high expression was related to tumor size, triple-negative subtype, basal phenotype, epithelial-stromal transformation, dysfunction of the DNA homologous repair pathway and poor prognosis.	('breast cancer', 'Disease', (37, 50))	('breast cancer', 'Phenotype', 'HP:0003002', (37, 50))	('CHEK1', 'Gene', '1111', (28, 33))	('dysfunction', 'Var', (196, 207))	('tumor', 'Disease', (107, 112))	('epithelial-stromal transformation', 'CPA', (161, 194))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('CHEK1', 'Gene', (28, 33))	('expression', 'MPA', (9, 19))	('related', 'Reg', (96, 103))	('DNA homologous repair pathway', 'Pathway', (215, 244))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('breast cancer', 'Disease', 'MESH:D001943', (37, 50))	('expression', 'MPA', (81, 91))
116956	32578582	CCNB1 is an influential biomarker for the prognosis of estrogen receptor (ER)+ breast cancer; targeting CCNB1 can prevent or even reverse resistance to hormone therapy and facilitate personalized treatment.	('CCNB1', 'Gene', (104, 109))	('resistance to hormone therapy', 'MPA', (138, 167))	('CCNB1', 'Gene', '891', (104, 109))	('breast cancer', 'Disease', 'MESH:D001943', (79, 92))	('facilitate', 'PosReg', (172, 182))	('resistance to hormone therapy', 'Phenotype', 'HP:0002930', (138, 167))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('breast cancer', 'Disease', (79, 92))	('personalized treatment', 'CPA', (183, 205))	('estrogen receptor', 'Gene', (55, 72))	('breast cancer', 'Phenotype', 'HP:0003002', (79, 92))	('CCNB1', 'Gene', (0, 5))	('estrogen receptor', 'Gene', '2099', (55, 72))	('prevent', 'NegReg', (114, 121))	('CCNB1', 'Gene', '891', (0, 5))	('reverse', 'NegReg', (130, 137))	('targeting', 'Var', (94, 103))	('ER', 'Gene', '2099', (74, 76))
116962	32578582	Studies have shown that dysregulated gene expression can lead to the occurrence of tumors.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumors', 'Disease', (83, 89))	('lead to', 'Reg', (57, 64))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('tumors', 'Disease', 'MESH:D009369', (83, 89))	('dysregulated gene', 'Var', (24, 41))
116963	32218699	Integrative analysis of DNA methylation-driven genes for the prognosis of lung squamous cell carcinoma using MethylMix Background: DNA methylation acts as a key component in epigenetic modifications of genomic function and functions as disease-specific prognostic biomarkers for lung squamous cell carcinoma (LUSC).	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (79, 102))	('lung squamous cell carcinoma', 'Disease', (74, 102))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (279, 307))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (279, 307))	('LUSC', 'Phenotype', 'HP:0030359', (309, 313))	('epigenetic', 'Var', (174, 184))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (284, 307))	('lung squamous cell carcinoma', 'Disease', (279, 307))	('carcinoma', 'Phenotype', 'HP:0030731', (298, 307))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (74, 102))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (74, 102))
116965	32218699	Univariate and multivariate Cox regression analyses showed that twelve aberrant methylated genes (ATP6V0CP3, AGGF1P3, RP11-264L1.4, HIST1H4K, LINC01158, CH17-140K24.1, CTC-523E23.14, ADCYAP1, COX11P1, TRIM58, FOXD4L6, CBLN1) were entered into a Cox predictive model associated with overall survival in LUSC patients.	('HIST1H4K', 'Gene', '8362', (132, 140))	('AGGF1P3', 'Gene', '391552', (109, 116))	('TRIM58', 'Gene', '25893', (201, 207))	('RP11', 'Gene', (118, 122))	('FOXD4L6', 'Gene', (209, 216))	('patients', 'Species', '9606', (307, 315))	('Cox', 'Gene', (245, 248))	('CTC-523E23.14', 'Var', (168, 181))	('LUSC', 'Phenotype', 'HP:0030359', (302, 306))	('ATP6V0CP3', 'Gene', '442211', (98, 107))	('AGGF1P3', 'Gene', (109, 116))	('TRIM58', 'Gene', (201, 207))	('Cox', 'Gene', '1351', (28, 31))	('COX11P1', 'Gene', '140468', (192, 199))	('CH17-140K24.1', 'Var', (153, 166))	('ADCYAP1', 'Gene', '116', (183, 190))	('CBLN1', 'Gene', (218, 223))	('LINC01158', 'Gene', '100506421', (142, 151))	('Cox', 'Gene', (28, 31))	('ATP6V0CP3', 'Gene', (98, 107))	('RP11', 'Gene', '26121', (118, 122))	('associated', 'Reg', (266, 276))	('ADCYAP1', 'Gene', (183, 190))	('HIST1H4K', 'Gene', (132, 140))	('LINC01158', 'Gene', (142, 151))	('COX11P1', 'Gene', (192, 199))	('FOXD4L6', 'Gene', '653404', (209, 216))	('CBLN1', 'Gene', '869', (218, 223))	('Cox', 'Gene', '1351', (245, 248))
116966	32218699	Methylation and gene expression combined survival analysis showed that the survival rate of hypermethylation and low-expression of DQX1 and WDR61 were low.	('WDR61', 'Gene', '80349', (140, 145))	('low-expression', 'NegReg', (113, 127))	('WDR61', 'Gene', (140, 145))	('low', 'NegReg', (151, 154))	('hypermethylation', 'Var', (92, 108))	('DQX1', 'Gene', (131, 135))	('DQX1', 'Gene', '165545', (131, 135))
116967	32218699	The expression of DQX1 had a significantly negatively correlated with the methylation site cg02034222.	('cg02034222', 'Chemical', '-', (91, 101))	('expression', 'MPA', (4, 14))	('DQX1', 'Gene', (18, 22))	('DQX1', 'Gene', '165545', (18, 22))	('negatively', 'NegReg', (43, 53))	('cg02034222', 'Var', (91, 101))	('methylation', 'MPA', (74, 85))
116974	32218699	DNA methylation is one of the most important elements in epigenetic modifications and participates in the regulation of cellular functions and carcinogenesis.	('participates', 'Reg', (86, 98))	('carcinogenesis', 'Disease', 'MESH:D063646', (143, 157))	('epigenetic', 'Var', (57, 67))	('carcinogenesis', 'Disease', (143, 157))	('cellular functions', 'MPA', (120, 138))
116975	32218699	Epigenetic modification, especially DNA methylation, plays a significant role in predicting the prognosis of lung cancer.	('lung cancer', 'Disease', (109, 120))	('lung cancer', 'Phenotype', 'HP:0100526', (109, 120))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('lung cancer', 'Disease', 'MESH:D008175', (109, 120))	('DNA', 'MPA', (36, 39))	('Epigenetic modification', 'Var', (0, 23))
116977	32218699	Aberrant ANK1 methylation contributes to miR-486-5p repression and discriminates lung tumors by histology and smoking status.	('Aberrant', 'Var', (0, 8))	('lung tumors', 'Phenotype', 'HP:0100526', (81, 92))	('lung tumors', 'Disease', (81, 92))	('ANK1', 'Gene', '286', (9, 13))	('miR-486-5p repression', 'MPA', (41, 62))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('ANK1', 'Gene', (9, 13))	('methylation', 'Var', (14, 25))	('lung tumors', 'Disease', 'MESH:D008175', (81, 92))
116986	32218699	We selected 92 aberrant methylated genes to submit to multivariate Cox regression analysis with the screening criteria P < 0.05.	('aberrant methylated genes', 'Var', (15, 40))	('Cox', 'Gene', '1351', (67, 70))	('Cox', 'Gene', (67, 70))
116992	32218699	In order to further explore the survival rate of methylation site cg02034222 in DQX1 in LUSC patients, we performed the Kaplan-Meier curve analysis of methylation site cg02034222 in DQX1 in LUSC patients.	('LUSC', 'Phenotype', 'HP:0030359', (190, 194))	('DQX1', 'Gene', (182, 186))	('LUSC', 'Phenotype', 'HP:0030359', (88, 92))	('DQX1', 'Gene', '165545', (182, 186))	('patients', 'Species', '9606', (195, 203))	('cg02034222', 'Chemical', '-', (168, 178))	('DQX1', 'Gene', (80, 84))	('cg02034222', 'Var', (168, 178))	('DQX1', 'Gene', '165545', (80, 84))	('patients', 'Species', '9606', (93, 101))	('cg02034222', 'Chemical', '-', (66, 76))
116995	32218699	The distribution of the methylation degree shows that DQX1 is hyper-methylated in non-LUSC patients and hypo-methylated in LUSC patients (Figure 1E).	('hypo-methylated', 'Var', (104, 119))	('patients', 'Species', '9606', (91, 99))	('LUSC', 'Phenotype', 'HP:0030359', (86, 90))	('hyper-methylated', 'PosReg', (62, 78))	('LUSC', 'Phenotype', 'HP:0030359', (123, 127))	('non-LUSC', 'Disease', (82, 90))	('patients', 'Species', '9606', (128, 136))	('DQX1', 'Gene', (54, 58))	('DQX1', 'Gene', '165545', (54, 58))
116998	32218699	As we can see from the Figure 4, the methylation-driven genes were most enriched in BARD1 signaling events, Protein processing in endoplasmic reticulum - Homo sapiens (human) and E3 ubiquitin ligases ubiquitinate target proteins (P<0.01).	('human', 'Species', '9606', (168, 173))	('BARD1', 'Gene', (84, 89))	('Homo sapiens', 'Species', '9606', (154, 166))	('E3 ubiquitin ligases ubiquitinate', 'Enzyme', (179, 212))	('methylation-driven genes', 'Var', (37, 61))	('BARD1', 'Gene', '580', (84, 89))
117003	32218699	The heat-map shows that 12 differentially methylated genes (ATP6V0CP3, AGGF1P3, RP11-264L1.4, HIST1H4K, LINC01158, CH17-140K24.1, CTC-523E23.14, ADCYAP1, COX11P1, TRIM58, FOXD4L6, CBLN1) were divided into two groups based on the median risk scores (Figure 5A).	('TRIM58', 'Gene', (163, 169))	('HIST1H4K', 'Gene', '8362', (94, 102))	('AGGF1P3', 'Gene', (71, 78))	('CH17-140K24.1', 'Var', (115, 128))	('ADCYAP1', 'Gene', '116', (145, 152))	('COX11P1', 'Gene', '140468', (154, 161))	('CBLN1', 'Gene', (180, 185))	('ATP6V0CP3', 'Gene', '442211', (60, 69))	('RP11', 'Gene', '26121', (80, 84))	('ADCYAP1', 'Gene', (145, 152))	('CBLN1', 'Gene', '869', (180, 185))	('LINC01158', 'Gene', '100506421', (104, 113))	('COX11P1', 'Gene', (154, 161))	('ATP6V0CP3', 'Gene', (60, 69))	('AGGF1P3', 'Gene', '391552', (71, 78))	('TRIM58', 'Gene', '25893', (163, 169))	('RP11', 'Gene', (80, 84))	('HIST1H4K', 'Gene', (94, 102))	('FOXD4L6', 'Gene', '653404', (171, 178))	('CTC-523E23.14', 'Var', (130, 143))	('LINC01158', 'Gene', (104, 113))	('FOXD4L6', 'Gene', (171, 178))
117018	32218699	As is shown in Figure 7C, the expression of DQX1 had a significant correlation (Cor = -0.725) with cg02034222 methylation (P = 1.26e-74).	('DQX1', 'Gene', '165545', (44, 48))	('methylation', 'MPA', (110, 121))	('cg02034222', 'Chemical', '-', (99, 109))	('cg02034222', 'Var', (99, 109))	('correlation', 'Interaction', (67, 78))	('DQX1', 'Gene', (44, 48))
117019	32218699	In order to further figure out whether the one methylation site (cg02034222) in DQX1 is responsible of the survival rate of LUSC patients, we performed survival analysis of methylation site (cg02034222) in DQX1 in hypermethylation and hypomethylation LUSC patients (Figure 7D).	('hypomethylation', 'Var', (235, 250))	('LUSC', 'Phenotype', 'HP:0030359', (124, 128))	('patients', 'Species', '9606', (129, 137))	('cg02034222', 'Chemical', '-', (191, 201))	('DQX1', 'Gene', (206, 210))	('patients', 'Species', '9606', (256, 264))	('cg02034222', 'Var', (191, 201))	('DQX1', 'Gene', '165545', (206, 210))	('hypermethylation', 'Var', (214, 230))	('DQX1', 'Gene', (80, 84))	('LUSC', 'Phenotype', 'HP:0030359', (251, 255))	('DQX1', 'Gene', '165545', (80, 84))	('cg02034222', 'Chemical', '-', (65, 75))
117020	32218699	The one CpG site cg02034222 in DQX1 in hypermethylation LUSC patients had a poor survival rate than the one CpG site cg02034222 in DQX1 in hypomethylation LUSC patients (P = 0.021).	('poor', 'NegReg', (76, 80))	('survival', 'CPA', (81, 89))	('patients', 'Species', '9606', (160, 168))	('LUSC', 'Phenotype', 'HP:0030359', (56, 60))	('LUSC', 'Phenotype', 'HP:0030359', (155, 159))	('patients', 'Species', '9606', (61, 69))	('DQX1', 'Gene', (31, 35))	('cg02034222', 'Chemical', '-', (17, 27))	('DQX1', 'Gene', '165545', (31, 35))	('DQX1', 'Gene', (131, 135))	('cg02034222', 'Chemical', '-', (117, 127))	('DQX1', 'Gene', '165545', (131, 135))	('cg02034222', 'Var', (17, 27))
117024	32218699	Accumulating evidences have demonstrated that DNA methylation acts as the major molecular mechanism of epigenetic modification was associated with the human malignant cancer, incorporating lung cancer.	('DNA', 'MPA', (46, 49))	('cancer', 'Disease', (194, 200))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('human', 'Species', '9606', (151, 156))	('cancer', 'Disease', (167, 173))	('associated', 'Reg', (131, 141))	('lung cancer', 'Phenotype', 'HP:0100526', (189, 200))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('lung cancer', 'Disease', (189, 200))	('epigenetic modification', 'Var', (103, 126))	('cancer', 'Disease', 'MESH:D009369', (194, 200))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('lung cancer', 'Disease', 'MESH:D008175', (189, 200))
117026	32218699	The methylation of L1RE1, RARB, and RASSF1 acts as potential disease specific biomarkers for predicting the prognosis of lung cancer.	('RASSF1', 'Gene', '11186', (36, 42))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('lung cancer', 'Disease', 'MESH:D008175', (121, 132))	('L1RE1', 'Gene', (19, 24))	('methylation', 'Var', (4, 15))	('lung cancer', 'Disease', (121, 132))	('RASSF1', 'Gene', (36, 42))	('RARB', 'Gene', (26, 30))	('L1RE1', 'Gene', '4029', (19, 24))	('lung cancer', 'Phenotype', 'HP:0100526', (121, 132))	('RARB', 'Gene', '5915', (26, 30))
117027	32218699	TRIM58/cg26157385 methylation associated with eight genes including A2ML1, CCNE1, COBL, ESCO2, GPR115, MMP10, OVOL1 and SCGB1A1 in lung squamous cell carcinoma.	('COBL', 'Gene', '23242', (82, 86))	('MMP10', 'Gene', (103, 108))	('A2ML1', 'Gene', '144568', (68, 73))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (131, 159))	('SCGB1A1', 'Gene', '7356', (120, 127))	('lung squamous cell carcinoma', 'Disease', (131, 159))	('carcinoma', 'Phenotype', 'HP:0030731', (150, 159))	('ESCO2', 'Gene', (88, 93))	('associated', 'Reg', (30, 40))	('COBL', 'Gene', (82, 86))	('TRIM58', 'Gene', '25893', (0, 6))	('OVOL1', 'Gene', '5017', (110, 115))	('CCNE1', 'Gene', (75, 80))	('A2ML1', 'Gene', (68, 73))	('SCGB1A1', 'Gene', (120, 127))	('TRIM58', 'Gene', (0, 6))	('CCNE1', 'Gene', '898', (75, 80))	('OVOL1', 'Gene', (110, 115))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (131, 159))	('GPR115', 'Gene', '221393', (95, 101))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (136, 159))	('methylation', 'Var', (18, 29))	('MMP10', 'Gene', '4319', (103, 108))	('GPR115', 'Gene', (95, 101))	('ESCO2', 'Gene', '157570', (88, 93))
117031	32218699	In our study, univariate and multivariate Cox regression analysis shows that ATP6V0CP3, AGGF1P3, RP11-264L1.4, HIST1H4K, LINC01158, CH17-140K24.1, CTC-523E23.14, ADCYAP1, COX11P1, TRIM58, FOXD4L6, CBLN1 were associated with overall survival and could establish a survival predictive model to predict the prognosis of LUSC.	('overall survival', 'MPA', (224, 240))	('ATP6V0CP3', 'Gene', '442211', (77, 86))	('AGGF1P3', 'Gene', (88, 95))	('RP11', 'Gene', '26121', (97, 101))	('CH17-140K24.1', 'Var', (132, 145))	('COX11P1', 'Gene', '140468', (171, 178))	('ADCYAP1', 'Gene', '116', (162, 169))	('LUSC', 'Phenotype', 'HP:0030359', (317, 321))	('LINC01158', 'Gene', '100506421', (121, 130))	('CBLN1', 'Gene', (197, 202))	('ATP6V0CP3', 'Gene', (77, 86))	('ADCYAP1', 'Gene', (162, 169))	('TRIM58', 'Gene', '25893', (180, 186))	('HIST1H4K', 'Gene', (111, 119))	('RP11', 'Gene', (97, 101))	('Cox', 'Gene', '1351', (42, 45))	('LINC01158', 'Gene', (121, 130))	('COX11P1', 'Gene', (171, 178))	('FOXD4L6', 'Gene', '653404', (188, 195))	('CBLN1', 'Gene', '869', (197, 202))	('FOXD4L6', 'Gene', (188, 195))	('CTC-523E23.14', 'Var', (147, 160))	('TRIM58', 'Gene', (180, 186))	('HIST1H4K', 'Gene', '8362', (111, 119))	('AGGF1P3', 'Gene', '391552', (88, 95))	('Cox', 'Gene', (42, 45))	('associated', 'Reg', (208, 218))
117037	32218699	TRIM58/cg26157385 methylation may play a significant role for predicting the prognosis of LUSC.	('TRIM58', 'Gene', (0, 6))	('TRIM58', 'Gene', '25893', (0, 6))	('LUSC', 'Phenotype', 'HP:0030359', (90, 94))	('LUSC', 'Disease', (90, 94))	('methylation', 'Var', (18, 29))
117039	32218699	In our study, the joint of methylation and gene expression combined survival analysis shows that the survival rate of hypermethylation and low-expression of DQX1 was significant lower than the survival rate of hypomethylation and high-expression of DQX1.	('lower', 'NegReg', (178, 183))	('DQX1', 'Gene', (157, 161))	('hypermethylation', 'Var', (118, 134))	('DQX1', 'Gene', '165545', (157, 161))	('low-expression', 'Var', (139, 153))	('survival', 'CPA', (101, 109))	('DQX1', 'Gene', (249, 253))	('DQX1', 'Gene', '165545', (249, 253))
117040	32218699	Epigenome-wide association studies (EWASs) suggested a novel association between T2D and cg06721411(DQX1; P value=1.18x10(-9)).	('T2D', 'Disease', (81, 84))	('DQX1', 'Gene', (100, 104))	('cg06721411', 'Var', (89, 99))	('DQX1', 'Gene', '165545', (100, 104))
117041	32218699	The survival rate of hypomethylation and high-expression of WDR61 was significant higher than the survival rate of hypermethylation and low-expression of WDR61.	('WDR61', 'Gene', '80349', (154, 159))	('hypomethylation', 'Var', (21, 36))	('survival', 'CPA', (4, 12))	('higher', 'PosReg', (82, 88))	('WDR61', 'Gene', (154, 159))	('WDR61', 'Gene', (60, 65))	('high-expression', 'Var', (41, 56))	('WDR61', 'Gene', '80349', (60, 65))
117042	32218699	The expression of DQX1 was significantly negatively associated with the methylation sites cg02034222 (P value= 1.26e-74), which might provide a significant horizon to explore prognostic biomarkers for predicting the diagnosis and prognosis of LUSC.	('negatively', 'NegReg', (41, 51))	('cg02034222', 'Chemical', '-', (90, 100))	('methylation sites cg02034222', 'Var', (72, 100))	('cg02034222', 'Var', (90, 100))	('expression', 'MPA', (4, 14))	('DQX1', 'Gene', (18, 22))	('DQX1', 'Gene', '165545', (18, 22))	('LUSC', 'Phenotype', 'HP:0030359', (243, 247))	('LUSC', 'Disease', (243, 247))
117045	32218699	In addition, the DNA methylation and gene expression levels of DQX1 and WDR61 are significantly associated with overall survival and the expression of DQX1 has a significantly negatively correlated with the methylation site cg02034222.	('WDR61', 'Gene', (72, 77))	('gene expression levels', 'MPA', (37, 59))	('expression', 'MPA', (137, 147))	('negatively', 'NegReg', (176, 186))	('DQX1', 'Gene', (151, 155))	('cg02034222', 'Var', (224, 234))	('associated', 'Reg', (96, 106))	('DQX1', 'Gene', '165545', (151, 155))	('WDR61', 'Gene', '80349', (72, 77))	('DQX1', 'Gene', (63, 67))	('DNA methylation', 'MPA', (17, 32))	('DQX1', 'Gene', '165545', (63, 67))	('overall survival', 'MPA', (112, 128))	('cg02034222', 'Chemical', '-', (224, 234))
117151	28529621	In addition, lung cancer cell lines transfected with wild-type or mutated p53 constructs were overexpressed with HOXA5 for invasion assay.	('mutated', 'Var', (66, 73))	('lung cancer', 'Disease', (13, 24))	('lung cancer', 'Phenotype', 'HP:0100526', (13, 24))	('HOXA5', 'Gene', '3202', (113, 118))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('p53', 'Gene', (74, 77))	('lung cancer', 'Disease', 'MESH:D008175', (13, 24))	('p53', 'Gene', '7157', (74, 77))	('HOXA5', 'Gene', (113, 118))
117154	28529621	In addition, poor prognosis is seen in group with both non-immunoreactive for p53 and HOXA5.	('HOXA5', 'Gene', '3202', (86, 91))	('HOXA5', 'Gene', (86, 91))	('non-immunoreactive for', 'Var', (55, 77))	('p53', 'Gene', (78, 81))	('p53', 'Gene', '7157', (78, 81))
117180	28529621	The expression vectors for human p53 wild-type and mutants were gifts from Dr. T.-M. Hong.	('mutants', 'Var', (51, 58))	('human', 'Species', '9606', (27, 32))	('expression vectors', 'Species', '29278', (4, 22))	('p53', 'Gene', (33, 36))	('p53', 'Gene', '7157', (33, 36))
117182	28529621	The invasiveness of tested cells transfected with HOXA5, various p53 mutant constructs or vector alone was examined in a transwell assay using chambers (8-mum pore size; Corning Costar, Cambridge, MA, USA) and transwell filters coated with Matrigel (BD Biosciences, Franklin Lakes, NJ, USA), as described previously.	('p53', 'Gene', (65, 68))	('p53', 'Gene', '7157', (65, 68))	('mutant', 'Var', (69, 75))	('Corning Costar', 'Disease', 'MESH:D002145', (170, 184))	('HOXA5', 'Gene', (50, 55))	('HOXA5', 'Gene', '3202', (50, 55))	('Corning Costar', 'Disease', (170, 184))
117222	28529621	Group with high mRNA expression levels of both p53 and HOXA5 is associated with better overall survival in lung cancer patients, HR=0.46 (0.29-0.75), P=0.0015 (Figure 2C).	('mRNA expression levels', 'MPA', (16, 38))	('overall survival', 'CPA', (87, 103))	('HOXA5', 'Gene', (55, 60))	('lung cancer', 'Disease', 'MESH:D008175', (107, 118))	('expression', 'Species', '29278', (21, 31))	('patients', 'Species', '9606', (119, 127))	('HOXA5', 'Gene', '3202', (55, 60))	('better', 'PosReg', (80, 86))	('lung cancer', 'Disease', (107, 118))	('high', 'Var', (11, 15))	('lung cancer', 'Phenotype', 'HP:0100526', (107, 118))	('p53', 'Gene', (47, 50))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('p53', 'Gene', '7157', (47, 50))
117227	28529621	First, various human p53 cDNA wild-typed or mutated expression vectors or control vectors were transiently transfected into H1299 cells and performed in vitro invasion assays.	('H1299', 'CellLine', 'CVCL:0060', (124, 129))	('p53', 'Gene', '7157', (21, 24))	('mutated', 'Var', (44, 51))	('expression vectors', 'Species', '29278', (52, 70))	('human', 'Species', '9606', (15, 20))	('p53', 'Gene', (21, 24))
117228	28529621	As shown in Figure 3A, wild-typed p53 expression could significantly inhibit H1299 cell invasive capabilities compared with pCEP4 vector control while p53 R248W mutant increases H1299 cell invasion.	('p53', 'Gene', (34, 37))	('p53', 'Gene', '7157', (34, 37))	('expression', 'Species', '29278', (38, 48))	('H1299 cell invasion', 'CPA', (178, 197))	('increases', 'PosReg', (168, 177))	('R248W', 'Mutation', 'rs121912651', (155, 160))	('p53', 'Gene', '7157', (151, 154))	('H1299 cell invasive capabilities', 'CPA', (77, 109))	('R248W', 'Var', (155, 160))	('H1299', 'CellLine', 'CVCL:0060', (77, 82))	('H1299', 'CellLine', 'CVCL:0060', (178, 183))	('p53', 'Gene', (151, 154))	('inhibit', 'NegReg', (69, 76))
117231	28529621	In addition, cotransfection of HOXA5 and wild-typed p53, p53 V173L or p53 L22Q/W23S mutated expression constructs could further lower the invasive capabilities of H1299 cells (Figure 3B).	('invasive capabilities of H1299 cells', 'CPA', (138, 174))	('HOXA5', 'Gene', '3202', (31, 36))	('V173L', 'Var', (61, 66))	('L22Q', 'Var', (74, 78))	('p53', 'Gene', (70, 73))	('p53', 'Gene', '7157', (70, 73))	('W23S', 'Var', (79, 83))	('HOXA5', 'Gene', (31, 36))	('p53', 'Gene', (52, 55))	('H1299', 'CellLine', 'CVCL:0060', (163, 168))	('p53', 'Gene', '7157', (52, 55))	('V173L', 'Mutation', 'rs876660754', (61, 66))	('lower', 'NegReg', (128, 133))	('p53', 'Gene', (57, 60))	('expression', 'Species', '29278', (92, 102))	('W23S', 'SUBSTITUTION', 'None', (79, 83))	('p53', 'Gene', '7157', (57, 60))	('L22Q', 'SUBSTITUTION', 'None', (74, 78))
117247	28529621	Group with high mRNA expression levels of both p53 and HOXA5 is associated with better overall survival in lung cancer patients which was consistent with our results.	('mRNA expression levels', 'MPA', (16, 38))	('overall survival', 'CPA', (87, 103))	('HOXA5', 'Gene', (55, 60))	('lung cancer', 'Disease', 'MESH:D008175', (107, 118))	('expression', 'Species', '29278', (21, 31))	('patients', 'Species', '9606', (119, 127))	('HOXA5', 'Gene', '3202', (55, 60))	('better', 'PosReg', (80, 86))	('lung cancer', 'Disease', (107, 118))	('high', 'Var', (11, 15))	('lung cancer', 'Phenotype', 'HP:0100526', (107, 118))	('p53', 'Gene', (47, 50))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('p53', 'Gene', '7157', (47, 50))
117260	28529621	Our results showed different invasion abilities in different p53 mutant genotypes of H1299 cells.	('mutant', 'Var', (65, 71))	('invasion abilities', 'CPA', (29, 47))	('H1299', 'CellLine', 'CVCL:0060', (85, 90))	('p53', 'Gene', '7157', (61, 64))	('p53', 'Gene', (61, 64))
117261	28529621	For example, to study the possible role for the p53 N-terminus, a doubly mutated form of human p53, L22Q/W23S, was examined.	('p53', 'Gene', (48, 51))	('human', 'Species', '9606', (89, 94))	('W23S', 'SUBSTITUTION', 'None', (105, 109))	('p53', 'Gene', '7157', (48, 51))	('L22Q', 'SUBSTITUTION', 'None', (100, 104))	('p53', 'Gene', (95, 98))	('L22Q', 'Var', (100, 104))	('p53', 'Gene', '7157', (95, 98))	('W23S', 'Var', (105, 109))
117262	28529621	Previous studies showed that these transactivation domain residues may interact with a number of proteins including Mdm2, adenovirus E1B, TAFs and p300.	('p300', 'Var', (147, 151))	('adenovirus E1B', 'Protein', (122, 136))	('adenovirus', 'Species', '28285', (122, 132))	('Mdm2', 'Gene', (116, 120))	('interact', 'Interaction', (71, 79))
117264	28529621	Moreover, several p53 hotspot mutations (R175H, R248W and R273H) were found not only lost p53-dependent tumor suppressor activities, but also acquired new oncogenic activities to promote progression of cancers.	('p53', 'Gene', (90, 93))	('p53', 'Gene', '7157', (18, 21))	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('R248W', 'Var', (48, 53))	('oncogenic activities', 'CPA', (155, 175))	('p53', 'Gene', (18, 21))	('cancers', 'Disease', 'MESH:D009369', (202, 209))	('R273H', 'Mutation', 'rs28934576', (58, 63))	('lost', 'NegReg', (85, 89))	('tumor', 'Disease', (104, 109))	('R273H', 'Var', (58, 63))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('R175H', 'Mutation', 'rs28934578', (41, 46))	('R248W', 'Mutation', 'rs121912651', (48, 53))	('R175H', 'Var', (41, 46))	('p53', 'Gene', '7157', (90, 93))	('promote', 'PosReg', (179, 186))	('cancers', 'Phenotype', 'HP:0002664', (202, 209))	('cancers', 'Disease', (202, 209))
117266	28529621	Even under the induction of p53 mutant proteins in H1299 cells, HOXA5 overexpression could significantly lower cancer cell invasive capabilities.	('p53', 'Gene', (28, 31))	('lower', 'NegReg', (105, 110))	('H1299', 'CellLine', 'CVCL:0060', (51, 56))	('p53', 'Gene', '7157', (28, 31))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('proteins', 'Protein', (39, 47))	('mutant', 'Var', (32, 38))	('HOXA5', 'Gene', '3202', (64, 69))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('expression', 'Species', '29278', (74, 84))	('HOXA5', 'Gene', (64, 69))
117267	28529621	These results suggested that after overexpression of HOXA5 might activate or suppress the expression levels of some downstream target genes and these effects could overcome the influences of various p53 mutants in the lung cancer cells.	('lung cancer', 'Disease', (218, 229))	('p53', 'Gene', (199, 202))	('p53', 'Gene', '7157', (199, 202))	('lung cancer', 'Phenotype', 'HP:0100526', (218, 229))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('overcome', 'NegReg', (164, 172))	('mutants', 'Var', (203, 210))	('expression levels', 'MPA', (90, 107))	('activate', 'PosReg', (65, 73))	('expression', 'Species', '29278', (90, 100))	('HOXA5', 'Gene', (53, 58))	('HOXA5', 'Gene', '3202', (53, 58))	('lung cancer', 'Disease', 'MESH:D008175', (218, 229))	('suppress', 'NegReg', (77, 85))	('expression', 'Species', '29278', (39, 49))
117277	28529621	To our knowledge, this is the first study demonstrate the association between HOXA5 and tumor invasion with and without p53 mutation in NSCLC.	('NSCLC', 'Disease', 'MESH:D002289', (136, 141))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('p53', 'Gene', '7157', (120, 123))	('NSCLC', 'Phenotype', 'HP:0030358', (136, 141))	('HOXA5', 'Gene', '3202', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('mutation', 'Var', (124, 132))	('tumor', 'Disease', (88, 93))	('HOXA5', 'Gene', (78, 83))	('p53', 'Gene', (120, 123))	('NSCLC', 'Disease', (136, 141))
117295	28529621	Recent studies reported that three miroRNAs, miR-196a, miR-130, and miR-1271, could regulate NSCLC cell proliferation, invasion, migration, and angiogenesis via the downregulation of HOXA5.	('regulate', 'Reg', (84, 92))	('NSCLC', 'Disease', (93, 98))	('invasion', 'CPA', (119, 127))	('NSCLC', 'Disease', 'MESH:D002289', (93, 98))	('HOXA5', 'Gene', (183, 188))	('migration', 'CPA', (129, 138))	('miR-196a', 'Var', (45, 53))	('miR-130', 'Var', (55, 62))	('HOXA5', 'Gene', '3202', (183, 188))	('downregulation', 'NegReg', (165, 179))	('angiogenesis', 'CPA', (144, 156))	('miR-1271', 'Var', (68, 76))	('NSCLC', 'Phenotype', 'HP:0030358', (93, 98))
117300	28529621	Therefore, it cannot be seen the correlation between HOXA5 and other mutation such as EGFR mutation and ALK translocation.	('mutation', 'Var', (91, 99))	('EGFR', 'Gene', '1956', (86, 90))	('HOXA5', 'Gene', (53, 58))	('EGFR', 'Gene', (86, 90))	('HOXA5', 'Gene', '3202', (53, 58))
117302	28529621	In addition, methylation of the HOXA5 gene was seen in some cancers and we did not perform the methylation tests in the current study.	('cancers', 'Phenotype', 'HP:0002664', (60, 67))	('methylation', 'Var', (13, 24))	('cancers', 'Disease', (60, 67))	('cancers', 'Disease', 'MESH:D009369', (60, 67))	('HOXA5', 'Gene', (32, 37))	('HOXA5', 'Gene', '3202', (32, 37))	('seen', 'Reg', (47, 51))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
117314	26181029	Whole-exome sequencing of pretreatment tumor and germline patient samples was performed at a quaternary care academic medical center, and a candidate somatic variant was experimentally investigated for mediating erlotinib response.	('patient', 'Species', '9606', (58, 65))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('variant', 'Var', (158, 165))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('erlotinib', 'Chemical', 'MESH:D000069347', (212, 221))	('tumor', 'Disease', (39, 44))
117317	26181029	Hypotheses were formulated regarding enhanced erlotinib response in preclinical models harboring the patient tumor somatic variant MAPK1 E322K following the identification of tumor somatic variants.	('E322K', 'Mutation', 'rs1057519911', (137, 142))	('tumor', 'Disease', (175, 180))	('MAPK1', 'Gene', '5594', (131, 136))	('erlotinib', 'Chemical', 'MESH:D000069347', (46, 55))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('MAPK1', 'Gene', (131, 136))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('erlotinib response', 'MPA', (46, 64))	('patient', 'Species', '9606', (101, 108))	('enhanced', 'PosReg', (37, 45))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('E322K', 'Var', (137, 142))	('tumor', 'Disease', (109, 114))
117319	26181029	Paradoxically, the tumor harbored an activating MAPK1 E322K mutation (allelic fraction 0.13), which predicts ERK activation and erlotinib resistance in EGFR-mutant lung cancer.	('erlotinib resistance', 'MPA', (128, 148))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('tumor', 'Disease', (19, 24))	('E322K', 'Mutation', 'rs1057519911', (54, 59))	('MAPK1', 'Gene', '5594', (48, 53))	('lung cancer', 'Disease', (164, 175))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('activation', 'PosReg', (113, 123))	('EGFR', 'Gene', (152, 156))	('E322K', 'Var', (54, 59))	('activating', 'PosReg', (37, 47))	('erlotinib', 'Chemical', 'MESH:D000069347', (128, 137))	('ERK', 'Gene', '5594', (109, 112))	('MAPK1', 'Gene', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('lung cancer', 'Disease', 'MESH:D008175', (164, 175))	('lung cancer', 'Phenotype', 'HP:0100526', (164, 175))	('EGFR', 'Gene', '1956', (152, 156))	('ERK', 'Gene', (109, 112))
117320	26181029	The HNSCC cells with MAPK1 E322K exhibited enhanced EGFR phosphorylation and erlotinib sensitivity compared with wild-type MAPK1 cells.	('E322K', 'Var', (27, 32))	('MAPK1', 'Gene', '5594', (21, 26))	('enhanced', 'PosReg', (43, 51))	('E322K', 'Mutation', 'rs1057519911', (27, 32))	('MAPK1', 'Gene', (123, 128))	('EGFR', 'Gene', '1956', (52, 56))	('EGFR', 'Gene', (52, 56))	('MAPK1', 'Gene', (21, 26))	('erlotinib', 'Chemical', 'MESH:D000069347', (77, 86))	('erlotinib sensitivity', 'MPA', (77, 98))	('HNSCC', 'Phenotype', 'HP:0012288', (4, 9))	('MAPK1', 'Gene', '5594', (123, 128))
117322	26181029	The discovery of activating mutations in the epidermal growth factor receptor (EGFR) gene accelerated the clinical deployment of small-molecule tyrosine kinase inhibitors (TKIs) that effectively target the altered protein, yielding clinical benefit in many patients with EGFR-mutant lung adenocarcinoma.	('man', 'Species', '9606', (252, 255))	('EGFR', 'Gene', '1956', (79, 83))	('epidermal growth factor receptor', 'Gene', (45, 77))	('EGFR', 'Gene', (271, 275))	('EGFR', 'Gene', (79, 83))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (283, 302))	('activating', 'PosReg', (17, 27))	('carcinoma', 'Phenotype', 'HP:0030731', (293, 302))	('lung adenocarcinoma', 'Disease', (283, 302))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (283, 302))	('epidermal growth factor receptor', 'Gene', '1956', (45, 77))	('patients', 'Species', '9606', (257, 265))	('accelerated', 'PosReg', (90, 101))	('mutations', 'Var', (28, 37))	('EGFR', 'Gene', '1956', (271, 275))
117334	26181029	MAPK1-deleted cells were transfected with vector, wild-type MAPK1 or MAPK1 E322K expression constructs.	('MAPK1', 'Gene', '5594', (69, 74))	('MAPK1', 'Gene', (60, 65))	('MAPK1', 'Gene', (0, 5))	('MAPK1', 'Gene', (69, 74))	('MAPK1', 'Gene', '5594', (60, 65))	('E322K', 'Var', (75, 80))	('MAPK1', 'Gene', '5594', (0, 5))	('E322K', 'Mutation', 'rs1057519911', (75, 80))
117337	26181029	The presence of MAPK1 E322K predicts resistance to erlotinib therapy in preclinical models but was identified in the tumor of an extraordinary responder.	('erlotinib', 'Chemical', 'MESH:D000069347', (51, 60))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumor', 'Disease', (117, 122))	('MAPK1', 'Gene', '5594', (16, 21))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('E322K', 'Mutation', 'rs1057519911', (22, 27))	('E322K', 'Var', (22, 27))	('resistance to erlotinib therapy', 'MPA', (37, 68))	('predicts', 'Reg', (28, 36))	('MAPK1', 'Gene', (16, 21))
117338	26181029	Engineered MAPK1 E322K cells exhibit enhanced erlotinib sensitivity compared with MAPK1 wild-type cells.	('E322K', 'Var', (17, 22))	('erlotinib sensitivity', 'MPA', (46, 67))	('MAPK1', 'Gene', '5594', (11, 16))	('erlotinib', 'Chemical', 'MESH:D000069347', (46, 55))	('MAPK1', 'Gene', (11, 16))	('MAPK1', 'Gene', '5594', (82, 87))	('enhanced', 'PosReg', (37, 45))	('MAPK1', 'Gene', (82, 87))	('E322K', 'Mutation', 'rs1057519911', (17, 22))
117339	26181029	MAPK1 E322K induces EGFR activation in head and neck squamous cell carcinoma (HNSCC) in vitro models.	('E322K', 'Mutation', 'rs1057519911', (6, 11))	('MAPK1', 'Gene', (0, 5))	('EGFR', 'Gene', (20, 24))	('neck squamous cell carcinoma', 'Disease', (48, 76))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (53, 76))	('EGFR', 'Gene', '1956', (20, 24))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (39, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('HNSCC', 'Phenotype', 'HP:0012288', (78, 83))	('MAPK1', 'Gene', '5594', (0, 5))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (48, 76))	('activation', 'PosReg', (25, 35))	('E322K', 'Var', (6, 11))
117340	26181029	MAPK1 E322K is present at low frequencies in HNSCC and cervical cancers.	('E322K', 'Mutation', 'rs1057519911', (6, 11))	('HNSCC', 'Disease', (45, 50))	('MAPK1', 'Gene', (0, 5))	('HNSCC', 'Phenotype', 'HP:0012288', (45, 50))	('cancers', 'Phenotype', 'HP:0002664', (64, 71))	('cervical cancers', 'Disease', (55, 71))	('MAPK1', 'Gene', '5594', (0, 5))	('cervical cancers', 'Disease', 'MESH:D002583', (55, 71))	('E322K', 'Var', (6, 11))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
117348	26181029	The patient's disease was clinically staged as T1N2cM0 oral cavity squamous cell carcinoma (stage IVA).	('IVA', 'Disease', 'MESH:C538167', (98, 101))	('patient', 'Species', '9606', (4, 11))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (67, 90))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('squamous cell carcinoma', 'Disease', (67, 90))	('T1N2cM0', 'Var', (47, 54))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (67, 90))	('IVA', 'Disease', (98, 101))
117357	26181029	No somatic mutations, short insertions or deletions, or copy number alterations were observed in EGFR (Figure 2A and eTables 3 and 4 in the Supplement), PTEN, PIK3CA, or HRAS.	('HRAS', 'Gene', '3265', (170, 174))	('EGFR', 'Gene', '1956', (97, 101))	('PTEN', 'Gene', (153, 157))	('HRAS', 'Gene', (170, 174))	('EGFR', 'Gene', (97, 101))	('deletions', 'Var', (42, 51))	('PTEN', 'Gene', '5728', (153, 157))	('PIK3CA', 'Gene', (159, 165))	('PIK3CA', 'Gene', '5290', (159, 165))
117359	26181029	The MAPK1 alteration (allelic fraction, 0.13; median, 0.15) was particularly unexpected in this patient.	('alteration', 'Var', (10, 20))	('MAPK1', 'Gene', (4, 9))	('MAPK1', 'Gene', '5594', (4, 9))	('patient', 'Species', '9606', (96, 103))
117361	26181029	The E322K mutation occurs in approximately 1% of HNSCC and 8% of cervical squamous cell carcinomas.	('HNSCC', 'Phenotype', 'HP:0012288', (49, 54))	('HNSCC', 'Disease', (49, 54))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (74, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('carcinomas', 'Phenotype', 'HP:0030731', (88, 98))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (74, 97))	('E322K', 'Var', (4, 9))	('E322K', 'Mutation', 'rs1057519911', (4, 9))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (74, 98))	('squamous cell carcinomas', 'Disease', (74, 98))
117362	26181029	MAPK1 E322K causes constitutive activation of ERK2.	('E322K', 'Mutation', 'rs1057519911', (6, 11))	('MAPK1', 'Gene', (0, 5))	('ERK2', 'Gene', '5594', (46, 50))	('MAPK1', 'Gene', '5594', (0, 5))	('E322K', 'Var', (6, 11))	('ERK2', 'Gene', (46, 50))	('constitutive activation', 'MPA', (19, 42))
117363	26181029	MAPK1 amplification, which may also activate ERK signaling, confers EGFR TKI resistance in lung adenocarcinoma pre-clinical models.	('ERK', 'Gene', (45, 48))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (91, 110))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (91, 110))	('MAPK1', 'Gene', (0, 5))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('lung adenocarcinoma', 'Disease', (91, 110))	('EGFR', 'Gene', '1956', (68, 72))	('MAPK1', 'Gene', '5594', (0, 5))	('activate', 'PosReg', (36, 44))	('amplification', 'Var', (6, 19))	('EGFR', 'Gene', (68, 72))	('ERK', 'Gene', '5594', (45, 48))
117364	26181029	Thus, the presence of MAPK1 E322K would be predicted to result in ERK signaling activation and intrinsic resistance, rather than exquisite sensitivity, to EGFR-directed therapies.	('EGFR', 'Gene', '1956', (155, 159))	('EGFR', 'Gene', (155, 159))	('MAPK1', 'Gene', '5594', (22, 27))	('intrinsic resistance', 'CPA', (95, 115))	('E322K', 'Mutation', 'rs1057519911', (28, 33))	('result', 'Reg', (56, 62))	('ERK', 'Gene', '5594', (66, 69))	('MAPK1', 'Gene', (22, 27))	('E322K', 'Var', (28, 33))	('ERK', 'Gene', (66, 69))	('activation', 'PosReg', (80, 90))
117365	26181029	To explore the possibility that the MAPK1 E322K mutation may have paradoxically conferred exquisite dependency on aberrant EGFR signaling in this patient, wild-type MAPK1 (CAL-33) and MAPK1 E322K (HSC-6) HNSCC cells were analyzed for relative EGFR protein and pathway activation (Figure 3A).	('EGFR', 'Gene', (123, 127))	('EGFR', 'Gene', '1956', (123, 127))	('MAPK1', 'Gene', (165, 170))	('conferred', 'Reg', (80, 89))	('MAPK1', 'Gene', '5594', (165, 170))	('MAPK1', 'Gene', '5594', (184, 189))	('E322K', 'Mutation', 'rs1057519911', (190, 195))	('EGFR', 'Gene', '1956', (243, 247))	('E322K', 'Mutation', 'rs1057519911', (42, 47))	('HNSCC', 'Phenotype', 'HP:0012288', (204, 209))	('MAPK1', 'Gene', '5594', (36, 41))	('patient', 'Species', '9606', (146, 153))	('MAPK1', 'Gene', (184, 189))	('EGFR', 'Gene', (243, 247))	('E322K', 'Var', (42, 47))	('HSC-6', 'CellLine', 'CVCL:A615', (197, 202))	('MAPK1', 'Gene', (36, 41))
117366	26181029	The HNSCC cells harboring endogenous MAPK1 E322K expressed higher basal levels of PY1068 EGFR, a surrogate for activated EGFR, and downstream AKT signaling compared with wild-type MAPK1 cells.	('EGFR', 'Gene', (89, 93))	('EGFR', 'Gene', '1956', (121, 125))	('MAPK1', 'Gene', '5594', (180, 185))	('MAPK1', 'Gene', '5594', (37, 42))	('AKT', 'Gene', (142, 145))	('EGFR', 'Gene', (121, 125))	('MAPK1', 'Gene', (180, 185))	('E322K', 'Var', (43, 48))	('E322K', 'Mutation', 'rs1057519911', (43, 48))	('higher', 'PosReg', (59, 65))	('AKT', 'Gene', '207', (142, 145))	('MAPK1', 'Gene', (37, 42))	('EGFR', 'Gene', '1956', (89, 93))	('HNSCC', 'Phenotype', 'HP:0012288', (4, 9))
117367	26181029	Because CAL-33 and HSC-6 cells have additional non-overlapping alterations, we also engineered FaDu cells, which have a preexisting heterozygous MAPK1 deletion and are wild type for PIK3CA, PTEN, NRAS, HRAS, and AKT, to express vector, wild-type MAPK1 or the MAPK1-E322K mutant.	('MAPK1', 'Gene', '5594', (145, 150))	('PTEN', 'Gene', '5728', (190, 194))	('deletion', 'Var', (151, 159))	('HRAS', 'Gene', '3265', (202, 206))	('NRAS', 'Gene', '4893', (196, 200))	('HRAS', 'Gene', (202, 206))	('AKT', 'Gene', (212, 215))	('MAPK1', 'Gene', '5594', (246, 251))	('PIK3CA', 'Gene', '5290', (182, 188))	('MAPK1', 'Gene', (145, 150))	('E322K', 'Mutation', 'rs1057519911', (265, 270))	('MAPK1', 'Gene', '5594', (259, 264))	('NRAS', 'Gene', (196, 200))	('AKT', 'Gene', '207', (212, 215))	('MAPK1', 'Gene', (246, 251))	('HSC-6', 'CellLine', 'CVCL:A615', (19, 24))	('PTEN', 'Gene', (190, 194))	('PIK3CA', 'Gene', (182, 188))	('MAPK1', 'Gene', (259, 264))
117368	26181029	The resulting engineered MAPK1 E322K cells expressed higher basal levels of PY1068 EGFR (Figure 3B) and demonstrated significantly increased senescence (Figure 3C and eFigure 1 in the Supplement) and significantly increased cell death (eFigure 2 in the Supplement) following erlotinib treatment compared with cells expressing wild-type MAPK1 or vector control cells.	('EGFR', 'Gene', '1956', (83, 87))	('E322K', 'Var', (31, 36))	('higher', 'PosReg', (53, 59))	('senescence', 'CPA', (141, 151))	('increased', 'PosReg', (131, 140))	('MAPK1', 'Gene', (336, 341))	('E322K', 'Mutation', 'rs1057519911', (31, 36))	('MAPK1', 'Gene', '5594', (25, 30))	('EGFR', 'Gene', (83, 87))	('increased', 'PosReg', (214, 223))	('MAPK1', 'Gene', (25, 30))	('MAPK1', 'Gene', '5594', (336, 341))	('cell death', 'CPA', (224, 234))	('erlotinib', 'Chemical', 'MESH:D000069347', (275, 284))
117369	26181029	Finally, knockdown of ERK2 protein levels in MAPK1 E322K cells (HSC-6) resulted in reduced cell death following erlotinib treatment compared with parental and nontargeting small interfering RNA transfected cells (eFigure 3 in the Supplement).	('cell death', 'CPA', (91, 101))	('E322K', 'Var', (51, 56))	('knockdown', 'Var', (9, 18))	('protein', 'Protein', (27, 34))	('ERK2', 'Gene', (22, 26))	('reduced', 'NegReg', (83, 90))	('E322K', 'Mutation', 'rs1057519911', (51, 56))	('HSC-6', 'CellLine', 'CVCL:A615', (64, 69))	('MAPK1', 'Gene', '5594', (45, 50))	('erlotinib', 'Chemical', 'MESH:D000069347', (112, 121))	('MAPK1', 'Gene', (45, 50))	('ERK2', 'Gene', '5594', (22, 26))
117370	26181029	In aggregate, these data are consistent with the clinical observation that the presence of MAPK1 E322K can contribute to erlotinib sensitivity in HNSCC.	('erlotinib', 'Chemical', 'MESH:D000069347', (121, 130))	('HNSCC', 'Phenotype', 'HP:0012288', (146, 151))	('HNSCC', 'Disease', (146, 151))	('E322K', 'Var', (97, 102))	('erlotinib sensitivity', 'MPA', (121, 142))	('E322K', 'Mutation', 'rs1057519911', (97, 102))	('MAPK1', 'Gene', '5594', (91, 96))	('contribute', 'Reg', (107, 117))	('MAPK1', 'Gene', (91, 96))
117372	26181029	This response occurred in the context of an activating somatic MAPK1 E322K mutation and thus was particularly noteworthy given that MAPK1 amplification or activation predicts erlotinib resistance (rather than sensitivity) in preclinical cancer models.	('E322K', 'Var', (69, 74))	('activating', 'PosReg', (44, 54))	('E322K', 'Mutation', 'rs1057519911', (69, 74))	('predicts', 'Reg', (166, 174))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('MAPK1', 'Gene', (63, 68))	('MAPK1', 'Gene', '5594', (132, 137))	('MAPK1', 'Gene', '5594', (63, 68))	('cancer', 'Disease', 'MESH:D009369', (237, 243))	('erlotinib', 'Chemical', 'MESH:D000069347', (175, 184))	('cancer', 'Disease', (237, 243))	('MAPK1', 'Gene', (132, 137))	('activation', 'PosReg', (155, 165))	('erlotinib resistance', 'MPA', (175, 195))
117373	26181029	We then demonstrated that EGFR and downstream pathway members show increased activation in HNSCC cells harboring MAPK1 E322K compared with wild-type MAPK1 cells.	('EGFR', 'Gene', (26, 30))	('MAPK1', 'Gene', (113, 118))	('activation', 'PosReg', (77, 87))	('MAPK1', 'Gene', '5594', (149, 154))	('MAPK1', 'Gene', '5594', (113, 118))	('HNSCC', 'Phenotype', 'HP:0012288', (91, 96))	('MAPK1', 'Gene', (149, 154))	('EGFR', 'Gene', '1956', (26, 30))	('E322K', 'Var', (119, 124))	('E322K', 'Mutation', 'rs1057519911', (119, 124))
117380	26181029	Toward this end, it is unknown whether this MAPK1 E322K mutation may contribute to similar sensitivity to erlotinib therapy in other tumor types (eg, cervical cancer), or with antibody-mediated EGFR inhibition (eg, cetuximab).	('cancer', 'Disease', (159, 165))	('contribute', 'Reg', (69, 79))	('cetuximab', 'Chemical', 'MESH:D000068818', (215, 224))	('MAPK1', 'Gene', (44, 49))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('erlotinib', 'Chemical', 'MESH:D000069347', (106, 115))	('EGFR', 'Gene', '1956', (194, 198))	('E322K', 'Var', (50, 55))	('tumor', 'Disease', (133, 138))	('EGFR', 'Gene', (194, 198))	('MAPK1', 'Gene', '5594', (44, 49))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('E322K', 'Mutation', 'rs1057519911', (50, 55))
117382	26181029	Furthermore, whereas forced overexpression of MAPK1 E322K did increase erlotinib sensitivity in MAPK1-deleted HNSCC cells, the MAPK1 E332K mutation's effect on erlotinib sensitivity was modest.	('MAPK1', 'Gene', '5594', (46, 51))	('E322K', 'Var', (52, 57))	('erlotinib', 'Chemical', 'MESH:D000069347', (160, 169))	('MAPK1', 'Gene', (127, 132))	('E322K', 'Mutation', 'rs1057519911', (52, 57))	('HNSCC', 'Phenotype', 'HP:0012288', (110, 115))	('E332K', 'Var', (133, 138))	('MAPK1', 'Gene', (96, 101))	('erlotinib', 'Chemical', 'MESH:D000069347', (71, 80))	('E332K', 'Mutation', 'p.E332K', (133, 138))	('erlotinib sensitivity', 'MPA', (71, 92))	('MAPK1', 'Gene', (46, 51))	('overexpression', 'PosReg', (28, 42))	('MAPK1', 'Gene', '5594', (127, 132))	('MAPK1', 'Gene', '5594', (96, 101))	('increase', 'PosReg', (62, 70))
117385	26181029	Importantly, although experimental studies did not fully phenocopy the exquisite erlotinib sensitivity of the patient tumor, the results tracked with the patient's response and countered the expectation that MAPK1 E332K would confer erlotinib resistance.	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('patient', 'Species', '9606', (154, 161))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('MAPK1', 'Gene', '5594', (208, 213))	('E332K', 'Var', (214, 219))	('MAPK1', 'Gene', (208, 213))	('E332K', 'Mutation', 'p.E332K', (214, 219))	('erlotinib', 'Chemical', 'MESH:D000069347', (81, 90))	('tumor', 'Disease', (118, 123))	('patient', 'Species', '9606', (110, 117))	('erlotinib', 'Chemical', 'MESH:D000069347', (233, 242))	('erlotinib resistance', 'MPA', (233, 253))	('confer', 'Reg', (226, 232))
117392	25871396	In HNSCC cell lines, knock-down of AGR2 induced apoptosis, reduced sphere formation, and down-regulated Survivin, Cyclin D1, Bcl2, Bcl2l1, Slug, Snail, Nanog and Oct4.	('SCC', 'Gene', '6317', (5, 8))	('down-regulated', 'NegReg', (89, 103))	('reduced', 'NegReg', (59, 66))	('sphere formation', 'CPA', (67, 83))	('Cyclin D1', 'Gene', '595', (114, 123))	('Oct4', 'Gene', (162, 166))	('Cyclin D1', 'Gene', (114, 123))	('Bcl2', 'Gene', (125, 129))	('SCC', 'Gene', (5, 8))	('Slug', 'Gene', '6591', (139, 143))	('Bcl2', 'Gene', '596', (125, 129))	('Snail', 'Gene', '6615', (145, 150))	('induced', 'Reg', (40, 47))	('Bcl2l1', 'Gene', '598', (131, 137))	('knock-down', 'Var', (21, 31))	('Bcl2', 'Gene', (131, 135))	('Survivin', 'Protein', (104, 112))	('Snail', 'Gene', (145, 150))	('Bcl2', 'Gene', '596', (131, 135))	('AGR2', 'Gene', (35, 39))	('Nanog', 'Gene', '79923', (152, 157))	('Oct4', 'Gene', '5460', (162, 166))	('Slug', 'Gene', (139, 143))	('Nanog', 'Gene', (152, 157))	('Bcl2l1', 'Gene', (131, 137))	('apoptosis', 'CPA', (48, 57))
117394	25871396	In vitro knockdown TGFBR1 in HNSCC cell lines increased AGR2 expression.	('SCC', 'Gene', (31, 34))	('knockdown', 'Var', (9, 18))	('increased', 'PosReg', (46, 55))	('TGFBR1', 'Gene', '7046', (19, 25))	('TGFBR1', 'Gene', (19, 25))	('SCC', 'Gene', '6317', (31, 34))	('AGR2', 'Gene', (56, 60))	('expression', 'MPA', (61, 71))
117404	25871396	Moreover, aberrant expression of Snail2 (Slug) can induce radio resistance in cancer cells.	('Slug', 'Gene', '6591', (41, 45))	('Snail2', 'Gene', (33, 39))	('Snail2', 'Gene', '6591', (33, 39))	('Slug', 'Gene', (41, 45))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('aberrant expression', 'Var', (10, 29))	('induce', 'PosReg', (51, 57))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))
117412	25871396	Emerging evidences showed that abnormal expression of AGR2 might be involved in tumorigenesis and progression of human cancers, such as prostate, breast, ovarian, esophagus, gastro-intestinal tract, and lung cancers, as reviewed by Brychtova et al.	('abnormal', 'Var', (31, 39))	('AGR2', 'Gene', (54, 58))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('lung cancers', 'Disease', (203, 215))	('prostate', 'Disease', (136, 144))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('lung cancers', 'Phenotype', 'HP:0100526', (203, 215))	('ovarian', 'Disease', (154, 161))	('human', 'Species', '9606', (113, 118))	('cancers', 'Phenotype', 'HP:0002664', (208, 215))	('cancers', 'Disease', (208, 215))	('cancers', 'Phenotype', 'HP:0002664', (119, 126))	('cancers', 'Disease', (119, 126))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('tumor', 'Disease', (80, 85))	('breast', 'Disease', (146, 152))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('involved', 'Reg', (68, 76))	('cancers', 'Disease', 'MESH:D009369', (119, 126))	('cancers', 'Disease', 'MESH:D009369', (208, 215))	('esophagus', 'Disease', (163, 172))	('lung cancers', 'Disease', 'MESH:D008175', (203, 215))	('gastro-intestinal tract', 'Disease', (174, 197))
117414	25871396	Recent reports showed that aberrant AGR2 expression helps breast cancer cells survive under serum-depleted conditions and/or hypoxic culture conditions, promotes angiogenesis, and increases cell invasion.	('AGR2', 'Gene', (36, 40))	('aberrant', 'Var', (27, 35))	('breast cancer', 'Disease', 'MESH:D001943', (58, 71))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('increases', 'PosReg', (180, 189))	('breast cancer', 'Disease', (58, 71))	('cell invasion', 'CPA', (190, 203))	('breast cancer', 'Phenotype', 'HP:0003002', (58, 71))	('promotes', 'PosReg', (153, 161))	('angiogenesis', 'CPA', (162, 174))
117423	25871396	dataset, which independently performed DNA copy number analysis on oral squamous cell carcinoma, 38 out of 112 OSCCs showed amplification of AGR2 copy number (Fig.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (72, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('SCC', 'Gene', '6317', (112, 115))	('amplification', 'MPA', (124, 137))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (67, 95))	('AGR2', 'Gene', (141, 145))	('copy number', 'Var', (146, 157))	('oral squamous cell carcinoma', 'Disease', (67, 95))	('SCC', 'Gene', (112, 115))
117435	25871396	S2, high AGR2 expression may indicate a rather poor prognosis of HNSCC patient, whereas log-Rank analysis indicated that cumulative rate of the patients with high AGR2 (P = 0.1161, n = 29) expression did not reach statistical significance.	('patient', 'Species', '9606', (144, 151))	('SCC', 'Gene', (67, 70))	('expression', 'MPA', (14, 24))	('patients', 'Species', '9606', (144, 152))	('high', 'Var', (4, 8))	('patient', 'Species', '9606', (71, 78))	('SCC', 'Gene', '6317', (67, 70))	('AGR2', 'Gene', (9, 13))
117450	25871396	To direct identify the function of AGR2, we used siRNA to knockdown AGR2 in human HNSCC CAL27 and FaDu cell lines.	('human', 'Species', '9606', (76, 81))	('HNSCC CAL27', 'CellLine', 'CVCL:1107', (82, 93))	('knockdown', 'Var', (58, 67))	('AGR2', 'Gene', (68, 72))
117454	25871396	Therefore, we performed the sphere-forming assay to investigate the potential role of AGR2 knock down in the self-renewal capacity of CAL27 cells.	('CAL27', 'CellLine', 'CVCL:1107', (134, 139))	('knock down', 'Var', (91, 101))	('AGR2', 'Gene', (86, 90))
117457	25871396	S4 A-C) To verify whether AGR2 knockdown downregulated the protein expressions of CSC and EMT markers, we performed a Western blot analysis in the whole-cell lysate collected from CAL27 cell and FaDu cell line with or without AGR2 siRNA treatment.	('CAL27', 'CellLine', 'CVCL:1107', (180, 185))	('downregulated', 'NegReg', (41, 54))	('protein expressions', 'MPA', (59, 78))	('AGR2', 'Gene', (26, 30))	('knockdown', 'Var', (31, 40))
117460	25871396	The results support the hypothesis that AGR2 knockdown can effectively inhibit the self-renewal capacity of human HNSCC cells in vitro.	('SCC', 'Gene', (116, 119))	('inhibit', 'NegReg', (71, 78))	('SCC', 'Gene', '6317', (116, 119))	('knockdown', 'Var', (45, 54))	('human', 'Species', '9606', (108, 113))	('AGR2', 'Gene', (40, 44))
117462	25871396	Our previous work showed that mice with tissue specific deletion of tumor suppressor gene Pten in epithalia had spontaneous HNSCC (Fig.	('deletion', 'Var', (56, 64))	('tumor', 'Disease', (68, 73))	('mice', 'Species', '10090', (30, 34))	('epithalia', 'Disease', 'None', (98, 107))	('epithalia', 'Disease', (98, 107))	('SCC', 'Gene', '6317', (126, 129))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('Pten', 'Gene', (90, 94))	('SCC', 'Gene', (126, 129))
117468	25871396	Combined deletion of Tgfbr1/Pten in mice epithelia would lead to rapid tumor formation (Fig.	('Tgfbr1/Pten', 'Gene', (21, 32))	('deletion', 'Var', (9, 17))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('lead to', 'Reg', (57, 64))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('mice', 'Species', '10090', (36, 40))	('epithelia', 'Disease', 'None', (41, 50))	('tumor', 'Disease', (71, 76))	('epithelia', 'Disease', (41, 50))
117472	25871396	The mRNA levels of AGR2 in Tgfbr1 cKO mice and Tgfbr1/Pten mice were significantly higher as compared with wild type mice mucosa (P < 0.001 respectively, Fig.	('AGR2', 'Gene', (19, 23))	('mRNA levels', 'MPA', (4, 15))	('mice', 'Species', '10090', (59, 63))	('mice', 'Species', '10090', (38, 42))	('higher', 'PosReg', (83, 89))	('mice', 'Species', '10090', (117, 121))	('cKO', 'Var', (34, 37))	('Tgfbr1 cKO', 'Var', (27, 37))
117475	25871396	The protein level of AGR2 in PTEN, TGFBR1 as well as in combined PTEN/TGFBR1 knock down was significantly higher than scramble siRNA in CAL27 cell line (Fig.	('protein level', 'MPA', (4, 17))	('TGFBR1', 'Gene', (35, 41))	('PTEN', 'Gene', (65, 69))	('TGFBR1', 'Gene', '7046', (70, 76))	('TGFBR1', 'Gene', '7046', (35, 41))	('PTEN', 'Gene', '5728', (65, 69))	('PTEN', 'Gene', (29, 33))	('AGR2', 'Gene', (21, 25))	('PTEN', 'Gene', '5728', (29, 33))	('higher', 'PosReg', (106, 112))	('knock down', 'Var', (77, 87))	('CAL27', 'CellLine', 'CVCL:1107', (136, 141))	('TGFBR1', 'Gene', (70, 76))
117488	25871396	Nevertheless, in our present study, AGR2 was not significantly correlated with the prognosis of HNSCC patients, even if patients with high expression of AGR2 seemed to have longer survival time than those with low expression of AGR2.	('longer', 'PosReg', (173, 179))	('high expression', 'Var', (134, 149))	('SCC', 'Gene', '6317', (98, 101))	('patients', 'Species', '9606', (102, 110))	('patients', 'Species', '9606', (120, 128))	('survival time', 'CPA', (180, 193))	('AGR2', 'Gene', (153, 157))	('SCC', 'Gene', (98, 101))
117494	25871396	Additionally, knockdown of AGR2 in vitro significantly decreased the protein levels of two EMT-related transcription factors, namely, Snail and Slug.	('Slug', 'Gene', '6591', (144, 148))	('protein levels of', 'MPA', (69, 86))	('Snail', 'Gene', '6615', (134, 139))	('Snail', 'Gene', (134, 139))	('Slug', 'Gene', (144, 148))	('AGR2', 'Gene', (27, 31))	('decreased', 'NegReg', (55, 64))	('knockdown', 'Var', (14, 23))
117498	25871396	Our previous study suggested that the loss of Tgfbr1 in epithelial cells would lead to the accumulation of TGFbeta1 in stroma.	('loss', 'Var', (38, 42))	('Tgfbr1', 'Gene', (46, 52))	('accumulation', 'PosReg', (91, 103))	('epithelia', 'Disease', 'None', (56, 65))	('lead to', 'Reg', (79, 86))	('TGFbeta1', 'Gene', '7040', (107, 115))	('TGFbeta1', 'Gene', (107, 115))	('epithelia', 'Disease', (56, 65))
117507	25871396	In the present study, we showed for the first time that in vitro knockdown AGR2 may be correlated with self-renewal markers, such as Sox2, ALDH1, and Oct4.	('knockdown', 'Var', (65, 74))	('Oct4', 'Gene', (150, 154))	('correlated', 'Reg', (87, 97))	('AGR2', 'Gene', (75, 79))	('ALDH1', 'Gene', (139, 144))	('Sox2', 'Gene', '6657', (133, 137))	('Oct4', 'Gene', '5460', (150, 154))	('ALDH1', 'Gene', '216', (139, 144))	('Sox2', 'Gene', (133, 137))
117509	25871396	This observation agreed with the results of similar studies on breast cancer, thereby suggesting that inhibition of AGR2 reduced the protein level of Survivin and Cyclin D1.	('Cyclin D1', 'Gene', '595', (163, 172))	('AGR2', 'Gene', (116, 120))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('Cyclin D1', 'Gene', (163, 172))	('breast cancer', 'Disease', 'MESH:D001943', (63, 76))	('inhibition', 'Var', (102, 112))	('reduced', 'NegReg', (121, 128))	('breast cancer', 'Disease', (63, 76))	('breast cancer', 'Phenotype', 'HP:0003002', (63, 76))	('protein level of Survivin', 'MPA', (133, 158))
117519	25871396	After being transfected AGR2 siRNA (Qiagen) in final concentration of 5nM, CAL27 cells were detached by trypsin-EDTA.	('transfected', 'Var', (12, 23))	('AGR2', 'Gene', (24, 28))	('EDTA', 'Chemical', 'MESH:D004492', (112, 116))	('CAL27', 'CellLine', 'CVCL:1107', (75, 80))
117541	25871396	Custom made tissue arrays of formalin-fixed tissues from HNSCC mentioned above were constructed with 1.5mm core from each patient (T12-412) and T12-412-2) mentioned above.	('T12-412-2', 'Var', (144, 153))	('SCC', 'Gene', (59, 62))	('formalin', 'Chemical', 'MESH:D005557', (29, 37))	('patient', 'Species', '9606', (122, 129))	('SCC', 'Gene', '6317', (59, 62))	('T12-412', 'Var', (131, 138))
117555	27880728	To this aim, miRNA profiling was performed in human lung epithelial cells (BEAS-2B) expressing active AKT1 (BEAS-AKT1-E17K), active PI3KCA (BEAS-PIK3CA-E545K) or with silenced PTEN (BEAS-shPTEN).	('PTEN', 'Gene', (189, 193))	('AKT1', 'Gene', '207', (102, 106))	('miR', 'Gene', (13, 16))	('active PI3KCA', 'Var', (125, 138))	('active', 'Var', (95, 101))	('PTEN', 'Gene', '5728', (189, 193))	('AKT1', 'Gene', (102, 106))	('BEAS-AKT1', 'Gene', (108, 117))	('human', 'Species', '9606', (46, 51))	('PIK3CA', 'Gene', (145, 151))	('AKT1', 'Gene', '207', (113, 117))	('PTEN', 'Gene', (176, 180))	('E17K', 'Mutation', 'rs121434592', (118, 122))	('E545K', 'Mutation', 'rs104886003', (152, 157))	('AKT1', 'Gene', (113, 117))	('BEAS-AKT1', 'Gene', '207', (108, 117))	('BEAS-2B', 'CellLine', 'CVCL:0168', (75, 82))	('miR', 'Gene', '220972', (13, 16))	('PTEN', 'Gene', '5728', (176, 180))	('PIK3CA', 'Gene', '5290', (145, 151))
117558	27880728	By manipulating the expression of miR-196a in BEAS-2B and NCI-H460 cells, we obtained compelling evidence that this miRNA acts downstream the PI3K/AKT pathway, mediating some of the proliferative, pro-migratory and tumorigenic activity that this pathway exerts in lung epithelial cells, possibly through the regulation of FoxO1, CDKN1B (hereafter p27) and HOXA9.	('196a', 'Chemical', '-', (38, 42))	('miR', 'Gene', '220972', (116, 119))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('CDKN1B', 'Gene', (329, 335))	('HOXA9', 'Gene', (356, 361))	('miR', 'Gene', (116, 119))	('miR', 'Gene', '220972', (34, 37))	('p27', 'Gene', '3429', (347, 350))	('p27', 'Gene', (347, 350))	('manipulating', 'Var', (3, 15))	('rat', 'Species', '10116', (189, 192))	('BEAS-2B', 'CellLine', 'CVCL:0168', (46, 53))	('AKT', 'Gene', (147, 150))	('HOXA9', 'Gene', '3205', (356, 361))	('rat', 'Species', '10116', (204, 207))	('miR', 'Gene', (34, 37))	('CDKN1B', 'Gene', '1027', (329, 335))	('tumor', 'Disease', (215, 220))	('proliferative', 'CPA', (182, 195))	('mediating', 'Reg', (160, 169))	('tumor', 'Disease', 'MESH:D009369', (215, 220))	('FoxO1', 'Gene', (322, 327))	('FoxO1', 'Gene', '2308', (322, 327))	('AKT', 'Gene', '207', (147, 150))	('pro-migratory', 'CPA', (197, 210))	('NCI-H460 cells', 'CellLine', 'CVCL:0459', (58, 72))
117566	27880728	AKT is activated by recruitment to cell membrane via binding of its PH domain to 3'-phosphorylated phosphatidylinositols generated by PI3K and subsequent phosphorylation at T308 and S473.	('AKT', 'Gene', (0, 3))	('rat', 'Species', '10116', (125, 128))	('S473', 'Var', (182, 186))	('PI3K', 'Var', (134, 138))	('phosphorylation', 'Var', (154, 169))	('phosphatidylinositols', 'Chemical', 'MESH:D010716', (99, 120))	('AKT', 'Gene', '207', (0, 3))	('activated', 'PosReg', (7, 16))	('binding', 'Interaction', (53, 60))	('recruitment', 'MPA', (20, 31))
117572	27880728	Expression of miRNAs is systematically altered in several cancers and the rearrangement of many genes encoding miRNAs has been associated to multiple cancers.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('associated', 'Reg', (127, 137))	('cancers', 'Phenotype', 'HP:0002664', (150, 157))	('Expression', 'MPA', (0, 10))	('cancers', 'Disease', (150, 157))	('cancers', 'Phenotype', 'HP:0002664', (58, 65))	('cancers', 'Disease', 'MESH:D009369', (150, 157))	('cancers', 'Disease', 'MESH:D009369', (58, 65))	('miR', 'Gene', '220972', (14, 17))	('miR', 'Gene', (14, 17))	('cancers', 'Disease', (58, 65))	('miR', 'Gene', '220972', (111, 114))	('altered', 'Reg', (39, 46))	('rearrangement', 'Var', (74, 87))	('miR', 'Gene', (111, 114))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
117575	27880728	To determine the role of miRNAs in lung cancer driven by aberrant PI3K/AKT signaling, we have examined changes in miRNA levels that are induced by alterations of this pathway through different mutations that are observed in human NSCLC, including a gain-of-function mutant of PIK3CA (E545K), a gain-of-function mutant of AKT1 (E17K) and the loss of PTEN expression.	('lung cancer', 'Disease', 'MESH:D008175', (35, 46))	('E17K', 'Mutation', 'rs121434592', (327, 331))	('mutations', 'Var', (193, 202))	('lung cancer', 'Phenotype', 'HP:0100526', (35, 46))	('miR', 'Gene', '220972', (114, 117))	('rat', 'Species', '10116', (151, 154))	('E545K', 'Mutation', 'rs104886003', (284, 289))	('AKT', 'Gene', '207', (71, 74))	('miR', 'Gene', '220972', (25, 28))	('human', 'Species', '9606', (224, 229))	('AKT', 'Gene', (321, 324))	('miR', 'Gene', (114, 117))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('AKT1', 'Gene', '207', (321, 325))	('E545K', 'Var', (284, 289))	('gain-of-function', 'PosReg', (249, 265))	('PIK3CA', 'Gene', '5290', (276, 282))	('miR', 'Gene', (25, 28))	('lung cancer', 'Disease', (35, 46))	('PTEN', 'Gene', (349, 353))	('AKT1', 'Gene', (321, 325))	('gain-of-function', 'PosReg', (294, 310))	('NSCLC', 'Disease', 'MESH:D002289', (230, 235))	('AKT', 'Gene', '207', (321, 324))	('expression', 'MPA', (354, 364))	('AKT', 'Gene', (71, 74))	('NSCLC', 'Disease', (230, 235))	('PIK3CA', 'Gene', (276, 282))	('PTEN', 'Gene', '5728', (349, 353))
117576	27880728	Here we report that miR-196a is modulated by mutant PI3K, mutant AKT1 and by loss of PTEN, and represent a pivotal mediator of proliferation, migration/invasion and tumorigenicity elicited by aberrant activation of PI3K/AKT pathway.	('mutant', 'Var', (58, 64))	('miR', 'Gene', '220972', (20, 23))	('loss', 'NegReg', (77, 81))	('PTEN', 'Gene', (85, 89))	('AKT', 'Gene', '207', (65, 68))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('AKT', 'Gene', (220, 223))	('proliferation', 'CPA', (127, 140))	('miR', 'Gene', (20, 23))	('rat', 'Species', '10116', (134, 137))	('PTEN', 'Gene', '5728', (85, 89))	('AKT1', 'Gene', '207', (65, 69))	('modulated', 'Reg', (32, 41))	('AKT', 'Gene', '207', (220, 223))	('rat', 'Species', '10116', (145, 148))	('tumor', 'Disease', (165, 170))	('196a', 'Chemical', '-', (24, 28))	('mutant', 'Var', (45, 51))	('migration/invasion', 'CPA', (142, 160))	('AKT', 'Gene', (65, 68))	('AKT1', 'Gene', (65, 69))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('PI3K', 'Gene', (52, 56))
117577	27880728	The aim of this study was to identify a miRNA signature of aberrant PI3K/AKT signaling in NSCLC cells.	('miR', 'Gene', '220972', (40, 43))	('miR', 'Gene', (40, 43))	('AKT', 'Gene', (73, 76))	('aberrant', 'Var', (59, 67))	('NSCLC', 'Disease', (90, 95))	('NSCLC', 'Disease', 'MESH:D002289', (90, 95))	('AKT', 'Gene', '207', (73, 76))
117579	27880728	Immortalized, non-tumorigenic human bronchial epithelial cells (BEAS-2B) were engineered to express gain-of-function mutations of PIK3CA (PIK3CA-E545K), of AKT1 (AKT1-E17K) or were silenced for PTEN (BEAS-AKT1-E17K, BEAS-PIK3CA-E545K and BEAS-shPTEN, respectively) as described in previous work.	('BEAS-AKT1', 'Gene', '207', (200, 209))	('AKT1', 'Gene', '207', (156, 160))	('E17K', 'Mutation', 'rs121434592', (167, 171))	('PTEN', 'Gene', '5728', (245, 249))	('gain-of-function', 'PosReg', (100, 116))	('AKT1', 'Gene', (205, 209))	('E545K', 'Mutation', 'rs104886003', (228, 233))	('PIK3CA', 'Gene', (130, 136))	('tumor', 'Disease', (18, 23))	('BEAS-2B', 'CellLine', 'CVCL:0168', (64, 71))	('AKT1', 'Gene', '207', (162, 166))	('PTEN', 'Gene', (194, 198))	('PIK3CA', 'Gene', (138, 144))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('AKT1', 'Gene', (156, 160))	('mutations', 'Var', (117, 126))	('PIK3CA', 'Gene', '5290', (221, 227))	('BEAS-AKT1', 'Gene', (200, 209))	('PTEN', 'Gene', '5728', (194, 198))	('E545K', 'Mutation', 'rs104886003', (145, 150))	('AKT1', 'Gene', (162, 166))	('E17K', 'Mutation', 'rs121434592', (210, 214))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('human', 'Species', '9606', (30, 35))	('PIK3CA', 'Gene', '5290', (130, 136))	('AKT1', 'Gene', '207', (205, 209))	('PTEN', 'Gene', (245, 249))	('PIK3CA', 'Gene', (221, 227))	('PIK3CA', 'Gene', '5290', (138, 144))
117581	27880728	The presence of exogenous mutant PIK3CA, mutant AKT1 or of endogenous wild-type PTEN proteins in transduced cells as well as the activation of PI3K/AKT signaling was determined by immunoblot and are shown in Figure 1.	('AKT', 'Gene', '207', (148, 151))	('PTEN', 'Gene', (80, 84))	('PIK3CA', 'Gene', '5290', (33, 39))	('mutant', 'Var', (41, 47))	('AKT', 'Gene', (48, 51))	('PTEN', 'Gene', '5728', (80, 84))	('AKT1', 'Gene', '207', (48, 52))	('AKT', 'Gene', (148, 151))	('AKT1', 'Gene', (48, 52))	('mutant', 'Var', (26, 32))	('PIK3CA', 'Gene', (33, 39))	('AKT', 'Gene', '207', (48, 51))
117584	27880728	Analysis of the results allowed to identify 105 differentially expressed miRNAs (DEMs) in cells expressing mutant AKT1, comprising 42 up-regulated and 63 down-regulated, 106 DEMs in cells expressing mutant PIK3CA, 54 up-regulated and 52 down-regulated, and 91 DEMs in cells silenced for PTEN, 45 up-regulated and 46 down-regulated (Figure 2A).	('up-regulated', 'PosReg', (217, 229))	('mutant', 'Var', (107, 113))	('down-regulated', 'NegReg', (154, 168))	('up-regulated', 'PosReg', (296, 308))	('down-regulated', 'NegReg', (237, 251))	('PIK3CA', 'Gene', (206, 212))	('PTEN', 'Gene', (287, 291))	('AKT1', 'Gene', '207', (114, 118))	('miR', 'Gene', '220972', (73, 76))	('PTEN', 'Gene', '5728', (287, 291))	('miR', 'Gene', (73, 76))	('AKT1', 'Gene', (114, 118))	('PIK3CA', 'Gene', '5290', (206, 212))	('up-regulated', 'PosReg', (134, 146))
117585	27880728	Based on the 3 lists of DEMs, we focused our attention on the miRNAs whose expression was influenced specifically by the oncogenic alteration of AKT1, PIK3CA or PTEN, and, alternatively, on those commonly deregulated by two or three of the above-mentioned alterations.	('rat', 'Species', '10116', (135, 138))	('miR', 'Gene', '220972', (62, 65))	('PIK3CA', 'Gene', (151, 157))	('miR', 'Gene', (62, 65))	('rat', 'Species', '10116', (260, 263))	('AKT1', 'Gene', '207', (145, 149))	('PIK3CA', 'Gene', '5290', (151, 157))	('PTEN', 'Gene', (161, 165))	('AKT1', 'Gene', (145, 149))	('alteration', 'Var', (131, 141))	('PTEN', 'Gene', '5728', (161, 165))	('expression', 'MPA', (75, 85))	('influenced', 'Reg', (90, 100))
117586	27880728	We thereby found that 41/1145 DEMs analyzed (3.5%) were modulated by mutant AKT1 (15 up-regulated, 26 down-regulated), 42 DEMs analyzed (3.6%) were modulated by mutant PIK3CA (25 up-regulated, 17 down-regulated) and 39 DEMs analyzed (3.4%) were modulated by PTEN loss (22 up-regulated, 17 down-regulated; listed in Supplementary Tables S4-S6).	('mutant', 'Var', (161, 167))	('PTEN', 'Gene', '5728', (258, 262))	('mutant', 'Var', (69, 75))	('PIK3CA', 'Gene', (168, 174))	('loss', 'NegReg', (263, 267))	('up-regulated', 'PosReg', (272, 284))	('PIK3CA', 'Gene', '5290', (168, 174))	('AKT1', 'Gene', '207', (76, 80))	('down-regulated', 'NegReg', (289, 303))	('AKT1', 'Gene', (76, 80))	('modulated', 'Reg', (56, 65))	('up-regulated', 'PosReg', (179, 191))	('PTEN', 'Gene', (258, 262))	('up-regulated', 'PosReg', (85, 97))
117588	27880728	These DEMs are more likely to be the most relevant mediators of aberrant PI3K/AKT signaling in transformed bronchial epithelial cells.	('AKT', 'Gene', (78, 81))	('aberrant', 'Var', (64, 72))	('AKT', 'Gene', '207', (78, 81))
117590	27880728	This indicates that, altogether, aberrant PTEN/PI3K/AKT signaling regulated the expression of 200/1145 miRNAs (17.5%), though only 24 were common to all three alterations (2%).	('rat', 'Species', '10116', (163, 166))	('PTEN', 'Gene', (42, 46))	('PTEN', 'Gene', '5728', (42, 46))	('AKT', 'Gene', (52, 55))	('miR', 'Gene', '220972', (103, 106))	('expression', 'MPA', (80, 90))	('miR', 'Gene', (103, 106))	('aberrant', 'Var', (33, 41))	('regulated', 'Reg', (66, 75))	('AKT', 'Gene', '207', (52, 55))
117598	27880728	In particular, aberrant expression of miR-196a has been frequently reported in various cancers including NSCLC and it represents a major regulator of migration in NSCLC cells.	('NSCLC', 'Disease', 'MESH:D002289', (105, 110))	('cancers', 'Disease', (87, 94))	('aberrant expression', 'Var', (15, 34))	('196a', 'Chemical', '-', (42, 46))	('rat', 'Species', '10116', (153, 156))	('NSCLC', 'Disease', (163, 168))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cancers', 'Phenotype', 'HP:0002664', (87, 94))	('miR', 'Gene', '220972', (38, 41))	('NSCLC', 'Disease', 'MESH:D002289', (163, 168))	('miR', 'Gene', (38, 41))	('reported', 'Reg', (67, 75))	('NSCLC', 'Disease', (105, 110))	('cancers', 'Disease', 'MESH:D009369', (87, 94))
117614	27880728	In fact, we exploited the TCGA dataset to correlate the presence of activating mutations in genes within the PI3K/AKT pathway with the expression of miR-196a in multiple NSCLCs.	('AKT', 'Gene', '207', (114, 117))	('activating', 'PosReg', (68, 78))	('AKT', 'Gene', (114, 117))	('NSCLC', 'Disease', (170, 175))	('196a', 'Chemical', '-', (153, 157))	('miR', 'Gene', '220972', (149, 152))	('miR', 'Gene', (149, 152))	('NSCLC', 'Disease', 'MESH:D002289', (170, 175))	('mutations', 'Var', (79, 88))
117615	27880728	Samples were divided into 2 different groups: i) tumors mutated for AKT1, PIK3CA and PTEN (n=32), and ii) the remaining wild type tumors (n=391).	('tumors', 'Disease', (130, 136))	('tumors', 'Disease', 'MESH:D009369', (130, 136))	('AKT1', 'Gene', (68, 72))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('PIK3CA', 'Gene', '5290', (74, 80))	('mutated', 'Var', (56, 63))	('type tumors', 'Disease', (125, 136))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('type tumors', 'Disease', 'MESH:D009369', (125, 136))	('tumors', 'Disease', (49, 55))	('tumors', 'Disease', 'MESH:D009369', (49, 55))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('PTEN', 'Gene', (85, 89))	('AKT1', 'Gene', '207', (68, 72))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('PTEN', 'Gene', '5728', (85, 89))	('PIK3CA', 'Gene', (74, 80))
117616	27880728	We found that in the group of mutant samples, 19/32 (59.3%) showed high levels of miR-196a whereas in the group of wild type samples, 192/391 (49.1%) showed high levels of miR-196a.	('miR', 'Gene', '220972', (82, 85))	('miR', 'Gene', (82, 85))	('196a', 'Chemical', '-', (86, 90))	('196a', 'Chemical', '-', (176, 180))	('miR', 'Gene', '220972', (172, 175))	('miR', 'Gene', (172, 175))	('mutant', 'Var', (30, 36))
117617	27880728	Subsequently, we added to the group under analysis tumors harbouring KRAS mutations, an alteration known to activate PI3K/AKT signaling.	('KRAS', 'Gene', (69, 73))	('KRAS', 'Gene', '3845', (69, 73))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('mutations', 'Var', (74, 83))	('rat', 'Species', '10116', (92, 95))	('tumors', 'Disease', (51, 57))	('tumors', 'Disease', 'MESH:D009369', (51, 57))	('AKT', 'Gene', '207', (122, 125))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('AKT', 'Gene', (122, 125))
117619	27880728	These contradictory results could be explained by the consideration that a correlation between mutated members of the PI3K/AKT pathway and miR-196a expression can be observed when simple systems such as cell lines are analyzed, but not when more complex and heterogeneous samples as tumors are considered.	('miR', 'Gene', '220972', (139, 142))	('miR', 'Gene', (139, 142))	('tumors', 'Disease', 'MESH:D009369', (283, 289))	('tumor', 'Phenotype', 'HP:0002664', (283, 288))	('rat', 'Species', '10116', (61, 64))	('AKT', 'Gene', '207', (123, 126))	('mutated', 'Var', (95, 102))	('tumors', 'Disease', (283, 289))	('196a', 'Chemical', '-', (143, 147))	('AKT', 'Gene', (123, 126))	('tumors', 'Phenotype', 'HP:0002664', (283, 289))
117621	27880728	To this aim we suppressed AKT1 and AKT2 expression in an established lung cancer cell line (NCI-H460) that harbours an activating mutation of PIK3CA (E545K) as reported.	('expression', 'MPA', (40, 50))	('PIK3CA', 'Gene', '5290', (142, 148))	('activating', 'PosReg', (119, 129))	('AKT1', 'Gene', (26, 30))	('AKT2', 'Gene', (35, 39))	('E545K', 'Mutation', 'rs104886003', (150, 155))	('lung cancer', 'Disease', 'MESH:D008175', (69, 80))	('E545K', 'Var', (150, 155))	('NCI-H460', 'CellLine', 'CVCL:0459', (92, 100))	('AKT2', 'Gene', '208', (35, 39))	('lung cancer', 'Disease', (69, 80))	('lung cancer', 'Phenotype', 'HP:0100526', (69, 80))	('PIK3CA', 'Gene', (142, 148))	('suppressed', 'NegReg', (15, 25))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('AKT1', 'Gene', '207', (26, 30))
117623	27880728	Silencing of AKT1 in NCI-H460, as assessed by immunoblot, resulted in a marked reduction of miR-196a levels as detected by quantitative RT-PCR (Figure 4A), indicating that AKT kinases play a significant role in the expression of miR-196a in NSCLC cells.	('196a', 'Chemical', '-', (96, 100))	('196a', 'Chemical', '-', (233, 237))	('AKT1', 'Gene', (13, 17))	('AKT', 'Gene', (172, 175))	('NSCLC', 'Disease', (241, 246))	('miR', 'Gene', '220972', (92, 95))	('miR', 'Gene', (92, 95))	('NCI-H460', 'CellLine', 'CVCL:0459', (21, 29))	('NSCLC', 'Disease', 'MESH:D002289', (241, 246))	('AKT', 'Gene', '207', (13, 16))	('AKT', 'Gene', (13, 16))	('AKT', 'Gene', '207', (172, 175))	('AKT1', 'Gene', '207', (13, 17))	('Silencing', 'Var', (0, 9))	('miR', 'Gene', '220972', (229, 232))	('reduction', 'NegReg', (79, 88))	('miR', 'Gene', (229, 232))
117624	27880728	Similarly to AKT1 suppression, also the silencing of AKT2 in NCI-H460 cells produced a marked decrease in the levels of miR-196a as detected by quantitative RT-PCR (Figure 4A).	('AKT1', 'Gene', '207', (13, 17))	('AKT1', 'Gene', (13, 17))	('196a', 'Chemical', '-', (124, 128))	('levels', 'MPA', (110, 116))	('miR', 'Gene', (120, 123))	('miR', 'Gene', '220972', (120, 123))	('AKT2', 'Gene', (53, 57))	('AKT2', 'Gene', '208', (53, 57))	('silencing', 'Var', (40, 49))	('NCI-H460 cells', 'CellLine', 'CVCL:0459', (61, 75))	('decrease', 'NegReg', (94, 102))
117625	27880728	In addition, exposure of A549 NSCLC cells to MK2206, a pharmacological inhibitor of all AKT isoforms, markedly decreased AKT phosphorylation and significantly impaired miR-196a expression (Figure 4B).	('NSCLC', 'Disease', 'MESH:D002289', (30, 35))	('196a', 'Chemical', '-', (172, 176))	('NSCLC', 'Disease', (30, 35))	('MK2206', 'Chemical', 'MESH:C548887', (45, 51))	('A549', 'CellLine', 'CVCL:0023', (25, 29))	('AKT', 'Gene', (121, 124))	('miR', 'Gene', '220972', (168, 171))	('decreased', 'NegReg', (111, 120))	('miR', 'Gene', (168, 171))	('AKT', 'Gene', '207', (88, 91))	('AKT', 'Gene', (88, 91))	('MK2206', 'Var', (45, 51))	('expression', 'MPA', (177, 187))	('AKT', 'Gene', '207', (121, 124))	('impaired', 'NegReg', (159, 167))
117636	27880728	As an alternative approach, we suppressed miR-196a in the NSCLC cell line NCI-H460, which harbors a heterozygous activating mutation (E545K) in PIK3CA, resulting in activation of the PI3K/AKT pathway.	('NSCLC', 'Disease', (58, 63))	('NCI-H460', 'CellLine', 'CVCL:0459', (74, 82))	('PIK3CA', 'Gene', (144, 150))	('NSCLC', 'Disease', 'MESH:D002289', (58, 63))	('E545K', 'Var', (134, 139))	('PIK3CA', 'Gene', '5290', (144, 150))	('196a', 'Chemical', '-', (46, 50))	('AKT', 'Gene', '207', (188, 191))	('miR', 'Gene', (42, 45))	('miR', 'Gene', '220972', (42, 45))	('suppressed', 'NegReg', (31, 41))	('activation', 'PosReg', (165, 175))	('AKT', 'Gene', (188, 191))	('E545K', 'Mutation', 'rs104886003', (134, 139))
117639	27880728	Analysis of cell proliferation showed that antimiR-196a transduced into BEAS-2B cells reduced the proliferative capability of BEAS-E17K cells.	('196a', 'Chemical', '-', (51, 55))	('proliferative capability of BEAS-E17K cells', 'CPA', (98, 141))	('reduced', 'NegReg', (86, 93))	('rat', 'Species', '10116', (105, 108))	('miR', 'Gene', '220972', (47, 50))	('miR', 'Gene', (47, 50))	('E17K', 'Mutation', 'rs121434592', (131, 135))	('BEAS-2B', 'CellLine', 'CVCL:0168', (72, 79))	('transduced', 'Var', (56, 66))	('rat', 'Species', '10116', (24, 27))
117650	27880728	First, we found that expression of miR-196a increased migration of BEAS-2B cells of approximately 3-fold, whereas its inhibition by the antimiRNA in BEAS-AKT1-E17K cells counteracted the pro-migratory effects induced by mutant AKT1 (Figure 6A).	('miR', 'Gene', '220972', (140, 143))	('migration', 'CPA', (54, 63))	('BEAS-AKT1', 'Gene', (149, 158))	('miR', 'Gene', '220972', (35, 38))	('rat', 'Species', '10116', (57, 60))	('expression', 'Var', (21, 31))	('inhibition', 'NegReg', (118, 128))	('miR', 'Gene', (140, 143))	('AKT1', 'Gene', '207', (227, 231))	('E17K', 'Mutation', 'rs121434592', (159, 163))	('miR', 'Gene', (35, 38))	('increased', 'PosReg', (44, 53))	('AKT1', 'Gene', '207', (154, 158))	('BEAS-AKT1', 'Gene', '207', (149, 158))	('AKT1', 'Gene', (227, 231))	('BEAS-2B', 'CellLine', 'CVCL:0168', (67, 74))	('rat', 'Species', '10116', (194, 197))	('AKT1', 'Gene', (154, 158))	('196a', 'Chemical', '-', (39, 43))
117651	27880728	On the other hand, inhibition of miR-196a markedly reduced NCI-H460 cell migration, assessed in Boyden chamber assays (140+-18.9 vs 10.5+-0.3 migrated cells; Figure 6B), whereas adoptive expression of miR-196a in NCI-H460-shAKT1 cells rescued the impairment of cell migration induced by interference of AKT1 (158+-26.8 vs 98+-6.7).	('reduced', 'NegReg', (51, 58))	('NCI-H460', 'CellLine', 'CVCL:0459', (59, 67))	('196a', 'Chemical', '-', (37, 41))	('miR', 'Gene', '220972', (201, 204))	('rat', 'Species', '10116', (269, 272))	('miR', 'Gene', (201, 204))	('miR', 'Gene', '220972', (33, 36))	('AKT1', 'Gene', '207', (224, 228))	('AKT1', 'Gene', '207', (303, 307))	('NCI-H460-shAKT1', 'CellLine', 'CVCL:0459', (213, 228))	('rat', 'Species', '10116', (145, 148))	('miR', 'Gene', (33, 36))	('rat', 'Species', '10116', (76, 79))	('cell migration', 'CPA', (261, 275))	('AKT1', 'Gene', (224, 228))	('interference', 'Var', (287, 299))	('196a', 'Chemical', '-', (205, 209))	('NCI-H460', 'CellLine', 'CVCL:0459', (213, 221))	('AKT1', 'Gene', (303, 307))	('NCI-H460 cell migration', 'CPA', (59, 82))
117666	27880728	These experiments demonstrated that the deletion of the seeds in both FoxO1 and p27 suppressed the activity of miR-196a, thus suggesting that miR-196a reduces the expression of FoxO1 and of p27 by directly binding the seed sequences in their 3'-UTR (Figure 7D, left and right, respectively).	('deletion', 'Var', (40, 48))	('p27', 'Gene', '3429', (80, 83))	('p27', 'Gene', (80, 83))	('p27', 'Gene', '3429', (190, 193))	('p27', 'Gene', (190, 193))	('196a', 'Chemical', '-', (146, 150))	('FoxO1', 'Gene', (177, 182))	('FoxO1', 'Gene', '2308', (177, 182))	('196a', 'Chemical', '-', (115, 119))	('activity', 'MPA', (99, 107))	('suppressed', 'NegReg', (84, 94))	('reduces', 'NegReg', (151, 158))	('miR', 'Gene', '220972', (142, 145))	('miR', 'Gene', '220972', (111, 114))	('FoxO1', 'Gene', (70, 75))	('FoxO1', 'Gene', '2308', (70, 75))	('binding', 'Interaction', (206, 213))	('expression', 'MPA', (163, 173))	('miR', 'Gene', (142, 145))	('rat', 'Species', '10116', (25, 28))	('miR', 'Gene', (111, 114))
117677	27880728	Changes in the expression of miRNAs are associated with many human diseases including cancer, which has suggested a potential diagnostic or prognostic utilization of miRNAs in cancer.	('human', 'Species', '9606', (61, 66))	('miR', 'Gene', '220972', (29, 32))	('miR', 'Gene', (29, 32))	('miR', 'Gene', (166, 169))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('expression', 'MPA', (15, 25))	('Changes', 'Var', (0, 7))	('miR', 'Gene', '220972', (166, 169))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('cancer', 'Disease', (176, 182))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('associated', 'Reg', (40, 50))	('cancer', 'Disease', (86, 92))
117679	27880728	Accordingly, although aberrant PI3K signaling is a frequent event in NSCLC cell lines and primary tumors, there is no information so far about the role of miRNAs in mediating the effects exerted by oncogenic signaling elicited by activated PI3K pathway.	('aberrant', 'Var', (22, 30))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('NSCLC', 'Disease', (69, 74))	('primary tumors', 'Disease', (90, 104))	('NSCLC', 'Disease', 'MESH:D002289', (69, 74))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('miR', 'Gene', '220972', (155, 158))	('miR', 'Gene', (155, 158))	('primary tumors', 'Disease', 'MESH:D009369', (90, 104))
117683	27880728	The data presented in this study demonstrate that aberrant PI3K signaling - induced by the adoptive expression of active mutant alleles of AKT1 or PI3KCA or by PTEN silencing - deregulates expression of 24 miRNAs in human bronchial epithelial cells.	('mutant', 'Var', (121, 127))	('human', 'Species', '9606', (216, 221))	('PI3KCA', 'Gene', (147, 153))	('PTEN', 'Gene', (160, 164))	('PI3K signaling', 'Pathway', (59, 73))	('deregulates', 'NegReg', (177, 188))	('rat', 'Species', '10116', (40, 43))	('silencing -', 'Var', (165, 176))	('miR', 'Gene', '220972', (206, 209))	('expression', 'MPA', (189, 199))	('miR', 'Gene', (206, 209))	('PTEN', 'Gene', '5728', (160, 164))	('AKT1', 'Gene', '207', (139, 143))	('AKT1', 'Gene', (139, 143))
117686	27880728	Expression of miR-196a expression in immortalized human bronchial epithelial cells (BEAS-2B) and/or its silencing in NSCLC cells harboring a PIK3CA mutation (NCI-H460), affected anchorage-dependent and -independent proliferation, migration and tumor growth in xenografts, further extending previous work performed in SPC-A1 and/or A549 cells in vitro.	('affected', 'Reg', (169, 177))	('NSCLC', 'Disease', 'MESH:D002289', (117, 122))	('miR', 'Gene', (14, 17))	('human', 'Species', '9606', (50, 55))	('SPC-A1', 'Gene', '27032', (317, 323))	('SPC-A1', 'Gene', (317, 323))	('tumor', 'Phenotype', 'HP:0002664', (244, 249))	('NSCLC', 'Disease', (117, 122))	('rat', 'Species', '10116', (222, 225))	('PIK3CA', 'Gene', '5290', (141, 147))	('196a', 'Chemical', '-', (18, 22))	('A549', 'CellLine', 'CVCL:0023', (331, 335))	('rat', 'Species', '10116', (233, 236))	('BEAS-2B', 'CellLine', 'CVCL:0168', (84, 91))	('silencing', 'NegReg', (104, 113))	('tumor', 'Disease', (244, 249))	('PIK3CA', 'Gene', (141, 147))	('NCI-H460', 'CellLine', 'CVCL:0459', (158, 166))	('miR', 'Gene', '220972', (14, 17))	('migration', 'CPA', (230, 239))	('mutation', 'Var', (148, 156))	('tumor', 'Disease', 'MESH:D009369', (244, 249))
117688	27880728	Conversely, dysregulation of miR-196 expression is frequently observed in many cancer types including pancreatic, breast, colorectal, esophageal and lung carcinomas, as well as leukemias.	('dysregulation', 'Var', (12, 25))	('miR', 'Gene', '220972', (29, 32))	('miR', 'Gene', (29, 32))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('carcinomas', 'Phenotype', 'HP:0030731', (154, 164))	('leukemias', 'Phenotype', 'HP:0001909', (177, 186))	('leukemias', 'Disease', (177, 186))	('esophageal and lung carcinomas', 'Disease', 'MESH:D004938', (134, 164))	('carcinoma', 'Phenotype', 'HP:0030731', (154, 163))	('colorectal', 'Disease', (122, 132))	('breast', 'Disease', (114, 120))	('pancreatic', 'Disease', 'MESH:D010195', (102, 112))	('leukemias', 'Disease', 'MESH:D007938', (177, 186))	('expression', 'MPA', (37, 47))	('pancreatic', 'Disease', (102, 112))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('observed', 'Reg', (62, 70))
117702	27880728	On the other hand, silencing of FoxO1 had a moderate effect on cell proliferation and no effect at all on migration.	('rat', 'Species', '10116', (75, 78))	('FoxO1', 'Gene', (32, 37))	('silencing', 'Var', (19, 28))	('FoxO1', 'Gene', '2308', (32, 37))	('cell proliferation', 'CPA', (63, 81))	('rat', 'Species', '10116', (109, 112))	('rat', 'Species', '10116', (48, 51))
117704	27880728	In conclusion, the data reported here provide strong support to the concept that expression of miR-196a is modulated by the most common alterations that contribute to the development of NSCLC, including activating mutations of PIK3CA (E545K) and AKT1 (E17K), and/or the loss of PTEN expression.	('PTEN', 'Gene', '5728', (278, 282))	('PIK3CA', 'Gene', (227, 233))	('E545K', 'Mutation', 'rs104886003', (235, 240))	('expression', 'MPA', (81, 91))	('AKT1', 'Gene', (246, 250))	('NSCLC', 'Disease', 'MESH:D002289', (186, 191))	('196a', 'Chemical', '-', (99, 103))	('E545K', 'Var', (235, 240))	('E17K', 'Var', (252, 256))	('miR', 'Gene', '220972', (95, 98))	('activating', 'PosReg', (203, 213))	('loss', 'NegReg', (270, 274))	('NSCLC', 'Disease', (186, 191))	('E17K', 'Mutation', 'rs121434592', (252, 256))	('PIK3CA', 'Gene', '5290', (227, 233))	('rat', 'Species', '10116', (140, 143))	('expression', 'MPA', (283, 293))	('PTEN', 'Gene', (278, 282))	('miR', 'Gene', (95, 98))	('AKT1', 'Gene', '207', (246, 250))	('modulated', 'Reg', (107, 116))
117758	27047702	As a result, we now know the most commonly mutated genes in dozens of cancers and can use this information to give patients targeted therapeutics.	('patients', 'Species', '9606', (115, 123))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('genes', 'Gene', (51, 56))	('mutated', 'Var', (43, 50))	('cancers', 'Disease', 'MESH:D009369', (70, 77))	('cancers', 'Phenotype', 'HP:0002664', (70, 77))	('cancers', 'Disease', (70, 77))
117759	27047702	Whereas well established statistical techniques exist for identifying mutations which are drivers instead of simply passengers (mut-drivers), identifying copy number aberrations, methylation changes, or non-coding mutations that alter expression of a gene and result in a growth advantage (epi-drivers) are more difficult to identify and represent a "dark matter" of cancer.	('expression', 'MPA', (235, 245))	('growth advantage', 'CPA', (272, 288))	('mutations', 'Var', (70, 79))	('cancer', 'Disease', 'MESH:D009369', (367, 373))	('copy', 'Var', (154, 158))	('methylation changes', 'Var', (179, 198))	('mutations', 'Var', (214, 223))	('cancer', 'Disease', (367, 373))	('cancer', 'Phenotype', 'HP:0002664', (367, 373))	('alter', 'Reg', (229, 234))
117822	27047702	To date, different cancers have been compared to each other through mRNA levels, miRNA levels, protein levels, networks, copy number alterations, DNA methylation, somatic mutations or some combination of these.	('miRNA levels', 'MPA', (81, 93))	('networks', 'MPA', (111, 119))	('cancers', 'Phenotype', 'HP:0002664', (19, 26))	('cancers', 'Disease', (19, 26))	('cancers', 'Disease', 'MESH:D009369', (19, 26))	('copy number alterations', 'Var', (121, 144))	('protein levels', 'MPA', (95, 109))	('mRNA levels', 'MPA', (68, 79))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('DNA methylation', 'MPA', (146, 161))
117845	27047702	Our results show that patients with high expression of genes utilizing oxygen survive longer, which underscores the importance of a metabolic shift in this cancer.	('high expression', 'Var', (36, 51))	('cancer', 'Disease', (156, 162))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('patients', 'Species', '9606', (22, 30))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('genes', 'Var', (55, 60))	('oxygen', 'Chemical', 'MESH:D010100', (71, 77))
117861	27047702	For example, currently EGFR inhibitors are recommended for LUAD patients with EGFR mutations, but EGFR mutations are rare in LUSC and patients with mutations do not respond well to tyrosine kinase inhibitors.	('EGFR', 'Gene', (98, 102))	('mutations', 'Var', (83, 92))	('LUAD', 'Phenotype', 'HP:0030078', (59, 63))	('patients', 'Species', '9606', (64, 72))	('patients', 'Species', '9606', (134, 142))	('EGFR', 'Gene', '1956', (23, 27))	('EGFR', 'Gene', '1956', (78, 82))	('EGFR', 'Gene', '1956', (98, 102))	('EGFR', 'Gene', (78, 82))	('EGFR', 'Gene', (23, 27))
117928	33381521	For example, abnormally methylated CH25H has been found to be a prognostic marker for lung squamous cell carcinoma patients (Gao et al.,).	('patients', 'Species', '9606', (115, 123))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (86, 114))	('abnormally methylated', 'Var', (13, 34))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (86, 114))	('CH25H', 'Gene', '9023', (35, 40))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (91, 114))	('lung squamous cell carcinoma', 'Disease', (86, 114))	('CH25H', 'Gene', (35, 40))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))
117931	33381521	LOC51089, also called C1QA, was found to be involved in the innate immune system and was associated with the expression of PD-L1 (Olkhov-Mitsel et al.,), and its abnormal expression in tumor tissues was confirmed in head and neck squamous cell carcinoma and clear cell renal cell carcinoma (Yu et al.,; Apanovich et al.,).	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (225, 253))	('associated', 'Reg', (89, 99))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (258, 289))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (230, 253))	('tumor', 'Disease', (185, 190))	('C1QA', 'Gene', (22, 26))	('C1QA', 'Gene', '712', (22, 26))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (216, 253))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (258, 289))	('carcinoma', 'Phenotype', 'HP:0030731', (244, 253))	('LOC51089', 'Var', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('clear cell renal cell carcinoma', 'Disease', (258, 289))	('involved', 'Reg', (44, 52))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (269, 289))	('carcinoma', 'Phenotype', 'HP:0030731', (280, 289))	('PD-L1', 'Gene', (123, 128))	('neck squamous cell carcinoma', 'Disease', (225, 253))	('PD-L1', 'Gene', '29126', (123, 128))
117933	33381521	Accordingly, kidney renal clear cell carcinoma patients with high expressions of MXRA8 had worse overall survival (Li and Xu,).	('kidney renal clear cell carcinoma', 'Disease', (13, 46))	('MXRA8', 'Gene', '54587', (81, 86))	('overall survival', 'MPA', (97, 113))	('patients', 'Species', '9606', (47, 55))	('carcinoma', 'Phenotype', 'HP:0030731', (37, 46))	('high expressions', 'Var', (61, 77))	('MXRA8', 'Gene', (81, 86))	('worse', 'NegReg', (91, 96))	('kidney renal clear cell carcinoma', 'Disease', 'MESH:C538614', (13, 46))
117934	33381521	RET is an important proto-oncogene that can undergo oncogenic activation through both cytogenetic rearrangement and the activation of point mutations, and alterations in RET have been identified as being oncogenic in multiple malignancies (Subbiah et al.,).	('RET', 'Gene', '5979', (0, 3))	('malignancies', 'Disease', 'MESH:D009369', (226, 238))	('RET', 'Gene', (170, 173))	('alterations', 'Var', (155, 166))	('point mutations', 'Var', (134, 149))	('malignancies', 'Disease', (226, 238))	('RET', 'Gene', '5979', (170, 173))	('RET', 'Gene', (0, 3))
117936	33381521	Alterations in SPI1 lead to cellular proliferation and differentiation arrest, resulting in oncogenic subversion (Roos-Weil et al.,).	('differentiation arrest', 'Disease', (55, 77))	('SPI1', 'Gene', (15, 19))	('Alterations', 'Var', (0, 11))	('lead to', 'Reg', (20, 27))	('differentiation arrest', 'Disease', 'MESH:D006323', (55, 77))	('cellular proliferation', 'CPA', (28, 50))	('SPI1', 'Gene', '6688', (15, 19))	('oncogenic subversion', 'CPA', (92, 112))
117947	32403421	Patients with high HIP1R expression had poorer progression-free survival (PFS) than patients with low HIP1R expression in univariate analysis (p = 0.037) and multivariate Cox analysis (hazard ratio = 2.098, p = 0.019).	('poorer', 'NegReg', (40, 46))	('HIP1R', 'Gene', '9026', (102, 107))	('patients', 'Species', '9606', (84, 92))	('HIP1R', 'Gene', '9026', (19, 24))	('high', 'Var', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('HIP1R', 'Gene', (19, 24))	('HIP1R', 'Gene', (102, 107))	('progression-free survival', 'CPA', (47, 72))
117948	32403421	The web-based mRNA dataset also showed that high HIP1R expression correlated with inferior overall survival in lung adenocarcinoma (p = 0.026).	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (111, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('high', 'Var', (44, 48))	('inferior', 'NegReg', (82, 90))	('lung adenocarcinoma', 'Disease', (111, 130))	('HIP1R', 'Gene', '9026', (49, 54))	('HIP1R', 'Gene', (49, 54))	('overall', 'MPA', (91, 98))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (111, 130))
117956	32403421	F-box only protein 38 (FBXO38) mediates PD-1 ubiquitination of T cells, and knockout of FBXO38 in such cells induces tumor progression in a mouse model due to increased PD-1 expression by tumor-infiltrating T cells.	('tumor', 'Disease', (188, 193))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('increased PD', 'Phenotype', 'HP:0008151', (159, 171))	('knockout', 'Var', (76, 84))	('induces', 'Reg', (109, 116))	('F-box only protein 38', 'Gene', (0, 21))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('FBXO38', 'Gene', '100513273', (88, 94))	('FBXO38', 'Gene', (88, 94))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('PD-1', 'Gene', (169, 173))	('mouse', 'Species', '10090', (140, 145))	('expression', 'MPA', (174, 184))	('F-box only protein 38', 'Gene', '100513273', (0, 21))	('tumor', 'Disease', (117, 122))	('increased', 'PosReg', (159, 168))	('ubiquitination', 'MPA', (45, 59))	('FBXO38', 'Gene', '100513273', (23, 29))	('FBXO38', 'Gene', (23, 29))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
117957	32403421	AXL expression displays a positive correlation with PD-L1 expression in lung adenocarcinoma with epidermal growth factor receptor (EGFR) mutation, and abolition of AXL kinase activity inhibits PD-L1 mRNA expression in a lung adenocarcinoma cell line with EGFR mutation.	('PD-L1', 'Gene', (193, 198))	('expression', 'MPA', (58, 68))	('mutation', 'Var', (260, 268))	('EGFR', 'Gene', (131, 135))	('carcinoma', 'Phenotype', 'HP:0030731', (230, 239))	('AXL', 'Gene', (164, 167))	('activity', 'MPA', (175, 183))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (220, 239))	('EGFR', 'Gene', (255, 259))	('mutation', 'Var', (137, 145))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (220, 239))	('abolition', 'Var', (151, 160))	('lung adenocarcinoma', 'Disease', (72, 91))	('AXL', 'Gene', '558', (0, 3))	('EGFR', 'Gene', '1956', (131, 135))	('PD-L1', 'Gene', (52, 57))	('EGFR', 'Gene', '1956', (255, 259))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (72, 91))	('AXL', 'Gene', '558', (164, 167))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('epidermal growth factor receptor', 'Gene', (97, 129))	('inhibits', 'NegReg', (184, 192))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (72, 91))	('AXL', 'Gene', (0, 3))	('lung adenocarcinoma', 'Disease', (220, 239))	('epidermal growth factor receptor', 'Gene', '1956', (97, 129))
117977	32403421	Thirteen (25%) of the 52 specimens were tested for both SP263 and 22C3, 27 (51.9%) for only SP263, and 12 (23.1%) for only 22C3.	('SP263', 'Chemical', '-', (56, 61))	('SP263', 'Var', (56, 61))	('tested', 'Reg', (40, 46))	('SP263', 'Var', (92, 97))	('SP263', 'Chemical', '-', (92, 97))
118010	32403421	HALLMARK_INTERFERON_GAMMA_RESPONSE is also upregulated in the low HIP1R mRNA expression group, although the statistical significance was marginal (p = 0.063).	('HIP1R', 'Gene', (66, 71))	('HIP1R', 'Gene', '9026', (66, 71))	('upregulated', 'PosReg', (43, 54))	('low', 'Var', (62, 65))
118013	32403421	Patients with high HIP1R expression had inferior PFS to patients with low HIP1R expression (p = 0.037, Figure 5A).	('patients', 'Species', '9606', (56, 64))	('inferior', 'NegReg', (40, 48))	('PFS', 'MPA', (49, 52))	('high', 'Var', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('HIP1R', 'Gene', (74, 79))	('HIP1R', 'Gene', (19, 24))	('HIP1R', 'Gene', '9026', (74, 79))	('HIP1R', 'Gene', '9026', (19, 24))
118014	32403421	Patients with high HIP1R expression also showed an inferior OS than patients with low HIP1R expression, however the statistical significance was not reached (p = 0.11, Figure 5B).	('inferior OS', 'CPA', (51, 62))	('HIP1R', 'Gene', (86, 91))	('HIP1R', 'Gene', '9026', (86, 91))	('patients', 'Species', '9606', (68, 76))	('high', 'Var', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('HIP1R', 'Gene', (19, 24))	('HIP1R', 'Gene', '9026', (19, 24))
118015	32403421	Patients with high PD-L1 expression had superior PFS or OS than patients with low PD-L1 expression (p = 0.028, Figure 5C and p = 0.031, Figure 5D, respectively).	('PD-L1', 'Gene', (19, 24))	('patients', 'Species', '9606', (64, 72))	('superior', 'PosReg', (40, 48))	('high', 'Var', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('PFS', 'CPA', (49, 52))
118016	32403421	Furthermore, patients with high HIP1R expression and low PD-L1 expression had lower PFS or OS than patients with other expression patterns (p < 0.001, Figure 5E and p = 0.001, Figure 5F, respectively).	('low', 'NegReg', (53, 56))	('PFS', 'CPA', (84, 87))	('expression', 'MPA', (38, 48))	('patients', 'Species', '9606', (13, 21))	('PD-L1', 'Gene', (57, 62))	('expression', 'MPA', (63, 73))	('high', 'Var', (27, 31))	('patients', 'Species', '9606', (99, 107))	('HIP1R', 'Gene', '9026', (32, 37))	('HIP1R', 'Gene', (32, 37))	('lower', 'NegReg', (78, 83))
118017	32403421	In multivariate analysis, high HIP1R expression was an independent prognostic factor for PFS (HR = 2.098, p = 0.019, Table 3).	('high', 'Var', (26, 30))	('HIP1R', 'Gene', (31, 36))	('HIP1R', 'Gene', '9026', (31, 36))	('PFS', 'Disease', (89, 92))	('expression', 'MPA', (37, 47))
118019	32403421	The group with high HIP1R mRNA expression exhibited poorer OS in patients with adenocarcinoma (p = 0.026, Figure S4A).	('high', 'Var', (15, 19))	('HIP1R', 'Gene', '9026', (20, 25))	('poorer', 'NegReg', (52, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('adenocarcinoma', 'Disease', (79, 93))	('adenocarcinoma', 'Disease', 'MESH:D000230', (79, 93))	('patients', 'Species', '9606', (65, 73))	('mRNA', 'Protein', (26, 30))	('HIP1R', 'Gene', (20, 25))
118021	32403421	First, we found that the expression of HIP1R was an independent predictive factor for anti-PD-1 treatment response by NSCLC patients.	('NSCLC', 'Disease', (118, 123))	('HIP1R', 'Gene', (39, 44))	('NSCLC', 'Disease', 'MESH:D002289', (118, 123))	('expression', 'Var', (25, 35))	('HIP1R', 'Gene', '9026', (39, 44))	('patients', 'Species', '9606', (124, 132))
118042	32403421	used HIP1R antibody (16814-1-AP) in Western Blott (WB) and immunofluorescence alone.	('16814-1-AP', 'Var', (21, 31))	('HIP1R', 'Gene', '9026', (5, 10))	('HIP1R', 'Gene', (5, 10))
118050	32403421	However, the sample we have is a small biopsy, and we have already performed several immunohistochemical stainings for diagnosis and ALK and EGFR mutation tests.	('EGFR', 'Gene', '1956', (141, 145))	('ALK', 'Gene', (133, 136))	('mutation tests', 'Var', (146, 160))	('EGFR', 'Gene', (141, 145))	('ALK', 'Gene', '238', (133, 136))
118123	32251457	IsomiRs were identified by differences such as additions or deletions compared with mature miRs.	('additions', 'Var', (47, 56))	('miR', 'Gene', (91, 94))	('', 'Phenotype', 'HP:0030731', (0, 0))	('', 'Phenotype', 'HP:0002664', (0, 0))	('', 'Phenotype', 'HP:0100751', (0, 0))	('deletions', 'Var', (60, 69))	('miR', 'Gene', (3, 6))	('miR', 'Gene', '29116', (91, 94))	('miR', 'Gene', '29116', (3, 6))	('', 'Phenotype', 'HP:0002860', (0, 0))
118133	32251457	Table 2 shows the profile of these candidates of miR/isomiRs, read number for ESCC and HC, fold change, and p-value in the 1st and 2nd group.	('', 'Phenotype', 'HP:0030731', (0, 0))	('miR', 'Gene', '29116', (56, 59))	('', 'Phenotype', 'HP:0002664', (0, 0))	('', 'Phenotype', 'HP:0100751', (0, 0))	('fold change', 'Var', (91, 102))	('miR', 'Gene', (49, 52))	('p-value', 'Var', (108, 115))	('miR', 'Gene', (56, 59))	('', 'Phenotype', 'HP:0002860', (0, 0))	('miR', 'Gene', '29116', (49, 52))
118163	32251457	Roberts et al reported that circulating small RNA, including isomiR, were associated with colorectal adenoma; and Mjelle et al identified circulating miR/isomiR associated with metastasis of rectal cancer.	('miR', 'Gene', (157, 160))	('rectal cancer', 'Phenotype', 'HP:0100743', (191, 204))	('colorectal adenoma', 'Disease', (90, 108))	('associated with', 'Reg', (161, 176))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('', 'Phenotype', 'HP:0002664', (0, 0))	('', 'Phenotype', 'HP:0002860', (0, 0))	('', 'Phenotype', 'HP:0030731', (0, 0))	('', 'Phenotype', 'HP:0100751', (0, 0))	('metastasis of rectal cancer', 'Disease', (177, 204))	('miR', 'Gene', '29116', (150, 153))	('miR', 'Gene', '29116', (64, 67))	('colorectal adenoma', 'Disease', 'MESH:D015179', (90, 108))	('miR', 'Gene', (150, 153))	('miR', 'Gene', (64, 67))	('circulating', 'Var', (138, 149))	('miR', 'Gene', '29116', (157, 160))	('associated', 'Reg', (74, 84))	('metastasis of rectal cancer', 'Disease', 'MESH:D012004', (177, 204))
118169	32251457	According to previous reports, miR-30a-5p plays a dual role in different types of cancer as either an oncogene or onco-suppressor.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('', 'Phenotype', 'HP:0030731', (0, 0))	('', 'Phenotype', 'HP:0100751', (0, 0))	('miR-30a-5p', 'Chemical', '-', (31, 41))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('miR-30a-5p', 'Var', (31, 41))	('', 'Phenotype', 'HP:0002664', (0, 0))	('', 'Phenotype', 'HP:0002860', (0, 0))
118198	32251457	You have demonstrated that your diagnostic panel index derived from the regression analysis with miR-30a-5p and isoforms of miR-574-3p and miR-205-5p had high accuracy in the diagnosis of ESCC.	('miR-205', 'Gene', (139, 146))	('', 'Phenotype', 'HP:0030731', (0, 0))	('', 'Phenotype', 'HP:0100751', (0, 0))	('miR-574-3p', 'Gene', (124, 134))	('ESCC', 'Disease', (188, 192))	('miR-574-3p', 'Gene', '693159', (124, 134))	('miR-205', 'Gene', '406988', (139, 146))	('miR-30a-5p', 'Chemical', '-', (97, 107))	('', 'Phenotype', 'HP:0002664', (0, 0))	('', 'Phenotype', 'HP:0002860', (0, 0))	('miR-30a-5p', 'Var', (97, 107))
118300	31410207	Inhibition of protein B is expected to block signaling to protein D (according to known signaling pathways), and thus a drug against protein B can be selected for patient 1.	('protein', 'Protein', (58, 65))	('protein', 'Protein', (14, 21))	('signaling', 'MPA', (45, 54))	('patient', 'Species', '9606', (163, 170))	('block', 'NegReg', (39, 44))	('Inhibition', 'Var', (0, 10))
118334	31410207	Patient TCGA-BP-4760 exhibited an upregulation in both pY(1068)EGFR and pS(473)Akt (Figure 2A, bottom).	('EGFR', 'Gene', '1956', (63, 67))	('EGFR', 'Gene', (63, 67))	('Akt', 'Gene', '207', (79, 82))	('Akt', 'Gene', (79, 82))	('Patient', 'Species', '9606', (0, 7))	('TCGA-BP-4760', 'Var', (8, 20))	('upregulation', 'PosReg', (34, 46))
118341	31410207	However, they are anti-correlated in the unbalanced processes 7, 10 and 13 (Figure S1G,J,M; appearing in 12.2% of the tumors), and non-correlated (pT(202)Y(204)MAPK is absent) in the unbalanced processes 4 and 5 (Figure S1D,E; appearing in 15.5% of the tumors).	('pT(202)Y(204', 'Var', (147, 159))	('tumors', 'Disease', (253, 259))	('tumors', 'Disease', 'MESH:D009369', (253, 259))	('tumors', 'Phenotype', 'HP:0002664', (253, 259))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumor', 'Phenotype', 'HP:0002664', (253, 258))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('tumors', 'Disease', (118, 124))	('tumors', 'Disease', 'MESH:D009369', (118, 124))
118426	31410207	We predicted that to collapse the entire imbalance in these cells, a triple combination, consisting of trametinib, LY2484702 (an inhibitor of p70S6K), and 4OHT would be more effective (Figure 6A,B, Table S6, Figure S8).	('imbalance', 'Phenotype', 'HP:0002172', (41, 50))	('trametinib', 'Chemical', 'MESH:C560077', (103, 113))	('imbalance', 'MPA', (41, 50))	('LY2484702', 'Chemical', '-', (115, 124))	('p70S6K', 'Gene', (142, 148))	('LY2484702', 'Var', (115, 124))	('p70S6K', 'Gene', '6198', (142, 148))	('4OHT', 'Chemical', 'MESH:C032278', (155, 159))
118428	31410207	Similar to the case in MDA-MB-468 cells, the double combination consisting of trametinib and LY2584702 was expected to target all unbalanced processes in these cells.	('LY2584702', 'Var', (93, 102))	('MDA-MB-468', 'CellLine', 'CVCL:0419', (23, 33))	('unbalanced processes', 'MPA', (130, 150))	('trametinib', 'Chemical', 'MESH:C560077', (78, 88))	('LY2584702', 'Chemical', 'MESH:C588151', (93, 102))	('target', 'Reg', (119, 125))
118522	31061410	1A-C), adenocarcinoma patients with high miR-130b expression had significantly poorer overall survival than those with low miR-130b expression (Fig.	('adenocarcinoma', 'Disease', (7, 21))	('poorer', 'NegReg', (79, 85))	('patients', 'Species', '9606', (22, 30))	('carcinoma', 'Phenotype', 'HP:0030731', (12, 21))	('miR-130b', 'Gene', '406920', (123, 131))	('adenocarcinoma', 'Disease', 'MESH:D000230', (7, 21))	('miR-130b', 'Gene', '406920', (41, 49))	('miR-130b', 'Gene', (123, 131))	('overall survival', 'MPA', (86, 102))	('high', 'Var', (36, 40))	('miR-130b', 'Gene', (41, 49))
118529	31061410	1F) and of the presence or absence of epidermal growth factor receptor gene mutation (Fig.	('epidermal growth factor receptor', 'Gene', (38, 70))	('mutation', 'Var', (76, 84))	('epidermal growth factor receptor', 'Gene', '1956', (38, 70))
118558	31061410	In contrast, miR-130b overexpression had no significant effect on luciferase activity in mutant TIMP-2-transfected A549 cells (Fig.	('TIMP-2-transfected', 'Gene', (96, 114))	('miR-130b', 'Gene', '406920', (13, 21))	('A549', 'CellLine', 'CVCL:0023', (115, 119))	('miR-130b', 'Gene', (13, 21))	('activity', 'MPA', (77, 85))	('mutant', 'Var', (89, 95))	('luciferase', 'Enzyme', (66, 76))
118586	31061410	Therefore, high miR-130b expression may function to promote metastasis via targeting TIMP-2 expression and subsequent upregulation of the active form of MMP-2 during the early stages of NSCLC.	('NSCLC', 'Phenotype', 'HP:0030358', (186, 191))	('miR-130b', 'Gene', (16, 24))	('TIMP-2', 'Gene', (85, 91))	('upregulation', 'PosReg', (118, 130))	('MMP-2', 'Gene', '4313', (153, 158))	('expression', 'MPA', (25, 35))	('NSCLC', 'Disease', (186, 191))	('MMP-2', 'Gene', (153, 158))	('active', 'MPA', (138, 144))	('miR-130b', 'Gene', '406920', (16, 24))	('NSCLC', 'Disease', 'MESH:D002289', (186, 191))	('metastasis', 'CPA', (60, 70))	('high', 'Var', (11, 15))	('promote', 'PosReg', (52, 59))	('expression', 'MPA', (92, 102))
118589	31061410	Moreover, TIMP-2 suppresses vascular permeability via the integrin alpha3beta1/Shp-1/cAMP/protein kinase A pathway independently of MMP inhibition in human vascular endothelial cells.	('human', 'Species', '9606', (150, 155))	('TIMP-2', 'Var', (10, 16))	('Shp-1', 'Gene', '5777', (79, 84))	('cAMP', 'Gene', (85, 89))	('cAMP', 'Gene', '820', (85, 89))	('suppresses', 'NegReg', (17, 27))	('vascular permeability', 'MPA', (28, 49))	('Shp-1', 'Gene', (79, 84))
118592	31061410	Therefore, high expression of miR-130b may affect the overall survival of patients with NSCLC by targeting TIMP-2, which in turn promotes cancer cell invasion and enhances the functions of endothelial cells and myeloid-derived suppressor cells in tumor tissues.	('enhances', 'PosReg', (163, 171))	('tumor', 'Phenotype', 'HP:0002664', (247, 252))	('cancer', 'Disease', (138, 144))	('NSCLC', 'Phenotype', 'HP:0030358', (88, 93))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('targeting', 'Var', (97, 106))	('affect', 'Reg', (43, 49))	('survival', 'CPA', (62, 70))	('cancer', 'Disease', 'MESH:D009369', (138, 144))	('promotes', 'PosReg', (129, 137))	('tumor', 'Disease', (247, 252))	('patients', 'Species', '9606', (74, 82))	('TIMP-2', 'Gene', (107, 113))	('NSCLC', 'Disease', 'MESH:D002289', (88, 93))	('tumor', 'Disease', 'MESH:D009369', (247, 252))	('NSCLC', 'Disease', (88, 93))	('functions', 'CPA', (176, 185))	('miR-130b', 'Gene', '406920', (30, 38))	('miR-130b', 'Gene', (30, 38))
118641	31061410	A549 cells were transfected with the reporter vector containing the predicted miR-130b binding site or mutated miR-130b binding site in the TIMP-2 3'-UTR (Supplementary Fig.	('mutated', 'Var', (103, 110))	('miR-130b', 'Gene', '406920', (111, 119))	('A549', 'CellLine', 'CVCL:0023', (0, 4))	('binding', 'Interaction', (120, 127))	('miR-130b', 'Gene', (111, 119))	('miR-130b', 'Gene', '406920', (78, 86))	('miR-130b', 'Gene', (78, 86))
118642	31061410	MiRIDIAN miRNA mimic for hsa-miR-130b-3p (C-300660-05-000), miRNA mimic negative control (CN-001000-01-05), miRIDIAN miRNA hairpin inhibitor for hsa-miR-130b-3p (IH-300660-07-0005), and miRNA hairpin inhibitor negative control (IN-001005-01-05) were purchased from GE Healthcare.	('miR-130b', 'Gene', '406920', (29, 37))	('miR-130b', 'Gene', '406920', (149, 157))	('miR-130b', 'Gene', (29, 37))	('miR-130b', 'Gene', (149, 157))	('C-300660-05-000', 'Var', (42, 57))
118654	30717708	Additionally, high CD133 expression signatures were found in intestinal subtypes and low tumor stage GCs as well as in those with microsatellite instabilities and high mutation burdens.	('expression signatures', 'MPA', (25, 46))	('GCs', 'Phenotype', 'HP:0012126', (101, 104))	('CD133', 'Gene', (19, 24))	('GC', 'Phenotype', 'HP:0012126', (101, 103))	('CD133', 'Gene', '8842', (19, 24))	('low tumor', 'Disease', 'MESH:D009800', (85, 94))	('microsatellite', 'Var', (130, 144))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('low tumor', 'Disease', (85, 94))
118660	30717708	Immunohistochemistry (IHC)-based quantification of expressed CD133 protein levels has been proposed as a GC prognostic marker and CD133 positivity indicates poor prognosis as well as chemoresistance and disease progression of GC.	('positivity', 'Var', (136, 146))	('GC', 'Phenotype', 'HP:0012126', (226, 228))	('disease progression', 'CPA', (203, 222))	('chemoresistance', 'CPA', (183, 198))	('CD133', 'Gene', (61, 66))	('CD133', 'Gene', (130, 135))	('CD133', 'Gene', '8842', (130, 135))	('CD133', 'Gene', '8842', (61, 66))	('poor prognosis', 'CPA', (157, 171))	('GC', 'Phenotype', 'HP:0012126', (105, 107))
118664	30717708	In this study, we performed microarray-based transcriptome analyses of CD133+ vs. CD133- cells obtained by cell sorting from three GC cell lines (KATO-III, SNU216 and SNU601).	('GC', 'Phenotype', 'HP:0012126', (131, 133))	('CD133', 'Gene', '8842', (82, 87))	('CD133', 'Gene', (82, 87))	('SNU601', 'Var', (167, 173))	('CD133', 'Gene', '8842', (71, 76))	('CD133', 'Gene', (71, 76))	('SNU216', 'Var', (156, 162))	('SNU216', 'CellLine', 'CVCL:3946', (156, 162))
118689	30717708	To evaluate the gene expression associated with the CD133 stem cell marker in GCs, we performed gene expression profiling of three gastric cancer cell lines (KATO-III, SNU216, and SNU601).	('gastric cancer', 'Disease', 'MESH:D013274', (131, 145))	('CD133', 'Gene', (52, 57))	('CD133', 'Gene', '8842', (52, 57))	('SNU601', 'Var', (180, 186))	('SNU216', 'CellLine', 'CVCL:3946', (168, 174))	('gastric cancer', 'Phenotype', 'HP:0012126', (131, 145))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('GCs', 'Phenotype', 'HP:0012126', (78, 81))	('GC', 'Phenotype', 'HP:0012126', (78, 80))	('gastric cancer', 'Disease', (131, 145))
118727	30717708	Among the major mutations of GC, mutations of TP53, PIK3CA, KRAS, ARID1A, and RHOA were evaluated, whereas only ARID1A mutations were significantly associated with CD133 expression signature (P = 0.0007; Fig.	('ARID1A', 'Gene', (112, 118))	('CD133', 'Gene', '8842', (164, 169))	('TP53', 'Gene', '7157', (46, 50))	('RHOA', 'Gene', '387', (78, 82))	('PIK3CA', 'Gene', (52, 58))	('mutations', 'Var', (16, 25))	('ARID1A', 'Gene', '8289', (66, 72))	('ARID1A', 'Gene', (66, 72))	('KRAS', 'Gene', (60, 64))	('GC', 'Phenotype', 'HP:0012126', (29, 31))	('RHOA', 'Gene', (78, 82))	('associated', 'Reg', (148, 158))	('TP53', 'Gene', (46, 50))	('KRAS', 'Gene', '3845', (60, 64))	('PIK3CA', 'Gene', '5290', (52, 58))	('ARID1A', 'Gene', '8289', (112, 118))	('CD133', 'Gene', (164, 169))
118779	30717708	In general, IHC-based CD133 positivity in GC has been regarded as a feature associated with high-stage and high-grade tumors with poor prognosis.	('GC', 'Phenotype', 'HP:0012126', (42, 44))	('positivity', 'Var', (28, 38))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('associated', 'Reg', (76, 86))	('CD133', 'Gene', (22, 27))	('high-stage', 'Disease', (92, 102))	('CD133', 'Gene', '8842', (22, 27))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('tumors', 'Disease', (118, 124))	('tumors', 'Disease', 'MESH:D009369', (118, 124))
118794	30310314	Kruppel-like factor 6 (KLF6) inactivation has been shown in some malignant tumors.	('malignant tumors', 'Disease', (65, 81))	('KLF6', 'Gene', (23, 27))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('Kruppel-like factor 6', 'Gene', (0, 21))	('Kruppel-like factor 6', 'Gene', '1316', (0, 21))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('malignant tumors', 'Disease', 'MESH:D018198', (65, 81))	('inactivation', 'Var', (29, 41))	('KLF6', 'Gene', '1316', (23, 27))
118801	30310314	The 5-year survival rate for 79 NSCLC patients was 40.5%, and it was significantly associated with differentiation (P<0.05), pN (P<0.01), pTNM stage (P<0.01) and high expression of KLF6-SV1 (P<0.01).	('TNM', 'Gene', (139, 142))	('differentiation', 'Disease', (99, 114))	('NSCLC', 'Disease', (32, 37))	('associated', 'Reg', (83, 93))	('KLF6-SV1', 'Gene', '1316', (181, 189))	('TNM', 'Gene', '10178', (139, 142))	('patients', 'Species', '9606', (38, 46))	('NSCLC', 'Disease', 'MESH:D002289', (32, 37))	('KLF6-SV1', 'Gene', (181, 189))	('high expression', 'Var', (162, 177))
118803	30310314	KLF6-SV1 expression in adenocarcinoma was significantly higher than that in the squamous cell carcinoma, and high expression of KLF6-SV1 was significantly associated with pN and pTNM stage and poor survival in NSCLC patients.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (80, 103))	('expression', 'MPA', (9, 19))	('KLF6-SV1', 'Gene', '1316', (0, 8))	('high', 'Var', (109, 113))	('TNM', 'Gene', '10178', (179, 182))	('adenocarcinoma', 'Disease', 'MESH:D000230', (23, 37))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (80, 103))	('TNM', 'Gene', (179, 182))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('squamous cell carcinoma', 'Disease', (80, 103))	('patients', 'Species', '9606', (216, 224))	('NSCLC', 'Disease', 'MESH:D002289', (210, 215))	('carcinoma', 'Phenotype', 'HP:0030731', (28, 37))	('KLF6-SV1', 'Gene', (128, 136))	('NSCLC', 'Disease', (210, 215))	('associated with', 'Reg', (155, 170))	('higher', 'PosReg', (56, 62))	('KLF6-SV1', 'Gene', (0, 8))	('KLF6-SV1', 'Gene', '1316', (128, 136))	('adenocarcinoma', 'Disease', (23, 37))
118812	30310314	KLF6 inactivation has been shown in some malignant tumors.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('KLF6', 'Gene', '1316', (0, 4))	('malignant tumors', 'Disease', (41, 57))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('inactivation', 'Var', (5, 17))	('malignant tumors', 'Disease', 'MESH:D018198', (41, 57))	('KLF6', 'Gene', (0, 4))
118854	30310314	Table 2 demonstrates that the high expression of KLF6-SV1 was significantly associated with pathological type (squamous cell carcinoma 45.2% vs adenocarcinoma 70.3%; P=0.025), pathological lymph node (pN- 39.3% vs pN+ 66.7%; P=0.019) and pTNM stage (pI, 31.6% vs pII, 60.5% vs pIIIa, 76.5%; P<0.05).	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (111, 134))	('carcinoma', 'Phenotype', 'HP:0030731', (149, 158))	('TNM', 'Gene', (239, 242))	('adenocarcinoma', 'Disease', (144, 158))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (111, 134))	('high', 'Var', (30, 34))	('associated', 'Reg', (76, 86))	('squamous cell carcinoma', 'Disease', (111, 134))	('adenocarcinoma', 'Disease', 'MESH:D000230', (144, 158))	('KLF6-SV1', 'Gene', '1316', (49, 57))	('TNM', 'Gene', '10178', (239, 242))	('KLF6-SV1', 'Gene', (49, 57))
118856	30310314	A univariate analysis was conducted using the log-rank test, and the 5-year survival rate was significantly associated with differentiation (P<0.05), pN (P=0.001), pTNM stage (P<0.01) and high expression of KLF6-SV1 (P=0.001) (Figure 3 and Table 4).	('KLF6-SV1', 'Gene', '1316', (207, 215))	('TNM', 'Gene', '10178', (165, 168))	('KLF6-SV1', 'Gene', (207, 215))	('differentiation', 'CPA', (124, 139))	('high expression', 'Var', (188, 203))	('TNM', 'Gene', (165, 168))
118882	30310314	To eliminate the impact of mixed factors on statistical analysis, we used multivariate analysis to determine prognostic factors, and the result showed that pN and high expression of KLF6-SV1 were relevant independent factors for a poor prognosis.	('high', 'Var', (163, 167))	('KLF6-SV1', 'Gene', (182, 190))	('KLF6-SV1', 'Gene', '1316', (182, 190))
118888	30310314	KLF6-SV1 expression in adenocarcinoma was significantly higher than that in the squamous cell carcinoma, and the high expression of KLF6-SV1 was significantly associated with pN and pTNM stage and poor survival in NSCLC patients.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (80, 103))	('expression', 'MPA', (9, 19))	('patients', 'Species', '9606', (220, 228))	('NSCLC', 'Disease', (214, 219))	('KLF6-SV1', 'Gene', '1316', (0, 8))	('KLF6-SV1', 'Gene', (132, 140))	('adenocarcinoma', 'Disease', 'MESH:D000230', (23, 37))	('associated with', 'Reg', (159, 174))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (80, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('KLF6-SV1', 'Gene', '1316', (132, 140))	('squamous cell carcinoma', 'Disease', (80, 103))	('TNM', 'Gene', '10178', (183, 186))	('carcinoma', 'Phenotype', 'HP:0030731', (28, 37))	('TNM', 'Gene', (183, 186))	('high', 'Var', (113, 117))	('higher', 'PosReg', (56, 62))	('KLF6-SV1', 'Gene', (0, 8))	('NSCLC', 'Disease', 'MESH:D002289', (214, 219))	('adenocarcinoma', 'Disease', (23, 37))
118896	30066847	On the whole, these findings suggest that circRNA_036186 likely regulates 14-3-3zeta expression by functioning as a ceRNA in the development and progression of HNSCC.	('14-3-3zeta', 'Gene', '7534', (74, 84))	('regulates', 'Reg', (64, 73))	('HNSCC', 'Disease', (160, 165))	('14-3-3zeta', 'Gene', (74, 84))	('circRNA_036186', 'Var', (42, 56))
118902	30066847	Increasing evidence suggests that miRNA dysregulation is associated with the tumorigenesis and progression of various cancer types.	('cancer', 'Disease', (118, 124))	('dysregulation', 'Var', (40, 53))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('miR', 'Gene', '220972', (34, 37))	('miR', 'Gene', (34, 37))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Disease', (77, 82))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('associated', 'Reg', (57, 67))
118904	30066847	Any RNA transcript with MREs may function as a ceRNA and compete with other RNA transcripts with similar MREs for the same miRNAs.	('MREs', 'Var', (24, 28))	('miR', 'Gene', (123, 126))	('miR', 'Gene', '220972', (123, 126))
118918	30066847	According to the results obtained using these three tools, we predicted that circRNA_036186 may promote the expression of tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein, zeta polypeptide (14-3-3zeta) by functioning as a sponge for the inhibitory miR-193b-3p.	('14-3-3zeta', 'Gene', (212, 222))	('tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein, zeta', 'Gene', '7534', (122, 198))	('miR-193b', 'Gene', '574455', (270, 278))	('promote', 'PosReg', (96, 103))	('miR-193b', 'Gene', (270, 278))	('14-3-3zeta', 'Gene', '7534', (212, 222))	('circRNA_036186', 'Var', (77, 91))	('expression', 'MPA', (108, 118))
118943	30066847	Furthermore, the most enriched MF terms were associated with receptor activity and receptor binding, including 'signaling receptor activity' (GO:0038023), 'signal transducer activity' (GO:0004871), 'activating transcription factor binding' (GO:0033613) and 'calcium-dependent protein binding' (GO:0048306).	('binding', 'Interaction', (92, 99))	('GO:0038023', 'Var', (142, 152))	("'calcium-dependent", 'Interaction', (257, 275))	("'signal transducer activity'", 'MPA', (155, 183))	('receptor activity', 'MPA', (61, 78))	('calcium', 'Chemical', 'MESH:D002118', (258, 265))	('GO:0033613', 'Var', (241, 251))	("'signaling receptor activity'", 'MPA', (111, 140))	("'activating transcription factor binding'", 'MPA', (198, 239))	('GO:0004871', 'Var', (185, 195))
118944	30066847	A total of 31 pathways associated with the upregulated mRNAs, and 6 related to the downregulated mRNAs were identified, including 'antigen processing and presentation' (hsa04612), 'natural killer cell mediated cytotoxicity' (hsa04650) and 'calcium signaling pathway' (hsa04020), among others.	("cytotoxicity'", 'Disease', 'MESH:D064420', (210, 223))	('upregulated', 'PosReg', (43, 54))	("'calcium", 'Pathway', (239, 247))	('hsa04650', 'Var', (225, 233))	("cytotoxicity'", 'Disease', (210, 223))	('calcium', 'Chemical', 'MESH:D002118', (240, 247))
118964	30066847	As a miRNA sponge, circRNAs can counteract, and even reverse, the functional differences caused by an alteration in miRNA expression.	('miR', 'Gene', '220972', (5, 8))	('miR', 'Gene', (5, 8))	('alteration', 'Var', (102, 112))	('miR', 'Gene', '220972', (116, 119))	('miR', 'Gene', (116, 119))
118966	30066847	8C), and the expression of circRNA_036186 was significantly higher in the HNSCC tumor tissues compared with the para-carcinoma tissues in the microarray data.	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('higher', 'PosReg', (60, 66))	('expression', 'MPA', (13, 23))	('para-carcinoma', 'Disease', 'MESH:D002277', (112, 126))	('circRNA_036186', 'Var', (27, 41))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('para-carcinoma', 'Disease', (112, 126))	('HNSCC tumor', 'Disease', (74, 85))	('HNSCC tumor', 'Disease', 'MESH:D000077195', (74, 85))
118969	30066847	This indicated that circRNA_036186 probably serves as a crucial and positive regulator of 14-3-3zeta and is significantly engaged in the Hippo signaling pathway in HNSCC.	('circRNA_036186', 'Var', (20, 34))	('14-3-3zeta', 'Gene', (90, 100))	('Hippo signaling pathway', 'Pathway', (137, 160))	('engaged', 'PosReg', (122, 129))	('HNSCC', 'Disease', (164, 169))	('14-3-3zeta', 'Gene', '7534', (90, 100))
118982	30066847	Additionally, by evaluating the associations between miRNA polymorphisms and HNSCC risk according to the cancer site, miR-605 rs2043556 and miR-196a2 rs11614913 have been shown as likely to affect genetic susceptibility to oral squamous cell carcinoma.	('miR', 'Gene', '220972', (53, 56))	('miR-605', 'Gene', (118, 125))	('miR', 'Gene', '220972', (140, 143))	('cancer', 'Disease', (105, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('miR', 'Gene', (53, 56))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (228, 251))	('miR', 'Gene', (140, 143))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (223, 251))	('rs2043556', 'Var', (126, 135))	('miR-196a2', 'Gene', '406973', (140, 149))	('oral squamous cell carcinoma', 'Disease', (223, 251))	('rs11614913', 'Var', (150, 160))	('rs11614913', 'Mutation', 'rs11614913', (150, 160))	('rs2043556', 'Mutation', 'rs2043556', (126, 135))	('miR-196a2', 'Gene', (140, 149))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('HNSCC', 'Disease', (77, 82))	('miR', 'Gene', '220972', (118, 121))	('affect', 'Reg', (190, 196))	('carcinoma', 'Phenotype', 'HP:0030731', (242, 251))	('miR-605', 'Gene', '693190', (118, 125))	('miR', 'Gene', (118, 121))
118986	30066847	Using bioinformatics analysis, we found that circRNA_036186 and 14-3-3zeta had the same seed sequence binding site to for interaction with miR-193b-3p.	('interaction', 'Interaction', (122, 133))	('circRNA_036186', 'Var', (45, 59))	('miR-193b', 'Gene', '574455', (139, 147))	('14-3-3zeta', 'Gene', '7534', (64, 74))	('miR-193b', 'Gene', (139, 147))	('14-3-3zeta', 'Gene', (64, 74))
118997	30066847	Considering the data from previous studies in addition to the results of the current study, the emerging endogenous circRNA molecule circRNA_036186 probably serves as a crucial regulator of 14-3-3zeta by acting as a miRNA sponge to inhibit miR-193b-3p function, and hence participates in the Hippo signaling pathway to exert an effect on the course of HNSCC.	('function', 'MPA', (252, 260))	('inhibit', 'NegReg', (232, 239))	('effect', 'Reg', (328, 334))	('miR', 'Gene', '220972', (216, 219))	('HNSCC', 'Disease', (352, 357))	('14-3-3zeta', 'Gene', (190, 200))	('miR', 'Gene', (216, 219))	('miR', 'Gene', '220972', (240, 243))	('miR', 'Gene', (240, 243))	('miR-193b', 'Gene', '574455', (240, 248))	('Hippo signaling pathway', 'Pathway', (292, 315))	('participates', 'Reg', (272, 284))	('circRNA_036186', 'Var', (133, 147))	('14-3-3zeta', 'Gene', '7534', (190, 200))	('miR-193b', 'Gene', (240, 248))
119005	28152520	After knock-down of AEG-1, the proliferation, migration and invasion of NSCLC cells were all inhibited, and the tumorigenic and angiogenic ability of NSCLC cells were weakened.	('AEG-1', 'Gene', (20, 25))	('NSCLC', 'Disease', 'MESH:D002289', (150, 155))	('invasion', 'CPA', (60, 68))	('proliferation', 'CPA', (31, 44))	('NSCLC', 'Disease', (72, 77))	('migration', 'CPA', (46, 55))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('AEG-1', 'Gene', '92140', (20, 25))	('knock-down', 'Var', (6, 16))	('weakened', 'NegReg', (167, 175))	('NSCLC', 'Disease', 'MESH:D002289', (72, 77))	('NSCLC', 'Phenotype', 'HP:0030358', (150, 155))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumor', 'Disease', (112, 117))	('NSCLC', 'Disease', (150, 155))	('NSCLC', 'Phenotype', 'HP:0030358', (72, 77))	('inhibited', 'NegReg', (93, 102))
119012	28152520	Inhibiting the expression of AEG-1 is expected to become a novel method in the therapeutic strategies of NSCLC.	('NSCLC', 'Disease', 'MESH:D002289', (105, 110))	('Inhibiting', 'Var', (0, 10))	('NSCLC', 'Phenotype', 'HP:0030358', (105, 110))	('expression', 'MPA', (15, 25))	('AEG-1', 'Gene', '92140', (29, 34))	('AEG-1', 'Gene', (29, 34))	('NSCLC', 'Disease', (105, 110))
119020	28152520	found that AEG-1 could act as an oncogene and the inhibition of AEG-1 expression could promote cell apoptosis, reduce cell viability and weaken the invasive ability of prostate cancer cells.	('prostate cancer', 'Disease', 'MESH:D011471', (168, 183))	('AEG-1', 'Gene', '92140', (11, 16))	('prostate cancer', 'Phenotype', 'HP:0012125', (168, 183))	('AEG-1', 'Gene', (64, 69))	('inhibition', 'Var', (50, 60))	('cell apoptosis', 'CPA', (95, 109))	('AEG-1', 'Gene', (11, 16))	('weaken', 'NegReg', (137, 143))	('cell viability', 'CPA', (118, 132))	('prostate cancer', 'Disease', (168, 183))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('reduce', 'NegReg', (111, 117))	('promote', 'PosReg', (87, 94))	('AEG-1', 'Gene', '92140', (64, 69))
119052	28152520	Additionally, a high expression of AEG-1 was pronouncedly related to a poor overall survival (OS) (HR=1.82, 95%CI: 1.35-2.28, P < 0.0001).	('overall survival', 'MPA', (76, 92))	('AEG-1', 'Gene', '92140', (35, 40))	('poor', 'NegReg', (71, 75))	('high', 'Var', (16, 20))	('expression', 'MPA', (21, 31))	('AEG-1', 'Gene', (35, 40))
119064	28152520	We found that the expression of AEG-1 in the sh00 group (0.50 +- 0.04) was obviously inhibited compared to the other groups (P = 0.005, mock control, NC, sh97, sh98 and sh99 was 0.99 +- 0.13, 0.88 +- 0.06, 0.90 +- 0.11, 1.17 +- 0.10 and 1.99 +- 0.28, respectively.	('inhibited', 'NegReg', (85, 94))	('sh00', 'Var', (45, 49))	('expression', 'MPA', (18, 28))	('AEG-1', 'Gene', '92140', (32, 37))	('AEG-1', 'Gene', (32, 37))
119082	28152520	The size of the tumor xenografts in the mock, NC and AEG-1-shRNA groups was 0.04 +-0.01, 0.02 +-0.01 and 0 cm3, respectively, indicating that the tumorigenic ability of the H460 cells was weakened by silencing AEG-1 expression (P < 0.05, Figure 12C).	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('weakened', 'NegReg', (188, 196))	('tumor', 'Disease', (146, 151))	('silencing', 'Var', (200, 209))	('AEG-1', 'Gene', (210, 215))	('AEG-1', 'Gene', '92140', (210, 215))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('H460', 'CellLine', 'CVCL:0459', (173, 177))	('tumor', 'Disease', (16, 21))	('AEG-1', 'Gene', '92140', (53, 58))	('AEG-1', 'Gene', (53, 58))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
119086	28152520	We searched for top 2000 co-expressed genes in five different probe sets for AEG-1 (212248_AT, 212250_AT, 212251_AT, 227277_AT and 1559822_S_At).	('AT', 'Disease', 'None', (124, 126))	('AT', 'Disease', 'None', (91, 93))	('AT', 'Disease', 'None', (113, 115))	('1559822_S_At', 'Var', (131, 143))	('AT', 'Disease', 'None', (102, 104))	('AEG-1', 'Gene', '92140', (77, 82))	('AEG-1', 'Gene', (77, 82))
119094	28152520	And we found that high expression of AEG-1 showed more robust correlation with high clinical stage, lymph node metastasis, distant metastasis, poorly histological differentiation and short overall survival (OS).	('overall survival', 'CPA', (189, 205))	('lymph node metastasis', 'CPA', (100, 121))	('high clinical stage', 'CPA', (79, 98))	('clinical', 'Species', '191496', (84, 92))	('AEG-1', 'Gene', '92140', (37, 42))	('AEG-1', 'Gene', (37, 42))	('poorly histological differentiation', 'CPA', (143, 178))	('high', 'Var', (18, 22))	('distant metastasis', 'CPA', (123, 141))	('expression', 'MPA', (23, 33))
119099	28152520	Generally, the clinical stage, status of tumor size, metastasis and overall survival could reflect the deterioration of a tumor, so the high AEG-1 expression could be closely related to the deterioration of NSCLC.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('NSCLC', 'Phenotype', 'HP:0030358', (207, 212))	('tumor', 'Disease', (41, 46))	('expression', 'MPA', (147, 157))	('high', 'Var', (136, 140))	('clinical', 'Species', '191496', (15, 23))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('AEG-1', 'Gene', '92140', (141, 146))	('AEG-1', 'Gene', (141, 146))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('related', 'Reg', (175, 182))	('NSCLC', 'Disease', (207, 212))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('tumor', 'Disease', (122, 127))	('NSCLC', 'Disease', 'MESH:D002289', (207, 212))
119104	28152520	We also performed direct experimental evidence by scratch assay, colony formation assay, Transwell migration and invasion assay and the CAM model to demonstrate that AEG-1 was a tumorigenic gene and that the high expression of AEG-1 promotes the proliferation, invasion and migration of the NSCLC cells.	('tumor', 'Disease', (178, 183))	('AEG-1', 'Gene', '92140', (227, 232))	('AEG-1', 'Gene', (227, 232))	('NSCLC', 'Phenotype', 'HP:0030358', (291, 296))	('promotes', 'PosReg', (233, 241))	('AEG-1', 'Gene', '92140', (166, 171))	('AEG-1', 'Gene', (166, 171))	('invasion', 'CPA', (261, 269))	('proliferation', 'CPA', (246, 259))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('NSCLC', 'Disease', (291, 296))	('high expression', 'Var', (208, 223))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('NSCLC', 'Disease', 'MESH:D002289', (291, 296))
119173	28152520	Our findings confirm that overexpression of AEG-1 can promote the proliferation, invasion and migration of NSCLC and the high AEG-1 level can accelerate tumorigenesis and the deterioration of NSCLC.	('NSCLC', 'Disease', (192, 197))	('NSCLC', 'Phenotype', 'HP:0030358', (192, 197))	('AEG-1', 'Gene', '92140', (44, 49))	('AEG-1', 'Gene', (44, 49))	('migration', 'CPA', (94, 103))	('NSCLC', 'Disease', 'MESH:D002289', (107, 112))	('tumor', 'Disease', (153, 158))	('accelerate', 'PosReg', (142, 152))	('promote', 'PosReg', (54, 61))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('NSCLC', 'Disease', (107, 112))	('invasion', 'CPA', (81, 89))	('deterioration', 'MPA', (175, 188))	('NSCLC', 'Phenotype', 'HP:0030358', (107, 112))	('AEG-1', 'Gene', '92140', (126, 131))	('AEG-1', 'Gene', (126, 131))	('NSCLC', 'Disease', 'MESH:D002289', (192, 197))	('proliferation', 'CPA', (66, 79))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('high', 'Var', (121, 125))
119202	33408336	A mouse model of mutant epidermal growth factor receptor-driven lung cancer recently showed complex alterations in lipid profiles, including decreases in different PI species and a saturated PE species (PE 16:0), while the contents of certain triglycerides and phosphatidylmethanol species were increased compared to those in normal lung tissue.	('lung cancer', 'Disease', (64, 75))	('phosphatidylmethanol', 'Chemical', '-', (261, 281))	('epidermal growth factor receptor', 'Gene', (24, 56))	('PE', 'Chemical', 'MESH:C483858', (203, 205))	('decreases', 'NegReg', (141, 150))	('lipid', 'Chemical', 'MESH:D008055', (115, 120))	('mutant', 'Var', (17, 23))	('alterations', 'Reg', (100, 111))	('lung cancer', 'Disease', 'MESH:D008175', (64, 75))	('triglycerides', 'Chemical', 'MESH:D014280', (243, 256))	('lung cancer', 'Phenotype', 'HP:0100526', (64, 75))	('epidermal growth factor receptor', 'Gene', '13649', (24, 56))	('contents', 'MPA', (223, 231))	('lipid profiles', 'MPA', (115, 129))	('increased', 'PosReg', (295, 304))	('PE', 'Chemical', 'MESH:C483858', (191, 193))	('triglycerides', 'MPA', (243, 256))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('saturated PE species', 'MPA', (181, 201))	('mouse', 'Species', '10090', (2, 7))
119204	33408336	Lipin-1, one of the enzymes responsible for the conversion of PA to DG, was shown to be upregulated in basal-like triple-negative breast cancer, and silencing lipin-1 significantly inhibited tumor growth in a breast cancer model in vivo.	('PA', 'Chemical', 'MESH:D010712', (62, 64))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('silencing', 'Var', (149, 158))	('Lipin-1', 'Gene', (0, 7))	('breast cancer', 'Phenotype', 'HP:0003002', (130, 143))	('breast cancer', 'Phenotype', 'HP:0003002', (209, 222))	('tumor', 'Disease', (191, 196))	('lipin-1', 'Gene', (159, 166))	('breast cancer', 'Disease', 'MESH:D001943', (130, 143))	('breast cancer', 'Disease', (130, 143))	('Lipin-1', 'Gene', '23175', (0, 7))	('breast cancer', 'Disease', 'MESH:D001943', (209, 222))	('upregulated', 'PosReg', (88, 99))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('lipin-1', 'Gene', '23175', (159, 166))	('breast cancer', 'Disease', (209, 222))	('inhibited', 'NegReg', (181, 190))
119205	33408336	Lipin-1 expression was shown to be elevated in NSCLC compared to normal lung tissue, and silencing lipin-1 in NSCLC cells induced endoplasmic reticulum stress and reduced proliferation and survival.	('induced', 'Reg', (122, 129))	('NSCLC', 'Disease', 'MESH:D002289', (110, 115))	('NSCLC', 'Disease', (47, 52))	('elevated', 'PosReg', (35, 43))	('endoplasmic', 'MPA', (130, 141))	('lipin-1', 'Gene', (99, 106))	('NSCLC', 'Phenotype', 'HP:0030358', (47, 52))	('NSCLC', 'Disease', (110, 115))	('survival', 'CPA', (189, 197))	('lipin-1', 'Gene', '23175', (99, 106))	('expression', 'MPA', (8, 18))	('proliferation', 'CPA', (171, 184))	('NSCLC', 'Phenotype', 'HP:0030358', (110, 115))	('Lipin-1', 'Gene', (0, 7))	('stress', 'Disease', 'MESH:D000079225', (152, 158))	('Lipin-1', 'Gene', '23175', (0, 7))	('reduced', 'NegReg', (163, 170))	('stress', 'Disease', (152, 158))	('silencing', 'Var', (89, 98))	('NSCLC', 'Disease', 'MESH:D002289', (47, 52))
119269	33408336	PE can be synthesized in mammalian cells via the CDP-ethanolamine pathway, by base exchange pathways from phosphatidylserine (PS) or PC, or by acylation of lyso-PE.	('acylation', 'Var', (143, 152))	('PC', 'Gene', '5091', (133, 135))	('mammalian', 'Species', '9606', (25, 34))	('lyso-PE', 'Chemical', 'MESH:C008301', (156, 163))	('CDP-ethanolamine', 'Enzyme', (49, 65))	('base exchange', 'MPA', (78, 91))	('PE', 'Chemical', 'MESH:C483858', (161, 163))	('PE', 'Chemical', 'MESH:C483858', (0, 2))	('CDP-ethanolamine', 'Chemical', 'MESH:C006933', (49, 65))	('phosphatidylserine', 'Chemical', 'MESH:D010718', (106, 124))	('PS', 'Chemical', 'MESH:D010718', (126, 128))
119289	33408336	In lung adenocarcinoma, high expression of EPT1 but low expression of CHKA, a choline kinase, was significantly associated with poor overall survival (Fig.	('poor', 'NegReg', (128, 132))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (3, 22))	('CHKA', 'Gene', '1119', (70, 74))	('CHKA', 'Gene', (70, 74))	('EPT1', 'Gene', (43, 47))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (3, 22))	('choline', 'Chemical', 'MESH:D002794', (78, 85))	('high', 'Var', (24, 28))	('overall survival', 'MPA', (133, 149))	('EPT1', 'Gene', '85465', (43, 47))	('expression', 'MPA', (29, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (13, 22))	('associated', 'Reg', (112, 122))	('lung adenocarcinoma', 'Disease', (3, 22))
119323	33408336	Polyunsaturated fatty acids are particularly prone to undergo peroxidation and trigger ferroptosis unless protected by glutathione peroxidase 4, a phospholipid peroxidase.	('lipid', 'Chemical', 'MESH:D008055', (154, 159))	('glutathione peroxidase 4', 'Gene', '2879', (119, 143))	('peroxidation', 'MPA', (62, 74))	('Polyunsaturated fatty acids', 'Var', (0, 27))	('Polyunsaturated fatty acids', 'Chemical', 'MESH:D005231', (0, 27))	('glutathione peroxidase 4', 'Gene', (119, 143))	('trigger', 'Reg', (79, 86))	('ferroptosis', 'Disease', (87, 98))
119328	33408336	Moreover, high expression of EPT1 was associated with poor overall survival in adenocarcinoma.	('EPT1', 'Gene', (29, 33))	('poor', 'NegReg', (54, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('adenocarcinoma', 'Disease', (79, 93))	('EPT1', 'Gene', '85465', (29, 33))	('adenocarcinoma', 'Disease', 'MESH:D000230', (79, 93))	('high', 'Var', (10, 14))	('overall survival', 'MPA', (59, 75))
119329	33408336	In a previous study, ETNK1 was found to be amplified in a subset of lung adenocarcinomas, and ETNK1 amplification was found to be correlated with poor prognosis.	('ETNK1', 'Gene', (94, 99))	('amplification', 'Var', (100, 113))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (68, 88))	('amplified', 'Reg', (43, 52))	('ETNK1', 'Gene', '55500', (21, 26))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (68, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('ETNK1', 'Gene', '55500', (94, 99))	('lung adenocarcinomas', 'Disease', (68, 88))	('ETNK1', 'Gene', (21, 26))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (68, 88))
119343	33438349	Anlotinib was determined to significantly inhibit cell growth in all groups, both alone, or in combination with radiotherapy.	('inhibit', 'NegReg', (42, 49))	('Anlotinib', 'Chemical', 'MESH:C000625192', (0, 9))	('cell growth', 'CPA', (50, 61))	('Anlotinib', 'Var', (0, 9))
119391	33438349	7 ,  8 ,  9  The probability of EGFR-sensitive mutations in Chinese patients with advanced lung adenocarcinoma is about 50%.	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (91, 110))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('EGFR', 'Gene', '1956', (32, 36))	('lung adenocarcinoma', 'Disease', (91, 110))	('mutations', 'Var', (47, 56))	('patients', 'Species', '9606', (68, 76))	('EGFR', 'Gene', (32, 36))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (91, 110))
119400	33438349	Studies in gastrointestinal tumors and hepatocellular carcinoma have shown that sorafenib, BD0801 or bevacizumab predominantly blocks G0/G1 phase, and in ovarian cancer, G2/M phase.	('ovarian cancer', 'Disease', 'MESH:D010051', (154, 168))	('gastrointestinal tumors', 'Disease', (11, 34))	('gastrointestinal tumors', 'Phenotype', 'HP:0007378', (11, 34))	('G2/M phase', 'CPA', (170, 180))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (39, 63))	('bevacizumab', 'Chemical', 'MESH:D000068258', (101, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (54, 63))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('G0/G1 phase', 'CPA', (134, 145))	('ovarian cancer', 'Disease', (154, 168))	('hepatocellular carcinoma', 'Disease', (39, 63))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('ovarian cancer', 'Phenotype', 'HP:0100615', (154, 168))	('gastrointestinal tumors', 'Disease', 'MESH:D004067', (11, 34))	('BD0801', 'Var', (91, 97))	('sorafenib', 'Chemical', 'MESH:D000077157', (80, 89))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (39, 63))	('blocks', 'NegReg', (127, 133))	('sorafenib', 'Gene', (80, 89))
119404	33438349	Hence theoretically, anlotinib could increase the radiosensitivity of H520 cells.	('anlotinib', 'Var', (21, 30))	('H520', 'CellLine', 'CVCL:1566', (70, 74))	('radiosensitivity', 'CPA', (50, 66))	('increase', 'PosReg', (37, 45))	('anlotinib', 'Chemical', 'MESH:C000625192', (21, 30))
119429	31134149	Epigenetic-Mediated Downregulation of Zinc Finger Protein 671 (ZNF671) Predicts Poor Prognosis in Multiple Solid Tumors Zinc finger protein 671 (ZNF671) is a member of the largest transcription factor family in the human genome.	('Zinc Finger Protein 671', 'Gene', (38, 61))	('Epigenetic-Mediated', 'Var', (0, 19))	('Tumors', 'Disease', (113, 119))	('Tumors', 'Disease', 'MESH:D009369', (113, 119))	('Downregulation', 'NegReg', (20, 34))	('Tumors', 'Phenotype', 'HP:0002664', (113, 119))	('Zinc finger protein 671', 'Gene', '79891', (120, 143))	('ZNF671', 'Gene', (63, 69))	('Zinc finger protein 671', 'Gene', (120, 143))	('Zinc Finger Protein 671', 'Gene', '79891', (38, 61))	('ZNF671', 'Gene', (145, 151))	('ZNF671', 'Gene', '79891', (63, 69))	('human', 'Species', '9606', (215, 220))	('ZNF671', 'Gene', '79891', (145, 151))
119438	31134149	Disruption of epigenetic processes can lead to activation of oncogenes and/or the inactivation of tumor suppressor pathways, and the accumulation of epigenetic changes in the molecular landscape is a hallmark of cancer.	('epigenetic', 'Var', (149, 159))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))	('hallmark of cancer', 'Disease', (200, 218))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('activation', 'PosReg', (47, 57))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('oncogenes', 'CPA', (61, 70))	('hallmark of cancer', 'Disease', 'MESH:D009369', (200, 218))	('tumor', 'Disease', (98, 103))	('inactivation', 'NegReg', (82, 94))	('Disruption', 'Var', (0, 10))
119439	31134149	DNA methylation is an early event in tumorigenesis and plays a major role in tumor initiation and progression.	('tumor initiation', 'Disease', (77, 93))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('methylation', 'Var', (4, 15))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor initiation', 'Disease', 'MESH:D009369', (77, 93))	('tumor', 'Disease', (77, 82))
119447	31134149	Our results provide important insights into ZNF671 hypermethylation as a promising biomarker for eight solid tumors and thereby provide novel perspectives for the treatment of tumors.	('tumors', 'Disease', 'MESH:D009369', (109, 115))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('hypermethylation', 'Var', (51, 67))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('tumors', 'Disease', (176, 182))	('ZNF671', 'Gene', '79891', (44, 50))	('solid tumors', 'Disease', 'MESH:D009369', (103, 115))	('solid tumors', 'Disease', (103, 115))	('tumors', 'Disease', 'MESH:D009369', (176, 182))	('tumors', 'Phenotype', 'HP:0002664', (176, 182))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumors', 'Disease', (109, 115))	('ZNF671', 'Gene', (44, 50))
119470	31134149	Overall, the results indicate that epigenetic-mediated downregulation of ZNF671 predicts poor survival in BRCA, CESC, HNSC, KIRP, LUAD, PAAD, UCEC, and SARC and that ZNF671 may play a tumor suppressor role in tumor progression, which is consistent with previous studies in HNSC, UCEC, and KIRP.	('UCEC', 'Disease', (142, 146))	('ZNF671', 'Gene', '79891', (166, 172))	('HNSC', 'Phenotype', 'HP:0012288', (118, 122))	('BRCA', 'Phenotype', 'HP:0003002', (106, 110))	('LUAD', 'Disease', (130, 134))	('downregulation', 'NegReg', (55, 69))	('KIRP', 'Disease', (124, 128))	('tumor', 'Disease', (209, 214))	('PAAD', 'Phenotype', 'HP:0006725', (136, 140))	('HNSC', 'Phenotype', 'HP:0012288', (273, 277))	('CESC', 'Disease', (112, 116))	('tumor', 'Disease', (184, 189))	('SARC', 'Disease', (152, 156))	('tumor', 'Disease', 'MESH:D009369', (209, 214))	('BRCA', 'Gene', '672', (106, 110))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('PAAD', 'Disease', (136, 140))	('poor', 'NegReg', (89, 93))	('ZNF671', 'Gene', (73, 79))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))	('epigenetic-mediated', 'Var', (35, 54))	('BRCA', 'Gene', (106, 110))	('SARC', 'Phenotype', 'HP:0100242', (152, 156))	('ZNF671', 'Gene', '79891', (73, 79))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('HNSC', 'Disease', (118, 122))	('ZNF671', 'Gene', (166, 172))	('LUAD', 'Phenotype', 'HP:0030078', (130, 134))
119477	31134149	Our previous studies demonstrated that ZNF671 is a tumor suppressor that is epigenetically silenced by DNA methylation in nasopharyngeal carcinoma, but there is limited information regarding the role of ZNF671 methylation among different solid cancer types.	('nasopharyngeal carcinoma', 'Disease', (122, 146))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('ZNF671', 'Gene', (203, 209))	('DNA methylation', 'Var', (103, 118))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (122, 146))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('ZNF671', 'Gene', '79891', (39, 45))	('tumor', 'Disease', (51, 56))	('cancer', 'Disease', 'MESH:D009369', (244, 250))	('silenced', 'NegReg', (91, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('nasopharyngeal carcinoma', 'Disease', 'MESH:D000077274', (122, 146))	('ZNF671', 'Gene', '79891', (203, 209))	('ZNF671', 'Gene', (39, 45))	('methylation', 'Var', (107, 118))	('cancer', 'Disease', (244, 250))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
119479	31134149	Functional assays and prognostic analysis found that high ZNF671 expression suppressed tumor cell proliferation, migration, and invasion, and downregulation of ZNF671 was associated with poor clinical prognosis in BRCA, CESC, HNSC, KIRP, LUAD, PAAD, and UCEC.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('HNSC', 'Phenotype', 'HP:0012288', (226, 230))	('BRCA', 'Gene', (214, 218))	('downregulation', 'NegReg', (142, 156))	('ZNF671', 'Gene', (58, 64))	('LUAD', 'Phenotype', 'HP:0030078', (238, 242))	('ZNF671', 'Gene', '79891', (58, 64))	('invasion', 'CPA', (128, 136))	('high', 'Var', (53, 57))	('tumor', 'Disease', (87, 92))	('BRCA', 'Phenotype', 'HP:0003002', (214, 218))	('PAAD', 'Phenotype', 'HP:0006725', (244, 248))	('suppressed', 'NegReg', (76, 86))	('LUAD', 'Disease', (238, 242))	('ZNF671', 'Gene', (160, 166))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('CESC', 'Disease', (220, 224))	('ZNF671', 'Gene', '79891', (160, 166))	('BRCA', 'Gene', '672', (214, 218))	('UCEC', 'Disease', (254, 258))	('KIRP', 'Disease', (232, 236))	('migration', 'CPA', (113, 122))	('PAAD', 'Disease', (244, 248))	('HNSC', 'Disease', (226, 230))
119481	31134149	In this study, we found that the ZNF671 promoter is significantly methylated in 17 solid tumors, based on the TCGA datasets, which is consistent with studies in urothelial carcinoma, clear cell renal cell carcinomas, and cervical cancer.	('cervical cancer', 'Disease', 'MESH:D002583', (221, 236))	('cervical cancer', 'Disease', (221, 236))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (161, 181))	('solid tumors', 'Disease', (83, 95))	('clear cell renal cell carcinomas', 'Phenotype', 'HP:0006770', (183, 215))	('ZNF671', 'Gene', (33, 39))	('clear cell renal cell carcinomas', 'Disease', (183, 215))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (194, 215))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('ZNF671', 'Gene', '79891', (33, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (205, 214))	('carcinomas', 'Phenotype', 'HP:0030731', (205, 215))	('carcinoma', 'Phenotype', 'HP:0030731', (172, 181))	('solid tumors', 'Disease', 'MESH:D009369', (83, 95))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('methylated', 'Var', (66, 76))	('urothelial carcinoma', 'Disease', (161, 181))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('clear cell renal cell carcinomas', 'Disease', 'MESH:C538614', (183, 215))
119489	31134149	In conclusion, this is the first report to systematically evaluate the correlation between methylation of ZNF671 and prognosis among 18 solid tumors.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('methylation', 'Var', (91, 102))	('solid tumors', 'Disease', (136, 148))	('ZNF671', 'Gene', (106, 112))	('ZNF671', 'Gene', '79891', (106, 112))	('solid tumors', 'Disease', 'MESH:D009369', (136, 148))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))
119490	31134149	The prognostic signature observed in our study was linked to hypermethylation of ZNF671.	('ZNF671', 'Gene', (81, 87))	('ZNF671', 'Gene', '79891', (81, 87))	('hypermethylation', 'Var', (61, 77))
119492	31134149	Further prognosis analysis indicated that high expression of ZNF671 was associated with longer overall survival (OS) and that ZNF671 expression is a favorable prognostic indicator in BRCA, CESC, HNSC, KIRP, LUAD, PAAD, SARC, and UCEC, but the mechanism remains unknown.	('HNSC', 'Disease', (195, 199))	('SARC', 'Disease', (219, 223))	('UCEC', 'Disease', (229, 233))	('ZNF671', 'Gene', '79891', (61, 67))	('LUAD', 'Phenotype', 'HP:0030078', (207, 211))	('overall survival', 'MPA', (95, 111))	('HNSC', 'Phenotype', 'HP:0012288', (195, 199))	('BRCA', 'Phenotype', 'HP:0003002', (183, 187))	('LUAD', 'Disease', (207, 211))	('SARC', 'Phenotype', 'HP:0100242', (219, 223))	('longer', 'PosReg', (88, 94))	('expression', 'MPA', (47, 57))	('KIRP', 'Disease', (201, 205))	('BRCA', 'Gene', '672', (183, 187))	('PAAD', 'Phenotype', 'HP:0006725', (213, 217))	('PAAD', 'Disease', (213, 217))	('CESC', 'Disease', (189, 193))	('ZNF671', 'Gene', (126, 132))	('BRCA', 'Gene', (183, 187))	('ZNF671', 'Gene', '79891', (126, 132))	('high', 'Var', (42, 46))	('ZNF671', 'Gene', (61, 67))
119582	29342219	Higher levels of EEF2 were significantly associated with poor RFS and PPS in basal subtype, but better RFS and DMFS in luminal subtypes.	('EEF2', 'Gene', '1938', (17, 21))	('RFS', 'Disease', (62, 65))	('poor', 'NegReg', (57, 61))	('EEF2', 'Gene', (17, 21))	('DMFS', 'Var', (111, 115))	('PPS', 'MPA', (70, 73))	('RFS', 'Disease', (103, 106))	('DMFS', 'Chemical', '-', (111, 115))	('RFS', 'Disease', 'MESH:D005198', (62, 65))	('PPS', 'Chemical', '-', (70, 73))	('RFS', 'Disease', 'MESH:D005198', (103, 106))
119843	31770286	However, prognosis from TCGA database showed inconsistent results in which high expression of Drp1 was correlated with worse survival probability of all, male, female in lung adenocarcinoma (P < .05), but not in LUSC (P > .05).	('worse', 'NegReg', (119, 124))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (170, 189))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (170, 189))	('carcinoma', 'Phenotype', 'HP:0030731', (180, 189))	('high', 'Var', (75, 79))	('Drp1', 'Gene', '10059', (94, 98))	('lung adenocarcinoma', 'Disease', (170, 189))	('LUSC', 'Disease', 'MESH:D002294', (212, 216))	('Drp1', 'Gene', (94, 98))	('LUSC', 'Disease', (212, 216))
119847	31770286	Despite advances in the level of health care, oncotherapy is still confronted with great challenges due to the delayed diagnosis, recurrence or metastasis, as well as cancer associated mutation.	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('cancer', 'Disease', (167, 173))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('mutation', 'Var', (185, 193))
119902	31770286	The chosen probe IDs (203105_s_at and 226154_at) for Drp1 has been listed in Table 1.	('Drp1', 'Gene', (53, 57))	('226154_at', 'Var', (38, 47))	('203105_s_at', 'Var', (22, 33))	('Drp1', 'Gene', '10059', (53, 57))
119915	31770286	On the contrary, high expression of Drp1was correlated with worse survival probability of all, male, female in LUAC (P < .05, Fig.	('LUAC', 'Disease', (111, 115))	('LUAC', 'Disease', 'MESH:C538231', (111, 115))	('high', 'Var', (17, 21))	('Drp1', 'Gene', '10059', (36, 40))	('survival', 'CPA', (66, 74))	('Drp1', 'Gene', (36, 40))	('LUAC', 'Phenotype', 'HP:0030078', (111, 115))	('worse', 'NegReg', (60, 65))
119945	31770286	documented an increase in Drp1 expression in tissue samples from patients with LUAC and inhibition of Drp1reduced proliferation and increases apoptosis of lung cancer cells.	('men', 'Species', '9606', (4, 7))	('Drp1', 'Gene', (26, 30))	('Drp1', 'Gene', (102, 106))	('inhibition', 'Var', (88, 98))	('increases apoptosis of lung cancer', 'Disease', 'MESH:D008175', (132, 166))	('LUAC', 'Phenotype', 'HP:0030078', (79, 83))	('expression', 'MPA', (31, 41))	('increases apoptosis of lung cancer', 'Disease', (132, 166))	('proliferation', 'CPA', (114, 127))	('Drp1', 'Gene', '10059', (102, 106))	('patients', 'Species', '9606', (65, 73))	('Drp1', 'Gene', '10059', (26, 30))	('lung cancer', 'Phenotype', 'HP:0100526', (155, 166))	('LUAC', 'Disease', (79, 83))	('LUAC', 'Disease', 'MESH:C538231', (79, 83))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('increase', 'PosReg', (14, 22))
119946	31770286	But, Kim and his colleague suggested that loss of Drp1 was associated with the progression of human lung cancer, and an identical pattern was observed in cultured lung cancer cell lines.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('lung cancer', 'Disease', 'MESH:D008175', (163, 174))	('loss', 'Var', (42, 46))	('Drp1', 'Gene', '10059', (50, 54))	('associated', 'Reg', (59, 69))	('lung cancer', 'Phenotype', 'HP:0100526', (100, 111))	('lung cancer', 'Phenotype', 'HP:0100526', (163, 174))	('lung cancer', 'Disease', (100, 111))	('human', 'Species', '9606', (94, 99))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('lung cancer', 'Disease', (163, 174))	('Drp1', 'Gene', (50, 54))	('lung cancer', 'Disease', 'MESH:D008175', (100, 111))
119951	31770286	Contrarily, the TCGA database showed that high expression of Drp1 was correlated with worse survival probability in all, male, female with LUAC, but not any relationship was observed in LUSC.	('LUAC', 'Disease', (139, 143))	('LUAC', 'Phenotype', 'HP:0030078', (139, 143))	('Drp1', 'Gene', (61, 65))	('LUSC', 'Disease', 'MESH:D002294', (186, 190))	('LUAC', 'Disease', 'MESH:C538231', (139, 143))	('worse', 'NegReg', (86, 91))	('high expression', 'Var', (42, 57))	('LUSC', 'Disease', (186, 190))	('survival probability', 'CPA', (92, 112))	('Drp1', 'Gene', '10059', (61, 65))
119958	31770286	One side, high expression and activation of Drp1 in tumor cells promotes mitochondrial fission, ultimately initiating apoptotic ways.	('Drp1', 'Gene', (44, 48))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('promotes', 'PosReg', (64, 72))	('tumor', 'Disease', (52, 57))	('activation', 'PosReg', (30, 40))	('initiating', 'Reg', (107, 117))	('mitochondrial fission', 'MPA', (73, 94))	('Drp1', 'Gene', '10059', (44, 48))	('high', 'Var', (10, 14))	('apoptotic', 'CPA', (118, 127))	('tumor', 'Disease', 'MESH:D009369', (52, 57))
119959	31770286	On the other hand, interestingly, suppression or depletion of Drp1 also induces tumor cells apoptosis.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('induces', 'Reg', (72, 79))	('Drp1', 'Gene', '10059', (62, 66))	('tumor', 'Disease', (80, 85))	('Drp1', 'Gene', (62, 66))	('depletion', 'Var', (49, 58))
119961	31770286	Persistent mitochondrial hyperfusion beyond the G1/S border which was caused by Drp1 depletion increases replication stress, leading to G2/M delay, chromosomal instability and DNA damage, ultimately inhibiting cell division and triggering apoptosis.	('chromosomal instability', 'CPA', (148, 171))	('DNA damage', 'MPA', (176, 186))	('apoptosis', 'CPA', (239, 248))	('inhibiting', 'NegReg', (199, 209))	('caused by', 'Reg', (70, 79))	('replication stress', 'MPA', (105, 123))	('Drp1', 'Gene', '10059', (80, 84))	('depletion', 'Var', (85, 94))	('G2/M', 'MPA', (136, 140))	('increases', 'PosReg', (95, 104))	('chromosomal instability', 'Phenotype', 'HP:0040012', (148, 171))	('cell division', 'CPA', (210, 223))	('Drp1', 'Gene', (80, 84))	('mitochondrial hyperfusion', 'MPA', (11, 36))	('triggering', 'Reg', (228, 238))
119987	30181502	One subset of genetic alterations would enable tumors to evade killing but does not impact the infiltration.	('tumors', 'Disease', (47, 53))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('genetic alterations', 'Var', (14, 33))	('evade killing', 'CPA', (57, 70))	('enable', 'Reg', (40, 46))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))
119988	30181502	These alterations include the mutations in antigen presentation machinery genes such as HLA and B2M, and extrinsic apoptosis genes such as CASP8.	('HLA', 'Gene', (88, 91))	('B2M', 'Gene', (96, 99))	('mutations', 'Var', (30, 39))	('CASP8', 'Gene', (139, 144))	('CASP8', 'Gene', '841', (139, 144))
119989	30181502	They also include amplifications in regions of genes that function in immunosuppression such as PDL1/2.	('PDL1/2', 'Gene', (96, 102))	('amplifications', 'Var', (18, 32))	('PDL1/2', 'Gene', '29126;80380', (96, 102))
119990	30181502	These alterations include the mutations in IDO1, IDO2, p53 and ALOX gene loci.	('p53', 'Gene', (55, 58))	('p53', 'Gene', '7157', (55, 58))	('ALOX gene', 'Gene', (63, 72))	('IDO1', 'Gene', '3620', (43, 47))	('mutations', 'Var', (30, 39))	('IDO2', 'Gene', '169355', (49, 53))	('IDO1', 'Gene', (43, 47))	('IDO2', 'Gene', (49, 53))
120120	30158769	In the south coastal region of India, chewing pan, use of commercial tobacco products, beedi (local type of cigarette), cigarette-smoking, alcohol-drinking and use of snuff are some of the common habits.	('alcohol-drinking', 'Var', (139, 155))	('alcohol', 'Chemical', 'MESH:D000438', (139, 146))	('cigarette-smoking', 'Disease', (120, 137))	('alcohol-drinking', 'Phenotype', 'HP:0030955', (139, 155))	('tobacco', 'Species', '4097', (69, 76))
120224	30158769	In addition, familial history of cancer has previously been studied as a possible risk factor for oral cancer.	('oral cancer', 'Disease', 'MESH:D009062', (98, 109))	('cancer', 'Disease', (33, 39))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('oral cancer', 'Disease', (98, 109))	('familial history', 'Var', (13, 29))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))
120242	28966935	Using pharmacological and genetic alterations, we mechanistically demonstrate the critical importance of BDNF-TrkB signaling in the tumor microenvironment.	('tumor', 'Disease', (132, 137))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('alterations', 'Var', (34, 45))	('tumor', 'Disease', 'MESH:D009369', (132, 137))
120265	28966935	The following antibodies were utilized: TrkA (sc-14024, Santa Cruz Biotechnology, Inc.), TrkB (sc-8316), TrkC (sc-117), NGF (sc-548), BDNF (sc-546), vimentin (sc-51719), GAPDH, MAPK (9107, Cell Signaling, Inc.), phospho-MAPK (9101), STAT3 (9132), phospho-STAT3 (9145), AKT (9272), phospho-AKTser473 (3787), Twist (4119), E-cadherin (4065), N-cadherin (4061), beta-catenin (9562), PCNA (2586), Slug, Snail and LYVE-1.	('AKT', 'Gene', '207', (289, 292))	('STAT3', 'Gene', (255, 260))	('AKT', 'Gene', (269, 272))	('beta-catenin', 'Gene', (359, 371))	('9562', 'Var', (373, 377))	('TrkA', 'Gene', '4914', (40, 44))	('N-cadherin', 'Gene', (340, 350))	('Slug', 'Gene', '6591', (393, 397))	('GAPDH', 'Gene', (170, 175))	('beta-catenin', 'Gene', '1499', (359, 371))	('TrkC', 'Gene', '4916', (105, 109))	('N-cadherin', 'Gene', '1000', (340, 350))	('STAT3', 'Gene', '6774', (255, 260))	('4061', 'Var', (352, 356))	('E-cadherin', 'Gene', (321, 331))	('E-cadherin', 'Gene', '999', (321, 331))	('4065', 'Var', (333, 337))	('LYVE-1', 'Gene', (409, 415))	('AKT', 'Gene', '207', (269, 272))	('Snail', 'Gene', (399, 404))	('TrkA', 'Gene', (40, 44))	('3787', 'Var', (300, 304))	('PCNA', 'Gene', (380, 384))	('AKT', 'Gene', (289, 292))	('LYVE-1', 'Gene', '10894', (409, 415))	('Slug', 'Gene', (393, 397))	('STAT3', 'Gene', (233, 238))	('vimentin', 'Gene', '7431', (149, 157))	('vimentin', 'Gene', (149, 157))	('TrkC', 'Gene', (105, 109))	('GAPDH', 'Gene', '2597', (170, 175))	('STAT3', 'Gene', '6774', (233, 238))	('PCNA', 'Gene', '5111', (380, 384))	('Snail', 'Gene', '6615', (399, 404))
120270	28966935	Small interfering RNA targeting BDNF, GAPDH (Ambion) and AKT (Sigma) were transfected into cells according to the manufacturer's protocol.	('GAPDH', 'Gene', '2597', (38, 43))	('GAPDH', 'Gene', (38, 43))	('BDNF', 'Gene', (32, 36))	('AKT', 'Gene', '207', (57, 60))	('Small interfering', 'Var', (0, 17))	('AKT', 'Gene', (57, 60))
120332	28966935	The wound scratch assay revealed significant impairment of HNSCC migration under conditions of BDNF knockdown in the CAF-CM, suggesting that potentiation of cellular motility is due in part to paracrine communication between tumor and stromal cells through BDNF-TrkB (Figure 4B).	('CAF-CM', 'Gene', '8850', (117, 123))	('impairment of HNSCC migration', 'Disease', (45, 74))	('tumor', 'Disease', 'MESH:D009369', (225, 230))	('knockdown', 'Var', (100, 109))	('impairment of HNSCC migration', 'Disease', 'MESH:D000077195', (45, 74))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('CAF-CM', 'Gene', (117, 123))	('tumor', 'Disease', (225, 230))	('cellular motility', 'CPA', (157, 174))	('BDNF', 'Gene', (95, 99))	('BDNF-TrkB', 'Protein', (257, 266))	('HNSCC', 'Phenotype', 'HP:0012288', (59, 64))	('potentiation', 'PosReg', (141, 153))
120343	28966935	We next tested the hypothesis that modulation of BDNF in the CAF compartment would profoundly impact MMP-9 activity in the tumor compartment.	('tested', 'Reg', (8, 14))	('tumor', 'Disease', (123, 128))	('modulation', 'Var', (35, 45))	('MMP-9', 'Gene', '4318', (101, 106))	('MMP-9', 'Gene', (101, 106))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('BDNF', 'Gene', (49, 53))	('impact', 'Reg', (94, 100))
120349	28966935	Serial measurements of cancer development with in vivo bioluminescence revealed abrogated growth in mice injected with shRNA-TrkB and CAF cells, compared to mice injected with shRNA-NT and CAF cells (Figure 6A).	('mice', 'Species', '10090', (157, 161))	('abrogated', 'NegReg', (80, 89))	('growth', 'CPA', (90, 96))	('mice', 'Species', '10090', (100, 104))	('cancer', 'Disease', (23, 29))	('cancer', 'Disease', 'MESH:D009369', (23, 29))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('shRNA-TrkB', 'Var', (119, 129))
120352	28966935	Moreover, the infiltration of tumoral lymphatics was significantly downmodulated (Figure 6C), suggesting that the absence of a functional BDNF-TrkB axis in the tumor milieu has a negative effect on lymphovascular recruitment and on the progression to lymph node metastasis in this orthotopic model.	('tumoral', 'Disease', (30, 37))	('absence', 'Var', (114, 121))	('tumoral', 'Disease', 'MESH:D009369', (30, 37))	('negative', 'NegReg', (179, 187))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('BDNF-TrkB', 'Gene', (138, 147))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('lymphovascular recruitment', 'CPA', (198, 224))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('tumor', 'Disease', (160, 165))	('tumor', 'Disease', (30, 35))
120371	28966935	Circumstantial evidence for this includes: (1) VEGF-C expression in CAFs is associated with increased nodal metastasis , (2) inhibition of CAF-secreted ECM components is associated with abrogated lymphangiogenesis  and (3) direct molecular targeting of CAFs inhibits lymphangiogenesis though an immunomodulatory mechanism.	('VEGF-C', 'Gene', '7424', (47, 53))	('abrogated', 'NegReg', (186, 195))	('inhibits', 'NegReg', (258, 266))	('lymphangiogenesis', 'CPA', (267, 284))	('increased', 'PosReg', (92, 101))	('VEGF-C', 'Gene', (47, 53))	('lymphangiogenesis', 'CPA', (196, 213))	('inhibition', 'Var', (125, 135))	('nodal metastasis', 'CPA', (102, 118))
120373	28966935	Our data suggest that CAFs play a complex role in tumor progression that can be modulated by manipulation of the BDNF intercellular signaling system, mediated in part through alterations in pro-lymphangiogenic cascade.	('modulated', 'Reg', (80, 89))	('pro-lymphangiogenic cascade', 'Pathway', (190, 217))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('alterations', 'Reg', (175, 186))	('manipulation', 'Var', (93, 105))	('tumor', 'Disease', (50, 55))
120415	25784838	In many studies the relationships between ICAM-1 polymorphisms and increased incidence of carcinomas with different origin, e.g.	('ICAM-1', 'Gene', (42, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('carcinomas', 'Phenotype', 'HP:0030731', (90, 100))	('carcinomas', 'Disease', 'MESH:D002277', (90, 100))	('carcinomas', 'Disease', (90, 100))	('polymorphisms', 'Var', (49, 62))	('ICAM-1', 'Gene', '3383', (42, 48))
120445	25784838	The presence of the higher content of sICAM-1 in supernatants of PBMCs was more frequent for tumours with more disseminated type of invasion determined by TFG scale and characterised by diffuse growth without distinct borderlines.	('tumours', 'Disease', (93, 100))	('ICAM-1', 'Gene', '3383', (39, 45))	('tumour', 'Phenotype', 'HP:0002664', (93, 99))	('TFG', 'Chemical', '-', (155, 158))	('ICAM-1', 'Gene', (39, 45))	('tumours', 'Phenotype', 'HP:0002664', (93, 100))	('presence', 'Var', (4, 12))	('tumours', 'Disease', 'MESH:D009369', (93, 100))
120492	25753424	Mice with ablation of Pten and Smad4 in airway epithelium develop metastatic adenosquamous tumors.	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('develop', 'Reg', (58, 65))	('Smad4', 'Gene', (31, 36))	('adenosquamous tumors', 'Disease', 'MESH:D018196', (77, 97))	('Pten', 'Gene', (22, 26))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('ablation', 'Var', (10, 18))	('Smad4', 'Gene', '43725', (31, 36))	('Mice', 'Species', '10090', (0, 4))	('adenosquamous tumors', 'Disease', (77, 97))
120493	25753424	Comparative transcriptomic and in vivo cistromic analyses determine that loss of PTEN and SMAD4 results in ELF3 and ErbB2 pathway activation due to decreased expression of ERRFI1, a negative regulator of ERBB2 in mouse and human cells.	('mouse', 'Species', '10090', (213, 218))	('loss', 'Var', (73, 77))	('human', 'Species', '9606', (223, 228))	('expression', 'MPA', (158, 168))	('activation', 'PosReg', (130, 140))	('decreased', 'NegReg', (148, 157))	('ERRFI1', 'Gene', '74155', (172, 178))	('ErbB2 pathway', 'Pathway', (116, 129))	('ERRFI1', 'Gene', (172, 178))	('PTEN', 'Gene', (81, 85))	('SMAD4', 'Gene', (90, 95))	('SMAD4', 'Gene', '43725', (90, 95))
120494	25753424	The combinatorial inhibition of ErbB2 and Akt signaling attenuate tumor progression and cell invasion, respectively.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('Akt signaling', 'Pathway', (42, 55))	('tumor', 'Disease', (66, 71))	('attenuate', 'NegReg', (56, 65))	('cell invasion', 'CPA', (88, 101))	('inhibition', 'Var', (18, 28))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('ErbB2', 'Protein', (32, 37))
120496	25753424	now show that ablation of Smad4 and Pten in the pulmonary epithelium results in the development of metastatic adenosquamous lung tumors through activation of the ErbB2/ELF3/AKT pathway.	('Pten', 'Gene', (36, 40))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('AKT', 'Gene', '11651', (173, 176))	('Smad4', 'Gene', '43725', (26, 31))	('AKT', 'Gene', (173, 176))	('lung tumors', 'Disease', 'MESH:D008175', (124, 135))	('lung tumor', 'Phenotype', 'HP:0100526', (124, 134))	('lung tumors', 'Phenotype', 'HP:0100526', (124, 135))	('activation', 'PosReg', (144, 154))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('Smad4', 'Gene', (26, 31))	('ablation', 'Var', (14, 22))	('lung tumors', 'Disease', (124, 135))
120503	25753424	Lung cancer initiation and progression is driven by the stepwise accumulation of genetic alterations, including inactivation of tumor suppressor genes, such as PTEN, p53, and SMAD4, and mutation and/or amplification of oncogenic genes, such as Kras, EGFR, and ERBB2 that control cell proliferation.	('Lung cancer initiation', 'Disease', (0, 22))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('EGFR', 'Gene', (250, 254))	('mutation', 'Var', (186, 194))	('EGFR', 'Gene', '13649', (250, 254))	('Lung cancer', 'Phenotype', 'HP:0100526', (0, 11))	('SMAD4', 'Gene', '43725', (175, 180))	('inactivation', 'NegReg', (112, 124))	('amplification', 'Var', (202, 215))	('ERBB2', 'Gene', (260, 265))	('p53', 'Gene', (166, 169))	('PTEN', 'Gene', (160, 164))	('Kras', 'Gene', (244, 248))	('tumor', 'Disease', (128, 133))	('p53', 'Gene', '22060', (166, 169))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('Lung cancer initiation', 'Disease', 'MESH:D008175', (0, 22))	('SMAD4', 'Gene', (175, 180))	('Kras', 'Gene', '16653', (244, 248))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))
120505	25753424	However, deletion of Pten in airway epithelial cells and its biological function in animal models of lung cancer has produced inconsistent results.	('lung cancer', 'Disease', 'MESH:D008175', (101, 112))	('deletion', 'Var', (9, 17))	('Pten', 'Gene', (21, 25))	('lung cancer', 'Phenotype', 'HP:0100526', (101, 112))	('lung cancer', 'Disease', (101, 112))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
120506	25753424	While deletion of Pten in the airway epithelial cells using the Cre recombinase under the Club Cell Secretory Protein promoter (CCSPCre) resulted in no discernible effect on bronchial epithelial cell morphology in mice, deletion of Pten in the distal airways and alveolar cells resulted in hyperplasia and lung AD in mice.	('bronchial epithelial cell morphology', 'CPA', (174, 210))	('lung AD', 'CPA', (306, 313))	('Pten', 'Gene', (232, 236))	('hyperplasia', 'Disease', (290, 301))	('mice', 'Species', '10090', (317, 321))	('CCSP', 'Gene', '22287', (128, 132))	('CCSP', 'Gene', (128, 132))	('deletion', 'Var', (220, 228))	('deletion', 'Var', (6, 14))	('Club', 'Phenotype', 'HP:0001217', (90, 94))	('Pten', 'Gene', (18, 22))	('mice', 'Species', '10090', (214, 218))	('hyperplasia', 'Disease', 'MESH:D006965', (290, 301))
120507	25753424	Recently, Pten deletion alone in airway basal cells was shown to initiate lung tumor formation, but with low incidence and long latency, and inactivation of Lkb1 and Pten using an Ad-Cre inhalation system resulted in development of lung cancer that closely resemble human lung SCC.	('Pten', 'Gene', (166, 170))	('Lkb1', 'Gene', '6794', (157, 161))	('SCC', 'Phenotype', 'HP:0002860', (277, 280))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('deletion', 'Var', (15, 23))	('lung tumor', 'Disease', (74, 84))	('lung cancer', 'Disease', 'MESH:D008175', (232, 243))	('inactivation', 'Var', (141, 153))	('Lkb1', 'Gene', (157, 161))	('Pten', 'Gene', (10, 14))	('lung tumor', 'Disease', 'MESH:D008175', (74, 84))	('lung cancer', 'Phenotype', 'HP:0100526', (232, 243))	('resulted in development', 'Reg', (205, 228))	('lung cancer', 'Disease', (232, 243))	('lung tumor', 'Phenotype', 'HP:0100526', (74, 84))	('human', 'Species', '9606', (266, 271))
120511	25753424	Concurrent ablation of Smad4 and Pten in the airways of mice resulted in the spontaneous development of proximal airway tumors with metastasis to distal organs.	('tumors', 'Disease', (120, 126))	('Smad4', 'Gene', '43725', (23, 28))	('tumors', 'Disease', 'MESH:D009369', (120, 126))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('metastasis', 'CPA', (132, 142))	('Pten', 'Gene', (33, 37))	('Smad4', 'Gene', (23, 28))	('mice', 'Species', '10090', (56, 60))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('ablation', 'Var', (11, 19))
120512	25753424	Transcriptomic and in vivo cistromic analyses of lung tumors demonstrated that ablation of Smad4 resulted in the activation of the ErbB2 signaling pathway.	('lung tumors', 'Phenotype', 'HP:0100526', (49, 60))	('ErbB2 signaling pathway', 'Pathway', (131, 154))	('Smad4', 'Gene', '43725', (91, 96))	('lung tumors', 'Disease', 'MESH:D008175', (49, 60))	('lung tumor', 'Phenotype', 'HP:0100526', (49, 59))	('activation', 'PosReg', (113, 123))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('Smad4', 'Gene', (91, 96))	('ablation', 'Var', (79, 87))	('lung tumors', 'Disease', (49, 60))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))
120517	25753424	Our previous study showed that CCSPCre-mediated lung-specific deletion of Pten in bronchial epithelial cells had no discernible phenotype unless combined with Kras activation.	('Kras', 'Gene', (159, 163))	('Pten', 'Gene', (74, 78))	('CCSP', 'Gene', (31, 35))	('CCSP', 'Gene', '22287', (31, 35))	('deletion', 'Var', (62, 70))	('Kras', 'Gene', '16653', (159, 163))
120518	25753424	The lack of histological change in the airway epithelial cell in mice with deletion of Pten may have been in part due to the low efficiency of Cre-induced recombination.	('deletion', 'Var', (75, 83))	('mice', 'Species', '10090', (65, 69))	('Pten', 'Gene', (87, 91))
120523	25753424	Mice with the floxed Pten allele (Ptenf/f) were crossed with CCSPicre mice to achieve airway-specific deletion of Pten (Ptend/d).	('CCSP', 'Gene', '22287', (61, 65))	('Pten', 'Gene', (114, 118))	('CCSP', 'Gene', (61, 65))	('Ptend/d', 'Gene', '19211', (120, 127))	('deletion', 'Var', (102, 110))	('mice', 'Species', '10090', (70, 74))	('Mice', 'Species', '10090', (0, 4))	('Ptend/d', 'Gene', (120, 127))
120527	25753424	To identify which genes are significantly altered in the absence of Pten, microarray analysis comparing lung RNAs isolated from control and Ptend/d mice was performed and identified 1,847 unique genes that were significantly altered when Pten was ablated (Figure 1D).	('Ptend/d', 'Gene', (140, 147))	('ablated', 'Var', (247, 254))	('Pten', 'Gene', (238, 242))	('Ptend/d', 'Gene', '19211', (140, 147))	('mice', 'Species', '10090', (148, 152))	('altered', 'Reg', (225, 232))
120534	25753424	In line with reported downregulated expression of SMAD4 in a subset of human primary lung tumors, TCGA expression analysis from a clinical database revealed the reverse correlation of SMAD4 copy number with tumor grades and patients' 5-year survival rate (Figure S1E).	('SMAD4', 'Gene', (184, 189))	('human', 'Species', '9606', (71, 76))	('SMAD4', 'Gene', '43725', (50, 55))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('lung tumors', 'Disease', (85, 96))	('SMAD4', 'Gene', (50, 55))	('tumor', 'Disease', (90, 95))	('lung tumors', 'Phenotype', 'HP:0100526', (85, 96))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('patients', 'Species', '9606', (224, 232))	('tumor', 'Disease', (207, 212))	('lung tumors', 'Disease', 'MESH:D008175', (85, 96))	('lung tumor', 'Phenotype', 'HP:0100526', (85, 95))	('SMAD4', 'Gene', '43725', (184, 189))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('copy number', 'Var', (190, 201))
120538	25753424	To determine if increased expression of SMAD4 plays an inhibitory role in lung tumor development in Ptend/d mice, we crossed Smad4f/f mice with CCSPicrePtenf/f mice to generate mice with a double deletion of Pten and Smad4 in the airway epithelium (Ptend/dSmad4d/d).	('mice', 'Species', '10090', (134, 138))	('Smad4', 'Gene', (125, 130))	('Ptend/d', 'Gene', '19211', (249, 256))	('SMAD4', 'Gene', (40, 45))	('lung tumor', 'Disease', (74, 84))	('Smad4', 'Gene', '43725', (217, 222))	('mice', 'Species', '10090', (108, 112))	('Ptend/d', 'Gene', (249, 256))	('lung tumor', 'Phenotype', 'HP:0100526', (74, 84))	('CCSP', 'Gene', (144, 148))	('CCSP', 'Gene', '22287', (144, 148))	('Smad4', 'Gene', '43725', (256, 261))	('Smad4', 'Gene', (217, 222))	('Pten', 'Gene', (208, 212))	('SMAD4', 'Gene', '43725', (40, 45))	('dSmad4', 'Gene', '43725', (255, 261))	('dSmad4', 'Gene', (255, 261))	('lung tumor', 'Disease', 'MESH:D008175', (74, 84))	('mice', 'Species', '10090', (160, 164))	('Ptend/d', 'Gene', '19211', (100, 107))	('Smad4', 'Gene', (256, 261))	('Smad4', 'Gene', '43725', (125, 130))	('mice', 'Species', '10090', (177, 181))	('Ptend/d', 'Gene', (100, 107))	('double deletion', 'Var', (189, 204))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
120539	25753424	Smad4d/d, although showing high deletion efficiency (Figure S2A), failed to show any discernable changes in the epithelium.	('Smad4', 'Gene', (0, 5))	('deletion', 'Var', (32, 40))	('Smad4', 'Gene', '43725', (0, 5))
120549	25753424	Double immunofluorescence in the lungs of CCSPiCre mice crossed to the R26R Lacz reporter mice showed that there was overlapping staining of p63 and Lacz in a subpopulation of basal cells in the tracheal and bronchial epithelium (Figure S2E), indicating that Cre activity was not limited to Club cells of the lungs.	('Club', 'Phenotype', 'HP:0001217', (291, 295))	('R26R', 'Mutation', 'rs1183677374', (71, 75))	('mice', 'Species', '10090', (51, 55))	('CCSP', 'Gene', '22287', (42, 46))	('CCSP', 'Gene', (42, 46))	('Lacz', 'Gene', (149, 153))	('mice', 'Species', '10090', (90, 94))	('p63', 'Var', (141, 144))
120550	25753424	Double staining of lungs with p63 and PTEN or SMAD4 in the tumors of the Ptend/dSmad4d/d mice determined if the increase in p63 positive cells had loss of PTEN and SMAD4 or if the increase in p63 was due to paracrine regulation of p63 cells that were then interspersed throughout the tumor mass.	('tumor', 'Disease', (59, 64))	('tumor', 'Disease', 'MESH:D009369', (284, 289))	('tumors', 'Disease', 'MESH:D009369', (59, 65))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('loss', 'NegReg', (147, 151))	('SMAD4', 'Gene', (164, 169))	('tumor', 'Phenotype', 'HP:0002664', (284, 289))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('SMAD4', 'Gene', '43725', (46, 51))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('SMAD4', 'Gene', (46, 51))	('p63', 'Var', (124, 127))	('mice', 'Species', '10090', (89, 93))	('tumors', 'Disease', (59, 65))	('dSmad4', 'Gene', '43725', (79, 85))	('increase', 'PosReg', (112, 120))	('dSmad4', 'Gene', (79, 85))	('SMAD4', 'Gene', '43725', (164, 169))	('tumor', 'Disease', (284, 289))	('PTEN', 'Protein', (155, 159))
120559	25753424	Consistent with a previous finding that Pten deletion induces senescence in a prostate tumor mouse model, Ptend/d mice had high levels of senescence in lung epithelium (Figure S2H).	('prostate tumor', 'Disease', 'MESH:D011471', (78, 92))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('Pten', 'Gene', (40, 44))	('mouse', 'Species', '10090', (93, 98))	('senescence', 'MPA', (62, 72))	('prostate tumor', 'Disease', (78, 92))	('Ptend/d', 'Gene', '19211', (106, 113))	('prostate tumor', 'Phenotype', 'HP:0100787', (78, 92))	('senescence', 'MPA', (138, 148))	('mice', 'Species', '10090', (114, 118))	('induces', 'Reg', (54, 61))	('deletion', 'Var', (45, 53))	('Ptend/d', 'Gene', (106, 113))
120560	25753424	Importantly, the senescence induced by Pten deletion was abolished upon Smad4 deletion in Ptend/dSmad4d/d mice (Figure S2H).	('mice', 'Species', '10090', (106, 110))	('Smad4', 'Gene', (72, 77))	('Smad4', 'Gene', '43725', (97, 102))	('Pten', 'Gene', (39, 43))	('deletion', 'Var', (44, 52))	('deletion', 'Var', (78, 86))	('Smad4', 'Gene', (97, 102))	('senescence', 'MPA', (17, 27))	('dSmad4', 'Gene', (96, 102))	('dSmad4', 'Gene', '43725', (96, 102))	('Smad4', 'Gene', '43725', (72, 77))	('abolished', 'NegReg', (57, 66))
120576	25753424	Intriguingly, p-AKT was further increased upon deletion of Smad4 (Ptend/dSmad4d/d versus Ptend/d) (Figures 4B and 4C), suggesting SMAD4 may prevent the full activation of AKT upon the deletion of Pten.	('Ptend/d', 'Gene', (66, 73))	('deletion', 'Var', (184, 192))	('Ptend/d', 'Gene', '19211', (89, 96))	('SMAD4', 'Gene', '43725', (130, 135))	('Ptend/d', 'Gene', (89, 96))	('Smad4', 'Gene', (59, 64))	('AKT', 'Gene', '11651', (16, 19))	('deletion', 'Var', (47, 55))	('AKT', 'Gene', (171, 174))	('Smad4', 'Gene', '43725', (73, 78))	('SMAD4', 'Gene', (130, 135))	('dSmad4', 'Gene', (72, 78))	('dSmad4', 'Gene', '43725', (72, 78))	('Smad4', 'Gene', (73, 78))	('Smad4', 'Gene', '43725', (59, 64))	('Pten', 'Gene', (196, 200))	('AKT', 'Gene', (16, 19))	('AKT', 'Gene', '11651', (171, 174))	('Ptend/d', 'Gene', '19211', (66, 73))	('increased', 'PosReg', (32, 41))
120578	25753424	Similar to ERBB2, other members of the ERBB family, including EGFR, ERBB3, and ERBB4, also had increased phosphorylation (albeit at variable levels) upon the deletion of Pten and Smad4, especially in the lung tumors (Figure S4E).	('phosphorylation', 'MPA', (105, 120))	('ERBB3', 'Gene', (68, 73))	('ERBB', 'Gene', (68, 72))	('ERBB4', 'Gene', (79, 84))	('Smad4', 'Gene', (179, 184))	('ERBB', 'Gene', '13649;2064;13866;13867;13869', (68, 72))	('Pten', 'Gene', (170, 174))	('lung tumors', 'Disease', 'MESH:D008175', (204, 215))	('deletion', 'Var', (158, 166))	('ERBB', 'Gene', (11, 15))	('tumors', 'Phenotype', 'HP:0002664', (209, 215))	('lung tumors', 'Phenotype', 'HP:0100526', (204, 215))	('ERBB', 'Gene', '13649;2064;13866;13867;13869', (11, 15))	('lung tumor', 'Phenotype', 'HP:0100526', (204, 214))	('ERBB', 'Gene', (79, 83))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))	('lung tumors', 'Disease', (204, 215))	('ERBB', 'Gene', (39, 43))	('ERBB', 'Gene', '13649;2064;13866;13867;13869', (79, 83))	('EGFR', 'Gene', '13649', (62, 66))	('Smad4', 'Gene', '43725', (179, 184))	('EGFR', 'Gene', (62, 66))	('ERBB4', 'Gene', '13869', (79, 84))	('ERBB', 'Gene', '13649;2064;13866;13867;13869', (39, 43))	('increased', 'PosReg', (95, 104))	('ERBB3', 'Gene', '13867', (68, 73))
120594	25753424	To investigate the role of Errfi1 in lung tumorigenesis, using the CCSPiCre, Errfi1 was conditionally ablated alone, Errfi1d/d, or in combination with Pten.	('ablated', 'Var', (102, 109))	('lung tumor', 'Disease', (37, 47))	('Errfi1', 'Gene', (77, 83))	('lung tumor', 'Disease', 'MESH:D008175', (37, 47))	('Errfi1', 'Gene', '74155', (77, 83))	('lung tumor', 'Phenotype', 'HP:0100526', (37, 47))	('Errfi1', 'Gene', (27, 33))	('Errfi1', 'Gene', '74155', (27, 33))	('Errfi1', 'Gene', (117, 123))	('Errfi1', 'Gene', '74155', (117, 123))	('CCSP', 'Gene', '22287', (67, 71))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('CCSP', 'Gene', (67, 71))
120595	25753424	Deletion of Errfi1 led to a great increase of ERBB2 phosphorylation in mouse lung upper airways (Figures 6C and 6D).	('Errfi1', 'Gene', (12, 18))	('Errfi1', 'Gene', '74155', (12, 18))	('mouse', 'Species', '10090', (71, 76))	('ERBB2', 'Protein', (46, 51))	('increase', 'PosReg', (34, 42))	('phosphorylation', 'MPA', (52, 67))	('Deletion', 'Var', (0, 8))
120599	25753424	Taken together, these results suggest that Errfi1 acts as a suppressor of ErbB2 signaling and prevents lung tumor growth in the Pten-null background; downregulation of Errfi1 upon the deletion of Smad4 in Ptend/dSmad4d/d mice led to increased ErbB2 signaling and lung tumorigenesis.	('lung tumor', 'Disease', (263, 273))	('deletion', 'Var', (184, 192))	('Errfi1', 'Gene', '74155', (43, 49))	('downregulation', 'NegReg', (150, 164))	('lung tumor', 'Disease', (103, 113))	('lung tumor', 'Phenotype', 'HP:0100526', (263, 273))	('dSmad4', 'Gene', (211, 217))	('dSmad4', 'Gene', '43725', (211, 217))	('Smad4', 'Gene', (196, 201))	('tumor', 'Phenotype', 'HP:0002664', (268, 273))	('lung tumor', 'Phenotype', 'HP:0100526', (103, 113))	('Errfi1', 'Gene', '74155', (168, 174))	('increased', 'PosReg', (233, 242))	('lung tumor', 'Disease', 'MESH:D008175', (263, 273))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('Errfi1', 'Gene', (43, 49))	('ErbB2 signaling', 'MPA', (243, 258))	('Smad4', 'Gene', '43725', (212, 217))	('lung tumor', 'Disease', 'MESH:D008175', (103, 113))	('Smad4', 'Gene', '43725', (196, 201))	('mice', 'Species', '10090', (221, 225))	('Errfi1', 'Gene', (168, 174))	('Smad4', 'Gene', (212, 217))
120605	25753424	Consistent with this in vivo finding, knockdown of PTEN and SMAD4 increased ELF3 mRNA expression in BEAS-2B cells (Figure 7E).	('increased', 'PosReg', (66, 75))	('SMAD4', 'Gene', (60, 65))	('SMAD4', 'Gene', '43725', (60, 65))	('ELF3', 'Gene', (76, 80))	('BEAS-2B', 'CellLine', 'CVCL:0168', (100, 107))	('knockdown', 'Var', (38, 47))	('PTEN', 'Gene', (51, 55))
120606	25753424	In addition, ELF3 was downregulated by TGF-beta1, an upstream stimulus of SMAD4, and depletion of SMAD4 abolished this inhibitory effect (Figure 7F).	('SMAD4', 'Gene', '43725', (74, 79))	('SMAD4', 'Gene', (74, 79))	('SMAD4', 'Gene', (98, 103))	('SMAD4', 'Gene', '43725', (98, 103))	('depletion', 'Var', (85, 94))	('TGF-beta1', 'Gene', '21803', (39, 48))	('ELF3', 'Gene', (13, 17))	('TGF-beta1', 'Gene', (39, 48))	('downregulated', 'NegReg', (22, 35))
120608	25753424	Knockdown of ELF3 significantly decreased both proliferation and invasion of BEAS-2B cells, most prominently in the context of both PTEN and SMAD4 double deletion (Figures 7G-7I).	('double deletion', 'Var', (147, 162))	('ELF3', 'Gene', (13, 17))	('invasion', 'CPA', (65, 73))	('proliferation', 'CPA', (47, 60))	('SMAD4', 'Gene', '43725', (141, 146))	('decreased', 'NegReg', (32, 41))	('SMAD4', 'Gene', (141, 146))	('BEAS-2B', 'CellLine', 'CVCL:0168', (77, 84))
120610	25753424	These results highlight the clinical relevance of the Ptend/d Smad4d/d lung tumor model: Pten deletion in airway epithelial cells induces airway epithelia cell hyperplasia probably secondary to the compensatory activation of SMAD4.	('Smad4', 'Gene', (62, 67))	('SMAD4', 'Gene', '43725', (225, 230))	('deletion', 'Var', (94, 102))	('Ptend/d', 'Gene', '19211', (54, 61))	('hyperplasia', 'Disease', (160, 171))	('lung tumor', 'Disease', 'MESH:D008175', (71, 81))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('lung tumor', 'Disease', (71, 81))	('epithelia cell hyperplasia', 'Phenotype', 'HP:0410340', (145, 171))	('Ptend/d', 'Gene', (54, 61))	('Pten', 'Gene', (89, 93))	('Smad4', 'Gene', '43725', (62, 67))	('lung tumor', 'Phenotype', 'HP:0100526', (71, 81))	('hyperplasia', 'Disease', 'MESH:D006965', (160, 171))	('airway epithelia', 'Disease', (138, 154))	('induces', 'Reg', (130, 137))	('SMAD4', 'Gene', (225, 230))
120611	25753424	Further depletion of Smad4 in Ptend/d mice results in activation of ErbB2, probably through the downregulation of ERRFI1, and further activates Akt signaling pathway and induces expression of ERBB2 target genes including Elf3, which promoted lung tumor growth and progression.	('tumor', 'Phenotype', 'HP:0002664', (247, 252))	('mice', 'Species', '10090', (38, 42))	('expression', 'MPA', (178, 188))	('activates', 'PosReg', (134, 143))	('progression', 'CPA', (264, 275))	('ERRFI1', 'Gene', '74155', (114, 120))	('Smad4', 'Gene', (21, 26))	('lung tumor', 'Disease', 'MESH:D008175', (242, 252))	('ErbB2', 'Gene', (68, 73))	('Elf3', 'Gene', (221, 225))	('Ptend/d', 'Gene', '19211', (30, 37))	('Akt signaling pathway', 'Pathway', (144, 165))	('Ptend/d', 'Gene', (30, 37))	('ERRFI1', 'Gene', (114, 120))	('depletion', 'Var', (8, 17))	('lung tumor', 'Disease', (242, 252))	('activation', 'PosReg', (54, 64))	('Smad4', 'Gene', '43725', (21, 26))	('lung tumor', 'Phenotype', 'HP:0100526', (242, 252))	('induces', 'PosReg', (170, 177))	('promoted', 'PosReg', (233, 241))	('downregulation', 'NegReg', (96, 110))
120614	25753424	However, initial investigations using the CCSPCre model to delete the Pten gene in mouse airway epithelial cells showed no discernible phenotype.	('delete', 'Var', (59, 65))	('CCSP', 'Gene', '22287', (42, 46))	('mouse', 'Species', '10090', (83, 88))	('CCSP', 'Gene', (42, 46))	('Pten', 'Gene', (70, 74))
120615	25753424	Here, we found that Pten ablation using the improved CCSPicre showed consistent airway epithelial hyperplasia without any progression to cancer (up to 15 months); these findings are in contrast to the reports that AD develop in the lungs of mice with SP-Ccre-mediated deletion of Pten.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('SP', 'Chemical', 'MESH:C000604007', (251, 253))	('Pten', 'Gene', (280, 284))	('SP', 'Chemical', 'MESH:C000604007', (55, 57))	('mice', 'Species', '10090', (241, 245))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('epithelial hyperplasia', 'Disease', 'MESH:D017573', (87, 109))	('cancer', 'Disease', (137, 143))	('deletion', 'Var', (268, 276))	('CCSP', 'Gene', '22287', (53, 57))	('epithelial hyperplasia', 'Disease', (87, 109))	('CCSP', 'Gene', (53, 57))
120619	25753424	In support of our findings, a protective role for SMAD4 has been described in other epithelial derived tumors, such as prostate cancer; our findings demonstrate for the first time that concurrent loss of Pten and Smad4 induces tumor growth and metastasis in lung cancer and shows how similar cancer driver genes behave in epithelial tumors.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('lung cancer', 'Disease', 'MESH:D008175', (258, 269))	('Pten', 'Gene', (204, 208))	('tumor', 'Disease', (227, 232))	('cancer', 'Disease', (263, 269))	('tumors', 'Disease', (103, 109))	('lung cancer', 'Phenotype', 'HP:0100526', (258, 269))	('cancer', 'Phenotype', 'HP:0002664', (263, 269))	('tumor', 'Disease', 'MESH:D009369', (227, 232))	('tumor', 'Phenotype', 'HP:0002664', (333, 338))	('cancer', 'Disease', (128, 134))	('loss', 'Var', (196, 200))	('tumors', 'Disease', (333, 339))	('epithelial tumors', 'Disease', (322, 339))	('SMAD4', 'Gene', '43725', (50, 55))	('epithelial tumors', 'Disease', 'MESH:D002277', (322, 339))	('tumors', 'Disease', 'MESH:D009369', (103, 109))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('cancer', 'Disease', (292, 298))	('prostate cancer', 'Disease', 'MESH:D011471', (119, 134))	('induces', 'PosReg', (219, 226))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))	('prostate cancer', 'Phenotype', 'HP:0012125', (119, 134))	('metastasis', 'CPA', (244, 254))	('cancer', 'Disease', 'MESH:D009369', (263, 269))	('cancer', 'Phenotype', 'HP:0002664', (292, 298))	('tumors', 'Disease', 'MESH:D009369', (333, 339))	('tumor', 'Disease', (103, 108))	('Smad4', 'Gene', '43725', (213, 218))	('prostate cancer', 'Disease', (119, 134))	('lung cancer', 'Disease', (258, 269))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('tumor', 'Disease', (333, 338))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('SMAD4', 'Gene', (50, 55))	('cancer', 'Disease', 'MESH:D009369', (292, 298))	('tumor', 'Disease', 'MESH:D009369', (333, 338))	('Smad4', 'Gene', (213, 218))	('tumors', 'Phenotype', 'HP:0002664', (333, 339))
120624	25753424	The hyperactivation of ErbB2 signaling is in parallel with remarkable reduction of Errfi1, a known inhibitor of ERBB2 activity, suggesting a molecular mechanism for the activation of ErbB2 signaling upon the loss of both Pten and Smad4.	('Smad4', 'Gene', (230, 235))	('reduction', 'NegReg', (70, 79))	('activation', 'PosReg', (169, 179))	('ErbB2', 'MPA', (183, 188))	('Smad4', 'Gene', '43725', (230, 235))	('loss', 'Var', (208, 212))	('Errfi1', 'Gene', '74155', (83, 89))	('Errfi1', 'Gene', (83, 89))	('Pten', 'Gene', (221, 225))
120630	25753424	To our knowledge, our study is the first to demonstrate that Elf3 is highly upregulated upon deletion of Smad4 and plays an important role in lung cell proliferation and invasion.	('lung cell proliferation', 'CPA', (142, 165))	('Smad4', 'Gene', '43725', (105, 110))	('plays', 'Reg', (115, 120))	('Elf3', 'Gene', (61, 65))	('upregulated', 'PosReg', (76, 87))	('Smad4', 'Gene', (105, 110))	('deletion', 'Var', (93, 101))	('invasion', 'CPA', (170, 178))
120633	25753424	In addition, we show that ELF3 is overexpressed in human lung cancer (Figures S7E and S7F) and its upregulation in human lung cancer cells with PI3KCA and SMAD4 mutations (Figures S7I and S7J).	('S7F', 'Mutation', 'p.S7F', (86, 89))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('lung cancer', 'Disease', 'MESH:D008175', (121, 132))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('lung cancer', 'Phenotype', 'HP:0100526', (57, 68))	('upregulation', 'PosReg', (99, 111))	('lung cancer', 'Disease', 'MESH:D008175', (57, 68))	('lung cancer', 'Disease', (121, 132))	('human', 'Species', '9606', (51, 56))	('human', 'Species', '9606', (115, 120))	('lung cancer', 'Phenotype', 'HP:0100526', (121, 132))	('mutations', 'Var', (161, 170))	('SMAD4', 'Gene', '43725', (155, 160))	('ELF3', 'Gene', (26, 30))	('lung cancer', 'Disease', (57, 68))	('SMAD4', 'Gene', (155, 160))	('overexpressed', 'PosReg', (34, 47))
120640	25753424	In summary, we successfully generated a metastatic lung tumor model with airway-specific deletion of Pten and Smad4 and showed that their sequential alterations induce oncogenic pathways including ErbB2/Akt/ELF3 and represses tumor suppressors, such as Errfi1, that are critical for lung tumor initiation and progression.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('lung tumor', 'Disease', 'MESH:D008175', (283, 293))	('ErbB2/Akt/ELF3', 'Pathway', (197, 211))	('lung tumor', 'Phenotype', 'HP:0100526', (51, 61))	('Smad4', 'Gene', (110, 115))	('lung tumor initiation', 'Disease', (283, 304))	('tumor', 'Disease', 'MESH:D009369', (226, 231))	('deletion', 'Var', (89, 97))	('induce', 'Reg', (161, 167))	('Errfi1', 'Gene', (253, 259))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('lung tumor initiation', 'Disease', 'MESH:D008175', (283, 304))	('lung tumor', 'Disease', 'MESH:D008175', (51, 61))	('tumor', 'Disease', (288, 293))	('tumor', 'Disease', (56, 61))	('oncogenic pathways', 'Pathway', (168, 186))	('tumor', 'Disease', 'MESH:D009369', (288, 293))	('lung tumor', 'Phenotype', 'HP:0100526', (283, 293))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('Smad4', 'Gene', '43725', (110, 115))	('alterations', 'Var', (149, 160))	('Errfi1', 'Gene', '74155', (253, 259))	('tumor', 'Phenotype', 'HP:0002664', (288, 293))	('Pten', 'Gene', (101, 105))	('tumor', 'Disease', (226, 231))	('lung tumor', 'Disease', (51, 61))
120660	25753424	Airway-specific Pten loss causes epithelial hyperplasia and alters TGF-beta signaling Loss of Smad4 in Ptend/d mice results in metastatic adenosquamous carcinomas Ablation of Smad4 and Pten causes repression of ERRFI1 and activation of ERBB2/ELF3 Loss of Errfi1 in Ptend/d mice promotes lung tumors	('ERRFI1', 'Gene', '74155', (211, 217))	('carcinoma', 'Phenotype', 'HP:0030731', (152, 161))	('Ptend/d', 'Gene', (265, 272))	('epithelial hyperplasia', 'Disease', (33, 55))	('repression', 'NegReg', (197, 207))	('TGF-beta', 'Gene', '21802', (67, 75))	('tumors', 'Phenotype', 'HP:0002664', (292, 298))	('lung tumors', 'Phenotype', 'HP:0100526', (287, 298))	('Smad4', 'Gene', (94, 99))	('lung tumor', 'Phenotype', 'HP:0100526', (287, 297))	('epithelial hyperplasia', 'Disease', 'MESH:D017573', (33, 55))	('lung tumors', 'Disease', (287, 298))	('tumor', 'Phenotype', 'HP:0002664', (292, 297))	('adenosquamous carcinomas', 'Disease', (138, 162))	('Smad4', 'Gene', '43725', (175, 180))	('carcinomas', 'Phenotype', 'HP:0030731', (152, 162))	('Loss', 'Var', (247, 251))	('TGF-beta', 'Gene', (67, 75))	('Ptend/d', 'Gene', '19211', (103, 110))	('Errfi1', 'Gene', '74155', (255, 261))	('mice', 'Species', '10090', (273, 277))	('ERRFI1', 'Gene', (211, 217))	('Ptend/d', 'Gene', (103, 110))	('adenosquamous carcinomas', 'Disease', 'MESH:D018196', (138, 162))	('Smad4', 'Gene', (175, 180))	('Smad4', 'Gene', '43725', (94, 99))	('Loss', 'NegReg', (86, 90))	('metastatic', 'CPA', (127, 137))	('Pten', 'Gene', (16, 20))	('mice', 'Species', '10090', (111, 115))	('ERBB2/ELF3', 'Gene', (236, 246))	('lung tumors', 'Disease', 'MESH:D008175', (287, 298))	('Ptend/d', 'Gene', '19211', (265, 272))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (143, 161))	('Errfi1', 'Gene', (255, 261))	('Ablation', 'NegReg', (163, 171))	('promotes', 'PosReg', (278, 286))	('loss', 'NegReg', (21, 25))
120661	32220892	Wee1 Kinase Inhibitor AZD1775 Effectively Sensitizes Esophageal Cancer to Radiotherapy Esophageal cancer (ESCA) is a deadly malignancy with a 5-year survival rate of only 5-20%, which has remained unchanged for decades.	('Wee1', 'Gene', (0, 4))	('AZD1775', 'Var', (22, 29))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('Cancer', 'Disease', (64, 70))	('Wee1', 'Gene', '7465', (0, 4))	('Cancer', 'Disease', 'MESH:D009369', (64, 70))	('Cancer', 'Phenotype', 'HP:0002664', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('deadly malignancy', 'Disease', 'MESH:D009369', (117, 134))	('cancer', 'Disease', (98, 104))	('Sensitizes', 'Reg', (42, 52))	('deadly malignancy', 'Disease', (117, 134))	('AZD1775', 'Chemical', 'MESH:C549567', (22, 29))
120662	32220892	ESCA possesses a high frequency of TP53 mutations leading to dysfunctional G1 cell cycle checkpoint, which likely makes ESCA cells highly reliant upon G2/M checkpoint for adaptation to DNA replication stress and DNA damage after radiation.	('TP53', 'Gene', '7157', (35, 39))	('leading to', 'Reg', (50, 60))	('TP53', 'Gene', (35, 39))	('dysfunctional', 'MPA', (61, 74))	('mutations', 'Var', (40, 49))
120666	32220892	AZD1775 (100 nM) as monotherapy did not alter the viability of ESCA cells, but significantly radiosensitized ESCA cells.	('radiosensitized', 'NegReg', (93, 108))	('AZD1775', 'Chemical', 'MESH:C549567', (0, 7))	('AZD1775', 'Var', (0, 7))	('ESCA', 'Disease', (109, 113))
120667	32220892	AZD1775 significantly abrogated radiation-induced G2/M phase arrest and attenuation of p-CDK1-Y15.	('arrest', 'Disease', (61, 67))	('AZD1775', 'Var', (0, 7))	('AZD1775', 'Chemical', 'MESH:C549567', (0, 7))	('CDK1', 'Gene', (89, 93))	('arrest', 'Disease', 'MESH:D006323', (61, 67))	('CDK1', 'Gene', '983', (89, 93))	('abrogated', 'NegReg', (22, 31))	('attenuation', 'NegReg', (72, 83))
120668	32220892	Moreover, AZD1775 increased radiation-induced mitotic catastrophe, which was accompanied by increased gammaH2AX levels, and subsequently reduced survival after radiation.	('radiation-induced mitotic catastrophe', 'CPA', (28, 65))	('increased', 'PosReg', (18, 27))	('H2AX', 'Gene', '3014', (107, 111))	('H2AX', 'Gene', (107, 111))	('AZD1775', 'Var', (10, 17))	('AZD1775', 'Chemical', 'MESH:C549567', (10, 17))	('increased', 'PosReg', (92, 101))	('survival', 'CPA', (145, 153))	('reduced', 'NegReg', (137, 144))
120669	32220892	Importantly, AZD1775 in combination with radiotherapy resulted in marked tumor regression of ESCA tumor xenografts.	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('AZD1775', 'Chemical', 'MESH:C549567', (13, 20))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumor', 'Disease', (73, 78))	('tumor', 'Disease', (98, 103))	('AZD1775', 'Var', (13, 20))
120671	32220892	Our findings suggest that inhibition of Wee1 by AZD1775 is an effective strategy for radiosensitization in esophageal cancer and warrants clinical testing.	('Wee1', 'Protein', (40, 44))	('esophageal cancer', 'Disease', (107, 124))	('AZD1775', 'Var', (48, 55))	('inhibition', 'NegReg', (26, 36))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('esophageal cancer', 'Disease', 'MESH:D004938', (107, 124))	('AZD1775', 'Chemical', 'MESH:C549567', (48, 55))
120679	32220892	Aberrant activation of CDKs and hence uncontrolled cell cycle progression is a hallmark of cancer cells.	('CDKs', 'Gene', (23, 27))	('activation', 'PosReg', (9, 19))	('Aberrant', 'Var', (0, 8))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('CDKs', 'Gene', '983;1017', (23, 27))
120680	32220892	Many human cancers have deficits in G1/S checkpoint due to mutations in the p53 signaling axis including mutations of TP53, CDKN2A, and RB.	('deficits', 'NegReg', (24, 32))	('CDKN2A', 'Gene', (124, 130))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('p53', 'Gene', (76, 79))	('p53', 'Gene', '7157', (76, 79))	('G1/S checkpoint', 'MPA', (36, 51))	('CDKN2A', 'Gene', '1029', (124, 130))	('TP53', 'Gene', '7157', (118, 122))	('TP53', 'Gene', (118, 122))	('mutations', 'Var', (105, 114))	('cancers', 'Phenotype', 'HP:0002664', (11, 18))	('mutations', 'Var', (59, 68))	('cancers', 'Disease', (11, 18))	('human', 'Species', '9606', (5, 10))	('cancers', 'Disease', 'MESH:D009369', (11, 18))
120687	32220892	Forced cell cycle progression in the setting of DNA damage perpetuates DNA and chromatin damage, and leads to cell death because of irreparable genetic lesions.	('DNA', 'MPA', (71, 74))	('genetic lesions', 'Disease', 'MESH:D020022', (144, 159))	('damage', 'Var', (52, 58))	('genetic lesions', 'Disease', (144, 159))	('chromatin damage', 'MPA', (79, 95))
120689	32220892	Given the pivotal role for Wee1 in the regulation of CDK1 activity, targeting Wee1 has been proposed for the sensitization of cancer cells to radiotherapy and chemotherapy.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('activity', 'MPA', (58, 66))	('CDK1', 'Gene', '983', (53, 57))	('CDK1', 'Gene', (53, 57))	('targeting', 'Var', (68, 77))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('Wee1', 'Gene', (78, 82))
120690	32220892	Large-scale genomic studies have found that esophageal cancer has an extremely high frequency of TP53 mutations, ranging from 44% to 93%.	('esophageal cancer', 'Disease', 'MESH:D004938', (44, 61))	('TP53', 'Gene', '7157', (97, 101))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('TP53', 'Gene', (97, 101))	('mutations', 'Var', (102, 111))	('esophageal cancer', 'Disease', (44, 61))
120691	32220892	Recently, The Cancer Genome Atlas (TCGA) demonstrated that TP53 mutations were the single most common significantly mutated gene in ESCA, occurring in ~71% and ~91% of esophageal adenocarcinoma and esophageal squamous cell carcinoma, respectively.	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (168, 193))	('carcinoma', 'Phenotype', 'HP:0030731', (223, 232))	('carcinoma', 'Phenotype', 'HP:0030731', (184, 193))	('TP53', 'Gene', (59, 63))	('adenocarcinoma', 'Disease', (179, 193))	('adenocarcinoma', 'Disease', 'MESH:D000230', (179, 193))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (198, 232))	('ESCA', 'Disease', (132, 136))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (209, 232))	('mutations', 'Var', (64, 73))	('Cancer', 'Phenotype', 'HP:0002664', (14, 20))	('Cancer', 'Disease', (14, 20))	('occurring', 'Reg', (138, 147))	('TP53', 'Gene', '7157', (59, 63))	('Cancer', 'Disease', 'MESH:D009369', (14, 20))	('esophageal squamous cell carcinoma', 'Disease', (198, 232))
120692	32220892	Therefore, esophageal cancer cells may depend on G2/M checkpoint for survival and may be very sensitive to G2/M checkpoint abrogation by Wee1 inhibition.	('esophageal cancer', 'Disease', 'MESH:D004938', (11, 28))	('inhibition', 'Var', (142, 152))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('esophageal cancer', 'Disease', (11, 28))
120693	32220892	AZD1775 is a novel small molecule inhibitor that disrupts G2/M checkpoint by directly inhibiting Wee1 kinase.	('G2/M checkpoint', 'MPA', (58, 73))	('AZD1775', 'Var', (0, 7))	('AZD1775', 'Chemical', 'MESH:C549567', (0, 7))	('disrupts', 'NegReg', (49, 57))	('inhibiting', 'NegReg', (86, 96))	('Wee1 kinase', 'Pathway', (97, 108))
120696	32220892	In addition to inhibiting G2/M checkpoint, AZD1775 has been shown to induce DNA replication stress via nucleotide exhaustion, and to reduce homologous recombination repair.	('AZD1775', 'Chemical', 'MESH:C549567', (43, 50))	('reduce', 'NegReg', (133, 139))	('nucleotide exhaustion', 'MPA', (103, 124))	('homologous recombination repair', 'MPA', (140, 171))	('induce', 'PosReg', (69, 75))	('DNA replication stress', 'MPA', (76, 98))	('inhibiting', 'NegReg', (15, 25))	('AZD1775', 'Var', (43, 50))	('G2/M', 'Protein', (26, 30))
120698	32220892	Thus, targeting Wee1 may force cells to enter mitosis in the presence of incomplete DNA replication, which might exacerbate replication stress and development of lethal DNA damage.	('incomplete DNA', 'Var', (73, 87))	('mitosis', 'CPA', (46, 53))	('force', 'Reg', (25, 30))	('enter', 'PosReg', (40, 45))	('targeting', 'Var', (6, 15))	('men', 'Species', '9606', (154, 157))	('Wee1', 'Gene', (16, 20))	('exacerbate', 'PosReg', (113, 123))	('replication stress', 'MPA', (124, 142))
120699	32220892	AZD1775 has been tested preclinically in many types of cancers, and has been shown to radiosensitize and chemosensitize certain cancers, including pancreatic, breast, prostate, lung, and glioblastoma cancers.	('cancers', 'Disease', 'MESH:D009369', (55, 62))	('AZD1775', 'Var', (0, 7))	('glioblastoma cancers', 'Disease', (187, 207))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('prostate', 'Disease', (167, 175))	('lung', 'Disease', (177, 181))	('glioblastoma', 'Phenotype', 'HP:0012174', (187, 199))	('cancers', 'Phenotype', 'HP:0002664', (128, 135))	('cancers', 'Disease', (128, 135))	('cancers', 'Phenotype', 'HP:0002664', (200, 207))	('cancers', 'Disease', (200, 207))	('glioblastoma cancers', 'Disease', 'MESH:D009369', (187, 207))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('cancers', 'Phenotype', 'HP:0002664', (55, 62))	('pancreatic', 'Disease', (147, 157))	('cancers', 'Disease', (55, 62))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('radiosensitize', 'CPA', (86, 100))	('cancers', 'Disease', 'MESH:D009369', (128, 135))	('cancers', 'Disease', 'MESH:D009369', (200, 207))	('AZD1775', 'Chemical', 'MESH:C549567', (0, 7))	('breast', 'Disease', (159, 165))	('chemosensitize', 'CPA', (105, 119))
120703	32220892	We found that abrogation of G2/M checkpoint by targeting Wee1 kinase with AZD1775 markedly sensitizes esophageal cancer cells to radiotherapy in vitro and in mouse xenografts.	('esophageal cancer', 'Disease', 'MESH:D004938', (102, 119))	('targeting', 'Reg', (47, 56))	('mouse', 'Species', '10090', (158, 163))	('AZD1775', 'Chemical', 'MESH:C549567', (74, 81))	('sensitizes', 'Reg', (91, 101))	('radiotherapy', 'CPA', (129, 141))	('Wee1', 'Gene', (57, 61))	('esophageal cancer', 'Disease', (102, 119))	('AZD1775', 'Gene', (74, 81))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('abrogation', 'Var', (14, 24))
120704	32220892	Our findings suggest that AZD1775 in combination with radiotherapy may improve the therapeutic outcome of esophageal cancer patients.	('esophageal cancer', 'Disease', 'MESH:D004938', (106, 123))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('therapeutic outcome', 'CPA', (83, 102))	('AZD1775', 'Var', (26, 33))	('esophageal cancer', 'Disease', (106, 123))	('AZD1775', 'Chemical', 'MESH:C549567', (26, 33))	('patients', 'Species', '9606', (124, 132))	('improve', 'PosReg', (71, 78))
120746	32220892	All four cell lines used in our study have TP53 mutation, including esophageal adenocarcinoma cell lines (OE33, SK4, and FLO1) and an esophageal squamous cell carcinoma cell line (KYSE30).	('carcinoma', 'Phenotype', 'HP:0030731', (159, 168))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (145, 168))	('SK4', 'Gene', '3783', (112, 115))	('esophageal squamous cell carcinoma', 'Disease', (134, 168))	('SK4', 'Gene', (112, 115))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('adenocarcinoma', 'Disease', (79, 93))	('mutation', 'Var', (48, 56))	('adenocarcinoma', 'Disease', 'MESH:D000230', (79, 93))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (68, 93))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (134, 168))	('TP53', 'Gene', '7157', (43, 47))	('TP53', 'Gene', (43, 47))
120751	32220892	In combination with radiation however, AZD1775 could effectively sensitize ESCA cells to radiation treatment, with dose enhancement ratios (DER) up to 3.14 in SK4 cells, 1.46 in OE33 cells, 1.34 in FLO1 cells, and 1.23 in KYSE cells (Fig.	('AZD1775', 'Chemical', 'MESH:C549567', (39, 46))	('ESCA', 'Disease', (75, 79))	('SK4', 'Gene', (159, 162))	('men', 'Species', '9606', (104, 107))	('AZD1775', 'Var', (39, 46))	('SK4', 'Gene', '3783', (159, 162))	('enhancement', 'PosReg', (120, 131))	('men', 'Species', '9606', (127, 130))	('sensitize', 'Reg', (65, 74))
120756	32220892	However, pre-treatment of cells with AZD1775 at 3 hrs before radiation significantly reduced the accumulation of G2/M phase cells after radiation (Fig.	('AZD1775', 'Chemical', 'MESH:C549567', (37, 44))	('men', 'Species', '9606', (18, 21))	('G2/M phase cells', 'CPA', (113, 129))	('reduced', 'NegReg', (85, 92))	('AZD1775', 'Var', (37, 44))
120758	32220892	Immunoblotting analyses showed AZD1775 inhibited Wee1 and CDK1 phosphorylation in a time-dependent manner, with maximal changes noted 24 hrs after treatment (Fig.	('inhibited', 'NegReg', (39, 48))	('AZD1775', 'Var', (31, 38))	('AZD1775', 'Chemical', 'MESH:C549567', (31, 38))	('men', 'Species', '9606', (152, 155))	('phosphorylation', 'MPA', (63, 78))	('CDK1', 'Gene', (58, 62))	('CDK1', 'Gene', '983', (58, 62))	('Wee1', 'Protein', (49, 53))
120760	32220892	Exposing cells to AZD1775 before radiation attenuated radiation-induced Wee1 and CDK1 phosphorylation, most notable at 24 hrs after radiation.	('Wee1', 'Protein', (72, 76))	('CDK1', 'Gene', '983', (81, 85))	('AZD1775', 'Var', (18, 25))	('phosphorylation', 'MPA', (86, 101))	('CDK1', 'Gene', (81, 85))	('AZD1775', 'Chemical', 'MESH:C549567', (18, 25))	('attenuated', 'NegReg', (43, 53))
120761	32220892	Interestingly, AZD1775 alone induced gammaH2AX expression and enhanced radiation-mediated increase of gammaH2AX particularly after 24 hrs of treatment.	('H2AX', 'Gene', '3014', (42, 46))	('H2AX', 'Gene', '3014', (107, 111))	('H2AX', 'Gene', (42, 46))	('H2AX', 'Gene', (107, 111))	('enhanced', 'PosReg', (62, 70))	('men', 'Species', '9606', (146, 149))	('AZD1775', 'Var', (15, 22))	('induced', 'PosReg', (29, 36))	('AZD1775', 'Chemical', 'MESH:C549567', (15, 22))	('expression', 'MPA', (47, 57))
120762	32220892	Most studies have shown that the therapeutic effects AZD1775 is related to the abrogation of the G2 checkpoint and/or unscheduled mitotic entry.	('AZD1775', 'Chemical', 'MESH:C549567', (53, 60))	('AZD1775', 'Var', (53, 60))	('G2 checkpoint', 'Protein', (97, 110))
120763	32220892	However, emerging evidence suggest that Wee1 inhibition suppresses DNA damage repair and induces replication stress, both of which leads to phosphorylation of H2AX.	('DNA damage repair', 'MPA', (67, 84))	('phosphorylation', 'MPA', (140, 155))	('induces', 'Reg', (89, 96))	('H2AX', 'Gene', '3014', (159, 163))	('H2AX', 'Gene', (159, 163))	('Wee1', 'Gene', (40, 44))	('leads to', 'Reg', (131, 139))	('replication stress', 'CPA', (97, 115))	('inhibition', 'Var', (45, 55))	('suppresses', 'NegReg', (56, 66))
120766	32220892	The abrogation of G2/M phase cell cycle arrest and enhancement of DNA damage by AZD1775 in ESCA cells treated with radiation suggests that AZD1775 can promote irradiated ESCA cells to prematurely enter into cell mitosis before completion of DNA repair.	('enhancement', 'PosReg', (51, 62))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (29, 46))	('AZD1775', 'Gene', (80, 87))	('promote', 'PosReg', (151, 158))	('AZD1775', 'Chemical', 'MESH:C549567', (80, 87))	('DNA', 'MPA', (66, 69))	('arrest', 'Disease', 'MESH:D006323', (40, 46))	('AZD1775', 'Var', (139, 146))	('AZD1775', 'Chemical', 'MESH:C549567', (139, 146))	('arrest', 'Disease', (40, 46))	('men', 'Species', '9606', (58, 61))
120767	32220892	To test this hypothesis, FLO1 and OE33 cells were cultured on cover slides, and treated with vehicle, AZD1775, 4Gy radiation, or the combination of AZD1775 for 3 hrs followed by 4Gy.	('AZD1775', 'Chemical', 'MESH:C549567', (102, 109))	('AZD1775', 'Var', (102, 109))	('AZD1775', 'Var', (148, 155))	('AZD1775', 'Chemical', 'MESH:C549567', (148, 155))
120770	32220892	Conversely, 4 Gy radiation treatment resulted in accumulation of cells experiencing mitotic catastrophe, which was significantly enhanced by AZD1775 in both cell lines (Fig.	('enhanced', 'PosReg', (129, 137))	('accumulation', 'PosReg', (49, 61))	('AZD1775', 'Var', (141, 148))	('men', 'Species', '9606', (32, 35))	('AZD1775', 'Chemical', 'MESH:C549567', (141, 148))	('cells experiencing mitotic catastrophe', 'CPA', (65, 103))
120771	32220892	Thus, the combination of AZD1775 with radiation resulted in a significantly higher incidence of mitotic catastrophe than radiation treatment alone.	('AZD1775', 'Var', (25, 32))	('AZD1775', 'Chemical', 'MESH:C549567', (25, 32))	('mitotic catastrophe', 'CPA', (96, 115))	('combination', 'Interaction', (10, 21))	('men', 'Species', '9606', (136, 139))
120772	32220892	We found that AZD1775 attenuates radiation-induced G2/M phase arrest, enhances radiation mediated DNA damage, causes premature entrance into mitosis, and finally leads to mitotic cell death.	('arrest', 'Disease', 'MESH:D006323', (62, 68))	('premature entrance into mitosis', 'MPA', (117, 148))	('AZD1775', 'Var', (14, 21))	('arrest', 'Disease', (62, 68))	('AZD1775', 'Chemical', 'MESH:C549567', (14, 21))	('leads to', 'Reg', (162, 170))	('radiation mediated DNA damage', 'MPA', (79, 108))	('causes', 'Reg', (110, 116))	('attenuates', 'NegReg', (22, 32))	('mitotic cell death', 'CPA', (171, 189))	('enhances', 'PosReg', (70, 78))
120778	32220892	2B, exposure of FLO1 or OE33 cells to AZD1775 before and during fractionated radiation still effectively radiosensitized ESCA cells and abrogated cell recovery (Fig.	('radiosensitized', 'NegReg', (105, 120))	('cell recovery', 'CPA', (146, 159))	('AZD1775', 'Var', (38, 45))	('AZD1775', 'Chemical', 'MESH:C549567', (38, 45))	('ESCA', 'Disease', (121, 125))	('abrogated', 'NegReg', (136, 145))
120779	32220892	These results indicate a comparable enhancement of cell death by AZD1775 in ESCA cells when combining AZD1775 with either fractionated or single fraction radiation.	('AZD1775', 'Chemical', 'MESH:C549567', (102, 109))	('AZD1775', 'Var', (65, 72))	('enhancement', 'PosReg', (36, 47))	('AZD1775', 'Chemical', 'MESH:C549567', (65, 72))	('cell death', 'CPA', (51, 61))	('men', 'Species', '9606', (43, 46))
120781	32220892	To determine if Wee1 inhibition could effectively radiosensitize ESCA cells in vivo, we further explored the combined treatment of AZD1775 and radiation in vivo using nude mice xenografts with FLO1 and OE33 cells.	('ESCA', 'Disease', (65, 69))	('nude mice', 'Species', '10090', (167, 176))	('inhibition', 'Var', (21, 31))	('men', 'Species', '9606', (123, 126))	('AZD1775', 'Chemical', 'MESH:C549567', (131, 138))
120782	32220892	When tumors reached 100-150 mm3, the mice were randomized to groups of treatment with vehicle, AZD1775 alone, 4 Gy radiation alone, or the combination of AZD1775 + 4Gy (mice were treated with AZD1775 2 hrs before radiation).	('tumors', 'Disease', (5, 11))	('AZD1775', 'Chemical', 'MESH:C549567', (95, 102))	('AZD1775', 'Chemical', 'MESH:C549567', (154, 161))	('tumors', 'Disease', 'MESH:D009369', (5, 11))	('AZD1775', 'Chemical', 'MESH:C549567', (192, 199))	('men', 'Species', '9606', (76, 79))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('mice', 'Species', '10090', (169, 173))	('AZD1775', 'Var', (95, 102))	('AZD1775', 'Var', (154, 161))	('tumors', 'Phenotype', 'HP:0002664', (5, 11))	('mice', 'Species', '10090', (37, 41))
120786	32220892	However, AZD1775 in combination with radiation treatment led to remarkable and sustained tumor regression of both FLO1 and OE33 xenografts (Fig.	('men', 'Species', '9606', (52, 55))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('AZD1775', 'Var', (9, 16))	('AZD1775', 'Chemical', 'MESH:C549567', (9, 16))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
120788	32220892	Consistent with our in vitro data, the combination of AZD1775 and IR significantly increased mitotic catastrophe in tumor xenografts compare to IR treatment alone (Fig.	('increased', 'PosReg', (83, 92))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('men', 'Species', '9606', (152, 155))	('mitotic catastrophe in', 'CPA', (93, 115))	('AZD1775', 'Var', (54, 61))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumor', 'Disease', (116, 121))	('AZD1775', 'Chemical', 'MESH:C549567', (54, 61))
120789	32220892	Moreover, the majority of FLO1 and OE33 tumors showed no evidence of tumor recurrence after treatment with AZD1775 in combination with radiation (survival curves shown in Supplementary Fig.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('FLO1', 'Gene', (26, 30))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('tumors', 'Disease', 'MESH:D009369', (40, 46))	('tumor', 'Disease', (69, 74))	('men', 'Species', '9606', (97, 100))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('AZD1775', 'Var', (107, 114))	('men', 'Species', '9606', (177, 180))	('AZD1775', 'Chemical', 'MESH:C549567', (107, 114))	('OE33', 'Gene', (35, 39))	('tumor', 'Disease', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('tumors', 'Disease', (40, 46))
120793	32220892	AZD1775 reduced the phosphorylation of Wee1 and CDK1 as well as the protein levels of cyclin A2, B1, E1 and E2, while increasing levels of phospho-histone H3 (a marker of mitotic cells) (Fig.	('increasing', 'PosReg', (118, 128))	('AZD1775', 'Var', (0, 7))	('AZD1775', 'Chemical', 'MESH:C549567', (0, 7))	('phospho-histone H3', 'MPA', (139, 157))	('reduced', 'NegReg', (8, 15))	('phosphorylation', 'MPA', (20, 35))	('levels', 'MPA', (129, 135))	('cyclin A2, B1, E1 and E2', 'Gene', '890;891;6080', (86, 110))	('protein levels', 'MPA', (68, 82))	('CDK1', 'Gene', (48, 52))	('Wee1', 'Gene', (39, 43))	('CDK1', 'Gene', '983', (48, 52))
120794	32220892	Taken together, these findings indicate AZD1775 is promoting G2/M phase cell cycle progression.	('promoting', 'PosReg', (51, 60))	('AZD1775', 'Chemical', 'MESH:C549567', (40, 47))	('AZD1775', 'Var', (40, 47))	('G2/M phase cell cycle progression', 'CPA', (61, 94))
120798	32220892	Esophageal cancer cells often lack a functional G1 checkpoint due to a high frequency of TP53 mutations.	('TP53', 'Gene', '7157', (89, 93))	('lack', 'NegReg', (30, 34))	('TP53', 'Gene', (89, 93))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('mutations', 'Var', (94, 103))	('cancer', 'Disease', 'MESH:D009369', (11, 17))	('cancer', 'Disease', (11, 17))
120799	32220892	Based on TCGA data, up to 91% of squamous cell carcinoma and 71% of adenocarcinoma esophageal cancers possess a TP53 mutation making them heavily dependent on the G2/M checkpoint to survive DNA damage and replication stress.	('adenocarcinoma esophageal cancers', 'Disease', (68, 101))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (33, 56))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (33, 56))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (47, 56))	('squamous cell carcinoma', 'Disease', (33, 56))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('TP53', 'Gene', '7157', (112, 116))	('mutation', 'Var', (117, 125))	('cancers', 'Phenotype', 'HP:0002664', (94, 101))	('adenocarcinoma esophageal cancers', 'Disease', 'MESH:D004938', (68, 101))	('TP53', 'Gene', (112, 116))
120801	32220892	In addition, AZD1775 treatment led to a comparable enhancement of cytotoxicity in ESCA cells treated with either fractionated radiation or single dose radiation.	('enhancement', 'PosReg', (51, 62))	('cytotoxicity', 'Disease', 'MESH:D064420', (66, 78))	('AZD1775', 'Chemical', 'MESH:C549567', (13, 20))	('men', 'Species', '9606', (26, 29))	('cytotoxicity', 'Disease', (66, 78))	('AZD1775', 'Var', (13, 20))	('men', 'Species', '9606', (58, 61))
120802	32220892	Mechanistically, AZD1775 attenuated radiation-induced G2/M phase arrest, which was accompanied by enhanced radiation-induced mitotic catastrophe and DNA damage.	('enhanced', 'PosReg', (98, 106))	('arrest', 'Disease', 'MESH:D006323', (65, 71))	('attenuated', 'NegReg', (25, 35))	('AZD1775', 'Chemical', 'MESH:C549567', (17, 24))	('arrest', 'Disease', (65, 71))	('DNA damage', 'CPA', (149, 159))	('AZD1775', 'Var', (17, 24))
120803	32220892	Our findings suggest that Wee1 kinase specific inhibitor AZD1775 is an effective radiosensitizer for esophageal cancer.	('AZD1775', 'Chemical', 'MESH:C549567', (57, 64))	('esophageal cancer', 'Disease', (101, 118))	('esophageal cancer', 'Disease', 'MESH:D004938', (101, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('AZD1775', 'Var', (57, 64))
120807	32220892	Previous studies have shown that AZD1775 is a potent and selective small molecule inhibitor of Wee1 kinase and has been shown to sensitize tumor cells to both chemotherapy and radiation.	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('Wee1', 'Enzyme', (95, 99))	('sensitize', 'Reg', (129, 138))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('AZD1775', 'Var', (33, 40))	('AZD1775', 'Chemical', 'MESH:C549567', (33, 40))
120809	32220892	Moreover, we demonstrated that AZD1775 potently inhibited the phosphorylation of both Wee1 and CDK1 in the absence or presence of radiation.	('Wee1', 'Protein', (86, 90))	('AZD1775', 'Var', (31, 38))	('CDK1', 'Gene', (95, 99))	('phosphorylation', 'MPA', (62, 77))	('CDK1', 'Gene', '983', (95, 99))	('AZD1775', 'Chemical', 'MESH:C549567', (31, 38))	('inhibited', 'NegReg', (48, 57))
120810	32220892	Consistent with the role for Wee1 in G2/M checkpoint regulation, AZD1775 prevented IR-induced G2/M phase cell cycle arrest, which was accompanied with enhanced mitotic catastrophe and gammaH2AX, indicative of enhanced cell death and DNA damage.	('mitotic catastrophe', 'CPA', (160, 179))	('H2AX', 'Gene', (189, 193))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (105, 122))	('enhanced', 'PosReg', (151, 159))	('AZD1775', 'Var', (65, 72))	('enhanced', 'PosReg', (209, 217))	('prevented', 'NegReg', (73, 82))	('AZD1775', 'Chemical', 'MESH:C549567', (65, 72))	('arrest', 'Disease', 'MESH:D006323', (116, 122))	('H2AX', 'Gene', '3014', (189, 193))	('arrest', 'Disease', (116, 122))
120811	32220892	Interestingly, we noted AZD1775 caused reductions in E, A, and B-type cyclins.	('cyclins', 'Gene', '891', (70, 77))	('AZD1775', 'Var', (24, 31))	('AZD1775', 'Chemical', 'MESH:C549567', (24, 31))	('reductions', 'NegReg', (39, 49))	('cyclins', 'Gene', (70, 77))	('B-type', 'Protein', (63, 69))
120815	32220892	Taken together, AZD1775 potently inhibits Wee1 in ESCA cells, thereby promoting entry from S and G2 through M phase, and thus preventing Wee1 from protecting ESCA cells from the effects of radiotherapy.	('promoting', 'PosReg', (70, 79))	('AZD1775', 'Var', (16, 23))	('AZD1775', 'Chemical', 'MESH:C549567', (16, 23))	('preventing', 'NegReg', (126, 136))	('inhibits', 'NegReg', (33, 41))	('entry', 'MPA', (80, 85))
120829	32220892	Our results showed that AZD1775 in combination with radiotherapy resulted in virtually complete tumor regression of ESCA tumor xenografts.	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('AZD1775', 'Var', (24, 31))	('AZD1775', 'Chemical', 'MESH:C549567', (24, 31))	('tumor', 'Disease', (96, 101))	('tumor', 'Disease', (121, 126))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
120832	32220892	All the four ESCA cell lines used in this study have TP53 mutations.	('mutations', 'Var', (58, 67))	('TP53', 'Gene', '7157', (53, 57))	('TP53', 'Gene', (53, 57))
120833	32220892	However, besides TP53 mutation, SK4 cells have additional KRAS and PIK3CA mutation (https://portals.broadinstitute.org/ccle).	('KRAS', 'Gene', (58, 62))	('SK4', 'Gene', (32, 35))	('mutation', 'Var', (74, 82))	('PIK3CA', 'Gene', '5290', (67, 73))	('KRAS', 'Gene', '3845', (58, 62))	('TP53', 'Gene', '7157', (17, 21))	('SK4', 'Gene', '3783', (32, 35))	('PIK3CA', 'Gene', (67, 73))	('TP53', 'Gene', (17, 21))
120834	32220892	KRAS and PIK3CA mutations drive tumorigenesis via multiple mechanisms, one of which is to induce DNA replication stress leading to genomic instability.	('drive', 'Reg', (26, 31))	('PIK3CA', 'Gene', '5290', (9, 15))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('mutations', 'Var', (16, 25))	('genomic instability', 'MPA', (131, 150))	('induce', 'Reg', (90, 96))	('DNA replication stress', 'MPA', (97, 119))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('PIK3CA', 'Gene', (9, 15))	('tumor', 'Disease', (32, 37))	('KRAS', 'Gene', (0, 4))	('KRAS', 'Gene', '3845', (0, 4))
120836	32220892	Thus, ESCA cells with KRAS and PIK3CA mutations might may have become more dependent on Wee1 kinase for survival due to increased replication stress.	('PIK3CA', 'Gene', (31, 37))	('PIK3CA', 'Gene', '5290', (31, 37))	('KRAS', 'Gene', (22, 26))	('KRAS', 'Gene', '3845', (22, 26))	('mutations', 'Var', (38, 47))
120837	32220892	It will be important to determine whether ESCA with KRAS and/or PIK3CA mutations are hypersensitive to Wee1 inhibitors in future preclinical and clinical studies.	('PIK3CA', 'Gene', (64, 70))	('KRAS', 'Gene', (52, 56))	('ESCA', 'Disease', (42, 46))	('KRAS', 'Gene', '3845', (52, 56))	('PIK3CA', 'Gene', '5290', (64, 70))	('mutations', 'Var', (71, 80))	('hypersensitive', 'Disease', 'MESH:D004342', (85, 99))	('hypersensitive', 'Disease', (85, 99))
120838	32220892	In addition, it will be critical to determine whether TP53 mutant status confers increased sensitivity to AZD1775 and radiation.	('TP53', 'Gene', (54, 58))	('AZD1775', 'Chemical', 'MESH:C549567', (106, 113))	('mutant', 'Var', (59, 65))	('TP53', 'Gene', '7157', (54, 58))	('increased', 'PosReg', (81, 90))	('sensitivity', 'MPA', (91, 102))
120839	32220892	In our preliminary studies, we found that the combination of AZD1775 and radiation did not radiosensitize TP53 intact AGS adenocarcinoma cells (Supplementary Fig.	('AGS adenocarcinoma', 'Disease', 'MESH:C535607', (118, 136))	('AZD1775', 'Chemical', 'MESH:C549567', (61, 68))	('AGS adenocarcinoma', 'Disease', (118, 136))	('men', 'Species', '9606', (150, 153))	('TP53', 'Gene', (106, 110))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('TP53', 'Gene', '7157', (106, 110))	('AZD1775', 'Var', (61, 68))
120840	32220892	Finally, further studies are needed to assess whether AZD1755 sensitizes ESCA cells to DNA-damaging chemotherapies such as platinum-based drugs or other chemotherapeutics which promote replication stress.	('AZD1755', 'Chemical', '-', (54, 61))	('AZD1755', 'Var', (54, 61))	('sensitizes', 'Reg', (62, 72))	('platinum', 'Chemical', 'MESH:D010984', (123, 131))
120843	32220892	This trial was based on preclinical data combining Wee1 inhibitor with gemcitabine and radiation.	('gemcitabine', 'Chemical', 'MESH:C056507', (71, 82))	('Wee1', 'Gene', (51, 55))	('inhibitor', 'Var', (56, 65))
120845	32220892	In summary, our results demonstrated a potent inhibitory role for Wee1 kinase inhibitor AZD1775 in cell cycle checkpoints in response to IR-induced DNA double strand breaks; importantly, AZD1775 enhanced IR-mediated cell death in vitro and maintained the suppression of ESCA mouse xenografts by radiotherapy in vivo.	('suppression', 'CPA', (255, 266))	('mouse', 'Species', '10090', (275, 280))	('enhanced', 'PosReg', (195, 203))	('AZD1775', 'Var', (187, 194))	('ESCA', 'Disease', (270, 274))	('IR-mediated cell death', 'CPA', (204, 226))	('AZD1775', 'Chemical', 'MESH:C549567', (187, 194))	('AZD1775', 'Chemical', 'MESH:C549567', (88, 95))
120847	32220892	Due to the high incidence of TP53 mutations and the dependence on the Wee1-mediated G2/M checkpoint to survive DNA damage, esophageal cancer is a logical site to consider the addition of a Wee1 kinase inhibitor to standard neoadjuvant therapy.	('esophageal cancer', 'Disease', (123, 140))	('esophageal cancer', 'Disease', 'MESH:D004938', (123, 140))	('TP53', 'Gene', '7157', (29, 33))	('TP53', 'Gene', (29, 33))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('mutations', 'Var', (34, 43))
120848	32220892	We believe our study warrants a phase I trial testing AZD1775 in combination with radiation or chemoradiation for esophageal cancer.	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('esophageal cancer', 'Disease', (114, 131))	('AZD1775', 'Var', (54, 61))	('esophageal cancer', 'Disease', 'MESH:D004938', (114, 131))	('AZD1775', 'Chemical', 'MESH:C549567', (54, 61))
120851	32220892	The majority of both esophageal adenocarcinoma and squamous cell carcinomas harbor mutations in TP53, an important tumor suppressor gene that also functions to promote cell cycle arrest in G1/S after DNA damage from radiation.	('arrest', 'Disease', 'MESH:D006323', (179, 185))	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('tumor', 'Disease', (115, 120))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (21, 46))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('promote', 'PosReg', (160, 167))	('adenocarcinoma', 'Disease', 'MESH:D000230', (32, 46))	('carcinomas', 'Phenotype', 'HP:0030731', (65, 75))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (51, 75))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (168, 185))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('TP53', 'Gene', (96, 100))	('arrest', 'Disease', (179, 185))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (51, 75))	('carcinoma', 'Phenotype', 'HP:0030731', (37, 46))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (51, 74))	('mutations', 'Var', (83, 92))	('squamous cell carcinomas', 'Disease', (51, 75))	('adenocarcinoma', 'Disease', (32, 46))	('TP53', 'Gene', '7157', (96, 100))
120853	32220892	We find that in TP53-mutated cells lacking an effective G1/S checkpoint, AZD1775 markedly radiosensitizes esophageal cancer cells to radiation both in cell culture assays and animal studies.	('esophageal cancer', 'Disease', 'MESH:D004938', (106, 123))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('AZD1775', 'Var', (73, 80))	('lacking', 'NegReg', (35, 42))	('radiosensitizes', 'NegReg', (90, 105))	('TP53', 'Gene', '7157', (16, 20))	('AZD1775', 'Chemical', 'MESH:C549567', (73, 80))	('esophageal cancer', 'Disease', (106, 123))	('TP53', 'Gene', (16, 20))
120854	32220892	Our results justify a clinical trial to determine the safety and efficacy of combining AZD1775 and radiation in patients with esophageal cancer.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('esophageal cancer', 'Disease', 'MESH:D004938', (126, 143))	('AZD1775', 'Var', (87, 94))	('AZD1775', 'Chemical', 'MESH:C549567', (87, 94))	('patients', 'Species', '9606', (112, 120))	('esophageal cancer', 'Disease', (126, 143))
120860	31054503	The results show that significance of the survival correlations of patient groups, assessed by a logrank test, are strongly affected by the segmentation parameter changes.	('changes', 'Var', (163, 170))	('patient', 'Species', '9606', (67, 74))	('affected', 'Reg', (124, 132))	('survival correlations', 'CPA', (42, 63))
120872	31054503	The results show that SMs lead to performance gains of 51x with a small mean absolute error (MAE) of 0.022 to the SA indices.	('SMs', 'Var', (22, 25))	('SA', 'Chemical', '-', (114, 116))	('gains', 'PosReg', (46, 51))	('SMs', 'Chemical', '-', (22, 25))	('performance', 'MPA', (34, 45))
120943	31054503	As is shown in Table 1, the CGR optimization significantly improved the execution without computation reused (CPU+Phi), whereas the RTM further accelerated the SA execution in about 1.5x.	('CPU', 'Gene', (110, 113))	('improved', 'PosReg', (59, 67))	('SA', 'Chemical', '-', (160, 162))	('accelerated', 'PosReg', (144, 155))	('optimization', 'Var', (32, 44))	('CPU', 'Gene', '1361', (110, 113))	('execution', 'MPA', (72, 81))
120967	31054503	We have also shown that changes in important parameters of the segmentation, identified in the SA studies, significantly affect other phases of application, such as, downstream correlation analysis.	('affect', 'Reg', (121, 127))	('changes', 'Var', (24, 31))	('SA', 'Chemical', '-', (95, 97))
120974	31827723	Either ULBP1 or ULBP2/5/6 overexpression was associated with squamous-cell carcinoma histology, whereas ULBP4 overexpression was associated with younger age and adenocarcinoma histology.	('ULBP1', 'Gene', (7, 12))	('squamous-cell carcinoma', 'Phenotype', 'HP:0002860', (61, 84))	('ULBP2', 'Gene', '80328', (16, 21))	('adenocarcinoma', 'Disease', 'MESH:D000230', (161, 175))	('overexpression', 'Var', (26, 40))	('carcinoma', 'Phenotype', 'HP:0030731', (166, 175))	('adenocarcinoma', 'Disease', (161, 175))	('ULBP4', 'Gene', '135250', (104, 109))	('associated', 'Reg', (45, 55))	('squamous-cell carcinoma', 'Disease', 'MESH:D002294', (61, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('ULBP4', 'Gene', (104, 109))	('ULBP2', 'Gene', (16, 21))	('squamous-cell carcinoma', 'Disease', (61, 84))	('ULBP1', 'Gene', '80329', (7, 12))
120986	31827723	However, there is no report evaluating the correlation between ULBP1-6 expression and clinical outcome in patients with NSCLC, although high concentrations of serum-soluble ULBP2 in NSCLC patients were reported to be correlated with poor prognosis.	('ULBP2', 'Gene', '80328', (173, 178))	('NSCLC', 'Disease', 'MESH:D002289', (120, 125))	('NSCLC', 'Disease', (182, 187))	('high', 'Var', (136, 140))	('NSCLC', 'Disease', 'MESH:D002289', (182, 187))	('patients', 'Species', '9606', (188, 196))	('NSCLC', 'Phenotype', 'HP:0030358', (120, 125))	('patients', 'Species', '9606', (106, 114))	('NSCLC', 'Disease', (120, 125))	('NSCLC', 'Phenotype', 'HP:0030358', (182, 187))	('ULBP1', 'Gene', '80329', (63, 68))	('ULBP2', 'Gene', (173, 178))	('ULBP1', 'Gene', (63, 68))
121073	24761979	Freshly obtained human PBLs were stained with the following anti-human monoclonal antibodies: anti-CD3-eFluor 605NC (0.25 mug/100 mul), anti-CD4-FITC (1.0 mug/100 mul), anti-CD25-APC (0.125 mug/100 mul), and anti-CD45RA-eFluor 450 (0.5 mug/100 mul) for surface staining.	('human', 'Species', '9606', (65, 70))	('CD4', 'Gene', '920', (213, 216))	('human', 'Species', '9606', (17, 22))	('CD4', 'Gene', (141, 144))	('anti-CD3-eFluor', 'Var', (94, 109))	('CD25', 'Gene', (174, 178))	('CD4', 'Gene', '920', (141, 144))	('CD45', 'Gene', '5788', (213, 217))	('CD45', 'Gene', (213, 217))	('CD4', 'Gene', (213, 216))	('CD25', 'Gene', '3559', (174, 178))
121079	24761979	Briefly, mAbs against surface markers CD3, CD4, CD25, and CD45RA were added to the cell suspension (1 x 107 cells/100 mul) and incubated on ice for 30 minutes in the dark.	('CD3', 'Var', (38, 41))	('CD25', 'Gene', '3559', (48, 52))	('CD4', 'Gene', '920', (58, 61))	('CD4', 'Gene', '920', (43, 46))	('CD45', 'Gene', '5788', (58, 62))	('CD25', 'Gene', (48, 52))	('CD4', 'Gene', (43, 46))	('CD45', 'Gene', (58, 62))	('CD4', 'Gene', (58, 61))
121104	24761979	The frequency of CD45RA-Foxp3high Tregs in patients with T3-4 or N+ was higher than in patients with T1-2 or N0, respectively (T3-4 vs. T1-2: 2.81 +- 0.89% vs. 1.83 +- 0.82%, P < 0.0001; N+ vs. N0: 2.92 +- 1.03% vs. 1.81 +- 0.65%, P < 0.0001).	('T3-4', 'Var', (57, 61))	('CD45', 'Gene', '5788', (17, 21))	('Foxp3', 'Gene', (24, 29))	('N+', 'Chemical', 'MESH:D009584', (187, 189))	('patients', 'Species', '9606', (43, 51))	('Tregs', 'Chemical', '-', (34, 39))	('higher', 'PosReg', (72, 78))	('CD45', 'Gene', (17, 21))	('patients', 'Species', '9606', (87, 95))	('N+', 'Chemical', 'MESH:D009584', (65, 67))	('Foxp3', 'Gene', '50943', (24, 29))
121105	24761979	The frequency of CD45RA+Foxp3low Tregs did not differ between patients with T3-4 and T1-2 (0.52 +- 0.18% vs. 0.54 +- 0.28%, P = 0.834) or with N+ and N0 (0.50 +- 0.17% vs. 0.55 +- 0.17%, P = 0.556).	('Tregs', 'Chemical', '-', (33, 38))	('CD45', 'Gene', '5788', (17, 21))	('Foxp3', 'Gene', (24, 29))	('T3-4', 'Var', (76, 80))	('N+', 'Chemical', 'MESH:D009584', (143, 145))	('CD45', 'Gene', (17, 21))	('patients', 'Species', '9606', (62, 70))	('Foxp3', 'Gene', '50943', (24, 29))
121106	24761979	The frequency of CD45RA-Foxp3lowCD4+ T cells in patients with T3-4 or N+ was higher than in patients with T1-2 or N0, respectively (T3-4 vs. T1-2: 6.26 +- 1.39% vs. 4.73 +- 1.49%, P < 0.0001; N+ vs. N0: 6.07 +- 1.81% vs. 4.93 +- 1.36%, P < 0.0001) (Table 2).	('CD4', 'Gene', (17, 20))	('CD45', 'Gene', '5788', (17, 21))	('higher', 'PosReg', (77, 83))	('Foxp3', 'Gene', (24, 29))	('CD4', 'Gene', '920', (17, 20))	('T3-4', 'Var', (62, 66))	('patients', 'Species', '9606', (92, 100))	('CD4', 'Gene', (32, 35))	('N+', 'Chemical', 'MESH:D009584', (192, 194))	('CD4', 'Gene', '920', (32, 35))	('CD45', 'Gene', (17, 21))	('patients', 'Species', '9606', (48, 56))	('N+', 'Chemical', 'MESH:D009584', (70, 72))	('Foxp3', 'Gene', '50943', (24, 29))
121113	24761979	showed that higher levels of Tregs do not show any significant influence on outcome of oro- and hypopharyngeal carcinoma patients, and other HNSCC studies even showed that expansion of Tregs is significant prognostic factor related to better locoregional control and overall survival.	('SCC', 'Gene', (143, 146))	('Tregs', 'Chemical', '-', (29, 34))	('hypopharyngeal carcinoma', 'Disease', 'MESH:D007012', (96, 120))	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('SCC', 'Gene', '6317', (143, 146))	('Tregs', 'Gene', (185, 190))	('HNSCC', 'Phenotype', 'HP:0012288', (141, 146))	('locoregional control', 'CPA', (242, 262))	('hypopharyngeal carcinoma', 'Phenotype', 'HP:0012182', (96, 120))	('Tregs', 'Chemical', '-', (185, 190))	('hypopharyngeal carcinoma', 'Disease', (96, 120))	('overall survival', 'CPA', (267, 283))	('expansion', 'Var', (172, 181))	('patients', 'Species', '9606', (121, 129))	('better', 'PosReg', (235, 241))
121138	24761979	However, recent studies of HNSCC showed that CD127low/- Tregs (including CD4+CD25interCD127low/- and CD4+CD25high CD127low/- Tregs) or CD4+CD25+Foxp3+ Tregs are associated with advanced stage and nodal involvement.	('SCC', 'Gene', '6317', (29, 32))	('CD25', 'Gene', (77, 81))	('associated', 'Reg', (161, 171))	('CD4', 'Gene', (135, 138))	('CD4', 'Gene', '920', (101, 104))	('SCC', 'Gene', (29, 32))	('CD25', 'Gene', (139, 143))	('nodal', 'Gene', (196, 201))	('nodal', 'Gene', '4838', (196, 201))	('CD25', 'Gene', (105, 109))	('HNSCC', 'Phenotype', 'HP:0012288', (27, 32))	('CD4', 'Gene', (101, 104))	('CD25', 'Gene', '3559', (77, 81))	('Tregs', 'Chemical', '-', (56, 61))	('Foxp3', 'Gene', (144, 149))	('advanced', 'Disease', (177, 185))	('CD25', 'Gene', '3559', (139, 143))	('CD4', 'Gene', '920', (73, 76))	('CD25', 'Gene', '3559', (105, 109))	('Tregs', 'Chemical', '-', (151, 156))	('Tregs', 'Chemical', '-', (125, 130))	('Foxp3', 'Gene', '50943', (144, 149))	('CD127low/-', 'Var', (45, 55))	('CD4', 'Gene', (73, 76))	('CD4', 'Gene', '920', (135, 138))
121143	24761979	The present findings provide important information of the future design of immunotherapeutic strategies for HNSCC patients, for example by monoclonal antibodies (anti-PD-1 Ab and anti-CTLA-4 Ab), to reduce the expansion, survival and suppressive function of the Tregs responsible for HNSCC-specific immune suppression - as ever the problem remains effective, specific targeting.	('SCC', 'Gene', '6317', (110, 113))	('expansion', 'CPA', (210, 219))	('suppressive function', 'CPA', (234, 254))	('HNSCC', 'Phenotype', 'HP:0012288', (108, 113))	('anti-CTLA-4', 'Var', (179, 190))	('SCC', 'Gene', (110, 113))	('SCC', 'Gene', (286, 289))	('reduce', 'NegReg', (199, 205))	('Tregs', 'Chemical', '-', (262, 267))	('SCC', 'Gene', '6317', (286, 289))	('HNSCC', 'Phenotype', 'HP:0012288', (284, 289))	('survival', 'CPA', (221, 229))	('patients', 'Species', '9606', (114, 122))
121187	31118085	The patient's diagnosis was accepted as T4N0M1 renal pelvis SCC, and she was admitted to the intensive care unit for respiratory distress on the seventh postoperative day.	('renal pelvis SCC', 'Disease', (47, 63))	('respiratory distress', 'Phenotype', 'HP:0002098', (117, 137))	('renal pelvis SCC', 'Disease', 'MESH:D010386', (47, 63))	('patient', 'Species', '9606', (4, 11))	('renal pelvis', 'Phenotype', 'HP:0000125', (47, 59))	('T4N0M1', 'Var', (40, 46))
121240	26263981	LAMP3 DNA copy number was amplified in 70% of ESCC tissues and positive correlated with mRNA expression (p = 0.037).	('ESCC', 'Disease', (46, 50))	('correlated', 'Reg', (72, 82))	('LAMP3', 'Gene', '27074', (0, 5))	('mRNA expression', 'MPA', (88, 103))	('LAMP3', 'Gene', (0, 5))	('copy number', 'Var', (10, 21))
121247	26263981	It has been reported that aberrant expression of several important genes was associated with the poor prognosis of ESCC, such as p53, Bcl-2 and p300.	('ESCC', 'Disease', (115, 119))	('aberrant expression', 'Var', (26, 45))	('p300', 'Gene', (144, 148))	('p53', 'Gene', (129, 132))	('Bcl-2', 'Gene', '596', (134, 139))	('p300', 'Gene', '2033', (144, 148))	('p53', 'Gene', '7157', (129, 132))	('Bcl-2', 'Gene', (134, 139))	('associated', 'Reg', (77, 87))
121261	26263981	Dysregulation of genes in this region might play an important role in the progression and prognosis of cancers.	('cancers', 'Disease', 'MESH:D009369', (103, 110))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('Dysregulation', 'Var', (0, 13))	('play', 'Reg', (44, 48))	('role', 'Reg', (62, 66))	('cancers', 'Phenotype', 'HP:0002664', (103, 110))	('cancers', 'Disease', (103, 110))
121277	26263981	This result suggested that the DNA amplification of LAMP3 might result in its transcript over expression in a certain degree.	('DNA', 'Var', (31, 34))	('result', 'Reg', (64, 70))	('transcript', 'MPA', (78, 88))	('LAMP3', 'Gene', '27074', (52, 57))	('over', 'PosReg', (89, 93))	('LAMP3', 'Gene', (52, 57))
121303	26263981	In our study, high expression of LAMP3 was more frequent at the primary sites of patients with lymph node metastasis than in those without metastasis (56.2% vs. 44.1%), although not statistically significant, which might due to the small sample size (50 vs. 30).	('patients', 'Species', '9606', (81, 89))	('LAMP3', 'Gene', (33, 38))	('high', 'Var', (14, 18))	('lymph', 'Disease', (95, 100))	('LAMP3', 'Gene', '27074', (33, 38))
121344	26263981	LAMP3 DNA copy number was positive correlated with its mRNA expression.	('mRNA expression', 'MPA', (55, 70))	('LAMP3', 'Gene', (0, 5))	('copy number', 'Var', (10, 21))	('LAMP3', 'Gene', '27074', (0, 5))
121356	25588551	In the group treated with chemotherapy combined with anti-EGFR drugs, patients with lowexpression of c-Met had a better OS than those with overexpression of c-Met (OS: 577 d vs 232 d, P = 0.007).	('EGFR', 'Gene', '1956', (58, 62))	('patients', 'Species', '9606', (70, 78))	('EGFR', 'Gene', (58, 62))	('c-Met', 'Gene', (101, 106))	('c-Met', 'Gene', '4233', (101, 106))	('lowexpression', 'Var', (84, 97))	('OS', 'Chemical', 'MESH:D009992', (120, 122))	('OS', 'Chemical', 'MESH:D009992', (164, 166))	('c-Met', 'Gene', (157, 162))	('c-Met', 'Gene', '4233', (157, 162))
121418	25588551	In TP plus nimotuzumab group, the OS of patients with c-Met low-expression was significantly better than those with c-Met over-expression (577d vs 232d, P = 0.007).	('patients', 'Species', '9606', (40, 48))	('nimotuzumab', 'Chemical', 'MESH:C501466', (11, 22))	('TP', 'Chemical', 'MESH:C011314', (3, 5))	('better', 'PosReg', (93, 99))	('c-Met', 'Gene', (54, 59))	('OS', 'Chemical', 'MESH:D009992', (34, 36))	('c-Met', 'Gene', (116, 121))	('c-Met', 'Gene', '4233', (54, 59))	('low-expression', 'Var', (60, 74))	('c-Met', 'Gene', '4233', (116, 121))
121423	25588551	The patients with c-Met low-expression had a trend of better prognosis with no statistical significance (P = 0.289).	('c-Met', 'Gene', (18, 23))	('c-Met', 'Gene', '4233', (18, 23))	('low-expression', 'Var', (24, 38))	('patients', 'Species', '9606', (4, 12))	('better', 'PosReg', (54, 60))
121430	25588551	One study reported that an increased expression of c-Met was seen along the metaplasia-adenocarcinoma sequence and patients with esophageal adenocarcinoma with c-Met positive tumors showed lower 6-month survival rates after surgical resection than those with c-Met negative tumors.	('tumors', 'Disease', (175, 181))	('carcinoma', 'Phenotype', 'HP:0030731', (145, 154))	('tumors', 'Disease', 'MESH:D009369', (274, 280))	('c-Met', 'Gene', '4233', (51, 56))	('c-Met', 'Gene', (259, 264))	('tumors', 'Disease', 'MESH:D009369', (175, 181))	('6-month survival rates', 'CPA', (195, 217))	('positive', 'Var', (166, 174))	('c-Met', 'Gene', '4233', (160, 165))	('tumors', 'Phenotype', 'HP:0002664', (274, 280))	('patients', 'Species', '9606', (115, 123))	('c-Met', 'Gene', (51, 56))	('metaplasia-adenocarcinoma', 'Disease', 'MESH:D008679', (76, 101))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (129, 154))	('c-Met', 'Gene', '4233', (259, 264))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (129, 154))	('tumor', 'Phenotype', 'HP:0002664', (274, 279))	('expression', 'MPA', (37, 47))	('tumors', 'Disease', (274, 280))	('tumors', 'Phenotype', 'HP:0002664', (175, 181))	('metaplasia-adenocarcinoma', 'Disease', (76, 101))	('lower', 'NegReg', (189, 194))	('esophageal adenocarcinoma', 'Disease', (129, 154))	('c-Met', 'Gene', (160, 165))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))
121439	25588551	In our study, patients with c-Met lowexpression had a better OS than those with c-Met overexpression both in TP plus nimotuzumab group and in TP group.	('lowexpression', 'Var', (34, 47))	('TP', 'Chemical', 'MESH:C011314', (142, 144))	('c-Met', 'Gene', '4233', (28, 33))	('c-Met', 'Gene', (80, 85))	('TP', 'Chemical', 'MESH:C011314', (109, 111))	('c-Met', 'Gene', '4233', (80, 85))	('OS', 'Chemical', 'MESH:D009992', (61, 63))	('nimotuzumab', 'Chemical', 'MESH:C501466', (117, 128))	('patients', 'Species', '9606', (14, 22))	('c-Met', 'Gene', (28, 33))
121444	25588551	However, a study finds out that in lung cancer, amplification of c-Met causes gefitinib resistance by driving ERBB3-dependent activation of PI3K, a pathway thought to be specific to EGFR/ERBB family receptors.	('c-Met', 'Gene', '4233', (65, 70))	('lung cancer', 'Disease', 'MESH:D008175', (35, 46))	('ERBB', 'Gene', '1956;2064;2065', (110, 114))	('ERBB3', 'Gene', '2065', (110, 115))	('gefitinib', 'Chemical', 'MESH:D000077156', (78, 87))	('lung cancer', 'Phenotype', 'HP:0100526', (35, 46))	('causes', 'Reg', (71, 77))	('gefitinib resistance', 'MPA', (78, 98))	('EGFR', 'Gene', '1956', (182, 186))	('ERBB', 'Gene', '1956;2064;2065', (187, 191))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('c-Met', 'Gene', (65, 70))	('activation', 'PosReg', (126, 136))	('lung cancer', 'Disease', (35, 46))	('ERBB3', 'Gene', (110, 115))	('PI3K', 'Pathway', (140, 144))	('ERBB', 'Gene', (110, 114))	('amplification', 'Var', (48, 61))	('EGFR', 'Gene', (182, 186))	('ERBB', 'Gene', (187, 191))
121445	25588551	Recently, another study in colorectal cancer highlights the role of c-Met in mediating primary and secondary resistance to anti-EGFR therapies and encourages the use of c-Met inhibitors in patients displaying resistance as a result of c-Met amplification.	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('c-Met', 'Gene', '4233', (68, 73))	('colorectal cancer', 'Phenotype', 'HP:0003003', (27, 44))	('EGFR', 'Gene', '1956', (128, 132))	('EGFR', 'Gene', (128, 132))	('c-Met', 'Gene', (169, 174))	('colorectal cancer', 'Disease', (27, 44))	('c-Met', 'Gene', '4233', (169, 174))	('c-Met', 'Gene', (235, 240))	('amplification', 'Var', (241, 254))	('c-Met', 'Gene', '4233', (235, 240))	('patients', 'Species', '9606', (189, 197))	('c-Met', 'Gene', (68, 73))	('colorectal cancer', 'Disease', 'MESH:D015179', (27, 44))
121446	25588551	In the breast cancer, c-Met contributes to trastuzumab resistance, as inhibition of c-Met sensitizes cells to trastuzumab-mediated growth inhibition.	('sensitizes', 'Reg', (90, 100))	('trastuzumab', 'Chemical', 'MESH:D000068878', (43, 54))	('breast cancer', 'Disease', 'MESH:D001943', (7, 20))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('breast cancer', 'Disease', (7, 20))	('trastuzumab', 'Chemical', 'MESH:D000068878', (110, 121))	('breast cancer', 'Phenotype', 'HP:0003002', (7, 20))	('c-Met', 'Gene', (84, 89))	('contributes', 'Reg', (28, 39))	('inhibition', 'Var', (70, 80))	('c-Met', 'Gene', '4233', (84, 89))	('c-Met', 'Gene', (22, 27))	('c-Met', 'Gene', '4233', (22, 27))
121447	25588551	High gene copy numbers of c-Met and HGF associate with an increased risk of trastuzumab-based therapy failure in HER2-positive metastatic breast cancer.	('HGF', 'Gene', '3082', (36, 39))	('High gene copy numbers', 'Var', (0, 22))	('HER2', 'Gene', (113, 117))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('trastuzumab', 'Chemical', 'MESH:D000068878', (76, 87))	('breast cancer', 'Disease', 'MESH:D001943', (138, 151))	('HER2', 'Gene', '2064', (113, 117))	('breast cancer', 'Phenotype', 'HP:0003002', (138, 151))	('breast cancer', 'Disease', (138, 151))	('c-Met', 'Gene', (26, 31))	('HGF', 'Gene', (36, 39))	('c-Met', 'Gene', '4233', (26, 31))
121457	24346345	Application of SNP microarrays to the Genome-wide Analysis of Chromosomal Instability in Premalignant Airway Lesions Chromosomal instability is central to the process of carcinogenesis.	('Chromosomal instability', 'Var', (117, 140))	('carcinogenesis', 'Disease', (170, 184))	('Chromosomal Instability', 'Phenotype', 'HP:0040012', (62, 85))	('Chromosomal instability', 'Phenotype', 'HP:0040012', (117, 140))	('carcinogenesis', 'Disease', 'MESH:D063646', (170, 184))
121490	24346345	In LRR, any deviations from zero are evidence for copy number change, whereas BAF refers to a normalized measure of relative signal intensity ratio of the B and A alleles.	('BAF', 'Gene', (78, 81))	('copy number', 'Var', (50, 61))	('BAF', 'Gene', '8815', (78, 81))
121494	24346345	In a rare case of balanced biallelic amplification (e.g., copy number is 4 with AABB alleles), delta-theta as well as BAF show normally distributed plots since there is no allelic imbalance.	('AABB', 'Gene', (80, 84))	('imbalance', 'Phenotype', 'HP:0002172', (180, 189))	('BAF', 'Gene', '8815', (118, 121))	('copy', 'Var', (58, 62))	('BAF', 'Gene', (118, 121))	('biallelic', 'Var', (27, 36))
121509	24346345	Unstained slides with paraffin-embedded sections were hybridized with a number of FISH probes including sequences of PIK3CA, TP63, D5S721-D5S23 (encompassing SEMA5A), CDKN2A, and NKX2-1, according to the previously published protocols.	('CDKN2A', 'Gene', (167, 173))	('CDKN2A', 'Gene', '1029', (167, 173))	('PIK3CA', 'Gene', (117, 123))	('D5S721-D5S23', 'Var', (131, 143))	('paraffin', 'Chemical', 'MESH:D010232', (22, 30))	('TP63', 'Gene', (125, 129))
121546	24346345	In cancer genome studies, finding somatically derived SCAs is critical in order to identify truly carcinogenic variants.	('carcinogenic', 'Disease', 'MESH:D063646', (98, 110))	('carcinogenic', 'Disease', (98, 110))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('variants', 'Var', (111, 119))	('cancer', 'Disease', (3, 9))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
121548	24346345	For example, RNF20 deficiency has been recently reported to trigger genomic instability.	('deficiency', 'Var', (19, 29))	('trigger', 'Reg', (60, 67))	('RNF20', 'Gene', '56254', (13, 18))	('RNF20', 'Gene', (13, 18))	('genomic instability', 'CPA', (68, 87))
121556	24346345	Although a wide variety of chromosomal alterations are thought to be important in the development of invasive cancer, these changes are identified in the airway of current or former smokers without known lung cancer.	('chromosomal alterations', 'Var', (27, 50))	('lung cancer', 'Disease', 'MESH:D008175', (204, 215))	('invasive cancer', 'Disease', 'MESH:D009362', (101, 116))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('lung cancer', 'Disease', (204, 215))	('lung cancer', 'Phenotype', 'HP:0100526', (204, 215))	('invasive cancer', 'Disease', (101, 116))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
121562	24346345	NGS not only provides efficient mutation analysis, but also can detect copy number variations under specific circumstances.	('detect', 'Reg', (64, 70))	('copy number variations', 'Var', (71, 93))	('mutation', 'MPA', (32, 40))	('GS', 'Disease', 'MESH:D011125', (1, 3))
121564	24346345	In conclusion, distinctive genomic variations were successfully detected across the whole genome by SNP arrays even in the heterogeneous cell population found in bronchial premalignancy, by using subtraction of allelic fractions, delta-theta.	('SNP', 'Gene', (100, 103))	('variations', 'Var', (35, 45))	('bronchial premalignancy', 'Disease', 'MESH:D001982', (162, 185))	('detected', 'Reg', (64, 72))	('bronchial premalignancy', 'Disease', (162, 185))
121566	24346345	SNP array technology can expand our ability to assess genomic instability in the airway epithelium as a biomarker of lung cancer risk.	('genomic instability', 'Var', (54, 73))	('lung cancer', 'Disease', (117, 128))	('lung cancer', 'Phenotype', 'HP:0100526', (117, 128))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('lung cancer', 'Disease', 'MESH:D008175', (117, 128))
121584	31310640	Nonetheless, the measurement of ITH by identifying sub-clones using genome profiles requires complex and intensive analytical procedures, such as the calculation of tumor purity, ploidy, variant allele frequency (VAF), cancer cell fraction (CCF), and clustering.	('variant', 'Var', (187, 194))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('cancer', 'Disease', 'MESH:D009369', (219, 225))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('cancer', 'Disease', (219, 225))	('tumor', 'Disease', (165, 170))
121601	31310640	Among the 63 tumor suppressor genes, 12 genes had mutations and a total of 147 mutations were present in tumors with high heterogeneity.	('tumors', 'Disease', (105, 111))	('tumor', 'Disease', (13, 18))	('tumors', 'Disease', 'MESH:D009369', (105, 111))	('mutations', 'Var', (50, 59))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('tumor', 'Disease', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
121623	31310640	Overall, the prediction ability was affected by tumor purity when using the mutation profile, and tended to decline at the setting of low purity.	('tumor', 'Disease', (48, 53))	('decline', 'NegReg', (108, 115))	('prediction', 'MPA', (13, 23))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('mutation', 'Var', (76, 84))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('affected', 'Reg', (36, 44))
121630	31310640	In the group with high tumor heterogeneity, mutations in the tumor suppressor genes and oncogenes were relatively more than in the group with low heterogeneity.	('oncogenes', 'Gene', (88, 97))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('mutations', 'Var', (44, 53))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Disease', (23, 28))	('tumor', 'Disease', (61, 66))
121631	31310640	Most mutations were detected in both high heterogeneity group and low heterogeneity group, with different percentage of mutations in PIK3CA, KRAS and APC.	('APC', 'Disease', 'MESH:D011125', (150, 153))	('KRAS', 'Gene', (141, 145))	('APC', 'Disease', (150, 153))	('PIK3CA', 'Gene', (133, 139))	('KRAS', 'Gene', '3845', (141, 145))	('PIK3CA', 'Gene', '5290', (133, 139))	('mutations', 'Var', (120, 129))
121633	31310640	Previous study shows that mutational heterogeneity in APC and KRAS could cause polyclonality in early colorectal tumorigenesis.	('APC', 'Disease', 'MESH:D011125', (54, 57))	('tumor', 'Disease', (113, 118))	('APC', 'Disease', (54, 57))	('KRAS', 'Gene', (62, 66))	('KRAS', 'Gene', '3845', (62, 66))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('mutational heterogeneity', 'Var', (26, 50))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('cause', 'Reg', (73, 78))
121714	29476168	The average BCP in malignant LNs was remarkably higher than that in benign LNs (57.1% versus 30.8%, P < 0.001).	('malignant', 'Var', (19, 28))	('higher', 'PosReg', (48, 54))	('BCP', 'Gene', (12, 15))	('BCP', 'Gene', '611', (12, 15))
121812	28572862	Hypomethylation of the Long interspersed nucleotide element-1 (LINE-1) repetitive elements, a widely accepted surrogate of overall genomic DNA methylation content, was found to be associated with a poor prognosis in several cancers.	('men', 'Species', '9606', (55, 58))	('cancers', 'Phenotype', 'HP:0002664', (224, 231))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('Hypomethylation', 'Var', (0, 15))	('men', 'Species', '9606', (85, 88))	('cancers', 'Disease', 'MESH:D009369', (224, 231))	('cancers', 'Disease', (224, 231))	('associated with', 'Reg', (180, 195))
121820	28572862	Using logistic regression model, we found that patients with hypomethylated LINE-1 were associated with a 3.5 higher risk of early relapse than hypermethylated ones (OR = 3.51; 95% CI 1.03-12.00).	('LINE-1', 'Gene', (76, 82))	('patients', 'Species', '9606', (47, 55))	('hypomethylated', 'Var', (61, 75))	('early relapse', 'CPA', (125, 138))
121837	28572862	Although HPV positivity represents a strong prognostic factor for both improved survival and reduced risk of relapse, there is a subset of HPV-positive OPSCC patients who still experience poor outcomes.	('positivity', 'Var', (13, 23))	('OPSCC', 'Phenotype', 'HP:0012182', (152, 157))	('HPV-positive', 'Gene', (139, 151))	('OPSCC', 'Disease', (152, 157))	('patients', 'Species', '9606', (158, 166))	('improved', 'PosReg', (71, 79))
121841	28572862	Aberrant DNA hypermethylation represents an early and frequent molecular event during multistep carcinogenesis in OPSCC, especially in long-term tobacco users, along with prolonged alcohol consumption.	('OPSCC', 'Phenotype', 'HP:0012182', (114, 119))	('carcinogenesis', 'Disease', 'MESH:D063646', (96, 110))	('tobacco', 'Species', '4097', (145, 152))	('alcohol', 'Chemical', 'MESH:D000438', (181, 188))	('carcinogenesis', 'Disease', (96, 110))	('Aberrant DNA hypermethylation', 'Var', (0, 29))	('OPSCC', 'Disease', (114, 119))	('hypermethylation', 'Var', (13, 29))	('prolonged alcohol consumption', 'Phenotype', 'HP:0030955', (171, 200))
121843	28572862	Besides gene-specific hypermethylation, genome-wide hypomethylation might contribute to tumorigenesis and cancer progression by promoting genomic instability, reactivating endogenous parasitic sequences, and inducing the expression of oncogenes.	('endogenous parasitic sequences', 'MPA', (172, 202))	('genome-wide', 'Var', (40, 51))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('contribute', 'Reg', (74, 84))	('reactivating', 'Reg', (159, 171))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('oncogenes', 'Protein', (235, 244))	('promoting', 'PosReg', (128, 137))	('cancer', 'Disease', (106, 112))	('inducing', 'Reg', (208, 216))	('hypomethylation', 'Var', (52, 67))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('expression', 'MPA', (221, 231))	('genomic instability', 'MPA', (138, 157))	('tumor', 'Disease', (88, 93))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
121845	28572862	These findings further validate the role of DNA methylation in maintaining the stability of the human genome and the suppression of transposable elements in mammalian cells.	('human', 'Species', '9606', (96, 101))	('men', 'Species', '9606', (148, 151))	('mammalian', 'Species', '9606', (157, 166))	('stability', 'CPA', (79, 88))	('methylation', 'Var', (48, 59))
121847	28572862	Along this line, hypomethylation of the long interspersed nucleotide element-1 (LINE-1) repetitive elements, a widely accepted surrogate of overall genomic DNA methylation content, has been associated with a poorer overall and/or progression-free survival in many different tumor types.	('progression-free survival', 'CPA', (230, 255))	('hypomethylation', 'Var', (17, 32))	('overall', 'CPA', (215, 222))	('men', 'Species', '9606', (72, 75))	('tumor', 'Disease', 'MESH:D009369', (274, 279))	('poorer', 'NegReg', (208, 214))	('associated', 'Reg', (190, 200))	('tumor', 'Phenotype', 'HP:0002664', (274, 279))	('tumor', 'Disease', (274, 279))	('men', 'Species', '9606', (102, 105))
121848	28572862	However, LINE-1 hypomethylation also correlated with improved overall survival in several malignancies, thus suggesting that the underlying biological effects of LINE-1 hypomethylation on patient outcome may depend on tumor histotype.	('malignancies', 'Disease', (90, 102))	('overall', 'MPA', (62, 69))	('LINE-1', 'Gene', (9, 15))	('patient', 'Species', '9606', (188, 195))	('tumor', 'Disease', 'MESH:D009369', (218, 223))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('hypomethylation', 'Var', (16, 31))	('malignancies', 'Disease', 'MESH:D009369', (90, 102))	('tumor', 'Disease', (218, 223))	('improved', 'PosReg', (53, 61))
121850	28572862	On these grounds, we designed a retrospective case-control study aimed at evaluating whether LINE-1 methylation could represent a useful prognostic molecular marker in predicting early tumor relapse in locally advanced OPSCC, in order to improve the clinical management of the disease.	('tumor', 'Disease', (185, 190))	('OPSCC', 'Phenotype', 'HP:0012182', (219, 224))	('men', 'Species', '9606', (265, 268))	('LINE-1', 'Gene', (93, 99))	('locally advanced OPSCC', 'Disease', (202, 224))	('methylation', 'Var', (100, 111))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))
121879	28572862	Using information on HPV16 status and smoking habits (current smoking was considered as a proxy of smoking >20 pack year), OPSCC were categorized as low risk of early relapse (non-smokers HPV16-positive), intermediate risk (smokers HPV16-positive or non-smokers HPV16-negative), and high risk (smokers HPV16-negative).	('HPV16', 'Species', '333760', (232, 237))	('HPV16', 'Species', '333760', (188, 193))	('early relapse', 'Disease', (161, 174))	('HPV16', 'Species', '333760', (21, 26))	('HPV16', 'Species', '333760', (262, 267))	('HPV16', 'Species', '333760', (302, 307))	('OPSCC', 'Phenotype', 'HP:0012182', (123, 128))	('HPV16-positive', 'Var', (232, 246))
121882	28572862	The HPV16 E6 DNA region was detected in 18 of 77 OPSCC patients (23.4%).	('OPSCC', 'Phenotype', 'HP:0012182', (49, 54))	('HPV16', 'Species', '333760', (4, 9))	('HPV16', 'Gene', (4, 9))	('patients', 'Species', '9606', (55, 63))	('E6 DNA', 'Var', (10, 16))
121883	28572862	Although HPV16 infection appeared to have no effect on the likelihood of early tumor relapse (p = 0.58), the percentage of OPSCC patients positive for HPV16 E6 DNA was higher in controls when compared to cases.	('HPV16', 'Species', '333760', (151, 156))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('tumor', 'Disease', (79, 84))	('patients', 'Species', '9606', (129, 137))	('HPV16 infection', 'Disease', 'MESH:D007239', (9, 24))	('positive', 'Reg', (138, 146))	('HPV16 infection', 'Disease', (9, 24))	('higher', 'PosReg', (168, 174))	('E6 DNA', 'Var', (157, 163))	('HPV16', 'Gene', (151, 156))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('OPSCC', 'Phenotype', 'HP:0012182', (123, 128))	('HPV16', 'Species', '333760', (9, 14))
121897	28572862	This is the first study showing that methylation of LINE-1 repetitive elements predicts the risk of early post-treatment relapse in OPSCC patients.	('men', 'Species', '9606', (73, 76))	('methylation', 'Var', (37, 48))	('OPSCC', 'Phenotype', 'HP:0012182', (132, 137))	('OPSCC', 'Disease', (132, 137))	('men', 'Species', '9606', (116, 119))	('patients', 'Species', '9606', (138, 146))	('predicts', 'Reg', (79, 87))
121914	28572862	Interestingly, the association between smoking habits and LINE-1 hypomethylation was stronger in HPV16-negative OPSCC cases, where tobacco exposure and alcohol consumption represent the major etiologic risk factor.	('OPSCC', 'Disease', (112, 117))	('stronger', 'PosReg', (85, 93))	('hypomethylation', 'Var', (65, 80))	('OPSCC', 'Phenotype', 'HP:0012182', (112, 117))	('HPV16', 'Species', '333760', (97, 102))	('alcohol', 'Chemical', 'MESH:D000438', (152, 159))	('tobacco', 'Species', '4097', (131, 138))	('HPV16-negative', 'Gene', (97, 111))
121916	28572862	Thus, within the poor prognosis of HPV16-negative tumors, low LINE-1 methylation could identify a subset of particularly high-risk patients that could benefit from enhanced post-treatment surveillance.	('patients', 'Species', '9606', (131, 139))	('HPV16', 'Species', '333760', (35, 40))	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('men', 'Species', '9606', (183, 186))	('low', 'NegReg', (58, 61))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('methylation', 'Var', (69, 80))	('LINE-1', 'Gene', (62, 68))	('tumors', 'Disease', (50, 56))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))
121917	28572862	These findings may highlight hypomethylation of LINE-1 as a promising biomarker for prospective studies specifically focused on HPV-negative OPSCC patients.	('OPSCC', 'Phenotype', 'HP:0012182', (141, 146))	('hypomethylation', 'Var', (29, 44))	('patients', 'Species', '9606', (147, 155))	('OPSCC', 'Disease', (141, 146))
121920	28572862	However, some studies suggest LINE-1 hypomethylation may have itself some biologic effects in promoting tumor progression.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('promoting', 'PosReg', (94, 103))	('tumor', 'Disease', (104, 109))	('LINE-1', 'Gene', (30, 36))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('hypomethylation', 'Var', (37, 52))
121921	28572862	This would occur through transcription of specific genomic portions within the promoter of hypomethylated LINE-1 elements that can lead to the aberrant expression of proto-oncogenes and/or non-coding RNA able to enhance the tumor metastatic potential.	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('enhance', 'PosReg', (212, 219))	('tumor', 'Disease', (224, 229))	('non-coding RNA', 'Var', (189, 203))	('expression', 'MPA', (152, 162))	('men', 'Species', '9606', (116, 119))	('lead to', 'Reg', (131, 138))	('tumor', 'Disease', 'MESH:D009369', (224, 229))
121922	28572862	Although our findings may suggest a role for LINE-1 elements in tumor progression, further studies are required to specifically investigate the potential mechanisms by which genome-wide DNA hypomethylation may affect the clinical course of OPSCC, especially in HPV-negative patients.	('affect', 'Reg', (210, 216))	('men', 'Species', '9606', (55, 58))	('tumor', 'Disease', (64, 69))	('patients', 'Species', '9606', (274, 282))	('OPSCC', 'Disease', (240, 245))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('hypomethylation', 'Var', (190, 205))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('OPSCC', 'Phenotype', 'HP:0012182', (240, 245))
121925	28572862	Therefore, future prospective studies are warranted to validate the prognostic potential of LINE-1 methylation in a larger cohort of OPSCC patients.	('methylation', 'Var', (99, 110))	('OPSCC', 'Phenotype', 'HP:0012182', (133, 138))	('OPSCC', 'Disease', (133, 138))	('patients', 'Species', '9606', (139, 147))
121927	28572862	In summary, our results highlight the role of LINE-1 hypomethylation in identifying OPSCC patients at higher risk for early relapse, independently of other classic risk factors.	('OPSCC', 'Phenotype', 'HP:0012182', (84, 89))	('OPSCC', 'Disease', (84, 89))	('patients', 'Species', '9606', (90, 98))	('hypomethylation', 'Var', (53, 68))
122002	27446558	A 60-year old man was diagnosed with SCC of the mandible (T4N0M0, stage IVA) and underwent segmental mandibulotomy, modified radical neck dissection and reconstruction with fibular osteocutaneous free flaps.	('SCC', 'Gene', '6317', (37, 40))	('osteocutaneous free flaps', 'Disease', (181, 206))	('IVA', 'Disease', (72, 75))	('man', 'Species', '9606', (14, 17))	('man', 'Species', '9606', (48, 51))	('T4N0M0', 'Var', (58, 64))	('osteocutaneous free flaps', 'Disease', 'MESH:D000070600', (181, 206))	('SCC', 'Gene', (37, 40))	('man', 'Species', '9606', (101, 104))	('IVA', 'Disease', 'MESH:C538167', (72, 75))
122011	27446558	A phase III trial of the Radiation Therapy Oncology Group indicated that EGFR expression, which varied considerably among HNSCCs, was a strong independent prognostic indicator for OS and disease-free survival and a robust predictor of locoregional relapse, and that blockade of EGFR signaling sensitizes cells to the effects of radiation.	('blockade', 'Var', (266, 274))	('EGFR', 'Gene', '1956', (278, 282))	('EGFR', 'Gene', '1956', (73, 77))	('Oncology', 'Phenotype', 'HP:0002664', (43, 51))	('OS', 'Chemical', '-', (180, 182))	('sensitizes', 'Reg', (293, 303))	('EGFR', 'Gene', (278, 282))	('locoregional relapse', 'CPA', (235, 255))	('EGFR', 'Gene', (73, 77))	('SCC', 'Gene', (124, 127))	('SCC', 'Gene', '6317', (124, 127))	('HNSCC', 'Phenotype', 'HP:0012288', (122, 127))
122013	27446558	From these reports, inhibition of EGFR has shown strong clinical evidence of improving clinical outcome.	('EGFR', 'Gene', (34, 38))	('inhibition', 'Var', (20, 30))	('improving', 'PosReg', (77, 86))	('clinical outcome', 'CPA', (87, 103))	('EGFR', 'Gene', '1956', (34, 38))
122016	27446558	Specifically, cetuximab therapy was shown to result in improved 1-year OS compared to the 1-year OS of the non-cetuximab therapy group using a historical-control study.	('improved', 'PosReg', (55, 63))	('cetuximab', 'Chemical', 'MESH:D000068818', (111, 120))	('OS', 'Chemical', '-', (97, 99))	('cetuximab', 'Var', (14, 23))	('OS', 'Chemical', '-', (71, 73))	('cetuximab', 'Chemical', 'MESH:D000068818', (14, 23))
122076	31093356	In this regard, aberrations of PI3K pathway have important clinical implications in the treatment of HNSCC.	('HNSCC', 'Disease', (101, 106))	('HNSCC', 'Phenotype', 'HP:0012288', (101, 106))	('PI3', 'Gene', '5266', (31, 34))	('aberrations', 'Var', (16, 27))	('PI3', 'Gene', (31, 34))
122086	31093356	In particular, HPV-related HNSCC frequently harbors mutations in the helical domain of PIK3CA, yet its biological significance has not been fully elucidated.	('mutations', 'Var', (52, 61))	('HNSCC', 'Phenotype', 'HP:0012288', (27, 32))	('harbors', 'Reg', (44, 51))	('HPV', 'Species', '10566', (15, 18))	('PIK3CA', 'Gene', (87, 93))	('HPV-related HNSCC', 'Disease', (15, 32))
122090	31093356	For class IA PI3K, there are three variants of catalytic subunit, p110alpha, p110beta and p110delta (encoded by PIK3CA, PIK3CB and PIK3CD), and five variants of regulatory subunit, p85alpha, p55alpha, p50alpha (encoded by PIK3R1 and splice variants), p85beta and p55delta (encoded by PIK3R2 and PIK3R3).	('p110delta', 'Gene', '5293', (90, 99))	('p85beta', 'Gene', '5296', (251, 258))	('PIK3R3', 'Gene', (295, 301))	('p110beta', 'Gene', (77, 85))	('p85beta', 'Gene', (251, 258))	('PIK3CD', 'Gene', '5293', (131, 137))	('PIK3R1', 'Gene', '5295', (222, 228))	('p55alpha', 'Var', (191, 199))	('p110beta', 'Gene', '5291', (77, 85))	('PIK3R2', 'Gene', (284, 290))	('PIK3CD', 'Gene', (131, 137))	('PI3', 'Gene', '5266', (13, 16))	('p50alpha', 'Var', (201, 209))	('PIK3R1', 'Gene', (222, 228))	('p85alpha', 'Gene', '5295', (181, 189))	('p110delta', 'Gene', (90, 99))	('PIK3R2', 'Gene', '5296', (284, 290))	('PIK3R3', 'Gene', '8503', (295, 301))	('p110alpha', 'Gene', (66, 75))	('PIK3CB', 'Gene', (120, 126))	('p110alpha', 'Gene', '5290', (66, 75))	('PIK3CB', 'Gene', '5291', (120, 126))	('p55delta', 'Var', (263, 271))	('PI3', 'Gene', (13, 16))	('p85alpha', 'Gene', (181, 189))
122117	31093356	Receptor dimerization stimulates tyrosine kinase activity in C terminal domain and initiates downstream phosphorylation cascade through PI3K-Akt-mTOR, Raf-MEK-MAP kinase or JAK/STAT pathways (Fig.	('stimulates', 'PosReg', (22, 32))	('dimerization', 'Var', (9, 21))	('mTOR', 'Gene', (145, 149))	('MEK', 'Gene', (155, 158))	('JAK/STAT pathways', 'Pathway', (173, 190))	('MEK', 'Gene', '5609', (155, 158))	('mTOR', 'Gene', '2475', (145, 149))	('PI3', 'Gene', '5266', (136, 139))	('Raf', 'Gene', (151, 154))	('tyrosine kinase activity in', 'MPA', (33, 60))	('Akt', 'Gene', '207', (141, 144))	('PI3', 'Gene', (136, 139))	('Raf', 'Gene', '22882', (151, 154))	('Akt', 'Gene', (141, 144))
122124	31093356	A well-known mutation of EGFR, T790M, enhances affinity of the kinase pocket for ATP, which competitively blocks binding of tyrosine kinase inhibitors.	('T790M', 'Var', (31, 36))	('EGFR', 'Gene', (25, 29))	('T790M', 'Mutation', 'rs121434569', (31, 36))	('blocks', 'NegReg', (106, 112))	('affinity', 'MPA', (47, 55))	('enhances', 'PosReg', (38, 46))	('EGFR', 'Gene', '1956', (25, 29))	('binding', 'Interaction', (113, 120))	('ATP', 'Chemical', 'MESH:D000255', (81, 84))
122125	31093356	For example, amplification of BRAF via copy number gains was found in 8% of the tumor samples from metastatic melanoma treated with BRAF inhibitors.	('melanoma', 'Disease', 'MESH:D008545', (110, 118))	('BRAF', 'Gene', (132, 136))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('melanoma', 'Disease', (110, 118))	('melanoma', 'Phenotype', 'HP:0002861', (110, 118))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('found', 'Reg', (61, 66))	('tumor', 'Disease', (80, 85))	('BRAF', 'Gene', (30, 34))	('BRAF', 'Gene', '673', (30, 34))	('amplification', 'Var', (13, 26))	('BRAF', 'Gene', '673', (132, 136))	('copy number gains', 'Var', (39, 56))
122126	31093356	Studies with HNSCC demonstrated as well that copy number alteration by amplification of 7p11.2 accounts for a number of cases of EGFR activation.	('copy number alteration', 'Var', (45, 67))	('activation', 'PosReg', (134, 144))	('EGFR', 'Gene', (129, 133))	('EGFR', 'Gene', '1956', (129, 133))	('7p11.2', 'Gene', (88, 94))	('HNSCC', 'Phenotype', 'HP:0012288', (13, 18))
122127	31093356	It was also hypothesized that ligand overexpression or receptor cross phosphorylation triggers uncontrolled EGFR hyperactivity.	('overexpression', 'PosReg', (37, 51))	('EGFR', 'Gene', '1956', (108, 112))	('EGFR', 'Gene', (108, 112))	('hyperactivity', 'Disease', 'MESH:D006948', (113, 126))	('hyperactivity', 'Disease', (113, 126))	('hyperactivity', 'Phenotype', 'HP:0000752', (113, 126))	('cross phosphorylation', 'Var', (64, 85))	('triggers', 'Reg', (86, 94))
122130	31093356	In consistent with this theory, whole-exome sequencing of melanoma cells that are resistant to BRAF inhibitor revealed diverse genetic alterations in the downstream MAPK pathway.	('melanoma', 'Disease', 'MESH:D008545', (58, 66))	('BRAF', 'Gene', '673', (95, 99))	('BRAF', 'Gene', (95, 99))	('genetic alterations', 'Var', (127, 146))	('melanoma', 'Phenotype', 'HP:0002861', (58, 66))	('melanoma', 'Disease', (58, 66))
122131	31093356	Similarly, KRAS amplification or mutation was found in tumor samples from colorectal cancer patients who developed resistance to EGFR inhibitors.	('KRAS', 'Gene', (11, 15))	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('mutation', 'Var', (33, 41))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('colorectal cancer', 'Disease', 'MESH:D015179', (74, 91))	('KRAS', 'Gene', '3845', (11, 15))	('patients', 'Species', '9606', (92, 100))	('tumor', 'Disease', (55, 60))	('EGFR', 'Gene', '1956', (129, 133))	('colorectal cancer', 'Phenotype', 'HP:0003003', (74, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('EGFR', 'Gene', (129, 133))	('colorectal cancer', 'Disease', (74, 91))	('found', 'Reg', (46, 51))
122132	31093356	Relevant to our review, compensatory activation of downstream pathway, mainly PI3K, has been proposed as one of the major resistance mechanisms to EGFR inhibitors in HNSCC.	('inhibitors', 'Var', (152, 162))	('EGFR', 'Gene', (147, 151))	('PI3', 'Gene', '5266', (78, 81))	('HNSCC', 'Phenotype', 'HP:0012288', (166, 171))	('HNSCC', 'Disease', (166, 171))	('activation', 'PosReg', (37, 47))	('PI3', 'Gene', (78, 81))	('downstream pathway', 'Pathway', (51, 69))	('EGFR', 'Gene', '1956', (147, 151))
122134	31093356	66% of HNSCC harbor genomic alterations in one of the major components of PI3K pathway.	('HNSCC', 'Disease', (7, 12))	('PI3', 'Gene', '5266', (74, 77))	('HNSCC', 'Phenotype', 'HP:0012288', (7, 12))	('genomic alterations', 'Var', (20, 39))	('PI3', 'Gene', (74, 77))
122135	31093356	An analysis of whole-exome sequencing of 151 HNSCC tumors revealed that PI3K is the most commonly mutated mitogenic pathway among PI3K, JAK/STAT and MAPK and that presence of multiple mutations in PI3K signaling pathway is correlated with more advanced disease.	('mutated', 'Reg', (98, 105))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('mitogenic pathway', 'Pathway', (106, 123))	('PI3', 'Gene', (72, 75))	('HNSCC', 'Phenotype', 'HP:0012288', (45, 50))	('PI3', 'Gene', '5266', (130, 133))	('correlated with', 'Reg', (223, 238))	('presence', 'Var', (163, 171))	('HNSCC tumors', 'Disease', (45, 57))	('PI3', 'Gene', (197, 200))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('PI3', 'Gene', (130, 133))	('PI3', 'Gene', '5266', (72, 75))	('HNSCC tumors', 'Disease', 'MESH:D000077195', (45, 57))	('more advanced disease', 'Disease', (239, 260))	('PI3', 'Gene', '5266', (197, 200))
122136	31093356	Physiologic data confirms that an aberrant PI3K-mTOR pathway is associated with cell motility, invasion and metastasis.	('associated', 'Reg', (64, 74))	('PI3', 'Gene', '5266', (43, 46))	('invasion', 'CPA', (95, 103))	('mTOR', 'Gene', '2475', (48, 52))	('mTOR', 'Gene', (48, 52))	('aberrant', 'Var', (34, 42))	('PI3', 'Gene', (43, 46))	('cell motility', 'CPA', (80, 93))
122140	31093356	PIK3CA mutations in HPV-positive HNSCCs are concentrated in helical domain, whereas mutations are more spread out in HPV-negative diseases.	('HPV', 'Species', '10566', (20, 23))	('HPV', 'Species', '10566', (117, 120))	('HNSCC', 'Phenotype', 'HP:0012288', (33, 38))	('PIK3CA', 'Gene', (0, 6))	('mutations', 'Var', (7, 16))
122141	31093356	Frequency of these 'hotspot' mutations is also higher in HPV-positive oropharyngeal cancers.	('HPV-positive oropharyngeal cancers', 'Disease', (57, 91))	('HPV-positive oropharyngeal cancers', 'Disease', 'MESH:D009959', (57, 91))	('cancers', 'Phenotype', 'HP:0002664', (84, 91))	('mutations', 'Var', (29, 38))	('higher', 'Reg', (47, 53))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))
122142	31093356	Targeting PIK3CA alteration in human squamous cell xenografts has demonstrated susceptibility to treatment in vitro and in vivo, leading a path for its clinical implication.	('PIK3CA', 'Gene', (10, 16))	('alteration', 'Var', (17, 27))	('human', 'Species', '9606', (31, 36))
122144	31093356	In a number of the patient-derived xenografts harboring E545K and H1047R mutations, PI3K inhibitors were effective in achieving control of tumor growth.	('PI3', 'Gene', '5266', (84, 87))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('patient', 'Species', '9606', (19, 26))	('E545K', 'Mutation', 'rs104886003', (56, 61))	('H1047R', 'Mutation', 'rs121913279', (66, 72))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('PI3', 'Gene', (84, 87))	('E545K', 'Var', (56, 61))	('H1047R', 'Var', (66, 72))
122145	31093356	Additionally, activation of PI3K/mTOR pathway from either mutation or gene amplification was positively correlated with tumor susceptibility to PI3K inhibitors in xenograft models.	('activation', 'PosReg', (14, 24))	('gene amplification', 'Var', (70, 88))	('mTOR', 'Gene', '2475', (33, 37))	('mutation', 'Var', (58, 66))	('mTOR', 'Gene', (33, 37))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('PI3', 'Gene', '5266', (144, 147))	('PI3', 'Gene', '5266', (28, 31))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('PI3', 'Gene', (144, 147))	('PI3', 'Gene', (28, 31))	('tumor', 'Disease', (120, 125))
122146	31093356	However, preclinical data also suggested that additional molecular change should interact with PIK3CA alteration for tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('PIK3CA', 'Gene', (95, 101))	('tumor', 'Disease', (117, 122))	('alteration', 'Var', (102, 112))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
122147	31093356	Cell lines engineered to harbor PIK3CA mutations in the 'hotspots' responded more favorably to PI3K/mTOR dual inhibition than PI3K inhibition only, indicating that tumor survival is not strictly dependent on the activated PI3K.	('PI3', 'Gene', '5266', (95, 98))	('tumor', 'Disease', (164, 169))	('mTOR', 'Gene', '2475', (100, 104))	('PI3', 'Gene', '5266', (222, 225))	('favorably', 'PosReg', (82, 91))	('PI3', 'Gene', '5266', (126, 129))	('mutations', 'Var', (39, 48))	('PI3', 'Gene', (95, 98))	('responded', 'MPA', (67, 76))	('PI3', 'Gene', (222, 225))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('PI3', 'Gene', (126, 129))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('mTOR', 'Gene', (100, 104))	('PIK3CA', 'Gene', (32, 38))
122151	31093356	Locations of mutations affect PI3K structure and function, resulting in different responsiveness to inhibition and clinical outcome.	('different', 'Reg', (72, 81))	('PI3', 'Gene', (30, 33))	('structure', 'MPA', (35, 44))	('function', 'MPA', (49, 57))	('affect', 'Reg', (23, 29))	('mutations', 'Var', (13, 22))	('responsiveness to inhibition', 'MPA', (82, 110))	('PI3', 'Gene', '5266', (30, 33))
122153	31093356	Consequently, C terminal truncation or internal deletion of p85 releases p110 from negative regulation and constitutively activates the PI3K pathway.	('p110', 'Gene', '100616443', (73, 77))	('negative regulation', 'MPA', (83, 102))	('p110', 'Gene', (73, 77))	('PI3', 'Gene', (136, 139))	('PI3', 'Gene', '5266', (136, 139))	('p85', 'Gene', '5296', (60, 63))	('internal deletion', 'Var', (39, 56))	('activates', 'PosReg', (122, 131))	('releases', 'PosReg', (64, 72))	('p85', 'Gene', (60, 63))
122154	31093356	Additionally, as frequently mutated E542 and E545 in p110 are located at a distance from the kinase domain, it is plausible that mutations at these spots alter regulatory control of p85.	('E542', 'Var', (36, 40))	('p85', 'Gene', (182, 185))	('regulatory control', 'MPA', (160, 178))	('mutations', 'Var', (129, 138))	('alter', 'Reg', (154, 159))	('mutated E542', 'Var', (28, 40))	('p110', 'Gene', '100616443', (53, 57))	('p110', 'Gene', (53, 57))	('p85', 'Gene', '5296', (182, 185))	('E545', 'Var', (45, 49))
122155	31093356	Indeed, E545K mutation in the helical domain of p110 changes acid-base charge and disrupts inhibitory interaction between p85 and p110.	('E545K', 'Var', (8, 13))	('p110', 'Gene', '100616443', (48, 52))	('p85', 'Gene', (122, 125))	('disrupts', 'NegReg', (82, 90))	('changes', 'Reg', (53, 60))	('p110', 'Gene', (48, 52))	('acid-base charge', 'MPA', (61, 77))	('E545K', 'Mutation', 'rs104886003', (8, 13))	('inhibitory interaction', 'MPA', (91, 113))	('p110', 'Gene', '100616443', (130, 134))	('p110', 'Gene', (130, 134))	('p85', 'Gene', '5296', (122, 125))
122156	31093356	H1047R mutation in the kinase domain, on the other hand, shifts orientation of the residue and changes conformation of the two loops of kinase that contact cell membrane.	('orientation', 'MPA', (64, 75))	('changes', 'Reg', (95, 102))	('conformation', 'MPA', (103, 115))	('H1047R', 'Mutation', 'rs121913279', (0, 6))	('shifts', 'Reg', (57, 63))	('H1047R', 'Var', (0, 6))
122162	31093356	Although not as frequent as in PIK3CA, mutations in PIK3R1 (encoding p85alpha) can be found in 3% of HPV-positive HNSCC and 1% of HPV-negative HNSCC according to TCGA data.	('found', 'Reg', (86, 91))	('HPV-positive', 'Disease', (101, 113))	('PIK3R1', 'Gene', '5295', (52, 58))	('PIK3R1', 'Gene', (52, 58))	('HNSCC', 'Phenotype', 'HP:0012288', (114, 119))	('mutations', 'Var', (39, 48))	('p85alpha', 'Gene', (69, 77))	('HPV', 'Species', '10566', (101, 104))	('HPV', 'Species', '10566', (130, 133))	('HNSCC', 'Phenotype', 'HP:0012288', (143, 148))	('p85alpha', 'Gene', '5295', (69, 77))
122163	31093356	Alteration of PTEN tumor suppressor gene is among the frequently found somatic mutations in human cancers as well as germline mutations causing hereditary cancer syndromes.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('PTEN', 'Gene', (14, 18))	('PTEN', 'Gene', '5728', (14, 18))	('hereditary cancer syndromes', 'Disease', (144, 171))	('hereditary cancer syndromes', 'Disease', 'MESH:D009386', (144, 171))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('Alteration', 'Var', (0, 10))	('cancers', 'Phenotype', 'HP:0002664', (98, 105))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('cancers', 'Disease', 'MESH:D009369', (98, 105))	('cancers', 'Disease', (98, 105))	('tumor', 'Disease', (19, 24))	('human', 'Species', '9606', (92, 97))
122166	31093356	Clinical data has shown that loss of PTEN expression is a poor prognostic marker in oral squamous cell cancer.	('oral squamous cell cancer', 'Disease', (84, 109))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('expression', 'MPA', (42, 52))	('PTEN', 'Gene', (37, 41))	('loss', 'Var', (29, 33))	('PTEN', 'Gene', '5728', (37, 41))	('oral squamous cell cancer', 'Disease', 'MESH:D002294', (84, 109))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (89, 109))
122175	31093356	In vivo, buparlisib inhibited PI3K activity in cell lines with wild-type PIK3CA as well as mutant form harboring any hotspot mutation of E542K, E545K or H1047R.	('H1047R', 'Var', (153, 159))	('E542K', 'Mutation', 'rs121913273', (137, 142))	('E545K', 'Mutation', 'rs104886003', (144, 149))	('E545K', 'Var', (144, 149))	('PI3', 'Gene', (30, 33))	('buparlisib', 'Chemical', 'MESH:C571178', (9, 19))	('inhibited', 'NegReg', (20, 29))	('H1047R', 'Mutation', 'rs121913279', (153, 159))	('E542K', 'Var', (137, 142))	('PI3', 'Gene', '5266', (30, 33))
122178	31093356	In this trial, comparable proportions of the patients had a mutation in PIK3CA, 11% and 13% in the buparlisib and control arm, respectively.	('buparlisib', 'Chemical', 'MESH:C571178', (99, 109))	('mutation', 'Var', (60, 68))	('patients', 'Species', '9606', (45, 53))	('PIK3CA', 'Gene', (72, 78))
122186	31093356	PX-866 also effectively overcame resistance to EGFR inhibitor in human lung cancer cells lacking expression of ErbB-3.	('human', 'Species', '9606', (65, 70))	('lung cancer', 'Phenotype', 'HP:0100526', (71, 82))	('resistance', 'MPA', (33, 43))	('PX-866', 'Var', (0, 6))	('lung cancer', 'Disease', 'MESH:D008175', (71, 82))	('overcame', 'PosReg', (24, 32))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('ErbB-3', 'Gene', '2065', (111, 117))	('EGFR', 'Gene', '1956', (47, 51))	('PX-866', 'Chemical', 'MESH:C496788', (0, 6))	('lung cancer', 'Disease', (71, 82))	('EGFR', 'Gene', (47, 51))	('ErbB-3', 'Gene', (111, 117))
122187	31093356	PX-866 induced cessation of tumor growth in xenograft models of human HNSCC which included one case of PIK3CA gene amplification and another case of E545K.	('human', 'Species', '9606', (64, 69))	('tumor', 'Disease', (28, 33))	('amplification', 'Var', (115, 128))	('PX-866', 'Gene', (0, 6))	('HNSCC', 'Phenotype', 'HP:0012288', (70, 75))	('PIK3CA', 'Gene', (103, 109))	('cessation', 'NegReg', (15, 24))	('E545K', 'Mutation', 'rs104886003', (149, 154))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('PX-866', 'Chemical', 'MESH:C496788', (0, 6))	('E545K', 'Var', (149, 154))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
122189	31093356	In phase II clinical trials, combined use of PX-866 with either cetuximab or docetaxel failed to achieve improved PFS or OS compared to each treatment alone.	('PFS', 'Disease', (114, 117))	('OS', 'Chemical', '-', (121, 123))	('PX-866', 'Var', (45, 51))	('docetaxel', 'Chemical', 'MESH:D000077143', (77, 86))	('PX-866', 'Chemical', 'MESH:C496788', (45, 51))	('cetuximab', 'Chemical', 'MESH:D000068818', (64, 73))
122192	31093356	The molecule inhibits wild-type PI3Kalpha (IC50 = 4.6 nmol/L) as well as PI3Kalpha with common PI3KCA mutations, such as E545K or H1047R (IC50 = 4 nmol/L), more potently than PI3Kdelta (IC50 = 290 nmol/L) or PI3Kgamma (IC50 = 250 nmol/L).	('PI3Kgamma', 'Gene', (208, 217))	('PI3', 'Gene', '5266', (73, 76))	('PI3Kalpha', 'Gene', (32, 41))	('PI3', 'Gene', '5266', (32, 35))	('PI3', 'Gene', '5266', (208, 211))	('inhibits', 'NegReg', (13, 21))	('PI3', 'Gene', '5266', (95, 98))	('PI3Kdelta', 'Gene', '5293', (175, 184))	('PI3Kalpha', 'Gene', '5290', (73, 82))	('H1047R', 'Var', (130, 136))	('PI3', 'Gene', '5266', (175, 178))	('H1047R', 'Mutation', 'rs121913279', (130, 136))	('PI3Kgamma', 'Gene', '5294', (208, 217))	('PI3', 'Gene', (73, 76))	('PI3', 'Gene', (32, 35))	('PI3', 'Gene', (208, 211))	('E545K', 'Mutation', 'rs104886003', (121, 126))	('PI3', 'Gene', (95, 98))	('PI3', 'Gene', (175, 178))	('PI3Kalpha', 'Gene', '5290', (32, 41))	('PI3Kdelta', 'Gene', (175, 184))	('PI3Kalpha', 'Gene', (73, 82))	('E545K', 'Var', (121, 126))
122193	31093356	Preclinical data also suggested that PIK3CA mutation makes cancer cells more vulnerable to PI3K inhibition by alpelisib.	('mutation', 'Var', (44, 52))	('PI3', 'Gene', (91, 94))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('vulnerable', 'MPA', (77, 87))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('alpelisib', 'Chemical', 'MESH:C585539', (110, 119))	('PI3', 'Gene', '5266', (91, 94))	('PIK3CA', 'Gene', (37, 43))
122194	31093356	In vitro pharmacologic sensitivity screen among a broad panel of cancer cell lines revealed that sensitivity to alpelisib was positively associated with the presence of PIK3CA mutation, amplification or copy number gain, which was confirmed by an in vivo study using mouse models.	('amplification', 'Var', (186, 199))	('associated', 'Reg', (137, 147))	('copy number gain', 'Var', (203, 219))	('alpelisib', 'Chemical', 'MESH:C585539', (112, 121))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('presence', 'Var', (157, 165))	('sensitivity', 'MPA', (97, 108))	('mouse', 'Species', '10090', (267, 272))	('mutation', 'Var', (176, 184))	('PIK3CA', 'Gene', (169, 175))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))
122195	31093356	In a HNSCC cell line (Cal-33) and a patient-derived xenograft model, both harboring H1047R mutation in PIK3CA, administration of alpelisib using nanoparticles induced inhibition of tumor growth and sensitization to radiation.	('H1047R', 'Var', (84, 90))	('alpelisib', 'Chemical', 'MESH:C585539', (129, 138))	('tumor', 'Disease', (181, 186))	('inhibition', 'NegReg', (167, 177))	('PIK3CA', 'Gene', (103, 109))	('sensitization to radiation', 'CPA', (198, 224))	('HNSCC', 'Phenotype', 'HP:0012288', (5, 10))	('H1047R', 'Mutation', 'rs121913279', (84, 90))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('a HNSCC', 'CellLine', 'CVCL:5985', (3, 10))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('patient', 'Species', '9606', (36, 43))
122196	31093356	Compared to HNSCC cell lines with wild-type PIK3CA, cell lines with PIK3CA H1047R mutation were more susceptible to antiproliferative effect of alpelisib.	('PIK3CA', 'Gene', (68, 74))	('H1047R', 'Var', (75, 81))	('HNSCC', 'Phenotype', 'HP:0012288', (12, 17))	('alpelisib', 'Chemical', 'MESH:C585539', (144, 153))	('susceptible', 'MPA', (101, 112))	('antiproliferative effect', 'MPA', (116, 140))	('H1047R', 'Mutation', 'rs121913279', (75, 81))
122197	31093356	In another in vivo study, PIK3CA mutation, regardless of its location, was the strongest predictive feature that correlated with favorable response to alpelisib.	('mutation', 'Var', (33, 41))	('PIK3CA', 'Gene', (26, 32))	('alpelisib', 'Chemical', 'MESH:C585539', (151, 160))
122199	31093356	Inhibition of PI3K with alpelisib enhanced tumor sensitivity to cetuximab in HNSCC xenograft models.	('enhanced', 'PosReg', (34, 42))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('alpelisib', 'Chemical', 'MESH:C585539', (24, 33))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('PI3', 'Gene', '5266', (14, 17))	('Inhibition', 'Var', (0, 10))	('HNSCC', 'Phenotype', 'HP:0012288', (77, 82))	('tumor', 'Disease', (43, 48))	('PI3', 'Gene', (14, 17))	('cetuximab', 'Chemical', 'MESH:D000068818', (64, 73))	('alpelisib', 'Gene', (24, 33))
122202	31093356	In a more recent phase I trial of alpelisib, any of complete response (CR), PR or SD was achieved in 13 out of 19 study participants with PIK3CA-mutant HNSCC (NCT01219699).	('HNSCC', 'Phenotype', 'HP:0012288', (152, 157))	('participants', 'Species', '9606', (120, 132))	('PIK3CA-mutant', 'Var', (138, 151))	('CR', 'Chemical', '-', (71, 73))	('alpelisib', 'Chemical', 'MESH:C585539', (34, 43))	('HNSCC', 'Gene', (152, 157))	('SD', 'Disease', 'MESH:D029461', (82, 84))
122205	31093356	It demonstrated superior inhibitory effect in cells with PIK3CA activating mutations over wild-type in breast cancer and non-small cell lung cancer xenografts.	('inhibitory effect', 'MPA', (25, 42))	('lung cancer', 'Phenotype', 'HP:0100526', (136, 147))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (125, 147))	('activating', 'PosReg', (64, 74))	('non-small cell lung cancer', 'Disease', (121, 147))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('breast cancer', 'Disease', 'MESH:D001943', (103, 116))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (121, 147))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('breast cancer', 'Disease', (103, 116))	('breast cancer', 'Phenotype', 'HP:0003002', (103, 116))	('mutations', 'Var', (75, 84))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (121, 147))	('PIK3CA', 'Gene', (57, 63))
122226	31093356	However, no objective response was achieved, nor did PI3KCA mutational status (H1048Y and G1050S) predict treatment success.	('H1048Y', 'Mutation', 'p.H1048Y', (79, 85))	('PI3', 'Gene', (53, 56))	('H1048Y', 'Var', (79, 85))	('G1050S', 'Mutation', 'rs139388758', (90, 96))	('G1050S', 'Var', (90, 96))	('PI3', 'Gene', '5266', (53, 56))
122239	31093356	SF1126 is a peptide-conjugated prodrug of LY294002, with improved water solubility and pharmacokinetics.	('LY294002', 'Var', (42, 50))	('water solubility', 'MPA', (66, 82))	('water', 'Chemical', 'MESH:D014867', (66, 71))	('LY294002', 'Chemical', 'MESH:C085911', (42, 50))	('improved', 'PosReg', (57, 65))	('SF1126', 'Chemical', 'MESH:C526549', (0, 6))
122241	31093356	LY294002 is a pan-PI3K inhibitor, with IC50 values of 720 nmol/L, 306 nmol/L, 1.33 mumol/L and 1.6 mumol/L for PI3Kalpha, PI3Kbeta, PI3Kdelta and PI3Kgamma respectively, and similar IC50 for mTOR (1.5 mumol/L).	('PI3', 'Gene', (132, 135))	('PI3Kalpha', 'Gene', (111, 120))	('PI3', 'Gene', '5266', (122, 125))	('PI3', 'Gene', '5266', (18, 21))	('PI3Kgamma', 'Gene', '5294', (146, 155))	('PI3', 'Gene', (146, 149))	('mTOR', 'Gene', (191, 195))	('PI3Kdelta', 'Gene', (132, 141))	('PI3', 'Gene', '5266', (111, 114))	('PI3Kbeta', 'Gene', (122, 130))	('PI3', 'Gene', (122, 125))	('PI3', 'Gene', (18, 21))	('LY294002', 'Var', (0, 8))	('PI3Kalpha', 'Gene', '5290', (111, 120))	('mTOR', 'Gene', '2475', (191, 195))	('PI3Kgamma', 'Gene', (146, 155))	('PI3', 'Gene', '5266', (132, 135))	('PI3Kbeta', 'Gene', '5291', (122, 130))	('PI3', 'Gene', (111, 114))	('LY294002', 'Chemical', 'MESH:C085911', (0, 8))	('PI3', 'Gene', '5266', (146, 149))	('PI3Kdelta', 'Gene', '5293', (132, 141))
122242	31093356	In a phase I trial, SF1126 as a single agent was effective in maintaining stable diseases in patients with GIST and clear cell renal cancer, and in combination with rituximab decreased absolute lymphocyte count and lymph node/spleen size in CLL.	('clear cell renal cancer', 'Disease', (116, 139))	('absolute lymphocyte count', 'CPA', (185, 210))	('renal cancer', 'Phenotype', 'HP:0009726', (127, 139))	('rituximab', 'Chemical', 'MESH:D000069283', (165, 174))	('GIST', 'Disease', 'MESH:D046152', (107, 111))	('lymph node/spleen size', 'CPA', (215, 237))	('GIST', 'Disease', (107, 111))	('SF1126', 'Var', (20, 26))	('SF1126', 'Chemical', 'MESH:C526549', (20, 26))	('clear cell renal cancer', 'Disease', 'MESH:C538614', (116, 139))	('patients', 'Species', '9606', (93, 101))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('decreased', 'NegReg', (175, 184))
122246	31093356	The inhibitory activity against PI3Kalpha with hotspot mutations, such as E545K and H1047R, are comparatively low (0.6 nmol/L and 0.8 nmol/L).	('H1047R', 'Var', (84, 90))	('H1047R', 'Mutation', 'rs121913279', (84, 90))	('inhibitory', 'MPA', (4, 14))	('PI3Kalpha', 'Gene', '5290', (32, 41))	('PI3Kalpha', 'Gene', (32, 41))	('E545K', 'Mutation', 'rs104886003', (74, 79))	('E545K', 'Var', (74, 79))
122247	31093356	Its antitumor activity was demonstrated in in vitro studies using mutant cells harboring E545K or H1047R in PIK3CA as well as wild-type.	('H1047R', 'Mutation', 'rs121913279', (98, 104))	('E545K', 'Mutation', 'rs104886003', (89, 94))	('E545K', 'Var', (89, 94))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('H1047R', 'Var', (98, 104))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('PIK3CA', 'Gene', (108, 114))	('tumor', 'Disease', (8, 13))
122248	31093356	Gedatolisib also inhibited cell proliferation and increased radiosensitivity of human nasopharyngeal cancer cells with PI3K/mTOR hyperactivation.	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('mTOR', 'Gene', '2475', (124, 128))	('PI3', 'Gene', '5266', (119, 122))	('mTOR', 'Gene', (124, 128))	('cancer', 'Disease', (101, 107))	('cell proliferation', 'CPA', (27, 45))	('increased', 'PosReg', (50, 59))	('Gedatolisib', 'Chemical', 'MESH:C549060', (0, 11))	('inhibited', 'NegReg', (17, 26))	('human', 'Species', '9606', (80, 85))	('PI3', 'Gene', (119, 122))	('radiosensitivity', 'CPA', (60, 76))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('nasopharyngeal cancer', 'Phenotype', 'HP:0100630', (86, 107))	('Gedatolisib', 'Var', (0, 11))	('increased radiosensitivity', 'Phenotype', 'HP:0010997', (50, 76))
122254	31093356	HNSCC cell lines with H1047R mutation were more susceptible to inhibition with lower IC50, whereas E545K conferred only slightly increased sensitivity.	('E545K', 'Mutation', 'rs104886003', (99, 104))	('E545K', 'Var', (99, 104))	('H1047R', 'Var', (22, 28))	('lower', 'NegReg', (79, 84))	('HNSCC', 'Phenotype', 'HP:0012288', (0, 5))	('H1047R', 'Mutation', 'rs121913279', (22, 28))	('IC50', 'MPA', (85, 89))
122263	31093356	For cancer cells that developed resistance to PI3K inhibition through alternative pathway activation, concurrent inhibition of HDAC can down-regulate other signaling proteins and circumvent treatment resistance.	('alternative pathway', 'Pathway', (70, 89))	('treatment resistance', 'CPA', (190, 210))	('PI3', 'Gene', (46, 49))	('down-regulate', 'NegReg', (136, 149))	('other signaling proteins', 'MPA', (150, 174))	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('inhibition', 'Var', (113, 123))	('PI3', 'Gene', '5266', (46, 49))	('cancer', 'Disease', 'MESH:D009369', (4, 10))	('HDAC', 'Gene', (127, 131))	('HDAC', 'Gene', '9734', (127, 131))	('cancer', 'Disease', (4, 10))	('circumvent', 'NegReg', (179, 189))
122267	31093356	There is an actively ongoing phase I trial of CUDC-907 for the patients with advanced or relapsed solid tumors (NCT02307240), and another phase I trial for the patients with metastatic or locally advanced thyroid cancer (NCT03002623).	('solid tumors', 'Disease', (98, 110))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('patients', 'Species', '9606', (160, 168))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('NCT02307240', 'Var', (112, 123))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('CUDC-907', 'Chemical', 'MESH:C576940', (46, 54))	('thyroid cancer', 'Phenotype', 'HP:0002890', (205, 219))	('thyroid cancer', 'Disease', (205, 219))	('advanced', 'Disease', (77, 85))	('solid tumors', 'Disease', 'MESH:D009369', (98, 110))	('CUDC-907', 'Gene', (46, 54))	('patients', 'Species', '9606', (63, 71))	('thyroid cancer', 'Disease', 'MESH:D013964', (205, 219))
122268	31093356	It has been well known that inhibitors of mTOR, such as sirolimus, modulate immune system.	('mTOR', 'Gene', '2475', (42, 46))	('mTOR', 'Gene', (42, 46))	('sirolimus', 'Chemical', 'MESH:D020123', (56, 65))	('modulate', 'Reg', (67, 75))	('inhibitors', 'Var', (28, 38))	('immune system', 'CPA', (76, 89))
122271	31093356	Especially, PI3Kgamma and PI3Kdelta are highly expressed in all subtypes of leukocyte, and inhibition of PI3Kgamma suppressed progression of breast cancer in an animal model by inhibiting tumor inflammation and myeloid cell-mediated angiogenesis.	('inhibiting', 'NegReg', (177, 187))	('PI3Kgamma', 'Gene', '5294', (12, 21))	('inhibition', 'Var', (91, 101))	('PI3Kgamma', 'Gene', '5294', (105, 114))	('PI3Kgamma', 'Gene', (105, 114))	('breast cancer', 'Phenotype', 'HP:0003002', (141, 154))	('myeloid cell-mediated angiogenesis', 'CPA', (211, 245))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('tumor inflammation', 'Disease', 'MESH:D007249', (188, 206))	('progression', 'CPA', (126, 137))	('tumor inflammation', 'Disease', (188, 206))	('breast cancer', 'Disease', 'MESH:D001943', (141, 154))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('PI3Kdelta', 'Gene', (26, 35))	('breast cancer', 'Disease', (141, 154))	('PI3Kdelta', 'Gene', '5293', (26, 35))	('suppressed', 'NegReg', (115, 125))	('PI3Kgamma', 'Gene', (12, 21))
122274	31093356	Therefore, inhibition of PI3Kdelta dampens regulatory T cells, enhances activity of cytotoxic T cells and induces tumor regression as shown in animal models of melanoma, lung cancer, thymoma and breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('melanoma', 'Phenotype', 'HP:0002861', (160, 168))	('melanoma', 'Disease', (160, 168))	('lung cancer', 'Disease', 'MESH:D008175', (170, 181))	('inhibition', 'Var', (11, 21))	('thymoma', 'Disease', 'MESH:D013945', (183, 190))	('lung cancer', 'Phenotype', 'HP:0100526', (170, 181))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('dampens', 'NegReg', (35, 42))	('breast cancer', 'Phenotype', 'HP:0003002', (195, 208))	('PI3Kdelta', 'Gene', '5293', (25, 34))	('tumor', 'Disease', (114, 119))	('enhances', 'PosReg', (63, 71))	('thymoma', 'Disease', (183, 190))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('thymoma', 'Phenotype', 'HP:0100522', (183, 190))	('breast cancer', 'Disease', 'MESH:D001943', (195, 208))	('breast cancer', 'Disease', (195, 208))	('melanoma', 'Disease', 'MESH:D008545', (160, 168))	('lung cancer', 'Disease', (170, 181))	('induces', 'Reg', (106, 113))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('PI3Kdelta', 'Gene', (25, 34))	('activity', 'CPA', (72, 80))	('regulatory T cells', 'CPA', (43, 61))
122275	31093356	Various mutations in genes encoding PI3Kdelta may as well lead to immunodeficiency syndromes.	('immunodeficiency', 'Phenotype', 'HP:0002721', (66, 82))	('immunodeficiency syndromes', 'Disease', (66, 92))	('mutations', 'Var', (8, 17))	('lead to', 'Reg', (58, 65))	('immunodeficiency syndromes', 'Disease', 'MESH:D007153', (66, 92))	('PI3Kdelta', 'Gene', '5293', (36, 45))	('PI3Kdelta', 'Gene', (36, 45))
122277	31093356	Interestingly, the level of immune checkpoint ligands such as programmed death ligand 1 (PD-L1) appears to be regulated by the PI3K-Akt-mTOR pathway: inhibition of PI3K, Akt or mTOR decreased expression of PD-L1 in a non-small cell lung cancer model in vitro and in vivo.	('PD-L1', 'Gene', (89, 94))	('non-small cell lung cancer', 'Disease', (217, 243))	('PD-L1', 'Gene', '29126', (89, 94))	('lung cancer', 'Phenotype', 'HP:0100526', (232, 243))	('expression', 'MPA', (192, 202))	('Akt', 'Gene', (132, 135))	('PI3', 'Gene', '5266', (127, 130))	('mTOR', 'Gene', (177, 181))	('programmed death ligand 1', 'Gene', (62, 87))	('mTOR', 'Gene', (136, 140))	('PD-L1', 'Gene', (206, 211))	('Akt', 'Gene', '207', (132, 135))	('PD-L1', 'Gene', '29126', (206, 211))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (221, 243))	('PI3', 'Gene', '5266', (164, 167))	('inhibition', 'Var', (150, 160))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (217, 243))	('decreased', 'NegReg', (182, 191))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('Akt', 'Gene', (170, 173))	('mTOR', 'Gene', '2475', (177, 181))	('mTOR', 'Gene', '2475', (136, 140))	('PI3', 'Gene', (127, 130))	('Akt', 'Gene', '207', (170, 173))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (217, 243))	('PI3', 'Gene', (164, 167))	('programmed death ligand 1', 'Gene', '29126', (62, 87))
122280	31093356	Inhibition of PI3Kgamma in macrophages, therefore, stimulated NFkappaB activation and promoted an immunostimulatory transcriptional program, restoring T cell activation.	('immunostimulatory transcriptional program', 'MPA', (98, 139))	('restoring', 'PosReg', (141, 150))	('activation', 'PosReg', (71, 81))	('stimulated', 'PosReg', (51, 61))	('NFkappaB', 'Protein', (62, 70))	('PI3Kgamma', 'Gene', '5294', (14, 23))	('PI3Kgamma', 'Gene', (14, 23))	('Inhibition', 'Var', (0, 10))	('promoted', 'PosReg', (86, 94))	('T cell activation', 'MPA', (151, 168))
122298	30563540	Our findings reveal that high preoperative SII associates with poor outcome and serves as a non-invasive, low-cost and powerful prognostic predictor for patients with OSCC.	('SCC', 'Gene', (168, 171))	('patients', 'Species', '9606', (153, 161))	('SCC', 'Gene', '6317', (168, 171))	('high', 'Var', (25, 29))	('OS', 'Chemical', '-', (167, 169))	('SII', 'Disease', (43, 46))	('SII', 'Disease', 'None', (43, 46))
122336	30563540	The SII, NLR and PLR scores were stratified into < 484.5 or >= 484.5 (484.5, < 2.9 or >= 2.9 and < 170.2 or >= 170.2 as high or low subgroups for all subsequent analyses.	('< 170.2 or >', 'Var', (97, 109))	('SII', 'Disease', 'None', (4, 7))	('SII', 'Disease', (4, 7))
122363	30563540	S2, patients with high NLR had significantly reduced OS and DFS compared to those with low NLR in training, validation and combined cohorts (Kaplan-Meier analyses, P < 0.01).	('reduced', 'NegReg', (45, 52))	('OS', 'Chemical', '-', (53, 55))	('DFS', 'CPA', (60, 63))	('patients', 'Species', '9606', (4, 12))	('high NLR', 'Var', (18, 26))
122364	30563540	Moreover, patients with high PLR had significant lower OS and DFS relative those with low PLR in training, validation and combined cohorts (Kaplan-Meier analyses, P < 0.05, Additional file 3: Fig.	('high PLR', 'Var', (24, 32))	('OS', 'Chemical', '-', (55, 57))	('DFS', 'MPA', (62, 65))	('lower', 'NegReg', (49, 54))	('patients', 'Species', '9606', (10, 18))
122369	30563540	S4F), the AUC for SII, NLR and PLR were 0.646, 0.597, 0.617, while the AUC for other four parameters were less than 0.56.	('0.597', 'Var', (47, 52))	('0.617', 'Var', (54, 59))	('SII', 'Disease', (18, 21))	('SII', 'Disease', 'None', (18, 21))
122376	30563540	Previous studies have indicated that high SII, NLR and PLR significantly associated with adverse survival in hepatocellular carcinoma, esophageal squamous cell carcinoma, pancreatic cancer, melanoma and small cell lung cancer.	('high SII', 'Disease', (37, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (160, 169))	('associated', 'Reg', (73, 83))	('adverse', 'NegReg', (89, 96))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (109, 133))	('high SII', 'Disease', 'MESH:D008228', (37, 45))	('pancreatic cancer', 'Disease', 'MESH:D010190', (171, 188))	('PLR', 'Var', (55, 58))	('melanoma', 'Phenotype', 'HP:0002861', (190, 198))	('hepatocellular carcinoma', 'Disease', (109, 133))	('pancreatic cancer', 'Disease', (171, 188))	('esophageal squamous cell carcinoma', 'Disease', (135, 169))	('melanoma and small cell lung cancer', 'Disease', 'MESH:D055752', (190, 225))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('NLR', 'Var', (47, 50))	('lung cancer', 'Phenotype', 'HP:0100526', (214, 225))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (146, 169))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (135, 169))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (171, 188))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (109, 133))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (203, 225))
122433	28659128	Patients with esophageal cancer staging as cT1N1M0 or cT2-3 N0-1 M0 were enrolled in the study, and it showed better R0 rate (92% vs 69%, P < 0.001), lower node-positive rate (31% vs 75%, P < 0.001) and longer overall survival (49.4 vs 24 months, P = 0.003) in the nCRT group without significant postoperative morbidities and mortalities.	('lower', 'NegReg', (150, 155))	('overall', 'MPA', (210, 217))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('cT1N1M0', 'Var', (43, 50))	('esophageal cancer', 'Disease', (14, 31))	('longer', 'PosReg', (203, 209))	('esophageal cancer', 'Disease', 'MESH:D004938', (14, 31))	('Patients', 'Species', '9606', (0, 8))	('better', 'PosReg', (110, 116))	('R0 rate', 'CPA', (117, 124))	('node-positive rate', 'CPA', (156, 174))
122435	28659128	However, accumulating evidence suggested that a significant level of toxicity resulted from nCRT for ESCC.	('toxicity', 'Disease', (69, 77))	('ESCC', 'Gene', (101, 105))	('nCRT', 'Var', (92, 96))	('toxicity', 'Disease', 'MESH:D064420', (69, 77))
122457	28659128	Histologically-confirmed squamous cell carcinoma of the esophagus; Tumors of the esophagus are located in the thoracic cavity; Pre-treatment stage as cT3-4aN0-1M0 (AJCC/UICC 7th Edition) (In case of stage cT4a, curative resectability has to be explicitly verified by the local surgical investigator prior to randomization).	('squamous cell carcinoma of the esophagus', 'Disease', (25, 65))	('Tumors', 'Phenotype', 'HP:0002664', (67, 73))	('squamous cell carcinoma of the esophagus', 'Disease', 'MESH:D002294', (25, 65))	('cT3-4aN0-1M0', 'Var', (150, 162))	('carcinoma of the esophagus', 'Phenotype', 'HP:0011459', (39, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (39, 48))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (25, 48))	('Tumors', 'Disease', (67, 73))	('Tumors', 'Disease', 'MESH:D009369', (67, 73))
122470	28659128	The dissected nodes in thoracic cavity should include the upper paraesophageal (no.105), paratracheal (no.106r and 106tb), subcarinal (no.107), middle paraesophageal (no.108), bilateral hilar lymph nodes (no.109), lower paraesophageal (no.110), posterior mediastinal lymph nodes (no.111), and diaphragmatic (no.112) ones.	('middle paraesophageal', 'Disease', 'MESH:D020244', (144, 165))	('upper paraesophageal', 'Disease', (58, 78))	('no.107', 'Var', (135, 141))	('upper paraesophageal', 'Disease', 'MESH:D006551', (58, 78))	('middle paraesophageal', 'Disease', (144, 165))	('no.106r', 'Var', (103, 110))	('no.108', 'Var', (167, 173))
122545	27635269	The etiologies of hyponatremia (SIADH or non-SIADH) were best differentiated by the plasma urea concentration (less than 30 mg/dL in SIADH), urate concentration (less than 4,0 mg/dL in SIADH), and creatinine concentration (less than 0,9 mg/dL in SIADH).	('urate', 'Chemical', 'MESH:D014527', (141, 146))	('hyponatremia', 'Disease', (18, 30))	('less than', 'Var', (111, 120))	('less than', 'Var', (162, 171))	('SIADH', 'Phenotype', 'HP:0031218', (45, 50))	('less', 'Var', (223, 227))	('urate concentration', 'MPA', (141, 160))	('SIADH', 'Phenotype', 'HP:0031218', (246, 251))	('SIADH', 'Phenotype', 'HP:0031218', (32, 37))	('SIADH', 'Phenotype', 'HP:0031218', (133, 138))	('hyponatremia', 'Phenotype', 'HP:0002902', (18, 30))	('plasma urea concentration', 'MPA', (84, 109))	('creatinine concentration', 'MPA', (197, 221))	('SIADH', 'Phenotype', 'HP:0031218', (185, 190))
122617	25628742	Anti-Hu and -ANNA-3 are predominantly associated with SCLC (94%), anti-Ma2/anti-Ta with testicular cancer, and anti-CV2/CRMP5 with lymphoma or SCLC.	('testicular cancer', 'Disease', 'MESH:D013736', (88, 105))	('SCLC', 'Disease', 'MESH:D018288', (143, 147))	('Ma2', 'Gene', '10687', (71, 74))	('CV2', 'Gene', '168667', (116, 119))	('associated', 'Reg', (38, 48))	('SCLC', 'Disease', 'MESH:D018288', (54, 58))	('CRMP5', 'Gene', (120, 125))	('lymphoma', 'Disease', (131, 139))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('testicular cancer', 'Disease', (88, 105))	('lymphoma', 'Disease', 'MESH:D008223', (131, 139))	('CRMP5', 'Gene', '56896', (120, 125))	('Anti-Hu', 'Var', (0, 7))	('testicular cancer', 'Phenotype', 'HP:0010788', (88, 105))	('SCLC', 'Disease', (143, 147))	('SCLC', 'Phenotype', 'HP:0030357', (143, 147))	('Ma2', 'Gene', (71, 74))	('SCLC', 'Disease', (54, 58))	('SCLC', 'Phenotype', 'HP:0030357', (54, 58))	('CV2', 'Gene', (116, 119))	('lymphoma', 'Phenotype', 'HP:0002665', (131, 139))
122624	24705290	Mechanisms of Base Substitution Mutagenesis in Cancer Genomes Cancer genome sequence data provide an invaluable resource for inferring the key mechanisms by which mutations arise in cancer cells, favoring their survival, proliferation and invasiveness.	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('Cancer', 'Disease', (47, 53))	('mutations', 'Var', (163, 172))	('Cancer', 'Disease', 'MESH:D009369', (47, 53))	('rat', 'Species', '10116', (228, 231))	('Cancer', 'Disease', (62, 68))	('Cancer', 'Phenotype', 'HP:0002664', (47, 53))	('Base Substitution', 'Var', (14, 31))	('proliferation', 'CPA', (221, 234))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('Cancer', 'Disease', 'MESH:D009369', (62, 68))	('Cancer', 'Phenotype', 'HP:0002664', (62, 68))	('invasiveness', 'CPA', (239, 251))	('cancer', 'Disease', (182, 188))	('favoring', 'PosReg', (196, 204))	('survival', 'CPA', (211, 219))
122625	24705290	Here we examine recent advances in understanding the molecular mechanisms responsible for the predominant type of genetic alteration found in cancer cells, somatic single base substitutions (SBSs).	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('single base substitutions', 'Var', (164, 189))	('SBSs', 'Chemical', '-', (191, 195))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('rat', 'Species', '10116', (126, 129))	('cancer', 'Disease', (142, 148))
122627	24705290	Although gene expression data on APOBEC3B enzymes provide support for a role in cancer mutagenesis through U:G mismatch intermediates, the enzyme preference for single-stranded DNA may limit its activity genome-wide.	('single-stranded', 'Var', (161, 176))	('APOBEC3B', 'Gene', (33, 41))	('limit', 'NegReg', (185, 190))	('U:G', 'MPA', (107, 110))	('APOBEC3B', 'Gene', '9582', (33, 41))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('mismatch', 'Var', (111, 119))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('cancer', 'Disease', (80, 86))	('activity', 'MPA', (195, 203))
122629	24705290	The explosion of cancer genome sequencing projects over the past few years has revealed the complexity of the processes whose alterations are associated with, and are often causative of, various types of cancer.	('cancer', 'Disease', (204, 210))	('cancer', 'Disease', 'MESH:D009369', (204, 210))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('cancer', 'Disease', (17, 23))	('rat', 'Species', '10116', (130, 133))	('alterations', 'Var', (126, 137))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
122631	24705290	Cancer genome studies have also served to catalogue the extent to which translocations, chromosomal gains and losses and focal copy-number alterations take place, often mediated by catastrophic chromosomal shattering events, as in the case of some bone and pediatric cancers.	('gains', 'PosReg', (100, 105))	('translocations', 'Var', (72, 86))	('losses', 'NegReg', (110, 116))	('chromosomal', 'Var', (88, 99))	('cancers', 'Phenotype', 'HP:0002664', (267, 274))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('pediatric cancers', 'Disease', 'MESH:D009369', (257, 274))	('rat', 'Species', '10116', (143, 146))	('pediatric cancers', 'Disease', (257, 274))	('cancer', 'Phenotype', 'HP:0002664', (267, 273))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))
122632	24705290	From a mechanistic and therapeutic perspective, the arsenal of gene classes and pathways that are frequently altered, such as signal transduction, metabolism, DNA repair, transcription, epigenetics, RNA splicing and protein homeostasis, has also greatly expanded.	('eta', 'Gene', '1909', (148, 151))	('eta', 'Gene', (148, 151))	('epigenetics', 'Var', (186, 197))	('altered', 'Reg', (109, 116))
122635	24705290	The goal of this review is to examine two prominent single base substitution (SBS) patterns observed in cancer genomes, both of which display sequence context-dependent signatures: C T transitions at CG:CG (the colon separates complementary bases written in a 5' 3' direction) dinucleotide sequences and substitutions at C:G base-pairs in the context of YC:GR (Y, pyrimidine; R, purine) motifs.	('colon', 'Disease', (211, 216))	('rat', 'Species', '10116', (221, 224))	('purine', 'Chemical', 'MESH:C030985', (379, 385))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('CG', 'Chemical', 'MESH:C028505', (203, 205))	('pyrimidine', 'Chemical', 'MESH:C030986', (364, 374))	('colon', 'Disease', 'MESH:D015179', (211, 216))	('substitutions', 'Var', (304, 317))	('CG', 'Chemical', 'MESH:C028505', (200, 202))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('dinucleotide', 'Chemical', 'MESH:D015226', (277, 289))
122639	24705290	Some of the largest meta-analyses have included 4,938,362 somatic substitutions and small insertions/deletions (indels) from 7,042 primary cancers of 30 different classes, ~1,000,000 somatic exome mutations from 4,800 tumors representing 19 different cancers, 617,354 somatic mutations in 3,281 tumors from 12 cancer types, 533,482 somatic SBSs from 1,149 cancer samples and 2 cell lines representing 14 different tissues, and 373,909 non-silent coding mutations in 3,083 tumor-normal pairs across 27 tumor types.	('tumor', 'Phenotype', 'HP:0002664', (501, 506))	('tumors', 'Disease', (295, 301))	('cancers', 'Phenotype', 'HP:0002664', (139, 146))	('cancers', 'Disease', (139, 146))	('tumor', 'Disease', (472, 477))	('cancer', 'Disease', 'MESH:D009369', (251, 257))	('cancers', 'Disease', 'MESH:D009369', (251, 258))	('tumor', 'Disease', (218, 223))	('mutations', 'Var', (453, 462))	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('cancer', 'Disease', (310, 316))	('tumors', 'Disease', 'MESH:D009369', (295, 301))	('tumor', 'Disease', 'MESH:D009369', (472, 477))	('mutations', 'Var', (276, 285))	('tumor', 'Disease', 'MESH:D009369', (218, 223))	('149 cancer', 'Disease', (352, 362))	('cancer', 'Phenotype', 'HP:0002664', (310, 316))	('cancer', 'Disease', (356, 362))	('tumors', 'Phenotype', 'HP:0002664', (218, 224))	('149 cancer', 'Disease', 'MESH:D009369', (352, 362))	('tumor', 'Disease', (295, 300))	('cancer', 'Phenotype', 'HP:0002664', (356, 362))	('eta', 'Gene', '1909', (21, 24))	('cancers', 'Disease', 'MESH:D009369', (139, 146))	('tumor', 'Disease', (501, 506))	('tumor', 'Phenotype', 'HP:0002664', (472, 477))	('mutations', 'Var', (197, 206))	('cancers', 'Phenotype', 'HP:0002664', (251, 258))	('tumor', 'Disease', 'MESH:D009369', (295, 300))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('cancers', 'Disease', (251, 258))	('SBSs', 'Chemical', '-', (340, 344))	('cancer', 'Disease', (251, 257))	('tumor', 'Disease', 'MESH:D009369', (501, 506))	('cancer', 'Disease', 'MESH:D009369', (310, 316))	('tumors', 'Phenotype', 'HP:0002664', (295, 301))	('tumors', 'Disease', (218, 224))	('cancer', 'Disease', (139, 145))	('substitutions', 'Var', (66, 79))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('eta', 'Gene', (21, 24))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('cancer', 'Disease', 'MESH:D009369', (356, 362))	('tumor', 'Phenotype', 'HP:0002664', (295, 300))	('tumors', 'Disease', 'MESH:D009369', (218, 224))
122642	24705290	The preponderance of C T transitions at CG:CG sequences has been attributed to high rates of spontaneous deamination of 5-methylcytosine (5mC) as compared to unmethylated cytosine; such deamination events yield T:G mismatches and, subsequently, G A transitions at the next round of DNA replication.	('yield', 'Reg', (205, 210))	('5mC', 'Chemical', 'MESH:D044503', (138, 141))	('T:G mismatches', 'Var', (211, 225))	('rat', 'Species', '10116', (84, 87))	('mismatches', 'Var', (215, 225))	('cytosine', 'Chemical', 'MESH:D003596', (171, 179))	('CG', 'Chemical', 'MESH:C028505', (43, 45))	('5-methylcytosine', 'Chemical', 'MESH:D044503', (120, 136))	('cytosine', 'Chemical', 'MESH:D003596', (128, 136))	('CG', 'Chemical', 'MESH:C028505', (40, 42))
122644	24705290	Cancer type-specific mutational signatures have also been identified, particularly in cancers of the lung and skin.	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('cancers of the lung', 'Disease', (86, 105))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('cancers of the lung', 'Disease', 'MESH:D008175', (86, 105))	('cancers', 'Phenotype', 'HP:0002664', (86, 93))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('skin', 'Disease', (110, 114))	('mutational', 'Var', (21, 31))
122645	24705290	For example, in a cohort of 17 non-small cell lung cancer patients, the total number of somatic mutations was ~10-fold higher in smokers (median 15,659, range 7,424-26,202) than in never-smokers (median 888, range 842-1,268), consistent with other reports that smoking-associated lung cancer is distinguished by a significantly high number of mutations per Mb.	('lung cancer', 'Phenotype', 'HP:0100526', (46, 57))	('non-small cell lung cancer', 'Disease', (31, 57))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (35, 57))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (31, 57))	('cancer', 'Phenotype', 'HP:0002664', (285, 291))	('lung cancer', 'Disease', 'MESH:D008175', (46, 57))	('higher', 'PosReg', (119, 125))	('lung cancer', 'Disease', 'MESH:D008175', (280, 291))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (31, 57))	('patients', 'Species', '9606', (58, 66))	('lung cancer', 'Disease', (280, 291))	('mutations', 'Var', (96, 105))	('lung cancer', 'Phenotype', 'HP:0100526', (280, 291))
122646	24705290	Tumors from smokers were also characterized by high fractions (up to 46%) of C:G A:T transversions (Table 1B), a signature of exposure to alkylating nitrosamines and polycyclic aromatic hydrocarbons (PAHs) present in tobacco smoke, which yield miscoding G adducts.	('C:G', 'Var', (77, 80))	('tobacco', 'Species', '4097', (217, 224))	('nitrosamines', 'Chemical', 'MESH:D009602', (149, 161))	('Tumors', 'Disease', (0, 6))	('PAHs', 'Chemical', 'MESH:D011084', (200, 204))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('polycyclic aromatic hydrocarbons', 'Chemical', 'MESH:D011084', (166, 198))
122647	24705290	This conclusion is further supported by a recent whole-genome sequencing analysis of an arsenic exposure-related lung squamous cell carcinoma, which was instead characterized by a high fraction (16.3%) of T:A G:C transversions but a low fraction (~6.1%) of C:G A:T transversions (Table 1B).	('lung squamous cell carcinoma', 'Disease', (113, 141))	('T:A G:C transversions', 'Var', (205, 226))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (118, 141))	('transversions', 'Var', (213, 226))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (113, 141))	('arsenic', 'Chemical', 'MESH:D001151', (88, 95))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (113, 141))
122648	24705290	In melanomas, up to 87% of all mutations were represented by C:G T:A transitions, mostly at pyrimidine dimers, consistent with DNA translesion synthesis across UV-induced covalently linked pyrimidine dimers.	('mutations', 'Var', (31, 40))	('mers', 'Species', '1335626', (202, 206))	('melanomas', 'Phenotype', 'HP:0002861', (3, 12))	('melanomas', 'Disease', (3, 12))	('pyrimidine dimers', 'MPA', (92, 109))	('pyrimidine', 'Chemical', 'MESH:C030986', (189, 199))	('melanoma', 'Phenotype', 'HP:0002861', (3, 11))	('C:G T:A', 'Gene', (61, 68))	('mers', 'Species', '1335626', (105, 109))	('pyrimidine', 'Chemical', 'MESH:C030986', (92, 102))	('melanomas', 'Disease', 'MESH:D008545', (3, 12))
122649	24705290	Mutations in skin cancer at pyrimidine dimers, particularly CC TT transitions on the non-transcribed strand of expressed genes, have also been attributed to APOBEC3A, a member of the APOBEC family of cytosine deaminases which are active mostly on single-stranded DNA, and expressed in skin keratinocytes (Table 1B).	('cytosine', 'Chemical', 'MESH:D003596', (200, 208))	('skin cancer', 'Phenotype', 'HP:0008069', (13, 24))	('APOBEC3A', 'Gene', '200315', (157, 165))	('mers', 'Species', '1335626', (41, 45))	('skin cancer', 'Disease', (13, 24))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('pyrimidine', 'Chemical', 'MESH:C030986', (28, 38))	('Mutations', 'Var', (0, 9))	('APOBEC3A', 'Gene', (157, 165))	('skin cancer', 'Disease', 'MESH:D012878', (13, 24))	('attributed', 'Reg', (143, 153))	('rat', 'Species', '10116', (292, 295))
122650	24705290	Other prominent patterns included T C transitions in hepatocellular carcinomas, which have been attributed to bulky DNA adducts on adenine, A T transversions in the TA:TA context, particularly in leukemia samples, a 2-fold increase in mutations at NGRA relative to NGRB (B = C or G or T) in melanomas (Table 1B) and several others, for which the underlying mechanisms remain unknown.	('leukemia', 'Disease', (196, 204))	('melanomas', 'Disease', (291, 300))	('leukemia', 'Disease', 'MESH:D007938', (196, 204))	('increase', 'PosReg', (223, 231))	('leukemia', 'Phenotype', 'HP:0001909', (196, 204))	('mutations', 'Var', (235, 244))	('melanomas', 'Disease', 'MESH:D008545', (291, 300))	('adenine', 'Chemical', 'MESH:D000225', (131, 138))	('melanomas', 'Phenotype', 'HP:0002861', (291, 300))	('hepatocellular carcinomas', 'Phenotype', 'HP:0001402', (53, 78))	('carcinoma', 'Phenotype', 'HP:0030731', (68, 77))	('melanoma', 'Phenotype', 'HP:0002861', (291, 299))	('hepatocellular carcinomas', 'Disease', 'MESH:D006528', (53, 78))	('hepatocellular carcinomas', 'Disease', (53, 78))	('carcinomas', 'Phenotype', 'HP:0030731', (68, 78))
122653	24705290	The MMR pathway comprises 6 genes (MSH2, MSH3, MSH6, MLH1, PMS1 and PMS2) whose products yield 4 types of heterodimeric complexes [MutSalpha (MSH2/6), MutSbeta (MSH2/3), MutLalpha (MLH1/PMS2) and MutLbeta (MLH1/PMS1)], active on mismatches, bulges, small loops, and a number of DNA lesions.	('MSH2', 'Gene', '4436', (161, 165))	('MLH1', 'Gene', '4292', (206, 210))	('MLH1', 'Gene', (181, 185))	('eta', 'Gene', (201, 204))	('MSH6', 'Gene', (47, 51))	('MSH2', 'Gene', (142, 146))	('PMS2', 'Gene', (68, 72))	('MSH2', 'Gene', '4436', (35, 39))	('bulges', 'Disease', (241, 247))	('MLH1', 'Gene', (53, 57))	('MSH6', 'Gene', '2956', (47, 51))	('MSH2/3), MutLalpha', 'Gene', '4436;4437', (161, 179))	('MLH1', 'Gene', '4292', (181, 185))	('PMS1', 'Gene', (211, 215))	('mismatches', 'Var', (229, 239))	('PMS1', 'Gene', '5378', (211, 215))	('PMS2', 'Gene', (186, 190))	('MSH2', 'Gene', '4436', (142, 146))	('small loops', 'Disease', (249, 260))	('PMS1', 'Gene', (59, 63))	('PMS1', 'Gene', '5378', (59, 63))	('MLH1', 'Gene', '4292', (53, 57))	('MMR pathway', 'Pathway', (4, 15))	('eta', 'Gene', '1909', (156, 159))	('MSH3', 'Gene', (41, 45))	('MSH3', 'Gene', '4437', (41, 45))	('PMS2', 'Gene', '5395', (68, 72))	('MSH2', 'Gene', (161, 165))	('MLH1', 'Gene', (206, 210))	('MSH2/6', 'Gene', '4436;2956', (142, 148))	('MSH2/6', 'Gene', (142, 148))	('eta', 'Gene', '1909', (201, 204))	('eta', 'Gene', (156, 159))	('MSH2', 'Gene', (35, 39))	('PMS2', 'Gene', '5395', (186, 190))
122654	24705290	More than 1,000 constitutional gene variants in MLH1, MSH2, MSH6 and PMS2 have been classified as pathogenic or likely pathogenic in patients affected by Lynch syndrome, an autosomal dominant condition also known as hereditary non-polyposis colorectal cancer (HNPCC) and characterized by increased susceptibility to colorectal (25%-70%), endometrial (30%-70%), and other types of cancer.	('cancer', 'Disease', 'MESH:D009369', (252, 258))	('PMS2', 'Gene', (69, 73))	('patients', 'Species', '9606', (133, 141))	('MLH1', 'Gene', '4292', (48, 52))	('MSH2', 'Gene', (54, 58))	('cancer', 'Disease', (380, 386))	('HNPCC', 'Phenotype', 'HP:0006716', (260, 265))	('MSH6', 'Gene', (60, 64))	('colorectal', 'Disease', 'MESH:D015179', (241, 251))	('Lynch syndrome', 'Disease', (154, 168))	('cancer', 'Phenotype', 'HP:0002664', (380, 386))	('MSH6', 'Gene', '2956', (60, 64))	('colorectal', 'Disease', (316, 326))	('MSH2', 'Gene', '4436', (54, 58))	('colorectal cancer', 'Phenotype', 'HP:0003003', (241, 258))	('cancer', 'Disease', (252, 258))	('PMS2', 'Gene', '5395', (69, 73))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('non-polyposis colorectal cancer', 'Disease', 'MESH:D015179', (227, 258))	('Lynch syndrome', 'Disease', 'MESH:D003123', (154, 168))	('non-polyposis colorectal cancer', 'Disease', (227, 258))	('hereditary non-polyposis colorectal cancer', 'Phenotype', 'HP:0006716', (216, 258))	('endometrial', 'Disease', (338, 349))	('cancer', 'Disease', 'MESH:D009369', (380, 386))	('colorectal', 'Disease', 'MESH:D015179', (316, 326))	('variants', 'Var', (36, 44))	('HNPCC', 'Disease', 'None', (260, 265))	('MLH1', 'Gene', (48, 52))	('HNPCC', 'Disease', (260, 265))	('colorectal', 'Disease', (241, 251))
122655	24705290	Such MMR defects have also been known to lead to an accumulation of mutations, mostly in the form of microsatellite length changes (microsatellite instability, MSI).	('microsatellite length changes', 'MPA', (101, 130))	('defects', 'Var', (9, 16))	('MSI', 'Gene', '5928', (160, 163))	('MSI', 'Gene', (160, 163))	('mutations', 'Var', (68, 77))
122658	24705290	By contrast, most samples with elevated SBS mutation rates also displayed somatic mutations in the proofreading POLE domain.	('rat', 'Species', '10116', (53, 56))	('mutation', 'Var', (44, 52))	('SBS', 'Gene', (40, 43))
122659	24705290	In addition, POLE-mutated samples could be classified into two distinct groups based on MLH1 status: group 1, with low SBS mutations rates, MLH1 inactivation and MSI-high; and group 2, with high SBS mutation rates, functional MLH1 and MSI-low.	('MSI', 'Gene', (162, 165))	('MLH1', 'Gene', '4292', (88, 92))	('MLH1', 'Gene', (88, 92))	('rat', 'Species', '10116', (208, 211))	('MLH1', 'Gene', '4292', (226, 230))	('MLH1', 'Gene', (226, 230))	('MSI', 'Gene', (235, 238))	('low SBS', 'Disease', 'MESH:C536611', (115, 122))	('low SBS', 'Disease', (115, 122))	('rat', 'Species', '10116', (133, 136))	('MLH1', 'Gene', '4292', (140, 144))	('MSI', 'Gene', '5928', (162, 165))	('MSI', 'Gene', '5928', (235, 238))	('MLH1', 'Gene', (140, 144))	('mutations', 'Var', (123, 132))
122660	24705290	Thus, paradoxically, concomitant POLE and MLH1 mutations do not appear to act synergistically on SBS mutation rates in most patients.	('rat', 'Species', '10116', (110, 113))	('SBS', 'Disease', (97, 100))	('mutations', 'Var', (47, 56))	('MLH1', 'Gene', '4292', (42, 46))	('MLH1', 'Gene', (42, 46))	('patients', 'Species', '9606', (124, 132))
122661	24705290	Mutations in the proofreading domains of POLE and POLD1 were also reported in two human colorectal cancer cell lines (DLD-1 and LoVo) and 1/76 colorectal cancer patients, all three samples exhibiting MMR deficiency.	('MMR deficiency', 'Disease', (200, 214))	('LoVo', 'CellLine', 'CVCL:0399', (128, 132))	('MMR deficiency', 'Disease', 'MESH:C536143', (200, 214))	('colorectal cancer', 'Disease', (88, 105))	('colorectal cancer', 'Disease', (143, 160))	('colorectal cancer', 'Disease', 'MESH:D015179', (88, 105))	('human', 'Species', '9606', (82, 87))	('reported', 'Reg', (66, 74))	('POLD1', 'Gene', (50, 55))	('POLD1', 'Gene', '5424', (50, 55))	('Mutations', 'Var', (0, 9))	('patients', 'Species', '9606', (161, 169))	('colorectal cancer', 'Disease', 'MESH:D015179', (143, 160))	('colorectal cancer', 'Phenotype', 'HP:0003003', (88, 105))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('colorectal cancer', 'Phenotype', 'HP:0003003', (143, 160))	('POLE', 'Gene', (41, 45))
122662	24705290	More recently, two recurrent germline mutations in the proofreading domains of POLE (L424V) and POLD1 (S478N) have been found in a cohort of 3,805 colorectal cancer patients selected for family history of colorectal tumors and multiple adenomas.	('POLD1', 'Gene', (96, 101))	('POLD1', 'Gene', '5424', (96, 101))	('colorectal cancer', 'Phenotype', 'HP:0003003', (147, 164))	('colorectal cancer', 'Disease', (147, 164))	('S478N', 'Mutation', 'rs397514632', (103, 108))	('S478N', 'Var', (103, 108))	('adenomas', 'Disease', 'MESH:D000236', (236, 244))	('colorectal tumors', 'Disease', (205, 222))	('colorectal tumors', 'Disease', 'MESH:D015179', (205, 222))	('found', 'Reg', (120, 125))	('tumors', 'Phenotype', 'HP:0002664', (216, 222))	('L424V', 'Var', (85, 90))	('adenomas', 'Disease', (236, 244))	('colorectal cancer', 'Disease', 'MESH:D015179', (147, 164))	('patients', 'Species', '9606', (165, 173))	('L424V', 'Mutation', 'rs1315928771', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
122663	24705290	In the 62 tumors analyzed, no MSI was found; rather, loss of heterozygosity, chromosomal instability and driver mutations in known cancer genes, including KRAS, BRAF, APC, PIK3CA, FBXW7, but not CTNNB1, were revealed, suggesting that mutant POLEL424V and POLD1S478N may promote tumor formation by increasing the rates of SBS, without any apparent bias for a predominant type of base substitution.	('tumor', 'Phenotype', 'HP:0002664', (278, 283))	('POLEL424V', 'Var', (241, 250))	('CTNNB1', 'Gene', (195, 201))	('KRAS', 'Gene', '3845', (155, 159))	('APC', 'Disease', 'MESH:D011125', (167, 170))	('L424V', 'Mutation', 'rs1315928771', (245, 250))	('tumors', 'Disease', (10, 16))	('APC', 'Disease', (167, 170))	('PIK3CA', 'Gene', (172, 178))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('promote', 'PosReg', (270, 277))	('KRAS', 'Gene', (155, 159))	('tumor', 'Disease', (10, 15))	('tumors', 'Disease', 'MESH:D009369', (10, 16))	('MSI', 'Gene', (30, 33))	('mutant POLEL424V', 'Var', (234, 250))	('MSI', 'Gene', '5928', (30, 33))	('rates', 'MPA', (312, 317))	('FBXW7', 'Gene', (180, 185))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('rat', 'Species', '10116', (45, 48))	('chromosomal instability', 'Phenotype', 'HP:0040012', (77, 100))	('increasing', 'PosReg', (297, 307))	('tumor', 'Disease', (278, 283))	('PIK3CA', 'Gene', '5290', (172, 178))	('SBS', 'Disease', (321, 324))	('CTNNB1', 'Gene', '1499', (195, 201))	('tumor', 'Disease', 'MESH:D009369', (278, 283))	('cancer', 'Disease', (131, 137))	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('FBXW7', 'Gene', '55294', (180, 185))	('tumors', 'Phenotype', 'HP:0002664', (10, 16))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('BRAF', 'Gene', (161, 165))	('rat', 'Species', '10116', (312, 315))	('BRAF', 'Gene', '673', (161, 165))	('POLD1S478N', 'Var', (255, 265))
122664	24705290	Twelve missense somatic mutations predicted to affect the proofreading domain of POLE, and all associated with microsatellite stability, have also been identified in a study of 173 endometrial cancers, P286R being the most commonly represented (6 times) POLE mutation.	('cancers', 'Phenotype', 'HP:0002664', (193, 200))	('microsatellite stability', 'MPA', (111, 135))	('endometrial cancers', 'Disease', 'MESH:D016889', (181, 200))	('P286R', 'Var', (202, 207))	('endometrial cancers', 'Disease', (181, 200))	('affect', 'Reg', (47, 53))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('proofreading domain', 'MPA', (58, 77))	('associated', 'Reg', (95, 105))	('P286R', 'Mutation', 'p.P286R', (202, 207))	('endometrial cancer', 'Phenotype', 'HP:0012114', (181, 199))
122665	24705290	Using a panel of 75 cancer genes, POLE-mutated tumors exhibited an ~6-fold increase in mutations relative to non-POLE-mutated tumors, with a prevalence of G:C T:A transversions, particularly at G:C base-pairs flanked 5' and 3' by an A:T base-pair.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('tumors', 'Disease', (47, 53))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('tumors', 'Disease', (126, 132))	('tumors', 'Disease', 'MESH:D009369', (126, 132))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('cancer', 'Disease', 'MESH:D009369', (20, 26))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))	('cancer', 'Disease', (20, 26))	('mutations', 'MPA', (87, 96))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('increase', 'PosReg', (75, 83))	('G:C', 'Var', (194, 197))	('G:C T:A transversions', 'Var', (155, 176))	('transversions', 'Var', (163, 176))
122666	24705290	Further validation of the putative role for POLE, and to a lesser extent POLD1, mutations in endometrial cancer has been obtained from an analysis of unpublished TCGA genomic data, where 21 (8.5%) and 1 (0.4%) tumors out of 248 samples were found to harbor POLE and POLD1 mutations, respectively, including 8 cases of P286R and 5 cases of V411L changes in POLE.	('mutations', 'Var', (272, 281))	('POLE', 'Gene', (257, 261))	('POLD1', 'Gene', '5424', (73, 78))	('V411L', 'Mutation', 'p.V411L', (339, 344))	('P286R', 'Mutation', 'p.P286R', (318, 323))	('endometrial cancer', 'Phenotype', 'HP:0012114', (93, 111))	('tumors', 'Disease', 'MESH:D009369', (210, 216))	('POLD1', 'Gene', (266, 271))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('endometrial cancer', 'Disease', (93, 111))	('endometrial cancer', 'Disease', 'MESH:D016889', (93, 111))	('POLD1', 'Gene', (73, 78))	('harbor', 'Reg', (250, 256))	('tumors', 'Phenotype', 'HP:0002664', (210, 216))	('POLD1', 'Gene', '5424', (266, 271))	('GA', 'Chemical', 'MESH:D005708', (164, 166))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('tumors', 'Disease', (210, 216))	('CG', 'Chemical', 'MESH:C028505', (163, 165))	('V411L', 'Var', (339, 344))	('P286R', 'Var', (318, 323))
122668	24705290	Likewise, cancers carrying the POLEP286R allele exhibited an overrepresentation of G:C T:A substitutions at AGA:TCT motifs (Table 1B), supporting a DNA sequence-specific proofreading defect for this particular POLE mutation.	('POLEP286R', 'Var', (31, 40))	('G:C T:A', 'Gene', (83, 90))	('P286R', 'Mutation', 'p.P286R', (35, 40))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('overrepresentation', 'PosReg', (61, 79))	('AGA:TCT motifs', 'Gene', (108, 122))	('cancers', 'Phenotype', 'HP:0002664', (10, 17))	('substitutions', 'Var', (91, 104))	('cancers', 'Disease', 'MESH:D009369', (10, 17))	('GA', 'Chemical', 'MESH:D005708', (109, 111))	('cancers', 'Disease', (10, 17))
122669	24705290	In summary, germline and somatic mutations in the POLE and POLD1 genes appear to predispose to, or promote, colorectal and endometrial cancers in part by increasing the rates of SBSs.	('rat', 'Species', '10116', (169, 172))	('cancers', 'Phenotype', 'HP:0002664', (135, 142))	('increasing', 'PosReg', (154, 164))	('colorectal and endometrial cancers', 'Disease', 'MESH:D016889', (108, 142))	('promote', 'PosReg', (99, 106))	('endometrial cancer', 'Phenotype', 'HP:0012114', (123, 141))	('mutations', 'Var', (33, 42))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('POLD1', 'Gene', (59, 64))	('POLE', 'Gene', (50, 54))	('predispose', 'Reg', (81, 91))	('POLD1', 'Gene', '5424', (59, 64))	('SBSs', 'Disease', (178, 182))	('SBSs', 'Chemical', '-', (178, 182))
122670	24705290	Less direct investigations from cell culture nuclear extracts suggest that defects in DNA replication fidelity might also be associated with ovarian cancers.	('ovarian cancers', 'Disease', 'MESH:D010051', (141, 156))	('associated', 'Reg', (125, 135))	('defects', 'Var', (75, 82))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('DNA', 'MPA', (86, 89))	('ovarian cancer', 'Phenotype', 'HP:0100615', (141, 155))	('ovarian cancers', 'Phenotype', 'HP:0100615', (141, 156))	('ovarian cancers', 'Disease', (141, 156))	('cancers', 'Phenotype', 'HP:0002664', (149, 156))
122679	24705290	At least three recent reports have suggested the involvement of aberrant APOBEC3B deaminase activity as a frequent cause of SBSs in cancer.	('SBSs', 'Disease', (124, 128))	('cancer', 'Disease', (132, 138))	('SBSs', 'Chemical', '-', (124, 128))	('deaminase', 'Enzyme', (82, 91))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('APOBEC3B', 'Gene', '9582', (73, 81))	('APOBEC3B', 'Gene', (73, 81))	('cause', 'Reg', (115, 120))	('activity', 'MPA', (92, 100))	('aberrant', 'Var', (64, 72))	('cancer', 'Disease', 'MESH:D009369', (132, 138))
122684	24705290	The top five cancer types with the majority of mutations at C:G base-pairs were also among the top six datasets in terms of APOBEC3B mRNA expression, and a positive correlation between the proportion of mutations at C:G base-pairs and median APOBEC3B levels was observed.	('APOBEC3B', 'Gene', '9582', (242, 250))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('C:G', 'Var', (60, 63))	('mutations', 'Var', (47, 56))	('cancer', 'Disease', (13, 19))	('cancer', 'Disease', 'MESH:D009369', (13, 19))	('APOBEC3B', 'Gene', '9582', (124, 132))	('APOBEC3B', 'Gene', (124, 132))	('APOBEC3B', 'Gene', (242, 250))
122685	24705290	Bladder, cervical, lung squamous cell carcinoma, lung adenocarcinoma, head and neck, and breast cancers shared a strong bias for TCN (N = A or C or G or T) mutation signatures, as observed for the recombinant APOBEC3B protein.	('APOBEC3B', 'Gene', (209, 217))	('cancers', 'Phenotype', 'HP:0002664', (96, 103))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (24, 47))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (19, 47))	('lung squamous cell carcinoma', 'Disease', (19, 47))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('cervical', 'Disease', (9, 17))	('carcinoma', 'Phenotype', 'HP:0030731', (38, 47))	('lung adenocarcinoma', 'Disease', (49, 68))	('breast cancers', 'Disease', 'MESH:D001943', (89, 103))	('breast cancers', 'Disease', (89, 103))	('APOBEC3B', 'Gene', '9582', (209, 217))	('carcinoma', 'Phenotype', 'HP:0030731', (59, 68))	('breast cancers', 'Phenotype', 'HP:0003002', (89, 103))	('Bladder', 'Disease', (0, 7))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (49, 68))	('breast cancer', 'Phenotype', 'HP:0003002', (89, 102))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (19, 47))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (49, 68))	('mutation', 'Var', (156, 164))
122686	24705290	Interestingly, a significant enrichment of strand-coordinated and clustered (2 or more per 10 kb) C T and C G mutations at TCW (W = A or T) motifs were discovered, a number of which were in close proximity to chromosomal rearrangement breakpoints, particularly in bladder, cervical, head and neck, breast and lung tumors, a phenomenon termed kataegis.	('bladder', 'Disease', (264, 271))	('mutations', 'Var', (110, 119))	('C G', 'Gene', (106, 109))	('tumor', 'Phenotype', 'HP:0002664', (314, 319))	('TCW', 'Gene', (123, 126))	('tumors', 'Phenotype', 'HP:0002664', (314, 320))	('lung tumors', 'Phenotype', 'HP:0100526', (309, 320))	('breast and lung tumors', 'Disease', 'MESH:D001943', (298, 320))	('cervical', 'Disease', (273, 281))
122687	24705290	In summary, these analyses are consistent with the possibility that aberrant APOBEC deaminase activity, particularly at TC:GA sites, may represent a general endogenous mutagen that contributes to several different types of human cancer.	('APOBEC', 'Gene', (77, 83))	('GA', 'Chemical', 'MESH:D005708', (123, 125))	('deaminase', 'Enzyme', (84, 93))	('cancer', 'Disease', (229, 235))	('cancer', 'Disease', 'MESH:D009369', (229, 235))	('human', 'Species', '9606', (223, 228))	('contributes', 'Reg', (181, 192))	('activity', 'MPA', (94, 102))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('aberrant', 'Var', (68, 76))
122690	24705290	In human osteosarcoma cells, shRNA knock-down of the WRN helicase gene, mutations in which are associated with the progeroid Werner syndrome, led to a doubling in genomic 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxoG) content and an increase in SBSs in the supF reporter gene, consisting largely of G C (49%), G A (28%) and G T (23%) substitutions at GA:TC dinucleotides within the supF reporter gene.	('supF reporter gene', 'Gene', (255, 273))	('human', 'Species', '9606', (3, 8))	('SBSs', 'MPA', (243, 247))	('substitutions', 'Var', (332, 345))	('osteosarcoma', 'Phenotype', 'HP:0002669', (9, 21))	('associated', 'Reg', (95, 105))	('doubling', 'PosReg', (151, 159))	('mutations', 'Var', (72, 81))	('WRN', 'Gene', (53, 56))	('WRN', 'Gene', '7486', (53, 56))	('supF', 'Gene', (380, 384))	('Werner syndrome', 'Disease', (125, 140))	('GA', 'Chemical', 'MESH:D005708', (349, 351))	("8-oxo-7,8-dihydro-2'-deoxyguanosine", 'Chemical', 'MESH:C067134', (171, 206))	('knock-down', 'Var', (35, 45))	('TC dinucleotides', 'Chemical', '-', (352, 368))	('osteosarcoma', 'Disease', (9, 21))	('osteosarcoma', 'Disease', 'MESH:D012516', (9, 21))	('Werner syndrome', 'Disease', 'MESH:D014898', (125, 140))	('increase', 'PosReg', (231, 239))	('SBSs', 'Chemical', '-', (243, 247))
122694	24705290	With the exception of two melanoma datasets, CGNN sequences were more frequently mutated than DGNN (D = A or G or T), consistent with the CG:CG dinucleotide, the most prominent substrate for cytosine methylation, being a common mutation hotspot (Table 1A).	('CGNN', 'Gene', (45, 49))	('cytosine', 'Chemical', 'MESH:D003596', (191, 199))	('CG', 'Chemical', 'MESH:C028505', (45, 47))	('CG', 'Chemical', 'MESH:C028505', (141, 143))	('CG dinucleotide', 'Chemical', 'MESH:C015772', (141, 156))	('mutated', 'Var', (81, 88))	('CG', 'Chemical', 'MESH:C028505', (138, 140))	('rat', 'Species', '10116', (182, 185))	('melanoma', 'Phenotype', 'HP:0002861', (26, 34))	('melanoma', 'Disease', (26, 34))	('melanoma', 'Disease', 'MESH:D008545', (26, 34))
122695	24705290	In 7 cancer datasets, including lung, head and neck and melanoma, for which association with exposure to either cigarette smoke or sunlight was documented, G followed by a 3' purine was associated with increased mutations as compared to a 3' pyrimidine, i.e., DGRN > DGYN (Table 1A).	('melanoma', 'Disease', 'MESH:D008545', (56, 64))	('cancer', 'Disease', 'MESH:D009369', (5, 11))	('melanoma', 'Phenotype', 'HP:0002861', (56, 64))	('melanoma', 'Disease', (56, 64))	('cancer', 'Disease', (5, 11))	('purine', 'Chemical', 'MESH:C030985', (175, 181))	('mutations', 'Var', (212, 221))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))	('pyrimidine', 'Chemical', 'MESH:C030986', (242, 252))
122696	24705290	Notably, significant correlations were observed between the fractions of mutated DGNN motifs and the sequence-dependent free energies of base stacking along the DGNN motifs for 5 of the 7 cancer datasets.	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('mutated', 'Var', (73, 80))	('free energies', 'MPA', (120, 133))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('cancer', 'Disease', (188, 194))	('DGNN', 'Gene', (81, 85))
122697	24705290	Significant correlations were also observed between the fractions of mutated DGNN motifs and the energies required to abstract an electron from the target guanines, as assessed from the values of vertical ionization energies computed for all G-centered trimer motifs.	('ionization', 'Disease', 'MESH:D004194', (205, 215))	('guanines', 'Chemical', 'MESH:D006147', (155, 163))	('abstract an electron', 'MPA', (118, 138))	('mutated', 'Var', (69, 76))	('ionization', 'Disease', (205, 215))	('DGNN', 'Gene', (77, 81))
122701	24705290	Chromatin correlating positively with gene expression, G + C-richness and active chromatin marks is replicated in early S phase in the nuclear interior, whereas chromatin associated with gene-poor regions, A + T-richness and repressive chromatin marks is preferentially replicated during late S phase at the nuclear periphery.	('T-richness', 'Disease', 'MESH:D000080203', (210, 220))	('G + C-richness', 'Var', (55, 69))	('gene expression', 'MPA', (38, 53))	('T-richness', 'Disease', (210, 220))
122704	24705290	Analyses of the mutation spectra indicated that, with the exception of A T (T A) transversions, which occurred more often in the constant late replicating regions in all five cancer types, the relative proportions of substitutions were very similar between constant early and constant late replicating regions, even though mutation frequencies were higher in the latter.	('cancer', 'Disease', (175, 181))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('transversions', 'Var', (81, 94))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
122705	24705290	Similarly, a large study of SBSs in exomes from 3,083 tumor-normal pairs representing 27 different cancer types also found that the average mutation fraction was higher (~2.9-fold) in the latest- as compared to the earliest-replicating percentiles.	('higher', 'PosReg', (162, 168))	('SBSs', 'Chemical', '-', (28, 32))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('mutation', 'Var', (140, 148))	('cancer', 'Disease', (99, 105))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumor', 'Disease', (54, 59))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
122710	24705290	In summary, these analyses suggest that the increased mutation rate in late- versus early-DNA replicating regions, which has been noted in both population and cancer genome studies, are potentially caused by mechanisms that share some commonalities between the germline and the soma.	('cancer', 'Disease', (159, 165))	('mutation', 'Var', (54, 62))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('caused', 'Reg', (198, 204))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('increased', 'PosReg', (44, 53))	('rat', 'Species', '10116', (63, 66))
122712	24705290	Chromatin condensation, or heterochromatin, is associated with reduced gene expression and involves the accumulation of specific histone marks, including methylation of lysines 9 and 27 on histone 3 (H3K9me2 and H3K27me3) by histone methyltransferases (HMT) such as G9a, GLP and SETBD1, and DNA methylation at C5 of cytosine, mainly at CG:CG dinucleotides, by DNA (cytosine-5)-methyltransferases (DNMT1, DNMT3a and DNMT3b).	('gene expression', 'MPA', (71, 86))	('cytosine', 'Chemical', 'MESH:D003596', (316, 324))	('CG dinucleotides', 'Chemical', 'MESH:C015772', (339, 355))	('cytosine', 'Chemical', 'MESH:D003596', (365, 373))	('DNMT1', 'Gene', (397, 402))	('CG', 'Chemical', 'MESH:C028505', (336, 338))	('reduced', 'NegReg', (63, 70))	('CG', 'Chemical', 'MESH:C028505', (339, 341))	('DNMT1', 'Gene', '1786', (397, 402))	('H3K27me3', 'Var', (212, 220))	('accumulation', 'PosReg', (104, 116))
122713	24705290	Among other critical interactions, H3K9me2 serves as a high-affinity binding site for the recruitment of heterochromatin protein 1 (HP1), a platform protein that collapses chromatin into higher-order fibers as a result of dimerization between nucleosomes.	('HP1', 'Gene', (132, 135))	('heterochromatin protein 1', 'Gene', (105, 130))	('dimerization', 'MPA', (222, 234))	('H3K9me2', 'Var', (35, 42))	('chromatin', 'MPA', (172, 181))	('collapses', 'NegReg', (162, 171))	('heterochromatin protein 1', 'Gene', '23468', (105, 130))	('HP1', 'Gene', '23468', (132, 135))
122715	24705290	On a megabase scale, cancer SBS density correlated with many features of somatic cell chromatin organization, with the highest positive correlations being represented by the repressive histone modification H3K9me3, followed by H3K9me2 and H4K20me3.	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('cancer SBS', 'Disease', 'MESH:C536611', (21, 31))	('H4K20me3', 'Var', (239, 247))	('H3K9me3', 'Var', (206, 213))	('cancer SBS', 'Disease', (21, 31))	('correlated', 'Reg', (40, 50))
122721	24705290	For example, failure to deacetylate H3K59ac marks following the S-phase in hst3Delta hst4Delta double-mutant yeast cells increased the rates of SBS ~10-fold and the rates of gross chromosomal rearrangements 15,600-fold, whereas lack of H3K59 acetylation in rtt109Delta cells led to a ~10-fold increase in complex mutations.	('SBS', 'Disease', (144, 147))	('increase', 'PosReg', (293, 301))	('gross chromosomal rearrangements', 'CPA', (174, 206))	('yeast', 'Species', '4932', (109, 114))	('increased', 'PosReg', (121, 130))	('rat', 'Species', '10116', (135, 138))	('hst3', 'Gene', (75, 79))	('failure', 'Var', (13, 20))	('hst3', 'Gene', '854190', (75, 79))	('rat', 'Species', '10116', (165, 168))	('complex', 'MPA', (305, 312))
122728	24705290	Recurrent gain-of-function mutations in IDH1 and/or IDH2 typify ~70% of sporadic high-grade gliomas and secondary glioblastomas, ~10% of acute myeloid leukemias and colangiocarcinomas, and have been reported in patients with acute lymphoblastic leukemia, chondrosarcomas, angioimmunoblastic T-cell lymphoma, cholangiocarcinoma and pancreatic cancers, where they have been found to induce DNA hypermethylation at CG:CG islands and shores in a tissue-specific manner.	('mutations', 'Var', (27, 36))	('cholangiocarcinoma', 'Disease', (308, 326))	('glioblastomas', 'Disease', 'MESH:D005909', (114, 127))	('IDH1', 'Gene', (40, 44))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (308, 326))	('leukemia', 'Phenotype', 'HP:0001909', (151, 159))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (143, 159))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (231, 253))	('gliomas', 'Disease', (92, 99))	('cell lymphoma', 'Phenotype', 'HP:0012191', (293, 306))	('cancer', 'Phenotype', 'HP:0002664', (342, 348))	('leukemia', 'Phenotype', 'HP:0001909', (245, 253))	('leukemias', 'Phenotype', 'HP:0001909', (151, 160))	('carcinoma', 'Phenotype', 'HP:0030731', (317, 326))	('chondrosarcomas, angioimmunoblastic T-cell lymphoma', 'Disease', 'MESH:D002813', (255, 306))	('patients', 'Species', '9606', (211, 219))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (137, 159))	('CG', 'Chemical', 'MESH:C028505', (415, 417))	('cancers', 'Phenotype', 'HP:0002664', (342, 349))	('IDH1', 'Gene', '3417', (40, 44))	('gliomas', 'Disease', 'MESH:D005910', (92, 99))	('acute myeloid leukemias', 'Phenotype', 'HP:0004808', (137, 160))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (331, 349))	('IDH2', 'Gene', (52, 56))	('glioblastomas', 'Phenotype', 'HP:0012174', (114, 127))	('myeloid leukemias', 'Phenotype', 'HP:0012324', (143, 160))	('acute lymphoblastic leukemia', 'Disease', (225, 253))	('chondrosarcomas', 'Phenotype', 'HP:0006765', (255, 270))	('IDH2', 'Gene', '3418', (52, 56))	('T-cell lymphoma', 'Phenotype', 'HP:0012190', (291, 306))	('pancreatic cancers', 'Disease', (331, 349))	('CG', 'Chemical', 'MESH:C028505', (412, 414))	('acute lymphoblastic leukemia', 'Disease', 'MESH:D054198', (225, 253))	('carcinoma', 'Phenotype', 'HP:0030731', (173, 182))	('carcinomas', 'Phenotype', 'HP:0030731', (173, 183))	('gliomas', 'Phenotype', 'HP:0009733', (92, 99))	('gain-of-function', 'PosReg', (10, 26))	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (225, 253))	('pancreatic cancers', 'Disease', 'MESH:D010190', (331, 349))	('acute myeloid leukemias and colangiocarcinomas', 'Disease', 'MESH:D015470', (137, 183))	('glioblastomas', 'Disease', (114, 127))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (308, 326))	('lymphoma', 'Phenotype', 'HP:0002665', (298, 306))
122729	24705290	The mutations, which occur at the active site of IDHs, alter the reaction order of the enzymes such that high concentrations of d-2-hydroxyglutarate (2-HG), rather than alpha-KG, are released (Figure 2).	('rat', 'Species', '10116', (117, 120))	('IDH', 'Gene', (49, 52))	('rat', 'Species', '10116', (144, 147))	('IDH', 'Gene', '3417', (49, 52))	('d-2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (128, 148))	('rat', 'Species', '10116', (157, 160))	('reaction order', 'MPA', (65, 79))	('mutations', 'Var', (4, 13))	('alter', 'Reg', (55, 60))
122731	24705290	In melanoma, loss of 5mC through oxidation to 5hmC has been observed both as a result of IDH1 or IDH2 neomorphic mutations as well as the downregulation of TET and IDH2 genes.	('IDH2', 'Gene', (97, 101))	('5hmC', 'Chemical', 'MESH:C011865', (46, 50))	('IDH2', 'Gene', '3418', (164, 168))	('5mC', 'Chemical', 'MESH:D044503', (21, 24))	('IDH2', 'Gene', '3418', (97, 101))	('mutations', 'Var', (113, 122))	('IDH2', 'Gene', (164, 168))	('TET', 'Chemical', 'MESH:C010349', (156, 159))	('melanoma', 'Phenotype', 'HP:0002861', (3, 11))	('IDH1', 'Gene', (89, 93))	('melanoma', 'Disease', (3, 11))	('downregulation', 'NegReg', (138, 152))	('melanoma', 'Disease', 'MESH:D008545', (3, 11))	('IDH1', 'Gene', '3417', (89, 93))
122734	24705290	In mouse embryonic stem cells, 5fC and 5hmC were found to be enriched in intragenic regions, especially within exons and enhancers, where they colocalized with histone acetyltransferase p300 sites, DNaseI hypersensitive sites and CTCF-bound regions, specifically at poised enhancers, which are marked by H3K4me1[+] and H3K27ac[-], in comparison to active enhancers (H3K4me1[+] H3K27ac[+]), concomitantly with a decrease in 5mC.	('5mC', 'Chemical', 'MESH:D044503', (423, 426))	('mouse', 'Species', '10090', (3, 8))	('5mC', 'MPA', (423, 426))	('5hmC', 'Chemical', 'MESH:C011865', (39, 43))	('H3K27ac[-]', 'Var', (319, 329))	('hypersensitive', 'Disease', 'MESH:D004342', (205, 219))	('decrease', 'NegReg', (411, 419))	('H3K4me1[+]', 'Var', (304, 314))	('hypersensitive', 'Disease', (205, 219))	('DNaseI', 'Gene', '13419', (198, 204))	('DNaseI', 'Gene', (198, 204))	('H3K4me1[+] H3K27ac[+]', 'Var', (366, 387))
122736	24705290	CG:CG hypermethylation at specific genes was also found to represent a marker for relapse-free survival time after surgery in a cohort of 444 patients with non-small cell lung cancer.	('hypermethylation', 'Var', (6, 22))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (156, 182))	('CG', 'Chemical', 'MESH:C028505', (0, 2))	('CG', 'Chemical', 'MESH:C028505', (3, 5))	('lung cancer', 'Phenotype', 'HP:0100526', (171, 182))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('non-small cell lung cancer', 'Disease', (156, 182))	('relapse-free survival', 'Disease', (82, 103))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (160, 182))	('patients', 'Species', '9606', (142, 150))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (156, 182))
122737	24705290	Specifically, patients with zero to one methylated markers in the HIST1H4F, PCDHGB6, NPBWR1, ALX1 and HOXA9 genes were characterized by a longer relapse-free survival time than those with two or more hypermethylated markers; 48% from the enriched methylated group relapsed, as compared with only 18% of those in the less methylated group.	('patients', 'Species', '9606', (14, 22))	('HIST1H4F', 'Gene', '8361', (66, 74))	('HOXA9', 'Gene', (102, 107))	('NPBWR1', 'Gene', '2831', (85, 91))	('ALX1', 'Gene', '8092', (93, 97))	('PCDHGB6', 'Gene', '56100', (76, 83))	('methylated markers', 'Var', (40, 58))	('ALX1', 'Gene', (93, 97))	('HIST1H4F', 'Gene', (66, 74))	('PCDHGB6', 'Gene', (76, 83))	('longer', 'PosReg', (138, 144))	('relapsed', 'CPA', (264, 272))	('Sp', 'Chemical', '-', (0, 2))	('NPBWR1', 'Gene', (85, 91))	('relapse-free survival time', 'CPA', (145, 171))	('HOXA9', 'Gene', '3205', (102, 107))
122739	24705290	In double-stranded DNA, deamination rates for C and 5mC are extremely slow, of the order of 10-13 s-1 (Table 2), which translates into half-lives ranging between ~30,000 to ~85,000 years.	('rat', 'Species', '10116', (36, 39))	('5mC', 'Chemical', 'MESH:D044503', (52, 55))	('double-stranded', 'Var', (3, 18))	('deamination', 'MPA', (24, 35))
122744	24705290	Further support is provided by the finding that C T transitions decrease gradually with increasing nucleosome occupancy score in comparative studies of S. cerevisiae, medaka (Oryzias lapites) and C. elegans genomes.	('decrease', 'NegReg', (64, 72))	('Oryzias lapites', 'Disease', 'None', (175, 190))	('C. elegans', 'Species', '6239', (196, 206))	('S. cerevisiae', 'Species', '4932', (152, 165))	('medaka', 'Species', '8090', (167, 173))	('Oryzias lapites', 'Disease', (175, 190))	('rat', 'Species', '10116', (134, 137))	('nucleosome', 'Var', (99, 109))	('C T', 'MPA', (48, 51))
122752	24705290	H2O2 may also generate free radicals, including the hydroxyl radical (OH), the most potent oxidizing radical generated by the cell, through routes including ionizing radiation, interactions with O2- through the Haber-Weiss reaction and by interactions with transition metal ions [Fe(II) and Cu(I)/Cu(II)] through Fenton chemistry, as exemplified in reaction 1.	('rat', 'Species', '10116', (18, 21))	('radical', 'Chemical', '-', (101, 108))	('O2', 'Chemical', '-', (2, 4))	('radical', 'Chemical', '-', (61, 68))	('O2-', 'Protein', (195, 198))	('metal', 'Chemical', 'MESH:D008670', (268, 273))	('free radicals', 'Chemical', 'MESH:D005609', (23, 36))	('radical', 'Chemical', '-', (28, 35))	('Cu(II)', 'Chemical', '-', (297, 303))	('interactions', 'Interaction', (177, 189))	('interactions', 'Interaction', (239, 251))	('Fe(II)', 'Chemical', '-', (280, 286))	('Cu(I)', 'Chemical', '-', (291, 296))	('hydroxyl radical', 'Chemical', 'MESH:D017665', (52, 68))	('free radicals', 'MPA', (23, 36))	('H2O2', 'Chemical', 'MESH:D006861', (0, 4))	('rat', 'Species', '10116', (113, 116))	('O2', 'Chemical', '-', (195, 197))	('H2O2', 'Var', (0, 4))
122765	24705290	Both ROS and copper concentrations have been found to be enhanced in tumors, raising the possibility that ROS-dependent deamination at methylated CG:CG sites may contribute to mutation in cancer.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('ROS', 'Chemical', 'MESH:D017382', (106, 109))	('copper', 'Chemical', 'MESH:D003300', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('enhanced', 'PosReg', (57, 65))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('CG', 'Chemical', 'MESH:C028505', (149, 151))	('CG', 'Chemical', 'MESH:C028505', (146, 148))	('tumors', 'Disease', (69, 75))	('rat', 'Species', '10116', (27, 30))	('cancer', 'Disease', (188, 194))	('tumors', 'Disease', 'MESH:D009369', (69, 75))	('mutation', 'Var', (176, 184))	('contribute', 'Reg', (162, 172))	('deamination', 'MPA', (120, 131))	('ROS', 'Chemical', 'MESH:D017382', (5, 8))
122767	24705290	In the high-resolution crystal structures of human APOBEC2 and the catalytic domain of APOBEC3G (aa 197-380), a water molecule serves as a hydrogen donor, whereas a conserved glutamate residue (E100 in APOBEC2 and E259 in APOBEC3G) functions as a proton shuffler during the hydrolytic cycle.	('APOBEC3G', 'Gene', (87, 95))	('hydrogen', 'Chemical', 'MESH:D006859', (139, 147))	('water', 'Chemical', 'MESH:D014867', (112, 117))	('glutamate', 'Chemical', 'MESH:D018698', (175, 184))	('APOBEC3G', 'Gene', '60489', (87, 95))	('E100', 'Var', (194, 198))	('human', 'Species', '9606', (45, 50))	('APOBEC3G', 'Gene', (222, 230))	('APOBEC2', 'Gene', '10930', (202, 209))	('APOBEC2', 'Gene', '10930', (51, 58))	('APOBEC2', 'Gene', (51, 58))	('APOBEC3G', 'Gene', '60489', (222, 230))	('APOBEC2', 'Gene', (202, 209))	('donor', 'Species', '9606', (148, 153))	('E259', 'Var', (214, 218))
122770	24705290	Experiments performed by scoring mutations either in viral DNA or in vitro with model sequences indicate strong effects on deamination rates by nucleotides flanking the target cytosine: optimal substrates include (C/G)TC(A/G) for APOBEC3B, T(T/C)C for APOBEC3C, CCCA for APOBEC3G, TTCT for APOBEC3F, WRCY (W = A or T; R = A or G; Y = C or T) for AID, although comparative analyses using enzymatic kinetic constants awaits further work.	('APOBEC3G', 'Gene', '60489', (271, 279))	('rat', 'Species', '10116', (365, 368))	('APOBEC3F', 'Gene', '200316', (290, 298))	('rat', 'Species', '10116', (135, 138))	('APOBEC3F', 'Gene', (290, 298))	('mutations', 'Var', (33, 42))	('AID', 'Gene', '57379', (346, 349))	('APOBEC3B', 'Gene', (230, 238))	('APOBEC3B', 'Gene', '9582', (230, 238))	('T(T/C)C', 'Var', (240, 247))	('AID', 'Gene', (346, 349))	('rat', 'Species', '10116', (199, 202))	('APOBEC3G', 'Gene', (271, 279))	('APOBEC3C', 'Gene', '27350', (252, 260))	('APOBEC3C', 'Gene', (252, 260))	('cytosine', 'Chemical', 'MESH:D003596', (176, 184))	('C/G)TC', 'Var', (214, 220))
122785	24705290	For example, although three main products were generally observed (Sp > Gh > Iz), at low riboflavin concentrations (<15 muM) oligonucleotides containing G8-oxoGG, C8-oxoGT and T8-oxoGC yielded relatively high levels of Sp that decreased as a function of increasing riboflavin concentration.	('muM', 'Gene', '56925', (120, 123))	('riboflavin', 'Chemical', 'MESH:D012256', (89, 99))	('C8-oxoGT', 'Var', (163, 171))	('Sp', 'Chemical', '-', (67, 69))	('T8-oxoGC', 'Var', (176, 184))	('low riboflavin', 'Phenotype', 'HP:0100504', (85, 99))	('muM', 'Gene', (120, 123))	('rat', 'Species', '10116', (283, 286))	('G8-oxoGG', 'Var', (153, 161))	('riboflavin', 'Chemical', 'MESH:D012256', (265, 275))	('rat', 'Species', '10116', (107, 110))	('Sp', 'Chemical', '-', (219, 221))	('oligonucleotides', 'Chemical', 'MESH:D009841', (125, 141))
122787	24705290	In contrast to riboflavin, nitrosoperoxycarbonate (ONOOCO2-), generated from macrophage-derived nitric oxide (NO) and superoxide (O2-), failed to yield sequence-dependent 8-oxoG reactivity and displayed a rather uniform spectrum of oxidation products, which were dominated by DGh > Oxaluric acid > NO2-DGh.	('O2', 'Chemical', '-', (299, 301))	('DGh', 'Chemical', 'MESH:C475501', (302, 305))	('DGh', 'Chemical', 'MESH:C475501', (276, 279))	('rat', 'Species', '10116', (205, 208))	('nitric oxide', 'Chemical', 'MESH:D009569', (96, 108))	('nitrosoperoxycarbonate', 'Chemical', 'MESH:C512272', (27, 49))	('NO2-DGh', 'Var', (298, 305))	('NO2', 'Chemical', 'MESH:D009585', (298, 301))	('superoxide', 'Chemical', 'MESH:D013481', (118, 128))	('O2', 'Chemical', '-', (130, 132))	('Oxaluric acid', 'Chemical', 'MESH:C008727', (282, 295))	('failed', 'NegReg', (136, 142))	('riboflavin', 'Chemical', 'MESH:D012256', (15, 25))	('8-oxoG reactivity', 'MPA', (171, 188))	('O2', 'Chemical', '-', (56, 58))	('DGh', 'MPA', (276, 279))	('rat', 'Species', '10116', (66, 69))	('ONOOCO2', 'Chemical', '-', (51, 58))
122801	24705290	Two monofunctional DNA glycosylases display a preference for correcting T:G and U:G mismatches in the CG:CG sequence context in double-stranded DNA, methyl-CpG binding domain protein 4 (MBD4) and thymine DNA glycosylase (TDG).	('CG', 'Chemical', 'MESH:C028505', (105, 107))	('thymine DNA glycosylase', 'Gene', '6996', (196, 219))	('mismatches', 'Var', (84, 94))	('CG', 'Chemical', 'MESH:C028505', (102, 104))	('methyl-CpG binding domain protein 4', 'Gene', '8930', (149, 184))	('thymine DNA glycosylase', 'Gene', (196, 219))	('methyl-CpG binding domain protein 4', 'Gene', (149, 184))	('correcting', 'Var', (61, 71))	('MBD4', 'Gene', '8930', (186, 190))	('MBD4', 'Gene', (186, 190))
122802	24705290	MBD4 contains an N-terminal methyl-CpG binding domain and a C-terminal DNA glycosylase domain that acts on T:G, 5hmU:G and U:G mismatches with relative rate constants of 0.5, 1.0 and 1.7 min-1, respectively, and on Tg:G with half the efficiency observed for T:G. Thus, the enzyme is poised to recognize deamination products of 5mC:G, 5hmC:G and C:G within CG:CG sequences.	('CG', 'Chemical', 'MESH:C028505', (356, 358))	('rat', 'Species', '10116', (152, 155))	('5mC', 'Chemical', 'MESH:D044503', (327, 330))	('Tg', 'Chemical', '-', (215, 217))	('CG', 'Chemical', 'MESH:C028505', (359, 361))	('MBD4', 'Gene', '8930', (0, 4))	('MBD4', 'Gene', (0, 4))	('mismatches', 'Var', (127, 137))	('5hmC', 'Chemical', 'MESH:C011865', (334, 338))
122804	24705290	Competition experiments indicate that CG:CG methylation enhances MBD4 binding and that, whereas glycosylase activity is observed on reconstituted chromatin, activity is enhanced upon histone tail acetylation, consistent with increased accessibility of the target sites on a less compact chromatin environment.	('methylation', 'Var', (44, 55))	('CG', 'Chemical', 'MESH:C028505', (38, 40))	('binding', 'Interaction', (70, 77))	('histone', 'Protein', (183, 190))	('iron', 'Chemical', 'MESH:D007501', (300, 304))	('CG', 'Chemical', 'MESH:C028505', (41, 43))	('MBD4', 'Gene', '8930', (65, 69))	('MBD4', 'Gene', (65, 69))	('activity', 'MPA', (157, 165))	('enhanced', 'PosReg', (169, 177))	('enhances', 'PosReg', (56, 64))
122805	24705290	TDG actively processes a number of lesions resulting from oxidation, alkylation and deamination of C, 5mC, 5hmC, T and A, with the strongest activities observed on U:G > T:G > Tg:G mismatches.	('5hmC', 'Chemical', 'MESH:C011865', (107, 111))	('Tg', 'Chemical', '-', (176, 178))	('oxidation', 'Var', (58, 67))	('U:G > T:G > Tg:G mismatches', 'Var', (164, 191))	('deamination', 'MPA', (84, 95))	('5mC', 'Chemical', 'MESH:D044503', (102, 105))	('mismatches', 'Var', (181, 191))	('alkylation', 'MPA', (69, 79))
122807	24705290	Loss of TDG expression is embryonic lethal in mice and, indeed, a number of investigations support a role for TDG in demethylation during embyogenesis, whereas interactions with transcription factors, transcriptional coregulators, DNMT3a, DNMT3b and others, suggest a scenario in which coordinated CG:CG methylation/demethylation and chromatin organization serve to regulate gene expression.	('CG', 'Chemical', 'MESH:C028505', (298, 300))	('regulate', 'Reg', (366, 374))	('mice', 'Species', '10090', (46, 50))	('TDG', 'Gene', (8, 11))	('demethylation', 'MPA', (117, 130))	('Loss', 'Var', (0, 4))	('CG', 'Chemical', 'MESH:C028505', (301, 303))
122811	24705290	By contrast, for nei endonuclease VIII-like 1 (NEIL1, a bifunctional enzyme with beta,delta-lyase activity), no stereoselectivity was detected; however, Tg:G was excised much more rapidly than Tg:A, suggesting that NEIL1 may be primarily involved in the repair of modified CG:CG sites.	('Tg:G', 'Var', (153, 157))	('eta', 'Gene', (82, 85))	('NEIL1', 'Gene', '79661', (47, 52))	('NEIL1', 'Gene', (47, 52))	('Tg', 'Chemical', '-', (153, 155))	('NEIL1', 'Gene', (215, 220))	('Tg', 'Chemical', '-', (193, 195))	('nei endonuclease VIII-like 1', 'Gene', (17, 45))	('nei endonuclease VIII-like 1', 'Gene', '79661', (17, 45))	('CG', 'Chemical', 'MESH:C028505', (273, 275))	('NEIL1', 'Gene', '79661', (215, 220))	('eta', 'Gene', '1909', (82, 85))	('CG', 'Chemical', 'MESH:C028505', (276, 278))
122812	24705290	Nth1-/-Neil1-/- double mutant, but not single mutant, mice developed a high incidence of lung and liver tumors after the first year, implying overlapping roles in DNA repair.	('liver tumors', 'Phenotype', 'HP:0002896', (98, 110))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('double mutant', 'Var', (16, 29))	('Neil1', 'Gene', '72774', (7, 12))	('Neil1', 'Gene', (7, 12))	('Nth1', 'Gene', '18207', (0, 4))	('mice', 'Species', '10090', (54, 58))	('lung and liver tumors', 'Disease', 'MESH:D008175', (89, 110))	('Nth1', 'Gene', (0, 4))
122818	24705290	In vitro, SMUG1 is active either on single-stranded or double-stranded DNA, depending on salt concentrations.	('rat', 'Species', '10116', (101, 104))	('salt', 'Chemical', 'MESH:D012492', (89, 93))	('SMUG1', 'Gene', '23583', (10, 15))	('SMUG1', 'Gene', (10, 15))	('double-stranded', 'Var', (55, 70))
122823	24705290	In chronic myeloid leukemia in chronic phase (CML-CP) hematopoietic stem cells, the kinase activity associated with the BCL-ABL1 translocation was found to inhibit UNG2 activity, thereby promoting mutations arising from increased ROS-mediated oxidative base lesions.	('UNG2', 'Enzyme', (164, 168))	('ROS', 'Chemical', 'MESH:D017382', (230, 233))	('inhibit', 'NegReg', (156, 163))	('chronic myeloid leukemia', 'Phenotype', 'HP:0005506', (3, 27))	('CML-CP', 'Disease', (46, 52))	('kinase activity', 'MPA', (84, 99))	('BCL-ABL1', 'Gene', (120, 128))	('chronic myeloid leukemia', 'Disease', (3, 27))	('mutations', 'Var', (197, 206))	('activity', 'MPA', (169, 177))	('chronic myeloid leukemia', 'Disease', 'MESH:D015464', (3, 27))	('promoting', 'PosReg', (187, 196))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (11, 27))	('BCL-ABL1', 'Gene', '25', (120, 128))	('CML-CP', 'Disease', 'MESH:D015464', (46, 52))	('leukemia', 'Phenotype', 'HP:0001909', (19, 27))
122831	24705290	In vitro, Oz in Oz:C and Gh in Gh:C mispairs in duplex oligonucleotides were cleaved by NEIL1 as efficiently as the well-recognized pyrimidine lesion 5hU:G, implying that guanine oxidation lesions, in addition to pyrimidine lesions, are good substrates for the enzyme.	('guanine', 'Chemical', 'MESH:D006147', (171, 178))	('NEIL1', 'Gene', (88, 93))	('mispairs', 'Var', (36, 44))	('pyrimidine', 'Chemical', 'MESH:C030986', (213, 223))	('NEIL1', 'Gene', '79661', (88, 93))	('rat', 'Species', '10116', (247, 250))	('oligonucleotides', 'Chemical', 'MESH:D009841', (55, 71))	('pyrimidine', 'Chemical', 'MESH:C030986', (132, 142))
122833	24705290	NEIL1 and NHTL1 also cleaved Oz:G as efficiently as Oz:C, which would give rise to G C transversions; Oz:G mispairs are predicted to arise from Pol alpha or epsilon replication across Oz, as mentioned below.	('arise from', 'Reg', (133, 143))	('Pol alpha', 'Gene', (144, 153))	('mispairs', 'Var', (107, 115))	('NEIL1', 'Gene', (0, 5))	('Pol alpha', 'Gene', '5422', (144, 153))	('NEIL1', 'Gene', '79661', (0, 5))
122836	24705290	The purified human catalytic domain of NEIL3 was also found to display strong preference for Sp and Gh when compared to several other lesions, including 5-OHC and 5-OHU, with the greatest turnover number (0.035 s-1) on Gh in single-stranded DNA, as assessed from single turnover experiments, ~2-fold higher than on double-stranded Gh and single-/double-stranded Sp.	('Sp', 'Chemical', '-', (362, 364))	('human', 'Species', '9606', (13, 18))	('Sp', 'Chemical', '-', (93, 95))	('5-OHU', 'Chemical', '-', (163, 168))	('higher', 'PosReg', (300, 306))	('NEIL3', 'Gene', '55247', (39, 44))	('single-stranded DNA', 'Var', (225, 244))	('NEIL3', 'Gene', (39, 44))	('5-OHC', 'Chemical', '-', (153, 158))
122846	24705290	Indeed, a Y567A mutant of RB69 was found to insert both bases with >100-fold increased efficiency, whereas extension was blocked.	('Y567A', 'Var', (10, 15))	('RB69', 'Gene', (26, 30))	('Y567A', 'Mutation', 'p.Y567A', (10, 15))	('increased', 'PosReg', (77, 86))	('RB69', 'Species', '12353', (26, 30))	('insert both bases', 'MPA', (44, 61))
122855	24705290	Given that cancer genome analyses have indicated that the number of SBSs is often lower at sites of putative base lesions on the transcribed strand than on the non-transcribed strand, we will briefly discuss some key aspects of transcription-coupled repair.	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('base lesions', 'Var', (109, 121))	('cancer', 'Disease', 'MESH:D009369', (11, 17))	('SBSs', 'Chemical', '-', (68, 72))	('cancer', 'Disease', (11, 17))	('lower', 'NegReg', (82, 87))
122856	24705290	Nucleotide excision repair (NER) is considered to be the main pathway for the repair of UV photo-induced DNA lesions; CPDs and 6-4 pyrimidine-pyrimidone photo products (6-4PP), and defects in NER components are associated with inherited DNA repair syndromes such as xeroderma pigmentosum and Cockayne syndrome, that display severe hypersensitivity to sunlight.	('6-4 pyrimidine-pyrimidone', 'Chemical', '-', (127, 152))	('CPDs', 'Disease', 'MESH:C565866', (118, 122))	('hypersensitivity', 'Disease', (331, 347))	('hypersensitivity', 'Disease', 'MESH:D004342', (331, 347))	('Cockayne syndrome', 'Disease', (292, 309))	('xeroderma pigmentosum', 'Disease', (266, 287))	('xeroderma pigmentosum', 'Disease', 'MESH:D014983', (266, 287))	('severe hypersensitivity to sunlight', 'Phenotype', 'HP:0007537', (324, 359))	('associated', 'Reg', (211, 221))	('hypersensitivity to sunlight', 'Phenotype', 'HP:0000992', (331, 359))	('defects', 'Var', (181, 188))	('CPDs', 'Disease', (118, 122))	('Cockayne syndrome', 'Disease', 'MESH:D003057', (292, 309))	('6-4PP', 'Chemical', '-', (169, 174))
122864	24705290	For example, exome sequencing of urothelial carcinomas of the upper urinary tract associated with chronic exposure to aristolochic acid, a natural compound from traditional herb medicine, revealed a characteristic A T (T A) mutational signature on non-transcribed strands leading to splicing defects, which was attributed to a failure of GG-NER, but not TC-NER, to recognize aristolactam-DNA adducts.	('mutational', 'Var', (224, 234))	('urothelial carcinomas', 'Disease', 'MESH:D014526', (33, 54))	('urothelial carcinomas of the upper urinary', 'Phenotype', 'HP:0010935', (33, 75))	('splicing defects', 'MPA', (283, 299))	('T (T A', 'Gene', (216, 222))	('carcinomas', 'Phenotype', 'HP:0030731', (44, 54))	('TC-NER', 'Chemical', '-', (354, 360))	('carcinoma', 'Phenotype', 'HP:0030731', (44, 53))	('aristolochic acid', 'Chemical', 'MESH:C000228', (118, 135))	('leading to', 'Reg', (272, 282))	('urothelial carcinomas', 'Disease', (33, 54))
122869	24705290	Finally, a rise in mutations was inferred on selected, transcribed, genes in NEIL2 knock-down compared to control cells.	('NEIL2', 'Gene', (77, 82))	('rise', 'PosReg', (11, 15))	('NEIL2', 'Gene', '252969', (77, 82))	('knock-down', 'Var', (83, 93))	('mutations', 'MPA', (19, 28))
122873	24705290	Herein we have provided information on the most prominent SBS mutation patterns found in cancer genomes, i.e., C T transitions at CG:CG sites and substitutions at C:G base-pairs in the context of YC:GR dinucleotides, in an attempt to examine the validity of currently proposed models of mutagenesis.	('CG', 'Chemical', 'MESH:C028505', (133, 135))	('CG', 'Chemical', 'MESH:C028505', (130, 132))	('substitutions', 'Var', (146, 159))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('cancer', 'Disease', (89, 95))	('mutation', 'Var', (62, 70))	('SBS', 'Gene', (58, 61))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('dinucleotides', 'Chemical', 'MESH:D015226', (202, 215))
122874	24705290	The main points may be summarized as follows: (i) higher fractions of SBSs have been found in cancer genomes within gene-poor regions, which are associated with heterochromatin and replicate late during the cell cycle, than in euchromatin, a pattern that mimics the one observed in population analyses; (ii) there are several established mechanisms for base substitutions at C residues, and their relative importance is only now being recognized.	('SBSs', 'Chemical', '-', (70, 74))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('base substitutions', 'Var', (353, 371))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
122878	24705290	Second, as noted, the modest (5-fold at the most) increase in spontaneous deamination rates for C5-substituted Cs relative to Cs contrasts with the larger fractions of mutated Cs at CG:CG sites relative to non-CG:CG sites (up to 10-50 times), both in cancer and the germline.	('rat', 'Species', '10116', (86, 89))	('CG', 'Chemical', 'MESH:C028505', (213, 215))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('CG', 'Chemical', 'MESH:C028505', (182, 184))	('CG', 'Chemical', 'MESH:C028505', (185, 187))	('CG', 'Chemical', 'MESH:C028505', (210, 212))	('C5-substituted', 'Var', (96, 110))	('increase', 'PosReg', (50, 58))	('cancer', 'Disease', 'MESH:D009369', (251, 257))	('cancer', 'Disease', (251, 257))	('spontaneous deamination', 'MPA', (62, 85))
122879	24705290	Third, there does not seem to be a rational barrier to the possibility that 5mC oxidation and further deamination may yield Tg:G mismatches at CG:CG sites, which would then lead to C T transitions during TLS.	('Tg', 'Chemical', '-', (124, 126))	('Tg:G', 'Gene', (124, 128))	('CG', 'Chemical', 'MESH:C028505', (143, 145))	('5mC', 'Chemical', 'MESH:D044503', (76, 79))	('CG', 'Chemical', 'MESH:C028505', (146, 148))	('mismatches', 'Var', (129, 139))	('rat', 'Species', '10116', (35, 38))	('C T transitions', 'MPA', (181, 196))	('lead to', 'Reg', (173, 180))	('yield', 'Reg', (118, 123))
122880	24705290	In fact, the observation that such a type of oxidation is facilitated by nucleosome occupancy raises the prospect for thymine glycols in Tg:G mispairs being a more prominent source of mutation at CG:CG sites than T:G mismatches, as previously pointed out.	('mispairs', 'Var', (142, 150))	('CG', 'Chemical', 'MESH:C028505', (196, 198))	('CG', 'Chemical', 'MESH:C028505', (199, 201))	('thymine glycols', 'Chemical', 'MESH:C029389', (118, 133))	('Tg', 'Chemical', '-', (137, 139))	('mutation', 'Var', (184, 192))
122881	24705290	The finding that C:G T:A substitutions at CG:CG dinucleotides showed a strong positive correlation with the age at cancer diagnosis in ER- cancers, but not in ER+ cancers, further supports the conclusion that spontaneous deamination of 5mC may not be the only mechanism leading to mutations at CG:CG.	('substitutions', 'Var', (25, 38))	('cancers', 'Phenotype', 'HP:0002664', (139, 146))	('5mC', 'Chemical', 'MESH:D044503', (236, 239))	('CG', 'Chemical', 'MESH:C028505', (42, 44))	('cancers', 'Disease', (139, 146))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('cancer', 'Disease', 'MESH:D009369', (163, 169))	('cancers', 'Disease', 'MESH:D009369', (163, 170))	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('ER- cancers', 'Disease', (135, 146))	('CG', 'Gene', (294, 296))	('CG', 'Chemical', 'MESH:C028505', (294, 296))	('cancers', 'Disease', 'MESH:D009369', (139, 146))	('ER- cancers', 'Disease', 'MESH:D009369', (135, 146))	('cancer', 'Disease', (163, 169))	('cancers', 'Phenotype', 'HP:0002664', (163, 170))	('cancer', 'Disease', (139, 145))	('cancer', 'Disease', (115, 121))	('cancers', 'Disease', (163, 170))	('CG', 'Chemical', 'MESH:C028505', (45, 47))	('CG dinucleotides', 'Chemical', 'MESH:C015772', (45, 61))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('mutations', 'Var', (281, 290))	('CG', 'Chemical', 'MESH:C028505', (297, 299))	('CG', 'Gene', (42, 44))
122886	24705290	One severe limitation in elucidating mechanisms of SBS is obviously the lack of information on the steady-state levels of modified bases and mismatches in cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('mismatches', 'Var', (141, 151))	('cancer', 'Disease', (155, 161))	('cancer', 'Disease', 'MESH:D009369', (155, 161))
122943	31747591	Non-genetic heterogeneity also influences subclonal dynamics, shaping the trajectory of tumor evolution.	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('Non-genetic heterogeneity', 'Var', (0, 25))	('influences', 'Reg', (31, 41))	('shaping', 'Reg', (62, 69))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor', 'Disease', (88, 93))
122947	31747591	Recent studies have suggested that immune editing influence both lung cancer evolution and survival, pointing toward complex interplay between the tumor and microenvironment.	('survival', 'CPA', (91, 99))	('tumor', 'Disease', (147, 152))	('lung cancer', 'Disease', 'MESH:D008175', (65, 76))	('immune editing', 'Var', (35, 49))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('lung cancer', 'Disease', (65, 76))	('lung cancer', 'Phenotype', 'HP:0100526', (65, 76))	('evolution', 'CPA', (77, 86))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('influence', 'Reg', (50, 59))
122957	31747591	This is in line with observations that nearly half of the somatic mutations in tumor genomes likely arise in progenitor cells prior to tumor development, while CNAs in pre-neoplastic tissues are rare.	('mutations', 'Var', (66, 75))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('tumor', 'Disease', (79, 84))	('tumor', 'Disease', (135, 140))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
122962	31747591	However, there are exceptions, e.g., in P2 potentially pathogenic mutation in KMT2D, a histone methyl-transferase implicated in non-small-cell lung cancer was only found in regions R2 and R3.	('pathogenic', 'Reg', (55, 65))	('KMT2D', 'Gene', '8085', (78, 83))	('lung cancer', 'Phenotype', 'HP:0100526', (143, 154))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('KMT2D', 'Gene', (78, 83))	('methyl', 'Chemical', 'MESH:C031105', (95, 101))	('non-small-cell lung cancer', 'Disease', (128, 154))	('mutation', 'Var', (66, 74))	('non-small-cell lung cancer', 'Disease', 'MESH:D002289', (128, 154))
122963	31747591	For instance, amplification of SOX2 was accompanied by higher SOX2 expression in tumors relative to matched non-malignant tissue (Figure S1; Data S2).	('SOX2', 'Gene', '6657', (62, 66))	('tumors', 'Disease', (81, 87))	('SOX2', 'Gene', (31, 35))	('SOX2', 'Gene', (62, 66))	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('SOX2', 'Gene', '6657', (31, 35))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('expression', 'MPA', (67, 77))	('higher', 'PosReg', (55, 61))	('amplification', 'Var', (14, 27))
122972	31747591	Somatic mutations carried mutation signatures for smoking, consistent with the etiology of lung squamous cell carcinoma (LUSC), as well as signatures of defective DNA mismatch repair, APOBEC, and 5-methylcytosine deamination (Figure 1E).	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (96, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('defective', 'Var', (153, 162))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (91, 119))	('DNA', 'Gene', (163, 166))	('APOBEC', 'Gene', (184, 190))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (91, 119))	('5-methylcytosine', 'MPA', (196, 212))	('5-methylcytosine', 'Chemical', 'MESH:D044503', (196, 212))	('lung squamous cell carcinoma', 'Disease', (91, 119))
122973	31747591	APOBEC mutation signature was proportionally higher in non-ubiquitous mutations, suggesting that it probably arises late during tumor development.	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('APOBEC', 'Gene', (0, 6))	('mutation', 'Var', (7, 15))	('tumor', 'Disease', (128, 133))	('higher', 'PosReg', (45, 51))
122975	31747591	P1-R1, P1-R3, and P2-R1 were closer to the non-malignant samples, which might be due to low tumor purity in these regions (Figure S1).	('P2-R1', 'Var', (18, 23))	('low tumor', 'Disease', 'MESH:D009800', (88, 97))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('low tumor', 'Disease', (88, 97))	('P1-R1', 'Var', (0, 5))	('P1-R3', 'Var', (7, 12))
122982	31747591	The nuclear factor kappaB (NFkappaB) activation pathway, which is associated with cell survival, was found to be highly deregulated in certain regions of tumors P3-R1 and P3-R3, P4-R1, and P5-R3.	('tumors', 'Disease', (154, 160))	('P4-R1', 'Var', (178, 183))	('nuclear factor kappaB', 'Gene', (4, 25))	('P3-R3', 'Var', (171, 176))	('P5-R3', 'Var', (189, 194))	('P3-R1', 'Var', (161, 166))	('NFkappaB', 'Gene', (27, 35))	('tumors', 'Disease', 'MESH:D009369', (154, 160))	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('NFkappaB', 'Gene', '4790', (27, 35))	('deregulated', 'PosReg', (120, 131))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('nuclear factor kappaB', 'Gene', '4790', (4, 25))
122989	31747591	PI score was typically high in the tumor regions compared to adjacent normal tissues, but there were intra-tumor regional differences, e.g., P2-R2, P4-R3, P4-5, and P5-R1-3 showed a higher PI score than other regions in the same tumors (Figure 2D).	('tumors', 'Disease', 'MESH:D009369', (229, 235))	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('intra-tumor', 'Disease', 'MESH:D009369', (101, 112))	('tumor', 'Disease', 'MESH:D009369', (229, 234))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('P2-R2', 'Var', (141, 146))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('tumor', 'Disease', (35, 40))	('intra-tumor', 'Disease', (101, 112))	('P4-R3', 'Var', (148, 153))	('tumor', 'Disease', (229, 234))	('higher', 'PosReg', (182, 188))	('tumors', 'Phenotype', 'HP:0002664', (229, 235))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('P4-5', 'Var', (155, 159))	('tumors', 'Disease', (229, 235))
122993	31747591	P4 and P5 samples showed heterogeneity in epithelial-mesenchymal (EM) characteristic score across different regions (Figure 2D), with P4-R3 and P4-R4 depicting higher epithelial signature relative to other regions.	('P4-R3', 'Var', (134, 139))	('P4 and P5', 'Gene', '201780;10130', (0, 9))	('higher', 'PosReg', (160, 166))	('epithelial signature', 'MPA', (167, 187))	('P4-R4', 'Var', (144, 149))
122994	31747591	Similarly P5-R1 and P5-R3 have a higher EM score than other regions.	('EM score', 'CPA', (40, 48))	('higher', 'PosReg', (33, 39))	('Si', 'Chemical', 'MESH:D012825', (0, 2))	('P5-R1', 'Var', (10, 15))
123008	31747591	Reduction in the burden of ubiquitous neo-epitopes relative to that observed for somatic mutations is suggestive of immune-mediated negative selection purging tumor cells carrying mutations that could elicit immune response.	('burden of ubiquitous neo-epitopes', 'MPA', (17, 50))	('purging', 'NegReg', (151, 158))	('mutations', 'Var', (180, 189))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('tumor', 'Disease', (159, 164))	('Reduction', 'NegReg', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (159, 164))
123015	31747591	In general, the abundance of immune cell types showed ITH higher than that at other levels, and joint patterns of regional variations in immune cell infiltration and neo-epitopes suggest that immunological pruning of tumor cell populations by neo-epitope depletion impose negative selection during tumor evolution, an emerging theme observed elsewhere as well.	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('tumor', 'Disease', (217, 222))	('tumor', 'Disease', (298, 303))	('depletion', 'Var', (255, 264))	('tumor', 'Disease', 'MESH:D009369', (217, 222))	('tumor', 'Disease', 'MESH:D009369', (298, 303))	('tumor', 'Phenotype', 'HP:0002664', (298, 303))
123033	31747591	Even though the extent of overall ITH differed between genetic and non-genetic levels, regional differences were biologically consistent at the meta-heterogeneity level, as evident from copy-number-mediated expression changes, association between TERT expression and telomere length, and immune-mediated selection on neo-epitope burden.	('copy-number-mediated', 'Var', (186, 206))	('TERT', 'Gene', (247, 251))	('TERT', 'Gene', '7015', (247, 251))	('association', 'Interaction', (227, 238))	('changes', 'Var', (218, 225))	('telomere length', 'CPA', (267, 282))
123053	31747591	Missense, nonsense, frameshift, or splicing mutations in known COSMIC cancer genes with high-predicted impact were marked.	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('splicing mutations', 'Var', (35, 53))	('nonsense', 'Var', (10, 18))	('frameshift', 'Var', (20, 30))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('Missense', 'Var', (0, 8))
123109	31395502	We discovered that SYT7 is significantly altered by TWIST1 expression.	('TWIST1', 'Gene', (52, 58))	('altered', 'Reg', (41, 48))	('TWIST1', 'Gene', '7291', (52, 58))	('SYT7', 'MPA', (19, 23))	('expression', 'Var', (59, 69))
123114	31395502	Knocking down of SYT7 increased the expression of E-cadherin and decreased the level of N-cadherin and Vimentin in cultured cells.	('N-cadherin', 'Gene', '1000', (88, 98))	('Knocking down', 'Var', (0, 13))	('Vimentin', 'Gene', (103, 111))	('E-cadherin', 'Gene', (50, 60))	('decreased', 'NegReg', (65, 74))	('SYT7', 'Gene', (17, 21))	('E-cadherin', 'Gene', '999', (50, 60))	('Vimentin', 'Gene', '7431', (103, 111))	('increased', 'PosReg', (22, 31))	('N-cadherin', 'Gene', (88, 98))	('expression', 'MPA', (36, 46))
123116	31395502	This project was supported by grants from the Major Scientific and Technological Innovation Project of Shandong Province (2018CXGC1212), Science and Technology Foundation of Shandong Province (2014GSF118084, 2016GSF121043), Medical and Health Technology Innovation Plan of Jinan City (201805002) and the National Natural Science Foundation of China (81372333).	('CXGC1212', 'CellLine', 'CVCL:1V55', (126, 134))	('2016GSF121043', 'Var', (208, 221))	('201805002', 'Var', (285, 294))
123126	31395502	Although the response rates in subsets of NSCLC with tyrosine kinase receptors (mutant EGFR, ALK, and ROS1) were high, drug resistance has been a major challenge.	('NSCLC', 'Disease', (42, 47))	('EGFR', 'Gene', '1956', (87, 91))	('ROS1', 'Gene', (102, 106))	('mutant', 'Var', (80, 86))	('NSCLC', 'Disease', 'MESH:D002289', (42, 47))	('ROS1', 'Gene', '6098', (102, 106))	('EGFR', 'Gene', (87, 91))	('NSCLC', 'Phenotype', 'HP:0030358', (42, 47))	('ALK', 'Gene', (93, 96))	('drug resistance', 'Phenotype', 'HP:0020174', (119, 134))
123193	31395502	2c-d, HCS experiments in TWIST1-OE H1975 cells showed that the most significant disruption of cell migration was from SYT7 gene knockdown (0.12, P < .05 in comparison with the control group, and Student's t-test) and CEP85 gene knockdown (0.35, P < .05 in comparison with the control group, and Student's t-test).	('disruption', 'NegReg', (80, 90))	('CEP85', 'Gene', (217, 222))	('TWIST1', 'Gene', (25, 31))	('SYT7 gene', 'Gene', (118, 127))	('TWIST1', 'Gene', '7291', (25, 31))	('knockdown', 'Var', (228, 237))	('knockdown', 'Var', (128, 137))	('H1975', 'CellLine', 'CVCL:1511', (35, 40))	('P < .05', 'Gene', '106479023', (245, 252))	('P < .05', 'Gene', (245, 252))	('cell migration', 'CPA', (94, 108))	('P < .05', 'Gene', (145, 152))	('CEP85', 'Gene', '64793', (217, 222))	('P < .05', 'Gene', '106479023', (145, 152))
123194	31395502	The suppression of cell migration by SYT7 and CEP85 gene knockdown was also demonstrated in A549 cells (0.28, P < .05; 0.57, P < .05, respectively; Student's t-test, Fig.	('P < .05', 'Gene', '106479023', (125, 132))	('suppression', 'NegReg', (4, 15))	('SYT7', 'Gene', (37, 41))	('P < .05', 'Gene', (125, 132))	('CEP85', 'Gene', '64793', (46, 51))	('knockdown', 'Var', (57, 66))	('CEP85', 'Gene', (46, 51))	('cell migration', 'CPA', (19, 33))	('A549', 'CellLine', 'CVCL:0023', (92, 96))	('P < .05', 'Gene', (110, 117))	('gene knockdown', 'Var', (52, 66))	('P < .05', 'Gene', '106479023', (110, 117))
123199	31395502	The results showed that SYT7 was significantly downregulated after the knockdown of TWIST1 (P < .001, Student's t-test, Fig.	('downregulated', 'NegReg', (47, 60))	('knockdown', 'Var', (71, 80))	('TWIST1', 'Gene', (84, 90))	('TWIST1', 'Gene', '7291', (84, 90))	('SYT7', 'Gene', (24, 28))
123214	31395502	In the LUAD patients, the high expression of SYT7 was significantly associated with gender (P = .03, Pearson's chi2 test), differentiation grade (P = .033, Pearson's chi2 test), and TNM stage (P = .03, Pearson's chi2 test).	('patients', 'Species', '9606', (12, 20))	('LUAD', 'Phenotype', 'HP:0030078', (7, 11))	('associated', 'Reg', (68, 78))	('high', 'Var', (26, 30))	('SYT7', 'Gene', (45, 49))	('TNM stage', 'CPA', (182, 191))	('differentiation grade', 'CPA', (123, 144))
123221	31395502	For the LUAD patients (n = 720), poor OS was also associated with high expression of SYT7 (HR = 1.64, P < .001, Kaplan-Meier, and the log-rank test; Fig.	('patients', 'Species', '9606', (13, 21))	('SYT7', 'Gene', (85, 89))	('LUAD', 'Phenotype', 'HP:0030078', (8, 12))	('high', 'Var', (66, 70))	('poor OS', 'Disease', (33, 40))
123230	31395502	5a), suggesting that SYT7 had a significant effect on the proliferation of A549 and H1299 cells.	('H1299', 'CellLine', 'CVCL:0060', (84, 89))	('proliferation', 'CPA', (58, 71))	('A549', 'CellLine', 'CVCL:0023', (75, 79))	('SYT7', 'Var', (21, 25))
123231	31395502	When compared with the shCtrl group, the apoptotic rates of A549 and H1299 cells in the shSYT7 group significantly increased (P < .01, Student's t-test; Fig.	('increased', 'PosReg', (115, 124))	('apoptotic rates', 'CPA', (41, 56))	('shSYT7', 'Var', (88, 94))	('A549', 'CellLine', 'CVCL:0023', (60, 64))	('H1299', 'CellLine', 'CVCL:0060', (69, 74))
123232	31395502	5b), suggesting that the knockout of SYT7 significantly increased apoptosis in A549 and H1299 cells.	('SYT7', 'Gene', (37, 41))	('increased', 'PosReg', (56, 65))	('A549', 'CellLine', 'CVCL:0023', (79, 83))	('H1299', 'CellLine', 'CVCL:0060', (88, 93))	('knockout', 'Var', (25, 33))	('apoptosis', 'CPA', (66, 75))
123234	31395502	The results showed that the expression of E-cadherin was significantly increased after the knockdown of SYT7.	('expression', 'MPA', (28, 38))	('knockdown', 'Var', (91, 100))	('SYT7', 'Gene', (104, 108))	('E-cadherin', 'Gene', (42, 52))	('increased', 'PosReg', (71, 80))	('E-cadherin', 'Gene', '999', (42, 52))
123236	31395502	These results indicated that the knockdown of SYT7 significantly inhibited EMT of H1299 cells.	('SYT7', 'Gene', (46, 50))	('knockdown', 'Var', (33, 42))	('inhibited', 'NegReg', (65, 74))	('H1299', 'CellLine', 'CVCL:0060', (82, 87))
123240	31395502	Similarly, the invasion assay revealed that the invasiveness was significantly elevated in the SYT7-OE groups of A549 and H1299 cells (P < .001, Student's t-test; Fig.	('invasiveness', 'CPA', (48, 60))	('SYT7-OE', 'Var', (95, 102))	('H1299', 'CellLine', 'CVCL:0060', (122, 127))	('A549', 'CellLine', 'CVCL:0023', (113, 117))	('elevated', 'PosReg', (79, 87))	('invasion assay', 'CPA', (15, 29))
123243	31395502	The results showed that the amount of fluorescence expression in the shSYT7 group significantly reduced compared with the shCtrl group (P < .05, Student's t-test; Fig.	('reduced', 'NegReg', (96, 103))	('P < .05', 'Gene', (136, 143))	('P < .05', 'Gene', '106479023', (136, 143))	('fluorescence expression', 'MPA', (38, 61))	('shSYT7', 'Var', (69, 75))
123249	31395502	We performed Western blotting to detect the protein expression of SYT7 in the lung tumor tissues, showing significantly decreased SYT7 protein levels in the shSYT7 group compared with the shCtrl group (Fig.	('decreased', 'NegReg', (120, 129))	('lung tumor', 'Phenotype', 'HP:0100526', (78, 88))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('SYT7 protein levels', 'MPA', (130, 149))	('lung tumor', 'Disease', (78, 88))	('lung tumor', 'Disease', 'MESH:D008175', (78, 88))	('shSYT7', 'Var', (157, 163))
123250	31395502	Taken together, these results indicated that the knockdown of SYT7 significantly inhibited the tumor growth of the lung cancer cells in vivo.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('knockdown', 'Var', (49, 58))	('inhibited', 'NegReg', (81, 90))	('lung cancer', 'Disease', 'MESH:D008175', (115, 126))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('lung cancer', 'Phenotype', 'HP:0100526', (115, 126))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('SYT7', 'Gene', (62, 66))	('lung cancer', 'Disease', (115, 126))	('tumor', 'Disease', (95, 100))
123255	31395502	The knockdown of SYT7 weakened the metastasis and invasion abilities of the TWIST1-OE H1975 cells.	('invasion abilities', 'CPA', (50, 68))	('weakened', 'NegReg', (22, 30))	('H1975', 'CellLine', 'CVCL:1511', (86, 91))	('SYT7', 'Gene', (17, 21))	('TWIST1', 'Gene', (76, 82))	('TWIST1', 'Gene', '7291', (76, 82))	('knockdown', 'Var', (4, 13))
123259	31395502	The knockdown of SYT7 significantly inhibited tumor promotion role of lung cancer cells in vivo.	('lung cancer', 'Disease', 'MESH:D008175', (70, 81))	('inhibited', 'NegReg', (36, 45))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('SYT7', 'Gene', (17, 21))	('tumor', 'Disease', (46, 51))	('lung cancer', 'Disease', (70, 81))	('lung cancer', 'Phenotype', 'HP:0100526', (70, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('knockdown', 'Var', (4, 13))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
123273	31395502	Furthermore, the repression of SYT7 inhibited the tumorigenicity and tumor growth of the NSCLC cells in vivo.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('NSCLC', 'Disease', 'MESH:D002289', (89, 94))	('inhibited', 'NegReg', (36, 45))	('tumor', 'Disease', (69, 74))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('NSCLC', 'Phenotype', 'HP:0030358', (89, 94))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('SYT7', 'Gene', (31, 35))	('repression', 'Var', (17, 27))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('NSCLC', 'Disease', (89, 94))	('tumor', 'Disease', (50, 55))
123277	31395502	After the knockdown of SYT7, the expression of E-cadherin significantly increased, and the expression of N-cadherin and Vimentin significantly reduced.	('expression', 'MPA', (91, 101))	('N-cadherin', 'Gene', '1000', (105, 115))	('Vimentin', 'Gene', '7431', (120, 128))	('SYT7', 'Gene', (23, 27))	('increased', 'PosReg', (72, 81))	('E-cadherin', 'Gene', (47, 57))	('E-cadherin', 'Gene', '999', (47, 57))	('expression', 'MPA', (33, 43))	('Vimentin', 'Gene', (120, 128))	('knockdown', 'Var', (10, 19))	('N-cadherin', 'Gene', (105, 115))	('reduced', 'NegReg', (143, 150))
123292	31395502	In vivo, the repression of SYT7 resulted in the dramatic suppression of tumor growth, which could be a vigorous therapeutic strategy for future NSCLC treatment.	('NSCLC', 'Disease', (144, 149))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('NSCLC', 'Disease', 'MESH:D002289', (144, 149))	('tumor', 'Disease', (72, 77))	('SYT7', 'Gene', (27, 31))	('suppression', 'NegReg', (57, 68))	('NSCLC', 'Phenotype', 'HP:0030358', (144, 149))	('repression', 'Var', (13, 23))	('tumor', 'Disease', 'MESH:D009369', (72, 77))
123293	31395502	This project was supported by grants from the  (2018CXGC1212),  (2014GSF118084, 2016GSF121043),  (201805002) and the  (81372333).	('2016GSF121043', 'Var', (80, 93))	('201805002', 'Var', (98, 107))	('CXGC1212', 'CellLine', 'CVCL:1V55', (52, 60))	('2014GSF118084', 'Var', (65, 78))
123315	27669705	The histological subtypes of lung cancer were classified as follows: carcinomas (International Classification of Diseases for Oncology third edition morphological codes 8010-8576), sarcoma (8800-8811, 8830, 8840-8921, 8990-8991, 9040, 9044, 9120-9133, 9150, and 9540-9581), other specified cancers, including pulmonary blastoma, and unspecified (8000-8005).	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('sarcoma', 'Disease', 'MESH:D012509', (181, 188))	('sarcoma', 'Disease', (181, 188))	('9540-9581', 'Var', (262, 271))	('carcinomas', 'Disease', (69, 79))	('cancers', 'Disease', 'MESH:D009369', (290, 297))	('Oncology', 'Phenotype', 'HP:0002664', (126, 134))	('pulmonary blastoma', 'Disease', (309, 327))	('lung cancer', 'Disease', (29, 40))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))	('9040', 'Var', (229, 233))	('unspecified', 'Disease', (333, 344))	('9044', 'Var', (235, 239))	('sarcoma', 'Phenotype', 'HP:0100242', (181, 188))	('pulmonary blastoma', 'Disease', 'MESH:D018202', (309, 327))	('8840-8921', 'Var', (207, 216))	('8800-8811', 'Var', (190, 199))	('8830', 'Var', (201, 205))	('unspecified', 'Species', '32644', (333, 344))	('9120-9133', 'Var', (241, 250))	('carcinomas', 'Phenotype', 'HP:0030731', (69, 79))	('carcinomas', 'Disease', 'MESH:D002277', (69, 79))	('cancers', 'Phenotype', 'HP:0002664', (290, 297))	('cancers', 'Disease', (290, 297))	('lung cancer', 'Disease', 'MESH:D008175', (29, 40))	('8990-8991', 'Var', (218, 227))	('cancer', 'Phenotype', 'HP:0002664', (290, 296))	('lung cancer', 'Phenotype', 'HP:0100526', (29, 40))
123316	27669705	Carcinomas were further classified as follows: squamous cell carcinoma (8050-8078 and 8083-8084), adenocarcinoma (8140, 8211, 8230-8231, 8250-8260, 8323, 8480-8490, 8550-8551, 8570-8574, and 8576), small-cell carcinoma (8041-8045 and 8246), large-cell carcinoma (8010-8012, 8014-8031, 8035, and 8310), and other specified carcinomas.	('Carcinomas', 'Disease', (0, 10))	('8570-8574', 'Var', (176, 185))	('8041-8045', 'Var', (220, 229))	('8480-8490', 'Var', (154, 163))	('large-cell carcinoma', 'Phenotype', 'HP:0030360', (241, 261))	('carcinomas', 'Disease', (322, 332))	('Carcinomas', 'Phenotype', 'HP:0030731', (0, 10))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('8576', 'Var', (191, 195))	('8014-8031', 'Var', (274, 283))	('8140', 'Var', (114, 118))	('8083-8084', 'Var', (86, 95))	('8550-8551', 'Var', (165, 174))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (47, 70))	('small-cell carcinoma', 'Phenotype', 'HP:0030357', (198, 218))	('adenocarcinoma', 'Disease', (98, 112))	('large-cell carcinoma', 'Disease', 'MESH:D018287', (241, 261))	('carcinoma', 'Phenotype', 'HP:0030731', (252, 261))	('carcinoma', 'Phenotype', 'HP:0030731', (322, 331))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('carcinomas', 'Phenotype', 'HP:0030731', (322, 332))	('8010-8012', 'Var', (263, 272))	('carcinomas', 'Disease', 'MESH:D002277', (322, 332))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (47, 70))	('Carcinomas', 'Disease', 'MESH:D002277', (0, 10))	('8230-8231', 'Var', (126, 135))	('adenocarcinoma', 'Disease', 'MESH:D000230', (98, 112))	('small-cell carcinoma', 'Disease', 'MESH:D018288', (198, 218))	('8250-8260', 'Var', (137, 146))	('large-cell carcinoma', 'Disease', (241, 261))	('carcinoma', 'Phenotype', 'HP:0030731', (209, 218))	('small-cell carcinoma', 'Disease', (198, 218))	('8323', 'Var', (148, 152))	('squamous cell carcinoma', 'Disease', (47, 70))	('8050-8078', 'Var', (72, 81))
123403	30652536	As shown by survival curves for BRCA (Fig 2E), MESO (Fig 2F), and PAAD (Fig 2G), the OS of patients with high levels of MAP2K1 and CDK4/6 was significantly lower than the OS of patients with low levels of MAP2K1 and CDK4/6.	('PAAD', 'Disease', 'MESH:D010195', (66, 70))	('CDK4/6', 'Gene', (131, 137))	('high', 'Var', (105, 109))	('MAP2K1', 'Gene', '5604', (205, 211))	('patients', 'Species', '9606', (91, 99))	('patients', 'Species', '9606', (177, 185))	('MAP2K1', 'Gene', '5604', (120, 126))	('BRCA', 'Gene', '672', (32, 36))	('MESO', 'Disease', 'MESH:D008654', (47, 51))	('MESO', 'Disease', (47, 51))	('MAP2K1', 'Gene', (205, 211))	('MAP2K1', 'Gene', (120, 126))	('BRCA', 'Gene', (32, 36))	('PAAD', 'Disease', (66, 70))	('lower', 'NegReg', (156, 161))
123407	30652536	As shown in Figure 3, synergistic effect was predicted for several MAPK1 combinations evidenced by short OS in the high (ie, more than the median) MAPK1-high other gene-expression group and significantly better OS within the cohort in which expression of both of these genes is low (ie, below median).	('MAPK1', 'Gene', (67, 72))	('MAPK1', 'Gene', (147, 152))	('combinations', 'Var', (73, 85))	('MAPK1', 'Gene', '5594', (67, 72))	('MAPK1', 'Gene', '5594', (147, 152))
123430	30652536	ERK inhibitors are being tested in the clinic for the treatment of tumors with aberrant MAPK pathway signaling; however, combination therapies will probably be necessary to achieve durable tumor control.	('tumor', 'Disease', (189, 194))	('MAPK pathway signaling', 'Pathway', (88, 110))	('tumors', 'Disease', 'MESH:D009369', (67, 73))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('aberrant', 'Var', (79, 87))	('ERK', 'Gene', '5594', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('tumor', 'Disease', (67, 72))	('ERK', 'Gene', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('tumors', 'Disease', (67, 73))
123432	30652536	ERK inhibition may also be the best way to disrupt this pathway in other RAS-driven tumors.	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('ERK', 'Gene', '5594', (0, 3))	('inhibition', 'Var', (4, 14))	('tumors', 'Disease', 'MESH:D009369', (84, 90))	('tumors', 'Disease', (84, 90))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('ERK', 'Gene', (0, 3))
123433	30652536	Our results show that expression of multiple novel targets might synergistically affect patient survival, and inhibition of these genes may increase the efficacy of ERK inhibitors.	('patient', 'Species', '9606', (88, 95))	('efficacy', 'MPA', (153, 161))	('ERK', 'Gene', '5594', (165, 168))	('affect', 'Reg', (81, 87))	('inhibition', 'Var', (110, 120))	('patient survival', 'CPA', (88, 104))	('increase', 'PosReg', (140, 148))	('ERK', 'Gene', (165, 168))
123434	30652536	We demonstrate that expression of MAPK1 and PKN3 both have to be low to predict better OS, and PKN3 inhibition may increase efficacy of the MAPK inhibitor sorafenib.	('MAPK', 'Enzyme', (140, 144))	('MAPK1', 'Gene', (34, 39))	('PKN3', 'Gene', '263803', (44, 48))	('PKN3', 'Gene', (44, 48))	('PKN3', 'Gene', (95, 99))	('sorafenib', 'Chemical', 'MESH:C471405', (155, 164))	('increase', 'PosReg', (115, 123))	('PKN3', 'Gene', '263803', (95, 99))	('inhibition', 'Var', (100, 110))	('efficacy', 'MPA', (124, 132))	('MAPK1', 'Gene', '5594', (34, 39))
123516	30930849	On the other hand, SIRT1 expression is found to be associated with good prognosis for head and neck squamous cell carcinoma patients, and colorectal cancer.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (100, 123))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (95, 123))	('colorectal cancer', 'Phenotype', 'HP:0003003', (138, 155))	('SIRT1', 'Gene', (19, 24))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('colorectal cancer', 'Disease', (138, 155))	('associated', 'Reg', (51, 61))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('neck squamous cell carcinoma', 'Disease', (95, 123))	('expression', 'Var', (25, 35))	('SIRT1', 'Gene', '23411', (19, 24))	('patients', 'Species', '9606', (124, 132))	('colorectal cancer', 'Disease', 'MESH:D015179', (138, 155))
123517	30930849	Therefore, the prognostic and clinicopathological significance of SIRT1 abnormal expression in cancers remain to be elucidated.	('cancers', 'Phenotype', 'HP:0002664', (95, 102))	('cancers', 'Disease', (95, 102))	('cancers', 'Disease', 'MESH:D009369', (95, 102))	('abnormal', 'Var', (72, 80))	('SIRT1', 'Gene', '23411', (66, 71))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('SIRT1', 'Gene', (66, 71))
123520	30930849	In the present study, we conducted an updated and more comprehensive meta-analysis and subgroup analysis to reveal the prognostic value and clinicopathological association of SIRT1 abnormal expression in cancers.	('cancers', 'Phenotype', 'HP:0002664', (204, 211))	('cancers', 'Disease', (204, 211))	('SIRT1', 'Gene', '23411', (175, 180))	('cancers', 'Disease', 'MESH:D009369', (204, 211))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('abnormal expression', 'Var', (181, 200))	('SIRT1', 'Gene', (175, 180))
123528	30930849	If the pooled HR < 1 and their 95% CI did not overlap the invalid line in the forest plot, the high expression of SIRT1 predicted a good OS.	('high', 'Var', (95, 99))	('SIRT1', 'Gene', (114, 119))	('SIRT1', 'Gene', '23411', (114, 119))	('OS', 'Chemical', '-', (137, 139))
123542	30930849	SIRT1 expression predicted a significantly worse DFS in Asian population with cancers (n = 13, HR: 1.683, 95% CI: [1.235, 2.294], P < 0.0010, I2 = 74.27%), whereas one article suggested that increased expression of SIRT1 is correlated with Caucasian patient DFS (HR: 1.344, 95% CI: [1.040; 1.736], P = 0.0237) (Supplementary Figure 2C).	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('SIRT1', 'Gene', '23411', (215, 220))	('SIRT1', 'Gene', '23411', (0, 5))	('SIRT1', 'Gene', (215, 220))	('cancers', 'Disease', 'MESH:D009369', (78, 85))	('cancers', 'Phenotype', 'HP:0002664', (78, 85))	('DFS', 'MPA', (49, 52))	('increased', 'PosReg', (191, 200))	('DFS', 'Disease', (258, 261))	('cancers', 'Disease', (78, 85))	('SIRT1', 'Gene', (0, 5))	('expression', 'MPA', (201, 211))	('expression', 'Var', (6, 16))	('patient', 'Species', '9606', (250, 257))	('worse', 'NegReg', (43, 48))
123560	30930849	This subgroup analysis demonstrated a significantly lower heterogeneity value in Asian group (n = 40, RR: 1.708, 95% CI: [1.406, 2.076], I2 = 69.59%), which suggests that the high SIRT1 expression has stronger efficacy in the Asian population than the Caucasian population.	('high', 'Var', (175, 179))	('SIRT1', 'Gene', (180, 185))	('SIRT1', 'Gene', '23411', (180, 185))	('efficacy', 'MPA', (210, 218))
123562	30930849	This subgroup analysis demonstrated a significantly lower heterogeneity value in China (n = 17, RR: 1.638, 95% CI: [1.404, 1.911], I2 = 41.16%), which suggests that the high SIRT1 expression has stronger efficacy in the China population than the other countries.	('efficacy', 'MPA', (204, 212))	('high', 'Var', (169, 173))	('SIRT1', 'Gene', (174, 179))	('SIRT1', 'Gene', '23411', (174, 179))
123565	30930849	The association between HRs (Supplementary Figure 7) or RRs (Supplementary Figure 8) and standard error for the SIRT1 expression was demonstrated in funnel plots, with each plot point representing a study.	('RRs', 'Var', (56, 59))	('SIRT1', 'Gene', (112, 117))	('SIRT1', 'Gene', '23411', (112, 117))	('association', 'Interaction', (4, 15))
123593	30930849	Our subgroup correlation analysis between SIRT1 expression and prognosis of cancer in different countries and ethnic groups showed that high expression of SIRT1 predicted poor OS and DFS in China, poor OS and EFS but not DFS in Korea, poor OS in Japan, EFS in USA, but not OS in USA or Netherlands.	('OS', 'Chemical', '-', (202, 204))	('SIRT1', 'Gene', (155, 160))	('OS', 'Chemical', '-', (240, 242))	('OS', 'Chemical', '-', (176, 178))	('high', 'Var', (136, 140))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('OS', 'Chemical', '-', (273, 275))	('SIRT1', 'Gene', '23411', (42, 47))	('SIRT1', 'Gene', '23411', (155, 160))	('SIRT1', 'Gene', (42, 47))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))
123602	30930849	Although the data on mutations and polymorphisms of SIRT1 are very limited, we speculate that difference in SIRT1 mutations and polymorphisms may be one of accounts for difference in predicting OS and TNM stage and lymphatic metastasis of cancer by SIRT1 expression.	('SIRT1', 'Gene', '23411', (249, 254))	('SIRT1', 'Gene', (108, 113))	('SIRT1', 'Gene', (249, 254))	('metastasis of cancer', 'Disease', (225, 245))	('mutations', 'Var', (114, 123))	('metastasis of cancer', 'Disease', 'MESH:D009362', (225, 245))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))	('TNM', 'Gene', '10178', (201, 204))	('OS', 'Chemical', '-', (194, 196))	('SIRT1', 'Gene', '23411', (52, 57))	('SIRT1', 'Gene', (52, 57))	('SIRT1', 'Gene', '23411', (108, 113))	('TNM', 'Gene', (201, 204))
123609	30930849	Consistently, the study by Hong et al showed that high SIRT1 expression correlated with vascular invasion and was not significantly correlated with overall survival rates in colon cancer.	('SIRT1', 'Gene', (55, 60))	('colon cancer', 'Phenotype', 'HP:0003003', (174, 186))	('colon cancer', 'Disease', 'MESH:D015179', (174, 186))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('expression', 'MPA', (61, 71))	('vascular invasion', 'CPA', (88, 105))	('correlated with', 'Reg', (72, 87))	('colon cancer', 'Disease', (174, 186))	('SIRT1', 'Gene', '23411', (55, 60))	('high', 'Var', (50, 54))
123610	30930849	Study with 3024 patients by Wu et al showed that high SIRT1 expression predicts poor survival in non-colorectal gastrointestinal cancer, but not in colorectal cancer.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('colorectal cancer', 'Disease', 'MESH:D015179', (148, 165))	('poor', 'NegReg', (80, 84))	('SIRT1', 'Gene', '23411', (54, 59))	('colorectal cancer', 'Phenotype', 'HP:0003003', (148, 165))	('patients', 'Species', '9606', (16, 24))	('SIRT1', 'Gene', (54, 59))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (112, 135))	('colorectal cancer', 'Disease', (148, 165))	('non-colorectal gastrointestinal cancer', 'Disease', 'MESH:D015179', (97, 135))	('high', 'Var', (49, 53))	('non-colorectal gastrointestinal cancer', 'Disease', (97, 135))	('colorectal gastrointestinal cancer', 'Phenotype', 'HP:0002672', (101, 135))
123612	30930849	In an analysis of 1,650 patients in seven studies, high SIRT1 expression predicts a poor prognosis of gastric cancer patients and linked with patients' age, T stage, N stage, and tumor differentiation.	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('gastric cancer', 'Disease', (102, 116))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('patients', 'Species', '9606', (117, 125))	('high', 'Var', (51, 55))	('gastric cancer', 'Disease', 'MESH:D013274', (102, 116))	('linked', 'Reg', (130, 136))	('patients', 'Species', '9606', (24, 32))	('SIRT1', 'Gene', '23411', (56, 61))	('patients', 'Species', '9606', (142, 150))	('gastric cancer', 'Phenotype', 'HP:0012126', (102, 116))	('SIRT1', 'Gene', (56, 61))	('tumor', 'Disease', (179, 184))
123619	30930849	Secondly, there is publication bias for SIRT1 expression and prognosis or clinicopathological characteristics as indicated by asymmetry of funnel plots for OS, DFS, EFS, RFS, CCS, PFS, and clinicopathological characteristics.	('RFS', 'Var', (170, 173))	('SIRT1', 'Gene', '23411', (40, 45))	('DFS', 'Var', (160, 163))	('SIRT1', 'Gene', (40, 45))	('OS', 'Chemical', '-', (156, 158))
123634	29545930	Whereas HAI-1 suppresses the neoplastic progression of keratinocytes to invasive squamous cell carcinoma (SCC) through matriptase inhibition, the role of HAI-2 in keratinocytes is poorly understood.	('HAI-1', 'Var', (8, 13))	('SCC', 'Phenotype', 'HP:0002860', (106, 109))	('SCC', 'Gene', '6317', (106, 109))	('invasive squamous cell carcinoma', 'Disease', 'MESH:D002294', (72, 104))	('inhibition', 'NegReg', (130, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('suppresses', 'NegReg', (14, 24))	('matriptase', 'Gene', (119, 129))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (81, 104))	('matriptase', 'Gene', '19143', (119, 129))	('neoplastic progression of keratinocytes', 'CPA', (29, 68))	('invasive squamous cell carcinoma', 'Disease', (72, 104))	('SCC', 'Gene', (106, 109))
123635	29545930	In vitro homozygous knockout of the SPINT2 gene suppressed the proliferation of two oral SCC (OSCC) lines (SAS and HSC3) but not the growth of a non-tumorigenic keratinocyte line (HaCaT).	('SCC', 'Gene', '6317', (95, 98))	('proliferation', 'CPA', (63, 76))	('SPINT2', 'Gene', (36, 42))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('SCC', 'Gene', '6317', (89, 92))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('suppressed', 'NegReg', (48, 58))	('SCC', 'Phenotype', 'HP:0002860', (89, 92))	('tumor', 'Disease', (149, 154))	('HSC3', 'Gene', '150353', (115, 119))	('knockout', 'Var', (20, 28))	('SCC', 'Gene', (95, 98))	('SCC', 'Phenotype', 'HP:0002860', (95, 98))	('HaCaT', 'CellLine', 'CVCL:0038', (180, 185))	('SCC', 'Gene', (89, 92))	('HSC3', 'Gene', (115, 119))
123637	29545930	The levels of prostasin protein were markedly increased in HAI-2-deficient cells, and knockdown of prostasin alleviated the HAI-2 loss-induced suppression of OSCC cell invasion.	('knockdown', 'Var', (86, 95))	('levels of prostasin protein', 'MPA', (4, 31))	('increased', 'PosReg', (46, 55))	('SCC', 'Gene', (159, 162))	('SCC', 'Phenotype', 'HP:0002860', (159, 162))	('HAI-2', 'Gene', (124, 129))	('alleviated', 'NegReg', (109, 119))	('SCC', 'Gene', '6317', (159, 162))	('loss-induced', 'NegReg', (130, 142))
123646	29545930	In oral squamous cell carcinoma (OSCC), HAI-1 insufficiency results in enhanced invasion of OSCC cells and increased cancer-associated fibroblasts through dysregulated pericellular activity of matriptase.	('dysregulated', 'Var', (155, 167))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (8, 31))	('SCC', 'Phenotype', 'HP:0002860', (34, 37))	('pericellular activity', 'MPA', (168, 189))	('SCC', 'Gene', (93, 96))	('increased', 'PosReg', (107, 116))	('SCC', 'Gene', '6317', (34, 37))	('matriptase', 'Gene', '19143', (193, 203))	('cancer', 'Disease', (117, 123))	('HAI-1 insufficiency', 'Disease', 'MESH:D000309', (40, 59))	('enhanced', 'PosReg', (71, 79))	('SCC', 'Gene', (34, 37))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('SCC', 'Phenotype', 'HP:0002860', (93, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('HAI-1 insufficiency', 'Disease', (40, 59))	('invasion', 'CPA', (80, 88))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (3, 31))	('matriptase', 'Gene', (193, 203))	('oral squamous cell carcinoma', 'Disease', (3, 31))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('SCC', 'Gene', '6317', (93, 96))
123649	29545930	Forced overexpression of HAI-1 or HAI-2 in keratinocytes has the potential to suppress the epidermal carcinogenesis and malignant progression in a matriptase transgenic mouse model using the keratin 5 promoter.	('matriptase', 'Gene', '19143', (147, 157))	('carcinogenesis', 'Disease', (101, 115))	('malignant progression', 'CPA', (120, 141))	('matriptase', 'Gene', (147, 157))	('suppress', 'NegReg', (78, 86))	('mouse', 'Species', '10090', (169, 174))	('HAI-1', 'Var', (25, 30))	('carcinogenesis', 'Disease', 'MESH:D063646', (101, 115))	('HAI-2', 'Var', (34, 39))
123662	29545930	Genome sequencing confirmed a frameshift near the initiation codon of the SPINT2 or SPINT1 gene, followed shortly by an in-frame stop codon (Supplementary Figure 2).	('SPINT1', 'Gene', '6692', (84, 90))	('SPINT2', 'Gene', (74, 80))	('frameshift', 'Var', (30, 40))	('SPINT1', 'Gene', (84, 90))
123669	29545930	Then, we analyzed the effect of SPINT2 deletion on tumor formation in nude mice using the SAS sublines.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('SPINT2', 'Gene', (32, 38))	('tumor', 'Disease', (51, 56))	('deletion', 'Var', (39, 47))	('nude mice', 'Species', '10090', (70, 79))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
123672	29545930	In agreement with the results of the in vitro growth study, SPINT2-/- cells formed smaller tumors than control SAS cells, but notable differences in histology were not observed (Figure 2E).	('tumors', 'Disease', (91, 97))	('tumors', 'Disease', 'MESH:D009369', (91, 97))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('SPINT2-/- cells', 'Var', (60, 75))	('smaller', 'NegReg', (83, 90))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))
123673	29545930	Previously, we reported that silencing of SPINT1 by short hairpin RNA enhanced the invasive capacity of cancer cells, including OSCC cells, indicating that HAI-1 is a suppressor of cancer cell invasion.	('N', 'Chemical', 'MESH:D009584', (67, 68))	('short hairpin RNA', 'Gene', (52, 69))	('SPINT1', 'Gene', '6692', (42, 48))	('SCC', 'Gene', '6317', (129, 132))	('SCC', 'Phenotype', 'HP:0002860', (129, 132))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('silencing', 'Var', (29, 38))	('SPINT1', 'Gene', (42, 48))	('SCC', 'Gene', (129, 132))	('N', 'Chemical', 'MESH:D009584', (45, 46))	('enhanced', 'PosReg', (70, 78))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('cancer', 'Disease', (181, 187))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))
123674	29545930	Therefore, we asked whether HAI-2 also suppressed cellular invasion of OSCC cells.	('HAI-2', 'Var', (28, 33))	('SCC', 'Gene', (72, 75))	('SCC', 'Phenotype', 'HP:0002860', (72, 75))	('SCC', 'Gene', '6317', (72, 75))	('suppressed', 'NegReg', (39, 49))
123677	29545930	Unexpectedly, the loss of HAI-2 significantly suppressed the invasion of SAS cells under both normoxic and hypoxic conditions.	('loss', 'Var', (18, 22))	('invasion of SAS cells', 'CPA', (61, 82))	('hypoxic conditions', 'Disease', (107, 125))	('hypoxic conditions', 'Disease', 'MESH:D009135', (107, 125))	('HAI-2', 'Gene', (26, 31))	('suppressed', 'NegReg', (46, 56))
123678	29545930	The pro-invasive role of HAI-2 was also observed in another OSCC cell line, HSC3 (Figure 3B).	('HAI-2', 'Var', (25, 30))	('SCC', 'Phenotype', 'HP:0002860', (61, 64))	('SCC', 'Gene', '6317', (61, 64))	('HSC3', 'Gene', '150353', (76, 80))	('SCC', 'Gene', (61, 64))	('HSC3', 'Gene', (76, 80))
123679	29545930	In contrast to SPINT2, knockout of SPINT1 resulted in enhanced Matrigel invasion capacity of SAS cells, confirming the previously reported anti-invasive role of HAI-1 in OSCC (Figure 3C).	('SCC', 'Gene', (171, 174))	('SCC', 'Phenotype', 'HP:0002860', (171, 174))	('knockout', 'Var', (23, 31))	('Matrigel invasion capacity of SAS cells', 'CPA', (63, 102))	('SCC', 'Gene', '6317', (171, 174))	('SPINT1', 'Gene', '6692', (35, 41))	('SPINT1', 'Gene', (35, 41))	('enhanced', 'PosReg', (54, 62))
123684	29545930	Next, we analyzed the molecular mechanism by which SPINT2 deletion suppressed OSCC cell migration and invasion.	('SCC', 'Gene', (79, 82))	('N', 'Chemical', 'MESH:D009584', (54, 55))	('invasion', 'CPA', (102, 110))	('N', 'Chemical', 'MESH:D009584', (0, 1))	('SCC', 'Phenotype', 'HP:0002860', (79, 82))	('SCC', 'Gene', '6317', (79, 82))	('SPINT2', 'Gene', (51, 57))	('deletion', 'Var', (58, 66))	('suppressed', 'NegReg', (67, 77))
123685	29545930	Gelatin zymography of serum-free culture supernatant showed gelatinolytic bands sensitive to GM6001, suggesting the presence of pro-matrix metalloprotease (MMP)-2 and -9; however, significant alterations of the gelatinolytic bands were not observed by the deletion of SPINT2 (Supplementary Figure 4A).	('SPINT2', 'Gene', (268, 274))	('pro-matrix metalloprotease (MMP)-2 and -9', 'Gene', '4313;4318', (128, 169))	('gelatinolytic', 'MPA', (60, 73))	('GM6001', 'Chemical', 'MESH:C078131', (93, 99))	('deletion', 'Var', (256, 264))
123688	29545930	Other membrane-anchored serine proteases, particularly TTSPs, may also be targets of HAI-2.	('HAI-2', 'Var', (85, 90))	('serine protease', 'Gene', (24, 39))	('TTSPs', 'Enzyme', (55, 60))	('serine protease', 'Gene', '2147', (24, 39))
123689	29545930	Therefore, we compared control cells and HAI-2 mutants for the expression levels of prostasin, matriptase and other membrane-anchored serine proteases.	('matriptase', 'Gene', (95, 105))	('expression', 'MPA', (63, 73))	('serine protease', 'Gene', (134, 149))	('matriptase', 'Gene', '19143', (95, 105))	('mutants', 'Var', (47, 54))	('serine protease', 'Gene', '2147', (134, 149))
123693	29545930	The endogenous prostasin protein levels were lower in OSCC cells than in HaCaT cells (Figure 4C), and loss of HAI-2 also upregulated the prostasin protein levels in both SAS and HSC3 cells (Figure 4D).	('HaCaT', 'CellLine', 'CVCL:0038', (73, 78))	('prostasin protein levels', 'MPA', (137, 161))	('endogenous prostasin protein levels', 'MPA', (4, 39))	('SCC', 'Gene', (55, 58))	('SCC', 'Phenotype', 'HP:0002860', (55, 58))	('HSC3', 'Gene', '150353', (178, 182))	('lower', 'NegReg', (45, 50))	('HAI-2', 'Gene', (110, 115))	('upregulated', 'PosReg', (121, 132))	('SCC', 'Gene', '6317', (55, 58))	('HSC3', 'Gene', (178, 182))	('loss', 'Var', (102, 106))
123695	29545930	To address this question, we examined how siRNA-mediated silencing of prostasin affected the migration and invasion of SPINT2-deleted OSCC cells.	('migration', 'CPA', (93, 102))	('N', 'Chemical', 'MESH:D009584', (122, 123))	('silencing', 'Var', (57, 66))	('SCC', 'Gene', (135, 138))	('SCC', 'Phenotype', 'HP:0002860', (135, 138))	('invasion', 'CPA', (107, 115))	('N', 'Chemical', 'MESH:D009584', (45, 46))	('affected', 'Reg', (80, 88))	('SCC', 'Gene', '6317', (135, 138))
123696	29545930	As shown in Figure 5A (SAS cells), Figure 5B (HSC3 cells) and Supplementary Figure 5, the silencing of prostasin resulted in the recovery of migratory and invasive capabilities of SPINT2-/- OSCC cells as judged by wound healing assays and Matrigel invasion assays, respectively, under normoxic conditions.	('migratory', 'CPA', (141, 150))	('HSC3', 'Gene', (46, 50))	('silencing', 'Var', (90, 99))	('prostasin', 'Gene', (103, 112))	('SCC', 'Gene', (191, 194))	('HSC3', 'Gene', '150353', (46, 50))	('SCC', 'Phenotype', 'HP:0002860', (191, 194))	('recovery', 'PosReg', (129, 137))	('Matrigel invasion assays', 'CPA', (239, 263))	('invasive capabilities', 'CPA', (155, 176))	('SCC', 'Gene', '6317', (191, 194))
123698	29545930	Decreased colony sizes in soft agar observed in HAI-2KO SAS was also alleviated by the silencing of prostasin, though the colony number was not altered (Supplementary Figure 5B).	('alleviated', 'NegReg', (69, 79))	('silencing', 'Var', (87, 96))	('HAI-2KO', 'Var', (48, 55))	('Decreased', 'NegReg', (0, 9))	('prostasin', 'Protein', (100, 109))	('colony sizes', 'CPA', (10, 22))	('agar', 'Chemical', 'MESH:D000362', (31, 35))
123704	29545930	Therefore, whereas the excess activation of matriptase occurred in the absence of HAI-2, it was inhibited by HAI-1.	('activation', 'PosReg', (30, 40))	('HAI-1', 'Var', (109, 114))	('matriptase', 'Gene', (44, 54))	('matriptase', 'Gene', '19143', (44, 54))
123705	29545930	The above in vitro and in vivo observations indicated that the function of HAI-2 was distinct from that of HAI-1 in neoplastic keratinocytes, and unlike HAI-1, HAI-2 expression may contribute to OSCC progression.	('SCC', 'Gene', (196, 199))	('HAI-2', 'Gene', (75, 80))	('SCC', 'Phenotype', 'HP:0002860', (196, 199))	('SCC', 'Gene', '6317', (196, 199))	('contribute', 'Reg', (181, 191))	('HAI-2', 'Var', (160, 165))
123711	29545930	In the invasive OSCC portion, 96% of the cases (24/25) showed HAI-2-high immunoreactivity, and 14 cases (56%) showed intense immunoreactivity in more than 50% of the cancer cells (i.e., score 4) (Table 1, Figure 6C).	('immunoreactivity', 'MPA', (73, 89))	('cancer', 'Disease', (166, 172))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('SCC', 'Phenotype', 'HP:0002860', (17, 20))	('immunoreactivity', 'MPA', (125, 141))	('SCC', 'Gene', '6317', (17, 20))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('HAI-2-high', 'Var', (62, 72))	('SCC', 'Gene', (17, 20))
123723	29545930	In our previous studies, we reported that loss of cell surface HAI-1 contributed to invasion of OSCC cells through dysregulation of its targeted protease, matriptase, but suppressed in vitro cellular proliferation.	('loss', 'Var', (42, 46))	('invasion', 'CPA', (84, 92))	('suppressed', 'NegReg', (171, 181))	('matriptase', 'Gene', '19143', (155, 165))	('SCC', 'Gene', (97, 100))	('matriptase', 'Gene', (155, 165))	('SCC', 'Phenotype', 'HP:0002860', (97, 100))	('SCC', 'Gene', '6317', (97, 100))	('HAI-1', 'Gene', (63, 68))	('dysregulation', 'MPA', (115, 128))
123724	29545930	In this study, depletion of HAI-2 also suppressed cell growth; however, in contrast to loss of HAI-1, the loss of HAI-2 significantly suppressed the migration and invasion of OSCC cells in vitro.	('suppressed', 'NegReg', (134, 144))	('SCC', 'Gene', (176, 179))	('SCC', 'Phenotype', 'HP:0002860', (176, 179))	('HAI-2', 'Gene', (114, 119))	('SCC', 'Gene', '6317', (176, 179))	('loss', 'Var', (106, 110))
123727	29545930	However, there is evidence for a physiological role for HAI-2 based on the discovery of SPINT2 mutations in the syndromic form of congenital sodium diarrhea.	('SPINT2', 'Gene', (88, 94))	('diarrhea', 'Phenotype', 'HP:0002014', (148, 156))	('diarrhea', 'Disease', (148, 156))	('sodium', 'Chemical', 'MESH:D012964', (141, 147))	('mutations', 'Var', (95, 104))	('diarrhea', 'Disease', 'MESH:D003967', (148, 156))
123728	29545930	The established critical roles of HAI-2 in embryogenesis and placenta formation are based on the studies of mutant mice.	('HAI-2', 'Gene', (34, 39))	('mutant', 'Var', (108, 114))	('mice', 'Species', '10090', (115, 119))
123733	29545930	The precise molecular mechanism by which loss of HAI-2 suppressed the invasiveness and growth of OSCC cells remains to be determined.	('SCC', 'Phenotype', 'HP:0002860', (98, 101))	('loss', 'Var', (41, 45))	('invasiveness', 'CPA', (70, 82))	('SCC', 'Gene', '6317', (98, 101))	('HAI-2', 'Gene', (49, 54))	('suppressed', 'NegReg', (55, 65))	('SCC', 'Gene', (98, 101))
123741	29545930	EMT is unlikely, as the E-cadherin level was not altered by HAI-2 loss.	('E-cadherin', 'Gene', (24, 34))	('E-cadherin', 'Gene', '999', (24, 34))	('HAI-2', 'Gene', (60, 65))	('loss', 'Var', (66, 70))
123756	29545930	Moreover, high HAI-2 expression in breast cancer was a significant predictor for poor clinical treatment response rate.	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('expression', 'MPA', (21, 31))	('breast cancer', 'Disease', 'MESH:D001943', (35, 48))	('breast cancer', 'Disease', (35, 48))	('high', 'Var', (10, 14))	('HAI-2', 'Gene', (15, 20))	('breast cancer', 'Phenotype', 'HP:0003002', (35, 48))
123765	29545930	Preparation and characterization of the mAbs M19, XY9, M24, M69 and 1N7 have been reported previously.	('N', 'Chemical', 'MESH:D009584', (69, 70))	('M69', 'Var', (60, 63))	('M19', 'Var', (45, 48))	('M24', 'Var', (55, 58))
123781	29545930	Knockout of the SPINT1 or SPINT2 gene was confirmed by genome sequencing, immunoblot analysis and immunocytochemistry.	('SPINT2', 'Gene', (26, 32))	('SPINT1', 'Gene', '6692', (16, 22))	('SPINT1', 'Gene', (16, 22))	('Knockout', 'Var', (0, 8))
123824	29097710	Percolation transition of cooperative mutational effects in colorectal tumorigenesis Cancer is caused by the accumulation of multiple genetic mutations, but their cooperative effects are poorly understood.	('Cancer', 'Phenotype', 'HP:0002664', (85, 91))	('Cancer', 'Disease', (85, 91))	('Cancer', 'Disease', 'MESH:D009369', (85, 91))	('caused by', 'Reg', (95, 104))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('mutational', 'Var', (38, 48))
123825	29097710	Using a genome-wide analysis of all the somatic mutations in colorectal cancer patients in a large-scale molecular interaction network, here we find that a giant cluster of mutation-propagating modules in the network undergoes a percolation transition, a sudden critical transition from scattered small modules to a large connected cluster, during colorectal tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (359, 364))	('percolation transition', 'CPA', (229, 251))	('colorectal cancer', 'Disease', (61, 78))	('mutation-propagating', 'Var', (173, 193))	('undergoes', 'Reg', (217, 226))	('tumor', 'Phenotype', 'HP:0002664', (359, 364))	('colorectal', 'Disease', (348, 358))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('tumor', 'Disease', (359, 364))	('colorectal cancer', 'Disease', 'MESH:D015179', (61, 78))	('patients', 'Species', '9606', (79, 87))	('colorectal cancer', 'Phenotype', 'HP:0003003', (61, 78))	('mutations', 'Var', (48, 57))
123827	29097710	Moreover, we find that the most commonly observed sequence of driver mutations in colorectal cancer has been optimized to maximize the giant percolated cluster.	('mutations', 'Var', (69, 78))	('colorectal cancer', 'Disease', (82, 99))	('giant percolated cluster', 'CPA', (135, 159))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('colorectal cancer', 'Disease', 'MESH:D015179', (82, 99))	('colorectal cancer', 'Phenotype', 'HP:0003003', (82, 99))
123830	29097710	Here, the authors investigate the cooperative effect of these mutations in colorectal cancer patients and identify a giant cluster of mutation-propagating modules that undergoes percolation transition during tumorigenesis.	('colorectal cancer', 'Disease', (75, 92))	('tumor', 'Disease', 'MESH:D009369', (208, 213))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('colorectal cancer', 'Disease', 'MESH:D015179', (75, 92))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('tumor', 'Disease', (208, 213))	('colorectal cancer', 'Phenotype', 'HP:0003003', (75, 92))	('patients', 'Species', '9606', (93, 101))	('mutations', 'Var', (62, 71))
123833	29097710	For instance, mutations of certain genes do not occur randomly but tend to co-occur in cancer patients, and colorectal cancer develops through the sequential accumulation of driver mutations such as APC, KRAS, PI3K, and TP53 .	('cancer', 'Disease', (87, 93))	('TP53', 'Gene', '7157', (220, 224))	('TP53', 'Gene', (220, 224))	('patients', 'Species', '9606', (94, 102))	('PI3K', 'Var', (210, 214))	('colorectal cancer', 'Disease', 'MESH:D015179', (108, 125))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('APC', 'Disease', 'MESH:D011125', (199, 202))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('colorectal cancer', 'Phenotype', 'HP:0003003', (108, 125))	('KRAS', 'Gene', (204, 208))	('cancer', 'Disease', (119, 125))	('KRAS', 'Gene', '3845', (204, 208))	('APC', 'Disease', (199, 202))	('colorectal cancer', 'Disease', (108, 125))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
123834	29097710	This suggests that the cooperativity of driver mutations might be an important factor for the development and progression of cancer.	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('mutations', 'Var', (47, 56))
123836	29097710	Most genetic alterations in cancer influence signal transduction, which is under complicated regulation.	('signal transduction', 'MPA', (45, 64))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('genetic alterations', 'Var', (5, 24))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('influence', 'Reg', (35, 44))	('cancer', 'Disease', (28, 34))
123837	29097710	Co-occurring mutations in cancer are often found to be involved in different signaling pathways, so we can infer that they provide additive or even synergistic effects on the selective growth advantage of cancer.	('cancer', 'Disease', 'MESH:D009369', (205, 211))	('cancer', 'Disease', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('cancer', 'Disease', (205, 211))	('selective growth advantage', 'CPA', (175, 201))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('mutations', 'Var', (13, 22))
123838	29097710	However, genes mutated in an exclusive way are likely to be involved in the same signaling pathway; these rarely confer any significant selective growth advantage on cancer due to the fact that the functional consequences of single mutations or double mutations are similar.	('double mutations', 'Var', (245, 261))	('cancer', 'Disease', (166, 172))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))
123839	29097710	These results suggest that whether a pair of somatic mutations is populated in the same signaling pathway or in distinct pathways might be crucial for tumorigenesis.	('tumor', 'Disease', (151, 156))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumor', 'Disease', 'MESH:D009369', (151, 156))	('mutations', 'Var', (53, 62))
123840	29097710	Recent network-based, pan-cancer analysis studies showed that the topological location of somatic mutations in the protein-protein interaction (PPI) network might be closely associated with the clinical outcome.	('associated', 'Reg', (174, 184))	('cancer', 'Disease', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('PPI', 'Gene', (144, 147))	('mutations', 'Var', (98, 107))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('protein-protein', 'Protein', (115, 130))
123845	29097710	To explore such a cooperative phenomenon of somatic mutations in tumorigenesis, we employ a network propagation method to measure the spreading of the influence of the somatic mutations on the molecular interaction network and then examined the cooperative effect of the somatic mutations by mapping all of the mutations observed in colorectal cancer from TCGA to a large-scale molecular interaction network.	('tumor', 'Disease', (65, 70))	('colorectal cancer', 'Disease', (333, 350))	('colorectal cancer', 'Disease', 'MESH:D015179', (333, 350))	('cancer', 'Phenotype', 'HP:0002664', (344, 350))	('mutations', 'Var', (311, 320))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('colorectal cancer', 'Phenotype', 'HP:0003003', (333, 350))
123847	29097710	Intriguingly, we further find that the most commonly observed sequence of driver mutations in colorectal cancer has been optimized to maximize the GPC.	('colorectal cancer', 'Disease', 'MESH:D015179', (94, 111))	('colorectal cancer', 'Disease', (94, 111))	('colorectal cancer', 'Phenotype', 'HP:0003003', (94, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('mutations', 'Var', (81, 90))
123857	29097710	Hence, these results suggest that the cooperation among somatic mutations in cancer cannot be attributed to a random selection of mutations but can be determined by topological properties of somatic mutations in the PPI network.	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('mutations', 'Var', (64, 73))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))
123863	29097710	We also asked if there is a relationship between the GC caused by somatic mutations from cancer patients and network characteristics of mutation pairs.	('mutations', 'Var', (74, 83))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('cancer', 'Disease', (89, 95))	('patients', 'Species', '9606', (96, 104))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
123864	29097710	We found that the average degree of genes that harbor somatic mutations in patients was significantly larger than that in random selection of nodes, whereas the average shortest distance between mutation pairs in patients was considerably shorter than the random expectation (Fig.	('genes', 'Gene', (36, 41))	('patients', 'Species', '9606', (75, 83))	('patients', 'Species', '9606', (213, 221))	('larger', 'PosReg', (102, 108))	('shorter', 'NegReg', (239, 246))	('mutations', 'Var', (62, 71))
123870	29097710	For instance, the co-occurrence of a mutation that persistently activates a proliferative signaling and another mutation that induces invasion and metastasis will promote cancer malignancy.	('cancer malignancy', 'Disease', 'MESH:D009369', (171, 188))	('mutation', 'Var', (112, 120))	('mutation', 'Var', (37, 45))	('cancer malignancy', 'Disease', (171, 188))	('proliferative signaling', 'MPA', (76, 99))	('activates', 'PosReg', (64, 73))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('promote', 'PosReg', (163, 170))
123874	29097710	By propagating all of the mutations of each colorectal cancer patient, we obtained a gene list included in the corresponding GC and estimated the enrichment of the hallmark gene sets in each patient through the hypergeometric test.	('colorectal cancer', 'Disease', (44, 61))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('patient', 'Species', '9606', (62, 69))	('mutations', 'Var', (26, 35))	('colorectal cancer', 'Disease', 'MESH:D015179', (44, 61))	('colorectal cancer', 'Phenotype', 'HP:0003003', (44, 61))	('patient', 'Species', '9606', (191, 198))
123886	29097710	Indeed, because most cancers have mutations in cancer-inducing genes, it is possible that cancer-related hallmark gene sets enriched in the GC come from such genes.	('cancer', 'Disease', 'MESH:D009369', (21, 27))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('cancer', 'Disease', (47, 53))	('cancers', 'Disease', 'MESH:D009369', (21, 28))	('cancers', 'Phenotype', 'HP:0002664', (21, 28))	('cancer', 'Disease', (21, 27))	('cancers', 'Disease', (21, 28))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('mutations', 'Var', (34, 43))
123898	29097710	A patient cluster characterized as stage 3 shows enrichment of the gene set related to the unfolded protein response, which induces metastasis through hypoxic activation, and p53 signaling which influences metastasis by the dysfunction of p53.	('influences', 'Reg', (195, 205))	('metastasis', 'CPA', (132, 142))	('hypoxic', 'MPA', (151, 158))	('dysfunction', 'Var', (224, 235))	('p53', 'Gene', '7157', (175, 178))	('induces', 'Reg', (124, 131))	('p53', 'Gene', (239, 242))	('p53', 'Gene', (175, 178))	('p53', 'Gene', '7157', (239, 242))	('patient', 'Species', '9606', (2, 9))	('metastasis', 'CPA', (206, 216))
123906	29097710	Therefore, in the context of percolation phenomenon, we propose that the GC resulting from somatic mutations of a cancer patient could be referred to as a ''giant percolated cluster'' (GPC), which is the largest percolating cluster that integrates the influences of scattered somatic mutations so that it confers phenotypic changes corresponding to cancer hallmarks.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('cancer', 'Phenotype', 'HP:0002664', (349, 355))	('cancer hallmarks', 'Disease', 'MESH:D009369', (349, 365))	('cancer', 'Disease', (349, 355))	('cancer', 'Disease', 'MESH:D009369', (349, 355))	('mutations', 'Var', (99, 108))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('patient', 'Species', '9606', (121, 128))	('cancer hallmarks', 'Disease', (349, 365))	('cancer', 'Disease', (114, 120))
123908	29097710	To address this question, we hypothesized that the dynamic behavior of the GPC in tumorigenesis would depend on detailed selection rules of somatic mutations, where the accumulation of somatic mutations, corresponding to the gradual addition of links in the percolation study of a random network, can be considered as a discrete time axis.	('depend', 'Reg', (102, 108))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('mutations', 'Var', (193, 202))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumor', 'Disease', (82, 87))
123916	29097710	APC mutations occurred ahead of other driver mutations; TP53 mutations always occurred as the last event among driver mutations; KRAS mutations was earlier events than TP53, PIK3CA, and SMAD4; and both PIK3CA and SMAD4 mutations occurred earlier than TP53, with high probabilities.	('TP53', 'Gene', (251, 255))	('APC', 'Disease', 'MESH:D011125', (0, 3))	('SMAD4', 'Gene', (213, 218))	('APC', 'Disease', (0, 3))	('KRAS', 'Gene', '3845', (129, 133))	('TP53', 'Gene', '7157', (168, 172))	('TP53', 'Gene', '7157', (56, 60))	('PIK3CA', 'Gene', (202, 208))	('KRAS', 'Gene', (129, 133))	('PIK3CA', 'Gene', '5290', (174, 180))	('mutations', 'Var', (134, 143))	('TP53', 'Gene', '7157', (251, 255))	('SMAD4', 'Gene', '4089', (213, 218))	('SMAD4', 'Gene', (186, 191))	('mutations', 'Var', (61, 70))	('PIK3CA', 'Gene', (174, 180))	('TP53', 'Gene', (168, 172))	('PIK3CA', 'Gene', '5290', (202, 208))	('TP53', 'Gene', (56, 60))	('SMAD4', 'Gene', '4089', (186, 191))
123917	29097710	We also found that the last rule, which is involved in both cancer promoting and suppressive processes, determined a similar order of driver mutations as the first rule (Fig.	('cancer', 'Disease', (60, 66))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('mutations', 'Var', (141, 150))
123918	29097710	Given that most early-stage colonic adenomas exhibited genetic alterations in APC , and most colorectal cancer patients with only a single driver mutation had APC mutations (Supplementary Fig.	('colonic adenomas', 'Disease', 'MESH:D000236', (28, 44))	('genetic alterations', 'Var', (55, 74))	('exhibited', 'Reg', (45, 54))	('mutations', 'Var', (163, 172))	('APC', 'Disease', 'MESH:D011125', (78, 81))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('colorectal cancer', 'Phenotype', 'HP:0003003', (93, 110))	('APC', 'Disease', (78, 81))	('APC', 'Disease', 'MESH:D011125', (159, 162))	('colorectal cancer', 'Disease', (93, 110))	('colonic adenomas', 'Disease', (28, 44))	('APC', 'Disease', (159, 162))	('colorectal cancer', 'Disease', 'MESH:D015179', (93, 110))	('patients', 'Species', '9606', (111, 119))
123923	29097710	These results indicate that, although the most commonly observed sequence of mutations in colorectal cancer is determined by the mechanism that suppresses the cooperative effect among mutations, such a sequence finally accelerates the increase in the size of the GPC to maximize the cooperative effect, therefore inducing the sudden transition during the development of cancer.	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('colorectal cancer', 'Disease', 'MESH:D015179', (90, 107))	('cooperative effect', 'MPA', (159, 177))	('cancer', 'Disease', (101, 107))	('accelerates', 'PosReg', (219, 230))	('inducing', 'Reg', (313, 321))	('cancer', 'Disease', 'MESH:D009369', (370, 376))	('suppresses', 'NegReg', (144, 154))	('colorectal cancer', 'Phenotype', 'HP:0003003', (90, 107))	('cancer', 'Disease', (370, 376))	('mutations', 'Var', (77, 86))	('increase', 'PosReg', (235, 243))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('cooperative', 'MPA', (283, 294))	('colorectal cancer', 'Disease', (90, 107))	('cancer', 'Phenotype', 'HP:0002664', (370, 376))	('size of the GPC', 'MPA', (251, 266))
123924	29097710	Taken together, our results have substantial implications for understanding the evolutionary process of tumorigenesis: (i) the GPC caused by cooperative effects of somatic mutations could undergo a percolation transition in colorectal tumorigenesis through the interplay between cancer suppressive mechanisms that minimize their cooperation and cancer promoting mechanisms that increase the size of the GPC, and (ii) the most commonly observed sequence of driver mutations in colorectal cancer could be essential for the sudden transition during tumorigenesis, consequently leading to the maximization of GPC size.	('leading to', 'Reg', (574, 584))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumor', 'Disease', 'MESH:D009369', (235, 240))	('cancer', 'Disease', (487, 493))	('cancer', 'Disease', 'MESH:D009369', (345, 351))	('cancer', 'Disease', (279, 285))	('cancer', 'Phenotype', 'HP:0002664', (487, 493))	('colorectal', 'Disease', (224, 234))	('tumor', 'Phenotype', 'HP:0002664', (546, 551))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('colorectal cancer', 'Disease', 'MESH:D015179', (476, 493))	('cancer', 'Phenotype', 'HP:0002664', (279, 285))	('colorectal cancer', 'Disease', (476, 493))	('tumor', 'Disease', (104, 109))	('cancer', 'Disease', 'MESH:D009369', (487, 493))	('cancer', 'Disease', 'MESH:D009369', (279, 285))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('cancer', 'Disease', (345, 351))	('mutations', 'Var', (172, 181))	('tumor', 'Disease', (546, 551))	('cancer', 'Phenotype', 'HP:0002664', (345, 351))	('tumor', 'Disease', (235, 240))	('colorectal cancer', 'Phenotype', 'HP:0003003', (476, 493))	('tumor', 'Disease', 'MESH:D009369', (546, 551))	('mutations', 'Var', (463, 472))
123926	29097710	18 and 19), suggesting that the cooperation of passenger mutations as well as driver mutations may play an important role in inducing the percolation transition, even in colorectal cancer patients with few driver mutations.	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('colorectal cancer', 'Disease', 'MESH:D015179', (170, 187))	('inducing', 'Reg', (125, 133))	('patients', 'Species', '9606', (188, 196))	('colorectal cancer', 'Phenotype', 'HP:0003003', (170, 187))	('mutations', 'Var', (85, 94))	('percolation transition', 'CPA', (138, 160))	('mutations', 'Var', (57, 66))	('colorectal cancer', 'Disease', (170, 187))
123928	29097710	In this process, the transition might not be gradual; not all of the somatic mutations directly contribute to the development of cancer, which is usually initiated after sufficient accumulation of mutations.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('mutations', 'Var', (77, 86))	('contribute', 'Reg', (96, 106))
123929	29097710	Moreover, previous studies have shown that half or even more of the somatic mutations observed in cancer of self-renewing tissues actually occur before tumor initiation, and sequential accumulation of driver mutations accompanied by APC is required for the onset of colon cancer in many cases.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('cancer', 'Phenotype', 'HP:0002664', (272, 278))	('mutations', 'Var', (76, 85))	('colon cancer', 'Disease', 'MESH:D015179', (266, 278))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('colon cancer', 'Phenotype', 'HP:0003003', (266, 278))	('APC', 'Disease', 'MESH:D011125', (233, 236))	('tumor initiation', 'Disease', 'MESH:D009369', (152, 168))	('mutations', 'Var', (208, 217))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('colon cancer', 'Disease', (266, 278))	('APC', 'Disease', (233, 236))	('cancer', 'Disease', 'MESH:D009369', (272, 278))	('cancer', 'Disease', (98, 104))	('tumor initiation', 'Disease', (152, 168))	('cancer', 'Disease', (272, 278))
123932	29097710	In this process, tumorigenesis can be initiated by a certain driver mutation that connects scattered clusters into one, leading to the formation of a GPC that represents cancer hallmarks (Fig.	('tumor', 'Disease', (17, 22))	('initiated', 'Reg', (38, 47))	('mutation', 'Var', (68, 76))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('cancer hallmarks', 'Disease', (170, 186))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('cancer hallmarks', 'Disease', 'MESH:D009369', (170, 186))
123933	29097710	Intriguingly, we found that the most frequently observed sequence of driver mutations characterizing colorectal cancer development might have been optimized to maximize the GPC.	('colorectal cancer', 'Disease', 'MESH:D015179', (101, 118))	('mutations', 'Var', (76, 85))	('colorectal cancer', 'Phenotype', 'HP:0003003', (101, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('colorectal cancer', 'Disease', (101, 118))
123936	29097710	First, we considered somatic mutations which are tumor-specific genetic changes, unlike germline mutations.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('mutations', 'Var', (29, 38))	('tumor', 'Disease', (49, 54))
123940	29097710	Third, the biased propagation of mutation influences based on a patient's gene expression profile better reflects the current state of the patient.	('patient', 'Species', '9606', (64, 71))	('mutation', 'Var', (33, 41))	('influences', 'Reg', (42, 52))	('patient', 'Species', '9606', (139, 146))
123942	29097710	Taken together, our results imply that a set of essential genes contained in the GPC obtained from the network propagation of somatic mutations can capture the important cancer-related features in the gene expression.	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('cancer', 'Disease', (170, 176))	('mutations', 'Var', (134, 143))
123946	29097710	Therefore, by considering such an effective boundary, we were able to obtain a GPC for the mutation profile of each patient and further confirmed the critical transition of the GPC during the development of cancer.	('cancer', 'Disease', 'MESH:D009369', (207, 213))	('mutation', 'Var', (91, 99))	('cancer', 'Disease', (207, 213))	('patient', 'Species', '9606', (116, 123))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))
123949	29097710	Our study showed that driver mutations are essential for triggering the onset of the GPC and also showed the significance of the cooperation of somatic mutations, including those not considered to directly affect tumorigenesis.	('tumor', 'Disease', (213, 218))	('mutations', 'Var', (29, 38))	('tumor', 'Disease', 'MESH:D009369', (213, 218))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('GPC', 'Disease', (85, 88))
123952	29097710	18 and 19), implying that the cooperative effect of driver and passenger mutations might play an important role in the development of cancer.	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('play', 'Reg', (89, 93))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('mutations', 'Var', (73, 82))
123953	29097710	Although many passenger mutations do not directly contribute to tumorigenesis, our results showed that the mutation effects of various passenger mutations found in individual cancer patients can converge to several cancer-related signaling pathways in which driver mutations occur, leading to the formation of a GPC and eventually contributing to tumorigenesis.	('mutations', 'Var', (265, 274))	('mutations', 'Var', (145, 154))	('cancer', 'Disease', (175, 181))	('patients', 'Species', '9606', (182, 190))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('tumor', 'Phenotype', 'HP:0002664', (347, 352))	('cancer', 'Disease', (215, 221))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('leading to', 'Reg', (282, 292))	('contributing to', 'Reg', (331, 346))	('tumor', 'Disease', (64, 69))	('tumor', 'Disease', (347, 352))	('cancer', 'Disease', 'MESH:D009369', (215, 221))	('GPC', 'MPA', (312, 315))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Disease', 'MESH:D009369', (347, 352))	('formation', 'MPA', (297, 306))
123954	29097710	The accumulation of mutations in tumorigenesis causes a cancer to diverge into different clones, resulting in subclonal diversification of the tumor cells.	('tumor', 'Disease', (143, 148))	('causes', 'Reg', (47, 53))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumor', 'Disease', (33, 38))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('subclonal', 'MPA', (110, 119))	('mutations', 'Var', (20, 29))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
123957	29097710	Therefore, we can predict that the formation of a GPC will be affected by the tumor heterogeneity because the formation of a GPC is determined by the mutation profile of a cancer.	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('mutation', 'Var', (150, 158))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('determined by', 'Reg', (132, 145))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('tumor', 'Disease', (78, 83))	('cancer', 'Disease', (172, 178))
123971	29097710	For nonsynonymous SNV, we included mutations that fulfilled at least two of the following five conditions: (i) SIFT prediction class with ''deleterious''; (ii) Polyphen2 HVAR with ''probably damaging'' or ''possibly damaging''; (iii) MutationTaster with ''disease causing automatic'' or ''disease causing''; (iv) MutatonAssessor with ''high'' or ''medium''; (v) CADD Phred-score with 20 (top 1% of predicted damaging effect).	("''disease", 'Disease', 'MESH:D004194', (287, 296))	('Polyphen2', 'Var', (160, 169))	("automatic''", 'PosReg', (272, 283))	('MutationTaster', 'Var', (234, 248))	("''disease", 'Disease', (287, 296))	('SIFT', 'Disease', (111, 115))	("''disease", 'Disease', 'MESH:D004194', (254, 263))	("''disease", 'Disease', (254, 263))	('SIFT', 'Disease', 'None', (111, 115))	('mutations', 'Var', (35, 44))
123973	29097710	We selected patients having less than 300 mutations from the 223 TCGA colorectal cancer patients to discard outliers having a very high number of mutations that result in a GPC covering the entire network, which left 198 patients.	('patients', 'Species', '9606', (12, 20))	('patients', 'Species', '9606', (221, 229))	('colorectal cancer', 'Disease', 'MESH:D015179', (70, 87))	('mutations', 'Var', (146, 155))	('colorectal cancer', 'Phenotype', 'HP:0003003', (70, 87))	('patients', 'Species', '9606', (88, 96))	('colorectal cancer', 'Disease', (70, 87))	('result in', 'Reg', (161, 170))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('mutations', 'Var', (42, 51))
123984	29097710	One of the important implications of our findings is that although driver mutations are essential for triggering the onset of the GPC, passenger mutations also contribute to the formation of the GPC and eventually to the development of cancer.	('cancer', 'Disease', 'MESH:D009369', (236, 242))	('contribute', 'Reg', (160, 170))	('cancer', 'Disease', (236, 242))	('mutations', 'Var', (74, 83))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))
124107	27976733	Multivariate analysis revealed that high levels of terminal effector Treg is an independent factor associated with increased PFS (HR = 3.47; 95% CI: 1.005-11.946, p = 0.049) and OS (HR = 7.417; 95% CI: 1.055-52.151, p = 0.044).	('increased', 'PosReg', (115, 124))	('PFS', 'Disease', (125, 128))	('Treg', 'Chemical', '-', (69, 73))	('high levels', 'Var', (36, 47))
124108	27976733	In contrast, high levels of naive Treg emerged as an independent factor associated with decreased OS (HR = 8.632; 95% CI: 2.226-33.468, p = 0.002; Table 3B).	('high levels', 'Var', (13, 24))	('Treg', 'Chemical', '-', (34, 38))	('decreased', 'NegReg', (88, 97))
124157	27976733	Several studies have also suggested the positive prognostic role of Treg in patients with different types of cancer such as in colorectal cancer; indeed, high levels of CD45RO+ and FoxP3+ infiltrating Treg have been associated with improved survival and could be emerged as independent prognostic factor for longer OS.	('cancer', 'Disease', (138, 144))	('colorectal cancer', 'Phenotype', 'HP:0003003', (127, 144))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('improved', 'PosReg', (232, 240))	('CD45', 'Gene', (169, 173))	('colorectal cancer', 'Disease', 'MESH:D015179', (127, 144))	('CD45', 'Gene', '5788', (169, 173))	('cancer', 'Disease', 'MESH:D009369', (138, 144))	('patients', 'Species', '9606', (76, 84))	('FoxP3', 'Gene', (181, 186))	('cancer', 'Disease', (109, 115))	('colorectal cancer', 'Disease', (127, 144))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('FoxP3', 'Gene', '50943', (181, 186))	('Treg', 'Chemical', '-', (68, 72))	('high', 'Var', (154, 158))	('survival', 'CPA', (241, 249))	('Treg', 'Chemical', '-', (201, 205))
124166	27976733	To conclude, the data presented in the current study demonstrate that the presence of naive and effector CD4+ Treg are clearly correlated with poor clinical outcome, while high expression of terminal effector cells correlates with better clinical outcome in patients with metastatic NSCLC.	('NSCLC', 'Phenotype', 'HP:0030358', (283, 288))	('CD4', 'Gene', (105, 108))	('Treg', 'Chemical', '-', (110, 114))	('presence', 'Var', (74, 82))	('CD4', 'Gene', '920', (105, 108))	('NSCLC', 'Disease', (283, 288))	('patients', 'Species', '9606', (258, 266))	('NSCLC', 'Disease', 'MESH:D002289', (283, 288))
124177	27976733	White blood cells were stained for expression of surface markers using anti-human monoclonal antibodies conjugated to fluorochrome against different molecules: anti-CD4-V500; anti- CD3-PE-CF594; anti-CD25-PE-Cy7; anti-CD127-V450 and anti-CD45RO-Alexa700 (BD Biosciences, USA).	('CD4', 'Gene', (165, 168))	('CD127', 'Gene', (218, 223))	('Alexa700', 'Chemical', '-', (245, 253))	('CD4', 'Gene', '920', (165, 168))	('CD25', 'Gene', '3559', (200, 204))	('CD45', 'Gene', (238, 242))	('anti- CD3-PE-CF594', 'Var', (175, 193))	('CD4', 'Gene', (238, 241))	('human', 'Species', '9606', (76, 81))	('CD4', 'Gene', '920', (238, 241))	('CD127', 'Gene', '3575', (218, 223))	('CD45', 'Gene', '5788', (238, 242))	('CD25', 'Gene', (200, 204))
124233	26119440	Bullous pemphigoid is caused by immunoglobulin G (IgG) autoantibodies against the hemidesmosomal bullous pemphigoid antigens BP230 (BPAg1) and BP180 (BPAg2).	('BPAg2', 'Gene', '1308', (150, 155))	('Bullous pemphigoid', 'Disease', (0, 18))	('BP180', 'Gene', '1308', (143, 148))	('BPAg2', 'Gene', (150, 155))	('BP180', 'Gene', (143, 148))	('caused by', 'Reg', (22, 31))	('BPAg1', 'Gene', '667', (132, 137))	('BPAg1', 'Gene', (132, 137))	('BP230', 'Var', (125, 130))
124383	30552315	One such finding is the common, but not universal, dysregulation of pentose and glucuronate interconversion (Fig.	('pentose', 'Chemical', 'MESH:D010429', (68, 75))	('glucuronate', 'Chemical', 'MESH:D020723', (80, 91))	('pentose', 'Enzyme', (68, 75))	('dysregulation', 'Var', (51, 64))
124407	30552315	Polyamines are small, positively charged molecules with many functions, impacting almost every aspect of cell survival.	('Polyamines', 'Var', (0, 10))	('impacting', 'Reg', (72, 81))	('Polyamines', 'Chemical', 'MESH:D011073', (0, 10))
124445	30552315	Additionally, the drug metformin, a first-generation biguanide, principally thought to be a mitochondrial complex 1 inhibitor, has been shown to decrease glucose metabolic flux through the CAC.	('metformin', 'Chemical', 'MESH:D008687', (23, 32))	('glucose', 'Chemical', 'MESH:D005947', (154, 161))	('glucose metabolic flux through the CAC', 'MPA', (154, 192))	('biguanide', 'Chemical', 'MESH:D001645', (53, 62))	('decrease', 'NegReg', (145, 153))	('metformin', 'Var', (23, 32))
124466	30552315	This is an important aspect of our pipeline, as it accounts for the varying degree of tumor-associated transcriptional drift across cancer types, as well as tissue procurement error and/or contaminating cell types associated with cohort samples at tissue-specific rates.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('cancer', 'Disease', (132, 138))	('tumor', 'Disease', (86, 91))	('transcriptional', 'MPA', (103, 118))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('drift', 'Var', (119, 124))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('cancer', 'Disease', 'MESH:D009369', (132, 138))
124475	30552315	3c, the significant gene expression changes in LUAD patient samples would be expected to divert metabolites towards the UDP-d-glucuronate production, which connects to several other pathways.	('divert', 'Reg', (89, 95))	('changes', 'Var', (36, 43))	('UDP-d-glucuronate production', 'MPA', (120, 148))	('metabolites', 'MPA', (96, 107))	('gene expression', 'MPA', (20, 35))	('UDP-d-glucuronate', 'Chemical', 'MESH:D014535', (120, 137))	('patient', 'Species', '9606', (52, 59))	('LUAD', 'Phenotype', 'HP:0030078', (47, 51))
124489	30552315	In order to address this, one would need mechanistic insights into why a wee-1 inhibitor (681640) and an anti-folate (methotrexate), for example, are more effective in cell types with dysregulated CAC and then experimentally manipulate the CAC, or the hypothesized co-occurring mechanism, to ask if this alters their efficacy.	('manipulate', 'Reg', (225, 235))	('CAC', 'Disease', (197, 200))	('dysregulated', 'Disease', (184, 196))	('methotrexate', 'Chemical', 'MESH:D008727', (118, 130))	('more', 'PosReg', (150, 154))	('681640', 'Var', (90, 96))	('wee-1', 'Gene', '7465', (73, 78))	('wee-1', 'Gene', (73, 78))	('folate', 'Chemical', 'MESH:D005492', (110, 116))
124513	30552315	(Supplementary Data 10) Using cBioPortal (http://www.cbioportal.org), patients in the PRAD cohort were queried for either co-occurent relationships or mutually exclusive relationships between the list of most commonly occurring mutations in PRAD and the four MMTRs in question.	('patients', 'Species', '9606', (70, 78))	('occurring', 'Reg', (218, 227))	('PRAD', 'Gene', (241, 245))	('mutations', 'Var', (228, 237))
124533	30552315	Microarray data can be downloaded from the NCBI Gene Expression Omnibus for prostate adenocarcinoma (GSE21032), lung adenocarcinoma (GSE2514,), and breast adenocarcinoma (GDS3324).	('breast adenocarcinoma', 'Disease', (148, 169))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (112, 131))	('prostate adenocarcinoma', 'Disease', (76, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (160, 169))	('breast adenocarcinoma', 'Disease', 'MESH:D000230', (148, 169))	('prostate adenocarcinoma', 'Disease', 'MESH:D011471', (76, 99))	('lung adenocarcinoma', 'Disease', (112, 131))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (112, 131))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('breast adenocarcinoma', 'Phenotype', 'HP:0003002', (148, 169))	('GSE21032', 'Var', (101, 109))
124552	29934580	There is growing evidence that deregulated TGFbeta signaling contributes to the acquisition of an EMT phenotype by lung cancer cells.	('contributes', 'Reg', (61, 72))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('TGFbeta', 'Gene', (43, 50))	('lung cancer', 'Disease', 'MESH:D008175', (115, 126))	('deregulated', 'Var', (31, 42))	('EMT phenotype', 'CPA', (98, 111))	('TGFbeta', 'Gene', '7040', (43, 50))	('lung cancer', 'Disease', (115, 126))	('lung cancer', 'Phenotype', 'HP:0100526', (115, 126))
124564	29934580	In the 2D migration assay we observed by analyzing more than 1000 of single cell tracks per condition that the TGFbeta treatment resulted in a two-fold increase in migration speed (from 4 to 8 microm/h) (Fig.	('increase', 'PosReg', (152, 160))	('TGFbeta', 'Gene', '7040', (111, 118))	('treatment', 'Var', (119, 128))	('migration speed', 'CPA', (164, 179))	('TGFbeta', 'Gene', (111, 118))
124605	29934580	Using the MYO10 mRNA expression ratio to separate the patient groups, we confirmed that LUSC patients with high MYO10 mRNA expression ratio demonstrate reduced overall survival independent of the tumor stage and treatment regimen (P = 0.008, Fig.	('patient', 'Species', '9606', (54, 61))	('tumor', 'Disease', (196, 201))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('reduced', 'NegReg', (152, 159))	('overall survival', 'MPA', (160, 176))	('MYO10', 'Gene', '4651', (10, 15))	('patient', 'Species', '9606', (93, 100))	('MYO10', 'Gene', (112, 117))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('high', 'Var', (107, 111))	('patients', 'Species', '9606', (93, 101))	('MYO10', 'Gene', (10, 15))	('MYO10', 'Gene', '4651', (112, 117))
124631	29934580	Here, we showed that siRNA-mediated knockdown of either MYO10, MYH9 or MYO1E was sufficient to abrogate TGFbeta-induced 3D collagen invasion of the LUSC cell line SK-MES1.	('TGFbeta', 'Gene', '7040', (104, 111))	('MYO10', 'Gene', (56, 61))	('abrogate', 'NegReg', (95, 103))	('MYO1E', 'Var', (71, 76))	('MYH9', 'Gene', '4627', (63, 67))	('MYO10', 'Gene', '4651', (56, 61))	('TGFbeta', 'Gene', (104, 111))	('MYH9', 'Gene', (63, 67))	('SK-MES1', 'CellLine', 'CVCL:0630', (163, 170))
124632	29934580	These observations are in agreement with previous work demonstrating that shRNA knockdown of MYO10 in the breast cancer cell line MDA-MB-231 inhibited Matrigel invasion and in vivo invasion in lung colonization and mammary fat pads assays.	('knockdown', 'Var', (80, 89))	('MYO10', 'Gene', (93, 98))	('Matrigel invasion', 'CPA', (151, 168))	('breast cancer', 'Disease', (106, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('breast cancer', 'Phenotype', 'HP:0003002', (106, 119))	('MYO10', 'Gene', '4651', (93, 98))	('inhibited', 'NegReg', (141, 150))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (130, 140))	('breast cancer', 'Disease', 'MESH:D001943', (106, 119))
124633	29934580	siRNA depletion of MYH9 in the esophageal squamous cell line KYSE-510 impaired migratory and invasive abilities in gap closure and transwell assays, respectively.	('esophageal squamous', 'Disease', 'MESH:D000077277', (31, 50))	('esophageal squamous', 'Disease', (31, 50))	('MYH9', 'Gene', (19, 23))	('KYSE-510', 'CellLine', 'CVCL:1354', (61, 69))	('depletion', 'Var', (6, 15))	('MYH9', 'Gene', '4627', (19, 23))	('transwell assays', 'CPA', (131, 147))	('impaired', 'NegReg', (70, 78))
124642	29934580	We observed that LUSC patients with high MYO10 mRNA expression ratio and pre-existing lymph node metastases have significantly poorer overall survival (P = 0.017, Fig.	('MYO10', 'Gene', (41, 46))	('metastases', 'Disease', (97, 107))	('poorer', 'NegReg', (127, 133))	('patients', 'Species', '9606', (22, 30))	('MYO10', 'Gene', '4651', (41, 46))	('metastases', 'Disease', 'MESH:D009362', (97, 107))	('overall survival', 'MPA', (134, 150))	('high', 'Var', (36, 40))
124686	29045845	However, the mechanisms by which cancer mutations perturb splicing remain unknown.	('cancer', 'Disease', (33, 39))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('mutations', 'Var', (40, 49))	('splicing', 'MPA', (58, 66))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('perturb', 'Reg', (50, 57))
124687	29045845	Here, we developed a network-based strategy, DrAS-Net, to investigate over 2.5 million variants across cancer types and link somatic mutations with cancer-specific splicing events.	('cancer', 'Disease', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('variants', 'Var', (87, 95))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))
124688	29045845	We identified over 40,000 driver variant candidates and their 80,000 putative splicing targets deregulated in 33 cancer types and inferred their functional impact.	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('variant', 'Var', (33, 40))	('deregulated', 'Reg', (95, 106))	('cancer', 'Disease', (113, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
124689	29045845	Strikingly, tumors with splicing perturbations show reduced expression of immune system-related genes, and increased expression of cell proliferation markers.	('expression', 'MPA', (60, 70))	('splicing perturbations', 'Var', (24, 46))	('reduced', 'NegReg', (52, 59))	('increased', 'PosReg', (107, 116))	('expression', 'MPA', (117, 127))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('cell proliferation', 'CPA', (131, 149))	('tumors', 'Disease', (12, 18))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('tumors', 'Disease', 'MESH:D009369', (12, 18))	('immune system-related genes', 'Gene', (74, 101))
124690	29045845	Tumors harboring different mutations in the same gene often exhibit distinct splicing perturbations.	('mutations', 'Var', (27, 36))	('splicing perturbations', 'MPA', (77, 99))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))
124694	29045845	In human cancer, for instance, the problem of tumor heterogeneity across patient populations is known to involve alternative splicing.	('cancer', 'Disease', (9, 15))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('human', 'Species', '9606', (3, 8))	('alternative splicing', 'Var', (113, 133))	('tumor', 'Disease', (46, 51))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('patient', 'Species', '9606', (73, 80))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
124695	29045845	However, the fundamental question of how genomic mutations influence the splicing process leading to cancer is essentially unknown (Figure 1A).	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('leading to', 'Reg', (90, 100))	('mutations', 'Var', (49, 58))	('cancer', 'Disease', (101, 107))	('influence', 'Reg', (59, 68))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('splicing', 'MPA', (73, 81))
124698	29045845	Aberrant AS events have been implicated in complex diseases, including various types of cancer.	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('Aberrant', 'Var', (0, 8))	('implicated', 'Reg', (29, 39))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))
124699	29045845	AS alterations may confer a selective advantage to the tumor, such as cell proliferation, invasion and apoptosis evasion.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('apoptosis evasion', 'CPA', (103, 120))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('cell proliferation', 'CPA', (70, 88))	('advantage', 'PosReg', (38, 47))	('tumor', 'Disease', (55, 60))	('alterations', 'Var', (3, 14))	('invasion', 'CPA', (90, 98))
124703	29045845	Lines of evidence have demonstrated that AS alterations in cancer may be caused by changes in expression, amplification and deletions in splicing factors and RNA-binding proteins.	('RNA-binding proteins', 'Protein', (158, 178))	('amplification', 'MPA', (106, 119))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('splicing factors', 'Protein', (137, 153))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('expression', 'MPA', (94, 104))	('cancer', 'Disease', (59, 65))	('deletions', 'Var', (124, 133))	('changes', 'Reg', (83, 90))
124705	29045845	For instance, genetic variants that affect splicing have been inferred by deep learning algorithms and mutations that lead to intron retention have been identified as a pervasive mechanism by which tumor suppressor genes are inactivated in certain cancers.	('cancers', 'Disease', (248, 255))	('mutations', 'Var', (103, 112))	('cancers', 'Disease', 'MESH:D009369', (248, 255))	('deep learning algorithms', 'Disease', 'MESH:D007859', (74, 98))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('cancer', 'Phenotype', 'HP:0002664', (248, 254))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('tumor', 'Disease', (198, 203))	('inactivated', 'NegReg', (225, 236))	('cancers', 'Phenotype', 'HP:0002664', (248, 255))	('variants', 'Var', (22, 30))	('deep learning algorithms', 'Disease', (74, 98))
124706	29045845	Nevertheless, the general principles by which somatic mutations lead to AS alterations across diverse cancer types are unknown and have the potential to reveal oncogenic mechanisms in diverse cancers.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('mutations', 'Var', (54, 63))	('cancers', 'Disease', 'MESH:D009369', (192, 199))	('cancers', 'Phenotype', 'HP:0002664', (192, 199))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('cancers', 'Disease', (192, 199))	('cancer', 'Disease', (192, 198))	('cancer', 'Disease', 'MESH:D009369', (192, 198))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))
124713	29045845	By integrating genomic mutations and AS events into functional association networks, we describe a framework to identify patient-specific potential driver mutations that mediate AS alterations in cancer.	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('mutations', 'Var', (155, 164))	('cancer', 'Disease', 'MESH:D009369', (196, 202))	('patient', 'Species', '9606', (121, 128))	('cancer', 'Disease', (196, 202))	('alterations', 'Reg', (181, 192))
124715	29045845	In this manner, DrAS-Net provides a valuable approach and resource for detecting candidate driver mutation-mediated AS events in cancer, and helps explain the heterogeneity observed across diverse patient populations.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('mutation-mediated', 'Var', (98, 115))	('patient', 'Species', '9606', (197, 204))
124722	29045845	We analyzed the distribution of these AS classes across cancer types, and observed that exon skipping was the most frequent class of splice event, while mutually exclusive exons represented a rare class (Figure S1B).	('cancer', 'Disease', (56, 62))	('exon skipping', 'Var', (88, 101))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))
124723	29045845	Defects in RNA splicing are an important factor contributing to disease, including cancer.	('RNA splicing', 'MPA', (11, 23))	('contributing', 'Reg', (48, 60))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('Defects', 'Var', (0, 7))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('cancer', 'Disease', (83, 89))
124736	29045845	This result is consistent with a recent study that demonstrated these two cancer types had distinct molecular characteristics in terms of mRNA expression, miRNA expression, DNA methylation and copy number variation.	('copy number variation', 'Var', (193, 214))	('mRNA expression', 'MPA', (138, 153))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Disease', (74, 80))	('miRNA expression', 'MPA', (155, 171))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('DNA methylation', 'MPA', (173, 188))
124742	29045845	For instance, exon skipping of FGFR1 was detected to be differential in glioblastoma multiforme (GBM), and exhibited high cancer-type specificity (Figure 2D).	('exon skipping', 'Var', (14, 27))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (72, 95))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('FGFR1', 'Gene', (31, 36))	('differential', 'Reg', (56, 68))	('glioblastoma multiforme', 'Disease', (72, 95))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('FGFR1', 'Gene', '2260', (31, 36))	('glioblastoma', 'Phenotype', 'HP:0012174', (72, 84))
124744	29045845	These results offered a preclinical proof of concept that targeting FGFR1 might be a new method to GBM therapy.	('FGFR1', 'Gene', (68, 73))	('FGFR1', 'Gene', '2260', (68, 73))	('targeting', 'Var', (58, 67))	('GBM', 'Disease', (99, 102))
124748	29045845	Here, we found that alternative promoter usage of LSP1 occurred in a prevalent manner in 15 types of cancer.	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('LSP1', 'Gene', '4046', (50, 54))	('cancer', 'Disease', (101, 107))	('LSP1', 'Gene', (50, 54))	('alternative', 'Var', (20, 31))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('occurred', 'Reg', (55, 63))
124757	29045845	These results suggest that there is increased cell proliferation in tumor samples with perturbed AS events.	('tumor', 'Disease', (68, 73))	('perturbed', 'Var', (87, 96))	('increased', 'PosReg', (36, 45))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('cell proliferation', 'CPA', (46, 64))
124762	29045845	Moreover, tumor aneuploidy and mutation load had recently been demonstrated as a possible marker for immune evasion with reduced response to immunotherapy.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('mutation load', 'Var', (31, 44))	('tumor aneuploidy', 'Disease', 'MESH:D000782', (10, 26))	('immune evasion', 'MPA', (101, 115))	('tumor aneuploidy', 'Disease', (10, 26))
124764	29045845	We found that tumor samples with altered AS events had significantly higher chromosome SCNA levels (p=4.2e-4, Wilcoxon rank-sum test, Figure S2E), arm SCNA levels (p=4.6e-4, Wilcoxon rank-sum test, Figure S2F), focal and normalized SCNA levels (p<0.001, Wilcoxon rank-sum test, Figure S2G and S2H), and greater number of mutations (p<2.2e-16, Wilcoxon rank-sum test, Figure 2J).	('tumor', 'Disease', (14, 19))	('chromosome SCNA levels', 'MPA', (76, 98))	('arm SCNA levels', 'MPA', (147, 162))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('mutations', 'Var', (321, 330))	('SCNA levels', 'MPA', (232, 243))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('higher', 'PosReg', (69, 75))
124765	29045845	In summary, our results indicate that AS perturbation in cancer provides a predictor of cytotoxic immune cell infiltration, together with other previously described tumor characteristics such as mutation load and aneuploidy.	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('aneuploidy', 'Disease', 'MESH:D000782', (213, 223))	('cancer', 'Disease', (57, 63))	('mutation load', 'Var', (195, 208))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('perturbation', 'Var', (41, 53))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('aneuploidy', 'Disease', (213, 223))	('tumor', 'Disease', (165, 170))
124769	29045845	As splicing changes may be triggered by genetic mutations, we investigated the extent to which somatic mutations could lead to differential AS of the same or different genomic loci across cancer types.	('mutations', 'Var', (103, 112))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('triggered', 'Reg', (27, 36))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('splicing', 'MPA', (3, 11))	('cancer', 'Disease', (188, 194))	('mutations', 'Var', (48, 57))
124771	29045845	We devised a network-based framework to identify mutations that could mediate differential AS events in cancer, referred to as DrAS-Net (Driver mutation-AS interactome Network; Figure 3A and Figure S3A).	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('mutations', 'Var', (49, 58))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))
124772	29045845	In addition to identifying common somatic mutations that mediate AS in cancer, characterizing personalized genomic mutations in individual cancer patients could reveal new details of complex cancer mechanisms.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('cancer', 'Disease', (191, 197))	('mutations', 'Var', (115, 124))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('cancer', 'Disease', 'MESH:D009369', (191, 197))	('cancer', 'Disease', (71, 77))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('patients', 'Species', '9606', (146, 154))	('cancer', 'Disease', (139, 145))
124774	29045845	Next, a greedy optimization approach was used to detect recurrent mutations that can explain the vast majority of the identified AS alterations in cancer (see details in methods).	('mutations', 'Var', (66, 75))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('cancer', 'Disease', (147, 153))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))
124780	29045845	In addition, the mutation frequencies of driver genes were higher in UCEC and SKCM than other cancer types, which may be explained by the higher mutation burden.	('higher', 'Reg', (59, 65))	('SKCM', 'Disease', (78, 82))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('UCEC', 'Disease', (69, 73))	('mutation frequencies', 'Var', (17, 37))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
124781	29045845	We next assessed the functional relevance of these driver genes in cancer by examining the Cancer Gene Census (CGC), a database that catalogues genes for which mutations have been causally implicated in cancer.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('Cancer', 'Disease', (91, 97))	('mutations', 'Var', (160, 169))	('cancer', 'Disease', (67, 73))	('Cancer', 'Disease', 'MESH:D009369', (91, 97))	('Cancer', 'Phenotype', 'HP:0002664', (91, 97))	('cancer', 'Disease', (203, 209))	('cancer', 'Disease', 'MESH:D009369', (203, 209))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))
124787	29045845	Cancer cells with defects in the antigrowth signaling pathway (such as the RB1 and E2F transcription factor mutations identified here) are missing a critical 'gatekeeper' of cell cycle progression, thus cancer cells keep growing and dividing.	('defects', 'NegReg', (18, 25))	('antigrowth signaling pathway', 'Pathway', (33, 61))	('mutations', 'Var', (108, 117))	('E2F transcription factor', 'Gene', (83, 107))	('RB1', 'Gene', (75, 78))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('missing', 'NegReg', (139, 146))	('Cancer', 'Disease', (0, 6))	('cancer', 'Disease', (203, 209))	('cancer', 'Disease', 'MESH:D009369', (203, 209))	('dividing', 'CPA', (233, 241))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('gatekeeper', 'Species', '111938', (159, 169))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))
124788	29045845	Altogether, these results indicate that the network-based method that makes use of both the cancer specific mutation and AS data could identify candidate driver genes that are likely to play a functional role in cancer (Table S3).	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('cancer', 'Disease', (212, 218))	('cancer', 'Disease', 'MESH:D009369', (212, 218))	('mutation', 'Var', (108, 116))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))
124790	29045845	Our results suggest that different genetic mutations likely influence distinctly different AS events in cancer (Figure S3K and Supplemental Note).	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('influence', 'Reg', (60, 69))	('mutations', 'Var', (43, 52))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))
124791	29045845	Mutations in the same genes are often associated with multiple clinically distinct phenotypes, including different types of cancer.	('cancer', 'Disease', (124, 130))	('associated', 'Reg', (38, 48))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('Mutations', 'Var', (0, 9))	('cancer', 'Disease', 'MESH:D009369', (124, 130))
124792	29045845	We observed that some mutated genes could influence different AS events across different cancer types (Figure 4A).	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('mutated', 'Var', (22, 29))	('cancer', 'Disease', (89, 95))	('influence', 'Reg', (42, 51))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
124793	29045845	To investigate how mutations in the same genes can cause different types of cancer or different subtypes of the same cancer, we proposed two models for explaining this heterogeneity: Different mutations of the same genes could influence distinct AS events in different patients of the same or different cancer types (model-1 and model-2, respectively, in Figure 4B).	('cancer', 'Disease', (303, 309))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('mutations', 'Var', (19, 28))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('mutations', 'Var', (193, 202))	('cancer', 'Phenotype', 'HP:0002664', (303, 309))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('cause', 'Reg', (51, 56))	('cancer', 'Disease', (117, 123))	('influence', 'Reg', (227, 236))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('patients', 'Species', '9606', (269, 277))	('cancer', 'Disease', 'MESH:D009369', (303, 309))
124796	29045845	Together, our results indicate that different driver candidate mutations are likely to influence distinct AS perturbations, accounting for different cancer phenotypes.	('mutations', 'Var', (63, 72))	('cancer', 'Disease', (149, 155))	('cancer', 'Disease', 'MESH:D009369', (149, 155))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))
124800	29045845	We found that several somatic mutations in IKZF1 could influence the AS pattern in cis.	('influence', 'Reg', (55, 64))	('IKZF1', 'Gene', (43, 48))	('mutations', 'Var', (30, 39))	('IKZF1', 'Gene', '10320', (43, 48))
124801	29045845	In total, five mutations modulated the exon 7-9 skipping while four mutations influenced the exon-6 skipping in multiple cancer types.	('exon-6 skipping', 'MPA', (93, 108))	('exon 7-9 skipping', 'MPA', (39, 56))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('mutations', 'Var', (15, 24))	('influenced', 'Reg', (78, 88))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('modulated', 'Reg', (25, 34))	('cancer', 'Disease', (121, 127))
124802	29045845	Specifically, the mutation A79T influenced an AS event (exon 7-9 skipping) in LUAD, resulting in the loss of the Zinc finger type 2-4 domains.	('loss', 'NegReg', (101, 105))	('A79T', 'Mutation', 'rs1353402014', (27, 31))	('LUAD', 'Disease', 'None', (78, 82))	('LUAD', 'Disease', (78, 82))	('finger type 2-', 'Phenotype', 'HP:0001233', (118, 132))	('LUAD', 'Phenotype', 'HP:0030078', (78, 82))	('A79T', 'Var', (27, 31))	('Zinc finger type 2-4 domains', 'MPA', (113, 141))
124803	29045845	Another mutation G43E led to the exon-6 skipping in LUSC, which caused the loss of the Zinc finger type-1 domain (Figure 4F).	('LUSC', 'Phenotype', 'HP:0030359', (52, 56))	('exon-6', 'MPA', (33, 39))	('Zinc', 'Protein', (87, 91))	('skipping', 'NegReg', (40, 48))	('loss', 'NegReg', (75, 79))	('G43E', 'Var', (17, 21))	('G43E', 'Mutation', 'rs754745738', (17, 21))
124809	29045845	We found that the mutation-perturbed AS genes we identified were more likely to be RBP targets than non-perturbed genes (Figure 4H, p<2.2e-16, Fisher's exact test).	('mutation-perturbed', 'Var', (18, 36))	('RBP', 'Gene', (83, 86))	('RBP', 'Gene', '57794', (83, 86))
124810	29045845	Our results have provided insights into possible protein-level effects of differential splicing in cancer, and have identified perturbations of different types of protein modules that are known to mediate crucial functions.	('effects', 'Reg', (63, 70))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('cancer', 'Disease', (99, 105))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('differential splicing', 'Var', (74, 95))
124811	29045845	For example, EIF4ENIF1 (also known as 4E-T) has been demonstrated to play critical roles in cancer and alternative splicing of this gene could promote pathological angiogenesis.	('alternative splicing', 'Var', (103, 123))	('cancer', 'Disease', (92, 98))	('EIF4ENIF1', 'Gene', '56478', (13, 22))	('4E-T', 'Gene', '56478', (38, 42))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('4E-T', 'Gene', (38, 42))	('promote', 'PosReg', (143, 150))	('EIF4ENIF1', 'Gene', (13, 22))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('pathological angiogenesis', 'CPA', (151, 176))
124812	29045845	Here, we found that aberrant splicing in EIF4ENIF1 was likely influenced by mutations in the RBP gene EIF4E2 in breast cancer (Figure 4I).	('breast cancer', 'Disease', 'MESH:D001943', (112, 125))	('breast cancer', 'Phenotype', 'HP:0003002', (112, 125))	('RBP', 'Gene', '57794', (93, 96))	('mutations', 'Var', (76, 85))	('breast cancer', 'Disease', (112, 125))	('EIF4ENIF1', 'Gene', '56478', (41, 50))	('aberrant splicing', 'Var', (20, 37))	('RBP', 'Gene', (93, 96))	('influenced', 'Reg', (62, 72))	('EIF4ENIF1', 'Gene', (41, 50))	('EIF4E2', 'Gene', '9470', (102, 108))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('EIF4E2', 'Gene', (102, 108))
124813	29045845	In cancer patients, different EIF4E2 mutations tended to affect distinct AS events in EIF4ENIF1.	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('affect', 'Reg', (57, 63))	('mutations', 'Var', (37, 46))	('cancer', 'Disease', (3, 9))	('EIF4E2', 'Gene', '9470', (30, 36))	('EIF4ENIF1', 'Gene', '56478', (86, 95))	('patients', 'Species', '9606', (10, 18))	('EIF4E2', 'Gene', (30, 36))	('EIF4ENIF1', 'Gene', (86, 95))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
124814	29045845	For instance, one of the patients harbored the R202Q mutation, which likely mediated the skipping of exons 6-7 of EIF4ENIF1.	('EIF4ENIF1', 'Gene', (114, 123))	('R202Q', 'Mutation', 'p.R202Q', (47, 52))	('patients', 'Species', '9606', (25, 33))	('EIF4ENIF1', 'Gene', '56478', (114, 123))	('R202Q', 'Var', (47, 52))
124817	29045845	In another patient, the EIF4E2 mutation W148L was identified to influence the skipping of exon 12 of EIF4ENIF1, resulting in the loss of residues 505-527 which do not encompass any known functional sites of the protein.	('W148L', 'Var', (40, 45))	('mutation W148L', 'Var', (31, 45))	('EIF4ENIF1', 'Gene', (101, 110))	('loss', 'NegReg', (129, 133))	('influence', 'Reg', (64, 73))	('patient', 'Species', '9606', (11, 18))	('W148L', 'Mutation', 'p.W148L', (40, 45))	('EIF4ENIF1', 'Gene', '56478', (101, 110))	('EIF4E2', 'Gene', '9470', (24, 30))	('skipping', 'MPA', (78, 86))	('EIF4E2', 'Gene', (24, 30))	('residues 505-527', 'MPA', (137, 153))
124820	29045845	Besides the loss of signal motifs by AS perturbation, we also observed in other patients that aberrant splicing might cause loss of signal transduction domains, non-domain functional regions, or catalytic domains in cancer (Figure S4).	('loss', 'NegReg', (124, 128))	('patients', 'Species', '9606', (80, 88))	('splicing', 'MPA', (103, 111))	('catalytic domains', 'MPA', (195, 212))	('non-domain functional regions', 'MPA', (161, 190))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('signal transduction domains', 'MPA', (132, 159))	('cancer', 'Disease', (216, 222))	('cancer', 'Disease', 'MESH:D009369', (216, 222))	('aberrant', 'Var', (94, 102))
124821	29045845	Together, our results that link single nucleotide mutations to AS events can provide mechanistic insights into how mutations can result in cancer progression.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('mutations', 'Var', (115, 124))	('single nucleotide mutations', 'Var', (32, 59))	('result in', 'Reg', (129, 138))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('cancer', 'Disease', (139, 145))
124822	29045845	It also suggests that the identification of AS profiles mediated by patient-specific mutations could be a valuable strategy and resource to help explain the phenotypic heterogeneity in the same or different cancer types.	('cancer', 'Disease', 'MESH:D009369', (207, 213))	('patient', 'Species', '9606', (68, 75))	('cancer', 'Disease', (207, 213))	('mutations', 'Var', (85, 94))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))
124838	29045845	Taken together, our data reveal critical driver mutations, important clinical and biological trends associated with AS in cancer, and suggest putative molecular mechanism for mutation-mediated regulation of specific AS events.	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('mutations', 'Var', (48, 57))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))
124839	29045845	The features provided in the resource, which will be continuously updated, should serve as a guide for biologists interested in identifying the genetic determinants of splicing specificity for various applications (for example, RNA editing and pleotropic studies) and understanding the consequences of mutations (for example, driver mutations and natural variation) in cancer patients and healthy individuals.	('patients', 'Species', '9606', (376, 384))	('cancer', 'Disease', (369, 375))	('mutations', 'Var', (302, 311))	('cancer', 'Phenotype', 'HP:0002664', (369, 375))	('cancer', 'Disease', 'MESH:D009369', (369, 375))
124844	29045845	Strikingly, we have found that tumors with aberrant splicing isoforms tend to exhibit decreased expression levels of immune system-related genes, and increased expression levels of cell cycle marker genes.	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('expression levels', 'MPA', (96, 113))	('tumors', 'Disease', (31, 37))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('tumors', 'Disease', 'MESH:D009369', (31, 37))	('decreased', 'NegReg', (86, 95))	('expression levels', 'MPA', (160, 177))	('increased', 'PosReg', (150, 159))	('aberrant splicing isoforms', 'Var', (43, 69))
124847	29045845	Previous studies have suggested AS alterations in cancer may be caused by changes in expression, amplification and deletions in splicing factors and RNA-binding proteins.	('expression', 'MPA', (85, 95))	('splicing factors', 'Protein', (128, 144))	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('changes', 'Reg', (74, 81))	('amplification', 'MPA', (97, 110))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('RNA-binding proteins', 'Protein', (149, 169))	('deletions', 'Var', (115, 124))
124850	29045845	In addition, identifying patient-specific driver mutations and the AS events they influence can provide mechanistic insights and enables a more personalized approach for cancer treatment.	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('influence', 'Reg', (82, 91))	('cancer', 'Disease', (170, 176))	('mutations', 'Var', (49, 58))	('patient', 'Species', '9606', (25, 32))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))
124852	29045845	These results indicate that deregulation of AS may rewire cellular networks or signaling pathways in cancer.	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('deregulation', 'Var', (28, 40))	('cancer', 'Disease', (101, 107))	('signaling pathways', 'Pathway', (79, 97))	('cellular networks', 'Pathway', (58, 75))	('rewire', 'Reg', (51, 57))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))
124858	29045845	Based on the observation that AS events in each cancer subtype are influenced by distinct mutations, we have proposed two models to help interpret the phenotypic heterogeneity.	('mutations', 'Var', (90, 99))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('influenced', 'Reg', (67, 77))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))
124860	29045845	Furthermore, our finding that cancer patients with AS perturbations exhibit reduced immune signature, has provided insights into strategies for potential immunotherapy.	('perturbations', 'Var', (54, 67))	('patients', 'Species', '9606', (37, 45))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('cancer', 'Disease', (30, 36))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('reduced', 'NegReg', (76, 83))	('immune signature', 'MPA', (84, 100))
124865	29045845	We developed an integrated analysis framework to identify the mutation-mediated AS in cancer.	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('cancer', 'Disease', (86, 92))	('mutation-mediated', 'Var', (62, 79))
124867	29045845	For each cancer, we transformed these mutations into a gene-patient matrix, M(i, j), which represents a binary matrix to indicate whether the mutations were observed in a specific patient.	('patient', 'Species', '9606', (60, 67))	('cancer', 'Disease', (9, 15))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('mutations', 'Var', (38, 47))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('patient', 'Species', '9606', (180, 187))
124871	29045845	We hypothesized that if the mutated genes in a patient can affect the AS of other genes, they should have some functional links in known functional networks.	('affect', 'Reg', (59, 65))	('mutated genes', 'Var', (28, 41))	('links', 'Interaction', (122, 127))	('patient', 'Species', '9606', (47, 54))
124879	29045845	Then the mutations in the identified genes in the corresponding sample were assembled as driver mutations in each cancer.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('mutations', 'Var', (9, 18))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('cancer', 'Disease', (114, 120))
124883	29045845	Alternative splicing profiles classify cancer patients into subtypes with distinct clinical features Somatic mutation-mediated alternative splicing helps explain cancer heterogeneity	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('patients', 'Species', '9606', (46, 54))	('cancer', 'Disease', (39, 45))	('mutation-mediated alternative splicing', 'Var', (109, 147))	('cancer', 'Disease', (162, 168))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))
124900	24393430	Many reports have shown that SBRT is safe and effective for stage I NSCLC, since SBRT produces superior dose distribution within the target, while reducing the irradiated normal tissue volume compared with conventional radiotherapy.	('NSCLC', 'Disease', 'MESH:D002289', (68, 73))	('reducing', 'NegReg', (147, 155))	('NSCLC', 'Phenotype', 'HP:0030358', (68, 73))	('SBRT', 'Var', (81, 85))	('dose distribution', 'MPA', (104, 121))	('NSCLC', 'Disease', (68, 73))
124906	24393430	Eligibility criteria of the study were as follows: (1) histologically confirmed primary NSCLC; (2) T1N0M0 or T2N0M0 disease according to the International Union Against Cancer (UICC) 1997 system by CT of the chest and upper abdomen, brain magnetic resonance imaging, and bone scintigraphy or 18-fluoro-deoxyglucose positron emission tomography; (3) greatest tumor dimension <= 5 cm; (4) World Health Organization performance status (PS) <= 2 or PS 3 when the cause was not a pulmonary disease; (5) no prior chest radiotherapy for the NSCLC to be treated by SBRT; (6) no active concurrent malignancy; and (7) written informed consent.	('NSCLC', 'Phenotype', 'HP:0030358', (88, 93))	('tumor', 'Phenotype', 'HP:0002664', (358, 363))	('T2N0M0', 'Var', (109, 115))	('malignancy', 'Disease', (588, 598))	('Cancer', 'Phenotype', 'HP:0002664', (169, 175))	('PS 3', 'Gene', (445, 449))	('PS 3', 'Gene', '448990', (445, 449))	('men', 'Species', '9606', (366, 369))	('NSCLC', 'Disease', 'MESH:D002289', (534, 539))	('Cancer', 'Disease', (169, 175))	('men', 'Species', '9606', (228, 231))	('NSCLC', 'Disease', (534, 539))	('tumor', 'Disease', (358, 363))	('T1N0M0', 'Var', (99, 105))	('pulmonary disease', 'Disease', 'MESH:D008171', (475, 492))	('NSCLC', 'Disease', 'MESH:D002289', (88, 93))	('Cancer', 'Disease', 'MESH:D009369', (169, 175))	('tumor', 'Disease', 'MESH:D009369', (358, 363))	('pulmonary disease', 'Disease', (475, 492))	('NSCLC', 'Phenotype', 'HP:0030358', (534, 539))	('malignancy', 'Disease', 'MESH:D009369', (588, 598))	('NSCLC', 'Disease', (88, 93))
124977	30693974	Thus, in the presence of GTP/GDP TG2 flips closed and in the presence of calcium it flips open.	('calcium', 'Chemical', 'MESH:D002118', (73, 80))	('GTP', 'Chemical', 'MESH:D006160', (25, 28))	('flips', 'Reg', (84, 89))	('TG2', 'Gene', (33, 36))	('GTP/GDP', 'Var', (25, 32))	('flips', 'MPA', (37, 42))	('GDP', 'Chemical', 'MESH:D006153', (29, 32))
124998	30693974	2A) TG2 TGase activity appears to be important for this death response, as TG2 knockdown or treatment with BAPTA-AM (to chelate intracellular calcium) reduces apoptosis and cell death in response to photodynamic therapy.	('cell death', 'CPA', (173, 183))	('calcium', 'Chemical', 'MESH:D002118', (142, 149))	('reduces', 'NegReg', (151, 158))	('TG2', 'Gene', (75, 78))	('BAPTA-AM', 'Chemical', 'MESH:C070379', (107, 115))	('knockdown', 'Var', (79, 88))	('apoptosis', 'CPA', (159, 168))
125004	30693974	This suggests that TG2 inhibitors, which suppress GTP binding by indirectly disordering the TG2 GTP binding site, may be a useful treatment for gastric cancer.	('GTP binding site', 'MPA', (96, 112))	('gastric cancer', 'Phenotype', 'HP:0012126', (144, 158))	('disordering', 'NegReg', (76, 87))	('inhibitors', 'Var', (23, 33))	('GTP', 'Protein', (50, 53))	('GTP', 'Chemical', 'MESH:D006160', (96, 99))	('TG2', 'Gene', (19, 22))	('TG2', 'Gene', (92, 95))	('gastric cancer', 'Disease', 'MESH:D013274', (144, 158))	('gastric cancer', 'Disease', (144, 158))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('suppress', 'NegReg', (41, 49))	('GTP', 'Chemical', 'MESH:D006160', (50, 53))
125006	30693974	TG1 expression is increased in patient tumors and in cultured gastric cancer cells, and TG1 knockdown inhibits cell proliferation, enhances apoptosis and increases gastric cancer cell susceptibility to chemotherapeutic agents.	('TG1', 'Gene', (0, 3))	('enhances', 'PosReg', (131, 139))	('gastric cancer', 'Phenotype', 'HP:0012126', (164, 178))	('knockdown', 'Var', (92, 101))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('gastric cancer', 'Disease', (62, 76))	('tumors', 'Disease', (39, 45))	('inhibits', 'NegReg', (102, 110))	('increases gastric cancer', 'Disease', 'MESH:D013274', (154, 178))	('apoptosis', 'CPA', (140, 149))	('cell proliferation', 'CPA', (111, 129))	('patient', 'Species', '9606', (31, 38))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('gastric cancer', 'Disease', 'MESH:D013274', (62, 76))	('increased', 'PosReg', (18, 27))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('rat', 'Species', '10116', (123, 126))	('gastric cancer', 'Disease', 'MESH:D013274', (164, 178))	('increases gastric cancer', 'Phenotype', 'HP:0006753', (154, 178))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('gastric cancer', 'Phenotype', 'HP:0012126', (62, 76))	('increases gastric cancer', 'Disease', (154, 178))	('TG1', 'Gene', (88, 91))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))
125011	30693974	TG3 may have a tumor suppressor role in oral cancer, as proteomic analysis reveals a marked reduction in TG3 levels in oral cancer samples due to hypermethylation of the TG3 gene locus.	('cancer', 'Disease', (124, 130))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('hypermethylation', 'Var', (146, 162))	('reduction', 'NegReg', (92, 101))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('TG3 levels', 'MPA', (105, 115))	('tumor', 'Disease', (15, 20))	('TG3', 'Gene', (170, 173))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('cancer', 'Disease', (45, 51))	('cancer', 'Disease', 'MESH:D009369', (124, 130))
125012	30693974	TG3 TGase activity is involved in crosslinking precursor structural proteins to facilitate terminal cell differentiation in stratified epithelia, and so loss of TG3 would be consistent with reduced cell differentiation during cancer progression.	('terminal cell differentiation', 'CPA', (91, 120))	('TG3', 'Gene', (0, 3))	('facilitate', 'PosReg', (80, 90))	('loss', 'Var', (153, 157))	('reduced', 'NegReg', (190, 197))	('cancer', 'Disease', (226, 232))	('cancer', 'Disease', 'MESH:D009369', (226, 232))	('cell differentiation', 'CPA', (198, 218))	('rat', 'Species', '10116', (126, 129))	('TG3', 'Gene', (161, 164))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
125023	30693974	The authors propose that TG2 forms a complex with keratin 19 and src and that TGase activity modifies keratin 19 to activate src signaling and enhance cancer cell survival (Fig.	('activate', 'PosReg', (116, 124))	('modifies', 'Var', (93, 101))	('enhance', 'PosReg', (143, 150))	('src', 'Gene', (125, 128))	('keratin 19', 'Gene', (50, 60))	('src', 'Gene', '6714', (65, 68))	('keratin 19', 'Gene', '3880', (102, 112))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('complex', 'Interaction', (37, 44))	('keratin 19', 'Gene', (102, 112))	('src', 'Gene', '6714', (125, 128))	('cancer', 'Disease', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('src', 'Gene', (65, 68))	('keratin 19', 'Gene', '3880', (50, 60))
125024	30693974	2B) Thus, it appears that TG2 TGase modification of K19 is necessary to form a scaffold that activates Src signaling.	('modification', 'Var', (36, 48))	('activates', 'PosReg', (93, 102))	('Src', 'Gene', (103, 106))	('Src', 'Gene', '6714', (103, 106))	('K19', 'Gene', '3880', (52, 55))	('K19', 'Gene', (52, 55))
125027	30693974	TG2 knockdown sensitizes cells to docetaxel.	('sensitizes', 'Reg', (14, 24))	('knockdown', 'Var', (4, 13))	('docetaxel', 'Chemical', 'MESH:D000077143', (34, 43))	('TG2', 'Gene', (0, 3))
125028	30693974	TG2 level is increased in breast cancer cells following treatment with rapamycin, an mTOR (mechanistic target of rapamycin complex 1) inhibitor and TG2 knockdown renders these cells hypersensitive to rapamycin.	('breast cancer', 'Disease', (26, 39))	('knockdown', 'Var', (152, 161))	('breast cancer', 'Phenotype', 'HP:0003002', (26, 39))	('TG2', 'Gene', (148, 151))	('rapamycin', 'Chemical', 'MESH:D020123', (200, 209))	('rapamycin', 'Chemical', 'MESH:D020123', (71, 80))	('TG2 level', 'MPA', (0, 9))	('rapamycin', 'Chemical', 'MESH:D020123', (113, 122))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('mTOR', 'Gene', '2475', (85, 89))	('breast cancer', 'Disease', 'MESH:D001943', (26, 39))	('mTOR', 'Gene', (85, 89))	('increased', 'PosReg', (13, 22))	('hypersensitive', 'PosReg', (182, 196))
125030	30693974	TG2 knockdown also restores breast cancer cell sensitivity to doxorubicin.	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('restores', 'PosReg', (19, 27))	('breast cancer', 'Disease', 'MESH:D001943', (28, 41))	('sensitivity to doxorubicin', 'MPA', (47, 73))	('breast cancer', 'Phenotype', 'HP:0003002', (28, 41))	('doxorubicin', 'Chemical', 'MESH:D004317', (62, 73))	('breast cancer', 'Disease', (28, 41))	('TG2', 'Gene', (0, 3))	('knockdown', 'Var', (4, 13))
125037	30693974	Both wild-type TG2 and TGase activity-inactive TG2 mutants stimulate NFkappaB leading to HIF-1alpha induction, suggesting that the regulation requires the TG2 GTP-binding domain.	('mutants', 'Var', (51, 58))	('HIF-1alpha', 'Gene', '3091', (89, 99))	('stimulate', 'PosReg', (59, 68))	('TG2', 'Gene', (47, 50))	('NFkappaB', 'Gene', (69, 77))	('GTP', 'Chemical', 'MESH:D006160', (159, 162))	('induction', 'MPA', (100, 109))	('NFkappaB', 'Gene', '4790', (69, 77))	('HIF-1alpha', 'Gene', (89, 99))
125041	30693974	Covalent modification of TG2 can also influence TG2 regulation of NFkappaB.	('TG2 regulation', 'MPA', (48, 62))	('influence', 'Reg', (38, 47))	('TG2', 'Gene', (25, 28))	('NFkappaB', 'Gene', (66, 74))	('NFkappaB', 'Gene', '4790', (66, 74))	('Covalent modification', 'Var', (0, 21))
125042	30693974	For example, protein kinase A phosphorylation of TG2 at serine-216 precedes NFkappaB activation and PTEN downregulation in MCF-7 and T47D cells (Fig.	('PTEN', 'Gene', (100, 104))	('NFkappaB', 'Gene', '4790', (76, 84))	('phosphorylation', 'MPA', (30, 45))	('PTEN', 'Gene', '5728', (100, 104))	('MCF-7', 'CellLine', 'CVCL:0031', (123, 128))	('downregulation', 'NegReg', (105, 119))	('serine', 'Chemical', 'MESH:D012694', (56, 62))	('protein kinase A', 'Enzyme', (13, 29))	('activation', 'PosReg', (85, 95))	('serine-216', 'Var', (56, 66))	('TG2', 'Gene', (49, 52))	('NFkappaB', 'Gene', (76, 84))	('T47D', 'CellLine', 'CVCL:0553', (133, 137))
125044	30693974	Moreover, IL-1beta induces IL-6 production in TG2 overexpressing MCF-7 cells via a mechanism that requires NFkappaB, PI3K and JNK, and leads to enhanced stemness, invasion, survival, and tumor growth, while suppressing IL-6 or IL-1beta production attenuates these events.	('TG2', 'Gene', (46, 49))	('IL-1beta', 'Gene', '3552', (10, 18))	('tumor', 'Disease', (187, 192))	('NFkappaB', 'Gene', '4790', (107, 115))	('invasion', 'CPA', (163, 171))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('enhanced', 'PosReg', (144, 152))	('JNK', 'Gene', (126, 129))	('NFkappaB', 'Gene', (107, 115))	('IL-1beta', 'Gene', (227, 235))	('IL-6', 'Gene', (27, 31))	('survival', 'CPA', (173, 181))	('JNK', 'Gene', '5599', (126, 129))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('IL-1beta', 'Gene', (10, 18))	('MCF-7', 'CellLine', 'CVCL:0031', (65, 70))	('IL-1beta', 'Gene', '3552', (227, 235))	('PI3K', 'Var', (117, 121))	('stemness', 'CPA', (153, 161))
125054	30693974	Treatment of cells with recombinant wild-type TG2 induced non-canonical NFkappaB signaling, but this was not observed with recombinant TG2(C277A), a TGase activity-inactive TG2 mutant, suggesting that TG2 TGase activity is required for malignant spread.	('NFkappaB', 'Gene', (72, 80))	('C277A', 'Var', (139, 144))	('C277A', 'Mutation', 'c.277C>A', (139, 144))	('NFkappaB', 'Gene', '4790', (72, 80))
125057	30693974	These events require interaction of TG2 with fibronectin, as inhibiting the TG2/fibronectin interaction reduces stability of the TGFbeta/fibronectin/TG2 complex to reduce adhesion and biological response.	('stability', 'MPA', (112, 121))	('fibronectin', 'Gene', (45, 56))	('fibronectin', 'Gene', (80, 91))	('TGFbeta', 'Gene', (129, 136))	('reduces', 'NegReg', (104, 111))	('reduce', 'NegReg', (164, 170))	('biological response', 'CPA', (184, 203))	('fibronectin', 'Gene', '2335', (137, 148))	('fibronectin', 'Gene', '2335', (45, 56))	('TGFbeta', 'Gene', '7039', (129, 136))	('fibronectin', 'Gene', '2335', (80, 91))	('inhibiting', 'Var', (61, 71))	('fibronectin', 'Gene', (137, 148))	('interaction', 'Interaction', (92, 103))	('adhesion', 'CPA', (171, 179))
125066	30693974	In A549 lung cancer cells, TG2 knockdown or pharmacologic suppression of JNK activity, reduces TGFbeta1-induced EMT, and additional studies suggest that TG2 activates JNK, via suppression of PP2A activity (Fig.	('JNK', 'Gene', (73, 76))	('TG2', 'Var', (153, 156))	('A549', 'CellLine', 'CVCL:0023', (3, 7))	('JNK', 'Gene', '5599', (73, 76))	('PP2A', 'Gene', '5524', (191, 195))	('suppression', 'NegReg', (176, 187))	('activates', 'PosReg', (157, 166))	('JNK', 'Gene', (167, 170))	('JNK', 'Gene', '5599', (167, 170))	('lung cancer', 'Disease', 'MESH:D008175', (8, 19))	('lung cancer', 'Phenotype', 'HP:0100526', (8, 19))	('activity', 'MPA', (196, 204))	('TGFbeta1', 'Gene', '7040', (95, 103))	('PP2A', 'Gene', (191, 195))	('reduces', 'NegReg', (87, 94))	('suppression', 'NegReg', (58, 69))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('TGFbeta1', 'Gene', (95, 103))	('lung cancer', 'Disease', (8, 19))	('knockdown', 'Var', (31, 40))
125067	30693974	TG2 also appears to influence drug sensitivity in these tumors, as treatment with TG2 inhibitor or TG2 knockdown restores TRAIL-induced apoptosis.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('TRAIL', 'Gene', (122, 127))	('restores', 'PosReg', (113, 121))	('TG2', 'Gene', (99, 102))	('tumors', 'Disease', (56, 62))	('influence', 'Reg', (20, 29))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('TG2', 'Gene', (82, 85))	('TRAIL', 'Gene', '8743', (122, 127))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('drug sensitivity', 'Phenotype', 'HP:0020174', (30, 46))	('drug sensitivity', 'MPA', (30, 46))	('knockdown', 'Var', (103, 112))
125069	30693974	Screening of the cancer genome atlas indicates a correlation between high TG2 expression and reduced overall patient survival.	('expression', 'MPA', (78, 88))	('patient', 'Species', '9606', (109, 116))	('reduced', 'NegReg', (93, 100))	('TG2', 'Gene', (74, 77))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('cancer', 'Disease', (17, 23))	('high', 'Var', (69, 73))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
125070	30693974	TG2 knockdown in pancreatic ductal adenocarcinoma cells reduces xenograft growth and enhances sensitivity to gemcitabine, and it has been suggested that TG2 released from pancreatic tumor cells activates fibroblasts in the tumor microenvironment to produce laminin which protects the cancer cells by constructing a dense desmoplastic stroma.	('desmoplastic stroma', 'Disease', 'MESH:D018220', (321, 340))	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('cancer', 'Disease', 'MESH:D009369', (284, 290))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (17, 49))	('knockdown', 'Var', (4, 13))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))	('sensitivity to gemcitabine', 'MPA', (94, 120))	('pancreatic tumor', 'Phenotype', 'HP:0002894', (171, 187))	('pancreatic ductal adenocarcinoma', 'Disease', (17, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (40, 49))	('xenograft growth', 'CPA', (64, 80))	('tumor', 'Disease', (223, 228))	('cancer', 'Disease', (284, 290))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (17, 49))	('reduces', 'NegReg', (56, 63))	('pancreatic tumor', 'Disease', (171, 187))	('tumor', 'Disease', 'MESH:D009369', (223, 228))	('cancer', 'Phenotype', 'HP:0002664', (284, 290))	('gemcitabine', 'Chemical', 'MESH:C056507', (109, 120))	('pancreatic tumor', 'Disease', 'MESH:D010190', (171, 187))	('tumor', 'Disease', (182, 187))	('desmoplastic stroma', 'Disease', (321, 340))	('TG2', 'Gene', (153, 156))	('enhances', 'PosReg', (85, 93))	('TG2', 'Gene', (0, 3))	('tumor', 'Disease', 'MESH:D009369', (182, 187))
125075	30693974	Moreover, knockdown of eEF2K reduces cell invasion and migration, and reduces TG2 mRNA and protein level.	('eEF2K', 'Gene', (23, 28))	('reduces', 'NegReg', (70, 77))	('eEF2K', 'Gene', '29904', (23, 28))	('rat', 'Species', '10116', (58, 61))	('reduces', 'NegReg', (29, 36))	('cell invasion', 'CPA', (37, 50))	('knockdown', 'Var', (10, 19))	('TG2', 'Protein', (78, 81))
125076	30693974	TG2 appears to have a role in regulating downstream signaling events, as knockdown of either eEF2K, or TG2, reduces Snail and ZEB1 level leading to reduced EMT (Fig.	('TG2', 'Gene', (103, 106))	('Snail', 'Gene', (116, 121))	('eEF2K', 'Gene', '29904', (93, 98))	('reduced', 'NegReg', (148, 155))	('Snail', 'Gene', '6615', (116, 121))	('EMT', 'CPA', (156, 159))	('reduces', 'NegReg', (108, 115))	('ZEB1', 'Gene', (126, 130))	('reduced EMT', 'Phenotype', 'HP:0032198', (148, 159))	('ZEB1', 'Gene', '6935', (126, 130))	('eEF2K', 'Gene', (93, 98))	('knockdown', 'Var', (73, 82))
125078	30693974	TG2 also regulates pancreatic cell morphology, since TG2 silencing reduces the 2-O-tetradecanoylphorbol-13-acetate dependent phosphorylation of keratin 8, and suppresses 2-O-tetradecanoylphorbol-13-acetate dependent keratin filament reorganization in PANC-1 cells.	('2-O-tetradecanoylphorbol-13-acetate', 'Chemical', '-', (79, 114))	('rat', 'Species', '10116', (146, 149))	('pancreatic', 'Disease', 'MESH:D010195', (19, 29))	('keratin 8', 'Gene', (144, 153))	('keratin 8', 'Gene', '3856', (144, 153))	('silencing', 'Var', (57, 66))	('TG2', 'Gene', (53, 56))	('rat', 'Species', '10116', (218, 221))	('PANC-1', 'CellLine', 'CVCL:0480', (251, 257))	('2-O-tetradecanoylphorbol-13-acetate', 'Chemical', '-', (170, 205))	('pancreatic', 'Disease', (19, 29))	('reduces', 'NegReg', (67, 74))	('regulates', 'Reg', (9, 18))	('suppresses', 'NegReg', (159, 169))
125080	30693974	TG2 is highly elevated in epidermal cancer stem cells (ECS cells) and TG2 knockdown or suppression of TG2 function with TG2 inhibitor (NC9) reduces ECS cell survival, spheroid formation, matrigel invasion, migration and EMT (Fig.	('NC9', 'Chemical', '-', (135, 138))	('reduces', 'NegReg', (140, 147))	('TG2', 'Gene', (70, 73))	('migration', 'CPA', (206, 215))	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('suppression', 'NegReg', (87, 98))	('matrigel invasion', 'CPA', (187, 204))	('cancer', 'Disease', (36, 42))	('knockdown', 'Var', (74, 83))	('spheroid formation', 'CPA', (167, 185))	('rat', 'Species', '10116', (209, 212))	('TG2', 'Gene', (102, 105))	('TG2', 'Gene', (0, 3))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('elevated', 'PosReg', (14, 22))
125081	30693974	This reduction in stem cell phenotype is associated with activation of apoptosis, and TG2 mutant studies reveal that TG2 GTP-binding activity, but not TGase activity, is required to maintain the ECS cell phenotype (Fig.	('GTP-binding', 'Protein', (121, 132))	('TG2', 'Gene', (117, 120))	('mutant', 'Var', (90, 96))	('GTP', 'Chemical', 'MESH:D006160', (121, 124))	('activity', 'MPA', (133, 141))	('stem cell phenotype', 'CPA', (18, 37))	('TG2', 'Gene', (86, 89))	('ECS', 'Disease', (195, 198))
125083	30693974	In this cascade TG2 interacts with alpha6/beta4-integrin to stimulate FAK/Src signaling leading to PI3K activation of PDK1.	('PI3K', 'Var', (99, 103))	('alpha6/beta4', 'Gene', '28898', (35, 47))	('PDK1', 'Gene', (118, 122))	('activation', 'PosReg', (104, 114))	('Src', 'Gene', '6714', (74, 77))	('TG2', 'Gene', (16, 19))	('alpha6/beta4', 'Gene', (35, 47))	('stimulate', 'PosReg', (60, 69))	('FAK', 'Gene', '5747', (70, 73))	('interacts', 'Interaction', (20, 29))	('PDK1', 'Gene', '5163', (118, 122))	('Src', 'Gene', (74, 77))	('FAK', 'Gene', (70, 73))
125090	30693974	Studies using ECS cells establish the intracellular mechanism of action of several transglutaminase 2 inhibitors, including NC9, VA4, VA5 and CP4d (Fig.	('transglutaminase 2', 'Gene', (83, 101))	('transglutaminase 2', 'Gene', '7052', (83, 101))	('CP4d', 'Var', (142, 146))	('NC9', 'Chemical', '-', (124, 127))
125099	30693974	Treatment with TG2 inhibitors, KC009 or ERW1227B, sensitives cultured glioblastoma cells to chemotherapeutic agents, and enhances apoptosis in glioblastoma xenografts, and the GK921 TG2 inhibitor suppresses tumor cell transition to the mesenchymal phenotype.	('GK921', 'Var', (176, 181))	('ERW1227B', 'Var', (40, 48))	('TG2', 'Gene', (15, 18))	('GK921', 'Chemical', 'MESH:C000588709', (176, 181))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('glioblastoma', 'Disease', (70, 82))	('enhances', 'PosReg', (121, 129))	('glioblastoma', 'Phenotype', 'HP:0012174', (70, 82))	('KC009', 'Var', (31, 36))	('KC009', 'Chemical', '-', (31, 36))	('apoptosis', 'CPA', (130, 139))	('glioblastoma', 'Disease', 'MESH:D005909', (143, 155))	('tumor', 'Disease', (207, 212))	('glioblastoma', 'Disease', (143, 155))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('TG2', 'Gene', (182, 185))	('suppresses', 'NegReg', (196, 206))	('glioblastoma', 'Phenotype', 'HP:0012174', (143, 155))	('glioblastoma', 'Disease', 'MESH:D005909', (70, 82))	('ERW1227B', 'Chemical', 'MESH:C561342', (40, 48))
125106	30693974	Moreover, TG2 expression is dependent upon retinoic acid which is produced by aldehyde dehydrogenase 1A3 (ALDH1A3), suggesting that ALDH1A3, in glioblastoma stem cells, maintains TG2 level.	('retinoic acid', 'Chemical', 'MESH:D014212', (43, 56))	('TG2 level', 'MPA', (179, 188))	('maintains', 'PosReg', (169, 178))	('glioblastoma', 'Disease', (144, 156))	('ALDH1A3', 'Var', (132, 139))	('glioblastoma', 'Disease', 'MESH:D005909', (144, 156))	('aldehyde dehydrogenase 1A3', 'Gene', '56847', (78, 104))	('glioblastoma', 'Phenotype', 'HP:0012174', (144, 156))	('aldehyde dehydrogenase 1A3', 'Gene', (78, 104))
125114	30693974	Another study reports a substantial increase in TG2 in hepatocellular carcinoma and shows that inhibition of TG2 in HepG2.2.15 or Hep3B cell suppresses cell proliferation, invasion and migration.	('Hep3B', 'CellLine', 'CVCL:0326', (130, 135))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (55, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('hepatocellular carcinoma', 'Disease', (55, 79))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (55, 79))	('inhibition', 'Var', (95, 105))	('TG2', 'Gene', (109, 112))	('increase', 'PosReg', (36, 44))	('TG2', 'Protein', (48, 51))	('rat', 'Species', '10116', (188, 191))	('rat', 'Species', '10116', (164, 167))	('suppresses', 'NegReg', (141, 151))	('cell proliferation', 'CPA', (152, 170))	('HepG2.2.15', 'CellLine', 'CVCL:L855', (116, 126))
125116	30693974	Acrylic retinoids inhibit post-surgery hepatocellular carcinoma recurrence via mechanisms that involve TG2 crosslinking of Sp1 transcription factor in the cell nucleus leading to loss of EGF receptor expression and cell apoptosis.	('EGF receptor', 'Gene', (187, 199))	('inhibit', 'NegReg', (18, 25))	('crosslinking', 'Var', (107, 119))	('cell apoptosis', 'CPA', (215, 229))	('carcinoma', 'Phenotype', 'HP:0030731', (54, 63))	('Acrylic retinoids', 'Chemical', '-', (0, 17))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (39, 63))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (39, 63))	('expression', 'MPA', (200, 210))	('EGF receptor', 'Gene', '1956', (187, 199))	('loss', 'NegReg', (179, 183))	('hepatocellular carcinoma', 'Disease', (39, 63))
125119	30693974	It is interesting that the miR-1285 microRNA regulates TG2 in renal cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('renal cancer', 'Disease', (62, 74))	('miR-1285', 'Var', (27, 35))	('miR-1285', 'Chemical', '-', (27, 35))	('renal cancer', 'Phenotype', 'HP:0009726', (62, 74))	('regulates', 'Reg', (45, 54))	('renal cancer', 'Disease', 'MESH:D007680', (62, 74))	('TG2', 'Gene', (55, 58))
125121	30693974	Moreover, silencing of TG2 or forced overexpression of miR-1285, reduce TG2 level and cell proliferation.	('overexpression', 'PosReg', (37, 51))	('miR-1285', 'Gene', (55, 63))	('TG2', 'Gene', (23, 26))	('rat', 'Species', '10116', (98, 101))	('cell proliferation', 'CPA', (86, 104))	('reduce', 'NegReg', (65, 71))	('TG2 level', 'MPA', (72, 81))	('miR-1285', 'Chemical', '-', (55, 63))	('silencing', 'Var', (10, 19))
125122	30693974	TG2 also regulates renal carcinoma cell survival, as TG2 knockdown leads to increased p53 level and enhanced apoptosis in 786-O, A498, CAKI-1 and ACHN cells.	('renal carcinoma', 'Disease', 'MESH:C538614', (19, 34))	('p53', 'Gene', '7157', (86, 89))	('increased', 'PosReg', (76, 85))	('renal carcinoma', 'Disease', (19, 34))	('enhanced', 'PosReg', (100, 108))	('apoptosis', 'CPA', (109, 118))	('knockdown', 'Var', (57, 66))	('TG2', 'Gene', (53, 56))	('renal carcinoma', 'Phenotype', 'HP:0005584', (19, 34))	('regulates', 'Reg', (9, 18))	('carcinoma', 'Phenotype', 'HP:0030731', (25, 34))	('p53', 'Gene', (86, 89))
125125	30693974	Moreover, treatment with GK921, a TG2 inhibitor, reduces ACHN and CAKI-1 renal carcinoma cell tumor growth in xenograft models.	('reduces', 'NegReg', (49, 56))	('renal carcinoma', 'Phenotype', 'HP:0005584', (73, 88))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('GK921', 'Chemical', 'MESH:C000588709', (25, 30))	('ACHN', 'Protein', (57, 61))	('CAKI-1 renal carcinoma cell tumor', 'Disease', (66, 99))	('CAKI-1 renal carcinoma cell tumor', 'Disease', 'MESH:C538557', (66, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('GK921', 'Var', (25, 30))
125126	30693974	Glycolysis is enhanced in renal carcinoma cells and high TG2 level increases glucose consumption and lactate production, while decreasing mitochondrial aconitase level.	('mitochondrial aconitase', 'Gene', (138, 161))	('mitochondrial aconitase', 'Gene', '50', (138, 161))	('lactate', 'Chemical', 'MESH:D019344', (101, 108))	('renal carcinoma', 'Disease', (26, 41))	('enhanced', 'PosReg', (14, 22))	('renal carcinoma', 'Phenotype', 'HP:0005584', (26, 41))	('glucose', 'Chemical', 'MESH:D005947', (77, 84))	('lactate production', 'MPA', (101, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (32, 41))	('decreasing', 'NegReg', (127, 137))	('Glycolysis', 'MPA', (0, 10))	('TG2', 'Gene', (57, 60))	('high', 'Var', (52, 56))	('increases', 'PosReg', (67, 76))	('glucose consumption', 'MPA', (77, 96))	('renal carcinoma', 'Disease', 'MESH:C538614', (26, 41))
125127	30693974	The ubiquitination system also influences TG2 function, as TG2 level is reduced following modification by CHIP (carboxyl-terminus of hsp70-interacting protein), an E3 ubiquitin ligase, and CHIP knockdown is associated with elevated TG2 and aggressive cancer (Fig.	('aggressive cancer', 'Disease', (240, 257))	('reduced', 'NegReg', (72, 79))	('TG2', 'Gene', (232, 235))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('TG2 level', 'MPA', (59, 68))	('influences', 'Reg', (31, 41))	('ubiquitination', 'MPA', (4, 18))	('function', 'MPA', (46, 54))	('CHIP knockdown', 'Var', (189, 203))	('aggressive cancer', 'Disease', 'MESH:D009369', (240, 257))	('elevated', 'PosReg', (223, 231))	('modification', 'Var', (90, 102))
125130	30693974	Silencing of TG2 in renal carcinoma cells reduces actin stress fiber formation and adhesion to fibronectin, collagen type I and laminin, leading to impaired invasion and migration, and reduced cancer stem cell marker expression.	('actin', 'MPA', (50, 55))	('impaired', 'NegReg', (148, 156))	('cancer', 'Disease', (193, 199))	('fibronectin', 'Gene', (95, 106))	('TG2', 'Gene', (13, 16))	('laminin', 'Protein', (128, 135))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('carcinoma', 'Phenotype', 'HP:0030731', (26, 35))	('Silencing', 'Var', (0, 9))	('reduced', 'NegReg', (185, 192))	('rat', 'Species', '10116', (173, 176))	('reduces', 'NegReg', (42, 49))	('renal carcinoma', 'Disease', 'MESH:C538614', (20, 35))	('renal carcinoma', 'Phenotype', 'HP:0005584', (20, 35))	('renal carcinoma', 'Disease', (20, 35))	('adhesion', 'CPA', (83, 91))	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('fibronectin', 'Gene', '2335', (95, 106))	('invasion', 'CPA', (157, 165))
125136	30693974	TG4 has a role in prostate cancer cell survival, as it stimulates cell motility and N-cadherin expression, changes which are reversed by TG4 knockdown.	('N-cadherin', 'Gene', '1000', (84, 94))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('TG4', 'Chemical', '-', (137, 140))	('prostate cancer', 'Disease', 'MESH:D011471', (18, 33))	('TG4', 'Chemical', '-', (0, 3))	('prostate cancer', 'Phenotype', 'HP:0012125', (18, 33))	('TG4', 'Var', (0, 3))	('cell motility', 'CPA', (66, 79))	('N-cadherin', 'Gene', (84, 94))	('stimulates', 'PosReg', (55, 65))	('prostate cancer', 'Disease', (18, 33))	('expression', 'MPA', (95, 105))
125138	30693974	In addition, prostate cancer cells are more motile following forced TG4 expression and this involves TG2 co-localization and interaction with RON, the hepatocyte growth factor-like/macrophage-stimulating protein receptor.	('RON', 'Gene', (142, 145))	('prostate cancer', 'Phenotype', 'HP:0012125', (13, 28))	('more', 'PosReg', (39, 43))	('TG2', 'Gene', (101, 104))	('TG4', 'Chemical', '-', (68, 71))	('interaction', 'Interaction', (125, 136))	('RON', 'Gene', '4486', (142, 145))	('prostate cancer', 'Disease', (13, 28))	('TG4', 'Gene', (68, 71))	('forced', 'Var', (61, 67))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('expression', 'Var', (72, 82))	('prostate cancer', 'Disease', 'MESH:D011471', (13, 28))	('co-localization', 'MPA', (105, 120))
125145	30693974	Consistent with a role of TG2 in meningioma cell survival, TG2 knockdown, or treatment with cystamine, induces meningioma cell death which is associated with reduced Akt signaling.	('meningioma', 'Disease', (33, 43))	('meningioma', 'Phenotype', 'HP:0002858', (33, 43))	('meningioma cell death', 'Disease', 'MESH:D003643', (111, 132))	('meningioma', 'Disease', 'MESH:D008577', (111, 121))	('Akt', 'Gene', '207', (166, 169))	('cystamine', 'Chemical', 'MESH:D003538', (92, 101))	('Akt', 'Gene', (166, 169))	('meningioma', 'Disease', 'MESH:D008577', (33, 43))	('meningioma cell death', 'Disease', (111, 132))	('induces', 'Reg', (103, 110))	('meningioma', 'Disease', (111, 121))	('TG2', 'Gene', (59, 62))	('knockdown', 'Var', (63, 72))	('meningioma', 'Phenotype', 'HP:0002858', (111, 121))
125152	30693974	It is interesting that inhibition of TG2 TGase activity, using calcium blockers, increases interaction of p65 with IkappaBalpha to reduce NFkappaB signaling and enhance mantle cell lymphoma cell sensitivity to bortezomib.	('IkappaBalpha', 'Gene', '4792', (115, 127))	('enhance', 'PosReg', (161, 168))	('inhibition', 'Var', (23, 33))	('TG2', 'Gene', (37, 40))	('p65', 'Gene', '5970', (106, 109))	('p65', 'Gene', (106, 109))	('IkappaBalpha', 'Gene', (115, 127))	('mantle cell lymphoma', 'Disease', 'MESH:D020522', (169, 189))	('bortezomib', 'Chemical', 'MESH:D000069286', (210, 220))	('cell lymphoma', 'Phenotype', 'HP:0012191', (176, 189))	('lymphoma', 'Phenotype', 'HP:0002665', (181, 189))	('mantle cell lymphoma', 'Disease', (169, 189))	('NFkappaB', 'Gene', (138, 146))	('interaction', 'Interaction', (91, 102))	('reduce', 'NegReg', (131, 137))	('NFkappaB', 'Gene', '4790', (138, 146))	('calcium', 'Chemical', 'MESH:D002118', (63, 70))	('increases', 'PosReg', (81, 90))
125160	30693974	The pro-cancer action of TG2 appears to require TG2 TGase activity, as expression of wild-type TG2, but not TGase inactive TG2, restores tumor formation in TG2 knockdown MC-1 cells.	('cancer', 'Disease', (8, 14))	('tumor', 'Disease', (137, 142))	('MC-1', 'CellLine', 'CVCL:H810', (170, 174))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('restores', 'PosReg', (128, 136))	('TG2', 'Var', (95, 98))	('cancer', 'Disease', 'MESH:D009369', (8, 14))
125168	30693974	This increase is linked to increased TG2 gene copy number, and TG2 levels are further increased in chemotherapy and radiation-resistant cancer cells.	('copy number', 'Var', (46, 57))	('radiation-resistant cancer', 'Disease', (116, 142))	('TG2', 'MPA', (63, 66))	('increased', 'PosReg', (27, 36))	('increased', 'PosReg', (86, 95))	('TG2', 'Gene', (37, 40))	('radiation-resistant cancer', 'Disease', 'MESH:D009369', (116, 142))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
125176	30693974	In this context, TG2 protects cells from apoptosis by suppressing Bax level and reducing cytochrome c release, and these protective actions are attenuated by TG2 knockdown; however, it is not known if the TG2 TGase activity mediates the change in intracellular distribution of Bax and cytochrome c. Elevated TG2 expression is also associated with osteosarcoma cell cisplatin resistance and TG2 knockdown restores chemosensitivity.	('Bax', 'Gene', '581', (66, 69))	('suppressing', 'NegReg', (54, 65))	('osteosarcoma', 'Disease', (347, 359))	('TG2', 'Gene', (308, 311))	('osteosarcoma', 'Disease', 'MESH:D012516', (347, 359))	('knockdown', 'Var', (394, 403))	('chemosensitivity', 'MPA', (413, 429))	('cytochrome c', 'Gene', '54205', (89, 101))	('expression', 'MPA', (312, 322))	('cytochrome c', 'Gene', '54205', (285, 297))	('cisplatin', 'Chemical', 'MESH:D002945', (365, 374))	('Elevated', 'PosReg', (299, 307))	('Bax', 'Gene', (277, 280))	('osteosarcoma', 'Phenotype', 'HP:0002669', (347, 359))	('cytochrome c', 'Gene', (89, 101))	('associated', 'Reg', (331, 341))	('Bax', 'Gene', '581', (277, 280))	('cytochrome c', 'Gene', (285, 297))	('restores', 'PosReg', (404, 412))	('TG2', 'Gene', (390, 393))	('sarcoma', 'Phenotype', 'HP:0100242', (352, 359))	('Bax', 'Gene', (66, 69))
125181	30693974	TG2 appears to act with oncostatin M receptor to drive tumor cell invasion and migration, and TG2 knockdown attenuates these actions (Fig.	('oncostatin M', 'Gene', '5008', (24, 36))	('oncostatin M', 'Gene', (24, 36))	('migration', 'CPA', (79, 88))	('TG2', 'Gene', (94, 97))	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('knockdown', 'Var', (98, 107))	('tumor', 'Disease', (55, 60))	('attenuates', 'NegReg', (108, 118))	('rat', 'Species', '10116', (82, 85))	('drive', 'PosReg', (49, 54))
125186	30693974	TG6 may also have a role in leukemia, as whole exome sequencing revealed a missense mutation in the TG6 gene which co-segregated with the cancer phenotype in a family, but was absent in healthy control patients.	('TG6', 'Gene', (100, 103))	('cancer', 'Disease', (138, 144))	('leukemia', 'Disease', (28, 36))	('leukemia', 'Phenotype', 'HP:0001909', (28, 36))	('leukemia', 'Disease', 'MESH:D007938', (28, 36))	('patients', 'Species', '9606', (202, 210))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('missense mutation', 'Var', (75, 92))	('cancer', 'Disease', 'MESH:D009369', (138, 144))
125189	30693974	Moreover, TG2 knockdown in HT-1080 cells suppresses invasion and migration, and this is associated with reduced NFkappaB, MMP-2 and MMP-9 level and activity.	('MMP-2', 'Gene', (122, 127))	('reduced', 'NegReg', (104, 111))	('NFkappaB', 'Gene', (112, 120))	('HT-1080', 'CellLine', 'CVCL:0317', (27, 34))	('NFkappaB', 'Gene', '4790', (112, 120))	('activity', 'MPA', (148, 156))	('MMP-9', 'Gene', '4318', (132, 137))	('rat', 'Species', '10116', (68, 71))	('MMP-2', 'Gene', '4313', (122, 127))	('MMP-9', 'Gene', (132, 137))	('suppresses', 'NegReg', (41, 51))	('knockdown', 'Var', (14, 23))	('TG2', 'Gene', (10, 13))
125192	30693974	Interestingly, knockdown of TG2 is associated with reduced beta1-integrin interaction with fibronectin and reduced secretion of MMP-9 and MMP-1 (Fig.	('beta1-integrin', 'Gene', '3688', (59, 73))	('fibronectin', 'Gene', '2335', (91, 102))	('reduced', 'NegReg', (51, 58))	('knockdown', 'Var', (15, 24))	('beta1-integrin', 'Gene', (59, 73))	('MMP-1', 'Gene', '4312', (138, 143))	('MMP-9', 'Gene', '4318', (128, 133))	('reduced', 'NegReg', (107, 114))	('MMP-9', 'Gene', (128, 133))	('MMP-1', 'Gene', (138, 143))	('interaction with', 'Interaction', (74, 90))	('fibronectin', 'Gene', (91, 102))	('TG2', 'Gene', (28, 31))
125196	30693974	Analysis of laryngeal squamous cell carcinoma tumors isolated from 148 patients showed that high TG2 expression is associated with reduced survival in patients receiving postoperative radiotherapy, suggesting that TG2 has a role in cancer survival.	('TG2', 'Gene', (97, 100))	('cancer', 'Disease', 'MESH:D009369', (232, 238))	('high', 'Var', (92, 96))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('rat', 'Species', '10116', (177, 180))	('cancer', 'Disease', (232, 238))	('patients', 'Species', '9606', (71, 79))	('survival', 'MPA', (139, 147))	('patients', 'Species', '9606', (151, 159))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (22, 45))	('reduced', 'NegReg', (131, 138))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (36, 45))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('squamous cell carcinoma tumors', 'Disease', 'MESH:D002294', (22, 52))	('expression', 'MPA', (101, 111))	('squamous cell carcinoma tumors', 'Disease', (22, 52))
125202	30693974	TG2 knockdown or treatment with a TG2 inhibitor, in hypoxia-challenged cells, reduces cancer stem cell viability.	('hypoxia', 'Disease', 'MESH:D000860', (52, 59))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('TG2', 'Gene', (0, 3))	('TG2', 'Gene', (34, 37))	('hypoxia', 'Disease', (52, 59))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('knockdown', 'Var', (4, 13))	('reduces', 'NegReg', (78, 85))	('cancer', 'Disease', (86, 92))
125203	30693974	Moreover, TG2 is highly expressed in mesothelioma cancer stem cells and knockdown results in reduced spheroid formation, matrigel invasion, migration and tumor formation (Fig.	('tumor', 'Disease', (154, 159))	('mesothelioma cancer', 'Disease', (37, 56))	('spheroid formation', 'CPA', (101, 119))	('reduced', 'NegReg', (93, 100))	('mesothelioma cancer', 'Phenotype', 'HP:0100001', (37, 56))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('rat', 'Species', '10116', (143, 146))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('mesothelioma cancer', 'Disease', 'MESH:D009369', (37, 56))	('TG2', 'Gene', (10, 13))	('migration', 'CPA', (140, 149))	('knockdown', 'Var', (72, 81))	('matrigel invasion', 'CPA', (121, 138))
125204	30693974	In xenograft mesothelioma tumor models, time to tumor first appearance is doubled from nine weeks for wild-type cells, to eighteen weeks for TG2 knockout cells.	('knockout', 'Var', (145, 153))	('tumor', 'Disease', (48, 53))	('mesothelioma tumor', 'Disease', (13, 31))	('mesothelioma tumor', 'Disease', 'MESH:D008654', (13, 31))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('time', 'MPA', (40, 44))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('mesothelioma tumor', 'Phenotype', 'HP:0100001', (13, 31))	('tumor', 'Disease', (26, 31))	('TG2', 'Gene', (141, 144))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
125208	30693974	Moreover, TG2 level is markedly elevated in cultured human colon cancer stem cells, and knockdown reduces cell proliferation, invasion, EMT, and stem cell marker (CD133, SOX2, and beta-catenin) expression.	('cell proliferation', 'CPA', (106, 124))	('SOX2', 'Gene', (170, 174))	('SOX2', 'Gene', '6657', (170, 174))	('colon cancer', 'Disease', 'MESH:D015179', (59, 71))	('reduces', 'NegReg', (98, 105))	('rat', 'Species', '10116', (118, 121))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('stem cell', 'CPA', (145, 154))	('colon cancer', 'Disease', (59, 71))	('elevated', 'PosReg', (32, 40))	('beta-catenin', 'Gene', (180, 192))	('knockdown', 'Var', (88, 97))	('TG2 level', 'MPA', (10, 19))	('beta-catenin', 'Gene', '1499', (180, 192))	('human', 'Species', '9606', (53, 58))	('CD133', 'Gene', (163, 168))	('colon cancer', 'Phenotype', 'HP:0003003', (59, 71))	('invasion', 'CPA', (126, 134))	('CD133', 'Gene', '8842', (163, 168))	('expression', 'MPA', (194, 204))	('EMT', 'CPA', (136, 139))
125213	30693974	TG2 knockdown in SW480 cells, a modestly aggressive colon cancer cell type, increases invasive behavior in a matrigel invasion assay.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('SW480', 'CellLine', 'CVCL:0546', (17, 22))	('increases', 'PosReg', (76, 85))	('aggressive colon cancer', 'Disease', 'MESH:D015179', (41, 64))	('aggressive colon cancer', 'Disease', (41, 64))	('TG2', 'Gene', (0, 3))	('colon cancer', 'Phenotype', 'HP:0003003', (52, 64))	('knockdown', 'Var', (4, 13))	('invasive behavior in a matrigel invasion assay', 'CPA', (86, 132))
125223	30693974	In renal cell carcinoma, cancer cell survival is increased due to TGase modification and inactivation of p53.	('carcinoma', 'Phenotype', 'HP:0030731', (14, 23))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('inactivation', 'Var', (89, 101))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (3, 23))	('increased', 'PosReg', (49, 58))	('p53', 'Gene', (105, 108))	('p53', 'Gene', '7157', (105, 108))	('cancer', 'Disease', 'MESH:D009369', (25, 31))	('renal cell carcinoma', 'Disease', (3, 23))	('TGase', 'Protein', (66, 71))	('cancer', 'Disease', (25, 31))	('modification', 'Var', (72, 84))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (3, 23))
125224	30693974	Thus, both GTP-bound/signaling-active and calcium-bound/transamidase-active TG2 conformations have been reported to enhance cancer cell survival.	('cancer', 'Disease', (124, 130))	('TG2', 'Gene', (76, 79))	('enhance', 'PosReg', (116, 123))	('GTP', 'Chemical', 'MESH:D006160', (11, 14))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('conformations', 'Var', (80, 93))	('calcium', 'Chemical', 'MESH:D002118', (42, 49))	('cancer', 'Disease', 'MESH:D009369', (124, 130))
125230	30693974	The first involves expression of TG2 GTP binding-deficient or TGase activity-deficient mutants in cells and assessing the impact on the cancer cell phenotype.	('TGase', 'Gene', (62, 67))	('mutants', 'Var', (87, 94))	('GTP', 'Protein', (37, 40))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('TG2', 'Gene', (33, 36))	('cancer', 'Disease', (136, 142))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('GTP', 'Chemical', 'MESH:D006160', (37, 40))
125241	30693974	In addition, high level expression of TG2 or treating cells with stress agents, that compromise plasma and endoplasmic reticulum membranes to increase intracellular calcium, cause massive activation of the open/extended transamidase-active form leading to crosslinking activation and cell death.	('increase', 'PosReg', (142, 150))	('crosslinking', 'MPA', (256, 268))	('intracellular calcium', 'MPA', (151, 172))	('cell death', 'CPA', (284, 294))	('open/extended transamidase-active form', 'Enzyme', (206, 244))	('increase intracellular calcium', 'Phenotype', 'HP:0003575', (142, 172))	('activation', 'PosReg', (188, 198))	('expression', 'Var', (24, 34))	('TG2', 'Gene', (38, 41))	('calcium', 'Chemical', 'MESH:D002118', (165, 172))	('activation', 'PosReg', (269, 279))
125305	31227749	Third, in both STAD and BRCA, patients with Th1 low and a Th2 high (namely, Th2 dominance) show a poorer prognosis, whereas those with Th1 dominance show a better prognosis.	('Th2', 'Chemical', '-', (58, 61))	('BRCA', 'Gene', '672', (24, 28))	('Th1', 'Gene', '51497', (135, 138))	('Th1', 'Gene', '51497', (44, 47))	('BRCA', 'Gene', (24, 28))	('Th2 high', 'Var', (58, 66))	('Th2', 'Chemical', '-', (76, 79))	('patients', 'Species', '9606', (30, 38))	('Th1', 'Gene', (135, 138))	('Th1', 'Gene', (44, 47))
125336	31227749	According to Ni et al., expression level of ILF2 is up-regulated in non-small cell lung cancer (NSCLC), and knockdown of ILF2 inhibits the cell proliferation and cell-cycle progression.	('cell lung cancer', 'Disease', (78, 94))	('inhibits', 'NegReg', (126, 134))	('knockdown', 'Var', (108, 117))	('expression level', 'MPA', (24, 40))	('ILF2', 'Gene', '3608', (44, 48))	('NSCLC', 'Disease', (96, 101))	('up-regulated', 'PosReg', (52, 64))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (68, 94))	('cell lung cancer', 'Disease', 'MESH:D008175', (78, 94))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (72, 94))	('NSCLC', 'Disease', 'MESH:D002289', (96, 101))	('ILF2', 'Gene', (121, 125))	('cell-cycle progression', 'CPA', (162, 184))	('cell proliferation', 'CPA', (139, 157))	('lung cancer', 'Phenotype', 'HP:0100526', (83, 94))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('ILF2', 'Gene', (44, 48))	('ILF2', 'Gene', '3608', (121, 125))
125353	31227749	Although specific functions of SMAP2 in cancer or immune are yet to be known, BioTarget seems to suggest that the altered expression of SMAP2 gene in GATA3 may mediate Th2 differentiation pathway in a cancer type specific manner, that is, through up-regulation in LUSC but through down-regulation in STAD and BRCA.	('cancer', 'Disease', (201, 207))	('BRCA', 'Gene', (309, 313))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('GATA3', 'Gene', '2625', (150, 155))	('up-regulation', 'PosReg', (247, 260))	('SMAP2', 'Gene', (136, 141))	('cancer', 'Disease', (40, 46))	('GATA3', 'Gene', (150, 155))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('Th2', 'Chemical', '-', (168, 171))	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('SMAP2', 'Gene', '64744', (136, 141))	('altered', 'Var', (114, 121))	('SMAP2', 'Gene', (31, 36))	('Th2 differentiation pathway', 'Pathway', (168, 195))	('BRCA', 'Gene', '672', (309, 313))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('LUSC', 'Disease', (264, 268))	('STAD', 'Disease', (300, 304))	('SMAP2', 'Gene', '64744', (31, 36))	('down-regulation', 'NegReg', (281, 296))	('mediate', 'Reg', (160, 167))
125358	31227749	Patient with ID of TCGA-E2-A1LH clearly has Th1 activated and Th2 suppressed with all target genes working consistently to support the concept.	('Th2', 'Chemical', '-', (62, 65))	('Th1', 'Gene', '51497', (44, 47))	('suppressed', 'NegReg', (66, 76))	('Th2', 'MPA', (62, 65))	('Th1', 'Gene', (44, 47))	('TCGA-E2-A1LH', 'Var', (19, 31))	('activated', 'PosReg', (48, 57))	('Patient', 'Species', '9606', (0, 7))
125359	31227749	In contradiction, patient with ID of TCGA-BH-A1EV has both Th1/Th2 suppressed with poor prognosis as a result.	('Th2', 'Chemical', '-', (63, 66))	('Th1', 'Gene', (59, 62))	('Th1', 'Gene', '51497', (59, 62))	('patient', 'Species', '9606', (18, 25))	('TCGA-BH-A1EV', 'Var', (37, 49))
125386	31227749	Patient stratification by this method showed a number of cancer-type specific effects of the immune response, with a notably poor prognosis for patients with high Th2 scores for stomach breast and colon cancers.	('Th2 scores', 'Gene', (163, 173))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('stomach breast and colon cancers', 'Disease', 'MESH:D013274', (178, 210))	('cancer', 'Disease', (57, 63))	('Th2', 'Chemical', '-', (163, 166))	('high', 'Var', (158, 162))	('patients', 'Species', '9606', (144, 152))	('cancer', 'Disease', (203, 209))	('cancer', 'Disease', 'MESH:D009369', (203, 209))	('colon cancers', 'Phenotype', 'HP:0003003', (197, 210))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('cancers', 'Phenotype', 'HP:0002664', (203, 210))	('effects', 'Reg', (78, 85))	('Patient', 'Species', '9606', (0, 7))	('colon cancer', 'Phenotype', 'HP:0003003', (197, 209))
125390	29702599	These interactions are often interconnected, thus aberrant expression of any network component could derail the complex regulatory circuitry, culminating in cancer development and progression.	('aberrant expression', 'Var', (50, 69))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('complex regulatory circuitry', 'MPA', (112, 140))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('culminating in', 'Reg', (142, 156))	('derail', 'NegReg', (101, 107))	('cancer', 'Disease', (157, 163))	('progression', 'CPA', (180, 191))
125401	29702599	Deregulation in their expression has been implicated in various diseases, including cancer.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('cancer', 'Disease', (84, 90))	('Deregulation', 'Var', (0, 12))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('implicated', 'Reg', (42, 52))	('expression', 'MPA', (22, 32))
125410	29702599	Although most miRNA targets in plants are cleaved due to their almost perfect miRNA complementarity, the miR-399 motif on IPS1 contains a mismatched loop at the miRNA cleavage site that abolishes cleavage.	('miR', 'Gene', (105, 108))	('abolishes', 'NegReg', (186, 195))	('miR', 'Gene', '220972', (78, 81))	('miR', 'Gene', (78, 81))	('cleavage', 'MPA', (196, 204))	('miR', 'Gene', '220972', (161, 164))	('miR', 'Gene', (161, 164))	('mismatched', 'Var', (138, 148))	('miR', 'Gene', '220972', (14, 17))	('miR', 'Gene', (14, 17))	('miR', 'Gene', '220972', (105, 108))
125417	29702599	also reported ceRNA-mediated regulation between proto-oncogene BRAF (B-Raf proto-oncogene, serine/threonine kinase) and its pseudogene BRAFP1 (B-Raf pseudogene 1), and their murine counterparts Braf and Braf-rs1, to induce malignancy in mice, further reinforcing the functionality of pseudogenes.	('malignancy', 'Disease', 'MESH:D009369', (223, 233))	('malignancy', 'Disease', (223, 233))	('Braf', 'Gene', (194, 198))	('rs1', 'Var', (208, 211))	('induce', 'PosReg', (216, 222))	('rs1', 'DBSNP_MENTION', 'None', (208, 211))	('murine', 'Species', '10090', (174, 180))	('mice', 'Species', '10090', (237, 241))	('Braf', 'Gene', '109880', (203, 207))	('BRAFP1', 'Gene', (135, 141))	('B-Raf proto-oncogene', 'Gene', '109880', (69, 89))	('Braf', 'Gene', '109880', (194, 198))	('B-Raf proto-oncogene', 'Gene', (69, 89))	('Braf', 'Gene', (203, 207))	('BRAF', 'Gene', (63, 67))	('BRAFP1', 'Gene', '286494', (135, 141))
125425	29702599	Although there were more copies of miR-16 per cell, each TYRP1 transcript carried three non-canonical miR-16 MREs, thus, the presence of TYRP1 alone could achieve effective target abundance to potentially sponge the entire pool of miR-16 per cell.	('miR-16', 'Gene', (102, 108))	('presence', 'Var', (125, 133))	('miR-16', 'Gene', '51573', (102, 108))	('TYRP1', 'Gene', '7306', (137, 142))	('miR-16', 'Gene', (35, 41))	('TYRP1', 'Gene', (57, 62))	('TYRP1', 'Gene', '7306', (57, 62))	('TYRP1', 'Gene', (137, 142))	('miR-16', 'Gene', '51573', (35, 41))	('miR-16', 'Gene', (231, 237))	('sponge', 'Reg', (205, 211))	('miR-16', 'Gene', '51573', (231, 237))
125432	29702599	Tumor suppressor p53 is also known to epigenetically suppress H19 expression.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('H19', 'Gene', (62, 65))	('epigenetically', 'Var', (38, 52))	('expression', 'MPA', (66, 76))	('H19', 'Gene', '283120', (62, 65))	('suppress', 'NegReg', (53, 61))	('p53', 'Gene', (17, 20))	('p53', 'Gene', '7157', (17, 20))
125454	29702599	XIST was shown to exhibit tumor suppressive properties in hepatocellular carcinoma (HCC) by acting as a miRNA decoy for tumor suppressor genes, SMAD7 (SMAD family member 7) and PTEN, by sponging miR-92b and miR-181a, respectively, and suppressing cell proliferation, metastasis, and invasion.	('invasion', 'CPA', (283, 291))	('miR', 'Gene', '220972', (195, 198))	('XIST', 'Gene', '7503', (0, 4))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (58, 82))	('suppressing', 'NegReg', (235, 246))	('cell proliferation', 'CPA', (247, 265))	('metastasis', 'CPA', (267, 277))	('sponging', 'Var', (186, 194))	('miR', 'Gene', (195, 198))	('miR', 'Gene', '220972', (104, 107))	('tumor', 'Disease', (26, 31))	('miR-92b', 'Gene', '693235', (195, 202))	('miR', 'Gene', '220972', (207, 210))	('tumor', 'Disease', (120, 125))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (58, 82))	('SMAD7', 'Gene', (144, 149))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('HCC', 'Phenotype', 'HP:0001402', (84, 87))	('SMAD', 'Gene', (151, 155))	('PTEN', 'Gene', (177, 181))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('SMAD', 'Gene', (144, 148))	('miR', 'Gene', (104, 107))	('miR', 'Gene', (207, 210))	('hepatocellular carcinoma', 'Disease', (58, 82))	('SMAD', 'Gene', '4092', (151, 155))	('SMAD', 'Gene', '4092', (144, 148))	('miR-92b', 'Gene', (195, 202))	('PTEN', 'Gene', '5728', (177, 181))	('XIST', 'Gene', (0, 4))	('SMAD7', 'Gene', '4092', (144, 149))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
125478	29702599	showed that PVT1 also epigenetically silences miR-200b by recruiting EZH2 to the miR-200b promoter to increase the repressive H3K27me3 mark, resulting in cervical cancer growth and progression.	('epigenetically', 'Var', (22, 36))	('miR-200b', 'Gene', (46, 54))	('PVT1', 'Gene', '5820', (12, 16))	('H3K27me3', 'Protein', (126, 134))	('EZH2', 'Gene', '2146', (69, 73))	('miR-200b', 'Gene', '406984', (81, 89))	('miR-200b', 'Gene', (81, 89))	('progression', 'CPA', (181, 192))	('cervical cancer', 'Disease', (154, 169))	('EZH2', 'Gene', (69, 73))	('cervical cancer', 'Disease', 'MESH:D002583', (154, 169))	('resulting in', 'Reg', (141, 153))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('increase', 'PosReg', (102, 110))	('miR-200b', 'Gene', '406984', (46, 54))	('repressive', 'MPA', (115, 125))	('silences', 'NegReg', (37, 45))	('PVT1', 'Gene', (12, 16))
125482	29702599	Consistent with this function, HOTAIR also epigenetically silences the expression of miRNAs that it sponges.	('expression', 'MPA', (71, 81))	('HOTAIR', 'Gene', '100124700', (31, 37))	('epigenetically', 'Var', (43, 57))	('miR', 'Gene', '220972', (85, 88))	('miR', 'Gene', (85, 88))	('HOTAIR', 'Gene', (31, 37))
125485	29702599	In a similar fashion, HOTAIR epigenetically silences miR-663b to upregulate its target IGF2 (insulin like growth factor 2) and promote pancreatic cancer growth.	('IGF2', 'Gene', (87, 91))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (135, 152))	('miR-663b', 'Gene', (53, 61))	('promote', 'PosReg', (127, 134))	('epigenetically silences', 'Var', (29, 52))	('HOTAIR', 'Gene', (22, 28))	('pancreatic cancer', 'Disease', (135, 152))	('insulin like growth factor 2', 'Gene', '3481', (93, 121))	('pancreatic cancer', 'Disease', 'MESH:D010190', (135, 152))	('HOTAIR', 'Gene', '100124700', (22, 28))	('IGF2', 'Gene', '3481', (87, 91))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('insulin like growth factor 2', 'Gene', (93, 121))	('upregulate', 'PosReg', (65, 75))	('miR-663b', 'Gene', '100313824', (53, 61))
125491	29702599	Furthermore, the last decade has seen the functional characterization of various pseudogenes as regulators of gene expression, mainly by acting as miRNA decoys.	('pseudogenes', 'Var', (81, 92))	('miR', 'Gene', '220972', (147, 150))	('miR', 'Gene', (147, 150))
125504	29702599	Perturbation of the network through a single miRNA or pseudogene disrupted iron homeostasis and enhanced prostate cancer growth, highlighting the delicate balance that governs a multicomponent ceRNA network.	('iron', 'Chemical', 'MESH:D007501', (75, 79))	('disrupted iron homeostasis', 'Phenotype', 'HP:0011031', (65, 91))	('enhanced', 'PosReg', (96, 104))	('prostate cancer', 'Disease', (105, 120))	('miR', 'Gene', '220972', (45, 48))	('Perturbation', 'Var', (0, 12))	('miR', 'Gene', (45, 48))	('disrupted', 'NegReg', (65, 74))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('prostate cancer', 'Disease', 'MESH:D011471', (105, 120))	('prostate cancer', 'Phenotype', 'HP:0012125', (105, 120))	('pseudogene', 'Var', (54, 64))	('iron homeostasis', 'MPA', (75, 91))
125532	29702599	Interestingly, circPVT1 expression can be transcriptionally enhanced by the mutant p53/YAP/TEAD complex, and functions as a decoy for miR-497-5p.	('PVT1', 'Gene', (19, 23))	('p53', 'Gene', (83, 86))	('p53', 'Gene', '7157', (83, 86))	('expression', 'MPA', (24, 34))	('miR', 'Gene', '220972', (134, 137))	('miR', 'Gene', (134, 137))	('YAP', 'Gene', (87, 90))	('mutant', 'Var', (76, 82))	('YAP', 'Gene', '10413', (87, 90))	('PVT1', 'Gene', '5820', (19, 23))	('enhanced', 'PosReg', (60, 68))
125534	29702599	Expression profile screens of bladder carcinoma identified circ-MYLK (myosin light chain kinase) as a highly expressed circRNA which binds miR-29a and derepresses VEGFA (vascular endothelial growth factor A) to activate VEGFA/VEGFR2 (kinase insert domain receptor) signaling and promote growth, angiogenesis and metastasis.	('bladder carcinoma', 'Disease', (30, 47))	('myosin light chain kinase', 'Gene', '4638', (70, 95))	('VEGFR2', 'Gene', (226, 232))	('promote', 'PosReg', (279, 286))	('growth', 'CPA', (287, 293))	('VEGFA', 'Gene', '7422', (220, 225))	('activate', 'PosReg', (211, 219))	('miR-29a', 'Gene', (139, 146))	('vascular endothelial growth factor A', 'Gene', (170, 206))	('miR-29a', 'Gene', '407021', (139, 146))	('VEGFA', 'Gene', '7422', (163, 168))	('VEGFR2', 'Gene', '3791', (226, 232))	('kinase insert domain receptor', 'Gene', (234, 263))	('kinase insert domain receptor', 'Gene', '3791', (234, 263))	('carcinoma', 'Phenotype', 'HP:0030731', (38, 47))	('MYLK', 'Gene', (64, 68))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (30, 47))	('MYLK', 'Gene', '4638', (64, 68))	('VEGFA', 'Gene', (220, 225))	('derepresses', 'Var', (151, 162))	('bladder carcinoma', 'Disease', 'MESH:D001749', (30, 47))	('vascular endothelial growth factor A', 'Gene', '7422', (170, 206))	('VEGFA', 'Gene', (163, 168))	('myosin light chain kinase', 'Gene', (70, 95))
125535	29702599	Conversely, circMTO1 was identified as a downregulated circRNA in HCC, and it functions as a tumor suppressor by sponging miR-9 to upregulate p21 and suppress HCC development.	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('p21', 'Gene', (142, 145))	('tumor', 'Disease', (93, 98))	('p21', 'Gene', '644914', (142, 145))	('miR', 'Gene', (122, 125))	('circMTO1', 'Var', (12, 20))	('miR', 'Gene', '220972', (122, 125))	('HCC development', 'CPA', (159, 174))	('HCC', 'Phenotype', 'HP:0001402', (159, 162))	('suppress', 'NegReg', (150, 158))	('upregulate', 'PosReg', (131, 141))	('HCC', 'Phenotype', 'HP:0001402', (66, 69))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
125560	29702599	As a proof of concept, the authors found two NEAT1-related DRCEs in invasive breast cancer that may lead to poor response to tamoxifen therapy for patients with TP53 mutations.	('invasive breast cancer', 'Disease', (68, 90))	('TP53', 'Gene', (161, 165))	('breast cancer', 'Phenotype', 'HP:0003002', (77, 90))	('mutations', 'Var', (166, 175))	('NEAT1', 'Gene', '283131', (45, 50))	('invasive breast cancer', 'Disease', 'MESH:D001943', (68, 90))	('patients', 'Species', '9606', (147, 155))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('NEAT1', 'Gene', (45, 50))	('tamoxifen', 'Chemical', 'MESH:D013629', (125, 134))	('TP53', 'Gene', '7157', (161, 165))
125566	29702599	demonstrated effective knockdown KRAS, CXCR4 and PPIB (peptidylprolyl isomerase B) mRNA using Cas13a.	('peptidylprolyl isomerase B', 'Gene', '5479', (55, 81))	('PPIB', 'Gene', (49, 53))	('CXCR4', 'Gene', (39, 44))	('knockdown', 'Var', (23, 32))	('peptidylprolyl isomerase B', 'Gene', (55, 81))	('KRAS', 'Gene', (33, 37))	('PPIB', 'Gene', '5479', (49, 53))	('KRAS', 'Gene', '3845', (33, 37))	('CXCR4', 'Gene', '7852', (39, 44))
125568	29702599	were able to program RNA editing to correct disease-relevant mutations, such as G878A (AVPR2 arginine vasopressin receptor 2) in X-linked nephrogenic diabetes insipidus and G1517A (FANCC Fanconi anemia complementation group C) in Fanconi anemia.	('FANCC Fanconi anemia complementation', 'Phenotype', 'HP:0001994', (181, 217))	('Fanconi anemia', 'Phenotype', 'HP:0001994', (187, 201))	('AVPR2', 'Gene', (87, 92))	('anemia', 'Phenotype', 'HP:0001903', (238, 244))	('X-linked nephrogenic diabetes insipidus', 'Disease', (129, 168))	('nephrogenic diabetes insipidus', 'Phenotype', 'HP:0009806', (138, 168))	('Fanconi anemia', 'Phenotype', 'HP:0001994', (230, 244))	('X-linked nephrogenic diabetes insipidus', 'Disease', 'MESH:D018500', (129, 168))	('AVPR2', 'Gene', '554', (87, 92))	('G878A', 'Mutation', 'rs1064797077', (80, 85))	('anemia', 'Phenotype', 'HP:0001903', (195, 201))	('Fanconi anemia', 'Disease', (187, 201))	('G1517A', 'Var', (173, 179))	('Fanconi anemia', 'Disease', 'MESH:D005199', (187, 201))	('diabetes insipidus', 'Phenotype', 'HP:0000873', (150, 168))	('Fanconi anemia', 'Disease', (230, 244))	('G1517A', 'Mutation', 'c.1517G>A', (173, 179))	('G878A', 'Var', (80, 85))	('Fanconi anemia', 'Disease', 'MESH:D005199', (230, 244))
125580	28355294	Especially, high expression of two topoisomerase isoforms, TOP2A and TOP3A, was found to be correlated to worse overall survival (OS) in all NSCLC and lung adenocarcinoma (Ade) patients, but not in lung squamous cell carcinoma (SCC) patients.	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (151, 170))	('NSCLC', 'Disease', 'MESH:D002289', (141, 146))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (151, 170))	('overall survival', 'MPA', (112, 128))	('NSCLC', 'Disease', (141, 146))	('SCC', 'Phenotype', 'HP:0002860', (228, 231))	('TOP3A', 'Gene', (69, 74))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (203, 226))	('NSCLC', 'Phenotype', 'HP:0030358', (141, 146))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (198, 226))	('worse', 'NegReg', (106, 111))	('patients', 'Species', '9606', (233, 241))	('SCC', 'Gene', '6317', (228, 231))	('lung adenocarcinoma', 'Disease', (151, 170))	('TOP3A', 'Gene', '7156', (69, 74))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (198, 226))	('lung squamous cell carcinoma', 'Disease', (198, 226))	('TOP2A', 'Gene', (59, 64))	('high', 'Var', (12, 16))	('patients', 'Species', '9606', (177, 185))	('SCC', 'Gene', (228, 231))	('OS', 'Chemical', '-', (130, 132))	('carcinoma', 'Phenotype', 'HP:0030731', (161, 170))	('carcinoma', 'Phenotype', 'HP:0030731', (217, 226))	('TOP2A', 'Gene', '7153', (59, 64))
125581	28355294	In a contrast, high expression of isoforms TOP1 and TOP2B indicated better OS in all NSCLC and Ade, but not in SCC patients.	('high', 'Var', (15, 19))	('NSCLC', 'Disease', (85, 90))	('patients', 'Species', '9606', (115, 123))	('expression', 'MPA', (20, 30))	('better', 'PosReg', (68, 74))	('NSCLC', 'Disease', 'MESH:D002289', (85, 90))	('NSCLC', 'Phenotype', 'HP:0030358', (85, 90))	('OS', 'Chemical', '-', (75, 77))	('SCC', 'Gene', (111, 114))	('TOP2B', 'Gene', (52, 57))	('TOP1', 'Gene', (43, 47))	('SCC', 'Phenotype', 'HP:0002860', (111, 114))	('SCC', 'Gene', '6317', (111, 114))	('Ade', 'Disease', (95, 98))
125597	28355294	However, TOP1MT knockout leads to increased negative supercoiling of mitochondrial DNA (mtDNA) in mice.	('TOP1MT', 'Gene', (9, 15))	('knockout', 'Var', (16, 24))	('negative supercoiling', 'MPA', (44, 65))	('increased', 'PosReg', (34, 43))	('mice', 'Species', '10090', (98, 102))
125625	28355294	Although the mRNA level of TOP3A was increased in Ade (Fig 1G), similar gene increment was not observed in SCC.	('mRNA level', 'MPA', (13, 23))	('Ade', 'Var', (50, 53))	('SCC', 'Gene', (107, 110))	('SCC', 'Phenotype', 'HP:0002860', (107, 110))	('increased', 'PosReg', (37, 46))	('SCC', 'Gene', '6317', (107, 110))	('TOP3A', 'Gene', (27, 32))	('TOP3A', 'Gene', '7156', (27, 32))
125629	28355294	TOP1 mRNA high expression was found to be correlated to significantly better OS for all NSCLC patients (HR 0.7 [0.61-0.8], p = 1.2e-07).	('TOP1', 'Gene', (0, 4))	('patients', 'Species', '9606', (94, 102))	('NSCLC', 'Phenotype', 'HP:0030358', (88, 93))	('better', 'PosReg', (70, 76))	('NSCLC', 'Disease', (88, 93))	('mRNA high expression', 'Var', (5, 25))	('OS', 'Chemical', '-', (77, 79))	('NSCLC', 'Disease', 'MESH:D002289', (88, 93))
125630	28355294	In addition, TOP1 mRNA high expression was also found to be correlated to significantly better OS in Ade (HR 0.53 [0.41-0.69], p = 9.7e-07), but not in SCC patients (HR 0.84 [0.66-1.08], p = 0.17).	('patients', 'Species', '9606', (156, 164))	('mRNA high expression', 'Var', (18, 38))	('SCC', 'Gene', (152, 155))	('OS', 'Chemical', '-', (95, 97))	('Ade', 'Disease', (101, 104))	('TOP1', 'Gene', (13, 17))	('SCC', 'Gene', '6317', (152, 155))	('SCC', 'Phenotype', 'HP:0002860', (152, 155))	('better', 'PosReg', (88, 94))
125632	28355294	In addition, TOP1MT mRNA high expression was not associated with OS in both Ade (HR 0.99 [0.77-1.27], p = 0.92) (Fig 3B) and SCC patients (HR 1.09 [0.79-1.51], p = 0.6) (Fig 3C).	('OS', 'Chemical', '-', (65, 67))	('patients', 'Species', '9606', (129, 137))	('Ade', 'Disease', (76, 79))	('SCC', 'Gene', (125, 128))	('SCC', 'Phenotype', 'HP:0002860', (125, 128))	('TOP1MT mRNA high expression', 'Var', (13, 40))	('SCC', 'Gene', '6317', (125, 128))
125634	28355294	TOP2A mRNA high expression was found to be correlated to significantly shorter OS for all NSCLC patients (HR 1.49 [1.31-1.7], p = 2.6e-09) (Fig 4A).	('TOP2A', 'Gene', (0, 5))	('mRNA high expression', 'Var', (6, 26))	('OS', 'Chemical', '-', (79, 81))	('HR 1.49', 'Disease', 'OMIM:617237', (106, 113))	('NSCLC', 'Disease', (90, 95))	('HR 1.49', 'Disease', (106, 113))	('NSCLC', 'Disease', 'MESH:D002289', (90, 95))	('patients', 'Species', '9606', (96, 104))	('TOP2A', 'Gene', '7153', (0, 5))	('shorter', 'NegReg', (71, 78))	('NSCLC', 'Phenotype', 'HP:0030358', (90, 95))
125635	28355294	In addition, TOP2A mRNA high expression was only found to be correlated to significantly shorter OS in Ade patients (HR 1.6 [1.25-2.05], p = 0.00017) (Fig 4B), but not in SCC patients (HR 0.92 [0.72-1.17], p = 0.5) (Fig 4C).	('SCC', 'Gene', (171, 174))	('TOP2A', 'Gene', (13, 18))	('patients', 'Species', '9606', (107, 115))	('SCC', 'Phenotype', 'HP:0002860', (171, 174))	('SCC', 'Gene', '6317', (171, 174))	('Ade', 'Disease', (103, 106))	('OS', 'Chemical', '-', (97, 99))	('patients', 'Species', '9606', (175, 183))	('TOP2A', 'Gene', '7153', (13, 18))	('mRNA high expression', 'Var', (19, 39))	('shorter', 'NegReg', (89, 96))
125636	28355294	Contrary to TOP2A, high mRNA expression of TOP2B showed favorable OS for all NSCLC patients (HR 0.88 [0.77-1], p = 0.059) (Fig 5A).	('NSCLC', 'Disease', 'MESH:D002289', (77, 82))	('OS', 'Chemical', '-', (66, 68))	('TOP2B', 'Gene', (43, 48))	('high', 'Var', (19, 23))	('patients', 'Species', '9606', (83, 91))	('NSCLC', 'Phenotype', 'HP:0030358', (77, 82))	('TOP2A', 'Gene', '7153', (12, 17))	('mRNA expression', 'MPA', (24, 39))	('TOP2A', 'Gene', (12, 17))	('NSCLC', 'Disease', (77, 82))
125637	28355294	In addition, TOP2B mRNA high expression was significantly associated with better OS only in Ade patients (HR 0.53 [0.41-0.68], p = 2.6e-07) (Fig 5B), but not in SCC patients (HR 1.09 [0.85-1.4], p = 0.48) (Fig 5C).	('Ade', 'Disease', (92, 95))	('SCC', 'Gene', (161, 164))	('better OS', 'Disease', (74, 83))	('SCC', 'Phenotype', 'HP:0002860', (161, 164))	('TOP2B', 'Gene', (13, 18))	('SCC', 'Gene', '6317', (161, 164))	('patients', 'Species', '9606', (165, 173))	('patients', 'Species', '9606', (96, 104))	('OS', 'Chemical', '-', (81, 83))	('mRNA high expression', 'Var', (19, 39))
125640	28355294	In addition, high transcriptional expression of TOP3A was only found to be correlated to significantly worse OS in Ade patients (HR 1.47 [1.15-1.88], p = 0.0017) (Fig 6B), but not in SCC patients (HR 1 [0.78-1.28], p = 0.99) (Fig 6C).	('patients', 'Species', '9606', (187, 195))	('worse', 'NegReg', (103, 108))	('high', 'Var', (13, 17))	('patients', 'Species', '9606', (119, 127))	('SCC', 'Gene', (183, 186))	('SCC', 'Phenotype', 'HP:0002860', (183, 186))	('TOP3A', 'Gene', (48, 53))	('Ade', 'Disease', (115, 118))	('OS', 'Chemical', '-', (109, 111))	('SCC', 'Gene', '6317', (183, 186))	('TOP3A', 'Gene', '7156', (48, 53))
125645	28355294	As showed in Table E in S1 File, TOP1 was found to be associated with significantly better OS in grade II NSCLC patients.	('NSCLC', 'Disease', 'MESH:D002289', (106, 111))	('TOP1', 'Var', (33, 37))	('patients', 'Species', '9606', (112, 120))	('NSCLC', 'Phenotype', 'HP:0030358', (106, 111))	('OS', 'Chemical', '-', (91, 93))	('better', 'PosReg', (84, 90))	('NSCLC', 'Disease', (106, 111))
125647	28355294	From Table F in S1 File, TOP1MT, TOP2A and TOP3A were found to be correlated to significantly worse OS in all stage I NSCLC patients while the expression of TOP1 and TOP2B indicated significantly better OS in stage I, II and II NSCLC patients respectively.	('NSCLC', 'Phenotype', 'HP:0030358', (118, 123))	('NSCLC', 'Phenotype', 'HP:0030358', (228, 233))	('TOP2B', 'Gene', (166, 171))	('TOP3A', 'Gene', (43, 48))	('OS', 'Chemical', '-', (100, 102))	('TOP2A', 'Gene', '7153', (33, 38))	('TOP3A', 'Gene', '7156', (43, 48))	('NSCLC', 'Disease', (118, 123))	('patients', 'Species', '9606', (234, 242))	('worse', 'NegReg', (94, 99))	('NSCLC', 'Disease', (228, 233))	('TOP1MT', 'Var', (25, 31))	('TOP2A', 'Gene', (33, 38))	('NSCLC', 'Disease', 'MESH:D002289', (118, 123))	('NSCLC', 'Disease', 'MESH:D002289', (228, 233))	('OS', 'Chemical', '-', (203, 205))	('patients', 'Species', '9606', (124, 132))
125662	28355294	The embryonic fibroblasts from TOP1MT knockout mice was found to show dysfunctional mitochondrial respiration and a marked increase of ROS production, glycolytic activity and fatty acid oxidation.	('fatty acid oxidation', 'MPA', (175, 195))	('increase of ROS production', 'Phenotype', 'HP:0025464', (123, 149))	('dysfunctional mitochondrial respiration', 'MPA', (70, 109))	('increase', 'PosReg', (123, 131))	('glycolytic activity', 'MPA', (151, 170))	('ROS', 'Chemical', '-', (135, 138))	('fatty acid', 'Chemical', 'MESH:D005227', (175, 185))	('knockout', 'Var', (38, 46))	('ROS production', 'MPA', (135, 149))	('mice', 'Species', '10090', (47, 51))	('TOP1MT', 'Gene', (31, 37))
125665	28355294	However, increased expression level of TOP1MT was correlated to better first progression (FP) for Ade patients (HR 0.69 [0.48-0.99], p = 0.044), but indicated worse postprogression survival (PPS) for NSCLC patients (HR 1.91 [1.14-3.19], p = 0.012) and Ade patients (HR 1.76 [1-3.1], p = 0.047).	('NSCLC', 'Phenotype', 'HP:0030358', (200, 205))	('better', 'PosReg', (64, 70))	('TOP1MT', 'Var', (39, 45))	('PPS', 'Chemical', '-', (191, 194))	('patients', 'Species', '9606', (102, 110))	('patients', 'Species', '9606', (256, 264))	('NSCLC', 'Disease', (200, 205))	('worse', 'NegReg', (159, 164))	('increased', 'PosReg', (9, 18))	('expression level', 'MPA', (19, 35))	('patients', 'Species', '9606', (206, 214))	('NSCLC', 'Disease', 'MESH:D002289', (200, 205))	('postprogression survival', 'CPA', (165, 189))	('first', 'MPA', (71, 76))
125670	28355294	The high expression of TOP2A in tumor tissue predicted poor prognosis in some tumor patients and also promoted lymph node metastasis and distant metastasis in malignant tumors.	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('expression', 'MPA', (9, 19))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('distant metastasis', 'CPA', (137, 155))	('lymph node metastasis', 'CPA', (111, 132))	('patients', 'Species', '9606', (84, 92))	('promoted', 'PosReg', (102, 110))	('tumor', 'Disease', (169, 174))	('TOP2A', 'Gene', (23, 28))	('malignant tumors', 'Disease', 'MESH:D018198', (159, 175))	('poor prognosis', 'CPA', (55, 69))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('TOP2A', 'Gene', '7153', (23, 28))	('tumors', 'Phenotype', 'HP:0002664', (169, 175))	('high', 'Var', (4, 8))	('malignant tumors', 'Disease', (159, 175))	('tumor', 'Disease', (78, 83))	('tumor', 'Disease', (32, 37))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))
125677	28355294	Knockout of TOP2B in mice impaired the development of appropriate neural innervation of skeletal muscle, implying that this enzyme might be crucial to mammalian neural development.	('mammalian', 'Species', '9606', (151, 160))	('TOP2B', 'Gene', (12, 17))	('mice', 'Species', '10090', (21, 25))	('Knockout', 'Var', (0, 8))	('impaired', 'NegReg', (26, 34))
125680	28355294	Song and co-workers showed that TOP2B high expression was correlated with favorable outcome in acute myeloid leukaemia patients.	('acute myeloid leukaemia', 'Disease', (95, 118))	('TOP2B', 'Gene', (32, 37))	('myeloid leukaemia', 'Phenotype', 'HP:0012324', (101, 118))	('acute myeloid leukaemia', 'Disease', 'MESH:D007938', (95, 118))	('patients', 'Species', '9606', (119, 127))	('high expression', 'Var', (38, 53))	('acute myeloid leukaemia', 'Phenotype', 'HP:0004808', (95, 118))
125681	28355294	In our results, the high expression of TOP2B statistically showed favorable OS for NSCLC patients.	('TOP2B', 'Gene', (39, 44))	('OS', 'Chemical', '-', (76, 78))	('NSCLC', 'Disease', (83, 88))	('NSCLC', 'Disease', 'MESH:D002289', (83, 88))	('high expression', 'Var', (20, 35))	('patients', 'Species', '9606', (89, 97))	('NSCLC', 'Phenotype', 'HP:0030358', (83, 88))
125682	28355294	In addition, the high expression of TOP2B was found to be correlated to better OS in Ade patients and also indicated a longer OS in only stage II patients.	('OS', 'Chemical', '-', (79, 81))	('TOP2B', 'Gene', (36, 41))	('high', 'Var', (17, 21))	('better', 'PosReg', (72, 78))	('patients', 'Species', '9606', (89, 97))	('OS', 'Chemical', '-', (126, 128))	('patients', 'Species', '9606', (146, 154))
125689	28355294	In addition, high expression of TOP3A indicated a worse OS in only stage I NSCLC patients, and the enzyme was also associated with smoking status and gender of NSCLC patients.	('TOP3A', 'Gene', (32, 37))	('OS', 'Chemical', '-', (56, 58))	('high', 'Var', (13, 17))	('NSCLC', 'Phenotype', 'HP:0030358', (75, 80))	('TOP3A', 'Gene', '7156', (32, 37))	('NSCLC', 'Phenotype', 'HP:0030358', (160, 165))	('patients', 'Species', '9606', (81, 89))	('associated', 'Reg', (115, 125))	('NSCLC', 'Disease', (75, 80))	('NSCLC', 'Disease', (160, 165))	('NSCLC', 'Disease', 'MESH:D002289', (75, 80))	('patients', 'Species', '9606', (166, 174))	('NSCLC', 'Disease', 'MESH:D002289', (160, 165))
125691	28355294	It has been demonstrated that TOP3B knockout cells decreased their repair capacity of double-strand breaks and increased histone gamma-H2AX phosphorylation level compared to control cells.	('knockout', 'Var', (36, 44))	('increased', 'PosReg', (111, 120))	('histone gamma-H2AX phosphorylation level', 'MPA', (121, 161))	('decreased', 'NegReg', (51, 60))	('TOP3B', 'Gene', (30, 35))	('TOP3B', 'Gene', '8940', (30, 35))	('repair capacity of double-strand breaks', 'MPA', (67, 106))
125693	28355294	High expression of TOP3B was reported to be correlated to worse disease-specific survival and metastasis-free survival in patients with invasive breast cancers.	('disease-specific survival', 'CPA', (64, 89))	('High', 'Var', (0, 4))	('worse', 'NegReg', (58, 63))	('TOP3B', 'Gene', (19, 24))	('breast cancers', 'Phenotype', 'HP:0003002', (145, 159))	('metastasis-free survival', 'CPA', (94, 118))	('invasive breast cancers', 'Disease', (136, 159))	('TOP3B', 'Gene', '8940', (19, 24))	('patients', 'Species', '9606', (122, 130))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('invasive breast cancers', 'Disease', 'MESH:D001943', (136, 159))	('breast cancer', 'Phenotype', 'HP:0003002', (145, 158))	('cancers', 'Phenotype', 'HP:0002664', (152, 159))
125695	28355294	However, high expression level of TOP3B predicted worse PPS for NSCLC patients (HR 1.3 [0.99-1.7], p = 0.063).	('patients', 'Species', '9606', (70, 78))	('NSCLC', 'Disease', 'MESH:D002289', (64, 69))	('PPS', 'Chemical', '-', (56, 59))	('PPS', 'Disease', (56, 59))	('TOP3B', 'Gene', '8940', (34, 39))	('NSCLC', 'Phenotype', 'HP:0030358', (64, 69))	('TOP3B', 'Gene', (34, 39))	('NSCLC', 'Disease', (64, 69))	('high', 'Var', (9, 13))
125699	28355294	However, high expression of TOP1 and TOP2B is found to be associated with better OS in all NSCLC patients as well as in Ade, but not in SCC patients.	('NSCLC', 'Disease', 'MESH:D002289', (91, 96))	('TOP2B', 'Gene', (37, 42))	('SCC', 'Gene', (136, 139))	('better OS', 'Disease', (74, 83))	('high expression', 'Var', (9, 24))	('NSCLC', 'Phenotype', 'HP:0030358', (91, 96))	('TOP1', 'Gene', (28, 32))	('SCC', 'Phenotype', 'HP:0002860', (136, 139))	('SCC', 'Gene', '6317', (136, 139))	('patients', 'Species', '9606', (140, 148))	('OS', 'Chemical', '-', (81, 83))	('NSCLC', 'Disease', (91, 96))	('patients', 'Species', '9606', (97, 105))
125704	33031101	LCNEC can be subdivided into 2 mutually exclusive molecular subgroups: STK11/KEAP1 and TP53 mutated with high neuroendocrine expression and transcriptional profile of ASCL1high/DLL3high/NOTCHlow (non-small cell lung carcinoma, NSCLC-like) or RB1 and TP53 mutated with reduced neuroendocrine markers and transcriptional pattern of ASCL1low/DLL3low/NOTCHhigh (small cell lung cancer, SCLC-like).	('small cell lung cancer', 'Disease', 'MESH:D055752', (358, 380))	('transcriptional', 'MPA', (303, 318))	('STK11', 'Gene', '6794', (71, 76))	('ASCL1', 'Gene', '429', (330, 335))	('small cell lung cancer', 'Disease', (358, 380))	('SCLC', 'Phenotype', 'HP:0030357', (228, 232))	('small cell lung carcinoma', 'Phenotype', 'HP:0030357', (200, 225))	('neuroendocrine markers', 'MPA', (276, 298))	('lung cancer', 'Phenotype', 'HP:0100526', (369, 380))	('cancer', 'Phenotype', 'HP:0002664', (374, 380))	('TP53', 'Gene', '7157', (87, 91))	('lung carcinoma', 'Disease', (211, 225))	('NSCLC', 'Disease', 'MESH:D002289', (227, 232))	('ASCL1', 'Gene', (330, 335))	('RB1', 'Gene', (242, 245))	('SCLC', 'Gene', '7864', (228, 232))	('SCLC', 'Gene', (228, 232))	('mutated', 'Var', (92, 99))	('TP53', 'Gene', (250, 254))	('ASCL1', 'Gene', '429', (167, 172))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (358, 380))	('NSCLC', 'Disease', (227, 232))	('SCLC', 'Phenotype', 'HP:0030357', (382, 386))	('RB1', 'Gene', '5925', (242, 245))	('KEAP1', 'Gene', '9817', (77, 82))	('NSCLC', 'Phenotype', 'HP:0030358', (227, 232))	('ASCL1', 'Gene', (167, 172))	('STK11', 'Gene', (71, 76))	('mutated', 'Var', (255, 262))	('KEAP1', 'Gene', (77, 82))	('SCLC', 'Gene', (382, 386))	('reduced', 'NegReg', (268, 275))	('TP53', 'Gene', (87, 91))	('lung carcinoma', 'Disease', 'MESH:D008175', (211, 225))	('SCLC', 'Gene', '7864', (382, 386))	('LCNEC', 'Phenotype', 'HP:0030360', (0, 5))	('TP53', 'Gene', '7157', (250, 254))	('carcinoma', 'Phenotype', 'HP:0030731', (216, 225))	('non-small cell lung carcinoma', 'Phenotype', 'HP:0030358', (196, 225))
125718	33031101	NSCLC-like LCNEC was characterized by biallelic TP53 and STK11/KEAP1 alterations and SCLC-like characterized by biallelic alterations of TP53 and RB1.	('alterations', 'Var', (69, 80))	('NSCLC', 'Phenotype', 'HP:0030358', (0, 5))	('SCLC', 'Phenotype', 'HP:0030357', (85, 89))	('KEAP1', 'Gene', '9817', (63, 68))	('TP53', 'Gene', '7157', (48, 52))	('KEAP1', 'Gene', (63, 68))	('SCLC', 'Gene', (85, 89))	('SCLC', 'Gene', '7864', (85, 89))	('TP53', 'Gene', (137, 141))	('STK11', 'Gene', (57, 62))	('RB1', 'Gene', (146, 149))	('SCLC', 'Phenotype', 'HP:0030357', (1, 5))	('LCNEC', 'Phenotype', 'HP:0030360', (11, 16))	('NSCLC', 'Disease', 'MESH:D002289', (0, 5))	('STK11', 'Gene', '6794', (57, 62))	('TP53', 'Gene', (48, 52))	('SCLC', 'Gene', '7864', (1, 5))	('SCLC', 'Gene', (1, 5))	('TP53', 'Gene', '7157', (137, 141))	('RB1', 'Gene', '5925', (146, 149))	('NSCLC', 'Disease', (0, 5))
125721	33031101	In addition, a recent report showed that LCNEC with wild-type RB1 gene had a better prognosis when treated with NSCLC-type chemotherapy (platinum-gemcitabine or paclitaxel) than with SCLC-type therapy (platinum-etoposide).	('SCLC', 'Gene', '7864', (183, 187))	('SCLC', 'Phenotype', 'HP:0030357', (183, 187))	('SCLC', 'Gene', (183, 187))	('RB1', 'Gene', '5925', (62, 65))	('LCNEC', 'Phenotype', 'HP:0030360', (41, 46))	('NSCLC', 'Phenotype', 'HP:0030358', (112, 117))	('SCLC', 'Gene', '7864', (113, 117))	('paclitaxel', 'Chemical', 'MESH:D017239', (161, 171))	('SCLC', 'Gene', (113, 117))	('gemcitabine', 'Chemical', 'MESH:C056507', (146, 157))	('etoposide', 'Chemical', 'MESH:D005047', (211, 220))	('platinum', 'Chemical', 'MESH:D010984', (137, 145))	('NSCLC', 'Disease', (112, 117))	('platinum', 'Chemical', 'MESH:D010984', (202, 210))	('wild-type', 'Var', (52, 61))	('SCLC', 'Phenotype', 'HP:0030357', (113, 117))	('RB1', 'Gene', (62, 65))	('NSCLC', 'Disease', 'MESH:D002289', (112, 117))
125733	33031101	SCLC with MYC alterations is sensitive to aurora kinase inhibitors (ie, alisertib).	('alterations', 'Var', (14, 25))	('SCLC', 'Gene', '7864', (0, 4))	('SCLC', 'Phenotype', 'HP:0030357', (0, 4))	('MYC', 'Gene', (10, 13))	('alisertib', 'Chemical', 'MESH:C550258', (72, 81))	('MYC', 'Gene', '4609', (10, 13))	('SCLC', 'Gene', (0, 4))
125757	33031101	All TTF-1+ LCNEC cases (n=12) showed positivity for at least 2 neuroendocrine markers, indicating high neuroendocrine expression.	('TTF-1', 'Gene', '7270', (4, 9))	('LCNEC', 'Disease', (11, 16))	('LCNEC', 'Phenotype', 'HP:0030360', (11, 16))	('positivity', 'Var', (37, 47))	('TTF-1', 'Gene', (4, 9))
125786	33031101	One case with EGFR mutation (L858R) received EGFR TKIs osimertinib and afatinib after CDDP+ETP, however, drug-induced interstitial pneumonia was suspected with disease progression, leading to TKI cessation.	('EGFR', 'Gene', '1956', (14, 18))	('mutation', 'Var', (19, 27))	('EGFR', 'Gene', (14, 18))	('EGFR', 'Gene', (45, 49))	('TKIs osimertinib', 'Disease', (50, 66))	('CDDP', 'Chemical', '-', (86, 90))	('interstitial pneumonia', 'Disease', (118, 140))	('ETP', 'Chemical', 'MESH:D005047', (91, 94))	('EGFR', 'Gene', '1956', (45, 49))	('TKI', 'Disease', (192, 195))	('pneumonia', 'Phenotype', 'HP:0002090', (131, 140))	('TKIs osimertinib', 'Disease', 'None', (50, 66))	('afatinib', 'Chemical', 'MESH:D000077716', (71, 79))	('interstitial pneumonia', 'Disease', 'MESH:D009395', (118, 140))	('L858R', 'Mutation', 'rs121434568', (29, 34))
125790	33031101	Two subgroups defined by TTF-1 and c-MYC protein expression may correspond to 2 mutually exclusive molecular subgroups: STK11/KEAP1 and TP53 mutated (NSCLC-like) or RB1 and TP53 mutated (SCLC-like), respectively.	('mutated', 'Var', (141, 148))	('NSCLC', 'Disease', 'MESH:D002289', (150, 155))	('TTF-1', 'Gene', (25, 30))	('SCLC', 'Phenotype', 'HP:0030357', (187, 191))	('c-MYC', 'Gene', '4609', (35, 40))	('TP53', 'Gene', (173, 177))	('TP53', 'Gene', '7157', (136, 140))	('NSCLC', 'Disease', (150, 155))	('RB1', 'Gene', (165, 168))	('SCLC', 'Gene', '7864', (187, 191))	('c-MYC', 'Gene', (35, 40))	('SCLC', 'Gene', (187, 191))	('NSCLC', 'Phenotype', 'HP:0030358', (150, 155))	('KEAP1', 'Gene', '9817', (126, 131))	('STK11', 'Gene', (120, 125))	('RB1', 'Gene', '5925', (165, 168))	('KEAP1', 'Gene', (126, 131))	('TTF-1', 'Gene', '7270', (25, 30))	('TP53', 'Gene', '7157', (173, 177))	('TP53', 'Gene', (136, 140))	('SCLC', 'Phenotype', 'HP:0030357', (151, 155))	('STK11', 'Gene', '6794', (120, 125))	('SCLC', 'Gene', '7864', (151, 155))	('SCLC', 'Gene', (151, 155))
125800	33031101	Unfortunately, enrollment in the phase III trial of Rova-T was stopped early due to shorter overall survival with associated treatment-emergent adverse events in the Rova-T arm compared with the topotecan arm.	('topotecan', 'Chemical', 'MESH:D019772', (195, 204))	('Rova-T', 'Chemical', 'MESH:C000620223', (52, 58))	('Rova-T', 'Var', (166, 172))	('overall survival', 'MPA', (92, 108))	('shorter', 'NegReg', (84, 91))	('Rova-T', 'Chemical', 'MESH:C000620223', (166, 172))
125802	33031101	Furthermore, MYC regulates the expression of aurora kinases A and B, which promote continuous cell growth in the loss of p53 function.	('promote', 'PosReg', (75, 82))	('p53', 'Gene', (121, 124))	('p53', 'Gene', '7157', (121, 124))	('aurora kinases A and B', 'Gene', '6790;9212', (45, 67))	('MYC', 'Gene', '4609', (13, 16))	('expression', 'MPA', (31, 41))	('loss', 'Var', (113, 117))	('continuous cell growth', 'CPA', (83, 105))	('MYC', 'Gene', (13, 16))
125807	33031101	A recent report showed that LCNEC with wild-type RB1 gene had a better prognosis when treated with NSCLC-type chemotherapy (platinum-gemcitabine or paclitaxel) than with SCLC-type therapy (platinum-ETP).	('platinum-ETP', 'Chemical', '-', (189, 201))	('gemcitabine', 'Chemical', 'MESH:C056507', (133, 144))	('SCLC', 'Gene', (100, 104))	('platinum', 'Chemical', 'MESH:D010984', (124, 132))	('SCLC', 'Gene', '7864', (100, 104))	('RB1', 'Gene', (49, 52))	('SCLC', 'Phenotype', 'HP:0030357', (100, 104))	('wild-type', 'Var', (39, 48))	('RB1', 'Gene', '5925', (49, 52))	('paclitaxel', 'Chemical', 'MESH:D017239', (148, 158))	('NSCLC', 'Phenotype', 'HP:0030358', (99, 104))	('SCLC', 'Gene', '7864', (170, 174))	('SCLC', 'Phenotype', 'HP:0030357', (170, 174))	('SCLC', 'Gene', (170, 174))	('LCNEC', 'Phenotype', 'HP:0030360', (28, 33))	('NSCLC', 'Disease', (99, 104))	('platinum', 'Chemical', 'MESH:D010984', (189, 197))	('NSCLC', 'Disease', 'MESH:D002289', (99, 104))
125851	33613113	Moreover, the results of the receiver operating characteristic curve (ROC) analysis showed that plasma has_circ_0001445 could be used as a more accurate marker to distinguish HCC cases from healthy people, cirrhosis, or hepatitis B patients.	('HCC', 'Gene', (175, 178))	('cirrhosis', 'Disease', (206, 215))	('patients', 'Species', '9606', (232, 240))	('has_circ_0001445', 'Var', (103, 119))	('ROC', 'Chemical', '-', (70, 73))	('people', 'Species', '9606', (198, 204))	('hepatitis B', 'Disease', 'MESH:D006509', (220, 231))	('HCC', 'Gene', '619501', (175, 178))	('cirrhosis', 'Phenotype', 'HP:0001394', (206, 215))	('hepatitis B', 'Disease', (220, 231))	('cirrhosis', 'Disease', 'MESH:D005355', (206, 215))	('hepatitis', 'Phenotype', 'HP:0012115', (220, 229))
125852	33613113	Similar studies also performed by detecting low expression of has_circ_0000190 detected in the serum of gastric cancer by Chen et al.	('gastric cancer', 'Disease', 'MESH:D013274', (104, 118))	('expression', 'MPA', (48, 58))	('gastric cancer', 'Phenotype', 'HP:0012126', (104, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('has_circ_0000190', 'Var', (62, 78))	('gastric cancer', 'Disease', (104, 118))
125855	33613113	identified that the expression of has_circ_0006848 in plasma was significantly inhibited in patients with early gastric cancer compared with healthy volunteers.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('expression', 'MPA', (20, 30))	('gastric cancer', 'Disease', 'MESH:D013274', (112, 126))	('gastric cancer', 'Disease', (112, 126))	('patients', 'Species', '9606', (92, 100))	('inhibited', 'NegReg', (79, 88))	('gastric cancer', 'Phenotype', 'HP:0012126', (112, 126))	('has_circ_0006848', 'Var', (34, 50))
125860	33613113	The differential expression of circRNA had a diagnostic value for oral squamous cell carcinoma, in which the AUC value of has_circ_0001874 was the highest; the diagnostic accuracy of the combined diagnosis of has_circ_0001874 and has_circ_0001971 was additionally enhanced.	('has_circ_0001874', 'Var', (122, 138))	('has_circ_0001874', 'Var', (209, 225))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (66, 94))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (71, 94))	('oral squamous cell carcinoma', 'Disease', (66, 94))	('enhanced', 'PosReg', (264, 272))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('has_circ_0001971', 'Var', (230, 246))
125884	33613113	Prior to this, studies have reported that in breast cancer epithelial cells, inhibition of IGF-1R increases cell stress, CC motif chemokine ligand 2 (CCL2), IL-10, and IL-6, and reduces TNF-alpha.	('CCL2', 'Gene', (150, 154))	('reduces', 'NegReg', (178, 185))	('CC motif chemokine ligand 2', 'Gene', (121, 148))	('increases', 'PosReg', (98, 107))	('IL-10', 'Gene', '3586', (157, 162))	('CC motif chemokine ligand 2', 'Gene', '6347', (121, 148))	('IL-10', 'Gene', (157, 162))	('TNF-alpha', 'Gene', '7124', (186, 195))	('TNF-alpha', 'Gene', (186, 195))	('breast cancer', 'Phenotype', 'HP:0003002', (45, 58))	('CCL2', 'Gene', '6347', (150, 154))	('stress', 'Disease', 'MESH:D000079225', (113, 119))	('breast cancer', 'Disease', 'MESH:D001943', (45, 58))	('breast cancer', 'Disease', (45, 58))	('stress', 'Disease', (113, 119))	('IL-6', 'Gene', '3569', (168, 172))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('inhibition', 'Var', (77, 87))	('IGF-1R', 'Gene', (91, 97))	('IGF-1R', 'Gene', '3480', (91, 97))	('IL-6', 'Gene', (168, 172))
125887	33613113	Circ-0008433 regulates the expression of matrix metallopeptidase 2 (MMP2) by competitively binding to miR-181c-5p and miR-181b-5p, which further recruits NK cells to attack arterial elastic fibers, remodel blood vessels, and promote the progression of aneurysms (Figure 2C).	('miR-181c', 'Gene', '406957', (102, 110))	('recruits', 'PosReg', (145, 153))	('miR-181b-5p', 'Var', (118, 129))	('MMP2', 'Gene', '4313', (68, 72))	('aneurysms', 'Disease', 'MESH:D000783', (252, 261))	('progression', 'CPA', (237, 248))	('matrix metallopeptidase 2', 'Gene', '4313', (41, 66))	('aneurysms', 'Disease', (252, 261))	('binding', 'Interaction', (91, 98))	('MMP2', 'Gene', (68, 72))	('aneurysms', 'Phenotype', 'HP:0002617', (252, 261))	('promote', 'PosReg', (225, 232))	('miR-181c', 'Gene', (102, 110))	('matrix metallopeptidase 2', 'Gene', (41, 66))
125894	33613113	found that knock out circUHRF1 in HCC cells improved the sensitivity of anti-PD-1 treatment and improved the overall survival rate of patients (Figure 2D), suggesting that exosomal circUHRF1 may lead to resistance to anti-PD-1 immunotherapy and provide a potential treatment strategy for patients with HCC.	('improved', 'PosReg', (96, 104))	('HCC', 'Gene', (34, 37))	('patients', 'Species', '9606', (134, 142))	('sensitivity', 'MPA', (57, 68))	('circUHRF1', 'Gene', (21, 30))	('HCC', 'Gene', '619501', (302, 305))	('PD-1', 'Gene', '9825', (222, 226))	('lead to', 'Reg', (195, 202))	('knock out', 'Var', (11, 20))	('HCC', 'Gene', (302, 305))	('PD-1', 'Gene', '9825', (77, 81))	('patients', 'Species', '9606', (288, 296))	('improved', 'PosReg', (44, 52))	('exosomal circUHRF1', 'Var', (172, 190))	('PD-1', 'Gene', (222, 226))	('resistance', 'CPA', (203, 213))	('circUHRF1', 'Var', (181, 190))	('HCC', 'Gene', '619501', (34, 37))	('PD-1', 'Gene', (77, 81))
125903	33613113	found that knock down of lncRNA UCA1 in serum exosomes blocked the mitogen-activated protein kinase (MAPK) signaling pathway, and up-regulated the expression of circHIPK3.	('knock down', 'Var', (11, 21))	('UCA1', 'Gene', '652995', (32, 36))	('UCA1', 'Gene', (32, 36))	('circHIPK3', 'Gene', (161, 170))	('expression', 'MPA', (147, 157))	('up-regulated', 'PosReg', (130, 142))	('blocked', 'NegReg', (55, 62))
125907	33613113	Survival analysis showed that the expression of circ-IARS negatively correlated with the survival time of patients with pancreatic cancer, suggesting that circ-IARS in serum exosomes may be a non-invasive biomarker for early diagnosis and prognosis of pancreatic cancer.	('pancreatic cancer', 'Disease', 'MESH:D010190', (120, 137))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (252, 269))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (120, 137))	('circ-IARS', 'Var', (155, 164))	('patients', 'Species', '9606', (106, 114))	('cancer', 'Phenotype', 'HP:0002664', (263, 269))	('pancreatic cancer', 'Disease', 'MESH:D010190', (252, 269))	('pancreatic cancer', 'Disease', (252, 269))	('negatively', 'NegReg', (58, 68))	('pancreatic cancer', 'Disease', (120, 137))
125908	33613113	found that the expression of exosomal circPDE8A in plasma was related to the progression and prognosis of PDAC patients, suggesting that exosomal circPDE8A may be an important indicator for early diagnosis and prognosis of PDAC.	('PDAC', 'Disease', (106, 110))	('exosomal', 'Var', (137, 145))	('related', 'Reg', (62, 69))	('PDAC', 'Disease', (223, 227))	('patients', 'Species', '9606', (111, 119))
125911	33613113	found that the expression levels of has_circ_0109046 and has_circ_0002577 in the serum exosomes of patients with endometrial cancer increased dramatically, indicating their potential as blood diagnostic markers for endometrial cancer.	('endometrial cancer', 'Disease', 'MESH:D016889', (215, 233))	('endometrial cancer', 'Phenotype', 'HP:0012114', (113, 131))	('has_circ_0002577', 'Var', (57, 73))	('endometrial cancer', 'Disease', 'MESH:D016889', (113, 131))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('increased', 'PosReg', (132, 141))	('patients', 'Species', '9606', (99, 107))	('expression levels', 'MPA', (15, 32))	('has_circ_0109046', 'Var', (36, 52))	('endometrial cancer', 'Disease', (215, 233))	('endometrial cancer', 'Disease', (113, 131))	('endometrial cancer', 'Phenotype', 'HP:0012114', (215, 233))
125921	33613113	Similar studies have found that has_circ_0010522 can promote white fat browning, and that its expression level in gastric cancer plasma is positively correlated with white fat browning.	('fat browning', 'Phenotype', 'HP:0031622', (172, 184))	('gastric cancer', 'Disease', (114, 128))	('white fat browning', 'MPA', (61, 79))	('has_circ_0010522', 'Var', (32, 48))	('expression level', 'MPA', (94, 110))	('gastric cancer', 'Disease', 'MESH:D013274', (114, 128))	('fat browning', 'Phenotype', 'HP:0031622', (67, 79))	('gastric cancer', 'Phenotype', 'HP:0012126', (114, 128))	('correlated', 'Reg', (150, 160))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('promote', 'PosReg', (53, 60))
126009	29512685	Apoptosis was assessed in MGC-803 and MKN-45 cells after treatment with 1, 10 and 25 microM deguelin for 48 h. The early (10.87+-0.46% at 1 microM, 20.20+-3.21% at 10 microM and 52.70+-4.88% at 25 microM), late (5.17+-1.28 at 1 microM, 17.60+-4.25% at 10 microM and 22.90+-4.58% at 25 microM) and total (16.03+-1.60% at 1 microM, 37.80+-7.02% at 10 microM and 75.60+-7.08% at 25 microM) apoptosis rates were increased significantly in MGC-803 cells compared with control (8.03+-1.31% of early, 4.60+-0.50% of late and 12.63+-1.76% of total apoptosis rate) (Fig.	('increased', 'PosReg', (408, 417))	('apoptosis rates', 'CPA', (387, 402))	('MKN-45', 'Chemical', '-', (38, 44))	('deguelin', 'Chemical', 'MESH:C107676', (92, 100))	('MGC-803', 'Var', (435, 442))
126047	29512685	Abnormalities of cell cycle checkpoint regulators have been recognized as critical factors in the development of human cancers.	('Abnormalities', 'Var', (0, 13))	('cancers', 'Disease', 'MESH:D009369', (119, 126))	('cancers', 'Phenotype', 'HP:0002664', (119, 126))	('cancers', 'Disease', (119, 126))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('human', 'Species', '9606', (113, 118))
126050	29512685	Overexpression of p21 has been identified as a crucial element resulting in cell cycle arrest at G0/G1, S and G2/M phase.	('cell cycle arrest', 'Phenotype', 'HP:0011018', (76, 93))	('p21', 'Gene', (18, 21))	('G2/M phase', 'CPA', (110, 120))	('cell cycle arrest', 'CPA', (76, 93))	('p21', 'Gene', '644914', (18, 21))	('Overexpression', 'Var', (0, 14))	('resulting', 'Reg', (63, 72))
126082	33649795	Here, we found that circ_0000003 expression was upregulated in TSCC tissues and cell lines, and high circ_0000003 expression was correlated with advanced TNM stage, increased tumor size and poor patient survival.	('tumor', 'Disease', (175, 180))	('circ_0000003', 'Gene', (20, 32))	('TNM', 'Gene', (154, 157))	('TSCC', 'Disease', (63, 67))	('TSCC', 'Phenotype', 'HP:0030413', (63, 67))	('patient', 'Species', '9606', (195, 202))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('high circ_0000003', 'Var', (96, 113))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('expression', 'MPA', (114, 124))	('TNM', 'Gene', '10178', (154, 157))	('increased', 'PosReg', (165, 174))	('upregulated', 'PosReg', (48, 59))
126083	33649795	Mechanistically, we found that circ_0000003 acted as a competing endogenous RNA (ceRNA) that sponged miR-330-3p, thereby elevating glutaminase (GLS) expression.	('glutaminase', 'Gene', (131, 142))	('circ_0000003', 'Var', (31, 43))	('elevating', 'PosReg', (121, 130))	('glutaminase', 'Gene', '2744', (131, 142))	('miR-330-3p', 'Chemical', '-', (101, 111))	('expression', 'MPA', (149, 159))	('GLS', 'Gene', '2744', (144, 147))	('GLS', 'Gene', (144, 147))
126084	33649795	Accordingly, cell invasion, migration, glutamine consumption, alpha-ketoglutarate (alpha-KG) production and ATP production were significantly decreased by circ_0000003 knockdown in TSCC cells, and these effects were reversed by miR-330-3p inhibition.	('migration', 'CPA', (28, 37))	('TSCC', 'Phenotype', 'HP:0030413', (181, 185))	('circ_0000003', 'Gene', (155, 167))	('ATP production', 'MPA', (108, 122))	('cell invasion', 'CPA', (13, 26))	('decreased', 'NegReg', (142, 151))	('glutamine', 'Chemical', 'MESH:D005973', (39, 48))	('ATP', 'Chemical', 'MESH:D000255', (108, 111))	('glutamine consumption', 'MPA', (39, 60))	('miR-330-3p', 'Chemical', '-', (228, 238))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (62, 81))	('knockdown', 'Var', (168, 177))	('alpha-KG', 'Chemical', 'MESH:D007656', (83, 91))
126085	33649795	In conclusion, circ_0000003 facilitates TSCC cell proliferation, migration, invasion and glutamine catabolism by regulating the miR-330-3p/GLS pathway.	('circ_0000003', 'Var', (15, 27))	('migration', 'CPA', (65, 74))	('glutamine catabolism', 'MPA', (89, 109))	('GLS', 'Gene', '2744', (139, 142))	('regulating', 'Reg', (113, 123))	('GLS', 'Gene', (139, 142))	('miR-330-3p', 'Chemical', '-', (128, 138))	('TSCC', 'Phenotype', 'HP:0030413', (40, 44))	('facilitates', 'PosReg', (28, 39))	('glutamine', 'Chemical', 'MESH:D005973', (89, 98))	('TSCC cell proliferation', 'CPA', (40, 63))	('invasion', 'CPA', (76, 84))
126089	33649795	For instance, hsa_circ_0001742 was found to promote TSCC progression by regulating the miR-431-5p/ATF3 or miR-634/RAB1A axis.	('miR-634', 'Gene', (106, 113))	('promote', 'PosReg', (44, 51))	('ATF3', 'Gene', '467', (98, 102))	('TSCC', 'Disease', (52, 56))	('TSCC', 'Phenotype', 'HP:0030413', (52, 56))	('miR-634', 'Gene', '693219', (106, 113))	('hsa_circ_0001742', 'Var', (14, 30))	('regulating', 'Reg', (72, 82))	('RAB1A', 'Gene', (114, 119))	('miR-431', 'Gene', '574038', (87, 94))	('ATF3', 'Gene', (98, 102))	('RAB1A', 'Gene', '5861', (114, 119))	('miR-431', 'Gene', (87, 94))
126091	33649795	Although the tumor-promoting role of circ_0000003 has been reported in NSCLC, its role in other tumors has not yet been reported.	('tumor', 'Disease', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('NSCLC', 'Phenotype', 'HP:0030358', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumors', 'Disease', (96, 102))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('tumor', 'Disease', (96, 101))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('NSCLC', 'Disease', (71, 76))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('circ_0000003', 'Var', (37, 49))	('NSCLC', 'Disease', 'MESH:D002289', (71, 76))
126093	33649795	In these tumors, not only tumor cell growth, but also tumor invasion and metastasis are promoted by dysregulated glutamate metabolism.	('promoted', 'PosReg', (88, 96))	('glutamate', 'Chemical', 'MESH:D018698', (113, 122))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('metastasis', 'CPA', (73, 83))	('glutamate metabolism', 'MPA', (113, 133))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('tumor', 'Disease', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumor', 'Disease', (9, 14))	('dysregulated glutamate metabolism', 'Phenotype', 'HP:0500148', (100, 133))	('tumors', 'Disease', (9, 15))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('tumors', 'Disease', 'MESH:D009369', (9, 15))	('dysregulated', 'Var', (100, 112))
126095	33649795	Among them are circHMGCS1, which was demonstrated to promote cell proliferation and glutaminolysis in hepatoblastoma cells by facilitating the expression of glutaminase (GLS), one of the key enzymes in glutamine metabolism, and circ_0016418, which was shown to facilitate glutamine catabolism in melanoma cells by upregulating GLS expression via interaction with miR-605-5p.	('melanoma', 'Disease', (296, 304))	('GLS', 'Gene', (327, 330))	('circHMGCS1', 'Gene', '3157', (15, 25))	('upregulating', 'PosReg', (314, 326))	('miR-605', 'Gene', (363, 370))	('glutamine', 'Chemical', 'MESH:D005973', (202, 211))	('glutamine', 'Chemical', 'MESH:D005973', (272, 281))	('glutaminase', 'Gene', '2744', (157, 168))	('melanoma', 'Phenotype', 'HP:0002861', (296, 304))	('hepatoblastoma', 'Phenotype', 'HP:0002884', (102, 116))	('glutamine catabolism', 'MPA', (272, 292))	('circ_0016418', 'Var', (228, 240))	('glutaminolysis', 'CPA', (84, 98))	('promote', 'PosReg', (53, 60))	('GLS', 'Gene', '2744', (170, 173))	('interaction', 'Interaction', (346, 357))	('melanoma', 'Disease', 'MESH:D008545', (296, 304))	('expression', 'MPA', (143, 153))	('glutaminase', 'Gene', (157, 168))	('cell proliferation', 'CPA', (61, 79))	('hepatoblastoma', 'Disease', (102, 116))	('circHMGCS1', 'Gene', (15, 25))	('GLS', 'Gene', '2744', (327, 330))	('facilitate', 'PosReg', (261, 271))	('GLS', 'Gene', (170, 173))	('hepatoblastoma', 'Disease', 'MESH:D018197', (102, 116))	('expression', 'MPA', (331, 341))	('miR-605', 'Gene', '693190', (363, 370))
126128	33649795	Subsequently, the luciferase reporters and miR-330-3p mimic or control mimic were co-transfected into the cells using Lipofectamine 2000 reagent (Invitrogen; Thermo Fisher Scientific, Inc.).	('miR-330-3p', 'Chemical', '-', (43, 53))	('luciferase', 'Enzyme', (18, 28))	('miR-330-3p', 'Var', (43, 53))	('Lipofectamine 2000 reagent', 'Chemical', '-', (118, 144))
126129	33649795	TSCC cell lysates were collected using RIPA buffer plus RNase inhibitor (Promega Corp.), followed by transfection with biotin-labeled wild-type (WT) miR-330-3p (Bio-miR-330-3p-WT), mutated (MUT) miR-330-3p (Bio-miR-330-3p-MUT) or antagonistic miR-330-3p probe (Bio-NC-probe), which were all designed and synthesized by GenePharma.	('miR-330-3p', 'Var', (149, 159))	('TSCC', 'Phenotype', 'HP:0030413', (0, 4))	('biotin', 'Chemical', 'MESH:D001710', (119, 125))	('miR-330-3p', 'Chemical', '-', (165, 175))	('miR-330-3p', 'Chemical', '-', (149, 159))	('RIPA buffer', 'Chemical', '-', (39, 50))	('miR-330-3p', 'Var', (195, 205))	('miR-330-3p', 'Chemical', '-', (211, 221))	('miR-330-3p', 'Chemical', '-', (195, 205))	('mutated', 'Var', (181, 188))	('miR-330-3p', 'Chemical', '-', (243, 253))
126131	33649795	After 6 washes, the immunocomplexes bound by Ago2 were eluted, and then incubated with proteinase K at 55 C for 30 min to digest the proteins, followed by RNA extraction and RT-qPCR analysis for the expression of circ_0000003 or GLS mRNA.	('GLS', 'Gene', '2744', (229, 232))	('GLS', 'Gene', (229, 232))	('circ_0000003', 'Var', (213, 225))	('Ago2', 'Gene', (45, 49))	('Ago2', 'Gene', '27161', (45, 49))
126133	33649795	Among circ_0000003, miR-330-3p and GLS mRNA, their linear correlations were assessed using Pearsons correlation analysis and two-tailed t-test.	('circ_0000003', 'Var', (6, 18))	('miR-330-3p', 'Var', (20, 30))	('GLS', 'Gene', (35, 38))	('GLS', 'Gene', '2744', (35, 38))	('miR-330-3p', 'Chemical', '-', (20, 30))
126134	33649795	We also examined circ_0000003 expression levels in HOKs and TSCC cell lines (SCC25, SCC4, Cal27 and SCC1), and found that circ_0000003 expression was significantly increased in the TSCC cells when compared with the HOKs cells (Fig.	('TSCC', 'Phenotype', 'HP:0030413', (181, 185))	('TSCC', 'Disease', (181, 185))	('circ_0000003', 'Var', (122, 134))	('SCC1', 'CellLine', 'CVCL:7707', (100, 104))	('HOK', 'CellLine', 'CVCL:B403', (215, 218))	('TSCC', 'Phenotype', 'HP:0030413', (60, 64))	('expression', 'MPA', (135, 145))	('SCC4', 'CellLine', 'CVCL:1684', (84, 88))	('HOK', 'CellLine', 'CVCL:B403', (51, 54))	('increased', 'PosReg', (164, 173))
126138	33649795	RT-qPCR analysis confirmed that circ_0000003 was significantly knocked down via sh-circ_0000003 in the Cal27 and SCC1 cells (Fig.	('knocked down', 'NegReg', (63, 75))	('circ_0000003', 'Gene', (32, 44))	('sh-circ_0000003', 'Var', (80, 95))	('SCC1', 'CellLine', 'CVCL:7707', (113, 117))
126141	33649795	1F), and circ_0000003 overexpression significantly promoted the cell proliferation of SCC25 and SCC4 cells (Fig.	('circ_0000003', 'Var', (9, 21))	('promoted', 'PosReg', (51, 59))	('cell proliferation', 'CPA', (64, 82))	('SCC4', 'CellLine', 'CVCL:1684', (96, 100))
126142	33649795	Bioinformatics analysis via Circular RNA Interactome  indicated that the top five predicted potential target miRNAs of circ_0000003 are miR-31, miR-197, miR-210, miR-330-3p and miR-338-3p (Table III).	('miR-210', 'Gene', (153, 160))	('miR-338-3p', 'Var', (177, 187))	('miR-31', 'Gene', (136, 142))	('miR-197', 'Gene', '406974', (144, 151))	('miR-210', 'Gene', '406992', (153, 160))	('miR-330-3p', 'Chemical', '-', (162, 172))	('miR-31', 'Gene', '407035', (136, 142))	('miR-197', 'Gene', (144, 151))	('circ_0000003', 'Gene', (119, 131))	('miR-330-3p', 'Var', (162, 172))
126143	33649795	The results of RT-qPCR demonstrated that circ_0000003 knockdown in Cal27 cells facilitated the expression of miR-197, miR-210, miR-330-3p and miR-338-3p, respectively, among which the increase in miR-330-3p expression was the most obvious (Fig.	('miR-338-3p', 'Var', (142, 152))	('miR-330-3p', 'Chemical', '-', (196, 206))	('miR-210', 'Gene', (118, 125))	('miR-210', 'Gene', '406992', (118, 125))	('miR-197', 'Gene', (109, 116))	('miR-330-3p', 'Var', (127, 137))	('miR-197', 'Gene', '406974', (109, 116))	('facilitated', 'PosReg', (79, 90))	('expression', 'MPA', (95, 105))	('miR-330-3p', 'Chemical', '-', (127, 137))
126144	33649795	The binding sites that miR-330-3p may share with circ_0000003 are showed in Fig.	('binding', 'Interaction', (4, 11))	('miR-330-3p', 'Var', (23, 33))	('miR-330-3p', 'Chemical', '-', (23, 33))
126145	33649795	Subsequently, the results from the dual-luciferase reporter assay verified that miR-330-3p could bind with circ_0000003 at the molecular level in Cal27 and SCC1 cells (Fig.	('bind', 'Interaction', (97, 101))	('miR-330-3p', 'Var', (80, 90))	('SCC1', 'CellLine', 'CVCL:7707', (156, 160))	('miR-330-3p', 'Chemical', '-', (80, 90))
126149	33649795	To determine whether circ_0000003 binds miR-330-3p in an AGO2-dependent manner, we conducted anti-AGO2 RIP in Cal27 and SCC1 cells overexpressing miR-330-3p via miR-330-3p mimics, and found that circ_0000003 enrichment was significantly increased after overexpression of miR-330-3p in Cal27 and SCC1 cells (Fig.	('increased', 'PosReg', (237, 246))	('miR-330-3p', 'Chemical', '-', (161, 171))	('AGO2', 'Gene', (57, 61))	('miR-330-3p', 'Chemical', '-', (271, 281))	('AGO2', 'Gene', (98, 102))	('AGO2', 'Gene', '27161', (57, 61))	('miR-330-3p', 'Chemical', '-', (146, 156))	('AGO2', 'Gene', '27161', (98, 102))	('miR-330-3p', 'Chemical', '-', (40, 50))	('miR-330-3p', 'Var', (271, 281))	('SCC1', 'CellLine', 'CVCL:7707', (295, 299))	('SCC1', 'CellLine', 'CVCL:7707', (120, 124))
126150	33649795	Furthermore, the two online bioinformatics databases, miRDB  and TargetScan , suggested that GLS mRNA 3'-UTR had the high associability with miR-330-3p (Fig.	('GLS', 'Gene', (93, 96))	('UTR', 'Gene', '2837', (105, 108))	('UTR', 'Gene', (105, 108))	('associability', 'Interaction', (122, 135))	('miR-330-3p', 'Chemical', '-', (141, 151))	('miR-330-3p', 'Var', (141, 151))	('GLS', 'Gene', '2744', (93, 96))
126151	33649795	Luciferase reporter assay verified that miR-330-3p covalently targeted GLS mRNA 3'-UTR in Cal27 and SCC1 cells (Fig.	('GLS', 'Gene', '2744', (71, 74))	('SCC1', 'CellLine', 'CVCL:7707', (100, 104))	('targeted', 'Reg', (62, 70))	('GLS', 'Gene', (71, 74))	('miR-330-3p', 'Var', (40, 50))	('miR-330-3p', 'Chemical', '-', (40, 50))	('UTR', 'Gene', '2837', (83, 86))	('UTR', 'Gene', (83, 86))
126152	33649795	Moreover, RIP assay revealed a higher level of GLS mRNA enrichment in the AGO2 group after overexpression of miR-330-3p in Cal27 and SCC1 cells (Fig.	('AGO2', 'Gene', (74, 78))	('overexpression', 'PosReg', (91, 105))	('miR-330-3p', 'Var', (109, 119))	('GLS', 'Gene', '2744', (47, 50))	('GLS', 'Gene', (47, 50))	('AGO2', 'Gene', '27161', (74, 78))	('higher', 'PosReg', (31, 37))	('miR-330-3p', 'Chemical', '-', (109, 119))	('SCC1', 'CellLine', 'CVCL:7707', (133, 137))
126153	33649795	Therefore, we here found that circ_0000003 has a direct effect on miR-330-3p, and miR-330-3p has a direct effect on GLS mRNA 3'-UTR.	('miR-330-3p', 'Chemical', '-', (82, 92))	('circ_0000003', 'Var', (30, 42))	('miR-330-3p', 'Chemical', '-', (66, 76))	('effect', 'Reg', (56, 62))	('UTR', 'Gene', '2837', (128, 131))	('effect', 'Reg', (106, 112))	('GLS', 'Gene', '2744', (116, 119))	('miR-330-3p', 'Var', (82, 92))	('GLS', 'Gene', (116, 119))	('miR-330-3p', 'MPA', (66, 76))	('UTR', 'Gene', (128, 131))
126154	33649795	Based on the above bioinformatics analyses and related verification experiments, there may be certain interactions among circ_0000003, miR-330-3p and GLS.	('miR-330-3p', 'Var', (135, 145))	('interactions', 'Interaction', (102, 114))	('GLS', 'Gene', '2744', (150, 153))	('miR-330-3p', 'Chemical', '-', (135, 145))	('circ_0000003', 'Gene', (121, 133))	('GLS', 'Gene', (150, 153))
126156	33649795	miR-330-3p expression in the 40 specimens of TSCC tissues was examined via RT-qPCR, and the result demonstrated that miR-330-3p expression was significantly lower in TSCC tissues compared with that noted in the adjacent nontumor tissues (Fig.	('miR-330-3p', 'Chemical', '-', (0, 10))	('miR-330-3p', 'Chemical', '-', (117, 127))	('TSCC', 'Phenotype', 'HP:0030413', (45, 49))	('tumor', 'Disease', (223, 228))	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('TSCC', 'Phenotype', 'HP:0030413', (166, 170))	('TSCC', 'Disease', (166, 170))	('miR-330-3p', 'Var', (117, 127))	('expression', 'MPA', (128, 138))	('tumor', 'Disease', 'MESH:D009369', (223, 228))	('lower', 'NegReg', (157, 162))
126158	33649795	After statistically analyzing the associations of their expressions, circ_0000003 expression was found to be negatively correlated with miR-330-3p expression (R=-0.783, P<0.01, Fig.	('expression', 'MPA', (82, 92))	('circ_0000003', 'Var', (69, 81))	('miR-330-3p expression', 'MPA', (136, 157))	('negatively', 'NegReg', (109, 119))	('miR-330-3p', 'Chemical', '-', (136, 146))
126160	33649795	Moreover, miR-330-3p expression was negatively correlated with GLS mRNA expression (R=-0.753, P<0.01, Fig.	('miR-330-3p', 'Chemical', '-', (10, 20))	('GLS', 'Gene', '2744', (63, 66))	('negatively', 'NegReg', (36, 46))	('miR-330-3p', 'Var', (10, 20))	('GLS', 'Gene', (63, 66))
126162	33649795	4A), while overexpression of circ_0000003 significantly inhibited miR-330-3p expression in the SCC25 and SCC4 cells (Fig.	('miR-330-3p expression', 'MPA', (66, 87))	('miR-330-3p', 'Chemical', '-', (66, 76))	('SCC4', 'CellLine', 'CVCL:1684', (105, 109))	('inhibited', 'NegReg', (56, 65))	('circ_0000003', 'Var', (29, 41))
126163	33649795	Furthermore, RT-qPCR assay indicated that overexpression of miR-330-3p via miR-330-3p mimics significantly decreased GLS mRNA expression in Cal27 and SCC1 cells (Fig.	('miR-330-3p mimics', 'Var', (75, 92))	('SCC1', 'CellLine', 'CVCL:7707', (150, 154))	('decreased', 'NegReg', (107, 116))	('miR-330-3p', 'Chemical', '-', (75, 85))	('miR-330-3p', 'Chemical', '-', (60, 70))	('GLS', 'Gene', '2744', (117, 120))	('GLS', 'Gene', (117, 120))
126165	33649795	Coincidentally, western blot analysis demonstrated that overexpression of miR-330-3p decreased GLS protein expression in Cal27 and SCC1 cells (Fig.	('decreased', 'NegReg', (85, 94))	('GLS', 'Gene', '2744', (95, 98))	('GLS', 'Gene', (95, 98))	('miR-330-3p', 'Var', (74, 84))	('SCC1', 'CellLine', 'CVCL:7707', (131, 135))	('miR-330-3p', 'Chemical', '-', (74, 84))
126166	33649795	4G), while inhibition of miR-330-3p increased GLS protein expression in SCC25 and SCC4 cells (Fig.	('miR-330-3p', 'Chemical', '-', (25, 35))	('GLS', 'Gene', '2744', (46, 49))	('GLS', 'Gene', (46, 49))	('increased', 'PosReg', (36, 45))	('miR-330-3p', 'Var', (25, 35))	('inhibition', 'NegReg', (11, 21))	('SCC4', 'CellLine', 'CVCL:1684', (82, 86))
126168	33649795	4I), while overexpression of circ_0000003 significantly increased GLS mRNA expression in the SCC25 and SCC4 cells (Fig.	('increased', 'PosReg', (56, 65))	('SCC4', 'CellLine', 'CVCL:1684', (103, 107))	('GLS', 'Gene', '2744', (66, 69))	('circ_0000003', 'Var', (29, 41))	('GLS', 'Gene', (66, 69))
126171	33649795	Overall, our results indicated that circ_0000003 downregulated miR-330-3p expression and upregulated GLS expression, and miR-330-3p downregulated GLS expression, suggesting circ_0000003 may promote GLS expression by restraining miR-330-3p.	('miR-330-3p', 'Chemical', '-', (63, 73))	('miR-330-3p', 'Gene', (63, 73))	('GLS', 'Gene', '2744', (198, 201))	('expression', 'MPA', (202, 212))	('miR-330-3p', 'Chemical', '-', (228, 238))	('restraining', 'NegReg', (216, 227))	('expression', 'MPA', (105, 115))	('expression', 'MPA', (74, 84))	('GLS', 'Gene', '2744', (101, 104))	('GLS', 'Gene', (198, 201))	('downregulated', 'NegReg', (49, 62))	('GLS', 'Gene', '2744', (146, 149))	('promote', 'PosReg', (190, 197))	('expression', 'MPA', (150, 160))	('miR-330-3p', 'Chemical', '-', (121, 131))	('GLS', 'Gene', (101, 104))	('upregulated', 'PosReg', (89, 100))	('circ_0000003', 'Var', (36, 48))	('circ_0000003', 'Var', (173, 185))	('miR-330-3p', 'Var', (121, 131))	('miR-330-3p', 'MPA', (228, 238))	('GLS', 'Gene', (146, 149))	('downregulated', 'NegReg', (132, 145))
126172	33649795	To clarify whether miR-330-3p was involved in the inhibition of cell invasion and migration capability elicited by circ_0000003 knockdown, co-transfection experiments were performed in Cal27 cells.	('miR-330-3p', 'Chemical', '-', (19, 29))	('knockdown', 'Var', (128, 137))	('inhibition', 'NegReg', (50, 60))	('circ_0000003', 'Gene', (115, 127))	('cell invasion', 'CPA', (64, 77))	('migration capability', 'CPA', (82, 102))
126175	33649795	These results indicated that the cell invasion and migration were significantly restrained by circ_0000003 knockdown, and then it was reversed after transfection with miR-330-3p inhibitor in TSCC cells.	('knockdown', 'Var', (107, 116))	('restrained', 'NegReg', (80, 90))	('TSCC', 'Phenotype', 'HP:0030413', (191, 195))	('miR-330-3p', 'Chemical', '-', (167, 177))	('circ_0000003 knockdown', 'Var', (94, 116))
126176	33649795	Since some circRNAs have been found to be involved in the progression of glutamine metabolism, we asked whether circ_0000003 could facilitate TSCC progression by regulating glutamine metabolism.	('glutamine metabolism', 'MPA', (73, 93))	('TSCC', 'Phenotype', 'HP:0030413', (142, 146))	('TSCC', 'Disease', (142, 146))	('facilitate', 'PosReg', (131, 141))	('glutamine metabolism', 'MPA', (173, 193))	('glutamine', 'Chemical', 'MESH:D005973', (173, 182))	('regulating', 'Reg', (162, 172))	('glutamine', 'Chemical', 'MESH:D005973', (73, 82))	('circ_0000003', 'Var', (112, 124))
126177	33649795	Interestingly, transfection of sh-circ_0000003 caused a dramatic reduction in glutamine consumption, alpha-KG production and ATP production in TSCC cells (Fig.	('sh-circ_0000003', 'Var', (31, 46))	('alpha-KG', 'Chemical', 'MESH:D007656', (101, 109))	('ATP production', 'MPA', (125, 139))	('glutamine', 'Chemical', 'MESH:D005973', (78, 87))	('TSCC', 'Phenotype', 'HP:0030413', (143, 147))	('ATP', 'Chemical', 'MESH:D000255', (125, 128))	('glutamine consumption', 'MPA', (78, 99))	('alpha-KG production', 'MPA', (101, 120))	('reduction', 'NegReg', (65, 74))
126178	33649795	To clarify whether miR-330-3p was involved in the inhibition of glutamine metabolism elicited by circ_0000003 knockdown, co-transfection experiments were performed in Cal27 cells.	('knockdown', 'Var', (110, 119))	('inhibition', 'NegReg', (50, 60))	('circ_0000003', 'Var', (97, 109))	('glutamine metabolism', 'MPA', (64, 84))	('glutamine', 'Chemical', 'MESH:D005973', (64, 73))	('miR-330-3p', 'Chemical', '-', (19, 29))
126180	33649795	Meanwhile, miR-330-3p inhibitor transfection reversed the decrease in glutamine consumption, alpha-KG production and ATP production induced by sh-circ_0000003 transfection (Fig.	('sh-circ_0000003', 'Gene', (143, 158))	('miR-330-3p', 'Chemical', '-', (11, 21))	('glutamine', 'Chemical', 'MESH:D005973', (70, 79))	('ATP production', 'MPA', (117, 131))	('glutamine consumption', 'MPA', (70, 91))	('transfection', 'Var', (159, 171))	('decrease', 'NegReg', (58, 66))	('ATP', 'Chemical', 'MESH:D000255', (117, 120))	('alpha-KG production', 'MPA', (93, 112))	('alpha-KG', 'Chemical', 'MESH:D007656', (93, 101))
126181	33649795	These results indicated that the glutamine consumption, alpha-KG production and ATP production were significantly restrained by circ_0000003 knockdown, and then it was reversed after transfection with miR-330-3p inhibitor in TSCC cells.	('knockdown', 'Var', (141, 150))	('alpha-KG', 'Chemical', 'MESH:D007656', (56, 64))	('ATP production', 'MPA', (80, 94))	('restrained', 'NegReg', (114, 124))	('glutamine', 'Chemical', 'MESH:D005973', (33, 42))	('miR-330-3p', 'Chemical', '-', (201, 211))	('glutamine consumption', 'MPA', (33, 54))	('circ_0000003', 'Gene', (128, 140))	('TSCC', 'Phenotype', 'HP:0030413', (225, 229))	('alpha-KG production', 'MPA', (56, 75))	('ATP', 'Chemical', 'MESH:D000255', (80, 83))
126184	33649795	Importantly, the current research demonstrated that circ_0000003 elevated glutaminase (GLS) expression by sponging miR-330-3p, leading to promotion of TSCC glutamine catabolism, invasion and metastasis (Fig.	('GLS', 'Gene', (87, 90))	('glutaminase', 'Gene', (74, 85))	('promotion', 'PosReg', (138, 147))	('glutamine', 'Chemical', 'MESH:D005973', (156, 165))	('miR-330-3p', 'Chemical', '-', (115, 125))	('circ_0000003', 'Var', (52, 64))	('metastasis', 'CPA', (191, 201))	('invasion', 'CPA', (178, 186))	('TSCC glutamine catabolism', 'MPA', (151, 176))	('elevated', 'PosReg', (65, 73))	('glutaminase', 'Gene', '2744', (74, 85))	('GLS', 'Gene', '2744', (87, 90))	('TSCC', 'Phenotype', 'HP:0030413', (151, 155))	('expression', 'MPA', (92, 102))
126185	33649795	Circ_0000003 has been demonstrated to facilitate the cell proliferation, invasion and migration of NSCLC cells via targeting the miR-338-3p/IRS2 axis.	('IRS2', 'Gene', (140, 144))	('Circ_0000003', 'Var', (0, 12))	('facilitate', 'PosReg', (38, 48))	('cell proliferation', 'CPA', (53, 71))	('NSCLC', 'Disease', (99, 104))	('migration', 'CPA', (86, 95))	('NSCLC', 'Phenotype', 'HP:0030358', (99, 104))	('IRS2', 'Gene', '8660', (140, 144))	('invasion', 'CPA', (73, 81))	('targeting', 'Reg', (115, 124))	('NSCLC', 'Disease', 'MESH:D002289', (99, 104))
126188	33649795	Thus, we detected circ_0000003 expression in TSCC tissues and cell lines, and found that circ_0000003 was upregulated in TSCC tissues and cell lines, and high circ_0000003 expression was associated with poor patient prognosis and advanced tumor progression, suggesting that circ_0000003 has an oncogenic function in TSCC.	('patient', 'Species', '9606', (208, 215))	('TSCC', 'Phenotype', 'HP:0030413', (45, 49))	('circ_0000003', 'Var', (89, 101))	('tumor', 'Disease', 'MESH:D009369', (239, 244))	('upregulated', 'PosReg', (106, 117))	('TSCC', 'Phenotype', 'HP:0030413', (316, 320))	('TSCC', 'Disease', (121, 125))	('high', 'Var', (154, 158))	('TSCC', 'Phenotype', 'HP:0030413', (121, 125))	('tumor', 'Phenotype', 'HP:0002664', (239, 244))	('associated', 'Reg', (187, 197))	('tumor', 'Disease', (239, 244))	('circ_0000003', 'Var', (274, 286))
126189	33649795	Then, we found that miR-330-3p expression was strongly increased by circ_0000003 knockdown in TSCC cells compared with other potential targeting miRNAs.	('increased', 'PosReg', (55, 64))	('TSCC', 'Phenotype', 'HP:0030413', (94, 98))	('knockdown', 'Var', (81, 90))	('miR-330-3p', 'Gene', (20, 30))	('circ_0000003', 'Gene', (68, 80))	('miR-330-3p', 'Chemical', '-', (20, 30))
126191	33649795	Several studies have revealed that miR-330-3p exerts a tumor-suppressive effect in various tumors.	('tumors', 'Disease', (91, 97))	('tumors', 'Disease', 'MESH:D009369', (91, 97))	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('miR-330-3p', 'Chemical', '-', (35, 45))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('tumor', 'Disease', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('miR-330-3p', 'Var', (35, 45))	('tumor', 'Disease', (91, 96))
126192	33649795	For instance, circ-0016068 restrained miR-330-3p expression and facilitated insertion region-1 (BMI-1) expression to promote the cell proliferation, invasion and migration of prostate cancer cells.	('cell proliferation', 'CPA', (129, 147))	('invasion', 'CPA', (149, 157))	('migration of prostate cancer', 'Disease', 'MESH:D011471', (162, 190))	('miR-330-3p', 'Chemical', '-', (38, 48))	('prostate cancer', 'Phenotype', 'HP:0012125', (175, 190))	('expression', 'MPA', (103, 113))	('BMI-1', 'Gene', '648', (96, 101))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('miR-330-3p expression', 'Var', (38, 59))	('migration of prostate cancer', 'Disease', (162, 190))	('promote', 'PosReg', (117, 124))	('BMI-1', 'Gene', (96, 101))
126193	33649795	Moreover, upregulation of miR-330-3p restricted the cell proliferation, colony formation and invasion of laryngeal squamous cell carcinoma (LSCC) cells by targeting transformer-2 protein homolog beta (Tra2beta) to repress Akt activation.	('colony formation', 'CPA', (72, 88))	('Akt', 'Gene', (222, 225))	('targeting', 'Reg', (155, 164))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (115, 138))	('Tra2beta', 'Gene', (201, 209))	('transformer-2 protein homolog beta', 'Gene', '29896', (165, 199))	('activation', 'PosReg', (226, 236))	('Akt', 'Gene', '207', (222, 225))	('squamous cell carcinoma', 'Disease', (115, 138))	('repress', 'NegReg', (214, 221))	('transformer-2 protein homolog beta', 'Gene', (165, 199))	('miR-330-3p', 'Chemical', '-', (26, 36))	('Tra2beta', 'Gene', '29896', (201, 209))	('cell proliferation', 'CPA', (52, 70))	('restricted', 'NegReg', (37, 47))	('miR-330-3p', 'Var', (26, 36))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (115, 138))	('invasion', 'CPA', (93, 101))	('upregulation', 'PosReg', (10, 22))
126194	33649795	In our current research, miR-330-3p expression was markedly reduced in TSCC tissues, and was negatively correlated with circ_0000003 expression in the TSCC tissues.	('miR-330-3p', 'Chemical', '-', (25, 35))	('negatively', 'NegReg', (93, 103))	('reduced', 'NegReg', (60, 67))	('miR-330-3p', 'Var', (25, 35))	('TSCC', 'Phenotype', 'HP:0030413', (71, 75))	('TSCC', 'Disease', (71, 75))	('TSCC', 'Phenotype', 'HP:0030413', (151, 155))
126195	33649795	More importantly, our present study revealed that circ_0000003 was a decoy for miR-330-3p, and circ_0000003 participated in the progression of TSCC by sponging miR-330-3p.	('miR-330-3p', 'MPA', (160, 170))	('participated', 'Reg', (108, 120))	('miR-330-3p', 'Chemical', '-', (160, 170))	('TSCC', 'Phenotype', 'HP:0030413', (143, 147))	('sponging', 'NegReg', (151, 159))	('circ_0000003', 'Var', (95, 107))	('miR-330-3p', 'Chemical', '-', (79, 89))	('TSCC', 'Disease', (143, 147))
126196	33649795	For instance, circ_0000003 has been shown to sponge miR-338-3p and restrain miR-338-3p expression, leading to promotion of cell proliferation and invasion of NSCLC cells.	('NSCLC', 'Disease', (158, 163))	('promotion', 'PosReg', (110, 119))	('cell proliferation', 'CPA', (123, 141))	('NSCLC', 'Disease', 'MESH:D002289', (158, 163))	('miR-338-3p expression', 'MPA', (76, 97))	('circ_0000003', 'Var', (14, 26))	('restrain', 'NegReg', (67, 75))	('NSCLC', 'Phenotype', 'HP:0030358', (158, 163))
126197	33649795	In the current research, our gain- and loss-of-function experiments indicated that circ_0000003 knockdown facilitated miR-330-3p expression, whereas circ_0000003 overexpression repressed miR-330-3p expression.	('knockdown', 'Var', (96, 105))	('circ_0000003', 'Gene', (83, 95))	('miR-330-3p expression', 'MPA', (118, 139))	('miR-330-3p', 'Chemical', '-', (187, 197))	('miR-330-3p', 'Chemical', '-', (118, 128))	('facilitated', 'PosReg', (106, 117))
126198	33649795	Moreover, our rescue experiments demonstrated that circ_0000003 facilitated cell proliferation, migration and invasion by counteracting the miR-330-3p-mediated effects on TSCC cells.	('migration', 'CPA', (96, 105))	('circ_0000003', 'Var', (51, 63))	('facilitated', 'PosReg', (64, 75))	('cell proliferation', 'CPA', (76, 94))	('TSCC', 'Phenotype', 'HP:0030413', (171, 175))	('invasion', 'CPA', (110, 118))	('miR-330-3p', 'Chemical', '-', (140, 150))
126199	33649795	Therefore, our current study presents strong evidence for a tumor-promoting role of the circ_0000003/miR-330-3p interaction in TSCC.	('circ_0000003/miR-330-3p interaction', 'Var', (88, 123))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('miR-330-3p', 'Chemical', '-', (101, 111))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('TSCC', 'Phenotype', 'HP:0030413', (127, 131))	('TSCC', 'Disease', (127, 131))	('tumor', 'Disease', (60, 65))
126200	33649795	Increasing evidence has revealed that miRNAs can bind to the 3'-UTR of their downstream target genes, thereby inhibiting the target gene expression at the post-transcriptional levels.	('bind', 'Interaction', (49, 53))	('UTR', 'Gene', '2837', (64, 67))	('UTR', 'Gene', (64, 67))	('inhibiting', 'NegReg', (110, 120))	('miRNAs', 'Var', (38, 44))
126201	33649795	Thus, we here used two bioinformatics databases (miRDB and TargetScan) to speculate potential target genes for miR-330-3p, and found GLS may be a target gene of miR-330-3p.	('miR-330-3p', 'Chemical', '-', (161, 171))	('miR-330-3p', 'Chemical', '-', (111, 121))	('GLS', 'Gene', '2744', (133, 136))	('GLS', 'Gene', (133, 136))	('miR-330-3p', 'Var', (111, 121))
126204	33649795	Moreover, circ_0016418 facilitated melanoma progression and glutamine catabolism by sponging miR-605-5p to promote GLS expression.	('melanoma', 'Disease', 'MESH:D008545', (35, 43))	('GLS', 'Gene', '2744', (115, 118))	('GLS', 'Gene', (115, 118))	('miR-605', 'Gene', (93, 100))	('melanoma', 'Phenotype', 'HP:0002861', (35, 43))	('facilitated', 'PosReg', (23, 34))	('glutamine catabolism', 'MPA', (60, 80))	('miR-605', 'Gene', '693190', (93, 100))	('circ_0016418', 'Var', (10, 22))	('glutamine', 'Chemical', 'MESH:D005973', (60, 69))	('promote', 'PosReg', (107, 114))	('melanoma', 'Disease', (35, 43))
126205	33649795	In the current research, we verified that miR-330-3p directly bound to GLS 3'-UTR and negatively regulated GLS expression.	('GLS', 'Gene', (107, 110))	('miR-330-3p', 'Chemical', '-', (42, 52))	('GLS', 'Gene', '2744', (71, 74))	('negatively', 'NegReg', (86, 96))	('UTR', 'Gene', '2837', (78, 81))	('GLS', 'Gene', (71, 74))	('bound', 'Interaction', (62, 67))	('UTR', 'Gene', (78, 81))	('miR-330-3p', 'Var', (42, 52))	('GLS', 'Gene', '2744', (107, 110))	('regulated', 'Reg', (97, 106))
126210	33649795	Moreover, dysfunction of glutamine metabolism has been found in oral squamous cell carcinoma (OSCC) and head and neck squamous cell carcinoma (HNSCC).	('found', 'Reg', (55, 60))	('glutamine', 'Chemical', 'MESH:D005973', (25, 34))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (69, 92))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (64, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (118, 141))	('oral squamous cell carcinoma', 'Disease', (64, 92))	('dysfunction', 'Var', (10, 21))	('neck squamous cell carcinoma', 'Disease', (113, 141))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))	('glutamine metabolism', 'MPA', (25, 45))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (113, 141))
126218	33649795	Herein, our current study demonstrated that circ_0000003 knockdown significantly repressed glutamine consumption, alpha-KG production and ATP production of TSCC cells, indicating that circ_0000003 knockdown impeded glutamine catabolism in TSCC cells.	('circ_0000003 knockdown', 'Var', (184, 206))	('ATP production', 'MPA', (138, 152))	('TSCC', 'Phenotype', 'HP:0030413', (156, 160))	('knockdown', 'Var', (197, 206))	('glutamine', 'Chemical', 'MESH:D005973', (215, 224))	('glutamine catabolism', 'MPA', (215, 235))	('glutamine', 'Chemical', 'MESH:D005973', (91, 100))	('TSCC', 'Phenotype', 'HP:0030413', (239, 243))	('ATP', 'Chemical', 'MESH:D000255', (138, 141))	('repressed', 'NegReg', (81, 90))	('alpha-KG production', 'MPA', (114, 133))	('alpha-KG', 'Chemical', 'MESH:D007656', (114, 122))	('glutamine consumption', 'MPA', (91, 112))	('impeded', 'NegReg', (207, 214))
126219	33649795	Moreover, in the current rescue experiments, miR-330-3p inhibitor reversed the reduction in glutamine consumption, alpha-KG production and ATP production induced by sh-circ_0000003 transfection in Cal27 cells, suggesting circ_0000003 knockdown may exert the inhibitory effects on the glutamine metabolism by facilitating miR-330-3p expression and function in TSCC.	('alpha-KG', 'Chemical', 'MESH:D007656', (115, 123))	('expression', 'MPA', (332, 342))	('miR-330-3p', 'Chemical', '-', (45, 55))	('facilitating', 'PosReg', (308, 320))	('TSCC', 'Phenotype', 'HP:0030413', (359, 363))	('TSCC', 'Disease', (359, 363))	('glutamine', 'Chemical', 'MESH:D005973', (92, 101))	('transfection', 'Var', (181, 193))	('miR-330-3p', 'Gene', (321, 331))	('ATP production', 'MPA', (139, 153))	('glutamine', 'Chemical', 'MESH:D005973', (284, 293))	('miR-330-3p', 'Chemical', '-', (321, 331))	('glutamine consumption', 'MPA', (92, 113))	('alpha-KG production', 'MPA', (115, 134))	('reduction', 'NegReg', (79, 88))	('ATP', 'Chemical', 'MESH:D000255', (139, 142))
126220	33649795	In summary, this research work suggests a vital role for circ_0000003 in glutamine metabolism and tumor progression by binding and restraining miR-330-3p to facilitate GLS expression in TSCC.	('miR-330-3p', 'Chemical', '-', (143, 153))	('glutamine metabolism', 'MPA', (73, 93))	('tumor', 'Disease', (98, 103))	('restraining', 'NegReg', (131, 142))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('TSCC', 'Phenotype', 'HP:0030413', (186, 190))	('GLS', 'Gene', '2744', (168, 171))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('GLS', 'Gene', (168, 171))	('miR-330-3p', 'MPA', (143, 153))	('circ_0000003', 'Var', (57, 69))	('glutamine', 'Chemical', 'MESH:D005973', (73, 82))	('binding', 'Interaction', (119, 126))	('facilitate', 'PosReg', (157, 167))
126232	33268765	Silencing of SKIL inhibited malignant phenotypes of NSCLC cells and promoted T cell infiltration.	('T cell infiltration', 'CPA', (77, 96))	('NSCLC', 'Phenotype', 'HP:0030358', (52, 57))	('malignant phenotypes of', 'CPA', (28, 51))	('promoted', 'PosReg', (68, 76))	('SKIL', 'Gene', (13, 17))	('NSCLC', 'Disease', (52, 57))	('NSCLC', 'Disease', 'MESH:D002289', (52, 57))	('inhibited', 'NegReg', (18, 27))	('Silencing', 'Var', (0, 9))
126233	33268765	SKIL-knockdown inhibited autophagy and activated the STING pathway in NSCLC cells through down-regulation of TAZ.	('inhibited', 'NegReg', (15, 24))	('STING', 'Gene', '340061', (53, 58))	('SKIL-knockdown', 'Var', (0, 14))	('activated', 'PosReg', (39, 48))	('autophagy', 'CPA', (25, 34))	('NSCLC', 'Disease', (70, 75))	('TAZ', 'Protein', (109, 112))	('STING', 'Gene', (53, 58))	('NSCLC', 'Disease', 'MESH:D002289', (70, 75))	('SKIL-knockdown', 'Gene', (0, 14))	('down-regulation', 'NegReg', (90, 105))	('NSCLC', 'Phenotype', 'HP:0030358', (70, 75))
126234	33268765	Silencing of TAZ cancelled the effects of SKIL overexpression on malignant phenotypes and autophagy of NSCLC cells.	('malignant phenotypes', 'CPA', (65, 85))	('autophagy', 'CPA', (90, 99))	('NSCLC', 'Disease', (103, 108))	('TAZ', 'Gene', (13, 16))	('NSCLC', 'Disease', 'MESH:D002289', (103, 108))	('NSCLC', 'Phenotype', 'HP:0030358', (103, 108))	('Silencing', 'Var', (0, 9))
126249	33268765	Previous studies reported that inhibiting DNA damage response proteins (poly-ADP-ribose polymerase (PARP) and checkpoint kinase 1 (CHK1)) could activate cGAS-STING-mediated anti-cancer immunity, and enhance the blockade of PD-1 checkpoint and infiltration of cytotoxic T cell.	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('cGAS', 'Gene', (153, 157))	('enhance', 'PosReg', (199, 206))	('PARP', 'Gene', (100, 104))	('STING', 'Gene', '340061', (158, 163))	('blockade', 'CPA', (211, 219))	('poly-ADP-ribose polymerase', 'Gene', '142', (72, 98))	('STING', 'Gene', (158, 163))	('CHK1', 'Gene', '1111', (131, 135))	('inhibiting', 'Var', (31, 41))	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('checkpoint kinase 1', 'Gene', '1111', (110, 129))	('PD-1', 'Gene', (223, 227))	('PD-1', 'Gene', '5133', (223, 227))	('cGAS', 'Gene', '115004', (153, 157))	('checkpoint kinase 1', 'Gene', (110, 129))	('poly-ADP-ribose polymerase', 'Gene', (72, 98))	('activate', 'PosReg', (144, 152))	('cancer', 'Disease', (178, 184))	('CHK1', 'Gene', (131, 135))	('PARP', 'Gene', '142', (100, 104))	('infiltration of cytotoxic T cell', 'CPA', (243, 275))
126252	33268765	Overexpression of SKIL was reported in esophageal squamous cell carcinoma (ESCC) and breast cancer, and amplification of SKIL was also found in NSCLC, prostate cancer, and head and neck squamous carcinoma (HNSC).	('NSCLC', 'Disease', (144, 149))	('head and neck squamous carcinoma', 'Disease', 'MESH:D000077195', (172, 204))	('NSCLC', 'Phenotype', 'HP:0030358', (144, 149))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (186, 204))	('Overexpression', 'PosReg', (0, 14))	('breast cancer', 'Phenotype', 'HP:0003002', (85, 98))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))	('HNSC', 'CellLine', 'CVCL:F234', (206, 210))	('esophageal squamous cell carcinoma', 'Disease', (39, 73))	('prostate cancer', 'Disease', 'MESH:D011471', (151, 166))	('breast cancer', 'Disease', 'MESH:D001943', (85, 98))	('prostate cancer', 'Phenotype', 'HP:0012125', (151, 166))	('found', 'Reg', (135, 140))	('breast cancer', 'Disease', (85, 98))	('prostate cancer', 'Disease', (151, 166))	('carcinoma', 'Phenotype', 'HP:0030731', (195, 204))	('SKIL', 'Gene', (121, 125))	('SKIL', 'Gene', (18, 22))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('amplification', 'Var', (104, 117))	('NSCLC', 'Disease', 'MESH:D002289', (144, 149))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (50, 73))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (39, 73))
126256	33268765	lower grade esophageal adenocarcinoma, lower grade ovarian adenocarcinoma, pancreatic adenocarcinoma, and breast ductal adenocarcinoma), and silencing of SKIL (or SnoN) upregulated proliferation of ESCC cell line, indicating a complex of SKIL in tumorigenesis.	('pancreatic adenocarcinoma', 'Disease', (75, 100))	('ESCC cell line', 'CPA', (198, 212))	('adenocarcinoma', 'Disease', 'MESH:D000230', (120, 134))	('ovarian adenocarcinoma', 'Disease', (51, 73))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('adenocarcinoma', 'Disease', (86, 100))	('SnoN', 'Gene', (163, 167))	('breast ductal adenocarcinoma', 'Disease', (106, 134))	('proliferation', 'CPA', (181, 194))	('silencing', 'Var', (141, 150))	('adenocarcinoma', 'Disease', 'MESH:D000230', (23, 37))	('breast ductal adenocarcinoma', 'Disease', 'MESH:D001943', (106, 134))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))	('upregulated', 'PosReg', (169, 180))	('adenocarcinoma', 'Disease', 'MESH:D000230', (86, 100))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D000230', (75, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (75, 100))	('adenocarcinoma', 'Disease', (59, 73))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (12, 37))	('ovarian adenocarcinoma', 'Disease', 'MESH:D000230', (51, 73))	('carcinoma', 'Phenotype', 'HP:0030731', (28, 37))	('tumor', 'Disease', (246, 251))	('adenocarcinoma', 'Disease', (120, 134))	('ovarian adenocarcinoma', 'Phenotype', 'HP:0025318', (51, 73))	('SnoN', 'Gene', '6498', (163, 167))	('tumor', 'Disease', 'MESH:D009369', (246, 251))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('adenocarcinoma', 'Disease', 'MESH:D000230', (59, 73))	('adenocarcinoma', 'Disease', (23, 37))
126286	33268765	Proteins were then stained at 4  C overnight with specific primary antibody: SNAIL1 (#3895, CST), SLUG (#9585, CST), E-cadherin (#14472, CST), vimentin (#3932, CST), GAPDH (#97166, CST), STING (#13647, CST), TBK1 (#3504, CST), p-TBK1 (#5483, CST), IRF3 (#4302, CST), p-IRF3 (#29047, CST), beta-actin (#58169, CST), Beclin-1 (#3738, CST), p62 (#39749, CST), LC3-I (#4599, CST), LC3-II (#2775, CST), TAZ (#4883, CST), CTGF (#10095, CST), CYR61 (#39382, CST), LATS2 (#5888, CST), Sav (#13301, CST), or p-TAZ (#59971, CST).	('CYR61', 'Gene', '3491', (436, 441))	('Sav', 'Gene', (477, 480))	('LC3', 'Gene', '84557', (377, 380))	('LC3', 'Gene', (357, 360))	('Beclin-1', 'Gene', '8678', (315, 323))	('TBK1', 'Gene', '29110', (208, 212))	('IRF3', 'Gene', '3661', (269, 273))	('TBK1', 'Gene', (208, 212))	('#5888', 'Var', (464, 469))	('CTGF', 'Gene', '1490', (416, 420))	('GAPDH', 'Gene', '2597', (166, 171))	('IRF3', 'Gene', (248, 252))	('Beclin-1', 'Gene', (315, 323))	('#2775', 'Var', (385, 390))	('TBK1', 'Gene', '29110', (229, 233))	('p62', 'Gene', (338, 341))	('p62', 'Gene', '8878', (338, 341))	('STING', 'Gene', (187, 192))	('vimentin', 'Gene', '7431', (143, 151))	('TBK1', 'Gene', (229, 233))	('vimentin', 'Gene', (143, 151))	('CYR61', 'Gene', (436, 441))	('STING', 'Gene', '340061', (187, 192))	('LC3', 'Gene', '84557', (357, 360))	('CTGF', 'Gene', (416, 420))	('LC3', 'Gene', (377, 380))	('IRF3', 'Gene', '3661', (248, 252))	('GAPDH', 'Gene', (166, 171))	('LATS2', 'Gene', (457, 462))	('LATS2', 'Gene', '26524', (457, 462))	('#13301', 'Var', (482, 488))	('SLUG', 'Gene', '6591', (98, 102))	('Sav', 'Gene', '60485', (477, 480))	('#10095', 'Var', (422, 428))	('SNAIL1', 'Gene', '6615', (77, 83))	('SLUG', 'Gene', (98, 102))	('IRF3', 'Gene', (269, 273))	('SNAIL1', 'Gene', (77, 83))	('#39382', 'Var', (443, 449))	('E-cadherin', 'Gene', (117, 127))	('E-cadherin', 'Gene', '999', (117, 127))
126287	33268765	On the next day, membranes were washed in 1x PBS, and cultured with anti-mouse IgG (#7076, CST) or anti-rabbit IgG (#7074, CST) secondary antibody depending on the type of primary antibody for 2 h at room temperature.	('PBS', 'Chemical', '-', (45, 48))	('mouse', 'Species', '10090', (73, 78))	('#7074', 'Var', (116, 121))	('#7076', 'Var', (84, 89))
126313	33268765	After blocking with 10% goat serum, cells were cultured with diluted LC3B primary antibody (#12741, CST, USA) for 1 h, and then secondary goat anti-rabbit IgG antibody conjugated with Alexa Fluor 594 (#8889, CST, USA) for 1 h at room temperature.	('Alexa Fluor 594', 'Chemical', '-', (184, 199))	('LC3B', 'Gene', (69, 73))	('#12741', 'Var', (92, 98))	('LC3B', 'Gene', '81631', (69, 73))	('IgG antibody', 'Phenotype', 'HP:0003237', (155, 167))
126332	33268765	In order to understand the relationship between SKIL and malignant phenotype of NSCLC, we silenced SKIL in CALU-3 and NCI-H520.	('NSCLC', 'Phenotype', 'HP:0030358', (80, 85))	('SKIL', 'Gene', (99, 103))	('NSCLC', 'Disease', (80, 85))	('NSCLC', 'Disease', 'MESH:D002289', (80, 85))	('silenced', 'Var', (90, 98))
126334	33268765	Expression levels of cancer stem cell markers (CD44, CD133, SOX2, OCT3/4, and NANOG) were also decreased after silencing of SKIL in CALU-3 and NCI-H520 (Fig.	('decreased', 'NegReg', (95, 104))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('CD133', 'MPA', (53, 58))	('silencing', 'Var', (111, 120))	('OCT3/4', 'MPA', (66, 72))	('Expression levels', 'MPA', (0, 17))	('SOX2', 'MPA', (60, 64))	('cancer', 'Disease', (21, 27))	('cancer', 'Disease', 'MESH:D009369', (21, 27))
126335	33268765	Overall, silencing of SKIL resulted in inhibited malignant phenotypes (viability, proliferation, invasion, migration, EMT, and cancer stem cell viability) in CALU-3 and NCI-H520.	('migration', 'CPA', (107, 116))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('inhibited', 'NegReg', (39, 48))	('silencing', 'Var', (9, 18))	('EMT', 'CPA', (118, 121))	('SKIL', 'Gene', (22, 26))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('proliferation', 'CPA', (82, 95))	('cancer', 'Disease', (127, 133))	('invasion', 'CPA', (97, 105))	('malignant phenotypes', 'CPA', (49, 69))
126344	33268765	3i, j), indicating that knockdown of SKIL might influence T cell infiltration and release of relevant chemokines through activation of the STING pathway.	('STING', 'Gene', '340061', (139, 144))	('SKIL', 'Gene', (37, 41))	('T cell infiltration', 'CPA', (58, 77))	('STING', 'Gene', (139, 144))	('release of relevant chemokines', 'MPA', (82, 112))	('influence', 'Reg', (48, 57))	('knockdown', 'Var', (24, 33))	('activation', 'PosReg', (121, 131))
126359	33268765	After silencing TAZ in M109 cell line, we transplanted those cells into BALB/c mice.	('TAZ', 'Gene', (16, 19))	('silencing', 'Var', (6, 15))	('mice', 'Species', '10090', (79, 83))
126362	33268765	qPCR results showed that levels of chemokines (CXCL10, CCL5, IFN-beta) were increased after silencing of TAZ in CALU-3, NCI-H520, and M109 at the presence of STING pathway agonist cGAMP and in SKIL-silenced NSCLC cell-derived tumor blocks (Fig.	('SKIL-silenced NSCLC', 'Disease', 'MESH:D002289', (193, 212))	('NSCLC', 'Phenotype', 'HP:0030358', (207, 212))	('IFN-beta', 'Gene', '3439', (61, 69))	('increased', 'PosReg', (76, 85))	('IFN-beta', 'Gene', (61, 69))	('silencing', 'Var', (92, 101))	('cGAMP', 'Chemical', 'MESH:C584311', (180, 185))	('SKIL-silenced NSCLC', 'Disease', (193, 212))	('tumor', 'Disease', 'MESH:D009369', (226, 231))	('STING', 'Gene', '340061', (158, 163))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('STING', 'Gene', (158, 163))	('M109', 'Var', (134, 138))	('tumor', 'Disease', (226, 231))	('TAZ', 'Gene', (105, 108))
126367	33268765	Further silencing of TAZ significantly increased the numbers of total and cytotoxic T cells in tumor blocks, compared to SKIL-overexpression group (Fig.	('TAZ', 'Gene', (21, 24))	('silencing', 'Var', (8, 17))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('increased', 'PosReg', (39, 48))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Disease', (95, 100))
126370	33268765	Further silencing of TAZ significantly increased the levels of STING, p-TBK1, and p-IRF3, compared to SKIL-overexpression group (Fig.	('STING', 'Gene', (63, 68))	('TBK1', 'Gene', '29110', (72, 76))	('TAZ', 'Gene', (21, 24))	('silencing', 'Var', (8, 17))	('STING', 'Gene', '340061', (63, 68))	('increased', 'PosReg', (39, 48))	('IRF3', 'Gene', (84, 88))	('IRF3', 'Gene', '3661', (84, 88))	('TBK1', 'Gene', (72, 76))
126386	33268765	Through upregulation on downstream factors (amphiregulin, CTGF and CYR61), TAZ could induce many malignant phenotypes of cancer, e.g., cancer stem cell viability, EMT, increased migration and invasion abilities, and higher potential of metastasis.	('upregulation', 'PosReg', (8, 20))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('amphiregulin', 'Gene', (44, 56))	('CTGF', 'Gene', '1490', (58, 62))	('invasion abilities', 'CPA', (192, 210))	('TAZ', 'Var', (75, 78))	('cancer', 'Disease', (135, 141))	('EMT', 'CPA', (163, 166))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('CYR61', 'Gene', '3491', (67, 72))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('amphiregulin', 'Gene', '374', (44, 56))	('CTGF', 'Gene', (58, 62))	('cancer', 'Disease', 'MESH:D009369', (135, 141))	('induce', 'PosReg', (85, 91))	('increased', 'PosReg', (168, 177))	('CYR61', 'Gene', (67, 72))	('higher', 'PosReg', (216, 222))	('cancer', 'Disease', (121, 127))
126390	33268765	Defected autophagy is commonly observed in cancer, and is involved in many malignant phenotypes of tumor, including motility, invasion, cancer stem cell viability, EMT, metastasis, etc..	('tumor', 'Disease', (99, 104))	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('cancer', 'Disease', (43, 49))	('metastasis', 'CPA', (169, 179))	('Defected', 'Var', (0, 8))	('involved', 'Reg', (58, 66))	('autophagy', 'CPA', (9, 18))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('cancer', 'Disease', (136, 142))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('EMT', 'CPA', (164, 167))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
126391	33268765	affecting release of cytokines, survival, and activation of lymphoid cells), and defects in autophagy could promote immune escape of developing tumors.	('tumors', 'Disease', (144, 150))	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('tumors', 'Disease', 'MESH:D009369', (144, 150))	('release of cytokines', 'MPA', (10, 30))	('autophagy', 'CPA', (92, 101))	('defects', 'Var', (81, 88))	('promote', 'PosReg', (108, 115))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))
126406	32793631	Moreover, low BTLA expression was correlated with poor overall survival in TCGA cohorts and Gene Expression Omnibus cohorts (GSE29623 and GSE17536).	('overall survival', 'MPA', (55, 71))	('expression', 'MPA', (19, 29))	('GSE29623', 'Var', (125, 133))	('BTLA', 'Chemical', '-', (14, 18))	('poor', 'NegReg', (50, 54))	('GSE17536', 'Var', (138, 146))	('low', 'NegReg', (10, 13))	('BTLA', 'Protein', (14, 18))
126409	32793631	Naive B cells, memory B cells, CD8 T cells, CD4 memory resting T cells, follicular helper T (Tfh) cells, monocytes, resting natural killing (NK) cells, M0 macrophages, M1 macrophages, resting mast cells, and activated mast cells were affected by BTLA expression (all p < 0.01).	('BTLA', 'Chemical', '-', (246, 250))	('BTLA', 'Gene', (246, 250))	('affected', 'Reg', (234, 242))	('expression', 'Var', (251, 261))
126414	32793631	Major immunotherapy trials in metastatic CRC have been focused on selective anti- programmd death 1 (PD-1), anti-PD-L1, and anti-Cytotoxic T lymphocyte antigen 4 (CTLA-4) monoclonal antibodies.	('CRC', 'Phenotype', 'HP:0003003', (41, 44))	('CTLA-4', 'Gene', (163, 169))	('anti-PD-L1', 'Var', (108, 118))	('CTLA-4', 'Chemical', '-', (163, 169))	('PD-1', 'Gene', (101, 105))
126436	32793631	The probe 236226_s_at was used in this research matching for BTLA.	('BTLA', 'Disease', (61, 65))	('236226_s_at', 'Var', (10, 21))	('BTLA', 'Chemical', '-', (61, 65))
126463	32793631	Naive B cells, memory B cells, CD4 memory resting T cells, CD8 T cells, follicular helper T (Tfh) cells, monocytes, resting NK cells, M0 macrophages, M1 macrophages, resting mast cells, and activated mast cells were affected by BTLA expression (all p < 0.05).	('expression', 'Var', (233, 243))	('affected', 'Reg', (216, 224))	('BTLA', 'Chemical', '-', (228, 232))	('BTLA', 'Gene', (228, 232))
126465	32793631	Conversely, the proportion of monocytes (p = 0.024), M0 macrophages (p < 0.0001), and activated mast cells (p < 0.0001) were infiltrated significantly less in high BTLA expression group compared with the other group (Figure 3A).	('high BTLA expression', 'Var', (159, 179))	('BTLA', 'Chemical', '-', (164, 168))	('M0 macrophages', 'CPA', (53, 67))	('less', 'NegReg', (151, 155))
126500	32793631	Prevenient studies have demonstrated that the level of tumor infiltration by CD8 + T cells can predict patient clinical prognosis in melanoma, ovarian, and CRC.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('CRC', 'Disease', (156, 159))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('melanoma, ovarian', 'Disease', 'MESH:D008545', (133, 150))	('tumor', 'Disease', (55, 60))	('melanoma', 'Phenotype', 'HP:0002861', (133, 141))	('CRC', 'Phenotype', 'HP:0003003', (156, 159))	('CD8 + T', 'Var', (77, 84))
126512	32793631	Publicly available datasets were analyzed in this study, these can be found in The Cancer Genome Atlas (https://portal.gdc.cancer.gov/) and the NCBI Gene Expression Omnibus (GSE29623 and GSE17536).	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('GSE29623', 'Var', (174, 182))	('GSE17536', 'Var', (187, 195))	('cancer', 'Disease', (123, 129))	('Cancer', 'Disease', (83, 89))	('Cancer', 'Phenotype', 'HP:0002664', (83, 89))	('Cancer', 'Disease', 'MESH:D009369', (83, 89))
126526	31976327	Robust data exist regarding the prevalence of EGFR mutations in adenocarcinoma patients, ranging from the highest EGFR mutation frequency of 47% in the Asia-Pacific subgroup to the lowest frequency of 12% in the Oceania subgroup.	('mutation', 'Var', (119, 127))	('mutations', 'Var', (51, 60))	('adenocarcinoma', 'Disease', (64, 78))	('EGFR', 'Gene', '1956', (46, 50))	('EGFR', 'Gene', '1956', (114, 118))	('Asia-Pacific', 'Disease', (152, 164))	('EGFR', 'Gene', (46, 50))	('EGFR', 'Gene', (114, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))
126544	29946268	A Meta-Analysis of miR-499 rs3746444 Polymorphism for Cancer Risk of Different Systems: Evidence From 65 Case-Control Studies MicroRNAs (miRNAs) are a class of endogenous, short and non-coding RNAs that may play important roles in the pathogenesis of tumor.	('miR-499', 'Gene', '574501', (19, 26))	('tumor', 'Disease', (251, 256))	('Cancer', 'Phenotype', 'HP:0002664', (54, 60))	('Cancer', 'Disease', (54, 60))	('rs3746444', 'Var', (27, 36))	('Cancer', 'Disease', 'MESH:D009369', (54, 60))	('rs3746444', 'Mutation', 'rs3746444', (27, 36))	('tumor', 'Disease', 'MESH:D009369', (251, 256))	('miR-499', 'Gene', (19, 26))	('tumor', 'Phenotype', 'HP:0002664', (251, 256))
126545	29946268	The associations between microRNA-499 rs3746444 polymorphism and cancer risk in different systems remain inconclusive.	('rs3746444', 'Var', (38, 47))	('microRNA-499', 'Gene', (25, 37))	('rs3746444', 'Mutation', 'rs3746444', (38, 47))	('microRNA-499', 'Gene', '574501', (25, 37))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))
126546	29946268	ORs and 95% CIs were used to estimate the associations between miR-499 polymorphism and cancer susceptibility in different systems.	('associations', 'Interaction', (42, 54))	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('miR-499', 'Gene', (63, 70))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('polymorphism', 'Var', (71, 83))
126547	29946268	Overall cancer analysis showed the association between miR-499 polymorphism and susceptibility to cancer was significant.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('cancer', 'Disease', (8, 14))	('polymorphism', 'Var', (63, 75))	('miR-499', 'Gene', (55, 62))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('cancer', 'Disease', (98, 104))	('cancer', 'Disease', 'MESH:D009369', (8, 14))
126548	29946268	MicroRNA-499 rs3746444 was found to be significantly associated with increased risk of cancer of the respiratory system (CC vs. TT: OR = 1.575, 95% CI = 1.268-1.955, CC vs. TC+TT: OR = 1.527, 95% CI = 1.232-1.892), digestive system (CC vs. TT: OR = 1.153, 95% CI = 1.027-1.295; TC vs. TT: OR = 1.109, 95% CI = 1.046-1.176; CC+TC vs. TT: OR = 1.112, 95% CI = 1.018-1.216; CC vs. TC+TT: OR = 1.137, 95% CI = 1.016-1.272; C vs. T: OR = 1.112, 95% CI = 1.025-1.206), urinary system (TC vs. TT: OR = 1.307, 95% CI = 1.130-1.512; CC+TC vs. TT: OR = 1.259, 95% CI = 1.097-1.446; C vs. T: OR = 1.132, 95% CI = 1.014-1.264), and gynecological system (C vs. T: OR = 1.169, 95% CI = 1.002-1.364).	('TC', 'Chemical', 'MESH:D013667', (173, 175))	('rs3746444', 'Var', (13, 22))	('urinary system', 'Disease', (463, 477))	('TC+TT', 'Chemical', '-', (173, 178))	('TC', 'Chemical', 'MESH:D013667', (479, 481))	('TC', 'Chemical', 'MESH:D013667', (527, 529))	('rs3746444', 'Mutation', 'rs3746444', (13, 22))	('cancer of the respiratory system', 'Disease', (87, 119))	('TC', 'Chemical', 'MESH:D013667', (378, 380))	('TC', 'Chemical', 'MESH:D013667', (326, 328))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('TC', 'Chemical', 'MESH:D013667', (278, 280))	('MicroRNA-499', 'Gene', (0, 12))	('cancer of the respiratory system', 'Disease', 'MESH:D015619', (87, 119))	('TC+TT', 'Chemical', '-', (378, 383))	('cancer of the respiratory system', 'Phenotype', 'HP:0100606', (87, 119))	('MicroRNA-499', 'Gene', '574501', (0, 12))
126550	29946268	Subgroup analysis based on type of tumor was also performed, miR-499 rs3746444 is associated with susceptibility of cervical squamous cell carcinoma, lung cancer, prostate cancer, and hepatocellular carcinoma.	('prostate cancer', 'Disease', (163, 178))	('rs3746444', 'Var', (69, 78))	('cervical squamous cell carcinoma', 'Disease', (116, 148))	('lung cancer', 'Disease', (150, 161))	('hepatocellular carcinoma', 'Disease', (184, 208))	('cervical squamous cell carcinoma', 'Disease', 'MESH:D002294', (116, 148))	('carcinoma', 'Phenotype', 'HP:0030731', (199, 208))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (125, 148))	('tumor', 'Disease', (35, 40))	('lung cancer', 'Disease', 'MESH:D008175', (150, 161))	('miR-499', 'Gene', (61, 68))	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('lung cancer', 'Phenotype', 'HP:0100526', (150, 161))	('rs3746444', 'Mutation', 'rs3746444', (69, 78))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (184, 208))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('carcinoma', 'Phenotype', 'HP:0030731', (139, 148))	('prostate cancer', 'Disease', 'MESH:D011471', (163, 178))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (184, 208))	('prostate cancer', 'Phenotype', 'HP:0012125', (163, 178))
126557	29946268	also found that miR-499 functions as a tumor suppressor in non-small cell lung cancer by targeting VAV3 (Li M. et al.,).	('VAV3', 'Gene', (99, 103))	('VAV3', 'Gene', '10451', (99, 103))	('lung cancer', 'Phenotype', 'HP:0100526', (74, 85))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (59, 85))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('targeting', 'Reg', (89, 98))	('miR-499', 'Var', (16, 23))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (59, 85))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('non-small cell lung cancer', 'Disease', (59, 85))	('tumor', 'Disease', (39, 44))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (63, 85))
126559	29946268	suggested that downregulation of the miR-499-5p level impaired the PI3K/AKT/GSK signaling pathway and glycogen synthesis by targeting PTEN.	('AKT', 'Gene', '207', (72, 75))	('downregulation', 'NegReg', (15, 29))	('miR-499-5p', 'Var', (37, 47))	('AKT', 'Gene', (72, 75))	('glycogen synthesis', 'MPA', (102, 120))	('impaired', 'NegReg', (54, 62))	('targeting', 'Reg', (124, 133))	('PTEN', 'Gene', (134, 138))	('glycogen', 'Chemical', 'MESH:D006003', (102, 110))	('PTEN', 'Gene', '5728', (134, 138))
126560	29946268	reported that the tumor-targeted delivery of miR-499 was very effective so as to implement cancer therapy.	('tumor', 'Disease', (18, 23))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('miR-499', 'Var', (45, 52))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
126561	29946268	found that APRPG-miR-499 may be a combination therapeutic agent for cancer treatment.	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('APRPG-miR-499', 'Var', (11, 24))	('cancer', 'Disease', (68, 74))
126562	29946268	Single nucleotide genetic variants that occur in miRNAs may influence microRNA biogenesis, stability of mature microRNA molecules, efficiency of target gene regulation, as well as specificity of targets, which may involve developing susceptibility to cancer, thus, miRNAs play an important role in the occurrence and development of malignant tumors (Nikolic et al.,).	('Single nucleotide genetic variants', 'Var', (0, 34))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('microRNA biogenesis', 'MPA', (70, 89))	('malignant tumors', 'Disease', (332, 348))	('influence', 'Reg', (60, 69))	('tumors', 'Phenotype', 'HP:0002664', (342, 348))	('malignant tumors', 'Disease', 'MESH:D018198', (332, 348))	('cancer', 'Disease', 'MESH:D009369', (251, 257))	('tumor', 'Phenotype', 'HP:0002664', (342, 347))	('cancer', 'Disease', (251, 257))	('stability', 'MPA', (91, 100))
126563	29946268	Accumulated evidence suggests that miR-499 rs3746444 is associated with the susceptibility to many cancers.	('miR-499', 'Gene', (35, 42))	('cancers', 'Disease', 'MESH:D009369', (99, 106))	('cancers', 'Phenotype', 'HP:0002664', (99, 106))	('associated', 'Reg', (56, 66))	('cancers', 'Disease', (99, 106))	('rs3746444', 'Var', (43, 52))	('susceptibility', 'Reg', (76, 90))	('rs3746444', 'Mutation', 'rs3746444', (43, 52))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
126564	29946268	reported that the miR-499 rs3746444 polymorphism is associated with the risk of oral squamous cell cancer in Chinese individuals.	('rs3746444', 'Mutation', 'rs3746444', (26, 35))	('associated', 'Reg', (52, 62))	('miR-499', 'Gene', (18, 25))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('oral squamous cell cancer', 'Disease', 'MESH:D002294', (80, 105))	('oral squamous cell cancer', 'Disease', (80, 105))	('rs3746444', 'Var', (26, 35))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (85, 105))
126565	29946268	found that the rs3746444 polymorphism in miR-499 can increase the risk of prostate cancer in an Iranian population.	('miR-499', 'Gene', (41, 48))	('prostate cancer', 'Disease', (74, 89))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('increase', 'PosReg', (53, 61))	('rs3746444', 'Var', (15, 24))	('prostate cancer', 'Disease', 'MESH:D011471', (74, 89))	('prostate cancer', 'Phenotype', 'HP:0012125', (74, 89))	('rs3746444', 'Mutation', 'rs3746444', (15, 24))
126566	29946268	The rs3746444 single nucleotide polymorphism was also found to be clearly associated with lung cancer (Li D. et al.,).	('lung cancer', 'Disease', 'MESH:D008175', (90, 101))	('rs3746444', 'Mutation', 'rs3746444', (4, 13))	('lung cancer', 'Disease', (90, 101))	('lung cancer', 'Phenotype', 'HP:0100526', (90, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('rs3746444 single nucleotide polymorphism', 'Var', (4, 44))	('associated', 'Reg', (74, 84))
126568	29946268	suggested that there is no association between miR-499 variant and the risk of hepatocellular carcinoma in the co-dominant, dominant, and recessive models.	('miR-499', 'Gene', (47, 54))	('variant', 'Var', (55, 62))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('hepatocellular carcinoma', 'Disease', (79, 103))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (79, 103))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (79, 103))
126570	29946268	In a Greek population, a case-control study demonstrated that the rs3746444 polymorphism in miR-499 is not associated with colorectal cancer (Dikaiakos et al.,).	('miR-499', 'Gene', (92, 99))	('colorectal cancer', 'Phenotype', 'HP:0003003', (123, 140))	('rs3746444', 'Var', (66, 75))	('associated', 'Reg', (107, 117))	('colorectal cancer', 'Disease', (123, 140))	('rs3746444', 'Mutation', 'rs3746444', (66, 75))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('colorectal cancer', 'Disease', 'MESH:D015179', (123, 140))
126572	29946268	The association between miR-499 rs3746444 and the susceptibility to cancer has not yet reached a clear consensus.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('miR-499', 'Gene', (24, 31))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('rs3746444', 'Var', (32, 41))	('cancer', 'Disease', (68, 74))	('rs3746444', 'Mutation', 'rs3746444', (32, 41))
126574	29946268	We retrieved articles from PubMed and EMBASE using the following terms "microRNA-499 or miR-499 or rs3746444" and "cancer or carcinoma" published prior to January 10, 2018.	('rs3746444', 'Mutation', 'rs3746444', (99, 108))	('cancer', 'Disease', (115, 121))	('carcinoma', 'Disease', 'MESH:D002277', (125, 134))	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('microRNA-499', 'Gene', (72, 84))	('carcinoma', 'Disease', (125, 134))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('miR-499', 'Var', (88, 95))	('microRNA-499', 'Gene', '574501', (72, 84))	('rs3746444', 'Var', (99, 108))	('cancer', 'Disease', 'MESH:D009369', (115, 121))
126575	29946268	All incorporated literature must clearly meet the following three criteria: (a) evaluation of the miR-499 rs3746444 polymorphism and cancer risks; (b) a case-control study; and (c) sufficient published data for the computation of odds ratios (ORs) with 95% confidence intervals (CIs).	('miR-499', 'Gene', (98, 105))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('cancer', 'Disease', (133, 139))	('rs3746444', 'Var', (106, 115))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('rs3746444', 'Mutation', 'rs3746444', (106, 115))
126578	29946268	ORs corresponding to 95% CI was used to estimate the strength of association between miR-499 rs3746444 T/C and different cancer risk.	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('rs3746444 T/C', 'Var', (93, 106))	('rs3746444', 'Mutation', 'rs3746444', (93, 102))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('cancer', 'Disease', (121, 127))	('miR-499', 'Gene', (85, 92))
126580	29946268	If there was obvious heterogeneity (I2 >= 50%), we conducted with a random-effects model (DerSimonian and Laird), otherwise, we analyzed with a fixed-effects model (Mantel-Haenszel) to obtain summary associations between miR-499 rs3746444 T/C and different cancer risk.	('cancer', 'Phenotype', 'HP:0002664', (257, 263))	('cancer', 'Disease', 'MESH:D009369', (257, 263))	('miR-499', 'Gene', (221, 228))	('rs3746444 T/C', 'Var', (229, 242))	('rs3746444', 'Mutation', 'rs3746444', (229, 238))	('cancer', 'Disease', (257, 263))
126584	29946268	Among all studies, we found significant associations between miR-499 rs3746444 polymorphism and cancer susceptibility in five kinds of genetic models.	('miR-499', 'Gene', (61, 68))	('polymorphism', 'Var', (79, 91))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('rs3746444', 'Mutation', 'rs3746444', (69, 78))	('rs3746444 polymorphism', 'Var', (69, 91))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Disease', (96, 102))
126588	29946268	Significant association was observed between rs3746444 and increased cancer risk in three genetic models in the urinary system (TC vs. TT: OR = 1.307, 95% CI = 1.130-1.512, P < 0.001; CC+TC vs. TT = 1.259, 95% CI = 1.097-1.446, P = 0.001; C vs. T: OR = 1.132, 95% CI = 1.014-1.264, P = 0.027; Figure 4), as well as for prostate cancer.	('TC', 'Chemical', 'MESH:D013667', (187, 189))	('rs3746444', 'Var', (45, 54))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('rs3746444', 'Mutation', 'rs3746444', (45, 54))	('prostate cancer', 'Disease', (319, 334))	('cancer', 'Disease', (328, 334))	('cancer', 'Disease', 'MESH:D009369', (328, 334))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('TC', 'Chemical', 'MESH:D013667', (128, 130))	('prostate cancer', 'Disease', 'MESH:D011471', (319, 334))	('cancer', 'Phenotype', 'HP:0002664', (328, 334))	('cancer', 'Disease', (69, 75))	('prostate cancer', 'Phenotype', 'HP:0012125', (319, 334))
126589	29946268	Our results showed that rs3746444 could increase cancer risk of the gynecological system in the allelic model (C vs. T: OR = 1.169, 95% CI = 1.002-1.364, P = 0.047; Figure 5), particularly for cervical squamous cell carcinoma.	('rs3746444', 'Var', (24, 33))	('rs3746444', 'Mutation', 'rs3746444', (24, 33))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('increase', 'PosReg', (40, 48))	('cervical squamous cell carcinoma', 'Disease', 'MESH:D002294', (193, 225))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('carcinoma', 'Phenotype', 'HP:0030731', (216, 225))	('cervical squamous cell carcinoma', 'Disease', (193, 225))	('cancer', 'Disease', (49, 55))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (202, 225))
126592	29946268	When results were stratified by ethnicity, significant association was found between miR-499 rs3746444 polymorphism and cancer risk in the Asians; (CC vs. TT: OR = 1.301, 95% CI = 1.180-1.434, P < 0.001; TC vs. TT: OR = 1.123, 95% CI = 1.040-1.213, P = 0.003; CC+TC vs. TT: OR = 1.152, 95% CI = 1.065-1.247, P < 0.001; CC vs. TC+TT: OR = 1.267, 95% CI = 1.151-1.394, P < 0.001; C vs. T: OR = 1.136, 95% CI = 1.072-1.237, P < 0.001) this association was absent in the Caucasians.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('rs3746444', 'Var', (93, 102))	('TC+TT', 'Chemical', '-', (326, 331))	('TC', 'Chemical', 'MESH:D013667', (326, 328))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('cancer', 'Disease', (120, 126))	('rs3746444', 'Mutation', 'rs3746444', (93, 102))	('TC', 'Chemical', 'MESH:D013667', (204, 206))	('TC', 'Chemical', 'MESH:D013667', (263, 265))	('miR-499', 'Gene', (85, 92))
126593	29946268	This further supported the significant association between miR-499 rs3746444 and cancer risk.	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('miR-499', 'Gene', (59, 66))	('cancer', 'Disease', (81, 87))	('rs3746444', 'Var', (67, 76))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('rs3746444', 'Mutation', 'rs3746444', (67, 76))
126597	29946268	Though several studies and meta-analyses have been carried out to evaluate the association between miR-499 rs3746444 T > C polymorphism and cancer risk, no conclusive findings have been obtained in different cancers.	('cancer', 'Disease', (208, 214))	('cancers', 'Phenotype', 'HP:0002664', (208, 215))	('cancers', 'Disease', (208, 215))	('cancers', 'Disease', 'MESH:D009369', (208, 215))	('rs3746444 T > C', 'Var', (107, 122))	('cancer', 'Disease', (140, 146))	('rs3746444', 'Mutation', 'rs3746444', (107, 116))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('cancer', 'Disease', 'MESH:D009369', (208, 214))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('miR-499', 'Gene', (99, 106))
126598	29946268	In this study, our results demonstrate significant associations between miR-499 rs3746444 polymorphism and cancer susceptibility for the first time, in five different genetic models from 65 case-control studies.	('miR-499', 'Gene', (72, 79))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('rs3746444', 'Var', (80, 89))	('rs3746444', 'Mutation', 'rs3746444', (80, 89))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('cancer', 'Disease', (107, 113))
126599	29946268	Meta-analyses of all types of cancer risks by other groups have found either no association between the miR-499 polymorphism and cancer susceptibility or significant associations in one or two genetic models (Xu et al.,).	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('miR-499', 'Gene', (104, 111))	('cancer', 'Disease', (30, 36))	('associations', 'Interaction', (166, 178))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('polymorphism', 'Var', (112, 124))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
126600	29946268	Several meta-analyses have explored the association between the miR-499 rs3746444 polymorphism and cancer risk and it is difficult to judge if the analysis without studies departing from HWE would be more valid or not.	('miR-499', 'Gene', (64, 71))	('rs3746444', 'Var', (72, 81))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('cancer', 'Disease', (99, 105))	('rs3746444', 'Mutation', 'rs3746444', (72, 81))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
126603	29946268	The most important feature of our study is that it is the first meta-analysis to explore the associations between miR-499 polymorphism and cancer susceptibility in different systems comprehensively.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('polymorphism', 'Var', (122, 134))	('associations', 'Interaction', (93, 105))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('miR-499', 'Gene', (114, 121))	('cancer', 'Disease', (139, 145))
126604	29946268	We found that microRNA-499 rs3746444 was significantly associated with an increased risk of cancer of the respiratory system in two genetic models, digestive system in all five genetic models, the urinary system in three genetic models, and gynecological system in an allelic model.	('microRNA-499', 'Gene', (14, 26))	('cancer of the respiratory system', 'Disease', 'MESH:D015619', (92, 124))	('rs3746444', 'Var', (27, 36))	('associated', 'Reg', (55, 65))	('microRNA-499', 'Gene', '574501', (14, 26))	('cancer of the respiratory system', 'Phenotype', 'HP:0100606', (92, 124))	('rs3746444', 'Mutation', 'rs3746444', (27, 36))	('cancer of the respiratory system', 'Disease', (92, 124))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
126606	29946268	We also found that miR-499 rs3746444 C allele might increase the risk of lung cancer in a homozygote comparison model.	('lung cancer', 'Disease', 'MESH:D008175', (73, 84))	('rs3746444 C', 'Var', (27, 38))	('increase', 'PosReg', (52, 60))	('rs3746444', 'Mutation', 'rs3746444', (27, 36))	('lung cancer', 'Disease', (73, 84))	('lung cancer', 'Phenotype', 'HP:0100526', (73, 84))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('miR-499', 'Gene', (19, 26))
126607	29946268	Previous studies have reported that rs3746444 was significantly associated with an increased risk of lung cancer and could contribute to a poor prognosis by modulating the expression of cancer-related genes leading to tumorigenesis and resistance to chemotherapy in lung cancer (Li D. et al.,).	('cancer', 'Disease', (106, 112))	('tumor', 'Disease', (218, 223))	('cancer', 'Disease', (271, 277))	('cancer', 'Disease', 'MESH:D009369', (186, 192))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('associated', 'Reg', (64, 74))	('cancer', 'Phenotype', 'HP:0002664', (271, 277))	('leading to', 'Reg', (207, 217))	('tumor', 'Disease', 'MESH:D009369', (218, 223))	('resistance to chemotherapy', 'CPA', (236, 262))	('rs3746444', 'Var', (36, 45))	('lung cancer', 'Disease', (101, 112))	('lung cancer', 'Disease', (266, 277))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('cancer', 'Disease', 'MESH:D009369', (271, 277))	('cancer', 'Disease', (186, 192))	('lung cancer', 'Disease', 'MESH:D008175', (101, 112))	('modulating', 'Reg', (157, 167))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('lung cancer', 'Disease', 'MESH:D008175', (266, 277))	('expression', 'MPA', (172, 182))	('lung cancer', 'Phenotype', 'HP:0100526', (101, 112))	('rs3746444', 'Mutation', 'rs3746444', (36, 45))	('lung cancer', 'Phenotype', 'HP:0100526', (266, 277))
126608	29946268	Our data differs from that of Li et al., since their analysis which included 12 gastrointestinal cancer studies, demonstrated no association between miR-499 rs3746444 and gastrointestinal cancer.	('rs3746444', 'Mutation', 'rs3746444', (157, 166))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('gastrointestinal cancer', 'Disease', 'MESH:D004067', (171, 194))	('gastrointestinal cancer', 'Disease', 'MESH:D004067', (80, 103))	('miR-499', 'Gene', (149, 156))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('gastrointestinal cancer', 'Disease', (171, 194))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (171, 194))	('rs3746444', 'Var', (157, 166))	('gastrointestinal cancer', 'Disease', (80, 103))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (80, 103))
126612	29946268	In addition, we found that miR-499 rs3746444 C allele can increase the risk of hepatocellular carcinoma in recessive and allelic models.	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('hepatocellular carcinoma', 'Disease', (79, 103))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (79, 103))	('rs3746444 C', 'Var', (35, 46))	('miR-499', 'Gene', (27, 34))	('rs3746444', 'Mutation', 'rs3746444', (35, 44))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (79, 103))
126613	29946268	Our findings from the allelic hepatocellular carcinoma model were consistent with those of Yu et al.. We also found that that rs3746444 could increase the risk of gynecological cancers in an allelic model.	('rs3746444', 'Var', (126, 135))	('increase', 'PosReg', (142, 150))	('cancers', 'Disease', 'MESH:D009369', (177, 184))	('rs3746444', 'Mutation', 'rs3746444', (126, 135))	('cancers', 'Phenotype', 'HP:0002664', (177, 184))	('cancers', 'Disease', (177, 184))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (30, 54))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (30, 54))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('hepatocellular carcinoma', 'Disease', (30, 54))	('carcinoma', 'Phenotype', 'HP:0030731', (45, 54))
126614	29946268	At the same time, miR-499 rs3746444 was associated with susceptibility to cervical squamous cell carcinoma.	('rs3746444', 'Mutation', 'rs3746444', (26, 35))	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (83, 106))	('miR-499', 'Gene', (18, 25))	('cervical squamous cell carcinoma', 'Disease', 'MESH:D002294', (74, 106))	('rs3746444', 'Var', (26, 35))	('associated', 'Reg', (40, 50))	('cervical squamous cell carcinoma', 'Disease', (74, 106))
126615	29946268	Consistent with the findings of Wang et al., we also found a significant association between rs3746444 and increased risk for cancer of the urinary system in two genetic models, but not the allelic model.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('rs3746444', 'Var', (93, 102))	('rs3746444', 'Mutation', 'rs3746444', (93, 102))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))
126616	29946268	Our results also suggested a significant association between miR-499 rs3746444 and prostate cancer risk in the heterozygote comparison and dominant models.	('miR-499', 'Gene', (61, 68))	('rs3746444', 'Var', (69, 78))	('rs3746444', 'Mutation', 'rs3746444', (69, 78))	('prostate cancer', 'Disease', 'MESH:D011471', (83, 98))	('prostate cancer', 'Phenotype', 'HP:0012125', (83, 98))	('prostate cancer', 'Disease', (83, 98))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
126618	29946268	found that rs3746444 qualifies for a genetic variant potentially associated with aggressive prostate cancer in the Serbian population (Nikolic et al.,).	('prostate cancer', 'Phenotype', 'HP:0012125', (92, 107))	('rs3746444', 'Var', (11, 20))	('rs3746444', 'Mutation', 'rs3746444', (11, 20))	('associated', 'Reg', (65, 75))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('aggressive prostate cancer', 'Disease', 'MESH:D011471', (81, 107))	('aggressive prostate cancer', 'Disease', (81, 107))
126619	29946268	Classifying cancer into different systems provides a new perspective and an in-depth understanding of the association between the miR-499 polymorphism and cancer susceptibility.	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('polymorphism', 'Var', (138, 150))	('association', 'Interaction', (106, 117))	('cancer', 'Disease', (12, 18))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('miR-499', 'Gene', (130, 137))	('cancer', 'Disease', (155, 161))	('cancer', 'Disease', 'MESH:D009369', (155, 161))
126620	29946268	We found an association between the miR-499 polymorphism and cancer risk in Asians, but not in Caucasians.	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('cancer', 'Disease', (61, 67))	('polymorphism', 'Var', (44, 56))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('miR-499', 'Gene', (36, 43))
126621	29946268	Our results suggest that miR-499 rs3746444 is associated with susceptibility to cervical squamous cell carcinoma, lung cancer, prostate cancer, and hepatocellular carcinoma, but not other cancer types, indicating that rs3746444 may have different effects on different cancer types.	('lung cancer', 'Disease', 'MESH:D008175', (114, 125))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (148, 172))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('cancer', 'Disease', (136, 142))	('lung cancer', 'Phenotype', 'HP:0100526', (114, 125))	('rs3746444', 'Mutation', 'rs3746444', (33, 42))	('cancer', 'Disease', 'MESH:D009369', (268, 274))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (148, 172))	('cancer', 'Disease', (119, 125))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('prostate cancer', 'Disease', 'MESH:D011471', (127, 142))	('prostate cancer', 'Phenotype', 'HP:0012125', (127, 142))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('hepatocellular carcinoma', 'Disease', (148, 172))	('rs3746444', 'Var', (33, 42))	('prostate cancer', 'Disease', (127, 142))	('cervical squamous cell carcinoma', 'Disease', (80, 112))	('lung cancer', 'Disease', (114, 125))	('cancer', 'Disease', (188, 194))	('cancer', 'Disease', (268, 274))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('miR-499', 'Gene', (25, 32))	('carcinoma', 'Phenotype', 'HP:0030731', (163, 172))	('cervical squamous cell carcinoma', 'Disease', 'MESH:D002294', (80, 112))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('cancer', 'Phenotype', 'HP:0002664', (268, 274))	('susceptibility', 'Reg', (62, 76))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (89, 112))	('rs3746444', 'Mutation', 'rs3746444', (218, 227))
126622	29946268	Compared to the previous studies, the difference in results could also be due to a lack of articles on miR-499 polymorphism and cancer risk.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('miR-499', 'Gene', (103, 110))	('polymorphism', 'Var', (111, 123))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('cancer', 'Disease', (128, 134))
126624	29946268	In conclusion, our meta-analysis found that miR-499 rs3746444 polymorphism is associated with the risk of cancer in five genetic models.	('associated', 'Reg', (78, 88))	('rs3746444', 'Var', (52, 61))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('rs3746444', 'Mutation', 'rs3746444', (52, 61))	('cancer', 'Disease', (106, 112))	('miR-499', 'Gene', (44, 51))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
126625	29946268	MicroRNA-499 rs3746444 was found to be significantly associated with increased risk of cancer of the respiratory, digestive, urinary, and gynecological systems.	('cancer', 'Disease', (87, 93))	('gynecological systems', 'Disease', (138, 159))	('rs3746444', 'Var', (13, 22))	('urinary', 'Disease', (125, 132))	('rs3746444', 'Mutation', 'rs3746444', (13, 22))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('MicroRNA-499', 'Gene', (0, 12))	('associated', 'Reg', (53, 63))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('MicroRNA-499', 'Gene', '574501', (0, 12))
126627	29946268	Our findings also suggest that the miR-499 rs3746444 C allele may increase the risk of cervical squamous cell carcinoma, lung cancer, prostate cancer, and hepatocellular carcinoma.	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (155, 179))	('lung cancer', 'Disease', 'MESH:D008175', (121, 132))	('lung cancer', 'Phenotype', 'HP:0100526', (121, 132))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (155, 179))	('prostate cancer', 'Disease', 'MESH:D011471', (134, 149))	('prostate cancer', 'Phenotype', 'HP:0012125', (134, 149))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('hepatocellular carcinoma', 'Disease', (155, 179))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('miR-499', 'Gene', (35, 42))	('prostate cancer', 'Disease', (134, 149))	('lung cancer', 'Disease', (121, 132))	('cervical squamous cell carcinoma', 'Disease', (87, 119))	('increase', 'PosReg', (66, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (170, 179))	('cervical squamous cell carcinoma', 'Disease', 'MESH:D002294', (87, 119))	('rs3746444', 'Mutation', 'rs3746444', (43, 52))	('rs3746444 C', 'Var', (43, 54))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (96, 119))
126643	25874173	NCRT in esophageal cancer could enhance curative resection and eradicate micrometastases, thereby eventually improving overall survival (OS) and disease-free survival.	('NCRT', 'Var', (0, 4))	('curative resection', 'CPA', (40, 58))	('micrometastases', 'CPA', (73, 88))	('improving', 'PosReg', (109, 118))	('eradicate', 'NegReg', (63, 72))	('esophageal cancer', 'Disease', (8, 25))	('disease-free survival', 'CPA', (145, 166))	('overall survival', 'CPA', (119, 135))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('enhance', 'PosReg', (32, 39))	('esophageal cancer', 'Disease', 'MESH:D004938', (8, 25))
126697	25874173	Of six RCTs, four RCTs available for evaluating the downstaging effect of NCRT showed that patients who had received NCRT were less likely to have an advanced stage of cancer at pathological examination than were controls.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('patients', 'Species', '9606', (91, 99))	('NCRT', 'Var', (117, 121))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('less', 'NegReg', (127, 131))	('cancer', 'Disease', (168, 174))
126747	24220575	We subsequently define mutations in microRNA target sites using the AGO-CLIP microRNA target atlas and TCGA exome-sequencing data.	('mutations', 'Var', (23, 32))	('CLIP', 'Gene', '7461', (72, 76))	('CLIP', 'Gene', (72, 76))
126847	24220575	To define additional novel mechanisms of microRNA regulation in tumours, we next integrated the AGO-CLIP data set with TCGA mutation data to identify somatic SNVs in microRNA target sites across tumours.	('CLIP', 'Gene', '7461', (100, 104))	('tumours', 'Phenotype', 'HP:0002664', (64, 71))	('tumour', 'Phenotype', 'HP:0002664', (64, 70))	('tumours', 'Disease', 'MESH:D009369', (64, 71))	('TCGA', 'Gene', (119, 123))	('tumours', 'Disease', (64, 71))	('tumours', 'Phenotype', 'HP:0002664', (195, 202))	('tumours', 'Disease', 'MESH:D009369', (195, 202))	('mutation', 'Var', (124, 132))	('CLIP', 'Gene', (100, 104))	('tumours', 'Disease', (195, 202))	('tumour', 'Phenotype', 'HP:0002664', (195, 201))
126848	24220575	In our analysis of COAD whole-genome sequencing (WGS) samples, 60% of mutations in coding mRNAs are in the 3'-UTR, highlighting the potential importance of mutations in these regions (Fig.	('COAD', 'Disease', 'MESH:D029424', (19, 23))	('mutations', 'Var', (70, 79))	('COAD', 'Disease', (19, 23))	('mRNAs', 'Gene', (90, 95))
126849	24220575	As such, analysing mutations intersecting with microRNA seed-complementary sites has the potential to greatly expand the search for relevant cancer mutations by imbuing silent mutations and 3'-UTR mutations with functional significance.	('silent mutations', 'Var', (169, 185))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('mutations', 'Var', (19, 28))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('cancer', 'Disease', (141, 147))
126852	24220575	Therefore, the majority of microRNA target mutations we define from the 12 pan-cancer tumours occur specifically in the coding region.	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('tumour', 'Phenotype', 'HP:0002664', (86, 92))	('tumours', 'Phenotype', 'HP:0002664', (86, 93))	('pan-cancer', 'Disease', 'MESH:C537931', (75, 85))	('mutations', 'Var', (43, 52))	('cancer tumours', 'Disease', 'MESH:D009369', (79, 93))	('cancer tumours', 'Disease', (79, 93))	('pan-cancer', 'Disease', (75, 85))
126855	24220575	To demonstrate the ability of the AGO-CLIP technology and the miSNP algorithm to detect relevant microRNA target-site mutations, we selected six binding site mutations for experimental validation (Supplementary Data 10).	('CLIP', 'Gene', (38, 42))	('mutations', 'Var', (158, 167))	('mutations', 'Var', (118, 127))	('CLIP', 'Gene', '7461', (38, 42))
126856	24220575	These sites were chosen based on the number of times the specific binding site was identified in the AGO-CLIP atlas, the location of the seed in the coding region or 3'-UTR, whether TargetScan called the site as highly conserved and the relative location of the mutation within the seed-complementary region of the binding site.	('mutation', 'Var', (262, 270))	('CLIP', 'Gene', '7461', (105, 109))	('CLIP', 'Gene', (105, 109))
126857	24220575	For the four target sites with validated target repression, we reproduced the endogenous tumour mutation in the 3'-UTR-luciferase construct.	('tumour', 'Disease', 'MESH:D009369', (89, 95))	('mutation', 'Var', (96, 104))	('tumour', 'Phenotype', 'HP:0002664', (89, 95))	('tumour', 'Disease', (89, 95))
126859	24220575	Mutations complementary to the Let-7 seed on ANP32E and miR-142 seed on FAM114A1 variably reduced, but did not ablate, the repressive ability of the microRNA on the luciferase reporter (Fig.	('FAM114A1', 'Gene', (72, 80))	('miR-142', 'Gene', '406934', (56, 63))	('reduced', 'NegReg', (90, 97))	('ANP32E', 'Gene', (45, 51))	('Let-7', 'Gene', (31, 36))	('repressive', 'MPA', (123, 133))	('miR-142', 'Gene', (56, 63))	('Mutations', 'Var', (0, 9))	('repressive ability', 'Phenotype', 'HP:0000716', (123, 141))	('ANP32E', 'Gene', '81611', (45, 51))	('FAM114A1', 'Gene', '92689', (72, 80))
126860	24220575	One microRNA target site mutation validated in our study was a deletion of a miR-17 seed family binding site in the SKI-like OC (SKIL/SnoN) 3'-UTR.	('SKIL', 'Gene', (129, 133))	('SnoN', 'Gene', (134, 138))	('SKIL', 'Gene', '6498', (129, 133))	('miR-17', 'Gene', (77, 83))	('deletion', 'Var', (63, 71))	('miR-17', 'Gene', '406952', (77, 83))	('SnoN', 'Gene', '6498', (134, 138))
126861	24220575	SKIL is a known OC and was ranked in the top 7% of pan-cancer OCs in our pan-cancer mRNA driver index due to expression gain and copy number amplification (Supplementary Data 6).	('expression', 'MPA', (109, 119))	('pan-cancer', 'Disease', 'MESH:C537931', (51, 61))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('pan-cancer', 'Disease', 'MESH:C537931', (73, 83))	('SKIL', 'Gene', (0, 4))	('SKIL', 'Gene', '6498', (0, 4))	('pan-cancer', 'Disease', (51, 61))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('copy number amplification', 'Var', (129, 154))	('pan-cancer', 'Disease', (73, 83))	('gain', 'PosReg', (120, 124))
126864	24220575	Mutation of the miR-17 seed-family binding site on the SKIL 3'-UTR may represent a mechanism to allow escape from this feedback regulation, allowing unregulated SKIL expression while simultaneously enhancing the oncogenicity of the miR-17 seed family and creating enhanced suppression of the TGFbeta pathway (Fig.	('SKIL', 'Gene', '6498', (55, 59))	('suppression', 'NegReg', (273, 284))	('miR-17', 'Gene', '406952', (16, 22))	('Mutation', 'Var', (0, 8))	('miR-17', 'Gene', (232, 238))	('SKIL', 'Gene', (161, 165))	('enhanced', 'PosReg', (264, 272))	('TGFbeta', 'Gene', (292, 299))	('miR-17', 'Gene', (16, 22))	('SKIL', 'Gene', '6498', (161, 165))	('SKIL', 'Gene', (55, 59))	('oncogenicity', 'CPA', (212, 224))	('miR-17', 'Gene', '406952', (232, 238))	('enhancing', 'PosReg', (198, 207))	('allowing', 'PosReg', (140, 148))	('TGFbeta', 'Gene', '7040', (292, 299))
126873	24220575	These mutations were discovered in the exome-sequencing-defined coding-region mutations available from the Pan-Cancer project, a small number of 3'-UTR mutations available from KIRC exome sequencing and whole-genome 3'-UTR mutations from 36 COAD WGS samples.	('Cancer', 'Phenotype', 'HP:0002664', (111, 117))	('COAD', 'Disease', (241, 245))	('COAD', 'Disease', 'MESH:D029424', (241, 245))	('mutations', 'Var', (78, 87))
126874	24220575	AGO-CLIP characterization of microRNA binding in additional tissue types and integration of additional 3'-UTR mutations from broader cohorts of WGS samples will improve the yield of relevant microRNA target site mutations in the future.	('CLIP', 'Gene', '7461', (4, 8))	('mutations', 'Var', (110, 119))	('mutations', 'Var', (212, 221))	('CLIP', 'Gene', (4, 8))
126876	24220575	Integration of the AGO-CLIP-defined microRNA-binding data with TCGA tumour data revealed several novel insights into microRNA regulation of human tumours, including the definition of a pan-cancer oncomiR superfamily and genome-wide identification of microRNA-binding site mutations.	('mutations', 'Var', (272, 281))	('miR', 'Gene', '220972', (200, 203))	('miR', 'Gene', (200, 203))	('tumours', 'Disease', 'MESH:D009369', (146, 153))	('tumour', 'Disease', (146, 152))	('tumours', 'Disease', (146, 153))	('human', 'Species', '9606', (140, 145))	('tumour', 'Phenotype', 'HP:0002664', (68, 74))	('pan-cancer', 'Disease', (185, 195))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('tumour', 'Disease', 'MESH:D009369', (68, 74))	('CLIP', 'Gene', (23, 27))	('tumour', 'Disease', (68, 74))	('tumour', 'Phenotype', 'HP:0002664', (146, 152))	('CLIP', 'Gene', '7461', (23, 27))	('tumours', 'Phenotype', 'HP:0002664', (146, 153))	('pan-cancer', 'Disease', 'MESH:C537931', (185, 195))	('tumour', 'Disease', 'MESH:D009369', (146, 152))
126877	24220575	AGO-CLIP sequence read archive (SRR) files corresponding to all publicly available human AGO-CLIP experiments were downloaded from the NIH sequence read archive (SRR codes: SRR048973, SRR048974, SRR048975, SRR048976, SRR048977, SRR048978, SRR048979, SRR048980, SRR048981, SRR359787, SRR189786, SRR189787, SRR189784, SRR189785, SRR189782, SRR189783, SRR580362, SRR580363, SRR580352, SRR580353, SRR580354, SRR580355, SRR580359, SRR580360, SRR580361, SRR580356, SRR580357, SRR343336, SRR343337, SRR343334, SRR343335, SRR592689, SRR592688, SRR592687, SRR592686, SRR592685; data were downloaded on 11 January 2013).	('SRR580360', 'Var', (426, 435))	('SRR580353', 'Var', (382, 391))	('CLIP', 'Gene', '7461', (93, 97))	('SRR580355', 'Var', (404, 413))	('SRR592688', 'Var', (525, 534))	('SRR580359', 'Var', (415, 424))	('CLIP', 'Gene', '7461', (4, 8))	('SRR580354', 'Var', (393, 402))	('SRR580352', 'Var', (371, 380))	('SRR343337', 'Var', (481, 490))	('SRR580361', 'Var', (437, 446))	('SRR580356', 'Var', (448, 457))	('SRR592689', 'Var', (514, 523))	('SRR592687', 'Var', (536, 545))	('SRR343334', 'Var', (492, 501))	('SRR580363', 'Var', (360, 369))	('SRR592686', 'Var', (547, 556))	('SRR343335', 'Var', (503, 512))	('CLIP', 'Gene', (93, 97))	('SRR580362', 'Var', (349, 358))	('SRR580357', 'Var', (459, 468))	('human', 'Species', '9606', (83, 88))	('SRR343336', 'Var', (470, 479))	('CLIP', 'Gene', (4, 8))
126883	24220575	The difference between the two methods lies in the use of photoactivatable ribonucleoside analogues in PAR-CLIP data sets, which allow experimental determination of physical interlinkage between protein-RNA pairs through a mismatch repair defect initialized at crosslinked nucleoside analogues during complementary DNA synthesis, leading to T C transitions in the generated cDNA.	('CLIP', 'Gene', (107, 111))	('nucleoside', 'Chemical', 'MESH:D009705', (273, 283))	('ribonucleoside', 'Chemical', 'MESH:D012263', (75, 89))	('T C transitions', 'MPA', (341, 356))	('CLIP', 'Gene', '7461', (107, 111))	('mismatch', 'Var', (223, 231))	('nucleoside', 'Chemical', 'MESH:D009705', (79, 89))	('defect', 'Var', (239, 245))
126908	24220575	This system equally weighted CNV, mRNA expression change and gene mutations as three orthogonal methods of identifying TS and OCs across tumours.	('mutations', 'Var', (66, 75))	('tumours', 'Phenotype', 'HP:0002664', (137, 144))	('OCs across tumours', 'Disease', (126, 144))	('OCs across tumours', 'Disease', 'MESH:D009369', (126, 144))	('tumour', 'Phenotype', 'HP:0002664', (137, 143))
126913	24220575	In sum, this analysis generated a continuous negative-to-positive scale that ranked pan-cancer drivers based on consistent mRNA, CNV or mutation changes across tumours.	('tumours', 'Disease', 'MESH:D009369', (160, 167))	('mutation', 'Var', (136, 144))	('CNV', 'MPA', (129, 132))	('tumours', 'Disease', (160, 167))	('pan-cancer', 'Disease', 'MESH:C537931', (84, 94))	('mRNA', 'MPA', (123, 127))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('pan-cancer', 'Disease', (84, 94))	('tumour', 'Phenotype', 'HP:0002664', (160, 166))	('tumours', 'Phenotype', 'HP:0002664', (160, 167))
126915	24220575	All tumours contain CNV data and mutation data.	('mutation', 'Var', (33, 41))	('tumour', 'Phenotype', 'HP:0002664', (4, 10))	('CNV data', 'MPA', (20, 28))	('tumours', 'Phenotype', 'HP:0002664', (4, 11))	('tumours', 'Disease', 'MESH:D009369', (4, 11))	('tumours', 'Disease', (4, 11))
126916	24220575	Mutation score is highly dominant in several genes such as TP53 with very high mutation frequencies (~50% of all tumours).	('tumour', 'Phenotype', 'HP:0002664', (113, 119))	('TP53', 'Gene', (59, 63))	('tumours', 'Phenotype', 'HP:0002664', (113, 120))	('tumours', 'Disease', 'MESH:D009369', (113, 120))	('Mutation score', 'Var', (0, 14))	('tumours', 'Disease', (113, 120))	('TP53', 'Gene', '7157', (59, 63))
126926	24220575	It first partition the tumour samples into those that contain mutations in microRNA binding site; the algorithm can be customized to consider only particular mutation types (for example, coding, silent).	('tumour', 'Phenotype', 'HP:0002664', (23, 29))	('tumour', 'Disease', 'MESH:D009369', (23, 29))	('coding', 'Disease', (187, 193))	('tumour', 'Disease', (23, 29))	('silent', 'Disease', (195, 201))	('mutations', 'Var', (62, 71))
126927	24220575	Finally, it identifies genes for which the expression associates with the mutation status in microRNA binding sites by comparing the gene expression distributions of tumour samples with or without common sites using a two tailed Welch's t-test; miSNP reports both the fold-change and the t-test P-value for each gene.	('tumour', 'Disease', 'MESH:D009369', (166, 172))	('mutation', 'Var', (74, 82))	('tumour', 'Disease', (166, 172))	('tumour', 'Phenotype', 'HP:0002664', (166, 172))
126928	24220575	In the current paper, we analysed all AGO-CLIP-defined microRNA target sites for mutations to define a global perspective of possible interactions, but selected sites for validation only from interactions with >=3 occurrences corresponding to a non-random event.	('CLIP', 'Gene', '7461', (42, 46))	('CLIP', 'Gene', (42, 46))	('mutations', 'Var', (81, 90))	('interactions', 'Interaction', (134, 146))
126950	33075110	In non-small cell lung cancer (NSCLC), epidermal growth factor receptor (EGFR) mutations are frequently detected.	('detected', 'Reg', (104, 112))	('lung cancer', 'Disease', 'MESH:D008175', (18, 29))	('EGFR', 'Gene', '1956', (73, 77))	('epidermal growth factor receptor', 'Gene', '1956', (39, 71))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (3, 29))	('NSCLC', 'Disease', (31, 36))	('EGFR', 'Gene', (73, 77))	('NSCLC', 'Disease', 'MESH:D002289', (31, 36))	('lung cancer', 'Phenotype', 'HP:0100526', (18, 29))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (7, 29))	('lung cancer', 'Disease', (18, 29))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('NSCLC', 'Phenotype', 'HP:0030358', (31, 36))	('mutations', 'Var', (79, 88))	('epidermal growth factor receptor', 'Gene', (39, 71))
126951	33075110	Erlotinib was developed as an inhibitor of EGFR to treat patients with NSCLC that have activating mutations in EGFR, but how effective this compound is in patients with wild type EGFR remains less clear.	('EGFR', 'Gene', (179, 183))	('NSCLC', 'Phenotype', 'HP:0030358', (71, 76))	('EGFR', 'Gene', '1956', (111, 115))	('patients', 'Species', '9606', (57, 65))	('mutations', 'Var', (98, 107))	('EGFR', 'Gene', (111, 115))	('activating', 'PosReg', (87, 97))	('EGFR', 'Gene', '1956', (43, 47))	('patients', 'Species', '9606', (155, 163))	('NSCLC', 'Disease', (71, 76))	('EGFR', 'Gene', (43, 47))	('Erlotinib', 'Chemical', 'MESH:D000069347', (0, 9))	('EGFR', 'Gene', '1956', (179, 183))	('NSCLC', 'Disease', 'MESH:D002289', (71, 76))
126955	33075110	While EGFR activating mutations are the biomarkers most closely associated with patient responses to this combined bevacizumab + erlotinib (BE) treatment, certain patients without such mutations have also been found to benefit from combination therapy.	('patients', 'Species', '9606', (163, 171))	('EGFR', 'Gene', (6, 10))	('bevacizumab', 'Chemical', 'MESH:D000068258', (115, 126))	('men', 'Species', '9606', (149, 152))	('activating', 'PosReg', (11, 21))	('BE', 'Chemical', '-', (140, 142))	('erlotinib', 'Chemical', 'MESH:D000069347', (129, 138))	('patient', 'Species', '9606', (163, 170))	('mutations', 'Var', (22, 31))	('patient', 'Species', '9606', (80, 87))	('EGFR', 'Gene', '1956', (6, 10))	('benefit', 'PosReg', (219, 226))
126992	33075110	EGFR and KRAS mutations were detected in 4 (9.5%) and 6 (14.3%) of patients, respectively.	('EGFR', 'Gene', (0, 4))	('patients', 'Species', '9606', (67, 75))	('KRAS', 'Gene', (9, 13))	('detected', 'Reg', (29, 37))	('KRAS', 'Gene', '3845', (9, 13))	('EGFR', 'Gene', '1956', (0, 4))	('mutations', 'Var', (14, 23))
127003	33075110	The key hub genes identified through these analyses differed between groups, with female hub genes including TEK, ERG, NONHSAT095695.2, LDB2, ENST00000552253.1, ENST00000588495.5, CDH5, and MEF2C, and male hub genes including ENST00000460756.5, G6PC3, ATF6, BMP2, SIX1, RAB7A, ENST00000575695.5, and SOX2 (S5 and S6 Tables).	('ATF6', 'Gene', '22926', (252, 256))	('LDB2', 'Gene', '9079', (136, 140))	('MEF2C', 'Gene', '4208', (190, 195))	('SIX1', 'Gene', '6495', (264, 268))	('BMP2', 'Gene', (258, 262))	('CDH5', 'Gene', '1003', (180, 184))	('ENST00000588495.5', 'Var', (161, 178))	('ENST00000552253.1', 'Var', (142, 159))	('ERG', 'Gene', (114, 117))	('SIX1', 'Gene', (264, 268))	('RAB7A', 'Gene', (270, 275))	('ERG', 'Gene', '2078', (114, 117))	('MEF2C', 'Gene', (190, 195))	('ATF6', 'Gene', (252, 256))	('TEK', 'Gene', (109, 112))	('G6PC3', 'Gene', (245, 250))	('CDH5', 'Gene', (180, 184))	('RAB7A', 'Gene', '7879', (270, 275))	('G6PC3', 'Gene', '92579', (245, 250))	('BMP2', 'Gene', '650', (258, 262))	('SOX2', 'Gene', (300, 304))	('SOX2', 'Gene', '6657', (300, 304))	('LDB2', 'Gene', (136, 140))	('TEK', 'Gene', '7010', (109, 112))
127004	33075110	NONHSAT095695.2, ENST00000552253.1, and ENST00000588495.5 primarily regulated LDB2, ENST00000460756.5 primarily regulated ATF6, and ENST00000575695.5 primarily regulated UBQLN1.	('regulated', 'Reg', (160, 169))	('UBQLN1', 'Gene', (170, 176))	('LDB2', 'Gene', '9079', (78, 82))	('LDB2', 'Gene', (78, 82))	('ATF6', 'Gene', (122, 126))	('regulated', 'Reg', (112, 121))	('ATF6', 'Gene', '22926', (122, 126))	('regulated', 'Reg', (68, 77))	('UBQLN1', 'Gene', '29979', (170, 176))	('ENST00000460756.5', 'Var', (84, 101))
127017	33075110	About 10% of Caucasian NSCLC patients and 40-50% of East Asian NSCLC patients exhibit EGFR mutations.	('NSCLC', 'Disease', (63, 68))	('patients', 'Species', '9606', (29, 37))	('NSCLC', 'Phenotype', 'HP:0030358', (23, 28))	('NSCLC', 'Disease', 'MESH:D002289', (63, 68))	('EGFR', 'Gene', '1956', (86, 90))	('EGFR', 'Gene', (86, 90))	('NSCLC', 'Disease', (23, 28))	('mutations', 'Var', (91, 100))	('NSCLC', 'Phenotype', 'HP:0030358', (63, 68))	('NSCLC', 'Disease', 'MESH:D002289', (23, 28))	('patients', 'Species', '9606', (69, 77))
127018	33075110	EGFR tyrosine kinase inhibitors (TKIs) have been shown to offer therapeutic benefit even in patients that do no exhibit such activating EGFR mutations, with a subset of EGFR wild-type patients exhibiting clinical responses to these treatments.	('EGFR', 'Gene', (0, 4))	('mutations', 'Var', (141, 150))	('patients', 'Species', '9606', (184, 192))	('EGFR', 'Gene', '1956', (169, 173))	('therapeutic', 'CPA', (64, 75))	('patients', 'Species', '9606', (92, 100))	('activating', 'PosReg', (125, 135))	('EGFR', 'Gene', (169, 173))	('EGFR', 'Gene', '1956', (136, 140))	('EGFR', 'Gene', '1956', (0, 4))	('EGFR', 'Gene', (136, 140))	('men', 'Species', '9606', (237, 240))
127031	33075110	Women have also been found to exhibit higher rates of EGFR mutations, thus making them more likely to respond to TKI treatment.	('Women', 'Species', '9606', (0, 5))	('more likely', 'PosReg', (87, 98))	('men', 'Species', '9606', (2, 5))	('EGFR', 'Gene', '1956', (54, 58))	('mutations', 'Var', (59, 68))	('respond', 'MPA', (102, 109))	('EGFR', 'Gene', (54, 58))	('men', 'Species', '9606', (122, 125))
127038	33075110	NONHSAT095695.2, ENST00000552253.1 and ENST00000588495.5 regulated LDB2, which inhibits liver cancer cell proliferation and migration via suppressing the expression of HEY1.	('HEY1', 'Gene', '23462', (168, 172))	('liver cancer', 'Disease', (88, 100))	('LDB2', 'Gene', '9079', (67, 71))	('inhibits', 'NegReg', (79, 87))	('LDB2', 'Gene', (67, 71))	('migration', 'CPA', (124, 133))	('HEY1', 'Gene', (168, 172))	('liver cancer', 'Disease', 'MESH:D006528', (88, 100))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('liver cancer', 'Phenotype', 'HP:0002896', (88, 100))	('suppressing', 'NegReg', (138, 149))	('ENST00000588495.5', 'Var', (39, 56))	('expression', 'MPA', (154, 164))
127131	32850421	We revealed that E6-overexpressing C33A cells grew faster and were more sensitive to radiotherapy than control cells in vitro and in vivo.	('grew', 'CPA', (46, 50))	('faster', 'PosReg', (51, 57))	('E6-overexpressing', 'Var', (17, 34))	('E6', 'Chemical', '-', (17, 19))
127142	32850421	The results of five randomized controlled clinical trials conducted by the Radiation Therapy Oncology Group (RTOG), the Gynecological Oncology Group (GOG), and the Southwest Cancer Group (SWOG) demonstrated that CCRT can significantly improve overall survival (OS) and progression-free survival (PFS) in patients with cervical cancer, making CCRT the "gold-standard" treatment for LACC.	('cervical cancer', 'Disease', 'MESH:D002583', (318, 333))	('Cancer', 'Disease', (174, 180))	('patients', 'Species', '9606', (304, 312))	('CCRT', 'Var', (212, 216))	('cervical cancer', 'Disease', (318, 333))	('Cancer', 'Disease', 'MESH:D009369', (174, 180))	('Cancer', 'Phenotype', 'HP:0002664', (174, 180))	('cancer', 'Phenotype', 'HP:0002664', (327, 333))	('progression-free survival', 'CPA', (269, 294))	('Oncology', 'Phenotype', 'HP:0002664', (134, 142))	('Oncology', 'Phenotype', 'HP:0002664', (93, 101))	('overall survival', 'CPA', (243, 259))	('improve', 'PosReg', (235, 242))
127153	32850421	E6 and E7 ORFs can act independently to induce malignant transformation.	('malignant transformation', 'CPA', (47, 71))	('induce', 'Reg', (40, 46))	('E6', 'Chemical', '-', (0, 2))	('E7 ORFs', 'Var', (7, 14))
127173	32850421	The HPV-negative human cervical squamous cell line C33A, which carries p53 mutations, was obtained from the Cell Resource Center, Shanghai Institute of Biochemistry and Cell Biology at the Chinese Academy of Sciences (Shanghai, China).	('HPV', 'Species', '10566', (4, 7))	('human', 'Species', '9606', (17, 22))	('p53', 'Gene', (71, 74))	('p53', 'Gene', '7157', (71, 74))	('mutations', 'Var', (75, 84))
127204	32850421	As shown in Figure 1B, the CCK-8 assay results revealed that the OD450 of C33AE6 cells was greater than that of C33AT cells from 48 h post-seeding onward (P < 0.05), indicating that the overexpression of E6 enhanced C33A cell growth.	('C33AT', 'Mutation', 'c.33C>AT', (112, 117))	('C33A cell growth', 'CPA', (216, 232))	('OD450', 'Enzyme', (65, 70))	('E6', 'Chemical', '-', (78, 80))	('enhanced', 'PosReg', (207, 215))	('greater', 'PosReg', (91, 98))	('E6', 'Chemical', '-', (204, 206))	('C33AE6', 'Var', (74, 80))
127205	32850421	The results of RT-PCR (Figures 1C-E) showed that the expression levels of EGFR, AKT, and ERK 1/2 were significantly higher in C33AE6 cells than in C33AT cells (P < 0.05), indicating that the expression of EGFR and downstream molecules AKT and ERK 1/2 were upregulated by the overexpression of E6.	('upregulated', 'PosReg', (256, 267))	('C33AE6', 'Var', (126, 132))	('C33AT', 'Mutation', 'c.33C>AT', (147, 152))	('E6', 'Chemical', '-', (130, 132))	('higher', 'PosReg', (116, 122))	('AKT', 'Gene', (80, 83))	('ERK', 'Gene', (89, 92))	('expression levels', 'MPA', (53, 70))	('EGFR', 'Gene', (74, 78))	('E6', 'Chemical', '-', (293, 295))
127207	32850421	We conducted several experiments to determine whether EGFR blockade could enhance the irradiation-mediated inhibition of cervical cell growth associated with E6 expression.	('E6', 'Chemical', '-', (158, 160))	('blockade', 'Var', (59, 67))	('inhibition', 'NegReg', (107, 117))	('EGFR', 'Gene', (54, 58))	('enhance', 'PosReg', (74, 81))
127209	32850421	In addition, the OD450 value of C33AE6 cells that received RT+Ni treatment was also significantly lower than that of C33AE6 cells treated with RT alone; this difference was detectable from 72 h post-treatment onward (P < 0.05).	('E6', 'Chemical', '-', (36, 38))	('OD450 value', 'Enzyme', (17, 28))	('E6', 'Chemical', '-', (121, 123))	('lower', 'NegReg', (98, 103))	('RT+Ni', 'Var', (59, 64))	('C33AE6', 'Var', (32, 38))
127211	32850421	As shown in Figures 2A-C, the proportion of RT+Ni-treated C33AE6 cells in the G0/G1 phase was significantly lower than that of untreated cells (P < 0.05).	('lower', 'NegReg', (108, 113))	('RT+Ni-treated', 'Var', (44, 57))	('G0/G1 phase', 'CPA', (78, 89))	('E6', 'Chemical', '-', (62, 64))
127212	32850421	The proportion of G2/M C33AE6 cells in the RT+Ni treatment group was higher than that in the control group, and this difference was statistically significant (P < 0.05).	('E6', 'Chemical', '-', (27, 29))	('RT+Ni', 'Var', (43, 48))	('higher', 'PosReg', (69, 75))	('G2/M C33AE6', 'Var', (18, 29))
127215	32850421	The expression levels of Fas and Caspase 3 in RT+Ni C33AE6 cells were significantly higher than in the RT C33AE6 cells (P < 0.05).	('expression levels', 'MPA', (4, 21))	('Caspase 3', 'Gene', (33, 42))	('Caspase 3', 'Gene', '836', (33, 42))	('RT+Ni C33AE6', 'Var', (46, 58))	('Fas', 'Protein', (25, 28))	('E6', 'Chemical', '-', (56, 58))	('higher', 'PosReg', (84, 90))	('E6', 'Chemical', '-', (110, 112))
127222	32850421	As shown in Figures 5A,B, in nude xenograft mice, the tumor growth of C33AE6 cells was significantly more rapid than that of C33AT cells from 4 days post-injection onward (P < 0.05).	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('E6', 'Chemical', '-', (74, 76))	('C33AE6', 'Var', (70, 76))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('C33AT', 'Mutation', 'c.33C>AT', (125, 130))	('more rapid', 'PosReg', (101, 111))	('tumor', 'Disease', (54, 59))	('mice', 'Species', '10090', (44, 48))
127232	32850421	In support of this assertion, our results also demonstrated that E6-overexpressing C33A cells grew faster and were more sensitive to radiotherapy than control cells, both in vitro and in vivo.	('grew', 'CPA', (94, 98))	('E6-overexpressing', 'Var', (65, 82))	('E6', 'Chemical', '-', (65, 67))	('faster', 'PosReg', (99, 105))	('C33A', 'Gene', (83, 87))
127244	32850421	Collectively, these findings suggest that EGFR inhibitors may improve the efficacy of radiotherapy in cervical cancer.	('inhibitors', 'Var', (47, 57))	('improve', 'PosReg', (62, 69))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('EGFR', 'Gene', (42, 46))	('cervical cancer', 'Disease', (102, 117))	('cervical cancer', 'Disease', 'MESH:D002583', (102, 117))	('efficacy of radiotherapy', 'CPA', (74, 98))
127254	32850421	found that nimotuzumab significantly enhanced apoptosis in A549 cells irradiated with 2 Gy, compared with A549 cells treated with nimotuzumab or irradiation alone.	('apoptosis', 'CPA', (46, 55))	('nimotuzumab', 'Var', (11, 22))	('A549', 'CellLine', 'CVCL:0023', (59, 63))	('nimotuzumab', 'Chemical', 'MESH:C501466', (130, 141))	('nimotuzumab', 'Chemical', 'MESH:C501466', (11, 22))	('enhanced', 'PosReg', (37, 45))	('A549', 'CellLine', 'CVCL:0023', (106, 110))
127255	32850421	Combining nimotuzumab with irradiation also significantly increased the number of cells arrested in the G2/M phase, compared with the use of radiotherapy or nimotuzumab treatment alone.	('increased', 'PosReg', (58, 67))	('arrest', 'Disease', 'MESH:D006323', (88, 94))	('nimotuzumab', 'Var', (10, 21))	('nimotuzumab', 'Chemical', 'MESH:C501466', (157, 168))	('nimotuzumab', 'Chemical', 'MESH:C501466', (10, 21))	('arrest', 'Disease', (88, 94))
127257	32850421	The results showed that the inhibition rate, the percentage of G2/M phase arrest, and the rate of apoptosis were all significantly higher in the group treated with nimotuzumab and radiation, compared with the group treated with radiation alone.	('apoptosis', 'CPA', (98, 107))	('higher', 'PosReg', (131, 137))	('nimotuzumab', 'Chemical', 'MESH:C501466', (164, 175))	('arrest', 'Disease', 'MESH:D006323', (74, 80))	('inhibition', 'NegReg', (28, 38))	('arrest', 'Disease', (74, 80))	('nimotuzumab', 'Var', (164, 175))
127264	32850421	Aberrant EGF-mediated abnormal signaling plays a vital role in increasing the ability of tumor cells to proliferate and migrate during the growth process.	('EGF', 'Gene', (9, 12))	('Aberrant', 'Var', (0, 8))	('EGF', 'Gene', '1950', (9, 12))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('increasing', 'PosReg', (63, 73))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
127275	32850421	In addition, our data also shows that nimotuzumab combined with radiotherapy can increase the radiotherapy sensitivity of p53 mutant C33A cells.	('p53', 'Gene', (122, 125))	('radiotherapy sensitivity', 'CPA', (94, 118))	('nimotuzumab', 'Chemical', 'MESH:C501466', (38, 49))	('increase', 'PosReg', (81, 89))	('mutant', 'Var', (126, 132))	('p53', 'Gene', '7157', (122, 125))
127276	32850421	Therefore, this work broadens our preclinical understanding that EGFR inhibitors can improve radiation anti-tumor and provides an ideal choice for the treatment of p53 mutant cervical squamous cell carcinoma.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (184, 207))	('mutant', 'Var', (168, 174))	('improve', 'PosReg', (85, 92))	('cervical squamous cell carcinoma', 'Disease', (175, 207))	('EGFR', 'Gene', (65, 69))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (198, 207))	('tumor', 'Disease', (108, 113))	('p53', 'Gene', (164, 167))	('cervical squamous cell carcinoma', 'Disease', 'MESH:D002294', (175, 207))	('p53', 'Gene', '7157', (164, 167))
127283	31987067	Moreover, functional experiments revealed that HOXA11-AS knockdown suppressed the proliferation and migration potential in FaDu cells.	('HOXA11-AS', 'Gene', (47, 56))	('knockdown', 'Var', (57, 66))	('migration potential in FaDu cells', 'CPA', (100, 133))	('suppressed', 'NegReg', (67, 77))	('HOXA11-AS', 'Gene', '221883', (47, 56))
127284	31987067	Furthermore, luciferase reporter gene assay combined with cellular functional experiments demonstrated that HOXA11-AS functioned as a molecular sponge for miR-155, and inhibition of miR-155 attenuated the suppressive effect of HOXA11-AS knockdown on the aggressive phenotype in HSCC.	('HSCC', 'Phenotype', 'HP:0012182', (278, 282))	('HOXA11-AS', 'Gene', (227, 236))	('HOXA11-AS', 'Gene', '221883', (108, 117))	('miR-155', 'Gene', (182, 189))	('inhibition', 'Var', (168, 178))	('HSCC', 'Disease', (278, 282))	('HOXA11-AS', 'Gene', '221883', (227, 236))	('attenuated', 'NegReg', (190, 200))	('HOXA11-AS', 'Gene', (108, 117))	('knockdown', 'Var', (237, 246))
127291	31987067	Long noncoding RNAs (lncRNAs) play essential roles in tumor initiation and progression through activating oncogenes or blocking tumor suppressors via different mechanisms, including miRNA decoy, mRNA alternative splicing, epigenetic and posttranslational regulation, and chromatin modification.	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('epigenetic', 'Var', (222, 232))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('oncogenes', 'Gene', (106, 115))	('chromatin modification', 'Var', (271, 293))	('tumor', 'Disease', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('miRNA decoy', 'Var', (182, 193))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('blocking', 'NegReg', (119, 127))	('tumor', 'Disease', (128, 133))	('mRNA alternative splicing', 'Var', (195, 220))	('activating', 'PosReg', (95, 105))
127292	31987067	Moreover, several studies have revealed that lncRNA expression is dysregulated in multiple types of cancers, and some lncRNAs are associated with cancer recurrence and poor prognosis.	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('cancers', 'Phenotype', 'HP:0002664', (100, 107))	('lncRNAs', 'Var', (118, 125))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('lncRNA expression', 'MPA', (45, 62))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('cancers', 'Disease', 'MESH:D009369', (100, 107))	('associated with', 'Reg', (130, 145))	('cancers', 'Disease', (100, 107))
127293	31987067	Our previous work, aiming to study the lncRNAs in HSCC utilizing the Arraystar Human LncRNA Microarray to screen for differentially expressed lncRNAs in three paired HSCC tumor specimens and matched normal controls, identified two novel lncRNAs, AB209630 and AB019562.	('AB209630', 'Var', (246, 254))	('HSCC tumor', 'Disease', (166, 176))	('Human', 'Species', '9606', (79, 84))	('AB019562', 'Var', (259, 267))	('HSCC', 'Phenotype', 'HP:0012182', (166, 170))	('HSCC tumor', 'Disease', 'MESH:D009369', (166, 176))	('HSCC', 'Phenotype', 'HP:0012182', (50, 54))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))
127313	31987067	The plasmids with the HOXA11-AS sequence containing the predicted miR-155 binding site or the mutant miR-155 binding site were generated using the dual-luciferase miRNA Target Expression vector pmirGlo kit (Promega, Madison WI, USA).	('HOXA11-AS', 'Gene', (22, 31))	('mutant', 'Var', (94, 100))	('miR-155', 'Gene', (66, 73))	('miR-155', 'Gene', (101, 108))	('HOXA11-AS', 'Gene', '221883', (22, 31))
127333	31987067	Cell proliferation assay revealed that knockdown of HOXA11-AS remarkably inhibited cell proliferation in FaDu cells (p < 0.0001) (Fig.	('knockdown', 'Var', (39, 48))	('HOXA11-AS', 'Gene', (52, 61))	('cell proliferation in FaDu cells', 'CPA', (83, 115))	('HOXA11-AS', 'Gene', '221883', (52, 61))	('inhibited', 'NegReg', (73, 82))
127340	31987067	Interestingly, the tumor suppressor miR-155 was found to be a potential target of HOXA11-AS by DIANA-LncBase v2, as well as the GSEA (see Supplemental Fig.	('HOXA11-AS', 'Gene', (82, 91))	('GSEA', 'Chemical', '-', (128, 132))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('tumor', 'Disease', (19, 24))	('DIANA-LncBase', 'Var', (95, 108))	('HOXA11-AS', 'Gene', '221883', (82, 91))
127344	31987067	The suppressive effect on cell proliferation of HOXA11-AS knockdown was reversed by adding inhibitor miR-155 (p < 0.0001) (Fig.	('HOXA11-AS', 'Gene', (48, 57))	('cell proliferation', 'CPA', (26, 44))	('knockdown', 'Var', (58, 67))	('HOXA11-AS', 'Gene', '221883', (48, 57))
127345	31987067	3D), and the suppressive effect on cell migration of HOXA11-AS knockdown was attenuated by adding inhibitor miR-155 (p < 0.0001) (Fig.	('cell migration', 'CPA', (35, 49))	('miR-155', 'Gene', (108, 115))	('knockdown', 'Var', (63, 72))	('attenuated', 'NegReg', (77, 87))	('HOXA11-AS', 'Gene', (53, 62))	('HOXA11-AS', 'Gene', '221883', (53, 62))
127350	31987067	As a preliminary screening effort, our group performed global profiling of human lncRNAs in three paired HSCC tumor specimens and the matched normal controls using the Arraystar Human LncRNA Microarray, and identified two novel lncRNAs, AB019562 and AB209630, which were subsequently proven to play critical roles in HSCC cell proliferation and invasion.	('AB019562', 'Var', (237, 245))	('human', 'Species', '9606', (75, 80))	('Human', 'Species', '9606', (178, 183))	('AB209630', 'Var', (250, 258))	('HSCC', 'Phenotype', 'HP:0012182', (317, 321))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('HSCC tumor', 'Disease', (105, 115))	('HSCC', 'Phenotype', 'HP:0012182', (105, 109))	('HSCC', 'Disease', (317, 321))	('HSCC tumor', 'Disease', 'MESH:D009369', (105, 115))
127353	31987067	The expression of HOXA11-AS was found to be significantly upregulated in HSCC tumor specimens compared with the adjacent normal tissues, and the high expression of HOXA11-AS was significantly associated with lymph node metastasis of HSCC.	('HSCC', 'Phenotype', 'HP:0012182', (233, 237))	('associated with', 'Reg', (192, 207))	('HSCC tumor', 'Disease', (73, 83))	('HSCC', 'Phenotype', 'HP:0012182', (73, 77))	('HOXA11-AS', 'Gene', (164, 173))	('lymph node metastasis', 'CPA', (208, 229))	('HOXA11-AS', 'Gene', '221883', (164, 173))	('expression', 'MPA', (4, 14))	('upregulated', 'PosReg', (58, 69))	('HOXA11-AS', 'Gene', (18, 27))	('HSCC', 'Disease', (233, 237))	('HOXA11-AS', 'Gene', '221883', (18, 27))	('HSCC tumor', 'Disease', 'MESH:D009369', (73, 83))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('high', 'Var', (145, 149))
127360	31987067	demonstrated that HOXA11-AS knockdown impairs the aggressive capacities in vitro and in vivo and induces the G0/G1 arrest of cell cycle via regulating beta-catenin and KLF2 in gastric cancer cells.	('KLF2', 'Gene', (168, 172))	('regulating', 'Reg', (140, 150))	('beta-catenin', 'Gene', '1499', (151, 163))	('G0/G1 arrest of cell cycle', 'CPA', (109, 135))	('induces', 'Reg', (97, 104))	('HOXA11-AS', 'Gene', (18, 27))	('gastric cancer', 'Phenotype', 'HP:0012126', (176, 190))	('HOXA11-AS', 'Gene', '221883', (18, 27))	('impairs', 'NegReg', (38, 45))	('gastric cancer', 'Disease', (176, 190))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('aggressive capacities', 'CPA', (50, 71))	('knockdown', 'Var', (28, 37))	('gastric cancer', 'Disease', 'MESH:D013274', (176, 190))	('KLF2', 'Gene', '10365', (168, 172))	('beta-catenin', 'Gene', (151, 163))
127362	31987067	Our data also revealed that knockdown of HOXA11-AS suppressed the proliferation and migration potential in HSCC FaDu cells, which supported the abovementioned findings that high expression of HOXA11-AS was associated with lymph node metastasis in HSCC patients.	('HSCC', 'Phenotype', 'HP:0012182', (107, 111))	('HSCC FaDu', 'CellLine', 'CVCL:1218', (107, 116))	('HOXA11-AS', 'Gene', (192, 201))	('HSCC', 'Disease', (247, 251))	('proliferation', 'CPA', (66, 79))	('HOXA11-AS', 'Gene', '221883', (192, 201))	('associated with', 'Reg', (206, 221))	('HOXA11-AS', 'Gene', (41, 50))	('patients', 'Species', '9606', (252, 260))	('HOXA11-AS', 'Gene', '221883', (41, 50))	('suppressed', 'NegReg', (51, 61))	('lymph node metastasis', 'CPA', (222, 243))	('knockdown', 'Var', (28, 37))	('HSCC', 'Phenotype', 'HP:0012182', (247, 251))
127398	27728803	The higher molecular complexity and the absence of predominant actionable driver alterations have hampered the development of preclinical models that mimic human LSCC at both genotype and phenotype levels.	('SCC', 'Gene', (163, 166))	('men', 'Species', '9606', (118, 121))	('SCC', 'Phenotype', 'HP:0002860', (163, 166))	('alterations', 'Var', (81, 92))	('LSCC', 'Phenotype', 'HP:0030359', (162, 166))	('SCC', 'Gene', '6317', (163, 166))	('human', 'Species', '9606', (156, 161))	('hampered', 'NegReg', (98, 106))
127399	27728803	Single oncogenic alterations introduced in the mouse failed to drive the development of LSCC while mostly promoting LADC.	('LSCC', 'Phenotype', 'HP:0030359', (88, 92))	('SCC', 'Gene', '6317', (89, 92))	('mouse', 'Species', '10090', (47, 52))	('LADC', 'MPA', (116, 120))	('men', 'Species', '9606', (80, 83))	('promoting', 'PosReg', (106, 115))	('alterations', 'Var', (17, 28))	('SCC', 'Gene', (89, 92))	('SCC', 'Phenotype', 'HP:0002860', (89, 92))
127400	27728803	The first model of LSCC morphologically resembling the human counterpart is based on the deregulation of IKKalpha, a protein kinase, whose reduced activity was already associated with SCC development in skin and oral cavity but rarely in lung.	('LSCC', 'Phenotype', 'HP:0030359', (19, 23))	('associated', 'Reg', (168, 178))	('SCC', 'Gene', (20, 23))	('deregulation', 'Var', (89, 101))	('SCC', 'Phenotype', 'HP:0002860', (20, 23))	('IKKalpha', 'Gene', (105, 113))	('men', 'Species', '9606', (195, 198))	('human', 'Species', '9606', (55, 60))	('SCC', 'Gene', '6317', (20, 23))	('SCC', 'Gene', (184, 187))	('reduced', 'NegReg', (139, 146))	('SCC', 'Phenotype', 'HP:0002860', (184, 187))	('SCC', 'Gene', '6317', (184, 187))	('activity', 'MPA', (147, 155))
127401	27728803	A dominant negative mutant form of IKKalpha causes SCC in a variety of tissues but at a very low frequency in lung.	('causes', 'Reg', (44, 50))	('SCC', 'Gene', (51, 54))	('SCC', 'Phenotype', 'HP:0002860', (51, 54))	('negative', 'NegReg', (11, 19))	('SCC', 'Gene', '6317', (51, 54))	('IKKalpha', 'Gene', (35, 43))	('mutant', 'Var', (20, 26))
127404	27728803	In one model, which combines Lkb1 and Pten deletion, mice develop LSCC morphologically resembling the human counterpart with a latency of 40-50 weeks.	('Lkb1', 'Gene', (29, 33))	('deletion', 'Var', (43, 51))	('SCC', 'Gene', (67, 70))	('SCC', 'Phenotype', 'HP:0002860', (67, 70))	('Pten', 'Gene', (38, 42))	('LSCC', 'Phenotype', 'HP:0030359', (66, 70))	('SCC', 'Gene', '6317', (67, 70))	('mice', 'Species', '10090', (53, 57))	('human', 'Species', '9606', (102, 107))
127406	27728803	Although the combination of genetic alterations is critical for the tumor phenotype, increasing evidence also points to the cell of origin as an important factor in determining tumor characteristics.	('tumor', 'Disease', (68, 73))	('genetic alterations', 'Var', (28, 47))	('alterations', 'Var', (36, 47))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('tumor', 'Disease', (177, 182))
127412	27728803	Their expression profile (p63, K5) and their stem cell properties make them a likely candidate for the cell of origin of LSCC.	('SCC', 'Gene', (122, 125))	('SCC', 'Phenotype', 'HP:0002860', (122, 125))	('SCC', 'Gene', '6317', (122, 125))	('p63', 'Var', (26, 29))	('LSCC', 'Phenotype', 'HP:0030359', (121, 125))
127420	27728803	Both Ad5-K14-Cre and Ad5-K5-Cre efficiently delivered and activated Cre-recombinase expression in keratinocytes, as indicated by GFP expression (Figure S1A), but not in MEFs (Figure S1B).	('K14', 'Gene', '16664', (9, 12))	('Ad5-K5-Cre', 'Var', (21, 31))	('K14', 'Gene', (9, 12))	('activated', 'PosReg', (58, 67))	('Cre-recombinase expression', 'Protein', (68, 94))	('MEFs', 'CellLine', 'CVCL:9115', (169, 173))
127422	27728803	To validate the specificity of adenovirus promoter targeting in vivo, we intratracheally injected mT/mG mice with a high titer of either Ad5-K14-Cre or Ad5-K5-Cre, and performed GFP staining on trachea and lungs collected 3 weeks after infection to identify switched cells.	('mice', 'Species', '10090', (104, 108))	('K14', 'Gene', (141, 144))	('Ad5-K5-Cre', 'Var', (152, 162))	('K14', 'Gene', '16664', (141, 144))
127425	27728803	In stark contrast, however, Ad5-CMV-Cre, Ad5-K14, and Ad5-K5-Cre showed a high level of infection of basal cells when injected following naphthalene administration (Figure 1A).	('Ad5-K5-Cre', 'Var', (54, 64))	('K14', 'Gene', (45, 48))	('infection', 'MPA', (88, 97))	('K14', 'Gene', '16664', (45, 48))	('naphthalene', 'Chemical', 'MESH:C031721', (137, 148))
127426	27728803	In the lung, Cre-recombinase-mediated switching occurred in the alveolar compartment of mice intratracheally injected with Ad5-CMV-Cre, regardless whether they were pretreated with naphthalene or corn oil (Figure 1B).	('naphthalene', 'Chemical', 'MESH:C031721', (181, 192))	('occurred', 'Reg', (48, 56))	('men', 'Species', '9606', (80, 83))	('corn', 'Species', '4577', (196, 200))	('Ad5-CMV-Cre', 'Var', (123, 134))	('mice', 'Species', '10090', (88, 92))
127428	27728803	To demonstrate that GFP was specifically expressed by basal cells, we performed dual immunofluorescence (IF) staining for GFP and K14, K5, or CC10 on tracheal sections collected at 7 days after intratracheal injection of either Ad5-K14-Cre or Ad5-K5-Cre in mice previously treated with naphthalene (Figure S1D).	('Ad5-K5-Cre', 'Var', (243, 253))	('mice', 'Species', '10090', (257, 261))	('K14', 'Gene', '16664', (232, 235))	('K14', 'Gene', (232, 235))	('naphthalene', 'Chemical', 'MESH:C031721', (286, 297))	('K14', 'Gene', '16664', (130, 133))	('K14', 'Gene', (130, 133))
127433	27728803	Taken together, our data indicate that Ad5-K14-Cre and Ad5-K5-Cre efficiently and specifically target tracheobronchial basal cells following naphthalene treatment.	('naphthalene', 'Chemical', 'MESH:C031721', (141, 152))	('target', 'Reg', (95, 101))	('K14', 'Gene', '16664', (43, 46))	('Ad5-K5-Cre', 'Var', (55, 65))	('K14', 'Gene', (43, 46))	('men', 'Species', '9606', (158, 161))
127434	27728803	To recapitulate the genomic complexity of LSCC, we developed a mouse model of LSCC based on the deregulation of multiple pathways involved in LSCC initiation and progression.	('SCC', 'Gene', (143, 146))	('deregulation', 'Var', (96, 108))	('mouse', 'Species', '10090', (63, 68))	('SCC', 'Phenotype', 'HP:0002860', (143, 146))	('SCC', 'Gene', '6317', (43, 46))	('SCC', 'Gene', (79, 82))	('SCC', 'Gene', '6317', (143, 146))	('LSCC', 'Phenotype', 'HP:0030359', (78, 82))	('SCC', 'Phenotype', 'HP:0002860', (79, 82))	('SCC', 'Gene', '6317', (79, 82))	('LSCC', 'Phenotype', 'HP:0030359', (42, 46))	('SCC', 'Gene', (43, 46))	('SCC', 'Phenotype', 'HP:0002860', (43, 46))	('LSCC', 'Phenotype', 'HP:0030359', (142, 146))
127435	27728803	We generated compound conditional mutant mice for: (1) overexpression of SOX2, a transcription factor involved in squamous differentiation by suppressing the Notch pathway and whose gene is one of the most frequently amplified in SCC; (2) overexpression of FGFR1, a tyrosine kinase receptor overexpressed in 27% of LSCC cases and as such a possible therapeutic target; (3) deletion of PTEN, which encodes a phosphatase that antagonizes the PI3K signaling pathway and found to be altered in 24% of LSCC cases; and (4) deletion of the CDKN2AB locus that encodes for p16INK4A, p15INK4B, and p14ARF, three cell-cycle inhibitors with a well-established tumor-suppressor function and inactivated in 72% of LSCC cases.	('tumor', 'Disease', 'MESH:D009369', (648, 653))	('SCC', 'Gene', '6317', (701, 704))	('SCC', 'Gene', (498, 501))	('deletion', 'Var', (517, 525))	('deletion', 'Var', (373, 381))	('p16INK4A', 'Gene', (564, 572))	('PTEN', 'Gene', (385, 389))	('SCC', 'Gene', (701, 704))	('p15INK4B', 'Gene', (574, 582))	('SCC', 'Phenotype', 'HP:0002860', (316, 319))	('SCC', 'Phenotype', 'HP:0002860', (230, 233))	('tumor', 'Phenotype', 'HP:0002664', (648, 653))	('p15INK4B', 'Gene', '12579', (574, 582))	('p16INK4A', 'Gene', '12578', (564, 572))	('LSCC', 'Phenotype', 'HP:0030359', (497, 501))	('mice', 'Species', '10090', (41, 45))	('LSCC', 'Phenotype', 'HP:0030359', (315, 319))	('PI3K signaling pathway', 'Pathway', (440, 462))	('SCC', 'Gene', '6317', (230, 233))	('CDKN2AB', 'Gene', (533, 540))	('SCC', 'Gene', '6317', (316, 319))	('SCC', 'Phenotype', 'HP:0002860', (498, 501))	('SCC', 'Gene', (230, 233))	('SCC', 'Phenotype', 'HP:0002860', (701, 704))	('SCC', 'Gene', (316, 319))	('LSCC', 'Phenotype', 'HP:0030359', (700, 704))	('tumor', 'Disease', (648, 653))	('SCC', 'Gene', '6317', (498, 501))
127438	27728803	These genetic alterations collectively cover a large fraction of the human cases (Figure 2A).	('cover', 'Reg', (39, 44))	('human', 'Species', '9606', (69, 74))	('genetic alterations', 'Var', (6, 25))
127440	27728803	Therefore, we generated mice carrying the combined conditional deletions of Pten and Cdkn2ab (hereafter PC mice).	('Cdkn2', 'Gene', (85, 90))	('mice', 'Species', '10090', (24, 28))	('deletions', 'Var', (63, 72))	('mice', 'Species', '10090', (107, 111))	('Cdkn2', 'Gene', '1029', (85, 90))	('Pten', 'Gene', (76, 80))
127442	27728803	To determine whether their inactivation in basal cells is sufficient to induce LSCC, we intratracheally injected 6- to 8-week-old PC mice with either Ad5-K14-Cre or Ad5-K5-Cre following naphthalene treatment (Figure 2B).	('SCC', 'Gene', '6317', (80, 83))	('SCC', 'Phenotype', 'HP:0002860', (80, 83))	('mice', 'Species', '10090', (133, 137))	('men', 'Species', '9606', (203, 206))	('naphthalene', 'Chemical', 'MESH:C031721', (186, 197))	('Ad5-K5-Cre', 'Var', (165, 175))	('K14', 'Gene', '16664', (154, 157))	('SCC', 'Gene', (80, 83))	('K14', 'Gene', (154, 157))	('LSCC', 'Phenotype', 'HP:0030359', (79, 83))
127449	27728803	Taken together, these data demonstrated that tracheobronchial basal cells can be efficiently transformed by loss of Pten and Cdkn2ab, giving rise to a variety of tumors.	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('loss', 'Var', (108, 112))	('Cdkn2', 'Gene', '1029', (125, 130))	('Pten', 'Gene', (116, 120))	('Cdkn2', 'Gene', (125, 130))	('giving rise to', 'Reg', (134, 148))	('tumors', 'Disease', (162, 168))	('tumors', 'Disease', 'MESH:D009369', (162, 168))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))
127450	27728803	To directly test the consequences of overexpressing fibroblast growth factor receptor 1 (FGFR1) in vivo, we targeted a bicistronic cDNA cassette containing a mutant active form of FGFR1 (K656E) and the YFP to the Col1a1 locus (Figure S2A).	('Col1a1', 'Gene', (213, 219))	('fibroblast growth factor receptor 1', 'Gene', '14182', (52, 87))	('K656E', 'Var', (187, 192))	('Col1a1', 'Gene', '12842', (213, 219))	('FGFR1', 'Gene', (180, 185))	('fibroblast growth factor receptor 1', 'Gene', (52, 87))	('K656E', 'Mutation', 'rs869320694', (187, 192))
127453	27728803	Fgfr1PC mice pretreated with naphthalene and intratracheally injected with either Ad5-K14-Cre or Ad5-K5-Cre developed tumors with a latency of 1.5-6.5 months and a frequency of 76% (16/21; Table S1).	('K14', 'Gene', (86, 89))	('developed', 'PosReg', (108, 117))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('naphthalene', 'Chemical', 'MESH:C031721', (29, 40))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('tumors', 'Disease', (118, 124))	('K14', 'Gene', '16664', (86, 89))	('Ad5-K5-Cre', 'Var', (97, 107))	('mice', 'Species', '10090', (8, 12))	('tumors', 'Disease', 'MESH:D009369', (118, 124))
127459	27728803	Successful targeting of ESCs and expression of LSL-Sox2 allele in vivo are described in Supplemental Experimental Procedures and Figures S2B, S2C, and S2E.	('S2B', 'Var', (137, 140))	('ESCs', 'Gene', (24, 28))	('men', 'Species', '9606', (94, 97))	('men', 'Species', '9606', (107, 110))
127469	27728803	All human cases showed positive IHC for p63 but were negative for TTF-1, a marker used to distinguish LSCC from LADC (Figure 4E and Table S2).	('positive', 'Reg', (23, 31))	('human', 'Species', '9606', (4, 9))	('SCC', 'Gene', (103, 106))	('LSCC', 'Phenotype', 'HP:0030359', (102, 106))	('p63', 'Var', (40, 43))	('SCC', 'Phenotype', 'HP:0002860', (103, 106))	('SCC', 'Gene', '6317', (103, 106))
127474	27728803	They were positive for GFP, SOX2, K5, and to a lesser extent p63, indicative of the early commitment toward squamous differentiation (Figure S3B).	('GFP', 'Gene', (23, 26))	('men', 'Species', '9606', (96, 99))	('SOX2', 'Gene', (28, 32))	('positive', 'Reg', (10, 18))	('S3B', 'Gene', '11778', (141, 144))	('p63', 'Var', (61, 64))	('S3B', 'Gene', (141, 144))
127486	27728803	In parallel, the gene expression profiles of 18 human LSCC with SOX2 amplification and CDKN2AB deletion, with or without PTEN deletion from the TCGA dataset, were compared with 17 human primary LADC (Table S3) to generate a list of genotype-specific LSCC genes.	('deletion', 'Var', (95, 103))	('LSCC', 'Phenotype', 'HP:0030359', (54, 58))	('SCC', 'Gene', '6317', (251, 254))	('SCC', 'Gene', (55, 58))	('human', 'Species', '9606', (48, 53))	('human', 'Species', '9606', (180, 185))	('LSCC', 'Phenotype', 'HP:0030359', (250, 254))	('SCC', 'Phenotype', 'HP:0002860', (55, 58))	('SCC', 'Phenotype', 'HP:0002860', (251, 254))	('CDKN2AB', 'Gene', (87, 94))	('SCC', 'Gene', '6317', (55, 58))	('SCC', 'Gene', (251, 254))
127495	27728803	Other p63 direct targets such as Fgfr2 and Irf6, with an important role in the homeostasis of squamous epithelia but deregulated in the presence of p63 mutations, were also upregulated (Figure 5D).	('squamous epithelia', 'Phenotype', 'HP:0002860', (94, 112))	('mutations', 'Var', (152, 161))	('Fgfr2', 'Gene', (33, 38))	('homeostasis of squamous epithelia', 'Disease', 'MESH:D002294', (79, 112))	('Irf6', 'Gene', '54139', (43, 47))	('Fgfr2', 'Gene', '14183', (33, 38))	('p63', 'Gene', (148, 151))	('Irf6', 'Gene', (43, 47))	('homeostasis of squamous epithelia', 'Disease', (79, 112))	('upregulated', 'PosReg', (173, 184))
127506	27728803	Surprisingly the squamous lesions of Fgfr1PC mice were also negative for LY6G and MPO (Figure 6A), in favor of a role for SOX2 in the activation of TANs.	('negative', 'NegReg', (60, 68))	('mice', 'Species', '10090', (45, 49))	('MPO', 'Gene', '17523', (82, 85))	('LY6G', 'Gene', '546644', (73, 77))	('LY6G', 'Gene', (73, 77))	('Fgfr1PC', 'Var', (37, 44))	('MPO', 'Gene', (82, 85))
127517	27728803	We injected 6- to 8-week-old Sox2PC mice intratracheally with either Ad5-CC10-Cre or Ad5-SPC-Cre.	('SPC', 'Gene', (89, 92))	('Ad5-CC10-Cre', 'Var', (69, 81))	('SPC', 'Gene', '6440', (89, 92))	('mice', 'Species', '10090', (36, 40))
127519	27728803	Histologically, these tumors showed the hallmarks of LSCC differentiation such as keratin pearls, cornification, necrosis, and inflammation (Figure S5A) and were positive for SOX2, p63, and K5 and negative for TTF-1 (Figure S5B and Table S2).	('keratin pearls', 'Protein', (82, 96))	('S5B', 'Gene', (224, 227))	('corn', 'Species', '4577', (98, 102))	('positive', 'Reg', (162, 170))	('SOX2', 'Protein', (175, 179))	('tumors', 'Phenotype', 'HP:0002664', (22, 28))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('cornification', 'CPA', (98, 111))	('SCC', 'Phenotype', 'HP:0002860', (54, 57))	('tumors', 'Disease', (22, 28))	('LSCC', 'Phenotype', 'HP:0030359', (53, 57))	('inflammation', 'Disease', 'MESH:D007249', (127, 139))	('p63', 'Var', (181, 184))	('tumors', 'Disease', 'MESH:D009369', (22, 28))	('necrosis', 'Disease', 'MESH:D009336', (113, 121))	('SCC', 'Gene', '6317', (54, 57))	('S5B', 'Gene', '66998', (224, 227))	('necrosis', 'Disease', (113, 121))	('inflammation', 'Disease', (127, 139))	('SCC', 'Gene', (54, 57))
127520	27728803	The number of carcinomas versus early lesions was substantially higher in Ad5-CC10-Cre-injected mice compared with Ad5-SPC-Cre (Figure 7A).	('SPC', 'Gene', '6440', (119, 122))	('mice', 'Species', '10090', (96, 100))	('carcinomas', 'Phenotype', 'HP:0030731', (14, 24))	('higher', 'PosReg', (64, 70))	('carcinomas versus early lesions', 'Disease', (14, 45))	('Ad5-CC10-Cre-injected', 'Var', (74, 95))	('SPC', 'Gene', (119, 122))	('carcinomas versus early lesions', 'Disease', 'MESH:D006086', (14, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (14, 23))
127524	27728803	Early lesions of either injection in mice strongly retained CC10 expression, as showed by GFP-CC10 dual IF (Figure 7D) and, in the case of Ad5-SPC-Cre-injected mice, lost the expression of SPC while progressing, as indicated by SPC-CC10 dual IF (Figure 7D and Table S5).	('expression', 'MPA', (175, 185))	('GFP-CC10', 'Var', (90, 98))	('SPC', 'Gene', (228, 231))	('CC10', 'Gene', (60, 64))	('SPC', 'Gene', '6440', (143, 146))	('SPC', 'Gene', '6440', (189, 192))	('expression', 'MPA', (65, 75))	('mice', 'Species', '10090', (160, 164))	('lost', 'NegReg', (166, 170))	('SPC', 'Gene', (143, 146))	('SPC', 'Gene', '6440', (228, 231))	('SPC', 'Gene', (189, 192))	('mice', 'Species', '10090', (37, 41))
127527	27728803	Taken together, our data indicate that SOX2 overexpression in combination with Pten and Cdkn2ab deletion is able to drive AT2 and Club cells toward LSCC.	('Club', 'Phenotype', 'HP:0001217', (130, 134))	('SCC', 'Gene', (149, 152))	('drive', 'PosReg', (116, 121))	('SCC', 'Phenotype', 'HP:0002860', (149, 152))	('SCC', 'Gene', '6317', (149, 152))	('deletion', 'Var', (96, 104))	('Cdkn2', 'Gene', '1029', (88, 93))	('Pten', 'Gene', (79, 83))	('Cdkn2', 'Gene', (88, 93))	('LSCC', 'Phenotype', 'HP:0030359', (148, 152))
127530	27728803	The tumor-free survivals of Sox2PC mice injected with Ad5-K14-Cre, Ad5-SPC-Cre, or Ad5-CC10-Cre are comparable, ranging between 7 and 9 months.	('tumor', 'Disease', (4, 9))	('SPC', 'Gene', '6440', (71, 74))	('Ad5-CC10-Cre', 'Var', (83, 95))	('SPC', 'Gene', (71, 74))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('mice', 'Species', '10090', (35, 39))	('K14', 'Gene', '16664', (58, 61))	('K14', 'Gene', (58, 61))
127531	27728803	In our model, Pten and Cdkn2ab deletion provides basal cells with the capability to transform in multiple heterogeneous lesions.	('Cdkn2', 'Gene', (23, 28))	('deletion', 'Var', (31, 39))	('Cdkn2', 'Gene', '1029', (23, 28))	('Pten', 'Gene', (14, 18))
127533	27728803	Early lesions arise in bronchi and bronchioles when Sox2PC mice are injected with Ad5-K14-Cre; bronchioles, BADJ, and, to a lesser extent, alveolar space when they are injected with Ad5-CC10-Cre, and BADJ and alveolar space when injected with Ad-SPC-Cre (upper panel, Figure 8C).	('K14', 'Gene', (86, 89))	('mice', 'Species', '10090', (59, 63))	('Ad5-CC10-Cre', 'Var', (182, 194))	('SPC', 'Gene', (246, 249))	('SPC', 'Gene', '6440', (246, 249))	('K14', 'Gene', '16664', (86, 89))
127541	27728803	Genome-wide transcriptional profiles of tumors from Sox2PC and Kras;p53+-Eed mice revealed the differential regulation of gene categories that typify human LSCC over LADC, indicating that SOX2 imposes squamous differentiation most likely by activating a p63-mediated transcriptional epithelial program.	('SCC', 'Gene', (157, 160))	('Kras;p53+-Eed', 'Gene', '13626', (63, 76))	('mice', 'Species', '10090', (77, 81))	('human', 'Species', '9606', (150, 155))	('SCC', 'Phenotype', 'HP:0002860', (157, 160))	('epithelia', 'Disease', 'None', (283, 292))	('epithelia', 'Disease', (283, 292))	('Kras;p53+-Eed', 'Gene', (63, 76))	('tumors', 'Disease', 'MESH:D009369', (40, 46))	('SCC', 'Gene', '6317', (157, 160))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('SOX2', 'Var', (188, 192))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('imposes', 'Reg', (193, 200))	('squamous differentiation', 'CPA', (201, 225))	('LSCC', 'Phenotype', 'HP:0030359', (156, 160))	('tumors', 'Disease', (40, 46))
127544	27728803	Nevertheless, loss of Pten and Cdkn2ab gave rise to a variety of tumors including sarcomas, osteomas, and histiocytic lesions.	('loss', 'Var', (14, 18))	('osteomas', 'Disease', (92, 100))	('Cdkn2', 'Gene', (31, 36))	('Cdkn2', 'Gene', '1029', (31, 36))	('histiocytic lesions', 'Disease', (106, 125))	('Pten', 'Gene', (22, 26))	('osteomas', 'Phenotype', 'HP:0100246', (92, 100))	('tumors', 'Disease', (65, 71))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('sarcoma', 'Phenotype', 'HP:0100242', (82, 89))	('sarcomas', 'Disease', 'MESH:D012509', (82, 90))	('sarcomas', 'Phenotype', 'HP:0100242', (82, 90))	('osteomas', 'Disease', 'MESH:D010016', (92, 100))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('sarcomas', 'Disease', (82, 90))
127547	27728803	The genotype including Cdkn2ab deletion might play an important role in this high plasticity, which becomes restricted to SCC only by forced SOX2 expression.	('SCC', 'Gene', (122, 125))	('SCC', 'Phenotype', 'HP:0002860', (122, 125))	('SCC', 'Gene', '6317', (122, 125))	('deletion', 'Var', (31, 39))	('Cdkn2', 'Gene', '1029', (23, 28))	('Cdkn2', 'Gene', (23, 28))
127552	27728803	It will be interesting to assess in future experiments whether the combination of FGFR1 and SOX2 results in exclusive LSCC with a much shorter latency period than observed with SOX2.	('men', 'Species', '9606', (49, 52))	('FGFR1', 'Gene', (82, 87))	('SCC', 'Gene', '6317', (119, 122))	('LSCC', 'Phenotype', 'HP:0030359', (118, 122))	('SOX2', 'Gene', (92, 96))	('combination', 'Var', (67, 78))	('SCC', 'Gene', (119, 122))	('SCC', 'Phenotype', 'HP:0002860', (119, 122))
127554	27728803	The most remarkable feature of LSCC is the amplification on chromosome 3q26 where both SOX2 and TP63 lie.	('TP63', 'Gene', '22061', (96, 100))	('amplification', 'Var', (43, 56))	('SCC', 'Gene', (32, 35))	('SCC', 'Phenotype', 'HP:0002860', (32, 35))	('LSCC', 'Phenotype', 'HP:0030359', (31, 35))	('TP63', 'Gene', (96, 100))	('SCC', 'Gene', '6317', (32, 35))
127573	27728803	These results indicate that the context of SOX2 overexpression with other cooperating mutations is decisive in driving these different cell types toward LSCC transformation.	('mutations', 'Var', (86, 95))	('SCC', 'Gene', '6317', (154, 157))	('LSCC', 'Phenotype', 'HP:0030359', (153, 157))	('SCC', 'Gene', (154, 157))	('SCC', 'Phenotype', 'HP:0002860', (154, 157))
127583	27728803	Since this mouse model is based on the mutations frequently found in human LSCC, it is likely that identical or, at least, very similar signaling pathways are involved.	('mouse', 'Species', '10090', (11, 16))	('LSCC', 'Phenotype', 'HP:0030359', (75, 79))	('SCC', 'Gene', (76, 79))	('human', 'Species', '9606', (69, 74))	('mutations', 'Var', (39, 48))	('SCC', 'Phenotype', 'HP:0002860', (76, 79))	('SCC', 'Gene', '6317', (76, 79))
127584	27728803	Furthermore, the set of mutations we used can impose both peripheral and central LSCC, dependent on the cell types targeted.	('SCC', 'Phenotype', 'HP:0002860', (82, 85))	('SCC', 'Gene', '6317', (82, 85))	('LSCC', 'Phenotype', 'HP:0030359', (81, 85))	('impose', 'Reg', (46, 52))	('mutations', 'Var', (24, 33))	('SCC', 'Gene', (82, 85))	('peripheral', 'Disease', (58, 68))
127597	27728803	On the fourth day they were intratracheally injected with 20 muL of 1 x 1010 pfu/mL purified Ad5-K14-Cre or Ad5-K5-Cre viruses (see Supplemental Experimental Procedures for details).	('men', 'Species', '9606', (151, 154))	('K14', 'Gene', '16664', (97, 100))	('K14', 'Gene', (97, 100))	('men', 'Species', '9606', (138, 141))	('Ad5-K5-Cre', 'Var', (108, 118))
127598	27728803	Mice injected with either Ad5-SPC-Cre or Ad5-CC10-Cre were only treated with cyclosporine A 1 week prior to and 2-3 weeks following adenovirus injection.	('cyclosporine A', 'Chemical', 'MESH:D016572', (77, 91))	('SPC', 'Gene', '6440', (30, 33))	('Ad5-CC10-Cre', 'Var', (41, 53))	('SPC', 'Gene', (30, 33))	('Mice', 'Species', '10090', (0, 4))
127626	26943773	Whole exome sequencing of our cohort identified a total 7,781 somatic mutations, and 79 somatic insertions and deletions events among 21 NS-LSCC and 16 S-LSCC tumor/normal pairs in coding regions.	('events', 'Reg', (121, 127))	('mutations', 'Var', (70, 79))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('insertions', 'Var', (96, 106))	('tumor', 'Disease', (159, 164))	('LSCC', 'Phenotype', 'HP:0030359', (154, 158))	('LSCC', 'Phenotype', 'HP:0030359', (140, 144))	('NS-LSCC', 'Disease', (137, 144))	('deletions', 'Var', (111, 120))	('tumor', 'Disease', 'MESH:D009369', (159, 164))
127628	26943773	The main reason for lower mutation rate in our study is that 21 out of 37 patients are never smokers in our cohort, and mutations in NS-LSCC are rarer.	('patients', 'Species', '9606', (74, 82))	('NS-LSCC', 'Gene', (133, 140))	('mutations', 'Var', (120, 129))	('LSCC', 'Phenotype', 'HP:0030359', (136, 140))
127630	26943773	We identified 17 highly recurrent mutated genes in both S-LSCC and NS-LSCC, including seven well-known LSCC genes (TP53, ARID1A, NFE2L2, DDR2, KEAP1, PIK3CA, CDKN2A), one tumor-associated gene (USH2A) that has not previously been described in LSCC, and two genes (DNAH5 and CCDC168) that have not been linked to LSCC previously.	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('DDR2', 'Gene', (137, 141))	('ARID1A', 'Gene', (121, 127))	('USH2A', 'Gene', '7399', (194, 199))	('LSCC', 'Phenotype', 'HP:0030359', (103, 107))	('ARID1A', 'Gene', '8289', (121, 127))	('PIK3CA', 'Gene', '5290', (150, 156))	('CCDC168', 'Gene', (274, 281))	('CCDC168', 'Gene', '643677', (274, 281))	('TP53', 'Gene', (115, 119))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('KEAP1', 'Gene', '9817', (143, 148))	('LSCC', 'Phenotype', 'HP:0030359', (70, 74))	('NFE2L2', 'Gene', '4780', (129, 135))	('DNAH5', 'Gene', '1767', (264, 269))	('KEAP1', 'Gene', (143, 148))	('LSCC', 'Phenotype', 'HP:0030359', (243, 247))	('CDKN2A', 'Gene', (158, 164))	('mutated', 'Var', (34, 41))	('PIK3CA', 'Gene', (150, 156))	('DDR2', 'Gene', '4921', (137, 141))	('TP53', 'Gene', '7157', (115, 119))	('NFE2L2', 'Gene', (129, 135))	('USH2A', 'Gene', (194, 199))	('LSCC', 'Phenotype', 'HP:0030359', (312, 316))	('LSCC', 'Phenotype', 'HP:0030359', (58, 62))	('CDKN2A', 'Gene', '1029', (158, 164))	('tumor', 'Disease', (171, 176))	('DNAH5', 'Gene', (264, 269))
127632	26943773	PIK3CA was mutated in 8.1% (3/37) of cases, and these three patients appeared to have poor prognosis.	('patients', 'Species', '9606', (60, 68))	('PIK3CA', 'Gene', '5290', (0, 6))	('mutated', 'Var', (11, 18))	('PIK3CA', 'Gene', (0, 6))
127634	26943773	Frequent inactivating mutations in multiple chromatin-remodeling genes (including MLL2, ARID1A and KDM family), and mutation in one of these genes occurred in almost half of the carcinomas sequenced.	('carcinomas', 'Disease', (178, 188))	('carcinomas', 'Disease', 'MESH:D002277', (178, 188))	('inactivating', 'NegReg', (9, 21))	('mutation', 'Var', (116, 124))	('MLL2', 'Gene', (82, 86))	('carcinomas', 'Phenotype', 'HP:0030731', (178, 188))	('carcinoma', 'Phenotype', 'HP:0030731', (178, 187))	('occurred', 'Reg', (147, 155))	('ARID1A', 'Gene', (88, 94))	('MLL2', 'Gene', '8085', (82, 86))	('ARID1A', 'Gene', '8289', (88, 94))
127636	26943773	We identified 36 nonsynonymous point mutations, eight stop-gain mutations and seven insertion or deletion mutations in 35 chromatin associated genes, including mutations within KDM4C, MLL2, SETD2, NSD1, PHF2, ZNF408 and ARID1A (see Supplementary Table S3).	('SETD2', 'Gene', (190, 195))	('KDM4C', 'Gene', (177, 182))	('mutations', 'Var', (160, 169))	('MLL2', 'Gene', (184, 188))	('KDM4C', 'Gene', '23081', (177, 182))	('ZNF408', 'Gene', (209, 215))	('PHF2', 'Gene', (203, 207))	('NSD1', 'Gene', '64324', (197, 201))	('ARID1A', 'Gene', '8289', (220, 226))	('PHF2', 'Gene', '5253', (203, 207))	('ARID1A', 'Gene', (220, 226))	('MLL2', 'Gene', '8085', (184, 188))	('ZNF408', 'Gene', '79797', (209, 215))	('chromatin associated genes', 'Gene', (122, 148))	('SETD2', 'Gene', '29072', (190, 195))	('NSD1', 'Gene', (197, 201))
127637	26943773	Frequent mutations in the ARID1A gene have been reported in gastric cancer and ovarian carcinomas, which were also detected in smoking and never smoking patients.	('ARID1A', 'Gene', (26, 32))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('ovarian carcinomas', 'Disease', (79, 97))	('patients', 'Species', '9606', (153, 161))	('mutations', 'Var', (9, 18))	('reported', 'Reg', (48, 56))	('gastric cancer', 'Disease', (60, 74))	('ovarian carcinomas', 'Phenotype', 'HP:0025318', (79, 97))	('carcinomas', 'Phenotype', 'HP:0030731', (87, 97))	('gastric cancer', 'Disease', 'MESH:D013274', (60, 74))	('ovarian carcinomas', 'Disease', 'MESH:D010051', (79, 97))	('gastric cancer', 'Phenotype', 'HP:0012126', (60, 74))	('ARID1A', 'Gene', '8289', (26, 32))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))
127639	26943773	Mutations in COL3A1 are associated with Ehlers-Danlos syndrome types IV, and with aortic and arterial aneurysms.	('Ehlers-Danlos syndrome', 'Disease', (40, 62))	('types IV', 'Disease', (63, 71))	('aneurysms', 'Phenotype', 'HP:0002617', (102, 111))	('associated', 'Reg', (24, 34))	('COL3A1', 'Gene', (13, 19))	('Mutations', 'Var', (0, 9))	('COL3A1', 'Gene', '1281', (13, 19))	('aortic and arterial aneurysms', 'Phenotype', 'HP:0004942', (82, 111))	('arterial aneurysms', 'Disease', (93, 111))	('arterial aneurysms', 'Disease', 'MESH:D002532', (93, 111))	('Ehlers-Danlos syndrome', 'Disease', 'MESH:D004535', (40, 62))
127646	26943773	Two genes of the ADAM (a disintegrin and metalloprotease domain) family, ADAM18 and ADAM21 are found to be mutated in some of the never-smoking patients.	('ADAM', 'Gene', (17, 21))	('ADAM21', 'Gene', (84, 90))	('ADAM18', 'Gene', (73, 79))	('mutated', 'Var', (107, 114))	('patients', 'Species', '9606', (144, 152))	('ADAM18', 'Gene', '8749', (73, 79))	('ADAM21', 'Gene', '8747', (84, 90))
127648	26943773	Through the comparative analysis between case-matched tumor and adjacent normal tissue exome-seq data, we have identified large-scale chromosome amplification at 3q (SOX2, PIK3CA and TP63), 5p (TERT, SLC12A7 and FGF10), 8q (FGFR1) and 11q (FGF19, FGF3, FGF4 and CCND1), and deletions at 3p (FHIT), 5q (FAT2 and CHD1), 9p21 (CDKN2A), 10q23 (PTEN), 13q (RB1 and PCDH9) and 17p (TP53 and NF1) in both S-LSCC and NS-LSCC (Figure 2A).	('S-LSCC', 'Disease', (398, 404))	('FGF4', 'Gene', (253, 257))	('CDKN2A', 'Gene', '1029', (324, 330))	('CHD1', 'Gene', '1105', (311, 315))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('FGF3', 'Gene', (247, 251))	('PIK3CA', 'Gene', (172, 178))	('tumor', 'Disease', (54, 59))	('FGFR1', 'Gene', (224, 229))	('FGF3', 'Gene', '2248', (247, 251))	('PTEN', 'Gene', '5728', (340, 344))	('TP63', 'Gene', '8626', (183, 187))	('SLC12A7', 'Gene', '10723', (200, 207))	('CHD1', 'Gene', (311, 315))	('PCDH9', 'Gene', (360, 365))	('FHIT', 'Gene', (291, 295))	('deletions', 'Var', (274, 283))	('CCND1', 'Gene', '595', (262, 267))	('TP53', 'Gene', (376, 380))	('FGF4', 'Gene', '2249', (253, 257))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('LSCC', 'Phenotype', 'HP:0030359', (412, 416))	('FGF10', 'Gene', (212, 217))	('CCND1', 'Gene', (262, 267))	('NF1', 'Gene', '4763', (385, 388))	('TERT', 'Gene', (194, 198))	('PCDH9', 'Gene', '5101', (360, 365))	('TERT', 'Gene', '7015', (194, 198))	('p21', 'Gene', (319, 322))	('RB1', 'Gene', (352, 355))	('FGF19', 'Gene', (240, 245))	('FGF19', 'Gene', '9965', (240, 245))	('SOX2', 'Gene', '6657', (166, 170))	('SOX2', 'Gene', (166, 170))	('FHIT', 'Gene', '2272', (291, 295))	('PIK3CA', 'Gene', '5290', (172, 178))	('FAT2', 'Gene', '2196', (302, 306))	('NS-LSCC', 'Disease', (409, 416))	('NF1', 'Gene', (385, 388))	('SLC12A7', 'Gene', (200, 207))	('FGFR1', 'Gene', '2260', (224, 229))	('CDKN2A', 'Gene', (324, 330))	('LSCC', 'Phenotype', 'HP:0030359', (400, 404))	('TP53', 'Gene', '7157', (376, 380))	('FGF10', 'Gene', '2255', (212, 217))	('RB1', 'Gene', '5925', (352, 355))	('FAT2', 'Gene', (302, 306))	('PTEN', 'Gene', (340, 344))	('TP63', 'Gene', (183, 187))	('p21', 'Gene', '644914', (319, 322))
127649	26943773	The previously reported characteristic copy number variations of LSCC, such as the amplifications of SOX2/PIK3CA on chromosome 3 and FGFR1 amplification on chromosome 8 are observed in both patient cohorts (Figure 2A and 2B).	('amplification', 'Var', (139, 152))	('FGFR1', 'Gene', (133, 138))	('FGFR1', 'Gene', '2260', (133, 138))	('SOX2', 'Gene', '6657', (101, 105))	('PIK3CA', 'Gene', (106, 112))	('SOX2', 'Gene', (101, 105))	('PIK3CA', 'Gene', '5290', (106, 112))	('LSCC', 'Gene', (65, 69))	('LSCC', 'Phenotype', 'HP:0030359', (65, 69))	('patient', 'Species', '9606', (190, 197))
127673	26943773	The specificity of these amplifications in smoking patients suggests some interesting mechanism of tumor driving mutations in a subset of squamous cell carcinoma.	('tumor', 'Disease', (99, 104))	('carcinoma', 'Phenotype', 'HP:0030731', (152, 161))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (138, 161))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (138, 161))	('squamous cell carcinoma', 'Disease', (138, 161))	('mutations', 'Var', (113, 122))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('patients', 'Species', '9606', (51, 59))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))
127683	26943773	Variations present in the tumor sample but absent in matched normal tissue were predicted to be somatic.	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('Variations', 'Var', (0, 10))	('tumor', 'Disease', 'MESH:D009369', (26, 31))
127698	26871598	By contrast, high levels of FoxP3+ regulatory TILs had a worse prognostic effect for overall and recurrence-free survival, with HRs of 1.69 (P = 0.042) and 1.79 (P = 0.001), respectively.	('TIL', 'Gene', (46, 49))	('FoxP3', 'Gene', '50943', (28, 33))	('high', 'Var', (13, 17))	('FoxP3', 'Gene', (28, 33))	('TIL', 'Gene', '7096', (46, 49))	('recurrence-free survival', 'CPA', (97, 121))
127713	26871598	Since many studies identified TILs by CD3+, CD4+, CD8+, and FoxP3+, we also analyzed the predictive value of these TILs subtypes, as well as of the ratios between these subsets in NSCLC.	('CD8', 'Gene', (50, 53))	('TIL', 'Gene', (115, 118))	('FoxP3', 'Gene', (60, 65))	('TIL', 'Gene', (30, 33))	('NSCLC', 'Disease', (180, 185))	('rat', 'Species', '10116', (148, 151))	('CD8', 'Gene', '925', (50, 53))	('CD4', 'Gene', '920', (44, 47))	('CD3+', 'Var', (38, 42))	('TIL', 'Gene', '7096', (115, 118))	('NSCLC', 'Disease', 'MESH:D002289', (180, 185))	('TIL', 'Gene', '7096', (30, 33))	('CD4', 'Gene', (44, 47))	('NSCLC', 'Phenotype', 'HP:0030358', (180, 185))	('FoxP3', 'Gene', '50943', (60, 65))
127724	26871598	These analyses revealed that high levels of CD8+ T lymphocytes were associated with improved overall survival in studies with large numbers of patients (>=200; HR = 0.73; 95% CI, 0.63-0.83), histology subtype (HR = 0.68; 95% CI, 0.54-0.86 for squamous cell carcinoma; and HR = 0.92; 95% CI, 0.85-0.99 for NSCLCs), European patients (HR = 0.76; 95% CI, 0.65-0.88).	('high', 'Var', (29, 33))	('CD8', 'Gene', (44, 47))	('patients', 'Species', '9606', (323, 331))	('CD8', 'Gene', '925', (44, 47))	('overall survival', 'MPA', (93, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (257, 266))	('NSCLC', 'Phenotype', 'HP:0030358', (305, 310))	('patients', 'Species', '9606', (143, 151))	('improved', 'PosReg', (84, 92))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (243, 266))	('NSCLC', 'Disease', (305, 310))	('squamous cell carcinoma', 'Disease', (243, 266))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (243, 266))	('NSCLC', 'Disease', 'MESH:D002289', (305, 310))
127727	26871598	Pooled HRs and 95% CIs pointed to a survival advantage associated with high levels of CD3+ T lymphocytes, with improved overall survival (HR = 0.77; 95% CI, 0.63-0.94; PHR = 0.009) and disease-specific survival (HR = 0.57; 95% CI, 0.41-0.78; PHR = 0.001), but no significant correlation was found for recurrence- or disease-free survival (HR = 0.91; 95% CI, 0.81-1.02; PHR = 0.115).	('PHR', 'Gene', (242, 245))	('PHR', 'Gene', '23077', (369, 372))	('PHR', 'Gene', '23077', (168, 171))	('high', 'Var', (71, 75))	('disease-specific survival', 'CPA', (185, 210))	('PHR', 'Gene', (369, 372))	('improved', 'PosReg', (111, 119))	('CD3+ T', 'Var', (86, 92))	('PHR', 'Gene', (168, 171))	('PHR', 'Gene', '23077', (242, 245))	('advantage', 'PosReg', (45, 54))	('overall survival', 'CPA', (120, 136))
127736	26871598	Figure 6A indicated that low levels of FoxP3+ Treg lymphocytes correlated with a good prognosis for overall survival (HR = 1.69; 95% CI, 1.02-2.81; PHR = 0.042), and recurrence-free survival (HR = 1.79; 95% CI, 1.29-2.48; PHR = 0.001).	('PHR', 'Gene', '23077', (222, 225))	('PHR', 'Gene', (148, 151))	('overall survival', 'CPA', (100, 116))	('PHR', 'Gene', (222, 225))	('FoxP3', 'Gene', '50943', (39, 44))	('low', 'Var', (25, 28))	('PHR', 'Gene', '23077', (148, 151))	('FoxP3', 'Gene', (39, 44))	('recurrence-free survival', 'CPA', (166, 190))
127744	26871598	We have demonstrated that comparing high and low densities of CD3+, CD4+, or CD8+ TILs alone in patients with NSCLC indicated that high densities of these subtypes of TILs alone could be a relatively pronounced predictive marker, with better associated outcomes than low infiltrate densities in terms of overall survival.	('CD8', 'Gene', (77, 80))	('CD8', 'Gene', '925', (77, 80))	('CD4', 'Gene', '920', (68, 71))	('rat', 'Species', '10116', (15, 18))	('TIL', 'Gene', (82, 85))	('TIL', 'Gene', (167, 170))	('NSCLC', 'Disease', (110, 115))	('NSCLC', 'Disease', 'MESH:D002289', (110, 115))	('rat', 'Species', '10116', (277, 280))	('patients', 'Species', '9606', (96, 104))	('TIL', 'Gene', '7096', (167, 170))	('TIL', 'Gene', '7096', (82, 85))	('CD4', 'Gene', (68, 71))	('CD3+', 'Var', (62, 66))	('NSCLC', 'Phenotype', 'HP:0030358', (110, 115))
127751	26871598	The authors of this study found an association between high levels of CD4+ T cells in cancer stroma and longer survival.	('high levels', 'Var', (55, 66))	('cancer stroma', 'Disease', (86, 99))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('CD4', 'Gene', (70, 73))	('high levels of CD4+ T', 'Phenotype', 'HP:0005407', (55, 76))	('longer survival', 'CPA', (104, 119))	('CD4', 'Gene', '920', (70, 73))	('cancer stroma', 'Disease', 'MESH:D009369', (86, 99))
127758	26871598	Stratified analysesrevealed that the survival of patients with squamous cell carcinoma has a positive association with high density of CD4+ or CD8+ TILs alone.	('TIL', 'Gene', (148, 151))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (63, 86))	('rat', 'Species', '10116', (2, 5))	('squamous cell carcinoma', 'Disease', (63, 86))	('CD8', 'Gene', (143, 146))	('high density', 'Var', (119, 131))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (63, 86))	('CD8', 'Gene', '925', (143, 146))	('CD4', 'Gene', (135, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('TIL', 'Gene', '7096', (148, 151))	('patients', 'Species', '9606', (49, 57))	('CD4', 'Gene', '920', (135, 138))
127791	26871598	In conclusion, despite these limitations, we have demonstrated that TILs might serve as a robust marker for prognosticating the survival of patients with NSCLC, especially in TIL subtypes CD3+, CD4+, CD8+, and FoxP3+.	('CD8', 'Gene', '925', (200, 203))	('NSCLC', 'Disease', 'MESH:D002289', (154, 159))	('FoxP3', 'Gene', '50943', (210, 215))	('TIL', 'Gene', (68, 71))	('NSCLC', 'Phenotype', 'HP:0030358', (154, 159))	('TIL', 'Gene', (175, 178))	('CD3+', 'Var', (188, 192))	('FoxP3', 'Gene', (210, 215))	('rat', 'Species', '10116', (57, 60))	('patients', 'Species', '9606', (140, 148))	('CD4', 'Gene', (194, 197))	('CD4', 'Gene', '920', (194, 197))	('CD8', 'Gene', (200, 203))	('TIL', 'Gene', '7096', (68, 71))	('TIL', 'Gene', '7096', (175, 178))	('NSCLC', 'Disease', (154, 159))
127806	33398370	miR-149-3p has been reported to serve multiple roles in the regulation of proliferation, apoptosis and metastasis.	('miR-149-3p', 'Chemical', '-', (0, 10))	('apoptosis', 'CPA', (89, 98))	('metastasis', 'CPA', (103, 113))	('miR-149-3p', 'Var', (0, 10))
127807	33398370	However, the effects and detailed mechanism of miR-149-3p in oral squamous cell carcinoma (OSCC) remain unclear.	('miR-149-3p', 'Var', (47, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('oral squamous cell carcinoma', 'Disease', (61, 89))	('miR-149-3p', 'Chemical', '-', (47, 57))	('OSCC', 'CellLine', 'CVCL:L894', (91, 95))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (61, 89))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (66, 89))
127812	33398370	The binding of miR-149-3p to the AKT2 3'-untranslated region was evaluated by a dual luciferase reporter assay.	('miR-149-3p', 'Chemical', '-', (15, 25))	('binding', 'Interaction', (4, 11))	('AKT2', 'Gene', (33, 37))	('AKT2', 'Gene', '208', (33, 37))	('miR-149-3p', 'Var', (15, 25))
127813	33398370	In the present study, overexpression of miR-149-3p reduced the viability and proliferation of OSCC cells.	('miR-149-3p', 'Var', (40, 50))	('reduced', 'NegReg', (51, 58))	('OSCC', 'CellLine', 'CVCL:L894', (94, 98))	('viability', 'CPA', (63, 72))	('miR-149-3p', 'Chemical', '-', (40, 50))	('proliferation of OSCC cells', 'CPA', (77, 104))
127814	33398370	By contrast, increased cell viability and proliferation was observed in miR-149-3p-deficient OSCC cells.	('miR-149-3p', 'Chemical', '-', (72, 82))	('OSCC', 'Disease', (93, 97))	('OSCC', 'CellLine', 'CVCL:L894', (93, 97))	('proliferation', 'CPA', (42, 55))	('cell viability', 'CPA', (23, 37))	('miR-149-3p-deficient', 'Var', (72, 92))	('increased', 'PosReg', (13, 22))
127815	33398370	Dual luciferase reporter assay indicated that miR-149-3p significantly decreased the luciferase activity of the wild-type AKT2 3'-untranslated region.	('activity', 'MPA', (96, 104))	('miR-149-3p', 'Chemical', '-', (46, 56))	('luciferase', 'Enzyme', (85, 95))	('AKT2', 'Gene', (122, 126))	('AKT2', 'Gene', '208', (122, 126))	('decreased', 'NegReg', (71, 80))	('miR-149-3p', 'Var', (46, 56))
127816	33398370	Moreover, overexpression of miR-149-3p downregulated the mRNA and protein expression levels of AKT2, suggesting that miR-149-3p was a negative modulator of AKT2.	('AKT2', 'Gene', (156, 160))	('AKT2', 'Gene', '208', (156, 160))	('miR-149-3p', 'Var', (28, 38))	('AKT2', 'Gene', (95, 99))	('miR-149-3p', 'Chemical', '-', (117, 127))	('miR-149-3p', 'Chemical', '-', (28, 38))	('AKT2', 'Gene', '208', (95, 99))	('downregulated', 'NegReg', (39, 52))
127817	33398370	Restoration of AKT2 efficiently reversed the miR-149-3p-mediated reduction in the proliferative capacity of OSCC cells.	('miR-149-3p-mediated', 'Var', (45, 64))	('OSCC', 'CellLine', 'CVCL:L894', (108, 112))	('AKT2', 'Gene', (15, 19))	('proliferative capacity of OSCC cells', 'CPA', (82, 118))	('AKT2', 'Gene', '208', (15, 19))	('miR-149-3p', 'Chemical', '-', (45, 55))	('reduction', 'NegReg', (65, 74))
127818	33398370	In addition, miR-149-3p enhanced the sensitivity of OSCC cells to the chemotherapeutic drug 5-fluorouracil.	('miR-149-3p', 'Var', (13, 23))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (92, 106))	('OSCC', 'CellLine', 'CVCL:L894', (52, 56))	('enhanced', 'PosReg', (24, 32))	('miR-149-3p', 'Chemical', '-', (13, 23))	('sensitivity', 'MPA', (37, 48))
127819	33398370	Taken together, the current findings revealed an inhibitory effect of miR-149-3p on the proliferation of OSCC cells through the post-transcriptional suppression of AKT2, and indicated a potential chemosensitizing function of miR-149-3p for the treatment of patients with OSCC.	('AKT2', 'Gene', '208', (164, 168))	('suppression', 'NegReg', (149, 160))	('post-transcriptional', 'MPA', (128, 148))	('inhibitory effect', 'NegReg', (49, 66))	('miR-149-3p', 'Chemical', '-', (225, 235))	('OSCC', 'CellLine', 'CVCL:L894', (105, 109))	('miR-149-3p', 'Var', (70, 80))	('OSCC', 'Disease', (271, 275))	('patients', 'Species', '9606', (257, 265))	('proliferation', 'CPA', (88, 101))	('AKT2', 'Gene', (164, 168))	('miR-149-3p', 'Chemical', '-', (70, 80))	('OSCC', 'CellLine', 'CVCL:L894', (271, 275))
127825	33398370	Accumulating evidence has indicated that the dysregulation of miRNAs contributes to the initiation and development of various types of human cancer, including pancreatic cancer, gastric cancer and breast cancer.	('cancer', 'Disease', 'MESH:D009369', (204, 210))	('cancer', 'Disease', (170, 176))	('pancreatic cancer', 'Disease', (159, 176))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('dysregulation', 'Var', (45, 58))	('gastric cancer', 'Phenotype', 'HP:0012126', (178, 192))	('cancer', 'Disease', 'MESH:D009369', (186, 192))	('breast cancer', 'Phenotype', 'HP:0003002', (197, 210))	('human', 'Species', '9606', (135, 140))	('miRNAs', 'Protein', (62, 68))	('cancer', 'Disease', (141, 147))	('breast cancer', 'Disease', 'MESH:D001943', (197, 210))	('development', 'CPA', (103, 114))	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('cancer', 'Disease', (204, 210))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (159, 176))	('breast cancer', 'Disease', (197, 210))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('gastric cancer', 'Disease', (178, 192))	('cancer', 'Disease', (186, 192))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('pancreatic cancer', 'Disease', 'MESH:D010190', (159, 176))	('contributes', 'Reg', (69, 80))	('gastric cancer', 'Disease', 'MESH:D013274', (178, 192))	('cancer', 'Disease', 'MESH:D009369', (141, 147))
127826	33398370	Numerous studies have revealed that miR-149-3p acts as a tumor suppressor.	('miR-149-3p', 'Var', (36, 46))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('miR-149-3p', 'Chemical', '-', (36, 46))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Disease', (57, 62))
127827	33398370	For example, miR-149-3p was shown to modulate polo-like kinase 1 (PLK1) levels by competing with heterogeneous nuclear ribonucleoprotein K in the 3'-UTR of PLK1 mRNA, which led to the decreased growth of HeLa cells.	('PLK1', 'Gene', (66, 70))	('polo-like kinase 1', 'Gene', '5347', (46, 64))	('PLK1', 'Gene', (156, 160))	('levels', 'MPA', (72, 78))	('heterogeneous nuclear ribonucleoprotein K', 'MPA', (97, 138))	('miR-149-3p', 'Var', (13, 23))	('polo-like kinase 1', 'Gene', (46, 64))	('PLK1', 'Gene', '5347', (66, 70))	('HeLa', 'CellLine', 'CVCL:0030', (204, 208))	('decreased growth', 'Phenotype', 'HP:0001510', (184, 200))	('PLK1', 'Gene', '5347', (156, 160))	('modulate', 'Reg', (37, 45))	('miR-149-3p', 'Chemical', '-', (13, 23))	('decreased', 'NegReg', (184, 193))	('growth', 'MPA', (194, 200))
127828	33398370	In addition, miR-149-3p downregulated S100A4 expression, and suppressed the proliferation and metastasis of bladder cancer.	('suppressed', 'NegReg', (61, 71))	('miR-149-3p', 'Var', (13, 23))	('metastasis of bladder cancer', 'Disease', 'MESH:D001749', (94, 122))	('downregulated', 'NegReg', (24, 37))	('S100A4', 'Gene', '6275', (38, 44))	('miR-149-3p', 'Chemical', '-', (13, 23))	('expression', 'MPA', (45, 55))	('S100A4', 'Gene', (38, 44))	('bladder cancer', 'Phenotype', 'HP:0009725', (108, 122))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('metastasis of bladder cancer', 'Disease', (94, 122))
127829	33398370	Conversely, a recent study reported that miR-149-3p attenuated the apoptosis and depletion of CD8+ T cells, suggesting a potential protective role of miR-149-3p in CD8+ T cells.	('apoptosis', 'CPA', (67, 76))	('CD8', 'Gene', (164, 167))	('miR-149-3p', 'Var', (150, 160))	('attenuated', 'NegReg', (52, 62))	('CD8', 'Gene', '925', (164, 167))	('miR-149-3p', 'Var', (41, 51))	('miR-149-3p', 'Chemical', '-', (150, 160))	('CD8', 'Gene', (94, 97))	('depletion', 'MPA', (81, 90))	('CD8', 'Gene', '925', (94, 97))	('miR-149-3p', 'Chemical', '-', (41, 51))
127830	33398370	Moreover, miR-149-3p promoted the aggressiveness of cancer cells via inhibition of DAB2-interacting protein in a cell-autonomous and non-autonomous manner.	('DAB2-interacting protein', 'Gene', (83, 107))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('aggressiveness of cancer', 'Disease', 'MESH:D009369', (34, 58))	('promoted', 'PosReg', (21, 29))	('miR-149-3p', 'Var', (10, 20))	('DAB2-interacting protein', 'Gene', '153090', (83, 107))	('aggressiveness', 'Phenotype', 'HP:0000718', (34, 48))	('aggressiveness of cancer', 'Disease', (34, 58))	('inhibition', 'NegReg', (69, 79))	('miR-149-3p', 'Chemical', '-', (10, 20))
127831	33398370	However, to the best of our knowledge, the functional role and mechanisms of miR-149-3p in OSCC remain unknown.	('miR-149-3p', 'Var', (77, 87))	('OSCC', 'Disease', (91, 95))	('miR-149-3p', 'Chemical', '-', (77, 87))	('OSCC', 'CellLine', 'CVCL:L894', (91, 95))
127832	33398370	In the present study, overexpression of miR-149-3p attenuated cell viability and proliferation, whereas miR-149-3p knockdown augmented the viability and proliferation of OSCC cells.	('miR-149-3p', 'Chemical', '-', (104, 114))	('miR-149-3p', 'Var', (40, 50))	('cell viability', 'CPA', (62, 76))	('OSCC', 'CellLine', 'CVCL:L894', (170, 174))	('augmented', 'PosReg', (125, 134))	('attenuated', 'NegReg', (51, 61))	('miR-149-3p', 'Chemical', '-', (40, 50))	('proliferation', 'CPA', (153, 166))	('viability', 'CPA', (139, 148))	('miR-149-3p', 'Var', (104, 114))	('proliferation', 'CPA', (81, 94))
127833	33398370	The data further demonstrated that miR-149-3p decreased AKT2 expression by directly binding to the 3'-UTR of AKT2 mRNA.	('AKT2', 'Gene', (56, 60))	('AKT2', 'Gene', '208', (56, 60))	('AKT2', 'Gene', (109, 113))	('AKT2', 'Gene', '208', (109, 113))	('miR-149-3p', 'Var', (35, 45))	('decreased', 'NegReg', (46, 55))	('binding', 'Interaction', (84, 91))	('expression', 'MPA', (61, 71))	('miR-149-3p', 'Chemical', '-', (35, 45))
127834	33398370	Moreover, AKT2 efficiently restored the inhibited proliferative capacity of OSCC cells induced by miR-149-3p.	('miR-149-3p', 'Var', (98, 108))	('inhibited', 'NegReg', (40, 49))	('proliferative capacity of', 'CPA', (50, 75))	('OSCC', 'CellLine', 'CVCL:L894', (76, 80))	('miR-149-3p', 'Chemical', '-', (98, 108))	('AKT2', 'Gene', (10, 14))	('AKT2', 'Gene', '208', (10, 14))
127835	33398370	Notably, miR-149-3p-overexpressing OSCC cells exhibited higher sensitivity to the chemotherapeutic drug 5-fluorouracil (5-Fu).	('miR-149-3p', 'Chemical', '-', (9, 19))	('miR-149-3p-overexpressing', 'Var', (9, 34))	('OSCC', 'CellLine', 'CVCL:L894', (35, 39))	('higher', 'PosReg', (56, 62))	('5-Fu', 'Chemical', 'MESH:D005472', (120, 124))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (104, 118))
127836	33398370	Taken together, to the best of our knowledge, the present study was the first to indicate that miR-149-3p inhibited the proliferation of OSCC cells and improved the efficacy of 5-Fu in OSCC cells by targeting AKT2.	('proliferation', 'CPA', (120, 133))	('miR-149-3p', 'Var', (95, 105))	('inhibited', 'NegReg', (106, 115))	('targeting', 'Reg', (199, 208))	('miR-149-3p', 'Chemical', '-', (95, 105))	('5-Fu', 'MPA', (177, 181))	('improved', 'PosReg', (152, 160))	('AKT2', 'Gene', (209, 213))	('efficacy', 'MPA', (165, 173))	('5-Fu', 'Chemical', 'MESH:D005472', (177, 181))	('OSCC', 'CellLine', 'CVCL:L894', (137, 141))	('AKT2', 'Gene', '208', (209, 213))	('OSCC', 'CellLine', 'CVCL:L894', (185, 189))
127853	33398370	U6 snRNA and beta-actin were used as an endogenous control for miR-149-3p and AKT2, respectively.	('AKT2', 'Gene', '208', (78, 82))	('miR-149-3p', 'Var', (63, 73))	('AKT2', 'Gene', (78, 82))	('miR-149-3p', 'Chemical', '-', (63, 73))
127857	33398370	3063; Cell Signaling Technology, Inc.), cleaved caspase-3 (1:1,000; cat.	('caspase-3', 'Gene', '836', (48, 57))	('cleaved', 'Var', (40, 47))	('caspase-3', 'Gene', (48, 57))
127858	33398370	9664; Cell Signaling Technology, Inc.), cleaved PARP (1:1,000; cat.	('PARP', 'Gene', (48, 52))	('cleaved', 'Var', (40, 47))	('PARP', 'Gene', '1302', (48, 52))
127871	33398370	Pearson correlation analysis was used to analyze the correlation between the expression levels of miR-149-3p and AKT2 in TCGA head and neck squamous cell carcinoma dataset .	('miR-149-3p', 'Var', (98, 108))	('AKT2', 'Gene', (113, 117))	('miR-149-3p', 'Chemical', '-', (98, 108))	('AKT2', 'Gene', '208', (113, 117))	('neck squamous cell carcinoma', 'Disease', (135, 163))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (140, 163))	('carcinoma', 'Phenotype', 'HP:0030731', (154, 163))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (135, 163))
127872	33398370	To explore the role of miR-149-3p in OSCC tumorigenesis, the expression levels of miR-149-3p were detected in OSCC cell lines (Cal27 and SCC-9 cells) and in the non-tumorigenic oral epithelial cell line MSK-Leuk1.	('tumor', 'Disease', (42, 47))	('miR-149-3p', 'Var', (82, 92))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('miR-149-3p', 'Chemical', '-', (23, 33))	('OSCC', 'CellLine', 'CVCL:L894', (37, 41))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('SCC-9', 'CellLine', 'CVCL:1685', (137, 142))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('miR-149-3p', 'Chemical', '-', (82, 92))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('OSCC', 'Disease', (110, 114))	('OSCC', 'CellLine', 'CVCL:L894', (110, 114))	('tumor', 'Disease', (165, 170))
127873	33398370	1, lower expression levels of miR-149-3p were observed in Cal27 and SCC-9 cells compared with in MSK-Leuk1 cells, indicating that miR-149-3p may be involved in OSCC progression.	('OSCC', 'Disease', (160, 164))	('miR-149-3p', 'Var', (130, 140))	('lower', 'NegReg', (3, 8))	('OSCC', 'CellLine', 'CVCL:L894', (160, 164))	('SCC-9', 'CellLine', 'CVCL:1685', (68, 73))	('expression levels', 'MPA', (9, 26))	('miR-149-3p', 'Chemical', '-', (130, 140))	('miR-149-3p', 'Chemical', '-', (30, 40))	('involved', 'Reg', (148, 156))
127876	33398370	The results revealed an ~8.1- and 5.4-fold increase in the expression levels of miR-149-3p in miR-149-3p mimic-transfected Cal27 and SCC-9 cells compared with in mimic control-transfected cells, respectively (Fig.	('expression levels', 'MPA', (59, 76))	('miR-149-3p', 'Chemical', '-', (94, 104))	('miR-149-3p', 'Chemical', '-', (80, 90))	('miR-149-3p mimic-transfected', 'Var', (94, 122))	('SCC-9', 'CellLine', 'CVCL:1685', (133, 138))	('miR-149-3p', 'Var', (80, 90))	('increase', 'PosReg', (43, 51))
127877	33398370	CCK-8 assays revealed that miR-149-3p overexpression significantly suppressed the viability of OSCC cells (Fig.	('viability of OSCC cells', 'CPA', (82, 105))	('suppressed', 'NegReg', (67, 77))	('miR-149-3p', 'Var', (27, 37))	('OSCC', 'CellLine', 'CVCL:L894', (95, 99))	('miR-149-3p', 'Chemical', '-', (27, 37))	('CCK-8', 'Chemical', '-', (0, 5))
127878	33398370	Moreover, the overexpression of miR-149-3p diminished the colony-forming ability of OSCC cells (Fig.	('colony-forming ability of OSCC cells', 'CPA', (58, 94))	('miR-149-3p', 'Chemical', '-', (32, 42))	('OSCC', 'CellLine', 'CVCL:L894', (84, 88))	('overexpression', 'PosReg', (14, 28))	('diminished', 'NegReg', (43, 53))	('miR-149-3p', 'Var', (32, 42))
127879	33398370	These data indicated that miR-149-3p inhibited the proliferation of OSCC cells.	('miR-149-3p', 'Var', (26, 36))	('inhibited', 'NegReg', (37, 46))	('proliferation of OSCC cells', 'CPA', (51, 78))	('OSCC', 'CellLine', 'CVCL:L894', (68, 72))	('miR-149-3p', 'Chemical', '-', (26, 36))
127881	33398370	The expression levels of miR-149-3p were downregulated in OSCC cells transfected with the miR-149-3p inhibitor compared with those transfected with the inhibitor control, as determined by RT-qPCR analysis (Fig.	('expression levels', 'MPA', (4, 21))	('OSCC', 'CellLine', 'CVCL:L894', (58, 62))	('miR-149-3p', 'Chemical', '-', (90, 100))	('downregulated', 'NegReg', (41, 54))	('miR-149-3p', 'Var', (25, 35))	('miR-149-3p', 'Gene', (90, 100))	('miR-149-3p', 'Chemical', '-', (25, 35))
127882	33398370	Silencing of miR-149-3p efficiently augmented the viability of OSCC cells (Fig.	('miR-149-3p', 'Gene', (13, 23))	('OSCC', 'Disease', (63, 67))	('miR-149-3p', 'Chemical', '-', (13, 23))	('viability', 'CPA', (50, 59))	('Silencing', 'Var', (0, 9))	('augmented', 'PosReg', (36, 45))	('OSCC', 'CellLine', 'CVCL:L894', (63, 67))
127883	33398370	These data indicated that miR-149-3p knockdown promoted the proliferation of OSCC cells.	('promoted', 'PosReg', (47, 55))	('knockdown', 'Var', (37, 46))	('miR-149-3p knockdown', 'Var', (26, 46))	('miR-149-3p', 'Chemical', '-', (26, 36))	('OSCC', 'CellLine', 'CVCL:L894', (77, 81))	('proliferation of OSCC cells', 'CPA', (60, 87))
127884	33398370	To explore the molecular mechanisms by which miR-149-3p suppresses the proliferation of OSCC cells, the target genes of miR-149-3p were analyzed using TargetScan and miRDB databases; the genes predicted by both analyses were considered potential target genes of miR-149-3p.	('miR-149-3p', 'Chemical', '-', (262, 272))	('miR-149-3p', 'Chemical', '-', (120, 130))	('miR-149-3p', 'Var', (45, 55))	('OSCC', 'CellLine', 'CVCL:L894', (88, 92))	('suppresses', 'NegReg', (56, 66))	('miR-149-3p', 'Chemical', '-', (45, 55))
127885	33398370	According to this strategy, a miR-149-3p binding site was identified in the 3'-UTR of AKT2 mRNA (Fig.	('miR-149-3p', 'Var', (30, 40))	('miR-149-3p', 'Chemical', '-', (30, 40))	('AKT2', 'Gene', (86, 90))	('AKT2', 'Gene', '208', (86, 90))
127888	33398370	To assess whether AKT2 is a direct target of miR-149-3p, luciferase reporter plasmids that contain WT or MT 3'-UTR target sequences of AKT2 were constructed.	('AKT2', 'Gene', '208', (18, 22))	('AKT2', 'Gene', (135, 139))	('AKT2', 'Gene', '208', (135, 139))	('miR-149-3p', 'Var', (45, 55))	('miR-149-3p', 'Chemical', '-', (45, 55))	('AKT2', 'Gene', (18, 22))
127889	33398370	The dual luciferase reporter assay demonstrated that the miR-149-3p mimic markedly decreased the luciferase activity of WT AKT2 3'-UTR-transfected Cal27 and SCC-9 cells compared with the mimic control group (Fig.	('luciferase', 'Enzyme', (97, 107))	('activity', 'MPA', (108, 116))	('miR-149-3p', 'Chemical', '-', (57, 67))	('decreased', 'NegReg', (83, 92))	('SCC-9', 'CellLine', 'CVCL:1685', (157, 162))	('miR-149-3p mimic', 'Var', (57, 73))	('AKT2', 'Gene', (123, 127))	('AKT2', 'Gene', '208', (123, 127))
127890	33398370	Conversely, no effects were noted on the luciferase activity of MT AKT2 3'-UTR following transfection with the miR-149-3p mimic (Fig.	('miR-149-3p', 'Chemical', '-', (111, 121))	('activity', 'MPA', (52, 60))	('AKT2', 'Gene', (67, 71))	('AKT2', 'Gene', '208', (67, 71))	('luciferase', 'Enzyme', (41, 51))	('miR-149-3p mimic', 'Var', (111, 127))
127891	33398370	Moreover, the overexpression of miR-149-3p resulted in a significant decrease in the mRNA and protein expression levels of AKT2 in OSCC cells (Fig.	('OSCC', 'CellLine', 'CVCL:L894', (131, 135))	('miR-149-3p', 'Chemical', '-', (32, 42))	('decrease', 'NegReg', (69, 77))	('AKT2', 'Gene', (123, 127))	('AKT2', 'Gene', '208', (123, 127))	('overexpression', 'PosReg', (14, 28))	('miR-149-3p', 'Var', (32, 42))
127892	33398370	In addition, a weak negative correlation between AKT2 and miR-149-3p expression was observed in a TCGA head and neck squamous cell carcinoma dataset (Fig.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (117, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (112, 140))	('negative', 'NegReg', (20, 28))	('miR-149-3p', 'Var', (58, 68))	('miR-149-3p', 'Chemical', '-', (58, 68))	('neck squamous cell carcinoma', 'Disease', (112, 140))	('AKT2', 'Gene', (49, 53))	('AKT2', 'Gene', '208', (49, 53))
127893	33398370	These results suggested that miR-149-3p could regulate AKT2 expression by directly binding to the AKT2 3'-UTR.	('regulate', 'Reg', (46, 54))	('expression', 'MPA', (60, 70))	('AKT2', 'Gene', (55, 59))	('AKT2', 'Gene', '208', (55, 59))	('miR-149-3p', 'Chemical', '-', (29, 39))	('binding', 'Interaction', (83, 90))	('AKT2', 'Gene', (98, 102))	('AKT2', 'Gene', '208', (98, 102))	('miR-149-3p', 'Var', (29, 39))
127894	33398370	To further examine the involvement of AKT2 in miR-149-3p-mediated cell proliferation, OSCC cells were transfected with AKT2 plasmid or empty pcDNA3 plasmid, and the expression levels of AKT2 were validated by RT-qPCR and western blot analysis.	('AKT2', 'Gene', (186, 190))	('OSCC', 'CellLine', 'CVCL:L894', (86, 90))	('miR-149-3p', 'Chemical', '-', (46, 56))	('AKT2', 'Gene', '208', (186, 190))	('AKT2', 'Gene', (119, 123))	('AKT2', 'Gene', '208', (119, 123))	('miR-149-3p-mediated', 'Var', (46, 65))	('AKT2', 'Gene', (38, 42))	('AKT2', 'Gene', '208', (38, 42))
127896	33398370	Enforced AKT2 expression did not alter miR-149-3p expression levels, whereas it rescued the decreased mRNA and protein expression levels of AKT2 induced by miR-149-3p (Fig.	('miR-149-3p', 'Chemical', '-', (39, 49))	('AKT2', 'Gene', (9, 13))	('miR-149-3p', 'Chemical', '-', (156, 166))	('AKT2', 'Gene', '208', (9, 13))	('AKT2', 'Gene', (140, 144))	('decreased', 'NegReg', (92, 101))	('miR-149-3p', 'Var', (156, 166))	('AKT2', 'Gene', '208', (140, 144))
127897	33398370	In addition, miR-149-3p-induced reduced cell viability was significantly attenuated by AKT2 overexpression in OSCC cells (Fig.	('miR-149-3p-induced', 'Var', (13, 31))	('AKT2', 'Gene', '208', (87, 91))	('overexpression', 'PosReg', (92, 106))	('reduced', 'NegReg', (32, 39))	('attenuated', 'NegReg', (73, 83))	('miR-149-3p', 'Chemical', '-', (13, 23))	('cell viability', 'CPA', (40, 54))	('AKT2', 'Gene', (87, 91))	('OSCC', 'CellLine', 'CVCL:L894', (110, 114))
127898	33398370	These data indicated that AKT2 was able to reverse the inhibitory effect of miR-149-3p on the proliferation of OSCC cells.	('OSCC', 'CellLine', 'CVCL:L894', (111, 115))	('AKT2', 'Gene', (26, 30))	('miR-149-3p', 'Var', (76, 86))	('AKT2', 'Gene', '208', (26, 30))	('miR-149-3p', 'Chemical', '-', (76, 86))
127899	33398370	To evaluate whether miR-149-3p contributes to the anti-tumor effect of chemotherapeutic agents, Cal27 and SCC-9 cells transfected with miR-149-3p mimic or mimic control were treated with 5-Fu for 24 h. A significant decrease in cell viability of 5-Fu-treated OSCC cells was noted compared with in the non-treated group (Fig.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('miR-149-3p', 'Chemical', '-', (135, 145))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('5-Fu', 'Chemical', 'MESH:D005472', (187, 191))	('SCC-9', 'CellLine', 'CVCL:1685', (106, 111))	('tumor', 'Disease', (55, 60))	('decrease', 'NegReg', (216, 224))	('OSCC', 'CellLine', 'CVCL:L894', (259, 263))	('5-Fu-treated', 'Var', (246, 258))	('miR-149-3p', 'Chemical', '-', (20, 30))	('cell viability', 'CPA', (228, 242))	('5-Fu', 'Chemical', 'MESH:D005472', (246, 250))
127900	33398370	Notably, miR-149-3p mimics enhanced the cytotoxic effects of 5-Fu on OSCC cells (Fig.	('OSCC', 'CellLine', 'CVCL:L894', (69, 73))	('miR-149-3p', 'Chemical', '-', (9, 19))	('miR-149-3p mimics', 'Var', (9, 26))	('enhanced', 'PosReg', (27, 35))	('5-Fu', 'Chemical', 'MESH:D005472', (61, 65))	('cytotoxic effects', 'CPA', (40, 57))	('OSCC', 'Disease', (69, 73))
127901	33398370	Moreover, the miR-149-3p mimic synergistically increased 5-Fu-induced elevated expression of cleaved caspase-3 and cleaved PARP (Fig.	('PARP', 'Gene', '1302', (123, 127))	('miR-149-3p', 'Chemical', '-', (14, 24))	('elevated', 'PosReg', (70, 78))	('PARP', 'Gene', (123, 127))	('cleaved', 'MPA', (115, 122))	('expression', 'MPA', (79, 89))	('caspase-3', 'Gene', '836', (101, 110))	('increased', 'PosReg', (47, 56))	('5-Fu-induced', 'MPA', (57, 69))	('miR-149-3p mimic', 'Var', (14, 30))	('5-Fu', 'Chemical', 'MESH:D005472', (57, 61))	('caspase-3', 'Gene', (101, 110))
127902	33398370	Flow cytometric analysis indicated that the number of Annexin V-positive OSCC cells was markedly increased following 5-Fu treatment in a dose- and time-dependent manner (Fig.	('OSCC', 'CellLine', 'CVCL:L894', (73, 77))	('increased', 'PosReg', (97, 106))	('5-Fu', 'Chemical', 'MESH:D005472', (117, 121))	('5-Fu', 'Var', (117, 121))	('Annexin V', 'Gene', '308', (54, 63))	('Annexin V', 'Gene', (54, 63))
127903	33398370	Notably, the miR-149-3p mimic combined with 5-Fu exhibited an additive effect on the apoptosis of OSCC cells (Fig.	('apoptosis', 'CPA', (85, 94))	('OSCC', 'Disease', (98, 102))	('miR-149-3p mimic', 'Var', (13, 29))	('miR-149-3p', 'Chemical', '-', (13, 23))	('OSCC', 'CellLine', 'CVCL:L894', (98, 102))	('5-Fu', 'Chemical', 'MESH:D005472', (44, 48))
127904	33398370	Subsequently, the effects of AKT2 were evaluated on miR-149-3p-modulated cell death following 5-Fu treatment.	('death', 'Disease', 'MESH:D003643', (78, 83))	('death', 'Disease', (78, 83))	('AKT2', 'Gene', (29, 33))	('5-Fu', 'Chemical', 'MESH:D005472', (94, 98))	('AKT2', 'Gene', '208', (29, 33))	('miR-149-3p-modulated', 'Var', (52, 72))	('miR-149-3p', 'Chemical', '-', (52, 62))
127905	33398370	AKT2 overexpression effectively rescued the reduced survival of OSCC cells caused by miR-149-3p in the presence of 5-Fu (Fig.	('miR-149-3p', 'Var', (85, 95))	('5-Fu', 'Chemical', 'MESH:D005472', (115, 119))	('miR-149-3p', 'Chemical', '-', (85, 95))	('survival', 'CPA', (52, 60))	('reduced', 'NegReg', (44, 51))	('OSCC', 'CellLine', 'CVCL:L894', (64, 68))	('AKT2', 'Gene', (0, 4))	('AKT2', 'Gene', '208', (0, 4))
127906	33398370	In addition, the exogenous introduction of AKT2 significantly reversed the activated caspase-3 and PARP proteins in miR-149-3p-expressing Cal27 and SCC-9 cells following 5-Fu administration (Fig.	('PARP', 'Gene', '1302', (99, 103))	('PARP', 'Gene', (99, 103))	('miR-149-3p-expressing', 'Var', (116, 137))	('activated', 'PosReg', (75, 84))	('AKT2', 'Gene', (43, 47))	('miR-149-3p', 'Chemical', '-', (116, 126))	('5-Fu', 'Chemical', 'MESH:D005472', (170, 174))	('caspase-3', 'Gene', (85, 94))	('AKT2', 'Gene', '208', (43, 47))	('SCC-9', 'CellLine', 'CVCL:1685', (148, 153))	('caspase-3', 'Gene', '836', (85, 94))
127907	33398370	These data revealed that miR-149-3p sensitized OSCC cells to 5-Fu by targeting AKT2.	('AKT2', 'Gene', '208', (79, 83))	('sensitized', 'PosReg', (36, 46))	('targeting', 'Reg', (69, 78))	('miR-149-3p', 'Var', (25, 35))	('OSCC', 'CellLine', 'CVCL:L894', (47, 51))	('miR-149-3p', 'Chemical', '-', (25, 35))	('AKT2', 'Gene', (79, 83))	('5-Fu', 'Chemical', 'MESH:D005472', (61, 65))
127909	33398370	A previous study demonstrated that both miR-149-5p (the guide strand) and miR-149-3p (the passenger strand) resulted in decreased migratory and invasive capacities by degrading the mRNA expression of FoxM1 in clear cell renal cell carcinoma.	('decreased', 'NegReg', (120, 129))	('miR-149-3p', 'Var', (74, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (231, 240))	('degrading', 'NegReg', (167, 176))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (209, 240))	('miR-149-3p', 'Chemical', '-', (74, 84))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (209, 240))	('clear cell renal cell carcinoma', 'Disease', (209, 240))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (220, 240))	('mRNA expression', 'MPA', (181, 196))	('miR-149-5p', 'Var', (40, 50))	('FoxM1', 'Gene', '2305', (200, 205))	('miR-149-5p', 'Chemical', '-', (40, 50))	('FoxM1', 'Gene', (200, 205))
127910	33398370	Moreover, miR-149-5p enhanced chemotherapeutic resistance through inactivation of the Hippo signaling pathway in ovarian cancer, whereas high levels of miR-149-3p were associated with the aggressive progression and poor prognosis of ovarian cancer.	('ovarian cancer', 'Phenotype', 'HP:0100615', (113, 127))	('associated', 'Reg', (168, 178))	('aggressive progression', 'CPA', (188, 210))	('chemotherapeutic resistance', 'MPA', (30, 57))	('ovarian cancer', 'Disease', 'MESH:D010051', (113, 127))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('enhanced', 'PosReg', (21, 29))	('miR-149-5p', 'Chemical', '-', (10, 20))	('ovarian cancer', 'Disease', 'MESH:D010051', (233, 247))	('miR-149-3p', 'Chemical', '-', (152, 162))	('miR-149-5p', 'Var', (10, 20))	('inactivation', 'NegReg', (66, 78))	('miR-149-3p', 'Var', (152, 162))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('ovarian cancer', 'Phenotype', 'HP:0100615', (233, 247))	('ovarian cancer', 'Disease', (113, 127))	('Hippo signaling pathway', 'Pathway', (86, 109))	('ovarian cancer', 'Disease', (233, 247))
127911	33398370	These results indicated a similar function between miR-149-3p and miR-149-5p.	('miR-149-3p', 'Var', (51, 61))	('miR-149-3p', 'Chemical', '-', (51, 61))	('miR-149-5p', 'Chemical', '-', (66, 76))	('miR-149-5p', 'Var', (66, 76))
127912	33398370	However, miR-149-5p and miR-149-3p exhibit diverse roles in cancer progression.	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('miR-149-3p', 'Var', (24, 34))	('miR-149-5p', 'Chemical', '-', (9, 19))	('cancer', 'Disease', (60, 66))	('miR-149-5p', 'Var', (9, 19))	('miR-149-3p', 'Chemical', '-', (24, 34))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
127914	33398370	Conversely, miR-149-5p acted as a tumor suppressor in NSCLC.	('tumor', 'Disease', (34, 39))	('NSCLC', 'Phenotype', 'HP:0030358', (54, 59))	('NSCLC', 'Disease', (54, 59))	('miR-149-5p', 'Chemical', '-', (12, 22))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('miR-149-5p', 'Var', (12, 22))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('NSCLC', 'Disease', 'MESH:D002289', (54, 59))
127915	33398370	In the present study, the data demonstrated that miR-149-3p overexpression reduced the viability and colony formation of OSCC cells, whereas knockdown of miR-149-3p induced the proliferation of OSCC cells.	('induced', 'PosReg', (165, 172))	('miR-149-3p', 'Var', (154, 164))	('OSCC', 'CellLine', 'CVCL:L894', (121, 125))	('colony formation of OSCC cells', 'CPA', (101, 131))	('viability', 'CPA', (87, 96))	('OSCC', 'CellLine', 'CVCL:L894', (194, 198))	('reduced', 'NegReg', (75, 82))	('miR-149-3p', 'Chemical', '-', (154, 164))	('miR-149-3p', 'Var', (49, 59))	('proliferation', 'CPA', (177, 190))	('miR-149-3p', 'Chemical', '-', (49, 59))
127916	33398370	Recent studies have revealed that lower levels of miR-149-5p were observed in OSCC tumor tissues compared with in adjacent normal tissues, whereas miR-149-5p overexpression resulted in attenuated proliferation and motility, as well as increased drug sensitivity, in OSCC cells.	('attenuated', 'NegReg', (185, 195))	('proliferation', 'CPA', (196, 209))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('miR-149-5p', 'Chemical', '-', (147, 157))	('miR-149-5p', 'Var', (147, 157))	('tumor', 'Disease', (83, 88))	('drug sensitivity', 'Phenotype', 'HP:0020174', (245, 261))	('OSCC', 'CellLine', 'CVCL:L894', (266, 270))	('OSCC', 'Disease', (78, 82))	('OSCC', 'CellLine', 'CVCL:L894', (78, 82))	('increased', 'PosReg', (235, 244))	('motility', 'CPA', (214, 222))	('overexpression', 'PosReg', (158, 172))	('miR-149-5p', 'Chemical', '-', (50, 60))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('drug sensitivity', 'CPA', (245, 261))
127917	33398370	These data, together with the present findings, indicated the tumor-suppressive functions of miR-149-5p and miR-149-3p in OSCC, and suggested that the dual strand of miR-149 may be a potential biomarker for the generation and development of OSCC.	('miR-149', 'Gene', '406941', (166, 173))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('OSCC', 'CellLine', 'CVCL:L894', (241, 245))	('dual strand', 'Var', (151, 162))	('tumor', 'Disease', (62, 67))	('miR-149-5p', 'Chemical', '-', (93, 103))	('miR-149', 'Gene', (108, 115))	('OSCC', 'Disease', (122, 126))	('miR-149', 'Gene', (93, 100))	('miR-149', 'Gene', (166, 173))	('miR-149', 'Gene', '406941', (93, 100))	('OSCC', 'CellLine', 'CVCL:L894', (122, 126))	('miR-149', 'Gene', '406941', (108, 115))	('OSCC', 'Disease', (241, 245))	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('miR-149-3p', 'Chemical', '-', (108, 118))
127920	33398370	In the present study, the results demonstrated that the miR-149-3p mimic significantly suppressed the mRNA and protein expression levels of AKT2.	('miR-149-3p mimic', 'Var', (56, 72))	('AKT2', 'Gene', (140, 144))	('suppressed', 'NegReg', (87, 97))	('miR-149-3p', 'Chemical', '-', (56, 66))	('AKT2', 'Gene', '208', (140, 144))
127921	33398370	In addition, miR-149-3p decreased the luciferase activity of WT AKT2 3'-UTR, whereas this effect was not noted in the MT AKT2 3'-UTR, suggesting that AKT2 was a direct target of miR-149-3p.	('AKT2', 'Gene', (121, 125))	('decreased', 'NegReg', (24, 33))	('activity', 'MPA', (49, 57))	('miR-149-3p', 'Var', (13, 23))	('AKT2', 'Gene', '208', (121, 125))	('AKT2', 'Gene', (64, 68))	('miR-149-3p', 'Chemical', '-', (13, 23))	('miR-149-3p', 'Chemical', '-', (178, 188))	('AKT2', 'Gene', '208', (64, 68))	('luciferase', 'Enzyme', (38, 48))	('AKT2', 'Gene', (150, 154))	('AKT2', 'Gene', '208', (150, 154))
127922	33398370	AKT2 overexpression reversed the miR-149-3p-mediated inhibitory effect on the proliferation of OSCC cells.	('proliferation of OSCC cells', 'CPA', (78, 105))	('miR-149-3p', 'Chemical', '-', (33, 43))	('OSCC', 'CellLine', 'CVCL:L894', (95, 99))	('miR-149-3p-mediated', 'Var', (33, 52))	('AKT2', 'Gene', (0, 4))	('AKT2', 'Gene', '208', (0, 4))
127926	33398370	Since AKT2 mRNA has been demonstrated to be regulated by diverse miRNAs, such as miR-194, miR-625-5p and miR-92a, the crosstalk of these miRNAs that controls the translational repression of AKT2 requires further exploration.	('mRNA', 'MPA', (11, 15))	('AKT2', 'Gene', '208', (6, 10))	('AKT2', 'Gene', (190, 194))	('AKT2', 'Gene', '208', (190, 194))	('miR-625', 'Gene', (90, 97))	('regulated', 'Reg', (44, 53))	('miR-92a', 'Var', (105, 112))	('AKT2', 'Gene', (6, 10))	('miR-625', 'Gene', '693210', (90, 97))	('miR-194', 'Var', (81, 88))
127931	33398370	In the present study, the results demonstrated that the miR-149-3p mimic strengthened 5-Fu-induced decreased cell viability, and increased protein expression levels of cleaved caspase-3 and cleaved PARP.	('protein expression levels', 'MPA', (139, 164))	('decreased', 'NegReg', (99, 108))	('cleaved', 'MPA', (190, 197))	('5-Fu', 'Chemical', 'MESH:D005472', (86, 90))	('increased', 'PosReg', (129, 138))	('caspase-3', 'Gene', '836', (176, 185))	('miR-149-3p', 'Var', (56, 66))	('strengthened', 'PosReg', (73, 85))	('5-Fu-induced', 'Disease', (86, 98))	('PARP', 'Gene', '1302', (198, 202))	('miR-149-3p', 'Chemical', '-', (56, 66))	('PARP', 'Gene', (198, 202))	('caspase-3', 'Gene', (176, 185))	('cell viability', 'CPA', (109, 123))
127933	33398370	PARP is one of the main cleavage targets of activated caspase-3, and cleavage of PARP facilitates cellular disassembly and promotes cell apoptosis.	('cell apoptosis', 'CPA', (132, 146))	('promotes', 'PosReg', (123, 131))	('PARP', 'Gene', '1302', (0, 4))	('caspase-3', 'Gene', (54, 63))	('cellular disassembly', 'CPA', (98, 118))	('PARP', 'Gene', (0, 4))	('PARP', 'Gene', (81, 85))	('cleavage', 'Var', (69, 77))	('facilitates', 'PosReg', (86, 97))	('caspase-3', 'Gene', '836', (54, 63))	('PARP', 'Gene', '1302', (81, 85))
127934	33398370	As cleaved caspase-3 and cleaved PARP are two representative markers of apoptosis, the present data further supported that miR-149-3p contributed to 5-Fu-mediated cell apoptosis.	('miR-149-3p', 'Var', (123, 133))	('caspase-3', 'Gene', '836', (11, 20))	('5-Fu', 'Chemical', 'MESH:D005472', (149, 153))	('caspase-3', 'Gene', (11, 20))	('miR-149-3p', 'Chemical', '-', (123, 133))	('PARP', 'Gene', '1302', (33, 37))	('PARP', 'Gene', (33, 37))	('5-Fu-mediated', 'MPA', (149, 162))
127936	33398370	In agreement with these findings, the methylation-mediated epigenetic silencing of miR-149-3p was previously discovered to be involved in chemoresistance in breast cancer cells.	('chemoresistance', 'CPA', (138, 153))	('breast cancer', 'Disease', 'MESH:D001943', (157, 170))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('miR-149-3p', 'Chemical', '-', (83, 93))	('breast cancer', 'Disease', (157, 170))	('involved', 'Reg', (126, 134))	('breast cancer', 'Phenotype', 'HP:0003002', (157, 170))	('miR-149-3p', 'Gene', (83, 93))	('methylation-mediated epigenetic silencing', 'Var', (38, 79))
127937	33398370	In addition, the decreased expression of miR-149-3p was noted in cisplatin-resistant colon cancer cells.	('cisplatin', 'Chemical', 'MESH:D002945', (65, 74))	('decreased', 'NegReg', (17, 26))	('colon cancer', 'Phenotype', 'HP:0003003', (85, 97))	('miR-149-3p', 'Var', (41, 51))	('expression', 'MPA', (27, 37))	('colon cancer', 'Disease', 'MESH:D015179', (85, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('miR-149-3p', 'Chemical', '-', (41, 51))	('colon cancer', 'Disease', (85, 97))
127938	33398370	Therefore, these observations indicated that miR-149-3p may be a promising target for overcoming chemotherapy resistance.	('miR-149-3p', 'Var', (45, 55))	('miR-149-3p', 'Chemical', '-', (45, 55))	('chemotherapy resistance', 'CPA', (97, 120))
127939	33398370	In conclusion, the present study revealed a novel molecular pathway by which miR-149-3p suppressed the proliferation of OSCC cells.	('miR-149-3p', 'Var', (77, 87))	('miR-149-3p', 'Chemical', '-', (77, 87))	('proliferation of OSCC cells', 'CPA', (103, 130))	('OSCC', 'CellLine', 'CVCL:L894', (120, 124))	('suppressed', 'NegReg', (88, 98))
127941	33398370	Furthermore, miR-149-3p enhanced the sensitivity of OSCC cells to 5-Fu.	('miR-149-3p', 'Var', (13, 23))	('OSCC', 'CellLine', 'CVCL:L894', (52, 56))	('5-Fu', 'Chemical', 'MESH:D005472', (66, 70))	('enhanced', 'PosReg', (24, 32))	('miR-149-3p', 'Chemical', '-', (13, 23))	('sensitivity', 'MPA', (37, 48))
127942	33398370	Therefore, these findings demonstrated an important role of miR-149-3p during OSCC progression and suggested that the restoration of miR-149-3p expression may be an effective therapeutic strategy for the treatment of OSCC.	('OSCC', 'CellLine', 'CVCL:L894', (217, 221))	('miR-149-3p', 'Var', (133, 143))	('restoration', 'Var', (118, 129))	('OSCC', 'Disease', (78, 82))	('OSCC', 'CellLine', 'CVCL:L894', (78, 82))	('miR-149-3p', 'Chemical', '-', (60, 70))	('miR-149-3p', 'Chemical', '-', (133, 143))	('OSCC', 'Disease', (217, 221))
127944	33322834	Efforts to develop such therapies are hindered by a genomic landscape dominated by the loss of tumor suppressor function, including NOTCH1 that is frequently mutated in HNSCC.	('loss', 'NegReg', (87, 91))	('NOTCH1', 'Gene', (132, 138))	('SCC', 'Phenotype', 'HP:0002860', (171, 174))	('HNSCC', 'Phenotype', 'HP:0012288', (169, 174))	('HNSCC', 'Disease', (169, 174))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('mutated', 'Var', (158, 165))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Disease', (95, 100))
127946	33322834	Structural characterization of NOTCH1 mutations in HNSCC demonstrates that most are predicted to cause loss of function, in agreement with NOTCH1's role as a tumor suppressor in this cancer.	('tumor', 'Disease', (158, 163))	('cancer', 'Disease', (183, 189))	('HNSCC', 'Phenotype', 'HP:0012288', (51, 56))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('loss of function', 'NegReg', (103, 119))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('NOTCH1', 'Gene', (31, 37))	('mutations', 'Var', (38, 47))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('cancer', 'Disease', 'MESH:D009369', (183, 189))	('SCC', 'Phenotype', 'HP:0002860', (53, 56))
127947	33322834	Experimental manipulation of NOTCH1 signaling in HNSCC cell lines harboring either mutant or wild-type NOTCH1 further supports a tumor suppressor function.	('HNSCC', 'Phenotype', 'HP:0012288', (49, 54))	('mutant', 'Var', (83, 89))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('SCC', 'Phenotype', 'HP:0002860', (51, 54))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('NOTCH1', 'Gene', (103, 109))	('tumor', 'Disease', (129, 134))
127950	33322834	The presence of NOTCH1 mutations may predict response to treatment with an immune checkpoint or phosphatidylinositol 3-kinase inhibitors.	('phosphatidylinositol 3-kinase', 'Gene', '5295', (96, 125))	('NOTCH1', 'Gene', (16, 22))	('mutations', 'Var', (23, 32))	('predict', 'Reg', (37, 44))	('phosphatidylinositol 3-kinase', 'Gene', (96, 125))
127956	33322834	Efforts to develop more targeted therapies for HNSCC are hampered by the genomic landscape of the disease, which is dominated by the loss or inactivation of tumor suppressor genes, and very few directly druggable oncogenic drivers.	('tumor', 'Disease', (157, 162))	('SCC', 'Phenotype', 'HP:0002860', (49, 52))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('inactivation', 'Var', (141, 153))	('HNSCC', 'Phenotype', 'HP:0012288', (47, 52))	('HNSCC', 'Disease', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))
127959	33322834	We recently reported that HNSCC cell lines harboring NOTCH1 loss of function (LOF) mutations are highly dependent on phosphatidylinositol 3-kinase (PI3K) signaling and that treatment with drugs blocking this pathway leads to tumor cell death in this genomic subtype.	('mutations', 'Var', (83, 92))	('tumor', 'Disease', 'MESH:D009369', (225, 230))	('loss of function', 'NegReg', (60, 76))	('NOTCH1', 'Gene', (53, 59))	('phosphatidylinositol 3-kinase', 'Gene', '5295', (117, 146))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('SCC', 'Phenotype', 'HP:0002860', (28, 31))	('tumor', 'Disease', (225, 230))	('HNSCC', 'Phenotype', 'HP:0012288', (26, 31))	('phosphatidylinositol 3-kinase', 'Gene', (117, 146))
127962	33322834	Given the importance of NOTCH1 in HNSCC, this review will provide an overview of NOTCH1 biology and signaling in HNSCC, a comprehensive examination of NOTCH1 mutations in HNSCC and other squamous cancers, and a discussion of NOTCH1's potential dual function in HNSCC.	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('HNSCC', 'Phenotype', 'HP:0012288', (261, 266))	('NOTCH1', 'Gene', (81, 87))	('SCC', 'Phenotype', 'HP:0002860', (173, 176))	('squamous cancers', 'Disease', (187, 203))	('cancers', 'Phenotype', 'HP:0002664', (196, 203))	('HNSCC', 'Disease', (171, 176))	('SCC', 'Phenotype', 'HP:0002860', (36, 39))	('SCC', 'Phenotype', 'HP:0002860', (115, 118))	('HNSCC', 'Phenotype', 'HP:0012288', (171, 176))	('HNSCC', 'Phenotype', 'HP:0012288', (113, 118))	('HNSCC', 'Phenotype', 'HP:0012288', (34, 39))	('NOTCH1', 'Gene', (151, 157))	('mutations', 'Var', (158, 167))	('HNSCC', 'Disease', (113, 118))	('SCC', 'Phenotype', 'HP:0002860', (263, 266))	('squamous cancers', 'Disease', 'MESH:D002294', (187, 203))
127963	33322834	Additionally, this review will provide an overview of clinical correlations and present our recent approach for targeting HNSCC patients whose tumors harbor NOTCH1 mutations.	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('HNSCC', 'Phenotype', 'HP:0012288', (122, 127))	('tumors', 'Disease', (143, 149))	('tumors', 'Disease', 'MESH:D009369', (143, 149))	('SCC', 'Phenotype', 'HP:0002860', (124, 127))	('NOTCH1', 'Gene', (157, 163))	('HNSCC', 'Disease', (122, 127))	('patients', 'Species', '9606', (128, 136))	('mutations', 'Var', (164, 173))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
127966	33322834	NOTCH1 is the most extensively studied and characterized NOTCH family member because its mutation prevalence among human cancers is higher than that for other members.	('cancers', 'Disease', (121, 128))	('higher', 'Reg', (132, 138))	('cancers', 'Disease', 'MESH:D009369', (121, 128))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('NOTCH', 'Gene', '31293', (57, 62))	('mutation', 'Var', (89, 97))	('human', 'Species', '9606', (115, 120))	('NOTCH', 'Gene', (57, 62))	('NOTCH', 'Gene', (0, 5))	('NOTCH', 'Gene', '31293', (0, 5))	('cancers', 'Phenotype', 'HP:0002664', (121, 128))
127967	33322834	Aberrant NOTCH1 signaling is implicated in the progression of various cancer types including breast cancer, leukemias, HNSCC and squamous cancers of the skin, esophagus, cervix, and lung.	('cancer', 'Disease', (138, 144))	('SCC', 'Phenotype', 'HP:0002860', (121, 124))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('breast cancer', 'Phenotype', 'HP:0003002', (93, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('squamous cancers', 'Disease', 'MESH:D002294', (129, 145))	('Aberrant', 'Var', (0, 8))	('leukemia', 'Phenotype', 'HP:0001909', (108, 116))	('esophagus', 'Disease', (159, 168))	('breast cancer', 'Disease', 'MESH:D001943', (93, 106))	('leukemias', 'Disease', 'MESH:D007938', (108, 117))	('breast cancer', 'Disease', (93, 106))	('cancer', 'Disease', (70, 76))	('HNSCC', 'Disease', (119, 124))	('cancer', 'Disease', 'MESH:D009369', (138, 144))	('leukemias', 'Phenotype', 'HP:0001909', (108, 117))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('squamous cancers of the skin', 'Phenotype', 'HP:0006739', (129, 157))	('cancer', 'Disease', (100, 106))	('HNSCC', 'Phenotype', 'HP:0012288', (119, 124))	('NOTCH1 signaling', 'Gene', (9, 25))	('leukemias', 'Disease', (108, 117))	('implicated', 'Reg', (29, 39))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('cancers of the skin', 'Phenotype', 'HP:0008069', (138, 157))	('cancers', 'Phenotype', 'HP:0002664', (138, 145))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('squamous cancers', 'Disease', (129, 145))
127978	33322834	Certain leukemias arise with inactivating FBXW7 mutations in the cancer cells that complement NOTCH1 activation by preventing ICN1 degradation.	('preventing', 'NegReg', (115, 125))	('FBXW7', 'Gene', '55294', (42, 47))	('inactivating', 'Var', (29, 41))	('leukemias', 'Phenotype', 'HP:0001909', (8, 17))	('FBXW7', 'Gene', (42, 47))	('ICN1 degradation', 'MPA', (126, 142))	('leukemias', 'Disease', (8, 17))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('leukemia', 'Phenotype', 'HP:0001909', (8, 16))	('arise', 'Reg', (18, 23))	('leukemias', 'Disease', 'MESH:D007938', (8, 17))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('mutations', 'Var', (48, 57))
127981	33322834	In a collaborative study by our group at the University of Texas MD Anderson Cancer Center and investigators at the Johns Hopkins University School of Medicine, WES performed with 32 primary tumors revealed frequent mutations of TP53, NOTCH1, CDKN2A, PIK3CA, FBXW7, and HRAS.	('Cancer', 'Disease', (77, 83))	('PIK3CA', 'Gene', (251, 257))	('CDKN2A', 'Gene', (243, 249))	('mutations', 'Var', (216, 225))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('tumors', 'Disease', (191, 197))	('Cancer', 'Disease', 'MESH:D009369', (77, 83))	('TP53', 'Gene', '7157', (229, 233))	('CDKN2A', 'Gene', '1029', (243, 249))	('tumors', 'Disease', 'MESH:D009369', (191, 197))	('FBXW7', 'Gene', (259, 264))	('tumors', 'Phenotype', 'HP:0002664', (191, 197))	('NOTCH1', 'Gene', (235, 241))	('HRAS', 'Gene', '3265', (270, 274))	('PIK3CA', 'Gene', '5290', (251, 257))	('HRAS', 'Gene', (270, 274))	('Cancer', 'Phenotype', 'HP:0002664', (77, 83))	('FBXW7', 'Gene', '55294', (259, 264))	('TP53', 'Gene', (229, 233))
127982	33322834	In that same work, focused sequencing of a validation cohort of 88 additional patient tumors established a NOTCH1 mutation prevalence rate of 15% in HNSCC cases.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('patient', 'Species', '9606', (78, 85))	('SCC', 'Phenotype', 'HP:0002860', (151, 154))	('HNSCC', 'Phenotype', 'HP:0012288', (149, 154))	('HNSCC', 'Disease', (149, 154))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('tumors', 'Disease', (86, 92))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('mutation', 'Var', (114, 122))	('NOTCH1', 'Gene', (107, 113))
127983	33322834	An independent study led by researchers at the Broad Institute and the UPMC Hillman Cancer Center demonstrated a similar incidence of frequently mutated genes and NOTCH1 mutations in 11% of HNSCC samples.	('NOTCH1', 'Gene', (163, 169))	('SCC', 'Phenotype', 'HP:0002860', (192, 195))	('mutations', 'Var', (170, 179))	('HNSCC', 'Disease', (190, 195))	('HNSCC', 'Phenotype', 'HP:0012288', (190, 195))	('UPMC Hillman Cancer', 'Disease', 'MESH:D009369', (71, 90))	('Cancer', 'Phenotype', 'HP:0002664', (84, 90))	('UPMC Hillman Cancer', 'Disease', (71, 90))
127985	33322834	Most missense mutations in both studies occurred within the EGF-like ligand binding domains, which was consistent with the hypothesis that these point mutations likely inactivate NOTCH1 function in tumors by interfering with receptor ligand binding.	('missense mutations', 'Var', (5, 23))	('inactivate', 'NegReg', (168, 178))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('tumors', 'Disease', (198, 204))	('point mutations', 'Var', (145, 160))	('function', 'MPA', (186, 194))	('NOTCH1', 'Gene', (179, 185))	('interfering', 'NegReg', (208, 219))	('tumors', 'Disease', 'MESH:D009369', (198, 204))	('tumors', 'Phenotype', 'HP:0002664', (198, 204))	('receptor ligand binding', 'Interaction', (225, 248))
127986	33322834	The locations and patterns of NOTCH1 mutations in HNSCC were in sharp contrast with the established NOTCH1 activating mutations in hematopoietic malignancies, as the latter are localized in the HD and PEST domains.	('hematopoietic malignancies', 'Disease', (131, 157))	('mutations', 'Var', (118, 127))	('activating', 'PosReg', (107, 117))	('NOTCH1', 'Gene', (30, 36))	('mutations', 'Var', (37, 46))	('HD', 'Disease', 'MESH:D006816', (194, 196))	('HNSCC', 'Phenotype', 'HP:0012288', (50, 55))	('SCC', 'Phenotype', 'HP:0002860', (52, 55))	('hematopoietic malignancies', 'Disease', 'MESH:D019337', (131, 157))	('NOTCH1', 'Gene', (100, 106))
127989	33322834	who reported that conditional knockout of Notch1 in mouse skin promoted cutaneous tumor formation.	('Notch1', 'Gene', (42, 48))	('mouse', 'Species', '10090', (52, 57))	('Notch1', 'Gene', '4851', (42, 48))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('cutaneous tumor', 'Phenotype', 'HP:0008069', (72, 87))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('promoted', 'PosReg', (63, 71))	('tumor', 'Disease', (82, 87))	('conditional knockout', 'Var', (18, 38))
127991	33322834	Following the initial discovery of NOTCH1 mutations in HNSCC, a number of groups reported frequent NOTCH1 mutations in multiple HNSCC patient cohorts spanning diverse geographical regions and etiological risk factors (Table 1).	('SCC', 'Phenotype', 'HP:0002860', (57, 60))	('SCC', 'Phenotype', 'HP:0002860', (130, 133))	('HNSCC', 'Phenotype', 'HP:0012288', (55, 60))	('HNSCC', 'Disease', (128, 133))	('HNSCC', 'Phenotype', 'HP:0012288', (128, 133))	('NOTCH1', 'Gene', (99, 105))	('mutations', 'Var', (106, 115))	('NOTCH1', 'Gene', (35, 41))	('mutations', 'Var', (42, 51))	('patient', 'Species', '9606', (134, 141))
127992	33322834	The same spectrum of NOTCH1 mutations is apparent regardless of whether smoking and alcohol use or smokeless tobacco use is the predominant risk factor.	('alcohol', 'Chemical', 'MESH:D000438', (84, 91))	('tobacco', 'Species', '4097', (109, 116))	('NOTCH1', 'Gene', (21, 27))	('alcohol use', 'Phenotype', 'HP:0030955', (84, 95))	('mutations', 'Var', (28, 37))
127993	33322834	Among HPV-negative enriched HNSCC patient cohorts, the reported frequencies of NOTCH1 truncating and missense mutations range from 4% to 10% and from 7% to 48%, respectively.	('missense mutations', 'Var', (101, 119))	('HNSCC', 'Phenotype', 'HP:0012288', (28, 33))	('HPV', 'Species', '10566', (6, 9))	('truncating', 'Var', (86, 96))	('patient', 'Species', '9606', (34, 41))	('NOTCH1', 'Gene', (79, 85))	('SCC', 'Phenotype', 'HP:0002860', (30, 33))
127994	33322834	The prevalence rate for NOTCH1 mutations is 17% in white and other non-Chinese HPV-negative HNSCC patient cohorts but 40% in Chinese patients.	('mutations', 'Var', (31, 40))	('patient', 'Species', '9606', (98, 105))	('HPV', 'Species', '10566', (79, 82))	('patient', 'Species', '9606', (133, 140))	('patients', 'Species', '9606', (133, 141))	('NOTCH1', 'Gene', (24, 30))	('HNSCC', 'Disease', (92, 97))	('SCC', 'Phenotype', 'HP:0002860', (94, 97))	('HNSCC', 'Phenotype', 'HP:0012288', (92, 97))
127995	33322834	Genomic studies of NOTCH1 mutations in HPV-driven oropharyngeal cancers (Table 1) demonstrated a spectrum of mutations similar to that in HPV-negative HNSCCs that are presumably inactivating.	('HNSCC', 'Phenotype', 'HP:0012288', (151, 156))	('HPV', 'Species', '10566', (138, 141))	('NOTCH1', 'Gene', (19, 25))	('HNSCCs', 'Phenotype', 'HP:0012288', (151, 157))	('cancers', 'Disease', 'MESH:D009369', (64, 71))	('HNSCCs', 'Disease', 'MESH:D000077195', (151, 157))	('cancers', 'Phenotype', 'HP:0002664', (64, 71))	('mutations', 'Var', (26, 35))	('cancers', 'Disease', (64, 71))	('HPV', 'Species', '10566', (39, 42))	('SCC', 'Phenotype', 'HP:0002860', (153, 156))	('HNSCCs', 'Disease', (151, 157))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
127996	33322834	The average frequency rate for NOTCH1 mutations in HPV-positive oropharyngeal cancers is 10%, which is roughly half of that in HPV-negative HNSCC.	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('HPV', 'Species', '10566', (51, 54))	('cancers', 'Disease', 'MESH:D009369', (78, 85))	('cancers', 'Phenotype', 'HP:0002664', (78, 85))	('SCC', 'Phenotype', 'HP:0002860', (142, 145))	('cancers', 'Disease', (78, 85))	('NOTCH1', 'Gene', (31, 37))	('mutations', 'Var', (38, 47))	('HPV', 'Species', '10566', (127, 130))	('HNSCC', 'Phenotype', 'HP:0012288', (140, 145))
127998	33322834	who used an elegant model of transposon-mediated insertional mutagenesis (i.e., "Sleeping Beauty") in mice with conditional co-expression of HPV E6/E7 in basal epithelium.	('HPV', 'Species', '10566', (141, 144))	('mice', 'Species', '10090', (102, 106))	('HPV', 'Gene', (141, 144))	('E6/E7', 'Var', (145, 150))
128002	33322834	Collectively, these data suggest that NOTCH1 LOF can contribute to carcinogenesis of both HPV-positive and -negative HNSCC, but that haploinsufficiency of NOTCH1 is sufficient when E6/E7 drivers are present too.	('HNSCC', 'Phenotype', 'HP:0012288', (117, 122))	('carcinogenesis', 'CPA', (67, 81))	('HNSCC', 'Disease', (117, 122))	('contribute', 'Reg', (53, 63))	('HPV', 'Species', '10566', (90, 93))	('haploinsufficiency', 'Disease', 'MESH:D058495', (133, 151))	('E6/E7 drivers', 'Var', (181, 194))	('NOTCH1', 'Gene', (38, 44))	('haploinsufficiency', 'Disease', (133, 151))	('NOTCH1', 'Gene', (155, 161))	('SCC', 'Phenotype', 'HP:0002860', (119, 122))	('LOF', 'NegReg', (45, 48))
128003	33322834	This hypothesis may explain the detection of fewer somatic NOTCH1 mutations in HPV-positive HNSCC cohorts, as there could be a reduced necessity to inactivate both alleles in this genomic subtype.	('mutations', 'Var', (66, 75))	('HPV', 'Species', '10566', (79, 82))	('SCC', 'Phenotype', 'HP:0002860', (94, 97))	('HNSCC', 'Phenotype', 'HP:0012288', (92, 97))	('NOTCH1', 'Gene', (59, 65))
128004	33322834	Because the locations and patterns of NOTCH1 mutations in HNSCC and T cell acute lymphoblastic leukemia (T-ALL) were distinct, we pooled data available from genomic studies in the Catalogue Of Somatic Mutations In Cancer (COSMIC) database and The Cancer Genome Atlas (TCGA) Pan-Cancer Analysis of Whole Genomes Consortium in order to compare the structure of NOTCH1 mutations in T-ALL and HNSCC patients.	('SCC', 'Phenotype', 'HP:0002860', (391, 394))	('Cancer', 'Disease', 'MESH:D009369', (214, 220))	('patients', 'Species', '9606', (395, 403))	('NOTCH1', 'Gene', (38, 44))	('HNSCC', 'Phenotype', 'HP:0012288', (58, 63))	('HNSCC and T cell acute lymphoblastic leukemia', 'Disease', 'MESH:D054218', (58, 103))	('Cancer', 'Phenotype', 'HP:0002664', (247, 253))	('Cancer', 'Phenotype', 'HP:0002664', (278, 284))	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (75, 103))	('Cancer', 'Phenotype', 'HP:0002664', (214, 220))	('T-ALL', 'Phenotype', 'HP:0006727', (379, 384))	('Cancer', 'Disease', (247, 253))	('HNSCC', 'Phenotype', 'HP:0012288', (389, 394))	('Cancer', 'Disease', (278, 284))	('SCC', 'Phenotype', 'HP:0002860', (60, 63))	('Cancer', 'Disease', (214, 220))	('NOTCH1', 'Gene', (359, 365))	('T cell acute lymphoblastic leukemia', 'Phenotype', 'HP:0006727', (68, 103))	('mutations', 'Var', (45, 54))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (81, 103))	('Cancer', 'Disease', 'MESH:D009369', (247, 253))	('Cancer', 'Disease', 'MESH:D009369', (278, 284))	('leukemia', 'Phenotype', 'HP:0001909', (95, 103))	('T-ALL', 'Phenotype', 'HP:0006727', (105, 110))
128006	33322834	C-terminal truncating mutations that delete the PEST domain in T-ALL cases are known to prevent ICN1's interaction with FBXW7 and contribute to prolonged nuclear signaling by ICN1.	('FBXW7', 'Gene', '55294', (120, 125))	('prevent', 'NegReg', (88, 95))	('FBXW7', 'Gene', (120, 125))	('prolonged', 'PosReg', (144, 153))	('T-ALL', 'Phenotype', 'HP:0006727', (63, 68))	('interaction', 'Interaction', (103, 114))	('PEST domain', 'MPA', (48, 59))	('delete', 'Var', (37, 43))	('nuclear signaling', 'MPA', (154, 171))	('ICN1', 'Gene', (96, 100))
128008	33322834	A second hotspot for activating NOTCH1 mutations in T-ALL patients is within the HD domain (Figure 3).	('NOTCH1', 'Gene', (32, 38))	('activating', 'PosReg', (21, 31))	('HD', 'Disease', 'MESH:D006816', (81, 83))	('mutations', 'Var', (39, 48))	('T-ALL', 'Phenotype', 'HP:0006727', (52, 57))	('patients', 'Species', '9606', (58, 66))
128009	33322834	As expected, the proportion of missense and INDEL mutations observed for HNSCC in the HD domain is extremely low.	('HNSCC', 'Gene', (73, 78))	('HD', 'Disease', 'MESH:D006816', (86, 88))	('missense', 'Var', (31, 39))	('INDEL mutations', 'Var', (44, 59))	('HNSCC', 'Phenotype', 'HP:0012288', (73, 78))	('SCC', 'Phenotype', 'HP:0002860', (75, 78))
128010	33322834	Observed missense mutations are enriched in the EGF2, EGF4, EGF8, EGF9, EGF10, EGF11, EGF12, EGF29, EGF31, RAM, and ANK1 domains in HNSCC, suggesting that mutations in these regions are likely to inactivate NOTCH1 signaling.	('EGF11', 'Gene', (79, 84))	('mutations', 'Var', (155, 164))	('SCC', 'Phenotype', 'HP:0002860', (134, 137))	('EGF29', 'Gene', (93, 98))	('EGF10', 'Gene', (72, 77))	('EGF12', 'Gene', (86, 91))	('EGF2', 'Gene', (48, 52))	('NOTCH1 signaling', 'MPA', (207, 223))	('EGF8', 'Gene', (60, 64))	('HNSCC', 'Phenotype', 'HP:0012288', (132, 137))	('EGF4', 'Gene', (54, 58))	('EGF9', 'Gene', (66, 70))	('inactivate', 'NegReg', (196, 206))	('ANK1', 'Gene', '286', (116, 120))	('missense mutations', 'Var', (9, 27))	('ANK1', 'Gene', (116, 120))
128011	33322834	Missense mutations observed less frequently for the other domains in HNSCC tumors may represent passenger events.	('HNSCC', 'Phenotype', 'HP:0012288', (69, 74))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('HNSCC tumors', 'Disease', (69, 81))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('SCC', 'Phenotype', 'HP:0002860', (71, 74))	('HNSCC tumors', 'Disease', 'MESH:D000077195', (69, 81))	('Missense mutations', 'Var', (0, 18))
128012	33322834	In support of this conclusion, we previously demonstrated loss of NOTCH1 signaling in the established HNSCC cell line HN31 that carries a homozygous NOTCH1 mutation (C478F) in the EGF12 domain.	('NOTCH1', 'Gene', (149, 155))	('NOTCH1 signaling', 'MPA', (66, 82))	('loss', 'NegReg', (58, 62))	('C478F', 'Mutation', 'p.C478F', (166, 171))	('C478F', 'Var', (166, 171))	('SCC', 'Phenotype', 'HP:0002860', (104, 107))	('HNSCC', 'Phenotype', 'HP:0012288', (102, 107))
128014	33322834	One limitation of the in silico analysis is that few NOTCH1 mutations have been functionally characterized as we did for C478F.	('mutations', 'Var', (60, 69))	('C478F', 'Mutation', 'p.C478F', (121, 126))	('NOTCH1', 'Gene', (53, 59))
128015	33322834	In T-ALL cases (Figure 3), we found many more missense/INDEL mutations in the HD domain than expected by chance (n = 768 out of 843) (35), which was consistent with previous studies demonstrating that missense and in-frame mutations in this domain activate NOTCH1 signaling.	('activate', 'PosReg', (248, 256))	('T-ALL', 'Phenotype', 'HP:0006727', (3, 8))	('missense', 'Var', (201, 209))	('HD', 'Disease', 'MESH:D006816', (78, 80))	('missense/INDEL mutations', 'Var', (46, 70))	('NOTCH1', 'Pathway', (257, 263))
128016	33322834	Because a disproportionally large number of observed NOTCH1 mutations in T-ALL cases mapped to the HD domain (92%), it skewed the estimated number of mutations expected to be randomly distributed over the remaining regions.	('mutations', 'Var', (60, 69))	('HD', 'Disease', 'MESH:D006816', (99, 101))	('NOTCH1', 'Gene', (53, 59))	('T-ALL', 'Phenotype', 'HP:0006727', (73, 78))
128017	33322834	We found enrichment in NOTCH1 missense mutations in the PEST and the Lin-12/NOTCH repeat 3 (LNR3) domains relative to the expected numbers, which was consistent with reports that mutations in these regulatory regions lead to NOTCH1 activation in hematological cancers.	('NOTCH', 'Gene', (76, 81))	('NOTCH', 'Gene', '31293', (76, 81))	('NOTCH', 'Gene', (225, 230))	('NOTCH', 'Gene', (23, 28))	('missense mutations', 'Var', (30, 48))	('activation', 'PosReg', (232, 242))	('NOTCH', 'Gene', '31293', (23, 28))	('cancers', 'Phenotype', 'HP:0002664', (260, 267))	('hematological cancers', 'Disease', 'MESH:D009369', (246, 267))	('mutations', 'Var', (179, 188))	('cancer', 'Phenotype', 'HP:0002664', (260, 266))	('hematological cancers', 'Disease', (246, 267))	('NOTCH', 'Gene', '31293', (225, 230))
128018	33322834	A more precise algorithm that takes these and other confounding issues into account while predicting the likely functional impact of NOTCH1 mutations in cancer patients is currently under development by our group (manuscript in preparation).	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('patients', 'Species', '9606', (160, 168))	('cancer', 'Disease', (153, 159))	('NOTCH1', 'Gene', (133, 139))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('mutations', 'Var', (140, 149))
128019	33322834	Activating NOTCH1 mutations are largely absent from HNSCCs based on more than 500 TCGA patient tumors analyzed and from the majority of other genomic studies in which NOTCH1 was sequenced, including patient cohorts in Japan, India, Europe, Latin America, or the United States (Table 1).	('HNSCCs', 'Disease', (52, 58))	('Activating', 'PosReg', (0, 10))	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('HNSCC', 'Phenotype', 'HP:0012288', (52, 57))	('HNSCCs', 'Phenotype', 'HP:0012288', (52, 58))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('patient', 'Species', '9606', (199, 206))	('HNSCCs', 'Disease', 'MESH:D000077195', (52, 58))	('patient', 'Species', '9606', (87, 94))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('NOTCH1', 'Gene', (11, 17))	('SCC', 'Phenotype', 'HP:0002860', (54, 57))	('tumors', 'Disease', (95, 101))	('mutations', 'Var', (18, 27))
128020	33322834	However, two independent groups examining HNSCC in Chinese patients reported NOTCH1 mutations that were potentially activating alongside the usual profile of LOF mutations.	('HNSCC', 'Phenotype', 'HP:0012288', (42, 47))	('activating', 'PosReg', (116, 126))	('NOTCH1', 'Gene', (77, 83))	('mutations', 'Var', (84, 93))	('patients', 'Species', '9606', (59, 67))	('SCC', 'Phenotype', 'HP:0002860', (44, 47))
128023	33322834	In fact, one of the scientists who originally reported a hotspot mutation (C1133Y) in the NOTCH1 Abruptex region of Chinese HNSCC patients subsequently cloned the mutation and discovered that it prevented expression of NOTCH1 at the cell surface and a complete loss of canonical NOTCH1 signaling.	('canonical NOTCH1 signaling', 'MPA', (269, 295))	('loss', 'NegReg', (261, 265))	('prevented', 'NegReg', (195, 204))	('expression', 'MPA', (205, 215))	('SCC', 'Phenotype', 'HP:0002860', (126, 129))	('C1133Y', 'Mutation', 'p.C1133Y', (75, 81))	('HNSCC', 'Phenotype', 'HP:0012288', (124, 129))	('patients', 'Species', '9606', (130, 138))	('NOTCH1', 'Gene', (90, 96))	('C1133Y', 'Var', (75, 81))
128024	33322834	A total of 18 potentially activating missense mutations in the NOTCH1 HD domain have been identified in tumors from Chinese HNSCC patients.	('missense mutations', 'Var', (37, 55))	('activating', 'PosReg', (26, 36))	('HD', 'Disease', 'MESH:D006816', (70, 72))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('SCC', 'Phenotype', 'HP:0002860', (126, 129))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('HNSCC', 'Phenotype', 'HP:0012288', (124, 129))	('tumors', 'Disease', (104, 110))	('patients', 'Species', '9606', (130, 138))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('NOTCH1', 'Gene', (63, 69))
128025	33322834	The majority of these were reported by Song et al., who identified two recurrent hotspot amino acid mutations (P1641S/L and N1713D) found in 10 patients.	('N1713D', 'Mutation', 'rs905363739', (124, 130))	('patients', 'Species', '9606', (144, 152))	('P1641S', 'SUBSTITUTION', 'None', (111, 117))	('P1641S', 'Var', (111, 117))	('N1713D', 'Var', (124, 130))
128027	33322834	HD and PEST domain missense mutations are prevalent in T-ALL, where they lead to increased NOTCH1 signaling, driving tumor formation.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumor', 'Disease', (117, 122))	('HD', 'Disease', 'MESH:D006816', (0, 2))	('NOTCH1 signaling', 'MPA', (91, 107))	('T-ALL', 'Phenotype', 'HP:0006727', (55, 60))	('increased', 'PosReg', (81, 90))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('missense mutations', 'Var', (19, 37))
128030	33322834	It is widely accepted that mutations occur in a more or less random fashion in tumors, but there is selective outgrowth (i.e., over-representation) only when a mutation conveys some advantage.	('mutation', 'Var', (160, 168))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('tumors', 'Disease', (79, 85))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
128031	33322834	If there is no advantage, then both non-impactful and impactful mutations will occur at theoretical frequencies that can be calculated based on the codon usage of a gene, known frequency of the different types of DNA base pair changes in a cancer type, and pre-calculated PROVEAN and SIFT scores for all possible mutations obtainable from single base pair substitutions.	('cancer', 'Disease', (240, 246))	('cancer', 'Disease', 'MESH:D009369', (240, 246))	('mutations', 'Var', (64, 73))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))
128033	33322834	Estimating the cancer type-specific frequencies of DNA base pair changes from whole exome sequencing in T-ALL or the HNSCC TCGA, we calculated the theoretical frequencies expected for impactful and non-impactful mutations in the HD and PEST domains, assuming a random mutation model, and compared them to what was observed (Supplementary Materials Table S1).	('HNSCC', 'Phenotype', 'HP:0012288', (117, 122))	('cancer', 'Disease', (15, 21))	('cancer', 'Disease', 'MESH:D009369', (15, 21))	('HD', 'Disease', 'MESH:D006816', (229, 231))	('mutations', 'Var', (212, 221))	('T-ALL', 'Phenotype', 'HP:0006727', (104, 109))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('SCC', 'Phenotype', 'HP:0002860', (119, 122))
128036	33322834	Hotspot mutations observed in multiple patients are represented by larger circles, with the diameter of each circle proportional to the number of patients with a specific cancer type having the mutation.	('patients', 'Species', '9606', (39, 47))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('mutations', 'Var', (8, 17))	('cancer', 'Disease', (171, 177))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('patients', 'Species', '9606', (146, 154))
128037	33322834	Many hotspot HD domain NOTCH1 mutations in the T-ALL patients mapped to the lower left quadrant, indicating a high probability that their amino acid substitutions altered protein function.	('T-ALL', 'Phenotype', 'HP:0006727', (47, 52))	('patients', 'Species', '9606', (53, 61))	('altered', 'Reg', (163, 170))	('mutations', 'Var', (30, 39))	('mapped', 'Reg', (62, 68))	('HD', 'Disease', 'MESH:D006816', (13, 15))	('protein', 'Protein', (171, 178))
128040	33322834	The majority of the T-ALL mutations predicted to be deleterious were in three distinct clusters, whereas the mutations in the Chinese HNSCC patients were outside these clusters and topologically overlapped the T-ALL mutations predicted to be neutral.	('SCC', 'Phenotype', 'HP:0002860', (136, 139))	('T-ALL', 'Phenotype', 'HP:0006727', (20, 25))	('T-ALL', 'Gene', (20, 25))	('mutations', 'Var', (26, 35))	('T-ALL', 'Phenotype', 'HP:0006727', (210, 215))	('patients', 'Species', '9606', (140, 148))	('HNSCC', 'Phenotype', 'HP:0012288', (134, 139))
128041	33322834	Collectively, these analyses suggest striking differences between the NOTCH1 HD domain missense mutations in T-ALL and Chinese HNSCC patients, decreasing the likelihood that the mutations in the latter group are strongly activating.	('SCC', 'Phenotype', 'HP:0002860', (129, 132))	('T-ALL', 'Phenotype', 'HP:0006727', (109, 114))	('HD', 'Disease', 'MESH:D006816', (77, 79))	('patients', 'Species', '9606', (133, 141))	('decreasing', 'NegReg', (143, 153))	('NOTCH1', 'Gene', (70, 76))	('activating', 'MPA', (221, 231))	('mutations', 'Var', (178, 187))	('HNSCC', 'Phenotype', 'HP:0012288', (127, 132))
128042	33322834	Some support for this comes from the missense mutations occurring in the LNR3 domain (immediately proximal to the HD domain region) found in four Chinese patient tumors from the study by Izumchenko et al., which are predicted to be deleterious by their PROVEAN/SIFT values (not shown).	('missense mutations', 'Var', (37, 55))	('LNR3', 'Gene', (73, 77))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('patient', 'Species', '9606', (154, 161))	('HD', 'Disease', 'MESH:D006816', (114, 116))	('tumors', 'Disease', (162, 168))	('tumors', 'Disease', 'MESH:D009369', (162, 168))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))
128043	33322834	Mutations in the HD domain far outnumber those in the LNR3 domain by two orders of magnitude in T-ALL, despite the only fivefold difference in size, further supporting that the latter may produce a weaker phenotype.	('T-ALL', 'Phenotype', 'HP:0006727', (96, 101))	('Mutations', 'Var', (0, 9))	('HD', 'Disease', 'MESH:D006816', (17, 19))	('T-ALL', 'MPA', (96, 101))
128044	33322834	Our group and others have comprehensively profiled the genetic alterations in established HNSCC cell lines and found that somatic mutations and DNA copy number changes faithfully recapitulate the genomic landscape and driver events identified for primary HNSCC tumors.	('HNSCC', 'Phenotype', 'HP:0012288', (255, 260))	('SCC', 'Phenotype', 'HP:0002860', (257, 260))	('tumor', 'Phenotype', 'HP:0002664', (261, 266))	('HNSCC', 'Phenotype', 'HP:0012288', (90, 95))	('tumors', 'Phenotype', 'HP:0002664', (261, 267))	('HNSCC tumors', 'Disease', (255, 267))	('mutations', 'Var', (130, 139))	('HNSCC tumors', 'Disease', 'MESH:D000077195', (255, 267))	('SCC', 'Phenotype', 'HP:0002860', (92, 95))
128045	33322834	WES of 56 HPV-negative and nine HPV-positive established HNSCC cell lines identified a total of 19 nonsynonymous NOTCH1 mutations among 17 cell lines (Supplementary Materials Table S2), including two that were also HPV positive.	('HPV', 'Species', '10566', (10, 13))	('SCC', 'Phenotype', 'HP:0002860', (59, 62))	('NOTCH1', 'Gene', (113, 119))	('HPV', 'Species', '10566', (215, 218))	('HPV', 'Species', '10566', (32, 35))	('mutations', 'Var', (120, 129))	('HNSCC', 'Phenotype', 'HP:0012288', (57, 62))
128046	33322834	Roughly, 25% of HPV-negative cell lines examined contained a NOTCH1 mutation and most were homozygous alterations predicted to be inactivating.	('contained', 'Reg', (49, 58))	('NOTCH1', 'Gene', (61, 67))	('mutation', 'Var', (68, 76))	('HPV', 'Species', '10566', (16, 19))
128048	33322834	Initially, the activated form of wt NOTCH1 (i.e., ICN1) was stably re-expressed in the NOTCH1 mutant HNSCC cell lines HN4, PCI-15B, UMSCC-47, and HN31 using a green fluorescent protein-tagged bicistronic retroviral vector (MigR1-ICN1).	('SCC', 'Phenotype', 'HP:0002860', (134, 137))	('HNSCC', 'Phenotype', 'HP:0012288', (101, 106))	('UMSCC-47', 'CellLine', 'CVCL:7759', (132, 140))	('HN4', 'Gene', '100463285', (118, 121))	('mutant', 'Var', (94, 100))	('SCC', 'Phenotype', 'HP:0002860', (103, 106))	('HN4', 'Gene', (118, 121))	('NOTCH1', 'Gene', (87, 93))
128049	33322834	To model a more physiological response, a full-length wt NOTCH1 gene was subcloned into MigR1 and expressed in NOTCH1 mutant cell lines where it was found to significantly impair proliferation in cells grown on JAG1 or injected into mice.	('proliferation', 'CPA', (179, 192))	('mice', 'Species', '10090', (233, 237))	('impair', 'NegReg', (172, 178))	('mutant', 'Var', (118, 124))	('NOTCH1', 'Gene', (111, 117))
128050	33322834	These experiments demonstrated the tumor-suppressive capacity of NOTCH1 signaling in naturally occurring NOTCH1 mutant cell lines.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('NOTCH1', 'Gene', (105, 111))	('tumor', 'Disease', (35, 40))	('mutant', 'Var', (112, 118))
128052	33322834	They studied the significance of recurrent but infrequently mutated genes ("long tail" mutations) in HNSCC using an in vivo CRISPR screen of 484 genes to identify those that lead to cancer formation when mutated in various, relevant oncogenic backgrounds.	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('long tail', 'Phenotype', 'HP:0002831', (76, 85))	('HNSCC', 'Phenotype', 'HP:0012288', (101, 106))	('mutated', 'Var', (204, 211))	('lead to', 'Reg', (174, 181))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('SCC', 'Phenotype', 'HP:0002860', (103, 106))	('cancer', 'Disease', (182, 188))
128054	33322834	They estimate that 67% of human HNSCC patients have NOTCH pathway inactivation:including about 27% with inactivating NOTCH1/2/3 mutations and about 40% with inactivating alterations of ADAM10, RIPK4, or AJUBA or amplification of NUMB, an AJUBA interactor.	('SCC', 'Phenotype', 'HP:0002860', (34, 37))	('ADAM10', 'Gene', (185, 191))	('patients', 'Species', '9606', (38, 46))	('human', 'Species', '9606', (26, 31))	('NOTCH', 'Gene', '31293', (52, 57))	('NOTCH', 'Gene', (117, 122))	('mutations', 'Var', (128, 137))	('alterations', 'Var', (170, 181))	('NUMB', 'Gene', (229, 233))	('inactivation', 'NegReg', (66, 78))	('ADAM10', 'Gene', '102', (185, 191))	('AJUBA', 'Gene', '84962', (238, 243))	('NOTCH', 'Gene', (52, 57))	('AJUBA', 'Gene', (238, 243))	('RIPK4', 'Gene', (193, 198))	('HNSCC', 'Phenotype', 'HP:0012288', (32, 37))	('NUMB', 'Gene', '8650', (229, 233))	('RIPK4', 'Gene', '54101', (193, 198))	('AJUBA', 'Gene', '84962', (203, 208))	('inactivating', 'NegReg', (104, 116))	('NOTCH', 'Gene', '31293', (117, 122))	('AJUBA', 'Gene', (203, 208))
128056	33322834	For example, basal levels of activated NOTCH1 are much lower in PJ34 compared to FaDu cells (Figure 7A), which may explain why the latter has frequently been used to study NOTCH1 function in HNSCC.	('NOTCH1', 'Gene', (39, 45))	('PJ34', 'Var', (64, 68))	('PJ34', 'Chemical', 'MESH:C434926', (64, 68))	('HNSCC', 'Phenotype', 'HP:0012288', (191, 196))	('lower', 'NegReg', (55, 60))	('SCC', 'Phenotype', 'HP:0002860', (193, 196))	('basal levels', 'MPA', (13, 25))
128065	33322834	Only one EMT marker was upregulated by JAG1 exposure, while two common markers of EMT, vimentin (VIM) and fibronectin 1 (FN1), went down.	('vimentin', 'Gene', '7431', (87, 95))	('VIM', 'Gene', (97, 100))	('vimentin', 'Gene', (87, 95))	('fibronectin 1', 'Gene', '2335', (106, 119))	('upregulated', 'PosReg', (24, 35))	('JAG1', 'Var', (39, 43))	('VIM', 'Gene', '7431', (97, 100))	('FN1', 'Gene', '2335', (121, 124))	('FN1', 'Gene', (121, 124))	('fibronectin 1', 'Gene', (106, 119))
128069	33322834	Multiple authors have reported that blocking NOTCH1 function with shRNA leads to a decrease in HNSCC tumor spheroid growth in three-dimensional (3-D) cultures, and conversely expression of ICN1 can increase survival and growth of spheroids or enhance tumor growth in mice.	('tumor', 'Disease', (251, 256))	('increase', 'PosReg', (198, 206))	('SCC', 'Phenotype', 'HP:0002860', (97, 100))	('tumor', 'Disease', 'MESH:D009369', (251, 256))	('mice', 'Species', '10090', (267, 271))	('growth of spheroids', 'CPA', (220, 239))	('HNSCC tumor', 'Disease', 'MESH:D000077195', (95, 106))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('decrease', 'NegReg', (83, 91))	('NOTCH1', 'Gene', (45, 51))	('tumor', 'Phenotype', 'HP:0002664', (251, 256))	('enhance', 'PosReg', (243, 250))	('expression', 'Var', (175, 185))	('ICN1', 'Gene', (189, 193))	('HNSCC', 'Phenotype', 'HP:0012288', (95, 100))	('tumor', 'Disease', (101, 106))	('HNSCC tumor', 'Disease', (95, 106))	('blocking', 'NegReg', (36, 44))	('function', 'MPA', (52, 60))	('survival', 'CPA', (207, 215))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
128075	33322834	Because NOTCH1 receptors compete with NOTCH2 receptors for the same ligands in the context of cis-inhibition (i.e., co-expression on the same cell), it is unknown how changing this dynamic could impact NOTCH2 signaling in cells where NOTCH1 is knocked down.	('NOTCH2', 'Gene', (202, 208))	('NOTCH2', 'Gene', (38, 44))	('impact', 'Reg', (195, 201))	('NOTCH2', 'Gene', '4853', (202, 208))	('knocked down', 'Var', (244, 256))	('NOTCH2', 'Gene', '4853', (38, 44))	('NOTCH1', 'Gene', (234, 240))
128078	33322834	Our laboratory confirmed that SOX2 and ALDH3A1 mRNA was strongly upregulated after NOTCH1 signaling in vitro (Supplementary Materials Table S3).	('ALDH3A1', 'Gene', '218', (39, 46))	('ALDH3A1', 'Gene', (39, 46))	('mRNA', 'MPA', (47, 51))	('SOX2', 'Gene', '6657', (30, 34))	('upregulated', 'PosReg', (65, 76))	('SOX2', 'Gene', (30, 34))	('NOTCH1', 'Var', (83, 89))
128085	33322834	Studies in mouse esophageal epithelium have demonstrated that loss of NOTCH1 signaling, rather than activation, leads to localized clonal expansion of basal stem cells harboring defective NOTCH1 that outcompete neighboring stem cells with NOTCH1 signaling still intact.	('loss', 'NegReg', (62, 66))	('basal stem cells', 'CPA', (151, 167))	('mouse', 'Species', '10090', (11, 16))	('defective', 'Var', (178, 187))	('NOTCH1', 'Gene', (188, 194))	('NOTCH1', 'Gene', (70, 76))
128086	33322834	Additional evidence demonstrating the selective advantage and clonal expansion of basal stem cells harboring NOTCH1 LOF mutations comes from mathematical modeling in a study that used deep sequencing data from non-cancerous sun-exposed skin in humans.	('cancer', 'Disease', (214, 220))	('NOTCH1', 'Gene', (109, 115))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('mutations', 'Var', (120, 129))	('LOF', 'NegReg', (116, 119))	('humans', 'Species', '9606', (244, 250))	('cancer', 'Disease', 'MESH:D009369', (214, 220))
128087	33322834	The basal stem cell marker keratin 14 (KRT14) was downregulated by NOTCH1 signaling, while the early differentiation markers KRT13 and KRT4 are conversely upregulated by NOTCH1 activation in vitro (Supplementary Materials Table S3).	('NOTCH1', 'Var', (170, 176))	('KRT13', 'Gene', '3860', (125, 130))	('keratin 14', 'Gene', '3861', (27, 37))	('keratin 14', 'Gene', (27, 37))	('NOTCH1 signaling', 'Var', (67, 83))	('KRT14', 'Gene', (39, 44))	('upregulated', 'PosReg', (155, 166))	('KRT13', 'Gene', (125, 130))	('downregulated', 'NegReg', (50, 63))	('KRT4', 'Gene', (135, 139))	('basal stem cell', 'CPA', (4, 19))	('KRT4', 'Gene', '3851', (135, 139))
128113	33322834	Moreover, NOTCH1 depletion in a HNSCC cell line led to c-Myc downregulation and thereby reduced EMT and invasion.	('c-Myc', 'Gene', '4609', (55, 60))	('downregulation', 'NegReg', (61, 75))	('SCC', 'Phenotype', 'HP:0002860', (34, 37))	('reduced EMT', 'Phenotype', 'HP:0032198', (88, 99))	('c-Myc', 'Gene', (55, 60))	('a HNSCC', 'CellLine', 'CVCL:5985', (30, 37))	('HNSCC', 'Phenotype', 'HP:0012288', (32, 37))	('depletion', 'Var', (17, 26))	('reduced', 'NegReg', (88, 95))	('NOTCH1', 'Gene', (10, 16))
128119	33322834	NOTCH pathway alterations have been implicated in many of these SCCs, with NOTCH1 being the most commonly mutated gene besides TP53.	('alterations', 'Var', (14, 25))	('implicated', 'Reg', (36, 46))	('NOTCH', 'Gene', (75, 80))	('NOTCH', 'Gene', '31293', (75, 80))	('NOTCH', 'Gene', (0, 5))	('NOTCH', 'Gene', '31293', (0, 5))	('SCCs', 'Disease', (64, 68))	('TP53', 'Gene', '7157', (127, 131))	('TP53', 'Gene', (127, 131))	('SCC', 'Phenotype', 'HP:0002860', (64, 67))
128121	33322834	A study of Japanese ESCC patients found LOF NOTCH1 mutations in 18.6% of ESCC.	('mutations', 'Var', (51, 60))	('LOF', 'NegReg', (40, 43))	('SCC', 'Phenotype', 'HP:0002860', (21, 24))	('NOTCH1', 'Gene', (44, 50))	('patients', 'Species', '9606', (25, 33))	('ESCC', 'Disease', (73, 77))	('SCC', 'Phenotype', 'HP:0002860', (74, 77))
128122	33322834	NOTCH1 mutations are found in roughly 7% of cervical squamous cell carcinoma (CSCC) TCGA patient samples.	('cervical squamous cell carcinoma', 'Disease', (44, 76))	('patient', 'Species', '9606', (89, 96))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (53, 76))	('SCC', 'Phenotype', 'HP:0002860', (79, 82))	('cervical squamous cell carcinoma', 'Disease', 'MESH:D002294', (44, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('NOTCH1', 'Gene', (0, 6))	('mutations', 'Var', (7, 16))
128123	33322834	Two of the CSCC NOTCH1 missense mutations that localize to the HD domain resemble those reported for HNSCC Chinese patients in that their combined SIFT and PROVEAN scores do not suggest a potent phenotype.	('missense mutations', 'Var', (23, 41))	('patients', 'Species', '9606', (115, 123))	('HNSCC', 'Phenotype', 'HP:0012288', (101, 106))	('CSCC NOTCH1', 'Gene', (11, 22))	('SCC', 'Phenotype', 'HP:0002860', (103, 106))	('SCC', 'Phenotype', 'HP:0002860', (12, 15))	('HD', 'Disease', 'MESH:D006816', (63, 65))
128127	33322834	found ICN1 staining by IHC in HNSCC tumor samples from patients with truncating NOTCH1 mutations, presumably due to a remaining wt allele.	('HNSCC tumor', 'Disease', 'MESH:D000077195', (30, 41))	('HNSCC tumor', 'Disease', (30, 41))	('SCC', 'Phenotype', 'HP:0002860', (32, 35))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('patients', 'Species', '9606', (55, 63))	('HNSCC', 'Phenotype', 'HP:0012288', (30, 35))	('NOTCH1', 'Gene', (80, 86))	('mutations', 'Var', (87, 96))
128128	33322834	When only the NOTCH1 mutational status is considered in studies, the proportion of NOTCH1-wt patients in the comparison arm that may have the NOTCH1 signaling pathway active, or silenced through other means, is likely to be variable and could confound the clinical behavior of tumors otherwise grouped together for analysis.	('NOTCH1-wt', 'Var', (83, 92))	('tumors', 'Disease', (277, 283))	('tumors', 'Phenotype', 'HP:0002664', (277, 283))	('NOTCH1 signaling pathway', 'Pathway', (142, 166))	('tumor', 'Phenotype', 'HP:0002664', (277, 282))	('confound', 'Reg', (243, 251))	('patients', 'Species', '9606', (93, 101))	('tumors', 'Disease', 'MESH:D009369', (277, 283))
128129	33322834	Mutations in NOTCH1 were strongly associated with shorter overall (OS) and disease-free survival (DFS) (p = 0.004 and p = 0.001, respectively) in Chinese oral squamous cell carcinoma (OSCC) patients compared to patients with wt NOTCH1.	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (154, 182))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (159, 182))	('disease-free survival', 'CPA', (75, 96))	('patients', 'Species', '9606', (211, 219))	('patients', 'Species', '9606', (190, 198))	('SCC', 'Phenotype', 'HP:0002860', (185, 188))	('carcinoma', 'Phenotype', 'HP:0030731', (173, 182))	('NOTCH1', 'Gene', (13, 19))	('oral squamous cell carcinoma', 'Disease', (154, 182))	('Mutations', 'Var', (0, 9))	('shorter', 'NegReg', (50, 57))
128131	33322834	Contradictory to these reports, Japanese OSCC patients with NOTCH1 mutations showed a longer median DFS (p < 0.05) in comparison to the patients with wt NOTCH1.	('patients', 'Species', '9606', (46, 54))	('SCC', 'Phenotype', 'HP:0002860', (42, 45))	('NOTCH1', 'Gene', (60, 66))	('mutations', 'Var', (67, 76))	('longer', 'PosReg', (86, 92))	('patients', 'Species', '9606', (136, 144))	('DFS', 'MPA', (100, 103))
128132	33322834	A similar trend was observed in patients with stage IV HNSCC (oropharynx and hypopharynx), with mutated NOTCH1 significantly correlating with improved OS (p = 0.04).	('mutated', 'Var', (96, 103))	('SCC', 'Phenotype', 'HP:0002860', (57, 60))	('patients', 'Species', '9606', (32, 40))	('HNSCC', 'Phenotype', 'HP:0012288', (55, 60))	('improved', 'PosReg', (142, 150))	('NOTCH1', 'Gene', (104, 110))
128142	33322834	Moreover, clinical impacts of NOTCH1 mRNA levels have also been ascertained in HNSCCs.	('HNSCCs', 'Disease', (79, 85))	('NOTCH1', 'Var', (30, 36))	('HNSCCs', 'Phenotype', 'HP:0012288', (79, 85))	('HNSCCs', 'Disease', 'MESH:D000077195', (79, 85))	('SCC', 'Phenotype', 'HP:0002860', (81, 84))	('HNSCC', 'Phenotype', 'HP:0012288', (79, 84))
128145	33322834	Because activating NOTCH1 mutations are largely absent from HNSCCs, therapies that target NOTCH are not useful for HNSCC.	('NOTCH', 'Gene', (90, 95))	('HNSCCs', 'Disease', 'MESH:D000077195', (60, 66))	('NOTCH', 'Gene', '31293', (90, 95))	('NOTCH', 'Gene', '31293', (19, 24))	('SCC', 'Phenotype', 'HP:0002860', (62, 65))	('HNSCC', 'Phenotype', 'HP:0012288', (115, 120))	('NOTCH', 'Gene', (19, 24))	('mutations', 'Var', (26, 35))	('SCC', 'Phenotype', 'HP:0002860', (117, 120))	('activating', 'PosReg', (8, 18))	('HNSCC', 'Phenotype', 'HP:0012288', (60, 65))	('HNSCCs', 'Disease', (60, 66))	('HNSCCs', 'Phenotype', 'HP:0012288', (60, 66))
128146	33322834	These therapies include gamma-secretase inhibitors, an inhibitor of the NOTCH transcription complex (CB-103), and antibodies to DLL-4, NOTCH1, and NOTCH2/3.	('NOTCH', 'Gene', (72, 77))	('NOTCH', 'Gene', '31293', (72, 77))	('NOTCH2', 'Gene', (147, 153))	('NOTCH', 'Gene', (135, 140))	('gamma-secretase inhibitors', 'Protein', (24, 50))	('DLL-4', 'Gene', (128, 133))	('DLL-4', 'Gene', '54567', (128, 133))	('NOTCH2', 'Gene', '4853', (147, 153))	('CB-103', 'Gene', (101, 107))	('NOTCH', 'Gene', '31293', (147, 152))	('NOTCH', 'Gene', (147, 152))	('NOTCH', 'Gene', '31293', (135, 140))	('antibodies', 'Var', (114, 124))
128152	33322834	More than 90% of HNSCCs have an upregulated PI3K/AKT/mTOR pathway which can be attributed to EGF receptor activation, PI3K overexpression, PIK3CA mutations and amplifications, and PTEN LOF mutations.	('HNSCCs', 'Phenotype', 'HP:0012288', (17, 23))	('PTEN', 'Gene', (180, 184))	('mTOR', 'Gene', '2475', (53, 57))	('PIK3CA', 'Gene', (139, 145))	('AKT', 'Gene', '207', (49, 52))	('HNSCCs', 'Disease', (17, 23))	('amplifications', 'Var', (160, 174))	('HNSCCs', 'Disease', 'MESH:D000077195', (17, 23))	('overexpression', 'PosReg', (123, 137))	('PTEN', 'Gene', '5728', (180, 184))	('activation', 'PosReg', (106, 116))	('mutations', 'Var', (189, 198))	('LOF', 'NegReg', (185, 188))	('HNSCC', 'Phenotype', 'HP:0012288', (17, 22))	('EGF receptor', 'Gene', '1956', (93, 105))	('upregulated', 'PosReg', (32, 43))	('PIK3CA', 'Gene', '5290', (139, 145))	('AKT', 'Gene', (49, 52))	('mutations', 'Var', (146, 155))	('mTOR', 'Gene', (53, 57))	('PI3K', 'Var', (118, 122))	('EGF receptor', 'Gene', (93, 105))	('SCC', 'Phenotype', 'HP:0002860', (19, 22))
128155	33322834	Previous research in our laboratory showed that PI3K pathway inhibition in HNSCCs induced growth arrest in PIK3CA mutant tumors, and significant cell death in NOTCH1 mutated tumors.	('HNSCCs', 'Disease', 'MESH:D000077195', (75, 81))	('PI3K pathway', 'Pathway', (48, 60))	('mutated', 'Var', (166, 173))	('growth arrest', 'Phenotype', 'HP:0001510', (90, 103))	('NOTCH1', 'Gene', (159, 165))	('mutant', 'Var', (114, 120))	('PIK3CA', 'Gene', (107, 113))	('tumors', 'Disease', 'MESH:D009369', (121, 127))	('HNSCC', 'Phenotype', 'HP:0012288', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('cell death', 'CPA', (145, 155))	('growth arrest', 'Disease', 'MESH:D006323', (90, 103))	('tumors', 'Disease', (174, 180))	('inhibition', 'NegReg', (61, 71))	('growth arrest', 'Disease', (90, 103))	('SCC', 'Phenotype', 'HP:0002860', (77, 80))	('tumors', 'Disease', 'MESH:D009369', (174, 180))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('PIK3CA', 'Gene', '5290', (107, 113))	('HNSCCs', 'Phenotype', 'HP:0012288', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumors', 'Disease', (121, 127))	('HNSCCs', 'Disease', (75, 81))	('tumors', 'Phenotype', 'HP:0002664', (174, 180))
128156	33322834	In vitro studies of HNSCC cell lines harboring NOTCH1 LOF mutations demonstrated sensitivity to PI3K/mTOR inhibitors, resulting in apoptosis and reduced clonogenic growth compared to cell lines with wt NOTCH1.	('mutations', 'Var', (58, 67))	('reduced', 'NegReg', (145, 152))	('mTOR', 'Gene', (101, 105))	('mTOR', 'Gene', '2475', (101, 105))	('LOF', 'NegReg', (54, 57))	('NOTCH1', 'Gene', (47, 53))	('apoptosis', 'CPA', (131, 140))	('SCC', 'Phenotype', 'HP:0002860', (22, 25))	('HNSCC', 'Phenotype', 'HP:0012288', (20, 25))	('clonogenic growth', 'CPA', (153, 170))
128157	33322834	Similarly, PI3K/mTOR inhibition showed markedly increased apoptosis and impaired tumor growth in NOTCH1 mutant HNSCC xenograft models.	('increased', 'PosReg', (48, 57))	('NOTCH1', 'Gene', (97, 103))	('HNSCC', 'Phenotype', 'HP:0012288', (111, 116))	('HNSCC', 'Disease', (111, 116))	('mutant', 'Var', (104, 110))	('mTOR', 'Gene', '2475', (16, 20))	('mTOR', 'Gene', (16, 20))	('apoptosis', 'CPA', (58, 67))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('impaired tumor growth', 'Disease', 'MESH:D006130', (72, 93))	('SCC', 'Phenotype', 'HP:0002860', (113, 116))	('impaired tumor growth', 'Disease', (72, 93))
128158	33322834	Moreover, genomic depletion of NOTCH1 sensitized most wt NOTCH1 HNSCC cell lines to PI3K/mTOR inhibitor-mediated apoptosis.	('mTOR', 'Gene', '2475', (89, 93))	('NOTCH1', 'Gene', (57, 63))	('sensitized', 'Reg', (38, 48))	('SCC', 'Phenotype', 'HP:0002860', (66, 69))	('HNSCC', 'Phenotype', 'HP:0012288', (64, 69))	('NOTCH1', 'Gene', (31, 37))	('genomic', 'Var', (10, 17))	('mTOR', 'Gene', (89, 93))
128159	33322834	Further mechanistic investigation of these findings revealed several differentially expressed proteins in NOTCH1 mutant HNSCC cells upon PI3K/mTOR inhibition compared to NOTCH1-wt cells.	('mTOR', 'Gene', (142, 146))	('SCC', 'Phenotype', 'HP:0002860', (122, 125))	('mTOR', 'Gene', '2475', (142, 146))	('proteins', 'Protein', (94, 102))	('NOTCH1', 'Gene', (106, 112))	('differentially', 'Reg', (69, 83))	('mutant', 'Var', (113, 119))	('HNSCC', 'Phenotype', 'HP:0012288', (120, 125))
128160	33322834	One of these proteins is PDK1, a downstream signaling molecule of the PI3K pathway, which was significantly downregulated upon PI3K/mTOR inhibition exclusively in NOTCH1 mutated HNSCC cell lines.	('HNSCC', 'Phenotype', 'HP:0012288', (178, 183))	('NOTCH1', 'Gene', (163, 169))	('mTOR', 'Gene', '2475', (132, 136))	('PI3K pathway', 'Pathway', (70, 82))	('mTOR', 'Gene', (132, 136))	('PDK1', 'Gene', '5170', (25, 29))	('PDK1', 'Gene', (25, 29))	('inhibition', 'Var', (137, 147))	('mutated', 'Var', (170, 177))	('SCC', 'Phenotype', 'HP:0002860', (180, 183))	('downregulated', 'NegReg', (108, 121))
128161	33322834	In addition, depletion or inhibition of total PDK1 in NOTCH1-wt HNSCC sensitized them to PI3K/AKT inhibition, resulting in apoptosis.	('AKT', 'Gene', '207', (94, 97))	('sensitized', 'Reg', (70, 80))	('SCC', 'Phenotype', 'HP:0002860', (66, 69))	('AKT', 'Gene', (94, 97))	('depletion', 'Var', (13, 22))	('inhibition', 'NegReg', (26, 36))	('apoptosis', 'CPA', (123, 132))	('HNSCC', 'Phenotype', 'HP:0012288', (64, 69))	('PDK1', 'Gene', '5170', (46, 50))	('PDK1', 'Gene', (46, 50))
128162	33322834	The potent PI3K inhibitor PX-886 significantly reduced tumor growth in two NOTCH1 mutant HNSCC patient-derived xenograft models.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('patient', 'Species', '9606', (95, 102))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('NOTCH1', 'Gene', (75, 81))	('tumor', 'Disease', (55, 60))	('PX-886', 'Chemical', '-', (26, 32))	('HNSCC', 'Phenotype', 'HP:0012288', (89, 94))	('reduced', 'NegReg', (47, 54))	('SCC', 'Phenotype', 'HP:0002860', (91, 94))	('mutant', 'Var', (82, 88))
128165	33322834	One HNSCC patient with a NOTCH1 LOF mutation had a partial response (85% reduction in the target lesion) on bimiralisib treatment that was sustained for 36 weeks.	('SCC', 'Phenotype', 'HP:0002860', (6, 9))	('LOF', 'NegReg', (32, 35))	('mutation', 'Var', (36, 44))	('patient', 'Species', '9606', (10, 17))	('NOTCH1', 'Gene', (25, 31))	('reduction', 'NegReg', (73, 82))	('HNSCC', 'Phenotype', 'HP:0012288', (4, 9))	('bimiralisib', 'Chemical', '-', (108, 119))
128166	33322834	Currently, this observation is being validated in a phase II study to test the efficacy of bimiralisib treatment in NOTCH1 mutant HNSCC patients (NCT03740100).	('NOTCH1', 'Gene', (116, 122))	('bimiralisib', 'Chemical', '-', (91, 102))	('patients', 'Species', '9606', (136, 144))	('SCC', 'Phenotype', 'HP:0002860', (132, 135))	('HNSCC', 'Phenotype', 'HP:0012288', (130, 135))	('mutant', 'Var', (123, 129))
128178	33322834	Somatic frame shift mutations of common tumor suppressor genes (NOTCH1 and SMARC4) were frequently observed in HPV-negative anti-PD-1/PD-L1 responders.	('NOTCH1', 'Gene', (64, 70))	('PD-L1', 'Gene', (134, 139))	('SMARC4', 'Gene', (75, 81))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('HPV', 'Species', '10566', (111, 114))	('observed', 'Reg', (99, 107))	('frame shift mutations', 'Var', (8, 29))	('PD-L1', 'Gene', '29126', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('PD-1', 'Gene', (129, 133))	('PD-1', 'Gene', '5133', (129, 133))
128179	33322834	Furthermore, a more recent study identified NOTCH1-3 LOF mutations as novel biomarkers predicting improved response to immune checkpoint inhibitor treatment in lung cancer patients.	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('LOF', 'NegReg', (53, 56))	('lung cancer', 'Disease', 'MESH:D008175', (160, 171))	('NOTCH1-3', 'Gene', (44, 52))	('mutations', 'Var', (57, 66))	('patients', 'Species', '9606', (172, 180))	('improved', 'PosReg', (98, 106))	('response', 'MPA', (107, 115))	('lung cancer', 'Disease', (160, 171))	('lung cancer', 'Phenotype', 'HP:0100526', (160, 171))
128181	33322834	A challenge to developing targeted therapy for HNSCC is the dominance of mutations in tumor suppressors including NOTCH1, which is mutated in about 17% of HPV-negative HNSCC.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('NOTCH1', 'Gene', (114, 120))	('HPV', 'Species', '10566', (155, 158))	('tumor', 'Disease', (86, 91))	('SCC', 'Phenotype', 'HP:0002860', (49, 52))	('HNSCC', 'Phenotype', 'HP:0012288', (47, 52))	('SCC', 'Phenotype', 'HP:0002860', (170, 173))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('HNSCC', 'Phenotype', 'HP:0012288', (168, 173))	('mutations', 'Var', (73, 82))
128182	33322834	Structural analysis of NOTCH1 mutations in HNSCCs demonstrate that most are LOF mutations.	('LOF', 'NegReg', (76, 79))	('NOTCH1', 'Gene', (23, 29))	('SCC', 'Phenotype', 'HP:0002860', (45, 48))	('HNSCCs', 'Disease', (43, 49))	('mutations', 'Var', (30, 39))	('HNSCC', 'Phenotype', 'HP:0012288', (43, 48))	('HNSCCs', 'Phenotype', 'HP:0012288', (43, 49))	('HNSCCs', 'Disease', 'MESH:D000077195', (43, 49))
128183	33322834	NOTCH1 missense mutations in HNSCCs are enriched in the EGF2, EGF4, EGF8, EGF9, EGF10, EGF11, EGF12, EGF29, RAM, and ANK1 domains in contrast to T-ALL, where NOTCH1 mutations are activating and there are more mutations in the HD domain.	('ANK1', 'Gene', '286', (117, 121))	('activating', 'PosReg', (179, 189))	('ANK1', 'Gene', (117, 121))	('HNSCCs', 'Disease', (29, 35))	('SCC', 'Phenotype', 'HP:0002860', (31, 34))	('missense mutations', 'Var', (7, 25))	('NOTCH1', 'Gene', (158, 164))	('HNSCC', 'Phenotype', 'HP:0012288', (29, 34))	('HNSCCs', 'Phenotype', 'HP:0012288', (29, 35))	('HD', 'Disease', 'MESH:D006816', (226, 228))	('T-ALL', 'Phenotype', 'HP:0006727', (145, 150))	('NOTCH1', 'Gene', (0, 6))	('mutations', 'Var', (165, 174))	('HNSCCs', 'Disease', 'MESH:D000077195', (29, 35))
128184	33322834	Additionally, manipulation of NOTCH signaling in NOTCH1 mutant HNSCC cell lines demonstrates that it functions as a tumor suppressor in vitro and in vivo.	('NOTCH', 'Gene', (49, 54))	('mutant', 'Var', (56, 62))	('NOTCH', 'Gene', '31293', (30, 35))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('HNSCC', 'Phenotype', 'HP:0012288', (63, 68))	('SCC', 'Phenotype', 'HP:0002860', (65, 68))	('NOTCH', 'Gene', (30, 35))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumor', 'Disease', (116, 121))	('NOTCH', 'Gene', '31293', (49, 54))
128185	33322834	Currently, the presence of a NOTCH1 mutation in HNSCCs does not affect clinical decision making, but this may change.	('NOTCH1', 'Gene', (29, 35))	('HNSCC', 'Phenotype', 'HP:0012288', (48, 53))	('HNSCCs', 'Phenotype', 'HP:0012288', (48, 54))	('HNSCCs', 'Disease', 'MESH:D000077195', (48, 54))	('SCC', 'Phenotype', 'HP:0002860', (50, 53))	('HNSCCs', 'Disease', (48, 54))	('mutation', 'Var', (36, 44))
128186	33322834	Defining the prognostic role of the NOTCH pathway is challenging because of the aforementioned limitations in measuring NOTCH pathway activation, as well as the difficulty in determining if some NOTCH1 mutations are passenger events or LOF mutations.	('NOTCH', 'Gene', '31293', (36, 41))	('NOTCH', 'Gene', '31293', (120, 125))	('NOTCH', 'Gene', '31293', (195, 200))	('NOTCH', 'Gene', (36, 41))	('NOTCH', 'Gene', (195, 200))	('NOTCH', 'Gene', (120, 125))	('mutations', 'Var', (202, 211))
128187	33322834	In regard to therapy, NOTCH1 mutant, HPV-negative HNSCC may be more responsive to immune checkpoint therapy.	('NOTCH1', 'Gene', (22, 28))	('mutant', 'Var', (29, 35))	('SCC', 'Phenotype', 'HP:0002860', (52, 55))	('HNSCC', 'Phenotype', 'HP:0012288', (50, 55))	('HPV', 'Species', '10566', (37, 40))
128188	33322834	In vitro, in vivo, and patient data support an ongoing clinical trial that is testing the hypothesis that HNSCCs with NOTCH1 mutations are highly sensitive to PI3K inhibitors due to the ensuing loss of total PDK1 protein.	('NOTCH1', 'Gene', (118, 124))	('mutations', 'Var', (125, 134))	('HNSCCs', 'Phenotype', 'HP:0012288', (106, 112))	('HNSCC', 'Phenotype', 'HP:0012288', (106, 111))	('HNSCCs', 'Disease', 'MESH:D000077195', (106, 112))	('loss', 'NegReg', (194, 198))	('SCC', 'Phenotype', 'HP:0002860', (108, 111))	('PDK1', 'Gene', '5170', (208, 212))	('HNSCCs', 'Disease', (106, 112))	('PDK1', 'Gene', (208, 212))	('patient', 'Species', '9606', (23, 30))
128189	33322834	Because NOTCH1 LOF mutations are common in other SCCs, including those of skin, esophagus, cervix, and lung, these findings may have implications for the treatment of cancers beyond HNSCC.	('NOTCH1', 'Gene', (8, 14))	('HNSCC', 'Phenotype', 'HP:0012288', (182, 187))	('LOF', 'NegReg', (15, 18))	('SCC', 'Phenotype', 'HP:0002860', (49, 52))	('esophagus', 'Disease', (80, 89))	('skin', 'Disease', (74, 78))	('mutations', 'Var', (19, 28))	('cancers', 'Phenotype', 'HP:0002664', (167, 174))	('cervix', 'Disease', (91, 97))	('cancers', 'Disease', (167, 174))	('cancers', 'Disease', 'MESH:D009369', (167, 174))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('SCC', 'Phenotype', 'HP:0002860', (184, 187))
128191	33322834	), National Cancer Institute (R01CA235620 to F.M.J.	('R01CA235620', 'Var', (30, 41))	('Cancer', 'Disease', 'MESH:D009369', (12, 18))	('Cancer', 'Phenotype', 'HP:0002664', (12, 18))	('Cancer', 'Disease', (12, 18))
128192	33322834	), and the Texas Cancer Prevention and Research Institute (RP200369 to F.M.J.	('RP200369', 'Var', (59, 67))	('Cancer', 'Disease', (17, 23))	('Cancer', 'Disease', 'MESH:D009369', (17, 23))	('Cancer', 'Phenotype', 'HP:0002664', (17, 23))
128205	31737112	Previous studies have demonstrated that GOLPH3 is highly expressed in various types of human cancer, including NSCLC, gastric cancer, breast cancer, hepatocellular cancer and prostate cancer, and overexpression of GOLPH3 promotes cancer cell proliferation, migration and invasion.	('cancer', 'Disease', (184, 190))	('overexpression', 'Var', (196, 210))	('NSCLC', 'Disease', (111, 116))	('GOLPH3', 'Gene', '64083', (40, 46))	('breast cancer', 'Phenotype', 'HP:0003002', (134, 147))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('NSCLC', 'Phenotype', 'HP:0030358', (111, 116))	('breast cancer', 'Disease', 'MESH:D001943', (134, 147))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('breast cancer', 'Disease', (134, 147))	('gastric cancer', 'Disease', (118, 132))	('human', 'Species', '9606', (87, 92))	('cancer', 'Disease', (126, 132))	('invasion', 'CPA', (271, 279))	('cancer', 'Disease', (230, 236))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('prostate cancer', 'Disease', 'MESH:D011471', (175, 190))	('cancer', 'Disease', (141, 147))	('hepatocellular cancer', 'Disease', (149, 170))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('prostate cancer', 'Phenotype', 'HP:0012125', (175, 190))	('hepatocellular cancer', 'Phenotype', 'HP:0001402', (149, 170))	('gastric cancer', 'Disease', 'MESH:D013274', (118, 132))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('prostate cancer', 'Disease', (175, 190))	('cancer', 'Disease', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('hepatocellular cancer', 'Disease', 'MESH:D006528', (149, 170))	('migration', 'CPA', (257, 266))	('cancer', 'Disease', (93, 99))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('NSCLC', 'Disease', 'MESH:D002289', (111, 116))	('GOLPH3', 'Gene', (214, 220))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('gastric cancer', 'Phenotype', 'HP:0012126', (118, 132))	('cancer', 'Disease', 'MESH:D009369', (230, 236))	('promotes', 'PosReg', (221, 229))	('GOLPH3', 'Gene', (40, 46))	('GOLPH3', 'Gene', '64083', (214, 220))
128217	31737112	If OR > 1 and the 95% CI doesn't include 1, it indicates that there is an association between high GOLPH3 expression and clinicopathological variable.	('GOLPH3', 'Gene', (99, 105))	('expression', 'MPA', (106, 116))	('high', 'Var', (94, 98))	('GOLPH3', 'Gene', '64083', (99, 105))
128248	31737112	These results indicated that high GOLPH3 expression could predict a poor prognosis for NSCLC patients.	('high', 'Var', (29, 33))	('NSCLC', 'Disease', (87, 92))	('expression', 'MPA', (41, 51))	('NSCLC', 'Disease', 'MESH:D002289', (87, 92))	('GOLPH3', 'Gene', '64083', (34, 40))	('NSCLC', 'Phenotype', 'HP:0030358', (87, 92))	('patients', 'Species', '9606', (93, 101))	('GOLPH3', 'Gene', (34, 40))
128271	28397399	CI combination index FBXO3 F-box protein 3 FBXW10 F-box and WD repeat domain containing 10 HDAC histone deacetylases IC50 half-maximum inhibitory concentrations MAPK mitogen-activated protein kinases NSCLC non-small-cell lung cancer PARP poly(ADP-ribose) polymerase PI propidium iodide PXD101 belinostat RT-qPCR quantitative real-time polymerase chain reaction SCC squamous cell carcinoma Scr scrambled control siRNA SOS son of sevenless STAT3 signal transducer and activator of transcription 3 UBE2C ubiquitin-conjugating enzyme E2 C Modification of histones through epigenetic dysregulation is an important oncogenic mechanism and has been exploited for cancer drug development.	('NSCLC', 'Phenotype', 'HP:0030358', (200, 205))	('FBXO3', 'Gene', '26273', (21, 26))	('STAT3', 'Gene', '6774', (438, 443))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (365, 388))	('FBXW10', 'Gene', (43, 49))	('WD', 'Disease', 'MESH:D006527', (60, 62))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (206, 232))	('cancer', 'Disease', 'MESH:D009369', (656, 662))	('histone deacetylase', 'Gene', (96, 115))	('HDAC', 'Gene', (91, 95))	('SCC', 'Gene', '6317', (361, 364))	('lung cancer', 'Disease', (221, 232))	('histones', 'Protein', (551, 559))	('belinostat', 'Chemical', 'MESH:C487081', (293, 303))	('SCC', 'Gene', (361, 364))	('UBE2C', 'Gene', (495, 500))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (365, 388))	('cancer', 'Disease', 'MESH:D009369', (226, 232))	('epigenetic dysregulation', 'Var', (568, 592))	('FBXW10', 'Gene', '10517', (43, 49))	('PARP', 'Gene', '142', (233, 237))	('carcinoma', 'Phenotype', 'HP:0030731', (379, 388))	('lung cancer', 'Disease', 'MESH:D008175', (221, 232))	('UBE2C', 'Gene', '11065', (495, 500))	('PARP', 'Gene', (233, 237))	('squamous cell carcinoma', 'Disease', (365, 388))	('NSCLC', 'Disease', 'MESH:D002289', (200, 205))	('FBXO3', 'Gene', (21, 26))	('cancer', 'Disease', (656, 662))	('lung cancer', 'Phenotype', 'HP:0100526', (221, 232))	('cancer', 'Phenotype', 'HP:0002664', (656, 662))	('Modification', 'Var', (535, 547))	('histone deacetylase', 'Gene', '9734', (96, 115))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (210, 232))	('NSCLC', 'Disease', (200, 205))	('STAT3', 'Gene', (438, 443))	('cancer', 'Disease', (226, 232))	('SCC', 'Phenotype', 'HP:0002860', (361, 364))	('HDAC', 'Gene', '9734', (91, 95))	('propidium iodide', 'Chemical', 'MESH:D011419', (269, 285))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
128273	28397399	Studies involving the knockdown of HDAC1 have shown that loss of HDAC1 expression blocked mitosis in tumor cells (Senese et al., 2007), while HDAC3 silencing reduces the growth of colon cancer cells (Wilson et al., 2006).	('HDAC1', 'Gene', '3065', (35, 40))	('growth', 'MPA', (170, 176))	('HDAC3', 'Gene', '8841', (142, 147))	('colon cancer', 'Disease', (180, 192))	('HDAC3', 'Gene', (142, 147))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('blocked', 'NegReg', (82, 89))	('colon cancer', 'Disease', 'MESH:D015179', (180, 192))	('HDAC1', 'Gene', (65, 70))	('mitosis in tumor', 'Disease', 'MESH:D009369', (90, 106))	('loss', 'Var', (57, 61))	('HDAC1', 'Gene', (35, 40))	('HDAC1', 'Gene', '3065', (65, 70))	('colon cancer', 'Phenotype', 'HP:0003003', (180, 192))	('mitosis in tumor', 'Disease', (90, 106))	('silencing reduces', 'NegReg', (148, 165))
128274	28397399	Furthermore, inhibition of HDACs sensitizes both chemotherapy and small-molecule inhibitors in drug-resistant cancer cells (Bangert et al., 2011; Chen et al., 2013; Sharma et al., 2010).	('HDAC', 'Gene', '9734', (27, 31))	('cancer', 'Disease', (110, 116))	('sensitizes', 'Reg', (33, 43))	('inhibition', 'Var', (13, 23))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('drug-resistant cancer', 'Phenotype', 'HP:0020174', (95, 116))	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('HDAC', 'Gene', (27, 31))
128281	28397399	Moreover, metastatic lung cells could be resensitized to EGFR inhibitors with HDAC inhibitors (Witta et al., 2006).	('EGFR', 'Gene', '1956', (57, 61))	('HDAC', 'Gene', (78, 82))	('inhibitors', 'Var', (62, 72))	('HDAC', 'Gene', '9734', (78, 82))	('EGFR', 'Gene', (57, 61))
128292	28397399	Lung SCC lines H226, H2170, H520, H596, and ChaGo-k-1 were maintained in RMPI-1640 (Nacalai Tesque), Calu-1 in McCoy's 5a (Nacalai Tesque, Kyoto, Japan), SK-MES-1 in DMEM (Nacalai Tesque), SW900 in Leibovitz's medium (Gibco, Life Technologies, Carlsbad, CA, USA), H1869 in ACL-4 (Gibco, Life Technologies), and H2066 in HITES medium (Gibco, Life Technologies).	('SCC', 'Gene', '6317', (5, 8))	('H520', 'CellLine', 'CVCL:1566', (28, 32))	('H226', 'CellLine', 'CVCL:J621', (15, 19))	('SW900', 'CellLine', 'CVCL:1731', (189, 194))	('H1869', 'Var', (264, 269))	('SCC', 'Gene', (5, 8))	('H2066', 'CellLine', 'CVCL:1520', (311, 316))	('SK-MES-1', 'CellLine', 'CVCL:0630', (154, 162))	('H2170', 'CellLine', 'CVCL:1535', (21, 26))	('SCC', 'Phenotype', 'HP:0002860', (5, 8))	('H2066', 'Var', (311, 316))
128295	28397399	For inhibitor studies, belinostat (PXD101), bortezomib (Velcade), GDC0879, PD0325901, RDEA119, and GSK1120212 were obtained from Selleck Chemicals (Houston, TX, USA); cisplatin from Hospira (Lake Forest, IL, USA); MG-132 from Sigma (St. Louis, MO, USA); and cetuximab was from Merck (Darmstadt, Germany).	('cetuximab', 'Chemical', 'MESH:D000068818', (258, 267))	('bortezomib', 'Chemical', 'MESH:D000069286', (44, 54))	('RDEA119', 'Var', (86, 93))	('Velcade', 'Chemical', 'MESH:D000069286', (56, 63))	('GSK1120212', 'Var', (99, 109))	('PD0325901', 'Var', (75, 84))	('MG-132', 'Chemical', 'MESH:C072553', (214, 220))	('GSK1120212', 'Chemical', 'MESH:C560077', (99, 109))	('PD0325901', 'Chemical', 'MESH:C506614', (75, 84))	('GDC0879', 'Chemical', 'MESH:C540167', (66, 73))	('belinostat', 'Chemical', 'MESH:C487081', (23, 33))	('RDEA119', 'Chemical', 'MESH:C544830', (86, 93))	('cisplatin', 'Chemical', 'MESH:D002945', (167, 176))
128315	28397399	For gene knockdown, Stat3 was obtained from Ambion (Thermo Fisher Scientific, Waltham, MA, USA).	('Stat3', 'Gene', '6774', (20, 25))	('knockdown', 'Var', (9, 18))	('Stat3', 'Gene', (20, 25))
128330	28397399	Interestingly, lung SCC cells (H2066, SW900, H2170, Calu-1, H520, and SK-MES-1), which we previously demonstrated to exhibit decreased sensitivity to cisplatin, were highly sensitive to belinostat (Kong et al., 2015).	('SK-MES-1', 'CellLine', 'CVCL:0630', (70, 78))	('SCC', 'Gene', (20, 23))	('belinostat', 'Chemical', 'MESH:C487081', (186, 196))	('H2066', 'CellLine', 'CVCL:1520', (31, 36))	('H520', 'Var', (60, 64))	('SCC', 'Phenotype', 'HP:0002860', (20, 23))	('H2066', 'Var', (31, 36))	('SCC', 'Gene', '6317', (20, 23))	('H520', 'CellLine', 'CVCL:1566', (60, 64))	('sensitivity', 'MPA', (135, 146))	('cisplatin', 'Chemical', 'MESH:D002945', (150, 159))	('H2170', 'Var', (45, 50))	('SW900', 'CellLine', 'CVCL:1731', (38, 43))	('H2170', 'CellLine', 'CVCL:1535', (45, 50))
128338	28397399	However, transcriptomic analyses offered little insight into the mechanism of action of belinostat, as gene ontology and pathway enrichment analyses could not identify differentially regulated signaling pathway across the belinostat-sensitive (H2066, SW900, H2170, and Calu-1) and belinostat-resistant (H226, H596, ChaGo-k-1, and H1869) cells (data not shown).	('SW900', 'Var', (251, 256))	('H2066', 'Var', (244, 249))	('belinostat', 'Chemical', 'MESH:C487081', (88, 98))	('belinostat', 'Chemical', 'MESH:C487081', (222, 232))	('H2170', 'Var', (258, 263))	('belinostat', 'Chemical', 'MESH:C487081', (281, 291))	('H226', 'CellLine', 'CVCL:J621', (303, 307))	('H2170', 'CellLine', 'CVCL:1535', (258, 263))	('H2066', 'CellLine', 'CVCL:1520', (244, 249))	('SW900', 'CellLine', 'CVCL:1731', (251, 256))
128349	28397399	Furthermore, belinostat dose-dependent treatment significantly increased Annexin-V-positive populations in belinostat-sensitive cells (Calu-1, H520, and H2170), but not in belinostat-resistant cells (ChaGo-k-1, H596, and H226) (Fig.	('H2170', 'Var', (153, 158))	('belinostat', 'Chemical', 'MESH:C487081', (172, 182))	('Annexin-V', 'Gene', '308', (73, 82))	('increased', 'PosReg', (63, 72))	('H2170', 'CellLine', 'CVCL:1535', (153, 158))	('H520', 'Var', (143, 147))	('H520', 'CellLine', 'CVCL:1566', (143, 147))	('belinostat', 'Chemical', 'MESH:C487081', (13, 23))	('H226', 'CellLine', 'CVCL:J621', (221, 225))	('Annexin-V', 'Gene', (73, 82))	('belinostat', 'Chemical', 'MESH:C487081', (107, 117))
128351	28397399	Accordingly, silencing of Bim partially reduced apoptosis in belinostat-treated Calu-1 and H520 cells, as shown by the decrease in Annexin-V-positive cells (Fig.	('Annexin-V', 'Gene', '308', (131, 140))	('Annexin-V', 'Gene', (131, 140))	('Bim', 'Gene', (26, 29))	('decrease', 'NegReg', (119, 127))	('belinostat', 'Chemical', 'MESH:C487081', (61, 71))	('reduced', 'NegReg', (40, 47))	('H520', 'CellLine', 'CVCL:1566', (91, 95))	('apoptosis', 'CPA', (48, 57))	('silencing', 'Var', (13, 22))
128355	28397399	This is in concordance with data from a recent study showing that MEK inhibition triggers autocrine activation of JAK/STAT3 pathway in oncogene-addicted cells as a positive feedback mechanism (Lee et al., 2014).	('STAT3', 'Gene', '6774', (118, 123))	('MEK', 'Gene', (66, 69))	('MEK', 'Gene', '5609', (66, 69))	('STAT3', 'Gene', (118, 123))	('inhibition', 'Var', (70, 80))	('autocrine activation', 'MPA', (90, 110))
128356	28397399	Likewise, treatment with the MEK inhibitors (PD0325901, RDEA119, and trametinib), but not the B-Raf inhibitor (GDC0879) or the EGFR inhibitor (cetuximab), significantly suppressed ERK activation and enhanced STAT3 phosphorylation in Calu-1 cells (Fig.	('STAT3', 'Gene', '6774', (208, 213))	('ERK', 'Gene', (180, 183))	('PD0325901', 'Chemical', 'MESH:C506614', (45, 54))	('B-Raf', 'Gene', '673', (94, 99))	('RDEA119', 'Chemical', 'MESH:C544830', (56, 63))	('MEK', 'Gene', '5609', (29, 32))	('cetuximab', 'Chemical', 'MESH:D000068818', (143, 152))	('enhanced', 'PosReg', (199, 207))	('GDC0879', 'Chemical', 'MESH:C540167', (111, 118))	('trametinib', 'Chemical', 'MESH:C560077', (69, 79))	('EGFR', 'Gene', (127, 131))	('MEK', 'Gene', (29, 32))	('suppressed', 'NegReg', (169, 179))	('activation', 'MPA', (184, 194))	('B-Raf', 'Gene', (94, 99))	('ERK', 'Gene', '5594', (180, 183))	('PD0325901', 'Var', (45, 54))	('STAT3', 'Gene', (208, 213))	('EGFR', 'Gene', '1956', (127, 131))
128365	28397399	Furthermore, combined treatment with cisplatin and belinostat resulted in increased apoptosis as demonstrated by the augmentation in PARP and caspase 3 cleavage (Fig.	('PARP', 'Gene', (133, 137))	('caspase 3', 'Gene', (142, 151))	('belinostat', 'Chemical', 'MESH:C487081', (51, 61))	('apoptosis', 'CPA', (84, 93))	('cisplatin', 'Var', (37, 46))	('caspase 3', 'Gene', '836', (142, 151))	('augmentation', 'PosReg', (117, 129))	('PARP', 'Gene', '142', (133, 137))	('cisplatin', 'Chemical', 'MESH:D002945', (37, 46))
128380	28397399	There was no significant perturbation of SOS1 and SOS2 in SCC cells within the same transcriptomic dataset, except for SW900 (Fig.	('SOS2', 'Gene', (50, 54))	('SCC', 'Gene', (58, 61))	('SCC', 'Phenotype', 'HP:0002860', (58, 61))	('SW900', 'Var', (119, 124))	('SCC', 'Gene', '6317', (58, 61))	('SOS1', 'Gene', (41, 45))	('SW900', 'CellLine', 'CVCL:1731', (119, 124))	('SOS2', 'Gene', '6655', (50, 54))	('SOS1', 'Gene', '6654', (41, 45))
128387	28397399	Taken together, the observations suggest a significant mechanism of functional protein regulation that occurs through epigenetic modulation of ubiquitin-proteasome pathways by belinostat treatment.	('epigenetic modulation', 'Var', (118, 139))	('belinostat', 'Chemical', 'MESH:C487081', (176, 186))	('ubiquitin-proteasome pathways', 'Pathway', (143, 172))	('functional protein regulation', 'MPA', (68, 97))
128399	28397399	On the contrary, high expression of HDAC1 has been linked with poor prognosis in patients with lung adenocarcinoma (Minamiya et al., 2011).	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (95, 114))	('HDAC1', 'Gene', (36, 41))	('patients', 'Species', '9606', (81, 89))	('high expression', 'Var', (17, 32))	('HDAC1', 'Gene', '3065', (36, 41))	('lung adenocarcinoma', 'Disease', (95, 114))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (95, 114))
128409	28397399	(2014) have previously demonstrated that MEK inhibition induces activation of STAT3 through a feedback mechanism, therefore supporting a strong mechanistic link between HDAC inhibition and MAPK signaling pathways (Vultur et al., 2014).	('MEK', 'Gene', (41, 44))	('MEK', 'Gene', '5609', (41, 44))	('HDAC', 'Gene', (169, 173))	('STAT3', 'Gene', '6774', (78, 83))	('HDAC', 'Gene', '9734', (169, 173))	('STAT3', 'Gene', (78, 83))	('activation', 'PosReg', (64, 74))	('inhibition', 'Var', (45, 55))
128410	28397399	HDAC inhibitors are known to augment the acetylation of lysine residues associated with histones and promote a relaxed chromatin structure to perturb gene transcriptions as a mean of shifting equilibrium toward proapoptosis (Moore et al., 2004; Struhl, 1998).	('HDAC', 'Gene', (0, 4))	('gene transcriptions', 'MPA', (150, 169))	('promote', 'PosReg', (101, 108))	('HDAC', 'Gene', '9734', (0, 4))	('proapoptosis', 'MPA', (211, 223))	('inhibitors', 'Var', (5, 15))	('equilibrium', 'MPA', (192, 203))	('histones', 'Protein', (88, 96))	('shifting', 'Reg', (183, 191))	('perturb', 'NegReg', (142, 149))	('acetylation', 'MPA', (41, 52))	('relaxed chromatin structure', 'MPA', (111, 138))	('augment', 'PosReg', (29, 36))	('lysine', 'Chemical', 'MESH:D008239', (56, 62))
128417	28397399	This epigenetic regulation of the ubiquitin-proteasome pathway relevant to oncogenesis affords therapeutic opportunity by HDAC inhibition and possibly DNA methylation inhibitors, and our work in lung SCC cells demonstrates this.	('SCC', 'Gene', '6317', (200, 203))	('epigenetic regulation', 'Var', (5, 26))	('SCC', 'Gene', (200, 203))	('SCC', 'Phenotype', 'HP:0002860', (200, 203))	('HDAC', 'Gene', (122, 126))	('ubiquitin-proteasome pathway', 'Pathway', (34, 62))	('HDAC', 'Gene', '9734', (122, 126))
128418	28397399	We further validated this using both chemical and genetic means whereby the depletion of SOS by belinostat was prevented through the addition of the proteasomal inhibitor bortezomib or siRNA knockdown of FBXO3 and FBXW10.	('FBXO3', 'Gene', (204, 209))	('bortezomib', 'Chemical', 'MESH:D000069286', (171, 181))	('FBXW10', 'Gene', (214, 220))	('knockdown', 'Var', (191, 200))	('depletion of SOS', 'MPA', (76, 92))	('FBXO3', 'Gene', '26273', (204, 209))	('prevented', 'NegReg', (111, 120))	('FBXW10', 'Gene', '10517', (214, 220))	('belinostat', 'Chemical', 'MESH:C487081', (96, 106))
128421	28397399	Nonetheless, we showed that silencing of either FBXO3 or FBXW10 could partially rescue cell viability under exposure to 1 mum belinostat in H520, but not in H226 cells, thus highlighting the role of F-box protein in facilitating the cytotoxicity of belinostat (Fig.	('FBXO3', 'Gene', '26273', (48, 53))	('cytotoxicity', 'Disease', 'MESH:D064420', (233, 245))	('cell viability', 'CPA', (87, 101))	('rescue', 'PosReg', (80, 86))	('FBXW10', 'Gene', (57, 63))	('cytotoxicity', 'Disease', (233, 245))	('H226', 'CellLine', 'CVCL:J621', (157, 161))	('belinostat', 'Chemical', 'MESH:C487081', (249, 259))	('FBXO3', 'Gene', (48, 53))	('belinostat', 'Chemical', 'MESH:C487081', (126, 136))	('FBXW10', 'Gene', '10517', (57, 63))	('silencing', 'Var', (28, 37))	('H520', 'CellLine', 'CVCL:1566', (140, 144))
128434	28397399	Interestingly, HDAC inhibitors have been previously implicated in the depletion of mutant p53 through the transcriptional induction of MDM2, an E3 ubiquitin ligase that negatively regulates p53, instead of directly affecting TP53 transcription (Blagosklonny et al., 2005).	('depletion', 'MPA', (70, 79))	('implicated', 'Reg', (52, 62))	('p53', 'Gene', (90, 93))	('affecting', 'Reg', (215, 224))	('mutant', 'Var', (83, 89))	('transcription', 'MPA', (230, 243))	('p53', 'Gene', '7157', (90, 93))	('TP53', 'Gene', '7157', (225, 229))	('p53', 'Gene', (190, 193))	('HDAC', 'Gene', (15, 19))	('negatively', 'NegReg', (169, 179))	('p53', 'Gene', '7157', (190, 193))	('HDAC', 'Gene', '9734', (15, 19))	('TP53', 'Gene', (225, 229))	('MDM2', 'Gene', '4193', (135, 139))	('MDM2', 'Gene', (135, 139))
128435	28397399	Likewise, a similar finding was earlier reported whereby a tyrosine kinase inhibitor, CI-1033, significantly enhanced ubiquitination in HER2 molecule together with the inhibition of kinase activity (Citri et al., 2002).	('CI-1033', 'Chemical', '-', (86, 93))	('HER2', 'Gene', (136, 140))	('CI-1033', 'Var', (86, 93))	('ubiquitination', 'MPA', (118, 132))	('HER2', 'Gene', '2064', (136, 140))	('enhanced', 'PosReg', (109, 117))
128520	25408577	Because the committee considered that synergistic interaction between smoking and asbestos itself, which means relatively low dose asbestos exposure comparing to asbestosis, might cause lung cancers.	('asbestosis', 'Disease', (162, 172))	('cancers', 'Phenotype', 'HP:0002664', (191, 198))	('lung cancers', 'Phenotype', 'HP:0100526', (186, 198))	('asbestos', 'Chemical', 'MESH:D001194', (162, 170))	('synergistic', 'Var', (38, 49))	('asbestos', 'Chemical', 'MESH:D001194', (131, 139))	('lung cancers', 'Disease', (186, 198))	('asbestosis', 'Disease', 'MESH:D001195', (162, 172))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('cause', 'Reg', (180, 185))	('asbestos', 'Chemical', 'MESH:D001194', (82, 90))	('lung cancer', 'Phenotype', 'HP:0100526', (186, 197))	('lung cancers', 'Disease', 'MESH:D008175', (186, 198))
128541	30630269	We identified patients with cN0 PNS carcinoma who underwent curative-intent treatment between 1992 and 2015.	('PNS carcinoma', 'Disease', 'MESH:D010523', (32, 45))	('cN0', 'Var', (28, 31))	('carcinoma', 'Phenotype', 'HP:0030731', (36, 45))	('PNS carcinoma', 'Disease', (32, 45))	('patients', 'Species', '9606', (14, 22))
128609	30630269	Between patients who had DFs ('DF (+) group', n = 34) and those who did not ('DF (-) group', n = 90), significantly worse survival outcome in all survival endpoints was noted in the failure-positive group (Fig.	('worse', 'NegReg', (116, 121))	('DFs', 'Var', (25, 28))	('patients', 'Species', '9606', (8, 16))
128612	30630269	The 5-year OS and PFS rates were 41% and 14%, respectively, in the RF (+) group, in contrast to 74% and 52%, respectively, in the RF (-) group (p < 0.01).	('OS', 'Chemical', '-', (11, 13))	('RF', 'Chemical', '-', (67, 69))	('RF (+', 'Var', (67, 72))	('PFS', 'CPA', (18, 21))	('RF', 'Chemical', '-', (130, 132))
128694	30630269	The 5-year OS and PFS rates were 41% and 14%, respectively, in the RF (+) group, which were significantly worse than those of the RF (-) group (p < 0.01).	('OS', 'Chemical', '-', (11, 13))	('RF', 'Chemical', '-', (67, 69))	('RF (+', 'Var', (67, 72))	('PFS', 'CPA', (18, 21))	('RF', 'Chemical', '-', (130, 132))
128782	24947688	Cannabis is usually smoked without a filter, and smoking dynamics studies among habitual marijuana users show that the overall burden of particulates delivered to the respiratory tract is about 4 times greater when smoking marijuana than when smoking the same amount of tobacco.	('tobacco', 'Species', '4097', (270, 277))	('marijuana', 'Species', '3483', (223, 232))	('marijuana', 'Var', (223, 232))	('burden of particulates delivered to the', 'MPA', (127, 166))	('marijuana', 'Species', '3483', (89, 98))
128793	25204415	The landscape of kinase fusions in cancer Human cancer genomes harbour a variety of alterations leading to the deregulation of key pathways in tumour cells.	('deregulation', 'MPA', (111, 123))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('Human', 'Species', '9606', (42, 47))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('tumour', 'Phenotype', 'HP:0002664', (143, 149))	('tumour', 'Disease', 'MESH:D009369', (143, 149))	('rat', 'Species', '10116', (88, 91))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('key pathways', 'Pathway', (127, 139))	('cancer', 'Disease', (48, 54))	('alterations', 'Var', (84, 95))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('tumour', 'Disease', (143, 149))	('cancer', 'Disease', (35, 41))	('fusions', 'Var', (24, 31))
128797	25204415	Kinases activated by gene fusions represent potentially important targets for the development of cancer drugs.	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('gene fusions', 'Var', (21, 33))	('cancer', 'Disease', (97, 103))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
128799	25204415	Kinases activated by gene fusions represent an important class of oncogenes associated with both hematopoietic malignancies and solid tumours.	('tumours', 'Phenotype', 'HP:0002664', (134, 141))	('hematopoietic malignancies and solid tumours', 'Disease', 'MESH:D019337', (97, 141))	('associated', 'Reg', (76, 86))	('gene fusions', 'Var', (21, 33))	('tumour', 'Phenotype', 'HP:0002664', (134, 140))
128800	25204415	They are produced by translocations or other chromosomal rearrangements, and their protein products often represent ideal targets for the development of cancer drugs.	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('translocations', 'Var', (21, 35))	('cancer', 'Disease', (153, 159))
128801	25204415	For example, imatinib induces remission in leukaemia patients who are positive for BCR-ABL1 fusions.	('patients', 'Species', '9606', (53, 61))	('BCR-ABL1', 'Gene', '613;25', (83, 91))	('leukaemia', 'Disease', 'MESH:D007938', (43, 52))	('fusions', 'Var', (92, 99))	('remission', 'MPA', (30, 39))	('leukaemia', 'Disease', (43, 52))	('imatinib', 'Chemical', 'MESH:D000068877', (13, 21))	('BCR-ABL1', 'Gene', (83, 91))
128804	25204415	While such studies have helped to identify numerous point mutations and small insertion/deletions in genes driving tumorigenesis, our understanding of the landscape of gene fusions in solid tumours is incomplete.	('solid tumours', 'Disease', 'MESH:D009369', (184, 197))	('insertion/deletions', 'Var', (78, 97))	('solid tumours', 'Disease', (184, 197))	('tumour', 'Phenotype', 'HP:0002664', (190, 196))	('tumours', 'Phenotype', 'HP:0002664', (190, 197))
128807	25204415	We identify several novel and recurrent fusions involving kinases that very likely play a role in cancer.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('role', 'Reg', (90, 94))	('fusions', 'Var', (40, 47))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('cancer', 'Disease', (98, 104))	('play', 'Reg', (83, 87))	('kinases', 'Protein', (58, 65))
128809	25204415	We then focused our detailed analysis exclusively on recurrent (n>=2 across all cancer types), putatively functional kinase fusions (Supplementary Fig.	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('kinase fusions', 'Var', (117, 131))	('fusions', 'Var', (124, 131))	('cancer', 'Disease', (80, 86))
128811	25204415	First, as has been observed for point mutations, the proportion of samples harbouring kinase fusions was markedly different between cancer types, reflecting differences in the aetiology of these tumours.	('kinase fusions', 'Var', (86, 100))	('cancer', 'Disease', (132, 138))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('tumours', 'Phenotype', 'HP:0002664', (195, 202))	('tumours', 'Disease', 'MESH:D009369', (195, 202))	('different', 'Reg', (114, 123))	('tumours', 'Disease', (195, 202))	('tumour', 'Phenotype', 'HP:0002664', (195, 201))
128812	25204415	For instance, sarcoma samples showed the highest frequency of kinase fusions (0.57 fusions per sample), consistent with the current understanding that a large fraction of sarcomas harbour specific translocations, but only 12% of those were recurrent kinase fusions (Supplementary Fig.	('sarcoma', 'Disease', (14, 21))	('sarcomas', 'Disease', (171, 179))	('sarcoma', 'Phenotype', 'HP:0100242', (14, 21))	('translocations', 'Var', (197, 211))	('kinase', 'Var', (62, 68))	('sarcoma', 'Disease', 'MESH:D012509', (171, 178))	('sarcomas', 'Disease', 'MESH:D012509', (171, 179))	('sarcoma', 'Disease', (171, 178))	('sarcoma', 'Phenotype', 'HP:0100242', (171, 178))	('sarcoma', 'Disease', 'MESH:D012509', (14, 21))
128814	25204415	Conversely, some cancer types, for example, clear cell and chromophobe renal cell carcinoma, showed a very low frequency of kinase fusions with no instances of recurrence (Supplementary Fig.	('chromophobe renal cell carcinoma', 'Disease', 'MESH:C538614', (59, 91))	('clear cell', 'Disease', (44, 54))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (71, 91))	('cancer', 'Disease', (17, 23))	('chromophobe renal cell carcinoma', 'Disease', (59, 91))	('kinase fusions', 'Var', (124, 138))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
128815	25204415	Overall, we detected recurrent kinase fusions in 3.0% of the samples, and all cancers except clear cell and chromophobe renal cell carcinoma harboured recurrent kinase fusions (0-12.9% of samples per cancer type, median=2.1%).	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('chromophobe renal cell carcinoma', 'Disease', 'MESH:C538614', (108, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('detected', 'Reg', (12, 20))	('cancers', 'Disease', 'MESH:D009369', (78, 85))	('cancers', 'Phenotype', 'HP:0002664', (78, 85))	('cancers', 'Disease', (78, 85))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (120, 140))	('cancer', 'Disease', 'MESH:D009369', (200, 206))	('clear cell', 'Disease', (93, 103))	('chromophobe renal cell carcinoma', 'Disease', (108, 140))	('kinase fusions', 'Var', (31, 45))	('cancer', 'Disease', (200, 206))
128817	25204415	Interestingly, we identified new tumour types harbouring such fusions and discovered several novel fusion partners for these kinases.	('tumour type', 'Disease', (33, 44))	('tumour type', 'Disease', 'MESH:D009369', (33, 44))	('fusion', 'Interaction', (99, 105))	('fusions', 'Var', (62, 69))	('tumour', 'Phenotype', 'HP:0002664', (33, 39))
128819	25204415	Third, we identified several novel and recurrent kinase fusions that very likely play a role in cancer, such as those involving the MET proto-oncogene and PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha).	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('play', 'Reg', (81, 85))	('role', 'Reg', (88, 92))	('PIK3CA', 'Gene', (155, 161))	('MET', 'Gene', (132, 135))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Disease', (96, 102))	('PIK3CA', 'Gene', '5290', (155, 161))	('kinase fusions', 'Var', (49, 63))
128820	25204415	Our analysis also uncovered novel, recurrent fusions in kinases with no known tumorigenic genomic alterations (that is, feline Gardner-Rasheed sarcoma viral oncogene homologue, FGR and protein kinase N1, PKN1), potentially resulting in active and oncogenic fusion proteins.	('protein kinase N1', 'Gene', '5585', (185, 202))	('sarcoma', 'Phenotype', 'HP:0100242', (143, 150))	('PKN1', 'Gene', (204, 208))	('kinases', 'Enzyme', (56, 63))	('Gardner-Rasheed sarcoma viral', 'Disease', (127, 156))	('Gardner-Rasheed sarcoma viral', 'Disease', 'MESH:D005736', (127, 156))	('oncogenic', 'MPA', (247, 256))	('rat', 'Species', '10116', (102, 105))	('active', 'MPA', (236, 242))	('fusion', 'Interaction', (257, 263))	('FGR', 'Gene', (177, 180))	('FGR', 'Gene', '2268', (177, 180))	('fusions', 'Var', (45, 52))	('protein kinase N1', 'Gene', (185, 202))	('PKN1', 'Gene', '5585', (204, 208))
128821	25204415	Finally, we discovered a recurrent fusion in sarcoma encoding the non-catalytic portion of TRIO kinase, which resulted in the upregulation of the transcription of telomerase reverse transcriptase (TERT) in those tumours.	('TERT', 'Gene', (197, 201))	('sarcoma', 'Disease', (45, 52))	('tumour', 'Phenotype', 'HP:0002664', (212, 218))	('TRIO', 'Gene', (91, 95))	('TRIO', 'Gene', '7204', (91, 95))	('sarcoma', 'Phenotype', 'HP:0100242', (45, 52))	('telomerase reverse transcriptase', 'Gene', (163, 195))	('TERT', 'Gene', '7015', (197, 201))	('telomerase reverse transcriptase', 'Gene', '7015', (163, 195))	('tumours', 'Phenotype', 'HP:0002664', (212, 219))	('transcription', 'MPA', (146, 159))	('fusion', 'Var', (35, 41))	('tumours', 'Disease', (212, 219))	('sarcoma', 'Disease', 'MESH:D012509', (45, 52))	('tumours', 'Disease', 'MESH:D009369', (212, 219))	('upregulation', 'PosReg', (126, 138))
128823	25204415	Consistent with previous studies, we detected EML4-ALK fusions in ~1% (5/513) of lung adenocarcinoma samples, multiple ALK fusions, including a single STRN-ALK fusion, in thyroid cancer (3/498) and one in papillary renal carcinoma.	('EML4', 'Gene', '27436', (46, 50))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('ALK', 'Gene', '238', (156, 159))	('papillary renal carcinoma', 'Disease', (205, 230))	('STRN', 'Gene', '6801', (151, 155))	('thyroid cancer', 'Disease', 'MESH:D013964', (171, 185))	('ALK', 'Gene', (156, 159))	('ALK', 'Gene', '238', (51, 54))	('papillary renal carcinoma', 'Disease', 'MESH:D007681', (205, 230))	('carcinoma', 'Phenotype', 'HP:0030731', (221, 230))	('lung adenocarcinoma', 'Disease', (81, 100))	('thyroid cancer', 'Phenotype', 'HP:0002890', (171, 185))	('ALK', 'Gene', (51, 54))	('fusions', 'Var', (123, 130))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (81, 100))	('ALK', 'Gene', '238', (119, 122))	('STRN', 'Gene', (151, 155))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (81, 100))	('papillary renal carcinoma', 'Phenotype', 'HP:0006766', (205, 230))	('ALK', 'Gene', (119, 122))	('renal carcinoma', 'Phenotype', 'HP:0005584', (215, 230))	('thyroid cancer', 'Disease', (171, 185))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('EML4', 'Gene', (46, 50))
128824	25204415	We also found several novel ALK fusion events, including a TPM1-ALK fusion in bladder cancer, a SMEK2-ALK fusion in rectal adenocarcinoma and a GTF2IRD1-ALK fusion in thyroid cancer (Fig.	('ALK', 'Gene', (102, 105))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('rectal adenocarcinoma', 'Disease', 'MESH:D012004', (116, 137))	('ALK', 'Gene', '238', (28, 31))	('fusion', 'Var', (68, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('thyroid cancer', 'Disease', (167, 181))	('ALK', 'Gene', (28, 31))	('GTF2IRD1', 'Gene', '9569', (144, 152))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('bladder cancer', 'Disease', 'MESH:D001749', (78, 92))	('bladder cancer', 'Disease', (78, 92))	('GTF2IRD1', 'Gene', (144, 152))	('ALK', 'Gene', '238', (153, 156))	('SMEK2', 'Gene', '57223', (96, 101))	('ALK', 'Gene', '238', (64, 67))	('thyroid cancer', 'Disease', 'MESH:D013964', (167, 181))	('SMEK2', 'Gene', (96, 101))	('rectal adenocarcinoma', 'Disease', (116, 137))	('ALK', 'Gene', (153, 156))	('bladder cancer', 'Phenotype', 'HP:0009725', (78, 92))	('ALK', 'Gene', (64, 67))	('thyroid cancer', 'Phenotype', 'HP:0002890', (167, 181))	('ALK', 'Gene', '238', (102, 105))
128826	25204415	We also identified multiple c-ros oncogene 1 (ROS1) fusions, including ROS1 fusions in 8/513 lung adenocarcinomas, all of which have been previously described.	('c-ros oncogene 1', 'Gene', '6098', (28, 44))	('ROS1', 'Gene', '6098', (71, 75))	('lung adenocarcinomas', 'Disease', (93, 113))	('carcinomas', 'Phenotype', 'HP:0030731', (103, 113))	('fusions', 'Var', (76, 83))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (93, 113))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (93, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('ROS1', 'Gene', (46, 50))	('c-ros oncogene 1', 'Gene', (28, 44))	('ROS1', 'Gene', '6098', (46, 50))	('ROS1', 'Gene', (71, 75))	('fusions', 'Var', (52, 59))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (93, 112))
128829	25204415	RET proto-oncogene fusions have been identified previously in both lung adenocarcinoma and thyroid cancer.	('RET', 'Gene', '5979', (0, 3))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (67, 86))	('fusions', 'Var', (19, 26))	('thyroid cancer', 'Phenotype', 'HP:0002890', (91, 105))	('thyroid cancer', 'Disease', (91, 105))	('RET', 'Gene', (0, 3))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('lung adenocarcinoma', 'Disease', (67, 86))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (67, 86))	('identified', 'Reg', (37, 47))	('thyroid cancer', 'Disease', 'MESH:D013964', (91, 105))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
128830	25204415	Consistent with these studies, we observed recurrent CCDC6-RET fusions in thyroid cancer but also identified several RET fusions with novel partners, including AKAP13, FKBP15, SPECC1L and TBL1XR1 (Fig.	('FKBP15', 'Gene', '23307', (168, 174))	('SPECC1L', 'Gene', (176, 183))	('RET', 'Gene', (59, 62))	('AKAP13', 'Gene', (160, 166))	('SPECC1L', 'Gene', '23384', (176, 183))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('thyroid cancer', 'Disease', (74, 88))	('TBL1XR1', 'Gene', '79718', (188, 195))	('RET', 'Gene', '5979', (117, 120))	('TBL1XR1', 'Gene', (188, 195))	('thyroid cancer', 'Disease', 'MESH:D013964', (74, 88))	('RET', 'Gene', '5979', (59, 62))	('CCDC6', 'Gene', (53, 58))	('FKBP15', 'Gene', (168, 174))	('AKAP13', 'Gene', '11214', (160, 166))	('CCDC6', 'Gene', '8030', (53, 58))	('thyroid cancer', 'Phenotype', 'HP:0002890', (74, 88))	('RET', 'Gene', (117, 120))	('fusions', 'Var', (63, 70))
128832	25204415	In addition, we detected previously identified RET fusions in new tumour indications, including a single CCDC6-RET fusion in colon adenocarcinoma and a single ERC1-RET fusion in breast cancer.	('colon adenocarcinoma', 'Disease', 'MESH:D003110', (125, 145))	('fusion', 'Var', (115, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('tumour', 'Phenotype', 'HP:0002664', (66, 72))	('CCDC6', 'Gene', (105, 110))	('RET', 'Gene', '5979', (111, 114))	('CCDC6', 'Gene', '8030', (105, 110))	('tumour', 'Disease', 'MESH:D009369', (66, 72))	('tumour', 'Disease', (66, 72))	('RET', 'Gene', '5979', (47, 50))	('RET', 'Gene', '5979', (164, 167))	('colon adenocarcinoma', 'Disease', (125, 145))	('ERC1', 'Gene', '23085', (159, 163))	('breast cancer', 'Phenotype', 'HP:0003002', (178, 191))	('RET', 'Gene', (111, 114))	('ERC1', 'Gene', (159, 163))	('RET', 'Gene', (47, 50))	('RET', 'Gene', (164, 167))	('breast cancer', 'Disease', 'MESH:D001943', (178, 191))	('breast cancer', 'Disease', (178, 191))
128834	25204415	BRAF (v-raf murine sarcoma viral oncogene homologue B) fusions have also been described previously in multiple cancer types, including prostate cancer, melanoma, radiation-induced thyroid cancer and pediatric low-grade gliomas.	('melanoma', 'Phenotype', 'HP:0002861', (152, 160))	('melanoma', 'Disease', (152, 160))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('cancer', 'Disease', (144, 150))	('thyroid cancer', 'Disease', 'MESH:D013964', (180, 194))	('sarcoma viral', 'Disease', 'MESH:D001102', (19, 32))	('cancer', 'Disease', (111, 117))	('BRAF', 'Gene', (0, 4))	('gliomas', 'Disease', 'MESH:D005910', (219, 226))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('sarcoma viral', 'Disease', (19, 32))	('glioma', 'Phenotype', 'HP:0009733', (219, 225))	('thyroid cancer', 'Phenotype', 'HP:0002890', (180, 194))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('v-raf', 'Gene', '110157', (6, 11))	('gliomas', 'Phenotype', 'HP:0009733', (219, 226))	('melanoma', 'Disease', 'MESH:D008545', (152, 160))	('murine', 'Species', '10090', (12, 18))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('prostate cancer', 'Disease', 'MESH:D011471', (135, 150))	('cancer', 'Disease', (188, 194))	('prostate cancer', 'Phenotype', 'HP:0012125', (135, 150))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('prostate cancer', 'Disease', (135, 150))	('thyroid cancer', 'Disease', (180, 194))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('v-raf', 'Gene', (6, 11))	('described', 'Reg', (78, 87))	('gliomas', 'Disease', (219, 226))	('sarcoma', 'Phenotype', 'HP:0100242', (19, 26))	('fusions', 'Var', (55, 62))
128835	25204415	Consistent with these studies, we identified a broad range of cancer types harbouring BRAF fusions, including prostate, melanoma and thyroid.	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('fusions', 'Var', (91, 98))	('BRAF', 'Var', (86, 90))	('melanoma', 'Phenotype', 'HP:0002861', (120, 128))	('melanoma', 'Disease', (120, 128))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('melanoma', 'Disease', 'MESH:D008545', (120, 128))	('prostate', 'Disease', (110, 118))	('thyroid', 'Disease', (133, 140))
128837	25204415	Interestingly, the BRAF fusions in melanoma are exclusive of other known oncogenic events such as BRAF and NRAS mutations.	('melanoma', 'Disease', 'MESH:D008545', (35, 43))	('BRAF', 'Disease', (98, 102))	('BRAF', 'Gene', (19, 23))	('NRAS', 'Gene', '4893', (107, 111))	('mutations', 'Var', (112, 121))	('NRAS', 'Gene', (107, 111))	('melanoma', 'Phenotype', 'HP:0002861', (35, 43))	('melanoma', 'Disease', (35, 43))	('fusions', 'Var', (24, 31))
128841	25204415	However, these fusions all remove at least the first eight exons of BRAF, which has previously been shown to promote BRAF dimerization, independent of activated RAS (rat sarcoma viral oncogene homologues) or other mechanisms of BRAF dimerization.	('promote', 'PosReg', (109, 116))	('rat', 'Species', '10116', (166, 169))	('sarcoma viral', 'Disease', 'MESH:D001102', (170, 183))	('fusions', 'Var', (15, 22))	('BRAF dimerization', 'MPA', (117, 134))	('BRAF', 'Gene', (68, 72))	('remove', 'NegReg', (27, 33))	('sarcoma', 'Phenotype', 'HP:0100242', (170, 177))	('sarcoma viral', 'Disease', (170, 183))
128842	25204415	Consistent with previous studies, we also found recurrent RAF1 (also known as CRAF) fusions in various tumour types (Fig.	('tumour type', 'Disease', 'MESH:D009369', (103, 114))	('fusions', 'Var', (84, 91))	('tumour', 'Phenotype', 'HP:0002664', (103, 109))	('tumour type', 'Disease', (103, 114))	('CRAF', 'Gene', (78, 82))	('RAF1', 'Gene', '5894', (58, 62))	('RAF1', 'Gene', (58, 62))	('CRAF', 'Gene', '5894', (78, 82))
128843	25204415	In addition to known tumour occurrences (four fusions in melanoma, two fusions in prostate adenocarcinoma), we identified AGGF1-RAF1 fusions in seven papillary thyroid carcinoma samples (1.4%).	('tumour', 'Phenotype', 'HP:0002664', (21, 27))	('tumour', 'Disease', 'MESH:D009369', (21, 27))	('melanoma', 'Phenotype', 'HP:0002861', (57, 65))	('melanoma', 'Disease', (57, 65))	('fusions', 'Var', (133, 140))	('tumour', 'Disease', (21, 27))	('AGGF1', 'Gene', (122, 127))	('papillary thyroid carcinoma', 'Phenotype', 'HP:0002895', (150, 177))	('prostate adenocarcinoma', 'Disease', (82, 105))	('carcinoma', 'Phenotype', 'HP:0030731', (168, 177))	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('papillary thyroid carcinoma', 'Disease', (150, 177))	('papillary thyroid carcinoma', 'Disease', 'MESH:D000077273', (150, 177))	('RAF1', 'Gene', '5894', (128, 132))	('prostate adenocarcinoma', 'Disease', 'MESH:D011471', (82, 105))	('melanoma', 'Disease', 'MESH:D008545', (57, 65))	('RAF1', 'Gene', (128, 132))	('AGGF1', 'Gene', '55109', (122, 127))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (160, 177))
128846	25204415	AGGF1-RAF1 fusions appear not to be limited to thyroid cancers, as we also found a single AGGF1-RAF1 fusion in prostate cancer.	('fusion', 'Var', (101, 107))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('thyroid cancers', 'Disease', (47, 62))	('prostate cancer', 'Disease', (111, 126))	('AGGF1', 'Gene', '55109', (0, 5))	('thyroid cancers', 'Disease', 'MESH:D013964', (47, 62))	('AGGF1', 'Gene', (90, 95))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('RAF1', 'Gene', '5894', (6, 10))	('prostate cancer', 'Disease', 'MESH:D011471', (111, 126))	('RAF1', 'Gene', (96, 100))	('RAF1', 'Gene', '5894', (96, 100))	('thyroid cancer', 'Phenotype', 'HP:0002890', (47, 61))	('prostate cancer', 'Phenotype', 'HP:0012125', (111, 126))	('AGGF1', 'Gene', '55109', (90, 95))	('RAF1', 'Gene', (6, 10))	('cancers', 'Phenotype', 'HP:0002664', (55, 62))	('AGGF1', 'Gene', (0, 5))
128847	25204415	We observed a broad distribution of the fibroblast growth factor receptors FGFR1, FGFR2 and FGFR3 fusions:in particular FGFR3-TACC3 fusions:across eight of the 20 tumour types analysed (Fig.	('tumour type', 'Disease', 'MESH:D009369', (163, 174))	('TACC3', 'Gene', (126, 131))	('fusions', 'Var', (132, 139))	('FGFR3', 'Gene', (120, 125))	('FGFR1', 'Gene', (75, 80))	('FGFR3', 'Gene', (92, 97))	('fusions', 'Var', (98, 105))	('FGFR3', 'Gene', '2261', (92, 97))	('FGFR1', 'Gene', '2260', (75, 80))	('tumour', 'Phenotype', 'HP:0002664', (163, 169))	('FGFR2', 'Gene', (82, 87))	('FGFR2', 'Gene', '2263', (82, 87))	('tumour type', 'Disease', (163, 174))	('TACC3', 'Gene', '10460', (126, 131))	('FGFR3', 'Gene', '2261', (120, 125))
128849	25204415	We also detected a single FGFR3-TACC3 fusion in a novel indication, papillary renal carcinoma, and a novel FGFR3-ELAVL3 fusion in low-grade glioma (Supplementary Fig.	('glioma', 'Disease', 'MESH:D005910', (140, 146))	('glioma', 'Phenotype', 'HP:0009733', (140, 146))	('ELAVL3', 'Gene', (113, 119))	('FGFR3', 'Gene', (26, 31))	('fusion', 'Var', (38, 44))	('FGFR3', 'Gene', '2261', (107, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('ELAVL3', 'Gene', '1995', (113, 119))	('papillary renal carcinoma', 'Phenotype', 'HP:0006766', (68, 93))	('papillary renal carcinoma', 'Disease', 'MESH:D007681', (68, 93))	('renal carcinoma', 'Phenotype', 'HP:0005584', (78, 93))	('FGFR3', 'Gene', (107, 112))	('glioma', 'Disease', (140, 146))	('TACC3', 'Gene', '10460', (32, 37))	('FGFR3', 'Gene', '2261', (26, 31))	('papillary renal carcinoma', 'Disease', (68, 93))	('TACC3', 'Gene', (32, 37))
128850	25204415	Similar to RET and NTRK1-3 (see below), fusions involving FGFR1-3 provide a therapeutic opportunity for current and future FGFR inhibitors in multiple patient subpopulations.	('RET', 'Gene', '5979', (11, 14))	('NTRK1', 'Gene', '4914', (19, 24))	('fusions', 'Var', (40, 47))	('patient', 'Species', '9606', (151, 158))	('RET', 'Gene', (11, 14))	('FGFR1', 'Gene', (58, 63))	('NTRK1', 'Gene', (19, 24))	('FGFR1', 'Gene', '2260', (58, 63))
128851	25204415	Recurrent fusions involving members of the NTRK family have been identified previously in congenital fibrosarcoma, human secretory breast carcinoma and papillary thyroid cancer, which represent clinical indications for which currently available non-kinase-targeted treatment options are usually adequate.	('sarcoma', 'Phenotype', 'HP:0100242', (106, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('papillary thyroid cancer', 'Phenotype', 'HP:0002895', (152, 176))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (101, 113))	('congenital fibrosarcoma', 'Disease', (90, 113))	('congenital fibrosarcoma', 'Disease', 'MESH:D005354', (90, 113))	('thyroid cancer', 'Phenotype', 'HP:0002890', (162, 176))	('identified', 'Reg', (65, 75))	('breast carcinoma and papillary thyroid cancer', 'Disease', 'MESH:D000077273', (131, 176))	('NTRK family', 'Gene', (43, 54))	('breast carcinoma', 'Phenotype', 'HP:0003002', (131, 147))	('human', 'Species', '9606', (115, 120))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('fusions', 'Var', (10, 17))
128852	25204415	However, recurrent NTRK1 and NTRK2 fusions have also been recently identified in diseases which represent significant unmet medical needs, including glioblastoma, cholangiocarcinoma and pediatric high-grade glioma.	('glioblastoma', 'Disease', (149, 161))	('glioblastoma', 'Disease', 'MESH:D005909', (149, 161))	('NTRK1', 'Gene', '4914', (19, 24))	('fusions', 'Var', (35, 42))	('glioblastoma', 'Phenotype', 'HP:0012174', (149, 161))	('glioma', 'Disease', (207, 213))	('cholangiocarcinoma', 'Disease', (163, 181))	('NTRK2', 'Gene', '4915', (29, 34))	('NTRK1', 'Gene', (19, 24))	('identified', 'Reg', (67, 77))	('glioma', 'Phenotype', 'HP:0009733', (207, 213))	('glioma', 'Disease', 'MESH:D005910', (207, 213))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (163, 181))	('carcinoma', 'Phenotype', 'HP:0030731', (172, 181))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (163, 181))	('NTRK2', 'Gene', (29, 34))
128853	25204415	Consistent with previous studies, we observed recurrent NTRK1 and NTRK3 fusions in papillary thyroid cancer and glioblastoma, but also identified a number of novel NTRK2 fusions in head and neck squamous cell carcinoma (PAN3-NTRK2), low-grade glioma (AFAP1-NTRK2) and lung adenocarcinoma (TRIM24-NTRK2) (Fig.	('lung adenocarcinoma', 'Disease', (268, 287))	('NTRK2', 'Gene', '4915', (225, 230))	('AFAP1', 'Gene', '60312', (251, 256))	('glioma', 'Disease', (243, 249))	('TRIM24', 'Gene', '8805', (289, 295))	('carcinoma', 'Phenotype', 'HP:0030731', (278, 287))	('papillary thyroid cancer', 'Phenotype', 'HP:0002895', (83, 107))	('NTRK2', 'Gene', '4915', (257, 262))	('NTRK2', 'Gene', '4915', (296, 301))	('glioma', 'Disease', 'MESH:D005910', (243, 249))	('NTRK2', 'Gene', (164, 169))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (268, 287))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (195, 218))	('AFAP1', 'Gene', (251, 256))	('neck squamous cell carcinoma', 'Disease', (190, 218))	('papillary thyroid cancer', 'Disease', 'MESH:D000077273', (83, 107))	('NTRK2', 'Gene', (225, 230))	('NTRK1', 'Gene', '4914', (56, 61))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (190, 218))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (268, 287))	('PAN3', 'Gene', (220, 224))	('glioma', 'Phenotype', 'HP:0009733', (243, 249))	('thyroid cancer', 'Phenotype', 'HP:0002890', (93, 107))	('glioblastoma', 'Disease', 'MESH:D005909', (112, 124))	('fusions', 'Var', (170, 177))	('NTRK1', 'Gene', (56, 61))	('NTRK2', 'Gene', (257, 262))	('NTRK2', 'Gene', (296, 301))	('fusions', 'Var', (72, 79))	('PAN3', 'Gene', '255967', (220, 224))	('NTRK3', 'Gene', '4916', (66, 71))	('TRIM24', 'Gene', (289, 295))	('glioblastoma', 'Disease', (112, 124))	('NTRK3', 'Gene', (66, 71))	('glioblastoma', 'Phenotype', 'HP:0012174', (112, 124))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('papillary thyroid cancer', 'Disease', (83, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (209, 218))	('NTRK2', 'Gene', '4915', (164, 169))
128855	25204415	Across all tumour types analysed, NTRK1-3 fusions were observed at low frequency in 9 of the 20 cancer types analysed, providing a therapeutic opportunity for the use of pan-NTRK inhibitors in multiple patient populations.	('NTRK1', 'Gene', (34, 39))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('tumour', 'Phenotype', 'HP:0002664', (11, 17))	('patient', 'Species', '9606', (202, 209))	('tumour type', 'Disease', (11, 22))	('NTRK1', 'Gene', '4914', (34, 39))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('tumour type', 'Disease', 'MESH:D009369', (11, 22))	('fusions', 'Var', (42, 49))	('cancer', 'Disease', (96, 102))
128856	25204415	Protein kinase C fusions have recently been described in papillary glioneuronal tumours and benign fibrous histiocytoma.	('Protein', 'Protein', (0, 7))	('benign fibrous histiocytoma', 'Disease', (92, 119))	('papillary glioneuronal tumours', 'Phenotype', 'HP:0025170', (57, 87))	('tumour', 'Phenotype', 'HP:0002664', (80, 86))	('fusions', 'Var', (17, 24))	('papillary glioneuronal tumours', 'Disease', 'MESH:D000077273', (57, 87))	('papillary glioneuronal tumours', 'Disease', (57, 87))	('tumours', 'Phenotype', 'HP:0002664', (80, 87))	('described', 'Reg', (44, 53))	('histiocytoma', 'Phenotype', 'HP:0012315', (107, 119))
128857	25204415	We found two new occurrences of PRKCA (protein kinase C, alpha) fusions in lung squamous cell carcinoma and three PRKCB (protein kinase C, beta) fusions in lung squamous cell carcinoma, lung adenocarcinoma and low-grade glioma (Fig.	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (75, 103))	('lung squamous cell carcinoma', 'Disease', (75, 103))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (80, 103))	('glioma', 'Disease', 'MESH:D005910', (220, 226))	('carcinoma', 'Phenotype', 'HP:0030731', (175, 184))	('PRKCA', 'Gene', (32, 37))	('glioma', 'Phenotype', 'HP:0009733', (220, 226))	('lung adenocarcinoma', 'Disease', (186, 205))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('PRKCB', 'Gene', (114, 119))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (186, 205))	('carcinoma', 'Phenotype', 'HP:0030731', (196, 205))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (186, 205))	('protein kinase C, alpha', 'Gene', '5578', (39, 62))	('PRKCA', 'Gene', '5578', (32, 37))	('glioma', 'Disease', (220, 226))	('fusions', 'Var', (64, 71))	('PRKCB', 'Gene', '5579', (114, 119))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (161, 184))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (156, 184))	('lung squamous cell carcinoma', 'Disease', (156, 184))
128861	25204415	In both cases, however, N-terminal truncation of PRKCA removes the autoinhibitory pseudosubstrate segment, possibly leading to a constitutively activated kinase in the absence of a functional fusion partner.	('PRKCA', 'Gene', (49, 54))	('autoinhibitory pseudosubstrate segment', 'MPA', (67, 105))	('N-terminal truncation', 'Var', (24, 45))	('leading to', 'Reg', (116, 126))	('removes', 'NegReg', (55, 62))	('PRKCA', 'Gene', '5578', (49, 54))	('constitutively activated kinase', 'MPA', (129, 160))	('rat', 'Species', '10116', (93, 96))
128863	25204415	These data suggest that PRKCA fusions are potential oncogenic events in lung squamous cell carcinoma, leading to overexpression as well as constitutive activation of PRKCA.	('PRKCA', 'Gene', '5578', (166, 171))	('activation', 'PosReg', (152, 162))	('PRKCA', 'Gene', (166, 171))	('overexpression', 'PosReg', (113, 127))	('fusions', 'Var', (30, 37))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (77, 100))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (72, 100))	('PRKCA', 'Gene', '5578', (24, 29))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('lung squamous cell carcinoma', 'Disease', (72, 100))	('PRKCA', 'Gene', (24, 29))
128864	25204415	In the same fashion, PRKCB fusions truncate the N-terminal part of the protein containing the autoinhibitory domain and are predicted to activate this kinase (Supplementary Fig.	('PRKCB', 'Gene', (21, 26))	('PRKCB', 'Gene', '5579', (21, 26))	('truncate', 'NegReg', (35, 43))	('fusions', 'Var', (27, 34))	('activate', 'PosReg', (137, 145))
128867	25204415	Anecdotally, a transforming TPR-MET fusion was previously generated in vitro via carcinogen-induced chromosomal rearrangement fusing the dimerization domain of TPR to the kinase domain of the MET receptor tyrosine kinase.	('TPR', 'Gene', '7175', (160, 163))	('fusing', 'Var', (126, 132))	('TPR', 'Gene', (28, 31))	('TPR', 'Gene', '7175', (28, 31))	('dimerization', 'MPA', (137, 149))	('rat', 'Species', '10116', (62, 65))	('TPR', 'Gene', (160, 163))
128872	25204415	We also identified single MET fusions in four other cancers: low-grade glioma, hepatocellular carcinoma, lung adenocarcinoma and thyroid carcinoma.	('cancers', 'Disease', (52, 59))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (79, 103))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (129, 146))	('hepatocellular carcinoma', 'Disease', (79, 103))	('lung adenocarcinoma', 'Disease', (105, 124))	('thyroid carcinoma', 'Disease', (129, 146))	('cancers', 'Disease', 'MESH:D009369', (52, 59))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('glioma', 'Disease', (71, 77))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (129, 146))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (105, 124))	('single MET fusions', 'Var', (19, 37))	('glioma', 'Disease', 'MESH:D005910', (71, 77))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (79, 103))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (105, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('glioma', 'Phenotype', 'HP:0009733', (71, 77))	('cancers', 'Phenotype', 'HP:0002664', (52, 59))
128875	25204415	Mutations and, to a lesser extent, increased copy numbers in another prevalent oncogene, PIK3CA, have been characterized in diverse cancers.	('cancers', 'Disease', (132, 139))	('increased', 'PosReg', (35, 44))	('cancers', 'Disease', 'MESH:D009369', (132, 139))	('PIK3CA', 'Gene', (89, 95))	('PIK3CA', 'Gene', '5290', (89, 95))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('Mutations', 'Var', (0, 9))	('copy numbers', 'Var', (45, 57))	('cancers', 'Phenotype', 'HP:0002664', (132, 139))
128876	25204415	While activating missense mutations in PIK3CA have been described as frequently as 50% in endometrial cancers, 30% in breast invasive carcinomas and 20% in colorectal as well as head and neck cancers, this gene has not been implicated in activating fusion events.	('missense mutations', 'Var', (17, 35))	('cancers', 'Phenotype', 'HP:0002664', (192, 199))	('neck cancers', 'Disease', (187, 199))	('head and neck cancers', 'Phenotype', 'HP:0012288', (178, 199))	('neck cancers', 'Disease', 'MESH:D006258', (187, 199))	('endometrial cancers', 'Disease', 'MESH:D016889', (90, 109))	('endometrial cancers', 'Disease', (90, 109))	('colorectal', 'Disease', 'MESH:D015179', (156, 166))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('PIK3CA', 'Gene', '5290', (39, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('carcinomas', 'Phenotype', 'HP:0030731', (134, 144))	('breast invasive carcinomas', 'Disease', (118, 144))	('activating', 'PosReg', (6, 16))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))	('PIK3CA', 'Gene', (39, 45))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('colorectal', 'Disease', (156, 166))	('breast invasive carcinomas', 'Disease', 'MESH:D018270', (118, 144))
128877	25204415	We found two TBL1XR1-PIK3CA fusions in 1,072 breast cancer samples, and a single occurrence of the same gene fusion in prostate adenocarcinoma (1/335).	('prostate adenocarcinoma', 'Disease', 'MESH:D011471', (119, 142))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('TBL1XR1', 'Gene', '79718', (13, 20))	('PIK3CA', 'Gene', (21, 27))	('breast cancer', 'Disease', 'MESH:D001943', (45, 58))	('TBL1XR1', 'Gene', (13, 20))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('breast cancer', 'Disease', (45, 58))	('breast cancer', 'Phenotype', 'HP:0003002', (45, 58))	('PIK3CA', 'Gene', '5290', (21, 27))	('fusions', 'Var', (28, 35))	('prostate adenocarcinoma', 'Disease', (119, 142))
128880	25204415	Indeed, in all samples where we detected PIK3CA translocations, and where PIK3CA was not amplified, PIK3CA mRNA expression levels were the highest within the respective tumour types (Fig.	('translocations', 'Var', (48, 62))	('highest', 'Reg', (139, 146))	('tumour type', 'Disease', 'MESH:D009369', (169, 180))	('PIK3CA', 'Gene', '5290', (74, 80))	('PIK3CA', 'Gene', (41, 47))	('PIK3CA', 'Gene', (100, 106))	('mRNA expression levels', 'MPA', (107, 129))	('tumour', 'Phenotype', 'HP:0002664', (169, 175))	('PIK3CA', 'Gene', '5290', (41, 47))	('PIK3CA', 'Gene', '5290', (100, 106))	('tumour type', 'Disease', (169, 180))	('PIK3CA', 'Gene', (74, 80))
128882	25204415	These results strongly suggest that PIK3CA overexpression is driven by its fusion partner, and that PIK3CA promoter fusions are an additional oncogenic mechanism to be considered for expanding the use of targeted therapies such as PI3K, AKT or mTOR inhibitors.	('AKT', 'Gene', (237, 240))	('mTOR', 'Gene', (244, 248))	('PIK3CA', 'Gene', '5290', (36, 42))	('overexpression', 'PosReg', (43, 57))	('PIK3CA', 'Gene', (100, 106))	('fusions', 'Var', (116, 123))	('AKT', 'Gene', '207', (237, 240))	('PIK3CA', 'Gene', '5290', (100, 106))	('PIK3CA', 'Gene', (36, 42))	('mTOR', 'Gene', '2475', (244, 248))
128883	25204415	In addition to fusions involving known oncogenes, we found several novel and recurrent fusions involving kinases that have not been previously directly linked to cancer (Fig.	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('fusions', 'Var', (87, 94))	('cancer', 'Disease', (162, 168))	('kinases', 'Enzyme', (105, 112))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))
128885	25204415	Here, we show for the first time that genetic events can lead to FGR overexpression in primary tumour samples.	('tumour', 'Disease', 'MESH:D009369', (95, 101))	('overexpression', 'MPA', (69, 83))	('tumour', 'Phenotype', 'HP:0002664', (95, 101))	('lead to', 'Reg', (57, 64))	('tumour', 'Disease', (95, 101))	('FGR', 'Gene', (65, 68))	('FGR', 'Gene', '2268', (65, 68))	('genetic events', 'Var', (38, 52))
128887	25204415	The WASF2 and FGR genes are located very proximally on the short arm of chromosome 1, and the fusion presumably results from a tandem repeat that puts their coding regions in close proximity (Supplementary Fig.	('results from', 'Reg', (112, 124))	('tandem repeat', 'Var', (127, 140))	('FGR', 'Gene', (14, 17))	('WASF2', 'Gene', '10163', (4, 9))	('FGR', 'Gene', '2268', (14, 17))	('short arm', 'Phenotype', 'HP:0009824', (59, 68))	('WASF2', 'Gene', (4, 9))
128889	25204415	In all three cases, FGR mRNA expression in the samples harbouring a fusion was among the highest compared with all other tumours of that tissue type (Supplementary Fig.	('tumours', 'Disease', 'MESH:D009369', (121, 128))	('tumours', 'Disease', (121, 128))	('fusion', 'Var', (68, 74))	('highest', 'Reg', (89, 96))	('FGR', 'Gene', (20, 23))	('tumour', 'Phenotype', 'HP:0002664', (121, 127))	('FGR', 'Gene', '2268', (20, 23))	('tumours', 'Phenotype', 'HP:0002664', (121, 128))
128891	25204415	Collectively, these data highlight a previously undocumented mechanism of genetic deregulation of a Src family member.	('genetic deregulation', 'Var', (74, 94))	('Src', 'Gene', '6714', (100, 103))	('Src', 'Gene', (100, 103))
128893	25204415	We detected fusions of PKN1 in samples of squamous cell carcinoma of the lung and hepatocellular carcinoma (Fig.	('squamous cell carcinoma of the lung and hepatocellular carcinoma', 'Disease', 'MESH:D002294', (42, 106))	('PKN1', 'Gene', '5585', (23, 27))	('fusions', 'Var', (12, 19))	('PKN1', 'Gene', (23, 27))	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (82, 106))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (42, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (56, 65))	('detected', 'Reg', (3, 11))
128900	25204415	Overall, 3.0% of tumour samples contained a likely oncogenic, recurrent kinase fusion (2.1% excluding thyroid cancer).	('thyroid cancer', 'Disease', 'MESH:D013964', (102, 116))	('tumour', 'Phenotype', 'HP:0002664', (17, 23))	('tumour', 'Disease', 'MESH:D009369', (17, 23))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('thyroid cancer', 'Phenotype', 'HP:0002890', (102, 116))	('thyroid cancer', 'Disease', (102, 116))	('tumour', 'Disease', (17, 23))	('kinase fusion', 'Var', (72, 85))
128901	25204415	The observed striking differences in the frequencies of kinase fusions across solid tumours are consistent with previous data on the relative contributions of diverse types of genetic aberrations to tumourigenesis.	('tumour', 'Phenotype', 'HP:0002664', (199, 205))	('tumour', 'Disease', (84, 90))	('solid tumours', 'Disease', 'MESH:D009369', (78, 91))	('tumour', 'Disease', 'MESH:D009369', (199, 205))	('solid tumours', 'Disease', (78, 91))	('tumour', 'Disease', (199, 205))	('rat', 'Species', '10116', (188, 191))	('tumour', 'Phenotype', 'HP:0002664', (84, 90))	('kinase', 'Var', (56, 62))	('tumours', 'Phenotype', 'HP:0002664', (84, 91))	('tumour', 'Disease', 'MESH:D009369', (84, 90))
128903	25204415	Other tumour types such as melanoma carry predominantly somatic point mutations.	('somatic point mutations', 'Var', (56, 79))	('tumour', 'Phenotype', 'HP:0002664', (6, 12))	('tumour type', 'Disease', (6, 17))	('melanoma', 'Disease', (27, 35))	('melanoma', 'Phenotype', 'HP:0002861', (27, 35))	('tumour type', 'Disease', 'MESH:D009369', (6, 17))	('melanoma', 'Disease', 'MESH:D008545', (27, 35))
128904	25204415	Consistent with these observations, our data suggest that certain cancers are heavily driven by kinase rearrangements.	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('cancers', 'Phenotype', 'HP:0002664', (66, 73))	('driven by', 'Reg', (86, 95))	('cancers', 'Disease', (66, 73))	('kinase rearrangements', 'Var', (96, 117))	('cancers', 'Disease', 'MESH:D009369', (66, 73))
128907	25204415	In stark contrast, clear cell and chromophobe renal cell carcinoma have the lowest frequencies of kinase fusions, none of which were recurrent in our analysis of this data set (Supplementary Fig.	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (46, 66))	('clear cell', 'Disease', (19, 29))	('chromophobe renal cell carcinoma', 'Disease', (34, 66))	('kinase', 'Var', (98, 104))	('carcinoma', 'Phenotype', 'HP:0030731', (57, 66))	('chromophobe renal cell carcinoma', 'Disease', 'MESH:C538614', (34, 66))
128909	25204415	Our study also revealed new cancer types harbouring known fusions (for example, BRAF fusion in rectal adenocarcinoma, FGFR3 fusion in prostate adenocarcinoma, RET fusions in colon adenocarcinoma and invasive breast carcinoma, EGFR-SEPT14 in low-grade glioma, and so on).	('fusion', 'Var', (85, 91))	('rectal adenocarcinoma', 'Disease', 'MESH:D012004', (95, 116))	('RET', 'Gene', '5979', (159, 162))	('SEPT14', 'Gene', '346288', (231, 237))	('glioma', 'Disease', 'MESH:D005910', (251, 257))	('colon adenocarcinoma', 'Disease', (174, 194))	('fusion', 'Var', (124, 130))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('FGFR3', 'Gene', (118, 123))	('glioma', 'Phenotype', 'HP:0009733', (251, 257))	('carcinoma', 'Phenotype', 'HP:0030731', (215, 224))	('FGFR3', 'Gene', '2261', (118, 123))	('RET', 'Gene', (159, 162))	('prostate adenocarcinoma', 'Disease', (134, 157))	('EGFR', 'Gene', '1956', (226, 230))	('rectal adenocarcinoma', 'Disease', (95, 116))	('carcinoma', 'Phenotype', 'HP:0030731', (148, 157))	('invasive breast carcinoma', 'Disease', 'MESH:D018270', (199, 224))	('breast carcinoma', 'Phenotype', 'HP:0003002', (208, 224))	('SEPT14', 'Gene', (231, 237))	('colon adenocarcinoma', 'Disease', 'MESH:D003110', (174, 194))	('cancer', 'Disease', (28, 34))	('prostate adenocarcinoma', 'Disease', 'MESH:D011471', (134, 157))	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('invasive breast carcinoma', 'Disease', (199, 224))	('carcinoma', 'Phenotype', 'HP:0030731', (185, 194))	('glioma', 'Disease', (251, 257))	('EGFR', 'Gene', (226, 230))
128914	25204415	For example, we found six cancer types with a single fusion in a gene of the NTRK family, but altogether, we detected a total of 23 NTRK1, NTRK2 and NTRK3 fusions across nine tumour types.	('NTRK2', 'Gene', (139, 144))	('NTRK1', 'Gene', '4914', (132, 137))	('cancer', 'Disease', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('NTRK3', 'Gene', '4916', (149, 154))	('NTRK2', 'Gene', '4915', (139, 144))	('NTRK', 'Gene', (77, 81))	('tumour type', 'Disease', (175, 186))	('NTRK1', 'Gene', (132, 137))	('tumour type', 'Disease', 'MESH:D009369', (175, 186))	('NTRK3', 'Gene', (149, 154))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('tumour', 'Phenotype', 'HP:0002664', (175, 181))	('fusions', 'Var', (155, 162))
128915	25204415	NTRK fusions therefore represent a low frequency, pan-cancer event that nevertheless may account for a significant fraction of patients who could benefit from a pan-NTRK inhibitor.	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('fusions', 'Var', (5, 12))	('cancer', 'Disease', (54, 60))	('patients', 'Species', '9606', (127, 135))	('NTRK', 'Gene', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
128917	25204415	In particular, we found recurrent fusions of MET and PIK3CA that are both bona fide oncogenes commonly activated by gene amplification or point mutations.	('fusions', 'Var', (34, 41))	('PIK3CA', 'Gene', (53, 59))	('MET', 'Gene', (45, 48))	('PIK3CA', 'Gene', '5290', (53, 59))
128918	25204415	In contrast, TBL1XR1-PIK3CA fusions likely drive increased PIK3CA mRNA expression by juxtaposing the promoter region of the partner gene to the 5' end of the intact PIK3CA coding sequence.	('TBL1XR1', 'Gene', '79718', (13, 20))	('PIK3CA', 'Gene', (165, 171))	('increased', 'PosReg', (49, 58))	('PIK3CA', 'Gene', (21, 27))	('TBL1XR1', 'Gene', (13, 20))	('PIK3CA', 'Gene', (59, 65))	('mRNA expression', 'MPA', (66, 81))	('PIK3CA', 'Gene', '5290', (165, 171))	('PIK3CA', 'Gene', '5290', (21, 27))	('fusions', 'Var', (28, 35))	('PIK3CA', 'Gene', '5290', (59, 65))
128920	25204415	We also observed fusions in some Ser/Thr kinases (for example, PRKCA, PKN1), where deletion of their regulatory N-terminal domain putatively leads to constitutive activation by de-repression of the kinase activity.	('Ser/Thr kinases', 'Enzyme', (33, 48))	('de-repression', 'NegReg', (177, 190))	('activity', 'MPA', (205, 213))	('PRKCA', 'Gene', '5578', (63, 68))	('PKN1', 'Gene', '5585', (70, 74))	('deletion', 'Var', (83, 91))	('PRKCA', 'Gene', (63, 68))	('PKN1', 'Gene', (70, 74))	('constitutive activation', 'MPA', (150, 173))
128925	25204415	However, the majority of singleton gene fusions in this set are predicted to be passenger events, occurring as a consequence of chromothripsis or genomic instability.	('chromothripsis', 'Disease', (128, 142))	('chromothripsis', 'Disease', 'MESH:D000072837', (128, 142))	('singleton gene fusions', 'Var', (25, 47))
128927	25204415	Although not the focus of this study, we describe here such an example: a recurrent fusion in two dedifferentiated liposarcoma samples (2/38; 5%) encoding the non-kinase portion of TRIO, which results in upregulation of its fusion partner TERT (Fig.	('TERT', 'Gene', (239, 243))	('liposarcoma', 'Disease', (115, 126))	('TRIO', 'Gene', (181, 185))	('TRIO', 'Gene', '7204', (181, 185))	('TERT', 'Gene', '7015', (239, 243))	('liposarcoma', 'Disease', 'MESH:D008080', (115, 126))	('upregulation', 'PosReg', (204, 216))	('liposarcoma', 'Phenotype', 'HP:0012034', (115, 126))	('sarcoma', 'Phenotype', 'HP:0100242', (119, 126))	('fusion', 'Var', (84, 90))
128928	25204415	Telomerase activity is a hallmark of many cancers, and two other genetic mechanisms of TERT reactivation have been described recently; both somatic mutations in the promoter of the TERT gene and DNA copy number gains of TERT were shown to activate its transcription.	('mutations in', 'Var', (148, 160))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('TERT', 'Gene', (181, 185))	('hallmark of many cancers', 'Disease', (25, 49))	('TERT', 'Gene', (220, 224))	('TERT', 'Gene', (87, 91))	('TERT', 'Gene', '7015', (181, 185))	('hallmark of many cancers', 'Disease', 'MESH:D009369', (25, 49))	('TERT', 'Gene', '7015', (220, 224))	('cancers', 'Phenotype', 'HP:0002664', (42, 49))	('TERT', 'Gene', '7015', (87, 91))	('transcription', 'MPA', (252, 265))	('activate', 'PosReg', (239, 247))
128940	25204415	This step relied on the analysis of a large number of samples to filter out highly recurrent fusions that were detected at improbable frequencies within a cancer type: for instance, fusions detected in >95% of samples, or fusions where both gene partners are themselves involved in >1 fusions in >25% of samples, were flagged as putative false positives.	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('fusions', 'Var', (222, 229))	('fusions', 'Var', (182, 189))	('cancer', 'Disease', (155, 161))	('cancer', 'Disease', 'MESH:D009369', (155, 161))
128966	24397835	Increasing evidence indicated that the presence of neutrophils in tumor tissue be associated with poor prognosis.	('tumor', 'Disease', (66, 71))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('neutrophils', 'Var', (51, 62))
128991	24397835	Double staining of CD66 and CD8 was carried out with DouSP KIT (Maixin-bio, Jinan, China) to analyze the densities and distributions of CD66+ neutrophils and CD8+ lymphocytes following the manufacturer's protocol with some modification.	('CD8', 'Gene', (158, 161))	('CD8', 'Gene', '925', (158, 161))	('CD8', 'Gene', (28, 31))	('CD8', 'Gene', '925', (28, 31))	('CD66+', 'Var', (136, 141))
129033	24397835	The 5-year DFS and OS rates for patients with increased intratumoral CD66+ neutrophils were 20% and 26.7%, compared with 51.1% and 55.5% for patients with decreased intratumoral CD66+ neutrophils, respectively.	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('patients', 'Species', '9606', (32, 40))	('increased', 'PosReg', (46, 55))	('patients', 'Species', '9606', (141, 149))	('CD66+ neutrophils', 'Var', (69, 86))	('DFS', 'MPA', (11, 14))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Disease', (170, 175))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Disease', (61, 66))
129042	24397835	The presence of tumor-associated neutrophils have been demonstrated to be associated with poor clinical outcomes of several malignancies including clear cell renal cell carcinoma, gastric cancer, colorectal cancer, and hepatocellular carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (169, 178))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('associated', 'Reg', (74, 84))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (219, 243))	('gastric cancer', 'Disease', (180, 194))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (147, 178))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('colorectal cancer', 'Disease', 'MESH:D015179', (196, 213))	('cell renal cell carcinoma', 'Disease', 'MESH:C538614', (153, 178))	('cell renal cell carcinoma', 'Disease', (153, 178))	('gastric cancer', 'Disease', 'MESH:D013274', (180, 194))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (219, 243))	('colorectal cancer', 'Disease', (196, 213))	('malignancies', 'Disease', 'MESH:D009369', (124, 136))	('tumor', 'Disease', (16, 21))	('malignancies', 'Disease', (124, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (234, 243))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (158, 178))	('presence', 'Var', (4, 12))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('hepatocellular carcinoma', 'Disease', (219, 243))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('gastric cancer', 'Phenotype', 'HP:0012126', (180, 194))	('colorectal cancer', 'Phenotype', 'HP:0003003', (196, 213))
129085	24397835	favoring a more aggressive regimen in tumors with an increased intratumoral neutrophils or misbalance of peritumoral neutrophil and CD8+ lymphocytes.	('tumor', 'Disease', (68, 73))	('tumor', 'Disease', (38, 43))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumors', 'Disease', (38, 44))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('tumors', 'Disease', 'MESH:D009369', (38, 44))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('increased', 'PosReg', (53, 62))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('misbalance', 'Var', (91, 101))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('CD8', 'Gene', (132, 135))	('CD8', 'Gene', '925', (132, 135))	('tumor', 'Disease', (109, 114))
129103	33910421	Deletion of chromosome 3p is one of the most common mutations in many solid tumors.	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumors', 'Disease', (76, 82))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('Deletion', 'Var', (0, 8))
129112	33910421	Zhu et al  also reported that RBMS3 was downregulated in breast cancer and ectopic RBMS3 expression inhibited cell migration and invasion in vitro, and inhibited lung metastasis in vivo.	('RBMS3', 'Gene', '27303', (83, 88))	('breast cancer', 'Disease', (57, 70))	('lung metastasis', 'CPA', (162, 177))	('breast cancer', 'Phenotype', 'HP:0003002', (57, 70))	('downregulated', 'NegReg', (40, 53))	('RBMS3', 'Gene', (30, 35))	('RBMS3', 'Gene', '27303', (30, 35))	('inhibited', 'NegReg', (100, 109))	('RBMS3', 'Gene', (83, 88))	('breast cancer', 'Disease', 'MESH:D001943', (57, 70))	('inhibited', 'NegReg', (152, 161))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('ectopic', 'Var', (75, 82))
129150	33910421	The analysis showed that the 5-year OS rate was 94.4% in patients with high RBMS3 expression, and 78% in those with low expression, indicating that low RBMS3 expression was associated with shorter OS (P = 0.017, Figure 3a).	('low', 'Var', (148, 151))	('RBMS3', 'Gene', '27303', (152, 157))	('high', 'Var', (71, 75))	('patients', 'Species', '9606', (57, 65))	('RBMS3', 'Gene', '27303', (76, 81))	('RBMS3', 'Gene', (76, 81))	('shorter OS', 'Disease', (189, 199))	('RBMS3', 'Gene', (152, 157))
129178	33910421	Our study showed that RBMS3 protein expression in patients with stage I/II (early clinical stage), T1/T2 (small tumor size), and N0/N1 (less lymph node metastasis) disease was associated with prognosis.	('RBMS3', 'Gene', (22, 27))	('patients', 'Species', '9606', (50, 58))	('protein', 'Protein', (28, 35))	('T1/T2', 'Gene', '921;292', (99, 104))	('associated', 'Reg', (176, 186))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('small tumor', 'Disease', 'MESH:D058405', (106, 117))	('N0/N1', 'Var', (129, 134))	('T1/T2', 'Gene', (99, 104))	('small tumor', 'Disease', (106, 117))	('RBMS3', 'Gene', '27303', (22, 27))
129180	33910421	Some patients with early-stage disease and high RBMS3 expression may be spared chemotherapy, while those with low RBMS3 expression may require more intensive therapy to obtain better outcomes.	('RBMS3', 'Gene', (114, 119))	('patients', 'Species', '9606', (5, 13))	('RBMS3', 'Gene', '27303', (114, 119))	('high', 'Var', (43, 47))	('RBMS3', 'Gene', (48, 53))	('RBMS3', 'Gene', '27303', (48, 53))
129214	33000180	In addition, high CENPM expression has been reported to be associated with primary melanoma, bladder cancer, hepatocellular carcinoma, and head and neck squamous cell carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (167, 176))	('CENPM', 'Gene', (18, 23))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (109, 133))	('CENPM', 'Gene', '79019', (18, 23))	('melanoma', 'Disease', 'MESH:D008545', (83, 91))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (139, 176))	('high', 'Var', (13, 17))	('expression', 'MPA', (24, 34))	('hepatocellular carcinoma', 'Disease', (109, 133))	('neck squamous cell carcinoma', 'Disease', (148, 176))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (148, 176))	('melanoma', 'Phenotype', 'HP:0002861', (83, 91))	('melanoma', 'Disease', (83, 91))	('bladder cancer', 'Disease', 'MESH:D001749', (93, 107))	('bladder cancer', 'Disease', (93, 107))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (153, 176))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('associated', 'Reg', (59, 69))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (109, 133))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('bladder cancer', 'Phenotype', 'HP:0009725', (93, 107))
129215	33000180	Based on these studies, the present study hypothesized that aberrant CENPM could function as an oncogene by intervening in the progression of the cell cycle.	('intervening', 'Reg', (108, 119))	('CENPM', 'Gene', (69, 74))	('progression of the cell cycle', 'CPA', (127, 156))	('CENPM', 'Gene', '79019', (69, 74))	('aberrant', 'Var', (60, 68))
129220	33000180	The COSMIC  is a database of gene mutations associated with various types of human cancer, which includes 1,420,135 samples and 26,878 papers (COSMIC v89).	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('mutations', 'Var', (34, 43))	('cancer', 'Disease', (83, 89))	('human', 'Species', '9606', (77, 82))
129221	33000180	Using this database, information about CENPM gene mutational signatures according to cancer types was extracted, and the association between CENPM mutations, including point mutations, insertions and deletions, and the risk of BC tumorigenesis was summarized.	('CENPM', 'Gene', (39, 44))	('tumor', 'Disease', (230, 235))	('mutations', 'Var', (147, 156))	('CENPM', 'Gene', '79019', (141, 146))	('insertions', 'Var', (185, 195))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('point mutations', 'Var', (168, 183))	('CENPM', 'Gene', '79019', (39, 44))	('cancer', 'Disease', (85, 91))	('tumor', 'Disease', 'MESH:D009369', (230, 235))	('BC', 'Phenotype', 'HP:0003002', (227, 229))	('deletions', 'Var', (200, 209))	('CENPM', 'Gene', (141, 146))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
129253	33000180	Three CENPM-targeting short hairpin (sh)RNAs were constructed; the sequences were as follows: shCEN #a, 5'-CCTGATCGTGTTTGTGGTTAA-3'; shCEN #b, 5'-GCTGACTCCATAAACATTCTC-3'; shCEN #c, 5'-GCGGACTCGATGCTCAAAGAG-3'.	('CENPM', 'Gene', '79019', (6, 11))	('CENPM', 'Gene', (6, 11))	('shCEN #a', 'Var', (94, 102))	('shCEN #b', 'Var', (133, 141))
129255	33000180	The detailed methods used for lentivirus infection and confirmation of CENPM knockdown are provided in a previous study.	('CENPM', 'Gene', (71, 76))	('knockdown', 'Var', (77, 86))	('CENPM', 'Gene', '79019', (71, 76))	('lentivirus infection', 'Disease', (30, 50))	('lentivirus infection', 'Disease', 'MESH:D016180', (30, 50))
129321	33000180	Of the 39 cancer types, 19 were associated with CENPM gene mutations, primarily 37 point mutations (total percentage of mutated, 0.077%), and two frameshift deletions (total percentage of mutated, 0.004%), and the corresponding specimens were further examined.	('CENPM', 'Gene', '79019', (48, 53))	('frameshift deletions', 'Var', (146, 166))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('point mutations', 'Var', (83, 98))	('mutations', 'Var', (59, 68))	('associated', 'Reg', (32, 42))	('CENPM', 'Gene', (48, 53))	('cancer', 'Disease', 'MESH:D009369', (10, 16))	('cancer', 'Disease', (10, 16))
129322	33000180	Among the CENPM gene point mutations, 19 were missense substitutions, and 18 were synonymous substitutions with no changes in the protein-coding sequence.	('missense substitutions', 'Var', (46, 68))	('CENPM', 'Gene', (10, 15))	('CENPM', 'Gene', '79019', (10, 15))
129336	33000180	Taken together, these results indicated that ectopic CENPM expression may accelerate the development of a BC-like state and control mitosis by regulating the expression of KIF4A, RECC6L, CKS2, CDC25C and SPAG5, and affect apoptosis in BC cells.	('RECC6L', 'Gene', (179, 185))	('accelerate', 'PosReg', (74, 84))	('CKS2', 'Gene', '1164', (187, 191))	('BC', 'Phenotype', 'HP:0003002', (235, 237))	('apoptosis', 'CPA', (222, 231))	('CKS2', 'Gene', (187, 191))	('regulating', 'Reg', (143, 153))	('KIF4A', 'Gene', (172, 177))	('development of a BC-like state', 'CPA', (89, 119))	('BC', 'Phenotype', 'HP:0003002', (106, 108))	('expression', 'Var', (59, 69))	('SPAG5', 'Gene', (204, 209))	('expression', 'MPA', (158, 168))	('ectopic', 'Var', (45, 52))	('control', 'PosReg', (124, 131))	('CDC25C', 'Gene', (193, 199))	('CENPM', 'Gene', (53, 58))	('mitosis', 'CPA', (132, 139))	('SPAG5', 'Gene', '10615', (204, 209))	('CDC25C', 'Gene', '995', (193, 199))	('KIF4A', 'Gene', '24137', (172, 177))	('CENPM', 'Gene', '79019', (53, 58))	('affect', 'Reg', (215, 221))
129339	33000180	Although mutations in proto-oncogenes or tumor suppressor genes may be major drivers of carcinogenesis, the epigenetic modification (including DNA methylation, acetylation, phosphorylation and ubiquitylation) of CENPM may still serve a critical role in gene expression regulation, which is also considered an important factor for tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('gene expression regulation', 'MPA', (253, 279))	('ubiquitylation', 'MPA', (193, 207))	('carcinogenesis', 'Disease', (88, 102))	('acetylation', 'MPA', (160, 171))	('tumor', 'Phenotype', 'HP:0002664', (330, 335))	('tumor', 'Disease', (41, 46))	('mutations', 'Var', (9, 18))	('epigenetic modification', 'MPA', (108, 131))	('tumor', 'Disease', (330, 335))	('CENPM', 'Gene', (212, 217))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('phosphorylation', 'MPA', (173, 188))	('CENPM', 'Gene', '79019', (212, 217))	('carcinogenesis', 'Disease', 'MESH:D063646', (88, 102))	('tumor', 'Disease', 'MESH:D009369', (330, 335))
129352	32178620	Altered regulation of MMPs can result in various diseases such as cancer, arthritis, nephritis, atherosclerosis, and ulcers.	('arthritis', 'Disease', (74, 83))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('nephritis', 'Phenotype', 'HP:0000123', (85, 94))	('ulcers', 'Disease', (117, 123))	('Altered', 'Var', (0, 7))	('atherosclerosis', 'Disease', 'MESH:D050197', (96, 111))	('MMPs', 'Gene', '4312;4313;4314;4316;4317;4318;17395;4319;17384;4321;4322;4323;4327', (22, 26))	('arthritis', 'Phenotype', 'HP:0001369', (74, 83))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('atherosclerosis', 'Disease', (96, 111))	('regulation', 'MPA', (8, 18))	('ulcers', 'Disease', 'MESH:D014456', (117, 123))	('MMPs', 'Gene', (22, 26))	('atherosclerosis', 'Phenotype', 'HP:0002621', (96, 111))	('nephritis', 'Disease', (85, 94))	('nephritis', 'Disease', 'MESH:D009393', (85, 94))	('arthritis', 'Disease', 'MESH:D001168', (74, 83))	('result in', 'Reg', (31, 40))	('cancer', 'Disease', (66, 72))
129381	32178620	Two pathways can be mentioned as underlying factors of inflammation in cancer: An intrinsic pathway which is related to genetic mutations that result in oncogene activation and tumor suppressor gene inactivation, an extrinsic pathway where inflammatory conditions are present, eventually causing cancer.	('ac', 'Chemical', 'MESH:D000186', (45, 47))	('cancer', 'Phenotype', 'HP:0002664', (296, 302))	('mutations', 'Var', (128, 137))	('cancer', 'Disease', (71, 77))	('ac', 'Chemical', 'MESH:D000186', (162, 164))	('ac', 'Chemical', 'MESH:D000186', (201, 203))	('cancer', 'Disease', 'MESH:D009369', (296, 302))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('tumor', 'Disease', (177, 182))	('inactivation', 'NegReg', (199, 211))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('inflammation', 'Disease', 'MESH:D007249', (55, 67))	('causing', 'Reg', (288, 295))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('cancer', 'Disease', (296, 302))	('oncogene', 'Gene', (153, 161))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('activation', 'PosReg', (162, 172))	('inflammation', 'Disease', (55, 67))
129463	32178620	Additionally, silencing CXCR2 on tumour cells indicated that the chemoattractant effect of ac-PGP is dependent on the presence of CXCR2 as well.	('silencing', 'Var', (14, 23))	('CXCR2', 'Gene', '3579', (24, 29))	('CXCR2', 'Gene', (130, 135))	('tumour', 'Disease', (33, 39))	('tumour', 'Phenotype', 'HP:0002664', (33, 39))	('CXCR2', 'Gene', (24, 29))	('ac', 'Chemical', 'MESH:D000186', (91, 93))	('tumour', 'Disease', 'MESH:D009369', (33, 39))	('CXCR2', 'Gene', '3579', (130, 135))	('ac', 'Chemical', 'MESH:D000186', (74, 76))
129508	32178620	A recent study performed on esophageal squamous cell carcinoma (ESCC) demonstrated that NFAT1 supports metastasis of ESCC cells through regulation of MMP-3 and silencing this gene could prevent cells from migrating.	('NFAT1', 'Gene', (88, 93))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (28, 62))	('silencing', 'Var', (160, 169))	('MMP-3', 'Gene', '4314', (150, 155))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (39, 62))	('MMP-3', 'Gene', (150, 155))	('esophageal squamous cell carcinoma', 'Disease', (28, 62))	('carcinoma', 'Phenotype', 'HP:0030731', (53, 62))	('NFAT1', 'Gene', '4773', (88, 93))	('cells', 'CPA', (194, 199))	('ESCC', 'Disease', (117, 121))	('prevent', 'NegReg', (186, 193))	('supports', 'PosReg', (94, 102))	('metastasis', 'CPA', (103, 113))
129525	32178620	Similarly, MMP-10 has been observed to restrict the pro-inflammatory activity of macrophages in mice with lung infection.	('lung infection', 'Disease', 'MESH:D012141', (106, 120))	('lung infection', 'Disease', (106, 120))	('pro-inflammatory activity', 'MPA', (52, 77))	('mice', 'Species', '10090', (96, 100))	('ac', 'Chemical', 'MESH:D000186', (69, 71))	('MMP-10', 'Var', (11, 17))	('restrict', 'NegReg', (39, 47))	('ac', 'Chemical', 'MESH:D000186', (82, 84))	('lung infection', 'Phenotype', 'HP:0006532', (106, 120))
129533	32651409	In this study, we synthesized nano-graphene oxide (NGO) nanoparticles with GRPR-specific peptides AF750-6Ahx-Sta-BBN via hydrogen bond and pi-pi bonds (NGO-BBN-AF750), and investigated their receptor binding, cell uptake and internalization in HSC-3 cells.	('investigated', 'Reg', (172, 184))	('NGO', 'Chemical', '-', (51, 54))	('AF750-6Ahx-Sta-BBN', 'Var', (98, 116))	('BBN-AF750', 'Chemical', '-', (156, 165))	('NGO', 'Chemical', '-', (152, 155))	('graphene oxide', 'Chemical', 'MESH:C000628730', (35, 49))	('HSC-3', 'Gene', (244, 249))	('hydrogen', 'Chemical', 'MESH:D006859', (121, 129))	('AF750-6Ahx-Sta-BBN', 'Chemical', '-', (98, 116))	('HSC-3', 'Gene', '150353', (244, 249))
129534	32651409	NGO-BBN-AF750 and AF750-6Ahx-Sta-BBN showed a similar binding affinity to GRPR on HSC-3 cells.	('AF750-6Ahx-Sta-BBN', 'Var', (18, 36))	('BBN-AF750', 'Chemical', '-', (4, 13))	('HSC-3', 'Gene', (82, 87))	('AF750-6Ahx-Sta-BBN', 'Chemical', '-', (18, 36))	('GRPR', 'Protein', (74, 78))	('HSC-3', 'Gene', '150353', (82, 87))	('binding', 'Interaction', (54, 61))	('NGO', 'Chemical', '-', (0, 3))
129562	32651409	For AF750-6Ahx-Sta-BBN peptide, the infrared peak at 3,428 cm-1 was the symmetric stretching of -OH.	('symmetric stretching', 'MPA', (72, 92))	('AF750-6Ahx-Sta-BBN', 'Var', (4, 22))	('AF750-6Ahx-Sta-BBN', 'Chemical', '-', (4, 22))
129564	32651409	For NGO-BBN-AF750, the peak for -COOH of NGO disappeared, and a new peak was observed at 1,409 cm-1.	('NGO', 'Chemical', '-', (4, 7))	('COOH', 'Chemical', '-', (33, 37))	('NGO', 'Chemical', '-', (41, 44))	('BBN-AF750', 'Chemical', '-', (8, 17))	('peak for -COOH', 'MPA', (23, 37))	('NGO-BBN-AF750', 'Var', (4, 17))
129565	32651409	The changes in these chemical bond vibration peaks confirmed the bond formations of NGO with AF750-6Ahx-Sta-BBN peptides, through hydrogen bond and pi-pi bond interactions.	('AF750-6Ahx-Sta-BBN', 'Var', (93, 111))	('AF750-6Ahx-Sta-BBN', 'Chemical', '-', (93, 111))	('pi-pi bond', 'CPA', (148, 158))	('chemical bond vibration peaks', 'MPA', (21, 50))	('hydrogen', 'Chemical', 'MESH:D006859', (130, 138))	('changes', 'Reg', (4, 11))	('hydrogen bond', 'CPA', (130, 143))	('NGO', 'Chemical', '-', (84, 87))
129566	32651409	Furthermore, the UV-Vis spectra of NGO and NGO-BBN-AF750 showed that NGO-BBN-AF750 had a strong absorption at 750 nm and a disappearance of the broadband peak at 320 nM compared with NGO (Fig.	('NGO-BBN-AF750', 'Var', (69, 82))	('absorption', 'MPA', (96, 106))	('NGO', 'Chemical', '-', (35, 38))	('NGO', 'Chemical', '-', (69, 72))	('BBN-AF750', 'Chemical', '-', (73, 82))	('NGO', 'Chemical', '-', (183, 186))	('disappearance', 'NegReg', (123, 136))	('broadband peak at 320 nM', 'MPA', (144, 168))	('NGO', 'Chemical', '-', (43, 46))	('BBN-AF750', 'Chemical', '-', (47, 56))
129567	32651409	Both the appearance of the peak at the NIR wavelength 750 nm and the disappearance of the broadband absorption at 320 nm further indicate the surface modification of the NGO with the AF750-6Ahx-Sta-BBN peptides.	('broadband absorption at 320', 'MPA', (90, 117))	('AF750-6Ahx-Sta-BBN', 'Var', (183, 201))	('surface', 'MPA', (142, 149))	('AF750-6Ahx-Sta-BBN', 'Chemical', '-', (183, 201))	('disappearance', 'NegReg', (69, 82))	('NGO', 'Chemical', '-', (170, 173))
129573	32651409	5B shows, equal amount of fluorescent probe targeted HSC-3 cells were detected in all six groups, despite the strong fluorescence intensity quenching effect at 0.1 mg/mL NGO (Fig.	('HSC-3', 'Gene', (53, 58))	('NGO', 'Var', (170, 173))	('fluorescence intensity', 'MPA', (117, 139))	('quenching', 'NegReg', (140, 149))	('NGO', 'Chemical', '-', (170, 173))	('HSC-3', 'Gene', '150353', (53, 58))
129576	32651409	The binding specificities of AF750-6Ahx-Sta-BBN were determined with HSC-3 cells of human oral tongue squamous cell carcinoma using previously described methods.	('AF750-6Ahx-Sta-BBN', 'Var', (29, 47))	('HSC-3', 'Gene', '150353', (69, 74))	('binding', 'Interaction', (4, 11))	('AF750-6Ahx-Sta-BBN', 'Chemical', '-', (29, 47))	('tongue squamous cell carcinoma', 'Disease', 'MESH:D002294', (95, 125))	('HSC-3', 'Gene', (69, 74))	('tongue squamous cell carcinoma', 'Disease', (95, 125))	('human', 'Species', '9606', (84, 89))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (102, 125))
129578	32651409	The result indicates that AF750-6Ahx-Sta-BBN specifically binds to the GRPR on HSC-3 cells.	('binds', 'Interaction', (58, 63))	('HSC-3', 'Gene', '150353', (79, 84))	('AF750-6Ahx-Sta-BBN', 'Var', (26, 44))	('AF750-6Ahx-Sta-BBN', 'Chemical', '-', (26, 44))	('HSC-3', 'Gene', (79, 84))	('GRPR', 'Protein', (71, 75))
129581	32651409	The half maximal replacement concentration (EC50) value of AF750-6Ahx-Sta-BBN was 0.47 +- 1.05 nM, the result further confirmed the specific interaction of AF750-6Ahx-Sta-BBN to the GRPR on HSC-3 cells.	('AF750-6Ahx-Sta-BBN', 'Chemical', '-', (59, 77))	('interaction', 'Interaction', (141, 152))	('AF750-6Ahx-Sta-BBN', 'Var', (59, 77))	('AF750-6Ahx-Sta-BBN', 'Var', (156, 174))	('AF750-6Ahx-Sta-BBN', 'Chemical', '-', (156, 174))	('HSC-3', 'Gene', '150353', (190, 195))	('HSC-3', 'Gene', (190, 195))
129582	32651409	The time-dependent experiment was carried out on HSC-3 cells for both AF750-6Ahx-Sta-BBN and NGO-BBN-AF750.	('AF750-6Ahx-Sta-BBN', 'Chemical', '-', (70, 88))	('NGO', 'Chemical', '-', (93, 96))	('HSC-3', 'Gene', '150353', (49, 54))	('BBN-AF750', 'Chemical', '-', (97, 106))	('HSC-3', 'Gene', (49, 54))	('AF750-6Ahx-Sta-BBN', 'Var', (70, 88))
129586	32651409	We further conducted confocal laser scanning microscope experiments to evaluate the internalization of AF750-6Ahx-Sta-BBN and NGO-BBN-AF750 into HSC-3 cells and HOK cells.	('NGO', 'Chemical', '-', (126, 129))	('AF750-6Ahx-Sta-BBN', 'Var', (103, 121))	('AF750-6Ahx-Sta-BBN', 'Chemical', '-', (103, 121))	('HSC-3', 'Gene', '150353', (145, 150))	('HOK', 'CellLine', 'CVCL:B403', (161, 164))	('HSC-3', 'Gene', (145, 150))	('internalization', 'MPA', (84, 99))	('BBN-AF750', 'Chemical', '-', (130, 139))
129589	32651409	9, AF750-6Ahx-Sta-BBN was observed on the membrane of HSC-3, agreeing with its GRPR antagonist's property on cell surface.	('HSC-3', 'Gene', (54, 59))	('HSC-3', 'Gene', '150353', (54, 59))	('AF750-6Ahx-Sta-BBN', 'Chemical', '-', (3, 21))	('AF750-6Ahx-Sta-BBN', 'Var', (3, 21))
129590	32651409	However, stronger fluorescence signals were appeared overlapping with the nucleus of HSC-3 cells in the NGO-BBN-AF750 group, indicating a cell internalization activity by NGO-BBN-AF750.	('BBN-AF750', 'Chemical', '-', (175, 184))	('NGO', 'Chemical', '-', (104, 107))	('BBN-AF750', 'Chemical', '-', (108, 117))	('HSC-3', 'Gene', (85, 90))	('cell internalization activity', 'CPA', (138, 167))	('fluorescence signals', 'MPA', (18, 38))	('NGO-BBN-AF750', 'Var', (171, 184))	('NGO', 'Chemical', '-', (171, 174))	('stronger', 'PosReg', (9, 17))	('HSC-3', 'Gene', '150353', (85, 90))
129592	32651409	Taken together, both AF750-6Ahx-Sta-BBN and NGO-BBN-AF750 showed a high specificity to HSC-3 cells mediated by the GRPR binding.	('HSC-3', 'Gene', '150353', (87, 92))	('BBN-AF750', 'Chemical', '-', (48, 57))	('NGO', 'Chemical', '-', (44, 47))	('specificity', 'MPA', (72, 83))	('GRPR', 'Protein', (115, 119))	('HSC-3', 'Gene', (87, 92))	('AF750-6Ahx-Sta-BBN', 'Var', (21, 39))	('AF750-6Ahx-Sta-BBN', 'Chemical', '-', (21, 39))
129595	32651409	Preliminary in vitro experiments showed that NGO-BBN-AF750 had a decrease in cell viability (82 +- 2%) compared to the control (Fig.	('NGO-BBN-AF750', 'Var', (45, 58))	('NGO', 'Chemical', '-', (45, 48))	('BBN-AF750', 'Chemical', '-', (49, 58))	('decrease', 'NegReg', (65, 73))	('cell viability', 'CPA', (77, 91))
129603	32651409	AF750-6Ahx-Sta-BBN had previously been shown with a high binding affinity and specificity to the GRPR overexpressed in a prostate cancer PC-3 cell line.	('prostate cancer', 'Disease', 'MESH:D011471', (121, 136))	('binding', 'Interaction', (57, 64))	('GRPR', 'Protein', (97, 101))	('prostate cancer', 'Phenotype', 'HP:0012125', (121, 136))	('prostate cancer', 'Disease', (121, 136))	('PC-3', 'CellLine', 'CVCL:0035', (137, 141))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('AF750-6Ahx-Sta-BBN', 'Var', (0, 18))	('AF750-6Ahx-Sta-BBN', 'Chemical', '-', (0, 18))	('overexpressed', 'PosReg', (102, 115))
129604	32651409	In the present study, we showed that AF750-6Ahx-Sta-BBN has a high binding affinity and specificity to the human tongue squamous cell carcinoma cell line HSC-3, and also to the primary OSCC tissue sections.	('binding affinity', 'Interaction', (67, 83))	('human', 'Species', '9606', (107, 112))	('HSC-3', 'Gene', (154, 159))	('AF750-6Ahx-Sta-BBN', 'Var', (37, 55))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (120, 143))	('AF750-6Ahx-Sta-BBN', 'Chemical', '-', (37, 55))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('tongue squamous cell carcinoma', 'Disease', 'MESH:D002294', (113, 143))	('tongue squamous cell carcinoma', 'Disease', (113, 143))	('HSC-3', 'Gene', '150353', (154, 159))	('specificity', 'MPA', (88, 99))
129607	32651409	This present study is the first study to demonstrate the potential of using a GRPR antagonist AF750-6Ahx-Sta-BBN as a potential near-infrared fluorescence imaging probe for OSCC detection.	('AF750-6Ahx-Sta-BBN', 'Var', (94, 112))	('OSCC', 'Disease', (173, 177))	('AF750-6Ahx-Sta-BBN', 'Chemical', '-', (94, 112))
129615	32651409	In this study, NGO carboxylation was used to increase its water solubility and stability, and then NGO was coupled with AF750-6Ahx-Sta-BBN via hydrogen bond and pi-pi bond.	('pi-pi', 'Var', (161, 166))	('stability', 'MPA', (79, 88))	('hydrogen', 'Chemical', 'MESH:D006859', (143, 151))	('water solubility', 'MPA', (58, 74))	('coupled', 'Interaction', (107, 114))	('water', 'Chemical', 'MESH:D014867', (58, 63))	('NGO', 'Chemical', '-', (15, 18))	('NGO', 'Chemical', '-', (99, 102))	('AF750-6Ahx-Sta-BBN', 'Chemical', '-', (120, 138))	('increase', 'PosReg', (45, 53))
129618	32651409	When the concentration of NGO was 0.1 mg/mL, the maximum fluorescence quenching was achieved, and the fluorescence was restored in HSC-3 cells upon the interaction between NGO-BBN-AF750 and HSC-3 cells.	('fluorescence', 'MPA', (102, 114))	('NGO-BBN-AF750', 'Var', (172, 185))	('NGO', 'Chemical', '-', (172, 175))	('BBN-AF750', 'Chemical', '-', (176, 185))	('HSC-3', 'Gene', '150353', (131, 136))	('HSC-3', 'Gene', '150353', (190, 195))	('interaction', 'Interaction', (152, 163))	('NGO', 'Chemical', '-', (26, 29))	('HSC-3', 'Gene', (131, 136))	('HSC-3', 'Gene', (190, 195))	('fluorescence', 'MPA', (57, 69))
129619	32651409	In this study, we evaluated the uptake and internalization of NGO-BBN-AF750 and AF750-6Ahx-Sta-BBN in cells.	('internalization', 'MPA', (43, 58))	('NGO', 'Chemical', '-', (62, 65))	('AF750-6Ahx-Sta-BBN', 'Var', (80, 98))	('NGO-BBN-AF750', 'Var', (62, 75))	('AF750-6Ahx-Sta-BBN', 'Chemical', '-', (80, 98))	('uptake', 'MPA', (32, 38))	('BBN-AF750', 'Chemical', '-', (66, 75))
129652	32651409	For internalization studies, HSC-3 cells were cultured in 24-well plates at 2 x 104 cells/well and grown for 24 h. Next, the original medium was replaced with fresh medium containing 50 nM AF750-6Ahx-Sta-BBN or NGO-BBN-AF750.	('AF750-6Ahx-Sta-BBN', 'Chemical', '-', (189, 207))	('HSC-3', 'Gene', '150353', (29, 34))	('NGO', 'Chemical', '-', (211, 214))	('AF750-6Ahx-Sta-BBN', 'Var', (189, 207))	('BBN-AF750', 'Chemical', '-', (215, 224))	('HSC-3', 'Gene', (29, 34))
129685	32336752	Therefore, the presence of 11betaHSD1 could increase in situ concentrations of cortisol available for GR.	('11betaHSD1', 'Gene', (27, 37))	('11betaHSD1', 'Gene', '3290', (27, 37))	('presence', 'Var', (15, 23))	('increase', 'PosReg', (44, 52))	('cortisol', 'Chemical', 'MESH:D006854', (79, 87))	('GR', 'Gene', '2908', (102, 104))
129725	32336752	Several hours later, the cells were washed with phosphate-buffered saline (PBS), and treated with 1 muM 11betaHSD1 inhibitor PF915275 (Tocris/Bio-Techne, Minneapolis, USA) in phenol red- and FBS-free RPMI 1640 medium.	('RPMI 1640 medium', 'Chemical', '-', (200, 216))	('PBS', 'Chemical', '-', (75, 78))	('phosphate-buffered saline', 'Chemical', '-', (48, 73))	('PF915275', 'Chemical', 'MESH:C525872', (125, 133))	('muM 11betaHSD1', 'Gene', '26206', (100, 114))	('PF915275', 'Var', (125, 133))	('phenol red', 'Chemical', 'MESH:D010637', (175, 185))	('muM 11betaHSD1', 'Gene', (100, 114))
129726	32336752	After 2 h, the cells were incubated in phenol red- and FBS-free RPMI 1640 medium with 1 muM 11betaHSD1 inhibitor PF915275 and 1 muM cortisone (Sigma Chemical Co., St. Louis, USA).	('cortisone', 'Chemical', 'MESH:D003348', (132, 141))	('phenol red', 'Chemical', 'MESH:D010637', (39, 49))	('muM 11betaHSD1', 'Gene', (88, 102))	('RPMI 1640 medium', 'Chemical', '-', (64, 80))	('PF915275', 'Chemical', 'MESH:C525872', (113, 121))	('muM 11betaHSD1', 'Gene', '26206', (88, 102))	('PF915275', 'Var', (113, 121))
129760	32336752	1j, a high gene expression level of 11betaHSD1 was independently and significantly associated with poor overall survival of patients with adenocarcinoma (univariate analysis: HR 1.54 [1.16-2.05], p = 0.0029) (multivariate analysis: 11betaHSD1: HR 1.38 [1.03-1.85], p = 0.0306, Stage: HR 1.79 [1.49-2.15], p < 0.001).	('poor', 'NegReg', (99, 103))	('high', 'Var', (6, 10))	('associated', 'Reg', (83, 93))	('11betaHSD1', 'Gene', (232, 242))	('adenocarcinoma', 'Disease', (138, 152))	('11betaHSD1', 'Gene', (36, 46))	('11betaHSD1', 'Gene', '3290', (232, 242))	('carcinoma', 'Phenotype', 'HP:0030731', (143, 152))	('adenocarcinoma', 'Disease', 'MESH:D000230', (138, 152))	('11betaHSD1', 'Gene', '3290', (36, 46))	('patients', 'Species', '9606', (124, 132))
129763	32336752	The results of a cortisol synthesis assay using LK2 are shown in Fig.	('cortisol synthesis assay', 'MPA', (17, 41))	('cortisol', 'Chemical', 'MESH:D006854', (17, 25))	('LK2', 'Var', (48, 51))
129854	31546725	There was a significant association between PD-L1 and vimentin positivity.	('vimentin', 'Gene', '7431', (54, 62))	('positivity', 'Var', (63, 73))	('vimentin', 'Gene', (54, 62))	('PD-L1', 'Gene', (44, 49))
129855	31546725	The level of PD-L1 expression was three times more frequent in the positive vimentin group (p = 0.011).	('vimentin', 'Gene', '7431', (76, 84))	('expression', 'MPA', (19, 29))	('vimentin', 'Gene', (76, 84))	('PD-L1', 'Protein', (13, 18))	('positive', 'Var', (67, 75))
129863	31546725	Finally, in multivariate analysis, poor differentiation (p = 0.011) and lymph node invasion (p = 0.033) were significantly associated with PD-L1 and vimentin co-expression whatever the histological types (p = 0.100).	('PD-L1', 'Gene', (139, 144))	('co-expression', 'Var', (158, 171))	('vimentin', 'Gene', '7431', (149, 157))	('vimentin', 'Gene', (149, 157))	('lymph node invasion', 'CPA', (72, 91))	('poor differentiation', 'CPA', (35, 55))
129874	31546725	On the contrary, taking into account both high PD-L1 and high EMT co-expression was associated with different patient outcomes.	('high', 'Var', (42, 46))	('patient', 'Species', '9606', (110, 117))	('associated', 'Reg', (84, 94))	('high EMT', 'Phenotype', 'HP:0008151', (57, 65))
129895	31546725	showed an up-regulation of PD-L1 in an EMT-activated human breast cancer cell by a mechanism involving ZEB1 and MIR-200.	('breast cancer', 'Disease', 'MESH:D001943', (59, 72))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('breast cancer', 'Disease', (59, 72))	('ZEB1', 'Gene', (103, 107))	('breast cancer', 'Phenotype', 'HP:0003002', (59, 72))	('human', 'Species', '9606', (53, 58))	('ZEB1', 'Gene', '6935', (103, 107))	('MIR-200', 'Var', (112, 119))	('PD-L1', 'Gene', (27, 32))	('up-regulation', 'PosReg', (10, 23))
129898	31546725	Alternatively, modulating PD-L1 expression was also shown to regulate EMT in human esophageal cancer cells.	('modulating', 'Var', (15, 25))	('esophageal cancer', 'Disease', (83, 100))	('EMT', 'CPA', (70, 73))	('regulate', 'Reg', (61, 69))	('PD-L1', 'Gene', (26, 31))	('esophageal cancer', 'Disease', 'MESH:D004938', (83, 100))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('human', 'Species', '9606', (77, 82))
129922	31546725	The co-expression of vimentin with PD-L1 may thus represent a promising tandem marker candidate to further refine patient selection and precise eligibility for adjuvant treatment, especially in the immune checkpoint area.	('co-expression', 'Var', (4, 17))	('patient', 'Species', '9606', (114, 121))	('vimentin', 'Gene', '7431', (21, 29))	('PD-L1', 'Gene', (35, 40))	('vimentin', 'Gene', (21, 29))
129941	29358382	It is assumed that some of these variants are more likely to contain information about the individual's inherited traits or susceptibility for many kinds of phenotypes, including complex diseases, such as common cancer.	('contain information', 'Reg', (61, 80))	('cancer', 'Disease', (212, 218))	('cancer', 'Disease', 'MESH:D009369', (212, 218))	('variants', 'Var', (33, 41))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))
129968	29358382	Furthermore, some SNP-Ss are present in one cluster but not in other clusters in the same cancer type.	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('SNP-Ss', 'Var', (18, 24))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))
129973	29358382	Another interesting observation is about inherited vs. somatically altered BRCA mutants (a subject not covered in this study).	('BRCA', 'Gene', '672', (75, 79))	('mutants', 'Var', (80, 87))	('BRCA', 'Gene', (75, 79))
129975	29358382	An examination of the exom sequence data of the BRCA cohort in TCGA reveals that, of our test set of 200 common BRCA cohorts, only 10 members (5% of the cohort) have somatic mutations of BRCA-1/2 genes of mostly unidentified penetrance, which agrees with the lower bound of an earlier observation of 5-10% for all breast cancers.	('BRCA', 'Gene', (112, 116))	('cancers', 'Phenotype', 'HP:0002664', (321, 328))	('BRCA', 'Gene', '672', (48, 52))	('BRCA', 'Gene', '672', (187, 191))	('BRCA', 'Gene', (48, 52))	('BRCA-1/2', 'Gene', (187, 195))	('cancer', 'Phenotype', 'HP:0002664', (321, 327))	('breast cancers', 'Phenotype', 'HP:0003002', (314, 328))	('BRCA', 'Gene', (187, 191))	('breast cancers', 'Disease', 'MESH:D001943', (314, 328))	('breast cancers', 'Disease', (314, 328))	('mutations', 'Var', (174, 183))	('breast cancer', 'Phenotype', 'HP:0003002', (314, 327))	('BRCA', 'Gene', '672', (112, 116))	('BRCA-1/2', 'Gene', '672;675', (187, 195))
129976	29358382	This observation suggests that, although the pathogenic BRCA-1 or -2 genes have been found to have high penetrance for BRCA and account for 20-25% of inherited BRCA, these somatic mutations participate (in collaboration with the mutations of many other genes or genomic elements as expected for a common cancer) in initiating common BRCA only in a very small fraction of the cohort.	('BRCA', 'Gene', (333, 337))	('BRCA', 'Gene', '672', (333, 337))	('mutations', 'Var', (180, 189))	('cancer', 'Disease', 'MESH:D009369', (304, 310))	('cancer', 'Disease', (304, 310))	('BRCA', 'Gene', (119, 123))	('BRCA', 'Gene', '672', (56, 60))	('BRCA-1 or -2', 'Gene', '672;675', (56, 68))	('BRCA', 'Gene', '672', (160, 164))	('BRCA', 'Gene', (56, 60))	('BRCA', 'Gene', (160, 164))	('BRCA', 'Gene', '672', (119, 123))	('cancer', 'Phenotype', 'HP:0002664', (304, 310))	('BRCA-1 or -2', 'Gene', (56, 68))
129977	29358382	Furthermore, of the 10 members, 8 members belong to the "E/L group" (the subcohort that acquired BRCA mostly due to environmental/lifestyle factors) of the BRCA testing cohort, suggesting that environmental and lifestyle factors had more influence in triggering somatic BRCA-1/2 mutations for this subgroup than inherited genomic factors, information useful for the close relatives of the carriers of the somatic mutants of BRCA genes.	('BRCA-1/2', 'Gene', '672;675', (270, 278))	('mutations', 'Var', (279, 288))	('BRCA', 'Gene', '672', (97, 101))	('BRCA', 'Gene', '672', (156, 160))	('BRCA', 'Gene', (97, 101))	('BRCA', 'Gene', (156, 160))	('BRCA-1/2', 'Gene', (270, 278))	('BRCA', 'Gene', '672', (270, 274))	('BRCA', 'Gene', '672', (424, 428))	('BRCA', 'Gene', (270, 274))	('BRCA', 'Gene', (424, 428))
129993	25960768	Tumor samples in different CIMP subclasses show distinctive correlations with gene expression profiles and recurrence of somatic mutations, copy number variations, and epigenetic silencing.	('copy number variations', 'Var', (140, 162))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('epigenetic silencing', 'Var', (168, 188))	('CIMP', 'Chemical', '-', (27, 31))
129997	25960768	We present a comprehensive computational study of CIMP that reveals pan-cancer commonalities and tissue-specific differences underlying concurrent hypermethylation of CpG islands across tumors.	('hypermethylation', 'Var', (147, 163))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('CIMP', 'Chemical', '-', (50, 54))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('tumors', 'Phenotype', 'HP:0002664', (186, 192))	('CpG', 'Gene', (167, 170))	('tumors', 'Disease', (186, 192))	('tumors', 'Disease', 'MESH:D009369', (186, 192))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('cancer', 'Disease', (72, 78))
130000	25960768	Recurrent patterns of aberrant DNA methylation are commonly observed in cancerous cells, implying that this epigenetic alteration is inherently linked to general mechanisms of oncogenesis and tumor progression.	('aberrant', 'Var', (22, 30))	('tumor', 'Disease', (192, 197))	('cancerous', 'Disease', (72, 81))	('DNA', 'Gene', (31, 34))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('cancerous', 'Disease', 'MESH:D009369', (72, 81))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('linked', 'Reg', (144, 150))
130002	25960768	Concurrent and widespread hypermethylation of CpG islands in clinically distinct cancer subtypes is known as CpG island methylator phenotype (CIMP).	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('cancer', 'Disease', (81, 87))	('hypermethylation', 'Var', (26, 42))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('CIMP', 'Chemical', '-', (142, 146))
130007	25960768	For example, the inactivation of mismatch repair gene MLH1 correlates strongly with CIMP in colon cancer.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('inactivation', 'Var', (17, 29))	('MLH1', 'Gene', '4292', (54, 58))	('MLH1', 'Gene', (54, 58))	('colon cancer', 'Disease', 'MESH:D015179', (92, 104))	('colon cancer', 'Phenotype', 'HP:0003003', (92, 104))	('CIMP', 'Chemical', '-', (84, 88))	('colon cancer', 'Disease', (92, 104))	('CIMP', 'Disease', (84, 88))
130008	25960768	Glioblastoma exhibits mutations in epigenetic regulators such as IDH1/2 and in histone encoding genes such as H3F3A, whereas CIMP in leukemia is associated with TET2 mutations (for a review, see Witte et al.).	('leukemia', 'Disease', 'MESH:D007938', (133, 141))	('CIMP', 'Chemical', '-', (125, 129))	('Glioblastoma', 'Disease', (0, 12))	('epigenetic regulators', 'MPA', (35, 56))	('Glioblastoma', 'Disease', 'MESH:D005909', (0, 12))	('IDH1/2', 'Gene', '3417;3418', (65, 71))	('TET2', 'Gene', '54790', (161, 165))	('leukemia', 'Phenotype', 'HP:0001909', (133, 141))	('H3F3A', 'Gene', '3020', (110, 115))	('mutations', 'Var', (22, 31))	('TET2', 'Gene', (161, 165))	('H3F3A', 'Gene', (110, 115))	('Glioblastoma', 'Phenotype', 'HP:0012174', (0, 12))	('IDH1/2', 'Gene', (65, 71))	('leukemia', 'Disease', (133, 141))
130051	25960768	An Ingenuity Pathway Analysis (IPA) evaluation of the genes associated with the differential methylation sites in individual cancers revealed a subset of canonical pathways that are collectively targeted in the CIMP probe sets (Figure 3A).	('cancers', 'Disease', 'MESH:D009369', (125, 132))	('cancers', 'Phenotype', 'HP:0002664', (125, 132))	('cancers', 'Disease', (125, 132))	('CIMP', 'Chemical', '-', (211, 215))	('canonical pathways', 'Pathway', (154, 172))	('sites', 'Var', (105, 110))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('methylation sites', 'Var', (93, 110))
130055	25960768	Using the IPA tool, we also identified a set of recurrent upstream regulators for the differentially methylated probe set associated with each cancer type (Figure 3B).	('associated', 'Reg', (122, 132))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('differentially methylated', 'Var', (86, 111))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))
130064	25960768	Also, we noted a strong correlation between the differentially methylated probe set and the set of 89 tumor-derived pan-cancer loci (Figure 4G), which supports the consistency of our findings between the cell lines and the tumor data.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('differentially methylated', 'Var', (48, 73))	('tumor', 'Disease', (223, 228))	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('tumor', 'Disease', 'MESH:D009369', (223, 228))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))
130079	25960768	Furthermore, less than half of the CIMP +  Hyper regions in the gene-associated set collocated with known transcription start sites annotated by Illumina (and a comparable number overlapped gene bodies), suggesting that aberrant hypermethylation in CIMP is not exclusive to gene promoters.	('CIMP', 'Chemical', '-', (35, 39))	('CIMP', 'Gene', (249, 253))	('CIMP', 'Chemical', '-', (249, 253))	('aberrant hypermethylation', 'Var', (220, 245))
130081	25960768	A subset of 121 regions associated with 93 genes exhibited significant levels of Spearman correlation between methylation and expression in all 12 cancer types, with varying magnitudes of effect in terms of actual differential expression (Figure 5B).	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('expression', 'MPA', (126, 136))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('methylation', 'Var', (110, 121))	('cancer', 'Disease', (147, 153))
130083	25960768	Additionally, FLI1 (which had been identified in our selected differentially methylated probe sets for 8 of 14 cancer types), contained a combination of CIMP +  Hyper and CIMP +  Hypo regions, which occurred at the gene promoter and the first exon, respectively.	('FLI1', 'Gene', '2313', (14, 18))	('CIMP +  Hyper', 'Var', (153, 166))	('FLI1', 'Gene', (14, 18))	('CIMP', 'Chemical', '-', (153, 157))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('CIMP', 'Chemical', '-', (171, 175))	('CIMP +  Hypo regions', 'Var', (171, 191))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))
130087	25960768	To address commonalities, we used characterizations of TCGA data generated by Ciriello et al., which consisted of 479 selected functional events (SFEs) including 116 copy number gains, 151 copy number losses, mutation of 199 genes, and epigenetic silencing of 13 genes (requiring promoter methylation and decreased expression).	('copy number', 'Var', (166, 177))	('expression', 'MPA', (315, 325))	('losses', 'NegReg', (201, 207))	('SFE', 'Gene', '4311', (146, 149))	('mutation', 'Var', (209, 217))	('copy number', 'Var', (189, 200))	('SFE', 'Gene', (146, 149))	('epigenetic silencing', 'Var', (236, 256))	('gains', 'PosReg', (178, 183))
130091	25960768	Events with strong effects in more than one tumor type included MGMT and MLH1 promoter methylation, as well as mutation of ARID1A, KRAS, BRAF, and PTEN.	('ARID1A', 'Gene', '8289', (123, 129))	('ARID1A', 'Gene', (123, 129))	('KRAS', 'Gene', (131, 135))	('BRAF', 'Gene', (137, 141))	('BRAF', 'Gene', '673', (137, 141))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('PTEN', 'Gene', '5728', (147, 151))	('MGMT', 'Gene', '4255', (64, 68))	('MGMT', 'Gene', (64, 68))	('KRAS', 'Gene', '3845', (131, 135))	('MLH1', 'Gene', '4292', (73, 77))	('promoter methylation', 'MPA', (78, 98))	('mutation', 'Var', (111, 119))	('MLH1', 'Gene', (73, 77))	('PTEN', 'Gene', (147, 151))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumor', 'Disease', (44, 49))
130092	25960768	Events that were strong but gave mixed results towards the CIMP phenotype included mutation of TP53, PIK3CA, FBXW7, and several amplification and deletion regions.	('PIK3CA', 'Gene', '5290', (101, 107))	('FBXW7', 'Gene', '55294', (109, 114))	('PIK3CA', 'Gene', (101, 107))	('FBXW7', 'Gene', (109, 114))	('mutation', 'Var', (83, 91))	('CIMP', 'Chemical', '-', (59, 63))	('TP53', 'Gene', '7157', (95, 99))	('TP53', 'Gene', (95, 99))
130096	25960768	In contrast, mutations in six genes (BRAF, PTEN, KRAS, SETD2, PIK3R1, and PBRM1) and two gene silencing events (MLH1 and MGMT, for which the smallest FDRs were recorded) were more frequent in CIMP+ samples.	('silencing', 'NegReg', (94, 103))	('MGMT', 'Gene', '4255', (121, 125))	('MLH1', 'Gene', '4292', (112, 116))	('KRAS', 'Gene', '3845', (49, 53))	('PIK3R1', 'Gene', '5295', (62, 68))	('PTEN', 'Gene', (43, 47))	('CIMP+', 'Chemical', '-', (192, 197))	('KRAS', 'Gene', (49, 53))	('BRAF', 'Gene', '673', (37, 41))	('MGMT', 'Gene', (121, 125))	('BRAF', 'Gene', (37, 41))	('PTEN', 'Gene', '5728', (43, 47))	('mutations', 'Var', (13, 22))	('SETD2', 'Gene', (55, 60))	('frequent', 'Reg', (180, 188))	('PBRM1', 'Gene', '55193', (74, 79))	('PIK3R1', 'Gene', (62, 68))	('MLH1', 'Gene', (112, 116))	('SETD2', 'Gene', '29072', (55, 60))	('PBRM1', 'Gene', (74, 79))
130098	25960768	The remaining mutations are well known due to their involvement in the PI3K/PTEN/AKT/mTOR and the Ras/Raf/MEK/ERK pathways.	('ERK', 'Gene', (110, 113))	('AKT', 'Gene', '207', (81, 84))	('MEK', 'Gene', (106, 109))	('PTEN', 'Gene', (76, 80))	('MEK', 'Gene', '5609', (106, 109))	('PTEN', 'Gene', '5728', (76, 80))	('Raf', 'Gene', (102, 105))	('Raf', 'Gene', '22882', (102, 105))	('AKT', 'Gene', (81, 84))	('mTOR', 'Gene', '2475', (85, 89))	('ERK', 'Gene', '5594', (110, 113))	('mTOR', 'Gene', (85, 89))	('mutations', 'Var', (14, 23))	('involvement', 'Reg', (52, 63))
130099	25960768	In particular, both BRAF and KRAS mutations have been linked to CIMP status (high and low, respectively) in colorectal cancer.	('colorectal cancer', 'Disease', 'MESH:D015179', (108, 125))	('KRAS', 'Gene', (29, 33))	('colorectal cancer', 'Phenotype', 'HP:0003003', (108, 125))	('CIMP', 'Chemical', '-', (64, 68))	('BRAF', 'Gene', '673', (20, 24))	('KRAS', 'Gene', '3845', (29, 33))	('colorectal cancer', 'Disease', (108, 125))	('BRAF', 'Gene', (20, 24))	('linked', 'Reg', (54, 60))	('mutations', 'Var', (34, 43))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
130102	25960768	CIMP+ samples for COAD, KIRC, LUSC, and READ exhibited a larger number of mutational events per sample than CIMP- samples, implicating impairment of DNA repair processes.	('CIMP-', 'Chemical', '-', (108, 113))	('COAD', 'Disease', (18, 22))	('mutational', 'Var', (74, 84))	('LUSC', 'Phenotype', 'HP:0030359', (30, 34))	('COAD', 'Disease', 'MESH:D029424', (18, 22))	('CIMP+', 'Chemical', '-', (0, 5))
130103	25960768	In contrast, copy number variation showed significant effects in CIMP- samples, where amplifications occurred more frequently in COAD and UCEC tumors, and deletions occurred more frequently in BRCA and UCEC tumors.	('UCEC tumors', 'Disease', 'MESH:D009369', (202, 213))	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('amplifications', 'MPA', (86, 100))	('COAD', 'Disease', 'MESH:D029424', (129, 133))	('UCEC tumors', 'Disease', (202, 213))	('tumors', 'Phenotype', 'HP:0002664', (207, 213))	('BRCA', 'Phenotype', 'HP:0003002', (193, 197))	('BRCA', 'Gene', '672', (193, 197))	('UCEC tumors', 'Disease', (138, 149))	('UCEC tumors', 'Disease', 'MESH:D009369', (138, 149))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('deletions', 'Var', (155, 164))	('BRCA', 'Gene', (193, 197))	('CIMP-', 'Chemical', '-', (65, 70))	('COAD', 'Disease', (129, 133))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
130104	25960768	However, these events are not always positively correlated, as shown by the reduction in deletions in COAD CIMP- samples.	('COAD', 'Disease', (102, 106))	('reduction', 'NegReg', (76, 85))	('deletions', 'Var', (89, 98))	('COAD', 'Disease', 'MESH:D029424', (102, 106))	('CIMP-', 'Chemical', '-', (107, 112))
130108	25960768	For example, MLH1 promoter methylation is observed in a subset of COAD and UCEC tumors with a very strong majority of CIMP+ labels.	('UCEC tumors', 'Disease', (75, 86))	('MLH1', 'Gene', (13, 17))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('MLH1', 'Gene', '4292', (13, 17))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('COAD', 'Disease', (66, 70))	('CIMP+', 'Chemical', '-', (118, 123))	('methylation', 'Var', (27, 38))	('UCEC tumors', 'Disease', 'MESH:D009369', (75, 86))	('observed', 'Reg', (42, 50))	('COAD', 'Disease', 'MESH:D029424', (66, 70))
130109	25960768	Similarly, a high proportion of CIMP+ labels was observed in samples with MGMT promoter methylation, combined with either (a) FBXW7 mutations or (b) APC and KRAS mutations or (c) absence of FBXW7 and APC mutations (Figure 7).	('KRAS', 'Gene', '3845', (157, 161))	('mutations', 'Var', (162, 171))	('FBXW7', 'Gene', '55294', (126, 131))	('APC', 'Disease', (200, 203))	('APC', 'Disease', 'MESH:D011125', (200, 203))	('FBXW7', 'Gene', (126, 131))	('FBXW7', 'Gene', '55294', (190, 195))	('mutations', 'Var', (132, 141))	('MGMT', 'Gene', (74, 78))	('APC', 'Disease', 'MESH:D011125', (149, 152))	('CIMP+', 'Chemical', '-', (32, 37))	('APC', 'Disease', (149, 152))	('KRAS', 'Gene', (157, 161))	('MGMT', 'Gene', '4255', (74, 78))	('FBXW7', 'Gene', (190, 195))
130110	25960768	Of note, subgroups containing these alterations consisted entirely of tumors of the aero-digestive tract (HNSC, LUSC, COAD, and READ).	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('COAD', 'Disease', 'MESH:D029424', (118, 122))	('LUSC', 'Phenotype', 'HP:0030359', (112, 116))	('alterations', 'Var', (36, 47))	('tumors of the aero-digestive tract', 'Phenotype', 'HP:0007378', (70, 104))	('HNSC', 'Phenotype', 'HP:0012288', (106, 110))	('tumors', 'Disease', (70, 76))	('tumors', 'Disease', 'MESH:D009369', (70, 76))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('COAD', 'Disease', (118, 122))	('LUSC', 'Disease', (112, 116))
130112	25960768	In our samples lacking MGMT and MLH1 promoter methylation, the highest proportions of CIMP+ samples were observed in a subgroup dominated by KIRC tumors that were characterized by a combination of SETD2 and PBRM1 mutations.	('MLH1', 'Gene', (32, 36))	('PBRM1', 'Gene', (207, 212))	('SETD2', 'Gene', '29072', (197, 202))	('CIMP+', 'Chemical', '-', (86, 91))	('PBRM1', 'Gene', '55193', (207, 212))	('tumors', 'Phenotype', 'HP:0002664', (146, 152))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('SETD2', 'Gene', (197, 202))	('tumors', 'Disease', 'MESH:D009369', (146, 152))	('MGMT', 'Gene', '4255', (23, 27))	('MGMT', 'Gene', (23, 27))	('tumors', 'Disease', (146, 152))	('MLH1', 'Gene', '4292', (32, 36))	('mutations', 'Var', (213, 222))
130113	25960768	We found co-occurrence of CCNE1 amplification and TP53 mutations in a subgroup derived from a mixture of BLCA, BRCA, UCEC, and LUAD tumors where all the samples were labeled as CIMP-.	('mutations', 'Var', (55, 64))	('CCNE1', 'Gene', '898', (26, 31))	('CCNE1', 'Gene', (26, 31))	('BRCA', 'Phenotype', 'HP:0003002', (111, 115))	('BRCA', 'Gene', '672', (111, 115))	('CIMP-', 'Chemical', '-', (177, 182))	('amplification', 'Var', (32, 45))	('TP53', 'Gene', '7157', (50, 54))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('BRCA', 'Gene', (111, 115))	('LUAD tumors', 'Disease', (127, 138))	('LUAD tumors', 'Disease', 'MESH:D009369', (127, 138))	('TP53', 'Gene', (50, 54))	('BLCA', 'Chemical', '-', (105, 109))	('LUAD', 'Phenotype', 'HP:0030078', (127, 131))
130115	25960768	Other copy number events, such as amplification of the region containing NKX2 and FOXA1 or deletion of HERC2 were observed in subgroups with a majority of CIMP+ samples and a large fraction of LUAD but also a few BRCA tumors.	('BRCA tumors', 'Disease', 'MESH:D009369', (213, 224))	('NKX2', 'Gene', (73, 77))	('HERC2', 'Gene', (103, 108))	('deletion', 'Var', (91, 99))	('FOXA1', 'Gene', (82, 87))	('BRCA', 'Phenotype', 'HP:0003002', (213, 217))	('CIMP+', 'Chemical', '-', (155, 160))	('FOXA1', 'Gene', '3169', (82, 87))	('tumors', 'Phenotype', 'HP:0002664', (218, 224))	('LUAD', 'Phenotype', 'HP:0030078', (193, 197))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('BRCA tumors', 'Disease', (213, 224))	('amplification', 'Var', (34, 47))	('HERC2', 'Gene', '8924', (103, 108))	('observed', 'Reg', (114, 122))
130116	25960768	Deletion of a region containing GALR1 was observed in a subset with a majority of CIMP+ tumors that came primarily from the COAD and HNSC types.	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('GALR1', 'Gene', '2587', (32, 37))	('HNSC', 'Phenotype', 'HP:0012288', (133, 137))	('COAD', 'Disease', (124, 128))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('CIMP+', 'Chemical', '-', (82, 87))	('GALR1', 'Gene', (32, 37))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('tumors', 'Disease', (88, 94))	('COAD', 'Disease', 'MESH:D029424', (124, 128))	('Deletion', 'Var', (0, 8))
130117	25960768	Our pan-cancer regression tree shows that VHL mutations correlate with significant reductions in average levels of CGI methylation in KIRC tumors (Additional file 1: Figure S2).	('reductions', 'NegReg', (83, 93))	('mutations', 'Var', (46, 55))	('CGI methylation', 'MPA', (115, 130))	('cancer', 'Disease', (8, 14))	('VHL', 'Disease', (42, 45))	('VHL', 'Disease', 'MESH:D006623', (42, 45))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('tumors', 'Disease', (139, 145))	('tumors', 'Disease', 'MESH:D009369', (139, 145))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('cancer', 'Disease', 'MESH:D009369', (8, 14))
130118	25960768	Similarly, amplification of two chromosomal regions in chromosome 17, including ERBB2 (a.k.a.	('ERBB2', 'Gene', '2064', (80, 85))	('amplification', 'Var', (11, 24))	('ERBB2', 'Gene', (80, 85))
130122	25960768	For example, our classification tree for BLCA highlights alterations affecting RB1 and ARID1A in CIMP+ tumors (Additional file 1: Figure S3), consistent with previous independent analyses.	('BLCA', 'Chemical', '-', (41, 45))	('RB1', 'Gene', (79, 82))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('RB1', 'Gene', '5925', (79, 82))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('CIMP+', 'Chemical', '-', (97, 102))	('tumors', 'Disease', (103, 109))	('alterations', 'Var', (57, 68))	('tumors', 'Disease', 'MESH:D009369', (103, 109))	('ARID1A', 'Gene', '8289', (87, 93))	('ARID1A', 'Gene', (87, 93))
130123	25960768	In BRCA, we found a strong association between CCND1 amplification and CIMP status (Additional file 1: Figures S3 and S4).	('BRCA', 'Gene', (3, 7))	('BRCA', 'Gene', '672', (3, 7))	('amplification', 'Var', (53, 66))	('CIMP', 'Chemical', '-', (71, 75))	('CCND1', 'Gene', (47, 52))	('CCND1', 'Gene', '595', (47, 52))	('CIMP status', 'Disease', (71, 82))	('BRCA', 'Phenotype', 'HP:0003002', (3, 7))
130124	25960768	Also, the presence of MYC amplifications delineated a subset of samples that consisted entirely of CIMP- tumors (Additional file 1: Figure S3).	('MYC', 'Gene', '4609', (22, 25))	('CIMP- tumors', 'Disease', 'MESH:D009369', (99, 111))	('CIMP- tumors', 'Disease', (99, 111))	('delineated', 'Reg', (41, 51))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('MYC', 'Gene', (22, 25))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('presence', 'Var', (10, 18))	('amplifications', 'Var', (26, 40))
130125	25960768	This is consistent with reports from TCGA identifying MYC amplification and high-expression in basal-like breast tumors, which tend to be hypomethylated.	('breast tumors', 'Phenotype', 'HP:0100013', (106, 119))	('MYC', 'Gene', '4609', (54, 57))	('breast tumors', 'Disease', 'MESH:D001943', (106, 119))	('breast tumors', 'Disease', (106, 119))	('MYC', 'Gene', (54, 57))	('high-expression', 'Var', (76, 91))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
130126	25960768	In KIRC, the presence of either mutations or deletions affecting gene SETD2 and methylation of the GSTP1 promoter correlate with an important increase in the frequency of CIMP+ cases (Additional file 1: Figures S3 and S4).	('GSTP1', 'Gene', (99, 104))	('increase', 'PosReg', (142, 150))	('methylation', 'MPA', (80, 91))	('GSTP1', 'Gene', '2950', (99, 104))	('deletions', 'Var', (45, 54))	('CIMP+ cases', 'Disease', (171, 182))	('mutations', 'Var', (32, 41))	('SETD2', 'Gene', '29072', (70, 75))	('SETD2', 'Gene', (70, 75))	('CIMP+', 'Chemical', '-', (171, 176))
130127	25960768	Also in KIRC, we found that deletion of a genomic region containing CDKN2A and CDKN2B on chromosome 9 is associated with increased levels of CGI methylation (Additional file 1: Figure S4).	('CDKN2B', 'Gene', '1030', (79, 85))	('increased', 'PosReg', (121, 130))	('CDKN2A', 'Gene', (68, 74))	('CDKN2A', 'Gene', '1029', (68, 74))	('deletion', 'Var', (28, 36))	('CGI methylation', 'MPA', (141, 156))	('CDKN2B', 'Gene', (79, 85))
130128	25960768	This kind of deletion has been linked to a more aggressive phenotype of clear cell carcinoma.	('linked to', 'Reg', (31, 40))	('deletion', 'Var', (13, 21))	('clear cell carcinoma', 'Disease', 'MESH:C538614', (72, 92))	('clear cell carcinoma', 'Disease', (72, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))
130129	25960768	In LUSC, methylation of the RBP1 promoter and amplification of a region containing KDM5A correlate with an increase in average CGI methylation (Additional file 1: Figure S4).	('KDM5A', 'Gene', (83, 88))	('methylation', 'Var', (9, 20))	('RBP1', 'Gene', (28, 32))	('increase', 'PosReg', (107, 115))	('KDM5A', 'Gene', '5927', (83, 88))	('RBP1', 'Gene', '5947', (28, 32))	('CGI methylation', 'MPA', (127, 142))	('LUSC', 'Phenotype', 'HP:0030359', (3, 7))
130130	25960768	In UCEC, our data show that methylation of the MLH1 promoter results in a very high probability of CIMP+ status.	('MLH1', 'Gene', '4292', (47, 51))	('CIMP+ status', 'Disease', (99, 111))	('MLH1', 'Gene', (47, 51))	('methylation', 'Var', (28, 39))	('CIMP+', 'Chemical', '-', (99, 104))
130131	25960768	For samples that do not exhibit this trait, the presence of TP53 mutations is associated with the opposite outcome.	('TP53', 'Gene', '7157', (60, 64))	('TP53', 'Gene', (60, 64))	('presence', 'Var', (48, 56))	('mutations', 'Var', (65, 74))
130132	25960768	Among the remaining samples, PIK3R1 mutations are linked to increased CIMP+ rates (Additional file 1: Figure S3).	('CIMP+ rates', 'MPA', (70, 81))	('CIMP+', 'Chemical', '-', (70, 75))	('mutations', 'Var', (36, 45))	('PIK3R1', 'Gene', '5295', (29, 35))	('PIK3R1', 'Gene', (29, 35))	('increased', 'PosReg', (60, 69))
130133	25960768	Thus, the presence of tumor-specific mutations provides a potential link to predicting methylation status.	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('mutations', 'Var', (37, 46))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('tumor', 'Disease', (22, 27))
130139	25960768	For these three types, the median age of CIMP+ patients is higher than the median age in CIMP- (consistent with an independent study of CIMP+ status in COAD).	('COAD', 'Disease', 'MESH:D029424', (152, 156))	('CIMP+', 'Chemical', '-', (41, 46))	('patients', 'Species', '9606', (47, 55))	('CIMP+', 'Var', (41, 46))	('COAD', 'Disease', (152, 156))	('CIMP-', 'Chemical', '-', (89, 94))	('higher', 'PosReg', (59, 65))	('CIMP+', 'Chemical', '-', (136, 141))
130140	25960768	We found no statistical association between CIMP status and gender in any cancer type, except KIRC (P = 0.025, Fisher's exact test with Holm's correction), where we observed a significantly higher frequency of CIMP+ labels in male samples (45%, 58 of 128) than in female samples (22%, 15 of 66).	('CIMP+', 'Chemical', '-', (210, 215))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('CIMP+ labels', 'Var', (210, 222))	('cancer', 'Disease', (74, 80))	('CIMP', 'Chemical', '-', (44, 48))	('CIMP', 'Chemical', '-', (210, 214))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('higher', 'PosReg', (190, 196))
130147	25960768	These results are consistent with independent reports of MSI in CIMP-high colorectal tumors and also with the division between UCEC serous and endometrioid samples (largely CIMP- and CIMP+ in our analysis, respectively), where endometrioid tumors carry microsatellite instability and serous tumors do not.	('serous tumors', 'Disease', 'MESH:D018284', (284, 297))	('MSI', 'Disease', (57, 60))	('CIMP-', 'Chemical', '-', (173, 178))	('tumors', 'Phenotype', 'HP:0002664', (240, 246))	('endometrioid tumors', 'Disease', (227, 246))	('serous tumors', 'Disease', (284, 297))	('microsatellite instability', 'Var', (253, 279))	('colorectal tumors', 'Disease', 'MESH:D015179', (74, 91))	('tumors', 'Phenotype', 'HP:0002664', (291, 297))	('CIMP+', 'Chemical', '-', (183, 188))	('tumor', 'Phenotype', 'HP:0002664', (291, 296))	('colorectal tumors', 'Disease', (74, 91))	('tumor', 'Phenotype', 'HP:0002664', (240, 245))	('endometrioid tumors', 'Disease', 'MESH:D016889', (227, 246))	('CIMP-', 'Chemical', '-', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('MSI', 'Disease', 'None', (57, 60))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))
130148	25960768	Thus, the MSI characteristic appears to be associated with CIMP+ status and mutually exclusive with TP53 mutations and copy number variation.	('CIMP+', 'Chemical', '-', (59, 64))	('TP53', 'Gene', '7157', (100, 104))	('copy number variation', 'Var', (119, 140))	('MSI', 'Disease', 'None', (10, 13))	('TP53', 'Gene', (100, 104))	('MSI', 'Disease', (10, 13))	('associated', 'Reg', (43, 53))	('CIMP+ status', 'Var', (59, 71))
130151	25960768	This conclusion is consistent with trends reported by TCGA, where many luminal B samples showed a hypermethylator phenotype while basal-like samples were hypomethylated and associated with very high rates of TP53 mutations.	('mutations', 'Var', (213, 222))	('hypermethylator phenotype', 'MPA', (98, 123))	('TP53', 'Gene', '7157', (208, 212))	('TP53', 'Gene', (208, 212))
130158	25960768	This variation appears to be proportional to distance along the intestinal tract and is consistent with a previous study of colorectal cancer samples collected from three anatomic locations and assessed at eight CIMP-specific promoters using MethyLight technology, as well as independent reports of a gradual decrease in the frequency of BRAF mutations and microsatellite instability within this same region of the intestinal tract.	('BRAF', 'Gene', '673', (338, 342))	('microsatellite instability', 'MPA', (357, 383))	('colorectal cancer', 'Phenotype', 'HP:0003003', (124, 141))	('colorectal cancer', 'Disease', (124, 141))	('CIMP-', 'Chemical', '-', (212, 217))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('decrease', 'NegReg', (309, 317))	('mutations', 'Var', (343, 352))	('BRAF', 'Gene', (338, 342))	('colorectal cancer', 'Disease', 'MESH:D015179', (124, 141))
130161	25960768	Also in HNSC, CIMP- samples exhibited significantly better survival curves for recurrence free status than CIMP+ samples (Additional file 1: Figure S5B).	('CIMP- samples', 'Var', (14, 27))	('HNSC', 'Phenotype', 'HP:0012288', (8, 12))	('CIMP+', 'Chemical', '-', (107, 112))	('better', 'PosReg', (52, 58))	('HNSC', 'Disease', (8, 12))	('CIMP-', 'Chemical', '-', (14, 19))	('S5B', 'Gene', '5711', (148, 151))	('recurrence free status', 'MPA', (79, 101))	('S5B', 'Gene', (148, 151))
130165	25960768	This is consistent with our finding of recurrent CDKN2A and CDKN2B deletions in CIMP+ samples from KIRC patients mentioned earlier (Additional file 1: Figure S4), which were independently linked to a more clinically aggressive phenotype of kidney clear cell carcinoma.	('kidney clear cell carcinoma', 'Disease', (240, 267))	('kidney clear cell carcinoma', 'Disease', 'MESH:C538614', (240, 267))	('CDKN2A', 'Gene', '1029', (49, 55))	('deletions', 'Var', (67, 76))	('CIMP+', 'Chemical', '-', (80, 85))	('CDKN2B', 'Gene', (60, 66))	('carcinoma', 'Phenotype', 'HP:0030731', (258, 267))	('CDKN2B', 'Gene', '1030', (60, 66))	('linked to', 'Reg', (188, 197))	('CDKN2A', 'Gene', (49, 55))	('patients', 'Species', '9606', (104, 112))
130168	25960768	In fact, the association between CIMP status and histological subtype extends to tumor grade (an indicator of how quickly a tumor is likely to grow and spread based on microscopic appearance), where CIMP- samples exhibit higher grades than CIMP+ samples (Additional file 1: Figure S6B, P = 9.6 x 10-4, Fisher's exact test, Bonferroni correction).	('CIMP+', 'Chemical', '-', (240, 245))	('tumor', 'Disease', 'MESH:D009369', (124, 129))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('CIMP', 'Chemical', '-', (33, 37))	('tumor', 'Disease', (124, 129))	('CIMP-', 'Var', (199, 204))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('CIMP-', 'Chemical', '-', (199, 204))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('CIMP', 'Chemical', '-', (240, 244))	('CIMP', 'Chemical', '-', (199, 203))	('tumor', 'Disease', (81, 86))	('higher', 'PosReg', (221, 227))
130170	25960768	Overall, our results support the existence of both commonalities and tissue-specific differences in CGI hypermethylation patterns across tumors.	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('tumors', 'Disease', (137, 143))	('hypermethylation', 'Var', (104, 120))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
130171	25960768	The most important similarity found in our analysis is the existence of consistent levels of average CGI hypermethylation that correlate with CIMP status and are independent of cancer type (Figure 2B,C).	('cancer', 'Disease', (177, 183))	('cancer', 'Disease', 'MESH:D009369', (177, 183))	('CGI', 'Protein', (101, 104))	('hypermethylation', 'Var', (105, 121))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('CIMP', 'Chemical', '-', (142, 146))
130173	25960768	Our genome-wide analyses (Additional file 1: Figure S1) show that much of the focal, cancer-related CGI hypermethylation occurs at loci that exhibit consistently baseline levels of methylation in control samples.	('hypermethylation', 'Var', (104, 120))	('CGI', 'Disease', (100, 103))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('cancer', 'Disease', (85, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
130177	25960768	For example, significantly recurrent functional events in CIMP+ samples correspond to mutated genes or silencing of MLH1 and MGMT, while recurrent events in CIMP- consist primarily of chromosomal amplifications and TP53 mutations (Table 2).	('CIMP+', 'Chemical', '-', (58, 63))	('MGMT', 'Gene', (125, 129))	('mutated genes', 'Var', (86, 99))	('MLH1', 'Gene', (116, 120))	('MGMT', 'Gene', '4255', (125, 129))	('MLH1', 'Gene', '4292', (116, 120))	('TP53', 'Gene', '7157', (215, 219))	('CIMP-', 'Chemical', '-', (157, 162))	('mutations', 'Var', (220, 229))	('TP53', 'Gene', (215, 219))	('silencing', 'NegReg', (103, 112))
130182	25960768	While mutations in gene H3F3A, which encodes histone variant H3.3, have been correlated with specific DNA methylation subgroups in pediatric glioblastoma, our analysis of upstream regulators implicates involvement in most of the cancer types that we evaluated, with the exception of LUAD and BLCA (Figure 3B).	('glioblastoma', 'Phenotype', 'HP:0012174', (141, 153))	('cancer', 'Disease', (229, 235))	('cancer', 'Disease', 'MESH:D009369', (229, 235))	('H3F3A', 'Gene', '3020', (24, 29))	('BLCA', 'Chemical', '-', (292, 296))	('pediatric glioblastoma', 'Disease', 'MESH:D005909', (131, 153))	('correlated', 'Reg', (77, 87))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('H3F3A', 'Gene', (24, 29))	('involvement', 'Reg', (202, 213))	('LUAD', 'Phenotype', 'HP:0030078', (283, 287))	('LUAD', 'Disease', (283, 287))	('BLCA', 'Disease', (292, 296))	('pediatric glioblastoma', 'Disease', (131, 153))	('mutations', 'Var', (6, 15))
130184	25960768	Loss-of-function mutations in the demethylating enzyme TET2 have been previously associated to CIMP in leukemia, and our results reveal recurrence of this mutation in CIMP+ for other types such as UCEC and READ (Figure 6A).	('Loss-of-function', 'NegReg', (0, 16))	('CIMP', 'Disease', (95, 99))	('TET2', 'Gene', (55, 59))	('UCEC', 'Disease', (197, 201))	('leukemia', 'Phenotype', 'HP:0001909', (103, 111))	('leukemia', 'Disease', 'MESH:D007938', (103, 111))	('CIMP', 'Chemical', '-', (167, 171))	('CIMP', 'Chemical', '-', (95, 99))	('leukemia', 'Disease', (103, 111))	('READ', 'Disease', (206, 210))	('TET2', 'Gene', '54790', (55, 59))	('CIMP+', 'Chemical', '-', (167, 172))	('mutations', 'Var', (17, 26))
130185	25960768	Also, mutations of ARID1A have been linked to MSI and CIMP in gastrointestinal cancers, and our results indicate importance in UCEC and BLCA.	('MSI', 'Disease', (46, 49))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('CIMP', 'Chemical', '-', (54, 58))	('BLCA', 'Disease', (136, 140))	('MSI', 'Disease', 'None', (46, 49))	('UCEC', 'Disease', (127, 131))	('gastrointestinal cancers', 'Disease', 'MESH:D004067', (62, 86))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('linked', 'Reg', (36, 42))	('gastrointestinal cancers', 'Disease', (62, 86))	('ARID1A', 'Gene', '8289', (19, 25))	('BLCA', 'Chemical', '-', (136, 140))	('ARID1A', 'Gene', (19, 25))	('mutations', 'Var', (6, 15))
130186	25960768	BRAF mutations, which are perhaps one of the most commonly accepted indicator events for CIMP in colorectal cancers, also appear to be relevant in LUAD, but not the other tumor types.	('colorectal cancers', 'Disease', (97, 115))	('LUAD', 'Disease', (147, 151))	('cancers', 'Phenotype', 'HP:0002664', (108, 115))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('mutations', 'Var', (5, 14))	('colorectal cancer', 'Phenotype', 'HP:0003003', (97, 114))	('BRAF', 'Gene', '673', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('colorectal cancers', 'Disease', 'MESH:D015179', (97, 115))	('CIMP', 'Chemical', '-', (89, 93))	('BRAF', 'Gene', (0, 4))	('tumor', 'Disease', (171, 176))	('LUAD', 'Phenotype', 'HP:0030078', (147, 151))
130187	25960768	For example, amplification of genes PIK3CA and CCNE1 occur significantly more frequently in CIMP- samples.	('CCNE1', 'Gene', '898', (47, 52))	('CCNE1', 'Gene', (47, 52))	('PIK3CA', 'Gene', '5290', (36, 42))	('CIMP-', 'Chemical', '-', (92, 97))	('CIMP- samples', 'Disease', (92, 105))	('amplification', 'Var', (13, 26))	('PIK3CA', 'Gene', (36, 42))
130189	25960768	Our pan-cancer regression tree revealed global CGI hypomethylation in samples with mutated NSD1, which came primarily from the HNSC data set (Additional file 1: Figure S2).	('NSD1', 'Gene', (91, 95))	('mutated', 'Var', (83, 90))	('cancer', 'Disease', (8, 14))	('hypomethylation', 'Var', (51, 66))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('HNSC', 'Phenotype', 'HP:0012288', (127, 131))	('NSD1', 'Gene', '64324', (91, 95))	('cancer', 'Disease', 'MESH:D009369', (8, 14))
130191	25960768	Our results also linked mutations in KDM6A, a H3K27me3 demethylase, to decreased CpG island methylation (Additional file 1: Figure S2).	('KDM6A', 'Gene', '7403', (37, 42))	('KDM6A', 'Gene', (37, 42))	('CpG island methylation', 'MPA', (81, 103))	('mutations', 'Var', (24, 33))	('decreased', 'NegReg', (71, 80))
130197	25960768	Our results help to clarify this apparent contradiction by showing that poor survival could be associated with luminal B patients with CIMP+ status and that luminal B patients with CIMP- can have good survival outcomes (Figure 8B).	('CIMP+ status', 'Var', (135, 147))	('patients', 'Species', '9606', (167, 175))	('CIMP+', 'Chemical', '-', (135, 140))	('CIMP-', 'Chemical', '-', (181, 186))	('patients', 'Species', '9606', (121, 129))	('poor', 'NegReg', (72, 76))
130198	25960768	Interestingly, the situation is reversed in luminal A tumors, where CIMP+ status is associated to good survival and CIMP- status is associated with poor survival (as originally reported by Fang et al.).	('poor', 'NegReg', (148, 152))	('luminal A tumors', 'Disease', 'MESH:D009369', (44, 60))	('CIMP-', 'Chemical', '-', (116, 121))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('luminal A tumors', 'Disease', (44, 60))	('CIMP+', 'Chemical', '-', (68, 73))	('CIMP- status', 'Var', (116, 128))
130215	25960768	In the case of the KIRP dataset, we excluded nine tumor samples that behaved as outliers based on PCA plots computed over variably methylated probes (these tumor samples clustered together with each other, away from the rest of tumors and closer to the set of controls; the actual sample IDs were TCGA-A4-7915-01, TCGA-F9-A4JJ-01, TCGA-G7-6793-01, TCGA-GL-7966-01, TCGA-P4-A5E8-01, TCGA-P4-A5EA-01, TCGA-BQ-5879-01, TCGA-BQ-5893-01, TCGA-BQ-5894-01).	('tumor', 'Disease', 'MESH:D009369', (228, 233))	('tumors', 'Phenotype', 'HP:0002664', (228, 234))	('tumor', 'Disease', (156, 161))	('TCGA-G7-6793-01', 'CellLine', 'CVCL:4V47', (331, 346))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('TCGA-BQ-5893-01', 'Var', (416, 431))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('TCGA-G7-6793-01', 'Var', (331, 346))	('tumors', 'Disease', (228, 234))	('tumor', 'Disease', (50, 55))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('TCGA-F9-A4JJ-01', 'Var', (314, 329))	('tumors', 'Disease', 'MESH:D009369', (228, 234))	('TCGA-BQ-5893-01', 'CellLine', 'CVCL:6383', (416, 431))	('TCGA-P4-A5EA-01', 'Var', (382, 397))	('TCGA-GL-7966-01', 'CellLine', 'CVCL:Y146', (348, 363))	('EA-01', 'CellLine', 'CVCL:E575', (392, 397))	('TCGA-BQ-5879-01', 'CellLine', 'CVCL:6383', (399, 414))	('TCGA-BQ-5894-01', 'CellLine', 'CVCL:6383', (433, 448))	('tumor', 'Disease', (228, 233))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('TCGA-F9-A4JJ-01', 'CellLine', 'CVCL:D605', (314, 329))
130234	25960768	For every cancer type, we observe differences in beta values of at least 0.1 and 0.3 when the variably methylated set and the differentially methylated set, respectively, are used to estimate average per-probe methylation in the CIMP+ and CIMP- subsets of samples.	('CIMP-', 'Chemical', '-', (239, 244))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('CIMP+', 'Chemical', '-', (229, 234))	('methylation', 'Var', (210, 221))	('cancer', 'Disease', 'MESH:D009369', (10, 16))	('cancer', 'Disease', (10, 16))
130258	25960768	For the comparison of the average number of mutation, amplification and deletion events per sample shown in Figure 6B, we provide a bar plot showing mean number of events of each category for each individual cancer type.	('cancer', 'Disease', (208, 214))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('deletion', 'Var', (72, 80))	('amplification', 'MPA', (54, 67))	('cancer', 'Disease', 'MESH:D009369', (208, 214))
130274	33888829	Further analysis showed that tumor subtypes were associated with distinct patterns of genomic alterations in genes coding for therapeutic targets.	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('genomic alterations', 'Var', (86, 105))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('tumor', 'Disease', (29, 34))
130299	33888829	We further evaluated the percentage of samples carrying mutations using averages from MuTect, VarScan 2, Somatic Sniper and MuSE in lung cancer therapeutic targets (Table 2).	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('mutations', 'Var', (56, 65))	('MuSE', 'Gene', '399806', (124, 128))	('lung cancer', 'Disease', 'MESH:D008175', (132, 143))	('lung cancer', 'Disease', (132, 143))	('lung cancer', 'Phenotype', 'HP:0100526', (132, 143))	('MuSE', 'Gene', (124, 128))
130300	33888829	Percentages of samples with mutations within each tumor subtype were highly consistent between the different variant-calling software.	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('mutations', 'Var', (28, 37))	('tumor', 'Disease', (50, 55))	('tumor', 'Disease', 'MESH:D009369', (50, 55))
130302	33888829	However, the LUAD-3 subtype had the most frequent mutations in EGFR.	('EGFR', 'Gene', '1956', (63, 67))	('mutations', 'Var', (50, 59))	('LUAD-3', 'Disease', (13, 19))	('EGFR', 'Gene', (63, 67))	('frequent', 'Reg', (41, 49))	('LUAD', 'Phenotype', 'HP:0030078', (13, 17))
130304	33888829	KDR and ROS1 were frequently mutated in LUSC.	('KDR', 'Gene', (0, 3))	('KDR', 'Gene', '3791', (0, 3))	('mutated', 'Var', (29, 36))	('ROS1', 'Gene', (8, 12))	('ROS1', 'Gene', '6098', (8, 12))
130324	33223572	For example, in pan-cancer network analysis, we have data from multiple types of cancer; for each type of cancer, we have multiomics data, such as gene expression, mutation, and DNA methylation; and according to biological knowledge, the links between different mutations, between different DNA methylations, and between mutations and DNA methylations are not meaningful and thus should be prohibited.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('cancer', 'Disease', (81, 87))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('cancer', 'Disease', 'MESH:D009369', (20, 26))	('cancer', 'Disease', (106, 112))	('cancer', 'Disease', (20, 26))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('mutations', 'Var', (262, 271))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
130348	33223572	In order to examine the associations among genomic variables, we jointly analyse not only the message RNA (mRNA) expression data but also mutations and DNA methylations for these types of cancer.	('methylations', 'Var', (156, 168))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('cancer', 'Disease', (188, 194))	('mutations', 'Var', (138, 147))
130353	33223572	In summary, the datasets consist of mRNA expression data, gene mutations, and DNA methylations for six types of cancer, with all observations preprocessed and treated as Gaussian or binary variables.	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('methylations', 'Var', (82, 94))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('cancer', 'Disease', (112, 118))
130361	33223572	As shown in Figure 5a, the mRNA-mRNA links are most common for all types of cancer, which implicate some direct functionalities between genes.	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('mRNA-mRNA', 'Var', (27, 36))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('common', 'Reg', (52, 58))
130364	33223572	For example, the link between TP53 mutations and the gene DDB2 has been identified in BRCA, COAD, and GBM networks.	('TP53', 'Gene', (30, 34))	('identified', 'Reg', (72, 82))	('COAD', 'Disease', 'MESH:D029424', (92, 96))	('BRCA', 'Phenotype', 'HP:0003002', (86, 90))	('BRCA', 'Gene', '672', (86, 90))	('DDB2', 'Gene', '1643', (58, 62))	('BRCA', 'Gene', (86, 90))	('DDB2', 'Gene', (58, 62))	('TP53', 'Gene', '7157', (30, 34))	('COAD', 'Disease', (92, 96))	('mutations', 'Var', (35, 44))
130365	33223572	The tumour suppressor protein p53 (TP53) is important in cellular responses to DNA damage, and mutations in the TP53 gene are frequently identified in human cancers.	('identified', 'Reg', (137, 147))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('tumour', 'Phenotype', 'HP:0002664', (4, 10))	('human', 'Species', '9606', (151, 156))	('TP53', 'Gene', '7157', (35, 39))	('TP53', 'Gene', (35, 39))	('cancers', 'Disease', 'MESH:D009369', (157, 164))	('cancers', 'Phenotype', 'HP:0002664', (157, 164))	('p53', 'Gene', (30, 33))	('p53', 'Gene', '7157', (30, 33))	('tumour', 'Disease', 'MESH:D009369', (4, 10))	('cancers', 'Disease', (157, 164))	('mutations', 'Var', (95, 104))	('tumour', 'Disease', (4, 10))	('TP53', 'Gene', '7157', (112, 116))	('TP53', 'Gene', (112, 116))
130367	33223572	These findings imply that some mutations and DNA methylations can have a high impact on gene expression for certain types of cancer.	('mutations', 'Var', (31, 40))	('gene expression', 'MPA', (88, 103))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('impact', 'Reg', (78, 84))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))
130383	33223572	This suggests that these genes might influence the cancerous state in different cancers through the same mechanism.	('influence', 'Reg', (37, 46))	('cancers', 'Disease', 'MESH:D009369', (80, 87))	('cancers', 'Phenotype', 'HP:0002664', (80, 87))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancers', 'Disease', (80, 87))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('cancerous', 'Disease', 'MESH:D009369', (51, 60))	('genes', 'Var', (25, 30))	('cancerous', 'Disease', (51, 60))
130399	32218862	Furthermore, RBM47 expression was higher in Xuanwei compared with that in non-Xuanwei NSCLC, suggesting that RBM47 is a more sensitive biomarker in Xuanwei NSCLC, and that it may serve as a candidate therapeutic target.	('non-Xuanwei NSCLC', 'Disease', 'MESH:C580335', (74, 91))	('expression', 'MPA', (19, 29))	('Xuanwei NSCLC', 'Disease', 'MESH:D002289', (78, 91))	('RBM47', 'Gene', (13, 18))	('higher', 'PosReg', (34, 40))	('Xuanwei', 'Var', (44, 51))	('Xuanwei NSCLC', 'Disease', (148, 161))	('non-Xuanwei NSCLC', 'Disease', (74, 91))	('Xuanwei NSCLC', 'Disease', 'MESH:D002289', (148, 161))
130403	32218862	In conclusion, the present study revealed that the upregulation of RBM47 accelerated the malignant progression of NSCLC, indicating that RBM47 may be a potential biomarker for NSCLC progression and a therapeutic target for NSCLC.	('upregulation', 'PosReg', (51, 63))	('NSCLC', 'Disease', (223, 228))	('RBM47', 'Gene', (67, 72))	('NSCLC', 'Disease', 'MESH:D002289', (223, 228))	('malignant progression of', 'CPA', (89, 113))	('NSCLC', 'Disease', (176, 181))	('NSCLC', 'Disease', (114, 119))	('RBM47', 'Var', (137, 142))	('NSCLC', 'Disease', 'MESH:D002289', (176, 181))	('NSCLC', 'Disease', 'MESH:D002289', (114, 119))	('accelerated', 'PosReg', (73, 84))
130431	32218862	RBM47 expression data were retrieved from the GEO database , using the Affymetrix platform  for the following six datasets; GSE27262 (25 NSCLC samples and 25 marginal samples collected for microarray analysis), GSE7670 (27 paired NSCLC samples and the corresponding adjacent non-cancerous samples as a control), GSE19804 (60 NSCLC tumor samples and 60 adjacent normal tissues), GSE10245 (40 LUAD and 18 LUSC samples), GSE14814 (71 LUAD and 52 LUSC samples) and GSE21933 (11 LUAD and 10 LUSC samples).	('NSCLC', 'Disease', 'MESH:D002289', (325, 330))	('NSCLC', 'Disease', (137, 142))	('C', 'Chemical', 'MESH:D002244', (139, 140))	('C', 'Chemical', 'MESH:D002244', (329, 330))	('NSCLC', 'Disease', (325, 330))	('cancer', 'Disease', (279, 285))	('GSE19804', 'Var', (312, 320))	('GSE21933', 'Var', (461, 469))	('C', 'Chemical', 'MESH:D002244', (327, 328))	('NSCLC', 'Disease', (230, 235))	('tumor', 'Phenotype', 'HP:0002664', (331, 336))	('C', 'Chemical', 'MESH:D002244', (406, 407))	('cancer', 'Phenotype', 'HP:0002664', (279, 285))	('C', 'Chemical', 'MESH:D002244', (232, 233))	('GSE7670', 'Chemical', '-', (211, 218))	('GSE27262', 'Var', (124, 132))	('C', 'Chemical', 'MESH:D002244', (446, 447))	('GSE7670', 'Var', (211, 218))	('NSCLC tumor', 'Disease', (325, 336))	('GSE10245', 'Var', (378, 386))	('cancer', 'Disease', 'MESH:D009369', (279, 285))	('GSE14814', 'Var', (418, 426))	('NSCLC', 'Disease', 'MESH:D002289', (230, 235))	('C', 'Chemical', 'MESH:D002244', (141, 142))	('NSCLC', 'Disease', 'MESH:D002289', (137, 142))	('NSCLC tumor', 'Disease', 'MESH:D009369', (325, 336))	('C', 'Chemical', 'MESH:D002244', (489, 490))	('C', 'Chemical', 'MESH:D002244', (234, 235))
130465	32218862	In order to verify the result, two additional datasets (GSE7670 and GSE19804; Fig.	('GSE7670', 'Var', (56, 63))	('GSE19804', 'Var', (68, 76))	('GSE7670', 'Chemical', '-', (56, 63))
130493	32218862	The present data revealed that a high RBM47 expression level in patients with NSCLC was significantly associated with poor prognosis compared with a low RBM47 expression level (P=0.009; Fig.	('high', 'Var', (33, 37))	('patients', 'Species', '9606', (64, 72))	('expression level', 'MPA', (44, 60))	('RBM47', 'Gene', (38, 43))	('NSCLC', 'Disease', (78, 83))	('NSCLC', 'Disease', 'MESH:D002289', (78, 83))
130507	32218862	RBM10 was reported to be consistently downregulated in LUAD, promoting NUMB mRNA exon 9 skipping to generate a NUMB isoform that blocks cell proliferation and inhibited Notch activity.	('blocks', 'NegReg', (129, 135))	('NUMB', 'Gene', (111, 115))	('Notch activity', 'MPA', (169, 183))	('NUMB', 'Gene', '8650', (111, 115))	('skipping', 'Var', (88, 96))	('NUMB', 'Gene', (71, 75))	('RBM10', 'Gene', '8241', (0, 5))	('promoting', 'PosReg', (61, 70))	('NUMB', 'Gene', '8650', (71, 75))	('RBM10', 'Gene', (0, 5))	('cell proliferation', 'CPA', (136, 154))	('inhibited', 'NegReg', (159, 168))
130508	32218862	Regarding mRNA stability, in multiple types of cancer, overexpressed Hu-Antigen R contributes to the accelerated proliferation of cancer cells by enhancing the stability of cell-cycle regulators containing cyclinA and cyclinB1 encoded by AU-rich element-containing mRNAs.	('accelerated', 'PosReg', (101, 112))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('cyclinA', 'Gene', '890', (206, 213))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('Hu-Antigen R', 'Gene', (69, 81))	('cyclinB1', 'Gene', '891', (218, 226))	('cancer', 'Disease', (130, 136))	('overexpressed', 'Var', (55, 68))	('cancer', 'Disease', (47, 53))	('enhancing', 'PosReg', (146, 155))	('cyclinB1', 'Gene', (218, 226))	('stability', 'MPA', (160, 169))	('Hu-Antigen R', 'Gene', '1994', (69, 81))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('proliferation', 'CPA', (113, 126))	('cyclinA', 'Gene', (206, 213))
130515	32218862	Subsequently, a higher expression level of RBM47 was detected in Xuanwei compared with non-Xuanwei NSCLC, which suggested that RBM47 was a more sensitive prognostic marker of Xuanwei NSCLC.	('higher', 'PosReg', (16, 22))	('RBM47', 'Gene', (43, 48))	('Xuanwei NSCLC', 'Disease', (175, 188))	('Xuanwei NSCLC', 'Disease', 'MESH:D002289', (91, 104))	('Xuanwei NSCLC', 'Disease', 'MESH:D002289', (175, 188))	('non-Xuanwei NSCLC', 'Disease', (87, 104))	('expression level', 'MPA', (23, 39))	('RBM47', 'Var', (127, 132))	('non-Xuanwei NSCLC', 'Disease', 'MESH:C580335', (87, 104))
130518	32218862	The data revealed that a high RBM47 expression was associated with a worse prognosis compared with a low RBM47 expression level in patients with NSCLC, including non-Xuanwei NSCLC.	('patients', 'Species', '9606', (131, 139))	('non-Xuanwei NSCLC', 'Disease', 'MESH:C580335', (162, 179))	('NSCLC', 'Disease', 'MESH:D002289', (174, 179))	('NSCLC', 'Disease', (145, 150))	('RBM47', 'Gene', (30, 35))	('non-Xuanwei NSCLC', 'Disease', (162, 179))	('NSCLC', 'Disease', 'MESH:D002289', (145, 150))	('high', 'Var', (25, 29))	('expression', 'MPA', (36, 46))	('NSCLC', 'Disease', (174, 179))
130524	32218862	Patients with breast cancer with high expression levels of RBM47 tend to achieve a relatively good clinical outcome, as demonstrated in a previous study.	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('high', 'Var', (33, 37))	('expression', 'MPA', (38, 48))	('breast cancer', 'Disease', 'MESH:D001943', (14, 27))	('RBM47', 'Gene', (59, 64))	('Patients', 'Species', '9606', (0, 8))	('breast cancer', 'Disease', (14, 27))	('breast cancer', 'Phenotype', 'HP:0003002', (14, 27))	('clinical', 'Species', '191496', (99, 107))
130549	31086173	LOXL2 is a marker of poor survival in oral squamous cell cancer.	('oral squamous cell cancer', 'Disease', 'MESH:D002294', (38, 63))	('oral squamous cell cancer', 'Disease', (38, 63))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (43, 63))	('LOXL2', 'Var', (0, 5))
130555	31086173	Inhibition of LOXL2 attenuated cancer growth and lymph node metastases in the orthotopic tongue mouse models.	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('mouse', 'Species', '10090', (96, 101))	('attenuated cancer', 'Disease', 'MESH:C538265', (20, 37))	('attenuated cancer', 'Disease', (20, 37))	('LOXL2', 'Gene', (14, 19))	('Inhibition', 'Var', (0, 10))	('lymph node metastases', 'Disease', 'MESH:D009362', (49, 70))	('lymph node metastases', 'Disease', (49, 70))
130570	31086173	LOX-like-2 (LOXL2) has emerged as a biomarker for OSCC and its overexpression is associated with poor prognosis in patients.	('patients', 'Species', '9606', (115, 123))	('LOX-like-2', 'Var', (0, 10))	('OSCC', 'Disease', (50, 54))	('overexpression', 'PosReg', (63, 77))
130576	31086173	Studies of mechanisms in vitro support that tumor cell-derived LOXL2 directly stimulated stromal fibroblast proliferation and activity by enhancing PDGF-AB-mediated signaling after modification of PDGFRbeta, while having no proliferative effect on tumor cells themselves.	('tumor', 'Disease', (248, 253))	('PDGF-A', 'Gene', '18590', (148, 154))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('stimulated', 'PosReg', (78, 88))	('PDGF-A', 'Gene', (148, 154))	('modification', 'Var', (181, 193))	('stromal fibroblast proliferation', 'CPA', (89, 121))	('PDGFRbeta', 'Gene', (197, 206))	('enhancing', 'PosReg', (138, 147))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumor', 'Disease', 'MESH:D009369', (248, 253))	('tumor', 'Phenotype', 'HP:0002664', (248, 253))	('activity', 'CPA', (126, 134))	('tumor', 'Disease', (44, 49))	('PDGFRbeta', 'Gene', '18596', (197, 206))
130610	31086173	Additional reagents were recombinant human PDGF-BB (#100-14B) and PDGF-AB (100-00AB) were purchased from Peprotech.	('PDGF-A', 'Gene', '18590', (66, 72))	('PDGF-A', 'Gene', (66, 72))	('PDGF-B', 'Gene', (43, 49))	('#100-14B', 'Var', (52, 60))	('PDGF-B', 'Gene', '18591', (43, 49))	('human', 'Species', '9606', (37, 42))
130615	31086173	The cDNA concentration was measured by NanoDrop spectrophotometer and then subjected to qPCR using TaqMan Universal PCR Master Mix (4304437, Thermo Fisher Scientific) and TaqMan probes for LOX (Hs00942480_m1 Gene LOX), LOXL1 (Hs00935937_m1 Gene LOXL1), LOXL2 (Hs00158757_m1 Gene LOXL2), LOXL3 (Mm01184865_m1 Gene Loxl3), LOXL4 (Hs00260059_m1 Gene LOXL4), and 18S (Hs99999901_s1 18S Human probe) as a control.	('Mm01184865_m1', 'Var', (294, 307))	('LOXL3', 'Gene', '84695', (287, 292))	('Human', 'Species', '9606', (382, 387))	('Loxl3', 'Gene', '84695', (313, 318))	('Hs00260059_m1', 'Var', (328, 341))	('LOXL3', 'Gene', (287, 292))	('Loxl3', 'Gene', (313, 318))
130619	31086173	The membranes were stripped using Western Blot stripping buffer (21059, Thermo Fisher Scientific) and re-probed with antibodies against either beta-tubulin (HRP Conjugate, #5346, Cell Signaling) or beta-actin (#4970, Cell Signaling) as a loading control.	('#4970', 'Var', (210, 215))	('beta-actin', 'Gene', '11461', (198, 208))	('beta-tubulin', 'Protein', (143, 155))	('beta-actin', 'Gene', (198, 208))
130621	31086173	A set of three PDGF A and two PDGF B MISSION small hairpin RNA (shRNA) lentiviral transduction particles (lentiviral-based shRNA vectors) were used to knock down PDGF A and PDGF B in HSC3 tumor cells.	('PDGF B', 'Gene', (30, 36))	('knock down', 'Var', (151, 161))	('HSC3 tumor', 'Disease', (183, 193))	('PDGF A', 'Gene', '18590', (15, 21))	('PDGF B', 'Gene', '18591', (30, 36))	('HSC3 tumor', 'Disease', 'MESH:D009369', (183, 193))	('PDGF B', 'Gene', '18591', (173, 179))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('PDGF A', 'Gene', (162, 168))	('PDGF A', 'Gene', (15, 21))	('PDGF B', 'Gene', (173, 179))	('PDGF A', 'Gene', '18590', (162, 168))
130622	31086173	Hexadimethrine bromide (8 microg/ml) and PDGFB MISSION shRNA Lentiviral Transduction Particles Human (TRCN0000010411 and TRCN0000010412), PDGFA MISSION shRNA Lentiviral Transduction Particle Human (TRCN0000158353, TRCN0000157461, and TRCN0000156591) and MISSION  pLKO.1-puro non-target shRNA control transduction particles were added to the cells at 2 MOI and incubated for 20 h at 37  C in a humidified incubator with 5% CO2.	('Human', 'Species', '9606', (95, 100))	('PDGFB', 'Gene', (41, 46))	('PDGFA', 'Gene', '5154', (138, 143))	('TRCN0000158353', 'Var', (198, 212))	('MOI', 'Disease', (352, 355))	('PDGFA', 'Gene', (138, 143))	('MOI', 'Disease', 'None', (352, 355))	('CO2', 'Chemical', '-', (422, 425))	('TRCN0000010412', 'Var', (121, 135))	('PDGFB', 'Gene', '5155', (41, 46))	('TRCN0000010411', 'Var', (102, 116))	('TRCN0000156591', 'Var', (234, 248))	('Human', 'Species', '9606', (191, 196))
130631	31086173	Data in Table S1 demonstrate that in oral cancer tissues LOXL2 was by far the most significantly upregulated LOX paralogue (9.8-fold), while other paralogues were modestly upregulated (1.6-2.3-fold).	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('oral cancer', 'Disease', (37, 48))	('LOXL2', 'Var', (57, 62))	('upregulated', 'PosReg', (97, 108))	('oral cancer', 'Disease', 'MESH:D009062', (37, 48))
130640	31086173	Due to the highest expression of LOXL2 in tongue oral cancer in the TCGA data, and the human histopathology and IHC in Fig.	('tongue oral cancer', 'Disease', (42, 60))	('expression', 'MPA', (19, 29))	('tongue oral cancer', 'Disease', 'MESH:D014062', (42, 60))	('human', 'Species', '9606', (87, 92))	('highest', 'Reg', (11, 18))	('LOXL2', 'Var', (33, 38))	('tongue oral', 'Phenotype', 'HP:0010806', (42, 53))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
130646	31086173	Tracking cancer cells by IVIS after 3 weeks of injections of vehicle or PXS-S1C (30 mg/kg) demonstrated that inhibition of LOXL2 by PXS-S1C significantly decreased the distribution of cancer cells to other tissues (Fig.	('cancer', 'Disease', (184, 190))	('decreased', 'NegReg', (154, 163))	('cancer', 'Disease', (9, 15))	('inhibition', 'Var', (109, 119))	('distribution of', 'MPA', (168, 183))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('cancer', 'Disease', 'MESH:D009369', (9, 15))
130667	31086173	Treatment with PXS-S1C induced tumor cell changes consistent with transformation from a poorly differentiated to a well-differentiated morphology characterized by a more cohesive tumor cell arrangement at the border of the tumors in the tongues (Fig.	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('tumor', 'Disease', (223, 228))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumors', 'Disease', (223, 229))	('tumors', 'Disease', 'MESH:D009369', (223, 229))	('tumor', 'Disease', (31, 36))	('tumors', 'Phenotype', 'HP:0002664', (223, 229))	('more', 'PosReg', (165, 169))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('tumor', 'Disease', 'MESH:D009369', (223, 228))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('tumor', 'Disease', (179, 184))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('PXS-S1C', 'Var', (15, 22))
130680	31086173	Data indicate that PXS-S1C-attenuated human gingival fibroblast proliferative responses to all oral cancer cell CM tested.	('oral cancer', 'Disease', (95, 106))	('human', 'Species', '9606', (38, 43))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('PXS-S1C-attenuated', 'Var', (19, 37))	('oral cancer', 'Disease', 'MESH:D009062', (95, 106))
130681	31086173	Proliferation of the HSC3 cell line was inhibited to the greatest degree by PXS-S1C (Fig.	('HSC3', 'Gene', '150353', (21, 25))	('inhibited', 'NegReg', (40, 49))	('HSC3', 'Gene', (21, 25))	('PXS-S1C', 'Var', (76, 83))
130691	31086173	Equal amounts of proteins were subjected to western blotting for phosphorylated (p-) PDGFRbeta Y771, p-PDGFRbeta Y857, p-PDGFRbeta Y751, PDGFRbeta, and beta actin (loading control).	('PDGFRbeta', 'Gene', (121, 130))	('Y771', 'Var', (95, 99))	('PDGFRbeta', 'Gene', '18596', (137, 146))	('PDGFRbeta', 'Gene', '18596', (85, 94))	('PDGFRbeta', 'Gene', '18596', (103, 112))	('PDGFRbeta', 'Gene', '18596', (121, 130))	('PDGFRbeta', 'Gene', (137, 146))	('PDGFRbeta', 'Gene', (85, 94))	('PDGFRbeta', 'Gene', (103, 112))
130692	31086173	PXS-S1C attenuated phosphorylation of PDGFRbeta Y771 and betaY857 in treated fibroblasts.	('phosphorylation', 'MPA', (19, 34))	('betaY857', 'Var', (57, 65))	('Y771', 'Var', (48, 52))	('PDGFRbeta', 'Gene', '18596', (38, 47))	('attenuated', 'NegReg', (8, 18))	('PDGFRbeta', 'Gene', (38, 47))
130693	31086173	However, PDGFRbeta Y751 phosphorylation was unexpectedly not inhibited by PXS-S1C in response to HSC3 CM treatment of oral fibroblasts (Fig.	('PDGFRbeta', 'Gene', (9, 18))	('Y751', 'Var', (19, 23))	('HSC3', 'Gene', '150353', (97, 101))	('phosphorylation', 'MPA', (24, 39))	('PDGFRbeta', 'Gene', '18596', (9, 18))	('HSC3', 'Gene', (97, 101))
130697	31086173	The blots showed that PXS-S1C surprisingly did not attenuate the activation AKT but did inhibit ERK1/2 signaling in fibroblasts treated with HSC3 CM (Fig.	('ERK1/2', 'Gene', (96, 102))	('PXS-S1C', 'Var', (22, 29))	('inhibit', 'NegReg', (88, 95))	('HSC3', 'Gene', '150353', (141, 145))	('HSC3', 'Gene', (141, 145))	('ERK1/2', 'Gene', '26417;26413', (96, 102))
130698	31086173	In summary, data indicate that LOXL2 activity present in HSC3-CM helps to promote activation of oral fibroblast PDGFR at Y771 and Y857 phosphorylation sites but not Y751 in PDGFR in response to CM treatment.	('HSC3', 'Gene', (57, 61))	('Y857', 'Var', (130, 134))	('oral fibroblast', 'CPA', (96, 111))	('activation', 'PosReg', (82, 92))	('Y771', 'Var', (121, 125))	('HSC3', 'Gene', '150353', (57, 61))
130704	31086173	Data indicate that PXS-S1C attenuated phosphorylation of all PDGFRbeta phosphorylation sites including PDGFRbeta Y751, and AKT in activating phosphorylations assayed in response to PDGF-BB (Fig.	('PDGFRbeta', 'Gene', '18596', (61, 70))	('PXS-S1C', 'Var', (19, 26))	('attenuated', 'NegReg', (27, 37))	('PDGF-B', 'Gene', '18591', (181, 187))	('phosphorylation', 'MPA', (38, 53))	('AKT', 'Pathway', (123, 126))	('PDGFRbeta', 'Gene', '18596', (103, 112))	('PDGFRbeta', 'Gene', (61, 70))	('Y751', 'Var', (113, 117))	('PDGF-B', 'Gene', (181, 187))	('activating phosphorylations', 'MPA', (130, 157))	('PDGFRbeta', 'Gene', (103, 112))
130705	31086173	6d), while PXS-S1C did not attenuate phosphorylation of PDGFRbeta in response to PDGF-CC (Fig.	('PDGFRbeta', 'Gene', (56, 65))	('PDGF-CC', 'Var', (81, 88))	('PDGFRbeta', 'Gene', '18596', (56, 65))
130706	31086173	Interestingly, in response to HSC3 CM treatment of oral fibroblasts, PXS-S1C attenuated phosphorylation of PDGFRbeta Y771 and betaY857 but not PDGFRbeta Y751 (Fig.	('phosphorylation', 'MPA', (88, 103))	('PDGFRbeta', 'Gene', (107, 116))	('HSC3', 'Gene', '150353', (30, 34))	('PDGFRbeta', 'Gene', '18596', (143, 152))	('Y771', 'Var', (117, 121))	('HSC3', 'Gene', (30, 34))	('PDGFRbeta', 'Gene', '18596', (107, 116))	('betaY857', 'Var', (126, 134))	('PXS-S1C', 'Var', (69, 76))	('PDGFRbeta', 'Gene', (143, 152))	('attenuated', 'NegReg', (77, 87))
130707	31086173	PXS-S1C attenuated ERK1/2-related PDGF signaling, while AKT was not affected by PXS-S1C (Fig.	('PXS-S1C', 'Var', (0, 7))	('ERK1/2', 'Gene', '26417;26413', (19, 25))	('ERK1/2', 'Gene', (19, 25))	('attenuated', 'NegReg', (8, 18))
130709	31086173	To confirm independently that PDGF-AB is the ligand secreted by HSC3 cells that stimulates oral fibroblast proliferation in collaboration with LOXL2 activity, shRNA lentiviral particles were used to knock down PDGF-A or PDGF-B in HSC3 cells.	('PDGF-A', 'Gene', '18590', (210, 216))	('HSC3', 'Gene', '150353', (64, 68))	('stimulates', 'PosReg', (80, 90))	('PDGF-B', 'Gene', '18591', (220, 226))	('HSC3', 'Gene', (64, 68))	('PDGF-A', 'Gene', (210, 216))	('HSC3', 'Gene', '150353', (230, 234))	('HSC3', 'Gene', (230, 234))	('oral fibroblast proliferation', 'CPA', (91, 120))	('PDGF-A', 'Gene', '18590', (30, 36))	('PDGF-A', 'Gene', (30, 36))	('PDGF-B', 'Gene', (220, 226))	('knock down', 'Var', (199, 209))
130712	31086173	Data indicated that the concentration of PDGF-AB ligand was decreased significantly in the knocked-down HSC3 medium (Fig.	('knocked-down', 'Var', (91, 103))	('concentration', 'MPA', (24, 37))	('decreased', 'NegReg', (60, 69))	('PDGF-A', 'Gene', '18590', (41, 47))	('PDGF-A', 'Gene', (41, 47))	('HSC3', 'Gene', '150353', (104, 108))	('HSC3', 'Gene', (104, 108))
130714	31086173	The result shows that fibroblast proliferation was significantly lower after PDGF ligand knockdowns in HSC3 cells in comparison with CM from HSC3 cells transduced with non-target shRNA control particles (HSC3 control) (Fig.	('HSC3', 'Gene', (204, 208))	('lower', 'NegReg', (65, 70))	('fibroblast proliferation', 'CPA', (22, 46))	('HSC3', 'Gene', '150353', (103, 107))	('knockdowns', 'Var', (89, 99))	('HSC3', 'Gene', '150353', (141, 145))	('HSC3', 'Gene', (103, 107))	('HSC3', 'Gene', (141, 145))	('HSC3', 'Gene', '150353', (204, 208))	('PDGF', 'Gene', (77, 81))
130715	31086173	To investigate whether the level of PDGF-A or PDGF-B knock down in HSC3 cells correlates with the proliferative response in fibroblasts treated with HSC3 CM, the relationship between the gingival fibroblast proliferation inhibition derived from Fig.	('HSC3', 'Gene', (149, 153))	('HSC3', 'Gene', '150353', (67, 71))	('HSC3', 'Gene', (67, 71))	('PDGF-B', 'Gene', (46, 52))	('knock down', 'Var', (53, 63))	('PDGF-A', 'Gene', '18590', (36, 42))	('proliferative', 'CPA', (98, 111))	('PDGF-A', 'Gene', (36, 42))	('HSC3', 'Gene', '150353', (149, 153))	('PDGF-B', 'Gene', '18591', (46, 52))
130720	31086173	We next considered the hypothesis that LOXL2 could optimize PDGF receptor signaling in response to PDGF-AB by oxidizing exposed lysine residues of the PDGFRbeta receptor protein, possibly similar to that found for the LOX paralogue (not LOXL2) on smooth muscle cells and megakaryocytes.	('PDGFRbeta', 'Gene', (151, 160))	('lysine', 'Chemical', 'MESH:D008239', (128, 134))	('optimize', 'PosReg', (51, 59))	('PDGF receptor signaling', 'MPA', (60, 83))	('PDGFRbeta', 'Gene', '18596', (151, 160))	('PDGF-A', 'Gene', '18590', (99, 105))	('PDGF-A', 'Gene', (99, 105))	('oxidizing', 'Var', (110, 119))
130725	31086173	Western blots of the samples probed with anti-PDGFRbeta antibody showed that LOXL2 inhibitor PXS-S1C decreased the oxidation of PDGFR compared to control samples lacking the LOXL2 inhibitor (Fig.	('PDGFRbeta', 'Gene', (46, 55))	('decreased', 'NegReg', (101, 110))	('oxidation of PDGFR', 'MPA', (115, 133))	('PDGFRbeta', 'Gene', '18596', (46, 55))	('PXS-S1C', 'Var', (93, 100))
130732	31086173	Interestingly, data indicate that PXS-S1C decreased the expression specifically of LOXL2 and no other paralogue in HSC3 cells in vitro (Fig.	('decreased', 'NegReg', (42, 51))	('LOXL2', 'Gene', (83, 88))	('PXS-S1C', 'Var', (34, 41))	('expression', 'MPA', (56, 66))	('HSC3', 'Gene', '150353', (115, 119))	('HSC3', 'Gene', (115, 119))
130747	31086173	There is now a considerable body of literature indicating that elevated LOXL2 in particular is associated with a variety of cancers, including oral cancer.	('oral cancer', 'Disease', 'MESH:D009062', (143, 154))	('oral cancer', 'Disease', (143, 154))	('LOXL2', 'Var', (72, 77))	('elevated LOXL2', 'Var', (63, 77))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('cancers', 'Phenotype', 'HP:0002664', (124, 131))	('associated', 'Reg', (95, 105))	('cancers', 'Disease', (124, 131))	('cancers', 'Disease', 'MESH:D009369', (124, 131))
130757	31086173	It was previously reported that optimization of PDGF signaling in vascular smooth muscle cells by LOX-dependent oxidation of PDGFRbeta accompanied enhanced smooth muscle cell chemotaxis and migration.	('enhanced', 'PosReg', (147, 155))	('PDGFRbeta', 'Gene', (125, 134))	('migration', 'CPA', (190, 199))	('oxidation', 'Var', (112, 121))	('smooth muscle cell chemotaxis', 'CPA', (156, 185))	('PDGFRbeta', 'Gene', '18596', (125, 134))
130769	30425522	Clinical characterization of ERBB2 exon 20 insertions and heterogeneity of outcomes responding to afatinib in Chinese lung cancer patients ERBB2 exon 20 insertions (20ins) have been identified as oncogenic drivers in lung cancers.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('ERBB2', 'Gene', '2064', (139, 144))	('ERBB2', 'Gene', (29, 34))	('lung cancer', 'Disease', 'MESH:D008175', (217, 228))	('lung cancers', 'Disease', (217, 229))	('lung cancer', 'Disease', 'MESH:D008175', (118, 129))	('lung cancer', 'Phenotype', 'HP:0100526', (217, 228))	('cancers', 'Phenotype', 'HP:0002664', (222, 229))	('lung cancer', 'Phenotype', 'HP:0100526', (118, 129))	('lung cancers', 'Disease', 'MESH:D008175', (217, 229))	('lung cancer', 'Disease', (118, 129))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('insertions', 'Var', (153, 163))	('lung cancers', 'Phenotype', 'HP:0100526', (217, 229))	('afatinib', 'Chemical', 'MESH:D000077716', (98, 106))	('ERBB2', 'Gene', '2064', (29, 34))	('ERBB2', 'Gene', (139, 144))
130779	30425522	The presence of a glycine at position 778 in ERBB2 was suggested to be a common feature of drug sensitivity mutations.	('glycine at position 778', 'Var', (18, 41))	('mutations', 'Var', (108, 117))	('drug sensitivity', 'Phenotype', 'HP:0020174', (91, 107))	('drug sensitivity', 'Disease', (91, 107))	('glycine', 'Chemical', 'MESH:D005998', (18, 25))	('ERBB2', 'Gene', '2064', (45, 50))	('presence', 'Var', (4, 12))	('ERBB2', 'Gene', (45, 50))
130780	30425522	Patients harboring G778_P780dup (G778) subtype achieved longer median progression-free survival and median overall survival than other 20ins (non-G778) subtypes (median progression-free survival, 10 vs 3.3 months, P=0.32; median overall survival, 19.7 vs 7 months, P=0.16).	('G778_P780dup', 'Var', (19, 31))	('progression-free survival', 'CPA', (70, 95))	('overall', 'MPA', (107, 114))	('longer', 'PosReg', (56, 62))	('Patients', 'Species', '9606', (0, 8))	('G778_P780dup', 'Mutation', 'p.778,780dupP', (19, 31))
130784	30425522	Genetic alterations of human epidermal growth factor receptor 2 (ERBB2, also known as HER2), occurring in 2%-4% of lung cancers, have been identified as a oncogenic driver.	('HER2', 'Gene', (86, 90))	('Genetic alterations', 'Var', (0, 19))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('lung cancers', 'Phenotype', 'HP:0100526', (115, 127))	('HER2', 'Gene', '2064', (86, 90))	('ERBB2', 'Gene', (65, 70))	('cancers', 'Phenotype', 'HP:0002664', (120, 127))	('ERBB2', 'Gene', '2064', (65, 70))	('lung cancers', 'Disease', (115, 127))	('epidermal growth factor receptor 2', 'Gene', '2064', (29, 63))	('epidermal growth factor receptor 2', 'Gene', (29, 63))	('human', 'Species', '9606', (23, 28))	('lung cancers', 'Disease', 'MESH:D008175', (115, 127))	('lung cancer', 'Phenotype', 'HP:0100526', (115, 126))
130786	30425522	In-frame insertions of ERBB2 exon 20 (20ins), resulting in constitutive activation of the downstream PI3K/AKT signaling, initiate the protumorigenic signaling cascade.	('activation', 'PosReg', (72, 82))	('ERBB2', 'Gene', (23, 28))	('AKT', 'Gene', (106, 109))	('ERBB2', 'Gene', '2064', (23, 28))	('initiate', 'Reg', (121, 129))	('tumor', 'Disease', (137, 142))	('insertions', 'Var', (9, 19))	('AKT', 'Gene', '207', (106, 109))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
130789	30425522	The most frequently occurring subtype is Y772_A775dup, accounting for approximately 60% of all 20ins in non-small-cell lung cancer.	('lung cancer', 'Disease', (119, 130))	('lung cancer', 'Phenotype', 'HP:0100526', (119, 130))	('A775dup', 'Mutation', 'c.775dupA', (46, 53))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('Y772_A775dup', 'Var', (41, 53))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (104, 130))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (108, 130))	('lung cancer', 'Disease', 'MESH:D008175', (119, 130))
130790	30425522	With the rapid advancement of genomic profiling technologies and targeted therapy, several ERBB2 inhibitors have been approved for the treatment of ERBB2-positive breast cancer, such as trastuzumab, lapatinib, and pertuzumab.	('lapatinib', 'Chemical', 'MESH:D000077341', (199, 208))	('ERBB2', 'Gene', '2064', (91, 96))	('breast cancer', 'Phenotype', 'HP:0003002', (163, 176))	('ERBB2', 'Gene', (91, 96))	('pertuzumab', 'Chemical', 'MESH:C485206', (214, 224))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('breast cancer', 'Disease', 'MESH:D001943', (163, 176))	('ERBB2', 'Gene', '2064', (148, 153))	('trastuzumab', 'Chemical', 'MESH:D000068878', (186, 197))	('ERBB2', 'Gene', (148, 153))	('breast cancer', 'Disease', (163, 176))	('inhibitors', 'Var', (97, 107))
130794	30425522	The response heterogeneity suggests that ERBB2 mutant patients do not represent a homogenous group.	('patients', 'Species', '9606', (54, 62))	('ERBB2', 'Gene', '2064', (41, 46))	('mutant', 'Var', (47, 53))	('ERBB2', 'Gene', (41, 46))
130798	30425522	A total of 171 patients with ERBB2 exon 20 insertions were identified.	('patients', 'Species', '9606', (15, 23))	('ERBB2', 'Gene', (29, 34))	('insertions', 'Var', (43, 53))	('ERBB2', 'Gene', '2064', (29, 34))
130799	30425522	Our profiling panels, consisting of 8, 56, 168, or 295 cancer-related genes, were designed and validated for identification of base substitutions, insertions, deletions, copy-number variations, and gene fusion.	('gene fusion', 'Var', (198, 209))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('insertions', 'Var', (147, 157))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('base substitutions', 'Var', (127, 145))	('deletions', 'Var', (159, 168))	('copy-number variations', 'Var', (170, 192))	('cancer', 'Disease', (55, 61))
130809	30425522	A total of 432 mutations were identified from the 171 patients harboring ERBB2 20ins, including 139 single-nucleotide variants (SNVs), 172 insertions and deletions (Indels), 83 copy-number amplifications, and 38 frameshift or splice variants.	('single-nucleotide variants', 'Var', (100, 126))	('copy-number amplifications', 'Var', (177, 203))	('patients', 'Species', '9606', (54, 62))	('deletions', 'Var', (154, 163))	('20ins', 'Var', (79, 84))	('insertions', 'Var', (139, 149))	('ERBB2', 'Gene', (73, 78))	('ERBB2', 'Gene', '2064', (73, 78))
130811	30425522	All ERBB2 20ins patients did not carry concurrent classic non-small-cell lung carcinoma driver genes (including EGFR, BRAF, MET, ROS1, ALK, RET, and KRAS), which is consistent with previous reports, confirming the strong mutual exclusivity of ERBB2 with other driver oncogenes.	('ALK', 'Gene', (135, 138))	('KRAS', 'Gene', (149, 153))	('patients', 'Species', '9606', (16, 24))	('ERBB2', 'Gene', '2064', (243, 248))	('RET', 'Gene', (140, 143))	('lung carcinoma', 'Disease', 'MESH:D008175', (73, 87))	('ROS1', 'Gene', '6098', (129, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('EGFR', 'Gene', (112, 116))	('BRAF', 'Gene', '673', (118, 122))	('BRAF', 'Gene', (118, 122))	('ERBB2', 'Gene', (4, 9))	('small-cell lung carcinoma', 'Phenotype', 'HP:0030357', (62, 87))	('RET', 'Gene', '5979', (140, 143))	('ROS1', 'Gene', (129, 133))	('lung carcinoma', 'Disease', (73, 87))	('ERBB2', 'Gene', '2064', (4, 9))	('ERBB2', 'Gene', (243, 248))	('KRAS', 'Gene', '3845', (149, 153))	('ALK', 'Gene', '238', (135, 138))	('non-small-cell lung carcinoma', 'Phenotype', 'HP:0030358', (58, 87))	('20ins', 'Var', (10, 15))	('EGFR', 'Gene', '1956', (112, 116))
130812	30425522	Moreover, we found 11.7% (20/171) patients with ERBB2 20ins harboring concomitant ERBB2 amplification.	('ERBB2', 'Gene', '2064', (82, 87))	('amplification', 'Var', (88, 101))	('ERBB2', 'Gene', (82, 87))	('20ins', 'Var', (54, 59))	('ERBB2', 'Gene', '2064', (48, 53))	('ERBB2', 'Gene', (48, 53))	('patients', 'Species', '9606', (34, 42))
130813	30425522	Of the 171 patients harboring ERBB2 20ins, 13 insertion subtypes were identified.	('20ins', 'Var', (36, 41))	('patients', 'Species', '9606', (11, 19))	('ERBB2', 'Gene', (30, 35))	('ERBB2', 'Gene', '2064', (30, 35))
130814	30425522	They included 12-base-pair insertions (Y772_A775dup, A775_G776insSVMA, A775_G776insVVMA, A775_G776insYVMS, Y772_V773insM-MAY), 9-bp insertions (G778_P780dup), 3-bp insertions (A775_G776insC), and deletions combined with insertions (G776delinsVC, G776delinsLC, G776delinsVV, G776de-linsAVGC, G776delinsIC, G776_V777delinsCVC).	('G776de-linsAVGC', 'Var', (274, 289))	('G776insC', 'Mutation', 'c.776insC', (181, 189))	('G776delinsIC', 'Mutation', 'c.776delinsG,IC', (291, 303))	('G778_P780dup', 'Var', (144, 156))	('Y772_V773insM', 'Mutation', 'p.772,773insM', (107, 120))	('G776delinsVC', 'Var', (232, 244))	('G776delinsVV', 'Mutation', 'c.776delinsG,VV', (260, 272))	('G776insSVMA', 'Mutation', 'c.776insG,SVMA', (58, 69))	('G776insYVMS', 'Mutation', 'c.776insG,YVMS', (94, 105))	('Y772_V773insM-MAY', 'Var', (107, 124))	('G776insVVMA', 'Mutation', 'c.776insG,VVMA', (76, 87))	('G776delinsLC', 'Var', (246, 258))	('A775dup', 'Mutation', 'c.775dupA', (44, 51))	('G776delinsVV', 'Var', (260, 272))	('G776delinsIC', 'Var', (291, 303))	('G776delinsVC', 'Mutation', 'c.776delinsG,VC', (232, 244))	('Y772_A775dup', 'Var', (39, 51))	('G778_P780dup', 'Mutation', 'p.778,780dupP', (144, 156))	('G776_V777delinsCVC', 'Mutation', 'c.776,777delinsCVC', (305, 323))	('G776_V777delinsCVC', 'Var', (305, 323))	('G776delinsLC', 'Mutation', 'c.776delinsG,LC', (246, 258))
130815	30425522	The nomenclature of these exon 20 insertions strictly followed the Human Genome Variation Society guidelines.	('Human', 'Species', '9606', (67, 72))	('insertions', 'Var', (34, 44))	('exon 20', 'Gene', (26, 33))
130816	30425522	The most frequently appearing subtype was a duplication of 12-bp which resulted in an insertion of YVMA at codon 775 (Y772_A775dup) (Figure 1B).	('YVMA', 'Gene', (99, 103))	('Y772_A775dup', 'Var', (118, 130))	('A775dup', 'Mutation', 'c.775dupA', (123, 130))
130818	30425522	The second most frequently occurring ERBB2 20ins subtype in our cohort was G778_P780dup, an in-frame 9-bp insertion, which was identified in 18 patients (10.5%).	('ERBB2', 'Gene', (37, 42))	('ERBB2', 'Gene', '2064', (37, 42))	('patients', 'Species', '9606', (144, 152))	('G778_P780dup', 'Var', (75, 87))	('G778_P780dup', 'Mutation', 'p.778,780dupP', (75, 87))
130819	30425522	Moreover, several rare or novel ERBB2 20 insertions were identified in this cohort.	('insertions', 'Var', (41, 51))	('ERBB2', 'Gene', (32, 37))	('ERBB2', 'Gene', '2064', (32, 37))
130821	30425522	Kaplan-Meier survival analysis revealed that patients with ERBB2 G778_P780dup mutations achieved longer median progression-free survival (PFS) (10.0, 3.7, 1.5, 2.5 months, respectively, P=0.69; Figure 3A) and median overall survival (OS) (19.7, 7.0, 1.5, 11.1 months, respectively, P=0.44; Figure 3B) than those harboring Y772_A775dup, G776delinsVC, and other subtypes.	('G776delinsVC', 'Var', (336, 348))	('G776delinsVC', 'Mutation', 'c.776delinsG,VC', (336, 348))	('Y772_A775dup', 'Var', (322, 334))	('progression-free survival', 'CPA', (111, 136))	('G778_P780dup mutations', 'Var', (65, 87))	('ERBB2', 'Gene', (59, 64))	('A775dup', 'Mutation', 'c.775dupA', (327, 334))	('ERBB2', 'Gene', '2064', (59, 64))	('G778_P780dup', 'Mutation', 'p.778,780dupP', (65, 77))	('patients', 'Species', '9606', (45, 53))	('longer', 'PosReg', (97, 103))	('overall', 'MPA', (216, 223))
130823	30425522	The glycine at ERBB2 778 site was reported to be a drug-sensitive mutation, which may facilitate inhibitor binding to ERBB2.	('ERBB2', 'Gene', (15, 20))	('ERBB2', 'Gene', (118, 123))	('glycine', 'Var', (4, 11))	('glycine', 'Chemical', 'MESH:D005998', (4, 11))	('ERBB2', 'Gene', '2064', (15, 20))	('facilitate', 'PosReg', (86, 96))	('inhibitor', 'MPA', (97, 106))	('ERBB2', 'Gene', '2064', (118, 123))
130824	30425522	Therefore, we stratified our ERBB2 20ins patients into two subgroups to compare survival between G778 patients (G778_P780dup) and non-G778 patients (other amino acids at 778 due to insertion).	('ERBB2', 'Gene', (29, 34))	('G778', 'Var', (97, 101))	('patients', 'Species', '9606', (139, 147))	('patients', 'Species', '9606', (102, 110))	('patients', 'Species', '9606', (41, 49))	('G778_P780dup', 'Var', (112, 124))	('G778_P780dup', 'Mutation', 'p.778,780dupP', (112, 124))	('ERBB2', 'Gene', '2064', (29, 34))
130825	30425522	The Kaplan-Meier analysis revealed that patients with G778 displayed longer median PFS (10.0 vs 3.3 months, P=0.32; Figure 3C) and median OS (19.7 vs 7.0 months, P=0.16; Figure 3D) than non-G778 patients.	('patients', 'Species', '9606', (40, 48))	('G778', 'Var', (54, 58))	('patients', 'Species', '9606', (195, 203))	('PFS', 'MPA', (83, 86))	('longer', 'PosReg', (69, 75))
130830	30425522	The overall outcomes of afatinib treatment of the 19 patients harboring ERBB2 20ins are demonstrated in a swimmer's plot in Figure 4.	('patients', 'Species', '9606', (53, 61))	('20ins', 'Var', (78, 83))	('afatinib', 'Chemical', 'MESH:D000077716', (24, 32))	('ERBB2', 'Gene', '2064', (72, 77))	('ERBB2', 'Gene', (72, 77))
130831	30425522	For the eleven Y772_A775dup patients, eight patients finally achieved PD, with a median PFS of 3 months.	('patients', 'Species', '9606', (44, 52))	('Y772_A775dup', 'Var', (15, 27))	('achieved', 'PosReg', (61, 69))	('PD', 'Disease', 'MESH:D010300', (70, 72))	('patients', 'Species', '9606', (28, 36))	('A775dup', 'Mutation', 'c.775dupA', (20, 27))
130835	30425522	As for rare subtypes of ERBB2 20ins, the patient with G776delinsVV had a PFS of 75 days; another patient with G776delinsLC achieved SD with a PFS of 333 days.	('G776delinsVV', 'Var', (54, 66))	('patient', 'Species', '9606', (41, 48))	('ERBB2', 'Gene', (24, 29))	('G776delinsLC', 'Mutation', 'c.776delinsG,LC', (110, 122))	('SD', 'Disease', 'MESH:D029461', (132, 134))	('ERBB2', 'Gene', '2064', (24, 29))	('patient', 'Species', '9606', (97, 104))	('G776delinsVV', 'Mutation', 'c.776delinsG,VV', (54, 66))	('G776delinsLC', 'Var', (110, 122))
130836	30425522	The patient detected with G776delinsIC obtained a PFS of 62 days.	('G776delinsIC', 'Mutation', 'c.776delinsG,IC', (26, 38))	('PFS', 'MPA', (50, 53))	('patient', 'Species', '9606', (4, 11))	('G776delinsIC', 'Var', (26, 38))
130838	30425522	Another G776delinsVC patient achieved PR to afatinib in the last visit at day 24 and was still under treatment.	('patient', 'Species', '9606', (21, 28))	('G776delinsVC', 'Var', (8, 20))	('G776delinsVC', 'Mutation', 'c.776delinsG,VC', (8, 20))	('afatinib', 'Chemical', 'MESH:D000077716', (44, 52))	('achieved', 'PosReg', (29, 37))
130845	30425522	Genomic profiling was performed and revealed the presence of ERBB2 exon 20 insertion G776delinsVC.	('G776delinsVC', 'Mutation', 'c.776delinsG,VC', (85, 97))	('G776delinsVC', 'Var', (85, 97))	('ERBB2', 'Gene', (61, 66))	('ERBB2', 'Gene', '2064', (61, 66))
130855	30425522	The insertion YVMA at codon 775 (Y772_A775dup) was the most frequently occurring subtype, accounting for 70% of all 20ins in our cohort, consistent with previous publications, which reported a prevalence of 60%.	('occurring', 'Reg', (71, 80))	('Y772_A775dup', 'Var', (33, 45))	('A775dup', 'Mutation', 'c.775dupA', (38, 45))
130856	30425522	As ERBB2 mutations were reported to be mutually exclusive with major mutations in EGFR and KRAS, ERBB2 20ins in all the 171 patients in our study displayed mutually exclusivity with other well-established oncogenic driver mutations, including EGFR, KRAS, BRAF, MET, ALK, ROS1, and RET.	('mutations', 'Var', (9, 18))	('ERBB2', 'Gene', '2064', (3, 8))	('ALK', 'Gene', '238', (266, 269))	('KRAS', 'Gene', '3845', (249, 253))	('ERBB2', 'Gene', '2064', (97, 102))	('patients', 'Species', '9606', (124, 132))	('KRAS', 'Gene', '3845', (91, 95))	('ALK', 'Gene', (266, 269))	('EGFR', 'Gene', (82, 86))	('RET', 'Gene', (281, 284))	('KRAS', 'Gene', (249, 253))	('ROS1', 'Gene', '6098', (271, 275))	('EGFR', 'Gene', (243, 247))	('EGFR', 'Gene', '1956', (243, 247))	('KRAS', 'Gene', (91, 95))	('mutations', 'Var', (69, 78))	('EGFR', 'Gene', '1956', (82, 86))	('ROS1', 'Gene', (271, 275))	('BRAF', 'Gene', '673', (255, 259))	('ERBB2', 'Gene', (3, 8))	('BRAF', 'Gene', (255, 259))	('ERBB2', 'Gene', (97, 102))	('RET', 'Gene', '5979', (281, 284))
130857	30425522	In addition, we found that 11.7% (20/171) ERBB2 20ins patients harbored concurrent ERBB2 amplification.	('amplification', 'MPA', (89, 102))	('patients', 'Species', '9606', (54, 62))	('ERBB2', 'Gene', '2064', (42, 47))	('ERBB2', 'Gene', (83, 88))	('ERBB2', 'Gene', (42, 47))	('ERBB2', 'Gene', '2064', (83, 88))	('20ins', 'Var', (48, 53))
130858	30425522	To date, the molecular association of ERBB2 mutation and gene amplification in lung cancers has not been distinctly defined.	('lung cancers', 'Disease', (79, 91))	('mutation', 'Var', (44, 52))	('cancers', 'Phenotype', 'HP:0002664', (84, 91))	('ERBB2', 'Gene', (38, 43))	('lung cancer', 'Phenotype', 'HP:0100526', (79, 90))	('ERBB2', 'Gene', '2064', (38, 43))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('lung cancers', 'Disease', 'MESH:D008175', (79, 91))	('lung cancers', 'Phenotype', 'HP:0100526', (79, 91))	('gene amplification', 'Var', (57, 75))
130860	30425522	Thus, further efforts are needed to interrogate the underlying association between ERBB2 mutation and amplification.	('ERBB2', 'Gene', (83, 88))	('mutation', 'Var', (89, 97))	('amplification', 'Disease', (102, 115))	('ERBB2', 'Gene', '2064', (83, 88))
130862	30425522	G778_P780dup were reported to be sensitive to ERBB2 targeted tyrosine kinase inhibitors than other 20ins subtypes in vitro, and the presence of a glycine at ERBB2 position 778 was supposed to be a common feature among the drug-sensitive insertion subtypes.	('G778_P780dup', 'Mutation', 'p.778,780dupP', (0, 12))	('ERBB2', 'Gene', (157, 162))	('ERBB2', 'Gene', '2064', (157, 162))	('glycine', 'Chemical', 'MESH:D005998', (146, 153))	('ERBB2', 'Gene', '2064', (46, 51))	('G778_P780dup', 'Var', (0, 12))	('ERBB2', 'Gene', (46, 51))	('sensitive', 'MPA', (33, 42))
130864	30425522	Kosaka et al reported an adenocarcinoma patient with ERBB2 G778_P780dup achieving significant tumor shrinkage for 7 months when afatinib was given as monotherapy.	('patient', 'Species', '9606', (40, 47))	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('ERBB2', 'Gene', '2064', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('G778_P780dup', 'Mutation', 'p.778,780dupP', (59, 71))	('afatinib', 'Chemical', 'MESH:D000077716', (128, 136))	('tumor', 'Disease', (94, 99))	('adenocarcinoma', 'Disease', (25, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (30, 39))	('adenocarcinoma', 'Disease', 'MESH:D000230', (25, 39))	('G778_P780dup', 'Var', (59, 71))	('ERBB2', 'Gene', (53, 58))
130877	27144065	These early studies have identified novel genetic mutations and pathway dysregulations across a variety of head and neck cancers.	('mutations', 'Var', (50, 59))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('pathway', 'Pathway', (64, 71))	('head and neck cancers', 'Disease', 'MESH:D006258', (107, 128))	('head and neck cancers', 'Phenotype', 'HP:0012288', (107, 128))	('cancers', 'Phenotype', 'HP:0002664', (121, 128))	('dysregulations', 'Var', (72, 86))
130899	27144065	The same study identified cyclin D1 as a predictor of LSCC overall and disease-specific survival, and overexpression of EGFR as associated with risk of death.	('cyclin D1', 'Gene', '595', (26, 35))	('associated', 'Reg', (128, 138))	('cyclin D1', 'Gene', (26, 35))	('EGFR', 'Gene', '1956', (120, 124))	('death', 'Disease', 'MESH:D003643', (152, 157))	('overexpression', 'Var', (102, 116))	('death', 'Disease', (152, 157))	('LSCC', 'Disease', (54, 58))	('EGFR', 'Gene', (120, 124))
130908	27144065	However, CASP8 has significantly less mutations in LSCCs compared to the other subsites (P<0.005).	('less', 'NegReg', (33, 37))	('mutations', 'Var', (38, 47))	('CASP8', 'Gene', '841', (9, 14))	('LSCCs', 'Disease', (51, 56))	('CASP8', 'Gene', (9, 14))
130909	27144065	Studies have suggested that CASP8 mutations indicate a distinct molecular profile of SCCs, but this subset does not seem to exist in LSCCs.	('SCCs', 'Disease', (85, 89))	('CASP8', 'Gene', (28, 33))	('CASP8', 'Gene', '841', (28, 33))	('mutations', 'Var', (34, 43))
130910	27144065	Additionally, mutations in PIK3CA trend towards occurring more frequently in LSCCs than other subsites (P=0.058), and copy number amplification of 3q26 which contains PIK3CA is found at significantly higher frequency in LSCCs compared to other HNSCCs (P<0.001, Table 2).	('LSCCs', 'Disease', (77, 82))	('PIK3CA', 'Gene', '5290', (167, 173))	('PIK3CA', 'Gene', (27, 33))	('LSCCs', 'Disease', (220, 225))	('copy number amplification', 'Var', (118, 143))	('PIK3CA', 'Gene', '5290', (27, 33))	('PIK3CA', 'Gene', (167, 173))	('mutations', 'Var', (14, 23))	('HNSCC', 'Phenotype', 'HP:0012288', (244, 249))
130925	27144065	Regardless as the methods for rapid detection and location of HPV insertion sites in the genome improve, so will our understanding of the prevalence and pathogenic role for this virus in LSCC.	('LSCC', 'Disease', (187, 191))	('HPV', 'Gene', (62, 65))	('insertion', 'Var', (66, 75))	('HPV', 'Species', '10566', (62, 65))
130926	27144065	The potential to improve patient survival by using genetic information to match optimal treatments can be seen in a growing number of successes in other cancers: imatinib for chronic myelogenous leukemia, trastuzumab for breast cancer with ERBB2 amplification, and erlotinib and gefitinib for lung cancers that express mutant EGFR.	('cancers', 'Disease', (153, 160))	('gefitinib', 'Chemical', 'MESH:D000077156', (279, 288))	('ERBB2', 'Gene', '2064', (240, 245))	('patient', 'Species', '9606', (25, 32))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('breast cancer', 'Disease', 'MESH:D001943', (221, 234))	('trastuzumab', 'Chemical', 'MESH:D000068878', (205, 216))	('breast cancer', 'Disease', (221, 234))	('erlotinib', 'Chemical', 'MESH:D000069347', (265, 274))	('mutant', 'Var', (319, 325))	('chronic myelogenous leukemia', 'Phenotype', 'HP:0005506', (175, 203))	('cancers', 'Disease', 'MESH:D009369', (298, 305))	('lung cancers', 'Disease', 'MESH:D008175', (293, 305))	('EGFR', 'Gene', (326, 330))	('cancers', 'Disease', 'MESH:D009369', (153, 160))	('leukemia', 'Phenotype', 'HP:0001909', (195, 203))	('imatinib', 'Chemical', 'MESH:D000068877', (162, 170))	('lung cancers', 'Disease', (293, 305))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('lung cancer', 'Phenotype', 'HP:0100526', (293, 304))	('lung cancers', 'Phenotype', 'HP:0100526', (293, 305))	('chronic myelogenous leukemia', 'Disease', (175, 203))	('chronic myelogenous leukemia', 'Disease', 'MESH:D015464', (175, 203))	('myelogenous leukemia', 'Phenotype', 'HP:0012324', (183, 203))	('cancers', 'Phenotype', 'HP:0002664', (298, 305))	('cancers', 'Disease', (298, 305))	('ERBB2', 'Gene', (240, 245))	('EGFR', 'Gene', '1956', (326, 330))	('cancers', 'Phenotype', 'HP:0002664', (153, 160))	('breast cancer', 'Phenotype', 'HP:0003002', (221, 234))	('cancer', 'Phenotype', 'HP:0002664', (298, 304))
130928	27144065	PIK3CA mutations and amplifications frequently occur in LSCCs.	('amplifications', 'Var', (21, 35))	('PIK3CA', 'Gene', (0, 6))	('PIK3CA', 'Gene', '5290', (0, 6))	('LSCCs', 'Disease', (56, 61))	('occur', 'Reg', (47, 52))	('mutations', 'Var', (7, 16))
130933	27144065	The majority of mutations found in PIK3CA have been defined as 'hotspot' mutations, where the specific amino acid residue is recurrently altered in multiple tumortypes.	('tumor', 'Disease', (157, 162))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('mutations', 'Var', (16, 25))	('PIK3CA', 'Gene', (35, 41))	('PIK3CA', 'Gene', '5290', (35, 41))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))
130934	27144065	These hotspot mutations, such as E542K, E545K, and H1047L/R, have functional consequences of increasing the lipid activity resulting in overactive AKT signaling and downstream effector pathway activation.	('E545K', 'Mutation', 'rs104886003', (40, 45))	('E545K', 'Var', (40, 45))	('H1047L', 'SUBSTITUTION', 'None', (51, 57))	('E542K', 'Var', (33, 38))	('activation', 'PosReg', (193, 203))	('H1047L', 'Var', (51, 57))	('lipid', 'Chemical', 'MESH:D008055', (108, 113))	('AKT', 'Gene', '207', (147, 150))	('E542K', 'Mutation', 'rs121913273', (33, 38))	('lipid activity', 'MPA', (108, 122))	('overactive', 'PosReg', (136, 146))	('increasing', 'PosReg', (93, 103))	('AKT', 'Gene', (147, 150))
130936	27144065	found that PIK3CA mutations were a significant biomarker of sensitivity for several drugs targeting the PI3K pathway after screening over 600 cancer cell lines, including 23 HNSCC lines, against 130 drugs at clinical and preclinical stages.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('clinical', 'Species', '191496', (224, 232))	('cancer', 'Disease', (142, 148))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('clinical', 'Species', '191496', (208, 216))	('PIK3CA', 'Gene', (11, 17))	('PIK3CA', 'Gene', '5290', (11, 17))	('sensitivity', 'Reg', (60, 71))	('HNSCC', 'Phenotype', 'HP:0012288', (174, 179))	('PI3K pathway', 'Pathway', (104, 116))	('mutations', 'Var', (18, 27))
130937	27144065	HNSCC cell lines with hotspot PIK3CA mutations demonstrated sensitivity to PI3K/mTOR inhibitors compared to PIK3CA wildtype cells, in both in vitro and in vivo models.	('PIK3CA', 'Gene', (30, 36))	('mTOR', 'Gene', (80, 84))	('mTOR', 'Gene', '2475', (80, 84))	('PIK3CA', 'Gene', '5290', (30, 36))	('mutations', 'Var', (37, 46))	('PIK3CA', 'Gene', (108, 114))	('HNSCC', 'Phenotype', 'HP:0012288', (0, 5))	('sensitivity', 'MPA', (60, 71))	('PIK3CA', 'Gene', '5290', (108, 114))
130939	27144065	In a phase 1 trial, patients containing PIK3CA mutations had significantly greater partial response rates to PI3K/AKT/mTOR therapy (6/17, 35%) than those without PIK3CA mutations (6/241, 6%).	('AKT', 'Gene', '207', (114, 117))	('PIK3CA', 'Gene', '5290', (162, 168))	('PIK3CA', 'Gene', (40, 46))	('PIK3CA', 'Gene', '5290', (40, 46))	('partial', 'NegReg', (83, 90))	('AKT', 'Gene', (114, 117))	('mTOR', 'Gene', (118, 122))	('mutations', 'Var', (47, 56))	('mTOR', 'Gene', '2475', (118, 122))	('patients', 'Species', '9606', (20, 28))	('PIK3CA', 'Gene', (162, 168))
130940	27144065	A following early-phase trial indicated that only the H1047R mutation predicted partial response (6/16, 38%) compared to other PIK3CA mutations (5/50, 10%) or PIK3CA wildtype (23/174, 13%).	('H1047R', 'Var', (54, 60))	('PIK3CA', 'Gene', (127, 133))	('partial response', 'MPA', (80, 96))	('PIK3CA', 'Gene', '5290', (127, 133))	('PIK3CA', 'Gene', (159, 165))	('PIK3CA', 'Gene', '5290', (159, 165))	('H1047R', 'Mutation', 'rs121913279', (54, 60))
130941	27144065	However, this study also noted that other hotspot PIK3CA mutations, such as E542K and E545K, had a strong association with KRAS mutations whereas the H1047R mutation did not.	('H1047R', 'Mutation', 'rs121913279', (150, 156))	('E542K', 'Var', (76, 81))	('association', 'Interaction', (106, 117))	('PIK3CA', 'Gene', '5290', (50, 56))	('E542K', 'Mutation', 'rs121913273', (76, 81))	('E545K', 'Mutation', 'rs104886003', (86, 91))	('E545K', 'Var', (86, 91))	('KRAS', 'Gene', (123, 127))	('KRAS', 'Gene', '3845', (123, 127))	('PIK3CA', 'Gene', (50, 56))
130942	27144065	As members of the Ras signaling pathway (KRAS, HRAS) have been known to mediate resistance to PI3K inhibition, it is unsurprising that patients with both gene mutations may not respond to PI3K-targeting monotherapies.	('patients', 'Species', '9606', (135, 143))	('KRAS', 'Gene', '3845', (41, 45))	('mutations', 'Var', (159, 168))	('HRAS', 'Gene', '3265', (47, 51))	('KRAS', 'Gene', (41, 45))	('HRAS', 'Gene', (47, 51))
130944	27144065	HRAS mutations occur with more prevalence, and of the 2 HRAS mutations in sequenced LSCCs both occur in tumors with additional PIK3CA hotspot mutations.	('mutations', 'Var', (142, 151))	('HRAS', 'Gene', (0, 4))	('occur', 'Reg', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('HRAS', 'Gene', '3265', (56, 60))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('PIK3CA', 'Gene', (127, 133))	('mutations', 'Var', (5, 14))	('HRAS', 'Gene', (56, 60))	('tumors', 'Disease', (104, 110))	('PIK3CA', 'Gene', '5290', (127, 133))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('HRAS', 'Gene', '3265', (0, 4))
130945	27144065	However, 68.4% (13/19) of the PIK3CA mutations in LSCCs are hotspot mutations without Ras mutations, and PI3K-targeted therapies could be a well-matched choice for this patient population.	('PIK3CA', 'Gene', (30, 36))	('mutations', 'Var', (37, 46))	('patient', 'Species', '9606', (169, 176))	('PIK3CA', 'Gene', '5290', (30, 36))
130947	27144065	It is still unclear how the amplification of the PIK3CA gene affects the signaling of the PI3K pathway.	('affects', 'Reg', (61, 68))	('PI3K pathway', 'Pathway', (90, 102))	('signaling', 'MPA', (73, 82))	('PIK3CA', 'Gene', (49, 55))	('PIK3CA', 'Gene', '5290', (49, 55))	('amplification', 'Var', (28, 41))
130948	27144065	While it has been shown that amplification of PIK3CA correlates with increased mRNA and protein expression of p110alpha, it does not necessarily lead to increased levels of phosphorylated Akt and mTOR as would be expected for increased pathway activation.	('PIK3CA', 'Gene', '5290', (46, 52))	('p110alpha', 'Gene', (110, 119))	('increased', 'PosReg', (69, 78))	('amplification', 'Var', (29, 42))	('p110alpha', 'Gene', '5290', (110, 119))	('Akt', 'Gene', '207', (188, 191))	('increased', 'PosReg', (153, 162))	('mTOR', 'Gene', '2475', (196, 200))	('Akt', 'Gene', (188, 191))	('mTOR', 'Gene', (196, 200))	('PIK3CA', 'Gene', (46, 52))
130949	27144065	Given the significant amplification of 3q26 in LSCCs specifically, it is crucial to understand the effects this amplification has on tumorigenesis whether PIK3CA or another nearby gene is the cause.	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('amplification', 'Var', (22, 35))	('PIK3CA', 'Gene', (155, 161))	('tumor', 'Disease', (133, 138))	('PIK3CA', 'Gene', '5290', (155, 161))
130957	27144065	However, contrasting the clear story of EGFR mutations in lung adenocarcinomas predicting sensitivity to EGFR-targeted therapies, there are still no biomarkers that predict response to cetuximab.	('lung adenocarcinomas', 'Disease', (58, 78))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (58, 78))	('mutations', 'Var', (45, 54))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (58, 78))	('EGFR', 'Gene', '1956', (105, 109))	('EGFR', 'Gene', '1956', (40, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (68, 77))	('EGFR', 'Gene', (40, 44))	('EGFR', 'Gene', (105, 109))	('cetuximab', 'Chemical', 'MESH:D000068818', (185, 194))
130959	27144065	On contrast to lung cancers where EGFR mutation is a common event, EGFR mutations are rare in HNSCCs (13/279, 4.7%), while amplifications have been reported to vary between 10%-30%.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('mutations', 'Var', (72, 81))	('lung cancers', 'Disease', 'MESH:D008175', (15, 27))	('EGFR', 'Gene', (34, 38))	('HNSCCs', 'Disease', (94, 100))	('lung cancers', 'Phenotype', 'HP:0100526', (15, 27))	('HNSCC', 'Phenotype', 'HP:0012288', (94, 99))	('cancers', 'Phenotype', 'HP:0002664', (20, 27))	('EGFR', 'Gene', '1956', (67, 71))	('EGFR', 'Gene', (67, 71))	('lung cancers', 'Disease', (15, 27))	('EGFR', 'Gene', '1956', (34, 38))	('lung cancer', 'Phenotype', 'HP:0100526', (15, 26))
130960	27144065	However, amplification of EGFR correlated with worse overall survival in LSCCs specifically.	('EGFR', 'Gene', (26, 30))	('amplification', 'Var', (9, 22))	('overall survival', 'MPA', (53, 69))	('LSCCs', 'Disease', (73, 78))	('EGFR', 'Gene', '1956', (26, 30))	('worse', 'NegReg', (47, 52))
130968	27144065	However, solid tumors such as lung squamous cell carcinoma, cutaneous squamous cell carcinoma, and HNSCC display loss-of-function mutations indicative of Notch signaling has playing a role as a tumor suppressor.	('solid tumors', 'Disease', 'MESH:D009369', (9, 21))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('HNSCC', 'Gene', (99, 104))	('tumor', 'Disease', (194, 199))	('HNSCC', 'Phenotype', 'HP:0012288', (99, 104))	('Notch', 'Gene', '4851;18128;4853;4854;4855', (154, 159))	('loss-of-function', 'NegReg', (113, 129))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('Notch', 'Gene', (154, 159))	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (70, 93))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (30, 58))	('cutaneous squamous cell carcinoma', 'Phenotype', 'HP:0006739', (60, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('tumor', 'Disease', (15, 20))	('solid tumors', 'Disease', (9, 21))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (35, 58))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (30, 58))	('lung squamous cell carcinoma', 'Disease', (30, 58))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('cutaneous squamous cell carcinoma', 'Disease', (60, 93))	('mutations', 'Var', (130, 139))	('cutaneous squamous cell carcinoma', 'Disease', 'MESH:D002294', (60, 93))
130971	27144065	In keratinocytes, it has been shown that Notch activity controls cell cycle exit as well as commitment to differentiation, where loss of NOTCH1 promotes tumorigenesis.	('commitment to differentiation', 'CPA', (92, 121))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('Notch', 'Gene', '4851;18128;4853;4854;4855', (41, 46))	('cell cycle exit', 'CPA', (65, 80))	('promotes', 'PosReg', (144, 152))	('Notch', 'Gene', (41, 46))	('tumor', 'Disease', (153, 158))	('loss', 'Var', (129, 133))	('NOTCH1', 'Gene', (137, 143))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))
130974	27144065	Indeed, the PORCN inhibitor (this gene palmitoylates WNT ligands enabling their secretion into the tumor niche) called WNT974 has shown inhibition of growth of HNSCC models with loss-of-function mutations in NOTCH1.	('tumor', 'Disease', (99, 104))	('NOTCH1', 'Gene', (208, 214))	('PORCN', 'Gene', '64840', (12, 17))	('loss-of-function', 'NegReg', (178, 194))	('growth', 'MPA', (150, 156))	('inhibition', 'NegReg', (136, 146))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('HNSCC', 'Disease', (160, 165))	('mutations', 'Var', (195, 204))	('HNSCC', 'Phenotype', 'HP:0012288', (160, 165))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('PORCN', 'Gene', (12, 17))
130976	27144065	As 17% of LSCCs contained mutations in NOTCH1, WNT974 is a potential targeted therapeutic that will be evaluated for further clinical advancement.	('NOTCH1', 'Gene', (39, 45))	('contained', 'Reg', (16, 25))	('clinical', 'Species', '191496', (125, 133))	('mutations', 'Var', (26, 35))	('LSCCs', 'Disease', (10, 15))
130983	27144065	The amplification or gain of 11q13, which contains CCND1, is a frequent event in LSCCs specifically (36.1%, Table 2).	('gain', 'PosReg', (21, 25))	('CCND1', 'Gene', (51, 56))	('LSCCs', 'Disease', (81, 86))	('CCND1', 'Gene', '595', (51, 56))	('amplification', 'Var', (4, 17))
130984	27144065	Importantly, high expression of cyclin D1 correlated with increased risk of death in advanced LSCC patients.	('high', 'Var', (13, 17))	('cyclin D1', 'Gene', '595', (32, 41))	('cyclin D1', 'Gene', (32, 41))	('patients', 'Species', '9606', (99, 107))	('death', 'Disease', 'MESH:D003643', (76, 81))	('LSCC', 'Disease', (94, 98))	('death', 'Disease', (76, 81))
130986	27144065	Currently, multiple clinical trials investigating CDK4/6 inhibitors in HNSCC are underway, and some of these inhibitors such as palbociclib have already shown efficacy in other cancers.	('inhibitors', 'Var', (57, 67))	('cancers', 'Disease', 'MESH:D009369', (177, 184))	('cancers', 'Phenotype', 'HP:0002664', (177, 184))	('cancers', 'Disease', (177, 184))	('CDK4/6', 'Protein', (50, 56))	('HNSCC', 'Disease', (71, 76))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('HNSCC', 'Phenotype', 'HP:0012288', (71, 76))	('clinical', 'Species', '191496', (20, 28))
131005	27144065	These include neoadjuvant vaccine administration (NCT02002182, NCT02609386), concomitant cetuximab and ipilimumab with intensity modulated radiation therapy (IMRT) (NCT01860430), and addition of nivolumab to concomitant cisplatin and IMRT (RTOG3504).	('cisplatin', 'Chemical', 'MESH:D002945', (220, 229))	('ipilimumab', 'Chemical', 'MESH:D000074324', (103, 113))	('NCT02002182', 'Var', (50, 61))	('nivolumab', 'Chemical', 'MESH:D000077594', (195, 204))	('cetuximab', 'Chemical', 'MESH:D000068818', (89, 98))	('NCT01860430', 'Var', (165, 176))
131038	27144065	U01DE025184 and P30: CA046592 S1).	('U01', 'CellLine', 'CVCL:2220', (0, 3))	('P30', 'Gene', (16, 19))	('U01DE025184', 'Var', (0, 11))	('P30', 'Gene', '201161', (16, 19))
131098	32902917	We also found that patients with high immune scores had longer survival time than did patients in the low immune score group (Figure S2, P = .0125).	('patients', 'Species', '9606', (19, 27))	('survival time', 'CPA', (63, 76))	('low immune score', 'Phenotype', 'HP:0002721', (102, 118))	('longer', 'PosReg', (56, 62))	('high immune scores', 'Var', (33, 51))	('patients', 'Species', '9606', (86, 94))
131100	32902917	SKCM is believed to be mostly driven by functionally based mutations of BRAF.	('SKCM', 'Disease', (0, 4))	('BRAF', 'Gene', (72, 76))	('BRAF', 'Gene', '673', (72, 76))	('mutations', 'Var', (59, 68))
131101	32902917	26  In our assessments, we found that both immune and stromal scores were relatively higher in such types of BRAF mutants (Figure 2A).	('mutants', 'Var', (114, 121))	('BRAF', 'Gene', '673', (109, 113))	('BRAF', 'Gene', (109, 113))	('higher', 'PosReg', (85, 91))
131113	32902917	Moreover, gene alteration in UBE2L6, PARP14, IFIH1, IRF2, and GBP4 were found to have occurred in only 1.4%, 4%, 4%, 4%, and 2.1% of sequenced cases respectively for data acquired from the OncoPrint schematic of cBioPortal (Figure 5C).	('UBE2L6', 'Gene', (29, 35))	('UBE2L6', 'Gene', '9246', (29, 35))	('gene alteration', 'Var', (10, 25))	('IRF2', 'Gene', (52, 56))	('PARP14', 'Gene', '54625', (37, 43))	('GBP4', 'Gene', (62, 66))	('IRF2', 'Gene', '3660', (52, 56))	('IFIH1', 'Gene', '64135', (45, 50))	('IFIH1', 'Gene', (45, 50))	('PARP14', 'Gene', (37, 43))	('GBP4', 'Gene', '115361', (62, 66))
131122	32902917	To validate the ability of the prognostic signature to predict immunotherapeutic benefits, we assigned 27 patients treated with PD-1 inhibitors in the GSE78220 cohort to high- and low-risk subgroups.	('inhibitors', 'Var', (133, 143))	('PD-1', 'Gene', (128, 132))	('PD-1', 'Gene', '5133', (128, 132))	('patients', 'Species', '9606', (106, 114))
131177	33123473	Compelling evidence has proven the critical role of lncRNAs in the occurrence and development of HNSCC by means of epigenetic modifications, regulation of gene transcription, and post-transcription level.	('ncRNA', 'Gene', (53, 58))	('HNSCC', 'Phenotype', 'HP:0012288', (97, 102))	('HNSCC', 'Disease', (97, 102))	('ncRNA', 'Gene', '54719', (53, 58))	('epigenetic modifications', 'Var', (115, 139))
131184	33123473	Mountains of evidence highlight the irreplaceable role of long non-coding RNA (lncRNA) in cancer metastasis, including HNSCC.	('long non-coding', 'Var', (58, 73))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('ncRNA', 'Gene', '54719', (80, 85))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('HNSCC', 'Phenotype', 'HP:0012288', (119, 124))	('cancer', 'Disease', (90, 96))	('HNSCC', 'Disease', (119, 124))	('ncRNA', 'Gene', (80, 85))
131201	33123473	Moreover, knocking down HOTAIR expression levels globally inhibits cell proliferation, migration, and invasion.	('migration', 'CPA', (87, 96))	('knocking down', 'Var', (10, 23))	('inhibits', 'NegReg', (58, 66))	('invasion', 'CPA', (102, 110))	('HOTAIR', 'Gene', (24, 30))	('cell proliferation', 'CPA', (67, 85))	('HOTAIR', 'Gene', '100124700', (24, 30))
131218	33123473	Mechanistically, Wu T. and colleagues report that H19 is overexpressed in laryngeal squamous cell carcinoma (LSCC) and accelerates LSCC tumor progression through miR-148a-3p attenuation and DNMT1 enhancement.	('DNMT1', 'Gene', (190, 195))	('miR-148a-3p', 'Var', (162, 173))	('DNMT1', 'Gene', '1786', (190, 195))	('accelerates', 'PosReg', (119, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('H19', 'Gene', '283120', (50, 53))	('attenuation', 'NegReg', (174, 185))	('H19', 'Gene', (50, 53))	('overexpressed', 'PosReg', (57, 70))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (84, 107))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (84, 107))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('squamous cell carcinoma', 'Disease', (84, 107))	('enhancement', 'PosReg', (196, 207))	('tumor', 'Disease', (136, 141))	('LSCC', 'Disease', (131, 135))
131234	33123473	MALAT1 knockdown significantly suppressed the expression levels of N-cadherin and Vimentin, but raised E-cadherin in vitro.	('Vimentin', 'Gene', '7431', (82, 90))	('MALAT1', 'Gene', '378938', (0, 6))	('E-cadherin', 'Gene', (103, 113))	('MALAT1', 'Gene', (0, 6))	('expression levels', 'MPA', (46, 63))	('Vimentin', 'Gene', (82, 90))	('suppressed', 'NegReg', (31, 41))	('N-cadherin', 'Gene', (67, 77))	('knockdown', 'Var', (7, 16))	('raised', 'PosReg', (96, 102))	('E-cadherin', 'Gene', '999', (103, 113))	('N-cadherin', 'Gene', '1000', (67, 77))
131236	33123473	It is noteworthy that targeting MALAT1 globally inhibits the proliferation capacity of TSCCA-induced xenograft tumor, suggesting MALAT1 as an important prognostic factor of OSCC and a satisfactory target with therapeutic potential.	('MALAT1', 'Gene', (129, 135))	('xenograft tumor', 'Disease', (101, 116))	('TSCC', 'Phenotype', 'HP:0030413', (87, 91))	('proliferation capacity', 'CPA', (61, 83))	('inhibits', 'NegReg', (48, 56))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('targeting', 'Var', (22, 31))	('xenograft tumor', 'Disease', 'MESH:D009369', (101, 116))	('MALAT1', 'Gene', '378938', (32, 38))	('TSCCA', 'Chemical', '-', (87, 92))	('OSCC', 'Disease', (173, 177))	('MALAT1', 'Gene', '378938', (129, 135))	('MALAT1', 'Gene', (32, 38))
131240	33123473	Meanwhile, HOTAIR is validated to trigger E-cadherin silencing through the recruitment of EZH2 and H3K27me3 in the promoter region of E-cadherin, indicating that HOTAIR might regulate OSCC metastasis in an epigenetic manner.	('HOTAIR', 'Gene', '100124700', (11, 17))	('HOTAIR', 'Gene', (162, 168))	('OSCC', 'Disease', (184, 188))	('silencing', 'NegReg', (53, 62))	('E-cadherin', 'Gene', (134, 144))	('regulate', 'Reg', (175, 183))	('H3K27me3', 'Var', (99, 107))	('E-cadherin', 'Gene', '999', (134, 144))	('EZH2', 'Gene', '2146', (90, 94))	('HOTAIR', 'Gene', '100124700', (162, 168))	('E-cadherin', 'Gene', (42, 52))	('E-cadherin', 'Gene', '999', (42, 52))	('HOTAIR', 'Gene', (11, 17))	('EZH2', 'Gene', (90, 94))
131242	33123473	Subsequently, H19 attenuation significantly suppresses cell motility in vitro through activation of beta-Catenin/GSK3beta/E-cadherin signaling.	('attenuation', 'Var', (18, 29))	('H19', 'Gene', '283120', (14, 17))	('H19', 'Gene', (14, 17))	('suppresses', 'NegReg', (44, 54))	('E-cadherin', 'Gene', (122, 132))	('E-cadherin', 'Gene', '999', (122, 132))	('GSK3beta', 'Gene', (113, 121))	('GSK3beta', 'Gene', '2931', (113, 121))	('beta-Catenin', 'Gene', (100, 112))	('cell motility in vitro', 'CPA', (55, 77))	('beta-Catenin', 'Gene', '1499', (100, 112))	('activation', 'PosReg', (86, 96))
131243	33123473	In addition, animal models show that H19 inhibition significantly impairs tumor progression and lung metastasis.	('impairs tumor', 'Disease', 'MESH:D060825', (66, 79))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('inhibition', 'Var', (41, 51))	('impairs tumor', 'Disease', (66, 79))	('H19', 'Gene', (37, 40))	('lung metastasis', 'CPA', (96, 111))	('H19', 'Gene', '283120', (37, 40))
131250	33123473	Similarly, the recruitment of miR-30a also reduces the stability of MALAT1 in HNSCC in order to inhibit the invasion capacity of tumor cells.	('miR-30a', 'Gene', (30, 37))	('MALAT1', 'Gene', (68, 74))	('tumor', 'Disease', (129, 134))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('miR-30a', 'Gene', '407029', (30, 37))	('stability', 'MPA', (55, 64))	('MALAT1', 'Gene', '378938', (68, 74))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('HNSCC', 'Phenotype', 'HP:0012288', (78, 83))	('recruitment', 'Var', (15, 26))	('inhibit', 'NegReg', (96, 103))	('reduces', 'NegReg', (43, 50))
131251	33123473	Additionally, MALAT1 knockdown is also seen to completely suppress tumor progression through miR-140-5p elevation and PAK1 inhibition, both in vitro and in TSCC-induced xenograft tumors.	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('tumor', 'Disease', (67, 72))	('knockdown', 'Var', (21, 30))	('xenograft tumors', 'Disease', (169, 185))	('suppress', 'NegReg', (58, 66))	('xenograft tumors', 'Disease', 'MESH:D009369', (169, 185))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('tumors', 'Phenotype', 'HP:0002664', (179, 185))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('MALAT1', 'Gene', (14, 20))	('inhibition', 'NegReg', (123, 133))	('elevation', 'PosReg', (104, 113))	('MALAT1', 'Gene', '378938', (14, 20))	('PAK1', 'Gene', (118, 122))	('miR-140', 'Gene', (93, 100))	('TSCC', 'Phenotype', 'HP:0030413', (156, 160))	('TSCC', 'Chemical', '-', (156, 160))	('PAK1', 'Gene', '5058', (118, 122))	('miR-140', 'Gene', '406932', (93, 100))	('tumor', 'Disease', (179, 184))
131312	32757102	The p40 antibody recognizes DeltaNP63, an isoform of p63, and DeltaNP63 has been suggested to be highly specific for squamous/basal cells.	('DeltaNP63', 'Var', (62, 71))	('p40', 'Gene', (4, 7))	('p63', 'Gene', '8626', (53, 56))	('squamous/basal', 'Disease', (117, 131))	('p40', 'Gene', '8626', (4, 7))	('DeltaNP63', 'Var', (28, 37))	('p63', 'Gene', (53, 56))
131341	29871649	Notably, the gene regulatory networks orchestrated by enhancer methylation across different cancer types are seen to converge on a common architecture.	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('methylation', 'Var', (63, 74))	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))
131343	29871649	Some genes have been verified to be regulated by aberrant promoter methylation with a causal effect on tumorigenesis, including CDKN2B, CDKN2A, RB, APC, BRCA1, and MLH1.	('CDKN2B', 'Gene', (128, 134))	('APC', 'Disease', (148, 151))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('effect', 'Reg', (93, 99))	('tumor', 'Disease', (103, 108))	('regulated', 'Reg', (36, 45))	('aberrant promoter methylation', 'Var', (49, 78))	('CDKN2B', 'Gene', '1030', (128, 134))	('BRCA1', 'Gene', '672', (153, 158))	('MLH1', 'Gene', (164, 168))	('CDKN2A', 'Gene', (136, 142))	('CDKN2A', 'Gene', '1029', (136, 142))	('MLH1', 'Gene', '4292', (164, 168))	('BRCA', 'Phenotype', 'HP:0003002', (153, 157))	('BRCA1', 'Gene', (153, 158))	('APC', 'Disease', 'MESH:D011125', (148, 151))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
131348	29871649	To identify the subset that are causal, we need solutions that enable us to: (1) genome-wide identify causal DNA methylation of enhancers and its gene targets in pan-cancers in an unbiased manner; and (2) directly validate a specific methylation event on the putative enhancer by experimentation.	('cancers', 'Disease', (166, 173))	('cancers', 'Disease', 'MESH:D009369', (166, 173))	('methylation', 'Var', (113, 124))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('cancers', 'Phenotype', 'HP:0002664', (166, 173))
131350	29871649	In this study, we designed a set of tools for identifying genome-wide DNA methylation of distal regulatory sites that result in a causal effect on tumorigenesis.	('DNA methylation', 'Var', (70, 85))	('tumor', 'Disease', (147, 152))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('effect', 'Reg', (137, 143))
131353	29871649	Our strategy recovered many known enhancers and unannotated regulatory sites from different cancer types, differential methylation of which regulated known or novel tumor-suppressor/oncogene with causal effect on cell malignancy and patient survival.	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('patient', 'Species', '9606', (233, 240))	('methylation', 'Var', (119, 130))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('malignancy', 'Disease', 'MESH:D009369', (218, 228))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('malignancy', 'Disease', (218, 228))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('tumor', 'Disease', (165, 170))
131364	29871649	We then compared both negatively and positively correlated DREs for the enrichment of active chromatin marks (H3K27ac, H3K4me1, p300, and DNase I hypersensitivity) and repressive marks (H3K9me3 and H3K27me3).	('hypersensitivity)', 'Disease', 'MESH:D004342', (146, 163))	('H3K9me3', 'Var', (186, 193))	('H3K27me3', 'Var', (198, 206))	('H3K27ac', 'Var', (110, 117))	('p300', 'Gene', (128, 132))	('H3K4me1', 'Var', (119, 126))	('p300', 'Gene', '2033', (128, 132))
131370	29871649	Remarkably, targeting DNMT3A-3 L to the region near cg02935351 downregulated WNT5B, while targeting TET1 to this region produced similar results to treatment with the global DNA methylation inhibitor, 5-AZA, and upregulated WNT5B (Fig.	('WNT5B', 'Gene', '81029', (77, 82))	('WNT5B', 'Gene', (77, 82))	('DNMT3A', 'Gene', (22, 28))	('DNMT3A', 'Gene', '1788', (22, 28))	('TET1', 'Gene', '80312', (100, 104))	('upregulated', 'PosReg', (212, 223))	('downregulated', 'NegReg', (63, 76))	('WNT5B', 'Gene', '81029', (224, 229))	('cg02935351', 'Var', (52, 62))	('WNT5B', 'Gene', (224, 229))	('5-AZA', 'Chemical', 'MESH:D001374', (201, 206))	('TET1', 'Gene', (100, 104))
131375	29871649	In addition, we verified several other genes, including MLEC, LLGL2, CDCA5, MEN1, CLDN7, SOX9, and FGFR1 by epigenetic modulation of distal DREs followed by quantitative polymerase chain reaction (qPCR), migration assay, and luciferase reporter assay (Fig.	('CLDN7', 'Gene', '1366', (82, 87))	('LLGL2', 'Gene', '3993', (62, 67))	('epigenetic modulation', 'Var', (108, 129))	('SOX9', 'Gene', (89, 93))	('FGFR1', 'Gene', (99, 104))	('CDCA5', 'Gene', (69, 74))	('MLEC', 'Gene', '9761', (56, 60))	('MEN1', 'Gene', (76, 80))	('SOX9', 'Gene', '6662', (89, 93))	('MEN1', 'Gene', '4221', (76, 80))	('FGFR1', 'Gene', '2260', (99, 104))	('CLDN7', 'Gene', (82, 87))	('LLGL2', 'Gene', (62, 67))	('CDCA5', 'Gene', '113130', (69, 74))	('MLEC', 'Gene', (56, 60))
131377	29871649	1, MICMIC predicted a distal DRE for CDCA5, cg02933228, which is > 240 kb away from the TSS of CDCA5 (Fig.	('CDCA5', 'Gene', (95, 100))	('CDCA5', 'Gene', '113130', (37, 42))	('cg02933228', 'Chemical', '-', (44, 54))	('CDCA5', 'Gene', '113130', (95, 100))	('cg02933228', 'Var', (44, 54))	('CDCA5', 'Gene', (37, 42))
131378	29871649	This same distal DRE, cg02933228, was also predicted to control the gene MEN1, which we were also able to experimentally confirm.	('cg02933228', 'Chemical', '-', (22, 32))	('MEN1', 'Gene', (73, 77))	('MEN1', 'Gene', '4221', (73, 77))	('cg02933228', 'Var', (22, 32))	('control', 'Reg', (56, 63))
131383	29871649	As expected, targeted methylation with DNMT3A-3 L to the cg03190578 region decreased HDAC11 expression, while targeted demethylation with TET1 dramatically increased HDAC11 expression (Fig.	('DNMT3A', 'Gene', (39, 45))	('TET1', 'Gene', (138, 142))	('DNMT3A', 'Gene', '1788', (39, 45))	('HDAC11', 'Gene', '79885', (85, 91))	('cg03190578', 'Chemical', '-', (57, 67))	('increased', 'PosReg', (156, 165))	('HDAC11', 'Gene', (166, 172))	('expression', 'MPA', (92, 102))	('HDAC11', 'Gene', (85, 91))	('TET1', 'Gene', '80312', (138, 142))	('expression', 'MPA', (173, 183))	('HDAC11', 'Gene', '79885', (166, 172))	('methylation', 'Var', (22, 33))	('decreased', 'NegReg', (75, 84))
131384	29871649	Consequently, we found that modulation of DNA methylation on the distal DRE, cg03190578, by dcas9-DNMT3A-3 L significantly decreased cancer cell migration suggesting an oncogenic function for HDAC11 in liver cancer, which was confirmed by increased cell migration upon overexpression of HDAC11 (Fig.	('cancer', 'Disease', (208, 214))	('modulation', 'Var', (28, 38))	('liver cancer', 'Disease', 'MESH:D006528', (202, 214))	('decreased', 'NegReg', (123, 132))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('DNMT3A', 'Gene', '1788', (98, 104))	('cell migration', 'CPA', (249, 263))	('HDAC11', 'Gene', '79885', (287, 293))	('liver cancer', 'Phenotype', 'HP:0002896', (202, 214))	('HDAC11', 'Gene', '79885', (192, 198))	('liver cancer', 'Disease', (202, 214))	('cancer', 'Disease', 'MESH:D009369', (208, 214))	('DNMT3A', 'Gene', (98, 104))	('HDAC11', 'Gene', (287, 293))	('cancer', 'Disease', (133, 139))	('increased', 'PosReg', (239, 248))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('HDAC11', 'Gene', (192, 198))	('cg03190578', 'Chemical', '-', (77, 87))
131387	29871649	APOA1 shared cg23193059 with APOC3 and CDT1 shared cg20283771 with CBFA2T3.	('APOA1', 'Gene', (0, 5))	('cg20283771', 'Chemical', '-', (51, 61))	('CBFA2T3', 'Gene', '863', (67, 74))	('APOC3', 'Gene', '345', (29, 34))	('CDT1', 'Gene', '81620', (39, 43))	('APOC3', 'Gene', (29, 34))	('APOA1', 'Gene', '335', (0, 5))	('CBFA2T3', 'Gene', (67, 74))	('cg20283771', 'Var', (51, 61))	('CDT1', 'Gene', (39, 43))	('cg23193059', 'Var', (13, 23))
131389	29871649	Both genes were verified to be causally regulated by methylation of cg20283771 with combined effect on cancer cell migration after dCas9-DNMT3A-3 L targeting (Fig.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('cg20283771', 'Gene', (68, 78))	('effect', 'Reg', (93, 99))	('DNMT3A', 'Gene', '1788', (137, 143))	('DNMT3A', 'Gene', (137, 143))	('cg20283771', 'Chemical', '-', (68, 78))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('methylation', 'Var', (53, 64))
131396	29871649	5a inset), suggesting that hypermethylated distal DREs from the negative-down group in conjunction with the decreased expression of the cognate tissue-specific TFs, lead to downregulation of its distal gene targets in cancer.	('cancer', 'Disease', 'MESH:D009369', (218, 224))	('cancer', 'Disease', (218, 224))	('hypermethylated', 'Var', (27, 42))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('downregulation', 'NegReg', (173, 187))
131398	29871649	For distal DREs positively correlated with its targets, we found significant enrichment of TFs with repressor activity (p value = 8e-7), suggesting that DNA methylation may affect the binding of TF repressors with implications in tumorigenesis (Additional file 1: Figure S14).	('tumor', 'Disease', (230, 235))	('DNA', 'Var', (153, 156))	('affect', 'Reg', (173, 179))	('methylation', 'Var', (157, 168))	('tumor', 'Disease', 'MESH:D009369', (230, 235))	('implications', 'Reg', (214, 226))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))	('binding', 'Interaction', (184, 191))
131400	29871649	We identified 1081 DRE methylation correlated with patient survival (q-value < 0.1, FDR by BH procedure) in bladder cancer (BLCA), breast cancer (BRCA), head and neck carcinoma (HNSC), liver cancer (LIHC), lung cancer (LUAD), and uterine corpus endometrial cancer (UCEC).	('BRCA', 'Phenotype', 'HP:0003002', (146, 150))	('cancer', 'Phenotype', 'HP:0002664', (257, 263))	('lung cancer', 'Disease', (206, 217))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('carcinoma', 'Phenotype', 'HP:0030731', (167, 176))	('correlated', 'Reg', (35, 45))	('methylation', 'Var', (23, 34))	('BRCA', 'Gene', '672', (146, 150))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('LIHC', 'Disease', (199, 203))	('breast cancer', 'Phenotype', 'HP:0003002', (131, 144))	('neck carcinoma (HNSC), liver cancer', 'Disease', 'MESH:D006528', (162, 197))	('lung cancer', 'Disease', 'MESH:D008175', (206, 217))	('liver cancer', 'Phenotype', 'HP:0002896', (185, 197))	('BRCA', 'Gene', (146, 150))	('lung cancer', 'Phenotype', 'HP:0100526', (206, 217))	('breast cancer', 'Disease', 'MESH:D001943', (131, 144))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('breast cancer', 'Disease', (131, 144))	('LIHC', 'Disease', 'None', (199, 203))	('bladder cancer', 'Disease', 'MESH:D001749', (108, 122))	('bladder cancer', 'Disease', (108, 122))	('LUAD', 'Phenotype', 'HP:0030078', (219, 223))	('1081', 'Var', (14, 18))	('bladder cancer', 'Phenotype', 'HP:0009725', (108, 122))	('endometrial cancer', 'Phenotype', 'HP:0012114', (245, 263))	('patient', 'Species', '9606', (51, 58))	('BLCA', 'Phenotype', 'HP:0009725', (124, 128))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('corpus endometrial cancer', 'Disease', 'MESH:D016889', (238, 263))	('corpus endometrial cancer', 'Disease', (238, 263))
131401	29871649	We then calculated the number of master cancer genes (via MRA) that are regulated by DNA methylation of the promoter or distal DREs and used the density distribution to quantify the effect that methylation of those DREs have on tumorigenesis (Fig.	('methylation', 'Var', (194, 205))	('tumor', 'Disease', 'MESH:D009369', (228, 233))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('master cancer', 'Disease', (33, 46))	('tumor', 'Disease', (228, 233))	('master cancer', 'Disease', 'MESH:D009369', (33, 46))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))
131418	29871649	In this study, we aimed to identify DNA methylation of distal regulatory regions with causal effects on tumorigenesis.	('methylation', 'Var', (40, 51))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('effects', 'Reg', (93, 100))	('tumor', 'Disease', (104, 109))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
131425	29871649	For instance, we can increase or decrease the DNA methylation level of the same DRE site in AGS cell line by dCas9 targeting, and consequentially change the gene expression level in both directions, upregulation or downregulation.	('gene expression level', 'MPA', (157, 178))	('decrease', 'NegReg', (33, 41))	('downregulation', 'NegReg', (215, 229))	('AGS', 'Disease', (92, 95))	('AGS', 'Disease', 'MESH:C535607', (92, 95))	('DNA methylation level', 'MPA', (46, 67))	('upregulation', 'PosReg', (199, 211))	('change', 'Reg', (146, 152))	('targeting', 'Var', (115, 124))	('dCas9', 'Gene', (109, 114))	('increase', 'PosReg', (21, 29))
131426	29871649	As shown above, both oncogene CDCA5 and tumor-suppressor MEN1 were verified to be regulated by the same distal DRE cg02933228.	('cg02933228', 'Var', (115, 125))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('CDCA5', 'Gene', '113130', (30, 35))	('MEN1', 'Gene', (57, 61))	('cg02933228', 'Chemical', '-', (115, 125))	('MEN1', 'Gene', '4221', (57, 61))	('tumor', 'Disease', (40, 45))	('CDCA5', 'Gene', (30, 35))
131427	29871649	However, the decreased cell migration phenotype after dCas9-DNMT3A-3 L targeting of cg02933228 was only consistent with CDCA5's function prediction.	('CDCA5', 'Gene', (120, 125))	('decreased', 'NegReg', (13, 22))	('cell migration phenotype', 'CPA', (23, 47))	('cg02933228', 'Var', (84, 94))	('DNMT3A', 'Gene', (60, 66))	('DNMT3A', 'Gene', '1788', (60, 66))	('CDCA5', 'Gene', '113130', (120, 125))	('cg02933228', 'Chemical', '-', (84, 94))
131430	29871649	Furthermore, we showed that the network topology of GRN derived from DNA methylation of distal DREs may have the same architecture across different cancer types, enriched for network motifs like "feed forwards loop," "regulated mutual," and "regulating mutual."	('cancer', 'Disease', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('regulated mutual', 'MPA', (218, 234))	('regulating mutual', 'MPA', (242, 259))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('methylation', 'Var', (73, 84))
131433	29871649	Our study reveals the prevalent regulation of genome-wide putative enhancers by DNA-methylation with causal effect on cellular malignancy and patient survival.	('malignancy', 'Disease', 'MESH:D009369', (127, 137))	('DNA-methylation', 'Var', (80, 95))	('malignancy', 'Disease', (127, 137))	('patient', 'Species', '9606', (142, 149))	('enhancers', 'PosReg', (67, 76))
131446	29871649	We downloaded chromatin marks including histone modifications of H3K4me1, H3K4me3, H3K9me3, H3K27me3, H3K27ac, and p300 ChIP-seq signals to evaluate the enhancer activity of distal DREs, from breast cancer cells (MCF-7), colon cancer cells (HCT116), cervical cancer cells (HeLa-S3), liver cancer cells (HepG2), and lung cancer cells (A549).	('breast cancer', 'Disease', 'MESH:D001943', (192, 205))	('A549', 'CellLine', 'CVCL:0023', (334, 338))	('p300', 'Gene', '2033', (115, 119))	('colon cancer', 'Disease', (221, 233))	('breast cancer', 'Disease', (192, 205))	('cancer', 'Phenotype', 'HP:0002664', (289, 295))	('HeLa', 'CellLine', 'CVCL:0030', (273, 277))	('HCT116', 'CellLine', 'CVCL:0291', (241, 247))	('cancer', 'Phenotype', 'HP:0002664', (320, 326))	('liver cancer', 'Phenotype', 'HP:0002896', (283, 295))	('liver cancer', 'Disease', (283, 295))	('lung cancer', 'Disease', (315, 326))	('HepG2', 'CellLine', 'CVCL:0027', (303, 308))	('MCF-7', 'CellLine', 'CVCL:0031', (213, 218))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('colon cancer', 'Phenotype', 'HP:0003003', (221, 233))	('cervical cancer', 'Disease', 'MESH:D002583', (250, 265))	('cervical cancer', 'Disease', (250, 265))	('cancer', 'Phenotype', 'HP:0002664', (259, 265))	('lung cancer', 'Disease', 'MESH:D008175', (315, 326))	('colon cancer', 'Disease', 'MESH:D015179', (221, 233))	('lung cancer', 'Phenotype', 'HP:0100526', (315, 326))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('breast cancer', 'Phenotype', 'HP:0003002', (192, 205))	('p300', 'Gene', (115, 119))	('liver cancer', 'Disease', 'MESH:D006528', (283, 295))	('H3K27ac', 'Var', (102, 109))
131470	29871649	For dCas9-TET1 targeting, we used these plasmids: pCAG-dCas9-5xPlat2AflD and pCAG-scFvGCN4sfGFPTET1CD (Addgene plasmid #82560 and #82561, gifts from Izuho Hatada).	('scFv', 'Gene', (82, 86))	('TET1', 'Gene', '80312', (95, 99))	('TET1', 'Gene', '80312', (10, 14))	('#82561', 'Var', (130, 136))	('TET1', 'Gene', (95, 99))	('TET1', 'Gene', (10, 14))	('scFv', 'Gene', '652070', (82, 86))
131471	29871649	We generated catalytically inactive TET1 with H1671Y and D1673A mutations with primers: Tet1-muH1671-Forward, TCC CTA CAG GGC CAT TCA CAA CAT GAA TAA TGG AAG CAC TG; and Tet1-muH1671-Reverse, AAT GGC CCT GTA GGG ATG AGC ACA GAA GTC CAG, with sequencing confirmation.	('Tet1', 'Gene', '80312', (170, 174))	('Tet1', 'Gene', (170, 174))	('D1673A', 'Mutation', 'p.D1673A', (57, 63))	('H1671Y', 'Mutation', 'p.H1671Y', (46, 52))	('TET1', 'Gene', (36, 40))	('Tet1', 'Gene', '80312', (88, 92))	('H1671Y', 'Var', (46, 52))	('Tet1', 'Gene', (88, 92))	('TET1', 'Gene', '80312', (36, 40))	('D1673A', 'Var', (57, 63))
131480	29871649	For these "untargeted," catalytically active DNMT3A-3 L/TET1 was overexpressed but targeted to nowhere due to the deletion of "linker" domain.	('TET1', 'Gene', (56, 60))	('DNMT3A', 'Gene', (45, 51))	('DNMT3A', 'Gene', '1788', (45, 51))	('TET1', 'Gene', '80312', (56, 60))	('deletion', 'Var', (114, 122))
131486	29871649	AGS, BEL-7402, and PLC8024 cell lines were treated with 10 muM 5-aza-dC (Sigma-Aldrich) for 48 h, followed by RNA purification and qRT-PCR as described.	('BEL-7402', 'CellLine', 'CVCL:5492', (5, 13))	('5-aza-dC', 'Var', (63, 71))	('AGS', 'Disease', (0, 3))	('AGS', 'Disease', 'MESH:C535607', (0, 3))	('5-aza', 'Chemical', 'MESH:D001374', (63, 68))
131489	29871649	We searched the AmiGO database with the key words "transcription repressor" and "negative regulation" to obtain a list of genes related to the transcriptional repression process and collected the repressor information from GO:0017053, GO:0090571, GO:0001206, GO:0001227, GO:0001191, GO:0000900, GO:0070491, GO:0070176, GO:0003714,GO:0032785, GO:2000143, GO:1903507, and GO:0001078.	('GO:2000143', 'Var', (342, 352))	('GO:0017053', 'Var', (223, 233))	('GO:0000900', 'Var', (283, 293))	('GO:0001191', 'Var', (271, 281))	('GO:0001206', 'Var', (247, 257))	('GO:0070176', 'Var', (307, 317))	('GO:1903507', 'Var', (354, 364))	('GO:0001078', 'Var', (370, 380))	('AmiGO', 'Gene', (16, 21))	('AmiGO', 'Gene', '57463', (16, 21))	('GO:0070491', 'Var', (295, 305))	('GO:0001227', 'Var', (259, 269))	('GO:0003714', 'Var', (319, 329))	('GO:0090571', 'Var', (235, 245))	('GO:0032785', 'Var', (330, 340))
131509	28604730	Logistic regression was then used to assess the association between variants (n=10,439,017 SNPs) and lung cancer risk, as well as by predominant histological types and by smoking behavior (Online Methods).	('variants', 'Var', (68, 76))	('lung cancer', 'Disease', 'MESH:D008175', (101, 112))	('lung cancer', 'Phenotype', 'HP:0100526', (101, 112))	('lung cancer', 'Disease', (101, 112))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
131514	28604730	Table 2 presents summary results of all loci with sentinel variants (defined as the variant with the lowest P-value at each locus) that reached genome-wide significance (P-value < 5x10-8) for lung cancer overall and by histological subtypes.	('lung cancer', 'Disease', (192, 203))	('lung cancer', 'Phenotype', 'HP:0100526', (192, 203))	('variants', 'Var', (59, 67))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('lung cancer', 'Disease', 'MESH:D008175', (192, 203))
131518	28604730	Variants at 4 novel loci (1p31.1, 6q27, 8p21, 15q21.1) were associated with lung cancer risk overall, with little evidence for heterogeneity among subtypes (Supplementary Figure 4).	('lung cancer', 'Disease', 'MESH:D008175', (76, 87))	('Variants', 'Var', (0, 8))	('lung cancer', 'Disease', (76, 87))	('lung cancer', 'Phenotype', 'HP:0100526', (76, 87))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('associated with', 'Reg', (60, 75))
131519	28604730	The 1p31.1 locus, recently identified in a pathway-based analysis of the TRICL data, represented by rs71658797 (Odds Ratio [OR]=1.14, 95% Confidence Interval [CI] 1.09-1.18, P-value=3.25 x 10-11), is located near FUBP1/DNAJB4 (Supplementary Figure 4).	('FUBP1', 'Gene', '8880', (213, 218))	('TRICL', 'Chemical', '-', (73, 78))	('DNAJB4', 'Gene', (219, 225))	('FUBP1', 'Gene', (213, 218))	('rs71658797', 'Var', (100, 110))	('rs71658797', 'Mutation', 'rs71658797', (100, 110))	('DNAJB4', 'Gene', '11080', (219, 225))
131520	28604730	At 6q27, rs6920364 was associated with lung cancer risk with an OR of 1.07 (95% CI 1.04-1.09, P-value=2.9x10-8) with little heterogeneity found by smoking status (Supplementary Figure 4).	('lung cancer', 'Phenotype', 'HP:0100526', (39, 50))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('lung cancer', 'Disease', (39, 50))	('lung cancer', 'Disease', 'MESH:D008175', (39, 50))	('associated', 'Reg', (23, 33))	('rs6920364', 'Var', (9, 18))	('rs6920364', 'Mutation', 'rs6920364', (9, 18))
131522	28604730	We identified rs6920364 as a lung cis-eQTL for RNASET2, an extracellular ribonuclease, in all five cohorts tested (Supplementary Table 6), with increased lung cancer risk correlating with increased RNASET2 expression (Figure 2).	('lung cancer', 'Phenotype', 'HP:0100526', (154, 165))	('RNASET2', 'Gene', '8635', (198, 205))	('expression', 'MPA', (206, 216))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('RNASET2', 'Gene', '8635', (47, 54))	('rs6920364', 'Var', (14, 23))	('rs6920364', 'Mutation', 'rs6920364', (14, 23))	('RNASET2', 'Gene', (198, 205))	('increased lung cancer', 'Disease', 'MESH:D008175', (144, 165))	('RNASET2', 'Gene', (47, 54))	('increased', 'PosReg', (188, 197))	('increased lung cancer', 'Disease', (144, 165))
131523	28604730	Variants correlated with rs6920364 (r2>0.88) have been noted in GWAS of Crohn's disease and inflammatory bowel disease.	("Crohn's disease", 'Phenotype', 'HP:0100280', (72, 87))	('Variants', 'Var', (0, 8))	('inflammatory bowel disease', 'Disease', (92, 118))	('GWAS', 'Disease', (64, 68))	("Crohn's disease", 'Disease', 'MESH:D003424', (72, 87))	("Crohn's disease", 'Disease', (72, 87))	('rs6920364', 'Var', (25, 34))	('rs6920364', 'Mutation', 'rs6920364', (25, 34))	('inflammatory bowel disease', 'Phenotype', 'HP:0002037', (92, 118))	('inflammatory bowel disease', 'Disease', 'MESH:D015212', (92, 118))
131525	28604730	It is a complex locus represented by sentinel variant rs11780471 associated with lung cancer (OR=0.87, 95% CI 0.83-0.91, P-value=1.69x10-8) (Supplementary Figure 4), but this region contained additional uncorrelated variants (pairwise r2< 0.10) associated with lung cancer (Supplementary Table 8).	('lung cancer', 'Disease', (81, 92))	('lung cancer', 'Phenotype', 'HP:0100526', (81, 92))	('rs11780471', 'Var', (54, 64))	('lung cancer', 'Disease', (261, 272))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('lung cancer', 'Phenotype', 'HP:0100526', (261, 272))	('associated', 'Reg', (65, 75))	('lung cancer', 'Disease', 'MESH:D008175', (81, 92))	('cancer', 'Phenotype', 'HP:0002664', (266, 272))	('rs11780471', 'Mutation', 'rs11780471', (54, 64))	('lung cancer', 'Disease', 'MESH:D008175', (261, 272))
131526	28604730	In contrast to lung tissue (Figure 3A, Supplementary Table 6, Supplementary Figure 3), we noted that the alleles associated with lung cancer tended to be associated with cerebellum expression of CHRNA2, a member of the cholinergic nicotinic receptor (Figure 3B).	('cerebellum', 'Disease', (170, 180))	('lung cancer', 'Disease', (129, 140))	('lung cancer', 'Phenotype', 'HP:0100526', (129, 140))	('lung cancer', 'Disease', 'MESH:D008175', (129, 140))	('CHRNA2', 'Gene', (195, 201))	('CHRNA2', 'Gene', '1135', (195, 201))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('alleles', 'Var', (105, 112))	('associated', 'Reg', (154, 164))
131527	28604730	The CHRNA2 rs11780471 cis-eQTL effect in the brain was limited to the cerebellum (Figure 3C), a region not traditionally linked with addictive behavior, but where an emerging role is suggested.	('CHRNA2', 'Gene', (4, 10))	('CHRNA2', 'Gene', '1135', (4, 10))	('rs11780471', 'Mutation', 'rs11780471', (11, 21))	('rs11780471', 'Var', (11, 21))	('addictive behavior', 'Phenotype', 'HP:0030858', (133, 151))
131529	28604730	Unlike the well-described 15q25.1 (rs55781567) CHRNA5 locus (Table 2), rs11780471 was not associated with number of cigarettes smoked per day or the FTND metrics (Figure 3D).	('rs11780471', 'Var', (71, 81))	('CHRNA5', 'Gene', (47, 53))	('rs55781567', 'Mutation', 'rs55781567', (35, 45))	('rs11780471', 'Mutation', 'rs11780471', (71, 81))	('CHRNA5', 'Gene', '1138', (47, 53))
131530	28604730	Nevertheless, lung cancer risk allele carriers of rs11780471 tended to be smokers and initiated smoking at earlier ages (Figure 3D), implying that this variant's association with lung cancer could potentially be mediated via influencing aspects of smoking behavior.	('lung cancer', 'Disease', (179, 190))	('rs11780471', 'Var', (50, 60))	('lung cancer', 'Phenotype', 'HP:0100526', (179, 190))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('lung cancer', 'Disease', (14, 25))	('lung cancer', 'Phenotype', 'HP:0100526', (14, 25))	('initiated', 'Reg', (86, 95))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('lung cancer', 'Disease', 'MESH:D008175', (179, 190))	('rs11780471', 'Mutation', 'rs11780471', (50, 60))	('lung cancer', 'Disease', 'MESH:D008175', (14, 25))
131532	28604730	Although the sentinel variant is not an eQTL for EPHX2 in lung tissues, other associated variants in the region are (e.g.	('EPHX2', 'Gene', '2053', (49, 54))	('variants', 'Var', (89, 97))	('EPHX2', 'Gene', (49, 54))
131533	28604730	rs146729428, p-value of 1.77x10-7 (Supplementary Table 2) and 5 x 10-4 for lung cancer risk and eQTL, respectively).	('lung cancer', 'Disease', (75, 86))	('lung cancer', 'Phenotype', 'HP:0100526', (75, 86))	('rs146729428', 'Mutation', 'rs146729428', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('lung cancer', 'Disease', 'MESH:D008175', (75, 86))	('rs146729428', 'Var', (0, 11))
131535	28604730	The genetic locus at 15q21 (rs66759488) was shown to be associated with lung cancer (OR=1.07, 95% CI 1.04-1.10, p=2.83x10-8) overall and across lung cancer histologies (Supplementary Figure 4).	('rs66759488', 'Var', (28, 38))	('lung cancer', 'Disease', (144, 155))	('lung cancer', 'Phenotype', 'HP:0100526', (144, 155))	('associated', 'Reg', (56, 66))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('lung cancer', 'Disease', (72, 83))	('lung cancer', 'Phenotype', 'HP:0100526', (72, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('lung cancer', 'Disease', 'MESH:D008175', (144, 155))	('rs66759488', 'Mutation', 'rs66759488', (28, 38))	('lung cancer', 'Disease', 'MESH:D008175', (72, 83))
131536	28604730	Genomic annotation suggests that genetic variants correlated with rs66759488 may influence the SEMA6D gene (Supplementary Table 7), but there was no clear eQTL effect (Supplementary Table 6), and this variant did not appear to have a major influence on smoking propensity or lung function (Table 2).	('rs66759488', 'Var', (66, 76))	('influence', 'Reg', (81, 90))	('SEMA6D', 'Gene', '80031', (95, 101))	('SEMA6D', 'Gene', (95, 101))	('rs66759488', 'Mutation', 'rs66759488', (66, 76))
131537	28604730	For specific lung cancer histology subtypes, we identified 6 novel loci associated with lung adenocarcinoma (15q21, 8p12, 10q24, 20q13.33, 11q23.3 and 9p21.3) (Table 2).	('15q21', 'Var', (109, 114))	('lung cancer', 'Disease', (13, 24))	('lung cancer', 'Phenotype', 'HP:0100526', (13, 24))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (88, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('associated', 'Reg', (72, 82))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('lung adenocarcinoma', 'Disease', (88, 107))	('lung cancer', 'Disease', 'MESH:D008175', (13, 24))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (88, 107))
131538	28604730	The locus at 15q21 (rs77468143, OR=0.86, 95% CI 0.82-0.89, p=1.15x10-16) is predicted to target SECISBP2L (Supplementary Figure 5), and expression analysis indicated rs77468143 to be a cis-eQTL for SECISBP2L in lung tissue in all eQTL cohorts tested (Supplementary Table 6).	('SECISBP2L', 'Gene', (96, 105))	('rs77468143', 'Mutation', 'rs77468143', (20, 30))	('rs77468143', 'Var', (20, 30))	('SECISBP2L', 'Gene', (198, 207))	('SECISBP2L', 'Gene', '9728', (96, 105))	('rs77468143', 'Mutation', 'rs77468143', (166, 176))	('rs77468143', 'Var', (166, 176))	('SECISBP2L', 'Gene', '9728', (198, 207))
131540	28604730	rs77468143 was nominally associated with lung function (Table 2), potentially implicating inflammation of lung as part of the mechanism at this locus.	('rs77468143', 'Mutation', 'rs77468143', (0, 10))	('inflammation of lung', 'Disease', 'MESH:D011014', (90, 110))	('associated', 'Reg', (25, 35))	('lung function', 'Disease', (41, 54))	('rs77468143', 'Var', (0, 10))	('inflammation of lung', 'Disease', (90, 110))
131541	28604730	At 8p12, expression analysis indicated that the alleles associated with lung adenocarcinoma (represented by the sentinel variant rs4236709 (Table 2)), also appear to be a lung cis-eQTL for the NRG1 gene (Supplementary Table 6, Supplementary Figure 5).	('lung adenocarcinoma', 'Disease', (72, 91))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (72, 91))	('NRG1', 'Gene', '3084', (193, 197))	('rs4236709', 'Mutation', 'rs4236709', (129, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('associated', 'Reg', (56, 66))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (72, 91))	('rs4236709', 'Var', (129, 138))	('variant rs4236709', 'Var', (121, 138))	('NRG1', 'Gene', (193, 197))
131543	28604730	While somatic translocations at 8p12 generally take place in never smokers and are linked with ectopic activation of NRG1, rs4236709 was associated with lung cancer in both ever and never smokers (Supplementary Figure 4) and its genetic risk correlated with decreased NRG1 expression (Figure 2).	('rs4236709', 'Var', (123, 132))	('NRG1', 'Gene', '3084', (117, 121))	('lung cancer', 'Disease', 'MESH:D008175', (153, 164))	('rs4236709', 'Mutation', 'rs4236709', (123, 132))	('NRG1', 'Gene', '3084', (268, 272))	('associated with', 'Reg', (137, 152))	('decreased', 'NegReg', (258, 267))	('lung cancer', 'Disease', (153, 164))	('lung cancer', 'Phenotype', 'HP:0100526', (153, 164))	('NRG1', 'Gene', (117, 121))	('NRG1', 'Gene', (268, 272))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('expression', 'MPA', (273, 283))
131544	28604730	Interestingly, 6q22.1 variants located near ROS1, another gene somatically translocated in lung adenocarcinoma and for which nearby germline variants were associated with never smoking lung adenocarcinoma in Asian women, were associated with lung adenocarcinoma at borderline genome wide significance (rs9387479; OR=0.92, 95% CI 0.89-0.95, p=6.57x10-8) (Supplementary Table 2).	('rs9387479', 'Mutation', 'rs9387479', (302, 311))	('ROS1', 'Gene', '6098', (44, 48))	('lung adenocarcinoma', 'Disease', (242, 261))	('lung adenocarcinoma', 'Disease', (91, 110))	('women', 'Species', '9606', (214, 219))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (242, 261))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (91, 110))	('lung adenocarcinoma', 'Disease', (185, 204))	('ROS1', 'Gene', (44, 48))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (242, 261))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (91, 110))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('associated', 'Reg', (155, 165))	('carcinoma', 'Phenotype', 'HP:0030731', (252, 261))	('carcinoma', 'Phenotype', 'HP:0030731', (195, 204))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (185, 204))	('associated', 'Reg', (226, 236))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (185, 204))	('variants', 'Var', (22, 30))
131545	28604730	Three of the sentinel variants associated with lung adenocarcinoma are located near genes related to telomere regulation; rs7902587 (10q24) and rs41309931 (20q13.33) near OBFC1 and RTEL1, respectively, and rs2853677 near TERT as previously noted.	('TERT', 'Gene', '7015', (221, 225))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (47, 66))	('rs7902587', 'Var', (122, 131))	('rs41309931', 'Var', (144, 154))	('RTEL1', 'Gene', '51750', (181, 186))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (47, 66))	('carcinoma', 'Phenotype', 'HP:0030731', (57, 66))	('associated', 'Reg', (31, 41))	('OBFC1', 'Gene', (171, 176))	('RTEL1', 'Gene', (181, 186))	('rs2853677', 'Mutation', 'rs2853677', (206, 215))	('lung adenocarcinoma', 'Disease', (47, 66))	('TERT', 'Gene', (221, 225))	('rs2853677', 'Var', (206, 215))	('rs41309931', 'Mutation', 'rs41309931', (144, 154))	('rs7902587', 'Mutation', 'rs7902587', (122, 131))	('OBFC1', 'Gene', '79991', (171, 176))
131546	28604730	The variants at 10q24 associated with lung adenocarcinoma also appear to be associated with telomere length (Supplementary Figure 6).	('carcinoma', 'Phenotype', 'HP:0030731', (48, 57))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (38, 57))	('associated', 'Reg', (76, 86))	('variants at', 'Var', (4, 15))	('associated', 'Reg', (22, 32))	('lung adenocarcinoma', 'Disease', (38, 57))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (38, 57))	('telomere length', 'MPA', (92, 107))
131547	28604730	By contrast, and consistent with observations with 20q13.33 variants associated with glioma, the variants associated with telomere length at 20q13.33 were not necessarily those associated with lung adenocarcinoma (Supplementary Figure 6).	('glioma', 'Disease', 'MESH:D005910', (85, 91))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (193, 212))	('associated', 'Reg', (69, 79))	('lung adenocarcinoma', 'Disease', (193, 212))	('carcinoma', 'Phenotype', 'HP:0030731', (203, 212))	('glioma', 'Disease', (85, 91))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (193, 212))	('variants', 'Var', (60, 68))	('glioma', 'Phenotype', 'HP:0009733', (85, 91))
131548	28604730	Nevertheless, more generally the variants associated by GWAS with longer telomere length appear linked with risk of lung adenocarcinoma and glioma, a finding consistent with our expanded analysis here (Supplementary Figure 6).	('glioma', 'Phenotype', 'HP:0009733', (140, 146))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (116, 135))	('linked', 'Reg', (96, 102))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('variants', 'Var', (33, 41))	('lung adenocarcinoma and glioma', 'Disease', 'MESH:D005910', (116, 146))
131549	28604730	The sentinel variant rs1056562 (OR=1.11, 95% CI 1.07-1.14, p=2.7x10-10) is more prominently associated with lung adenocarcinoma (Supplementary Figure 4).	('rs1056562', 'Mutation', 'rs1056562', (21, 30))	('lung adenocarcinoma', 'Disease', (108, 127))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (108, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('rs1056562', 'Var', (21, 30))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (108, 127))	('associated', 'Reg', (92, 102))
131550	28604730	rs1056562 was correlated with expression of two genes at this locus, AMICA1 and MPZL3 (Supplementary Table 6).	('MPZL3', 'Gene', (80, 85))	('MPZL3', 'Gene', '196264', (80, 85))	('AMICA1', 'Gene', (69, 75))	('AMICA1', 'Gene', '120425', (69, 75))	('rs1056562', 'Var', (0, 9))	('rs1056562', 'Mutation', 'rs1056562', (0, 9))
131552	28604730	At 9p21.3 we identified rs885518 that appeared to be associated with lung adenocarcinoma (OR=1.17, 95% CI 1.11-1.23, p=6.8x10-10).	('lung adenocarcinoma', 'Disease', (69, 88))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (69, 88))	('rs885518', 'Mutation', 'rs885518', (24, 32))	('rs885518', 'Var', (24, 32))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('associated', 'Reg', (53, 63))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (69, 88))
131553	28604730	9p21.3 is a region containing CDNK2A and variants associated with multiple cancer types, including lung cancer.	('variants', 'Var', (41, 49))	('CDNK2A', 'Gene', (30, 36))	('lung cancer', 'Disease', (99, 110))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('cancer', 'Disease', (75, 81))	('lung cancer', 'Disease', 'MESH:D008175', (99, 110))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('associated', 'Reg', (50, 60))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('lung cancer', 'Phenotype', 'HP:0100526', (99, 110))
131554	28604730	Nevertheless, rs885518 is located approximately 200kb centromeric the previously described variants (Supplementary Figure 4) and shows little evidence for LD (all pairwise r2< 0.01) with rs1333040, a variant previously associated with lung squamous cell carcinoma and rs62560775, another variant suggested to be associated with lung adenocarcinoma that we confirm to genome significance here.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (240, 263))	('lung squamous cell carcinoma', 'Disease', (235, 263))	('associated', 'Reg', (219, 229))	('rs1333040', 'Var', (187, 196))	('rs1333040', 'Mutation', 'rs1333040', (187, 196))	('carcinoma', 'Phenotype', 'HP:0030731', (338, 347))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (328, 347))	('carcinoma', 'Phenotype', 'HP:0030731', (254, 263))	('rs62560775', 'Mutation', 'rs62560775', (268, 278))	('rs62560775', 'Var', (268, 278))	('rs885518', 'Mutation', 'rs885518', (14, 22))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (235, 263))	('rs885518', 'Var', (14, 22))	('lung adenocarcinoma', 'Disease', (328, 347))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (328, 347))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (235, 263))
131555	28604730	Intriguingly, these variants appear to confer predominant associations with different lung cancer histologies suggesting that they are independent associations (Supplementary Figure 7).	('variants', 'Var', (20, 28))	('associations', 'Interaction', (58, 70))	('lung cancer', 'Phenotype', 'HP:0100526', (86, 97))	('lung cancer', 'Disease', (86, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('lung cancer', 'Disease', 'MESH:D008175', (86, 97))
131556	28604730	Aside from the clear smoking-related effects on lung cancer risk through the CHRNA5 and CYP2A6 regions and association with CHRNA2 noted above, the rest of variants we have identified do not appear to clearly influence smoking behaviors (Table 2), implying that these associations are likely mediated by other mechanisms.	('CYP2A6', 'Gene', '1548', (88, 94))	('CHRNA5', 'Gene', '1138', (77, 83))	('CHRNA2', 'Gene', (124, 130))	('smoking', 'Disease', (219, 226))	('CHRNA2', 'Gene', '1135', (124, 130))	('lung cancer', 'Disease', 'MESH:D008175', (48, 59))	('CYP2A6', 'Gene', (88, 94))	('influence', 'Reg', (209, 218))	('variants', 'Var', (156, 164))	('CHRNA5', 'Gene', (77, 83))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('lung cancer', 'Disease', (48, 59))	('lung cancer', 'Phenotype', 'HP:0100526', (48, 59))
131557	28604730	Nevertheless, there is shared genetic architecture between smoking behavior and lung cancer risk, consistent with the notion that genetic variants do influence lung cancer risk also through behavioral mechanisms (Supplementary Figure 8).	('lung cancer', 'Disease', 'MESH:D008175', (80, 91))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('influence', 'Reg', (150, 159))	('variants', 'Var', (138, 146))	('lung cancer', 'Disease', 'MESH:D008175', (160, 171))	('lung cancer', 'Disease', (80, 91))	('lung cancer', 'Phenotype', 'HP:0100526', (80, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('lung cancer', 'Disease', (160, 171))	('lung cancer', 'Phenotype', 'HP:0100526', (160, 171))
131566	28604730	We excluded poorly imputed SNPs defined by imputation quality R2 < 0.3 or Info < 0.4 for each meta-analysis component and SNPs with a Minor allele frequency (MAF) >0.01 (except for CHEK2 rs17879961 and BRCA2 rs11571833 which we have validated extensively previously.	('rs11571833', 'Var', (208, 218))	('CHEK2', 'Gene', '11200', (181, 186))	('CHEK2', 'Gene', (181, 186))	('BRCA2', 'Gene', '675', (202, 207))	('rs17879961', 'Var', (187, 197))	('rs11571833', 'Mutation', 'rs11571833', (208, 218))	('rs17879961', 'Mutation', 'rs17879961', (187, 197))	('BRCA2', 'Gene', (202, 207))
131567	28604730	Due to the smaller sample size and fewer sites contributing in the strata of Never Smokers and SCLC, we additionally required variants to be present in each of the meta-analysis components to be retained for these 2 stratified analyses.	('SCLC', 'Disease', (95, 99))	('SCLC', 'Disease', 'MESH:D018288', (95, 99))	('variants', 'Var', (126, 134))
131582	28604730	We assessed associations between sentinel genetic variant associated with lung cancer and other phenotypes, including smoking behavior Fagerstrom Test for Nicotine Dependence, lung function and telomere length.	('lung cancer', 'Disease', (74, 85))	('associated', 'Reg', (58, 68))	('lung cancer', 'Phenotype', 'HP:0100526', (74, 85))	('variant', 'Var', (50, 57))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('lung cancer', 'Disease', 'MESH:D008175', (74, 85))	('Nicotine', 'Chemical', 'MESH:D009538', (155, 163))	('associations', 'Interaction', (12, 24))
131603	28243326	As we known, growth factors and receptors play essential roles in the regulation of epithelial cell proliferation, and abnormalities in their expression and signaling pathways, contributing to progression and maintenance of the malignant phenotype in human cancers.	('cancer', 'Phenotype', 'HP:0002664', (257, 263))	('human', 'Species', '9606', (251, 256))	('cancers', 'Disease', 'MESH:D009369', (257, 264))	('cancers', 'Phenotype', 'HP:0002664', (257, 264))	('contributing', 'Reg', (177, 189))	('abnormalities', 'Var', (119, 132))	('cancers', 'Disease', (257, 264))
131604	28243326	The deregulation of EGFR activation has been shown to be closely associated with the development and progression of cSCC.	('deregulation', 'Var', (4, 16))	('EGFR', 'Gene', (20, 24))	('cSCC', 'Phenotype', 'HP:0006739', (116, 120))	('associated', 'Reg', (65, 75))	('cSCC', 'Disease', (116, 120))	('EGFR', 'Gene', '1956', (20, 24))
131642	28243326	When being treated with lapatinib at 0.1, 1 and 5 muM for 48 hours, respectively, lapatinib significantly induced G2/M phase arrest in A431 cell lines (Figure 3 A-C).	('lapatinib', 'Chemical', 'MESH:D000077341', (24, 33))	('lapatinib', 'Var', (82, 91))	('induced', 'Reg', (106, 113))	('muM', 'Gene', '56925', (50, 53))	('lapatinib', 'Chemical', 'MESH:D000077341', (82, 91))	('A431', 'CellLine', 'CVCL:0037', (135, 139))	('G2/M phase arrest', 'CPA', (114, 131))	('muM', 'Gene', (50, 53))
131665	28243326	The biomarkers including AKT, mTOR and PTEN exerts an important role in the regulation of chromosome assembly and its inactivation of these proteins results in G2/M arrest.	('AKT', 'Gene', (25, 28))	('inactivation', 'Var', (118, 130))	('G2/M arrest', 'CPA', (160, 171))	('PTEN', 'Gene', (39, 43))	('AKT', 'Gene', '207', (25, 28))	('PTEN', 'Gene', '5728', (39, 43))	('mTOR', 'Gene', '2475', (30, 34))	('mTOR', 'Gene', (30, 34))	('results in', 'Reg', (149, 159))
131666	28243326	In the present study, our findings clearly showed that lapatinib treatment remarkably decreased the ratio of p-AKT and p-mTOR over AKT and mTOR in A431 cell lines, suggesting that lapatinib may induce cell cycle arrest in G2/M phase.	('AKT', 'Gene', '207', (111, 114))	('AKT', 'Gene', '207', (131, 134))	('mTOR', 'Gene', '2475', (121, 125))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (201, 218))	('A431', 'CellLine', 'CVCL:0037', (147, 151))	('mTOR', 'Gene', (121, 125))	('lapatinib', 'Chemical', 'MESH:D000077341', (180, 189))	('mTOR', 'Gene', (139, 143))	('lapatinib', 'Var', (180, 189))	('mTOR', 'Gene', '2475', (139, 143))	('AKT', 'Gene', (131, 134))	('ratio', 'MPA', (100, 105))	('lapatinib', 'Chemical', 'MESH:D000077341', (55, 64))	('induce', 'Reg', (194, 200))	('decreased', 'NegReg', (86, 95))	('AKT', 'Gene', (111, 114))	('cell cycle arrest in G2/M phase', 'CPA', (201, 232))
131671	28243326	Numerous evidence has shown that aberrant Wnt/beta- catenin signaling accounts for tumor initiation and inhibits mitochondrial apoptosis.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('mitochondrial apoptosis', 'CPA', (113, 136))	('inhibits', 'NegReg', (104, 112))	('tumor initiation', 'Disease', (83, 99))	('aberrant', 'Var', (33, 41))	('beta- catenin', 'Gene', '1499', (46, 59))	('tumor initiation', 'Disease', 'MESH:D009369', (83, 99))	('beta- catenin', 'Gene', (46, 59))
131675	28243326	Inhibition of snail/slug expression enable to suppress the EMT progression in cSCC.	('cSCC', 'Phenotype', 'HP:0006739', (78, 82))	('suppress', 'NegReg', (46, 54))	('slug', 'Gene', '6591', (20, 24))	('cSCC', 'Disease', (78, 82))	('snail', 'Gene', '6615', (14, 19))	('Inhibition', 'Var', (0, 10))	('EMT progression', 'CPA', (59, 74))	('slug', 'Gene', (20, 24))	('snail', 'Gene', (14, 19))
131686	25035393	Kinase domain activation of FGFR2 yields high-grade lung adenocarcinoma sensitive to a pan-FGFR inhibitor in a mouse model of NSCLC Somatic mutations in Fibroblast Growth Factor Receptor 2 (FGFR2) are present in 4-5% of patients diagnosed with non-small cell lung cancer (NSCLC).	('FGFR2', 'Gene', (28, 33))	('lung adenocarcinoma', 'Disease', (52, 71))	('lung cancer', 'Phenotype', 'HP:0100526', (259, 270))	('NSCLC', 'Disease', 'MESH:D002289', (126, 131))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (244, 270))	('mouse', 'Species', '10090', (111, 116))	('Fibroblast Growth Factor Receptor 2', 'Gene', '2263', (153, 188))	('patients', 'Species', '9606', (220, 228))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (248, 270))	('NSCLC', 'Disease', (126, 131))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (52, 71))	('cancer', 'Phenotype', 'HP:0002664', (264, 270))	('FGFR2', 'Gene', '14183', (190, 195))	('pan', 'Gene', '51816', (87, 90))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (244, 270))	('NSCLC', 'Phenotype', 'HP:0030358', (126, 131))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (52, 71))	('Kinase domain activation', 'Var', (0, 24))	('carcinoma', 'Phenotype', 'HP:0030731', (62, 71))	('NSCLC', 'Disease', 'MESH:D002289', (272, 277))	('pan', 'Gene', (87, 90))	('FGFR2', 'Gene', (190, 195))	('mutations', 'Var', (140, 149))	('non-small cell lung cancer', 'Disease', (244, 270))	('Fibroblast Growth Factor Receptor 2', 'Gene', (153, 188))	('NSCLC', 'Disease', (272, 277))	('FGFR2', 'Gene', '14183', (28, 33))	('NSCLC', 'Phenotype', 'HP:0030358', (272, 277))
131687	25035393	Amplification and mutations in FGFR genes have been identified in patients with NSCLC and clinical trials are testing the efficacy of anti-FGFR therapies.	('NSCLC', 'Phenotype', 'HP:0030358', (80, 85))	('identified', 'Reg', (52, 62))	('NSCLC', 'Disease', (80, 85))	('NSCLC', 'Disease', 'MESH:D002289', (80, 85))	('FGFR', 'Gene', (31, 35))	('patients', 'Species', '9606', (66, 74))	('mutations', 'Var', (18, 27))
131688	25035393	FGFR2 and other FGFR kinase family gene alterations have been found in both lung squamous cell carcinoma and lung adenocarcinoma though mouse models of FGFR driven lung cancers have not been reported.	('FGFR', 'Gene', (16, 20))	('lung cancers', 'Disease', (164, 176))	('mouse', 'Species', '10090', (136, 141))	('lung squamous cell carcinoma and lung adenocarcinoma', 'Disease', 'MESH:D000077192', (76, 128))	('lung cancer', 'Phenotype', 'HP:0100526', (164, 175))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (109, 128))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (76, 104))	('alterations', 'Var', (40, 51))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('lung cancers', 'Disease', 'MESH:D008175', (164, 176))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (81, 104))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('lung cancers', 'Phenotype', 'HP:0100526', (164, 176))	('FGFR2', 'Gene', (0, 5))	('found', 'Reg', (62, 67))	('cancers', 'Phenotype', 'HP:0002664', (169, 176))
131689	25035393	Here, we generated a genetically engineered mouse model (GEMM) of NSCLC driven by a kinase domain mutation in FGFR2.	('kinase domain mutation', 'Var', (84, 106))	('NSCLC', 'Disease', (66, 71))	('FGFR2', 'Gene', (110, 115))	('NSCLC', 'Disease', 'MESH:D002289', (66, 71))	('driven by', 'Reg', (72, 81))	('NSCLC', 'Phenotype', 'HP:0030358', (66, 71))	('mouse', 'Species', '10090', (44, 49))
131690	25035393	Combined with p53 ablation, primary grade III/IV adenocarcinoma was induced in the lung epithelial compartment exhibiting locally invasive and pleiotropic tendencies largely made up of multinucleated cells.	('IV adenocarcinoma', 'Disease', (46, 63))	('ablation', 'Var', (18, 26))	('IV adenocarcinoma', 'Disease', 'MESH:D000230', (46, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (54, 63))
131698	25035393	FGFR2 mutations have been most highly represented in 12% of endometrial carcinoma patients, both major subtypes of NSCLC with the squamous cell population displaying a higher rate of mutation and gastric tumors, as well.	('represented', 'Reg', (38, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (60, 81))	('patients', 'Species', '9606', (82, 90))	('gastric tumors', 'Disease', 'MESH:D013274', (196, 210))	('NSCLC', 'Disease', (115, 120))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('gastric tumors', 'Disease', (196, 210))	('NSCLC', 'Disease', 'MESH:D002289', (115, 120))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (60, 81))	('tumors', 'Phenotype', 'HP:0002664', (204, 210))	('FGFR2', 'Gene', (0, 5))	('gastric tumors', 'Phenotype', 'HP:0006753', (196, 210))	('endometrial carcinoma', 'Disease', (60, 81))	('mutations', 'Var', (6, 15))	('NSCLC', 'Phenotype', 'HP:0030358', (115, 120))
131701	25035393	FGFR2/3/4 mutations were also identified in NSCLC providing the rationale for the creation of GEMMs driven by FGFR-dependent activity.	('NSCLC', 'Disease', 'MESH:D002289', (44, 49))	('NSCLC', 'Phenotype', 'HP:0030358', (44, 49))	('FGFR2/3/4', 'Gene', (0, 9))	('mutations', 'Var', (10, 19))	('NSCLC', 'Disease', (44, 49))
131706	25035393	Given that FGF3/7/10 ligands predominantly signal through FGFR2, the pre-clinical need for additional FGFR-driven models of invasive carcinoma is needed, as mutations in all FGFRs have been identified in various next generation sequencing efforts in various cancer indications, including NSCLC.	('FGFRs', 'Gene', (174, 179))	('cancer', 'Phenotype', 'HP:0002664', (258, 264))	('invasive carcinoma', 'Disease', 'MESH:D009361', (124, 142))	('NSCLC', 'Disease', 'MESH:D002289', (288, 293))	('FGF3/7/10', 'Gene', (11, 20))	('signal', 'Reg', (43, 49))	('NSCLC', 'Phenotype', 'HP:0030358', (288, 293))	('invasive carcinoma', 'Disease', (124, 142))	('identified', 'Reg', (190, 200))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('mutations', 'Var', (157, 166))	('cancer', 'Disease', 'MESH:D009369', (258, 264))	('FGF3/7/10', 'Gene', '14174;14178;14165', (11, 20))	('cancer', 'Disease', (258, 264))	('FGFR2', 'Gene', (58, 63))	('NSCLC', 'Disease', (288, 293))
131707	25035393	While there have been many FGFR mutations identified in NSCLC, limited knowledge as to which are oncogenic drivers continues to be an obstacle.	('identified', 'Reg', (42, 52))	('NSCLC', 'Disease', (56, 61))	('FGFR', 'Gene', (27, 31))	('NSCLC', 'Disease', 'MESH:D002289', (56, 61))	('mutations', 'Var', (32, 41))	('NSCLC', 'Phenotype', 'HP:0030358', (56, 61))
131710	25035393	Upon further evaluation of FGFR2, several key mutations in both the extracellular and kinase domains showed transforming capabilities in vitro and in xenograft studies with profound sensitivity to pan-FGFR inhibitors, such as BGJ-398 and AZD4547.	('FGFR2', 'Gene', (27, 32))	('mutations', 'Var', (46, 55))	('pan', 'Gene', (197, 200))	('BGJ-398', 'Chemical', 'MESH:C568950', (226, 233))	('pan', 'Gene', '51816', (197, 200))	('AZD4547', 'Chemical', 'MESH:C572463', (238, 245))
131711	25035393	Based on these findings and the clear void of mouse models of human lung squamous cell carcinoma, here we report the generation and characterization of FGFR2 mutant GEMMs conditionally expressing an extracellular (W290C) or kinase (K660N) domain activating mutation.	('mutant', 'Var', (158, 164))	('W290C', 'Var', (214, 219))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (73, 96))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (68, 96))	('lung squamous cell carcinoma', 'Disease', (68, 96))	('K660N', 'Mutation', 'p.K660N', (232, 237))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (68, 96))	('human', 'Species', '9606', (62, 67))	('FGFR2', 'Gene', (152, 157))	('mouse', 'Species', '10090', (46, 51))	('activating', 'PosReg', (246, 256))	('K660N', 'Var', (232, 237))	('W290C', 'SUBSTITUTION', 'None', (214, 219))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))
131712	25035393	Point mutations W290C and K660N within human FGFR2's cDNA (isoform IIIb) were introduced as described elsewhere.	('W290C', 'Var', (16, 21))	('K660N', 'Var', (26, 31))	('K660N', 'Mutation', 'p.K660N', (26, 31))	('FGFR2', 'Gene', (45, 50))	('W290C', 'SUBSTITUTION', 'None', (16, 21))	('human', 'Species', '9606', (39, 44))
131718	25035393	For all studies, mice were on a mixed genetic background and FGFR2 mutant mice were hemizygosed.	('mice', 'Species', '10090', (74, 78))	('FGFR2', 'Gene', (61, 66))	('mice', 'Species', '10090', (17, 21))	('mutant', 'Var', (67, 73))
131719	25035393	Adenovirus-Cre (5x107 pfu - University of Iowa) was administered intranasally to excise the loxP sites, activating mutant FGFR2 expression and inactivating p53 activity in the lung epithelial compartment.	('lox', 'Gene', (92, 95))	('p53', 'Enzyme', (156, 159))	('mutant', 'Var', (115, 121))	('lox', 'Gene', '16948', (92, 95))	('activity', 'MPA', (160, 168))	('activating', 'PosReg', (104, 114))	('inactivating', 'NegReg', (143, 155))	('expression', 'MPA', (128, 138))	('FGFR2', 'Gene', (122, 127))
131738	25035393	We interrogated three publically available NSCLC datasets for mutation in FGFR2 (Supplemental Table 1).	('NSCLC', 'Phenotype', 'HP:0030358', (43, 48))	('FGFR2', 'Gene', (74, 79))	('mutation', 'Var', (62, 70))	('NSCLC', 'Disease', (43, 48))	('NSCLC', 'Disease', 'MESH:D002289', (43, 48))
131739	25035393	Mutations in FGFR2 are spread across the gene, primarily focused in the extracellular or kinase domains, in NSCLC (Figure 1A).	('NSCLC', 'Phenotype', 'HP:0030358', (108, 113))	('NSCLC', 'Disease', (108, 113))	('Mutations', 'Var', (0, 9))	('NSCLC', 'Disease', 'MESH:D002289', (108, 113))	('FGFR2', 'Gene', (13, 18))
131740	25035393	Patients with FGFR2 mutations ranged in age from 42 to 81, averaging 66 years of age upon diagnosis.	('FGFR2', 'Gene', (14, 19))	('Patients', 'Species', '9606', (0, 8))	('mutations', 'Var', (20, 29))
131742	25035393	Due to an overwhelming need for mouse models of novel oncogenic drivers in lung cancer, we set out to evaluate newly characterized FGFR2 mutations which were established to be transforming and oncogenic in vitro and in vivo.	('lung cancer', 'Disease', (75, 86))	('lung cancer', 'Phenotype', 'HP:0100526', (75, 86))	('FGFR2', 'Gene', (131, 136))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('mutations', 'Var', (137, 146))	('lung cancer', 'Disease', 'MESH:D008175', (75, 86))	('mouse', 'Species', '10090', (32, 37))
131743	25035393	We generated inducible models of human FGFR2-IIIb mutations found in the extracellular (W290C) or kinase domains (K660N) (Supplemental Figure 1).	('W290C', 'SUBSTITUTION', 'None', (88, 93))	('W290C', 'Var', (88, 93))	('K660N', 'Var', (114, 119))	('human', 'Species', '9606', (33, 38))	('FGFR2-IIIb', 'Gene', (39, 49))	('K660N', 'Mutation', 'p.K660N', (114, 119))
131744	25035393	Patients with previously reported FGFR2 mutations were largely devoid of intact p53 activity (>85%), therefore, the FGFR2 GEMMs were crossed with the Trp53fl/fl model to obtain a bi-allelic mouse (Figure 1B).	('FGFR2', 'Gene', (34, 39))	('Patients', 'Species', '9606', (0, 8))	('mouse', 'Species', '10090', (190, 195))	('mutations', 'Var', (40, 49))
131746	25035393	At 6 weeks of age, bi-allelic mice were induced via intranasal delivery of adenovirus-cre (5x107 pfu), activating mutant FGFR2 activity while inactivating p53.	('mice', 'Species', '10090', (30, 34))	('inactivating', 'NegReg', (142, 154))	('FGFR2', 'Gene', (121, 126))	('activating', 'PosReg', (103, 113))	('mutant', 'Var', (114, 120))	('activity', 'MPA', (127, 135))
131749	25035393	As expected, bi-allelic FGFR2K660N;p53-/- tumor bearing animals displayed a significant decrease in overall survival as compared to un-induced littermate controls (Figure 1C).	('decrease', 'NegReg', (88, 96))	('overall survival', 'CPA', (100, 116))	('tumor', 'Disease', (42, 47))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('FGFR2K660N', 'Var', (24, 34))
131754	25035393	FGFR2 mutant models displayed similar phenotypes, but the penetrance for the extracellular domain (ECD) was less than the kinase domain (KD), 35% versus 92%, respectively.	('ECD', 'Disease', (99, 102))	('extracellular domain', 'MPA', (77, 97))	('mutant', 'Var', (6, 12))	('penetrance', 'MPA', (58, 68))	('KD', 'Disease', 'MESH:C537017', (137, 139))	('FGFR2', 'Gene', (0, 5))	('ECD', 'Disease', 'MESH:C574275', (99, 102))	('less', 'NegReg', (108, 112))
131755	25035393	Furthermore, the ECD (W290C) model's tumor latency was substantially longer than that of the K660N (KD) animals.	('W290C', 'Var', (22, 27))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('ECD', 'Disease', 'MESH:C574275', (17, 20))	('ECD', 'Disease', (17, 20))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('KD', 'Disease', 'MESH:C537017', (100, 102))	('longer', 'PosReg', (69, 75))	('K660N', 'Mutation', 'p.K660N', (93, 98))	('W290C', 'SUBSTITUTION', 'None', (22, 27))
131756	25035393	Thus, we chose to move forward with the kinase domain mutant for treatment studies because of its increased oncogenic activity and recurrent mutation in patient samples (Supplemental Table 1).	('patient', 'Species', '9606', (153, 160))	('increased', 'PosReg', (98, 107))	('kinase domain mutant', 'Var', (40, 60))	('oncogenic activity', 'CPA', (108, 126))
131757	25035393	Loss of p53 activity yielded increased penetrance (40% vs. 92% for p53 wt and null, respectively) and decreased tumor latency (Supplemental Table 2).	('p53', 'Var', (67, 70))	('activity', 'MPA', (12, 20))	('increased', 'PosReg', (29, 38))	('Loss', 'NegReg', (0, 4))	('decreased tumor', 'Disease', 'MESH:D009369', (102, 117))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('decreased tumor', 'Disease', (102, 117))	('penetrance', 'MPA', (39, 49))	('p53', 'Protein', (8, 11))
131762	25035393	A tumor driven by mutant Kras activity showed no staining (Supplemental Figure 5A).	('tumor', 'Disease', 'MESH:D009369', (2, 7))	('mutant', 'Var', (18, 24))	('tumor', 'Phenotype', 'HP:0002664', (2, 7))	('Kras', 'Gene', '16653', (25, 29))	('Kras', 'Gene', (25, 29))	('tumor', 'Disease', (2, 7))
131763	25035393	Expected phosphorylation of various downstream signaling molecules, including AKT, ERK1/2 and FRS2alpha were present in tumor nodules from both the kinase domain mutant (Figure 2C) and the extracellular domain mutant (Supplemental Figure 4).	('FRS2alpha', 'Gene', (94, 103))	('FRS2alpha', 'Gene', '327826', (94, 103))	('ERK1/2', 'Gene', (83, 89))	('tumor', 'Disease', (120, 125))	('AKT', 'Gene', '11651', (78, 81))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('ERK1/2', 'Gene', '26417;26413', (83, 89))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('AKT', 'Gene', (78, 81))	('present', 'Reg', (109, 116))	('kinase domain mutant', 'Var', (148, 168))	('phosphorylation', 'MPA', (9, 24))
131767	25035393	In a tumor efficacy study, we treated FGFR2K660N;p53-/- lung tumor bearing animals with either BGJ-398 (n=10), a pan FGFR inhibitor or vehicle (n=5).	('K660N', 'Mutation', 'p.K660N', (43, 48))	('lung tumor', 'Phenotype', 'HP:0100526', (56, 66))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('BGJ-398', 'Chemical', 'MESH:C568950', (95, 102))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Disease', (5, 10))	('pan', 'Gene', '51816', (113, 116))	('pan', 'Gene', (113, 116))	('lung tumor', 'Disease', 'MESH:D008175', (56, 66))	('tumor', 'Disease', (61, 66))	('FGFR2K660N', 'Var', (38, 48))	('lung tumor', 'Disease', (56, 66))
131781	25035393	These tumors developed well beyond the normal lung tumor latency (> 50 weeks), likely as a direct result of nasally delivered adenovirus cre and resulted in lethality due to obstruction of the nasal cavity, affecting the animal's normal respiration.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('lung tumor', 'Disease', (46, 56))	('adenovirus cre', 'Var', (126, 140))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('lung tumor', 'Disease', 'MESH:D008175', (46, 56))	('tumors', 'Disease', (6, 12))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('normal respiration', 'MPA', (230, 248))	('lung tumor', 'Phenotype', 'HP:0100526', (46, 56))	('resulted in', 'Reg', (145, 156))	('obstruction of the nasal', 'Phenotype', 'HP:0001742', (174, 198))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('affecting', 'Reg', (207, 216))
131783	25035393	Recently, a group reported an inducible mouse model driving FGF9 expression in the adult airway epithelia leading to the formation of papillary adenomas, which were shown to progress into primary adenocarcinomas with a metastatic potential.	('adenocarcinomas', 'Disease', 'MESH:D000230', (196, 211))	('papillary adenomas', 'Disease', (134, 152))	('papillary adenomas', 'Disease', 'MESH:D000236', (134, 152))	('adenocarcinomas', 'Disease', (196, 211))	('carcinoma', 'Phenotype', 'HP:0030731', (201, 210))	('carcinomas', 'Phenotype', 'HP:0030731', (201, 211))	('FGF9', 'Gene', '14180', (60, 64))	('FGF9', 'Gene', (60, 64))	('mouse', 'Species', '10090', (40, 45))	('leading to', 'Reg', (106, 116))	('expression', 'Var', (65, 75))
131785	25035393	Furthermore, while widespread expression of FGF3 and FGF7 in the adult mouse lung was shown to produce type II cell hyperplasia, FGF9 or FGF10 expression led to the development of cancer or adenomas, respectively.	('adenomas', 'Disease', 'MESH:D000236', (190, 198))	('FGF7', 'Gene', '14178', (53, 57))	('adenomas', 'Disease', (190, 198))	('expression', 'Var', (30, 40))	('FGF7', 'Gene', (53, 57))	('mouse', 'Species', '10090', (71, 76))	('FGF10', 'Gene', (137, 142))	('FGF3', 'Gene', '14174', (44, 48))	('type II cell hyperplasia', 'Disease', (103, 127))	('cancer', 'Disease', (180, 186))	('FGF10', 'Gene', '14165', (137, 142))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('type II cell hyperplasia', 'Disease', 'MESH:D006965', (103, 127))	('FGF3', 'Gene', (44, 48))	('FGF9', 'Gene', '14180', (129, 133))	('FGF9', 'Gene', (129, 133))	('expression', 'Var', (143, 153))	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('led to', 'Reg', (154, 160))
131787	25035393	Activating mutations in FGFR2 have recently been unveiled as novel targets in NSCLC, both in lung squamous cell and adenocarcinoma.	('lung squamous cell and adenocarcinoma', 'Disease', 'MESH:D002294', (93, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('targets', 'Reg', (67, 74))	('Activating mutations', 'Var', (0, 20))	('NSCLC', 'Phenotype', 'HP:0030358', (78, 83))	('NSCLC', 'Disease', (78, 83))	('NSCLC', 'Disease', 'MESH:D002289', (78, 83))	('FGFR2', 'Gene', (24, 29))
131788	25035393	Inherent in their clinical relevance, models driven by FGFR2 activating mutations have the potential to help researchers explore the biology of the receptor tyrosine kinase and to evaluate novel targeted therapies for patients that fall into this genetically defined subset of cancers.	('mutations', 'Var', (72, 81))	('fall', 'Phenotype', 'HP:0002527', (232, 236))	('patients', 'Species', '9606', (218, 226))	('cancers', 'Phenotype', 'HP:0002664', (277, 284))	('FGFR2', 'Gene', (55, 60))	('cancers', 'Disease', (277, 284))	('cancers', 'Disease', 'MESH:D009369', (277, 284))	('cancer', 'Phenotype', 'HP:0002664', (277, 283))	('activating', 'PosReg', (61, 71))
131789	25035393	A multitude of FGFR2 mutations have been identified in NSCLC, although it has been unclear as to which are, in fact, oncogenic drivers up until recently.	('identified', 'Reg', (41, 51))	('NSCLC', 'Disease', (55, 60))	('NSCLC', 'Disease', 'MESH:D002289', (55, 60))	('FGFR2', 'Gene', (15, 20))	('NSCLC', 'Phenotype', 'HP:0030358', (55, 60))	('mutations', 'Var', (21, 30))
131792	25035393	We developed conditional bi-allelic mice that upon exposure to nasally delivered adenovirus-cre led to activated FGFR2 signaling, while also abrogating p53 function concurrently.	('p53', 'Protein', (152, 155))	('FGFR2 signaling', 'MPA', (113, 128))	('mice', 'Species', '10090', (36, 40))	('function', 'MPA', (156, 164))	('activated', 'PosReg', (103, 112))	('abrogating', 'NegReg', (141, 151))	('adenovirus-cre', 'Var', (81, 95))
131806	25035393	This sustained response was durable and strikingly resembled our study of EGFR tyrosine kinase inhibitors in mutant EGFR-driven mouse lung cancers.	('lung cancer', 'Phenotype', 'HP:0100526', (134, 145))	('EGFR-driven', 'Gene', (116, 127))	('cancers', 'Phenotype', 'HP:0002664', (139, 146))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('lung cancers', 'Disease', 'MESH:D008175', (134, 146))	('lung cancers', 'Phenotype', 'HP:0100526', (134, 146))	('mouse', 'Species', '10090', (128, 133))	('mutant', 'Var', (109, 115))	('lung cancers', 'Disease', (134, 146))
131811	25035393	Although the mutations in FGFR2 were identified in an SqCC patient population, elevated FGFR2-related activity is seen across both major subtypes of NSCLC.	('FGFR2-related', 'Gene', (88, 101))	('NSCLC', 'Disease', 'MESH:D002289', (149, 154))	('patient', 'Species', '9606', (59, 66))	('NSCLC', 'Disease', (149, 154))	('FGFR2', 'Gene', (26, 31))	('activity', 'MPA', (102, 110))	('elevated', 'PosReg', (79, 87))	('mutations', 'Var', (13, 22))	('SqCC', 'Phenotype', 'HP:0002860', (54, 58))	('NSCLC', 'Phenotype', 'HP:0030358', (149, 154))
131816	25035393	They reported inactivation of IKKalpha (kinase-dead IKKalpha knock-in) drives the up-regulation of SqCC-associated markers including p63, Trim29 and keratin 5 leading to down-regulation of LKB1 (STK11) activity.	('IKKalpha', 'Gene', (52, 60))	('STK11', 'Gene', (195, 200))	('SqCC', 'Phenotype', 'HP:0002860', (99, 103))	('LKB1', 'Gene', (189, 193))	('inactivation', 'Var', (14, 26))	('SqCC-associated', 'Disease', (99, 114))	('IKKalpha', 'Gene', '12675', (30, 38))	('keratin 5', 'Gene', (149, 158))	('IKKalpha', 'Gene', '12675', (52, 60))	('p63', 'Gene', (133, 136))	('Trim29', 'Gene', (138, 144))	('Trim29', 'Gene', '72169', (138, 144))	('STK11', 'Gene', '20869', (195, 200))	('p63', 'Gene', '22061', (133, 136))	('activity', 'MPA', (202, 210))	('down-regulation', 'NegReg', (170, 185))	('keratin 5', 'Gene', '110308', (149, 158))	('LKB1', 'Gene', '20869', (189, 193))	('up-regulation', 'PosReg', (82, 95))	('IKKalpha', 'Gene', (30, 38))
131818	25035393	Third, there is also a strong possibility that those patients with FGFR2 mutations may require another collaborating oncogene to drive the differentiation into the squamous cell histology, or perhaps the loss of another tumor suppressor.	('drive', 'PosReg', (129, 134))	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('patients', 'Species', '9606', (53, 61))	('tumor', 'Disease', (220, 225))	('FGFR2', 'Gene', (67, 72))	('differentiation', 'CPA', (139, 154))	('tumor', 'Disease', 'MESH:D009369', (220, 225))	('mutations', 'Var', (73, 82))
131827	33863293	High expression of GMFG predicted worse OS in GBM (HR = 1.5, P = 0.017), LGG (HR = 2.2, P < 0.001), LUSC (HR = 1.4, P = 0.022) and ocular melanomas (UVM) (HR = 7, P < 0.001), as well as worse DFS in LGG (HR = 1.8, P < 0.001) and prostate cancer (PRAD) (HR = 1.9, P = 0.004).	('melanoma', 'Phenotype', 'HP:0002861', (138, 146))	('High expression', 'Var', (0, 15))	('LUSC', 'Disease', (100, 104))	('ocular melanomas', 'Phenotype', 'HP:0025534', (131, 147))	('prostate cancer', 'Disease', (229, 244))	('LGG', 'Disease', (199, 202))	('ocular melanomas', 'Disease', 'MESH:D008545', (131, 147))	('LGG', 'Disease', (73, 76))	('GMFG', 'Gene', (19, 23))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('GBM', 'Disease', (46, 49))	('ocular melanomas', 'Disease', (131, 147))	('prostate cancer', 'Disease', 'MESH:D011471', (229, 244))	('prostate cancer', 'Phenotype', 'HP:0012125', (229, 244))	('melanomas', 'Phenotype', 'HP:0002861', (138, 147))	('GBM', 'Phenotype', 'HP:0012174', (46, 49))	('LUSC', 'Phenotype', 'HP:0030359', (100, 104))
131828	33863293	In contrast, high expression of GMFG was associated with better OS in skin cutaneous melanoma (SKCM) (HR = 0.59, P < 0.001) and thymoma (THYM) (HR = 0.098, P = 0.031), as well as better DFS in bile duct cancer (CHOL) (HR = 0.2, P = 0.003).	('THYM', 'Phenotype', 'HP:0100522', (137, 141))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (70, 93))	('GMFG', 'Gene', (32, 36))	('bile duct cancer', 'Phenotype', 'HP:0030153', (193, 209))	('high expression', 'Var', (13, 28))	('bile duct cancer', 'Disease', (193, 209))	('thymoma', 'Phenotype', 'HP:0100522', (128, 135))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('skin cutaneous melanoma', 'Disease', (70, 93))	('thymoma', 'Disease', 'MESH:D013945', (128, 135))	('bile duct cancer', 'Disease', 'MESH:D001650', (193, 209))	('thymoma', 'Disease', (128, 135))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (75, 93))	('CHOL', 'Disease', (211, 215))	('CHOL', 'Disease', 'None', (211, 215))
131830	33863293	Our study preliminarily identified that GMFG may cause different survivals for different cancers through modulating tumor progression, immune response status and tissue-specific tumor microenvironment (TME).	('iron', 'Chemical', 'MESH:D007501', (192, 196))	('immune response', 'CPA', (135, 150))	('tumor', 'Disease', (178, 183))	('GMFG', 'Var', (40, 44))	('cancers', 'Phenotype', 'HP:0002664', (89, 96))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('cancers', 'Disease', 'MESH:D009369', (89, 96))	('cancers', 'Disease', (89, 96))	('survivals', 'Disease', (65, 74))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('cause', 'Reg', (49, 54))	('tumor', 'Disease', (116, 121))	('modulating', 'Reg', (105, 115))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
131836	33863293	These two studies demonstrated that GMFG could promote the migration and proliferation of ovarian and colorectal cancer cells, and the high expression of GMFG was related to poor survival outcome for ovarian cancer patients.	('ovarian', 'Disease', 'MESH:D010049', (200, 207))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('ovarian cancer', 'Disease', 'MESH:D010051', (200, 214))	('related', 'Reg', (163, 170))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('high', 'Var', (135, 139))	('ovarian', 'Disease', (90, 97))	('colorectal cancer', 'Disease', 'MESH:D015179', (102, 119))	('migration', 'CPA', (59, 68))	('ovarian cancer', 'Disease', (200, 214))	('colorectal cancer', 'Disease', (102, 119))	('promote', 'PosReg', (47, 54))	('ovarian cancer', 'Phenotype', 'HP:0100615', (200, 214))	('ovarian', 'Disease', (200, 207))	('patients', 'Species', '9606', (215, 223))	('ovarian', 'Disease', 'MESH:D010049', (90, 97))	('proliferation', 'CPA', (73, 86))	('rectal cancer', 'Phenotype', 'HP:0100743', (106, 119))	('colorectal cancer', 'Phenotype', 'HP:0003003', (102, 119))
131854	33863293	1c, high expression of GMFG was correlated with early pathological stage in bladder cancer (BLCA) (P = 0.016), LUAD (P = 0.015), skin cutaneous melanoma (SKCM) (P = 0.006) and thyroid cancer (THCA) (P = 0.01), but was linked with advanced pathological stage in stomach cancer (STAD) (P = 0.028).	('skin cutaneous melanoma', 'Disease', (129, 152))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('high expression', 'Var', (4, 19))	('melanoma', 'Phenotype', 'HP:0002861', (144, 152))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (134, 152))	('thyroid cancer', 'Disease', (176, 190))	('stomach cancer', 'Disease', 'MESH:D013274', (261, 275))	('stomach cancer', 'Phenotype', 'HP:0012126', (261, 275))	('LUAD', 'Phenotype', 'HP:0030078', (111, 115))	('THCA', 'Phenotype', 'HP:0002890', (192, 196))	('thyroid cancer', 'Disease', 'MESH:D013964', (176, 190))	('cancer', 'Phenotype', 'HP:0002664', (269, 275))	('correlated', 'Reg', (32, 42))	('GMFG', 'Gene', (23, 27))	('LUAD', 'Disease', (111, 115))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('bladder cancer', 'Disease', 'MESH:D001749', (76, 90))	('bladder cancer', 'Disease', (76, 90))	('thyroid cancer', 'Phenotype', 'HP:0002890', (176, 190))	('stomach cancer', 'Disease', (261, 275))	('bladder cancer', 'Phenotype', 'HP:0009725', (76, 90))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (129, 152))	('BLCA', 'Phenotype', 'HP:0009725', (92, 96))
131855	33863293	For survival outcome, high expression of GMFG predicted worse OS in GBM (HR = 1.5, P = 0.017), LGG (HR = 2.2, P < 0.001), LUSC (HR = 1.4, P = 0.022) and UVM (HR = 7, P < 0.001), as well as worse DFS in LGG (HR = 1.8, P < 0.001) and prostate cancer (PRAD) (HR = 1.9, P = 0.004).	('high expression', 'Var', (22, 37))	('LUSC', 'Disease', (122, 126))	('prostate cancer', 'Disease', (232, 247))	('LGG', 'Disease', (202, 205))	('GBM', 'Phenotype', 'HP:0012174', (68, 71))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('prostate cancer', 'Disease', 'MESH:D011471', (232, 247))	('prostate cancer', 'Phenotype', 'HP:0012125', (232, 247))	('LUSC', 'Phenotype', 'HP:0030359', (122, 126))	('LGG', 'Disease', (95, 98))	('GMFG', 'Gene', (41, 45))	('UVM', 'Disease', (153, 156))	('GBM', 'Disease', (68, 71))
131856	33863293	In contrast, high expression of GMFG was associated with better OS in SKCM (HR = 0.59, P < 0.001) and THYM (HR = 0.098, P = 0.031), as well as better DFS in bile duct cancer (CHOL) (HR = 0.2, P = 0.003) (Fig.	('bile duct cancer', 'Disease', 'MESH:D001650', (157, 173))	('CHOL', 'Disease', 'None', (175, 179))	('THYM', 'Phenotype', 'HP:0100522', (102, 106))	('SKCM', 'Disease', (70, 74))	('CHOL', 'Disease', (175, 179))	('GMFG', 'Gene', (32, 36))	('high expression', 'Var', (13, 28))	('THYM', 'Disease', (102, 106))	('bile duct cancer', 'Phenotype', 'HP:0030153', (157, 173))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('bile duct cancer', 'Disease', (157, 173))
131862	33863293	We also summarized the top 10 most significant items of GO/KEGG pathways for each individual cancer (Supplementary file 1-4: Table S1-S4), and we found that GMFG was notably associated with the biological process of immune response in most cancers, so we decided to analyze the correlation between GMFG and its immunomodulators co-expression genes.	('cancer', 'Disease', (93, 99))	('associated with', 'Reg', (174, 189))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('cancer', 'Disease', (240, 246))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('GMFG', 'Var', (157, 161))	('cancer', 'Disease', 'MESH:D009369', (240, 246))	('cancers', 'Phenotype', 'HP:0002664', (240, 247))	('cancers', 'Disease', (240, 247))	('cancers', 'Disease', 'MESH:D009369', (240, 247))
131864	33863293	As for co-stimulators, GMFG was highly associated with CD80 and CD28 in most cancers.	('cancers', 'Disease', 'MESH:D009369', (77, 84))	('CD28', 'Gene', (64, 68))	('cancers', 'Phenotype', 'HP:0002664', (77, 84))	('GMFG', 'Var', (23, 27))	('cancers', 'Disease', (77, 84))	('CD28', 'Gene', '940', (64, 68))	('CD80', 'Gene', (55, 59))	('associated', 'Reg', (39, 49))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('CD80', 'Gene', '941', (55, 59))
131874	33863293	In addition, high expression of GMFG was associated with early pathological stage in four cancers (BLCA, LUAD, SKCM, and THCA), but was correlated with advanced pathological stage in STAD.	('cancers', 'Disease', (90, 97))	('SKCM', 'Disease', (111, 115))	('associated', 'Reg', (41, 51))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('high', 'Var', (13, 17))	('BLCA', 'Phenotype', 'HP:0009725', (99, 103))	('GMFG', 'Gene', (32, 36))	('LUAD', 'Disease', (105, 109))	('THCA', 'Phenotype', 'HP:0002890', (121, 125))	('correlated', 'Reg', (136, 146))	('LUAD', 'Phenotype', 'HP:0030078', (105, 109))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('cancers', 'Disease', 'MESH:D009369', (90, 97))
131875	33863293	Moreover, the associations of GMFG expression with OS and DFS were also investigated, and high expression of GMFG predicted worse OS in four cancers (GBM, LGG, LUSC, and UVM), and worse DFS for LGG and PRAD, but was associated with better OS in SKCM and THYM, better DFS in CHOL.	('better OS', 'Disease', (232, 241))	('PRAD', 'Disease', (202, 206))	('LUSC', 'Phenotype', 'HP:0030359', (160, 164))	('high expression', 'Var', (90, 105))	('SKCM', 'Disease', (245, 249))	('cancers', 'Phenotype', 'HP:0002664', (141, 148))	('CHOL', 'Disease', 'None', (274, 278))	('cancers', 'Disease', (141, 148))	('LGG', 'Disease', (155, 158))	('THYM', 'Phenotype', 'HP:0100522', (254, 258))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('GMFG', 'Gene', (109, 113))	('CHOL', 'Disease', (274, 278))	('GBM', 'Phenotype', 'HP:0012174', (150, 153))	('worse OS', 'Disease', (124, 132))	('LUSC', 'Disease', (160, 164))	('LGG', 'Disease', (194, 197))	('cancers', 'Disease', 'MESH:D009369', (141, 148))	('THYM', 'Disease', (254, 258))
131883	33863293	Taken together, that GMFG enhances both the cancer progression and the immune defense, and patients' survival outcome may depend on the balance between the speed of cancer development and the ability of immune system against cancer tissues.	('immune defense', 'CPA', (71, 85))	('cancer', 'Disease', 'MESH:D009369', (225, 231))	('patients', 'Species', '9606', (91, 99))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('cancer', 'Disease', (225, 231))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('GMFG', 'Var', (21, 25))	('enhances', 'PosReg', (26, 34))	('cancer', 'Disease', (165, 171))	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
132014	30417146	Alterations of the genome are among the main factors that have been implicated in the etiology of cancer.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('Alterations', 'Var', (0, 11))	('cancer', 'Disease', (98, 104))	('cancer', 'Disease', 'MESH:D009369', (98, 104))
132015	30417146	These alterations can be observed as the insertion, deletion or substitution of nucleotides or chromosomal abnormalities leading to the manifestation of a defective phenotype.	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (95, 120))	('substitution', 'Var', (64, 76))	('chromosomal abnormalities', 'Disease', (95, 120))	('deletion', 'Var', (52, 60))
132022	30417146	This RNA-seq study identified several genetic alterations that can explain the highly invasive behavioural pattern of tongue squamous cell carcinoma.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (125, 148))	('tongue squamous cell carcinoma', 'Phenotype', 'HP:0030413', (118, 148))	('carcinoma', 'Phenotype', 'HP:0030731', (139, 148))	('tongue squamous cell carcinoma', 'Disease', 'MESH:D002294', (118, 148))	('tongue squamous cell carcinoma', 'Disease', (118, 148))	('alterations', 'Var', (46, 57))
132036	30417146	The 'immunoscore' is one such method based upon a standardized algorithm, where CD3+ and CD8+ TILs are quantified in the tumour core (CT) and invasive margin (IM).	('CD', 'Chemical', 'MESH:D002104', (80, 82))	('CD3+', 'Var', (80, 84))	('CD8', 'Gene', (89, 92))	('tumour', 'Phenotype', 'HP:0002664', (121, 127))	('CD8', 'Gene', '925', (89, 92))	('CD', 'Chemical', 'MESH:D002104', (89, 91))	('tumour', 'Disease', 'MESH:D009369', (121, 127))	('tumour', 'Disease', (121, 127))
132083	30417146	The depletion of TANS reduces tumour growth and inhibits immunosuppression in the tumour microenvironment, thus leading to increased CD8+ cytotoxic T lymphocytes.	('tumour growth', 'Disease', (30, 43))	('increased', 'PosReg', (123, 132))	('tumour', 'Phenotype', 'HP:0002664', (82, 88))	('tumour growth', 'Disease', 'MESH:D006130', (30, 43))	('inhibits', 'NegReg', (48, 56))	('TANS', 'Gene', (17, 21))	('immunosuppression', 'CPA', (57, 74))	('CD8', 'Gene', (133, 136))	('tumour', 'Disease', 'MESH:D009369', (30, 36))	('tumour', 'Disease', 'MESH:D009369', (82, 88))	('depletion', 'Var', (4, 13))	('tumour', 'Disease', (30, 36))	('CD8', 'Gene', '925', (133, 136))	('TANS', 'Chemical', '-', (17, 21))	('tumour', 'Disease', (82, 88))	('reduces', 'NegReg', (22, 29))	('tumour', 'Phenotype', 'HP:0002664', (30, 36))
132084	30417146	Alterations of myelopoiesis-associated tumour growth leads to the recruitment of immunosuppressive MDSCs.	('tumour growth', 'Disease', 'MESH:D006130', (39, 52))	('Alterations', 'Var', (0, 11))	('tumour', 'Phenotype', 'HP:0002664', (39, 45))	('recruitment', 'MPA', (66, 77))	('tumour growth', 'Disease', (39, 52))
132088	30417146	This MDSC-specific methylation is responsible for the downregulation of S1PR4, RUNX1, AQP9, LMO2 or FYN genes.	('RUNX1', 'Gene', '861', (79, 84))	('S1PR4', 'Gene', '8698', (72, 77))	('LMO2', 'Gene', '4005', (92, 96))	('methylation', 'Var', (19, 30))	('LMO2', 'Gene', (92, 96))	('downregulation', 'NegReg', (54, 68))	('RUNX1', 'Gene', (79, 84))	('S1PR4', 'Gene', (72, 77))	('AQP9', 'Gene', (86, 90))	('FYN', 'Gene', (100, 103))	('AQP9', 'Gene', '366', (86, 90))	('FYN', 'Gene', '2534', (100, 103))
132095	30417146	It has been observed that amplification of this particular chromosomal band is often associated with worse prognosis during the investigation of cell lines obtained from oral cancer patients.	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('amplification', 'Var', (26, 39))	('associated', 'Reg', (85, 95))	('patients', 'Species', '9606', (182, 190))	('oral cancer', 'Disease', 'MESH:D009062', (170, 181))	('oral cancer', 'Disease', (170, 181))
132098	30417146	CCND1 (encodes cyclin D1 that promotes the G1-S phase transition during the cell cycle) and CTTN (coding for cortactin, an F-actin binding protein that permit various protein interactions) are two of the most frequently associated drivers of locus 11q13.	('associated', 'Reg', (220, 230))	('cyclin D1', 'Gene', '595', (15, 24))	('locus', 'Var', (242, 247))	('cortactin', 'Gene', (109, 118))	('CTTN', 'Gene', (92, 96))	('cyclin D1', 'Gene', (15, 24))	('CTTN', 'Gene', '2017', (92, 96))	('G1-S', 'CPA', (43, 47))	('CCND1', 'Gene', (0, 5))	('cortactin', 'Gene', '2017', (109, 118))	('CCND1', 'Gene', '595', (0, 5))
132099	30417146	The amplification of CTTN confers resistance to the anticancer drug gefitinib, while amplification of CCND1 is associated with resistance to cisplatin.	('cisplatin', 'Chemical', 'MESH:D002945', (141, 150))	('associated', 'Reg', (111, 121))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('resistance', 'MPA', (34, 44))	('CTTN', 'Gene', '2017', (21, 25))	('CCND1', 'Gene', (102, 107))	('amplification', 'Var', (4, 17))	('amplification', 'Var', (85, 98))	('CTTN', 'Gene', (21, 25))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('CCND1', 'Gene', '595', (102, 107))	('gefitinib', 'Chemical', 'MESH:D000077156', (68, 77))
132100	30417146	The presence of these oncogenes influencesthe clinicopathological characteristics, such as lymph node involvement, poor tumour differentiationand low survival, observed in OSCC.	('tumour', 'Phenotype', 'HP:0002664', (120, 126))	('tumour', 'Disease', 'MESH:D009369', (120, 126))	('lymph node involvement', 'CPA', (91, 113))	('low survival', 'CPA', (146, 158))	('tumour', 'Disease', (120, 126))	('influencesthe', 'Reg', (32, 45))	('presence', 'Var', (4, 12))	('OSCC', 'Disease', (172, 176))
132103	30417146	Actin cytoskeleton remodelling through activation of FAK/Src signalling and a decrease in cortactin phosphorylation due to epigallocatechin-3 gallate treatment resulted in inhibition of oral cancer cell invasiveness and motility.	('motility', 'CPA', (220, 228))	('epigallocatechin-3', 'Var', (123, 141))	('cortactin', 'Gene', (90, 99))	('Src', 'Gene', (57, 60))	('Src', 'Gene', '6714', (57, 60))	('decrease', 'NegReg', (78, 86))	('activation', 'PosReg', (39, 49))	('cortactin', 'Gene', '2017', (90, 99))	('FAK', 'Gene', '5747', (53, 56))	('FAK', 'Gene', (53, 56))	('epigallocatechin-3 gallate', 'Chemical', 'MESH:C045651', (123, 149))	('oral cancer cell invasiveness', 'Disease', 'MESH:D009062', (186, 215))	('oral cancer cell invasiveness', 'Disease', (186, 215))	('Actin', 'MPA', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('inhibition', 'NegReg', (172, 182))
132117	30417146	This phenomenon can be attributed to genomic amplification in 11q13.3, impacting the regulation of the FADD gene.	('impacting', 'Reg', (71, 80))	('genomic amplification', 'Var', (37, 58))	('FADD', 'Gene', (103, 107))	('FADD', 'Gene', '8772', (103, 107))	('regulation', 'MPA', (85, 95))
132120	30417146	Overexpression of FADD is more likely to make the carcinoma metastatic.	('carcinoma', 'Disease', 'MESH:D002277', (50, 59))	('carcinoma', 'Phenotype', 'HP:0030731', (50, 59))	('FADD', 'Gene', '8772', (18, 22))	('carcinoma', 'Disease', (50, 59))	('FADD', 'Gene', (18, 22))	('Overexpression', 'Var', (0, 14))
132125	30417146	Loss of theTP53 allele has long been associated with defects in cell cycle regulation, leading to uncontrolled amplification.	('cell', 'MPA', (64, 68))	('TP53', 'Gene', '7157', (11, 15))	('TP53', 'Gene', (11, 15))	('defects', 'NegReg', (53, 60))	('uncontrolled amplification', 'MPA', (98, 124))	('Loss', 'Var', (0, 4))
132130	30417146	Genetic signatures indicate that mutations in several cancer genes, including USP9X, MLL4, ARID2, UNC13C and TRPM3, are specific to OSCC-GB.	('USP9X', 'Gene', (78, 83))	('MLL4', 'Gene', '9757', (85, 89))	('MLL4', 'Gene', (85, 89))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('USP9X', 'Gene', '8239', (78, 83))	('TRPM3', 'Gene', (109, 114))	('UNC13C', 'Gene', (98, 104))	('mutations', 'Var', (33, 42))	('cancer', 'Disease', (54, 60))	('ARID2', 'Gene', '196528', (91, 96))	('TRPM3', 'Gene', '80036', (109, 114))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('ARID2', 'Gene', (91, 96))	('UNC13C', 'Gene', '440279', (98, 104))
132134	30417146	A very high proportion of C4G mutations, especially among tobacco users, was observed by the India Project Team of the International Cancer Genome Consortium.	('C4G', 'Gene', (26, 29))	('tobacco', 'Species', '4097', (58, 65))	('mutations', 'Var', (30, 39))	('Cancer', 'Phenotype', 'HP:0002664', (133, 139))
132135	30417146	It seems that mutations in tumour suppressor genes are more prevalent than mutations of oncogenes in oral cancer.	('oral cancer', 'Disease', (101, 112))	('tumour', 'Phenotype', 'HP:0002664', (27, 33))	('oral cancer', 'Disease', 'MESH:D009062', (101, 112))	('tumour', 'Disease', 'MESH:D009369', (27, 33))	('prevalent', 'Reg', (60, 69))	('tumour', 'Disease', (27, 33))	('mutations', 'Var', (14, 23))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
132142	30417146	As expected, loss of the tumour suppressor gene TP53 and copy number gains of the oncogenes MYC, CCND1, ERBB2 and EGFR were detected in tumoural lesions.	('CCND1', 'Gene', (97, 102))	('tumoural lesions', 'Disease', (136, 152))	('copy number', 'Var', (57, 68))	('TP53', 'Gene', '7157', (48, 52))	('gains', 'PosReg', (69, 74))	('MYC', 'Gene', '4609', (92, 95))	('CCND1', 'Gene', '595', (97, 102))	('TP53', 'Gene', (48, 52))	('tumoural lesions', 'Disease', 'MESH:D009062', (136, 152))	('loss of the tumour', 'Disease', 'MESH:D009369', (13, 31))	('MYC', 'Gene', (92, 95))	('EGFR', 'Gene', '1956', (114, 118))	('tumour', 'Phenotype', 'HP:0002664', (25, 31))	('ERBB2', 'Gene', '2064', (104, 109))	('EGFR', 'Gene', (114, 118))	('loss of the tumour', 'Disease', (13, 31))	('ERBB2', 'Gene', (104, 109))	('tumour', 'Phenotype', 'HP:0002664', (136, 142))
132152	30417146	On the other hand, deletions were detected for Caspase8 and MTAP.	('Caspase8', 'Gene', '841', (47, 55))	('MTAP', 'Gene', (60, 64))	('Caspase8', 'Gene', (47, 55))	('MTAP', 'Gene', '4507', (60, 64))	('deletions', 'Var', (19, 28))
132156	30417146	Copy number gain at 3q26.3 and 11q13 was present irrespective of HPV status, although its effect was more severe in HPV-negative tumours.	('tumour', 'Phenotype', 'HP:0002664', (129, 135))	('HPV', 'Species', '10566', (116, 119))	('tumours', 'Phenotype', 'HP:0002664', (129, 136))	('HPV', 'Species', '10566', (65, 68))	('tumours', 'Disease', 'MESH:D009369', (129, 136))	('tumours', 'Disease', (129, 136))	('Copy number', 'Var', (0, 11))
132158	30417146	Loss of 16q in HPV-related OSCC was found to be a strong indicator of favourable outcome with no recurrence.	('Loss of 16q', 'Var', (0, 11))	('HPV', 'Species', '10566', (15, 18))	('HPV-related', 'Gene', (15, 26))
132167	30417146	Emerging technologies that can provide both genetic and epigenetic information have the potential to provide an overall picture of tumour progression.	('tumour', 'Disease', (131, 137))	('tumour', 'Phenotype', 'HP:0002664', (131, 137))	('tumour', 'Disease', 'MESH:D009369', (131, 137))	('epigenetic', 'Var', (56, 66))
132170	30417146	Alterations in MHC can be reversible regulatory defects or irreversible structural defects that can influence the outcome of cancer immunotherapy.	('Alterations', 'Var', (0, 11))	('MHC', 'Gene', (15, 18))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('influence', 'Reg', (100, 109))
132173	30417146	Loss of heterozygosity on chromosome 15, which codes for beta-2 microglobulin, is quite prevalent in some cancers.	('Loss of heterozygosity', 'Var', (0, 22))	('beta-2 microglobulin', 'Gene', '567', (57, 77))	('cancers', 'Phenotype', 'HP:0002664', (106, 113))	('prevalent', 'Reg', (88, 97))	('cancers', 'Disease', (106, 113))	('cancers', 'Disease', 'MESH:D009369', (106, 113))	('beta-2 microglobulin', 'Gene', (57, 77))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
132175	30417146	Another example of the integrity between genomic alterations and immunomodulation in many different types of cancer can be observed in copy number gains of chromosome 9p involving PD-L1.	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('cancer', 'Disease', (109, 115))	('copy number gains', 'Var', (135, 152))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('PD-L1', 'Gene', (180, 185))
132177	30417146	JAK2 is a transcriptional activator of both PD-1 ligands and amplification of this locus provides a distinct molecular subtype in breast cancer, gastric cancer and lymphomas.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('gastric cancer', 'Disease', 'MESH:D013274', (145, 159))	('breast cancer', 'Disease', (130, 143))	('breast cancer', 'Phenotype', 'HP:0003002', (130, 143))	('lymphomas', 'Phenotype', 'HP:0002665', (164, 173))	('JAK2', 'Gene', '3717', (0, 4))	('gastric cancer', 'Phenotype', 'HP:0012126', (145, 159))	('lymphomas', 'Disease', 'MESH:D008223', (164, 173))	('amplification', 'Var', (61, 74))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('JAK2', 'Gene', (0, 4))	('lymphoma', 'Phenotype', 'HP:0002665', (164, 172))	('lymphomas', 'Disease', (164, 173))	('breast cancer', 'Disease', 'MESH:D001943', (130, 143))	('gastric cancer', 'Disease', (145, 159))
132179	30417146	The genetic basis of PD-1 ligand deregulation and overexpression in Hodgkin's lymphoma suggests that a blockade with an anti-PD-1 antibody could be used to treat this disease.	('overexpression', 'PosReg', (50, 64))	('PD-1', 'Gene', (21, 25))	('lymphoma', 'Phenotype', 'HP:0002665', (78, 86))	("Hodgkin's lymphoma", 'Disease', 'MESH:D006689', (68, 86))	("Hodgkin's lymphoma", 'Disease', (68, 86))	('deregulation', 'Var', (33, 45))	("Hodgkin's lymphoma", 'Phenotype', 'HP:0012189', (68, 86))
132181	30417146	It is quite obvious that increased neoantigen diversity caused by genomic alterations will have an effect on the immune infiltrate within TME.	('genomic alterations', 'Var', (66, 85))	('TME', 'Chemical', '-', (138, 141))	('increased', 'PosReg', (25, 34))	('effect', 'Reg', (99, 105))	('immune', 'CPA', (113, 119))	('neoantigen diversity', 'MPA', (35, 55))
132261	30185791	The groups S1: (Pep8_LTA4H, Pep12_CSTB), S2: (Pep8_LTA4H, Pep9_COL6A1, Pep12_CSTB), S3: (Pep8_LTA4H, Pep9_COL6A1), and S4: (LTA4H) are the most relevant signatures (Si) considering accuracy and AUC (Fig.	('Pep8_LTA4H', 'Var', (16, 26))	('CSTB', 'Gene', '1476', (34, 38))	('COL6A1', 'Gene', '1291', (106, 112))	('COL6A1', 'Gene', (106, 112))	('Pep8_LTA4H', 'Var', (89, 99))	('CSTB', 'Gene', (34, 38))	('COL6A1', 'Gene', '1291', (63, 69))	('COL6A1', 'Gene', (63, 69))	('CSTB', 'Gene', '1476', (77, 81))	('CSTB', 'Gene', (77, 81))	('Pep8_LTA4H', 'Var', (46, 56))
132282	30185791	It is interesting that it has previously been reported that low levels of CSTB result in an increase in extracellular matrix (ECM) degradation, migration, and cell invasion.	('low levels', 'Var', (60, 70))	('CSTB', 'Gene', (74, 78))	('increase', 'PosReg', (92, 100))	('cell invasion', 'CPA', (159, 172))	('CSTB', 'Gene', '1476', (74, 78))	('migration', 'CPA', (144, 153))
132288	30185791	Another recent study has indicated that LTA4H regulates the cell cycle and the knockout of the protein reduced skin cancer development in mouse model.	('skin cancer', 'Disease', 'MESH:D012878', (111, 122))	('mouse', 'Species', '10090', (138, 143))	('reduced', 'NegReg', (103, 110))	('LTA4H', 'Gene', (40, 45))	('skin cancer', 'Phenotype', 'HP:0008069', (111, 122))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('knockout', 'Var', (79, 87))	('skin cancer', 'Disease', (111, 122))	('cell cycle', 'CPA', (60, 70))	('regulates', 'Reg', (46, 55))
132290	30185791	Furthermore, high levels of ITGAV have previously been associated with tumor growth regulation and metastasis in tumors of the hypopharynx and larynx and tumor progression in colorectal cancer, but not previously in oral cancer.	('ITGAV', 'Gene', '3685', (28, 33))	('tumors of the hypopharynx', 'Disease', 'MESH:D009369', (113, 138))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('colorectal cancer', 'Disease', 'MESH:D015179', (175, 192))	('ITGAV', 'Gene', (28, 33))	('tumor', 'Disease', (154, 159))	('colorectal cancer', 'Disease', (175, 192))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('high levels', 'Var', (13, 24))	('tumor', 'Disease', (113, 118))	('tumors of the hypopharynx', 'Disease', (113, 138))	('oral cancer', 'Disease', 'MESH:D009062', (216, 227))	('oral cancer', 'Disease', (216, 227))	('associated with', 'Reg', (55, 70))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('metastasis', 'CPA', (99, 109))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('tumor', 'Disease', (71, 76))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))	('colorectal cancer', 'Phenotype', 'HP:0003003', (175, 192))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))
132305	30185791	identified high levels of CSTB as an independent marker for bladder cancer recurrence.	('CSTB', 'Gene', '1476', (26, 30))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('CSTB', 'Gene', (26, 30))	('high levels', 'Var', (11, 22))	('bladder cancer', 'Phenotype', 'HP:0009725', (60, 74))	('bladder cancer recurrence', 'Phenotype', 'HP:0012786', (60, 85))	('bladder cancer', 'Disease', 'MESH:D001749', (60, 74))	('bladder cancer', 'Disease', (60, 74))
132308	30185791	The lymph node status was the prioritized clinical parameter employed because lymph node metastasis is the most important factor for prognosis in oral cancer and its presence is highly associated with a poor prognosis.	('clinical', 'Species', '191496', (42, 50))	('presence', 'Var', (166, 174))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('lymph node metastasis', 'CPA', (78, 99))	('oral cancer', 'Disease', 'MESH:D009062', (146, 157))	('oral cancer', 'Disease', (146, 157))
132344	30185791	For protein extraction and digestion, samples were treated with 8 M urea, followed by protein reduction with dithiothreitol (5 mM for 25 min at 56  C) and alkylation with iodoacetamide (14 mM for 30 min at room temperature in the dark).	('iodoacetamide', 'Chemical', 'MESH:D007460', (171, 184))	('reduction', 'NegReg', (94, 103))	('protein', 'Protein', (86, 93))	('alkylation', 'Var', (155, 165))	('dithiothreitol', 'Chemical', 'MESH:D004229', (109, 123))	('urea', 'Chemical', 'MESH:D014508', (68, 72))
132362	30185791	The antibodies were anti-CSTB (1:500, Sigma:HPA017380), anti-LTA4H (1:500, Sigma:HPA008399), anti-NDRG1 (1:500 Sigma:HPA006881), anti-PGK1 (1:500, Sigma:SAB1300102), anti-COL6A1 (1:1000, Sigma:HPA019142), anti-ITGAV (1:1000, Sigma:HPA004856), anti-MB (Sigma:HPA003123).	('1:500', 'Var', (140, 145))	('NDRG1', 'Gene', '10397', (98, 103))	('COL6A1', 'Gene', '1291', (171, 177))	('COL6A1', 'Gene', (171, 177))	('ITGAV', 'Gene', (210, 215))	('CSTB', 'Gene', '1476', (25, 29))	('CSTB', 'Gene', (25, 29))	('1:500', 'Var', (68, 73))	('ITGAV', 'Gene', '3685', (210, 215))	('1:500', 'Var', (31, 36))	('NDRG1', 'Gene', (98, 103))	('PGK1', 'Gene', '5230', (134, 138))	('PGK1', 'Gene', (134, 138))	('MB', 'Gene', '4151', (248, 250))	('1:1000', 'Var', (217, 223))
132378	30185791	The stable isotope-labeled peptides (SIL) were synthesized with heavy isotopes on lysine, arginine or leucine (+8, +10, or +7 Da, respectively), localized, preferentially, at the C-terminal of the peptide (Thermo Fisher Scientific).	('leucine', 'Chemical', 'MESH:D007930', (102, 109))	('SIL', 'Disease', 'None', (37, 40))	('+8', 'Var', (111, 113))	('lysine', 'Chemical', 'MESH:D008239', (82, 88))	('arginine', 'Chemical', 'MESH:D001120', (90, 98))	('SIL', 'Disease', (37, 40))
132404	30185791	; performed the sample preparation and laser microdissection of tumor tissues: C.C.S.M., N.K.C.	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('tumor', 'Disease', (64, 69))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('C.C.S.M.', 'Var', (79, 87))
132405	30185791	; performed the tumor tissue sample preparation for mass spectrometry analysis: C.M.C., R.R.D., A.F.B.L.	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('R.R.D.', 'Var', (88, 94))	('tumor', 'Disease', (16, 21))	('C.M.C.', 'Var', (80, 86))
132406	30185791	; performed the LC-MS/MS of tumor tissue samples: R.R.D, B.A.P., C.M.C; performed the proteomics data analysis of tumor tissue samples: C.M.C., C.C.S.M.	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('tumor', 'Disease', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('C.M.C.', 'Var', (136, 142))	('tumor', 'Disease', (114, 119))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
132407	30185791	; performed the statistical analysis of targeted data: D.C.G., T.D.R., C.R., G.P.T, H.H.	('H.H', 'CellLine', 'CVCL:Y658', (84, 87))	('C.R.', 'Var', (71, 75))	('T.D.R.', 'Var', (63, 69))	('D.C.G.', 'Var', (55, 61))	('G.P.T', 'Var', (77, 82))
132495	24312435	An epidemiological study conducted in Taiwan has shown that the odds ratio for esophageal cancer is greater for alcohol drinking than smoking (17.6 vs 5.4).	('esophageal cancer', 'Disease', (79, 96))	('alcohol', 'Chemical', 'MESH:D000438', (112, 119))	('alcohol drinking', 'Phenotype', 'HP:0030955', (112, 128))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('esophageal cancer', 'Disease', 'MESH:D004938', (79, 96))	('alcohol drinking', 'Var', (112, 128))
132526	24205245	Expression of the Mismatch Repair Gene hMLH1 Is Enhanced in Non-Small Cell Lung Cancer with EGFR Mutations Mismatch repair (MMR) plays a pivotal role in keeping the genome stable.	('Non-Small Cell Lung Cancer', 'Disease', (60, 86))	('Enhanced', 'PosReg', (48, 56))	('Expression', 'MPA', (0, 10))	('Lung Cancer', 'Phenotype', 'HP:0100526', (75, 86))	('Non-Small Cell Lung Cancer', 'Disease', 'MESH:D002289', (60, 86))	('Non-Small Cell Lung Cancer', 'Phenotype', 'HP:0030358', (60, 86))	('Small Cell Lung Cancer', 'Phenotype', 'HP:0030357', (64, 86))	('Cancer', 'Phenotype', 'HP:0002664', (80, 86))	('EGFR', 'Gene', '1956', (92, 96))	('EGFR', 'Gene', (92, 96))	('hMLH1', 'Gene', (39, 44))	('Mutations', 'Var', (97, 106))	('hMLH1', 'Gene', '4292', (39, 44))
132531	24205245	Stronger hMLH1 expression correlated to a higher frequency of EGFR mutations in exon 19 and 21 (p<0.0005).	('Stronger', 'PosReg', (0, 8))	('EGFR', 'Gene', (62, 66))	('mutations', 'Var', (67, 76))	('expression', 'MPA', (15, 25))	('hMLH1', 'Gene', (9, 14))	('hMLH1', 'Gene', '4292', (9, 14))
132532	24205245	Overexpression of hMLH1 and the adenocarcinoma subtype were both independent factors that related to EGFR mutations in NSCLCs (p=0.013 and p<0.0005).	('adenocarcinoma subtype', 'Disease', (32, 54))	('NSCLC', 'Disease', 'MESH:D002289', (119, 124))	('adenocarcinoma subtype', 'Disease', 'MESH:D000230', (32, 54))	('hMLH1', 'Gene', (18, 23))	('carcinoma', 'Phenotype', 'HP:0030731', (37, 46))	('EGFR', 'Gene', (101, 105))	('NSCLC', 'Phenotype', 'HP:0030358', (119, 124))	('hMLH1', 'Gene', '4292', (18, 23))	('mutations', 'Var', (106, 115))	('NSCLC', 'Disease', (119, 124))
132533	24205245	The expression of hMLH1, hMSH2 and PCNA increased, while Ki67 expression significantly decreased (p=0.030) in NSCLCs with EGFR mutations.	('PCNA', 'Gene', '5111', (35, 39))	('decreased', 'NegReg', (87, 96))	('hMLH1', 'Gene', (18, 23))	('NSCLC', 'Disease', (110, 115))	('expression', 'MPA', (4, 14))	('expression', 'MPA', (62, 72))	('hMLH1', 'Gene', '4292', (18, 23))	('NSCLC', 'Disease', 'MESH:D002289', (110, 115))	('hMSH2', 'Gene', (25, 30))	('increased', 'PosReg', (40, 49))	('hMSH2', 'Gene', '4436', (25, 30))	('mutations', 'Var', (127, 136))	('PCNA', 'Gene', (35, 39))	('EGFR', 'Gene', (122, 126))	('NSCLC', 'Phenotype', 'HP:0030358', (110, 115))
132535	24205245	Furthermore, EGFR mutations might be an early event of NSCLC that occur before MMR dysfunction.	('NSCLC', 'Disease', (55, 60))	('NSCLC', 'Disease', 'MESH:D002289', (55, 60))	('NSCLC', 'Phenotype', 'HP:0030358', (55, 60))	('EGFR', 'Gene', (13, 17))	('mutations', 'Var', (18, 27))
132537	24205245	Carcinogenesis of NSCLC is a multistep process involving alterations of multiple genes including oncogene activation and tumor suppressor gene inactivation.	('oncogene', 'Gene', (97, 105))	('NSCLC', 'Disease', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('NSCLC', 'Disease', 'MESH:D002289', (18, 23))	('tumor', 'Disease', (121, 126))	('alterations', 'Var', (57, 68))	('tumor', 'Disease', 'MESH:D009369', (121, 126))	('NSCLC', 'Phenotype', 'HP:0030358', (18, 23))	('activation', 'PosReg', (106, 116))	('inactivation', 'NegReg', (143, 155))
132538	24205245	Recent development of new agents with specific molecular targets, especially epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), has enhanced scientific interest in particular gene mutations and challenged some of the established paradigms in the therapeutic intervention of NSCLC.	('NSCLC', 'Disease', (296, 301))	('men', 'Species', '9606', (14, 17))	('epidermal growth factor receptor', 'Gene', '1956', (77, 109))	('enhanced', 'PosReg', (154, 162))	('NSCLC', 'Disease', 'MESH:D002289', (296, 301))	('NSCLC', 'Phenotype', 'HP:0030358', (296, 301))	('epidermal growth factor receptor', 'Gene', (77, 109))	('mutations', 'Var', (202, 211))
132539	24205245	Approximately 30-50% of NSCLCs have mutations in key genes, such as EGFR, KRAS, BRAF, PI3K and AKT.	('NSCLC', 'Disease', (24, 29))	('BRAF', 'Gene', (80, 84))	('NSCLC', 'Disease', 'MESH:D002289', (24, 29))	('AKT', 'Gene', '207', (95, 98))	('mutations', 'Var', (36, 45))	('KRAS', 'Gene', (74, 78))	('NSCLC', 'Phenotype', 'HP:0030358', (24, 29))	('AKT', 'Gene', (95, 98))	('BRAF', 'Gene', '673', (80, 84))	('EGFR', 'Gene', (68, 72))	('PI3K', 'Gene', (86, 90))
132540	24205245	These gene mutations are often related to the NSCLC patient response to molecular targeted drugs.	('mutations', 'Var', (11, 20))	('NSCLC', 'Disease', (46, 51))	('NSCLC', 'Disease', 'MESH:D002289', (46, 51))	('patient', 'Species', '9606', (52, 59))	('related', 'Reg', (31, 38))	('NSCLC', 'Phenotype', 'HP:0030358', (46, 51))
132541	24205245	For example, tumors with EGFR mutations in exon 19 or 21 are often sensitive to EGFR TKIs.	('EGFR', 'Gene', (25, 29))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Disease', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('mutations in', 'Var', (30, 42))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('sensitive', 'Reg', (67, 76))
132542	24205245	In contrast, patients with mutant KRAS tumors fail to benefit from adjuvant chemotherapy and do not respond to EGFR inhibitors.	('mutant', 'Var', (27, 33))	('patients', 'Species', '9606', (13, 21))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('KRAS tumors', 'Disease', 'MESH:D009369', (34, 45))	('KRAS tumors', 'Disease', (34, 45))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))
132543	24205245	Interestingly, half of the NSCLCs with the mutation in EGFR exon 19 or exon 21 produce secondary mutations in EGFR exon 20 and become resistant to TKIs after treatment for one year.	('mutations', 'Var', (97, 106))	('NSCLC', 'Disease', (27, 32))	('mutation', 'Var', (43, 51))	('EGFR', 'Gene', (110, 114))	('EGFR', 'Gene', (55, 59))	('men', 'Species', '9606', (163, 166))	('NSCLC', 'Disease', 'MESH:D002289', (27, 32))	('NSCLC', 'Phenotype', 'HP:0030358', (27, 32))	('resistant', 'MPA', (134, 143))
132545	24205245	Not only is there a higher mutation frequency in NSCLC, but also some genes like EGFR can easily produce secondary mutations.	('NSCLC', 'Disease', (49, 54))	('NSCLC', 'Disease', 'MESH:D002289', (49, 54))	('mutation', 'Var', (27, 35))	('NSCLC', 'Phenotype', 'HP:0030358', (49, 54))	('EGFR', 'Gene', (81, 85))
132547	24205245	The hMSH2 and hMLH1 genes, which are the key components of the MMR system, recognize and excise single-base mismatches and insertion/deletion loops that occur during DNA replication or DNA damage.	('hMLH1', 'Gene', (14, 19))	('hMSH2', 'Gene', '4436', (4, 9))	('single-base mismatches', 'Var', (96, 118))	('hMSH2', 'Gene', (4, 9))	('hMLH1', 'Gene', '4292', (14, 19))	('insertion/deletion loops', 'Var', (123, 147))
132549	24205245	The dysregulation of hMLH1 or hMSH2 expression, usually from a loss of heterozygosity (LOH) at the DNA MMR loci, by mutation or promoter methylation, is the main reason for MMR dysfunction.	('MMR dysfunction', 'Disease', (173, 188))	('hMSH2', 'Gene', '4436', (30, 35))	('mutation', 'Var', (116, 124))	('dysregulation', 'Var', (4, 17))	('hMLH1', 'Gene', (21, 26))	('hMSH2', 'Gene', (30, 35))	('hMLH1', 'Gene', '4292', (21, 26))	('loss', 'NegReg', (63, 67))
132550	24205245	The loss of hMLH1 or hMSH2 expression is associated with a hypermutation phenotype, including KRAS, BRAF, APC, P53, and TGF-beta mutations in colorectal cancer.	('associated', 'Reg', (41, 51))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('loss', 'NegReg', (4, 8))	('P53', 'Gene', (111, 114))	('colorectal cancer', 'Disease', 'MESH:D015179', (142, 159))	('BRAF', 'Gene', '673', (100, 104))	('colorectal cancer', 'Disease', (142, 159))	('TGF-beta', 'Gene', '7040', (120, 128))	('hMLH1', 'Gene', (12, 17))	('BRAF', 'Gene', (100, 104))	('hMLH1', 'Gene', '4292', (12, 17))	('P53', 'Gene', '7157', (111, 114))	('hMSH2', 'Gene', '4436', (21, 26))	('TGF-beta', 'Gene', (120, 128))	('KRAS', 'Disease', (94, 98))	('colorectal cancer', 'Phenotype', 'HP:0003003', (142, 159))	('mutations', 'Var', (129, 138))	('APC', 'Disease', 'MESH:D011125', (106, 109))	('hypermutation', 'Disease', (59, 72))	('APC', 'Disease', (106, 109))	('hMSH2', 'Gene', (21, 26))
132552	24205245	In order to study the correlation between MMR and NSCLC mutations, we detected EGFR and KRAS mutations and measured hMLH1, hMSH2, PCNA and Ki67 expression in NSCLC tumors.	('PCNA', 'Gene', (130, 134))	('NSCLC', 'Disease', 'MESH:D002289', (158, 163))	('NSCLC', 'Phenotype', 'HP:0030358', (50, 55))	('hMSH2', 'Gene', (123, 128))	('NSCLC tumors', 'Disease', 'MESH:D009369', (158, 170))	('hMLH1', 'Gene', (116, 121))	('NSCLC', 'Disease', (158, 163))	('tumors', 'Phenotype', 'HP:0002664', (164, 170))	('hMLH1', 'Gene', '4292', (116, 121))	('PCNA', 'Gene', '5111', (130, 134))	('NSCLC', 'Phenotype', 'HP:0030358', (158, 163))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('mutations', 'Var', (93, 102))	('EGFR', 'Gene', (79, 83))	('KRAS', 'Gene', (88, 92))	('NSCLC', 'Disease', 'MESH:D002289', (50, 55))	('NSCLC tumors', 'Disease', (158, 170))	('hMSH2', 'Gene', '4436', (123, 128))	('NSCLC', 'Disease', (50, 55))
132580	24205245	Out of the 181 patients with NSCLCs, there were 10 cases (5.5%) with a KRAS mutation and 66 cases (36.5%) with an EGFR mutation (24 cases in exon 19 and 42 cases in exon 21) (Figure 2).	('patients', 'Species', '9606', (15, 23))	('NSCLC', 'Phenotype', 'HP:0030358', (29, 34))	('KRAS', 'Gene', (71, 75))	('NSCLC', 'Disease', (29, 34))	('NSCLC', 'Disease', 'MESH:D002289', (29, 34))	('mutation', 'Var', (76, 84))
132581	24205245	KRAS mutations were more frequent in men than in women (p=0.008).	('women', 'Species', '9606', (49, 54))	('men', 'Species', '9606', (51, 54))	('mutations', 'Var', (5, 14))	('men', 'Species', '9606', (37, 40))	('KRAS', 'Gene', (0, 4))
132582	24205245	The frequency of EGFR mutations, either in exon 19 or exon 21, was higher in women than in men (p=0.015; p<0.0005), in adenocarcinoma than in squamous cell carcinoma (p<0.0005; p<0.0005), and in the non-smokers than in smokers (p=0.031; p=0.002).	('men', 'Species', '9606', (79, 82))	('adenocarcinoma', 'Disease', (119, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (156, 165))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (142, 165))	('higher', 'Reg', (67, 73))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('squamous cell carcinoma', 'Disease', (142, 165))	('women', 'Species', '9606', (77, 82))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (142, 165))	('men', 'Species', '9606', (91, 94))	('adenocarcinoma', 'Disease', 'MESH:D000230', (119, 133))	('mutations', 'Var', (22, 31))	('EGFR', 'Gene', (17, 21))
132583	24205245	There was no significant correlation of EGFR mutations to patient age, lymph node metastasis, tumor site or clinical stage (Table 1).	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('mutations', 'Var', (45, 54))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('patient', 'Species', '9606', (58, 65))	('tumor', 'Disease', (94, 99))	('EGFR', 'Gene', (40, 44))
132584	24205245	There was no significant difference in the frequency of Ki67 or PCNA expression between NSCLCs with and without EGFR mutation in exon 19 or exon 21 (p>0.05, Table 3).	('EGFR', 'Gene', (112, 116))	('PCNA', 'Gene', (64, 68))	('NSCLC', 'Phenotype', 'HP:0030358', (88, 93))	('PCNA', 'Gene', '5111', (64, 68))	('Ki67', 'Var', (56, 60))	('NSCLC', 'Disease', (88, 93))	('mutation', 'Var', (117, 125))	('NSCLC', 'Disease', 'MESH:D002289', (88, 93))
132585	24205245	But Ki67 expression was less frequent in NSCLCs with EGFR mutations (both in exon 19 and 21) than in those without the mutations (51.5% to 67.8%, p=0.030), but PCNA was not (85.2% to 93.9%, p=0.078).	('PCNA', 'Gene', (160, 164))	('mutations', 'Var', (58, 67))	('PCNA', 'Gene', '5111', (160, 164))	('NSCLC', 'Disease', (41, 46))	('NSCLC', 'Disease', 'MESH:D002289', (41, 46))	('EGFR', 'Gene', (53, 57))	('NSCLC', 'Phenotype', 'HP:0030358', (41, 46))
132586	24205245	The frequency of hMLH1 expression was higher in NSCLCs with an EGFR exon 19 mutation than in those without the mutation (91.7% to 68.2%, p=0.018) and in NSCLCs with an EGFR exon 21 mutation than in those without the mutation (88.1% to 66.2%, p=0.006).	('NSCLC', 'Phenotype', 'HP:0030358', (153, 158))	('NSCLC', 'Disease', (48, 53))	('hMLH1', 'Gene', (17, 22))	('NSCLC', 'Disease', 'MESH:D002289', (48, 53))	('EGFR exon 19', 'Gene', (63, 75))	('NSCLC', 'Disease', (153, 158))	('hMLH1', 'Gene', '4292', (17, 22))	('higher', 'PosReg', (38, 44))	('NSCLC', 'Disease', 'MESH:D002289', (153, 158))	('NSCLC', 'Phenotype', 'HP:0030358', (48, 53))	('mutation', 'Var', (76, 84))	('expression', 'MPA', (23, 33))
132587	24205245	As hMLH1 expression increases (from -, + to ++), the frequency of EGFR mutations (exon 19 and 21) were 13.2%, 38.7% and 53.0% respectively (p<0.0005).	('hMLH1', 'Gene', (3, 8))	('EGFR', 'Gene', (66, 70))	('expression', 'MPA', (9, 19))	('mutations', 'Var', (71, 80))	('hMLH1', 'Gene', '4292', (3, 8))	('increases', 'PosReg', (20, 29))
132589	24205245	The adenocarcinoma subtype and hMLH1 overexpression were two independent factors that relate to EGFR mutations (p<0.0005 and p=0.013), but gender and smoking history do not (p=0.070 and p=0.538).	('mutations', 'Var', (101, 110))	('carcinoma', 'Phenotype', 'HP:0030731', (9, 18))	('EGFR', 'Gene', (96, 100))	('adenocarcinoma subtype', 'Disease', (4, 26))	('adenocarcinoma subtype', 'Disease', 'MESH:D000230', (4, 26))	('hMLH1', 'Gene', (31, 36))	('hMLH1', 'Gene', '4292', (31, 36))
132592	24205245	EGFR and KRAS mutations are two well-known markers that indicate the sensitivity and resistance to EGFR-TKIs of NSCLC patients.	('EGFR', 'Gene', (0, 4))	('KRAS', 'Gene', (9, 13))	('NSCLC', 'Phenotype', 'HP:0030358', (112, 117))	('patients', 'Species', '9606', (118, 126))	('NSCLC', 'Disease', (112, 117))	('mutations', 'Var', (14, 23))	('NSCLC', 'Disease', 'MESH:D002289', (112, 117))
132593	24205245	For example, the frequency of EGFR mutations is higher in East Asians with NSCLC than in Caucasians.	('EGFR', 'Gene', (30, 34))	('NSCLC', 'Phenotype', 'HP:0030358', (75, 80))	('NSCLC', 'Disease', (75, 80))	('NSCLC', 'Disease', 'MESH:D002289', (75, 80))	('higher', 'Reg', (48, 54))	('mutations', 'Var', (35, 44))
132594	24205245	However, many NSCLC patients do not have EGFR or KRAS mutations.	('EGFR', 'Gene', (41, 45))	('NSCLC', 'Disease', (14, 19))	('NSCLC', 'Disease', 'MESH:D002289', (14, 19))	('mutations', 'Var', (54, 63))	('patients', 'Species', '9606', (20, 28))	('NSCLC', 'Phenotype', 'HP:0030358', (14, 19))	('KRAS', 'Gene', (49, 53))
132596	24205245	To the best of our knowledge, we report here for the first time that hMLH1 expression is related to EGFR mutations in both exon 19 and exon 21, but hMSH2 expression is not.	('mutations in', 'Var', (105, 117))	('related', 'Reg', (89, 96))	('EGFR', 'Gene', (100, 104))	('hMLH1', 'Gene', (69, 74))	('hMLH1', 'Gene', '4292', (69, 74))	('hMSH2', 'Gene', '4436', (148, 153))	('hMSH2', 'Gene', (148, 153))	('expression', 'MPA', (75, 85))
132597	24205245	Generally, women and non-smoking patients with adenocarcinoma have a relatively high probability of EGFR mutations.	('carcinoma', 'Phenotype', 'HP:0030731', (52, 61))	('patients', 'Species', '9606', (33, 41))	('EGFR', 'Gene', (100, 104))	('adenocarcinoma', 'Disease', 'MESH:D000230', (47, 61))	('mutations', 'Var', (105, 114))	('women', 'Species', '9606', (11, 16))	('adenocarcinoma', 'Disease', (47, 61))
132599	24205245	We found hMLH1 expression and adenocarcinoma were independent factors related to EGFR mutations.	('mutations', 'Var', (86, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (35, 44))	('adenocarcinoma', 'Disease', (30, 44))	('adenocarcinoma', 'Disease', 'MESH:D000230', (30, 44))	('hMLH1', 'Gene', (9, 14))	('related', 'Reg', (70, 77))	('hMLH1', 'Gene', '4292', (9, 14))	('EGFR', 'Gene', (81, 85))
132600	24205245	Moreover, the stronger the hMLH1 expression, the higher EGFR mutation frequency.	('mutation', 'Var', (61, 69))	('hMLH1', 'Gene', (27, 32))	('hMLH1', 'Gene', '4292', (27, 32))	('EGFR', 'Gene', (56, 60))	('expression', 'MPA', (33, 43))	('stronger', 'PosReg', (14, 22))	('higher', 'PosReg', (49, 55))
132610	24205245	independently found that exposure to tobacco smoke inactivates MMR function by inducing chromosomal instability and polymorphisms of the hMLH1 gene.	('polymorphisms', 'Var', (116, 129))	('inactivates', 'NegReg', (51, 62))	('MMR', 'CPA', (63, 66))	('inducing', 'Reg', (79, 87))	('tobacco', 'Species', '4097', (37, 44))	('hMLH1', 'Gene', (137, 142))	('chromosomal instability', 'CPA', (88, 111))	('hMLH1', 'Gene', '4292', (137, 142))	('chromosomal instability', 'Phenotype', 'HP:0040012', (88, 111))
132613	24205245	In this study, we found cases with EGFR mutations have a higher frequency of both hMLH1 and PCNA expression, but a trend toward lower Ki67 expression.	('hMLH1', 'Gene', '4292', (82, 87))	('PCNA', 'Gene', (92, 96))	('PCNA', 'Gene', '5111', (92, 96))	('EGFR', 'Gene', (35, 39))	('mutations', 'Var', (40, 49))	('lower', 'NegReg', (128, 133))	('Ki67 expression', 'MPA', (134, 149))	('expression', 'MPA', (97, 107))	('hMLH1', 'Gene', (82, 87))
132614	24205245	This suggests that an EGFR mutation might stimulate and initiate the process of DNA repair by increasing hMLH1 and PCNA expression, and then prolong the cell cycle.	('PCNA', 'Gene', (115, 119))	('hMLH1', 'Gene', '4292', (105, 110))	('prolong', 'PosReg', (141, 148))	('EGFR', 'Gene', (22, 26))	('PCNA', 'Gene', '5111', (115, 119))	('mutation', 'Var', (27, 35))	('cell cycle', 'CPA', (153, 163))	('stimulate', 'PosReg', (42, 51))	('increasing', 'PosReg', (94, 104))	('hMLH1', 'Gene', (105, 110))
132615	24205245	Therefore, EGFR mutations in NSCLCs would activate the MMR function, instead of being the result of genomic instability caused by MMR dysfunction.	('NSCLC', 'Phenotype', 'HP:0030358', (29, 34))	('activate', 'PosReg', (42, 50))	('EGFR', 'Gene', (11, 15))	('mutations', 'Var', (16, 25))	('NSCLC', 'Disease', (29, 34))	('NSCLC', 'Disease', 'MESH:D002289', (29, 34))	('MMR function', 'CPA', (55, 67))
132616	24205245	EGFR mutations might be an early event in the carcinogenesis of NSCLC before MMR dysfunction.	('NSCLC', 'Disease', 'MESH:D002289', (64, 69))	('EGFR', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))	('NSCLC', 'Phenotype', 'HP:0030358', (64, 69))	('NSCLC', 'Disease', (64, 69))
132620	24205245	reported that specific polymorphisms of hMLH1 are related to the susceptibility and prognosis of lung cancer and occurred more often in lung squamous cell carcinoma than in adenocarcinoma.	('polymorphisms', 'Var', (23, 36))	('carcinoma', 'Phenotype', 'HP:0030731', (155, 164))	('related', 'Reg', (50, 57))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (136, 164))	('hMLH1', 'Gene', '4292', (40, 45))	('lung cancer', 'Disease', 'MESH:D008175', (97, 108))	('lung squamous cell carcinoma', 'Disease', (136, 164))	('occurred', 'Reg', (113, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (178, 187))	('lung cancer', 'Disease', (97, 108))	('adenocarcinoma', 'Disease', (173, 187))	('lung cancer', 'Phenotype', 'HP:0100526', (97, 108))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (136, 164))	('hMLH1', 'Gene', (40, 45))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (141, 164))	('adenocarcinoma', 'Disease', 'MESH:D000230', (173, 187))
132623	24205245	In summary, EGFR mutations in exon 19 and 21 correlate with MMR dysfunction in NSCLC.	('NSCLC', 'Disease', 'MESH:D002289', (79, 84))	('MMR dysfunction', 'Disease', (60, 75))	('NSCLC', 'Phenotype', 'HP:0030358', (79, 84))	('EGFR', 'Gene', (12, 16))	('mutations', 'Var', (17, 26))	('NSCLC', 'Disease', (79, 84))
132624	24205245	Overexpression of hMLH1 could be a new marker for patient sensitivity to EGFR-TKIs.	('patient', 'Species', '9606', (50, 57))	('hMLH1', 'Gene', (18, 23))	('Overexpression', 'Var', (0, 14))	('hMLH1', 'Gene', '4292', (18, 23))
132625	24205245	However, EGFR mutations could also increase hMLH1 overexpression as a compensatory mechanism.	('hMLH1', 'Gene', (44, 49))	('increase', 'PosReg', (35, 43))	('hMLH1', 'Gene', '4292', (44, 49))	('overexpression', 'MPA', (50, 64))	('increase hMLH1', 'Phenotype', 'HP:0030269', (35, 49))	('EGFR', 'Gene', (9, 13))	('mutations', 'Var', (14, 23))
132628	33034274	Accumulating evidence indicates that alterations of this protein are involved in human carcinogenesis, especially in the regulation of chemotherapeutic drug response.	('involved', 'Reg', (69, 77))	('carcinogenesis', 'Disease', 'MESH:D063646', (87, 101))	('alterations', 'Var', (37, 48))	('carcinogenesis', 'Disease', (87, 101))	('human', 'Species', '9606', (81, 86))
132632	33034274	In contrast, loss of Nipped-B-like protein stimulated the growth of EC9706 and Eca-109 cells with high levels of the protein, and resulted in resistance to cisplatin.	('resulted in', 'Reg', (130, 141))	('stimulated', 'PosReg', (43, 53))	('EC9706', 'CellLine', 'CVCL:E307', (68, 74))	('Nipped-B-like protein', 'Gene', (21, 42))	('resistance to cisplatin', 'MPA', (142, 165))	('cisplatin', 'Chemical', 'MESH:D002945', (156, 165))	('growth', 'MPA', (58, 64))	('Nipped-B-like protein', 'Gene', '25836', (21, 42))	('loss', 'Var', (13, 17))
132634	33034274	Restoration of this pro-apoptotic protein in Nipped-B-like protein-overexpressing esophageal squamous cell carcinoma cells effectively increased cisplatin sensitivity.	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('Nipped-B-like protein', 'Gene', (45, 66))	('esophageal squamous cell carcinoma', 'Disease', (82, 116))	('Restoration', 'Var', (0, 11))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (93, 116))	('cisplatin', 'Chemical', 'MESH:D002945', (145, 154))	('Nipped-B-like protein', 'Gene', '25836', (45, 66))	('increased', 'PosReg', (135, 144))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (82, 116))	('cisplatin sensitivity', 'MPA', (145, 166))
132635	33034274	Conversely, the silencing of P53-upregulated modulator of apoptosis in Nipped-B-like protein-depleted esophageal squamous cell carcinoma rendered cells resistant to cisplatin.	('esophageal squamous cell carcinoma', 'Disease', (102, 136))	('P53', 'Gene', (29, 32))	('Nipped-B-like protein', 'Gene', '25836', (71, 92))	('modulator of', 'MPA', (45, 57))	('resistant', 'CPA', (152, 161))	('P53', 'Gene', '7157', (29, 32))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (113, 136))	('silencing', 'Var', (16, 25))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (102, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('cisplatin', 'Chemical', 'MESH:D002945', (165, 174))	('Nipped-B-like protein', 'Gene', (71, 92))
132650	33034274	NIPBL has been implicated in transcriptional regulation, and shows mutations in the majority of individuals afflicted with Cornelia de Lange syndrome (CdLS), a developmental disorder characterized by dysmorphic facial features, growth delay, limb reduction defects, and mental retardation.	('Cornelia de Lange syndrome', 'Disease', 'MESH:D003635', (123, 149))	('developmental disorder', 'Phenotype', 'HP:0001263', (160, 182))	('dysmorphic facial', 'Disease', (200, 217))	('limb reduction defects', 'Disease', (242, 264))	('mental retardation', 'Disease', (270, 288))	('limb reduction', 'Phenotype', 'HP:0009826', (242, 256))	('developmental disorder', 'Disease', 'MESH:D002658', (160, 182))	('CdLS', 'Disease', (151, 155))	('growth delay', 'Phenotype', 'HP:0001510', (228, 240))	('Cornelia de Lange syndrome', 'Disease', (123, 149))	('dysmorphic facial features', 'Phenotype', 'HP:0001999', (200, 226))	('developmental disorder', 'Disease', (160, 182))	('NIPBL', 'Gene', (0, 5))	('growth delay', 'CPA', (228, 240))	('CdLS', 'Disease', 'MESH:D003635', (151, 155))	('mental retardation', 'Phenotype', 'HP:0001249', (270, 288))	('mutations', 'Var', (67, 76))	('mental retardation', 'Disease', 'MESH:D008607', (270, 288))	('limb reduction defects', 'Disease', 'MESH:D007022', (242, 264))	('dysmorphic facial', 'Disease', 'None', (200, 217))
132651	33034274	Heterozygous mutations of NIPBL account for 65% of the total cases of CdLS.	('NIPBL', 'Gene', (26, 31))	('CdLS', 'Disease', 'MESH:D003635', (70, 74))	('CdLS', 'Disease', (70, 74))	('Heterozygous mutations', 'Var', (0, 22))
132652	33034274	Increasing evidence has shown that alterations of NIPBL expression are involved in human carcinogenesis, especially in the regulation of chemotherapy sensitivity.	('NIPBL', 'Gene', (50, 55))	('alterations', 'Var', (35, 46))	('involved', 'Reg', (71, 79))	('carcinogenesis', 'Disease', 'MESH:D063646', (89, 103))	('carcinogenesis', 'Disease', (89, 103))	('human', 'Species', '9606', (83, 88))	('expression', 'MPA', (56, 66))
132653	33034274	Genome-wide functional profiling has shown that the silencing of NIPBL renders breast cancer cells resistant to tamoxifen.	('silencing', 'Var', (52, 61))	('tamoxifen', 'Chemical', 'MESH:D013629', (112, 121))	('breast cancer', 'Disease', 'MESH:D001943', (79, 92))	('NIPBL', 'Gene', (65, 70))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('breast cancer', 'Disease', (79, 92))	('breast cancer', 'Phenotype', 'HP:0003002', (79, 92))
132656	33034274	Human ESCC cell lines, including COLO-680N, KYSE-140, KYSE-150, KYSE-180, KYSE-450, TE-10, and TE-13, were obtained from the American Type Culture Collection (ATCC, Manassas, VA, USA).	('Human', 'Species', '9606', (0, 5))	('KYSE', 'Chemical', '-', (64, 68))	('KYSE-450', 'Var', (74, 82))	('KYSE-180', 'Var', (64, 72))	('KYSE', 'Chemical', '-', (44, 48))	('TE', 'Chemical', 'MESH:D013691', (84, 86))	('TE', 'Chemical', 'MESH:D013691', (95, 97))	('SA', 'Gene', '6296', (180, 182))	('KYSE', 'Chemical', '-', (54, 58))	('KYSE', 'Chemical', '-', (74, 78))
132690	33034274	previously measured the IC50 of cisplatin in different kinds of ESCC cell lines, including KYSE-140, KYSE-150, TE-1, TE-4, TE-8, TE-10, TE-11, TE-12, and TE-15.	('TE', 'Chemical', 'MESH:D013691', (123, 125))	('TE', 'Chemical', 'MESH:D013691', (154, 156))	('TE', 'Chemical', 'MESH:D013691', (143, 145))	('IC50', 'MPA', (24, 28))	('KYSE-150', 'Var', (101, 109))	('TE', 'Chemical', 'MESH:D013691', (117, 119))	('KYSE', 'Chemical', '-', (91, 95))	('TE-15', 'Disease', 'MESH:D012559', (154, 159))	('TE', 'Chemical', 'MESH:D013691', (111, 113))	('TE-15', 'Disease', (154, 159))	('cisplatin', 'Chemical', 'MESH:D002945', (32, 41))	('KYSE', 'Chemical', '-', (101, 105))	('TE', 'Chemical', 'MESH:D013691', (129, 131))	('TE', 'Chemical', 'MESH:D013691', (136, 138))
132698	33034274	On the contrary, NIPBL knockdown decreased cisplatin sensitivity of EC9706 and Eca-109 cells, as measured using flow cytometry (Figure 3C, D) and a cell viability assay (Figure 3E, F), respectively.	('cisplatin sensitivity', 'MPA', (43, 64))	('EC9706', 'CellLine', 'CVCL:E307', (68, 74))	('NIPBL', 'Gene', (17, 22))	('knockdown', 'Var', (23, 32))	('cisplatin', 'Chemical', 'MESH:D002945', (43, 52))	('decreased', 'NegReg', (33, 42))
132703	33034274	Interestingly, PUMA expression in COLO-680N cells was remarkably upregulated after ectopic expression of NIPBL (Figure 4A, B).	('NIPBL', 'Gene', (105, 110))	('PUMA', 'Gene', '27113', (15, 19))	('PUMA', 'Gene', (15, 19))	('upregulated', 'PosReg', (65, 76))	('ectopic expression', 'Var', (83, 101))
132705	33034274	Furthermore, we found that the silencing of PUMA rescues the effect of NIPBL overexpression on cell viability after cisplatin treatment.	('silencing', 'Var', (31, 40))	('cell viability', 'MPA', (95, 109))	('overexpression', 'PosReg', (77, 91))	('effect', 'MPA', (61, 67))	('rescues', 'PosReg', (49, 56))	('PUMA', 'Gene', (44, 48))	('cisplatin', 'Chemical', 'MESH:D002945', (116, 125))	('PUMA', 'Gene', '27113', (44, 48))	('NIPBL', 'Gene', (71, 76))
132706	33034274	On the other hand, ectopic expression of PUMA reverses the effect of NIPBL depletion on cell growth after cisplatin treatment (Figure 4E, F).	('ectopic expression', 'Var', (19, 37))	('PUMA', 'Gene', '27113', (41, 45))	('cell growth', 'MPA', (88, 99))	('reverses', 'NegReg', (46, 54))	('PUMA', 'Gene', (41, 45))	('cisplatin', 'Chemical', 'MESH:D002945', (106, 115))	('effect', 'MPA', (59, 65))
132711	33034274	Interestingly, several HDACs, including HDAC1, HDAC3, HDAC6, SIRT2, SIRT3, SIRT5, SIRT6, and SIRT7, were significantly downregulated following silencing of NIPBL (Figure 5B).	('HDAC1', 'Gene', (40, 45))	('silencing', 'Var', (143, 152))	('SIRT3', 'Gene', '23410', (68, 73))	('SIRT3', 'Gene', (68, 73))	('SIRT7', 'Gene', (93, 98))	('SIRT2', 'Gene', (61, 66))	('HDAC1', 'Gene', '3065', (40, 45))	('HDAC3', 'Gene', '8841', (47, 52))	('SIRT5', 'Gene', (75, 80))	('NIPBL', 'Gene', (156, 161))	('SIRT2', 'Gene', '22933', (61, 66))	('HDAC6', 'Gene', (54, 59))	('SIRT5', 'Gene', '23408', (75, 80))	('HD', 'Disease', 'MESH:D006816', (40, 42))	('downregulated', 'NegReg', (119, 132))	('SIRT7', 'Gene', '51547', (93, 98))	('SIRT6', 'Gene', (82, 87))	('HD', 'Disease', 'MESH:D006816', (54, 56))	('HD', 'Disease', 'MESH:D006816', (23, 25))	('HD', 'Disease', 'MESH:D006816', (47, 49))	('HDAC3', 'Gene', (47, 52))	('HDAC6', 'Gene', '10013', (54, 59))	('SIRT6', 'Gene', '51548', (82, 87))
132718	33034274	In this study, we found that NIPBL-induced dysregulation of PUMA affects cisplatin sensitivity in ESCC.	('cisplatin', 'Chemical', 'MESH:D002945', (73, 82))	('dysregulation', 'Var', (43, 56))	('PUMA', 'Gene', (60, 64))	('cisplatin sensitivity', 'MPA', (73, 94))	('affects', 'Reg', (65, 72))	('PUMA', 'Gene', '27113', (60, 64))
132724	33034274	identified heterozygous somatic missense mutations in the SMC1A, SMC4, STAG3, and NIPBL genes in 9 out of 132 patients with colorectal adenocarcinomas.	('missense mutations', 'Var', (32, 50))	('colorectal adenocarcinomas', 'Disease', (124, 150))	('SMC1A', 'Gene', (58, 63))	('SMC4', 'Gene', '10051', (65, 69))	('STAG3', 'Gene', '10734', (71, 76))	('SMC4', 'Gene', (65, 69))	('colorectal adenocarcinomas', 'Disease', 'MESH:D015179', (124, 150))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))	('STAG3', 'Gene', (71, 76))	('SMC1A', 'Gene', '8243', (58, 63))	('patients', 'Species', '9606', (110, 118))	('NIPBL', 'Gene', (82, 87))
132726	33034274	Subsequently, NIPBL mutations were identified with high microsatellite instability in gastric and colorectal cancers.	('colorectal cancers', 'Disease', (98, 116))	('high microsatellite instability', 'Disease', 'MESH:D053842', (51, 82))	('gastric', 'Disease', (86, 93))	('cancers', 'Phenotype', 'HP:0002664', (109, 116))	('NIPBL', 'Gene', (14, 19))	('colorectal cancer', 'Phenotype', 'HP:0003003', (98, 115))	('high microsatellite instability', 'Disease', (51, 82))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('mutations', 'Var', (20, 29))	('colorectal cancers', 'Disease', 'MESH:D015179', (98, 116))
132727	33034274	Recent cancer genomic analyses discovered a high frequency of NIPBL mutations in a select subset of cancers, including gliomas, endometrial carcinoma, and acute megakaryoblastic leukemia, suggesting that these mutations may underlie the development of human cancers.	('NIPBL', 'Gene', (62, 67))	('cancer', 'Disease', 'MESH:D009369', (258, 264))	('gliomas', 'Phenotype', 'HP:0009733', (119, 126))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('cancers', 'Disease', 'MESH:D009369', (100, 107))	('acute megakaryoblastic leukemia', 'Disease', 'MESH:D007947', (155, 186))	('acute megakaryoblastic leukemia', 'Disease', (155, 186))	('endometrial carcinoma', 'Disease', (128, 149))	('acute megakaryoblastic leukemia', 'Phenotype', 'HP:0006733', (155, 186))	('cancer', 'Disease', (7, 13))	('cancers', 'Disease', 'MESH:D009369', (258, 265))	('leukemia', 'Phenotype', 'HP:0001909', (178, 186))	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('gliomas', 'Disease', (119, 126))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (128, 149))	('cancer', 'Disease', (258, 264))	('cancer', 'Disease', (100, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))	('cancers', 'Phenotype', 'HP:0002664', (100, 107))	('human', 'Species', '9606', (252, 257))	('cancers', 'Disease', (100, 107))	('cancer', 'Phenotype', 'HP:0002664', (258, 264))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (128, 149))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('gliomas', 'Disease', 'MESH:D005910', (119, 126))	('cancer', 'Disease', 'MESH:D009369', (7, 13))	('mutations', 'Var', (68, 77))	('cancers', 'Phenotype', 'HP:0002664', (258, 265))	('cancers', 'Disease', (258, 265))
132728	33034274	We searched the COSMIC database and found recurrent NIPBL mutations in patients with esophageal cancer (26/1513, 1.72%), with 14 of these mutations occurring in patients with ESCC (Supplementary Figure 2).	('mutations', 'Var', (58, 67))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('patients', 'Species', '9606', (71, 79))	('NIPBL', 'Gene', (52, 57))	('patients', 'Species', '9606', (161, 169))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Disease', (96, 102))
132729	33034274	The only ESCC cell line used in this study that had a NIPBL mutation was KYSE-450.	('KYSE', 'Chemical', '-', (73, 77))	('mutation', 'Var', (60, 68))	('NIPBL', 'Gene', (54, 59))
132730	33034274	The mutation in KYSE450 is silent, and does not affect the amino acid sequence of NIPBL.	('KYSE450', 'Enzyme', (16, 23))	('mutation', 'Var', (4, 12))	('KYSE', 'Chemical', '-', (16, 20))
132744	33034274	BBC3 Bcl-2 binding component 3 ChIP Chromatin immunoprecipitation COSMIC Catalogue of Somatic Mutations in Cancer CTCF CCCTC-binding factor ESCC Esophageal squamous cell carcinoma HDACs Histone deacetylases NIPBL Nipped-B-like protein PUMA p53-upregulated modulator of apoptosis SMC Structural maintenance of chromosomes RAD21 double-strand-break repair protein rad21 homolog SA stromal antigen MAU2 MAU2 chromatid cohesion factor homolog SCC sister chromatid cohesion TME Tumor microenvironment.	('CTCF', 'Gene', '10664', (114, 118))	('Nipped-B-like protein', 'Gene', (213, 234))	('MAU2 chromatid cohesion factor homolog', 'Gene', '23383', (400, 438))	('p53', 'Gene', '7157', (240, 243))	('MAU2', 'Gene', (395, 399))	('Bcl-2 binding component 3', 'Gene', '27113', (5, 30))	('RAD21', 'Gene', '5885', (321, 326))	('squamous cell carcinoma', 'Disease', (156, 179))	('Cancer', 'Disease', (107, 113))	('p53', 'Gene', (240, 243))	('MAU2', 'Gene', '23383', (395, 399))	('CTCF', 'Gene', (114, 118))	('rad21', 'Gene', (362, 367))	('stromal antigen', 'Gene', '6296', (379, 394))	('PUMA', 'Gene', '27113', (235, 239))	('Cancer', 'Disease', 'MESH:D009369', (107, 113))	('SA', 'Gene', '6296', (376, 378))	('MAU2', 'Gene', (400, 404))	('MAU2 chromatid cohesion factor homolog', 'Gene', (400, 438))	('rad21', 'Gene', '5885', (362, 367))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (156, 179))	('Nipped-B-like protein', 'Gene', '25836', (213, 234))	('Bcl-2 binding component 3', 'Gene', (5, 30))	('MAU2', 'Gene', '23383', (400, 404))	('BBC3', 'Gene', '27113', (0, 4))	('Mutations', 'Var', (94, 103))	('HD', 'Disease', 'MESH:D006816', (180, 182))	('Tumor', 'Phenotype', 'HP:0002664', (473, 478))	('CCCTC-binding factor', 'Gene', (119, 139))	('CCCTC-binding factor', 'Gene', '10664', (119, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (170, 179))	('PUMA', 'Gene', (235, 239))	('RAD21', 'Gene', (321, 326))	('stromal antigen', 'Gene', (379, 394))	('Cancer', 'Phenotype', 'HP:0002664', (107, 113))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (156, 179))	('BBC3', 'Gene', (0, 4))
132765	31876743	In past clinical practice, the excision of the submandibular gland together with the involved lymph nodes in the level Ib region resulted in submandibular gland function loss and xerostomia, thereby affecting patients' quality of life.	('xerostomia', 'Disease', 'MESH:D014987', (179, 189))	('loss', 'NegReg', (170, 174))	('excision', 'Var', (31, 39))	('affecting', 'Reg', (199, 208))	('xerostomia', 'Disease', (179, 189))	('submandibular gland', 'Disease', (141, 160))	('patients', 'Species', '9606', (209, 217))	('xerostomia', 'Phenotype', 'HP:0000217', (179, 189))
132857	32830120	Patients with NSCLC carrying mutant epidermal growth factor receptor (EGFR) obtain reduced survival benefits from immunotherapy compared with those harbouring wild-type EGFR.	('survival benefits', 'CPA', (91, 108))	('NSCLC', 'Disease', (14, 19))	('epidermal growth factor receptor', 'Gene', '1956', (36, 68))	('reduced', 'NegReg', (83, 90))	('NSCLC', 'Disease', 'MESH:D002289', (14, 19))	('EGFR', 'Gene', '1956', (70, 74))	('mutant', 'Var', (29, 35))	('EGFR', 'Gene', '1956', (169, 173))	('Patients', 'Species', '9606', (0, 8))	('EGFR', 'Gene', (70, 74))	('EGFR', 'Gene', (169, 173))	('NSCLC', 'Phenotype', 'HP:0030358', (14, 19))	('epidermal growth factor receptor', 'Gene', (36, 68))
132858	32830120	The objective response rate (ORR) of ICIs monotherapy is low for NSCLC patients with actionable driver alterations (EGFR mutant ORR: 12%, ALK-rearranged ORR: 0%) in the IMMUNOTARGET registry.	('ALK', 'Gene', '238', (138, 141))	('patients', 'Species', '9606', (71, 79))	('NSCLC', 'Disease', 'MESH:D002289', (65, 70))	('EGFR', 'Gene', (116, 120))	('low', 'NegReg', (57, 60))	('NSCLC', 'Phenotype', 'HP:0030358', (65, 70))	('ALK', 'Gene', (138, 141))	('EGFR', 'Gene', '1956', (116, 120))	('mutant ORR', 'Var', (121, 131))	('NSCLC', 'Disease', (65, 70))
132860	32830120	Thus, an urgent need exists to develop new immunotherapy strategies for NSCLC patients carrying actionable driver alterations.	('alterations', 'Var', (114, 125))	('NSCLC', 'Disease', (72, 77))	('patients', 'Species', '9606', (78, 86))	('NSCLC', 'Disease', 'MESH:D002289', (72, 77))	('NSCLC', 'Phenotype', 'HP:0030358', (72, 77))
132863	32830120	CD47-SIRPalpha axis blockade enhances macrophage phagocytic activity, leading to tumour growth impairment and inhibition of metastasis and tumour progression.	('CD47', 'Gene', '961', (0, 4))	('tumour', 'Disease', (139, 145))	('inhibition', 'NegReg', (110, 120))	('tumour', 'Disease', 'MESH:D009369', (81, 87))	('CD47', 'Gene', (0, 4))	('enhances', 'PosReg', (29, 37))	('tumour', 'Phenotype', 'HP:0002664', (81, 87))	('tumour growth impairment', 'Disease', 'MESH:D006130', (81, 105))	('SIRPalpha', 'Gene', (5, 14))	('tumour', 'Disease', (81, 87))	('age', 'Gene', (45, 48))	('age', 'Gene', '5973', (45, 48))	('blockade', 'Var', (20, 28))	('tumour', 'Phenotype', 'HP:0002664', (139, 145))	('growth impairment', 'Phenotype', 'HP:0001510', (88, 105))	('tumour', 'Disease', 'MESH:D009369', (139, 145))	('SIRPalpha', 'Gene', '140885', (5, 14))	('tumour growth impairment', 'Disease', (81, 105))
132926	32830120	The presence of M2-TAMs and M1-TAMs further characterised M2-TAMs with more extensive tumour area infiltration (figure 1H and 89 vs 57, p=0.001).	('TAMs', 'Chemical', 'MESH:D013629', (31, 35))	('tumour', 'Phenotype', 'HP:0002664', (86, 92))	('TAMs', 'Chemical', 'MESH:D013629', (19, 23))	('TAMs', 'Chemical', 'MESH:D013629', (61, 65))	('tumour', 'Disease', 'MESH:D009369', (86, 92))	('M2-TAMs', 'Var', (58, 65))	('tumour', 'Disease', (86, 92))
132932	32830120	The results in figure 2B, C show that CD47pos expression correlated with EGFR mutation (p<0.001).	('EGFR', 'Gene', '1956', (73, 77))	('mutation', 'Var', (78, 86))	('CD47', 'Gene', '961', (38, 42))	('CD47', 'Gene', (38, 42))	('EGFR', 'Gene', (73, 77))	('correlated', 'Reg', (57, 67))
132944	32830120	Patients with M2-TAM infiltration in T&NT had poorer survival (Wald test, HR=2.036 (1.3 to 3.2), p=0.002) and exhibited shorter median DFS than patients with M2-TAMs infiltration only in NT (56.6 vs 100.2 months, figure 3E).	('NT', 'Chemical', '-', (39, 41))	('NT', 'Chemical', '-', (187, 189))	('exhibited', 'NegReg', (110, 119))	('had', 'NegReg', (42, 45))	('M2-TAM infiltration', 'Var', (14, 33))	('TAM', 'Chemical', '-', (17, 20))	('infiltration', 'Var', (21, 33))	('shorter median', 'MPA', (120, 134))	('patients', 'Species', '9606', (144, 152))	('Patients', 'Species', '9606', (0, 8))	('TAM', 'Chemical', '-', (161, 164))	('poorer', 'MPA', (46, 52))	('TAMs', 'Chemical', 'MESH:D013629', (161, 165))	('T&NT', 'Chemical', '-', (37, 41))
132956	32830120	Our study indicates that: (1) tumour CD47pos expression was more frequently detected in adenocarcinoma, female and never-smoking NSCLC cases; (2) CD47pos expression correlates with EGFR mutation in patients with NSCLC; (3) the tumour CD47 expression (H-score) in NSCLC negatively correlated with tumour PD-L1 expression (TPS) or TMB; (4) CD47pos expression was identified as an independent prognostic factor in the resected NSCLC group DFS; and (5) different immune component characteristics provide greater recurrence prognostic power in resected NSCLC.	('CD47', 'Gene', '961', (234, 238))	('NSCLC', 'Disease', 'MESH:D002289', (212, 217))	('NSCLC', 'Phenotype', 'HP:0030358', (263, 268))	('patients', 'Species', '9606', (198, 206))	('tumour', 'Disease', 'MESH:D009369', (30, 36))	('CD47', 'Gene', '961', (146, 150))	('adenocarcinoma', 'Disease', 'MESH:D000230', (88, 102))	('tumour', 'Phenotype', 'HP:0002664', (227, 233))	('tumour', 'Disease', (30, 36))	('NSCLC', 'Phenotype', 'HP:0030358', (548, 553))	('tumour', 'Disease', 'MESH:D009369', (227, 233))	('tumour', 'Disease', (227, 233))	('TMB', 'Chemical', '-', (329, 332))	('NSCLC', 'Disease', (212, 217))	('mutation', 'Var', (186, 194))	('EGFR', 'Gene', '1956', (181, 185))	('tumour', 'Phenotype', 'HP:0002664', (296, 302))	('CD47', 'Gene', (338, 342))	('NSCLC', 'Phenotype', 'HP:0030358', (212, 217))	('tumour', 'Disease', 'MESH:D009369', (296, 302))	('NSCLC', 'Disease', 'MESH:D002289', (424, 429))	('NSCLC', 'Disease', 'MESH:D002289', (129, 134))	('CD47', 'Gene', (37, 41))	('tumour', 'Disease', (296, 302))	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('CD47', 'Gene', (234, 238))	('CD47', 'Gene', (146, 150))	('NSCLC', 'Disease', (424, 429))	('NSCLC', 'Disease', (129, 134))	('tumour PD-L1', 'Disease', 'MESH:D010300', (296, 308))	('NSCLC', 'Disease', 'MESH:D002289', (263, 268))	('adenocarcinoma', 'Disease', (88, 102))	('NSCLC', 'Disease', 'MESH:D002289', (548, 553))	('NSCLC', 'Phenotype', 'HP:0030358', (129, 134))	('EGFR', 'Gene', (181, 185))	('NSCLC', 'Phenotype', 'HP:0030358', (424, 429))	('CD47', 'Gene', '961', (338, 342))	('tumour PD-L1', 'Disease', (296, 308))	('NSCLC', 'Disease', (263, 268))	('CD47', 'Gene', '961', (37, 41))	('NSCLC', 'Disease', (548, 553))	('tumour', 'Phenotype', 'HP:0002664', (30, 36))
132970	32830120	This finding led to the possible association between CD47pos expression and EGFR mutation in NSCLC.	('NSCLC', 'Disease', (93, 98))	('EGFR', 'Gene', '1956', (76, 80))	('mutation', 'Var', (81, 89))	('NSCLC', 'Disease', 'MESH:D002289', (93, 98))	('CD47', 'Gene', '961', (53, 57))	('EGFR', 'Gene', (76, 80))	('NSCLC', 'Phenotype', 'HP:0030358', (93, 98))	('CD47', 'Gene', (53, 57))	('association', 'Interaction', (33, 44))
132971	32830120	As expected, CD47pos expression indeed correlated with EGFR mutation.	('EGFR', 'Gene', '1956', (55, 59))	('mutation', 'Var', (60, 68))	('correlated', 'Reg', (39, 49))	('EGFR', 'Gene', (55, 59))	('CD47', 'Gene', '961', (13, 17))	('CD47', 'Gene', (13, 17))
132972	32830120	Arrieta et al also found that high CD47 expression (using a cut-off value of 150 based on staining index scores) was associated with presence of EGFR (+) mutations (66.7% vs 33.3%, p=0.04).	('expression', 'MPA', (40, 50))	('EGFR', 'Gene', '1956', (145, 149))	('CD47', 'Gene', '961', (35, 39))	('CD47', 'Gene', (35, 39))	('EGFR', 'Gene', (145, 149))	('mutations', 'Var', (154, 163))
132973	32830120	However, the biological association between EGFR mutation and CD47pos expression remains unclear.	('CD47', 'Gene', '961', (62, 66))	('CD47', 'Gene', (62, 66))	('mutation', 'Var', (49, 57))	('EGFR', 'Gene', '1956', (44, 48))	('EGFR', 'Gene', (44, 48))
132977	32830120	We hypothesise that CD47/SIRPalpha axis inhibition is a potential antitumour immunotherapy strategy for EGFR mutant NSCLC with acquired resistance to EGFR-TKI.	('NSCLC', 'Disease', 'MESH:D002289', (116, 121))	('EGFR', 'Gene', (150, 154))	('EGFR', 'Gene', (104, 108))	('tumour', 'Phenotype', 'HP:0002664', (70, 76))	('CD47/SIRPalpha', 'Gene', (20, 34))	('NSCLC', 'Phenotype', 'HP:0030358', (116, 121))	('CD47/SIRPalpha', 'Gene', '961;140885', (20, 34))	('mutant', 'Var', (109, 115))	('tumour', 'Disease', 'MESH:D009369', (70, 76))	('NSCLC', 'Disease', (116, 121))	('EGFR', 'Gene', '1956', (150, 154))	('tumour', 'Disease', (70, 76))	('EGFR', 'Gene', '1956', (104, 108))
132990	32830120	For CD47pos NSCLC with EGFR mutation, EGFR-CD47 bsAb might represent another option.	('EGFR', 'Gene', '1956', (38, 42))	('CD47', 'Gene', '961', (4, 8))	('NSCLC', 'Phenotype', 'HP:0030358', (12, 17))	('CD47', 'Gene', (4, 8))	('EGFR', 'Gene', (38, 42))	('NSCLC', 'Disease', (12, 17))	('mutation', 'Var', (28, 36))	('EGFR', 'Gene', '1956', (23, 27))	('CD47', 'Gene', '961', (43, 47))	('NSCLC', 'Disease', 'MESH:D002289', (12, 17))	('EGFR', 'Gene', (23, 27))	('CD47', 'Gene', (43, 47))
132994	32830120	Arrieta et al revealed that high expression of CD47 were associated with shortened OS in EGFR mutant patients.	('patients', 'Species', '9606', (101, 109))	('EGFR', 'Gene', (89, 93))	('associated', 'Reg', (57, 67))	('mutant', 'Var', (94, 100))	('CD47', 'Gene', '961', (47, 51))	('EGFR', 'Gene', '1956', (89, 93))	('shortened OS', 'Disease', (73, 85))	('CD47', 'Gene', (47, 51))
133010	32210009	Mitochondria play an important role in controlling imperative cellular parameters, and anomalies in mitochondrial function might be crucial for cancer development.	('anomalies', 'Var', (87, 96))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('cancer', 'Disease', (144, 150))	('anomalies in mitochondrial function', 'Phenotype', 'HP:0003287', (87, 122))	('anomalies in mitochondria', 'Phenotype', 'HP:0012103', (87, 112))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
133012	32210009	Here, we identified a spectrum of mitochondrial genome mutations in early-stage lung adenocarcinoma and explored their association with prognosis and clinical outcomes.	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('mutations', 'Var', (55, 64))	('lung adenocarcinoma', 'Disease', (80, 99))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (80, 99))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (80, 99))	('mitochondrial genome', 'Gene', (34, 54))
133018	32210009	Driver mutations in EGFR, ALK, and ROS1 have been identified for non-smoking-associated LUAD.	('ALK', 'Gene', (26, 29))	('non-smoking-associated LUAD', 'Disease', (65, 92))	('EGFR', 'Gene', (20, 24))	('ROS1', 'Gene', '6098', (35, 39))	('ALK', 'Gene', '238', (26, 29))	('LUAD', 'Phenotype', 'HP:0030078', (88, 92))	('ROS1', 'Gene', (35, 39))	('identified', 'Reg', (50, 60))	('EGFR', 'Gene', '1956', (20, 24))	('mutations', 'Var', (7, 16))
133019	32210009	EGFR-activating mutations are frequently observed in East Asian, female, and non-smoking LUAD patients.	('EGFR', 'Gene', (0, 4))	('patients', 'Species', '9606', (94, 102))	('mutations', 'Var', (16, 25))	('EGFR', 'Gene', '1956', (0, 4))	('LUAD', 'Phenotype', 'HP:0030078', (89, 93))
133029	32210009	The role of mitochondria in cancer progression has been investigated in a few cancer types, and it has been suggested that the acquisition of mitochondrial mutations impairing pathways of energy generation might be elemental for cancer progression.	('mitochondrial', 'Gene', (142, 155))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('cancer', 'Disease', (229, 235))	('cancer', 'Disease', 'MESH:D009369', (229, 235))	('mutations', 'Var', (156, 165))	('cancer', 'Disease', (78, 84))	('impairing', 'NegReg', (166, 175))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('cancer', 'Disease', (28, 34))	('pathways of energy generation', 'MPA', (176, 205))
133030	32210009	Mutations in mitochondria were found to promote metastasis by modulating ROS production.	('promote', 'PosReg', (40, 47))	('modulating', 'Reg', (62, 72))	('ROS', 'Chemical', 'MESH:D017382', (73, 76))	('Mutations', 'Var', (0, 9))	('ROS production', 'MPA', (73, 87))	('metastasis', 'CPA', (48, 58))
133031	32210009	Decreased ATP production and apoptotic rate, increased cell growth, and increased risk of certain cancers have been associated with mitochondrial mutations.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('mutations', 'Var', (146, 155))	('increased', 'PosReg', (45, 54))	('ATP production', 'MPA', (10, 24))	('cancers', 'Phenotype', 'HP:0002664', (98, 105))	('Decreased', 'NegReg', (0, 9))	('ATP', 'Chemical', 'MESH:D000255', (10, 13))	('cancers', 'Disease', 'MESH:D009369', (98, 105))	('apoptotic rate', 'CPA', (29, 43))	('mitochondrial mutations', 'Var', (132, 155))	('cancers', 'Disease', (98, 105))	('cell growth', 'CPA', (55, 66))
133039	32210009	A total of 36 (59.02%) patients were carriers of EGFR-activating mutations, and in 25 patients (40.98%), no EGFR-activating mutations were identified.	('EGFR', 'Gene', '1956', (49, 53))	('EGFR', 'Gene', '1956', (108, 112))	('EGFR', 'Gene', (49, 53))	('EGFR', 'Gene', (108, 112))	('patients', 'Species', '9606', (23, 31))	('carriers', 'Reg', (37, 45))	('mutations', 'Var', (65, 74))	('patients', 'Species', '9606', (86, 94))
133042	32210009	The D-loop region was the most susceptible to germline mutations (23.81% mutations, mutation frequency of 8.34 per kbp), followed by the CYTB gene (20.65% mutations, mutation frequency of 3.97 per kbp).	('kbp', 'Gene', '26128', (197, 200))	('kbp', 'Gene', (115, 118))	('kbp', 'Gene', '26128', (115, 118))	('kbp', 'Gene', (197, 200))	('CYTB', 'Gene', '4519', (137, 141))	('CYTB', 'Gene', (137, 141))	('mutations', 'Var', (73, 82))
133045	32210009	In patients with EGFR-activating mutations, rRNA genes were highly mutated (p = 0.027), whereas CYTB or Complex III genes were highly mutated in patients without EGFR-activating mutations (p = 0.053, Figure S3).	('patients', 'Species', '9606', (145, 153))	('rRNA genes', 'Gene', (44, 54))	('CYTB', 'Gene', (96, 100))	('EGFR', 'Gene', '1956', (162, 166))	('EGFR', 'Gene', (162, 166))	('mutations', 'Var', (33, 42))	('patients', 'Species', '9606', (3, 11))	('EGFR', 'Gene', '1956', (17, 21))	('CYTB', 'Gene', '4519', (96, 100))	('EGFR', 'Gene', (17, 21))
133047	32210009	To elucidate the variability of the mitochondrial genome in LUAD tumors, we analyzed their mutational spectra and identified 284 somatic mutations in the mitochondrial genomes of 56 (92%) patients (Figure 2a).	('LUAD tumors', 'Disease', 'MESH:D009369', (60, 71))	('mutations', 'Var', (137, 146))	('patients', 'Species', '9606', (188, 196))	('mitochondrial genomes', 'Gene', (154, 175))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('LUAD tumors', 'Disease', (60, 71))	('LUAD', 'Phenotype', 'HP:0030078', (60, 64))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
133051	32210009	About 64% of the somatic variants of OXPHOS complex genes were missense, and Complex I genes had the highest number of mutations (117/198 mutations), whereas Complex V genes were the least mutated (14/198 mutations, Table S7).	('variants', 'Var', (25, 33))	('missense', 'Var', (63, 71))	('OXPHOS complex genes', 'Gene', (37, 57))	('Complex I genes', 'Gene', (77, 92))	('S7', 'Gene', '6264', (222, 224))	('OXPHOS', 'Chemical', '-', (37, 43))	('mutations', 'Var', (138, 147))
133052	32210009	The frequency of somatic mutations in the ND4 gene was higher in patients with EGFR-activating mutations (p = 0.053, Figure S9).	('EGFR', 'Gene', '1956', (79, 83))	('EGFR', 'Gene', (79, 83))	('ND4', 'Gene', '4538', (42, 45))	('mutations', 'Var', (95, 104))	('patients', 'Species', '9606', (65, 73))	('higher', 'PosReg', (55, 61))	('ND4', 'Gene', (42, 45))
133059	32210009	Among various cancer types, the highest mutation frequency was observed in lung squamous cell carcinoma followed by LUAD in the D-loop region and Complex I genes (Figure S13).	('cancer', 'Disease', (14, 20))	('mutation', 'Var', (40, 48))	('lung squamous cell carcinoma', 'Disease', (75, 103))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (75, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (80, 103))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (75, 103))	('cancer', 'Disease', 'MESH:D009369', (14, 20))	('LUAD', 'Phenotype', 'HP:0030078', (116, 120))	('highest', 'Reg', (32, 39))
133061	32210009	Most cancers had negligible proportions of C:G G:C germline transversions (Figure 3a).	('cancers', 'Phenotype', 'HP:0002664', (5, 12))	('cancers', 'Disease', (5, 12))	('C:G G', 'Var', (43, 48))	('cancers', 'Disease', 'MESH:D009369', (5, 12))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))
133063	32210009	Among all cancers, C:G T:A transitions were the predominant substitution, whereas LUAD exhibited more C:G A:T transversions (Figure 3b).	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('cancers', 'Phenotype', 'HP:0002664', (10, 17))	('cancers', 'Disease', 'MESH:D009369', (10, 17))	('LUAD', 'Phenotype', 'HP:0030078', (82, 86))	('cancers', 'Disease', (10, 17))	('C:G T:A transitions', 'Var', (19, 38))
133064	32210009	The next most predominant substitution among most cancers was A:T G:C transition followed by C:G A:T transversions, whereas Taiwan LUAD had a prevalence of C:G A:T followed by A:T G:C.  Interestingly, distinct profiles of somatic mutations in mitochondrial and nuclear genome substitutions were observed in LUADs (Figure 4a).	('C:G A:T', 'Var', (156, 163))	('cancers', 'Disease', 'MESH:D009369', (50, 57))	('cancers', 'Phenotype', 'HP:0002664', (50, 57))	('cancers', 'Disease', (50, 57))	('substitution', 'Var', (26, 38))	('LUAD', 'Phenotype', 'HP:0030078', (307, 311))	('LUAD', 'Phenotype', 'HP:0030078', (131, 135))	('LUADs', 'Disease', (307, 312))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('A:T G', 'Var', (62, 67))
133065	32210009	However, in the mitochondrial genome, the percentage of C:G A:T was higher and C:G T:A was lower than in the nuclear genome (both p < 0.001, Figure S14).	('lower', 'NegReg', (91, 96))	('S14', 'Gene', '5714', (148, 151))	('S14', 'Gene', (148, 151))	('C:G T:A', 'Var', (79, 86))	('C:G A:T', 'Var', (56, 63))
133067	32210009	However, patients with EGFR-activating mutations had more C:G A:T somatic substitutions in mitochondrial genomes than patients without EGFR-activating mutations (p = 0.02, Figure 4b).	('patients', 'Species', '9606', (9, 17))	('EGFR', 'Gene', '1956', (135, 139))	('C:G', 'Var', (58, 61))	('EGFR', 'Gene', '1956', (23, 27))	('EGFR', 'Gene', (135, 139))	('EGFR', 'Gene', (23, 27))	('patients', 'Species', '9606', (118, 126))
133068	32210009	Additionally, in patients with EGFR-activating mutations, fewer C:G T:A substitutions were observed (p = 0.098, Figure 4b).	('EGFR', 'Gene', '1956', (31, 35))	('substitutions', 'Var', (72, 85))	('C:G T:A', 'MPA', (64, 71))	('EGFR', 'Gene', (31, 35))	('mutations', 'Var', (47, 56))	('patients', 'Species', '9606', (17, 25))	('fewer', 'NegReg', (58, 63))
133069	32210009	Further dissection of this association revealed that the C:G T:A transitions were completely absent in the mitochondrial genomes of female patients without EGFR-activating mutations (Figure S16).	('transitions', 'Var', (65, 76))	('patients', 'Species', '9606', (139, 147))	('S16', 'Gene', (190, 193))	('EGFR', 'Gene', '1956', (156, 160))	('absent', 'NegReg', (93, 99))	('EGFR', 'Gene', (156, 160))	('S16', 'Gene', '6217', (190, 193))	('C:G T:A transitions', 'Var', (57, 76))
133070	32210009	Patients with mutations in the D-loop region had longer RFS (median survival: not reached vs. 5.79 years, p = 0.021, Figure 5a), but showed no association with OS (Figure S17).	('S17', 'Gene', (171, 174))	('RFS', 'MPA', (56, 59))	('S17', 'Gene', '6218', (171, 174))	('Patients', 'Species', '9606', (0, 8))	('longer', 'PosReg', (49, 55))	('mutations', 'Var', (14, 23))
133071	32210009	For mitochondrially encoded Complex IV or Complex V genes, patients with mutations had shorter RFS (median survival: 4.41 years vs. not reached, p = 0.018, Figure 5c and median survival: 4.01 years vs. not reached, p = 0.018, Figure 5d, respectively), though no significant association with OS was identified (Figure S18, Table S7).	('Complex V genes', 'Gene', (42, 57))	('RFS', 'MPA', (95, 98))	('S18', 'Gene', '6222', (317, 320))	('shorter', 'NegReg', (87, 94))	('mutations', 'Var', (73, 82))	('patients', 'Species', '9606', (59, 67))	('S7', 'Gene', '6264', (328, 330))	('S18', 'Gene', (317, 320))
133072	32210009	For mutations in tRNA and rRNA regions, mitochondrially encoded Complex I, and Complex III genes, no significant associations were observed with either OS or RFS (Figure 5b, Figures S18 and S19).	('mutations', 'Var', (4, 13))	('S18', 'Gene', (182, 185))	('S18', 'Gene', '6222', (182, 185))
133078	32210009	Mitochondrial mutations and/or dysfunction play a crucial role in shifting cellular metabolism to a state more favorable for cancer proliferation.	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('shifting', 'Reg', (66, 74))	('cancer', 'Disease', (125, 131))	('cellular metabolism', 'MPA', (75, 94))	('mutations', 'Var', (14, 23))
133080	32210009	Given the critical role of mitochondria in metabolism, somatic mutations in the mitochondrial genome might be important drivers of deregulated tumor metabolism.	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('somatic mutations', 'Var', (55, 72))	('tumor', 'Disease', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
133089	32210009	Studies identifying association of BRCA1 mutation with haplogroup M in China and haplogroup X in Europe have suggested a role of these haplogroups to present population-specific alterations in genes conferring risk to familial breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('BRCA1', 'Gene', '672', (35, 40))	('familial breast cancer', 'Disease', 'MESH:D001943', (218, 240))	('association', 'Interaction', (20, 31))	('mutation', 'Var', (41, 49))	('breast cancer', 'Phenotype', 'HP:0003002', (227, 240))	('BRCA1', 'Gene', (35, 40))	('familial breast cancer', 'Disease', (218, 240))
133091	32210009	Mutations in the EGFR gene have been discovered to be strongly associated with lung cancers, especially LUAD.	('lung cancers', 'Disease', (79, 91))	('LUAD', 'Disease', (104, 108))	('LUAD', 'Phenotype', 'HP:0030078', (104, 108))	('cancers', 'Phenotype', 'HP:0002664', (84, 91))	('associated', 'Reg', (63, 73))	('lung cancer', 'Phenotype', 'HP:0100526', (79, 90))	('Mutations', 'Var', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('lung cancers', 'Disease', 'MESH:D008175', (79, 91))	('lung cancers', 'Phenotype', 'HP:0100526', (79, 91))	('EGFR', 'Gene', '1956', (17, 21))	('EGFR', 'Gene', (17, 21))
133092	32210009	LUAD patients with mutated EGFR have a significant response to TKI inhibitors.	('EGFR', 'Gene', '1956', (27, 31))	('EGFR', 'Gene', (27, 31))	('patients', 'Species', '9606', (5, 13))	('mutated', 'Var', (19, 26))	('response', 'MPA', (51, 59))	('LUAD', 'Phenotype', 'HP:0030078', (0, 4))
133096	32210009	On the other hand, MTRNR2 (germline) and ND4 (somatic) genes had higher mutation frequencies in patients with EGFR-activating mutations.	('EGFR', 'Gene', '1956', (110, 114))	('EGFR', 'Gene', (110, 114))	('mutation frequencies', 'MPA', (72, 92))	('MTRNR2', 'Gene', (19, 25))	('MTRNR2', 'Gene', '4550', (19, 25))	('ND4', 'Gene', '4538', (41, 44))	('patients', 'Species', '9606', (96, 104))	('mutations', 'Var', (126, 135))	('higher', 'PosReg', (65, 71))	('ND4', 'Gene', (41, 44))
133097	32210009	The different association patterns of variants in protein-coding genes and rRNA genes with EGFR mutations indicate a distinct effect of EGFR mutations over the integrity of mitochondrial genome, and may have some functional implications as well.	('rRNA genes', 'Gene', (75, 85))	('EGFR', 'Gene', (91, 95))	('mutations', 'Var', (141, 150))	('variants', 'Var', (38, 46))	('association', 'Interaction', (14, 25))	('integrity', 'MPA', (160, 169))	('EGFR', 'Gene', '1956', (91, 95))	('EGFR', 'Gene', '1956', (136, 140))	('effect', 'Reg', (126, 132))	('EGFR', 'Gene', (136, 140))	('mutations', 'Var', (96, 105))
133099	32210009	A to G substitutions are frequently observed in mitochondrial genomes and might be due to the lack of proofreading activity in Pol-G.	('Pol-G', 'Gene', (127, 132))	('substitutions', 'Var', (7, 20))	('Pol-G', 'Gene', '5428', (127, 132))
133102	32210009	The mitochondrial nucleotide substitution profiles of lung squamous cell carcinoma also demonstrated a large proportion of C to T mutations that might have been induced by smoking or tobacco exposure.	('C to T', 'Gene', (123, 129))	('mutations', 'Var', (130, 139))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (54, 82))	('tobacco', 'Species', '4097', (183, 190))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (59, 82))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (54, 82))	('lung squamous cell carcinoma', 'Disease', (54, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
133103	32210009	Patients carrying mutations in the D-loop were observed to have longer RFS, whereas shorter RFS was noted for carriers of mutations in mitochondrial OXPHOS genes (Figure 5).	('RFS', 'MPA', (71, 74))	('Patients', 'Species', '9606', (0, 8))	('OXPHOS', 'Chemical', '-', (149, 155))	('mutations', 'Var', (18, 27))
133104	32210009	In the present study, patients carrying mutations in the D-loop were observed to have longer RFS (Figure 5a, Table 2).	('RFS', 'MPA', (93, 96))	('patients', 'Species', '9606', (22, 30))	('D-loop', 'Gene', (57, 63))	('longer', 'PosReg', (86, 92))	('mutations', 'Var', (40, 49))
133105	32210009	Although mutations in the D-loop region may impede mitochondrial replication and alter the transcription process, mechanisms of how these mutations influence cancer prognosis still need to be investigated.	('mitochondrial replication', 'CPA', (51, 76))	('mutations', 'Var', (9, 18))	('alter', 'Reg', (81, 86))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('transcription process', 'MPA', (91, 112))	('impede', 'NegReg', (44, 50))	('cancer', 'Disease', (158, 164))	('influence', 'Reg', (148, 157))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
133108	32210009	The advancement in TKI-based therapies, radiotherapy, or chemotherapies for lung cancer patients could have been potential influential factors in the estimation of the association of OS with mitochondrial mutations.	('lung cancer', 'Disease', 'MESH:D008175', (76, 87))	('association', 'Interaction', (168, 179))	('patients', 'Species', '9606', (88, 96))	('mutations', 'Var', (205, 214))	('lung cancer', 'Disease', (76, 87))	('lung cancer', 'Phenotype', 'HP:0100526', (76, 87))	('mitochondrial', 'Gene', (191, 204))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))
133110	32210009	No significant association was observed for OS in the TCGA_LUAD dataset, although the trend of OS in LUAD_TCGA was similar to that in our data (Figure S20) Mutations in mitochondrial genes encoding for key subunits of OXPHOS complexes were associated with shortened RFS.	('LUAD', 'Phenotype', 'HP:0030078', (59, 63))	('shortened RFS', 'Disease', (256, 269))	('LUAD', 'Phenotype', 'HP:0030078', (101, 105))	('S20', 'Gene', (151, 154))	('associated', 'Reg', (240, 250))	('S20', 'Gene', '6224', (151, 154))	('OXPHOS', 'Chemical', '-', (218, 224))	('Mutations', 'Var', (156, 165))
133111	32210009	Characterization of mutations in mitochondrially encoded OXPHOS complex genes provided evidence for their role in tumor development and progression.	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('progression', 'CPA', (136, 147))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumor', 'Disease', (114, 119))	('OXPHOS', 'Chemical', '-', (57, 63))	('mutations', 'Var', (20, 29))
133112	32210009	Previous studies have demonstrated that mitochondrial mutations are associated with elevated ROS production, increased invasion ability, decimated mitochondria copy number, and higher risk of breast cancer, oral squamous cell carcinoma, colorectal cancer, and thyroid oncocytoma.	('breast cancer', 'Disease', 'MESH:D001943', (192, 205))	('elevated', 'PosReg', (84, 92))	('colorectal cancer', 'Phenotype', 'HP:0003003', (237, 254))	('breast cancer', 'Disease', (192, 205))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (207, 235))	('increased', 'PosReg', (109, 118))	('oral squamous cell carcinoma', 'Disease', (207, 235))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('invasion ability', 'CPA', (119, 135))	('mutations', 'Var', (54, 63))	('cancer', 'Phenotype', 'HP:0002664', (248, 254))	('ROS production', 'MPA', (93, 107))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (212, 235))	('colorectal cancer', 'Disease', 'MESH:D015179', (237, 254))	('thyroid oncocytoma', 'Disease', 'MESH:D018249', (260, 278))	('thyroid oncocytoma', 'Disease', (260, 278))	('ROS', 'Chemical', 'MESH:D017382', (93, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (226, 235))	('colorectal cancer', 'Disease', (237, 254))	('mitochondrial mutations', 'Var', (40, 63))	('breast cancer', 'Phenotype', 'HP:0003002', (192, 205))	('elevated ROS production', 'Phenotype', 'HP:0025464', (84, 107))
133113	32210009	The existence of empirical evidence for mitochondrial genomic mutations and subsequent mitochondrial dysfunction in several cancers suggests that mitochondrial mutations may have potential in evaluating the risk of cancer progression.	('cancer', 'Disease', (124, 130))	('mutations', 'Var', (160, 169))	('mitochondrial dysfunction', 'Disease', 'MESH:D028361', (87, 112))	('cancer', 'Disease', (215, 221))	('cancer', 'Disease', 'MESH:D009369', (215, 221))	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (87, 112))	('mitochondrial genomic mutations', 'Var', (40, 71))	('mitochondrial dysfunction', 'Disease', (87, 112))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('cancers', 'Phenotype', 'HP:0002664', (124, 131))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('cancers', 'Disease', (124, 131))	('cancer', 'Disease', 'MESH:D009369', (124, 130))	('cancers', 'Disease', 'MESH:D009369', (124, 131))
133124	32210009	The EGFR mutation detection was performed via matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS), following the user's manual for the MassARRAY  system (SEQUENOM , CA, USA).	('EGFR', 'Gene', (4, 8))	('mutation', 'Var', (9, 17))	('EGFR', 'Gene', '1956', (4, 8))
133125	32210009	Customized primers and probes were used for detection and analysis of the EGFR mutations.	('EGFR', 'Gene', '1956', (74, 78))	('EGFR', 'Gene', (74, 78))	('mutations', 'Var', (79, 88))
133130	32210009	Variants showing significant associations with OS or RFS were then analyzed using multivariate Cox proportional hazard regression with covariates age, sex, EGFR mutation, tumor size, and smoking status to identify the independent prognostic mutations.	('Variants', 'Var', (0, 8))	('EGFR', 'Gene', '1956', (156, 160))	('mutation', 'Var', (161, 169))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('EGFR', 'Gene', (156, 160))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', (171, 176))	('RFS', 'Disease', (53, 56))
133132	32210009	Mutations in the mitochondrial genome may lead to dysregulated OXPHOS; the key to attaining Warburg phenotype.	('Mutations', 'Var', (0, 9))	('dysregulated OXPHOS', 'MPA', (50, 69))	('OXPHOS', 'Chemical', '-', (63, 69))	('lead to', 'Reg', (42, 49))
133133	32210009	Anomalies in D-loop and OXPHOS genes showed association with prognosis of lung adenocarcinoma and revealed an undiscovered regime.	('Anomalies', 'Var', (0, 9))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (74, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('OXPHOS genes', 'Gene', (24, 36))	('association', 'Reg', (44, 55))	('lung adenocarcinoma', 'Disease', (74, 93))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (74, 93))	('D-loop', 'Gene', (13, 19))	('OXPHOS', 'Chemical', '-', (24, 30))
133134	32210009	Future functional studies are required to clarify the relationship between mitochondrial mutations and the prognosis of lung adenocarcinoma.	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (120, 139))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (120, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('mutations', 'Var', (89, 98))	('lung adenocarcinoma', 'Disease', (120, 139))
133136	32210009	The following are available online at , Figure S1: Positional distribution of germline mitochondrial variant in lung adenocarcinoma.	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (112, 131))	('variant', 'Var', (101, 108))	('germline', 'Var', (78, 86))	('lung adenocarcinoma', 'Disease', (112, 131))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (112, 131))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))
133148	32158227	Furthermore, inhibiting SNHG1 decreased xenograft tumor growth by regulating miR-204 and HOXC8.	('SNHG1', 'Gene', (24, 29))	('miR-204', 'Protein', (77, 84))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('regulating', 'Reg', (66, 76))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('HOXC8', 'MPA', (89, 94))	('inhibiting', 'Var', (13, 23))	('tumor', 'Disease', (50, 55))	('decreased', 'NegReg', (30, 39))
133149	32158227	SNHG1 knockdown suppresses migration and invasion but induces apoptosis of esophageal squamous cell cancer cells by increasing miR-204 and decreasing HOXC8.	('SNHG1', 'Gene', (0, 5))	('decreasing', 'NegReg', (139, 149))	('suppresses', 'NegReg', (16, 26))	('esophageal squamous cell cancer', 'Disease', 'MESH:D018307', (75, 106))	('miR-204', 'Protein', (127, 134))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (86, 106))	('esophageal squamous cell cancer', 'Disease', (75, 106))	('increasing', 'PosReg', (116, 126))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('apoptosis', 'CPA', (62, 71))	('knockdown', 'Var', (6, 15))	('HOXC8', 'MPA', (150, 155))	('induces', 'Reg', (54, 61))
133163	32158227	More importantly, recent works indicate that abnormally expressed SNHG1 is involved in the regulation of esophageal squamous cell cancer progression.	('involved', 'Reg', (75, 83))	('esophageal squamous cell cancer', 'Disease', (105, 136))	('SNHG1', 'Gene', (66, 71))	('abnormally expressed', 'Var', (45, 65))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (116, 136))	('esophageal squamous cell cancer', 'Disease', 'MESH:D018307', (105, 136))
133167	32158227	The expression levels of SNHG1, miR-204 and HOXC8 in esophageal cancer were analyzed via TCGA.	('SNHG1', 'Gene', (25, 30))	('esophageal cancer', 'Disease', (53, 70))	('esophageal cancer', 'Disease', 'MESH:D004938', (53, 70))	('miR-204', 'Var', (32, 39))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
133171	32158227	The human esophageal squamous cell cancer cell lines (EC9706, KYSE450, KYSE150 and Eca109) and normal esophageal epithelium cell Het-1A were purchased from BeNa Culture Collection (Beijing, China) and verified by the company.	('human', 'Species', '9606', (4, 9))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('KYSE150', 'Var', (71, 78))	('esophageal squamous cell cancer', 'Disease', 'MESH:D018307', (10, 41))	('KYSE150', 'CellLine', 'CVCL:1348', (71, 78))	('esophageal squamous cell cancer', 'Disease', (10, 41))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (21, 41))	('EC9706', 'CellLine', 'CVCL:E307', (54, 60))
133184	32158227	The membranes were blocked with 5% non-fat milk for 2 h, incubated with specific primary antibodies overnight and secondary antibody (ab97051, 1:20,000 dilution) for 2 h. The antibody against HOXC8 (ab86236, 1:1000 dilution) was purchased from Abcam (Cambridge, MA, USA), with beta-actin (ab227387, 1:10,000 dilution) as a loading control.	('beta-actin', 'Gene', '728378', (277, 287))	('beta-actin', 'Gene', (277, 287))	('ab86236', 'Var', (199, 206))
133187	32158227	EC9706 and KYSE150 cells transfected with miR-204 or miR-NC were lysed for RIP assay with a Magna RNA immunoprecipitation kit (Millipore) following the manufacturer's protocols.	('miR-NC', 'Var', (53, 59))	('miR-204', 'Var', (42, 49))	('KYSE150', 'CellLine', 'CVCL:1348', (11, 18))	('EC9706', 'CellLine', 'CVCL:E307', (0, 6))
133198	32158227	The patients with high SNHG1 level displayed poor overall survival compared with those in low expression group (P=0.027) (Figure 1C).	('overall survival', 'CPA', (50, 66))	('poor', 'NegReg', (45, 49))	('high SNHG1 level', 'Var', (18, 34))	('patients', 'Species', '9606', (4, 12))
133201	32158227	As shown in Figure 2A and B, the abundance of SNHG1 in EC9706 and KYSE150 cells was effectively decreased 60-65% by transfection of si-SNHG1 in comparison to that in the si-NC group and Blank group.	('KYSE150', 'CellLine', 'CVCL:1348', (66, 73))	('decreased', 'NegReg', (96, 105))	('abundance', 'MPA', (33, 42))	('SNHG1', 'Gene', (46, 51))	('EC9706', 'CellLine', 'CVCL:E307', (55, 61))	('si-SNHG1', 'Var', (132, 140))
133203	32158227	Besides, interference of SNHG1 led to great apoptosis production in EC9706 and KYSE150 cells (Figure 2I and J).	('interference', 'Var', (9, 21))	('EC9706', 'CellLine', 'CVCL:E307', (68, 74))	('SNHG1', 'Gene', (25, 30))	('KYSE150', 'CellLine', 'CVCL:1348', (79, 86))	('apoptosis production', 'MPA', (44, 64))
133205	32158227	Moreover, the addition of miR-204 led to a markedly increased level of SNHG1 enriched by Ago2 RIP in EC9706 and KYSE150 cells (Figure 3D and E).	('KYSE150', 'CellLine', 'CVCL:1348', (112, 119))	('miR-204', 'Var', (26, 33))	('increased', 'PosReg', (52, 61))	('Ago2', 'Gene', (89, 93))	('level', 'MPA', (62, 67))	('SNHG1', 'Gene', (71, 76))	('Ago2', 'Gene', '27161', (89, 93))	('EC9706', 'CellLine', 'CVCL:E307', (101, 107))
133208	32158227	Besides, miR-204 level in EC9706 and KYSE150 cells was evidently decreased by overexpressing SNHG1 and increased via silencing SNHG1 (Figure 3G and H).	('SNHG1', 'Gene', (127, 132))	('increased', 'PosReg', (103, 112))	('silencing', 'Var', (117, 126))	('decreased', 'NegReg', (65, 74))	('SNHG1', 'Gene', (93, 98))	('overexpressing', 'PosReg', (78, 92))	('KYSE150', 'CellLine', 'CVCL:1348', (37, 44))	('miR-204 level', 'MPA', (9, 22))	('EC9706', 'CellLine', 'CVCL:E307', (26, 32))
133209	32158227	In order to explore whether miR-204 was associated with SNHG1-mediated progression of esophageal squamous cell cancer, EC9706 and KYSE150 cells were transfected with si-NC, si-SNHG1, si-SNHG1 and anti-miR-NC or anti-miR-204.	('anti-miR-204', 'Var', (211, 223))	('si-SNHG1', 'Var', (173, 181))	('EC9706', 'CellLine', 'CVCL:E307', (119, 125))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (97, 117))	('esophageal squamous cell cancer', 'Disease', 'MESH:D018307', (86, 117))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('anti-miR-NC', 'Var', (196, 207))	('esophageal squamous cell cancer', 'Disease', (86, 117))	('si-NC', 'Var', (166, 171))	('KYSE150', 'CellLine', 'CVCL:1348', (130, 137))	('si-SNHG1', 'Var', (183, 191))	('associated', 'Reg', (40, 50))
133210	32158227	After the transfection, the abundance of miR-204 in EC9706 and KYSE150 cells increased by SNHG1 knockdown was obviously decreased by the transfection of anti-miR-204 (Figure 4A and B).	('knockdown', 'Var', (96, 105))	('abundance', 'MPA', (28, 37))	('decreased', 'NegReg', (120, 129))	('anti-miR-204', 'Var', (153, 165))	('KYSE150', 'CellLine', 'CVCL:1348', (63, 70))	('EC9706', 'CellLine', 'CVCL:E307', (52, 58))	('SNHG1', 'Gene', (90, 95))	('miR-204', 'Gene', (41, 48))
133211	32158227	In addition, the suppressive effect of SNHG1 knockdown on migration and invasion of EC9706 and KYSE150 cells was weakened via miR-204 deficiency (Figure 4E-H).	('weakened', 'NegReg', (113, 121))	('deficiency', 'Var', (134, 144))	('migration', 'CPA', (58, 67))	('miR-204', 'Gene', (126, 133))	('suppressive', 'NegReg', (17, 28))	('SNHG1', 'Gene', (39, 44))	('EC9706', 'CellLine', 'CVCL:E307', (84, 90))	('KYSE150', 'CellLine', 'CVCL:1348', (95, 102))	('invasion', 'CPA', (72, 80))	('knockdown', 'Var', (45, 54))
133217	32158227	In addition, the abundance of HOXC8 protein in EC9706 and KYSE150 cells was conspicuously reduced via miR-204 addition and elevated by miR-204 exhaustion (Figure 5G and H).	('EC9706', 'CellLine', 'CVCL:E307', (47, 53))	('miR-204', 'Var', (135, 142))	('reduced', 'NegReg', (90, 97))	('KYSE150', 'CellLine', 'CVCL:1348', (58, 65))	('miR-204', 'Var', (102, 109))	('abundance of HOXC8 protein', 'MPA', (17, 43))	('elevated', 'PosReg', (123, 131))	('EC9706', 'Var', (47, 53))
133220	32158227	To explore whether SNHG1-regulated progression of esophageal squamous cell cancer was mediated by HOXC8, EC9706 and KYSE150 cells were transfected with si-NC, si-SNHG1, si-SNHG1 and pcDNA or HOXC8.	('esophageal squamous cell cancer', 'Disease', 'MESH:D018307', (50, 81))	('si-SNHG1', 'Var', (169, 177))	('KYSE150', 'CellLine', 'CVCL:1348', (116, 123))	('esophageal squamous cell cancer', 'Disease', (50, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('si-NC', 'Var', (152, 157))	('si-SNHG1', 'Var', (159, 167))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (61, 81))	('EC9706', 'CellLine', 'CVCL:E307', (105, 111))
133221	32158227	As shown in Figure 6A and B, the protein level of HOXC8 in EC9706 and KYSE150 cells was significantly decreased by silencing SNHG1, which was restored by the introduction of HOXC8 overexpression vector.	('KYSE150', 'CellLine', 'CVCL:1348', (70, 77))	('silencing', 'Var', (115, 124))	('SNHG1', 'Gene', (125, 130))	('EC9706', 'CellLine', 'CVCL:E307', (59, 65))	('protein level of', 'MPA', (33, 49))	('decreased', 'NegReg', (102, 111))
133223	32158227	Meanwhile, the inhibition of migration and invasion mediated by SNHG1 knockdown was abated by the restoration of HOXC8 in EC9706 and KYSE150 cells (Figure 6E-H).	('SNHG1', 'Gene', (64, 69))	('inhibition', 'NegReg', (15, 25))	('EC9706', 'CellLine', 'CVCL:E307', (122, 128))	('knockdown', 'Var', (70, 79))	('abated', 'NegReg', (84, 90))	('HOXC8', 'MPA', (113, 118))	('KYSE150', 'CellLine', 'CVCL:1348', (133, 140))
133224	32158227	Additionally, the introduction of HOXC8 significantly relieved the apoptosis of EC9706 and KYSE150 cells induced by silencing SNHG1 (Figure 6I and J).	('apoptosis', 'CPA', (67, 76))	('relieved', 'NegReg', (54, 62))	('EC9706', 'CellLine', 'CVCL:E307', (80, 86))	('KYSE150', 'CellLine', 'CVCL:1348', (91, 98))	('silencing', 'Var', (116, 125))	('SNHG1', 'Gene', (126, 131))
133225	32158227	Besides, knockdown of HOXC8 also weakened the promoting role of SNHG1 in esophageal squamous cell cancer development in vitro (Supplementary Figure 2).	('SNHG1', 'Gene', (64, 69))	('promoting', 'MPA', (46, 55))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('knockdown', 'Var', (9, 18))	('weakened', 'NegReg', (33, 41))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (84, 104))	('esophageal squamous cell cancer', 'Disease', 'MESH:D018307', (73, 104))	('esophageal squamous cell cancer', 'Disease', (73, 104))
133236	32158227	Former findings suggested that SNHG1 could serve as a ceRNA to be implicated in the development of human cancers.	('SNHG1', 'Var', (31, 36))	('cancers', 'Phenotype', 'HP:0002664', (105, 112))	('cancers', 'Disease', (105, 112))	('cancers', 'Disease', 'MESH:D009369', (105, 112))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('human', 'Species', '9606', (99, 104))
133241	32158227	In our study, we also found the tumor suppressive role of miR-204, revealed by which its knockdown abated silencing SNHG1-mediated inhibition of esophageal squamous cell cancer progression.	('SNHG1-mediated', 'Gene', (116, 130))	('miR-204', 'Gene', (58, 65))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (156, 176))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('silencing', 'Var', (106, 115))	('esophageal squamous cell cancer', 'Disease', (145, 176))	('esophageal squamous cell cancer', 'Disease', 'MESH:D018307', (145, 176))	('abated', 'NegReg', (99, 105))	('tumor', 'Disease', (32, 37))	('inhibition', 'NegReg', (131, 141))
133243	32158227	HOXC8 has been regarded as an oncogene and predicts poor prognosis in multiple cancers, including hepatocellular carcinoma, ovarian cancer, non-small cell lung cancer and cervical cancer.	('multiple cancers', 'Disease', (70, 86))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('ovarian cancer', 'Disease', (124, 138))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (140, 166))	('ovarian cancer', 'Phenotype', 'HP:0100615', (124, 138))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (98, 122))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (144, 166))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (140, 166))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('cervical cancer', 'Disease', 'MESH:D002583', (171, 186))	('HOXC8', 'Var', (0, 5))	('cervical cancer', 'Disease', (171, 186))	('multiple cancers', 'Disease', 'MESH:D009369', (70, 86))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (98, 122))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('non-small cell lung cancer', 'Disease', (140, 166))	('lung cancer', 'Phenotype', 'HP:0100526', (155, 166))	('ovarian cancer', 'Disease', 'MESH:D010051', (124, 138))	('hepatocellular carcinoma', 'Disease', (98, 122))
133245	32158227	Here we first using luciferase reporter assay and RIP confirmed HOXC8 as a target of miR-204 and found that restoration or knockdown of HOXC8 abolished the effect of SNHG1 silence or overexpression on cancer progression, indicating that SNHG1 regulated esophageal squamous cell cancer development by increasing HOXC8 via competitively sponging miR-204.	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (264, 284))	('esophageal squamous cell cancer', 'Disease', (253, 284))	('cancer', 'Phenotype', 'HP:0002664', (278, 284))	('cancer', 'Disease', (201, 207))	('regulated', 'Reg', (243, 252))	('HOXC8', 'MPA', (311, 316))	('cancer', 'Disease', 'MESH:D009369', (278, 284))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('increasing', 'PosReg', (300, 310))	('cancer', 'Disease', (278, 284))	('SNHG1', 'Var', (237, 242))	('esophageal squamous cell cancer', 'Disease', 'MESH:D018307', (253, 284))
133247	32158227	Hence, we also established the murine xenograft model using esophageal squamous cell cancer cells and found the anti-cancer role of SNHG1 knockdown in this cancer in vivo by regulating miR-204/HOXC8 axis.	('knockdown', 'Var', (138, 147))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('cancer', 'Disease', (156, 162))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('miR-204/HOXC8 axis', 'Pathway', (185, 203))	('regulating', 'Reg', (174, 184))	('esophageal squamous cell cancer', 'Disease', (60, 91))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('SNHG1', 'Gene', (132, 137))	('cancer', 'Disease', (85, 91))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (71, 91))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('cancer', 'Disease', (117, 123))	('murine', 'Species', '10090', (31, 37))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('esophageal squamous cell cancer', 'Disease', 'MESH:D018307', (60, 91))
133316	31068670	Studies on lung cancer tissue have shown that adenocarcinomas tend to exhibit less allelic loss than squamous cell carcinomas and that asbestos exposure correlates with a greater frequency of p53 mutation, which again implies a tumour promoting effect through loss of suppression.	('tumour', 'Disease', (228, 234))	('carcinomas', 'Phenotype', 'HP:0030731', (51, 61))	('lung cancer', 'Phenotype', 'HP:0100526', (11, 22))	('adenocarcinomas', 'Disease', 'MESH:D000230', (46, 61))	('p53', 'Gene', (192, 195))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (101, 125))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (101, 125))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('allelic loss', 'MPA', (83, 95))	('lung cancer', 'Disease', 'MESH:D008175', (11, 22))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (101, 124))	('less', 'NegReg', (78, 82))	('lung cancer', 'Disease', (11, 22))	('squamous cell carcinomas', 'Disease', (101, 125))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('mutation', 'Var', (196, 204))	('carcinomas', 'Phenotype', 'HP:0030731', (115, 125))	('asbestos', 'Chemical', 'MESH:D001194', (135, 143))	('tumour', 'Phenotype', 'HP:0002664', (228, 234))	('p53', 'Gene', '7157', (192, 195))	('tumour', 'Disease', 'MESH:D009369', (228, 234))	('adenocarcinomas', 'Disease', (46, 61))	('carcinoma', 'Phenotype', 'HP:0030731', (51, 60))
133317	31068670	In mesotheliomas, increased mutation frequency has consistently been reported in tumour suppressors such as neurofibromatosis type 2 (NF2) and the nuclear deubiquitinase Bap1.	('mesotheliomas', 'Disease', 'MESH:D008654', (3, 16))	('mesotheliomas', 'Disease', (3, 16))	('tumour', 'Disease', 'MESH:D009369', (81, 87))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (108, 125))	('Bap1', 'Gene', '8314', (170, 174))	('tumour', 'Disease', (81, 87))	('NF2', 'Gene', '4771', (134, 137))	('neurofibromatosis type 2', 'Disease', 'MESH:C537392', (108, 132))	('mutation', 'Var', (28, 36))	('Bap1', 'Gene', (170, 174))	('neurofibromatosis type 2', 'Disease', (108, 132))	('NF2', 'Gene', (134, 137))	('tumour', 'Phenotype', 'HP:0002664', (81, 87))
133318	31068670	Monosomy of chromosome 22 or deletions in 22q that include NF2 as well as homozygous deletions in 9p21, which encompass the cyclin-dependent kinase inhibitor 2A (CDKN2A locus), are reported in up to 72% cases of mesothelioma, but there are also frequent deletions at other sites, including 1p, 3p, 4p, 6q, 13q, 14q, and 15q.	('Monosomy', 'Var', (0, 8))	('NF2', 'Gene', (59, 62))	('CDKN2A', 'Gene', (162, 168))	('mesothelioma', 'Disease', (212, 224))	('reported', 'Reg', (181, 189))	('deletions', 'Var', (85, 94))	('CDKN2A', 'Gene', '1029', (162, 168))	('NF2', 'Gene', '4771', (59, 62))	('mesothelioma', 'Disease', 'MESH:D008654', (212, 224))	('deletions', 'Var', (29, 38))	('cyclin-dependent kinase inhibitor 2A', 'Gene', (124, 160))	('cyclin-dependent kinase inhibitor 2A', 'Gene', '1029', (124, 160))
133322	31068670	Notably, gene copy number changes are very common in oesophageal adenocarcinoma with a large number of chromosomal rearrangements reported.	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('oesophageal adenocarcinoma', 'Disease', 'MESH:D005764', (53, 79))	('men', 'Species', '9606', (124, 127))	('common', 'Reg', (43, 49))	('gene copy number changes', 'Var', (9, 33))	('oesophageal adenocarcinoma', 'Disease', (53, 79))
133323	31068670	It is perhaps not surprising that there is some overlap with the typical chromosomal alterations found in mesothelioma such as 9p21 deletions, which have long been known to occur early in disease pathogenesis, including in premalignant Barrett's oesophagus.	('mesothelioma', 'Disease', (106, 118))	("premalignant Barrett's oesophagus", 'Disease', (223, 256))	('mesothelioma', 'Disease', 'MESH:D008654', (106, 118))	('9p21', 'Gene', (127, 131))	('deletions', 'Var', (132, 141))	("Barrett's oesophagus", 'Phenotype', 'HP:0100580', (236, 256))
133325	31068670	A complementary approach that has been facilitated by the advent of whole genome sequencing is to identify and classify mutational processes through the statistical analysis of the frequency of base changes (A > C, T > G, etc.)	('men', 'Species', '9606', (8, 11))	('A > C', 'Var', (208, 213))	('T > G', 'Var', (215, 220))
133328	31068670	The most frequent and specific signatures observed in oesophageal adenocarcinoma are T>G substitutions in a CTT context, called the 'S17 signature'.	('oesophageal adenocarcinoma', 'Disease', (54, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('oesophageal adenocarcinoma', 'Disease', 'MESH:D005764', (54, 80))	('T>G substitutions', 'Var', (85, 102))	('substitutions', 'Var', (89, 102))
133329	31068670	Other signatures reflect ageing (S1); a complex pattern caused by defects in the BRCA1/2-led homologous recombination pathway (S3); C>T mutations in a TCA/TCT context, which is due to mutations in the apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like (APOBEC) proteins (S2); and C>A/T dominant in a GCA/TCT context (S18), which is also found in gastric carcinoma as well as neuroblastoma.	('neuroblastoma', 'Disease', 'MESH:D009447', (389, 402))	('BRCA1', 'Gene', (81, 86))	('gastric carcinoma', 'Disease', 'MESH:D013274', (360, 377))	('neuroblastoma', 'Disease', (389, 402))	('neuroblastoma', 'Phenotype', 'HP:0003006', (389, 402))	('gastric carcinoma', 'Disease', (360, 377))	('apolipoprotein B', 'Protein', (201, 217))	('C>A/T', 'Var', (294, 299))	('carcinoma', 'Phenotype', 'HP:0030731', (368, 377))	('BRCA1', 'Gene', '672', (81, 86))	('defects', 'NegReg', (66, 73))	('C>T mutations', 'Var', (132, 145))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (360, 377))
133360	30885149	A significantly poorer prognosis was observed in 28 patients with MET FISH-positivity (disease free survival/DFS, P < 0.001 and overall survival/OS, P = 0.001).	('MET FISH-positivity', 'Var', (66, 85))	('OS', 'Chemical', '-', (145, 147))	('patients', 'Species', '9606', (52, 60))	('disease free survival/DFS', 'CPA', (87, 112))
133374	30885149	Aberrant MET activation has been reported in various types of cancer, and promotes tumor cell proliferation, motility, invasion and metastasis.	('promotes', 'PosReg', (74, 82))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('Aberrant', 'Var', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('metastasis', 'CPA', (132, 142))	('tumor', 'Disease', (83, 88))	('activation', 'PosReg', (13, 23))	('MET', 'Protein', (9, 12))	('cancer', 'Disease', (62, 68))	('motility', 'CPA', (109, 117))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
133376	30885149	Recent studies found different tumors with MET amplification were extraordinarily susceptible to the selective MET tyrosine kinase inhibitor (TKI), and MET amplification was responsible for approximately 20% of the acquired resistance to epidermal growth factor receptor (EGFR) TKI treatment in lung adenocarcinomas.	('EGFR', 'Gene', '1956', (272, 276))	('MET amplification', 'Var', (43, 60))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('EGFR', 'Gene', (272, 276))	('tumors', 'Disease', (31, 37))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (295, 315))	('responsible', 'Reg', (174, 185))	('amplification', 'Var', (47, 60))	('MET', 'Var', (152, 155))	('tumors', 'Disease', 'MESH:D009369', (31, 37))	('lung adenocarcinomas', 'Disease', (295, 315))	('epidermal growth factor receptor', 'Gene', (238, 270))	('carcinoma', 'Phenotype', 'HP:0030731', (305, 314))	('men', 'Species', '9606', (287, 290))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (295, 315))	('epidermal growth factor receptor', 'Gene', '1956', (238, 270))
133379	30885149	And MET amplification is thought to be associated with metastasis and poorer outcome in gastric, lung and colorectal cancers.	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('MET amplification', 'Var', (4, 21))	('colorectal cancers', 'Disease', (106, 124))	('lung', 'Disease', (97, 101))	('associated', 'Reg', (39, 49))	('cancers', 'Phenotype', 'HP:0002664', (117, 124))	('colorectal cancers', 'Disease', 'MESH:D015179', (106, 124))	('gastric', 'Disease', (88, 95))
133406	30885149	MET FISH-positivity was significantly associated with DFS (2.2% in patients without disease progression vs. 8.6% in patients with disease progression, P = 0.002) and OS (2.6% vs. 8.4%, P = 0.005).	('DFS', 'Disease', (54, 57))	('associated', 'Reg', (38, 48))	('patients', 'Species', '9606', (67, 75))	('patients', 'Species', '9606', (116, 124))	('MET FISH-positivity', 'Var', (0, 19))	('OS', 'Chemical', '-', (166, 168))
133411	30885149	The 5-year DFS (17.9%) and OS (17.8%) rates for patients with MET FISH-positivity were significantly lower than the corresponding rates (45.7 and 46.0%) for patients with MET FISH-negativity.	('MET', 'Var', (62, 65))	('OS', 'Chemical', '-', (27, 29))	('DFS', 'MPA', (11, 14))	('patients', 'Species', '9606', (157, 165))	('lower', 'NegReg', (101, 106))	('patients', 'Species', '9606', (48, 56))
133421	30885149	MET FISH-positivity was also associated with DFS (P = 0.020) and OS (P = 0.024) in patients with stage III-IVa ESCC (n = 223) (Fig.	('OS', 'Chemical', '-', (65, 67))	('MET FISH-positivity', 'Var', (0, 19))	('DFS', 'Disease', (45, 48))	('associated', 'Reg', (29, 39))	('patients', 'Species', '9606', (83, 91))
133428	30885149	found the survival outcome of patients with a mean MET gene copy number per cell higher than 5 and higher than 6 was similar, and worse than the other four groups with a mean copy number lower than 5 in NSCLC.	('NSCLC', 'Disease', 'MESH:D002289', (203, 208))	('NSCLC', 'Disease', (203, 208))	('MET gene copy number', 'Var', (51, 71))	('patients', 'Species', '9606', (30, 38))
133430	30885149	Since Lennerz etal has demonstrated that 2% of patients (10/489) with esophagogastric adenocarcinoma, who harbored MET amplification and were treated with a MET inhibitor, experienced tumor shrinkage in 2011, MET gene status has gained considerable interest in solid tumors.	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('tumor', 'Disease', 'MESH:D009369', (267, 272))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('esophagogastric adenocarcinoma', 'Disease', (70, 100))	('solid tumors', 'Disease', (261, 273))	('esophagogastric adenocarcinoma', 'Disease', 'MESH:C537006', (70, 100))	('patients', 'Species', '9606', (47, 55))	('tumor', 'Phenotype', 'HP:0002664', (267, 272))	('tumor', 'Disease', (184, 189))	('tumors', 'Phenotype', 'HP:0002664', (267, 273))	('MET amplification', 'Var', (115, 132))	('tumor', 'Disease', (267, 272))	('esophagogastric adenocarcinoma', 'Phenotype', 'HP:0011459', (70, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('solid tumors', 'Disease', 'MESH:D009369', (261, 273))
133433	30885149	Moreover, MET FISH-positivity was an independent prognostic factor for both DFS and OS, further indicating increased MET gene copy number is a negative prognostic factor in ESCC.	('negative', 'NegReg', (143, 151))	('ESCC', 'Disease', (173, 177))	('OS', 'Chemical', '-', (84, 86))	('DFS', 'Disease', (76, 79))	('MET gene copy number', 'Var', (117, 137))
133434	30885149	reported in gastric cancer, MET amplification did not have an impact on prognosis in early TNM stage (stage I or II), unlike in advanced TNM stage (stage III or IV).	('early TNM stage', 'Disease', (85, 100))	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('gastric cancer', 'Disease', (12, 26))	('gastric cancer', 'Disease', 'MESH:D013274', (12, 26))	('MET amplification', 'Var', (28, 45))	('gastric cancer', 'Phenotype', 'HP:0012126', (12, 26))
133470	30815429	showed an association between fascin overexpression and the expression of high-risk papilloma viruses E6/E7 oncoproteins in colorectal cancer (CRC).	('expression', 'MPA', (60, 70))	('papilloma', 'Phenotype', 'HP:0012740', (84, 93))	('colorectal cancer', 'Phenotype', 'HP:0003003', (124, 141))	('oncoproteins', 'Protein', (108, 120))	('colorectal cancer', 'Disease', (124, 141))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('papilloma viruses', 'Disease', 'MESH:D010212', (84, 101))	('papilloma viruses', 'Disease', (84, 101))	('CRC', 'Phenotype', 'HP:0003003', (143, 146))	('colorectal cancer', 'Disease', 'MESH:D015179', (124, 141))	('E6/E7', 'Var', (102, 107))
133478	29416000	In addition, we found that knockout of miR-195 promotes cancer cell growth.	('promotes', 'PosReg', (47, 55))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('knockout', 'Var', (27, 35))	('miR-195', 'Gene', (39, 46))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('miR-195', 'Gene', '406971', (39, 46))
133482	29416000	Specifically, we found that BIRC5, which codes for survivin, is upregulated in both adenocarcinoma and squamous cell carcinoma tissues and that high expression of BIRC5 is associated with poor survival in adenocarcinoma, but not squamous cell carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (210, 219))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('BIRC5', 'Gene', '332', (28, 33))	('adenocarcinoma', 'Disease', (84, 98))	('BIRC5', 'Gene', (28, 33))	('adenocarcinoma', 'Disease', (205, 219))	('BIRC5', 'Gene', '332', (163, 168))	('BIRC5', 'Gene', (163, 168))	('high expression', 'Var', (144, 159))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (103, 126))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (229, 252))	('adenocarcinoma', 'Disease', 'MESH:D000230', (84, 98))	('adenocarcinoma', 'Disease', 'MESH:D000230', (205, 219))	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('carcinoma', 'Phenotype', 'HP:0030731', (243, 252))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (103, 126))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (229, 252))	('adenocarcinoma and squamous cell carcinoma', 'Disease', 'MESH:D002294', (84, 126))	('upregulated', 'PosReg', (64, 75))	('squamous cell carcinoma', 'Disease', (103, 126))	('squamous cell carcinoma', 'Disease', (229, 252))
133513	29416000	Similarly, knockout of miR-195 using CRISPR-Cas9 promotes cancer cell growth (Fig.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('promotes', 'PosReg', (49, 57))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('cancer', 'Disease', (58, 64))	('miR-195', 'Gene', (23, 30))	('miR-195', 'Gene', '406971', (23, 30))	('knockout', 'Var', (11, 19))
133535	29416000	We confirmed that mRNA and protein levels of CCND3 and BIRC5 are decreased by miR-195 and increased by miR-195 inhibitors in NSCLC cells (Fig.	('CCND3', 'Gene', (45, 50))	('increased', 'PosReg', (90, 99))	('NSCLC', 'Disease', (125, 130))	('miR-195', 'Gene', (103, 110))	('decreased', 'NegReg', (65, 74))	('NSCLC', 'Disease', 'MESH:D002289', (125, 130))	('NSCLC', 'Phenotype', 'HP:0030358', (125, 130))	('miR-195', 'Gene', '406971', (103, 110))	('CCND3', 'Gene', '896', (45, 50))	('inhibitors', 'Var', (111, 121))	('miR-195', 'Gene', '406971', (78, 85))	('BIRC5', 'Gene', '332', (55, 60))	('miR-195', 'Gene', (78, 85))	('BIRC5', 'Gene', (55, 60))
133539	29416000	As predicted, knockdown of CCND3 or BIRC5 inhibits the growth of cancer cells (Fig.	('inhibits', 'NegReg', (42, 50))	('BIRC5', 'Gene', '332', (36, 41))	('BIRC5', 'Gene', (36, 41))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('CCND3', 'Gene', '896', (27, 32))	('knockdown', 'Var', (14, 23))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('CCND3', 'Gene', (27, 32))
133541	29416000	Additionally, knockdown of CCND3 causes cell cycle arrest at G1, and knockdown of BIRC5 induces apoptosis and senescence (Supplementary Figure 6A, B; Fig.	('induces', 'Reg', (88, 95))	('cell cycle arrest at G1', 'CPA', (40, 63))	('senescence', 'CPA', (110, 120))	('BIRC5', 'Gene', '332', (82, 87))	('BIRC5', 'Gene', (82, 87))	('CCND3', 'Gene', '896', (27, 32))	('apoptosis', 'CPA', (96, 105))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (40, 57))	('knockdown', 'Var', (14, 23))	('knockdown', 'Var', (69, 78))	('CCND3', 'Gene', (27, 32))
133551	29416000	BIRC5 levels are negatively correlated with miR-195 levels in both LUAD and LUSC patients and high expression of BIRC5 is associated with worse overall survival and recurrence-free survival in LUAD patients but not in LUSC patients (Fig.	('patients', 'Species', '9606', (198, 206))	('LUAD', 'Disease', (193, 197))	('recurrence-free survival', 'CPA', (165, 189))	('LUAD', 'Disease', (67, 71))	('miR-195', 'Gene', (44, 51))	('worse', 'NegReg', (138, 143))	('LUAD', 'Disease', 'None', (193, 197))	('LUAD', 'Disease', 'None', (67, 71))	('BIRC5', 'Gene', '332', (113, 118))	('BIRC5', 'Gene', '332', (0, 5))	('BIRC5', 'Gene', (113, 118))	('BIRC5', 'Gene', (0, 5))	('high expression', 'Var', (94, 109))	('patients', 'Species', '9606', (81, 89))	('LUAD', 'Phenotype', 'HP:0030078', (193, 197))	('LUAD', 'Phenotype', 'HP:0030078', (67, 71))	('patients', 'Species', '9606', (223, 231))	('overall survival', 'CPA', (144, 160))	('miR-195', 'Gene', '406971', (44, 51))
133558	29416000	First, it has not been demonstrated whether loss of miR-195 is oncogenic in NSCLC.	('NSCLC', 'Disease', (76, 81))	('miR-195', 'Gene', (52, 59))	('miR-195', 'Gene', '406971', (52, 59))	('NSCLC', 'Disease', 'MESH:D002289', (76, 81))	('loss', 'Var', (44, 48))	('NSCLC', 'Phenotype', 'HP:0030358', (76, 81))
133564	29416000	We demonstrate that repression of miR-195 accelerates NSCLC growth, while activation of miR-195 represses NSCLC growth in vitro and in vivo.	('NSCLC', 'Disease', 'MESH:D002289', (106, 111))	('represses', 'NegReg', (96, 105))	('miR-195', 'Gene', (34, 41))	('NSCLC', 'Phenotype', 'HP:0030358', (54, 59))	('miR-195', 'Gene', '406971', (34, 41))	('NSCLC', 'Phenotype', 'HP:0030358', (106, 111))	('activation', 'PosReg', (74, 84))	('repression', 'Var', (20, 30))	('accelerates', 'PosReg', (42, 53))	('NSCLC', 'Disease', (54, 59))	('miR-195', 'Gene', (88, 95))	('miR-195', 'Gene', '406971', (88, 95))	('NSCLC', 'Disease', (106, 111))	('NSCLC', 'Disease', 'MESH:D002289', (54, 59))
133567	29416000	Dysregulation of cell cycle progression is a common feature of all types of cancer.	('cell cycle progression', 'CPA', (17, 39))	('Dysregulation', 'Var', (0, 13))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))
133568	29416000	Cyclin D3 is an important regulator of G1/S cell cycle progression; inhibition of CCND3 causes G1 phase arrest.	('Cyclin D3', 'Gene', '896', (0, 9))	('CCND3', 'Gene', '896', (82, 87))	('Cyclin D3', 'Gene', (0, 9))	('inhibition', 'Var', (68, 78))	('CCND3', 'Gene', (82, 87))	('G1 phase arrest', 'CPA', (95, 110))
133581	29416000	In conclusion, we demonstrated that miR-195 inhibits the growth of NSCLC cells by regulating cell cycle progression, apoptosis, and senescence, that miR-195 suppresses NSCLC, at least partially, through targeting CCND3 and BIRC5, and that dysregulation of the miR-195/BIRC5 axis may contribute to the progression of lung adenocarcinoma, establishing the relevance of levels of miR-195 and BIRC5 as prognostic factors and of the miR-195/BIRC5 axis as a therapeutic target for lung adenocarcinoma.	('contribute', 'Reg', (283, 293))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (316, 335))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (475, 494))	('cell cycle progression', 'CPA', (93, 115))	('miR-195', 'Gene', '406971', (377, 384))	('CCND3', 'Gene', '896', (213, 218))	('NSCLC', 'Phenotype', 'HP:0030358', (168, 173))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (475, 494))	('carcinoma', 'Phenotype', 'HP:0030731', (326, 335))	('BIRC5', 'Gene', '332', (436, 441))	('miR-195', 'Gene', (36, 43))	('apoptosis', 'CPA', (117, 126))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (316, 335))	('carcinoma', 'Phenotype', 'HP:0030731', (485, 494))	('miR-195', 'Gene', (377, 384))	('miR-195', 'Gene', (428, 435))	('inhibits', 'NegReg', (44, 52))	('NSCLC', 'Disease', 'MESH:D002289', (67, 72))	('dysregulation', 'Var', (239, 252))	('growth', 'MPA', (57, 63))	('miR-195', 'Gene', '406971', (149, 156))	('NSCLC', 'Disease', (67, 72))	('CCND3', 'Gene', (213, 218))	('BIRC5', 'Gene', '332', (223, 228))	('NSCLC', 'Disease', (168, 173))	('BIRC5', 'Gene', (223, 228))	('miR-195', 'Gene', '406971', (260, 267))	('miR-195', 'Gene', '406971', (428, 435))	('lung adenocarcinoma', 'Disease', (316, 335))	('lung adenocarcinoma', 'Disease', (475, 494))	('BIRC5', 'Gene', '332', (389, 394))	('BIRC5', 'Gene', (389, 394))	('NSCLC', 'Phenotype', 'HP:0030358', (67, 72))	('NSCLC', 'Disease', 'MESH:D002289', (168, 173))	('miR-195', 'Gene', (149, 156))	('suppresses', 'NegReg', (157, 167))	('miR-195', 'Gene', '406971', (36, 43))	('miR-195', 'Gene', (260, 267))	('BIRC5', 'Gene', (268, 273))	('BIRC5', 'Gene', (436, 441))	('BIRC5', 'Gene', '332', (268, 273))
133583	29416000	Two negative control oligos were purchased from Dharmacon: D-001810-10-05 (CTL) and CN-001000-01-20 (NC).	('D-001810-10-05', 'Var', (59, 73))	('oligos', 'Chemical', 'MESH:C023505', (21, 27))	('CN-001000-01-20', 'Var', (84, 99))
133586	29416000	Two siRNAs for CCND3 were purchased from Sigma-Aldrich: SASI_Hs01_00050184 targeting TGGTCAAAAAGCATGCCCAGA, and SASI_Hs01_00050186 targeting CCTAGGGAAGCTCAAGTGGGA.	('SASI_Hs01_00050186', 'Var', (112, 130))	('CCND3', 'Gene', '896', (15, 20))	('CCND3', 'Gene', (15, 20))
133587	29416000	Two siRNAs for BIRC5 were purchased from Sigma-Aldrich: SASI_Hs01_00052228 targeting ACTTGGCCCAGTGTTTCTTCT, and SASI_Hs01_00052229 targeting GTGTCTGGACCTCATGTTGTT.	('SASI_Hs01_00052229', 'Var', (112, 130))	('BIRC5', 'Gene', (15, 20))	('BIRC5', 'Gene', '332', (15, 20))
133596	29416000	An miRNA library was obtained from GE Dharmacon (CS-001010 Human Mimics Lot 09167 and CS-001015 Supplement Human Mimic 16.0 Lot 11144).	('Human', 'Species', '9606', (59, 64))	('miR', 'Gene', (3, 6))	('CS-001015', 'Var', (86, 95))	('miR', 'Gene', '220972', (3, 6))	('Human', 'Species', '9606', (107, 112))
133613	29416000	Primers for CCND3 3'UTR with mutations in the first binding site of miR-195: forward-TGTGATTGACAGCTTTAATCGTGAAGGCTCATTTTAATTTATTAATTGC and reverse-TGAGCCTTCACGATTAAAGCTGTCAATCACACAGGAGAA.	('miR-195', 'Gene', '406971', (68, 75))	('CCND3', 'Gene', '896', (12, 17))	('mutations', 'Var', (29, 38))	('CCND3', 'Gene', (12, 17))	('miR-195', 'Gene', (68, 75))
133614	29416000	Primers for CCND3 3'UTR with mutations in the second binding site of miR-195: forward-GCCAAGGAGAACGTATAGCCTGGGGTGGGGTCATG and reverse-AGGCTATACGTTCTCCTTGGCCACAAAGATCCTTTTG.	('CCND3', 'Gene', '896', (12, 17))	('miR-195', 'Gene', (69, 76))	('mutations', 'Var', (29, 38))	('CCND3', 'Gene', (12, 17))	('miR-195', 'Gene', '406971', (69, 76))
133616	29416000	Primers for BIRC5 3'UTR with mutations in the binding site of miR-195: forward-CTGCCTGTGCAGCGGGTCGTCGTGGTAACAGTGGCTGCTTCTCTCTCTC and reverse-GAGAGAGAGAAGCAGCCACTGTTACCACGACGACCCGCTGCACAGGCAG.	('BIRC5', 'Gene', '332', (12, 17))	('miR-195', 'Gene', (62, 69))	('miR-195', 'Gene', '406971', (62, 69))	('BIRC5', 'Gene', (12, 17))	('mutations', 'Var', (29, 38))
133624	29416000	Antibodies to p53 (#2527S), p21 (#2947S), actin (#4970P), survivin (#2808T), phospho-Rb (#8180), vimentin (#5471), parp (#9542P) were purchased from Cell Signaling Technology (MA, USA).	('parp', 'Gene', (115, 119))	('#2527S', 'Var', (19, 25))	('p53', 'Gene', (14, 17))	('p53', 'Gene', '7157', (14, 17))	('vimentin', 'Gene', '7431', (97, 105))	('#2947S', 'Var', (33, 39))	('#5471', 'Var', (107, 112))	('vimentin', 'Gene', (97, 105))	('#2808T', 'Var', (68, 74))	('p21', 'Gene', (28, 31))	('p21', 'Gene', '644914', (28, 31))	('parp', 'Gene', '1302', (115, 119))	('#4970P', 'Var', (49, 55))	('Rb', 'Phenotype', 'HP:0009919', (85, 87))	('#8180', 'Var', (89, 94))	('#9542P', 'Var', (121, 127))
133636	33471949	As previously described [2], 256 locally advanced (T1-2N1-2M0 or T3-4N0-2M0 according to the Union for International Cancer Control [2002]) OSCC patients were enrolled in this prospective, open-labeled, randomized phase III trial.	('patients', 'Species', '9606', (145, 153))	('T1-2N1-2M0', 'Var', (51, 61))	('T3-4N0-2M0', 'Var', (65, 75))	('Cancer', 'Disease', (117, 123))	('OSCC', 'Disease', (140, 144))	('Cancer', 'Disease', 'MESH:D009369', (117, 123))	('Cancer', 'Phenotype', 'HP:0002664', (117, 123))
133644	33471949	Patients with FPR after TPF induction chemotherapy had significant survival improvement compared to those without FPR after induction chemotherapy or those in the control group (Figure 1).	('survival', 'CPA', (67, 75))	('improvement', 'PosReg', (76, 87))	('TPF', 'Chemical', '-', (24, 27))	('Patients', 'Species', '9606', (0, 8))	('FPR', 'Var', (14, 17))
133656	33471949	No significant difference in baseline characteristics, including the T stage or TNM stage, was observed between patients with and without FPR, suggesting that FPR could be considered as a prognostic predictor for induction chemotherapy in OSCC.	('TNM', 'Gene', (80, 83))	('OSCC', 'Disease', (239, 243))	('patients', 'Species', '9606', (112, 120))	('TNM', 'Gene', '10178', (80, 83))	('FPR', 'Var', (159, 162))
133663	33471949	However, patients achieving FPR from TPF induction chemotherapy had significantly improved OS, DFS, LRFS, DMFS, and DSS, compared to patients who failed to achieve FPR or did not receive induction chemotherapy.	('DFS', 'MPA', (95, 98))	('LRFS', 'Disease', (100, 104))	('TPF', 'Chemical', '-', (37, 40))	('patients', 'Species', '9606', (9, 17))	('patients', 'Species', '9606', (133, 141))	('DSS', 'Gene', (116, 119))	('TPF', 'Gene', (37, 40))	('DSS', 'Gene', '5376', (116, 119))	('FPR', 'Var', (28, 31))	('improved', 'PosReg', (82, 90))	('DMFS', 'Chemical', '-', (106, 110))
133667	32212791	 Arg399Gln XRCC1 Polymorphism and Risk of Squamous Cell Carcinoma of the Head and Neck in Jordanian Patients X-ray repair cross-complementing group1 (XRCC1) is a key protein in base excision repair and closely associated with the coordination of the base excision repair pathway.	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (42, 65))	('XRCC1', 'Gene', '7515', (11, 16))	('XRCC1', 'Gene', (150, 155))	('associated', 'Reg', (210, 220))	('X-ray repair cross-complementing group1', 'Gene', '7515', (109, 148))	('Carcinoma of the Head and Neck', 'Phenotype', 'HP:0012288', (56, 86))	('XRCC1', 'Gene', (11, 16))	('Squamous Cell Carcinoma', 'Disease', 'MESH:D002294', (42, 65))	('Arg399Gln', 'Var', (1, 10))	('Carcinoma', 'Phenotype', 'HP:0030731', (56, 65))	('Arg399Gln', 'Chemical', '-', (1, 10))	('XRCC1', 'Gene', '7515', (150, 155))	('Squamous Cell Carcinoma', 'Disease', (42, 65))	('X-ray repair cross-complementing group1', 'Gene', (109, 148))
133669	32212791	There are many single nucleotide polymorphisms XRCC1 gene (SNPs) and the most common SNP that result in amino acid substitutions is exon 10 (Arg399Gln).	('substitutions', 'Var', (115, 128))	('XRCC1', 'Gene', (47, 52))	('XRCC1', 'Gene', '7515', (47, 52))	('Arg399Gln', 'Var', (141, 150))	('Arg399Gln', 'Chemical', '-', (141, 150))	('amino', 'MPA', (104, 109))	('single nucleotide polymorphisms', 'Var', (15, 46))
133670	32212791	This study aimed to investigate the association between Arg399Gln SNP and the risk of squamous cell carcinoma of the head and neck.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (86, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (86, 109))	('squamous cell carcinoma', 'Disease', (86, 109))	('Arg399Gln', 'Chemical', '-', (56, 65))	('Arg399Gln SNP', 'Var', (56, 69))	('carcinoma of the head and neck', 'Phenotype', 'HP:0012288', (100, 130))
133672	32212791	The Arg399Gln in XRCC1 allele was genotyped using polymerase chain reaction-restriction fragment length polymorphism method.	('XRCC1', 'Gene', (17, 22))	('Arg399Gln', 'Chemical', '-', (4, 13))	('Arg399Gln', 'Var', (4, 13))	('XRCC1', 'Gene', '7515', (17, 22))
133675	32212791	The findings indicated that Arg399Gln allele was associated with squamous cell carcinoma of the head and neck among Jordanian patients.	('Arg399Gln', 'Var', (28, 37))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (65, 88))	('Arg399Gln', 'Chemical', '-', (28, 37))	('squamous cell carcinoma', 'Disease', (65, 88))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (65, 88))	('associated', 'Reg', (49, 59))	('patients', 'Species', '9606', (126, 134))	('carcinoma of the head and neck', 'Phenotype', 'HP:0012288', (79, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))
133680	32212791	Many studies have illustrated that the genetic variants in BER cause biochemical alterations that are associated with risk of various cancers (de Laat et al., 1999).	('associated', 'Reg', (102, 112))	('genetic variants', 'Var', (39, 55))	('cancers', 'Disease', 'MESH:D009369', (134, 141))	('cancers', 'Phenotype', 'HP:0002664', (134, 141))	('cause', 'Reg', (63, 68))	('cancers', 'Disease', (134, 141))	('BER', 'Gene', (59, 62))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('biochemical alterations', 'MPA', (69, 92))
133682	32212791	There are many single nucleotide polymorphisms of XRCC1 gene (SNPs), some are located in the promoter region of the gene and others are located in the exons (Caldecott et al., 1996; Marintchev et al., 2000).	('XRCC1', 'Gene', '7515', (50, 55))	('XRCC1', 'Gene', (50, 55))	('single nucleotide polymorphisms', 'Var', (15, 46))
133683	32212791	The most common SNPs that result in amino acid substitutions are in exon 6 (Arg194Trp), exon 9 (Arg280His), and exon 10 (Arg399Gln).	('Arg', 'Gene', '27', (96, 99))	('Arg', 'Gene', (96, 99))	('Arg', 'Gene', '27', (121, 124))	('Arg399Gln', 'Chemical', '-', (121, 130))	('amino acid substitutions', 'Var', (36, 60))	('Arg', 'Gene', (76, 79))	('Arg', 'Gene', (121, 124))	('Arg', 'Gene', '27', (76, 79))
133684	32212791	Interestingly, these amino acid alterations may affect the protein-protein interaction between XRCC1 and other BER proteins, which in turn may alter DNA repair capability (Shen et al., 1998).	('affect', 'Reg', (48, 54))	('protein-protein interaction', 'MPA', (59, 86))	('XRCC1', 'Gene', (95, 100))	('alterations', 'Var', (32, 43))	('alter', 'Reg', (143, 148))	('DNA repair', 'MPA', (149, 159))	('XRCC1', 'Gene', '7515', (95, 100))	('amino', 'Var', (21, 26))
133685	32212791	Many studies have focused on XRCC1 Arg399Gln SNP and have shown its association with the risk of several types of cancers, including head and neck cancer (Caldecott et al., 1996; de Laat et al., 1999).	('cancers', 'Disease', 'MESH:D009369', (114, 121))	('cancers', 'Phenotype', 'HP:0002664', (114, 121))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('cancers', 'Disease', (114, 121))	('association', 'Reg', (68, 79))	('head and neck cancer', 'Disease', 'MESH:D006258', (133, 153))	('Arg399Gln', 'Chemical', '-', (35, 44))	('XRCC1', 'Gene', '7515', (29, 34))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('head and neck cancer', 'Phenotype', 'HP:0012288', (133, 153))	('Arg399Gln SNP', 'Var', (35, 48))	('XRCC1', 'Gene', (29, 34))
133686	32212791	Interestingly, a meta-analysis that focused on the association between Arg399Gln and head and neck cancer recommended further studies to assess Arg399Gln SNPs in XRCC1 as risk factors for developing head and neck cancer (Olshan et al., 2002).	('Arg399Gln', 'Var', (144, 153))	('head and neck cancer', 'Phenotype', 'HP:0012288', (85, 105))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('Arg399Gln', 'Chemical', '-', (144, 153))	('head and neck cancer', 'Phenotype', 'HP:0012288', (199, 219))	('XRCC1', 'Gene', '7515', (162, 167))	('head and neck cancer', 'Disease', 'MESH:D006258', (85, 105))	('head and neck cancer', 'Disease', 'MESH:D006258', (199, 219))	('XRCC1', 'Gene', (162, 167))	('Arg399Gln', 'Var', (71, 80))	('Arg399Gln', 'Chemical', '-', (71, 80))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
133704	32212791	In this study, we investigated the association between the most common polymorphism on XRCC1 gene, Arg399Gln, and the risk of head and neck cancer.	('Arg399Gln', 'Chemical', '-', (99, 108))	('head and neck cancer', 'Phenotype', 'HP:0012288', (126, 146))	('XRCC1', 'Gene', '7515', (87, 92))	('XRCC1', 'Gene', (87, 92))	('head and neck cancer', 'Disease', 'MESH:D006258', (126, 146))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('Arg399Gln', 'Var', (99, 108))
133708	32212791	The observed protective effect of the codon 399Gln allele in our study was also found in several previous studies on association between cancer and XRCC1 genotype.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('XRCC1', 'Gene', '7515', (148, 153))	('association', 'Interaction', (117, 128))	('codon 399Gln', 'Var', (38, 50))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('cancer', 'Disease', (137, 143))	('XRCC1', 'Gene', (148, 153))
133710	32212791	The reduced cancer risk found in our study, as well as other studies, was congruent with the hypothesis that the variant XRCC1 protein and its diminished DNA repair could enhance damage-related apoptosis in individual cells.	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('enhance', 'PosReg', (171, 178))	('reduced', 'NegReg', (4, 11))	('DNA repair', 'MPA', (154, 164))	('cancer', 'Disease', (12, 18))	('XRCC1', 'Gene', '7515', (121, 126))	('variant', 'Var', (113, 120))	('diminished', 'NegReg', (143, 153))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('XRCC1', 'Gene', (121, 126))	('damage-related apoptosis', 'CPA', (179, 203))	('protein', 'Protein', (127, 134))
133711	32212791	who investigated the association between XRCC1 polymorphisms and secondary (treatment-related) leukemia and found a similar inverse association between cancer risk and XRCC1 polymorphism (Seedhouse et al., 2002).	('XRCC1', 'Gene', '7515', (168, 173))	('cancer', 'Disease', (152, 158))	('polymorphisms', 'Var', (47, 60))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('investigated', 'Reg', (4, 16))	('XRCC1', 'Gene', '7515', (41, 46))	('association', 'Interaction', (21, 32))	('XRCC1', 'Gene', (168, 173))	('XRCC1', 'Gene', (41, 46))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('polymorphism', 'Var', (174, 186))	('leukemia', 'Disease', (95, 103))	('leukemia', 'Disease', 'MESH:D007938', (95, 103))	('leukemia', 'Phenotype', 'HP:0001909', (95, 103))
133712	32212791	On the other hand, some reports indicated that the Arg399Gln genotype increased the risk of HNSCC (Tae et al., 2004).	('HNSCC', 'Disease', (92, 97))	('Arg399Gln', 'Var', (51, 60))	('Arg399Gln', 'Chemical', '-', (51, 60))	('HNSCC', 'Disease', 'MESH:D000077195', (92, 97))
133713	32212791	Previous studies showed that the variant allele increased the accumulation of DNA damage, leading to increased incidence of malignancy (Tae et al., 2004).	('increased', 'PosReg', (48, 57))	('variant', 'Var', (33, 40))	('malignancy', 'Disease', 'MESH:D009369', (124, 134))	('accumulation', 'MPA', (62, 74))	('DNA damage', 'MPA', (78, 88))	('malignancy', 'Disease', (124, 134))
133714	32212791	More extensive studies with larger sample sizes are needed to validate the genetic effects of XRCC1 polymorphisms on head and neck squamous cell carcinoma.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (131, 154))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (117, 154))	('carcinoma', 'Phenotype', 'HP:0030731', (145, 154))	('neck squamous cell carcinoma', 'Disease', (126, 154))	('effects', 'Reg', (83, 90))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (126, 154))	('XRCC1', 'Gene', '7515', (94, 99))	('polymorphisms', 'Var', (100, 113))	('XRCC1', 'Gene', (94, 99))
133740	32792861	Next, Drosha cleaves two strands of the stem in the pri-miRNA hairpin, and form a stem-loop named "pre-miRNA".	('cleaves', 'Var', (13, 20))	('Drosha', 'Gene', '29102', (6, 12))	('Drosha', 'Gene', (6, 12))	('miR', 'Gene', '220972', (56, 59))	('miR', 'Gene', (103, 106))	('miR', 'Gene', (56, 59))	('miR', 'Gene', '220972', (103, 106))
133756	32792861	The third class involves 7-methylguanosine (m7G)-capped pre-miRNAs, which are synthesized from the 5' end of genes by Pol II directly, characterized by small RNA Cap-Seq, and exported by Exportin 1.	('Exportin 1', 'Gene', (187, 197))	('miR', 'Gene', '220972', (60, 63))	('miR', 'Gene', (60, 63))	('m7G', 'Var', (44, 47))	('Exportin 1', 'Gene', '7514', (187, 197))	('7-methylguanosine', 'Chemical', 'MESH:C016578', (25, 42))
133768	32792861	In brief, the biogenesis process of miRNAs is in tight temporal and spatial regulation, and faulty biogenesis in human body would be associated with a great number of diseases, particularly cancer.	('cancer', 'Disease', (190, 196))	('cancer', 'Disease', 'MESH:D009369', (190, 196))	('diseases', 'Disease', (167, 175))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('faulty', 'Var', (92, 98))	('miR', 'Gene', '220972', (36, 39))	('miR', 'Gene', (36, 39))	('human', 'Species', '9606', (113, 118))	('associated', 'Reg', (133, 143))
133781	32792861	Apart from the degradation of miRNA targets, GW182-mediated interaction with CCR4-NOT can also promote translational repression by the recruitment of a known translational inhibitor, the DEAD-box ATPase DEAD-box protein 6 (DDX6).	('miR', 'Gene', '220972', (30, 33))	('miR', 'Gene', (30, 33))	('DEAD-box protein 6', 'Gene', (203, 221))	('translational repression', 'MPA', (103, 127))	('promote', 'PosReg', (95, 102))	('CCR4-NOT', 'Gene', (77, 85))	('DDX6', 'Gene', '1656', (223, 227))	('GW182-mediated', 'Var', (45, 59))	('interaction', 'Interaction', (60, 71))	('DEAD-box protein 6', 'Gene', '1656', (203, 221))	('DDX6', 'Gene', (223, 227))
133797	32792861	In 2002, the deletion and low-expression of miR-15 and miR-16 cluster in chronic lymphocytic leukemia were demonstrated, firstly suggesting the role of miRNAs in the progression of cancers.	('miR', 'Gene', '220972', (44, 47))	('chronic lymphocytic leukemia', 'Disease', 'MESH:D015451', (73, 101))	('miR-1', 'Gene', '79187', (44, 49))	('low-expression', 'NegReg', (26, 40))	('miR-16', 'Gene', (55, 61))	('chronic lymphocytic leukemia', 'Disease', (73, 101))	('cancers', 'Disease', 'MESH:D009369', (181, 188))	('miR', 'Gene', (44, 47))	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (73, 101))	('miR-1', 'Gene', (55, 60))	('leukemia', 'Phenotype', 'HP:0001909', (93, 101))	('deletion', 'Var', (13, 21))	('miR-16', 'Gene', '51573', (55, 61))	('miR', 'Gene', '220972', (152, 155))	('miR', 'Gene', '220972', (55, 58))	('miR-1', 'Gene', (44, 49))	('cancers', 'Phenotype', 'HP:0002664', (181, 188))	('miR-1', 'Gene', '79187', (55, 60))	('cancers', 'Disease', (181, 188))	('miR', 'Gene', (152, 155))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('miR', 'Gene', (55, 58))
133800	32792861	The dysregulation of miRNAs can also link to alterations in genes that govern cancer progression.	('alterations', 'Var', (45, 56))	('miR', 'Gene', '220972', (21, 24))	('cancer', 'Disease', (78, 84))	('miR', 'Gene', (21, 24))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('dysregulation', 'MPA', (4, 17))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))
133802	32792861	In oral squamous cell carcinoma (OSCC) patients, miR-9 is downregulated, whose expression induces G0/G1 cell cycle arrest, while the use of miR-9 mimics significantly halts cell proliferation by repressing cyclin-dependent kinase 6 (CDK6) and cyclin D1.	('patients', 'Species', '9606', (39, 47))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (8, 31))	('miR', 'Gene', '220972', (140, 143))	('CDK6', 'Gene', (233, 237))	('cyclin-dependent kinase 6', 'Gene', (206, 231))	('cyclin-dependent kinase 6', 'Gene', '1021', (206, 231))	('miR', 'Gene', (140, 143))	('arrest', 'Disease', (115, 121))	('miR', 'Gene', '220972', (49, 52))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (104, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('induces', 'Reg', (90, 97))	('cyclin D1', 'Gene', (243, 252))	('expression', 'Var', (79, 89))	('miR', 'Gene', (49, 52))	('repressing', 'PosReg', (195, 205))	('cell proliferation', 'CPA', (173, 191))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (3, 31))	('halts', 'NegReg', (167, 172))	('arrest', 'Disease', 'MESH:D006323', (115, 121))	('cyclin D1', 'Gene', '595', (243, 252))	('oral squamous cell carcinoma', 'Disease', (3, 31))	('CDK6', 'Gene', '1021', (233, 237))
133810	32792861	The dysregulation of p53 has been widely reported to enable cancer cells against apoptosis, which could be triggered by the low-expression of miR-192, miR-194, and miR-215 in multiple myeloma.	('miR-1', 'Gene', (142, 147))	('nab', 'Chemical', '-', (54, 57))	('dysregulation', 'Var', (4, 17))	('miR-192', 'Gene', '406967', (142, 149))	('miR-1', 'Gene', (151, 156))	('multiple myeloma', 'Disease', (175, 191))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('miR-215', 'Gene', '406997', (164, 171))	('miR-1', 'Gene', '79187', (142, 147))	('p53', 'Gene', '7157', (21, 24))	('enable', 'PosReg', (53, 59))	('miR-215', 'Gene', (164, 171))	('miR-192', 'Gene', (142, 149))	('miR-1', 'Gene', '79187', (151, 156))	('p53', 'Gene', (21, 24))	('multiple myeloma', 'Phenotype', 'HP:0006775', (175, 191))	('low-expression', 'NegReg', (124, 138))	('apoptosis', 'CPA', (81, 90))	('cancer', 'Disease', (60, 66))	('multiple myeloma', 'Disease', 'MESH:D009101', (175, 191))
133830	32792861	For myeloid-derived suppressor cells (MDSCs), miR-34a can also regulate oncoprotein MUC1 and then results in the MDSC increase in acute myeloid leukemia (AML).	('leukemia', 'Phenotype', 'HP:0001909', (144, 152))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (130, 152))	('increase', 'PosReg', (118, 126))	('AML', 'Disease', 'MESH:D015470', (154, 157))	('MDSC', 'MPA', (113, 117))	('results in', 'Reg', (98, 108))	('MUC1', 'Gene', (84, 88))	('acute myeloid leukemia', 'Disease', (130, 152))	('MUC1', 'Gene', '4582', (84, 88))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (136, 152))	('AML', 'Disease', (154, 157))	('regulate', 'Reg', (63, 71))	('miR-34a', 'Var', (46, 53))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (130, 152))	('AML', 'Phenotype', 'HP:0004808', (154, 157))
133858	32792861	As so many functions miRNAs have in cancer development, the dysregulation of one specific miRNA or a group of miRNAs may be closely associated with human cancer progression.	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('miR', 'Gene', '220972', (90, 93))	('miR', 'Gene', '220972', (21, 24))	('cancer', 'Disease', (36, 42))	('miR', 'Gene', (21, 24))	('cancer', 'Disease', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('human', 'Species', '9606', (148, 153))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('associated', 'Reg', (132, 142))	('miR', 'Gene', '220972', (110, 113))	('miR', 'Gene', (90, 93))	('miR', 'Gene', (110, 113))	('dysregulation', 'Var', (60, 73))
133871	32792861	Equally exciting is, some researchers exploited a digital amplification-free quantification manner by the use of NanoString Technologies, the nCounter technology, which can identify dysregulated exosomal serum miRNAs (ex-miRNAs) for progressive prostate cancer.	('cancer', 'Phenotype', 'HP:0002664', (254, 260))	('prostate cancer', 'Disease', (245, 260))	('prostate cancer', 'Phenotype', 'HP:0012125', (245, 260))	('prostate cancer', 'Disease', 'MESH:D011471', (245, 260))	('miR', 'Gene', '220972', (210, 213))	('miR', 'Gene', (210, 213))	('dysregulated', 'Var', (182, 194))	('miR', 'Gene', '220972', (221, 224))	('miR', 'Gene', (221, 224))
133901	32792861	In related experiments, it has been confirmed that transfection of miR-126 mimic into breast cancer cells can enhance its sensitivity to fourteen chemotherapy drugs such as trimetinib and alpelisib, and prevent the emergence of drug resistance.	('drug resistance', 'MPA', (228, 243))	('emergence', 'MPA', (215, 224))	('enhance', 'PosReg', (110, 117))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('trimetinib', 'Chemical', '-', (173, 183))	('sensitivity to fourteen chemotherapy drugs', 'MPA', (122, 164))	('breast cancer', 'Disease', 'MESH:D001943', (86, 99))	('transfection', 'Var', (51, 63))	('alpelisib', 'Chemical', 'MESH:C585539', (188, 197))	('breast cancer', 'Phenotype', 'HP:0003002', (86, 99))	('prevent', 'NegReg', (203, 210))	('breast cancer', 'Disease', (86, 99))	('drug resistance', 'Phenotype', 'HP:0020174', (228, 243))	('miR-126', 'Gene', '406913', (67, 74))	('miR-126', 'Gene', (67, 74))
133906	32792861	Correspondingly, it was confirmed that forced expression of miR-634 can induce programmed cell death in a variety of cell lines containing pancreatic cancer cells, and intravenous injection of lipid nanoparticles containing miR-634 can greatly reduce xenograft tumor progress in mouse BxPC-3 cells.	('BxPC-3', 'CellLine', 'CVCL:0186', (285, 291))	('death', 'Disease', 'MESH:D003643', (95, 100))	('tumor', 'Disease', (261, 266))	('death', 'Disease', (95, 100))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (139, 156))	('tumor', 'Phenotype', 'HP:0002664', (261, 266))	('induce', 'Reg', (72, 78))	('mouse', 'Species', '10090', (279, 284))	('miR-634', 'Chemical', '-', (224, 231))	('lipid', 'Chemical', 'MESH:D008055', (193, 198))	('pancreatic cancer', 'Disease', (139, 156))	('miR-634', 'Gene', (60, 67))	('pancreatic cancer', 'Disease', 'MESH:D010190', (139, 156))	('reduce', 'NegReg', (244, 250))	('tumor', 'Disease', 'MESH:D009369', (261, 266))	('miR-634', 'Chemical', '-', (60, 67))	('miR-634', 'Var', (224, 231))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
133911	32792861	In an animal experiment, scientists studied the cooperative relationship between miR-34a and radiation therapy, finding that overexpression of miR-34a (which bound to the 3'-UTR site of RAD51) enhanced gamma-H2AX foci and inhibited the formation of HR and RAD51 foci, thereby inhibiting tumor cell DNA repair.	('miR-34a', 'Var', (143, 150))	('RAD51', 'Gene', '5888', (256, 261))	('formation', 'MPA', (236, 245))	('tumor', 'Disease', 'MESH:D009369', (287, 292))	('inhibited', 'NegReg', (222, 231))	('H2AX', 'Gene', '3014', (208, 212))	('H2AX', 'Gene', (208, 212))	('RAD51', 'Gene', (186, 191))	('RAD51', 'Gene', '5888', (186, 191))	('enhanced', 'PosReg', (193, 201))	('RAD51', 'Gene', (256, 261))	('tumor', 'Disease', (287, 292))	('tumor', 'Phenotype', 'HP:0002664', (287, 292))	('inhibiting', 'NegReg', (276, 286))
133914	32792861	miR-328-3p can directly interact with the 3'-UTR of H2AX transcript and reduce its protein expression level, whose overexpression promotes radiation-induced cellular DNA damage.	('miR-328-3p', 'Chemical', '-', (0, 10))	('protein expression level', 'MPA', (83, 107))	('miR-328-3p', 'Var', (0, 10))	('promotes', 'PosReg', (130, 138))	('H2AX', 'Gene', (52, 56))	('reduce', 'NegReg', (72, 78))	('radiation-induced cellular DNA damage', 'CPA', (139, 176))	('H2AX', 'Gene', '3014', (52, 56))
133915	32792861	Investigators then introduced miR-328-3p mimic into animal models of NSCLC, and the tumor cells were significantly reduced in mice after radiotherapy, proving that overexpressed miR-328-3p can improve cell radiosensitivity with the change of DNA damage/repair signaling pathways.	('DNA damage/repair signaling pathways', 'Pathway', (242, 278))	('miR-328-3p', 'Chemical', '-', (178, 188))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('miR-328-3p', 'Var', (178, 188))	('mice', 'Species', '10090', (126, 130))	('NSCLC', 'Disease', (69, 74))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('cell radiosensitivity', 'Phenotype', 'HP:0010997', (201, 222))	('NSCLC', 'Disease', 'MESH:D002289', (69, 74))	('tumor', 'Disease', (84, 89))	('NSCLC', 'Phenotype', 'HP:0030358', (69, 74))	('miR-328-3p', 'Chemical', '-', (30, 40))	('improve', 'PosReg', (193, 200))	('cell radiosensitivity', 'CPA', (201, 222))
133939	32792861	Drugs against cancers are connected with target proteins, and abnormal regulation of these proteins often leads to drug resistance.	('cancers', 'Disease', (14, 21))	('leads to', 'Reg', (106, 114))	('cancers', 'Phenotype', 'HP:0002664', (14, 21))	('abnormal', 'Var', (62, 70))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('drug resistance', 'CPA', (115, 130))	('drug resistance', 'Phenotype', 'HP:0020174', (115, 130))	('cancers', 'Disease', 'MESH:D009369', (14, 21))
133948	32792861	It has been found that the up-regulation of ERalpha36 is in connection with the inhibition of methylation in the promoter region, which may suggest that hypermethylation may inhibit miRNA biogenesis and processing, but the specific mechanism has not been clearly studied.	('ERalpha', 'Gene', (44, 51))	('up-regulation', 'PosReg', (27, 40))	('inhibition', 'NegReg', (80, 90))	('methylation', 'MPA', (94, 105))	('miR', 'Gene', '220972', (182, 185))	('miR', 'Gene', (182, 185))	('inhibit', 'NegReg', (174, 181))	('hypermethylation', 'Var', (153, 169))	('processing', 'MPA', (203, 213))	('ERalpha', 'Gene', '2099', (44, 51))
133957	32792861	When cancer cells overexpress miR-328-3p, it can obviously limit the expression of ABCG2 and decrease the drug resistance of breast cancer cells.	('ABCG2', 'Gene', (83, 88))	('drug resistance', 'CPA', (106, 121))	('ABCG2', 'Gene', '9429', (83, 88))	('limit', 'NegReg', (59, 64))	('decrease', 'NegReg', (93, 101))	('breast cancer', 'Phenotype', 'HP:0003002', (125, 138))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('miR-328-3p', 'Chemical', '-', (30, 40))	('cancer', 'Disease', 'MESH:D009369', (5, 11))	('overexpress', 'PosReg', (18, 29))	('breast cancer', 'Disease', 'MESH:D001943', (125, 138))	('breast cancer', 'Disease', (125, 138))	('miR-328-3p', 'Var', (30, 40))	('drug resistance', 'Phenotype', 'HP:0020174', (106, 121))	('cancer', 'Disease', (132, 138))	('cancer', 'Disease', (5, 11))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('expression', 'MPA', (69, 79))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))
133962	32792861	For example, for the treatment of leukemia patients, researchers found that miR-138 can restrain the expression of NF-kB/p65 and then inhibit the production of Multidrug resistance 1 (MDR1).	('MDR1', 'Gene', '5243', (184, 188))	('miR-138', 'Chemical', '-', (76, 83))	('p65', 'Gene', '5970', (121, 124))	('leukemia', 'Disease', (34, 42))	('leukemia', 'Phenotype', 'HP:0001909', (34, 42))	('patients', 'Species', '9606', (43, 51))	('leukemia', 'Disease', 'MESH:D007938', (34, 42))	('inhibit', 'NegReg', (134, 141))	('drug resistance', 'Phenotype', 'HP:0020174', (165, 180))	('restrain', 'NegReg', (88, 96))	('Multidrug resistance 1', 'Gene', '5243', (160, 182))	('p65', 'Gene', (121, 124))	('expression', 'MPA', (101, 111))	('Multidrug resistance 1', 'Gene', (160, 182))	('MDR1', 'Gene', (184, 188))	('miR-138', 'Var', (76, 83))
133996	32792861	Dysregulation of miRNAs can link to cancer development processes such as interfering with the cell cycle and evading immune destruction.	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('Dysregulation', 'Var', (0, 13))	('miR', 'Gene', '220972', (17, 20))	('miR', 'Gene', (17, 20))	('cancer', 'Disease', (36, 42))	('interfering', 'NegReg', (73, 84))	('cell cycle', 'CPA', (94, 104))	('link', 'Reg', (28, 32))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))
134008	31296790	And Cyfra21-1 was observed with significantly improved performances by the combination of THBS2 to distinguish early stage NSCLC (P<0.05) as well as SC (P<0.05) from the control subjects.	('THBS2', 'Gene', '7058', (90, 95))	('NSCLC', 'Disease', (123, 128))	('SC', 'Phenotype', 'HP:0002860', (149, 151))	('SC', 'Phenotype', 'HP:0002860', (124, 126))	('NSCLC', 'Disease', 'MESH:D002289', (123, 128))	('improved', 'PosReg', (46, 54))	('early', 'Disease', (111, 116))	('THBS2', 'Gene', (90, 95))	('NSCLC', 'Phenotype', 'HP:0030358', (123, 128))	('combination', 'Var', (75, 86))	('performances', 'MPA', (55, 67))
134010	31296790	In summary, the present study suggested that serum THBS2 might be an early diagnostic biomarker for NSCLC.	('serum', 'Var', (45, 50))	('NSCLC', 'Disease', (100, 105))	('SC', 'Phenotype', 'HP:0002860', (101, 103))	('NSCLC', 'Disease', 'MESH:D002289', (100, 105))	('THBS2', 'Gene', (51, 56))	('NSCLC', 'Phenotype', 'HP:0030358', (100, 105))	('THBS2', 'Gene', '7058', (51, 56))
134085	31296790	Possible reasons are as follows: the postoperative blood samples were collected 2 weeks after surgery, and this time interval may be too short for the THBS2 protein in the blood to fully degraded, especially taken into consideration the fact that polymorphisms in thrombospondin genes could increase the conformational stability of the proteins.	('polymorphisms', 'Var', (247, 260))	('conformational stability of the', 'MPA', (304, 335))	('THBS2', 'Gene', (151, 156))	('increase', 'PosReg', (291, 299))	('thrombospondin genes', 'Gene', (264, 284))	('THBS2', 'Gene', '7058', (151, 156))	('proteins', 'Protein', (336, 344))
134096	28856073	Correlation of TP53 Overexpression and Clinical Parameters with Five-Year Survival in Oral Squamous Cell Carcinoma Patients Introduction TP53 mutation and overexpression have been correlated with poor survival in many cancers including oral squamous cell carcinoma (OSCC).	('carcinoma', 'Phenotype', 'HP:0030731', (255, 264))	('squamous cell carcinoma', 'Disease', (241, 264))	('mutation', 'Var', (142, 150))	('Carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (241, 264))	('Oral Squamous Cell Carcinoma', 'Disease', (86, 114))	('cancers', 'Disease', 'MESH:D009369', (218, 225))	('cancers', 'Phenotype', 'HP:0002664', (218, 225))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (241, 264))	('cancers', 'Disease', (218, 225))	('TP53', 'Gene', '7157', (15, 19))	('TP53', 'Gene', (15, 19))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('TP53', 'Gene', '7157', (137, 141))	('overexpression', 'PosReg', (155, 169))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (91, 114))	('Oral Squamous Cell Carcinoma', 'Disease', 'MESH:D002294', (86, 114))	('TP53', 'Gene', (137, 141))
134106	28856073	The progress of OSCC at the molecular level is still unclear but latest developments present it to be the result of environmental factors causing mutations in oncogenes and tumor suppressor genes, particularly those involved in cell proliferation, differentiation, apoptosis and deoxyribonucleic acid (DNA) repair.	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('mutations', 'Var', (146, 155))	('result', 'Reg', (106, 112))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumor', 'Disease', (173, 178))	('oncogenes', 'Gene', (159, 168))
134110	28856073	Among all the mutations found in OSCC, the TP53 tumor suppressor gene is most frequently mutated.	('tumor', 'Disease', (48, 53))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('TP53', 'Gene', '7157', (43, 47))	('TP53', 'Gene', (43, 47))	('mutations', 'Var', (14, 23))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
134114	28856073	It has been established by the International Cancer Genome Consortium that the missense mutation is the most commonly occurring type (79%) among all TP53 mutations.	('missense mutation', 'Var', (79, 96))	('TP53', 'Gene', '7157', (149, 153))	('Cancer', 'Phenotype', 'HP:0002664', (45, 51))	('Cancer', 'Disease', (45, 51))	('TP53', 'Gene', (149, 153))	('Cancer', 'Disease', 'MESH:D009369', (45, 51))	('occurring', 'Reg', (118, 127))
134115	28856073	Mutations in TP53 make it more stable and hence easy to detect by immunohistochemistry.	('TP53', 'Gene', (13, 17))	('more', 'PosReg', (26, 30))	('Mutations', 'Var', (0, 9))	('TP53', 'Gene', '7157', (13, 17))	('stable', 'MPA', (31, 37))
134116	28856073	However, any loss-of-function mutation in the TP53 does not directly transform the cells into neoplastic cells as loss of guardian function has no direct effect on proliferation.	('mutation', 'Var', (30, 38))	('loss-of-function', 'NegReg', (13, 29))	('TP53', 'Gene', (46, 50))	('TP53', 'Gene', '7157', (46, 50))
134118	28856073	Furthermore, the association of TP53 mutation and five-year survival of OSCC patients is still unclear.	('OSCC', 'Disease', (72, 76))	('mutation', 'Var', (37, 45))	('TP53', 'Gene', '7157', (32, 36))	('patients', 'Species', '9606', (77, 85))	('TP53', 'Gene', (32, 36))
134119	28856073	Correlation of TP53 mutation with gender, age, OSCC risk factors like alcohol and tobacco, site and grading are currently being established in different researches around the world in order to provide detailed information on OSCC patient prognosis at the time of presentation.	('OSCC', 'Disease', (225, 229))	('tobacco', 'Species', '4097', (82, 89))	('mutation', 'Var', (20, 28))	('patient', 'Species', '9606', (230, 237))	('TP53', 'Gene', '7157', (15, 19))	('TP53', 'Gene', (15, 19))	('alcohol', 'Chemical', 'MESH:D000438', (70, 77))
134122	28856073	Subsequently, the aim of this study is to continue work on these patients and establish any and all such correlations between TP53 mutation and OSCC patient prognosis using a fixed five-year survival rate as it is the optimum method to validate prognostic use of any marker.	('TP53', 'Gene', (126, 130))	('patient', 'Species', '9606', (65, 72))	('patient', 'Species', '9606', (149, 156))	('patients', 'Species', '9606', (65, 73))	('OSCC', 'Disease', (144, 148))	('TP53', 'Gene', '7157', (126, 130))	('mutation', 'Var', (131, 139))
134129	28856073	Univariate Cox analysis was done to investigate the effect of clinicopathologic factors on mean five-year survival and a multivariate analysis was done for AJCC staging and TP53 positivity.	('positivity', 'Var', (178, 188))	('Cox', 'Gene', '1351', (11, 14))	('Cox', 'Gene', (11, 14))	('TP53', 'Gene', '7157', (173, 177))	('TP53', 'Gene', (173, 177))
134140	28856073	However, a significant association was observed between the anterior tongue as the site of tumor and TP53 positivity (p = 0.038).	('TP53', 'Gene', '7157', (101, 105))	('positivity', 'Var', (106, 116))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('TP53', 'Gene', (101, 105))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor', 'Disease', (91, 96))
134147	28856073	The carcinogenesis of the gastrointestinal tract epithelium is an intricate process that involves abnormalities of oncogenes and tumor suppressor genes.	('carcinogenesis of the gastrointestinal tract', 'Disease', (4, 48))	('carcinogenesis of the gastrointestinal tract', 'Disease', 'MESH:D063646', (4, 48))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('abnormalities', 'Var', (98, 111))	('tumor', 'Disease', (129, 134))
134149	28856073	Western countries have a high incidence of TP53 mutations in OSCC associated with these risk factors with India reported to have low incidence and Taiwan with high incidence from Asia.	('TP53', 'Gene', '7157', (43, 47))	('TP53', 'Gene', (43, 47))	('associated', 'Reg', (66, 76))	('mutations', 'Var', (48, 57))
134153	28856073	Almost all types of cancers are reported to have TP53 mutations, from 10% in hematopoietic malignancies to close to 100% in high-grade serous carcinoma of the ovary.	('hematopoietic malignancies', 'Disease', 'MESH:D019337', (77, 103))	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('TP53', 'Gene', '7157', (49, 53))	('TP53', 'Gene', (49, 53))	('serous carcinoma of the ovary', 'Disease', 'MESH:D010051', (135, 164))	('mutations', 'Var', (54, 63))	('serous carcinoma of the ovary', 'Disease', (135, 164))	('cancers', 'Phenotype', 'HP:0002664', (20, 27))	('hematopoietic malignancies', 'Disease', (77, 103))	('cancers', 'Disease', (20, 27))	('cancers', 'Disease', 'MESH:D009369', (20, 27))	('carcinoma', 'Phenotype', 'HP:0030731', (142, 151))
134154	28856073	According to "The TP53 website" lung cancers have the highest TP53 mutation rate (70%) followed by colorectal (60%) and head and neck cancers (60%).	('TP53', 'Gene', '7157', (62, 66))	('lung cancers', 'Phenotype', 'HP:0100526', (32, 44))	('mutation', 'Var', (67, 75))	('TP53', 'Gene', '7157', (18, 22))	('head and neck cancers', 'Disease', 'MESH:D006258', (120, 141))	('cancers', 'Phenotype', 'HP:0002664', (134, 141))	('cancers', 'Phenotype', 'HP:0002664', (37, 44))	('head and neck cancers', 'Phenotype', 'HP:0012288', (120, 141))	('TP53', 'Gene', (62, 66))	('TP53', 'Gene', (18, 22))	('lung cancers', 'Disease', (32, 44))	('colorectal', 'Disease', (99, 109))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('lung cancers', 'Disease', 'MESH:D008175', (32, 44))
134157	28856073	On the other hand in a study conducted on 16 patients with recurrent squamous cell carcinoma of the head and neck, a poor prognosis with positive TP53 expression was observed.	('positive', 'Var', (137, 145))	('TP53', 'Gene', '7157', (146, 150))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (69, 92))	('squamous cell carcinoma', 'Disease', (69, 92))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (69, 92))	('TP53', 'Gene', (146, 150))	('patients', 'Species', '9606', (45, 53))	('carcinoma of the head and neck', 'Phenotype', 'HP:0012288', (83, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))
134158	28856073	The presence of TP53 mutation was associated with a significantly decreased overall survival and even stronger association with disruptive mutations as shown by Poeta, et al..	('overall survival', 'MPA', (76, 92))	('stronger', 'PosReg', (102, 110))	('decreased', 'NegReg', (66, 75))	('mutation', 'Var', (21, 29))	('association', 'Interaction', (111, 122))	('TP53', 'Gene', '7157', (16, 20))	('presence', 'Var', (4, 12))	('TP53', 'Gene', (16, 20))
134165	28856073	Our previous study highlighted the importance of TP53 mutation when dealt with overall survival ranging from months to years.	('TP53', 'Gene', (49, 53))	('mutation', 'Var', (54, 62))	('TP53', 'Gene', '7157', (49, 53))
134188	32102656	The potential objects regulated and controlled by miR-204-5p in the course of NSCLC were identified by estimated target prediction and analysis.	('miR-204-5p', 'Var', (50, 60))	('miR-204-5p', 'Chemical', '-', (50, 60))	('NSCLC', 'Disease', 'MESH:D002289', (78, 83))	('NSCLC', 'Disease', (78, 83))
134190	32102656	The expression of miR-204-5p was downregulated in NSCLC, and the downtrend was related to gender, histological type, vascular invasion, tumor size, clinicopathologic grade and lymph node metastasis (P<0.05).	('miR-204-5p', 'Var', (18, 28))	('miR-204-5p', 'Chemical', '-', (18, 28))	('vascular invasion', 'CPA', (117, 134))	('expression', 'MPA', (4, 14))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('NSCLC', 'Disease', (50, 55))	('NSCLC', 'Disease', 'MESH:D002289', (50, 55))	('tumor', 'Disease', (136, 141))	('downregulated', 'NegReg', (33, 46))
134191	32102656	MiR-204-5p was useful in prognosis, but was deemed unsuitable at present as an auxiliary diagnostic or prognostic risk factor for NSCLC due to the lack of statistical significance in meta-analyses and absence of large-scale investigations.	('NSCLC', 'Disease', 'MESH:D002289', (130, 135))	('MiR-204-5p', 'Var', (0, 10))	('NSCLC', 'Disease', (130, 135))
134193	32102656	The predicted TFs, like MAX, MYC, and RUNX1, interfered in regulatory networks involving miR-204-5p and its predicted hub genes, though a modulatory loop or axis of the miRNA-TF-gene that was out of range with shortage in database prediction, experimental proof and literature confirmation.	('RUNX1', 'Gene', '861', (38, 43))	('MYC', 'Gene', '4609', (29, 32))	('regulatory networks', 'MPA', (59, 78))	('miR', 'Gene', '220972', (89, 92))	('miR', 'Gene', (89, 92))	('interfered', 'NegReg', (45, 55))	('miR', 'Gene', '220972', (169, 172))	('TFs', 'Var', (14, 17))	('miR-204-5p', 'Chemical', '-', (89, 99))	('MYC', 'Gene', (29, 32))	('RUNX1', 'Gene', (38, 43))	('miR', 'Gene', (169, 172))
134195	32102656	The estimated target genes and TFs contributed to the anti-oncogene effects of miR-204-5p.	('miR-204-5p', 'Var', (79, 89))	('anti-oncogene effects', 'MPA', (54, 75))	('miR-204-5p', 'Chemical', '-', (79, 89))
134204	32102656	Previous studies on the mechanisms of miR-204-5p on NSCLC has mainly focused on the repression of specific mRNAs, so knowledge about its multilateral functions or its clinical prospects remains limited.	('mRNAs', 'Gene', (107, 112))	('NSCLC', 'Disease', (52, 57))	('NSCLC', 'Disease', 'MESH:D002289', (52, 57))	('miR-204-5p', 'Chemical', '-', (38, 48))	('miR-204-5p', 'Var', (38, 48))
134205	32102656	Aberrant expression of miR-204-5p is now a well-established feature of pulmonary carcinogenesis; however, what is still unclear is the clinical contribution of miR-204-5p and particularly its potential role in the early detection of NSCLC.	('NSCLC', 'Disease', (233, 238))	('Aberrant', 'Var', (0, 8))	('NSCLC', 'Disease', 'MESH:D002289', (233, 238))	('miR-204-5p', 'Chemical', '-', (160, 170))	('miR-204-5p', 'Var', (160, 170))	('miR-204-5p', 'Chemical', '-', (23, 33))	('pulmonary carcinogenesis', 'Disease', (71, 95))	('pulmonary carcinogenesis', 'Disease', 'MESH:D063646', (71, 95))
134206	32102656	The mechanism by which miR-204-5p mediates its target mRNA-protein signaling networks to regulate tumor progression is also not yet established.	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('miR-204-5p', 'Chemical', '-', (23, 33))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('miR-204-5p', 'Var', (23, 33))	('tumor', 'Disease', (98, 103))
134207	32102656	The current work describes distinctive features of miR-204-5p expression in NSCLC by integrative analysis of results from real-time quantitative polymerase chain reaction (RT-qPCR) and from sequence and genechip data from the cancer genome atlas (TCGA), Gene Expression Omnibus (GEO), and the current literature, in addition to relevant prediction materials from online tools.	('NSCLC', 'Disease', (76, 81))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))	('NSCLC', 'Disease', 'MESH:D002289', (76, 81))	('cancer', 'Disease', (226, 232))	('cancer', 'Disease', 'MESH:D009369', (226, 232))	('miR-204-5p', 'Chemical', '-', (51, 61))	('miR-204-5p', 'Var', (51, 61))
134208	32102656	Our goals were to explore the possibility that miR-204-5p might be a promising indicator for NSCLC process and to identify our perspective on other underlying regulatory mechanisms at the molecular level (Fig.	('miR-204-5p', 'Var', (47, 57))	('NSCLC', 'Disease', 'MESH:D002289', (93, 98))	('miR-204-5p', 'Chemical', '-', (47, 57))	('NSCLC', 'Disease', (93, 98))
134216	32102656	The Xena Public Data Hubs online analysis program (https://xena.ucsc.edu/public-hubs/) was used to calculate expression level of miR-204-5p and to assess the difference between 999 NSCLC and 91 normal tissues.	('NSCLC', 'Disease', 'MESH:D002289', (181, 186))	('miR-204-5p', 'Chemical', '-', (129, 139))	('expression level', 'MPA', (109, 125))	('miR-204-5p', 'Var', (129, 139))	('NSCLC', 'Disease', (181, 186))
134220	32102656	The microarray chip data and publications had to fulfill the following conditions for inclusion in the current study:1) the research object focused on human beings, 2) the publication was in English or Chinese, 3) participants were confirmed cases with NSCLC, 4) cases included normal controls and contained at least 2 samples, and 5) pertinent expression of miR-204-5p in NSCLC and corresponding non-tumorous specimens was explored.	('NSCLC', 'Disease', (373, 378))	('miR-204-5p', 'Var', (359, 369))	('participants', 'Species', '9606', (214, 226))	('NSCLC', 'Disease', 'MESH:D002289', (373, 378))	('human', 'Species', '9606', (151, 156))	('tumor', 'Disease', 'MESH:D009369', (401, 406))	('NSCLC', 'Disease', (253, 258))	('tumor', 'Phenotype', 'HP:0002664', (401, 406))	('NSCLC', 'Disease', 'MESH:D002289', (253, 258))	('tumor', 'Disease', (401, 406))	('miR-204-5p', 'Chemical', '-', (359, 369))
134224	32102656	Due to the decrease of miR-204-5p in NSCLC, the target genes were expected to be expressed at a higher level to a large extent, so up-regulated DEGs from TCGA were adopted for further work.	('miR-204-5p', 'Chemical', '-', (23, 33))	('NSCLC', 'Disease', (37, 42))	('decrease', 'NegReg', (11, 19))	('miR-204-5p', 'Var', (23, 33))	('NSCLC', 'Disease', 'MESH:D002289', (37, 42))
134238	32102656	The association between survival data in the two groups and miR-204-5p expression were analyzed by Kaplan-Meier (K-M) curves and univariate Cox regression analysis using SPSS v22.0.	('Cox', 'Gene', '1351', (140, 143))	('miR-204-5p expression', 'Var', (60, 81))	('Cox', 'Gene', (140, 143))	('miR-204-5p', 'Chemical', '-', (60, 70))
134239	32102656	The hazard ratio (HR), 95% confidence interval (95% CI), and other data available from public resources were either extracted directly or obtained indirectly by recommendations of Tierney et al.. Comprehensive meta-analysis was then preformed for the HRs to appraise the efficiency of miR-204-5p in NSCLC prognosis.	('miR-204-5p', 'Chemical', '-', (285, 295))	('NSCLC', 'Disease', 'MESH:D002289', (299, 304))	('NSCLC', 'Disease', (299, 304))	('miR-204-5p', 'Var', (285, 295))
134244	32102656	Apart from age and smoking behavior, lower of miR-204-5p expression was noted in sex, tumor size, vascular invasion, TNM grade, lymph node metastasis, and pathological grading in the LUAD group than in the LUSC group (P<0.05).	('lymph node metastasis', 'CPA', (128, 149))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('LUSC', 'Disease', (206, 210))	('LUAD', 'Disease', (183, 187))	('miR-204-5p', 'Chemical', '-', (46, 56))	('tumor', 'Disease', (86, 91))	('LUAD', 'Disease', 'MESH:C538231', (183, 187))	('vascular invasion', 'CPA', (98, 115))	('miR-204-5p expression', 'Var', (46, 67))	('lower', 'NegReg', (37, 42))	('TNM grade', 'CPA', (117, 126))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('LUSC', 'Disease', 'MESH:D002294', (206, 210))
134245	32102656	Therefore, miR-204-5p expression was reduced in NSCLC and was related to clinical parameters other than age and smoking, especially in the LUAD group.	('miR-204-5p', 'Chemical', '-', (11, 21))	('NSCLC', 'Disease', (48, 53))	('NSCLC', 'Disease', 'MESH:D002289', (48, 53))	('LUAD', 'Disease', (139, 143))	('LUAD', 'Disease', 'MESH:C538231', (139, 143))	('related', 'Reg', (62, 69))	('reduced', 'NegReg', (37, 44))	('miR-204-5p', 'Var', (11, 21))
134246	32102656	In this validation set, the levels of miR-204-5p were markedly decreased in NSCLC when compared to the normal control tissues (P = 0.000) (Fig.	('decreased', 'NegReg', (63, 72))	('NSCLC', 'Disease', (76, 81))	('NSCLC', 'Disease', 'MESH:D002289', (76, 81))	('miR-204-5p', 'Chemical', '-', (38, 48))	('miR-204-5p', 'Var', (38, 48))
134248	32102656	The detected levels of miR-204-5p was lower in TCGA-LUAD, which was consistent with our results (P = 0.006) (Fig.	('lower', 'NegReg', (38, 43))	('LUAD', 'Disease', (52, 56))	('LUAD', 'Disease', 'MESH:C538231', (52, 56))	('miR-204-5p', 'Chemical', '-', (23, 33))	('miR-204-5p', 'Var', (23, 33))
134253	32102656	Each meta-analysis was first individually processed to evaluate level of miR-204-5p in the GEO data which covered 1747 NSCLC patients and 1105 control samples.	('NSCLC', 'Disease', 'MESH:D002289', (119, 124))	('miR-204-5p', 'Chemical', '-', (73, 83))	('miR-204-5p', 'Var', (73, 83))	('NSCLC', 'Disease', (119, 124))	('patients', 'Species', '9606', (125, 133))
134254	32102656	Dysregulation of miR-204-5p was evident in NSCLC (SMD = - 0.098, 95% CI: - 0.310 to 0.114), but with poor statistical significance (P = 0.366) and high heterogeneity (I2 = 81.8%, P = 0.000) (Fig.	('NSCLC', 'Disease', (43, 48))	('miR-204-5p', 'Chemical', '-', (17, 27))	('NSCLC', 'Disease', 'MESH:D002289', (43, 48))	('miR-204-5p', 'Var', (17, 27))
134260	32102656	In total,31 records, which included 4368 samples derived from 28 GEO datasets, 1 TCGA, 1 publication and our study (Table 5), were used for diagnosis meta-analysis to survey the clinical role of miR-204-5p in NSCLC.	('miR-204-5p', 'Chemical', '-', (195, 205))	('NSCLC', 'Disease', (209, 214))	('NSCLC', 'Disease', 'MESH:D002289', (209, 214))	('miR-204-5p', 'Var', (195, 205))
134261	32102656	The miR-204-5p diagnostic accuracy and its significance in NSCLC was further examined in SROC plots integrating all GEO datasets, TCGA, publications and our study to arrive at a reliable conclusion.	('miR-204-5p', 'Var', (4, 14))	('NSCLC', 'Disease', 'MESH:D002289', (59, 64))	('miR-204-5p', 'Chemical', '-', (4, 14))	('NSCLC', 'Disease', (59, 64))
134265	32102656	The K-M plots of our RT-qPCR data indicated a correlation between the NSCLC survival rate and miR-204-5p expression, as patients with higher levels of miR-204-5p survived longer than those with lower expression, although the difference did not meet statistical significance (Log Rank P = 0.231) (Fig.	('longer', 'PosReg', (171, 177))	('NSCLC', 'Disease', (70, 75))	('NSCLC', 'Disease', 'MESH:D002289', (70, 75))	('patients', 'Species', '9606', (120, 128))	('miR-204-5p', 'Chemical', '-', (151, 161))	('miR-204-5p', 'Chemical', '-', (94, 104))	('miR-204-5p', 'Var', (151, 161))
134276	32102656	In addition to GDNF (aliases ATF or ATF2) identified from the available literature, EPHB2 and DLG1 have been proposed as suitable targets of miR-204-5p.	('miR-204-5p', 'Var', (141, 151))	('ATF', 'Gene', '2668', (36, 39))	('GDNF', 'Gene', (15, 19))	('ATF2', 'Gene', (36, 40))	('ATF', 'Gene', (36, 39))	('ATF', 'Gene', '2668', (29, 32))	('ATF', 'Gene', (29, 32))	('EPHB2', 'Gene', '2048', (84, 89))	('DLG1', 'Gene', (94, 98))	('DLG1', 'Gene', '1739', (94, 98))	('GDNF', 'Gene', '2668', (15, 19))	('ATF2', 'Gene', '1386', (36, 40))	('miR-204-5p', 'Chemical', '-', (141, 151))	('EPHB2', 'Gene', (84, 89))
134281	32102656	The intersection outcome revealed MAX, MYC, and RUNX1 as the main TFs associated with miR-204-5p, GDNF, EPHB2, and DLG1(Fig.	('GDNF', 'Gene', '2668', (98, 102))	('EPHB2', 'Gene', '2048', (104, 109))	('MYC', 'Gene', '4609', (39, 42))	('miR-204-5p', 'Chemical', '-', (86, 96))	('GDNF', 'Gene', (98, 102))	('DLG1', 'Gene', (115, 119))	('MAX', 'Disease', (34, 37))	('EPHB2', 'Gene', (104, 109))	('MYC', 'Gene', (39, 42))	('miR-204-5p', 'Var', (86, 96))	('RUNX1', 'Gene', (48, 53))	('DLG1', 'Gene', '1739', (115, 119))	('RUNX1', 'Gene', '861', (48, 53))
134282	32102656	16), while MAX was associated with miR-204-5p by TFBS prediction in JASPAR, which included some similar sequences in miR-204-5p, EPHB2, and GDNF.	('GDNF', 'Gene', (140, 144))	('GDNF', 'Gene', '2668', (140, 144))	('EPHB2', 'Gene', '2048', (129, 134))	('EPHB2', 'Gene', (129, 134))	('TFBS', 'Gene', (49, 53))	('JASPAR', 'Disease', (68, 74))	('miR-204-5p', 'Chemical', '-', (117, 127))	('miR-204-5p', 'Chemical', '-', (35, 45))	('miR-204-5p', 'Var', (117, 127))
134285	32102656	The data presented here verified the decrease in miR-204-5p expression in NSCLC by comprehensive analysis of RT-qPCR, microarrays, sequencing data, and publications and revealed an obvious decrease in cancerous tissues and the LUAD subtype.	('decrease', 'NegReg', (37, 45))	('miR-204-5p', 'Var', (49, 59))	('cancerous', 'Disease', (201, 210))	('LUAD', 'Disease', (227, 231))	('LUAD', 'Disease', 'MESH:C538231', (227, 231))	('cancerous', 'Disease', 'MESH:D009369', (201, 210))	('decrease', 'NegReg', (189, 197))	('NSCLC', 'Disease', (74, 79))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('NSCLC', 'Disease', 'MESH:D002289', (74, 79))	('miR-204-5p', 'Chemical', '-', (49, 59))
134286	32102656	An auxiliary role for miR-204-5p was also identified by in NSCLC, particularly in tissues and LUAD, which was verified by the meta-analysis.	('NSCLC', 'Disease', 'MESH:D002289', (59, 64))	('miR-204-5p', 'Var', (22, 32))	('miR-204-5p', 'Chemical', '-', (22, 32))	('LUAD', 'Disease', (94, 98))	('LUAD', 'Disease', 'MESH:C538231', (94, 98))	('NSCLC', 'Disease', (59, 64))
134288	32102656	Nevertheless, the information provided by GO annotation and KEGG analysis indicated that the target genes of miR-204-5p were associated with neuron projection, transcription factor activity, RNA polymerase II transcription regulation, extracellular matrix (ECM) metabolism, and ion channel activity, as well as were connected with microRNAs in cancer, cell adhesion molecules (CAMs) and signaling pathways regulating pluripotency of stem cells.	('cancer', 'Disease', (344, 350))	('miR-204-5p', 'Chemical', '-', (109, 119))	('associated', 'Reg', (125, 135))	('CAM', 'Gene', '808', (377, 380))	('cancer', 'Phenotype', 'HP:0002664', (344, 350))	('miR-204-5p', 'Var', (109, 119))	('CAM', 'Gene', (377, 380))	('connected', 'Reg', (316, 325))	('cancer', 'Disease', 'MESH:D009369', (344, 350))
134291	32102656	At present, miR-204-5p has aroused considerable interest in cancer research for its dual function as an oncogene and tumor suppressor.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('miR-204-5p', 'Chemical', '-', (12, 22))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('tumor', 'Disease', (117, 122))	('miR-204-5p', 'Var', (12, 22))	('cancer', 'Disease', (60, 66))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
134292	32102656	MiR-204-5p is clearly attenuated in NSCLC, and its expression is negatively linked with tumor size, clinical stage, and metastasis.	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('negatively', 'NegReg', (65, 75))	('MiR-204-5p', 'Var', (0, 10))	('NSCLC', 'Disease', 'MESH:D002289', (36, 41))	('expression', 'MPA', (51, 61))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('NSCLC', 'Disease', (36, 41))	('attenuated', 'NegReg', (22, 32))	('tumor', 'Disease', (88, 93))
134295	32102656	In addition, miR-204-5p serves as a cancer suppressor gene by modulating oncogenic Wnt/FZD signaling pathways, inhibiting NUAK family kinase 1 (NUAK1) in NSCLC, and mediating a long-noncoding RNA (lncRNA) MALAT1 effect on the epithelial-to-mesenchymal transition (EMT) and cells invasion.	('mediating', 'Reg', (165, 174))	('epithelial-to-mesenchymal transition', 'CPA', (226, 262))	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('NUAK1', 'Gene', '9891', (144, 149))	('Wnt', 'Gene', (83, 86))	('MALAT1', 'Gene', (205, 211))	('NUAK1', 'Gene', (144, 149))	('FZD', 'Gene', (87, 90))	('NSCLC', 'Disease', 'MESH:D002289', (154, 159))	('MALAT1', 'Gene', '378938', (205, 211))	('modulating', 'Reg', (62, 72))	('miR-204-5p', 'Chemical', '-', (13, 23))	('miR-204-5p', 'Var', (13, 23))	('FZD', 'Gene', '11211;8322', (87, 90))	('inhibiting', 'NegReg', (111, 121))	('NUAK family kinase 1', 'Gene', (122, 142))	('NSCLC', 'Disease', (154, 159))	('cancer', 'Disease', (36, 42))	('Wnt', 'Gene', '7473', (83, 86))	('cells invasion', 'CPA', (273, 287))	('NUAK family kinase 1', 'Gene', '9891', (122, 142))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))
134297	32102656	The integrative meta-analysis also indicated a promising role for miR-204-5p for NSCLC screening, as did subgroup SROC curves, even though the sample origins were different.	('miR-204-5p', 'Var', (66, 76))	('NSCLC', 'Disease', 'MESH:D002289', (81, 86))	('miR-204-5p', 'Chemical', '-', (66, 76))	('NSCLC', 'Disease', (81, 86))
134298	32102656	The variation in miR-204-5p expression in tissues was helpful in diagnosis of LUAD than of LUSC.	('miR-204-5p', 'Gene', (17, 27))	('variation', 'Var', (4, 13))	('LUAD', 'Disease', (78, 82))	('LUAD', 'Disease', 'MESH:C538231', (78, 82))	('miR-204-5p', 'Chemical', '-', (17, 27))	('LUSC', 'Disease', 'MESH:D002294', (91, 95))	('LUSC', 'Disease', (91, 95))
134302	32102656	Consequently, no conclusion can be made in terms of miR-204-5p for NSCLC, at least for now.	('miR-204-5p', 'Var', (52, 62))	('NSCLC', 'Disease', 'MESH:D002289', (67, 72))	('miR-204-5p', 'Chemical', '-', (52, 62))	('NSCLC', 'Disease', (67, 72))
134303	32102656	The GO analysis indicated that the estimated target genes were mainly enriched in neuron projection, transcription factor activity, RNA polymerase II transcription regulation, ECM metabolism and ion channel activity, suggesting a potential involvement of miR-204-5p in the molecular function and signal modulation associated with NSCLC biological processes.	('miR-204-5p', 'Var', (255, 265))	('NSCLC', 'Disease', (330, 335))	('NSCLC', 'Disease', 'MESH:D002289', (330, 335))	('involvement', 'Reg', (240, 251))	('miR-204-5p', 'Chemical', '-', (255, 265))
134308	32102656	Consequently, miR-204-5p and its target genes could serve as important determinants of NSCLC pathogenesis and development.	('miR-204-5p', 'Var', (14, 24))	('NSCLC', 'Disease', 'MESH:D002289', (87, 92))	('NSCLC', 'Disease', (87, 92))	('miR-204-5p', 'Chemical', '-', (14, 24))
134310	32102656	However, only GDNF has been investigated for a direct relationship with miR-204-5p in NSCLC.	('miR-204-5p', 'Var', (72, 82))	('NSCLC', 'Disease', (86, 91))	('GDNF', 'Gene', '2668', (14, 18))	('NSCLC', 'Disease', 'MESH:D002289', (86, 91))	('GDNF', 'Gene', (14, 18))	('miR-204-5p', 'Chemical', '-', (72, 82))
134317	32102656	GDNF is also targeted and regulated by miR-204-5p which inversely affects GDNF mRNA and protein levels, to inhibit NSCLC growth, migration, and cell cycle alteration and promote apoptosis.	('inhibit', 'NegReg', (107, 114))	('miR-204-5p', 'Chemical', '-', (39, 49))	('GDNF', 'Gene', '2668', (0, 4))	('cell cycle alteration', 'Phenotype', 'HP:0011018', (144, 165))	('miR-204-5p', 'Var', (39, 49))	('NSCLC', 'Disease', (115, 120))	('migration', 'CPA', (129, 138))	('apoptosis', 'CPA', (178, 187))	('NSCLC', 'Disease', 'MESH:D002289', (115, 120))	('GDNF', 'Gene', (74, 78))	('affects', 'Reg', (66, 73))	('GDNF', 'Gene', '2668', (74, 78))	('GDNF', 'Gene', (0, 4))	('cell cycle alteration', 'CPA', (144, 165))	('promote', 'PosReg', (170, 177))
134318	32102656	Therefore, the interaction between miR-204-5p and GDNF appears to be critical in the development and progression of NSCLC and requires thorough research.	('NSCLC', 'Disease', 'MESH:D002289', (116, 121))	('miR-204-5p', 'Var', (35, 45))	('GDNF', 'Gene', (50, 54))	('GDNF', 'Gene', '2668', (50, 54))	('interaction', 'Interaction', (15, 26))	('NSCLC', 'Disease', (116, 121))	('miR-204-5p', 'Chemical', '-', (35, 45))
134319	32102656	DLG1 is a vital participant in the control of cellular processes like polarity, proliferation and migration, so its dysregulation and mutation give rise to pathologies that include oncogenic processes.	('give rise to', 'Reg', (143, 155))	('dysregulation', 'Var', (116, 129))	('DLG1', 'Gene', (0, 4))	('DLG1', 'Gene', '1739', (0, 4))	('mutation', 'Var', (134, 142))	('participant', 'Species', '9606', (16, 27))	('migration', 'CPA', (98, 107))	('oncogenic', 'Disease', (181, 190))
134320	32102656	DLG1 is mainly identified as a tumor suppressor, since overexpression is observed early in the onset of cervical cancer (CeCa) and elevated DLG1 promotes intestinal tumorigenesis, predicts poor prognosis in people with CRC and increases the invasiveness of NSCLC cell lines.	('CeCa', 'Disease', 'MESH:D002583', (121, 125))	('increases', 'PosReg', (227, 236))	('elevated DLG1', 'Phenotype', 'HP:0030269', (131, 144))	('DLG1', 'Gene', (140, 144))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('CRC', 'Disease', (219, 222))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('invasiveness of', 'CPA', (241, 256))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('DLG1', 'Gene', '1739', (140, 144))	('people', 'Species', '9606', (207, 213))	('CeCa', 'Disease', (121, 125))	('DLG1', 'Gene', (0, 4))	('CRC', 'Disease', 'MESH:D015179', (219, 222))	('NSCLC', 'Disease', 'MESH:D002289', (257, 262))	('promotes', 'PosReg', (145, 153))	('tumor', 'Disease', (165, 170))	('NSCLC', 'Disease', (257, 262))	('DLG1', 'Gene', '1739', (0, 4))	('tumor', 'Disease', (31, 36))	('elevated', 'Var', (131, 139))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('cervical cancer', 'Disease', (104, 119))	('cervical cancer', 'Disease', 'MESH:D002583', (104, 119))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
134323	32102656	Moreover, DLG1 deficiency results in incorrect spindle polarity and a delay in cells transiting orientation, which disrupts cellular structure and distribution.	('DLG1', 'Gene', '1739', (10, 14))	('incorrect spindle polarity', 'CPA', (37, 63))	('DLG1', 'Gene', (10, 14))	('cellular structure', 'MPA', (124, 142))	('cells transiting orientation', 'CPA', (79, 107))	('delay', 'NegReg', (70, 75))	('deficiency', 'Var', (15, 25))
134325	32102656	One possible reason is that DLG1 dysregulation in advanced tumor progression or in more malignant forms depends on its spatial/temporal distribution.	('dysregulation', 'Var', (33, 46))	('tumor', 'Disease', (59, 64))	('DLG1', 'Gene', '1739', (28, 32))	('DLG1', 'Gene', (28, 32))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
134331	32102656	Activation of EPHB2 promotes the progression of cutaneous squamous cell carcinoma cells by accelerating the production of invasive proteinases like MMP13 and MMP1.	('cutaneous squamous cell carcinoma', 'Disease', (48, 81))	('MMP13', 'Gene', '4322', (148, 153))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('MMP1', 'Gene', '4312', (158, 162))	('MMP1', 'Gene', (148, 152))	('promotes', 'PosReg', (20, 28))	('EPHB2', 'Gene', '2048', (14, 19))	('cutaneous squamous cell carcinoma', 'Disease', 'MESH:D002294', (48, 81))	('MMP1', 'Gene', '4312', (148, 152))	('EPHB2', 'Gene', (14, 19))	('Activation', 'Var', (0, 10))	('MMP1', 'Gene', (158, 162))	('accelerating', 'PosReg', (91, 103))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (58, 81))	('production of invasive proteinases', 'MPA', (108, 142))	('MMP13', 'Gene', (148, 153))	('progression', 'CPA', (33, 44))
134333	32102656	Future research could identify where whether specific differences in the interaction of EPHB2 and miR-204-5p are associated with NSCLC.	('EPHB2', 'Gene', (88, 93))	('interaction', 'Interaction', (73, 84))	('miR-204-5p', 'Var', (98, 108))	('miR-204-5p', 'Chemical', '-', (98, 108))	('NSCLC', 'Disease', (129, 134))	('NSCLC', 'Disease', 'MESH:D002289', (129, 134))	('associated', 'Reg', (113, 123))	('EPHB2', 'Gene', '2048', (88, 93))
134337	32102656	In addition to combining with and regulating its target genes, miR-204-5p also attenuates some angiogenic inducers like hypoxia inducible factor-1alpha (HIF-1alpha) to impair angiogenesis in LUAD.	('attenuates', 'NegReg', (79, 89))	('miR-204-5p', 'Var', (63, 73))	('impair', 'NegReg', (168, 174))	('HIF-1alpha', 'Gene', (153, 163))	('LUAD', 'Disease', (191, 195))	('LUAD', 'Disease', 'MESH:C538231', (191, 195))	('hypoxia inducible factor-1alpha', 'Gene', '3091', (120, 151))	('miR-204-5p', 'Chemical', '-', (63, 73))	('angiogenesis', 'CPA', (175, 187))	('HIF-1alpha', 'Gene', '3091', (153, 163))	('hypoxia inducible factor-1alpha', 'Gene', (120, 151))
134341	32102656	A positive FFL between Hepatitis B virus, miR-204-5p, and STAT3 appears to contribute to HCC incidence.	('contribute', 'Reg', (75, 85))	('Hepatitis', 'Phenotype', 'HP:0012115', (23, 32))	('HCC', 'Disease', 'MESH:D006528', (89, 92))	('Hepatitis B virus', 'Species', '10407', (23, 40))	('HCC', 'Disease', (89, 92))	('Hepatitis', 'Protein', (23, 32))	('STAT3', 'Gene', '6774', (58, 63))	('miR-204-5p', 'Var', (42, 52))	('miR-204-5p', 'Chemical', '-', (42, 52))	('STAT3', 'Gene', (58, 63))
134342	32102656	Other work has suggested that miR-204-5p reciprocally represses TrkB expression; however, TrkB expression noticeably increases JAK2 and STAT3 phosphorylation.	('TrkB', 'Gene', '4915', (90, 94))	('JAK2', 'Gene', '3717', (127, 131))	('TrkB', 'Gene', '4915', (64, 68))	('TrkB', 'Gene', (90, 94))	('increases', 'PosReg', (117, 126))	('expression', 'Var', (95, 105))	('STAT3', 'Gene', '6774', (136, 141))	('JAK2', 'Gene', (127, 131))	('TrkB', 'Gene', (64, 68))	('miR-204-5p', 'Chemical', '-', (30, 40))	('STAT3', 'Gene', (136, 141))
134369	32102656	The activities of miR-204-5p as an anti-oncogene were induced by its regulatory axes or circuits with target genes and TFs that participated in specific genetic pathways and biological processes.	('miR-204-5p', 'Var', (18, 28))	('miR-204-5p', 'Chemical', '-', (18, 28))	('activities', 'MPA', (4, 14))	('participated', 'Reg', (128, 140))
134371	29464035	Upregulation of cell cycle genes in head and neck cancer patients may be antagonized by erufosine's down regulation of cell cycle processes in OSCC cells The TCGA database was analyzed to identify deregulation of cell cycle genes across 24 cancer types and ensuing effects on patient survival.	('Upregulation', 'PosReg', (0, 12))	('effects', 'Reg', (265, 272))	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('patient', 'Species', '9606', (57, 64))	('patient', 'Species', '9606', (276, 283))	('patients', 'Species', '9606', (57, 65))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('cell cycle genes', 'Gene', (16, 32))	('deregulation', 'Var', (197, 209))	('cancer', 'Disease', 'MESH:D009369', (240, 246))	('head and neck cancer', 'Phenotype', 'HP:0012288', (36, 56))	('erufosine', 'Chemical', 'MESH:C472787', (88, 97))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('cancer', 'Disease', (240, 246))	('cell cycle genes', 'Gene', (213, 229))
134380	29464035	Erufosine caused a G2/M block and inhibition of colony formation.	('colony formation', 'CPA', (48, 64))	('G2/M block', 'CPA', (19, 29))	('Erufosine', 'Chemical', 'MESH:C472787', (0, 9))	('Erufosine', 'Var', (0, 9))	('inhibition', 'NegReg', (34, 44))
134406	29464035	As the changes in gene expression levels caused by erufosine correspond to the potential therapeutic targets in clinical settings, we extended the translational importance by characterizing erufosine's anti-neoplastic activity in-vitro as well as by a xenograft mouse model.	('erufosine', 'Chemical', 'MESH:C472787', (51, 60))	('mouse', 'Species', '10090', (262, 267))	('erufosine', 'Chemical', 'MESH:C472787', (190, 199))	('anti-neoplastic activity', 'MPA', (202, 226))	('gene expression levels', 'MPA', (18, 40))	('erufosine', 'Var', (190, 199))
134427	29464035	We investigated the global changes in gene expression (N = 25,359 genes) between erufosine treated HN-5 cells (at IC25, IC50 and IC75 concentrations) and untreated controls in triplicates (N = 12; 9 treated i.e.	('IC75 concentrations', 'Var', (129, 148))	('HN-5', 'Gene', (99, 103))	('erufosine', 'Chemical', 'MESH:C472787', (81, 90))	('HN-5', 'Gene', '100463289', (99, 103))
134434	29464035	HN-5 and SCC-61 cells were exposed to IC25, IC50 and IC75 concentrations of erufosine for 24 h and lysed for protein blotting.	('IC25', 'Var', (38, 42))	('IC75', 'Var', (53, 57))	('SCC-61', 'CellLine', 'CVCL:7118', (9, 15))	('erufosine', 'Chemical', 'MESH:C472787', (76, 85))	('HN-5', 'Gene', '100463289', (0, 4))	('IC50', 'Var', (44, 48))	('HN-5', 'Gene', (0, 4))
134440	29464035	The share of G2/M phase cells in erufosine treated HN-5 cells (65%) was 3.8 fold higher than that in control cells (18%).	('higher', 'PosReg', (81, 87))	('G2/M phase cells', 'CPA', (13, 29))	('HN-5', 'Gene', '100463289', (51, 55))	('erufosine', 'Chemical', 'MESH:C472787', (33, 42))	('HN-5', 'Gene', (51, 55))	('erufosine treated', 'Var', (33, 50))
134449	29464035	These results show that in addition to inhibiting the expression of cyclins and CDK's, erufosine also confers a strong functional block in cell cycle progression from G2 to M phases and inhibits the ability of cells to form colonies.	('expression', 'MPA', (54, 64))	('CDK', 'Gene', (80, 83))	('erufosine', 'Chemical', 'MESH:C472787', (87, 96))	('cyclins', 'Gene', (68, 75))	('erufosine', 'Var', (87, 96))	('inhibits', 'NegReg', (186, 194))	('cell cycle progression from G2 to M phases', 'CPA', (139, 181))	('cyclins', 'Gene', '891', (68, 75))	('block', 'NegReg', (130, 135))	('inhibiting', 'NegReg', (39, 49))
134450	29464035	Having demonstrated that erufosine causes down regulation of cell cycle processes in-vitro by inhibiting cyclins and CDKs, and causing a G2/M transition block, the anti-neoplastic efficacy of erufosine was tested in a xenograft mouse model.	('down regulation', 'NegReg', (42, 57))	('cell cycle processes', 'CPA', (61, 81))	('cyclins', 'Gene', (105, 112))	('erufosine', 'Chemical', 'MESH:C472787', (25, 34))	('CDKs', 'Gene', '983;1017;1019;12567;1021', (117, 121))	('erufosine', 'Var', (25, 34))	('G2/M transition block', 'CPA', (137, 158))	('CDKs', 'Gene', (117, 121))	('inhibiting', 'NegReg', (94, 104))	('mouse', 'Species', '10090', (228, 233))	('cyclins', 'Gene', '891', (105, 112))	('erufosine', 'Chemical', 'MESH:C472787', (192, 201))
134453	29464035	The treatment of xenograft bearing mice with erufosine caused a significantly reduced increase (22 mm2, +- 6) in the tumor area when compared to the control animals (60.6 mm2 +- 4; Figure 5B).	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('erufosine', 'Chemical', 'MESH:C472787', (45, 54))	('tumor', 'Disease', (117, 122))	('erufosine', 'Var', (45, 54))	('mice', 'Species', '10090', (35, 39))	('reduced', 'NegReg', (78, 85))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
134458	29464035	Our data revealed that erufosine not only decreases cyclins and CDKs in-vitro but also in-vivo.	('decreases', 'NegReg', (42, 51))	('cyclins', 'Gene', '891', (52, 59))	('CDKs', 'Gene', '983;1017;1019;12567;1021', (64, 68))	('erufosine', 'Chemical', 'MESH:C472787', (23, 32))	('cyclins', 'Gene', (52, 59))	('erufosine', 'Var', (23, 32))	('CDKs', 'Gene', (64, 68))
134461	29464035	In line with this, H&E stains showed that adenoid structures as well as necrotic areas were reduced in erufosine treated compared to untreated tumors (Figure 5E).	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('erufosine', 'Chemical', 'MESH:C472787', (103, 112))	('tumors', 'Disease', (143, 149))	('necrotic', 'Disease', (72, 80))	('tumors', 'Disease', 'MESH:D009369', (143, 149))	('were', 'NegReg', (87, 91))	('in erufosine', 'Var', (100, 112))	('that adenoid', 'CPA', (37, 49))	('necrotic', 'Disease', 'MESH:D009336', (72, 80))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
134462	29464035	Deregulation of cell cycle has been implicated in most human cancers and leads to cell proliferation, chromosome instability and loss of genomic integrity.	('chromosome instability', 'Phenotype', 'HP:0040012', (102, 124))	('Deregulation', 'Var', (0, 12))	('cell proliferation', 'CPA', (82, 100))	('implicated', 'Reg', (36, 46))	('loss', 'NegReg', (129, 133))	('human', 'Species', '9606', (55, 60))	('cancers', 'Disease', 'MESH:D009369', (61, 68))	('chromosome instability', 'CPA', (102, 124))	('leads to', 'Reg', (73, 81))	('cancers', 'Disease', (61, 68))	('cancers', 'Phenotype', 'HP:0002664', (61, 68))	('genomic integrity', 'CPA', (137, 154))	('cell cycle', 'CPA', (16, 26))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))
134463	29464035	In a recent study it was shown that aberration in cell cycle genes was seen in 39% of cancers analyzed from patient samples.	('aberration', 'Var', (36, 46))	('aberration in cell cycle', 'Phenotype', 'HP:0011018', (36, 60))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('cell cycle genes', 'Gene', (50, 66))	('cancers', 'Phenotype', 'HP:0002664', (86, 93))	('patient', 'Species', '9606', (108, 115))	('cancers', 'Disease', (86, 93))	('cancers', 'Disease', 'MESH:D009369', (86, 93))
134472	29464035	CCND1 has an oncogene status and substantial evidence exists for its involvement in amplification and overexpression in breast, lung, and oral squamous cell cancers as well as melanomas.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('oral squamous cell cancers', 'Disease', (138, 164))	('melanomas', 'Disease', 'MESH:D008545', (176, 185))	('lung', 'Disease', (128, 132))	('amplification', 'Var', (84, 97))	('overexpression', 'PosReg', (102, 116))	('oral squamous cell cancers', 'Disease', 'MESH:D002294', (138, 164))	('cancers', 'Phenotype', 'HP:0002664', (157, 164))	('melanomas', 'Disease', (176, 185))	('CCND1', 'Gene', (0, 5))	('squamous cell cancers', 'Phenotype', 'HP:0002860', (143, 164))	('breast', 'Disease', (120, 126))	('involvement', 'Reg', (69, 80))	('melanomas', 'Phenotype', 'HP:0002861', (176, 185))
134483	29464035	As expected, erufosine caused cytotoxicity in HN-5 and SCC-61 OSCC cells and for better understanding of its mode of action we investigated global changes in gene expression in response to erufosine exposure in HN-5 cells in a dose and time dependent manner.	('HN-5', 'Gene', '100463289', (46, 50))	('HN-5', 'Gene', '100463289', (211, 215))	('HN-5', 'Gene', (46, 50))	('erufosine', 'Chemical', 'MESH:C472787', (13, 22))	('HN-5', 'Gene', (211, 215))	('erufosine', 'Chemical', 'MESH:C472787', (189, 198))	('erufosine', 'Var', (13, 22))	('cytotoxicity', 'Disease', (30, 42))	('cytotoxicity', 'Disease', 'MESH:D064420', (30, 42))	('SCC-61 OSCC', 'CellLine', 'CVCL:L894', (55, 66))
134485	29464035	Confirmatory investigations with qRT-PCR and Western blot showed that erufosine not only inhibited the expression of these genes but also caused inhibition of almost all other cyclins and CDK's.	('erufosine', 'Chemical', 'MESH:C472787', (70, 79))	('expression', 'MPA', (103, 113))	('inhibited', 'NegReg', (89, 98))	('cyclins', 'Gene', '891', (176, 183))	('erufosine', 'Var', (70, 79))	('cyclins', 'Gene', (176, 183))	('inhibition', 'NegReg', (145, 155))
134502	29464035	This is the first study, which shows that erufosine inhibits HNSCC tumor growth in-vivo.	('erufosine', 'Chemical', 'MESH:C472787', (42, 51))	('HNSCC tumor', 'Disease', 'MESH:D000077195', (61, 72))	('erufosine', 'Var', (42, 51))	('HNSCC tumor', 'Disease', (61, 72))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('inhibits', 'NegReg', (52, 60))
134514	29464035	Only cells with specific mutations may tolerate such alterations, which in turn will not help in elucidating erufosine's mechanism of action.	('mutations', 'Var', (25, 34))	('erufosine', 'Chemical', 'MESH:C472787', (109, 118))	('alterations', 'Var', (53, 64))
134526	29464035	The cell lines had been authenticated by MD Anderson center using short tandem repeat analysis and were routinely tested for mycoplasma contamination.	('short tandem repeat analysis', 'Var', (66, 94))	('mycoplasma', 'Disease', (125, 135))	('mycoplasma', 'Disease', 'MESH:D009175', (125, 135))
134548	29259372	Low expression of miR-30a-3p/5p was closely associated with advanced ESCC progression and poor prognosis of patients with ESCC.	('associated', 'Reg', (44, 54))	('miR-30a-3p/5p', 'Var', (18, 31))	('expression', 'MPA', (4, 14))	('ESCC', 'Disease', (69, 73))	('patients', 'Species', '9606', (108, 116))	('Low', 'NegReg', (0, 3))
134551	29259372	Core tip: In this work, we found that low expression of miR-30a-3p/5p was closely associated with advanced esophageal squamous cell carcinoma (ESCC) progression and poor prognosis of patients with ESCC.	('associated with', 'Reg', (82, 97))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (107, 141))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (118, 141))	('miR-30a-3p/5p', 'Var', (56, 69))	('esophageal squamous cell carcinoma', 'Disease', (107, 141))	('low', 'NegReg', (38, 41))	('patients', 'Species', '9606', (183, 191))
134552	29259372	Furthermore, miR-30a-3p and miR-30a-5p could inhibit the activity of the Wnt signaling pathway by targeting the 3' untranslated regions of Wnt2 and Fzd2, respectively.	('Wnt2', 'Gene', (139, 143))	('miR-30a-3p', 'Var', (13, 23))	('targeting', 'Reg', (98, 107))	('miR-30a-5p', 'Var', (28, 38))	('Wnt signaling pathway', 'Pathway', (73, 94))	('Fzd2', 'Gene', (148, 152))	('Fzd2', 'Gene', '2535', (148, 152))	('activity', 'MPA', (57, 65))	('Wnt2', 'Gene', '7472', (139, 143))	('inhibit', 'NegReg', (45, 52))
134557	29259372	Highly conserved across species, microRNAs not only participate in biological processes, but also in the pathogenesis of human cancers.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('microRNAs', 'Var', (33, 42))	('human', 'Species', '9606', (121, 126))	('cancers', 'Disease', 'MESH:D009369', (127, 134))	('cancers', 'Phenotype', 'HP:0002664', (127, 134))	('cancers', 'Disease', (127, 134))	('biological processes', 'CPA', (67, 87))	('participate', 'Reg', (52, 63))
134563	29259372	Emerging evidence has indicated that the two strands of miR-30a (miR-30a-3p and miR-30a-5p) are involved in various kinds of cancer.	('involved', 'Reg', (96, 104))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('miR-30a', 'Gene', (56, 63))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('miR-30a-5p', 'Var', (80, 90))
134588	29259372	Statistical analyses further revealed no difference in the miR-30a-3p/5p expression between different differentiation statuses of ESCC (Figure 2A), but miR-30a-3p/5p expression was inversely correlated with classifications of primary tumor and lymphatic metastasis (Figures 2B and C).	('tumor', 'Disease', (234, 239))	('lymphatic metastasis', 'CPA', (244, 264))	('correlated', 'Reg', (191, 201))	('inversely', 'NegReg', (181, 190))	('miR-30a-3p/5p', 'Var', (152, 165))	('tumor', 'Disease', 'MESH:D009369', (234, 239))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))
134589	29259372	Most importantly, survival analysis indicated that the group of lower miR-30a-3p/5p expression had shorter 5-year overall survival, and was associated with poorer prognosis of patients with ESCC (Figure 2D, log-rank, P < 0.05).	('shorter', 'NegReg', (99, 106))	('ESCC', 'Disease', (190, 194))	('patients', 'Species', '9606', (176, 184))	('lower', 'NegReg', (64, 69))	('miR-30a-3p/5p expression', 'Var', (70, 94))
134590	29259372	As shown in Figure 3A, expression of miR-30a-3p/5p was significantly lower in ESCC cell lines KYSE30 and KYSE150 than in normal esophageal epithelial cell line Het-1A.	('ESCC', 'Disease', (78, 82))	('lower', 'NegReg', (69, 74))	('Het-1A', 'CellLine', 'CVCL:3702', (160, 166))	('KYSE150', 'Var', (105, 112))	('miR-30a-3p/5p', 'Var', (37, 50))	('KYSE30', 'Var', (94, 100))	('KYSE150', 'CellLine', 'CVCL:1348', (105, 112))	('expression', 'MPA', (23, 33))
134592	29259372	MTT and colony formation assays indicated that over-expression of miR-30a-3p/5p significantly repressed the proliferation of HYSE30 cells in comparison with the control group.	('over-expression', 'PosReg', (47, 62))	('repressed', 'NegReg', (94, 103))	('miR-30a-3p/5p', 'Var', (66, 79))	('MTT', 'Chemical', 'MESH:C070243', (0, 3))	('proliferation', 'CPA', (108, 121))
134593	29259372	It should be noted that the anchorage-independent growth ability of KYSE30 cells was also attenuated by over-expression of miR-30a-3p/5p in the soft-agar assays.	('miR-30a-3p/5p', 'Var', (123, 136))	('anchorage-independent growth ability', 'CPA', (28, 64))	('over-expression', 'PosReg', (104, 119))	('attenuated', 'NegReg', (90, 100))	('agar', 'Chemical', 'MESH:D000362', (149, 153))
134595	29259372	Results showed that the miR-30a-3p/5p over-expression group exhibited remarkably smaller tumor volume and slower tumor growth rate in comparison with the control group (Figures 3F, G, and H).	('smaller', 'NegReg', (81, 88))	('tumor', 'Disease', (113, 118))	('miR-30a-3p/5p', 'Var', (24, 37))	('slower', 'NegReg', (106, 112))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))	('over-expression', 'PosReg', (38, 53))
134597	29259372	As indicated by the MTT and colony formation assays (Figure 4A bottom and B), inhibition of miR-30a-3p/5p significantly increased the proliferation of KYSE150 cells in comparison with the control groups.	('KYSE150', 'CellLine', 'CVCL:1348', (151, 158))	('miR-30a-3p/5p', 'Gene', (92, 105))	('increased', 'PosReg', (120, 129))	('MTT', 'Chemical', 'MESH:C070243', (20, 23))	('inhibition', 'Var', (78, 88))	('proliferation', 'CPA', (134, 147))
134599	29259372	Tumorigenesis assays performed in the nude mice showed that inhibition of miR-30a-3p/5p increased the tumor volume and tumor growth rate in comparison with the control group (Figure 4D, E, and F).	('tumor', 'Disease', (119, 124))	('inhibition', 'Var', (60, 70))	('miR-30a-3p/5p', 'Gene', (74, 87))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('increased', 'PosReg', (88, 97))	('nude mice', 'Species', '10090', (38, 47))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))
134600	29259372	Both in vitro and in vivo experiments indicated that miR-30a-3p/5p served as tumor suppressors in ESCC.	('ESCC', 'Disease', (98, 102))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Disease', (77, 82))	('miR-30a-3p/5p', 'Var', (53, 66))
134603	29259372	In contrast, inhibition of miR-30a increased the expression of Cyclin D1 and decreased the expression of p27 and p21, both at protein and mRNA levels, as indicated by the results of Western blot and qPCR analyses, respectively (Figures 5C, D, E, and F).	('expression', 'MPA', (91, 101))	('increased', 'PosReg', (35, 44))	('inhibition', 'Var', (13, 23))	('miR-30a', 'Gene', (27, 34))	('Cyclin D1', 'Gene', (63, 72))	('expression', 'MPA', (49, 59))	('Cyclin D1', 'Gene', '595', (63, 72))	('p27', 'Gene', '3429', (105, 108))	('p21', 'Gene', (113, 116))	('decreased', 'NegReg', (77, 86))	('p21', 'Gene', '644914', (113, 116))	('p27', 'Gene', (105, 108))
134604	29259372	Results showed that mRNA expression of Wnt2 was repressed by transfecting miR-30a-3p-mimics, and Fzd2 was inhibited by miR-30a-5p-mimics (Figure 6A).	('miR-30a-5p-mimics', 'Var', (119, 136))	('Wnt2', 'Gene', (39, 43))	('inhibited', 'NegReg', (106, 115))	('miR-30a-3p-mimics', 'Var', (74, 91))	('Fzd2', 'Gene', '2535', (97, 101))	('mRNA expression', 'MPA', (20, 35))	('Fzd2', 'Gene', (97, 101))	('Wnt2', 'Gene', '7472', (39, 43))
134607	29259372	As shown in Figure 6C, over-expression of miR-30a-3p decreased the expression of Wnt2, while inhibition of miR-30a-3p increased it, at both protein and mRNA levels.	('miR-30a-3p', 'Var', (42, 52))	('miR-30a-3p', 'Var', (107, 117))	('increased', 'PosReg', (118, 127))	('Wnt2', 'Gene', (81, 85))	('expression', 'MPA', (67, 77))	('decreased', 'NegReg', (53, 62))	('over-expression', 'PosReg', (23, 38))	('Wnt2', 'Gene', '7472', (81, 85))
134608	29259372	The miR-30a-5p showed the same effects on Fzd2 expression.	('Fzd2', 'Gene', '2535', (42, 46))	('miR-30a-5p', 'Var', (4, 14))	('expression', 'MPA', (47, 57))	('Fzd2', 'Gene', (42, 46))
134609	29259372	Luciferase reporter assays also demonstrated that over-expression of miR-30a-3p significantly reduced luciferase activity of the wild-type Wnt2-3'-UTR in a dose-dependent pattern, while it had no effects on the mutant type.	('Wnt2', 'Gene', (139, 143))	('reduced', 'NegReg', (94, 101))	('luciferase', 'Enzyme', (102, 112))	('miR-30a-3p', 'Var', (69, 79))	('activity', 'MPA', (113, 121))	('Wnt2', 'Gene', '7472', (139, 143))	('over-expression', 'PosReg', (50, 65))
134610	29259372	Likewise, miR-30a-5p had the same effects on the wild-type FZD2-3'-UTR and the mutant one (Figure 6D).	('mutant', 'Var', (79, 85))	('FZD2', 'Gene', '2535', (59, 63))	('FZD2', 'Gene', (59, 63))	('miR-30a-5p', 'Var', (10, 20))
134611	29259372	Emerging evidence has shown that the dysregulation of microRNAs plays an important role in multiple tumor-related processes, such as cell differentiation, proliferation, apoptosis, autophagy, angiogenesis, invasion, and metastasis.	('autophagy', 'CPA', (181, 190))	('microRNAs', 'Protein', (54, 63))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('dysregulation', 'Var', (37, 50))	('role', 'Reg', (83, 87))	('tumor', 'Disease', (100, 105))	('proliferation', 'CPA', (155, 168))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('invasion', 'CPA', (206, 214))	('angiogenesis', 'CPA', (192, 204))	('cell differentiation', 'CPA', (133, 153))	('apoptosis', 'CPA', (170, 179))	('metastasis', 'CPA', (220, 230))
134612	29259372	It was interesting that aberrant expression of miR-30a-3p/5p was found in many kinds of cancer and showed opposite tendencies.	('miR-30a-3p/5p', 'Var', (47, 60))	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('found', 'Reg', (65, 70))
134619	29259372	Apart from the expression pattern, it has been observed that miR-30a-3p/5p exhibited multiple roles in the regulation of tumor progression.	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('miR-30a-3p/5p', 'Var', (61, 74))	('tumor', 'Disease', (121, 126))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
134621	29259372	In non-small cell lung cancer (NSCLC), miR-30a has been found to be inversely associated with invasive ability, and it suppressed epithelial to mesenchymal transition (EMT) of NSCLC cells.	('associated', 'Reg', (78, 88))	('invasive ability', 'CPA', (94, 110))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (3, 29))	('suppressed', 'NegReg', (119, 129))	('epithelial to mesenchymal transition', 'CPA', (130, 166))	('NSCLC', 'Disease', (176, 181))	('NSCLC', 'Disease', (31, 36))	('NSCLC', 'Phenotype', 'HP:0030358', (176, 181))	('NSCLC', 'Disease', 'MESH:D002289', (176, 181))	('NSCLC', 'Disease', 'MESH:D002289', (31, 36))	('lung cancer', 'Phenotype', 'HP:0100526', (18, 29))	('miR-30a', 'Var', (39, 46))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (3, 29))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('non-small cell lung cancer', 'Disease', (3, 29))	('NSCLC', 'Phenotype', 'HP:0030358', (31, 36))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (7, 29))
134623	29259372	In contrast, miR-30a-5p has been identified as an oncogenic factor in glioma, and knock-down of miR-30a-5p inhibited glioma cell growth and cell invasion, while over-expression of miR-30a-5p had had opposite effects.	('cell invasion', 'CPA', (140, 153))	('knock-down', 'Var', (82, 92))	('glioma', 'Disease', (70, 76))	('glioma', 'Disease', 'MESH:D005910', (117, 123))	('glioma', 'Disease', 'MESH:D005910', (70, 76))	('glioma', 'Phenotype', 'HP:0009733', (117, 123))	('glioma', 'Phenotype', 'HP:0009733', (70, 76))	('miR-30a-5p', 'Var', (96, 106))	('glioma', 'Disease', (117, 123))	('inhibited', 'NegReg', (107, 116))
134624	29259372	Our functional approach showed that miR-30a-3p/5p function as tumor suppressors in ESCC.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', (62, 67))	('ESCC', 'Disease', (83, 87))	('miR-30a-3p/5p', 'Var', (36, 49))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
134626	29259372	Colorectal tumorigenesis is initiated by mutations in the Wnt signaling pathway (e.g., APC or beta-catenin) that constitutively activate the pathway, and also by binding a Wnt-protein ligand to a Frizzled family receptor, passing the biological signal to the dishevelled protein inside the cell, and leading to the regulation of gene transcription.	('mutations', 'Var', (41, 50))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('gene transcription', 'MPA', (329, 347))	('tumor', 'Disease', (11, 16))	('beta-catenin', 'Gene', (94, 106))	('initiated by', 'Reg', (28, 40))	('activate', 'PosReg', (128, 136))	('APC', 'Disease', 'MESH:D011125', (87, 90))	('beta-catenin', 'Gene', '1499', (94, 106))	('binding', 'Interaction', (162, 169))	('regulation', 'MPA', (315, 325))	('tumor', 'Disease', 'MESH:D009369', (11, 16))	('APC', 'Disease', (87, 90))	('passing', 'PosReg', (222, 229))	('biological signal', 'MPA', (234, 251))	('leading to', 'Reg', (300, 310))
134629	29259372	In addition, miR-30a-5p has been found to directly suppress PRDM1, resulting in activation of Wnt/beta-catenin (carotene) signaling in glioma.	('suppress', 'NegReg', (51, 59))	('glioma', 'Disease', (135, 141))	('carotene', 'Chemical', 'MESH:D002338', (112, 120))	('miR-30a-5p', 'Var', (13, 23))	('glioma', 'Phenotype', 'HP:0009733', (135, 141))	('PRDM1', 'Gene', '639', (60, 65))	('activation', 'PosReg', (80, 90))	('glioma', 'Disease', 'MESH:D005910', (135, 141))	('beta-catenin', 'Gene', (98, 110))	('beta-catenin', 'Gene', '1499', (98, 110))	('PRDM1', 'Gene', (60, 65))
134630	29259372	We demonstrated that miR-30a-3p and miR-30a-5p directly target the 3'-UTRs of Wnt2 and Fzd2 and inhibit their expression, respectively.	('miR-30a-5p', 'Var', (36, 46))	('Wnt2', 'Gene', (78, 82))	('miR-30a-3p', 'Var', (21, 31))	('Fzd2', 'Gene', '2535', (87, 91))	('Fzd2', 'Gene', (87, 91))	('expression', 'MPA', (110, 120))	('inhibit', 'NegReg', (96, 103))	('Wnt2', 'Gene', '7472', (78, 82))
134631	29259372	In conclusion, low expression of miR-30a-3p/5p was closely associated with advanced ESCC progression and poor prognosis of patients with ESCC.	('expression', 'MPA', (19, 29))	('ESCC', 'Disease', (84, 88))	('patients', 'Species', '9606', (123, 131))	('associated', 'Reg', (59, 69))	('miR-30a-3p/5p', 'Var', (33, 46))	('low', 'NegReg', (15, 18))
134632	29259372	Furthermore, miR-30a-3p and miR-30a-5p could inhibit the activity of the Wnt signaling pathway by targeting the 3'UTRs of WNT2 and FZD2, respectively.	('miR-30a-3p', 'Var', (13, 23))	('targeting', 'Reg', (98, 107))	('miR-30a-5p', 'Var', (28, 38))	('Wnt signaling pathway', 'Pathway', (73, 94))	('FZD2', 'Gene', '2535', (131, 135))	('FZD2', 'Gene', (131, 135))	('WNT2', 'Gene', (122, 126))	('activity', 'MPA', (57, 65))	('inhibit', 'NegReg', (45, 52))	('WNT2', 'Gene', '7472', (122, 126))
134758	28580352	Fine particulate pollution was associated with a significant increase in lung cancer mortality for the exposure periods from 1979 to 1983 and 1999-2000 of 8 and 13%, respectively, after controlling for age, sex, race, smoking, education, marital status, body mass, alcohol consumption, occupational exposure, and diet.	('Fine particulate pollution', 'Var', (0, 26))	('alcohol', 'Chemical', 'MESH:D000438', (265, 272))	('increase in lung cancer', 'Disease', (61, 84))	('lung cancer', 'Phenotype', 'HP:0100526', (73, 84))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('increase in lung cancer', 'Disease', 'MESH:D008175', (61, 84))
134813	27284551	A previous study on OSCC cells indicated that transfecting with miR-125b or miR-100 significantly decreased cell proliferation; however, co-transfection had a greater effect on proliferation than individual transfection.	('miR-100', 'Gene', '406892', (76, 83))	('miR-125b', 'Var', (64, 72))	('SCC', 'Phenotype', 'HP:0002860', (21, 24))	('miR-125b', 'Chemical', '-', (64, 72))	('miR-100', 'Gene', (76, 83))	('proliferation', 'CPA', (177, 190))	('cell proliferation', 'CPA', (108, 126))	('decreased', 'NegReg', (98, 107))
134814	27284551	miR-128 also acts as a tumor suppressor and inhibits the growth of HNSCC cells.	('SCC', 'Phenotype', 'HP:0002860', (69, 72))	('miR-128', 'Chemical', '-', (0, 7))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('miR-128', 'Var', (0, 7))	('HNSCC', 'Phenotype', 'HP:0012288', (67, 72))	('inhibits', 'NegReg', (44, 52))	('growth of HNSCC cells', 'CPA', (57, 78))
134818	27284551	The role of miRNAs in cancer development and metastasis  Previous studies have indicated that dysregulation of miRNAs plays a crucial role in the progression of oral precancerous lesion from dysplasia to OSCC.	('oral precancerous lesion', 'Disease', (161, 185))	('OSCC', 'Disease', (204, 208))	('dysplasia', 'Disease', (191, 200))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('oral precancerous lesion', 'Disease', 'MESH:D011230', (161, 185))	('dysplasia', 'Disease', 'MESH:D004476', (191, 200))	('SCC', 'Phenotype', 'HP:0002860', (205, 208))	('miRNAs', 'Protein', (111, 117))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('dysregulation', 'Var', (94, 107))
134833	27284551	miR-125b has also been shown to have a role in tumor suppression by inhibiting cancer cell proliferation, migration, and invasion in skin SCC by down-regulation of matrix metalloproteinase -13 (MMP13).	('down-regulation', 'NegReg', (145, 160))	('cancer cell proliferation', 'CPA', (79, 104))	('inhibiting', 'NegReg', (68, 78))	('skin SCC', 'Disease', (133, 141))	('MMP13', 'Gene', (194, 199))	('tumor suppression', 'CPA', (47, 64))	('MMP1', 'Gene', (194, 198))	('miR-125b', 'Var', (0, 8))	('matrix metalloproteinase -13', 'Gene', '4322', (164, 192))	('MMP13', 'Gene', '4322', (194, 199))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('SCC', 'Phenotype', 'HP:0002860', (138, 141))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('invasion', 'CPA', (121, 129))	('migration', 'CPA', (106, 115))	('MMP1', 'Gene', '4312', (194, 198))	('matrix metalloproteinase -13', 'Gene', (164, 192))
134836	27284551	MSN, an actin binding protein, involved in cell motility, is a novel target of miR-133a.	('miR-133a', 'Var', (79, 87))	('MSN', 'Gene', (0, 3))	('MSN', 'Gene', '4478', (0, 3))
134839	27284551	miR-153 prevents EMT, returns the mesenchymal phenotype (MET phenomenon) of cells to epithelial-like cells, and decreases cellular invasive ability.	('returns', 'PosReg', (22, 29))	('miR-153', 'Var', (0, 7))	('mesenchymal phenotype', 'CPA', (34, 55))	('miR-153', 'Chemical', '-', (0, 7))	('cellular invasive ability', 'CPA', (122, 147))	('EMT', 'CPA', (17, 20))	('prevents', 'NegReg', (8, 16))	('decreases', 'NegReg', (112, 121))
134852	27284551	miR-155-5p induces metastasis and is associated with poor prognosis; miR-155-5p inhibitor down-regulates signal transducer and activator of transcription 3 (STAT3) by activating suppressor of cytokine signaling 1 (SOCS1).	('miR-155-5p', 'Var', (69, 79))	('signal transducer and activator of transcription 3', 'Gene', '6774', (105, 155))	('SOCS1', 'Gene', '8651', (214, 219))	('STAT3', 'Gene', '6774', (157, 162))	('suppressor of cytokine signaling 1', 'Gene', '8651', (178, 212))	('down-regulates', 'NegReg', (90, 104))	('STAT3', 'Gene', (157, 162))	('SOCS1', 'Gene', (214, 219))	('suppressor of cytokine signaling 1', 'Gene', (178, 212))	('activating', 'PosReg', (167, 177))
134856	27284551	Reduced level of miR-223 has been observed in hematopoietic malignancies; however, elevated expression of miR-223 is indicated in several types of solid tumors of head and neck area.	('solid tumors', 'Disease', (147, 159))	('hematopoietic malignancies', 'Disease', (46, 72))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumors of head and neck', 'Phenotype', 'HP:0012288', (153, 176))	('solid tumors', 'Disease', 'MESH:D009369', (147, 159))	('tumors', 'Phenotype', 'HP:0002664', (153, 159))	('miR-223', 'Var', (106, 113))	('elevated', 'PosReg', (83, 91))	('expression', 'MPA', (92, 102))	('hematopoietic malignancies', 'Disease', 'MESH:D019337', (46, 72))
134858	27284551	Besides, a previous study showed that the miRNA expression profile differs in different sites of the head and neck area and reflects the developmental origin of tissue; moreover, miRNAs can distinguish the cancers from benign tumors, non-neoplastic lesions and normal tissue.	('benign tumors', 'Disease', (219, 232))	('tumors', 'Phenotype', 'HP:0002664', (226, 232))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('distinguish', 'Reg', (190, 201))	('neoplastic lesions', 'Phenotype', 'HP:0002664', (238, 256))	('benign tumors', 'Disease', 'MESH:D009369', (219, 232))	('cancers', 'Phenotype', 'HP:0002664', (206, 213))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('cancers', 'Disease', (206, 213))	('miRNAs', 'Var', (179, 185))
134865	27284551	mir34a/c may function as a metastasis suppressor in breast cancer through targeting Fos-related antigen 1 (FOSL1).	('mir34a/c', 'Var', (0, 8))	('Fos-related antigen 1', 'Gene', '8061', (84, 105))	('FOSL1', 'Gene', (107, 112))	('FOSL1', 'Gene', '8061', (107, 112))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('breast cancer', 'Disease', (52, 65))	('breast cancer', 'Phenotype', 'HP:0003002', (52, 65))	('Fos-related antigen 1', 'Gene', (84, 105))
134866	27284551	miR-133a acts as a tumor suppressor in esophageal squamous cell carcinoma by targeting Fascin Actin-Bundling Protein 1 (FSCN1), an actin bundling protein which promotes the degradation of ECM, and matrix metalloproteinase 14 (MMP14).	('promotes', 'PosReg', (160, 168))	('FSCN1', 'Gene', (120, 125))	('matrix metalloproteinase 14', 'Gene', '4323', (197, 224))	('MMP14', 'Gene', '4323', (226, 231))	('Fascin Actin-Bundling Protein 1', 'Gene', '6624', (87, 118))	('MMP14', 'Gene', (226, 231))	('degradation', 'MPA', (173, 184))	('esophageal squamous cell carcinoma', 'Disease', (39, 73))	('miR-133a', 'Var', (0, 8))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (50, 73))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))	('Fascin Actin-Bundling Protein 1', 'Gene', (87, 118))	('matrix metalloproteinase 14', 'Gene', (197, 224))	('ECM', 'MPA', (188, 191))	('FSCN1', 'Gene', '6624', (120, 125))
134872	27284551	In addition, miR-181a and mir-181b suppress glioma tumor growth, but contributes to tumor progression in thyroid papillary carcinoma.	('thyroid papillary carcinoma', 'Phenotype', 'HP:0002895', (105, 132))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('glioma tumor', 'Disease', (44, 56))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('thyroid papillary carcinoma', 'Disease', (105, 132))	('glioma tumor', 'Disease', 'MESH:D005910', (44, 56))	('miR-181a', 'Var', (13, 21))	('thyroid papillary carcinoma', 'Disease', 'MESH:D000077273', (105, 132))	('mir-181b', 'Var', (26, 34))	('suppress', 'NegReg', (35, 43))	('glioma', 'Phenotype', 'HP:0009733', (44, 50))
134873	27284551	miR-211 acts as a tumor suppressor in melanoma, whereas; it functions as an oncomir in colon cancer.	('colon cancer', 'Disease', (87, 99))	('melanoma', 'Disease', 'MESH:D008545', (38, 46))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('colon cancer', 'Phenotype', 'HP:0003003', (87, 99))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('melanoma', 'Phenotype', 'HP:0002861', (38, 46))	('melanoma', 'Disease', (38, 46))	('miR-211', 'Var', (0, 7))
134874	27284551	Up-regulation of miR-222 in gastric carcinoma is associated with lymph node metastasis, vascular invasion and TNM stage, but miR-222 regulates OSCC as a tumor suppressor and inhibits tumor invasion and metastasis.	('gastric carcinoma', 'Phenotype', 'HP:0012126', (28, 45))	('TNM stage', 'CPA', (110, 119))	('SCC', 'Phenotype', 'HP:0002860', (144, 147))	('gastric carcinoma', 'Disease', 'MESH:D013274', (28, 45))	('inhibits', 'NegReg', (174, 182))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('vascular invasion', 'CPA', (88, 105))	('carcinoma', 'Phenotype', 'HP:0030731', (36, 45))	('Up-regulation', 'PosReg', (0, 13))	('gastric carcinoma', 'Disease', (28, 45))	('miR-222', 'Gene', (17, 24))	('OSCC', 'MPA', (143, 147))	('lymph node metastasis', 'CPA', (65, 86))	('miR-222', 'Var', (125, 132))
134876	27284551	miR-363 is a tumor suppressor in T cell lymphoma, however; it acts as an oncogene in breast cancer.	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('T cell lymphoma', 'Disease', (33, 48))	('breast cancer', 'Disease', (85, 98))	('lymphoma', 'Phenotype', 'HP:0002665', (40, 48))	('breast cancer', 'Phenotype', 'HP:0003002', (85, 98))	('miR-363', 'Var', (0, 7))	('cell lymphoma', 'Phenotype', 'HP:0012191', (35, 48))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('T cell lymphoma', 'Phenotype', 'HP:0012190', (33, 48))	('T cell lymphoma', 'Disease', 'MESH:D016399', (33, 48))
134884	32099064	This study highlights the importance of protein modifications in apoptotic tumor cells as a mechanism of generating immunogenic neoantigens that can be targeted for T cell-based immunotherapy.	('modifications', 'Var', (48, 61))	('immunogenic neoantigens', 'MPA', (116, 139))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', (75, 80))
134886	32099064	Additionally, NSCLC is molecularly heterogeneous, because of the amazing diversity of somatic genome mutations, including mutations of genes contributing to carcinogenesis (driver genes; e.g., KRAS, EGFR, TP53, etc.	('NSCLC', 'Disease', (14, 19))	('mutations', 'Var', (101, 110))	('EGFR', 'Gene', (199, 203))	('NSCLC', 'Disease', 'MESH:D002289', (14, 19))	('KRAS', 'Gene', (193, 197))	('TP53', 'Gene', '7157', (205, 209))	('TP53', 'Gene', (205, 209))	('KRAS', 'Gene', '3845', (193, 197))	('mutations', 'Var', (122, 131))	('NSCLC', 'Phenotype', 'HP:0030358', (14, 19))	('EGFR', 'Gene', '1956', (199, 203))
134887	32099064	), and passenger mutations of genes unrelated to tumor growth, a large part of which are patient specific (private) and confers a huge antigenic heterogeneity to various tumors including NSCLC.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('patient', 'Species', '9606', (89, 96))	('NSCLC', 'Phenotype', 'HP:0030358', (187, 192))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('tumor', 'Disease', (49, 54))	('NSCLC', 'Disease', (187, 192))	('tumor', 'Disease', (170, 175))	('tumors', 'Disease', 'MESH:D009369', (170, 176))	('mutations', 'Var', (17, 26))	('NSCLC', 'Disease', 'MESH:D002289', (187, 192))	('tumors', 'Phenotype', 'HP:0002664', (170, 176))	('tumors', 'Disease', (170, 176))
134892	32099064	T cells specific to either public or private neoAgs, which are encoded by somatic gene mutations, are not purged by central tolerance, can migrate in the periphery, and be of particular relevance to tumor control.	('tumor', 'Disease', (199, 204))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('mutations', 'Var', (87, 96))
134893	32099064	This conclusion is supported by the association between tumor T cell infiltration and mutational load, or between the expansion of mutated neoAg-specific T cells and the reinvigoration of anti-tumor T cell immunity following ICB.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('expansion', 'Var', (118, 127))	('association', 'Interaction', (36, 47))	('ICB', 'Chemical', '-', (225, 228))	('mutated', 'Var', (131, 138))	('tumor', 'Disease', (56, 61))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('neoAg-specific T cells', 'Gene', (139, 161))	('tumor', 'Disease', (193, 198))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('mutational', 'Var', (86, 96))
134894	32099064	However, despite the high mutational burden and the huge tumor T cell infiltration in several tumors including NSCLC, the frequencies of the related neoAg-specific T cells are relatively very low.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('NSCLC', 'Disease', (111, 116))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('NSCLC', 'Disease', 'MESH:D002289', (111, 116))	('tumor', 'Disease', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumors', 'Disease', (94, 100))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('mutational', 'Var', (26, 36))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('tumor', 'Disease', (57, 62))	('NSCLC', 'Phenotype', 'HP:0030358', (111, 116))
134895	32099064	In the light of these evidences, it is possible that a consistent proportion of tumor-associated T cells may be specific to non-mutated (NM)-neoAgs generated by various forms of protein modifications occurring at post-transcriptional level, such as protein splicing, dysregulated phosphorylation or glycosylation, proteasome generation of spliced peptides, peptide citrullination, impaired peptide processing in TAP-deficient tumor cells, or proteasomal degradation of defective ribosomal products (DRiPs).	('peptide citrullination', 'MPA', (357, 379))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (426, 431))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumor', 'Disease', (426, 431))	('modifications', 'Var', (186, 199))	('peptides', 'Chemical', 'MESH:D010455', (347, 355))	('peptide processing', 'MPA', (390, 408))	('tumor', 'Disease', (80, 85))	('proteasomal degradation', 'MPA', (442, 465))	('tumor', 'Disease', 'MESH:D009369', (426, 431))	('impaired', 'NegReg', (381, 389))	('TAP-deficient tumor', 'Disease', (412, 431))	('dysregulated', 'Var', (267, 279))	('TAP-deficient tumor', 'Disease', 'MESH:D009369', (412, 431))
134909	32099064	Non-labeled EpT1Lu cells were grown in light medium (12C6-Lys and 12C6-14N4-Arg) and maintained in viable condition.	('12C6-Lys', 'Var', (53, 61))	('12C6-14N4-Arg', 'Var', (66, 79))	('EpT1Lu', 'CellLine', 'CVCL:S574', (12, 18))	('12C6-14N4-Arg', 'Chemical', '-', (66, 79))	('12C6-Lys', 'Chemical', '-', (53, 61))
134926	32099064	To assess the functional relevance of SILAC findings, we compared the immunogenicity of proteins resulted fragmented or not in CDDP-ap or live NSCLC cell line (EpT1Lu).	('fragmented', 'Var', (106, 116))	('NSCLC', 'Disease', (143, 148))	('EpT1Lu', 'CellLine', 'CVCL:S574', (160, 166))	('NSCLC', 'Disease', 'MESH:D002289', (143, 148))	('NSCLC', 'Phenotype', 'HP:0030358', (143, 148))	('SILAC', 'Chemical', '-', (38, 43))	('proteins', 'Protein', (88, 96))	('CDDP-ap', 'Chemical', '-', (127, 134))
134931	32099064	The effector (eff) responses were evaluated by calculating the percentage of CD8+ or CD4+ T cells promptly producing interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha), or both ex vivo (i.e., without a previous stimulation in vitro), in response to a peptide matrix composed of 12 peptide pools.	('CD8', 'Gene', (77, 80))	('CD4+', 'Var', (85, 89))	('TNF-alpha', 'Gene', '7124', (176, 185))	('CD8', 'Gene', '925', (77, 80))	('interferon-gamma', 'Gene', (117, 133))	('tumor necrosis factor-alpha', 'Gene', (147, 174))	('tumor necrosis factor-alpha', 'Gene', '7124', (147, 174))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('IFN-gamma', 'Gene', '3458', (135, 144))	('IFN-gamma', 'Gene', (135, 144))	('TNF-alpha', 'Gene', (176, 185))	('interferon-gamma', 'Gene', '3458', (117, 133))
134945	32099064	The treatment of CDDP-ap NSCLC cells with C8I (but not with K) blocked the cross-presentation (Fig.	('cross-presentation', 'MPA', (75, 93))	('C8I', 'Chemical', '-', (42, 45))	('CDDP-ap', 'Chemical', '-', (17, 24))	('NSCLC', 'Disease', (25, 30))	('NSCLC', 'Disease', 'MESH:D002289', (25, 30))	('NSCLC', 'Phenotype', 'HP:0030358', (25, 30))	('C8I', 'Var', (42, 45))
134948	32099064	This analysis showed that patients' survival was correlated with the capacity of CD8+ Teff cells, but not CD4+ Teff cells, to produce high IFN-gamma or TNF-alpha levels in response to NM-neoAgs (one standard deviation above the average) at T2 (following the nivolumab treatment) (Fig.	('CD8', 'Gene', (81, 84))	('TNF-alpha', 'Gene', '7124', (152, 161))	('CD8', 'Gene', '925', (81, 84))	('TNF-alpha', 'Gene', (152, 161))	('IFN-gamma', 'Gene', '3458', (139, 148))	('patients', 'Species', '9606', (26, 34))	('NM-neoAgs', 'Var', (184, 193))	('IFN-gamma', 'Gene', (139, 148))	('nivolumab', 'Chemical', 'MESH:D000077594', (258, 267))
134956	32099064	DCs, upon phagocytosis of immunogenic apoptotic cells, have been demonstrated to efficiently process caspase-cleaved cellular fragmented proteins by proteasomes, and then to cross-present the resulting peptides on major histocompatibility complex (MHC) molecules priming T cells.	('cross-present', 'Reg', (174, 187))	('peptides', 'Chemical', 'MESH:D010455', (202, 210))	('peptides', 'Var', (202, 210))
134980	32099064	Consistent with this finding, PD-1 blockade has been proposed to induce a pattern of metabolic and effector T cell-specific changes that was related with an enhancement of effector molecules (e.g., IFN-gamma and granzymes) and in a decrease of the exhaustion markers TIM-3 and LAG-3.	('decrease', 'NegReg', (232, 240))	('metabolic', 'CPA', (85, 94))	('PD-1', 'Gene', (30, 34))	('PD-1', 'Gene', '5133', (30, 34))	('LAG-3', 'Gene', '3902', (277, 282))	('LAG-3', 'Gene', (277, 282))	('TIM-3', 'Gene', (267, 272))	('IFN-gamma', 'Gene', (198, 207))	('IFN-gamma', 'Gene', '3458', (198, 207))	('blockade', 'Var', (35, 43))	('TIM-3', 'Gene', '84868', (267, 272))	('enhancement', 'PosReg', (157, 168))
134988	32099064	Possible EGFR and KRAS mutations were detected by Real-Time PCR (Applied Biosystems 7500, USA).	('KRAS', 'Gene', (18, 22))	('KRAS', 'Gene', '3845', (18, 22))	('mutations', 'Var', (23, 32))	('EGFR', 'Gene', '1956', (9, 13))	('EGFR', 'Gene', (9, 13))
135006	32099064	Primary NSCLC cells were grown in either SILAC heavy (13C615N4-arginine and 13C6-lysine) or SILAC light (12C614N4-arginine and 12C6-lysine) conditions for eight passages before the first experiment.	('NSCLC', 'Phenotype', 'HP:0030358', (8, 13))	('NSCLC', 'Disease', 'MESH:D002289', (8, 13))	('13C615N4-arginine', 'Chemical', '-', (54, 71))	('12C614N4-arginine', 'Chemical', '-', (105, 122))	('12C614N4-arginine', 'Var', (105, 122))	('SILAC', 'Chemical', '-', (92, 97))	('13C615N4-arginine', 'Var', (54, 71))	('12C6-lysine', 'Chemical', '-', (127, 138))	('NSCLC', 'Disease', (8, 13))	('13C6-lysine', 'Chemical', '-', (76, 87))	('SILAC', 'Chemical', '-', (41, 46))
135009	32099064	Total metabolic incorporations were verified by MS. Then, cultured NSCLC cells that were metabolically labeled with heavy isotope medium were induced to apoptosis by 0.625 microM CDDP treatment (72 h).	('0.625 microM', 'Var', (166, 178))	('NSCLC', 'Phenotype', 'HP:0030358', (67, 72))	('CDDP', 'Gene', (179, 183))	('NSCLC', 'Disease', (67, 72))	('CDDP', 'Chemical', '-', (179, 183))	('NSCLC', 'Disease', 'MESH:D002289', (67, 72))
135019	32099064	D5545, Sigma-Aldrich)/0.1 M ammonium bicarbonate and incubated for 40 min at 56  C for cysteine reduction.	('ammonium bicarbonate', 'Chemical', 'MESH:C027043', (28, 48))	('D5545', 'Var', (0, 5))	('cysteine', 'Chemical', 'MESH:D003545', (87, 95))	('cysteine reduction', 'MPA', (87, 105))
135030	32099064	The Paragon algorithm was used with SILAC (Lys+6, Arg+10) selected as the sample type, iodoacetamide as cysteine alkylation, with the search option "biological modifications" checked, and trypsin as the selected enzyme.	('Lys+6', 'Var', (43, 48))	('cysteine', 'Chemical', 'MESH:D003545', (104, 112))	('iodoacetamide', 'Chemical', 'MESH:D007460', (87, 100))	('iodoacetamide', 'MPA', (87, 100))	('SILAC', 'Chemical', '-', (36, 41))	('Arg', 'Chemical', 'MESH:D001120', (50, 53))	('Lys', 'Chemical', 'MESH:D008239', (43, 46))	('cysteine', 'MPA', (104, 112))	('Arg+10', 'Var', (50, 56))
135035	32099064	Antibodies used were: anti-PSAP (Abcam, Cambridge, UK), anti-LYRIC/AEG1 (Abcam, Cambridge, UK) and anti-cleaved caspase-3 (Cell Signaling Technology, Danvers, MA) (Supplementary Table 2).	('PSAP', 'Gene', (27, 31))	('anti-cleaved', 'Var', (99, 111))	('LYRIC', 'Gene', (61, 66))	('AEG1', 'Gene', '92140', (67, 71))	('PSAP', 'Gene', '5660', (27, 31))	('caspase-3', 'Gene', (112, 121))	('AEG1', 'Gene', (67, 71))	('caspase-3', 'Gene', '836', (112, 121))	('LYRIC', 'Gene', '92140', (61, 66))
135050	32099064	Fresh NSCLC cells (10 x 106) were cultured in the presence or absence of 14 mug/mL C8I (ZIETD-FMK) or a negative caspase control (K, Z-FA-FMK) (BD Biosciences) for 1 h at 37  C. Then, they were induced to undergo apoptosis by CDDP treatment and processed for validating apoptosis, as described above.	('NSCLC', 'Disease', 'MESH:D002289', (6, 11))	('C8I', 'Chemical', '-', (83, 86))	('BD Biosciences', 'Disease', 'MESH:D001528', (144, 158))	('ZIETD-FMK', 'Chemical', 'MESH:C403753', (88, 97))	('Z-FA-FMK', 'Chemical', 'MESH:C057383', (133, 141))	('NSCLC', 'Phenotype', 'HP:0030358', (6, 11))	('apoptosis', 'CPA', (213, 222))	('CDDP', 'Chemical', '-', (226, 230))	('C8I', 'Var', (83, 86))	('NSCLC', 'Disease', (6, 11))	('BD Biosciences', 'Disease', (144, 158))
135062	32099064	performed and discussed proteomics analyses; F.L., F.B, J.R.G.B., and S.T.	('F.B', 'Var', (51, 54))	('S.T', 'Disease', 'MESH:D018455', (70, 73))	('S.T', 'Disease', (70, 73))	('J.R.G.B.', 'Var', (56, 64))
135063	32099064	procured samples, recruited patients, and discussed results; M.P., R.C., and G.P.S.	('patients', 'Species', '9606', (28, 36))	('R.C.', 'Var', (67, 71))	('M.P.', 'Var', (61, 65))
135344	25997441	Alterations in the expression of astrocyte elevated gene 1 exerts a predictive value in the prognosis of LSCC.	('LSCC', 'Disease', (105, 109))	('expression', 'MPA', (19, 29))	('Alterations', 'Var', (0, 11))	('astrocyte elevated gene 1', 'Gene', (33, 58))	('astrocyte elevated gene 1', 'Gene', '92140', (33, 58))	('astrocyte elevated', 'Phenotype', 'HP:0002446', (33, 51))
135345	25997441	Recurrent alterations in the levels of DNA methylation of Fanconi anemia-associated genes including FANCA, BRCA1 and BRCA2 contribute to the development of LSCC.	('BRCA1', 'Gene', '672', (107, 112))	('alterations', 'Var', (10, 21))	('Fanconi anemia', 'Disease', 'MESH:D005199', (58, 72))	('BRCA2', 'Gene', '675', (117, 122))	('levels', 'MPA', (29, 35))	('anemia', 'Phenotype', 'HP:0001903', (66, 72))	('contribute', 'Reg', (123, 133))	('BRCA1', 'Gene', (107, 112))	('Fanconi anemia', 'Disease', (58, 72))	('Fanconi anemia-', 'Phenotype', 'HP:0001994', (58, 73))	('FANCA', 'Gene', '2175', (100, 105))	('BRCA2', 'Gene', (117, 122))	('LSCC', 'Disease', (156, 160))	('FANCA', 'Gene', (100, 105))
135347	25997441	Larynx tissues with regional lymph node metastasis and corresponding adjacent non-neoplastic tissues samples from 10 patients (all males; age range, 52-74 years) who underwent surgery for primary LSCC at the Department of Head and Neck Surgery (Beijing Tongren Hospital, Beijing, China) were available for GSE51985, while GSE10288 contained 13 lesion tissue samples of LSCC from LSCC patients (12 males and 1 female; age range, 44-73 years; two repeats were obtained from each patient) and 10 non-matched normal larynx tissue samples (each had two repeats) from non-neoplastic larynx from the Arnaldo Vieira de Carvalho Hospital (Sao Paulo, Brazil).	('patient', 'Species', '9606', (384, 391))	('neoplastic larynx', 'Phenotype', 'HP:0100605', (566, 583))	('patient', 'Species', '9606', (477, 484))	('GSE51985', 'Var', (306, 314))	('neoplastic tissue', 'Phenotype', 'HP:0002664', (82, 99))	('patients', 'Species', '9606', (384, 392))	('patient', 'Species', '9606', (117, 124))	('patients', 'Species', '9606', (117, 125))	('GSE10288', 'Var', (322, 330))
135353	25997441	Among the 294 genes, 64 were enriched in several specific pathways (Table III), including the cell cycle (hsa04110), pathways in cancer (hsa05200), small cell lung cancer (has05222) and focal adhesion (hsa04510).	('focal adhesion', 'Disease', (186, 200))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('small cell lung cancer', 'Disease', 'MESH:D055752', (148, 170))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (148, 170))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('cell cycle', 'CPA', (94, 104))	('cancer', 'Disease', (164, 170))	('hsa04110', 'Var', (106, 114))	('hsa04510', 'Var', (202, 210))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('lung cancer', 'Phenotype', 'HP:0100526', (159, 170))	('small cell lung cancer', 'Disease', (148, 170))	('has05222', 'Var', (172, 180))
135380	33029866	This review aimed to summarize the current knowledge on the potential significance and molecular mechanisms of m6A RNA modification in the initiation and progression of cancer.	('m6A RNA', 'Gene', (111, 118))	('cancer', 'Disease', (169, 175))	('modification', 'Var', (119, 131))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('cancer', 'Disease', 'MESH:D009369', (169, 175))
135382	33029866	m6A methylation is catalysed by methyltransferase complexes (writers), reversed by demethylases (erasers) and functionally facilitated by m6A-binding proteins (readers).	('methyltransferase complexes', 'Enzyme', (32, 59))	('methylation', 'Var', (4, 15))	('demethylase', 'Gene', (83, 94))	('demethylase', 'Gene', '8932', (83, 94))	('m6A', 'Gene', (0, 3))
135383	33029866	m6A methylation participates in carcinogenesis and tumor progression.	('carcinogenesis', 'Disease', (32, 46))	('participates', 'Reg', (16, 28))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor', 'Disease', (51, 56))	('methylation', 'Var', (4, 15))	('m6A', 'Protein', (0, 3))	('carcinogenesis', 'Disease', 'MESH:D063646', (32, 46))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
135385	33029866	Among these, m6A methylation is the primary form of post-transcriptional modification of RNAs, accounting for 0.1%-0.4% of adenylation in mammalian RNAs and 50% of all methylated ribonucleotides.	('mammalian', 'Species', '9606', (138, 147))	('m6A methylation', 'Var', (13, 28))	('adenylation', 'MPA', (123, 134))
135392	33029866	m6A modification can regulate RNA metabolism (Figure 1), affect cell fate and functionally participate in a variety of pathophysiological processes, such as stem cell differentiation, cell division, immune homeostasis, mitosis, gametogenesis, sex determination and biological rhythm, and occurrence of numerous human diseases.	('cell fate', 'CPA', (64, 73))	('cell division', 'CPA', (184, 197))	('RNA metabolism', 'MPA', (30, 44))	('immune homeostasis', 'CPA', (199, 217))	('participate', 'Reg', (91, 102))	('regulate', 'Reg', (21, 29))	('sex determination', 'CPA', (243, 260))	('affect', 'Reg', (57, 63))	('stem cell differentiation', 'CPA', (157, 182))	('modification', 'Var', (4, 16))	('mitosis', 'CPA', (219, 226))	('gametogenesis', 'CPA', (228, 241))	('biological rhythm', 'CPA', (265, 282))	('m6A', 'Gene', (0, 3))	('human', 'Species', '9606', (311, 316))
135394	33029866	The deposition of m6A modification is catalysed by a multicomponent methyltransferase complex composed mainly of methyltransferase-like protein 3 (METTL3), methyltransferase-like protein 14 (METTL14) and Wilms' tumour 1-associated protein (WTAP), which are all the earliest known writer proteins.	('m6A', 'Var', (18, 21))	('methyltransferase-like protein 14', 'Gene', (156, 189))	("Wilms' tumour 1-associated protein", 'Gene', '9589', (204, 238))	('methyltransferase-like protein 3', 'Gene', '56339', (113, 145))	('methyltransferase-like protein 3', 'Gene', (113, 145))	("Wilms' tumour 1-associated protein", 'Gene', (204, 238))	('methyltransferase-like protein 14', 'Gene', '57721', (156, 189))	("Wilms' tumour", 'Phenotype', 'HP:0002667', (204, 217))	('tumour', 'Phenotype', 'HP:0002664', (211, 217))
135396	33029866	18  Knocking down METTL3 or METTL14 in mouse embryonic stem cells can eliminate up to 99% of total m6A level at thousands of sites.	('eliminate', 'NegReg', (70, 79))	('Knocking down', 'Var', (4, 17))	('METTL14', 'Gene', (28, 35))	('m6A level', 'MPA', (99, 108))	('METTL3', 'Gene', (18, 24))	('mouse', 'Species', '10090', (39, 44))
135399	33029866	24 ,  25  The knockdown of KIAA1429 results in a decrease of in the m6A content, which is greater than that achieved by METTL3 and METTL14 knockdown in A549 cells.	('A549', 'CellLine', 'CVCL:0023', (152, 156))	('decrease', 'NegReg', (49, 57))	('KIAA1429', 'Gene', (27, 35))	('METTL14', 'Gene', (131, 138))	('knockdown', 'Var', (14, 23))	('m6A content', 'MPA', (68, 79))
135407	33029866	32  ALKBH5 can directly catalyse the methylation of m6A-modified adenosines without producing intermediates.	('adenosines', 'Chemical', 'MESH:D000241', (65, 75))	('m6A-modified', 'Var', (52, 64))	('ALKBH5', 'Gene', '54890', (4, 10))	('ALKBH5', 'Gene', (4, 10))	('methylation', 'MPA', (37, 48))
135413	33029866	37  YTHDF1 promotes the ribosome loading of m6A-modified RNA and improves targeted RNA translation by interacting with translation initiation factors.	('RNA', 'Protein', (57, 60))	('targeted RNA translation', 'MPA', (74, 98))	('ribosome loading', 'MPA', (24, 40))	('interacting', 'Interaction', (102, 113))	('promotes', 'PosReg', (11, 19))	('improves', 'PosReg', (65, 73))	('YTHDF1', 'Gene', '54915', (4, 10))	('YTHDF1', 'Gene', (4, 10))	('m6A-modified', 'Var', (44, 56))
135417	33029866	6 ,  42  Although HNRNPC and HNRNPG cannot directly bind to the m6A site, they can mediate the selective splicing of m6A-modified transcripts by recognizing and combining m6A-dependent structural switches.	('HNRNPG', 'Gene', '3186', (29, 35))	('m6A-dependent', 'Var', (171, 184))	('structural switches', 'MPA', (185, 204))	('selective splicing', 'MPA', (95, 113))	('m6A-modified', 'Var', (117, 129))	('mediate', 'Reg', (83, 90))	('combining', 'Interaction', (161, 170))	('HNRNPG', 'Gene', (29, 35))	('HNRNPC', 'Gene', '3183', (18, 24))	('HNRNPC', 'Gene', (18, 24))
135421	33029866	11 ,  47 ,  48  The m6A modification can be traced from systemic lupus erythematosus, 49  single nucleotide polymorphism (genetic variant), 50  type 2 diabetes, 51  inflammatory response and so on.	('diabetes', 'Disease', (151, 159))	('systemic lupus erythematosus', 'Disease', (56, 84))	('diabetes', 'Disease', 'MESH:D003920', (151, 159))	('single nucleotide polymorphism', 'Var', (90, 120))	('systemic lupus erythematosus', 'Phenotype', 'HP:0002725', (56, 84))	('type 2 diabetes', 'Phenotype', 'HP:0005978', (144, 159))	('systemic lupus erythematosus', 'Disease', 'MESH:D008180', (56, 84))	('m6A', 'Var', (20, 23))
135422	33029866	52   Recently, emerging evidence indicates the crucial parts of m6A methylation in carcinogenesis and tumour progression by regulating the expression of oncogenes and tumour suppressor genes.	('tumour', 'Phenotype', 'HP:0002664', (167, 173))	('tumour', 'Disease', 'MESH:D009369', (167, 173))	('tumour', 'Phenotype', 'HP:0002664', (102, 108))	('tumour', 'Disease', (167, 173))	('methylation', 'Var', (68, 79))	('carcinogenesis', 'Disease', 'MESH:D063646', (83, 97))	('tumour', 'Disease', 'MESH:D009369', (102, 108))	('oncogenes', 'Protein', (153, 162))	('tumour', 'Disease', (102, 108))	('m6A', 'Gene', (64, 67))	('regulating', 'Reg', (124, 134))	('carcinogenesis', 'Disease', (83, 97))	('expression', 'MPA', (139, 149))
135423	33029866	1 ,  14 ,  53  Analogous to other epigenetic modifications, m6A methylation participates in cell proliferation, apoptosis, migration, angiogenesis, autophagy, chemoradiotherapy resistance, energy metabolism, immune escape, self-renewal and differentiation during the initiation and progression of cancers.	('differentiation', 'CPA', (240, 255))	('apoptosis', 'CPA', (112, 121))	('chemoradiotherapy resistance', 'CPA', (159, 187))	('autophagy', 'CPA', (148, 157))	('participates', 'Reg', (76, 88))	('methylation', 'Var', (64, 75))	('cancers', 'Disease', (297, 304))	('cancers', 'Disease', 'MESH:D009369', (297, 304))	('m6A', 'Gene', (60, 63))	('immune escape', 'CPA', (208, 221))	('cancers', 'Phenotype', 'HP:0002664', (297, 304))	('energy metabolism', 'CPA', (189, 206))	('angiogenesis', 'CPA', (134, 146))	('self-renewal', 'CPA', (223, 235))	('cancer', 'Phenotype', 'HP:0002664', (297, 303))	('cell proliferation', 'CPA', (92, 110))	('migration', 'CPA', (123, 132))
135429	33029866	Firstly, METTL3 increases the expression of the target genes, c-MYC, BCL-2 and PTEN, by m6A methylation-mediated translation of mRNAs.	('c-MYC', 'Gene', (62, 67))	('expression', 'MPA', (30, 40))	('BCL-2', 'Gene', '596', (69, 74))	('m6A', 'Var', (88, 91))	('methylation-mediated translation', 'MPA', (92, 124))	('BCL-2', 'Gene', (69, 74))	('increases', 'PosReg', (16, 25))	('c-MYC', 'Gene', '4609', (62, 67))	('METTL3', 'Gene', (9, 15))	('PTEN', 'Gene', (79, 83))	('PTEN', 'Gene', '5728', (79, 83))
135430	33029866	57  Second, METTL3 combines with the CCAAT-box-binding factor of m6A-modified mRNAs in a CEBPZ-dependent manner, promoting AML deterioration.	('AML deterioration', 'Disease', (123, 140))	('m6A-modified', 'Var', (65, 77))	('AML', 'Phenotype', 'HP:0004808', (123, 126))	('CEBPZ', 'Gene', '10153', (89, 94))	('AML deterioration', 'Disease', 'MESH:D015470', (123, 140))	('CEBPZ', 'Gene', (89, 94))	('promoting', 'PosReg', (113, 122))
135431	33029866	59  In SPI1-METTL14-MYB/MYC axis, METTL14 is down-regulated by SPI1 and enhances MYB and MYC expression through m6A modification.	('MYB', 'Gene', (20, 23))	('MYC', 'Gene', (24, 27))	('METTL14', 'Gene', (34, 41))	('SPI1', 'Gene', '6688', (7, 11))	('SPI1', 'Gene', '6688', (63, 67))	('MYC', 'Gene', '4609', (89, 92))	('MYB', 'Gene', '4602', (81, 84))	('down-regulated', 'NegReg', (45, 59))	('MYB', 'Gene', (81, 84))	('SPI1', 'Gene', (7, 11))	('SPI1', 'Gene', (63, 67))	('m6A', 'Var', (112, 115))	('MYB', 'Gene', '4602', (20, 23))	('MYC', 'Gene', '4609', (24, 27))	('MYC', 'Gene', (89, 92))	('enhances', 'PosReg', (72, 80))
135441	33029866	62  R-2-hydroxyglutarate (R-2HG), the metabolite of isocitrate dehydrogenase 1 and 2 (IDH1/2) mutant, suppresses cell proliferation, induces apoptosis and displays anti-leukaemic activity by targeting the FTO/m6A/MYC/CEBPA axis.	('targeting', 'Reg', (191, 200))	('cell proliferation', 'CPA', (113, 131))	('anti-leukaemic activity', 'CPA', (164, 187))	('IDH1/2', 'Gene', '3417;3418', (86, 92))	('MYC', 'Gene', '4609', (213, 216))	('mutant', 'Var', (94, 100))	('suppresses', 'NegReg', (102, 112))	('CEBPA', 'Gene', '1050', (217, 222))	('R-2-hydroxyglutarate', 'Chemical', '-', (4, 24))	('CEBPA', 'Gene', (217, 222))	('IDH1/2', 'Gene', (86, 92))	('apoptosis', 'CPA', (141, 150))	('MYC', 'Gene', (213, 216))	('induces', 'PosReg', (133, 140))
135442	33029866	63 ,  64  Mechanically, R-2HG binds to FTO and competitively suppresses its demethylase activity, thus resulting in the up-regulation of global m6A modification, which in turn impairs the stability of MYC/CEBPA mRNAs and MYC/CEBPA involving signalling pathways in leukaemia cells sensitive to R-2HG.	('CEBPA', 'Gene', (225, 230))	('MYC', 'Gene', '4609', (221, 224))	('MYC', 'Gene', (201, 204))	('demethylase', 'Gene', (76, 87))	('up-regulation', 'PosReg', (120, 133))	('demethylase', 'Gene', '8932', (76, 87))	('leukaemia', 'Disease', (264, 273))	('global', 'MPA', (137, 143))	('signalling pathways', 'Pathway', (241, 260))	('MYC', 'Gene', '4609', (201, 204))	('MYC', 'Gene', (221, 224))	('stability', 'CPA', (188, 197))	('CEBPA', 'Gene', '1050', (205, 210))	('leukaemia', 'Disease', 'MESH:D007938', (264, 273))	('impairs', 'NegReg', (176, 183))	('CEBPA', 'Gene', '1050', (225, 230))	('CEBPA', 'Gene', (205, 210))	('FTO', 'Gene', (39, 42))	('suppresses', 'NegReg', (61, 71))	('m6A', 'Protein', (144, 147))	('R-2HG', 'Var', (24, 29))
135443	33029866	IDH mutations can weaken FTO activity in about 20% of patients with AML; they improve m6A modification without affecting FTO expression, 65  which provides a novel target for the clinical treatment of leukaemia.	('improve', 'PosReg', (78, 85))	('m6A modification', 'MPA', (86, 102))	('IDH', 'Gene', (0, 3))	('leukaemia', 'Disease', (201, 210))	('patients', 'Species', '9606', (54, 62))	('IDH', 'Gene', '3417', (0, 3))	('AML', 'Disease', 'MESH:D015470', (68, 71))	('AML', 'Phenotype', 'HP:0004808', (68, 71))	('AML', 'Disease', (68, 71))	('mutations', 'Var', (4, 13))	('weaken', 'NegReg', (18, 24))	('FTO activity', 'MPA', (25, 37))	('leukaemia', 'Disease', 'MESH:D007938', (201, 210))
135444	33029866	YTHDF2 is not necessary to maintain the function of hematopoietic stem cells (HSCs); on the contrary, the absence of YTHDF2 helps in enhancing the activity of HSCs.	('YTHDF2', 'Gene', (117, 123))	('YTHDF2', 'Gene', '51441', (117, 123))	('HSCs', 'CPA', (159, 163))	('YTHDF2', 'Gene', '51441', (0, 6))	('absence', 'Var', (106, 113))	('YTHDF2', 'Gene', (0, 6))	('activity', 'MPA', (147, 155))	('enhancing', 'PosReg', (133, 142))
135447	33029866	58  However, increased FTO can decrease the tumour suppressor genes ASB2 and RARA and promote the proliferation of AML cells.	('AML', 'Disease', 'MESH:D015470', (115, 118))	('tumour', 'Disease', 'MESH:D009369', (44, 50))	('ASB2', 'Gene', (68, 72))	('FTO', 'Var', (23, 26))	('AML', 'Phenotype', 'HP:0004808', (115, 118))	('decrease', 'NegReg', (31, 39))	('AML', 'Disease', (115, 118))	('tumour', 'Disease', (44, 50))	('promote', 'PosReg', (86, 93))	('RARA', 'Gene', '5914', (77, 81))	('proliferation', 'CPA', (98, 111))	('RARA', 'Gene', (77, 81))	('tumour', 'Phenotype', 'HP:0002664', (44, 50))	('ASB2', 'Gene', '51676', (68, 72))
135449	33029866	m6A modification can regulate the occurrence and development of AML by regulating the mRNAs of critical genes in AML.	('regulating', 'Reg', (71, 81))	('mRNAs of critical genes', 'MPA', (86, 109))	('AML', 'Disease', 'MESH:D015470', (113, 116))	('regulate', 'Reg', (21, 29))	('AML', 'Disease', 'MESH:D015470', (64, 67))	('modification', 'Var', (4, 16))	('AML', 'Phenotype', 'HP:0004808', (113, 116))	('development', 'CPA', (49, 60))	('AML', 'Disease', (113, 116))	('AML', 'Phenotype', 'HP:0004808', (64, 67))	('AML', 'Disease', (64, 67))
135450	33029866	67  Compared with other epigenetic modifications, the m6A methylation in AML can be easily targeted chemical medications, thus providing a theoretical basis for the investigation of new drugs against AML.	('AML', 'Disease', 'MESH:D015470', (200, 203))	('AML', 'Disease', (73, 76))	('AML', 'Phenotype', 'HP:0004808', (73, 76))	('m6A methylation', 'Var', (54, 69))	('AML', 'Phenotype', 'HP:0004808', (200, 203))	('AML', 'Disease', (200, 203))	('AML', 'Disease', 'MESH:D015470', (73, 76))
135453	33029866	The blockade of METTL3 or METTL14 enhances the proliferation, self-renewal and tumorigenesis of glioblastoma stem cells (GSCs) concomitant with increased expressions of the ADAM19, EPHA3 and KLF4, and decreased expression of the tumour suppressor genes TP53I11, CDKN2A and BRCA2.	('tumour', 'Disease', 'MESH:D009369', (229, 235))	('tumour', 'Disease', (229, 235))	('EPHA3', 'Gene', (181, 186))	('blockade', 'Var', (4, 12))	('enhances', 'PosReg', (34, 42))	('self-renewal', 'CPA', (62, 74))	('proliferation', 'CPA', (47, 60))	('BRCA2', 'Gene', '12190', (273, 278))	('METTL14', 'Gene', (26, 33))	('METTL3', 'Gene', (16, 22))	('EPHA3', 'Gene', '13837', (181, 186))	('glioblastoma', 'Disease', 'MESH:D005909', (96, 108))	('ADAM19', 'Gene', (173, 179))	('tumor', 'Disease', (79, 84))	('expressions', 'MPA', (154, 165))	('glioblastoma', 'Disease', (96, 108))	('glioblastoma', 'Phenotype', 'HP:0012174', (96, 108))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('CDKN2A', 'Gene', '12578', (262, 268))	('ADAM19', 'Gene', '11492', (173, 179))	('increased', 'PosReg', (144, 153))	('CDKN2A', 'Gene', (262, 268))	('TP53I11', 'Gene', '277414', (253, 260))	('decreased', 'NegReg', (201, 210))	('BRCA2', 'Gene', (273, 278))	('tumour', 'Phenotype', 'HP:0002664', (229, 235))	('expression', 'MPA', (211, 221))	('TP53I11', 'Gene', (253, 260))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
135461	33029866	In turn, METTL3 increases the HBXIP level via stimulating its m6A modification, which creates a positive feedback loop of HBXIP/let-7g/METTL3/HBXIP, thus accelerating the malignant proliferation of BC cells.	('malignant proliferation of BC cells', 'CPA', (171, 206))	('HBXIP', 'Gene', (30, 35))	('HBXIP', 'Gene', '10542', (30, 35))	('stimulating', 'Reg', (46, 57))	('let-7g', 'Gene', '406890', (128, 134))	('HBXIP', 'Gene', '10542', (122, 127))	('m6A', 'Enzyme', (62, 65))	('HBXIP', 'Gene', (122, 127))	('accelerating', 'PosReg', (154, 166))	('HBXIP', 'Gene', (142, 147))	('HBXIP', 'Gene', '10542', (142, 147))	('increases', 'PosReg', (16, 25))	('METTL3', 'Var', (9, 15))	('let-7g', 'Gene', (128, 134))
135465	33029866	ALKBH5 deletion reverses hypoxia-induced BCSCs enrichment and tumorigenesis.	('ALKBH5', 'Gene', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', (62, 67))	('hypoxia', 'Disease', (25, 32))	('hypoxia', 'Disease', 'MESH:D000860', (25, 32))	('reverses', 'NegReg', (16, 24))	('ALKBH5', 'Gene', '54890', (0, 6))	('deletion', 'Var', (7, 15))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
135475	33029866	79  Mechanistically, METTL3 potentiates the degradation of SOCS2 mRNA (tumour suppressor gene) via the m6A-YTHDF2-dependent pathway.	('potentiates', 'PosReg', (28, 39))	('SOCS2', 'Gene', (59, 64))	('tumour', 'Disease', (71, 77))	('METTL3', 'Var', (21, 27))	('YTHDF2', 'Gene', '51441', (107, 113))	('degradation', 'MPA', (44, 55))	('SOCS2', 'Gene', '8835', (59, 64))	('tumour', 'Phenotype', 'HP:0002664', (71, 77))	('YTHDF2', 'Gene', (107, 113))	('tumour', 'Disease', 'MESH:D009369', (71, 77))
135476	33029866	79  Equally, METTL3-mediated m6A modification activates Wnt/beta-catenin signalling by promoting CTNNB1 expression to drive the growth of hepatoblastoma.	('drive', 'PosReg', (118, 123))	('modification', 'Var', (33, 45))	('promoting', 'PosReg', (87, 96))	('activates', 'PosReg', (46, 55))	('hepatoblastoma', 'Disease', 'MESH:D018197', (138, 152))	('hepatoblastoma', 'Disease', (138, 152))	('CTNNB1', 'Gene', '1499', (97, 103))	('hepatoblastoma', 'Phenotype', 'HP:0002884', (138, 152))	('beta-catenin', 'Gene', (60, 72))	('expression', 'MPA', (104, 114))	('beta-catenin', 'Gene', '1499', (60, 72))	('CTNNB1', 'Gene', (97, 103))	('growth', 'MPA', (128, 134))
135481	33029866	79  KIAA1429 inhibits ID2 expression and promotes the invasion and metastasis of HCC cells.	('metastasis of HCC cells', 'CPA', (67, 90))	('expression', 'MPA', (26, 36))	('ID2', 'Gene', '3398', (22, 25))	('ID2', 'Gene', (22, 25))	('promotes', 'PosReg', (41, 49))	('inhibits', 'NegReg', (13, 21))	('79  KIAA1429', 'Var', (0, 12))
135487	33029866	86 ,  87 ,  88 ,  89  P300-mediated H3K27 acetylation activation in the METTL3 promoter accounts for the ectopic expression of METTL3 in GC, leading to the enrichment m6A modification on HDGF mRNA.	('HDGF', 'Gene', (187, 191))	('METTL3', 'Gene', (127, 133))	('P300-mediated', 'Var', (22, 35))	('activation', 'PosReg', (54, 64))	('HDGF', 'Gene', '3068', (187, 191))	('H3K27', 'Protein', (36, 41))	('m6A', 'Var', (167, 170))	('acetylation', 'MPA', (42, 53))
135488	33029866	IGF2BP3 subsequently recognizes and binds to the methylated HDGF mRNA and augments the stability of HDGF mRNA.	('HDGF', 'Gene', '3068', (60, 64))	('stability', 'MPA', (87, 96))	('IGF2BP3', 'Gene', '10643', (0, 7))	('IGF2BP3', 'Gene', (0, 7))	('HDGF', 'Gene', '3068', (100, 104))	('HDGF', 'Gene', (60, 64))	('methylated', 'Var', (49, 59))	('HDGF', 'Gene', (100, 104))	('binds', 'Interaction', (36, 41))	('augments', 'NegReg', (74, 82))
135490	33029866	89  miRNA-4429 inhibits GC progression by targeting METTL3 to abrogate the m6A-mediated stabilization of SEC62 mRNA.	('miRNA-4429', 'Var', (4, 14))	('m6A-mediated stabilization', 'MPA', (75, 101))	('SEC62', 'Gene', (105, 110))	('GC progression', 'CPA', (24, 38))	('METTL3', 'Gene', (52, 58))	('targeting', 'Reg', (42, 51))	('inhibits', 'NegReg', (15, 23))	('SEC62', 'Gene', '7095', (105, 110))	('abrogate', 'NegReg', (62, 70))
135492	33029866	91  Jeopardizing m6A modification was associated with oncogene signalling and phenotypes by scrutinizing bioinformatics, 92  and overriding m6A with METTL14 silencing accelerated the proliferation and invasion of GC cells by activating Wnt/PI3K/Akt signalling, which was reversed by FTO depletion.	('Akt', 'Gene', '207', (245, 248))	('Akt', 'Gene', (245, 248))	('METTL14', 'Gene', (149, 156))	('proliferation', 'CPA', (183, 196))	('accelerated', 'PosReg', (167, 178))	('silencing', 'Var', (157, 166))	('activating', 'PosReg', (225, 235))	('invasion', 'CPA', (201, 209))
135493	33029866	92  In GC, low YTHDF2 expression retarded cell proliferation and promote cell apoptosis.	('cell apoptosis', 'CPA', (73, 87))	('YTHDF2', 'Gene', (15, 21))	('retarded', 'NegReg', (33, 41))	('cell proliferation', 'CPA', (42, 60))	('promote', 'PosReg', (65, 72))	('low', 'Var', (11, 14))	('YTHDF2', 'Gene', '51441', (15, 21))	('expression', 'MPA', (22, 32))
135494	33029866	93  Conclusively, histone modification and ncRNAs affects the expression and regulation of METTL3, contributing to better understand the physiological functions and regulatory mechanisms of METTL3 in cancers.	('METTL3', 'Gene', (91, 97))	('affects', 'Reg', (50, 57))	('cancers', 'Disease', 'MESH:D009369', (200, 207))	('cancers', 'Phenotype', 'HP:0002664', (200, 207))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('cancers', 'Disease', (200, 207))	('expression', 'MPA', (62, 72))	('histone modification', 'Var', (18, 38))	('regulation', 'MPA', (77, 87))
135504	33029866	The blockade of YTHDF1 suppresses cell proliferation and enhances the chemosensitivity of cancer cells to 5-fluorouracil (5-FU) and L-OHP.	('5-FU', 'Chemical', 'MESH:D005472', (122, 126))	('cell proliferation', 'CPA', (34, 52))	('YTHDF1', 'Gene', '54915', (16, 22))	('YTHDF1', 'Gene', (16, 22))	('L-OHP', 'Chemical', 'MESH:D000077150', (132, 137))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('suppresses', 'NegReg', (23, 33))	('enhances', 'PosReg', (57, 65))	('blockade', 'Var', (4, 12))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (106, 120))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))
135507	33029866	99  YTHDF2 promotes the metastasis of CRC by promoting the HIF-1alpha translation, and knocking out YTHDF2 can weaken HIF-1alpha expression and inhibit the metastasis of CRC cells in vitro and in vivo.	('HIF-1alpha', 'Gene', '3091', (59, 69))	('metastasis of CRC cells', 'CPA', (156, 179))	('knocking out', 'Var', (87, 99))	('expression', 'MPA', (129, 139))	('promoting', 'PosReg', (45, 54))	('HIF-1alpha', 'Gene', (59, 69))	('YTHDF2', 'Gene', '51441', (100, 106))	('HIF-1alpha', 'Gene', (118, 128))	('YTHDF2', 'Gene', '51441', (4, 10))	('YTHDF2', 'Gene', (4, 10))	('weaken', 'NegReg', (111, 117))	('inhibit', 'NegReg', (144, 151))	('YTHDF2', 'Gene', (100, 106))	('CRC', 'Disease', (38, 41))	('metastasis', 'CPA', (24, 34))	('HIF-1alpha', 'Gene', '3091', (118, 128))
135511	33029866	101  METTL3 silencing expedites cell apoptosis via AKT signalling pathway and inhibits the proliferation, migration and invasion of lung cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('cell apoptosis', 'CPA', (32, 46))	('METTL3', 'Gene', (5, 11))	('expedites', 'PosReg', (22, 31))	('AKT', 'Gene', (51, 54))	('lung cancer', 'Disease', 'MESH:D008175', (132, 143))	('silencing', 'Var', (12, 21))	('lung cancer', 'Disease', (132, 143))	('lung cancer', 'Phenotype', 'HP:0100526', (132, 143))	('inhibits', 'NegReg', (78, 86))	('AKT', 'Gene', '207', (51, 54))
135517	33029866	104  The knockdown of FTO inhibits the proliferation of lung cancer cells by modulating the mRNA stability of USP7 via FTO-mediated m6A demethylase.	('inhibits', 'NegReg', (26, 34))	('USP7', 'Gene', (110, 114))	('knockdown', 'Var', (9, 18))	('lung cancer', 'Disease', 'MESH:D008175', (56, 67))	('FTO', 'Gene', (22, 25))	('demethylase', 'Gene', (136, 147))	('demethylase', 'Gene', '8932', (136, 147))	('lung cancer', 'Phenotype', 'HP:0100526', (56, 67))	('proliferation', 'CPA', (39, 52))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('mRNA stability', 'MPA', (92, 106))	('lung cancer', 'Disease', (56, 67))	('modulating', 'Reg', (77, 87))	('USP7', 'Gene', '7874', (110, 114))
135521	33029866	Intermittent hypoxia-induced ALKBH5 amplification in lung adenocarcinoma promotes cell proliferation and invasion by decreasing the m6A level of FOXM1 mRNA and increasing the translation of FOXM1 mRNA.	('FOXM1', 'Gene', '2305', (145, 150))	('increasing', 'PosReg', (160, 170))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (53, 72))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))	('invasion', 'CPA', (105, 113))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (53, 72))	('FOXM1', 'Gene', '2305', (190, 195))	('cell proliferation', 'CPA', (82, 100))	('amplification', 'Var', (36, 49))	('FOXM1', 'Gene', (145, 150))	('ALKBH5', 'Gene', (29, 35))	('hypoxia', 'Disease', (13, 20))	('translation', 'MPA', (175, 186))	('promotes', 'PosReg', (73, 81))	('m6A level', 'MPA', (132, 141))	('ALKBH5', 'Gene', '54890', (29, 35))	('FOXM1', 'Gene', (190, 195))	('lung adenocarcinoma', 'Disease', (53, 72))	('hypoxia', 'Disease', 'MESH:D000860', (13, 20))	('decreasing', 'NegReg', (117, 127))
135522	33029866	106   Enrichment of m6A modification is associated with bladder cancer.	('m6A modification', 'Var', (20, 36))	('bladder cancer', 'Phenotype', 'HP:0009725', (56, 70))	('bladder cancer', 'Disease', (56, 70))	('associated', 'Reg', (40, 50))	('bladder cancer', 'Disease', 'MESH:D001749', (56, 70))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
135525	33029866	108  The ectopic expression of METTL3 potentiates bladder cancer progression through the AFF4/NF-kappaB/MYC network.	('ectopic expression', 'Var', (9, 27))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('bladder cancer', 'Disease', 'MESH:D001749', (50, 64))	('MYC', 'Gene', (104, 107))	('AFF4', 'Gene', (89, 93))	('bladder cancer', 'Disease', (50, 64))	('METTL3', 'Gene', (31, 37))	('MYC', 'Gene', '4609', (104, 107))	('AFF4', 'Gene', '27125', (89, 93))	('NF-kappaB', 'Gene', '4790', (94, 103))	('potentiates', 'PosReg', (38, 49))	('NF-kappaB', 'Gene', (94, 103))	('bladder cancer', 'Phenotype', 'HP:0009725', (50, 64))
135526	33029866	109   m6A abnormity plays a crucial role in ccRCC.	('RCC', 'Disease', 'MESH:C538614', (46, 49))	('109   m6A', 'Var', (0, 9))	('RCC', 'Disease', (46, 49))
135527	33029866	PI3K/mTOR and p53 pathways may function as downstream targets of m6A modification in RCC.	('p53', 'Gene', (14, 17))	('p53', 'Gene', '7157', (14, 17))	('mTOR', 'Gene', (5, 9))	('RCC', 'Disease', 'MESH:C538614', (85, 88))	('mTOR', 'Gene', '2475', (5, 9))	('modification', 'Var', (69, 81))	('RCC', 'Disease', (85, 88))	('m6A', 'Gene', (65, 68))
135533	33029866	113   The expression of METTL3 increases at both protein and mRNA levels in pancreatic cancer; METTL3 knockdown inhibits cell proliferation, invasion and migration.	('METTL3', 'Gene', (24, 30))	('pancreatic cancer', 'Disease', (76, 93))	('increases', 'PosReg', (31, 40))	('expression', 'MPA', (10, 20))	('cell proliferation', 'CPA', (121, 139))	('knockdown', 'Var', (102, 111))	('pancreatic cancer', 'Disease', 'MESH:D010190', (76, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('inhibits', 'NegReg', (112, 120))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (76, 93))	('METTL3', 'Gene', (95, 101))
135534	33029866	114  Pancreatic cancer cells with METTL3 silencing are more susceptible to irradiation, gemcitabine, 5-FU and L-OHP, but cell morphology and proliferation are not affected.	('gemcitabine', 'Chemical', 'MESH:C056507', (88, 99))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('silencing', 'Var', (41, 50))	('METTL3', 'Gene', (34, 40))	('Pancreatic cancer', 'Disease', 'MESH:D010190', (5, 22))	('L-OHP', 'Chemical', 'MESH:D000077150', (110, 115))	('Pancreatic cancer', 'Phenotype', 'HP:0002894', (5, 22))	('L-OHP', 'MPA', (110, 115))	('5-FU', 'MPA', (101, 105))	('5-FU', 'Chemical', 'MESH:D005472', (101, 105))	('Pancreatic cancer', 'Disease', (5, 22))	('more', 'PosReg', (55, 59))	('gemcitabine', 'MPA', (88, 99))	('susceptible', 'MPA', (60, 71))
135545	33029866	m6A modification is frequently found at low levels in gynaecological cancers, such as endometrial cancer, 120  cervical cancer 121 ,  122 ,  123  and epithelial ovarian cancer.	('cancer', 'Disease', (169, 175))	('endometrial cancer', 'Phenotype', 'HP:0012114', (86, 104))	('cancer', 'Disease', (120, 126))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('cancer', 'Disease', (98, 104))	('epithelial ovarian cancer', 'Phenotype', 'HP:0025318', (150, 175))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('m6A', 'Var', (0, 3))	('cancers', 'Disease', 'MESH:D009369', (69, 76))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('endometrial cancer', 'Disease', (86, 104))	('endometrial cancer', 'Disease', 'MESH:D016889', (86, 104))	('epithelial ovarian cancer', 'Disease', (150, 175))	('122', 'Disease', (134, 137))	('cancer', 'Disease', 'MESH:D009369', (169, 175))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('epithelial ovarian cancer', 'Disease', 'MESH:D000077216', (150, 175))	('cancers', 'Phenotype', 'HP:0002664', (69, 76))	('cancer', 'Disease', (69, 75))	('cancers', 'Disease', (69, 76))	('cervical cancer 121', 'Phenotype', 'HP:0030159', (111, 130))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('ovarian cancer', 'Phenotype', 'HP:0100615', (161, 175))
135546	33029866	124  Low m6A level, as an independent prognostic indicator, was found to be associated with cancer progression and poor outcome through screening 286 cervical cancer samples, and augmenting m6A modification with the FTO inhibitor MA2 suppressed the tumour development in mouse models.	('cancer', 'Disease', (159, 165))	('tumour', 'Phenotype', 'HP:0002664', (249, 255))	('tumour', 'Disease', 'MESH:D009369', (249, 255))	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('mouse', 'Species', '10090', (271, 276))	('suppressed', 'NegReg', (234, 244))	('associated', 'Reg', (76, 86))	('augmenting m6A modification', 'Var', (179, 206))	('tumour', 'Disease', (249, 255))	('Low', 'NegReg', (5, 8))	('MA2', 'Chemical', 'MESH:C029090', (230, 233))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('m6A level', 'MPA', (9, 18))
135548	33029866	121 ,  123  Patients with cervical cancer and co-expression of FTO and beta-catenin have a worse prognosis.	('Patients', 'Species', '9606', (12, 20))	('FTO', 'Gene', (63, 66))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('co-expression', 'Var', (46, 59))	('beta-catenin', 'Gene', (71, 83))	('cancer', 'Disease', (35, 41))	('beta-catenin', 'Gene', '1499', (71, 83))
135556	33029866	Administration of cSCC cells with the methylation inhibitor cycloleucine or silencing METTL3 expression affects the colony-forming efficiency in vitro and carcinogenesis in vivo partly through modulating DeltaNp63 in an m6A-dependent manner.	('DeltaNp63', 'MPA', (204, 213))	('cycloleucine', 'Chemical', 'MESH:D003515', (60, 72))	('silencing', 'Var', (76, 85))	('DeltaNp63', 'Chemical', '-', (204, 213))	('METTL3', 'Gene', (86, 92))	('carcinogenesis', 'Disease', 'MESH:D063646', (155, 169))	('colony-forming efficiency', 'CPA', (116, 141))	('cSCC', 'Phenotype', 'HP:0006739', (18, 22))	('affects', 'Reg', (104, 111))	('modulating', 'Reg', (193, 203))	('carcinogenesis', 'Disease', (155, 169))
135559	33029866	Zhang et al uncovered that the ZNF750/FGF14 axis accelerated cell apoptosis and inhibited the growth of nasopharyngeal carcinoma in vitro and in vivo; METTL3-dependent m6A modification was enriched in the CDS of ZNF750 mRNAs and impaired ZNF750 expression, 127  thus proving the oncogene role of METTL3 in nasopharyngeal carcinoma.	('carcinoma', 'Disease', (321, 330))	('ZNF750', 'Gene', (31, 37))	('modification', 'Var', (172, 184))	('ZNF750', 'Gene', '79755', (212, 218))	('ZNF750', 'Gene', (212, 218))	('carcinoma', 'Disease', 'MESH:D009369', (321, 330))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (306, 330))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('FGF14', 'Gene', (38, 43))	('METTL3-dependent', 'Var', (151, 167))	('carcinoma', 'Disease', (119, 128))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (104, 128))	('growth', 'CPA', (94, 100))	('inhibited', 'NegReg', (80, 89))	('cell apoptosis', 'CPA', (61, 75))	('ZNF750', 'Gene', '79755', (238, 244))	('FGF14', 'Gene', '2259', (38, 43))	('m6A modification', 'Var', (168, 184))	('carcinoma', 'Disease', 'MESH:D009369', (119, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (321, 330))	('ZNF750', 'Gene', (238, 244))	('ZNF750', 'Gene', '79755', (31, 37))
135565	33029866	115  CRC cells with YTHDF1 silencing are more sensitive to L-OHP and 5-FU.	('L-OHP', 'MPA', (59, 64))	('silencing', 'Var', (27, 36))	('5-FU', 'MPA', (69, 73))	('YTHDF1', 'Gene', '54915', (20, 26))	('YTHDF1', 'Gene', (20, 26))	('5-FU', 'Chemical', 'MESH:D005472', (69, 73))	('L-OHP', 'Chemical', 'MESH:D000077150', (59, 64))	('sensitive', 'MPA', (46, 55))
135567	33029866	The aforementioned findings on m6A methylation and chemotherapeutic drugs provide a promising strategy for tumour therapy.	('tumour', 'Phenotype', 'HP:0002664', (107, 113))	('tumour', 'Disease', 'MESH:D009369', (107, 113))	('methylation', 'Var', (35, 46))	('m6A', 'Gene', (31, 34))	('tumour', 'Disease', (107, 113))
135572	33029866	Moreover, N-CDPCB, CHTB and entacapone can also exert potent suppressive activities against FTO.	('N-CDPCB', 'Var', (10, 17))	('FTO', 'Disease', (92, 95))	('entacapone', 'Chemical', 'MESH:C071192', (28, 38))	('N-CDPCB', 'Chemical', '-', (10, 17))	('suppressive activities', 'CPA', (61, 83))
135573	33029866	130 ,  133 ,  137 ,  138  As the first obesity-related gene identified by genome-wide association analysis analysis, 28  not only FTO is closely associated with obesity and tumour, but also its common variant rs9939609 may be associated with central nervous system diseases, such as brain volume loss and alcohol dependence.	('alcohol dependence', 'Phenotype', 'HP:0030955', (305, 323))	('tumour', 'Disease', (173, 179))	('obesity', 'Phenotype', 'HP:0001513', (161, 168))	('obesity', 'Disease', 'MESH:D009765', (39, 46))	('rs9939609', 'Var', (209, 218))	('rs9939609', 'Mutation', 'rs9939609', (209, 218))	('central nervous system diseases', 'Disease', (242, 273))	('brain volume loss', 'Disease', (283, 300))	('alcohol dependence', 'Disease', 'MESH:D000437', (305, 323))	('FTO', 'Gene', (130, 133))	('central nervous system diseases', 'Disease', 'MESH:D002493', (242, 273))	('obesity', 'Disease', (161, 168))	('obesity', 'Phenotype', 'HP:0001513', (39, 46))	('central nervous system diseases', 'Phenotype', 'HP:0002011', (242, 273))	('first obesity', 'Phenotype', 'HP:0025499', (33, 46))	('obesity', 'Disease', 'MESH:D009765', (161, 168))	('alcohol dependence', 'Disease', (305, 323))	('associated', 'Reg', (226, 236))	('obesity', 'Disease', (39, 46))	('associated', 'Reg', (145, 155))	('tumour', 'Phenotype', 'HP:0002664', (173, 179))	('tumour', 'Disease', 'MESH:D009369', (173, 179))
135580	33029866	m6A modification, as a "double-edged sword", can promote or inhibit the initiation and progression of tumours mainly by regulating mRNA levels of oncogenes or tumour suppressor genes.	('tumour', 'Disease', (159, 165))	('tumour', 'Phenotype', 'HP:0002664', (102, 108))	('mRNA levels of', 'MPA', (131, 145))	('m6A modification', 'Var', (0, 16))	('inhibit', 'NegReg', (60, 67))	('regulating', 'Reg', (120, 130))	('tumour', 'Disease', 'MESH:D009369', (102, 108))	('tumours', 'Phenotype', 'HP:0002664', (102, 109))	('tumours', 'Disease', 'MESH:D009369', (102, 109))	('tumour', 'Disease', (102, 108))	('modification', 'Var', (4, 16))	('tumour', 'Phenotype', 'HP:0002664', (159, 165))	('promote', 'PosReg', (49, 56))	('tumour', 'Disease', 'MESH:D009369', (159, 165))	('tumours', 'Disease', (102, 109))
135581	33029866	However, whether m6A modification is implicated in a tumour microenvironment has not been reported.	('tumour', 'Disease', (53, 59))	('tumour', 'Phenotype', 'HP:0002664', (53, 59))	('tumour', 'Disease', 'MESH:D009369', (53, 59))	('m6A', 'Var', (17, 20))
135630	32079077	The aim of this retrospective study was to analyze the appearance of HNE-protein adducts in oropharyngeal squamous cell carcinoma and to confirm the assumed onset of oxidative stress and lipid peroxidation in its carcinogenesis.	('adducts', 'Var', (81, 88))	('oropharyngeal squamous cell carcinoma', 'Disease', 'MESH:D002294', (92, 129))	('oropharyngeal squamous cell carcinoma', 'Phenotype', 'HP:0012182', (92, 129))	('carcinogenesis', 'Disease', 'MESH:D063646', (213, 227))	('HNE', 'Chemical', 'MESH:C027576', (69, 72))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('HNE-protein', 'Protein', (69, 80))	('carcinogenesis', 'Disease', (213, 227))	('oxidative stress', 'Phenotype', 'HP:0025464', (166, 182))	('lipid', 'Chemical', 'MESH:D008055', (187, 192))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (106, 129))	('oropharyngeal squamous cell carcinoma', 'Disease', (92, 129))
135680	32079077	Namely, the phenomenon of spontaneous regression of W256 murine tumors was found to be associated with pronounced oxidative bust and anticancer activities of neutrophil granulocytes generating HNE and acrolein, resembling the effects of granulocytes and HNE on melanoma B16, while in patients with metastatic lung cancer the onset of inflammation related to the invading metastatic cancer and the accumulation of HNE-protein adducts were found to be more pronounced than in the case of primary lung cancer.	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('patients', 'Species', '9606', (284, 292))	('primary lung cancer', 'Disease', 'MESH:D008175', (486, 505))	('HNE', 'Chemical', 'MESH:C027576', (254, 257))	('lung cancer', 'Disease', (309, 320))	('cancer', 'Disease', (137, 143))	('lung cancer', 'Disease', 'MESH:D008175', (494, 505))	('melanoma', 'Phenotype', 'HP:0002861', (261, 269))	('W256', 'Var', (52, 56))	('melanoma', 'Disease', (261, 269))	('cancer', 'Disease', 'MESH:D009369', (314, 320))	('acrolein', 'Chemical', 'MESH:D000171', (201, 209))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('tumors', 'Disease', (64, 70))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('lung cancer', 'Phenotype', 'HP:0100526', (494, 505))	('primary lung cancer', 'Disease', (486, 505))	('cancer', 'Disease', (382, 388))	('cancer', 'Phenotype', 'HP:0002664', (382, 388))	('neutrophil granulocytes', 'Phenotype', 'HP:0032310', (158, 181))	('inflammation', 'Disease', 'MESH:D007249', (334, 346))	('lung cancer', 'Disease', 'MESH:D008175', (309, 320))	('cancer', 'Disease', (499, 505))	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('cancer', 'Phenotype', 'HP:0002664', (499, 505))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('oxidative bust', 'MPA', (114, 128))	('lung cancer', 'Phenotype', 'HP:0100526', (309, 320))	('HNE', 'Chemical', 'MESH:C027576', (193, 196))	('melanoma', 'Disease', 'MESH:D008545', (261, 269))	('inflammation', 'Disease', (334, 346))	('cancer', 'Disease', 'MESH:D009369', (382, 388))	('murine', 'Species', '10090', (57, 63))	('cancer', 'Disease', (314, 320))	('cancer', 'Phenotype', 'HP:0002664', (314, 320))	('HNE', 'Chemical', 'MESH:C027576', (413, 416))	('cancer', 'Disease', 'MESH:D009369', (499, 505))
135718	31145232	In the past decades, molecular targeted therapy had led to a great shift in the treatment landscape of advanced lung cancer patients harboring genetic aberrations, such as EGFR mutation and ALK translocation.	('ALK', 'Gene', (190, 193))	('EGFR', 'Gene', '1956', (172, 176))	('mutation', 'Var', (177, 185))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('EGFR', 'Gene', (172, 176))	('lung cancer', 'Phenotype', 'HP:0100526', (112, 123))	('ALK', 'Gene', '238', (190, 193))	('advanced lung cancer', 'Disease', 'MESH:D008175', (103, 123))	('advanced lung cancer', 'Disease', (103, 123))	('patients', 'Species', '9606', (124, 132))
135733	31145232	We classified PD-L1 expression on TC into 4 levels: PD-L1 TPS <1%, PD-L1 TPS 1%-49%, and PD-L1 TPS >=50%.	('TPS', 'Var', (73, 76))	('PD-L1 TPS', 'Var', (67, 76))	('TC', 'Chemical', '-', (34, 36))
135771	31145232	MicroRNA-197 regulates lung cancer drug resistance and tumor progression by directly targeting the cyclin-dependent kinase CKS1B as well as by indirectly targeting the transcription factor STAT3.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('lung cancer', 'Disease', (23, 34))	('lung cancer', 'Phenotype', 'HP:0100526', (23, 34))	('MicroRNA-197', 'Var', (0, 12))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('targeting', 'Reg', (85, 94))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('drug resistance', 'Phenotype', 'HP:0020174', (35, 50))	('CKS1B', 'Gene', '1163', (123, 128))	('targeting', 'Reg', (154, 163))	('tumor', 'Disease', (55, 60))	('CKS1B', 'Gene', (123, 128))	('regulates', 'Reg', (13, 22))	('lung cancer', 'Disease', 'MESH:D008175', (23, 34))	('STAT3', 'Gene', '6774', (189, 194))	('STAT3', 'Gene', (189, 194))
135775	31145232	Presently, non-small cell lung cancer patients with low PD-L1 expression may receive immunotherapy after chemotherapy.	('non-small cell lung cancer', 'Disease', (11, 37))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (15, 37))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('lung cancer', 'Phenotype', 'HP:0100526', (26, 37))	('receive', 'Reg', (77, 84))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (11, 37))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (11, 37))	('patients', 'Species', '9606', (38, 46))	('PD-L1', 'Gene', (56, 61))	('low', 'Var', (52, 55))
135782	30367091	Here, we conducted our data mining analysis for LUSC by integrating the differentially expressed genes acquired from Gene Expression Omnibus (GEO) database by comparing tumor tissues versus normal tissues (GSE8569, GSE21933, GSE33479, GSE33532, GSE40275, GSE62113, GSE74706) into The Cancer Genome Atlas (TCGA) database which includes 502 tumors and 49 adjacent non-tumor lung tissues.	('tumor', 'Disease', (339, 344))	('GSE33479', 'Var', (225, 233))	('GSE33532', 'Var', (235, 243))	('GSE21933', 'Var', (215, 223))	('tumor', 'Disease', 'MESH:D009369', (339, 344))	('GSE8569', 'Chemical', '-', (206, 213))	('tumors', 'Phenotype', 'HP:0002664', (339, 345))	('GSE8569', 'Var', (206, 213))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (284, 303))	('LUSC', 'Phenotype', 'HP:0030359', (48, 52))	('tumor', 'Disease', (169, 174))	('tumor', 'Phenotype', 'HP:0002664', (339, 344))	('Cancer Genome Atlas', 'Disease', (284, 303))	('tumor', 'Disease', (366, 371))	('tumors', 'Disease', (339, 345))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('GSE40275', 'Var', (245, 253))	('tumor', 'Disease', 'MESH:D009369', (366, 371))	('GSE62113', 'Var', (255, 263))	('tumor lung', 'Phenotype', 'HP:0100526', (366, 376))	('tumors', 'Disease', 'MESH:D009369', (339, 345))	('Cancer', 'Phenotype', 'HP:0002664', (284, 290))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('tumor', 'Phenotype', 'HP:0002664', (366, 371))
135791	30367091	Besides, datasets GSE40275 and GSE61223 only have 5 and 2 tumor samples respectively and using few samples can affect the performance of statistical analysis and provides unreliable results.	('GSE61223', 'Var', (31, 39))	('tumor', 'Disease', (58, 63))	('GSE40275', 'Var', (18, 26))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('affect', 'Reg', (111, 117))	('tumor', 'Disease', 'MESH:D009369', (58, 63))
135802	30367091	The results showed that normal samples vs. tumor samples in the datasets (GSE8569, GSE21933, GSE33532, GSE40275, GSE62113, GSE74706) displayed a significant difference except for dataset GSE33479, whose two tumor samples GSM828337 and GSM828345 were close to normal samples, so we removed these two samples for the subsequent analysis (Fig.	('GSE74706', 'Var', (123, 131))	('GSE40275', 'Var', (103, 111))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('GSE8569', 'Chemical', '-', (74, 81))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('GSE62113', 'Var', (113, 121))	('GSE21933', 'Var', (83, 91))	('GSM828345', 'Chemical', '-', (235, 244))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('GSE33532', 'Var', (93, 101))	('tumor', 'Disease', (43, 48))	('tumor', 'Disease', (207, 212))	('GSE8569', 'Var', (74, 81))	('GSM828337', 'Chemical', '-', (221, 230))
135817	30367091	We also found that LncRNAs KC6, PART1, SFTA1P, and SNHG1 were statistically related to the overall survival rate (Supplementary Fig.	('SNHG1', 'Gene', '23642', (51, 56))	('KC6', 'Gene', (27, 30))	('SNHG1', 'Gene', (51, 56))	('SFTA1P', 'Gene', '207107', (39, 45))	('SFTA1P', 'Gene', (39, 45))	('LncRNAs', 'Var', (19, 26))	('KC6', 'Gene', '641516', (27, 30))	('related', 'Reg', (76, 83))
135820	30367091	The mutations of epidermal growth factor receptor (EGFR) kinase, as well as fusions in the anaplastic lymphoma kinase (ALK), lead to a dramatic change in the treatment of patients with lung adenocarcinoma.	('lung adenocarcinoma', 'Disease', (185, 204))	('carcinoma', 'Phenotype', 'HP:0030731', (195, 204))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (185, 204))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (91, 110))	('anaplastic lymphoma kinase', 'Gene', (91, 117))	('EGFR', 'Gene', (51, 55))	('change', 'Reg', (144, 150))	('fusions', 'Var', (76, 83))	('ALK', 'Gene', (119, 122))	('lymphoma', 'Phenotype', 'HP:0002665', (102, 110))	('epidermal growth factor receptor', 'Gene', '1956', (17, 49))	('patients', 'Species', '9606', (171, 179))	('EGFR', 'Gene', '1956', (51, 55))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (185, 204))	('ALK', 'Gene', '238', (119, 122))	('mutations', 'Var', (4, 13))	('anaplastic lymphoma kinase', 'Gene', '238', (91, 117))	('epidermal growth factor receptor', 'Gene', (17, 49))
135821	30367091	Unfortunately, EGFR mutations and ALK fusions are typically not present in LUSC, and novel targeted agents for adenocarcinoma of the lung ineffective against LUSC.	('ALK', 'Gene', '238', (34, 37))	('EGFR', 'Gene', '1956', (15, 19))	('ALK', 'Gene', (34, 37))	('EGFR', 'Gene', (15, 19))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('adenocarcinoma of the lung', 'Disease', (111, 137))	('LUSC', 'Phenotype', 'HP:0030359', (75, 79))	('adenocarcinoma of the lung', 'Disease', 'MESH:D000077192', (111, 137))	('LUSC', 'Phenotype', 'HP:0030359', (158, 162))	('mutations', 'Var', (20, 29))
135822	30367091	In our present studies, PCA results showed that tumor groups were independent of normal groups in each of the seven datasets (GSE8569, GSE21933, GSE33479, GSE33532, GSE40275, GSE62113, GSE74706).	('GSE40275', 'Var', (165, 173))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('GSE33479', 'Var', (145, 153))	('tumor', 'Disease', (48, 53))	('GSE74706', 'Var', (185, 193))	('GSE33532', 'Var', (155, 163))	('GSE62113', 'Var', (175, 183))	('GSE8569', 'Chemical', '-', (126, 133))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('GSE21933', 'Var', (135, 143))	('GSE8569', 'Var', (126, 133))
135823	30367091	Previously studies confirmed that the skewed X chromosome inactivation was associated with early development of lung cancer in females.	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('early development', 'CPA', (91, 108))	('lung cancer', 'Disease', (112, 123))	('lung cancer', 'Phenotype', 'HP:0100526', (112, 123))	('skewed X chromosome inactivation', 'Var', (38, 70))	('lung cancer', 'Disease', 'MESH:D008175', (112, 123))	('associated', 'Reg', (75, 85))
135825	30367091	Our results indicated that the dysregulation of FHL1 and FIGF on X chromosome may be associated with LUSC in females.	('LUSC', 'Phenotype', 'HP:0030359', (101, 105))	('FHL1', 'Gene', (48, 52))	('LUSC', 'Disease', (101, 105))	('FHL1', 'Gene', '2273', (48, 52))	('dysregulation', 'Var', (31, 44))	('FIGF', 'Gene', (57, 61))	('associated', 'Reg', (85, 95))
135830	30367091	Above are critical cellular processes for maintenance of cell homeostasis, dysregulation of these processes tends to promote carcinogenesis.	('promote', 'PosReg', (117, 124))	('carcinogenesis', 'Disease', (125, 139))	('carcinogenesis', 'Disease', 'MESH:D063646', (125, 139))	('dysregulation', 'Var', (75, 88))
135841	30367091	Previous studies reported that PART1 was associated with poor prognosis and tumor recurrence in stage I-III non-small cell lung cancer.	('lung cancer', 'Phenotype', 'HP:0100526', (123, 134))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('PART1', 'Var', (31, 36))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (112, 134))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (108, 134))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('cell lung cancer', 'Disease', (118, 134))	('cell lung cancer', 'Disease', 'MESH:D008175', (118, 134))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
135873	28796401	DMEM (11960-077), sodium pyruvate, (11360-070), L-Glutamine (25030-164), penicillin-streptomycin solution (15140-122) and 0.25% trypsin-EDTA (25200-056) were purchased from Gibco (Grand Island, NY).	('penicillin', 'Chemical', 'MESH:D010406', (73, 83))	('DMEM', 'Chemical', '-', (0, 4))	('11360-070', 'Var', (36, 45))	('L-Glutamine', 'Chemical', 'MESH:D005973', (48, 59))	('sodium pyruvate', 'Chemical', '-', (18, 33))	('11960-077', 'Var', (6, 15))	('streptomycin', 'Chemical', 'MESH:D013307', (84, 96))	('EDTA', 'Chemical', 'MESH:D004492', (136, 140))	('15140-122', 'Var', (107, 116))	('25030-164', 'Var', (61, 70))
135875	28796401	Procaspase-9 (9502), procaspase-8 (9746) and procaspase-3 (9665) antibodies were from Cell Signaling (Danvers, MA) and the PARP antibody (556494) was from BD Pharmingen (San Diego, CA).	('procaspase-8', 'Gene', (21, 33))	('556494', 'Var', (138, 144))	('procaspase-3', 'Gene', (45, 57))	('9502', 'Var', (14, 18))	('9746', 'Var', (35, 39))	('procaspase-3', 'Gene', '836', (45, 57))
135908	28796401	1A/B shows that SFN and cisplatin markedly suppress SCC-13 cell proliferation at concentrations of 10 microM and 5 microM, respectively.	('rat', 'Species', '10116', (71, 74))	('rat', 'Species', '10116', (88, 91))	('suppress', 'NegReg', (43, 51))	('SCC-13 cell proliferation', 'CPA', (52, 77))	('SCC-13', 'CellLine', 'CVCL:4029', (52, 58))	('cisplatin', 'Chemical', 'MESH:D002945', (24, 33))	('1A/B', 'Var', (0, 4))	('1A/B', 'SUBSTITUTION', 'None', (0, 4))
135909	28796401	1C/D shows that SFN and cisplatin suppress SCC-13 spheroid formation at concentrations of 0.5 microM and 0.05 microM, respectively.	('1C/D', 'SUBSTITUTION', 'None', (0, 4))	('1C/D', 'Var', (0, 4))	('SCC-13', 'CellLine', 'CVCL:4029', (43, 49))	('SCC-13 spheroid formation', 'CPA', (43, 68))	('rat', 'Species', '10116', (79, 82))	('suppress', 'NegReg', (34, 42))	('cisplatin', 'Chemical', 'MESH:D002945', (24, 33))
135911	28796401	In addition, combined treatment with 0.5 microM SFN and 0.5 microM cisplatin produces a more dramatic reduction in spheroid number than treatment with each individual agent (Fig.	('0.5', 'Var', (56, 59))	('reduction', 'NegReg', (102, 111))	('cisplatin', 'Gene', (67, 76))	('cisplatin', 'Chemical', 'MESH:D002945', (67, 76))	('spheroid number', 'CPA', (115, 130))
135918	28796401	1H/I shows that 5 microM SFN and 1 microM cisplatin produce a more substantial reduction in matrigel invasion.	('cisplatin', 'Chemical', 'MESH:D002945', (42, 51))	('1H/I', 'SUBSTITUTION', 'None', (0, 4))	('1H/I', 'Var', (0, 4))	('matrigel invasion', 'CPA', (92, 109))	('reduction', 'NegReg', (79, 88))
135923	28796401	2A/B shows that cisplatin and SFN reduce tumor size and the combination produces a more substantial reduction.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Disease', (41, 46))	('2A/B', 'SUBSTITUTION', 'None', (0, 4))	('reduce', 'NegReg', (34, 40))	('2A/B', 'Var', (0, 4))	('cisplatin', 'Chemical', 'MESH:D002945', (16, 25))	('tumor', 'Disease', 'MESH:D009369', (41, 46))
135938	28796401	3F/G shows that both agents suppress matrigel invasion and that combined treatment further suppresses invasion.	('suppress', 'NegReg', (28, 36))	('3F/G', 'SUBSTITUTION', 'None', (0, 4))	('3F/G', 'Var', (0, 4))	('suppresses', 'NegReg', (91, 101))	('matrigel invasion', 'CPA', (37, 54))	('invasion', 'CPA', (102, 110))
135946	28796401	It is interesting that p21Cip1 level is markedly increased by SFN treated cells, but not in cisplatin or combination-treated cells (Fig.	('p21Cip1', 'Gene', '1026', (23, 30))	('increased', 'PosReg', (49, 58))	('cisplatin', 'Chemical', 'MESH:D002945', (92, 101))	('p21Cip1', 'Gene', (23, 30))	('SFN', 'Var', (62, 65))
135992	33084541	Methylation profile analysis found 4 CpG sites (cg12199376, cg14437634, cg17641252, and cg06724236) had at least a weakly negative correlation with PLEK2 expression, among which cg12199376, cg14437634 and cg17641252 locate around the first exon of the gene.	('cg17641252', 'Var', (205, 215))	('cg14437634', 'Chemical', '-', (190, 200))	('cg12199376', 'Chemical', '-', (178, 188))	('cg14437634', 'Var', (190, 200))	('cg12199376', 'Chemical', '-', (48, 58))	('cg17641252', 'Chemical', '-', (72, 82))	('negative', 'NegReg', (122, 130))	('PLEK2', 'Gene', (148, 153))	('cg06724236', 'Var', (88, 98))	('cg14437634', 'Var', (60, 70))	('PLEK2', 'Gene', '26499', (148, 153))	('cg17641252', 'Chemical', '-', (205, 215))	('cg14437634', 'Chemical', '-', (60, 70))	('cg12199376', 'Var', (178, 188))	('cg12199376', 'Var', (48, 58))	('cg17641252', 'Var', (72, 82))	('expression', 'MPA', (154, 164))
136020	33084541	Two-sided Fisher's exact test was performed by analyzing the difference in clinicopathological parameters and PFS between patients with high and low PLEK2 expression.	('high', 'Var', (136, 140))	('PLEK2', 'Gene', (149, 154))	('patients', 'Species', '9606', (122, 130))	('low', 'NegReg', (145, 148))	('PLEK2', 'Gene', '26499', (149, 154))
136032	33084541	Using the same cutoff in Figure 3, we confirmed that LUAD patients with high PLEK2 expression had significantly worse PFS (Figure 4B).	('LUAD', 'Phenotype', 'HP:0030078', (53, 57))	('PLEK2', 'Gene', (77, 82))	('expression', 'MPA', (83, 93))	('patients', 'Species', '9606', (58, 66))	('PFS', 'MPA', (118, 121))	('high', 'Var', (72, 76))	('worse', 'NegReg', (112, 117))	('PLEK2', 'Gene', '26499', (77, 82))
136036	33084541	Two-sided Fisher's exact test suggested that the high PLEK2 expression group had a significantly higher proportion of patients with nodal positive tumors (104/248 vs. 64/243, p < 0.001).	('expression', 'MPA', (60, 70))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumors', 'Disease', (147, 153))	('tumors', 'Phenotype', 'HP:0002664', (147, 153))	('nodal', 'Gene', (132, 137))	('nodal', 'Gene', '4838', (132, 137))	('tumors', 'Disease', 'MESH:D009369', (147, 153))	('high', 'Var', (49, 53))	('PLEK2', 'Gene', (54, 59))	('patients', 'Species', '9606', (118, 126))	('PLEK2', 'Gene', '26499', (54, 59))
136041	33084541	Among the 14 functional states assessed, PLEK2 expression showed significant positive correlations with invasion, cell cycle, DNA damage and DNA repair of LUAD cells in both GSE69405 and GSE85534 (Figure 5A and B).	('correlations', 'Interaction', (86, 98))	('GSE69405', 'Var', (174, 182))	('PLEK2', 'Gene', (41, 46))	('positive', 'PosReg', (77, 85))	('LUAD', 'Phenotype', 'HP:0030078', (155, 159))	('GSE85534', 'Var', (187, 195))	('PLEK2', 'Gene', '26499', (41, 46))	('cell cycle', 'CPA', (114, 124))	('invasion', 'CPA', (104, 112))
136043	33084541	Among 494 out of 513 LUAD cases had gene-level copy number data (germline copy number variation deleted), the correlation between PLEK2 expression and its copy number was weak (Pearson's r = 0.175) (Figure 6A and B).	('PLEK2', 'Gene', (130, 135))	('copy number', 'Var', (47, 58))	('LUAD', 'Phenotype', 'HP:0030078', (21, 25))	('PLEK2', 'Gene', '26499', (130, 135))
136044	33084541	Regression analysis found 4 CpG sites (cg12199376, cg14437634, cg17641252 and cg06724236) had at least a weakly negative correlation with PLEK2 expression (Figure 6A and C).	('negative', 'NegReg', (112, 120))	('cg14437634', 'Chemical', '-', (51, 61))	('cg17641252', 'Chemical', '-', (63, 73))	('cg12199376', 'Var', (39, 49))	('expression', 'MPA', (144, 154))	('PLEK2', 'Gene', '26499', (138, 143))	('cg06724236', 'Var', (78, 88))	('cg17641252', 'Var', (63, 73))	('cg12199376', 'Chemical', '-', (39, 49))	('PLEK2', 'Gene', (138, 143))	('cg14437634', 'Var', (51, 61))
136045	33084541	cg12199376, cg14437634 and cg17641252 locate around the first exon (Figure 6A).	('cg14437634', 'Chemical', '-', (12, 22))	('cg12199376', 'Chemical', '-', (0, 10))	('cg14437634', 'Var', (12, 22))	('cg17641252', 'Var', (27, 37))	('cg12199376', 'Var', (0, 10))	('cg17641252', 'Chemical', '-', (27, 37))
136058	33084541	Furthermore, PLEK2 expression was associated with increased DNA repair of LUAD cells, which is an important mechanism of drug resistance.	('PLEK2', 'Gene', '26499', (13, 18))	('drug resistance', 'Phenotype', 'HP:0020174', (121, 136))	('increased', 'PosReg', (50, 59))	('expression', 'Var', (19, 29))	('DNA repair of LUAD cells', 'CPA', (60, 84))	('LUAD', 'Phenotype', 'HP:0030078', (74, 78))	('PLEK2', 'Gene', (13, 18))
136062	33084541	One previous study reported PLEK2 amplification and associated enhanced gene expression in SW613-S cells, a human colon carcinoma cell line, suggesting that gene amplification might contribute to its upregulation in cancer cells.	('colon carcinoma', 'Disease', 'MESH:D003110', (114, 129))	('PLEK2', 'Gene', (28, 33))	('cancer', 'Disease', 'MESH:D009369', (216, 222))	('PLEK2', 'Gene', '26499', (28, 33))	('upregulation', 'PosReg', (200, 212))	('enhanced', 'PosReg', (63, 71))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('colon carcinoma', 'Disease', (114, 129))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('human', 'Species', '9606', (108, 113))	('gene expression', 'MPA', (72, 87))	('cancer', 'Disease', (216, 222))	('amplification', 'Var', (34, 47))	('SW613-S', 'CellLine', 'CVCL:F650', (91, 98))
136068	33084541	These findings suggest that promoter hypomethylation might be an important mechanism resulting in upregulated PLEK2 expression in LUAD.	('expression', 'MPA', (116, 126))	('upregulated', 'PosReg', (98, 109))	('PLEK2', 'Gene', (110, 115))	('promoter hypomethylation', 'Var', (28, 52))	('PLEK2', 'Gene', '26499', (110, 115))	('LUAD', 'Disease', (130, 134))	('LUAD', 'Phenotype', 'HP:0030078', (130, 134))
136073	26139243	Using RNAi, cancer-specific vulnerabilities have been identified in SWI/SNF mutant tumors, including SMARCA4-deficient lung cancer, however, the contribution of conserved, druggable protein domains to this anticancer phenotype is unknown.	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('deficient lung', 'Phenotype', 'HP:0002089', (109, 123))	('tumors', 'Disease', 'MESH:D009369', (83, 89))	('SMARCA4-deficient lung cancer', 'Disease', 'MESH:D008175', (101, 130))	('cancer', 'Disease', 'MESH:D009369', (124, 130))	('SWI/SNF', 'Gene', (68, 75))	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('cancer', 'Disease', 'MESH:D009369', (210, 216))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('lung cancer', 'Phenotype', 'HP:0100526', (119, 130))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('SMARCA4-deficient lung cancer', 'Disease', (101, 130))	('cancer', 'Disease', (124, 130))	('cancer', 'Disease', (12, 18))	('mutant', 'Var', (76, 82))	('tumors', 'Disease', (83, 89))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('cancer', 'Disease', (210, 216))
136077	26139243	Taken together, our complementary genetic and pharmacological studies exemplify a general strategy for multi-domain protein drug-target validation and in case of SMARCA2/4 highlight the potential for drugging the more challenging helicase/ATPase domain to deliver on the promise of synthetic-lethality therapy.	('ATPase', 'Gene', (239, 245))	('drugging', 'Var', (200, 208))	('helicase', 'Gene', '164045', (230, 238))	('ATPase', 'Gene', '1769', (239, 245))	('helicase', 'Gene', (230, 238))
136078	26139243	Epigenetic dysregulation plays a fundamental role in the development of cancer.	('Epigenetic dysregulation', 'Var', (0, 24))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('cancer', 'Disease', (72, 78))
136079	26139243	Large-scale genome sequencing have uncovered recurrent somatic mutations and copy-number (CN) changes in histone-modifying enzymes and chromatin remodeling complexes supporting a causal role for altered epigenetics states in tumorigenesis.	('mutations', 'Var', (63, 72))	('tumor', 'Disease', 'MESH:D009369', (225, 230))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('tumor', 'Disease', (225, 230))	('changes', 'Reg', (94, 101))	('copy-number', 'Var', (77, 88))
136084	26139243	Accordingly, knock-out of mouse SMARCB1 results in fully penetrant and lethal cancers with 11 weeks median onset.	('results in', 'Reg', (40, 50))	('SMARCB1', 'Gene', (32, 39))	('cancers', 'Disease', 'MESH:D009369', (78, 85))	('cancers', 'Phenotype', 'HP:0002664', (78, 85))	('cancers', 'Disease', (78, 85))	('knock-out', 'Var', (13, 22))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('mouse', 'Species', '10090', (26, 31))	('fully penetrant', 'CPA', (51, 66))
136085	26139243	In human synovial carcinoma, recurrent chromosomal translocations, which are diagnostic of the malignancy, result in oncogenic fusions (SS18-SSX) that alter the composition/function of the SWI/SNF complex.	('synovial carcinoma', 'Disease', (9, 27))	('carcinoma', 'Phenotype', 'HP:0030731', (18, 27))	('SS18', 'Gene', '6760', (136, 140))	('synovial carcinoma', 'Phenotype', 'HP:0012570', (9, 27))	('human', 'Species', '9606', (3, 8))	('chromosomal translocations', 'Var', (39, 65))	('malignancy', 'Disease', 'MESH:D009369', (95, 105))	('recurrent chromosomal translocation', 'Phenotype', 'HP:0040012', (29, 64))	('SS18', 'Gene', (136, 140))	('synovial carcinoma', 'Disease', 'MESH:D013581', (9, 27))	('SSX', 'Gene', (141, 144))	('alter', 'Reg', (151, 156))	('SSX', 'Gene', '6757', (141, 144))	('composition/function', 'MPA', (161, 181))	('malignancy', 'Disease', (95, 105))	('result in', 'Reg', (107, 116))
136086	26139243	Pointing to the broader relevance of SWI/SNF in cancers are frequent inactivating mutations in accessory subunits, including ARID1A in ovarian and endometrial carcinomas, and PBRM1 in renal cell carcinomas.	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (147, 169))	('cancers', 'Disease', (48, 55))	('carcinoma', 'Phenotype', 'HP:0030731', (159, 168))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (184, 205))	('carcinomas', 'Phenotype', 'HP:0030731', (159, 169))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('inactivating mutations', 'Var', (69, 91))	('cancers', 'Phenotype', 'HP:0002664', (48, 55))	('PBRM1', 'Gene', (175, 180))	('renal cell carcinomas', 'Disease', (184, 205))	('PBRM1', 'Gene', '55193', (175, 180))	('ARID1A', 'Gene', '8289', (125, 131))	('ARID1A', 'Gene', (125, 131))	('carcinoma', 'Phenotype', 'HP:0030731', (195, 204))	('carcinomas', 'Phenotype', 'HP:0030731', (195, 205))	('cancers', 'Disease', 'MESH:D009369', (48, 55))	('renal cell carcinomas', 'Disease', 'MESH:C538614', (184, 205))	('ovarian and endometrial carcinomas', 'Disease', 'MESH:D016889', (135, 169))
136092	26139243	In this report we conduct complementary cDNA rescue and pharmacological studies to explore whether the bromodomain of SMARCA2/4 represents a tractable target in SWI/SNF mutant cancers.	('cancers', 'Disease', (176, 183))	('SWI/SNF', 'Gene', (161, 168))	('cancers', 'Disease', 'MESH:D009369', (176, 183))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('mutant', 'Var', (169, 175))	('cancers', 'Phenotype', 'HP:0002664', (176, 183))
136099	26139243	ATPase-dead (K785A) and Bromodomain mutations (Y1497F and N1540W) were made in human SMARCA4 cDNA (GeneCopoeia #GC-Y3533) using site-directed mutagenesis (QuickChange, Agilent Technologies) with equivalent mutations in SMARCA2 (GeneCopoeia #GC-Z4424).	('Y1497F', 'Var', (47, 53))	('human', 'Species', '9606', (79, 84))	('ATPase', 'Gene', '1769', (0, 6))	('ATPase', 'Gene', (0, 6))	('Y1497F', 'Mutation', 'p.Y1497F', (47, 53))	('N1540W', 'Mutation', 'p.N1540W', (58, 64))	('N1540W', 'Var', (58, 64))	('K785A', 'Mutation', 'p.K785A', (13, 18))
136101	26139243	To build upon recent meta-analysis, we first examined both SWI/SNF mutation and CN variation drawing on a larger set of patient tumors (n = 10,038) from 45 genome sequencing studies (Supplementary Table S1).	('SWI/SNF', 'Gene', (59, 66))	('mutation', 'Var', (67, 75))	('patient', 'Species', '9606', (120, 127))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumors', 'Disease', (128, 134))	('tumors', 'Disease', 'MESH:D009369', (128, 134))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))
136105	26139243	In contrast, SWI/SNF mutations do not emerge as significant recurrent alterations in glioblastoma, thyroid cancer, multiple myeloma and acute myeloid leukemia (AML).	('SWI/SNF', 'Gene', (13, 20))	('glioblastoma', 'Disease', 'MESH:D005909', (85, 97))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (142, 158))	('thyroid cancer', 'Disease', (99, 113))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (136, 158))	('AML', 'Disease', 'MESH:D015470', (160, 163))	('leukemia', 'Phenotype', 'HP:0001909', (150, 158))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (136, 158))	('multiple myeloma', 'Phenotype', 'HP:0006775', (115, 131))	('glioblastoma', 'Disease', (85, 97))	('AML', 'Disease', (160, 163))	('AML', 'Phenotype', 'HP:0004808', (160, 163))	('glioblastoma', 'Phenotype', 'HP:0012174', (85, 97))	('thyroid cancer', 'Disease', 'MESH:D013964', (99, 113))	('multiple myeloma', 'Disease', 'MESH:D009101', (115, 131))	('thyroid cancer', 'Phenotype', 'HP:0002890', (99, 113))	('mutations', 'Var', (21, 30))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('acute myeloid leukemia', 'Disease', (136, 158))	('multiple myeloma', 'Disease', (115, 131))
136108	26139243	In primary human lung adenocarcinoma (LUAD) about half of the SMARCA4 mutations are deleterious (nonsense and frameshift mutations) and occur at a 7% frequency in TCGA patient samples (Fig.	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (17, 36))	('carcinoma', 'Phenotype', 'HP:0030731', (27, 36))	('mutations', 'Var', (70, 79))	('SMARCA4', 'Gene', (62, 69))	('LUAD', 'Phenotype', 'HP:0030078', (38, 42))	('human', 'Species', '9606', (11, 16))	('frameshift mutations', 'Var', (110, 130))	('patient', 'Species', '9606', (168, 175))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (17, 36))	('lung adenocarcinoma', 'Disease', (17, 36))
136109	26139243	Overall, SWI/SNF complex components are mutated in 71/229 patients with an average mutation rate of ~1.7 per sample.	('SWI/SNF', 'Gene', (9, 16))	('mutated', 'Var', (40, 47))	('patients', 'Species', '9606', (58, 66))
136111	26139243	Because heterozygous SMARCA4 knockout mice are haploinsufficient and tumor prone, we also analyzed copy-number driven mRNA expression and conclude that loss of one allele is also sufficient to decrease SMARCA4 expression (Fig.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('haploinsufficient', 'Disease', 'MESH:D058495', (47, 64))	('SMARCA4', 'Gene', (202, 209))	('mice', 'Species', '10090', (38, 42))	('tumor', 'Disease', (69, 74))	('expression', 'MPA', (210, 220))	('loss', 'Var', (152, 156))	('haploinsufficient', 'Disease', (47, 64))	('decrease', 'NegReg', (193, 201))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
136112	26139243	Focusing on LUAD and lung squamous cell carcinoma (LUSC), mapping of the genomic annotation onto individual patient samples revealed that loss of SMARCA2 and SMARCA4 are largely mutually exclusive (Fig.	('SMARCA4', 'Gene', (158, 165))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (21, 49))	('loss', 'Var', (138, 142))	('lung squamous cell carcinoma', 'Disease', (21, 49))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (26, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (40, 49))	('LUAD', 'Phenotype', 'HP:0030078', (12, 16))	('patient', 'Species', '9606', (108, 115))	('LUAD', 'Disease', (12, 16))	('SMARCA2', 'Gene', (146, 153))
136119	26139243	The recent discovery that SMARCA2 knockdown inhibits the growth of SMARCA4-deficient cancer cells has opened a potential therapeutic avenue and received considerable attention.	('SMARCA2', 'Gene', (26, 33))	('SMARCA4-deficient cancer', 'Disease', 'MESH:D009369', (67, 91))	('knockdown', 'Var', (34, 43))	('growth', 'CPA', (57, 63))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('inhibits', 'NegReg', (44, 52))	('SMARCA4-deficient cancer', 'Disease', (67, 91))
136127	26139243	As a negative control, JQ1 did not inhibit the binding of ectopically expressed SMARCA2 bromodomain, but selectively displaced GFP-tagged BRD4 (Fig.	('GFP-tagged', 'Var', (127, 137))	('displaced', 'NegReg', (117, 126))	('BRD4', 'Gene', '23476', (138, 142))	('BRD4', 'Gene', (138, 142))
136129	26139243	To elaborate on this, the binding of endogenous (full-length) SMARCA2 to chromatin was monitored by immunofluorescence (IF) in A549 cells using SMARCA2 knockdown as a specificity control (Fig.	('knockdown', 'Var', (152, 161))	('SMARCA2', 'Gene', (62, 69))	('binding', 'Interaction', (26, 33))	('A549', 'CellLine', 'CVCL:0023', (127, 131))
136132	26139243	As alterations in SWI/SNF have been implicated in disease progression of synovial sarcomas, we also evaluated the pharmacological activity of PFI-3 in Yamato and Aska cells.	('sarcomas', 'Phenotype', 'HP:0100242', (82, 90))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (73, 89))	('implicated', 'Reg', (36, 46))	('SWI/SNF', 'Gene', (18, 25))	('synovial sarcomas', 'Phenotype', 'HP:0012570', (73, 90))	('synovial sarcomas', 'Disease', 'MESH:D013584', (73, 90))	('alterations', 'Var', (3, 14))	('synovial sarcomas', 'Disease', (73, 90))	('sarcoma', 'Phenotype', 'HP:0100242', (82, 89))
136135	26139243	The altered SWI/SNF complex binds to the Sox2 locus resulting in aberrant Sox2 expression, which is essential for proliferation of synovial sarcomas.	('synovial sarcomas', 'Disease', (131, 148))	('sarcomas', 'Phenotype', 'HP:0100242', (140, 148))	('sarcoma', 'Phenotype', 'HP:0100242', (140, 147))	('expression', 'MPA', (79, 89))	('altered', 'Var', (4, 11))	('Sox2', 'Gene', '6657', (74, 78))	('aberrant', 'Var', (65, 73))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (131, 147))	('SWI/SNF', 'Gene', (12, 19))	('Sox2', 'Gene', '6657', (41, 45))	('Sox2', 'Gene', (74, 78))	('synovial sarcomas', 'Phenotype', 'HP:0012570', (131, 148))	('synovial sarcomas', 'Disease', 'MESH:D013584', (131, 148))	('Sox2', 'Gene', (41, 45))
136141	26139243	Rhabdoid tumors are distinctly characterized by biallelic inactivation of SMARCB1, a core subunit of the SWI/SNF complex and genetic studies have demonstrated that oncogenesis mediated by SMARCB1 loss is dependent on the residual activity of SMARCA4-containing SWI/SNF complex.	('Rhabdoid tumors', 'Disease', (0, 15))	('oncogenesis', 'CPA', (164, 175))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('SMARCB1', 'Gene', (188, 195))	('SMARCB1', 'Gene', (74, 81))	('loss', 'NegReg', (196, 200))	('biallelic', 'Var', (48, 57))	('Rhabdoid tumors', 'Disease', 'MESH:D018335', (0, 15))
136146	26139243	To genetically validate the PFI-3 results, we next used a 3'UTR targeting shRNA (shS2) to knockdown endogenous SMARCA2 in H1299 cells engineered to express either wildtype (WT), ATP-binding pocket deficient (K755A) or bromodomain mutant (N1482W) forms of SMARCA2 (Fig.	('ATP', 'Chemical', 'MESH:D000255', (178, 181))	('SMARCA2', 'Gene', (255, 262))	('H1299', 'CellLine', 'CVCL:0060', (122, 127))	('K755A', 'Var', (208, 213))	('K755A', 'Mutation', 'p.K755A', (208, 213))	('N1482W', 'Mutation', 'p.N1482W', (238, 244))	('N1482W', 'Var', (238, 244))
136147	26139243	Ectopic expression of either SMARCA2 WT or the bromodomain binding-deficient mutant (BRD-Mut), but not the ATPase-dead form (ATP-Dead), completely rescued the RNAi-mediated LOF phenotype (Fig.	('ATPase', 'Gene', '1769', (107, 113))	('RNAi-mediated LOF phenotype', 'CPA', (159, 186))	('rescued', 'PosReg', (147, 154))	('ATPase', 'Gene', (107, 113))	('ATP', 'Chemical', 'MESH:D000255', (107, 110))	('ATP', 'Chemical', 'MESH:D000255', (125, 128))	('mutant', 'Var', (77, 83))
136148	26139243	Likewise, A549 cells reconstituted with SMARCA4 WT or BRD-Mut (N1540W, Y1497F), but not ATP-Dead (K785A), were able to grow upon SMARCA2 knockdown (Fig.	('A549', 'CellLine', 'CVCL:0023', (10, 14))	('N1540W', 'Var', (63, 69))	('ATP', 'Chemical', 'MESH:D000255', (88, 91))	('SMARCA2', 'Gene', (129, 136))	('grow', 'CPA', (119, 123))	('Y1497F', 'Mutation', 'p.Y1497F', (71, 77))	('knockdown', 'Var', (137, 146))	('K785A', 'Mutation', 'p.K785A', (98, 103))	('N1540W', 'Mutation', 'p.N1540W', (63, 69))	('Y1497F', 'Var', (71, 77))
136155	26139243	Hence, the transcriptional profiles reinforce the view that BRD-Mut is able to perform similar functions to the WT gene while ATP-Dead, despite retaining its ability to bind chromatin (Fig.	('bind', 'Interaction', (169, 173))	('ability', 'MPA', (158, 165))	('ATP', 'Chemical', 'MESH:D000255', (126, 129))	('chromatin', 'Protein', (174, 183))	('BRD-Mut', 'Var', (60, 67))
136160	26139243	When comparing ATP-Dead to WT, the enrichment profiles suggest that the ATPase enzymatic activity preferentially reverses expression of genes that are up-regulated upon RNAi-mediated (synthetic lethal) knock-down of SMARCA2 (Fig 7E).	('ATPase', 'Gene', '1769', (72, 78))	('expression of genes', 'MPA', (122, 141))	('ATPase', 'Gene', (72, 78))	('SMARCA2', 'Gene', (216, 223))	('knock-down', 'Var', (202, 212))	('ATP', 'Chemical', 'MESH:D000255', (72, 75))	('reverses', 'NegReg', (113, 121))	('ATP', 'Chemical', 'MESH:D000255', (15, 18))	('up-regulated', 'PosReg', (151, 163))
136165	26139243	re-expression) and the SMARCA2 RNAi rescue experiments are consistent with the observed lack of pharmacological activity of PFI-3 in SWI/SNF mutant cancers and we demonstrate for the first time that selective SMARCA2/4 bromodomain inhibition is not a feasible therapeutic strategy for targeting aberrant SWI/SNF activity in SWI/SNF-mutant cancers.	('SWI/SNF', 'Gene', (133, 140))	('cancers', 'Disease', 'MESH:D009369', (148, 155))	('cancers', 'Phenotype', 'HP:0002664', (148, 155))	('mutant', 'Var', (141, 147))	('cancers', 'Disease', (148, 155))	('PFI-3', 'Gene', (124, 129))	('cancers', 'Phenotype', 'HP:0002664', (339, 346))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('cancers', 'Disease', (339, 346))	('cancers', 'Disease', 'MESH:D009369', (339, 346))	('cancer', 'Phenotype', 'HP:0002664', (339, 345))
136169	26139243	We further showed that expression of either SMARCA2 or SMARCA4 completely rescued the effects of SMARCA2 knockdown in SMARCA4-deficient cells indicating paralog dependence and reciprocal role of these two subunits in tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('tumor', 'Disease', (217, 222))	('knockdown', 'Var', (105, 114))	('effects', 'MPA', (86, 93))	('tumor', 'Disease', 'MESH:D009369', (217, 222))	('SMARCA2', 'Gene', (97, 104))
136171	26139243	Furthermore, genomic analysis revealed mutual exclusivity of SMARCA2 and SMARCA4 mutations in LUSC and LUAD carcinoma and expression-based biomarker analysis outlined a SMARCA4-deficient patient population predicted to depend exclusively on SMARCA2 activity (Fig.	('LUAD carcinoma', 'Disease', 'MESH:D002277', (103, 117))	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('LUAD', 'Phenotype', 'HP:0030078', (103, 107))	('SMARCA2', 'Gene', (61, 68))	('LUSC', 'Disease', (94, 98))	('LUAD carcinoma', 'Disease', (103, 117))	('SMARCA4', 'Gene', (73, 80))	('mutations', 'Var', (81, 90))	('patient', 'Species', '9606', (187, 194))
136172	26139243	Because SMARCA2-deficient mice are viable showing no overt phenotype, while SMARCA4 inactivation is embryonic lethal, one might anticipate a significant therapeutic window, if selective small-molecule SMARCA2 inhibitors can be developed that mimic the RNAi knockdown phenotype.	('mice', 'Species', '10090', (26, 30))	('inactivation', 'Var', (84, 96))	('SMARCA2', 'Gene', (201, 208))
136178	26139243	Likewise, in models harboring defined SWI/SNF alterations, including synovial sarcoma (SSX-fusion), rhabdoid tumors (SMARCB1-null), and leukemia (SMARCA4-dependent), PFI-3 didn't mimic the anti-cancer phenotype observed upon RNAi-mediated knockdown of SMARCA2/4.	('synovial sarcoma', 'Phenotype', 'HP:0012570', (69, 85))	('synovial sarcoma', 'Disease', 'MESH:D013584', (69, 85))	('cancer', 'Disease', (194, 200))	('leukemia', 'Disease', (136, 144))	('SWI/SNF', 'Gene', (38, 45))	('leukemia', 'Disease', 'MESH:D007938', (136, 144))	('leukemia', 'Phenotype', 'HP:0001909', (136, 144))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('alterations', 'Var', (46, 57))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('rhabdoid tumors', 'Disease', (100, 115))	('rhabdoid tumors', 'Disease', 'MESH:D018335', (100, 115))	('synovial sarcoma', 'Disease', (69, 85))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('sarcoma', 'Phenotype', 'HP:0100242', (78, 85))	('SSX', 'Gene', (87, 90))	('cancer', 'Disease', 'MESH:D009369', (194, 200))	('SSX', 'Gene', '6757', (87, 90))
136183	26139243	Additional vulnerabilities like antagonism between SMARCB1 and EZH2, which renders rhabdoid tumors dependent on EZH2 for disease maintenance, present another promising approach to target SWI/SNF mutant cancers.	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('antagonism', 'Var', (32, 42))	('EZH2', 'Gene', (112, 116))	('EZH2', 'Gene', '2146', (63, 67))	('rhabdoid tumors', 'Disease', 'MESH:D018335', (83, 98))	('EZH2', 'Gene', (63, 67))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('SWI/SNF', 'Gene', (187, 194))	('cancers', 'Phenotype', 'HP:0002664', (202, 209))	('rhabdoid tumors', 'Disease', (83, 98))	('cancers', 'Disease', (202, 209))	('cancers', 'Disease', 'MESH:D009369', (202, 209))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('mutant', 'Var', (195, 201))	('SMARCB1', 'Gene', (51, 58))	('EZH2', 'Gene', '2146', (112, 116))
136184	26139243	The anti-proliferative response to SMARCA4 knockdown and EZH2 inhibitor treatment highlights clear dependencies on SWI/SNF activity (Fig.	('EZH2', 'Gene', (57, 61))	('knockdown', 'Var', (43, 52))	('SMARCA4', 'Gene', (35, 42))	('anti-proliferative', 'MPA', (4, 22))	('EZH2', 'Gene', '2146', (57, 61))
136186	26139243	For SWI/SNF mutant cancers, our target validation approach has focused on dissecting the functional contribution of an impaired SMARCA2/4 bromodomain or ATPase domain to cellular phenotype through parallel cDNA complementation and rescue experiments.	('SWI/SNF', 'Gene', (4, 11))	('cancers', 'Phenotype', 'HP:0002664', (19, 26))	('ATPase', 'Gene', '1769', (153, 159))	('cancers', 'Disease', (19, 26))	('cancers', 'Disease', 'MESH:D009369', (19, 26))	('mutant', 'Var', (12, 18))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('SMARCA2/4', 'Gene', (128, 137))	('ATPase', 'Gene', (153, 159))
136187	26139243	The observation that expression of BRD-Mut, but not ATP-Dead, can rescue the SMARCA2 knockdown phenotype is consistent with the pharmacological PFI-3 inhibitor data.	('SMARCA2', 'Gene', (77, 84))	('rescue', 'PosReg', (66, 72))	('BRD-Mut', 'Var', (35, 42))	('knockdown phenotype', 'MPA', (85, 104))	('ATP', 'Chemical', 'MESH:D000255', (52, 55))
136191	26139243	While the importance of ATPase activity has previously been shown for chromatin remodeling, our studies pinpoint the ATPase activity as the molecular synthetic-lethal target providing a genetically validated strategy for targeting SWI/SNF mutant lung cancer.	('ATPase', 'Gene', '1769', (117, 123))	('ATPase', 'Gene', (24, 30))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('ATPase', 'Gene', (117, 123))	('lung cancer', 'Disease', 'MESH:D008175', (246, 257))	('ATPase', 'Gene', '1769', (24, 30))	('SWI/SNF', 'Gene', (231, 238))	('mutant', 'Var', (239, 245))	('lung cancer', 'Disease', (246, 257))	('lung cancer', 'Phenotype', 'HP:0100526', (246, 257))
136207	26139243	Moreover, the SMARCA4-deficient patient population generally lacks targetable oncogenes (such as mutant EGFR or ALK translocations), which further emphasize the potential medical impact of developing inhibitors of the ATPase domain of SMARCA2/4.	('patient', 'Species', '9606', (32, 39))	('ALK', 'Gene', (112, 115))	('EGFR', 'Gene', (104, 108))	('mutant', 'Var', (97, 103))	('lacks', 'NegReg', (61, 66))	('SMARCA4-deficient', 'Disease', (14, 31))	('ATPase', 'Gene', '1769', (218, 224))	('ALK', 'Gene', '238', (112, 115))	('ATPase', 'Gene', (218, 224))	('EGFR', 'Gene', '1956', (104, 108))
136209	33892811	Four Gene Expression Omnibus (GEO) datasets were integratedly analyzed using bioinformatics approaches, including identification of differentially expressed genes (DEGs), GO and KEGG analysis, construction of protein-protein interaction (PPI) network, selection of hub genes, analysis of prognostic information and genetic alterations of hub genes.	('hub', 'Gene', (338, 341))	('KEGG', 'Chemical', '-', (178, 182))	('hub', 'Gene', '1993', (265, 268))	('genetic alterations', 'Var', (315, 334))	('hub', 'Gene', '1993', (338, 341))	('hub', 'Gene', (265, 268))
136227	33892811	After a systematic review, OSCC and non-tumor oral tissues gene expression profiles of GSE23558, GSE30784, GSE74530, and GSE37991 were selected and downloaded through getGEO function in "GEOquery" package.	('GSE74530', 'Var', (107, 115))	('GSE37991', 'Var', (121, 129))	('GSE23558', 'Var', (87, 95))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('tumor', 'Disease', (40, 45))	('tumor oral tissues', 'Phenotype', 'HP:0100649', (40, 58))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('GSE30784', 'Var', (97, 105))
136244	33892811	The four datasets (GSE23558, GSE30784, GSE74530, and GSE37991), including 240 OSCC tissues and 95 non-tumor tissues, were included in this study.	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('GSE74530', 'Var', (39, 47))	('GSE37991', 'Var', (53, 61))	('GSE23558', 'Var', (19, 27))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('GSE30784', 'Var', (29, 37))
136247	33892811	KEGG enrichment showed that upregulated DEGs were mainly involved in pathway in cancer, PI3K-Akt pathway, ECM receptor interaction, and focal adhesion (Figure S1c).	('focal adhesion', 'CPA', (136, 150))	('KEGG', 'Chemical', '-', (0, 4))	('Akt', 'Gene', (93, 96))	('DEGs', 'Var', (40, 44))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('ECM receptor', 'Protein', (106, 118))	('upregulated', 'PosReg', (28, 39))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('Akt', 'Gene', '207', (93, 96))	('cancer', 'Disease', (80, 86))
136267	33892811	These 10 genes were changed in 217 (44%) of 496 sequenced patients (496 total), and that FOXM1 and TPX2 were changed most often (15% and 14%), including amplification, missense mutation, and deep deletion.	('missense mutation', 'Var', (168, 185))	('amplification', 'Var', (153, 166))	('deep deletion', 'Var', (191, 204))	('TPX2', 'Gene', (99, 103))	('FOXM1', 'Gene', '2305', (89, 94))	('FOXM1', 'Gene', (89, 94))	('patients', 'Species', '9606', (58, 66))	('changed', 'Reg', (20, 27))
136289	33892811	Each OSCC patient was assigned a risk score calculated as follows: risk score = (-0.32654 x expression value of TEX101) + (0.10257 x expression value of DSG2) + (0.15022 x expression value of SCG5) + (0.18621 x expression value of ADA) + (-0.29365 x expression value of BOC) + (-0.26023 x expression value of SCARA5) + (0.10796 x expression value of FST) + (-0.26676 x expression value of SOCS1) + (0.15679 x expression value of STC2).	('BOC', 'Gene', (270, 273))	('SCG5', 'Gene', '6447', (192, 196))	('SOCS1', 'Gene', '8651', (389, 394))	('STC2', 'Gene', (429, 433))	('DSG2', 'Gene', '1829', (153, 157))	('SCG5', 'Gene', (192, 196))	('TEX101', 'Gene', '83639', (112, 118))	('SOCS1', 'Gene', (389, 394))	('patient', 'Species', '9606', (10, 17))	('-0.32654', 'Var', (81, 89))	('BOC', 'Gene', '91653', (270, 273))	('SCARA5', 'Gene', (309, 315))	('DSG2', 'Gene', (153, 157))	('SCARA5', 'Gene', '286133', (309, 315))	('TEX101', 'Gene', (112, 118))	('ADA', 'Gene', '100', (231, 234))	('ADA', 'Gene', (231, 234))	('STC2', 'Gene', '8614', (429, 433))
136302	33892811	Additionally, genetic analysis demonstrated that hub genes were changed in about 44% OSCC patients and these genetic alternations include amplification, missense mutation and so on.	('hub', 'Gene', '1993', (49, 52))	('OSCC', 'Disease', (85, 89))	('missense mutation', 'Var', (153, 170))	('changed', 'Reg', (64, 71))	('amplification', 'Var', (138, 151))	('patients', 'Species', '9606', (90, 98))	('hub', 'Gene', (49, 52))
136311	33892811	Huang et al found that overexpressed SPP1 was linked to carcinogenesis and progression of OSCC.	('SPP1', 'Gene', '6696', (37, 41))	('OSCC', 'Disease', (90, 94))	('SPP1', 'Gene', (37, 41))	('linked', 'Reg', (46, 52))	('overexpressed', 'Var', (23, 36))
136313	33892811	Cai et al confirmed that downregulated FN1 could inhibit colorectal carcinogenesis through suppressing proliferation, migration, and invasion.	('suppressing', 'NegReg', (91, 102))	('FN1', 'Gene', '2335', (39, 42))	('proliferation', 'CPA', (103, 116))	('invasion', 'CPA', (133, 141))	('FN1', 'Gene', (39, 42))	('colorectal carcinogenesis', 'Disease', (57, 82))	('colorectal carcinogenesis', 'Disease', 'MESH:D015179', (57, 82))	('downregulated', 'Var', (25, 38))	('inhibit', 'NegReg', (49, 56))
136321	33892811	Consistently, our results showed that PLAUR was considered as a cancer therapeutic target and high expression of PLAUR can predicted poor OS in OSCC patients.	('predicted', 'Reg', (123, 132))	('PLAUR', 'Gene', (38, 43))	('poor OS', 'Disease', (133, 140))	('patients', 'Species', '9606', (149, 157))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('PLAUR', 'Gene', '5329', (113, 118))	('PLAUR', 'Gene', '5329', (38, 43))	('OSCC', 'Disease', (144, 148))	('high', 'Var', (94, 98))	('PLAUR', 'Gene', (113, 118))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
136323	33892811	For example, FOXM1-induced epigenetic signature may serve as ideal biomarkers for early cancer screening in head and neck carcinoma.	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('FOXM1', 'Gene', (13, 18))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('FOXM1', 'Gene', '2305', (13, 18))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('head and neck carcinoma', 'Disease', 'MESH:D006258', (108, 131))	('epigenetic', 'Var', (27, 37))
136340	33892811	Recent studies reported that TPX2 dysregulation was related to the progression of esophageal cancer, hepatocellular carcinoma, and colorectal cancer.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('TPX2', 'Gene', (29, 33))	('dysregulation', 'Var', (34, 47))	('colorectal cancer', 'Disease', 'MESH:D015179', (131, 148))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (101, 125))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('colorectal cancer', 'Phenotype', 'HP:0003003', (131, 148))	('hepatocellular carcinoma', 'Disease', (101, 125))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (101, 125))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('colorectal cancer', 'Disease', (131, 148))	('related', 'Reg', (52, 59))	('cancer', 'Disease', (142, 148))
136407	32119697	The same bin size was used for each patient to calculate the histogram distribution of the parameters within the lesion; in particular, the bin sizes were 0.05 min-1, 0.3 min-1, and 0.02 for Ktrans, Kep, and ve, respectively.	('min-1', 'Gene', (171, 176))	('min-1', 'Gene', (160, 165))	('min-1', 'Gene', '966', (171, 176))	('min-1', 'Gene', '966', (160, 165))	('0.02', 'Var', (182, 186))	('Ktrans', 'Chemical', '-', (191, 197))	('patient', 'Species', '9606', (36, 43))
136437	32119697	Our results on DCE-MRI are in line with previous investigations that did not report any difference in perfusion parameters according to HPV status, for both PTs and metastatic LNs.	('PTs', 'Disease', (157, 160))	('PTs', 'Disease', 'MESH:D001932', (157, 160))	('DCE', 'Chemical', 'MESH:C024565', (15, 18))	('DCE-MRI', 'Var', (15, 22))	('HPV', 'Species', '10566', (136, 139))
136447	32119697	Moreover, it has been suggested that the evidence of these correlations may also depend on tumor grading, with G1/G2 PTs showing significant associations, while no correlations are evident in G3 PTs.	('PTs', 'Disease', (195, 198))	('PTs', 'Disease', 'MESH:D001932', (195, 198))	('associations', 'Interaction', (141, 153))	('PTs', 'Disease', (117, 120))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('PTs', 'Disease', 'MESH:D001932', (117, 120))	('G1/G2', 'Var', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor', 'Disease', (91, 96))
136527	28295222	 TRAF3/CYLD mutations identify a distinct subset of human papillomavirus-associated head and neck squamous cell carcinoma The incidence of human papillomavirus (HPV)-associated (HPV-positive) head and neck squamous cell carcinoma (HNSCC) of the oropharynx has dramatically increased over the last decade and continues to rise.	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (84, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('HPV', 'Species', '10566', (178, 181))	('TRAF3', 'Gene', (1, 6))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (206, 229))	('human papillomavirus', 'Species', '10566', (52, 72))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (192, 229))	('carcinoma', 'Phenotype', 'HP:0030731', (220, 229))	('HPV', 'Species', '10566', (161, 164))	('human papillomavirus', 'Species', '10566', (139, 159))	('CYLD', 'Gene', (7, 11))	('neck squamous cell carcinoma', 'Disease', (93, 121))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (93, 121))	('mutations', 'Var', (12, 21))	('CYLD', 'Gene', '1540', (7, 11))	('neck squamous cell carcinoma', 'Disease', (201, 229))	('TRAF3', 'Gene', '7187', (1, 6))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (98, 121))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (201, 229))
136535	28295222	The current investigations identified a subset of HPV-positive HNSCCs with mutations in the genes TRAF3 (tumor necrosis factor receptor-associated factor 3) and CYLD (cylindromatosis lysine 63 deubiquitinase).	('tumor necrosis factor receptor-associated factor 3', 'Gene', '7187', (105, 155))	('TRAF3', 'Gene', (98, 103))	('cylindromatosis lysine 63 deubiquitinase', 'Gene', '1540', (167, 207))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('mutations', 'Var', (75, 84))	('cylindromatosis lysine 63 deubiquitinase', 'Gene', (167, 207))	('HPV', 'Species', '10566', (50, 53))	('tumor necrosis factor receptor-associated factor 3', 'Gene', (105, 155))
136536	28295222	Defects in TRAF3 and CYLD correlated with the activation of transcriptional factor nuclear factor kappaB, episomal HPV status of tumors, and improved patient survival.	('episomal HPV status of tumors', 'Disease', (106, 135))	('patient', 'Species', '9606', (150, 157))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('activation', 'PosReg', (46, 56))	('Defects', 'Var', (0, 7))	('kappaB', 'Gene', '4790', (98, 104))	('kappaB', 'Gene', (98, 104))	('improved', 'PosReg', (141, 149))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('transcriptional', 'MPA', (60, 75))	('episomal HPV status of tumors', 'Disease', 'MESH:D030361', (106, 135))	('TRAF3', 'Gene', (11, 16))	('patient survival', 'CPA', (150, 166))
136541	28295222	Somatic mutations in the genes TRAF3 and CYLD identified in The Cancer Genome Atlas data set are correlated with the activation of nuclear factor-kappaB, define a distinct etiologic subset of head and neck cancers, and will be useful as biomarkers for predicting improved prognosis and selecting patients with human papillomavirus-positive head and neck cancer who may be successfully treated with de-escalating therapy.	('head and neck cancer', 'Phenotype', 'HP:0012288', (340, 360))	('Cancer', 'Disease', 'MESH:D009369', (64, 70))	('head and neck cancers', 'Phenotype', 'HP:0012288', (192, 213))	('papillomavirus-positive head and neck cancer', 'Disease', 'MESH:D006258', (316, 360))	('neck cancers', 'Disease', (201, 213))	('mutations', 'Var', (8, 17))	('head and neck cancer', 'Disease', 'MESH:D006258', (340, 360))	('cancers', 'Phenotype', 'HP:0002664', (206, 213))	('nuclear factor-kappaB', 'Gene', '4790', (131, 152))	('neck cancers', 'Disease', 'MESH:D006258', (201, 213))	('head and neck cancer', 'Phenotype', 'HP:0012288', (192, 212))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('Cancer', 'Phenotype', 'HP:0002664', (64, 70))	('nuclear factor-kappaB', 'Gene', (131, 152))	('activation', 'PosReg', (117, 127))	('patients', 'Species', '9606', (296, 304))	('TRAF3', 'Gene', (31, 36))	('Cancer', 'Disease', (64, 70))	('cancer', 'Phenotype', 'HP:0002664', (354, 360))	('head and neck cancer', 'Disease', 'MESH:D006258', (192, 212))	('human papillomavirus', 'Species', '10566', (310, 330))
136552	28295222	A seminal finding of the TCGA head and neck study identified tumor necrosis factor receptor-associated factor 3 (TRAF3) as 1 of the most commonly mutated genes in HPV-positive HNSCC.12 It is noteworthy that TRAF3 mutations are not described in HPV-negative HNSCC, suggesting that TRAF3 inactivation is required only for HPV-driven carcinogenesis in HNSCC.	('tumor necrosis factor receptor-associated factor 3', 'Gene', (61, 111))	('TRAF3', 'Gene', (207, 212))	('HPV', 'Species', '10566', (244, 247))	('HPV-driven carcinogenesis', 'Disease', (320, 345))	('HPV', 'Species', '10566', (320, 323))	('tumor necrosis factor receptor-associated factor 3', 'Gene', '7187', (61, 111))	('HPV', 'Species', '10566', (163, 166))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('HPV-driven carcinogenesis', 'Disease', 'MESH:D030361', (320, 345))	('HNSCC.12', 'CellLine', 'CVCL:5985', (176, 184))	('mutations', 'Var', (213, 222))
136553	28295222	Receptors that signal through TRAF proteins include those involved in inflammation, innate immune responses, and cell death, most notably: tumor necrosis factor receptors (TNFR), Toll-like receptors (TLRs), RIG-1-like receptors (RLRs), and interleukin-1 receptors (IL-1Rs).14 These receptors initiate signaling that ultimately leads to activation of the innate immune response and nuclear factor-kappaB (NF-kappaB), a potent transcription factor central to the cell's control of apoptosis, inflammation, and several aspects of the immune response.14, 15 It has long been noted that NF-kappaB signaling is activated in many HNSCCs.16, 17, 18, 19 It has been demonstrated that constitutive NF-kappaB activation is induced by carcinogens or oncogenic viruses in patients with head and neck cancer or in cell lines.20, 21 TRAF3 is unique, in that it plays a role in negatively regulating canonical and noncanonical NF-kappaB pathways while simultaneously stimulating a potent antiviral response, which is mediated through type I interferon (IFN) signaling.14, 22 Here, we report that the gene cylindromatosis lysine 63 deubiquitinase (CYLD), which, like TRAF3, inhibits NF-kappaB pathways,23 is also mutated in a subset of HPV-positive HNSCC.	('inflammation', 'Disease', 'MESH:D007249', (70, 82))	('nuclear factor-kappaB', 'Gene', (381, 402))	('carcinogens or oncogenic viruses', 'Disease', 'MESH:D000074723', (723, 755))	('inflammation', 'Disease', 'MESH:D007249', (490, 502))	('cylindromatosis lysine 63 deubiquitinase', 'Gene', '1540', (1089, 1129))	('patients', 'Species', '9606', (759, 767))	('carcinogens or oncogenic viruses', 'Disease', (723, 755))	('HPV', 'Species', '10566', (1219, 1222))	('tumor necrosis factor receptors', 'Gene', '7132', (139, 170))	('inhibits', 'NegReg', (1157, 1165))	('inflammation', 'Disease', (70, 82))	('mutated', 'Var', (1196, 1203))	('interferon', 'Gene', (1025, 1035))	('head and neck cancer', 'Phenotype', 'HP:0012288', (773, 793))	('cancer', 'Phenotype', 'HP:0002664', (787, 793))	('inflammation', 'Disease', (490, 502))	('interferon', 'Gene', '3439', (1025, 1035))	('IFN', 'Gene', '3439', (1037, 1040))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor necrosis factor receptors', 'Gene', (139, 170))	('head and neck cancer', 'Disease', 'MESH:D006258', (773, 793))	('TNFR', 'Gene', '7132', (172, 176))	('CYLD', 'Gene', (1131, 1135))	('cylindromatosis lysine 63 deubiquitinase', 'Gene', (1089, 1129))	('nuclear factor-kappaB', 'Gene', '4790', (381, 402))	('IFN', 'Gene', (1037, 1040))	('TNFR', 'Gene', (172, 176))
136554	28295222	Mutations in TRAF3 and CYLD leading to constitutive activation of NF-kappaB have been identified in other cancers, such as multiple myeloma; however, among solid tumors, inactivating TRAF3/CYLD gene defects were most common in HPV-positive HNSCC.	('inactivating', 'Var', (170, 182))	('cancers', 'Phenotype', 'HP:0002664', (106, 113))	('cancers', 'Disease', (106, 113))	('CYLD gene defects', 'Disease', 'MESH:D025063', (189, 206))	('constitutive', 'MPA', (39, 51))	('solid tumors', 'Disease', (156, 168))	('multiple myeloma', 'Phenotype', 'HP:0006775', (123, 139))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('HPV', 'Species', '10566', (227, 230))	('Mutations', 'Var', (0, 9))	('CYLD gene defects', 'Disease', (189, 206))	('multiple myeloma', 'Disease', 'MESH:D009101', (123, 139))	('common', 'Reg', (217, 223))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('solid tumors', 'Disease', 'MESH:D009369', (156, 168))	('cancers', 'Disease', 'MESH:D009369', (106, 113))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))	('multiple myeloma', 'Disease', (123, 139))	('TRAF3', 'Gene', (13, 18))	('NF-kappaB', 'Gene', (66, 75))	('HPV-positive HNSCC', 'Disease', (227, 245))
136555	28295222	The absence of frequent mutations in uterine cervical cancer24, 25 provides yet another difference between these HPV-associated tumor types.	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('cancer', 'Disease', (54, 60))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('tumor', 'Disease', (128, 133))	('mutations', 'Var', (24, 33))	('HPV', 'Species', '10566', (113, 116))
136556	28295222	In the current report, through in-depth analysis of the TCGA HNSCC data set, we propose that inactivating mutations in TRAF3 or CYLD identify a distinct subset of HPV-positive HNSCC and that this subset has constitutive activation of NF-kappaB signaling.	('HNSCC', 'Disease', (176, 181))	('inactivating mutations', 'Var', (93, 115))	('NF-kappaB', 'MPA', (234, 243))	('HPV', 'Species', '10566', (163, 166))	('TRAF3', 'Gene', (119, 124))	('CYLD', 'Gene', (128, 132))	('activation', 'PosReg', (220, 230))
136557	28295222	This previously undescribed subtype of HPV-positive HNSCC marked by TRAF3 or CYLD mutations is associated with the absence of integrated HPV and improved patient survival.	('absence', 'NegReg', (115, 122))	('HNSCC', 'Disease', (52, 57))	('patient survival', 'CPA', (154, 170))	('patient', 'Species', '9606', (154, 161))	('mutations', 'Var', (82, 91))	('improved', 'PosReg', (145, 153))	('TRAF3', 'Gene', (68, 73))	('HPV', 'Species', '10566', (39, 42))	('HPV', 'Species', '10566', (137, 140))
136561	28295222	3B,C), in the TRAF3/CYLD or PIK3CA wild-type and mutant groups were produced using GraphPad Prism 6 software, and P values were calculated using Fisher exact tests and chi-square tests.	('PIK3CA', 'Gene', (28, 34))	('PIK3CA', 'Gene', '5290', (28, 34))	('mutant', 'Var', (49, 55))
136566	28295222	3; see online supporting information) was performed using software available from The Broad Institute (available at: http://software.broadinstitute.org/gsea/index.jsp).28, 29  One unexpected discovery from TCGA head and neck cancer project was the finding of deletions and/or mutations of TRAF3 in 25% of HPV-associated HNSCCs.12 The majority of TRAF3 alterations were homozygous gene deletions (55%), whereas the remainder were truncating mutations (45%), consistent with TRAF3 inactivation in these tumors (Fig.	('tumor', 'Phenotype', 'HP:0002664', (501, 506))	('head and neck cancer', 'Disease', 'MESH:D006258', (211, 231))	('tumors', 'Phenotype', 'HP:0002664', (501, 507))	('TRAF3', 'Gene', (346, 351))	('tumors', 'Disease', 'MESH:D009369', (501, 507))	('tumors', 'Disease', (501, 507))	('alterations', 'Var', (352, 363))	('HPV', 'Species', '10566', (305, 308))	('head and neck cancer', 'Phenotype', 'HP:0012288', (211, 231))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))
136567	28295222	Notably, 2 mutations, namely, p.R310*/c.928C>T and p.R505*/c.1513C>T, have been reported previously in diffuse large-B cell (DLBC) lymphoma30 and gastric adenocarcinoma, respectively (Fig.	('carcinoma', 'Phenotype', 'HP:0030731', (159, 168))	('c.928C>T', 'Mutation', 'rs201794033', (38, 46))	('diffuse large-B cell', 'Disease', (103, 123))	('p.R310*', 'Mutation', 'p.R310*', (30, 37))	('p.R505*/c.1513C>T', 'Var', (51, 68))	('p.R505*', 'Mutation', 'p.R505*', (51, 58))	('p.R310*/c.928C>T', 'Var', (30, 46))	('lymphoma', 'Disease', (131, 139))	('c.1513C>T', 'Mutation', 'rs765227761', (59, 68))	('reported', 'Reg', (80, 88))	('gastric adenocarcinoma', 'Disease', 'MESH:D013274', (146, 168))	('lymphoma', 'Disease', 'MESH:D008223', (131, 139))	('gastric adenocarcinoma', 'Disease', (146, 168))	('lymphoma', 'Phenotype', 'HP:0002665', (131, 139))
136570	28295222	Because the antiviral activity of TRAF3 requires a full-length, wild-type TRAF3 protein,35, 36 alterations in the TRAF3 gene observed in HPV-positive HNSCC most likely result in the loss of TRAF3 antiviral activity.	('loss', 'NegReg', (182, 186))	('TRAF3', 'Gene', (114, 119))	('antiviral activity', 'MPA', (196, 214))	('alterations', 'Var', (95, 106))	('antiviral activity', 'MPA', (12, 30))	('HPV', 'Species', '10566', (137, 140))
136573	28295222	These analyses revealed that the tumor suppressor CYLD, which inhibits NF-kappaB pathways at various steps, was mutated in 11% of HPV-positive HNSCCs (Fig.	('NF-kappaB pathways', 'Pathway', (71, 89))	('inhibits', 'NegReg', (62, 70))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumor', 'Disease', (33, 38))	('mutated', 'Var', (112, 119))	('HPV', 'Species', '10566', (130, 133))	('HNSCCs', 'Disease', (143, 149))
136574	28295222	The p.S371*/ c.1112C>A, nonsense substitution, has been described previously in adnexal skin tumors.41 In addition, another amino acid 618 substitution in the CYLD gene, an aspartic acid-to-asparagine substitution at codon 618 (D618N) (identified in HPV-positive HNSCC) has been recently reported in cutaneous squamous cell carcinoma.42 It is noteworthy that, the copy number status of mutated CYLD indicates a shallow loss (a possible heterozygous deletion) in all 4 CYLD-mutant samples (Table 1).	('adnexal skin tumors', 'Disease', (80, 99))	('aspartic acid-to-asparagine substitution at codon 618', 'Mutation', 'p.D618N', (173, 226))	('loss', 'NegReg', (419, 423))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (310, 333))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('cutaneous squamous cell carcinoma', 'Disease', (300, 333))	('D618N', 'Mutation', 'p.D618N', (228, 233))	('carcinoma', 'Phenotype', 'HP:0030731', (324, 333))	('c.1112C>A', 'Mutation', 'rs886040872', (13, 22))	('p.S371*', 'Var', (4, 11))	('mutated', 'Var', (386, 393))	('p.S371*', 'SUBSTITUTION', 'None', (4, 11))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('CYLD', 'Gene', (394, 398))	('cutaneous squamous cell carcinoma', 'Disease', 'MESH:D002294', (300, 333))	('HPV', 'Species', '10566', (250, 253))	('adnexal skin tumors', 'Disease', 'MESH:D018294', (80, 99))	('CYLD-mutant', 'Var', (468, 479))
136577	28295222	Like TRAF3, CYLD inhibits NF-kappaB pathways at various steps including, binding, deubiquitinating, and inhibiting the NF-kappaB essential modulator (NEMO).	('inhibits', 'NegReg', (17, 25))	('NEMO', 'Gene', (150, 154))	('NF-kappaB pathways', 'Pathway', (26, 44))	('deubiquitinating', 'MPA', (82, 98))	('binding', 'Interaction', (73, 80))	('NEMO', 'Gene', '8517', (150, 154))	('CYLD', 'Var', (12, 16))	('inhibiting', 'NegReg', (104, 114))	('NF-kappaB essential modulator', 'Gene', '8517', (119, 148))	('NF-kappaB essential modulator', 'Gene', (119, 148))
136579	28295222	These findings suggest that up to 36% of HPV-positive HNSCCs harboring defective TRAF3 or CYLD may rely on overactive NF-kappaB and defective innate immunity.	('overactive', 'PosReg', (107, 117))	('HPV', 'Species', '10566', (41, 44))	('NF-kappaB', 'Protein', (118, 127))	('TRAF3', 'Gene', (81, 86))	('defective', 'Var', (71, 80))
136580	28295222	The above data suggest that a portion of HPV-positive HNSCCs may rely on TRAF3 or CYLD mutations.	('HPV', 'Species', '10566', (41, 44))	('HNSCCs', 'Disease', (54, 60))	('rely on', 'Reg', (65, 72))	('CYLD', 'Var', (82, 86))	('HPV-positive', 'Gene', (41, 53))	('TRAF3', 'Gene', (73, 78))
136582	28295222	Surprisingly, TRAF3 defects detected in uterine cervical cancer, which is associated with high-risk HPVs in about 93% of cases, were reminiscent of the pattern observed in HPV-negative HNSCCs.	('defects', 'Var', (20, 27))	('HPV', 'Species', '10566', (100, 103))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('HPV', 'Species', '10566', (172, 175))	('cancer', 'Disease', (57, 63))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('TRAF3', 'Gene', (14, 19))
136583	28295222	Uterine cervical cancers had infrequent TRAF3 alterations that included both amplifications and deletions (Fig.	('TRAF3', 'Gene', (40, 45))	('cancers', 'Phenotype', 'HP:0002664', (17, 24))	('amplifications', 'MPA', (77, 91))	('deletions', 'Var', (96, 105))	('cervical cancers', 'Disease', (8, 24))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))	('cervical cancers', 'Disease', 'MESH:D002583', (8, 24))
136584	28295222	Alterations of the CYLD gene in uterine cervical cancer were even less frequent (2%), comprising 1 missense mutation and 2 deletions (Fig.	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('Alterations', 'Var', (0, 11))	('CYLD gene', 'Gene', (19, 28))	('deletions', 'Var', (123, 132))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('missense mutation', 'Var', (99, 116))	('cancer', 'Disease', (49, 55))
136585	28295222	Compared with HPV-positive HNSCC, in which TRAF3 and CYLD defects were mutually exclusive, TRAF3 and CYLD defects overlapped in 2 of the 9 uterine cervical cancers that had alterations in either gene.	('cancers', 'Phenotype', 'HP:0002664', (156, 163))	('HPV', 'Species', '10566', (14, 17))	('TRAF3', 'Gene', (91, 96))	('cervical cancers', 'Disease', (147, 163))	('alterations', 'Var', (173, 184))	('CYLD defects', 'Disease', 'MESH:D005128', (101, 113))	('cervical cancers', 'Disease', 'MESH:D002583', (147, 163))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('CYLD defects', 'Disease', 'MESH:D005128', (53, 65))	('CYLD defects', 'Disease', (101, 113))	('CYLD defects', 'Disease', (53, 65))
136586	28295222	To extend these analyses, deep-sequencing data from multiple tumor types was queried for mutations in the TRAF3 and CYLD genes.	('CYLD', 'Gene', (116, 120))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('TRAF3', 'Gene', (106, 111))	('mutations', 'Var', (89, 98))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Disease', (61, 66))
136587	28295222	Tumor types with > 10% alterations of TRAF/CYLD were: breast (data from xenografted tumors), neuroendocrine prostate cancer (NEPC), DLBC lymphoma, and lung squamous cell carcinoma.	('neuroendocrine prostate cancer', 'Disease', 'MESH:D011471', (93, 123))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('carcinoma', 'Phenotype', 'HP:0030731', (170, 179))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (151, 179))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('prostate cancer', 'Phenotype', 'HP:0012125', (108, 123))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (156, 179))	('lymphoma', 'Phenotype', 'HP:0002665', (137, 145))	('lung squamous cell carcinoma', 'Disease', (151, 179))	('alterations', 'Var', (23, 34))	('tumors', 'Disease', (84, 90))	('tumors', 'Disease', 'MESH:D009369', (84, 90))	('breast', 'Disease', (54, 60))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('DLBC lymphoma', 'Disease', (132, 145))	('DLBC lymphoma', 'Disease', 'MESH:D008223', (132, 145))	('neuroendocrine prostate cancer', 'Disease', (93, 123))
136589	28295222	DLBC lymphoma and lung squamous cancer each had a significant proportion of total TRAF/CYLD alterations (mutations and deletions) and relatively few samples had amplification.	('lymphoma', 'Phenotype', 'HP:0002665', (5, 13))	('DLBC lymphoma', 'Disease', (0, 13))	('deletions', 'Var', (119, 128))	('lung squamous cancer', 'Disease', 'MESH:D008175', (18, 38))	('lung squamous cancer', 'Phenotype', 'HP:0030359', (18, 38))	('DLBC lymphoma', 'Disease', 'MESH:D008223', (0, 13))	('squamous cancer', 'Phenotype', 'HP:0002860', (23, 38))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('lung squamous cancer', 'Disease', (18, 38))
136591	28295222	A recent study of another EBV-associated cancer, nasopharyngeal carcinoma, identified numerous inactivating mutations in NF-kappaB-negative regulators, including CYLD, NF-kappaB inhibitor alpha (NFKBIA), and tumor necrosis factor alpha-induced protein 3 (TNFAIP3), in 17% of these tumors.46  Across all solid tumor types, frequent inactivating TRAF3 and CYLD alterations, which are predicted to constitutively activate NF-kappaB pathways while inhibiting innate immunity, occur only in HPV-positive HNSCC.	('tumors', 'Disease', 'MESH:D009369', (281, 287))	('nasopharyngeal carcinoma', 'Disease', (49, 73))	('NF-kappaB pathways', 'Pathway', (419, 437))	('innate', 'MPA', (455, 461))	('cancer', 'Disease', (41, 47))	('activate', 'PosReg', (410, 418))	('tumor', 'Disease', (281, 286))	('TRAF3', 'Gene', (344, 349))	('nasopharyngeal carcinoma', 'Disease', 'MESH:D000077274', (49, 73))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('tumor', 'Disease', 'MESH:D009369', (281, 286))	('HPV', 'Species', '10566', (486, 489))	('tumor', 'Disease', (208, 213))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))	('tumors', 'Phenotype', 'HP:0002664', (281, 287))	('tumor', 'Disease', (309, 314))	('inactivating', 'NegReg', (331, 343))	('tumor', 'Disease', 'MESH:D009369', (208, 213))	('alterations', 'Var', (359, 370))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (49, 73))	('tumor necrosis', 'Disease', 'MESH:D009336', (208, 222))	('EBV', 'Species', '10376', (26, 29))	('tumor', 'Disease', 'MESH:D009369', (309, 314))	('CYLD', 'Gene', (354, 358))	('tumor', 'Phenotype', 'HP:0002664', (281, 286))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('tumor necrosis', 'Disease', (208, 222))	('inhibiting', 'NegReg', (444, 454))	('tumors', 'Disease', (281, 287))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('tumor', 'Phenotype', 'HP:0002664', (309, 314))
136593	28295222	We and others previously reported that HPV-associated head and neck cancer more frequently, although not exclusively, contained alterations in the PIK3CA gene47, 48 In contrast to TRAF3/CYLD mutations, PIK3CA mutations or amplifications are commonly detected in cervical and head and neck cancers regardless of HPV status (Supporting Fig.	('neck cancers regardless of HPV status', 'Disease', 'MESH:D030361', (284, 321))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('alterations', 'Var', (128, 139))	('head and neck cancer', 'Disease', 'MESH:D006258', (54, 74))	('head and neck cancer', 'Phenotype', 'HP:0012288', (275, 295))	('cancer', 'Phenotype', 'HP:0002664', (289, 295))	('cervical', 'Disease', (262, 270))	('PIK3CA', 'Gene', (202, 208))	('PIK3CA', 'Gene', (147, 153))	('head and neck cancers', 'Phenotype', 'HP:0012288', (275, 296))	('PIK3CA', 'Gene', '5290', (202, 208))	('cancers', 'Phenotype', 'HP:0002664', (289, 296))	('PIK3CA', 'Gene', '5290', (147, 153))	('head and neck cancer', 'Disease', 'MESH:D006258', (275, 295))	('HPV', 'Species', '10566', (311, 314))	('HPV', 'Species', '10566', (39, 42))	('head and neck cancer', 'Phenotype', 'HP:0012288', (54, 74))	('neck cancers regardless of HPV status', 'Disease', (284, 321))
136594	28295222	It is noteworthy that, among 20 HPV-positive head and neck tumors with alterations in PIK3CA gene, 4 samples harbored mutations in TRAF3/CYLD; whereas, among 16 tumors without PIK3CA mutations, 9 contained alterations in TRAF3/CYLD, indicating a tendency toward mutual exclusivity (log odds ratio, -1.1; P = .25) (Supporting Fig.	('alterations', 'Reg', (206, 217))	('tumors', 'Disease', (161, 167))	('tumors', 'Disease', 'MESH:D009369', (59, 65))	('neck tumors', 'Disease', (54, 65))	('mutual', 'MPA', (262, 268))	('tumors', 'Disease', 'MESH:D009369', (161, 167))	('PIK3CA', 'Gene', (176, 182))	('PIK3CA', 'Gene', '5290', (86, 92))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('mutations', 'Var', (118, 127))	('neck tumors', 'Disease', 'MESH:D006258', (54, 65))	('alterations', 'Var', (71, 82))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('HPV', 'Species', '10566', (32, 35))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('tumors', 'Phenotype', 'HP:0002664', (161, 167))	('PIK3CA', 'Gene', (86, 92))	('tumors', 'Disease', (59, 65))	('head and neck tumors', 'Phenotype', 'HP:0012288', (45, 65))	('PIK3CA', 'Gene', '5290', (176, 182))	('TRAF3/CYLD', 'Gene', (131, 141))
136595	28295222	In addition to high-risk HPV infection, several cofactors are associated with uterine cervical tumorigenesis, including alcohol consumption, coinfection with other infectious agents, and smoking.49, 50, 51 In contrast, tobacco smoking is not etiologically implicated in HPV-positive head and neck cancer, but it is associated with decreased survival in patients who have HPV-positive head and neck cancer.4, 52 It is noteworthy that there were relatively high numbers of patients who had a history of smoking in the HPV-positive TCGA cohort.12 Querying the TCGA cohort for TRAF3/CYLD mutations and smoking history revealed a correlation between the absence of smoking and TRAF3/CYLD gene defects, but this association did not reach statistical significance (P = .064) (Fig.	('tobacco', 'Species', '4097', (219, 226))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('head and neck cancer', 'Phenotype', 'HP:0012288', (283, 303))	('head and neck cancer', 'Phenotype', 'HP:0012288', (384, 404))	('cancer', 'Phenotype', 'HP:0002664', (398, 404))	('HPV infection', 'Disease', 'MESH:D030361', (25, 38))	('patients', 'Species', '9606', (353, 361))	('HPV infection', 'Disease', (25, 38))	('HPV', 'Species', '10566', (25, 28))	('head and neck cancer', 'Disease', 'MESH:D006258', (283, 303))	('head and neck cancer', 'Disease', 'MESH:D006258', (384, 404))	('CYLD gene defects', 'Disease', 'MESH:D025063', (678, 695))	('HPV', 'Species', '10566', (270, 273))	('patients', 'Species', '9606', (471, 479))	('absence', 'Var', (649, 656))	('tumor', 'Disease', (95, 100))	('HPV', 'Species', '10566', (516, 519))	('CYLD gene defects', 'Disease', (678, 695))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('cancer', 'Phenotype', 'HP:0002664', (297, 303))	('HPV', 'Species', '10566', (371, 374))
136598	28295222	The majority of TRAF3/CYLD mutant tumors (54%) had no HPV integration, whereas only 10% of TRAF3/CYLD wild-type samples lacked HPV integration (Fig.	('tumors', 'Disease', (34, 40))	('tumors', 'Disease', 'MESH:D009369', (34, 40))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('mutant', 'Var', (27, 33))	('TRAF3/CYLD', 'Gene', (16, 26))	('HPV integration', 'MPA', (54, 69))	('HPV', 'Species', '10566', (54, 57))	('HPV', 'Species', '10566', (127, 130))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
136599	28295222	These data suggest that defects in TRAF3/CYLD may not be required if tumors contain integrated HPV or, alternatively, that the maintenance of episomal HPV pressures cells to mutate TRAF3/CYLD.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('mutate', 'Var', (174, 180))	('episomal HPV', 'Disease', (142, 154))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('TRAF3/CYLD', 'Gene', (181, 191))	('episomal HPV', 'Disease', 'MESH:D030361', (142, 154))	('tumors', 'Disease', (69, 75))	('tumors', 'Disease', 'MESH:D009369', (69, 75))	('HPV', 'Species', '10566', (95, 98))	('HPV', 'Species', '10566', (151, 154))
136602	28295222	These data led the authors of a previous publication to propose that a subset of HPV-positive HNSCC tumors contain both episomal and integrated HPV DNA.13 The incorporation of tumors suspected to harbor both integrated and episomal forms of HPV into the TRAF3/CYLD mutation analyses revealed that 11 of 13 tumors (85%) with mutant TRAF3/CYLD contained episomal HPV, whereas 6 of 21 (29%) TRAF3/CYLD wild-type tumors harbored episomal HPV DNA (Fig.	('episomal HPV', 'Disease', (352, 364))	('tumors', 'Disease', 'MESH:D009369', (409, 415))	('tumors harbored episomal HPV', 'Disease', 'MESH:D030361', (409, 437))	('tumors', 'Disease', 'MESH:D009369', (176, 182))	('HPV', 'Species', '10566', (434, 437))	('HPV', 'Species', '10566', (241, 244))	('contained', 'Reg', (342, 351))	('HPV', 'Species', '10566', (361, 364))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('tumors', 'Phenotype', 'HP:0002664', (306, 312))	('HPV', 'Species', '10566', (81, 84))	('tumor', 'Phenotype', 'HP:0002664', (409, 414))	('tumors harbored episomal HPV', 'Disease', (409, 437))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('HPV-positive HNSCC tumors', 'Disease', 'MESH:D000077195', (81, 106))	('tumor', 'Phenotype', 'HP:0002664', (306, 311))	('mutant', 'Var', (324, 330))	('tumors', 'Disease', (306, 312))	('tumors', 'Disease', (100, 106))	('HPV-positive HNSCC tumors', 'Disease', (81, 106))	('tumors', 'Phenotype', 'HP:0002664', (176, 182))	('tumors', 'Phenotype', 'HP:0002664', (409, 415))	('HPV', 'Species', '10566', (144, 147))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('episomal HPV', 'Disease', 'MESH:D030361', (425, 437))	('tumors', 'Disease', (409, 415))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('tumors', 'Disease', (176, 182))	('tumors', 'Disease', 'MESH:D009369', (306, 312))	('episomal HPV', 'Disease', 'MESH:D030361', (352, 364))
136604	28295222	Mechanistically, mutations in TRAF3 or CYLD may create a cellular microenvironment needed to support the maintenance of the HPV episome as an alternative to classic HPV carcinogenesis, which that depends on the integration and loss of episomal HPV.	('HPV episome', 'Disease', 'MESH:D030361', (124, 135))	('CYLD', 'Gene', (39, 43))	('HPV episome', 'Disease', (124, 135))	('loss of episomal HPV', 'Disease', 'MESH:D030361', (227, 247))	('TRAF3', 'Gene', (30, 35))	('HPV carcinogenesis', 'Disease', (165, 183))	('mutations', 'Var', (17, 26))	('loss of episomal HPV', 'Disease', (227, 247))	('HPV carcinogenesis', 'Disease', 'MESH:D030361', (165, 183))
136605	28295222	Studies from EBV-related cancers or hepatocellular carcinoma, along with HNSCC, suggest that PIK3CA mutations are common in virally associated cancers and may be mediated by viral infection.	('viral infection', 'Disease', (174, 189))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (36, 60))	('EBV', 'Species', '10376', (13, 16))	('cancers', 'Phenotype', 'HP:0002664', (25, 32))	('PIK3CA', 'Gene', (93, 99))	('cancers', 'Disease', (25, 32))	('viral infection', 'Disease', 'MESH:D001102', (174, 189))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('cancers', 'Phenotype', 'HP:0002664', (143, 150))	('cancers', 'Disease', (143, 150))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (36, 60))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('common', 'Reg', (114, 120))	('hepatocellular carcinoma', 'Disease', (36, 60))	('cancers', 'Disease', 'MESH:D009369', (25, 32))	('mutations', 'Var', (100, 109))	('PIK3CA', 'Gene', '5290', (93, 99))	('cancers', 'Disease', 'MESH:D009369', (143, 150))	('carcinoma', 'Phenotype', 'HP:0030731', (51, 60))
136613	28295222	In contrast, PIK3CA mutations did not influence the overall survival of patients in this cohort (Supporting Fig.	('PIK3CA', 'Gene', '5290', (13, 19))	('mutations', 'Var', (20, 29))	('PIK3CA', 'Gene', (13, 19))	('patients', 'Species', '9606', (72, 80))
136615	28295222	Genes that were highly expressed in tumors with TRAF3/CYLD mutations were enriched for those that shared NF-kappaB or epidermal growth factor 1 (EGR-1) binding sites (Fig.	('EGR-1', 'Gene', (145, 150))	('tumors', 'Disease', 'MESH:D009369', (36, 42))	('highly', 'PosReg', (16, 22))	('EGR-1', 'Gene', '1958', (145, 150))	('binding', 'Interaction', (152, 159))	('NF-kappaB', 'Protein', (105, 114))	('epidermal growth factor 1', 'Gene', '1958', (118, 143))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('mutations', 'Var', (59, 68))	('TRAF3/CYLD', 'Gene', (48, 58))	('tumors', 'Disease', (36, 42))	('epidermal growth factor 1', 'Gene', (118, 143))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))
136617	28295222	4B), whereas genes that are highly expressed in tumors with altered PIK3CA are enriched for those that share androgen receptor or hypoxia-inducible factor 1alpha binding sites (Supporting Fig.	('hypoxia', 'Disease', (130, 137))	('PIK3CA', 'Gene', (68, 74))	('hypoxia', 'Disease', 'MESH:D000860', (130, 137))	('tumors', 'Disease', (48, 54))	('tumors', 'Disease', 'MESH:D009369', (48, 54))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('PIK3CA', 'Gene', '5290', (68, 74))	('altered', 'Var', (60, 67))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
136620	28295222	To identify additional biologic functions or pathways associated with TRAF3/CYLD mutations, we ran GSEA using data sets of oncogenic and immunologic signatures as well as hallmark gene sets.	('GSEA', 'Chemical', '-', (99, 103))	('mutations', 'Var', (81, 90))	('TRAF3/CYLD', 'Gene', (70, 80))
136623	28295222	Conversely, mutant tumors were enriched in DNA replication genes,53, 63 in genes that distinguished HPV-positive from HPV-negative HNSCC,53 and in genes that were up-regulated in nasopharyngeal carcinoma compared with normal tissue64 (Fig.	('nasopharyngeal carcinoma', 'Disease', 'MESH:D000077274', (179, 203))	('tumors', 'Disease', (19, 25))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('HPV', 'Species', '10566', (100, 103))	('nasopharyngeal carcinoma', 'Disease', (179, 203))	('up-regulated', 'PosReg', (163, 175))	('carcinoma', 'Phenotype', 'HP:0030731', (194, 203))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (179, 203))	('HPV', 'Species', '10566', (118, 121))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('mutant', 'Var', (12, 18))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('DNA', 'Gene', (43, 46))
136627	28295222	5C) had a high representation of DNA repair and replication genes.64  Confirming our previous finding that mutant PIK3CA in HPV-positive tumors correlated with activation of the mechanistic target of rapamycin (mTOR) pathway, tumors with altered PIK3CA in the TCGA cohort overexpressed genes that were up-regulated by activation of the mTORC1 complex or during the unfolded protein response (Supporting Fig.	('PIK3CA', 'Gene', '5290', (114, 120))	('HPV-positive tumors', 'Disease', (124, 143))	('tumors', 'Disease', (137, 143))	('tumors', 'Disease', 'MESH:D009369', (226, 232))	('up-regulated', 'PosReg', (302, 314))	('HPV-positive tumors', 'Disease', 'MESH:D030361', (124, 143))	('PIK3CA', 'Gene', '5290', (246, 252))	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('overexpressed', 'PosReg', (272, 285))	('PIK3CA', 'Gene', (114, 120))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('mTORC1', 'Gene', (336, 342))	('tumors', 'Phenotype', 'HP:0002664', (226, 232))	('mTORC1', 'Gene', '382056', (336, 342))	('activation', 'PosReg', (160, 170))	('genes', 'Gene', (286, 291))	('PIK3CA', 'Gene', (246, 252))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('mutant', 'Var', (107, 113))	('tumors', 'Disease', (226, 232))	('altered', 'Var', (238, 245))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
136629	28295222	The data presented here suggest that, within HPV-positive tumors, there are 2 major subgroups that can be distinguished based on TRAF3 or CYLD mutations.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('TRAF3', 'Gene', (129, 134))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('HPV-positive tumors', 'Disease', 'MESH:D030361', (45, 64))	('HPV-positive tumors', 'Disease', (45, 64))	('mutations', 'Var', (143, 152))
136630	28295222	Comparison of HPV-positive tumors with and without TRAF3 or CYLD mutations revealed that mutant tumors had improved survival and expressed genes that were enriched in HPV-positive gene sets, suggesting that the tumors harboring TRAF3 or CYLD defects are the drivers of differences in gene expression between HPV-positive versus HPV-negative HNSCC and contribute significantly to the improved survival of patients with HPV-positive tumors.	('tumors', 'Disease', 'MESH:D009369', (211, 217))	('HPV', 'Species', '10566', (14, 17))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('patients', 'Species', '9606', (404, 412))	('HPV-positive tumors', 'Disease', 'MESH:D030361', (418, 437))	('tumors', 'Disease', (96, 102))	('tumors', 'Disease', 'MESH:D009369', (27, 33))	('HPV-positive tumors', 'Disease', 'MESH:D030361', (14, 33))	('improved', 'PosReg', (383, 391))	('mutant', 'Var', (89, 95))	('tumors', 'Disease', 'MESH:D009369', (431, 437))	('gene expression', 'MPA', (284, 299))	('mutations', 'Var', (65, 74))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('differences', 'Reg', (269, 280))	('tumors', 'Phenotype', 'HP:0002664', (211, 217))	('HPV', 'Species', '10566', (328, 331))	('HPV-positive tumors', 'Disease', (14, 33))	('CYLD defects', 'Disease', 'MESH:D005128', (237, 249))	('CYLD defects', 'Disease', (237, 249))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('tumors', 'Disease', (211, 217))	('tumors', 'Phenotype', 'HP:0002664', (431, 437))	('HPV', 'Species', '10566', (167, 170))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('improved', 'PosReg', (107, 115))	('TRAF3', 'Gene', (228, 233))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('tumors', 'Disease', (27, 33))	('HPV-positive tumors', 'Disease', (418, 437))	('tumor', 'Phenotype', 'HP:0002664', (431, 436))	('tumors', 'Disease', (431, 437))	('HPV', 'Species', '10566', (308, 311))	('HPV', 'Species', '10566', (418, 421))
136631	28295222	Our data also suggest that TRAF3 or CYLD mutations harbor episomal HPV and have activated NF-kappaB, which may be required for episomal maintenance.	('mutations', 'Var', (41, 50))	('harbor', 'Reg', (51, 57))	('NF-kappaB', 'Protein', (90, 99))	('episomal HPV', 'Disease', 'MESH:D030361', (58, 70))	('TRAF3', 'Gene', (27, 32))	('CYLD', 'Gene', (36, 40))	('activated', 'PosReg', (80, 89))	('episomal HPV', 'Disease', (58, 70))
136633	28295222	It is noteworthy that the transcriptome of tumors with altered TRAF3/CYLD is highly enriched in genes that are overexpressed in well differentiated squamous cells (Fig.	('altered', 'Var', (55, 62))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumors', 'Disease', (43, 49))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('TRAF3/CYLD', 'Gene', (63, 73))	('tumors', 'Disease', 'MESH:D009369', (43, 49))
136637	28295222	We observed that patients who had wild-type TRAF3 and CYLD tumors had worse survival, which may implicate IFN signaling in therapeutic resistance (Fig.	('survival', 'MPA', (76, 84))	('worse', 'NegReg', (70, 75))	('IFN', 'Gene', '3439', (106, 109))	('TRAF3', 'Gene', (44, 49))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('IFN', 'Gene', (106, 109))	('CYLD tumors', 'Disease', (54, 65))	('CYLD tumors', 'Disease', 'MESH:D009369', (54, 65))	('wild-type', 'Var', (34, 43))	('patients', 'Species', '9606', (17, 25))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
136639	28295222	Further profiling of HPV-associated head and neck samples is needed to confirm the significance of TRAF3/CYLD mutations in HNSCC and to determine whether additional regulators of NF-kappaB, which is known to be mutated in human cancer (Fig.	('HPV', 'Species', '10566', (21, 24))	('cancer', 'Disease', (228, 234))	('mutations', 'Var', (110, 119))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('HNSCC', 'Gene', (123, 128))	('human', 'Species', '9606', (222, 227))	('cancer', 'Disease', 'MESH:D009369', (228, 234))
136640	28295222	Although additional data may improve biomarker selection for predicting prognosis, these studies suggest that TRAF3 and CYLD mutations are useful for selecting patients who have HPV-positive HNSCC with an improved outcome and suggest that these patients may be most appropriate for trials of therapeutic de-escalation.	('TRAF3', 'Gene', (110, 115))	('mutations', 'Var', (125, 134))	('patients', 'Species', '9606', (160, 168))	('patients', 'Species', '9606', (245, 253))	('CYLD', 'Gene', (120, 124))	('HNSCC', 'Disease', (191, 196))	('HPV', 'Species', '10566', (178, 181))
136642	28295222	These groups are distinguished by the presence or absence of TRAF3/CYLD mutations, which are associated with the presence of HPV episomes and a lack of HPV genome integration.	('mutations', 'Var', (72, 81))	('TRAF3/CYLD', 'Gene', (61, 71))	('HPV', 'Species', '10566', (152, 155))	('HPV', 'Species', '10566', (125, 128))	('HPV episomes', 'Disease', 'MESH:D030361', (125, 137))	('HPV episomes', 'Disease', (125, 137))
136643	28295222	The presence of HPV episomes is not well described in other HPV-associated cancers, and uterine cervical cancers do not have frequent mutations in TRAF3 or CYLD.	('cancers', 'Phenotype', 'HP:0002664', (105, 112))	('cancers', 'Disease', 'MESH:D009369', (75, 82))	('cancers', 'Phenotype', 'HP:0002664', (75, 82))	('cancers', 'Disease', (105, 112))	('cancers', 'Disease', (75, 82))	('cervical cancers', 'Disease', (96, 112))	('cancers', 'Disease', 'MESH:D009369', (105, 112))	('cervical cancers', 'Disease', 'MESH:D002583', (96, 112))	('HPV', 'Species', '10566', (16, 19))	('HPV episomes', 'Disease', 'MESH:D030361', (16, 28))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('HPV', 'Species', '10566', (60, 63))	('mutations', 'Var', (134, 143))	('TRAF3', 'Gene', (147, 152))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('HPV episomes', 'Disease', (16, 28))
136644	28295222	The co-occurrence of episomal HPV with TRAF3 or CYLD mutations suggests an alternative route of HPV carcinogenesis based on selection for HPV integration and high levels of HPV E6 and E7 expression (classic) or for TRAF3 or CYLD mutations with low HPV oncogene expression (alternative).	('HPV', 'Species', '10566', (96, 99))	('episomal HPV', 'Disease', 'MESH:D030361', (21, 33))	('HPV carcinogenesis', 'Disease', (96, 114))	('TRAF3', 'Gene', (39, 44))	('HPV', 'Species', '10566', (138, 141))	('HPV', 'Species', '10566', (248, 251))	('HPV', 'Species', '10566', (173, 176))	('mutations', 'Var', (53, 62))	('HPV', 'Species', '10566', (30, 33))	('episomal HPV', 'Disease', (21, 33))	('HPV carcinogenesis', 'Disease', 'MESH:D030361', (96, 114))	('E6 and E7', 'Gene', '25479186', (177, 186))
136646	28295222	In the classic pathway, HPV integrates to avoid recognition by PRR; whereas, in the alternative pathway, episomal HPV can be recognized, but somatic mutations that block innate immune response while activating NF-kappaB to promote cell survival are selected.	('block', 'NegReg', (164, 169))	('NF-kappaB', 'Protein', (210, 219))	('mutations', 'Var', (149, 158))	('activating', 'PosReg', (199, 209))	('HPV', 'Species', '10566', (24, 27))	('HPV', 'Species', '10566', (114, 117))	('episomal HPV', 'Disease', (105, 117))	('cell survival', 'CPA', (231, 244))	('episomal HPV', 'Disease', 'MESH:D030361', (105, 117))	('promote', 'PosReg', (223, 230))
136647	28295222	Significantly, HNSCC with defects in the TRAF3/CYLD genes have a better prognosis compared with tumors that lack mutations (Fig.	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumors', 'Disease', (96, 102))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('HNSCC', 'Disease', (15, 20))	('defects', 'Var', (26, 33))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('TRAF3/CYLD', 'Gene', (41, 51))
136649	28295222	Our data suggest that constitutively active NF-kappaB resulting from somatic mutations in TRAF3 or CYLD may serve as a biomarker to predict an improved prognosis for patients with HPV-positive head and neck cancer.	('TRAF3', 'Gene', (90, 95))	('improved', 'PosReg', (143, 151))	('HPV', 'Species', '10566', (180, 183))	('head and neck cancer', 'Phenotype', 'HP:0012288', (193, 213))	('NF-kappaB', 'Protein', (44, 53))	('mutations', 'Var', (77, 86))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('patients', 'Species', '9606', (166, 174))	('head and neck cancer', 'Disease', 'MESH:D006258', (193, 213))
136660	32632840	1c) that often exhibit an eosinophilic-glassy cytoplasm and basally located nuclei with well-developed (florid) nuclear features of PTC, columnar cell variants often display subnuclear vacuolization and/or cytoplasmic clearing along with elongated nuclei, dark chromatin, and less florid nuclear features of classic PTCs.	('display', 'Reg', (166, 173))	('variants', 'Var', (151, 159))	('PTC', 'Gene', '5979', (132, 135))	('PTC', 'Gene', (316, 319))	('cytoplasmic clearing', 'CPA', (206, 226))	('PTC', 'Gene', '5979', (316, 319))	('subnuclear vacuolization', 'CPA', (174, 198))	('PTC', 'Gene', (132, 135))
136662	32632840	While there are also PTCs consisting of mixed columnar cell and tall cell variants, combined tumors in association with mucoepidermoid carcinoma and columnar cell variants with hyaline globules that can simulate adenoid cystic carcinoma have been recognized.	('carcinoma', 'Phenotype', 'HP:0030731', (227, 236))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('hyaline globules', 'Phenotype', 'HP:0025115', (177, 193))	('mucoepidermoid carcinoma', 'Disease', (120, 144))	('tumors', 'Disease', 'MESH:D009369', (93, 99))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('PTC', 'Gene', (21, 24))	('PTC', 'Gene', '5979', (21, 24))	('cystic carcinoma', 'Disease', (220, 236))	('tumors', 'Disease', (93, 99))	('variants', 'Var', (74, 82))	('mucoepidermoid carcinoma', 'Disease', 'MESH:D018277', (120, 144))	('cystic carcinoma', 'Disease', 'MESH:D009369', (220, 236))
136668	32632840	Positivity for CDX2, a putative intestinal-type transcription factor, has been reported in some cases.	('CDX2', 'Gene', (15, 19))	('CDX2', 'Gene', '1045', (15, 19))	('Positivity', 'Var', (0, 10))
136675	32632840	It is important to distinguish hobnail cell variants from a cystic degenerate classical variant PTCs with hobnail cell-like change.	('PTC', 'Gene', '5979', (96, 99))	('hobnail cell', 'Disease', (31, 43))	('PTC', 'Gene', (96, 99))	('variants', 'Var', (44, 52))
136678	32632840	Synchronous or metachronous association of this variant with poorly differentiated thyroid carcinoma or with anaplastic thyroid carcinoma has also been described.	('thyroid carcinoma', 'Disease', (83, 100))	('anaplastic thyroid carcinoma', 'Disease', 'MESH:D065646', (109, 137))	('anaplastic thyroid carcinoma', 'Phenotype', 'HP:0011779', (109, 137))	('anaplastic thyroid carcinoma', 'Disease', (109, 137))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (120, 137))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (120, 137))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (83, 100))	('variant', 'Var', (48, 55))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (83, 100))
136681	32632840	BRAFV600E and TP53 mutations are the most common molecular alterations in this variant of PTC.	('TP53', 'Gene', '7157', (14, 18))	('TP53', 'Gene', (14, 18))	('PTC', 'Gene', (90, 93))	('BRAFV600E', 'Mutation', 'rs113488022', (0, 9))	('BRAFV600E', 'Var', (0, 9))	('PTC', 'Gene', '5979', (90, 93))
136682	32632840	TERT promoter mutations, PIK3CA, CTNNB1, EGFR, AKT1 and NOTCH1 mutations, and RET/PTC1 rearrangements have also been reported.	('mutations', 'Var', (63, 72))	('PTC1', 'Gene', (82, 86))	('EGFR', 'Gene', (41, 45))	('RET', 'Gene', (78, 81))	('PTC1', 'Gene', '5727', (82, 86))	('AKT1', 'Gene', '207', (47, 51))	('CTNNB1', 'Gene', '1499', (33, 39))	('EGFR', 'Gene', '1956', (41, 45))	('TERT', 'Gene', (0, 4))	('PIK3CA', 'Gene', (25, 31))	('TERT', 'Gene', '7015', (0, 4))	('PIK3CA', 'Gene', '5290', (25, 31))	('NOTCH1', 'Gene', '4851', (56, 62))	('NOTCH1', 'Gene', (56, 62))	('CTNNB1', 'Gene', (33, 39))	('RET', 'Gene', '5979', (78, 81))	('AKT1', 'Gene', (47, 51))
136698	32632840	The peculiar endodermal (intestinal-like) tumor phenotype is due to the permanent activation of the WNT/beta-catenin pathway secondary to germline and/or somatic mutations in APC, CTNNB1, and/or AXIN1.	('mutations', 'Var', (162, 171))	('tumor', 'Disease', (42, 47))	('beta-catenin', 'Gene', (104, 116))	('CTNNB1', 'Gene', '1499', (180, 186))	('APC', 'Disease', 'MESH:D011125', (175, 178))	('beta-catenin', 'Gene', '1499', (104, 116))	('APC', 'Disease', (175, 178))	('activation', 'PosReg', (82, 92))	('CTNNB1', 'Gene', (180, 186))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('AXIN1', 'Gene', '8312', (195, 200))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('AXIN1', 'Gene', (195, 200))
136699	32632840	RET/PTC rearrangements and mutations in PIK3CA or RAS genes can act as additional upstream effectors in this pathway in sporadic and FAP-associated cribriform-morular thyroid carcinoma.	('mutations', 'Var', (27, 36))	('RET', 'Gene', '5979', (0, 3))	('FAP', 'Disease', 'MESH:C567782', (133, 136))	('PIK3CA', 'Gene', (40, 46))	('PIK3CA', 'Gene', '5290', (40, 46))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (167, 184))	('RET', 'Gene', (0, 3))	('PTC', 'Gene', (4, 7))	('FAP', 'Disease', (133, 136))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (167, 184))	('thyroid carcinoma', 'Disease', (167, 184))	('carcinoma', 'Phenotype', 'HP:0030731', (175, 184))	('RAS', 'Gene', (50, 53))	('rearrangements', 'Var', (8, 22))	('PTC', 'Gene', '5979', (4, 7))
136702	32632840	However, positivity for TTF1 often facilitates the appropriate diagnosis.	('positivity', 'Var', (9, 19))	('TTF1', 'Gene', (24, 28))	('TTF1', 'Gene', '7270', (24, 28))	('facilitates', 'PosReg', (35, 46))
136715	32632840	While TTF-1 is typically expressed in most medullary thyroid carcinomas, one should also note that PAX8 antibodies can show reactivity depending on their clones; for instance, most C-terminus specific PAX8 antibodies and N-terminus-specific MRQ-50 PAX8 antibody are often negative in medullary thyroid carcinomas.	('medullary thyroid carcinoma', 'Phenotype', 'HP:0002865', (43, 70))	('thyroid carcinomas', 'Disease', 'MESH:D013964', (294, 312))	('thyroid carcinomas', 'Disease', (294, 312))	('C-terminus specific', 'Var', (181, 200))	('TTF-1', 'Gene', (6, 11))	('PAX8', 'Gene', (201, 205))	('thyroid carcinomas', 'Disease', 'MESH:D013964', (53, 71))	('thyroid carcinomas', 'Disease', (53, 71))	('carcinomas', 'Phenotype', 'HP:0030731', (302, 312))	('medullary thyroid carcinomas', 'Phenotype', 'HP:0002865', (43, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (302, 311))	('PAX8', 'Gene', (99, 103))	('thyroid carcinomas', 'Phenotype', 'HP:0002890', (294, 312))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (53, 70))	('PAX8', 'Gene', '7849', (201, 205))	('PAX8', 'Gene', (248, 252))	('PAX8', 'Gene', '7849', (99, 103))	('thyroid carcinomas', 'Phenotype', 'HP:0002890', (53, 71))	('PAX8', 'Gene', '7849', (248, 252))	('negative', 'NegReg', (272, 280))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('carcinomas', 'Phenotype', 'HP:0030731', (61, 71))	('medullary thyroid carcinomas', 'Phenotype', 'HP:0002865', (284, 312))	('TTF-1', 'Gene', '7270', (6, 11))	('medullary thyroid carcinoma', 'Phenotype', 'HP:0002865', (284, 311))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (294, 311))
136717	32632840	This is an extremely rare cytomorphological variant of PTC that was reported in a patient with Marfan syndrome due to FBN1 gene mutation.	('patient', 'Species', '9606', (82, 89))	('Marfan syndrome', 'Disease', (95, 110))	('FBN1', 'Gene', (118, 122))	('due to', 'Reg', (111, 117))	('FBN1', 'Gene', '2200', (118, 122))	('Marfan syndrome', 'Disease', 'MESH:D008382', (95, 110))	('PTC', 'Gene', (55, 58))	('mutation', 'Var', (128, 136))	('PTC', 'Gene', '5979', (55, 58))
136731	32632840	Gain-of-function mutation of TSHR might also contribute to the development of clear cell appearance in thyroid tumors.	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('thyroid tumors', 'Disease', (103, 117))	('mutation', 'Var', (17, 25))	('thyroid tumors', 'Disease', 'MESH:D013964', (103, 117))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('Gain-of-function', 'PosReg', (0, 16))	('TSHR', 'Gene', '7253', (29, 33))	('thyroid tumor', 'Phenotype', 'HP:0100031', (103, 116))	('TSHR', 'Gene', (29, 33))	('clear', 'Disease', (78, 83))
136745	32632840	At a molecular level, functional follicular adenomas have been linked to activating mutations in TSHR, GNAS, and/or EZH1 genes.	('GNAS', 'Gene', '2778', (103, 107))	('adenomas', 'Disease', 'MESH:D000236', (44, 52))	('linked', 'Reg', (63, 69))	('TSHR', 'Gene', '7253', (97, 101))	('adenomas', 'Disease', (44, 52))	('EZH1', 'Gene', '2145', (116, 120))	('EZH1', 'Gene', (116, 120))	('GNAS', 'Gene', (103, 107))	('TSHR', 'Gene', (97, 101))	('activating mutations', 'Var', (73, 93))
136746	32632840	In most cases, EZH1 gene mutation has been detected in association with either TSHR or GNAS mutations, suggesting a 2-hit model for the pathogenesis of autonomous thyroid adenomas.	('TSHR', 'Gene', '7253', (79, 83))	('GNAS', 'Gene', '2778', (87, 91))	('EZH1', 'Gene', '2145', (15, 19))	('autonomous thyroid adenomas', 'Disease', (152, 179))	('mutation', 'Var', (25, 33))	('autonomous thyroid adenomas', 'Disease', 'MESH:D013964', (152, 179))	('mutations', 'Var', (92, 101))	('TSHR', 'Gene', (79, 83))	('GNAS', 'Gene', (87, 91))	('EZH1', 'Gene', (15, 19))	('thyroid adenomas', 'Phenotype', 'HP:0000854', (163, 179))
136748	32632840	Most cases carry mutations in the TSHR signaling pathway; cases with concurrent mutations in TSHR and RAS genes, as well as concomitant TSHR mutation and PAX8-PPARgamma rearrangement, have been reported (Fig.	('PAX8', 'Gene', '7849', (154, 158))	('PPARgamma', 'Gene', '5468', (159, 168))	('TSHR', 'Gene', '7253', (93, 97))	('TSHR', 'Gene', (136, 140))	('PAX8', 'Gene', (154, 158))	('TSHR', 'Gene', (34, 38))	('mutations', 'Var', (80, 89))	('TSHR', 'Gene', '7253', (136, 140))	('mutations', 'Var', (17, 26))	('TSHR', 'Gene', (93, 97))	('RAS', 'Gene', (102, 105))	('mutation', 'Var', (141, 149))	('TSHR', 'Gene', '7253', (34, 38))	('PPARgamma', 'Gene', (159, 168))
136775	32632840	Positivity for chromogranin A, GATA3, GCM2, and PTH can distinguish parathyroid origin (Fig.	('GCM2', 'Gene', (38, 42))	('chromogranin A', 'Gene', '1113', (15, 29))	('GATA3', 'Gene', (31, 36))	('parathyroid origin', 'Disease', (68, 86))	('GATA3', 'Gene', '2625', (31, 36))	('chromogranin A', 'Gene', (15, 29))	('PTH', 'Gene', (48, 51))	('GCM2', 'Gene', '9247', (38, 42))	('Positivity', 'Var', (0, 10))	('PTH', 'Gene', '5741', (48, 51))
136776	32632840	One should also be aware that parathyroid proliferations can display aberrant reactivity for calcitonin and CGRP; therefore, positivity for GATA3 and GCM2 and negativity for monoclonal CEA and TTF1 can be used to confirm the parathyroid origin.	('CGRP', 'Gene', (108, 112))	('CEA', 'Gene', '1084', (185, 188))	('TTF1', 'Gene', '7270', (193, 197))	('GCM2', 'Gene', (150, 154))	('calcitonin', 'Gene', '796', (93, 103))	('positivity', 'Var', (125, 135))	('GCM2', 'Gene', '9247', (150, 154))	('GATA3', 'Gene', (140, 145))	('CGRP', 'Gene', '796', (108, 112))	('TTF1', 'Gene', (193, 197))	('calcitonin', 'Gene', (93, 103))	('reactivity', 'MPA', (78, 88))	('GATA3', 'Gene', '2625', (140, 145))	('CEA', 'Gene', (185, 188))
136785	32632840	One should be aware that thyroglobulin can cause diffusion-type staining in some cases; a few primary neuroendocrine thyroid tumors show concomitant positivity for neuroendocrine markers and thyroglobulin along with negativity for calcitonin and monoclonal CEA.	('thyroglobulin', 'Gene', (191, 204))	('neuroendocrine thyroid tumors', 'Disease', (102, 131))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('thyroglobulin', 'Gene', (25, 38))	('thyroglobulin', 'Gene', '7038', (25, 38))	('positivity', 'Var', (149, 159))	('calcitonin', 'Gene', '796', (231, 241))	('neuroendocrine thyroid tumors', 'Disease', 'MESH:D018358', (102, 131))	('thyroid tumor', 'Phenotype', 'HP:0100031', (117, 130))	('CEA', 'Gene', (257, 260))	('thyroglobulin', 'Gene', '7038', (191, 204))	('CEA', 'Gene', '1084', (257, 260))	('calcitonin', 'Gene', (231, 241))
136803	32632840	Positivity for galectin-3, HBME1, and CK19 can also be seen in some cases.	('CK19', 'Gene', '3880', (38, 42))	('galectin-3', 'Gene', '3958', (15, 25))	('HBME1', 'CellLine', 'CVCL:U718', (27, 32))	('Positivity', 'Var', (0, 10))	('HBME1', 'Gene', (27, 32))	('galectin-3', 'Gene', (15, 25))	('CK19', 'Gene', (38, 42))
136808	32632840	Recent evidence suggests that PAX8-GLIS3 and PAX8-GLIS1 fusions appear to be a pathognomonic genetic alteration of these neoplasms.	('fusions', 'Var', (56, 63))	('PAX8', 'Gene', '7849', (45, 49))	('neoplasms', 'Disease', 'MESH:D009369', (121, 130))	('neoplasms', 'Disease', (121, 130))	('PAX8', 'Gene', (30, 34))	('PAX8', 'Gene', (45, 49))	('neoplasm', 'Phenotype', 'HP:0002664', (121, 129))	('GLIS1', 'Gene', '148979', (50, 55))	('GLIS3', 'Gene', (35, 40))	('GLIS3', 'Gene', '169792', (35, 40))	('GLIS1', 'Gene', (50, 55))	('neoplasms', 'Phenotype', 'HP:0002664', (121, 130))	('PAX8', 'Gene', '7849', (30, 34))
136817	32632840	This infiltrative thyroid tumor shows expression for PAX8 and cytokeratin 19 and can mimic PTC, but the tumor cells are negative for thyroglobulin and show negativity (clone 8G7G3/1) or focal positivity (clone SPT24) for TFF1.	('thyroid tumor', 'Disease', (18, 31))	('thyroglobulin', 'Gene', '7038', (133, 146))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('clone', 'Var', (168, 173))	('thyroid tumor', 'Disease', 'MESH:D013964', (18, 31))	('PAX8', 'Gene', '7849', (53, 57))	('cytokeratin 19', 'Gene', (62, 76))	('tumor', 'Disease', (26, 31))	('cytokeratin 19', 'Gene', '3880', (62, 76))	('thyroglobulin', 'Gene', (133, 146))	('expression', 'MPA', (38, 48))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('tumor', 'Disease', (104, 109))	('thyroid tumor', 'Phenotype', 'HP:0100031', (18, 31))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('PTC', 'Gene', (91, 94))	('PTC', 'Gene', '5979', (91, 94))	('negative', 'NegReg', (120, 128))	('negativity', 'NegReg', (156, 166))	('TFF1', 'Gene', '7031', (221, 225))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('TFF1', 'Gene', (221, 225))	('PAX8', 'Gene', (53, 57))
136839	32632840	Nevertheless, positivity for thyroglobulin (Fig.	('positivity', 'Var', (14, 24))	('thyroglobulin', 'Gene', (29, 42))	('positivity for thyroglobulin', 'Phenotype', 'HP:0032069', (14, 42))	('thyroglobulin', 'Gene', '7038', (29, 42))
136852	32632840	P53 overexpression and BRAF mutation can also be detected in primary squamous cell thyroid carcinoma.	('squamous cell thyroid carcinoma', 'Disease', (69, 100))	('BRAF', 'Gene', '673', (23, 27))	('squamous cell thyroid carcinoma', 'Disease', 'MESH:D002294', (69, 100))	('BRAF', 'Gene', (23, 27))	('mutation', 'Var', (28, 36))	('P53', 'Gene', (0, 3))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('P53', 'Gene', '7157', (0, 3))	('overexpression', 'PosReg', (4, 18))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (83, 100))
136862	32632840	RET/PTC rearrangements were found in combined PTC and mucoepidermoid carcinoma, whereas no BRAF or RAS mutations were detected in mucoepidermoid carcinomas.	('carcinoma', 'Phenotype', 'HP:0030731', (145, 154))	('carcinomas', 'Disease', 'MESH:D009369', (145, 155))	('carcinomas', 'Phenotype', 'HP:0030731', (145, 155))	('rearrangements', 'Var', (8, 22))	('RET', 'Gene', '5979', (0, 3))	('mucoepidermoid carcinoma', 'Disease', (130, 154))	('mucoepidermoid carcinoma', 'Disease', 'MESH:D018277', (130, 154))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))	('PTC', 'Gene', (46, 49))	('PTC', 'Gene', '5979', (46, 49))	('carcinomas', 'Disease', (145, 155))	('RET', 'Gene', (0, 3))	('mucoepidermoid carcinoma', 'Disease', (54, 78))	('BRAF', 'Gene', '673', (91, 95))	('BRAF', 'Gene', (91, 95))	('PTC', 'Gene', (4, 7))	('mucoepidermoid carcinoma', 'Disease', 'MESH:D018277', (54, 78))	('found', 'Reg', (28, 33))	('PTC', 'Gene', '5979', (4, 7))
136863	32632840	More recently, a targeted next-generation sequence analysis of a case of concurrent mucoepidermoid and PTC revealed a monoallelic germline MUTYH mutation combined with somatic mutations of the BCOR and MSH2 genes in the mucoepidermoid carcinoma and PTC components, respectively.	('mutations', 'Var', (176, 185))	('PTC', 'Gene', '5979', (103, 106))	('MSH2', 'Gene', (202, 206))	('BCOR', 'Gene', (193, 197))	('PTC', 'Gene', (249, 252))	('PTC', 'Gene', '5979', (249, 252))	('carcinoma', 'Phenotype', 'HP:0030731', (235, 244))	('mucoepidermoid carcinoma', 'Disease', (220, 244))	('mucoepidermoid carcinoma', 'Disease', 'MESH:D018277', (220, 244))	('MSH2', 'Gene', '4436', (202, 206))	('BCOR', 'Gene', '54880', (193, 197))	('PTC', 'Gene', (103, 106))	('MUTYH', 'Gene', (139, 144))	('MUTYH', 'Gene', '4595', (139, 144))	('mutation', 'Var', (145, 153))
136872	32632840	BRAFV600E mutation was detected in two cases, and an APC gene variant of uncertain significance was also found in another case of SMECE.	('BRAFV600E', 'Mutation', 'rs113488022', (0, 9))	('APC', 'Disease', (53, 56))	('APC', 'Disease', 'MESH:D011125', (53, 56))	('BRAFV600E', 'Var', (0, 9))
136903	32632840	Positivity for TTF1, PAX8, and thyroglobulin and coexistence of spindle cells with well-differentiated follicles support this diagnosis.	('TTF1', 'Gene', '7270', (15, 19))	('PAX8', 'Gene', (21, 25))	('thyroglobulin', 'Gene', (31, 44))	('thyroglobulin', 'Gene', '7038', (31, 44))	('Positivity', 'Var', (0, 10))	('TTF1', 'Gene', (15, 19))	('PAX8', 'Gene', '7849', (21, 25))
136905	32632840	The follicular epithelial origin of this tumor should be confirmed using immunohistochemistry including positivity for thyroglobulin (Fig.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Disease', (41, 46))	('thyroglobulin', 'Gene', '7038', (119, 132))	('thyroglobulin', 'Gene', (119, 132))	('positivity', 'Var', (104, 114))	('positivity for thyroglobulin', 'Phenotype', 'HP:0032069', (104, 132))	('tumor', 'Disease', 'MESH:D009369', (41, 46))
136913	32632840	Lack of nuclear beta-catenin expression in the stroma, lack of follicular epithelial differentiation, positivity for PAX8 and/or TTF1, and presence of increased proliferative activity are features that can help in the distinction of anaplastic thyroid carcinomas.	('increased', 'PosReg', (151, 160))	('TTF1', 'Gene', '7270', (129, 133))	('Lack', 'NegReg', (0, 4))	('PAX8', 'Gene', '7849', (117, 121))	('beta-catenin', 'Gene', (16, 28))	('beta-catenin', 'Gene', '1499', (16, 28))	('follicular epithelial differentiation', 'CPA', (63, 100))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (244, 261))	('positivity', 'Var', (102, 112))	('proliferative activity', 'CPA', (161, 183))	('TTF1', 'Gene', (129, 133))	('anaplastic thyroid carcinomas', 'Disease', (233, 262))	('anaplastic thyroid carcinomas', 'Disease', 'MESH:D065646', (233, 262))	('carcinoma', 'Phenotype', 'HP:0030731', (252, 261))	('carcinomas', 'Phenotype', 'HP:0030731', (252, 262))	('anaplastic thyroid carcinoma', 'Phenotype', 'HP:0011779', (233, 261))	('thyroid carcinomas', 'Phenotype', 'HP:0002890', (244, 262))	('anaplastic thyroid carcinomas', 'Phenotype', 'HP:0011779', (233, 262))	('PAX8', 'Gene', (117, 121))
136919	32632840	At a molecular level, EWSR1/FLI1 rearrangement is pathognomonic as the latter has been detected in all reported tumors.	('EWSR1', 'Gene', '2130', (22, 27))	('FLI1', 'Gene', (28, 32))	('FLI1', 'Gene', '2313', (28, 32))	('tumors', 'Disease', (112, 118))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('EWSR1', 'Gene', (22, 27))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumors', 'Disease', 'MESH:D009369', (112, 118))	('rearrangement', 'Var', (33, 46))
136920	32632840	The association of EWSR1 rearrangements in PTC also supports the hypothesis that CEFTEs probably represent a "trans-dedifferentiation" phenomenon in PTCs.	('PTC', 'Gene', '5979', (149, 152))	('association', 'Interaction', (4, 15))	('CEFTEs', 'Chemical', '-', (81, 87))	('PTC', 'Gene', (43, 46))	('rearrangements', 'Var', (25, 39))	('PTC', 'Gene', '5979', (43, 46))	('EWSR1', 'Gene', (19, 24))	('PTC', 'Gene', (149, 152))	('EWSR1', 'Gene', '2130', (19, 24))
136924	32632840	Negativity for vimentin and presence of epithelial differentiation and the co-existence of PTC component support the diagnosis of CEFTE.	('PTC', 'Gene', (91, 94))	('PTC', 'Gene', '5979', (91, 94))	('vimentin', 'Gene', '7431', (15, 23))	('vimentin', 'Gene', (15, 23))	('Negativity', 'Var', (0, 10))	('CEFTE', 'Disease', (130, 135))	('CEFTE', 'Chemical', '-', (130, 135))	('epithelial differentiation', 'CPA', (40, 66))
136930	32632840	Unlike CEFTEs, this aggressive primitive multiphenotypic malignancy showing organotypical elements and frequent DICER1 alterations has been recently referred to as the term "thyroblastoma" (Fig.	('malignancy', 'Disease', (57, 67))	('thyroblastoma', 'Disease', (174, 187))	('DICER1', 'Gene', '23405', (112, 118))	('DICER1', 'Gene', (112, 118))	('malignancy', 'Disease', 'MESH:D009369', (57, 67))	('alterations', 'Var', (119, 130))	('CEFTEs', 'Chemical', '-', (7, 13))	('thyroblastoma', 'Disease', 'None', (174, 187))
136944	32632840	Somatic RET mutations have been detected exclusively in the medullary thyroid carcinoma component of MMFTC.	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (70, 87))	('RET', 'Gene', '5979', (8, 11))	('mutations', 'Var', (12, 21))	('MMFTC', 'Disease', (101, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('medullary thyroid carcinoma', 'Phenotype', 'HP:0002865', (60, 87))	('detected', 'Reg', (32, 40))	('MMFTC', 'Chemical', '-', (101, 106))	('thyroid carcinoma component', 'Disease', 'MESH:D013964', (70, 97))	('thyroid carcinoma component', 'Disease', (70, 97))	('RET', 'Gene', (8, 11))
136984	31937294	Recent studies have shown that aberrant MMP expression is associated with the invasion and metastasis of several malignant tumours (colorectal, prostate, liver, breast, retinoblastoma, and lung) both in vitro and vivo.	('metastasis of several malignant tumours', 'Disease', 'MESH:D009362', (91, 130))	('breast', 'Disease', (161, 167))	('MMP', 'Protein', (40, 43))	('associated with', 'Reg', (58, 73))	('colorectal', 'Disease', (132, 142))	('invasion', 'CPA', (78, 86))	('liver', 'Disease', (154, 159))	('aberrant', 'Var', (31, 39))	('tumours', 'Phenotype', 'HP:0002664', (123, 130))	('metastasis of several malignant tumours', 'Disease', (91, 130))	('retinoblastoma', 'Gene', (169, 183))	('retinoblastoma', 'Gene', '5925', (169, 183))	('tumour', 'Phenotype', 'HP:0002664', (123, 129))	('prostate', 'Disease', (144, 152))	('retinoblastoma', 'Phenotype', 'HP:0009919', (169, 183))	('colorectal', 'Disease', 'MESH:D015179', (132, 142))
137017	31937294	The cell migration assays were performed in 24-well Transwell chambers without Matrigel (#353097; Falcon Corning, USA) and with Matrigel (#354480; Falcon Corning, USA).	('#353097;', 'Var', (89, 97))	('cell migration', 'CPA', (4, 18))	('C', 'Chemical', 'MESH:D002244', (105, 106))	('#354480;', 'Var', (138, 146))	('C', 'Chemical', 'MESH:D002244', (154, 155))
137029	31937294	LN4 cells with stable knockdown of MMP7 and control cells (1 x 106) were suspended in 20 mul serum-free DMEM and then were injected into the right axillary fossa of each mouse.	('knockdown', 'Var', (22, 31))	('mouse', 'Species', '10090', (170, 175))	('MMP7', 'Gene', (35, 39))	('LN4', 'CellLine', 'CVCL:F127', (0, 3))
137039	31937294	Because MMP7 was upregulated in TSCC and had clinical relevance, we explored whether MMP7 could accelerate the malignant behavior of tongue cancer cells in vitro.	('tongue cancer', 'Disease', 'MESH:D014062', (133, 146))	('tongue cancer', 'Disease', (133, 146))	('MMP7', 'Var', (85, 89))	('upregulated', 'PosReg', (17, 28))	('MMP7', 'Gene', (8, 12))	('TSCC', 'Disease', 'MESH:D002294', (32, 36))	('accelerate', 'PosReg', (96, 106))	('TSCC', 'Phenotype', 'HP:0030413', (32, 36))	('TSCC', 'Disease', (32, 36))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('malignant behavior of', 'CPA', (111, 132))	('clinical', 'Species', '191496', (45, 53))
137041	31937294	To specifically knock down or overexpress MMP7, the corresponding siRNA or plasmid (pCDH-CMV-MCS-EF1-Puro-MMP7) was transfected into the TSCC cell lines CAL27 and SCC9.	('SCC9', 'CellLine', 'CVCL:1685', (163, 167))	('C', 'Chemical', 'MESH:D002244', (165, 166))	('knock', 'Var', (16, 21))	('C', 'Chemical', 'MESH:D002244', (94, 95))	('C', 'Chemical', 'MESH:D002244', (139, 140))	('C', 'Chemical', 'MESH:D002244', (153, 154))	('MMP7', 'Gene', (42, 46))	('C', 'Chemical', 'MESH:D002244', (164, 165))	('TSCC', 'Phenotype', 'HP:0030413', (137, 141))	('C', 'Chemical', 'MESH:D002244', (85, 86))	('TSCC', 'Disease', 'MESH:D002294', (137, 141))	('C', 'Chemical', 'MESH:D002244', (89, 90))	('C', 'Chemical', 'MESH:D002244', (140, 141))	('TSCC', 'Disease', (137, 141))	('overexpress', 'PosReg', (30, 41))
137045	31937294	In the colony formation assay, the effect of MMP7 knockdown in SCC9 (only 30% inhibition) was lower than that in CAL27 cells (> 50% inhibition) which may be due to the lower expression level of endogenous MMP7 (Fig.	('C', 'Chemical', 'MESH:D002244', (65, 66))	('knockdown', 'Var', (50, 59))	('lower', 'NegReg', (168, 173))	('MMP7', 'Gene', (45, 49))	('colony formation assay', 'CPA', (7, 29))	('expression level', 'MPA', (174, 190))	('lower', 'NegReg', (94, 99))	('SCC9', 'CellLine', 'CVCL:1685', (63, 67))	('C', 'Chemical', 'MESH:D002244', (113, 114))	('C', 'Chemical', 'MESH:D002244', (64, 65))
137058	31937294	All the functional studies intensively indicated that MMP7 could promote the tongue cancer cell motility in vitro and confirmed its oncogenic role in the tumourigenesis and progression of tongue cancer.	('tumour', 'Phenotype', 'HP:0002664', (154, 160))	('MMP7', 'Var', (54, 58))	('tongue cancer', 'Disease', (188, 201))	('tongue cancer', 'Disease', (77, 90))	('tumour', 'Disease', 'MESH:D009369', (154, 160))	('tongue cancer', 'Disease', 'MESH:D014062', (188, 201))	('tongue cancer', 'Disease', 'MESH:D014062', (77, 90))	('tumour', 'Disease', (154, 160))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('promote', 'PosReg', (65, 72))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
137060	31937294	To explore the effects of MMP7 in vivo, we constructed an orthotopic nude mouse tongue cancer model with silenced MMP7 in a CAL27-derived high-metastasis tongue cancer cell line LN4 (Fig.	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('tongue cancer', 'Disease', (154, 167))	('C', 'Chemical', 'MESH:D002244', (124, 125))	('tongue cancer', 'Disease', 'MESH:D014062', (154, 167))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('LN4', 'CellLine', 'CVCL:F127', (178, 181))	('mouse', 'Species', '10090', (74, 79))	('silenced', 'Var', (105, 113))	('tongue cancer', 'Disease', (80, 93))	('tongue cancer', 'Disease', 'MESH:D014062', (80, 93))	('MMP7', 'Gene', (114, 118))
137063	31937294	These findings demonstrate that the metastatic potential of tongue cancer cells was reduced in vivo when MMP7 is knocked down, consistent with the conclusions from the molecular function trials in vitro.	('tongue cancer', 'Disease', 'MESH:D014062', (60, 73))	('knocked down', 'Var', (113, 125))	('metastatic potential of', 'CPA', (36, 59))	('reduced', 'NegReg', (84, 91))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('MMP7', 'Gene', (105, 109))	('tongue cancer', 'Disease', (60, 73))
137082	31937294	Furthermore, many authors have proposed that MMP7 may indirectly destroy the vital components of the extracellular matrix by activating other individual MMPs or associating with other MMPs to promote tumour cell metastasis.	('destroy', 'NegReg', (65, 72))	('tumour cell metastasis', 'Disease', (200, 222))	('vital components of the extracellular', 'MPA', (77, 114))	('MMPs', 'Gene', '4312;4313;17390;4314;4316;17393;4317;4318;4322;4323', (184, 188))	('promote', 'PosReg', (192, 199))	('activating', 'Reg', (125, 135))	('MMP7', 'Var', (45, 49))	('MMPs', 'Gene', '4312;4313;17390;4314;4316;17393;4317;4318;4322;4323', (153, 157))	('tumour', 'Phenotype', 'HP:0002664', (200, 206))	('tumour cell metastasis', 'Disease', 'MESH:D009362', (200, 222))	('MMPs', 'Gene', (153, 157))	('MMPs', 'Gene', (184, 188))
137084	31937294	and F Q Wang indicated that gelatinases (e.g., MMP2 and MMP9) could be activated by MMP7, and Imai K et al.	('gelatinases', 'Enzyme', (28, 39))	('activated', 'PosReg', (71, 80))	('MMP9', 'Gene', (56, 60))	('MMP9', 'Gene', '4318', (56, 60))	('MMP7', 'Var', (84, 88))
137085	31937294	demonstrated that MMP7 could enhance MMP1 activity and partially activate pro-MMP9 in human rectal carcinoma cells.	('rectal carcinoma', 'Disease', (92, 108))	('rectal carcinoma', 'Phenotype', 'HP:0100743', (92, 108))	('activate', 'PosReg', (65, 73))	('MMP1', 'Gene', (37, 41))	('human', 'Species', '9606', (86, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('MMP7', 'Var', (18, 22))	('MMP9', 'Gene', (78, 82))	('enhance', 'PosReg', (29, 36))	('MMP9', 'Gene', '4318', (78, 82))	('rectal carcinoma', 'Disease', 'MESH:D012004', (92, 108))	('MMP1', 'Gene', '4312', (37, 41))
137091	31937294	First, CD34, an endothelial progenitor biomarker, was discovered in renal cell carcinoma expressing MMP7, suggesting that MMP7 may contribute to tumourigenesis by correlating with tumour-induced neovascularization.	('correlating', 'Reg', (163, 174))	('tumour', 'Disease', (145, 151))	('MMP7', 'Var', (122, 126))	('CD34', 'Gene', '947', (7, 11))	('tumour', 'Phenotype', 'HP:0002664', (180, 186))	('MMP7', 'Gene', (100, 104))	('renal cell carcinoma', 'Disease', (68, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('tumour', 'Disease', 'MESH:D009369', (180, 186))	('renal cell carcinoma', 'Disease', 'MESH:D002292', (68, 88))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (68, 88))	('contribute', 'Reg', (131, 141))	('tumour', 'Disease', 'MESH:D009369', (145, 151))	('tumour', 'Phenotype', 'HP:0002664', (145, 151))	('CD34', 'Gene', (7, 11))	('tumour', 'Disease', (180, 186))
137101	31937294	It was also reported that MMP7 was associated with the acquisition of the chemosensitivity of 5-FU and doxorubicin because of its role in tumour cell escape from Fas-mediated apoptosis.	('chemosensitivity', 'MPA', (74, 90))	('MMP7', 'Var', (26, 30))	('doxorubicin', 'Chemical', 'MESH:D004317', (103, 114))	('associated', 'Reg', (35, 45))	('tumour', 'Phenotype', 'HP:0002664', (138, 144))	('5-FU', 'Chemical', 'MESH:D005472', (94, 98))	('tumour', 'Disease', 'MESH:D009369', (138, 144))	('acquisition', 'PosReg', (55, 66))	('tumour', 'Disease', (138, 144))
137125	29625051	Transcriptional and epigenetic dysregulation of cancer cells frequently leads to oncogenic de-differentiation and acquisition of stemness features by altering core signaling pathways that regulate the phenotypes of normal stem cells.	('altering', 'Reg', (150, 158))	('core signaling pathways', 'Pathway', (159, 182))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('epigenetic dysregulation', 'Var', (20, 44))	('acquisition', 'CPA', (114, 125))	('stemness features', 'CPA', (129, 146))	('oncogenic de-differentiation', 'CPA', (81, 109))	('leads to', 'Reg', (72, 80))	('cancer', 'Disease', (48, 54))	('dysregulation', 'Var', (31, 44))	('cancer', 'Disease', 'MESH:D009369', (48, 54))
137165	29625051	This result could arise from a high frequency of IDH1/2 mutations and resulting DNA hypermethylation.	('IDH1/2', 'Gene', '3417;3418', (49, 55))	('DNA hypermethylation', 'MPA', (80, 100))	('mutations', 'Var', (56, 65))	('IDH1/2', 'Gene', (49, 55))
137168	29625051	BRCA samples with high mRNAsi were more likely to be ER-negative, and enriched for FAT3 and TP53 mutations.	('mutations', 'Var', (97, 106))	('BRCA', 'Gene', (0, 4))	('FAT3', 'Gene', (83, 87))	('TP53', 'Gene', '7157', (92, 96))	('TP53', 'Gene', (92, 96))	('FAT3', 'Gene', '120114', (83, 87))	('BRCA', 'Gene', '672', (0, 4))
137177	29625051	High mRNAsi was associated with higher expression of miR-181c-3p, miR-22-3p, and miR-30b-3p (Figure 3B, right bottom).	('miR-22-3p', 'Gene', '407008', (66, 75))	('higher', 'PosReg', (32, 38))	('miR-30b-3p', 'Var', (81, 91))	('miR-181c-3p', 'Var', (53, 64))	('expression', 'MPA', (39, 49))	('miR-22-3p', 'Gene', (66, 75))
137178	29625051	We found a strong association between high mDNAsi, high pathologic grade and recently published molecular subtypes of glioma (Figure 3C).	('glioma', 'Disease', (118, 124))	('high', 'Var', (38, 42))	('glioma', 'Disease', 'MESH:D005910', (118, 124))	('mole', 'Phenotype', 'HP:0003764', (96, 100))	('glioma', 'Phenotype', 'HP:0009733', (118, 124))
137179	29625051	mDNAsi was low in less aggressive gliomas that are characterized by codel and G-CIMP-high features and was highest in highly aggressive GBMs characterized by IDH mutations (G-CIMP-low) and poor clinical outcome.	('glioma', 'Phenotype', 'HP:0009733', (34, 40))	('aggressive gliomas', 'Disease', 'MESH:D005910', (23, 41))	('mutations', 'Var', (162, 171))	('IDH', 'Gene', '3417', (158, 161))	('less', 'Disease', (18, 22))	('G-CIMP', 'Chemical', '-', (173, 179))	('low', 'NegReg', (11, 14))	('gliomas', 'Phenotype', 'HP:0009733', (34, 41))	('aggressive gliomas', 'Disease', (23, 41))	('G-CIMP', 'Chemical', '-', (78, 84))	('IDH', 'Gene', (158, 161))	('highest', 'Reg', (107, 114))
137180	29625051	Also, high mDNAsi is strongly associated with more aggressive classical and mesenchymal subtypes of GBM, suggesting that it can stratify tumors with distinct clinical outcomes.	('associated', 'Reg', (30, 40))	('tumors', 'Disease', (137, 143))	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('GBM', 'Disease', (100, 103))	('high', 'Var', (6, 10))	('mDNAsi', 'Gene', (11, 17))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
137181	29625051	We also found that high mDNAsi was associated with mutations in NF1 and EGFR and infrequent mutations in IDH1, TP53, CIC, and ATRX (Figure 3C, left), with higher expression of ANNEXIN-A1 protein and lower expression of ANNEXIN-A7, and with expression of the miR-200 family (Figure 3C, right bottom).	('mutations', 'Var', (51, 60))	('EGFR', 'Gene', '1956', (72, 76))	('ATRX', 'Gene', (126, 130))	('mDNAsi', 'Disease', (24, 30))	('NF1', 'Gene', (64, 67))	('IDH1', 'Gene', '3417', (105, 109))	('ATRX', 'Gene', '546', (126, 130))	('ANNEXIN-A7', 'Gene', '310', (219, 229))	('TP53', 'Gene', '7157', (111, 115))	('CIC', 'Gene', (117, 120))	('ANNEXIN-A7', 'Gene', (219, 229))	('higher', 'PosReg', (155, 161))	('ANNEXIN-A1', 'Gene', (176, 186))	('lower', 'NegReg', (199, 204))	('EGFR', 'Gene', (72, 76))	('expression', 'MPA', (205, 215))	('ANNEXIN-A1', 'Gene', '301', (176, 186))	('IDH1', 'Gene', (105, 109))	('TP53', 'Gene', (111, 115))	('expression', 'MPA', (162, 172))	('NF1', 'Gene', '4763', (64, 67))
137184	29625051	IDH1 mutations are known to reduce cell differentiation, and high values of the mRNAsi in a subset of IDH mutant gliomas might capture this phenomenon.	('IDH', 'Gene', '3417', (102, 105))	('IDH', 'Gene', (0, 3))	('mutant', 'Var', (106, 112))	('mRNAsi', 'MPA', (80, 86))	('glioma', 'Phenotype', 'HP:0009733', (113, 119))	('cell differentiation', 'CPA', (35, 55))	('IDH', 'Gene', '3417', (0, 3))	('mutations', 'Var', (5, 14))	('gliomas', 'Disease', (113, 120))	('gliomas', 'Disease', 'MESH:D005910', (113, 120))	('reduce', 'NegReg', (28, 34))	('gliomas', 'Phenotype', 'HP:0009733', (113, 120))	('IDH1', 'Gene', (0, 4))	('IDH', 'Gene', (102, 105))	('IDH1', 'Gene', '3417', (0, 4))
137187	29625051	The most salient associations of mRNAsi and mDNAsi are presented in Figure 4, while the following results of the comprehensive analyses are shown in the supplementary material: associations with mutations (Figure S3), associations with miRNA expression and protein abundance (Figure S4), associations with the tumor grading and clinical outcome (Figure S5).	('tumor', 'Disease', 'MESH:D009369', (310, 315))	('tumor', 'Phenotype', 'HP:0002664', (310, 315))	('miRNA expression', 'MPA', (236, 252))	('tumor', 'Disease', (310, 315))	('mutations', 'Var', (195, 204))	('protein abundance', 'MPA', (257, 274))	('associations', 'Interaction', (218, 230))	('associations', 'Interaction', (288, 300))	('associations', 'Interaction', (177, 189))
137188	29625051	We found a strong association between mDNAsi and known molecular subtypes, somatic mutations in SETD2 and TP53 genes, and with tobacco smoking status in LUAD (Figures 4A and S3).	('mutations', 'Var', (83, 92))	('tobacco', 'Species', '4097', (127, 134))	('mDNAsi', 'Disease', (38, 44))	('SETD2', 'Gene', '29072', (96, 101))	('mole', 'Phenotype', 'HP:0003764', (55, 59))	('SETD2', 'Gene', (96, 101))	('TP53', 'Gene', '7157', (106, 110))	('TP53', 'Gene', (106, 110))
137195	29625051	Analyses of HNSC samples revealed that high indices are correlated with NSD1 mutation, E-cadherin protein expression, miR-200-3p, and previously identified classical molecular subtypes (Figure 4B).	('NSD1', 'Gene', '64324', (72, 76))	('E-cadherin', 'Gene', (87, 97))	('E-cadherin', 'Gene', '999', (87, 97))	('mole', 'Phenotype', 'HP:0003764', (166, 170))	('mutation', 'Var', (77, 85))	('miR-200-3p', 'Var', (118, 128))	('expression', 'MPA', (106, 116))	('NSD1', 'Gene', (72, 76))
137196	29625051	NSD1 mutation was recently linked in HNSC tumors to blockade of cellular differentiation and promotion of oncogenesis.	('cellular differentiation', 'CPA', (64, 88))	('NSD1', 'Gene', (0, 4))	('linked', 'Reg', (27, 33))	('promotion', 'PosReg', (93, 102))	('oncogenesis', 'CPA', (106, 117))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('HNSC tumors', 'Disease', 'MESH:D009369', (37, 48))	('blockade', 'NegReg', (52, 60))	('mutation', 'Var', (5, 13))	('NSD1', 'Gene', '64324', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('HNSC tumors', 'Disease', (37, 48))
137205	29625051	Detailed analyses of ACC samples revealed an association between high mRNAsi and defined molecular subtypes, clinical stage, and mutations in PRKAR1A and TP53 genes (Figure 4D).	('TP53', 'Gene', (154, 158))	('ACC', 'Gene', (21, 24))	('PRKAR1A', 'Gene', '5573', (142, 149))	('mutations', 'Var', (129, 138))	('ACC', 'Gene', '31', (21, 24))	('mole', 'Phenotype', 'HP:0003764', (89, 93))	('PRKAR1A', 'Gene', (142, 149))	('TP53', 'Gene', '7157', (154, 158))
137212	29625051	Roughly 80% of LGG tumors carry an IDH1/2 mutation and, as demonstrated by our group and others, tconfers a genome-wide hypermethylator phenotype (G-CIMP).	('G-CIMP', 'Chemical', '-', (147, 153))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('LGG tumors', 'Disease', (15, 25))	('IDH1/2', 'Gene', '3417;3418', (35, 41))	('mutation', 'Var', (42, 50))	('hypermethylator', 'MPA', (120, 135))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('LGG tumors', 'Disease', 'MESH:D009369', (15, 25))	('IDH1/2', 'Gene', (35, 41))
137215	29625051	Compared to G-CIMP-high tumors, G-CIMP-low tumors are known to be more proliferative, express cell-cycle-related genes, and have various stem cell-like genomic features.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumors', 'Disease', (24, 30))	('G-CIMP-low', 'Var', (32, 42))	('tumors', 'Disease', 'MESH:D009369', (24, 30))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('G-CIMP', 'Chemical', '-', (12, 18))	('proliferative', 'CPA', (71, 84))	('G-CIMP', 'Chemical', '-', (32, 38))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('cell-cycle-related', 'Gene', (94, 112))	('more', 'PosReg', (66, 70))	('tumors', 'Disease', (43, 49))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('tumors', 'Disease', 'MESH:D009369', (43, 49))
137270	29625051	High mRNAsi was associated with basal breast carcinomas but also Her2 and lumB subtypes that are more aggressive than the hormone-dependent lumA group.	('carcinoma', 'Phenotype', 'HP:0030731', (45, 54))	('Her2', 'Gene', '2064', (65, 69))	('lumA', 'Gene', (140, 144))	('breast carcinomas', 'Disease', 'MESH:D001943', (38, 55))	('carcinomas', 'Phenotype', 'HP:0030731', (45, 55))	('breast carcinomas', 'Disease', (38, 55))	('High mRNAsi', 'Var', (0, 11))	('breast carcinomas', 'Phenotype', 'HP:0003002', (38, 55))	('lumB', 'Disease', (74, 78))	('associated', 'Reg', (16, 26))	('Her2', 'Gene', (65, 69))	('lumA', 'Gene', '79188', (140, 144))
137271	29625051	In contrast, high mDNAsi was strongly associated with high-grade glioblastomas, poor overall and progression-free survival.	('mDNAsi', 'Gene', (18, 24))	('associated', 'Reg', (38, 48))	('poor', 'NegReg', (80, 84))	('high', 'Var', (13, 17))	('glioblastomas', 'Phenotype', 'HP:0012174', (65, 78))	('glioblastomas', 'Disease', 'MESH:D005909', (65, 78))	('glioblastomas', 'Disease', (65, 78))	('glioblastoma', 'Phenotype', 'HP:0012174', (65, 77))
137273	29625051	Dedifferentiated cells can arise from different sources: from long-lived stem or progenitor cells that accumulate mutations in oncogenic pathways, or via dedifferentiation from non-stem cancer cells that convert to CSCs through deregulation of developmental and/or non-developmental pathways.	('deregulation', 'Reg', (228, 240))	('mutations', 'Var', (114, 123))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('oncogenic pathways', 'Pathway', (127, 145))	('developmental and/or', 'Pathway', (244, 264))	('cancer', 'Disease', (186, 192))	('cancer', 'Disease', 'MESH:D009369', (186, 192))
137279	29625051	Cancer cells in many primary solid tumors are basically epithelial regardless of their degrees of dedifferentiation, but some cells in such contexts could acquire mesenchymal characteristics, either by accumulating additional mutations or by undergoing epigenetic changes shaped by the tumor microenvironment.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (286, 291))	('tumor', 'Disease', (286, 291))	('solid tumors', 'Disease', 'MESH:D009369', (29, 41))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('tumor', 'Disease', (35, 40))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('epigenetic changes', 'Var', (253, 271))	('undergoing', 'Reg', (242, 252))	('mutations', 'Var', (226, 235))	('mesenchymal characteristics', 'CPA', (163, 190))	('acquire', 'PosReg', (155, 162))	('tumor', 'Disease', 'MESH:D009369', (286, 291))	('solid tumors', 'Disease', (29, 41))	('accumulating', 'PosReg', (202, 214))
137319	29625051	Additionally, we downloaded independent, non-TCGA datasets of gliomas [ (GSE36245, GSE36278) and (GSE30339)] and BRCA samples (GSE59000) and applied our metrics to measure the stemness in the validation data.	('gliomas', 'Disease', 'MESH:D005910', (62, 69))	('glioma', 'Phenotype', 'HP:0009733', (62, 68))	('GSE59000', 'Var', (127, 135))	('BRCA', 'Gene', '672', (113, 117))	('GSE30339)]', 'Var', (98, 108))	('gliomas', 'Disease', (62, 69))	('BRCA', 'Gene', (113, 117))	('GSE36278', 'Var', (83, 91))	('gliomas', 'Phenotype', 'HP:0009733', (62, 69))
137323	29625051	To eliminate somatic tissue-specific probes, we removed probes that were consistently methylated (standard deviation beta value > 0.05) in non-tumor adult tissues available through TCGA.	('non-tumor', 'Disease', 'MESH:D009369', (139, 148))	('methylated', 'Var', (86, 96))	('non-tumor', 'Disease', (139, 148))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
137360	27042856	Here, we first analyzed multi-omics data (including ChIP-Seq data of six types of histone modifications: H3K27ac, H3K4me1, H3K9me3, H3K36me3, H3K27me3, and H3K4me3) obtained from 26 lung adenocarcinoma cell lines and a normal cell line.	('H3K4me3', 'Var', (156, 163))	('carcinoma', 'Phenotype', 'HP:0030731', (192, 201))	('lung adenocarcinoma cell lines', 'Disease', (182, 212))	('H3K9me3', 'Var', (123, 130))	('H3K4me1', 'Var', (114, 121))	('H3K36me3', 'Var', (132, 140))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (182, 201))	('H3K27ac', 'Var', (105, 112))	('H3K27me3', 'Var', (142, 150))	('lung adenocarcinoma cell lines', 'Disease', 'MESH:D000077192', (182, 212))
137361	27042856	We identified six genes with both H3K27ac and H3K4me3 histone modifications in their promoter regions, which were not present in the normal cell line, but present in >=85% (22 out of 26) and <=96% (25 out of 26) of the lung adenocarcinoma cell lines.	('H3K4me3 histone modifications', 'Var', (46, 75))	('H3K27ac', 'Var', (34, 41))	('carcinoma', 'Phenotype', 'HP:0030731', (229, 238))	('lung adenocarcinoma cell lines', 'Disease', (219, 249))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (219, 238))	('lung adenocarcinoma cell lines', 'Disease', 'MESH:D000077192', (219, 249))
137365	27042856	Failure of the epigenetic modifications can result in inappropriate activation or inhibition of various signaling pathways and lead to diseases such as cancer.	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('result', 'Reg', (44, 50))	('lead to', 'Reg', (127, 134))	('activation', 'PosReg', (68, 78))	('inhibition', 'NegReg', (82, 92))	('signaling pathways', 'Pathway', (104, 122))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('epigenetic modifications', 'Var', (15, 39))
137366	27042856	Cancer cells experience dramatic epigenetic changes, including CpG dinucleotide hypermethylation and loss of acetylation, leading to tumor suppressor genes (TSG) downregulation and, on the other hand, pronounced hypomethylation of the promoter regions of oncogenes and microsatellite regions that lead to their activation.	('loss', 'NegReg', (101, 105))	('acetylation', 'MPA', (109, 120))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('hypomethylation', 'MPA', (212, 227))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('tumor', 'Disease', (133, 138))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('downregulation', 'NegReg', (162, 176))	('dinucleotide', 'Chemical', 'MESH:D015226', (67, 79))	('dinucleotide hypermethylation', 'Var', (67, 96))
137367	27042856	Epigenetic alterations, including aberrant DNA methylation in the promoter and alterations in histone modifications, can be used as epigenetic biomarkers of cancer diagnosis and promising targets for epigenetic cancer therapy that aims to reverse cancer-specific epigenetic alterations to a more normal epigenetic state.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('cancer', 'Disease', 'MESH:D009369', (211, 217))	('aberrant', 'Var', (34, 42))	('cancer', 'Disease', (211, 217))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('cancer', 'Disease', (247, 253))	('cancer', 'Disease', 'MESH:D009369', (247, 253))	('cancer', 'Disease', (157, 163))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))
137369	27042856	However, epigenetic alterations have physiological functions in both normal and cancer cells.	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('epigenetic alterations', 'Var', (9, 31))	('cancer', 'Disease', (80, 86))
137371	27042856	Toward the development of epigenetic therapies with higher cancer cell specificity, a recent genome-wide study explored DNA methylation and H3K27me3 histone modification that are more frequent in human cancer cells than in normal cells.	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('human', 'Species', '9606', (196, 201))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('H3K27me3', 'Var', (140, 148))	('cancer', 'Disease', 'MESH:D009369', (202, 208))	('DNA methylation', 'Var', (120, 135))	('cancer', 'Disease', (202, 208))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))
137372	27042856	In the study, the frequency of methylated genes, which also presented H3K27me3 (i.e., dual modification) was higher in colon, breast, and prostate cancer cell lines than in normal cells.	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('colon', 'Disease', (119, 124))	('prostate cancer', 'Disease', 'MESH:D011471', (138, 153))	('higher', 'PosReg', (109, 115))	('prostate cancer', 'Phenotype', 'HP:0012125', (138, 153))	('prostate cancer', 'Disease', (138, 153))	('H3K27me3', 'Var', (70, 78))	('breast', 'Disease', (126, 132))
137376	27042856	We extended the target to six types of histone modifications (H3K27ac, H3K4me1, H3K9me3, H3K36me3, and H3K27me3 in addition to H3K4me3) across a human genome, including regions that cannot be analyzed by microarray.	('H3K27ac', 'Var', (62, 69))	('H3K9me3', 'Var', (80, 87))	('H3K36me3', 'Var', (89, 97))	('human', 'Species', '9606', (145, 150))	('H3K4me1', 'Var', (71, 78))	('H3K27me3', 'Var', (103, 111))
137377	27042856	We also explore associations between the histone modifications and aberrant gene expression that are highly specific to lung adenocarcinomas.	('aberrant gene', 'Var', (67, 80))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (120, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('lung adenocarcinomas', 'Disease', (120, 140))	('carcinomas', 'Phenotype', 'HP:0030731', (130, 140))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (120, 140))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (120, 140))
137379	27042856	We determined that NUP210 gene encoding a main component of the nuclear pore complex presented both H3K27ac and H3K4me3 histone modifications in its promoter regions among >=85% (22 out of 26) and <=96% (25 out of 26) of the lung adenocarcinoma cell lines.	('H3K27ac', 'Var', (100, 107))	('lung adenocarcinoma cell lines', 'Disease', 'MESH:D000077192', (225, 255))	('NUP210', 'Gene', (19, 25))	('carcinoma', 'Phenotype', 'HP:0030731', (235, 244))	('H3K4me3 histone', 'Var', (112, 127))	('lung adenocarcinoma cell lines', 'Disease', (225, 255))	('NUP210', 'Gene', '23225', (19, 25))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (225, 244))
137384	27042856	To identify the regions of histone modifications, "peaks" of ChIP-Seq tags were called by MACS2 for the six types of histone modifications (H3K27ac, H3K4me3, H3K4me1, H3K9me3, H3K36me3, and H3K27me3) in each cell line.	('H3K27me3', 'Var', (190, 198))	('H3K27ac', 'Var', (140, 147))	('H3K4me3', 'Var', (149, 156))	('MACS', 'Gene', '4082', (90, 94))	('H3K9me3', 'Var', (167, 174))	('MACS', 'Gene', (90, 94))	('H3K36me3', 'Var', (176, 184))	('H3K4me1', 'Var', (158, 165))
137385	27042856	Narrow peaks (H3K27ac, H3K4me3, and H3K4me1) were detected by MACS2 with default options.	('MACS', 'Gene', (62, 66))	('H3K4me3', 'Var', (23, 30))	('H3K27ac', 'Var', (14, 21))	('H3K4me1', 'Var', (36, 43))	('MACS', 'Gene', '4082', (62, 66))
137386	27042856	Broad peaks (H3K9me3, H3K36me3, and H3K27me3) were detected by MACS2 using "-broad" and "-nomodel" options and specifying "-q (q-value)" to be 0.05 according to the official website of MACS (https://github.com/taoliu/MACS/).	('H3K27me3', 'Var', (36, 44))	('H3K36me3', 'Var', (22, 30))	('MACS', 'Gene', (217, 221))	('H3K9me3', 'Var', (13, 20))	('MACS', 'Gene', '4082', (185, 189))	('MACS', 'Gene', '4082', (63, 67))	('MACS', 'Gene', '4082', (217, 221))	('MACS', 'Gene', (185, 189))	('MACS', 'Gene', (63, 67))
137403	27042856	We also examined to what extent the aberrant gene expression was specific to lung-adenocarcinoma when compared to the remaining 10 cancers and carcinomas.	('cancers', 'Disease', 'MESH:D009369', (131, 138))	('cancers', 'Phenotype', 'HP:0002664', (131, 138))	('carcinomas', 'Phenotype', 'HP:0030731', (143, 153))	('carcinomas', 'Disease', (143, 153))	('carcinomas', 'Disease', 'MESH:D002277', (143, 153))	('cancers', 'Disease', (131, 138))	('lung-adenocarcinoma', 'Disease', (77, 96))	('lung-adenocarcinoma', 'Phenotype', 'HP:0030078', (77, 96))	('aberrant gene', 'Var', (36, 49))	('lung-adenocarcinoma', 'Disease', 'MESH:D000077192', (77, 96))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('carcinoma', 'Phenotype', 'HP:0030731', (143, 152))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))
137404	27042856	To identify genes presenting epigenetic modifications highly specific to lung adenocarcinoma, we analyzed ChIP-Seq data of six types of histone modifications (H3K27ac, H3K4me3, H3K4me1, H3K9me3, H3K36me3, and H3K27me3) in 26 lung adenocarcinoma cell lines and SAEC stored in the DBTSS database.	('H3K9me3', 'Var', (186, 193))	('lung adenocarcinoma', 'Disease', (73, 92))	('SAEC', 'Chemical', '-', (260, 264))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (73, 92))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (73, 92))	('lung adenocarcinoma cell lines', 'Disease', 'MESH:D000077192', (225, 255))	('H3K27ac', 'Var', (159, 166))	('H3K36me3', 'Var', (195, 203))	('carcinoma', 'Phenotype', 'HP:0030731', (235, 244))	('H3K4me1', 'Var', (177, 184))	('H3K4me3', 'Var', (168, 175))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (225, 244))	('H3K27me3', 'Var', (209, 217))	('DBTSS', 'Chemical', '-', (279, 284))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))	('lung adenocarcinoma cell lines', 'Disease', (225, 255))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (225, 244))
137408	27042856	The average number of each of the six lung adenocarcinoma-specific histone modifications among the 26 lung adenocarcinoma cell lines was 19,691 (H3K27ac), 5,149 (H3K4me3), 32,908 (H3K4me1), 18,113 (H3K9me3), 23,938 (H3K36me3), and 43,275 (H3K27me3), respectively (S1 Fig and S3 Table).	('lung adenocarcinoma cell lines', 'Disease', (102, 132))	('H3K9me3', 'Var', (198, 205))	('H3K27ac', 'Var', (145, 152))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (38, 57))	('H3K36me3', 'Var', (216, 224))	('H3K27me3', 'Var', (239, 247))	('H3K4me1', 'Var', (180, 187))	('lung adenocarcinoma cell lines', 'Disease', 'MESH:D000077192', (102, 132))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (102, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (102, 121))	('lung adenocarcinoma', 'Disease', (38, 57))	('H3K4me3', 'Var', (162, 169))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (38, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (48, 57))
137410	27042856	Among them, as indicated in Table 1, four genes with H3K4me3 histone modifications shared in all 26 lung adenocarcinoma cell lines were identified (Table 2).	('H3K4me3 histone modifications', 'Var', (53, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('lung adenocarcinoma cell lines', 'Disease', 'MESH:D000077192', (100, 130))	('lung adenocarcinoma cell lines', 'Disease', (100, 130))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (100, 119))
137411	27042856	We also identified six other genes carrying both the H3K27ac and H3K4me3 marks that are highly specific to lung adenocarcinoma (Table 3).	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('lung adenocarcinoma', 'Disease', (107, 126))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (107, 126))	('H3K4me3', 'Var', (65, 72))	('H3K27ac', 'Var', (53, 60))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (107, 126))
137412	27042856	Read coverage of the H3K27ac and H3K4me histone modifications for two out of the six genes (NUP210 and PKN1) is shown in Fig 1(A) and 1(B) as an example.	('H3K27ac', 'Var', (21, 28))	('H3K4me', 'Var', (33, 39))	('NUP210', 'Gene', (92, 98))	('PKN1', 'Gene', '5585', (103, 107))	('PKN1', 'Gene', (103, 107))	('NUP210', 'Gene', '23225', (92, 98))
137416	27042856	However, among the six genes in Table 3, NUP210 did not carry H3K27ac or H3K4me3 marks in its promoter region in NHLF (Fig 2(A)).	('NUP210', 'Gene', (41, 47))	('H3K27ac', 'Var', (62, 69))	('NUP210', 'Gene', '23225', (41, 47))	('H3K4me3', 'Var', (73, 80))
137418	27042856	We also determined that although, in NHLF, another gene PKN1 (member of the protein kinase C superfamily) carried the dual histone modifications in the promoter region, differences were observed in the location of the H3K27ac histone modifications compared to those highly shared among the lung adenocarcinoma cell lines (Fig 2(B)-A (lung adenocarcinoma) compared to B (NHLF)).	('carcinoma', 'Phenotype', 'HP:0030731', (300, 309))	('lung adenocarcinoma', 'Disease', (334, 353))	('lung adenocarcinoma cell lines', 'Disease', (290, 320))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (334, 353))	('carcinoma', 'Phenotype', 'HP:0030731', (344, 353))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (290, 309))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (290, 309))	('lung adenocarcinoma cell lines', 'Disease', 'MESH:D000077192', (290, 320))	('PKN1', 'Gene', '5585', (56, 60))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (334, 353))	('H3K27ac', 'Var', (218, 225))	('PKN1', 'Gene', (56, 60))
137419	27042856	The H3K27ac histone modification of PKN1 was located near the TSS in the lung adenocarcinoma cell lines (chr19:14544446-14544776 on hg19) (Fig 2(B)-A), while it was detected about 1 kb downstream of the TSS in NHLF (chr19: 14545611-14545886 and chr19:14546141-14546522 on hg19) (Fig 2(B)-B).	('PKN1', 'Gene', (36, 40))	('chr19:14544446-14544776', 'STRUCTURAL_ABNORMALITY', 'None', (105, 128))	('chr19:14544446-14544776', 'Var', (105, 128))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (73, 92))	('H3K27ac', 'Var', (4, 11))	('chr19:14546141-14546522', 'STRUCTURAL_ABNORMALITY', 'None', (245, 268))	('lung adenocarcinoma cell lines', 'Disease', (73, 103))	('PKN1', 'Gene', '5585', (36, 40))	('lung adenocarcinoma cell lines', 'Disease', 'MESH:D000077192', (73, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))
137440	27042856	These results support that the dual chromatin marks (H3K27ac and H3K4me3) highly specific to lung adenocarcinoma change the chromatin structure, which can lead to the aberrant expression of these genes.	('lung adenocarcinoma change', 'Disease', 'MESH:D000077192', (93, 119))	('H3K4me3', 'Var', (65, 72))	('chromatin structure', 'MPA', (124, 143))	('expression', 'MPA', (176, 186))	('lead to', 'Reg', (155, 162))	('H3K27ac', 'Var', (53, 60))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('lung adenocarcinoma change', 'Disease', (93, 119))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (93, 112))
137444	27042856	These results support that histone modifications are the primary cause of aberrant gene expression in lung adenocarcinoma.	('histone modifications', 'Var', (27, 48))	('cause', 'Reg', (65, 70))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (102, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('lung adenocarcinoma', 'Disease', (102, 121))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (102, 121))	('aberrant', 'Var', (74, 82))
137451	27042856	The RERFLCad2 cell line lacks the H3K4me3 histone modification in all three genes (NUP210, PKN1, and PPP1R9A) ("presence/absence of H3K4me3 modification" in S8 Table).	('NUP210', 'Gene', (83, 89))	('PKN1', 'Gene', '5585', (91, 95))	('lacks', 'NegReg', (24, 29))	('H3K4me3 histone', 'Protein', (34, 49))	('PKN1', 'Gene', (91, 95))	('PPP1R9A', 'Gene', '55607', (101, 108))	('NUP210', 'Gene', '23225', (83, 89))	('PPP1R9A', 'Gene', (101, 108))	('H3K4me3', 'Var', (132, 139))
137452	27042856	Therefore, the combination of SMYD3 and MLL2 could explain the high specificity of H3K4me3 histone modification to lung adenocarcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('SMYD3', 'Gene', '64754', (30, 35))	('MLL2', 'Gene', (40, 44))	('lung adenocarcinoma', 'Disease', (115, 134))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (115, 134))	('MLL2', 'Gene', '8085', (40, 44))	('H3K4me3', 'Var', (83, 90))	('SMYD3', 'Gene', (30, 35))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (115, 134))
137455	27042856	In contrast, the high specificity of the H3K27ac histone modification to lung adenocarcinoma could not be similarly explained.	('lung adenocarcinoma', 'Disease', (73, 92))	('H3K27ac', 'Var', (41, 48))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (73, 92))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (73, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))
137456	27042856	We did not find a combination of histone acetyltransferases or histone deacetylases that were overexpressed or underexpressed among the lung adenocarcinoma cell lines, even if we excluded a cell line, A427, that lacks the H3K27ac histone modification among all three genes (NUP210, PKN1, and PPP1R9A) ("presence/absence of H3K27ac modification" in S8 Table).	('PPP1R9A', 'Gene', '55607', (292, 299))	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('lung adenocarcinoma cell lines', 'Disease', (136, 166))	('NUP210', 'Gene', '23225', (274, 280))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (136, 155))	('PPP1R9A', 'Gene', (292, 299))	('H3K27ac', 'Var', (323, 330))	('NUP210', 'Gene', (274, 280))	('A427', 'CellLine', 'CVCL:1055', (201, 205))	('lung adenocarcinoma cell lines', 'Disease', 'MESH:D000077192', (136, 166))	('PKN1', 'Gene', '5585', (282, 286))	('PKN1', 'Gene', (282, 286))	('H3K27ac', 'Var', (222, 229))
137457	27042856	In the analysis described above, we identified three marker genes, NUP210, PKN1, and PPP1R9A, carrying histone modifications in their promoter regions and showing aberrant gene expression, both of which are highly specific to lung adenocarcinoma.	('PPP1R9A', 'Gene', (85, 92))	('histone', 'Reg', (103, 110))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (226, 245))	('modifications', 'Var', (111, 124))	('PKN1', 'Gene', '5585', (75, 79))	('NUP210', 'Gene', (67, 73))	('PKN1', 'Gene', (75, 79))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (226, 245))	('carcinoma', 'Phenotype', 'HP:0030731', (236, 245))	('PPP1R9A', 'Gene', '55607', (85, 92))	('NUP210', 'Gene', '23225', (67, 73))	('expression', 'MPA', (177, 187))	('lung adenocarcinoma', 'Disease', (226, 245))
137463	27042856	Frequency of lung adenocarcinoma tissue samples showing aberrant NUP210 expression was about 19.3% and that of the other 10 types of carcinoma was 0-17.7% (Fig 4(A) and S10 Table).	('NUP210', 'Gene', (65, 71))	('lung adenocarcinoma', 'Disease', (13, 32))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (13, 32))	('carcinoma', 'Disease', 'MESH:D002277', (23, 32))	('carcinoma', 'Disease', 'MESH:D002277', (133, 142))	('aberrant', 'Var', (56, 64))	('expression', 'MPA', (72, 82))	('NUP210', 'Gene', '23225', (65, 71))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (13, 32))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('carcinoma', 'Phenotype', 'HP:0030731', (23, 32))	('carcinoma', 'Disease', (23, 32))	('carcinoma', 'Disease', (133, 142))
137464	27042856	Further examination of its fold-change revealed that the frequency of 57 lung adenocarcinoma tissue samples showing >=3-, >=2-, and >=1-fold RPKM compared to the paired control was about 28%, 44%, and 84%, respectively (Fig 5).	('lung adenocarcinoma', 'Disease', (73, 92))	('RPKM', 'Var', (141, 145))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (73, 92))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (73, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))
137468	27042856	By utilizing it, we determined that the dual modification of H3K27ac and H3K4me3 in the promoter regions was associated with lung adenocarcinoma.	('H3K27ac', 'Var', (61, 68))	('associated', 'Reg', (109, 119))	('lung adenocarcinoma', 'Disease', (125, 144))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (125, 144))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('H3K4me3', 'Protein', (73, 80))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (125, 144))
137469	27042856	These epigenetic modifications are not present in SAEC, but present in >=85% (22 out of 26) and <= 96% (25 out of 26) of the lung adenocarcinoma cell lines.	('lung adenocarcinoma cell lines', 'Disease', 'MESH:D000077192', (125, 155))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('epigenetic modifications', 'Var', (6, 30))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (125, 144))	('SAEC', 'Chemical', '-', (50, 54))	('lung adenocarcinoma cell lines', 'Disease', (125, 155))
137473	27042856	Compared to our study, the focus was the diversity of mutations and aberrations in the epigenome and transcriptome among the 26 lung adenocarcinoma cell lines.	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('lung adenocarcinoma cell lines', 'Disease', 'MESH:D000077192', (128, 158))	('mutations', 'Var', (54, 63))	('lung adenocarcinoma cell lines', 'Disease', (128, 158))	('aberrations', 'Var', (68, 79))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (128, 147))
137475	27042856	In contrast, we explored epigenetic modifications highly shared among the 26 lung adenocarcinoma cell lines.	('lung adenocarcinoma cell lines', 'Disease', (77, 107))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (77, 96))	('epigenetic modifications', 'Var', (25, 49))	('lung adenocarcinoma cell lines', 'Disease', 'MESH:D000077192', (77, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))
137480	27042856	The most important finding was the dual modifications of H3K27ac and H3K4me3 in the promoter region of NUP210.	('H3K4me3', 'Protein', (69, 76))	('NUP210', 'Gene', (103, 109))	('NUP210', 'Gene', '23225', (103, 109))	('H3K27ac', 'Var', (57, 64))
137481	27042856	The dual modification was associated with its aberrant overexpression in all 26 lung adenocarcinoma cell lines, although the validation analysis showed that the extent of overexpression was smaller in other lung adenocarcinoma tissue samples There is a statistically significant difference in terms of age and sex between the lung adenocarcinoma tissue samples and the cell lines (S1 and S2 Tables) (P = 0.0002 by Wilcoxon rank sum test for age, P = 0.02 by Chi-square test for sex), which could be a factor behind it.	('overexpression', 'PosReg', (55, 69))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (207, 226))	('lung adenocarcinoma cell lines', 'Disease', 'MESH:D000077192', (80, 110))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (326, 345))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (217, 226))	('lung adenocarcinoma', 'Disease', (207, 226))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (80, 99))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (207, 226))	('lung adenocarcinoma cell lines', 'Disease', (80, 110))	('carcinoma', 'Phenotype', 'HP:0030731', (336, 345))	('lung adenocarcinoma', 'Disease', (326, 345))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (80, 99))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (326, 345))	('modification', 'Var', (9, 21))
137485	33763651	Pan-cancer image-based detection of clinically actionable genetic alterations Molecular alterations in cancer can cause phenotypic changes in tumor cells and their micro-environment.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('tumor', 'Disease', (142, 147))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('genetic alterations', 'Var', (58, 77))	('cancer', 'Disease', 'MESH:D009369', (4, 10))	('cancer', 'Disease', (103, 109))	('cause', 'Reg', (114, 119))	('cancer', 'Disease', (4, 10))
137493	33763651	However, in most tumor types, routine testing includes only a handful of alterations, such as KRAS, NRAS, BRAF mutations and microsatellite instability (MSI) in colorectal cancer.	('mutations', 'Var', (111, 120))	('NRAS', 'Gene', '4893', (100, 104))	('tumor', 'Disease', (17, 22))	('colorectal cancer', 'Disease', (161, 178))	('KRAS', 'Gene', (94, 98))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('BRAF', 'Gene', '673', (106, 110))	('microsatellite', 'MPA', (125, 139))	('KRAS', 'Gene', '3845', (94, 98))	('BRAF', 'Gene', (106, 110))	('colorectal cancer', 'Disease', 'MESH:D015179', (161, 178))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('colorectal cancer', 'Phenotype', 'HP:0003003', (161, 178))	('NRAS', 'Gene', (100, 104))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
137496	33763651	The rationale for this hypothesis is that genetic changes in tumor cells cause functional changes, which can influence tumor cell morphology.	('tumor', 'Disease', (119, 124))	('genetic changes', 'Var', (42, 57))	('functional', 'MPA', (79, 89))	('influence', 'Reg', (109, 118))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('tumor', 'Disease', (61, 66))
137497	33763651	In addition to such first-order genotype-phenotype correlations, genetic changes in tumor cells can influence the tumor microenvironment, resulting in higher-order genotype-phenotype correlations.	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('genetic changes', 'Var', (65, 80))	('tumor', 'Disease', (114, 119))	('tumor', 'Disease', (84, 89))	('higher-order genotype-phenotype correlations', 'MPA', (151, 195))	('influence', 'Reg', (100, 109))
137503	33763651	We hypothesized that deep learning can infer molecular alterations directly from routine histology images across multiple common solid tumor types.	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('solid tumor', 'Disease', (129, 140))	('molecular alterations', 'Var', (45, 66))	('solid tumor', 'Disease', 'MESH:D009369', (129, 140))
137510	33763651	In particular, in major cancer types such as lung adenocarcinoma, colorectal cancer, breast cancer and gastric cancer, alterations of several genes of particular clinical and/or biological examples were detectable (Fig.	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('cancer', 'Disease', (24, 30))	('colorectal cancer', 'Disease', (66, 83))	('cancer', 'Disease', (111, 117))	('gastric cancer', 'Disease', 'MESH:D013274', (103, 117))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (45, 64))	('breast cancer', 'Phenotype', 'HP:0003002', (85, 98))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (45, 64))	('breast cancer', 'Disease', 'MESH:D001943', (85, 98))	('gastric cancer', 'Phenotype', 'HP:0012126', (103, 117))	('cancer', 'Disease', (92, 98))	('breast cancer', 'Disease', (85, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (55, 64))	('cancer', 'Disease', (77, 83))	('colorectal cancer', 'Phenotype', 'HP:0003003', (66, 83))	('cancer', 'Disease', 'MESH:D009369', (24, 30))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('alterations', 'Var', (119, 130))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('gastric cancer', 'Disease', (103, 117))	('lung adenocarcinoma', 'Disease', (45, 64))	('colorectal cancer', 'Disease', 'MESH:D015179', (66, 83))
137511	33763651	Examples include mutations in TP53, which could be significantly detected in all four of these cancer types, as well as mutations of BRAF in colorectal cancer (TCGA-COAD and TCGA-READ, N=555, Fig.	('cancer', 'Disease', (152, 158))	('TP53', 'Gene', (30, 34))	('colorectal cancer', 'Disease', 'MESH:D015179', (141, 158))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('BRAF', 'Gene', '673', (133, 137))	('colorectal cancer', 'Phenotype', 'HP:0003003', (141, 158))	('cancer', 'Disease', (95, 101))	('BRAF', 'Gene', (133, 137))	('colorectal cancer', 'Disease', (141, 158))	('mutations', 'Var', (120, 129))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('TP53', 'Gene', '7157', (30, 34))	('mutations', 'Var', (17, 26))
137513	33763651	2d) and FBXW7 mutation in lung adenocarcinoma (TCGA-LUAD, N=457, Fig.	('FBXW7', 'Gene', (8, 13))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (26, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (36, 45))	('mutation', 'Var', (14, 22))	('lung adenocarcinoma', 'Disease', (26, 45))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (26, 45))	('FBXW7', 'Gene', '55294', (8, 13))
137515	33763651	Mutations of PIK3CA (which is directly targetable by a small molecule inhibitor) was significantly detectable in breast cancer (TCGA-BRCA, N=995, Fig.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('breast cancer', 'Disease', 'MESH:D001943', (113, 126))	('PIK3CA', 'Gene', (13, 19))	('breast cancer', 'Disease', (113, 126))	('breast cancer', 'Phenotype', 'HP:0003002', (113, 126))	('PIK3CA', 'Gene', '5290', (13, 19))	('Mutations', 'Var', (0, 9))	('detectable', 'Reg', (99, 109))
137517	33763651	In addition, in breast cancer, mutations of MAP2K4 (which is a potential biomarker for response to MEK inhibitors) were significantly detectable (Fig.	('MEK', 'Gene', '5609', (99, 102))	('breast cancer', 'Disease', (16, 29))	('mutations', 'Var', (31, 40))	('breast cancer', 'Phenotype', 'HP:0003002', (16, 29))	('detectable', 'Reg', (134, 144))	('MAP2K4', 'Gene', '6416', (44, 50))	('MAP2K4', 'Gene', (44, 50))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('breast cancer', 'Disease', 'MESH:D001943', (16, 29))	('MEK', 'Gene', (99, 102))
137520	33763651	For all statistically significant features, the mean cross-validated area under the receiver operating curve (AUROC) for the top eight mutations ranged from 0.60 to 0.78 in lung adenocarcinoma (Extended Data Fig.	('carcinoma', 'Phenotype', 'HP:0030731', (183, 192))	('lung adenocarcinoma', 'Disease', (173, 192))	('mutations', 'Var', (135, 144))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (173, 192))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (173, 192))
137525	33763651	3i-p), in melanoma metastases, mutations in FBXW7 and PIK3CA were sig-nificantly detectable (Fig.	('FBXW7', 'Gene', '55294', (44, 49))	('mutations', 'Var', (31, 40))	('FBXW7', 'Gene', (44, 49))	('melanoma metastases', 'Disease', (10, 29))	('PIK3CA', 'Gene', '5290', (54, 60))	('melanoma', 'Phenotype', 'HP:0002861', (10, 18))	('melanoma metastases', 'Disease', 'MESH:D009362', (10, 29))	('PIK3CA', 'Gene', (54, 60))
137527	33763651	4a-h), our method detected TP53 and FOXA1 mutations from histology, among others.	('TP53', 'Gene', '7157', (27, 31))	('TP53', 'Gene', (27, 31))	('FOXA1', 'Gene', '3169', (36, 41))	('FOXA1', 'Gene', (36, 41))	('mutations', 'Var', (42, 51))
137531	33763651	Thus, it is plausible that in this cancer type, tumor histomorphology is not well correlated to mutations and correspondingly, few mutations were significantly detectable in this tumor type in our experiments (TCGA-LUSC, N=413, Fig.	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('tumor', 'Disease', (48, 53))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('cancer', 'Disease', (35, 41))	('mutations', 'Var', (96, 105))	('tumor', 'Disease', (179, 184))
137535	33763651	5q-x), alterations in multiple genes including KRAS and PBRM were highly significantly detectable while in chromophobe renal cell carcinoma (Fig.	('chromophobe renal cell carcinoma', 'Disease', 'MESH:C538614', (107, 139))	('PBRM', 'Gene', (56, 60))	('KRAS', 'Gene', (47, 51))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (119, 139))	('KRAS', 'Gene', '3845', (47, 51))	('alterations', 'Var', (7, 18))	('chromophobe renal cell carcinoma', 'Disease', (107, 139))
137537	33763651	In head and neck squamous cell carcinoma (TCGA-HNSC, N=435 patients), genotype of CASP8, which is linked to resistance to cell death, was significantly detected (Fig.	('CASP8', 'Gene', (82, 87))	('CASP8', 'Gene', '841', (82, 87))	('detected', 'Reg', (152, 160))	('death', 'Disease', 'MESH:D003643', (127, 132))	('neck squamous cell carcinoma', 'Disease', (12, 40))	('death', 'Disease', (127, 132))	('patients', 'Species', '9606', (59, 67))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (12, 40))	('genotype', 'Var', (70, 78))	('carcinoma', 'Phenotype', 'HP:0030731', (31, 40))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (17, 40))
137538	33763651	In cervical cancer (TCGA-CESC, N=261 patients), mutations in TCERG1, STK11, AMER1, among others, were significantly detectable with high AUROC values (Fig.	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('TCERG1', 'Gene', '10915', (61, 67))	('cancer', 'Disease', (12, 18))	('patients', 'Species', '9606', (37, 45))	('AMER1', 'Gene', '139285', (76, 81))	('AMER1', 'Gene', (76, 81))	('TCERG1', 'Gene', (61, 67))	('STK11', 'Gene', (69, 74))	('detectable', 'Reg', (116, 126))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('STK11', 'Gene', '6794', (69, 74))	('mutations', 'Var', (48, 57))
137539	33763651	With this criterion, the absolute number of patients affected by a particular mutation was lower and thus, fewer genes met the threshold of at least four positive cases in a given tumor type.	('lower', 'NegReg', (91, 96))	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('patients', 'Species', '9606', (44, 52))	('mutation', 'Var', (78, 86))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('tumor', 'Disease', (180, 185))
137540	33763651	Genetic variants in classical oncogenes such as TP53 and KRAS are almost always oncogenic drivers and correspondingly, mutations of these genes reached similar prediction accuracy valued in the "drivers only" experiment when compared to the "all variants" approach (Fig.	('TP53', 'Gene', '7157', (48, 52))	('TP53', 'Gene', (48, 52))	('variants', 'Var', (8, 16))	('KRAS', 'Gene', (57, 61))	('KRAS', 'Gene', '3845', (57, 61))	('mutations', 'Var', (119, 128))
137541	33763651	For mutations in other genes, prediction accuracy increased when limited to oncogenic drivers: a notable example was EGFR in lung adenocarcinoma (Fig.	('lung adenocarcinoma', 'Disease', (125, 144))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (125, 144))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('EGFR', 'Gene', '1956', (117, 121))	('EGFR', 'Gene', (117, 121))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (125, 144))	('mutations', 'Var', (4, 13))
137542	33763651	In summary, these data show that deep learning can detect targetable and potentially targetable point mutations in a wide range of genes directly from histology across multiple prevalent tumor types.	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('tumor', 'Disease', (187, 192))	('point mutations', 'Var', (96, 111))	('tumor', 'Disease', 'MESH:D009369', (187, 192))
137571	33763651	As a large-scale, systematic screening study, this work identifies a number of mutations which are significantly linked to a detectable phenotype in histological images, including those in key oncogenic pathways including the products of TP53, FBXW7, KRAS, BRAF and CTNNB1.	('KRAS', 'Gene', '3845', (251, 255))	('FBXW7', 'Gene', '55294', (244, 249))	('mutations', 'Var', (79, 88))	('CTNNB1', 'Gene', '1499', (266, 272))	('TP53', 'Gene', '7157', (238, 242))	('FBXW7', 'Gene', (244, 249))	('BRAF', 'Gene', (257, 261))	('BRAF', 'Gene', '673', (257, 261))	('TP53', 'Gene', (238, 242))	('linked', 'Reg', (113, 119))	('KRAS', 'Gene', (251, 255))	('CTNNB1', 'Gene', (266, 272))
137584	33763651	Similarly, visualizing histomorphology in the highest predicted tiles in BRAF mutant patients in the validation cohort (Fig.	('patients', 'Species', '9606', (85, 93))	('BRAF', 'Gene', (73, 77))	('BRAF', 'Gene', '673', (73, 77))	('mutant', 'Var', (78, 84))
137585	33763651	5j-k) demonstrated poorly differentiated areas and mucinous areas as recurring features in BRAF mutant image tiles, which is consistent with previous studies.	('BRAF', 'Gene', '673', (91, 95))	('mutant', 'Var', (96, 102))	('BRAF', 'Gene', (91, 95))
137587	33763651	in AMER1 and MTOR) which could help to form new hypotheses on how these specific mutations influence cancer cell behavior and morphology.	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('AMER1', 'Gene', '139285', (3, 8))	('influence', 'Reg', (91, 100))	('cancer', 'Disease', (101, 107))	('AMER1', 'Gene', (3, 8))	('MTOR', 'Gene', (13, 17))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('mutations', 'Var', (81, 90))	('MTOR', 'Gene', '2475', (13, 17))
137622	33763651	External validation was performed for BRAF mutation status and CpG island methylator phenotype (CIMP) in colorectal cancer in N=408 patients, a subset of the multicenter DACHS study which was previously collected and described.	('colorectal cancer', 'Disease', 'MESH:D015179', (105, 122))	('mutation', 'Var', (43, 51))	('BRAF', 'Gene', '673', (38, 42))	('colorectal cancer', 'Phenotype', 'HP:0003003', (105, 122))	('BRAF', 'Gene', (38, 42))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('CIMP', 'Chemical', '-', (96, 100))	('patients', 'Species', '9606', (132, 140))	('colorectal cancer', 'Disease', (105, 122))
137703	31856248	Impact of HFE variants and sex in lung cancer The homeostatic iron regulator protein HFE is involved in regulation of iron acquisition for cells.	('lung cancer', 'Disease', (34, 45))	('iron', 'Chemical', 'MESH:D007501', (62, 66))	('variants', 'Var', (14, 22))	('lung cancer', 'Phenotype', 'HP:0100526', (34, 45))	('HFE', 'Gene', '3077', (10, 13))	('HFE', 'Gene', (85, 88))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('lung cancer', 'Disease', 'MESH:D008175', (34, 45))	('HFE', 'Gene', (10, 13))	('iron', 'Chemical', 'MESH:D007501', (118, 122))	('HFE', 'Gene', '3077', (85, 88))
137704	31856248	The prevalence of two common HFE gene variants (H63D, C282Y) has been studied in many cancer types; however, the impact of HFE variants, sex and HFE gene expression in lung cancer has not been studied.	('HFE', 'Gene', (145, 148))	('HFE', 'Gene', '3077', (123, 126))	('C282Y', 'Var', (54, 59))	('HFE', 'Gene', (29, 32))	('lung cancer', 'Disease', (168, 179))	('lung cancer', 'Phenotype', 'HP:0100526', (168, 179))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('HFE', 'Gene', (123, 126))	('HFE', 'Gene', '3077', (145, 148))	('cancer type', 'Disease', (86, 97))	('cancer type', 'Disease', 'MESH:D009369', (86, 97))	('C282Y', 'Mutation', 'rs1800562', (54, 59))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('HFE variant', 'CellLine', 'CVCL:7204', (123, 134))	('HFE', 'Gene', '3077', (29, 32))	('lung cancer', 'Disease', 'MESH:D008175', (168, 179))	('H63D', 'SUBSTITUTION', 'None', (48, 52))	('H63D', 'Var', (48, 52))
137705	31856248	We determined the prevalence of HFE variants and their impact on cancer phenotypes in lung cancer cell lines, in lung cancer patient specimens, and using The Cancer Genome Atlas (TCGA) database.	('men', 'Species', '9606', (138, 141))	('lung cancer', 'Disease', (86, 97))	('lung cancer', 'Disease', 'MESH:D008175', (113, 124))	('cancer', 'Disease', (65, 71))	('lung cancer', 'Phenotype', 'HP:0100526', (113, 124))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('lung cancer', 'Disease', 'MESH:D008175', (86, 97))	('cancer', 'Disease', (118, 124))	('Cancer', 'Phenotype', 'HP:0002664', (158, 164))	('lung cancer', 'Phenotype', 'HP:0100526', (86, 97))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('patient', 'Species', '9606', (125, 132))	('impact', 'Reg', (55, 61))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('lung cancer', 'Disease', (113, 124))	('HFE', 'Gene', (32, 35))	('cancer', 'Disease', (91, 97))	('HFE variant', 'CellLine', 'CVCL:7204', (32, 43))	('variants', 'Var', (36, 44))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (118, 124))
137706	31856248	We found that seven out of ten human lung cancer cell lines carry the H63D or C282Y HFE variant.	('H63D', 'SUBSTITUTION', 'None', (70, 74))	('lung cancer', 'Disease', (37, 48))	('C282Y', 'Var', (78, 83))	('H63D', 'Var', (70, 74))	('lung cancer', 'Phenotype', 'HP:0100526', (37, 48))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('HFE', 'Gene', (84, 87))	('human', 'Species', '9606', (31, 36))	('C282Y', 'Mutation', 'rs1800562', (78, 83))	('lung cancer', 'Disease', 'MESH:D008175', (37, 48))	('HFE variant', 'CellLine', 'CVCL:7204', (84, 95))
137707	31856248	Analysis of lung cancer specimens from our institute (Penn State Hershey Medical Center) revealed a sex and genotype interaction risk for metastasis in lung adenocarcinoma (LUAD) patients; H63D HFE is associated with less metastasis in males compared to wild type (WT) HFE; however, females with the H63D HFE variant tend to develop more metastatic tumors than WT female patients.	('less metastasis', 'CPA', (217, 232))	('tumors', 'Phenotype', 'HP:0002664', (349, 355))	('metastasis in lung adenocarcinoma', 'Disease', (138, 171))	('patients', 'Species', '9606', (371, 379))	('tumor', 'Phenotype', 'HP:0002664', (349, 354))	('LUAD', 'Disease', 'MESH:C538231', (173, 177))	('H63D', 'SUBSTITUTION', 'None', (189, 193))	('develop', 'PosReg', (325, 332))	('H63D', 'SUBSTITUTION', 'None', (300, 304))	('HFE', 'Gene', '3077', (194, 197))	('lung cancer', 'Phenotype', 'HP:0100526', (12, 23))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))	('HFE', 'Gene', (305, 308))	('lung cancer', 'Disease', (12, 23))	('patients', 'Species', '9606', (179, 187))	('H63D', 'Var', (189, 193))	('metastasis in lung adenocarcinoma', 'Disease', 'MESH:C538231', (138, 171))	('H63D', 'Var', (300, 304))	('HFE', 'Gene', (194, 197))	('HFE', 'Gene', '3077', (269, 272))	('LUAD', 'Phenotype', 'HP:0030078', (173, 177))	('carcinoma', 'Phenotype', 'HP:0030731', (162, 171))	('tumor', 'Disease', (349, 354))	('lung cancer', 'Disease', 'MESH:D008175', (12, 23))	('tumor', 'Disease', 'MESH:D009369', (349, 354))	('men', 'Species', '9606', (29, 32))	('LUAD', 'Disease', (173, 177))	('HFE', 'Gene', (269, 272))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (152, 171))	('HFE', 'Gene', '3077', (305, 308))
137708	31856248	In the TCGA LUAD dataset, the H63D HFE variant was associated with poorer survival in females compared to females with WT HFE.	('survival', 'CPA', (74, 82))	('HFE', 'Gene', '3077', (122, 125))	('HFE', 'Gene', '3077', (35, 38))	('H63D', 'SUBSTITUTION', 'None', (30, 34))	('LUAD', 'Phenotype', 'HP:0030078', (12, 16))	('H63D', 'Var', (30, 34))	('poorer', 'NegReg', (67, 73))	('LUAD', 'Disease', (12, 16))	('LUAD', 'Disease', 'MESH:C538231', (12, 16))	('HFE', 'Gene', (122, 125))	('HFE', 'Gene', (35, 38))
137710	31856248	In the TCGA LUSC dataset, C282Y HFE patients (especially females) had poorer survival than WT HFE patients.	('C282Y', 'Var', (26, 31))	('survival', 'CPA', (77, 85))	('patients', 'Species', '9606', (36, 44))	('HFE', 'Gene', (32, 35))	('poorer', 'NegReg', (70, 76))	('LUSC', 'Phenotype', 'HP:0030359', (12, 16))	('patients', 'Species', '9606', (98, 106))	('C282Y', 'Mutation', 'rs1800562', (26, 31))	('LUSC', 'Disease', (12, 16))	('HFE', 'Gene', '3077', (94, 97))	('LUSC', 'Disease', 'MESH:D002294', (12, 16))	('HFE', 'Gene', '3077', (32, 35))	('HFE', 'Gene', (94, 97))
137712	31856248	In summary, these data suggest that there is a sexually dimorphic effect of HFE polymorphisms in the survival and metastatic disease in lung cancer.	('HFE', 'Gene', (76, 79))	('metastatic disease', 'CPA', (114, 132))	('lung cancer', 'Phenotype', 'HP:0100526', (136, 147))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('lung cancer', 'Disease', 'MESH:D008175', (136, 147))	('polymorphisms', 'Var', (80, 93))	('HFE', 'Gene', '3077', (76, 79))	('survival', 'CPA', (101, 109))	('lung cancer', 'Disease', (136, 147))
137720	31856248	Molecular profiling of NSCLC found higher gene mutations in multiple oncogenes, such as epidermal growth factor receptor (EGFR) (10-35%), K-ras (KRAS) (15-25%), and Phosphatase and tensin homolog (PTEN) (4-8%).	('K-ras', 'Gene', (138, 143))	('K-ras', 'Gene', '3845', (138, 143))	('NSCLC', 'Disease', 'MESH:D002289', (23, 28))	('NSCLC', 'Phenotype', 'HP:0030358', (23, 28))	('SCLC', 'Phenotype', 'HP:0030357', (24, 28))	('KRAS', 'Gene', (145, 149))	('tensin', 'Chemical', 'MESH:C406010', (181, 187))	('epidermal growth factor receptor', 'Gene', '1956', (88, 120))	('mutations', 'Var', (47, 56))	('NSCLC', 'Disease', (23, 28))	('PTEN', 'Gene', (197, 201))	('KRAS', 'Gene', '3845', (145, 149))	('PTEN', 'Gene', '5728', (197, 201))	('oncogenes', 'Gene', (69, 78))	('EGFR', 'Gene', '1956', (122, 126))	('epidermal growth factor receptor', 'Gene', (88, 120))	('EGFR', 'Gene', (122, 126))
137721	31856248	Fibroblast growth factor receptor 1 (FGFR1) amplification (20%) and anaplastic lymphoma kinase (ALK) rearrangement (3-7%) are also found in NSCLC.	('FGFR1', 'Gene', (37, 42))	('anaplastic lymphoma kinase', 'Gene', '238', (68, 94))	('NSCLC', 'Disease', 'MESH:D002289', (140, 145))	('ALK', 'Gene', '238', (96, 99))	('FGFR1', 'Gene', '2260', (37, 42))	('Fibroblast growth factor receptor 1', 'Gene', (0, 35))	('men', 'Species', '9606', (110, 113))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (68, 87))	('SCLC', 'Phenotype', 'HP:0030357', (141, 145))	('amplification', 'Var', (44, 57))	('NSCLC', 'Phenotype', 'HP:0030358', (140, 145))	('anaplastic lymphoma kinase', 'Gene', (68, 94))	('rearrangement', 'Var', (101, 114))	('lymphoma', 'Phenotype', 'HP:0002665', (79, 87))	('ALK', 'Gene', (96, 99))	('Fibroblast growth factor receptor 1', 'Gene', '2260', (0, 35))	('NSCLC', 'Disease', (140, 145))
137722	31856248	Interestingly, many driver mutations found in lung adenocarcinoma (LUAD) are rarely found in lung squamous cell carcinoma (LUSC), which suggests distinct cancer development processes among lung cancer sub-types.	('mutations', 'Var', (27, 36))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('LUAD', 'Disease', (67, 71))	('men', 'Species', '9606', (168, 171))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (46, 65))	('cancer', 'Disease', 'MESH:D009369', (194, 200))	('carcinoma', 'Phenotype', 'HP:0030731', (56, 65))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('lung cancer', 'Disease', (189, 200))	('LUAD', 'Disease', 'MESH:C538231', (67, 71))	('LUSC', 'Disease', (123, 127))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (93, 121))	('LUSC', 'Phenotype', 'HP:0030359', (123, 127))	('LUSC', 'Disease', 'MESH:D002294', (123, 127))	('lung cancer', 'Disease', 'MESH:D008175', (189, 200))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (46, 65))	('cancer', 'Disease', (194, 200))	('lung adenocarcinoma', 'Disease', (46, 65))	('cancer', 'Disease', (154, 160))	('lung cancer', 'Phenotype', 'HP:0100526', (189, 200))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (98, 121))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (93, 121))	('lung squamous cell carcinoma', 'Disease', (93, 121))	('LUAD', 'Phenotype', 'HP:0030078', (67, 71))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))
137728	31856248	Polymorphisms in the HFE gene occur more frequently in Caucasians than in other races.	('Polymorphisms', 'Var', (0, 13))	('HFE', 'Gene', '3077', (21, 24))	('HFE', 'Gene', (21, 24))
137730	31856248	One is H63D, a single mutation of C to G at nucleotide 187, which results in a substitution of aspartate for histidine at amino acid 63.	('C to G', 'Gene', (34, 40))	('C to G at nucleotide 187', 'Mutation', 'rs1799945', (34, 58))	('substitution', 'Var', (79, 91))	('H63D', 'SUBSTITUTION', 'None', (7, 11))	('H63D', 'Var', (7, 11))	('results in', 'Reg', (66, 76))	('aspartate for histidine at amino acid 63', 'Mutation', 'rs1799945', (95, 135))	('aspartate', 'MPA', (95, 104))
137731	31856248	The other one is C282Y, a mutation of G to A at nucleotide 845, which results in the substitution of tyrosine for cysteine at amino acid 282.	('tyrosine for cysteine at amino acid 282', 'Mutation', 'rs1800562', (101, 140))	('C282Y', 'Mutation', 'rs1800562', (17, 22))	('C282Y', 'Var', (17, 22))	('G to A at nucleotide 845', 'Mutation', 'rs1800562', (38, 62))	('substitution', 'Var', (85, 97))	('tyrosine for cysteine', 'MPA', (101, 122))	('results in', 'Reg', (70, 80))
137732	31856248	In the normal Caucasian population, the frequency of H63D and C282Y HFE genotype is around 26% (24% heterozygote and 2.4% homozygote) and 10% (10% heterozygote and 0.44% homozygote), respectively.	('C282Y', 'Mutation', 'rs1800562', (62, 67))	('HFE', 'Gene', '3077', (68, 71))	('H63D', 'SUBSTITUTION', 'None', (53, 57))	('HFE', 'Gene', (68, 71))	('H63D', 'Var', (53, 57))	('C282Y', 'Var', (62, 67))
137733	31856248	The allelic frequency of H63D and C282Y HFE in the general Caucasian population is 15.3% and 6.8%.	('HFE', 'Gene', (40, 43))	('C282Y', 'Var', (34, 39))	('C282Y', 'Mutation', 'rs1800562', (34, 39))	('H63D', 'SUBSTITUTION', 'None', (25, 29))	('H63D', 'Var', (25, 29))	('HFE', 'Gene', '3077', (40, 43))
137734	31856248	Increased frequency of the HFE variants have been reported in acute lymphoblastic leukemia and breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('variants', 'Var', (31, 39))	('breast cancer', 'Disease', (95, 108))	('breast cancer', 'Phenotype', 'HP:0003002', (95, 108))	('acute lymphoblastic leukemia', 'Disease', (62, 90))	('acute lymphoblastic leukemia', 'Disease', 'MESH:D054198', (62, 90))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (68, 90))	('HFE', 'Gene', (27, 30))	('reported', 'Reg', (50, 58))	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (62, 90))	('leukemia', 'Phenotype', 'HP:0001909', (82, 90))	('HFE variant', 'CellLine', 'CVCL:7204', (27, 38))	('breast cancer', 'Disease', 'MESH:D001943', (95, 108))
137735	31856248	Increased frequency of H63D HFE variant was observed in malignant gliomas.	('HFE', 'Gene', (28, 31))	('H63D', 'SUBSTITUTION', 'None', (23, 27))	('H63D', 'Var', (23, 27))	('malignant gliomas', 'Disease', (56, 73))	('malignant gliomas', 'Disease', 'MESH:D005910', (56, 73))	('gliomas', 'Phenotype', 'HP:0009733', (66, 73))
137736	31856248	The H63D HFE variant is also a risk factor for colorectal cancer, hepatocellular carcinoma, and pancreatic cancer.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('colorectal cancer', 'Disease', (47, 64))	('pancreatic cancer', 'Disease', (96, 113))	('HFE', 'Gene', (9, 12))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (66, 90))	('pancreatic cancer', 'Disease', 'MESH:D010190', (96, 113))	('hepatocellular carcinoma', 'Disease', (66, 90))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (66, 90))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('H63D', 'Var', (4, 8))	('colorectal cancer', 'Disease', 'MESH:D015179', (47, 64))	('H63D', 'SUBSTITUTION', 'None', (4, 8))	('risk', 'Reg', (31, 35))	('colorectal cancer', 'Phenotype', 'HP:0003003', (47, 64))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (96, 113))
137737	31856248	Increased frequency of C282Y HFE variant was observed in colorectal cancer and hepatocellular carcinoma.	('colorectal cancer', 'Disease', (57, 74))	('hepatocellular carcinoma', 'Disease', (79, 103))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (79, 103))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('C282Y', 'Mutation', 'rs1800562', (23, 28))	('HFE variant', 'CellLine', 'CVCL:7204', (29, 40))	('HFE', 'Protein', (29, 32))	('colorectal cancer', 'Disease', 'MESH:D015179', (57, 74))	('colorectal cancer', 'Phenotype', 'HP:0003003', (57, 74))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (79, 103))	('C282Y', 'Var', (23, 28))
137738	31856248	In addition, the C282Y HFE variant is a risk factor for breast cancer, colorectal cancer, hepatocellular carcinoma, liver cancer, and ovarian cancer.	('liver cancer', 'Disease', 'MESH:D006528', (116, 128))	('breast cancer', 'Disease', 'MESH:D001943', (56, 69))	('HFE variant', 'CellLine', 'CVCL:7204', (23, 34))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('breast cancer', 'Disease', (56, 69))	('liver cancer', 'Phenotype', 'HP:0002896', (116, 128))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('liver cancer', 'Disease', (116, 128))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (90, 114))	('colorectal cancer', 'Disease', 'MESH:D015179', (71, 88))	('colorectal cancer', 'Disease', (71, 88))	('ovarian cancer', 'Disease', 'MESH:D010051', (134, 148))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (90, 114))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('C282Y', 'Var', (17, 22))	('HFE', 'Protein', (23, 26))	('hepatocellular carcinoma', 'Disease', (90, 114))	('ovarian cancer', 'Disease', (134, 148))	('breast cancer', 'Phenotype', 'HP:0003002', (56, 69))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('colorectal cancer', 'Phenotype', 'HP:0003003', (71, 88))	('C282Y', 'Mutation', 'rs1800562', (17, 22))	('ovarian cancer', 'Phenotype', 'HP:0100615', (134, 148))
137739	31856248	The risk of C282Y HFE variant in colorectal cancer has been reported as both increased and decreased.	('HFE variant', 'CellLine', 'CVCL:7204', (18, 29))	('HFE', 'Protein', (18, 21))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('C282Y', 'Mutation', 'rs1800562', (12, 17))	('colorectal cancer', 'Disease', 'MESH:D015179', (33, 50))	('colorectal cancer', 'Phenotype', 'HP:0003003', (33, 50))	('decreased', 'NegReg', (91, 100))	('colorectal cancer', 'Disease', (33, 50))	('C282Y', 'Var', (12, 17))
137740	31856248	In our previous study using Penn State Health Milton S. Hershey Medical Center (PSHMC) glioblastoma (GBM) patient's samples, we demonstrated poorer overall survival in male GBM patients with H63D HFE than male WT HFE GBM patients although this finding was not observed in TCGA GBM samples.	('H63D', 'Var', (191, 195))	('patients', 'Species', '9606', (221, 229))	('GBM', 'Phenotype', 'HP:0012174', (277, 280))	('patient', 'Species', '9606', (106, 113))	('HFE', 'Gene', (196, 199))	('glioblastoma', 'Phenotype', 'HP:0012174', (87, 99))	('GBM', 'Phenotype', 'HP:0012174', (101, 104))	('GBM', 'Disease', (217, 220))	('GBM', 'Disease', 'MESH:D005909', (217, 220))	('patient', 'Species', '9606', (221, 228))	('overall survival', 'MPA', (148, 164))	('HFE', 'Gene', '3077', (213, 216))	('GBM', 'Disease', (173, 176))	('GBM', 'Phenotype', 'HP:0012174', (217, 220))	('GBM', 'Disease', 'MESH:D005909', (173, 176))	('glioblastoma', 'Disease', 'MESH:D005909', (87, 99))	('GBM', 'Disease', (277, 280))	('GBM', 'Disease', 'MESH:D005909', (277, 280))	('H63D', 'SUBSTITUTION', 'None', (191, 195))	('patients', 'Species', '9606', (177, 185))	('HFE', 'Gene', '3077', (196, 199))	('poorer', 'NegReg', (141, 147))	('HFE', 'Gene', (213, 216))	('GBM', 'Disease', (101, 104))	('glioblastoma', 'Disease', (87, 99))	('GBM', 'Disease', 'MESH:D005909', (101, 104))	('GBM', 'Phenotype', 'HP:0012174', (173, 176))	('patient', 'Species', '9606', (177, 184))
137741	31856248	Despite the prevalence of lung cancer and the prevalence of the HFE gene variants, the impact of HFE genotype on lung cancer has not been studied systematically and this knowledge gap is addressed in this study.	('HFE', 'Gene', '3077', (64, 67))	('lung cancer', 'Disease', (113, 124))	('HFE', 'Gene', (97, 100))	('lung cancer', 'Phenotype', 'HP:0100526', (113, 124))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('variants', 'Var', (73, 81))	('lung cancer', 'Disease', 'MESH:D008175', (26, 37))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('HFE', 'Gene', (64, 67))	('HFE', 'Gene', '3077', (97, 100))	('lung cancer', 'Disease', 'MESH:D008175', (113, 124))	('lung cancer', 'Disease', (26, 37))	('lung cancer', 'Phenotype', 'HP:0100526', (26, 37))
137751	31856248	For HFE genotype data analysis, we used only Caucasian lung cancer patients' samples, because HFE polymorphisms are most prevalent in the Caucasian population.	('lung cancer', 'Disease', 'MESH:D008175', (55, 66))	('patients', 'Species', '9606', (67, 75))	('polymorphisms', 'Var', (98, 111))	('HFE', 'Gene', '3077', (4, 7))	('lung cancer', 'Disease', (55, 66))	('HFE', 'Gene', '3077', (94, 97))	('HFE', 'Gene', (4, 7))	('lung cancer', 'Phenotype', 'HP:0100526', (55, 66))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('HFE', 'Gene', (94, 97))
137753	31856248	The HFE genotype of lung cancer patients was compared with samples from individuals without cancer or with neurological disease in our Institute of Personalized Medicine and 1000Genome data which was downloaded the frequency of Single Nucleotide Variants (SNVs) in the HFE gene using Variant Call Format (VCF) file from The International Genome Sample Resource.	('Single', 'Var', (228, 234))	('neurological disease', 'Disease', (107, 127))	('type of lung cancer', 'Disease', (12, 31))	('patients', 'Species', '9606', (32, 40))	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('HFE', 'Gene', '3077', (4, 7))	('HFE', 'Gene', '3077', (269, 272))	('type of lung cancer', 'Disease', 'MESH:D008175', (12, 31))	('lung cancer', 'Phenotype', 'HP:0100526', (20, 31))	('neurological disease', 'Phenotype', 'HP:0000707', (107, 127))	('cancer', 'Disease', 'MESH:D009369', (25, 31))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('HFE', 'Gene', (4, 7))	('cancer', 'Disease', (25, 31))	('HFE', 'Gene', (269, 272))	('neurological disease', 'Disease', 'MESH:D020271', (107, 127))
137760	31856248	We accessed HFE gene variant data from Cancer Genomics Hub (CGHub) using GeneTorrent and GTFuse software (AnnaiSystems, Carlsbad, CA) to extract and download only HFE genes from complete mapped sequence (BAM) files.	('HFE', 'Gene', (163, 166))	('Cancer', 'Phenotype', 'HP:0002664', (39, 45))	('TF', 'Gene', '7018', (90, 92))	('HFE', 'Gene', (12, 15))	('variant', 'Var', (21, 28))	('HFE', 'Gene', '3077', (163, 166))	('HFE', 'Gene', '3077', (12, 15))
137761	31856248	Genome Analysis Toolkit (GATK) software, based on the GATK best practices pipeline, was used to identify HFE gene variants (H63D, C282Y) from the sequences as we previously reported.	('H63D', 'Var', (124, 128))	('C282Y', 'Var', (130, 135))	('HFE', 'Gene', (105, 108))	('C282Y', 'Mutation', 'rs1800562', (130, 135))	('HFE', 'Gene', '3077', (105, 108))	('H63D', 'SUBSTITUTION', 'None', (124, 128))
137768	31856248	Kruskal-Wallis tests or Wilcoxon rank sum tests were used to compare HFE expression values in the following groups: (i) HFE variant vs. HFE wild type (WT), (ii) females vs. males.	('HFE', 'Gene', '3077', (136, 139))	('HFE', 'Gene', '3077', (120, 123))	('HFE', 'Gene', '3077', (69, 72))	('HFE', 'Gene', (120, 123))	('HFE', 'Gene', (136, 139))	('HFE variant', 'CellLine', 'CVCL:7204', (120, 131))	('HFE', 'Gene', (69, 72))	('variant', 'Var', (124, 131))
137770	31856248	Additionally, H63D and C282Y variants were considered separately in each tumor type, and the variant status for matched normal samples was determined by the status of the matched primary tumor sample.	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('C282Y', 'Mutation', 'rs1800562', (23, 28))	('tumor', 'Disease', (187, 192))	('tumor', 'Disease', (73, 78))	('H63D', 'Var', (14, 18))	('H63D', 'SUBSTITUTION', 'None', (14, 18))	('C282Y', 'Var', (23, 28))
137774	31856248	Comparisons of HFE gene variant frequency between samples were determined using Fisher's exact test or Chi-square test.	('HFE', 'Gene', (15, 18))	('variant', 'Var', (24, 31))	('HFE', 'Gene', '3077', (15, 18))
137775	31856248	Additionally, the associations between HFE gene variant and sex were examined using Fisher's exact test.	('HFE', 'Gene', '3077', (39, 42))	('HFE', 'Gene', (39, 42))	('variant', 'Var', (48, 55))
137776	31856248	The association between patients' overall survival and HFE polymorphisms (H63D, C282Y) was indicated by Kaplan-Meier survival curve and analyzed by log-rank test.	('C282Y', 'Mutation', 'rs1800562', (80, 85))	('H63D', 'SUBSTITUTION', 'None', (74, 78))	('H63D', 'Var', (74, 78))	('HFE', 'Gene', '3077', (55, 58))	('patients', 'Species', '9606', (24, 32))	('C282Y', 'Var', (80, 85))	('HFE', 'Gene', (55, 58))
137779	31856248	Of the ten lung cancer cell lines investigated, 6 expressed the H63D HFE variant and 1 had the C282Y HFE variant (Table 1).	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('HFE variant', 'CellLine', 'CVCL:7204', (69, 80))	('HFE variant', 'CellLine', 'CVCL:7204', (101, 112))	('C282Y', 'Var', (95, 100))	('lung cancer', 'Disease', (11, 22))	('H63D', 'SUBSTITUTION', 'None', (64, 68))	('lung cancer', 'Phenotype', 'HP:0100526', (11, 22))	('H63D', 'Var', (64, 68))	('C282Y', 'Mutation', 'rs1800562', (95, 100))	('lung cancer', 'Disease', 'MESH:D008175', (11, 22))
137780	31856248	Only 1 large cell lung cancer cell line did not have a HFE gene variant and the only squamous cell carcinoma cell line was heterozygote for C282Y.	('cell lung cancer', 'Disease', (13, 29))	('C282Y', 'Var', (140, 145))	('cell lung cancer', 'Disease', 'MESH:D008175', (13, 29))	('HFE', 'Gene', '3077', (55, 58))	('variant', 'Var', (64, 71))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (85, 108))	('lung cancer', 'Phenotype', 'HP:0100526', (18, 29))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('large cell lung cancer', 'Phenotype', 'HP:0030360', (7, 29))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (85, 108))	('C282Y', 'Mutation', 'rs1800562', (140, 145))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('squamous cell carcinoma', 'Disease', (85, 108))	('HFE', 'Gene', (55, 58))
137781	31856248	We determined the frequency of HFE gene variants in lung cancer patients (adenocarcinoma of the lung, squamous cell lung cancer) seen in our Penn State Hershey Medical Center (PSHMC), and publically available lung cancer databases.	('lung cancer', 'Disease', 'MESH:D008175', (52, 63))	('lung cancer', 'Phenotype', 'HP:0100526', (116, 127))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('lung cancer', 'Phenotype', 'HP:0100526', (209, 220))	('lung cancer', 'Phenotype', 'HP:0100526', (52, 63))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('adenocarcinoma of the lung', 'Disease', (74, 100))	('squamous cell lung cancer', 'Phenotype', 'HP:0030359', (102, 127))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('adenocarcinoma of the lung', 'Disease', 'MESH:C538231', (74, 100))	('variants', 'Var', (40, 48))	('squamous cell lung cancer', 'Disease', (102, 127))	('lung cancer', 'Disease', (209, 220))	('squamous cell lung cancer', 'Disease', 'MESH:D018307', (102, 127))	('HFE', 'Gene', '3077', (31, 34))	('lung cancer', 'Disease', (52, 63))	('patients', 'Species', '9606', (64, 72))	('lung cancer', 'Disease', 'MESH:D008175', (116, 127))	('lung cancer', 'Disease', 'MESH:D008175', (209, 220))	('HFE', 'Gene', (31, 34))
137783	31856248	We limited our analysis to Caucasians because of the higher frequency of HFE polymorphisms compared to other races.	('HFE', 'Gene', '3077', (73, 76))	('HFE', 'Gene', (73, 76))	('polymorphisms', 'Var', (77, 90))
137784	31856248	Among 53 lung adenocarcinoma patients in PSHMC, the frequency of H63D and C282Y HFE gene variant was 32.0% and 13.2%, respectively (S1 Table).	('C282Y', 'Var', (74, 79))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (9, 28))	('patients', 'Species', '9606', (29, 37))	('HFE', 'Gene', (80, 83))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (9, 28))	('carcinoma', 'Phenotype', 'HP:0030731', (19, 28))	('lung adenocarcinoma', 'Disease', (9, 28))	('C282Y', 'Mutation', 'rs1800562', (74, 79))	('H63D', 'Var', (65, 69))	('HFE', 'Gene', '3077', (80, 83))	('H63D', 'SUBSTITUTION', 'None', (65, 69))
137785	31856248	In squamous cell lung cancer patients, the frequency of H63D and C282Y HFE variant was 14.6% and 12.2%, respectively (S1 Table).	('H63D', 'SUBSTITUTION', 'None', (56, 60))	('patients', 'Species', '9606', (29, 37))	('H63D', 'Var', (56, 60))	('squamous cell lung cancer', 'Disease', (3, 28))	('HFE', 'Gene', (71, 74))	('lung cancer', 'Phenotype', 'HP:0100526', (17, 28))	('C282Y', 'Var', (65, 70))	('HFE variant', 'CellLine', 'CVCL:7204', (71, 82))	('squamous cell lung cancer', 'Phenotype', 'HP:0030359', (3, 28))	('squamous cell lung cancer', 'Disease', 'MESH:D018307', (3, 28))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('C282Y', 'Mutation', 'rs1800562', (65, 70))
137786	31856248	The allele frequency of H63D HFE was 20.8% and 8.5% for C282Y HFE in lung adenocarcinoma, and 7.3% for H63D HFE and 7.3% for C282Y HFE in lung squamous cell carcinoma.	('C282Y', 'Mutation', 'rs1800562', (56, 61))	('lung adenocarcinoma', 'Disease', (69, 88))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (138, 166))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (143, 166))	('lung squamous cell carcinoma', 'Disease', (138, 166))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('H63D', 'Var', (24, 28))	('HFE', 'Gene', '3077', (131, 134))	('H63D', 'Var', (103, 107))	('HFE', 'Gene', (108, 111))	('C282Y', 'Mutation', 'rs1800562', (125, 130))	('HFE', 'Gene', (29, 32))	('carcinoma', 'Phenotype', 'HP:0030731', (157, 166))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (69, 88))	('HFE', 'Gene', (131, 134))	('HFE', 'Gene', '3077', (62, 65))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (138, 166))	('HFE', 'Gene', (62, 65))	('HFE', 'Gene', '3077', (108, 111))	('H63D', 'SUBSTITUTION', 'None', (24, 28))	('H63D', 'SUBSTITUTION', 'None', (103, 107))	('HFE', 'Gene', '3077', (29, 32))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (69, 88))
137787	31856248	Statistical analysis revealed a lower frequency of H63D HFE alleles in squamous cell carcinoma compared to adenocarcinoma (p = 0.007).	('HFE', 'Gene', (56, 59))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (71, 94))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (71, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('squamous cell carcinoma', 'Disease', (71, 94))	('adenocarcinoma', 'Disease', (107, 121))	('HFE', 'Gene', '3077', (56, 59))	('H63D', 'Var', (51, 55))	('H63D', 'SUBSTITUTION', 'None', (51, 55))	('adenocarcinoma', 'Disease', 'MESH:D000230', (107, 121))	('lower', 'NegReg', (32, 37))
137788	31856248	In comparison to non-cancer population adenocarcinoma tended to have higher C282Y HFE allele frequency (p = 0.08) compared to 1000Genome database.	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('HFE', 'Gene', '3077', (82, 85))	('C282Y', 'Var', (76, 81))	('adenocarcinoma', 'Disease', 'MESH:D000230', (39, 53))	('C282Y', 'Mutation', 'rs1800562', (76, 81))	('HFE', 'Gene', (82, 85))	('cancer', 'Disease', (21, 27))	('cancer', 'Disease', 'MESH:D009369', (21, 27))	('carcinoma', 'Phenotype', 'HP:0030731', (44, 53))	('adenocarcinoma', 'Disease', (39, 53))
137789	31856248	Squamous cell carcinoma had significantly lower H63D HFE allelic frequency than the PSHMC control samples (p = 0.0336) or 1000Genome data (p = 0.04).	('carcinoma', 'Phenotype', 'HP:0030731', (14, 23))	('HFE', 'Gene', '3077', (53, 56))	('Squamous cell carcinoma', 'Disease', 'MESH:D002294', (0, 23))	('lower', 'NegReg', (42, 47))	('Squamous cell carcinoma', 'Phenotype', 'HP:0002860', (0, 23))	('HFE', 'Gene', (53, 56))	('Squamous cell carcinoma', 'Disease', (0, 23))	('H63D', 'SUBSTITUTION', 'None', (48, 52))	('H63D', 'Var', (48, 52))
137791	31856248	The summary of allele frequencies for H63D HFE and C282Y HFE in lung cancers and controls are summarized in Fig 1.	('lung cancer', 'Phenotype', 'HP:0100526', (64, 75))	('cancers', 'Phenotype', 'HP:0002664', (69, 76))	('C282Y', 'Mutation', 'rs1800562', (51, 56))	('lung cancers', 'Disease', 'MESH:D008175', (64, 76))	('HFE', 'Gene', '3077', (57, 60))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('lung cancers', 'Phenotype', 'HP:0100526', (64, 76))	('HFE', 'Gene', (43, 46))	('HFE', 'Gene', (57, 60))	('H63D', 'SUBSTITUTION', 'None', (38, 42))	('C282Y', 'Var', (51, 56))	('H63D', 'Var', (38, 42))	('lung cancers', 'Disease', (64, 76))	('HFE', 'Gene', '3077', (43, 46))
137793	31856248	There was an increase in the C282Y HFE allelic frequency in female LUAD patients in the TCGA database (p = 0.0474) (Table 3) but not in the PSHMC database (S3 Table).	('C282Y', 'Var', (29, 34))	('C282Y', 'Mutation', 'rs1800562', (29, 34))	('HFE', 'Gene', '3077', (35, 38))	('LUAD', 'Disease', (67, 71))	('LUAD', 'Disease', 'MESH:C538231', (67, 71))	('LUAD', 'Phenotype', 'HP:0030078', (67, 71))	('HFE', 'Gene', (35, 38))	('patients', 'Species', '9606', (72, 80))
137794	31856248	There were no sex differences in the H63D HFE allele groups.	('H63D', 'SUBSTITUTION', 'None', (37, 41))	('HFE', 'Gene', (42, 45))	('H63D', 'Var', (37, 41))	('HFE', 'Gene', '3077', (42, 45))
137796	31856248	There were no differences between WT and H63D or C282Y HFE variants in matched normal or primary tumors of LUAD and LUSC lung cancer patients in two sample t-test (S1 and S2 Figs).	('lung cancer', 'Disease', 'MESH:D008175', (121, 132))	('HFE variant', 'CellLine', 'CVCL:7204', (55, 66))	('C282Y', 'Mutation', 'rs1800562', (49, 54))	('patients', 'Species', '9606', (133, 141))	('LUAD', 'Disease', (107, 111))	('lung cancer', 'Phenotype', 'HP:0100526', (121, 132))	('LUAD', 'Disease', 'MESH:C538231', (107, 111))	('tumor', 'Disease', (97, 102))	('LUSC', 'Disease', (116, 120))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('lung cancer', 'Disease', (121, 132))	('H63D', 'SUBSTITUTION', 'None', (41, 45))	('C282Y', 'Var', (49, 54))	('LUSC', 'Disease', 'MESH:D002294', (116, 120))	('LUSC', 'Phenotype', 'HP:0030359', (116, 120))	('LUAD', 'Phenotype', 'HP:0030078', (107, 111))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('H63D', 'Var', (41, 45))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('HFE', 'Gene', (55, 58))
137798	31856248	There were no HFE expression differences between WT and HFE variants in male or female LUAD and LUSC in the TCGA lung cancer dataset (Fig 2).	('HFE', 'Gene', (56, 59))	('LUSC', 'Disease', (96, 100))	('HFE', 'Gene', (14, 17))	('LUSC', 'Disease', 'MESH:D002294', (96, 100))	('lung cancer', 'Disease', (113, 124))	('LUSC', 'Phenotype', 'HP:0030359', (96, 100))	('lung cancer', 'Phenotype', 'HP:0100526', (113, 124))	('HFE variant', 'CellLine', 'CVCL:7204', (56, 67))	('LUAD', 'Phenotype', 'HP:0030078', (87, 91))	('LUAD', 'Disease', (87, 91))	('LUAD', 'Disease', 'MESH:C538231', (87, 91))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('HFE', 'Gene', '3077', (14, 17))	('lung cancer', 'Disease', 'MESH:D008175', (113, 124))	('HFE', 'Gene', '3077', (56, 59))	('variants', 'Var', (60, 68))
137801	31856248	None of the H63D HFE male adenocarcinoma patients developed metastases while 50% of WT HFE male patients did (p = 0.0189); whereas in females the findings were opposite with H63D HFE carriers tending to develop more metastases than WT HFE (p = 0.0596).	('HFE', 'Gene', (87, 90))	('HFE', 'Gene', '3077', (179, 182))	('metastases', 'Disease', (60, 70))	('H63D', 'SUBSTITUTION', 'None', (174, 178))	('metastases', 'Disease', 'MESH:D009362', (216, 226))	('HFE', 'Gene', '3077', (17, 20))	('HFE', 'Gene', (235, 238))	('metastases', 'Disease', (216, 226))	('H63D', 'Var', (174, 178))	('HFE', 'Gene', (179, 182))	('carcinoma', 'Phenotype', 'HP:0030731', (31, 40))	('H63D', 'SUBSTITUTION', 'None', (12, 16))	('HFE', 'Gene', '3077', (87, 90))	('patients', 'Species', '9606', (41, 49))	('HFE', 'Gene', (17, 20))	('patients', 'Species', '9606', (96, 104))	('develop', 'PosReg', (203, 210))	('H63D', 'Var', (12, 16))	('male adenocarcinoma', 'Disease', (21, 40))	('male adenocarcinoma', 'Disease', 'MESH:D000230', (21, 40))	('metastases', 'Disease', 'MESH:D009362', (60, 70))	('HFE', 'Gene', '3077', (235, 238))
137803	31856248	In squamous cell lung cancer, neither of the HFE variants (H63D and C282Y) or sex impacted metastatic rate.	('HFE variant', 'CellLine', 'CVCL:7204', (45, 56))	('squamous cell lung cancer', 'Disease', (3, 28))	('lung cancer', 'Phenotype', 'HP:0100526', (17, 28))	('C282Y', 'Var', (68, 73))	('H63D', 'SUBSTITUTION', 'None', (59, 63))	('squamous cell lung cancer', 'Disease', 'MESH:D018307', (3, 28))	('H63D', 'Var', (59, 63))	('squamous cell lung cancer', 'Phenotype', 'HP:0030359', (3, 28))	('C282Y', 'Mutation', 'rs1800562', (68, 73))	('metastatic rate', 'CPA', (91, 106))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))
137804	31856248	There was no survival difference between WT and H63D HFE (p = 0.2866 for LUAD; p = 0.3740 for LUSC), or WT and C282Y HFE (p = 0.6568 for LUAD; p = 0.2498 for LUSC) lung cancer patients who enrolled at PSHMC (S3 Fig).	('HFE', 'Gene', '3077', (53, 56))	('LUAD', 'Phenotype', 'HP:0030078', (73, 77))	('C282Y', 'Mutation', 'rs1800562', (111, 116))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('LUSC', 'Disease', (158, 162))	('H63D', 'Var', (48, 52))	('LUAD', 'Disease', (137, 141))	('HFE', 'Gene', (117, 120))	('lung cancer', 'Disease', (164, 175))	('LUAD', 'Disease', (73, 77))	('HFE', 'Gene', (53, 56))	('LUSC', 'Disease', (94, 98))	('LUSC', 'Disease', 'MESH:D002294', (158, 162))	('LUSC', 'Phenotype', 'HP:0030359', (158, 162))	('LUAD', 'Disease', 'MESH:C538231', (137, 141))	('LUSC', 'Disease', 'MESH:D002294', (94, 98))	('LUSC', 'Phenotype', 'HP:0030359', (94, 98))	('LUAD', 'Disease', 'MESH:C538231', (73, 77))	('C282Y', 'Var', (111, 116))	('lung cancer', 'Disease', 'MESH:D008175', (164, 175))	('patients', 'Species', '9606', (176, 184))	('lung cancer', 'Phenotype', 'HP:0100526', (164, 175))	('HFE', 'Gene', '3077', (117, 120))	('LUAD', 'Phenotype', 'HP:0030078', (137, 141))	('H63D', 'SUBSTITUTION', 'None', (48, 52))
137805	31856248	In TCGA database, the Kaplan-Meier survival curve for lung adenocarcinoma patients showed a trend toward poorer survival in H63D HFE variants compared to WT HFE patients (p = 0.0763) (Fig 3A).	('H63D', 'Var', (124, 128))	('poorer', 'NegReg', (105, 111))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (54, 73))	('HFE', 'Gene', '3077', (129, 132))	('HFE', 'Gene', '3077', (157, 160))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (54, 73))	('patients', 'Species', '9606', (74, 82))	('HFE', 'Gene', (129, 132))	('patients', 'Species', '9606', (161, 169))	('lung adenocarcinoma', 'Disease', (54, 73))	('HFE', 'Gene', (157, 160))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))	('variants', 'Var', (133, 141))	('H63D', 'SUBSTITUTION', 'None', (124, 128))
137806	31856248	When the analysis focused on H63D homozygotes compared to WT HFE patients, the survival difference was marginally significant (p = 0.0539) (S4A Fig).	('H63D', 'Var', (29, 33))	('HFE', 'Gene', '3077', (61, 64))	('H63D', 'SUBSTITUTION', 'None', (29, 33))	('HFE', 'Gene', (61, 64))	('patients', 'Species', '9606', (65, 73))
137807	31856248	The survival for WT HFE patients and C282Y HFE patients was not different (Fig 3B).	('HFE', 'Gene', '3077', (20, 23))	('C282Y', 'Mutation', 'rs1800562', (37, 42))	('patients', 'Species', '9606', (47, 55))	('HFE', 'Gene', (43, 46))	('patients', 'Species', '9606', (24, 32))	('HFE', 'Gene', (20, 23))	('HFE', 'Gene', '3077', (43, 46))	('C282Y', 'Var', (37, 42))
137808	31856248	The Kaplan-Meier survival curve for LUSC patients revealed a significant survival difference between WT HFE patients and C282Y HFE patients (p = 0.0067), but not between WT HFE and H63D HFE variants (Fig 3C and 3D).	('HFE', 'Gene', (173, 176))	('patients', 'Species', '9606', (131, 139))	('HFE', 'Gene', '3077', (127, 130))	('C282Y', 'Mutation', 'rs1800562', (121, 126))	('LUSC', 'Phenotype', 'HP:0030359', (36, 40))	('HFE', 'Gene', (186, 189))	('HFE', 'Gene', '3077', (186, 189))	('LUSC', 'Disease', 'MESH:D002294', (36, 40))	('LUSC', 'Disease', (36, 40))	('patients', 'Species', '9606', (41, 49))	('HFE', 'Gene', '3077', (104, 107))	('H63D', 'SUBSTITUTION', 'None', (181, 185))	('H63D', 'Var', (181, 185))	('HFE', 'Gene', (127, 130))	('patients', 'Species', '9606', (108, 116))	('HFE', 'Gene', '3077', (173, 176))	('C282Y', 'Var', (121, 126))	('HFE', 'Gene', (104, 107))
137809	31856248	We performed multiplex Cox regression to double check the bivariate associations (Kaplan-Meier curve) between HFE gene variant and overall survival by further controlling other possible factors (tumor stage etc.)	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('tumor', 'Disease', (195, 200))	('Cox', 'Gene', (23, 26))	('variant', 'Var', (119, 126))	('HFE', 'Gene', '3077', (110, 113))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('HFE', 'Gene', (110, 113))	('Cox', 'Gene', '1351', (23, 26))
137810	31856248	The effect of C282Y HFE variant on LUSC patient survival remains significant after controlling for age, tumor stage, and smoking status in multiple Cox regression (Table 5).	('patient', 'Species', '9606', (40, 47))	('HFE variant', 'CellLine', 'CVCL:7204', (20, 31))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('LUSC', 'Disease', 'MESH:D002294', (35, 39))	('LUSC', 'Phenotype', 'HP:0030359', (35, 39))	('tumor', 'Disease', (104, 109))	('LUSC', 'Disease', (35, 39))	('C282Y', 'Var', (14, 19))	('Cox', 'Gene', '1351', (148, 151))	('Cox', 'Gene', (148, 151))	('HFE', 'Gene', (20, 23))	('C282Y', 'Mutation', 'rs1800562', (14, 19))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
137811	31856248	When we stratify the survival data by sex and HFE genotype we found that male LUAD patients with H63D HFE had no survival difference compared to WT HFE and female LUAD patients with H63D HFE had significantly poorer survival compared to WT HFE (p = 0.0455) (Fig 4A and 4B).	('H63D', 'Var', (97, 101))	('HFE', 'Gene', (46, 49))	('HFE', 'Gene', (102, 105))	('LUAD', 'Disease', (163, 167))	('H63D', 'SUBSTITUTION', 'None', (182, 186))	('survival', 'MPA', (216, 224))	('HFE', 'Gene', (187, 190))	('poorer', 'NegReg', (209, 215))	('HFE', 'Gene', (148, 151))	('HFE', 'Gene', '3077', (240, 243))	('LUAD', 'Disease', 'MESH:C538231', (163, 167))	('patients', 'Species', '9606', (83, 91))	('H63D', 'Var', (182, 186))	('LUAD', 'Phenotype', 'HP:0030078', (78, 82))	('LUAD', 'Disease', (78, 82))	('HFE', 'Gene', '3077', (46, 49))	('HFE', 'Gene', (240, 243))	('H63D', 'SUBSTITUTION', 'None', (97, 101))	('HFE', 'Gene', '3077', (102, 105))	('LUAD', 'Phenotype', 'HP:0030078', (163, 167))	('patients', 'Species', '9606', (168, 176))	('HFE', 'Gene', '3077', (148, 151))	('HFE', 'Gene', '3077', (187, 190))	('LUAD', 'Disease', 'MESH:C538231', (78, 82))
137812	31856248	The dramatic difference in survival for male LUSC patients with C282Y HFE compared to WT HFE did not reach statistical significance (p = 0.0665); however, female LUSC patients with C282Y HFE had significantly poorer survival compared to WT HFE (p = 0.0283) (Fig 4C and 4D).	('C282Y', 'Mutation', 'rs1800562', (64, 69))	('C282Y', 'Mutation', 'rs1800562', (181, 186))	('survival', 'MPA', (216, 224))	('LUSC', 'Disease', (45, 49))	('HFE', 'Gene', (70, 73))	('HFE', 'Gene', (187, 190))	('HFE', 'Gene', '3077', (89, 92))	('poorer', 'NegReg', (209, 215))	('HFE', 'Gene', '3077', (240, 243))	('LUSC', 'Disease', 'MESH:D002294', (45, 49))	('LUSC', 'Phenotype', 'HP:0030359', (45, 49))	('patients', 'Species', '9606', (50, 58))	('LUSC', 'Disease', (162, 166))	('HFE', 'Gene', (89, 92))	('HFE', 'Gene', (240, 243))	('LUSC', 'Disease', 'MESH:D002294', (162, 166))	('LUSC', 'Phenotype', 'HP:0030359', (162, 166))	('C282Y', 'Var', (181, 186))	('patients', 'Species', '9606', (167, 175))	('HFE', 'Gene', '3077', (70, 73))	('HFE', 'Gene', '3077', (187, 190))
137818	31856248	The present study determined the frequency of HFE polymorphisms in lung cancer cell lines and human lung cancer patients.	('HFE', 'Gene', (46, 49))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('lung cancer', 'Disease', 'MESH:D008175', (67, 78))	('patients', 'Species', '9606', (112, 120))	('lung cancer', 'Phenotype', 'HP:0100526', (100, 111))	('lung cancer', 'Disease', (100, 111))	('human', 'Species', '9606', (94, 99))	('lung cancer', 'Disease', 'MESH:D008175', (100, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('HFE', 'Gene', '3077', (46, 49))	('lung cancer', 'Disease', (67, 78))	('lung cancer', 'Phenotype', 'HP:0100526', (67, 78))	('polymorphisms', 'Var', (50, 63))
137819	31856248	We found 7 of 10 lung cancer cell lines had the H63D or C282Y variant of the HFE gene.	('HFE', 'Gene', '3077', (77, 80))	('C282Y', 'Mutation', 'rs1800562', (56, 61))	('lung cancer', 'Disease', (17, 28))	('lung cancer', 'Phenotype', 'HP:0100526', (17, 28))	('HFE', 'Gene', (77, 80))	('C282Y', 'Var', (56, 61))	('lung cancer', 'Disease', 'MESH:D008175', (17, 28))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('H63D', 'SUBSTITUTION', 'None', (48, 52))	('H63D', 'Var', (48, 52))
137820	31856248	This result provided motivation to interrogate lung cancer samples from our institute and existing database such as TCGA for the frequency and impact of HFE gene variants on lung cancer.	('lung cancer', 'Disease', (174, 185))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('lung cancer', 'Phenotype', 'HP:0100526', (174, 185))	('lung cancer', 'Disease', (47, 58))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('lung cancer', 'Phenotype', 'HP:0100526', (47, 58))	('HFE', 'Gene', (153, 156))	('variants', 'Var', (162, 170))	('lung cancer', 'Disease', 'MESH:D008175', (174, 185))	('lung cancer', 'Disease', 'MESH:D008175', (47, 58))	('HFE', 'Gene', '3077', (153, 156))
137822	31856248	In the TCGA lung cancer database, adenocarcinoma patients with H63D HFE trended to have poorer survival outcomes than WT HFE, but when the outcome data were stratified by sex the difference in survival outcome became statistically significant for females.	('HFE', 'Gene', (121, 124))	('HFE', 'Gene', '3077', (68, 71))	('adenocarcinoma', 'Disease', (34, 48))	('lung cancer', 'Disease', 'MESH:D008175', (12, 23))	('survival', 'MPA', (95, 103))	('HFE', 'Gene', (68, 71))	('HFE', 'Gene', '3077', (121, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (39, 48))	('adenocarcinoma', 'Disease', 'MESH:D000230', (34, 48))	('poorer', 'NegReg', (88, 94))	('lung cancer', 'Disease', (12, 23))	('patients', 'Species', '9606', (49, 57))	('H63D', 'SUBSTITUTION', 'None', (63, 67))	('H63D', 'Var', (63, 67))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))	('lung cancer', 'Phenotype', 'HP:0100526', (12, 23))
137823	31856248	The TCGA database does not include information on metastatic disease so we used our smaller internal database (PSHMC) and found a sex and genotype dependent effect for adenocarcinoma patients; males with the H63D HFE variant had less metastasis and females with the H63D HFE variant had more metastasis.	('H63D', 'SUBSTITUTION', 'None', (266, 270))	('H63D', 'SUBSTITUTION', 'None', (208, 212))	('H63D', 'Var', (266, 270))	('less', 'NegReg', (229, 233))	('H63D', 'Var', (208, 212))	('carcinoma', 'Phenotype', 'HP:0030731', (173, 182))	('HFE', 'Gene', (213, 216))	('adenocarcinoma', 'Disease', (168, 182))	('adenocarcinoma', 'Disease', 'MESH:D000230', (168, 182))	('patients', 'Species', '9606', (183, 191))	('metastasis', 'CPA', (292, 302))	('metastasis', 'CPA', (234, 244))
137824	31856248	There is no frequency increase in H63D HFE in the squamous cell cancer population or impact on the disease noted in our studies.	('HFE', 'Gene', '3077', (39, 42))	('squamous cell cancer', 'Disease', (50, 70))	('HFE', 'Gene', (39, 42))	('squamous cell cancer', 'Disease', 'MESH:D018307', (50, 70))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (50, 70))	('H63D', 'SUBSTITUTION', 'None', (34, 38))	('H63D', 'Var', (34, 38))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
137825	31856248	These interesting results suggest that H63D HFE variant protects lung cancer metastasis in males, but enables metastasis in females.	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('metastasis', 'CPA', (110, 120))	('HFE', 'Gene', (44, 47))	('lung cancer metastasis', 'Disease', (65, 87))	('lung cancer metastasis', 'Disease', 'MESH:D008175', (65, 87))	('H63D', 'SUBSTITUTION', 'None', (39, 43))	('H63D', 'Var', (39, 43))	('lung cancer', 'Phenotype', 'HP:0100526', (65, 76))	('protects', 'NegReg', (56, 64))	('variant', 'Var', (48, 55))
137826	31856248	As far as we know, this is the first report for the impact of HFE variants and sex on lung cancer patients' outcome.	('patients', 'Species', '9606', (98, 106))	('variants', 'Var', (66, 74))	('lung cancer', 'Phenotype', 'HP:0100526', (86, 97))	('lung cancer', 'Disease', (86, 97))	('HFE', 'Gene', (62, 65))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('HFE variant', 'CellLine', 'CVCL:7204', (62, 73))	('lung cancer', 'Disease', 'MESH:D008175', (86, 97))
137827	31856248	In addition to the H63D variant of the HFE gene, the C282Y HFE variant is also found in the general population although at a lower prevalence.	('HFE variant', 'CellLine', 'CVCL:7204', (59, 70))	('HFE', 'Gene', '3077', (39, 42))	('H63D', 'SUBSTITUTION', 'None', (19, 23))	('H63D', 'Var', (19, 23))	('HFE', 'Gene', (39, 42))	('HFE', 'Gene', '3077', (59, 62))	('C282Y', 'Mutation', 'rs1800562', (53, 58))	('HFE', 'Gene', (59, 62))	('C282Y', 'Var', (53, 58))
137828	31856248	This gene variant has received considerable attention in hepatic cancers because of its tendency to be associated with hemochromatosis, the iron overload disease.	('iron', 'Chemical', 'MESH:D007501', (140, 144))	('iron overload disease', 'Disease', (140, 161))	('associated', 'Reg', (103, 113))	('hepatic cancers', 'Disease', 'MESH:D009369', (57, 72))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('hemochromatosis', 'Gene', (119, 134))	('cancers', 'Phenotype', 'HP:0002664', (65, 72))	('variant', 'Var', (10, 17))	('hepatic cancers', 'Disease', (57, 72))	('hemochromatosis', 'Gene', '3077', (119, 134))
137829	31856248	In the TCGA database, individuals with squamous cell carcinoma that carry C282Y HFE have poorer survival than WT HFE.	('C282Y', 'Var', (74, 79))	('poorer', 'NegReg', (89, 95))	('HFE', 'Gene', (80, 83))	('C282Y', 'Mutation', 'rs1800562', (74, 79))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (39, 62))	('HFE', 'Gene', (113, 116))	('carcinoma', 'Phenotype', 'HP:0030731', (53, 62))	('squamous cell carcinoma', 'Disease', (39, 62))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (39, 62))	('HFE', 'Gene', '3077', (80, 83))	('HFE', 'Gene', '3077', (113, 116))
137832	31856248	There is no statistically significant effect of C282Y HFE on the adenocarcinoma population, but there is a trend toward greater frequency of metastatic disease in males compared to females although the sample size is small.	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('HFE', 'Gene', (54, 57))	('C282Y', 'Mutation', 'rs1800562', (48, 53))	('C282Y', 'Var', (48, 53))	('adenocarcinoma', 'Disease', (65, 79))	('metastatic disease', 'CPA', (141, 159))	('adenocarcinoma', 'Disease', 'MESH:D000230', (65, 79))	('HFE', 'Gene', '3077', (54, 57))
137837	31856248	For example, we observed higher frequency of C282Y HFE allele in female lung adenocarcinoma patients than male patients in TCGA; however, there was no survival difference between female C282Y HFE and male C282Y HFE lung adenocarcinoma patients.	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (215, 234))	('HFE', 'Gene', '3077', (51, 54))	('C282Y', 'Var', (45, 50))	('HFE', 'Gene', '3077', (192, 195))	('patients', 'Species', '9606', (235, 243))	('HFE', 'Gene', (211, 214))	('C282Y', 'Mutation', 'rs1800562', (205, 210))	('patients', 'Species', '9606', (92, 100))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (72, 91))	('HFE', 'Gene', (51, 54))	('lung adenocarcinoma', 'Disease', (72, 91))	('C282Y', 'Mutation', 'rs1800562', (45, 50))	('C282Y', 'Mutation', 'rs1800562', (186, 191))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (215, 234))	('lung adenocarcinoma', 'Disease', (215, 234))	('HFE', 'Gene', (192, 195))	('carcinoma', 'Phenotype', 'HP:0030731', (225, 234))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (72, 91))	('HFE', 'Gene', '3077', (211, 214))	('patients', 'Species', '9606', (111, 119))
137838	31856248	Instead, we found survival difference between female H63D HFE adenocarcinoma patients and female WT HFE adenocarcinoma patients.	('HFE', 'Gene', '3077', (58, 61))	('patients', 'Species', '9606', (119, 127))	('adenocarcinoma', 'Disease', 'MESH:D000230', (62, 76))	('adenocarcinoma', 'Disease', (62, 76))	('HFE', 'Gene', '3077', (100, 103))	('H63D', 'Var', (53, 57))	('HFE', 'Gene', (58, 61))	('H63D', 'SUBSTITUTION', 'None', (53, 57))	('patients', 'Species', '9606', (77, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('adenocarcinoma', 'Disease', (104, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('HFE', 'Gene', (100, 103))	('adenocarcinoma', 'Disease', 'MESH:D000230', (104, 118))
137839	31856248	In the present study, the level of HFE gene expression was not different between WT HFE and HFE variants of lung cancer patients (matched normal, primary tumors) in TCGA lung cancer data.	('HFE', 'Gene', '3077', (92, 95))	('lung cancer', 'Disease', 'MESH:D008175', (170, 181))	('HFE', 'Gene', '3077', (35, 38))	('lung cancer', 'Phenotype', 'HP:0100526', (170, 181))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('tumor', 'Disease', (154, 159))	('variants', 'Var', (96, 104))	('HFE', 'Gene', (92, 95))	('HFE', 'Gene', (84, 87))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('lung cancer', 'Disease', (108, 119))	('HFE variant', 'CellLine', 'CVCL:7204', (92, 103))	('HFE', 'Gene', (35, 38))	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('lung cancer', 'Disease', (170, 181))	('lung cancer', 'Disease', 'MESH:D008175', (108, 119))	('patients', 'Species', '9606', (120, 128))	('lung cancer', 'Phenotype', 'HP:0100526', (108, 119))	('HFE', 'Gene', '3077', (84, 87))
137841	31856248	These results suggest that poor survival in female lung adenocarcinoma with H63D HFE and female lung squamous cell cancer with C282Y HFE is not due to the expression level of HFE variants or frequency of HFE genotype but rather the function of HFE variant itself.	('lung squamous cell cancer', 'Disease', 'MESH:D018307', (96, 121))	('HFE', 'Gene', (133, 136))	('C282Y', 'Mutation', 'rs1800562', (127, 132))	('HFE', 'Gene', '3077', (81, 84))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (51, 70))	('HFE', 'Gene', (244, 247))	('lung adenocarcinoma', 'Disease', (51, 70))	('HFE variant', 'CellLine', 'CVCL:7204', (244, 255))	('HFE', 'Gene', (204, 207))	('lung squamous cell cancer', 'Disease', (96, 121))	('H63D', 'SUBSTITUTION', 'None', (76, 80))	('HFE', 'Gene', '3077', (175, 178))	('HFE', 'Gene', (81, 84))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (101, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (51, 70))	('HFE', 'Gene', '3077', (133, 136))	('lung squamous cell cancer', 'Phenotype', 'HP:0030359', (96, 121))	('H63D', 'Var', (76, 80))	('C282Y', 'Var', (127, 132))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('HFE', 'Gene', (175, 178))	('HFE', 'Gene', '3077', (244, 247))	('HFE variant', 'CellLine', 'CVCL:7204', (175, 186))	('HFE', 'Gene', '3077', (204, 207))
137842	31856248	There are many reports for the function of H63D or C282Y HFE in human cancer.	('human', 'Species', '9606', (64, 69))	('C282Y', 'Mutation', 'rs1800562', (51, 56))	('HFE', 'Gene', '3077', (57, 60))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('H63D', 'SUBSTITUTION', 'None', (43, 47))	('H63D', 'Var', (43, 47))	('HFE', 'Gene', (57, 60))	('C282Y', 'Var', (51, 56))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))
137843	31856248	For example, at the cellular level, the HFE H63D variant alters cholesterol metabolism, Endoplasmic Reticulum stress and alters cancer phenotype including the protein profiles of exosomes.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('cholesterol metabolism', 'MPA', (64, 86))	('protein profiles of exosomes', 'MPA', (159, 187))	('HFE', 'Gene', (40, 43))	('cholesterol', 'Chemical', 'MESH:D002784', (64, 75))	('H63D', 'SUBSTITUTION', 'None', (44, 48))	('H63D', 'Var', (44, 48))	('Endoplasmic Reticulum stress', 'MPA', (88, 116))	('alters', 'Reg', (121, 127))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('alters', 'Reg', (57, 63))	('HFE', 'Gene', '3077', (40, 43))	('cancer', 'Disease', (128, 134))
137844	31856248	Mouse H67D Hfe variant (human equivalent for H63D HFE variant) also alters macrophage function.	('human', 'Species', '9606', (24, 29))	('H67D', 'Var', (6, 10))	('H67D', 'SUBSTITUTION', 'None', (6, 10))	('macrophage function', 'CPA', (75, 94))	('alters', 'Reg', (68, 74))	('variant', 'Var', (15, 22))	('Hfe', 'Gene', '15216', (11, 14))	('Hfe', 'Gene', (11, 14))	('Mouse', 'Species', '10090', (0, 5))	('H63D', 'SUBSTITUTION', 'None', (45, 49))	('H63D', 'Var', (45, 49))
137845	31856248	The C282Y HFE variant contributes therapy resistance and increased tumor burden.	('tumor', 'Disease', (67, 72))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('therapy resistance', 'MPA', (34, 52))	('C282Y', 'Var', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('HFE', 'Gene', (10, 13))	('increased', 'PosReg', (57, 66))	('C282Y', 'Mutation', 'rs1800562', (4, 9))	('HFE variant', 'CellLine', 'CVCL:7204', (10, 21))
137846	31856248	Therefore, we will pursue the impact of sex and HFE variants in LUAD and LUSC in animal models as a future direction.	('LUSC', 'Disease', 'MESH:D002294', (73, 77))	('LUSC', 'Disease', (73, 77))	('HFE variant', 'CellLine', 'CVCL:7204', (48, 59))	('variants', 'Var', (52, 60))	('LUAD', 'Disease', (64, 68))	('LUAD', 'Disease', 'MESH:C538231', (64, 68))	('LUAD', 'Phenotype', 'HP:0030078', (64, 68))	('LUSC', 'Phenotype', 'HP:0030359', (73, 77))
137850	31856248	In summary, the H63D HFE gene variant is associated with poor survival and increased metastasis in female, but not male, LUAD patients.	('LUAD', 'Phenotype', 'HP:0030078', (121, 125))	('poor', 'NegReg', (57, 61))	('LUAD', 'Disease', (121, 125))	('H63D', 'SUBSTITUTION', 'None', (16, 20))	('H63D', 'Var', (16, 20))	('LUAD', 'Disease', 'MESH:C538231', (121, 125))	('HFE', 'Gene', '3077', (21, 24))	('patients', 'Species', '9606', (126, 134))	('metastasis', 'CPA', (85, 95))	('HFE', 'Gene', (21, 24))	('increased', 'PosReg', (75, 84))
137851	31856248	Although the frequency of C282Y HFE gene variant is higher in female LUAD patients than males, there was no gene effect on survival in these patients.	('LUAD', 'Phenotype', 'HP:0030078', (69, 73))	('C282Y', 'Var', (26, 31))	('LUAD', 'Disease', (69, 73))	('HFE', 'Gene', (32, 35))	('LUAD', 'Disease', 'MESH:C538231', (69, 73))	('patients', 'Species', '9606', (74, 82))	('C282Y', 'Mutation', 'rs1800562', (26, 31))	('HFE', 'Gene', '3077', (32, 35))	('patients', 'Species', '9606', (141, 149))
137852	31856248	However, the C282Y HFE gene variant is associated with poor survival in LUSC patients, especially females.	('HFE', 'Gene', '3077', (19, 22))	('LUSC', 'Disease', 'MESH:D002294', (72, 76))	('LUSC', 'Disease', (72, 76))	('HFE', 'Gene', (19, 22))	('LUSC', 'Phenotype', 'HP:0030359', (72, 76))	('C282Y', 'Var', (13, 18))	('patients', 'Species', '9606', (77, 85))	('poor', 'NegReg', (55, 59))	('C282Y', 'Mutation', 'rs1800562', (13, 18))
137853	31856248	The present findings indicate that there is a distinct impact of H63D and C282Y HFE variants in two different subtype of human lung cancers and impact of the genotype is influenced by sex.	('lung cancers', 'Disease', (127, 139))	('C282Y', 'Var', (74, 79))	('cancers', 'Phenotype', 'HP:0002664', (132, 139))	('HFE', 'Gene', (80, 83))	('HFE variant', 'CellLine', 'CVCL:7204', (80, 91))	('lung cancer', 'Phenotype', 'HP:0100526', (127, 138))	('lung cancers', 'Disease', 'MESH:D008175', (127, 139))	('C282Y', 'Mutation', 'rs1800562', (74, 79))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('human', 'Species', '9606', (121, 126))	('lung cancers', 'Phenotype', 'HP:0100526', (127, 139))	('impact', 'Reg', (55, 61))	('H63D', 'Var', (65, 69))	('H63D', 'SUBSTITUTION', 'None', (65, 69))
137854	31856248	ALK Anaplastic lymphoma kinase ATCC American Type Culture Collection EGFR Epidermal growth factor receptor FGFR1 Fibroblast growth factor receptor 1 GBM glioblastoma KRAS K-ras MHC major histocompatibility complex LUAD lung adenocarcinoma LUSC lung squamous cell carcinoma NB blood derived normal NSCLC non-small cell lung cancer PSHMC Penn State Hershey Medical Center PTEN Phosphatase and tensin homolog RPMI Roswell Park Memorial Institute SCLC small cell lung cancer SLC11A1 Natural resistance-associated macrophage protein 1gene SNP Single Nucleotide Polymorphism SNVs Single Nucleotide Variants TCGA The Cancer Genome Atlas TF transferrin TFRC transferrin receptor TP primary solid tumor WT wild type	('SCLC', 'Phenotype', 'HP:0030357', (443, 447))	('tumor', 'Disease', 'MESH:D009369', (688, 693))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (448, 470))	('SCLC', 'Gene', (443, 447))	('NSCLC', 'Disease', 'MESH:D002289', (297, 302))	('PTEN', 'Gene', '5728', (370, 374))	('glioblastoma', 'Disease', 'MESH:D005909', (153, 165))	('Single Nucleotide Variants', 'Var', (574, 600))	('small cell lung cancer', 'Disease', 'MESH:D055752', (307, 329))	('transferrin', 'Gene', '7018', (633, 644))	('KRAS', 'Gene', '3845', (166, 170))	('FGFR1', 'Gene', (107, 112))	('Natural resistance-associated macrophage protein 1', 'Gene', '6556', (479, 529))	('Anaplastic lymphoma', 'Phenotype', 'HP:0012193', (4, 23))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (249, 272))	('lung squamous cell carcinoma', 'Disease', (244, 272))	('ALK', 'Gene', (0, 3))	('LUAD', 'Disease', 'MESH:C538231', (214, 218))	('LUSC', 'Disease', (239, 243))	('lung adenocarcinoma', 'Disease', (219, 238))	('lymphoma', 'Disease', 'MESH:D008223', (15, 23))	('cancer', 'Phenotype', 'HP:0002664', (464, 470))	('Fibroblast growth factor receptor 1', 'Gene', '2260', (113, 148))	('transferrin receptor', 'Gene', (650, 670))	('LUSC', 'Disease', 'MESH:D002294', (239, 243))	('PTEN', 'Gene', (370, 374))	('Fibroblast growth factor receptor 1', 'Gene', (113, 148))	('SCLC', 'Gene', '7864', (443, 447))	('transferrin', 'Gene', (633, 644))	('TCGA', 'Gene', (601, 605))	('SCLC', 'Gene', (298, 302))	('LUAD', 'Phenotype', 'HP:0030078', (214, 218))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (244, 272))	('NSCLC', 'Disease', (297, 302))	('Natural resistance-associated macrophage protein 1', 'Gene', (479, 529))	('K-ras', 'Gene', '3845', (171, 176))	('glioblastoma', 'Disease', (153, 165))	('NSCLC', 'Phenotype', 'HP:0030358', (297, 302))	('GBM', 'Phenotype', 'HP:0012174', (149, 152))	('lymphoma', 'Disease', (15, 23))	('carcinoma', 'Phenotype', 'HP:0030731', (263, 272))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (307, 329))	('FGFR1', 'Gene', '2260', (107, 112))	('TFRC', 'Gene', '7037', (645, 649))	('SCLC', 'Phenotype', 'HP:0030357', (298, 302))	('EGFR', 'Gene', '1956', (69, 73))	('tumor', 'Phenotype', 'HP:0002664', (688, 693))	('non-small cell lung cancer', 'Disease', (303, 329))	('GBM', 'Disease', (149, 152))	('small cell lung cancer', 'Disease', 'MESH:D055752', (448, 470))	('GBM', 'Disease', 'MESH:D005909', (149, 152))	('transferrin', 'Gene', '7018', (650, 661))	('LUAD', 'Disease', (214, 218))	('tensin', 'Chemical', 'MESH:C406010', (391, 397))	('glioblastoma', 'Phenotype', 'HP:0012174', (153, 165))	('EGFR', 'Gene', (69, 73))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (219, 238))	('cancer', 'Phenotype', 'HP:0002664', (323, 329))	('LUSC', 'Phenotype', 'HP:0030359', (239, 243))	('K-ras', 'Gene', (171, 176))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (303, 329))	('TFRC', 'Gene', (645, 649))	('carcinoma', 'Phenotype', 'HP:0030731', (229, 238))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (219, 238))	('transferrin', 'Gene', (650, 661))	('SCLC', 'Gene', '7864', (298, 302))	('lymphoma', 'Phenotype', 'HP:0002665', (15, 23))	('lung cancer', 'Phenotype', 'HP:0100526', (318, 329))	('TF', 'Gene', '7018', (630, 632))	('Cancer', 'Phenotype', 'HP:0002664', (610, 616))	('small cell lung cancer', 'Disease', (448, 470))	('transferrin receptor', 'Gene', '7037', (650, 670))	('ALK', 'Gene', '238', (0, 3))	('TF', 'Gene', '7018', (645, 647))	('lung cancer', 'Phenotype', 'HP:0100526', (459, 470))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (244, 272))	('KRAS', 'Gene', (166, 170))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (303, 329))	('tumor', 'Disease', (688, 693))
137864	33277602	For SCC, UV radiation has further been postulated to induce DNA damage and mutations in the tumor suppressor gene p53 and reactivate latent HPV and HIV infections, thus increasing the risk for conjunctival SCC.	('SCC', 'Phenotype', 'HP:0002860', (206, 209))	('p53', 'Gene', (114, 117))	('p53', 'Gene', '7157', (114, 117))	('SCC', 'Phenotype', 'HP:0002860', (4, 7))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('DNA damage', 'MPA', (60, 70))	('reactivate', 'PosReg', (122, 132))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('HIV infections', 'Disease', (148, 162))	('latent HPV', 'MPA', (133, 143))	('mutations', 'Var', (75, 84))	('conjunctival SCC', 'Disease', (193, 209))	('tumor', 'Disease', (92, 97))	('HIV infections', 'Disease', 'MESH:D015658', (148, 162))	('increasing', 'PosReg', (169, 179))	('HPV', 'Species', '10566', (140, 143))
137901	33277602	Furthermore, keratins function in immune recognition, tenacity to cellular stresses, posttranslational modifications that modulate intermediate filament assembly and cellular motility and thereby are highly relevant in cancer progression and tumor cell dissemination.	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('intermediate filament assembly', 'MPA', (131, 161))	('relevant', 'Reg', (207, 215))	('modifications', 'Var', (103, 116))	('stresses', 'Disease', 'MESH:D000079225', (75, 83))	('keratins', 'Protein', (13, 21))	('tumor', 'Disease', 'MESH:D009369', (242, 247))	('tumor', 'Phenotype', 'HP:0002664', (242, 247))	('cancer', 'Disease', 'MESH:D009369', (219, 225))	('modulate', 'Reg', (122, 130))	('stresses', 'Disease', (75, 83))	('function', 'Reg', (22, 30))	('cancer', 'Disease', (219, 225))	('tumor', 'Disease', (242, 247))	('cellular motility', 'CPA', (166, 183))
137907	33277602	Altered S100A7 expression has been linked to poor clinical outcomes in several solid cancer types by promoting invasiveness of cancer cells via upregulation of MMPs.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('S100A7', 'Gene', '6278', (8, 14))	('S100A7', 'Gene', (8, 14))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('Altered', 'Var', (0, 7))	('promoting', 'PosReg', (101, 110))	('cancer', 'Disease', (85, 91))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('cancer', 'Disease', (127, 133))	('MMPs', 'Protein', (160, 164))	('upregulation', 'PosReg', (144, 156))
137939	31244293	Patients with high-risk features, including high histological grade or poor differentiation, advanced stage, perineural invasion, extracapsular lymph node extension and positive surgical margin (Pires et al., 2004; McHugh et al., 2012) may proceed to post-operative RT or CCRT with the aim of achieving maximum disease control and increasing the chance of cure based on potential radiation sensitizer effect of chemotherapy.	('high histological', 'Var', (44, 61))	('Patients', 'Species', '9606', (0, 8))	('poor', 'Var', (71, 75))	('CCRT', 'Disease', (272, 276))
137971	31244293	According to multivariable analysis, CCRT was significantly associated with a 71% lower risk of disease progression or death than RT alone (HR 0.29; 95% CI 0.10 to 0.86; p = 0.02).	('disease progression', 'CPA', (96, 115))	('CCRT', 'Var', (37, 41))	('death', 'Disease', 'MESH:D003643', (119, 124))	('death', 'Disease', (119, 124))	('lower', 'NegReg', (82, 87))
137977	31244293	After adjusting for multiple prognostic factors, we found that CCRT was significantly associated with a 92% lower risk of death than RT (HR 0.08; 95% CI 0.01 to 0.43; p = 0.003).	('lower', 'NegReg', (108, 113))	('death', 'Disease', 'MESH:D003643', (122, 127))	('CCRT', 'Var', (63, 67))	('death', 'Disease', (122, 127))
137988	31244293	A significantly higher proportion of patients who received CCRT than of those who received RT alone had high-risk prognostic factors, including large tumor, high stage, poor differentiation, extranodular extension, and lymphovascular and perineural invasion.	('poor differentiation', 'CPA', (169, 189))	('patients', 'Species', '9606', (37, 45))	('extranodular extension', 'CPA', (191, 213))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('CCRT', 'Var', (59, 63))	('high stage', 'CPA', (157, 167))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('tumor', 'Disease', (150, 155))	('large', 'Disease', (144, 149))
138017	31081062	Moreover, the analysis of The Cancer Genome Atlas (TCGA) data revealed a decreased INKA2 expression in tumour samples carrying p53 mutations compared with p53 wild-type samples.	('mutations', 'Var', (131, 140))	('expression', 'MPA', (89, 99))	('Cancer Genome Atlas', 'Disease', (30, 49))	('decreased', 'NegReg', (73, 82))	('Cancer', 'Phenotype', 'HP:0002664', (30, 36))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (30, 49))	('tumour', 'Phenotype', 'HP:0002664', (103, 109))	('tumour', 'Disease', 'MESH:D009369', (103, 109))	('INKA2', 'Gene', (83, 88))	('INKA2', 'Gene', '109050', (83, 88))	('tumour', 'Disease', (103, 109))	('p53', 'Gene', (127, 130))
138022	31081062	The cyclin-dependent kinase inhibitor 1 (also known as CDKN1A) represents one of the major targets of p53.	('cyclin-dependent kinase inhibitor 1', 'Gene', '1026', (4, 39))	('p53', 'Var', (102, 105))	('cyclin-dependent kinase inhibitor 1', 'Gene', (4, 39))
138027	31081062	From the same data, our previous study revealed 3,551 upregulated genes and 2,576 downregulated genes induced by p53 in all mouse tissues.	('p53', 'Var', (113, 116))	('upregulated', 'PosReg', (54, 65))	('mouse', 'Species', '10090', (124, 129))
138038	31081062	is GSE98727 for the MCF10A cells and GSE125787 for the HCT116 cells.	('GSE125787', 'Var', (37, 46))	('HCT116', 'CellLine', 'CVCL:0291', (55, 61))	('MCF10A', 'CellLine', 'CVCL:0598', (20, 26))	('GSE98727', 'Var', (3, 11))
138039	31081062	In the mouse transcriptome data, genes with a low expression were defined as those with a maximum expression in all groups (W, p53+/+; WX, irradiated p53+/+; K, p53-/-; KX, irradiated p53-/-) among all 24 tissues inferior to 1 fragment per kilobase million (FPKM), and were excluded from the screening.	('mouse', 'Species', '10090', (7, 12))	('WX', 'Chemical', '-', (135, 137))	('irradiated p53+/+; K', 'Var', (139, 159))	('KX', 'Chemical', '-', (169, 171))	('expression', 'MPA', (98, 108))
138047	31081062	The HCT116 p53+/+ and HCT116 p53-/- cells were gifts from Dr B. Vogelstein (Johns Hopkins University, Baltimore, MD, USA).	('HCT116 p53-/-', 'Var', (22, 35))	('HCT116 p53+/+', 'Var', (4, 17))	('HCT116', 'CellLine', 'CVCL:0291', (22, 28))	('HCT116', 'CellLine', 'CVCL:0291', (4, 10))
138077	31081062	The H1299 cells were co-transfected with the pGL4.24 control vector or pGL4.24 containing the target p53 binding site, accompanied by the empty vector pcDNA3.1, wild-type p53, or mutant p53 (p53R175H for human p53 and p53R172H for mouse p53) expression vector.	('p53R172H', 'Var', (218, 226))	('pGL4', 'Gene', (45, 49))	('p53R175H', 'Var', (191, 199))	('pGL4', 'Gene', '6390', (71, 75))	('pGL4', 'Gene', '6390', (45, 49))	('mouse', 'Species', '10090', (231, 236))	('p53', 'Gene', (186, 189))	('H1299', 'CellLine', 'CVCL:0060', (4, 9))	('human', 'Species', '9606', (204, 209))	('pGL4', 'Gene', (71, 75))
138105	31081062	In total, 22 genes fulfilled our criteria, including 13 genes that were previously reported as p53 downstream targets: Mgmt, LIF, interleukin 6 family cytokine (Lif), sestrin 2 (Sesn2), D630023F18Rik, BCL2 binding component 3 (Bbc3), cyclin G1 (Ccng1), zinc finger protein 365 (Zfp365), 1700007K13Rik, pleckstrin homology like domain family A member 3 (Phlda3), proline and serine rich coiled-coil 1 (Psrc1), cyclin dependent kinase inhibitor 1A (Cdkn1a), growth differentiation factor 15 (Gdf15) and ectodysplasin A2 receptor (Eda2r).	('1700007K13Rik', 'Var', (287, 300))	('zinc finger protein 365', 'Gene', (253, 276))	('Lif', 'Gene', (161, 164))	('cyclin dependent kinase inhibitor 1A', 'Gene', (409, 445))	('cyclin G1', 'Gene', '900', (234, 243))	('ectodysplasin A2 receptor', 'Gene', '60401', (501, 526))	('Mgmt', 'Gene', '4255', (119, 123))	('LIF', 'Gene', (125, 128))	('Bbc3', 'Gene', (227, 231))	('Psrc1', 'Gene', '84722', (401, 406))	('Ccng1', 'Gene', (245, 250))	('Cdkn1a', 'Gene', (447, 453))	('Zfp365', 'Gene', '22891', (278, 284))	('Cdkn1a', 'Gene', '1026', (447, 453))	('BCL2 binding component 3', 'Gene', (201, 225))	('sestrin 2', 'Gene', '83667', (167, 176))	('D630023F18Rik', 'Var', (186, 199))	('ectodysplasin A2 receptor', 'Gene', (501, 526))	('BCL2 binding component 3', 'Gene', '27113', (201, 225))	('sestrin 2', 'Gene', (167, 176))	('Phlda3', 'Gene', '23612', (353, 359))	('pleckstrin homology like domain family A member 3', 'Gene', '23612', (302, 351))	('Mgmt', 'Gene', (119, 123))	('Gdf15', 'Gene', '9518', (490, 495))	('Sesn2', 'Gene', '83667', (178, 183))	('Eda2r', 'Gene', (528, 533))	('Psrc1', 'Gene', (401, 406))	('Bbc3', 'Gene', '27113', (227, 231))	('Phlda3', 'Gene', (353, 359))	('Zfp365', 'Gene', (278, 284))	('pleckstrin homology like domain family A member 3', 'Gene', (302, 351))	('Eda2r', 'Gene', '60401', (528, 533))	('cyclin G1', 'Gene', (234, 243))	('Sesn2', 'Gene', (178, 183))	('growth differentiation factor 15', 'Gene', '9518', (456, 488))	('growth differentiation factor 15', 'Gene', (456, 488))	('Lif', 'Gene', '3976', (161, 164))	('LIF', 'Gene', '3976', (125, 128))	('cyclin dependent kinase inhibitor 1A', 'Gene', '1026', (409, 445))	('Gdf15', 'Gene', (490, 495))	('zinc finger protein 365', 'Gene', '22891', (253, 276))	('Ccng1', 'Gene', '900', (245, 250))
138107	31081062	The rest of the resulting genes consisted of 2 non-coding RNAs, one gene without any corresponding human homolog, and 6 genes remaining as candidates: Fam212b (Inka2), 4632434I11Rik (Ddias), Celf5, 9030617O03Rik, Cd80 and Plcd4 (Table I).	('Inka2', 'Gene', (160, 165))	('Cd80', 'Gene', (213, 217))	('Celf5', 'Gene', (191, 196))	('Inka2', 'Gene', '109050', (160, 165))	('Plcd4', 'Gene', (222, 227))	('9030617O03Rik', 'Var', (198, 211))	('4632434I11Rik', 'Var', (168, 181))	('Plcd4', 'Gene', '84812', (222, 227))	('Cd80', 'Gene', '941', (213, 217))	('Fam212b', 'Gene', (151, 158))	('Fam212b', 'Gene', '55924', (151, 158))	('Celf5', 'Gene', '60680', (191, 196))	('human', 'Species', '9606', (99, 104))
138121	31081062	A significant increase in the mRNA levels of the INKA2 was observed in the cells treated with ADR.	('INKA2', 'Gene', (49, 54))	('mRNA levels', 'MPA', (30, 41))	('INKA2', 'Gene', '109050', (49, 54))	('ADR', 'Var', (94, 97))	('increase', 'PosReg', (14, 22))
138129	31081062	We observed significantly a higher INKA2 expression in p53 wild-type samples compared with p53 mutant samples in 4 cohorts: BLCA, COAD/READ, KIPAN and PRAD (Fig.	('COAD', 'Disease', (130, 134))	('expression', 'MPA', (41, 51))	('INKA2', 'Gene', '109050', (35, 40))	('p53', 'Gene', (91, 94))	('higher', 'PosReg', (28, 34))	('COAD', 'Disease', 'MESH:D029424', (130, 134))	('mutant', 'Var', (95, 101))	('INKA2', 'Gene', (35, 40))
138139	31081062	We then performed luciferase reporter assays in the H1299 cells expressing wild-type human p53 or the p53R175H mutant, or wild-type mouse p53 or the p53R172H mutant (Fig.	('p53R175H', 'Var', (102, 110))	('mouse', 'Species', '10090', (132, 137))	('human', 'Species', '9606', (85, 90))	('p53R172H', 'Var', (149, 157))	('H1299', 'CellLine', 'CVCL:0060', (52, 57))
138149	31081062	These results indicate that DNA methylation and p53 mutations synergistically suppresses INKA2 expression in cancer tissues.	('mutations', 'Var', (52, 61))	('p53', 'Gene', (48, 51))	('INKA2', 'Gene', '109050', (89, 94))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('cancer', 'Disease', (109, 115))	('INKA2', 'Gene', (89, 94))	('suppresses', 'NegReg', (78, 88))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('expression', 'MPA', (95, 105))
138150	31081062	Furthermore, the p53 mutation status is associated with INKA2 expression, but not with DNA methylation.	('p53', 'Gene', (17, 20))	('expression', 'MPA', (62, 72))	('INKA2', 'Gene', (56, 61))	('INKA2', 'Gene', '109050', (56, 61))	('mutation status', 'Var', (21, 36))	('associated', 'Reg', (40, 50))
138152	31081062	Using an antibody against HA-tag, we performed immunoprecipitation using whole-cell lysates obtained from 293T cells overexpressing HA-tagged INKA2 to determine its function in human cells.	('INKA2', 'Gene', (142, 147))	('INKA2', 'Gene', '109050', (142, 147))	('human', 'Species', '9606', (177, 182))	('HA-tagged', 'Var', (132, 141))	('293T', 'CellLine', 'CVCL:0063', (106, 110))
138156	31081062	On the other hand, PAK4 contains an auto-inhibitory domain (AID) that interacts with the substrate-docking site situated in the catalytic domain via the RPK peptide: R49PKPLVDP (Fig.	('PAK4', 'Gene', (19, 23))	('PAK4', 'Gene', '10298', (19, 23))	('R49PKPLVDP', 'Var', (166, 176))
138159	31081062	Compared with INKA1, INKA2 maintains the iBox domain (137-174) with a high degree of sequence identity, where the essential PAK4-inhibitory motif is NRQPLVLG instead of SRQPLVLG (Fig.	('INKA1', 'Gene', (14, 19))	('iBox domain', 'MPA', (41, 52))	('INKA2', 'Gene', (21, 26))	('INKA2', 'Gene', '109050', (21, 26))	('NRQPLVLG', 'Var', (149, 157))	('PAK4', 'Gene', (124, 128))	('INKA1', 'Gene', '389119', (14, 19))	('PAK4', 'Gene', '10298', (124, 128))
138164	31081062	The PAK4-inhibitory motif was deleted in INKA2 Delta150-160, and part of the C-terminal catalytic domain (326-591) was deleted in PAK4 1-325 (Fig.	('Delta150', 'Mutation', 'c.del150', (47, 55))	('PAK4', 'Gene', '10298', (130, 134))	('Delta150-160', 'Var', (47, 59))	('PAK4', 'Gene', (130, 134))	('INKA2', 'Gene', '109050', (41, 46))	('PAK4', 'Gene', (4, 8))	('PAK4', 'Gene', '10298', (4, 8))	('INKA2', 'Gene', (41, 46))
138165	31081062	Following immunoprecipitation, both deletions disrupted the interaction between INKA2 and PAK4, suggesting that the targeted binding motif of iBox was located in the kinase domain of PAK4 (Fig.	('disrupted', 'NegReg', (46, 55))	('INKA2', 'Gene', '109050', (80, 85))	('PAK4', 'Gene', '10298', (90, 94))	('deletions', 'Var', (36, 45))	('PAK4', 'Gene', '10298', (183, 187))	('interaction', 'Interaction', (60, 71))	('PAK4', 'Gene', (183, 187))	('INKA2', 'Gene', (80, 85))	('PAK4', 'Gene', (90, 94))
138168	31081062	Ser675 phosphorylation protects beta-catenin from the destruction complex and thus stabilises the protein in the cytoplasm.	('Ser675', 'Chemical', '-', (0, 6))	('beta-catenin', 'Gene', (32, 44))	('beta-catenin', 'Gene', '1499', (32, 44))	('phosphorylation', 'Var', (7, 22))	('Ser675 phosphorylation', 'Var', (0, 22))
138180	31081062	The knockdown of inka1 causes severe defects in both Xenopus and zebrafish embryos, suggesting its essential role in development.	('defects', 'MPA', (37, 44))	('zebrafish', 'Species', '7955', (65, 74))	('Xenopus', 'Species', '8355', (53, 60))	('inka1', 'Gene', '389119', (17, 22))	('inka1', 'Gene', (17, 22))	('knockdown', 'Var', (4, 13))
138181	31081062	In a mouse model, the Inka1 gene affects neural tube closure, and a deficiency in the protein causes exencephaly.	('exencephaly', 'Disease', 'MESH:D009436', (101, 112))	('neural tube closure', 'CPA', (41, 60))	('deficiency', 'Var', (68, 78))	('affects', 'Reg', (33, 40))	('Inka1', 'Gene', '68176', (22, 27))	('exencephaly', 'Disease', (101, 112))	('mouse', 'Species', '10090', (5, 10))	('causes', 'Reg', (94, 100))	('exencephaly', 'Phenotype', 'HP:0030769', (101, 112))	('Inka1', 'Gene', (22, 27))
138198	31081062	Specific PAK4 inhibitors, such as PF-3758309, have been developed as anti-tumour agents.	('PAK4', 'Gene', '10298', (9, 13))	('PAK4', 'Gene', (9, 13))	('tumour', 'Disease', 'MESH:D009369', (74, 80))	('tumour', 'Disease', (74, 80))	('PF-3758309', 'Var', (34, 44))	('PF-3758309', 'Chemical', 'MESH:C550923', (34, 44))	('tumour', 'Phenotype', 'HP:0002664', (74, 80))
138232	28548087	In addition, the selective acquisition of KRAS or BRAF mutations in response to glucose deprivation has been shown to upregulate GLUT1 expression.	('glucose deprivation', 'Disease', (80, 99))	('KRAS', 'Gene', (42, 46))	('BRAF', 'Gene', (50, 54))	('upregulate', 'PosReg', (118, 128))	('mutations', 'Var', (55, 64))	('GLUT1', 'Protein', (129, 134))	('glucose deprivation', 'Disease', 'MESH:D012892', (80, 99))	('BRAF', 'Gene', '673', (50, 54))
138261	28548087	The KL mice, in which oncogenic mutant Kras, KrasG12D, is expressed and tumour suppressor Lkb1 is deleted upon intratracheal inhalation of adenovirus-Cre, exhibit a full spectrum of NSCLC subtypes, allowing the characterization of different tumour types within the same mouse (Supplementary Fig.	('NSCLC', 'Phenotype', 'HP:0030358', (182, 187))	('NSCLC', 'Disease', (182, 187))	('tumour', 'Phenotype', 'HP:0002664', (241, 247))	('tumour', 'Phenotype', 'HP:0002664', (72, 78))	('NSCLC', 'Disease', 'MESH:D002289', (182, 187))	('mice', 'Species', '10090', (7, 11))	('Lkb1', 'Gene', '20869', (90, 94))	('tumour', 'Disease', 'MESH:D009369', (241, 247))	('tumour', 'Disease', 'MESH:D009369', (72, 78))	('tumour', 'Disease', (241, 247))	('tumour', 'Disease', (72, 78))	('Lkb1', 'Gene', (90, 94))	('mouse', 'Species', '10090', (270, 275))	('deleted', 'Var', (98, 105))
138267	28548087	In all KL tumours we examined, p63 and CK5 were co-localized in SqCC tumours, whereas TTF-1-expressing tumours (ADC) were negative for SqCC marker CK5 expression and vice versa (Supplementary Fig.	('CK5', 'Gene', (147, 150))	('tumour', 'Phenotype', 'HP:0002664', (69, 75))	('CK5', 'Gene', '3852', (39, 42))	('tumours', 'Disease', (10, 17))	('SqCC', 'Phenotype', 'HP:0002860', (64, 68))	('TTF-1', 'Gene', (86, 91))	('ADC', 'Gene', '242669', (112, 115))	('tumours', 'Phenotype', 'HP:0002664', (10, 17))	('tumours', 'Disease', 'MESH:D009369', (10, 17))	('ADC', 'Gene', (112, 115))	('SqCC', 'Phenotype', 'HP:0002860', (135, 139))	('CK5', 'Gene', '3852', (147, 150))	('p63', 'Var', (31, 34))	('tumours', 'Disease', (103, 110))	('SqCC tumours', 'Disease', 'MESH:D009369', (64, 76))	('tumour', 'Phenotype', 'HP:0002664', (10, 16))	('tumour', 'Phenotype', 'HP:0002664', (103, 109))	('tumours', 'Phenotype', 'HP:0002664', (103, 110))	('tumours', 'Disease', 'MESH:D009369', (103, 110))	('tumours', 'Disease', (69, 76))	('CK5', 'Gene', (39, 42))	('SqCC tumours', 'Disease', (64, 76))	('KL tumours', 'Disease', 'MESH:D009369', (7, 17))	('KL tumours', 'Disease', (7, 17))	('TTF-1', 'Gene', '7270', (86, 91))	('tumours', 'Phenotype', 'HP:0002664', (69, 76))	('tumours', 'Disease', 'MESH:D009369', (69, 76))
138278	28548087	We performed short-hairpin RNA (shRNA)-mediated knockdown of GLUT1 in SqCC HCC95 and HCC1588 cells using two different GLUT1-targeting sequences (Fig.	('HCC1588', 'CellLine', 'CVCL:A351', (85, 92))	('GLUT1', 'Gene', (61, 66))	('SqCC', 'Phenotype', 'HP:0002860', (70, 74))	('knockdown', 'Var', (48, 57))
138279	28548087	GLUT1 knockdown markedly suppressed the proliferative capacity of SqCC cells compared to shGFP control cells even in high-glucose (25 mM) conditions (Fig.	('proliferative capacity', 'CPA', (40, 62))	('high-glucose', 'Phenotype', 'HP:0003074', (117, 129))	('GLUT1', 'Gene', (0, 5))	('suppressed', 'NegReg', (25, 35))	('SqCC', 'Phenotype', 'HP:0002860', (66, 70))	('knockdown', 'Var', (6, 15))	('glucose', 'Chemical', 'MESH:D005947', (122, 129))
138281	28548087	In contrast, GLUT1 knockdown in ADC cell lines A549 and H522 only moderately suppressed proliferation with no induction of apoptosis or cell death (Supplementary Fig.	('suppressed', 'NegReg', (77, 87))	('ADC', 'Gene', '242669', (32, 35))	('GLUT1', 'Gene', (13, 18))	('knockdown', 'Var', (19, 28))	('ADC', 'Gene', (32, 35))	('proliferation', 'CPA', (88, 101))	('A549', 'CellLine', 'CVCL:0023', (47, 51))
138284	28548087	Consistently, transient GLUT1 knockdown using short interfering RNA (siRNA) was more pronounced in SqCC cell lines, with a complete suppression of proliferation in SqCC but not ADC cells despite reduced glucose uptake in both SqCC and ADC cell lines (Supplementary Fig.	('SqCC', 'Phenotype', 'HP:0002860', (226, 230))	('reduced', 'NegReg', (195, 202))	('glucose', 'Chemical', 'MESH:D005947', (203, 210))	('SqCC', 'Phenotype', 'HP:0002860', (99, 103))	('ADC', 'Gene', (177, 180))	('SqCC', 'Phenotype', 'HP:0002860', (164, 168))	('ADC', 'Gene', '242669', (235, 238))	('suppression', 'NegReg', (132, 143))	('GLUT1', 'Gene', (24, 29))	('short interfering RNA', 'Var', (46, 67))	('ADC', 'Gene', (235, 238))	('glucose', 'MPA', (203, 210))	('knockdown', 'Var', (30, 39))	('ADC', 'Gene', '242669', (177, 180))	('proliferation', 'CPA', (147, 160))
138285	28548087	Intriguingly, A549 was more sensitive to transient GLUT1 knockdown than H522, in accordance with previous reports that loss of LKB1 sensitizes cells to metabolic disruption; however, both ADC cell lines continued to proliferate even after depletion of GLUT1 (Supplementary Fig.	('LKB1', 'Gene', (127, 131))	('A549', 'CellLine', 'CVCL:0023', (14, 18))	('ADC', 'Gene', '242669', (188, 191))	('sensitizes', 'Reg', (132, 142))	('metabolic disruption', 'MPA', (152, 172))	('ADC', 'Gene', (188, 191))	('loss', 'Var', (119, 123))	('proliferate', 'PosReg', (216, 227))
138287	28548087	Consistently, GLUT1 knockdown in HCC2814 markedly suppressed in vitro proliferation, which is associated with increased apoptosis and decreased intracellular ATP levels (Supplementary Fig.	('decreased', 'NegReg', (134, 143))	('suppressed', 'NegReg', (50, 60))	('ATP', 'Chemical', 'MESH:D000255', (158, 161))	('HCC2814', 'Gene', (33, 40))	('intracellular ATP levels', 'MPA', (144, 168))	('knockdown', 'Var', (20, 29))	('in vitro proliferation', 'CPA', (61, 83))
138288	28548087	To determine whether GLUT1 knockdown inhibits tumour growth in vivo in SqCC, we implanted HCC95-expressing stable shGLUT1 or shGFP into nude mice.	('knockdown', 'Var', (27, 36))	('tumour', 'Phenotype', 'HP:0002664', (46, 52))	('nude mice', 'Species', '10090', (136, 145))	('tumour growth', 'Disease', (46, 59))	('SqCC', 'Phenotype', 'HP:0002860', (71, 75))	('inhibits', 'NegReg', (37, 45))	('tumour growth', 'Disease', 'MESH:D006130', (46, 59))	('shGLUT1', 'Gene', (114, 121))
138289	28548087	In accordance with in vitro proliferation, GLUT1 knockdown significantly inhibited the growth of HCC95 tumours (Fig.	('GLUT1', 'Gene', (43, 48))	('knockdown', 'Var', (49, 58))	('HCC95 tumours', 'Disease', 'MESH:D009369', (97, 110))	('tumour', 'Phenotype', 'HP:0002664', (103, 109))	('inhibited', 'NegReg', (73, 82))	('tumours', 'Phenotype', 'HP:0002664', (103, 110))	('HCC95 tumours', 'Disease', (97, 110))
138291	28548087	The selective cytotoxicity of GLUT1 knockdown in SqCC strongly suggests glycolytic addiction and a specific reliance on glucose metabolism.	('cytotoxicity', 'Disease', 'MESH:D064420', (14, 26))	('GLUT1', 'Gene', (30, 35))	('glycolytic addiction', 'Disease', (72, 92))	('SqCC', 'Phenotype', 'HP:0002860', (49, 53))	('knockdown', 'Var', (36, 45))	('cytotoxicity', 'Disease', (14, 26))	('glucose', 'Chemical', 'MESH:D005947', (120, 127))
138306	28548087	It is possible that the change in SqCC bioenergetics represents a higher capacity for glucose uptake and utilization, whereas in 25 mM glucose, glucose uptake in ADC becomes saturated.	('bioenergetics', 'MPA', (39, 52))	('SqCC', 'Phenotype', 'HP:0002860', (34, 38))	('ADC', 'Gene', (162, 165))	('change', 'Var', (24, 30))	('glucose', 'Chemical', 'MESH:D005947', (135, 142))	('glucose', 'Chemical', 'MESH:D005947', (144, 151))	('higher', 'PosReg', (66, 72))	('ADC', 'Gene', '242669', (162, 165))	('utilization', 'MPA', (105, 116))	('glucose', 'Chemical', 'MESH:D005947', (86, 93))	('glucose uptake', 'MPA', (86, 100))
138318	28548087	We chose WZB117, a selective, small-molecule GLUT1 inhibitor, and measured glucose uptake and ECAR in response to WZB117 treatment.	('WZB117', 'Var', (114, 120))	('measured', 'Reg', (66, 74))	('ECAR', 'MPA', (94, 98))	('glucose uptake', 'MPA', (75, 89))	('glucose', 'Chemical', 'MESH:D005947', (75, 82))	('WZB117', 'Chemical', 'MESH:C576807', (9, 15))	('WZB117', 'Chemical', 'MESH:C576807', (114, 120))
138323	28548087	Considering that WZB117 inhibited glucose uptake and glycolysis in both ADC and SqCC, these results suggest a crucial reliance on GLUT1 for survival and proliferation of SqCC as well as a glycolytic independence in ADC.	('ADC', 'Gene', '242669', (215, 218))	('ADC', 'Gene', (72, 75))	('glycolysis', 'MPA', (53, 63))	('glucose', 'Chemical', 'MESH:D005947', (34, 41))	('WZB117', 'Chemical', 'MESH:C576807', (17, 23))	('inhibited', 'NegReg', (24, 33))	('ADC', 'Gene', (215, 218))	('SqCC', 'Phenotype', 'HP:0002860', (80, 84))	('glucose uptake', 'MPA', (34, 48))	('SqCC', 'Phenotype', 'HP:0002860', (170, 174))	('WZB117', 'Var', (17, 23))	('ADC', 'Gene', '242669', (72, 75))
138324	28548087	Although GLUT1 is the predominant glucose transporter expressed in both lung ADC and SqCC cells, a recent study as well as our computational docking analysis (AutoDock Vina, Scripps Research Institute) suggest that WZB117 may exert its effects by binding both GLUT1 and GLUT3 transporters.	('GLUT3', 'Gene', (270, 275))	('ADC', 'Gene', '242669', (77, 80))	('binding', 'Interaction', (247, 254))	('SqCC', 'Phenotype', 'HP:0002860', (85, 89))	('WZB117', 'Chemical', 'MESH:C576807', (215, 221))	('GLUT1', 'Protein', (260, 265))	('WZB117', 'Var', (215, 221))	('ADC', 'Gene', (77, 80))	('GLUT3', 'Gene', '6515', (270, 275))	('glucose', 'Chemical', 'MESH:D005947', (34, 41))
138347	28548087	It has previously been shown that human SqCC tumours and cell lines exhibit high prevalence of genomic copy number gains in chromosome 3q, the genomic region containing the gene of the catalytic subunit of the PI3K complex, PIK3CA.	('SqCC tumours', 'Disease', (40, 52))	('human', 'Species', '9606', (34, 39))	('tumour', 'Phenotype', 'HP:0002664', (45, 51))	('copy number gains', 'Var', (103, 120))	('tumours', 'Phenotype', 'HP:0002664', (45, 52))	('PIK3CA', 'Gene', (224, 230))	('PIK3CA', 'Gene', '5290', (224, 230))	('SqCC', 'Phenotype', 'HP:0002860', (40, 44))	('SqCC tumours', 'Disease', 'MESH:D009369', (40, 52))
138348	28548087	Given that PI3K/AKT signalling has been shown to enhance the translation of HIF-1alpha under non-hypoxic conditions, we hypothesized that aberrantly activated PI3K/AKT signalling may contribute to GLUT1 expression through oncogenically stabilized HIF-1alpha signalling.	('GLUT1', 'Gene', (197, 202))	('aberrantly', 'Var', (138, 148))	('contribute', 'Reg', (183, 193))	('HIF-1alpha', 'Gene', (76, 86))	('PI3K/AKT signalling', 'Pathway', (159, 178))	('expression', 'MPA', (203, 213))	('translation', 'MPA', (61, 72))	('enhance', 'PosReg', (49, 56))	('HIF-1alpha', 'Gene', '3091', (247, 257))	('HIF-1alpha', 'Gene', '3091', (76, 86))	('HIF-1alpha', 'Gene', (247, 257))
138349	28548087	A previous TCGA analysis has identified significant enrichment of PI3K pathway-activating alterations, which include oncogenic or genomic alterations of PIK3CA, PTEN and mTOR in 47% of the TCGA cohort of lung SqCC.	('PI3K pathway-activating', 'Pathway', (66, 89))	('PIK3CA', 'Gene', '5290', (153, 159))	('alterations', 'Reg', (90, 101))	('SqCC', 'Phenotype', 'HP:0002860', (209, 213))	('alterations', 'Var', (138, 149))	('mTOR', 'Gene', (170, 174))	('mTOR', 'Gene', '2475', (170, 174))	('PTEN', 'Gene', (161, 165))	('PIK3CA', 'Gene', (153, 159))	('lung SqCC', 'Disease', (204, 213))
138366	28548087	To validate whether non-hypoxic HIF-1alpha mediates GLUT1 expression in SqCC, we knocked down HIF-1alpha in SqCC cells.	('non-hypoxic HIF-1alpha', 'Disease', (20, 42))	('knocked down', 'Var', (81, 93))	('HIF-1alpha', 'Gene', (94, 104))	('HIF-1alpha', 'Gene', (32, 42))	('SqCC', 'Phenotype', 'HP:0002860', (108, 112))	('SqCC', 'Phenotype', 'HP:0002860', (72, 76))	('non-hypoxic HIF-1alpha', 'Disease', 'MESH:C580335', (20, 42))	('HIF-1alpha', 'Gene', '3091', (94, 104))	('HIF-1alpha', 'Gene', '3091', (32, 42))
138367	28548087	We found that HIF-1alpha knockdown resulted in a marked decrease in GLUT1 expression level under non-hypoxic conditions (Fig.	('HIF-1alpha', 'Gene', (14, 24))	('HIF-1alpha', 'Gene', '3091', (14, 24))	('decrease', 'NegReg', (56, 64))	('GLUT1 expression level', 'MPA', (68, 90))	('knockdown', 'Var', (25, 34))
138376	28548087	Interestingly, we determined high GLUT1 expression to be associated with poor survival in lung ADC patients (Supplementary Fig.	('expression', 'MPA', (40, 50))	('high', 'Var', (29, 33))	('ADC', 'Gene', '242669', (95, 98))	('ADC', 'Gene', (95, 98))	('patients', 'Species', '9606', (99, 107))	('GLUT1', 'Protein', (34, 39))	('poor', 'NegReg', (73, 77))
138379	28548087	High GLUT1 expression is associated with poor tumour cell differentiation (Table 1).	('GLUT1', 'Protein', (5, 10))	('High', 'Var', (0, 4))	('expression', 'MPA', (11, 21))	('tumour', 'Disease', (46, 52))	('tumour', 'Phenotype', 'HP:0002664', (46, 52))	('tumour', 'Disease', 'MESH:D009369', (46, 52))
138393	28548087	Although previous studies have reported an increase in GLUT1-mediated aerobic glycolysis by EGFR, KRAS, BRAF or other frequent oncogenic mutations in ADC, our analysis found no significant increase in GLUT1 mRNA expression in ADC patients possessing KRAS, EGFR, BRAF, LKB1, PIK3CA or PTEN mutations compared to those who did not (Supplementary Fig.	('mutations', 'Var', (289, 298))	('LKB1', 'Gene', (268, 272))	('BRAF', 'Gene', (262, 266))	('BRAF', 'Gene', '673', (262, 266))	('increase', 'PosReg', (189, 197))	('ADC', 'Gene', '242669', (150, 153))	('PIK3CA', 'Gene', (274, 280))	('GLUT1-mediated aerobic glycolysis', 'MPA', (55, 88))	('KRAS', 'Gene', (250, 254))	('ADC', 'Gene', (150, 153))	('EGFR', 'Gene', '1956', (92, 96))	('EGFR', 'Gene', (256, 260))	('GLUT1 mRNA expression', 'MPA', (201, 222))	('increase', 'PosReg', (43, 51))	('PIK3CA', 'Gene', '5290', (274, 280))	('ADC', 'Gene', '242669', (226, 229))	('PTEN', 'Gene', (284, 288))	('patients', 'Species', '9606', (230, 238))	('BRAF', 'Gene', '673', (104, 108))	('EGFR', 'Gene', '1956', (256, 260))	('EGFR', 'Gene', (92, 96))	('BRAF', 'Gene', (104, 108))	('ADC', 'Gene', (226, 229))
138396	28548087	LBK1 inactivation has been linked to increased HIF-1alpha signalling; however, a slight but statistically significantly lower expression of GLUT1 was detected in tumours with LKB1 mutations compared to LKB1 wild-type tumours (P=0.0076, Mann-Whitney u-test, Supplementary Fig.	('tumours', 'Disease', (162, 169))	('tumours', 'Phenotype', 'HP:0002664', (217, 224))	('type tumours', 'Disease', 'MESH:D009369', (212, 224))	('tumours', 'Disease', 'MESH:D009369', (217, 224))	('tumours', 'Phenotype', 'HP:0002664', (162, 169))	('inactivation', 'Var', (5, 17))	('LBK1', 'Gene', (0, 4))	('tumours', 'Disease', 'MESH:D009369', (162, 169))	('tumour', 'Phenotype', 'HP:0002664', (217, 223))	('tumour', 'Phenotype', 'HP:0002664', (162, 168))	('lower', 'NegReg', (120, 125))	('expression', 'MPA', (126, 136))	('mutations', 'Var', (180, 189))	('HIF-1alpha', 'Gene', '3091', (47, 57))	('GLUT1', 'Protein', (140, 145))	('type tumours', 'Disease', (212, 224))	('LKB1', 'Gene', (175, 179))	('HIF-1alpha', 'Gene', (47, 57))	('tumours', 'Disease', (217, 224))
138402	28548087	These observations suggest a mechanistic involvement of aberrantly activated PIK3 pathway signalling in elevated glucose metabolism in NSCLC.	('aberrantly', 'Var', (56, 66))	('PIK3', 'Gene', '5294', (77, 81))	('elevated glucose metabolism', 'Disease', 'MESH:D044882', (104, 131))	('NSCLC', 'Disease', (135, 140))	('elevated glucose', 'Phenotype', 'HP:0003074', (104, 120))	('NSCLC', 'Disease', 'MESH:D002289', (135, 140))	('elevated glucose metabolism', 'Disease', (104, 131))	('PIK3', 'Gene', (77, 81))	('NSCLC', 'Phenotype', 'HP:0030358', (135, 140))
138408	28548087	In addition, a recent metabolic tracing study revealed a significant increase in serine biosynthesis among NSCLC cell lines with high Nrf2 activity.	('serine', 'Chemical', 'MESH:D012694', (81, 87))	('increase', 'PosReg', (69, 77))	('NSCLC', 'Disease', (107, 112))	('high', 'Var', (129, 133))	('Nrf2', 'Gene', (134, 138))	('NSCLC', 'Disease', 'MESH:D002289', (107, 112))	('serine biosynthesis', 'MPA', (81, 100))	('activity', 'MPA', (139, 147))	('NSCLC', 'Phenotype', 'HP:0030358', (107, 112))	('Nrf2', 'Gene', '4780', (134, 138))
138411	28548087	The KL mouse model, as well as SqCC cell line HCC1588, features a KRAS mutation whose role in driving SqCC tumour formation is not well understood.	('SqCC', 'Phenotype', 'HP:0002860', (102, 106))	('mutation', 'Var', (71, 79))	('mouse', 'Species', '10090', (7, 12))	('HCC1588', 'CellLine', 'CVCL:A351', (46, 53))	('SqCC', 'Phenotype', 'HP:0002860', (31, 35))	('tumour', 'Phenotype', 'HP:0002664', (107, 113))	('tumour', 'Disease', 'MESH:D009369', (107, 113))	('tumour', 'Disease', (107, 113))	('KRAS', 'Gene', (66, 70))
138421	28548087	1a) that significantly correlates with Ki67 and PCNA mRNA levels (Supplementary Fig.	('PCNA', 'Gene', (48, 52))	('PCNA', 'Gene', '5111', (48, 52))	('Ki67', 'Var', (39, 43))
138424	28548087	Genetic deletion of PTEN, a phosphatase that negatively regulates PI3K/AKT activity, resulted in SqCC in LKB1-deficient mice, suggesting that the PI3K/AKT pathway is critically implicated in SqCC.	('LKB1-deficient', 'Disease', (105, 119))	('LKB1-deficient', 'Disease', 'MESH:D007153', (105, 119))	('mice', 'Species', '10090', (120, 124))	('resulted in', 'Reg', (85, 96))	('SqCC', 'Phenotype', 'HP:0002860', (97, 101))	('SqCC', 'Phenotype', 'HP:0002860', (191, 195))	('PTEN', 'Gene', (20, 24))	('SqCC', 'Disease', (97, 101))	('deletion', 'Var', (8, 16))
138432	28548087	These results propose potential mechanisms underlying SqCC-specific GLUT1 induction by which oncogenic PI3K/AKT-mediated stabilization of HIF-1alpha leads to overexpression of GLUT1 and other glycolytic enzymes, which subsequently results in heightened glucose metabolism in SqCC.	('heightened glucose metabolism', 'Disease', (242, 271))	('heightened glucose metabolism', 'Disease', 'MESH:D044882', (242, 271))	('results in', 'Reg', (231, 241))	('HIF-1alpha', 'Gene', (138, 148))	('glycolytic enzyme', 'Gene', '3098', (192, 209))	('SqCC', 'Phenotype', 'HP:0002860', (275, 279))	('overexpression', 'PosReg', (158, 172))	('stabilization', 'Var', (121, 134))	('glycolytic enzyme', 'Gene', (192, 209))	('HIF-1alpha', 'Gene', '3091', (138, 148))	('GLUT1', 'Protein', (176, 181))	('SqCC', 'Phenotype', 'HP:0002860', (54, 58))
138434	28548087	In addition, it has been shown that mTOR inhibitor MLN0128 attenuates HIF-1alpha and GLUT1 expression in NSCLC cell lines and the KL model of NSCLC, which is associated with decreased 18F-FDG uptake, further corroborating the regulation of PI3K/AKT/mTOR pathway signalling on GLUT1 expression through HIF-1alpha (ref.).	('expression', 'MPA', (91, 101))	('NSCLC', 'Phenotype', 'HP:0030358', (105, 110))	('GLUT1', 'Gene', (85, 90))	('HIF-1alpha', 'Gene', (70, 80))	('NSCLC', 'Disease', (142, 147))	('mTOR', 'Gene', '2475', (36, 40))	('mTOR', 'Gene', (249, 253))	('18F-FDG uptake', 'MPA', (184, 198))	('NSCLC', 'Phenotype', 'HP:0030358', (142, 147))	('attenuates', 'NegReg', (59, 69))	('mTOR', 'Gene', '2475', (249, 253))	('18F-FDG', 'Chemical', 'MESH:D019788', (184, 191))	('MLN0128', 'Var', (51, 58))	('decreased', 'NegReg', (174, 183))	('HIF-1alpha', 'Gene', '3091', (301, 311))	('HIF-1alpha', 'Gene', '3091', (70, 80))	('NSCLC', 'Disease', 'MESH:D002289', (105, 110))	('mTOR', 'Gene', (36, 40))	('MLN0128', 'Chemical', 'MESH:C572449', (51, 58))	('NSCLC', 'Disease', 'MESH:D002289', (142, 147))	('HIF-1alpha', 'Gene', (301, 311))	('NSCLC', 'Disease', (105, 110))
138440	28548087	For example, Von Hippel-Lindau factor (VHL) deletion and inactivation are among the most common mutations observed in renal cell carcinoma leading to oncogenic stabilization of HIF-1alpha.	('HIF-1alpha', 'Gene', '3091', (177, 187))	('oncogenic stabilization', 'MPA', (150, 173))	('renal cell carcinoma', 'Disease', (118, 138))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (118, 138))	('Von Hippel-Lindau factor', 'Gene', (13, 37))	('deletion', 'Var', (44, 52))	('VHL', 'Gene', (39, 42))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (118, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('HIF-1alpha', 'Gene', (177, 187))	('VHL', 'Gene', '7428', (39, 42))	('inactivation', 'Var', (57, 69))	('Von Hippel-Lindau factor', 'Gene', '7428', (13, 37))
138446	28548087	Our study establishing aberrantly elevated GLUT1 expression and glycolytic metabolism as a specific metabolic feature of SqCC may facilitate the development of the targeted therapeutic strategy for the treatment of SqCC as well as novel diagnostic and prognostic parameters defining histological subtype-specific metabolic dependencies within NSCLC.	('metabolic dependencies within NSCLC', 'Disease', 'MESH:D001929', (313, 348))	('GLUT1', 'Protein', (43, 48))	('expression', 'MPA', (49, 59))	('aberrantly', 'Var', (23, 33))	('NSCLC', 'Phenotype', 'HP:0030358', (343, 348))	('SqCC', 'Phenotype', 'HP:0002860', (121, 125))	('elevated', 'PosReg', (34, 42))	('metabolic dependencies within NSCLC', 'Disease', (313, 348))	('SqCC', 'Disease', (121, 125))	('facilitate', 'PosReg', (130, 140))	('SqCC', 'Phenotype', 'HP:0002860', (215, 219))	('glycolytic', 'MPA', (64, 74))
138459	28548087	In all, 24 mice were used for shGLUT1 knockdown xenograft experiments and 86 mice were used for the treatment of glycolytic inhibitors 2-DG or WZB117.	('2-DG', 'Chemical', 'MESH:D003847', (135, 139))	('mice', 'Species', '10090', (77, 81))	('shGLUT1', 'Gene', (30, 37))	('mice', 'Species', '10090', (11, 15))	('WZB117', 'Chemical', 'MESH:C576807', (143, 149))	('WZB117', 'Var', (143, 149))
138495	28548087	The following primary antibodies were used: GLUT1 (1:250; Alpha Diagnostic; GT11-A), p63 (1:200; Biocare Medical; CM163A), CK5 (1:200; Abcam; ab52635), TTF1 (1:1,000; Dako; M3575), HIF-1alpha (1:1,000; Novus Biologicals; NB100-449), Ki67 (1:500; Cell Signaling; 12202), Cleaved Caspase-3 (CC3, 1:200; Cell Signaling; 9664), Ser473-p-AKT (1:200; Cell Signaling; 4060), Ser235/236-p-S6 (1:200; Cell Signaling; 4858) and Thr37/46-p-4EBP1 (1:200; Cell Signaling; 2855).	('p-S6', 'Gene', '338413', (379, 383))	('CK5', 'Gene', (123, 126))	('p-S6', 'Gene', (379, 383))	('HIF-1alpha', 'Gene', '3091', (181, 191))	('4EBP1', 'Gene', '1978', (429, 434))	('Ser473-p-AKT', 'Mutation', 'p.S473AKT', (324, 336))	('CK5', 'Gene', '3852', (123, 126))	('HIF-1alpha', 'Gene', (181, 191))	('TTF1', 'Gene', (152, 156))	('Ser473-p-AKT', 'Var', (324, 336))	('4EBP1', 'Gene', (429, 434))	('TTF1', 'Gene', '7270', (152, 156))
138564	33637113	Because the first-line treatment for patients with advanced SqCLC is still based on platinum-based doublet chemotherapy, which is associated with poor survival, rare gene mutations, and poor effects when using TKIs, the proposal of anti-tumor angiogenesis theory provides a new research direction for patients with SqCLC.	('tumor', 'Disease', (237, 242))	('patients', 'Species', '9606', (37, 45))	('platinum', 'Chemical', 'MESH:D010984', (84, 92))	('patients', 'Species', '9606', (301, 309))	('SqCLC', 'Phenotype', 'HP:0030359', (60, 65))	('SqCLC', 'Phenotype', 'HP:0030359', (315, 320))	('tumor', 'Disease', 'MESH:D009369', (237, 242))	('mutations', 'Var', (171, 180))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))
138616	32467674	Mature circRNAs mainly are localized in the cytoplasm, but exon-intron circRNAs mainly appear to have nuclear origin due to their role in transcriptional regulation.	('cir', 'Gene', (71, 74))	('cir', 'Gene', '9541', (71, 74))	('cir', 'Gene', (7, 10))	('cir', 'Gene', '9541', (7, 10))	('exon-intron', 'Var', (59, 70))
138629	32467674	Exon skipping (ES) is a common type of alternative splicing with a well-known effect on mRNA formation.	('mRNA formation', 'MPA', (88, 102))	('Exon skipping', 'Var', (0, 13))	('ES', 'Chemical', '-', (15, 17))
138648	32467674	This is followed by the incision of exonic and intronic sequences in the binding portion of the spliceosome, and finally, the formation of mature circRNA as the residual introns are stitched together (Fig.	('cir', 'Gene', '9541', (146, 149))	('incision', 'Var', (24, 32))	('cir', 'Gene', (146, 149))
138667	32467674	Its knockdown is shown to suppress circRNA formation.	('cir', 'Gene', (35, 38))	('knockdown', 'Var', (4, 13))	('cir', 'Gene', '9541', (35, 38))	('suppress', 'NegReg', (26, 34))
138682	32467674	Therefore, the excess of circRNA in body fluids and blood due to high RNAase resistance allows them to serve as potential biomarkers in various diseases.	('RNAase', 'Protein', (70, 76))	('excess', 'PosReg', (15, 21))	('high', 'Var', (65, 69))	('cir', 'Gene', (25, 28))	('cir', 'Gene', '9541', (25, 28))
138742	32467674	In primary breast cancers, circRNAs of CREBBP, CNOT2, and RERE and RNAi-mediated knockdown of circRNA circCNOT2 was shown to significantly reduce the viability of two breast cancer cell lines: MCF-7 and BT-474.	('breast cancer', 'Disease', (167, 180))	('CNOT2', 'Gene', (47, 52))	('cancers', 'Phenotype', 'HP:0002664', (18, 25))	('viability', 'CPA', (150, 159))	('cir', 'Gene', '9541', (94, 97))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('breast cancers', 'Disease', 'MESH:D001943', (11, 25))	('CNOT2', 'Gene', '4848', (106, 111))	('breast cancers', 'Disease', (11, 25))	('cir', 'Gene', '9541', (102, 105))	('reduce', 'NegReg', (139, 145))	('cir', 'Gene', (94, 97))	('RERE', 'Gene', (58, 62))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('CREBBP', 'Gene', (39, 45))	('CNOT2', 'Gene', (106, 111))	('breast cancers', 'Phenotype', 'HP:0003002', (11, 25))	('cir', 'Gene', (102, 105))	('knockdown', 'Var', (81, 90))	('breast cancer', 'Phenotype', 'HP:0003002', (11, 24))	('cir', 'Gene', '9541', (27, 30))	('RERE', 'Gene', '473', (58, 62))	('breast cancer', 'Phenotype', 'HP:0003002', (167, 180))	('breast cancer', 'Disease', 'MESH:D001943', (11, 24))	('CNOT2', 'Gene', '4848', (47, 52))	('cir', 'Gene', (27, 30))	('CREBBP', 'Gene', '1387', (39, 45))	('MCF-7', 'CellLine', 'CVCL:0031', (193, 198))	('breast cancer', 'Disease', 'MESH:D001943', (167, 180))
138756	32467674	The dysregulation of crosstalk between miRNAs and ceRNAs significantly affect cancer pathogenesis, suggesting a correlation with miRNAs as well as the involvement of circRNAs in malignant tumors.	('correlation', 'Interaction', (112, 123))	('crosstalk', 'Interaction', (21, 30))	('tumors', 'Phenotype', 'HP:0002664', (188, 194))	('malignant tumors', 'Disease', (178, 194))	('cir', 'Gene', '9541', (166, 169))	('dysregulation', 'Var', (4, 17))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('affect', 'Reg', (71, 77))	('malignant tumors', 'Disease', 'MESH:D009369', (178, 194))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('cir', 'Gene', (166, 169))
138761	32467674	Additionally, E6/E7 a viral oncogene is known to overexpress miR-7 activity in HPV-positive human HeLa cells.	('miR-7', 'Gene', '10859', (61, 66))	('E6/E7', 'Var', (14, 19))	('HeLa', 'CellLine', 'CVCL:0030', (98, 102))	('overexpress', 'PosReg', (49, 60))	('activity', 'MPA', (67, 75))	('miR-7', 'Gene', (61, 66))	('human', 'Species', '9606', (92, 97))
138782	32467674	There are several other miRNAs that on downregulation are involved in PD such as let-7, miR-153 and miR-34a/b.	('miR-34a/b', 'Gene', (100, 109))	('miR-34a/b', 'Gene', '407040', (100, 109))	('let-7', 'Gene', (81, 86))	('miR-153', 'Var', (88, 95))	('PD', 'Disease', 'MESH:D010300', (70, 72))	('downregulation', 'NegReg', (39, 53))
138785	32467674	Its link to circRNA function and regulation in neurodegenerative processes may lead to new understanding into the mechanism of mutant FUS-associated ALS and related disorders.	('mutant', 'Var', (127, 133))	('cir', 'Gene', (12, 15))	('ALS', 'Gene', (149, 152))	('ALS', 'Gene', '6647', (149, 152))	('cir', 'Gene', '9541', (12, 15))	('neurodegenerative processes', 'Phenotype', 'HP:0002180', (47, 74))	('lead', 'Reg', (79, 83))	('FUS', 'Gene', '233908', (134, 137))	('FUS', 'Gene', (134, 137))
138788	32467674	In neuropathy, suppression of a transcription factor, RUNX3 I in an autoimmune disease by miR-138 could balance the expression of CD4+ T cells.	('balance', 'NegReg', (104, 111))	('CD4', 'Gene', '920', (130, 133))	('neuropathy', 'Disease', 'MESH:D009422', (3, 13))	('neuropathy', 'Phenotype', 'HP:0009830', (3, 13))	('autoimmune disease', 'Disease', (68, 86))	('neuropathy', 'Disease', (3, 13))	('miR-138', 'Chemical', '-', (90, 97))	('autoimmune disease', 'Phenotype', 'HP:0002960', (68, 86))	('suppression', 'NegReg', (15, 26))	('miR-138', 'Var', (90, 97))	('RUNX3', 'Gene', (54, 59))	('autoimmune disease', 'Disease', 'MESH:D001327', (68, 86))	('RUNX3', 'Gene', '864', (54, 59))	('CD4', 'Gene', (130, 133))
138801	32467674	It was confirmed through silencing of hsa_circ_0003575, which would provide a therapeutic strategy for endothelial cell injury in atherosclerosis.	('silencing', 'Var', (25, 34))	('atherosclerosis', 'Disease', 'MESH:D050197', (130, 145))	('atherosclerosis', 'Phenotype', 'HP:0002621', (130, 145))	('atherosclerosis', 'Disease', (130, 145))	('cir', 'Gene', (42, 45))	('cir', 'Gene', '9541', (42, 45))
138803	32467674	Genome wide Association studies (GWAS) have revealed the correlation between small nucleotide polymorphisms (SNPs) near INK4/ARF locus and Arteriosclerotic Vascular Disease (ASVD).	('INK4', 'Gene', (120, 124))	('ARF', 'Disease', 'MESH:D058186', (125, 128))	('ASVD', 'Phenotype', 'HP:0002634', (174, 178))	('Arteriosclerotic Vascular Disease', 'Disease', 'MESH:D015140', (139, 172))	('small nucleotide polymorphisms', 'Var', (77, 107))	('INK4', 'Gene', '1029', (120, 124))	('ARF', 'Disease', (125, 128))	('Arteriosclerotic Vascular Disease', 'Phenotype', 'HP:0002634', (139, 172))	('ASVD', 'Disease', (174, 178))	('ASVD', 'Disease', 'None', (174, 178))	('Arteriosclerotic Vascular Disease', 'Disease', (139, 172))
138808	32467674	Its sponging activity was elucidated through RNAi mechanism when knockdown of circRNA_010567 upregulated miR-141 and downregulated TGF- beta1.	('miR-141', 'Gene', (105, 112))	('cir', 'Gene', (78, 81))	('downregulated', 'NegReg', (117, 130))	('cir', 'Gene', '9541', (78, 81))	('miR-141', 'Gene', '406933', (105, 112))	('upregulated', 'PosReg', (93, 104))	('knockdown', 'Var', (65, 74))	('TGF- beta1', 'Gene', '7040', (131, 141))	('TGF- beta1', 'Gene', (131, 141))
138815	32467674	In stress related pathways, circ-FOXO3 plays an important role as its dysregulation results in sequestration of various proteins.	('sequestration of various proteins', 'MPA', (95, 128))	('stress related pathways', 'Pathway', (3, 26))	('results in', 'Reg', (84, 94))	('FOXO3', 'Gene', '2309', (33, 38))	('dysregulation', 'Var', (70, 83))	('cir', 'Gene', (28, 31))	('cir', 'Gene', '9541', (28, 31))	('FOXO3', 'Gene', (33, 38))
138829	32467674	Silencing of circCCDC66 in colorectal cell lines demonstrated the oncogenic role of this circRNA in various cancer-related processes like proliferation, invasion, migration and anchorage independence.	('invasion', 'CPA', (153, 161))	('migration', 'CPA', (163, 172))	('proliferation', 'CPA', (138, 151))	('cir', 'Gene', (13, 16))	('anchorage independence', 'CPA', (177, 199))	('cir', 'Gene', (89, 92))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('cir', 'Gene', '9541', (89, 92))	('cir', 'Gene', '9541', (13, 16))	('Silencing', 'Var', (0, 9))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
138831	32467674	Many of oncogenes were downregulated once the circCCDC66 was silenced one of them being MYC that was extensively studied.	('downregulated', 'NegReg', (23, 36))	('oncogenes', 'Gene', (8, 17))	('cir', 'Gene', (46, 49))	('MYC', 'Gene', '4609', (88, 91))	('cir', 'Gene', '9541', (46, 49))	('MYC', 'Gene', (88, 91))	('silenced', 'Var', (61, 69))
138832	32467674	In HCC tissues and cell lines, circZKSCAN1 was found to be significantly lower and knockdown promoted cell proliferation, migration and invasion in both in vitro and in vivo.	('cir', 'Gene', '9541', (31, 34))	('invasion', 'CPA', (136, 144))	('cir', 'Gene', (31, 34))	('lower', 'NegReg', (73, 78))	('migration', 'CPA', (122, 131))	('HCC', 'Phenotype', 'HP:0001402', (3, 6))	('promoted', 'PosReg', (93, 101))	('knockdown', 'Var', (83, 92))	('cell proliferation', 'CPA', (102, 120))
138833	32467674	While as in GC, hsa_circ_0000096 levels were significantly downregulated in gastric cancer tissues and gastric cancer cell lines and its knockdown inhibited cell proliferation and migration in vitro and in vivo.	('gastric cancer', 'Disease', 'MESH:D013274', (76, 90))	('gastric cancer', 'Phenotype', 'HP:0012126', (103, 117))	('levels', 'MPA', (33, 39))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('downregulated', 'NegReg', (59, 72))	('gastric cancer', 'Phenotype', 'HP:0012126', (76, 90))	('GC', 'Phenotype', 'HP:0012126', (12, 14))	('knockdown', 'Var', (137, 146))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('cir', 'Gene', (20, 23))	('gastric cancer', 'Disease', (103, 117))	('inhibited', 'NegReg', (147, 156))	('cir', 'Gene', '9541', (20, 23))	('gastric cancer', 'Disease', 'MESH:D013274', (103, 117))	('gastric cancer', 'Disease', (76, 90))
138841	32467674	CDR1as loss-of-function mutant mice were generated.	('mutant', 'Var', (24, 30))	('CDR1as', 'Gene', '103611090', (0, 6))	('loss-of-function', 'NegReg', (7, 23))	('mice', 'Species', '10090', (31, 35))	('CDR1as', 'Gene', (0, 6))
138842	32467674	But mostly genome editing based knockout of circRNAs involve deletions of circRNA exons, which is difficult as CRISPR/Cas9 off target effects can't be ruled.	('deletions', 'Var', (61, 70))	('cir', 'Gene', (74, 77))	('cir', 'Gene', (44, 47))	('cir', 'Gene', '9541', (74, 77))	('cir', 'Gene', '9541', (44, 47))
138845	32467674	So, CRISPR/Cas9 technology offers an unprecedented prospect for fractional or whole knockdown of circRNAs involved in cancer.	('cir', 'Gene', (97, 100))	('cancer', 'Disease', (118, 124))	('cir', 'Gene', '9541', (97, 100))	('knockdown', 'Var', (84, 93))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('cancer', 'Disease', 'MESH:D009369', (118, 124))
138863	31059025	Comprehensive analysis of the aberrantly expressed lncRNA-associated ceRNA network in breast cancer Previous studies have suggested that long non-coding RNAs (lncRNAs) are closely associated with human diseases, particularly cancer, including cancer of the lung, breast and stomach.	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('cancer', 'Disease', 'MESH:D009369', (225, 231))	('human', 'Species', '9606', (196, 201))	('cancer', 'Disease', (225, 231))	('associated', 'Reg', (180, 190))	('cancer', 'Disease', (243, 249))	('long non-coding RNAs', 'Var', (137, 157))	('cancer', 'Disease', 'MESH:D009369', (243, 249))	('breast cancer', 'Disease', 'MESH:D001943', (86, 99))	('breast', 'Disease', (263, 269))	('breast cancer', 'Phenotype', 'HP:0003002', (86, 99))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('stomach', 'Disease', (274, 281))	('breast cancer', 'Disease', (86, 99))	('cancer', 'Phenotype', 'HP:0002664', (243, 249))	('cancer of the lung', 'Phenotype', 'HP:0100526', (243, 261))
138871	31059025	In addition, 5 lncRNAs (ADAM metallopeptidase with thrombospondin type 1 motif 9-antisense RNA 1, AL513123.1, chromosome 10 open reading frame 126, long intergenic non-protein coding RNA 536 and Wilms tumor 1 antisense RNA) were identified to be significantly associated with overall survival (P<0.05, log rank test).	('Wilms tumor 1 antisense RNA', 'Gene', '51352', (195, 222))	('AL513123.1', 'Var', (98, 108))	('overall survival', 'MPA', (276, 292))	('Wilms tumor', 'Phenotype', 'HP:0002667', (195, 206))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('Wilms tumor 1 antisense RNA', 'Gene', (195, 222))	('associated', 'Reg', (260, 270))
138887	31059025	Previous studies have demonstrated that ceRNAs affect the proliferation, growth, differentiation, apoptosis and other biological behaviors of cancer cells.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('apoptosis', 'CPA', (98, 107))	('proliferation', 'CPA', (58, 71))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('growth', 'CPA', (73, 79))	('biological behaviors', 'CPA', (118, 138))	('affect', 'Reg', (47, 53))	('differentiation', 'CPA', (81, 96))	('ceRNAs', 'Var', (40, 46))	('cancer', 'Disease', (142, 148))
138891	31059025	Among these, the interaction mechanisms between lncRNA and miRNA include: miRNA binding to and degrading lncRNA; lncRNA acting as miRNA sponge by binding to adsorbed miRNA; and truncation of lncRNA to generate miRNA.	('miR', 'Gene', (74, 77))	('interaction', 'Interaction', (17, 28))	('adsorbed', 'Interaction', (157, 165))	('miR', 'Gene', '220972', (74, 77))	('miR', 'Gene', '220972', (166, 169))	('truncation', 'Var', (177, 187))	('degrading', 'NegReg', (95, 104))	('miR', 'Gene', '220972', (130, 133))	('miR', 'Gene', (130, 133))	('binding', 'Interaction', (146, 153))	('miR', 'Gene', '220972', (59, 62))	('miR', 'Gene', (59, 62))	('miR', 'Gene', '220972', (210, 213))	('miR', 'Gene', (210, 213))	('lncRNA', 'Protein', (191, 197))	('binding', 'Interaction', (80, 87))	('miR', 'Gene', (166, 169))	('lncRNA', 'Protein', (105, 111))
138926	31059025	These included: ADAM metallopeptidase with thrombospondin type 1 motif 9-antisense RNA 1 (ADAMTS9-AS1), AC061992.1, Wilms tumor 1 antisense RNA (WT1-AS), long intergenic non-protein coding RNA 536 (LINC00536), AL391421.1, SLIT-ROBO Rho GTPase activating protein 3 antisense RNA 2 (SRGAP3-AS2), Prader-Willi region non-protein coding RNA 1 (PWRN1), family with sequence similarity 230 member G (AC007731.1), chromosome 10 open reading frame 126 (C10orf126) and AL513123.1.	('SRGAP3-AS2', 'Gene', (281, 291))	('SRGAP3-AS2', 'Gene', '101927416', (281, 291))	('Wilms tumor', 'Phenotype', 'HP:0002667', (116, 127))	('AL391421.1', 'Var', (210, 220))	('WT1-AS', 'Gene', '51352', (145, 151))	('LINC00536', 'Gene', '100859921', (198, 207))	('Prader-Willi region non-protein coding RNA 1', 'Gene', '791114', (294, 338))	('PWRN1', 'Gene', (340, 345))	('ADAMTS9-AS1', 'Gene', '101929335;56999;5729', (90, 101))	('Wilms tumor 1 antisense RNA', 'Gene', (116, 143))	('C10orf126', 'Gene', '283080', (445, 454))	('PWRN1', 'Gene', '791114', (340, 345))	('Prader-Willi region non-protein coding RNA 1', 'Gene', (294, 338))	('ADAMTS9-AS1', 'Gene', (90, 101))	('C10orf126', 'Gene', (445, 454))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('WT1-AS', 'Gene', (145, 151))	('AL513123.1', 'Var', (460, 470))	('LINC00536', 'Gene', (198, 207))	('SLIT-ROBO Rho GTPase activating protein 3 antisense RNA 2', 'Gene', '101927416', (222, 279))	('Wilms tumor 1 antisense RNA', 'Gene', '51352', (116, 143))
138936	31059025	5, the expression levels of 5 DElncRNAs, including ADAMTS9-AS1, AL513123.1, C10orf126, LINC00536 and WT1-AS, were associated with overall survival (P<0.05).	('C10orf126', 'Gene', '283080', (76, 85))	('ADAMTS9-AS1', 'Gene', '101929335;56999;5729', (51, 62))	('WT1-AS', 'Gene', (101, 107))	('WT1-AS', 'Gene', '51352', (101, 107))	('expression levels', 'MPA', (7, 24))	('LINC00536', 'Gene', (87, 96))	('AL513123.1', 'Var', (64, 74))	('associated', 'Reg', (114, 124))	('C10orf126', 'Gene', (76, 85))	('LINC00536', 'Gene', '100859921', (87, 96))	('overall', 'MPA', (130, 137))	('ADAMTS9-AS1', 'Gene', (51, 62))
138940	31059025	Nik-Zainal et al analyzed genome-wide data from 560 patients with breast cancer and identified that 93 oncogenes involved in the encoded proteins may cause breast cancer.	('Nik', 'Gene', (0, 3))	('cause', 'Reg', (150, 155))	('Nik', 'Gene', '9448', (0, 3))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('breast cancer', 'Disease', 'MESH:D001943', (66, 79))	('oncogenes', 'Var', (103, 112))	('breast cancer', 'Disease', 'MESH:D001943', (156, 169))	('breast cancer', 'Disease', (66, 79))	('breast cancer', 'Disease', (156, 169))	('breast cancer', 'Phenotype', 'HP:0003002', (66, 79))	('breast cancer', 'Phenotype', 'HP:0003002', (156, 169))	('patients', 'Species', '9606', (52, 60))
138955	31059025	Furthermore, it was observed that the lncRNAs ADAMTS9-AS1, AL513123.1, C10orf126, LINC00536 and WT1-AS were included in the ceRNA network.	('LINC00536', 'Gene', '100859921', (82, 91))	('C10orf126', 'Gene', (71, 80))	('ADAMTS9-AS1', 'Gene', (46, 57))	('C10orf126', 'Gene', '283080', (71, 80))	('ADAMTS9-AS1', 'Gene', '101929335;56999;5729', (46, 57))	('WT1-AS', 'Gene', '51352', (96, 102))	('LINC00536', 'Gene', (82, 91))	('WT1-AS', 'Gene', (96, 102))	('AL513123.1', 'Var', (59, 69))
138957	31059025	Wang et al revealed that antisense lncRNA ADAMTS9-AS1 was associated with the nearby coding gene ADAMTS9, which was involved in ovarian cancer progression.	('ADAMTS9-AS1', 'Gene', (42, 53))	('associated', 'Reg', (58, 68))	('ADAMTS9', 'Gene', '56999', (97, 104))	('ADAMTS9', 'Gene', (97, 104))	('ovarian cancer', 'Disease', (128, 142))	('ADAMTS9-AS1', 'Gene', '101929335;56999;5729', (42, 53))	('ovarian cancer', 'Phenotype', 'HP:0100615', (128, 142))	('ADAMTS9', 'Gene', (42, 49))	('ADAMTS9', 'Gene', '56999', (42, 49))	('ovarian cancer', 'Disease', 'MESH:D010051', (128, 142))	('antisense', 'Var', (25, 34))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
138971	31059025	ceRNAs have been implicated in several biological processes, and abnormalities in the ceRNA network may lead to tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumor', 'Disease', (112, 117))	('lead to', 'Reg', (104, 111))	('abnormalities', 'Var', (65, 78))
139002	30139373	Numerous studies have demonstrated that changes in MT expression are associated with the process of carcinogenesis and cancer progression.	('carcinogenesis', 'Disease', (100, 114))	('changes', 'Var', (40, 47))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('associated', 'Reg', (69, 79))	('cancer', 'Disease', (119, 125))	('carcinogenesis', 'Disease', 'MESH:D063646', (100, 114))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
139019	30139373	Any changes at the cellular, genetic, and epigenetic levels that disrupt the balance between proliferation and programmed cell death, in the form of apoptosis, such as DNA mutations and epimutations, can contribute to the development of cancer.	('contribute', 'Reg', (204, 214))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('disrupt', 'NegReg', (65, 72))	('DNA', 'Disease', (168, 171))	('cancer', 'Disease', 'MESH:D009369', (237, 243))	('epimutations', 'Var', (186, 198))	('programmed cell', 'CPA', (111, 126))	('cancer', 'Disease', (237, 243))
139036	30139373	Intriguingly, in vitro experiments have confirmed that MT1F transfection into colon cancer cells could decrease cell proliferation and colony formation and increase cell apoptosis rates to inhibit cell growth.	('MT1F', 'Gene', (55, 59))	('transfection', 'Var', (60, 72))	('MT1F', 'Gene', '4494', (55, 59))	('colon cancer', 'Phenotype', 'HP:0003003', (78, 90))	('colon cancer', 'Disease', 'MESH:D015179', (78, 90))	('increase', 'PosReg', (156, 164))	('cell apoptosis rates', 'CPA', (165, 185))	('cell growth', 'CPA', (197, 208))	('colon cancer', 'Disease', (78, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('decrease', 'NegReg', (103, 111))	('inhibit', 'NegReg', (189, 196))
139040	30139373	In detail, the induced expression of MT1H reduced the colony formation and decreased the entry of prostate cells into the S and M phases to suppress cell growth.	('MT1H', 'Gene', (37, 41))	('reduced', 'NegReg', (42, 49))	('cell growth', 'CPA', (149, 160))	('colony formation', 'CPA', (54, 70))	('expression', 'Var', (23, 33))	('MT1H', 'Gene', '4496', (37, 41))	('entry of prostate cells into the', 'CPA', (89, 121))	('suppress', 'NegReg', (140, 148))	('decreased', 'NegReg', (75, 84))
139076	30139373	In conclusion, MTs can induce the upregulation of angiogenesis-related genes, such as VEGF and MMP-9; act on ECs, SMCs, and macrophages; and result in the formation of new blood vessels to promote tumor growth, progression, and metastasis (Fig.	('result in', 'Reg', (141, 150))	('MMP-9', 'Gene', (95, 100))	('MTs', 'Var', (15, 18))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('VEGF', 'Gene', (86, 90))	('metastasis', 'CPA', (228, 238))	('angiogenesis-related genes', 'Gene', (50, 76))	('upregulation', 'PosReg', (34, 46))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('promote', 'PosReg', (189, 196))	('MMP-9', 'Gene', '4318', (95, 100))	('tumor', 'Disease', (197, 202))	('progression', 'CPA', (211, 222))
139092	30139373	demonstrated a significant positive association of MT1G hypermethylation with lymph node metastasis in 178 papillary thyroid cancer patients.	('papillary thyroid cancer', 'Phenotype', 'HP:0002895', (107, 131))	('thyroid cancer', 'Phenotype', 'HP:0002890', (117, 131))	('MT1G', 'Gene', (51, 55))	('hypermethylation', 'Var', (56, 72))	('MT1G', 'Gene', '4495', (51, 55))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('lymph node metastasis', 'CPA', (78, 99))	('positive', 'PosReg', (27, 35))	('papillary thyroid cancer', 'Disease', (107, 131))	('papillary thyroid cancer', 'Disease', 'MESH:D000077273', (107, 131))	('patients', 'Species', '9606', (132, 140))
139094	30139373	Collectively, these data suggest that MTs contribute to tumor metastasis by enhancing the invasion and migration of tumor cells and tumor microenvironment remodeling.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('tumor', 'Disease', (56, 61))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor', 'Disease', (132, 137))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('enhancing', 'PosReg', (76, 85))	('MTs', 'Var', (38, 41))	('tumor', 'Disease', (116, 121))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
139096	30139373	Subramanian Vignesh and Deepe elucidated the immunomodulatory role of MTs and demonstrated MTs as an important component of the innate and adaptive immune systems regulating metal homeostasis, particularly zinc and thus impacting the immune cell redox status, enzyme function, and cell signaling.	('metal', 'Chemical', 'MESH:D008670', (174, 179))	('cell signaling', 'MPA', (281, 295))	('MTs', 'Var', (91, 94))	('metal homeostasis', 'MPA', (174, 191))	('zinc', 'MPA', (206, 210))	('immune cell redox status', 'MPA', (234, 258))	('enzyme function', 'MPA', (260, 275))	('impacting', 'Reg', (220, 229))
139097	30139373	observed that metastatic CMM cases were associated with the presence of tumor-infiltrating CD68+ (p = 0.001) and CD163+ (p < 0.001) macrophages.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('CMM', 'Gene', (25, 28))	('CD163+', 'Var', (113, 119))	('tumor', 'Disease', (72, 77))	('CD68', 'Gene', '968', (91, 95))	('CMM', 'Gene', '1243', (25, 28))	('CMM', 'Phenotype', 'HP:0012056', (25, 28))	('CD68', 'Gene', (91, 95))	('tumor', 'Disease', 'MESH:D009369', (72, 77))
139116	30139373	Reducible poly(oligo-d-arginine) (rPOA) was used to deliver short hairpin RNAs against MTs (shMT) into cells and resulted in the downregulation of MT expression and enhanced the anticancer effect of cisplatin.	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('cisplatin', 'Chemical', 'MESH:D002945', (199, 208))	('downregulation', 'NegReg', (129, 143))	('enhanced', 'PosReg', (165, 173))	('poly(oligo-d-arginine)', 'Chemical', '-', (10, 32))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('cancer', 'Disease', (182, 188))	('short', 'Var', (60, 65))
139169	30139373	also showed a significant correlation between MT expression and mutant p53 in ovarian carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (78, 95))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (78, 95))	('p53', 'Gene', (71, 74))	('significant correlation', 'Reg', (14, 37))	('MT expression', 'MPA', (46, 59))	('p53', 'Gene', '7157', (71, 74))	('ovarian carcinoma', 'Disease', (78, 95))	('mutant', 'Var', (64, 70))
139175	30139373	Numerous studies have demonstrated that the elimination of tumor suppressor gene activity by promoter methylation is responsible for carcinogenesis, a mechanism that has been confirmed in many human cancers.	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('tumor', 'Disease', (59, 64))	('promoter methylation', 'Var', (93, 113))	('carcinogenesis', 'Disease', 'MESH:D063646', (133, 147))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('cancers', 'Phenotype', 'HP:0002664', (199, 206))	('cancers', 'Disease', 'MESH:D009369', (199, 206))	('carcinogenesis', 'Disease', (133, 147))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('activity', 'MPA', (81, 89))	('elimination', 'NegReg', (44, 55))	('cancers', 'Disease', (199, 206))	('human', 'Species', '9606', (193, 198))
139182	30139373	Moreover, DNA methylation of MT3 from - 127 to - 8 sites was shown to be significantly correlated with advanced tumor stages and lymph node metastasis, implying that the methylation of promoter regions may be involved in tumor progression.	('MT3', 'Gene', (29, 32))	('correlated', 'Reg', (87, 97))	('involved', 'Reg', (209, 217))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('tumor', 'Disease', (221, 226))	('MT3', 'Gene', '4504', (29, 32))	('lymph node metastasis', 'CPA', (129, 150))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('methylation', 'Var', (14, 25))	('tumor', 'Disease', (112, 117))	('tumor', 'Disease', 'MESH:D009369', (221, 226))
139183	30139373	DNA methylation of MT3 was also confirmed in esophageal squamous cell carcinoma, but there was no significant association between the MT3 methylation status and prognosis.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (56, 79))	('MT3', 'Gene', (19, 22))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('MT3', 'Gene', (134, 137))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (45, 79))	('methylation', 'Var', (4, 15))	('MT3', 'Gene', '4504', (19, 22))	('esophageal squamous cell carcinoma', 'Disease', (45, 79))	('MT3', 'Gene', '4504', (134, 137))
139184	30139373	observed epigenetic inactivation of MT3 via promoter hypermethylation in pediatric acute myeloid leukemia, and MT3 could act as a tumor suppressor by inhibiting tumor cell proliferation and inducing apoptosis.	('MT3', 'Gene', '4504', (36, 39))	('myeloid leukemia', 'Disease', 'MESH:D007951', (89, 105))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (89, 105))	('tumor', 'Disease', (130, 135))	('tumor', 'Disease', (161, 166))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('MT3', 'Gene', (111, 114))	('inducing', 'Reg', (190, 198))	('promoter hypermethylation', 'Var', (44, 69))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('epigenetic inactivation', 'Var', (9, 32))	('MT3', 'Gene', (36, 39))	('inhibiting', 'NegReg', (150, 160))	('myeloid leukemia', 'Disease', (89, 105))	('MT3', 'Gene', '4504', (111, 114))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (83, 105))	('leukemia', 'Phenotype', 'HP:0001909', (97, 105))	('apoptosis', 'CPA', (199, 208))
139194	30139373	found that single nucleotide polymorphism (SNP) (rs28336003) could affect the expression of MT2A in prostate cancer and that this may be associated with metal accumulation, causing the cells to lose protection against heavy metal toxicity and carcinogenicity.	('associated', 'Reg', (137, 147))	('toxicity', 'Disease', 'MESH:D064420', (230, 238))	('lose', 'NegReg', (194, 198))	('protection against', 'CPA', (199, 217))	('metal', 'Chemical', 'MESH:D008670', (224, 229))	('single nucleotide polymorphism', 'Var', (11, 41))	('rs28336003', 'Var', (49, 59))	('MT2A', 'Gene', '4502', (92, 96))	('carcinogenicity', 'CPA', (243, 258))	('rs28336003', 'Mutation', 'rs28336003', (49, 59))	('toxicity', 'Disease', (230, 238))	('affect', 'Reg', (67, 73))	('MT2A', 'Gene', (92, 96))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('prostate cancer', 'Disease', 'MESH:D011471', (100, 115))	('expression', 'MPA', (78, 88))	('prostate cancer', 'Phenotype', 'HP:0012125', (100, 115))	('metal', 'Chemical', 'MESH:D008670', (153, 158))	('prostate cancer', 'Disease', (100, 115))
139195	30139373	As described above, many potential molecular mechanisms of MTs in tumorigenesis have been reported by scholars (Table 3), but countless challenges remain to be overcome.	('tumor', 'Disease', (66, 71))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('MTs', 'Var', (59, 62))
139205	30139373	reported that silencing the MT2A gene by siRNAs induced entosis (the internalization of a cell into another cell) in breast cancer, and this result may provide new insights into strategies to limit tumor cell growth.	('silencing', 'Var', (14, 23))	('internalization of a', 'MPA', (69, 89))	('entosis', 'Disease', (56, 63))	('MT2A', 'Gene', '4502', (28, 32))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('breast cancer', 'Disease', 'MESH:D001943', (117, 130))	('MT2A', 'Gene', (28, 32))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('siRNAs', 'Gene', (41, 47))	('breast cancer', 'Disease', (117, 130))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('breast cancer', 'Phenotype', 'HP:0003002', (117, 130))	('tumor', 'Disease', (198, 203))	('entosis', 'Disease', 'None', (56, 63))	('induced', 'Reg', (48, 55))
139207	30139373	Antisense approaches targeting unique mRNA molecules are intended to reduce the expression of specific proteins, and this strategy is possibly applicable for cancer therapy.	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('specific', 'Protein', (94, 102))	('cancer', 'Disease', (158, 164))	('expression of', 'MPA', (80, 93))	('reduce', 'NegReg', (69, 75))	('Antisense', 'Var', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('mRNA', 'Protein', (38, 42))
139208	30139373	The downregulation of MTs by antisense approaches has been shown to induce growth inhibition in breast cancer cells, leukemia cells, and nasopharyngeal cancer.	('nasopharyngeal cancer', 'Phenotype', 'HP:0100630', (137, 158))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('growth inhibition', 'CPA', (75, 92))	('leukemia', 'Phenotype', 'HP:0001909', (117, 125))	('breast cancer', 'Disease', 'MESH:D001943', (96, 109))	('leukemia', 'Disease', 'MESH:D007938', (117, 125))	('nasopharyngeal cancer', 'Disease', (137, 158))	('leukemia', 'Disease', (117, 125))	('downregulation', 'NegReg', (4, 18))	('breast cancer', 'Disease', (96, 109))	('MTs', 'Gene', (22, 25))	('nasopharyngeal cancer', 'Disease', 'MESH:D009303', (137, 158))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('breast cancer', 'Phenotype', 'HP:0003002', (96, 109))	('antisense approaches', 'Var', (29, 49))
139215	30139373	However, the data on the relationship between MT expression and tumor types are variable, that is, MT expression is not universal in all human cancers not only because the functions of MTs are isoform- and tissue-specific but also because MT expression varies with different environmental stimuli or gene mutations and interactions with other cell signaling pathways or the tumor microenvironment.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('human', 'Species', '9606', (137, 142))	('tumor', 'Disease', (64, 69))	('tumor', 'Disease', (374, 379))	('interactions', 'Interaction', (319, 331))	('tumor', 'Phenotype', 'HP:0002664', (374, 379))	('cancers', 'Disease', 'MESH:D009369', (143, 150))	('tumor', 'Disease', 'MESH:D009369', (374, 379))	('mutations', 'Var', (305, 314))	('cancers', 'Phenotype', 'HP:0002664', (143, 150))	('cancers', 'Disease', (143, 150))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('varies', 'Reg', (253, 259))
139227	27270440	Exogenous TGFbeta promotes EMT in a unique pathway of PRMT5-MEP50 catalyzed histone mono- and dimethylation of chromatin at key metastasis suppressor and EMT genes, defining a new mechanism regulating cancer invasivity.	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('Exogenous', 'Var', (0, 9))	('EMT', 'Gene', (27, 30))	('TGFbeta', 'Gene', '7040', (10, 17))	('cancer', 'Disease', (201, 207))	('EMT', 'Gene', '3702', (27, 30))	('PRMT5', 'Gene', (54, 59))	('promotes', 'PosReg', (18, 26))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('MEP50', 'Gene', '79084', (60, 65))	('TGFbeta', 'Gene', (10, 17))	('MEP50', 'Gene', (60, 65))	('PRMT5', 'Gene', '10419', (54, 59))	('EMT', 'Gene', (154, 157))	('EMT', 'Gene', '3702', (154, 157))
139228	27270440	PRMT5 methylation of histone H3R2me1 induced transcriptional activation by recruitment of WDR5 and concomitant H3K4 methylation at targeted genes.	('histone H3R2me1', 'Protein', (21, 36))	('activation', 'PosReg', (61, 71))	('PRMT5', 'Gene', (0, 5))	('methylation', 'Var', (6, 17))	('WDR5', 'Gene', '11091', (90, 94))	('PRMT5', 'Gene', '10419', (0, 5))	('recruitment', 'PosReg', (75, 86))	('WDR5', 'Gene', (90, 94))	('H3K4 methylation', 'MPA', (111, 127))	('transcriptional', 'MPA', (45, 60))
139231	27270440	Alterations in the histone code signaling of epigenetic information is highly correlated with cancer etiology and the epithelial-to-mesenchymal transition (EMT) that leads to metastasis .	('Alterations', 'Var', (0, 11))	('epithelial-to-mesenchymal transition', 'CPA', (118, 154))	('cancer', 'Disease', 'MESH:D009369', (94, 100))	('metastasis', 'CPA', (175, 185))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('EMT', 'Gene', (156, 159))	('EMT', 'Gene', '3702', (156, 159))	('correlated', 'Reg', (78, 88))	('cancer', 'Disease', (94, 100))	('histone code signaling', 'MPA', (19, 41))
139232	27270440	Arginine methylation is a significant regulator of biological function  and of oncogenesis and tumor progression .	('Arginine', 'Chemical', 'MESH:D001120', (0, 8))	('Arginine', 'Var', (0, 8))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Disease', (95, 100))
139235	27270440	H4R3me2a and H3R2me2s have been correlated with transcriptional activation, while H4R3me2s, H3R2me2a, and H3R8me2s repress transcription .	('H3R2me2s', 'Var', (13, 21))	('transcriptional activation', 'MPA', (48, 74))	('H4R3me2a', 'Var', (0, 8))	('transcription', 'MPA', (123, 136))	('H4R3me2s', 'Var', (82, 90))	('H3R8me2s', 'Var', (106, 114))	('repress', 'NegReg', (115, 122))	('H4R3me2s', 'Chemical', '-', (82, 90))	('H3R2me2a', 'Var', (92, 100))
139245	27270440	To systematically identify the major human cancers correlated with altered PRMT5 and MEP50 expression, we probed The Cancer Genome Atlas (TCGA) and determined that lung cancers had the most significant positive alteration in expression (Figure 1A) .	('lung cancers', 'Disease', (164, 176))	('expression', 'MPA', (91, 101))	('cancers', 'Disease', (169, 176))	('cancers', 'Phenotype', 'HP:0002664', (43, 50))	('cancers', 'Disease', (43, 50))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (117, 136))	('lung cancers', 'Phenotype', 'HP:0100526', (164, 176))	('expression', 'MPA', (225, 235))	('Cancer Genome Atlas', 'Disease', (117, 136))	('PRMT5', 'Gene', (75, 80))	('altered', 'Var', (67, 74))	('cancers', 'Disease', 'MESH:D009369', (169, 176))	('cancers', 'Disease', 'MESH:D009369', (43, 50))	('human', 'Species', '9606', (37, 42))	('Cancer', 'Phenotype', 'HP:0002664', (117, 123))	('MEP50', 'Gene', (85, 90))	('lung cancer', 'Phenotype', 'HP:0100526', (164, 175))	('lung cancers', 'Disease', 'MESH:D008175', (164, 176))	('PRMT5', 'Gene', '10419', (75, 80))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('MEP50', 'Gene', '79084', (85, 90))	('cancers', 'Phenotype', 'HP:0002664', (169, 176))
139252	27270440	A549 cells had elevated PRMT5 and MEP50 compared with IMR90 cells and also had increased H3R2me2s and H2A/H4 R3me2s, PRMT5-catalyzed histone PTMs previously shown to up- and down-regulate transcription, respectively (Figure 1E).	('PRMT5', 'Gene', '10419', (117, 122))	('transcription', 'MPA', (188, 201))	('increased', 'PosReg', (79, 88))	('elevated', 'PosReg', (15, 23))	('MEP50', 'Gene', (34, 39))	('IMR90', 'CellLine', 'CVCL:0347', (54, 59))	('H3R2me2s', 'Protein', (89, 97))	('MEP50', 'Gene', '79084', (34, 39))	('A549', 'CellLine', 'CVCL:0023', (0, 4))	('PRMT5', 'Gene', (24, 29))	('down-regulate', 'NegReg', (174, 187))	('PTMs', 'Gene', '5763', (141, 145))	('PRMT5', 'Gene', '10419', (24, 29))	('A549', 'Var', (0, 4))	('up-', 'PosReg', (166, 169))	('PTMs', 'Gene', (141, 145))	('PRMT5', 'Gene', (117, 122))	('H2A/H4 R3me2s', 'Protein', (102, 115))
139255	27270440	PRMT5 knockdown caused loss of MEP50 expression while MEP50 knockdown caused PRMT5 loss, confirming the obligate pairing of these proteins .	('MEP50', 'Gene', '79084', (31, 36))	('MEP50', 'Gene', (31, 36))	('PRMT5', 'Gene', (77, 82))	('PRMT5', 'Gene', (0, 5))	('PRMT5', 'Gene', '10419', (77, 82))	('loss', 'NegReg', (23, 27))	('knockdown', 'Var', (60, 69))	('MEP50', 'Gene', '79084', (54, 59))	('MEP50', 'Gene', (54, 59))	('knockdown', 'Var', (6, 15))	('expression', 'MPA', (37, 47))	('PRMT5', 'Gene', '10419', (0, 5))	('loss', 'NegReg', (83, 87))
139256	27270440	Knockdown of PRMT5 did not result in free MEP50 nor did MEP50 knockdown result in free PRMT5 or other subcomplexes (Figure 1H).	('MEP50', 'Gene', '79084', (42, 47))	('MEP50', 'Gene', (42, 47))	('PRMT5', 'Gene', '10419', (87, 92))	('MEP50', 'Gene', '79084', (56, 61))	('MEP50', 'Gene', (56, 61))	('PRMT5', 'Gene', (13, 18))	('PRMT5', 'Gene', '10419', (13, 18))	('PRMT5', 'Gene', (87, 92))	('knockdown', 'Var', (62, 71))
139258	27270440	We tested compensatory expression of other PRMTs by comparing FPKM of the PRMT genes from each replicate, validating the targeted knockdown of PRMT5 and MEP50 (Figure 2A).	('MEP50', 'Gene', '79084', (153, 158))	('knockdown', 'Var', (130, 139))	('MEP50', 'Gene', (153, 158))	('PRMT5', 'Gene', (143, 148))	('PRMT5', 'Gene', '10419', (143, 148))
139259	27270440	We measured the differentially expressed genes in these cells using the overlap of DESeq2 and edgeR output (Figure 2B, padj <0.01) and confirmed that the replicates of the PRMT5 and MEP50 knockdown RNA-Seq are highly correlated (DESeq2 clustering, Supplemental Figure S2A).	('MEP50', 'Gene', '79084', (182, 187))	('MEP50', 'Gene', (182, 187))	('knockdown', 'Var', (188, 197))	('PRMT5', 'Gene', (172, 177))	('PRMT5', 'Gene', '10419', (172, 177))
139265	27270440	Genes involved in cellular adhesion, typically downregulated in lung cancer, were upregulated in the knockdowns (normalized enrichment score = +2.5), while genes known to be upregulated in kras mutated lung and breast cancers were downregulated in the knockdowns (NES = -1.69) (Figure 2F).	('lung', 'Disease', (202, 206))	('lung cancer', 'Disease', (64, 75))	('lung cancer', 'Phenotype', 'HP:0100526', (64, 75))	('knockdowns', 'Var', (101, 111))	('downregulated', 'NegReg', (47, 60))	('cancers', 'Phenotype', 'HP:0002664', (218, 225))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('upregulated', 'PosReg', (82, 93))	('lung cancer', 'Disease', 'MESH:D008175', (64, 75))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('mutated', 'Var', (194, 201))	('breast cancers', 'Phenotype', 'HP:0003002', (211, 225))	('cellular adhesion', 'Protein', (18, 35))	('breast cancer', 'Phenotype', 'HP:0003002', (211, 224))	('breast cancers', 'Disease', 'MESH:D001943', (211, 225))	('breast cancers', 'Disease', (211, 225))
139268	27270440	Highly significant upregulated GO terms upon PRMT5-MEP50 knockdown included cell adhesion, differentiation, and extracellular matrix organization, while downregulated GO terms included cell-cell signaling, proliferation, and metabolic processes (Figure 2G).	('upregulated', 'PosReg', (19, 30))	('PRMT5', 'Gene', '10419', (45, 50))	('metabolic processes', 'CPA', (225, 244))	('proliferation', 'CPA', (206, 219))	('MEP50', 'Gene', '79084', (51, 56))	('MEP50', 'Gene', (51, 56))	('cell adhesion', 'CPA', (76, 89))	('knockdown', 'Var', (57, 66))	('differentiation', 'CPA', (91, 106))	('extracellular matrix organization', 'CPA', (112, 145))	('cell-cell signaling', 'CPA', (185, 204))	('PRMT5', 'Gene', (45, 50))	('downregulated', 'NegReg', (153, 166))
139272	27270440	First, we demonstrated that PRMT5 and MEP50 knockdowns have modest, but significant negative effects on proliferation after 6 days of culture (Figure 3A).	('MEP50', 'Gene', '79084', (38, 43))	('proliferation', 'CPA', (104, 117))	('knockdowns', 'Var', (44, 54))	('PRMT5', 'Gene', (28, 33))	('PRMT5', 'Gene', '10419', (28, 33))	('negative', 'NegReg', (84, 92))	('MEP50', 'Gene', (38, 43))
139273	27270440	To test anchorage-independent growth behavior, we performed a soft-agar colony formation assay in which we observed a dramatic and significant loss of colony formation in both PRMT5 and MEP50 knockdowns (Figure 3B and Figure S3A), consistent with loss of cell autonomous behavior in the knockdowns.	('PRMT5', 'Gene', '10419', (176, 181))	('MEP50', 'Gene', '79084', (186, 191))	('knockdowns', 'Var', (192, 202))	('MEP50', 'Gene', (186, 191))	('colony formation', 'CPA', (151, 167))	('loss', 'NegReg', (143, 147))	('PRMT5', 'Gene', (176, 181))
139274	27270440	We observed pronounced and significant loss of migration (Figure 3C) and invasion through Matrigel (Figure 3D) in the PRMT5 and MEP50 knockdowns compared with the control, consistent with our hypothesis.	('PRMT5', 'Gene', (118, 123))	('knockdowns', 'Var', (134, 144))	('PRMT5', 'Gene', '10419', (118, 123))	('MEP50', 'Gene', (128, 133))	('loss of migration', 'Disease', (39, 56))	('MEP50', 'Gene', '79084', (128, 133))	('invasion through Matrigel', 'CPA', (73, 98))	('loss of migration', 'Disease', 'MESH:D014085', (39, 56))
139276	27270440	Loss of either PRMT5 or MEP50 dramatically and significantly reduced the rate of growth and the spheroid volume of the cultured cells embedded in Matrigel (Figure 3F).	('MEP50', 'Gene', '79084', (24, 29))	('PRMT5', 'Gene', (15, 20))	('PRMT5', 'Gene', '10419', (15, 20))	('rate of growth', 'CPA', (73, 87))	('Loss', 'Var', (0, 4))	('reduced', 'NegReg', (61, 68))	('MEP50', 'Gene', (24, 29))
139279	27270440	To provide additional support for this hypothesis we used GSK591/EPZ015866, a recently developed potent and specific PRMT5 chemical probe .	('PRMT5', 'Gene', '10419', (117, 122))	('GSK591', 'Chemical', '-', (58, 64))	('PRMT5', 'Gene', (117, 122))	('GSK591/EPZ015866', 'Var', (58, 74))
139286	27270440	After 2 days of TGFbeta treatment we observed non-contacting cells in the GFPkd control but adhering cells in the PRMT5 and MEP50 knockdowns (Figure 4A).	('PRMT5', 'Gene', (114, 119))	('PRMT5', 'Gene', '10419', (114, 119))	('MEP50', 'Gene', '79084', (124, 129))	('MEP50', 'Gene', (124, 129))	('knockdowns', 'Var', (130, 140))	('TGFbeta', 'Gene', '7040', (16, 23))	('TGFbeta', 'Gene', (16, 23))
139299	27270440	TGFbeta caused much higher levels of H3R2me1 (of currently unknown function), H3R2me2s (correlated with gene activation), and H4R3me2s (correlated with gene repression) histone PTMs (Figure 5A, bottom blots).	('PTMs', 'Gene', (177, 181))	('H3R2me1', 'MPA', (37, 44))	('H3R2me2s', 'MPA', (78, 86))	('H4R3me2s', 'Var', (126, 134))	('TGFbeta', 'Gene', (0, 7))	('higher', 'PosReg', (20, 26))	('PTMs', 'Gene', '5763', (177, 181))	('TGFbeta', 'Gene', '7040', (0, 7))	('H4R3me2s', 'Chemical', '-', (126, 134))
139301	27270440	These experiments showed that H3R2me1, H3R2me2s, and H4R3me2s were all dependent on PRMT5 activity (Figure 5B bottom blots), as were the loss of expression of E-cadherin protein and gain of expression of Vimentin and Snail proteins, key players in EMT.	('H4R3me2s', 'Var', (53, 61))	('PRMT5', 'Gene', (84, 89))	('E-cadherin', 'Gene', '999', (159, 169))	('gain', 'PosReg', (182, 186))	('Snail', 'Gene', (217, 222))	('EMT', 'Gene', (248, 251))	('Vimentin', 'Gene', (204, 212))	('PRMT5', 'Gene', '10419', (84, 89))	('EMT', 'Gene', '3702', (248, 251))	('expression', 'MPA', (145, 155))	('Snail', 'Gene', '6615', (217, 222))	('loss', 'NegReg', (137, 141))	('H4R3me2s', 'Chemical', '-', (53, 61))	('Vimentin', 'Gene', '7431', (204, 212))	('expression', 'MPA', (190, 200))	('E-cadherin', 'Gene', (159, 169))
139307	27270440	To test this hypothesis, we designed methylarginine chromatin-immunoprecipitation (ChIP) studies at key genes around their promoter elements (-1kb, TSS, and +1kb) in the presence or absence of TGFbeta and in the PRMT5 and MEP50 knockdowns.	('TGFbeta', 'Gene', (193, 200))	('methylarginine', 'Chemical', '-', (37, 51))	('TGFbeta', 'Gene', '7040', (193, 200))	('PRMT5', 'Gene', (212, 217))	('-1kb', 'Var', (142, 146))	('MEP50', 'Gene', '79084', (222, 227))	('MEP50', 'Gene', (222, 227))	('PRMT5', 'Gene', '10419', (212, 217))
139312	27270440	These observations strongly suggested that PRMT5 histone methylation may directly regulate transcription of these target genes.	('transcription', 'MPA', (91, 104))	('methylation', 'Var', (57, 68))	('regulate', 'Reg', (82, 90))	('PRMT5', 'Gene', (43, 48))	('PRMT5', 'Gene', '10419', (43, 48))	('histone', 'Protein', (49, 56))
139313	27270440	We therefore systematically used ChIP to probe known PRMT5-catalyzed PTMs including H3R2me1, H3R2me2s, H3R8me2s, H4R3me1, H4R3me2s, and the asymmetric mark H4R3me2a as a negative control for PRMT5 activity, on targeted genes (Figure 6C).	('H4R3me1', 'Var', (113, 120))	('PTMs', 'Gene', '5763', (69, 73))	('PRMT5', 'Gene', (53, 58))	('PRMT5', 'Gene', (191, 196))	('PRMT5', 'Gene', '10419', (53, 58))	('H4R3me2s', 'Var', (122, 130))	('PRMT5', 'Gene', '10419', (191, 196))	('H3R2me2s', 'Var', (93, 101))	('H3R8me2s', 'Var', (103, 111))	('PTMs', 'Gene', (69, 73))	('H4R3me2s', 'Chemical', '-', (122, 130))
139314	27270440	TGFbeta silenced genes were strikingly enriched in the H4R3me2s silencing mark in the control cells but not the knockdown cells (Figure 6C), while we observed enrichment of the previously unexplored H3R2me1 in TGFbeta activated EMT genes (Figure 6C).	('TGFbeta', 'Gene', '7040', (210, 217))	('activated', 'PosReg', (218, 227))	('TGFbeta', 'Gene', (0, 7))	('EMT', 'Gene', (228, 231))	('H4R3me2s', 'Var', (55, 63))	('TGFbeta', 'Gene', (210, 217))	('silencing', 'NegReg', (64, 73))	('EMT', 'Gene', '3702', (228, 231))	('TGFbeta', 'Gene', '7040', (0, 7))	('H4R3me2s', 'Chemical', '-', (55, 63))
139315	27270440	To highlight this novel independent up- and down-regulation of key metastasis markers by the same enzyme targeting distinct histone modifications, ChIP-qPCR for H3R2me1, H4R3me2s, and H3 are shown for CDH1 and SPDEF (downregulated by TGFbeta) and SNAIL1 and VIM (upregulated by TGFbeta) (Figure 6D and Supplementary Figure S5B).	('downregulated', 'NegReg', (217, 230))	('VIM', 'Gene', '7431', (258, 261))	('TGFbeta', 'Gene', (278, 285))	('VIM', 'Gene', (258, 261))	('H3R2me1', 'Var', (161, 168))	('TGFbeta', 'Gene', '7040', (278, 285))	('SNAIL1', 'Gene', '6615', (247, 253))	('CDH1', 'Gene', '999', (201, 205))	('SNAIL1', 'Gene', (247, 253))	('SPDEF', 'Gene', '25803', (210, 215))	('H4R3me2s', 'Chemical', '-', (170, 178))	('down-regulation', 'NegReg', (44, 59))	('CDH1', 'Gene', (201, 205))	('TGFbeta', 'Gene', (234, 241))	('TGFbeta', 'Gene', '7040', (234, 241))	('SPDEF', 'Gene', (210, 215))	('upregulated', 'PosReg', (263, 274))	('up-', 'PosReg', (36, 39))	('H4R3me2s', 'Var', (170, 178))
139318	27270440	The structure of H3R2me2s bound to WDR5 suggested that H3R2me1 may also recruit WDR5 through a similar mechanism, so we hypothesized that H3R2me1 may promote H3K4me3 and stimulate transcription.	('promote', 'PosReg', (150, 157))	('H3R2me1', 'Var', (138, 145))	('transcription', 'MPA', (180, 193))	('WDR5', 'Gene', '11091', (35, 39))	('WDR5', 'Gene', '11091', (80, 84))	('stimulate', 'PosReg', (170, 179))	('H3K4me3', 'Protein', (158, 165))	('WDR5', 'Gene', (35, 39))	('WDR5', 'Gene', (80, 84))
139320	27270440	Strikingly, both WDR5 inhibition or depletion partially abrogated the TGFbeta stimulation of Snail and Vimentin expression (Figure 7B,C), consistent with our hypothesis that PRMT5-catalyzed H3R2me1 is responsible for their upregulation.	('TGFbeta', 'Gene', '7040', (70, 77))	('stimulation', 'PosReg', (78, 89))	('abrogated', 'NegReg', (56, 65))	('Vimentin', 'Gene', (103, 111))	('depletion', 'Var', (36, 45))	('WDR5', 'Gene', (17, 21))	('Snail', 'Gene', (93, 98))	('Vimentin', 'Gene', '7431', (103, 111))	('PRMT5', 'Gene', (174, 179))	('TGFbeta', 'Gene', (70, 77))	('Snail', 'Gene', '6615', (93, 98))	('PRMT5', 'Gene', '10419', (174, 179))	('WDR5', 'Gene', '11091', (17, 21))
139321	27270440	To directly test this mechanism, we ChIPed H3R2me1 and H3K4me3 in the control and PRMT5kd A549 cells and probed Snail and Vimentin.	('Snail', 'Gene', '6615', (112, 117))	('Snail', 'Gene', (112, 117))	('Vimentin', 'Gene', '7431', (122, 130))	('PRMT5', 'Gene', (82, 87))	('A549', 'CellLine', 'CVCL:0023', (90, 94))	('PRMT5', 'Gene', '10419', (82, 87))	('H3R2me1', 'Protein', (43, 50))	('H3K4me3', 'Var', (55, 62))	('Vimentin', 'Gene', (122, 130))
139331	27270440	Symmetric dimethylation of histones H2A and H4 on R3 or histone H3 on R8, and asymmetric dimethylation of H3R2, repress transcription .	('H3R2', 'Gene', (106, 110))	('transcription', 'MPA', (120, 133))	('H2A and H4 on R3', 'Gene', '8337', (36, 52))	('histone H3', 'Protein', (56, 66))	('asymmetric dimethylation', 'Var', (78, 102))	('repress', 'NegReg', (112, 119))	('Symmetric', 'Var', (0, 9))
139332	27270440	Conversely, we showed here that H3R2me1 and others have shown that H3R2me2s promote transcription by recruiting the WDR5 and the MLL methyltransferase that is responsible for transcriptional activation by H3K4 methylation .	('promote', 'PosReg', (76, 83))	('WDR5', 'Gene', '11091', (116, 120))	('MLL', 'Gene', (129, 132))	('WDR5', 'Gene', (116, 120))	('H3R2me1', 'Var', (32, 39))	('transcription', 'MPA', (84, 97))	('H3R2me2s', 'Var', (67, 75))	('recruiting', 'PosReg', (101, 111))	('MLL', 'Gene', '4297', (129, 132))
139333	27270440	Multiple PRMTs target similar residues with altered modification state (for example, H4 is monomethylated by PRMTs 1,5,7, asymmetric-dimethylated by PRMT1 and symmetric dimethylated by PRMT5).	('monomethylated', 'MPA', (91, 105))	('PRMT1', 'Gene', '3276', (149, 154))	('PRMT5', 'Gene', (185, 190))	('asymmetric-dimethylated', 'Var', (122, 145))	('PRMT1', 'Gene', (149, 154))	('PRMT5', 'Gene', '10419', (185, 190))
139337	27270440	In vitro, PRMT5-MEP50 methylates H2A and H4, but not H3 .	('methylates', 'Var', (22, 32))	('H2A and H4', 'Gene', '8337', (33, 43))	('MEP50', 'Gene', '79084', (16, 21))	('MEP50', 'Gene', (16, 21))	('PRMT5', 'Gene', (10, 15))	('PRMT5', 'Gene', '10419', (10, 15))
139339	27270440	Our conclusions are important in that PRMT5-catalyzed histone methylation can simultaneously upregulate transcription through histone H3R2 methylation and repress transcription through H4R3 methylation, on independent genes in common biological pathways.	('H3R2', 'Protein', (134, 138))	('PRMT5', 'Gene', '10419', (38, 43))	('repress', 'NegReg', (155, 162))	('methylation', 'Var', (62, 73))	('transcription', 'MPA', (104, 117))	('transcription', 'MPA', (163, 176))	('methylation', 'Var', (139, 150))	('histone H3R2', 'Protein', (126, 138))	('H4R3', 'Protein', (185, 189))	('PRMT5', 'Gene', (38, 43))	('upregulate', 'PosReg', (93, 103))
139343	27270440	We also provide strong evidence for the essential partnership between PRMT5 and MEP50 as both knockdowns elicit identical phenotypes to each other and to drug treatment.	('knockdowns', 'Var', (94, 104))	('elicit', 'Reg', (105, 111))	('PRMT5', 'Gene', '10419', (70, 75))	('MEP50', 'Gene', '79084', (80, 85))	('MEP50', 'Gene', (80, 85))	('PRMT5', 'Gene', (70, 75))
139356	27270440	siRNA depletion of WDR5 in A549 was performed according to the manufacturer's instructions with siRNA negative control (Ambion, 4390843) and WDR5-Silencer  Select Pre-Designed & Validated siRNA (Ambion, 4392420 with siRNA ID s21862 and s21863).	('A549', 'CellLine', 'CVCL:0023', (27, 31))	('WDR5', 'Gene', (19, 23))	('WDR5-Silencer', 'Disease', 'None', (141, 154))	('WDR5', 'Gene', '11091', (141, 145))	('and s21863', 'Var', (232, 242))	('WDR5', 'Gene', '11091', (19, 23))	('WDR5-Silencer', 'Disease', (141, 154))	('WDR5', 'Gene', (141, 145))
139377	26926340	Then the shRNA specific for BDNF was transfected into LK2 or A549 cells to further elucidate the BDNF knockdown on cell proliferation, apoptosis and invasion, which were confirmed by MTT, flow cytometry and transwell examinations.	('apoptosis', 'CPA', (135, 144))	('invasion', 'CPA', (149, 157))	('knockdown', 'Var', (102, 111))	('BDNF', 'Gene', '627', (28, 32))	('BDNF', 'Gene', '627', (97, 101))	('cell proliferation', 'CPA', (115, 133))	('MTT', 'Chemical', 'MESH:C070243', (183, 186))	('BDNF', 'Gene', (28, 32))	('A549', 'CellLine', 'CVCL:0023', (61, 65))	('BDNF', 'Gene', (97, 101))
139403	26926340	Moreover, the BDNF mRNA variant containing exon IX was important to the higher expression in SCC cells, and BDNF was critical to the proliferation and invasion of lung cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('lung cancer', 'Disease', 'MESH:D008175', (163, 174))	('expression', 'MPA', (79, 89))	('SCC', 'Gene', '6317', (93, 96))	('SCC', 'Gene', (93, 96))	('BDNF', 'Gene', '627', (14, 18))	('SCC', 'Phenotype', 'HP:0002860', (93, 96))	('invasion', 'CPA', (151, 159))	('lung cancer', 'Phenotype', 'HP:0100526', (163, 174))	('BDNF', 'Gene', '627', (108, 112))	('higher', 'PosReg', (72, 78))	('lung cancer', 'Disease', (163, 174))	('BDNF', 'Gene', (14, 18))	('exon', 'Var', (43, 47))	('BDNF', 'Gene', (108, 112))
139416	26926340	LK2 and A549 cells were selected to perform the establishment of stable cell strain with BDNF knockdown for their better condition and vitality.	('BDNF', 'Gene', (89, 93))	('knockdown', 'Var', (94, 103))	('A549', 'CellLine', 'CVCL:0023', (8, 12))	('BDNF', 'Gene', '627', (89, 93))
139464	26926340	Statistical analysis proved that SK and LK2 cells expressed more BDNF variant IX than HBE, A549 and LTE cells (p = 0.000).	('BDNF', 'Gene', (65, 69))	('HBE', 'Gene', '3046', (86, 89))	('BDNF', 'Gene', '627', (65, 69))	('HBE', 'Gene', (86, 89))	('variant', 'Var', (70, 77))	('A549', 'CellLine', 'CVCL:0023', (91, 95))
139468	26926340	According to the cell growth curves during the 5 days, we found that both LK2 and A549 cells with BDNF-shRNA transfection showed a decreased proliferative activity compared with other groups.	('BDNF', 'Gene', '627', (98, 102))	('transfection', 'Var', (109, 121))	('decreased', 'NegReg', (131, 140))	('BDNF', 'Gene', (98, 102))	('A549', 'CellLine', 'CVCL:0023', (82, 86))	('proliferative activity', 'CPA', (141, 163))
139469	26926340	When retreated with rhBDNF, BDNF knockdown LK2 or A549 cells showed enhanced proliferative abilities (Fig.	('BDNF', 'Gene', '627', (22, 26))	('enhanced', 'PosReg', (68, 76))	('proliferative abilities', 'CPA', (77, 100))	('knockdown', 'Var', (33, 42))	('BDNF', 'Gene', (22, 26))	('BDNF', 'Gene', '627', (28, 32))	('A549', 'CellLine', 'CVCL:0023', (50, 54))	('BDNF', 'Gene', (28, 32))
139474	26926340	When retreated with rhBDNF, the apoptotic LK2 or A549 cells with BDNF knockdown were apparently reduced (Fig.	('BDNF', 'Gene', '627', (22, 26))	('apoptotic LK2', 'CPA', (32, 45))	('knockdown', 'Var', (70, 79))	('A549', 'CellLine', 'CVCL:0023', (49, 53))	('BDNF', 'Gene', (22, 26))	('BDNF', 'Gene', '627', (65, 69))	('BDNF', 'Gene', (65, 69))	('reduced', 'NegReg', (96, 103))
139479	26926340	These results showed that BDNF knockdown significantly attenuated the invasive ability of transfected cells.	('BDNF', 'Gene', '627', (26, 30))	('attenuated', 'NegReg', (55, 65))	('BDNF', 'Gene', (26, 30))	('invasive ability of transfected cells', 'CPA', (70, 107))	('knockdown', 'Var', (31, 40))
139484	26926340	Gotz R also revealed that the cooperation of TrkB and EGFR signaling enhances migration and dispersal of lung tumor cells.	('lung tumor', 'Disease', (105, 115))	('lung tumor', 'Disease', 'MESH:D008175', (105, 115))	('cooperation', 'Var', (30, 41))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('EGFR', 'Gene', '1956', (54, 58))	('TrkB', 'Gene', '4915', (45, 49))	('enhances', 'PosReg', (69, 77))	('lung tumor', 'Phenotype', 'HP:0100526', (105, 115))	('EGFR', 'Gene', (54, 58))	('TrkB', 'Gene', (45, 49))
139490	26926340	It has been reported that the positive TrkB staining in SCC correlated specifically with improved disease-specific survival and overall survival.	('improved', 'PosReg', (89, 97))	('disease-specific survival', 'CPA', (98, 123))	('positive', 'Var', (30, 38))	('SCC', 'Gene', (56, 59))	('overall survival', 'CPA', (128, 144))	('TrkB', 'Gene', '4915', (39, 43))	('TrkB', 'Gene', (39, 43))	('staining', 'Var', (44, 52))	('SCC', 'Phenotype', 'HP:0002860', (56, 59))	('SCC', 'Gene', '6317', (56, 59))
139498	26926340	As we expected, the SCC cells of LK2 and SK had more secretion of BDNF in supernatant, compared to HBE and the ADC cells of A549 and LTE.	('HBE', 'Gene', '3046', (99, 102))	('SCC', 'Gene', (20, 23))	('SCC', 'Phenotype', 'HP:0002860', (20, 23))	('A549', 'CellLine', 'CVCL:0023', (124, 128))	('HBE', 'Gene', (99, 102))	('SCC', 'Gene', '6317', (20, 23))	('LK2', 'Var', (33, 36))	('BDNF', 'Gene', '627', (66, 70))	('more', 'PosReg', (48, 52))	('BDNF', 'Gene', (66, 70))
139505	26926340	According to the previous research, three BDNF mRNA transcripts containing exons IV, VI or IX, which are expressed relatively higher in lung tissue, were selected to be examined in this study to evaluate the significance of the above variants to the higher expression of BDNF in lung cancer cells.	('lung cancer', 'Disease', 'MESH:D008175', (279, 290))	('higher', 'PosReg', (250, 256))	('variants', 'Var', (234, 242))	('BDNF', 'Gene', '627', (271, 275))	('expression', 'MPA', (257, 267))	('lung cancer', 'Disease', (279, 290))	('BDNF', 'Gene', '627', (42, 46))	('lung cancer', 'Phenotype', 'HP:0100526', (279, 290))	('BDNF', 'Gene', (271, 275))	('cancer', 'Phenotype', 'HP:0002664', (284, 290))	('BDNF', 'Gene', (42, 46))
139507	26926340	These results suggested that variant IX was responsible for the higher expression and secretion of BDNF protein, which was probably helpful to the development of SCC.	('expression', 'MPA', (71, 81))	('BDNF', 'Gene', '627', (99, 103))	('higher', 'PosReg', (64, 70))	('variant', 'Var', (29, 36))	('BDNF', 'Gene', (99, 103))	('SCC', 'Gene', (162, 165))	('SCC', 'Phenotype', 'HP:0002860', (162, 165))	('secretion', 'MPA', (86, 95))	('SCC', 'Gene', '6317', (162, 165))
139508	26926340	We have previously supported that blocking of receptor TrkB signaling inhibited invasion of A549 cells.	('TrkB', 'Gene', (55, 59))	('invasion of A549 cells', 'CPA', (80, 102))	('blocking', 'Var', (34, 42))	('TrkB', 'Gene', '4915', (55, 59))	('A549', 'CellLine', 'CVCL:0023', (92, 96))	('inhibited', 'NegReg', (70, 79))
139509	26926340	In this study, we explored the function of BDNF on proliferation, apoptosis and invasion by specific shRNA transfection in LK2 and A549 cells.	('BDNF', 'Gene', (43, 47))	('transfection', 'Var', (107, 119))	('A549', 'CellLine', 'CVCL:0023', (131, 135))	('BDNF', 'Gene', '627', (43, 47))
139511	26926340	Our data indicate that BDNF promotes cell proliferation and invasion, and silencing BDNF probably confers the disadvantage to the growth of lung cancer cells.	('lung cancer', 'Disease', (140, 151))	('lung cancer', 'Phenotype', 'HP:0100526', (140, 151))	('invasion', 'CPA', (60, 68))	('BDNF', 'Gene', (84, 88))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('BDNF', 'Gene', (23, 27))	('silencing', 'Var', (74, 83))	('lung cancer', 'Disease', 'MESH:D008175', (140, 151))	('BDNF', 'Gene', '627', (84, 88))	('cell proliferation', 'CPA', (37, 55))	('BDNF', 'Gene', '627', (23, 27))
139515	26926340	The LK2 and A549 cells with shBDNF transfection were stimulated by recombined human BDNF.	('BDNF', 'Gene', '627', (30, 34))	('BDNF', 'Gene', (84, 88))	('transfection', 'Var', (35, 47))	('BDNF', 'Gene', (30, 34))	('A549', 'CellLine', 'CVCL:0023', (12, 16))	('BDNF', 'Gene', '627', (84, 88))	('human', 'Species', '9606', (78, 83))
139524	25886188	Methylation of RASSF1A gene promoter and the correlation with DNMT1 expression that may contribute to esophageal squamous cell carcinoma Esophageal squamous cell carcinoma is one of the most common malignancies in the world.	('esophageal squamous cell carcinoma', 'Disease', (102, 136))	('contribute', 'Reg', (88, 98))	('DNMT1', 'Gene', '1786', (62, 67))	('carcinoma', 'Phenotype', 'HP:0030731', (162, 171))	('malignancies', 'Disease', (198, 210))	('RASSF1A', 'Gene', '11186', (15, 22))	('Methylation', 'Var', (0, 11))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (148, 171))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (113, 136))	('Esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (137, 171))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (102, 136))	('RASSF1A', 'Gene', (15, 22))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('malignancies', 'Disease', 'MESH:D009369', (198, 210))	('DNMT1', 'Gene', (62, 67))	('Esophageal squamous cell carcinoma', 'Disease', (137, 171))
139526	25886188	The objective is to detect methylation of the RASSF1A gene promoter and the expression of the DNA methyltransferase 1 (DNMT1) protein in esophageal cancer tissue and discuss their relationship with esophageal squamous cell carcinoma.	('RASSF1A', 'Gene', '11186', (46, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (223, 232))	('esophageal cancer', 'Disease', 'MESH:D004938', (137, 154))	('DNA methyltransferase 1', 'Gene', (94, 117))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('methylation', 'Var', (27, 38))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (198, 232))	('DNA methyltransferase 1', 'Gene', '1786', (94, 117))	('DNMT1', 'Gene', (119, 124))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (209, 232))	('RASSF1A', 'Gene', (46, 53))	('DNMT1', 'Gene', '1786', (119, 124))	('esophageal cancer', 'Disease', (137, 154))	('detect', 'Reg', (20, 26))	('esophageal squamous cell carcinoma', 'Disease', (198, 232))
139530	25886188	The RASSF1A gene promoter was highly methylated in cancer tissues, and there were significant differences between normal esophagus tissues and esophageal squamous carcinoma (P < 0.05).	('esophageal squamous carcinoma', 'Disease', (143, 172))	('esophageal squamous carcinoma', 'Phenotype', 'HP:0011459', (143, 172))	('carcinoma', 'Phenotype', 'HP:0030731', (163, 172))	('RASSF1A', 'Gene', (4, 11))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (154, 172))	('RASSF1A', 'Gene', '11186', (4, 11))	('differences', 'Reg', (94, 105))	('esophageal squamous carcinoma', 'Disease', 'MESH:D000077277', (143, 172))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('methylated', 'Var', (37, 47))
139533	25886188	In positive cases for methylation of RASSF1A, the DNMT1 protein had been detected in 41 out of 45 (91%), while in non-methylated cancer cases, 20 out of 55(36.3%), and the difference is significant (P < 0.05).	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('RASSF1A', 'Gene', (37, 44))	('RASSF1A', 'Gene', '11186', (37, 44))	('cancer', 'Disease', (129, 135))	('DNMT1', 'Gene', (50, 55))	('protein', 'Protein', (56, 63))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('DNMT1', 'Gene', '1786', (50, 55))	('methylation', 'Var', (22, 33))
139534	25886188	Esophageal squamous carcinoma tumorigenesis may be related with hypermethylation of DNMT1 and RASSF1A promoter CpG island due to their high expression and also their hypermethylation.	('carcinoma', 'Phenotype', 'HP:0030731', (20, 29))	('hypermethylation', 'MPA', (166, 182))	('expression', 'MPA', (140, 150))	('high', 'PosReg', (135, 139))	('DNMT1', 'Gene', (84, 89))	('DNMT1', 'Gene', '1786', (84, 89))	('Esophageal squamous carcinoma', 'Disease', 'MESH:D000077277', (0, 29))	('RASSF1A', 'Gene', (94, 101))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (11, 29))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('Esophageal squamous carcinoma', 'Phenotype', 'HP:0011459', (0, 29))	('hypermethylation', 'Var', (64, 80))	('Esophageal squamous carcinoma', 'Disease', (0, 29))	('RASSF1A', 'Gene', '11186', (94, 101))	('related', 'Reg', (51, 58))	('tumor', 'Disease', (30, 35))
139546	25886188	Using the known positive section as the positive criteria, PBS displaces the primary antibody as the negative criteria.	('displaces', 'NegReg', (63, 72))	('PBS', 'Var', (59, 62))	('PBS', 'Chemical', 'MESH:D007854', (59, 62))
139562	25886188	Previous studies have reported the involvement of RASSF1A promoter methylation in several cancers, including prostate, ovarian, endometrial, gastric, lung, and breast cancer.	('cancers', 'Disease', (90, 97))	('lung', 'Disease', (150, 154))	('endometrial', 'Disease', (128, 139))	('prostate', 'Disease', (109, 117))	('RASSF1A', 'Gene', '11186', (50, 57))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('cancers', 'Disease', 'MESH:D009369', (90, 97))	('gastric', 'Disease', (141, 148))	('RASSF1A', 'Gene', (50, 57))	('breast cancer', 'Disease', 'MESH:D001943', (160, 173))	('ovarian', 'Disease', (119, 126))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('breast cancer', 'Disease', (160, 173))	('involvement', 'Reg', (35, 46))	('breast cancer', 'Phenotype', 'HP:0003002', (160, 173))	('methylation', 'Var', (67, 78))
139565	25886188	It was conjectured that the promoter CpG island hypermethylation of RASSF1A in human esophageal squamous carcinoma plays a powerful role in the inactivation and transcriptional gene silencing of the RASSF1A gene.	('inactivation', 'NegReg', (144, 156))	('esophageal squamous carcinoma', 'Disease', (85, 114))	('human', 'Species', '9606', (79, 84))	('RASSF1A', 'Gene', (199, 206))	('esophageal squamous carcinoma', 'Phenotype', 'HP:0011459', (85, 114))	('RASSF1A', 'Gene', '11186', (68, 75))	('hypermethylation', 'Var', (48, 64))	('RASSF1A', 'Gene', '11186', (199, 206))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('esophageal squamous carcinoma', 'Disease', 'MESH:D000077277', (85, 114))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (96, 114))	('RASSF1A', 'Gene', (68, 75))
139566	25886188	But it does not exist in esophageal RASSF1A promoter methylation, and the gene expressed negatively in several patients with the possible mutual adjustment of a bit of a mutation and loss of heterozygosity.	('RASSF1A', 'Gene', '11186', (36, 43))	('mutation', 'Var', (170, 178))	('RASSF1A', 'Gene', (36, 43))	('negatively', 'NegReg', (89, 99))	('patients', 'Species', '9606', (111, 119))
139567	25886188	Not only did we focus on the status of RASSF1A methylation, but we also explored its possible mechanism preliminarily.	('RASSF1A', 'Gene', '11186', (39, 46))	('methylation', 'Var', (47, 58))	('RASSF1A', 'Gene', (39, 46))
139571	25886188	DNMT1 expression abnormalities may be involved in the process of esophageal cancer, but the development in the majority of esophageal cancers is related to multiple factors, genes, and multiple-step processes.	('esophageal cancers', 'Disease', (123, 141))	('esophageal cancer', 'Disease', (65, 82))	('cancers', 'Phenotype', 'HP:0002664', (134, 141))	('esophageal cancers', 'Disease', 'MESH:D004938', (123, 141))	('esophageal cancer', 'Disease', 'MESH:D004938', (123, 140))	('esophageal cancer', 'Disease', 'MESH:D004938', (65, 82))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('DNMT1', 'Gene', (0, 5))	('DNMT1', 'Gene', '1786', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('abnormalities', 'Var', (17, 30))
139576	25886188	And furthermore, we also found that in the positive cases for methylation of RASSF1A, the DNMT1 protein had overexpressed in non-methylated cancer cases with significant difference (41 DNMT1 positive cases in 45 RASSF1A positive cases).	('RASSF1A', 'Gene', '11186', (77, 84))	('RASSF1A', 'Gene', (212, 219))	('DNMT1', 'Gene', (90, 95))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('DNMT1', 'Gene', '1786', (90, 95))	('methylation', 'Var', (62, 73))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('overexpressed', 'PosReg', (108, 121))	('RASSF1A', 'Gene', '11186', (212, 219))	('DNMT1', 'Gene', (185, 190))	('DNMT1', 'Gene', '1786', (185, 190))	('RASSF1A', 'Gene', (77, 84))
139581	25886188	Epigenetics may play an important role in tumor diagnosis and treatment gradually.	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('Epigenetics', 'Var', (0, 11))	('tumor', 'Disease', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
139585	25886188	On the basis of prophase studies, future research should peg where certain methylation differences are associated with esophageal cancer, establish the esophageal-cancer-related gene methylation spectrum, and focus on DNMT's family roles and specific mechanisms.	('associated', 'Reg', (103, 113))	('esophageal cancer', 'Disease', 'MESH:D004938', (119, 136))	('esophageal-cancer', 'Disease', 'MESH:D004938', (152, 169))	('DNMT', 'Gene', '1786', (218, 222))	('peg', 'Chemical', '-', (57, 60))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('DNMT', 'Gene', (218, 222))	('methylation differences', 'Var', (75, 98))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('esophageal-cancer', 'Disease', (152, 169))	('esophageal cancer', 'Disease', (119, 136))
139594	32839509	FAM83H-AS1 silencing impairs two important breast cancer related pathways: cell migration and cell death.	('silencing', 'Var', (11, 20))	('breast cancer', 'Disease', (43, 56))	('breast cancer', 'Disease', 'MESH:D001943', (43, 56))	('breast cancer', 'Phenotype', 'HP:0003002', (43, 56))	('impairs', 'NegReg', (21, 28))	('FAM83H-AS1', 'Gene', '100128338', (0, 10))	('cell migration', 'CPA', (75, 89))	('cell death', 'CPA', (94, 104))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('FAM83H-AS1', 'Gene', (0, 10))
139595	32839509	Among the most relevant potential FAM83H-AS1 gene targets, we found p63 and claudin 1 (CLDN1) to be deregulated after FAM83H-AS1 knockdown.	('FAM83H-AS1', 'Gene', '100128338', (34, 44))	('FAM83H-AS1', 'Gene', (118, 128))	('CLDN1', 'Gene', '9076', (87, 92))	('knockdown', 'Var', (129, 138))	('p63', 'Gene', '8626', (68, 71))	('claudin 1', 'Gene', '9076', (76, 85))	('FAM83H-AS1', 'Gene', (34, 44))	('CLDN1', 'Gene', (87, 92))	('FAM83H-AS1', 'Gene', '100128338', (118, 128))	('deregulated', 'PosReg', (100, 111))	('claudin 1', 'Gene', (76, 85))	('p63', 'Gene', (68, 71))
139606	32839509	In this regard, recent papers have focused on the role of long non coding RNAs (lncRNAs) in cancer biology and in the role of specific lncRNAs in breast cancer.	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('long non coding RNAs', 'Var', (58, 78))	('cancer', 'Disease', (153, 159))	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('breast cancer', 'Disease', 'MESH:D001943', (146, 159))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('breast cancer', 'Disease', (146, 159))	('breast cancer', 'Phenotype', 'HP:0003002', (146, 159))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
139607	32839509	FAM83H-AS1 is a lncRNA whose expression impairs important cancer-related pathways such as cell proliferation, migration, invasion and cell death in lung, colorectal, glial, bladder, ovarian and cervical cancer cells.	('expression', 'Var', (29, 39))	('bladder', 'Disease', (173, 180))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('cell proliferation', 'CPA', (90, 108))	('cancer', 'Disease', 'MESH:D009369', (203, 209))	('migration', 'CPA', (110, 119))	('glial', 'Disease', (166, 171))	('FAM83H-AS1', 'Gene', '100128338', (0, 10))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('invasion', 'CPA', (121, 129))	('cell death', 'CPA', (134, 144))	('lung', 'Disease', (148, 152))	('cancer', 'Disease', (203, 209))	('ovarian and cervical cancer', 'Disease', 'MESH:D002575', (182, 209))	('FAM83H-AS1', 'Gene', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('impairs', 'NegReg', (40, 47))	('colorectal', 'Disease', (154, 164))	('cancer', 'Disease', (58, 64))
139608	32839509	At the molecular level, one report showed that MET/EGFR signaling is regulated by FAM83H-AS1, and showed that FAM83H-AS1 epigenetically silenced CDKN1A by binding to EZH2 in glioma cells.	('glioma', 'Disease', 'MESH:D005910', (174, 180))	('FAM83H-AS1', 'Gene', '100128338', (82, 92))	('glioma', 'Phenotype', 'HP:0009733', (174, 180))	('EGFR', 'Gene', (51, 55))	('binding', 'Interaction', (155, 162))	('CDKN1A', 'Gene', '1026', (145, 151))	('EGFR', 'Gene', '1956', (51, 55))	('FAM83H-AS1', 'Gene', (82, 92))	('glioma', 'Disease', (174, 180))	('EZH2', 'Gene', (166, 170))	('EZH2', 'Gene', '2146', (166, 170))	('silenced', 'NegReg', (136, 144))	('epigenetically', 'Var', (121, 135))	('CDKN1A', 'Gene', (145, 151))	('FAM83H-AS1', 'Gene', '100128338', (110, 120))	('FAM83H-AS1', 'Gene', (110, 120))
139627	32839509	Altogether, these widespread alterations in FAM83H-AS1 expression suggested that its expression could be a prognostic biomarker for all BRCA subtypes: but as mentioned above, FAM83H-AS1 was previously reported to have particular prognostic association with the BRCA luminal subtype.	('FAM83H-AS1', 'Gene', '100128338', (44, 54))	('FAM83H-AS1', 'Gene', '100128338', (175, 185))	('BRCA', 'Phenotype', 'HP:0003002', (261, 265))	('BRCA', 'Gene', '672', (261, 265))	('FAM83H-AS1', 'Gene', (44, 54))	('FAM83H-AS1', 'Gene', (175, 185))	('alterations', 'Var', (29, 40))	('BRCA', 'Gene', (261, 265))	('BRCA', 'Gene', '672', (136, 140))	('luminal', 'Chemical', 'MESH:D010634', (266, 273))	('BRCA', 'Phenotype', 'HP:0003002', (136, 140))	('BRCA', 'Gene', (136, 140))
139675	32839509	Caspase 3 assays identified a significantly increase in enzymatic activity (T-test; p = 0.032) after 72 h of FAM83H-AS1 silencing, which corroborates its role in apoptosis mediated cell death.	('FAM83H-AS1', 'Gene', '100128338', (109, 119))	('enzymatic activity', 'MPA', (56, 74))	('FAM83H-AS1', 'Gene', (109, 119))	('increase', 'PosReg', (44, 52))	('Caspase 3', 'Gene', (0, 9))	('silencing', 'Var', (120, 129))	('Caspase 3', 'Gene', '836', (0, 9))
139690	32839509	4) or after FAM83H-AS1 knockdown in MCF7 cells (Fig.	('FAM83H-AS1', 'Gene', '100128338', (12, 22))	('FAM83H-AS1', 'Gene', (12, 22))	('knockdown', 'Var', (23, 32))	('MCF7', 'CellLine', 'CVCL:0031', (36, 40))
139693	32839509	Long non-coding RNAs are molecules that exert numerous roles in human cancers, as their biological activities involve regulation of cell proliferation, cell death, differentiation, migration and invasion.	('differentiation', 'CPA', (164, 179))	('human', 'Species', '9606', (64, 69))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('Long non-coding', 'Var', (0, 15))	('invasion', 'CPA', (195, 203))	('cell proliferation', 'CPA', (132, 150))	('cancers', 'Disease', 'MESH:D009369', (70, 77))	('cancers', 'Phenotype', 'HP:0002664', (70, 77))	('migration', 'CPA', (181, 190))	('cancers', 'Disease', (70, 77))	('cell death', 'CPA', (152, 162))
139705	32839509	Accordingly, we also found that FAM83H-AS1 knockdown significantly deregulates migration and apoptosis-related genes, such as TP63 and CLND1.	('FAM83H-AS1', 'Gene', (32, 42))	('CLND1', 'Gene', (135, 140))	('deregulates', 'NegReg', (67, 78))	('knockdown', 'Var', (43, 52))	('TP63', 'Gene', (126, 130))	('TP63', 'Gene', '8626', (126, 130))	('migration and', 'CPA', (79, 92))	('FAM83H-AS1', 'Gene', '100128338', (32, 42))
139710	32839509	FAM83H-AS1 was involved in regulation of cell proliferation, migration and invasion processes that were decreased after FAM83H-AS1 knockdown in lung cancer cells.	('FAM83H-AS1', 'Gene', '100128338', (120, 130))	('knockdown', 'Var', (131, 140))	('invasion processes', 'CPA', (75, 93))	('lung cancer', 'Disease', (144, 155))	('lung cancer', 'Phenotype', 'HP:0100526', (144, 155))	('cell proliferation', 'CPA', (41, 59))	('FAM83H-AS1', 'Gene', '100128338', (0, 10))	('decreased', 'NegReg', (104, 113))	('FAM83H-AS1', 'Gene', (120, 130))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('migration', 'CPA', (61, 70))	('lung cancer', 'Disease', 'MESH:D008175', (144, 155))	('FAM83H-AS1', 'Gene', (0, 10))
139713	32839509	In vitro assays also show that FAM83H-AS1 silencing increases cellular death, possibly by up regulating genes like p63.	('silencing', 'Var', (42, 51))	('up regulating', 'PosReg', (90, 103))	('increases', 'PosReg', (52, 61))	('FAM83H-AS1', 'Gene', '100128338', (31, 41))	('p63', 'Gene', (115, 118))	('cellular death', 'CPA', (62, 76))	('FAM83H-AS1', 'Gene', (31, 41))	('p63', 'Gene', '8626', (115, 118))
139714	32839509	One previous report showed that cell death was markedly increased after with FAM83H-AS1 knockdown in colorectal cell lines.	('cell death', 'CPA', (32, 42))	('increased', 'PosReg', (56, 65))	('FAM83H-AS1', 'Gene', (77, 87))	('knockdown', 'Var', (88, 97))	('FAM83H-AS1', 'Gene', '100128338', (77, 87))
139716	32839509	Cell proliferation was inhibited with FAM83H-AS1 knockdown and this effect mediated by FAM83H-AS1 could be reversed by Notch1 regulators.	('Notch1', 'Gene', (119, 125))	('knockdown', 'Var', (49, 58))	('FAM83H-AS1', 'Gene', (87, 97))	('inhibited', 'NegReg', (23, 32))	('Notch1', 'Gene', '4851', (119, 125))	('FAM83H-AS1', 'Gene', '100128338', (38, 48))	('FAM83H-AS1', 'Gene', (38, 48))	('FAM83H-AS1', 'Gene', '100128338', (87, 97))	('Cell proliferation', 'CPA', (0, 18))
139718	32839509	In this regard, it has been shown that FAM83H-AS1 epigenetically silenced CDKN1A by binding to EZH2 in glioma cells.	('silenced', 'NegReg', (65, 73))	('epigenetically', 'Var', (50, 64))	('EZH2', 'Gene', (95, 99))	('FAM83H-AS1', 'Gene', (39, 49))	('CDKN1A', 'Gene', (74, 80))	('glioma', 'Disease', 'MESH:D005910', (103, 109))	('glioma', 'Phenotype', 'HP:0009733', (103, 109))	('CDKN1A', 'Gene', '1026', (74, 80))	('FAM83H-AS1', 'Gene', '100128338', (39, 49))	('binding', 'Interaction', (84, 91))	('glioma', 'Disease', (103, 109))	('EZH2', 'Gene', '2146', (95, 99))
139726	32839509	FAM83H-AS1 deregulation is associated with migration and cell death impairment in BRCA samples and breast cancer cells, and may regulate a plethora of cancer-related gene targets, such as p63, BAX, LEP and CLDN1.	('LEP', 'Gene', '3952', (198, 201))	('CLDN1', 'Gene', '9076', (206, 211))	('cancer', 'Disease', (106, 112))	('BRCA', 'Phenotype', 'HP:0003002', (82, 86))	('LEP', 'Gene', (198, 201))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('plethora', 'Phenotype', 'HP:0001050', (139, 147))	('FAM83H-AS1', 'Gene', '100128338', (0, 10))	('cancer', 'Disease', (151, 157))	('death impairment', 'Disease', 'MESH:D003643', (62, 78))	('BRCA', 'Gene', '672', (82, 86))	('p63', 'Gene', (188, 191))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('breast cancer', 'Phenotype', 'HP:0003002', (99, 112))	('p63', 'Gene', '8626', (188, 191))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('CLDN1', 'Gene', (206, 211))	('regulate', 'Reg', (128, 136))	('migration', 'CPA', (43, 52))	('FAM83H-AS1', 'Gene', (0, 10))	('breast cancer', 'Disease', 'MESH:D001943', (99, 112))	('BRCA', 'Gene', (82, 86))	('breast cancer', 'Disease', (99, 112))	('deregulation', 'Var', (11, 23))	('associated', 'Reg', (27, 37))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('death impairment', 'Disease', (62, 78))	('BAX', 'Gene', (193, 196))	('BAX', 'Gene', '581', (193, 196))
139762	32839509	GAPDH (Hs99999905) and SCARNA5 (Hs03391742_cn) transcripts were used as endogenous controls.	('SCARNA5', 'Gene', '677775', (23, 30))	('SCARNA5', 'Gene', (23, 30))	('GAPDH', 'Gene', '2597', (0, 5))	('Hs03391742_cn', 'Var', (32, 45))	('Hs99999905', 'Var', (7, 17))	('GAPDH', 'Gene', (0, 5))
139789	31262333	Biomass fuel is associated with increased risk of Esophageal squamous cell carcinoma.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (61, 84))	('Esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (50, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('Biomass', 'Var', (0, 7))	('Esophageal squamous cell carcinoma', 'Disease', (50, 84))
139798	31262333	An association of biomass smoke with lung cancer is established but suggested with ESCC though polycyclic aromatic hydrocarbons (PAHs), a major component of biomass fuel, have carcinogenic properties on mucosal and endothelial lining of upper aero digestive tract from inhalation.	('lung cancer', 'Disease', (37, 48))	('lung cancer', 'Phenotype', 'HP:0100526', (37, 48))	('polycyclic aromatic hydrocarbons', 'Chemical', 'MESH:D011084', (95, 127))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('lung cancer', 'Disease', 'MESH:D008175', (37, 48))	('carcinogenic', 'Disease', 'MESH:D063646', (176, 188))	('polycyclic', 'Var', (95, 105))	('carcinogenic', 'Disease', (176, 188))	('PAHs', 'Chemical', 'MESH:D011084', (129, 133))
139814	31262333	In South Africa, SULT1A1*2/*2, GSTP1 341C/T and T/T genotypes and single nucleotide polymorphisms in miR-423 together with environmental smoke exposure was associated with increased risk of ESCC.	('ESCC', 'Disease', (190, 194))	('miR-423', 'Gene', (101, 108))	('GSTP1', 'Gene', '2950', (31, 36))	('single nucleotide polymorphisms', 'Var', (66, 97))	('SULT1A1', 'Gene', (17, 24))	('T/T', 'Var', (48, 51))	('SULT1A1', 'Gene', '6817', (17, 24))	('miR-423', 'Gene', '494335', (101, 108))	('341C/T', 'Mutation', 'rs1138272', (37, 43))	('GSTP1', 'Gene', (31, 36))
139882	32688345	In this study, we systematically analyzed the differential expression and genetic alterations in ferroptosis-related genes (FRGs) in 32 cancer types.	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('FRGs', 'Gene', (124, 128))	('cancer', 'Disease', (136, 142))	('genetic alterations', 'Var', (74, 93))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
139888	32688345	Ferroptosis is also triggered by perturbations in lipid metabolism.	('perturbations', 'Var', (33, 46))	('triggered by', 'Reg', (20, 32))	('lipid metabolism', 'MPA', (50, 66))	('Ferroptosis', 'Disease', (0, 11))	('lipid', 'Chemical', 'MESH:D008055', (50, 55))
139889	32688345	We then used the GSCA database to determine the single nucleotide variations (SNV) and copy number variations (CNV) in the 36 FRGs in the 32 cancer types.	('copy number variations', 'Var', (87, 109))	('FRGs', 'Gene', (126, 130))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('single nucleotide variations', 'Var', (48, 76))	('cancer', 'Disease', (141, 147))
139891	32688345	The average mutation rate of TP53 was the highest among all FRGs at 82%; majority of the genetic aberrations were missense mutations and were more common in lung adenocarcinoma (LUAD) and squamous cell carcinoma(LUSC) (Supplementary Figure 1A, 1B).	('common', 'Reg', (147, 153))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (188, 211))	('LUAD', 'Phenotype', 'HP:0030078', (178, 182))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (157, 176))	('TP53', 'Gene', '7157', (29, 33))	('carcinoma', 'Phenotype', 'HP:0030731', (167, 176))	('TP53', 'Gene', (29, 33))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (188, 211))	('lung adenocarcinoma', 'Disease', (157, 176))	('carcinoma', 'Phenotype', 'HP:0030731', (202, 211))	('squamous cell carcinoma', 'Disease', (188, 211))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (157, 176))	('missense mutations', 'Var', (114, 132))
139892	32688345	We also analyzed the CNVs in the FRGs among the 32 cancer types and found heterozygous mutations in TP53 and ALOX15B and heterozygous amplifications in RPL8 and PTGS2 (Supplementary Figure 1C).	('RPL8', 'Gene', (152, 156))	('TP53', 'Gene', '7157', (100, 104))	('RPL8', 'Gene', '6132', (152, 156))	('PTGS2', 'Gene', '5743', (161, 166))	('ALOX15B', 'Gene', (109, 116))	('TP53', 'Gene', (100, 104))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('ALOX15B', 'Gene', '247', (109, 116))	('cancer', 'Disease', (51, 57))	('PTGS2', 'Gene', (161, 166))	('mutations', 'Var', (87, 96))
139925	32688345	CCK8 proliferation assay shows that CARS knockdown 786-O cells showed significant reduction in proliferation compared to the control 786-O cells (Figure 7D).	('reduction', 'NegReg', (82, 91))	('CARS', 'Gene', (36, 40))	('proliferation', 'CPA', (95, 108))	('knockdown', 'Var', (41, 50))	('CARS', 'Gene', '833', (36, 40))
139954	32511103	We identified one adenocarcinoma-specific CpG probe, cg14326354PRODH, with effects significantly modified by age (HRinteraction = 0.989; 95% CI: 0.986-0.994; P = 9.18x10-7).	('adenocarcinoma', 'Disease', 'MESH:D000230', (18, 32))	('modified', 'Reg', (97, 105))	('carcinoma', 'Phenotype', 'HP:0030731', (23, 32))	('cg14326354PRODH', 'Chemical', '-', (53, 68))	('adenocarcinoma', 'Disease', (18, 32))	('cg14326354PRODH', 'Var', (53, 68))	('effects', 'MPA', (75, 82))
139955	32511103	The effect of low methylation was reversed for young and elderly patients categorized by the boundary of 95% CI standard (HRyoung = 2.44; 95% CI: 1.26-4.72; P = 8.34x10-3; HRelderly = 0.58; 95% CI: 0.42-0.82; P = 1.67x10-3).	('low', 'Var', (14, 17))	('methylation', 'MPA', (18, 29))	('patients', 'Species', '9606', (65, 73))
139956	32511103	Moreover, there was an antagonistic interaction between low cg14326354PRODH methylation and elderly age (HRinteraction = 0.21; 95% CI: 0.11-0.40; P = 2.20x10-6).	('cg14326354PRODH', 'Chemical', '-', (60, 75))	('methylation', 'Var', (76, 87))	('low cg14326354PRODH methylation', 'Var', (56, 87))
139957	32511103	In summary, low methylation of cg14326354PRODH might benefit survival of elderly lung adenocarcinoma patients, providing new insight to age-specific prediction and potential drug targeting.	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (81, 100))	('patients', 'Species', '9606', (101, 109))	('survival', 'CPA', (61, 69))	('cg14326354PRODH', 'Chemical', '-', (31, 46))	('cg14326354PRODH', 'Var', (31, 46))	('lung adenocarcinoma', 'Disease', (81, 100))	('benefit', 'PosReg', (53, 60))	('methylation', 'MPA', (16, 27))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (81, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('low', 'NegReg', (12, 15))
139966	32511103	DNA methylation, a reversible epigenetic modification, correlates with tumor prognosis in almost all cancers including non-small cell lung cancer (NSCLC).	('lung cancer', 'Disease', (134, 145))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (123, 145))	('correlates with', 'Reg', (55, 70))	('cancers', 'Disease', 'MESH:D009369', (101, 108))	('lung cancer', 'Disease', 'MESH:D008175', (134, 145))	('lung cancer', 'Phenotype', 'HP:0100526', (134, 145))	('NSCLC', 'Disease', 'MESH:D002289', (147, 152))	('methylation', 'Var', (4, 15))	('DNA methylation', 'Var', (0, 15))	('tumor', 'Disease', (71, 76))	('NSCLC', 'Disease', (147, 152))	('cancers', 'Phenotype', 'HP:0002664', (101, 108))	('cancers', 'Disease', (101, 108))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('NSCLC', 'Phenotype', 'HP:0030358', (147, 152))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (119, 145))
139967	32511103	DNA methylation events may potentially be cancer biomarkers as well as therapeutic targets to improve cancer treatment.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('men', 'Species', '9606', (114, 117))	('methylation', 'Var', (4, 15))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))
139981	32511103	Low methylation of cg14326354PRODH interacted with age to affect survival of patients (discovery phase: hazard ratio (HR)interaction = 0.982; 95% CI: 0.976-0.989; P = 1.11x10-7; validation phase: HRinteraction = 0.981; 95% CI: 0.966-0.997; P = 0.0202; combined data: HRinteraction = 0.989; 95% CI: 0.986-0.994; P = 9.18x10-7).	('cg14326354PRODH', 'Chemical', '-', (19, 34))	('methylation', 'MPA', (4, 15))	('Low', 'Var', (0, 3))	('patients', 'Species', '9606', (77, 85))	('survival', 'CPA', (65, 73))	('affect', 'Reg', (58, 64))	('cg14326354PRODH', 'Var', (19, 34))
139986	32511103	With increased age, there was an increased protective effect for low methylation of cg14326354PRODH on LUAD survival (Figure 2A, Supplementary Figure 4).	('cg14326354PRODH', 'Var', (84, 99))	('LUAD', 'Phenotype', 'HP:0030078', (103, 107))	('LUAD', 'Disease', (103, 107))	('men', 'Species', '9606', (135, 138))	('low methylation', 'Var', (65, 80))	('cg14326354PRODH', 'Chemical', '-', (84, 99))
139990	32511103	Low methylation of cg14326354PRODH showed a risk effect on survival for young patients (HRBoCI = 1.20; 95% CI: 1.03-1.40; P = 1.97x10-2; HRUN = 1.10; 95% CI: 0.99-1.22; P = 8.71x10-2) but benefited survival of elderly LUAD patients (HRBoCI = 0.81; 95% CI: 0.75-0.88; P = 5.38x10-7; HRUN = 0.81; 95% CI: 0.75-0.88; P = 5.38x10-7) (Figure 2B).	('patients', 'Species', '9606', (78, 86))	('survival', 'MPA', (198, 206))	('benefited', 'PosReg', (188, 197))	('methylation', 'Var', (4, 15))	('Low methylation', 'Var', (0, 15))	('LUAD', 'Phenotype', 'HP:0030078', (218, 222))	('patients', 'Species', '9606', (223, 231))	('cg14326354PRODH', 'Chemical', '-', (19, 34))	('cg14326354PRODH', 'Var', (19, 34))
139991	32511103	There was significant heterogeneity of the low cg14326354PRODH methylation effect between young and elderly patients (I2 = 93.03%, Q = 14.35, P = 1.52x10-4) (Figure 2C).	('patients', 'Species', '9606', (108, 116))	('low cg14326354PRODH', 'Var', (43, 62))	('cg14326354PRODH', 'Chemical', '-', (47, 62))	('cg14326354PRODH', 'Var', (47, 62))
139992	32511103	These results indicated that elderly LUAD patients had better survival with lower methylation of cg14326354PRODH.	('lower', 'NegReg', (76, 81))	('cg14326354PRODH', 'Chemical', '-', (97, 112))	('LUAD', 'Phenotype', 'HP:0030078', (37, 41))	('better', 'PosReg', (55, 61))	('cg14326354PRODH', 'Var', (97, 112))	('patients', 'Species', '9606', (42, 50))	('methylation', 'MPA', (82, 93))
139993	32511103	In addition, we evaluated the joint effect of cg14326354PRODH methylation level (low vs high) and age (elderly vs young) on LUAD survival (Table 1).	('LUAD', 'Phenotype', 'HP:0030078', (124, 128))	('cg14326354PRODH', 'Chemical', '-', (46, 61))	('cg14326354PRODH', 'Var', (46, 61))	('methylation level', 'MPA', (62, 79))
139995	32511103	The main effect of low cg14326354PRODH methylation was HR = 2.84 (95% CI: 1.59-5.08, P = 4.35x10-4), and the main effect of elderly age was HR = 3.18 (95% CI: 1.85-5.46, P = 2.64x10-5).	('low', 'NegReg', (19, 22))	('cg14326354PRODH', 'Var', (23, 38))	('cg14326354PRODH', 'Chemical', '-', (23, 38))	('methylation', 'MPA', (39, 50))
139996	32511103	This result indicates an antagonistic interaction between low cg14326354PRODH methylation and elderly age (HRinteraction = 0.21; 95% CI: 0.11-0.40; P = 2.20x10-6).	('cg14326354PRODH', 'Var', (62, 77))	('low cg14326354PRODH', 'Var', (58, 77))	('cg14326354PRODH', 'Chemical', '-', (62, 77))
139998	32511103	Moreover, genome-wide trans-regulation analysis revealed that expression of 821 genes was significantly correlated with methylation level of cg14326354PRODH (Supplementary Material 3, Figure 3B).	('methylation level', 'MPA', (120, 137))	('correlated', 'Reg', (104, 114))	('expression', 'MPA', (62, 72))	('cg14326354PRODH', 'Chemical', '-', (141, 156))	('cg14326354PRODH', 'Var', (141, 156))	('men', 'Species', '9606', (164, 167))
140016	32511103	Further, our results suggest that low methylation of cg14326354PRODH may potentially promote PRODH expression, further heighten autophagy to some extent, and then result in poor prognosis (Figure 4).	('expression', 'MPA', (99, 109))	('heighten', 'PosReg', (119, 127))	('low methylation', 'Var', (34, 49))	('promote', 'PosReg', (85, 92))	('autophagy', 'CPA', (128, 137))	('PRODH', 'Gene', '5625', (63, 68))	('PRODH', 'Gene', '5625', (93, 98))	('cg14326354PRODH', 'Chemical', '-', (53, 68))	('PRODH', 'Gene', (63, 68))	('result', 'Reg', (163, 169))	('PRODH', 'Gene', (93, 98))
140025	32511103	Notably, cellular senescence was involved in these pathways, again indicting potential indirect induction of cg14326354PRODH on senescence.	('cg14326354PRODH', 'Chemical', '-', (109, 124))	('involved', 'Reg', (33, 41))	('cg14326354PRODH', 'Var', (109, 124))
140028	32511103	Expression of these genes were significantly correlated with cg14326354PRODH methylation and affected LUAD survival, including MKI67, BTG2, KIAA1524, and CDC123 (Supplementary Table 7).	('CDC123', 'Gene', '8872', (154, 160))	('KIAA1524', 'Gene', '57650', (140, 148))	('Expression', 'MPA', (0, 10))	('MKI67', 'Gene', (127, 132))	('BTG2', 'Gene', (134, 138))	('MKI67', 'Gene', '4288', (127, 132))	('LUAD survival', 'CPA', (102, 115))	('CDC123', 'Gene', (154, 160))	('BTG2', 'Gene', '7832', (134, 138))	('cg14326354PRODH', 'Chemical', '-', (61, 76))	('KIAA1524', 'Gene', (140, 148))	('men', 'Species', '9606', (168, 171))	('affected', 'Reg', (93, 101))	('LUAD', 'Phenotype', 'HP:0030078', (102, 106))	('correlated', 'Reg', (45, 55))	('cg14326354PRODH methylation', 'Var', (61, 88))
140029	32511103	Our previous study of BTG2 expression and methylation already indicated it is a prognostic biomarker of NSCLC.	('NSCLC', 'Disease', (104, 109))	('BTG2', 'Gene', (22, 26))	('BTG2', 'Gene', '7832', (22, 26))	('NSCLC', 'Disease', 'MESH:D002289', (104, 109))	('methylation', 'Var', (42, 53))	('NSCLC', 'Phenotype', 'HP:0030358', (104, 109))
140030	32511103	These results also indicate the potential role of cg14326354PRODH in indirect induction of autophagy, senescence, and survival.	('cg14326354PRODH', 'Var', (50, 65))	('survival', 'CPA', (118, 126))	('autophagy', 'CPA', (91, 100))	('cg14326354PRODH', 'Chemical', '-', (50, 65))	('senescence', 'CPA', (102, 112))
140031	32511103	Further functional studies are warranted to elucidate the mechanism of cg14326354PRODH and age interaction on LUAD survival.	('LUAD', 'Phenotype', 'HP:0030078', (110, 114))	('LUAD survival', 'Disease', (110, 123))	('cg14326354PRODH', 'Var', (71, 86))	('cg14326354PRODH', 'Chemical', '-', (71, 86))
140036	32511103	Further clinical studies will provide additional insight into cg14326354PRODH and its age-specific effects in tumors, which may lead to new age-specific biomarkers and therapeutic strategies that improve prediction accuracy and treatment efficacy.	('cg14326354PRODH', 'Chemical', '-', (62, 77))	('cg14326354PRODH', 'Var', (62, 77))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumors', 'Disease', (110, 116))	('tumors', 'Disease', 'MESH:D009369', (110, 116))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('lead', 'Reg', (128, 132))	('men', 'Species', '9606', (233, 236))
140037	32511103	First, this is the first epigenome-wide study to investigate the interaction between DNA methylation and age on NSCLC survival, which provides new evidence to account for the missing heritability of complex diseases and may further reveal the role of age in heterogeneity of NSCLC prognosis and treatment efficacy.	('NSCLC', 'Disease', (275, 280))	('men', 'Species', '9606', (300, 303))	('NSCLC', 'Phenotype', 'HP:0030358', (112, 117))	('methylation', 'Var', (89, 100))	('NSCLC', 'Disease', 'MESH:D002289', (275, 280))	('NSCLC', 'Disease', (112, 117))	('NSCLC', 'Phenotype', 'HP:0030358', (275, 280))	('NSCLC', 'Disease', 'MESH:D002289', (112, 117))
140041	32511103	This effect might be because >62% (240/385) of young patients defined using the UN standard (57-65 years) attenuated the effect of cg14326354PRODH methylation.	('methylation', 'MPA', (147, 158))	('attenuated', 'NegReg', (106, 116))	('patients', 'Species', '9606', (53, 61))	('cg14326354PRODH', 'Chemical', '-', (131, 146))	('cg14326354PRODH', 'Var', (131, 146))
140042	32511103	Therefore, high methylation of cg14326354PRODH might benefit survival of young LUAD patients.	('patients', 'Species', '9606', (84, 92))	('LUAD', 'Phenotype', 'HP:0030078', (79, 83))	('survival', 'CPA', (61, 69))	('cg14326354PRODH', 'Chemical', '-', (31, 46))	('cg14326354PRODH', 'Var', (31, 46))	('benefit', 'PosReg', (53, 60))	('methylation', 'MPA', (16, 27))	('high', 'Var', (11, 15))
140045	32511103	Last, the cis-regulation pattern of cg14326354PRODH requires more biological evidence, although methylation is believed to play a crucial role in regulating gene expression and further influence disease gene function.	('cg14326354PRODH', 'Chemical', '-', (36, 51))	('cg14326354PRODH', 'Var', (36, 51))	('gene expression', 'MPA', (157, 172))	('influence', 'Reg', (185, 194))
140047	32511103	In conclusion, low methylation of cg14326354PRODH benefited survival of elderly LUAD patients.	('survival', 'CPA', (60, 68))	('cg14326354PRODH', 'Var', (34, 49))	('cg14326354PRODH', 'Chemical', '-', (34, 49))	('benefited', 'PosReg', (50, 59))	('patients', 'Species', '9606', (85, 93))	('LUAD', 'Phenotype', 'HP:0030078', (80, 84))	('methylation', 'MPA', (19, 30))	('low', 'NegReg', (15, 18))
140067	32511103	In the discovery phase, histology-stratified analysis and Cox proportional hazards model adjusted for age, smoking status, sex, clinical stage, and study center were applied to test the methylation-age interaction effect on overall survival in LUAD and LUSC patients using the R package survival.	('LUAD', 'Phenotype', 'HP:0030078', (244, 248))	('methylation-age', 'Var', (186, 201))	('LUSC', 'Phenotype', 'HP:0030359', (253, 257))	('patients', 'Species', '9606', (258, 266))	('test', 'Reg', (177, 181))
140068	32511103	Hazard ratio (HR) and 95% confidence interval (CI) were described per 5% level of methylation decrement.	('methylation', 'Var', (82, 93))	('decrement', 'NegReg', (94, 103))	('men', 'Species', '9606', (99, 102))
140093	32333246	On the cell membrane, AKT is recruited via its PH domain ascribing to the accumulation of PI(3,4,5)P3 and PI(3,4)P2 (less extent), and plays a catalytic role by activating two regulatory sites, including a threonine phosphorylated by PDK1 at Thr308(AKT1), Thr309(AKT2), Thr305(AKT3) and a serine phosphorylated by the mammalian Target of Rapamycin (mTOR) Complex mTORC2 at Ser473(AKT1), Ser474(AKT2), Ser472(AKT3) respectively as well as specifically.	('Ser474', 'Var', (387, 393))	('AKT2', 'Gene', '208', (394, 398))	('activating', 'PosReg', (161, 171))	('AKT', 'Gene', '207', (249, 252))	('AKT', 'Gene', (22, 25))	('AKT3', 'Gene', (277, 281))	('AKT2', 'Gene', (394, 398))	('AKT', 'Gene', (277, 280))	('AKT', 'Gene', (394, 397))	('AKT1', 'Gene', (380, 384))	('AKT', 'Gene', '207', (263, 266))	('AKT', 'Gene', '207', (380, 383))	('PDK1', 'Gene', (234, 238))	('AKT1', 'Gene', '207', (249, 253))	('AKT2', 'Gene', '208', (263, 267))	('serine', 'Chemical', 'MESH:D012694', (289, 295))	('AKT', 'Gene', (408, 411))	('AKT1', 'Gene', '207', (380, 384))	('AKT', 'Gene', '207', (22, 25))	('AKT3', 'Gene', '10000', (408, 412))	('mTORC2', 'Gene', (363, 369))	('AKT2', 'Gene', (263, 267))	('AKT', 'Gene', '207', (277, 280))	('AKT', 'Gene', '207', (394, 397))	('Ser473', 'Var', (373, 379))	('AKT', 'Gene', (249, 252))	('AKT1', 'Gene', (249, 253))	('AKT3', 'Gene', (408, 412))	('Ser472', 'Var', (401, 407))	('PDK1', 'Gene', '5163', (234, 238))	('AKT', 'Gene', '207', (408, 411))	('mammalian Target of Rapamycin', 'Gene', '2475', (318, 347))	('AKT', 'Gene', (263, 266))	('AKT', 'Gene', (380, 383))	('AKT3', 'Gene', '10000', (277, 281))	('mammalian Target of Rapamycin', 'Gene', (318, 347))
140097	32333246	As a lipid phosphatase, PTEN directly suppresses the activation of PI3K/AKT pathway via converting the PIP3 generated by PI3K back to PIP2.	('AKT', 'Gene', '207', (72, 75))	('PTEN', 'Gene', '5728', (24, 28))	('AKT', 'Gene', (72, 75))	('PI3K', 'Var', (121, 125))	('suppresses', 'NegReg', (38, 48))	('PIP3 generated', 'MPA', (103, 117))	('PIP3', 'Chemical', '-', (103, 107))	('PTEN', 'Gene', (24, 28))
140100	32333246	Indeed, the abnormality of PTEN have been validated in diverse cancers, even directly related with carcinogenesis in some cancers.	('carcinogenesis', 'Disease', 'MESH:D063646', (99, 113))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('cancers', 'Phenotype', 'HP:0002664', (63, 70))	('carcinogenesis', 'Disease', (99, 113))	('cancers', 'Disease', 'MESH:D009369', (122, 129))	('cancers', 'Phenotype', 'HP:0002664', (122, 129))	('cancers', 'Disease', (122, 129))	('abnormality', 'Var', (12, 23))	('PTEN', 'Gene', (27, 31))	('PTEN', 'Gene', '5728', (27, 31))	('cancers', 'Disease', (63, 70))	('cancers', 'Disease', 'MESH:D009369', (63, 70))
140101	32333246	Following the emerging alterations of PI3K/AKT pathway genes have been widely reported in cancers recently, the inhibitors of PI3K/AKT pathway have brought a new era for targeted therapy of cancer.	('cancer', 'Disease', (190, 196))	('cancers', 'Disease', (90, 97))	('AKT', 'Gene', '207', (131, 134))	('cancer', 'Disease', 'MESH:D009369', (190, 196))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('inhibitors', 'Var', (112, 122))	('AKT', 'Gene', '207', (43, 46))	('AKT', 'Gene', (131, 134))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('AKT', 'Gene', (43, 46))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('cancers', 'Disease', 'MESH:D009369', (90, 97))
140112	32333246	Considering that the incidence and mortality of the brain and central nervous system tumors is 1.6% and 2.5% respectively in the worldwide (https://gco.iarc.fr/, Table 1), particularly the most common primary malignant tumor, glioblastoma multiforme (GBM), contributes to the poor prognosis partly for its tolerance of radiation therapy, hyper-activation of PI3K/AKT pathway in GBM caused by the mutations of PIK3CA or PIK3R1 (18.3%) and other PI3K family genes (6.8%) has urged researchers to seek novel targeted treatments to control the disease.	('GBM', 'Disease', (378, 381))	('men', 'Species', '9606', (519, 522))	('PIK3R1', 'Gene', (419, 425))	('AKT', 'Gene', (363, 366))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('central nervous system tumors', 'Disease', (62, 91))	('mutations', 'Var', (396, 405))	('PIK3CA', 'Gene', (409, 415))	('glioblastoma', 'Phenotype', 'HP:0012174', (226, 238))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('malignant tumor', 'Disease', (209, 224))	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('mortality', 'Disease', (35, 44))	('PIK3R1', 'Gene', '5295', (419, 425))	('AKT', 'Gene', '207', (363, 366))	('glioblastoma multiforme', 'Disease', (226, 249))	('central nervous system tumors', 'Disease', 'MESH:D016543', (62, 91))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (226, 249))	('malignant tumor', 'Disease', 'MESH:D009369', (209, 224))	('hyper-activation', 'PosReg', (338, 354))	('mortality', 'Disease', 'MESH:D003643', (35, 44))
140113	32333246	Moreover, knockdown of PIK3CA or PIK3R1 significantly inhibits cell viability, migration and invasion in GBM cells via hypo-activation of AKT and FAK.	('FAK', 'Gene', (146, 149))	('migration', 'CPA', (79, 88))	('invasion in GBM cells', 'CPA', (93, 114))	('PIK3CA', 'Gene', (23, 29))	('AKT', 'Gene', (138, 141))	('cell viability', 'CPA', (63, 77))	('inhibits', 'NegReg', (54, 62))	('PIK3R1', 'Gene', '5295', (33, 39))	('PIK3R1', 'Gene', (33, 39))	('FAK', 'Gene', '5747', (146, 149))	('knockdown', 'Var', (10, 19))	('AKT', 'Gene', '207', (138, 141))
140115	32333246	PIK3CB knockdown suppresses cell proliferation and induces caspase-dependent apoptosis in GBM in vitro and vivo instead of suppressing GBM cell migration.	('GBM cell migration', 'CPA', (135, 153))	('suppressing', 'NegReg', (123, 134))	('induces', 'Reg', (51, 58))	('PIK3CB', 'Gene', (0, 6))	('cell proliferation', 'CPA', (28, 46))	('caspase-dependent apoptosis', 'MPA', (59, 86))	('suppresses', 'NegReg', (17, 27))	('PIK3CB', 'Gene', '5291', (0, 6))	('knockdown', 'Var', (7, 16))
140117	32333246	Some p110alpha isoform-selective inhibitors, such as A66 or PIK-75, could effectively suppress the GBM cell growth, survival and migration in vitro, while inhibition of p110beta by TGX-221 only arrests cell migration, and inhibition of p110delta by IC87114 or CAL-101 moderately blocks cell proliferation and migration.	('p110beta', 'Gene', '5291', (169, 177))	('IC87114', 'Chemical', 'MESH:C477872', (249, 256))	('suppress', 'NegReg', (86, 94))	('cell migration', 'CPA', (202, 216))	('p110alpha', 'Gene', '5290', (5, 14))	('CAL-101', 'Chemical', 'MESH:C552946', (260, 267))	('p110beta', 'Gene', (169, 177))	('GBM cell growth', 'CPA', (99, 114))	('PIK-75', 'Gene', (60, 66))	('p110alpha', 'Gene', (5, 14))	('cell proliferation', 'CPA', (286, 304))	('migration', 'CPA', (129, 138))	('blocks', 'NegReg', (279, 285))	('TGX-221', 'Gene', (181, 188))	('p110delta', 'Var', (236, 245))
140118	32333246	However, PI3K inhibitors including A66 and BEZ235 are observed to increase the expression of cancer stem cell (CSC) genes (SOX2, OCT4 and MSI1) in GBM CSC models, which exhibit therapy resistance.	('A66', 'Var', (35, 38))	('increase', 'PosReg', (66, 74))	('cancer', 'Disease', (93, 99))	('MSI1', 'Gene', (138, 142))	('expression', 'MPA', (79, 89))	('PI3K', 'Var', (9, 13))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('OC', 'Phenotype', 'HP:0100615', (129, 131))	('SOX2', 'Gene', (123, 127))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('OCT4', 'Gene', '5460', (129, 133))	('OCT4', 'Gene', (129, 133))	('MSI1', 'Gene', '4440', (138, 142))	('SOX2', 'Gene', '6657', (123, 127))	('BEZ235', 'Var', (43, 49))	('BEZ235', 'Chemical', 'MESH:C531198', (43, 49))
140121	32333246	Notably, building on that 22% genetic alterations of PTEN was detected in GBM (https://www.cbioportal.org, Table 1), especially deep deletion, which caused the loss of function of PTEN tumor suppressor, PTEN was deeply involved in the pathological effects of PI3K/AKT pathway in GBM.	('PTEN', 'Gene', (203, 207))	('PTEN', 'Gene', '5728', (203, 207))	('AKT', 'Gene', (264, 267))	('deep deletion', 'Var', (128, 141))	('PTEN', 'Gene', (180, 184))	('involved', 'Reg', (219, 227))	('PTEN tumor', 'Disease', 'MESH:D006223', (180, 190))	('PTEN tumor', 'Disease', (180, 190))	('PTEN', 'Gene', '5728', (180, 184))	('PTEN', 'Gene', (53, 57))	('PTEN', 'Gene', '5728', (53, 57))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('AKT', 'Gene', '207', (264, 267))	('loss of function', 'NegReg', (160, 176))
140122	32333246	Meanwhile, genetic loss of PTEN is associated with each subtype of GBM.	('PTEN', 'Gene', '5728', (27, 31))	('associated', 'Reg', (35, 45))	('GBM', 'Disease', (67, 70))	('PTEN', 'Gene', (27, 31))	('genetic loss', 'Var', (11, 23))
140128	32333246	The loss of FBW7 function increases SOX9 protein levels, increasing the malignancy of cancer and resistance to cisplatin.	('increasing', 'PosReg', (57, 67))	('FBW7', 'Gene', '55294', (12, 16))	('cisplatin', 'Chemical', 'MESH:D002945', (111, 120))	('FBW7', 'Gene', (12, 16))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('SOX9', 'Gene', (36, 40))	('resistance', 'CPA', (97, 107))	('malignancy of cancer', 'Disease', 'MESH:D009369', (72, 92))	('increases', 'PosReg', (26, 35))	('SOX9', 'Gene', '6662', (36, 40))	('malignancy of cancer', 'Disease', (72, 92))	('loss', 'Var', (4, 8))
140129	32333246	As a major oncoprotein inhibitor, once FBW7 is deleted or mutated, it can cause tumors to occur directly.	('FBW7', 'Gene', '55294', (39, 43))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('FBW7', 'Gene', (39, 43))	('tumors', 'Disease', (80, 86))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('mutated', 'Var', (58, 65))	('deleted', 'Var', (47, 54))	('cause', 'Reg', (74, 79))
140130	32333246	Moreover, experiments show that combination of PI3K inhibitor, mTOR inhibitor and cisplatin can achieve better therapeutic effect, and how well LY3023414 works in recurrent MBM is being tested in an ongoing clinical trial (NCT03213678, Table 2).	('MBM', 'Disease', (173, 176))	('therapeutic effect', 'MPA', (111, 129))	('men', 'Species', '9606', (16, 19))	('cisplatin', 'Chemical', 'MESH:D002945', (82, 91))	('LY3023414', 'Chemical', 'MESH:C000621566', (144, 153))	('LY3023414', 'Var', (144, 153))
140134	32333246	Obviously, the overall genetic alterations of PI3K/AKT pathway in TC are inconspicuous (Table 1), but genetic mutations in PI3K/AKT pathway are common in PDTC and ATC, specifically more common in ATC than in PDTC.	('ATC', 'Disease', (196, 199))	('PDTC', 'Chemical', '-', (154, 158))	('TC', 'Phenotype', 'HP:0002890', (164, 166))	('common', 'Reg', (186, 192))	('TC', 'Phenotype', 'HP:0002890', (66, 68))	('AKT', 'Gene', (51, 54))	('TC', 'Phenotype', 'HP:0002890', (210, 212))	('AKT', 'Gene', (128, 131))	('genetic mutations', 'Var', (102, 119))	('PDTC', 'Chemical', '-', (208, 212))	('TC', 'Phenotype', 'HP:0002890', (156, 158))	('PDTC', 'Disease', (154, 158))	('common', 'Reg', (144, 150))	('AKT', 'Gene', '207', (128, 131))	('TC', 'Phenotype', 'HP:0002890', (197, 199))	('AKT', 'Gene', '207', (51, 54))
140135	32333246	Besides PIK3CA (18% vs. 2%) and PTEN (15% vs. 4%), mutations of PIK3C2G (6% vs. 1%), PIK3CG (6% vs. 1%), PIK3C3 (0 vs. 1%), PIK3R1 (0 vs. 1%), PIK3R2 (3% vs. 0), AKT3 (0 vs. 1%) are also observed in ATC and PDTC respectively.	('PIK3C2G', 'Gene', (64, 71))	('mutations', 'Var', (51, 60))	('PDTC', 'Chemical', '-', (207, 211))	('PIK3C2G', 'Gene', '5288', (64, 71))	('PIK3R1', 'Gene', (124, 130))	('PIK3R2', 'Gene', (143, 149))	('AKT3', 'Gene', '10000', (162, 166))	('PIK3C3', 'Gene', '5289', (105, 111))	('PIK3C3', 'Gene', (105, 111))	('PIK3R2', 'Gene', '5296', (143, 149))	('PDTC', 'Disease', (207, 211))	('AKT3', 'Gene', (162, 166))	('PTEN', 'Gene', (32, 36))	('PIK3R1', 'Gene', '5295', (124, 130))	('PIK3CG', 'Gene', (85, 91))	('ATC', 'Disease', (199, 202))	('PIK3CG', 'Gene', '5294', (85, 91))	('TC', 'Phenotype', 'HP:0002890', (209, 211))	('PTEN', 'Gene', '5728', (32, 36))	('TC', 'Phenotype', 'HP:0002890', (200, 202))
140137	32333246	Actually, exclusive activating mutations of BRAF (60% vs. 33% and 38%) in PTC are more frequently observed than in PDTC and ATC, while mice experiments show that co-mutation of BRAF and PIK3CA can promote the development of lethal ATC, but neither BRAF nor PIK3CA mutations alone can.	('men', 'Species', '9606', (216, 219))	('development of lethal ATC', 'CPA', (209, 234))	('activating', 'PosReg', (20, 30))	('BRAF', 'Gene', (177, 181))	('TC', 'Phenotype', 'HP:0002890', (117, 119))	('BRAF', 'Gene', (44, 48))	('co-mutation', 'Var', (162, 173))	('men', 'Species', '9606', (146, 149))	('TC', 'Phenotype', 'HP:0002890', (125, 127))	('PTC', 'Disease', (74, 77))	('PIK3CA', 'Gene', (186, 192))	('mice', 'Species', '10090', (135, 139))	('PDTC', 'Chemical', '-', (115, 119))	('TC', 'Phenotype', 'HP:0002890', (232, 234))	('TC', 'Phenotype', 'HP:0002890', (75, 77))	('promote', 'PosReg', (197, 204))
140138	32333246	In addition, mutations in BRAF and PIK3CA can activate the MAPK pathway and the PI3K/AKT pathway respectively and lead to the occurrence of ATC, whereas dual blocking PI3K and MAPK pathways can effectively inhibit ATC.	('MAPK pathway', 'Pathway', (59, 71))	('AKT', 'Gene', '207', (85, 88))	('BRAF', 'Gene', (26, 30))	('TC', 'Phenotype', 'HP:0002890', (141, 143))	('PIK3CA', 'Gene', (35, 41))	('activate', 'PosReg', (46, 54))	('AKT', 'Gene', (85, 88))	('mutations', 'Var', (13, 22))	('lead to', 'Reg', (114, 121))	('TC', 'Phenotype', 'HP:0002890', (215, 217))	('ATC', 'Disease', (140, 143))
140145	32333246	Apart from those widely recognized alterations, such as EGFR and KRAS gene mutations, MET amplification, EML4-ALK rearrangements in NSCLC, somatic mutations and amplification in PIK3CA are described in 3-10% vs. 35% of SCC and 0-2.7% vs. 7% of ADC respectively.	('mutations', 'Var', (147, 156))	('EGFR', 'Gene', '1956', (56, 60))	('SCC', 'Disease', (219, 222))	('CC', 'Phenotype', 'HP:0002664', (220, 222))	('PIK3CA', 'Gene', (178, 184))	('KRAS', 'Gene', '3845', (65, 69))	('amplification', 'Var', (161, 174))	('NSCLC', 'Disease', 'MESH:D002289', (132, 137))	('EML4', 'Gene', (105, 109))	('KRAS', 'Gene', (65, 69))	('EML4', 'Gene', '27436', (105, 109))	('ADC', 'Disease', (244, 247))	('NSCLC', 'Disease', (132, 137))	('EGFR', 'Gene', (56, 60))	('NSCLC', 'Phenotype', 'HP:0030358', (132, 137))	('ALK', 'Gene', '238', (110, 113))	('SCC', 'Phenotype', 'HP:0002860', (219, 222))	('LC', 'Phenotype', 'HP:0100526', (135, 137))	('rearrangements', 'Var', (114, 128))	('ALK', 'Gene', (110, 113))	('men', 'Species', '9606', (123, 126))	('SCLC', 'Phenotype', 'HP:0030357', (133, 137))
140152	32333246	Whether combining daily BKM120 with cisplatin and etoposide was safe and effective in extensive stage SCLC patients had been attempted in a completed clinical trial (NCT02194049, Table 3).	('SCLC', 'Phenotype', 'HP:0030357', (102, 106))	('BKM120', 'Chemical', 'MESH:C571178', (24, 30))	('LC', 'Phenotype', 'HP:0100526', (104, 106))	('etoposide', 'Chemical', 'MESH:D005047', (50, 59))	('SCLC', 'Gene', '7864', (102, 106))	('cisplatin', 'Chemical', 'MESH:D002945', (36, 45))	('SCLC', 'Gene', (102, 106))	('BKM120', 'Var', (24, 30))	('patients', 'Species', '9606', (107, 115))
140154	32333246	As expected, NPC has a relatively lower mutational burdens with PIK3CA mutations of 1.8% (Table 1), however, there are still numerous of researches involved in PI3K/AKT pathway in NPC.	('AKT', 'Gene', (165, 168))	('PIK3CA', 'Gene', (64, 70))	('NPC', 'Phenotype', 'HP:0100630', (180, 183))	('NPC', 'Gene', (180, 183))	('NPC', 'Gene', '4864', (180, 183))	('NPC', 'Phenotype', 'HP:0100630', (13, 16))	('mutations', 'Var', (71, 80))	('NPC', 'Gene', (13, 16))	('AKT', 'Gene', '207', (165, 168))	('PC', 'Phenotype', 'HP:0002894', (181, 183))	('PC', 'Phenotype', 'HP:0002894', (14, 16))	('NPC', 'Gene', '4864', (13, 16))
140158	32333246	A series of studies show the mutational events of PI3K pathway (30.5%) in 151 head and neck squamous cell carcinomas (HNSCCs) containing 29 laryngeal squamous cell carcinomas (LSCCs), particularly PIK3CA mutations of 12.6%.	('PIK3CA', 'Gene', (197, 203))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (150, 173))	('HNSCC', 'Disease', 'MESH:D000077195', (118, 123))	('squamous cell carcinomas', 'Disease', (150, 174))	('carcinomas', 'Phenotype', 'HP:0030731', (106, 116))	('SCC', 'Phenotype', 'HP:0002860', (120, 123))	('CC', 'Phenotype', 'HP:0002664', (178, 180))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (92, 116))	('CC', 'Phenotype', 'HP:0002664', (121, 123))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (92, 116))	('mutations', 'Var', (204, 213))	('HNSCC', 'Disease', (118, 123))	('PI3K pathway', 'Pathway', (50, 62))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (92, 115))	('carcinoma', 'Phenotype', 'HP:0030731', (164, 173))	('carcinomas', 'Phenotype', 'HP:0030731', (164, 174))	('neck squamous cell carcinomas', 'Disease', (87, 116))	('mutational', 'Var', (29, 39))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (150, 174))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('SCC', 'Phenotype', 'HP:0002860', (177, 180))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (150, 174))	('neck squamous cell carcinomas', 'Disease', 'MESH:D000077195', (87, 116))
140162	32333246	Even more, the safety and efficacy of AKT inhibitor MK2206 in NPC patients had been evaluated in a completed clinical trial (Table 3).	('AKT', 'Gene', (38, 41))	('MK2206', 'Chemical', 'MESH:C548887', (52, 58))	('NPC', 'Phenotype', 'HP:0100630', (62, 65))	('MK2206', 'Var', (52, 58))	('AKT', 'Gene', '207', (38, 41))	('NPC', 'Gene', (62, 65))	('PC', 'Phenotype', 'HP:0002894', (63, 65))	('patients', 'Species', '9606', (66, 74))	('NPC', 'Gene', '4864', (62, 65))
140165	32333246	In general, the genetic alterations of PIK3CA (24%), and PTEN (7%) are observed in ESCA (Table 1), especially the somatic mutations of PIK3CA (7.2% vs 12.5%), PIK3C2A (0.7% vs. 0), PIK3CG (2.9% vs. 4.2%) and PIK3C2G (0 vs. 37.5%) are observed respectively in 139 paired ESCC cases and 24 cell lines.	('PIK3C2G', 'Gene', (208, 215))	('PIK3CG', 'Gene', (181, 187))	('ESCC', 'Disease', (270, 274))	('PIK3C2G', 'Gene', '5288', (208, 215))	('SCC', 'Phenotype', 'HP:0002860', (271, 274))	('PIK3CG', 'Gene', '5294', (181, 187))	('CC', 'Phenotype', 'HP:0002664', (272, 274))	('ESCA', 'Disease', (83, 87))	('PTEN', 'Gene', (57, 61))	('PIK3CA', 'Gene', (135, 141))	('PTEN', 'Gene', '5728', (57, 61))	('mutations', 'Var', (122, 131))	('PIK3C2A', 'Gene', '5286', (159, 166))	('PIK3C2A', 'Gene', (159, 166))
140166	32333246	Even more, PIK3CA mutations are frequent in ESCC associated with chagasic megaesophagus and are associated with a worse patient outcome.	('ESCC', 'Disease', (44, 48))	('associated', 'Reg', (96, 106))	('associated', 'Reg', (49, 59))	('patient', 'Species', '9606', (120, 127))	('SCC', 'Phenotype', 'HP:0002860', (45, 48))	('PIK3CA', 'Gene', (11, 17))	('chagasic megaesophagus', 'Disease', (65, 87))	('CC', 'Phenotype', 'HP:0002664', (46, 48))	('mutations', 'Var', (18, 27))
140171	32333246	But one research reveals that PI3K/AKT pathway genetic mutations are found in 69 (16%) of the 431 GC patients including PIK3CA (13.2%) and PTEN (4.0%), as well as PIK3CA amplifications are found in 206 (47.8%) of the patients.	('patients', 'Species', '9606', (101, 109))	('PIK3CA', 'Gene', (120, 126))	('AKT', 'Gene', (35, 38))	('mutations', 'Var', (55, 64))	('PTEN', 'Gene', (139, 143))	('PTEN', 'Gene', '5728', (139, 143))	('AKT', 'Gene', '207', (35, 38))	('patients', 'Species', '9606', (217, 225))	('found', 'Reg', (69, 74))
140172	32333246	Another research shows that advanced GC patient have more frequency of PIK3CA mutations in codon 545 than in codon 1047.	('patient', 'Species', '9606', (40, 47))	('advanced GC', 'Disease', (28, 39))	('mutations', 'Var', (78, 87))	('PIK3CA', 'Gene', (71, 77))
140175	32333246	Table 2) and AKT inhibitors (MK2206, GSK2110183 and GDC-0068.	('MK2206', 'Var', (29, 35))	('GDC-0068', 'Chemical', 'MESH:C583616', (52, 60))	('GSK2110183', 'Chemical', 'MESH:C000595148', (37, 47))	('AKT', 'Gene', '207', (13, 16))	('MK2206', 'Chemical', 'MESH:C548887', (29, 35))	('AKT', 'Gene', (13, 16))
140179	32333246	Contrary to predictions, PIK3CA mutations do not predict aggressive clinicopathological characteristics in CRC, whereas they are closely associated with KRAS mutations, as well as PIK3CA exon 9 and 20 mutations show different tendencies with respect to BRAF mutation and MSI status.	('CRC', 'Disease', (107, 110))	('associated', 'Reg', (137, 147))	('CRC', 'Phenotype', 'HP:0003003', (107, 110))	('KRAS', 'Gene', (153, 157))	('PIK3CA', 'Gene', (25, 31))	('mutations', 'Var', (32, 41))	('PIK3CA', 'Gene', (180, 186))	('KRAS', 'Gene', '3845', (153, 157))
140181	32333246	CXCL12, NLRC3, Wnt/beta-catenin target genes including BAMBI, BOP1, CKS2 and NFIL3, as well as miRNA-135b, Linc00659 and CRNDE are associated with the proliferation, invasion or metastasis of CRC cells via PI3K/AKT signaling.	('CXCL12', 'Gene', (0, 6))	('NFIL3', 'Gene', '4783', (77, 82))	('CKS2', 'Gene', '1164', (68, 72))	('CKS2', 'Gene', (68, 72))	('CRNDE', 'Gene', '643911', (121, 126))	('CRNDE', 'Gene', (121, 126))	('NLRC3', 'Gene', (8, 13))	('BAMBI', 'Gene', (55, 60))	('proliferation', 'CPA', (151, 164))	('NLRC3', 'Gene', '197358', (8, 13))	('AKT', 'Gene', (211, 214))	('BAMBI', 'Gene', '25805', (55, 60))	('BOP1', 'Gene', (62, 66))	('CRC', 'Phenotype', 'HP:0003003', (192, 195))	('metastasis', 'CPA', (178, 188))	('Linc00659', 'Gene', (107, 116))	('Linc00659', 'Gene', '100652730', (107, 116))	('invasion', 'CPA', (166, 174))	('NFIL3', 'Gene', (77, 82))	('BOP1', 'Gene', '23246', (62, 66))	('AKT', 'Gene', '207', (211, 214))	('CXCL12', 'Gene', '6387', (0, 6))	('associated with', 'Reg', (131, 146))	('beta-catenin', 'Gene', (19, 31))	('miRNA-135b', 'Var', (95, 105))	('beta-catenin', 'Gene', '1499', (19, 31))
140183	32333246	As the most common mesenchymal tumor of the digestive system, gastrointestinal stromal tumors (GISTs) mainly harbor mutually exclusive KIT or PDGFRA mutations, which lead to constitutive activation of the encoded receptor tyrosine kinase (RTK) and activation of downstream pathways including PI3K/AKT pathway.	('receptor tyrosine kinase', 'Gene', (213, 237))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('activation', 'PosReg', (187, 197))	('PDGFRA', 'Gene', '5156', (142, 148))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('PDGFRA', 'Gene', (142, 148))	('GISTs', 'Phenotype', 'HP:0100723', (95, 100))	('KIT', 'Gene', '3815', (135, 138))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (62, 93))	('AKT', 'Gene', (297, 300))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (62, 93))	('RTK', 'Gene', (239, 242))	('activation', 'PosReg', (248, 258))	('RTK', 'Gene', '5979', (239, 242))	('mutations', 'Var', (149, 158))	('mesenchymal tumor', 'Disease', 'MESH:C535700', (19, 36))	('gastrointestinal stromal tumors', 'Disease', (62, 93))	('receptor tyrosine kinase', 'Gene', '5979', (213, 237))	('AKT', 'Gene', '207', (297, 300))	('KIT', 'Gene', (135, 138))	('mesenchymal tumor', 'Disease', (19, 36))
140184	32333246	Genetic alterations of PIK3CA and PTEN are observed more frequency in malignant GISTs than in less malignant GISTs in 65 GIST samples with 14/65 overall genetic alterations of PI3K/AKT pathway.	('Genetic alterations', 'Var', (0, 19))	('PIK3CA', 'Gene', (23, 29))	('AKT', 'Gene', (181, 184))	('genetic alterations', 'Var', (153, 172))	('GISTs', 'Phenotype', 'HP:0100723', (109, 114))	('AKT', 'Gene', '207', (181, 184))	('GISTs', 'Phenotype', 'HP:0100723', (80, 85))	('PTEN', 'Gene', (34, 38))	('PTEN', 'Gene', '5728', (34, 38))	('malignant', 'Disease', (70, 79))
140185	32333246	It is noted that FASN overexpression often occurs in high-risk and metastatic GISTs, whereas combination therapy with imatinib and C75 targeting FASN has been demonstrated in vitro and vivo to down-regulate the phosphorylation levels of the KIT and PI3K/AKT/mTOR pathway.	('imatinib', 'Chemical', 'MESH:D000068877', (118, 126))	('FASN', 'Gene', (17, 21))	('overexpression', 'PosReg', (22, 36))	('AKT', 'Gene', (254, 257))	('phosphorylation levels', 'MPA', (211, 233))	('FASN', 'Gene', '2194', (17, 21))	('AKT', 'Gene', '207', (254, 257))	('C75', 'Var', (131, 134))	('KIT', 'Gene', '3815', (241, 244))	('FASN', 'Gene', (145, 149))	('FASN', 'Gene', '2194', (145, 149))	('down-regulate', 'NegReg', (193, 206))	('GISTs', 'Phenotype', 'HP:0100723', (78, 83))	('KIT', 'Gene', (241, 244))
140187	32333246	Combination of imatinib mesylate (IM) and MK2206 provide obviously greater efficacy than treatment with IM or MK2206 alone in vitro and vivo preclinical study of GIST.	('MK2206', 'Chemical', 'MESH:C548887', (42, 48))	('men', 'Species', '9606', (94, 97))	('efficacy', 'MPA', (75, 83))	('MK2206', 'Chemical', 'MESH:C548887', (110, 116))	('MK2206', 'Var', (42, 48))	('imatinib mesylate', 'Chemical', 'MESH:D000068877', (15, 32))	('greater', 'PosReg', (67, 74))
140192	32333246	A small amount of clinical trials of PI3K inhibitors (SF1126, GSK2636771) and AKT inhibitors (MK2206) in HCC patients may give them an opportunity for relief (Tables 2 and 3).	('HCC', 'Disease', (105, 108))	('patients', 'Species', '9606', (109, 117))	('CC', 'Phenotype', 'HP:0002664', (106, 108))	('HCC', 'Phenotype', 'HP:0001402', (105, 108))	('SF1126', 'Var', (54, 60))	('SF1126', 'Chemical', 'MESH:C526549', (54, 60))	('AKT', 'Gene', '207', (78, 81))	('MK2206', 'Chemical', 'MESH:C548887', (94, 100))	('AKT', 'Gene', (78, 81))	('GSK2636771', 'Chemical', 'MESH:C000627739', (62, 72))	('PI3K', 'Protein', (37, 41))
140193	32333246	Regarding gallbladder cancer (GBC) is the most common malignancy of the biliary tract, the general genetic abnormalities of PIK3CA (10%) and PTEN (2.3%) are found (Table 1), especially the PIK3CA E545K mutation rate (6.15%).	('genetic abnormalities', 'Disease', 'MESH:D030342', (99, 120))	('PTEN', 'Gene', (141, 145))	('PTEN', 'Gene', '5728', (141, 145))	('genetic abnormalities', 'Disease', (99, 120))	('PIK3CA', 'Gene', (189, 195))	('E545K', 'Mutation', 'rs104886003', (196, 201))	('E545K', 'Var', (196, 201))	('PIK3CA', 'Gene', (124, 130))	('BC', 'Phenotype', 'HP:0003002', (31, 33))	('bladder cancer', 'Phenotype', 'HP:0009725', (14, 28))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('malignancy', 'Disease', 'MESH:D009369', (54, 64))	('gallbladder cancer', 'Disease', (10, 28))	('gallbladder cancer', 'Disease', 'MESH:D005706', (10, 28))	('malignancy', 'Disease', (54, 64))
140194	32333246	Due to ErbB2 and ErbB3 mutations at a frequency of 7-8% in GBC, ErbB2/ErbB3 mutation inducing PD-L1 overexpression can mediate immune escape of tumor cells via PI3K/AKT pathway in vitro.	('mediate', 'Reg', (119, 126))	('BC', 'Phenotype', 'HP:0003002', (60, 62))	('ErbB3', 'Gene', '2065', (17, 22))	('ErbB3', 'Gene', (70, 75))	('overexpression', 'PosReg', (100, 114))	('mutation', 'Var', (76, 84))	('AKT', 'Gene', (165, 168))	('mutations', 'Var', (23, 32))	('ErbB3', 'Gene', '2065', (70, 75))	('ErbB2', 'Gene', '2064', (64, 69))	('ErbB2', 'Gene', '2064', (7, 12))	('tumor', 'Disease', (144, 149))	('PD-L1', 'Gene', (94, 99))	('PD-L1', 'Gene', '29126', (94, 99))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('AKT', 'Gene', '207', (165, 168))	('ErbB3', 'Gene', (17, 22))	('ErbB2', 'Gene', (64, 69))	('ErbB2', 'Gene', (7, 12))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))
140196	32333246	Currently, only MK2206 was tested in clinical trials (NCT01859182 and NCT01425879) in GBC patients.	('GBC', 'Disease', (86, 89))	('NCT01859182', 'Var', (54, 65))	('NCT01425879', 'Var', (70, 81))	('MK2206', 'Chemical', 'MESH:C548887', (16, 22))	('BC', 'Phenotype', 'HP:0003002', (87, 89))	('patients', 'Species', '9606', (90, 98))
140201	32333246	Significantly, the mutations of PIK3CG in PDAC are also revealed.	('PIK3CG', 'Gene', (32, 38))	('PIK3CG', 'Gene', '5294', (32, 38))	('PDAC', 'Chemical', '-', (42, 46))	('mutations', 'Var', (19, 28))
140202	32333246	EG-VEGF, TMEM158, miR-107, as well as LncRNA ABHD11-AS1, SNHG1 and AB209630 are involved in proliferation, apoptosis, metastasis or carcinogenesis of PDAC cells through PI3K/AKT pathway.	('TMEM158', 'Gene', '25907', (9, 16))	('PDAC', 'Chemical', '-', (150, 154))	('AS1', 'Gene', '5729', (52, 55))	('AB209630', 'Var', (67, 75))	('EG-VEGF', 'Gene', (0, 7))	('ABHD11', 'Gene', '83451', (45, 51))	('SNHG1', 'Gene', (57, 62))	('carcinogenesis', 'Disease', (132, 146))	('metastasis', 'CPA', (118, 128))	('ABHD11', 'Gene', (45, 51))	('AKT', 'Gene', '207', (174, 177))	('proliferation', 'CPA', (92, 105))	('apoptosis', 'CPA', (107, 116))	('involved', 'Reg', (80, 88))	('carcinogenesis', 'Disease', 'MESH:D063646', (132, 146))	('AS1', 'Gene', (52, 55))	('miR-107', 'Gene', (18, 25))	('SNHG1', 'Gene', '23642', (57, 62))	('EG-VEGF', 'Gene', '84432', (0, 7))	('TMEM158', 'Gene', (9, 16))	('miR-107', 'Gene', '406901', (18, 25))	('AKT', 'Gene', (174, 177))
140203	32333246	Plenty of clinical trials of PI3K inhibitors (BKM120, BYL719, GSK2636771, PKI-587, BEZ235 and LY3023414.	('BKM120', 'Chemical', 'MESH:C571178', (46, 52))	('LY3023414', 'Chemical', 'MESH:C000621566', (94, 103))	('LY3023414', 'Var', (94, 103))	('BKM120', 'Var', (46, 52))	('BEZ235', 'Chemical', 'MESH:C531198', (83, 89))	('GSK2636771', 'Chemical', 'MESH:C000627739', (62, 72))
140207	32333246	Compared to the recognized genetically diverse of Her2 and TOP2A of BCs, the overall genetic alterations of PI3K/AKT pathway are not uncommon, especially PIK3CA (37%) and PTEN (8%, Table 1).	('Her2', 'Gene', (50, 54))	('TOP2A', 'Gene', (59, 64))	('PIK3CA', 'Var', (154, 160))	('BC', 'Phenotype', 'HP:0003002', (68, 70))	('AKT', 'Gene', '207', (113, 116))	('Her2', 'Gene', '2064', (50, 54))	('PTEN', 'Gene', (171, 175))	('AKT', 'Gene', (113, 116))	('PTEN', 'Gene', '5728', (171, 175))	('TOP2A', 'Gene', '7153', (59, 64))
140208	32333246	Remarkably, hotspot mutations in PIK3CA are frequent in ER+BCs, which account for up to 80% of BCs, and Her2 mutations hyperactivate the HER3/PI3K/AKT/mTOR axis, leading to anti-ER resistance in ER+BCs.	('BC', 'Phenotype', 'HP:0003002', (95, 97))	('BC', 'Phenotype', 'HP:0003002', (198, 200))	('Her2', 'Gene', '2064', (104, 108))	('ER+BCs', 'Disease', (56, 62))	('BC', 'Phenotype', 'HP:0003002', (59, 61))	('AKT', 'Gene', '207', (147, 150))	('HER3', 'Gene', (137, 141))	('PIK3CA', 'Gene', (33, 39))	('mutations', 'Var', (109, 118))	('hyperactivate', 'PosReg', (119, 132))	('HER3', 'Gene', '2065', (137, 141))	('Her2', 'Gene', (104, 108))	('leading to', 'Reg', (162, 172))	('anti-ER resistance', 'MPA', (173, 191))	('mutations', 'Var', (20, 29))	('AKT', 'Gene', (147, 150))
140209	32333246	Hence, dual blockade of the Her2 and ER pathways is necessary for the treatment of ER+/Her2 mutant BCs.	('Her2', 'Gene', '2064', (28, 32))	('Her2', 'Gene', '2064', (87, 91))	('BC', 'Phenotype', 'HP:0003002', (99, 101))	('men', 'Species', '9606', (75, 78))	('mutant', 'Var', (92, 98))	('Her2', 'Gene', (28, 32))	('Her2', 'Gene', (87, 91))
140210	32333246	Moreover, PIK3CA and MAP3K1 alterations reveal Luminal A status in ER+ metastatic BCs and the patients are likely to clinically benefit from BKM120.	('patients', 'Species', '9606', (94, 102))	('BC', 'Phenotype', 'HP:0003002', (82, 84))	('alterations', 'Var', (28, 39))	('Luminal', 'Chemical', 'MESH:D010634', (47, 54))	('PIK3CA', 'Gene', (10, 16))	('MAP3K1', 'Gene', (21, 27))	('BKM120', 'Chemical', 'MESH:C571178', (141, 147))	('MAP3K1', 'Gene', '4214', (21, 27))	('ER+ metastatic BCs', 'Disease', (67, 85))	('Luminal A status', 'MPA', (47, 63))	('reveal', 'Reg', (40, 46))
140211	32333246	On the other hand, top to 70% of patients with breast cancer brain metastases (BCBM) show the activated PI3K pathway, and GDC-0084 induces apoptosis of PIK3CA-mutant BCBM cells by suppressing activation of AKT and p70 S6 kinase.	('AKT', 'Gene', (206, 209))	('breast cancer brain metastases', 'Disease', 'MESH:D001943', (47, 77))	('breast cancer', 'Phenotype', 'HP:0003002', (47, 60))	('p70', 'Gene', (214, 217))	('BCBM', 'Chemical', '-', (79, 83))	('suppressing', 'NegReg', (180, 191))	('BCBM', 'Chemical', '-', (166, 170))	('breast cancer brain metastases', 'Disease', (47, 77))	('AKT', 'Gene', '207', (206, 209))	('PIK3CA-mutant', 'Gene', (152, 165))	('apoptosis', 'CPA', (139, 148))	('GDC-0084', 'Var', (122, 130))	('BC', 'Phenotype', 'HP:0003002', (79, 81))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('p70', 'Gene', '84959', (214, 217))	('PI3K pathway', 'Pathway', (104, 116))	('BC', 'Phenotype', 'HP:0003002', (166, 168))	('patients', 'Species', '9606', (33, 41))	('induces', 'PosReg', (131, 138))
140216	32333246	Ovarian serous cystadenocarcinoma (OSC), the leading common subtype of epithelial ovarian cancers (EOC) accounting for 90% of OC, harbors overall genetic alterations of PIK3CA (29%), PIK3R1 (5%), PIK3R2 (9%), AKT1 (5%), AKT2 (8%) and PTEN (7%, Table 1) besides the mutant p53 in high-grade OSC (HGOSC), germline BRCA1 and BRCA2 mutations.	('p53', 'Gene', '7157', (272, 275))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('mutant', 'Var', (265, 271))	('Ovarian serous cystadenocarcinoma', 'Disease', (0, 33))	('BRCA1', 'Gene', '672', (312, 317))	('PIK3R1', 'Gene', '5295', (183, 189))	('serous cystadenocarcinoma', 'Phenotype', 'HP:0012887', (8, 33))	('OC', 'Phenotype', 'HP:0100615', (100, 102))	('PTEN', 'Gene', (234, 238))	('carcinoma', 'Phenotype', 'HP:0030731', (24, 33))	('BRCA1', 'Gene', (312, 317))	('high-grade OSC', 'Disease', (279, 293))	('p53', 'Gene', (272, 275))	('OS', 'Phenotype', 'HP:0002669', (297, 299))	('ovarian cancers', 'Phenotype', 'HP:0100615', (82, 97))	('OS', 'Phenotype', 'HP:0002669', (290, 292))	('OS', 'Phenotype', 'HP:0002669', (35, 37))	('PTEN', 'Gene', '5728', (234, 238))	('AKT1', 'Gene', '207', (209, 213))	('PIK3R2', 'Gene', (196, 202))	('epithelial ovarian cancers', 'Disease', (71, 97))	('BRCA2', 'Gene', (322, 327))	('PIK3R1', 'Gene', (183, 189))	('ovarian cancer', 'Phenotype', 'HP:0100615', (82, 96))	('AKT2', 'Gene', '208', (220, 224))	('PIK3R2', 'Gene', '5296', (196, 202))	('AKT1', 'Gene', (209, 213))	('OC', 'Phenotype', 'HP:0100615', (126, 128))	('epithelial ovarian cancers', 'Disease', 'MESH:D000077216', (71, 97))	('mutations', 'Var', (328, 337))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('BRCA2', 'Gene', '675', (322, 327))	('AKT2', 'Gene', (220, 224))	('Ovarian serous cystadenocarcinoma', 'Disease', 'MESH:D018284', (0, 33))
140217	32333246	Furthermore, another subtype of EOC, ovarian clear cell carcinomas (OCCCs), shows more frequently mutations of PIK3CA (33%) and PTEN (5%) in overall 97 OCCC cases, especially mutations of PIK3CA (46%) in the 28 cases of affinity purified OCCCs and OCCC cell lines, than the mutation of PIK3CA and PTEN (both < 5%) in HGOSC.	('PIK3CA', 'Gene', (188, 194))	('CC', 'Phenotype', 'HP:0002664', (69, 71))	('mutations', 'Var', (175, 184))	('carcinoma', 'Phenotype', 'HP:0030731', (56, 65))	('ovarian clear cell carcinomas', 'Disease', (37, 66))	('carcinomas', 'Phenotype', 'HP:0030731', (56, 66))	('OC', 'Phenotype', 'HP:0100615', (68, 70))	('PTEN', 'Gene', (297, 301))	('CC', 'Phenotype', 'HP:0002664', (153, 155))	('ovarian clear cell carcinomas', 'Disease', 'MESH:D008649', (37, 66))	('OC', 'Phenotype', 'HP:0100615', (33, 35))	('CC', 'Phenotype', 'HP:0002664', (249, 251))	('PTEN', 'Gene', (128, 132))	('PIK3CA', 'Gene', (111, 117))	('OS', 'Phenotype', 'HP:0002669', (319, 321))	('PTEN', 'Gene', '5728', (297, 301))	('OC', 'Phenotype', 'HP:0100615', (248, 250))	('OC', 'Phenotype', 'HP:0100615', (238, 240))	('OC', 'Phenotype', 'HP:0100615', (152, 154))	('CC', 'Phenotype', 'HP:0002664', (239, 241))	('PTEN', 'Gene', '5728', (128, 132))	('mutations', 'Var', (98, 107))
140221	32333246	Furthermore, aberrant p53/KRASV12/c-Myc or p53/KRASV12/PI3K/AKT signaling is the minimum requirement for fallopian tube secretory epithelial cells (FTSECs) carcinogenesis, and increased copy number of PIK3CA has been observed in six fallopian tube carcinomas (FTCs).	('copy number', 'Var', (186, 197))	('c-Myc', 'Gene', (34, 39))	('fallopian tube carcinomas', 'Disease', 'MESH:D005185', (233, 258))	('EC', 'Phenotype', 'HP:0012114', (151, 153))	('FTCs', 'Phenotype', 'HP:0030394', (260, 264))	('SE', 'Disease', 'None', (150, 152))	('p53', 'Gene', (43, 46))	('c-Myc', 'Gene', '4609', (34, 39))	('men', 'Species', '9606', (96, 99))	('carcinomas', 'Phenotype', 'HP:0030731', (248, 258))	('carcinogenesis', 'Disease', (156, 170))	('TC', 'Phenotype', 'HP:0002890', (261, 263))	('fallopian tube carcinomas', 'Disease', (233, 258))	('p53', 'Gene', '7157', (22, 25))	('PIK3CA', 'Gene', (201, 207))	('AKT', 'Gene', (60, 63))	('KRAS', 'Gene', '3845', (26, 30))	('aberrant', 'Var', (13, 21))	('TCs', 'Chemical', 'MESH:D013667', (261, 264))	('carcinogenesis', 'Disease', 'MESH:D063646', (156, 170))	('fallopian tube carcinomas', 'Phenotype', 'HP:0030394', (233, 258))	('fallopian tube carcinoma', 'Phenotype', 'HP:0030394', (233, 257))	('increased', 'PosReg', (176, 185))	('p53', 'Gene', (22, 25))	('KRAS', 'Gene', (26, 30))	('KRAS', 'Gene', '3845', (47, 51))	('AKT', 'Gene', '207', (60, 63))	('EC', 'Gene', '1913', (151, 153))	('KRAS', 'Gene', (47, 51))	('p53', 'Gene', '7157', (43, 46))	('observed', 'Reg', (217, 225))	('carcinoma', 'Phenotype', 'HP:0030731', (248, 257))
140224	32333246	A litany of genetic alterations induced by HPVs in CC activate four major upstream pathways (GFR, Notch receptor, RAS isoforms and p110alpha) to stimulate host cell survival, proliferation and carcinogenesis through the PI3K/AKT/mTOR pathway.	('GFR', 'Gene', (93, 96))	('p110alpha', 'Gene', (131, 140))	('p110alpha', 'Gene', '5290', (131, 140))	('host cell survival', 'CPA', (155, 173))	('AKT', 'Gene', '207', (225, 228))	('carcinogenesis', 'Disease', (193, 207))	('genetic alterations', 'Var', (12, 31))	('CC', 'Phenotype', 'HP:0002664', (51, 53))	('AKT', 'Gene', (225, 228))	('stimulate', 'PosReg', (145, 154))	('carcinogenesis', 'Disease', 'MESH:D063646', (193, 207))	('HPV', 'Species', '10566', (43, 46))	('proliferation', 'CPA', (175, 188))
140225	32333246	Considerable overall genetic alterations of PI3K/AKT pathway in CC have emerged with PIK3CA (39%) and PTEN (13%, Table 1).	('AKT', 'Gene', (49, 52))	('CC', 'Phenotype', 'HP:0002664', (64, 66))	('PTEN', 'Gene', (102, 106))	('AKT', 'Gene', '207', (49, 52))	('genetic alterations', 'Var', (21, 40))	('PTEN', 'Gene', '5728', (102, 106))
140226	32333246	In particular, the mutations of PIK3CA E542K and E545K promote glycolysis and proliferation of CC in vitro and vivo.	('CC', 'Phenotype', 'HP:0002664', (95, 97))	('E542K', 'Var', (39, 44))	('E545K', 'Mutation', 'rs104886003', (49, 54))	('E545K', 'Var', (49, 54))	('proliferation', 'CPA', (78, 91))	('E542K', 'Mutation', 'rs121913273', (39, 44))	('promote', 'PosReg', (55, 62))	('glycolysis', 'MPA', (63, 73))	('PIK3CA', 'Gene', (32, 38))
140228	32333246	Currently, only preclinical trials of PI3K inhibitor LY294002 has revealed it significantly radiosensitized CC cell lines in vitro and vivo, and the terminated clinical trials of AKT inhibitor GSK2141795 (NCT01958112, Table 3) has tried to display a novel treatment approach to patients of CC.	('AKT', 'Gene', (179, 182))	('men', 'Species', '9606', (261, 264))	('CC', 'Phenotype', 'HP:0002664', (290, 292))	('LY294002', 'Chemical', 'MESH:C085911', (53, 61))	('radiosensitized', 'NegReg', (92, 107))	('LY294002', 'Var', (53, 61))	('CC', 'Phenotype', 'HP:0002664', (108, 110))	('AKT', 'Gene', '207', (179, 182))	('patients', 'Species', '9606', (278, 286))	('GSK2141795', 'Chemical', 'MESH:C000595149', (193, 203))
140230	32333246	Particularly, the endometrioid type of EC (EEC) progressing from intraepithelial endometrial neoplasia in a large proportion of cases belongs to ER-related cancer, and is directly associated with inactivation of PTEN.	('EC', 'Phenotype', 'HP:0012114', (44, 46))	('endometrioid type', 'Disease', (18, 35))	('inactivation', 'Var', (196, 208))	('EC', 'Gene', '1913', (44, 46))	('cancer', 'Disease', (156, 162))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('neoplasia', 'Phenotype', 'HP:0002664', (93, 102))	('associated', 'Reg', (180, 190))	('EEC', 'Gene', (43, 46))	('EC', 'Gene', '1913', (39, 41))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('EEC', 'Gene', '1913', (43, 46))	('PTEN', 'Gene', (212, 216))	('EC', 'Phenotype', 'HP:0012114', (39, 41))	('PTEN', 'Gene', '5728', (212, 216))	('endometrial neoplasia', 'Disease', 'MESH:D014591', (81, 102))	('endometrial neoplasia', 'Disease', (81, 102))
140232	32333246	What's more, it's revealed that the majority of the G3 EEC samples have exhibited PIK3CA mutations (39%) and PTEN mutations (67%).	('EEC', 'Gene', '1913', (55, 58))	('PIK3CA', 'Gene', (82, 88))	('mutations', 'Var', (114, 123))	('PTEN', 'Gene', (109, 113))	('EC', 'Phenotype', 'HP:0012114', (56, 58))	('PTEN', 'Gene', '5728', (109, 113))	('mutations', 'Var', (89, 98))	('EEC', 'Gene', (55, 58))
140233	32333246	Moreover, JQ1, NEDD4, PDCD4, miR-101, -494-3p, Lnc RNA LINP1 and MEG3 have shown their aptitudes for controlling tumorigenesis, proliferation, apoptosis, invasion, progression of EC cells via PI3K/AKT pathway.	('PDCD4', 'Gene', '27250', (22, 27))	('AKT', 'Gene', (197, 200))	('proliferation', 'CPA', (128, 141))	('apoptosis', 'CPA', (143, 152))	('miR-101', 'Var', (29, 36))	('LINP1', 'Gene', '108570035', (55, 60))	('MEG3', 'Gene', '55384', (65, 69))	('EC', 'Gene', '1913', (179, 181))	('invasion', 'CPA', (154, 162))	('NEDD4', 'Gene', (15, 20))	('tumor', 'Disease', (113, 118))	('progression', 'CPA', (164, 175))	('AKT', 'Gene', '207', (197, 200))	('EC', 'Phenotype', 'HP:0012114', (179, 181))	('controlling', 'PosReg', (101, 112))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('LINP1', 'Gene', (55, 60))	('PDCD4', 'Gene', (22, 27))	('NEDD4', 'Gene', '4734', (15, 20))	('MEG3', 'Gene', (65, 69))
140236	32333246	Seeing that loss of function of PTEN, resulting in dysregulated activation of the PI3K signaling network, is recognized as one of the most common driving events in PCa development, the overall genetic alterations of PI3K/AKT pathway in PCa have demonstrated with PIK3CA (6%), and visible PTEN (18%, Table 1).	('PCa', 'Phenotype', 'HP:0012125', (236, 239))	('AKT', 'Gene', '207', (221, 224))	('PI3K signaling network', 'Pathway', (82, 104))	('PTEN', 'Gene', (32, 36))	('dysregulated', 'MPA', (51, 63))	('genetic alterations', 'Var', (193, 212))	('PTEN', 'Gene', '5728', (32, 36))	('PC', 'Phenotype', 'HP:0002894', (236, 238))	('AKT', 'Gene', (221, 224))	('PTEN', 'Gene', (288, 292))	('PCa', 'Phenotype', 'HP:0012125', (164, 167))	('PC', 'Phenotype', 'HP:0002894', (164, 166))	('PTEN', 'Gene', '5728', (288, 292))	('activation', 'PosReg', (64, 74))	('loss of function', 'NegReg', (12, 28))	('men', 'Species', '9606', (175, 178))
140247	32333246	Indeed, PIK3CA mutations are considered as an early genetic alteration associated with FGFR3 mutations in superficial papillary NMIBC and the activation of the PI3K/AKT pathway is identified to induce urothelial carcinoma of the renal pelvis.	('AKT', 'Gene', (165, 168))	('mutations', 'Var', (93, 102))	('activation', 'PosReg', (142, 152))	('FGFR3', 'Gene', '2261', (87, 92))	('renal pelvis', 'Phenotype', 'HP:0000125', (229, 241))	('mutations', 'Var', (15, 24))	('induce', 'Reg', (194, 200))	('carcinoma', 'Phenotype', 'HP:0030731', (212, 221))	('FGFR3', 'Gene', (87, 92))	('AKT', 'Gene', '207', (165, 168))	('BC', 'Phenotype', 'HP:0003002', (131, 133))	('urothelial carcinoma of the renal pelvis', 'Disease', 'MESH:C538614', (201, 241))	('urothelial carcinoma of the renal pelvis', 'Disease', (201, 241))	('PIK3CA', 'Gene', (8, 14))
140261	32333246	Furthermore, differences related to EBV status or histological subtypes are observed for PI3K signaling in pediatric HL patients by using hybrid capture-targeted next-generation sequencing of circulating cell-free DNA (ccfDNA), where MCCHL and EBV+ cases were less frequently affected by mutations in ITPKB and GNA13 genes.	('EBV', 'Species', '10376', (244, 247))	('ITPKB', 'Gene', (301, 306))	('CC', 'Phenotype', 'HP:0002664', (235, 237))	('HL', 'CellLine', 'CVCL:2492', (117, 119))	('HL', 'Phenotype', 'HP:0012189', (117, 119))	('GNA13', 'Gene', '10672', (311, 316))	('ITPKB', 'Gene', '3707', (301, 306))	('EBV', 'Species', '10376', (36, 39))	('HL', 'Phenotype', 'HP:0012189', (237, 239))	('CHL', 'Disease', (236, 239))	('HL', 'CellLine', 'CVCL:2492', (237, 239))	('CHL', 'Disease', 'MESH:D006689', (236, 239))	('patients', 'Species', '9606', (120, 128))	('GNA13', 'Gene', (311, 316))	('mutations', 'Var', (288, 297))
140269	32333246	Despite the recognized fact that overwhelming majority of FL cases have the characteristic (14;18) translocation involving the IgH/bcl-2 genes, while B-cells "arrested" in germinal centers of FL acquire dozens of additional genetic aberrations that influence key pathways controlling their physiological development including B Cell Receptor (BCR) signaling, PI3K/AKT pathway, and so on.	('translocation', 'Var', (99, 112))	('AKT', 'Gene', (364, 367))	('BC', 'Phenotype', 'HP:0003002', (343, 345))	('IgH', 'Gene', '3492', (127, 130))	('IgH', 'Gene', (127, 130))	('bcl-2', 'Gene', '596', (131, 136))	('bcl-2', 'Gene', (131, 136))	('men', 'Species', '9606', (311, 314))	('AKT', 'Gene', '207', (364, 367))	('influence', 'Reg', (249, 258))
140270	32333246	Especially, the facts that deletion of PIK3CD results in decreased number of marginal zone (MZ) B cells and pleural/peritoneal cavities in mice, as well as the evidences that PIK3CD-depleted B cells also fail to proliferate in vitro in response to BCR or CD40 signals and have impaired both humoral T-cell-dependent and T-cell-independent responses suggest that p110delta plays a critical role in B cell homeostasis and function.	('T-cell-independent responses', 'CPA', (320, 348))	('PIK3CD', 'Gene', (39, 45))	('impaired both humoral T', 'Disease', (277, 300))	('impaired both humoral T', 'Disease', 'MESH:C562390', (277, 300))	('deletion', 'Var', (27, 35))	('mice', 'Species', '10090', (139, 143))	('BC', 'Phenotype', 'HP:0003002', (248, 250))	('CD40', 'Gene', '21939', (255, 259))	('decreased', 'NegReg', (57, 66))	('CD40', 'Gene', (255, 259))
140271	32333246	Consequently, following with the world's first selective PI3Kdelta inhibitor CAL-101 was approved by the FDA for the treatment of FL, CLL and SLL in 2014 [NCT01282424, NCT02136511], the PI3K/AKT inhibitors have shown remarkable activity in an increasing subset of patients with NHL (Tables 2, 3).	('HL', 'CellLine', 'CVCL:2492', (279, 281))	('SLL', 'Gene', (142, 145))	('AKT', 'Gene', '207', (191, 194))	('NCT02136511]', 'Var', (168, 180))	('CAL-101', 'Chemical', 'MESH:C552946', (77, 84))	('HL', 'Phenotype', 'HP:0012189', (279, 281))	('NHL', 'Disease', (278, 281))	('AKT', 'Gene', (191, 194))	('patients', 'Species', '9606', (264, 272))	('SLL', 'Gene', '347734', (142, 145))	('activity', 'MPA', (228, 236))	('PI3Kdelta', 'Gene', (57, 66))	('men', 'Species', '9606', (122, 125))	('PI3Kdelta', 'Gene', '5293', (57, 66))
140274	32333246	One study shows that deregulation of the PI3K/AKT pathway by the inactivation of PTEN are found in 55% of GCB-DLBCL cases, but only in 14% of non-GCB-DLBCL and worsens prognosis in 248 primary DLBCL patients.	('AKT', 'Gene', '207', (46, 49))	('BC', 'Phenotype', 'HP:0003002', (112, 114))	('deregulation', 'PosReg', (21, 33))	('inactivation', 'Var', (65, 77))	('BC', 'Phenotype', 'HP:0003002', (195, 197))	('AKT', 'Gene', (46, 49))	('PTEN', 'Gene', (81, 85))	('GCB-DLBCL', 'Disease', (106, 115))	('patients', 'Species', '9606', (199, 207))	('PTEN', 'Gene', '5728', (81, 85))	('BC', 'Phenotype', 'HP:0003002', (152, 154))
140277	32333246	Preclinical trial of BAY80-6946 in DLBCL cells and the clinical trials of BAY80-6946, INCB050465, CUDC-907 and MK2206 in patients with DLBCL have improved our ability to manage patients with this disorder (Table 2).	('BAY80-6946', 'Chemical', 'MESH:C000589253', (74, 84))	('INCB050465', 'Var', (86, 96))	('patients', 'Species', '9606', (177, 185))	('MK2206', 'Chemical', 'MESH:C548887', (111, 117))	('BC', 'Phenotype', 'HP:0003002', (137, 139))	('BAY80-6946', 'Var', (74, 84))	('improved', 'PosReg', (146, 154))	('BAY80-6946', 'Chemical', 'MESH:C000589253', (21, 31))	('BAY80-6946', 'Var', (21, 31))	('CUDC-907', 'Chemical', 'MESH:C576940', (98, 106))	('MK2206', 'Var', (111, 117))	('DLBCL', 'Disease', (135, 140))	('patients', 'Species', '9606', (121, 129))	('BC', 'Phenotype', 'HP:0003002', (37, 39))
140278	32333246	T/NK-NHL is a heterogeneous group of malignancies often associated with poor clinical outcomes, and each malignancy within this group is characterized by unique clinicopathologic features, while T cell receptor/NF/kB (TCR/NF/kB) signaling highly enriched and dysregulation of JAK/STAT pathway, specifically aberrant STAT3 activation, are the common feature among these lymphomas.	('STAT', 'Gene', '6774', (280, 284))	('lymphoma', 'Phenotype', 'HP:0002665', (369, 377))	('STAT', 'Gene', (280, 284))	('associated', 'Reg', (56, 66))	('STAT3', 'Gene', (316, 321))	('lymphomas', 'Disease', 'MESH:D008223', (369, 378))	('lymphomas', 'Phenotype', 'HP:0002665', (369, 378))	('HL', 'CellLine', 'CVCL:2492', (6, 8))	('STAT3', 'Gene', '6774', (316, 321))	('aberrant', 'Var', (307, 315))	('malignancy', 'Disease', 'MESH:D009369', (105, 115))	('TC', 'Phenotype', 'HP:0002890', (218, 220))	('STAT', 'Gene', '6774', (316, 320))	('malignancies', 'Disease', 'MESH:D009369', (37, 49))	('STAT', 'Gene', (316, 320))	('HL', 'Phenotype', 'HP:0012189', (6, 8))	('malignancies', 'Disease', (37, 49))	('activation', 'PosReg', (322, 332))	('lymphomas', 'Disease', (369, 378))	('malignancy', 'Disease', (105, 115))	('dysregulation', 'Var', (259, 272))
140279	32333246	A study with 426 adult T cell leukemia/lymphoma (ATL) cases associated with human T cell leukemia virus type-1 (HTLV-1) infection shows that PI3KCD mutation is also observed in 9 of 370 (2.4%) cases besides the highly enriched for TCR/NF/kB signaling, T cell trafficking and other T cell-related pathways.	('KC', 'Phenotype', 'HP:0009726', (144, 146))	('lymphoma', 'Phenotype', 'HP:0002665', (39, 47))	('human T cell leukemia virus type-1 (HTLV-1) infection', 'Disease', 'MESH:D015490', (76, 129))	('leukemia', 'Phenotype', 'HP:0001909', (30, 38))	('leukemia', 'Phenotype', 'HP:0001909', (89, 97))	('adult T cell leukemia/lymphoma', 'Disease', 'MESH:D015459', (17, 47))	('mutation', 'Var', (148, 156))	('PI3KCD mutation', 'Var', (141, 156))	('TCR/NF/kB signaling', 'Pathway', (231, 250))	('TC', 'Phenotype', 'HP:0002890', (231, 233))	('adult T cell leukemia/lymphoma', 'Disease', (17, 47))
140283	32333246	Despite that hotspot mutations of PIK3CA (E542K, E545K and H1047R) and AKT1 genes (E17K) are absent in MM, the R310C mutation of PIK3CA gene is identified in some cases of MM, as well as ROR2 drives the interaction of MM cells with TME through AKT activation.	('R310C', 'Var', (111, 116))	('E545K', 'Var', (49, 54))	('ROR2', 'Gene', '4920', (187, 191))	('ROR2', 'Gene', (187, 191))	('AKT1', 'Gene', (71, 75))	('R310C', 'Mutation', 'rs780572147', (111, 116))	('PIK3CA', 'Gene', (34, 40))	('AKT', 'Gene', '207', (71, 74))	('AKT', 'Gene', (244, 247))	('H1047R', 'Var', (59, 65))	('activation', 'PosReg', (248, 258))	('PIK3CA', 'Gene', (129, 135))	('interaction', 'Interaction', (203, 214))	('H1047R', 'Mutation', 'rs121913279', (59, 65))	('E542K', 'Mutation', 'rs121913273', (42, 47))	('E542K', 'Var', (42, 47))	('AKT', 'Gene', '207', (244, 247))	('E17K', 'Mutation', 'rs121434592', (83, 87))	('E545K', 'Mutation', 'rs104886003', (49, 54))	('AKT', 'Gene', (71, 74))	('AKT1', 'Gene', '207', (71, 75))
140284	32333246	Furthermore, only the blockade of PIK3CA is sufficient to induce cell death in a sizeable subgroup of MM samples, and PIK3CA inhibitor BYL-719 in combination treatments with other compounds establishes anti-myeloma agents resulted in strongly enhanced MM cell death.	('myeloma', 'Disease', (207, 214))	('enhanced', 'PosReg', (243, 251))	('death', 'Disease', 'MESH:D003643', (260, 265))	('PIK3CA', 'Gene', (34, 40))	('blockade', 'Var', (22, 30))	('MM cell death', 'Disease', (252, 265))	('men', 'Species', '9606', (163, 166))	('MM cell death', 'Disease', 'MESH:D003643', (252, 265))	('death', 'Disease', (260, 265))	('myeloma', 'Disease', 'MESH:D009101', (207, 214))	('death', 'Disease', 'MESH:D003643', (70, 75))	('death', 'Disease', (70, 75))	('PIK3CA', 'Gene', (118, 124))	('BYL-719', 'Chemical', 'MESH:C585539', (135, 142))
140285	32333246	Therefore, some preclinical studies have examined PI3K/AKT pathway inhibitors in MM, such as TAS-117, PI-103 and BEZ235.	('PI-103', 'Var', (102, 108))	('AKT', 'Gene', (55, 58))	('BEZ235', 'Chemical', 'MESH:C531198', (113, 119))	('PI-103', 'Chemical', 'MESH:C522973', (102, 108))	('AKT', 'Gene', '207', (55, 58))	('TAS', 'Chemical', 'MESH:D013635', (93, 96))
140286	32333246	Fortunately, some of the clinical trials of PI3K/AKT inhibitors have demonstrated encouraging clinical activity in relapsed and relapsed/refractory (R/R) MM (NCT01002248; NCT01476137; NCT00881946) (Tables 2 and 3).	('AKT', 'Gene', '207', (49, 52))	('NCT01002248', 'Var', (158, 169))	('AKT', 'Gene', (49, 52))
140293	32333246	Since CAL-101 has been approved for marketing in patients with CLL/SLL, the clinical trials of PI3K/AKT inhibitors such as: BAY80-6946, KM120, YY-20394, BEZ235, PKI-587, IPI-145, CAL-101, TGR-1202, MK2206 and GSK2141795 try to seek new therapeutic approach in relapse or refractory patients with CLL or newly diagnosed AML and acute lymphocytic leukemia (ALL, Tables 2 and 3).	('KM120', 'Var', (136, 141))	('AML', 'Disease', 'MESH:D015470', (319, 322))	('AML', 'Disease', (319, 322))	('CAL-101', 'Chemical', 'MESH:C552946', (179, 186))	('acute lymphocytic leukemia', 'Disease', 'MESH:D054198', (327, 353))	('AML', 'Phenotype', 'HP:0004808', (319, 322))	('AKT', 'Gene', (100, 103))	('acute lymphocytic leukemia', 'Phenotype', 'HP:0006721', (327, 353))	('IPI-145', 'Chemical', 'MESH:C586691', (170, 177))	('patients', 'Species', '9606', (282, 290))	('GSK2141795', 'Chemical', 'MESH:C000595149', (209, 219))	('leukemia', 'Phenotype', 'HP:0001909', (345, 353))	('MK2206', 'Chemical', 'MESH:C548887', (198, 204))	('patients', 'Species', '9606', (49, 57))	('BAY80-6946', 'Chemical', 'MESH:C000589253', (124, 134))	('AKT', 'Gene', '207', (100, 103))	('SLL', 'Gene', '347734', (67, 70))	('CLL', 'Disease', (296, 299))	('SLL', 'Gene', (67, 70))	('acute lymphocytic leukemia', 'Disease', (327, 353))	('CAL-101', 'Chemical', 'MESH:C552946', (6, 13))	('BEZ235', 'Chemical', 'MESH:C531198', (153, 159))
140297	32333246	Besides the alterations of TP53, RB1, ATRX and DLG2 in OS, total genetic alterations in the PI3K/AKT/mTOR pathway are observed in 14 of 59 (24%) OS patients, and PIK3CA and mTOR are vital for the proliferation and survival of OS cells (Table 1).	('AKT', 'Gene', '207', (97, 100))	('TP53', 'Gene', '7157', (27, 31))	('alterations', 'Reg', (73, 84))	('TP53', 'Gene', (27, 31))	('patients', 'Species', '9606', (148, 156))	('OS', 'Phenotype', 'HP:0002669', (55, 57))	('OS', 'Phenotype', 'HP:0002669', (145, 147))	('alterations', 'Var', (12, 23))	('DLG2', 'Gene', '1740', (47, 51))	('ATRX', 'Gene', (38, 42))	('AKT', 'Gene', (97, 100))	('RB1', 'Gene', (33, 36))	('OS', 'Phenotype', 'HP:0002669', (226, 228))	('ATRX', 'Gene', '546', (38, 42))	('DLG2', 'Gene', (47, 51))	('RB1', 'Gene', '5925', (33, 36))
140298	32333246	Furthermore, dual PI3K/mTOR inhibitors are effective at inducing apoptosis in primary OS cell cultures in vitro in both human and mouse OS, while specific PI3K or mTOR inhibitors are not effective, which is consistent with the preclinical study's result that BEZ235 inhibits proliferation and tumor development of OS cells in vivo.	('human', 'Species', '9606', (120, 125))	('tumor', 'Disease', 'MESH:D009369', (293, 298))	('men', 'Species', '9606', (306, 309))	('tumor', 'Phenotype', 'HP:0002664', (293, 298))	('OS', 'Phenotype', 'HP:0002669', (136, 138))	('inducing', 'Reg', (56, 64))	('tumor', 'Disease', (293, 298))	('apoptosis', 'CPA', (65, 74))	('BEZ235', 'Chemical', 'MESH:C531198', (259, 265))	('inhibits', 'NegReg', (266, 274))	('OS', 'Phenotype', 'HP:0002669', (86, 88))	('PI3K/mTOR', 'Var', (18, 27))	('mouse', 'Species', '10090', (130, 135))	('OS', 'Phenotype', 'HP:0002669', (314, 316))
140302	32333246	In addition, hnRNPM motifs are significantly enriched under the inhibition of the PI3K/AKT/mTOR pathway by BEZ235 in EWS cells.	('EWS', 'Phenotype', 'HP:0012254', (117, 120))	('EWS', 'Gene', '2130', (117, 120))	('EWS', 'Gene', (117, 120))	('AKT', 'Gene', (87, 90))	('BEZ235', 'Var', (107, 113))	('inhibition', 'NegReg', (64, 74))	('BEZ235', 'Chemical', 'MESH:C531198', (107, 113))	('hnRNPM', 'Gene', (13, 19))	('hnRNPM', 'Gene', '4670', (13, 19))	('AKT', 'Gene', '207', (87, 90))
140304	32333246	Currently, pediatric patients of OS or EWS may be beneficial from the ongoing clinical trials of BAY80-6946 (NCT03458728) and LY3023414 (NCT03213678, Table 2).	('BAY80-6946', 'Chemical', 'MESH:C000589253', (97, 107))	('OS', 'Phenotype', 'HP:0002669', (33, 35))	('NCT03458728', 'Var', (109, 120))	('patients', 'Species', '9606', (21, 29))	('EWS', 'Gene', '2130', (39, 42))	('EWS', 'Gene', (39, 42))	('EWS', 'Phenotype', 'HP:0012254', (39, 42))	('LY3023414', 'Chemical', 'MESH:C000621566', (126, 135))	('BAY80-6946 (NCT03458728', 'Var', (97, 120))	('LY3023414', 'Var', (126, 135))
140307	32333246	Even though solar ultraviolet exposure is the main environmental risk factor for cutaneous melanoma development, there are still genetic susceptibility factors, such as germline mutations in p16 or CDK4, and genesis of melanoma, such as the main genetic drivers BRAF, NF1 and NRAS mutations.	('men', 'Species', '9606', (107, 110))	('melanoma', 'Disease', 'MESH:D008545', (91, 99))	('CDK4', 'Gene', '1019', (198, 202))	('NRAS', 'Gene', '4893', (276, 280))	('BRAF', 'Gene', (262, 266))	('melanoma', 'Disease', 'MESH:D008545', (219, 227))	('NF1', 'Gene', '4763', (268, 271))	('p16', 'Gene', (191, 194))	('NF1', 'Gene', (268, 271))	('NRAS', 'Gene', (276, 280))	('melanoma', 'Phenotype', 'HP:0002861', (91, 99))	('melanoma', 'Disease', (91, 99))	('p16', 'Gene', '1029', (191, 194))	('melanoma', 'Phenotype', 'HP:0002861', (219, 227))	('melanoma', 'Disease', (219, 227))	('CDK4', 'Gene', (198, 202))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (81, 99))	('mutations', 'Var', (281, 290))	('cutaneous melanoma', 'Disease', (81, 99))	('mutations', 'Var', (178, 187))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (81, 99))	('men', 'Species', '9606', (58, 61))
140308	32333246	Since BRAFV600E-mutated melanomagenesis is often accompanied by silencing of PTEN, the increasing genetic alterations in PI3K/AKT pathway have been observed in melanoma including: PIK3CA (5%) and PTEN (12%, Table 1).	('BRAFV600E', 'Mutation', 'rs113488022', (6, 15))	('melanoma', 'Disease', 'MESH:D008545', (24, 32))	('AKT', 'Gene', (126, 129))	('melanoma', 'Phenotype', 'HP:0002861', (160, 168))	('melanoma', 'Disease', (160, 168))	('melanoma', 'Disease', 'MESH:D008545', (160, 168))	('PTEN', 'Gene', (77, 81))	('PTEN', 'Gene', '5728', (77, 81))	('silencing', 'NegReg', (64, 73))	('PTEN', 'Gene', (196, 200))	('AKT', 'Gene', '207', (126, 129))	('PTEN', 'Gene', '5728', (196, 200))	('melanoma', 'Phenotype', 'HP:0002861', (24, 32))	('melanoma', 'Disease', (24, 32))	('BRAFV600E-mutated', 'Var', (6, 23))
140309	32333246	Notably, dysfunction mutations of NF1 induce BRAF inhibitor resistance by activating RAS and its downstreams including both MAPK and PI3K/AKT/mTOR pathways in cutaneous melanoma.	('activating', 'PosReg', (74, 84))	('MAPK', 'Pathway', (124, 128))	('melanoma', 'Phenotype', 'HP:0002861', (169, 177))	('AKT', 'Gene', (138, 141))	('dysfunction mutations', 'Var', (9, 30))	('cutaneous melanoma', 'Disease', (159, 177))	('RAS', 'Pathway', (85, 88))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (159, 177))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (159, 177))	('BRAF inhibitor resistance', 'MPA', (45, 70))	('NF1', 'Gene', (34, 37))	('NF1', 'Gene', '4763', (34, 37))	('AKT', 'Gene', '207', (138, 141))
140310	32333246	Even more, the onset of MEK1/2 inhibitor resistance in BRAF-mutated melanoma can be forestalled by PI3K blockade.	('MEK', 'Gene', (24, 27))	('melanoma', 'Phenotype', 'HP:0002861', (68, 76))	('MEK', 'Gene', '5609', (24, 27))	('melanoma', 'Disease', (68, 76))	('melanoma', 'Disease', 'MESH:D008545', (68, 76))	('BRAF-mutated', 'Var', (55, 67))
140312	32333246	And now, a limited number of clinical trials of PI3K/AKT pathway inhibitors (BKM120, PX-866, GSK2636771, GSK2141795 and MK2206) try to find new ways other than current classic RAF/MEK/MAPK pathway inhibitors to treat the patients with metastatic or advanced melanomas (Tables 2 and 3).	('melanomas', 'Disease', 'MESH:D008545', (258, 267))	('patients', 'Species', '9606', (221, 229))	('melanomas', 'Disease', (258, 267))	('MEK', 'Gene', '5609', (180, 183))	('RAF', 'Gene', (176, 179))	('PX-866', 'Chemical', 'MESH:C496788', (85, 91))	('MEK', 'Gene', (180, 183))	('AKT', 'Gene', (53, 56))	('melanomas', 'Phenotype', 'HP:0002861', (258, 267))	('MK2206', 'Chemical', 'MESH:C548887', (120, 126))	('BKM120', 'Chemical', 'MESH:C571178', (77, 83))	('GSK2636771', 'Chemical', 'MESH:C000627739', (93, 103))	('RAF', 'Gene', '673;109880', (176, 179))	('melanoma', 'Phenotype', 'HP:0002861', (258, 266))	('GSK2141795', 'Chemical', 'MESH:C000595149', (105, 115))	('metastatic', 'Disease', (235, 245))	('MK2206', 'Var', (120, 126))	('AKT', 'Gene', '207', (53, 56))	('GSK2141795', 'Var', (105, 115))
140313	32333246	In general, ATC, NSCLC, EC, GC, CRC, BC, OC, CC, EC and BLCA exhibit higher frequencies of PIK3CA mutations than other tumors, while PTEN mutations are predominantly found in GBM, EC and PCa (Fig.	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('NSCLC', 'Disease', (17, 22))	('EC', 'Phenotype', 'HP:0012114', (24, 26))	('CC', 'Phenotype', 'HP:0002664', (45, 47))	('PCa', 'Disease', (187, 190))	('EC', 'Phenotype', 'HP:0012114', (180, 182))	('PTEN', 'Gene', '5728', (133, 137))	('NSCLC', 'Phenotype', 'HP:0030358', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('LC', 'Phenotype', 'HP:0100526', (20, 22))	('PIK3CA', 'Gene', (91, 97))	('tumors', 'Disease', (119, 125))	('GBM', 'Disease', (175, 178))	('SCLC', 'Phenotype', 'HP:0030357', (18, 22))	('tumors', 'Disease', 'MESH:D009369', (119, 125))	('CRC', 'Disease', (32, 35))	('TC', 'Phenotype', 'HP:0002890', (13, 15))	('EC', 'Gene', '1913', (49, 51))	('LC', 'Phenotype', 'HP:0100526', (57, 59))	('CRC', 'Phenotype', 'HP:0003003', (32, 35))	('OC', 'Phenotype', 'HP:0100615', (41, 43))	('BLCA', 'Phenotype', 'HP:0009725', (56, 60))	('BC', 'Phenotype', 'HP:0003002', (37, 39))	('PC', 'Phenotype', 'HP:0002894', (187, 189))	('NSCLC', 'Disease', 'MESH:D002289', (17, 22))	('EC', 'Gene', '1913', (24, 26))	('mutations', 'Var', (98, 107))	('PTEN', 'Gene', (133, 137))	('EC', 'Phenotype', 'HP:0012114', (49, 51))	('EC', 'Gene', '1913', (180, 182))	('PCa', 'Phenotype', 'HP:0012125', (187, 190))
140314	32333246	No matter what kind of the genetic alteration happens in PI3K/AKT pathway, or the factor influences cellular behaviors via PI3K/AKT pathway, it leads to the hyper-activation of PI3K/AKT pathway.	('AKT', 'Gene', (62, 65))	('influences', 'Reg', (89, 99))	('AKT', 'Gene', (128, 131))	('cellular behaviors', 'CPA', (100, 118))	('AKT', 'Gene', '207', (182, 185))	('genetic alteration', 'Var', (27, 45))	('AKT', 'Gene', '207', (62, 65))	('alteration', 'Var', (35, 45))	('AKT', 'Gene', '207', (128, 131))	('hyper-activation', 'PosReg', (157, 173))	('AKT', 'Gene', (182, 185))
140320	32333246	Obviously, CAL-101 not only causes a rapid and sustained reduction in lymphadenopathy, but also regulates the immune environment in CLL.	('immune environment', 'MPA', (110, 128))	('lymphadenopathy', 'Disease', (70, 85))	('men', 'Species', '9606', (124, 127))	('reduction', 'NegReg', (57, 66))	('CAL-101', 'Var', (11, 18))	('lymphadenopathy', 'Disease', 'MESH:D008206', (70, 85))	('lymphadenopathy', 'Phenotype', 'HP:0002716', (70, 85))	('regulates', 'Reg', (96, 105))	('CAL-101', 'Chemical', 'MESH:C552946', (11, 18))
140323	32333246	There are some other embarrassments findings that small molecule PI3K/AKT pathway inhibitors could promote the (re)phosphorylation of AKT2 which is linked to the redistribution and adaptive reprogramming of mitochondria, contributing to drug resistance and metastasis in GBM cells.	('metastasis', 'CPA', (257, 267))	('AKT', 'Gene', (134, 137))	('AKT', 'Gene', '207', (70, 73))	('drug resistance', 'CPA', (237, 252))	('drug resistance', 'Phenotype', 'HP:0020174', (237, 252))	('promote', 'PosReg', (99, 106))	('AKT', 'Gene', (70, 73))	('inhibitors', 'Var', (82, 92))	('contributing', 'Reg', (221, 233))	('AKT2', 'Gene', (134, 138))	('AKT', 'Gene', '207', (134, 137))	('men', 'Species', '9606', (30, 33))	('AKT2', 'Gene', '208', (134, 138))
140353	32408907	Liyi Xie demonstrated high PDPN expression significantly associated with worse clinicopathological features (pleural invasion, et al) and worse progression-free survival (PFS).	('PDPN', 'Gene', '10630', (27, 31))	('PDPN', 'Gene', (27, 31))	('expression', 'MPA', (32, 42))	('progression-free survival', 'CPA', (144, 169))	('high', 'Var', (22, 26))	('pleural invasion', 'Disease', 'MESH:D010995', (109, 125))	('pleural invasion', 'Disease', (109, 125))	('associated', 'Reg', (57, 67))
140376	32408907	After the deletion of Juan Li study, PDPN expression showed significant associations with better OS in LUSC patients (HR = 2.14, 95% CI 1.45-3.15, P = 0.0001, fixed effect) (Fig.	('LUSC', 'Disease', (103, 107))	('LUSC', 'Phenotype', 'HP:0030359', (103, 107))	('deletion', 'Var', (10, 18))	('patients', 'Species', '9606', (108, 116))	('PDPN', 'Gene', '10630', (37, 41))	('PDPN', 'Gene', (37, 41))	('better OS', 'Disease', (90, 99))
140412	32408907	Thus, it could explain why low PDPN may predict poor survival in LUSC.	('LUSC', 'Phenotype', 'HP:0030359', (65, 69))	('LUSC', 'Disease', (65, 69))	('PDPN', 'Gene', '10630', (31, 35))	('PDPN', 'Gene', (31, 35))	('low', 'Var', (27, 30))
140460	30662515	PD-L1 expression was separated in three categories based on the recommendation from Dako and pembrolizumab clinical trial: (1) if TPS <1%, no expression; (2) if 50%> TPS >=1%, low PD-L1 expression; (3) IF TPS >=50%, high PD-L1 expression.	('pembrolizumab', 'Chemical', 'MESH:C582435', (93, 106))	('TPS <1%', 'Var', (130, 137))	('PD-L1', 'Gene', '29126', (180, 185))	('PD-L1', 'Gene', '29126', (221, 226))	('TPS >=50%', 'Var', (205, 214))	('expression', 'MPA', (227, 237))	('PD-L1', 'Gene', (0, 5))	('expression', 'MPA', (186, 196))	('expression', 'MPA', (142, 152))	('PD-L1', 'Gene', (180, 185))	('PD-L1', 'Gene', '29126', (0, 5))	('low', 'NegReg', (176, 179))	('PD-L1', 'Gene', (221, 226))
140467	30662515	Fisher's exact test was used as appropriate to compare the percentages of PD-L1 high- and low-expression in both AC and SCC.	('low-expression', 'NegReg', (90, 104))	('SCC', 'Phenotype', 'HP:0002860', (120, 123))	('PD-L1', 'Gene', (74, 79))	('SCC', 'Gene', '6317', (120, 123))	('high-', 'Var', (80, 85))	('PD-L1', 'Gene', '29126', (74, 79))	('SCC', 'Gene', (120, 123))
140493	30662515	In summary, of total 391 NSCLC TMA cases, 156 (39.90%) cases were positive for PD-L1 expression including 99 (25.32%) cases with TPS 1%-49% and 57 (14.58%) cases with TPS >=50%.	('NSCLC TMA', 'Disease', (25, 34))	('NSCLC TMA', 'Disease', 'MESH:D002289', (25, 34))	('positive', 'Reg', (66, 74))	('PD-L1', 'Gene', (79, 84))	('TPS 1%-49%', 'Var', (129, 139))	('NSCLC', 'Phenotype', 'HP:0030358', (25, 30))	('PD-L1', 'Gene', '29126', (79, 84))
140499	30662515	In a large randomized controlled trial also using Dako 22C3 antibody, 1475 of 2222 (66.38%) patients had PD-L1 expression including 623 (28.49%) cases with TPS >=50% and 842 (37.89%) cases with TPS 1%-49%.	('TPS >=50%', 'Var', (156, 165))	('PD-L1', 'Gene', '29126', (105, 110))	('patients', 'Species', '9606', (92, 100))	('PD-L1', 'Gene', (105, 110))
140527	30662515	Our data from TMA showed relative low PD-L1 expression in both TPS >=50% group (15%) and TPS 1%-49% group (25%) as compared to the previous clinical trial.	('expression', 'MPA', (44, 54))	('low', 'NegReg', (34, 37))	('TMA', 'Disease', (14, 17))	('PD-L1', 'Gene', (38, 43))	('TPS >=50%', 'Var', (63, 72))	('TMA', 'Disease', 'MESH:D000783', (14, 17))	('PD-L1', 'Gene', '29126', (38, 43))
140538	27723786	Genetic Polymorphisms in the Apoptosis-Associated Gene CASP3 and the Risk of Lung Cancer in Chinese Population Caspase-3 (CASP3) plays a central role in executing cell apoptosis and thus in carcinogenesis.	('carcinogenesis', 'Disease', (190, 204))	('CASP3', 'Gene', (122, 127))	('carcinogenesis', 'Disease', 'MESH:D063646', (190, 204))	('Lung Cancer', 'Disease', (77, 88))	('Lung Cancer', 'Disease', 'MESH:D008175', (77, 88))	('Lung Cancer', 'Phenotype', 'HP:0100526', (77, 88))	('Cancer', 'Phenotype', 'HP:0002664', (82, 88))	('Caspase-3', 'Gene', (111, 120))	('CASP3', 'Gene', '836', (55, 60))	('CASP3', 'Gene', (55, 60))	('Caspase-3', 'Gene', '836', (111, 120))	('CASP3', 'Gene', '836', (122, 127))	('cell apoptosis', 'CPA', (163, 177))	('Polymorphisms', 'Var', (8, 21))
140539	27723786	We previously investigated the relationship between functional polymorphisms in CAPS3 829 A>C and 20541 C>T and risk of esophageal squamous cell carcinoma.	('20541 C>T', 'Var', (98, 107))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (131, 154))	('carcinoma', 'Phenotype', 'HP:0030731', (145, 154))	('20541 C>T', 'Mutation', 'rs1049216', (98, 107))	('esophageal squamous cell carcinoma', 'Disease', (120, 154))	('829 A>C', 'Mutation', 'rs4647602', (86, 93))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (120, 154))	('CAPS3 829 A>C', 'Var', (80, 93))
140540	27723786	However little is known about the role of CASP3 variants in susceptibility to lung cancer.	('lung cancer', 'Disease', (78, 89))	('CASP3', 'Gene', '836', (42, 47))	('lung cancer', 'Phenotype', 'HP:0100526', (78, 89))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('variants', 'Var', (48, 56))	('CASP3', 'Gene', (42, 47))	('lung cancer', 'Disease', 'MESH:D008175', (78, 89))
140544	27723786	To further explore the possible impact of 829 A>C SNP on CASP3 transcriptional activity, we detected the dual luciferase activity of PGL3-promoter vectors containing 829A or 829C alleles in lung cancer cell lines and found that report gene expressions driven by 829A containing CASP3 promoter were 1.64-fold, 1.94-fold greater than those driven by CASP3 829C containing counterparts in A549 and NCI-H1975 cells (P<0.001).	('CASP3', 'Gene', (57, 62))	('PGL3', 'Gene', '6391', (133, 137))	('CASP3', 'Gene', '836', (278, 283))	('PGL3', 'Gene', (133, 137))	('lung cancer', 'Disease', 'MESH:D008175', (190, 201))	('NCI-H1975', 'CellLine', 'CVCL:1511', (395, 404))	('A549', 'CellLine', 'CVCL:0023', (386, 390))	('CASP3', 'Gene', (278, 283))	('829A', 'Var', (262, 266))	('CASP3', 'Gene', '836', (348, 353))	('CASP3', 'Gene', (348, 353))	('CASP3', 'Gene', '836', (57, 62))	('greater', 'PosReg', (319, 326))	('829 A>C', 'Mutation', 'rs4647602', (42, 49))	('lung cancer', 'Disease', (190, 201))	('lung cancer', 'Phenotype', 'HP:0100526', (190, 201))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
140547	27723786	We also found that 829AC or 829CC genotype increased adenocarcinoma risk compared with the AA genotype with OR (95%CI) of 1.33 (1.04-1.70) and 1.51(1.09-2.07).	('adenocarcinoma', 'Disease', (53, 67))	('adenocarcinoma', 'Disease', 'MESH:D000230', (53, 67))	('829AC', 'Var', (19, 24))	('increased', 'PosReg', (43, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))	('829CC', 'Var', (28, 33))
140548	27723786	CASP3 polymorphism and smoking interaction was demonstrated related with higher risk of lung cancer.	('polymorphism', 'Var', (6, 18))	('CASP3', 'Gene', (0, 5))	('lung cancer', 'Disease', (88, 99))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('lung cancer', 'Disease', 'MESH:D008175', (88, 99))	('CASP3', 'Gene', '836', (0, 5))	('lung cancer', 'Phenotype', 'HP:0100526', (88, 99))
140550	27723786	Among carriers with 20541CT genotype, the ORs (95%CI) of risk with lung cancer for smoking <16, 16-28, or > 28 pack-years were 1.16(0.65-2.07), 1.66(0.98-2.82) and 5.01(3.31-7.58) compared with the 20541CC carriers.	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('lung cancer', 'Disease', 'MESH:D008175', (67, 78))	('20541CT', 'Var', (20, 27))	('lung cancer', 'Disease', (67, 78))	('lung cancer', 'Phenotype', 'HP:0100526', (67, 78))
140551	27723786	These results highlight apoptosis-related CASP3 as an important gene in human carcinogenesis and further support the CASP3 polymorphisms confer to the lung cancer susceptibility.	('CASP3', 'Gene', '836', (42, 47))	('carcinogenesis', 'Disease', 'MESH:D063646', (78, 92))	('CASP3', 'Gene', '836', (117, 122))	('CASP3', 'Gene', (117, 122))	('CASP3', 'Gene', (42, 47))	('polymorphisms', 'Var', (123, 136))	('carcinogenesis', 'Disease', (78, 92))	('human', 'Species', '9606', (72, 77))	('lung cancer', 'Disease', (151, 162))	('lung cancer', 'Phenotype', 'HP:0100526', (151, 162))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('lung cancer', 'Disease', 'MESH:D008175', (151, 162))
140557	27723786	Therefore apoptosis may cause the somatic mutations and now thought to contribute to a number of human diseases, ranging from neurodegenerative disorders to malignancy.	('malignancy', 'Disease', 'MESH:D009369', (157, 167))	('malignancy', 'Disease', (157, 167))	('contribute', 'Reg', (71, 81))	('neurodegenerative disorders', 'Disease', 'MESH:D019636', (126, 153))	('cause', 'Reg', (24, 29))	('human', 'Species', '9606', (97, 102))	('apoptosis', 'CPA', (10, 19))	('neurodegenerative disorders', 'Phenotype', 'HP:0002180', (126, 153))	('neurodegenerative disorders', 'Disease', (126, 153))	('mutations', 'Var', (42, 51))
140566	27723786	CASP3 mutations were detected many types of tumor, including colon carcinomas, non-small cell lung cancers, non-Hodgkin lymphomas, stomach carcinomas, hepatocellular carcinomas, and multiple myelomas.	('non-small cell lung cancers', 'Disease', (79, 106))	('lung cancers', 'Phenotype', 'HP:0100526', (94, 106))	('non-small cell lung cancers', 'Phenotype', 'HP:0030358', (79, 106))	('stomach carcinomas', 'Disease', (131, 149))	('non-Hodgkin lymphomas', 'Disease', (108, 129))	('stomach carcinomas', 'Disease', 'MESH:D013274', (131, 149))	('tumor', 'Disease', (44, 49))	('hepatocellular carcinomas', 'Disease', 'MESH:D006528', (151, 176))	('CASP3', 'Gene', (0, 5))	('carcinoma', 'Phenotype', 'HP:0030731', (166, 175))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('hepatocellular carcinomas', 'Phenotype', 'HP:0001402', (151, 176))	('small cell lung cancers', 'Phenotype', 'HP:0030357', (83, 106))	('CASP3', 'Gene', '836', (0, 5))	('mutations', 'Var', (6, 15))	('non-Hodgkin lymphomas', 'Phenotype', 'HP:0012539', (108, 129))	('non-small cell lung cancers', 'Disease', 'MESH:D002289', (79, 106))	('hepatocellular carcinomas', 'Disease', (151, 176))	('carcinomas', 'Phenotype', 'HP:0030731', (166, 176))	('lung cancer', 'Phenotype', 'HP:0100526', (94, 105))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('non-Hodgkin lymphomas', 'Disease', 'MESH:D008228', (108, 129))	('lymphomas', 'Phenotype', 'HP:0002665', (120, 129))	('multiple myelomas', 'Phenotype', 'HP:0006775', (182, 199))	('Hodgkin lymphomas', 'Phenotype', 'HP:0012189', (112, 129))	('cancers', 'Phenotype', 'HP:0002664', (99, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (139, 148))	('carcinomas', 'Phenotype', 'HP:0030731', (139, 149))	('colon carcinomas', 'Disease', (61, 77))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('carcinomas', 'Phenotype', 'HP:0030731', (67, 77))	('multiple myelomas', 'Disease', (182, 199))	('multiple myelomas', 'Disease', 'MESH:D009101', (182, 199))	('detected', 'Reg', (21, 29))	('colon carcinomas', 'Disease', 'MESH:D015179', (61, 77))
140568	27723786	They identified three single nucleotide polymorphisms (SNPs), 829 A>C, 17532 A>C, and 20541 C>T, which located in 5'-regulatory region, intron 4, and 3'-regulatory region of CASP3, respectively.	('17532 A>C', 'Var', (71, 80))	('20541 C>T', 'Mutation', 'rs1049216', (86, 95))	('17532 A>C', 'Mutation', 'g.17532A>C', (71, 80))	('CASP3', 'Gene', (174, 179))	('829 A>C', 'Mutation', 'rs4647602', (62, 69))	('20541 C>T', 'Var', (86, 95))	('829 A>C', 'Var', (62, 69))	('CASP3', 'Gene', '836', (174, 179))
140570	27723786	Based on these, we final investigated CASP3 829 A>C and 20541 C>T polymorphisms in this lung cancer case-control study.	('investigated', 'Reg', (25, 37))	('lung cancer', 'Disease', (88, 99))	('829 A>C', 'Mutation', 'rs4647602', (44, 51))	('CASP3', 'Gene', '836', (38, 43))	('CASP3', 'Gene', (38, 43))	('829 A>C', 'Var', (44, 51))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('lung cancer', 'Disease', 'MESH:D008175', (88, 99))	('20541 C>T', 'Var', (56, 65))	('20541 C>T', 'Mutation', 'rs1049216', (56, 65))	('lung cancer', 'Phenotype', 'HP:0100526', (88, 99))
140581	27723786	Briefly, to produce CASP3 region containing the 829 A>C (rs4647602) site, the PCR primer pairs was 5'-TAG TTG CAG GGT TTA AAC TCC AAT GC-3' and 5'-CTA ACT CCT CAC GGC CTG GGA T-3'.	('AAT', 'Gene', (130, 133))	('CASP3', 'Gene', (20, 25))	('829 A>C', 'Mutation', 'rs4647602', (48, 55))	('AAT', 'Gene', '5265', (130, 133))	('CCT', 'Gene', (155, 158))	('rs4647602', 'Mutation', 'rs4647602', (57, 66))	('CASP3', 'Gene', '836', (20, 25))	('rs4647602', 'Var', (57, 66))	('CCT', 'Gene', '907', (155, 158))
140582	27723786	The primer pairs used to amplify CASP3 20541 C>T (rs1049216) was 5'-GTG AAA AAG TTA AAC ATT GAA TTA A-3' and 5'-TTC TTC CAC ATC ATC ATT TCT A-3'.	('20541 C>T', 'Mutation', 'rs1049216', (39, 48))	('20541 C>T (rs1049216', 'Var', (39, 59))	('CASP3', 'Gene', '836', (33, 38))	('rs1049216', 'Var', (50, 59))	('CASP3', 'Gene', (33, 38))	('rs1049216', 'Mutation', 'rs1049216', (50, 59))
140586	27723786	The 829C allele had one BglI restriction site that resulted in two bands (112 bp and 25 bp) and the 20541C allele had one AseI restriction site that resulted in two bands of 82 bp and 21 bp.	('829C', 'Var', (4, 8))	('AseI', 'Chemical', '-', (122, 126))	('resulted in', 'Reg', (51, 62))	('20541C', 'Var', (100, 106))
140587	27723786	The CASP3 829 A>C and 20541 C>T genotypes revealed by PCR-RFLP analysis were further confirmed by direct DNA sequencing (Figs 1B and 2B).	('20541 C>T', 'Var', (22, 31))	('CASP3', 'Gene', (4, 9))	('20541 C>T', 'Mutation', 'rs1049216', (22, 31))	('829 A>C', 'Mutation', 'rs4647602', (10, 17))	('CASP3', 'Gene', '836', (4, 9))
140590	27723786	To produce the luciferase construct containing the 829A allele, a pair of primers 5'-GGT TTAAAC TCCAATTCATTT TCGGCC C-3' and 5'-GAA TTG GAGTTTAAACCC TGCAACTATCTC-3' was used to make the single site mutagenesis (Invitrogen, Carlsbad, CA, USA).	('mutagenesis', 'Var', (198, 209))	('AAT', 'Gene', (99, 102))	('AAT', 'Gene', '5265', (99, 102))
140600	27723786	Table 2 displayed that the genotype distributions of CASP3 829 A>C and 20541 C>T in the cases and controls respectively.	('20541 C>T', 'Var', (71, 80))	('20541 C>T', 'Mutation', 'rs1049216', (71, 80))	('829 A>C', 'Mutation', 'rs4647602', (59, 66))	('CASP3', 'Gene', '836', (53, 58))	('CASP3', 'Gene', (53, 58))
140601	27723786	All observed genotype frequencies of 829 A>C and 20541 C>T in the controls conform to Hardy Weinberg equilibrium (P = 0.915 and P = 0.078, respectively).	('829 A>C', 'Var', (37, 44))	('829 A>C', 'Mutation', 'rs4647602', (37, 44))	('20541 C>T', 'Mutation', 'rs1049216', (49, 58))	('20541 C>T', 'Var', (49, 58))
140603	27723786	No significant changed risk of lung cancer was found to relate to the 20541 C>T genotype.	('lung cancer', 'Disease', 'MESH:D008175', (31, 42))	('20541 C>T', 'Var', (70, 79))	('lung cancer', 'Disease', (31, 42))	('lung cancer', 'Phenotype', 'HP:0100526', (31, 42))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('20541 C>T', 'Mutation', 'rs1049216', (70, 79))
140605	27723786	We operated a multivariate regression model to obtain the association between CASP3 829A>C and 20541 C>T genotypes and risk of lung cancer with adjustment for age, gender and smoking status.	('lung cancer', 'Disease', (127, 138))	('lung cancer', 'Phenotype', 'HP:0100526', (127, 138))	('20541 C>T', 'Var', (95, 104))	('20541 C>T', 'Mutation', 'rs1049216', (95, 104))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('829A>C', 'Mutation', 'rs4647602', (84, 90))	('CASP3', 'Gene', '836', (78, 83))	('lung cancer', 'Disease', 'MESH:D008175', (127, 138))	('CASP3', 'Gene', (78, 83))
140608	27723786	We found that 829AC or 829CC genotype increased adenocarcinoma risk compared with the AA genotype with OR (95%CI) of 1.33 (1.04-1.70) and 1.51(1.09-2.07).	('829CC', 'Var', (23, 28))	('adenocarcinoma', 'Disease', (48, 62))	('carcinoma', 'Phenotype', 'HP:0030731', (53, 62))	('829AC', 'Var', (14, 19))	('adenocarcinoma', 'Disease', 'MESH:D000230', (48, 62))	('increased', 'PosReg', (38, 47))
140612	27723786	Moreover, these variant genotypes were significantly associated with a two- or three-fold increased risk of lung cancer in smokers (OR = 2.68, 95%CI = 1.89-3.81; OR = 3.23, 95%CI = 2.21-4.92).	('lung cancer', 'Disease', 'MESH:D008175', (108, 119))	('variant', 'Var', (16, 23))	('lung cancer', 'Disease', (108, 119))	('lung cancer', 'Phenotype', 'HP:0100526', (108, 119))	('associated', 'Reg', (53, 63))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
140614	27723786	Report gene expressions driven by 829A containing CASP3 promoter were 1.64-fold, 1.94-fold greater than those driven by CASP 829C containing counterparts in A549 and NCI-H1975 cells (P<0.001) (Fig 3).	('NCI-H1975', 'CellLine', 'CVCL:1511', (166, 175))	('A549', 'CellLine', 'CVCL:0023', (157, 161))	('829A', 'Var', (34, 38))	('CASP', 'Gene', (50, 54))	('CASP', 'Gene', (120, 124))	('CASP3', 'Gene', (50, 55))	('CASP', 'Gene', '10491', (50, 54))	('greater', 'PosReg', (91, 98))	('CASP3', 'Gene', '836', (50, 55))	('Report gene expressions', 'MPA', (0, 23))	('CASP', 'Gene', '10491', (120, 124))
140615	27723786	These results suggest that the 829 A>C polymorphism influences CASP3 promoter activity.	('CASP3', 'Gene', (63, 68))	('influences', 'Reg', (52, 62))	('829 A>C', 'Mutation', 'rs4647602', (31, 38))	('829 A>C', 'Var', (31, 38))	('CASP3', 'Gene', '836', (63, 68))
140617	27723786	In the current study, we investigated the potential association of CASP3 polymorphisms (829 A>C and 20541 C>T) and with the risk of lung cancer in Chinese population.	('20541 C>T', 'Mutation', 'rs1049216', (100, 109))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('lung cancer', 'Disease', 'MESH:D008175', (132, 143))	('829 A>C', 'Mutation', 'rs4647602', (88, 95))	('association', 'Interaction', (52, 63))	('829 A>C', 'Var', (88, 95))	('CASP3', 'Gene', '836', (67, 72))	('lung cancer', 'Disease', (132, 143))	('lung cancer', 'Phenotype', 'HP:0100526', (132, 143))	('20541 C>T', 'Var', (100, 109))	('CASP3', 'Gene', (67, 72))
140624	27723786	Some research demonstrated the mutation of CASP3 existed in human tumor tissues and cell lines as expected.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('CASP3', 'Gene', (43, 48))	('tumor', 'Disease', (66, 71))	('mutation', 'Var', (31, 39))	('CASP3', 'Gene', '836', (43, 48))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('human', 'Species', '9606', (60, 65))
140627	27723786	Mandruzzato and Wang have reported that a large number of caspases mutations in human tumor cells, which caused reduced apoptotic activities.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Disease', (86, 91))	('caspases', 'Gene', '834;839;841;842;843', (58, 66))	('mutations', 'Var', (67, 76))	('caspases', 'Gene', (58, 66))	('human', 'Species', '9606', (80, 85))	('apoptotic activities', 'CPA', (120, 140))	('reduced', 'NegReg', (112, 119))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
140628	27723786	It suggested that the mutation of CASP3 was particularly prone to occur in human cancer tissues, or CASP3 mutation genotype resulted in carcinogenesis.	('CASP3', 'Gene', '836', (34, 39))	('mutation', 'Var', (22, 30))	('CASP3', 'Gene', (34, 39))	('carcinogenesis', 'Disease', 'MESH:D063646', (136, 150))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('CASP3', 'Gene', '836', (100, 105))	('carcinogenesis', 'Disease', (136, 150))	('cancer', 'Disease', (81, 87))	('mutation', 'Var', (106, 114))	('CASP3', 'Gene', (100, 105))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('human', 'Species', '9606', (75, 80))	('resulted in', 'Reg', (124, 135))
140630	27723786	It is possible that this CASP3 mutation may have resulted that the target tissue operated the apoptosis disadvantageously and thus raised the potential risk of carcinogenesis.	('carcinogenesis', 'Disease', 'MESH:D063646', (160, 174))	('disadvantageously', 'NegReg', (104, 121))	('CASP3', 'Gene', '836', (25, 30))	('carcinogenesis', 'Disease', (160, 174))	('operated', 'Reg', (81, 89))	('mutation', 'Var', (31, 39))	('CASP3', 'Gene', (25, 30))	('apoptosis', 'CPA', (94, 103))
140632	27723786	One study determined nine potentially functional polymorphisms in the Caspase on survival of early-stage NSCLC patients.	('NSCLC', 'Disease', 'MESH:D002289', (105, 110))	('NSCLC', 'Disease', (105, 110))	('polymorphisms', 'Var', (49, 62))	('Caspase', 'Protein', (70, 77))	('patients', 'Species', '9606', (111, 119))
140633	27723786	Their conclusion was that the CASP7 rs2227310 and CASP9 rs4645981 polymorphisms may affect survival in early-stage NSCLC.	('CASP7', 'Gene', (30, 35))	('rs4645981', 'Var', (56, 65))	('NSCLC', 'Disease', (115, 120))	('rs2227310', 'Mutation', 'rs2227310', (36, 45))	('affect', 'Reg', (84, 90))	('NSCLC', 'Disease', 'MESH:D002289', (115, 120))	('CASP9', 'Gene', (50, 55))	('CASP7', 'Gene', '840', (30, 35))	('CASP9', 'Gene', '842', (50, 55))	('rs4645981', 'Mutation', 'rs4645981', (56, 65))	('rs2227310', 'Var', (36, 45))	('survival', 'Disease', (91, 99))
140634	27723786	Some association studies have suggested possible links between CASP3 polymorphism and the susceptibility to several of cancers, including endometrial cancer, prostrate cancer and head and neck cancer.	('polymorphism', 'Var', (69, 81))	('cancer', 'Disease', (193, 199))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('cancer', 'Disease', (168, 174))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('head and neck cancer', 'Phenotype', 'HP:0012288', (179, 199))	('CASP3', 'Gene', (63, 68))	('cancers', 'Phenotype', 'HP:0002664', (119, 126))	('cancer', 'Disease', (119, 125))	('cancer', 'Disease', (150, 156))	('cancers', 'Disease', (119, 126))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('association', 'Interaction', (5, 16))	('CASP3', 'Gene', '836', (63, 68))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('endometrial cancer', 'Phenotype', 'HP:0012114', (138, 156))	('head and neck cancer', 'Disease', 'MESH:D006258', (179, 199))	('endometrial cancer', 'Disease', (138, 156))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('cancers', 'Disease', 'MESH:D009369', (119, 126))	('endometrial cancer', 'Disease', 'MESH:D016889', (138, 156))	('links', 'Interaction', (49, 54))
140635	27723786	One case-control study was demonstrated that CASP3 rs4647601 TT genotype was related with an increased dangerous impact of squamous cell carcinoma of the Head and Neck.	('squamous cell carcinoma', 'Disease', (123, 146))	('CASP3', 'Gene', '836', (45, 50))	('rs4647601', 'Mutation', 'rs4647601', (51, 60))	('CASP3', 'Gene', (45, 50))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (123, 146))	('rs4647601', 'Var', (51, 60))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (123, 146))
140636	27723786	A meta-analysis showed that the homozygote (CC) of rs2705897 (A/C) in the CASP3 gene had a positive association with cancer susceptibility.	('rs2705897', 'Mutation', 'rs2705897', (51, 60))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('rs2705897', 'Var', (51, 60))	('CASP3', 'Gene', '836', (74, 79))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('cancer', 'Disease', (117, 123))	('CASP3', 'Gene', (74, 79))
140637	27723786	demonstrated that individuals carried at least one variant allele of the CASP3 -928A>G, 77G>A, and 17532A>C polymorphisms contributed to the genetic susceptibility to lung cancer.	('17532A>C', 'Var', (99, 107))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('lung cancer', 'Disease', (167, 178))	('77G>A', 'Mutation', 'c.77G>A', (88, 93))	('lung cancer', 'Phenotype', 'HP:0100526', (167, 178))	('17532A>C', 'Mutation', 'g.17532A>C', (99, 107))	('CASP3', 'Gene', '836', (73, 78))	('-928A>G', 'Mutation', 'rs751529936', (79, 86))	('susceptibility', 'Reg', (149, 163))	('lung cancer', 'Disease', 'MESH:D008175', (167, 178))	('CASP3', 'Gene', (73, 78))	('77G>A', 'Var', (88, 93))
140638	27723786	Similarity, our present study showed that functional CASP3 829 A>C polymorphism, another significant SNP of CASP3, increased the susceptibility of lung cancer.	('829 A>C polymorphism', 'Var', (59, 79))	('increased', 'PosReg', (115, 124))	('lung cancer', 'Disease', (147, 158))	('CASP3', 'Gene', '836', (108, 113))	('lung cancer', 'Phenotype', 'HP:0100526', (147, 158))	('829 A>C', 'Mutation', 'rs4647602', (59, 66))	('CASP3', 'Gene', (108, 113))	('CASP3', 'Gene', (53, 58))	('CASP3', 'Gene', '836', (53, 58))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('lung cancer', 'Disease', 'MESH:D008175', (147, 158))
140643	27723786	This result implied that the 829 A>C polymorphism caused the decline of CASP3 transcriptional activity and further contribute to the increased risk of developing lung cancer.	('lung cancer', 'Disease', 'MESH:D008175', (162, 173))	('CASP3', 'Gene', '836', (72, 77))	('829 A>C', 'Mutation', 'rs4647602', (29, 36))	('CASP3', 'Gene', (72, 77))	('829 A>C', 'Var', (29, 36))	('lung cancer', 'Disease', (162, 173))	('lung cancer', 'Phenotype', 'HP:0100526', (162, 173))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('decline', 'NegReg', (61, 68))	('transcriptional activity', 'MPA', (78, 102))
140644	27723786	Our findings of a significantly elevated risk, most evident in male and younger subjects with a tendency of increased risk with more variant alleles, suggested that for genetic susceptibility the CASP3 SNPs might be typical markers for lung cancer, because characteristics of genetic susceptibility include an early age of lung cancer onset.	('lung cancer', 'Phenotype', 'HP:0100526', (236, 247))	('CASP3', 'Gene', '836', (196, 201))	('lung cancer', 'Disease', 'MESH:D008175', (323, 334))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('lung cancer', 'Disease', 'MESH:D008175', (236, 247))	('CASP3', 'Gene', (196, 201))	('variant', 'Var', (133, 140))	('lung cancer', 'Phenotype', 'HP:0100526', (323, 334))	('lung cancer', 'Disease', (323, 334))	('cancer', 'Phenotype', 'HP:0002664', (328, 334))	('lung cancer', 'Disease', (236, 247))
140651	27723786	An analysis of CASP9 promoter polymorphisms contributing to genetic susceptibility to lung cancer suggested that CASP9 polymorphisms and their haplotypes interacted with tobacco smoking.	('CASP9', 'Gene', '842', (113, 118))	('polymorphisms', 'Var', (119, 132))	('interacted', 'Reg', (154, 164))	('lung cancer', 'Phenotype', 'HP:0100526', (86, 97))	('CASP9', 'Gene', (15, 20))	('lung cancer', 'Disease', (86, 97))	('CASP9', 'Gene', (113, 118))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('lung cancer', 'Disease', 'MESH:D008175', (86, 97))	('CASP9', 'Gene', '842', (15, 20))	('tobacco', 'Species', '4097', (170, 177))
140652	27723786	One of our published study observed that tobacco smoking worsened the trend of the susceptibility of lung cancer by genetic variant.	('lung cancer', 'Disease', 'MESH:D008175', (101, 112))	('tobacco', 'Species', '4097', (41, 48))	('genetic variant', 'Var', (116, 131))	('lung cancer', 'Phenotype', 'HP:0100526', (101, 112))	('lung cancer', 'Disease', (101, 112))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
140653	27723786	Therefore we investigated gene-environment interaction between the CASP3 polymorphisms and smoking.	('investigated', 'Reg', (13, 25))	('polymorphisms', 'Var', (73, 86))	('CASP3', 'Gene', '836', (67, 72))	('CASP3', 'Gene', (67, 72))
140654	27723786	An important point of our study was CASP3 polymorphisms had an interaction with cigarette.	('polymorphisms', 'Var', (42, 55))	('CASP3', 'Gene', '836', (36, 41))	('interaction', 'Interaction', (63, 74))	('CASP3', 'Gene', (36, 41))
140670	33712005	SOCS6 is correlated with better prognosis in ESCC patients.	('SOCS6', 'Var', (0, 5))	('ESCC', 'Disease', (45, 49))	('patients', 'Species', '9606', (50, 58))
140672	33712005	SOCS6 significantly decreased the population of CSCs expressing the surface biomarker CD271 or CD24low/CD44high and their ability of sphere formation.	('decreased', 'NegReg', (20, 29))	('CD24low/CD44high', 'Var', (95, 111))	('CD271', 'Gene', '4804', (86, 91))	('sphere formation', 'CPA', (133, 149))	('CD271', 'Gene', (86, 91))
140684	33712005	In ESCC, our previous study found that HPV is a negative prognostic factor and that HPV attenuates the radiosensitivity of ESCC cells .	('radiosensitivity', 'CPA', (103, 119))	('ESCC', 'Disease', (3, 7))	('attenuates', 'NegReg', (88, 98))	('HPV', 'Species', '10566', (39, 42))	('HPV', 'Species', '10566', (84, 87))	('HPV', 'Var', (84, 87))
140694	33712005	The surface markers CD271 (also named p75NTR) and a CD24low/CD44high phenotype have been reported to be biomarkers for human esophageal CSCs.	('esophageal CSCs', 'Disease', (125, 140))	('CD271', 'Gene', '4804', (20, 25))	('p75NTR', 'Gene', '4804', (38, 44))	('human', 'Species', '9606', (119, 124))	('CD271', 'Gene', (20, 25))	('CD24low/CD44high', 'Var', (52, 68))	('p75NTR', 'Gene', (38, 44))
140697	33712005	In addition, c-Kit is a CSC marker, and inhibition of c-Kit reduces the stemness of cancer cells .	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('c-Kit', 'Gene', (54, 59))	('inhibition', 'Var', (40, 50))	('cancer', 'Disease', (84, 90))	('c-Kit', 'Gene', (13, 18))	('c-Kit', 'Gene', '3815', (54, 59))	('c-Kit', 'Gene', '3815', (13, 18))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('reduces', 'NegReg', (60, 67))
140709	33712005	Membranes were then blocked in 5% nonfat milk and incubated overnight at 4 C with the following monoclonal antibodies: anti-SOCS6 (ab197335, Abcam, 1:500), anti-c-Kit (#3074; Cell Signaling Technology (CST), Beverly, MA, USA; 1:1000), anti-Ku70 (#4588; CST, 1:1000), anti-Ku80 (#2753; CST, 1:1000), anti-RAD51 (#8875; CST, 1:1000), anti-p-ATR (#2853; CST, 1:1000), anti-HPV16 E6 (ab70; Abcam, 1:500), anti-CD24 (18330-1-AP, Proteintech, 1:500), anti-CD44 (15675-1-AP, Proteintech, 1:500), and anti-GAPDH (10494-1-AP, Proteintech, 1:1000).	('Ku80', 'Gene', (272, 276))	('HPV', 'Species', '10566', (370, 373))	('15675-1-AP', 'Var', (456, 466))	('c-Kit', 'Gene', (161, 166))	('Ku70', 'Gene', (240, 244))	('ATR', 'Gene', '545', (339, 342))	('10494-1-AP', 'Var', (505, 515))	('ATR', 'Gene', (339, 342))	('c-Kit', 'Gene', '3815', (161, 166))	('RAD51', 'Gene', (304, 309))	('Ku70', 'Gene', '2547', (240, 244))	('Ku80', 'Gene', '7520', (272, 276))	('RAD51', 'Gene', '5888', (304, 309))
140716	33712005	Cells were incubated with antibodies: anti-SOCS6 (#3074; Santa Cruz Biotechnology, Santa Cruz, CA, USA, 1:200), anti-c-KIT (#3074; CST, 1:200).	('#3074;', 'Var', (124, 130))	('c-KIT', 'Gene', (117, 122))	('c-KIT', 'Gene', '3815', (117, 122))	('anti-SOCS6', 'Var', (38, 48))	('#3074', 'Var', (50, 55))
140733	33712005	The primary antibodies used were anti-SOCS6 (ab197335, Abcam, 1:100) and anti-c-Kit (#3074, CST, 1:100) antibodies.	('c-Kit', 'Gene', (78, 83))	('#3074', 'Var', (85, 90))	('ab197335', 'Var', (45, 53))	('c-Kit', 'Gene', '3815', (78, 83))
140736	33712005	Patients with high SOCS6 expression presented better progression-free survival (PFS, P = 0.023, Fig.	('better', 'PosReg', (46, 52))	('expression', 'MPA', (25, 35))	('high', 'Var', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('SOCS6', 'Gene', (19, 24))	('progression-free survival', 'CPA', (53, 78))
140737	33712005	Since low expression of SOCS6 is correlated with poor prognosis in ESCC patients, we suspected that SOCS6 is a negative regulator of ESCC and that SOCS6 might promote radiosensitivity.	('ESCC', 'Disease', (67, 71))	('SOCS6', 'Gene', (24, 29))	('SOCS6', 'Var', (147, 152))	('expression', 'MPA', (10, 20))	('low', 'NegReg', (6, 9))	('promote', 'PosReg', (159, 166))	('radiosensitivity', 'CPA', (167, 183))	('patients', 'Species', '9606', (72, 80))
140753	33712005	The viability of cells overexpressing SOCS6 was decreased, indicating that SOCS6 can significantly increase cisplatin sensitivity in ESCC cells (Fig.	('SOCS6', 'Var', (75, 80))	('increase', 'PosReg', (99, 107))	('cisplatin', 'Chemical', 'MESH:D002945', (108, 117))	('cisplatin sensitivity', 'MPA', (108, 129))
140755	33712005	As for cisplatin sensitivity, knockdown of SOCS6 decreased Eca109 and KYSE-150 cells' sensitivity to cisplatin at some concentrations (Fig.	('KYSE-150', 'CellLine', 'CVCL:1348', (70, 78))	('cisplatin', 'Chemical', 'MESH:D002945', (7, 16))	('sensitivity to cisplatin', 'MPA', (86, 110))	('cisplatin', 'Chemical', 'MESH:D002945', (101, 110))	('decreased', 'NegReg', (49, 58))	('knockdown', 'Var', (30, 39))	('SOCS6', 'Gene', (43, 48))
140759	33712005	The number of spheres formed by Eca109-SOCS6 and KYSE-150-SOCS6 cells was obviously decreased compared with the number formed by the corresponding control cells on day 14 (Fig.	('Eca109-SOCS6', 'Var', (32, 44))	('decreased', 'NegReg', (84, 93))	('KYSE-150-SOCS6', 'CellLine', 'CVCL:1348', (49, 63))	('KYSE-150-SOCS6', 'Var', (49, 63))
140761	33712005	CD24low/CD44high is the surface marker phenotype of CSCs, and CD271 is an ESCC stem cell-specific marker.	('CSCs', 'Disease', (52, 56))	('CD24low/CD44high', 'Var', (0, 16))	('CD271', 'Gene', '4804', (62, 67))	('CD271', 'Gene', (62, 67))
140763	33712005	Similarly, the proportion of CD24low/CD44high cells decreased in SOCS6 overexpression group in Eca109 (P < 0.001) and KYSE-150 (P < 0.01) cells (Fig.	('CD24low/CD44high', 'Var', (29, 45))	('overexpression', 'PosReg', (71, 85))	('SOCS6', 'Gene', (65, 70))	('decreased', 'NegReg', (52, 61))	('KYSE-150', 'CellLine', 'CVCL:1348', (118, 126))
140773	33712005	HPV+ Eca109 cells were treated with MG132 (20 microg/mL) for 4 h, and then endogenous c-Kit was immunoprecipitated, and the level of ubiquitylation was monitored by immunoblotting.	('HPV', 'Species', '10566', (0, 3))	('c-Kit', 'Gene', (86, 91))	('MG132', 'Var', (36, 41))	('c-Kit', 'Gene', '3815', (86, 91))	('MG132', 'Chemical', 'MESH:C072553', (36, 41))
140778	33712005	Results showed that SOCS6 could accelerate c-Kit degradation (Fig.	('SOCS6', 'Var', (20, 25))	('c-Kit', 'Gene', (43, 48))	('accelerate', 'PosReg', (32, 42))	('c-Kit', 'Gene', '3815', (43, 48))
140780	33712005	Results showed that SOCS6 could significantly accelerate the degradation of c-Kit in both Eca109 and KYSE-150 cells (Additional file 4: Fig.	('accelerate', 'PosReg', (46, 56))	('KYSE-150', 'CellLine', 'CVCL:1348', (101, 109))	('SOCS6', 'Var', (20, 25))	('degradation', 'MPA', (61, 72))	('c-Kit', 'Gene', (76, 81))	('c-Kit', 'Gene', '3815', (76, 81))
140799	33712005	Survival analysis of 57 ESCC patients showed that SOCS6 is correlated with better prognosis.	('SOCS6', 'Var', (50, 55))	('patients', 'Species', '9606', (29, 37))	('ESCC', 'Disease', (24, 28))
140810	33712005	In this work, flow cytometric analyses and sphere formation assays showed that SOCS6 protein expression sensitizes ESCC cells to radiation and cisplatin by reducing the population of CSCs.	('sensitizes', 'Reg', (104, 114))	('expression', 'Var', (93, 103))	('population of CSCs', 'CPA', (169, 187))	('cisplatin', 'Chemical', 'MESH:D002945', (143, 152))	('SOCS6', 'Gene', (79, 84))	('reducing', 'NegReg', (156, 164))	('protein', 'Protein', (85, 92))
140826	33712005	Gain-of-function mutations in c-Kit can promote tumor formation and progression in GIST, AML, mast cell leukemia and melanoma.	('melanoma', 'Disease', 'MESH:D008545', (117, 125))	('AML', 'Disease', 'MESH:D015470', (89, 92))	('c-Kit', 'Gene', '3815', (30, 35))	('Gain-of-function', 'PosReg', (0, 16))	('AML', 'Phenotype', 'HP:0004808', (89, 92))	('AML', 'Disease', (89, 92))	('mutations', 'Var', (17, 26))	('promote', 'PosReg', (40, 47))	('c-Kit', 'Gene', (30, 35))	('mast cell leukemia', 'Phenotype', 'HP:0100495', (94, 112))	('GIST', 'Disease', (83, 87))	('GIST', 'Phenotype', 'HP:0100723', (83, 87))	('melanoma', 'Phenotype', 'HP:0002861', (117, 125))	('melanoma', 'Disease', (117, 125))	('tumor', 'Disease', (48, 53))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('mast cell leukemia', 'Disease', 'MESH:D007946', (94, 112))	('mast cell leukemia', 'Disease', (94, 112))	('progression', 'CPA', (68, 79))	('leukemia', 'Phenotype', 'HP:0001909', (104, 112))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
140829	33712005	This study showed that SOCS6 promotes the ubiquitylation and degradation of c-Kit, which may be the mechanism underlying the decrease in CSC properties in ESCC cells overexpressing SOCS6.	('c-Kit', 'Gene', '3815', (76, 81))	('CSC properties', 'MPA', (137, 151))	('SOCS6', 'Var', (181, 186))	('ubiquitylation', 'MPA', (42, 56))	('degradation', 'MPA', (61, 72))	('decrease', 'NegReg', (125, 133))	('SOCS6', 'Gene', (23, 28))	('c-Kit', 'Gene', (76, 81))	('promotes', 'PosReg', (29, 37))
140833	33712005	In our previous study, we found that HPV+ ESCC cells are more resistant to radiation and we demonstrated a novel mechanism by which E6/E7 proteins enhance the stemness of ESCC cells.	('enhance', 'PosReg', (147, 154))	('ESCC', 'Disease', (171, 175))	('E6/E7 proteins', 'Var', (132, 146))	('stemness of', 'CPA', (159, 170))	('HPV', 'Species', '10566', (37, 40))
140855	33263865	Several targeted therapies have demonstrated clinical benefits for patients with specific biomarkers, and current National Comprehensive Cancer Network (NCCN) guidelines (version 6.2020) recommend these regimens as first-line (1L) treatment for patients with sensitizing epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), ROS proto-oncogene 1 receptor tyrosine kinase (ROS1), proto-oncogene B-Raf (BRAF) V600E, neurotrophic tyrosine kinase (NTRK) gene fusion, or programmed death-ligand 1 (PD-L1) biomarkers.	('ALK', 'Gene', '238', (340, 343))	('patients', 'Species', '9606', (245, 253))	('ALK', 'Gene', (340, 343))	('B-Raf', 'Gene', (415, 420))	('V600E', 'Var', (428, 433))	('anaplastic lymphoma kinase', 'Gene', '238', (312, 338))	('programmed death-ligand 1', 'Gene', '29126', (487, 512))	('ROS1', 'Gene', '6098', (393, 397))	('EGFR', 'Gene', (305, 309))	('anaplastic lymphoma kinase', 'Gene', (312, 338))	('Cancer', 'Phenotype', 'HP:0002664', (137, 143))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (312, 331))	('V600E', 'SUBSTITUTION', 'None', (428, 433))	('patients', 'Species', '9606', (67, 75))	('Cancer', 'Disease', (137, 143))	('PD-L1', 'Gene', (514, 519))	('B-Raf', 'Gene', '673', (415, 420))	('PD-L1', 'Gene', '29126', (514, 519))	('EGFR', 'Gene', '1956', (305, 309))	('ROS1', 'Gene', (393, 397))	('lymphoma', 'Phenotype', 'HP:0002665', (323, 331))	('epidermal growth factor receptor', 'Gene', (271, 303))	('BRAF', 'Gene', (422, 426))	('BRAF', 'Gene', '673', (422, 426))	('Cancer', 'Disease', 'MESH:D009369', (137, 143))	('epidermal growth factor receptor', 'Gene', '1956', (271, 303))	('programmed death-ligand 1', 'Gene', (487, 512))
140857	33263865	For example, recommended 1L therapies for patients with sensitizing EGFR mutations include osimertinib (preferred, category 1), erlotinib (alone or with ramucirumab or bevacizumab), afatinib, gefitinib, and dacomitinib.	('sensitizing', 'PosReg', (56, 67))	('erlotinib', 'Chemical', 'MESH:D000069347', (128, 137))	('EGFR', 'Gene', (68, 72))	('gefitinib', 'Chemical', 'MESH:D000077156', (192, 201))	('afatinib', 'Chemical', 'MESH:D000077716', (182, 190))	('EGFR', 'Gene', '1956', (68, 72))	('bevacizumab', 'Chemical', 'MESH:D000068258', (168, 179))	('ramucirumab', 'Chemical', 'MESH:C543333', (153, 164))	('dacomitinib', 'Chemical', 'MESH:C525726', (207, 218))	('patients', 'Species', '9606', (42, 50))	('osimertinib', 'Chemical', '-', (91, 102))	('mutations', 'Var', (73, 82))
140880	33263865	Additionally, patients with documented EGFR mutations or ALK rearrangements were excluded to focus on patients who would be eligible for 1L IO therapies, which are generally indicated for patients with an EGFR- and ALK-negative status.	('ALK', 'Gene', (215, 218))	('ALK', 'Gene', (57, 60))	('patients', 'Species', '9606', (102, 110))	('ALK', 'Gene', '238', (215, 218))	('EGFR', 'Gene', '1956', (205, 209))	('EGFR', 'Gene', (205, 209))	('patients', 'Species', '9606', (188, 196))	('mutations', 'Var', (44, 53))	('EGFR', 'Gene', '1956', (39, 43))	('EGFR', 'Gene', (39, 43))	('IO', 'Chemical', '-', (140, 142))	('ALK', 'Gene', '238', (57, 60))	('patients', 'Species', '9606', (14, 22))
140959	33263865	Likewise, the proportion of patients who died prior to 2L treatment was lower in the IO treatment group than in the chemotherapy or targeted therapy groups.	('patients', 'Species', '9606', (28, 36))	('IO', 'Chemical', '-', (85, 87))	('IO treatment', 'Var', (85, 97))	('lower', 'NegReg', (72, 77))
140982	33263865	However, comparisons of results for IO combination therapies must be made with caution, as the results for KEYNOTE-407 and IMpower131 were specifically for squamous disease and the results for IMpower150 were specifically for non-squamous disease (Jotte et al.	('squamous disease', 'Disease', 'MESH:D002294', (230, 246))	('squamous disease', 'Disease', (156, 172))	('non-squamous disease', 'Disease', 'MESH:D002294', (226, 246))	('squamous disease', 'Phenotype', 'HP:0002860', (230, 246))	('squamous disease', 'Disease', 'MESH:D002294', (156, 172))	('non-squamous disease', 'Disease', (226, 246))	('IO', 'Chemical', '-', (36, 38))	('squamous disease', 'Phenotype', 'HP:0002860', (156, 172))	('IMpower131', 'Var', (123, 133))
140987	33263865	Several factors were associated with a decreased risk of treatment discontinuation and death, including overweight BMI (vs normal).	('BMI', 'Disease', (115, 118))	('death', 'Disease', 'MESH:D003643', (87, 92))	('overweight', 'Var', (104, 114))	('death', 'Disease', (87, 92))	('overweight', 'Phenotype', 'HP:0025502', (104, 114))	('decreased', 'NegReg', (39, 48))
140997	33263865	An exploratory analysis was performed to assess exclusion of the small proportion of patients who received targeted therapies indicated for 1L treatment of patients with EGFR mutations or ALK rearrangements (n = 116 [1.5% of the study population]).	('patients', 'Species', '9606', (156, 164))	('rearrangements', 'Var', (192, 206))	('ALK', 'Gene', (188, 191))	('EGFR', 'Gene', '1956', (170, 174))	('patients', 'Species', '9606', (85, 93))	('EGFR', 'Gene', (170, 174))	('mutations', 'Var', (175, 184))	('ALK', 'Gene', '238', (188, 191))
141035	33372594	For example, colon cancer cells that are deficient in p53, one of the most important tumor suppressors, activate the mevalonate pathway to adapt to the lack of oxygen and nutrients.	('tumor', 'Disease', (85, 90))	('mevalonate pathway', 'Pathway', (117, 135))	('adapt', 'MPA', (139, 144))	('colon cancer', 'Phenotype', 'HP:0003003', (13, 25))	('colon cancer', 'Disease', 'MESH:D015179', (13, 25))	('activate', 'PosReg', (104, 112))	('p53', 'Gene', (54, 57))	('mevalonate', 'Chemical', 'MESH:D008798', (117, 127))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('colon cancer', 'Disease', (13, 25))	('p53', 'Gene', '7157', (54, 57))	('deficient', 'Var', (41, 50))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('oxygen', 'Chemical', 'MESH:D010100', (160, 166))
141062	33372594	Of the 29 metabolic pathways tested in the 33 cancer types, the OS analyses affirmed statistical significance for 166 cancer-pathway combinations post permutation and multiple test correction (Supplementary Table S3), and the DSS analyses affirmed 170 similarly (Supplementary Table S4).	('combinations', 'Var', (133, 145))	('cancer', 'Disease', (118, 124))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('cancer', 'Disease', (46, 52))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('DSS', 'Gene', (226, 229))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('DSS', 'Gene', '5376', (226, 229))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('metabolic pathways', 'Pathway', (10, 28))
141068	33372594	Pyruvate can directly induce the Warburg effect and it has been suggested to be a cancer therapeutic target.	('Pyruvate', 'Chemical', 'MESH:D019289', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('Warburg effect', 'CPA', (33, 47))	('Pyruvate', 'Var', (0, 8))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('induce', 'Reg', (22, 28))
141096	33372594	Of all possible 493 (49x17) cancer-pathway combinations, 328 (66%) showed significantly different expression post multiple test adjustment, signaling significant expression alteration between tumor and normal samples for the metabolic pathways tested.	('tumor', 'Disease', (192, 197))	('combinations', 'Var', (43, 55))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('alteration', 'Reg', (173, 183))	('expression', 'MPA', (162, 172))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('different', 'Reg', (88, 97))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('cancer', 'Disease', (28, 34))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('expression', 'MPA', (98, 108))
141097	33372594	Of these 328 dysregulated cancer-pathway combinations, 126 had higher expression in tumor samples and 202 had higher expression in normal samples (Fig.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('cancer', 'Disease', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('expression', 'MPA', (117, 127))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('combinations', 'Var', (41, 53))	('tumor', 'Disease', (84, 89))	('expression', 'MPA', (70, 80))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('higher', 'PosReg', (63, 69))
141111	33372594	Overall, 166 and 170 cancer-pathway combinations were found to be significantly associated with survival for OS and DSS respectively.	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('DSS', 'Gene', (116, 119))	('associated with', 'Reg', (80, 95))	('DSS', 'Gene', '5376', (116, 119))	('cancer', 'Disease', (21, 27))	('cancer', 'Disease', 'MESH:D009369', (21, 27))	('combinations', 'Var', (36, 48))
141120	33372594	Interruption of folate metabolism pathway may produce substantial toxic effect on cell division process, the key to tumorigenesis.	('tumor', 'Disease', (116, 121))	('Interruption', 'Var', (0, 12))	('cell division process', 'CPA', (82, 103))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('folate', 'Enzyme', (16, 22))	('folate', 'Chemical', 'MESH:D005492', (16, 22))
141121	33372594	Inhibition of folate metabolism pathway has been used in cancer treatment.	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('cancer', 'Disease', (57, 63))	('folate', 'Chemical', 'MESH:D005492', (14, 20))	('Inhibition', 'Var', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('folate metabolism pathway', 'Pathway', (14, 39))
141150	33372594	YG was supported by Cancer Center Support Grant from National Cancer Institute (P30CA118100).	('Cancer', 'Phenotype', 'HP:0002664', (20, 26))	('Cancer', 'Disease', (20, 26))	('Cancer', 'Disease', (62, 68))	('P30CA118100', 'Var', (80, 91))	('Cancer', 'Disease', 'MESH:D009369', (20, 26))	('Cancer', 'Disease', 'MESH:D009369', (62, 68))	('Cancer', 'Phenotype', 'HP:0002664', (62, 68))
141175	33153411	GSE126044, GSE110390 and GSE136961 were obtained from the GEO database by searching for the keywords checkpoint inhibitor or immunotherapy or PD-1 and lung cancer.	('lung cancer', 'Phenotype', 'HP:0100526', (151, 162))	('lung cancer', 'Disease', (151, 162))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('GSE110390', 'Var', (11, 20))	('lung cancer', 'Disease', 'MESH:D008175', (151, 162))
141188	33153411	Our results showed that the areas under the ROC curve of CSF1 R, HCST and CD274 for predicting the clinical benefit of immunotherapy were 0.8909, 0.9818 and 0.7273, respectively (Figure 6).	('0.7273', 'Var', (157, 163))	('CSF1', 'Gene', '1435', (57, 61))	('CD274', 'Gene', (74, 79))	('HCST', 'Gene', '10870', (65, 69))	('CSF1', 'Gene', (57, 61))	('0.9818', 'Var', (146, 152))	('HCST', 'Gene', (65, 69))	('CD274', 'Gene', '29126', (74, 79))
141198	33153411	Previous studies have shown that the KRAS and TP53 mutation status could predict the response to PD-1 blockade, and STK11/LKB1 mutations were a significant negative biomarker correlating with PDL1.	('LKB1', 'Gene', (122, 126))	('STK11', 'Gene', (116, 121))	('predict', 'Reg', (73, 80))	('LKB1', 'Gene', '6794', (122, 126))	('PDL1', 'Gene', (192, 196))	('TP53', 'Gene', '7157', (46, 50))	('STK11', 'Gene', '6794', (116, 121))	('KRAS', 'Gene', (37, 41))	('TP53', 'Gene', (46, 50))	('mutation', 'Var', (51, 59))	('response', 'MPA', (85, 93))	('mutations', 'Var', (127, 136))	('KRAS', 'Gene', '3845', (37, 41))	('PDL1', 'Gene', '29126', (192, 196))
141207	33153411	More importantly, our results indicated that, compared to the currently recognized expression of CD274, the expression of CSF1 R and HCST had better efficacy in predicting the response to anti-PD-1 therapy in NSCLC.	('HCST', 'Gene', '10870', (133, 137))	('response', 'MPA', (176, 184))	('NSCLC', 'Disease', 'MESH:D002289', (209, 214))	('CSF1', 'Gene', '1435', (122, 126))	('HCST', 'Gene', (133, 137))	('CSF1', 'Gene', (122, 126))	('NSCLC', 'Phenotype', 'HP:0030358', (209, 214))	('CD274', 'Gene', '29126', (97, 102))	('NSCLC', 'Disease', (209, 214))	('CD274', 'Gene', (97, 102))	('expression', 'Var', (108, 118))
141273	29177066	There are several other polymorphisms that have been studied that showed a suggestive association (P<0.05), which are ADH1B Arg48His (rs1229984), COX-2-1195G>A (rs689466), CASP8 Asp302His (rs1045485) and MGMT Leu84Phe (rs2234767).	('rs689466', 'Mutation', 'rs689466', (161, 169))	('Asp302His', 'SUBSTITUTION', 'None', (178, 187))	('MGMT', 'Gene', (204, 208))	('rs2234767', 'Mutation', 'rs2234767', (219, 228))	('rs1229984', 'Mutation', 'rs1229984', (134, 143))	('Leu84Phe', 'Var', (209, 217))	('rs1045485', 'Mutation', 'rs1045485', (189, 198))	('rs2234767', 'Var', (219, 228))	('ADH1B', 'Gene', '125', (118, 123))	('Arg48His', 'Var', (124, 132))	('CASP8', 'Gene', '841', (172, 177))	('MGMT', 'Gene', '4255', (204, 208))	('Arg48His', 'SUBSTITUTION', 'None', (124, 132))	('rs1229984', 'Var', (134, 143))	('ADH1B', 'Gene', (118, 123))	('rs689466', 'Var', (161, 169))	('CASP8', 'Gene', (172, 177))	('rs1045485', 'Var', (189, 198))	('Leu84Phe', 'SUBSTITUTION', 'None', (209, 217))	('Asp302His', 'Var', (178, 187))
141303	29177066	This study aims to primarily determine the association of non-acid GER and OSCC in the high-risk Black South African male patient population referred to the Gastroenterology Department at Steve Biko Academic Hospital.	('association', 'Interaction', (43, 54))	('patient', 'Species', '9606', (122, 129))	('men', 'Species', '9606', (180, 183))	('non-acid', 'Var', (58, 66))	('OSCC', 'Disease', (75, 79))
141357	27888708	RESULT: The T stage (P = .008), smoking history (P = .042), alcohol history (P = .048), need for radiotherapy (P = .012) and microscopic extracapsular spread (ECS) (P = .012) were associated with the TIL level.	('alcohol', 'Chemical', 'MESH:D000438', (60, 67))	('associated', 'Reg', (180, 190))	('TIL level', 'MPA', (200, 209))	('T stage', 'CPA', (12, 19))	('microscopic', 'Var', (125, 136))
141378	27888708	Patients who had UICC stages pT3 and 4, pN+, perineural invasion and/or vascular emboli were recommended to receive radiation treatment, whereas patients who presented with extracapsular spread and/or positive margins were recommended to receive chemo-radiotherapy.	('patients', 'Species', '9606', (145, 153))	('pN+', 'Var', (40, 43))	('Patients', 'Species', '9606', (0, 8))	('perineural invasion', 'CPA', (45, 64))	('vascular emboli', 'CPA', (72, 87))
141425	27888708	Patients with high TIL levels showed a better outcome in both DFS and DSS.	('DSS', 'Gene', '5376', (70, 73))	('DFS', 'Disease', (62, 65))	('high', 'Var', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('DSS', 'Gene', (70, 73))
141444	27888708	Currently, immunohistochemistry (IHC) is commonly used in research on TILs (e.g., to detect CD3+, CD8+, and CD45+ cells), but the effect of T lymphocyte subsets remains unclear.	('CD45+ cells', 'Var', (108, 119))	('CD8', 'Gene', (98, 101))	('CD8', 'Gene', '925', (98, 101))	('CD3+', 'Var', (92, 96))
141617	26735857	This behavior of HPV-LCNEC represents a sharp departure from that typically expected of HPV-related oropharyngeal squamous cell carcinoma, where HPV positivity is associated with an expectation of a relatively good prognosis and potential for long-term survival.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (114, 137))	('LCNEC', 'Chemical', '-', (21, 26))	('HPV', 'Species', '10566', (145, 148))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (114, 137))	('oropharyngeal squamous cell carcinoma', 'Phenotype', 'HP:0012182', (100, 137))	('squamous cell carcinoma', 'Disease', (114, 137))	('positivity', 'Var', (149, 159))	('HPV', 'Species', '10566', (88, 91))	('HPV', 'Species', '10566', (17, 20))
141641	31842801	Among these genes, ZAP70, CD3E, CD3G, CD3D, and CD247 were part of the TCR 'signal-triggering module'; (3) High expression of the PIGs involved in the TCR signaling pathway was associated with improved OS in 5 cancer types (breast invasive carcinoma (BRCA), cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), head and neck squamous cell carcinoma (HNSC), lung adenocarcinoma (LUAD), and sarcoma (SARC)), but was associated with decreased OS in brain lower-grade glioma (LGG).	('BRCA', 'Gene', '672', (251, 255))	('carcinoma', 'Phenotype', 'HP:0030731', (359, 368))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (331, 368))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('TCR', 'Gene', '6962', (151, 154))	('carcinoma', 'Phenotype', 'HP:0030731', (281, 290))	('lung adenocarcinoma', 'Disease', (377, 396))	('head and neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (331, 368))	('breast invasive carcinoma', 'Phenotype', 'HP:0003002', (224, 249))	('BRCA', 'Gene', (251, 255))	('TCR', 'Gene', (71, 74))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (267, 290))	('cervical squamous cell carcinoma and endocervical adenocarcinoma', 'Disease', 'MESH:D002294', (258, 322))	('carcinoma', 'Phenotype', 'HP:0030731', (387, 396))	('sarcoma', 'Disease', 'MESH:D012509', (409, 416))	('cancer', 'Disease', 'MESH:D009369', (210, 216))	('glioma', 'Disease', (484, 490))	('TCR', 'Gene', (151, 154))	('sarcoma', 'Disease', (409, 416))	('decreased', 'NegReg', (450, 459))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (377, 396))	('glioma', 'Disease', 'MESH:D005910', (484, 490))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (377, 396))	('PIGs', 'Species', '9823', (130, 134))	('carcinoma', 'Phenotype', 'HP:0030731', (313, 322))	('glioma', 'Phenotype', 'HP:0009733', (484, 490))	('breast invasive carcinoma', 'Disease', (224, 249))	('sarcoma', 'Phenotype', 'HP:0100242', (409, 416))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (345, 368))	('improved', 'PosReg', (193, 201))	('High expression', 'Var', (107, 122))	('breast invasive carcinoma', 'Disease', 'MESH:D001943', (224, 249))	('carcinoma', 'Phenotype', 'HP:0030731', (240, 249))	('cancer', 'Disease', (210, 216))	('TCR', 'Gene', '6962', (71, 74))
141653	31842801	In addition, pembrolizumab was associated with a significantly longer OS for platinum-refractory advanced urothelial carcinoma than standard therapy.	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('platinum', 'Chemical', 'MESH:D010984', (77, 85))	('urothelial carcinoma', 'Disease', (106, 126))	('pembrolizumab', 'Var', (13, 26))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (106, 126))	('pembrolizumab', 'Chemical', 'MESH:C582435', (13, 26))
141700	31842801	Eleven genes (ZAP70, PTPRC, LCK, ICOS, CD3E, CD3G, CD3D, ITK, CD247, CD40LG, and GRAP2) were identified as participating in the TCR signaling pathway (Fig.	('TCR', 'Gene', (128, 131))	('CD247', 'Var', (62, 67))	('ICOS', 'Gene', (33, 37))	('PTPRC', 'Gene', '100522631', (21, 26))	('PTPRC', 'Gene', (21, 26))	('ICOS', 'Gene', '733597', (33, 37))	('GRAP2', 'Gene', '100516438', (81, 86))	('GRAP2', 'Gene', (81, 86))	('participating', 'Reg', (107, 120))	('CD3G', 'Gene', (45, 49))	('TCR', 'Gene', '6962', (128, 131))	('CD40LG', 'Gene', (69, 75))	('ITK', 'Gene', (57, 60))	('ZAP70', 'Var', (14, 19))	('CD40LG', 'Gene', '397231', (69, 75))	('CD3D', 'Gene', (51, 55))	('ITK', 'Gene', '100523474', (57, 60))	('CD3E', 'Gene', (39, 43))
141702	31842801	ZAP70, CD3E, CD3G, CD3D, and CD247 were classified into a 'TCR signal triggering module' by Acuto et al., which was crucial to the successful initiation of T cell activation.	('CD3E', 'Var', (7, 11))	('CD3G', 'Var', (13, 17))	('CD3D', 'Var', (19, 23))	('ZAP70', 'Var', (0, 5))	('TCR', 'Gene', '6962', (59, 62))	('CD247', 'Var', (29, 34))	('TCR', 'Gene', (59, 62))
141705	31842801	Second, 6 (LCK, ZAP70, CD3E, CD3G, CD3D, and CD247) out of 11 PIGs played crucial roles in activating T cell activation.	('CD247', 'Var', (45, 50))	('activating T cell activation', 'MPA', (91, 119))	('PIGs', 'Species', '9823', (62, 66))
141716	31842801	High-level expression of the PIGs participating in the TCR signaling pathway was associated with improved OS in 5 cancer types (BRCA, CESC, HNSC, LUAD, and SARC), but with decreased OS in LGG.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('HNSC', 'Disease', (140, 144))	('improved', 'PosReg', (97, 105))	('LUAD', 'Disease', (146, 150))	('BRCA', 'Gene', (128, 132))	('BRCA', 'Gene', '672', (128, 132))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('TCR', 'Gene', '6962', (55, 58))	('CESC', 'Disease', (134, 138))	('PIGs', 'Species', '9823', (29, 33))	('High-level expression', 'Var', (0, 21))	('TCR', 'Gene', (55, 58))	('cancer', 'Disease', (114, 120))
141735	31842801	Eleven PIGs (ZAP70, PTPRC, LCK, ICOS, CD3E, CD3G, CD3D, ITK, CD247, CD40LG, and GRAP2) were mainly shared by the 6 cancer types (BRCA, CESC, HNSC, LUAD, SARC, and LGG) involved in the TCR signaling pathway.	('CD40LG', 'Gene', '397231', (68, 74))	('CD3D', 'Var', (50, 54))	('ITK', 'Gene', '100523474', (56, 59))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('PIGs', 'Species', '9823', (7, 11))	('ZAP70', 'Var', (13, 18))	('CD40LG', 'Gene', (68, 74))	('TCR', 'Gene', (184, 187))	('PTPRC', 'Gene', '100522631', (20, 25))	('BRCA', 'Gene', '672', (129, 133))	('ICOS', 'Gene', (32, 36))	('GRAP2', 'Gene', (80, 85))	('BRCA', 'Gene', (129, 133))	('CD3G', 'Var', (44, 48))	('PTPRC', 'Gene', (20, 25))	('cancer', 'Disease', (115, 121))	('ITK', 'Gene', (56, 59))	('ICOS', 'Gene', '733597', (32, 36))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('CD247', 'Var', (61, 66))	('GRAP2', 'Gene', '100516438', (80, 85))	('TCR', 'Gene', '6962', (184, 187))
141736	31842801	Six genes (ZAP70, LCK, CD3E, CD3G, CD3D, and CD247) played a key role in triggering the TCR signaling pathway.	('CD3D', 'Gene', (35, 39))	('CD3G', 'Gene', (29, 33))	('LCK', 'Gene', (18, 21))	('CD247', 'Gene', (45, 50))	('TCR', 'Gene', (88, 91))	('ZAP70', 'Var', (11, 16))	('triggering', 'Reg', (73, 83))	('TCR', 'Gene', '6962', (88, 91))	('CD3E', 'Gene', (23, 27))
141742	31842801	In this study, there was no significant difference between the OS in patients with high expression of CTLA4 and PD1 and that of patients with low expression of CTLA4 and PD1 in most cancer types.	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('CTLA4', 'Gene', (102, 107))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('high expression', 'Var', (83, 98))	('cancer', 'Disease', (182, 188))	('patients', 'Species', '9606', (69, 77))	('patients', 'Species', '9606', (128, 136))	('PD1', 'Gene', (112, 115))
141744	31842801	High expression of 11 PIGs was associated with good prognosis in BRCA, CESC, HNSC, LUAD, and SARC but poor prognosis in LGG.	('High expression', 'Var', (0, 15))	('BRCA', 'Gene', (65, 69))	('LUAD', 'Disease', (83, 87))	('CESC', 'Disease', (71, 75))	('SARC but', 'Disease', (93, 101))	('BRCA', 'Gene', '672', (65, 69))	('PIGs', 'Species', '9823', (22, 26))	('HNSC', 'Disease', (77, 81))
141749	31842801	Among them, CD45 can modulate LCK activation or inactivation by the dephosphorylation of Tyr505 of LCK or the dephosphorylation of Tyr394 of LCK.	('CD45', 'Var', (12, 16))	('Tyr505', 'Var', (89, 95))	('LCK', 'Protein', (141, 144))	('inactivation', 'NegReg', (48, 60))	('Tyr394', 'Chemical', '-', (131, 137))	('dephosphorylation', 'MPA', (110, 127))	('Tyr505', 'Chemical', '-', (89, 95))	('LCK', 'Protein', (99, 102))	('activation', 'PosReg', (34, 44))	('LCK', 'Protein', (30, 33))	('modulate', 'Reg', (21, 29))	('dephosphorylation', 'MPA', (68, 85))
141824	33973529	Among different immune subgroups, the mutations of TP53, KRAS, KMT2D, NFE2L2, PIK3CA, EGFR, LRRK2, SETBP1, CDKN2A, PIK3CG were found to be distributed in a significantly biased manner (Figure 5D).	('PIK3CA', 'Gene', (78, 84))	('SETBP1', 'Gene', (99, 105))	('NFE2L2', 'Gene', (70, 76))	('KMT2D', 'Gene', (63, 68))	('CDKN2A', 'Gene', '1029', (107, 113))	('TP53', 'Gene', (51, 55))	('EGFR', 'Gene', '1956', (86, 90))	('KRAS', 'Gene', '3845', (57, 61))	('mutations', 'Var', (38, 47))	('LRRK2', 'Gene', (92, 97))	('PIK3CA', 'Gene', '5290', (78, 84))	('KRAS', 'Gene', (57, 61))	('KMT2D', 'Gene', '8085', (63, 68))	('TP53', 'Gene', '7157', (51, 55))	('PIK3CG', 'Gene', (115, 121))	('NFE2L2', 'Gene', '4780', (70, 76))	('SETBP1', 'Gene', '26040', (99, 105))	('EGFR', 'Gene', (86, 90))	('PIK3CG', 'Gene', '5294', (115, 121))	('CDKN2A', 'Gene', (107, 113))	('LRRK2', 'Gene', '120892', (92, 97))
141825	33973529	In TCGA-NSCLC patients, we found that CDKN2A, CDKN2B and MTAP mainly had copy number deletions (Figure 5E), whereas PIK3CA, SOX2, BCL6 had a large number of copy number amplifications and were significantly concentrated in cluster 1.	('PIK3CA', 'Gene', (116, 122))	('NSCLC', 'Phenotype', 'HP:0030358', (8, 13))	('SOX2', 'Gene', '6657', (124, 128))	('NSCLC', 'Disease', 'MESH:D002289', (8, 13))	('SOX2', 'Gene', (124, 128))	('MTAP', 'Gene', (57, 61))	('CDKN2B', 'Gene', (46, 52))	('BCL6', 'Gene', '604', (130, 134))	('had', 'Reg', (69, 72))	('PIK3CA', 'Gene', '5290', (116, 122))	('CDKN2B', 'Gene', '1030', (46, 52))	('NSCLC', 'Disease', (8, 13))	('CDKN2A', 'Gene', (38, 44))	('BCL6', 'Gene', (130, 134))	('MTAP', 'Gene', '4507', (57, 61))	('copy number deletions', 'Var', (73, 94))	('CDKN2A', 'Gene', '1029', (38, 44))	('patients', 'Species', '9606', (14, 22))
141854	33973529	As a rare oncogene related to the potential treatment of NSCLC, PIK3CA also showed a similar tendency for mutation enrichment, with more mutations in cluster 1 and 2 samples.	('PIK3CA', 'Gene', (64, 70))	('NSCLC', 'Phenotype', 'HP:0030358', (57, 62))	('PIK3CA', 'Gene', '5290', (64, 70))	('mutations', 'Var', (137, 146))	('NSCLC', 'Disease', (57, 62))	('NSCLC', 'Disease', 'MESH:D002289', (57, 62))
141855	33973529	It was reported that PIK3CA mutations could confer a relapse-free survival advantage for squamous cell carcinoma in NSCLC.	('NSCLC', 'Disease', 'MESH:D002289', (116, 121))	('relapse-free survival', 'CPA', (53, 74))	('advantage', 'PosReg', (75, 84))	('PIK3CA', 'Gene', (21, 27))	('NSCLC', 'Phenotype', 'HP:0030358', (116, 121))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (89, 112))	('PIK3CA', 'Gene', '5290', (21, 27))	('NSCLC', 'Disease', (116, 121))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (89, 112))	('mutations', 'Var', (28, 37))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('squamous cell carcinoma', 'Disease', (89, 112))
141856	33973529	On the contrary, EGFR and KRAS mutations were abundantly enriched in cluster 3 samples, which was consistent with the function of suppressing immune infiltration as reported in some studies.	('mutations', 'Var', (31, 40))	('EGFR', 'Gene', '1956', (17, 21))	('KRAS', 'Gene', (26, 30))	('KRAS', 'Gene', '3845', (26, 30))	('EGFR', 'Gene', (17, 21))
141873	33435818	In LUAD, the occurrence of oncogenic driver mutations in KRAS, EGFR, HER2, MET and FGFR1/2, as well as oncogene fusions involving anaplastic lymphoma kinase (ALK), the ROS1 receptor tyrosine kinase (RTK), neuregulin 1 (NRG1), neurotrophic tyrosine kinase receptor type 1 (NTRK1) and RET, offer possibilities for new targeted therapies.	('EGFR', 'Gene', '1956', (63, 67))	('NRG1', 'Gene', '3084', (219, 223))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (130, 149))	('RET', 'Gene', (283, 286))	('LUAD', 'Phenotype', 'HP:0030078', (3, 7))	('ROS1', 'Gene', (168, 172))	('MET', 'Gene', '79811', (75, 78))	('NTRK1', 'Gene', '4914', (272, 277))	('neuregulin 1', 'Gene', (205, 217))	('FGFR1/2', 'Gene', (83, 90))	('anaplastic lymphoma kinase', 'Gene', '238', (130, 156))	('NTRK1', 'Gene', (272, 277))	('neuregulin 1', 'Gene', '3084', (205, 217))	('neurotrophic tyrosine kinase receptor type 1', 'Gene', (226, 270))	('anaplastic lymphoma kinase', 'Gene', (130, 156))	('KRAS', 'Gene', '3845', (57, 61))	('FGFR1/2', 'Gene', '2260;2263', (83, 90))	('RTK', 'Gene', (199, 202))	('HER2', 'Gene', '2064', (69, 73))	('EGFR', 'Gene', (63, 67))	('RTK', 'Gene', '5979', (199, 202))	('receptor tyrosine kinase', 'Gene', '5979', (173, 197))	('KRAS', 'Gene', (57, 61))	('neurotrophic tyrosine kinase receptor type 1', 'Gene', '4914', (226, 270))	('ROS1', 'Gene', '6098', (168, 172))	('ALK', 'Gene', '238', (158, 161))	('RET', 'Gene', '5979', (283, 286))	('MET', 'Gene', (75, 78))	('lymphoma', 'Phenotype', 'HP:0002665', (141, 149))	('ALK', 'Gene', (158, 161))	('receptor tyrosine kinase', 'Gene', (173, 197))	('NRG1', 'Gene', (219, 223))	('mutations', 'Var', (44, 53))	('HER2', 'Gene', (69, 73))
141880	33435818	Targeted therapy has predominantly focussed on inhibiting the constitutive activation of mutated forms of the epidermal growth factor receptor (EGFR).	('EGFR', 'Gene', (144, 148))	('inhibiting', 'NegReg', (47, 57))	('constitutive', 'MPA', (62, 74))	('epidermal growth factor receptor', 'Gene', (110, 142))	('mutated', 'Var', (89, 96))	('EGFR', 'Gene', '1956', (144, 148))	('epidermal growth factor receptor', 'Gene', '1956', (110, 142))
141893	33435818	Sequencing efforts from the Wellcome Trust Sanger Institute's cell lines project  and the Broad Institute's Cancer Cell Line Encyclopedia  have identified the mutational status for 110 and 136 NSCLC cell lines, respectively.	('NSCLC', 'Phenotype', 'HP:0030358', (193, 198))	('mutational', 'Var', (159, 169))	('SCLC', 'Phenotype', 'HP:0030357', (194, 198))	('Cancer', 'Disease', (108, 114))	('NSCLC', 'Disease', (193, 198))	('Cancer', 'Disease', 'MESH:D009369', (108, 114))	('NSCLC', 'Disease', 'MESH:D002289', (193, 198))	('Cancer', 'Phenotype', 'HP:0002664', (108, 114))
141916	33435818	Genetically engineered mouse models (GEMMs) are typically inbred mouse strains that have been genetically manipulated to express oncogenic alleles or delete tumour suppressor genes to generate autochthonous tumours.	('tumours', 'Disease', 'MESH:D009369', (207, 214))	('tumour', 'Disease', (207, 213))	('mouse', 'Species', '10090', (65, 70))	('tumour', 'Phenotype', 'HP:0002664', (157, 163))	('tumours', 'Disease', (207, 214))	('tumour', 'Disease', 'MESH:D009369', (157, 163))	('tumours', 'Phenotype', 'HP:0002664', (207, 214))	('mouse', 'Species', '10090', (23, 28))	('tumour', 'Phenotype', 'HP:0002664', (207, 213))	('tumour', 'Disease', (157, 163))	('delete', 'Var', (150, 156))	('tumour', 'Disease', 'MESH:D009369', (207, 213))
141918	33435818	Simplified genetic models with alterations to a few typically strong oncogenes or tumour suppressor genes are useful to dissect complex pathological mechanisms and test putative therapies in controlled conditions.	('tumour', 'Disease', (82, 88))	('alterations', 'Var', (31, 42))	('tumour', 'Disease', 'MESH:D009369', (82, 88))	('tumour', 'Phenotype', 'HP:0002664', (82, 88))
141922	33435818	Incorporating additional mutagenesis, caused either by chemicals or the expression of proteins known to cause mutations, such as cytosine deaminases, might bring mouse models closer to human tumour mutational burden.	('mutagenesis', 'Var', (25, 36))	('tumour', 'Disease', 'MESH:D009369', (191, 197))	('human', 'Species', '9606', (185, 190))	('tumour', 'Disease', (191, 197))	('mutations', 'Var', (110, 119))	('mouse', 'Species', '10090', (162, 167))	('tumour', 'Phenotype', 'HP:0002664', (191, 197))
141925	33435818	Most NSCLC GEMMs result in adenocarcinoma and there has been a particular focus on those caused by Kras mutations.	('SCLC', 'Phenotype', 'HP:0030357', (6, 10))	('mutations', 'Var', (104, 113))	('Kras', 'Gene', (99, 103))	('NSCLC', 'Phenotype', 'HP:0030358', (5, 10))	('carcinoma', 'Phenotype', 'HP:0030731', (32, 41))	('adenocarcinoma', 'Disease', (27, 41))	('NSCLC', 'Disease', (5, 10))	('result in', 'Reg', (17, 26))	('adenocarcinoma', 'Disease', 'MESH:D000230', (27, 41))	('NSCLC', 'Disease', 'MESH:D002289', (5, 10))
141927	33435818	Adenocarcinomas can be produced by Kras-G12D expression in AT2 cells expressing either Sftpc or Scgb1a1 (CCSP; CC10).	('CC10', 'Gene', (111, 115))	('Scgb1a1', 'Gene', '7356', (96, 103))	('Sftpc', 'Gene', '6440', (87, 92))	('Adenocarcinomas', 'Disease', (0, 15))	('Adenocarcinomas', 'Disease', 'MESH:D000230', (0, 15))	('carcinoma', 'Phenotype', 'HP:0030731', (5, 14))	('Scgb1a1', 'Gene', (96, 103))	('G12D', 'Mutation', 'rs121913529', (40, 44))	('Sftpc', 'Gene', (87, 92))	('CCSP', 'Gene', '7356', (105, 109))	('CC10', 'Gene', '7356', (111, 115))	('CCSP', 'Gene', (105, 109))	('Kras-G12D expression', 'Var', (35, 55))	('carcinomas', 'Phenotype', 'HP:0030731', (5, 15))
141928	33435818	Although Scgb1a1 is expressed in bronchiolar club cells in this model, they do not form invasive cancers unless Trp53 mutations are introduced.	('cancers', 'Phenotype', 'HP:0002664', (97, 104))	('club', 'Phenotype', 'HP:0001217', (45, 49))	('invasive cancers', 'Disease', (88, 104))	('mutations', 'Var', (118, 127))	('invasive cancers', 'Disease', 'MESH:D009362', (88, 104))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('Scgb1a1', 'Gene', '7356', (9, 16))	('Scgb1a1', 'Gene', (9, 16))	('Trp53', 'Gene', (112, 117))
141930	33435818	Indeed, during homeostasis, only a subpopulation of AT2 cells are Wnt active stem cells within a fibroblastic niche and Wnt signalling has been implicated in the progression of Kras/Trp53 adenocarcinoma models.	('adenocarcinoma', 'Disease', (188, 202))	('carcinoma', 'Phenotype', 'HP:0030731', (193, 202))	('adenocarcinoma', 'Disease', 'MESH:D000230', (188, 202))	('implicated', 'Reg', (144, 154))	('Kras/Trp53', 'Var', (177, 187))
141931	33435818	Multiple other Kras combinations have been generated, including those with activating PIK3CA mutations or MYC overexpression.	('MYC', 'Gene', (106, 109))	('mutations', 'Var', (93, 102))	('PIK3CA', 'Gene', (86, 92))	('MYC', 'Gene', '4609', (106, 109))	('PIK3CA', 'Gene', '5290', (86, 92))	('activating', 'PosReg', (75, 85))
141934	33435818	Combining Sox2 overexpression with tumour suppressive Pten and Cdkn2a mutations leads to LUSC-like tumours regardless of whether the Cre-driver gene is expressed by basal, club or AT2 cells.	('tumour', 'Disease', (35, 41))	('mutations', 'Var', (70, 79))	('tumour', 'Disease', 'MESH:D009369', (99, 105))	('tumours', 'Phenotype', 'HP:0002664', (99, 106))	('tumours', 'Disease', 'MESH:D009369', (99, 106))	('tumour', 'Disease', (99, 105))	('LUSC', 'Chemical', '-', (89, 93))	('club', 'Phenotype', 'HP:0001217', (172, 176))	('tumour', 'Phenotype', 'HP:0002664', (35, 41))	('leads to', 'Reg', (80, 88))	('tumours', 'Disease', (99, 106))	('tumour', 'Disease', 'MESH:D009369', (35, 41))	('tumour', 'Phenotype', 'HP:0002664', (99, 105))	('LUSC', 'Phenotype', 'HP:0030359', (89, 93))	('Cdkn2a', 'Gene', (63, 69))
141936	33435818	Hybrid approaches using mouse genetics and in vitro organoids have also allowed the development of tumorigenic mouse organoids that overexpress Sox2 and harbour deletions in the key LUSC tumour suppressor genes Trp53, Cdkn2a and Pten.	('LUSC', 'Phenotype', 'HP:0030359', (182, 186))	('tumour', 'Disease', (187, 193))	('mouse', 'Species', '10090', (24, 29))	('Pten', 'Gene', (229, 233))	('deletions', 'Var', (161, 170))	('Cdkn2a', 'Gene', (218, 224))	('mouse', 'Species', '10090', (111, 116))	('LUSC', 'Chemical', '-', (182, 186))	('men', 'Species', '9606', (91, 94))	('tumour', 'Phenotype', 'HP:0002664', (187, 193))	('overexpress', 'PosReg', (132, 143))	('Trp53', 'Gene', (211, 216))	('tumour', 'Disease', 'MESH:D009369', (187, 193))	('Sox2', 'Gene', (144, 148))
141938	33435818	In LUAD, the addition of Lkb1 mutations to Kras-driven GEMMs has confirmed that they modify histology, as dual mutants give rise to LUAD, LUSC and mixed adenosquamous lesions.	('LUSC', 'Phenotype', 'HP:0030359', (138, 142))	('LUAD', 'Phenotype', 'HP:0030078', (3, 7))	('LUSC', 'Disease', (138, 142))	('LUAD', 'Phenotype', 'HP:0030078', (132, 136))	('LUAD', 'Disease', (132, 136))	('Lkb1', 'Gene', (25, 29))	('modify', 'Reg', (85, 91))	('histology', 'MPA', (92, 101))	('mutations', 'Var', (30, 39))	('LUSC', 'Chemical', '-', (138, 142))	('mixed adenosquamous lesions', 'Disease', (147, 174))	('give rise to', 'Reg', (119, 131))
141939	33435818	In established Kras-driven tumours, Lkb1 loss promotes the transition to squamous histology with redox balance and epigenetic mechanisms involving polycomb repressive complex 2 (PRC2) both implicated mechanistically in LUSC formation.	('epigenetic', 'Var', (115, 125))	('Lkb1', 'Gene', (36, 40))	('LUSC', 'Phenotype', 'HP:0030359', (219, 223))	('PRC2', 'Gene', (178, 182))	('transition', 'CPA', (59, 69))	('tumour', 'Phenotype', 'HP:0002664', (27, 33))	('tumours', 'Phenotype', 'HP:0002664', (27, 34))	('LUSC', 'Chemical', '-', (219, 223))	('tumours', 'Disease', 'MESH:D009369', (27, 34))	('promotes', 'PosReg', (46, 54))	('tumours', 'Disease', (27, 34))	('loss', 'NegReg', (41, 45))
141943	33435818	Multiple carcinogen-driven LUSC models are also available: benzo[a]pyrene causes squamous bronchial lesions in hamsters; repeated intra-tracheal injection of 3-methylcholanthrene (MCA) in mice causes metaplastic lesions throughout the bronchial tree which progress to invasive and metastatic LUSC; and N-nitroso-tris-chloroethylurea (NTCU) produces a LUSC-like lung cancer when applied to the back skin of mice.	('invasive and metastatic LUSC', 'CPA', (268, 296))	('MCA', 'Chemical', 'MESH:D008748', (180, 183))	('mice', 'Species', '10090', (188, 192))	('LUSC', 'Phenotype', 'HP:0030359', (351, 355))	('lung cancer', 'Disease', 'MESH:D008175', (361, 372))	('LUSC', 'Chemical', '-', (351, 355))	('cancer', 'Phenotype', 'HP:0002664', (366, 372))	('lung cancer', 'Phenotype', 'HP:0100526', (361, 372))	('squamous bronchial lesions', 'Disease', 'MESH:D000081483', (81, 107))	('N-nitroso-tris-chloroethylurea', 'Chemical', 'MESH:C572573', (302, 332))	('metaplastic lesions', 'CPA', (200, 219))	('benzo[a]pyrene', 'Chemical', 'MESH:D001564', (59, 73))	('LUSC', 'Phenotype', 'HP:0030359', (292, 296))	('LUSC', 'Chemical', '-', (292, 296))	('mice', 'Species', '10090', (406, 410))	('3-methylcholanthrene', 'Chemical', 'MESH:D008748', (158, 178))	('LUSC', 'Phenotype', 'HP:0030359', (27, 31))	('lung cancer', 'Disease', (361, 372))	('progress', 'PosReg', (256, 264))	('LUSC', 'Chemical', '-', (27, 31))	('squamous bronchial lesions', 'Disease', (81, 107))	('NTCU', 'Chemical', 'MESH:C572573', (334, 338))	('N-nitroso-tris-chloroethylurea', 'Var', (302, 332))
141945	33435818	The use of clonal cell culture to expand single progenitor cells has allowed whole-genome sequencing of histologically normal airway epithelium, revealing the presence of somatic mutations, including known cancer driver mutations.	('cancer', 'Disease', (206, 212))	('cancer', 'Disease', 'MESH:D009369', (206, 212))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('mutations', 'Var', (179, 188))
141946	33435818	As expected, the mutational burden increased with age and was significantly higher in adults with a tobacco smoking history.	('tobacco', 'Species', '4097', (100, 107))	('higher', 'PosReg', (76, 82))	('mutational', 'Var', (17, 27))
141947	33435818	The detected cancer driver mutations were those typical of LUSC, with TP53, NOTCH1 and FAT1 mutations being the most frequent.	('mutations', 'Var', (27, 36))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('TP53', 'Gene', '7157', (70, 74))	('LUSC', 'Chemical', '-', (59, 63))	('cancer', 'Disease', (13, 19))	('cancer', 'Disease', 'MESH:D009369', (13, 19))	('TP53', 'Gene', (70, 74))	('FAT1', 'Gene', '2195', (87, 91))	('NOTCH1', 'Gene', '4851', (76, 82))	('NOTCH1', 'Gene', (76, 82))	('FAT1', 'Gene', (87, 91))	('LUSC', 'Phenotype', 'HP:0030359', (59, 63))
141953	33435818	Robust and scalable primary airway and alveolar culture methodologies have the potential to improve our understanding of the effect of specific somatic mutations on cellular dynamics in human epithelia and are compatible with CRISPR-Cas9-mediated gene editing approaches that might allow temporal reconstruction of NSCLC molecular events, as has been possible in studies of colorectal carcinogenesis.	('NSCLC', 'Disease', 'MESH:D002289', (315, 320))	('mutations', 'Var', (152, 161))	('SCLC', 'Phenotype', 'HP:0030357', (316, 320))	('NSCLC', 'Phenotype', 'HP:0030358', (315, 320))	('human', 'Species', '9606', (186, 191))	('colorectal carcinogenesis', 'Disease', (374, 399))	('colorectal carcinogenesis', 'Disease', 'MESH:D015179', (374, 399))	('NSCLC', 'Disease', (315, 320))
141958	33435818	Primary or immortalized cell cultures from carcinoma-in-situ or adenomatous lesions have not yet been derived but progression to malignancy can be investigated through the introduction of cancer mutations into immortalized 'normal' basal cell lines.	('adenomatous lesions', 'Disease', (64, 83))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('malignancy', 'Disease', (129, 139))	('adenomatous lesions', 'Disease', 'MESH:D011125', (64, 83))	('carcinoma', 'Phenotype', 'HP:0030731', (43, 52))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('carcinoma-in-situ', 'Disease', 'MESH:D002278', (43, 60))	('mutations', 'Var', (195, 204))	('cancer', 'Disease', (188, 194))	('malignancy', 'Disease', 'MESH:D009369', (129, 139))	('carcinoma-in-situ', 'Disease', (43, 60))
141959	33435818	This approach has identified a subpopulation of basal epithelial cells with enhanced motility and has been used as an organotypic model of dysplasia by introducing TP53 inactivation and SOX2 overexpression.	('TP53', 'Gene', '7157', (164, 168))	('TP53', 'Gene', (164, 168))	('dysplasia', 'Disease', 'MESH:C536170', (139, 148))	('overexpression', 'PosReg', (191, 205))	('dysplasia', 'Disease', (139, 148))	('SOX2', 'Gene', '6657', (186, 190))	('SOX2', 'Gene', (186, 190))	('enhanced', 'PosReg', (76, 84))	('inactivation', 'Var', (169, 181))	('motility', 'CPA', (85, 93))
141963	33435818	Consistent with patient data, Kras mutations are identified as an early event, Cdkn2a can be epigenetically downregulated in early foci and later deleted in both adenomas and adenocarcinomas, while Trp53 mutations are found in adenocarcinomas but not hyperplasias, supporting a role for Trp53 in invasion.	('adenocarcinomas', 'Disease', 'MESH:D000230', (175, 190))	('adenomas', 'Disease', 'MESH:D000236', (162, 170))	('adenocarcinomas', 'Disease', 'MESH:D000230', (227, 242))	('adenomas', 'Disease', (162, 170))	('adenocarcinomas', 'Disease', (227, 242))	('carcinoma', 'Phenotype', 'HP:0030731', (180, 189))	('adenocarcinomas', 'Disease', (175, 190))	('carcinomas', 'Phenotype', 'HP:0030731', (180, 190))	('carcinomas', 'Phenotype', 'HP:0030731', (232, 242))	('carcinoma', 'Phenotype', 'HP:0030731', (232, 241))	('deleted', 'Var', (146, 153))	('downregulated', 'NegReg', (108, 121))	('hyperplasias', 'Disease', (251, 263))	('patient', 'Species', '9606', (16, 23))	('Cdkn2a', 'Gene', (79, 85))	('hyperplasias', 'Disease', 'MESH:D006965', (251, 263))	('mutations', 'Var', (35, 44))
141964	33435818	However, it is noteworthy that Kras G12C mutations are not found in either urethane- (Q61R/Q61 L) or nitrosomethylurea-induced (NMU; G12D) mouse tumours as these carcinogens do not induce the requisite base substitution.	('NMU', 'Chemical', '-', (128, 131))	('G12C', 'Mutation', 'rs121913530', (36, 40))	('tumours', 'Phenotype', 'HP:0002664', (145, 152))	('G12D', 'Mutation', 'rs121913529', (133, 137))	('mouse', 'Species', '10090', (139, 144))	('urethane', 'Chemical', 'MESH:D014520', (75, 83))	('tumour', 'Phenotype', 'HP:0002664', (145, 151))	('nitrosomethylurea', 'Chemical', 'MESH:D008770', (101, 118))	('Kras G12C', 'Var', (31, 40))	('tumours', 'Disease', 'MESH:D009369', (145, 152))	('Q61R', 'Var', (86, 90))	('tumours', 'Disease', (145, 152))	('Q61R', 'SUBSTITUTION', 'None', (86, 90))
141967	33435818	In spite of the differences in cellular composition between mouse and human airways, the model recapitulates key aspects of LUSC natural history, with KRT5-expressing lesions and apparent PI3 K signalling.	('LUSC', 'Phenotype', 'HP:0030359', (124, 128))	('lesions', 'Var', (167, 174))	('LUSC', 'Disease', (124, 128))	('KRT5', 'Gene', (151, 155))	('human', 'Species', '9606', (70, 75))	('LUSC', 'Chemical', '-', (124, 128))	('KRT5', 'Gene', '3852', (151, 155))	('mouse', 'Species', '10090', (60, 65))
141973	33435818	The use of cell lines to predict the efficacy of treatment in relation to particular tumour features, such as histology or particular mutations, will probably require investigating a large number of cell lines in order to generate robust data.	('tumour', 'Disease', 'MESH:D009369', (85, 91))	('tumour', 'Disease', (85, 91))	('men', 'Species', '9606', (54, 57))	('mutations', 'Var', (134, 143))	('tumour', 'Phenotype', 'HP:0002664', (85, 91))
141986	33435818	This concern might be minimized by targeting truncal mutations and perhaps by using as much as possible of the tumour material remaining after clinical diagnostics to generate more representative models.	('tumour', 'Disease', (111, 117))	('tumour', 'Disease', 'MESH:D009369', (111, 117))	('truncal mutations', 'Var', (45, 62))	('tumour', 'Phenotype', 'HP:0002664', (111, 117))
141999	33435818	Fully describing CAF subsets, the epigenetic stability of the CAF state and the extent to which targeting CAFs can be therapeutically beneficial are active areas of research.	('CAF', 'Gene', '8850', (106, 109))	('CAF', 'Gene', (106, 109))	('CAF', 'Gene', (17, 20))	('CAF', 'Gene', (62, 65))	('epigenetic', 'Var', (34, 44))	('CAF', 'Gene', '8850', (17, 20))	('CAF', 'Gene', '8850', (62, 65))
142040	33435818	The development of new barcoding technologies, such as high-throughput barcode sequencing (Tuba-seq), coupled with CRISPR-Cas9-mediated gene editing, will facilitate studies to determine the effects of other additional mutations on tumour evolution and to identify pro-metastatic factors.	('Tuba', 'Gene', '23268', (91, 95))	('tumour', 'Disease', (232, 238))	('Tuba', 'Gene', (91, 95))	('tumour', 'Disease', 'MESH:D009369', (232, 238))	('mutations', 'Var', (219, 228))	('tumour', 'Phenotype', 'HP:0002664', (232, 238))	('men', 'Species', '9606', (11, 14))
142041	33435818	It is noteworthy that the Kras G12D-driven GEMM also releases tumour-derived cell-free DNA (cfDNA) into circulation which might provide a tractable model to study mechanistic questions about cfDNA release as liquid biopsies move towards clinical application in the early detection and relapse settings.	('G12D', 'Mutation', 'rs121913529', (31, 35))	('tumour', 'Phenotype', 'HP:0002664', (62, 68))	('tumour', 'Disease', 'MESH:D009369', (62, 68))	('Kras G12D-driven', 'Var', (26, 42))	('tumour', 'Disease', (62, 68))
142065	33435818	holds European patents relating to assay technology to detect tumour recurrence (PCT/GB2017/053289), targeting neoantigens (PCT/EP2016/059401), identifying patent response to immune checkpoint blockade (PCT/EP2016/071471), determining HLA LOH (PCT/GB2018/052004), predicting survival rates of patients with cancer (PCT/GB2020/050221) and identifying patients who respond to cancer treatment (PCT/GB2018/051912), a US patent relating to detecting tumour mutations (PCT/US2017/28013), and both a European and US patent related to identifying insertion/deletion mutation targets (PCT/GB2018/051892).	('PCT/GB2018/051892', 'Var', (577, 594))	('cancer', 'Disease', (307, 313))	('cancer', 'Disease', 'MESH:D009369', (307, 313))	('cancer', 'Phenotype', 'HP:0002664', (374, 380))	('tumour', 'Phenotype', 'HP:0002664', (62, 68))	('tumour', 'Phenotype', 'HP:0002664', (446, 452))	('cancer', 'Phenotype', 'HP:0002664', (307, 313))	('cancer', 'Disease', (374, 380))	('cancer', 'Disease', 'MESH:D009369', (374, 380))	('men', 'Species', '9606', (386, 389))	('patients', 'Species', '9606', (350, 358))	('tumour', 'Disease', 'MESH:D009369', (62, 68))	('tumour', 'Disease', 'MESH:D009369', (446, 452))	('tumour', 'Disease', (62, 68))	('patients', 'Species', '9606', (293, 301))	('tumour', 'Disease', (446, 452))	('PCT/GB2020/050221', 'Var', (315, 332))
142076	32961679	Here, we report that the combination of ACY-241 and JQ1 shows synergistic cell growth inhibition, viability reduction, and apoptosis induction in HNSCC cells through inactivation of AKT and NF-kappaB signaling.	('NF-kappaB', 'Gene', (190, 199))	('JQ1', 'Var', (52, 55))	('ACY-241', 'Var', (40, 47))	('HNSCC', 'Phenotype', 'HP:0012288', (146, 151))	('apoptosis induction', 'CPA', (123, 142))	('reduction', 'NegReg', (108, 117))	('inactivation', 'NegReg', (166, 178))	('ACY-241', 'Chemical', '-', (40, 47))	('AKT', 'Gene', '207', (182, 185))	('cell growth inhibition', 'CPA', (74, 96))	('NF-kappaB', 'Gene', '4790', (190, 199))	('AKT', 'Gene', (182, 185))	('viability', 'CPA', (98, 107))
142077	32961679	Importantly, we demonstrate that combined treatment of ACY-241 and JQ1 synergistically suppresses TNF-alpha-induced migration and invasion via dysregulating matrix metalloproteinase (MMP)-2, MMP-9, and MT1-MMP.	('ACY-241', 'Chemical', '-', (55, 62))	('MT1-MMP', 'Gene', (202, 209))	('JQ1', 'Var', (67, 70))	('MT1-MMP', 'Gene', '4323', (202, 209))	('invasion', 'CPA', (130, 138))	('MMP-9', 'Gene', '4318', (191, 196))	('TNF-alpha', 'Gene', '7124', (98, 107))	('matrix metalloproteinase (MMP)-2', 'Gene', '4313', (157, 189))	('MMP-9', 'Gene', (191, 196))	('ACY-241', 'Var', (55, 62))	('TNF-alpha', 'Gene', (98, 107))	('suppresses', 'NegReg', (87, 97))
142078	32961679	Overall, the combination of ACY-241 and JQ1 significantly suppresses proliferation and metastasis in HPV-positive and HPV-negative HNSCC.	('ACY-241', 'Chemical', '-', (28, 35))	('proliferation', 'CPA', (69, 82))	('metastasis', 'CPA', (87, 97))	('HNSCC', 'Phenotype', 'HP:0012288', (131, 136))	('HPV', 'Species', '10566', (118, 121))	('ACY-241', 'Var', (28, 35))	('HPV', 'Species', '10566', (101, 104))	('suppresses', 'NegReg', (58, 68))	('JQ1', 'Gene', (40, 43))
142079	32961679	Collectively, these findings suggest that the co-inhibition of BET and HDAC6 can be a new therapeutic strategy in HNSCC.	('co-inhibition', 'Var', (46, 59))	('HDAC6', 'Gene', (71, 76))	('BET', 'Gene', (63, 66))	('HNSCC', 'Disease', (114, 119))	('HNSCC', 'Phenotype', 'HP:0012288', (114, 119))	('BET', 'Gene', '92737', (63, 66))	('HDAC6', 'Gene', '10013', (71, 76))
142084	32961679	Interestingly, HPV-positive HNSCCs are more metastatic to cervical lymph nodes compared to HPV-negative tumors.	('HNSCC', 'Phenotype', 'HP:0012288', (28, 33))	('metastatic to cervical lymph nodes', 'CPA', (44, 78))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('HPV-positive', 'Var', (15, 27))	('HNSCCs', 'Disease', 'MESH:D000077195', (28, 34))	('tumors', 'Disease', (104, 110))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('HPV', 'Species', '10566', (15, 18))	('HPV', 'Species', '10566', (91, 94))	('HNSCCs', 'Disease', (28, 34))
142096	32961679	High protein and mRNA levels of HDAC6 are detected in oral squamous cell carcinoma (OSCC), and inhibition of HDAC6 synergistically induces autophagy and apoptosis together with Bortezomib in HNSCC.	('Bortezomib', 'Chemical', 'MESH:D000069286', (177, 187))	('HDAC6', 'Gene', '10013', (109, 114))	('HDAC6', 'Gene', (109, 114))	('HDAC6', 'Gene', '10013', (32, 37))	('oral squamous cell carcinoma', 'Disease', (54, 82))	('inhibition', 'Var', (95, 105))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (59, 82))	('autophagy', 'CPA', (139, 148))	('HNSCC', 'Phenotype', 'HP:0012288', (191, 196))	('induces', 'Reg', (131, 138))	('mRNA levels', 'MPA', (17, 28))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (54, 82))	('HDAC6', 'Gene', (32, 37))	('apoptosis', 'CPA', (153, 162))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
142102	32961679	As a result, JQ1 impairs cell proliferation and metastasis while inducing apoptosis and cell cycle arrest in HNSCC.	('apoptosis', 'CPA', (74, 83))	('inducing', 'Reg', (65, 73))	('impairs', 'NegReg', (17, 24))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (88, 105))	('JQ1', 'Var', (13, 16))	('arrest', 'Disease', 'MESH:D006323', (99, 105))	('HNSCC', 'Phenotype', 'HP:0012288', (109, 114))	('arrest', 'Disease', (99, 105))
142106	32961679	Our work demonstrates that the combination treatment of ACY-241 and JQ1 to HNSCC cells increases apoptosis while suppressing cell growth, viability, migration, and invasion.	('cell growth', 'CPA', (125, 136))	('increases', 'PosReg', (87, 96))	('suppressing', 'NegReg', (113, 124))	('migration', 'CPA', (149, 158))	('ACY-241', 'Chemical', '-', (56, 63))	('JQ1', 'Var', (68, 71))	('HNSCC', 'Phenotype', 'HP:0012288', (75, 80))	('invasion', 'CPA', (164, 172))	('ACY-241', 'Var', (56, 63))	('apoptosis', 'CPA', (97, 106))
142110	32961679	This result shows that ACY-241 and JQ1 exhibit anti-proliferative effects in HNSCC cells regardless of HPV infection.	('ACY-241', 'Var', (23, 30))	('JQ1', 'Gene', (35, 38))	('HPV infection', 'Disease', 'MESH:D030361', (103, 116))	('anti-proliferative effects', 'CPA', (47, 73))	('ACY-241', 'Chemical', '-', (23, 30))	('HNSCC', 'Phenotype', 'HP:0012288', (77, 82))	('HPV infection', 'Disease', (103, 116))
142112	32961679	The combination of ACY-241 and JQ1 showed synergistic cytotoxicity with a combination index (CI) of <1.0 (Figure 2A,B).	('cytotoxicity', 'Disease', (54, 66))	('cytotoxicity', 'Disease', 'MESH:D064420', (54, 66))	('ACY-241', 'Chemical', '-', (19, 26))	('CI', 'Chemical', '-', (93, 95))	('JQ1', 'Var', (31, 34))	('ACY-241', 'Var', (19, 26))
142113	32961679	These data confirmed the robust anti-proliferative effect when ACY-241 and JQ1 were combined in both HPV-positive and HPV-negative HNSCC cells.	('ACY-241', 'Chemical', '-', (63, 70))	('HNSCC', 'Phenotype', 'HP:0012288', (131, 136))	('HPV', 'Species', '10566', (118, 121))	('ACY-241', 'Var', (63, 70))	('HPV', 'Species', '10566', (101, 104))	('JQ1', 'Gene', (75, 78))	('anti-proliferative effect', 'CPA', (32, 57))
142116	32961679	ACY-241 increased acetylation of alpha-tubulin, and JQ1 decreased c-Myc in both HPV-positive 2A3 and HPV-negative FaDu HNSCC cells.	('JQ1', 'Var', (52, 55))	('c-Myc', 'Gene', '4609', (66, 71))	('c-Myc', 'Gene', (66, 71))	('ACY-241', 'Var', (0, 7))	('decreased', 'NegReg', (56, 65))	('HPV', 'Species', '10566', (80, 83))	('increased', 'PosReg', (8, 17))	('alpha-tubulin', 'Gene', (33, 46))	('HPV', 'Species', '10566', (101, 104))	('FaDu HNSCC', 'CellLine', 'CVCL:1218', (114, 124))	('HNSCC', 'Phenotype', 'HP:0012288', (119, 124))	('alpha-tubulin', 'Gene', '10376', (33, 46))	('ACY-241', 'Chemical', '-', (0, 7))	('acetylation', 'MPA', (18, 29))
142117	32961679	Furthermore, HDAC6 protein level remained unchanged by ACY-241 (Figure 2C,D).	('ACY-241', 'Var', (55, 62))	('HDAC6', 'Gene', (13, 18))	('ACY-241', 'Chemical', '-', (55, 62))	('HDAC6', 'Gene', '10013', (13, 18))
142120	32961679	As c-Myc oncogene is known to induce proliferation, we next performed immunoblotting to determine whether ACY-241 and JQ1 disrupt the apoptotic signaling pathway.	('JQ1', 'Var', (118, 121))	('c-Myc', 'Gene', (3, 8))	('apoptotic signaling pathway', 'Pathway', (134, 161))	('ACY-241', 'Var', (106, 113))	('c-Myc', 'Gene', '4609', (3, 8))	('ACY-241', 'Chemical', '-', (106, 113))	('disrupt', 'NegReg', (122, 129))
142123	32961679	However, Bcl-2 associated pro-apoptotic proteins, such as Bak, Bax, and Bad, remained unchanged by ACY-241 and JQ1 combination (Figure S2).	('ACY-241', 'Var', (99, 106))	('Bad', 'MPA', (72, 75))	('Bcl-2', 'Gene', (9, 14))	('Bcl-2', 'Gene', '596', (9, 14))	('JQ1 combination', 'Var', (111, 126))	('Bax', 'Gene', '581', (63, 66))	('ACY-241', 'Chemical', '-', (99, 106))	('Bak', 'Gene', (58, 61))	('Bax', 'Gene', (63, 66))	('Bak', 'Gene', '578', (58, 61))
142126	32961679	Collectively, these data show that simultaneous inhibition of HDAC6 and BET is an effective treatment strategy to promote apoptosis in both HPV-positive and HPV-negative HNSCC cells.	('HPV', 'Species', '10566', (140, 143))	('HPV', 'Species', '10566', (157, 160))	('BET', 'Gene', '92737', (72, 75))	('BET', 'Gene', (72, 75))	('apoptosis', 'CPA', (122, 131))	('HDAC6', 'Gene', '10013', (62, 67))	('HDAC6', 'Gene', (62, 67))	('HNSCC', 'Phenotype', 'HP:0012288', (170, 175))	('inhibition', 'Var', (48, 58))	('promote', 'PosReg', (114, 121))
142129	32961679	Single treatments of ACY-241 and JQ1 substantially downregulated MMP-2, rather than MMP-9, in both HPV-positive 2A3 and HPV-negative FaDu HNSCC cells (Figure 4A,B).	('HNSCC', 'Phenotype', 'HP:0012288', (138, 143))	('MMP-2', 'Gene', (65, 70))	('ACY-241', 'Chemical', '-', (21, 28))	('ACY-241', 'Var', (21, 28))	('MMP-9', 'Gene', '4318', (84, 89))	('JQ1', 'Var', (33, 36))	('FaDu HNSCC', 'CellLine', 'CVCL:1218', (133, 143))	('MMP-9', 'Gene', (84, 89))	('downregulated', 'NegReg', (51, 64))	('MMP-2', 'Gene', '4313', (65, 70))	('HPV', 'Species', '10566', (99, 102))	('HPV', 'Species', '10566', (120, 123))
142130	32961679	The combination of ACY-241 and JQ1 also synergistically reduced MMP-2 and MMP-9, the type IV collagenase that has a significant function in EMT by altering cell-matrix and cell-cell interactions.	('altering', 'Reg', (147, 155))	('MMP-2', 'Gene', (64, 69))	('reduced', 'NegReg', (56, 63))	('MMP-9', 'Gene', '4318', (74, 79))	('ACY-241', 'Chemical', '-', (19, 26))	('MMP-2', 'Gene', '4313', (64, 69))	('MMP-9', 'Gene', (74, 79))	('JQ1', 'Var', (31, 34))	('ACY-241', 'Var', (19, 26))
142133	32961679	In addition to MT1-MMP, tumor necrosis factor-alpha (TNF-alpha), an inducer of MMP-9 secretion in hypopharyngeal and OSCC cell lines, was synergistically suppressed by a combination of ACY-241 and JQ1 in both HNSCC cells (Figure 4C,D and Figure S1G).	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('MMP-9', 'Gene', (79, 84))	('MMP-9', 'Gene', '4318', (79, 84))	('tumor necrosis factor-alpha', 'Gene', (24, 51))	('suppressed', 'NegReg', (154, 164))	('MT1-MMP', 'Gene', '4323', (15, 22))	('JQ1', 'Var', (197, 200))	('secretion', 'MPA', (85, 94))	('tumor necrosis factor-alpha', 'Gene', '7124', (24, 51))	('ACY-241', 'Var', (185, 192))	('TNF-alpha', 'Gene', '7124', (53, 62))	('HNSCC', 'Phenotype', 'HP:0012288', (209, 214))	('MT1-MMP', 'Gene', (15, 22))	('TNF-alpha', 'Gene', (53, 62))	('ACY-241', 'Chemical', '-', (185, 192))
142135	32961679	Among three EMT transcription factors (Snail, Twist1, and Zeb2), the mRNA level of SNAI1 was decreased by ACY-241 and JQ1 (Figure S1H-J).	('Snail', 'Gene', (39, 44))	('JQ1', 'Var', (118, 121))	('Zeb2', 'Gene', '9839', (58, 62))	('Twist1', 'Gene', '7291', (46, 52))	('ACY-241', 'Var', (106, 113))	('mRNA level', 'MPA', (69, 79))	('decreased', 'NegReg', (93, 102))	('Twist1', 'Gene', (46, 52))	('SNAI1', 'Gene', '6615', (83, 88))	('SNAI1', 'Gene', (83, 88))	('ACY-241', 'Chemical', '-', (106, 113))	('Zeb2', 'Gene', (58, 62))	('Snail', 'Gene', '6615', (39, 44))
142138	32961679	Thus, we investigated whether ACY-241 and JQ1 affect the AKT/NF-kappaB signaling pathway in HPV-positive and HPV-negative HNSCC cells.	('NF-kappaB', 'Gene', (61, 70))	('ACY-241', 'Chemical', '-', (30, 37))	('affect', 'Reg', (46, 52))	('AKT', 'Gene', '207', (57, 60))	('HPV', 'Species', '10566', (92, 95))	('HPV', 'Species', '10566', (109, 112))	('HNSCC', 'Phenotype', 'HP:0012288', (122, 127))	('JQ1', 'Var', (42, 45))	('AKT', 'Gene', (57, 60))	('ACY-241', 'Var', (30, 37))	('NF-kappaB', 'Gene', '4790', (61, 70))
142140	32961679	Together, our results indicate that the combination of ACY-241 and JQ1 suppresses TNF-alpha-induced responses by dysregulating MT1-MMP, MMP-2, and MMP-9 and by modulating AKT/NF-kappaB signaling pathways in both HPV-positive and HPV-negative HNSCC cells.	('MMP-2', 'Gene', (136, 141))	('ACY-241', 'Chemical', '-', (55, 62))	('NF-kappaB', 'Gene', (175, 184))	('HNSCC', 'Phenotype', 'HP:0012288', (242, 247))	('NF-kappaB', 'Gene', '4790', (175, 184))	('TNF-alpha', 'Gene', '7124', (82, 91))	('ACY-241', 'Var', (55, 62))	('TNF-alpha', 'Gene', (82, 91))	('modulating', 'Reg', (160, 170))	('MMP-9', 'Gene', '4318', (147, 152))	('AKT', 'Gene', (171, 174))	('MT1-MMP', 'Gene', (127, 134))	('MMP-9', 'Gene', (147, 152))	('suppresses', 'NegReg', (71, 81))	('JQ1', 'Var', (67, 70))	('MMP-2', 'Gene', '4313', (136, 141))	('MT1-MMP', 'Gene', '4323', (127, 134))	('AKT', 'Gene', '207', (171, 174))	('HPV', 'Species', '10566', (229, 232))	('HPV', 'Species', '10566', (212, 215))
142147	32961679	The Kaplan-Meier plot showing the overall survival (OS) of HNSCC patients regarding gene expressions of HDAC6, BRD2, and BRD4 demonstrates that patients with high BRD2 or BRD4 display low survival (Figure S3).	('low', 'NegReg', (184, 187))	('BRD4', 'Gene', '23476', (121, 125))	('BRD2', 'Gene', '6046', (111, 115))	('BRD2', 'Gene', (111, 115))	('high', 'Var', (158, 162))	('BRD4', 'Gene', (171, 175))	('HDAC6', 'Gene', '10013', (104, 109))	('BRD2', 'Gene', (163, 167))	('patients', 'Species', '9606', (144, 152))	('HDAC6', 'Gene', (104, 109))	('patients', 'Species', '9606', (65, 73))	('BRD2', 'Gene', '6046', (163, 167))	('survival', 'MPA', (188, 196))	('BRD4', 'Gene', '23476', (171, 175))	('HNSCC', 'Phenotype', 'HP:0012288', (59, 64))	('BRD4', 'Gene', (121, 125))
142151	32961679	Anti-apoptotic protein Bcl-xL is downregulated to promote apoptosis, but other Bcl-2 associated pro-apoptotic proteins remain unchanged by ACY-241 and JQ1 combination (Figure S2).	('JQ1 combination', 'Var', (151, 166))	('Bcl-xL', 'Gene', '598', (23, 29))	('promote', 'PosReg', (50, 57))	('Bcl-xL', 'Gene', (23, 29))	('ACY-241', 'Chemical', '-', (139, 146))	('apoptosis', 'CPA', (58, 67))	('Bcl-2', 'Gene', (79, 84))	('Bcl-2', 'Gene', '596', (79, 84))	('downregulated', 'NegReg', (33, 46))	('ACY-241', 'Var', (139, 146))
142152	32961679	Moreover, we show by flow cytometry that co-inhibition of HDAC6 and BET causes apoptosis in HNSCC cells.	('HDAC6', 'Gene', '10013', (58, 63))	('HDAC6', 'Gene', (58, 63))	('BET', 'Gene', '92737', (68, 71))	('HNSCC', 'Phenotype', 'HP:0012288', (92, 97))	('co-inhibition', 'Var', (41, 54))	('BET', 'Gene', (68, 71))
142168	32961679	In the case of HNSCC, ACY-241 significantly inhibits MMP-2 expression more than it does MMP-9.	('MMP-2', 'Gene', '4313', (53, 58))	('ACY-241', 'Chemical', '-', (22, 29))	('MMP-9', 'Gene', '4318', (88, 93))	('HNSCC', 'Phenotype', 'HP:0012288', (15, 20))	('expression', 'MPA', (59, 69))	('MMP-9', 'Gene', (88, 93))	('MMP-2', 'Gene', (53, 58))	('inhibits', 'NegReg', (44, 52))	('ACY-241', 'Var', (22, 29))
142175	32961679	Further investigations are required to confirm which member of BET is deregulated by JQ1 to induce anticancer effects.	('JQ1', 'Gene', (85, 88))	('BET', 'Gene', (63, 66))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('deregulated', 'Var', (70, 81))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('BET', 'Gene', '92737', (63, 66))	('induce', 'PosReg', (92, 98))
142177	32961679	JQ1 is often called a BRD4 inhibitor due to its strong inhibitory potency for BRD4.	('BRD4', 'Gene', (22, 26))	('BRD4', 'Gene', (78, 82))	('BRD4', 'Gene', '23476', (78, 82))	('JQ1', 'Var', (0, 3))	('inhibitory potency', 'MPA', (55, 73))	('BRD4', 'Gene', '23476', (22, 26))
142180	32961679	This suggests that BRD2 inhibition may synergize with HDAC6 inhibition to suppress metastasis in HNSCC.	('HDAC6', 'Gene', (54, 59))	('metastasis', 'CPA', (83, 93))	('HNSCC', 'Phenotype', 'HP:0012288', (97, 102))	('HNSCC', 'Disease', (97, 102))	('suppress', 'NegReg', (74, 82))	('inhibition', 'Var', (24, 34))	('BRD2', 'Gene', '6046', (19, 23))	('BRD2', 'Gene', (19, 23))	('HDAC6', 'Gene', '10013', (54, 59))
142181	32961679	This hypothesis is supported by the study that ZNF281, an EMT transcription factor, is enriched in the BRD2-binding genes that are downregulated by JQ1.	('JQ1', 'Var', (148, 151))	('BRD2', 'Gene', (103, 107))	('ZNF281', 'Gene', '23528', (47, 53))	('BRD2', 'Gene', '6046', (103, 107))	('ZNF281', 'Gene', (47, 53))	('downregulated', 'NegReg', (131, 144))
142183	32961679	Thus, BRD2 knockdown or JQ1 treatment reduced the transcription of genes involved in EMT.	('reduced', 'NegReg', (38, 45))	('BRD2', 'Gene', '6046', (6, 10))	('BRD2', 'Gene', (6, 10))	('knockdown', 'Var', (11, 20))	('transcription of genes', 'MPA', (50, 72))
142187	32961679	We have shown by GEO analysis that the BRD2 mRNA level is upregulated and displays a stronger positive correlation with HDAC6 mRNA in HPV-positive HNSCC samples compared to HPV-negative samples (Figure S4).	('HDAC6', 'Gene', '10013', (120, 125))	('HDAC6', 'Gene', (120, 125))	('HPV', 'Species', '10566', (173, 176))	('upregulated', 'PosReg', (58, 69))	('HNSCC', 'Disease', (147, 152))	('HPV-positive', 'Var', (134, 146))	('BRD2', 'Gene', '6046', (39, 43))	('BRD2', 'Gene', (39, 43))	('HPV', 'Species', '10566', (134, 137))	('HNSCC', 'Phenotype', 'HP:0012288', (147, 152))
142188	32961679	In addition, we interestingly observed that adhesion and migration abilities in HPV-positive 2A3 cells are more impaired compared with those in HPV-negative FaDu cells in the cell culture.	('HPV', 'Species', '10566', (144, 147))	('HPV-positive', 'Var', (80, 92))	('HPV', 'Species', '10566', (80, 83))	('impaired', 'NegReg', (112, 120))	('adhesion', 'CPA', (44, 52))
142193	32961679	Antibodies against alpha-tubulin (sc-32293), c-Myc (sc-40), Snail (sc-28199), p-AKT (sc-7985-R), AKT (sc-8312), p65 (sc-8008), and TNF-alpha (sc-52746) were purchased from Santa Cruz Biotechnology (Santa Cruz, CA, USA).	('AKT', 'Gene', '207', (97, 100))	('alpha-tubulin', 'Gene', '10376', (19, 32))	('Snail', 'Gene', (60, 65))	('AKT', 'Gene', '207', (80, 83))	('TNF-alpha', 'Gene', '7124', (131, 140))	('p65', 'Gene', (112, 115))	('Snail', 'Gene', '6615', (60, 65))	('AKT', 'Gene', (97, 100))	('c-Myc', 'Gene', (45, 50))	('sc-32293', 'Var', (34, 42))	('TNF-alpha', 'Gene', (131, 140))	('alpha-tubulin', 'Gene', (19, 32))	('AKT', 'Gene', (80, 83))	('p65', 'Gene', '5970', (112, 115))	('c-Myc', 'Gene', '4609', (45, 50))
142194	32961679	Antibodies against GAPDH (AP0066) and p-p65 (BS4138) were from Bioworld Technology (Bloomington, MN, USA).	('p65', 'Gene', (40, 43))	('BS4138', 'Var', (45, 51))	('GAPDH', 'Gene', '2597', (19, 24))	('MN', 'CellLine', 'CVCL:U508', (97, 99))	('p65', 'Gene', '5970', (40, 43))	('AP0066', 'Var', (26, 32))	('GAPDH', 'Gene', (19, 24))
142195	32961679	Antibodies against MMP-2 (A2454) and MMP-9 (A0289) were from ABclonal Technology (Woburn, MA, USA).	('A0289', 'Var', (44, 49))	('MMP-2', 'Gene', '4313', (19, 24))	('MMP-9', 'Gene', '4318', (37, 42))	('A2454', 'Var', (26, 31))	('MMP-9', 'Gene', (37, 42))	('MMP-2', 'Gene', (19, 24))
142196	32961679	Antibodies against PARP (551024) and XIAP (610716) were from BD Biosciences (San Jose, CA, USA).	('PARP', 'Gene', '1302', (19, 23))	('XIAP', 'Gene', '331', (37, 41))	('XIAP', 'Gene', (37, 41))	('PARP', 'Gene', (19, 23))	('551024', 'Var', (25, 31))
142197	32961679	Antibodies against caspase-3 (#9662), Bcl-xL (#2762), and MT1-MMP (#13130) were from Cell Signaling Technology (Danvers, MA, USA).	('#9662', 'Var', (30, 35))	('MT1-MMP', 'Gene', (58, 65))	('MT1-MMP', 'Gene', '4323', (58, 65))	('Bcl-xL', 'Gene', '598', (38, 44))	('caspase-3', 'Gene', (19, 28))	('Bcl-xL', 'Gene', (38, 44))	('#13130', 'Var', (67, 73))	('caspase-3', 'Gene', '836', (19, 28))	('#2762', 'Var', (46, 51))
142198	32961679	Antibody against acetyl alpha-tubulin (T6793) was from Sigma-Aldrich (St. Louis, MO, USA).	('alpha-tubulin', 'Gene', '10376', (24, 37))	('T6793', 'Var', (39, 44))	('alpha-tubulin', 'Gene', (24, 37))
142221	32961679	Collectively, we demonstrate that the combined targeting of HDAC6 and BET in HNSCC synergistically promotes apoptosis and suppresses cell growth and viability, migration, and invasion.	('HDAC6', 'Gene', (60, 65))	('BET', 'Gene', (70, 73))	('migration', 'CPA', (160, 169))	('targeting', 'Var', (47, 56))	('promotes', 'PosReg', (99, 107))	('invasion', 'CPA', (175, 183))	('suppresses', 'NegReg', (122, 132))	('HNSCC', 'Phenotype', 'HP:0012288', (77, 82))	('apoptosis', 'CPA', (108, 117))	('BET', 'Gene', '92737', (70, 73))	('HDAC6', 'Gene', '10013', (60, 65))
142222	32961679	ACY-241 and JQ1 induce apoptosis by modulating anti-apoptotic proteins.	('apoptosis', 'CPA', (23, 32))	('ACY-241', 'Var', (0, 7))	('anti-apoptotic proteins', 'MPA', (47, 70))	('JQ1', 'Gene', (12, 15))	('ACY-241', 'Chemical', '-', (0, 7))	('modulating', 'Reg', (36, 46))
142229	32961679	Supplementary Figure S2: Bcl-2 related pro-apoptotic proteins are unaffected by ACY-241 and JQ1 treatments.	('Bcl-2', 'Gene', (25, 30))	('Bcl-2', 'Gene', '596', (25, 30))	('ACY-241', 'Chemical', '-', (80, 87))	('JQ1', 'Var', (92, 95))	('ACY-241', 'Var', (80, 87))
142233	32961679	Primary antibodies against Bak (sc-832) and Bad (sc-8044) were purchased from Santa Cruz Biotechnology (Santa Cruz, CA), and Bax (#2772) was from Cell Signaling Technology (Danvers, MA).	('Bax', 'Gene', (125, 128))	('sc-8044', 'Var', (49, 56))	('Bax', 'Gene', '581', (125, 128))	('Bak', 'Gene', (27, 30))	('Bak', 'Gene', '578', (27, 30))
142241	32961679	* p < 0.05, ** p < 0.01 or *** p < 0.001 vs. HPV-negative HNSCC samples.	('*** p <', 'Var', (27, 34))	('HPV', 'Species', '10566', (45, 48))	('** p < 0.01', 'Var', (12, 23))	('HNSCC', 'Phenotype', 'HP:0012288', (58, 63))
142255	30683880	Inherited genetic variation plays an important role in cancer etiology.	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('Inherited genetic variation', 'Var', (0, 27))	('cancer', 'Disease', (55, 61))
142258	30683880	Additional evidence for a shared genetic component have been demonstrated by cross-cancer genome-wide association study (GWAS) meta-analyses, which set out to identify genetic variants associated with more than one cancer type.	('cross-cancer', 'Disease', (77, 89))	('cancer', 'Disease', (215, 221))	('cancer', 'Disease', 'MESH:D009369', (215, 221))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('variants', 'Var', (176, 184))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('cancer', 'Disease', (83, 89))	('cross-cancer', 'Disease', 'MESH:C537866', (77, 89))
142271	30683880	Our comprehensive analysis identifies statistically significant genetic correlations between lung and head/neck cancer, breast and ovarian cancer, breast and lung cancer, and breast and colorectal cancer.	('significant', 'Reg', (52, 63))	('genetic', 'Var', (64, 71))	('head/neck cancer', 'Disease', (102, 118))	('lung cancer', 'Phenotype', 'HP:0100526', (158, 169))	('breast and lung cancer', 'Disease', 'MESH:D001943', (147, 169))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('lung', 'Disease', (93, 97))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('ovarian cancer', 'Phenotype', 'HP:0100615', (131, 145))	('head/neck cancer', 'Disease', 'MESH:D006258', (102, 118))	('colorectal cancer', 'Phenotype', 'HP:0003003', (186, 203))	('neck cancer', 'Phenotype', 'HP:0012288', (107, 118))	('head/neck cancer', 'Phenotype', 'HP:0012288', (102, 118))	('breast and ovarian cancer', 'Disease', 'MESH:D010051', (120, 145))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('breast and colorectal cancer', 'Disease', 'MESH:D015179', (175, 203))
142291	30683880	Further, we observed a significantly larger genetic correlation of lung cancer with ER- (rg = 0.29, se = 0.06) than with ER + breast cancer (rg = 0.13, se = 0.04) (pdifference = 0.002).	('ER-', 'Var', (84, 87))	('breast cancer', 'Disease', 'MESH:D001943', (126, 139))	('breast cancer', 'Phenotype', 'HP:0003002', (126, 139))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('lung cancer', 'Disease', 'MESH:D008175', (67, 78))	('breast cancer', 'Disease', (126, 139))	('lung cancer', 'Disease', (67, 78))	('lung cancer', 'Phenotype', 'HP:0100526', (67, 78))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
142295	30683880	Similarly, although the genome-wide genetic correlation between lung and prostate cancer was negligible (rg = -0.03), two previously identified pleiotropic regions (chr6:30-31 M or 6p21.33, p = 5.7 x 10-7 and chr20:62M or 20q13.33, p = 2.8 x 10-6) exhibited significant local genetic correlations (rg = -0.00060 and rg = 0.00067).	('prostate cancer', 'Disease', (73, 88))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('chr6:30-31', 'STRUCTURAL_ABNORMALITY', 'None', (165, 175))	('chr6:30-31', 'Var', (165, 175))	('prostate cancer', 'Disease', 'MESH:D011471', (73, 88))	('prostate cancer', 'Phenotype', 'HP:0012125', (73, 88))	('chr20:62M or 20q13.33', 'Var', (209, 230))	('lung', 'Disease', (64, 68))
142316	30683880	In addition, multiple histone modifications of epigenetic markers H3K9ac, H3K4me3, and H3K27ac, were all significantly enriched for cancer heritability.	('cancer', 'Disease', (132, 138))	('H3K4me3', 'Var', (74, 81))	('enriched', 'Reg', (119, 127))	('H3K27ac', 'Var', (87, 94))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('H3K9ac', 'Var', (66, 72))	('cancer', 'Disease', 'MESH:D009369', (132, 138))
142319	30683880	For breast cancer, 3 out of 8 statistically significant tissues were adipose nuclei (H3K4me1, H3K9ac) and breast myoepithelial (H3K4me1) cells.	('breast myoepithelial', 'Disease', (106, 126))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('breast cancer', 'Disease', 'MESH:D001943', (4, 17))	('breast cancer', 'Phenotype', 'HP:0003002', (4, 17))	('H3K4me1', 'Var', (128, 135))	('breast cancer', 'Disease', (4, 17))	('H3K4me1', 'Var', (85, 92))	('breast myoepithelial', 'Disease', 'MESH:D009208', (106, 126))	('H3K9ac', 'Var', (94, 100))
142328	30683880	Our results are, however, in line with a recent study, which analyzed a subset of the data included here, and identified a significant genetic correlation between lung and colorectal cancer.	('colorectal cancer', 'Disease', 'MESH:D015179', (172, 189))	('colorectal cancer', 'Phenotype', 'HP:0003003', (172, 189))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('colorectal cancer', 'Disease', (172, 189))	('lung', 'Disease', (163, 167))	('genetic', 'Var', (135, 142))
142330	30683880	We also for the first time observed a significant genetic correlation between breast and ovarian cancer (rg = 0.24), two cancers that are known to share rare genetic factors including BRCA1/2 mutations, and environmental exposures associated with endogenous and exogenous hormone exposures.	('cancers', 'Disease', (121, 128))	('cancers', 'Disease', 'MESH:D009369', (121, 128))	('BRCA1/2', 'Gene', (184, 191))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('breast and ovarian cancer', 'Disease', 'MESH:D010051', (78, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('BRCA1/2', 'Gene', '672;675', (184, 191))	('mutations', 'Var', (192, 201))	('cancers', 'Phenotype', 'HP:0002664', (121, 128))	('ovarian cancer', 'Phenotype', 'HP:0100615', (89, 103))
142331	30683880	Prostate cancer is also considered as hormone-dependent and associated with BRCA1/2 mutations, but interestingly, we only observed a nominally significant and modest (rg = 0.07) genetic correlation between breast and prostate cancer, while ovarian and prostate cancer showed no genetic correlation (rg = 0.02, se = 0.07).	('Prostate cancer', 'Phenotype', 'HP:0012125', (0, 15))	('prostate cancer', 'Phenotype', 'HP:0012125', (217, 232))	('BRCA1/2', 'Gene', (76, 83))	('Prostate cancer', 'Disease', (0, 15))	('cancer', 'Phenotype', 'HP:0002664', (261, 267))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('breast and prostate cancer', 'Disease', 'MESH:D011471', (206, 232))	('ovarian and prostate cancer', 'Disease', 'MESH:D010051', (240, 267))	('mutations', 'Var', (84, 93))	('BRCA1/2', 'Gene', '672;675', (76, 83))	('prostate cancer', 'Phenotype', 'HP:0012125', (252, 267))	('Prostate cancer', 'Disease', 'MESH:D011471', (0, 15))	('associated', 'Reg', (60, 70))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
142337	30683880	This suggests that rare high penetrance variants may play a more important role in driving the similarities behind ER- breast cancer and serous ovarian cancer than common genetic variation.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('breast cancer', 'Disease', 'MESH:D001943', (119, 132))	('ovarian cancer', 'Phenotype', 'HP:0100615', (144, 158))	('breast cancer', 'Disease', (119, 132))	('breast cancer', 'Phenotype', 'HP:0003002', (119, 132))	('serous ovarian cancer', 'Disease', (137, 158))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('variants', 'Var', (40, 48))	('serous ovarian cancer', 'Disease', 'MESH:D010051', (137, 158))
142338	30683880	Heritability analysis confirms that common cancers have a polygenic component that involves a large number of variants.	('cancers', 'Phenotype', 'HP:0002664', (43, 50))	('variants', 'Var', (110, 118))	('cancers', 'Disease', (43, 50))	('cancers', 'Disease', 'MESH:D009369', (43, 50))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))
142339	30683880	Although susceptibility variants identified at genome-wide significance explain an appreciable fraction of the heritability for some cancers, we estimate that the majority of the polygenic effect is attributable to other, yet undiscovered variants, presumably with effects that are too weak to have been identified with current sample sizes.	('variants', 'Var', (24, 32))	('cancers', 'Phenotype', 'HP:0002664', (133, 140))	('cancers', 'Disease', (133, 140))	('cancers', 'Disease', 'MESH:D009369', (133, 140))	('variants', 'Var', (239, 247))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
142353	30683880	Pan-cancer tumor-based studies have demonstrated that different cancers are sometimes driven by similar somatic functional events such as specific copy number abnormalities and mutations.	('number abnormalities', 'Disease', 'MESH:D007674', (152, 172))	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('Pan-cancer tumor', 'Disease', 'MESH:D009369', (0, 16))	('mutations', 'Var', (177, 186))	('cancers', 'Disease', 'MESH:D009369', (64, 71))	('cancers', 'Phenotype', 'HP:0002664', (64, 71))	('number abnormalities', 'Disease', (152, 172))	('cancers', 'Disease', (64, 71))	('driven by', 'Reg', (86, 95))	('Pan-cancer tumor', 'Disease', (0, 16))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
142355	30683880	Compared to normal cells, cancer cells have a unique spectrum of transcribed ultra-conservative regions, suggesting that variation in expression of these regions are involved in the malignant process.	('expression', 'MPA', (134, 144))	('cancer', 'Disease', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('variation', 'Var', (121, 130))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('involved', 'Reg', (166, 174))
142360	30683880	Unfortunately, we did not have data on prostate-specific tissues, but we note that tissue-specific enrichment of prostate cancer heritability for epigenetic markers has been observed previously.	('epigenetic', 'Var', (146, 156))	('prostate cancer', 'Disease', (113, 128))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('prostate cancer', 'Disease', 'MESH:D011471', (113, 128))	('prostate cancer', 'Phenotype', 'HP:0012125', (113, 128))
142381	30683880	Note that the quantity estimated by LDSC is the causal heritability of common SNPs, which is different from the SNP-heritability as defined in Yang et al.. To estimate  attributable to undiscovered loci, we identified SNPs that were associated with a given cancer at genome-wide significance (p < 5 x 10-8) and removed all SNPs within (+/-) 500,000 base-pairs of those loci prior to calculation (number of regions (+/- 500 kb) for each cancer that reach the 5 x 10-8 threshold and measures of effect size are shown in Supplementary Data 1).	('associated', 'Reg', (233, 243))	('SNPs', 'Var', (218, 222))	('cancer', 'Phenotype', 'HP:0002664', (257, 263))	('cancer', 'Phenotype', 'HP:0002664', (436, 442))	('cancer', 'Disease', 'MESH:D009369', (257, 263))	('cancer', 'Disease', 'MESH:D009369', (436, 442))	('cancer', 'Disease', (257, 263))	('cancer', 'Disease', (436, 442))
142390	30683880	Each cell-type-specific annotation corresponds to a histone mark in a single cell type (for example, H3K27ac in CD19 immune cells), and there were 220 such annotations in total.	('corresponds', 'Reg', (35, 46))	('histone mark', 'MPA', (52, 64))	('CD19', 'Gene', (112, 116))	('H3K27ac', 'Var', (101, 108))	('CD19', 'Gene', '930', (112, 116))
142397	30683880	Breast cancer: summary results for all variants are available at http://bcac.ccge.medschl.cam.ac.uk/.	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('Breast cancer', 'Phenotype', 'HP:0003002', (0, 13))	('Breast cancer', 'Disease', 'MESH:D001943', (0, 13))	('Breast cancer', 'Disease', (0, 13))	('variants', 'Var', (39, 47))
142402	30683880	Colorectal cancer: genotype data have been deposited at the database of Genotypes and Phenotypes (dbGaP) under accession number phs001415.v1.p1 and phs001078.v1.p1.	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('Colorectal cancer', 'Phenotype', 'HP:0003003', (0, 17))	('Colorectal cancer', 'Disease', (0, 17))	('phs001078.v1.p1', 'Var', (148, 163))	('Colorectal cancer', 'Disease', 'MESH:D015179', (0, 17))
142451	27668986	In the past years, candidate-gene studies and genome-wide association studies (GWASs) have discovered important germline variants (especially SNPs) that are associated with cancer risk using case-control designs, indicating sporadic cancers bear genetic components .	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('associated', 'Reg', (157, 167))	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('cancer', 'Disease', (173, 179))	('variants', 'Var', (121, 129))	('cancer', 'Disease', (233, 239))	('cancer', 'Disease', 'MESH:D009369', (233, 239))	('cancers', 'Disease', 'MESH:D009369', (233, 240))	('cancers', 'Phenotype', 'HP:0002664', (233, 240))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('cancers', 'Disease', (233, 240))
142459	27668986	(2) SNPs level: 1) non-autosomal chromosomes; 2) call rate < 95%; 3) MAF in controls < 0.05; 4) deviated from Hardy-Weinberg Equilibrium (HWE) in controls (P<0.05); 5) missing rate discrepancies between cases and controls (P<0.05).	('missing rate', 'MPA', (168, 180))	('deviated', 'Var', (96, 104))	('MAF', 'Gene', '4094', (69, 72))	('call rate', 'CPA', (49, 58))	('MAF', 'Gene', (69, 72))	('non-autosomal', 'Var', (19, 32))
142485	27668986	Analogous to other studies for heritability of cancer, we found either known SNPs or known regions (+-250kb or 500kb from the known SNPs) from previous GWAS partitioned a small variance (the value were obtained through subtracting the variance excluding known regions from the total variance).	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('+-250kb', 'Var', (100, 107))	('cancer', 'Disease', (47, 53))
142489	27668986	For example, prevalence of BRCA1 or BRCA2 mutation (important genetic risk factors for ovarian cancer) differs significantly among race/ethnic groups, which is much lower in Chinese or Asian population .	('lower', 'NegReg', (165, 170))	('BRCA1', 'Gene', '672', (27, 32))	('ovarian cancer', 'Phenotype', 'HP:0100615', (87, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('BRCA1', 'Gene', (27, 32))	('BRCA2', 'Gene', (36, 41))	('ovarian cancer', 'Disease', 'MESH:D010051', (87, 101))	('mutation', 'Var', (42, 50))	('BRCA2', 'Gene', '675', (36, 41))	('ovarian cancer', 'Disease', (87, 101))
142497	27668986	Also intriguingly, we found changes after removing SNPs within 500kb of known variants varied among cancers.	('cancers', 'Phenotype', 'HP:0002664', (100, 107))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('cancers', 'Disease', 'MESH:D009369', (100, 107))	('variants', 'Var', (78, 86))	('cancers', 'Disease', (100, 107))
142499	27668986	The possible reason is more SNPs from breast and prostate cancer GWASs have been discovered, for example, nearly 90 variants have been discovered for breast cancer and prostate cancer, respectively.	('prostate cancer', 'Disease', 'MESH:D011471', (168, 183))	('variants', 'Var', (116, 124))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('breast cancer', 'Disease', 'MESH:D001943', (150, 163))	('prostate cancer', 'Phenotype', 'HP:0012125', (168, 183))	('breast cancer', 'Phenotype', 'HP:0003002', (150, 163))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('prostate cancer', 'Disease', 'MESH:D011471', (49, 64))	('breast cancer', 'Disease', (150, 163))	('breast and prostate cancer', 'Disease', 'MESH:D011471', (38, 64))	('prostate cancer', 'Phenotype', 'HP:0012125', (49, 64))	('prostate cancer', 'Disease', (168, 183))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('discovered', 'Reg', (135, 145))	('prostate cancer', 'Disease', (49, 64))
142501	27668986	For instance, although only 9 variants  have so far been discovered associated with nasopharyngeal cancer, a disease mostly occurs in Southern China , they (250kb and 500kb up and downwards expanded) seem to explain larger proportion of the overall heritability (21.4% and 21.1%).	('nasopharyngeal cancer', 'Disease', (84, 105))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('nasopharyngeal cancer', 'Disease', 'MESH:D009303', (84, 105))	('250kb', 'Var', (157, 162))
142510	27668986	It is possible that mutate rate differs among chromosomes, and certain chromosomes bear larger numbers or larger effects of mutations towards tendency for different cancers .	('mutations', 'Var', (124, 133))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('cancers', 'Phenotype', 'HP:0002664', (165, 172))	('cancers', 'Disease', 'MESH:D009369', (165, 172))	('cancers', 'Disease', (165, 172))
142520	27668986	The results indicate polygenic architecture of the nine cancer types (explained heritability ranged from 10.19% to 20.26%).	('cancer', 'Disease', (56, 62))	('polygenic architecture', 'Var', (21, 43))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))
142526	28337964	In the current study, we investigated the effects of anti-CD47 treatment on the antitumor immune response in an esophageal squamous cell cancer preclinical model.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('esophageal squamous cell cancer', 'Disease', (112, 143))	('anti-CD47', 'Var', (53, 62))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumor', 'Disease', (84, 89))	('esophageal squamous cell cancer', 'Disease', 'MESH:D002294', (112, 143))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (123, 143))
142527	28337964	We found that anti-CD47 treatment enhanced proinflammatory responses and increased CD8+ T-cell infiltration in tumor tissue in the animal model.	('increased', 'PosReg', (73, 82))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('proinflammatory', 'MPA', (43, 58))	('enhanced', 'PosReg', (34, 42))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('anti-CD47', 'Var', (14, 23))	('tumor', 'Disease', (111, 116))	('CD8', 'Gene', (83, 86))	('CD8', 'Gene', '925', (83, 86))
142528	28337964	T cells in anti-CD47-treated tumors showed higher PD-1 and CTLA-4 expression, indicating T-cell activation and the rationale of combining anti-CD47 with anti-PD-1 and CLTA-4.	('CTLA-4', 'Gene', (59, 65))	('higher', 'PosReg', (43, 49))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('expression', 'MPA', (66, 76))	('anti-CD47-treated', 'Var', (11, 28))	('anti-CD47', 'Var', (138, 147))	('tumors', 'Disease', 'MESH:D009369', (29, 35))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('tumors', 'Disease', (29, 35))	('PD-1', 'Gene', (50, 54))	('activation', 'PosReg', (96, 106))
142534	28337964	The ligation of SIRPalpha on phagocytes by CD47-expressed tumor cells results in phosphorylation of SIRPalpha cytoplasmic immunoreceptor tyrosine-based inhibition (ITIM) motifs, leading to a negative regulation of the phagocytosis of tumor cells and, consequently, impairment of antigen presentation.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('tumor', 'Disease', (234, 239))	('phosphorylation', 'MPA', (81, 96))	('SIRPalpha', 'Gene', '19261', (16, 25))	('SIRPalpha', 'Gene', (100, 109))	('impairment', 'NegReg', (265, 275))	('antigen presentation', 'MPA', (279, 299))	('SIRPalpha', 'Gene', '19261', (100, 109))	('SIRPalpha', 'Gene', (16, 25))	('tyrosine', 'Chemical', 'MESH:D014443', (137, 145))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('tumor', 'Disease', 'MESH:D009369', (234, 239))	('negative regulation', 'NegReg', (191, 210))	('ligation', 'Var', (4, 12))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))
142535	28337964	However, the clinical potential of anti-CD47 in cancer treatment is still under debate.	('anti-CD47', 'Var', (35, 44))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))
142545	28337964	Based on these facts, we aimed to investigate whether anti-CD47 could synergize with current ICBs, therefore being a novel target for esophageal squamous cell cancer treatment.	('esophageal squamous cell cancer', 'Disease', (134, 165))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (145, 165))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('ICBs', 'Chemical', '-', (93, 97))	('esophageal squamous cell cancer', 'Disease', 'MESH:D002294', (134, 165))	('anti-CD47', 'Var', (54, 63))
142546	28337964	The mechanisms by which anti-C47 synergizes in cancer immunotherapy were also investigated.	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('cancer', 'Disease', (47, 53))	('anti-C47', 'Var', (24, 32))
142580	28337964	Tumors treated with anti-CD47 antibody had an increased number of CD8+ T and TH1 cells, but a decreased number of TH2 cells when compared with the control group (treated with IgG) (Fig.	('TH1', 'Gene', '57314', (77, 80))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('TH1', 'Gene', (77, 80))	('increased', 'PosReg', (46, 55))	('CD8', 'Gene', (66, 69))	('anti-CD47', 'Var', (20, 29))	('CD8', 'Gene', '925', (66, 69))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('TH2', 'Gene', '15111', (114, 117))	('TH2', 'Gene', (114, 117))
142582	28337964	This evidence suggested that anti-CD47 treatment might enhance the antitumor immunity in a DC-dependent way in esophageal squamous cell cancer.	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('esophageal squamous cell cancer', 'Disease', 'MESH:D002294', (111, 142))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('enhance', 'PosReg', (55, 62))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('esophageal squamous cell cancer', 'Disease', (111, 142))	('tumor', 'Disease', (71, 76))	('anti-CD47', 'Var', (29, 38))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (122, 142))
142584	28337964	We found that the tumors treated with anti-CD47 antibody had an increased level of proinflammatory cytokines, including IL-2, IFN-gamma, TNF-beta, and IL-12 (Fig.	('IL-12', 'MPA', (151, 156))	('TNF-beta', 'Gene', (137, 145))	('TNF-beta', 'Gene', '21926', (137, 145))	('anti-CD47 antibody', 'Var', (38, 56))	('IFN-gamma', 'Gene', '15978', (126, 135))	('tumors', 'Disease', (18, 24))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('level of proinflammatory cytokines', 'MPA', (74, 108))	('IL-2', 'Gene', '16183', (120, 124))	('increased', 'PosReg', (64, 73))	('IFN-gamma', 'Gene', (126, 135))	('IL-2', 'Gene', (120, 124))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
142586	28337964	However, anti-CD47 did not change the cytokine expression in the CD11c-DTR background mice.	('mice', 'Species', '10090', (86, 90))	('CD11c', 'Gene', (65, 70))	('CD11c', 'Gene', '16411', (65, 70))	('anti-CD47', 'Var', (9, 18))	('cytokine expression', 'MPA', (38, 57))
142587	28337964	Taken together with the data that anti-CD47 increased the number of TH1 cells, we believed that anti-CD47 could trigger a strong antitumor immune response by enhancing inflammation in cancer tissues and that this effect depended on DCs.	('cancer', 'Disease', (184, 190))	('TH1', 'Gene', '57314', (68, 71))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('enhancing', 'PosReg', (158, 167))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('TH1', 'Gene', (68, 71))	('anti-CD47', 'Var', (96, 105))	('tumor', 'Disease', (133, 138))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('inflammation', 'Disease', 'MESH:D007249', (168, 180))	('inflammation', 'Disease', (168, 180))
142589	28337964	The MFIs of PD-1 and CTLA-4 on CD8+ T cells were significantly increased in the tumors treated with anti-CD47 antibody (Fig.	('CTLA-4', 'Gene', (21, 27))	('increased', 'PosReg', (63, 72))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('CD8', 'Gene', (31, 34))	('anti-CD47', 'Gene', (100, 109))	('CD8', 'Gene', '925', (31, 34))	('tumors', 'Disease', (80, 86))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('anti-CD47', 'Var', (100, 109))	('PD-1', 'Gene', (12, 16))	('MFIs', 'MPA', (4, 8))
142592	28337964	Considering that anti-CD47 treatment stimulated antitumor immune response and promoted the expression of immune checkpoint proteins, we hypothesized that anti-CD47 treatment might synergize with the anti-PD-1 and anti-CTLA-4 therapy in esophageal squamous cell cancer.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('expression', 'MPA', (91, 101))	('stimulated', 'PosReg', (37, 47))	('esophageal squamous cell cancer', 'Disease', (236, 267))	('tumor', 'Disease', (52, 57))	('anti-CD47', 'Var', (154, 163))	('cancer', 'Phenotype', 'HP:0002664', (261, 267))	('promoted', 'PosReg', (78, 86))	('anti-CD47', 'Var', (17, 26))	('esophageal squamous cell cancer', 'Disease', 'MESH:D002294', (236, 267))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (247, 267))
142594	28337964	The tumors accepting anti-CD47 antibody treatment plus ICB therapy (anti-CTLA-4 + anti-PD-1 antibodies) had the slowest tumor growth when compared with the tumors treated with either anti-CD47 antibody or ICB antibodies alone (Fig.	('tumor', 'Disease', (4, 9))	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Disease', (156, 161))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('tumor', 'Disease', (120, 125))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('anti-CD47', 'Var', (21, 30))	('tumors', 'Disease', (156, 162))	('ICB', 'Chemical', '-', (55, 58))	('ICB', 'Chemical', '-', (205, 208))	('tumors', 'Disease', (4, 10))	('slowest', 'NegReg', (112, 119))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('tumors', 'Disease', 'MESH:D009369', (156, 162))
142595	28337964	Consistently, the mice treated with anti-CD47 antibody plus ICB antibodies had a better overall survival than the other groups (Fig.	('better', 'PosReg', (81, 87))	('anti-CD47', 'Var', (36, 45))	('mice', 'Species', '10090', (18, 22))	('ICB', 'Chemical', '-', (60, 63))	('overall survival', 'CPA', (88, 104))
142598	28337964	Patients with a high CD47 expression had lower average CD8+ cell density in tumor tissues, validating that high expression of CD47 is a negative immune regulator in esophageal squamous cell cancer patients.	('esophageal squamous cell cancer', 'Disease', 'MESH:D002294', (165, 196))	('CD47', 'Gene', (21, 25))	('patients', 'Species', '9606', (197, 205))	('expression', 'Var', (26, 36))	('high', 'Var', (16, 20))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('lower', 'NegReg', (41, 46))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (176, 196))	('Patients', 'Species', '9606', (0, 8))	('CD8', 'Gene', (55, 58))	('esophageal squamous cell cancer', 'Disease', (165, 196))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('CD8', 'Gene', '925', (55, 58))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
142605	28337964	The commercialized anti-CD47 antibody used in previous studies is a blockade of the CD47 signaling pathway by competing with SIRPalphas without stimulating the downstream pathways.	('anti-CD47', 'Var', (19, 28))	('CD47 signaling pathway', 'Pathway', (84, 106))	('SIRPalpha', 'Gene', '19261', (125, 134))	('SIRPalpha', 'Gene', (125, 134))
142606	28337964	In the present study, we investigated the potential synergistic effects of anti-CD47 and the currently used ICBs, anti-PD-1, and CTLA-4 in an esophageal squamous cell cancer preclinical model.	('esophageal squamous cell cancer', 'Disease', (142, 173))	('anti-CD47', 'Var', (75, 84))	('ICBs', 'Chemical', '-', (108, 112))	('esophageal squamous cell cancer', 'Disease', 'MESH:D002294', (142, 173))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (153, 173))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))
142607	28337964	We first evaluated the effects of anti-CD47 on immune infiltration and antitumor inflammatory response in animal models.	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Disease', (75, 80))	('anti-CD47', 'Var', (34, 43))
142608	28337964	Anti-CD47 significantly increased the number of CD8+ T cells, a major indicator of antitumor immune response, in tumor tissues in wild-type host mice.	('tumor', 'Disease', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Disease', (87, 92))	('Anti-CD47', 'Var', (0, 9))	('CD8', 'Gene', (48, 51))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('mice', 'Species', '10090', (145, 149))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('CD8', 'Gene', '925', (48, 51))	('increased', 'PosReg', (24, 33))
142611	28337964	Here we found that anti-CD47 increased the number of TH1 cells while decreasing the number of TH2 cells in tumors in wild-type host mice.	('anti-CD47', 'Var', (19, 28))	('TH1', 'Gene', '57314', (53, 56))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('TH1', 'Gene', (53, 56))	('tumors', 'Disease', (107, 113))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('increased', 'PosReg', (29, 38))	('tumors', 'Disease', 'MESH:D009369', (107, 113))	('mice', 'Species', '10090', (132, 136))	('TH2', 'Gene', '15111', (94, 97))	('decreasing', 'NegReg', (69, 79))	('TH2', 'Gene', (94, 97))
142612	28337964	The expression of proinflammatory cytokines, such as IL-2, IL-12, TNF-beta, and IFN-gamma, was also stimulated by anti-CD47 treatment.	('IL-12', 'Gene', (59, 64))	('TNF-beta', 'Gene', '21926', (66, 74))	('expression', 'MPA', (4, 14))	('IFN-gamma', 'Gene', (80, 89))	('IL-2', 'Gene', '16183', (53, 57))	('IFN-gamma', 'Gene', '15978', (80, 89))	('TNF-beta', 'Gene', (66, 74))	('anti-CD47', 'Var', (114, 123))	('stimulated', 'PosReg', (100, 110))	('IL-2', 'Gene', (53, 57))
142613	28337964	However, in the CD11c-DTR mouse model, which has a small number of DCs, the anti-CD47 treatment could only raise a weak response.	('CD11c', 'Gene', '16411', (16, 21))	('mouse', 'Species', '10090', (26, 31))	('anti-CD47', 'Var', (76, 85))	('CD11c', 'Gene', (16, 21))
142614	28337964	These observations implied that anti-CD47 could promote antitumor inflammation and immune response by enhancing the function of DCs.	('function', 'MPA', (116, 124))	('enhancing', 'PosReg', (102, 111))	('inflammation', 'Disease', (66, 78))	('anti-CD47', 'Var', (32, 41))	('tumor', 'Disease', (60, 65))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('DCs', 'Protein', (128, 131))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('immune response', 'CPA', (83, 98))	('promote', 'PosReg', (48, 55))	('inflammation', 'Disease', 'MESH:D007249', (66, 78))
142616	28337964	Thus, we measured the function of CD8+ T cells in tumors treated with anti-CD47.	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('measured', 'Reg', (9, 17))	('CD8', 'Gene', (34, 37))	('CD8', 'Gene', '925', (34, 37))	('anti-CD47', 'Gene', (70, 79))	('anti-CD47', 'Var', (70, 79))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('tumors', 'Disease', (50, 56))
142617	28337964	It is worth noting that CD8+ T cells in anti-CD47-treated tumors showed a high expression of PD-1 and CTLA-4, two important inhibitory immune checkpoint proteins.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('expression', 'MPA', (79, 89))	('anti-CD47-treated', 'Var', (40, 57))	('tumors', 'Disease', (58, 64))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('CD8', 'Gene', (24, 27))	('CD8', 'Gene', '925', (24, 27))	('PD-1', 'Gene', (93, 97))	('CTLA-4', 'Gene', (102, 108))
142619	28337964	These data indicate that CD8+ T cells in anti-CD47-treated tumors were well activated, but because of upregulation of the inhibitory immune checkpoint, their tumor killing effect was impaired, suggesting that combining anti-CD47 with anti-PD-1 and CTLA-4 may induce a strong tumor-eliminating response.	('tumor', 'Disease', (59, 64))	('tumor', 'Disease', (275, 280))	('tumors', 'Disease', 'MESH:D009369', (59, 65))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('tumor', 'Disease', 'MESH:D009369', (275, 280))	('CD8', 'Gene', (25, 28))	('anti-CD47-treated', 'Var', (41, 58))	('upregulation', 'PosReg', (102, 114))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('impaired', 'NegReg', (183, 191))	('tumor', 'Phenotype', 'HP:0002664', (275, 280))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('anti-CD47', 'Var', (219, 228))	('inhibitory immune', 'MPA', (122, 139))	('induce', 'PosReg', (259, 265))	('tumor', 'Disease', (158, 163))	('tumors', 'Disease', (59, 65))	('CD8', 'Gene', '925', (25, 28))	('tumor', 'Disease', 'MESH:D009369', (158, 163))
142627	28337964	This observation suggests that CD47 expression might negatively influence the antitumor immune response in esophageal squamous cell cancer patients and supports the findings of the animal studies.	('esophageal squamous cell cancer', 'Disease', 'MESH:D002294', (107, 138))	('patients', 'Species', '9606', (139, 147))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (118, 138))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('expression', 'Var', (36, 46))	('CD47', 'Gene', (31, 35))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('influence', 'Reg', (64, 73))	('negatively', 'NegReg', (53, 63))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('esophageal squamous cell cancer', 'Disease', (107, 138))	('tumor', 'Disease', (82, 87))
142628	28337964	In conclusion, our study indicates that high expression of CD47 is a protective factor for esophageal squamous cell cancer to escape immune killing.	('esophageal squamous cell cancer', 'Disease', (91, 122))	('high expression', 'Var', (40, 55))	('CD47', 'Gene', (59, 63))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('esophageal squamous cell cancer', 'Disease', 'MESH:D002294', (91, 122))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (102, 122))
142629	28337964	Anti-CD47 could enhance antitumor inflammation and T-cell recruitment in a DC-dependent manner.	('inflammation', 'Disease', (34, 46))	('tumor', 'Disease', (28, 33))	('Anti-CD47', 'Var', (0, 9))	('T-cell recruitment', 'CPA', (51, 69))	('enhance', 'PosReg', (16, 23))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('inflammation', 'Disease', 'MESH:D007249', (34, 46))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
142682	32054542	One possible explanation for HPV-associated SCC in the rectum is circulating HPV DNA as discussed by Ambrosio et al.. An alternative pathogenetic pathway may be a misplacement of HPV-infected neoplastic epithelial cells from the anal canal with subsequent implantation of these tumor cells into the rectal mucosa.	('SCC', 'Phenotype', 'HP:0002860', (44, 47))	('tumor', 'Phenotype', 'HP:0002664', (278, 283))	('SCC', 'Disease', (44, 47))	('HPV', 'Species', '10566', (179, 182))	('tumor', 'Disease', (278, 283))	('HPV', 'Species', '10566', (29, 32))	('SCC', 'Disease', 'MESH:D002294', (44, 47))	('HPV', 'Species', '10566', (77, 80))	('men', 'Species', '9606', (171, 174))	('tumor', 'Disease', 'MESH:D009369', (278, 283))	('HPV-infected', 'Gene', (179, 191))	('misplacement', 'Var', (163, 175))
142769	31126271	The mechanism of cryotherapy improves survival of patients with MEM could be the improvement of performance status in current study.	('improves', 'PosReg', (29, 37))	('patients', 'Species', '9606', (50, 58))	('MEM', 'Disease', (64, 67))	('cryotherapy', 'Var', (17, 28))	('survival', 'MPA', (38, 46))
142818	30803369	Recent studies have suggested that all lung cancers aberrantly express VEGF and that LUADs have the highest VEGF expression, which increases tumor aggressiveness and worsens prognosis.	('VEGF', 'Gene', (108, 112))	('increases', 'PosReg', (131, 140))	('tumor aggressiveness', 'Disease', (141, 161))	('aggressiveness', 'Phenotype', 'HP:0000718', (147, 161))	('aberrantly', 'Var', (52, 62))	('expression', 'MPA', (113, 123))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (141, 161))	('lung cancers', 'Disease', 'MESH:D008175', (39, 51))	('lung cancers', 'Disease', (39, 51))	('LUAD', 'Phenotype', 'HP:0030078', (85, 89))	('VEGF', 'Gene', '7422', (71, 75))	('lung cancer', 'Phenotype', 'HP:0100526', (39, 50))	('cancers', 'Phenotype', 'HP:0002664', (44, 51))	('lung cancers', 'Phenotype', 'HP:0100526', (39, 51))	('VEGF', 'Gene', '7422', (108, 112))	('VEGF', 'Gene', (71, 75))	('prognosis', 'CPA', (174, 183))	('worsens', 'NegReg', (166, 173))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
142820	30803369	Furthermore, a recent study has shown that gene polymorphisms of some interleukins correlate with prognosis in NSCLC and has identified that IL16 rs7170924 and IL12A rs662959 may act as prognostic factors in patients with NSCLC.	('patients', 'Species', '9606', (208, 216))	('rs7170924', 'Mutation', 'rs7170924', (146, 155))	('NSCLC', 'Disease', (111, 116))	('NSCLC', 'Phenotype', 'HP:0030358', (222, 227))	('rs662959', 'Mutation', 'rs662959', (166, 174))	('NSCLC', 'Disease', 'MESH:D002289', (111, 116))	('IL12A', 'Gene', (160, 165))	('rs7170924', 'Var', (146, 155))	('NSCLC', 'Disease', (222, 227))	('IL16', 'Gene', '3603', (141, 145))	('rs662959', 'Var', (166, 174))	('NSCLC', 'Disease', 'MESH:D002289', (222, 227))	('NSCLC', 'Phenotype', 'HP:0030358', (111, 116))	('IL12A', 'Gene', '3592', (160, 165))	('IL16', 'Gene', (141, 145))
142837	30803369	Because the transcriptional regulation information of multiple target genes is not recorded in the database, the coexpression method was used to construct transcriptional regulatory networks of deregulated TFs and deregulated anti-lung cancer genes in each stage.	('lung cancer', 'Disease', (231, 242))	('lung cancer', 'Phenotype', 'HP:0100526', (231, 242))	('deregulated', 'Var', (194, 205))	('deregulated', 'Var', (214, 225))	('TFs', 'Gene', (206, 209))	('lung cancer', 'Disease', 'MESH:D008175', (231, 242))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))
142860	30803369	And survival analysis also showed that the high expression of APC, BRIP1, and PTTG1 reduce patients' overall survival in total patients (Supplementary Figures 3-5).	('reduce', 'NegReg', (84, 90))	('PTTG1', 'Gene', (78, 83))	('overall survival', 'MPA', (101, 117))	('patients', 'Species', '9606', (91, 99))	('high', 'Var', (43, 47))	('PTTG1', 'Gene', '9232', (78, 83))	('APC', 'Disease', 'MESH:D011125', (62, 65))	('BRIP1', 'Gene', (67, 72))	('APC', 'Disease', (62, 65))	('patients', 'Species', '9606', (127, 135))	('BRIP1', 'Gene', '83990', (67, 72))
142863	30803369	Therefore, combined with previous transcriptional regulatory relationships and KEGG pathway enrichment results, we speculated that elevated APC, BRIP1, and PTTG1 leads to high FGF22 expression, thereby influencing multiple signal transduction pathways and carcinogenic pathways, ultimately exacerbating the progress of lung cancer (Figure 5E).	('influencing', 'Reg', (202, 213))	('PTTG1', 'Gene', (156, 161))	('lung cancer', 'Disease', (319, 330))	('expression', 'MPA', (182, 192))	('BRIP1', 'Gene', (145, 150))	('carcinogenic', 'Disease', 'MESH:D063646', (256, 268))	('PTTG1', 'Gene', '9232', (156, 161))	('lung cancer', 'Phenotype', 'HP:0100526', (319, 330))	('carcinogenic', 'Disease', (256, 268))	('APC', 'Disease', 'MESH:D011125', (140, 143))	('high', 'Var', (171, 175))	('APC', 'Disease', (140, 143))	('BRIP1', 'Gene', '83990', (145, 150))	('exacerbating', 'PosReg', (290, 302))	('cancer', 'Phenotype', 'HP:0002664', (324, 330))	('signal transduction pathways', 'Pathway', (223, 251))	('FGF22', 'Gene', (176, 181))	('lung cancer', 'Disease', 'MESH:D008175', (319, 330))
142871	30803369	Studies have shown that mutations in BRAF affect patient prognosis and have identified multiple risk sites.	('affect', 'Reg', (42, 48))	('BRAF', 'Gene', '673', (37, 41))	('BRAF', 'Gene', (37, 41))	('patient', 'Species', '9606', (49, 56))	('patient prognosis', 'CPA', (49, 66))	('mutations', 'Var', (24, 33))
142878	30803369	A recent study has shown that inhibition of AKT1 enhances migration and invasion in KRAS- or EGFR-mutant A549 cells, suggesting that development of myristoylated alanine-rich C-kinase substrate targeted therapy may improve the therapeutic benefit of AKT inhibitors in patients with NSCLC.	('KRAS', 'Gene', (84, 88))	('AKT1', 'Gene', '207', (44, 48))	('enhances', 'PosReg', (49, 57))	('patients', 'Species', '9606', (268, 276))	('EGFR', 'Gene', '1956', (93, 97))	('NSCLC', 'Disease', 'MESH:D002289', (282, 287))	('AKT', 'Gene', (250, 253))	('AKT', 'Gene', (44, 47))	('rat', 'Species', '10116', (189, 192))	('AKT1', 'Gene', (44, 48))	('NSCLC', 'Disease', (282, 287))	('rat', 'Species', '10116', (61, 64))	('NSCLC', 'Phenotype', 'HP:0030358', (282, 287))	('invasion', 'CPA', (72, 80))	('migration', 'CPA', (58, 67))	('inhibition', 'Var', (30, 40))	('AKT', 'Gene', '207', (250, 253))	('AKT', 'Gene', '207', (44, 47))	('EGFR', 'Gene', (93, 97))	('KRAS', 'Gene', '3845', (84, 88))	('A549', 'CellLine', 'CVCL:0023', (105, 109))
142886	30803369	A previous study found a rare frameshift mutation in the BRIP1 gene increases the ovarian cancer risk.	('ovarian cancer', 'Phenotype', 'HP:0100615', (82, 96))	('increases the ovarian cancer', 'Disease', 'MESH:D010051', (68, 96))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('BRIP1', 'Gene', (57, 62))	('frameshift mutation', 'Var', (30, 49))	('increases the ovarian cancer', 'Disease', (68, 96))	('BRIP1', 'Gene', '83990', (57, 62))
142887	30803369	Recent studies showed BRIP1 loss-of-function mutation and protein-truncating mutation all significantly increase the risk of ovarian cancer.	('ovarian cancer', 'Disease', (125, 139))	('loss-of-function', 'NegReg', (28, 44))	('ovarian cancer', 'Phenotype', 'HP:0100615', (125, 139))	('mutation', 'Var', (45, 53))	('protein-truncating', 'MPA', (58, 76))	('BRIP1', 'Gene', (22, 27))	('ovarian cancer', 'Disease', 'MESH:D010051', (125, 139))	('BRIP1', 'Gene', '83990', (22, 27))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
142893	30803369	Gene amplification or missense mutation of FGFR2 occurs in lung cancer, gastric cancer, breast cancer, and other cancers.	('lung cancer', 'Disease', 'MESH:D008175', (59, 70))	('cancers', 'Phenotype', 'HP:0002664', (113, 120))	('cancers', 'Disease', (113, 120))	('lung cancer', 'Phenotype', 'HP:0100526', (59, 70))	('FGFR2', 'Gene', (43, 48))	('occurs', 'Reg', (49, 55))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('gastric cancer', 'Disease', 'MESH:D013274', (72, 86))	('gastric cancer', 'Disease', (72, 86))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('FGFR2', 'Gene', '2263', (43, 48))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('gastric cancer', 'Phenotype', 'HP:0012126', (72, 86))	('cancers', 'Disease', 'MESH:D009369', (113, 120))	('lung cancer', 'Disease', (59, 70))	('breast cancer', 'Phenotype', 'HP:0003002', (88, 101))	('missense mutation', 'Var', (22, 39))	('breast cancer', 'Disease', (88, 101))	('breast cancer', 'Disease', 'MESH:D001943', (88, 101))
142907	32848755	Previous researches have demonstrated that long noncoding RNAs (lncRNAs) can be used as oncogenes or tumor suppressor genes in the occurrence and development of cancer and regulate cancer through various ways including epigenetic regulation and post-transcriptional regulation.	('tumor suppressor', 'Gene', (101, 117))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('tumor suppressor', 'Gene', '7248', (101, 117))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('epigenetic regulation', 'Var', (219, 240))	('ncRNA', 'Gene', (65, 70))	('long', 'Protein', (43, 47))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('regulate', 'Reg', (172, 180))	('cancer', 'Disease', (161, 167))	('cancer', 'Disease', (181, 187))	('ncRNA', 'Gene', '220202', (65, 70))
142918	32848755	Changes in lncRNAs can participate in tumor chromatin remodeling and transcriptional regulation and play an important role in tumorigenesis and development.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('ncRNA', 'Gene', (12, 17))	('development', 'CPA', (144, 155))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('role', 'Reg', (118, 122))	('ncRNA', 'Gene', '220202', (12, 17))	('participate', 'Reg', (23, 34))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('Changes', 'Var', (0, 7))	('transcriptional regulation', 'CPA', (69, 95))	('play', 'Reg', (100, 104))	('tumor', 'Disease', (126, 131))
142923	32848755	When proto-oncogenes or tumor suppressor genes are abnormally expressed or mutated, the quantity or activity of gene products changes, which may form tumors.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumors', 'Disease', (150, 156))	('tumors', 'Disease', 'MESH:D009369', (150, 156))	('tumors', 'Phenotype', 'HP:0002664', (150, 156))	('quantity', 'MPA', (88, 96))	('mutated', 'Var', (75, 82))	('changes', 'Reg', (126, 133))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('tumor suppressor', 'Gene', (24, 40))	('activity', 'MPA', (100, 108))	('tumor suppressor', 'Gene', '7248', (24, 40))
142924	32848755	This section summarizes the relationship between dysregulated lncRNA in LSCC and proliferation, invasion, migration, and apoptosis.	('ncRNA', 'Gene', (63, 68))	('dysregulated', 'Var', (49, 61))	('LSCC', 'Disease', (72, 76))	('ncRNA', 'Gene', '220202', (63, 68))
142930	32848755	OIP5-AS1 was confirmed to serve as a competing endogenous RNA (ceRNA) of miR-204-5p in LSCC cells.	('miR-204-5p', 'Chemical', '-', (73, 83))	('OIP5-AS1', 'Gene', '729082;11339;5729', (0, 8))	('miR-204-5p', 'Var', (73, 83))	('OIP5-AS1', 'Gene', (0, 8))
142931	32848755	ZEB1 is a target gene of miR-204-5p in LSCC.	('LSCC', 'Disease', (39, 43))	('miR-204-5p', 'Var', (25, 35))	('ZEB1', 'Gene', (0, 4))	('ZEB1', 'Gene', '6935', (0, 4))	('miR-204-5p', 'Chemical', '-', (25, 35))
142934	32848755	The major cause for expression under LINC00886 in Human LSCC cell lines (AMC-HN-8, Tu 177) is abnormal methylation of LINC00886 transcriptional start site (TSS).	('Human', 'Species', '9606', (50, 55))	('LINC00886', 'Gene', '730091', (37, 46))	('expression', 'MPA', (20, 30))	('cause', 'Reg', (10, 15))	('methylation', 'MPA', (103, 114))	('abnormal', 'Var', (94, 102))	('LINC00886', 'Gene', (118, 127))	('AMC-HN-8', 'Chemical', '-', (73, 81))	('LINC00886', 'Gene', (37, 46))	('LINC00886', 'Gene', '730091', (118, 127))
142938	32848755	It was also discovered that the CpG site of ZNF667-AS1 close to TSS was aberrant hypermethylated, which led to gene silencing.	('ZNF667-AS1', 'Gene', '100128252', (44, 54))	('gene', 'MPA', (111, 115))	('hypermethylated', 'Var', (81, 96))	('silencing', 'NegReg', (116, 125))	('ZNF667-AS1', 'Gene', (44, 54))	('aberrant', 'Var', (72, 80))
142947	32848755	Overexpression of SSTR5-AS1 inhibits the proliferation, migration, and invasion of Human LSCC cell lines [AMC-HN-8, Tu 177 Tu 212 (RRID: CVCL_4915) and Tu 686 (RRID: CVCL_4916)].	('migration', 'CPA', (56, 65))	('inhibits', 'NegReg', (28, 36))	('Tu 212', 'Chemical', '-', (123, 129))	('AMC-HN-8', 'Chemical', '-', (106, 114))	('invasion', 'CPA', (71, 79))	('Human', 'Species', '9606', (83, 88))	('SSTR5-AS1', 'Gene', '146336;6755;5729', (18, 27))	('Tu 177 Tu 212', 'Var', (116, 129))	('SSTR5-AS1', 'Gene', (18, 27))
142952	32848755	In vitro, knockout of MEG3 gene in HEp-2 (RRID: CVCL_1906) cells greatly upgraded cell proliferation, migration, invasion, and EMT process by upregulating Twist1 and Vimentin and reducing E-cadherin.	('Twist1', 'Gene', (155, 161))	('invasion', 'CPA', (113, 121))	('reducing', 'NegReg', (179, 187))	('cell proliferation', 'CPA', (82, 100))	('EMT process', 'CPA', (127, 138))	('HEp-2', 'CellLine', 'CVCL:1906', (35, 40))	('MEG3', 'Gene', (22, 26))	('knockout', 'Var', (10, 18))	('Vimentin', 'Protein', (166, 174))	('upregulating', 'PosReg', (142, 154))	('MEG3', 'Gene', '55384', (22, 26))	('upgraded', 'PosReg', (73, 81))	('migration', 'CPA', (102, 111))	('Twist1', 'Gene', '7291', (155, 161))	('E-cadherin', 'Protein', (188, 198))
142955	32848755	LncRNA microarray analysis of LSCC tissue showed that the transcription of AC026166.2-001 and RP11-169D4.1-001was abnormal.	('ncRNA', 'Gene', '220202', (1, 6))	('transcription', 'MPA', (58, 71))	('AC026166.2-001', 'Gene', (75, 89))	('RP11-169D4.1-001was', 'Var', (94, 113))	('abnormal', 'Reg', (114, 122))	('ncRNA', 'Gene', (1, 6))	('AC026166', 'Chemical', '-', (75, 83))
142957	32848755	The upregulation of AC026166.2-001 in AMC-HN-8 and Tu 212 cells induced cell cycle arrest in the G0/G1 phase, inhibited the proliferation and migration of LSCC cells, and upgraded apoptosis.	('cell cycle arrest', 'Phenotype', 'HP:0011018', (72, 89))	('AC026166.2-001', 'Var', (20, 34))	('arrest', 'Disease', 'MESH:D006323', (83, 89))	('AC026166', 'Chemical', '-', (20, 28))	('proliferation', 'CPA', (124, 137))	('arrest', 'Disease', (83, 89))	('upgraded', 'PosReg', (171, 179))	('Tu 212', 'Chemical', '-', (51, 57))	('AMC-HN-8', 'Chemical', '-', (38, 46))	('LSCC cells', 'CPA', (155, 165))	('upregulation', 'PosReg', (4, 16))	('inhibited', 'NegReg', (110, 119))	('apoptosis', 'CPA', (180, 189))
142958	32848755	In addition, AC026166.2-001 can inhibit the growth and induce apoptosis of LSCC xenografts in mice.	('AC026166', 'Chemical', '-', (13, 21))	('AC026166.2-001', 'Var', (13, 27))	('inhibit', 'NegReg', (32, 39))	('apoptosis', 'CPA', (62, 71))	('induce', 'PosReg', (55, 61))	('mice', 'Species', '10090', (94, 98))	('growth', 'CPA', (44, 50))
142960	32848755	It was confirmed that there was a binding site between miR-205-5p and RP11-169D4.1, and miR-205-5p could inhibit the expression of RP11-169D4.1.	('miR-205-5p', 'Var', (55, 65))	('inhibit', 'NegReg', (105, 112))	('expression', 'MPA', (117, 127))	('miR-205-5p', 'Var', (88, 98))	('binding site', 'Interaction', (34, 46))	('miR-205-5p', 'Chemical', '-', (55, 65))	('RP11-169D4.1', 'Var', (131, 143))	('miR-205-5p', 'Chemical', '-', (88, 98))
142961	32848755	High expression of RP11-169D4.1 in SNU-899 (RRID: CVCL_5105) and SNU-46 (RRID: CVCL_5063) cells increased the level of E-cadherin but decreased the level of Snail2 and Vimentin.	('decreased', 'NegReg', (134, 143))	('increased', 'PosReg', (96, 105))	('SNU-899', 'Chemical', '-', (35, 42))	('level', 'MPA', (148, 153))	('level', 'MPA', (110, 115))	('E-cadherin', 'Protein', (119, 129))	('Snail2', 'Gene', (157, 163))	('Snail2', 'Gene', '6591', (157, 163))	('Vimentin', 'MPA', (168, 176))	('RP11-169D4.1', 'Var', (19, 31))
142967	32848755	Knockout of ANRIL gene or overexpression of miR-181a can greatly inhibit the proliferation, clonogenicity, invasion, migration, and EMT process of LSCC cells and elevate apoptosis.	('clonogenicity', 'CPA', (92, 105))	('invasion', 'CPA', (107, 115))	('miR-181a', 'Chemical', '-', (44, 52))	('migration', 'CPA', (117, 126))	('LSCC', 'Disease', (147, 151))	('ANRIL', 'Gene', '100048912', (12, 17))	('ANRIL', 'Gene', (12, 17))	('overexpression', 'PosReg', (26, 40))	('Knockout', 'Var', (0, 8))	('elevate', 'PosReg', (162, 169))	('EMT process', 'CPA', (132, 143))	('miR-181a', 'Gene', (44, 52))	('inhibit', 'NegReg', (65, 72))	('apoptosis', 'CPA', (170, 179))
142968	32848755	LINC00467 is activated in HNSCC (head and neck squamous cell carcinoma) cells (HN6, SCC25, HN4, Cal27, SCC4), and silencing LINC00467 inhibited the growth, migration, and EMT process of HNSCC cells.	('LINC00467', 'Gene', '84791', (124, 133))	('HN6', 'Gene', '100463482', (79, 82))	('LINC00467', 'Gene', (124, 133))	('EMT process', 'CPA', (171, 182))	('neck squamous cell carcinoma', 'Disease', (42, 70))	('inhibited', 'NegReg', (134, 143))	('silencing', 'Var', (114, 123))	('growth', 'CPA', (148, 154))	('HN4', 'Gene', '100463285', (91, 94))	('SCC4', 'Gene', '23383', (103, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('SCC4', 'Gene', (103, 107))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (47, 70))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (42, 70))	('LINC00467', 'Gene', '84791', (0, 9))	('LINC00467', 'Gene', (0, 9))	('HN4', 'Gene', (91, 94))	('HN6', 'Gene', (79, 82))
142971	32848755	LINC00339 silencing inhibited the proliferation, invasion, and EMT progression of LSCC cells.	('proliferation', 'CPA', (34, 47))	('LSCC', 'Disease', (82, 86))	('LINC00339', 'Gene', (0, 9))	('inhibited', 'NegReg', (20, 29))	('invasion', 'CPA', (49, 57))	('LINC00339', 'Gene', '29092', (0, 9))	('EMT progression', 'CPA', (63, 78))	('silencing', 'Var', (10, 19))
142972	32848755	In addition, LINC00339 has a binding site to miR-145, and silencing LINC00339 elevates the transcription of miR-145 in LSCC cells.	('LINC00339', 'Gene', '29092', (68, 77))	('transcription', 'MPA', (91, 104))	('LINC00339', 'Gene', '29092', (13, 22))	('LINC00339', 'Gene', (68, 77))	('LINC00339', 'Gene', (13, 22))	('miR-145', 'Gene', '406937', (108, 115))	('miR-145', 'Gene', (108, 115))	('miR-145', 'Gene', (45, 52))	('miR-145', 'Gene', '406937', (45, 52))	('binding', 'Interaction', (29, 36))	('elevates', 'PosReg', (78, 86))	('silencing', 'Var', (58, 67))
142981	32848755	Silencing MALAT1 in human laryngeal carcinoma cell line HEp-2 and pharynx cancer cell line FaDu (RRID: CVCL_1218) can induce apoptosis and inhibit cell proliferation, resulting in cell cycle arrest in the G1/G2 phase and significant relief in the S phase.	('MALAT1', 'Gene', (10, 16))	('laryngeal carcinoma', 'Phenotype', 'HP:0012118', (26, 45))	('cell proliferation', 'CPA', (147, 165))	('cancer', 'Disease', (74, 80))	('apoptosis', 'CPA', (125, 134))	('Silencing', 'Var', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('MALAT1', 'Gene', '378938', (10, 16))	('carcinoma', 'Disease', 'MESH:D009369', (36, 45))	('pharynx cancer', 'Phenotype', 'HP:0100638', (66, 80))	('arrest', 'Disease', 'MESH:D006323', (191, 197))	('relief', 'NegReg', (233, 239))	('S phase', 'CPA', (247, 254))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('induce', 'PosReg', (118, 124))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (180, 197))	('human', 'Species', '9606', (20, 25))	('HEp-2', 'CellLine', 'CVCL:1906', (56, 61))	('inhibit', 'NegReg', (139, 146))	('carcinoma', 'Phenotype', 'HP:0030731', (36, 45))	('arrest', 'Disease', (191, 197))	('carcinoma', 'Disease', (36, 45))
142984	32848755	Inhibition of MALAT1 expression in Tu 686 and LSC-1 cells could increase the expression of E-cadherin and alleviate the expression of N-cadherin/Vimentin.	('expression', 'MPA', (77, 87))	('MALAT1', 'Gene', '378938', (14, 20))	('expression', 'MPA', (120, 130))	('alleviate', 'NegReg', (106, 115))	('E-cadherin', 'Protein', (91, 101))	('N-cadherin/Vimentin', 'Protein', (134, 153))	('increase', 'PosReg', (64, 72))	('MALAT1', 'Gene', (14, 20))	('Inhibition', 'Var', (0, 10))
142990	32848755	Silencing MIR31HG promotes cell cycle arrest in G1 or S phase.	('MIR31HG', 'Gene', '554202', (10, 17))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (27, 44))	('arrest', 'Disease', (38, 44))	('promotes', 'PosReg', (18, 26))	('Silencing', 'Var', (0, 9))	('arrest', 'Disease', 'MESH:D006323', (38, 44))	('MIR31HG', 'Gene', (10, 17))
142994	32848755	In addition, silencing NEAT1 gene inhibited the proliferation of HEp-2 cells and induced apoptosis and cell cycle arrest in G1 phase.	('HEp-2', 'CellLine', 'CVCL:1906', (65, 70))	('NEAT1', 'Gene', (23, 28))	('proliferation', 'CPA', (48, 61))	('induced', 'Reg', (81, 88))	('apoptosis', 'CPA', (89, 98))	('inhibited', 'NegReg', (34, 43))	('arrest', 'Disease', 'MESH:D006323', (114, 120))	('arrest', 'Disease', (114, 120))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (103, 120))	('NEAT1', 'Gene', '283131', (23, 28))	('silencing', 'Var', (13, 22))
142995	32848755	It was further revealed that silencing NEAT1 gene could inhibit the growth of LSCC transplanted tumor.	('NEAT1', 'Gene', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('silencing', 'Var', (29, 38))	('tumor', 'Disease', (96, 101))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('NEAT1', 'Gene', '283131', (39, 44))	('inhibit', 'NegReg', (56, 63))
143001	32848755	Silencing PVT1 significantly inhibited the proliferation of LSCC cells, promoted apoptosis, and reduced migration.	('inhibited', 'NegReg', (29, 38))	('migration', 'CPA', (104, 113))	('LSCC cells', 'CPA', (60, 70))	('PVT1', 'Gene', (10, 14))	('apoptosis', 'CPA', (81, 90))	('proliferation', 'CPA', (43, 56))	('PVT1', 'Gene', '5820', (10, 14))	('Silencing', 'Var', (0, 9))	('promoted', 'PosReg', (72, 80))	('reduced', 'NegReg', (96, 103))
143006	32848755	Mechanism studies have shown that SOX2-OT interacts with EZH2 (enhancer of zeste homolog 2), recruits EZH2 to induce H3K27me3, and epigenetically inhibits PTEN expression in LSCC cells, thus promoting the development of LSCC.	('EZH2', 'Gene', (57, 61))	('expression', 'MPA', (160, 170))	('EZH2', 'Gene', (102, 106))	('SOX2-OT', 'Gene', (34, 41))	('PTEN', 'Gene', (155, 159))	('EZH2', 'Gene', '2146', (102, 106))	('enhancer of zeste homolog 2', 'Gene', '2146', (63, 90))	('SOX2-OT', 'Gene', '347689', (34, 41))	('PTEN', 'Gene', '5728', (155, 159))	('enhancer of zeste homolog 2', 'Gene', (63, 90))	('LSCC', 'Disease', (220, 224))	('H3K27me3', 'Protein', (117, 125))	('epigenetically', 'Var', (131, 145))	('induce', 'PosReg', (110, 116))	('promoting', 'PosReg', (191, 200))	('EZH2', 'Gene', '2146', (57, 61))
143008	32848755	With few exceptions, the SNHGs are recognized as inducing increased proliferation, cell cycle progression, invasion, and metastasis of cancer cells, which makes this class of transcripts a viable biomarker for cancer development and aggressiveness.	('metastasis', 'CPA', (121, 131))	('proliferation', 'CPA', (68, 81))	('cell cycle progression', 'CPA', (83, 105))	('increased', 'PosReg', (58, 67))	('cancer', 'Disease', (135, 141))	('inducing', 'Reg', (49, 57))	('aggressiveness', 'Disease', 'MESH:D001523', (233, 247))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('aggressiveness', 'Disease', (233, 247))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('aggressiveness', 'Phenotype', 'HP:0000718', (233, 247))	('cancer', 'Disease', 'MESH:D009369', (210, 216))	('SNHGs', 'Var', (25, 30))	('invasion', 'CPA', (107, 115))	('cancer', 'Disease', (210, 216))	('cancer', 'Disease', 'MESH:D009369', (135, 141))
143010	32848755	SNHG1 gene knockout can inhibit the proliferation, migration, and invasion of AMC-HN-8 and HEp-2 and induce apoptosis.	('SNHG1', 'Gene', (0, 5))	('AMC-HN-8', 'Chemical', '-', (78, 86))	('migration', 'CPA', (51, 60))	('HEp-2', 'CPA', (91, 96))	('AMC-HN-8', 'Protein', (78, 86))	('knockout', 'Var', (11, 19))	('induce', 'Reg', (101, 107))	('HEp-2', 'CellLine', 'CVCL:1906', (91, 96))	('proliferation', 'CPA', (36, 49))	('invasion', 'CPA', (66, 74))	('inhibit', 'NegReg', (24, 31))	('apoptosis', 'CPA', (108, 117))
143012	32848755	Mechanism studies have shown that SNHG1 is the ceRNA of miR-375 and can improve the activity of YAP1.	('miR-375', 'Gene', (56, 63))	('YAP1', 'Gene', (96, 100))	('YAP1', 'Gene', '10413', (96, 100))	('improve', 'PosReg', (72, 79))	('activity', 'MPA', (84, 92))	('miR-375', 'Gene', '494324', (56, 63))	('SNHG1', 'Var', (34, 39))
143015	32848755	Silencing SNHG1 gene inhibits the proliferation of HEp-2 cells and promotes apoptosis.	('proliferation', 'CPA', (34, 47))	('inhibits', 'NegReg', (21, 29))	('promotes', 'PosReg', (67, 75))	('SNHG1', 'Gene', (10, 15))	('HEp-2', 'CellLine', 'CVCL:1906', (51, 56))	('apoptosis', 'CPA', (76, 85))	('Silencing', 'Var', (0, 9))
143016	32848755	Additional evidence showed that SNHG1 gene knockout inhibits the invasion and migration of HEp-2 cells by inhibiting the EMT process and the expression of matrix metalloproteinase-2 (MMP-2) and MMP-9.	('matrix metalloproteinase-2', 'Gene', '4313', (155, 181))	('MMP-2', 'Gene', '4313', (183, 188))	('inhibiting', 'NegReg', (106, 116))	('knockout', 'Var', (43, 51))	('EMT process', 'CPA', (121, 132))	('MMP-9', 'Gene', (194, 199))	('inhibits', 'NegReg', (52, 60))	('MMP-9', 'Gene', '4318', (194, 199))	('MMP-2', 'Gene', (183, 188))	('SNHG1', 'Gene', (32, 37))	('expression', 'MPA', (141, 151))	('HEp-2', 'CellLine', 'CVCL:1906', (91, 96))	('matrix metalloproteinase-2', 'Gene', (155, 181))
143019	32848755	Inhibition of miR-129-5p considerably increased proliferation and invasion of AMC-HN-8 cells and ameliorated the suppressive effects of si-SNHG12.	('ameliorated', 'PosReg', (97, 108))	('AMC-HN-8', 'Chemical', '-', (78, 86))	('miR-129-5p', 'Gene', (14, 24))	('proliferation', 'CPA', (48, 61))	('SNHG12', 'Gene', (139, 145))	('SNHG12', 'Gene', '85028', (139, 145))	('Inhibition', 'Var', (0, 10))	('invasion', 'CPA', (66, 74))	('increased', 'PosReg', (38, 47))	('miR-129-5p', 'Gene', '100302178', (14, 24))
143023	32848755	Moreover, when SNHG12 was suppressed, rescue of WWP1 restored the proliferation and invasion abilities of AMC-HN-8 cells.	('SNHG12', 'Gene', '85028', (15, 21))	('proliferation', 'CPA', (66, 79))	('AMC-HN-8', 'Chemical', '-', (106, 114))	('WWP1', 'Gene', '11059', (48, 52))	('SNHG12', 'Gene', (15, 21))	('invasion abilities', 'CPA', (84, 102))	('WWP1', 'Gene', (48, 52))	('rescue', 'Var', (38, 44))	('restored', 'PosReg', (53, 61))
143025	32848755	The proliferation ability of AMC-HN-8 and HEp-2 cells with SNHG20 gene knockout was dramatically lessened.	('AMC-HN-8', 'Chemical', '-', (29, 37))	('lessened', 'NegReg', (97, 105))	('HEp-2', 'CellLine', 'CVCL:1906', (42, 47))	('proliferation ability', 'CPA', (4, 25))	('gene knockout', 'Var', (66, 79))	('SNHG20', 'Gene', (59, 65))	('SNHG20', 'Gene', '654434', (59, 65))
143029	32848755	In addition, ectopic expression of Gas5 significantly inhibited cell proliferation and facilitated cell apoptosis.	('inhibited', 'NegReg', (54, 63))	('facilitated', 'PosReg', (87, 98))	('Gas5', 'Gene', (35, 39))	('cell proliferation', 'CPA', (64, 82))	('cell apoptosis', 'CPA', (99, 113))	('Gas5', 'Gene', '60674', (35, 39))	('ectopic expression', 'Var', (13, 31))
143035	32848755	The expression level of HOTAIR in LSCC was considerably higher than that in the corresponding paracancerous nontumor tissues.	('expression level', 'MPA', (4, 20))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('paracancerous nontumor', 'Disease', 'None', (94, 116))	('HOTAIR', 'Var', (24, 30))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('paracancerous nontumor', 'Disease', (94, 116))	('higher', 'PosReg', (56, 62))
143036	32848755	siRNA-mediated HOTAIR gene knockout can reduce the invasiveness of HEp-2 cells in vitro, increase apoptosis, and significantly inhibit the growth of LSCC xenografts in mice.	('apoptosis', 'CPA', (98, 107))	('reduce', 'NegReg', (40, 46))	('mice', 'Species', '10090', (168, 172))	('growth of', 'CPA', (139, 148))	('LSCC', 'Disease', (149, 153))	('knockout', 'Var', (27, 35))	('inhibit', 'NegReg', (127, 134))	('invasiveness of HEp-2 cells', 'CPA', (51, 78))	('HEp-2', 'CellLine', 'CVCL:1906', (67, 72))	('increase', 'PosReg', (89, 97))
143037	32848755	Indeed, several recent experiments have beautifully shown that PTEN methylation was dramatically increased in HEp-2 cells overexpressing HOTAIR, while PTEN methylation was markedly lessened in HEp-2 cells depleted HOTAIR.	('PTEN', 'Gene', '5728', (63, 67))	('increased', 'PosReg', (97, 106))	('HOTAIR', 'Var', (137, 143))	('HEp-2', 'CellLine', 'CVCL:1906', (110, 115))	('HEp-2', 'CellLine', 'CVCL:1906', (193, 198))	('methylation', 'MPA', (68, 79))	('PTEN', 'Gene', (151, 155))	('PTEN', 'Gene', (63, 67))	('PTEN', 'Gene', '5728', (151, 155))
143038	32848755	It is suggested that the carcinogenic effect of HOTAIR in LSCC is related to the promotion of PTEN methylation.	('PTEN', 'Gene', (94, 98))	('PTEN', 'Gene', '5728', (94, 98))	('HOTAIR', 'Var', (48, 54))	('carcinogenic', 'Disease', 'MESH:D063646', (25, 37))	('carcinogenic', 'Disease', (25, 37))	('LSCC', 'Disease', (58, 62))	('promotion', 'PosReg', (81, 90))	('methylation', 'MPA', (99, 110))
143045	32848755	lncRNA XIST gene knockout can inhibit the proliferation, migration, and invasion of LSCC cell line HEp-2 and HEK293T (RRID: CVCL_0063).	('HEp-2', 'CellLine', 'CVCL:1906', (99, 104))	('proliferation', 'CPA', (42, 55))	('HEK293T', 'CellLine', 'CVCL:0063', (109, 116))	('inhibit', 'NegReg', (30, 37))	('ncRNA', 'Gene', '220202', (1, 6))	('knockout', 'Var', (17, 25))	('migration', 'CPA', (57, 66))	('invasion', 'CPA', (72, 80))	('ncRNA', 'Gene', (1, 6))	('LSCC cell line HEp-2', 'CPA', (84, 104))
143049	32848755	After knockout of XIST gene, the proliferation, colony formation, migration, and invasion of Tu 212 cells were dramatically inhibited, while apoptosis was significantly increased.	('colony formation', 'CPA', (48, 64))	('apoptosis', 'CPA', (141, 150))	('migration', 'CPA', (66, 75))	('invasion', 'CPA', (81, 89))	('increased', 'PosReg', (169, 178))	('knockout', 'Var', (6, 14))	('Tu 212', 'Chemical', '-', (93, 99))	('XIST gene', 'Gene', (18, 27))	('inhibited', 'NegReg', (124, 133))
143052	32848755	XIST gene knockout can also inhibit the growth of LSCC xenografts in mice.	('mice', 'Species', '10090', (69, 73))	('XIST gene', 'Gene', (0, 9))	('knockout', 'Var', (10, 18))	('growth of', 'CPA', (40, 49))	('LSCC', 'Disease', (50, 54))	('inhibit', 'NegReg', (28, 35))
143054	32848755	Silencing DLX6-AS1 significantly inhibited the growth of HEp-2 cells and enhanced the transcription of miR-376c in HEp-2 cells at an unprecedented rate.	('Silencing', 'Var', (0, 9))	('DLX6-AS1', 'Gene', (10, 18))	('HEp-2', 'CellLine', 'CVCL:1906', (115, 120))	('transcription', 'MPA', (86, 99))	('enhanced', 'PosReg', (73, 81))	('HEp-2', 'CellLine', 'CVCL:1906', (57, 62))	('miR-376c', 'Gene', '442913', (103, 111))	('DLX6-AS1', 'Gene', '285987;1750;5729', (10, 18))	('miR-376c', 'Gene', (103, 111))	('growth', 'CPA', (47, 53))	('inhibited', 'NegReg', (33, 42))
143057	32848755	The role of LncRNA Loc285194 in several cancers is a tumor suppressor, and it confirmed the significant downregulation of loc285194 in patients with LSCC.	('loc285194', 'Var', (122, 131))	('patients', 'Species', '9606', (135, 143))	('cancers', 'Phenotype', 'HP:0002664', (40, 47))	('tumor suppressor', 'Gene', (53, 69))	('cancers', 'Disease', 'MESH:D009369', (40, 47))	('cancers', 'Disease', (40, 47))	('LSCC', 'Disease', (149, 153))	('ncRNA', 'Gene', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor suppressor', 'Gene', '7248', (53, 69))	('Loc285194', 'Var', (19, 28))	('downregulation', 'NegReg', (104, 118))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('ncRNA', 'Gene', '220202', (13, 18))
143058	32848755	There was a negative correlation between the transcription of Loc285194 and hexokinase 2 (HK-2) mRNA in LSCC patients but no correlation in healthy controls.	('patients', 'Species', '9606', (109, 117))	('transcription', 'MPA', (45, 58))	('HK-2', 'Gene', '3099', (90, 94))	('hexokinase 2', 'Gene', '3099', (76, 88))	('Loc285194', 'Var', (62, 71))	('HK-2', 'Gene', (90, 94))	('LSCC', 'Disease', (104, 108))	('negative', 'NegReg', (12, 20))	('mRNA', 'MPA', (96, 100))	('hexokinase 2', 'Gene', (76, 88))
143059	32848755	In addition, it is confirmed that HK-2 mRNA is the downstream target of loc285194 in Human LSCC cell line UM-SCC-17A.	('loc285194', 'Var', (72, 81))	('HK-2', 'Gene', (34, 38))	('Human', 'Species', '9606', (85, 90))	('HK-2', 'Gene', '3099', (34, 38))
143060	32848755	In vivo experiments, the transcription of loc285194 was negatively correlated with tumor size but not with metastasis.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('negatively', 'NegReg', (56, 66))	('tumor', 'Disease', (83, 88))	('transcription', 'MPA', (25, 38))	('loc285194', 'Var', (42, 51))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
143061	32848755	Therefore, overexpression of loc285194 can inhibit HK-2 mRNA and the proliferation of LSCC cells.	('proliferation', 'CPA', (69, 82))	('mRNA', 'MPA', (56, 60))	('HK-2', 'Gene', (51, 55))	('inhibit', 'NegReg', (43, 50))	('loc285194', 'Var', (29, 38))	('HK-2', 'Gene', '3099', (51, 55))
143068	32848755	It was confirmed that the transcriptional level of lncRNA LOC554202 in LSCC tissues increased, while that of miR-31 alleviated.	('ncRNA', 'Gene', '220202', (52, 57))	('transcriptional level', 'MPA', (26, 47))	('LOC554202', 'Var', (58, 67))	('miR-31', 'Gene', '407035', (109, 115))	('increased', 'PosReg', (84, 93))	('ncRNA', 'Gene', (52, 57))	('miR-31', 'Gene', (109, 115))
143069	32848755	Mechanism studies have shown that the high expression of LOC554202 plays the role of oncogenes by inhibiting miR-31, to facilitate the target gene RhoA of miR-31.	('inhibiting', 'NegReg', (98, 108))	('miR-31', 'Gene', '407035', (109, 115))	('miR-31', 'Gene', (155, 161))	('miR-31', 'Gene', '407035', (155, 161))	('RhoA', 'Gene', (147, 151))	('LOC554202', 'Var', (57, 66))	('miR-31', 'Gene', (109, 115))	('RhoA', 'Gene', '387', (147, 151))	('facilitate', 'PosReg', (120, 130))
143075	32848755	It was also found that silencing TUG1 significantly increased the expression of p53 mRNA and protein.	('increased', 'PosReg', (52, 61))	('p53', 'Gene', (80, 83))	('TUG1', 'Gene', '55000', (33, 37))	('expression', 'MPA', (66, 76))	('silencing', 'Var', (23, 32))	('p53', 'Gene', '7157', (80, 83))	('TUG1', 'Gene', (33, 37))
143079	32848755	MiR-6840-3p negatively controls PLXNB1.	('PLXNB1', 'Gene', '5364', (32, 38))	('PLXNB1', 'Gene', (32, 38))	('MiR-6840-3p', 'Var', (0, 11))	('negatively', 'NegReg', (12, 22))	('MiR-6840', 'Chemical', '-', (0, 8))	('controls', 'Reg', (23, 31))
143080	32848755	Therefore, overexpression of ZEB2-AS1 modulated the enhancement of PLXNB1 by blocking the expression of miR-6840-3p, which in turn promotes the progression of LSCC.	('PLXNB1', 'Gene', '5364', (67, 73))	('enhancement', 'PosReg', (52, 63))	('PLXNB1', 'Gene', (67, 73))	('ZEB2', 'Gene', (29, 33))	('AS1', 'Gene', (34, 37))	('expression', 'MPA', (90, 100))	('blocking', 'NegReg', (77, 85))	('AS1', 'Gene', '5729', (34, 37))	('miR-6840-3p', 'Var', (104, 115))	('LSCC', 'Disease', (159, 163))	('promotes', 'PosReg', (131, 139))	('ZEB2', 'Gene', '9839', (29, 33))
143083	32848755	Silencing RGMB-AS1 inhibits the proliferation and invasion of HEp-2 and AMC-HN-8 cells in vitro and inhibits the growth of LSCC xenografts in mice.	('invasion', 'CPA', (50, 58))	('inhibits', 'NegReg', (100, 108))	('HEp-2', 'CellLine', 'CVCL:1906', (62, 67))	('mice', 'Species', '10090', (142, 146))	('RGMB-AS1', 'Gene', (10, 18))	('AMC-HN-8', 'Chemical', '-', (72, 80))	('inhibits', 'NegReg', (19, 27))	('growth of LSCC xenografts in mice', 'CPA', (113, 146))	('Silencing', 'Var', (0, 9))	('RGMB-AS1', 'Gene', '503569', (10, 18))
143109	32848755	In addition, silence of DGCR5 could inhibit the stemness and enhance the radiosensitivity of HEp-2R cells.	('enhance', 'PosReg', (61, 68))	('DGCR5', 'Gene', '26220', (24, 29))	('inhibit', 'NegReg', (36, 43))	('radiosensitivity of HEp-2R cells', 'CPA', (73, 105))	('stemness', 'CPA', (48, 56))	('DGCR5', 'Gene', (24, 29))	('HEp-2R', 'CellLine', 'CVCL:1906', (93, 99))	('silence', 'Var', (13, 20))
143112	32848755	DGCR5 inhibition could repress Wnt signaling activity by sponging miR-506.	('DGCR5', 'Gene', '26220', (0, 5))	('DGCR5', 'Gene', (0, 5))	('Wnt signaling', 'Pathway', (31, 44))	('inhibition', 'Var', (6, 16))	('miR-506', 'Gene', '574511', (66, 73))	('miR-506', 'Gene', (66, 73))	('repress', 'NegReg', (23, 30))
143116	32848755	In this signaling pathway, PI3K activates phosphorylation and leads to the activation of Akt.	('PI3K', 'Var', (27, 31))	('phosphorylation', 'MPA', (42, 57))	('Akt', 'Gene', '207', (89, 92))	('activation', 'PosReg', (75, 85))	('activates', 'PosReg', (32, 41))	('Akt', 'Gene', (89, 92))
143126	32848755	It was confirmed that there was a binding site between miR-205-5p and RP11-169D4.1, and RP11-169D4.1 could regulate the expression of E-cadherin.	('RP11-169D4.1', 'Var', (88, 100))	('expression', 'MPA', (120, 130))	('binding', 'Interaction', (34, 41))	('miR-205-5p', 'Chemical', '-', (55, 65))	('E-cadherin', 'Protein', (134, 144))	('regulate', 'Reg', (107, 115))
143128	32848755	After knockout of XIST gene, the proliferation, colony formation, migration, and invasion of human LSCC Tu 212 cells were substantially inhibited, while apoptosis was considerably increased.	('colony formation', 'CPA', (48, 64))	('invasion of human LSCC Tu 212 cells', 'CPA', (81, 116))	('migration', 'CPA', (66, 75))	('inhibited', 'NegReg', (136, 145))	('increased', 'PosReg', (180, 189))	('human', 'Species', '9606', (93, 98))	('LSCC Tu 212', 'CellLine', 'CVCL:4915', (99, 110))	('knockout', 'Var', (6, 14))	('XIST gene', 'Gene', (18, 27))	('apoptosis', 'CPA', (153, 162))
143132	32848755	XIST gene knockout drastically inhibited the activation of PI3K/AKT pathway in Tu 212 cells.	('PI3K/AKT pathway', 'Pathway', (59, 75))	('Tu 212', 'Chemical', '-', (79, 85))	('XIST gene', 'Gene', (0, 9))	('knockout', 'Var', (10, 18))	('inhibited', 'NegReg', (31, 40))
143134	32848755	Further experiments identified that PTEN methylation was dramatically increased in HEp-2 cells overexpressing HOTAIR, while PTEN methylation was substantially declined in HEp-2 cells depleted HOTAIR.	('PTEN', 'Gene', (124, 128))	('HEp-2', 'CellLine', 'CVCL:1906', (83, 88))	('increased', 'PosReg', (70, 79))	('methylation', 'MPA', (41, 52))	('PTEN', 'Gene', '5728', (124, 128))	('PTEN', 'Gene', (36, 40))	('PTEN', 'Gene', '5728', (36, 40))	('HEp-2', 'CellLine', 'CVCL:1906', (171, 176))	('HOTAIR', 'Var', (110, 116))
143150	32848755	In addition, disorders in the Hippo pathway can lead to the development of cancer.	('Hippo', 'Gene', (30, 35))	('disorders', 'Var', (13, 22))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('cancer', 'Disease', (75, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('Hippo', 'Gene', '37247', (30, 35))	('lead to', 'Reg', (48, 55))
143167	32848755	Moreover, there seemed great potential for overexpressed MALAT1 to enhance the chemo-resistance of both the Tu 686 and LSC-1 cell lines.	('chemo-resistance', 'CPA', (79, 95))	('MALAT1', 'Gene', '378938', (57, 63))	('enhance', 'PosReg', (67, 74))	('overexpressed', 'Var', (43, 56))	('MALAT1', 'Gene', (57, 63))
143168	32848755	Not only that, silencing of MALAT1 tended to undermine the proliferative and metastatic power of Tu 686 and LSC-1 cell lines.	('silencing', 'Var', (15, 24))	('MALAT1', 'Gene', '378938', (28, 34))	('undermine', 'NegReg', (45, 54))	('MALAT1', 'Gene', (28, 34))
143174	32848755	reported that inhibiting HOTAIR could stimulate EZH2, upgrade the proliferation of AMC-HN8 cells, and increase the sensitivity of LSCC cells to cis-platinum.	('cis-platinum', 'Chemical', 'MESH:D002945', (144, 156))	('proliferation', 'CPA', (66, 79))	('inhibiting', 'Var', (14, 24))	('EZH2', 'Gene', '2146', (48, 52))	('AMC-HN8', 'CellLine', 'CVCL:5966', (83, 90))	('stimulate', 'PosReg', (38, 47))	('EZH2', 'Gene', (48, 52))	('increase', 'PosReg', (102, 110))	('sensitivity', 'MPA', (115, 126))	('HOTAIR', 'Gene', (25, 31))	('upgrade', 'PosReg', (54, 61))
143183	32848755	Silencing DGCR5 can inhibit the proliferation of HEp-2R cells and make them sensitive to radiation.	('HEp-2R cells', 'CPA', (49, 61))	('DGCR5', 'Gene', '26220', (10, 15))	('HEp-2R', 'CellLine', 'CVCL:1906', (49, 55))	('proliferation', 'CPA', (32, 45))	('inhibit', 'NegReg', (20, 27))	('Silencing', 'Var', (0, 9))	('make', 'Reg', (66, 70))	('DGCR5', 'Gene', (10, 15))
143190	32848755	It is the abnormal expression of these genes that often leads to the deterioration of tumor.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('expression', 'MPA', (19, 29))	('abnormal', 'Var', (10, 18))	('tumor', 'Disease', (86, 91))	('leads to', 'Reg', (56, 64))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
143199	32848755	At present, it is reliable to use abnormally expressed ncRNA in cancer as a marker of diagnosis and prognosis, which not only indicates the importance of ncRNA function research, but also indicates that the current research is still in its infancy.	('ncRNA', 'Gene', '220202', (55, 60))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('ncRNA', 'Gene', (154, 159))	('ncRNA', 'Gene', '220202', (154, 159))	('ncRNA', 'Gene', (55, 60))	('abnormally', 'Var', (34, 44))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
143215	28109369	Anti-PD-1/PD-L1 antibodies have been shown to counteract this tumor-induced tolerance.	('antibodies', 'Var', (16, 26))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', (62, 67))	('PD-L1', 'Gene', (10, 15))	('PD-1', 'Gene', (5, 9))	('PD-1', 'Gene', '5133', (5, 9))	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('PD-L1', 'Gene', '29126', (10, 15))
143236	28109369	Efficacy may be particularly good in tobacco-related malignancies that likely harbor a large mutational load, especially those located higher up in the aerodigestive tract.	('tobacco', 'Species', '4097', (37, 44))	('malignancies', 'Disease', 'MESH:D009369', (53, 65))	('mutational load', 'Var', (93, 108))	('malignancies', 'Disease', (53, 65))
143254	30862113	This PLK1 inhibition phenotype is conserved from the yeast cdc5-null strains to Drosophila polo-null mutants up to higher mammalian organisms such as mice where plk1-null embryos die at the morula stage due to a massive mitotic arrest.	('yeast', 'Species', '4932', (53, 58))	('mice', 'Species', '10090', (150, 154))	('inhibition', 'NegReg', (10, 20))	('polo', 'Gene', '40232', (91, 95))	('PLK1', 'Gene', (5, 9))	('polo', 'Gene', (91, 95))	('plk1', 'Gene', '18817', (161, 165))	('mitotic arrest', 'Disease', (220, 234))	('mitotic arrest', 'Disease', 'MESH:D006323', (220, 234))	('cdc5', 'Gene', '855013', (59, 63))	('mutants', 'Var', (101, 108))	('cdc5', 'Gene', (59, 63))	('mammalian', 'Species', '9606', (122, 131))	('plk1', 'Gene', (161, 165))	('Drosophila', 'Species', '7227', (80, 90))
143256	30862113	Ferris laboratory, where ectopic Plk1 overexpression experiments in murine fibroblast, were reflected in a higher proliferation index and caused oncogenic focus formation and xenograft tumoral growth.	('xenograft tumoral growth', 'Disease', 'MESH:D006130', (175, 199))	('oncogenic focus formation', 'CPA', (145, 170))	('caused', 'Reg', (138, 144))	('xenograft tumoral growth', 'Disease', (175, 199))	('murine', 'Species', '10090', (68, 74))	('overexpression', 'PosReg', (38, 52))	('ectopic', 'Var', (25, 32))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('higher', 'PosReg', (107, 113))
143271	30862113	In addition, many tumors that do not exhibit mutations on TP53 have inactivated the p53 function by other means, resulting in almost all tumoral malignancies having an impaired p53 function.	('mutations', 'Var', (45, 54))	('TP53', 'Gene', '7157', (58, 62))	('TP53', 'Gene', (58, 62))	('p53', 'Gene', (177, 180))	('p53', 'Gene', '7157', (177, 180))	('tumoral malignancies', 'Disease', (137, 157))	('tumors', 'Disease', (18, 24))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('p53', 'Gene', (84, 87))	('p53', 'Gene', '7157', (84, 87))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('tumoral malignancies', 'Phenotype', 'HP:0002664', (137, 157))	('tumoral malignancies', 'Disease', 'MESH:D018198', (137, 157))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('inactivated', 'NegReg', (68, 79))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
143279	30862113	MDM2 is phosphorylated in Ser260 residue by Plk1, and this increases the p53 destabilization.	('Ser260 residue', 'Var', (26, 40))	('p53', 'Gene', (73, 76))	('p53', 'Gene', '7157', (73, 76))	('Plk1', 'Gene', (44, 48))	('MDM2', 'Gene', '4193', (0, 4))	('MDM2', 'Gene', (0, 4))	('Ser260', 'Chemical', '-', (26, 32))	('increases', 'PosReg', (59, 68))
143301	30862113	Plk1 phosphorylates REST at Ser1030 generating an SCFbetaTRCP phosphodegron, thus priming REST to protein degradation by the proteasome.	('REST', 'MPA', (90, 94))	('Ser1030', 'Var', (28, 35))	('Ser1030', 'Chemical', '-', (28, 35))	('Plk1', 'Gene', (0, 4))	('protein degradation', 'MPA', (98, 117))	('priming', 'PosReg', (82, 89))
143308	30862113	Plk1 increased activity leads to SUZ12 phosphorylation at residues Ser539, Ser541, and Ser546; and ZNF198 phosphorylation in Ser303, Ser305, and Ser309.	('phosphorylation', 'MPA', (106, 121))	('Ser539', 'Var', (67, 73))	('ZNF198', 'Gene', '7750', (99, 105))	('increased', 'PosReg', (5, 14))	('Ser303', 'Var', (125, 131))	('ZNF198', 'Gene', (99, 105))	('Ser541', 'Var', (75, 81))	('Ser541', 'Chemical', '-', (75, 81))	('activity', 'MPA', (15, 23))	('Ser309', 'Chemical', '-', (145, 151))	('Ser546', 'Chemical', '-', (87, 93))	('SUZ12', 'Gene', (33, 38))	('Plk1', 'Gene', (0, 4))	('Ser546', 'Var', (87, 93))	('Ser539', 'Chemical', '-', (67, 73))	('Ser309', 'Var', (145, 151))	('Ser305', 'Chemical', '-', (133, 139))	('SUZ12', 'Gene', '23512', (33, 38))	('Ser305', 'Var', (133, 139))	('Ser303', 'Chemical', '-', (125, 131))
143314	30862113	This nuclear localization is reduced in cancer cells, and the presence of PTEN at the cytoplasm, where it is less active, may help as an indicator of poor prognosis.	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('nuclear localization', 'MPA', (5, 25))	('cancer', 'Disease', (40, 46))	('PTEN', 'Gene', (74, 78))	('reduced', 'NegReg', (29, 36))	('PTEN', 'Gene', '5728', (74, 78))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('presence', 'Var', (62, 70))
143315	30862113	Plk1 is able to phosphorylate PTEN at Ser385 resulting in the inhibition of PTEN mono-ubiquitination, avoiding PTEN degradation, and helping to facilitate its accumulation at the cytoplasm, where it is less active.	('facilitate', 'PosReg', (144, 154))	('PTEN', 'Gene', (111, 115))	('PTEN', 'Gene', (76, 80))	('PTEN', 'Gene', '5728', (111, 115))	('PTEN', 'Gene', '5728', (76, 80))	('Plk1', 'Gene', (0, 4))	('accumulation', 'MPA', (159, 171))	('avoiding', 'NegReg', (102, 110))	('mono-ubiquitination', 'MPA', (81, 100))	('degradation', 'MPA', (116, 127))	('Ser385', 'Var', (38, 44))	('PTEN', 'Gene', (30, 34))	('inhibition', 'NegReg', (62, 72))	('Ser385', 'Chemical', '-', (38, 44))	('PTEN', 'Gene', '5728', (30, 34))
143318	30862113	Therefore, the activation of the PI3K pathway, upon Plk1 overexpression, leads to an increased proliferation rate also accompanied by an elevated Warburg effect and higher tumorigenesis rates.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('activation', 'PosReg', (15, 25))	('Warburg effect', 'CPA', (146, 160))	('tumor', 'Disease', (172, 177))	('PI3K pathway', 'Pathway', (33, 45))	('elevated', 'PosReg', (137, 145))	('higher', 'PosReg', (165, 171))	('increased', 'PosReg', (85, 94))	('overexpression', 'Var', (57, 71))	('proliferation rate', 'CPA', (95, 113))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('Plk1', 'Gene', (52, 56))
143319	30862113	The original preliminary idea that reduced levels of Plk1 are also related to an oncogenic scenario, came in 2001 with the description of Plk1 mutations in certain tumoral cell lines.	('tumor', 'Disease', (164, 169))	('Plk1', 'Gene', (138, 142))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('mutations', 'Var', (143, 152))
143320	30862113	These mutations make Plk1 more unstable due to their incapacity to bind to the chaperone Hsp90.	('Hsp90', 'Gene', '3320', (89, 94))	('unstable', 'MPA', (31, 39))	('bind', 'Interaction', (67, 71))	('Plk1', 'Gene', (21, 25))	('Hsp90', 'Gene', (89, 94))	('mutations', 'Var', (6, 15))
143323	30862113	Indeed, Plk1 is rarely found mutated in tumors (about 1% of 74402 tumoral samples (as depicted from the cBioPortal database:), and when mutated, this probably happens at late stages of the tumoral progression.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Disease', (189, 194))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('tumor', 'Disease', (66, 71))	('tumors', 'Disease', 'MESH:D009369', (40, 46))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('Plk1', 'Gene', (8, 12))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('mutated', 'Var', (136, 143))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('tumors', 'Disease', (40, 46))
143334	30862113	In addition, authors suggest a possible mechanism by which PLK1 might phosphorylate the histone-lysine N-methyltransferase (MLL2) at Ser4822.	('PLK1', 'Gene', (59, 63))	('Ser4822', 'Var', (133, 140))	('Ser4822', 'Chemical', '-', (133, 140))
143336	30862113	In this trend, and despite classical studies showing that Plk1 expression confers poor outcomes in breast cancer patients, there are reports showing the beneficial effects of Plk1 activity in breast cancer.	('breast cancer', 'Disease', 'MESH:D001943', (99, 112))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('breast cancer', 'Disease', 'MESH:D001943', (192, 205))	('breast cancer', 'Disease', (99, 112))	('activity', 'MPA', (180, 188))	('breast cancer', 'Disease', (192, 205))	('beneficial', 'PosReg', (153, 163))	('patients', 'Species', '9606', (113, 121))	('breast cancer', 'Phenotype', 'HP:0003002', (192, 205))	('breast cancer', 'Phenotype', 'HP:0003002', (99, 112))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('expression', 'Var', (63, 73))	('Plk1', 'Gene', (58, 62))
143355	30862113	The proposed mechanism relays on a hampered Spindle Assembly Checkpoint (SAC) due to the truncated APC expression, which gets even further weakened when Plk1 is downregulated or inhibited.	('truncated', 'Var', (89, 98))	('downregulated', 'NegReg', (161, 174))	('Plk1', 'Gene', (153, 157))	('APC', 'Gene', '324', (99, 102))	('hampered', 'NegReg', (35, 43))	('inhibited', 'NegReg', (178, 187))	('Spindle Assembly Checkpoint', 'CPA', (44, 71))	('APC', 'Gene', (99, 102))
143367	30862113	For example, breast cancer patients with concomitant expression of Plk1 and the Estrogen Receptor (ER+) have a significantly worse relapse-free survival (RFS) index when compared to ER+ patients that have little or no Plk1 expression.	('Estrogen Receptor', 'Gene', (80, 97))	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('relapse-free survival', 'CPA', (131, 152))	('ER', 'Gene', '2099', (182, 184))	('expression', 'Var', (53, 63))	('breast cancer', 'Disease', 'MESH:D001943', (13, 26))	('breast cancer', 'Phenotype', 'HP:0003002', (13, 26))	('Plk1', 'Gene', (67, 71))	('worse', 'NegReg', (125, 130))	('breast cancer', 'Disease', (13, 26))	('patients', 'Species', '9606', (27, 35))	('Estrogen Receptor', 'Gene', '2099', (80, 97))	('ER', 'Gene', '2099', (99, 101))	('patients', 'Species', '9606', (186, 194))
143369	30862113	In case of the APC colorectal tumors, Strebhardt and colleagues showed similar data also using the TCGA database, identifying one hundred colon cancer patient samples that harbor the APC non-sense mutations for which PLK1 expression and clinical data is also available.	('APC', 'Gene', '324', (15, 18))	('colon cancer', 'Disease', (138, 150))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('patient', 'Species', '9606', (151, 158))	('APC colorectal tumors', 'Disease', (15, 36))	('APC', 'Gene', (183, 186))	('non-sense mutations', 'Var', (187, 206))	('APC', 'Gene', '324', (183, 186))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('APC', 'Gene', (15, 18))	('colon cancer', 'Disease', 'MESH:D015179', (138, 150))	('colon cancer', 'Phenotype', 'HP:0003003', (138, 150))	('PLK1', 'Gene', (217, 221))	('APC colorectal tumors', 'Disease', 'MESH:D015179', (15, 36))
143399	30862113	Thus, we can find cases where CIN synergizes with tumor progression and on the contrary, high levels of CIN have been associated with improved prognosis.	('improved', 'PosReg', (134, 142))	('CIN', 'Disease', (30, 33))	('CIN', 'Disease', 'MESH:D007674', (30, 33))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('CIN', 'Disease', (104, 107))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Disease', (50, 55))	('CIN', 'Disease', 'MESH:D007674', (104, 107))	('high levels', 'Var', (89, 100))
143400	30862113	It is very well known that Plk1 is intimately involved in chromosome segregation, and any alteration in Plk1 levels or activity can alter the balance of chromosome segregation, leading to CIN.	('CIN', 'Disease', (188, 191))	('leading to', 'Reg', (177, 187))	('CIN', 'Disease', 'MESH:D007674', (188, 191))	('balance of chromosome segregation', 'MPA', (142, 175))	('levels', 'MPA', (109, 115))	('activity', 'MPA', (119, 127))	('Plk1', 'Gene', (104, 108))	('alteration', 'Var', (90, 100))	('alter', 'Reg', (132, 137))
143401	30862113	The fact that this CIN derived from Plk1 activity alterations can promote or stop cancer progression demonstrates that the role of Plk1 in tumorigenesis is much more complex to understand, and deserves further attention.	('CIN', 'Disease', (19, 22))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('Plk1', 'Gene', (36, 40))	('CIN', 'Disease', 'MESH:D007674', (19, 22))	('alterations', 'Var', (50, 61))	('cancer', 'Disease', (82, 88))	('promote', 'PosReg', (66, 73))	('tumor', 'Disease', (139, 144))	('stop', 'NegReg', (77, 81))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))
143421	27903243	Both COPS2 and COPS3 knockout are embryonic lethal at E3.5 and E8.5 respectively.	('knockout', 'Var', (21, 29))	('COPS3', 'Gene', (15, 20))	('COPS2', 'Gene', '9318', (5, 10))	('E3.5', 'Var', (54, 58))	('E8.5', 'Var', (63, 67))	('COPS2', 'Gene', (5, 10))
143423	27903243	COPS8 knockout is also embryonic lethal (E7.5) with impaired growth and differentiation.	('COPS8', 'Gene', (0, 5))	('impaired growth', 'Disease', 'MESH:D006130', (52, 67))	('impaired growth', 'Disease', (52, 67))	('knockout', 'Var', (6, 14))
143425	27903243	Identification of functional groups with which COP9 signalosome may interact in normal physiology may provide an important clue to understand how dysregulation of COP9 may facilitate tumorigenesis.	('COP9', 'Gene', (163, 167))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('facilitate', 'PosReg', (172, 182))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('tumor', 'Disease', (183, 188))	('dysregulation', 'Var', (146, 159))
143435	27903243	For a gene with cytoband of ApB.N or AqB.N, a float value was generated by A - (B.N)/100 or A + (B.N)/100, respectively.	('A - (B.N)/100', 'Var', (75, 88))	('A + (B.N)/100', 'Var', (92, 105))	('AqB.N', 'Gene', (37, 42))	('ApB', 'Gene', (28, 31))	('ApB', 'Gene', '6051', (28, 31))
143539	25804888	However, inorganic arsenic is also clearly a human pulmonary carcinogen after oral intake, primarily from naturally contaminated drinking water, which now is the major source of exposure in humans.	('humans', 'Species', '9606', (190, 196))	('drinking water', 'Chemical', 'MESH:D060766', (129, 143))	('human', 'Species', '9606', (45, 50))	('inorganic', 'Var', (9, 18))	('human', 'Species', '9606', (190, 195))	('inorganic arsenic', 'Chemical', '-', (9, 26))	('pulmonary carcinogen', 'Disease', (51, 71))	('pulmonary carcinogen', 'Disease', 'MESH:D008171', (51, 71))
143622	25804888	Together, these gene expression changes all support acquisition of cancer cell characteristics in CATLE cells.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('cancer', 'Disease', (67, 73))	('changes', 'Var', (32, 39))
143652	25804888	In addition, RAS signaling appears blocked and KRAS is minimally increased in bronchial epithelial cells transformed by arsenic, which is distinctly different from the robust increases that are seen in KRAS expression in arsenic-converted peripheral epithelial CATLE cells of the present study.	('arsenic', 'Chemical', 'MESH:D001151', (120, 127))	('arsenic', 'Var', (120, 127))	('arsenic', 'Chemical', 'MESH:D001151', (221, 228))	('KRAS', 'Gene', (47, 51))	('KRAS', 'Gene', '3845', (47, 51))	('KRAS', 'Gene', (202, 206))	('RAS signaling', 'MPA', (13, 26))	('blocked', 'NegReg', (35, 42))	('KRAS', 'Gene', '3845', (202, 206))
143661	25804888	AKT activation in cancer is often associated with PTEN inactivation including inactivation in human lung cancer, a relationship similarly observed in CATLE cells.	('AKT', 'Gene', (0, 3))	('cancer', 'Disease', 'MESH:D009369', (18, 24))	('human lung cancer', 'Disease', 'MESH:D008175', (94, 111))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('inactivation', 'Var', (55, 67))	('PTEN', 'Gene', (50, 54))	('activation', 'PosReg', (4, 14))	('lung cancer', 'Phenotype', 'HP:0100526', (100, 111))	('PTEN', 'Gene', '5728', (50, 54))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('AKT', 'Gene', '207', (0, 3))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('human lung cancer', 'Disease', (94, 111))	('cancer', 'Disease', (18, 24))	('inactivation', 'NegReg', (78, 90))
143686	25804888	In summary, the present work demonstrates that chronic exposure to low-level arsenic was associated with acquisition of multiple tumor cell characteristics in human peripheral lung epithelial cells.	('associated', 'Reg', (89, 99))	('peripheral lung epithelia', 'Disease', (165, 190))	('rat', 'Species', '10116', (36, 39))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('human', 'Species', '9606', (159, 164))	('low-level', 'Var', (67, 76))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('arsenic', 'Chemical', 'MESH:D001151', (77, 84))	('tumor', 'Disease', (129, 134))	('peripheral lung epithelia', 'Disease', 'MESH:D010523', (165, 190))
143695	33752475	HNF1A mutations widely exist in tumors and interact with different genes involved in various processes.	('HNF1A', 'Gene', '6927', (0, 5))	('interact', 'Reg', (43, 51))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('HNF1A', 'Gene', (0, 5))	('tumors', 'Disease', (32, 38))	('mutations', 'Var', (6, 15))	('tumors', 'Disease', 'MESH:D009369', (32, 38))
143724	33752475	As presented in Figure 2, the mutation types of HNF1A included nonsense mutations, missense mutations, synonymous substitutions, in-frame insertions, frameshift insertions, in-frame deletions, frameshift deletions, complex mutations, and others.	('complex mutations', 'Var', (215, 232))	('synonymous substitutions', 'Var', (103, 127))	('frameshift deletions', 'Var', (193, 213))	('nonsense mutations', 'Var', (63, 81))	('HNF1A', 'Gene', '6927', (48, 53))	('in-frame insertions', 'Var', (129, 148))	('in-frame deletions', 'Var', (173, 191))	('missense mutations', 'Var', (83, 101))	('frameshift insertions', 'Var', (150, 171))	('HNF1A', 'Gene', (48, 53))
143725	33752475	Missense mutation was the main mutation type in breast cancer (48.78%), endometrial cancer (51.52%), hematopoietic and lymphoid cancer (23.53%), kidney cancer (66.67%), cancer of the large intestine (41.91%), liver cancer (54.12%), lung cancer (67.12%), esophageal cancer (35.71%), prostate cancer (37.93%), skin cancer (62.22), soft tissue cancer (50.00%), and cancer of the urinary tract (68.42%).	('soft tissue cancer', 'Phenotype', 'HP:0031459', (329, 347))	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('cancer', 'Disease', (169, 175))	('endometrial cancer', 'Disease', (72, 90))	('cancer', 'Disease', 'MESH:D009369', (291, 297))	('kidney cancer', 'Disease', 'MESH:D007680', (145, 158))	('prostate cancer', 'Disease', 'MESH:D011471', (282, 297))	('breast cancer', 'Disease', 'MESH:D001943', (48, 61))	('lung cancer', 'Disease', 'MESH:D008175', (232, 243))	('prostate cancer', 'Phenotype', 'HP:0012125', (282, 297))	('endometrial cancer', 'Disease', 'MESH:D016889', (72, 90))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('breast cancer', 'Disease', (48, 61))	('cancer', 'Disease', (341, 347))	('lymphoid cancer', 'Disease', 'MESH:D009369', (119, 134))	('cancer', 'Disease', (128, 134))	('prostate cancer', 'Disease', (282, 297))	('cancer', 'Disease', 'MESH:D009369', (362, 368))	('Missense mutation', 'Var', (0, 17))	('cancer', 'Disease', (152, 158))	('liver cancer', 'Disease', 'MESH:D006528', (209, 221))	('lung cancer', 'Phenotype', 'HP:0100526', (232, 243))	('cancer of the large intestine', 'Phenotype', 'HP:0100834', (169, 198))	('cancer', 'Disease', (215, 221))	('skin cancer', 'Disease', 'MESH:D012878', (308, 319))	('kidney cancer', 'Phenotype', 'HP:0009726', (145, 158))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('kidney cancer', 'Disease', (145, 158))	('cancer', 'Disease', (237, 243))	('cancer', 'Disease', 'MESH:D009369', (265, 271))	('cancer', 'Disease', 'MESH:D009369', (313, 319))	('cancer', 'Disease', (55, 61))	('cancer', 'Disease', 'MESH:D009369', (169, 175))	('liver cancer', 'Phenotype', 'HP:0002896', (209, 221))	('cancer', 'Disease', (84, 90))	('cancer', 'Disease', (291, 297))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('liver cancer', 'Disease', (209, 221))	('lymphoid cancer', 'Phenotype', 'HP:0002665', (119, 134))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('cancer', 'Disease', 'MESH:D009369', (341, 347))	('lymphoid cancer', 'Disease', (119, 134))	('lung cancer', 'Disease', (232, 243))	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('skin cancer', 'Disease', (308, 319))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('cancer', 'Disease', (362, 368))	('cancer', 'Disease', 'MESH:D009369', (215, 221))	('endometrial cancer', 'Phenotype', 'HP:0012114', (72, 90))	('breast cancer', 'Phenotype', 'HP:0003002', (48, 61))	('cancer of the urinary tract', 'Phenotype', 'HP:0010786', (362, 389))	('cancer', 'Disease', 'MESH:D009369', (237, 243))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('cancer', 'Disease', (265, 271))	('cancer', 'Disease', (313, 319))	('skin cancer', 'Phenotype', 'HP:0008069', (308, 319))
143726	33752475	Additionally, C > T and G > A mutations were most commonly observed in the HNF1A coding strand.	('HNF1A', 'Gene', '6927', (75, 80))	('HNF1A', 'Gene', (75, 80))	('G > A mutations', 'Var', (24, 39))	('C > T', 'Var', (14, 19))
143727	33752475	Other types of mutations were also found in different cancers.	('cancers', 'Phenotype', 'HP:0002664', (54, 61))	('cancers', 'Disease', (54, 61))	('cancers', 'Disease', 'MESH:D009369', (54, 61))	('mutations', 'Var', (15, 24))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('found', 'Reg', (35, 40))
143738	33752475	As illustrated in Figure 6a, CD8+ T cell counts were positively associated with overall survival in the low HNF1A expression group in SKCM (HR = 0.627, P = 0.0362).	('HNF1A', 'Gene', (108, 113))	('overall survival', 'MPA', (80, 96))	('CD8', 'Gene', '925', (29, 32))	('HNF1A', 'Gene', '6927', (108, 113))	('expression', 'MPA', (114, 124))	('low', 'Var', (104, 107))	('CD8', 'Gene', (29, 32))
143739	33752475	In uveal melanoma, CD8+ T cell infiltration was negatively associated with overall survival in the low HNF1A expression group (HR = 24.8, P = 3e-04).	('negatively', 'NegReg', (48, 58))	('HNF1A', 'Gene', (103, 108))	('CD8', 'Gene', (19, 22))	('CD8', 'Gene', '925', (19, 22))	('melanoma', 'Phenotype', 'HP:0002861', (9, 17))	('melanoma', 'Disease', (9, 17))	('low', 'Var', (99, 102))	('melanoma', 'Disease', 'MESH:D008545', (9, 17))	('HNF1A', 'Gene', '6927', (103, 108))	('overall survival', 'MPA', (75, 91))	('uveal melanoma', 'Phenotype', 'HP:0007716', (3, 17))
143741	33752475	B cell infiltration was revealed to be negatively associated with overall survival in the high HNF1A expression group in LGG (HR = 1.92, P = 0.0115) and COAD (HR = 2.02, P = 0.043) (Figure 6c).	('HNF1A', 'Gene', '6927', (95, 100))	('COAD', 'Disease', 'MESH:D029424', (153, 157))	('negatively', 'NegReg', (39, 49))	('HNF1A', 'Gene', (95, 100))	('COAD', 'Disease', (153, 157))	('high', 'Var', (90, 94))
143742	33752475	High B cell infiltration indicated better overall survival in the high HNF1A expression group in LUAD (HR = 0.601, P = 0.012).	('overall survival', 'CPA', (42, 58))	('LUAD', 'Phenotype', 'HP:0030078', (97, 101))	('LUAD', 'Disease', (97, 101))	('HNF1A', 'Gene', (71, 76))	('better', 'PosReg', (35, 41))	('high', 'Var', (66, 70))	('HNF1A', 'Gene', '6927', (71, 76))
143749	33752475	Studies revealed that HNF1A gene mutations are closely related to maturity-onset diabetes of the young type 3, type 2 diabetes, pancreatic cancer, and obesity.	('diabetes', 'Disease', 'MESH:D003920', (81, 89))	('pancreatic cancer', 'Disease', 'MESH:D010190', (128, 145))	('obesity', 'Phenotype', 'HP:0001513', (151, 158))	('diabetes', 'Disease', (118, 126))	('pancreatic cancer', 'Disease', (128, 145))	('maturity-onset diabetes of the young', 'Phenotype', 'HP:0004904', (66, 102))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('HNF1A', 'Gene', (22, 27))	('mutations', 'Var', (33, 42))	('diabetes', 'Disease', 'MESH:D003920', (118, 126))	('type 2 diabetes', 'Phenotype', 'HP:0005978', (111, 126))	('HNF1A', 'Gene', '6927', (22, 27))	('obesity', 'Disease', 'MESH:D009765', (151, 158))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (128, 145))	('diabetes', 'Disease', (81, 89))	('obesity', 'Disease', (151, 158))	('related', 'Reg', (55, 62))
143750	33752475	Our results revealed the wide existence of HNF1A mutations in human cancers.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('mutations', 'Var', (49, 58))	('human', 'Species', '9606', (62, 67))	('cancers', 'Phenotype', 'HP:0002664', (68, 75))	('cancers', 'Disease', (68, 75))	('HNF1A', 'Gene', (43, 48))	('cancers', 'Disease', 'MESH:D009369', (68, 75))	('HNF1A', 'Gene', '6927', (43, 48))
143751	33752475	The analysis indicated that C > T and G > A mutations widely occur in tumors.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumors', 'Disease', (70, 76))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('tumors', 'Disease', 'MESH:D009369', (70, 76))	('G > A', 'Gene', (38, 43))	('C > T', 'Var', (28, 33))
143763	33752475	HNF1A mutations are widely found in cancers, and this mutant gene interacts with different genes in different cancer types, which may affect the different prognostic value of HNF1A.	('interacts', 'Reg', (66, 75))	('HNF1A', 'Gene', '6927', (0, 5))	('cancer', 'Disease', (110, 116))	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('cancers', 'Disease', 'MESH:D009369', (36, 43))	('HNF1A', 'Gene', '6927', (175, 180))	('cancers', 'Phenotype', 'HP:0002664', (36, 43))	('cancer', 'Disease', (36, 42))	('cancers', 'Disease', (36, 43))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('affect', 'Reg', (134, 140))	('HNF1A', 'Gene', (0, 5))	('mutant', 'Var', (54, 60))	('HNF1A', 'Gene', (175, 180))	('mutations', 'Var', (6, 15))
143765	32067422	Spectrum of EGFR aberrations and potential clinical implications: insights from integrative pan-cancer analysis Human epidermal growth factor receptor (EGFR) is an oncogenic gene and one of top targets of precision therapy in lung cancer with EGFR mutations.	('mutations', 'Var', (248, 257))	('cancer', 'Disease', 'MESH:D009369', (231, 237))	('lung cancer', 'Disease', (226, 237))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('epidermal growth factor receptor', 'Gene', '1956', (118, 150))	('lung cancer', 'Phenotype', 'HP:0100526', (226, 237))	('cancer', 'Disease', (231, 237))	('Human', 'Species', '9606', (112, 117))	('epidermal growth factor receptor', 'Gene', (118, 150))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('lung cancer', 'Disease', 'MESH:D008175', (226, 237))	('EGFR', 'Gene', (243, 247))	('cancer', 'Disease', (96, 102))
143766	32067422	Although there are many reports for some individual cancers, comprehensive profiling of EGFR mutations, overexpression, amplification, DNA methylation, and their clinical associations across many different cancers simultaneously was not available.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('cancers', 'Disease', (52, 59))	('mutations', 'Var', (93, 102))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('cancers', 'Disease', 'MESH:D009369', (206, 213))	('cancers', 'Phenotype', 'HP:0002664', (206, 213))	('cancers', 'Phenotype', 'HP:0002664', (52, 59))	('cancers', 'Disease', (206, 213))	('EGFR', 'Gene', (88, 92))	('cancers', 'Disease', 'MESH:D009369', (52, 59))
143768	32067422	The Cancer Genome Atlas (TCGA) datasets for 32 cancer types involving 11,314 patients were analyzed for alterations (mutations and amplification/deletion), abnormal expression and DNA methylation in EGFR gene.	('mutations', 'Var', (117, 126))	('rat', 'Species', '10116', (108, 111))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('EGFR', 'Gene', (199, 203))	('Cancer', 'Disease', 'MESH:D009369', (4, 10))	('DNA methylation', 'Var', (180, 195))	('cancer', 'Disease', (47, 53))	('expression', 'MPA', (165, 175))	('amplification/deletion', 'Var', (131, 153))	('patients', 'Species', '9606', (77, 85))	('Cancer', 'Phenotype', 'HP:0002664', (4, 10))	('Cancer', 'Disease', (4, 10))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('abnormal', 'Reg', (156, 164))
143770	32067422	EGFR alteration frequency, mutation sites across functional domains, amplification, overexpression, and DNA methylation patterns differed greatly among different cancer types.	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('rat', 'Species', '10116', (9, 12))	('EGFR', 'Gene', (0, 4))	('alteration', 'Var', (5, 15))	('cancer', 'Disease', (162, 168))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))
143772	32067422	Targetable mutations, mainly in lung cancer, were primarily found in the Pkinase_Tyr domain.	('mutations', 'Var', (11, 20))	('lung cancer', 'Disease', 'MESH:D008175', (32, 43))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('lung cancer', 'Disease', (32, 43))	('lung cancer', 'Phenotype', 'HP:0100526', (32, 43))
143773	32067422	Glioblastoma multiforme had the highest rate of alterations, but it was dominated by gene amplification and most mutations were in the Furin-like domain where targeted therapy was less effective.	('rat', 'Species', '10116', (52, 55))	('Glioblastoma multiforme', 'Disease', 'MESH:D005909', (0, 23))	('rat', 'Species', '10116', (40, 43))	('Glioblastoma multiforme', 'Disease', (0, 23))	('mutations', 'Var', (113, 122))	('Glioblastoma', 'Phenotype', 'HP:0012174', (0, 12))	('Furin', 'Gene', '5045', (135, 140))	('Furin', 'Gene', (135, 140))
143774	32067422	Low-grade glioma often had gene amplification and increased EGFR expression which was associated with poor outcome.	('gene amplification', 'Var', (27, 45))	('glioma', 'Phenotype', 'HP:0009733', (10, 16))	('increased', 'PosReg', (50, 59))	('glioma', 'Disease', 'MESH:D005910', (10, 16))	('expression', 'MPA', (65, 75))	('EGFR', 'Gene', (60, 64))	('glioma', 'Disease', (10, 16))
143775	32067422	Colon and pancreatic adenocarcinoma had very few EGFR mutations; however, high EGFR expression was significantly associated with short patient survival.	('patient', 'Species', '9606', (135, 142))	('Colon and pancreatic adenocarcinoma', 'Disease', 'MESH:D003110', (0, 35))	('EGFR', 'Gene', (79, 83))	('EGFR', 'Gene', (49, 53))	('mutations', 'Var', (54, 63))	('short', 'NegReg', (129, 134))	('carcinoma', 'Phenotype', 'HP:0030731', (26, 35))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (10, 35))	('expression', 'MPA', (84, 94))	('associated', 'Reg', (113, 123))
143777	32067422	DNA methylation was highly associated with EGFR expression and patient outcomes in some cancers.	('cancers', 'Disease', 'MESH:D009369', (88, 95))	('expression', 'MPA', (48, 58))	('associated', 'Reg', (27, 37))	('methylation', 'Var', (4, 15))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('cancers', 'Disease', (88, 95))	('patient', 'Species', '9606', (63, 70))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('EGFR', 'Gene', (43, 47))
143779	32067422	While mutations in the Pkinase_Tyr domain are more important for treatment selection, increased expression from amplification or deregulation affects more tumor types and leads to worse outcome, which calls for new treatment strategies for these EGFR-driven tumors.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('rat', 'Species', '10116', (227, 230))	('tumor', 'Phenotype', 'HP:0002664', (258, 263))	('leads to', 'Reg', (171, 179))	('increased', 'PosReg', (86, 95))	('tumors', 'Disease', (258, 264))	('tumors', 'Phenotype', 'HP:0002664', (258, 264))	('tumor', 'Disease', (258, 263))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('amplification', 'Var', (112, 125))	('deregulation', 'MPA', (129, 141))	('expression', 'MPA', (96, 106))	('tumor', 'Disease', (155, 160))	('tumors', 'Disease', 'MESH:D009369', (258, 264))	('affects', 'Reg', (142, 149))	('tumor', 'Disease', 'MESH:D009369', (258, 263))	('mutations', 'Var', (6, 15))
143781	32067422	Five functional domains are characterized for EGFR according to the database of protein families (Pfam, http://pfam.xfam.org/protein/P00533): Recep_L (57-168aa), Furin-like (177-338aa), Recep_L (361-481aa), GF_recep_IV (505-637aa), and Pkinase_Tyr domains (712-968aa).	('177-338aa', 'Var', (174, 183))	('712-968aa', 'Var', (257, 266))	('Furin', 'Gene', (162, 167))	('Furin', 'Gene', '5045', (162, 167))	('505-637aa', 'Var', (220, 229))
143783	32067422	Upon stimulation by its ligands, dimerization (both homodimerization and heterodimerization) of EGFR results in its intracellular tyrosine kinase activation and autophosphorylation at multiple tyrosine residues, which activates a number of downstream signaling cascades that not only promote proliferation, growth, and survival of normal cells but also contribute to processes that are crucial to cancer progression, including angiogenesis, metastasis, and apoptosis [4, 5].	('activation', 'PosReg', (146, 156))	('cancer', 'Disease', (397, 403))	('proliferation', 'CPA', (292, 305))	('promote', 'PosReg', (284, 291))	('tyrosine', 'Chemical', 'MESH:D014443', (193, 201))	('EGFR', 'Gene', (96, 100))	('dimerization', 'Var', (33, 45))	('survival', 'CPA', (319, 327))	('metastasis', 'CPA', (441, 451))	('growth', 'CPA', (307, 313))	('activates', 'PosReg', (218, 227))	('contribute', 'Reg', (353, 363))	('cancer', 'Phenotype', 'HP:0002664', (397, 403))	('autophosphorylation', 'MPA', (161, 180))	('tyrosine', 'Chemical', 'MESH:D014443', (130, 138))	('intracellular tyrosine kinase', 'MPA', (116, 145))	('cancer', 'Disease', 'MESH:D009369', (397, 403))	('rat', 'Species', '10116', (299, 302))
143785	32067422	It is frequently activated by gene mutation, amplification, or overexpression through abnormal regulation in human cancers.	('human', 'Species', '9606', (109, 114))	('cancers', 'Disease', 'MESH:D009369', (115, 122))	('cancers', 'Phenotype', 'HP:0002664', (115, 122))	('cancers', 'Disease', (115, 122))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('gene mutation', 'Var', (30, 43))	('activated', 'PosReg', (17, 26))	('amplification', 'Var', (45, 58))	('overexpression', 'PosReg', (63, 77))
143787	32067422	In cancers like non-small-cell lung cancer (NSCLC) [13] and colon adenocarcinoma (COAD) [14], EGFR mutation status is considered as a poor prognostic factor, which is often associated with a more aggressive behavior and decreased patient survival.	('COAD', 'Disease', (82, 86))	('lung cancer', 'Disease', (31, 42))	('colon adenocarcinoma', 'Disease', 'MESH:D003110', (60, 80))	('aggressive behavior', 'Phenotype', 'HP:0000718', (196, 215))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('patient', 'Species', '9606', (230, 237))	('mutation', 'Var', (99, 107))	('cancers', 'Disease', 'MESH:D009369', (3, 10))	('lung cancer', 'Disease', 'MESH:D008175', (31, 42))	('NSCLC', 'Disease', 'MESH:D002289', (44, 49))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (20, 42))	('lung cancer', 'Phenotype', 'HP:0100526', (31, 42))	('COAD', 'Disease', 'MESH:D029424', (82, 86))	('colon adenocarcinoma', 'Disease', (60, 80))	('NSCLC', 'Disease', (44, 49))	('NSCLC', 'Phenotype', 'HP:0030358', (44, 49))	('cancers', 'Phenotype', 'HP:0002664', (3, 10))	('EGFR', 'Gene', (94, 98))	('cancers', 'Disease', (3, 10))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (16, 42))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
143790	32067422	Such treatments are very effective and provide significantly improved patient outcomes, particularly for lung adenocarcinoma (LUAD) patients with EGFR mutations [20, 21].	('improved', 'PosReg', (61, 69))	('LUAD', 'Phenotype', 'HP:0030078', (126, 130))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (105, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('patient', 'Species', '9606', (70, 77))	('EGFR', 'Gene', (146, 150))	('lung adenocarcinoma', 'Disease', (105, 124))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (105, 124))	('patient', 'Species', '9606', (132, 139))	('patients', 'Species', '9606', (132, 140))	('mutations', 'Var', (151, 160))
143792	32067422	Although many literature reports are available on EGFR mutation, overexpression, or amplification for particular cancer types [12, 13, 14, 23, 24], a simultaneous comprehensive profiling over multiple cancer types to explore their similarity and difference is not available.	('rat', 'Species', '10116', (18, 21))	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('cancer', 'Disease', (201, 207))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('cancer', 'Disease', (113, 119))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('mutation', 'Var', (55, 63))	('EGFR', 'Gene', (50, 54))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
143795	32067422	We first examined the patterns of EGFR mutations, including single nucleotide variant (SNV) and short insertion/deletion (indel), across tumors and their implications for targeted therapies.	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('tumors', 'Disease', (137, 143))	('single nucleotide variant', 'Var', (60, 85))	('EGFR', 'Gene', (34, 38))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('short insertion/deletion', 'Var', (96, 120))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
143799	32067422	The mutation data included SNVs, indels, and CNVs (defined by GISTIC 2.0 as following for log ratio value: -2/-1 = deletion; 0 = diploid; 1 = gain; 2 = amplification).	('deletion', 'Var', (115, 123))	('rat', 'Species', '10116', (94, 97))	('gain', 'PosReg', (142, 146))
143809	32067422	The prognostic values of EGFR alterations and its CpG methylation were analyzed with Cox proportional hazard model.	('alterations', 'Var', (30, 41))	('EGFR', 'Gene', (25, 29))	('rat', 'Species', '10116', (34, 37))
143810	32067422	The overall EGFR mutation frequency was 2.8% (320/11,410) for all tumor samples and 2.4% (268/11,314) for all patients across the 32 tumor types.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumor', 'Disease', (66, 71))	('mutation', 'Var', (17, 25))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumor', 'Disease', (133, 138))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('EGFR', 'Gene', (12, 16))	('patients', 'Species', '9606', (110, 118))
143811	32067422	The most common tumors with EGFR mutations were glioblastoma multiforme (GBM, 26.8%), LUAD (14.4%), diffuse large B-cell lymphoma (DLBC, 8.3%), and skin cutaneous melanoma (SKCM, 6.5%).	('glioblastoma', 'Phenotype', 'HP:0012174', (48, 60))	('EGFR', 'Gene', (28, 32))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('mutations', 'Var', (33, 42))	('tumors', 'Disease', (16, 22))	('lymphoma', 'Phenotype', 'HP:0002665', (121, 129))	('B-cell lymphoma', 'Disease', 'MESH:D016393', (114, 129))	('tumors', 'Disease', 'MESH:D009369', (16, 22))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (114, 129))	('LUAD', 'Phenotype', 'HP:0030078', (86, 90))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (148, 171))	('skin cutaneous melanoma', 'Disease', (148, 171))	('melanoma', 'Phenotype', 'HP:0002861', (163, 171))	('B-cell lymphoma', 'Disease', (114, 129))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (153, 171))	('LUAD', 'Disease', (86, 90))	('glioblastoma multiforme', 'Disease', (48, 71))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (48, 71))
143812	32067422	On the contrary, kidney chromophobe cell carcinoma (KICH), mesothelioma (MESO), pheochromocytoma and paraganglioma (PCPG), thymoma (THYM), thyroid carcinoma (THCA), uterine carcinosarcoma (UCS), and uveal melanoma (UVM) showed almost no EGFR mutations (Figure 1A).	('mesothelioma', 'Disease', (59, 71))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (80, 96))	('THCA', 'Phenotype', 'HP:0002890', (158, 162))	('thymoma', 'Disease', (123, 130))	('mesothelioma', 'Disease', 'MESH:D008654', (59, 71))	('carcinosarcoma', 'Disease', 'MESH:D002296', (173, 187))	('thymoma', 'Phenotype', 'HP:0100522', (123, 130))	('UCS', 'Phenotype', 'HP:0002891', (189, 192))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (139, 156))	('carcinoma', 'Phenotype', 'HP:0030731', (41, 50))	('melanoma', 'Phenotype', 'HP:0002861', (205, 213))	('UVM', 'Phenotype', 'HP:0007716', (215, 218))	('melanoma', 'Disease', (205, 213))	('thyroid carcinoma', 'Disease', (139, 156))	('glioma', 'Phenotype', 'HP:0009733', (108, 114))	('paraganglioma', 'Phenotype', 'HP:0002668', (101, 114))	('kidney chromophobe cell carcinoma', 'Disease', (17, 50))	('pheochromocytoma and paraganglioma', 'Disease', 'MESH:D010673', (80, 114))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (139, 156))	('sarcoma', 'Phenotype', 'HP:0100242', (180, 187))	('kidney chromophobe cell carcinoma', 'Disease', 'MESH:C538614', (17, 50))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (165, 187))	('uveal melanoma', 'Phenotype', 'HP:0007716', (199, 213))	('thymoma', 'Disease', 'MESH:D013945', (123, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (147, 156))	('melanoma', 'Disease', 'MESH:D008545', (205, 213))	('mutations', 'Var', (242, 251))	('THYM', 'Phenotype', 'HP:0100522', (132, 136))	('carcinosarcoma', 'Disease', (173, 187))
143814	32067422	The 320 EGFR somatic mutations (from 268 tumor samples) were observed across all cancer types and were widely distributed along different functional domains of EGFR gene.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('tumor', 'Disease', (41, 46))	('cancer', 'Disease', (81, 87))	('observed', 'Reg', (61, 69))	('EGFR', 'Gene', (160, 164))	('EGFR', 'Gene', (8, 12))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('mutations', 'Var', (21, 30))
143816	32067422	The location distribution of these EGFR mutations was dramatically different among different cancers (Figure 1B, Supplementary Table S2).	('cancers', 'Disease', (93, 100))	('cancers', 'Phenotype', 'HP:0002664', (93, 100))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('EGFR', 'Gene', (35, 39))	('mutations', 'Var', (40, 49))	('different', 'Reg', (67, 76))	('cancers', 'Disease', 'MESH:D009369', (93, 100))
143817	32067422	Mutations in GBM and brain lower-grade glioma (LGG) were most commonly located in the Furin-like domain, about 5 times more than the mutations located in the Pkinase_Tyr domain.	('glioma', 'Disease', (39, 45))	('GBM', 'Gene', (13, 16))	('Mutations', 'Var', (0, 9))	('located', 'Reg', (71, 78))	('Furin', 'Gene', (86, 91))	('Furin', 'Gene', '5045', (86, 91))	('glioma', 'Disease', 'MESH:D005910', (39, 45))	('glioma', 'Phenotype', 'HP:0009733', (39, 45))
143818	32067422	On the contrary, mutations in NSCLC were primarily in the Pkinase_Tyr domain, especially for LUAD, which amounted to four fifths of all mutations.	('NSCLC', 'Disease', 'MESH:D002289', (30, 35))	('NSCLC', 'Phenotype', 'HP:0030358', (30, 35))	('LUAD', 'Phenotype', 'HP:0030078', (93, 97))	('NSCLC', 'Disease', (30, 35))	('mutations', 'Var', (17, 26))
143819	32067422	Mutations in stomach adenocarcinoma (STAD), head and neck squamous cell carcinoma (HNSC), and SKCM were mostly in other domains whose functions were less known.	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (53, 81))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('adenocarcinoma', 'Disease', (21, 35))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (44, 81))	('Mutations', 'Var', (0, 9))	('carcinoma', 'Phenotype', 'HP:0030731', (26, 35))	('adenocarcinoma', 'Disease', 'MESH:D000230', (21, 35))	('HNSC', 'Phenotype', 'HP:0012288', (83, 87))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (58, 81))	('neck squamous cell carcinoma', 'Disease', (53, 81))
143820	32067422	The 289aa in the Furin-like domain was the most frequently mutated position, which was observed in 27 samples (3 samples with A289D, 1 with A289I, 1 with A289N, 6 with A289T, 15 with A289V, and 1 with A289Rfs*9).	('A289Rfs*9', 'Mutation', 'p.A289RfsX9', (201, 210))	('A289V', 'Var', (183, 188))	('A289D', 'Mutation', 'p.A289D', (126, 131))	('A289T', 'Mutation', 'rs769696078', (168, 173))	('A289I', 'Mutation', 'p.A289I', (140, 145))	('Furin', 'Gene', (17, 22))	('A289I', 'Var', (140, 145))	('Furin', 'Gene', '5045', (17, 22))	('A289N', 'Var', (154, 159))	('A289N', 'Mutation', 'p.A289N', (154, 159))	('A289V', 'Mutation', 'p.A289V', (183, 188))	('A289D', 'Var', (126, 131))	('A289T', 'Var', (168, 173))
143821	32067422	A289V is known to be oncogenic, while other mutation types (A289D/T/N/I) are likely oncogenic.	('A289V', 'Mutation', 'p.A289V', (0, 5))	('A289V', 'Var', (0, 5))	('A289D/T/N/I', 'Var', (60, 71))	('A289D', 'Mutation', 'p.A289D', (60, 65))
143822	32067422	The only other tumor with mutations at this position was HNSC (1 sample with A289T and 1 with A289Rfs*9), and their importance was little known to this cancer.	('A289Rfs*', 'Var', (94, 102))	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('HNSC', 'Phenotype', 'HP:0012288', (57, 61))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('A289T', 'Mutation', 'rs769696078', (77, 82))	('mutations', 'Var', (26, 35))	('tumor', 'Disease', (15, 20))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('A289T', 'Var', (77, 82))	('A289Rfs*9', 'Mutation', 'p.A289RfsX9', (94, 103))
143823	32067422	The second most mutated position was 598aa in the GF_recep_IV domain: 16 GBMs had G598V, 2 GBMs had G598A, and 1 esophageal squamous cell carcinoma (ESCC) had G598E.	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('G598V', 'Mutation', 'rs139236063', (82, 87))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (124, 147))	('G598A', 'Mutation', 'rs139236063', (100, 105))	('esophageal squamous cell carcinoma', 'Disease', (113, 147))	('G598E', 'Mutation', 'p.G598E', (159, 164))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (113, 147))	('G598E', 'Var', (159, 164))	('G598A', 'Var', (100, 105))	('G598V', 'Var', (82, 87))
143824	32067422	Most mutations in LUAD (35 of 45 mutations) were located in the Pkinase_Tyr domain, especially at the positions of 858aa (8 samples with L858R) and 746-750aa (6 with E746_A750del, 2 with L747_E749del, and 1 with L747_T751del) (Figure 1E).	('E746_A750del', 'Var', (166, 178))	('L747_T751del', 'Var', (212, 224))	('L747_T751del', 'Mutation', 'p.747,751delT', (212, 224))	('L747_E749del', 'Var', (187, 199))	('LUAD', 'Phenotype', 'HP:0030078', (18, 22))	('L858R', 'Mutation', 'rs121434568', (137, 142))	('LUAD', 'Gene', (18, 22))	('E746_A750del', 'Mutation', 'p.746,750delA', (166, 178))	('L747_E749del', 'Mutation', 'p.747,749delE', (187, 199))
143826	32067422	All Level 1 mutations were found in NSCLC (28 in LUAD and 2 in lung squamous cell carcinoma [LUSC]), and these mutations were concentrated in exons 19-21, which included L858R, L861Q, G719A, S768I, L833F, E796_A750del, L747_E749del, E709_T710delinsD, L747_T751del, and T751_E758del (Figure 3).	('S768I', 'Var', (191, 196))	('LUAD', 'Phenotype', 'HP:0030078', (49, 53))	('L747_T751del', 'Var', (251, 263))	('E709_T710delinsD', 'Mutation', 'p.709,710delinsT,D', (233, 249))	('L833F', 'Mutation', 'p.L833F', (198, 203))	('L858R', 'Mutation', 'rs121434568', (170, 175))	('T751_E758del', 'Mutation', 'p.751,758delE', (269, 281))	('E709_T710delinsD', 'Var', (233, 249))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (63, 91))	('S768I', 'Mutation', 'rs121913465', (191, 196))	('rat', 'Species', '10116', (133, 136))	('L833F', 'Var', (198, 203))	('NSCLC', 'Disease', 'MESH:D002289', (36, 41))	('L747_T751del', 'Mutation', 'p.747,751delT', (251, 263))	('G719A', 'Mutation', 'rs121913428', (184, 189))	('L747_E749del', 'Mutation', 'p.747,749delE', (219, 231))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (63, 91))	('lung squamous cell carcinoma', 'Disease', (63, 91))	('L858R', 'Var', (170, 175))	('NSCLC', 'Disease', (36, 41))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (68, 91))	('L747_E749del', 'Var', (219, 231))	('E796_A750del', 'Var', (205, 217))	('L861Q', 'Mutation', 'rs121913444', (177, 182))	('NSCLC', 'Phenotype', 'HP:0030358', (36, 41))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('G719A', 'Var', (184, 189))	('E796_A750del', 'Mutation', 'p.796,750delA', (205, 217))	('L861Q', 'Var', (177, 182))	('T751_E758del', 'Var', (269, 281))
143830	32067422	The combined EGFR mutation and CNV frequency in all tumors was about 7.0% (746 of 11,314 patients, 748 of 11,410 samples).	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('tumors', 'Disease', (52, 58))	('patients', 'Species', '9606', (89, 97))	('mutation', 'Var', (18, 26))	('EGFR', 'Gene', (13, 17))
143832	32067422	Other cancers with dominantEGFR amplification but at much lower amplification rate included ESCA (13.0%), HNSC (9.4%), STAD (5.2%), LGG (5.4%), LUSC (6.4%), and BLCA (4.4%).	('LUSC', 'Disease', (144, 148))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('dominantEGFR', 'Var', (19, 31))	('amplification', 'Var', (32, 45))	('BLCA', 'Disease', (161, 165))	('HNSC', 'Disease', (106, 110))	('rat', 'Species', '10116', (78, 81))	('HNSC', 'Phenotype', 'HP:0012288', (106, 110))	('LGG', 'Disease', (132, 135))	('cancers', 'Disease', 'MESH:D009369', (6, 13))	('cancers', 'Phenotype', 'HP:0002664', (6, 13))	('cancers', 'Disease', (6, 13))	('ESCA', 'Disease', (92, 96))	('STAD', 'Disease', (119, 123))
143834	32067422	Over half of the mutations (47 of 82 mutations) in the Furin-like domain were accompanied by EGFR amplification, while nearly half of mutations (40 of 85 mutations) in the Pkinase_Tyr domain had copy gain.	('copy', 'MPA', (195, 199))	('EGFR amplification', 'MPA', (93, 111))	('mutations', 'Var', (37, 46))	('Furin', 'Gene', (55, 60))	('mutations', 'Var', (17, 26))	('Furin', 'Gene', '5045', (55, 60))
143835	32067422	In order to evaluate the clinical significance of EGFR alterations, we analyzed patient survival for pan-cancer and for each cancer type separately by alteration status (mutations and CNVs alone or in combination).	('rat', 'Species', '10116', (141, 144))	('alterations', 'Var', (55, 66))	('mutations', 'Var', (170, 179))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('rat', 'Species', '10116', (59, 62))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('rat', 'Species', '10116', (155, 158))	('patient', 'Species', '9606', (80, 87))
143836	32067422	When all tumors were analyzed together, patients with any EGFR alteration had significantly shorter median OS and DFS than those without EGFR alteration (both P < 0.001, Supplementary Figure S1).	('rat', 'Species', '10116', (67, 70))	('rat', 'Species', '10116', (146, 149))	('DFS', 'CPA', (114, 117))	('patients', 'Species', '9606', (40, 48))	('EGFR', 'Gene', (58, 62))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('tumors', 'Disease', (9, 15))	('alteration', 'Var', (63, 73))	('tumors', 'Disease', 'MESH:D009369', (9, 15))	('shorter', 'NegReg', (92, 99))	('median', 'MPA', (100, 106))
143837	32067422	When analysis was performed for CNV and mutation separately, the presence of either aberration was associated with shortened patients' OS and DFS (all P < 0.001, Supplementary Figure S2 and S3).	('DFS', 'CPA', (142, 145))	('presence', 'Var', (65, 73))	('rat', 'Species', '10116', (88, 91))	('rat', 'Species', '10116', (53, 56))	('shortened', 'NegReg', (115, 124))	('patients', 'Species', '9606', (125, 133))
143838	32067422	For survival association in individual cancer types, only those cancer types with at least 10 tumor samples containing either EGFR mutations or CNVs were included in the analysis.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('mutations', 'Var', (131, 140))	('cancer', 'Disease', (39, 45))	('EGFR', 'Gene', (126, 130))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('tumor', 'Disease', (94, 99))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
143839	32067422	Among patients with HNSC, LGG, or LUAD, EGFR amplification was associated with short survival (Figure 6A).	('LUAD', 'Phenotype', 'HP:0030078', (34, 38))	('HNSC', 'Disease', (20, 24))	('short survival', 'MPA', (79, 93))	('EGFR', 'Gene', (40, 44))	('patients', 'Species', '9606', (6, 14))	('HNSC', 'Phenotype', 'HP:0012288', (20, 24))	('LGG', 'Disease', (26, 29))	('amplification', 'Var', (45, 58))
143841	32067422	Not surprisingly, EGFR-amplified tumors had significantly higher EGFR expression than those without EGFR amplification in all 9 cancers types (all P < 0.001, Figure 6C); however, there was no much EGFR expression difference between tumors with or without EGFR mutations except that EGFR mutation status was associated with significantly increased EGFR expression in GBM (P = 0.024) and LUAD (P = 0.001, Figure 6D).	('cancers', 'Disease', 'MESH:D009369', (128, 135))	('cancers', 'Phenotype', 'HP:0002664', (128, 135))	('mutation', 'Var', (287, 295))	('cancers', 'Disease', (128, 135))	('increased', 'PosReg', (337, 346))	('tumors', 'Disease', 'MESH:D009369', (232, 238))	('EGFR', 'Gene', (282, 286))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('LUAD', 'Phenotype', 'HP:0030078', (386, 390))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('tumors', 'Disease', 'MESH:D009369', (33, 39))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('tumors', 'Phenotype', 'HP:0002664', (232, 238))	('tumors', 'Disease', (33, 39))	('EGFR expression', 'MPA', (347, 362))	('tumors', 'Disease', (232, 238))
143861	32067422	In individual cancer type analysis, most tumor types had the similar patterns of methylation association with gene expression in promoter and gene body, but a few others had predominant hypomethylation in both regions, such as GBM, LUSC, PRAD, THYM, KIRC, and KICH (Supplementary Figure S5).	('cancer', 'Disease', (14, 20))	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('methylation', 'Var', (81, 92))	('tumor', 'Disease', (41, 46))	('THYM', 'Phenotype', 'HP:0100522', (244, 248))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('hypomethylation', 'Var', (186, 201))	('cancer', 'Disease', 'MESH:D009369', (14, 20))	('gene expression', 'MPA', (110, 125))
143862	32067422	Survival analysis for all tumors with tumor type as a covariate only found 2 CpG sites (cg07311521 and cg16751451) significantly associated with OS, and both were in the promoter region (TSS1500).	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('associated with', 'Reg', (129, 144))	('cg16751451', 'Var', (103, 113))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('cg07311521', 'Var', (88, 98))	('tumor', 'Disease', (26, 31))	('tumors', 'Disease', (26, 32))
143865	32067422	For both cancer types, the CpGs with significant associations were mostly located in the gene body, where higher CpG methylation was associated with a better outcome.	('cancer', 'Disease', (9, 15))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('higher', 'PosReg', (106, 112))	('methylation', 'Var', (117, 128))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('CpG', 'MPA', (113, 116))
143867	32067422	GBM had the highest rate of EGFR alterations, and amplification was the primary alteration.	('rat', 'Species', '10116', (84, 87))	('rat', 'Species', '10116', (37, 40))	('alterations', 'Var', (33, 44))	('EGFR', 'MPA', (28, 32))	('rat', 'Species', '10116', (20, 23))
143870	32067422	Other common tumor types with EGFR alterations include ESCA, HNSC, LGG, LUSC, and BLCA, all with similar characteristics: alteration frequency of about 5.0% and amplification as a dominant type.	('tumor', 'Disease', (13, 18))	('alterations', 'Var', (35, 46))	('EGFR', 'Gene', (30, 34))	('alteration', 'Var', (122, 132))	('LUSC', 'Disease', (72, 76))	('BLCA', 'Disease', (82, 86))	('HNSC', 'Phenotype', 'HP:0012288', (61, 65))	('ESCA', 'Disease', (55, 59))	('LGG', 'Disease', (67, 70))	('rat', 'Species', '10116', (39, 42))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('rat', 'Species', '10116', (126, 129))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('HNSC', 'Disease', (61, 65))
143872	32067422	On the other side of the spectrum, tumors such as DLBC and SKCM mainly had SNV mutations but rarely CNV; tumors including KIRC, MESO, THCA, THYM, UCS and UVM almost had no EGFR alterations.	('tumors', 'Disease', (105, 111))	('THCA', 'Phenotype', 'HP:0002890', (134, 138))	('THYM', 'Phenotype', 'HP:0100522', (140, 144))	('tumors', 'Disease', 'MESH:D009369', (35, 41))	('mutations', 'Var', (79, 88))	('tumors', 'Disease', 'MESH:D009369', (105, 111))	('THYM', 'Disease', (140, 144))	('rat', 'Species', '10116', (181, 184))	('UCS', 'Phenotype', 'HP:0002891', (146, 149))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('THCA', 'Disease', (134, 138))	('UVM', 'Phenotype', 'HP:0007716', (154, 157))	('tumors', 'Disease', (35, 41))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('UCS', 'Disease', (146, 149))	('SNV', 'Gene', (75, 78))	('MESO', 'Disease', (128, 132))
143873	32067422	Mutations in the Furin-like and Pkinase_Tyr domains accounted for most of EGFR single nucleotide or indel mutations.	('single nucleotide', 'Var', (79, 96))	('Furin', 'Gene', (17, 22))	('Mutations', 'Var', (0, 9))	('Furin', 'Gene', '5045', (17, 22))	('EGFR', 'Gene', (74, 78))
143874	32067422	However, the Pkinase_Tyr domain was far more important in terms of targeted therapy with TKIs as 90% EGFR mutations in LUAD occurred in this region, particularly the exon 19 deletion and the L858R point mutation in exon 21.	('L858R', 'Mutation', 'rs121434568', (191, 196))	('L858R point', 'Var', (191, 202))	('LUAD', 'Gene', (119, 123))	('mutations', 'Var', (106, 115))	('LUAD', 'Phenotype', 'HP:0030078', (119, 123))	('exon 19 deletion', 'Var', (166, 182))
143875	32067422	Mutations in these regions are proven predictive markers for effective TKI therapy for NSCLC in clinical practice [7, 33, 34, 35], with significantly prolonged survival as compared with traditional combination chemotherapy [21, 36, 37].	('NSCLC', 'Disease', (87, 92))	('prolonged', 'PosReg', (150, 159))	('survival', 'MPA', (160, 168))	('NSCLC', 'Disease', 'MESH:D002289', (87, 92))	('Mutations', 'Var', (0, 9))	('NSCLC', 'Phenotype', 'HP:0030358', (87, 92))
143877	32067422	For other uncommon EGFR mutations in NSCLC, targeted therapy generated inconsistent results [34, 40, 41, 42].	('NSCLC', 'Phenotype', 'HP:0030358', (37, 42))	('EGFR', 'Gene', (19, 23))	('NSCLC', 'Disease', (37, 42))	('NSCLC', 'Disease', 'MESH:D002289', (37, 42))	('mutations', 'Var', (24, 33))	('rat', 'Species', '10116', (65, 68))
143878	32067422	In this large TCGA dataset, the combined alteration rate (amplification, deletion, or mutation) reached 67.3% in GBM.	('rat', 'Species', '10116', (52, 55))	('deletion', 'Var', (73, 81))	('rat', 'Species', '10116', (45, 48))	('mutation', 'Var', (86, 94))
143880	32067422	Compared with LUAD, most EGFR mutations in GBM were located in extracellular domain or single-span transmembrane segment, which was known to be associated with tumorigenesis but not responsiveness to TKIs.	('associated with', 'Reg', (144, 159))	('EGFR', 'Gene', (25, 29))	('LUAD', 'Phenotype', 'HP:0030078', (14, 18))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('GBM', 'Gene', (43, 46))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('mutations', 'Var', (30, 39))	('tumor', 'Disease', (160, 165))
143881	32067422	Although EGFR amplification was a predictor of poor prognosis for several cancer types, it was not significantly associated with GBM, consistent with the paradox phenomenon reported in the literature [46].	('rat', 'Species', '10116', (193, 196))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Disease', (74, 80))	('EGFR', 'Gene', (9, 13))	('GBM', 'Disease', (129, 132))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('amplification', 'Var', (14, 27))
143882	32067422	Both amplification and high expression of EGFR were correlated with short patient survival in this dataset as reported previously [49, 50].	('amplification', 'Var', (5, 18))	('patient', 'Species', '9606', (74, 81))	('EGFR', 'Gene', (42, 46))	('short patient survival', 'CPA', (68, 90))
143883	32067422	More interestingly, we found that LGG had the highest number of CpGs whose methylation level was associated with patient survival (i.e., hypermethylation of CpGs in the gene body with better survival), which has not been reported before.	('patient', 'Species', '9606', (113, 120))	('methylation', 'MPA', (75, 86))	('hypermethylation', 'Var', (137, 153))	('patient survival', 'CPA', (113, 129))	('associated', 'Reg', (97, 107))
143884	32067422	COAD and PAAD had very few EGFR mutations in this TCGA dataset.	('PAAD', 'Phenotype', 'HP:0006725', (9, 13))	('COAD', 'Disease', (0, 4))	('EGFR', 'Gene', (27, 31))	('mutations', 'Var', (32, 41))	('COAD', 'Disease', 'MESH:D029424', (0, 4))
143885	32067422	However, high EGFR expression was significantly associated with short patient survival.	('patient', 'Species', '9606', (70, 77))	('expression', 'MPA', (19, 29))	('EGFR', 'Gene', (14, 18))	('high', 'Var', (9, 13))
143887	32067422	Squamous cell carcinomas in the head and neck (HNSC), lung (LUSC), and esophagus (ESCA) have some commonalities: significantly increased EGFR expression, high frequency of EGFR amplification, and low rate of SNV/indel mutations.	('EGFR', 'Gene', (137, 141))	('carcinomas', 'Phenotype', 'HP:0030731', (14, 24))	('amplification', 'Var', (177, 190))	('rat', 'Species', '10116', (200, 203))	('Squamous cell carcinoma', 'Phenotype', 'HP:0002860', (0, 23))	('EGFR', 'Gene', (172, 176))	('Squamous cell carcinomas', 'Phenotype', 'HP:0002860', (0, 24))	('HNSC', 'Phenotype', 'HP:0012288', (47, 51))	('Squamous cell carcinomas', 'Disease', 'MESH:D002294', (0, 24))	('Squamous cell carcinomas', 'Disease', (0, 24))	('esophagus', 'Disease', (71, 80))	('expression', 'MPA', (142, 152))	('lung', 'Disease', (54, 58))	('increased', 'PosReg', (127, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (14, 23))
143892	32067422	Our analysis provides a comprehensive view of EGFR mutation, abnormal expression, DNA methylation, and their interplay and clinical implications for 32 cancer types covering over ten thousand tumor samples.	('tumor', 'Disease', (192, 197))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('cancer', 'Disease', (152, 158))	('mutation', 'Var', (51, 59))	('EGFR', 'Gene', (46, 50))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))
143893	32067422	While some alternations are involved more in tumorigenesis, others are more therapeutic.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumor', 'Disease', (45, 50))	('involved', 'Reg', (28, 36))	('alternations', 'Var', (11, 23))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
143894	32067422	Some cancer types have a higher frequency of EGFR alternations where mutation, amplification, or abnormal expression is associated with outcome or indicated for clinical action.	('associated', 'Reg', (120, 130))	('cancer', 'Disease', 'MESH:D009369', (5, 11))	('EGFR', 'Gene', (45, 49))	('alternations', 'Var', (50, 62))	('cancer', 'Disease', (5, 11))	('abnormal expression', 'MPA', (97, 116))	('mutation', 'Var', (69, 77))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))	('amplification', 'Var', (79, 92))
143908	31827646	Eighteen upregulated miRNAs (miR-375, miR-200b-3p, miR-24-3p, miR-483-5p, miR-29b, miR-191-5p, miR-374b-5p, miR-425-5p, miR-22, miR-572, miR-638, miR-1234, miR-103, miR-29a, mir-let-7c, miR-196a, miR-17, and miR-20a) and four downregulated miRNAs (miR-9, miR-187*, miR-29c, and miR-223) were found associated with very poor survival in head and neck cancers.	('head and neck cancers', 'Phenotype', 'HP:0012288', (336, 357))	('miR-483-5p', 'Var', (62, 72))	('miR-29b', 'Gene', (74, 81))	('miR-187', 'Gene', '406963', (255, 262))	('miR-187', 'Gene', (255, 262))	('cancer', 'Phenotype', 'HP:0002664', (350, 356))	('miR-572', 'Gene', (128, 135))	('miR-191', 'Gene', '406966', (83, 90))	('miR-425', 'Gene', (108, 115))	('miR-223', 'Gene', (278, 285))	('miR-191', 'Gene', (83, 90))	('miR-103', 'Var', (156, 163))	('cancers', 'Phenotype', 'HP:0002664', (350, 357))	('miR-22', 'Gene', '407004', (120, 126))	('miR-374b', 'Gene', (95, 103))	('miR-29c', 'Gene', '407026', (265, 272))	('miR-196a', 'Var', (186, 194))	('miR-22', 'Gene', (120, 126))	('miR-1234', 'Gene', (146, 154))	('miR-20a', 'Gene', (208, 215))	('mir-let-7c', 'Gene', (174, 184))	('miR-572', 'Gene', '693157', (128, 135))	('miR-22', 'Gene', '407004', (278, 284))	('miR-20a', 'Gene', '406982', (208, 215))	('head and neck cancer', 'Phenotype', 'HP:0012288', (336, 356))	('miR-17', 'Gene', '406952', (196, 202))	('miR-200b-3p', 'Var', (38, 49))	('miR-22', 'Gene', (278, 284))	('miR-29b', 'Gene', '407024', (74, 81))	('mir-let-7c', 'Gene', '406885', (174, 184))	('miR-29c', 'Gene', (265, 272))	('poor', 'NegReg', (319, 323))	('miR-374b', 'Gene', '100126317', (95, 103))	('miR-638', 'Gene', (137, 144))	('miR-223', 'Gene', '407008', (278, 285))	('upregulated', 'PosReg', (9, 20))	('miR-29a', 'Gene', (165, 172))	('miR-29a', 'Gene', '407021', (165, 172))	('miR-375', 'Var', (29, 36))	('miR-9', 'Var', (248, 253))	('miR-24-3p', 'Var', (51, 60))	('miR-425', 'Gene', '494337', (108, 115))	('miR-638', 'Gene', '693223', (137, 144))	('miR-17', 'Gene', (196, 202))	('miR-1234', 'Gene', '100302196', (146, 154))
143912	31827646	Similarly, high levels of miR-9 in esophageal squamous cell carcinoma (ESCC) tumor tissue specimens were strongly associated with clinical progression, lymph node metastasis, and poor overall survival.	('high levels', 'Var', (11, 22))	('lymph node metastasis', 'CPA', (152, 173))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (35, 69))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (46, 69))	('overall survival', 'CPA', (184, 200))	('miR-9', 'Gene', (26, 31))	('associated with', 'Reg', (114, 129))	('esophageal squamous cell carcinoma', 'Disease', (35, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (60, 69))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('clinical progression', 'CPA', (130, 150))
143915	31827646	Many studies have reported the association of miR-483-5p with patient's clinicopathological characteristics and prognosis in several cancer types such as multiple myeloma, NPC, and ESCC.	('multiple myeloma', 'Disease', (154, 170))	('NPC', 'Disease', (172, 175))	('multiple myeloma', 'Phenotype', 'HP:0006775', (154, 170))	('association', 'Interaction', (31, 42))	('ESCC', 'Disease', (181, 185))	('miR-483-5p', 'Var', (46, 56))	('NPC', 'Phenotype', 'HP:0100630', (172, 175))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('multiple myeloma', 'Disease', 'MESH:D009101', (154, 170))
143919	31827646	Although miR-21 and miR-155 were considered as one of the most studied oncogenic miRNAs for head and neck cancer prognosis, the studies selected in our meta-analysis did not analyse them individually.	('miR-155', 'Gene', '406947', (20, 27))	('miR-155', 'Gene', (20, 27))	('miR-21', 'Var', (9, 15))	('head and neck cancer', 'Phenotype', 'HP:0012288', (92, 112))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
143920	31827646	Some reports show congruence between tissue and serum:for example, high expression of miR-29b was found to be significantly correlated with poor survival in both serum and tissue samples from oral cancer patients.	('high', 'Var', (67, 71))	('oral cancer', 'Disease', (192, 203))	('miR-29b', 'Gene', (86, 93))	('poor', 'NegReg', (140, 144))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('oral cancer', 'Disease', 'MESH:D009369', (192, 203))
143930	28331341	Increased apoptosis and decreased cell proliferation and migration were observed in the anti-PADI2 siRNA-treated MNK-45 cells, and increased cell proliferation and migration and decreased apoptosis were observed in the treated Bel-7402 cells with suppressed PADI2 expression.	('PADI2', 'Gene', (258, 263))	('decreased', 'NegReg', (24, 33))	('increased', 'PosReg', (131, 140))	('cell proliferation', 'CPA', (34, 52))	('rat', 'Species', '10116', (46, 49))	('rat', 'Species', '10116', (153, 156))	('rat', 'Species', '10116', (60, 63))	('MNK', 'Gene', '538', (113, 116))	('cell proliferation', 'CPA', (141, 159))	('Bel-7402', 'CellLine', 'CVCL:5492', (227, 235))	('rat', 'Species', '10116', (167, 170))	('anti-PADI2', 'Var', (88, 98))	('MNK', 'Gene', (113, 116))	('migration', 'CPA', (164, 173))
143931	28331341	PCR arrays and real-time PCR detected significantly decreased CXCR2 and EPO expression in the MNK-45 cells and Bel-7402 cells, respectively, with the anti-PADI2 siRNA treatments.	('anti-PADI2', 'Var', (150, 160))	('CXCR2', 'Gene', '3579', (62, 67))	('EPO', 'Gene', (72, 75))	('MNK', 'Gene', (94, 97))	('decreased', 'NegReg', (52, 61))	('Bel-7402', 'CellLine', 'CVCL:5492', (111, 119))	('CXCR2', 'Gene', (62, 67))	('EPO', 'Gene', '2056', (72, 75))	('MNK', 'Gene', '538', (94, 97))
143942	28331341	We recently reported that PADI2 is a gene susceptible to breast cancer risk, and its expression contributes to tumorigenesis via ACSL4, BINC3 and CA9 signaling.	('breast cancer', 'Disease', (57, 70))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('BINC3', 'MPA', (136, 141))	('breast cancer', 'Phenotype', 'HP:0003002', (57, 70))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('ACSL4', 'Gene', '2182', (129, 134))	('ACSL4', 'Gene', (129, 134))	('contributes', 'Reg', (96, 107))	('tumor', 'Disease', (111, 116))	('CA9', 'Gene', (146, 149))	('expression', 'Var', (85, 95))	('CA9', 'Gene', '768', (146, 149))	('PADI2', 'Gene', (26, 31))	('breast cancer', 'Disease', 'MESH:D001943', (57, 70))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
143973	28331341	MNK-45 and Bel-7402 tumor cells were transfected with the anti-PADI2 siRNAs at 20 nM using the HiPerFect transfection reagent (Qiagen).	('MNK', 'Gene', (0, 3))	('Bel-7402', 'CellLine', 'CVCL:5492', (11, 19))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('anti-PADI2', 'Var', (58, 68))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('MNK', 'Gene', '538', (0, 3))	('tumor', 'Disease', (20, 25))
144011	28331341	Compared with the Allstar siRNA-treated cells, the annexin V/PE and 7-AAD double staining detected significantly increased apoptosis in the anti-PADI2 siRNA-treated MNK-45 cells (P=4.98x10-5), but the analysis measured a considerably decreased apoptosis in the siRNA-treated Bel-7402 cells (P=3x10-4).	('decreased', 'NegReg', (234, 243))	('anti-PADI2', 'Var', (140, 150))	('MNK', 'Gene', (165, 168))	('7-AAD', 'Chemical', 'MESH:C025942', (68, 73))	('annexin V', 'Gene', '308', (51, 60))	('Bel-7402', 'CellLine', 'CVCL:5492', (275, 283))	('annexin V', 'Gene', (51, 60))	('apoptosis', 'CPA', (123, 132))	('PE', 'Chemical', '-', (61, 63))	('MNK', 'Gene', '538', (165, 168))
144013	28331341	The analysis detected a significantly decreased migration of MNK-45 cells when the PADI2 expression was suppressed by anti-PADI2 siRNA compared with the cells treated with Allstar siRNA (P=6.03x10-5); meanwhile, the assay observed a significantly increased cell migration in the siRNA-treated Bel-7402 cells (P=3.6x10-4).	('migration', 'CPA', (48, 57))	('decreased', 'NegReg', (38, 47))	('expression', 'MPA', (89, 99))	('PADI2', 'Gene', (83, 88))	('rat', 'Species', '10116', (51, 54))	('cell migration', 'CPA', (257, 271))	('MNK', 'Gene', '538', (61, 64))	('Bel-7402', 'CellLine', 'CVCL:5492', (293, 301))	('suppressed', 'NegReg', (104, 114))	('anti-PADI2', 'Var', (118, 128))	('increased', 'PosReg', (247, 256))	('rat', 'Species', '10116', (265, 268))	('MNK', 'Gene', (61, 64))
144028	28331341	Our study indicated that the single nucleotide polymorphisms rs2746533, rs2076616 and rs10788656 show significant differences in allele frequency, genotype frequency or both between breast cancer, cervical carcinoma, gastric carcinoma, lung cancer and rectal carcinoma cases and the controls, indicating that PADI2 has genetic susceptibility to these tumor risks.	('cervical carcinoma', 'Disease', (197, 215))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (217, 234))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('breast cancer', 'Phenotype', 'HP:0003002', (182, 195))	('rectal carcinoma', 'Phenotype', 'HP:0100743', (252, 268))	('cervical carcinoma', 'Disease', 'MESH:D002575', (197, 215))	('lung cancer', 'Disease', (236, 247))	('breast cancer', 'Disease', 'MESH:D001943', (182, 195))	('tumor', 'Disease', (351, 356))	('breast cancer', 'Disease', (182, 195))	('rs2746533', 'Mutation', 'rs2746533', (61, 70))	('tumor', 'Disease', 'MESH:D009369', (351, 356))	('rs2076616', 'Mutation', 'rs2076616', (72, 81))	('rectal carcinoma', 'Disease', (252, 268))	('carcinoma', 'Phenotype', 'HP:0030731', (206, 215))	('rs10788656', 'Mutation', 'rs10788656', (86, 96))	('lung cancer', 'Disease', 'MESH:D008175', (236, 247))	('carcinoma', 'Phenotype', 'HP:0030731', (259, 268))	('rectal carcinoma', 'Disease', 'MESH:D012004', (252, 268))	('rs2746533', 'Var', (61, 70))	('lung cancer', 'Phenotype', 'HP:0100526', (236, 247))	('tumor', 'Phenotype', 'HP:0002664', (351, 356))	('carcinoma', 'Phenotype', 'HP:0030731', (225, 234))	('gastric carcinoma', 'Disease', 'MESH:D013274', (217, 234))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('rs2076616', 'Var', (72, 81))	('gastric carcinoma', 'Disease', (217, 234))	('rs10788656', 'Var', (86, 96))	('differences', 'Reg', (114, 125))
144040	28331341	These reports are similar to our observation of decreased cell proliferation and cell migration in anti-PADI2-treated MNK-45 cells while CXCR2 expression was depressed.	('MNK', 'Gene', '538', (118, 121))	('rat', 'Species', '10116', (70, 73))	('CXCR2', 'Gene', '3579', (137, 142))	('cell proliferation', 'CPA', (58, 76))	('CXCR2', 'Gene', (137, 142))	('decreased', 'NegReg', (48, 57))	('MNK', 'Gene', (118, 121))	('rat', 'Species', '10116', (89, 92))	('cell migration', 'CPA', (81, 95))	('anti-PADI2-treated', 'Var', (99, 117))
144051	28331341	These reports correspond to our observation in which increased cell proliferation and cell migration were detected in anti-PADI2 siRNA-treated Bel-7402 cells with inhibited EPO expression.	('Bel-7402', 'CellLine', 'CVCL:5492', (143, 151))	('rat', 'Species', '10116', (94, 97))	('EPO', 'Gene', (173, 176))	('rat', 'Species', '10116', (75, 78))	('anti-PADI2', 'Var', (118, 128))	('cell proliferation', 'CPA', (63, 81))	('cell migration', 'CPA', (86, 100))	('increased', 'PosReg', (53, 62))	('EPO', 'Gene', '2056', (173, 176))	('inhibited', 'NegReg', (163, 172))
144054	28331341	The present study shows decreased cell proliferation and cell migration and increased apoptosis in anti-PADI2 siRNA MNK-45 cells with decreased CXCR2 expression.	('decreased', 'NegReg', (24, 33))	('CXCR2', 'Gene', '3579', (144, 149))	('rat', 'Species', '10116', (46, 49))	('cell proliferation', 'CPA', (34, 52))	('anti-PADI2', 'Var', (99, 109))	('CXCR2', 'Gene', (144, 149))	('MNK', 'Gene', '538', (116, 119))	('cell migration', 'CPA', (57, 71))	('MNK', 'Gene', (116, 119))	('apoptosis', 'CPA', (86, 95))	('rat', 'Species', '10116', (65, 68))
144056	28331341	We previously found that inhibiting PADI2 expression significantly increased the expression of CA9 and decreased the expression of ACSL4 and BIRC3 in MCF-7 cells, originating from breast cancer.	('BIRC3', 'Gene', (141, 146))	('ACSL4', 'Gene', '2182', (131, 136))	('inhibiting', 'Var', (25, 35))	('ACSL4', 'Gene', (131, 136))	('BIRC3', 'Gene', '330', (141, 146))	('expression', 'MPA', (117, 127))	('decreased', 'NegReg', (103, 112))	('breast cancer', 'Disease', 'MESH:D001943', (180, 193))	('increased', 'PosReg', (67, 76))	('MCF-7', 'CellLine', 'CVCL:0031', (150, 155))	('CA9', 'Gene', (95, 98))	('breast cancer', 'Disease', (180, 193))	('PADI2', 'Gene', (36, 41))	('breast cancer', 'Phenotype', 'HP:0003002', (180, 193))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('CA9', 'Gene', '768', (95, 98))	('expression', 'MPA', (81, 91))
144057	28331341	Inhibiting PADI2 expression also significantly decreased the cell migration ability of MCF-7 cells but did not affect cell proliferation and apoptosis.	('PADI2', 'Gene', (11, 16))	('Inhibiting', 'Var', (0, 10))	('cell migration ability', 'CPA', (61, 83))	('MCF-7', 'CellLine', 'CVCL:0031', (87, 92))	('rat', 'Species', '10116', (130, 133))	('rat', 'Species', '10116', (69, 72))	('decreased', 'NegReg', (47, 56))
144084	26848256	In addition, high levels of FRalpha expression appear to be associated with aggressive cancers.	('high', 'Var', (13, 17))	('aggressive cancers', 'Disease', 'MESH:D009369', (76, 94))	('aggressive cancers', 'Disease', (76, 94))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cancers', 'Phenotype', 'HP:0002664', (87, 94))	('FRalpha', 'Protein', (28, 35))	('associated', 'Reg', (60, 70))
144127	26848256	The feasibility of FRalpha detection using LK26 (the mouse parent of farletuzumab) or 26B3 monoclonal antibodies was demonstrated in SK-OV-3 and HCT-116 tumor cells using two methods: flow cytometry and LSC.	('HCT-116', 'CellLine', 'CVCL:0291', (145, 152))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('26B3', 'Gene', (86, 90))	('LK26', 'Var', (43, 47))	('mouse', 'Species', '10090', (53, 58))	('farletuzumab', 'Chemical', 'MESH:C527484', (69, 81))	('SK-OV-3', 'CellLine', 'CVCL:0532', (133, 140))
144138	26848256	CellSearch  enrichment is dependent on the expression of antibody accessible EpCAM on the cell, whereas ApoStream  enrichment is antibody independent and relies on a generalized physical property of tumor cells.	('tumor', 'Disease', (199, 204))	('antibody', 'Var', (57, 65))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('EpCAM', 'Gene', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('EpCAM', 'Gene', '4072', (77, 82))
144166	26848256	All CK+CD45- CTCs recovered from blood samples from ovarian cancer patients were FRalpha+, while no FRalpha expression was detected in the CK+CD45- CTCs from squamous lung cancer patients demonstrate that the FRalpha CTC assay was specific for FRalpha.	('ovarian cancer', 'Disease', (52, 66))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('CD45', 'Gene', (142, 146))	('squamous lung cancer', 'Disease', 'MESH:D008175', (158, 178))	('patients', 'Species', '9606', (67, 75))	('lung cancer', 'Phenotype', 'HP:0100526', (167, 178))	('squamous lung cancer', 'Phenotype', 'HP:0030359', (158, 178))	('ovarian cancer', 'Phenotype', 'HP:0100615', (52, 66))	('CD45', 'Gene', '5788', (7, 11))	('squamous lung cancer', 'Disease', (158, 178))	('CD45', 'Gene', '5788', (142, 146))	('ovarian cancer', 'Disease', 'MESH:D010051', (52, 66))	('patients', 'Species', '9606', (179, 187))	('FRalpha+', 'Var', (81, 89))	('CD45', 'Gene', (7, 11))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
144169	26848256	Both the proportion of FRalpha+ cells and the level of FRalpha expression on those cells may have clinical implications as, for example, in HER2 positivity in breast cancer where the percentage of positive cells and the degree of positivity dictate eligibility to anti-HER2 therapy.	('HER2', 'Gene', (269, 273))	('HER2', 'Gene', '2064', (269, 273))	('breast cancer', 'Phenotype', 'HP:0003002', (159, 172))	('positivity', 'Var', (145, 155))	('breast cancer', 'Disease', 'MESH:D001943', (159, 172))	('HER2', 'Gene', (140, 144))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('breast cancer', 'Disease', (159, 172))	('dictate', 'Reg', (241, 248))	('HER2', 'Gene', '2064', (140, 144))
144300	27478431	In terms of the depth of invasion, T2, T3, T4a, and T4b occurred in 1 (6.7%), 9 (60%), 3 (20%), and 2 (13.3%) patients, respectively, regional lymph nodes metastases of N1, N2, and N3 occurred in 3 (20%), 1 (6.7%), and 3 (20%) cases, respectively, and stages IB, IIA, IIB, IIIA, IIIB, IIIC, and IV were detected in 1 (6.7%), 5 (33.3%), 2 (13.3%), 1 (6.7%), 3 (20%), 2 (13.3%), and 1 (6.7%) patients, respectively.	('patients', 'Species', '9606', (390, 398))	('metastases', 'Disease', 'MESH:D009362', (155, 165))	('T4b', 'Var', (52, 55))	('T4a', 'Var', (43, 46))	('patients', 'Species', '9606', (110, 118))	('metastases', 'Disease', (155, 165))
144344	26427800	Especially, PLGA/NR7 NP exhibited a superior apoptosis effect in HN6 cancer cells with around ~45 % (early and late apoptotic stage) and ~59 % after 24 and 48 h incubation, respectively.	('apoptosis effect', 'CPA', (45, 61))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('HN6', 'CellLine', 'CVCL:5516', (65, 68))	('PLGA/NR7 NP', 'Var', (12, 23))	('cancer', 'Disease', (69, 75))
144361	26427800	Several studies have reported that nanosized PLGA-PEG NP would effectively increase the intracellular concentration of anticancer drugs by enhancing the blood circulation time of nanocarriers and avoids the reticuloendothelial system (RES) mediated clearance.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('blood circulation', 'CPA', (153, 170))	('increase the intracellular concentration', 'Phenotype', 'HP:0003575', (75, 115))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('nanosized PLGA-PEG NP', 'Var', (35, 56))	('avoids', 'NegReg', (196, 202))	('PEG', 'Chemical', 'MESH:D011092', (50, 53))	('cancer', 'Disease', (123, 129))	('increase', 'PosReg', (75, 83))	('enhancing', 'PosReg', (139, 148))
144368	26427800	We expected that when NR7-conjugated delivery system is administered, it will enhance the overall chemotherapeutic efficiency in cancers.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('enhance', 'PosReg', (78, 85))	('cancers', 'Disease', 'MESH:D009369', (129, 136))	('chemotherapeutic efficiency', 'CPA', (98, 125))	('cancers', 'Phenotype', 'HP:0002664', (129, 136))	('cancers', 'Disease', (129, 136))	('NR7-conjugated', 'Var', (22, 36))
144376	26427800	Studies have shown that nanocarriers caused better selective accumulation of CDDP in tumors while lessening its distribution in normal tissue.	('lessening', 'NegReg', (98, 107))	('CDDP', 'Var', (77, 81))	('CDDP', 'Chemical', '-', (77, 81))	('distribution', 'MPA', (112, 124))	('tumors', 'Disease', (85, 91))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('tumors', 'Disease', 'MESH:D009369', (85, 91))
144398	26427800	Notably, NR7 conjugated polymeric nanoparticle showed significantly (p < 0.01) higher cellular uptake than that of non-targeted PLGA NP.	('higher', 'PosReg', (79, 85))	('polymer', 'Chemical', 'MESH:D011108', (24, 31))	('NR7 conjugated polymeric', 'Var', (9, 33))	('cellular uptake', 'CPA', (86, 101))
144410	26427800	Specifically, PLGA/NR7 NP showed a significantly (p < 0.01) higher cytotoxic effect than compared to either free CDDP or PLGA NP.	('CDDP', 'Chemical', '-', (113, 117))	('cytotoxic effect', 'CPA', (67, 83))	('PLGA/NR7 NP', 'Var', (14, 25))	('higher', 'PosReg', (60, 66))
144508	33758232	Heart V10 > 84% was also associated with worse PFS (p = 0.005), DSS (p = 0.01) and FFDM (p = 0.021), but was not associated with FFLR (see Supplementary Fig.	('DSS', 'Disease', (64, 67))	('PFS', 'MPA', (47, 50))	('Heart V10 > 84%', 'Var', (0, 15))	('FFDM', 'Disease', (83, 87))	('DSS', 'Chemical', '-', (64, 67))
144510	33758232	Follow-up NLR > 7.4 was also associated with worse PFS (p = 0.024) and DSS (p = 0.011) but not associated with FFDM or FFLR (see Supplementary Fig.	('PFS', 'MPA', (51, 54))	('NLR', 'Var', (10, 13))	('DSS', 'Chemical', '-', (71, 74))	('DSS', 'Disease', (71, 74))
144517	33758232	There are limited data about the relationship between heart dose and survival outcomes in esophageal cancer, and heart V30 > 45% is found to be independently associated with worse survival.	('esophageal cancer', 'Disease', (90, 107))	('esophageal cancer', 'Disease', 'MESH:D004938', (90, 107))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('heart V30 > 45%', 'Var', (113, 128))
144518	33758232	Moreover, based on the data for lung cancer, the RTOG 0617 trial suggested heart V5 and heart V30 were associated with an increased risk of death.	('heart V30', 'Var', (88, 97))	('heart V5', 'Var', (75, 83))	('associated', 'Reg', (103, 113))	('death', 'Disease', 'MESH:D003643', (140, 145))	('death', 'Disease', (140, 145))	('lung cancer', 'Disease', 'MESH:D008175', (32, 43))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('lung cancer', 'Disease', (32, 43))	('lung cancer', 'Phenotype', 'HP:0100526', (32, 43))
144554	31906954	Genome-wide analysis reveals the association between alternative splicing and DNA methylation across human solid tumors Dysregulation of alternative splicing (AS) is a critical signature of cancer.	('cancer', 'Disease', (190, 196))	('Dysregulation', 'Var', (120, 133))	('cancer', 'Disease', 'MESH:D009369', (190, 196))	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('tumors', 'Disease', (113, 119))	('human', 'Species', '9606', (101, 106))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
144559	31906954	The different DNA methylation patterns between tumor and normal tissues at the corresponding alternative spliced exon boundaries were shown, and 51.3% of CpG sites (CpGs) revealed hypomethylated in tumors.	('methyl', 'Chemical', 'MESH:C031105', (18, 24))	('hypomethylated', 'Var', (180, 194))	('methyl', 'Chemical', 'MESH:C031105', (184, 190))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumors', 'Disease', 'MESH:D009369', (198, 204))	('tumors', 'Disease', (198, 204))	('tumor', 'Disease', (198, 203))	('tumors', 'Phenotype', 'HP:0002664', (198, 204))	('tumor', 'Disease', (47, 52))
144560	31906954	Notably, 607 CpGs were found to be highly correlated with 369 cancer-specific AS events after permutation tests.	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('CpGs', 'Var', (13, 17))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('correlated', 'Reg', (42, 52))
144561	31906954	Among them, the hypomethylated CpGs account for 52.7%, and the number of down-regulated exons was 173.	('down-regulated', 'NegReg', (73, 87))	('methyl', 'Chemical', 'MESH:C031105', (20, 26))	('hypomethylated', 'Var', (16, 30))
144566	31906954	Several lines of evidence have shown that the disruption of AS is frequently associated with the inactivation of tumor suppressors and activation of oncogenes.	('tumor', 'Disease', (113, 118))	('disruption', 'Var', (46, 56))	('inactivation', 'Var', (97, 109))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('associated', 'Reg', (77, 87))
144570	31906954	Other studies have also reported the prognostic value of AS events in multiple cancer types, such as ovarian cancer, breast cancer, glioblastma and gastrointestinal adenocarcinomas, suggesting a predominant role of splicing dysregulation in cancers.	('glioblastma and gastrointestinal adenocarcinomas', 'Disease', 'MESH:D005767', (132, 180))	('carcinoma', 'Phenotype', 'HP:0030731', (170, 179))	('splicing dysregulation', 'Var', (215, 237))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('ovarian cancer', 'Disease', (101, 115))	('breast cancer', 'Disease', 'MESH:D001943', (117, 130))	('cancer type', 'Disease', (79, 90))	('cancers', 'Phenotype', 'HP:0002664', (241, 248))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('breast cancer', 'Disease', (117, 130))	('breast cancer', 'Phenotype', 'HP:0003002', (117, 130))	('cancers', 'Disease', 'MESH:D009369', (241, 248))	('cancer type', 'Disease', 'MESH:D009369', (79, 90))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('ovarian cancer', 'Phenotype', 'HP:0100615', (101, 115))	('ovarian cancer', 'Disease', 'MESH:D010051', (101, 115))	('cancers', 'Disease', (241, 248))
144575	31906954	have found that DNA methylation could affect the splicing of more than 20% of alternative exons.	('splicing of', 'MPA', (49, 60))	('methylation', 'Var', (20, 31))	('methyl', 'Chemical', 'MESH:C031105', (20, 26))	('affect', 'Reg', (38, 44))
144585	31906954	To further understand the function and mechanism of the genes containing methylation-associated cancer-specific AS events, functional enrichment, and network analyses were applied.	('methyl', 'Chemical', 'MESH:C031105', (73, 79))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('methylation-associated', 'Var', (73, 95))	('cancer', 'Disease', (96, 102))
144600	31906954	Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were conducted on genes with methylation-associated cancer-specific AS events using "ClusterProfiler" package in R software.	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('methylation-associated', 'Var', (127, 149))	('cancer', 'Disease', (150, 156))	('methyl', 'Chemical', 'MESH:C031105', (127, 133))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
144605	31906954	Splicing alterations were most abundant in KIRC and LUAD, while least in COAD (Additional file 1: Table S2).	('COAD', 'Disease', 'MESH:D015179', (73, 77))	('KIRC', 'Disease', (43, 47))	('KIRC', 'Disease', 'MESH:D002292', (43, 47))	('LUAD', 'Disease', (52, 56))	('LUAD', 'Disease', 'MESH:C538231', (52, 56))	('LUAD', 'Phenotype', 'HP:0030078', (52, 56))	('COAD', 'Disease', (73, 77))	('Splicing alterations', 'Var', (0, 20))
144616	31906954	Taken together, hypomethylation was a more frequently observed form of differential methylation in tumor tissues, compared to hypermethylation.	('tumor', 'Disease', (99, 104))	('methyl', 'Chemical', 'MESH:C031105', (131, 137))	('methyl', 'Chemical', 'MESH:C031105', (84, 90))	('differential methylation', 'MPA', (71, 95))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('hypomethylation', 'Var', (16, 31))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('methyl', 'Chemical', 'MESH:C031105', (20, 26))
144619	31906954	After performing the permutation test, 891 CpGs were found to be highly correlated with 483 cancer-specific AS events (permuted P < 0.05) (Additional file 1: Table S4).	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('correlated', 'Interaction', (72, 82))	('CpGs', 'Var', (43, 47))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
144622	31906954	Among them, 320 CpGs were hypomethylated, and 287 were hypermethylated in tumor tissues.	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('hypomethylated', 'Var', (26, 40))	('methyl', 'Chemical', 'MESH:C031105', (30, 36))	('tumor', 'Disease', (74, 79))	('methyl', 'Chemical', 'MESH:C031105', (60, 66))
144623	31906954	Expect for COAD, LIHC, LUAD, LUSC, and PRAD, the hypomethylated CpGs account for more than half of AS-associated CpGs in cancers (ranging from 54.5 to 95.7%)(Additional file 2: Figure S1-A).	('PRAD', 'Disease', (39, 43))	('cancers', 'Disease', (121, 128))	('cancers', 'Disease', 'MESH:D009369', (121, 128))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('COAD', 'Disease', 'MESH:D015179', (11, 15))	('LUSC', 'Disease', 'MESH:D002294', (29, 33))	('methyl', 'Chemical', 'MESH:C031105', (53, 59))	('COAD', 'Disease', (11, 15))	('LIHC', 'Disease', (17, 21))	('PRAD', 'Disease', 'MESH:D011471', (39, 43))	('LUSC', 'Disease', (29, 33))	('LUAD', 'Disease', (23, 27))	('LUAD', 'Phenotype', 'HP:0030078', (23, 27))	('LUAD', 'Disease', 'MESH:C538231', (23, 27))	('LIHC', 'Disease', 'MESH:D006528', (17, 21))	('cancers', 'Phenotype', 'HP:0002664', (121, 128))	('hypomethylated', 'Var', (49, 63))
144629	31906954	The CpG site, cg11269599, also showed significantly hypermethylated in HNSC, KIRC, KIRP, LUSC, and PRAD.	('PRAD', 'Disease', (99, 103))	('KIRC', 'Disease', (77, 81))	('KIRC', 'Disease', 'MESH:D002292', (77, 81))	('LUSC', 'Disease', (89, 93))	('PRAD', 'Disease', 'MESH:D011471', (99, 103))	('methyl', 'Chemical', 'MESH:C031105', (57, 63))	('hypermethylated', 'PosReg', (52, 67))	('cg11269599', 'Var', (14, 24))	('LUSC', 'Disease', 'MESH:D002294', (89, 93))	('KIRP', 'Disease', (83, 87))	('KIRP', 'Disease', 'MESH:D007681', (83, 87))
144645	31906954	14 (20.6%) CpGs in 8 (21.1%) AS exons were found significantly associated with the overall survival of cancer patients.	('CpGs', 'Var', (11, 15))	('overall survival', 'CPA', (83, 99))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('associated with', 'Reg', (63, 78))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('patients', 'Species', '9606', (110, 118))
144648	31906954	The boundaries of alternatively spliced exons were more likely to be hypomethylated in tumor tissues compared with adjacent normal tissues.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('methyl', 'Chemical', 'MESH:C031105', (73, 79))	('tumor', 'Disease', (87, 92))	('alternatively spliced exons', 'Var', (18, 45))	('hypomethylated', 'MPA', (69, 83))	('tumor', 'Disease', 'MESH:D009369', (87, 92))
144659	31906954	We performed an association analysis between cancer-specific AS events and CpGs at their exon boundaries.	('cancer', 'Disease', (45, 51))	('CpGs', 'Var', (75, 79))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))
144667	31906954	These signatures were potential candidates for actively selected variants, which might drive tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('variants', 'Var', (65, 73))	('tumor', 'Disease', (93, 98))	('drive', 'PosReg', (87, 92))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
144668	31906954	For example, we found the consistent changes of AS event and cg11269599 in gene ZNF577 (zinc finger protein 577) across several tumor types.	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('cg11269599', 'Var', (61, 71))	('zinc finger protein 577', 'Gene', (88, 111))	('changes', 'Reg', (37, 44))	('ZNF577', 'Gene', (80, 86))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('ZNF577', 'Gene', '84765', (80, 86))	('tumor', 'Disease', (128, 133))	('zinc finger protein 577', 'Gene', '84765', (88, 111))
144671	31906954	It has been suggested that DNA methylation at exonic regions could affect the binding of methyl-sensitive DNA-binding proteins, such as MeCp2, CTCF, and HP1.	('binding', 'Interaction', (78, 85))	('methyl', 'Chemical', 'MESH:C031105', (89, 95))	('methyl', 'Chemical', 'MESH:C031105', (31, 37))	('MeCp2', 'Gene', (136, 141))	('HP1', 'Gene', '23468', (153, 156))	('CTCF', 'Gene', '10664', (143, 147))	('HP1', 'Gene', (153, 156))	('affect', 'Reg', (67, 73))	('methylation', 'Var', (31, 42))	('MeCp2', 'Gene', '4204', (136, 141))	('CTCF', 'Gene', (143, 147))
144673	31906954	found the DNA methylation-mediated splicing of CD45 pre-mRNA, which inhibited CTCF binding.	('CTCF', 'Gene', '10664', (78, 82))	('CD45', 'Gene', '5788', (47, 51))	('methylation-mediated splicing', 'Var', (14, 43))	('methyl', 'Chemical', 'MESH:C031105', (14, 20))	('CD45', 'Gene', (47, 51))	('CTCF', 'Gene', (78, 82))
144675	31906954	In addition, DNA methylation had also been reported to determine nucleosome positioning and affected the transcriptional elongation rate.	('affected', 'Reg', (92, 100))	('methylation', 'Var', (17, 28))	('transcriptional', 'MPA', (105, 120))	('determine', 'Reg', (55, 64))	('methyl', 'Chemical', 'MESH:C031105', (17, 23))	('nucleosome positioning', 'MPA', (65, 87))
144677	31906954	We found 38 methylation-related cancer-specific AS events could significantly distinguish patients with longer versus shorter survival prognoses.	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('cancer', 'Disease', (32, 38))	('methyl', 'Chemical', 'MESH:C031105', (12, 18))	('methylation-related', 'Var', (12, 31))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('patients', 'Species', '9606', (90, 98))
144683	31906954	Additionally, 14 CpGs at the exon boundaries of 8 survival-related AS also showed significant association with overall survival, even after adjusting for age, gender, TNM stage, and adjuvant therapy.	('TNM', 'Gene', (167, 170))	('overall survival', 'MPA', (111, 127))	('TNM', 'Gene', '10178', (167, 170))	('CpGs', 'Var', (17, 21))
144684	31906954	These results led us to speculate that the identified CpGs might be the specific cancer drivers, and serve as prognostic biomarkers for cancers.	('cancers', 'Phenotype', 'HP:0002664', (136, 143))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('CpGs', 'Var', (54, 58))	('cancers', 'Disease', (136, 143))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('cancer', 'Disease', (81, 87))	('cancers', 'Disease', 'MESH:D009369', (136, 143))	('cancer', 'Disease', (136, 142))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
144691	31906954	Overall, our analyses identified a significant association between DNA methylation and cancer-specific AS events.	('cancer', 'Disease', (87, 93))	('methylation', 'Var', (71, 82))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('DNA', 'Protein', (67, 70))	('methyl', 'Chemical', 'MESH:C031105', (71, 77))	('cancer', 'Disease', 'MESH:D009369', (87, 93))
144692	31906954	The present study contributes to the understanding of the role of methylation in exon usage during transcriptional process and carcinogenesis.	('methylation', 'Var', (66, 77))	('carcinogenesis', 'Disease', (127, 141))	('carcinogenesis', 'Disease', 'MESH:D063646', (127, 141))	('methyl', 'Chemical', 'MESH:C031105', (66, 72))
144713	31835584	When GPR15 controls the homing of FOXP3+ regulatory T cells (Tregs) to the large intestine lamina propria, it alleviates colonic inflammation.	('alleviates', 'NegReg', (110, 120))	('colonic inflammation', 'Disease', 'MESH:D007249', (121, 141))	('colonic inflammation', 'Disease', (121, 141))	('FOXP3', 'Gene', (34, 39))	('homing', 'CPA', (24, 30))	('FOXP3', 'Gene', '50943', (34, 39))	('GPR15', 'Var', (5, 10))
144728	31835584	It is most frequently mutated in uterine corpus endometrial carcinoma (UCEC), uterine carcinosarcoma (UCS), lung squamous carcinoma (LUSC), rectal adenocarcinoma (READ), and colon adenocarcinoma (COAD) (Figure 1A).	('carcinoma', 'Phenotype', 'HP:0030731', (152, 161))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (48, 69))	('READ', 'Disease', (163, 167))	('carcinosarcoma', 'Disease', 'MESH:D002296', (86, 100))	('mutated', 'Var', (22, 29))	('colon adenocarcinoma', 'Disease', (174, 194))	('LUSC', 'Disease', (133, 137))	('UCS', 'Phenotype', 'HP:0002891', (102, 105))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (78, 100))	('rectal adenocarcinoma', 'Disease', 'MESH:D012004', (140, 161))	('READ', 'Disease', 'MESH:D012004', (163, 167))	('LUSC', 'Disease', 'MESH:D002294', (133, 137))	('colon adenocarcinoma', 'Disease', 'MESH:D015179', (174, 194))	('LUSC', 'Phenotype', 'HP:0030359', (133, 137))	('COAD', 'Disease', (196, 200))	('lung squamous carcinoma', 'Phenotype', 'HP:0030359', (108, 131))	('endometrial carcinoma', 'Disease', (48, 69))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (113, 131))	('rectal adenocarcinoma', 'Disease', (140, 161))	('lung squamous carcinoma', 'Disease', (108, 131))	('COAD', 'Disease', 'MESH:D015179', (196, 200))	('carcinoma', 'Phenotype', 'HP:0030731', (60, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (48, 69))	('lung squamous carcinoma', 'Disease', 'MESH:D002294', (108, 131))	('carcinoma', 'Phenotype', 'HP:0030731', (185, 194))	('carcinosarcoma', 'Disease', (86, 100))
144730	31835584	Most mutations in GPR15 are missense mutations while the minority mutational pattern is heterogenous, and the variant classification varies from frameshift deletion (COAD), frameshift insertion (LUSC), and nonsense mutation (LUSC, READ) to missense mutation (Figure 2).	('LUSC', 'Phenotype', 'HP:0030359', (195, 199))	('missense mutation', 'Var', (240, 257))	('READ', 'Disease', (231, 235))	('COAD', 'Disease', 'MESH:D015179', (166, 170))	('mutations', 'Var', (5, 14))	('frameshift deletion', 'Var', (145, 164))	('LUSC', 'Disease', (225, 229))	('GPR15', 'Gene', (18, 23))	('frameshift insertion', 'Var', (173, 193))	('missense mutations', 'Var', (28, 46))	('COAD', 'Disease', (166, 170))	('nonsense mutation', 'Var', (206, 223))	('LUSC', 'Disease', 'MESH:D002294', (225, 229))	('READ', 'Disease', 'MESH:D012004', (231, 235))	('LUSC', 'Phenotype', 'HP:0030359', (225, 229))	('LUSC', 'Disease', 'MESH:D002294', (195, 199))	('LUSC', 'Disease', (195, 199))
144731	31835584	Moreover, it is worth noting that GPR15 in COAD is both hypermutated and significantly downregulated compared to that in normal tissues.	('COAD', 'Disease', (43, 47))	('GPR15', 'Var', (34, 39))	('downregulated', 'NegReg', (87, 100))	('COAD', 'Disease', 'MESH:D015179', (43, 47))
144732	31835584	This pattern implies that alterations in GPR15-meditor T-cell homing may have undiscovered effects on the pathophysiology of COAD.	('COAD', 'Disease', 'MESH:D015179', (125, 129))	('COAD', 'Disease', (125, 129))	('alterations', 'Var', (26, 37))	('effects', 'Reg', (91, 98))	('GPR15-meditor', 'Gene', (41, 54))
144735	31835584	Integrated network analysis revealed that, apart from immunity control, GPR15 may have effects on cell growth, thereby affecting carcinogenesis.	('GPR15', 'Var', (72, 77))	('carcinogenesis', 'Disease', 'MESH:D063646', (129, 143))	('effects', 'Reg', (87, 94))	('carcinogenesis', 'Disease', (129, 143))	('affecting', 'Reg', (119, 128))	('cell growth', 'CPA', (98, 109))
144744	31835584	GPR15 can reduce the inflammation level in the large intestine by controlling T-cell homing.	('T-cell homing', 'CPA', (78, 91))	('inflammation', 'Disease', 'MESH:D007249', (21, 33))	('inflammation', 'Disease', (21, 33))	('GPR15', 'Var', (0, 5))	('reduce', 'NegReg', (10, 16))
144763	31835584	We found that TRP89, SER109, ARG172, LYS180, CYS183, TRP195, PHE257, and LYS261 residues were located in the active region in GPR15.	('LYS261', 'CellLine', 'CVCL:2490', (73, 79))	('PHE257', 'Var', (61, 67))	('CYS183', 'Var', (45, 51))	('GPR15', 'Gene', (126, 131))	('TRP89', 'Var', (14, 19))	('ARG172', 'Var', (29, 35))	('LYS180', 'Var', (37, 43))	('SER109', 'Var', (21, 27))	('ARG172', 'Chemical', 'MESH:C545206', (29, 35))	('CYS183', 'Chemical', 'MESH:C082474', (45, 51))	('LYS261 residues', 'Var', (73, 88))	('PHE257', 'Chemical', 'MESH:C040798', (61, 67))	('TRP195', 'Var', (53, 59))
144765	31835584	Compound 5 showed more than 90% salt bridge interaction with Lys261 (Figure S9) in the MD trajectories.	('Lys261', 'Var', (61, 67))	('Lys261', 'Chemical', 'MESH:C046598', (61, 67))	('salt bridge interaction', 'MPA', (32, 55))
144766	31835584	The fluctuation in RMSD was further supported by the MM/PBSA results (Table S4), which showed that compound 5 (C34H47O6N3) had a stronger binding affinity (lowest binding free energy) among the hits with consistently lower RMSD values.	('C34H47O6N3', 'Chemical', 'MESH:C010808', (111, 121))	('stronger', 'PosReg', (129, 137))	('binding', 'Interaction', (163, 170))	('C34H47O6N3', 'Var', (111, 121))	('binding affinity', 'Interaction', (138, 154))
144775	31835584	GPR15 was proven to mediate regulatory T cells (Tregs) to migrate to the large intestine and reduce inflammation in the mouse model, but it is preferentially expressed on human effector T cells.	('inflammation', 'Disease', (100, 112))	('inflammation', 'Disease', 'MESH:D007249', (100, 112))	('GPR15', 'Var', (0, 5))	('reduce', 'NegReg', (93, 99))	('human', 'Species', '9606', (171, 176))	('mouse', 'Species', '10090', (120, 125))
144776	31835584	Further research supported that GPR15-dependent human CD8+ T cells can migrate into the inflamed gut, and GPR15 can also help dendritic epidermal T cells migrate to the skin.	('CD8', 'Gene', '925', (54, 57))	('help', 'PosReg', (121, 125))	('dendritic epidermal T', 'Disease', 'MESH:D007635', (126, 147))	('human', 'Species', '9606', (48, 53))	('dendritic epidermal T', 'Disease', (126, 147))	('inflamed gut', 'Phenotype', 'HP:0002037', (88, 100))	('GPR15', 'Var', (106, 111))	('CD8', 'Gene', (54, 57))
144785	31835584	MD simulation and free energy calculation conducted on the top eight compounds led to the discovery of the best compound, compund 5 (C34H47O6N3), which could be a hit for novel drugs targeting STAD.	('STAD', 'Disease', 'MESH:D013274', (193, 197))	('C34H47O6N3', 'Var', (133, 143))	('C34H47O6N3', 'Chemical', 'MESH:C010808', (133, 143))	('STAD', 'Disease', (193, 197))
144817	29954411	Molecular carcinogenesis of head and neck squamous cell carcinoma (HNSCC) is attributed to several cytogenetic alterations in oncogenes and receptors for growth factors including p53, p27, p16, cyclin D1, and epidermal growth factor receptor (EGFR).	('p53', 'Gene', (179, 182))	('cyclin D1', 'Gene', '595', (194, 203))	('SCC', 'Gene', (69, 72))	('HNSCC', 'Phenotype', 'HP:0012288', (67, 72))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (28, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (56, 65))	('EGFR', 'Gene', (243, 247))	('EGFR', 'Gene', '1956', (243, 247))	('epidermal growth factor receptor', 'Gene', (209, 241))	('SCC', 'Phenotype', 'HP:0002860', (69, 72))	('epidermal growth factor receptor', 'Gene', '1956', (209, 241))	('carcinogenesis of head and neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (10, 65))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (42, 65))	('p53', 'Gene', '7157', (179, 182))	('alterations', 'Var', (111, 122))	('cyclin D1', 'Gene', (194, 203))	('p16', 'Gene', (189, 192))	('SCC', 'Gene', '6317', (69, 72))	('p27', 'Gene', '3429', (184, 187))	('p27', 'Gene', (184, 187))	('p16', 'Gene', '1029', (189, 192))
144874	29954411	reported no significant association of EGFR over-expression with gene amplification by FISH or CISH.	('EGFR', 'Gene', (39, 43))	('over-expression', 'PosReg', (44, 59))	('gene amplification', 'Var', (65, 83))	('EGFR', 'Gene', '1956', (39, 43))
144882	27186987	Dysregulations in RBP-mediated mechanisms have been found to be associated with many steps of cancer initiation and progression.	('associated', 'Reg', (64, 74))	('steps of cancer initiation', 'Disease', (85, 111))	('steps of cancer initiation', 'Disease', 'MESH:D009369', (85, 111))	('RBP', 'Gene', (18, 21))	('Dysregulations', 'Var', (0, 14))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('RBP', 'Gene', '57794', (18, 21))
144884	27186987	To this end, we developed a lasso regression model that predicts gene expression in cancer by incorporating RBP-mediated regulation as well as the effects of other well-studied factors such as copy-number variation, DNA methylation, TFs and miRNAs.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('cancer', 'Disease', (84, 90))	('RBP', 'Gene', (108, 111))	('copy-number variation', 'Var', (193, 214))	('RBP', 'Gene', '57794', (108, 111))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))
144890	27186987	Aberrant gene expression is a main feature of cancer development.	('cancer', 'Disease', (46, 52))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('Aberrant gene', 'Var', (0, 13))
144892	27186987	Differential gene expression in cancer can occur due to several factors including copy-number variation (CNV), DNA methylation changes, and alterations in transcriptional and post-transcriptional regulatory mechanisms.	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('cancer', 'Disease', (32, 38))	('changes', 'Reg', (127, 134))	('copy-number variation', 'Var', (82, 103))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('alterations', 'Reg', (140, 151))
144905	27186987	These and many other example indicate that dysregulation of the function or the expression of RBPs has profound implications for cancer development.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('dysregulation', 'Var', (43, 56))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('RBP', 'Gene', (94, 97))	('RBP', 'Gene', '57794', (94, 97))	('implications', 'Reg', (112, 124))	('function', 'MPA', (64, 72))
144944	27186987	In particular, aberrant expression of RBPs have been found to be associated with cancer initiation and progression.	('aberrant expression', 'Var', (15, 34))	('cancer initiation', 'Disease', 'MESH:D009369', (81, 98))	('associated', 'Reg', (65, 75))	('cancer initiation', 'Disease', (81, 98))	('RBP', 'Gene', (38, 41))	('RBP', 'Gene', '57794', (38, 41))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('progression', 'CPA', (103, 114))
144953	27186987	Indeed, a recent study revealed FXR1 as a driver for non-small cell lung cancer (NSCLC), and showed that increased FXR1 promotes tumor progression, and is associated with poor survival.	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (53, 79))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (53, 79))	('increased', 'Var', (105, 114))	('FXR1', 'Gene', '8087', (115, 119))	('FXR1', 'Gene', '8087', (32, 36))	('non-small cell lung cancer', 'Disease', (53, 79))	('lung cancer', 'Phenotype', 'HP:0100526', (68, 79))	('promotes', 'PosReg', (120, 128))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (57, 79))	('NSCLC', 'Disease', (81, 86))	('FXR1', 'Gene', (115, 119))	('FXR1', 'Gene', (32, 36))	('tumor', 'Disease', (129, 134))	('NSCLC', 'Disease', 'MESH:D002289', (81, 86))
144965	27186987	The strong association of methylation and TFs with gene expression have been previously observed several times, whereas the remarkably high effect of RBP-mediated regulation in explaining gene expression in cancer is a novel result.	('methylation', 'Var', (26, 37))	('cancer', 'Disease', 'MESH:D009369', (207, 213))	('RBP', 'Gene', '57794', (150, 153))	('cancer', 'Disease', (207, 213))	('association', 'Interaction', (11, 22))	('gene expression', 'MPA', (51, 66))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('RBP', 'Gene', (150, 153))
144969	27186987	In fact, cytoplasmic ELAVL1 expression has been previously found to be associated with high tumor grade and poor survival rate in non-small cell lung carcinoma.	('high tumor', 'Disease', (87, 97))	('cytoplasmic', 'Var', (9, 20))	('cell lung carcinoma', 'Disease', (140, 159))	('small cell lung carcinoma', 'Phenotype', 'HP:0030357', (134, 159))	('ELAVL1', 'Gene', '1994', (21, 27))	('high tumor', 'Disease', 'MESH:D009369', (87, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (150, 159))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('ELAVL1', 'Gene', (21, 27))	('non-small cell lung carcinoma', 'Phenotype', 'HP:0030358', (130, 159))	('cell lung carcinoma', 'Disease', 'MESH:D055752', (140, 159))	('associated', 'Reg', (71, 81))
144979	27186987	The LFCs that are calculated with our differential expression analysis are in agreement with these studies (LFCs -3.47 and -2.09 for miR-1 and miR-218 respectively).	('miR-218', 'Var', (143, 150))	('miR-1', 'Gene', '79187', (133, 138))	('miR-1', 'Gene', (133, 138))
144991	27186987	Next, we utilized a previously published ELAVL1 knockdown dataset that includes genome-wide measurements of transcripts upon ELAVL1 depletion in HEK293 cells.	('depletion', 'Var', (132, 141))	('ELAVL1', 'Gene', '1994', (41, 47))	('ELAVL1', 'Gene', '1994', (125, 131))	('ELAVL1', 'Gene', (41, 47))	('ELAVL1', 'Gene', (125, 131))	('HEK293', 'CellLine', 'CVCL:0045', (145, 151))
145003	27186987	We were able to accurately predict the expression of genes in held-out sets by incorporating a comprehensive set of regulatory elements that are bound by TFs, miRNAs and RBPs, as well as genetic and epigenetic alterations as features in our statistical model.	('epigenetic alterations', 'Var', (199, 221))	('RBP', 'Gene', (170, 173))	('TFs', 'Gene', (154, 157))	('RBP', 'Gene', '57794', (170, 173))
145029	24296828	Acquired resistance to dasatinib in lung cancer cell lines conferred by DDR2 gatekeeper mutation and NF1 loss The treatment of non-small cell lung cancer has evolved dramatically over the past decade with the adoption of widespread use of effective targeted therapies in patients with distinct molecular alterations.	('small cell lung cancer', 'Phenotype', 'HP:0030357', (131, 153))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (127, 153))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('gatekeeper', 'Species', '111938', (77, 87))	('conferred', 'Reg', (59, 68))	('DDR2', 'Gene', '4921', (72, 76))	('dasatinib', 'Chemical', 'MESH:D000069439', (23, 32))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('NF1', 'Gene', '4763', (101, 104))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (127, 153))	('lung cancer', 'Disease', (36, 47))	('mutation', 'Var', (88, 96))	('NF1', 'Gene', (101, 104))	('DDR2', 'Gene', (72, 76))	('lung cancer', 'Disease', 'MESH:D008175', (142, 153))	('patients', 'Species', '9606', (271, 279))	('lung cancer', 'Phenotype', 'HP:0100526', (142, 153))	('non-small cell lung cancer', 'Disease', (127, 153))	('lung cancer', 'Disease', 'MESH:D008175', (36, 47))	('lung cancer', 'Phenotype', 'HP:0100526', (36, 47))
145030	24296828	In lung squamous cell carcinoma (lung SqCC) recent studies have suggested that DDR2 mutations are a biomarker for therapeutic response to dasatinib and clinical trials are underway testing this hypothesis.	('lung SqCC', 'Phenotype', 'HP:0030359', (33, 42))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (8, 31))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (3, 31))	('lung squamous cell carcinoma', 'Disease', (3, 31))	('dasatinib', 'Chemical', 'MESH:D000069439', (138, 147))	('mutations', 'Var', (84, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('DDR2', 'Gene', '4921', (79, 83))	('DDR2', 'Gene', (79, 83))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (3, 31))
145033	24296828	We perform targeted exome sequencing to identify two distinct mechanisms of acquired resistance: acquisition of the T654I gatekeeper mutation in DDR2 and loss of NF1.	('T654I', 'Mutation', 'p.T654I', (116, 121))	('NF1', 'Gene', (162, 165))	('DDR2', 'Gene', (145, 149))	('NF1', 'Gene', '4763', (162, 165))	('DDR2', 'Gene', '4921', (145, 149))	('gatekeeper', 'Species', '111938', (122, 132))	('T654I', 'Var', (116, 121))	('loss', 'NegReg', (154, 158))
145035	24296828	These results indicate that acquired resistance to dasatinib can occur via both second-site mutations in DDR2 and by activation of bypass pathways.	('DDR2', 'Gene', '4921', (105, 109))	('DDR2', 'Gene', (105, 109))	('bypass pathways', 'Pathway', (131, 146))	('mutations', 'Var', (92, 101))	('dasatinib', 'Chemical', 'MESH:D000069439', (51, 60))	('second-site mutations', 'Var', (80, 101))
145038	24296828	Alterations in EGFR and ALK, and more recently, BRAF, ROS1 and RET, have been associated with marked responses to small molecule kinase inhibitors in clinical trials and therapies targeting EGFR and ALK genomic alterations are FDA approved.	('ROS1', 'Gene', '6098', (54, 58))	('ALK', 'Gene', '238', (199, 202))	('ALK', 'Gene', '238', (24, 27))	('RET', 'Gene', '5979', (63, 66))	('responses', 'MPA', (101, 110))	('Alterations', 'Var', (0, 11))	('EGFR', 'Gene', '1956', (190, 194))	('ALK', 'Gene', (199, 202))	('EGFR', 'Gene', '1956', (15, 19))	('RET', 'Gene', (63, 66))	('EGFR', 'Gene', (190, 194))	('EGFR', 'Gene', (15, 19))	('ALK', 'Gene', (24, 27))	('BRAF', 'Gene', (48, 52))	('BRAF', 'Gene', '673', (48, 52))	('ROS1', 'Gene', (54, 58))
145042	24296828	Recent studies of lung SqCC have identified recurrent alterations in tyrosine kinases including amplifications, mutations and translocations of Fibroblast Growth Factor Receptors (FGFRs) and mutations in the Discoidin Domain Receptor 2 gene (DDR2).	('tyrosine kinases', 'MPA', (69, 85))	('FGFRs', 'Gene', (180, 185))	('mutations', 'Var', (191, 200))	('DDR2', 'Gene', (242, 246))	('alterations', 'Reg', (54, 65))	('mutations', 'Var', (112, 121))	('Discoidin Domain Receptor 2', 'Gene', '4921', (208, 235))	('lung SqCC', 'Phenotype', 'HP:0030359', (18, 27))	('DDR2', 'Gene', '4921', (242, 246))	('Discoidin Domain Receptor 2', 'Gene', (208, 235))
145043	24296828	FGFR1 amplification and DDR2 mutation have been associated with response to targeted agents in pre-clinical models and in early phase clinical trials.	('mutation', 'Var', (29, 37))	('associated', 'Reg', (48, 58))	('FGFR1', 'Gene', (0, 5))	('response', 'MPA', (64, 72))	('FGFR1', 'Gene', '2260', (0, 5))	('DDR2', 'Gene', '4921', (24, 28))	('DDR2', 'Gene', (24, 28))	('amplification', 'Var', (6, 19))
145044	24296828	Several ongoing clinical trials are investigating therapeutic biomarkers in lung SqCCs including FGFR mutations and amplifications as well as BRAF, PIK3CA and DDR2 mutations (www.clinicaltrials.gov).	('amplifications', 'Var', (116, 130))	('PIK3CA', 'Gene', '5290', (148, 154))	('DDR2', 'Gene', (159, 163))	('lung SqCCs', 'Disease', (76, 86))	('mutations', 'Var', (102, 111))	('FGFR', 'Gene', (97, 101))	('PIK3CA', 'Gene', (148, 154))	('BRAF', 'Gene', '673', (142, 146))	('DDR2', 'Gene', '4921', (159, 163))	('mutations', 'Var', (164, 173))	('BRAF', 'Gene', (142, 146))	('lung SqCC', 'Phenotype', 'HP:0030359', (76, 85))
145046	24296828	Studies of lung cancer cell lines with sensitizing mutations and patient-derived re-biopsy specimens have demonstrated that acquired resistance can occur as a result of secondary mutations in the original target, such as EGFR T790M and ALK L1196M, or by activation of parallel pathways which bypass the original target such as MET or ERBB2 amplification.	('acquired resistance', 'MPA', (124, 143))	('EGFR', 'Gene', '1956', (221, 225))	('lung cancer', 'Disease', (11, 22))	('T790M', 'Mutation', 'rs121434569', (226, 231))	('lung cancer', 'Phenotype', 'HP:0100526', (11, 22))	('ALK', 'Gene', '238', (236, 239))	('L1196M', 'Var', (240, 246))	('patient', 'Species', '9606', (65, 72))	('T790M', 'Var', (226, 231))	('EGFR', 'Gene', (221, 225))	('L1196M', 'Mutation', 'rs1057519784', (240, 246))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('ERBB2', 'Gene', (334, 339))	('ERBB2', 'Gene', '2064', (334, 339))	('ALK', 'Gene', (236, 239))	('lung cancer', 'Disease', 'MESH:D008175', (11, 22))
145050	24296828	While the response rate to dasatinib as a single agent has been low in general, several responders have been reported, including two individuals with DDR2 S768R mutations and an individual with a BRAF mutation, suggesting that specific biomarkers may be predictive of response to dasatinib.	('S768R', 'Mutation', 'rs267598140', (155, 160))	('DDR2', 'Gene', '4921', (150, 154))	('BRAF', 'Gene', '673', (196, 200))	('dasatinib', 'Chemical', 'MESH:D000069439', (27, 36))	('BRAF', 'Gene', (196, 200))	('dasatinib', 'Chemical', 'MESH:D000069439', (280, 289))	('S768R mutations', 'Var', (155, 170))	('DDR2', 'Gene', (150, 154))
145051	24296828	An international clinical trial is now accruing patients with these genotypes to address the efficacy of dasatinib in genomically selected patient cohorts with advanced NSCLC (NCT01514864).	('NSCLC', 'Phenotype', 'HP:0030358', (169, 174))	('dasatinib', 'Chemical', 'MESH:D000069439', (105, 114))	('NSCLC', 'Disease', (169, 174))	('patient', 'Species', '9606', (48, 55))	('NCT01514864', 'Var', (176, 187))	('NSCLC', 'Disease', 'MESH:D002289', (169, 174))	('patients', 'Species', '9606', (48, 56))	('patient', 'Species', '9606', (139, 146))
145054	24296828	Activation of DDR2 has been associated with a number of cellular phenotypes including transformation, migration and differentiation.	('transformation', 'CPA', (86, 100))	('associated', 'Reg', (28, 38))	('DDR2', 'Gene', '4921', (14, 18))	('Activation', 'Var', (0, 10))	('migration', 'CPA', (102, 111))	('DDR2', 'Gene', (14, 18))	('differentiation', 'CPA', (116, 131))
145055	24296828	DDR2 mutations are present in 3-4% of patients with lung SqCC and have been reported in other cancer types at comparable frequencies including lung adenocarcinoma, uterine cancer, stomach cancer, bladder cancer, melanoma, colorectal cancer and head and neck cancer (www.cbioportal.org).	('cancer', 'Disease', 'MESH:D009369', (204, 210))	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('head and neck cancer', 'Phenotype', 'HP:0012288', (244, 264))	('carcinoma', 'Phenotype', 'HP:0030731', (153, 162))	('DDR2', 'Gene', '4921', (0, 4))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('cancer', 'Disease', 'MESH:D009369', (258, 264))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (143, 162))	('patients', 'Species', '9606', (38, 46))	('stomach cancer', 'Disease', 'MESH:D013274', (180, 194))	('stomach cancer', 'Phenotype', 'HP:0012126', (180, 194))	('colorectal cancer', 'Disease', 'MESH:D015179', (222, 239))	('cancer', 'Disease', 'MESH:D009369', (233, 239))	('melanoma', 'Phenotype', 'HP:0002861', (212, 220))	('melanoma', 'Disease', (212, 220))	('DDR2', 'Gene', (0, 4))	('head and neck cancer', 'Disease', 'MESH:D006258', (244, 264))	('lung SqCC', 'Phenotype', 'HP:0030359', (52, 61))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', (204, 210))	('colorectal cancer', 'Disease', (222, 239))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('mutations', 'Var', (5, 14))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('cancer', 'Disease', (188, 194))	('cancer', 'Disease', (258, 264))	('cancer', 'Disease', (172, 178))	('lung adenocarcinoma', 'Disease', (143, 162))	('bladder cancer', 'Disease', (196, 210))	('bladder cancer', 'Disease', 'MESH:D001749', (196, 210))	('lung SqCC', 'Disease', (52, 61))	('uterine cancer', 'Phenotype', 'HP:0010784', (164, 178))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('bladder cancer', 'Phenotype', 'HP:0009725', (196, 210))	('cancer', 'Disease', (233, 239))	('stomach cancer', 'Disease', (180, 194))	('melanoma', 'Disease', 'MESH:D008545', (212, 220))	('colorectal cancer', 'Phenotype', 'HP:0003003', (222, 239))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (143, 162))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
145058	24296828	While all of these kinase inhibitors are active against DDR2 mutated lung cancer cell lines dasatinib is the most potent in vitro and in vivo.	('dasatinib', 'Chemical', 'MESH:D000069439', (92, 101))	('DDR2', 'Gene', (56, 60))	('lung cancer', 'Disease', 'MESH:D008175', (69, 80))	('lung cancer', 'Disease', (69, 80))	('lung cancer', 'Phenotype', 'HP:0100526', (69, 80))	('mutated', 'Var', (61, 68))	('DDR2', 'Gene', '4921', (56, 60))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
145059	24296828	The potency of dasatinib against DDR2 has led to the design of clinical trials testing its efficacy in lung cancer patients with DDR2 mutations.	('DDR2', 'Gene', '4921', (129, 133))	('patients', 'Species', '9606', (115, 123))	('lung cancer', 'Disease', 'MESH:D008175', (103, 114))	('DDR2', 'Gene', (33, 37))	('DDR2', 'Gene', (129, 133))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('lung cancer', 'Disease', (103, 114))	('lung cancer', 'Phenotype', 'HP:0100526', (103, 114))	('mutations', 'Var', (134, 143))	('dasatinib', 'Chemical', 'MESH:D000069439', (15, 24))	('DDR2', 'Gene', '4921', (33, 37))
145060	24296828	Here we report the generation of two cell line models of acquired resistance to dasatinib in DDR2 mutated lung cancer cell lines (HCC-366 and NCI-H2286) which have been previously shown to be dasatinib-sensitive and DDR2-dependent.	('dasatinib', 'Chemical', 'MESH:D000069439', (80, 89))	('NCI-H2286', 'CellLine', 'CVCL:1545', (142, 151))	('DDR2', 'Gene', (93, 97))	('lung cancer', 'Disease', (106, 117))	('lung cancer', 'Phenotype', 'HP:0100526', (106, 117))	('DDR2', 'Gene', '4921', (216, 220))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('dasatinib', 'Chemical', 'MESH:D000069439', (192, 201))	('DDR2', 'Gene', '4921', (93, 97))	('DDR2', 'Gene', (216, 220))	('mutated', 'Var', (98, 105))	('lung cancer', 'Disease', 'MESH:D008175', (106, 117))
145061	24296828	Targeted exome sequencing analysis of these lines demonstrated acquisition of a second-site mutation (T654I) in DDR2 in HCC-366 as the only novel mutation as compared to the parental cell line.	('DDR2', 'Gene', '4921', (112, 116))	('T654I', 'Mutation', 'p.T654I', (102, 107))	('T654I', 'Var', (102, 107))	('DDR2', 'Gene', (112, 116))
145071	24296828	Primary antibodies used were: NF1 (Santa Cruz Biotechnology), DDR2 (Bethyl Laboratories), p-TYR clone 4G10 (Millipore), Erk (Cell Signaling Technologies), p-Erk1/2 (Thr202/Tyr204) (Cell Signaling Technologies), Src (Cell Signaling Technologies), p-Src (Tyr416) (Cell Signaling Technologies), Mek (Cell Signaling Technologies), p-Mek (Ser217/221) (Cell Signaling Technologies), Akt (Cell Signaling Technologies), p-Akt (Ser473) (Cell Signaling Technologies), beta-actin (Sigma), and vinculin (Sigma).	('Akt', 'Gene', '207', (414, 417))	('Mek', 'Gene', (329, 332))	('Mek', 'Gene', '5609', (329, 332))	('NF1', 'Gene', '4763', (30, 33))	('Src', 'Gene', '6714', (248, 251))	('NF1', 'Gene', (30, 33))	('beta-actin (Sigma),', 'Gene', '728378', (458, 477))	('DDR2', 'Gene', '4921', (62, 66))	('Akt', 'Gene', (377, 380))	('beta-actin (Sigma),', 'Gene', (458, 477))	('Erk', 'Gene', (120, 123))	('Src', 'Gene', (211, 214))	('vinculin', 'Gene', (482, 490))	('Erk', 'Gene', '5594', (120, 123))	('Akt', 'Gene', '207', (377, 380))	('Erk1/2', 'Gene', (157, 163))	('Mek', 'Gene', '5609', (292, 295))	('Mek', 'Gene', (292, 295))	('Erk', 'Gene', (157, 160))	('Src', 'Gene', '6714', (211, 214))	('DDR2', 'Gene', (62, 66))	('Erk', 'Gene', '5594', (157, 160))	('Erk1/2', 'Gene', '5595;5594', (157, 163))	('Akt', 'Gene', (414, 417))	('Src', 'Gene', (248, 251))	('vinculin', 'Gene', '7414', (482, 490))	('Ser473', 'Var', (419, 425))
145079	24296828	ERK1/2 knockdown was performed using siRNAs purchased from Cell Signaling Technologies (SignalSilence).	('knockdown', 'Var', (7, 16))	('ERK1/2', 'Gene', '5595;5594', (0, 6))	('ERK1/2', 'Gene', (0, 6))
145091	24296828	DDR2 T654I is a gatekeeper mutation site which confers dasatinib resistance in a manner analogous to EGFR T790M.	('confers', 'Reg', (47, 54))	('gatekeeper', 'Species', '111938', (16, 26))	('EGFR', 'Gene', '1956', (101, 105))	('EGFR', 'Gene', (101, 105))	('DDR2', 'Gene', '4921', (0, 4))	('T654I', 'Var', (5, 10))	('T790M', 'Mutation', 'rs121434569', (106, 111))	('dasatinib', 'Chemical', 'MESH:D000069439', (55, 64))	('DDR2', 'Gene', (0, 4))	('T654I', 'Mutation', 'p.T654I', (5, 10))	('dasatinib resistance', 'MPA', (55, 75))
145092	24296828	We have shown previously that expression of DDR2 T654I mutants in HCC-366 and NCI-H2286 confers dasatinib resistance, with an increase in GI50 of 209- and 35-fold respectively for dasatinib in HCC-366 and NCI-H2286.	('HCC-366', 'Gene', (66, 73))	('GI50', 'MPA', (138, 142))	('DDR2', 'Gene', '4921', (44, 48))	('T654I', 'Var', (49, 54))	('NCI-H2286', 'CellLine', 'CVCL:1545', (205, 214))	('DDR2', 'Gene', (44, 48))	('T654I', 'Mutation', 'p.T654I', (49, 54))	('NCI-H2286', 'CellLine', 'CVCL:1545', (78, 87))	('dasatinib', 'Chemical', 'MESH:D000069439', (96, 105))	('NCI-H2286', 'Gene', (78, 87))	('dasatinib resistance', 'MPA', (96, 116))	('dasatinib', 'Chemical', 'MESH:D000069439', (180, 189))	('increase', 'PosReg', (126, 134))
145093	24296828	While dasatinib treatment led to decreased phosphorylation of mutated DDR2 in parental NCI-H2286 and HCC-366 cells, expression of the DDR2 T654I acquired mutation blocked this effect (Supplemental Figure 1).	('DDR2', 'Gene', (70, 74))	('phosphorylation', 'MPA', (43, 58))	('dasatinib', 'Chemical', 'MESH:D000069439', (6, 15))	('DDR2', 'Gene', '4921', (134, 138))	('T654I', 'Var', (139, 144))	('DDR2', 'Gene', (134, 138))	('T654I', 'Mutation', 'p.T654I', (139, 144))	('decreased', 'NegReg', (33, 42))	('DDR2', 'Gene', '4921', (70, 74))	('NCI-H2286', 'CellLine', 'CVCL:1545', (87, 96))	('mutated', 'Var', (62, 69))
145095	24296828	In NCI-H2286-DR clones, we did not identify any second-site mutations in DDR2, but we did identify variants including a splice-site mutation in NF1 and missense mutation in EPHA7 (V560L) in one clone and IL6ST (A664S) in a second clone (Table 1).	('A664S', 'Var', (211, 216))	('V560L', 'Var', (180, 185))	('NF1', 'Gene', (144, 147))	('EPHA7', 'Gene', '2045', (173, 178))	('A664S', 'Mutation', 'p.A664S', (211, 216))	('NCI-H2286-DR', 'CellLine', 'CVCL:1545', (3, 15))	('missense mutation', 'Var', (152, 169))	('IL6ST', 'Gene', (204, 209))	('V560L', 'Mutation', 'p.V560L', (180, 185))	('DDR2', 'Gene', '4921', (73, 77))	('EPHA7', 'Gene', (173, 178))	('NF1', 'Gene', '4763', (144, 147))	('DDR2', 'Gene', (73, 77))	('IL6ST', 'Gene', '3572', (204, 209))
145096	24296828	Given that the DDR2 T654I has been extensively characterized in the past by our group, we did not pursue additional experiments to further characterize the gatekeeper mutation.	('DDR2', 'Gene', '4921', (15, 19))	('T654I', 'Mutation', 'p.T654I', (20, 25))	('gatekeeper', 'Species', '111938', (156, 166))	('DDR2', 'Gene', (15, 19))	('T654I', 'Var', (20, 25))
145100	24296828	Ectopic expression of IL6ST A664S in parental NCI-H2286 cells resulted in no effect on dasatinib sensitivity and was not pursued further (Supplemental Figure 2).	('IL6ST', 'Gene', '3572', (22, 27))	('NCI-H2286', 'CellLine', 'CVCL:1545', (46, 55))	('dasatinib sensitivity', 'MPA', (87, 108))	('A664S', 'Var', (28, 33))	('dasatinib', 'Chemical', 'MESH:D000069439', (87, 96))	('IL6ST', 'Gene', (22, 27))	('A664S', 'Mutation', 'p.A664S', (28, 33))
145101	24296828	Given recent reports that EPHA7 is a tumor suppressor we also evaluated whether knock-down of EPHA7 might drive dasatinib resistance but this was not observed (Supplemental Figure 2).	('dasatinib', 'Chemical', 'MESH:D000069439', (112, 121))	('EPHA7', 'Gene', '2045', (94, 99))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('drive', 'PosReg', (106, 111))	('dasatinib resistance', 'MPA', (112, 132))	('EPHA7', 'Gene', '2045', (26, 31))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('knock-down', 'Var', (80, 90))	('tumor', 'Disease', (37, 42))	('EPHA7', 'Gene', (94, 99))	('EPHA7', 'Gene', (26, 31))
145102	24296828	In contrast, we screened four shRNAs to evaluate knock-down of NF1 in NCI-H2286 by immunoblot and real-time PCR (Figures 2A and 2B).	('NCI-H2286', 'CellLine', 'CVCL:1545', (70, 79))	('NCI-H2286', 'Gene', (70, 79))	('knock-down', 'Var', (49, 59))	('NF1', 'Gene', (63, 66))	('NF1', 'Gene', '4763', (63, 66))
145104	24296828	We then assessed whether NF1 knockdown in parental NCI-H2286 cells impacted the sensitivity to dasatinib and observed a decrease in dasatinib sensitivity using all of the shRNA vectors (Figure 2C).	('NCI-H2286', 'CellLine', 'CVCL:1545', (51, 60))	('dasatinib sensitivity', 'MPA', (132, 153))	('knockdown', 'Var', (29, 38))	('dasatinib', 'Chemical', 'MESH:D000069439', (95, 104))	('decrease', 'NegReg', (120, 128))	('NF1', 'Gene', (25, 28))	('NF1', 'Gene', '4763', (25, 28))	('dasatinib', 'Chemical', 'MESH:D000069439', (132, 141))	('impacted', 'Reg', (67, 75))	('sensitivity to dasatinib', 'MPA', (80, 104))
145114	24296828	Given that we observed increased p-ERK1/2 in NCI-H2286-DR, we measured RAS activity by RAS GTPase assay.	('ERK1/2', 'Gene', (35, 41))	('ERK1/2', 'Gene', '5595;5594', (35, 41))	('NCI-H2286-DR', 'CellLine', 'CVCL:1545', (45, 57))	('increased', 'PosReg', (23, 32))	('NCI-H2286-DR', 'Var', (45, 57))
145115	24296828	We observed RAS activity was elevated in NCI-H2286-DR as compared to NCI-H2286 by RAS GTPase assay (Figure 4A).	('NCI-H2286', 'CellLine', 'CVCL:1545', (69, 78))	('elevated', 'PosReg', (29, 37))	('NCI-H2286-DR', 'CellLine', 'CVCL:1545', (41, 53))	('NCI-H2286-DR', 'Var', (41, 53))	('RAS', 'CPA', (12, 15))	('NCI-H2286', 'CellLine', 'CVCL:1545', (41, 50))
145116	24296828	Since we observed that ERK1/2 but not MEK phosphorylation was elevated in NCI-H2286-DR as compared to parental NCI-H2286 in the setting of dasatinib, we hypothesized that ERK1/2 may be required for cell viability or proliferation in the dasatinib resistant cells.	('NCI-H2286', 'CellLine', 'CVCL:1545', (111, 120))	('NCI-H2286-DR', 'CellLine', 'CVCL:1545', (74, 86))	('NCI-H2286', 'CellLine', 'CVCL:1545', (74, 83))	('MEK', 'Gene', (38, 41))	('dasatinib', 'Chemical', 'MESH:D000069439', (237, 246))	('MEK', 'Gene', '5609', (38, 41))	('NCI-H2286-DR', 'Var', (74, 86))	('ERK1/2', 'Gene', '5595;5594', (171, 177))	('ERK1/2', 'Gene', (171, 177))	('ERK1/2', 'Gene', '5595;5594', (23, 29))	('dasatinib', 'Chemical', 'MESH:D000069439', (139, 148))	('ERK1/2', 'Gene', (23, 29))	('elevated', 'PosReg', (62, 70))
145118	24296828	To address whether analogous activation of ERK1/2 downstream of NF1-mediated RAS activation was required for the resistance phenotype we used RNAi to knock-down ERK1/2 in NCI-H2286 and NCI-H2286-DR (Figure 4B).	('ERK1/2', 'Gene', '5595;5594', (161, 167))	('knock-down', 'Var', (150, 160))	('NCI-H2286', 'CellLine', 'CVCL:1545', (171, 180))	('NCI-H2286-DR', 'CellLine', 'CVCL:1545', (185, 197))	('ERK1/2', 'Gene', (43, 49))	('NF1', 'Gene', (64, 67))	('NF1', 'Gene', '4763', (64, 67))	('ERK1/2', 'Gene', '5595;5594', (43, 49))	('NCI-H2286', 'CellLine', 'CVCL:1545', (185, 194))	('ERK1/2', 'Gene', (161, 167))
145119	24296828	We observed that knock-down of ERK1/2 led to a dramatic decrease in cell viability and proliferation in both the parental and dasatinib-resistant cell line (Figure 4B), suggesting that ongoing ERK1/2 activity is required in the setting of dasatinib resistance in NCI-H2286-DR as well as in the parental cell line.	('cell viability', 'CPA', (68, 82))	('ERK1/2', 'Gene', (31, 37))	('proliferation', 'CPA', (87, 100))	('ERK1/2', 'Gene', '5595;5594', (31, 37))	('dasatinib', 'Chemical', 'MESH:D000069439', (126, 135))	('knock-down', 'Var', (17, 27))	('ERK1/2', 'Gene', (193, 199))	('ERK1/2', 'Gene', '5595;5594', (193, 199))	('dasatinib', 'Chemical', 'MESH:D000069439', (239, 248))	('decrease', 'NegReg', (56, 64))	('NCI-H2286-DR', 'CellLine', 'CVCL:1545', (263, 275))
145124	24296828	We selected two cell lines for this analysis: HCC-366 which harbors the DDR2 mutation L239R, and NCI-H1703 which has no DDR2 mutations but is dasatinib-sensitive due to dependence on PDGFRA amplification.	('mutation L239R', 'Var', (77, 91))	('L239R', 'Mutation', 'rs578015216', (86, 91))	('L239R', 'Var', (86, 91))	('DDR2', 'Gene', (72, 76))	('DDR2', 'Gene', '4921', (120, 124))	('NCI-H1703', 'CellLine', 'CVCL:1490', (97, 106))	('dasatinib', 'Chemical', 'MESH:D000069439', (142, 151))	('DDR2', 'Gene', (120, 124))	('DDR2', 'Gene', '4921', (72, 76))
145125	24296828	We knocked-down NF1 in both lines using the shRNA construct in Figure 2 which led to the greatest degree of NF1 depletion (Figure 5A).	('NF1', 'Gene', '4763', (108, 111))	('NF1', 'Gene', (16, 19))	('NF1', 'Gene', '4763', (16, 19))	('depletion', 'MPA', (112, 121))	('knocked-down', 'Var', (3, 15))	('NF1', 'Gene', (108, 111))
145126	24296828	We observed that NF1 knock-down in both HCC-366 and NCI-H1703 led to a decrease in dasatinib sensitivity (Figure 5B).	('dasatinib sensitivity', 'MPA', (83, 104))	('NCI-H1703', 'CellLine', 'CVCL:1490', (52, 61))	('decrease', 'NegReg', (71, 79))	('knock-down', 'Var', (21, 31))	('dasatinib', 'Chemical', 'MESH:D000069439', (83, 92))	('NF1', 'Gene', (17, 20))	('NF1', 'Gene', '4763', (17, 20))
145127	24296828	The calculated GI50 shifts were 11.1-fold for NCI-H1703 (4.8 to 53.5 nM) and 3.0-fold for HCC-366 (10.6 to 32 nM) when comparing lines expressing the shRNA targeting NF1 as compared to an shRNA targeting GFP.	('NF1', 'Gene', (166, 169))	('NF1', 'Gene', '4763', (166, 169))	('NCI-H1703', 'Gene', (46, 55))	('NCI-H1703', 'CellLine', 'CVCL:1490', (46, 55))	('shRNA targeting', 'Var', (150, 165))
145128	24296828	Here we have generated cellular models of acquired resistance to dasatinib using two independent DDR2 mutated lung cancer cell lines, both previously shown to be sensitive to dasatinib at comparable concentrations.	('lung cancer', 'Disease', 'MESH:D008175', (110, 121))	('dasatinib', 'Chemical', 'MESH:D000069439', (175, 184))	('DDR2', 'Gene', (97, 101))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('dasatinib', 'Chemical', 'MESH:D000069439', (65, 74))	('lung cancer', 'Disease', (110, 121))	('lung cancer', 'Phenotype', 'HP:0100526', (110, 121))	('DDR2', 'Gene', '4921', (97, 101))	('mutated', 'Var', (102, 109))
145129	24296828	Targeted exome sequencing of resistant lines identified two different modes or acquired resistance to dasatinib, second site (gatekeeper) mutations in DDR2 and loss of NF1.	('dasatinib', 'Chemical', 'MESH:D000069439', (102, 111))	('resistance', 'MPA', (88, 98))	('loss', 'NegReg', (160, 164))	('DDR2', 'Gene', '4921', (151, 155))	('NF1', 'Gene', (168, 171))	('gatekeeper', 'Species', '111938', (126, 136))	('DDR2', 'Gene', (151, 155))	('NF1', 'Gene', '4763', (168, 171))	('mutations', 'Var', (138, 147))
145130	24296828	These results are analogous to the cases of EGFR and ALK resistance in lung cancer in which both cis events such as gatekeeper mutations as well as trans events involving activation of other genes and bypass pathways have been shown to drive acquired resistance to EGFR- or ALK-directed therapy.	('drive', 'Reg', (236, 241))	('ALK', 'Gene', (274, 277))	('genes', 'Gene', (191, 196))	('ALK', 'Gene', (53, 56))	('lung cancer', 'Disease', 'MESH:D008175', (71, 82))	('EGFR', 'Gene', '1956', (265, 269))	('gatekeeper', 'Species', '111938', (116, 126))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('activation', 'PosReg', (171, 181))	('ALK', 'Gene', '238', (53, 56))	('EGFR', 'Gene', (265, 269))	('ALK', 'Gene', '238', (274, 277))	('EGFR', 'Gene', '1956', (44, 48))	('EGFR', 'Gene', (44, 48))	('acquired resistance', 'CPA', (242, 261))	('mutations', 'Var', (127, 136))	('lung cancer', 'Disease', (71, 82))	('lung cancer', 'Phenotype', 'HP:0100526', (71, 82))
145131	24296828	The development of pharmaceutical agents to selectively target gatekeeper mutations has been successful in the case of EGFR T790M with compounds such as WZ-4002 and CO-1686 and for BCR-ABL with second- and third-generation ABL inhibitors.	('T790M', 'Var', (124, 129))	('CO-1686', 'Chemical', 'MESH:C000589977', (165, 172))	('EGFR', 'Gene', '1956', (119, 123))	('gatekeeper', 'Species', '111938', (63, 73))	('WZ-4002', 'Chemical', 'MESH:C571455', (153, 160))	('EGFR', 'Gene', (119, 123))	('T790M', 'Mutation', 'rs121434569', (124, 129))
145133	24296828	Loss of NF1 has recently been reported to drive resistance to tyrosine kinase inhibitors in a number of settings including BRAF-driven melanoma and EGFR-driven lung cancer.	('NF1', 'Gene', (8, 11))	('resistance to tyrosine kinase inhibitors', 'MPA', (48, 88))	('melanoma', 'Disease', 'MESH:D008545', (135, 143))	('NF1', 'Gene', '4763', (8, 11))	('drive', 'Reg', (42, 47))	('melanoma', 'Disease', (135, 143))	('EGFR', 'Gene', '1956', (148, 152))	('melanoma', 'Phenotype', 'HP:0002861', (135, 143))	('BRAF', 'Gene', (123, 127))	('EGFR', 'Gene', (148, 152))	('BRAF', 'Gene', '673', (123, 127))	('lung cancer', 'Disease', 'MESH:D008175', (160, 171))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('Loss', 'Var', (0, 4))	('lung cancer', 'Disease', (160, 171))	('lung cancer', 'Phenotype', 'HP:0100526', (160, 171))
145137	24296828	While knockdown of ERK1/2 was sufficient to kill NCI-H2286 dasatinib resistant cells in our assays there remains a need to develop improved inhibitors of RAS pathway effectors given the central role of this pathway in cancer development, progression and therapeutic resistance.	('cancer', 'Disease', 'MESH:D009369', (218, 224))	('NCI-H2286', 'CellLine', 'CVCL:1545', (49, 58))	('dasatinib', 'Chemical', 'MESH:D000069439', (59, 68))	('cancer', 'Disease', (218, 224))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('ERK1/2', 'Gene', (19, 25))	('ERK1/2', 'Gene', '5595;5594', (19, 25))	('knockdown', 'Var', (6, 15))
145141	24296828	Our data are unlikely to represent a full accounting of mechanisms of acquired resistance to dasatinib in lung cancer and it is also likely that some patients with DDR2 mutations in ongoing clinical trials will display primary resistance to dasatinib given that many DDR2 mutations have been described and some of these may not confer sensitivity to dasatinib.	('dasatinib', 'Chemical', 'MESH:D000069439', (350, 359))	('mutations', 'Var', (169, 178))	('lung cancer', 'Disease', (106, 117))	('DDR2', 'Gene', '4921', (267, 271))	('lung cancer', 'Phenotype', 'HP:0100526', (106, 117))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('DDR2', 'Gene', (267, 271))	('DDR2', 'Gene', '4921', (164, 168))	('primary resistance to dasatinib', 'MPA', (219, 250))	('dasatinib', 'Chemical', 'MESH:D000069439', (241, 250))	('patients', 'Species', '9606', (150, 158))	('dasatinib', 'Chemical', 'MESH:D000069439', (93, 102))	('DDR2', 'Gene', (164, 168))	('lung cancer', 'Disease', 'MESH:D008175', (106, 117))
145142	24296828	As we only profiled 645 genes in our sequencing assay and since knock-down of NF1 did not fully recapitulate the degree of dasatinib resistance observed in NCI-H2286-DR, we expect that additional mechanisms will likely be found as has been the case for acquired resistance to EGFR and BRAF directed therapies.	('knock-down', 'Var', (64, 74))	('dasatinib', 'Chemical', 'MESH:D000069439', (123, 132))	('NF1', 'Gene', (78, 81))	('EGFR', 'Gene', '1956', (276, 280))	('EGFR', 'Gene', (276, 280))	('BRAF', 'Gene', '673', (285, 289))	('NF1', 'Gene', '4763', (78, 81))	('BRAF', 'Gene', (285, 289))	('NCI-H2286-DR', 'CellLine', 'CVCL:1545', (156, 168))
145150	31572671	MTT proliferation, colony formation, migration and invasion assays and immunoblotting assay in NCI-H358 and A549 cell lines suggested that OTUD7B enhances EGF-induced Akt signal transduction and promotes lung cancer cell proliferation and migration.	('enhances', 'PosReg', (146, 154))	('EGF', 'Gene', '1950', (155, 158))	('lung cancer', 'Disease', 'MESH:D008175', (204, 215))	('Akt', 'Gene', '207', (167, 170))	('promotes', 'PosReg', (195, 203))	('migration', 'CPA', (239, 248))	('lung cancer', 'Disease', (204, 215))	('EGF', 'Gene', (155, 158))	('lung cancer', 'Phenotype', 'HP:0100526', (204, 215))	('MTT', 'Chemical', 'MESH:C022616', (0, 3))	('Akt', 'Gene', (167, 170))	('OTUD7B', 'Var', (139, 145))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
145153	31572671	NCI-H358 tumor model demonstrated OTUD7B is required for lung tumor progression by facilitating activation of Akt signaling.	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('Akt', 'Gene', (110, 113))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('lung tumor', 'Disease', 'MESH:D008175', (57, 67))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumor', 'Disease', (62, 67))	('lung tumor', 'Disease', (57, 67))	('tumor', 'Disease', (9, 14))	('OTUD7B', 'Var', (34, 40))	('lung tumor', 'Phenotype', 'HP:0100526', (57, 67))	('Akt', 'Gene', '207', (110, 113))	('activation', 'PosReg', (96, 106))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
145167	31572671	Antibodies for OTUD7B (16605-1-AP) and JNK (10023-1-AP) were from Proteintech Group, Inc. (Chicago, USA).	('10023-1-AP', 'Chemical', 'None', (44, 54))	('10023-1-AP', 'Var', (44, 54))	('JNK', 'Gene', (39, 42))	('OTUD7B', 'Gene', (15, 21))	('JNK', 'Gene', '5599', (39, 42))	('16605-1-AP', 'Var', (23, 33))
145169	31572671	Antibodies for p70S6K (2708), p-p70S6K T389 (9206), p-p70S6K T421/S424 (9204), ERK1/2 (9102), p-ERK1/2 T202/Y204 (9101), p-Akt S473 (4060), p-p38 T180/Y182 (9215), and p-JNK T183/Y185 (4668) were purchased from Cell Signaling Technology (Boston, USA).	('p70S6K', 'Gene', (32, 38))	('p70S6K', 'Gene', '6198', (15, 21))	('p70S6K', 'Gene', '6198', (32, 38))	('p70S6K', 'Gene', (54, 60))	('p70S6K', 'Gene', (15, 21))	('JNK', 'Gene', (170, 173))	('p38', 'Gene', (142, 145))	('p70S6K', 'Gene', '6198', (54, 60))	('Akt', 'Gene', '207', (123, 126))	('JNK', 'Gene', '5599', (170, 173))	('S424', 'Chemical', 'MESH:C100253', (66, 70))	('p-ERK1/2 T202/Y204 (9101', 'Var', (94, 118))	('p38', 'Gene', '5594', (142, 145))	('Akt', 'Gene', (123, 126))
145181	31572671	Incubation with polyclonal antibodies against OTUD7B (16605-1-AP; 1:1,000 dilution; Proteintech), VEGF (19003-1-AP; 1:500 dilution; Proteintech) was performed at 4 C overnight followed by incubation with horseradish-peroxidase (HRP)-conjungated secondary antibody kit.	('horseradish', 'Species', '3704', (204, 215))	('VEGF', 'Gene', '7422', (98, 102))	('OTUD7B', 'Gene', (46, 52))	('VEGF', 'Gene', (98, 102))	('16605-1-AP', 'Var', (54, 64))
145185	31572671	All cell lines were cultured in a humidified atmosphere with 5% CO2 at 37 C. For gene silencing, lentiviral particles were prepared by transfecting HEK293 cells with LV3 lentiviral vectors encoding specific shRNAs or control shRNAs along with packaging plasmids.	('specific', 'Var', (198, 206))	('silencing', 'NegReg', (86, 95))	('CO2', 'Chemical', 'MESH:D002245', (64, 67))	('shRNAs', 'Gene', (207, 213))
145207	31572671	To better understand the relevance of OTUD7B to cancer a follow-up analysis of patient survival was performed, and the result demonstrated that patients whose tumor had high OTUD7B levels had significantly poorer survival than those with low OTUD7B levels (Figure 1B).	('high', 'Var', (169, 173))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('poorer', 'NegReg', (206, 212))	('patient', 'Species', '9606', (144, 151))	('tumor', 'Disease', (159, 164))	('patients', 'Species', '9606', (144, 152))	('patient', 'Species', '9606', (79, 86))	('OTUD7B', 'MPA', (174, 180))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('survival', 'MPA', (213, 221))
145213	31572671	Transducing specific shRNA targeting OTUD7B into NCI-H358 cells further confirmed that knockdown of endogenous OTUD7B correlates with decreased cell growth (Figure 2B, Supplementary Figure S4B).	('decreased', 'NegReg', (134, 143))	('OTUD7B', 'Gene', (111, 117))	('S4B', 'Chemical', 'MESH:D013455', (189, 192))	('cell growth', 'CPA', (144, 155))	('knockdown', 'Var', (87, 96))
145233	31572671	To confirm the relevance between OTUD7B and VEGF, we further examined the VEGF concentration in conditional media of NSCLC cell lines that stably overexpress or knockdown OTUD7B.	('VEGF', 'Gene', '7422', (74, 78))	('NSCLC', 'Disease', (117, 122))	('VEGF', 'Gene', (74, 78))	('VEGF', 'Gene', (44, 48))	('NSCLC', 'Disease', 'MESH:D002289', (117, 122))	('NSCLC', 'Phenotype', 'HP:0030358', (117, 122))	('overexpress', 'PosReg', (146, 157))	('knockdown', 'Var', (161, 170))	('VEGF', 'Gene', '7422', (44, 48))	('OTUD7B', 'Gene', (171, 177))
145234	31572671	Conditioned media (CM) from NCI-H358 cells stably expressing control-GFP (GFP-CM) or GFP-OTUD7B (GFP-OTUD7B-CM) were collected and secreted VEGF levels were examined using ELISA assay.	('GFP-OTUD7B', 'Var', (85, 95))	('VEGF', 'Gene', '7422', (140, 144))	('VEGF', 'Gene', (140, 144))
145236	31572671	When knockdown of endogenous OTUD7B, secreted VEGF levels decreased (Supplementary Figure S8A).	('knockdown', 'Var', (5, 14))	('decreased', 'NegReg', (58, 67))	('VEGF', 'Gene', (46, 50))	('OTUD7B', 'Gene', (29, 35))	('endogenous', 'Var', (18, 28))	('VEGF', 'Gene', '7422', (46, 50))
145251	31572671	Knockdown of OTUD7B in NCI-H358 cells significantly decreased Akt phosphorylation at S473 and inhibited tumor growth (Supplementary Figures S10A-D).	('S10A', 'Var', (140, 144))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('inhibited', 'NegReg', (94, 103))	('decreased', 'NegReg', (52, 61))	('tumor', 'Disease', (104, 109))	('Akt', 'Gene', '207', (62, 65))	('phospho', 'Chemical', 'MESH:C033601', (66, 73))	('S10A', 'SUBSTITUTION', 'None', (140, 144))	('OTUD7B', 'Gene', (13, 19))	('Akt', 'Gene', (62, 65))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
145252	31572671	These results suggest that OTUD7B is required for lung tumor progression at least partially by facilitating activation of Akt signaling.	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('lung tumor', 'Disease', (50, 60))	('lung tumor', 'Disease', 'MESH:D008175', (50, 60))	('Akt', 'Gene', '207', (122, 125))	('OTUD7B', 'Var', (27, 33))	('lung tumor', 'Phenotype', 'HP:0100526', (50, 60))	('Akt', 'Gene', (122, 125))	('activation', 'PosReg', (108, 118))
145257	31572671	High expression of OTUD7B predicts metastasis and poor survival in NSCLC patients, which suggested potential role of OTUD7B in lung cancer initiation and progression.	('metastasis', 'CPA', (35, 45))	('High', 'Var', (0, 4))	('poor', 'NegReg', (50, 54))	('lung cancer initiation', 'Disease', 'MESH:D008175', (127, 149))	('lung cancer', 'Phenotype', 'HP:0100526', (127, 138))	('NSCLC', 'Phenotype', 'HP:0030358', (67, 72))	('patients', 'Species', '9606', (73, 81))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('NSCLC', 'Disease', (67, 72))	('OTUD7B', 'Gene', (19, 25))	('lung cancer initiation', 'Disease', (127, 149))	('NSCLC', 'Disease', 'MESH:D002289', (67, 72))
145268	31572671	Patients whose NSCLC featured high OTUD7B expression had high a VEGF level and especially poor prognosis.	('NSCLC', 'Phenotype', 'HP:0030358', (15, 20))	('OTUD7B', 'Gene', (35, 41))	('high', 'PosReg', (57, 61))	('VEGF', 'Gene', (64, 68))	('high', 'Var', (30, 34))	('Patients', 'Species', '9606', (0, 8))	('NSCLC', 'Disease', (15, 20))	('NSCLC', 'Disease', 'MESH:D002289', (15, 20))	('VEGF', 'Gene', '7422', (64, 68))
145270	31572671	In addition, OTUD7B was demonstrated to promote tumor growth in NCI-H358 lung cancer xenografts.	('NCI-H358 lung cancer', 'Disease', 'MESH:D008175', (64, 84))	('promote', 'PosReg', (40, 47))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('tumor', 'Disease', (48, 53))	('NCI-H358 lung cancer', 'Disease', (64, 84))	('OTUD7B', 'Var', (13, 19))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('lung cancer', 'Phenotype', 'HP:0100526', (73, 84))
145274	31572671	Strategies to silencing OTUD7B in carcinoma tissues may inform the development of novel therapies to fight against LUSC and LAD.	('silencing', 'Var', (14, 23))	('LAD', 'Disease', (124, 127))	('LAD', 'Disease', 'MESH:C538231', (124, 127))	('LUSC', 'Disease', 'MESH:D002294', (115, 119))	('LUSC', 'Disease', (115, 119))	('LUSC', 'Phenotype', 'HP:0030359', (115, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (34, 43))	('OTUD7B', 'Gene', (24, 30))	('LAD', 'Phenotype', 'HP:0030078', (124, 127))
145275	30071841	Association between H19 SNP rs217727 and lung cancer risk in a Chinese population: a case control study H19 was the first long non-coding RNA (lncRNA) to be confirmed.	('H19', 'Gene', (20, 23))	('H19', 'Gene', '283120', (20, 23))	('H19', 'Gene', '283120', (104, 107))	('SNP', 'Var', (24, 27))	('H19', 'Gene', (104, 107))	('lung cancer', 'Disease', (41, 52))	('lung cancer', 'Phenotype', 'HP:0100526', (41, 52))	('rs217727', 'Mutation', 'rs217727', (28, 36))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('rs217727', 'Var', (28, 36))	('Association', 'Interaction', (0, 11))	('lung cancer', 'Disease', 'MESH:D008175', (41, 52))
145277	30071841	This study assessed whether single nucleotide polymorphisms (SNPs) in H19 are associated with the risk of LC in a Chinese population.	('single nucleotide polymorphisms', 'Var', (28, 59))	('associated', 'Reg', (78, 88))	('LC', 'Phenotype', 'HP:0100526', (106, 108))	('H19', 'Gene', '283120', (70, 73))	('H19', 'Gene', (70, 73))
145278	30071841	A case-control study was performed, and H19 SNP rs217727 was analyzed in 555 lung cancer patients from two hospitals and 618 healthy controls to test the association between this SNP and the susceptibility to LC.	('lung cancer', 'Phenotype', 'HP:0100526', (77, 88))	('association', 'Interaction', (154, 165))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('lung cancer', 'Disease', 'MESH:D008175', (77, 88))	('H19', 'Gene', '283120', (40, 43))	('rs217727', 'Mutation', 'rs217727', (48, 56))	('patients', 'Species', '9606', (89, 97))	('H19', 'Gene', (40, 43))	('rs217727', 'Var', (48, 56))	('LC', 'Phenotype', 'HP:0100526', (209, 211))	('lung cancer', 'Disease', (77, 88))
145280	30071841	Furthermore, the A/A genotype had a higher risk of LC than those of G/G in the squamous cell carcinoma (OR = 2.022, P = 0.004) and adenocarcinoma (OR = 1.606, P = 0.045) subgroups.	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('adenocarcinoma', 'Disease', 'MESH:D000230', (131, 145))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (79, 102))	('squamous cell carcinoma', 'Disease', (79, 102))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (79, 102))	('LC', 'Phenotype', 'HP:0100526', (51, 53))	('adenocarcinoma', 'Disease', (131, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('A/A', 'Var', (17, 20))
145281	30071841	The rs217727 SNP in lncRNA H19 was significantly associated with susceptibility to LC, particularly in squamous cell carcinoma and adenocarcinoma, and identified the homozygous A/A genotype as a risk factor for LC.	('H19', 'Gene', '283120', (27, 30))	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('H19', 'Gene', (27, 30))	('rs217727 SNP', 'Var', (4, 16))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (103, 126))	('squamous cell carcinoma and adenocarcinoma', 'Disease', 'MESH:D002294', (103, 145))	('associated', 'Reg', (49, 59))	('LC', 'Phenotype', 'HP:0100526', (83, 85))	('susceptibility', 'Reg', (65, 79))	('rs217727', 'Mutation', 'rs217727', (4, 12))	('LC', 'Phenotype', 'HP:0100526', (211, 213))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))
145289	30071841	Thus far, the association between H19_rs217727 polymorphisms and LC has not been studied in the Chinese population.	('H19', 'Gene', (34, 37))	('LC', 'Phenotype', 'HP:0100526', (65, 67))	('polymorphisms', 'Var', (47, 60))	('rs217727', 'Mutation', 'rs217727', (38, 46))	('H19', 'Gene', '283120', (34, 37))
145290	30071841	In this hospital-based case-control study, we hypothesized a possible association between variant genotypes of the human H19 gene (rs217727) and LC.	('H19', 'Gene', '283120', (121, 124))	('H19', 'Gene', (121, 124))	('LC', 'Phenotype', 'HP:0100526', (145, 147))	('human', 'Species', '9606', (115, 120))	('rs217727', 'Var', (131, 139))	('rs217727', 'Mutation', 'rs217727', (131, 139))
145301	30071841	Based on the HapMap data and the criteria of minor allele frequency (MAF) > 0.05 in CB population, we found two SNPs rs217727 and rs2107425 in H19, and they are in high linkage disequilibrium (LD).	('rs2107425', 'Mutation', 'rs2107425', (130, 139))	('rs217727', 'Var', (117, 125))	('rs217727', 'Mutation', 'rs217727', (117, 125))	('rs2107425', 'Var', (130, 139))	('H19', 'Gene', (143, 146))	('H19', 'Gene', '283120', (143, 146))
145303	30071841	The role of rs2107425 polymorphism had been identified in lung cancer.	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('lung cancer', 'Disease', (58, 69))	('lung cancer', 'Phenotype', 'HP:0100526', (58, 69))	('rs2107425', 'Var', (12, 21))	('rs2107425', 'Mutation', 'rs2107425', (12, 21))	('lung cancer', 'Disease', 'MESH:D008175', (58, 69))
145310	30071841	The deionized water was used as a negative control and the rs3219073/GG SNP of PARP-1 was used as a positive control, which was previously detected in many lung cancer samples.	('PARP-1', 'Gene', (79, 85))	('rs3219073', 'DBSNP_MENTION', 'None', (59, 68))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('PARP-1', 'Gene', '142', (79, 85))	('lung cancer', 'Disease', 'MESH:D008175', (156, 167))	('water', 'Chemical', 'MESH:D014867', (14, 19))	('lung cancer', 'Disease', (156, 167))	('lung cancer', 'Phenotype', 'HP:0100526', (156, 167))	('rs3219073', 'Var', (59, 68))
145319	30071841	We found that the rs217727 A/A genotype was associated with an increased cancer risk for squamous cell carcinoma (P = 0.004, adjusted OR = 1.996, 95% CI = 1.142 to 3.489, P = 0.015) and adenocarcinoma (P = 0.045, adjusted OR = 1.767, 95% CI = 1.096 to 2.850, P = 0.019), but not for small cell carcinoma (P = 0.123, adjusted OR = 1.799, 95% CI = 0.846 to 3.827, P = 0.127).	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('small cell carcinoma', 'Phenotype', 'HP:0030357', (283, 303))	('small cell carcinoma', 'Disease', (283, 303))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (191, 200))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (89, 112))	('rs217727', 'Mutation', 'rs217727', (18, 26))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (294, 303))	('adenocarcinoma', 'Disease', (186, 200))	('small cell carcinoma', 'Disease', 'MESH:D018288', (283, 303))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (89, 112))	('adenocarcinoma', 'Disease', 'MESH:D000230', (186, 200))	('rs217727 A/A', 'Var', (18, 30))	('squamous cell carcinoma', 'Disease', (89, 112))
145325	30071841	Therefore, abnormalities of the expression of lncRNAs may be involved in the tumorigenesis of LC.	('abnormalities', 'Var', (11, 24))	('lncRNAs', 'Gene', (46, 53))	('involved', 'Reg', (61, 69))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('LC', 'Phenotype', 'HP:0100526', (94, 96))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Disease', (77, 82))
145326	30071841	Genetic variants in lncRNAs could be a biomarker for the prediction of cancer susceptibility in humans.	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('cancer', 'Disease', (71, 77))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('humans', 'Species', '9606', (96, 102))	('Genetic variants', 'Var', (0, 16))	('lncRNAs', 'Gene', (20, 27))
145327	30071841	found that lncRNAs-MALAT1_rs619586 was associated with decreased hepatocellular carcinoma risk.	('decreased hepatocellular carcinoma', 'Disease', (55, 89))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('rs619586', 'Mutation', 'rs619586', (26, 34))	('lncRNAs-MALAT1_rs619586', 'Var', (11, 34))	('decreased hepatocellular carcinoma', 'Disease', 'MESH:D006528', (55, 89))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (65, 89))
145328	30071841	LncRNAs-HOTAIR_rs12826786 in strong linkage disequilibrium with rs1899663 (r2 = 1) was associated with the risk of gastric cardia adenocarcinoma.	('gastric cardia adenocarcinoma', 'Disease', 'MESH:D004938', (115, 144))	('HOTAIR', 'Gene', (8, 14))	('rs1899663', 'Var', (64, 73))	('gastric cardia adenocarcinoma', 'Disease', (115, 144))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('HOTAIR', 'Gene', '100124700', (8, 14))	('rs12826786', 'Mutation', 'rs12826786', (15, 25))	('associated', 'Reg', (87, 97))	('rs1899663', 'Mutation', 'rs1899663', (64, 73))
145331	30071841	Deregulation of oncofetal RNA plays a critical role in tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('Deregulation', 'Var', (0, 12))	('oncofetal RNA', 'Protein', (16, 29))	('tumor', 'Disease', (55, 60))
145335	30071841	found that the knockdown of H19 inhibited colony formation and anchorage-independent growth in lung cancer cells.	('lung cancer', 'Disease', (95, 106))	('H19', 'Gene', '283120', (28, 31))	('lung cancer', 'Phenotype', 'HP:0100526', (95, 106))	('knockdown', 'Var', (15, 24))	('H19', 'Gene', (28, 31))	('inhibited', 'NegReg', (32, 41))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('lung cancer', 'Disease', 'MESH:D008175', (95, 106))	('anchorage-independent growth', 'CPA', (63, 91))	('colony formation', 'CPA', (42, 58))
145337	30071841	Moreover, the knockdown of H19 could significantly suppress hypoxia-induced cancer cell proliferation in vivo.	('H19', 'Gene', '283120', (27, 30))	('suppress', 'NegReg', (51, 59))	('hypoxia', 'Disease', (60, 67))	('hypoxia', 'Disease', 'MESH:D000860', (60, 67))	('H19', 'Gene', (27, 30))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('knockdown', 'Var', (14, 23))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))
145338	30071841	Furthermore, high expression of H19 was positively associated with advanced TNM stage and was a predictor of overall survival (OS) in gastric cancer patients.	('patients', 'Species', '9606', (149, 157))	('gastric cancer', 'Disease', (134, 148))	('advanced TNM stage', 'CPA', (67, 85))	('high expression', 'Var', (13, 28))	('H19', 'Gene', '283120', (32, 35))	('gastric cancer', 'Disease', 'MESH:D013274', (134, 148))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('associated', 'Reg', (51, 61))	('H19', 'Gene', (32, 35))	('overall survival', 'CPA', (109, 125))	('gastric cancer', 'Phenotype', 'HP:0012126', (134, 148))
145342	30071841	reported that the variant H19 genotypes (CT + TT rs217727, CT + TT rs2839698) were correlated with an increased risk of gastric cancer (P = 0.040, P = 0.033), and the CT and TT genotypes in rs2839698 were also related to higher H19 mRNA levels in serum.	('rs2839698', 'Var', (190, 199))	('rs2839698', 'Mutation', 'rs2839698', (190, 199))	('gastric cancer', 'Disease', (120, 134))	('rs2839698', 'Mutation', 'rs2839698', (67, 76))	('CT + TT rs2839698', 'Var', (59, 76))	('H19', 'Gene', '283120', (228, 231))	('gastric cancer', 'Disease', 'MESH:D013274', (120, 134))	('H19', 'Gene', '283120', (26, 29))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('H19', 'Gene', (228, 231))	('rs217727', 'Mutation', 'rs217727', (49, 57))	('H19', 'Gene', (26, 29))	('gastric cancer', 'Phenotype', 'HP:0012126', (120, 134))	('higher', 'PosReg', (221, 227))
145343	30071841	In contrast, the rs217727 polymorphism did not affect the H19 mRNA level.	('H19', 'Gene', (58, 61))	('rs217727', 'Var', (17, 25))	('H19', 'Gene', '283120', (58, 61))	('rs217727', 'Mutation', 'rs217727', (17, 25))
145348	30071841	Additional studies are also necessary to understand the mechanism by which the rs217727 SNP affects H19 mRNA expression, alters the translational efficiency, or leads to alterations in the H19 structure in LC.	('LC', 'Phenotype', 'HP:0100526', (206, 208))	('H19', 'Gene', '283120', (100, 103))	('leads to alterations', 'Reg', (161, 181))	('H19', 'Gene', '283120', (189, 192))	('H19', 'Gene', (189, 192))	('H19', 'Gene', (100, 103))	('affects', 'Reg', (92, 99))	('alters', 'Reg', (121, 127))	('rs217727', 'Var', (79, 87))	('rs217727', 'Mutation', 'rs217727', (79, 87))	('translational efficiency', 'MPA', (132, 156))	('mRNA expression', 'MPA', (104, 119))	('structure', 'MPA', (193, 202))
145352	30071841	AD Adenocarcinoma CI Confidence interval DMR Differentially methylated regions HWE Hardy-Weinberg equilibrium LC Lung cancer LD Linkage disequilibrium lncRNA Long non-coding RNA MAF Minor allele frequency OR Odds ratio SCC Squamous cell carcinoma SCLC Small cell lung cancer SD Standard derivation SNPs Single nucleotide polymorphisms LL analyzed and interpreted the patient data regarding the lung cancer and was a major contributor in writing the manuscript.	('Lung cancer', 'Phenotype', 'HP:0100526', (113, 124))	('Small cell lung cancer', 'Disease', 'MESH:D055752', (252, 274))	('patient', 'Species', '9606', (367, 374))	('Lung cancer', 'Disease', (113, 124))	('Adenocarcinoma', 'Disease', 'MESH:D000230', (3, 17))	('LC', 'Phenotype', 'HP:0100526', (110, 112))	('SCC', 'Gene', '6317', (219, 222))	('cancer', 'Phenotype', 'HP:0002664', (399, 405))	('AD', 'Disease', (0, 2))	('SCC', 'Gene', (219, 222))	('carcinoma', 'Phenotype', 'HP:0030731', (8, 17))	('lung cancer', 'Disease', (394, 405))	('AD', 'Disease', 'MESH:D000544', (0, 2))	('lung cancer', 'Disease', 'MESH:D008175', (263, 274))	('Small cell lung cancer', 'Phenotype', 'HP:0030357', (252, 274))	('SCLC', 'Phenotype', 'HP:0030357', (247, 251))	('carcinoma', 'Phenotype', 'HP:0030731', (237, 246))	('lung cancer', 'Phenotype', 'HP:0100526', (263, 274))	('Adenocarcinoma', 'Disease', (3, 17))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('Small cell lung cancer', 'Disease', (252, 274))	('SCLC', 'Gene', '7864', (247, 251))	('LC', 'Phenotype', 'HP:0100526', (249, 251))	('SCLC', 'Gene', (247, 251))	('lung cancer', 'Disease', 'MESH:D008175', (394, 405))	('DMR', 'Chemical', '-', (41, 44))	('SCC', 'Phenotype', 'HP:0002860', (219, 222))	('Single nucleotide polymorphisms', 'Var', (303, 334))	('Squamous cell carcinoma', 'Phenotype', 'HP:0002860', (223, 246))	('lung cancer', 'Phenotype', 'HP:0100526', (394, 405))	('cancer', 'Phenotype', 'HP:0002664', (268, 274))	('Squamous cell carcinoma', 'Disease', (223, 246))	('Lung cancer', 'Disease', 'MESH:D008175', (113, 124))	('Squamous cell carcinoma', 'Disease', 'MESH:D002294', (223, 246))
145364	26498364	Consequentially, deregulation of RBPs can lead to cancer progression.	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('RBPs', 'Protein', (33, 37))	('lead to', 'Reg', (42, 49))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('deregulation', 'Var', (17, 29))
145367	26498364	Lastly, AUF1 regulates epithelial-mesenchymal transition and modified AUF1 activity, promotes cancer progression in various tissues.	('AUF1', 'Gene', (8, 12))	('modified', 'Var', (61, 69))	('AUF1', 'Gene', '3184', (70, 74))	('promotes', 'PosReg', (85, 93))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('regulates', 'Reg', (13, 22))	('AUF1', 'Gene', '3184', (8, 12))	('activity', 'MPA', (75, 83))	('epithelial-mesenchymal transition', 'CPA', (23, 56))	('AUF1', 'Gene', (70, 74))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
145386	26498364	Moreover, the identified mRNAs encoded proteins that were enriched in several biological pathways that play critical roles in cancer progression such as: kinase signaling, cytoskeleton regulation and apoptosis (Figure 1C and Table S3).	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('mRNAs', 'Var', (25, 30))	('encoded', 'Reg', (31, 38))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('proteins', 'Protein', (39, 47))
145409	26498364	Although it was determined that the splicing of the IR (insulin receptor), cTnT (cardiac tropinin T), CLC-1 (chloride channel type 1) and PKM (pyruvate kinase) by CELF1 can promote insulin resistance, cardiac abnormalities and muscle wasting in DM1 disease, the identity of the CELF1 cancer associated pre-mRNA splicing targets remain elusive.	('cancer', 'Disease', 'MESH:D009369', (284, 290))	('cTnT', 'Gene', '7139', (75, 79))	('muscle wasting', 'Disease', (227, 241))	('insulin receptor', 'Gene', (56, 72))	('muscle wasting', 'Phenotype', 'HP:0003202', (227, 241))	('cardiac tropinin T', 'Gene', (81, 99))	('muscle wasting', 'Disease', 'MESH:D009133', (227, 241))	('DM1 disease', 'Disease', 'MESH:D009223', (245, 256))	('splicing', 'Var', (36, 44))	('CELF1', 'Gene', (163, 168))	('IR', 'Gene', '3643', (52, 54))	('cTnT', 'Gene', (75, 79))	('promote', 'PosReg', (173, 180))	('insulin resistance', 'CPA', (181, 199))	('cardiac abnormalities', 'Phenotype', 'HP:0001627', (201, 222))	('DM1 disease', 'Disease', (245, 256))	('CLC-1', 'Gene', '1180', (102, 107))	('chloride channel type 1) and PKM', 'Gene', '5315', (109, 141))	('cancer', 'Disease', (284, 290))	('cardiac abnormalities', 'Disease', (201, 222))	('cancer', 'Phenotype', 'HP:0002664', (284, 290))	('cardiac tropinin T', 'Gene', '7139', (81, 99))	('CLC-1', 'Gene', (102, 107))	('cardiac abnormalities', 'Disease', 'MESH:D006331', (201, 222))	('insulin resistance', 'Phenotype', 'HP:0000855', (181, 199))	('insulin receptor', 'Gene', '3643', (56, 72))
145414	26498364	Most notably, compared to the expression of flanking exons in UMSCC-74B cells, CELF1 depletion caused a 5-fold increase in the exclusion of exon 49 in COL16A1 (collagen type XVI), which encodes an extracellular matrix protein involved in oral cancer cell proliferation and glioma cell invasion (Figure 2C).	('glioma', 'Phenotype', 'HP:0009733', (273, 279))	('cancer', 'Phenotype', 'HP:0002664', (243, 249))	('increase', 'PosReg', (111, 119))	('CELF1', 'Gene', (79, 84))	('COL16A1', 'Gene', (151, 158))	('UMSCC-74B', 'CellLine', 'CVCL:7780', (62, 71))	('exclusion', 'MPA', (127, 136))	('depletion', 'Var', (85, 94))	('glioma', 'Disease', (273, 279))	('oral cancer', 'Disease', 'MESH:D009062', (238, 249))	('glioma', 'Disease', 'MESH:D005910', (273, 279))	('oral cancer', 'Disease', (238, 249))	('COL16A1', 'Gene', '1307', (151, 158))
145416	26498364	The loss of exon 49 in COL16A1 according to our analysis, results in increased expression of a COL16A1 noncoding RNA product with the Ensembl transcript ID ENST00000488128 and a loss of expression of the APPRIS predicted principle isoform ENST00000373672 (NM_001856) in CELF1 knockdown cells.	('ID ENST00000488128', 'Disease', (153, 171))	('COL16A1', 'Gene', (95, 102))	('increased', 'PosReg', (69, 78))	('expression', 'MPA', (79, 89))	('COL16A1', 'Gene', '1307', (95, 102))	('COL16A1', 'Gene', '1307', (23, 30))	('ID ENST00000488128', 'Disease', 'MESH:C537985', (153, 171))	('expression', 'MPA', (186, 196))	('COL16A1', 'Gene', (23, 30))	('loss', 'NegReg', (178, 182))	('loss', 'Var', (4, 8))
145421	26498364	According to our RNA-seq data, the loss of CELF1 promoted the exclusion of exon 25 in ITGA6 (Figure 2E) a regulator of cell motility, invasion and proliferation.	('exclusion', 'NegReg', (62, 71))	('loss', 'Var', (35, 39))	('ITGA6', 'Gene', '3655', (86, 91))	('CELF1', 'Gene', (43, 48))	('ITGA6', 'Gene', (86, 91))
145441	26498364	We hypothesize, that if these CELF1 controlled mRNAs were important for tumor formation and/or progression, OHKC-CELF1 cells would have distinct relative mRNA and splice variant expression levels in comparison to control OHKC cells.	('tumor', 'Disease', (72, 77))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('OHKC-CELF1', 'Var', (108, 118))
145444	26498364	Although, an enhancement in the exclusion of exon 3 in TACC2 was observed in OHKC-CELF1 cells compared to control OHKC cells, this difference was not statistically significant (Figure 4F).	('TACC2', 'Gene', '10579', (55, 60))	('TACC2', 'Gene', (55, 60))	('enhancement', 'PosReg', (13, 24))	('OHKC-CELF1', 'Var', (77, 87))	('exon', 'Protein', (45, 49))	('exclusion', 'MPA', (32, 41))
145448	26498364	Interestingly, overexpression of CELF1 led to an increase in total EGFR as well as phosphorylated (Y1148) EGFR protein (Figure 4G).	('increase', 'PosReg', (49, 57))	('overexpression', 'PosReg', (15, 29))	('phosphorylated', 'MPA', (83, 97))	('CELF1', 'Gene', (33, 38))	('Y1148', 'Var', (99, 104))	('EGFR', 'Gene', '1956', (106, 110))	('EGFR', 'Gene', '1956', (67, 71))	('EGFR', 'Gene', (67, 71))	('EGFR', 'Gene', (106, 110))
145449	26498364	The elevated EGFR levels resulted in enhanced expression of downstream EGFR targets such as pAKT (S473) and pPTEN (S380) (Figure 4G).	('EGFR', 'Gene', '1956', (13, 17))	('pAKT', 'Disease', (92, 96))	('EGFR', 'Gene', '1956', (71, 75))	('S473', 'Var', (98, 102))	('enhanced', 'PosReg', (37, 45))	('expression', 'MPA', (46, 56))	('EGFR', 'Gene', (71, 75))	('EGFR', 'Gene', (13, 17))
145454	26498364	Lastly, E-cadherin, is known to regulate cell proliferation and is a key player in the epithelial-mesenchymal transition (EMT); however, the loss of E-cadherin can protect cells from the induction of apoptosis.	('E-cadherin', 'Gene', (8, 18))	('E-cadherin', 'Gene', '999', (8, 18))	('loss', 'Var', (141, 145))	('E-cadherin', 'Gene', (149, 159))	('E-cadherin', 'Gene', '999', (149, 159))
145456	26498364	OHKC-CELF1 cells had a marked reduction in E-cadherin protein and ~1.5 fold reduction in E-cadherin mRNA compared to OHKC control cells (Figure 4G).	('reduction', 'NegReg', (76, 85))	('E-cadherin', 'Gene', (43, 53))	('OHKC-CELF1', 'Var', (0, 10))	('E-cadherin', 'Gene', '999', (43, 53))	('E-cadherin', 'Gene', (89, 99))	('E-cadherin', 'Gene', '999', (89, 99))	('reduction', 'NegReg', (30, 39))
145459	26498364	In the presence of 1muM Gefitinib, OHKC-CELF1 cells treated with H2O2 exhibited a significant ~20% reduction in cell survival compared to OHKC-CELF1 cells treated with DMSO and H2O2 (Figure 4H).	('Gefitinib', 'Chemical', 'MESH:D000077156', (24, 33))	('reduction', 'NegReg', (99, 108))	('H2O2', 'Chemical', 'MESH:D006861', (177, 181))	('DMSO', 'Chemical', 'MESH:D004121', (168, 172))	('cell survival', 'CPA', (112, 125))	('H2O2', 'Chemical', 'MESH:D006861', (65, 69))	('H2O2', 'Var', (65, 69))
145477	26498364	Interestingly, the loss of CELF1 protein promotes the alternative splicing of COL16A1, resulting in the expression of a noncoding COL16A1 RNA product.	('COL16A1', 'Gene', (78, 85))	('CELF1', 'Gene', (27, 32))	('alternative splicing', 'MPA', (54, 74))	('COL16A1', 'Gene', '1307', (130, 137))	('COL16A1', 'Gene', '1307', (78, 85))	('promotes', 'PosReg', (41, 49))	('expression', 'MPA', (104, 114))	('loss', 'Var', (19, 23))	('protein', 'Protein', (33, 40))	('COL16A1', 'Gene', (130, 137))
145519	32003423	Additionally, genetic mutations of ID family members were identified in lung cancer, and it was suggested that amplification and deep deletion were the main mutation types.	('deep deletion', 'Var', (129, 142))	('lung cancer', 'Disease', (72, 83))	('lung cancer', 'Phenotype', 'HP:0100526', (72, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('lung cancer', 'Disease', 'MESH:D008175', (72, 83))
145521	32003423	The aberrant expression of ID family members may affect the occurrence and prognosis of lung cancer, and may be related to cell metabolism and transcriptional regulation.	('affect', 'Reg', (49, 55))	('lung cancer', 'Disease', (88, 99))	('related', 'Reg', (112, 119))	('occurrence', 'CPA', (60, 70))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('lung cancer', 'Disease', 'MESH:D008175', (88, 99))	('aberrant expression', 'Var', (4, 23))	('prognosis', 'CPA', (75, 84))	('lung cancer', 'Phenotype', 'HP:0100526', (88, 99))
145573	32003423	For AJCC stages, it was demonstrated that ID1 (AJCC stage N0), ID2 (AJCC stage M0) and ID3 (AJCC stage T4) were significantly associated with unfavorable OS in lung cancer.	('OS', 'Chemical', '-', (154, 156))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('associated with', 'Reg', (126, 141))	('ID1', 'Gene', (42, 45))	('lung cancer', 'Disease', 'MESH:D008175', (160, 171))	('ID2', 'Gene', '3398', (63, 66))	('ID1', 'Gene', '3397', (42, 45))	('ID3', 'Var', (87, 90))	('ID2', 'Gene', (63, 66))	('lung cancer', 'Disease', (160, 171))	('lung cancer', 'Phenotype', 'HP:0100526', (160, 171))
145581	32003423	As shown in Figure 5A, genetic mutations in ID family members were present in different lung cancer types, including lung squamous cell carcinoma and lung adenocarcinoma, compared with other cancer types.	('lung cancer', 'Disease', (88, 99))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (150, 169))	('carcinoma', 'Phenotype', 'HP:0030731', (160, 169))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('cancer', 'Disease', (191, 197))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('lung cancer', 'Disease', 'MESH:D008175', (88, 99))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('lung cancer', 'Phenotype', 'HP:0100526', (88, 99))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (117, 145))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (150, 169))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (122, 145))	('present', 'Reg', (67, 74))	('lung adenocarcinoma', 'Disease', (150, 169))	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (191, 197))	('genetic mutations', 'Var', (23, 40))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (117, 145))	('lung squamous cell carcinoma', 'Disease', (117, 145))
145583	32003423	In lung squamous cell carcinoma (TCGA; Provisional), the mutation frequencies of ID1/2/3/4 were 6, 1.8, 0.4 and 3%, respectively, and gene amplification accounted for the majority of genetic changes for ID1/2/4, while deep deletions accounted for the majority of changes for ID3.	('ID1/2/3/4', 'Gene', (81, 90))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (8, 31))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (3, 31))	('lung squamous cell carcinoma', 'Disease', (3, 31))	('deep deletions', 'Var', (218, 232))	('ID1/2/4', 'Gene', '3397;3398;3400', (203, 210))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (3, 31))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('ID1/2/4', 'Gene', (203, 210))	('ID1/2/3/4', 'Gene', '3397;3398;3399;3400', (81, 90))	('gene amplification', 'Var', (134, 152))
145608	32003423	found that 26.7% of ID3-/- mice developed lymphoma, while none of the ID3+/+ or ID3+/- mice had lymphoma.	('ID3-/-', 'Var', (20, 26))	('mice', 'Species', '10090', (27, 31))	('lymphoma', 'Disease', (96, 104))	('mice', 'Species', '10090', (87, 91))	('lymphoma', 'Disease', (42, 50))	('lymphoma', 'Disease', 'MESH:D008223', (96, 104))	('developed', 'PosReg', (32, 41))	('lymphoma', 'Disease', 'MESH:D008223', (42, 50))	('lymphoma', 'Phenotype', 'HP:0002665', (96, 104))	('lymphoma', 'Phenotype', 'HP:0002665', (42, 50))
145609	32003423	Therefore, a deficiency of the ID3 gene increases the possibility of gammadelta T-cell lymphoma.	('ID3', 'Gene', (31, 34))	('deficiency', 'Var', (13, 23))	('cell lymphoma', 'Phenotype', 'HP:0012191', (82, 95))	('T-cell lymphoma', 'Phenotype', 'HP:0012190', (80, 95))	('lymphoma', 'Phenotype', 'HP:0002665', (87, 95))	('T-cell lymphoma', 'Disease', (80, 95))	('T-cell lymphoma', 'Disease', 'MESH:D016399', (80, 95))
145612	32003423	The present results suggested that there were mutations in ID1/2/3/4, which were predominately amplification and deep deletion mutations.	('ID1/2/3/4', 'Gene', '3397;3398;3399;3400', (59, 68))	('deep deletion mutations', 'Var', (113, 136))	('ID1/2/3/4', 'Gene', (59, 68))
145619	32003423	Moreover, previous studies have reported that inactivation of tumor suppressors and activation of oncogenes can promote the occurrence and development of tumors by regulating the biosynthesis of nucleotides.	('occurrence', 'CPA', (124, 134))	('development', 'CPA', (139, 150))	('tumors', 'Disease', (154, 160))	('tumors', 'Disease', 'MESH:D009369', (154, 160))	('promote', 'PosReg', (112, 119))	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('tumor', 'Disease', (62, 67))	('oncogenes', 'Gene', (98, 107))	('regulating', 'Reg', (164, 174))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('biosynthesis of nucleotides', 'MPA', (179, 206))	('inactivation', 'Var', (46, 58))	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('tumor', 'Disease', (154, 159))
145623	32003423	The present results suggested that genetic mutations and mRNA expression levels were abnormal in patients with lung cancer.	('mRNA expression levels', 'MPA', (57, 79))	('lung cancer', 'Disease', 'MESH:D008175', (111, 122))	('abnormal', 'Reg', (85, 93))	('lung cancer', 'Phenotype', 'HP:0100526', (111, 122))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('lung cancer', 'Disease', (111, 122))	('genetic mutations', 'Var', (35, 52))	('patients', 'Species', '9606', (97, 105))
145628	30647454	APOBEC-induced mutations and their cancer effect size in head and neck squamous cell carcinoma Recent studies have revealed the mutational signatures underlying the somatic evolution of cancer, and the prevalences of associated somatic genetic variants.	('APOBEC-induced', 'Gene', (0, 14))	('neck squamous cell carcinoma', 'Disease', (66, 94))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (71, 94))	('mutations', 'Var', (15, 24))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (66, 94))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (57, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('cancer', 'Disease', (35, 41))	('cancer', 'Disease', (186, 192))	('cancer', 'Disease', 'MESH:D009369', (186, 192))
145629	30647454	Here we estimate the intensity of positive selection that drives mutations to high frequency in tumors, yielding higher prevalences than expected on the basis of mutation and neutral drift alone.	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumors', 'Disease', (96, 102))	('prevalences', 'MPA', (120, 131))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('higher', 'PosReg', (113, 119))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('mutations', 'Var', (65, 74))
145630	30647454	We apply this approach to a sample of 525 head and neck squamous cell carcinoma exomes, producing a rank-ordered list of gene variants by selection intensity.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (56, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('variants', 'Var', (126, 134))	('neck squamous cell carcinoma', 'Disease', (51, 79))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (51, 79))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (42, 79))
145632	30647454	Furthermore, we extend our analysis of effect size by quantifying the degree to which mutational processes (such as APOBEC mutagenesis) contributes mutations that are highly selected, driving head and neck squamous cell carcinoma.	('driving', 'PosReg', (184, 191))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (206, 229))	('mutations', 'Var', (148, 157))	('neck squamous cell carcinoma', 'Disease', (201, 229))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (192, 229))	('carcinoma', 'Phenotype', 'HP:0030731', (220, 229))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (201, 229))
145633	30647454	We calculate the substitutions caused by APOBEC mutagenesis that make the greatest contribution to cancer phenotype among patients.	('mutagenesis', 'Var', (48, 59))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('APOBEC', 'Gene', (41, 47))	('cancer', 'Disease', (99, 105))	('patients', 'Species', '9606', (122, 130))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
145634	30647454	Lastly, we demonstrate via in vitro biochemical experiments that the APOBEC3B protein can deaminate the cytosine bases at two sites whose mutant states are subject to high net realized selection intensities:PIK3CA E545K and E542K.	('E545K', 'Var', (214, 219))	('PIK3CA', 'Gene', '5290', (207, 213))	('deaminate the cytosine bases', 'MPA', (90, 118))	('E542K', 'Mutation', 'rs121913273', (224, 229))	('APOBEC3B', 'Gene', '9582', (69, 77))	('APOBEC3B', 'Gene', (69, 77))	('PIK3CA', 'Gene', (207, 213))	('cytosine', 'Chemical', 'MESH:D003596', (104, 112))	('protein', 'Protein', (78, 85))	('E545K', 'Mutation', 'rs104886003', (214, 219))	('E542K', 'Var', (224, 229))
145635	30647454	By quantifying the effects of mutations, we deepen the molecular understanding of carcinogenesis in head and neck squamous cell carcinoma.	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (109, 137))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (114, 137))	('carcinogenesis', 'Disease', 'MESH:D063646', (82, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('carcinogenesis', 'Disease', (82, 96))	('mutations', 'Var', (30, 39))	('neck squamous cell carcinoma', 'Disease', (109, 137))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (100, 137))
145636	30647454	Cancer has long been known to have a basis in somatic mutations that alter a diversity of cellular functions resulting in sustained proliferative signaling, evasion of growth suppressors, and genome instability.	('mutations', 'Var', (54, 63))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('genome instability', 'CPA', (192, 210))	('alter', 'Reg', (69, 74))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('evasion', 'MPA', (157, 164))	('sustained proliferative signaling', 'MPA', (122, 155))	('growth suppressors', 'CPA', (168, 186))
145638	30647454	However, knowing the source of mutations and the rate at which they occur provides only the first step to understanding the genetic origins of substitutions that drive tumorigenesis and cancer development.	('tumor', 'Disease', (168, 173))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('drive', 'PosReg', (162, 167))	('substitutions', 'Var', (143, 156))	('cancer', 'Disease', (186, 192))	('cancer', 'Disease', 'MESH:D009369', (186, 192))
145639	30647454	After mutations occur, the mutations that are important to cancer cell survival and propagation become prevalent in tumors because of their oncogenic effect on cancer cell lineages.	('tumors', 'Disease', (116, 122))	('tumors', 'Disease', 'MESH:D009369', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('cancer', 'Disease', (160, 166))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('mutations', 'Var', (6, 15))
145640	30647454	Quantifying the strength of selection of each mutation provides insight into the relative importance of mutations in driver genes, while examination of the relative contributions of different mutational processes can reveal the relative importance of each process to tumorigenesis.	('mutations', 'Var', (104, 113))	('tumor', 'Disease', 'MESH:D009369', (267, 272))	('tumor', 'Phenotype', 'HP:0002664', (267, 272))	('tumor', 'Disease', (267, 272))	('mutation', 'Var', (46, 54))
145641	30647454	Mutational processes are of particular importance in head and neck squamous cell carcinoma (HNSCC) because of the high proportion of mutations that are attributed to APOBEC (apolipoprotein B mRNA editing catalytic polypeptide-like) enzymes in HNSCC tumors.	('tumors', 'Phenotype', 'HP:0002664', (249, 255))	('apolipoprotein B', 'Gene', '338', (174, 190))	('neck squamous cell carcinoma', 'Disease', (62, 90))	('HNSCC tumors', 'Disease', (243, 255))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (62, 90))	('tumor', 'Phenotype', 'HP:0002664', (249, 254))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (67, 90))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (53, 90))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('mutations', 'Var', (133, 142))	('HNSCC tumors', 'Disease', 'MESH:D000077195', (243, 255))	('APOBEC', 'Gene', (166, 172))	('apolipoprotein B', 'Gene', (174, 190))
145643	30647454	Consequently, APOBEC mutagenesis is believed to play a role in the genesis of human papillomavirus-associated (HPV+) HNSCC.	('HPV', 'Species', '10566', (111, 114))	('human papillomavirus', 'Species', '10566', (78, 98))	('mutagenesis', 'Var', (21, 32))	('human papillomavirus-associated', 'Disease', (78, 109))
145649	30647454	Among HPV-associated cancers, the predominant substitutions occurring are activating mutations of PIK3CA, inactivating mutations of TRAF3 or CYLD, and amplification of FGFR3 and the cell cycle gene E2F.	('activating', 'PosReg', (74, 84))	('FGFR3', 'Gene', '2261', (168, 173))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('HPV', 'Species', '10566', (6, 9))	('TRAF3', 'Gene', (132, 137))	('substitutions', 'Var', (46, 59))	('CYLD', 'Disease', 'None', (141, 145))	('PIK3CA', 'Gene', (98, 104))	('FGFR3', 'Gene', (168, 173))	('PIK3CA', 'Gene', '5290', (98, 104))	('CYLD', 'Disease', (141, 145))	('TRAF3', 'Gene', '7187', (132, 137))	('cancers', 'Disease', 'MESH:D009369', (21, 28))	('cancers', 'Phenotype', 'HP:0002664', (21, 28))	('cancers', 'Disease', (21, 28))	('E2F', 'Gene', (198, 201))	('inactivating mutations', 'Var', (106, 128))	('amplification', 'Var', (151, 164))
145650	30647454	Among HPV-unrelated cancers, inactivating substitutions in the tumor suppressor genes TP53 and CDKN2A are predominant.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('tumor', 'Disease', (63, 68))	('TP53', 'Gene', '7157', (86, 90))	('CDKN2A', 'Gene', (95, 101))	('TP53', 'Gene', (86, 90))	('CDKN2A', 'Gene', '1029', (95, 101))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('inactivating substitutions', 'Var', (29, 55))	('cancers', 'Phenotype', 'HP:0002664', (20, 27))	('HPV-unrelated cancers', 'Disease', 'MESH:D030361', (6, 27))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('HPV-unrelated cancers', 'Disease', (6, 27))
145654	30647454	A previous report suggests that HPV- HNSCC is characterized by a tobacco-associated mutational signature, while HPV+ cancers display an APOBEC3 signature and APOBEC3-mediated driver mutations, including characteristic helical domain PIK3CA mutations.	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('PIK3CA', 'Gene', (233, 239))	('helical domain', 'Var', (218, 232))	('PIK3CA', 'Gene', '5290', (233, 239))	('tobacco', 'Species', '4097', (65, 72))	('HPV', 'Species', '10566', (32, 35))	('cancers', 'Phenotype', 'HP:0002664', (117, 124))	('HPV- HNSCC', 'Disease', (32, 42))	('HPV', 'Species', '10566', (112, 115))	('cancers', 'Disease', 'MESH:D009369', (117, 124))	('mutations', 'Var', (240, 249))	('cancers', 'Disease', (117, 124))
145659	30647454	Sequencing-based analyses have expanded our molecular understanding of the disease, and have equated the prevalence of a somatic substitution in tumors of the affected population with its importance in perturbing signaling pathways and tumor development.	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('substitution', 'Var', (129, 141))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('signaling pathways', 'Pathway', (213, 231))	('tumor', 'Disease', 'MESH:D009369', (236, 241))	('tumors', 'Disease', (145, 151))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('tumor', 'Disease', (145, 150))	('perturbing', 'Reg', (202, 212))	('tumor', 'Phenotype', 'HP:0002664', (236, 241))	('tumors', 'Disease', 'MESH:D009369', (145, 151))	('tumor', 'Disease', (236, 241))
145661	30647454	In contrast, quantification of the effects that mutations confer upon the cancer phenotype should assist with prioritization of future precision-targeted therapies, as well as identify rare substitutions that are significant drivers of tumorigenesis and tumor maintenance.	('effects', 'Reg', (35, 42))	('tumor', 'Disease', (254, 259))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('substitutions', 'Var', (190, 203))	('tumor', 'Disease', 'MESH:D009369', (236, 241))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('cancer', 'Disease', (74, 80))	('tumor', 'Phenotype', 'HP:0002664', (254, 259))	('tumor', 'Phenotype', 'HP:0002664', (236, 241))	('tumor', 'Disease', 'MESH:D009369', (254, 259))	('tumor', 'Disease', (236, 241))	('mutations', 'Var', (48, 57))
145662	30647454	To characterize these effects, we analyzed a sample of 508 HNSCC tumors from the National Cancer Institute Genomic Data Commons and 17 HNSCC tumors from Hedberg et al.. We evaluated the mutational signatures characteristic of HPV- and HPV+ HNSCC, quantifying the role that APOBEC plays as a mutagenic factor in HNSCC.	('Cancer', 'Phenotype', 'HP:0002664', (90, 96))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('HNSCC tumors', 'Disease', 'MESH:D000077195', (135, 147))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('HNSCC tumors', 'Disease', (59, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('Cancer', 'Disease', (90, 96))	('Cancer', 'Disease', 'MESH:D009369', (90, 96))	('HNSCC tumors', 'Disease', 'MESH:D000077195', (59, 71))	('HPV', 'Species', '10566', (235, 238))	('HPV+', 'Var', (235, 239))	('HNSCC tumors', 'Disease', (135, 147))	('HPV', 'Species', '10566', (226, 229))
145663	30647454	We then examined individual substitutions to evaluate the characteristic mutational signature of APOBEC-induced mutations in HNSCC and, noting in particular whether the APOBEC signature is characterized by TCW transition and transversion mutations (wherein the mutated cytosine is underlined), confirmed informatic analysis with in vitro experiment.	('mutations', 'Var', (112, 121))	('cytosine', 'Chemical', 'MESH:D003596', (269, 277))	('TC', 'Chemical', 'MESH:D013667', (206, 208))	('HNSCC', 'Gene', (125, 130))
145666	30647454	Our analysis confirmed well-known HNSCC tumorigenic targets, but also highlights low-prevalence mutations that are major drivers in a minority of patients, and implicates novel targets as potential drivers in HNSCC development.	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('HNSCC', 'Disease', (209, 214))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('patients', 'Species', '9606', (146, 154))	('mutations', 'Var', (96, 105))
145670	30647454	Non-HPV-driven cancer frequently exhibited TP53 substitutions and an absence of p16 expression, although in some cases HPV was present at low viral load.	('substitutions', 'Var', (48, 61))	('HPV', 'Species', '10566', (4, 7))	('TP53', 'Gene', '7157', (43, 47))	('Non-HPV-driven cancer', 'Disease', 'MESH:D030361', (0, 21))	('exhibited', 'Reg', (33, 42))	('Non-HPV-driven cancer', 'Disease', (0, 21))	('absence', 'NegReg', (69, 76))	('p16', 'Protein', (80, 83))	('expression', 'MPA', (84, 94))	('TP53', 'Gene', (43, 47))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('HPV', 'Species', '10566', (119, 122))
145672	30647454	Indeed, 93 out of 508 TCGA HNSCC tumors had detectable portions of the HPV genome using this method, and 24 of these 93 tumors had substitutions in TP53, meaning they were unlikely to be driven by viral oncogenesis due to the criteria outlined above; thus, we applied an alternate method of detecting viral sequences in RNA-Seq data that has been relied upon in previous studies.	('tumors', 'Disease', (120, 126))	('tumors', 'Disease', 'MESH:D009369', (120, 126))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('TC', 'Chemical', 'MESH:D013667', (22, 24))	('TP53', 'Gene', '7157', (148, 152))	('TP53', 'Gene', (148, 152))	('substitutions', 'Var', (131, 144))	('HNSCC tumors', 'Disease', (27, 39))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumors', 'Disease', 'MESH:D009369', (33, 39))	('HPV', 'Species', '10566', (71, 74))	('HNSCC tumors', 'Disease', 'MESH:D000077195', (27, 39))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('tumors', 'Disease', (33, 39))
145673	30647454	Among TCGA samples with available HPV status and available mRNA expression data (429 HPV- and 66 HPV+ tumors, mRNA expression data obtained from cBioPortal), mRNA expression was higher for APOBEC3B, APOBEC3C, APOBEC3D, APOBEC3F, APOBEC3G, and APOBEC3H in HPV+ vs HPV- tumors (P < 0.001, one-sided Welch's t tests), and APOBEC3A mRNA expression levels were not significantly different between the two HPV classifications (P = 0.38, one-sided Welch's t test; Figure S1), as previously reported on a smaller subset of HNSC tumors.	('APOBEC3H', 'Gene', '164668', (243, 251))	('HPV- tumors', 'Disease', 'MESH:D030361', (263, 274))	('HPV+ tumors', 'Disease', (97, 108))	('APOBEC3B', 'Gene', '9582', (189, 197))	('APOBEC3H', 'Gene', (243, 251))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('APOBEC3C', 'Var', (199, 207))	('HNSC tumors', 'Disease', 'MESH:D009369', (515, 526))	('tumor', 'Phenotype', 'HP:0002664', (268, 273))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('HNSC tumors', 'Disease', (515, 526))	('tumors', 'Phenotype', 'HP:0002664', (520, 526))	('APOBEC3D', 'Var', (209, 217))	('tumors', 'Phenotype', 'HP:0002664', (268, 274))	('APOBEC3G', 'Gene', '60489', (229, 237))	('TC', 'Chemical', 'MESH:D013667', (6, 8))	('HPV', 'Species', '10566', (400, 403))	('HPV- tumors', 'Disease', (263, 274))	('mRNA', 'MPA', (110, 114))	('HPV', 'Species', '10566', (34, 37))	('HPV', 'Species', '10566', (255, 258))	('tumor', 'Phenotype', 'HP:0002664', (520, 525))	('HPV', 'Species', '10566', (97, 100))	('mRNA expression', 'MPA', (158, 173))	('higher', 'PosReg', (178, 184))	('APOBEC3B', 'Gene', (189, 197))	('APOBEC3F', 'Var', (219, 227))	('HPV', 'Species', '10566', (263, 266))	('HPV+ tumors', 'Disease', 'MESH:D030361', (97, 108))	('APOBEC3A', 'Gene', (319, 327))	('APOBEC3A', 'Gene', '200315', (319, 327))	('APOBEC3G', 'Gene', (229, 237))	('HPV', 'Species', '10566', (85, 88))
145674	30647454	Within the germline TCGA data, the distribution of the global APOBEC3H haplotypes are 27.6% haplotype 1, 17.7% haplotype 2, 11.8% haplotype 3, 42.3% haplotype 4, and 0.6% other.	('haplotype 3', 'Var', (130, 141))	('APOBEC3H', 'Gene', (62, 70))	('haplotype 1', 'Var', (92, 103))	('haplotype', 'Var', (149, 158))	('TC', 'Chemical', 'MESH:D013667', (20, 22))	('APOBEC3H', 'Gene', '164668', (62, 70))	('haplotype 2', 'Var', (111, 122))
145679	30647454	The dominant signatures in these trinucleotide mutation profiles include APOBEC-related C T and C G mutations in the TCW motif context, and C T mutations in a 5'-CG-3' context that are likely reflective of spontaneous deamination of 5-methylcytosine and correlated with aging (Signature 1 of 30).	('mutations', 'Var', (100, 109))	('C G', 'Gene', (96, 99))	('C T', 'Gene', (140, 143))	('trinucleotide', 'Chemical', '-', (33, 46))	('TC', 'Chemical', 'MESH:D013667', (117, 119))	('APOBEC-related C T', 'Gene', (73, 91))	('5-methylcytosine', 'Chemical', 'MESH:D044503', (233, 249))	('mutations', 'Var', (144, 153))
145680	30647454	All 30 COSMIC mutational signatures were represented in one or more of the 461 HNSCC primary tumors examined that exhibited greater than 50 mutations (Fig.	('primary tumors', 'Disease', 'MESH:D009369', (85, 99))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('mutations', 'Var', (140, 149))	('primary tumors', 'Disease', (85, 99))
145689	30647454	Among tumors with an APOBEC signature, HPV+ samples typically exhibited a higher proportion of the TCW to TKW mutations that are commonly attributed to APOBEC (P = 0.008, two-sided Wilcoxon rank-sum test).	('mutations', 'Var', (110, 119))	('higher', 'PosReg', (74, 80))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('TC', 'Chemical', 'MESH:D013667', (99, 101))	('TCW to', 'Gene', (99, 105))	('tumors', 'Disease', (6, 12))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('HPV', 'Species', '10566', (39, 42))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))
145690	30647454	Nevertheless, the majority of TCW to TKW mutations among tumors with an APOBEC signal occurred within HPV- tumors, as a supermajority of tumors were HPV-.	('tumors', 'Disease', (137, 143))	('TCW to TKW', 'Gene', (30, 40))	('tumors', 'Disease', 'MESH:D009369', (57, 63))	('mutations', 'Var', (41, 50))	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('TC', 'Chemical', 'MESH:D013667', (30, 32))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('HPV- tumors', 'Disease', 'MESH:D030361', (102, 113))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumors', 'Disease', (107, 113))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('HPV- tumors', 'Disease', (102, 113))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('occurred', 'Reg', (86, 94))	('HPV', 'Species', '10566', (149, 152))	('tumors', 'Disease', 'MESH:D009369', (107, 113))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumors', 'Disease', (57, 63))	('HPV', 'Species', '10566', (102, 105))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
145692	30647454	Much of the difference in the frequencies of substitutions between HPV+ and HPV- HNSCC can be attributed to different selective intensities imposed by mutations occurring in the HPV+ vs. HPV- context.	('substitutions', 'Var', (45, 58))	('HPV', 'Species', '10566', (187, 190))	('HPV', 'Species', '10566', (76, 79))	('HPV', 'Species', '10566', (67, 70))	('mutations', 'Var', (151, 160))	('HPV', 'Species', '10566', (178, 181))
145693	30647454	These recurrent variants represent the point mutations that are the strongest drivers of the neoplastic HNSCC disease phenotype.	('variants', 'Var', (16, 24))	('neoplastic HNSCC disease', 'Disease', 'MESH:D000077195', (93, 117))	('neoplastic HNSCC disease', 'Disease', (93, 117))
145695	30647454	Substitutions in TP53 and HRAS are frequent in HPV-, but are almost never found in HPV+.	('HPV', 'Species', '10566', (83, 86))	('HPV-', 'Disease', (47, 51))	('Substitutions', 'Var', (0, 13))	('HRAS', 'Gene', '3265', (26, 30))	('frequent', 'Reg', (35, 43))	('TP53', 'Gene', '7157', (17, 21))	('HPV', 'Species', '10566', (47, 50))	('TP53', 'Gene', (17, 21))	('HRAS', 'Gene', (26, 30))
145696	30647454	Among all variants, four recurrent substitutions are shared (MAPK1 E322K, PIK3CA E542K and E545K, and FBXW7 R505G) and have similar selection intensities within the two tumor types (Fig.	('FBXW7', 'Gene', '55294', (102, 107))	('E545K', 'Var', (91, 96))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('R505G', 'Mutation', 'rs149680468', (108, 113))	('PIK3CA', 'Gene', '5290', (74, 80))	('FBXW7', 'Gene', (102, 107))	('R505G', 'Var', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('MAPK1', 'Gene', '5594', (61, 66))	('E542K', 'Var', (81, 86))	('E542K', 'Mutation', 'rs121913273', (81, 86))	('E322K', 'Mutation', 'rs1057519911', (67, 72))	('tumor', 'Disease', (169, 174))	('E322K', 'Var', (67, 72))	('E545K', 'Mutation', 'rs104886003', (91, 96))	('PIK3CA', 'Gene', (74, 80))	('MAPK1', 'Gene', (61, 66))
145698	30647454	Several of the most-selected variants occurred in genes:TP53, HRAS, PIK3CA, MAPK1: previously associated with the landscape of substitutions observed in HNSCC via genomic screening.	('HRAS', 'Gene', '3265', (62, 66))	('PIK3CA', 'Gene', (68, 74))	('MAPK1', 'Gene', '5594', (76, 81))	('TP53', 'Gene', '7157', (56, 60))	('HRAS', 'Gene', (62, 66))	('PIK3CA', 'Gene', '5290', (68, 74))	('variants', 'Var', (29, 37))	('associated', 'Reg', (94, 104))	('TP53', 'Gene', (56, 60))	('MAPK1', 'Gene', (76, 81))
145699	30647454	Interestingly, one of the most strongly selected variants among HPV- HNSCC (and the strongest selected variant in HPV+ HNSCCs) is characterized by a low expected mutation frequency and a low prevalence of oncogenic substitution, occurring in the E3 ubiquitin ligase-encoding gene FBXW7, a known tumor suppressor which has been molecularly characterized as a regulator of common HNSCC oncogenes.	('FBXW7', 'Gene', (280, 285))	('variants', 'Var', (49, 57))	('HPV', 'Species', '10566', (114, 117))	('tumor', 'Disease', 'MESH:D009369', (295, 300))	('tumor', 'Phenotype', 'HP:0002664', (295, 300))	('tumor', 'Disease', (295, 300))	('HPV', 'Species', '10566', (64, 67))	('FBXW7', 'Gene', '55294', (280, 285))
145701	30647454	Other variants with high inferred intensity of selection implicate novel candidate genes in HNSCC tumorigenesis or cancer development also deserve further attention to validate their role.	('cancer', 'Disease', (115, 121))	('variants', 'Var', (6, 14))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('HNSCC', 'Disease', (92, 97))	('tumor', 'Disease', (98, 103))	('cancer', 'Disease', 'MESH:D009369', (115, 121))
145703	30647454	The four lowest selection intensities among recurrently observed mutations in HPV+ tumors were one substitution within the second longest human protein MUC16 (the MUC16 gene is subject to frequent mutation in cancers and is likely spuriously associated with tumorigenesis), and three synonymous substitutions within ALPK3, PCDHA6, and COL6A6.	('ALPK3', 'Gene', '57538', (316, 321))	('tumor', 'Disease', (258, 263))	('tumor', 'Disease', (83, 88))	('MUC16', 'Gene', '94025', (152, 157))	('tumor', 'Disease', 'MESH:D009369', (258, 263))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('MUC16', 'Gene', (163, 168))	('mutations', 'Var', (65, 74))	('cancers', 'Disease', 'MESH:D009369', (209, 216))	('HPV+ tumors', 'Disease', (78, 89))	('tumor', 'Phenotype', 'HP:0002664', (258, 263))	('COL6A6', 'Gene', (335, 341))	('MUC16', 'Gene', (152, 157))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('PCDHA6', 'Gene', '56142', (323, 329))	('PCDHA6', 'Gene', (323, 329))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('COL6A6', 'Gene', '131873', (335, 341))	('associated', 'Reg', (242, 252))	('lowest', 'NegReg', (9, 15))	('human', 'Species', '9606', (138, 143))	('cancers', 'Phenotype', 'HP:0002664', (209, 216))	('cancers', 'Disease', (209, 216))	('MUC16', 'Gene', '94025', (163, 168))	('ALPK3', 'Gene', (316, 321))	('HPV+ tumors', 'Disease', 'MESH:D030361', (78, 89))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
145704	30647454	Among the 314 recurrent amino acid substitutions in the HPV+ and HPV- datasets, 62 were the product of a TCW to TKW nucleotide mutation, and thus can be putatively associated with APOBEC mutagenesis.	('amino acid substitutions', 'Var', (24, 48))	('TC', 'Chemical', 'MESH:D013667', (105, 107))	('HPV', 'Species', '10566', (65, 68))	('associated', 'Reg', (164, 174))	('APOBEC', 'Disease', (180, 186))	('HPV', 'Species', '10566', (56, 59))
145705	30647454	Substitutions that could putatively be attributed to APOBEC mutagenesis typically exhibited a lower selection intensity than substitutions that are not in a TCW to TKW trinucleotide context (Fig.	('trinucleotide', 'Chemical', '-', (168, 181))	('TC', 'Chemical', 'MESH:D013667', (157, 159))	('lower', 'NegReg', (94, 99))	('Substitutions', 'Var', (0, 13))	('mutagenesis', 'Var', (60, 71))	('selection intensity', 'MPA', (100, 119))
145706	30647454	Next, we quantified tumor burden arising from APOBEC processes by evaluating which mutations have the largest effect on cancer growth and the highest prevalences among tumors, and distinguished whether these mutations most likely result from APOBEC mutagenesis.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('mutations', 'Var', (83, 92))	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('tumor', 'Disease', (168, 173))	('tumors', 'Disease', (168, 174))	('prevalences', 'MPA', (150, 161))	('cancer', 'Disease', (120, 126))	('tumors', 'Disease', 'MESH:D009369', (168, 174))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('tumor', 'Disease', (20, 25))
145707	30647454	Among mutations that were likely APOBEC-independent, FBXW7 R505G, EP300 D1399N, PIK3CA H1047R, and several mutations in TP53 had the highest net realized selection intensity.	('FBXW7', 'Gene', (53, 58))	('H1047R', 'Var', (87, 93))	('R505G', 'Var', (59, 64))	('D1399N', 'Mutation', 'p.D1399N', (72, 78))	('EP300 D1399N', 'Var', (66, 78))	('H1047R', 'Mutation', 'rs121913279', (87, 93))	('PIK3CA', 'Gene', (80, 86))	('FBXW7', 'Gene', '55294', (53, 58))	('PIK3CA', 'Gene', '5290', (80, 86))	('TP53', 'Gene', '7157', (120, 124))	('R505G', 'Mutation', 'rs149680468', (59, 64))	('TP53', 'Gene', (120, 124))
145708	30647454	Among mutations that were likely APOBEC induced, FBXW7 R505G, PIK3CA E545K, FGFR3 S249C, PIK3CA E542K, and DHX15 R399H had the highest net realized selection intensities.	('S249C', 'Mutation', 'rs121913483', (82, 87))	('R399H', 'Mutation', 'rs754378482', (113, 118))	('PIK3CA', 'Gene', (89, 95))	('PIK3CA', 'Gene', (62, 68))	('E545K', 'Mutation', 'rs104886003', (69, 74))	('FBXW7', 'Gene', '55294', (49, 54))	('PIK3CA', 'Gene', '5290', (89, 95))	('E542K', 'Mutation', 'rs121913273', (96, 101))	('R505G', 'Mutation', 'rs149680468', (55, 60))	('FGFR3', 'Gene', '2261', (76, 81))	('DHX15', 'Gene', (107, 112))	('E545K', 'Var', (69, 74))	('PIK3CA', 'Gene', '5290', (62, 68))	('FBXW7', 'Gene', (49, 54))	('DHX15', 'Gene', '1665', (107, 112))	('FGFR3', 'Gene', (76, 81))	('E542K', 'Var', (96, 101))
145710	30647454	Using a recombinantly expressed and purified preparation of full-length APOBEC3B:the APOBEC3 member most closely associated to human cancers:we tested its activity on two 25-mer substrates mimicking the DNA sequence surrounding the E542 and E545 sites.	('APOBEC3B', 'Gene', '9582', (72, 80))	('activity', 'MPA', (155, 163))	('E542', 'Var', (232, 236))	('human', 'Species', '9606', (127, 132))	('E545', 'Var', (241, 245))	('tested', 'Reg', (144, 150))	('cancers', 'Phenotype', 'HP:0002664', (133, 140))	('cancers', 'Disease', (133, 140))	('cancers', 'Disease', 'MESH:D009369', (133, 140))	('APOBEC3B', 'Gene', (72, 80))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
145718	30647454	Our analysis of the effect sizes of mutations underlying HPV+ and HPV- HNSCC tumors not only substantiates the difference in genetic architecture between these tumors based on HPV status, but also identifies some rare oncogenic mutations that contribute strongly to tumorigenesis in both HPV+ and HPV- HNSCC tumors (e.g.	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('HPV', 'Species', '10566', (297, 300))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('tumor', 'Phenotype', 'HP:0002664', (308, 313))	('tumors', 'Disease', (160, 166))	('tumor', 'Disease', (266, 271))	('tumors', 'Phenotype', 'HP:0002664', (308, 314))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('HPV', 'Species', '10566', (66, 69))	('HPV- HNSCC tumors', 'Disease', 'MESH:D000077195', (297, 314))	('tumor', 'Disease', 'MESH:D009369', (266, 271))	('HPV', 'Species', '10566', (288, 291))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumors', 'Disease', 'MESH:D009369', (160, 166))	('tumors', 'Disease', (77, 83))	('HPV- HNSCC tumors', 'Disease', 'MESH:D000077195', (66, 83))	('tumors', 'Disease', (308, 314))	('HPV', 'Species', '10566', (176, 179))	('mutations', 'Var', (228, 237))	('tumor', 'Phenotype', 'HP:0002664', (266, 271))	('tumor', 'Disease', (160, 165))	('tumor', 'Disease', (308, 313))	('HPV', 'Species', '10566', (57, 60))	('HPV- HNSCC tumors', 'Disease', (297, 314))	('tumors', 'Disease', 'MESH:D009369', (308, 314))	('tumors', 'Disease', 'MESH:D009369', (77, 83))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('tumor', 'Disease', 'MESH:D009369', (308, 313))	('mutations', 'Var', (36, 45))	('HPV- HNSCC tumors', 'Disease', (66, 83))	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('tumor', 'Disease', (77, 82))
145719	30647454	FBXW7 R505G), as well as oncogenic mutations that are somatically selected for in either HPV+ (e.g.	('FBXW7', 'Gene', '55294', (0, 5))	('FBXW7', 'Gene', (0, 5))	('HPV', 'Species', '10566', (89, 92))	('R505G', 'Var', (6, 11))	('R505G', 'Mutation', 'rs149680468', (6, 11))
145720	30647454	EP300 D1399N, FGFR3 F249C) or HPV- tumors (e.g.	('EP300 D1399N', 'Var', (0, 12))	('FGFR3', 'Gene', '2261', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('D1399N', 'Mutation', 'p.D1399N', (6, 12))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('F249C', 'Mutation', 'p.F249C', (20, 25))	('FGFR3', 'Gene', (14, 19))	('HPV- tumors', 'Disease', 'MESH:D030361', (30, 41))	('HPV- tumors', 'Disease', (30, 41))
145721	30647454	PIK3CA H1047R, oncogenic mutations in HRAS and TP53).	('H1047R', 'Mutation', 'rs121913279', (7, 13))	('HRAS', 'Gene', (38, 42))	('PIK3CA', 'Gene', (0, 6))	('PIK3CA', 'Gene', '5290', (0, 6))	('TP53', 'Gene', '7157', (47, 51))	('H1047R', 'Var', (7, 13))	('TP53', 'Gene', (47, 51))	('HRAS', 'Gene', '3265', (38, 42))
145722	30647454	Our results primarily agree with the existing literature on the strongest driver mutations in HNSCC, but segregate the contributions of oncogenes in particular as major contributors to one or the other of HPV+ and HPV- HNSCC tumors.	('HPV- HNSCC tumors', 'Disease', (214, 231))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('HNSCC', 'Disease', (94, 99))	('HPV- HNSCC tumors', 'Disease', 'MESH:D000077195', (214, 231))	('HPV', 'Species', '10566', (205, 208))	('HPV', 'Species', '10566', (214, 217))	('mutations', 'Var', (81, 90))	('tumors', 'Phenotype', 'HP:0002664', (225, 231))
145723	30647454	It has been previously remarked that mutations arising from APOBEC-related processes could be a two-edged sword: while APOBEC-related processes provide innate immunity against viruses by targeting them for mutation, they also are a source of numerous mutations driving cancer.	('driving', 'Reg', (261, 268))	('mutations', 'Var', (251, 260))	('cancer', 'Phenotype', 'HP:0002664', (269, 275))	('cancer', 'Disease', (269, 275))	('cancer', 'Disease', 'MESH:D009369', (269, 275))
145724	30647454	Our analysis implies that it would on average be preferable during tumorigenesis for a person to exchange an unknown, non-APOBEC neoplastic mutation for an unknown, putatively APOBEC neoplastic mutation.	('person', 'Species', '9606', (87, 93))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('mutation', 'Var', (140, 148))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Disease', (67, 72))
145725	30647454	Regardless, it remains highly plausible that prevention of APOBEC mutagenesis during tumorigenesis would diminish the rate of substitution and decelerate cancer progression and even the evolution of therapeutic resistance.	('tumor', 'Disease', (85, 90))	('substitution', 'MPA', (126, 138))	('decelerate', 'NegReg', (143, 153))	('diminish', 'NegReg', (105, 113))	('cancer', 'Disease', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('APOBEC', 'Gene', (59, 65))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('rate', 'MPA', (118, 122))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('mutagenesis', 'Var', (66, 77))
145726	30647454	Indeed, some of the variants with the highest net realized selection intensities among patients are attributable to APOBEC activity.	('patients', 'Species', '9606', (87, 95))	('variants', 'Var', (20, 28))	('APOBEC', 'Protein', (116, 122))
145727	30647454	The net realized selection intensity of mutations quantifies the amount of cancer phenotype at the population level that is attributable to their cause, incorporating both the prevalence of each substitution and the degree to which it contributes to the cancer phenotype in the patients with that substitution.	('cancer', 'Phenotype', 'HP:0002664', (254, 260))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('cancer', 'Disease', (75, 81))	('cancer', 'Disease', 'MESH:D009369', (254, 260))	('substitution', 'Var', (195, 207))	('mutations', 'Var', (40, 49))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('cancer', 'Disease', (254, 260))	('patients', 'Species', '9606', (278, 286))	('contributes', 'Reg', (235, 246))
145728	30647454	Accordingly, it quantifies the population-wide amount of cancer phenotype that could be eliminated by universal patient prescription of a perfect therapeutic that abrogates oncogenic function of each mutation, corresponding to potential population health benefits of a perfect mutation-targeted therapeutic.	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('abrogates', 'NegReg', (163, 172))	('oncogenic function', 'CPA', (173, 191))	('patient', 'Species', '9606', (112, 119))	('cancer', 'Disease', (57, 63))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('mutation', 'Var', (200, 208))
145730	30647454	The mutations in PIK3CA that are highly selected in HPV+ HNSCC:E542K and E545K:lie in its helical domain.	('E542K', 'Mutation', 'rs121913273', (63, 68))	('PIK3CA', 'Gene', (17, 23))	('PIK3CA', 'Gene', '5290', (17, 23))	('HPV', 'Species', '10566', (52, 55))	('E545K', 'Mutation', 'rs104886003', (73, 78))	('E542K', 'Var', (63, 68))	('E545K', 'Var', (73, 78))
145732	30647454	(2014) analysis reported these helical domain substitutions to be HPV+ HNSCC-specific based on correlations between APOBEC3B expression, and HPV status and the prevalence of TCW TKW substitutions, yet it appears that the cancer effect size of these mutations is substantial in both HPV- HNSCC and HPV+ HNSCC.	('HPV', 'Species', '10566', (66, 69))	('HPV+ HNSCC', 'Disease', (297, 307))	('cancer', 'Disease', 'MESH:D009369', (221, 227))	('substitutions', 'Var', (46, 59))	('HPV- HNSCC', 'Disease', (282, 292))	('cancer', 'Disease', (221, 227))	('APOBEC3B', 'Gene', (116, 124))	('mutations', 'Var', (249, 258))	('TC', 'Chemical', 'MESH:D013667', (174, 176))	('APOBEC3B', 'Gene', '9582', (116, 124))	('HPV', 'Species', '10566', (141, 144))	('HPV', 'Species', '10566', (282, 285))	('HPV', 'Species', '10566', (297, 300))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))
145736	30647454	In light of these bioinformatic discoveries, our biochemical result demonstrating context-specific targeting of APOBEC3B provides an additional layer of validation of APOBEC mutagenesis in cancer, and opens new questions in the field:including questions regarding the molecular mechanisms by which APOBEC enzymes target these sites in specific genes.	('APOBEC3B', 'Gene', (112, 120))	('APOBEC3B', 'Gene', '9582', (112, 120))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('mutagenesis', 'Var', (174, 185))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('cancer', 'Disease', (189, 195))
145737	30647454	flagged deletions in the gene TRAF3, demonstrating the importance of nonsense mutations in this gene to the genetic architecture of HPV+ HNSCC.	('TRAF3', 'Gene', (30, 35))	('TRAF3', 'Gene', '7187', (30, 35))	('HPV', 'Species', '10566', (132, 135))	('deletions', 'Var', (8, 17))
145738	30647454	Because our approach enables the estimation of expected frequencies of nucleotide mutations, but not expected frequencies of deletions, the lack of recurrent TRAF3 substitutions precluded it from any estimation of selective pressure using our current methodology.	('nucleotide mutations', 'Var', (71, 91))	('TRAF3', 'Gene', (158, 163))	('substitutions', 'Var', (164, 177))	('TRAF3', 'Gene', '7187', (158, 163))
145739	30647454	One of the somatic variants with very high effect sizes in both HPV+ and HPV- tumors, FBXW7 R505G, occurs in an E3 ubiquitin ligase and modifies E3 ligase binding to the substrates.	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('HPV- tumors', 'Disease', 'MESH:D030361', (73, 84))	('E3 ubiquitin ligase', 'Protein', (112, 131))	('binding to the substrates', 'Interaction', (155, 180))	('occurs', 'Reg', (99, 105))	('HPV- tumors', 'Disease', (73, 84))	('HPV', 'Species', '10566', (73, 76))	('FBXW7', 'Gene', '55294', (86, 91))	('R505G', 'Mutation', 'rs149680468', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('modifies', 'Reg', (136, 144))	('R505G', 'Var', (92, 97))	('FBXW7', 'Gene', (86, 91))	('HPV', 'Species', '10566', (64, 67))
145741	30647454	FBXW7 mutation has been demonstrated to associate with NOTCH1 activation in T-cell acute lymphoblastic leukemia; however, not until NOTCH1's implication in HNSCC tumorigenesis was FBXW7 linked to this disease.	('tumor', 'Disease', (162, 167))	('leukemia', 'Phenotype', 'HP:0001909', (103, 111))	('FBXW7', 'Gene', (0, 5))	('NOTCH1', 'Gene', (55, 61))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('FBXW7', 'Gene', (180, 185))	('NOTCH1', 'Gene', '4851', (55, 61))	('T-cell acute lymphoblastic leukemia', 'Phenotype', 'HP:0006727', (76, 111))	('NOTCH1', 'Gene', (132, 138))	('FBXW7', 'Gene', '55294', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (83, 111))	('NOTCH1', 'Gene', '4851', (132, 138))	('T-cell acute lymphoblastic leukemia', 'Disease', 'MESH:D054218', (76, 111))	('T-cell acute lymphoblastic leukemia', 'Disease', (76, 111))	('linked', 'Reg', (186, 192))	('mutation', 'Var', (6, 14))	('FBXW7', 'Gene', '55294', (180, 185))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (89, 111))
145744	30647454	Nonetheless, comparisons of selection intensities on somatic single nucleotide variants only paint part of the complex picture of tumorigenesis: copy number variation, epigenetic alterations, tumor heterogeneity and microenvironment, germline variants, and other factors also contribute to the cancer phenotype.	('tumor', 'Disease', (192, 197))	('contribute', 'Reg', (276, 286))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('cancer', 'Disease', 'MESH:D009369', (294, 300))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('cancer', 'Disease', (294, 300))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('epigenetic alterations', 'Var', (168, 190))	('copy number variation', 'Var', (145, 166))	('tumor', 'Disease', (130, 135))	('cancer', 'Phenotype', 'HP:0002664', (294, 300))
145754	30647454	dataset were obtained from published supplementary material, and underwent the following processing: 1) variants with labels other than 'Transmitted' and 'Primary Only' were removed to obtain the set of primary tumor variants, 2) neighboring SNVs were redesignated as DNVs and extraneous alleles (denoted with lower case) were removed, 3) variants were re-annotated using the software vcf2maf v1.6.13, 4) those variants annotated as 'common' or classified as intronic and flanking were removed, and 5) shared variants for five tumors that were identified as duplicated in the NCI dataset (PY-19T, PY-1T, PY-14T, PY-13T, PY-7T) were removed.	('PY-19T', 'Var', (589, 595))	('tumors', 'Phenotype', 'HP:0002664', (527, 533))	('tumors', 'Disease', 'MESH:D009369', (527, 533))	('PY-14T', 'Var', (604, 610))	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('tumor', 'Disease', 'MESH:D009369', (527, 532))	('PY-1T', 'Var', (597, 602))	('PY-7T', 'Var', (620, 625))	('PY-7T', 'CellLine', 'CVCL:A336', (620, 625))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('tumor', 'Disease', (211, 216))	('PY-13T', 'Var', (612, 618))	('tumor', 'Phenotype', 'HP:0002664', (527, 532))	('tumor', 'Disease', (527, 532))	('tumors', 'Disease', (527, 533))
145757	30647454	The effect of the trinucleotide context was quantified as the average distribution of trinucleotide contexts for that tissue calculated analyzing all HNSCC tumors with greater than 50 mutations with deconstructSigs.	('mutations', 'Var', (184, 193))	('HNSCC tumors', 'Disease', (150, 162))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('trinucleotide', 'Chemical', '-', (18, 31))	('trinucleotide', 'Chemical', '-', (86, 99))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('HNSCC tumors', 'Disease', 'MESH:D000077195', (150, 162))
145758	30647454	This observed frequency of substitutions was divided by the expected frequency of mutations to determine , the selection intensity on a point mutation during the intratumoral fixation process.	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('substitutions', 'Var', (27, 40))	('tumor', 'Disease', (167, 172))	('tumor', 'Disease', 'MESH:D009369', (167, 172))
145770	30647454	The E542 and E545 sites are located very close to one another in PI3KCA; thus, when we constructed the 25-mer PI3KCA test oligos, the sequences had significant overlap.	('PI3', 'Gene', '5266', (65, 68))	('E542', 'Var', (4, 8))	('PI3', 'Gene', '5266', (110, 113))	('E545', 'Var', (13, 17))	('PI3', 'Gene', (65, 68))	('PI3', 'Gene', (110, 113))
145772	30647454	The test oligonucleotide sequences, E542: 5'-TGCTTAGTGATTTCAGAGAGAGGAT-3', and E545: 5'-TGCTCAGTGATTTTAGAGAGAGGAT-3', were based on the cDNA sequence of PIK3CA surrounding the test sites.	('PIK3CA', 'Gene', '5290', (153, 159))	('TC', 'Chemical', 'MESH:D013667', (57, 59))	('TC', 'Chemical', 'MESH:D013667', (91, 93))	('oligonucleotide', 'Chemical', 'MESH:D009841', (9, 24))	("E545: 5'-TGCTCAGTGATTTTAGAGAGAGGAT-3", 'Var', (79, 115))	('PIK3CA', 'Gene', (153, 159))
145776	33936158	Previous studies have shown that dysregulation of MCMs are implicated in tumorigenesis of lung cancer.	('dysregulation', 'Var', (33, 46))	('lung cancer', 'Disease', 'MESH:D008175', (90, 101))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('lung cancer', 'Disease', (90, 101))	('lung cancer', 'Phenotype', 'HP:0100526', (90, 101))	('tumor', 'Disease', (73, 78))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('implicated', 'Reg', (59, 69))	('MCMs', 'Protein', (50, 54))
145792	33936158	Meanwhile, several lines of evidence showed that MCMs could also serve as the markers for precancerous and recurrent conditions, and aberrant expressions of MCMs were implicated in the initiation and progression of many malignancies.	('cancerous', 'Disease', (93, 102))	('MCMs', 'Gene', (157, 161))	('aberrant expressions', 'Var', (133, 153))	('malignancies', 'Disease', 'MESH:D009369', (220, 232))	('implicated', 'Reg', (167, 177))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('cancerous', 'Disease', 'MESH:D009369', (93, 102))	('malignancies', 'Disease', (220, 232))
145829	33936158	Queried MCMs were mutated in 228 out of 503 samples from patients with LUAD (45%), and 296 out of 466 samples from patients with LUSC (64%) (Figure 5A).	('patients', 'Species', '9606', (115, 123))	('mutated', 'Var', (18, 25))	('patients', 'Species', '9606', (57, 65))	('LUAD', 'Phenotype', 'HP:0030078', (71, 75))	('LUAD', 'Disease', (71, 75))
145830	33936158	In LUAD samples, the mutation rate of MCM4 was the highest, at a percentage of 18%, compared with other MCM proteins, while in LUSC samples, the highest mutation rate was found in MCM2, accounting for 23% (Figure 5B).	('MCM2', 'Gene', '4171', (180, 184))	('MCM4', 'Gene', (38, 42))	('MCM2', 'Gene', (180, 184))	('LUAD', 'Phenotype', 'HP:0030078', (3, 7))	('mutation', 'Var', (21, 29))	('MCM4', 'Gene', '4173', (38, 42))
145837	33936158	Meanwhile, in patients with LUSC, the MCM alterations were closely associated with cell cycle- and DNA replication-related genes, such as RCF4, ATR, RAD1, and TOPBP1 (Figure 5D).	('LUSC', 'Disease', (28, 32))	('alterations', 'Var', (42, 53))	('TOPBP1', 'Gene', (159, 165))	('RAD1', 'Gene', '5810', (149, 153))	('ATR', 'Gene', '545', (144, 147))	('associated', 'Reg', (67, 77))	('ATR', 'Gene', (144, 147))	('TOPBP1', 'Gene', '11073', (159, 165))	('patients', 'Species', '9606', (14, 22))	('RCF4', 'Gene', (138, 142))	('cell cycle-', 'Gene', (83, 94))	('RAD1', 'Gene', (149, 153))
145838	33936158	Given that MCM2 and MCM4 not only constantly showed association with the clinical stages and OS, but also exhibited the highest mutation rate in LUAD and LUSC patients, respectively, we then set out to validate the overexpression of MCM2 and MCM4 in NSCLC tissues.	('NSCLC', 'Disease', 'MESH:D002289', (250, 255))	('association', 'Reg', (52, 63))	('SCLC', 'Phenotype', 'HP:0030357', (251, 255))	('NSCLC', 'Phenotype', 'HP:0030358', (250, 255))	('MCM4', 'Gene', '4173', (242, 246))	('MCM4', 'Gene', (242, 246))	('LUAD', 'Disease', (145, 149))	('MCM4', 'Gene', '4173', (20, 24))	('MCM2', 'Gene', '4171', (233, 237))	('LUAD', 'Phenotype', 'HP:0030078', (145, 149))	('MCM2', 'Gene', (233, 237))	('mutation', 'Var', (128, 136))	('patients', 'Species', '9606', (159, 167))	('NSCLC', 'Disease', (250, 255))	('MCM2', 'Gene', '4171', (11, 15))	('MCM4', 'Gene', (20, 24))	('MCM2', 'Gene', (11, 15))
145848	33936158	Evidence from tumor genome sequencing shows that dys-regulation of Rb/E2F and G1/S phase can aggravate oncogenic replication stress, resulting in genomic instability caused by DNA double-strand break (DSB), and subsequent loss of key regulators such as the p53 tumor suppressor, and eventually lead to tumorigenesis.	('genomic instability', 'MPA', (146, 165))	('tumor', 'Phenotype', 'HP:0002664', (302, 307))	('stress', 'Disease', (125, 131))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (261, 266))	('loss', 'NegReg', (222, 226))	('tumor', 'Disease', (302, 307))	('aggravate', 'PosReg', (93, 102))	('dys-regulation', 'Var', (49, 63))	('tumor', 'Disease', 'MESH:D009369', (302, 307))	('p53', 'Gene', '7157', (257, 260))	('tumor', 'Disease', (14, 19))	('stress', 'Disease', 'MESH:D000079225', (125, 131))	('lead to', 'Reg', (294, 301))	('tumor', 'Disease', (261, 266))	('Rb/E2F', 'Gene', (67, 73))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('DNA double-strand break', 'MPA', (176, 199))	('tumor', 'Disease', 'MESH:D009369', (261, 266))	('p53', 'Gene', (257, 260))
145849	33936158	For instance, MCMs are the targets of E2F, thus E2F can promote tumorigenesis through MCMs by enhancing cell proliferation.	('tumor', 'Disease', (64, 69))	('MCMs', 'Disease', (86, 90))	('E2F', 'Var', (48, 51))	('cell proliferation', 'CPA', (104, 122))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('enhancing', 'PosReg', (94, 103))	('promote', 'PosReg', (56, 63))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
145854	33936158	Also, overexpression of MCM2 was an independent unfavorable prognostic factor for LUSC patients.	('overexpression', 'Var', (6, 20))	('patients', 'Species', '9606', (87, 95))	('MCM2', 'Gene', '4171', (24, 28))	('MCM2', 'Gene', (24, 28))	('LUSC', 'Disease', (82, 86))
145867	33936158	Knock-out of TMCMPRSS4 could lead to down-regulation of MCM6 in NSCLC, which in turn leads to down-regulated proliferation and migration of cancer cells.	('TMCMPRSS4', 'Gene', (13, 22))	('NSCLC', 'Disease', 'MESH:D002289', (64, 69))	('SCLC', 'Phenotype', 'HP:0030357', (65, 69))	('Knock-out', 'Var', (0, 9))	('MCM6', 'Gene', '4175', (56, 60))	('cancer', 'Disease', (140, 146))	('down-regulation', 'NegReg', (37, 52))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('NSCLC', 'Phenotype', 'HP:0030358', (64, 69))	('down-regulated', 'NegReg', (94, 108))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('proliferation', 'CPA', (109, 122))	('NSCLC', 'Disease', (64, 69))	('MCM6', 'Gene', (56, 60))
145880	33936158	Specifically, overexpressed MCM2 and MCM4 may play important roles in NSCLC tumorigenesis, and they could serve as potential indicators to identify high-risk subgroups of NSCLC patients.	('tumor', 'Disease', (76, 81))	('NSCLC', 'Disease', 'MESH:D002289', (70, 75))	('MCM4', 'Gene', (37, 41))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('NSCLC', 'Disease', 'MESH:D002289', (171, 176))	('play', 'Reg', (46, 50))	('SCLC', 'Phenotype', 'HP:0030357', (172, 176))	('NSCLC', 'Disease', (70, 75))	('NSCLC', 'Disease', (171, 176))	('NSCLC', 'Phenotype', 'HP:0030358', (70, 75))	('overexpressed', 'Var', (14, 27))	('NSCLC', 'Phenotype', 'HP:0030358', (171, 176))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('MCM2', 'Gene', (28, 32))	('roles', 'Reg', (61, 66))	('patients', 'Species', '9606', (177, 185))	('MCM4', 'Gene', '4173', (37, 41))	('MCM2', 'Gene', '4171', (28, 32))	('SCLC', 'Phenotype', 'HP:0030357', (71, 75))
146040	30477531	The OS rates and median OS were also higher in the CCRT group compared to the chemotherapy-alone group (one-year: 58.0% versus 43.0%; two-year: 25.5% versus 14.0%; three-year: 10.7% versus 4.7%; median: 14 months versus 11 months, p = 0.007) (Fig.	('CR', 'Chemical', '-', (52, 54))	('higher', 'PosReg', (37, 43))	('OS', 'Chemical', '-', (24, 26))	('OS', 'Chemical', '-', (4, 6))	('CCRT', 'Var', (51, 55))
146046	30477531	Patients who received CCRT suffered more frequent grade 3 or higher leucocytopenia than those who received chemotherapy alone (41.8% versus 24.4%, p = 0.040).	('CCRT', 'Var', (22, 26))	('leucocytopenia', 'Disease', (68, 82))	('Patients', 'Species', '9606', (0, 8))	('CR', 'Chemical', '-', (23, 25))	('grade 3', 'MPA', (50, 57))	('leucocytopenia', 'Disease', 'None', (68, 82))
146094	30477531	The incidence of grade 3 or higher leucopenia was significantly greater in the CCRT group than in the chemotherapy-alone group (41.8% versus 24.4%, p = 0.040).	('CCRT', 'Var', (79, 83))	('leucopenia', 'Disease', (35, 45))	('leucopenia', 'Disease', 'MESH:C536227', (35, 45))	('CR', 'Chemical', '-', (80, 82))
146109	29347960	Unresectable status and M1LYM were significantly associated with poor LRC (p < 0.05) and OS (p < 0.05).	('OS', 'Chemical', '-', (89, 91))	('poor', 'Disease', (65, 69))	('M1LYM', 'Var', (24, 29))
146186	29347960	Unresectable and M1LYM statuses were associated with a poor OS rate [p = 0.025; hazard ratio (HR) = 3.05 (95% CI, 1.15-8.08) and p < 0.0001; HR = 11.5 (95% CI, 3.87-34.0), respectively].	('OS', 'Chemical', '-', (60, 62))	('M1LYM statuses', 'Var', (17, 31))	('poor OS', 'MPA', (55, 62))
146189	29347960	The 5-year LRC rate was 80% (95% CI, 40.9-94.6) for patients with resectable status vs. 30.1% (95% CI, 11.5-51.3) for those with unresectable status and 75.5% (95% CI, 46.9-90.1) for patients with M0 vs. 8.3% (95% CI, 0.5-31.1) for those with M1LYM (Fig.	('LRC', 'CPA', (11, 14))	('patients', 'Species', '9606', (52, 60))	('patients', 'Species', '9606', (183, 191))	('M1LYM', 'Var', (243, 248))
146230	29347960	The cardiovascular diseases after radiotherapy for CESCC were not mentioned except one report, although patients with CESCC possibly have a risk of developing cardiovascular disease because of their lifestyle, similar to patients with squamous cell carcinoma of the head and neck.	('patients', 'Species', '9606', (221, 229))	('cardiovascular disease', 'Phenotype', 'HP:0001626', (4, 26))	('CESCC', 'Chemical', '-', (51, 56))	('cardiovascular diseases', 'Disease', (4, 27))	('cardiovascular disease', 'Disease', 'MESH:D002318', (4, 26))	('CESCC', 'Chemical', '-', (118, 123))	('cardiovascular disease', 'Disease', (159, 181))	('cardiovascular diseases', 'Phenotype', 'HP:0001626', (4, 27))	('carcinoma', 'Phenotype', 'HP:0030731', (249, 258))	('cardiovascular diseases', 'Disease', 'MESH:D002318', (4, 27))	('CESCC', 'Var', (118, 123))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (235, 258))	('cardiovascular disease', 'Phenotype', 'HP:0001626', (159, 181))	('cardiovascular disease', 'Disease', 'MESH:D002318', (159, 181))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (235, 258))	('squamous cell carcinoma', 'Disease', (235, 258))	('patients', 'Species', '9606', (104, 112))
146247	28423699	Further experiments showed that LUCAT1 knockdown inhibited cell proliferation both in vitro and in vivo.	('LUCAT1', 'Gene', '100505994', (32, 38))	('knockdown', 'Var', (39, 48))	('LUCAT1', 'Gene', (32, 38))	('cell proliferation', 'CPA', (59, 77))	('inhibited', 'NegReg', (49, 58))
146249	28423699	We further demonstrated that LUCAT1 was associated with polycomb repressor complexes (PRC2) and that this association was required for epigenetically repression of p21 and p57, thus contributing to the regulation of NSCLC cell cycle and proliferation.	('NSCLC', 'Disease', (216, 221))	('LUCAT1', 'Gene', '100505994', (29, 35))	('contributing', 'Reg', (182, 194))	('LUCAT1', 'Gene', (29, 35))	('NSCLC', 'Disease', 'MESH:D002289', (216, 221))	('proliferation', 'CPA', (237, 250))	('associated', 'Interaction', (40, 50))	('p57', 'Gene', '1028', (172, 175))	('NSCLC', 'Phenotype', 'HP:0030358', (216, 221))	('p57', 'Gene', (172, 175))	('epigenetically repression', 'Var', (135, 160))	('p21', 'Gene', '1026', (164, 167))	('p21', 'Gene', (164, 167))	('regulation', 'MPA', (202, 212))
146254	28423699	Recently, with the development of molecular genetics and molecular biology, non-coding RNAs have risen to the forefront of cancer research.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('cancer', 'Disease', (123, 129))	('non-coding RNAs', 'Var', (76, 91))	('cancer', 'Disease', 'MESH:D009369', (123, 129))
146255	28423699	The dysregulation of lncRNAs has a functional role in diverse cancers, such as lung cancer, gastric cancer, and breast cancer.	('breast cancer', 'Disease', 'MESH:D001943', (112, 125))	('lung cancer', 'Disease', 'MESH:D008175', (79, 90))	('breast cancer', 'Phenotype', 'HP:0003002', (112, 125))	('breast cancer', 'Disease', (112, 125))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('dysregulation', 'Var', (4, 17))	('gastric cancer', 'Disease', (92, 106))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('lncRNAs', 'Protein', (21, 28))	('lung cancer', 'Disease', (79, 90))	('gastric cancer', 'Disease', 'MESH:D013274', (92, 106))	('lung cancer', 'Phenotype', 'HP:0100526', (79, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('cancers', 'Disease', 'MESH:D009369', (62, 69))	('cancers', 'Phenotype', 'HP:0002664', (62, 69))	('gastric cancer', 'Phenotype', 'HP:0012126', (92, 106))	('cancers', 'Disease', (62, 69))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
146259	28423699	Previous studies have shown that the dysregulated expression of EZH2, one of the three core components of PRC2 (EZH2, SUZ12, and EED), could be a biomarker in diverse cancers, such as lung cancer, gastric cancer, hepatocellular carcinoma and cervical cancer.	('dysregulated', 'Var', (37, 49))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('SUZ12', 'Gene', (118, 123))	('EZH2', 'Gene', (64, 68))	('expression', 'MPA', (50, 60))	('EZH2', 'Gene', '2146', (64, 68))	('EZH2', 'Gene', '2146', (112, 116))	('EZH2', 'Gene', (112, 116))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (213, 237))	('gastric cancer', 'Disease', (197, 211))	('EED', 'Gene', (129, 132))	('lung cancer', 'Disease', 'MESH:D008175', (184, 195))	('cancers', 'Phenotype', 'HP:0002664', (167, 174))	('SUZ12', 'Gene', '23512', (118, 123))	('cancers', 'Disease', (167, 174))	('lung cancer', 'Phenotype', 'HP:0100526', (184, 195))	('cervical cancer', 'Disease', (242, 257))	('hepatocellular carcinoma', 'Disease', (213, 237))	('cervical cancer', 'Disease', 'MESH:D002583', (242, 257))	('carcinoma', 'Phenotype', 'HP:0030731', (228, 237))	('gastric cancer', 'Disease', 'MESH:D013274', (197, 211))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('EED', 'Gene', '8726', (129, 132))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('cancers', 'Disease', 'MESH:D009369', (167, 174))	('gastric cancer', 'Phenotype', 'HP:0012126', (197, 211))	('lung cancer', 'Disease', (184, 195))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (213, 237))
146265	28423699	In addition, LUCAT1 knockdown repressed NSCLC proliferation both in vitro and in vivo.	('NSCLC', 'Phenotype', 'HP:0030358', (40, 45))	('knockdown', 'Var', (20, 29))	('LUCAT1', 'Gene', '100505994', (13, 19))	('LUCAT1', 'Gene', (13, 19))	('NSCLC', 'Disease', (40, 45))	('NSCLC', 'Disease', 'MESH:D002289', (40, 45))
146266	28423699	RNA-binding protein and chromatin immunoprecipitation (RIP and ChIP) assays revealed that LUCAT1 epigenetically repressed the expression of p21 and p57 via associating with PRC2.	('epigenetically', 'Var', (97, 111))	('RNA-binding protein', 'Gene', (0, 19))	('LUCAT1', 'Gene', '100505994', (90, 96))	('RIP', 'Gene', '3267', (55, 58))	('associating', 'Reg', (156, 167))	('RNA-binding protein', 'Gene', '84549', (0, 19))	('p57', 'Gene', '1028', (148, 151))	('PRC2', 'Gene', (173, 177))	('p57', 'Gene', (148, 151))	('p21', 'Gene', '1026', (140, 143))	('RIP', 'Gene', (55, 58))	('LUCAT1', 'Gene', (90, 96))	('p21', 'Gene', (140, 143))
146289	28423699	As shown in Figure 4A, knockdown of LUCAT1 expression markedly inhibited cell proliferation compared to the control cells.	('LUCAT1', 'Gene', '100505994', (36, 42))	('LUCAT1', 'Gene', (36, 42))	('knockdown', 'Var', (23, 32))	('cell proliferation', 'CPA', (73, 91))	('inhibited', 'NegReg', (63, 72))
146295	28423699	In addition, the results of flow-cytometric analysis of apoptosis showed that LUCAT1 knockdown increased the proportion of apoptotic cells (Figure 4E).	('increased', 'PosReg', (95, 104))	('knockdown', 'Var', (85, 94))	('LUCAT1', 'Gene', '100505994', (78, 84))	('LUCAT1', 'Gene', (78, 84))
146296	28423699	In summary, these data suggest that LUCAT1 plays a critical role in human NSCLC and that knockdown of LUCAT1 inhibits cell proliferation and induces apoptosis in NSCLC cells.	('apoptosis', 'CPA', (149, 158))	('human', 'Species', '9606', (68, 73))	('LUCAT1', 'Gene', '100505994', (36, 42))	('NSCLC', 'Phenotype', 'HP:0030358', (74, 79))	('LUCAT1', 'Gene', (36, 42))	('NSCLC', 'Disease', (162, 167))	('induces', 'Reg', (141, 148))	('NSCLC', 'Disease', 'MESH:D002289', (162, 167))	('LUCAT1', 'Gene', '100505994', (102, 108))	('NSCLC', 'Disease', (74, 79))	('LUCAT1', 'Gene', (102, 108))	('cell proliferation', 'CPA', (118, 136))	('inhibits', 'NegReg', (109, 117))	('knockdown', 'Var', (89, 98))	('NSCLC', 'Disease', 'MESH:D002289', (74, 79))	('NSCLC', 'Phenotype', 'HP:0030358', (162, 167))
146313	28423699	The results showed that p21 and p57 were increased with knockdown of LUCAT1 (Figure 7A).	('LUCAT1', 'Gene', (69, 75))	('increased', 'PosReg', (41, 50))	('p21', 'Gene', (24, 27))	('p21', 'Gene', '1026', (24, 27))	('p57', 'Gene', '1028', (32, 35))	('p57', 'Gene', (32, 35))	('knockdown', 'Var', (56, 65))	('LUCAT1', 'Gene', '100505994', (69, 75))
146314	28423699	Then we evaluated the protein levels of p21 and p57 by western blotting and showed that the levels of both proteins were increased with LUCAT1 knockdown.	('increased', 'PosReg', (121, 130))	('p57', 'Gene', '1028', (48, 51))	('LUCAT1', 'Gene', '100505994', (136, 142))	('LUCAT1', 'Gene', (136, 142))	('p21', 'Gene', '1026', (40, 43))	('p57', 'Gene', (48, 51))	('levels', 'MPA', (92, 98))	('knockdown', 'Var', (143, 152))	('p21', 'Gene', (40, 43))
146320	28423699	We conducted ChIP analysis in the SPC-A1 cell line after LUCAT1-knockdown, and the results showed that knockdown of LUCAT1 decreased the binding of EZH2 and dimethylation of lysine 27 on histone 3(H3K27me3) levels across the p21 and p57 promoters compared to the control group (Figure 7C).	('p57', 'Gene', '1028', (233, 236))	('binding', 'Interaction', (137, 144))	('dimethylation', 'MPA', (157, 170))	('LUCAT1', 'Gene', '100505994', (57, 63))	('H3', 'Chemical', 'MESH:C012616', (197, 199))	('decreased', 'NegReg', (123, 132))	('p57', 'Gene', (233, 236))	('LUCAT1', 'Gene', '100505994', (116, 122))	('LUCAT1', 'Gene', (57, 63))	('LUCAT1', 'Gene', (116, 122))	('p21', 'Gene', '1026', (225, 228))	('EZH2', 'Gene', (148, 152))	('EZH2', 'Gene', '2146', (148, 152))	('lysine', 'Chemical', 'MESH:D008239', (174, 180))	('p21', 'Gene', (225, 228))	('knockdown', 'Var', (103, 112))
146321	28423699	These results suggest that LUCAT1 promotes NSCLC cell proliferation through epigenetically silencing p21 and p57 expression, which is required to target EZH2 occupancy.	('p57', 'Gene', (109, 112))	('p21', 'Gene', '1026', (101, 104))	('promotes', 'PosReg', (34, 42))	('NSCLC', 'Phenotype', 'HP:0030358', (43, 48))	('p21', 'Gene', (101, 104))	('epigenetically silencing', 'Var', (76, 100))	('EZH2', 'Gene', (153, 157))	('EZH2', 'Gene', '2146', (153, 157))	('LUCAT1', 'Gene', '100505994', (27, 33))	('NSCLC', 'Disease', (43, 48))	('LUCAT1', 'Gene', (27, 33))	('p57', 'Gene', '1028', (109, 112))	('NSCLC', 'Disease', 'MESH:D002289', (43, 48))
146326	28423699	demonstrated that lncRNA TUG1 is regulated by P53-dependent cell proliferation in NSCLC via epigenetic regulation of HOXB7 expression.	('NSCLC', 'Phenotype', 'HP:0030358', (82, 87))	('TUG1', 'Gene', (25, 29))	('P53', 'Gene', '7157', (46, 49))	('HOXB7', 'Gene', (117, 122))	('epigenetic regulation', 'Var', (92, 113))	('NSCLC', 'Disease', (82, 87))	('P53', 'Gene', (46, 49))	('TUG1', 'Gene', '55000', (25, 29))	('HOXB7', 'Gene', '3217', (117, 122))	('NSCLC', 'Disease', 'MESH:D002289', (82, 87))
146329	28423699	Numerous studies have found that many lncRNAs could promote or inhibit cell proliferation, and their abnormal expression could lead to cancer cell growth.	('cancer', 'Disease', (135, 141))	('cancer', 'Disease', 'MESH:D009369', (135, 141))	('lead to', 'Reg', (127, 134))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('abnormal', 'Var', (101, 109))	('expression', 'MPA', (110, 120))	('inhibit', 'NegReg', (63, 70))	('cell proliferation', 'CPA', (71, 89))	('promote', 'PosReg', (52, 59))
146332	28423699	In addition, aberrant expression of lncRNAs is involved in diverse tumors and can function as prognostic indicators.	('lncRNAs', 'Protein', (36, 43))	('involved', 'Reg', (47, 55))	('tumors', 'Disease', 'MESH:D009369', (67, 73))	('aberrant expression', 'Var', (13, 32))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('tumors', 'Disease', (67, 73))
146334	28423699	We also demonstrated that LUCAT1 knockdown led to a significant suppression of cell proliferation both in vitro and in vivo, induced G0/G1 arrest, and promoted cell apoptosis.	('cell proliferation', 'CPA', (79, 97))	('knockdown', 'Var', (33, 42))	('cell apoptosis', 'CPA', (160, 174))	('LUCAT1', 'Gene', (26, 32))	('promoted', 'PosReg', (151, 159))	('LUCAT1', 'Gene', '100505994', (26, 32))	('G0/G1 arrest', 'CPA', (133, 145))	('suppression', 'NegReg', (64, 75))
146335	28423699	Moreover, we showed that NSCLC patients with elevated expression of LUCAT1 had a shorter overall survival than those with low expression, suggesting that lncRNA LUCAT1 has a high prognostic value in NSCLC.	('expression', 'MPA', (54, 64))	('NSCLC', 'Disease', 'MESH:D002289', (199, 204))	('NSCLC', 'Disease', (25, 30))	('NSCLC', 'Disease', 'MESH:D002289', (25, 30))	('LUCAT1', 'Gene', '100505994', (68, 74))	('LUCAT1', 'Gene', (68, 74))	('LUCAT1', 'Gene', '100505994', (161, 167))	('lncRNA', 'Var', (154, 160))	('elevated', 'PosReg', (45, 53))	('overall survival', 'MPA', (89, 105))	('patients', 'Species', '9606', (31, 39))	('NSCLC', 'Phenotype', 'HP:0030358', (199, 204))	('LUCAT1', 'Gene', (161, 167))	('NSCLC', 'Phenotype', 'HP:0030358', (25, 30))	('shorter', 'NegReg', (81, 88))	('NSCLC', 'Disease', (199, 204))
146338	28423699	And it can medicate the marks which is associated with genetic silence, such as dimethylation of lysine 9 (H3K9me2) and H3K27me3.	('lysine', 'Chemical', 'MESH:D008239', (97, 103))	('H3', 'Chemical', 'MESH:C012616', (120, 122))	('H3K27me3', 'Var', (120, 128))	('dimethylation', 'MPA', (80, 93))	('H3', 'Chemical', 'MESH:C012616', (107, 109))
146348	28423699	The results showed that the expression of p21 and p57 clearly increased as a result of LUCAT1 knockdown.	('increased', 'PosReg', (62, 71))	('knockdown', 'Var', (94, 103))	('p21', 'Gene', '1026', (42, 45))	('LUCAT1', 'Gene', (87, 93))	('LUCAT1', 'Gene', '100505994', (87, 93))	('p21', 'Gene', (42, 45))	('expression', 'MPA', (28, 38))	('p57', 'Gene', '1028', (50, 53))	('p57', 'Gene', (50, 53))
146349	28423699	Previous studies have revealed that promoter hypermethylation of p21 is present in 30% of NSCLCs.	('p21', 'Gene', '1026', (65, 68))	('promoter hypermethylation', 'Var', (36, 61))	('p21', 'Gene', (65, 68))	('NSCLC', 'Disease', (90, 95))	('NSCLC', 'Disease', 'MESH:D002289', (90, 95))	('NSCLC', 'Phenotype', 'HP:0030358', (90, 95))
146350	28423699	Additionally, the inactivation of the p57 gene resulting from promoter DNA methylation was observed in NSCLC and in lymphoid malignancies of B-cells.	('promoter DNA methylation', 'Var', (62, 86))	('inactivation', 'NegReg', (18, 30))	('p57', 'Gene', '1028', (38, 41))	('NSCLC', 'Disease', (103, 108))	('p57', 'Gene', (38, 41))	('NSCLC', 'Disease', 'MESH:D002289', (103, 108))	('lymphoid malignancies', 'Disease', 'MESH:D008223', (116, 137))	('lymphoid malignancies', 'Disease', (116, 137))	('NSCLC', 'Phenotype', 'HP:0030358', (103, 108))	('lymphoid malignancies', 'Phenotype', 'HP:0002665', (116, 137))
146352	28423699	We then employed a ChIP assay and our data revealed that knockdown of LUCAT1 decreased both the binding of EZH2 and H3K27me3 levels across the p21 and p57 promoters compared to the control group (Figure 6C).	('p21', 'Gene', (143, 146))	('p57', 'Gene', '1028', (151, 154))	('binding', 'Interaction', (96, 103))	('H3', 'Chemical', 'MESH:C012616', (116, 118))	('decreased', 'NegReg', (77, 86))	('knockdown', 'Var', (57, 66))	('p57', 'Gene', (151, 154))	('H3K27me3 levels', 'MPA', (116, 131))	('EZH2', 'Gene', '2146', (107, 111))	('EZH2', 'Gene', (107, 111))	('p21', 'Gene', '1026', (143, 146))	('LUCAT1', 'Gene', '100505994', (70, 76))	('LUCAT1', 'Gene', (70, 76))
146354	28423699	Taken together, we concluded that LUCAT1 might play a vital role in the cell cycle of NSCLC via epigenetically silencing p21 and p57 expression.	('p21', 'Gene', '1026', (121, 124))	('p57', 'Gene', (129, 132))	('NSCLC', 'Disease', (86, 91))	('epigenetically silencing', 'Var', (96, 120))	('p21', 'Gene', (121, 124))	('LUCAT1', 'Gene', '100505994', (34, 40))	('NSCLC', 'Disease', 'MESH:D002289', (86, 91))	('LUCAT1', 'Gene', (34, 40))	('NSCLC', 'Phenotype', 'HP:0030358', (86, 91))	('p57', 'Gene', '1028', (129, 132))
146356	28423699	Its abnormal expression can predict a poor prognosis of NSCLC patients, and it may be an independent prognostic marker.	('abnormal', 'Var', (4, 12))	('NSCLC', 'Disease', (56, 61))	('NSCLC', 'Disease', 'MESH:D002289', (56, 61))	('patients', 'Species', '9606', (62, 70))	('NSCLC', 'Phenotype', 'HP:0030358', (56, 61))
146358	28423699	LUCAT1 mediated the oncogenic effects is partially through its epigenetic silencing of the p21 and p57 expression by binding to PRC2 (Figure 8).	('p57', 'Gene', (99, 102))	('epigenetic', 'Var', (63, 73))	('PRC2', 'Gene', (128, 132))	('binding', 'Interaction', (117, 124))	('p21', 'Gene', '1026', (91, 94))	('oncogenic effects', 'CPA', (20, 37))	('p21', 'Gene', (91, 94))	('p57', 'Gene', '1028', (99, 102))	('LUCAT1', 'Gene', '100505994', (0, 6))	('LUCAT1', 'Gene', (0, 6))
146404	27958224	The cell-tracer binding ratio for the A549 cells using the 18F-FDG was greater than the ratio using 18F-FLT (P < 0.05).	('A549', 'CellLine', 'CVCL:0023', (38, 42))	('18F-FDG', 'Var', (59, 66))	('FLT', 'Gene', '2321', (104, 107))	('FLT', 'Gene', (104, 107))	('cell-tracer', 'MPA', (4, 15))	('18F-FDG', 'Chemical', 'MESH:D019788', (59, 66))	('greater', 'PosReg', (71, 78))
146406	27958224	The tumor-to-nontumor uptake ratio of 18F-FDG imaging in xenografts was higher than that of 18F-FLT imaging.	('FLT', 'Gene', (96, 99))	('tumor', 'Disease', (4, 9))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('18F-FDG', 'Chemical', 'MESH:D019788', (38, 45))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Disease', (16, 21))	('higher', 'PosReg', (72, 78))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('FLT', 'Gene', '2321', (96, 99))	('18F-FDG', 'Var', (38, 45))
146419	27958224	However, subsequent studies warned of the potential for false-positive and false-negative findings in the diagnosis of SPNs using 2-[18F]-fluoro-2-deoxy-D-glucose (18F-FDG) PET/CT and reported that 18F-FDG PET exhibited low sensitivity to nodules with a diameter of <10 mm, resulting in false-negative findings for lung adenocarcinoma and carcinoid and mucinous adenocarcinomas and false-positive reports due to infectious diseases, tuberculosis, fungal infection, and sarcoidosis.	('carcinoid', 'Phenotype', 'HP:0100570', (339, 348))	('2-[18F]-fluoro-2-deoxy-D-glucose', 'Chemical', 'MESH:D019788', (130, 162))	('SPN', 'Gene', (119, 122))	('tuberculosis', 'Disease', 'MESH:D014376', (433, 445))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (315, 334))	('sarcoidosis', 'Disease', (469, 480))	('carcinoma', 'Phenotype', 'HP:0030731', (325, 334))	('tuberculosis', 'Disease', (433, 445))	('infectious diseases', 'Disease', 'MESH:D003141', (412, 431))	('SPN', 'Gene', '10522', (119, 122))	('lung adenocarcinoma and carcinoid and mucinous adenocarcinomas', 'Disease', 'MESH:D002288', (315, 377))	('fungal infection', 'Disease', 'MESH:D009181', (447, 463))	('infectious diseases', 'Disease', (412, 431))	('18F-FDG', 'Chemical', 'MESH:D019788', (198, 205))	('18F-FDG', 'Chemical', 'MESH:D019788', (164, 171))	('carcinoma', 'Phenotype', 'HP:0030731', (367, 376))	('fungal infection', 'Disease', (447, 463))	('18F-FDG', 'Var', (198, 205))	('sarcoidosis', 'Disease', 'MESH:D012507', (469, 480))
146459	27958224	Positron emission tomography/computed tomography analysis Dose of injection tracer: The dose was 555 MBq/kg for both 18F-FDG and 18F-FLT.	('18F-FDG', 'Var', (117, 124))	('18F-FDG', 'Chemical', 'MESH:D019788', (117, 124))	('FLT', 'Gene', '2321', (133, 136))	('FLT', 'Gene', (133, 136))
146464	27958224	After binding lung cancer A549 cells with 18F-FDG and 18F-FLT for 180 min, the uptake rate (mean +- standard deviation for six replicates) in lung cancer A549 cells for 18F-FDG was higher than that for 18F-FLT (2.41% +- 0.37% vs. 1.83% +- 0.46%, P < 0.05, cells were adjusted to 105).	('A549', 'CellLine', 'CVCL:0023', (154, 158))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('lung cancer', 'Disease', (142, 153))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('18F-FDG', 'Chemical', 'MESH:D019788', (169, 176))	('A549', 'CellLine', 'CVCL:0023', (26, 30))	('FLT', 'Gene', (206, 209))	('18F-FDG', 'Var', (169, 176))	('lung cancer', 'Disease', (14, 25))	('higher', 'PosReg', (181, 187))	('18F-FDG', 'Chemical', 'MESH:D019788', (42, 49))	('FLT', 'Gene', '2321', (206, 209))	('lung cancer', 'Disease', 'MESH:D008175', (142, 153))	('lung cancer', 'Phenotype', 'HP:0100526', (142, 153))	('FLT', 'Gene', (58, 61))	('lung cancer', 'Disease', 'MESH:D008175', (14, 25))	('uptake', 'MPA', (79, 85))	('lung cancer', 'Phenotype', 'HP:0100526', (14, 25))	('FLT', 'Gene', '2321', (58, 61))
146467	27958224	The correlation between the Ki-67 A488nm value and 18F-FDG or 18F-FLT A549 cell uptake rates in A549 cells are shown in Figure 1.	('FLT', 'Gene', '2321', (66, 69))	('FLT', 'Gene', (66, 69))	('A549', 'CellLine', 'CVCL:0023', (96, 100))	('Ki-67', 'Var', (28, 33))	('A488nm', 'Var', (34, 40))	('A549', 'CellLine', 'CVCL:0023', (70, 74))	('18F-FDG', 'Chemical', 'MESH:D019788', (51, 58))
146471	27958224	In addition, imaging of tumors with 18F-FDG PET showed a slightly higher radioactivity concentration than with 18F-FLT.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('18F-FDG PET', 'Var', (36, 47))	('tumors', 'Disease', (24, 30))	('tumors', 'Disease', 'MESH:D009369', (24, 30))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('FLT', 'Gene', '2321', (115, 118))	('radioactivity concentration', 'MPA', (73, 100))	('FLT', 'Gene', (115, 118))	('higher', 'PosReg', (66, 72))	('18F-FDG', 'Chemical', 'MESH:D019788', (36, 43))
146525	27958224	The relationship between the A549 cell division cycle and 18F-FLT uptake showed a strong positive connection of the tracer uptake ratio of cells with TK-1 activity.	('tracer uptake ratio', 'MPA', (116, 135))	('TK-1', 'Gene', (150, 154))	('activity', 'Var', (155, 163))	('A549', 'CellLine', 'CVCL:0023', (29, 33))	('FLT', 'Gene', '2321', (62, 65))	('TK-1', 'Gene', '7083', (150, 154))	('FLT', 'Gene', (62, 65))
146542	27958224	Our results of animal imaging showed that the tumor-to-nontumor uptake ratio of 18F-FDG was higher than that of 18F-FLT, similar to the cytological experimental results.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('higher', 'PosReg', (92, 98))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Disease', (46, 51))	('18F-FDG', 'Var', (80, 87))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('FLT', 'Gene', '2321', (116, 119))	('FLT', 'Gene', (116, 119))	('18F-FDG', 'Chemical', 'MESH:D019788', (80, 87))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
146587	33535184	Results: For patients with lung squamous cell carcinoma, only high expression of SLC39A3, SLC39A4 and SLC39A7 have significant affections to the prognosis.	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (27, 55))	('carcinoma', 'Phenotype', 'HP:0030731', (46, 55))	('SLC39A4', 'Gene', (90, 97))	('SLC39A7', 'Gene', '7922', (102, 109))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (27, 55))	('SLC39A4', 'Gene', '55630', (90, 97))	('affections', 'Reg', (127, 137))	('SLC39A3', 'Gene', '29985', (81, 88))	('patients', 'Species', '9606', (13, 21))	('SLC39A3', 'Gene', (81, 88))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (32, 55))	('lung squamous cell carcinoma', 'Disease', (27, 55))	('SLC39A7', 'Gene', (102, 109))	('high', 'Var', (62, 66))
146607	33535184	Inhibition of SLC39A5 causes cyclooxygenase 2 downregulation and E-cadherin expression increased and reduces growth esophageal cancer in vivo and in vitro.	('downregulation', 'NegReg', (46, 60))	('cyclooxygenase 2', 'Gene', (29, 45))	('increased', 'PosReg', (87, 96))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('SLC39A5', 'Gene', (14, 21))	('reduces', 'NegReg', (101, 108))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('expression', 'MPA', (76, 86))	('Inhibition', 'Var', (0, 10))	('E-cadherin', 'Gene', '999', (65, 75))	('cancer', 'Disease', (127, 133))	('SLC39A5', 'Gene', '283375', (14, 21))	('E-cadherin', 'Gene', (65, 75))	('cyclooxygenase 2', 'Gene', '5743', (29, 45))
146617	33535184	High expressed SLC39A7 was related to better OS in patients with LUSC.	('LUSC', 'Phenotype', 'HP:0030359', (65, 69))	('SLC39A7', 'Gene', '7922', (15, 22))	('better', 'PosReg', (38, 44))	('High expressed', 'Var', (0, 14))	('LUSC', 'Disease', (65, 69))	('SLC39A7', 'Gene', (15, 22))	('patients', 'Species', '9606', (51, 59))
146619	33535184	As shown in Figure 3, high expression of SLC39A1, 2, 4, 5, 7, 8, 11 and 13 was significantly associated with inferior prognostic values in patients with LUAD.	('inferior', 'NegReg', (109, 117))	('high expression', 'Var', (22, 37))	('patients', 'Species', '9606', (139, 147))	('LUAD', 'Disease', (153, 157))	('LUAD', 'Phenotype', 'HP:0030078', (153, 157))	('SLC39A1, 2, 4, 5, 7, 8, 11 and 13', 'Gene', '27173;6569', (41, 74))
146623	33535184	As shown in Table 1, overexpressed SLC39A1, 4, 5, 7, and 11 was significantly associated with more undesirable prognostic value in patients with Stage I LUAD.	('patients', 'Species', '9606', (131, 139))	('overexpressed', 'Var', (21, 34))	('SLC39A1, 4, 5, 7', 'Gene', '27173', (35, 51))	('LUAD', 'Phenotype', 'HP:0030078', (153, 157))	('Stage I LUAD', 'Disease', (145, 157))
146625	33535184	For patients with Stage II LUAD, high expression of SLC39A1, 2, 4 and 5 suggested inferior prognosis, but high expression of SLC39A6, 8, 9, 10, 12 and 14 were associated with better prognosis.	('high', 'Var', (33, 37))	('LUAD', 'Phenotype', 'HP:0030078', (27, 31))	('inferior', 'NegReg', (82, 90))	('SLC39A6', 'Gene', '25800', (125, 132))	('SLC39A1', 'Gene', '27173', (52, 59))	('SLC39A1', 'Gene', (52, 59))	('SLC39A6', 'Gene', (125, 132))	('patients', 'Species', '9606', (4, 12))
146626	33535184	In Stage III LUAD patients, only high expressed SLC39A9 suggested poorer prognosis, but high expressed SLC39A2, 4, 12 and 14 were associated with preferable prognosis.	('high expressed', 'Var', (33, 47))	('SLC39A2', 'Gene', (103, 110))	('SLC39A9', 'Gene', (48, 55))	('SLC39A9', 'Gene', '55334', (48, 55))	('SLC39A2', 'Gene', '29986', (103, 110))	('patients', 'Species', '9606', (18, 26))	('LUAD', 'Phenotype', 'HP:0030078', (13, 17))
146629	33535184	As shown in Table 3, for never smoking patients, high mRNA expression of SLC39A1, 2, 4, 7, 11 and 13 indicated as inferior OS.	('patients', 'Species', '9606', (39, 47))	('mRNA expression', 'MPA', (54, 69))	('SLC39A1', 'Gene', '27173', (73, 80))	('SLC39A1', 'Gene', (73, 80))	('inferior OS', 'Disease', (114, 125))	('high', 'Var', (49, 53))
146634	33535184	Western bolt showed SLC39A7 was downregulated with siR-SLC39A7 transfected in A549 cells (Figure 4B).	('downregulated', 'NegReg', (32, 45))	('SLC39A7', 'Gene', (55, 62))	('transfected', 'Var', (63, 74))	('SLC39A7', 'Gene', '7922', (20, 27))	('SLC39A7', 'Gene', '7922', (55, 62))	('A549', 'CellLine', 'CVCL:0023', (78, 82))	('SLC39A7', 'Gene', (20, 27))
146637	33535184	When knocking down SLC39A7 expression, the size and number of cell colony was significantly inhibited (Figure 4D).	('inhibited', 'NegReg', (92, 101))	('knocking down', 'Var', (5, 18))	('SLC39A7', 'Gene', (19, 26))	('SLC39A7', 'Gene', '7922', (19, 26))	('expression', 'Protein', (27, 37))
146654	33535184	(P=2.2E-16, Figure 6F) To determine the expression relationship between SLC39A7 and RRBP1, siR-SLC39A7 or siR-RRBP1 were transfected into A549 cells for 48 h. As shown in Figure 6G, 6H, knocking down of SLC39A7 cannot inhibit the expression of RRBP1.	('SLC39A7', 'Gene', '7922', (95, 102))	('RRBP1', 'Gene', '6238', (84, 89))	('RRBP1', 'Gene', (84, 89))	('RRBP1', 'Gene', '6238', (110, 115))	('A549', 'CellLine', 'CVCL:0023', (138, 142))	('knocking down', 'Var', (186, 199))	('SLC39A7', 'Gene', (95, 102))	('RRBP1', 'Gene', (244, 249))	('SLC39A7', 'Gene', (72, 79))	('SLC39A7', 'Gene', '7922', (72, 79))	('SLC39A7', 'Gene', '7922', (203, 210))	('RRBP1', 'Gene', '6238', (244, 249))	('SLC39A7', 'Gene', (203, 210))	('RRBP1', 'Gene', (110, 115))
146655	33535184	On the contrary, knocking down of RRBP1 significantly reduce the expression of SLC39A7.	('SLC39A7', 'Gene', (79, 86))	('reduce', 'NegReg', (54, 60))	('RRBP1', 'Gene', (34, 39))	('expression', 'MPA', (65, 75))	('RRBP1', 'Gene', '6238', (34, 39))	('SLC39A7', 'Gene', '7922', (79, 86))	('knocking down', 'Var', (17, 30))
146682	33535184	High expressed SLC39A4 is found in several malignances and associated with poorer prognosis, including lung cancer.	('lung cancer', 'Disease', 'MESH:D008175', (103, 114))	('High expressed', 'Var', (0, 14))	('associated', 'Reg', (59, 69))	('found', 'Reg', (26, 31))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('lung cancer', 'Disease', (103, 114))	('lung cancer', 'Phenotype', 'HP:0100526', (103, 114))	('SLC39A4', 'Gene', (15, 22))	('SLC39A4', 'Gene', '55630', (15, 22))
146688	33535184	SLC39A6 was highly expressed in cancer tissues, but high expressed SLC39A6 was correlated with a favorable OS of LUAD patients.	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('LUAD patients', 'Disease', (113, 126))	('cancer', 'Disease', (32, 38))	('SLC39A6', 'Gene', '25800', (67, 74))	('SLC39A6', 'Gene', (67, 74))	('high expressed', 'Var', (52, 66))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('LUAD', 'Phenotype', 'HP:0030078', (113, 117))	('SLC39A6', 'Gene', '25800', (0, 7))	('patients', 'Species', '9606', (118, 126))	('SLC39A6', 'Gene', (0, 7))
146689	33535184	have found that PTCH1-3'UTR could attract miR-101-3p approach and increased expression of SLC39A6, and high expressed SLC39A6 was associated with progression of NSCLC.	('SLC39A6', 'Gene', '25800', (90, 97))	('NSCLC', 'Disease', 'MESH:D002289', (161, 166))	('increased', 'PosReg', (66, 75))	('SLC39A6', 'Gene', (90, 97))	('SLC39A6', 'Gene', '25800', (118, 125))	('miR-101-3p approach', 'MPA', (42, 61))	('SLC39A6', 'Gene', (118, 125))	('PTCH1', 'Gene', '5727', (16, 21))	('NSCLC', 'Phenotype', 'HP:0030358', (161, 166))	('attract', 'PosReg', (34, 41))	('expression', 'MPA', (76, 86))	('high expressed', 'Var', (103, 117))	('NSCLC', 'Disease', (161, 166))	('associated with', 'Reg', (130, 145))	('PTCH1', 'Gene', (16, 21))
146690	33535184	Through subgroup analysis, our results suggested that high level of SLC39A6 predicated good prognosis in different groups, which support the comprehensive results.	('SLC39A6', 'Gene', (68, 75))	('SLC39A6', 'Gene', '25800', (68, 75))	('high level', 'Var', (54, 64))
146694	33535184	And our findings suggested that high expression of SLC39A8 suggested an inferior prognosis.	('SLC39A8', 'Gene', (51, 58))	('high', 'Var', (32, 36))	('SLC39A8', 'Gene', '64116', (51, 58))	('expression', 'MPA', (37, 47))
146696	33535184	Additional subgroup analysis suggested that for clinical stage I and stage II LUAD patients, high expression of SLC39A9 indicated a preferable OS, but suggested an inferior prognosis for stage III patients, which suggested that SLC39A9 plays various roles in different stages of the disease.	('patients', 'Species', '9606', (197, 205))	('LUAD', 'Phenotype', 'HP:0030078', (78, 82))	('SLC39A9', 'Gene', '55334', (228, 235))	('SLC39A9', 'Gene', (228, 235))	('SLC39A9', 'Gene', (112, 119))	('high expression', 'Var', (93, 108))	('patients', 'Species', '9606', (83, 91))	('SLC39A9', 'Gene', '55334', (112, 119))
146702	33535184	Downregulated SLC39A7 significantly suppressed cell growth and cell colony which suggested that SLC39A7 was important for LUAD cell survival.	('Downregulated', 'Var', (0, 13))	('suppressed', 'NegReg', (36, 46))	('SLC39A7', 'Gene', '7922', (96, 103))	('cell growth', 'CPA', (47, 58))	('cell colony', 'CPA', (63, 74))	('SLC39A7', 'Gene', '7922', (14, 21))	('LUAD', 'Phenotype', 'HP:0030078', (122, 126))	('SLC39A7', 'Gene', (96, 103))	('SLC39A7', 'Gene', (14, 21))
146703	33535184	For biological function, high expression of SLC39A7 mainly enhanced multicellular organismal homeostasis, positive regulation of cell-cell adhesion, and maintenance of gastrointestinal epithelium, which may contribute to progress of cancer.	('multicellular organismal homeostasis', 'MPA', (68, 104))	('cell-cell adhesion', 'CPA', (129, 147))	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('contribute', 'Reg', (207, 217))	('positive', 'PosReg', (106, 114))	('enhanced', 'PosReg', (59, 67))	('high expression', 'Var', (25, 40))	('cancer', 'Disease', (233, 239))	('SLC39A7', 'Gene', (44, 51))	('cancer', 'Disease', 'MESH:D009369', (233, 239))	('gastrointestinal', 'MPA', (168, 184))	('SLC39A7', 'Gene', '7922', (44, 51))
146704	33535184	By suppressing expression of SLC39A7 and activity of Wnt/beta-catenin, miR-15a-3p inhibits cell proliferation and invasion in prostate cancer.	('SLC39A7', 'Gene', '7922', (29, 36))	('prostate cancer', 'Phenotype', 'HP:0012125', (126, 141))	('suppressing', 'NegReg', (3, 14))	('cell proliferation', 'CPA', (91, 109))	('SLC39A7', 'Gene', (29, 36))	('inhibits', 'NegReg', (82, 90))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('prostate cancer', 'Disease', (126, 141))	('expression', 'MPA', (15, 25))	('miR-15a-3p', 'Chemical', '-', (71, 81))	('beta-catenin', 'Gene', (57, 69))	('miR-15a-3p', 'Var', (71, 81))	('activity', 'MPA', (41, 49))	('beta-catenin', 'Gene', '1499', (57, 69))	('prostate cancer', 'Disease', 'MESH:D011471', (126, 141))
146707	33535184	Knocking down of RRBP1 promotes to stress of endoplasmic reticulum and significantly reduced cell viability and tumorigenicity.	('Knocking down', 'Var', (0, 13))	('promotes', 'PosReg', (23, 31))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('cell viability', 'CPA', (93, 107))	('stress of endoplasmic reticulum', 'MPA', (35, 66))	('RRBP1', 'Gene', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('RRBP1', 'Gene', '6238', (17, 22))	('tumor', 'Disease', (112, 117))	('reduced', 'NegReg', (85, 92))
146708	33535184	In the present study, we found that RRBP1 was accounted for expression of SLC39A7, and high expressed RRBP1 suggested poor prognosis of LUAD.	('SLC39A7', 'Gene', '7922', (74, 81))	('RRBP1', 'Gene', (36, 41))	('RRBP1', 'Gene', '6238', (102, 107))	('RRBP1', 'Gene', (102, 107))	('RRBP1', 'Gene', '6238', (36, 41))	('SLC39A7', 'Gene', (74, 81))	('high expressed', 'Var', (87, 101))	('LUAD', 'Disease', (136, 140))	('LUAD', 'Phenotype', 'HP:0030078', (136, 140))
146867	24349556	beta4GalNAc-T4 is also expressed in some fetal tissues, such as kidney and lung, while beta4GalNAc-T3 is expressed in the stomach, colon and testis.	('beta4GalNAc-T4', 'Var', (0, 14))	('colon', 'Disease', (131, 136))	('colon', 'Disease', 'MESH:D015179', (131, 136))
146871	32992842	High NRF2 Levels Correlate with Poor Prognosis in Colorectal Cancer Patients and with Sensitivity to the Kinase Inhibitor AT9283 In Vitro Aberrant hyperactivation of nuclear factor erythroid 2 (NF-E2) p45-related factor 2 (NRF2) is a common event in many tumour types and associates with resistance to therapy and poor patient prognosis; however, its relevance in colorectal tumours is not well-established.	('patient', 'Species', '9606', (319, 326))	('AT9283', 'Chemical', 'MESH:C535237', (122, 128))	('Colorectal Cancer', 'Disease', 'MESH:D015179', (50, 67))	('tumours', 'Phenotype', 'HP:0002664', (375, 382))	('NRF2', 'Gene', (5, 9))	('Colorectal Cancer', 'Disease', (50, 67))	('hyperactivation', 'PosReg', (147, 162))	('nuclear factor erythroid 2', 'Gene', '4778', (166, 192))	('tumour', 'Phenotype', 'HP:0002664', (375, 381))	('NRF2', 'Gene', '4780', (223, 227))	('tumour', 'Disease', 'MESH:D009369', (375, 381))	('colorectal tumours', 'Disease', 'MESH:D015179', (364, 382))	('tumour', 'Disease', (375, 381))	('nuclear factor erythroid 2', 'Gene', (166, 192))	('Colorectal Cancer', 'Phenotype', 'HP:0003003', (50, 67))	('tumour', 'Phenotype', 'HP:0002664', (255, 261))	('tumour', 'Disease', 'MESH:D009369', (255, 261))	('tumour', 'Disease', (255, 261))	('NF-E2', 'Gene', (194, 199))	('Cancer', 'Phenotype', 'HP:0002664', (61, 67))	('NRF2', 'Gene', (223, 227))	('NRF2', 'Gene', '4780', (5, 9))	('Patients', 'Species', '9606', (68, 76))	('Aberrant', 'Var', (138, 146))	('colorectal tumours', 'Disease', (364, 382))
146875	32992842	We identified AT9283, an Aurora kinase inhibitor, for its selectivity towards killing cancer cells with hyperactive NRF2 as a consequence to either genetic or pharmacological activation.	('AT9283', 'Chemical', 'MESH:C535237', (14, 20))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('hyperactive', 'Disease', (104, 115))	('NRF2', 'Gene', '4780', (116, 120))	('hyperactive', 'Disease', 'MESH:D006948', (104, 115))	('AT9283', 'Var', (14, 20))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('NRF2', 'Gene', (116, 120))	('cancer', 'Disease', (86, 92))
146880	32992842	Sustained activation of the NRF2 pathway is mainly due to either loss-of-function (LOF) mutations in KEAP1 or gain-of-function (GOF) mutations in NFE2L2.	('NRF2', 'Gene', (28, 32))	('KEAP1', 'Gene', '9817', (101, 106))	('mutations', 'Var', (88, 97))	('loss-of-function', 'NegReg', (65, 81))	('mutations', 'Var', (133, 142))	('NRF2', 'Gene', '4780', (28, 32))	('KEAP1', 'Gene', (101, 106))	('gain-of-function', 'PosReg', (110, 126))	('NFE2L2', 'Gene', '4780', (146, 152))	('activation', 'PosReg', (10, 20))	('NFE2L2', 'Gene', (146, 152))
146883	32992842	It is estimated that 34% LuSCC and 18% of LuAD patients harbour mutations in NRF2 or KEAP1, which correlates with poor survival.	('LuAD', 'Phenotype', 'HP:0030078', (42, 46))	('LuAD', 'Disease', (42, 46))	('KEAP1', 'Gene', (85, 90))	('LuAD', 'Disease', 'None', (42, 46))	('patients', 'Species', '9606', (47, 55))	('NRF2', 'Gene', '4780', (77, 81))	('mutations', 'Var', (64, 73))	('KEAP1', 'Gene', '9817', (85, 90))	('NRF2', 'Gene', (77, 81))
146884	32992842	Additionally, aberrant activation of NRF2 in cancer cells also occurs through alternative mechanisms, including the oncogene-induced transcription of NRF2 via KRAS, BRAF, MYC activation or epigenetic silencing of KEAP1.	('NRF2', 'Gene', (150, 154))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('KRAS', 'Gene', (159, 163))	('epigenetic silencing', 'Var', (189, 209))	('KEAP1', 'Gene', (213, 218))	('BRAF', 'Gene', '673', (165, 169))	('NRF2', 'Gene', '4780', (37, 41))	('activation', 'PosReg', (23, 33))	('MYC', 'Gene', '4609', (171, 174))	('BRAF', 'Gene', (165, 169))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('KRAS', 'Gene', '3845', (159, 163))	('NRF2', 'Gene', '4780', (150, 154))	('NRF2', 'Gene', (37, 41))	('cancer', 'Disease', (45, 51))	('transcription', 'MPA', (133, 146))	('MYC', 'Gene', (171, 174))	('KEAP1', 'Gene', '9817', (213, 218))
146885	32992842	Altogether, this shows that the aberrant activation of the NRF2 pathway might be a common pro-oncogenic event in many cancer types, and thus, the identification of ways to overcome the protection provided by NRF2 is a desirable goal.	('cancer', 'Disease', (118, 124))	('NRF2', 'Gene', (59, 63))	('NRF2', 'Gene', '4780', (208, 212))	('NRF2', 'Gene', '4780', (59, 63))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('NRF2', 'Gene', (208, 212))	('activation', 'PosReg', (41, 51))	('aberrant', 'Var', (32, 40))	('cancer', 'Disease', 'MESH:D009369', (118, 124))
146894	32992842	This is in contrast with lung cancer, where, in addition to the existence of well-characterised cell lines harbouring mutant hyperactive NRF2 (e.g., the lung cancer cell line A549), several models have been developed to study NRF2 hyperactivation, and a number of associated vulnerabilities have been identified by using KEAP1-deficient or loss-of-function mutant models.	('KEAP1', 'Gene', (321, 326))	('lung cancer', 'Disease', 'MESH:D008175', (153, 164))	('NRF2', 'Gene', '4780', (137, 141))	('hyperactive', 'Disease', 'MESH:D006948', (125, 136))	('lung cancer', 'Phenotype', 'HP:0100526', (153, 164))	('hyperactive', 'Disease', (125, 136))	('NRF2', 'Gene', (226, 230))	('lung cancer', 'Disease', 'MESH:D008175', (25, 36))	('A549', 'CellLine', 'CVCL:0023', (175, 179))	('lung cancer', 'Phenotype', 'HP:0100526', (25, 36))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('NRF2', 'Gene', (137, 141))	('mutant', 'Var', (118, 124))	('lung cancer', 'Disease', (153, 164))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('loss-of-function', 'NegReg', (340, 356))	('lung cancer', 'Disease', (25, 36))	('NRF2', 'Gene', '4780', (226, 230))	('KEAP1', 'Gene', '9817', (321, 326))
146898	32992842	Furthermore, we generated isogenic colorectal DLD1 cell lines harbouring gain-of-function (GOF) mutations in NRF2.	('NRF2', 'Gene', '4780', (109, 113))	('gain-of-function', 'PosReg', (73, 89))	('mutations', 'Var', (96, 105))	('NRF2', 'Gene', (109, 113))
146912	32992842	The primers used were obtained from Thermo Fisher Scientific (Waltham, MA, USA) as follows: NQO1 (Hs00168547_m1), AKR1B10 (Hs00252524_m1), NFE2L2 (Hs00975961_g1), HPRT1 (Hs02800695_m1) and beta-actin (Hs01060665_g1).	('Hs00252524_m1', 'Var', (123, 136))	('Hs00975961_g1', 'Var', (147, 160))	('Hs02800695_m1', 'Var', (170, 183))	('Hs00168547_m1', 'Var', (98, 111))	('NFE2L2', 'Gene', '4780', (139, 145))	('AKR1B10', 'Gene', (114, 121))	('AKR1B10', 'Gene', '57016', (114, 121))	('HPRT1', 'Gene', (163, 168))	('HPRT1', 'Gene', '3251', (163, 168))	('Hs01060665_g1', 'Var', (201, 214))	('NFE2L2', 'Gene', (139, 145))
146962	32992842	Indeed, high protein levels of nuclear NRF2, correlated with a decreased survival of colorectal cancer patients (p = 0.041) (Figure 1C), with a mean difference in cancer-specific survival of 17 months between those patients with high NRF2 expressions versus those with low NRF2 expressions.	('NRF2', 'Gene', '4780', (273, 277))	('cancer', 'Disease', (96, 102))	('cancer', 'Disease', 'MESH:D009369', (163, 169))	('high', 'Var', (229, 233))	('colorectal cancer', 'Phenotype', 'HP:0003003', (85, 102))	('survival', 'MPA', (73, 81))	('NRF2', 'Gene', (234, 238))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('decreased', 'NegReg', (63, 72))	('expressions', 'Var', (239, 250))	('NRF2', 'Gene', (273, 277))	('protein levels', 'MPA', (13, 27))	('NRF2', 'Gene', '4780', (39, 43))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('colorectal cancer', 'Disease', 'MESH:D015179', (85, 102))	('cancer', 'Disease', (163, 169))	('patients', 'Species', '9606', (215, 223))	('colorectal cancer', 'Disease', (85, 102))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('NRF2', 'Gene', (39, 43))	('NRF2', 'Gene', '4780', (234, 238))	('patients', 'Species', '9606', (103, 111))
146963	32992842	In addition, nuclear NRF2 levels significantly correlated with both the proliferation index and defective DNA mismatch repair (MMR) status but not with other studied clinical factors (Supplementary Figure S1C).	('NRF2', 'Gene', (21, 25))	('proliferation index', 'CPA', (72, 91))	('defective', 'Var', (96, 105))	('correlated', 'Reg', (47, 57))	('NRF2', 'Gene', '4780', (21, 25))
146967	32992842	This motif is one of the two KEAP1-binding motifs within NRF2, and thus, its deletion disrupts the functional interaction between NRF2 and KEAP1.	('KEAP1', 'Gene', (139, 144))	('NRF2', 'Gene', '4780', (57, 61))	('NRF2', 'Gene', '4780', (130, 134))	('deletion', 'Var', (77, 85))	('KEAP1', 'Gene', '9817', (139, 144))	('KEAP1', 'Gene', '9817', (29, 34))	('disrupts', 'NegReg', (86, 94))	('functional interaction', 'MPA', (99, 121))	('NRF2', 'Gene', (57, 61))	('NRF2', 'Gene', (130, 134))	('KEAP1', 'Gene', (29, 34))
146969	32992842	However, most of the cell clones in which the DNA is repaired in-frame will result in NRF2-GOF clones (as described in) due to a mutation or deletion of the KEAP1-binding sequence.	('KEAP1', 'Gene', (157, 162))	('deletion', 'Var', (141, 149))	('NRF2', 'Gene', '4780', (86, 90))	('mutation', 'Var', (129, 137))	('clones', 'Var', (95, 101))	('NRF2', 'Gene', (86, 90))	('result', 'Reg', (76, 82))	('KEAP1', 'Gene', '9817', (157, 162))
146970	32992842	These gain-of-function (GOF) deletions would functionally resemble some of the NRF2 mutations found in tumours.	('tumours', 'Disease', 'MESH:D009369', (103, 110))	('tumours', 'Disease', (103, 110))	('NRF2', 'Gene', (79, 83))	('tumour', 'Phenotype', 'HP:0002664', (103, 109))	('mutations', 'Var', (84, 93))	('gain-of-function', 'PosReg', (6, 22))	('tumours', 'Phenotype', 'HP:0002664', (103, 110))	('NRF2', 'Gene', '4780', (79, 83))	('deletions', 'Var', (29, 38))
146978	32992842	Altogether, using the CRISPR/Cas9 system, we generated stable DLD1 cells harbouring the constitutive activation of NRF2 by truncating one of the domains required for KEAP1 binding.	('binding', 'Interaction', (172, 179))	('KEAP1', 'Gene', '9817', (166, 171))	('NRF2', 'Gene', '4780', (115, 119))	('activation', 'PosReg', (101, 111))	('truncating', 'Var', (123, 133))	('domains', 'MPA', (145, 152))	('KEAP1', 'Gene', (166, 171))	('NRF2', 'Gene', (115, 119))
146985	32992842	This analysis identified the Aurora kinase inhibitor AT9283 as the top candidate with selectivity against NRF2-GOF DLD1 cells (Figure 3A,B and Supplementary Figure S3A,B).	('AT9283', 'Var', (53, 59))	('NRF2', 'Gene', '4780', (106, 110))	('AT9283', 'Chemical', 'MESH:C535237', (53, 59))	('NRF2', 'Gene', (106, 110))
146986	32992842	AT9283 is a synthetic small heterocyclic molecule that potently inhibits several kinases, including Aurora A (3 nM), Aurora B (3 nM), JAK2 (1.2 nM), JAK3 (1.1 nM) and Abl (4.0 nM, T315I).	('JAK3', 'Gene', (149, 153))	('Aurora A', 'Gene', '6790', (100, 108))	('AT9283', 'Var', (0, 6))	('JAK2', 'Gene', '3717', (134, 138))	('kinases', 'Pathway', (81, 88))	('JAK3', 'Gene', '3718', (149, 153))	('Abl', 'Gene', (167, 170))	('Aurora B', 'Gene', '9212', (117, 125))	('JAK2', 'Gene', (134, 138))	('Aurora A', 'Gene', (100, 108))	('Aurora B', 'Gene', (117, 125))	('T315I', 'Mutation', 'rs121913459', (180, 185))	('Abl', 'Gene', '25', (167, 170))	('inhibits', 'NegReg', (64, 72))	('AT9283', 'Chemical', 'MESH:C535237', (0, 6))
146989	32992842	The drug screen also included other known Aurora kinase inhibitors (TAK 901, ENMD 2076, AZD A552-HQPA and MK-8745) that, although they did not pass the set threshold, displayed a selective trend against NRF2-GOF cells.	('NRF2', 'Gene', (203, 207))	('Aurora kinase', 'Enzyme', (42, 55))	('AZD', 'Var', (88, 91))	('MK-8745', 'Chemical', 'MESH:C574019', (106, 113))	('AZD A552', 'Chemical', '-', (88, 96))	('NRF2', 'Gene', '4780', (203, 207))
146990	32992842	Altogether, these analyses suggest that AT9283 selectively kill DLD1 cells harbouring NRF2 hyperactivation through the inhibition of Aurora kinases.	('AT9283', 'Var', (40, 46))	('NRF2', 'Gene', '4780', (86, 90))	('NRF2', 'Gene', (86, 90))	('inhibition', 'NegReg', (119, 129))	('Aurora kinases', 'Enzyme', (133, 147))	('hyperactivation', 'PosReg', (91, 106))	('AT9283', 'Chemical', 'MESH:C535237', (40, 46))
146991	32992842	AT9283 showed antimyeloma, antilymphoma, antileukaemia and anticolorectal cancer activity in preclinical studies, and its safety and efficacy against myeloma, lymphoma and leukaemia has been tested in various Phase I and II clinical trials.	('leukaemia', 'Disease', (45, 54))	('colorectal cancer', 'Disease', 'MESH:D015179', (63, 80))	('lymphoma', 'Phenotype', 'HP:0002665', (159, 167))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('antileukaemia', 'Disease', (41, 54))	('antileukaemia', 'Disease', 'None', (41, 54))	('AT9283', 'Var', (0, 6))	('myeloma', 'Disease', 'MESH:D009101', (18, 25))	('colorectal cancer', 'Disease', (63, 80))	('lymphoma', 'Phenotype', 'HP:0002665', (31, 39))	('myeloma', 'Disease', 'MESH:D009101', (150, 157))	('leukaemia', 'Disease', 'MESH:D007938', (172, 181))	('leukaemia', 'Disease', 'MESH:D007938', (45, 54))	('lymphoma', 'Disease', (159, 167))	('lymphoma', 'Disease', 'MESH:D008223', (159, 167))	('myeloma', 'Disease', (18, 25))	('AT9283', 'Chemical', 'MESH:C535237', (0, 6))	('colorectal cancer', 'Phenotype', 'HP:0003003', (63, 80))	('lymphoma', 'Disease', (31, 39))	('myeloma', 'Disease', (150, 157))	('lymphoma', 'Disease', 'MESH:D008223', (31, 39))	('leukaemia', 'Disease', (172, 181))
146993	32992842	To validate the top hit from the screen, we tested the effect of AT9283 on the viability of NRF2-WT and NRF2-GOF DLD1 cells after three days, using the Alamar blue assay as the readout (Figure 4A).	('AT9283', 'Chemical', 'MESH:C535237', (65, 71))	('NRF2', 'Gene', (104, 108))	('NRF2', 'Gene', '4780', (92, 96))	('tested', 'Reg', (44, 50))	('AT9283', 'Var', (65, 71))	('NRF2', 'Gene', (92, 96))	('NRF2', 'Gene', '4780', (104, 108))	('Alamar blue', 'Chemical', 'MESH:C005843', (152, 163))
146994	32992842	This assay confirmed the increased (by ~10-fold) sensitivity of the NRF2-GOF compared to NRF2-WT cells: AT9283 had a half maximal inhibitory concentration (IC50) of 28 nM in NRF2-GOF cells versus an IC50 of 320 nM in NRF2-WT cells.	('AT9283', 'Chemical', 'MESH:C535237', (104, 110))	('NRF2', 'Gene', (217, 221))	('NRF2', 'Gene', (89, 93))	('AT9283', 'Var', (104, 110))	('NRF2', 'Gene', '4780', (68, 72))	('NRF2', 'Gene', '4780', (174, 178))	('NRF2', 'Gene', '4780', (217, 221))	('NRF2', 'Gene', '4780', (89, 93))	('NRF2', 'Gene', (68, 72))	('NRF2', 'Gene', (174, 178))
146996	32992842	This analysis showed that AT9283 successfully "discriminates" between cell lines based on their NRF2 activity, with cells with high levels of NRF2 activity (GOF) having an increased sensitivity to AT9283.	('NRF2', 'Gene', (96, 100))	('NRF2', 'Gene', (142, 146))	('activity', 'MPA', (101, 109))	('AT9283', 'Chemical', 'MESH:C535237', (26, 32))	('AT9283', 'Chemical', 'MESH:C535237', (197, 203))	('AT9283', 'Var', (26, 32))	('NRF2', 'Gene', '4780', (96, 100))	('NRF2', 'Gene', '4780', (142, 146))
147000	32992842	By contrast, HB229 is a nonelectrophilic small molecule that disrupts the KEAP1-NRF2 protein complex.	('HB229', 'CellLine', 'CVCL:3694', (13, 18))	('NRF2', 'Gene', '4780', (80, 84))	('disrupts', 'NegReg', (61, 69))	('NRF2', 'Gene', (80, 84))	('HB229', 'Var', (13, 18))	('KEAP1', 'Gene', '9817', (74, 79))	('KEAP1', 'Gene', (74, 79))
147002	32992842	Critically, the effect on cell viability was completely dependent on AT9283 acting together with the NRF2 activator, as, at these concentrations, neither AT9283 (Figure 4A,B) nor any of the NRF2 activators by themselves (Figure 4B, lower panel) affected the viability of the cells.	('AT9283', 'Var', (154, 160))	('Critically', 'Disease', (0, 10))	('NRF2', 'Gene', '4780', (101, 105))	('AT9283', 'Chemical', 'MESH:C535237', (69, 75))	('NRF2', 'Gene', '4780', (190, 194))	('NRF2', 'Gene', (101, 105))	('NRF2', 'Gene', (190, 194))	('AT9283', 'Chemical', 'MESH:C535237', (154, 160))	('Critically', 'Disease', 'MESH:D016638', (0, 10))
147004	32992842	Nevertheless, these results demonstrate that, similar to the genetic, the pharmacological activation of NRF2 also sensitises DLD1 cells towards AT9283-mediated killing and further suggests that AT9283 could be used in combination with an NRF2 activator to sensitise cells with normal NRF2 levels.	('activation', 'PosReg', (90, 100))	('NRF2', 'Gene', (104, 108))	('NRF2', 'Gene', '4780', (238, 242))	('AT9283', 'Chemical', 'MESH:C535237', (144, 150))	('AT9283', 'Chemical', 'MESH:C535237', (194, 200))	('NRF2', 'Gene', '4780', (284, 288))	('NRF2', 'Gene', (238, 242))	('sensitises', 'Reg', (114, 124))	('NRF2', 'Gene', (284, 288))	('AT9283', 'Var', (194, 200))	('NRF2', 'Gene', '4780', (104, 108))
147011	32992842	and Figure S4: NRF2-WT and GOF DLD1 cells were exposed to increasing concentrations of AT9283 as indicated.	('NRF2', 'Gene', (15, 19))	('AT9283', 'Var', (87, 93))	('AT9283', 'Chemical', 'MESH:C535237', (87, 93))	('NRF2', 'Gene', '4780', (15, 19))
147013	32992842	This work was supported by the Medical Research Institute of the University of Dundee, Cancer Research UK (C52419/A22869 and C20953/A18644) (L.d.l.V., A.J.	('C20953/A18644', 'Var', (125, 138))	('Cancer', 'Disease', 'MESH:D009369', (87, 93))	('C52419/A22869', 'Var', (107, 120))	('Cancer', 'Disease', (87, 93))	('Cancer', 'Phenotype', 'HP:0002664', (87, 93))
147019	32290144	The main upregulated microRNAs associated with oral carcinoma are miR-21, miR-455-5p, miR-155-5p, miR-372, miR-373, miR-29b, miR-1246, miR-196a, and miR-181, while the main downregulated miRNAs are miR-204, miR-101, miR-32, miR-20a, miR-16, miR-17, and miR-125b.	('miR-372', 'Gene', '442917', (98, 105))	('miR-155', 'Gene', (86, 93))	('miR-455-5p', 'Var', (74, 84))	('miR-181', 'Var', (149, 156))	('miR-21', 'Gene', '406991', (66, 72))	('miR-155', 'Gene', '406947', (86, 93))	('miR-17', 'Gene', (241, 247))	('miR-204', 'Gene', (198, 205))	('oral carcinoma', 'Disease', (47, 61))	('miR-20a', 'Gene', (224, 231))	('miR-32', 'Gene', '407036', (216, 222))	('miR-20a', 'Gene', '406982', (224, 231))	('miR-1246', 'Gene', '100302142', (125, 133))	('miR-29b', 'Gene', '407024', (116, 123))	('miR-16', 'Gene', (233, 239))	('miR-21', 'Gene', (66, 72))	('miR-101', 'Var', (207, 214))	('oral carcinoma', 'Disease', 'MESH:D009062', (47, 61))	('miR-32', 'Gene', (216, 222))	('miR-204', 'Gene', '406987', (198, 205))	('carcinoma', 'Phenotype', 'HP:0030731', (52, 61))	('miR-373', 'Gene', (107, 114))	('upregulated', 'PosReg', (9, 20))	('miR-372', 'Gene', (98, 105))	('miR-17', 'Gene', '406952', (241, 247))	('miR-16', 'Gene', '51573', (233, 239))	('miR-29b', 'Gene', (116, 123))	('miR-1246', 'Gene', (125, 133))	('miR-373', 'Gene', '442918', (107, 114))	('miR-196a', 'Var', (135, 143))
147030	32290144	Among these, alterations in oncosuppressors (APC, p53), proto-oncogenes (Myc), oncogenes (Ras), and genes that control normal cellular processes (EIF3E, GSTM1) play a fundamental role in cancer development.	('cancer', 'Disease', 'MESH:D009369', (187, 193))	('GSTM1', 'Gene', '2944', (153, 158))	('GSTM1', 'Gene', (153, 158))	('cancer', 'Disease', (187, 193))	('men', 'Species', '9606', (201, 204))	('EIF3E', 'Gene', (146, 151))	('APC', 'Gene', (45, 48))	('Myc', 'Gene', '4609', (73, 76))	('p53', 'Gene', (50, 53))	('p53', 'Gene', '7157', (50, 53))	('APC', 'Gene', '324', (45, 48))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('alterations', 'Var', (13, 24))	('Myc', 'Gene', (73, 76))	('EIF3E', 'Gene', '3646', (146, 151))	('men', 'Species', '9606', (172, 175))
147031	32290144	Events such as DNA methylation, histone modifications, and noncoding alterations of RNA (e.g., microRNAs (miRNAs)) are also involved in the onset and progression of oral cancer.	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('histone', 'Protein', (32, 39))	('methylation', 'Var', (19, 30))	('cancer', 'Disease', (170, 176))	('RNA', 'Gene', (84, 87))	('noncoding', 'MPA', (59, 68))	('involved', 'Reg', (124, 132))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('modifications', 'Var', (40, 53))
147038	32290144	Dysregulation mechanisms include chromosomal abnormalities such as those resulting from amplification or gene deletion, alterations of transcriptional control, epigenetic alterations, and defects of proteins involved in the biogenesis of miRNAs.	('epigenetic alterations', 'CPA', (160, 182))	('proteins', 'Protein', (199, 207))	('transcriptional control', 'MPA', (135, 158))	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (33, 58))	('chromosomal abnormalities', 'Disease', (33, 58))	('amplification', 'Var', (88, 101))	('gene deletion', 'Var', (105, 118))	('defects', 'Var', (188, 195))	('alterations', 'Reg', (120, 131))
147039	32290144	The dysregulation of a miRNA allows the cancer cell to develop specific cancer capacities including support of the proliferative signal with avoidance of the suppressing mechanisms, resistance to apoptosis, invasion and metastasis capabilities, and the induction of angiogenesis.	('angiogenesis', 'CPA', (266, 278))	('resistance', 'CPA', (182, 192))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('dysregulation', 'Var', (4, 17))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('develop', 'PosReg', (55, 62))	('cancer', 'Disease', (40, 46))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('proliferative signal', 'CPA', (115, 135))	('cancer', 'Disease', (72, 78))
147040	32290144	A previous meta-analysis from our group reported that dysregulated miRNA expression in tissue can be used as a predictor of worse prognosis in OSCC patients.	('miRNA', 'Protein', (67, 72))	('patients', 'Species', '9606', (148, 156))	('dysregulated', 'Var', (54, 66))	('OSCC', 'Disease', (143, 147))
147041	32290144	In particular, upregulated miRNAs with prognostic capabilities were miR-21, miR-455-5p, miR-155-5p, miR-372, miR-373, miR-29b, miR-1246, miR-196a, and miR-181, while the downregulated miRNAs were miR-204, miR-101, miR-32, miR-20a, miR-16, miR-17, and miR-125b.	('miR-155', 'Gene', (88, 95))	('upregulated', 'PosReg', (15, 26))	('miR-1246', 'Gene', '100302142', (127, 135))	('miR-29b', 'Gene', '407024', (118, 125))	('miR-181', 'Var', (151, 158))	('miR-21', 'Gene', '406991', (68, 74))	('miR-155', 'Gene', '406947', (88, 95))	('miR-16', 'Gene', '51573', (231, 237))	('miR-17', 'Gene', '406952', (239, 245))	('miR-373', 'Gene', (109, 116))	('miR-204', 'Gene', (196, 203))	('miR-372', 'Gene', (100, 107))	('miR-32', 'Gene', '407036', (214, 220))	('miR-29b', 'Gene', (118, 125))	('miR-21', 'Gene', (68, 74))	('miR-373', 'Gene', '442918', (109, 116))	('miR-196a', 'Var', (137, 145))	('miR-1246', 'Gene', (127, 135))	('miR-17', 'Gene', (239, 245))	('miR-372', 'Gene', '442917', (100, 107))	('miR-455-5p', 'Var', (76, 86))	('miR-32', 'Gene', (214, 220))	('miR-204', 'Gene', '406987', (196, 203))	('miR-20a', 'Gene', (222, 229))	('miR-20a', 'Gene', '406982', (222, 229))	('miR-16', 'Gene', (231, 237))
147044	32290144	reported that serum levels of miR-21, miR-24, and miR-29a can be used as markers for the detection of carcinoma and, therefore, also potentially used to develop new therapeutic strategies.	('miR-29a', 'Gene', '407021', (50, 57))	('miR-24', 'Var', (38, 44))	('carcinoma', 'Disease', 'MESH:D009369', (102, 111))	('serum', 'MPA', (14, 19))	('miR-21', 'Gene', '406991', (30, 36))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('miR-29a', 'Gene', (50, 57))	('carcinoma', 'Disease', (102, 111))	('miR-21', 'Gene', (30, 36))
147068	32290144	analyzed 50 HNSCC patients and 30 healthy controls, reporting a sensitivity of 83.3% and a specificity of 51.9% with an AUC of 0.741, suggesting that the presence of miR-21 could be used as a biomarker in the plasma of HNSCC patients.	('HNSCC', 'Disease', (219, 224))	('miR-21', 'Gene', '406991', (166, 172))	('patients', 'Species', '9606', (225, 233))	('HNSCC', 'Phenotype', 'HP:0012288', (12, 17))	('patients', 'Species', '9606', (18, 26))	('miR-21', 'Gene', (166, 172))	('presence', 'Var', (154, 162))	('HNSCC', 'Phenotype', 'HP:0012288', (219, 224))
147079	32290144	To date, this meta-analysis is the first that examines the diagnostic accuracy of circulating miR-21 on oral cancer and head and neck neoplasms.	('circulating', 'Var', (82, 93))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('neoplasms', 'Phenotype', 'HP:0002664', (134, 143))	('neck neoplasms', 'Phenotype', 'HP:0012288', (129, 143))	('cancer', 'Disease', (109, 115))	('head and neck neoplasms', 'Disease', 'MESH:D006258', (120, 143))	('miR-21', 'Gene', (94, 100))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('neoplasm', 'Phenotype', 'HP:0002664', (134, 142))	('miR-21', 'Gene', '406991', (94, 100))
147101	31772577	Mutations in key driver genes : such as those that inactivate genes responsible for DNA repair : are a primary cause of cancer pathogenesis, although the HMP supported the idea that a dysbiotic microbiota can substantially contribute to cancer progression.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('Mutations', 'Var', (0, 9))	('contribute', 'Reg', (223, 233))	('cancer', 'Disease', 'MESH:D009369', (237, 243))	('cancer', 'Disease', (237, 243))	('cause', 'Reg', (111, 116))
147103	31772577	Comparison of the number of publications in the last 10 years revealed a strikingly higher growth rate of the topic "microbiome AND cancer" vs "gene mutation AND cancer" (Figure 1(b)).	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('cancer', 'Disease', (132, 138))	('cancer', 'Disease', (162, 168))	('growth', 'MPA', (91, 97))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('gene mutation', 'Var', (144, 157))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('higher', 'PosReg', (84, 90))
147118	31772577	In this condition, other microbes, such as Fusobacterium nucleatum (F. nucleatum), can become opportunistically pathogenic and lead to dysregulated immune response and increased risk to develop periodontal diseases and OSCC.	('periodontal diseases', 'Disease', (194, 214))	('OSCC', 'Disease', 'MESH:D002294', (219, 223))	('periodontal diseases', 'Phenotype', 'HP:0000704', (194, 214))	('SCC', 'Phenotype', 'HP:0002860', (220, 223))	('F. nucleatum', 'Species', '851', (68, 80))	('dysregulated immune response', 'Phenotype', 'HP:0002958', (135, 163))	('lead to', 'Reg', (127, 134))	('develop', 'PosReg', (186, 193))	('OSCC', 'Disease', (219, 223))	('Fusobacterium nucleatum', 'Species', '851', (43, 66))	('periodontal diseases', 'Disease', 'MESH:D010510', (194, 214))	('Fusobacterium', 'Var', (43, 56))	('dysregulated immune', 'MPA', (135, 154))
147121	31772577	It has been recently demonstrated that prolonged infections of oral cancer cells by P. gingivalis promote migratory and invasive properties.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('promote', 'PosReg', (98, 105))	('infections of oral cancer', 'Disease', 'MESH:D009062', (49, 74))	('infections of oral cancer', 'Disease', (49, 74))	('infections of oral cancer', 'Phenotype', 'HP:0100649', (49, 74))	('P. gingivalis', 'Species', '837', (84, 97))	('P. gingivalis', 'Var', (84, 97))	('prolonged infections', 'Phenotype', 'HP:0002719', (39, 59))
147123	31772577	Moreover, P. gingivalis mutant strains lacking the fimbrial protein FimA were attenuated in their ability to activate Zeb1 expression, demonstrating a role for the FimA adhesin in triggering EMT.	('mutant', 'Var', (24, 30))	('P. gingivalis', 'Species', '837', (10, 23))	('Zeb1', 'Gene', (118, 122))	('Zeb1', 'Gene', '6935', (118, 122))	('activate', 'PosReg', (109, 117))	('lacking', 'NegReg', (39, 46))	('attenuated', 'NegReg', (78, 88))
147124	31772577	In addition to mediating these physiological functions, changes in the microbiota composition are often associated with several immunological diseases of the nasal cavity including allergic rhinitis and chronic rhinosinusitis.	('chronic rhinosinusitis', 'Disease', (203, 225))	('diseases of the nasal cavity', 'Phenotype', 'HP:0012720', (142, 170))	('chronic rhinosinusitis', 'Disease', 'MESH:D002908', (203, 225))	('allergic rhinitis', 'Disease', 'MESH:D012220', (181, 198))	('rhinitis', 'Phenotype', 'HP:0012384', (190, 198))	('associated', 'Reg', (104, 114))	('allergic rhinitis', 'Phenotype', 'HP:0003193', (181, 198))	('allergic rhinitis', 'Disease', (181, 198))	('changes', 'Var', (56, 63))
147135	31772577	As an example, a LUAD mouse model carrying Kras mutations and p53 deletion was utilized to compare germ-free and specific pathogen-free conditions, revealing that germ-free mice are significantly protected against LUAD.	('LUAD', 'Disease', 'MESH:C538231', (214, 218))	('Kras', 'Gene', (43, 47))	('p53', 'Gene', '22060', (62, 65))	('Kras', 'Gene', '16653', (43, 47))	('LUAD', 'Disease', (214, 218))	('LUAD', 'Disease', (17, 21))	('mouse', 'Species', '10090', (22, 27))	('LUAD', 'Phenotype', 'HP:0030078', (214, 218))	('LUAD', 'Phenotype', 'HP:0030078', (17, 21))	('p53', 'Gene', (62, 65))	('deletion', 'Var', (66, 74))	('mutations', 'Var', (48, 57))	('mice', 'Species', '10090', (173, 177))	('LUAD', 'Disease', 'MESH:C538231', (17, 21))
147172	31772577	LPS induces innate immune responses by upregulating proinflammatory cytokine genes through the Toll-like receptor (TLR) 4 and the downstream NF-kappaB pathways.	('innate immune responses', 'MPA', (12, 35))	('LPS', 'Var', (0, 3))	('TLR', 'Gene', (115, 118))	('induces', 'Reg', (4, 11))	('NF-kappaB', 'Gene', '4790', (141, 150))	('proinflammatory cytokine genes', 'Gene', (52, 82))	('NF-kappaB', 'Gene', (141, 150))	('upregulating', 'PosReg', (39, 51))
147184	31772577	The signaling pathway induced by Streptococci upon adhesion to CD44 involves cytoskeletal reorganization via Rac1 and ezrin, as well as loss of intercellular junctions by changed distribution of the junctional proteins ZO-1 and E-cadherin.	('ZO-1', 'Gene', '7082', (219, 223))	('distribution', 'MPA', (179, 191))	('ezrin', 'Protein', (118, 123))	('intercellular junctions', 'MPA', (144, 167))	('E-cadherin', 'Gene', (228, 238))	('E-cadherin', 'Gene', '999', (228, 238))	('Rac1', 'Protein', (109, 113))	('ZO-1', 'Gene', (219, 223))	('changed', 'Reg', (171, 178))	('cytoskeletal reorganization', 'CPA', (77, 104))	('CD44', 'Species', '1151267', (63, 67))	('loss', 'NegReg', (136, 140))	('CD44', 'Gene', (63, 67))	('adhesion', 'Var', (51, 59))
147214	31772577	Accumulating data also support a role for the B. fragilis in inducing tumorigenesis in human and animal models of CRC.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('B. fragilis', 'Species', '817', (46, 57))	('human', 'Species', '9606', (87, 92))	('tumor', 'Disease', (70, 75))	('CRC', 'Phenotype', 'HP:0003003', (114, 117))	('CRC', 'Disease', 'MESH:D015179', (114, 117))	('inducing', 'Reg', (61, 69))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('CRC', 'Disease', (114, 117))	('B. fragilis', 'Var', (46, 57))
147249	31772577	Alterations of the vaginal microbial community have been also proved to impact pregnancy, bacterial vaginosis, and carcinogenesis.	('Alterations', 'Var', (0, 11))	('bacterial vaginosis', 'Disease', (90, 109))	('pregnancy', 'CPA', (79, 88))	('bacterial vaginosis', 'Disease', 'MESH:D016585', (90, 109))	('carcinogenesis', 'Disease', 'MESH:D063646', (115, 129))	('impact', 'Reg', (72, 78))	('carcinogenesis', 'Disease', (115, 129))	('bacterial vaginosis', 'Phenotype', 'HP:0030683', (90, 109))
147272	31772577	In culture, 6-HAP selectively inhibits the proliferation of tumor cell lines but does not inhibit primary keratinocyte growth.	('6-HAP', 'Chemical', 'MESH:C032610', (12, 17))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('6-HAP', 'Var', (12, 17))	('tumor', 'Disease', (60, 65))	('inhibits', 'NegReg', (30, 38))
147280	31772577	As described in the previous sections, infection of the oral mucosa by P.  gingivalis leads to overexpression of EMT factors such as Zeb1.	('infection', 'Disease', (39, 48))	('infection', 'Disease', 'MESH:D007239', (39, 48))	('overexpression', 'PosReg', (95, 109))	('P.  gingivalis', 'Species', '837', (71, 85))	('P.  gingivalis', 'Var', (71, 85))	('Zeb1', 'Gene', (133, 137))	('Zeb1', 'Gene', '6935', (133, 137))
147288	31772577	In the intestinal mucosa, B. fragilis induces an inflammatory cascade through IL-17R and Stat3.	('B. fragilis', 'Species', '817', (26, 37))	('IL-17R', 'Gene', '23765', (78, 84))	('IL-17R', 'Gene', (78, 84))	('inflammatory cascade', 'MPA', (49, 69))	('induces', 'Reg', (38, 45))	('B. fragilis', 'Var', (26, 37))	('Stat3', 'MPA', (89, 94))
147321	28835003	This epigenetic regulation of miRNAs in drug transporters or enzymes has a greater impact on drug responses.	('miR', 'Gene', '220972', (30, 33))	('drug responses', 'CPA', (93, 107))	('miR', 'Gene', (30, 33))	('epigenetic regulation', 'Var', (5, 26))	('impact', 'Reg', (83, 89))
147322	28835003	The influence of the epigenetic changes in cancer diseases can be expected to be even greater.	('epigenetic changes', 'Var', (21, 39))	('cancer diseases', 'Disease', 'MESH:D009369', (43, 58))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('cancer diseases', 'Disease', (43, 58))
147324	28835003	The Cancer Genome Atlas (TCGA) Research Network has profiled and analyzed large numbers of human tumors to discover molecular aberrations at the DNA, RNA, and protein level, and also examined epigenetic changes, including those related to miRNA.	('miR', 'Gene', (239, 242))	('miR', 'Gene', '220972', (239, 242))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (4, 23))	('epigenetic changes', 'Var', (192, 210))	('examined', 'Reg', (183, 191))	('Cancer', 'Phenotype', 'HP:0002664', (4, 10))	('tumors', 'Disease', (97, 103))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('Cancer Genome Atlas', 'Disease', (4, 23))	('tumors', 'Disease', 'MESH:D009369', (97, 103))	('human', 'Species', '9606', (91, 96))
147341	28835003	For evaluate with our founding, we collected expression datasets of miRNA and mRNA for tumor and non-tumor tissues derived from colonic adenocarcinoma (GSE29623) and intrahepatic cholangiocarcinoma and hepatocellular carcinoma patients (GSE57555).	('GSE29623', 'Var', (152, 160))	('miR', 'Gene', '220972', (68, 71))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (202, 226))	('miR', 'Gene', (68, 71))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('patients', 'Species', '9606', (227, 235))	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('mRNA', 'MPA', (78, 82))	('tumor', 'Disease', (87, 92))	('colonic adenocarcinoma', 'Disease', 'MESH:D003110', (128, 150))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('colonic adenocarcinoma', 'Disease', (128, 150))	('carcinoma', 'Phenotype', 'HP:0030731', (188, 197))	('intrahepatic cholangiocarcinoma and hepatocellular carcinoma', 'Disease', 'MESH:D018281', (166, 226))	('GSE57555', 'Var', (237, 245))	('tumor', 'Disease', (101, 106))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (179, 197))	('carcinoma', 'Phenotype', 'HP:0030731', (217, 226))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
147383	28835003	let-7 family members such as let-7, let-7a, let-7b, let-7c, let-7d, let-7e, let-7f, let-7g, let-7i, and miR-98 were previously shown to target ADRB2, but to our knowledge this is the first study to show that hsa-miR-98 can also regulate ADRB2 expression.	('let-7e', 'Gene', (68, 74))	('let-7b', 'Gene', '406884', (44, 50))	('expression', 'MPA', (243, 253))	('miR-98', 'Gene', (212, 218))	('let-7e', 'Gene', '406887', (68, 74))	('miR-98', 'Gene', '407054', (104, 110))	('let-7i', 'Gene', '406891', (92, 98))	('let-7c', 'Gene', (52, 58))	('regulate', 'Reg', (228, 236))	('let-7b', 'Gene', (44, 50))	('let-7a', 'Var', (36, 42))	('let-7c', 'Gene', '406885', (52, 58))	('let-7g', 'Gene', '406890', (84, 90))	('let-7i', 'Gene', (92, 98))	('let-7d', 'Gene', '406886', (60, 66))	('ADRB2', 'Gene', '154', (143, 148))	('miR-98', 'Gene', '407054', (212, 218))	('ADRB2', 'Gene', (237, 242))	('ADRB2', 'Gene', '154', (237, 242))	('ADRB2', 'Gene', (143, 148))	('let-7g', 'Gene', (84, 90))	('miR-98', 'Gene', (104, 110))	('hsa-miR-98', 'Gene', '407054', (208, 218))	('let-7f', 'Var', (76, 82))	('hsa-miR-98', 'Gene', (208, 218))	('let-7d', 'Gene', (60, 66))
147389	28835003	In conclusion, epigenomic changes, including miRNA-induced regulation of expression of genes encoding drug-metabolizing enzymes, transporters, or targets, can potentially lead to changes in drug activity that may contribute to drug sensitivity, resistance, and toxicity.	('drug sensitivity', 'Phenotype', 'HP:0020174', (227, 243))	('resistance', 'Disease', (245, 255))	('changes', 'Var', (26, 33))	('lead to changes', 'Reg', (171, 186))	('drug activity', 'MPA', (190, 203))	('regulation', 'Reg', (59, 69))	('toxicity', 'Disease', 'MESH:D064420', (261, 269))	('contribute', 'Reg', (213, 223))	('toxicity', 'Disease', (261, 269))	('drug', 'MPA', (227, 231))	('miR', 'Gene', (45, 48))	('expression', 'MPA', (73, 83))	('miR', 'Gene', '220972', (45, 48))
147400	33335424	KCNMB2-AS1 silencing hindered NSCLC cell proliferation, migration, and invasion and promoted apoptosis in vitro.	('migration', 'CPA', (56, 65))	('hindered', 'NegReg', (21, 29))	('silencing', 'Var', (11, 20))	('NSCLC', 'Disease', 'MESH:D002289', (30, 35))	('KCNMB2-AS1', 'Gene', (0, 10))	('promoted', 'PosReg', (84, 92))	('invasion', 'CPA', (71, 79))	('si', 'Chemical', 'MESH:D012825', (75, 77))	('NSCLC', 'Phenotype', 'HP:0030358', (30, 35))	('si', 'Chemical', 'MESH:D012825', (99, 101))	('si', 'Chemical', 'MESH:D012825', (11, 13))	('apoptosis', 'CPA', (93, 102))	('NSCLC', 'Disease', (30, 35))	('KCNMB2-AS1', 'Gene', '104797538;10242;5729', (0, 10))
147401	33335424	Additionally, KCNMB2-AS1 knockdown decreased tumor growth in vivo.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('KCNMB2-AS1', 'Gene', '104797538;10242;5729', (14, 24))	('KCNMB2-AS1', 'Gene', (14, 24))	('decreased tumor growth', 'Disease', (35, 57))	('decreased tumor growth', 'Disease', 'MESH:D006130', (35, 57))	('knockdown', 'Var', (25, 34))
147416	33335424	Consistently, several studies have revealed the differential expression of lncRNAs in NSCLC, and dysregulation of lncRNAs in NSCLC contributes to cancer oncogenesis.	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('si', 'Chemical', 'MESH:D012825', (67, 69))	('NSCLC', 'Disease', (125, 130))	('NSCLC', 'Disease', (86, 91))	('NSCLC', 'Disease', 'MESH:D002289', (86, 91))	('NSCLC', 'Disease', 'MESH:D002289', (125, 130))	('dysregulation', 'Var', (97, 110))	('si', 'Chemical', 'MESH:D012825', (3, 5))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('si', 'Chemical', 'MESH:D012825', (161, 163))	('NSCLC', 'Phenotype', 'HP:0030358', (86, 91))	('contributes', 'Reg', (131, 142))	('NSCLC', 'Phenotype', 'HP:0030358', (125, 130))
147484	33335424	The wild-type fragments of KCNMB2-AS1 (111679-112253 nt) and ROCK1 3'-UTR (0-356 nt) containing miR-374a-3p binding sites were amplified and inserted into the pmirGlO Dual-luciferase miRNA Target Expression Vector (Promega, Madison, WI, USA).	('KCNMB2-AS1', 'Gene', (27, 37))	('miR-374a-3p', 'Chemical', '-', (96, 107))	('ROCK1', 'Gene', '6093', (61, 66))	('ROCK1', 'Gene', (61, 66))	('111679-112253', 'Var', (39, 52))	('si', 'Chemical', 'MESH:D012825', (116, 118))	('KCNMB2-AS1', 'Gene', '104797538;10242;5729', (27, 37))	('miR', 'Gene', '220972', (96, 99))	('miR', 'Gene', (96, 99))	('si', 'Chemical', 'MESH:D012825', (202, 204))	('miR', 'Gene', '220972', (183, 186))	('miR', 'Gene', (183, 186))
147487	33335424	The mutant luciferase reporter plasmids were produced by replacing the wild-type sequences with mutant sequences, and the resulting reporter plasmids were referred to as KCNMB2-AS1-mut and ROCK1-mut.	('mutant', 'Var', (96, 102))	('KCNMB2-AS1', 'Gene', '104797538;10242;5729', (170, 180))	('ROCK1', 'Gene', '6093', (189, 194))	('KCNMB2-AS1', 'Gene', (170, 180))	('ROCK1', 'Gene', (189, 194))
147489	33335424	Lipofectamine 2000 was used to cotransfect wild-type or mutant reporter plasmids and miR-374a-3p mimic or miR-NC.	('miR', 'Gene', '220972', (85, 88))	('miR', 'Gene', (85, 88))	('miR', 'Gene', (106, 109))	('mutant', 'Var', (56, 62))	('miR', 'Gene', '220972', (106, 109))	('Lipofectamine 2000', 'Chemical', 'MESH:C086724', (0, 18))	('miR-374a-3p', 'Chemical', '-', (85, 96))
147507	33335424	As exhibited in Table 2, a high KCNMB2-AS1 expression was closely related with the lymph node metastasis, but manifested none association with gender, age, tumor size, differentiation or TNM stage.	('KCNMB2-AS1', 'Gene', '104797538;10242;5729', (32, 42))	('si', 'Chemical', 'MESH:D012825', (162, 164))	('si', 'Chemical', 'MESH:D012825', (101, 103))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('high', 'Var', (27, 31))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('TNM', 'Gene', '10178', (187, 190))	('KCNMB2-AS1', 'Gene', (32, 42))	('related', 'Reg', (66, 73))	('tumor', 'Disease', (156, 161))	('expression', 'MPA', (43, 53))	('si', 'Chemical', 'MESH:D012825', (49, 51))	('TNM', 'Gene', (187, 190))	('lymph node metastasis', 'CPA', (83, 104))
147514	33335424	The CCK-8 assay results revealed that the proliferation of H460 and SK-MES-1 cells was evidently reduced after KCNMB2-AS1 knockdown (Figure 2B).	('KCNMB2-AS1', 'Gene', '104797538;10242;5729', (111, 121))	('H460', 'CellLine', 'CVCL:0459', (59, 63))	('proliferation', 'CPA', (42, 55))	('KCNMB2-AS1', 'Gene', (111, 121))	('knockdown', 'Var', (122, 131))	('reduced', 'NegReg', (97, 104))	('SK-MES-1', 'CellLine', 'CVCL:0630', (68, 76))
147515	33335424	In addition, flow cytometry analysis was used to detect cell apoptosis, and the results demonstrated that KCNMB2-AS1 deficiency notably increased the apoptosis rate of H460 and SK-MES-1 cells (Figure 2C).	('si', 'Chemical', 'MESH:D012825', (33, 35))	('si', 'Chemical', 'MESH:D012825', (156, 158))	('si', 'Chemical', 'MESH:D012825', (67, 69))	('deficiency', 'Var', (117, 127))	('SK-MES-1', 'CellLine', 'CVCL:0630', (177, 185))	('apoptosis rate', 'CPA', (150, 164))	('H460', 'CellLine', 'CVCL:0459', (168, 172))	('KCNMB2-AS1', 'Gene', '104797538;10242;5729', (106, 116))	('increased', 'PosReg', (136, 145))	('KCNMB2-AS1', 'Gene', (106, 116))
147526	33335424	Furthermore, miR-374a-3p was weakly expressed in NSCLC tissues (Figure 3D) and exhibited a negative correlation with KCNMB2-AS1 expression (Figure 3E; r = -0.6957, P < 0.0001).	('KCNMB2-AS1', 'Gene', (117, 127))	('NSCLC', 'Disease', (49, 54))	('NSCLC', 'Disease', 'MESH:D002289', (49, 54))	('si', 'Chemical', 'MESH:D012825', (134, 136))	('miR-374a-3p', 'Var', (13, 24))	('expression', 'MPA', (128, 138))	('NSCLC', 'Phenotype', 'HP:0030358', (49, 54))	('negative', 'NegReg', (91, 99))	('KCNMB2-AS1', 'Gene', '104797538;10242;5729', (117, 127))	('miR-374a-3p', 'Chemical', '-', (13, 24))
147527	33335424	Luciferase reporter plasmids KCNMB2-AS1-wt and KCNMB2-AS1-mut harboring wild-type and mutant miR-374a-3p binding sites (Figure 3F) were constructed and cotransfected with miR-374a-3p mimic or miR-NC into H460 and SK-MES-1 cells.	('miR-374a-3p', 'Chemical', '-', (171, 182))	('KCNMB2-AS1', 'Gene', '104797538;10242;5729', (29, 39))	('miR', 'Gene', '220972', (192, 195))	('mutant', 'Var', (86, 92))	('miR', 'Gene', (192, 195))	('miR', 'Gene', '220972', (171, 174))	('miR', 'Gene', (171, 174))	('KCNMB2-AS1', 'Gene', (29, 39))	('si', 'Chemical', 'MESH:D012825', (113, 115))	('KCNMB2-AS1', 'Gene', '104797538;10242;5729', (47, 57))	('miR-374a-3p', 'Chemical', '-', (93, 104))	('SK-MES-1', 'CellLine', 'CVCL:0630', (213, 221))	('KCNMB2-AS1', 'Gene', (47, 57))	('miR', 'Gene', (93, 96))	('H460', 'CellLine', 'CVCL:0459', (204, 208))	('miR', 'Gene', '220972', (93, 96))
147528	33335424	The luciferase activity of KCNMB2-AS1-wt was inhibited by miR-374a-3p upregulation in H460 and SK-MES-1 cells.	('miR-374a-3p', 'Chemical', '-', (58, 69))	('KCNMB2-AS1', 'Gene', (27, 37))	('upregulation', 'PosReg', (70, 82))	('SK-MES-1', 'CellLine', 'CVCL:0630', (95, 103))	('KCNMB2-AS1', 'Gene', '104797538;10242;5729', (27, 37))	('activity', 'MPA', (15, 23))	('H460', 'CellLine', 'CVCL:0459', (86, 90))	('miR-374a-3p', 'Var', (58, 69))	('inhibited', 'NegReg', (45, 54))	('luciferase', 'Enzyme', (4, 14))
147530	33335424	Moreover, miR-374a-3p and KCNMB2-AS1 were dramatically enriched by the Ago2 antibody in H460 and SK-MES-1 cells, suggesting the potential endogenous direct interaction between miR-374a-3p and KCNMB2-AS1 (Figure 3H).	('SK-MES-1', 'CellLine', 'CVCL:0630', (97, 105))	('miR-374a-3p', 'Chemical', '-', (10, 21))	('KCNMB2-AS1', 'Gene', '104797538;10242;5729', (26, 36))	('miR-374a-3p', 'Chemical', '-', (176, 187))	('Ago2', 'Gene', '27161', (71, 75))	('H460', 'CellLine', 'CVCL:0459', (88, 92))	('interaction', 'Interaction', (156, 167))	('KCNMB2-AS1', 'Gene', '104797538;10242;5729', (192, 202))	('KCNMB2-AS1', 'Gene', (26, 36))	('Ago2', 'Gene', (71, 75))	('KCNMB2-AS1', 'Gene', (192, 202))	('miR-374a-3p', 'Var', (176, 187))
147531	33335424	To explore whether miR-374a-3p can affect KCNMB2-AS1expression, the relative expression of KCNMB2-AS1 was detected in NSCLC cells after activating miR-374a-3p.	('miR-374a-3p', 'Chemical', '-', (147, 158))	('activating', 'PosReg', (136, 146))	('NSCLC', 'Phenotype', 'HP:0030358', (118, 123))	('KCNMB2-AS1', 'Gene', '104797538;10242;5729', (91, 101))	('NSCLC', 'Disease', (118, 123))	('si', 'Chemical', 'MESH:D012825', (83, 85))	('si', 'Chemical', 'MESH:D012825', (58, 60))	('KCNMB2-AS1', 'Gene', (91, 101))	('miR-374a-3p', 'Var', (147, 158))	('KCNMB2-AS1', 'Gene', '104797538;10242;5729', (42, 52))	('NSCLC', 'Disease', 'MESH:D002289', (118, 123))	('miR-374a-3p', 'Chemical', '-', (19, 30))	('KCNMB2-AS1', 'Gene', (42, 52))
147532	33335424	The results were shown that transfection with miR-374a-3p mimic did not alter the expression of KCNMB2-AS1 in H460 and SK-MES-1 cells (Figure 3I).	('KCNMB2-AS1', 'Gene', (96, 106))	('miR-374a-3p', 'Var', (46, 57))	('SK-MES-1', 'CellLine', 'CVCL:0630', (119, 127))	('H460', 'CellLine', 'CVCL:0459', (110, 114))	('si', 'Chemical', 'MESH:D012825', (88, 90))	('miR-374a-3p', 'Chemical', '-', (46, 57))	('KCNMB2-AS1', 'Gene', '104797538;10242;5729', (96, 106))
147534	33335424	We next examined in detail the roles of miR-374a-3p in NSCLC cells.	('miR-374a-3p', 'Var', (40, 51))	('NSCLC', 'Disease', (55, 60))	('NSCLC', 'Disease', 'MESH:D002289', (55, 60))	('miR-374a-3p', 'Chemical', '-', (40, 51))	('NSCLC', 'Phenotype', 'HP:0030358', (55, 60))
147536	33335424	Transfection with miR-374a-3p mimic caused a clear reduction of H460 and SK-MES-1 cell proliferation, as demonstrated by the CCK-8 assay results (Figure 4B).	('reduction', 'NegReg', (51, 60))	('SK-MES-1', 'CellLine', 'CVCL:0630', (73, 81))	('miR-374a-3p', 'Chemical', '-', (18, 29))	('miR-374a-3p mimic', 'Var', (18, 35))	('H460', 'CellLine', 'CVCL:0459', (64, 68))
147537	33335424	Flow cytometry analysis further revealed that exogenous miR-374a-3p expression promoted the apoptosis of H460 and SK-MES-1 cells (Figure 4C).	('SK-MES-1', 'CellLine', 'CVCL:0630', (114, 122))	('apoptosis', 'CPA', (92, 101))	('miR-374a-3p', 'Chemical', '-', (56, 67))	('si', 'Chemical', 'MESH:D012825', (74, 76))	('promoted', 'PosReg', (79, 87))	('si', 'Chemical', 'MESH:D012825', (98, 100))	('si', 'Chemical', 'MESH:D012825', (20, 22))	('H460', 'CellLine', 'CVCL:0459', (105, 109))	('miR-374a-3p', 'Var', (56, 67))
147538	33335424	Furthermore, the migration (Figure 4D) and invasion (Figure 4E) abilities of H460 and SK-MES-1 cells were evidently suppressed by miR-374a-3p overexpression.	('migration', 'CPA', (17, 26))	('overexpression', 'PosReg', (142, 156))	('SK-MES-1', 'CellLine', 'CVCL:0630', (86, 94))	('si', 'Chemical', 'MESH:D012825', (152, 154))	('invasion', 'CPA', (43, 51))	('suppressed', 'NegReg', (116, 126))	('miR-374a-3p', 'Var', (130, 141))	('si', 'Chemical', 'MESH:D012825', (47, 49))	('miR-374a-3p', 'Chemical', '-', (130, 141))	('SK-MES-1 cells', 'CPA', (86, 100))	('H460', 'CellLine', 'CVCL:0459', (77, 81))
147540	33335424	miR-374a-3p was predicted to interact with ROCK1 via complementary sequences (Figure 5A), and because of its critical roles in NSCLC tumorigenesis, ROCK1 was selected for further investigation.	('NSCLC', 'Disease', (127, 132))	('miR-374a-3p', 'Chemical', '-', (0, 11))	('ROCK1', 'Gene', '6093', (43, 48))	('NSCLC', 'Disease', 'MESH:D002289', (127, 132))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('ROCK1', 'Gene', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('interact', 'Interaction', (29, 37))	('NSCLC', 'Phenotype', 'HP:0030358', (127, 132))	('tumor', 'Disease', (133, 138))	('si', 'Chemical', 'MESH:D012825', (143, 145))	('miR-374a-3p', 'Var', (0, 11))	('ROCK1', 'Gene', '6093', (148, 153))	('ROCK1', 'Gene', (148, 153))
147541	33335424	A luciferase reporter assay was conducted to determine whether ROCK1 was a functional target of miR-374a-3p.	('ROCK1', 'Gene', '6093', (63, 68))	('ROCK1', 'Gene', (63, 68))	('miR-374a-3p', 'Var', (96, 107))	('miR-374a-3p', 'Chemical', '-', (96, 107))
147553	33335424	First, miR-374a-3p was demonstrated to be decreased in H460 and SK-MES-1 cells after miR-374a-3p inhibitor transfection (Figure 6A).	('miR-374a-3p', 'Chemical', '-', (7, 18))	('decreased', 'NegReg', (42, 51))	('miR-374a-3p inhibitor transfection', 'Var', (85, 119))	('SK-MES-1', 'CellLine', 'CVCL:0630', (64, 72))	('H460', 'CellLine', 'CVCL:0459', (55, 59))	('miR-374a-3p', 'Chemical', '-', (85, 96))
147556	33335424	Furthermore, loss of KCNMB2-AS1evidently facilitated cell apoptosis (Figure 6C) and attenuated H460 and SK-MES-1 cell migration (Figure 6D) and invasion (Figure 6E), whereas miR-374a-3p inhibitor cotransfection counteracted these effects.	('KCNMB2-AS1', 'Gene', (21, 31))	('cell apoptosis', 'CPA', (53, 67))	('H460', 'CellLine', 'CVCL:0459', (95, 99))	('si', 'Chemical', 'MESH:D012825', (148, 150))	('invasion', 'CPA', (144, 152))	('attenuated', 'NegReg', (84, 94))	('si', 'Chemical', 'MESH:D012825', (64, 66))	('KCNMB2-AS1', 'Gene', '104797538;10242;5729', (21, 31))	('facilitated', 'PosReg', (41, 52))	('loss', 'Var', (13, 17))	('miR-374a-3p', 'Chemical', '-', (174, 185))	('SK-MES-1', 'CellLine', 'CVCL:0630', (104, 112))
147567	33335424	RT-qPCR analysis indicated that KCNMB2-AS1 expression remained low (Figure 8D), whereas the expression of miR-374a-3p was elevated (Figure 8E) in the tumors originating from KCNMB2-AS1-depleted H460 cells.	('tumors', 'Disease', (150, 156))	('miR-374a-3p', 'Chemical', '-', (106, 117))	('tumors', 'Disease', 'MESH:D009369', (150, 156))	('tumors', 'Phenotype', 'HP:0002664', (150, 156))	('KCNMB2-AS1', 'Gene', '104797538;10242;5729', (32, 42))	('si', 'Chemical', 'MESH:D012825', (49, 51))	('miR-374a-3p', 'Var', (106, 117))	('elevated', 'PosReg', (122, 130))	('KCNMB2-AS1', 'Gene', (32, 42))	('low', 'NegReg', (63, 66))	('si', 'Chemical', 'MESH:D012825', (98, 100))	('si', 'Chemical', 'MESH:D012825', (13, 15))	('KCNMB2-AS1', 'Gene', '104797538;10242;5729', (174, 184))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('expression', 'MPA', (43, 53))	('KCNMB2-AS1', 'Gene', (174, 184))	('H460', 'CellLine', 'CVCL:0459', (194, 198))	('expression', 'MPA', (92, 102))
147568	33335424	Furthermore, the ROCK1 protein expression was downregulated by KCNMB2-AS1 silencing (Figure 8F), which was consistent with the in vitro results.	('si', 'Chemical', 'MESH:D012825', (110, 112))	('KCNMB2-AS1', 'Gene', (63, 73))	('si', 'Chemical', 'MESH:D012825', (37, 39))	('si', 'Chemical', 'MESH:D012825', (74, 76))	('silencing', 'Var', (74, 83))	('ROCK1', 'Gene', '6093', (17, 22))	('ROCK1', 'Gene', (17, 22))	('downregulated', 'NegReg', (46, 59))	('KCNMB2-AS1', 'Gene', '104797538;10242;5729', (63, 73))
147581	33335424	Various experiments were conducted to determine the influences of KCNMB2-AS1 silencing on the malignant processes in NSCLC cells in vitro and in vivo.	('KCNMB2-AS1', 'Gene', (66, 76))	('NSCLC', 'Disease', (117, 122))	('si', 'Chemical', 'MESH:D012825', (77, 79))	('malignant processes', 'CPA', (94, 113))	('NSCLC', 'Disease', 'MESH:D002289', (117, 122))	('silencing', 'Var', (77, 86))	('NSCLC', 'Phenotype', 'HP:0030358', (117, 122))	('KCNMB2-AS1', 'Gene', '104797538;10242;5729', (66, 76))
147582	33335424	After KCNMB2-AS1 silencing, the proliferation, migration, and invasion abilities of NSCLC cells were hindered.	('NSCLC', 'Phenotype', 'HP:0030358', (84, 89))	('KCNMB2-AS1', 'Gene', (6, 16))	('NSCLC', 'Disease', (84, 89))	('migration', 'CPA', (47, 56))	('hindered', 'NegReg', (101, 109))	('si', 'Chemical', 'MESH:D012825', (17, 19))	('NSCLC', 'Disease', 'MESH:D002289', (84, 89))	('si', 'Chemical', 'MESH:D012825', (66, 68))	('silencing', 'Var', (17, 26))	('KCNMB2-AS1', 'Gene', '104797538;10242;5729', (6, 16))
147583	33335424	Additionally, KCNMB2-AS1 knockdown promoted apoptosis of NSCLC cells in vitro and decreased tumor growth in vivo.	('NSCLC', 'Disease', 'MESH:D002289', (57, 62))	('apoptosis', 'CPA', (44, 53))	('KCNMB2-AS1', 'Gene', '104797538;10242;5729', (14, 24))	('KCNMB2-AS1', 'Gene', (14, 24))	('si', 'Chemical', 'MESH:D012825', (50, 52))	('NSCLC', 'Phenotype', 'HP:0030358', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('decreased tumor growth', 'Disease', 'MESH:D006130', (82, 104))	('promoted', 'PosReg', (35, 43))	('NSCLC', 'Disease', (57, 62))	('knockdown', 'Var', (25, 34))	('decreased tumor growth', 'Disease', (82, 104))
147591	33335424	RT-qPCR results confirmed that KCNMB2-AS1 interference increased the expression of miR-374a-3p in NSCLC cells.	('KCNMB2-AS1', 'Gene', (31, 41))	('miR-374a-3p', 'Chemical', '-', (83, 94))	('NSCLC', 'Phenotype', 'HP:0030358', (98, 103))	('increased', 'PosReg', (55, 64))	('si', 'Chemical', 'MESH:D012825', (75, 77))	('expression', 'MPA', (69, 79))	('NSCLC', 'Disease', (98, 103))	('miR-374a-3p', 'Var', (83, 94))	('NSCLC', 'Disease', 'MESH:D002289', (98, 103))	('KCNMB2-AS1', 'Gene', '104797538;10242;5729', (31, 41))
147592	33335424	Further investigations revealed that miR-374a-3p was weakly expressed in NSCLC tissues and exhibited an inverse correlation with KCNMB2-AS1 expression.	('si', 'Chemical', 'MESH:D012825', (146, 148))	('miR-374a-3p', 'Var', (37, 48))	('NSCLC', 'Disease', (73, 78))	('KCNMB2-AS1', 'Gene', '104797538;10242;5729', (129, 139))	('NSCLC', 'Phenotype', 'HP:0030358', (73, 78))	('NSCLC', 'Disease', 'MESH:D002289', (73, 78))	('KCNMB2-AS1', 'Gene', (129, 139))	('miR-374a-3p', 'Chemical', '-', (37, 48))
147595	33335424	The results showed that KCNMB2-AS1 deficiency resulted in a substantial decrease in ROCK1 mRNA and protein expression in NSCLC cells, and cotransfection with miR-374a-3p inhibitor abrogated these impacts.	('ROCK1', 'Gene', '6093', (84, 89))	('ROCK1', 'Gene', (84, 89))	('KCNMB2-AS1', 'Gene', (24, 34))	('NSCLC', 'Disease', (121, 126))	('deficiency', 'Var', (35, 45))	('si', 'Chemical', 'MESH:D012825', (113, 115))	('NSCLC', 'Disease', 'MESH:D002289', (121, 126))	('KCNMB2-AS1', 'Gene', '104797538;10242;5729', (24, 34))	('decrease', 'NegReg', (72, 80))	('miR-374a-3p', 'Chemical', '-', (158, 169))	('NSCLC', 'Phenotype', 'HP:0030358', (121, 126))
147601	33335424	Collectively, a novel ceRNA model was defined in which KCNMB2-AS1 functions as a molecular sponge to competitively adsorb miR-374a-3p with ROCK1 in NSCLC cells, thereby resulting in the suppression of miR-374a-3p and recovering ROCK1 expression and activities.	('miR-374a-3p', 'Chemical', '-', (122, 133))	('KCNMB2-AS1', 'Gene', '104797538;10242;5729', (55, 65))	('ROCK1', 'Gene', (228, 233))	('si', 'Chemical', 'MESH:D012825', (193, 195))	('expression', 'MPA', (234, 244))	('NSCLC', 'Disease', 'MESH:D002289', (148, 153))	('si', 'Chemical', 'MESH:D012825', (240, 242))	('ROCK1', 'Gene', (139, 144))	('KCNMB2-AS1', 'Gene', (55, 65))	('NSCLC', 'Disease', (148, 153))	('miR-374a-3p', 'Var', (122, 133))	('NSCLC', 'Phenotype', 'HP:0030358', (148, 153))	('activities', 'MPA', (249, 259))	('ROCK1', 'Gene', '6093', (228, 233))	('ROCK1', 'Gene', '6093', (139, 144))	('recovering', 'PosReg', (217, 227))	('miR-374a-3p', 'Chemical', '-', (201, 212))	('suppression', 'NegReg', (186, 197))	('miR-374a-3p', 'MPA', (201, 212))
147605	33335424	However, we did not investigate the correlation between KCNMB2-AS1 and miR-374a-3p as well as miR-374a-3p and ROCK1 in TCGA.	('KCNMB2-AS1', 'Gene', (56, 66))	('miR-374a-3p', 'Chemical', '-', (94, 105))	('ROCK1', 'Gene', '6093', (110, 115))	('miR-374a-3p', 'Chemical', '-', (71, 82))	('miR-374a-3p', 'Var', (94, 105))	('ROCK1', 'Gene', (110, 115))	('KCNMB2-AS1', 'Gene', '104797538;10242;5729', (56, 66))
147691	30338036	Moreover, we also confirmed that the specific inhibition of HHAT by siRNA reduced HHAT protein levels in eSAS cells (Figure 7G-i, arrow) and demonstrated that the knockdown of HHAT apparently suppressed the spheroid formation (Figure 7H).	('HHAT protein levels', 'MPA', (82, 101))	('eSAS', 'Chemical', '-', (105, 109))	('knockdown', 'Var', (163, 172))	('suppressed', 'NegReg', (192, 202))	('inhibition', 'NegReg', (46, 56))	('N', 'Chemical', 'MESH:D009584', (71, 72))	('spheroid formation', 'CPA', (207, 225))	('reduced', 'NegReg', (74, 81))	('HHAT', 'Gene', (176, 180))
147692	30338036	Furthermore, the knockdown of HHAT also slightly reduced the protein levels of stem cell markers, such as OCT-4A, SOX2, and NANOG (Figure 7G-ii, top, second, and third panels).	('OCT-4A', 'MPA', (106, 112))	('reduced', 'NegReg', (49, 56))	('protein levels', 'MPA', (61, 75))	('HHAT', 'Gene', (30, 34))	('NANOG', 'Gene', '71950', (124, 129))	('SOX2', 'Gene', (114, 118))	('knockdown', 'Var', (17, 26))	('SOX2', 'Gene', '20674', (114, 118))	('NANOG', 'Gene', (124, 129))
147705	30338036	Moreover, invasive eSAS cells were observed in the lymph nodes of mice implanted with eSAS cells but not in those implanted with SAS cells (Figure 4C).	('eSAS', 'Chemical', '-', (86, 90))	('eSAS', 'Chemical', '-', (19, 23))	('eSAS', 'Var', (86, 90))	('mice', 'Species', '10090', (66, 70))	('invasive eSAS cells', 'CPA', (10, 29))
147720	30338036	Notably, CTOSs form xenograft tumors that retain the features of the parental tumors, suggesting that primary cancer cells from surgical specimens could provide a unique preclinical model for personalized medicine.	('tumors', 'Disease', (30, 36))	('tumors', 'Disease', (78, 84))	('cancer', 'Disease', (110, 116))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('N', 'Chemical', 'MESH:D009584', (0, 1))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('CTOSs', 'Var', (9, 14))	('parental tumors', 'Disease', 'MESH:D063129', (69, 84))	('parental tumors', 'Disease', (69, 84))
147890	26220060	Verruca vulgaris is principally caused by HPV 2 and HPV 4, and this cutaneous lesion is most commonly observed in children on the hands and fingers.	('HPV 2', 'Species', '12083', (42, 47))	('HPV', 'Species', '10566', (42, 45))	('children', 'Species', '9606', (114, 122))	('HPV 4', 'Var', (52, 57))	('HPV', 'Species', '10566', (52, 55))	('Verruca', 'Phenotype', 'HP:0200043', (0, 7))	('caused', 'Reg', (32, 38))	('HPV 2', 'Var', (42, 47))	('Verruca vulgaris', 'Disease', (0, 16))
147894	26220060	The risk factors for infection include crowded unhygienic living conditions and the HLA-DR4 allele.	('allele', 'Var', (92, 98))	('HLA-DR4', 'Gene', (84, 91))	('infection', 'Disease', 'MESH:D007239', (21, 30))	('infection', 'Disease', (21, 30))
147911	26220060	Patients must be counseled that HPV is a sexually transmitted disease that has the potential to create mutations in cells that eventually cause malignant tumors.	('mutations', 'Var', (103, 112))	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('malignant tumors', 'Disease', (144, 160))	('cause', 'Reg', (138, 143))	('Patients', 'Species', '9606', (0, 8))	('HPV', 'Species', '10566', (32, 35))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('malignant tumors', 'Disease', 'MESH:D018198', (144, 160))	('HPV', 'Disease', (32, 35))
147950	26099335	Oncogenes and tumor suppressor genes: comparative genomics and network perspectives Defective tumor suppressor genes (TSGs) and hyperactive oncogenes (OCGs) heavily contribute to cell proliferation and apoptosis during cancer development through genetic variations such as somatic mutations and deletions.	('cell proliferation', 'CPA', (179, 197))	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('tumor', 'Disease', (14, 19))	('deletions', 'Var', (295, 304))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('TSG', 'Gene', (118, 121))	('tumor', 'Disease', (94, 99))	('cancer', 'Disease', 'MESH:D009369', (219, 225))	('apoptosis', 'CPA', (202, 211))	('contribute', 'Reg', (165, 175))	('TSG', 'Gene', '57045', (118, 121))	('cancer', 'Disease', (219, 225))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('Defective', 'NegReg', (84, 93))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
147954	26099335	Based on the data from Pan-Cancer project, we found that TSGs had the highest mutation frequency in most tumor types and the OCGs second.	('TSG', 'Gene', '57045', (57, 60))	('mutation', 'Var', (78, 86))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('Cancer', 'Phenotype', 'HP:0002664', (27, 33))	('TSG', 'Gene', (57, 60))	('tumor', 'Disease', (105, 110))
147959	26099335	The integration of the mutation frequency with the TSG-OCG network offered a network view of TSGs, OCGs, and their interactions, which may provide new insights into how the TSGs and OCGs jointly contribute to the cancer development.	('TSG', 'Gene', (51, 54))	('TSG', 'Gene', (93, 96))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('TSG', 'Gene', (173, 176))	('mutation', 'Var', (23, 31))	('contribute', 'Reg', (195, 205))	('TSG', 'Gene', '57045', (93, 96))	('TSG', 'Gene', '57045', (51, 54))	('cancer', 'Disease', 'MESH:D009369', (213, 219))	('TSG', 'Gene', '57045', (173, 176))	('interactions', 'Interaction', (115, 127))	('cancer', 'Disease', (213, 219))
147971	26099335	Considering the gain-of-function of OCG mutations and loss-of-function of TSG mutations, TSGs and OCGs may be involved in the regulation of cellular functions in a yin-yang fashion.	('OCG', 'Gene', (36, 39))	('TSG', 'Gene', (74, 77))	('mutations', 'Var', (78, 87))	('mutations', 'Var', (40, 49))	('TSG', 'Gene', (89, 92))	('TSG', 'Gene', '57045', (74, 77))	('loss-of-function', 'NegReg', (54, 70))	('TSG', 'Gene', '57045', (89, 92))	('gain-of-function', 'PosReg', (16, 32))
147973	26099335	TSG mutations tend to be recessive, so that they should follow the famous Knudson's 'two-hit hypothesis': that both copies of tumor suppressor genes need mutate to cause loss of function.	('TSG', 'Gene', (0, 3))	('TSG', 'Gene', '57045', (0, 3))	('mutate', 'Var', (154, 160))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('mutations', 'Var', (4, 13))	('loss of function', 'NegReg', (170, 186))	('tumor', 'Disease', (126, 131))
147974	26099335	However, more and more evidence shows that even partial inactivation of TSGs could critically contribute to tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('TSG', 'Gene', (72, 75))	('partial inactivation', 'Var', (48, 68))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('tumor', 'Disease', (108, 113))	('TSG', 'Gene', '57045', (72, 75))	('contribute', 'Reg', (94, 104))
147979	26099335	Based on the genetic data from Pan-Cancer project, we found that TSGs had the highest mutation frequency in most tumor types and the OCGs second.	('TSG', 'Gene', (65, 68))	('tumor', 'Disease', (113, 118))	('TSG', 'Gene', '57045', (65, 68))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('mutation', 'Var', (86, 94))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('Cancer', 'Phenotype', 'HP:0002664', (35, 41))
147984	26099335	The study presents the data and analytical results for point mutations and small insertions/deletions from 3,281 tumours across 12 tumour types.	('tumour', 'Disease', (131, 137))	('tumour', 'Phenotype', 'HP:0002664', (113, 119))	('tumour', 'Disease', 'MESH:D009369', (113, 119))	('tumours', 'Phenotype', 'HP:0002664', (113, 120))	('tumours', 'Disease', 'MESH:D009369', (113, 120))	('small insertions/deletions', 'Var', (75, 101))	('tumour', 'Disease', (113, 119))	('tumours', 'Disease', (113, 120))	('point mutations', 'Var', (55, 70))	('tumour', 'Phenotype', 'HP:0002664', (131, 137))	('tumour', 'Disease', 'MESH:D009369', (131, 137))
147999	26099335	The TSGs had the highest average mutation frequency (4.34%), which was significantly higher than that of OCGs (2.36%, P = 0.002), target genes (1.32%, P = 1.04 x 10-10), essential genes (0.59%, P = 2.08 x10-20), and other genes (0.98%, P = 7.29 x 10-17).	('TSG', 'Gene', '57045', (4, 7))	('TSG', 'Gene', (4, 7))	('mutation', 'Var', (33, 41))	('higher', 'PosReg', (85, 91))
148001	26099335	The mutation frequency in the TSGs was significantly higher than that of all other tumor types except for GBM, LAML, LUSC, and OV (p <0.05).	('GBM', 'Disease', (106, 109))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('higher', 'PosReg', (53, 59))	('tumor', 'Disease', (83, 88))	('mutation', 'Var', (4, 12))	('TSG', 'Gene', (30, 33))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('TSG', 'Gene', '57045', (30, 33))
148003	26099335	In summary, these results indicated that TSGs had the highest mutation frequency in most tumour types, and the OCGs were the second.	('TSG', 'Gene', '57045', (41, 44))	('tumour', 'Phenotype', 'HP:0002664', (89, 95))	('tumour', 'Disease', 'MESH:D009369', (89, 95))	('tumour', 'Disease', (89, 95))	('mutation', 'Var', (62, 70))	('TSG', 'Gene', (41, 44))
148035	26099335	The observation indicated that the higher direct associations among these genes with higher mutation frequencies might contribute to the cancer development jointly.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('contribute', 'Reg', (119, 129))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('mutation frequencies', 'Var', (92, 112))	('cancer', 'Disease', (137, 143))
148053	26099335	The study of Pan-Cancer analysis presents the data and analytical results for point mutations and small insertions/deletions from 3,281 tumours across 12 tumour types as part of the TCGA Pan-Cancer effort.	('tumour', 'Phenotype', 'HP:0002664', (154, 160))	('tumours', 'Phenotype', 'HP:0002664', (136, 143))	('Cancer', 'Phenotype', 'HP:0002664', (191, 197))	('tumour', 'Disease', 'MESH:D009369', (154, 160))	('tumour', 'Disease', 'MESH:D009369', (136, 142))	('point mutations', 'Var', (78, 93))	('tumours', 'Disease', 'MESH:D009369', (136, 143))	('tumour', 'Disease', (136, 142))	('tumours', 'Disease', (136, 143))	('tumour', 'Disease', (154, 160))	('Cancer', 'Phenotype', 'HP:0002664', (17, 23))	('tumour', 'Phenotype', 'HP:0002664', (136, 142))
148057	26099335	We found that the TSGs had the highest mutation frequency in most tumour types and the OCGs second.	('TSG', 'Gene', (18, 21))	('mutation', 'Var', (39, 47))	('tumour', 'Phenotype', 'HP:0002664', (66, 72))	('TSG', 'Gene', '57045', (18, 21))	('tumour', 'Disease', 'MESH:D009369', (66, 72))	('tumour', 'Disease', (66, 72))
148058	26099335	The results might be interpreted by the theory that the gain-of-function mutations that convert proto-oncogenes to oncogenes acts dominantly while the loss-of-function mutation in tumor suppressor genes acts recessively.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('tumor', 'Disease', (180, 185))	('gain-of-function', 'PosReg', (56, 72))	('mutations', 'Var', (73, 82))
148059	26099335	In addition, we observed that the essential genes had the lowest mutation frequency in all tumor types, which might reflect the fundamental roles in the survival of the essential genes.	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('lowest', 'NegReg', (58, 64))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('mutation', 'Var', (65, 73))	('tumor', 'Disease', (91, 96))
148071	26099335	It might be very interesting to further examine if the mutations in OCGs or TSGs are necessary for both the establishment and maintenance of protein-protein interactions, which might lead to the identification of logical drug targets.	('TSG', 'Gene', (76, 79))	('mutations', 'Var', (55, 64))	('protein-protein', 'Protein', (141, 156))	('TSG', 'Gene', '57045', (76, 79))	('OCGs', 'Gene', (68, 72))	('lead', 'Reg', (183, 187))
148089	31512325	Previously, we developed mouse monoclonal antibodies against human CAR and found that one, mu6G10A, significantly inhibited tumor growth in xenografts of human cancer cells.	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('human', 'Species', '9606', (154, 159))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('cancer', 'Disease', (160, 166))	('mouse', 'Species', '10090', (25, 30))	('tumor', 'Disease', (124, 129))	('mu6G10A', 'Var', (91, 98))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('human', 'Species', '9606', (61, 66))	('inhibited', 'NegReg', (114, 123))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
148091	31512325	ch6G10A had binding activity, inducing antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity, and in vivo anti-tumor activity against CAR-expressing prostate cancer DU-145 cells.	('cytotoxicity and complement-dependent cytotoxicity', 'Disease', 'MESH:D064420', (67, 117))	('prostate cancer', 'Phenotype', 'HP:0012125', (174, 189))	('antibody-dependent', 'CPA', (39, 57))	('ch6G10A', 'Var', (0, 7))	('prostate cancer', 'Disease', (174, 189))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('binding', 'Interaction', (12, 19))	('inducing', 'PosReg', (30, 38))	('prostate cancer', 'Disease', 'MESH:D011471', (174, 189))	('DU-145', 'CellLine', 'CVCL:0105', (190, 196))	('tumor', 'Disease', (136, 141))
148092	31512325	In addition, cancer tissue array analysis confirmed that CAR is highly expressed in neuroendocrine lung cancers including small cell lung cancer, and treatment with ch6G10A effectively inhibited in vivo subcutaneous tumor growth of NCI-H69 small cell lung cancer cells in nude mice.	('cancer', 'Disease', (138, 144))	('ch6G10A', 'Var', (165, 172))	('lung cancers', 'Phenotype', 'HP:0100526', (99, 111))	('cancer', 'Disease', (256, 262))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('cancer', 'Disease', 'MESH:D009369', (13, 19))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (122, 144))	('cancers', 'Phenotype', 'HP:0002664', (104, 111))	('cancer', 'Phenotype', 'HP:0002664', (256, 262))	('cancer', 'Disease', (104, 110))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (240, 262))	('NCI-H69 small cell lung cancer', 'Disease', (232, 262))	('tumor', 'Disease', (216, 221))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('inhibited', 'NegReg', (185, 194))	('neuroendocrine lung cancers', 'Disease', (84, 111))	('NCI-H69 small cell lung cancer', 'Disease', 'MESH:D055752', (232, 262))	('tumor', 'Disease', 'MESH:D009369', (216, 221))	('cancer', 'Disease', 'MESH:D009369', (138, 144))	('cancer', 'Disease', 'MESH:D009369', (256, 262))	('cancer', 'Disease', (13, 19))	('small cell lung cancer', 'Disease', 'MESH:D055752', (122, 144))	('subcutaneous tumor', 'Phenotype', 'HP:0001482', (203, 221))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('small cell lung cancer', 'Disease', 'MESH:D055752', (240, 262))	('small cell lung cancer', 'Disease', (122, 144))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('lung cancer', 'Phenotype', 'HP:0100526', (133, 144))	('lung cancer', 'Phenotype', 'HP:0100526', (251, 262))	('nude mice', 'Species', '10090', (272, 281))	('neuroendocrine lung cancers', 'Disease', 'MESH:D008175', (84, 111))	('lung cancer', 'Phenotype', 'HP:0100526', (99, 110))
148093	31512325	Moreover, treatment with mu6G10A effectively inhibited both in vivo orthotopic tumor growth and distant metastatic formation in mouse xenograft models of a highly metastatic subline of human small cell lung cancer DMS273 cells.	('mu6G10A', 'Var', (25, 32))	('human', 'Species', '9606', (185, 190))	('tumor', 'Disease', (79, 84))	('small cell lung cancer', 'Disease', 'MESH:D055752', (191, 213))	('lung cancer', 'Phenotype', 'HP:0100526', (202, 213))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (191, 213))	('mouse', 'Species', '10090', (128, 133))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('distant metastatic formation', 'CPA', (96, 124))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('inhibited', 'NegReg', (45, 54))	('small cell lung cancer', 'Disease', (191, 213))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
148096	31512325	It has been reported that high CAR expression levels occur in various human cancers.4, 5, 6, 7, 8, 9, 10 Moreover, CAR promotes tumor growth in some cancer types.	('promotes', 'PosReg', (119, 127))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('cancer', 'Disease', (149, 155))	('cancers', 'Disease', 'MESH:D009369', (76, 83))	('cancers', 'Phenotype', 'HP:0002664', (76, 83))	('cancers', 'Disease', (76, 83))	('expression', 'Species', '29278', (35, 45))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('human', 'Species', '9606', (70, 75))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('CAR', 'Var', (115, 118))	('tumor', 'Disease', (128, 133))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (149, 155))
148103	31512325	A mouse anti-human CAR mAb, mu6G10A, was developed as described previously.14 Generation of mouse-human chimeric anti-human CAR (ch6G10A) was previously described.18 Briefly, the appropriate V H and V L cDNAs of mu6G10A and C H and C L of human IgG1 were subcloned into pcDNA3.3/Neo or pcDNA3.1/Zeo vectors (Thermo Fisher Scientific Inc.), respectively.	('human', 'Species', '9606', (13, 18))	('C H', 'Chemical', 'MESH:D006859', (224, 227))	('IgG1', 'Gene', (245, 249))	('mouse', 'Species', '10090', (2, 7))	('human', 'Species', '9606', (118, 123))	('mouse', 'Species', '10090', (92, 97))	('human', 'Species', '9606', (239, 244))	('human', 'Species', '9606', (98, 103))	('mu6G10A', 'Var', (212, 219))	('IgG1', 'Gene', '105243590', (245, 249))
148113	31512325	Cancer tissue arrays (BC041115c for lung cancer, BC19013 for prostate cancer, and GL803b for brain cancer) were purchased from US Biomax.	('GL803b', 'Var', (82, 88))	('lung cancer', 'Disease', (36, 47))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('brain cancer', 'Disease', (93, 105))	('prostate cancer', 'Phenotype', 'HP:0012125', (61, 76))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('prostate cancer', 'Disease', (61, 76))	('lung cancer', 'Disease', 'MESH:D008175', (36, 47))	('brain cancer', 'Disease', 'MESH:D001932', (93, 105))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('brain cancer', 'Phenotype', 'HP:0030692', (93, 105))	('prostate cancer', 'Disease', 'MESH:D011471', (61, 76))	('lung cancer', 'Phenotype', 'HP:0100526', (36, 47))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('BC041115c', 'Var', (22, 31))
148118	31512325	For CDC activity, target cells (2 x 104 cells) were inoculated into 96-well plates and incubated with 5% rabbit complement (Cedarlane) and ch6G10A, mu6G10A, control human IgG, or control mouse IgG for 4 hours at 37 C. Cell viability was determined using MTT assay.	('MTT', 'Chemical', 'MESH:C022616', (254, 257))	('human', 'Species', '9606', (165, 170))	('IgG', 'Gene', (171, 174))	('mu6G10A', 'Var', (148, 155))	('Cedarlane', 'Chemical', 'None', (124, 133))	('IgG', 'Gene', '16059', (193, 196))	('rabbit', 'Species', '9986', (105, 111))	('mouse', 'Species', '10090', (187, 192))	('IgG', 'Gene', (193, 196))	('IgG', 'Gene', '16059', (171, 174))
148125	31512325	Previously, we developed a mouse mAb against human CAR (mu6G10A) that recognized an extra-membranous region of CAR and showed anti-tumor activities against CAR-expressing cancer cells in xenograft models.14 To reduce the immunogenicity of antibodies in humans, we attempted to generate a mouse-human chimeric antibody (ch6G10A) by fusing the V H and V L regions of mu6G10A with the C H and C L regions of human IgG1, respectively.	('mouse', 'Species', '10090', (288, 293))	('IgG1', 'Gene', (411, 415))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('human', 'Species', '9606', (405, 410))	('human', 'Species', '9606', (294, 299))	('mouse', 'Species', '10090', (27, 32))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('IgG1', 'Gene', '105243590', (411, 415))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('cancer', 'Disease', (171, 177))	('mu6G10A', 'Var', (365, 372))	('tumor', 'Disease', (131, 136))	('humans', 'Species', '9606', (253, 259))	('human', 'Species', '9606', (45, 50))	('C H', 'Chemical', 'MESH:D006859', (382, 385))	('human', 'Species', '9606', (253, 258))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))
148127	31512325	Because mu6G10A can induce both ADCC and CDC,14 we next examined whether ch6G10A can also induce both ADCC and CDC.	('CDC,14', 'Gene', '8556', (41, 47))	('induce', 'Reg', (20, 26))	('mu6G10A', 'Var', (8, 15))	('ADCC', 'Disease', (32, 36))	('ch6G10A', 'Var', (73, 80))	('ADCC', 'Disease', (102, 106))
148128	31512325	When a human NK cell line, KHYG-1/FcgammaRIIIA, which stably expresses FcgammaRIIIA was used as effector cells,16 ADCC by ch6G10A was observed against DU-145 cells (Figure 1B).	('FcgammaRIIIA', 'Gene', '2214', (71, 83))	('FcgammaRIIIA', 'Gene', (71, 83))	('ch6G10A', 'Var', (122, 129))	('human', 'Species', '9606', (7, 12))	('DU-145', 'CellLine', 'CVCL:0105', (151, 157))	('FcgammaRIIIA', 'Gene', '2214', (34, 46))	('FcgammaRIIIA', 'Gene', (34, 46))
148129	31512325	ch6G10A also significantly induced CDC activity against DU-145 cells when using rabbit complement (Figure 1C).	('rabbit', 'Species', '9986', (80, 86))	('induced', 'PosReg', (27, 34))	('ch6G10A', 'Var', (0, 7))	('DU-145', 'CellLine', 'CVCL:0105', (56, 62))	('CDC activity against DU-145 cells', 'CPA', (35, 68))
148130	31512325	Then, we evaluated the anti-tumor activity of ch6G10A against DU-145 cells in vivo using a subcutaneous xenograft model in nude mice.	('tumor', 'Disease', (28, 33))	('DU-145', 'CellLine', 'CVCL:0105', (62, 68))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('nude mice', 'Species', '10090', (123, 132))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('ch6G10A', 'Var', (46, 53))
148131	31512325	ch6G10A, control human IgG (500 mug/mice) or saline was injected i.v.	('ch6G10A', 'Var', (0, 7))	('human', 'Species', '9606', (17, 22))	('IgG', 'Gene', '16059', (23, 26))	('mice', 'Species', '10090', (36, 40))	('IgG', 'Gene', (23, 26))
148132	31512325	at days 0 and 7, and human NK cells KHYG-1/FcgammaRIIIA were also injected around the tumors at days 0 and 7. ch6G10A significantly inhibited the growth of xenograft DU-145 tumors in vivo (43% inhibition compared with control human IgG, P < .01) without significant body weight loss in the host mice (Figure 2, data not shown).	('FcgammaRIIIA', 'Gene', '2214', (43, 55))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('growth', 'CPA', (146, 152))	('tumors', 'Phenotype', 'HP:0002664', (173, 179))	('IgG', 'Gene', (232, 235))	('inhibited', 'NegReg', (132, 141))	('weight loss', 'Disease', 'MESH:D015431', (271, 282))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumors', 'Disease', (86, 92))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('weight loss', 'Phenotype', 'HP:0001824', (271, 282))	('tumors', 'Disease', (173, 179))	('FcgammaRIIIA', 'Gene', (43, 55))	('weight loss', 'Disease', (271, 282))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('tumors', 'Disease', 'MESH:D009369', (173, 179))	('human', 'Species', '9606', (226, 231))	('mice', 'Species', '10090', (295, 299))	('human', 'Species', '9606', (21, 26))	('IgG', 'Gene', '16059', (232, 235))	('inhibition', 'NegReg', (193, 203))	('ch6G10A', 'Var', (110, 117))	('DU-145', 'CellLine', 'CVCL:0105', (166, 172))
148133	31512325	These results showed that ch6G10A had ADCC-/CDC-inducing activities and in vivo anti-tumor activity against CAR-expressing prostate cancer cells and that we successfully generated a mouse-human chimeric anti-CAR antibody with potent anti-tumor activity.	('tumor', 'Disease', (85, 90))	('prostate cancer', 'Phenotype', 'HP:0012125', (123, 138))	('human', 'Species', '9606', (188, 193))	('tumor', 'Disease', 'MESH:D009369', (238, 243))	('mouse', 'Species', '10090', (182, 187))	('tumor', 'Phenotype', 'HP:0002664', (238, 243))	('prostate cancer', 'Disease', (123, 138))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('tumor', 'Disease', (238, 243))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('prostate cancer', 'Disease', 'MESH:D011471', (123, 138))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('ADCC-/CDC-inducing', 'CPA', (38, 56))	('ch6G10A', 'Var', (26, 33))
148140	31512325	ch6G10A or control human IgG (500 mug/mice) was injected i.v.	('mice', 'Species', '10090', (38, 42))	('ch6G10A', 'Var', (0, 7))	('IgG', 'Gene', (25, 28))	('human', 'Species', '9606', (19, 24))	('IgG', 'Gene', '16059', (25, 28))
148142	31512325	As shown in Figure 4B,C, ch6G10A significantly inhibited the growth of xenograft NCI-H69 tumors in vivo (37% inhibition compared with control human IgG, P < .01) without significant body weight loss in the host mice (data not shown).	('tumors', 'Disease', (89, 95))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('inhibited', 'NegReg', (47, 56))	('growth', 'MPA', (61, 67))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('IgG', 'Gene', '16059', (148, 151))	('ch6G10A', 'Var', (25, 32))	('NCI-H69', 'CellLine', 'CVCL:1579', (81, 88))	('human', 'Species', '9606', (142, 147))	('weight loss', 'Disease', 'MESH:D015431', (187, 198))	('inhibition', 'NegReg', (109, 119))	('mice', 'Species', '10090', (211, 215))	('IgG', 'Gene', (148, 151))	('weight loss', 'Disease', (187, 198))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('weight loss', 'Phenotype', 'HP:0001824', (187, 198))
148143	31512325	These results showed that ch6G10A had anti-tumor activity against CAR-expressing SCLC cells and suggested that SCLC might be a candidate disease for targeting therapy to CAR with therapeutic antibody.	('SCLC', 'Disease', (111, 115))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('SCLC', 'Disease', 'MESH:D055752', (81, 85))	('SCLC', 'Disease', (81, 85))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Disease', (43, 48))	('ch6G10A', 'Var', (26, 33))	('SCLC', 'Disease', 'MESH:D055752', (111, 115))
148146	31512325	Intravenous injection with mu6G10A or control mouse IgG (250 mug/mice) was started a day after orthotopic transplantation of C5B cells.	('mu6G10A', 'Var', (27, 34))	('IgG', 'Gene', '16059', (52, 55))	('mice', 'Species', '10090', (65, 69))	('mouse', 'Species', '10090', (46, 51))	('IgG', 'Gene', (52, 55))	('C5B', 'Gene', (125, 128))	('C5B', 'Gene', '727', (125, 128))
148147	31512325	Orthotopic tumor growth was prominently inhibited by mu6G10A (78% inhibition compared with control mouse IgG, P < .005) without significant body weight loss in the host mice (Figure 5, data not shown).	('mouse', 'Species', '10090', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('inhibited', 'NegReg', (40, 49))	('weight loss', 'Disease', 'MESH:D015431', (145, 156))	('tumor', 'Disease', (11, 16))	('IgG', 'Gene', '16059', (105, 108))	('mu6G10A', 'Var', (53, 60))	('weight loss', 'Disease', (145, 156))	('mice', 'Species', '10090', (169, 173))	('weight loss', 'Phenotype', 'HP:0001824', (145, 156))	('IgG', 'Gene', (105, 108))	('tumor', 'Disease', 'MESH:D009369', (11, 16))	('inhibition', 'NegReg', (66, 76))
148148	31512325	Incidence of distant metastases formation was 67% in the control mouse IgG-treated group and 33% in the mu6G10A-treated group, and significantly fewer metastasis-positive organs were observed in the mu6G10A-treated group compared with the control mouse IgG-treated group (P < .05; Figure 5B).	('mouse', 'Species', '10090', (247, 252))	('metastases', 'Disease', 'MESH:D009362', (21, 31))	('mu6G10A-treated', 'Var', (199, 214))	('fewer', 'NegReg', (145, 150))	('mouse', 'Species', '10090', (65, 70))	('mu6G10A-treated', 'Var', (104, 119))	('IgG', 'Gene', '16059', (71, 74))	('IgG', 'Gene', '16059', (253, 256))	('metastases', 'Disease', (21, 31))	('IgG', 'Gene', (71, 74))	('IgG', 'Gene', (253, 256))	('metastasis-positive organs', 'CPA', (151, 177))
148154	31512325	Our CTA analysis showed significantly higher expression of CAR in neuroendocrine lung cancers including SCLC compared with normal lung tissues (Figure 3), consistent with the findings of previous studies.5, 8, 10 Furthermore, treatment with anti-CAR antibody effectively inhibited both in vivo tumor growth (subcutaneous and orthotopic) and distant metastasis formation in mouse xenograft models of human SCLC cell lines (Figures 4 and 5).	('anti-CAR', 'Var', (241, 249))	('SCLC', 'Disease', 'MESH:D055752', (104, 108))	('human', 'Species', '9606', (399, 404))	('tumor', 'Phenotype', 'HP:0002664', (294, 299))	('lung cancer', 'Phenotype', 'HP:0100526', (81, 92))	('mouse', 'Species', '10090', (373, 378))	('expression', 'Species', '29278', (45, 55))	('SCLC', 'Disease', 'MESH:D055752', (405, 409))	('cancers', 'Phenotype', 'HP:0002664', (86, 93))	('neuroendocrine lung cancers', 'Disease', 'MESH:D008175', (66, 93))	('SCLC', 'Disease', (104, 108))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('lung cancers', 'Phenotype', 'HP:0100526', (81, 93))	('SCLC', 'Disease', (405, 409))	('inhibited', 'NegReg', (271, 280))	('tumor', 'Disease', (294, 299))	('neuroendocrine lung cancers', 'Disease', (66, 93))	('distant metastasis formation', 'CPA', (341, 369))	('tumor', 'Disease', 'MESH:D009369', (294, 299))
148161	31512325	Therefore, it is presumed that ch6G10A also exerts its anti-tumor activity primarily through both ADCC and CDC.	('CDC', 'CPA', (107, 110))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('ch6G10A', 'Var', (31, 38))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Disease', (60, 65))	('ADCC', 'Disease', (98, 102))
148162	31512325	If this is the case, the anti-tumor activity of ch6G10A could be enhanced by ADCC-enhancing technologies such as afucosylation of the Fc domain.21 Thus, ch6G10A could be a potent lead antibody for cancer immunotherapy.	('cancer', 'Disease', 'MESH:D009369', (197, 203))	('cancer', 'Disease', (197, 203))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('ch6G10A', 'Var', (153, 160))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('tumor', 'Disease', (30, 35))
148163	31512325	We showed that the treatment with mu6G10A efficiently inhibited tumor growth in the lung as well as metastasis in the SCLC metastatic model (Figure 5).	('inhibited', 'NegReg', (54, 63))	('SCLC', 'Disease', 'MESH:D055752', (118, 122))	('tumor', 'Disease', (64, 69))	('mu6G10A', 'Var', (34, 41))	('SCLC', 'Disease', (118, 122))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
148164	31512325	Although it is very important as to whether ch6G10A also inhibits SCLC metastasis, there are no suitable metastatic models for the evaluation of chimeric mAb at this point.	('ch6G10A', 'Var', (44, 51))	('SCLC', 'Disease', (66, 70))	('inhibits', 'NegReg', (57, 65))	('SCLC', 'Disease', 'MESH:D055752', (66, 70))
148165	31512325	However, there is an interesting humanized mouse strain, NOG-IL-2 Tg, which can induce human NK cells from hematopoietic stem cells (HSC).22 The report suggested that chimeric anti-human CCR4 mAb (Poteligeo, Kyowa-Kirin, Tokyo, Japa) suppressed tumor growth of human lymphoma cells in human HSC-transferred NOG-IL-2 Tg mice through ADCC.	('human', 'Species', '9606', (181, 186))	('lymphoma', 'Disease', 'MESH:D008223', (267, 275))	('lymphoma', 'Phenotype', 'HP:0002665', (267, 275))	('mice', 'Species', '10090', (319, 323))	('human', 'Species', '9606', (87, 92))	('tumor', 'Disease', 'MESH:D009369', (245, 250))	('human', 'Species', '9606', (261, 266))	('chimeric', 'Var', (167, 175))	('suppressed', 'NegReg', (234, 244))	('human', 'Species', '9606', (285, 290))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('human', 'Species', '9606', (33, 38))	('tumor', 'Disease', (245, 250))	('mouse', 'Species', '10090', (43, 48))	('CCR4', 'Gene', (187, 191))	('CCR4', 'Gene', '1233', (187, 191))	('lymphoma', 'Disease', (267, 275))
148167	31512325	Another important point about the result of Figure 5 is the mechanism by which anti-CAR mAb inhibited SCLC metastasis.	('SCLC', 'Disease', 'MESH:D055752', (102, 106))	('inhibited', 'NegReg', (92, 101))	('SCLC', 'Disease', (102, 106))	('anti-CAR', 'Var', (79, 87))
148173	31512325	We previously showed that mu6G10A reacts with normal skin, prostate, and kidney tissue.14 At this point, we could not avoid the possibility that the reactivity of 6G10A to normal tissues could cause some adverse events when the 6G10A-based antibody is given to humans.	('6G10A', 'Var', (163, 168))	('cause', 'Reg', (193, 198))	('humans', 'Species', '9606', (261, 267))
148175	31512325	If the reactivity of 6G10A to normal tissues causes severe problems, cancer specificity of the antibody should be improved.	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('6G10A', 'Var', (21, 26))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('cancer', 'Disease', (69, 75))
148179	25322863	In this review, we summarize genetic and epigenetic alterations including mutation, deletion, amplification, and promoter methylation of PTPRs in cancer and consider the consequences of PTPR alterations in different types of cancers.	('mutation', 'Var', (74, 82))	('amplification', 'Var', (94, 107))	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('deletion', 'Var', (84, 92))	('cancers', 'Disease', 'MESH:D009369', (225, 232))	('PTPRs', 'Gene', (137, 142))	('cancer', 'Disease', 'MESH:D009369', (225, 231))	('cancer', 'Disease', (225, 231))	('cancers', 'Disease', (225, 232))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('PTPRs', 'Gene', '5802', (137, 142))	('cancers', 'Phenotype', 'HP:0002664', (225, 232))
148199	25322863	This review focus on the impact of PTPR alterations across a spectrum of cancers and the clinical implications of targeting PTPRs therein.	('cancers', 'Disease', (73, 80))	('PTPRs', 'Gene', '5802', (124, 129))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('alterations', 'Var', (40, 51))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('PTPRs', 'Gene', (124, 129))	('cancers', 'Disease', 'MESH:D009369', (73, 80))
148200	25322863	Genetic alterations that are frequently seen in cancers include mutation, copy number loss/deletion, and copy number amplification.	('cancers', 'Disease', (48, 55))	('mutation', 'Var', (64, 72))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('cancers', 'Phenotype', 'HP:0002664', (48, 55))	('copy number loss/deletion', 'Var', (74, 99))	('copy number amplification', 'Var', (105, 130))	('cancers', 'Disease', 'MESH:D009369', (48, 55))
148201	25322863	Gain-of-function mutations can increase the activity of an oncogene, and loss-of-function mutations may silence a tumor suppressor gene.	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('mutations', 'Var', (90, 99))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('loss-of-function', 'NegReg', (73, 89))	('silence', 'NegReg', (104, 111))	('tumor', 'Disease', (114, 119))	('activity', 'MPA', (44, 52))	('Gain-of-function', 'PosReg', (0, 16))	('oncogene', 'Protein', (59, 67))	('mutations', 'Var', (17, 26))	('increase', 'PosReg', (31, 39))
148202	25322863	Of the 21 PTPRs, 20 are mutated in multiple cancers, per The Cancer Genome Atlas (TCGA) data (summarized in Figure 1).	('Cancer Genome Atlas', 'Disease', (61, 80))	('mutated', 'Var', (24, 31))	('Cancer', 'Phenotype', 'HP:0002664', (61, 67))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (61, 80))	('cancers', 'Phenotype', 'HP:0002664', (44, 51))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('multiple cancers', 'Disease', 'MESH:D009369', (35, 51))	('PTPRs', 'Gene', (10, 15))	('PTPRs', 'Gene', '5802', (10, 15))	('multiple cancers', 'Disease', (35, 51))
148203	25322863	Mutation appears to be the most common mechanism by which PTPRs are genetically modified when compared with copy number amplification or loss.	('Mutation', 'Var', (0, 8))	('PTPRs', 'Gene', (58, 63))	('PTPRs', 'Gene', '5802', (58, 63))
148205	25322863	reported that PTPRT was mutated in 27% of colorectal cancers (CRCs), 17% of gastric cancers, and 18% of lung cancers.	('mutated', 'Var', (24, 31))	('colorectal cancers', 'Disease', 'MESH:D015179', (42, 60))	('gastric cancer', 'Phenotype', 'HP:0012126', (76, 90))	('lung cancers', 'Disease', 'MESH:D008175', (104, 116))	('lung cancers', 'Disease', (104, 116))	('PTPRT', 'Gene', '11122', (14, 19))	('lung cancer', 'Phenotype', 'HP:0100526', (104, 115))	('lung cancers', 'Phenotype', 'HP:0100526', (104, 116))	('cancers', 'Phenotype', 'HP:0002664', (53, 60))	('cancers', 'Phenotype', 'HP:0002664', (109, 116))	('colorectal cancers', 'Disease', (42, 60))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('cancers', 'Phenotype', 'HP:0002664', (84, 91))	('gastric cancers', 'Disease', 'MESH:D013274', (76, 91))	('PTPRT', 'Gene', (14, 19))	('gastric cancers', 'Disease', (76, 91))	('gastric cancers', 'Phenotype', 'HP:0012126', (76, 91))
148206	25322863	They tested the functional consequences of 5 mutations in the catalytic domains of PTPRT and all 5 showed reduced phosphatase activity compared with wild-type PTPRT, indicating that these are loss-of-function mutations.	('mutations', 'Var', (45, 54))	('tested', 'Reg', (5, 11))	('phosphatase activity', 'MPA', (114, 134))	('PTPRT', 'Gene', '11122', (83, 88))	('PTPRT', 'Gene', (83, 88))	('PTPRT', 'Gene', (159, 164))	('PTPRT', 'Gene', '11122', (159, 164))	('reduced', 'NegReg', (106, 113))
148207	25322863	PTPRT mutation has also been reported in other cancers including head and neck squamous cell carcinoma (HNSCC), acute myeloid leukemia, and T-cell large granular lymphocytic.	('T-cell large granular lymphocytic', 'Disease', (140, 173))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (112, 134))	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (79, 102))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (74, 102))	('leukemia', 'Phenotype', 'HP:0001909', (126, 134))	('acute myeloid leukemia', 'Disease', (112, 134))	('PTPRT', 'Gene', (0, 5))	('PTPRT', 'Gene', '11122', (0, 5))	('mutation', 'Var', (6, 14))	('cancers', 'Disease', 'MESH:D009369', (47, 54))	('cancers', 'Phenotype', 'HP:0002664', (47, 54))	('cancers', 'Disease', (47, 54))	('reported', 'Reg', (29, 37))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (112, 134))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (118, 134))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('neck squamous cell carcinoma', 'Disease', (74, 102))
148208	25322863	Functional analysis of PTPRT mutation in HNSCC revealed that normal function, signal transducer and activator of transcription 3 (STAT3) dephosphorylation, was abrogated for the mutant protein.	('mutation', 'Var', (29, 37))	('mutant', 'Var', (178, 184))	('abrogated', 'NegReg', (160, 169))	('STAT3', 'Gene', '6774', (130, 135))	('signal transducer and activator of transcription 3', 'Gene', '6774', (78, 128))	('normal function', 'MPA', (61, 76))	('STAT3', 'Gene', (130, 135))	('PTPRT', 'Gene', '11122', (23, 28))	('PTPRT', 'Gene', (23, 28))
148210	25322863	PTPRD mutation has been reported in cutaneous squamous cell carcinoma, glioblastoma multiforme (GBM), melanoma, CRC, HNSCC, and lung cancer.	('glioblastoma multiforme', 'Disease', (71, 94))	('PTPRD', 'Gene', (0, 5))	('glioblastoma', 'Phenotype', 'HP:0012174', (71, 83))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (71, 94))	('lung cancer', 'Disease', 'MESH:D008175', (128, 139))	('PTPRD', 'Gene', '5789', (0, 5))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (46, 69))	('melanoma', 'Phenotype', 'HP:0002861', (102, 110))	('melanoma', 'Disease', (102, 110))	('lung cancer', 'Phenotype', 'HP:0100526', (128, 139))	('cutaneous squamous cell carcinoma', 'Phenotype', 'HP:0006739', (36, 69))	('HNSCC', 'Disease', (117, 122))	('reported', 'Reg', (24, 32))	('CRC', 'Disease', (112, 115))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('mutation', 'Var', (6, 14))	('cutaneous squamous cell carcinoma', 'Disease', (36, 69))	('lung cancer', 'Disease', (128, 139))	('melanoma', 'Disease', 'MESH:D008545', (102, 110))	('carcinoma', 'Phenotype', 'HP:0030731', (60, 69))	('cutaneous squamous cell carcinoma', 'Disease', 'MESH:D002294', (36, 69))
148211	25322863	Functional studies of PTPRD mutation in neuroblastoma, melanoma, and GBM showed that mutation inactivated the function of PTPRD and that cancer cells harboring PTPRD mutations displayed decreased viability, thus suggesting PTPRD acts as a tumor suppressor in these cancers.	('PTPRD', 'Gene', '5789', (122, 127))	('cancer', 'Phenotype', 'HP:0002664', (265, 271))	('PTPRD', 'Gene', (223, 228))	('mutation', 'Var', (85, 93))	('mutation', 'Var', (28, 36))	('cancer', 'Disease', (137, 143))	('melanoma', 'Phenotype', 'HP:0002861', (55, 63))	('PTPRD', 'Gene', (160, 165))	('melanoma', 'Disease', (55, 63))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('mutations', 'Var', (166, 175))	('PTPRD', 'Gene', '5789', (223, 228))	('function', 'MPA', (110, 118))	('neuroblastoma', 'Disease', (40, 53))	('tumor', 'Disease', (239, 244))	('cancers', 'Disease', (265, 272))	('cancer', 'Disease', 'MESH:D009369', (265, 271))	('PTPRD', 'Gene', '5789', (160, 165))	('cancers', 'Disease', 'MESH:D009369', (265, 272))	('neuroblastoma', 'Phenotype', 'HP:0003006', (40, 53))	('PTPRD', 'Gene', (22, 27))	('tumor', 'Disease', 'MESH:D009369', (239, 244))	('neuroblastoma', 'Disease', 'MESH:D009447', (40, 53))	('inactivated', 'NegReg', (94, 105))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('PTPRD', 'Gene', '5789', (22, 27))	('melanoma', 'Disease', 'MESH:D008545', (55, 63))	('PTPRD', 'Gene', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (239, 244))	('decreased', 'NegReg', (186, 195))	('cancers', 'Phenotype', 'HP:0002664', (265, 272))	('cancer', 'Disease', (265, 271))
148212	25322863	also reported 6 (3%) PTPRF mutations in CRCs, 1 (9%) in lung cancer, and 1 (9%) in breast cancer.	('mutations', 'Var', (27, 36))	('lung cancer', 'Disease', 'MESH:D008175', (56, 67))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('breast cancer', 'Disease', 'MESH:D001943', (83, 96))	('breast cancer', 'Disease', (83, 96))	('breast cancer', 'Phenotype', 'HP:0003002', (83, 96))	('PTPRF', 'Gene', (21, 26))	('CRCs', 'Disease', (40, 44))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('lung cancer', 'Disease', (56, 67))	('lung cancer', 'Phenotype', 'HP:0100526', (56, 67))
148213	25322863	reported 14 PTPRB mutations in 10 of the 39 angiosarcomas studied.	('PTPRB', 'Gene', '5787', (12, 17))	('angiosarcomas', 'Disease', (44, 57))	('sarcomas', 'Phenotype', 'HP:0100242', (49, 57))	('sarcoma', 'Phenotype', 'HP:0100242', (49, 56))	('PTPRB', 'Gene', (12, 17))	('angiosarcomas', 'Disease', 'MESH:D006394', (44, 57))	('angiosarcomas', 'Phenotype', 'HP:0200058', (44, 57))	('angiosarcoma', 'Phenotype', 'HP:0200058', (44, 56))	('mutations', 'Var', (18, 27))
148214	25322863	In tumors that were secondary and/or had MYC amplification, which is a radiation-associated biomarker of secondary angiosarcoma, the PTPRB mutation rate was up to 45% (10 of 22 cases).	('sarcoma', 'Phenotype', 'HP:0100242', (120, 127))	('angiosarcoma', 'Disease', 'MESH:D006394', (115, 127))	('tumors', 'Phenotype', 'HP:0002664', (3, 9))	('PTPRB', 'Gene', '5787', (133, 138))	('mutation', 'Var', (139, 147))	('PTPRB', 'Gene', (133, 138))	('tumors', 'Disease', (3, 9))	('angiosarcoma', 'Disease', (115, 127))	('MYC amplification', 'Var', (41, 58))	('tumors', 'Disease', 'MESH:D009369', (3, 9))	('angiosarcoma', 'Phenotype', 'HP:0200058', (115, 127))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))
148215	25322863	PTPRB inhibits angiogenesis, and inactivating mutations of PTPRB are considered driver events in angiosarcoma.	('angiogenesis', 'CPA', (15, 27))	('inhibits', 'NegReg', (6, 14))	('angiosarcoma', 'Disease', (97, 109))	('PTPRB', 'Gene', '5787', (0, 5))	('PTPRB', 'Gene', '5787', (59, 64))	('inactivating mutations', 'Var', (33, 55))	('PTPRB', 'Gene', (0, 5))	('PTPRB', 'Gene', (59, 64))	('angiosarcoma', 'Phenotype', 'HP:0200058', (97, 109))	('sarcoma', 'Phenotype', 'HP:0100242', (102, 109))	('angiosarcoma', 'Disease', 'MESH:D006394', (97, 109))
148216	25322863	Copy number loss/deletion is common in cancers.	('cancers', 'Phenotype', 'HP:0002664', (39, 46))	('Copy number loss/deletion', 'Var', (0, 25))	('cancers', 'Disease', (39, 46))	('cancers', 'Disease', 'MESH:D009369', (39, 46))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))
148217	25322863	Homozygous deletion usually contributes to loss of function of tumor suppressor genes.	('tumor', 'Disease', (63, 68))	('loss of function', 'NegReg', (43, 59))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('Homozygous deletion', 'Var', (0, 19))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
148218	25322863	Many PTPRs negatively regulate cell proliferation, migration, and invasion, and homozygous deletion of these PTPRs may contribute to carcinogenesis.	('PTPRs', 'Gene', (5, 10))	('deletion', 'Var', (91, 99))	('negatively', 'NegReg', (11, 21))	('PTPRs', 'Gene', (109, 114))	('migration', 'CPA', (51, 60))	('contribute', 'Reg', (119, 129))	('regulate', 'Reg', (22, 30))	('carcinogenesis', 'Disease', 'MESH:D063646', (133, 147))	('cell proliferation', 'CPA', (31, 49))	('PTPRs', 'Gene', '5802', (5, 10))	('carcinogenesis', 'Disease', (133, 147))	('PTPRs', 'Gene', '5802', (109, 114))	('invasion', 'CPA', (66, 74))
148221	25322863	In addition, PTPRF deletion was reported in pheochromocytomas.	('pheochromocytomas', 'Disease', 'MESH:D010673', (44, 61))	('deletion', 'Var', (19, 27))	('PTPRF', 'Gene', (13, 18))	('reported', 'Reg', (32, 40))	('pheochromocytomas', 'Phenotype', 'HP:0002666', (44, 61))	('pheochromocytomas', 'Disease', (44, 61))
148223	25322863	Tumor suppressors are often silenced by promoter hypermethylation in cancer.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('promoter hypermethylation', 'Var', (40, 65))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Disease', (69, 75))
148227	25322863	A study of childhood acute lymphoblastic leukemia suggested that PTPRG methylation is induced by Ras mutations.	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (21, 49))	('methylation', 'Var', (71, 82))	('PTPRG', 'Gene', '5793', (65, 70))	('mutations', 'Var', (101, 110))	('leukemia', 'Phenotype', 'HP:0001909', (41, 49))	('acute lymphoblastic leukemia', 'Disease', (21, 49))	('Ras', 'Gene', (97, 100))	('acute lymphoblastic leukemia', 'Disease', 'MESH:D054198', (21, 49))	('PTPRG', 'Gene', (65, 70))	('induced', 'Reg', (86, 93))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (27, 49))
148228	25322863	Promoter hypermethylation is also the primary mechanism of PTPRO dysregulation.	('PTPRO', 'Gene', (59, 64))	('PTPRO', 'Gene', '5800', (59, 64))	('Promoter hypermethylation', 'Var', (0, 25))
148229	25322863	PTPRO hypermethylation has been reported in hepatocellular carcinoma, colon cancer, lung cancer, and chronic lymphocytic leukemia.	('lung cancer', 'Phenotype', 'HP:0100526', (84, 95))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (44, 68))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('colon cancer', 'Disease', (70, 82))	('PTPRO', 'Gene', (0, 5))	('reported', 'Reg', (32, 40))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (44, 68))	('PTPRO', 'Gene', '5800', (0, 5))	('lung cancer', 'Disease', (84, 95))	('hypermethylation', 'Var', (6, 22))	('chronic lymphocytic leukemia', 'Disease', 'MESH:D015451', (101, 129))	('hepatocellular carcinoma', 'Disease', (44, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (59, 68))	('colon cancer', 'Phenotype', 'HP:0003003', (70, 82))	('chronic lymphocytic leukemia', 'Disease', (101, 129))	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (101, 129))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('leukemia', 'Phenotype', 'HP:0001909', (121, 129))	('lung cancer', 'Disease', 'MESH:D008175', (84, 95))	('colon cancer', 'Disease', 'MESH:D015179', (70, 82))
148232	25322863	A study of breast cancer showed that PTPRO methylation was associated with lymph node involvement (P = 0.014), poorly differentiated histology (P = 0.037), depth of invasion (P = 0.004), and HER2 amplification (P = 0.001).	('PTPRO', 'Gene', (37, 42))	('HER2', 'Gene', (191, 195))	('HER2', 'Gene', '2064', (191, 195))	('breast cancer', 'Disease', 'MESH:D001943', (11, 24))	('lymph node involvement', 'CPA', (75, 97))	('depth of invasion', 'CPA', (156, 173))	('associated', 'Reg', (59, 69))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('breast cancer', 'Disease', (11, 24))	('breast cancer', 'Phenotype', 'HP:0003002', (11, 24))	('poorly differentiated histology', 'CPA', (111, 142))	('amplification', 'Var', (196, 209))	('PTPRO', 'Gene', '5800', (37, 42))
148233	25322863	PTPRO methylation was detected in 54% (53 of 98) of breast tumors and 34% (33 of 98) of matched peripheral blood samples from patients with breast cancer but in none of the normal peripheral blood samples from 30 healthy individuals.	('breast cancer', 'Disease', 'MESH:D001943', (140, 153))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('breast cancer', 'Disease', (140, 153))	('breast tumors', 'Disease', 'MESH:D001943', (52, 65))	('breast cancer', 'Phenotype', 'HP:0003002', (140, 153))	('breast tumors', 'Phenotype', 'HP:0100013', (52, 65))	('PTPRO', 'Gene', (0, 5))	('PTPRO', 'Gene', '5800', (0, 5))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('methylation', 'Var', (6, 17))	('patients', 'Species', '9606', (126, 134))	('breast tumor', 'Phenotype', 'HP:0100013', (52, 64))	('detected', 'Reg', (22, 30))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('breast tumors', 'Disease', (52, 65))
148236	25322863	In particular, PTPRD was found to be methylated in CRC, breast cancer, HNSCC, and GBM.	('methylated', 'Var', (37, 47))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('breast cancer', 'Disease', 'MESH:D001943', (56, 69))	('HNSCC', 'Disease', (71, 76))	('breast cancer', 'Phenotype', 'HP:0003002', (56, 69))	('breast cancer', 'Disease', (56, 69))	('CRC', 'Disease', (51, 54))	('PTPRD', 'Gene', '5789', (15, 20))	('GBM', 'Disease', (82, 85))	('PTPRD', 'Gene', (15, 20))
148237	25322863	PTPRF hypermethylation is associated with phenobarbital-induced liver tumorigenesis, whereas PTPRJ hypermethylation was induced by microduplications in 2 patients with early-onset CRC.	('phenobarbital-induced liver', 'Disease', (42, 69))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('hypermethylation', 'Var', (6, 22))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('PTPRJ', 'Gene', (93, 98))	('PTPRF', 'Gene', (0, 5))	('tumor', 'Disease', (70, 75))	('liver', 'Disease', (64, 69))	('patients', 'Species', '9606', (154, 162))	('phenobarbital', 'Chemical', 'MESH:D010634', (42, 55))	('PTPRJ', 'Gene', '5795', (93, 98))	('associated', 'Reg', (26, 36))
148240	25322863	PTPRC has the highest proportion of copy number amplifications among the PTPR genes, based on data for all cancers in the TCGA database.	('PTPR', 'Gene', (73, 77))	('cancers', 'Disease', (107, 114))	('cancers', 'Disease', 'MESH:D009369', (107, 114))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('copy number amplifications', 'Var', (36, 62))	('PTPRC', 'Gene', '5788', (0, 5))	('cancers', 'Phenotype', 'HP:0002664', (107, 114))	('PTPRC', 'Gene', (0, 5))
148243	25322863	Furthermore, in samples in the TCGA repository, melanomas, lung adenocarcinomas, and sarcomas with PTPRR copy number amplifications have higher PTPRR mRNA levels than samples without copy number amplifications (Figure 2).	('PTPRR', 'Gene', (144, 149))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))	('sarcomas', 'Phenotype', 'HP:0100242', (85, 93))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (59, 79))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (59, 79))	('sarcomas', 'Disease', (85, 93))	('melanoma', 'Phenotype', 'HP:0002861', (48, 56))	('copy number amplifications', 'Var', (105, 131))	('higher', 'PosReg', (137, 143))	('PTPRR', 'Gene', '5801', (99, 104))	('PTPRR', 'Gene', '5801', (144, 149))	('melanomas', 'Disease', (48, 57))	('sarcoma', 'Phenotype', 'HP:0100242', (85, 92))	('melanomas', 'Phenotype', 'HP:0002861', (48, 57))	('PTPRR', 'Gene', (99, 104))	('lung adenocarcinomas', 'Disease', (59, 79))	('sarcomas', 'Disease', 'MESH:D012509', (85, 93))	('melanomas', 'Disease', 'MESH:D008545', (48, 57))
148246	25322863	In their study, PTPRA copy number gain was detected in 5 of 13 primary gastric tumors and 3 of 7 gastric cell lines, and PTPRA overexpression was associated with copy number gain.	('copy number gain', 'Var', (162, 178))	('copy number', 'Var', (22, 33))	('gain', 'PosReg', (34, 38))	('PTPRA', 'Gene', (121, 126))	('gastric tumors', 'Phenotype', 'HP:0006753', (71, 85))	('PTPRA', 'Gene', '5786', (121, 126))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('PTPRA', 'Gene', (16, 21))	('PTPRA', 'Gene', '5786', (16, 21))	('gastric tumors', 'Disease', (71, 85))	('gastric tumors', 'Disease', 'MESH:D013274', (71, 85))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
148250	25322863	PTPRF amplification was reported in a small cell lung cancer cell line and has also been observed in liver cancer.	('small cell lung cancer', 'Phenotype', 'HP:0030357', (38, 60))	('small cell lung cancer', 'Disease', (38, 60))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('PTPRF', 'Gene', (0, 5))	('liver cancer', 'Phenotype', 'HP:0002896', (101, 113))	('liver cancer', 'Disease', 'MESH:D006528', (101, 113))	('lung cancer', 'Phenotype', 'HP:0100526', (49, 60))	('amplification', 'Var', (6, 19))	('small cell lung cancer', 'Disease', 'MESH:D055752', (38, 60))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('liver cancer', 'Disease', (101, 113))
148255	25322863	Thus, dysregulation of PTPRs leads to signaling alterations.	('dysregulation', 'Var', (6, 19))	('PTPRs', 'Gene', (23, 28))	('PTPRs', 'Gene', '5802', (23, 28))	('signaling alterations', 'MPA', (38, 59))
148258	25322863	In estrogen-receptor-negative breast cancer cell lines as well as colon cancer cell lines, siRNA-mediated knockdown of PTPRA reduced Src activity and induced apoptosis.	('estrogen-receptor', 'Gene', (3, 20))	('colon cancer', 'Disease', (66, 78))	('PTPRA', 'Gene', '5786', (119, 124))	('breast cancer', 'Disease', 'MESH:D001943', (30, 43))	('Src', 'Gene', (133, 136))	('Src', 'Gene', '6714', (133, 136))	('induced', 'Reg', (150, 157))	('breast cancer', 'Phenotype', 'HP:0003002', (30, 43))	('breast cancer', 'Disease', (30, 43))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('apoptosis', 'CPA', (158, 167))	('reduced', 'NegReg', (125, 132))	('knockdown', 'Var', (106, 115))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('colon cancer', 'Phenotype', 'HP:0003003', (66, 78))	('colon cancer', 'Disease', 'MESH:D015179', (66, 78))	('PTPRA', 'Gene', (119, 124))	('estrogen-receptor', 'Gene', '2099', (3, 20))
148259	25322863	found that inhibition of PTPRA reduced the growth of HER2-positive breast cancer cells and decreased Akt phosphorylation.	('Akt', 'Gene', '207', (101, 104))	('growth', 'MPA', (43, 49))	('breast cancer', 'Phenotype', 'HP:0003002', (67, 80))	('reduced', 'NegReg', (31, 38))	('PTPRA', 'Gene', (25, 30))	('Akt', 'Gene', (101, 104))	('PTPRA', 'Gene', '5786', (25, 30))	('HER2', 'Gene', (53, 57))	('HER2', 'Gene', '2064', (53, 57))	('inhibition', 'Var', (11, 21))	('breast cancer', 'Disease', 'MESH:D001943', (67, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('decreased', 'NegReg', (91, 100))	('breast cancer', 'Disease', (67, 80))
148268	25322863	A study of PTPRG's role as a tumor suppressor revealed that PTPRG inhibited breast tumor formation in vivo and that PTPRG up-regulated p21cip and p27kip proteins through the ERK1/2 pathway in a breast cancer cell model.	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('tumor', 'Disease', (83, 88))	('PTPRG', 'Gene', (60, 65))	('breast tumor', 'Disease', (76, 88))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('PTPRG', 'Gene', (11, 16))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('PTPRG', 'Gene', '5793', (60, 65))	('PTPRG', 'Gene', '5793', (11, 16))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('inhibited', 'NegReg', (66, 75))	('ERK1/2', 'Gene', (174, 180))	('ERK1/2', 'Gene', '5595;5594', (174, 180))	('breast cancer', 'Phenotype', 'HP:0003002', (194, 207))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('p21cip', 'Var', (135, 141))	('breast cancer', 'Disease', 'MESH:D001943', (194, 207))	('up-regulated', 'PosReg', (122, 134))	('breast cancer', 'Disease', (194, 207))	('p27kip', 'Var', (146, 152))	('breast tumor', 'Disease', 'MESH:D001943', (76, 88))	('PTPRG', 'Gene', (116, 121))	('tumor', 'Disease', (29, 34))	('breast tumor', 'Phenotype', 'HP:0100013', (76, 88))	('PTPRG', 'Gene', '5793', (116, 121))
148276	25322863	Namely, after phosphorylation at Y1311 and Y1320 in a Src- and Fyn-dependent manner, PTPRJ then dephosphorylated the Y529 inhibitory site of Src, activated it, and caused vascular endothelial growth factor (VEGF)-induced phosphorylation of vascular endothelial (VE)-cadherin and cortactin.	('Fyn', 'Gene', '2534', (63, 66))	('Src', 'Gene', (141, 144))	('activated', 'PosReg', (146, 155))	('Src', 'Gene', (54, 57))	('PTPRJ', 'Gene', (85, 90))	('Y1311', 'Var', (33, 38))	('cortactin', 'Gene', (279, 288))	('vascular endothelial growth factor', 'Gene', '7422', (171, 205))	('Y1320', 'Var', (43, 48))	('PTPRJ', 'Gene', '5795', (85, 90))	('Src', 'Gene', '6714', (141, 144))	('VEGF', 'Gene', '7422', (207, 211))	('phosphorylation', 'MPA', (221, 236))	('vascular endothelial growth factor', 'Gene', (171, 205))	('VEGF', 'Gene', (207, 211))	('Src', 'Gene', '6714', (54, 57))	('cortactin', 'Gene', '2017', (279, 288))	('Fyn', 'Gene', (63, 66))	('caused', 'PosReg', (164, 170))	('vascular endothelial (VE)-cadherin', 'Gene', '1003', (240, 274))	('Y529', 'Var', (117, 121))
148279	25322863	Two PTPRs regulate STAT3 phosphorylation at Y705.	('PTPRs', 'Gene', (4, 9))	('STAT3', 'Gene', '6774', (19, 24))	('STAT3', 'Gene', (19, 24))	('regulate', 'Reg', (10, 18))	('Y705', 'Var', (44, 48))	('PTPRs', 'Gene', '5802', (4, 9))
148280	25322863	When mutated, deleted, or hypermethylated in cancer, PTPRT and PTPRD drive hyperactivation of STAT3, which is accompanied by cell proliferation and, likely, migration in multiple cancers.	('STAT3', 'Gene', '6774', (94, 99))	('PTPRT', 'Gene', (53, 58))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('multiple cancers', 'Disease', (170, 186))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('PTPRD', 'Gene', '5789', (63, 68))	('hypermethylated', 'Var', (26, 41))	('PTPRD', 'Gene', (63, 68))	('STAT3', 'Gene', (94, 99))	('multiple cancers', 'Disease', 'MESH:D009369', (170, 186))	('hyperactivation', 'PosReg', (75, 90))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('mutated', 'Var', (5, 12))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('cancers', 'Phenotype', 'HP:0002664', (179, 186))	('cancer', 'Disease', (45, 51))	('cancer', 'Disease', (179, 185))	('PTPRT', 'Gene', '11122', (53, 58))
148281	25322863	PTPRA is reported to interact with focal adhesion kinase (FAK) at Y407 in breast cancer.	('breast cancer', 'Disease', (74, 87))	('at Y407', 'Var', (63, 70))	('focal adhesion kinase', 'Gene', '5747', (35, 56))	('interact', 'Reg', (21, 29))	('FAK', 'Gene', (58, 61))	('FAK', 'Gene', '5747', (58, 61))	('focal adhesion kinase', 'Gene', (35, 56))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('breast cancer', 'Disease', 'MESH:D001943', (74, 87))	('PTPRA', 'Gene', (0, 5))	('breast cancer', 'Phenotype', 'HP:0003002', (74, 87))	('PTPRA', 'Gene', '5786', (0, 5))
148298	25322863	Recurrence-free survival was worse for patients with the signature compared with those without.	('worse', 'NegReg', (29, 34))	('Recurrence-free survival', 'CPA', (0, 24))	('patients', 'Species', '9606', (39, 47))	('signature', 'Var', (57, 66))
148303	25322863	also discovered a PTPRJ agonist peptide, PTPRJ-pep19.4, and determined that the peptide inhibited in vitro tube formation, ERK1/2 phosphorylation, and proliferation in breast cancer cells but had no effect on primary normal human mammary endothelial cells.	('phosphorylation', 'MPA', (130, 145))	('inhibited', 'NegReg', (88, 97))	('PTPRJ', 'Gene', (18, 23))	('PTPRJ', 'Gene', (41, 46))	('PTPRJ', 'Gene', '5795', (41, 46))	('ERK1/2', 'Gene', '5595;5594', (123, 129))	('breast cancer', 'Disease', 'MESH:D001943', (168, 181))	('proliferation', 'CPA', (151, 164))	('tube formation', 'CPA', (107, 121))	('breast cancer', 'Disease', (168, 181))	('breast cancer', 'Phenotype', 'HP:0003002', (168, 181))	('human', 'Species', '9606', (224, 229))	('peptide', 'Var', (80, 87))	('PTPRJ', 'Gene', '5795', (18, 23))	('ERK1/2', 'Gene', (123, 129))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
148307	25322863	Alterations of these phosphatases, whether by mutation, deletion, amplification, or promoter methylation, are reported to cause aberrations in crucial cellular pathways related to proliferation, apoptosis, survival, migration, and invasion, suggesting these PTPRs are critical components in carcinogenesis.	('deletion', 'Var', (56, 64))	('amplification', 'Var', (66, 79))	('invasion', 'CPA', (231, 239))	('carcinogenesis', 'Disease', 'MESH:D063646', (291, 305))	('cause', 'Reg', (122, 127))	('phosphatases', 'Enzyme', (21, 33))	('Alterations', 'Var', (0, 11))	('PTPRs', 'Gene', (258, 263))	('carcinogenesis', 'Disease', (291, 305))	('survival', 'CPA', (206, 214))	('apoptosis', 'CPA', (195, 204))	('proliferation', 'CPA', (180, 193))	('promoter methylation', 'Var', (84, 104))	('migration', 'CPA', (216, 225))	('mutation', 'Var', (46, 54))	('PTPRs', 'Gene', '5802', (258, 263))
148332	24472378	Exposure to hardwood dust, leather dust, flour milling, polycyclic aromatic hydrocarbons (PAH), and asbestos are known to be associated with adenocarcinoma.	('polycyclic aromatic', 'Var', (56, 75))	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('PAH', 'Chemical', 'MESH:D011084', (90, 93))	('associated', 'Reg', (125, 135))	('adenocarcinoma', 'Disease', (141, 155))	('adenocarcinoma', 'Disease', 'MESH:D000230', (141, 155))	('polycyclic aromatic hydrocarbons', 'Chemical', 'MESH:D011084', (56, 88))
148389	24472378	The maximum level of each hazardous compound detected was as follows: during the painting process at Workplace 1: 0.0013 mg/m3 hexavalent chromium, 0.0047 mg/m3 nickel (insoluble inorganic compounds), and 0.3244 ppm formaldehyde; during the painting process at Workplace 2: 0.0006 mg/m3 lead chromate, 0.0001 mg/m3 nickel (insoluble inorganic compounds), and 0.1069 ppm formaldehyde.	('nickel', 'Chemical', 'MESH:D009532', (161, 167))	('tin', 'Chemical', 'MESH:D014001', (245, 248))	('0.0047', 'Var', (148, 154))	('formaldehyde', 'Chemical', 'MESH:D005557', (370, 382))	('0.0006 mg/m3', 'Var', (274, 286))	('chromate', 'Chemical', 'MESH:D002840', (292, 300))	('formaldehyde', 'Chemical', 'MESH:D005557', (216, 228))	('tin', 'Chemical', 'MESH:D014001', (85, 88))	('hexavalent', 'MPA', (127, 137))	('0.0001 mg/m3', 'Var', (302, 314))	('0.1069 ppm', 'Var', (359, 369))	('0.3244 ppm', 'Var', (205, 215))	('chromium', 'Chemical', 'MESH:D002857', (138, 146))	('formaldehyde', 'MPA', (370, 382))	('nickel', 'Chemical', 'MESH:D009532', (315, 321))
148419	24472378	A low level of chromium is an essential mineral for the human body, but it has been reported that high-dose exposure to hexavalent chromium can lead to respiratory or paranasal sinus cancers.	('chromium', 'Chemical', 'MESH:D002857', (131, 139))	('chromium', 'Chemical', 'MESH:D002857', (15, 23))	('paranasal sinus cancer', 'Phenotype', 'HP:0030072', (167, 189))	('human', 'Species', '9606', (56, 61))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('lead to', 'Reg', (144, 151))	('respiratory or paranasal sinus cancers', 'Disease', (152, 190))	('respiratory or paranasal sinus cancers', 'Disease', 'MESH:D010255', (152, 190))	('hexavalent chromium', 'Var', (120, 139))	('cancers', 'Phenotype', 'HP:0002664', (183, 190))
148422	24472378	One study reported that microsatellite instability due to DNA mismatch repair system alterations was higher in the chromium-exposed group than in the non-exposed group.	('chromium', 'Chemical', 'MESH:D002857', (115, 123))	('higher', 'PosReg', (101, 107))	('DNA mismatch repair system', 'Gene', (58, 84))	('alterations', 'Var', (85, 96))	('microsatellite instability', 'MPA', (24, 50))
148429	24472378	In mammalian nasal cavity tissue, formaldehyde exposure has been observed to cause an increase in DNA adducts, DNA-protein cross-links, DNA-DNA cross-links, and DNA single-strand breaks.	('increase', 'PosReg', (86, 94))	('cross-links', 'MPA', (123, 134))	('DNA adducts', 'MPA', (98, 109))	('formaldehyde', 'Chemical', 'MESH:D005557', (34, 46))	('single-strand breaks', 'Var', (165, 185))	('cross-links', 'Interaction', (144, 155))	('mammalian', 'Species', '9606', (3, 12))
148476	33371795	AL121839.2 and LINC02147 interacted with has-miR-1246.	('LINC02147', 'Chemical', '-', (15, 24))	('AL121839', 'Chemical', '-', (0, 8))	('miR-1246', 'Gene', '100302142', (45, 53))	('LINC02147', 'Var', (15, 24))	('interacted', 'Reg', (25, 35))	('AL121839.2', 'Var', (0, 10))	('miR-1246', 'Gene', (45, 53))
148478	33371795	Based on the TCGA and external datasets (GSE127165 and GSE133632), DGCR5 and AC004943.2 were significantly up-regulated while AL121839.2 and LINC02147, has-miR-338-3p, has-miR-139-5p and has-miR-582-5p were significantly down-regulated, which were consistent with our integration analysis.	('GSE127165', 'Var', (41, 50))	('up-regulated', 'PosReg', (107, 119))	('AC004943.2', 'Gene', (77, 87))	('miR-139', 'Gene', (172, 179))	('AL121839.2', 'Var', (126, 136))	('AL121839', 'Chemical', '-', (126, 134))	('DGCR5', 'Gene', (67, 72))	('LINC02147', 'Var', (141, 150))	('miR-582', 'Gene', (191, 198))	('miR-139', 'Gene', '406931', (172, 179))	('miR-582', 'Gene', '693167', (191, 198))	('down-regulated', 'NegReg', (221, 235))	('has-miR-338-3p', 'Var', (152, 166))	('LINC02147', 'Chemical', '-', (141, 150))	('DGCR5', 'Gene', '26220', (67, 72))
148479	33371795	DGCR5, AL121839.2, LINC02147, AC004943.2, has-miR-338-3p, has-miR-139-5p and has-miR-582-5p could predict the occurrence of LSCC.	('LINC02147', 'Chemical', '-', (19, 28))	('DGCR5', 'Gene', '26220', (0, 5))	('miR-139', 'Gene', (62, 69))	('has-miR-338-3p', 'Var', (42, 56))	('miR-139', 'Gene', '406931', (62, 69))	('AL121839', 'Chemical', '-', (7, 15))	('AL121839.2', 'Var', (7, 17))	('LSCC', 'Disease', (124, 128))	('DGCR5', 'Gene', (0, 5))	('predict', 'Reg', (98, 105))	('miR-582', 'Gene', (81, 88))	('miR-582', 'Gene', '693167', (81, 88))
148480	33371795	Survival analysis suggested that only, AL121839.2 has potential prognostic value for LSCC.	('AL121839', 'Chemical', '-', (39, 47))	('AL121839.2', 'Var', (39, 49))	('LSCC', 'Disease', (85, 89))
148498	33371795	Subsequently, a DElncRNAs in the cytoplasm-DEmiRNAs-DEmRNAs network was built, including 3 lncRNAs (HMGA2-AS1, AC004943.2 and AC079328.2), 2 down-regulated lncRNAs (AL121839.2 and LINC02147), up-regulated has-miR-1246, 3 down-regulated miRNAs (has-miR-582-5p, has-miR-3137 and has-miR-3185), 404 up-regulated mRNAs and 59 down-regulated mRNAs (Figure 4).	('miR-3137', 'Gene', (264, 272))	('AS1', 'Gene', '5729', (106, 109))	('miR-3185', 'Gene', '100422978', (281, 289))	('miR-1246', 'Gene', (209, 217))	('down-regulated', 'NegReg', (141, 155))	('down-regulated', 'NegReg', (221, 235))	('down-regulated', 'NegReg', (322, 336))	('HMGA2', 'Gene', (100, 105))	('mRNAs', 'MPA', (309, 314))	('miR-3185', 'Gene', (281, 289))	('LINC02147', 'Var', (180, 189))	('miR-582', 'Gene', '693167', (248, 255))	('AS1', 'Gene', (106, 109))	('AL121839.2', 'Var', (165, 175))	('miR-3137', 'Gene', '100422926', (264, 272))	('up-regulated', 'PosReg', (192, 204))	('AL121839', 'Chemical', '-', (165, 173))	('up-regulated', 'PosReg', (296, 308))	('miR-1246', 'Gene', '100302142', (209, 217))	('miR-582', 'Gene', (248, 255))	('HMGA2', 'Gene', '8091', (100, 105))	('LINC02147', 'Chemical', '-', (180, 189))
148499	33371795	Moreover, AL121839.2 and LINC021147 were interacted with has-miR-1246.	('miR-1246', 'Gene', '100302142', (61, 69))	('LINC021147', 'Var', (25, 35))	('LINC021147', 'Chemical', '-', (25, 35))	('AL121839', 'Chemical', '-', (10, 18))	('miR-1246', 'Gene', (61, 69))	('interacted', 'Reg', (41, 51))	('AL121839.2', 'Var', (10, 20))
148501	33371795	The expression of 4 DElncRNAs (DGCR5, AL121839.2, LINC02147 and AC004943.2) and 3 DEmiRNAs (has-miR-338-3p, has-miR-139-5p and has-miR-582-5p) were verified in TCGA dataset.	('DGCR5', 'Gene', (31, 36))	('AC004943.2', 'Var', (64, 74))	('miR-139', 'Gene', '406931', (112, 119))	('AL121839', 'Chemical', '-', (38, 46))	('DGCR5', 'Gene', '26220', (31, 36))	('AL121839.2', 'Var', (38, 48))	('miR-582', 'Gene', (131, 138))	('miR-582', 'Gene', '693167', (131, 138))	('has-miR-338-3p', 'Var', (92, 106))	('LINC02147', 'Chemical', '-', (50, 59))	('miR-139', 'Gene', (112, 119))
148502	33371795	Two DElncRNAs (AL121839.2 and LINC02147) and 3 DEmiRNAs (has-miR-338-3p, has-miR-139-5p and has-miR-582-5p) were down-regulated while 2 DElncRNAs (DGCR5 and AC004943.2) were up-regulated in LSCC, suggesting that our results were convincing.	('down-regulated', 'NegReg', (113, 127))	('miR-582', 'Gene', '693167', (96, 103))	('miR-139', 'Gene', '406931', (77, 84))	('LINC02147', 'Chemical', '-', (30, 39))	('miR-582', 'Gene', (96, 103))	('DGCR5', 'Gene', '26220', (147, 152))	('DGCR5', 'Gene', (147, 152))	('up-regulated', 'PosReg', (174, 186))	('miR-139', 'Gene', (77, 84))	('AL121839', 'Chemical', '-', (15, 23))	('AL121839.2', 'Var', (15, 25))	('has-miR-338-3p', 'Var', (57, 71))
148503	33371795	We evaluated the diagnostic value of 4 DElncRNAs (DGCR5, AL121839.2, LINC02147 and AC004943.2) and 3 DEmiRNAs (has-miR-338-3p, has-miR-139-5p and has-miR-582-5p) in LSCC.	('miR-139', 'Gene', '406931', (131, 138))	('DGCR5', 'Gene', '26220', (50, 55))	('LSCC', 'Disease', (165, 169))	('DGCR5', 'Gene', (50, 55))	('has-miR-338-3p', 'Var', (111, 125))	('LINC02147', 'Chemical', '-', (69, 78))	('miR-139', 'Gene', (131, 138))	('miR-582', 'Gene', (150, 157))	('miR-582', 'Gene', '693167', (150, 157))	('AL121839', 'Chemical', '-', (57, 65))
148504	33371795	DGCR5 (AUC = 0.765), AL121839.2 (AUC = 0.837), LINC02147 (AUC = 0.890), AC004943.2 (AUC = 0.773), has-miR-338-3p (AUC = 0.789), has-miR-139-5p (AUC = 0.945) and has-miR-582-5p (AUC = 0.724) were capable of discriminating LSCC and normal controls (Figure 6).	('miR-582', 'Gene', '693167', (165, 172))	('DGCR5', 'Gene', '26220', (0, 5))	('AL121839', 'Chemical', '-', (21, 29))	('AC004943.2', 'Var', (72, 82))	('miR-582', 'Gene', (165, 172))	('LINC02147', 'Chemical', '-', (47, 56))	('AL121839.2', 'Var', (21, 31))	('miR-139', 'Gene', (132, 139))	('DGCR5', 'Gene', (0, 5))	('LSCC', 'Disease', (221, 225))	('miR-139', 'Gene', '406931', (132, 139))	('has-miR-338-3p', 'Var', (98, 112))	('LINC02147', 'Var', (47, 56))
148505	33371795	Among which, only AL121839.2 was associated with the survival of patients with LSCC.	('LSCC', 'Disease', (79, 83))	('AL121839', 'Chemical', '-', (18, 26))	('associated', 'Reg', (33, 43))	('patients', 'Species', '9606', (65, 73))	('AL121839.2', 'Var', (18, 28))
148506	33371795	Four key DElncRNAs (DGCR5, AL121839.2, LINC02147 and AC004943.2) were selected to verify in GSE127165.	('LINC02147', 'Chemical', '-', (39, 48))	('DGCR5', 'Gene', '26220', (20, 25))	('AL121839', 'Chemical', '-', (27, 35))	('AL121839.2', 'Var', (27, 37))	('DGCR5', 'Gene', (20, 25))
148507	33371795	Three key DEmiRNAs (has-miR-338-3p, has-miR-139-5p and has-miR-582-5p) were selected to verify in GSE133632.	('miR-139', 'Gene', '406931', (40, 47))	('miR-582', 'Gene', (59, 66))	('miR-582', 'Gene', '693167', (59, 66))	('has-miR-338-3p', 'Var', (20, 34))	('miR-139', 'Gene', (40, 47))
148508	33371795	The gene differential expression analysis found that DGCR5 and AC004943.2 were significantly up-regulated while AL121839.2 and LINC02147, has-miR-338-3p, has-miR-139-5p and has-miR-582-5p were significantly down-regulated, which were consistent with our integration analysis (Figure S10).	('miR-139', 'Gene', (158, 165))	('AL121839.2', 'Var', (112, 122))	('up-regulated', 'PosReg', (93, 105))	('AL121839', 'Chemical', '-', (112, 120))	('LINC02147', 'Var', (127, 136))	('miR-139', 'Gene', '406931', (158, 165))	('AC004943.2', 'Var', (63, 73))	('DGCR5', 'Gene', (53, 58))	('LINC02147', 'Chemical', '-', (127, 136))	('has-miR-338-3p', 'Var', (138, 152))	('miR-582', 'Gene', '693167', (177, 184))	('miR-582', 'Gene', (177, 184))	('DGCR5', 'Gene', '26220', (53, 58))	('down-regulated', 'NegReg', (207, 221))
148509	33371795	The ROC results displayed that DGCR5 (AUC = 0.721), AL121839.2 (AUC = 0.936), LINC02147 (AUC = 0.948), AC004943.2 (AUC = 0.729), has-miR-338-3p (AUC = 0.704), has-miR-139-5p (AUC = 0.921) and has-miR-582-5p (AUC = 0.825) were capable of discriminating LSCC and normal controls (Figure S11).	('DGCR5', 'Gene', (31, 36))	('miR-582', 'Gene', (196, 203))	('has-miR-338-3p', 'Var', (129, 143))	('LSCC', 'Disease', (252, 256))	('LINC02147', 'Chemical', '-', (78, 87))	('miR-582', 'Gene', '693167', (196, 203))	('AC004943.2', 'Var', (103, 113))	('miR-139', 'Gene', (163, 170))	('DGCR5', 'Gene', '26220', (31, 36))	('AL121839', 'Chemical', '-', (52, 60))	('LINC02147', 'Var', (78, 87))	('AL121839.2', 'Var', (52, 62))	('miR-139', 'Gene', '406931', (163, 170))
148518	33371795	Besides, they highlight that silencing lncRNA DCGR5 increases the radiosensitivity of human laryngeal carcinoma cells via targeting downstream miR-195.	('miR-195', 'Gene', (143, 150))	('miR-195', 'Gene', '406971', (143, 150))	('radiosensitivity of', 'CPA', (66, 85))	('silencing', 'Var', (29, 38))	('increases', 'PosReg', (52, 61))	('targeting', 'Reg', (122, 131))	('carcinoma', 'Disease', 'MESH:D009369', (102, 111))	('human', 'Species', '9606', (86, 91))	('laryngeal carcinoma', 'Phenotype', 'HP:0012118', (92, 111))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('DCGR5', 'Gene', (46, 51))	('lncRNA', 'Protein', (39, 45))	('carcinoma', 'Disease', (102, 111))
148519	33371795	Later, this research group investigates the relationship between lncRNA DCGR5 and cancer stem cells (CSC)-like properties of human LSCC lines, and finds that lncRNA DCGR5 can induce CSC-like properties by regulating miR-506 and Wnt signaling pathway in radioresistant laryngeal carcinoma cells.	('induce', 'PosReg', (175, 181))	('lncRNA DCGR5', 'Var', (158, 170))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('laryngeal carcinoma', 'Phenotype', 'HP:0012118', (268, 287))	('carcinoma', 'Disease', (278, 287))	('human', 'Species', '9606', (125, 130))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('CSC-like properties', 'CPA', (182, 201))	('miR-506', 'Gene', '574511', (216, 223))	('miR-506', 'Gene', (216, 223))	('Wnt signaling pathway', 'Pathway', (228, 249))	('carcinoma', 'Disease', 'MESH:D009369', (278, 287))	('carcinoma', 'Phenotype', 'HP:0030731', (278, 287))	('regulating', 'Reg', (205, 215))
148520	33371795	Previous studies have demonstrated that has-miR-338-3p is down-regulated in many cancers, such as colorectal cancer cells, breast cancer and gastric cancer, which is similar to our result.	('colorectal cancer', 'Disease', (98, 115))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('has-miR-338-3p', 'Var', (40, 54))	('breast cancer', 'Disease', 'MESH:D001943', (123, 136))	('down-regulated', 'NegReg', (58, 72))	('gastric cancer', 'Phenotype', 'HP:0012126', (141, 155))	('cancers', 'Phenotype', 'HP:0002664', (81, 88))	('breast cancer', 'Disease', (123, 136))	('cancers', 'Disease', (81, 88))	('colorectal cancer', 'Disease', 'MESH:D015179', (98, 115))	('cancers', 'Disease', 'MESH:D009369', (81, 88))	('breast cancer', 'Phenotype', 'HP:0003002', (123, 136))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('colorectal cancer', 'Phenotype', 'HP:0003003', (98, 115))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('gastric cancer', 'Disease', (141, 155))	('gastric cancer', 'Disease', 'MESH:D013274', (141, 155))
148527	33371795	We found that AL121839.2 and LINC02147 were closely interacted with down-regulated has-miR-1246.	('LINC02147', 'Chemical', '-', (29, 38))	('down-regulated', 'NegReg', (68, 82))	('AL121839', 'Chemical', '-', (14, 22))	('LINC02147', 'Var', (29, 38))	('miR-1246', 'Gene', '100302142', (87, 95))	('miR-1246', 'Gene', (87, 95))	('AL121839.2', 'Var', (14, 24))
148530	33371795	Besides, they highlight that lack of miR-1246 in Small extracellular vesicle can abrogate the tumorigenesis of LSCC.	('lack', 'Var', (29, 33))	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('miR-1246', 'Gene', '100302142', (37, 45))	('miR-1246', 'Gene', (37, 45))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('abrogate', 'NegReg', (81, 89))	('tumor', 'Disease', (94, 99))	('LSCC', 'Disease', (111, 115))
148533	33371795	Additionally, 5 cytoplasmic lncRNAs (AL121839.2, LINC021147, AC004943.2, AC079328.2 and HMGA2-AS1) may act as ceRNAs and involve in the pathogenesis of LSCC.	('HMGA2', 'Gene', '8091', (88, 93))	('AL121839.2', 'Var', (37, 47))	('AS1', 'Gene', (94, 97))	('HMGA2', 'Gene', (88, 93))	('LINC021147', 'Chemical', '-', (49, 59))	('LSCC', 'Disease', (152, 156))	('AC004943.2', 'Var', (61, 71))	('AL121839', 'Chemical', '-', (37, 45))	('AS1', 'Gene', '5729', (94, 97))	('involve', 'Reg', (121, 128))
148534	33371795	DGCR5, AL121839.2, LINC02147, AC004943.2, has-miR-338-3p, has-miR-139-5p and has-miR-582-5p were capable of discriminating LSCC and normal controls.	('LSCC', 'Disease', (123, 127))	('DGCR5', 'Gene', '26220', (0, 5))	('miR-139', 'Gene', (62, 69))	('LINC02147', 'Chemical', '-', (19, 28))	('has-miR-338-3p', 'Var', (42, 56))	('miR-139', 'Gene', '406931', (62, 69))	('AL121839', 'Chemical', '-', (7, 15))	('AL121839.2', 'Var', (7, 17))	('DGCR5', 'Gene', (0, 5))	('LINC02147', 'Var', (19, 28))	('miR-582', 'Gene', (81, 88))	('miR-582', 'Gene', '693167', (81, 88))
148535	33371795	Meanwhile, AL121839.2 had potential prognostic value for LSCC.	('LSCC', 'Disease', (57, 61))	('AL121839.2', 'Var', (11, 21))	('AL121839', 'Chemical', '-', (11, 19))
148566	33114763	Therefore, it is postulated that the CCL18 gene arose from duplication and the subsequent fusion of two MIP-1alpha-like genes, hence its occurrence in primates but not in rodents.	('MIP-1alpha', 'Gene', (104, 114))	('CCL18', 'Gene', '6362', (37, 42))	('CCL18', 'Gene', (37, 42))	('duplication', 'Var', (59, 70))	('MIP-1alpha', 'Gene', '6348', (104, 114))
148573	33114763	It is a chemoattractant for CD38-IgG- mantle zone B lymphocytes and CD45RA+ naive T lymphocytes, but not for CD45RO+ memory T cells, monocytes, granulocytes, and mature DCs, although it is a chemoattractant for 3- to 4-day-old monocytes.	('CD45RO', 'Gene', '5788', (109, 115))	('CD45RO', 'Gene', (109, 115))	('CD45RA', 'Gene', (68, 74))	('CD38-IgG-', 'Var', (28, 37))	('CD45RA', 'Gene', '5788', (68, 74))
148670	33114763	Particularly, CCL18 is a target gene of miR-128, miR-205, and miR-622.	('CCL18', 'Gene', (14, 19))	('miR-128', 'Var', (40, 47))	('miR-622', 'Gene', (62, 69))	('miR-622', 'Gene', '693207', (62, 69))	('miR-205', 'Gene', (49, 56))	('miR-205', 'Gene', '406988', (49, 56))	('CCL18', 'Gene', '6362', (14, 19))
148674	33114763	Moreover, miR-181b decreases NF-kappaB expression, which interferes with the function of CCL18, as this transcription factor is important in the induction of migration and EMT by CCL18.	('NF-kappaB', 'Gene', (29, 38))	('NF-kappaB', 'Gene', '4790', (29, 38))	('miR-181b', 'Chemical', '-', (10, 18))	('miR-181b', 'Var', (10, 18))	('decreases', 'NegReg', (19, 28))	('CCL18', 'Gene', '6362', (89, 94))	('expression', 'MPA', (39, 49))	('CCL18', 'Gene', '6362', (179, 184))	('CCL18', 'Gene', (89, 94))	('CCL18', 'Gene', (179, 184))	('EMT', 'CPA', (172, 175))
148720	33114763	This acidification induces alternative activated M2 phenotype macrophages polarization and, thus, the production of CCL18 in TAMs is further increased.	('increased', 'PosReg', (141, 150))	('acidification', 'Var', (5, 18))	('TAMs', 'Chemical', '-', (125, 129))	('CCL18', 'Gene', '6362', (116, 121))	('CCL18', 'Gene', (116, 121))	('induces', 'Reg', (19, 26))
148726	33114763	For this reason, chemokines such as CCL1/I-309 (in breast cancer), CCL17/TARC, CCL22/MDC (in gastric cancer and hepatocellular carcinoma), and CCL28/MEC (in hepatocellular carcinoma) cause Treg recruitment into the tumor niche.	('TARC', 'Gene', (73, 77))	('CCL17', 'Gene', '6361', (67, 72))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('MDC', 'Gene', (85, 88))	('CCL1/I-309', 'Var', (36, 46))	('gastric cancer', 'Phenotype', 'HP:0012126', (93, 107))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('CCL22', 'Gene', (79, 84))	('cause', 'Reg', (183, 188))	('hepatocellular carcinoma', 'Disease', (112, 136))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (157, 181))	('CCL28', 'Gene', '56477', (143, 148))	('CCL22', 'Gene', '6367', (79, 84))	('CCL17', 'Gene', (67, 72))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('hepatocellular carcinoma', 'Disease', (157, 181))	('TARC', 'Gene', '6361', (73, 77))	('gastric cancer', 'Disease', (93, 107))	('CCL28', 'Gene', (143, 148))	('Treg recruitment', 'CPA', (189, 205))	('Treg', 'Chemical', '-', (189, 193))	('breast cancer', 'Phenotype', 'HP:0003002', (51, 64))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (112, 136))	('tumor', 'Disease', (215, 220))	('MEC', 'Gene', (149, 152))	('carcinoma', 'Phenotype', 'HP:0030731', (172, 181))	('gastric cancer', 'Disease', 'MESH:D013274', (93, 107))	('tumor', 'Disease', 'MESH:D009369', (215, 220))	('MDC', 'Gene', '6367', (85, 88))	('MEC', 'Gene', '56477', (149, 152))	('breast cancer', 'Disease', 'MESH:D001943', (51, 64))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (157, 181))	('breast cancer', 'Disease', (51, 64))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (112, 136))
148786	33114763	The chemokines more strongly displaced by CCL18 are CXCL14/breast and kidney chemokine (BRAK), CCL1/I-309, CCL11/Eotaxin-1, CCL19/MIP-3beta, CCL25/thymus expressed chemokine (TECK), and CCL26/Eotaxin-3.	('BRAK', 'Gene', '9547', (88, 92))	('MIP-3beta', 'Gene', (130, 139))	('CCL25/thymus expressed chemokine', 'Gene', (141, 173))	('CCL11', 'Gene', '6356', (107, 112))	('Eotaxin-1', 'Gene', '6356', (113, 122))	('CXCL14', 'Gene', (52, 58))	('TECK', 'Gene', '6370', (175, 179))	('TECK', 'Gene', (175, 179))	('CXCL14', 'Gene', '9547', (52, 58))	('BRAK', 'Gene', (88, 92))	('CCL25/thymus expressed chemokine', 'Gene', '6370', (141, 173))	('CCL26', 'Gene', '10344', (186, 191))	('CCL1/I-309', 'Var', (95, 105))	('Eotaxin-3', 'Gene', (192, 201))	('CCL19', 'Gene', '6363', (124, 129))	('CCL26', 'Gene', (186, 191))	('CCL18', 'Gene', (42, 47))	('Eotaxin-1', 'Gene', (113, 122))	('MIP-3beta', 'Gene', '6364', (130, 139))	('Eotaxin-3', 'Gene', '10344', (192, 201))	('CCL11', 'Gene', (107, 112))	('CCL19', 'Gene', (124, 129))	('CCL18', 'Gene', '6362', (42, 47))
148818	33114763	In vivo studies on NOD/SCID mice inoculated with MDA-MB-231 breast cancer cells showed that blocking CCL18 activity does not affect tumor growth or metastasis to the lungs.	('breast cancer', 'Disease', (60, 73))	('SCID', 'Disease', 'MESH:D053632', (23, 27))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('CCL18', 'Gene', '6362', (101, 106))	('SCID', 'Disease', (23, 27))	('activity', 'MPA', (107, 115))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (49, 59))	('CCL18', 'Gene', (101, 106))	('mice', 'Species', '10090', (28, 32))	('metastasis', 'CPA', (148, 158))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('tumor', 'Disease', (132, 137))	('breast cancer', 'Disease', 'MESH:D001943', (60, 73))	('breast cancer', 'Phenotype', 'HP:0003002', (60, 73))	('blocking', 'Var', (92, 100))
148845	32486001	Programmed cell death protein 1 (PD-1) and programmed cell death ligand 1 (PD-L1) are important immune checkpoint molecules, and blocking PD-1/PD-L1 reduces the tumor burden and indicate promising outcomes in many tumor types.	('blocking', 'Var', (129, 137))	('PD-L1', 'Gene', '574058', (75, 80))	('PD-1/PD-L1 reduces the tumor', 'Disease', 'MESH:D010300', (138, 166))	('tumor', 'Disease', 'MESH:D009369', (214, 219))	('PD-L1', 'Gene', (75, 80))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('programmed cell death ligand 1', 'Gene', '574058', (43, 73))	('PD-L1', 'Gene', '574058', (143, 148))	('Programmed cell death protein 1', 'Gene', (0, 31))	('PD-L1', 'Gene', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('tumor', 'Disease', (214, 219))	('PD-1/PD-L1 reduces the tumor', 'Disease', (138, 166))	('Programmed cell death protein 1', 'Gene', '100533201', (0, 31))	('tumor', 'Disease', (161, 166))	('programmed cell death ligand 1', 'Gene', (43, 73))
148848	32486001	Growing evidence points to the aberrant activity of STAT3 in cancer providing a potential therapeutic option.	('STAT3', 'Gene', (52, 57))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('cancer', 'Disease', (61, 67))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('aberrant activity', 'Var', (31, 48))
148895	32486001	Similarly, the moderate or strong correlations between STAT3 and infiltrating levels were shown, involving neutrophils (r = 0.47) and DC (r = 0.476) in COAD; B-cell (r = 0.534) and DC (r = 0.742) in KICH; neutrophils (r = 0.411) in KIRC; CD8+ T-cells (r = 0.567), macrophages (r = 0.497), neutrophils (r = 0.505) and DCs (r = 0.502) in PRAD; DCs (r = 0.463) in READ (Figure 3).	('COAD', 'Disease', 'MESH:D029424', (152, 156))	('KICH', 'Disease', (199, 203))	('r = 0.502', 'Var', (322, 331))	('KICH', 'Disease', 'None', (199, 203))	('COAD', 'Disease', (152, 156))	('CD8', 'Gene', (238, 241))	('CD8', 'Gene', '925', (238, 241))
148938	32486001	Several compounds were targeting the PI3K/AKT pathway, such as rigosertib, MK-2206, AZD6482, TGX-221, NVP-BEZ235, and targeting the JAK/STAT pathway, like ruxolitinib and AZD1480, which were significantly correlated to STAT3 expression in cancer cell lines.	('STAT', 'Gene', '6772;6774;20848;6775', (219, 223))	('rigosertib', 'Gene', (63, 73))	('targeting', 'Reg', (23, 32))	('AKT', 'Gene', (42, 45))	('AKT', 'Gene', '207', (42, 45))	('AZD6482', 'Var', (84, 91))	('AZD6482', 'Chemical', 'MESH:C578518', (84, 91))	('cancer', 'Disease', 'MESH:D009369', (239, 245))	('ruxolitinib', 'Chemical', 'MESH:C540383', (155, 166))	('AZD1480', 'Chemical', 'MESH:C545606', (171, 178))	('STAT', 'Gene', (136, 140))	('cancer', 'Disease', (239, 245))	('MK-2206', 'Var', (75, 82))	('rigosertib', 'Chemical', 'MESH:C507134', (63, 73))	('MK-2206', 'Chemical', 'MESH:C548887', (75, 82))	('STAT', 'Gene', '6772;6774;20848;6775', (136, 140))	('STAT', 'Gene', (219, 223))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))
148955	32486001	The expression level of p-STAT3 could reflect the activity in cancer progression better than total STAT3 protein expression.	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('expression', 'MPA', (4, 14))	('p-STAT3', 'Var', (24, 31))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))
149001	32486001	Based on the above findings, we made the conclusion that STAT3 was particularly correlated with immune suppression in the tumor microenvironment.	('correlated', 'Reg', (80, 90))	('immune suppression', 'CPA', (96, 114))	('STAT3', 'Var', (57, 62))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumor', 'Disease', (122, 127))
149057	29527332	Within the subset of patients with oropharyngeal primary tumors, p16 positivity conferred a survival advantage with 2-year overall survivals of 65% and 20% for p16-positive and p16-negative disease, respectively (p < 0.05) (Fig.	('p16', 'Gene', (160, 163))	('p16', 'Gene', '1029', (65, 68))	('p16', 'Gene', '1029', (177, 180))	('positivity', 'Var', (69, 79))	('patients', 'Species', '9606', (21, 29))	('p16', 'Gene', '1029', (160, 163))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('p16', 'Gene', (65, 68))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('tumors', 'Disease', (57, 63))	('advantage', 'PosReg', (101, 110))	('p16', 'Gene', (177, 180))	('tumors', 'Disease', 'MESH:D009369', (57, 63))
149128	29285191	In lung cancer, the CIZ1 b-variant is specifically overexpressed in non-small cell lung cancer samples compared with adjacent tissues or small cell lung cancer samples.	('small cell lung cancer', 'Disease', 'MESH:D055752', (72, 94))	('lung cancer', 'Disease', 'MESH:D008175', (83, 94))	('small cell lung cancer', 'Disease', (137, 159))	('lung cancer', 'Phenotype', 'HP:0100526', (3, 14))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('lung cancer', 'Phenotype', 'HP:0100526', (83, 94))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('CIZ1', 'Gene', '25792', (20, 24))	('non-small cell lung cancer', 'Disease', (68, 94))	('overexpressed', 'PosReg', (51, 64))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (137, 159))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (72, 94))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (68, 94))	('lung cancer', 'Disease', (3, 14))	('lung cancer', 'Disease', 'MESH:D008175', (148, 159))	('b-variant', 'Var', (25, 34))	('CIZ1', 'Gene', (20, 24))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (68, 94))	('small cell lung cancer', 'Disease', 'MESH:D055752', (137, 159))	('lung cancer', 'Phenotype', 'HP:0100526', (148, 159))	('lung cancer', 'Disease', 'MESH:D008175', (3, 14))
149129	29285191	Non-small cell lung cancer can be efficiently distinguished from benign lung nodules with an accuracy of 95% by detecting the expression level of CIZ1 b-variant.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('b-variant', 'Var', (151, 160))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (4, 26))	('detecting', 'Reg', (112, 121))	('CIZ1', 'Gene', '25792', (146, 150))	('Non-small cell lung cancer', 'Disease', 'MESH:D002289', (0, 26))	('Non-small cell lung cancer', 'Disease', (0, 26))	('Non-small cell lung cancer', 'Phenotype', 'HP:0030358', (0, 26))	('CIZ1', 'Gene', (146, 150))	('lung cancer', 'Phenotype', 'HP:0100526', (15, 26))	('expression level', 'MPA', (126, 142))
149183	29285191	The deficiency of p21Cip1/Waf1 induces the proliferation of tumor cells and cancerous angiogenesis.	('cancerous', 'Disease', (76, 85))	('Waf1', 'Gene', (26, 30))	('Waf1', 'Gene', '1026', (26, 30))	('p21Cip1', 'Gene', (18, 25))	('induces', 'Reg', (31, 38))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('deficiency', 'Var', (4, 14))	('cancerous', 'Disease', 'MESH:D009369', (76, 85))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('p21Cip1', 'Gene', '1026', (18, 25))	('tumor', 'Disease', (60, 65))
149195	29285191	Interfering with CIZ1 expression has been previously demonstrated to be able to efficiently cause the interruption of DNA replication, cell cycle arrest at G1 phase and inhibition of cellular proliferation.	('inhibition', 'NegReg', (169, 179))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (135, 152))	('cellular proliferation', 'CPA', (183, 205))	('Interfering', 'Var', (0, 11))	('CIZ1', 'Gene', (17, 21))	('cell cycle arrest at G1 phase', 'CPA', (135, 164))	('CIZ1', 'Gene', '25792', (17, 21))	('DNA', 'MPA', (118, 121))	('interruption', 'NegReg', (102, 114))
149227	33132329	We experienced a case of EGFR mutant lung squamous cell carcinoma in which fifth-line treatment with osimertinib was effective after T790M EGFR mutation turned positive.	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (37, 65))	('lung squamous cell carcinoma', 'Disease', (37, 65))	('EGFR', 'Gene', (25, 29))	('T790M', 'Mutation', 'rs121434569', (133, 138))	('EGFR', 'Gene', '1956', (139, 143))	('osimertinib', 'Chemical', '-', (101, 112))	('EGFR', 'Gene', (139, 143))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (37, 65))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (42, 65))	('mutant', 'Var', (30, 36))	('EGFR', 'Gene', '1956', (25, 29))	('carcinoma', 'Phenotype', 'HP:0030731', (56, 65))
149229	33132329	Osimertinib may be a promising treatment option for EGFR mutant lung squamous cell carcinoma.	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (64, 92))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (69, 92))	('EGFR', 'Gene', '1956', (52, 56))	('lung squamous cell carcinoma', 'Disease', (64, 92))	('EGFR', 'Gene', (52, 56))	('mutant', 'Var', (57, 63))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (64, 92))	('Osimertinib', 'Chemical', '-', (0, 11))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))
149231	33132329	Epidermal growth factor receptor (EGFR) mutations can sometimes be found in lung squamous cell carcinoma.	('EGFR', 'Gene', (34, 38))	('Epidermal growth factor receptor', 'Gene', (0, 32))	('EGFR', 'Gene', '1956', (34, 38))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (76, 104))	('found', 'Reg', (67, 72))	('mutations', 'Var', (40, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (76, 104))	('Epidermal growth factor receptor', 'Gene', '1956', (0, 32))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (81, 104))	('lung squamous cell carcinoma', 'Disease', (76, 104))
149232	33132329	This is markedly lower than in lung adenocarcinoma, in which EGFR mutations are found in 19.2% of Caucasians and 47.9% of Asians.	('mutations', 'Var', (66, 75))	('carcinoma', 'Phenotype', 'HP:0030731', (41, 50))	('lung adenocarcinoma', 'Disease', (31, 50))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (31, 50))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (31, 50))	('EGFR', 'Gene', '1956', (61, 65))	('EGFR', 'Gene', (61, 65))
149233	33132329	The efficacy of EGFR-tyrosine kinase inhibitors (TKIs) in EGFR mutant lung squamous cell carcinoma is also reported to be lower than in adenocarcinoma.	('lower', 'NegReg', (122, 127))	('EGFR', 'Gene', '1956', (58, 62))	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('tyrosine kinase', 'Gene', '7294', (21, 36))	('adenocarcinoma', 'Disease', (136, 150))	('mutant', 'Var', (63, 69))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (70, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('EGFR', 'Gene', (58, 62))	('adenocarcinoma', 'Disease', 'MESH:D000230', (136, 150))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (70, 98))	('tyrosine kinase', 'Gene', (21, 36))	('EGFR', 'Gene', '1956', (16, 20))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (75, 98))	('efficacy', 'MPA', (4, 12))	('lung squamous cell carcinoma', 'Disease', (70, 98))	('EGFR', 'Gene', (16, 20))
149236	33132329	We experienced a case of EGFR mutant lung squamous cell carcinoma with a secondary T790M EGFR mutation that showed good response to fifth-line treatment with osimertinib as well as subsequent rechallenge as seventh-line therapy.	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (37, 65))	('lung squamous cell carcinoma', 'Disease', (37, 65))	('osimertinib', 'Chemical', '-', (158, 169))	('EGFR', 'Gene', (89, 93))	('EGFR', 'Gene', (25, 29))	('EGFR', 'Gene', '1956', (89, 93))	('T790M', 'Mutation', 'rs121434569', (83, 88))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (37, 65))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (42, 65))	('EGFR', 'Gene', '1956', (25, 29))	('carcinoma', 'Phenotype', 'HP:0030731', (56, 65))	('T790M', 'Var', (83, 88))
149246	33132329	EGFR exon 21 L858R was identified on a molecular analysis.	('L858R', 'Mutation', 'rs121434568', (13, 18))	('L858R', 'Var', (13, 18))	('EGFR', 'Gene', '1956', (0, 4))	('EGFR', 'Gene', (0, 4))
149254	33132329	A liquid biopsy revealed a positive T790M EGFR mutation.	('EGFR', 'Gene', (42, 46))	('EGFR', 'Gene', '1956', (42, 46))	('T790M', 'Var', (36, 41))	('T790M', 'Mutation', 'rs121434569', (36, 41))
149262	33132329	A case of EGFR mutant squamous cell carcinoma with a secondary T790M EGFR mutation showed a good response to fifth-line treatment with osimertinib for seven months in addition to two months as a rechallenge.	('EGFR', 'Gene', '1956', (10, 14))	('EGFR', 'Gene', '1956', (69, 73))	('EGFR', 'Gene', (10, 14))	('EGFR', 'Gene', (69, 73))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (22, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (36, 45))	('T790M', 'Mutation', 'rs121434569', (63, 68))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (22, 45))	('T790M', 'Var', (63, 68))	('squamous cell carcinoma', 'Disease', (22, 45))	('osimertinib', 'Chemical', '-', (135, 146))
149263	33132329	Osimertinib may be a reasonable choice of treatment in patients with EGFR mutant lung squamous cell carcinoma.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (86, 109))	('EGFR', 'Gene', '1956', (69, 73))	('lung squamous cell carcinoma', 'Disease', (81, 109))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (81, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('EGFR', 'Gene', (69, 73))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (81, 109))	('patients', 'Species', '9606', (55, 63))	('mutant', 'Var', (74, 80))	('Osimertinib', 'Chemical', '-', (0, 11))
149264	33132329	The efficacy of EGFR-TKIs in EGFR mutant lung squamous cell carcinoma is reported to be lower than in adenocarcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (41, 69))	('adenocarcinoma', 'Disease', (102, 116))	('adenocarcinoma', 'Disease', 'MESH:D000230', (102, 116))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (46, 69))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (41, 69))	('lung squamous cell carcinoma', 'Disease', (41, 69))	('EGFR', 'Gene', '1956', (29, 33))	('EGFR', 'Gene', (29, 33))	('EGFR', 'Gene', '1956', (16, 20))	('carcinoma', 'Phenotype', 'HP:0030731', (60, 69))	('lower', 'NegReg', (88, 93))	('EGFR', 'Gene', (16, 20))	('mutant', 'Var', (34, 40))
149265	33132329	A previous study showed that 33 (13.3%) of 249 patients with squamous cell carcinoma had EGFR mutations.	('EGFR', 'Gene', (89, 93))	('mutations', 'Var', (94, 103))	('patients', 'Species', '9606', (47, 55))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (61, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (61, 84))	('squamous cell carcinoma', 'Disease', (61, 84))	('EGFR', 'Gene', '1956', (89, 93))
149267	33132329	A pooled analysis of EGFR mutant non-adenocarcinoma non-small-cell lung carcinoma (NSCLC) patients treated with gefitinib reported a 27% response rate, 67-70% disease control rate, and 3.0-month median PFS.	('EGFR', 'Gene', '1956', (21, 25))	('EGFR', 'Gene', (21, 25))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('NSCLC', 'Disease', (83, 88))	('adenocarcinoma non-small-cell lung carcinoma', 'Disease', (37, 81))	('NSCLC', 'Disease', 'MESH:D002289', (83, 88))	('disease control', 'CPA', (159, 174))	('adenocarcinoma non-small-cell lung carcinoma', 'Disease', 'MESH:D002289', (37, 81))	('mutant', 'Var', (26, 32))	('patients', 'Species', '9606', (90, 98))	('gefitinib', 'Chemical', 'MESH:D000077156', (112, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (42, 51))
149268	33132329	The overall effect was significantly poorer than in EGFR mutant adenocarcinoma patients but better than in EGFR wild-type squamous cell carcinoma.	('EGFR', 'Gene', '1956', (107, 111))	('adenocarcinoma', 'Disease', (64, 78))	('EGFR', 'Gene', '1956', (52, 56))	('EGFR', 'Gene', (52, 56))	('EGFR', 'Gene', (107, 111))	('mutant', 'Var', (57, 63))	('adenocarcinoma', 'Disease', 'MESH:D000230', (64, 78))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (122, 145))	('patients', 'Species', '9606', (79, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('squamous cell carcinoma', 'Disease', (122, 145))	('poorer', 'NegReg', (37, 43))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (122, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))
149269	33132329	Therefore, the Japanese guidelines state the recommendation level regarding the use of EGFR-TKIs in advanced EGFR mutant lung squamous cell carcinoma as "2D," in contrast to "1A" for adenocarcinoma.	('adenocarcinoma', 'Disease', (183, 197))	('EGFR', 'Gene', '1956', (87, 91))	('adenocarcinoma', 'Disease', 'MESH:D000230', (183, 197))	('EGFR', 'Gene', (87, 91))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (121, 149))	('mutant', 'Var', (114, 120))	('EGFR', 'Gene', '1956', (109, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (121, 149))	('lung squamous cell carcinoma', 'Disease', (121, 149))	('EGFR', 'Gene', (109, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (188, 197))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (126, 149))
149270	33132329	A recent study including 1709 adenocarcinoma and 77 non-adenocarcinoma patients with an EGFR mutation-positive status investigated the efficacy of erlotinib and gefitinib on these patients.	('gefitinib', 'Chemical', 'MESH:D000077156', (161, 170))	('carcinoma', 'Phenotype', 'HP:0030731', (35, 44))	('adenocarcinoma', 'Disease', (30, 44))	('patients', 'Species', '9606', (71, 79))	('erlotinib', 'Chemical', 'MESH:D000069347', (147, 156))	('adenocarcinoma', 'Disease', 'MESH:D000230', (30, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('EGFR', 'Gene', '1956', (88, 92))	('adenocarcinoma', 'Disease', (56, 70))	('adenocarcinoma', 'Disease', 'MESH:D000230', (56, 70))	('mutation-positive', 'Var', (93, 110))	('EGFR', 'Gene', (88, 92))	('patients', 'Species', '9606', (180, 188))
149276	33132329	In two of these cases as well as our present case, osimertinib was effective once T790M turned positive after other EGFR-TKI failures.	('T790M', 'Mutation', 'rs121434569', (82, 87))	('osimertinib', 'Chemical', '-', (51, 62))	('T790M', 'Var', (82, 87))	('EGFR', 'Gene', '1956', (116, 120))	('EGFR', 'Gene', (116, 120))
149277	33132329	Recently, osimertinib has been approved as the first-line therapy for EGFR mutant NSCLC.	('EGFR', 'Gene', '1956', (70, 74))	('osimertinib', 'Chemical', '-', (10, 21))	('EGFR', 'Gene', (70, 74))	('mutant', 'Var', (75, 81))	('NSCLC', 'Disease', (82, 87))	('NSCLC', 'Disease', 'MESH:D002289', (82, 87))
149278	33132329	The effect of osimertinib as a first-line treatment for EGFR mutant lung squamous cell carcinoma has also been reported in only two cases.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (73, 96))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (68, 96))	('lung squamous cell carcinoma', 'Disease', (68, 96))	('osimertinib', 'Chemical', '-', (14, 25))	('EGFR', 'Gene', '1956', (56, 60))	('EGFR', 'Gene', (56, 60))	('mutant', 'Var', (61, 67))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (68, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))
149280	33132329	Few reports have documented the efficacy of osimertinib for lung adenocarcinoma with secondary T790M mutation-positive squamous cell carcinoma transformation after failure of other EGFR-TKIs.	('squamous cell carcinoma transformation', 'Disease', (119, 157))	('osimertinib for lung adenocarcinoma', 'Disease', (44, 79))	('EGFR', 'Gene', (181, 185))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (60, 79))	('T790M', 'Mutation', 'rs121434569', (95, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('squamous cell carcinoma transformation', 'Disease', 'MESH:D002294', (119, 157))	('T790M', 'Var', (95, 100))	('osimertinib for lung adenocarcinoma', 'Disease', 'MESH:D000077192', (44, 79))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (119, 142))	('EGFR', 'Gene', '1956', (181, 185))
149288	33132329	They stated that, regardless of the histology, the sensitivity of EGFR-TKIs in patients with non-adenocarcinoma harboring EGFR mutations might depend on the proportion of EGFR mutated adenocarcinoma components within the whole tumor.	('EGFR', 'Gene', (171, 175))	('adenocarcinoma', 'Disease', 'MESH:D000230', (97, 111))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))	('EGFR', 'Gene', '1956', (171, 175))	('tumor', 'Disease', (227, 232))	('EGFR', 'Gene', '1956', (66, 70))	('EGFR', 'Gene', (66, 70))	('carcinoma', 'Phenotype', 'HP:0030731', (189, 198))	('adenocarcinoma', 'Disease', (184, 198))	('patients', 'Species', '9606', (79, 87))	('tumor', 'Disease', 'MESH:D009369', (227, 232))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('adenocarcinoma', 'Disease', (97, 111))	('mutations', 'Var', (127, 136))	('EGFR', 'Gene', '1956', (122, 126))	('EGFR', 'Gene', (122, 126))	('adenocarcinoma', 'Disease', 'MESH:D000230', (184, 198))
149290	33132329	In addition, the positive T790M EGFR mutation status may have been responsible for the substantial effect of osimertinib in our case.	('T790M', 'Mutation', 'rs121434569', (26, 31))	('EGFR', 'Gene', '1956', (32, 36))	('T790M', 'Var', (26, 31))	('EGFR', 'Gene', (32, 36))	('osimertinib', 'Chemical', '-', (109, 120))
149293	33132329	As EGFR mutations have been found more frequently in never-smokers than in ever-smokers, it may therefore be important to test for EGFR in never-smoker NSCLC patients.	('EGFR', 'Gene', '1956', (3, 7))	('EGFR', 'Gene', (3, 7))	('NSCLC', 'Disease', (152, 157))	('mutations', 'Var', (8, 17))	('EGFR', 'Gene', '1956', (131, 135))	('EGFR', 'Gene', (131, 135))	('NSCLC', 'Disease', 'MESH:D002289', (152, 157))	('patients', 'Species', '9606', (158, 166))
149294	33132329	Current ESMO guidelines also recommend testing for EGFR mutations in current non-smokers or light smokers.	('testing', 'Reg', (39, 46))	('mutations', 'Var', (56, 65))	('EGFR', 'Gene', '1956', (51, 55))	('EGFR', 'Gene', (51, 55))
149295	33132329	There are no known factors that contribute to patients with EGFR mutant lung squamous cell carcinoma showing a good response to EGFR-TKIs.	('patients', 'Species', '9606', (46, 54))	('EGFR', 'Gene', '1956', (128, 132))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (72, 100))	('mutant', 'Var', (65, 71))	('EGFR', 'Gene', (128, 132))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (77, 100))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (72, 100))	('EGFR', 'Gene', '1956', (60, 64))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('lung squamous cell carcinoma', 'Disease', (72, 100))	('EGFR', 'Gene', (60, 64))
149299	33132329	EGFR mutant patients with these features may benefit from osimertinib, even if the morphology is squamous cell carcinoma.	('patients', 'Species', '9606', (12, 20))	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('EGFR', 'Gene', (0, 4))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (97, 120))	('benefit', 'PosReg', (45, 52))	('osimertinib', 'Chemical', '-', (58, 69))	('squamous cell carcinoma', 'Disease', (97, 120))	('mutant', 'Var', (5, 11))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (97, 120))	('EGFR', 'Gene', '1956', (0, 4))
149307	33132329	In patients with EGFR mutant lung cancer, osimertinib may also be a promising treatment choice, especially in late lines where there are few options left.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('lung cancer', 'Disease', 'MESH:D008175', (29, 40))	('osimertinib', 'Chemical', '-', (42, 53))	('patients', 'Species', '9606', (3, 11))	('mutant', 'Var', (22, 28))	('EGFR', 'Gene', '1956', (17, 21))	('lung cancer', 'Disease', (29, 40))	('lung cancer', 'Phenotype', 'HP:0100526', (29, 40))	('EGFR', 'Gene', (17, 21))
149309	33132329	Osimertinib may be a reasonable treatment choice in patients with EGFR mutant lung squamous cell carcinoma.	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (78, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (83, 106))	('EGFR', 'Gene', '1956', (66, 70))	('lung squamous cell carcinoma', 'Disease', (78, 106))	('EGFR', 'Gene', (66, 70))	('mutant', 'Var', (71, 77))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (78, 106))	('Osimertinib', 'Chemical', '-', (0, 11))	('patients', 'Species', '9606', (52, 60))
149315	31766723	Inhibition of Cx43 expression using siRNA increased Bcl-2 protein levels in SCC25 (tongue squamous cell carcinoma) cells, while forced Cx43 expression reduced Bcl-2 levels and supported paclitaxel cytotoxicity in FaDu (hypopharynx squamous cell carcinoma) cells.	('Inhibition', 'NegReg', (0, 10))	('paclitaxel', 'Chemical', 'MESH:D017239', (186, 196))	('Bcl-2 protein levels', 'MPA', (52, 72))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (231, 254))	('cytotoxicity in FaDu', 'Disease', (197, 217))	('tongue squamous cell carcinoma', 'Disease', 'MESH:D002294', (83, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (245, 254))	('Cx43 expression', 'Var', (135, 150))	('increased', 'PosReg', (42, 51))	('tongue squamous cell carcinoma', 'Disease', (83, 113))	('reduced', 'NegReg', (151, 158))	('supported', 'PosReg', (176, 185))	('Bcl-2 levels', 'MPA', (159, 171))	('hypopharynx squamous cell carcinoma', 'Disease', (219, 254))	('cytotoxicity in FaDu', 'Disease', 'MESH:D064420', (197, 217))	('hypopharynx squamous cell carcinoma', 'Disease', 'MESH:D002294', (219, 254))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (90, 113))	('hypopharynx squamous cell carcinoma', 'Phenotype', 'HP:0012182', (219, 254))	('tongue squamous cell carcinoma', 'Phenotype', 'HP:0030413', (83, 113))	('SCC25', 'CellLine', 'CVCL:1682', (76, 81))
149318	31766723	On the contrary, silencing of the Cx43 gene GJA1 (gap junction protein alpha-1) can result in increased Bcl-2 expression and reduced paclitaxel efficiency.	('GJA1', 'Gene', '2697', (44, 48))	('Bcl-2 expression', 'MPA', (104, 120))	('gap junction protein alpha-1', 'Gene', (50, 78))	('increased', 'PosReg', (94, 103))	('reduced', 'NegReg', (125, 132))	('paclitaxel', 'Chemical', 'MESH:D017239', (133, 143))	('paclitaxel efficiency', 'MPA', (133, 154))	('silencing', 'Var', (17, 26))	('gap junction protein alpha-1', 'Gene', '2697', (50, 78))	('GJA1', 'Gene', (44, 48))
149334	31766723	Paclitaxel therapy was also found to have the highest effect when high Cx43 expression was coupled with decreased expression of the specific antiapoptotic protein Bcl-2 (B-cell lymphoma 2).	('Cx43', 'Protein', (71, 75))	('Bcl-2', 'Gene', (163, 168))	('lymphoma', 'Phenotype', 'HP:0002665', (177, 185))	('Paclitaxel', 'Chemical', 'MESH:D017239', (0, 10))	('decreased', 'NegReg', (104, 113))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (170, 185))	('expression', 'MPA', (76, 86))	('high', 'Var', (66, 70))	('expression', 'MPA', (114, 124))
149335	31766723	Besides, Cx43 is also a tumor suppressor.	('tumor', 'Disease', (24, 29))	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('Cx43', 'Var', (9, 13))
149351	31766723	To reveal the mechanism of cell death caused by paclitaxel, we performed flow cytometry experiments using Annexin V-FLUOS and PI (propidium iodide) double staining at one treatment time (48 h) and five paclitaxel concentrations (1 nM, 3 nM, 10 nM, 33 nM, 100 nM).	('paclitaxel', 'Chemical', 'MESH:D017239', (202, 212))	('Annexin V', 'Gene', (106, 115))	('propidium iodide', 'Chemical', 'MESH:D011419', (130, 146))	('1 nM', 'Var', (229, 233))	('Annexin V', 'Gene', '308', (106, 115))	('paclitaxel', 'Chemical', 'MESH:D017239', (48, 58))
149359	31766723	In order to investigate whether Cx43 has any impact on the level of Bcl-2 protein, Cx43 gene (GJA1, gap junction protein alpha-1) silencing and plasmid transfection were performed on HNSCC cell lines.	('Cx43 gene', 'Gene', (83, 92))	('gap junction protein alpha-1', 'Gene', '2697', (100, 128))	('GJA1', 'Gene', '2697', (94, 98))	('GJA1', 'Gene', (94, 98))	('silencing', 'Var', (130, 139))	('gap junction protein alpha-1', 'Gene', (100, 128))
149360	31766723	After GJA1 siRNA knockdown the Cx43 protein expression was significantly reduced in all three cell lines (Detroit 562 p = 0.01, FaDu p = 3e-07, SCC25 p = e-11).	('Cx43 protein expression', 'MPA', (31, 54))	('GJA1', 'Gene', '2697', (6, 10))	('reduced', 'NegReg', (73, 80))	('GJA1', 'Gene', (6, 10))	('SCC25', 'CellLine', 'CVCL:1682', (144, 149))	('knockdown', 'Var', (17, 26))
149361	31766723	However, knockdown of Cx43 in SCC25 resulted in a significant increase in Bcl-2 expression (p = 6e-04).	('knockdown', 'Var', (9, 18))	('Cx43', 'Var', (22, 26))	('SCC25', 'CellLine', 'CVCL:1682', (30, 35))	('SCC25', 'Gene', (30, 35))	('Bcl-2 expression', 'MPA', (74, 90))	('increase', 'PosReg', (62, 70))
149362	31766723	(Figure 4A,C) Plasmid transfection upregulated Cx43 protein levels in all three cell lines, but the difference was only significant in FaDu cells (p < 0.05) but not in Detroit 562 (p = 0.07), and SCC25 (p = 0.22) cells.	('Cx43 protein levels', 'MPA', (47, 66))	('Plasmid transfection', 'Var', (14, 34))	('upregulated', 'PosReg', (35, 46))	('SCC25', 'CellLine', 'CVCL:1682', (196, 201))
149368	31766723	Thus, GJA1 gene silencing explicitly reduced the effect of paclitaxel in SCC25 cell line (Figure 5).	('SCC25', 'CellLine', 'CVCL:1682', (73, 78))	('effect of paclitaxel', 'MPA', (49, 69))	('paclitaxel', 'Chemical', 'MESH:D017239', (59, 69))	('GJA1', 'Gene', '2697', (6, 10))	('GJA1', 'Gene', (6, 10))	('gene silencing', 'Var', (11, 25))	('reduced', 'NegReg', (37, 44))
149373	31766723	This could explain the lack of change in paclitaxel sensitivity of Detroit 562 cells after silencing GJA1 gene.	('paclitaxel', 'Chemical', 'MESH:D017239', (41, 51))	('paclitaxel sensitivity', 'MPA', (41, 63))	('GJA1', 'Gene', (101, 105))	('GJA1', 'Gene', '2697', (101, 105))	('silencing', 'Var', (91, 100))
149378	31766723	Although the flow cytometry analysis showed a non-significant effect, the results of the trypan blue exclusion test revealed that the Cx43 transfection can sensitizes FaDu cells to paclitaxel treatment.	('sensitizes', 'Reg', (156, 166))	('transfection', 'Var', (139, 151))	('Cx43 transfection', 'Var', (134, 151))	('trypan blue', 'Chemical', 'MESH:D014343', (89, 100))	('paclitaxel', 'Chemical', 'MESH:D017239', (181, 191))
149379	31766723	Cx43 plasmid transfected FaDu cells had lower paclitaxel IC50 values (Figure 6).	('paclitaxel IC50 values', 'MPA', (46, 68))	('paclitaxel', 'Chemical', 'MESH:D017239', (46, 56))	('lower', 'NegReg', (40, 45))	('Cx43 plasmid transfected', 'Var', (0, 24))
149381	31766723	The Cx43 status did not correlate with tumor localization (p = 0.779), tumor size (p = 0.824), stage (p = 0.638), lymph node metastasis (p = 0.351) or response to neoadjuvant chemotherapy (p > 0.05).	('lymph node metastasis', 'CPA', (114, 135))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('Cx43', 'Var', (4, 8))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Disease', (39, 44))	('tumor', 'Disease', (71, 76))
149393	31766723	Loss of function mutations of these gap junction channels have been described in many disorders including various cancers.	('cancers', 'Disease', 'MESH:D009369', (114, 121))	('cancers', 'Phenotype', 'HP:0002664', (114, 121))	('cancers', 'Disease', (114, 121))	('Loss of function', 'NegReg', (0, 16))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('mutations', 'Var', (17, 26))
149397	31766723	also found frame-shift mutations at the carboxyl-terminal region of Cx43 in human colon adenocarcinomas, which affects its phosphorylation, localization and function of the protein and also its staining with different antibodies.	('staining', 'MPA', (194, 202))	('colon adenocarcinomas', 'Disease', 'MESH:D015179', (82, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('phosphorylation', 'MPA', (123, 138))	('function', 'MPA', (157, 165))	('frame-shift mutations', 'Var', (11, 32))	('Cx43', 'Gene', (68, 72))	('protein', 'Protein', (173, 180))	('human', 'Species', '9606', (76, 81))	('carboxyl', 'Chemical', 'MESH:C041069', (40, 48))	('colon adenocarcinomas', 'Disease', (82, 103))	('affects', 'Reg', (111, 118))	('localization', 'MPA', (140, 152))
149399	31766723	However, it has been observed that transfection with Cx43 decreased cell growth in several cancer cell lines such as lung, breast or prostate.	('prostate', 'Disease', (133, 141))	('lung', 'Disease', (117, 121))	('cancer', 'Disease', (91, 97))	('decreased', 'NegReg', (58, 67))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('transfection', 'Var', (35, 47))	('Cx43', 'Gene', (53, 57))	('cell growth', 'CPA', (68, 79))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('breast', 'Disease', (123, 129))
149406	31766723	At the same time, low level of Cx43 was associated with increased Bcl-2 protein level and relatively lower paclitaxel sensitivity in the remaining two cell lines.	('paclitaxel', 'Chemical', 'MESH:D017239', (107, 117))	('paclitaxel sensitivity', 'MPA', (107, 129))	('increased', 'PosReg', (56, 65))	('low level', 'Var', (18, 27))	('lower', 'NegReg', (101, 106))	('Cx43', 'Var', (31, 35))	('Bcl-2 protein level', 'MPA', (66, 85))
149413	31766723	Another possible mechanism could affect through signal transduction, because Cx43 exhibits SH2 and SH3 binding sites, and inhibits the activity of c-Src.	('SH3', 'Protein', (99, 102))	('inhibits', 'NegReg', (122, 130))	('Cx43', 'Var', (77, 81))	('affect', 'Reg', (33, 39))	('binding', 'Interaction', (103, 110))	('activity', 'MPA', (135, 143))	('SH2', 'Protein', (91, 94))	('c-Src', 'Gene', (147, 152))	('c-Src', 'Gene', '6714', (147, 152))
149423	31766723	GJA1 gene transfection resulted in increased Cx43 protein expression in all three cell lines, but the difference was significant only in FaDu cells.	('Cx43 protein expression', 'MPA', (45, 68))	('increased', 'PosReg', (35, 44))	('GJA1', 'Gene', '2697', (0, 4))	('GJA1', 'Gene', (0, 4))	('transfection', 'Var', (10, 22))
149425	31766723	Though GJA1 transfection did not induce significant apoptosis, it could sensitize FaDu cells to paclitaxel treatment transfection by itself cased some cell death, and since it was more efficient with the smaller control plasmid compared to the construct this led to a non-significant difference in cell death between these experiments.	('paclitaxel', 'Chemical', 'MESH:D017239', (96, 106))	('sensitize', 'Reg', (72, 81))	('cased', 'Reg', (140, 145))	('GJA1', 'Gene', '2697', (7, 11))	('GJA1', 'Gene', (7, 11))	('cell death', 'CPA', (151, 161))	('transfection', 'Var', (12, 24))
149451	31766723	7076, dilution 1:8000), Anti-rabbit IgG (Cat.	('Anti-rabbit', 'Var', (24, 35))	('IgG', 'Gene', (36, 39))	('IgG', 'Gene', '16065', (36, 39))
149494	31766723	Paclitaxel-induced apoptosis of SCC25 cells, Table S14: Changes in the levels of Cx43 and Bcl-2 after GJA1 siRNA knockdown in HNSCC cell lines, Table S15: Changes in the levels of Cx43 and Bcl-2 after GJA1 siRNA knockdown in HNSCC cell lines, Table S16: Changes in the levels of Cx43 and Bcl-2 after Cx43 plasmid transfection in HNSCC cell lines, Table S17: Changes in the levels of Cx43 and Bcl-2 after Cx43 plasmid transfection in HNSCC cell lines, Table S18: Changes in the effect of paclitaxel on cell viability after knocking down Cx43, Table S19: Changes in the paclitaxel-induced apoptosis of SCC25 after knocking down Cx43, Table S20: Changes in the paclitaxel-induced apoptosis of SCC25 after knocking down Cx43, Table S21: Changes in the paclitaxel-induced apoptosis of Detroit 562 after knocking down Cx43, Table S22: Changes in the paclitaxel-induced apoptosis of Detroit 562 after knocking down Cx43, Table S23: Changes in the paclitaxel-induced apoptosis of FaDu after knocking down Cx43, Table S24: Changes in the paclitaxel-induced apoptosis of FaDu after knocking down Cx43, Table S25.	('SCC25', 'CellLine', 'CVCL:1682', (32, 37))	('knocking down', 'Var', (1072, 1085))	('GJA1', 'Gene', (102, 106))	('GJA1', 'Gene', '2697', (102, 106))	('paclitaxel', 'Chemical', 'MESH:D017239', (568, 578))	('paclitaxel', 'Chemical', 'MESH:D017239', (658, 668))	('Paclitaxel', 'Chemical', 'MESH:D017239', (0, 10))	('SCC25', 'CellLine', 'CVCL:1682', (600, 605))	('GJA1', 'Gene', (201, 205))	('paclitaxel', 'Chemical', 'MESH:D017239', (940, 950))	('GJA1', 'Gene', '2697', (201, 205))	('paclitaxel', 'Chemical', 'MESH:D017239', (844, 854))	('SCC25', 'CellLine', 'CVCL:1682', (690, 695))	('paclitaxel', 'Chemical', 'MESH:D017239', (1029, 1039))	('paclitaxel', 'Chemical', 'MESH:D017239', (748, 758))	('paclitaxel', 'Chemical', 'MESH:D017239', (487, 497))
149495	31766723	Changes in the effect of paclitaxel on cell viability after transfection Cx43, Table S26: Data tables summarizing the results of Cx43 and Bcl-2 immunohistochemical analysis.	('transfection', 'Var', (60, 72))	('paclitaxel', 'Chemical', 'MESH:D017239', (25, 35))	('Changes', 'Reg', (0, 7))	('Cx43', 'Gene', (73, 77))
149502	30382525	There was also a significant difference between ET-axis expression and the degree of histological differentiation and mode of invasion, and the survival rate of the positive cases was significantly lower than that of the negative cases.	('survival rate', 'CPA', (144, 157))	('positive', 'Var', (165, 173))	('ET', 'Gene', '1906', (48, 50))	('difference', 'Reg', (29, 39))	('lower', 'NegReg', (198, 203))
149576	29617336	Single Nucleotide Polymorphisms in HMGB1 Correlate with Lung Cancer Risk in the Northeast Chinese Han Population Lung cancer is the principal cause of cancer-associated deaths.	('death', 'Disease', (169, 174))	('Lung Cancer', 'Phenotype', 'HP:0100526', (56, 67))	('cancer', 'Disease', (118, 124))	('Lung cancer', 'Phenotype', 'HP:0100526', (113, 124))	('Cancer', 'Phenotype', 'HP:0002664', (61, 67))	('Lung Cancer', 'Disease', (56, 67))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('Single Nucleotide Polymorphisms', 'Var', (0, 31))	('Lung cancer', 'Disease', (113, 124))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('HMGB1', 'Gene', (35, 40))	('Lung cancer', 'Disease', 'MESH:D008175', (113, 124))	('cancer', 'Disease', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('HMGB1', 'Gene', '3146', (35, 40))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('death', 'Disease', 'MESH:D003643', (169, 174))
149578	29617336	This study aimed to investigate the relationship between rs1412125 and rs1360485 polymorphisms in HMGB1 and the risk and survival of lung cancer.	('HMGB1', 'Gene', (98, 103))	('HMGB1', 'Gene', '3146', (98, 103))	('rs1360485', 'Mutation', 'rs1360485', (71, 80))	('lung cancer', 'Disease', (133, 144))	('lung cancer', 'Phenotype', 'HP:0100526', (133, 144))	('rs1412125', 'Var', (57, 66))	('lung cancer', 'Disease', 'MESH:D008175', (133, 144))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('rs1360485', 'Var', (71, 80))	('rs1412125', 'Mutation', 'rs1412125', (57, 66))
149581	29617336	Results indicated that rs1412125 polymorphism was associated with lung cancer risk, especially with the risk of lung adenocarcinoma and small cell lung cancer.	('lung adenocarcinoma and small cell lung cancer', 'Disease', 'MESH:D055752', (112, 158))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (112, 131))	('rs1412125', 'Var', (23, 32))	('lung cancer', 'Disease', (66, 77))	('lung cancer', 'Disease', (147, 158))	('lung cancer', 'Phenotype', 'HP:0100526', (66, 77))	('lung cancer', 'Phenotype', 'HP:0100526', (147, 158))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (136, 158))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('associated', 'Reg', (50, 60))	('rs1412125', 'Mutation', 'rs1412125', (23, 32))	('lung cancer', 'Disease', 'MESH:D008175', (66, 77))	('lung cancer', 'Disease', 'MESH:D008175', (147, 158))
149583	29617336	For rs1360485 polymorphism, AG and GG genotypes could decrease the risk of lung adenocarcinoma and female lung cancer by 0.771-fold and 0.789-fold.	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (75, 94))	('decrease', 'NegReg', (54, 62))	('lung cancer', 'Disease', (106, 117))	('lung cancer', 'Phenotype', 'HP:0100526', (106, 117))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('rs1360485', 'Mutation', 'rs1360485', (4, 13))	('lung adenocarcinoma', 'Disease', (75, 94))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (75, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('lung cancer', 'Disease', 'MESH:D008175', (106, 117))	('rs1360485', 'Var', (4, 13))
149585	29617336	This study indicated polymorphisms in HMGB1 may be a novel biomarker for female lung adenocarcinoma risk.	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('lung adenocarcinoma', 'Disease', (80, 99))	('HMGB1', 'Gene', (38, 43))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (80, 99))	('HMGB1', 'Gene', '3146', (38, 43))	('polymorphisms', 'Var', (21, 34))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (80, 99))
149596	29617336	Previous studies have reported the HMGB1 polymorphisms might efficiently predict the risk of susceptibility to different cancers such as hepatocellular carcinoma, uterine cervical neoplasia as well as colorectal cancer.	('carcinoma', 'Phenotype', 'HP:0030731', (152, 161))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('polymorphisms', 'Var', (41, 54))	('cancers', 'Phenotype', 'HP:0002664', (121, 128))	('cancers', 'Disease', (121, 128))	('neoplasia', 'Disease', 'MESH:D009369', (180, 189))	('colorectal cancer', 'Phenotype', 'HP:0003003', (201, 218))	('cervical neoplasia', 'Phenotype', 'HP:0032241', (171, 189))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (137, 161))	('predict', 'Reg', (73, 80))	('neoplasia', 'Disease', (180, 189))	('HMGB1', 'Gene', (35, 40))	('HMGB1', 'Gene', '3146', (35, 40))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (137, 161))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))	('colorectal cancer', 'Disease', 'MESH:D015179', (201, 218))	('cancers', 'Disease', 'MESH:D009369', (121, 128))	('neoplasia', 'Phenotype', 'HP:0002664', (180, 189))	('colorectal cancer', 'Disease', (201, 218))	('hepatocellular carcinoma', 'Disease', (137, 161))
149597	29617336	Thus we conducted this study to evaluate the association between the two SNPs (rs1412125 and rs1360485) in HMGB1 and the susceptibility as well as the survival of lung cancer to provide a new biomarker for the diagnosis, susceptibility and prognosis of lung cancer (as shown in Figure 1).	('lung cancer', 'Phenotype', 'HP:0100526', (253, 264))	('lung cancer', 'Disease', 'MESH:D008175', (163, 174))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('cancer', 'Phenotype', 'HP:0002664', (258, 264))	('lung cancer', 'Disease', (253, 264))	('rs1360485', 'Var', (93, 102))	('rs1412125', 'Mutation', 'rs1412125', (79, 88))	('HMGB1', 'Gene', (107, 112))	('lung cancer', 'Disease', 'MESH:D008175', (253, 264))	('HMGB1', 'Gene', '3146', (107, 112))	('lung cancer', 'Phenotype', 'HP:0100526', (163, 174))	('rs1412125', 'Var', (79, 88))	('lung cancer', 'Disease', (163, 174))	('rs1360485', 'Mutation', 'rs1360485', (93, 102))
149600	29617336	Table 2 summarizes the distributions of rs1412125 and rs1360485 alleles and genotypes between cases and controls as well as the associations between genotypes and the susceptibility to lung cancer.	('lung cancer', 'Disease', 'MESH:D008175', (185, 196))	('rs1412125', 'Mutation', 'rs1412125', (40, 49))	('rs1360485', 'Mutation', 'rs1360485', (54, 63))	('associations', 'Interaction', (128, 140))	('lung cancer', 'Disease', (185, 196))	('rs1360485', 'Var', (54, 63))	('rs1412125', 'Var', (40, 49))	('lung cancer', 'Phenotype', 'HP:0100526', (185, 196))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))
149601	29617336	Genotype frequencies of rs1412125 (p = 0.529) and rs1360485 (p = 0.945) polymorphisms were satisfied to HWE in controls.	('rs1412125', 'Var', (24, 33))	('rs1412125', 'Mutation', 'rs1412125', (24, 33))	('rs1360485', 'Var', (50, 59))	('rs1360485', 'Mutation', 'rs1360485', (50, 59))
149602	29617336	For the distribution of rs1412125 polymorphism, significant difference existed between TT and CT genotypes that carriers with CT genotype had a 0.744-fold decreased risk of susceptibility to lung cancer than carriers with TT genotype.	('CT', 'Chemical', 'MESH:D002251', (126, 128))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('lung cancer', 'Disease', 'MESH:D008175', (191, 202))	('rs1412125', 'Mutation', 'rs1412125', (24, 33))	('CT', 'Chemical', 'MESH:D002251', (94, 96))	('decreased', 'NegReg', (155, 164))	('susceptibility', 'MPA', (173, 187))	('lung cancer', 'Disease', (191, 202))	('rs1412125', 'Var', (24, 33))	('lung cancer', 'Phenotype', 'HP:0100526', (191, 202))
149603	29617336	The distribution of rs1412125 polymorphism was also prominently different in the dominant model between the cases and controls that subjects with CT and CC genotypes had a 0.736-fold decreased risk of susceptibility to lung cancer than those carrying TT genotype.	('lung cancer', 'Phenotype', 'HP:0100526', (219, 230))	('rs1412125', 'Mutation', 'rs1412125', (20, 29))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('lung cancer', 'Disease', (219, 230))	('decreased', 'NegReg', (183, 192))	('rs1412125', 'Var', (20, 29))	('lung cancer', 'Disease', 'MESH:D008175', (219, 230))	('CT', 'Chemical', 'MESH:D002251', (146, 148))
149604	29617336	For the allele comparison of rs1360485 polymorphism, G allele decreased the risk for lung cancer by 0.829-fold while different rs1360485 genotypes were not associated with the risk of susceptibility to lung cancer.	('rs1360485', 'Mutation', 'rs1360485', (29, 38))	('lung cancer', 'Disease', (85, 96))	('lung cancer', 'Phenotype', 'HP:0100526', (85, 96))	('decreased', 'NegReg', (62, 71))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('lung cancer', 'Disease', (202, 213))	('lung cancer', 'Phenotype', 'HP:0100526', (202, 213))	('lung cancer', 'Disease', 'MESH:D008175', (85, 96))	('rs1360485', 'Var', (29, 38))	('rs1360485', 'Mutation', 'rs1360485', (127, 136))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('lung cancer', 'Disease', 'MESH:D008175', (202, 213))
149605	29617336	Results in Table 3 and Table 4 indicated that rs1412125 polymorphism might have an effect on the risk of susceptibility to LAD and SCLC.	('rs1412125', 'Var', (46, 55))	('effect', 'Reg', (83, 89))	('SCLC', 'Disease', 'MESH:D018288', (131, 135))	('SCLC', 'Disease', (131, 135))	('LAD', 'Disease', 'MESH:C535887', (123, 126))	('SCLC', 'Phenotype', 'HP:0030357', (131, 135))	('LAD', 'Phenotype', 'HP:0030078', (123, 126))	('rs1412125', 'Mutation', 'rs1412125', (46, 55))	('LAD', 'Disease', (123, 126))
149609	29617336	Results of stratified analyses for SNP rs1360485 suggested that AG and GG genotypes could decrease the risk for LAD by 0.771-fold and decrease the risk for female lung cancer by 0.789-fold when the AA genotype was considered as a reference (Tables S1 and S2).	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('lung cancer', 'Disease', 'MESH:D008175', (163, 174))	('rs1360485', 'Mutation', 'rs1360485', (39, 48))	('LAD', 'Disease', 'MESH:C535887', (112, 115))	('decrease', 'NegReg', (134, 142))	('LAD', 'Disease', (112, 115))	('LAD', 'Phenotype', 'HP:0030078', (112, 115))	('lung cancer', 'Phenotype', 'HP:0100526', (163, 174))	('rs1360485', 'Var', (39, 48))	('lung cancer', 'Disease', (163, 174))	('decrease', 'NegReg', (90, 98))
149610	29617336	When compared with non-smokers who carried CT and CC genotypes, TT genotype carriers with tobacco exposure, CT and CC carriers with tobacco exposure and TT genotype carriers without tobacco exposure obtained 3.456-fold, 2.467-fold and 1.399-fold increased risk of susceptibility to lung cancer respectively for rs1412125 polymorphism.	('CT', 'Chemical', 'MESH:D002251', (43, 45))	('rs1412125', 'Mutation', 'rs1412125', (311, 320))	('lung cancer', 'Disease', 'MESH:D008175', (282, 293))	('tobacco', 'Species', '4097', (182, 189))	('CT', 'Chemical', 'MESH:D002251', (108, 110))	('rs1412125 polymorphism', 'Var', (311, 333))	('cancer', 'Phenotype', 'HP:0002664', (287, 293))	('tobacco', 'Species', '4097', (90, 97))	('lung cancer', 'Disease', (282, 293))	('lung cancer', 'Phenotype', 'HP:0100526', (282, 293))	('tobacco', 'Species', '4097', (132, 139))
149611	29617336	Nevertheless, there was no addictive interaction or multiplicative interaction between rs1412125 or rs1360485 polymorphisms and tobacco exposure (Table 6 and Table 7).	('rs1360485', 'Var', (100, 109))	('rs1412125', 'Mutation', 'rs1412125', (87, 96))	('tobacco', 'Species', '4097', (128, 135))	('rs1360485', 'Mutation', 'rs1360485', (100, 109))	('rs1412125', 'Var', (87, 96))	('addictive interaction', 'Phenotype', 'HP:0030858', (27, 48))
149613	29617336	In addition, no significant difference could be observed in the distribution of rs1412125 or rs1360485 polymorphisms in different clinical stages (Table S3).	('rs1412125', 'Mutation', 'rs1412125', (80, 89))	('rs1360485', 'Var', (93, 102))	('rs1360485', 'Mutation', 'rs1360485', (93, 102))	('rs1412125', 'Var', (80, 89))
149616	29617336	Genetic mutations involve in the tumorigenesis, cancer progression and prognosis while SNPs could regulate the expression of gene or affect gene's functions and then alter the phenotypes.	('involve', 'Reg', (18, 25))	('functions', 'MPA', (147, 156))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('gene', 'Protein', (125, 129))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('regulate', 'Reg', (98, 106))	('mutations', 'Var', (8, 17))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('expression of', 'MPA', (111, 124))	('cancer', 'Disease', (48, 54))	('tumor', 'Disease', (33, 38))	('affect', 'Reg', (133, 139))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('alter', 'Reg', (166, 171))	('gene', 'MPA', (140, 144))
149618	29617336	The mutant allele C would lose the inhibition function and result into the overexpression of HMGB1.	('mutant', 'Var', (4, 10))	('overexpression', 'PosReg', (75, 89))	('result into', 'Reg', (59, 70))	('lose', 'NegReg', (26, 30))	('HMGB1', 'Gene', (93, 98))	('HMGB1', 'Gene', '3146', (93, 98))	('inhibition function', 'MPA', (35, 54))
149619	29617336	SNP rs1360485 is located in the intron region of HMGB1.	('HMGB1', 'Gene', '3146', (49, 54))	('HMGB1', 'Gene', (49, 54))	('SNP rs1360485', 'Var', (0, 13))	('rs1360485', 'Mutation', 'rs1360485', (4, 13))
149620	29617336	Although polymorphism rs1360485 could not change the sequence of HMGB1 protein, it might regulate transcription process of HMGB1 or other gene.	('rs1360485', 'Mutation', 'rs1360485', (22, 31))	('HMGB1', 'Gene', (123, 128))	('HMGB1', 'Gene', (65, 70))	('HMGB1', 'Gene', '3146', (123, 128))	('regulate', 'Reg', (89, 97))	('polymorphism', 'Var', (9, 21))	('transcription process', 'MPA', (98, 119))	('HMGB1', 'Gene', '3146', (65, 70))	('rs1360485', 'Var', (22, 31))
149621	29617336	A series of studies have reported the association between polymorphisms rs1412125 or rs1360485 and the risk of cancers such as oral squamous cell carcinoma, hepatocellular carcinoma, uterine cervical neoplasia, colorectal cancer as well as the lung cancer chemotherapy response.	('cancers', 'Disease', 'MESH:D009369', (111, 118))	('association', 'Interaction', (38, 49))	('neoplasia', 'Disease', (200, 209))	('rs1360485', 'Mutation', 'rs1360485', (85, 94))	('colorectal cancer', 'Phenotype', 'HP:0003003', (211, 228))	('polymorphisms', 'Var', (58, 71))	('cervical neoplasia', 'Phenotype', 'HP:0032241', (191, 209))	('rs1412125', 'Mutation', 'rs1412125', (72, 81))	('cancer', 'Phenotype', 'HP:0002664', (249, 255))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (157, 181))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (127, 155))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('oral squamous cell carcinoma', 'Disease', (127, 155))	('lung cancer', 'Disease', (244, 255))	('neoplasia', 'Phenotype', 'HP:0002664', (200, 209))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('rs1412125', 'Var', (72, 81))	('hepatocellular carcinoma', 'Disease', (157, 181))	('rs1360485', 'Var', (85, 94))	('cancers', 'Phenotype', 'HP:0002664', (111, 118))	('cancers', 'Disease', (111, 118))	('colorectal cancer', 'Disease', 'MESH:D015179', (211, 228))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (132, 155))	('colorectal cancer', 'Disease', (211, 228))	('carcinoma', 'Phenotype', 'HP:0030731', (172, 181))	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('lung cancer', 'Disease', 'MESH:D008175', (244, 255))	('neoplasia', 'Disease', 'MESH:D009369', (200, 209))	('lung cancer', 'Phenotype', 'HP:0100526', (244, 255))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (157, 181))
149622	29617336	conducted a study to verify the association between four SNPs (rs1412125, rs2249825, rs1045411, and rs1360485) in HMGB1 and the risk of oral squamous cell carcinoma (OSCC).	('rs1360485', 'Mutation', 'rs1360485', (100, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (155, 164))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (136, 164))	('rs1045411', 'Var', (85, 94))	('rs2249825', 'Mutation', 'rs2249825', (74, 83))	('rs1412125', 'Mutation', 'rs1412125', (63, 72))	('rs1360485', 'Var', (100, 109))	('rs1045411', 'Mutation', 'rs1045411', (85, 94))	('oral squamous cell carcinoma', 'Disease', (136, 164))	('HMGB1', 'Gene', (114, 119))	('rs1412125', 'Var', (63, 72))	('rs2249825', 'Var', (74, 83))	('HMGB1', 'Gene', '3146', (114, 119))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (141, 164))
149623	29617336	They found that only the rs1045411 polymorphism could affect the risk of OSCC while other three SNPs might not be related to the susceptibility to OSCC.	('affect', 'Reg', (54, 60))	('OSCC', 'Disease', (73, 77))	('rs1045411', 'Var', (25, 34))	('rs1045411', 'Mutation', 'rs1045411', (25, 34))
149624	29617336	Wu's study showed an association of SNPs of HMGB1 with the risk of susceptibility to uterine cervical neoplasia for Taiwanese women.	('SNPs', 'Var', (36, 40))	('cervical neoplasia', 'Phenotype', 'HP:0032241', (93, 111))	('HMGB1', 'Gene', '3146', (44, 49))	('association', 'Interaction', (21, 32))	('neoplasia', 'Disease', (102, 111))	('women', 'Species', '9606', (126, 131))	('neoplasia', 'Phenotype', 'HP:0002664', (102, 111))	('neoplasia', 'Disease', 'MESH:D009369', (102, 111))	('HMGB1', 'Gene', (44, 49))
149625	29617336	Results indicated that the risk of cervical invasive cancer was 1.85-fold for women with TC and 1.99-fold for women with TC/CC when compared with TT carriers in HMGB1 rs1412125 polymorphism.	('women', 'Species', '9606', (110, 115))	('HMGB1', 'Gene', (161, 166))	('HMGB1', 'Gene', '3146', (161, 166))	('women', 'Species', '9606', (78, 83))	('cervical invasive cancer', 'Disease', 'MESH:D002583', (35, 59))	('rs1412125', 'Var', (167, 176))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('cervical invasive cancer', 'Disease', (35, 59))	('rs1412125', 'Mutation', 'rs1412125', (167, 176))
149626	29617336	The association of HMGB1 polymorphisms with the risk of colorectal carcinoma was also investigated in a Chinese population.	('HMGB1', 'Gene', '3146', (19, 24))	('colorectal carcinoma', 'Disease', (56, 76))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (56, 76))	('polymorphisms', 'Var', (25, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('HMGB1', 'Gene', (19, 24))
149627	29617336	However, there was no significant association between the rs1412125 polymorphism and the risk of susceptibility to colorectal cancer.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('colorectal cancer', 'Disease', 'MESH:D015179', (115, 132))	('rs1412125', 'Mutation', 'rs1412125', (58, 67))	('colorectal cancer', 'Phenotype', 'HP:0003003', (115, 132))	('rs1412125', 'Var', (58, 67))	('colorectal cancer', 'Disease', (115, 132))
149628	29617336	reported the effects of four HMGB1 SNPs (rs1412125, rs1045411, rs2249825, and rs1360485) on the susceptibility and development of hepatocellular cancer and results indicated that carriers with TT genotype had a higher risk of distant metastasis compared with individuals carrying at least one C allele for rs1412125 polymorphism.	('hepatocellular cancer', 'Disease', 'MESH:D006528', (130, 151))	('rs1360485', 'Mutation', 'rs1360485', (78, 87))	('rs2249825', 'Var', (63, 72))	('rs1045411', 'Var', (52, 61))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('hepatocellular cancer', 'Disease', (130, 151))	('distant metastasis', 'CPA', (226, 244))	('rs1412125', 'Mutation', 'rs1412125', (41, 50))	('HMGB1', 'Gene', '3146', (29, 34))	('rs1412125', 'Mutation', 'rs1412125', (306, 315))	('rs1360485', 'Var', (78, 87))	('rs2249825', 'Mutation', 'rs2249825', (63, 72))	('hepatocellular cancer', 'Phenotype', 'HP:0001402', (130, 151))	('rs1412125', 'Var', (41, 50))	('rs1045411', 'Mutation', 'rs1045411', (52, 61))	('HMGB1', 'Gene', (29, 34))	('effects', 'Reg', (13, 20))
149629	29617336	Significant associations were found between rs1412125 polymorphism and the platinum-based chemotherapy response in both genotypic and recessive models.	('platinum', 'Chemical', 'MESH:D010984', (75, 83))	('platinum-based chemotherapy response', 'CPA', (75, 111))	('rs1412125', 'Var', (44, 53))	('rs1412125', 'Mutation', 'rs1412125', (44, 53))
149630	29617336	In this current study, we estimated the association between SNPs (rs1412125 and rs1360485) in HMGB1 and the susceptibility of lung cancer among 850 cases and 733 controls.	('rs1360485', 'Var', (80, 89))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('lung cancer', 'Disease', (126, 137))	('rs1412125', 'Mutation', 'rs1412125', (66, 75))	('HMGB1', 'Gene', (94, 99))	('lung cancer', 'Phenotype', 'HP:0100526', (126, 137))	('rs1412125', 'Var', (66, 75))	('HMGB1', 'Gene', '3146', (94, 99))	('lung cancer', 'Disease', 'MESH:D008175', (126, 137))	('rs1360485', 'Mutation', 'rs1360485', (80, 89))
149631	29617336	There are two main reasons why we did not study the other two SNPs (rs2249825 and rs1045411): (1) the results of our previous GWAS study indicated that an association between the two SNPs (rs1412125 and rs1360485) and the risk of lung cancer might exist.	('rs1360485', 'Var', (203, 212))	('rs1045411', 'Mutation', 'rs1045411', (82, 91))	('lung cancer', 'Disease', (230, 241))	('rs1412125', 'Mutation', 'rs1412125', (189, 198))	('rs2249825', 'Mutation', 'rs2249825', (68, 77))	('lung cancer', 'Phenotype', 'HP:0100526', (230, 241))	('rs1360485', 'Mutation', 'rs1360485', (203, 212))	('rs1412125', 'Var', (189, 198))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))	('lung cancer', 'Disease', 'MESH:D008175', (230, 241))
149632	29617336	However, the other two SNPs (rs2249825 and rs1045411) did not exist in the GWAS loci of lung cancer; (2) according to the results of the ensembl database (the website of the ensembl database: ) and the previous articles, a strong linkage disequilibrium exists not only between rs1360485 and rs1045411 but also between rs1360485 and rs2249825.	('rs1360485', 'Mutation', 'rs1360485', (318, 327))	('lung cancer', 'Disease', (88, 99))	('rs1045411', 'Mutation', 'rs1045411', (43, 52))	('rs1045411', 'Mutation', 'rs1045411', (291, 300))	('rs1360485', 'Mutation', 'rs1360485', (277, 286))	('lung cancer', 'Phenotype', 'HP:0100526', (88, 99))	('rs2249825', 'Mutation', 'rs2249825', (332, 341))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('lung cancer', 'Disease', 'MESH:D008175', (88, 99))	('rs1360485', 'Var', (318, 327))	('rs1360485', 'Var', (277, 286))	('rs1045411', 'Var', (291, 300))	('rs2249825', 'Var', (332, 341))	('rs2249825', 'Mutation', 'rs2249825', (29, 38))
149634	29617336	Among these three SNPs, rs1360485 is the most common one so that we selected the rs1360485 as a tagSNP rather than studying all of these three SNPs.	('rs1360485', 'Mutation', 'rs1360485', (24, 33))	('rs1360485', 'Var', (81, 90))	('rs1360485', 'Mutation', 'rs1360485', (81, 90))	('rs1360485', 'Var', (24, 33))
149635	29617336	Therefore, only rs1412125 and rs1360485 were contained in this study.	('rs1360485', 'Var', (30, 39))	('rs1360485', 'Mutation', 'rs1360485', (30, 39))	('rs1412125', 'Var', (16, 25))	('rs1412125', 'Mutation', 'rs1412125', (16, 25))
149636	29617336	Results indicated that rs1412125 polymorphism in HMGB1 was associated with the risk of susceptibility to lung cancer, especially with the risk of susceptibility to LAD and SCLC.	('lung cancer', 'Phenotype', 'HP:0100526', (105, 116))	('SCLC', 'Disease', 'MESH:D018288', (172, 176))	('SCLC', 'Phenotype', 'HP:0030357', (172, 176))	('rs1412125', 'Var', (23, 32))	('LAD', 'Disease', 'MESH:C535887', (164, 167))	('LAD', 'Phenotype', 'HP:0030078', (164, 167))	('associated', 'Reg', (59, 69))	('lung cancer', 'Disease', 'MESH:D008175', (105, 116))	('HMGB1', 'Gene', (49, 54))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('HMGB1', 'Gene', '3146', (49, 54))	('LAD', 'Disease', (164, 167))	('rs1412125', 'Mutation', 'rs1412125', (23, 32))	('SCLC', 'Disease', (172, 176))	('lung cancer', 'Disease', (105, 116))
149638	29617336	For rs1360485 polymorphism, the G allele could reduce the risk for lung cancer and results of stratified analyses demonstrated that AG and GG genotypes could reduce the risk for LAD as well as female lung cancer compared with the AA genotype.	('lung cancer', 'Disease', 'MESH:D008175', (200, 211))	('reduce', 'NegReg', (47, 53))	('LAD', 'Disease', 'MESH:C535887', (178, 181))	('reduce', 'NegReg', (158, 164))	('lung cancer', 'Disease', 'MESH:D008175', (67, 78))	('LAD', 'Phenotype', 'HP:0030078', (178, 181))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('rs1360485', 'Mutation', 'rs1360485', (4, 13))	('lung cancer', 'Disease', (200, 211))	('lung cancer', 'Phenotype', 'HP:0100526', (200, 211))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('LAD', 'Disease', (178, 181))	('lung cancer', 'Disease', (67, 78))	('lung cancer', 'Phenotype', 'HP:0100526', (67, 78))	('rs1360485', 'Var', (4, 13))
149639	29617336	They examined four HMGB1 SNPs (rs2249825, rs1360485, rs1045411 and rs1412125) in 190 lung cancer cases and 187 healthy controls.	('HMGB1', 'Gene', '3146', (19, 24))	('rs1360485', 'Var', (42, 51))	('rs1412125', 'Mutation', 'rs1412125', (67, 76))	('lung cancer', 'Disease', (85, 96))	('lung cancer', 'Phenotype', 'HP:0100526', (85, 96))	('rs1412125', 'Var', (67, 76))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('rs1045411', 'Mutation', 'rs1045411', (53, 62))	('lung cancer', 'Disease', 'MESH:D008175', (85, 96))	('rs2249825', 'Var', (31, 40))	('rs1360485', 'Mutation', 'rs1360485', (42, 51))	('rs2249825', 'Mutation', 'rs2249825', (31, 40))	('HMGB1', 'Gene', (19, 24))	('rs1045411', 'Var', (53, 62))
149640	29617336	Results indicated CT or TT + CT genotypes of rs1045411 polymorphism could reduce the risk of lung cancer and the T/C/G haplotypes of rs1045411, rs2249825 and rs1360485 also decreased the risk of lung cancer by 0.486-fold while no significant association was found between rs1412125 polymorphism and the risk of susceptibility to lung cancer.	('lung cancer', 'Phenotype', 'HP:0100526', (329, 340))	('rs1045411', 'Mutation', 'rs1045411', (133, 142))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('lung cancer', 'Phenotype', 'HP:0100526', (195, 206))	('rs1045411 polymorphism', 'Var', (45, 67))	('rs1360485', 'Var', (158, 167))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('cancer', 'Phenotype', 'HP:0002664', (334, 340))	('rs2249825', 'Mutation', 'rs2249825', (144, 153))	('CT', 'Chemical', 'MESH:D002251', (18, 20))	('lung cancer', 'Disease', (93, 104))	('rs1045411', 'Mutation', 'rs1045411', (45, 54))	('rs1045411', 'Var', (133, 142))	('lung cancer', 'Disease', (329, 340))	('rs2249825', 'Var', (144, 153))	('lung cancer', 'Phenotype', 'HP:0100526', (93, 104))	('lung cancer', 'Disease', (195, 206))	('decreased', 'NegReg', (173, 182))	('CT', 'Chemical', 'MESH:D002251', (29, 31))	('TT + CT', 'Chemical', '-', (24, 31))	('polymorphism', 'Var', (55, 67))	('lung cancer', 'Disease', 'MESH:D008175', (93, 104))	('reduce', 'NegReg', (74, 80))	('rs1412125', 'Mutation', 'rs1412125', (272, 281))	('rs1360485', 'Mutation', 'rs1360485', (158, 167))	('lung cancer', 'Disease', 'MESH:D008175', (329, 340))	('lung cancer', 'Disease', 'MESH:D008175', (195, 206))
149646	29617336	Finally, not only the pooled analysis but also the stratified analysis was conducted according to the smoking status, genders as well as the pathological types to provide a detailed analysis of the association between the single nucleotide polymorphism in HMGB1 and the lung cancer risk.	('association', 'Interaction', (198, 209))	('lung cancer', 'Disease', (270, 281))	('single nucleotide polymorphism', 'Var', (222, 252))	('HMGB1', 'Gene', (256, 261))	('lung cancer', 'Phenotype', 'HP:0100526', (270, 281))	('HMGB1', 'Gene', '3146', (256, 261))	('cancer', 'Phenotype', 'HP:0002664', (275, 281))	('lung cancer', 'Disease', 'MESH:D008175', (270, 281))
149647	29617336	In summary, this study provided evidence that polymorphisms in table (rs1412125 and rs1360485) might alter the individual susceptibility to lung cancer.	('rs1360485', 'Mutation', 'rs1360485', (84, 93))	('rs1412125', 'Var', (70, 79))	('lung cancer', 'Disease', (140, 151))	('lung cancer', 'Phenotype', 'HP:0100526', (140, 151))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('rs1412125', 'Mutation', 'rs1412125', (70, 79))	('rs1360485', 'Var', (84, 93))	('lung cancer', 'Disease', 'MESH:D008175', (140, 151))	('alter', 'Reg', (101, 106))
149655	29617336	The SNP genotyping was conducted by the 7500 Fast Real-Time PCR system (Applied Biosystems, Foster City, CA, USA) and the PCR Taqman probes and primers were designed by the same company (assay ID C___8690889_10 for rs1412125 and C___8690872_10 for rs1360485).	('rs1412125', 'Mutation', 'rs1412125', (215, 224))	('C___8690872_10', 'Var', (229, 243))	('rs1360485', 'Var', (248, 257))	('rs1412125', 'Var', (215, 224))	('rs1360485', 'Mutation', 'rs1360485', (248, 257))
149657	29617336	Therefore, the wild homozygous of rs1412125 and rs1360485 SNPs is TT and AA respectively, and the mutant homozygous of the two SNPs is CC and GG respectively.	('rs1360485', 'Var', (48, 57))	('rs1360485', 'Mutation', 'rs1360485', (48, 57))	('rs1412125', 'Var', (34, 43))	('rs1412125', 'Mutation', 'rs1412125', (34, 43))
149663	29617336	Results of this current study suggested that polymorphisms in HMGB1 showed an association with the risk of lung cancer in non-smokers and female population and it could be used as a biomarker for the risk of lung cancer, especially for the risk of LAD and SCLC.	('lung cancer', 'Phenotype', 'HP:0100526', (208, 219))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('LAD', 'Disease', (248, 251))	('lung cancer', 'Disease', 'MESH:D008175', (107, 118))	('HMGB1', 'Gene', (62, 67))	('SCLC', 'Disease', (256, 260))	('association', 'Reg', (78, 89))	('polymorphisms', 'Var', (45, 58))	('lung cancer', 'Disease', 'MESH:D008175', (208, 219))	('SCLC', 'Disease', 'MESH:D018288', (256, 260))	('LAD', 'Disease', 'MESH:C535887', (248, 251))	('lung cancer', 'Disease', (107, 118))	('HMGB1', 'Gene', '3146', (62, 67))	('lung cancer', 'Phenotype', 'HP:0100526', (107, 118))	('LAD', 'Phenotype', 'HP:0030078', (248, 251))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('SCLC', 'Phenotype', 'HP:0030357', (256, 260))	('lung cancer', 'Disease', (208, 219))
149666	29617336	HMGB1 High-mobility group box protein 1  SNP single nucleotide polymorphism  NSCLC non-small cell lung cancer  qRT-PCR quantitative real-time Polymerase Chain Reaction  min minute  HWE Hardy-Weinberg equilibrium  OR Odd ratio  95% CI 95% Confident Interval  RERI Relative Excess Risk due to Interaction  AP Attributable Proportion due to Interaction  S Synergy Index  HR Hazard Ratio  LAD lung adenocarcinoma  LSCC lung squamous cell carcinoma  SCLC small cell lung cancer  OSCC oral squamous cell carcinoma	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (415, 443))	('oral squamous cell carcinoma', 'Disease', (479, 507))	('carcinoma', 'Phenotype', 'HP:0030731', (399, 408))	('SCLC', 'Disease', 'MESH:D018288', (445, 449))	('High-mobility group box protein 1', 'Gene', (6, 39))	('High-mobility group box protein 1', 'Gene', '3146', (6, 39))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (484, 507))	('LAD', 'Disease', (385, 388))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('lung cancer', 'Phenotype', 'HP:0100526', (98, 109))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (83, 109))	('SCLC', 'Disease', 'MESH:D018288', (78, 82))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (415, 443))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (420, 443))	('lung squamous cell carcinoma', 'Disease', (415, 443))	('NSCLC non-small cell lung cancer', 'Disease', 'MESH:D002289', (77, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (498, 507))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (87, 109))	('small cell lung cancer', 'Disease', 'MESH:D055752', (450, 472))	('LSCC', 'Phenotype', 'HP:0030359', (410, 414))	('lung adenocarcinoma', 'Disease', (389, 408))	('SCLC', 'Disease', (445, 449))	('carcinoma', 'Phenotype', 'HP:0030731', (434, 443))	('NSCLC non-small cell lung cancer', 'Disease', (77, 109))	('small cell lung cancer', 'Disease', (450, 472))	('LAD', 'Disease', 'MESH:C535887', (385, 388))	('SCLC', 'Phenotype', 'HP:0030357', (445, 449))	('cancer', 'Phenotype', 'HP:0002664', (466, 472))	('lung cancer', 'Phenotype', 'HP:0100526', (461, 472))	('Interaction', 'Var', (338, 349))	('HMGB1', 'Gene', (0, 5))	('HMGB1', 'Gene', '3146', (0, 5))	('SCLC', 'Disease', (78, 82))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (389, 408))	('SCLC', 'Phenotype', 'HP:0030357', (78, 82))	('LAD', 'Phenotype', 'HP:0030078', (385, 388))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (479, 507))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (389, 408))	('small cell lung cancer', 'Disease', 'MESH:D055752', (87, 109))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (450, 472))
149705	24962247	Concordance between HPV and p16 expression in the untreated primary tumor was 97% (36 of 37 cases); the only discordant case was in a HPV-positive/p16-negative T4 N2c tonsillar SCC in a former 25 pack-year smoker.	('tumor', 'Disease', (68, 73))	('p16', 'Gene', '1029', (28, 31))	('HPV', 'Species', '10566', (20, 23))	('T4 N2c', 'Var', (160, 166))	('p16', 'Gene', (147, 150))	('SCC', 'Gene', (177, 180))	('p16', 'Gene', (28, 31))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('SCC', 'Gene', '6317', (177, 180))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('p16', 'Gene', '1029', (147, 150))	('HPV', 'Species', '10566', (134, 137))
149710	24962247	In one of these initially HPV+/p16+ cases, ISH for HPV on the recurrent tumor was negative, though subsequent PCR on the recurrent tumor revealed the presence of HPV16 DNA.	('p16', 'Gene', '1029', (31, 34))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('HPV', 'Species', '10566', (51, 54))	('tumor', 'Disease', (72, 77))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('HPV', 'Species', '10566', (162, 165))	('HPV16 DNA', 'Var', (162, 171))	('tumor', 'Disease', (131, 136))	('p16', 'Gene', (31, 34))	('HPV', 'Species', '10566', (26, 29))	('HPV16', 'Species', '333760', (162, 167))	('tumor', 'Disease', 'MESH:D009369', (72, 77))
149713	24962247	The first case was a 67 year old male 80 pack-year former smoker with a poorly differentiated T4N2cM0 SCC of the base of tongue, who experienced a suspected local recurrence within the base of tongue immediately adjacent to his original primary tumor 5 years after completion of chemoradiation.	('SCC', 'Gene', '6317', (102, 105))	('tumor', 'Disease', 'MESH:D009369', (245, 250))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('T4N2cM0', 'Var', (94, 101))	('tumor', 'Disease', (245, 250))	('SCC', 'Gene', (102, 105))
149714	24962247	The untreated original primary tumor demonstrated the presence of HPV DNA by both ISH and PCR and diffuse positive immunostaining for p16, whereas the moderately differentiated tumor that developed five years later was negative for HPV by both ISH and PCR and negative for p16 expression by immunohistochemistry.	('HPV', 'Species', '10566', (66, 69))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('p16', 'Gene', (273, 276))	('p16', 'Gene', (134, 137))	('tumor', 'Disease', (31, 36))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('HPV', 'Species', '10566', (232, 235))	('p16', 'Gene', '1029', (273, 276))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('HPV DNA', 'Var', (66, 73))	('p16', 'Gene', '1029', (134, 137))	('tumor', 'Disease', (177, 182))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
149715	24962247	The second case was a 51 year old male 25 pack-year former smoker with a T4N2c tonsillar SCC, who developed an isolated pulmonary metastasis 3 1/2 years after completing chemoradiation.	('SCC', 'Gene', '6317', (89, 92))	('T4N2c', 'Var', (73, 78))	('SCC', 'Gene', (89, 92))
149819	27337949	CD34-MVD expression was significantly higher in the LNM positive group than the LNM negative group (P<0.05).	('LNM positive', 'Var', (52, 64))	('higher', 'PosReg', (38, 44))	('CD34', 'Gene', (0, 4))	('CD34', 'Gene', '947', (0, 4))
149878	27337949	The co-existence of OPN and infiltrating M2TAMs correlates with disease progression and poor survival, and thus can serve as a prognostic marker in gastric cancer.	('TAMs', 'Chemical', '-', (43, 47))	('gastric cancer', 'Disease', (148, 162))	('OPN', 'Gene', (20, 23))	('co-existence', 'Var', (4, 16))	('gastric cancer', 'Disease', 'MESH:D013274', (148, 162))	('disease progression', 'CPA', (64, 83))	('gastric cancer', 'Phenotype', 'HP:0012126', (148, 162))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('M2TAMs', 'Protein', (41, 47))	('OPN', 'Gene', '6696', (20, 23))
149880	27337949	In the high CD68 expressing group, the average survival time was 56.3+-9.1 months and the 5-year survival rate was 42% (10/24).	('CD68', 'Gene', (12, 16))	('CD68', 'Gene', '968', (12, 16))	('high', 'Var', (7, 11))
149901	27337949	The CD68 and CD34 positivity were significantly associated with lymph node metastasis.	('CD68', 'Gene', '968', (4, 8))	('associated', 'Reg', (48, 58))	('lymph node metastasis', 'CPA', (64, 85))	('CD34', 'Gene', (13, 17))	('CD34', 'Gene', '947', (13, 17))	('positivity', 'Var', (18, 28))	('CD68', 'Gene', (4, 8))
149903	33203919	TP53 Mutations and CDKN2A Mutations/Deletions are Highly Recurrent Molecular Alterations in the Malignant Progression of Sinonasal Papillomas Sinonasal papillomas are benign epithelial tumors of the sinonasal tract that are associated with a synchronous or metachronous sinonasal carcinoma in a subset of cases.	('Sinonasal Papillomas', 'Disease', (121, 141))	('Sinonasal papillomas', 'Disease', 'MESH:D010212', (142, 162))	('tumors', 'Disease', (185, 191))	('Papillomas', 'Phenotype', 'HP:0012740', (131, 141))	('Sinonasal Papillomas', 'Disease', 'MESH:D010212', (121, 141))	('TP53', 'Gene', '7157', (0, 4))	('CDKN2A', 'Gene', (19, 25))	('Sinonasal papillomas', 'Disease', (142, 162))	('tumors', 'Disease', 'MESH:D009369', (185, 191))	('papillomas', 'Phenotype', 'HP:0012740', (152, 162))	('Mutations/Deletions', 'Var', (26, 45))	('CDKN2A', 'Gene', '1029', (19, 25))	('synchronous or metachronous sinonasal carcinoma', 'Disease', 'MESH:D009378', (242, 289))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('papilloma', 'Phenotype', 'HP:0012740', (152, 161))	('tumors of the sinonasal tract', 'Phenotype', 'HP:0030072', (185, 214))	('synchronous or metachronous sinonasal carcinoma', 'Disease', (242, 289))	('Mutations', 'Var', (5, 14))	('TP53', 'Gene', (0, 4))	('carcinoma', 'Phenotype', 'HP:0030731', (280, 289))	('tumors', 'Phenotype', 'HP:0002664', (185, 191))
149904	33203919	Our group recently identified mutually exclusive EGFR mutations and human papillomavirus (HPV) infection in inverted sinonasal papillomas and frequent KRAS mutations in oncocytic sinonasal papillomas.	('papillomas', 'Disease', (189, 199))	('KRAS', 'Gene', '3845', (151, 155))	('EGFR', 'Gene', '1956', (49, 53))	('human', 'Species', '9606', (68, 73))	('papilloma', 'Phenotype', 'HP:0012740', (74, 83))	('papillomas', 'Phenotype', 'HP:0012740', (127, 137))	('mutations', 'Var', (156, 165))	('EGFR', 'Gene', (49, 53))	('mutations', 'Var', (54, 63))	('papillomavirus (HPV) infection', 'Disease', 'MESH:D030361', (74, 104))	('papillomas', 'Phenotype', 'HP:0012740', (189, 199))	('papilloma', 'Phenotype', 'HP:0012740', (127, 136))	('papilloma', 'Phenotype', 'HP:0012740', (189, 198))	('papillomas', 'Disease', 'MESH:D010212', (127, 137))	('papillomas', 'Disease', 'MESH:D010212', (189, 199))	('KRAS', 'Gene', (151, 155))	('papillomas', 'Disease', (127, 137))
149905	33203919	We also demonstrated concordant mutational and HPV infection status in sinonasal papilloma-associated sinonasal carcinomas, confirming a clonal relationship between these tumors.	('HPV infection', 'Disease', (47, 60))	('papilloma-associated sinonasal carcinomas', 'Disease', 'MESH:D010212', (81, 122))	('tumors', 'Disease', 'MESH:D009369', (171, 177))	('mutational', 'Var', (32, 42))	('papilloma', 'Phenotype', 'HP:0012740', (81, 90))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('carcinomas', 'Phenotype', 'HP:0030731', (112, 122))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('HPV infection', 'Disease', 'MESH:D030361', (47, 60))	('papilloma-associated sinonasal carcinomas', 'Disease', (81, 122))	('tumors', 'Disease', (171, 177))	('tumors', 'Phenotype', 'HP:0002664', (171, 177))
149909	33203919	In addition, highly recurrent TP53 mutations, CDKN2A mutations, and/or CDKN2A copy number losses were detected; overall, nearly all tumors (n = 28/29; 96.6%) harbored at least one TP53 or CDKN2A alteration.	('TP53', 'Gene', (30, 34))	('CDKN2A', 'Gene', (71, 77))	('CDKN2A', 'Gene', (46, 52))	('harbored', 'Reg', (158, 166))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('TP53', 'Gene', '7157', (180, 184))	('alteration', 'Var', (195, 205))	('TP53', 'Gene', (180, 184))	('CDKN2A', 'Gene', '1029', (71, 77))	('CDKN2A', 'Gene', '1029', (46, 52))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('CDKN2A', 'Gene', (188, 194))	('CDKN2A', 'Gene', '1029', (188, 194))	('tumors', 'Disease', (132, 138))	('TP53', 'Gene', '7157', (30, 34))	('tumors', 'Disease', 'MESH:D009369', (132, 138))
149911	33203919	Other recurrent molecular alterations included NFE2L2 and PIK3CA mutations and SOX2, CCND1, MYC, FGFR1, and EGFR copy number gains.	('FGFR1', 'Gene', '2260', (97, 102))	('CCND1', 'Gene', '595', (85, 90))	('NFE2L2', 'Gene', '4780', (47, 53))	('SOX2', 'Gene', '6657', (79, 83))	('EGFR', 'Gene', '1956', (108, 112))	('NFE2L2', 'Gene', (47, 53))	('EGFR', 'Gene', (108, 112))	('MYC', 'Gene', '4609', (92, 95))	('PIK3CA', 'Gene', (58, 64))	('CCND1', 'Gene', (85, 90))	('PIK3CA', 'Gene', '5290', (58, 64))	('FGFR1', 'Gene', (97, 102))	('copy number gains', 'Var', (113, 130))	('MYC', 'Gene', (92, 95))	('mutations', 'Var', (65, 74))	('SOX2', 'Gene', (79, 83))
149912	33203919	Importantly, TP53 mutations and CDKN2A alterations were not detected in matched sinonasal papillomas, suggesting that these molecular events are associated with malignant transformation.	('TP53', 'Gene', (13, 17))	('papillomas', 'Disease', 'MESH:D010212', (90, 100))	('CDKN2A', 'Gene', (32, 38))	('papillomas', 'Disease', (90, 100))	('associated', 'Reg', (145, 155))	('CDKN2A', 'Gene', '1029', (32, 38))	('papillomas', 'Phenotype', 'HP:0012740', (90, 100))	('TP53', 'Gene', '7157', (13, 17))	('papilloma', 'Phenotype', 'HP:0012740', (90, 99))	('mutations', 'Var', (18, 27))
149913	33203919	Compared to aerodigestive tract squamous cell carcinomas from The Cancer Genome Atlas (TCGA) project, sinonasal papilloma-associated sinonasal carcinomas have a distinct molecular phenotype, including more frequent EGFR, KRAS, and CDKN2A mutations, TERT copy number gains, and low-risk human papillomavirus (HPV) infection.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (32, 55))	('Cancer', 'Phenotype', 'HP:0002664', (66, 72))	('squamous cell carcinomas', 'Disease', (32, 56))	('papilloma', 'Phenotype', 'HP:0012740', (292, 301))	('carcinoma', 'Phenotype', 'HP:0030731', (46, 55))	('mutations', 'Var', (238, 247))	('human', 'Species', '9606', (286, 291))	('EGFR', 'Gene', (215, 219))	('Cancer', 'Disease', (66, 72))	('papilloma-associated sinonasal carcinomas', 'Disease', (112, 153))	('carcinoma', 'Phenotype', 'HP:0030731', (143, 152))	('papillomavirus (HPV) infection', 'Disease', 'MESH:D030361', (292, 322))	('TERT', 'Gene', (249, 253))	('TERT', 'Gene', '7015', (249, 253))	('carcinomas', 'Phenotype', 'HP:0030731', (143, 153))	('papilloma-associated sinonasal carcinomas', 'Disease', 'MESH:D010212', (112, 153))	('CDKN2A', 'Gene', (231, 237))	('KRAS', 'Gene', '3845', (221, 225))	('carcinomas', 'Phenotype', 'HP:0030731', (46, 56))	('Cancer', 'Disease', 'MESH:D009369', (66, 72))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (32, 56))	('KRAS', 'Gene', (221, 225))	('papilloma', 'Phenotype', 'HP:0012740', (112, 121))	('EGFR', 'Gene', '1956', (215, 219))	('CDKN2A', 'Gene', '1029', (231, 237))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (32, 56))	('more', 'PosReg', (201, 205))
149916	33203919	Over the past several years, our group has utilized a variety of conventional and next-generation sequencing approaches to define the oncogenic events that occur in specific sinonasal papilloma subtypes, including mutually-exclusive EGFR mutations and HPV infection in inverted sinonasal papilloma and KRAS mutations in oncocytic sinonasal papillomas.	('papillomas', 'Disease', (340, 350))	('papilloma', 'Phenotype', 'HP:0012740', (340, 349))	('EGFR', 'Gene', (233, 237))	('mutations', 'Var', (238, 247))	('mutations', 'Var', (307, 316))	('papilloma', 'Disease', (184, 193))	('KRAS', 'Gene', '3845', (302, 306))	('papilloma', 'Disease', 'MESH:D010212', (184, 193))	('papilloma', 'Disease', (288, 297))	('HPV infection', 'Disease', 'MESH:D030361', (252, 265))	('papillomas', 'Disease', 'MESH:D010212', (340, 350))	('papilloma', 'Phenotype', 'HP:0012740', (184, 193))	('EGFR', 'Gene', '1956', (233, 237))	('HPV infection', 'Disease', (252, 265))	('papilloma', 'Disease', 'MESH:D010212', (288, 297))	('KRAS', 'Gene', (302, 306))	('papilloma', 'Phenotype', 'HP:0012740', (288, 297))	('papillomas', 'Phenotype', 'HP:0012740', (340, 350))	('papilloma', 'Disease', (340, 349))	('papilloma', 'Disease', 'MESH:D010212', (340, 349))
149919	33203919	While several studies have reported a high incidence of TP53 mutations in sinonasal papilloma-associated sinonasal carcinomas, a comprehensive assessment of the molecular landscape of these tumors is lacking.	('papilloma', 'Phenotype', 'HP:0012740', (84, 93))	('tumors', 'Disease', 'MESH:D009369', (190, 196))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('carcinomas', 'Phenotype', 'HP:0030731', (115, 125))	('TP53', 'Gene', '7157', (56, 60))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('mutations', 'Var', (61, 70))	('TP53', 'Gene', (56, 60))	('papilloma-associated sinonasal carcinomas', 'Disease', (84, 125))	('tumors', 'Disease', (190, 196))	('tumors', 'Phenotype', 'HP:0002664', (190, 196))	('papilloma-associated sinonasal carcinomas', 'Disease', 'MESH:D010212', (84, 125))
149933	33203919	Briefly, an allele-specific PCR assay was performed, targeting the most common TERT promoter mutations including c.-146C>T (Chr.5:1295250C>T), c.-124C>T (Chr.5:1295228C>T), c.-138_139CC>TT (Chr.5:1295242_1295243CC>TT) and c.-124_125CC>TT (Chr.5:1295228_1295229CC>TT).	('c.-138_139CC>TT', 'Mutation', 'c.-138_139CC>TT', (173, 188))	('c.-124C>T', 'Mutation', 'rs1242535815', (143, 152))	('c.-146C>T', 'Var', (113, 122))	('1295242_1295243CC>TT', 'Mutation', 'c.1295242_1295243CC>TT', (196, 216))	('c.-124_125CC>TT', 'Mutation', 'c.-124_125CC>TT', (222, 237))	('c.-124C>T', 'Var', (143, 152))	('TERT', 'Gene', (79, 83))	('c.-146C>T', 'Mutation', 'c.-146C>T', (113, 122))	('TERT', 'Gene', '7015', (79, 83))	('1295228_1295229CC>TT', 'Mutation', 'c.1295228_1295229CC>TT', (245, 265))	('1295250C>T', 'Mutation', 'g.1295250C>T', (130, 140))	('c.-138_139CC>TT', 'Var', (173, 188))	('c.-124_125CC>TT', 'Var', (222, 237))	('1295228C>T', 'Mutation', 'g.1295228C>T', (160, 170))
149935	33203919	Genes with one or more prioritized alterations in the sinonasal papilloma-associated sinonasal carcinoma cohort were selected for comparison to the TCGA cohorts, and only mutations classified as putative drivers or significant copy number alterations (i.e., amplifications and deep deletions) in the TCGA datasets were retained for subsequent analysis.	('amplifications', 'Var', (258, 272))	('papilloma', 'Phenotype', 'HP:0012740', (64, 73))	('papilloma-associated sinonasal carcinoma', 'Disease', (64, 104))	('deep deletions', 'Var', (277, 291))	('papilloma-associated sinonasal carcinoma', 'Disease', 'MESH:D010212', (64, 104))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))
149939	33203919	To explore the molecular landscape of these tumors, we utilized targeted DNAseq using a custom pan-cancer 133-gene panel that detects mutations and copy number changes in recurrently altered oncogenes and tumor suppressor genes.	('tumors', 'Disease', (44, 50))	('tumors', 'Disease', 'MESH:D009369', (44, 50))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('copy number changes', 'Var', (148, 167))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('cancer', 'Disease', (99, 105))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumor', 'Disease', (205, 210))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('mutations', 'Var', (134, 143))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumor', 'Disease', (44, 49))
149940	33203919	Overall, a total of 76 mutations (median per tumor = 3; range = 0-6) and 38 copy number alterations (median per tumor = 1; range = 0-4) were identified by this panel (see Figure 1 and Supplemental Table 1 for details).	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor', 'Disease', (45, 50))	('copy number alterations', 'Var', (76, 99))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('mutations', 'Var', (23, 32))	('tumor', 'Disease', (112, 117))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
149941	33203919	As expected, targeted DNAseq confirmed the presence of recurrent mutually-exclusive EGFR (n = 21) and KRAS (n = 5) mutations in sinonasal papilloma-associated sinonasal carcinomas; three tumors lacked both EGFR and KRAS mutations - two of which harbored low-risk HPV subtype 11, and one for which HPV PCR analysis failed.	('papilloma-associated sinonasal carcinomas', 'Disease', (138, 179))	('carcinoma', 'Phenotype', 'HP:0030731', (169, 178))	('carcinomas', 'Phenotype', 'HP:0030731', (169, 179))	('papilloma-associated sinonasal carcinomas', 'Disease', 'MESH:D010212', (138, 179))	('HPV', 'Species', '10566', (297, 300))	('EGFR', 'Gene', '1956', (84, 88))	('KRAS', 'Gene', '3845', (215, 219))	('tumors', 'Phenotype', 'HP:0002664', (187, 193))	('KRAS', 'Gene', (102, 106))	('papilloma', 'Phenotype', 'HP:0012740', (138, 147))	('EGFR', 'Gene', (206, 210))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('KRAS', 'Gene', (215, 219))	('HPV', 'Species', '10566', (263, 266))	('tumors', 'Disease', (187, 193))	('KRAS', 'Gene', '3845', (102, 106))	('mutations', 'Var', (115, 124))	('tumors', 'Disease', 'MESH:D009369', (187, 193))	('EGFR', 'Gene', (84, 88))	('EGFR', 'Gene', '1956', (206, 210))
149942	33203919	As described previously, nearly all EGFR mutations occurred in exons 19 or 20; however, a nonsynonymous exon 6 mutation (p.R222C) was detected in one case.	('mutations', 'Var', (41, 50))	('p.R222C', 'Var', (121, 128))	('EGFR', 'Gene', '1956', (36, 40))	('p.R222C', 'Mutation', 'p.R222C', (121, 128))	('EGFR', 'Gene', (36, 40))	('occurred', 'Reg', (51, 59))
149944	33203919	Integration of mutation and copy number data revealed that nearly all tumors (n = 28; 96.6%) harbored at least one TP53 or CDKN2A alteration; in addition, three tumors with EGFR mutations harbored concurrent EGFR copy number gain (two of the mutant allele and one of the wild type allele), while one tumor with a KRAS mutation showed copy number gain of the mutant allele.	('tumors', 'Disease', (161, 167))	('KRAS', 'Gene', '3845', (313, 317))	('gain', 'PosReg', (225, 229))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('CDKN2A', 'Gene', (123, 129))	('tumor', 'Disease', (161, 166))	('KRAS', 'Gene', (313, 317))	('tumor', 'Phenotype', 'HP:0002664', (300, 305))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumors', 'Disease', 'MESH:D009369', (161, 167))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('tumors', 'Disease', (70, 76))	('EGFR', 'Gene', '1956', (173, 177))	('TP53', 'Gene', (115, 119))	('EGFR', 'Gene', (208, 212))	('CDKN2A', 'Gene', '1029', (123, 129))	('tumors', 'Disease', 'MESH:D009369', (70, 76))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('tumors', 'Phenotype', 'HP:0002664', (161, 167))	('tumor', 'Disease', (300, 305))	('TP53', 'Gene', '7157', (115, 119))	('tumor', 'Disease', (70, 75))	('copy number', 'MPA', (213, 224))	('EGFR', 'Gene', '1956', (208, 212))	('EGFR', 'Gene', (173, 177))	('tumor', 'Disease', 'MESH:D009369', (300, 305))	('mutations', 'Var', (178, 187))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
149947	33203919	As expected, EGFR and KRAS genotypes were concordant for all matched papilloma-carcinoma pairs; however, no copy number alterations were identified in any of the matched sinonasal papillomas, and aside from EGFR and KRAS, only one other mutation (an inactivating PIK3R1 frameshift mutation present in one matched papilloma-carcinoma pair) was detected (see Figure 2 and Table 1 for details).	('papilloma-carcinoma', 'Disease', 'MESH:D010212', (313, 332))	('KRAS', 'Gene', (22, 26))	('papilloma', 'Phenotype', 'HP:0012740', (69, 78))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('EGFR', 'Gene', '1956', (13, 17))	('KRAS', 'Gene', '3845', (216, 220))	('papilloma', 'Phenotype', 'HP:0012740', (180, 189))	('frameshift mutation', 'Var', (270, 289))	('EGFR', 'Gene', (207, 211))	('PIK3R1', 'Gene', (263, 269))	('KRAS', 'Gene', (216, 220))	('papilloma', 'Phenotype', 'HP:0012740', (313, 322))	('papillomas', 'Disease', 'MESH:D010212', (180, 190))	('carcinoma', 'Phenotype', 'HP:0030731', (323, 332))	('papilloma-carcinoma', 'Disease', (69, 88))	('papillomas', 'Phenotype', 'HP:0012740', (180, 190))	('EGFR', 'Gene', (13, 17))	('papillomas', 'Disease', (180, 190))	('papilloma-carcinoma', 'Disease', (313, 332))	('EGFR', 'Gene', '1956', (207, 211))	('inactivating', 'Var', (250, 262))	('papilloma-carcinoma', 'Disease', 'MESH:D010212', (69, 88))	('PIK3R1', 'Gene', '5295', (263, 269))	('KRAS', 'Gene', '3845', (22, 26))
149949	33203919	Strikingly, despite the high prevalence of TP53 and CDKN2A alterations in associated sinonasal carcinomas, these alterations were not identified in any of the 11 matched sinonasal papillomas, suggesting that TP53 and/or CDKN2A alterations are early molecular events in the progression to sinonasal carcinoma.	('TP53', 'Gene', '7157', (208, 212))	('CDKN2A', 'Gene', '1029', (52, 58))	('CDKN2A', 'Gene', '1029', (220, 226))	('papilloma', 'Phenotype', 'HP:0012740', (180, 189))	('alterations', 'Var', (59, 70))	('carcinoma', 'Disease', 'MESH:D009369', (298, 307))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('carcinomas', 'Disease', 'MESH:D009369', (95, 105))	('carcinomas', 'Phenotype', 'HP:0030731', (95, 105))	('TP53', 'Gene', (43, 47))	('carcinoma', 'Disease', (95, 104))	('papillomas', 'Disease', 'MESH:D010212', (180, 190))	('carcinoma', 'Phenotype', 'HP:0030731', (298, 307))	('papillomas', 'Phenotype', 'HP:0012740', (180, 190))	('TP53', 'Gene', (208, 212))	('papillomas', 'Disease', (180, 190))	('carcinoma', 'Disease', 'MESH:D009369', (95, 104))	('CDKN2A', 'Gene', (52, 58))	('CDKN2A', 'Gene', (220, 226))	('TP53', 'Gene', '7157', (43, 47))	('carcinomas', 'Disease', (95, 105))	('carcinoma', 'Disease', (298, 307))
149952	33203919	As expected, EGFR and KRAS mutations are significantly enriched in sinonasal papilloma-associated sinonasal carcinomas relative to other aerodigestive tract squamous cell carcinomas (P < 0.001); CDKN2A mutations, TERT copy number gains, and low-risk HPV infection also occur more frequently in these tumors (P < 0.05) (see Figure 3 and Table 2).	('mutations', 'Var', (27, 36))	('papilloma-associated sinonasal carcinomas', 'Disease', 'MESH:D010212', (77, 118))	('HPV infection', 'Disease', (250, 263))	('TERT', 'Gene', (213, 217))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (157, 181))	('tumors', 'Phenotype', 'HP:0002664', (300, 306))	('CDKN2A', 'Gene', '1029', (195, 201))	('KRAS', 'Gene', (22, 26))	('TERT', 'Gene', '7015', (213, 217))	('EGFR', 'Gene', '1956', (13, 17))	('tumor', 'Phenotype', 'HP:0002664', (300, 305))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (157, 181))	('papilloma', 'Phenotype', 'HP:0012740', (77, 86))	('tumors', 'Disease', (300, 306))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (157, 180))	('squamous cell carcinomas', 'Disease', (157, 181))	('tumors', 'Disease', 'MESH:D009369', (300, 306))	('carcinoma', 'Phenotype', 'HP:0030731', (171, 180))	('carcinomas', 'Phenotype', 'HP:0030731', (171, 181))	('EGFR', 'Gene', (13, 17))	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('CDKN2A', 'Gene', (195, 201))	('carcinomas', 'Phenotype', 'HP:0030731', (108, 118))	('HPV infection', 'Disease', 'MESH:D030361', (250, 263))	('KRAS', 'Gene', '3845', (22, 26))	('papilloma-associated sinonasal carcinomas', 'Disease', (77, 118))	('mutations', 'Var', (202, 211))
149955	33203919	Thus, we performed TERT promoter mutation testing on a subset of sinonasal carcinoma and papilloma cases from our cohort using an allele-specific PCR-based approach that detects the majority of such mutations in cancer and has been previously validated in a large cohort of urothelial carcinoma specimens.	('TERT', 'Gene', (19, 23))	('carcinoma and papilloma', 'Disease', 'MESH:D010212', (75, 98))	('TERT', 'Gene', '7015', (19, 23))	('carcinoma', 'Phenotype', 'HP:0030731', (285, 294))	('urothelial carcinoma', 'Disease', (274, 294))	('papilloma', 'Phenotype', 'HP:0012740', (89, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (274, 294))	('cancer', 'Disease', (212, 218))	('cancer', 'Disease', 'MESH:D009369', (212, 218))	('mutations', 'Var', (199, 208))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))
149956	33203919	Surprisingly, we found no evidence of TERT promoter mutations in sinonasal papillomas or carcinomas, suggesting that such mutations are uncommon in these tumors.	('mutations', 'Var', (52, 61))	('carcinomas', 'Disease', (89, 99))	('tumors', 'Disease', (154, 160))	('tumors', 'Disease', 'MESH:D009369', (154, 160))	('carcinomas', 'Phenotype', 'HP:0030731', (89, 99))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('TERT', 'Gene', (38, 42))	('papillomas', 'Disease', 'MESH:D010212', (75, 85))	('papilloma', 'Phenotype', 'HP:0012740', (75, 84))	('papillomas', 'Disease', (75, 85))	('TERT', 'Gene', '7015', (38, 42))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('carcinomas', 'Disease', 'MESH:D009369', (89, 99))	('papillomas', 'Phenotype', 'HP:0012740', (75, 85))
149957	33203919	In this manuscript, we report the first comprehensive assessment of mutations and copy number alterations in sinonasal papilloma-associated sinonasal carcinomas.	('copy number alterations', 'Var', (82, 105))	('papilloma-associated sinonasal carcinomas', 'Disease', 'MESH:D010212', (119, 160))	('carcinomas', 'Phenotype', 'HP:0030731', (150, 160))	('carcinoma', 'Phenotype', 'HP:0030731', (150, 159))	('papilloma', 'Phenotype', 'HP:0012740', (119, 128))	('mutations', 'Var', (68, 77))	('papilloma-associated sinonasal carcinomas', 'Disease', (119, 160))
149958	33203919	As expected, based on our previous work (which constitutes most of the specimens profiled in this study), the majority of tumors harbored either activating EGFR or KRAS mutations, while a small subset of tumors demonstrated low-risk HPV infection.	('tumors', 'Phenotype', 'HP:0002664', (122, 128))	('tumors', 'Disease', (122, 128))	('tumors', 'Disease', 'MESH:D009369', (204, 210))	('tumors', 'Disease', 'MESH:D009369', (122, 128))	('KRAS', 'Gene', '3845', (164, 168))	('mutations', 'Var', (169, 178))	('EGFR', 'Gene', '1956', (156, 160))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('HPV infection', 'Disease', (233, 246))	('activating', 'PosReg', (145, 155))	('EGFR', 'Gene', (156, 160))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumors', 'Disease', (204, 210))	('tumors', 'Phenotype', 'HP:0002664', (204, 210))	('KRAS', 'Gene', (164, 168))	('HPV infection', 'Disease', 'MESH:D030361', (233, 246))
149959	33203919	Inactivating TP53 and/or CDKN2A mutations with loss of heterozygosity or two-copy loss ("deep deletion") of CDKN2A was frequently observed in sinonasal carcinomas but was not present in matched sinonasal papillomas, indicating that these alterations may be early molecular events in malignant progression to sinonasal carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (152, 161))	('TP53', 'Gene', (13, 17))	('carcinoma', 'Phenotype', 'HP:0030731', (318, 327))	('carcinoma', 'Disease', (152, 161))	('carcinoma', 'Disease', (318, 327))	('papilloma', 'Phenotype', 'HP:0012740', (204, 213))	('CDKN2A', 'Gene', '1029', (108, 114))	('carcinomas', 'Disease', 'MESH:D009369', (152, 162))	('Inactivating', 'Var', (0, 12))	('carcinomas', 'Phenotype', 'HP:0030731', (152, 162))	('mutations', 'Var', (32, 41))	('loss', 'NegReg', (82, 86))	('carcinoma', 'Disease', 'MESH:D009369', (152, 161))	('CDKN2A', 'Gene', (25, 31))	('TP53', 'Gene', '7157', (13, 17))	('loss of', 'NegReg', (47, 54))	('carcinoma', 'Disease', 'MESH:D009369', (318, 327))	('papillomas', 'Disease', 'MESH:D010212', (204, 214))	('papillomas', 'Phenotype', 'HP:0012740', (204, 214))	('CDKN2A', 'Gene', '1029', (25, 31))	('papillomas', 'Disease', (204, 214))	('carcinomas', 'Disease', (152, 162))	('CDKN2A', 'Gene', (108, 114))
149960	33203919	In addition, sinonasal papilloma-associated sinonasal carcinomas harbor a number of recurrent molecular alterations that are commonly found in other aerodigestive tract squamous cell carcinomas, although subsets of these alterations are relatively enriched in sinonasal carcinomas - suggesting potential novel carcinogenic pathways in these tumors.	('tumor', 'Phenotype', 'HP:0002664', (341, 346))	('tumors', 'Disease', (341, 347))	('papilloma', 'Phenotype', 'HP:0012740', (23, 32))	('carcinomas', 'Disease', (54, 64))	('carcinoma', 'Phenotype', 'HP:0030731', (54, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (183, 192))	('carcinomas', 'Disease', 'MESH:D009369', (183, 193))	('carcinomas', 'Phenotype', 'HP:0030731', (183, 193))	('carcinoma', 'Phenotype', 'HP:0030731', (270, 279))	('carcinomas', 'Disease', 'MESH:D009369', (270, 280))	('tumors', 'Disease', 'MESH:D009369', (341, 347))	('carcinomas', 'Phenotype', 'HP:0030731', (270, 280))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (169, 193))	('alterations', 'Var', (104, 115))	('carcinomas', 'Disease', 'MESH:D009369', (54, 64))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (169, 193))	('carcinomas', 'Phenotype', 'HP:0030731', (54, 64))	('papilloma-associated sinonasal carcinomas', 'Disease', (23, 64))	('papilloma-associated sinonasal carcinomas', 'Disease', 'MESH:D010212', (23, 64))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (169, 192))	('tumors', 'Phenotype', 'HP:0002664', (341, 347))	('squamous cell carcinomas', 'Disease', (169, 193))	('carcinomas', 'Disease', (183, 193))	('carcinomas', 'Disease', (270, 280))
149961	33203919	Previous studies have implicated TP53 mutations and HPV infection (particularly high-risk subtypes) in the malignant progression of sinonasal papillomas.	('HPV infection', 'Disease', 'MESH:D030361', (52, 65))	('papillomas', 'Disease', 'MESH:D010212', (142, 152))	('TP53', 'Gene', '7157', (33, 37))	('papillomas', 'Disease', (142, 152))	('papillomas', 'Phenotype', 'HP:0012740', (142, 152))	('HPV infection', 'Disease', (52, 65))	('TP53', 'Gene', (33, 37))	('mutations', 'Var', (38, 47))	('papilloma', 'Phenotype', 'HP:0012740', (142, 151))
149962	33203919	While our results clearly support the hypothesis that TP53 mutations are early molecular events in malignant progression to sinonasal carcinoma, there appears to be an emerging consensus against a role for high-risk HPV infection in these tumors.	('carcinoma', 'Disease', (134, 143))	('tumors', 'Disease', (239, 245))	('tumors', 'Disease', 'MESH:D009369', (239, 245))	('tumors', 'Phenotype', 'HP:0002664', (239, 245))	('carcinoma', 'Disease', 'MESH:D009369', (134, 143))	('tumor', 'Phenotype', 'HP:0002664', (239, 244))	('HPV infection', 'Disease', (216, 229))	('TP53', 'Gene', '7157', (54, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('mutations', 'Var', (59, 68))	('TP53', 'Gene', (54, 58))	('HPV infection', 'Disease', 'MESH:D030361', (216, 229))
149968	33203919	In addition to TP53 mutations, our study highlights a central role for CDKN2A inactivation - either through mutation and subsequent loss of heterozygosity or focal "deep deletion" of the gene locus - in sinonasal papilloma-associated sinonasal carcinoma.	('CDKN2A', 'Gene', (71, 77))	('CDKN2A', 'Gene', '1029', (71, 77))	('TP53', 'Gene', '7157', (15, 19))	('papilloma-associated sinonasal carcinoma', 'Disease', (213, 253))	('loss of heterozygosity', 'NegReg', (132, 154))	('TP53', 'Gene', (15, 19))	('papilloma-associated sinonasal carcinoma', 'Disease', 'MESH:D010212', (213, 253))	('papilloma', 'Phenotype', 'HP:0012740', (213, 222))	('mutation', 'Var', (108, 116))	('carcinoma', 'Phenotype', 'HP:0030731', (244, 253))	('inactivation', 'NegReg', (78, 90))
149969	33203919	Indeed, the vast majority of tumors (72.4%) showed evidence of at least one CDKN2A alteration, and all except one (96.6%) harbored at least one TP53 or CDKN2A alteration.	('TP53', 'Gene', '7157', (144, 148))	('CDKN2A', 'Gene', (152, 158))	('TP53', 'Gene', (144, 148))	('CDKN2A', 'Gene', '1029', (76, 82))	('CDKN2A', 'Gene', '1029', (152, 158))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('CDKN2A', 'Gene', (76, 82))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('tumors', 'Disease', 'MESH:D009369', (29, 35))	('tumors', 'Disease', (29, 35))	('alteration', 'Var', (83, 93))
149971	33203919	The frequency of these alterations also suggests that tobacco exposure may play an etiologic role in many sinonasal papilloma-associated sinonasal carcinomas, as the concurrent presence of TP53 and CDKN2A alterations is strongly associated with tobacco exposure in the TCGA head and neck squamous cell carcinoma cohort.	('tobacco', 'Species', '4097', (54, 61))	('TP53', 'Gene', '7157', (189, 193))	('papilloma-associated sinonasal carcinomas', 'Disease', 'MESH:D010212', (116, 157))	('tobacco', 'Species', '4097', (245, 252))	('CDKN2A', 'Gene', (198, 204))	('CDKN2A', 'Gene', '1029', (198, 204))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (283, 311))	('carcinoma', 'Phenotype', 'HP:0030731', (302, 311))	('carcinoma', 'Phenotype', 'HP:0030731', (147, 156))	('TP53', 'Gene', (189, 193))	('alterations', 'Var', (205, 216))	('papilloma', 'Phenotype', 'HP:0012740', (116, 125))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (288, 311))	('papilloma-associated sinonasal carcinomas', 'Disease', (116, 157))	('neck squamous cell carcinoma', 'Disease', (283, 311))	('associated', 'Reg', (229, 239))	('carcinomas', 'Phenotype', 'HP:0030731', (147, 157))
149976	33203919	These secondary alterations include NFE2L2 mutations and SOX2, CCND1, MYC, and FGFR1 copy number gains, which are frequently observed in other aerodigestive tract squamous cell carcinomas.	('NFE2L2', 'Gene', (36, 42))	('CCND1', 'Gene', '595', (63, 68))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (163, 186))	('copy number gains', 'Var', (85, 102))	('NFE2L2', 'Gene', '4780', (36, 42))	('carcinoma', 'Phenotype', 'HP:0030731', (177, 186))	('MYC', 'Gene', (70, 73))	('FGFR1', 'Gene', (79, 84))	('squamous cell carcinomas', 'Disease', (163, 187))	('mutations', 'Var', (43, 52))	('SOX2', 'Gene', (57, 61))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (163, 187))	('carcinomas', 'Phenotype', 'HP:0030731', (177, 187))	('SOX2', 'Gene', '6657', (57, 61))	('FGFR1', 'Gene', '2260', (79, 84))	('CCND1', 'Gene', (63, 68))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (163, 187))	('MYC', 'Gene', '4609', (70, 73))
149984	33203919	The results of this study (and others) clearly indicate that sinonasal papilloma-associated sinonasal carcinomas are similarly molecularly distinct from other aerodigestive tract squamous cell carcinomas, with frequent EGFR and KRAS mutations that are only exceptionally seen at other anatomic sites.	('EGFR', 'Gene', '1956', (219, 223))	('papilloma', 'Phenotype', 'HP:0012740', (71, 80))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (179, 203))	('squamous cell carcinomas', 'Disease', (179, 203))	('EGFR', 'Gene', (219, 223))	('carcinoma', 'Phenotype', 'HP:0030731', (193, 202))	('KRAS', 'Gene', (228, 232))	('papilloma-associated sinonasal carcinomas', 'Disease', (71, 112))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (179, 203))	('carcinomas', 'Phenotype', 'HP:0030731', (193, 203))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('KRAS', 'Gene', '3845', (228, 232))	('mutations', 'Var', (233, 242))	('papilloma-associated sinonasal carcinomas', 'Disease', 'MESH:D010212', (71, 112))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (179, 202))	('carcinomas', 'Phenotype', 'HP:0030731', (102, 112))
149988	33203919	As we have shown previously, the presence of activating EGFR mutations in a large subset of these tumors indicates the potential for targeted therapeutic approaches with EGFR inhibitors, including next-generation molecules that have increased efficacy against tumors with exon 20 insertions (e.g., poziotinib).	('tumors', 'Disease', (98, 104))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('tumors', 'Disease', 'MESH:D009369', (260, 266))	('EGFR', 'Gene', '1956', (170, 174))	('EGFR', 'Gene', '1956', (56, 60))	('tumors', 'Disease', 'MESH:D009369', (98, 104))	('tumors', 'Phenotype', 'HP:0002664', (260, 266))	('mutations', 'Var', (61, 70))	('poziotinib', 'Chemical', 'MESH:C557213', (298, 308))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('activating', 'PosReg', (45, 55))	('EGFR', 'Gene', (56, 60))	('EGFR', 'Gene', (170, 174))	('tumor', 'Phenotype', 'HP:0002664', (260, 265))	('tumors', 'Disease', (260, 266))
149989	33203919	In contrast, based on collective experience in lung and colon cancers, the presence of KRAS mutations in a subset of sinonasal papilloma-associated sinonasal carcinomas likely predicts primary resistance to anti-EGFR-based therapies.	('colon cancers', 'Disease', (56, 69))	('predicts', 'Reg', (176, 184))	('KRAS', 'Gene', (87, 91))	('KRAS', 'Gene', '3845', (87, 91))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('papilloma-associated sinonasal carcinomas', 'Disease', 'MESH:D010212', (127, 168))	('colon cancers', 'Phenotype', 'HP:0003003', (56, 69))	('colon cancers', 'Disease', 'MESH:D015179', (56, 69))	('mutations', 'Var', (92, 101))	('papilloma', 'Phenotype', 'HP:0012740', (127, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (158, 167))	('cancers', 'Phenotype', 'HP:0002664', (62, 69))	('primary resistance', 'MPA', (185, 203))	('papilloma-associated sinonasal carcinomas', 'Disease', (127, 168))	('EGFR', 'Gene', '1956', (212, 216))	('carcinomas', 'Phenotype', 'HP:0030731', (158, 168))	('EGFR', 'Gene', (212, 216))
149991	33203919	Importantly, the results of our current study suggest that subsets of sinonasal papilloma-associated sinonasal carcinomas harbor potentially therapeutically targetable alterations, including PI3K/AKT pathway alterations (i.e., PIK3CA or PIK3R1 mutations, PTEN deletion, etc.)	('papilloma', 'Phenotype', 'HP:0012740', (80, 89))	('AKT', 'Gene', (196, 199))	('AKT', 'Gene', '207', (196, 199))	('carcinomas', 'Phenotype', 'HP:0030731', (111, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('PIK3R1', 'Gene', (237, 243))	('PIK3R1', 'Gene', '5295', (237, 243))	('PIK3CA', 'Gene', (227, 233))	('papilloma-associated sinonasal carcinomas', 'Disease', (80, 121))	('deletion', 'Var', (260, 268))	('alterations', 'Reg', (208, 219))	('PTEN', 'Gene', (255, 259))	('PIK3CA', 'Gene', '5290', (227, 233))	('mutations', 'Var', (244, 253))	('PTEN', 'Gene', '5728', (255, 259))	('papilloma-associated sinonasal carcinomas', 'Disease', 'MESH:D010212', (80, 121))
150000	29533972	High expression of NOTCH1 was associated with better overall survival (p = 0.013) and disease-free survival (p = 0.040).	('High expression', 'Var', (0, 15))	('NOTCH1', 'Gene', '4851', (19, 25))	('NOTCH1', 'Gene', (19, 25))	('disease-free survival', 'CPA', (86, 107))	('overall survival', 'CPA', (53, 69))	('better', 'PosReg', (46, 52))
150014	29533972	Alterations in NOTCH signaling have been described in several cancers and result in tumor promotion or suppression depending on the cancer entity and context.	('cancer', 'Disease', (132, 138))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('NOTCH', 'Gene', '31293', (15, 20))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('described', 'Reg', (41, 50))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('Alterations', 'Var', (0, 11))	('NOTCH', 'Gene', (15, 20))	('suppression', 'NegReg', (103, 114))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('tumor', 'Disease', (84, 89))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('cancers', 'Disease', 'MESH:D009369', (62, 69))	('cancers', 'Phenotype', 'HP:0002664', (62, 69))	('cancers', 'Disease', (62, 69))	('cancer', 'Disease', 'MESH:D009369', (132, 138))
150016	29533972	Frequent mutations of the NOTCH receptor family were detected in HNSCC and most likely result in loss of function of the receptors.	('HNSCC', 'Disease', (65, 70))	('mutations', 'Var', (9, 18))	('NOTCH', 'Gene', (26, 31))	('NOTCH', 'Gene', '31293', (26, 31))	('detected', 'Reg', (53, 61))	('loss of function', 'NegReg', (97, 113))	('HNSCC', 'Phenotype', 'HP:0012288', (65, 70))
150017	29533972	A high incidence of nonsynonymous mutations was identified in 43% of Chinese patients with oral squamous cell carcinoma (OSCC) and the occurrence of mutations was associated with poor overall survival.	('oral squamous cell carcinoma', 'Disease', (91, 119))	('nonsynonymous mutations', 'Var', (20, 43))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('patients', 'Species', '9606', (77, 85))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (91, 119))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (96, 119))
150022	29533972	Significant associations between high NOTCH1 expression and nodal stage and p16 status were found.	('high', 'Var', (33, 37))	('p16', 'Gene', '1029', (76, 79))	('nodal stage', 'CPA', (60, 71))	('expression', 'MPA', (45, 55))	('NOTCH1', 'Gene', '4851', (38, 44))	('NOTCH1', 'Gene', (38, 44))	('p16', 'Gene', (76, 79))
150026	29533972	In HNSCC patients, high mRNA expression of NOTCH1 was associated with better overall survival (OS, p = 0.013) and better disease-free survival (DFS, p = 0.040), as illustrated in Figure 2 and Table 3.	('patients', 'Species', '9606', (9, 17))	('HNSCC', 'Phenotype', 'HP:0012288', (3, 8))	('NOTCH1', 'Gene', '4851', (43, 49))	('NOTCH1', 'Gene', (43, 49))	('better', 'PosReg', (70, 76))	('disease-free survival', 'CPA', (121, 142))	('overall survival', 'CPA', (77, 93))	('better', 'PosReg', (114, 120))	('high mRNA', 'Var', (19, 28))	('HNSCC', 'Disease', (3, 8))
150027	29533972	Multivariate Cox regression confirmed the significant influence of high NOTCH1 expression on OS (p = 0.033) and DFS (p = 0.029) (Table 4).	('high', 'Var', (67, 71))	('Cox', 'Gene', (13, 16))	('DFS', 'Disease', (112, 115))	('NOTCH1', 'Gene', '4851', (72, 78))	('NOTCH1', 'Gene', (72, 78))	('Cox', 'Gene', '1351', (13, 16))
150029	29533972	Prolonged DFS was seen in patients with high mRNA expression of downstream HEY1 (p = 0.077).	('high mRNA expression', 'Var', (40, 60))	('HEY1', 'Gene', (75, 79))	('patients', 'Species', '9606', (26, 34))	('DFS', 'MPA', (10, 13))	('HEY1', 'Gene', '23462', (75, 79))
150036	29533972	Patients with p16-positive tumors with high NOTCH1 expression had longer overall survival (n = 50, p = 0.139, Figure 4).	('p16', 'Gene', '1029', (14, 17))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('high', 'Var', (39, 43))	('NOTCH1', 'Gene', '4851', (44, 50))	('tumors', 'Disease', (27, 33))	('tumors', 'Disease', 'MESH:D009369', (27, 33))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('NOTCH1', 'Gene', (44, 50))	('p16', 'Gene', (14, 17))	('Patients', 'Species', '9606', (0, 8))	('longer', 'PosReg', (66, 72))	('overall survival', 'MPA', (73, 89))
150041	29533972	NOTCH1 (NTM) protein expression was higher in the HPV-positive cell lines compared with in the HPV-negative cell lines, but this was not statistically significant (p = 0.068).	('NTM', 'Gene', (8, 11))	('higher', 'PosReg', (36, 42))	('NOTCH1', 'Gene', (0, 6))	('NTM', 'Gene', '50863', (8, 11))	('HPV-positive', 'Var', (50, 62))	('NOTCH1', 'Gene', '4851', (0, 6))	('HPV', 'Species', '10566', (50, 53))	('HPV', 'Species', '10566', (95, 98))
150047	29533972	The subgroup with high NOTCH1 expression had significantly longer overall survival and disease-free survival.	('expression', 'MPA', (30, 40))	('overall survival', 'CPA', (66, 82))	('NOTCH1', 'Gene', '4851', (23, 29))	('NOTCH1', 'Gene', (23, 29))	('longer', 'PosReg', (59, 65))	('disease-free survival', 'CPA', (87, 108))	('high', 'Var', (18, 22))
150048	29533972	Corresponding to this result, patients with high expression of downstream effector HEY1 showed significantly longer DFS.	('longer', 'PosReg', (109, 115))	('HEY1', 'Gene', '23462', (83, 87))	('HEY1', 'Gene', (83, 87))	('high expression', 'Var', (44, 59))	('DFS', 'MPA', (116, 119))	('patients', 'Species', '9606', (30, 38))
150051	29533972	Consistent with these results, in oropharyngeal squamous cell carcinoma patients, NOTCH1 staining correlated with improved survival.	('oropharyngeal squamous cell carcinoma', 'Disease', (34, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (62, 71))	('survival', 'Disease', (123, 131))	('patients', 'Species', '9606', (72, 80))	('NOTCH1', 'Gene', '4851', (82, 88))	('improved', 'PosReg', (114, 122))	('oropharyngeal squamous cell carcinoma', 'Phenotype', 'HP:0012182', (34, 71))	('oropharyngeal squamous cell carcinoma', 'Disease', 'MESH:D002294', (34, 71))	('NOTCH1', 'Gene', (82, 88))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (48, 71))	('staining', 'Var', (89, 97))
150053	29533972	However, in two reports, HNSCC patients with high NOTCH1 protein expression in immunohistochemistry showed poor prognosis.	('NOTCH1', 'Gene', '4851', (50, 56))	('HNSCC', 'Disease', (25, 30))	('HNSCC', 'Phenotype', 'HP:0012288', (25, 30))	('NOTCH1', 'Gene', (50, 56))	('high', 'Var', (45, 49))	('patients', 'Species', '9606', (31, 39))
150056	29533972	Moreover, NOTCH1 receptor mutation can alter downstream activation significantly, and downstream alterations can also change the effect of NOTCH signaling.	('downstream activation', 'MPA', (45, 66))	('alter', 'Reg', (39, 44))	('mutation', 'Var', (26, 34))	('NOTCH', 'Gene', (139, 144))	('NOTCH', 'Gene', '31293', (139, 144))	('effect', 'MPA', (129, 135))	('NOTCH1', 'Gene', '4851', (10, 16))	('change', 'Reg', (118, 124))	('NOTCH', 'Gene', (10, 15))	('NOTCH', 'Gene', '31293', (10, 15))	('NOTCH1', 'Gene', (10, 16))
150057	29533972	reported that patients with mutant NOTCH1 receptor expressed downstream HES1/HEY1 similar to normal epithelium but a large subset of NOTCH1 wildtype patients showed an overexpression of HES1/HEY1.	('HES1', 'Gene', (186, 190))	('NOTCH1', 'Gene', '4851', (35, 41))	('mutant', 'Var', (28, 34))	('patients', 'Species', '9606', (149, 157))	('HEY1', 'Gene', '23462', (191, 195))	('HES1', 'Gene', '3280', (72, 76))	('HES1', 'Gene', '3280', (186, 190))	('NOTCH1', 'Gene', '4851', (133, 139))	('NOTCH1', 'Gene', (133, 139))	('HEY1', 'Gene', (191, 195))	('HEY1', 'Gene', '23462', (77, 81))	('HES1', 'Gene', (72, 76))	('overexpression', 'PosReg', (168, 182))	('HEY1', 'Gene', (77, 81))	('patients', 'Species', '9606', (14, 22))	('NOTCH1', 'Gene', (35, 41))
150061	29533972	Both high NOTCH1 expression and p16 staining were independent significant factors in the multiple stepwise Cox regression analysis for overall survival.	('high', 'Var', (5, 9))	('p16', 'Gene', '1029', (32, 35))	('expression', 'MPA', (17, 27))	('Cox', 'Gene', '1351', (107, 110))	('Cox', 'Gene', (107, 110))	('NOTCH1', 'Gene', '4851', (10, 16))	('p16', 'Gene', (32, 35))	('NOTCH1', 'Gene', (10, 16))
150062	29533972	A nonsignificant association was found between patients with high NOTCH1 expression and longer overall survival in the p16-positive patient group (n = 50, p = 0.139), but not in the p16-negative group (n = 118, p = 0.967).	('p16', 'Gene', (119, 122))	('patient', 'Species', '9606', (47, 54))	('p16', 'Gene', (182, 185))	('high', 'Var', (61, 65))	('patients', 'Species', '9606', (47, 55))	('p16', 'Gene', '1029', (119, 122))	('expression', 'MPA', (73, 83))	('NOTCH1', 'Gene', '4851', (66, 72))	('overall', 'MPA', (95, 102))	('p16', 'Gene', '1029', (182, 185))	('patient', 'Species', '9606', (132, 139))	('longer', 'PosReg', (88, 94))	('NOTCH1', 'Gene', (66, 72))
150065	29533972	High NOTCH1 expression is therefore probably an independent positive prognostic factor in p16-positive patients only.	('p16', 'Gene', '1029', (90, 93))	('High', 'Var', (0, 4))	('NOTCH1', 'Gene', '4851', (5, 11))	('NOTCH1', 'Gene', (5, 11))	('p16', 'Gene', (90, 93))	('patients', 'Species', '9606', (103, 111))	('expression', 'MPA', (12, 22))
150068	29533972	After validation in a bigger p16-positive patient cohort, high NOTCH1 expression could be further analyzed for use as a predictive marker and potentially used, e.g., in future de-escalation studies in p16-positive patients.	('p16', 'Gene', (29, 32))	('patient', 'Species', '9606', (214, 221))	('patients', 'Species', '9606', (214, 222))	('p16', 'Gene', '1029', (201, 204))	('p16', 'Gene', '1029', (29, 32))	('patient', 'Species', '9606', (42, 49))	('expression', 'MPA', (70, 80))	('high', 'Var', (58, 62))	('p16', 'Gene', (201, 204))	('NOTCH1', 'Gene', '4851', (63, 69))	('NOTCH1', 'Gene', (63, 69))
150075	29533972	Pickering also analyzed NOTCH1 expression in different HNSCC cell lines and detected an association between NOTCH1 mutational status and NOTCH1 expression.	('HNSCC', 'Phenotype', 'HP:0012288', (55, 60))	('expression', 'MPA', (144, 154))	('NOTCH1', 'Gene', '4851', (137, 143))	('mutational status', 'Var', (115, 132))	('NOTCH1', 'Gene', '4851', (24, 30))	('NOTCH1', 'Gene', (24, 30))	('NOTCH1', 'Gene', (137, 143))	('NOTCH1', 'Gene', (108, 114))	('NOTCH1', 'Gene', '4851', (108, 114))	('association', 'Interaction', (88, 99))
150076	29533972	Interestingly, NOTCH1 mutations were predominantly found in HPV-negative patient tissue in another investigation.	('NOTCH1', 'Gene', '4851', (15, 21))	('NOTCH1', 'Gene', (15, 21))	('patient', 'Species', '9606', (73, 80))	('HPV', 'Species', '10566', (60, 63))	('mutations', 'Var', (22, 31))
150078	29533972	Moreover, it has been reported that cutaneous HPV E6 proteins inactivate NOTCH1 signaling downstream via interaction with mastermind-like (MAML) and thus promotes dedifferentiation.	('dedifferentiation', 'CPA', (163, 180))	('E6 proteins', 'Var', (50, 61))	('promotes', 'PosReg', (154, 162))	('HPV', 'Species', '10566', (46, 49))	('inactivate', 'NegReg', (62, 72))	('HPV', 'Gene', (46, 49))	('interaction', 'Interaction', (105, 116))	('NOTCH1', 'Gene', '4851', (73, 79))	('NOTCH1', 'Gene', (73, 79))
150082	29533972	Patients with high expression of NOTCH1 showed significantly better prognosis.	('NOTCH1', 'Gene', '4851', (33, 39))	('NOTCH1', 'Gene', (33, 39))	('better', 'PosReg', (61, 67))	('Patients', 'Species', '9606', (0, 8))	('high expression', 'Var', (14, 29))
150083	29533972	The favorable prognostic relevance of high NOTCH1 expression was only seen in p16-positive patients.	('p16', 'Gene', (78, 81))	('patients', 'Species', '9606', (91, 99))	('NOTCH1', 'Gene', '4851', (43, 49))	('NOTCH1', 'Gene', (43, 49))	('high', 'Var', (38, 42))	('p16', 'Gene', '1029', (78, 81))	('expression', 'MPA', (50, 60))
150084	29533972	High NOTCH1 expression should therefore be further evaluated as a prognostic marker in a larger cohort of p16-positive patients.	('High', 'Var', (0, 4))	('NOTCH1', 'Gene', '4851', (5, 11))	('NOTCH1', 'Gene', (5, 11))	('p16', 'Gene', (106, 109))	('patients', 'Species', '9606', (119, 127))	('expression', 'MPA', (12, 22))	('p16', 'Gene', '1029', (106, 109))
150086	29533972	Inhibitors of NOTCH signaling are already in clinical testing in other malignancies such as pancreatic and small-cell lung cancers.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('lung cancers', 'Phenotype', 'HP:0100526', (118, 130))	('small-cell lung cancers', 'Disease', 'MESH:D055752', (107, 130))	('pancreatic', 'Disease', 'MESH:D010195', (92, 102))	('malignancies', 'Disease', (71, 83))	('Inhibitors', 'Var', (0, 10))	('small-cell lung cancers', 'Disease', (107, 130))	('pancreatic', 'Disease', (92, 102))	('cancers', 'Phenotype', 'HP:0002664', (123, 130))	('NOTCH', 'Gene', '31293', (14, 19))	('NOTCH', 'Gene', (14, 19))	('malignancies', 'Disease', 'MESH:D009369', (71, 83))
150087	29533972	However, NOTCH inhibition seems less promising in HNSCC, since patients with high NOTCH1 expression demonstrated better survival in our study.	('NOTCH', 'Gene', (9, 14))	('NOTCH', 'Gene', '31293', (9, 14))	('better', 'PosReg', (113, 119))	('high', 'Var', (77, 81))	('survival', 'CPA', (120, 128))	('NOTCH', 'Gene', '31293', (82, 87))	('NOTCH1', 'Gene', '4851', (82, 88))	('NOTCH', 'Gene', (82, 87))	('HNSCC', 'Phenotype', 'HP:0012288', (50, 55))	('NOTCH1', 'Gene', (82, 88))	('patients', 'Species', '9606', (63, 71))
150189	29258175	studied the effect of capsaicin on human pharyngeal SCC cells (FaDu) and found that capsaicin inhibits growth and proliferation in a time and dose dependent manner and induces apoptosis via mitochondrial pathways.	('induces', 'Reg', (168, 175))	('human', 'Species', '9606', (35, 40))	('mitochondrial pathways', 'Pathway', (190, 212))	('SCC', 'Gene', (52, 55))	('SCC', 'Phenotype', 'HP:0002860', (52, 55))	('inhibits', 'NegReg', (94, 102))	('capsaicin', 'Chemical', 'MESH:D002211', (84, 93))	('capsaicin', 'Var', (84, 93))	('capsaicin', 'Chemical', 'MESH:D002211', (22, 31))	('apoptosis', 'CPA', (176, 185))	('SCC', 'Gene', '6317', (52, 55))
150193	29258175	studied the chemoprotective effect of capsaicin against tumorigenesis and mutagenesis produced by vinyl carbamate (VC) and N-nitrosodimethylamine(NDMA) also on female ICR mice.	('capsaicin', 'Chemical', 'MESH:D002211', (38, 47))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('mice', 'Species', '10090', (171, 175))	('N-nitrosodimethylamine', 'Var', (123, 145))	('tumor', 'Disease', (56, 61))	('N-nitrosodimethylamine', 'Chemical', 'MESH:D004128', (123, 145))	('NDMA', 'Chemical', 'MESH:D004128', (146, 150))	('VC', 'Chemical', 'MESH:C017963', (115, 117))	('carbamate', 'Chemical', 'MESH:D002219', (104, 113))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('mutagenesis', 'CPA', (74, 85))
150244	29258175	Another study published in 2010 showed that topical application of capsaicin on the skin of TRPV1 wildtype mice and TRPV1 knockout mice, which were previously subjected to the two-stage skin carcinogenesis experiment with DMBA (9,10-Dimethyl-1,2-benzanthracene) and TPA, was associated with significantly more and larger tumors than TPA treatment alone.	('TPA', 'Chemical', '-', (333, 336))	('TPA', 'Chemical', '-', (266, 269))	('9,10-Dimethyl-1,2-benzanthracene', 'Chemical', 'MESH:D015127', (228, 260))	('TRPV1', 'Gene', (92, 97))	('DMBA', 'Chemical', 'MESH:D015127', (222, 226))	('skin carcinogenesis', 'Disease', 'MESH:D063646', (186, 205))	('TRPV1', 'Gene', (116, 121))	('tumors', 'Disease', 'MESH:D009369', (321, 327))	('tumor', 'Phenotype', 'HP:0002664', (321, 326))	('mice', 'Species', '10090', (107, 111))	('knockout', 'Var', (122, 130))	('capsaicin', 'Chemical', 'MESH:D002211', (67, 76))	('TRPV1', 'Gene', '193034', (92, 97))	('mice', 'Species', '10090', (131, 135))	('TRPV1', 'Gene', '193034', (116, 121))	('skin carcinogenesis', 'Disease', (186, 205))	('tumors', 'Phenotype', 'HP:0002664', (321, 327))	('tumors', 'Disease', (321, 327))
150245	29258175	TRPV1 knockout mice were more affected than TRPV1 wildtype mice.	('TRPV1', 'Gene', '193034', (0, 5))	('mice', 'Species', '10090', (59, 63))	('TRPV1', 'Gene', (44, 49))	('TRPV1', 'Gene', (0, 5))	('knockout', 'Var', (6, 14))	('mice', 'Species', '10090', (15, 19))	('TRPV1', 'Gene', '193034', (44, 49))
150253	29258175	Moreover, the phosphorylation level of EGFR was significantly increased in AMG9810 treated mice compared to the control groups.	('increased', 'PosReg', (62, 71))	('AMG9810 treated', 'Var', (75, 90))	('mice', 'Species', '10090', (91, 95))	('phosphorylation level', 'MPA', (14, 35))	('EGFR', 'Gene', (39, 43))	('EGFR', 'Gene', '13649', (39, 43))	('AMG9810', 'Chemical', 'MESH:C500530', (75, 82))
150254	29258175	EGFR phosphorylation activates the Akt/mTOR-signaling pathway which has an important role in tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (93, 98))	('EGFR', 'Gene', (0, 4))	('EGFR', 'Gene', '13649', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('phosphorylation', 'Var', (5, 20))	('tumor', 'Disease', (93, 98))	('mTOR', 'Gene', (39, 43))	('mTOR', 'Gene', '56717', (39, 43))	('Akt', 'Gene', '11651', (35, 38))	('activates', 'PosReg', (21, 30))	('Akt', 'Gene', (35, 38))
150255	29258175	It was therefore concluded that the TRPV1 antagonist induces carcinogenesis by activating the EGFR/Akt/mTOR signaling pathway.	('mTOR', 'Gene', (103, 107))	('activating', 'PosReg', (79, 89))	('mTOR', 'Gene', '56717', (103, 107))	('Akt', 'Gene', '11651', (99, 102))	('carcinogenesis', 'Disease', (61, 75))	('TRPV1', 'Gene', (36, 41))	('EGFR', 'Gene', (94, 98))	('EGFR', 'Gene', '13649', (94, 98))	('Akt', 'Gene', (99, 102))	('induces', 'PosReg', (53, 60))	('antagonist', 'Var', (42, 52))	('TRPV1', 'Gene', '193034', (36, 41))	('carcinogenesis', 'Disease', 'MESH:D063646', (61, 75))
150256	29258175	also studied the effect of topical applications of capsaicin on the dorsal skin of mice in which carcinogenesis was induced by DMBA/TPA.	('carcinogenesis', 'Disease', (97, 111))	('capsaicin', 'Chemical', 'MESH:D002211', (51, 60))	('mice', 'Species', '10090', (83, 87))	('DMBA/TPA', 'Chemical', '-', (127, 135))	('DMBA/TPA', 'Var', (127, 135))	('carcinogenesis', 'Disease', 'MESH:D063646', (97, 111))
150276	31638244	Cisplatin is activated via the replacement of a chloride ligand with H2O in the cancer cell cytoplasm.	('Cisplatin', 'Enzyme', (0, 9))	('replacement', 'Var', (31, 42))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('Cisplatin', 'Chemical', 'MESH:D002945', (0, 9))	('H2O', 'Chemical', 'MESH:D014867', (69, 72))	('activated', 'PosReg', (13, 22))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('H2O', 'Gene', (69, 72))	('chloride', 'Chemical', 'MESH:D002712', (48, 56))	('cancer', 'Disease', (80, 86))
150280	31638244	Some research indicates that cisplatin resistance can result from variations of genetic and protein expression at the cellular level.	('result from', 'Reg', (54, 65))	('cisplatin', 'MPA', (29, 38))	('variations', 'Var', (66, 76))	('cisplatin', 'Chemical', 'MESH:D002945', (29, 38))
150329	31638244	The specimens were incubated with ATP7B (1:250), Ki-67 (1:250) or IL-6 (1:100) antibodies overnight at 4 C, followed by Alexa Fluor 488 anti-rabbit IgG (1:1,000) as a secondary antibody.	('1:250', 'Var', (56, 61))	('IL-6', 'Gene', '3569', (66, 70))	('Ki-67', 'Gene', '17345', (49, 54))	('Ki-67', 'Gene', (49, 54))	('rabbit', 'Species', '9986', (141, 147))	('Alexa', 'Chemical', 'MESH:C569686', (120, 125))	('1:100', 'Var', (72, 77))	('IL-6', 'Gene', (66, 70))
150361	31638244	The total area of radiographic osteolytic lesions from all tibiae was significantly suppressed by the TM+cisplatin treatment compared to treatment with cisplatin treatment (P<0.05).	('TM+cisplatin', 'Var', (102, 114))	('TM', 'Chemical', 'MESH:C020809', (102, 104))	('osteolytic lesions', 'Disease', (31, 49))	('cisplatin', 'Chemical', 'MESH:D002945', (152, 161))	('cisplatin', 'Chemical', 'MESH:D002945', (105, 114))	('suppressed', 'NegReg', (84, 94))	('osteolytic lesions', 'Disease', 'MESH:D030981', (31, 49))	('osteolytic lesions', 'Phenotype', 'HP:0002797', (31, 49))
150363	31638244	The dual treatment with TM+cisplatin markedly decreased the tumor burden (Fig.	('cisplatin', 'Chemical', 'MESH:D002945', (27, 36))	('TM', 'Chemical', 'MESH:C020809', (24, 26))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('decreased', 'NegReg', (46, 55))	('tumor', 'Disease', (60, 65))	('TM+cisplatin', 'Var', (24, 36))
150369	31638244	Whereas TM alone did not increase the expression of cleaved caspase-3, the dual treatment of TM+cisplatin enhanced the expression of cleaved caspase-3 compared to the treatment with either TM or cisplatin alone (Fig.	('expression', 'MPA', (119, 129))	('TM+cisplatin', 'Var', (93, 105))	('cisplatin', 'Chemical', 'MESH:D002945', (96, 105))	('enhanced', 'PosReg', (106, 114))	('TM', 'Chemical', 'MESH:C020809', (189, 191))	('TM', 'Chemical', 'MESH:C020809', (93, 95))	('cleaved', 'MPA', (133, 140))	('TM', 'Chemical', 'MESH:C020809', (8, 10))	('cisplatin', 'Chemical', 'MESH:D002945', (195, 204))
150387	31638244	Copper metabolism is critical for cell proliferation, and it is strictly regulated by the copper transporters Crt1, ATP7A, and ATP7B.	('copper', 'Chemical', 'MESH:D003300', (90, 96))	('Copper', 'Chemical', 'MESH:D003300', (0, 6))	('Crt1', 'Gene', (110, 114))	('Crt1', 'Gene', '1404', (110, 114))	('ATP7A', 'Gene', (116, 121))	('ATP7A', 'Gene', '538', (116, 121))	('ATP7B', 'Var', (127, 132))
150388	31638244	ATP7B is expressed in mitochondria and excretes copper from the cytoplasm to the extracellular space.	('ATP7B', 'Var', (0, 5))	('excretes', 'MPA', (39, 47))	('copper', 'Chemical', 'MESH:D003300', (48, 54))
150418	31638244	The expression of ATP7B in parental A431 and cisplatin-resistant A431 (A431 CDDP-R) cells was evaluated, and notably, the ATP7B expression in the A431CDDP-R cells was markedly increased compared to the expression in the parental A431 cells.	('CDDP', 'Chemical', 'MESH:D002945', (150, 154))	('increased', 'PosReg', (176, 185))	('cisplatin', 'Chemical', 'MESH:D002945', (45, 54))	('A431', 'CellLine', 'CVCL:0037', (65, 69))	('ATP7B', 'Gene', (122, 127))	('A431', 'CellLine', 'CVCL:0037', (146, 150))	('CDDP', 'Chemical', 'MESH:D002945', (76, 80))	('A431', 'CellLine', 'CVCL:0037', (229, 233))	('expression', 'MPA', (128, 138))	('A431CDDP-R', 'Var', (146, 156))	('A431', 'CellLine', 'CVCL:0037', (36, 40))	('A431', 'CellLine', 'CVCL:0037', (71, 75))
150422	31638244	However, the present data revealed one possibility that ATP7B expression is associated to cisplatin resistance.	('associated', 'Reg', (76, 86))	('cisplatin resistance', 'Disease', (90, 110))	('ATP7B', 'Var', (56, 61))	('cisplatin', 'Chemical', 'MESH:D002945', (90, 99))
150482	31667016	A large number of studies have shown that high infiltration mast cells in tumors are associated with a good prognosis of patients, which runs counter to our results.	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('high infiltration', 'Var', (42, 59))	('tumors', 'Disease', (74, 80))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('patients', 'Species', '9606', (121, 129))	('tumors', 'Disease', 'MESH:D009369', (74, 80))
150491	28880866	Here we combined whole genome data from >700 tumors and paired normal tissues to provide a portrait of rDNA variation in human tissues and cancers of diverse mutational signatures, including stomach and lung adenocarcinomas, ovarian cancers, and others of the TCGA panel.	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('cancers', 'Phenotype', 'HP:0002664', (139, 146))	('cancers', 'Disease', (139, 146))	('human', 'Species', '9606', (121, 126))	('ovarian cancers', 'Phenotype', 'HP:0100615', (225, 240))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('cancers', 'Disease', 'MESH:D009369', (233, 240))	('variation', 'Var', (108, 117))	('carcinoma', 'Phenotype', 'HP:0030731', (213, 222))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (203, 223))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('cancers', 'Disease', 'MESH:D009369', (139, 146))	('tumors', 'Disease', (45, 51))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (203, 222))	('ovarian cancers', 'Disease', (225, 240))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (203, 223))	('ovarian cancers', 'Disease', 'MESH:D010051', (225, 240))	('rDNA', 'Gene', (103, 107))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('tumors', 'Disease', 'MESH:D009369', (45, 51))	('cancers', 'Phenotype', 'HP:0002664', (233, 240))	('cancers', 'Disease', (233, 240))	('lung adenocarcinomas', 'Disease', (203, 223))
150493	28880866	These somatic changes in rDNA CN occur in a background of over 10-fold naturally occurring rDNA CN variation across individuals and cCNV of 5S-45S arrays in some but not all tissues.	('5S', 'Chemical', '-', (140, 142))	('variation', 'Var', (99, 108))	('5S', 'Chemical', '-', (144, 146))	('rDNA CN', 'Gene', (91, 98))
150494	28880866	Analysis of genetic context revealed associations between cancer rDNA CN amplification or loss and the presence of specific somatic alterations, including somatic SNPs and copy number gain/losses in protein coding genes across the cancer genome.	('protein', 'Protein', (199, 206))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('cancer', 'Disease', 'MESH:D009369', (231, 237))	('loss', 'NegReg', (90, 94))	('cancer', 'Disease', (231, 237))	('rDNA CN', 'Gene', (65, 72))	('copy number', 'Var', (172, 183))	('gain/losses', 'PosReg', (184, 195))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('cancer', 'Disease', (58, 64))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('amplification', 'Var', (73, 86))
150495	28880866	For instance, somatic inactivation of the tumor suppressor gene TP53 emerged with a strong association with coupled 5S expansion / 45S loss in several cancers.	('tumor', 'Disease', (42, 47))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('loss', 'NegReg', (135, 139))	('5S expansion / 45S', 'Var', (116, 134))	('TP53', 'Gene', '7157', (64, 68))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('TP53', 'Gene', (64, 68))	('5S', 'Chemical', '-', (132, 134))	('cancers', 'Disease', 'MESH:D009369', (151, 158))	('cancers', 'Phenotype', 'HP:0002664', (151, 158))	('cancers', 'Disease', (151, 158))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('5S', 'Chemical', '-', (116, 118))
150497	28880866	We suggest that 5S rDNA amplification facilitates increased proliferation, nucleolar activity, and ribosomal synthesis in cancer, whereas 45S rDNA loss emerges as a byproduct of transcription-replication conflict in rapidly replicating tumor cells.	('facilitates', 'PosReg', (38, 49))	('cancer', 'Disease', (122, 128))	('increased', 'PosReg', (50, 59))	('5S', 'Chemical', '-', (16, 18))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('tumor', 'Disease', 'MESH:D009369', (236, 241))	('5S', 'Chemical', '-', (139, 141))	('amplification', 'Var', (24, 37))	('nucleolar activity', 'MPA', (75, 93))	('tumor', 'Phenotype', 'HP:0002664', (236, 241))	('proliferation', 'CPA', (60, 73))	('ribosomal synthesis', 'MPA', (99, 118))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('tumor', 'Disease', (236, 241))
150502	28880866	The coupled 5S amplification and 45S loss is associated with the presence of certain somatic genetic alterations, as well as increased estimates of cancerous cell proliferation rate and nucleolar activity.	('5S', 'Chemical', '-', (34, 36))	('increased', 'PosReg', (125, 134))	('nucleolar activity', 'CPA', (186, 204))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('cancerous', 'Disease', 'MESH:D009369', (148, 157))	('loss', 'NegReg', (37, 41))	('5S', 'Chemical', '-', (12, 14))	('5S amplification', 'Var', (12, 28))	('cancerous', 'Disease', (148, 157))
150510	28880866	It is thus not surprising that altered ribosomal biogenesis and rRNA regulation has been linked to a variety of human diseases.	('altered', 'Var', (31, 38))	('rRNA regulation', 'MPA', (64, 79))	('ribosomal biogenesis', 'MPA', (39, 59))	('human', 'Species', '9606', (112, 117))	('linked', 'Reg', (89, 95))
150511	28880866	The dysregulation of cRP genes (cRPGs) can destabilize rRNAs and/or disturb their synthesis, or alternatively participate in tumorigenesis through TP53-related pathways.	('rRNAs', 'MPA', (55, 60))	('TP53', 'Gene', (147, 151))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('dysregulation', 'Var', (4, 17))	('disturb', 'NegReg', (68, 75))	('destabilize', 'NegReg', (43, 54))	('tumor', 'Disease', (125, 130))	('cRP genes (cRPGs', 'Gene', (21, 37))	('cRPGs', 'Gene', (32, 37))	('synthesis', 'MPA', (82, 91))	('TP53', 'Gene', '7157', (147, 151))	('participate', 'Reg', (110, 121))
150523	28880866	We applied new methods and corrections for aneuploidy and sequencing batch to provide a comprehensive portrait of rDNA variation in cancer and normal tissues.	('cancer', 'Disease', (132, 138))	('variation', 'Var', (119, 128))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('aneuploidy', 'Disease', (43, 53))	('rDNA', 'Gene', (114, 118))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('aneuploidy', 'Disease', 'MESH:D000782', (43, 53))
150530	28880866	Hence, we accounted for ploidy variation in tumors using estimates of per gene copy number amplification/loss from the FireBrowse portal, which were ascertained by the GISTIC 2.0 pipeline using the genome-wide SNP array data.	('tumors', 'Disease', (44, 50))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('tumors', 'Disease', 'MESH:D009369', (44, 50))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('copy number amplification/loss', 'Var', (79, 109))
150543	28880866	We compared paired tumor and adjacent tissue within an individual to obtain estimates of rDNA fold-change amplification and loss in cancer lineages.	('loss', 'NegReg', (124, 128))	('cancer', 'Disease', (132, 138))	('rDNA', 'Gene', (89, 93))	('fold-change amplification', 'Var', (94, 119))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('amplification', 'Var', (106, 119))	('tumor', 'Disease', (19, 24))	('cancer', 'Disease', 'MESH:D009369', (132, 138))
150554	28880866	Multiple mutations are involved in cancer development.	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('mutations', 'Var', (9, 18))	('involved', 'Reg', (23, 31))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('cancer', 'Disease', (35, 41))
150558	28880866	Reassuringly, the strongest association for 5S is its positive correlation with 1q42.3 amplification in STAD (Fig 4A).	('STAD', 'Disease', (104, 108))	('1q42.3 amplification', 'Var', (80, 100))	('5S', 'Chemical', '-', (44, 46))
150560	28880866	Besides 1q42 amplification, most other significant rDNA-associated SCNAs are physically unlinked to either the 45S or the 5S rDNA array.	('5S', 'Chemical', '-', (112, 114))	('rDNA-associated', 'Disease', (51, 66))	('1q42', 'Var', (8, 12))	('5S', 'Chemical', '-', (122, 124))
150561	28880866	For example, 9q34.3 amplification is significantly associated with the accumulation of 5S (Fig 4A, linear regression's coefficient = 31.15 and P = 5.23e-6), whereas 15q11.2 deletion is associated with 45S loss in STAD (Fig 4A, coefficient = -91.86 and P = 0.00022).	('STAD', 'Disease', (213, 217))	('15q11.2 deletion', 'Var', (165, 181))	('loss', 'NegReg', (205, 209))	('5S', 'Chemical', '-', (202, 204))	('5S', 'Chemical', '-', (87, 89))	('9q34.3', 'Gene', (13, 19))
150564	28880866	Specifically, 9/14 amplification events and 23/25 deletion events resulted in greater 45S rDNA loss (binomial test for total, P = 7.025e-05).	('5S', 'Chemical', '-', (87, 89))	('amplification events', 'Var', (19, 39))	('deletion events', 'Var', (50, 65))	('45S rDNA', 'CPA', (86, 94))	('loss', 'NegReg', (95, 99))
150566	28880866	Specifically, 15/19 amplification events and 11/19 deletion events resulted in greater 5S amplification (P = 0.034 for total).	('deletion events', 'Var', (51, 66))	('greater', 'PosReg', (79, 86))	('5S', 'Chemical', '-', (87, 89))	('5S amplification', 'MPA', (87, 103))	('amplification', 'Var', (20, 33))
150570	28880866	First, we observed significant positive correlations between estimates of 1q42.13 ploidy and 5S rDNA CN in LUAD, LUSC and STAD (Fig 5).	('ploidy', 'Var', (82, 88))	('LUAD', 'Phenotype', 'HP:0030078', (107, 111))	('LUSC', 'Phenotype', 'HP:0030359', (113, 117))	('5S', 'Chemical', '-', (93, 95))	('1q42.13 ploidy', 'Var', (74, 88))
150572	28880866	This suggests that amplification of the 1q42 segment is a common and recurrent mechanism causing increased 5S CN across distinct cancers.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('increased', 'PosReg', (97, 106))	('amplification', 'Var', (19, 32))	('cancers', 'Disease', 'MESH:D009369', (129, 136))	('cancers', 'Phenotype', 'HP:0002664', (129, 136))	('cancers', 'Disease', (129, 136))	('5S', 'Chemical', '-', (107, 109))	('5S CN', 'Disease', (107, 112))
150578	28880866	We next examined somatic mutations associated with rDNA CN amplification or loss in each cancer type.	('loss', 'NegReg', (76, 80))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('rDNA CN', 'Gene', (51, 58))	('cancer', 'Disease', (89, 95))	('amplification', 'Var', (59, 72))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
150580	28880866	We examined a total of 17,035 genes containing somatic mutations with 1,481 of which being present in ten to a few hundred individuals in at least one cancer type.	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('cancer', 'Disease', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('mutations', 'Var', (55, 64))
150581	28880866	Strikingly, we found that TP53 mutations are negatively associated with 45S CN in STAD, HNSC (P < 0.005, Wilcoxon rank sum test) and LUAD (P = 0.012, Wilcoxon rank sum test) (Fig 4C and S4 Table).	('TP53', 'Gene', (26, 30))	('mutations', 'Var', (31, 40))	('negatively', 'NegReg', (45, 55))	('45S CN', 'Disease', (72, 78))	('LUAD', 'Phenotype', 'HP:0030078', (133, 137))	('HNSC', 'Phenotype', 'HP:0012288', (88, 92))	('5S', 'Chemical', '-', (73, 75))	('TP53', 'Gene', '7157', (26, 30))
150582	28880866	On the other hand, most LUSC tumors show TP53 mutations while most KIRC tumors do not show TP53 mutations, leading to low statistical power for TP53-rDNA association in both cases.	('low', 'NegReg', (118, 121))	('association', 'Interaction', (154, 165))	('TP53', 'Gene', (41, 45))	('TP53', 'Gene', (91, 95))	('TP53', 'Gene', (144, 148))	('mutations', 'Var', (46, 55))	('TP53', 'Gene', '7157', (41, 45))	('TP53', 'Gene', '7157', (144, 148))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumors', 'Disease', (72, 78))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('tumors', 'Disease', 'MESH:D009369', (29, 35))	('tumors', 'Disease', (29, 35))	('TP53', 'Gene', '7157', (91, 95))	('LUSC', 'Phenotype', 'HP:0030359', (24, 28))
150586	28880866	Overall, the associations between mutation presence and rDNA CN are particularly apparent in LUAD, the cancer with the largest sample size.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('LUAD', 'Disease', (93, 97))	('mutation', 'Var', (34, 42))	('LUAD', 'Phenotype', 'HP:0030078', (93, 97))	('rDNA CN', 'Disease', (56, 63))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))
150587	28880866	In this case, the associations between mutation presence and 45S rDNA CN are predominantly negative (Fig 4D, 49/50, binomial test P = 9.059e-14), whereas the association between mutation presence and 5S CN are predominantly positive (19/20, P = 4.005e-5).	('mutation', 'Var', (39, 47))	('associations', 'Interaction', (18, 30))	('5S', 'Chemical', '-', (62, 64))	('45S rDNA CN', 'Disease', (61, 72))	('5S', 'Chemical', '-', (200, 202))	('negative', 'NegReg', (91, 99))
150594	28880866	In this analysis TP53 mutations emerged again as one of the top candidates associated with significantly lower 45S (P = 0.0015), as well as significantly higher 5S / 45S ratio (P = 5.24e-9).	('lower', 'NegReg', (105, 110))	('5S', 'Chemical', '-', (161, 163))	('5S / 45S ratio', 'MPA', (161, 175))	('higher', 'PosReg', (154, 160))	('45S', 'MPA', (111, 114))	('mutations', 'Var', (22, 31))	('5S', 'Chemical', '-', (167, 169))	('5S', 'Chemical', '-', (112, 114))	('TP53', 'Gene', '7157', (17, 21))	('TP53', 'Gene', (17, 21))
150595	28880866	Among genes associated with the 5S we find that 89.5% (128/143) of them displayed positive associations, indicating higher 5S rDNA CN in the presence of the mutation.	('5S', 'Chemical', '-', (123, 125))	('higher', 'PosReg', (116, 122))	('mutation', 'Var', (157, 165))	('5S', 'Chemical', '-', (32, 34))	('5S rDNA CN', 'Disease', (123, 133))
150596	28880866	In this pan-cancer analysis, >95% of all significant associations between the presence of the somatic mutation and the 5S / 45S ratio are positive.	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('5S', 'Chemical', '-', (119, 121))	('cancer', 'Disease', (12, 18))	('5S', 'Chemical', '-', (125, 127))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('presence', 'Var', (78, 86))
150598	28880866	We then asked if rDNA CN variation is associated with specific TP53 mutations.	('mutations', 'Var', (68, 77))	('TP53', 'Gene', (63, 67))	('associated', 'Reg', (38, 48))	('TP53', 'Gene', '7157', (63, 67))
150599	28880866	To address this, we did a pan-cancer analysis for TP53 mutations that recurred in at least 5 patients.	('mutations', 'Var', (55, 64))	('cancer', 'Disease', (30, 36))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('TP53', 'Gene', '7157', (50, 54))	('TP53', 'Gene', (50, 54))	('patients', 'Species', '9606', (93, 101))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
150601	28880866	All these mutations are missense and all of them are associated with increased 5S / 45S ratio, as expected from our previous analysis with every TP53 mutation merged.	('increased', 'PosReg', (69, 78))	('5S / 45S ratio', 'MPA', (79, 93))	('missense', 'Var', (24, 32))	('5S', 'Chemical', '-', (79, 81))	('TP53', 'Gene', '7157', (145, 149))	('TP53', 'Gene', (145, 149))	('mutations', 'Var', (10, 19))	('5S', 'Chemical', '-', (85, 87))
150602	28880866	We hypothesize that contrasting rDNA CN variation may reflect increased nucleolar activity as well as rapid tumor cell proliferation.	('variation', 'Var', (40, 49))	('increased', 'PosReg', (62, 71))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('nucleolar activity', 'MPA', (72, 90))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('tumor', 'Disease', (108, 113))
150608	28880866	Notably, higher PRI is associated with lower survival probability (S7A and S7B Fig, also in), as well as more advanced tumor stages (S7C and S7D Fig).	('tumor', 'Disease', (119, 124))	('PRI', 'MPA', (16, 19))	('S7B', 'Var', (75, 78))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('lower', 'NegReg', (39, 44))	('survival probability', 'CPA', (45, 65))
150620	28880866	Finally, the negative correlation of TP53 mutation with 45S, and positive correlations of TP53 mutation and PRI with 5S / 45S ratio remain significant even when they were analyzed together in a multivariate model (S8 Table).	('negative', 'NegReg', (13, 21))	('5S', 'Chemical', '-', (123, 125))	('5S', 'Chemical', '-', (117, 119))	('TP53', 'Gene', '7157', (90, 94))	('mutation', 'Var', (42, 50))	('TP53', 'Gene', (90, 94))	('TP53', 'Gene', '7157', (37, 41))	('TP53', 'Gene', (37, 41))	('5S', 'Chemical', '-', (57, 59))
150624	28880866	For instance, coupled 5S gain / 45S loss are particularly salient in lineages with TP53 inactivation from stomach and lung adenocarcinomas, but can also be observed in head and neck squamous cell carcinoma.	('TP53', 'Gene', '7157', (83, 87))	('lung adenocarcinomas', 'Disease', (118, 138))	('gain', 'PosReg', (25, 29))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (118, 138))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (177, 205))	('TP53', 'Gene', (83, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('loss', 'NegReg', (36, 40))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (118, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (196, 205))	('5S', 'Chemical', '-', (33, 35))	('neck squamous cell carcinoma', 'Disease', (177, 205))	('5S', 'Chemical', '-', (22, 24))	('stomach', 'Disease', (106, 113))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (118, 137))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (182, 205))	('inactivation', 'Var', (88, 100))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (168, 205))
150630	28880866	The naturally occurring "normal" variation also indicates that excess 45S rDNA CN does not limit cell viability, and argues against a model in which lower 45S rDNA CN facilitates tumorigenesis.	('facilitates', 'PosReg', (167, 178))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('5S', 'Chemical', '-', (71, 73))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('5S', 'Chemical', '-', (156, 158))	('lower 45S rDNA CN', 'Var', (149, 166))	('tumor', 'Disease', (179, 184))
150634	28880866	For instance, our analyses indicated that mutation in TP53 is among the strongest determinants of coupled 5S gain and 45S loss in cancer lineages.	('45S', 'CPA', (118, 121))	('5S', 'Chemical', '-', (119, 121))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('5S', 'Chemical', '-', (106, 108))	('cancer', 'Disease', (130, 136))	('TP53', 'Gene', '7157', (54, 58))	('mutation', 'Var', (42, 50))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('loss', 'NegReg', (122, 126))	('gain', 'PosReg', (109, 113))	('TP53', 'Gene', (54, 58))
150640	28880866	This is because excess of rDNA copies has been suggested to promote global genome stability, and epigenetic regulation of the 45S rDNA could compensate for the loss of 45S rDNA alleles.	('epigenetic regulation', 'Var', (97, 118))	('promote', 'PosReg', (60, 67))	('5S', 'Chemical', '-', (127, 129))	('5S', 'Chemical', '-', (169, 171))	('global genome stability', 'CPA', (68, 91))
150661	28880866	Note that cancer genomes suffer from large-scale structural variation, with frequent gain or loss of whole genes, partial segments as well as large-scale chromosomal duplications/losses.	('chromosomal duplications/losses', 'Var', (154, 185))	('gain', 'PosReg', (85, 89))	('loss', 'NegReg', (93, 97))	('whole genes', 'Protein', (101, 112))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('cancer', 'Disease', 'MESH:D009369', (10, 16))	('cancer', 'Disease', (10, 16))
150664	28880866	In this pipeline, genomic regions that undergo focal or arm-level amplification or deletion in tumors were identified by using the software GISTIC2 from the human SNP array 6.0 datasets.	('amplification', 'Var', (66, 79))	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('deletion', 'Var', (83, 91))	('tumors', 'Disease', (95, 101))	('human', 'Species', '9606', (157, 162))
150706	27586041	For example, next generation sequencing (RNA-Seq and miRNA-Seq) data are read counts; expression profiles from microarray and methylation array are continuous values; mutations and CNVs are usually represented in binary, with value one represents the gene is mutated, amplified or deleted in the patient, or value zero otherwise (Table 1).	('patient', 'Species', '9606', (296, 303))	('deleted', 'Var', (281, 288))	('mutations', 'Var', (167, 176))
150711	27586041	Figure 1 shows that the data is more appropriate for Poisson family graphical models after being preprocessed with the processSeq function as given in the following code snippets:  To estimate the underlying network structure of the count-valued data, XMRF implements four different models from the Poisson family graphical models: regular Poisson graphical model (PGM) that only permits negative conditional dependencies, truncated Poisson (TPGM), sub-linear Poisson (SPGM), and local Poisson (LPGM).	('sub-linear', 'Var', (449, 459))	('local Poisson', 'Var', (480, 493))	('MRF', 'Gene', (253, 256))	('MRF', 'Gene', '745', (253, 256))	('truncated Poisson', 'Var', (423, 440))
150738	32060100	SDCs exhibited high levels of immune infiltration, with corresponding higher levels of T cell dysfunction, and higher mutational load.	('SDCs', 'Chemical', '-', (0, 4))	('T cell dysfunction', 'Phenotype', 'HP:0005435', (87, 105))	('mutational', 'Var', (118, 128))	('SDC', 'Phenotype', 'HP:0100684', (0, 3))	('higher', 'PosReg', (70, 76))	('immune infiltration', 'MPA', (30, 49))	('T cell dysfunction', 'MPA', (87, 105))
150753	32060100	ACCs account for approximately 10% of salivary gland malignancies, have low numbers of mutations, but have oncogenic fusions of MYB-NFIB or MYBL1-NFIB in approximately 60% of cases.	('fusions', 'Var', (117, 124))	('NFIB', 'Gene', (132, 136))	('NFIB', 'Gene', (146, 150))	('MYB', 'Gene', (128, 131))	('malignancies', 'Disease', (53, 65))	('NFIB', 'Gene', '4781', (146, 150))	('NFIB', 'Gene', '4781', (132, 136))	('MYBL1', 'Gene', (140, 145))	('salivary gland malignancies', 'Phenotype', 'HP:0100684', (38, 65))	('MYB', 'Gene', '4602', (140, 143))	('MYBL1', 'Gene', '4603', (140, 145))	('malignancies', 'Disease', 'MESH:D009369', (53, 65))	('MYB', 'Gene', (140, 143))	('MYB', 'Gene', '4602', (128, 131))
150759	32060100	Targetable mutations in the PIK3CA and MAPK pathways have also been identified.	('MAPK pathways', 'Pathway', (39, 52))	('PIK3CA', 'Gene', (28, 34))	('mutations', 'Var', (11, 20))	('PIK3CA', 'Gene', '5290', (28, 34))
150771	32060100	Two pairs of ACCs were matched primary and metastatic tumors from two individual patients (ACC_P3 and ACC_M3; ACC_P12 and ACC_M12).	('tumors', 'Disease', 'MESH:D009369', (54, 60))	('ACC_M12', 'Var', (122, 129))	('patients', 'Species', '9606', (81, 89))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumors', 'Disease', (54, 60))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))
150785	32060100	Sequencing was performed on HiSeq 2500 (Illumina) with paired-end reads of 50 (PE50) and 137M-234M reads per sample (SDCs), 104M-194M reads per sample (MECA frozen), 92M-400M reads per sample (MECA FFPE) and 170M-321M reads per sample (ACC).	('SDC', 'Phenotype', 'HP:0100684', (117, 120))	('SDCs', 'Chemical', '-', (117, 121))	('92M-400M reads', 'Var', (166, 180))	('104M-194M reads', 'Var', (124, 139))
150840	32060100	We observed that SDCs ex-PA had a significantly lower IIS and TIS than SDCs de novo (p=.04 and p=.03, respectively; Supplementary Figure S11A-B).	('SDCs', 'Chemical', '-', (17, 21))	('TIS', 'CPA', (62, 65))	('S11A', 'SUBSTITUTION', 'None', (137, 141))	('lower', 'NegReg', (48, 53))	('SDC', 'Phenotype', 'HP:0100684', (71, 74))	('SDC', 'Phenotype', 'HP:0100684', (17, 20))	('SDCs', 'Chemical', '-', (71, 75))	('IIS', 'CPA', (54, 57))	('S11A', 'Var', (137, 141))
150842	32060100	In MECA, while IIS and TIS were numerically lower in ex-PA cancers, these differences were not statistically significant (p=.09 and p=.11, respectively; Supplementary Figure S11C-D).	('lower', 'NegReg', (44, 49))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('S11C', 'SUBSTITUTION', 'None', (174, 178))	('cancers', 'Disease', 'MESH:D009369', (59, 66))	('cancers', 'Phenotype', 'HP:0002664', (59, 66))	('S11C', 'Var', (174, 178))	('MECA', 'Disease', (3, 7))	('cancers', 'Disease', (59, 66))
150851	32060100	Gene fusions are particularly prevalent in salivary carcinomas, and represent common oncogenic alterations in ACC and MECA.	('salivary carcinomas', 'Disease', (43, 62))	('ACC', 'Disease', (110, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (52, 61))	('carcinomas', 'Phenotype', 'HP:0030731', (52, 62))	('MECA', 'Disease', (118, 122))	('Gene fusions', 'Var', (0, 12))	('salivary carcinomas', 'Phenotype', 'HP:0100684', (43, 62))	('salivary carcinomas', 'Disease', 'MESH:D012468', (43, 62))	('prevalent', 'Reg', (30, 39))
150853	32060100	As expected, the number of neoantigens generated by missense mutations (single nucleotide variant neoantigens, SNV-NeoAg) was tightly correlated with the number of SNVs in the tumor (Spearman r=.82, p<.0001; Supplementary Figure S5).	('tumor', 'Disease', (176, 181))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('tumor', 'Disease', 'MESH:D009369', (176, 181))	('missense mutations', 'Var', (52, 70))
150860	32060100	These associations demonstrate that, among these SGC histologies, which harbor very low (ACC, MECA), or moderate (SDC) mutational load, that the degree of immune infiltration in the tumor microenvironment does appear to correlate with the abundance of neoantigens that derive either from mutations or gene fusions.	('SGC', 'Gene', (49, 52))	('mutational load', 'Var', (119, 134))	('SDC', 'Phenotype', 'HP:0100684', (114, 117))	('tumor', 'Disease', (182, 187))	('SGC', 'Gene', '6443', (49, 52))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
150862	32060100	For these reasons, salivary cancers with low mutational load and, consequently, low neoantigen load, which also have the least inflamed tumor microenvironments, appear to be the least poised to respond to immune checkpoint inhibitors, at least as monotherapy.	('mutational', 'Var', (45, 55))	('low', 'NegReg', (80, 83))	('neoantigen load', 'MPA', (84, 99))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('salivary cancers', 'Disease', 'MESH:D009369', (19, 35))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('cancers', 'Phenotype', 'HP:0002664', (28, 35))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('salivary cancer', 'Phenotype', 'HP:0100684', (19, 34))	('tumor', 'Disease', (136, 141))	('salivary cancers', 'Disease', (19, 35))
150891	32060100	In this study, we found that fusion-derived neoantigens were associated with higher levels of T cell inflammation.	('higher', 'PosReg', (77, 83))	('inflammation', 'Disease', (101, 113))	('inflammation', 'Disease', 'MESH:D007249', (101, 113))	('neoantigens', 'Var', (44, 55))
150900	32060100	Clinical data from immune checkpoint blockade in SGCs has been limited to the KEYNOTE-028 study, but we await the results of a number of ongoing phase II trials enrolling more patients with SGC (KEYNOTE-158, NCT02628067; NISCAHN, NCT03132038; NCT02538510).	('SGC', 'Gene', (49, 52))	('patients', 'Species', '9606', (176, 184))	('NISCAHN', 'Disease', 'None', (221, 228))	('SGC', 'Gene', '6443', (49, 52))	('SGC', 'Gene', (190, 193))	('SGCs', 'Phenotype', 'HP:0100684', (49, 53))	('NCT02538510', 'Var', (243, 254))	('SGC', 'Gene', '6443', (190, 193))	('NISCAHN', 'Disease', (221, 228))
150908	32060100	Across all SGCs, immune infiltration was associated with mutation- and fusion-derived neoantigens.	('associated', 'Reg', (41, 51))	('SGC', 'Gene', '6443', (11, 14))	('mutation-', 'Var', (57, 66))	('SGCs', 'Phenotype', 'HP:0100684', (11, 15))	('immune infiltration', 'CPA', (17, 36))	('SGC', 'Gene', (11, 14))
150968	33137960	Ultimately, this can eventually progress to haphazard oral cell proliferation and cytoskeletal abnormalities, as well as the inhibition of apoptosis of mutated cells that occurs via the modulation of the Bcl-2 family of proteins and the inactivation of retinoblastoma protein (pRb) as well as the activation of transcription factors such as STAT3 and NFAT.	('activation', 'PosReg', (297, 307))	('pro', 'Chemical', 'MESH:D011392', (220, 223))	('STAT3', 'Gene', (341, 346))	('pro', 'Chemical', 'MESH:D011392', (268, 271))	('Bcl-2', 'Gene', (204, 209))	('inactivation', 'Var', (237, 249))	('modulation', 'Var', (186, 196))	('retinoblastoma', 'Disease', (253, 267))	('cytoskeletal abnormalities', 'Disease', 'MESH:D018376', (82, 108))	('pRb', 'Gene', '5925', (277, 280))	('STAT3', 'Gene', '6774', (341, 346))	('Bcl-2', 'Gene', '596', (204, 209))	('cytoskeletal abnormalities', 'Disease', (82, 108))	('apoptosis', 'CPA', (139, 148))	('retinoblastoma', 'Disease', 'MESH:D012175', (253, 267))	('pro', 'Chemical', 'MESH:D011392', (32, 35))	('pro', 'Chemical', 'MESH:D011392', (64, 67))	('pRb', 'Gene', (277, 280))	('retinoblastoma', 'Phenotype', 'HP:0009919', (253, 267))
150977	33137960	Thus, the oral microbiome may be an important source for unopposed oxidative stress in epithelial cells that may finally lead to unrepaired DNA mutations, cell division of these abnormally mutated cells and their eventual progression to metastasis.	('DNA', 'Gene', (140, 143))	('lead to', 'Reg', (121, 128))	('mutations', 'Var', (144, 153))	('oxidative stress', 'Phenotype', 'HP:0025464', (67, 83))	('pro', 'Chemical', 'MESH:D011392', (222, 225))	('cell division', 'CPA', (155, 168))
150985	33137960	Volatile sulphur compounds, predominantly hydrogen sulphide and methyl mercaptan, are normally known to cause halitosis, and are produced by bacteria such as Porphyromonas gingivalis, Prevotella intermedia and Fusobacterium nucleatum, i.e., periodontal pathogens.	('Prevotella intermedia', 'Species', '28131', (184, 205))	('halitosis', 'Disease', (110, 119))	('halitosis', 'Phenotype', 'HP:0100812', (110, 119))	('methyl', 'Var', (64, 70))	('Fusobacterium nucleatum', 'Species', '851', (210, 233))	('sulphur compounds', 'Chemical', 'MESH:D013457', (9, 26))	('hydrogen sulphide', 'Chemical', 'MESH:D006862', (42, 59))	('Porphyromonas gingivalis', 'Species', '837', (158, 182))	('cause', 'Reg', (104, 109))	('methyl mercaptan', 'Chemical', 'MESH:C005231', (64, 80))	('halitosis', 'Disease', 'MESH:D006209', (110, 119))	('pro', 'Chemical', 'MESH:D011392', (129, 132))
151009	33137960	Fusobacterium nucleatum has been associated with high-grade dysplasia, lymph node metastasis and poor cancer progression.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('Fusobacterium', 'Var', (0, 13))	('nod', 'Gene', '1822', (77, 80))	('dysplasia', 'Disease', 'MESH:C536170', (60, 69))	('lymph', 'Disease', (71, 76))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('associated', 'Reg', (33, 43))	('dysplasia', 'Disease', (60, 69))	('pro', 'Chemical', 'MESH:D011392', (109, 112))	('nod', 'Gene', (77, 80))	('Fusobacterium nucleatum', 'Species', '851', (0, 23))
151019	33137960	In OSCC lesions with CpG island methylation, over expression of the immune checkpoint receptor programmed death-ligand 1 (PD-1) has also been shown and thus these tumours may be more sensitive to immune checkpoint blockade.	('methylation', 'Var', (32, 43))	('tumours', 'Disease', (163, 170))	('PD-1', 'Gene', (122, 126))	('CpG island methylation', 'Var', (21, 43))	('tumours', 'Phenotype', 'HP:0002664', (163, 170))	('tumour', 'Phenotype', 'HP:0002664', (163, 169))	('over expression', 'PosReg', (45, 60))	('pro', 'Chemical', 'MESH:D011392', (95, 98))	('OSCC', 'Disease', (3, 7))	('tumours', 'Disease', 'MESH:D009369', (163, 170))
151021	33137960	Porphyromonas gingivalis, on the other hand, has been identified as an independent and significant risk factor in cancer-related deaths in the oral cavity and throughout the remaining oral digestive tract, pharynx, oesophagus, stomach, pancreas, liver, and colon and rectum.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('colon', 'Disease', 'MESH:D003110', (257, 262))	('Porphyromonas gingivalis', 'Species', '837', (0, 24))	('colon', 'Disease', (257, 262))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('deaths', 'Disease', (129, 135))	('risk factor', 'Reg', (99, 110))	('Porphyromonas gingivalis', 'Var', (0, 24))	('deaths', 'Disease', 'MESH:D003643', (129, 135))	('cancer', 'Disease', (114, 120))
151022	33137960	Higher levels of antibodies against Porphyromonas gingivalis infection have been associated with a much higher increased risk of pancreatic cancer.	('Porphyromonas gingivalis', 'Species', '837', (36, 60))	('increased risk of pancreatic cancer', 'Phenotype', 'HP:0002894', (111, 146))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (129, 146))	('gingivalis infection', 'Disease', (50, 70))	('antibodies', 'Var', (17, 27))	('pancreatic cancer', 'Disease', 'MESH:D010190', (129, 146))	('gingivalis infection', 'Disease', 'MESH:D007239', (50, 70))	('pancreatic cancer', 'Disease', (129, 146))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('associated', 'Reg', (81, 91))
151027	33137960	Porphyromonas gingivalis works intracellularly to prevent cell apoptosis through the inhibition of cytochrome C, downregulation of caspase 3 activity, secretion of the anti-apoptotic enzyme nucleoside diphosphate kinase that causes the inhibition of the P2X receptors on epithelial cells and the upregulation of microRNA 203, with the subsequent result of apoptosis quelling while also upregulating the anti-apoptotic genes Bcl-2 and survivin.	('microRNA 203', 'Protein', (312, 324))	('P2X receptors', 'Protein', (254, 267))	('downregulation', 'NegReg', (113, 127))	('inhibition', 'NegReg', (236, 246))	('inhibition', 'Var', (85, 95))	('Bcl-2', 'Gene', (424, 429))	('apoptosis', 'CPA', (356, 365))	('anti-apoptotic', 'MPA', (403, 417))	('Bcl-2', 'Gene', '596', (424, 429))	('Porphyromonas gingivalis', 'Species', '837', (0, 24))	('upregulating', 'PosReg', (386, 398))	('survivin', 'Gene', (434, 442))	('upregulation', 'PosReg', (296, 308))
151028	33137960	(2010), Porphyromonas gingivalis was found to be associated with the upregulation of colon cancer-associated transcript 1, a long, non-coding RNA that has been found to be upregulated in several cancers and has also been described in oral epithelial cells, as well as in the upregulation of the enzyme production; nicotinamide N methyltransferase, which has been associated with malignancy and cancer stem cells, and was also detected in OSCC patients.	('OSCC', 'Disease', (438, 442))	('malignancy', 'Disease', 'MESH:D009369', (379, 389))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('upregulated', 'PosReg', (172, 183))	('cancer', 'Disease', 'MESH:D009369', (394, 400))	('colon cancer', 'Disease', 'MESH:D015179', (85, 97))	('patients', 'Species', '9606', (443, 451))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('cancers', 'Disease', 'MESH:D009369', (195, 202))	('malignancy', 'Disease', (379, 389))	('nicotinamide N methyltransferase', 'Enzyme', (314, 346))	('upregulation', 'PosReg', (275, 287))	('colon cancer', 'Disease', (85, 97))	('upregulation', 'PosReg', (69, 81))	('Porphyromonas gingivalis', 'Var', (8, 32))	('cancer', 'Disease', (195, 201))	('cancer', 'Disease', (394, 400))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('cancer', 'Phenotype', 'HP:0002664', (394, 400))	('colon cancer', 'Phenotype', 'HP:0003003', (85, 97))	('cancer', 'Disease', (91, 97))	('pro', 'Chemical', 'MESH:D011392', (302, 305))	('cancers', 'Phenotype', 'HP:0002664', (195, 202))	('nicotinamide', 'Chemical', 'MESH:D009536', (314, 326))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('cancers', 'Disease', (195, 202))	('Porphyromonas gingivalis', 'Species', '837', (8, 32))
151030	33137960	Furthermore, Porphyromonas gingivalis can help OSCC cells to bypass the immune system by activating PD-L1 to bind to its receptor, PD-1, mediating profound T cell inhibition, and can induce the expression of the B7-H1 and B7-DC receptors in OSCC cells that leads to the apoptosis of activated T cells.	('B7-DC', 'Gene', '58205', (222, 227))	('leads to', 'Reg', (257, 265))	('activating', 'PosReg', (89, 99))	('pro', 'Chemical', 'MESH:D011392', (147, 150))	('PD-L1', 'Gene', '29126', (100, 105))	('B7-H1', 'Protein', (212, 217))	('apoptosis', 'CPA', (270, 279))	('Porphyromonas', 'Var', (13, 26))	('Porphyromonas gingivalis', 'Species', '837', (13, 37))	('bind', 'Interaction', (109, 113))	('expression', 'MPA', (194, 204))	('B7-DC', 'Gene', (222, 227))	('induce', 'PosReg', (183, 189))	('PD-L1', 'Gene', (100, 105))
151031	33137960	Porphyromonas gingivalis has been shown to induce epithelial to mesenchymal transition and can accelerate the cell cycle by affecting the p53, PI3K and cyclin pathways, primarily through its FimA adhesin molecule.	('accelerate', 'PosReg', (95, 105))	('p53', 'Gene', (138, 141))	('epithelial to mesenchymal transition', 'CPA', (50, 86))	('p53', 'Gene', '7157', (138, 141))	('cell cycle', 'CPA', (110, 120))	('Porphyromonas gingivalis', 'Species', '837', (0, 24))	('Porphyromonas gingivalis', 'Var', (0, 24))	('induce', 'PosReg', (43, 49))	('affecting', 'Reg', (124, 133))
151050	33137960	In another study, Lactobacillus plantarum was found to induce apoptosis of oral cancer cells by the upregulation of PTEN and MAPK signalling and was thus proposed as a potential probiotic adjuvant in OSCC treatment.	('oral cancer', 'Disease', (75, 86))	('MAPK', 'MPA', (125, 129))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('apoptosis', 'CPA', (62, 71))	('oral cancer', 'Disease', 'MESH:D009369', (75, 86))	('induce', 'PosReg', (55, 61))	('Lactobacillus plantarum', 'Species', '1590', (18, 41))	('upregulation', 'PosReg', (100, 112))	('PTEN', 'Gene', (116, 120))	('pro', 'Chemical', 'MESH:D011392', (154, 157))	('PTEN', 'Gene', '5728', (116, 120))	('Lactobacillus plantarum', 'Var', (18, 41))	('pro', 'Chemical', 'MESH:D011392', (178, 181))
151052	33137960	Other acids produced by these bacteria include acetic, butyric, isobutyric, isovaleric, and isocaproic acids, which all reduce the environmental pH of an OSCC, contributing to cancer growth and spread.	('acetic', 'Chemical', 'MESH:D019342', (47, 53))	('reduce', 'NegReg', (120, 126))	('butyric, isobutyric, isovaleric, and isocaproic acids', 'Chemical', '-', (55, 108))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('spread', 'CPA', (194, 200))	('pro', 'Chemical', 'MESH:D011392', (97, 100))	('isocaproic acids', 'Var', (92, 108))	('pro', 'Chemical', 'MESH:D011392', (12, 15))	('contributing', 'Reg', (160, 172))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('cancer', 'Disease', (176, 182))	('environmental pH of an OSCC', 'MPA', (131, 158))	('isobutyric', 'Var', (64, 74))
151067	33137960	Smoking has also been shown to reduce the host response to Porphyromonas gingivalis and it is thought that the local immunosuppression caused by smoking can be one cause of a more novel and pathogenic microbiome picture.	('Smoking', 'Var', (0, 7))	('Porphyromonas gingivalis', 'Species', '837', (59, 83))	('reduce', 'NegReg', (31, 37))	('host response', 'CPA', (42, 55))
151178	30558313	Contrary, some PPGLs mixed with pancreatic neuroendocrine tumors or neuroblastomas.	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (43, 64))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('neuroblastoma', 'Phenotype', 'HP:0003006', (68, 81))	('pancreatic neuroendocrine tumor', 'Phenotype', 'HP:0030405', (32, 63))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('mixed', 'Reg', (21, 26))	('neuroblastomas', 'Phenotype', 'HP:0003006', (68, 82))	('neuroblastomas', 'Disease', 'MESH:D009447', (68, 82))	('pancreatic neuroendocrine tumors', 'Disease', (32, 64))	('pancreatic neuroendocrine tumors', 'Disease', 'MESH:D018358', (32, 64))	('neuroendocrine tumor', 'Phenotype', 'HP:0100634', (43, 63))	('neuroblastomas', 'Disease', (68, 82))	('PPGLs', 'Var', (15, 20))
151185	30558313	Similarly, PPGLs are separated into 4 groups named after their molecular characteristics: pseudohypoxia related to succinate dehydrogenase or VHL/EPAS1 disturbances, wnt-altered and kinase-signaling pathways.	('pseudohypoxia', 'Disease', 'None', (90, 103))	('VHL', 'Disease', 'MESH:D006623', (142, 145))	('EPAS1', 'Gene', '2034', (146, 151))	('VHL', 'Disease', (142, 145))	('EPAS1', 'Gene', (146, 151))	('disturbances', 'Var', (152, 164))	('pseudohypoxia', 'Disease', (90, 103))
151225	30558313	Results showed a separation into two clusters, one consisting of low and high grade gliomas and a second including NBL, PNET, and PPGL (Figure 4, Supplementary Figures S10A-C and S11A-C).	('NBL', 'Phenotype', 'HP:0003006', (115, 118))	('S11A', 'Var', (179, 183))	('S10A', 'Var', (168, 172))	('gliomas', 'Disease', (84, 91))	('gliomas', 'Disease', 'MESH:D005910', (84, 91))	('S11A', 'SUBSTITUTION', 'None', (179, 183))	('gliomas', 'Phenotype', 'HP:0009733', (84, 91))	('glioma', 'Phenotype', 'HP:0009733', (84, 90))	('S10A', 'SUBSTITUTION', 'None', (168, 172))
151243	30558313	This includes presence of both telomerase activation and alternative lengthening of telomeres due to ATRX or DAXX truncation as well as somatic or germline driver mutations in MEN1.	('telomerase', 'Enzyme', (31, 41))	('mutations', 'Var', (163, 172))	('DAXX', 'Gene', '1616', (109, 113))	('MEN1', 'Gene', (176, 180))	('MEN1', 'Gene', '4221', (176, 180))	('activation', 'PosReg', (42, 52))	('ATRX', 'Gene', (101, 105))	('DAXX', 'Gene', (109, 113))	('ATRX', 'Gene', '546', (101, 105))
151295	28881838	R1 margins adversely affect the outcomes, with a decline in 5-year overall survival from 62% to 37% in patients with stage I diseases.	('overall survival', 'MPA', (67, 83))	('R1 margins', 'Var', (0, 10))	('patients', 'Species', '9606', (103, 111))	('affect', 'Reg', (21, 27))	('decline', 'NegReg', (49, 56))
151299	28881838	In recent years, accumulated evidences have demonstrated genetic, epigenetic or transcriptional alterations in microscopically normal-appearing tissues adjacent to cancers in head, neck, colon, rectum, prostate, breast, lung, liver, esophagus, stomach, and skin et al, that is referred as the "field effect" of cancerization.	('stomach', 'Disease', (244, 251))	('esophagus', 'Disease', (233, 242))	('transcriptional', 'MPA', (80, 95))	('cancer', 'Disease', (311, 317))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('cancers', 'Disease', 'MESH:D009369', (164, 171))	('epigenetic', 'Var', (66, 76))	('colon', 'Disease', (187, 192))	('cancer', 'Phenotype', 'HP:0002664', (311, 317))	('breast', 'Disease', (212, 218))	('liver', 'Disease', (226, 231))	('lung', 'Disease', (220, 224))	('cancer', 'Disease', 'MESH:D009369', (311, 317))	('cancers', 'Phenotype', 'HP:0002664', (164, 171))	('head', 'Disease', (175, 179))	('cancers', 'Disease', (164, 171))	('cancer', 'Disease', (164, 170))	('prostate', 'Disease', (202, 210))	('alterations', 'Reg', (96, 107))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))
151300	28881838	TP53 gene mutations, methylation at promoters of a series of genes, gene expression profiles in non-malignant airways were proposed as biomarkers for early detection of lung cancer.	('TP53', 'Gene', '7157', (0, 4))	('lung cancer', 'Disease', 'MESH:D008175', (169, 180))	('TP53', 'Gene', (0, 4))	('lung cancer', 'Phenotype', 'HP:0100526', (169, 180))	('lung cancer', 'Disease', (169, 180))	('mutations', 'Var', (10, 19))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))
151339	28881838	Consistent with the cellular phenotypic changes, genes well-defined as mesenchymal markers, such as N-cadherin, Vimentin, ZEB1 and Snail, were activated in the transformed cells (Supplementary Table S3).	('transformed', 'Var', (160, 171))	('ZEB1', 'Gene', '6935', (122, 126))	('N-cadherin', 'Gene', (100, 110))	('Vimentin', 'Gene', (112, 120))	('ZEB1', 'Gene', (122, 126))	('activated', 'PosReg', (143, 152))	('N-cadherin', 'Gene', '1000', (100, 110))	('Snail', 'Gene', '6615', (131, 136))	('Snail', 'Gene', (131, 136))	('Vimentin', 'Gene', '7431', (112, 120))
151344	28881838	The histologically normal-appearing lung tissues or the bronchial epithelium adjacent to neoplastic lesions were detected with genetic alterations, epigenetic abnormalities, and gene-expression significance.	('neoplastic lesions', 'Phenotype', 'HP:0002664', (89, 107))	('epigenetic abnormalities', 'Var', (148, 172))	('gene-expression significance', 'Var', (178, 206))	('neoplastic lesions', 'Disease', 'MESH:D051437', (89, 107))	('neoplastic lesions', 'Disease', (89, 107))	('genetic alterations', 'Var', (127, 146))
151358	28881838	Tessema et.al reported that methylation of MAP1B promoter was more frequent in lung tumors with chronic obstructive pulmonary disease (COPD) than those without COPD.	('frequent', 'Reg', (67, 75))	('chronic obstructive pulmonary disease', 'Disease', (96, 133))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('MAP1B', 'Gene', '4131', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('lung tumors', 'Disease', 'MESH:D008175', (79, 90))	('obstructive pulmonary disease', 'Phenotype', 'HP:0006536', (104, 133))	('Tessema', 'Disease', (0, 7))	('lung tumors', 'Phenotype', 'HP:0100526', (79, 90))	('MAP1B', 'Gene', (43, 48))	('Tessema', 'Disease', 'None', (0, 7))	('lung tumors', 'Disease', (79, 90))	('COPD', 'Disease', 'MESH:D029424', (160, 164))	('methylation', 'Var', (28, 39))	('COPD', 'Disease', (160, 164))	('chronic obstructive pulmonary disease', 'Phenotype', 'HP:0006510', (96, 133))	('chronic obstructive pulmonary disease', 'Disease', 'MESH:D029424', (96, 133))	('COPD', 'Disease', 'MESH:D029424', (135, 139))	('COPD', 'Disease', (135, 139))
151403	27328734	Several therapeutic options have been developed for clinical T1N0M0 (UICC-TNM classification, 7th edition) thoracic esophageal squamous cell carcinoma (ESCC): surgery, radiotherapy (RT), chemoradiotherapy (CRT), endoscopic resection (ER) including endoscopic mucosal resection (EMR), and endoscopic submucosal dissection (ESD).	('esophageal squamous cell carcinoma', 'Disease', (116, 150))	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('endoscopic submucosal dissection', 'Disease', (288, 320))	('T1N0M0', 'Var', (61, 67))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (116, 150))	('endoscopic mucosal resection', 'Disease', (248, 276))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (127, 150))
151413	27328734	They concluded that based on the rate of lymph node metastasis, clinical T1N0M0 ESCC invading the MM or SM should be distinguished from EP/LPM cancer.	('LPM cancer', 'Disease', 'MESH:D009369', (139, 149))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('LPM cancer', 'Disease', (139, 149))	('MM', 'Disease', 'MESH:D009101', (98, 100))	('T1N0M0', 'Var', (73, 79))	('ESCC', 'Disease', (80, 84))
151414	27328734	In organ-conserving treatments for clinical T1N0M0 ESCC, the depth of tumor invasion is closely related to the treatment approach.	('T1N0M0 ESCC', 'Var', (44, 55))	('tumor', 'Disease', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))
151488	27328734	The present analysis of organ-conserving treatment for patients with clinical T1N0M0 thoracic ESCC demonstrated that PS was an independent prognostic factor for both DSS and DFS.	('DFS', 'Disease', (174, 177))	('patients', 'Species', '9606', (55, 63))	('T1N0M0', 'Var', (78, 84))	('PS', 'Chemical', '-', (117, 119))	('DSS', 'Chemical', '-', (166, 169))	('DSS', 'Disease', (166, 169))
151493	27328734	reported that CRT resulted in increased OS rate compared to RT alone, but their trial included locally advanced squamous cell carcinoma and adenocarcinoma cases.	('OS rate', 'MPA', (40, 47))	('CRT', 'Var', (14, 17))	('carcinoma', 'Phenotype', 'HP:0030731', (145, 154))	('adenocarcinoma', 'Disease', (140, 154))	('adenocarcinoma', 'Disease', 'MESH:D000230', (140, 154))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (112, 135))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (112, 135))	('increased', 'PosReg', (30, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('squamous cell carcinoma', 'Disease', (112, 135))
151523	27328734	In our multivariate analysis for patients with clinical T1N0M0 thoracic ESCC invading the MM or SM, ER showed significance regarding the local control rate.	('T1N0M0', 'Var', (56, 62))	('patients', 'Species', '9606', (33, 41))	('MM', 'Disease', 'MESH:D009101', (90, 92))	('local control', 'CPA', (137, 150))
151531	27328734	analyzed 53 patients with T1N0-T4N1 ESCC without distant metastases treated with RT, and they concluded that the omission of ENI was not associated with a significant amount of failure in lymph node regions.	('patients', 'Species', '9606', (12, 20))	('T1N0-T4N1', 'Var', (26, 35))	('metastases', 'Disease', (57, 67))	('failure', 'Disease', 'MESH:D017093', (177, 184))	('ENI', 'Chemical', '-', (125, 128))	('failure', 'Disease', (177, 184))	('metastases', 'Disease', 'MESH:D009362', (57, 67))
151536	27328734	The results of this study showed that PS was an independent prognostic factor for both DSS and DFS in patients with clinical T1N0M0 thoracic ESCC invading the MM or SM.	('patients', 'Species', '9606', (102, 110))	('DSS', 'Chemical', '-', (87, 90))	('PS', 'Chemical', '-', (38, 40))	('DSS', 'Disease', (87, 90))	('MM', 'Disease', 'MESH:D009101', (159, 161))	('T1N0M0', 'Var', (125, 131))
151552	31717588	The five-year survival rate of patients with advanced lung cancer remains very low, in spite of the introduction of targeted therapies for patients with specific genetic alterations such as EGFR mutations, or ALK and ROS translocations, and, more recently, of immunotherapy with anti-PD1 or anti-PD-L1 antibodies as first or second line therapy.	('lung cancer', 'Disease', (54, 65))	('PD-L1', 'Gene', '29126', (296, 301))	('lung cancer', 'Phenotype', 'HP:0100526', (54, 65))	('patients', 'Species', '9606', (139, 147))	('EGFR', 'Gene', '1956', (190, 194))	('ROS', 'Chemical', '-', (217, 220))	('ALK', 'Gene', (209, 212))	('alterations', 'Var', (170, 181))	('lung cancer', 'Disease', 'MESH:D008175', (54, 65))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('low', 'NegReg', (79, 82))	('EGFR', 'Gene', (190, 194))	('PD1', 'Gene', (284, 287))	('mutations', 'Var', (195, 204))	('patients', 'Species', '9606', (31, 39))	('PD1', 'Gene', '9825', (284, 287))	('PD-L1', 'Gene', (296, 301))	('ALK', 'Gene', '238', (209, 212))
151561	31717588	SCD1 pharmacological inhibition determined a decreased efficiency of 3D spheroid formation accompanied by a negative impact on the architecture of 3D spheroids.	('SCD1', 'Gene', '6319', (0, 4))	('3D spheroid formation', 'CPA', (69, 90))	('decreased', 'NegReg', (45, 54))	('inhibition', 'Var', (21, 31))	('SCD1', 'Gene', (0, 4))
151562	31717588	Moreover, SCD1 depletion induced a reduction in ALDH1A1 activity, a marker of cancer stem cells, determining apoptosis specifically in ALDH1A1-positive cells.	('depletion', 'Var', (15, 24))	('ALDH1A1', 'Gene', '216', (135, 142))	('activity', 'MPA', (56, 64))	('SCD1', 'Gene', '6319', (10, 14))	('ALDH1A1', 'Gene', (48, 55))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('ALDH1A1', 'Gene', (135, 142))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('ALDH1A1', 'Gene', '216', (48, 55))	('reduction', 'NegReg', (35, 44))	('SCD1', 'Gene', (10, 14))
151563	31717588	Silencing of SCD1 impaired in vivo tumorigenicity of 3D lung cancer stem cells.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('SCD1', 'Gene', '6319', (13, 17))	('impaired', 'NegReg', (18, 26))	('lung cancer', 'Disease', 'MESH:D008175', (56, 67))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumor', 'Disease', (35, 40))	('SCD1', 'Gene', (13, 17))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('Silencing', 'Var', (0, 9))	('lung cancer', 'Disease', (56, 67))	('lung cancer', 'Phenotype', 'HP:0100526', (56, 67))
151564	31717588	We also observed that LUAD 3D spheroids treated with an SCD1 inhibitor reverted resistance to cisplatin.	('inhibitor', 'Var', (61, 70))	('resistance to cisplatin', 'MPA', (80, 103))	('SCD1', 'Gene', (56, 60))	('cisplatin', 'Chemical', 'MESH:D002945', (94, 103))	('reverted', 'Reg', (71, 79))	('SCD1', 'Gene', '6319', (56, 60))	('LUAD', 'Phenotype', 'HP:0030078', (22, 26))
151567	31717588	In this context, the study of epigenetic alterations in CSCs acquires particular relevance, also because epigenetic alterations might deregulate signalling pathways controlling self-renewal and differentiation, including Wnt, Myc, Notch, and Hedgehog pathways.	('Hedgehog pathways', 'Pathway', (242, 259))	('deregulate', 'Reg', (134, 144))	('self-renewal', 'CPA', (177, 189))	('Myc', 'Gene', '4609', (226, 229))	('Notch', 'Pathway', (231, 236))	('Myc', 'Gene', (226, 229))	('epigenetic alterations', 'Var', (105, 127))	('epigenetic', 'Var', (30, 40))	('Wnt', 'Pathway', (221, 224))	('signalling pathways', 'Pathway', (145, 164))
151600	31717588	In particular, the 3D spheroids cell population exhibited a significant enrichment of gene pathways involved in oncogenesis and cancer progression, including EMT (FDR < 10-13), Hypoxia (FDR < 10-10), Cholesterol homeostasis (FDR < 10-5), and Apoptosis (FDR < 10-4) (Figure 2B).	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('gene pathways', 'Pathway', (86, 99))	('EMT', 'CPA', (158, 161))	('FDR < 10-13', 'Var', (163, 174))	('Apoptosis', 'CPA', (242, 251))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('FDR < 10-5', 'Var', (225, 235))	('Hypoxia', 'Disease', 'MESH:D000860', (177, 184))	('Cholesterol', 'Chemical', 'MESH:D002784', (200, 211))	('Hypoxia', 'Disease', (177, 184))	('FDR < 10-10', 'Var', (186, 197))	('cancer', 'Disease', (128, 134))
151624	31717588	Transient knockdown of B4GALT1 strongly impaired 3D spheroids formation, both as to number and size (Figure 5A,B).	('3D spheroids formation', 'CPA', (49, 71))	('B4GALT1', 'Gene', '2683', (23, 30))	('impaired', 'NegReg', (40, 48))	('B4GALT1', 'Gene', (23, 30))	('knockdown', 'Var', (10, 19))
151626	31717588	Moreover, the silencing of B4GALT1 affected SCD1 mRNA levels in 3D cells.	('silencing', 'Var', (14, 23))	('SCD1', 'Gene', (44, 48))	('affected', 'Reg', (35, 43))	('B4GALT1', 'Gene', '2683', (27, 34))	('B4GALT1', 'Gene', (27, 34))	('SCD1', 'Gene', '6319', (44, 48))
151628	31717588	As shown in Figure 5D, inhibition of B4GALT1 resulted in a significant reduction of ALDH activity in 3D cells, as well as a decrease of Nanog protein expression compared to control scrambled siRNA (data not shown).	('inhibition', 'Var', (23, 33))	('reduction', 'NegReg', (71, 80))	('Nanog', 'Gene', '79923', (136, 141))	('B4GALT1', 'Gene', '2683', (37, 44))	('B4GALT1', 'Gene', (37, 44))	('decrease', 'NegReg', (124, 132))	('Nanog', 'Gene', (136, 141))	('ALDH', 'Protein', (84, 88))	('activity', 'MPA', (89, 97))
151632	31717588	In this regard, modifications of chromatin openness are linked to the activation and inhibition of regulatory pathways able to confer a selective growth advantage to cancer cells.	('growth advantage', 'CPA', (146, 162))	('cancer', 'Disease', (166, 172))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('openness', 'Disease', (43, 51))	('inhibition', 'NegReg', (85, 95))	('regulatory pathways', 'Pathway', (99, 118))	('modifications', 'Var', (16, 29))	('openness', 'Disease', 'MESH:D005597', (43, 51))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))
151634	31717588	Our data predict that significant chromatin openness changes might collectively affect several hundreds of genes.	('openness', 'Disease', (44, 52))	('openness', 'Disease', 'MESH:D005597', (44, 52))	('changes', 'Var', (53, 60))	('affect', 'Reg', (80, 86))
151644	31717588	We have observed that B4GALT1 silencing potently inhibits the 3D spheroid formation and impairs the expression of a set of stem cell markers.	('impairs', 'NegReg', (88, 95))	('expression of a set of', 'MPA', (100, 122))	('inhibits', 'NegReg', (49, 57))	('B4GALT1', 'Gene', '2683', (22, 29))	('3D spheroid formation', 'CPA', (62, 83))	('B4GALT1', 'Gene', (22, 29))	('silencing', 'Var', (30, 39))
151649	31717588	TCGA data clearly show that co-overexpression of B4GALT1 and SCD1 is a negative prognostic factor.	('co-overexpression', 'Var', (28, 45))	('SCD1', 'Gene', (61, 65))	('B4GALT1', 'Gene', (49, 56))	('B4GALT1', 'Gene', '2683', (49, 56))	('SCD1', 'Gene', '6319', (61, 65))
151656	31717588	This work was supported by Italian Association for Cancer Research (AIRC) (grants IG17007 to R. Mancini and IG15216 to G. Ciliberto), by the LazioInnova (grant 2018 n. 85-2017-13750 to R. Mancini) and by Fondo di Ateneo 2018, grant/Award number: B86C19001510005 to R. Mancini.	('Cancer', 'Disease', 'MESH:D009369', (51, 57))	('Cancer', 'Disease', (51, 57))	('Cancer', 'Phenotype', 'HP:0002664', (51, 57))	('IG15216', 'Var', (108, 115))
151665	31706280	Moreover, high DUOX1 mRNA levels were significantly associated with both favorable overall survival and disease-free survival in cervical cancer patients.	('patients', 'Species', '9606', (145, 153))	('overall survival', 'CPA', (83, 99))	('DUOX1', 'Gene', '53905', (15, 20))	('cervical cancer', 'Disease', (129, 144))	('DUOX1', 'Gene', (15, 20))	('cervical cancer', 'Disease', 'MESH:D002583', (129, 144))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('disease-free survival', 'CPA', (104, 125))	('high', 'Var', (10, 14))
151668	31706280	Cell-type identification by estimating relative subsets of known RNA transcript analyses indicated that the fraction of innate immune cells, including NK cells, monocytes, dendritic cells, and mast cells, was elevated in patients with high DUOX1 expression.	('fraction', 'MPA', (108, 116))	('high', 'Var', (235, 239))	('patients', 'Species', '9606', (221, 229))	('elevated', 'PosReg', (209, 217))	('DUOX1', 'Gene', '53905', (240, 245))	('DUOX1', 'Gene', (240, 245))
151709	31706280	DUOX1 and DUOX2 mRNA levels were significantly higher in patients with HPV 16 than in patients with HPV 18 and HPV 45 (Fig.	('HPV', 'Species', '10566', (100, 103))	('HPV 16', 'Species', '333760', (71, 77))	('DUOX2', 'Gene', '50506', (10, 15))	('higher', 'PosReg', (47, 53))	('patients', 'Species', '9606', (57, 65))	('DUOX1', 'Gene', '53905', (0, 5))	('HPV', 'Species', '10566', (111, 114))	('HPV', 'Species', '10566', (71, 74))	('DUOX2', 'Gene', (10, 15))	('DUOX1', 'Gene', (0, 5))	('HPV 16', 'Var', (71, 77))	('patients', 'Species', '9606', (86, 94))
151714	31706280	High mRNA expression of DUOX1 (hazard ratio 0.45, 95% confidence interval, p = 0.0069) was significantly associated with better prognosis of CESC patients in disease-free survival (Fig.	('DUOX1', 'Gene', (24, 29))	('High', 'Var', (0, 4))	('disease-free', 'Disease', (158, 170))	('mRNA expression', 'MPA', (5, 20))	('better', 'PosReg', (121, 127))	('DUOX1', 'Gene', '53905', (24, 29))	('patients', 'Species', '9606', (146, 154))	('CESC', 'Disease', (141, 145))
151729	31706280	Increased abundances of innate immune cells, including NK cells, monocytes, dendritic cells, and mast cells, and decreased abundances of adaptive immune cells, including B cells, CD8 T cells, and CD4 T cells, were identified in the patients with high DUOX1 expression compared to the patients with low DUOX1 expression (Fig.	('CD4', 'Gene', (196, 199))	('CD4', 'Gene', '920', (196, 199))	('high', 'Var', (246, 250))	('DUOX1', 'Gene', (302, 307))	('patients', 'Species', '9606', (284, 292))	('patients', 'Species', '9606', (232, 240))	('CD8', 'Gene', (179, 182))	('abundances', 'MPA', (123, 133))	('CD8', 'Gene', '925', (179, 182))	('DUOX1', 'Gene', '53905', (251, 256))	('DUOX1', 'Gene', '53905', (302, 307))	('decreased', 'NegReg', (113, 122))	('DUOX1', 'Gene', (251, 256))
151730	31706280	Additionally, in the validation data set, high mRNA levels of DUOX1 were also associated with increased innate immune cells, including NK cells and mast cells, and a decreased fraction of B cells (Additional file 5).	('NK cells', 'CPA', (135, 143))	('DUOX1', 'Gene', (62, 67))	('high', 'Var', (42, 46))	('increased', 'PosReg', (94, 103))	('decreased', 'NegReg', (166, 175))	('innate immune cells', 'CPA', (104, 123))	('DUOX1', 'Gene', '53905', (62, 67))	('mRNA levels', 'MPA', (47, 58))	('mast cells', 'CPA', (148, 158))
151739	31706280	Moreover, in our study, high expression levels of DUOX1 mRNA were significantly associated with favorable overall survival as well as disease-free survival in cervical cancer patients.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('DUOX1', 'Gene', '53905', (50, 55))	('overall', 'CPA', (106, 113))	('patients', 'Species', '9606', (175, 183))	('high', 'Var', (24, 28))	('DUOX1', 'Gene', (50, 55))	('cervical cancer', 'Disease', 'MESH:D002583', (159, 174))	('favorable', 'PosReg', (96, 105))	('cervical cancer', 'Disease', (159, 174))
151743	31706280	In contrast, in the respiratory tract, DUOX1 is mostly expressed in the tracheal and bronchial epithelium, and DUOX1 mRNA and protein are suppressed in lung cancer as a consequence of hypermethylation in the promoter region, and this suppression is associated with poor prognosis.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('DUOX1', 'Gene', '53905', (39, 44))	('DUOX1', 'Gene', (111, 116))	('lung cancer', 'Disease', 'MESH:D008175', (152, 163))	('hypermethylation', 'Var', (184, 200))	('DUOX1', 'Gene', (39, 44))	('lung cancer', 'Phenotype', 'HP:0100526', (152, 163))	('suppressed', 'NegReg', (138, 148))	('DUOX1', 'Gene', '53905', (111, 116))	('lung cancer', 'Disease', (152, 163))
151749	31706280	It has been reported that strong DUOX2 expression accelerates the development of colorectal and pancreatic cancers in patients with inflammatory bowel disease and chronic pancreatitis, respectively.	('accelerates', 'PosReg', (50, 61))	('DUOX2', 'Gene', (33, 38))	('chronic pancreatitis', 'Disease', (163, 183))	('expression', 'Var', (39, 49))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('development', 'CPA', (66, 77))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (96, 114))	('pancreatitis', 'Phenotype', 'HP:0001733', (171, 183))	('inflammatory bowel disease', 'Phenotype', 'HP:0002037', (132, 158))	('DUOX2', 'Gene', '50506', (33, 38))	('inflammatory bowel disease', 'Disease', 'MESH:D015212', (132, 158))	('chronic pancreatitis', 'Phenotype', 'HP:0006280', (163, 183))	('chronic pancreatitis', 'Disease', 'MESH:D050500', (163, 183))	('patients', 'Species', '9606', (118, 126))	('cancers', 'Phenotype', 'HP:0002664', (107, 114))	('colorectal and pancreatic cancers', 'Disease', 'MESH:D015179', (81, 114))	('inflammatory bowel disease', 'Disease', (132, 158))
151750	31706280	Overexpression of DUOX2/DUOX2A during ulcerative colitis is also thought to be responsible for oxidative DNA damage, which predisposes these patients to colon cancer development.	('ulcerative colitis', 'Disease', 'MESH:D003093', (38, 56))	('colon cancer', 'Disease', 'MESH:D015179', (153, 165))	('DUOX2', 'Gene', '50506', (24, 29))	('colon cancer', 'Disease', (153, 165))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('DUOX2', 'Gene', '50506', (18, 23))	('colitis', 'Phenotype', 'HP:0002583', (49, 56))	('ulcerative colitis', 'Phenotype', 'HP:0100279', (38, 56))	('DUOX2', 'Gene', (18, 23))	('DUOX2', 'Gene', (24, 29))	('Overexpression', 'Var', (0, 14))	('ulcerative colitis', 'Disease', (38, 56))	('oxidative DNA damage', 'MPA', (95, 115))	('patients', 'Species', '9606', (141, 149))	('colon cancer', 'Phenotype', 'HP:0003003', (153, 165))
151756	31706280	Indeed, it has been indicated that high levels of NOX2 mRNA are implicated in promoting oncogenic characteristics in breast cancer, rectal cancer, and prostate cancer.	('rectal cancer', 'Phenotype', 'HP:0100743', (132, 145))	('prostate cancer', 'Phenotype', 'HP:0012125', (151, 166))	('oncogenic characteristics', 'CPA', (88, 113))	('breast cancer', 'Disease', 'MESH:D001943', (117, 130))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('breast cancer', 'Disease', (117, 130))	('promoting', 'PosReg', (78, 87))	('prostate cancer', 'Disease', (151, 166))	('breast cancer', 'Phenotype', 'HP:0003002', (117, 130))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('rectal cancer', 'Disease', 'MESH:D012004', (132, 145))	('NOX2', 'Gene', '1536', (50, 54))	('prostate cancer', 'Disease', 'MESH:D011471', (151, 166))	('NOX2', 'Gene', (50, 54))	('high', 'Var', (35, 39))	('rectal cancer', 'Disease', (132, 145))
151797	30565803	We performed qRT-PCR and ELISA to evaluate the underlying mechanism, and found that CEACAM1 expression in tongue carcinoma cells upregulated transforming growth factor beta1 (TGF-beta1) expression, while blocking of TGF-beta1 inhibited the neutrophils' changes in the coculture system.	('tongue carcinoma', 'Phenotype', 'HP:0030415', (106, 122))	('expression', 'Var', (92, 102))	('tongue carcinoma', 'Disease', 'MESH:D014062', (106, 122))	('tongue carcinoma', 'Disease', (106, 122))	('upregulated', 'PosReg', (129, 140))	('CEACAM1', 'Gene', (84, 91))	('transforming growth factor beta1', 'Gene', '7040', (141, 173))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('expression', 'MPA', (186, 196))	('TGF-beta1', 'Gene', '7040', (216, 225))	('TGF-beta1', 'Gene', '7040', (175, 184))	('TGF-beta1', 'Gene', (216, 225))	('TGF-beta1', 'Gene', (175, 184))	('transforming growth factor beta1', 'Gene', (141, 173))
151816	30565803	CEACAM1-4L and CEACAM1-4S are common isoforms in human tumor tissues, which has 4 extracellular immunoglobulin-like domains with a long or short cytoplasmic tail.11, 25 The cDNA sequences of CEACAM1-4L and CEACAM1-4S were a kind gift from Professor John E. Shively.28 The lentivirus transfection vectors were constructed and transfected into carcinoma cells as our previous study.20 Cal-27 and SCC-6 cells were divided into four groups for transfection: CEACAM1-4L, CEACAM1-4S, vector and blank.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('SCC-6', 'CellLine', 'CVCL:7773', (394, 399))	('CEACAM1-4L', 'Var', (454, 464))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('human', 'Species', '9606', (49, 54))	('carcinoma', 'Disease', 'MESH:D002277', (342, 351))	('tumor', 'Disease', (55, 60))	('carcinoma', 'Phenotype', 'HP:0030731', (342, 351))	('carcinoma', 'Disease', (342, 351))
151846	30565803	To assess the roles of neutrophils in this tumor-formation process, IHC was used to evaluate the infiltration of CD11b+ (1:200, ab133357; Abcam) neutrophils in the xenograft tumors.	('tumor', 'Disease', (174, 179))	('xenograft tumors', 'Disease', 'MESH:D009369', (164, 180))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('xenograft tumors', 'Disease', (164, 180))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('tumor', 'Disease', (43, 48))	('CD11b+', 'Var', (113, 119))	('tumors', 'Phenotype', 'HP:0002664', (174, 180))
151851	30565803	Based on the results of qRT-PCR and western blot analyses, CEACAM1-4L and CEACAM1-4S expression of SCC-6 were clearly elevated in CEACAM1-4L and -4S transfection group respectively, relative to the vector or blank control group (Figure 1B,C).	('transfection', 'Var', (149, 161))	('expression', 'MPA', (85, 95))	('CEACAM1-4L', 'Var', (130, 140))	('elevated', 'PosReg', (118, 126))	('SCC-6', 'Gene', (99, 104))	('SCC-6', 'CellLine', 'CVCL:7773', (99, 104))
151853	30565803	Overexpression of CEACAM1-4L and CEACAM1-4S in Cal-27 cells both additionally upregulated the mRNA expressions of VEGF-A, MMP9, and IL-8, and further downregulated TNF-alpha mRNA expression relative to the vector and blank control groups (P < 0.05, respectively) (Figure 2).	('CEACAM1-4L', 'Var', (18, 28))	('IL-8', 'Gene', '3576', (132, 136))	('downregulated', 'NegReg', (150, 163))	('TNF-alpha', 'Gene', (164, 173))	('upregulated', 'PosReg', (78, 89))	('TNF-alpha', 'Gene', '7124', (164, 173))	('mRNA expressions', 'MPA', (94, 110))	('CEACAM1-4S', 'Var', (33, 43))	('VEGF-A', 'Gene', '7422', (114, 120))	('VEGF-A', 'Gene', (114, 120))	('MMP9', 'Gene', (122, 126))	('IL-8', 'Gene', (132, 136))	('MMP9', 'Gene', '4318', (122, 126))
151855	30565803	After the direct coculture, the MTT results revealed that cell vitality was clearly lower in the CEACAM1-4L and CEACAM1-4S overexpression groups, relative to the vector or blank control groups.	('CEACAM1-4L', 'Var', (97, 107))	('overexpression', 'PosReg', (123, 137))	('cell vitality', 'CPA', (58, 71))	('lower', 'NegReg', (84, 89))	('MTT', 'Chemical', 'MESH:C070243', (32, 35))
151858	30565803	The mRNA expressions of TGF-beta1 and IFN-beta1 in each group of Cal-27 cells were analyzed using qRT-PCR, which revealed that both CEACAM1-4L and CEACAM1-4S significantly upregulated TGF-beta1 mRNA expression (P < 0.05, respectively) compared with vector and blank group (Figure 4), but has no significant effect on IFN-beta1 expression (data not shown).	('TGF-beta1', 'Gene', '7040', (24, 33))	('TGF-beta1', 'Gene', (24, 33))	('CEACAM1-4S', 'Var', (147, 157))	('CEACAM1-4L', 'Var', (132, 142))	('mRNA expression', 'MPA', (194, 209))	('TGF-beta1', 'Gene', '7040', (184, 193))	('TGF-beta1', 'Gene', (184, 193))	('upregulated', 'PosReg', (172, 183))	('IFN-beta', 'Gene', '3456', (38, 46))	('IFN-beta', 'Gene', '3456', (317, 325))	('IFN-beta', 'Gene', (38, 46))	('IFN-beta', 'Gene', (317, 325))
151861	30565803	Thus, overexpression of CEACAM1-4L and CEACAM1-4S can promote both expression and secretion of TGF-beta1 protein in tongue carcinoma cells.	('TGF-beta1', 'Gene', (95, 104))	('promote', 'PosReg', (54, 61))	('secretion', 'MPA', (82, 91))	('tongue carcinoma', 'Disease', 'MESH:D014062', (116, 132))	('tongue carcinoma', 'Disease', (116, 132))	('CEACAM1-4S', 'Var', (39, 49))	('expression', 'MPA', (67, 77))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('protein', 'Protein', (105, 112))	('tongue carcinoma', 'Phenotype', 'HP:0030415', (116, 132))	('TGF-beta1', 'Gene', '7040', (95, 104))
151862	30565803	Adding the TGF-beta1-neutralizing antibodies into the indirect coculture system revealed that blocking TGF-beta1 led to clear downregulation of VEGF-A, MMP9, and IL-8, but upregulation of TNF-alpha in dHL-60 cells, relative to the corresponding groups without the TGF-beta1-neutralizing antibodies (P < 0.05, respectively) in both Cal-27 and SCC-6 cells (Figure 2).	('downregulation', 'NegReg', (126, 140))	('TGF-beta1', 'Gene', (264, 273))	('TGF-beta1', 'Gene', (11, 20))	('TNF-alpha', 'Gene', '7124', (188, 197))	('VEGF-A', 'Gene', (144, 150))	('TNF-alpha', 'Gene', (188, 197))	('TGF-beta1', 'Gene', (103, 112))	('TGF-beta1', 'Gene', '7040', (264, 273))	('TGF-beta1', 'Gene', '7040', (11, 20))	('IL-8', 'Gene', '3576', (162, 166))	('blocking', 'Var', (94, 102))	('SCC-6', 'CellLine', 'CVCL:7773', (342, 347))	('TGF-beta1', 'Gene', '7040', (103, 112))	('HL-60', 'CellLine', 'CVCL:0002', (202, 207))	('VEGF-A', 'Gene', '7422', (144, 150))	('upregulation', 'PosReg', (172, 184))	('MMP9', 'Gene', (152, 156))	('MMP9', 'Gene', '4318', (152, 156))	('IL-8', 'Gene', (162, 166))
151863	30565803	The direct coculture system also showed that the kill rates of Cal-27 were 57.93 +- 1.74% for the CEACAM1-4L overexpression group, 59.17 +- 2.27% for the CEACAM1-4S overexpression group, 62.53 +- 1.65% for the vector group, and 60.71 +- 1.83% for the blank group, while the killing rates of SCC-6 were 58.67 +- 2.08, 57.01 +- 1.96, 61.67 +- 1.34 and 59.56 +- 1.71 in each corresponding group, which confirmed that TGF-beta1 blockade strengthened the cytotoxicity ability of dHL-60 cells relative to the corresponding groups without the TGF-beta1-neutralizing antibodies (P < 0.05, respectively) (Figure 3).	('strengthened', 'PosReg', (433, 445))	('TGF-beta1', 'Gene', '7040', (536, 545))	('TGF-beta1', 'Gene', '7040', (414, 423))	('TGF-beta1', 'Gene', (536, 545))	('cytotoxicity', 'Disease', (450, 462))	('TGF-beta1', 'Gene', (414, 423))	('HL-60', 'CellLine', 'CVCL:0002', (475, 480))	('cytotoxicity', 'Disease', 'MESH:D064420', (450, 462))	('SCC-6', 'CellLine', 'CVCL:7773', (291, 296))	('blockade', 'Var', (424, 432))
151868	30565803	The nude mouse xenograft model of Cal-27 cells revealed significantly larger tumor sizes in the CEACAM1-4L group (1257.49 +- 78.37 mm3) and the CEACAM1-4S group (1167.53 +- 122.84 mm3) than in the vector group (589.25 +- 114.36 mm3, P < 0.05) (Figure 6A,B).	('CEACAM1-4L', 'Var', (96, 106))	('larger', 'PosReg', (70, 76))	('mouse', 'Species', '10090', (9, 14))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Disease', (77, 82))
151879	30565803	Furthermore, overexpression of CEACAM1-4L and CEACAM1-4S further upregulated the mRNA expressions of VEGF-A, MMP9, and IL-8, and further downregulated TNF-alpha mRNA expression in transfected dHL-60 cells, relative to the vector and blank groups (P < 0.05) (Figure 2).	('downregulated', 'NegReg', (137, 150))	('TNF-alpha', 'Gene', '7124', (151, 160))	('HL-60', 'CellLine', 'CVCL:0002', (193, 198))	('IL-8', 'Gene', '3576', (119, 123))	('TNF-alpha', 'Gene', (151, 160))	('IL-8', 'Gene', (119, 123))	('CEACAM1-4S', 'Var', (46, 56))	('MMP9', 'Gene', '4318', (109, 113))	('MMP9', 'Gene', (109, 113))	('upregulated', 'PosReg', (65, 76))	('VEGF-A', 'Gene', '7422', (101, 107))	('VEGF-A', 'Gene', (101, 107))	('mRNA expressions', 'MPA', (81, 97))	('CEACAM1-4L', 'Var', (31, 41))
151898	27977008	The recurrent architecture of tumour initiation, progression and drug sensitivity Recent studies across multiple tumour types are starting to reveal a recurrent regulatory architecture in which genomic alterations cluster upstream of functional master regulator (MR) proteins, the aberrant activity of which is both necessary and sufficient to maintain tumour cell state.	('tumour initiation', 'Disease', (30, 47))	('tumour', 'Phenotype', 'HP:0002664', (113, 119))	('tumour', 'Phenotype', 'HP:0002664', (353, 359))	('tumour', 'Disease', 'MESH:D009369', (113, 119))	('tumour', 'Disease', 'MESH:D009369', (353, 359))	('tumour', 'Disease', 'MESH:D009369', (30, 36))	('tumour', 'Disease', (30, 36))	('tumour', 'Phenotype', 'HP:0002664', (30, 36))	('tumour', 'Disease', (113, 119))	('tumour', 'Disease', (353, 359))	('genomic alterations', 'Var', (194, 213))	('drug sensitivity', 'Phenotype', 'HP:0020174', (65, 81))	('tumour initiation', 'Disease', 'MESH:D009369', (30, 47))	('alterations', 'Var', (202, 213))
151907	27977008	We used standard unsupervised cluster analysis to identify the best four clusters based on distinct data types - somatic coding mutations (SCMs; part a of the figure), copy number variants (CNVs; part b of the figure), gene expression profiles (GEPs; part c of the figure) and master regulator activity (MRA; part d of the figure).	('copy number variants', 'Var', (168, 188))	('GEP', 'Gene', (245, 248))	('GEP', 'Gene', '2896', (245, 248))	('gene expression', 'MPA', (219, 234))
151918	27977008	Consistent with these observations, although genomic alterations represent valuable predictors of targeted inhibitor sensitivity against the corresponding oncoproteins, they have proved less effective in stratifying more general properties of cancer, such as tumour subtype, metastatic potential and clinical outcome, which are more often captured by transcriptional or proteomic profiles (BOX 1).	('tumour subtype', 'Disease', 'MESH:C535673', (259, 273))	('alterations', 'Var', (53, 64))	('cancer', 'Disease', (243, 249))	('tumour subtype', 'Disease', (259, 273))	('cancer', 'Disease', 'MESH:D009369', (243, 249))	('tumour', 'Phenotype', 'HP:0002664', (259, 265))	('cancer', 'Phenotype', 'HP:0002664', (243, 249))	('metastatic potential', 'CPA', (275, 295))
151924	27977008	According to the latter, TP53 (which encodes p53) and ERBB2 (which encodes HER2) are often presented as cancer MRs, even though many alternative genomic alterations may induce transcriptional tumour states that are virtually indistinguishable from those in which those genes are mutated (BOX 1).	('p53', 'Gene', (45, 48))	('p53', 'Gene', '7157', (45, 48))	('ERBB2', 'Gene', '2064', (54, 59))	('TP53', 'Gene', (25, 29))	('tumour', 'Phenotype', 'HP:0002664', (192, 198))	('alterations', 'Var', (153, 164))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('ERBB2', 'Gene', (54, 59))	('transcriptional', 'MPA', (176, 191))	('HER2', 'Gene', (75, 79))	('tumour', 'Disease', 'MESH:D009369', (192, 198))	('TP53', 'Gene', '7157', (25, 29))	('induce', 'Reg', (169, 175))	('HER2', 'Gene', '2064', (75, 79))	('tumour', 'Disease', (192, 198))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))
151934	27977008	For instance, xenograft tumours in mice and even cancer cell lines can maintain a relatively high-fidelity representation of the transcriptional state of the original tumour, despite aberrant ploidy, mutational drift and massive changes in the repertoire of microenvironment signals to which they are exposed.	('ploidy', 'Var', (192, 198))	('tumour', 'Phenotype', 'HP:0002664', (24, 30))	('tumour', 'Phenotype', 'HP:0002664', (167, 173))	('changes', 'Reg', (229, 236))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('mutational drift', 'Var', (200, 216))	('original tumour', 'Disease', (158, 173))	('xenograft tumours', 'Disease', (14, 31))	('tumours', 'Phenotype', 'HP:0002664', (24, 31))	('mice', 'Species', '10090', (35, 39))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('original tumour', 'Disease', 'MESH:D009369', (158, 173))	('xenograft tumours', 'Disease', 'MESH:D009369', (14, 31))	('cancer', 'Disease', (49, 55))
151937	27977008	Recent results suggest that dystatic cell states may be implemented by a handful of tumour-specific MR proteins : working cooperatively within tight modular structures (tumour checkpoints) : the aberrant activity of which is necessary and sufficient for tumour phenotype presentation and maintenance.	('tumour', 'Disease', (84, 90))	('tumour', 'Disease', (169, 175))	('aberrant', 'Var', (195, 203))	('tumour', 'Disease', 'MESH:D009369', (254, 260))	('tumour', 'Disease', (254, 260))	('tumour', 'Phenotype', 'HP:0002664', (84, 90))	('tumour', 'Phenotype', 'HP:0002664', (169, 175))	('tumour', 'Disease', 'MESH:D009369', (169, 175))	('tumour', 'Disease', 'MESH:D009369', (84, 90))	('tumour', 'Phenotype', 'HP:0002664', (254, 260))
151941	27977008	Indeed, aberrant NF-kappaB activity was shown to arise from several mutations in its upstream pathways, including in TNF-induced protein 3 (TNFAIP3), myeloid differentiation primary response 88 (MYD88), TNF receptor associated factor 2 (TRAF2), TRAF5, CD79A, CD79B, MAP3K7 (also known as TAK1), TNFRSF11A (which encodes RANK) and caspase recruitment domain family member 11 (CARD11) (FIG.	('CARD11', 'Gene', (375, 381))	('CARD11', 'Gene', '84433', (375, 381))	('CD79A', 'Gene', '973', (252, 257))	('TRAF5', 'Gene', '7188', (245, 250))	('TRAF2', 'Gene', (237, 242))	('MYD88', 'Gene', '4615', (195, 200))	('TNF receptor associated factor 2', 'Gene', (203, 235))	('MAP3K7', 'Gene', (266, 272))	('TNFRSF11A', 'Gene', '8792', (295, 304))	('TRAF2', 'Gene', '7186', (237, 242))	('TNFRSF11A', 'Gene', (295, 304))	('TAK1', 'Gene', '6885', (288, 292))	('arise', 'Reg', (49, 54))	('MAP3K7', 'Gene', '6885', (266, 272))	('NF-kappaB', 'Protein', (17, 26))	('TAK1', 'Gene', (288, 292))	('activity', 'MPA', (27, 35))	('MYD88', 'Gene', (195, 200))	('CD79B', 'Gene', (259, 264))	('TNF-induced', 'Gene', (117, 128))	('CD79B', 'Gene', '974', (259, 264))	('TNFAIP3', 'Gene', '7128', (140, 147))	('CD79A', 'Gene', (252, 257))	('TNF receptor associated factor 2', 'Gene', '7186', (203, 235))	('mutations', 'Var', (68, 77))	('TRAF5', 'Gene', (245, 250))	('TNFAIP3', 'Gene', (140, 147))
151999	27977008	Indeed, their silencing in trastuzumab-treated, resistant tumours elicited synthetic lethality in vitro and in vivo, leading to the discovery of an autocrine STAT3-interleukin 6 (IL-6)-IL-6 receptor (IL6R)-Janus kinase (JAK)-STAT3 autoregulatory loop, independent of trastuzumab-mediated inhibition of HER2.	('tumours', 'Phenotype', 'HP:0002664', (58, 65))	('STAT3-interleukin 6', 'Gene', '3569', (158, 177))	('tumours', 'Disease', 'MESH:D009369', (58, 65))	('IL-6', 'Gene', '3569', (179, 183))	('STAT3', 'Gene', (158, 163))	('IL6R', 'Gene', (200, 204))	('silencing', 'Var', (14, 23))	('HER2', 'Gene', '2064', (302, 306))	('tumour', 'Phenotype', 'HP:0002664', (58, 64))	('IL-6', 'Gene', (179, 183))	('STAT3', 'Gene', '6774', (158, 163))	('trastuzumab', 'Chemical', 'MESH:D000068878', (267, 278))	('IL-6', 'Gene', '3569', (185, 189))	('IL6R', 'Gene', '3570', (200, 204))	('STAT3', 'Gene', (225, 230))	('trastuzumab', 'Chemical', 'MESH:D000068878', (27, 38))	('IL-6', 'Gene', (185, 189))	('STAT3', 'Gene', '6774', (225, 230))	('HER2', 'Gene', (302, 306))	('STAT3-interleukin 6', 'Gene', (158, 177))	('tumours', 'Disease', (58, 65))
152004	27977008	Indeed, because of the extensive genomic diversity of individual tumour cells, it is only a matter of time before one or more drug-resistant subclones emerges with bypass or alternative mutations.	('tumour', 'Disease', 'MESH:D009369', (65, 71))	('tumour', 'Phenotype', 'HP:0002664', (65, 71))	('tumour', 'Disease', (65, 71))	('mutations', 'Var', (186, 195))
152014	27977008	Consistently, treatment with MK2006 (an AKT1 inhibitor) rescued dexamethasone sensitivity in vitro and in vivo, including in PDXs transplanted with leukaemic cells from patients with GC-resistant disease.	('MK2006', 'Var', (29, 35))	('dexamethasone', 'Chemical', 'MESH:D003907', (64, 77))	('patients', 'Species', '9606', (169, 177))	('dexamethasone sensitivity', 'MPA', (64, 89))	('AKT1', 'Gene', '207', (40, 44))	('MK2006', 'Chemical', '-', (29, 35))	('rescued', 'PosReg', (56, 63))	('AKT1', 'Gene', (40, 44))
152015	27977008	AKT1 thus emerged as a key tumour checkpoint MR downstream of recurrent T-ALL mutations, including in PI3K and PTEN and further mediating resistance by inducing mTOR-mediated increase in the expression of the MCL1 antiapoptotic gene.	('AKT1', 'Gene', '207', (0, 4))	('PTEN', 'Gene', (111, 115))	('AKT1', 'Gene', (0, 4))	('PTEN', 'Gene', '5728', (111, 115))	('mTOR', 'Gene', '2475', (161, 165))	('MCL1', 'Gene', '4170', (209, 213))	('tumour', 'Phenotype', 'HP:0002664', (27, 33))	('PI3K', 'Gene', (102, 106))	('mutations', 'Var', (78, 87))	('MCL1', 'Gene', (209, 213))	('inducing', 'Reg', (152, 160))	('tumour', 'Disease', 'MESH:D009369', (27, 33))	('increase', 'PosReg', (175, 183))	('T-ALL', 'Gene', (72, 77))	('tumour', 'Disease', (27, 33))	('expression', 'MPA', (191, 201))	('mTOR', 'Gene', (161, 165))
152025	27977008	Although several algorithms can detect association of genomic alterations with differential gene expression (genetical-genomics) or perform network-based clustering of genomic alterations (see REF for a review), there are no methods for the genome-wide, tumour-specific exploration of alterations in signalling pathways upstream of candidate MR proteins.	('differential gene expression', 'MPA', (79, 107))	('tumour', 'Disease', 'MESH:D009369', (254, 260))	('tumour', 'Disease', (254, 260))	('alterations', 'Var', (62, 73))	('tumour', 'Phenotype', 'HP:0002664', (254, 260))
152026	27977008	For instance, among the multitude of genes of which the expression was affected by recurrent copy number alterations (CNAs) in the MES-GBM subtype, MINDy inferred that only 92 genes were either MRs or upstream MR-activity modulators.	('affected', 'Reg', (71, 79))	('expression', 'MPA', (56, 66))	('copy number alterations', 'Var', (93, 116))	('MES', 'Chemical', 'MESH:C004550', (131, 134))
152030	27977008	Consistent with this result, IHC analysis of KLHL9-/- tumours showed significant increase in CEBPbeta and CEBPdelta protein abundance, and their in vivo viability was dramatically reduced by ectopic KLHL9 expression.	('KLHL9', 'Gene', '55958', (199, 204))	('CEBPdelta', 'Gene', '1052', (106, 115))	('KLHL9', 'Gene', (199, 204))	('tumours', 'Disease', 'MESH:D009369', (54, 61))	('tumours', 'Phenotype', 'HP:0002664', (54, 61))	('tumours', 'Disease', (54, 61))	('KLHL9', 'Gene', '55958', (45, 50))	('reduced', 'NegReg', (180, 187))	('CEBPbeta', 'Gene', '1051', (93, 101))	('KLHL9', 'Gene', (45, 50))	('increase', 'PosReg', (81, 89))	('CEBPdelta', 'Gene', (106, 115))	('ectopic', 'Var', (191, 198))	('CEBPbeta', 'Gene', (93, 101))	('tumour', 'Phenotype', 'HP:0002664', (54, 60))
152033	27977008	The second class includes MR modulators, dysregulation of which by mutations or aberrant signals induces aberrant MR activity (for example, KLHL9 and CEBPdelta).	('CEBPdelta', 'Gene', '1052', (150, 159))	('KLHL9', 'Gene', (140, 145))	('mutations', 'Var', (67, 76))	('MR activity', 'MPA', (114, 125))	('induces', 'Reg', (97, 104))	('CEBPdelta', 'Gene', (150, 159))	('KLHL9', 'Gene', '55958', (140, 145))
152036	27977008	In rare cases in which aberrant MR activity results from genetic alterations at its locus (for example, CEBPD), these two classes may overlap.	('genetic alterations', 'Var', (57, 76))	('CEBPD', 'Gene', (104, 109))	('results', 'Reg', (44, 51))	('MR activity', 'MPA', (32, 43))	('CEBPD', 'Gene', '1052', (104, 109))
152037	27977008	When combined with identification of mutations in pathways upstream of NF-kappaB in DLBCL and with conservation of prostate cancer MRs in four different genetically engineered mouse models with distinct driver mutations, these studies further confirm that tumour checkpoints represent the cellular logic that is responsible for integrating the effect of large and heterogeneous genomic alteration repertoires into virtually indistinguishable tumour states.	('prostate cancer', 'Disease', (115, 130))	('tumour', 'Disease', 'MESH:D009369', (442, 448))	('tumour', 'Disease', 'MESH:D009369', (256, 262))	('tumour', 'Disease', (442, 448))	('tumour', 'Disease', (256, 262))	('mouse', 'Species', '10090', (176, 181))	('tumour', 'Phenotype', 'HP:0002664', (256, 262))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('mutations', 'Var', (37, 46))	('prostate cancer', 'Disease', 'MESH:D011471', (115, 130))	('tumour', 'Phenotype', 'HP:0002664', (442, 448))	('prostate cancer', 'Phenotype', 'HP:0012125', (115, 130))
152042	27977008	Indeed, whenever relapse is induced by alternative or bypass mutations or by epigenetic mechanisms that act upstream of the same tumour checkpoint, its direct targeting should mitigate relapse.	('tumour', 'Phenotype', 'HP:0002664', (129, 135))	('relapse', 'MPA', (185, 192))	('relapse', 'Disease', (17, 24))	('mitigate', 'NegReg', (176, 184))	('tumour', 'Disease', 'MESH:D009369', (129, 135))	('bypass mutations', 'Var', (54, 70))	('tumour', 'Disease', (129, 135))	('epigenetic mechanisms', 'Var', (77, 98))	('induced', 'Reg', (28, 35))	('alternative', 'Var', (39, 50))
152044	27977008	Even assuming a single functional mutation per gene product, the activity of oncoproteins regulated by >=100 other gene products, such as MYC, could be dysregulated by any combination of mutated oncogenes out of the 100 possible ones.	('activity', 'MPA', (65, 73))	('mutated', 'Var', (187, 194))	('MYC', 'Gene', (138, 141))	('dysregulated', 'Disease', (152, 164))	('MYC', 'Gene', '4609', (138, 141))	('oncoproteins', 'Protein', (77, 89))
152045	27977008	For instance, PTEN activity in glioma was shown to be dysregulated by multiple deletions of any among 13 frequently deleted genes, each individually affecting PTEN expression by less than 20%.	('PTEN', 'Gene', (14, 18))	('dysregulated', 'Reg', (54, 66))	('PTEN', 'Gene', '5728', (14, 18))	('PTEN', 'Gene', (159, 163))	('expression', 'MPA', (164, 174))	('PTEN', 'Gene', '5728', (159, 163))	('glioma', 'Disease', 'MESH:D005910', (31, 37))	('deletions', 'Var', (79, 88))	('glioma', 'Phenotype', 'HP:0009733', (31, 37))	('activity', 'MPA', (19, 27))	('affecting', 'Reg', (149, 158))	('glioma', 'Disease', (31, 37))
152046	27977008	First, despite successful identification of key recurrent, high-penetrance driver mutations : such as BCR-ABL translocation events in CML, KRAS mutations in up to 90% of pancreatic ductal adenocarcinomas, BRAF mutations in almost 50% of melanomas and ERBB2 amplification in 20-30% of breast ductal adenocarcinomas : we are starting to run out of such low-hanging fruits.	('mutations', 'Var', (210, 219))	('carcinoma', 'Phenotype', 'HP:0030731', (193, 202))	('KRAS', 'Gene', '3845', (139, 143))	('melanomas', 'Phenotype', 'HP:0002861', (237, 246))	('mutations', 'Var', (144, 153))	('BRAF', 'Gene', '673', (205, 209))	('BRAF', 'Gene', (205, 209))	('breast ductal adenocarcinomas', 'Disease', 'MESH:D018270', (284, 313))	('KRAS', 'Gene', (139, 143))	('low-hanging fruits', 'Disease', 'MESH:D009800', (351, 369))	('BCR-ABL', 'Gene', '25', (102, 109))	('melanoma', 'Phenotype', 'HP:0002861', (237, 245))	('CML', 'Disease', 'MESH:D015464', (134, 137))	('low-hanging fruits', 'Disease', (351, 369))	('CML', 'Disease', (134, 137))	('ERBB2', 'Gene', (251, 256))	('pancreatic ductal adenocarcinomas', 'Disease', 'MESH:D021441', (170, 203))	('melanomas', 'Disease', 'MESH:D008545', (237, 246))	('pancreatic ductal adenocarcinomas', 'Disease', (170, 203))	('breast ductal adenocarcinomas', 'Disease', (284, 313))	('melanomas', 'Disease', (237, 246))	('BCR-ABL', 'Gene', (102, 109))	('ERBB2', 'Gene', '2064', (251, 256))	('mutations', 'Var', (82, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (303, 312))
152048	27977008	Indeed, pharmacological inhibition of aberrantly activated oncoproteins can elicit oncogene dependency, which represents the basis for the oncogene addiction paradigm and the foundation of current efforts in precision cancer medicine.	('cancer', 'Disease', 'MESH:D009369', (218, 224))	('oncogene dependency', 'MPA', (83, 102))	('oncoproteins', 'Protein', (59, 71))	('cancer', 'Disease', (218, 224))	('elicit', 'Reg', (76, 82))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('aberrantly', 'Var', (38, 48))	('pharmacological', 'Var', (8, 23))
152050	27977008	For instance, lung adenocarcinoma (LUAD) cells with activating mutations in a specific oncogene (for example, the epidermal growth factor receptor (ECFR)) may be sensitive to the corresponding targeted inhibitor (erlotinib).	('mutations', 'Var', (63, 72))	('erlotinib', 'Chemical', 'MESH:D000069347', (213, 222))	('lung adenocarcinoma', 'Disease', (14, 33))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (14, 33))	('activating', 'PosReg', (52, 62))	('carcinoma', 'Phenotype', 'HP:0030731', (24, 33))	('epidermal growth factor receptor', 'Gene', (114, 146))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (14, 33))	('epidermal growth factor receptor', 'Gene', '1956', (114, 146))	('sensitive', 'MPA', (162, 171))
152053	27977008	Indeed, samples from The Cancer Genome Atlas (TCGA) LUAD cohort show striking enrichment of activating EGFR mutations in samples with the highest Virtual Inference of Protein Activity by Enriched Regulon Analysis (VIPER)-inferred EGFR activity (part b of the figure - the expanded inset shows samples with the highest activity).	('EGFR', 'Gene', '1956', (230, 234))	('EGFR', 'Gene', (230, 234))	('EGFR', 'Gene', '1956', (103, 107))	('mutations', 'Var', (108, 117))	('EGFR', 'Gene', (103, 107))	('Cancer', 'Phenotype', 'HP:0002664', (25, 31))	('Cancer Genome Atlas', 'Disease', (25, 44))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (25, 44))	('activating', 'PosReg', (92, 102))	('VIPER', 'Species', '31156', (214, 219))
152066	27977008	These data were valuable for the identification of drugs and drug combinations that abrogateviability of aggressive follicular lymphoma cells following transformation to DLBCL, by targeting experimentally validated MRs and synergistic MR pairs.	('aggressive follicular lymphoma', 'Disease', (105, 135))	('abrogateviability', 'CPA', (84, 101))	('lymphoma', 'Phenotype', 'HP:0002665', (127, 135))	('combinations', 'Var', (66, 78))	('abrogateviability', 'NegReg', (84, 101))	('aggressive follicular lymphoma', 'Disease', 'MESH:D008224', (105, 135))
152083	27977008	Oncotecture The regulatory architecture responsible for implementing tumour dystasis, comprising one or more tumour checkpoints that are responsible for integrating the effect of multiple mutations and aberrant signals in their upstream pathways to implement a conserved repertoire of downstream transcriptional programmes that are necessary and sufficient for tumour phenotype presentation.	('tumour', 'Disease', (69, 75))	('implementing tumour dystasis', 'Disease', 'MESH:D009369', (56, 84))	('tumour', 'Disease', 'MESH:D009369', (109, 115))	('tumour', 'Phenotype', 'HP:0002664', (109, 115))	('implementing tumour dystasis', 'Disease', (56, 84))	('tumour', 'Disease', (109, 115))	('tumour', 'Phenotype', 'HP:0002664', (361, 367))	('tumour', 'Phenotype', 'HP:0002664', (69, 75))	('tumour', 'Disease', 'MESH:D009369', (69, 75))	('mutations', 'Var', (188, 197))	('tumour', 'Disease', 'MESH:D009369', (361, 367))	('tumour', 'Disease', (361, 367))
152087	27835880	Targeted depletion of PIK3R2 induces regression of lung squamous cell carcinoma Oncogenic mutations in the PI3K/AKT pathway are present in nearly half of human tumors.	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (56, 79))	('human', 'Species', '9606', (154, 159))	('mutations', 'Var', (90, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('regression', 'NegReg', (37, 47))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (51, 79))	('AKT', 'Gene', (112, 115))	('lung squamous cell carcinoma', 'Disease', (51, 79))	('AKT', 'Gene', '207', (112, 115))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (51, 79))	('PIK3R2', 'Gene', (22, 28))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('tumors', 'Disease', (160, 166))	('PIK3R2', 'Gene', '5296', (22, 28))	('depletion', 'NegReg', (9, 18))	('tumors', 'Disease', 'MESH:D009369', (160, 166))
152092	27835880	In tumors with high PIK3R2 expression, and independently of PIK3CA, KRAS, or PTEN mutations, PIK3R2 depletion induced lung SQCC xenograft regression without triggering PI3K/AKT pathway rebound.	('high', 'Var', (15, 19))	('AKT', 'Gene', '207', (173, 176))	('tumors', 'Phenotype', 'HP:0002664', (3, 9))	('PIK3CA', 'Gene', (60, 66))	('tumors', 'Disease', (3, 9))	('PIK3CA', 'Gene', '5290', (60, 66))	('tumors', 'Disease', 'MESH:D009369', (3, 9))	('AKT', 'Gene', (173, 176))	('expression', 'MPA', (27, 37))	('PIK3R2', 'Gene', (93, 99))	('KRAS', 'Gene', (68, 72))	('PTEN', 'Gene', (77, 81))	('PTEN', 'Gene', '5728', (77, 81))	('KRAS', 'Gene', '3845', (68, 72))	('PIK3R2', 'Gene', (20, 26))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))	('depletion', 'Var', (100, 109))	('lung SQCC', 'Disease', (118, 127))
152099	27835880	A variety of agents that target EGFR (epidermal growth factor receptor), ALK (anaplastic lymphoma kinase), or ROS1 (c-ros oncogene 1) have improved the outcome of lung cancer patients bearing specific driver mutations.	('mutations', 'Var', (208, 217))	('c-ros oncogene 1', 'Gene', (116, 132))	('ROS1', 'Gene', (110, 114))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('epidermal growth factor receptor', 'Gene', (38, 70))	('lymphoma', 'Phenotype', 'HP:0002665', (89, 97))	('EGFR', 'Gene', (32, 36))	('c-ros oncogene 1', 'Gene', '6098', (116, 132))	('epidermal growth factor receptor', 'Gene', '1956', (38, 70))	('lung cancer', 'Disease', (163, 174))	('ALK', 'Gene', '238', (73, 76))	('ROS1', 'Gene', '6098', (110, 114))	('anaplastic lymphoma kinase', 'Gene', '238', (78, 104))	('ALK', 'Gene', (73, 76))	('lung cancer', 'Disease', 'MESH:D008175', (163, 174))	('anaplastic lymphoma kinase', 'Gene', (78, 104))	('EGFR', 'Gene', '1956', (32, 36))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (78, 97))	('patients', 'Species', '9606', (175, 183))	('improved', 'PosReg', (139, 147))	('lung cancer', 'Phenotype', 'HP:0100526', (163, 174))
152103	27835880	The most frequent alterations found are TP53, NFE2L2, KEAP1, several genes involved in squamous cell differentiation, CDKN2A, RB1, FGFR1 amplifications, and other mutations at low frequencies; the class IA phosphoinositide 3-kinase (PI3K) is also deregulated in SQCC.	('CDKN2A', 'Gene', (118, 124))	('FGFR1', 'Gene', '2260', (131, 136))	('alterations', 'Var', (18, 29))	('KEAP1', 'Gene', (54, 59))	('NFE2L2', 'Gene', (46, 52))	('CDKN2A', 'Gene', '1029', (118, 124))	('SQCC', 'Disease', (262, 266))	('RB1', 'Gene', '5925', (126, 129))	('deregulated', 'PosReg', (247, 258))	('TP53', 'Gene', '7157', (40, 44))	('TP53', 'Gene', (40, 44))	('NFE2L2', 'Gene', '4780', (46, 52))	('KEAP1', 'Gene', '9817', (54, 59))	('FGFR1', 'Gene', (131, 136))	('RB1', 'Gene', (126, 129))
152104	27835880	PI3K are dimers formed by a catalytic subunit (p110alpha, p110beta or the hematopoietic isoform p110delta, encoded by PIK3CA, CB, and CD) and a regulatory subunit (p85alpha, p85beta, or the muscle-specific p55gamma isoform, encoded by PIK3R1, R2, and R3, respectively).	('p110beta', 'Gene', (58, 66))	('CD', 'Disease', 'MESH:D006223', (134, 136))	('p85alpha', 'Gene', (164, 172))	('p110delta', 'Gene', (96, 105))	('p110beta', 'Gene', '5291', (58, 66))	('p110alpha', 'Var', (47, 56))	('R2, and R3', 'Gene', '913', (243, 253))	('PIK3CA', 'Gene', (118, 124))	('p110delta', 'Gene', '5293', (96, 105))	('PIK3CA', 'Gene', '5290', (118, 124))	('p85alpha', 'Gene', '5295', (164, 172))
152105	27835880	PI3K catalyzes the formation of phosphatidylinositol (PI) 3,4,5-trisphosphate (PIP3), which activates a signaling cascade that involves protein kinase B (PKB o Akt), the target of rapamycin (TOR), etc; PIP3 levels are downregulated by the phosphatase PTEN.	('downregulated', 'NegReg', (218, 231))	('PKB', 'Gene', (154, 157))	('PI3K', 'Var', (0, 4))	('PIP3', 'Chemical', 'MESH:C060974', (202, 206))	('TOR', 'Chemical', '-', (191, 194))	('3,4,5-trisphosphate', 'Chemical', '-', (58, 77))	('Akt', 'Gene', '207', (160, 163))	('rapamycin', 'Chemical', 'MESH:D020123', (180, 189))	('activates', 'PosReg', (92, 101))	('PIP3', 'Chemical', 'MESH:C060974', (79, 83))	('Akt', 'Gene', (160, 163))	('phosphatidylinositol', 'Chemical', 'MESH:D010716', (32, 52))	('PTEN', 'Gene', (251, 255))	('PKB', 'Gene', '207', (154, 157))	('PTEN', 'Gene', '5728', (251, 255))
152106	27835880	PI3K activation induces cell survival and contributes to promote cell cycle progression, cell migration and the cancer-associated metabolic switch.	('cell survival', 'CPA', (24, 37))	('cancer', 'Disease', (112, 118))	('promote', 'PosReg', (57, 64))	('cell cycle progression', 'CPA', (65, 87))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('induces', 'PosReg', (16, 23))	('PI3K activation', 'Var', (0, 15))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('cell migration', 'CPA', (89, 103))
152107	27835880	Alterations in the PI3K pathway in SQCC include amplification of PIK3CA (3q.26.3), PIK3CB (3q.22.3) and PIK3R2 (19q13.2-4).	('PIK3R2', 'Gene', (104, 110))	('PI3K pathway', 'Pathway', (19, 31))	('PIK3CA', 'Gene', (65, 71))	('SQCC', 'Disease', (35, 39))	('PIK3CB', 'Gene', (83, 89))	('PIK3CB', 'Gene', '5291', (83, 89))	('PIK3CA', 'Gene', '5290', (65, 71))	('amplification', 'Var', (48, 61))
152108	27835880	PIK3CA is altered in 15% of SQCC samples, and PTEN defects are found at similar frequency, making PI3K a promising candidate for targeted therapy.	('altered', 'Reg', (10, 17))	('PTEN', 'Gene', (46, 50))	('PTEN', 'Gene', '5728', (46, 50))	('PIK3CA', 'Gene', (0, 6))	('PIK3CA', 'Gene', '5290', (0, 6))	('PI3K', 'Var', (98, 102))
152111	27835880	In addition to PTEN mutation, or PI3KCA/CB amplification, PI3K activity is enhanced by mutations or deregulated expression of its regulatory subunits.	('activity', 'MPA', (63, 71))	('enhanced', 'PosReg', (75, 83))	('mutation', 'Var', (20, 28))	('mutations', 'Var', (87, 96))	('PTEN', 'Gene', (15, 19))	('PTEN', 'Gene', '5728', (15, 19))	('deregulated', 'Var', (100, 111))	('PI3K', 'CPA', (58, 62))	('expression', 'MPA', (112, 122))
152113	27835880	p85beta exhibits a higher affinity for the enzyme substrate (PI4,5P2); in addition, whereas p85alpha fully inhibits the activity of associated p110 and functions as a tumor suppressor, p85beta/p110 show a residual activity in the absence of growth factors; in addition, p85beta exhibits oncogenic activity.	('PI4,5P2', 'Gene', '5267', (61, 68))	('p85alpha', 'Gene', (92, 100))	('p110', 'Gene', '100616443', (193, 197))	('oncogenic activity', 'CPA', (287, 305))	('p110', 'Gene', (193, 197))	('activity', 'MPA', (214, 222))	('inhibits', 'NegReg', (107, 115))	('p85alpha', 'Gene', '5295', (92, 100))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('p110', 'Gene', '100616443', (143, 147))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('activity', 'MPA', (120, 128))	('p110', 'Gene', (143, 147))	('tumor', 'Disease', (167, 172))	('p85beta', 'Var', (270, 277))
152114	27835880	Although p85beta overexpression accelerated tumor progression in the mouse, it was unknown whether depletion of p85beta in an already developed tumor might induce tumor regression.	('p85beta', 'Var', (112, 119))	('tumor', 'Disease', (144, 149))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('accelerated', 'PosReg', (32, 43))	('mouse', 'Species', '10090', (69, 74))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('tumor', 'Disease', (163, 168))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('tumor', 'Disease', (44, 49))
152122	27835880	We gave a value of 1 to the signal intensity of p85alpha and of p85beta in JK cell lanes, and refer the signal intensity of the different lines to that of JK cells (considered 1).	('p85alpha', 'Gene', '5295', (48, 56))	('p85alpha', 'Gene', (48, 56))	('p85beta', 'Var', (64, 71))
152126	27835880	The expression of p85beta/p110alpha complexes in NIH3T3 cells enhances basal PI3K pathway activation (in the absence of growth factors).	('activation', 'PosReg', (90, 100))	('basal PI3K pathway', 'Pathway', (71, 89))	('NIH3T3', 'CellLine', 'CVCL:0594', (49, 55))	('p85beta/p110alpha complexes', 'Var', (18, 45))	('enhances', 'PosReg', (62, 70))
152131	27835880	In H226 cells, PIK3R2 depletion reduced pAkt, pPRAS40 and p70S6K, with no notable effect on pErk (Figure 2).	('pErk', 'Gene', (92, 96))	('pErk', 'Gene', '9451', (92, 96))	('PRAS40', 'Gene', '84335', (47, 53))	('PRAS40', 'Gene', (47, 53))	('depletion', 'Var', (22, 31))	('reduced', 'NegReg', (32, 39))	('p70S6K', 'Gene', (58, 64))	('Akt', 'Gene', '207', (41, 44))	('H226', 'CellLine', 'CVCL:J621', (3, 7))	('p70S6K', 'Gene', '6198', (58, 64))	('PIK3R2', 'Gene', (15, 21))	('Akt', 'Gene', (41, 44))
152132	27835880	In CaLu-1 cells, pAkt levels were lower than in H226 cells; nonetheless, PIK3R2 knockdown also reduced pS473-Akt, pT308-Akt, pPRAS40 and pT389-p70S6K levels, mainly at 1 h post-activation (Figure 2).	('knockdown', 'Var', (80, 89))	('Akt', 'Gene', (18, 21))	('Akt', 'Gene', '207', (109, 112))	('PRAS40', 'Gene', '84335', (126, 132))	('PRAS40', 'Gene', (126, 132))	('Akt', 'Gene', '207', (120, 123))	('p70S6K', 'Gene', (143, 149))	('PIK3R2', 'Gene', (73, 79))	('p70S6K', 'Gene', '6198', (143, 149))	('Akt', 'Gene', '207', (18, 21))	('H226', 'CellLine', 'CVCL:J621', (48, 52))	('Akt', 'Gene', (109, 112))	('reduced', 'NegReg', (95, 102))	('CaLu-1', 'CellLine', 'CVCL:0608', (3, 9))	('Akt', 'Gene', (120, 123))	('pT389', 'Chemical', '-', (137, 142))	('pT308', 'Chemical', '-', (114, 119))
152133	27835880	In a similar assay, PIK3R1 silencing did not markedly affect pErk levels (a moderate reduction was seen in H226).	('PIK3R1', 'Gene', (20, 26))	('silencing', 'Var', (27, 36))	('pErk', 'Gene', (61, 65))	('pErk', 'Gene', '9451', (61, 65))	('H226', 'CellLine', 'CVCL:J621', (107, 111))
152136	27835880	The increased activation of the remaining PI3K effectors after PIK3R1 silencing, despite reduction of p110 levels, suggests that p85alpha depletion causes enrichment in p85beta/p110 complexes (Figure 2), which enhance PI3K activation.	('activation', 'PosReg', (14, 24))	('p85alpha', 'Gene', (129, 137))	('silencing', 'Var', (70, 79))	('enhance', 'PosReg', (210, 217))	('p85alpha', 'Gene', '5295', (129, 137))	('p110', 'Gene', '100616443', (177, 181))	('PIK3R1', 'Gene', (63, 69))	('p110', 'Gene', '100616443', (102, 106))	('p110', 'Gene', (177, 181))	('p110', 'Gene', (102, 106))
152137	27835880	These observations show that p85beta is the main regulatory isoform that mediates PI3K pathway activation in H226 and CaLu-1 lung SQCC cells.	('H226', 'CellLine', 'CVCL:J621', (109, 113))	('CaLu-1', 'CellLine', 'CVCL:0608', (118, 124))	('activation', 'PosReg', (95, 105))	('PI3K pathway', 'Pathway', (82, 94))	('p85beta', 'Var', (29, 36))
152139	27835880	As PIK3R2 expression is increased in SQCC tumors, we postulated that interference with PIK3R2 in an established SQCC tumor would halt tumor progression.	('PIK3R2', 'Gene', (3, 9))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumor', 'Disease', (42, 47))	('SQCC tumors', 'Disease', 'MESH:D009369', (37, 48))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('tumor', 'Disease', (117, 122))	('expression', 'MPA', (10, 20))	('PIK3R2', 'Gene', (87, 93))	('SQCC tumors', 'Disease', (37, 48))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('halt', 'NegReg', (129, 133))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('increased', 'PosReg', (24, 33))	('tumor', 'Disease', (134, 139))	('interference', 'Var', (69, 81))
152145	27835880	In HCC15, H2170, PIK3R2 depletion did not affect tumor size (Figure 3B; Supplementary Figure S2B).	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('PIK3R2', 'Gene', (17, 23))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('HCC15', 'CellLine', 'CVCL:2057', (3, 8))	('tumor', 'Disease', (49, 54))	('H2170', 'Var', (10, 15))	('H2170', 'CellLine', 'CVCL:1535', (10, 15))
152149	27835880	We detected two types of response after PIK3R2 depletion, tumors derived from four lines were almost completely eliminated (H2882, H520, H226, CaLu-1; Figure 4A, Supplementary Figure S3A), whereas tumor from the other two lines (SK-MES-1, EPLC-272H) showed reduced growth, although the response was not as marked (Figure 4B, Supplementary Figure S3B).	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('PIK3R2', 'Gene', (40, 46))	('CaLu-1', 'CellLine', 'CVCL:0608', (143, 149))	('tumor', 'Disease', (58, 63))	('H520', 'Var', (131, 135))	('H226', 'Var', (137, 141))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('H2882', 'CellLine', 'CVCL:5158', (124, 129))	('eliminated', 'NegReg', (112, 122))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('SK-MES-1', 'CellLine', 'CVCL:0630', (229, 237))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumors', 'Disease', (58, 64))	('H226', 'CellLine', 'CVCL:J621', (137, 141))	('depletion', 'Var', (47, 56))	('H2882', 'Var', (124, 129))	('tumor', 'Disease', (197, 202))
152150	27835880	The response to PIK3R2 depletion was detected in SQCC cell lines with predominant PIK3R2 expression, but it was not proportional to the p85beta/p85alpha ratio, and did not correlate with PTEN, KRAS or PIK3CA mutation or with higher PIK3CA or PIK3CB expression (Figure 4, Supplementary Table S2).	('PIK3CA', 'Gene', '5290', (201, 207))	('PIK3CA', 'Gene', '5290', (232, 238))	('mutation', 'Var', (208, 216))	('expression', 'MPA', (89, 99))	('PIK3CB', 'Gene', '5291', (242, 248))	('PTEN', 'Gene', (187, 191))	('KRAS', 'Gene', (193, 197))	('p85alpha', 'Gene', (144, 152))	('PTEN', 'Gene', '5728', (187, 191))	('KRAS', 'Gene', '3845', (193, 197))	('PIK3CA', 'Gene', (201, 207))	('p85alpha', 'Gene', '5295', (144, 152))	('PIK3CB', 'Gene', (242, 248))	('PIK3R2', 'Gene', (82, 88))	('PIK3CA', 'Gene', (232, 238))
152153	27835880	Histological examination of these tumor samples showed a low mitotic index (Figure 5, red arrows), which was even lower after PIK3R2 depletion.	('tumor', 'Disease', (34, 39))	('mitotic index', 'CPA', (61, 74))	('depletion', 'Var', (133, 142))	('low', 'NegReg', (57, 60))	('lower', 'NegReg', (114, 119))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('PIK3R2', 'Gene', (126, 132))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
152155	27835880	Immunostaining of Ki-67+ and active caspase 3 in control, PIK3R1 and PIK3R2 shRNA-treated samples showed a lower number of dividing cells and a larger number of apoptotic cells after PIK3R2 shRNA treatment (Figure 5).	('apoptotic cells', 'CPA', (161, 176))	('PIK3R2 shRNA', 'Var', (183, 195))	('lower', 'NegReg', (107, 112))	('PIK3R2', 'Gene', (69, 75))	('caspase 3', 'Gene', (36, 45))	('caspase 3', 'Gene', '836', (36, 45))
152156	27835880	In one of the cell lines, we tested whether rescue of p85beta expression restores tumor growth; we also tested the efficacy of a prolonged treatment.	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tested', 'Reg', (104, 110))	('restores', 'PosReg', (73, 81))	('tumor', 'Disease', (82, 87))	('tested', 'Reg', (29, 35))	('p85beta expression', 'Var', (54, 72))
152166	27835880	In conclusion, PIK3R2 depletion reduced growth of all SQCC tumors with enhanced p85beta levels and was sufficient to trigger tumor regression in the six SQCC lines with this phenotype (Figure 4).	('enhanced', 'PosReg', (71, 79))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('tumor', 'Disease', (59, 64))	('growth', 'MPA', (40, 46))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('p85beta levels', 'MPA', (80, 94))	('depletion', 'Var', (22, 31))	('reduced', 'NegReg', (32, 39))	('tumor', 'Disease', (125, 130))	('SQCC tumors', 'Disease', (54, 65))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('PIK3R2', 'Gene', (15, 21))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('SQCC tumors', 'Disease', 'MESH:D009369', (54, 65))
152168	27835880	We also examined the effect on cell cycle progression of depleting PIK3R2 in responsive (H226 and CaLu-1) and non-responsive (HCC15) cells.	('H226', 'CellLine', 'CVCL:J621', (89, 93))	('PIK3R2', 'Gene', (67, 73))	('CaLu-1', 'CellLine', 'CVCL:0608', (98, 104))	('examined', 'Reg', (8, 16))	('HCC15', 'CellLine', 'CVCL:2057', (126, 131))	('depleting', 'Var', (57, 66))
152174	27835880	PIK3R2 depletion did not affect S to G2/M transition, or exit from G2/M to G0/G1 in HCC15 cells (Figure 6C).	('depletion', 'Var', (7, 16))	('HCC15', 'CellLine', 'CVCL:2057', (84, 89))	('PIK3R2', 'Gene', (0, 6))
152177	27835880	In some cases, this effect is observed with p110alpha inhibitors alone and is corrected by the combined addition of p110alpha plus p110beta inhibitors; in other models, even pan-PI3K inhibitors induce pathway reactivation after long incubation periods.	('pan-PI3K inhibitors', 'Var', (174, 193))	('pathway', 'Pathway', (201, 208))	('p110beta', 'Gene', (131, 139))	('induce', 'Reg', (194, 200))	('p110beta', 'Gene', '5291', (131, 139))
152179	27835880	We optimized the dose of these compounds used for short-term inhibition of PI3K effectors; we tested rapamycin, a pan-PI3K inhibitor (Ly294002, Ly), a p110beta-specific inhibitor (TGX221, TGX) and a p110alpha inhibitor (PIK75, PIK).	('rapamycin', 'Chemical', 'MESH:D020123', (101, 110))	('Ly', 'Chemical', 'MESH:D008239', (134, 136))	('TGX', 'Chemical', '-', (188, 191))	('Ly294002', 'Var', (134, 142))	('Ly', 'Chemical', 'MESH:D008239', (144, 146))	('p110beta', 'Gene', '5291', (151, 159))	('TGX', 'Chemical', '-', (180, 183))	('p110beta', 'Gene', (151, 159))	('Ly294002', 'Chemical', 'MESH:C085911', (134, 142))	('TGX221', 'Chemical', 'MESH:C504718', (180, 186))
152196	27835880	PIK3CA copy number gains are present are higher frequencies in SQCC than in lung adenocarcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('SQCC', 'Disease', (63, 67))	('lung adenocarcinoma', 'Disease', (76, 95))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (76, 95))	('copy number gains', 'Var', (7, 24))	('PIK3CA', 'Gene', (0, 6))	('PIK3CA', 'Gene', '5290', (0, 6))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (76, 95))
152202	27835880	At the molecular level, p85beta exhibits higher affinity for the enzyme substrate (PI4,5P2) than p85alpha, and a lower capacity to restrain p110 activity in the absence of growth factors.	('p110', 'Gene', (140, 144))	('p85alpha', 'Gene', '5295', (97, 105))	('PI4,5P2', 'Gene', '5267', (83, 90))	('p85beta', 'Var', (24, 31))	('higher', 'PosReg', (41, 47))	('affinity', 'MPA', (48, 56))	('p85alpha', 'Gene', (97, 105))	('p110', 'Gene', '100616443', (140, 144))
152203	27835880	In agreement with these features, p85beta overexpression but not that of p85alpha induced cell transformation.	('p85alpha', 'Gene', '5295', (73, 81))	('cell transformation', 'CPA', (90, 109))	('p85beta', 'Var', (34, 41))	('p85alpha', 'Gene', (73, 81))	('overexpression', 'PosReg', (42, 56))
152204	27835880	Finally, although it was unknown whether depletion of p85beta in an already developed tumor might induce tumor regression, pik3r2-deficient mice exhibit reduced colon cancer formation whereas p85beta overexpression accelerated tumor progression in the mouse.	('accelerated', 'PosReg', (215, 226))	('tumor', 'Disease', (227, 232))	('reduced', 'NegReg', (153, 160))	('colon cancer', 'Phenotype', 'HP:0003003', (161, 173))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('tumor', 'Disease', 'MESH:D009369', (227, 232))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('mice', 'Species', '10090', (140, 144))	('colon cancer', 'Disease', 'MESH:D015179', (161, 173))	('mouse', 'Species', '10090', (252, 257))	('tumor', 'Disease', (105, 110))	('pik3r2', 'Gene', '18709', (123, 129))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))	('p85beta', 'Var', (192, 199))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('colon cancer', 'Disease', (161, 173))	('pik3r2', 'Gene', (123, 129))	('tumor', 'Disease', (86, 91))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
152205	27835880	Here we show that PIK3R2 depletion, but not that of PIK3R1, induced regression of established SQCC tumors exhibiting high PIK3R2 levels (Figure 3 and 4).	('SQCC tumors', 'Disease', (94, 105))	('regression', 'NegReg', (68, 78))	('SQCC tumors', 'Disease', 'MESH:D009369', (94, 105))	('depletion', 'Var', (25, 34))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))
152208	27835880	PIK3R2 depletion in SQCC tumors with high PIK3R2 expression caused sustained PI3K inhibition without inducing pathway reactivation (Figure 4 and 7), which would reduce the probability of resistance, an important drawback of enzyme inhibitors.	('PIK3R2', 'Gene', (42, 48))	('resistance', 'MPA', (187, 197))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('high', 'Var', (37, 41))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('PI3K', 'Pathway', (77, 81))	('depletion', 'NegReg', (7, 16))	('SQCC tumors', 'Disease', 'MESH:D009369', (20, 31))	('reduce', 'NegReg', (161, 167))	('SQCC tumors', 'Disease', (20, 31))
152214	27835880	Rescue of p85beta expression, resulted in tumor regrowth.	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('tumor', 'Disease', (42, 47))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('p85beta expression', 'Var', (10, 28))
152216	27835880	One of the alterations found in SQCC is PIK3CA mutation or amplification.	('PIK3CA', 'Gene', (40, 46))	('PIK3CA', 'Gene', '5290', (40, 46))	('mutation', 'Var', (47, 55))	('amplification', 'MPA', (59, 72))	('SQCC', 'Gene', (32, 36))
152217	27835880	Although any of the tested cell lines had PIK3CA mutations (Supplementary Table S2), CaLu-1 cells exhibit a K-Ras mutation that enhances PI3Kalpha activity and responded to PIK3R2 deletion.	('K-Ras', 'Gene', (108, 113))	('deletion', 'Var', (180, 188))	('mutations', 'Var', (49, 58))	('PI3Kalpha', 'Gene', '5290', (137, 146))	('PIK3CA', 'Gene', (42, 48))	('responded', 'MPA', (160, 169))	('PIK3R2', 'Gene', (173, 179))	('CaLu-1', 'CellLine', 'CVCL:0608', (85, 91))	('PIK3CA', 'Gene', '5290', (42, 48))	('K-Ras', 'Gene', '3845', (108, 113))	('mutation', 'Var', (114, 122))	('PI3Kalpha', 'Gene', (137, 146))	('enhances', 'PosReg', (128, 136))
152218	27835880	Future studies will definitively conclude on whether or not PIK3CA alteration affects p85beta-dependence in lung SQCC.	('alteration', 'Var', (67, 77))	('PIK3CA', 'Gene', (60, 66))	('affects', 'Reg', (78, 85))	('PIK3CA', 'Gene', '5290', (60, 66))	('p85beta-dependence', 'MPA', (86, 104))	('lung SQCC', 'Disease', (108, 117))
152219	27835880	The strength of antisense or interfering RNA gene expression regulators has been demonstrated extensively, although their use as therapeutic tools in patients has been hampered by difficulty in delivering the RNA to the tumor; this might be facilitated in tumors accessible by aerosol therapy such as lung SQCC.	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('lung SQCC', 'Disease', (301, 310))	('tumor', 'Disease', (220, 225))	('tumors', 'Phenotype', 'HP:0002664', (256, 262))	('antisense', 'Var', (16, 25))	('tumor', 'Disease', 'MESH:D009369', (256, 261))	('patients', 'Species', '9606', (150, 158))	('tumors', 'Disease', 'MESH:D009369', (256, 262))	('tumor', 'Phenotype', 'HP:0002664', (256, 261))	('tumors', 'Disease', (256, 262))	('tumor', 'Disease', 'MESH:D009369', (220, 225))	('tumor', 'Disease', (256, 261))
152221	27835880	Finally, the CRISP-Cas approach, which has been successful in mice, might also be useful for PIK3R2 deletion in lung SQCC with enhanced PIK3R2 expression.	('enhanced', 'PosReg', (127, 135))	('lung SQCC', 'Disease', (112, 121))	('expression', 'MPA', (143, 153))	('mice', 'Species', '10090', (62, 66))	('PIK3R2', 'Gene', (93, 99))	('deletion', 'Var', (100, 108))	('PIK3R2', 'Gene', (136, 142))
152230	27835880	Western blotting (WB) was performed as described using the following antibodies: anti-p110alpha, -p110beta, -phospho(p)-Akt S473, -p-Akt T308, -Akt total, -p-p70S6K T389, -PRAS40, -pERK T202/T204, and -ERK total (from Cell Signaling), anti-p85alpha (Millipore), anti-p70S6K (Santa Cruz), anti-p-PRAS40 T246 (R&D Systems), anti-alpha-tubulin (Calbiochem) and anti-beta-actin (Sigma).	('Akt', 'Gene', (144, 147))	('p70S6K', 'Gene', '6198', (267, 273))	('beta-actin (Sigma', 'Gene', (363, 380))	('Akt', 'Gene', '207', (120, 123))	('Akt', 'Gene', (133, 136))	('Akt', 'Gene', '207', (144, 147))	('p85alpha', 'Gene', '5295', (240, 248))	('ERK', 'Gene', (202, 205))	('beta-actin (Sigma)', 'Gene', '728378', (363, 381))	('PRAS40', 'Gene', '84335', (295, 301))	('p70S6K', 'Gene', (158, 164))	('Akt', 'Gene', '207', (133, 136))	('p85alpha', 'Gene', (240, 248))	('PRAS40', 'Gene', (172, 178))	('ERK', 'Gene', '2048', (202, 205))	('p110beta', 'Gene', (98, 106))	('and', 'Var', (354, 357))	('p70S6K', 'Gene', (267, 273))	('p110beta', 'Gene', '5291', (98, 106))	('ERK', 'Gene', (182, 185))	('pERK', 'Gene', '9451', (181, 185))	('PRAS40', 'Gene', (295, 301))	('pERK', 'Gene', (181, 185))	('PRAS40', 'Gene', '84335', (172, 178))	('p70S6K', 'Gene', '6198', (158, 164))	('ERK', 'Gene', '2048', (182, 185))	('Akt', 'Gene', (120, 123))
152257	33519235	TCGA LUAD cohort analysis also showed that high expression of PKP2 indicated unfavorable outcomes in LUAD patients.	('high', 'Var', (43, 47))	('LUAD', 'Disease', (101, 105))	('LUAD', 'Phenotype', 'HP:0030078', (101, 105))	('LUAD', 'Phenotype', 'HP:0030078', (5, 9))	('patients', 'Species', '9606', (106, 114))	('PKP2', 'Gene', (62, 66))
152259	33519235	Functionally, knockdown of PKP2 suppressed lung cancer cell proliferation and invasion in vitro, while inhibited xenograft lung tumor development in vivo.	('lung tumor', 'Phenotype', 'HP:0100526', (123, 133))	('lung cancer', 'Disease', (43, 54))	('lung cancer', 'Phenotype', 'HP:0100526', (43, 54))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('invasion', 'CPA', (78, 86))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('inhibited', 'NegReg', (103, 112))	('lung tumor', 'Disease', (123, 133))	('PKP2', 'Gene', (27, 31))	('lung cancer', 'Disease', 'MESH:D008175', (43, 54))	('lung tumor', 'Disease', 'MESH:D008175', (123, 133))	('knockdown', 'Var', (14, 23))	('suppressed', 'NegReg', (32, 42))
152269	33519235	In bladder cancer, high expression of PKP2 is associated with enhanced tumor cell invasion and metastasis, but not cell proliferation.	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('bladder cancer', 'Phenotype', 'HP:0009725', (3, 17))	('high expression', 'Var', (19, 34))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('enhanced', 'PosReg', (62, 70))	('PKP2', 'Gene', (38, 42))	('metastasis', 'CPA', (95, 105))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('bladder cancer', 'Disease', 'MESH:D001749', (3, 17))	('bladder cancer', 'Disease', (3, 17))	('tumor', 'Disease', (71, 76))
152271	33519235	The oncogenic role of PKP2 has also been studied in glioma and knockdown of PKP2 inhibits the glioma cell proliferation and migration.	('inhibits', 'NegReg', (81, 89))	('glioma', 'Disease', (94, 100))	('glioma', 'Disease', 'MESH:D005910', (52, 58))	('glioma', 'Phenotype', 'HP:0009733', (52, 58))	('glioma', 'Disease', 'MESH:D005910', (94, 100))	('glioma', 'Phenotype', 'HP:0009733', (94, 100))	('glioma', 'Disease', (52, 58))	('knockdown', 'Var', (63, 72))	('PKP2', 'Gene', (76, 80))
152304	33519235	Intriguingly, LUAD patients with high PKP2 levels had a worse prognosis, with lower overall survival (OS) and disease-free survival (DFS) than that in LUAD patients with low PKP2 levels (Figure 2C and D).	('patients', 'Species', '9606', (156, 164))	('LUAD', 'Phenotype', 'HP:0030078', (151, 155))	('patients', 'Species', '9606', (19, 27))	('LUAD', 'Phenotype', 'HP:0030078', (14, 18))	('high PKP2 levels', 'Var', (33, 49))	('overall survival', 'CPA', (84, 100))	('disease-free survival', 'CPA', (110, 131))	('lower', 'NegReg', (78, 83))
152309	33519235	Consistently, in LUAD TCGA cohort, patients with high PKP2 expression had worse OS and DFS compared with patients with low PKP2 levels (Figure 3D and E).	('patients', 'Species', '9606', (105, 113))	('DFS', 'CPA', (87, 90))	('PKP2', 'Gene', (54, 58))	('high', 'Var', (49, 53))	('patients', 'Species', '9606', (35, 43))	('LUAD', 'Phenotype', 'HP:0030078', (17, 21))
152313	33519235	EdU incorporation and colony formation assays demonstrated that knockdown of PKP2 suppressed cell proliferation and colony formation (Figure 4C and D).	('PKP2', 'Gene', (77, 81))	('suppressed', 'NegReg', (82, 92))	('colony formation', 'CPA', (116, 132))	('cell proliferation', 'CPA', (93, 111))	('knockdown', 'Var', (64, 73))	('EdU', 'Chemical', '-', (0, 3))
152314	33519235	In addition, inhibition of PKP2 dampened the invasive capability of lung cancer cells, as demonstrated by transwell assay (Figure 4E).	('PKP2', 'Enzyme', (27, 31))	('lung cancer', 'Disease', (68, 79))	('lung cancer', 'Phenotype', 'HP:0100526', (68, 79))	('inhibition', 'Var', (13, 23))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('lung cancer', 'Disease', 'MESH:D008175', (68, 79))	('dampened', 'NegReg', (32, 40))
152316	33519235	Xenograft tumor model was established by subcutaneous injection of A549 cells stably knocking down PKP2 (sh-PKP2) or control cells (MOCK) to further investigate the function of PKP2 in vivo.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('tumor', 'Disease', (10, 15))	('PKP2', 'Gene', (99, 103))	('sh-PKP2', 'Gene', '5318', (105, 112))	('A549', 'CellLine', 'CVCL:0023', (67, 71))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('knocking down', 'Var', (85, 98))	('sh-PKP2', 'Gene', (105, 112))
152318	33519235	The tumor weights from PKP2 knockdown group were markedly lower than those from MOCK group (Figure 5C).	('tumor', 'Disease', (4, 9))	('lower', 'NegReg', (58, 63))	('PKP2', 'Gene', (23, 27))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('knockdown', 'Var', (28, 37))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))
152320	33519235	Taken together, these results indicate that knockdown of PKP2 inhibits xenograft lung tumor development in vivo.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('inhibits', 'NegReg', (62, 70))	('lung tumor', 'Disease', (81, 91))	('PKP2', 'Gene', (57, 61))	('lung tumor', 'Disease', 'MESH:D008175', (81, 91))	('knockdown', 'Var', (44, 53))	('lung tumor', 'Phenotype', 'HP:0100526', (81, 91))
152323	33519235	Gene Set Enrichment Analysis (GSEA) also confirmed that the signature gene sets of EMT and focal adhesion were enriched in PKP2 high-expression LUAD (Figure 6E and F).	('LUAD', 'Phenotype', 'HP:0030078', (144, 148))	('EMT', 'Gene', (83, 86))	('EMT', 'Gene', '3702', (83, 86))	('PKP2', 'Gene', (123, 127))	('high-expression LUAD', 'Var', (128, 148))	('focal adhesion', 'CPA', (91, 105))
152325	33519235	The results showed that knockdown of PKP2 suppressed EMT, with enhanced E-cadherin expression and decreased Vimentin/N-cadherin expression (Figure 7A).	('Vimentin', 'Gene', (108, 116))	('enhanced', 'PosReg', (63, 71))	('E-cadherin', 'Gene', (72, 82))	('N-cadherin', 'Gene', (117, 127))	('PKP2', 'Gene', (37, 41))	('Vimentin', 'Gene', '7431', (108, 116))	('suppressed', 'NegReg', (42, 52))	('E-cadherin', 'Gene', '999', (72, 82))	('N-cadherin', 'Gene', '1000', (117, 127))	('expression', 'MPA', (83, 93))	('EMT', 'Gene', (53, 56))	('decreased', 'NegReg', (98, 107))	('knockdown', 'Var', (24, 33))	('EMT', 'Gene', '3702', (53, 56))
152326	33519235	Silencing PKP2 also inhibited the focal adhesion and suppressed the expression of BMP4, ICAM1 and VCAM1 (Figure 7A).	('focal adhesion', 'CPA', (34, 48))	('BMP4', 'Gene', (82, 86))	('VCAM1', 'Gene', '7412', (98, 103))	('expression', 'MPA', (68, 78))	('ICAM1', 'Gene', (88, 93))	('inhibited', 'NegReg', (20, 29))	('BMP4', 'Gene', '652', (82, 86))	('VCAM1', 'Gene', (98, 103))	('PKP2', 'Gene', (10, 14))	('Silencing', 'Var', (0, 9))	('suppressed', 'NegReg', (53, 63))	('ICAM1', 'Gene', '3383', (88, 93))
152327	33519235	Consistently, we demonstrated that overexpression of PKP2 promoted the expression of EMT and focal adhesion markers while knockdown of PKP2 showed the opposite effects in HCC827 or A549 cells in vitro (Figure 7B).	('EMT', 'Gene', '3702', (85, 88))	('expression', 'MPA', (71, 81))	('PKP2', 'Gene', (135, 139))	('A549', 'CellLine', 'CVCL:0023', (181, 185))	('PKP2', 'Gene', (53, 57))	('knockdown', 'Var', (122, 131))	('focal adhesion', 'CPA', (93, 107))	('promoted', 'PosReg', (58, 66))	('EMT', 'Gene', (85, 88))
152334	33519235	The dysregulated PKP2 expression has been found in cancer pathogenesis.	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('cancer', 'Disease', (51, 57))	('found', 'Reg', (42, 47))	('PKP2', 'Enzyme', (17, 21))	('dysregulated', 'Var', (4, 16))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('expression', 'MPA', (22, 32))
152339	33519235	Knockdown of PKP2 suppressed cell proliferation and invasion, while silencing PKP2 inhibited xenograft lung tumor growth in vivo.	('lung tumor', 'Disease', 'MESH:D008175', (103, 113))	('lung tumor', 'Phenotype', 'HP:0100526', (103, 113))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('PKP2', 'Gene', (78, 82))	('PKP2', 'Gene', (13, 17))	('inhibited', 'NegReg', (83, 92))	('cell proliferation', 'CPA', (29, 47))	('silencing', 'Var', (68, 77))	('lung tumor', 'Disease', (103, 113))	('suppressed', 'NegReg', (18, 28))	('invasion', 'CPA', (52, 60))
152340	33519235	Bioinformatics analysis was performed to investigate the signaling pathway involved in PKP2 regulation and we found high PKP2 expression enhanced EMT and focal adhesion.	('enhanced', 'PosReg', (137, 145))	('EMT', 'Gene', (146, 149))	('expression', 'Var', (126, 136))	('EMT', 'Gene', '3702', (146, 149))	('PKP2', 'Gene', (121, 125))
152364	31393394	Although a large number of studies have shown that the patients with high plasma Fbg have much poorer prognosis for both NSCLC and small cell lung cancer (SCLC) patients, it is still unclear which clinical parameters are associated with elevated plasma Fbg.	('small cell lung cancer', 'Phenotype', 'HP:0030357', (131, 153))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('Fbg', 'Gene', (253, 256))	('SCLC', 'Disease', 'MESH:D055752', (122, 126))	('Fbg', 'Gene', '2244', (81, 84))	('SCLC', 'Disease', (155, 159))	('SCLC', 'Phenotype', 'HP:0030357', (155, 159))	('SCLC', 'Disease', (122, 126))	('high', 'Var', (69, 73))	('SCLC', 'Phenotype', 'HP:0030357', (122, 126))	('small cell lung cancer', 'Disease', 'MESH:D055752', (131, 153))	('Fbg', 'Gene', (81, 84))	('small cell lung cancer', 'Disease', (131, 153))	('patients', 'Species', '9606', (161, 169))	('NSCLC', 'Disease', 'MESH:D002289', (121, 126))	('lung cancer', 'Phenotype', 'HP:0100526', (142, 153))	('Fbg', 'Gene', '2244', (253, 256))	('poorer', 'NegReg', (95, 101))	('NSCLC', 'Disease', (121, 126))	('patients', 'Species', '9606', (55, 63))	('SCLC', 'Disease', 'MESH:D055752', (155, 159))	('NSCLC', 'Phenotype', 'HP:0030358', (121, 126))
152395	31393394	Moreover, the crosslink of Fbg and various blood cells can form blood clots and protect circulating cancer cells from the killing effect of immune cells, thereby increasing the potential of cancer metastasis.	('cancer', 'Disease', (190, 196))	('cancer', 'Disease', 'MESH:D009369', (190, 196))	('Fbg', 'Gene', '2244', (27, 30))	('crosslink', 'Var', (14, 23))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('blood clots', 'Phenotype', 'HP:0001907', (64, 75))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('Fbg', 'Gene', (27, 30))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('increasing', 'PosReg', (162, 172))
152437	33044045	Multivariate analysis identified light or never smoking, poor PS, histological type of squamous cell carcinoma, and interstitial septal thickening as independent negative predictors of progression free survival (PFS).	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (87, 110))	('poor', 'Var', (57, 61))	('progression', 'Disease', (185, 196))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (87, 110))	('squamous cell carcinoma', 'Disease', (87, 110))	('negative', 'NegReg', (162, 170))
152481	33044045	Univariate Cox proportional hazard analysis revealed that poorer ECOG PS, squamous cell carcinoma, and interstitial septal thickening were predictors of shorter PFS in the patients treated with nivolumab (Table 3).	('nivolumab', 'Chemical', 'MESH:D000077594', (194, 203))	('PFS', 'MPA', (161, 164))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (74, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('shorter', 'NegReg', (153, 160))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (74, 97))	('patients', 'Species', '9606', (172, 180))	('squamous cell carcinoma', 'Disease', (74, 97))	('poorer', 'Var', (58, 64))
152495	33044045	21 ,  22 ,  23  Consistent with the results of a previous study, poorer PS was associated with shorter PFS and OS during nivolumab treatment in the present study.	('shorter', 'NegReg', (95, 102))	('poorer', 'Var', (65, 71))	('nivolumab', 'Chemical', 'MESH:D000077594', (121, 130))	('PFS', 'CPA', (103, 106))	('men', 'Species', '9606', (136, 139))
152511	32290321	In cancer, tumor-specific dysfunctions of PRDM genes alter their expression by genetic and/or epigenetic modifications.	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('alter', 'Reg', (53, 58))	('dysfunctions', 'Var', (26, 38))	('tumor', 'Disease', (11, 16))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('epigenetic modifications', 'Var', (94, 118))	('genetic', 'Var', (79, 86))	('cancer', 'Disease', (3, 9))	('expression', 'MPA', (65, 75))	('PRDM genes', 'Gene', (42, 52))	('tumor', 'Disease', 'MESH:D009369', (11, 16))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
152512	32290321	They are generated by either alternative splicing or alternative use of different promoters and play opposite roles, particularly in cancer where their imbalance can be often observed.	('imbalance', 'Phenotype', 'HP:0002172', (152, 161))	('alternative splicing', 'Var', (29, 49))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('cancer', 'Disease', (133, 139))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
152525	32290321	Some evidence suggests that PRDMs are involved in human malignancy through modulation of several processes such as epigenetic modifications, genetic reprogramming, inflammation, and metabolic homeostasis.	('inflammation', 'Disease', (164, 176))	('malignancy', 'Disease', 'MESH:D009369', (56, 66))	('modulation', 'Reg', (75, 85))	('involved', 'Reg', (38, 46))	('PRDMs', 'Chemical', '-', (28, 33))	('malignancy', 'Disease', (56, 66))	('genetic reprogramming', 'CPA', (141, 162))	('PRDMs', 'Gene', (28, 33))	('inflammation', 'Disease', 'MESH:D007249', (164, 176))	('metabolic homeostasis', 'CPA', (182, 203))	('epigenetic modifications', 'Var', (115, 139))	('human', 'Species', '9606', (50, 55))
152526	32290321	These two isoforms, generated by either alternative splicing or alternative use of different promoters, play opposite roles, particularly in cancer.	('alternative splicing', 'Var', (40, 60))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('cancer', 'Disease', (141, 147))	('cancer', 'Disease', 'MESH:D009369', (141, 147))
152528	32290321	The imbalance in favor of PR- is observed in many human malignancies and it can be due to inactivating mutations or silencing of the complete form and/or to increased expression of the PR- form.	('inactivating mutations', 'Var', (90, 112))	('malignancies', 'Disease', 'MESH:D009369', (56, 68))	('human', 'Species', '9606', (50, 55))	('increased', 'PosReg', (157, 166))	('silencing', 'Var', (116, 125))	('malignancies', 'Disease', (56, 68))	('expression', 'MPA', (167, 177))	('imbalance', 'Phenotype', 'HP:0002172', (4, 13))
152530	32290321	An overview of cancer-specific alterations affecting PRDM family members, taking into account putative causes, produced effects, and underlying molecular mechanisms, is detailed below and summarized in Table 1.	('alterations', 'Var', (31, 42))	('cancer', 'Disease', (15, 21))	('cancer', 'Disease', 'MESH:D009369', (15, 21))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('PRDM', 'Gene', (53, 57))
152535	32290321	Initially, in 2006, structural alterations inactivating PRDM1/BLIMP1 were identified in DLBCLs in two independent studies.	('BCL', 'Phenotype', 'HP:0012191', (90, 93))	('BLIMP1', 'Gene', '639', (62, 68))	('inactivating', 'Var', (43, 55))	('DLBCLs', 'Disease', (88, 94))	('BLIMP1', 'Gene', (62, 68))
152537	32290321	Particularly, disruption of PRDM1/BLIMP1 function is frequently observed in the activated B-cell-like (ABC) subtype of DLBCL by distinct mechanisms including inactivating mutations, chromosomal deletion, and epigenetic silencing.	('BCL', 'Phenotype', 'HP:0012191', (121, 124))	('inactivating mutations', 'Var', (158, 180))	('BLIMP1', 'Gene', '639', (34, 40))	('function', 'MPA', (41, 49))	('ABC', 'Gene', (103, 106))	('ABC', 'Gene', '10058', (103, 106))	('activated B-cell-like', 'Disease', (80, 101))	('epigenetic silencing', 'Var', (208, 228))	('BLIMP1', 'Gene', (34, 40))	('chromosomal deletion', 'Var', (182, 202))	('disruption', 'NegReg', (14, 24))
152538	32290321	Of note, a more recent study demonstrated that its genetic loss could contribute to the overall poor prognosis for ABC-DLBCL but not germinal center B-cell-like (GCB)-DLBCLs.	('BCL', 'Phenotype', 'HP:0012191', (121, 124))	('BCL', 'Phenotype', 'HP:0012191', (169, 172))	('ABC', 'Gene', (115, 118))	('ABC', 'Gene', '10058', (115, 118))	('genetic loss', 'Var', (51, 63))
152539	32290321	Furthermore, the lack of BLIMP1 expression correlated with an impaired p53 signaling pathway and Myc overexpression; gene expression profiling data also indicated that inactivated BLIMP1 could facilitate DLBCL progression through Myc and BCR (B cell receptor) signaling, which are essential for ABC-DLBCL survival.	('DLBCL', 'Disease', (204, 209))	('BLIMP1', 'Gene', (25, 31))	('BCL', 'Phenotype', 'HP:0012191', (301, 304))	('BLIMP1', 'Gene', (180, 186))	('ABC', 'Gene', '10058', (295, 298))	('BLIMP1', 'Gene', '639', (25, 31))	('BLIMP1', 'Gene', '639', (180, 186))	('BCL', 'Phenotype', 'HP:0012191', (206, 209))	('inactivated', 'Var', (168, 179))	('facilitate', 'PosReg', (193, 203))	('Myc', 'MPA', (230, 233))	('ABC', 'Gene', (295, 298))
152542	32290321	In addition, PRDM1 ectopic expression in a DLBCL-derived cell line triggered cell cycle arrest.	('PRDM1', 'Gene', (13, 18))	('ectopic expression', 'Var', (19, 37))	('arrest', 'Disease', 'MESH:D006323', (88, 94))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (77, 94))	('arrest', 'Disease', (88, 94))	('BCL', 'Phenotype', 'HP:0012191', (45, 48))	('triggered', 'Reg', (67, 76))
152544	32290321	Consistently, an in vivo study showed that mouse Prdm1 deletion cooperated with constitutive activation of the NF-kappaB pathway to support a neoplastic phenotype.	('activation', 'PosReg', (93, 103))	('support', 'PosReg', (132, 139))	('Prdm1', 'Gene', '12142', (49, 54))	('NF-kappaB', 'Gene', '18033', (111, 120))	('Prdm1', 'Gene', (49, 54))	('deletion', 'Var', (55, 63))	('neoplastic phenotype', 'CPA', (142, 162))	('mouse', 'Species', '10090', (43, 48))	('NF-kappaB', 'Gene', (111, 120))
152546	32290321	For instance, array comparative genomic hybridization and gene expression profiling in extranodal NK/T-cell lymphoma (EN-NK/T) revealed that the most frequently deleted chromosomal region 6q21-6q25, induced a downregulation of several tumor-suppressor genes including PRDM1.	('T-cell lymphoma', 'Phenotype', 'HP:0012190', (101, 116))	('NK/T-cell lymphoma', 'Disease', 'MESH:D054391', (98, 116))	('NK/T-cell lymphoma', 'Disease', (98, 116))	('downregulation', 'NegReg', (209, 223))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('cell lymphoma', 'Phenotype', 'HP:0012191', (103, 116))	('tumor-suppressor', 'Gene', (235, 251))	('PRDM1', 'Gene', (268, 273))	('6q21-6q25', 'Var', (188, 197))	('lymphoma', 'Phenotype', 'HP:0002665', (108, 116))	('tumor-suppressor', 'Gene', '7248', (235, 251))
152550	32290321	PRDM1 mutations occurred in patients with plasmablastic lymphoma; interestingly, in this rare neoplasm, PRDM1 genetic alterations did not impair terminal B-cell differentiation, but contributed to the oncogenicity of MYC, which is usually dysregulated by translocation or amplification.	('lymphoma', 'Phenotype', 'HP:0002665', (56, 64))	('plasmablastic lymphoma', 'Disease', (42, 64))	('MYC', 'Gene', '4609', (217, 220))	('genetic alterations', 'Var', (110, 129))	('MYC', 'Gene', (217, 220))	('neoplasm', 'Disease', (94, 102))	('plasmablastic lymphoma', 'Disease', 'MESH:D000069293', (42, 64))	('PRDM1', 'Gene', (104, 109))	('oncogenicity', 'MPA', (201, 213))	('neoplasm', 'Disease', 'MESH:D009369', (94, 102))	('neoplasm', 'Phenotype', 'HP:0002664', (94, 102))	('patients', 'Species', '9606', (28, 36))	('contributed to', 'Reg', (182, 196))
152552	32290321	This is in accordance with the study on ABC-DLBCL patients where the lack of BLIMP1 expression correlated with Myc overexpression.	('BLIMP1', 'Gene', '639', (77, 83))	('patients', 'Species', '9606', (50, 58))	('BCL', 'Phenotype', 'HP:0012191', (46, 49))	('correlated', 'Reg', (95, 105))	('ABC', 'Gene', (40, 43))	('BLIMP1', 'Gene', (77, 83))	('lack', 'Var', (69, 73))	('expression', 'MPA', (84, 94))	('Myc overexpression', 'Disease', (111, 129))	('ABC', 'Gene', '10058', (40, 43))
152563	32290321	In colorectal tumor cells, PRDM1 knockdown by small-interfering RNA (siRNA) results in both apoptosis and growth arrest through regulation of p53 transcription.	('apoptosis', 'CPA', (92, 101))	('p53', 'Gene', (142, 145))	('growth arrest', 'Disease', (106, 119))	('knockdown', 'Var', (33, 42))	('growth arrest', 'Disease', 'MESH:D006323', (106, 119))	('PRDM1', 'Gene', (27, 32))	('regulation', 'Reg', (128, 138))	('growth arrest', 'Phenotype', 'HP:0001510', (106, 119))	('transcription', 'MPA', (146, 159))	('colorectal tumor', 'Disease', (3, 19))	('colorectal tumor', 'Disease', 'MESH:D015179', (3, 19))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('small-interfering', 'Var', (46, 63))
152564	32290321	Interestingly, both p53 mRNA and protein levels are considerably increased after PRDM1/BLIMP1 depletion, which is accompanied by the induction of p53 target genes.	('BLIMP1', 'Gene', (87, 93))	('BLIMP1', 'Gene', '639', (87, 93))	('depletion', 'Var', (94, 103))	('increased', 'PosReg', (65, 74))
152571	32290321	In addition, PRDM1 reduced the expression of DKK1 thus exerting its antitumor effect via antagonizing the activity of Wnt/beta-catenin pathway (Figure 3A).	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('beta-catenin', 'Gene', '1499', (122, 134))	('tumor', 'Disease', (72, 77))	('antagonizing', 'NegReg', (89, 101))	('DKK1', 'Gene', '22943', (45, 49))	('DKK1', 'Gene', (45, 49))	('activity', 'MPA', (106, 114))	('expression', 'MPA', (31, 41))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('reduced', 'NegReg', (19, 26))	('PRDM1', 'Var', (13, 18))	('beta-catenin', 'Gene', (122, 134))
152573	32290321	Specifically, the ectopic expression of the transcription factor Aiolos induced anoikis resistance to cancer cells by downregulating PRDM1.	('Aiolos', 'Gene', (65, 71))	('Aiolos', 'Gene', '22806', (65, 71))	('ectopic expression', 'Var', (18, 36))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('induced', 'PosReg', (72, 79))	('cancer', 'Disease', (102, 108))	('downregulating', 'NegReg', (118, 132))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('PRDM1', 'Gene', (133, 138))
152576	32290321	Additionally, mutations were revealed in some solid tumors, such as skin cutaneous melanoma and uterine carcinosarcoma, which displayed more than 5% of patients carrying PRDM1 mutations.	('revealed', 'Reg', (29, 37))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('mutations', 'Var', (176, 185))	('skin cutaneous melanoma', 'Disease', (68, 91))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('tumors', 'Disease', (52, 58))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('carcinosarcoma', 'Disease', 'MESH:D002296', (104, 118))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (73, 91))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (96, 118))	('sarcoma', 'Phenotype', 'HP:0100242', (111, 118))	('PRDM1', 'Gene', (170, 175))	('carcinosarcoma', 'Disease', (104, 118))	('mutations', 'Var', (14, 23))	('patients', 'Species', '9606', (152, 160))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (68, 91))	('melanoma', 'Phenotype', 'HP:0002861', (83, 91))
152582	32290321	Indeed, both genetic inactivation or epigenetic silencing of RIZ1 and/or an increase of RIZ2 expression levels were frequently revealed in many human cancer tissues and cell lines.	('increase', 'PosReg', (76, 84))	('human', 'Species', '9606', (144, 149))	('revealed', 'Reg', (127, 135))	('genetic inactivation', 'Var', (13, 33))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('expression levels', 'MPA', (93, 110))	('cancer', 'Disease', (150, 156))	('RIZ2', 'Gene', '7799', (88, 92))	('RIZ2', 'Gene', (88, 92))	('RIZ1', 'Gene', (61, 65))	('epigenetic silencing', 'Var', (37, 57))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
152586	32290321	Riz1 knockout mice, carrying normal Riz2, were tumor prone in both wild-type and mutant p53 genetic backgrounds.	('prone', 'PosReg', (53, 58))	('mice', 'Species', '10090', (14, 18))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('p53', 'Gene', (88, 91))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('mutant', 'Var', (81, 87))	('Riz2', 'Gene', '7799', (36, 40))	('Riz2', 'Gene', (36, 40))	('tumor', 'Disease', (47, 52))
152587	32290321	Indeed, an accelerated tumorigenesis was associated with Riz1 deficiency (Riz1-/-) on the p53+/- background.	('Riz1', 'Gene', (57, 61))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('deficiency', 'Var', (62, 72))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('accelerated', 'PosReg', (11, 22))	('tumor', 'Disease', (23, 28))
152590	32290321	Indeed, frameshift mutations of microsatellite repeats localized in the C-terminal coding region were frequently detected in colorectal, gastric, endometrial, and pancreatic microsatellite instability (MIN) positive cancers.	('gastric', 'Disease', (137, 144))	('colorectal', 'Disease', (125, 135))	('endometrial', 'Disease', (146, 157))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('frameshift mutations', 'Var', (8, 28))	('pancreatic microsatellite instability (MIN) positive cancers', 'Disease', 'MESH:D053842', (163, 223))	('cancers', 'Phenotype', 'HP:0002664', (216, 223))	('detected', 'Reg', (113, 121))
152594	32290321	Despite their high occurrence, the functional significance in tumorigenesis of these C-terminal PRDM2 truncated forms induced by frameshift mutations is still unknown and deserves investigation.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', (62, 67))	('PRDM2', 'Gene', (96, 101))	('frameshift mutations', 'Var', (129, 149))	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('induced', 'Reg', (118, 125))
152595	32290321	Interestingly, the restoration of the wild-type PRDM2 gene sequence of one mutant c.4467delA allele by genome editing in homozygous mutant human colorectal cancer cells, repaired its H3K9me2 activity, impaired tumor cell growth, reduced anchorage-independent growth, cellular migration, and colony forming ability in vitro, as well as decreased the tumor growth in a mouse xenograft model.	('colony forming ability in vitro', 'CPA', (291, 322))	('colorectal cancer', 'Disease', 'MESH:D015179', (145, 162))	('mouse', 'Species', '10090', (367, 372))	('activity', 'MPA', (191, 199))	('impaired tumor', 'Disease', 'MESH:D060825', (201, 215))	('tumor', 'Phenotype', 'HP:0002664', (349, 354))	('colorectal cancer', 'Disease', (145, 162))	('decreased', 'NegReg', (335, 344))	('tumor', 'Disease', (210, 215))	('H3K9me2', 'Protein', (183, 190))	('tumor', 'Disease', 'MESH:D009369', (210, 215))	('c.4467delA', 'Var', (82, 92))	('PRDM2', 'Gene', (48, 53))	('colorectal cancer', 'Phenotype', 'HP:0003003', (145, 162))	('reduced', 'NegReg', (229, 236))	('repaired', 'NegReg', (170, 178))	('cellular migration', 'CPA', (267, 285))	('tumor', 'Disease', (349, 354))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('mutant', 'Var', (132, 138))	('anchorage-independent growth', 'CPA', (237, 265))	('impaired tumor', 'Disease', (201, 215))	('tumor', 'Disease', 'MESH:D009369', (349, 354))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('human', 'Species', '9606', (139, 144))	('c.4467delA', 'Mutation', 'rs57173229', (82, 92))
152596	32290321	Furthermore, H3K9me2 activity restoration determined the downregulation of several genes involved in cancer pathways, mostly of EMT, thus contributing to a more aggressive cancer phenotype (Figure 1E).	('downregulation', 'NegReg', (57, 71))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('H3K9me2', 'Protein', (13, 20))	('cancer', 'Disease', (101, 107))	('aggressive cancer', 'Disease', 'MESH:D009369', (161, 178))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('restoration', 'Var', (30, 41))	('cancer', 'Disease', (172, 178))	('aggressive cancer', 'Disease', (161, 178))	('more', 'PosReg', (156, 160))
152597	32290321	In addition, frameshift mutations in the (A)9 tract were also found in samples of malignant melanoma and nevi and in leukemia cell lines.	('nevi', 'Disease', (105, 109))	('malignant melanoma', 'Disease', 'MESH:D008545', (82, 100))	('malignant melanoma', 'Disease', (82, 100))	('leukemia', 'Phenotype', 'HP:0001909', (117, 125))	('leukemia', 'Disease', 'MESH:D007938', (117, 125))	('melanoma', 'Phenotype', 'HP:0002861', (92, 100))	('nevi', 'Phenotype', 'HP:0003764', (105, 109))	('leukemia', 'Disease', (117, 125))	('frameshift mutations', 'Var', (13, 33))	('found', 'Reg', (62, 67))	('malignant melanoma', 'Phenotype', 'HP:0002861', (82, 100))	('A)9', 'Gene', (42, 45))
152598	32290321	Interestingly, in most cases of MIN pathway cancers these frameshift mutations were biallelic or homozygous/hemizygous, indicating that PRDM2 follows the two-hit model of tumor suppressor genes, with one hit achieved either by mutations/deletions affecting the PR domain or by frameshift mutations in the 3' end affecting the interactions between the N-terminal PR domain of RIZ1 and its C-terminal region, including the PR-binding motif.	('affecting', 'Reg', (312, 321))	('RIZ1', 'Gene', (375, 379))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('cancers', 'Phenotype', 'HP:0002664', (44, 51))	('cancers', 'Disease', (44, 51))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('cancers', 'Disease', 'MESH:D009369', (44, 51))	('mutations/deletions', 'Var', (227, 246))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', (171, 176))	('frameshift mutations', 'Var', (277, 297))	('interactions', 'Interaction', (326, 338))
152600	32290321	Interestingly, some PRDM2 polymorphisms have also been associated with carcinogenesis.	('polymorphisms', 'Var', (26, 39))	('PRDM2', 'Gene', (20, 25))	('carcinogenesis', 'Disease', (71, 85))	('associated', 'Reg', (55, 65))	('carcinogenesis', 'Disease', 'MESH:D063646', (71, 85))
152602	32290321	A CpG island in the PRDM2/RIZ1 promoter is frequently methylated in many cancer types, such as breast carcinomas and liver tumors, as well as in colon and lung cancer cell lines.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', (160, 166))	('liver tumors', 'Disease', 'MESH:D008113', (117, 129))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('liver tumors', 'Phenotype', 'HP:0002896', (117, 129))	('breast carcinomas', 'Disease', 'MESH:D001943', (95, 112))	('methylated', 'Var', (54, 64))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('breast carcinomas', 'Disease', (95, 112))	('breast carcinoma', 'Phenotype', 'HP:0003002', (95, 111))	('liver tumors', 'Disease', (117, 129))	('PRDM2/RIZ1', 'Gene', (20, 30))	('carcinomas', 'Phenotype', 'HP:0030731', (102, 112))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('breast carcinomas', 'Phenotype', 'HP:0003002', (95, 112))	('colon and lung cancer', 'Disease', 'MESH:D008175', (145, 166))	('lung cancer', 'Phenotype', 'HP:0100526', (155, 166))
152603	32290321	Additionally, epigenetic silencing of RIZ1 expression was also detected in pituitary adenomas and nasopharyngeal carcinoma specimens.	('detected', 'Reg', (63, 71))	('epigenetic silencing', 'Var', (14, 34))	('carcinoma', 'Disease', 'MESH:D009369', (113, 122))	('men', 'Species', '9606', (128, 131))	('pituitary adenomas', 'Disease', 'MESH:D010911', (75, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (98, 122))	('RIZ1', 'Gene', (38, 42))	('pituitary adenomas', 'Phenotype', 'HP:0002893', (75, 93))	('carcinoma', 'Disease', (113, 122))	('pituitary adenomas', 'Disease', (75, 93))
152610	32290321	Noteworthy, a later study demonstrated that estradiol induced the preferential synthesis of transcripts with exon 9a, whereas it reduced those containing exons 9b and 10.	('synthesis', 'MPA', (79, 88))	('preferential', 'PosReg', (66, 78))	('exon 9a', 'Var', (109, 116))	('reduced', 'NegReg', (129, 136))	('estradiol', 'Chemical', 'MESH:D004958', (44, 53))
152619	32290321	Specifically, tumor suppressor function requires the establishment of the H4K20me1-H3K9me1 trans-tail 'histone code' at specific loci through the direct interaction of RIZ1 PR-binding motif to PR-Set7 monomethyltransferase, an essential component of the mammalian cell cycle, which is needed for proper DNA replication and mitosis, thus hypothesizing an additional mechanism of action.	('men', 'Species', '9606', (62, 65))	('mitosis', 'Disease', 'None', (323, 330))	('tumor', 'Disease', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('interaction', 'Interaction', (153, 164))	('mammalian', 'Species', '9606', (254, 263))	('PR-Set7', 'Gene', (193, 200))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('H4K20me1-H3K9me1', 'Var', (74, 90))	('PR-Set7', 'Gene', '387893', (193, 200))	('RIZ1', 'Gene', (168, 172))	('mitosis', 'Disease', (323, 330))
152621	32290321	Since the loss of PR-Set7 produced persistent DNA double-strand breaks (DSBs), it was conceivable that H4K20me1, and possibly Riz1-mediated H3K9me1, had a role in DNA repair.	('loss', 'Var', (10, 14))	('DNA double-strand breaks', 'MPA', (46, 70))	('DSBs', 'Chemical', '-', (72, 76))	('H4K20me1', 'Var', (103, 111))	('PR-Set7', 'Gene', (18, 25))	('PR-Set7', 'Gene', '387893', (18, 25))
152632	32290321	It is well established that chromosomal rearrangements or proviral insertion at the PRDM3 locus gene, MECOM, are found in up to 10% of acute myeloid leukemia (AML) cases with poor survival outcomes.	('men', 'Species', '9606', (49, 52))	('AML', 'Phenotype', 'HP:0004808', (159, 162))	('AML', 'Disease', (159, 162))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (135, 157))	('MECOM', 'Gene', (102, 107))	('found', 'Reg', (113, 118))	('leukemia', 'Phenotype', 'HP:0001909', (149, 157))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (141, 157))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (135, 157))	('AML', 'Disease', 'MESH:D015470', (159, 162))	('acute myeloid leukemia', 'Disease', (135, 157))	('chromosomal rearrangements', 'Var', (28, 54))
152636	32290321	Later, in ovarian tumors a high frequency of aberrant EVI1 splicing, generating novel isoforms, could contribute to the pathophysiology of these cancers.	('cancers', 'Disease', (145, 152))	('ovarian tumors', 'Disease', (10, 24))	('EVI1', 'Gene', (54, 58))	('ovarian tumors', 'Phenotype', 'HP:0100615', (10, 24))	('cancers', 'Phenotype', 'HP:0002664', (145, 152))	('aberrant', 'Var', (45, 53))	('ovarian tumors', 'Disease', 'MESH:D010051', (10, 24))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('isoforms', 'MPA', (86, 94))	('contribute', 'Reg', (102, 112))	('EVI1', 'Gene', '14013', (54, 58))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('cancers', 'Disease', 'MESH:D009369', (145, 152))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
152637	32290321	EVI1 is usually upregulated through the generation of oncogenic fusion proteins as a consequence of rearrangements; alternatively, it can also be upregulated by leukemogenic factors at the transcriptional level.	('upregulated', 'PosReg', (16, 27))	('rearrangements', 'Var', (100, 114))	('EVI1', 'Gene', (0, 4))	('upregulated', 'PosReg', (146, 157))	('men', 'Species', '9606', (109, 112))	('EVI1', 'Gene', '14013', (0, 4))
152648	32290321	For instance, the proximal set of EVI1 zinc fingers is able to bind the N-terminal domain of the zinc finger transcription factor hypermethylated in cancer 1 (HIC1); in turn, this interaction deregulates the DNA binding and transcriptional activity of EVI1 on the BCL-XL promoter, thus compromising the anti-apoptotic activity of EVI1 (Figure 2).	('transcriptional', 'MPA', (224, 239))	('hypermethylated in cancer 1', 'Gene', (130, 157))	('EVI1', 'Gene', (252, 256))	('EVI1', 'Gene', '14013', (252, 256))	('BCL-XL', 'Gene', (264, 270))	('compromising', 'NegReg', (286, 298))	('anti-apoptotic activity', 'CPA', (303, 326))	('EVI1', 'Gene', (34, 38))	('deregulates', 'NegReg', (192, 203))	('HIC1', 'Gene', (159, 163))	('EVI1', 'Gene', '14013', (34, 38))	('BCL-XL', 'Gene', '598', (264, 270))	('hypermethylated in cancer 1', 'Gene', '3090', (130, 157))	('interaction', 'Var', (180, 191))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('DNA binding', 'Interaction', (208, 219))	('HIC1', 'Gene', '3090', (159, 163))	('EVI1', 'Gene', (330, 334))	('BCL', 'Phenotype', 'HP:0012191', (264, 267))	('EVI1', 'Gene', '14013', (330, 334))
152651	32290321	EVI1 knockdown impaired PC cell proliferation through a cell cycle progression blockade.	('blockade', 'NegReg', (79, 87))	('cell cycle progression', 'CPA', (56, 78))	('impaired', 'NegReg', (15, 23))	('knockdown', 'Var', (5, 14))	('PC', 'Phenotype', 'HP:0012125', (24, 26))	('EVI1', 'Gene', (0, 4))	('EVI1', 'Gene', '14013', (0, 4))
152652	32290321	Mechanistically, these changes might be at least in part mediated by reactivation of SMAD3, a known transcriptional target of EVI1.	('SMAD3', 'Gene', '4088', (85, 90))	('SMAD3', 'Gene', (85, 90))	('EVI1', 'Gene', (126, 130))	('reactivation', 'Var', (69, 81))	('EVI1', 'Gene', '14013', (126, 130))
152653	32290321	EVI1 knockdown in PC cells also reduced migratory potential and anchorage-independent growth while enhancing apoptosis sensitivity.	('enhancing', 'PosReg', (99, 108))	('anchorage-independent growth', 'CPA', (64, 92))	('apoptosis sensitivity', 'CPA', (109, 130))	('migratory potential', 'CPA', (40, 59))	('knockdown', 'Var', (5, 14))	('reduced', 'NegReg', (32, 39))	('EVI1', 'Gene', (0, 4))	('PC', 'Phenotype', 'HP:0012125', (18, 20))	('EVI1', 'Gene', '14013', (0, 4))
152664	32290321	In addition, EVI1 knockdown demonstrated its requirement for metastasis of colon cancer cells.	('knockdown', 'Var', (18, 27))	('colon cancer', 'Phenotype', 'HP:0003003', (75, 87))	('men', 'Species', '9606', (52, 55))	('EVI1', 'Gene', (13, 17))	('metastasis of colon cancer', 'Disease', (61, 87))	('EVI1', 'Gene', '14013', (13, 17))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('metastasis of colon cancer', 'Disease', 'MESH:D015179', (61, 87))
152669	32290321	Recent findings have suggested MECOM as a novel candidate gene for hereditary hematological malignancies; indeed, a novel germline mutation within the ninth zinc finger motif was reported in a family with developed myeloid malignancies.	('reported', 'Reg', (179, 187))	('myeloid malignancies', 'Disease', 'MESH:D009369', (215, 235))	('hematological malignancies', 'Phenotype', 'HP:0004377', (78, 104))	('hereditary hematological malignancies', 'Disease', (67, 104))	('myeloid malignancies', 'Disease', (215, 235))	('hereditary hematological malignancies', 'Disease', 'MESH:D019337', (67, 104))	('germline mutation within', 'Var', (122, 146))
152670	32290321	As for PRDM2 gene, a mononucleotide repeat (A7) in exon 8 of MECOM coding sequences was found to be a target for frameshift mutation (loss-of-function mutation) in colorectal cancers with MIN.	('colorectal cancer', 'Phenotype', 'HP:0003003', (164, 181))	('colorectal cancers', 'Disease', 'MESH:D015179', (164, 182))	('mononucleotide', 'Chemical', '-', (21, 35))	('colorectal cancers', 'Disease', (164, 182))	('cancers', 'Phenotype', 'HP:0002664', (175, 182))	('frameshift mutation', 'Var', (113, 132))	('mononucleotide repeat', 'Var', (21, 42))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
152671	32290321	In the same study, the authors also observed intratumor heterogeneity (an important cancer hallmark) of MECOM mutations in four of 16 analyzed cases (25%).	('MECOM', 'Gene', (104, 109))	('mutations', 'Var', (110, 119))	('cancer hallmark', 'Disease', (84, 99))	('cancer hallmark', 'Disease', 'MESH:D009369', (84, 99))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Disease', (50, 55))
152681	32290321	Later, epigenetic PRDM5 silencing was also shown in gastric and colorectal cancers, where its ectopic expression determined a cell growth suppression.	('colorectal cancers', 'Disease', 'MESH:D015179', (64, 82))	('cancers', 'Phenotype', 'HP:0002664', (75, 82))	('colorectal cancers', 'Disease', (64, 82))	('epigenetic PRDM5', 'Var', (7, 23))	('gastric', 'Disease', (52, 59))	('colorectal cancer', 'Phenotype', 'HP:0003003', (64, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('silencing', 'NegReg', (24, 33))	('cell growth', 'CPA', (126, 137))
152682	32290321	Of note, PRDM5 promoter methylation was detected in both primary colorectal and gastric cancers but not in noncancerous tissue specimens collected from areas adjacent to the tumors.	('tumors', 'Disease', (174, 180))	('tumors', 'Disease', 'MESH:D009369', (174, 180))	('cancerous', 'Disease', (110, 119))	('colorectal and gastric cancers', 'Disease', 'MESH:D013274', (65, 95))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('detected', 'Reg', (40, 48))	('methylation', 'Var', (24, 35))	('men', 'Species', '9606', (132, 135))	('gastric cancer', 'Phenotype', 'HP:0012126', (80, 94))	('PRDM5', 'Gene', (9, 14))	('cancerous', 'Disease', 'MESH:D009369', (110, 119))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('gastric cancers', 'Phenotype', 'HP:0012126', (80, 95))	('tumors', 'Phenotype', 'HP:0002664', (174, 180))
152685	32290321	Recently, a significant PRDM5 promoter methylation was observed in BRAF mutant cancers of the serrated pathway whereas minimal levels of methylation were detected in the BRAF wild-type cancers of the traditional pathway; moreover, PRDM5 methylation was evident in a small proportion of serrated type polyps indicating that this may be an early event in tumorigenesis.	('polyps', 'Disease', (300, 306))	('serrated pathway', 'Pathway', (94, 110))	('cancers', 'Phenotype', 'HP:0002664', (185, 192))	('cancers', 'Disease', (185, 192))	('tumor', 'Disease', (353, 358))	('mutant', 'Var', (72, 78))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('serrated type', 'Disease', (286, 299))	('tumor', 'Disease', 'MESH:D009369', (353, 358))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('polyps', 'Disease', 'MESH:D011127', (300, 306))	('cancers', 'Disease', (79, 86))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('PRDM5', 'Gene', (231, 236))	('cancers', 'Disease', 'MESH:D009369', (185, 192))	('tumor', 'Phenotype', 'HP:0002664', (353, 358))	('BRAF', 'Gene', '673', (170, 174))	('BRAF', 'Gene', '673', (67, 71))	('BRAF', 'Gene', (170, 174))	('PRDM5', 'Gene', (24, 29))	('serrated type polyps', 'Phenotype', 'HP:0032222', (286, 306))	('BRAF', 'Gene', (67, 71))	('cancers', 'Disease', 'MESH:D009369', (79, 86))
152687	32290321	For example, aberrant DNA methylation reduced PRDM5 expression in about 40.5% of cervical cancers, whereas normal tissues were unmethylated.	('reduced', 'NegReg', (38, 45))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('cervical cancers', 'Disease', (81, 97))	('PRDM5', 'Gene', (46, 51))	('cervical cancers', 'Disease', 'MESH:D002583', (81, 97))	('expression', 'MPA', (52, 62))	('DNA', 'Protein', (22, 25))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('aberrant', 'Var', (13, 21))
152688	32290321	Similarly, PRDM5 was frequently silenced by promoter methylation in multiple cancer cell lines and tumor specimens, including nasopharyngeal, esophageal, gastric, cervical, and hepatocellular carcinoma.	('tumor', 'Disease', (99, 104))	('carcinoma', 'Phenotype', 'HP:0030731', (192, 201))	('silenced', 'NegReg', (32, 40))	('men', 'Species', '9606', (110, 113))	('cancer', 'Disease', (77, 83))	('PRDM5', 'Gene', (11, 16))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (177, 201))	('promoter methylation', 'Var', (44, 64))	('nasopharyngeal', 'Disease', (126, 140))	('hepatocellular carcinoma', 'Disease', (177, 201))	('cervical', 'Disease', (163, 171))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (177, 201))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('esophageal', 'Disease', (142, 152))	('gastric', 'Disease', (154, 161))
152694	32290321	Accordingly, this concept is also supported by a study in which repression of PRDM5 function, due to deletions in its locus along with miR-182 sequence amplification, was shown to play a co-operative role in ovarian cancers.	('ovarian cancers', 'Disease', 'MESH:D010051', (208, 223))	('miR-182', 'Gene', '406958', (135, 142))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('deletions', 'Var', (101, 110))	('repression', 'NegReg', (64, 74))	('cancers', 'Phenotype', 'HP:0002664', (216, 223))	('ovarian cancer', 'Phenotype', 'HP:0100615', (208, 222))	('PRDM5', 'Gene', (78, 83))	('ovarian cancers', 'Phenotype', 'HP:0100615', (208, 223))	('ovarian cancers', 'Disease', (208, 223))	('miR-182', 'Gene', (135, 142))
152700	32290321	Noteworthy, a meta-analysis of genome-wide association studies correlated a single nucleotide polymorphism in PRDM6 gene with both mammographic density and breast cancer susceptibility.	('PRDM6', 'Gene', (110, 115))	('PRDM6', 'Gene', '93166', (110, 115))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('single nucleotide polymorphism', 'Var', (76, 106))	('breast cancer', 'Disease', 'MESH:D001943', (156, 169))	('breast cancer', 'Disease', (156, 169))	('mammographic density', 'Disease', (131, 151))	('breast cancer', 'Phenotype', 'HP:0003002', (156, 169))
152704	32290321	A whole-exome sequencing analysis on a small group of pituitary adenomas revealed genetic variants in several genes, including PRDM8.	('pituitary adenomas', 'Disease', (54, 72))	('PRDM8', 'Gene', (127, 132))	('variants', 'Var', (90, 98))	('pituitary adenomas', 'Disease', 'MESH:D010911', (54, 72))	('PRDM8', 'Gene', '56978', (127, 132))	('pituitary adenomas', 'Phenotype', 'HP:0002893', (54, 72))
152716	32290321	Indeed, meiotic recombination is crucial for accurate chromosomal disjunction and genomic stability maintenance during meiosis; likewise, homologous recombination also promotes genomic stability by repairing DSBs in cells undergoing mitosis.	('homologous recombination', 'Var', (138, 162))	('meiosis', 'Disease', 'MESH:C536875', (119, 126))	('DSBs', 'Chemical', '-', (208, 212))	('DSBs', 'MPA', (208, 212))	('promotes', 'PosReg', (168, 176))	('genomic stability', 'CPA', (177, 194))	('meiosis', 'Disease', (119, 126))	('repairing', 'NegReg', (198, 207))	('mitosis', 'Disease', 'None', (233, 240))	('mitosis', 'Disease', (233, 240))
152717	32290321	Furthermore, the two processes involve overlapping molecular machinery and comparable mechanisms whose dysregulation can often lead to diseases, including cancer.	('diseases', 'Disease', (135, 143))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('lead to', 'Reg', (127, 134))	('dysregulation', 'Var', (103, 116))	('cancer', 'Disease', (155, 161))	('cancer', 'Disease', 'MESH:D009369', (155, 161))
152723	32290321	Since PRDM9 variability has been suggested to influence genomic instability, the authors of this study argued that these rare allelic forms could be involved in the development of preleukemic clones in B-ALL patients and proposed that an altered PRDM9 function in the parental germline could lead to the genomic instability associated with childhood ALL.	('PRDM9', 'Gene', '56979', (6, 11))	('function', 'MPA', (252, 260))	('LL', 'Phenotype', 'HP:0005526', (351, 353))	('patients', 'Species', '9606', (208, 216))	('childhood ALL', 'Disease', (340, 353))	('LL', 'Phenotype', 'HP:0005526', (205, 207))	('genomic instability', 'MPA', (304, 323))	('B-ALL', 'Phenotype', 'HP:0004812', (202, 207))	('altered', 'Var', (238, 245))	('PRDM9', 'Gene', (246, 251))	('lead to', 'Reg', (292, 299))	('PRDM9', 'Gene', '56979', (246, 251))	('involved', 'Reg', (149, 157))	('PRDM9', 'Gene', (6, 11))	('men', 'Species', '9606', (172, 175))
152724	32290321	PRDM9 mutations have also been correlated with specific solid tumors.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumors', 'Disease', (62, 68))	('tumors', 'Disease', 'MESH:D009369', (62, 68))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('PRDM9', 'Gene', (0, 5))	('mutations', 'Var', (6, 15))	('correlated', 'Reg', (31, 41))	('PRDM9', 'Gene', '56979', (0, 5))
152725	32290321	Indeed, in a study defining a landscape of non-coding RNA (ncRNA) in the head and neck squamous cell carcinoma (HNSCC), 307 non-coding transcripts differentially expressed in HNSCC were significantly correlated with patient survival, and associated with known gene mutations and chromosome alterations, including PRDM9 mutations; particularly, piR-34736 was upregulated two-fold in HNSCC and correlated to patient survival and PRDM9 mutation.	('neck squamous cell carcinoma', 'Disease', (82, 110))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (82, 110))	('HNSCC', 'Disease', (382, 387))	('mutation', 'Var', (433, 441))	('PRDM9', 'Gene', (427, 432))	('patient', 'Species', '9606', (216, 223))	('mutations', 'Var', (319, 328))	('PRDM9', 'Gene', '56979', (427, 432))	('patient', 'Species', '9606', (406, 413))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (87, 110))	('PRDM9', 'Gene', (313, 318))	('PRDM9', 'Gene', '56979', (313, 318))	('correlated', 'Reg', (200, 210))	('HNSCC', 'Phenotype', 'HP:0012288', (382, 387))	('HNSCC', 'Phenotype', 'HP:0012288', (112, 117))	('HNSCC', 'Phenotype', 'HP:0012288', (175, 180))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (73, 110))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('upregulated', 'PosReg', (358, 369))	('piR-34736', 'Var', (344, 353))
152726	32290321	Very recently, a mutation analysis of histone lysine methyltransferases in bladder cancer from TCGA datasets identified PRDM9 among the six genes with a potential critical role in oncogenesis and prognosis of this cancer type.	('PRDM9', 'Gene', '56979', (120, 125))	('cancer', 'Disease', (214, 220))	('bladder cancer', 'Disease', 'MESH:D001749', (75, 89))	('bladder cancer', 'Disease', (75, 89))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('mutation', 'Var', (17, 25))	('bladder cancer', 'Phenotype', 'HP:0009725', (75, 89))	('lysine', 'Chemical', 'MESH:D008239', (46, 52))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('PRDM9', 'Gene', (120, 125))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('cancer', 'Disease', (83, 89))	('cancer', 'Disease', 'MESH:D009369', (214, 220))
152727	32290321	Noteworthy, our pan-cancer mutation analysis recognized PRDM9 as one of the most mutated genes of the PRDM family with frequencies ranging from 0.5% to 15.4% and higher than 5% in multiple cancers, such as DLBCL, HNSCC, endometrial, esophageal, stomach, and colon carcinomas, kidney and lung tumors, and melanoma.	('colon carcinomas', 'Disease', (258, 274))	('tumors', 'Phenotype', 'HP:0002664', (292, 298))	('BCL', 'Phenotype', 'HP:0012191', (208, 211))	('lung tumors', 'Phenotype', 'HP:0100526', (287, 298))	('multiple cancers', 'Disease', (180, 196))	('cancer', 'Disease', 'MESH:D009369', (20, 26))	('mutation', 'Var', (27, 35))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('colon carcinomas', 'Disease', 'MESH:D003110', (258, 274))	('tumor', 'Phenotype', 'HP:0002664', (292, 297))	('lung tumors', 'Disease', (287, 298))	('melanoma', 'Disease', 'MESH:D008545', (304, 312))	('DLBCL', 'Disease', (206, 211))	('HNSCC', 'Disease', (213, 218))	('esophageal', 'Disease', (233, 243))	('cancer', 'Disease', (20, 26))	('multiple cancers', 'Disease', 'MESH:D009369', (180, 196))	('cancers', 'Phenotype', 'HP:0002664', (189, 196))	('HNSCC', 'Phenotype', 'HP:0012288', (213, 218))	('endometrial', 'Disease', (220, 231))	('cancer', 'Disease', (189, 195))	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('PRDM9', 'Gene', (56, 61))	('melanoma', 'Phenotype', 'HP:0002861', (304, 312))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('melanoma', 'Disease', (304, 312))	('PRDM9', 'Gene', '56979', (56, 61))	('lung tumors', 'Disease', 'MESH:D008175', (287, 298))	('stomach', 'Disease', (245, 252))	('carcinoma', 'Phenotype', 'HP:0030731', (264, 273))	('carcinomas', 'Phenotype', 'HP:0030731', (264, 274))
152728	32290321	In a newly published pan-cancer analysis of TCGA data the authors revealed that aberrant expression of PRDM9 was associated with an enrichment of somatic structural variants at sites of binding and activity in several cancer types, thus hypothesizing a novel mechanism underlying genomic instability during tumorigenesis based on the possibility that there are putative uncharacterized genomic features and binding sites leading to these variants.	('PRDM9', 'Gene', (103, 108))	('cancer', 'Disease', 'MESH:D009369', (218, 224))	('expression', 'MPA', (89, 99))	('variants', 'Var', (165, 173))	('tumor', 'Disease', 'MESH:D009369', (307, 312))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('cancer', 'Disease', (218, 224))	('men', 'Species', '9606', (138, 141))	('tumor', 'Phenotype', 'HP:0002664', (307, 312))	('PRDM9', 'Gene', '56979', (103, 108))	('tumor', 'Disease', (307, 312))	('activity', 'MPA', (198, 206))	('cancer', 'Disease', 'MESH:D009369', (25, 31))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('binding', 'Interaction', (186, 193))	('cancer', 'Disease', (25, 31))	('aberrant', 'Var', (80, 88))	('associated', 'Reg', (113, 123))
152730	32290321	Using RNA-seq and other methodologies, analysis of 84 soft tissue sarcomas revealed that a significant subset of low-grade undifferentiated pleomorphic sarcoma (UPS) showed a gene fusion of PRDM10 either with MED12 or CITED2, suggesting that these rearrangements were specific for this less aggressive UPS subset.	('undifferentiated pleomorphic sarcoma', 'Disease', (123, 159))	('men', 'Species', '9606', (257, 260))	('aggressive UPS', 'Disease', 'MESH:D017118', (291, 305))	('sarcomas', 'Disease', 'MESH:D012509', (66, 74))	('CITED2', 'Gene', '10370', (218, 224))	('sarcoma', 'Phenotype', 'HP:0100242', (66, 73))	('gene fusion', 'Var', (175, 186))	('sarcomas', 'Phenotype', 'HP:0100242', (66, 74))	('MED12', 'Gene', (209, 214))	('PRDM10', 'Gene', '56980', (190, 196))	('sarcoma', 'Phenotype', 'HP:0100242', (152, 159))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (54, 74))	('sarcomas', 'Disease', (66, 74))	('MED12', 'Gene', '9968', (209, 214))	('PRDM10', 'Gene', (190, 196))	('aggressive UPS', 'Disease', (291, 305))	('undifferentiated pleomorphic sarcoma', 'Disease', 'MESH:D002277', (123, 159))	('CITED2', 'Gene', (218, 224))
152734	32290321	In childhood ALL, whole-exome-sequencing and whole-genome-sequencing revealed that homozygous non-synonymous coding mutations negatively affected PRDM11 function.	('non-synonymous coding mutations', 'Var', (94, 125))	('PRDM11', 'Gene', (146, 152))	('LL', 'Phenotype', 'HP:0005526', (14, 16))	('affected', 'Reg', (137, 145))	('PRDM11', 'Chemical', '-', (146, 152))	('negatively', 'NegReg', (126, 136))	('function', 'MPA', (153, 161))
152736	32290321	Indeed, deletion of PRDM11 accelerated Myc-driven lymphomagenesis, while its overexpression induced apoptosis and delayed lymphoma onset.	('PRDM11', 'Chemical', '-', (20, 26))	('lymphoma', 'Disease', 'MESH:D008223', (50, 58))	('overexpression', 'PosReg', (77, 91))	('delayed lymphoma', 'Disease', (114, 130))	('lymphoma', 'Disease', (122, 130))	('lymphoma', 'Phenotype', 'HP:0002665', (50, 58))	('PRDM11', 'Gene', (20, 26))	('lymphoma', 'Disease', 'MESH:D008223', (122, 130))	('lymphoma', 'Phenotype', 'HP:0002665', (122, 130))	('accelerated', 'PosReg', (27, 38))	('delayed lymphoma', 'Disease', 'MESH:D008223', (114, 130))	('lymphoma', 'Disease', (50, 58))	('apoptosis', 'CPA', (100, 109))	('deletion', 'Var', (8, 16))
152741	32290321	Several studies indicated that PRDM12 might act as a tumor suppressor gene in human chronic myeloid leukemia with derivative chromosome 9 deletions or rearrangements.	('myeloid leukemia', 'Phenotype', 'HP:0012324', (92, 108))	('chronic myeloid leukemia', 'Disease', (84, 108))	('rearrangements', 'Var', (151, 165))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('leukemia', 'Phenotype', 'HP:0001909', (100, 108))	('PRDM12', 'Gene', '59335', (31, 37))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('PRDM12', 'Gene', (31, 37))	('deletions', 'Var', (138, 147))	('tumor', 'Disease', (53, 58))	('men', 'Species', '9606', (160, 163))	('human', 'Species', '9606', (78, 83))	('chronic myeloid leukemia', 'Phenotype', 'HP:0005506', (84, 108))	('chronic myeloid leukemia', 'Disease', 'MESH:D015464', (84, 108))
152756	32290321	The analysis of gene copy number suggested that the mechanism could be gene amplification on chromosome 8q13, a region frequently altered in a wide variety of human tumors.	('tumors', 'Disease', (165, 171))	('tumors', 'Disease', 'MESH:D009369', (165, 171))	('tumors', 'Phenotype', 'HP:0002664', (165, 171))	('human', 'Species', '9606', (159, 164))	('gene amplification', 'Var', (71, 89))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))
152758	32290321	In vitro experiments showed that while ectopic PRDM14 expression enhanced cancer cell growth and resistance to chemotherapeutic drugs, PRDM14 knockdown was able to induce apoptosis and increase sensitivity to chemotherapeutic drugs.	('increase', 'PosReg', (185, 193))	('PRDM14', 'Gene', (47, 53))	('sensitivity to chemotherapeutic drugs', 'MPA', (194, 231))	('ectopic', 'Var', (39, 46))	('induce', 'PosReg', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('apoptosis', 'CPA', (171, 180))	('enhanced', 'PosReg', (65, 73))	('resistance to chemotherapeutic drugs', 'MPA', (97, 133))	('cancer', 'Disease', (74, 80))	('men', 'Species', '9606', (15, 18))	('PRDM14', 'Gene', (135, 141))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('knockdown', 'Var', (142, 151))
152759	32290321	More recently, in vitro and in vivo experiments were set up to ascertain whether and how PRDM14 could also confer stem cell-like properties and epigenetic changes to cancer cells.	('cancer', 'Disease', (166, 172))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('men', 'Species', '9606', (42, 45))	('stem cell-like properties', 'CPA', (114, 139))	('confer', 'Reg', (107, 113))	('epigenetic changes', 'Var', (144, 162))	('PRDM14', 'Gene', (89, 95))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))
152763	32290321	PRDM14 silencing strongly reduced the stem cell phenotype and inhibited breast cancer cell line proliferation, tumorsphere formation, and suppressed cell growth in the presence of low concentrations of anticancer drugs.	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumors', 'Disease', (111, 117))	('PRDM14', 'Gene', (0, 6))	('reduced', 'NegReg', (26, 33))	('breast cancer', 'Disease', 'MESH:D001943', (72, 85))	('breast cancer', 'Disease', (72, 85))	('silencing', 'Var', (7, 16))	('tumors', 'Disease', 'MESH:D009369', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (206, 212))	('cancer', 'Disease', (206, 212))	('cancer', 'Disease', (79, 85))	('cell growth', 'CPA', (149, 160))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('stem cell phenotype', 'CPA', (38, 57))	('inhibited', 'NegReg', (62, 71))	('suppressed', 'NegReg', (138, 148))	('breast cancer', 'Phenotype', 'HP:0003002', (72, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))
152766	32290321	In particular, miR-424 knockdown induces cdc42 expression that in turn positively regulates PRDM14 through the activation of p-21-activated kinase 1 (pak1) and stat5 (Figure 1F).	('activation', 'PosReg', (111, 121))	('pak1', 'Gene', '5058', (150, 154))	('regulates', 'Reg', (82, 91))	('knockdown', 'Var', (23, 32))	('p-21-activated kinase 1', 'Gene', '5058', (125, 148))	('stat5', 'Gene', (160, 165))	('cdc42', 'Gene', '998', (41, 46))	('p-21-activated kinase 1', 'Gene', (125, 148))	('pak1', 'Gene', (150, 154))	('miR-424', 'Gene', '494336', (15, 22))	('cdc42', 'Gene', (41, 46))	('miR-424', 'Gene', (15, 22))	('induces', 'PosReg', (33, 40))	('stat5', 'Gene', '6776', (160, 165))	('expression', 'MPA', (47, 57))	('PRDM14', 'Gene', (92, 98))
152773	32290321	As in human ALL, mice with LL induced by Prdm14 aberrant expression showed widespread aneuploidy and copy number alterations, indicating significant chromosomal damage due to failure to activate genes involved in chromosomal stability and DNA repair pathways.	('human', 'Species', '9606', (6, 11))	('mice', 'Species', '10090', (17, 21))	('aneuploidy', 'Disease', (86, 96))	('LL', 'Phenotype', 'HP:0005526', (13, 15))	('aneuploidy', 'Disease', 'MESH:D000782', (86, 96))	('aberrant expression', 'Var', (48, 67))	('copy number alterations', 'CPA', (101, 124))	('activate', 'PosReg', (186, 194))	('Prdm14', 'Gene', (41, 47))	('LL', 'Phenotype', 'HP:0005526', (27, 29))
152781	32290321	Consistently, PRDM14 overexpression promoted cell migration through extracellular matrix degradation in a human lung cancer cell line.	('human', 'Species', '9606', (106, 111))	('overexpression', 'Var', (21, 35))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('lung cancer', 'Disease', (112, 123))	('lung cancer', 'Phenotype', 'HP:0100526', (112, 123))	('cell migration', 'CPA', (45, 59))	('extracellular matrix degradation', 'CPA', (68, 100))	('lung cancer', 'Disease', 'MESH:D008175', (112, 123))	('PRDM14', 'Gene', (14, 20))	('promoted', 'PosReg', (36, 44))
152784	32290321	More recently, overexpression of PRDM14 was observed also in pancreatic cancer, where it could sustain cell pluripotency; indeed, PRDM14 knockdown suppressed cancer stem-like phenotypes, including liver metastasis, via miR-125a-3p regulating Fyn expression (Figure 1F).	('PRDM14', 'Gene', (130, 136))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('suppressed', 'NegReg', (147, 157))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (61, 78))	('cancer', 'Disease', (158, 164))	('knockdown', 'Var', (137, 146))	('Fyn', 'Gene', (242, 245))	('liver metastasis', 'Disease', 'MESH:D009362', (197, 213))	('Fyn', 'Gene', '2534', (242, 245))	('expression', 'MPA', (246, 256))	('pancreatic cancer', 'Disease', 'MESH:D010190', (61, 78))	('liver metastasis', 'Disease', (197, 213))	('pancreatic cancer', 'Disease', (61, 78))	('cancer', 'Disease', (72, 78))
152786	32290321	Alterations of the 8q13.2 region with PRDM14 copy number gain were also found in intracranial germ cell tumors and in head and neck cancer.	('head and neck cancer', 'Disease', 'MESH:D006258', (118, 138))	('found', 'Reg', (72, 77))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('head and neck cancer', 'Phenotype', 'HP:0012288', (118, 138))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('PRDM14', 'Gene', (38, 44))	('tumors', 'Disease', (104, 110))	('copy number', 'Var', (45, 56))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('germ cell tumors', 'Phenotype', 'HP:0100728', (94, 110))	('gain', 'PosReg', (57, 61))
152792	32290321	Later, PRDM14 silencing was found through hypermethylation of its promoter in HPV-positive cancers, and ectopic expression of PRDM14 in HPV16-positive cancer cell lines induced apoptosis, possibly due to a direct upregulation of the pro-apoptotic genes NOXA and PUMA.	('hypermethylation', 'Var', (42, 58))	('PRDM14', 'Gene', (126, 132))	('PUMA', 'Gene', '27113', (262, 266))	('PRDM14', 'Gene', (7, 13))	('HPV-positive cancers', 'Disease', 'MESH:D030361', (78, 98))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('cancer', 'Disease', (151, 157))	('upregulation', 'PosReg', (213, 225))	('PUMA', 'Gene', (262, 266))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('HPV16', 'Species', '333760', (136, 141))	('HPV-positive cancers', 'Disease', (78, 98))	('NOXA', 'Gene', '5366', (253, 257))	('ectopic expression', 'Var', (104, 122))	('apoptosis', 'CPA', (177, 186))	('cancers', 'Phenotype', 'HP:0002664', (91, 98))	('cancer', 'Disease', (91, 97))	('induced', 'PosReg', (169, 176))	('NOXA', 'Gene', (253, 257))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('silencing', 'NegReg', (14, 23))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))
152799	32290321	PRDM15 was identified as a candidate tumor suppressor gene, since localized homozygous deletions were revealed at 21q22 chromosome region in several pancreatic cancer cell lines.	('PRDM15', 'Gene', (0, 6))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (149, 166))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('pancreatic cancer', 'Disease', 'MESH:D010190', (149, 166))	('tumor', 'Disease', (37, 42))	('deletions', 'Var', (87, 96))	('pancreatic cancer', 'Disease', (149, 166))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('PRDM15', 'Gene', '63977', (0, 6))
152808	32290321	Moreover, the aberrant expression of MEL1S/sPRDM16, associated with DNA hypomethylation, was correlated with dysregulation of TGF-beta-mediated signaling suggesting that MEL1S might be responsible for TGF-beta resistance in leukemogenesis of adult T-cell leukemia.	('TGF-beta', 'Gene', (126, 134))	('leukemogenesis of adult T-cell leukemia', 'Disease', (224, 263))	('MEL1', 'Gene', (170, 174))	('MEL1', 'Gene', '63976', (170, 174))	('leukemogenesis of adult T-cell leukemia', 'Disease', 'MESH:D015459', (224, 263))	('correlated', 'Reg', (93, 103))	('leukemia', 'Phenotype', 'HP:0001909', (255, 263))	('TGF-beta', 'Gene', '7039', (126, 134))	('MEL1', 'Gene', (37, 41))	('associated', 'Reg', (52, 62))	('TGF-beta', 'Gene', (201, 209))	('MEL1', 'Gene', '63976', (37, 41))	('aberrant', 'Var', (14, 22))	('dysregulation', 'MPA', (109, 122))	('TGF-beta', 'Gene', '7039', (201, 209))	('expression', 'MPA', (23, 33))
152812	32290321	In addition, cryptic and partial deletions of PRDM16 and RUNX1 without t(1;21)(p36;q22) and/or RUNX1-PRDM16 fusion were detected in a case of progressive CML suggesting that different mechanisms of chromosomal rearrangement may occur in these malignancies.	('CML', 'Phenotype', 'HP:0005506', (154, 157))	('men', 'Species', '9606', (219, 222))	('malignancies', 'Disease', (243, 255))	('CML', 'Disease', (154, 157))	('t(1;21)(p36;q22)', 'STRUCTURAL_ABNORMALITY', 'None', (71, 87))	('cryptic', 'Gene', '55997', (13, 20))	('RUNX1', 'Gene', (57, 62))	('PRDM16', 'Gene', (46, 52))	('cryptic', 'Gene', (13, 20))	('partial deletions', 'Var', (25, 42))	('RUNX1', 'Gene', (95, 100))	('RUNX1', 'Gene', '861', (57, 62))	('RUNX1', 'Gene', '861', (95, 100))	('detected', 'Reg', (120, 128))	('malignancies', 'Disease', 'MESH:D009369', (243, 255))
152813	32290321	Successively, additional PRDM16 translocation partners, fusion transcripts and other rearrangements have been detected in leukemia cases with a poor prognosis, most of them showing an upregulation of this gene as a common feature.	('detected', 'Reg', (110, 118))	('PRDM16', 'Gene', (25, 31))	('leukemia', 'Disease', (122, 130))	('leukemia', 'Phenotype', 'HP:0001909', (122, 130))	('leukemia', 'Disease', 'MESH:D007938', (122, 130))	('men', 'Species', '9606', (94, 97))	('upregulation', 'PosReg', (184, 196))	('fusion transcripts', 'Var', (56, 74))
152814	32290321	Actually, several studies have established that high PRDM16 expression is independently associated with adverse outcomes in both adult and pediatric AML patients.	('expression', 'MPA', (60, 70))	('AML', 'Disease', (149, 152))	('AML', 'Phenotype', 'HP:0004808', (149, 152))	('patients', 'Species', '9606', (153, 161))	('PRDM16', 'Gene', (53, 59))	('AML', 'Disease', 'MESH:D015470', (149, 152))	('high', 'Var', (48, 52))	('associated with', 'Reg', (88, 103))
152819	32290321	The mouse model of conditional Prdm16 deletion elucidated the role of these two isoforms in normal and leukemic hematopoiesis and identified sPrdm16 as one of the drivers of prognostically adverse inflammation in leukemia.	('leukemic hematopoiesis', 'Disease', (103, 125))	('mouse', 'Species', '10090', (4, 9))	('inflammation', 'Disease', 'MESH:D007249', (197, 209))	('leukemia', 'Disease', (213, 221))	('leukemia', 'Phenotype', 'HP:0001909', (213, 221))	('leukemia', 'Disease', 'MESH:D007938', (213, 221))	('inflammation', 'Disease', (197, 209))	('leukemic hematopoiesis', 'Disease', 'MESH:C536227', (103, 125))	('Prdm16', 'Gene', (31, 37))	('deletion', 'Var', (38, 46))
152820	32290321	To date, rearrangements of the chromosomal region encompassing PRDM16 have been observed not only in hematopoietic malignancies but also in several solid tumors though with different and/or conflicting results, which altogether indicate this gene may function as both oncogene and tumor suppressor gene.	('tumors', 'Disease', (154, 160))	('tumors', 'Disease', 'MESH:D009369', (154, 160))	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('PRDM16', 'Gene', (63, 69))	('observed', 'Reg', (80, 88))	('men', 'Species', '9606', (18, 21))	('tumor', 'Disease', 'MESH:D009369', (281, 286))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('rearrangements', 'Var', (9, 23))	('tumor', 'Phenotype', 'HP:0002664', (281, 286))	('malignancies', 'Disease', 'MESH:D009369', (115, 127))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('malignancies', 'Disease', (115, 127))	('tumor', 'Disease', (281, 286))	('tumor', 'Disease', (154, 159))
152821	32290321	For instance, genome-wide array based comparative genomic hybridization (array-CGH) defined distinct amplifications in osteosarcoma, involving PRDM16.	('osteosarcoma', 'Disease', 'MESH:D012516', (119, 131))	('sarcoma', 'Phenotype', 'HP:0100242', (124, 131))	('amplifications', 'Var', (101, 115))	('osteosarcoma', 'Disease', (119, 131))	('osteosarcoma', 'Phenotype', 'HP:0002669', (119, 131))	('PRDM16', 'Gene', (143, 149))
152822	32290321	Otherwise, array-CGH integrated with gene expression analysis of leiomyosarcoma revealed a frequent loss at 1p36, which contains PRDM16, suggesting that this defect could promote muscle differentiation in this context.	('p36', 'Gene', (109, 112))	('sarcoma', 'Phenotype', 'HP:0100242', (72, 79))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (65, 79))	('p36', 'Gene', '51251', (109, 112))	('promote', 'PosReg', (171, 178))	('muscle differentiation', 'CPA', (179, 201))	('leiomyosarcoma', 'Disease', (65, 79))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (65, 79))	('defect', 'Var', (158, 164))	('loss', 'NegReg', (100, 104))	('PRDM16', 'Gene', (129, 135))
152823	32290321	Similarly, integrated analysis of uterine leiomyosarcoma revealed PRDM16 deletions and/or reduced expression.	('sarcoma', 'Phenotype', 'HP:0100242', (49, 56))	('reduced', 'NegReg', (90, 97))	('PRDM16', 'Gene', (66, 72))	('deletions', 'Var', (73, 82))	('leiomyosarcoma', 'Disease', (42, 56))	('uterine leiomyosarcoma', 'Phenotype', 'HP:0002891', (34, 56))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (42, 56))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (42, 56))	('expression', 'MPA', (98, 108))
152829	32290321	A possible role as a tumor suppressor gene has been proposed in lung cancer where PRDM16 is aberrantly methylated and its expression is low or absent.	('PRDM16', 'Gene', (82, 88))	('lung cancer', 'Disease', (64, 75))	('absent', 'NegReg', (143, 149))	('expression', 'MPA', (122, 132))	('lung cancer', 'Phenotype', 'HP:0100526', (64, 75))	('tumor', 'Disease', (21, 26))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('aberrantly methylated', 'Var', (92, 113))	('low', 'NegReg', (136, 139))	('lung cancer', 'Disease', 'MESH:D008175', (64, 75))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
152830	32290321	Accordingly, the median overall survival of both non-small cell lung cancer and LUAD patients with high levels of PRDM16 was significantly longer than that of cases with low levels of this gene.	('lung cancer', 'Phenotype', 'HP:0100526', (64, 75))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (53, 75))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (49, 75))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('PRDM16', 'Gene', (114, 120))	('patients', 'Species', '9606', (85, 93))	('LUAD', 'Phenotype', 'HP:0030078', (80, 84))	('longer', 'PosReg', (139, 145))	('high levels', 'Var', (99, 110))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (49, 75))	('non-small cell lung cancer', 'Disease', (49, 75))
152835	32290321	Altogether, these findings indicate that PRDM16 methylation status, both hypermethylation and hypomethylation, is often affected in distinct cancers, where this gene can play alternatively a role as an oncogene or as a tumor suppressor gene.	('cancers', 'Disease', 'MESH:D009369', (141, 148))	('PRDM16', 'Gene', (41, 47))	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('hypermethylation', 'Var', (73, 89))	('tumor', 'Disease', (219, 224))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('affected', 'Reg', (120, 128))	('cancers', 'Phenotype', 'HP:0002664', (141, 148))	('hypomethylation', 'MPA', (94, 109))	('tumor', 'Disease', 'MESH:D009369', (219, 224))	('cancers', 'Disease', (141, 148))
152837	32290321	Additionally, PRDM16 is highly overexpressed also in atypical teratoid/rhabdoid tumor, a highly malignant brain tumor predominantly arising in infants; moreover, it could have a functional role in human rhabdoid tumor cells since PRDM16 knockdown resulted in reduced metabolic activity and proliferation.	('rhabdoid tumor', 'Disease', 'MESH:D018335', (71, 85))	('rhabdoid tumor', 'Disease', (71, 85))	('PRDM16', 'Gene', (230, 236))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('infants', 'Species', '9606', (143, 150))	('rhabdoid tumor', 'Disease', 'MESH:D018335', (203, 217))	('brain tumor', 'Phenotype', 'HP:0030692', (106, 117))	('malignant brain tumor', 'Disease', 'MESH:D001932', (96, 117))	('malignant brain tumor', 'Disease', (96, 117))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('proliferation', 'CPA', (290, 303))	('rhabdoid tumor', 'Disease', (203, 217))	('reduced', 'NegReg', (259, 266))	('knockdown', 'Var', (237, 246))	('metabolic activity', 'CPA', (267, 285))	('human', 'Species', '9606', (197, 202))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))
152845	32290321	Moreover, knockdown of ciRS-133 reduced cancer cachexia in tumor-implanted mice, decreasing oxygen consumption and heat production.	('oxygen consumption', 'MPA', (92, 110))	('mice', 'Species', '10090', (75, 79))	('tumor', 'Disease', (59, 64))	('ciRS-133 reduced cancer cachexia', 'Disease', (23, 55))	('decreasing', 'NegReg', (81, 91))	('heat production', 'MPA', (115, 130))	('cachexia', 'Phenotype', 'HP:0004326', (47, 55))	('ciRS-133 reduced cancer cachexia', 'Disease', 'MESH:D002100', (23, 55))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('oxygen', 'Chemical', 'MESH:D010100', (92, 98))	('knockdown', 'Var', (10, 19))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
152847	32290321	Our TCGA analysis found that PRDM16 gene was mutated in about 6-7% of DLBCL and it was frequently altered in many cases of skin cutaneous melanoma (7.8%) and endometrial carcinoma (5.6%).	('endometrial carcinoma', 'Disease', 'MESH:D016889', (158, 179))	('melanoma', 'Phenotype', 'HP:0002861', (138, 146))	('BCL', 'Phenotype', 'HP:0012191', (72, 75))	('carcinoma', 'Phenotype', 'HP:0030731', (170, 179))	('skin cutaneous melanoma', 'Disease', (123, 146))	('endometrial carcinoma', 'Disease', (158, 179))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (158, 179))	('PRDM16', 'Gene', (29, 35))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (128, 146))	('DLBCL', 'Disease', (70, 75))	('altered', 'Reg', (98, 105))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (123, 146))	('mutated', 'Var', (45, 52))
152867	32290321	Moreover, high expression of ZFPM1 was related with good prognosis of LUAD through the analysis of RNA-seq, DNA methylation, and miRNA-seq data of squamous cell cancer samples downloaded from TCGA.	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('LUAD', 'Disease', (70, 74))	('related', 'Reg', (39, 46))	('LUAD', 'Phenotype', 'HP:0030078', (70, 74))	('expression', 'MPA', (15, 25))	('squamous cell cancer', 'Disease', (147, 167))	('high', 'Var', (10, 14))	('ZFPM1', 'Gene', (29, 34))	('squamous cell cancer', 'Disease', 'MESH:D002294', (147, 167))	('ZFPM1', 'Gene', '161882', (29, 34))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (147, 167))
152869	32290321	Indeed, our pan-cancer analysis revealed ZFPM1/FOG1 mutation occurrence in about 50% of ACC patients.	('cancer', 'Disease', 'MESH:D009369', (16, 22))	('cancer', 'Disease', (16, 22))	('ZFPM1', 'Gene', (41, 46))	('patients', 'Species', '9606', (92, 100))	('ACC', 'Disease', (88, 91))	('ACC', 'Phenotype', 'HP:0006744', (88, 91))	('ZFPM1', 'Gene', '161882', (41, 46))	('mutation', 'Var', (52, 60))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))
152870	32290321	Interestingly, these mutations were localized in a hotspot region and OncodriveCLUST results suggested it could be putatively considered a cancer driver gene in this malignancy.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('malignancy', 'Disease', 'MESH:D009369', (166, 176))	('cancer', 'Disease', (139, 145))	('malignancy', 'Disease', (166, 176))	('mutations', 'Var', (21, 30))
152871	32290321	These results were confirmed by a complete analysis of the mutational data of ACC, which was performed on the same public database and validated through further algorithms (Mutsig and 20/20 rule); this study identified a new ACC-specific gene mutation signature, also comprising ZFPM1 among the six genes.	('ACC', 'Phenotype', 'HP:0006744', (225, 228))	('mutation', 'Var', (243, 251))	('ACC-specific', 'Disease', (225, 237))	('ZFPM1', 'Gene', (279, 284))	('ACC', 'Phenotype', 'HP:0006744', (78, 81))	('ZFPM1', 'Gene', '161882', (279, 284))
152872	32290321	In addition, in our analysis we found that ZFPM1 is mutated also in colorectal cancers at relatively high frequencies.	('colorectal cancers', 'Disease', 'MESH:D015179', (68, 86))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('mutated', 'Var', (52, 59))	('colorectal cancers', 'Disease', (68, 86))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('colorectal cancer', 'Phenotype', 'HP:0003003', (68, 85))	('ZFPM1', 'Gene', '161882', (43, 48))	('ZFPM1', 'Gene', (43, 48))
152879	32290321	It is known that GATA3 is an essential regulator of mammary-gland morphogenesis and luminal-cell differentiation; FOG2 was shown to act during mammary development even though the consequences of Gata3 gene ablation in murine models were more severe than that of Fog2, whose excision induced premature mammary gland involution.	('induced', 'Reg', (283, 290))	('Fog2', 'Gene', '22762', (262, 266))	('murine', 'Species', '10090', (218, 224))	('Fog2', 'Gene', (262, 266))	('gene', 'Var', (201, 205))	('Gata3', 'Gene', (195, 200))	('Gata3', 'Gene', '14462', (195, 200))	('men', 'Species', '9606', (158, 161))
152883	32290321	Bioinformatics analysis of microarray data and genotyping of a ZFPM2 polymorphism indicated its possible role in glioma and glioblastoma.	('glioma', 'Disease', 'MESH:D005910', (113, 119))	('glioma', 'Phenotype', 'HP:0009733', (113, 119))	('polymorphism', 'Var', (69, 81))	('ZFPM2', 'Gene', (63, 68))	('role', 'Reg', (105, 109))	('glioma', 'Disease', (113, 119))	('glioblastoma', 'Disease', (124, 136))	('glioblastoma', 'Disease', 'MESH:D005909', (124, 136))	('glioblastoma', 'Phenotype', 'HP:0012174', (124, 136))
152890	32290321	Indeed, we found that, after PRDM9, ZFPM2/FOG2 was the most mutated PRDM gene with pan-cancer frequencies of protein-affecting mutations higher than 1%; specifically, we detected mutation frequencies higher than 5% in patients with skin cutaneous melanoma, lung tumors, uterine carcinosarcoma, esophageal carcinoma, and stomach and rectum adenocarcinomas.	('skin cutaneous melanoma', 'Disease', (232, 255))	('tumor', 'Phenotype', 'HP:0002664', (262, 267))	('carcinoma', 'Phenotype', 'HP:0030731', (344, 353))	('PRDM9', 'Gene', (29, 34))	('carcinomas', 'Phenotype', 'HP:0030731', (344, 354))	('mutation', 'Var', (179, 187))	('tumors', 'Phenotype', 'HP:0002664', (262, 268))	('PRDM9', 'Gene', '56979', (29, 34))	('lung tumors', 'Disease', (257, 268))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (294, 314))	('sarcoma', 'Phenotype', 'HP:0100242', (285, 292))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (270, 292))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (237, 255))	('mutations', 'Var', (127, 136))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (232, 255))	('cancer', 'Disease', (87, 93))	('patients', 'Species', '9606', (218, 226))	('rectum adenocarcinomas', 'Disease', 'MESH:D012004', (332, 354))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('carcinosarcoma', 'Disease', (278, 292))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (294, 314))	('carcinosarcoma', 'Disease', 'MESH:D002296', (278, 292))	('lung tumors', 'Disease', 'MESH:D008175', (257, 268))	('carcinoma', 'Phenotype', 'HP:0030731', (305, 314))	('melanoma', 'Phenotype', 'HP:0002861', (247, 255))	('lung tumors', 'Phenotype', 'HP:0100526', (257, 268))	('esophageal carcinoma', 'Disease', (294, 314))	('rectum adenocarcinomas', 'Disease', (332, 354))	('cancer', 'Disease', 'MESH:D009369', (87, 93))
152895	32290321	In this scenario, being involved in a multitude of pathways regulating several cancer-related processes, ranging from cell metabolism to stemness, the pharmacological control of PRDM epigenetic modulators represent a potential multi-target approach in cancer therapy (Figure 5).	('cancer', 'Disease', 'MESH:D009369', (252, 258))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('cancer', 'Disease', (252, 258))	('epigenetic modulators', 'Var', (183, 204))	('PRDM', 'Gene', (178, 182))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))
152896	32290321	A hallmark of cancer is the genomic instability that accounts for the increase in mutation frequency.	('cancer', 'Disease', (14, 20))	('increase', 'PosReg', (70, 78))	('mutation', 'Var', (82, 90))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('cancer', 'Disease', 'MESH:D009369', (14, 20))
152900	32290321	For instance, PRDM2a/RIZ1 was shown to counteract the IGF-1 receptor and the downstream components ERK1/2 and AKT (Figure 3B).	('IGF-1', 'Gene', '3479', (54, 59))	('AKT', 'Gene', (110, 113))	('IGF-1', 'Gene', (54, 59))	('ERK1/2', 'Gene', '5595;5594', (99, 105))	('ERK1/2', 'Gene', (99, 105))	('PRDM2a/RIZ1', 'Var', (14, 25))	('AKT', 'Gene', '207', (110, 113))
152924	32290321	PRDM14 knockdown decreased cancer stem-like phenotypes through upregulation of miR-125a-3p that subsequently downregulated Fyna mechanism that is reported to regulate tumor phenotypes in pancreatic cancer (Figure 1F).	('Fyn', 'Gene', (123, 126))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (187, 204))	('PRDM14', 'Gene', (0, 6))	('upregulation', 'PosReg', (63, 75))	('decreased', 'NegReg', (17, 26))	('cancer', 'Disease', (198, 204))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('pancreatic cancer', 'Disease', 'MESH:D010190', (187, 204))	('cancer', 'Disease', 'MESH:D009369', (27, 33))	('tumor', 'Disease', (167, 172))	('Fyn', 'Gene', '2534', (123, 126))	('miR-125a-3p', 'Gene', (79, 90))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('pancreatic cancer', 'Disease', (187, 204))	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('downregulated', 'NegReg', (109, 122))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('cancer', 'Disease', (27, 33))	('knockdown', 'Var', (7, 16))
152932	32290321	Indeed, its silencing in breast cancer cells reduces cancer stem cells phenotype and tumorsphere formation (Table 1 and Figure 1).	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('cancer', 'Disease', (53, 59))	('tumors', 'Disease', 'MESH:D009369', (85, 91))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('cancer', 'Disease', (32, 38))	('reduces', 'NegReg', (45, 52))	('breast cancer', 'Disease', 'MESH:D001943', (25, 38))	('silencing', 'Var', (12, 21))	('breast cancer', 'Disease', (25, 38))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('breast cancer', 'Phenotype', 'HP:0003002', (25, 38))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('tumors', 'Disease', (85, 91))
152936	32290321	MAGL blockade impairs migration, invasiveness, and tumorigenicity in aggressive human cancer.	('blockade', 'Var', (5, 13))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('MAGL', 'Gene', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('tumor', 'Disease', (51, 56))	('invasiveness', 'CPA', (33, 45))	('migration', 'CPA', (22, 31))	('impairs', 'NegReg', (14, 21))	('human', 'Species', '9606', (80, 85))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('cancer', 'Disease', (86, 92))
152941	32290321	Additionally, since some PRDMs (e.g., PRDM1, 9, 11, 14, 16) are able to orchestrate the differentiation of B and T lymphocytes, their involvement in the control of a more incisive immune response to neoplasia cannot be excluded.	('PRDM1', 'Var', (38, 43))	('neoplasia', 'Phenotype', 'HP:0002664', (199, 208))	('men', 'Species', '9606', (141, 144))	('neoplasia', 'Disease', 'MESH:D009369', (199, 208))	('neoplasia', 'Disease', (199, 208))	('PRDMs', 'Chemical', '-', (25, 30))
152943	32290321	Currently, as reported for other families, many studies have highlighted the consequences of aberrant isoform expression in triggering tumorigenesis and drug resistance, suggesting that dysregulation of alternative transcription may be a key mechanism leading to cancer progression and drug resistance.	('cancer', 'Disease', 'MESH:D009369', (263, 269))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('cancer', 'Disease', (263, 269))	('tumor', 'Disease', (135, 140))	('drug resistance', 'CPA', (286, 301))	('leading', 'Reg', (252, 259))	('aberrant', 'Var', (93, 101))	('drug resistance', 'CPA', (153, 168))	('drug resistance', 'Phenotype', 'HP:0020174', (153, 168))	('drug resistance', 'Phenotype', 'HP:0020174', (286, 301))	('cancer', 'Phenotype', 'HP:0002664', (263, 269))	('dysregulation', 'Var', (186, 199))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
152962	31754330	CMTM1 overexpression in the glioblastoma cell line A172 also promotes the proliferation and migration of tumor cells, which is likely to be achieved by the activation of epidermal growth factor receptor (EGFR), Src family kinase, and Wnt signaling.	('epidermal growth factor receptor', 'Gene', '1956', (170, 202))	('CMTM1', 'Gene', '113540', (0, 5))	('activation', 'PosReg', (156, 166))	('overexpression', 'Var', (6, 20))	('promotes', 'PosReg', (61, 69))	('glioblastoma', 'Phenotype', 'HP:0012174', (28, 40))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('Src family kinase', 'Pathway', (211, 228))	('glioblastoma', 'Disease', (28, 40))	('EGFR', 'Gene', '1956', (204, 208))	('epidermal growth factor receptor', 'Gene', (170, 202))	('migration', 'CPA', (92, 101))	('glioblastoma', 'Disease', 'MESH:D005909', (28, 40))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('proliferation', 'CPA', (74, 87))	('CMTM1', 'Gene', (0, 5))	('EGFR', 'Gene', (204, 208))	('tumor', 'Disease', (105, 110))
152979	31754330	After 3 weeks, CMTM5 adenovirus was injected into the tumor, and CMTM5 was shown to inhibit the growth of prostate cancer by downregulating the expression of vascular endothelia growth factor and NF-kappaB.	('prostate cancer', 'Phenotype', 'HP:0012125', (106, 121))	('downregulating', 'NegReg', (125, 139))	('NF-kappaB', 'Gene', '4790', (196, 205))	('expression', 'MPA', (144, 154))	('inhibit', 'NegReg', (84, 91))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('CMTM5', 'Var', (65, 70))	('vascular endothelia growth factor', 'Protein', (158, 191))	('prostate cancer', 'Disease', (106, 121))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('growth', 'MPA', (96, 102))	('NF-kappaB', 'Gene', (196, 205))	('tumor', 'Disease', (54, 59))	('prostate cancer', 'Disease', 'MESH:D011471', (106, 121))
152980	31754330	Another team confirmed that CMTM5 inhibits the proliferation and migration capacity of prostate cancer cells.	('prostate cancer', 'Disease', (87, 102))	('inhibits', 'NegReg', (34, 42))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('prostate cancer', 'Disease', 'MESH:D011471', (87, 102))	('prostate cancer', 'Phenotype', 'HP:0012125', (87, 102))	('CMTM5', 'Var', (28, 33))	('proliferation', 'CPA', (47, 60))
152987	31754330	High CMTM6 expression is also associated with poor prognosis in malignant gliomas, which is caused by the inhibition of T-cell-mediated anti-tumor immunity.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('malignant gliomas', 'Disease', 'MESH:D005910', (64, 81))	('CMTM6', 'Gene', '54918', (5, 10))	('High', 'Var', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumor', 'Disease', (141, 146))	('CMTM6', 'Gene', (5, 10))	('gliomas', 'Phenotype', 'HP:0009733', (74, 81))	('malignant gliomas', 'Disease', (64, 81))	('glioma', 'Phenotype', 'HP:0009733', (74, 80))
152989	31754330	recently reported the regulation of PD-L1 by CMTM6 and its pro-oncogenic role in several cell lines following clustered regularly interspaced palindromic repeats (CRISPR)-CRISPR-associated protein (Cas)9 deletion of CMTM6 and subsequent decrease in PD-L1 expression.	('PD-L1', 'Gene', (249, 254))	('deletion', 'Var', (204, 212))	('CMTM6', 'Gene', (45, 50))	('PD-L1', 'Gene', (36, 41))	('CMTM6', 'Gene', '54918', (216, 221))	('expression', 'MPA', (255, 265))	('PD-L1', 'Gene', '29126', (249, 254))	('decrease', 'NegReg', (237, 245))	('PD-L1', 'Gene', '29126', (36, 41))	('CMTM6', 'Gene', '54918', (45, 50))	('CMTM6', 'Gene', (216, 221))
152994	31754330	carried out RNA interference and CRISPR-Cas0 knockout of CMTM6 in the lung adenocarcinoma cell line, HCC-827, resulting in the reduction of PD-L1.	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('CMTM6', 'Gene', '54918', (57, 62))	('HCC', 'Phenotype', 'HP:0001402', (101, 104))	('HCC-827', 'CellLine', 'CVCL:4Z68', (101, 108))	('PD-L1', 'Gene', (140, 145))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (70, 89))	('CMTM6', 'Gene', (57, 62))	('knockout', 'Var', (45, 53))	('PD-L1', 'Gene', '29126', (140, 145))	('reduction', 'NegReg', (127, 136))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (70, 89))	('lung adenocarcinoma', 'Disease', (70, 89))
153002	31754330	Total expression was either increased (43/127), decreased (54/127), or remained unchanged (30/127) in these patients, with abnormal expression always associated with a lower survival rate.	('increased', 'PosReg', (28, 37))	('lower', 'NegReg', (168, 173))	('expression', 'MPA', (6, 16))	('decreased', 'NegReg', (48, 57))	('survival', 'MPA', (174, 182))	('patients', 'Species', '9606', (108, 116))	('abnormal', 'Var', (123, 131))
153009	31754330	CMTM7 knockdown also decreased EGFR ubiquitination, which further delayed its degradation.	('ubiquitination', 'MPA', (36, 50))	('CMTM7', 'Gene', '112616', (0, 5))	('EGFR', 'Gene', '1956', (31, 35))	('decreased', 'NegReg', (21, 30))	('delayed', 'NegReg', (66, 73))	('EGFR', 'Gene', (31, 35))	('degradation', 'MPA', (78, 89))	('CMTM7', 'Gene', (0, 5))	('knockdown', 'Var', (6, 15))
153033	31205520	Regarding to the mutation context, more prevailing of signature 1 in LN metastasis lesion was observed than that of primary lesion, indicating that the spontaneous deamination of cytosine may contribute to the accumulation of mutations during tumor development and immigration.	('spontaneous deamination of cytosine', 'MPA', (152, 187))	('LN metastasis lesion', 'Disease', (69, 89))	('tumor', 'Disease', 'MESH:D009369', (243, 248))	('cytosine', 'Chemical', 'MESH:D003596', (179, 187))	('mutations', 'Var', (226, 235))	('LN metastasis lesion', 'Disease', 'MESH:D009362', (69, 89))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))	('tumor', 'Disease', (243, 248))
153037	31205520	The identification of oncogenic mutations using variant sequencing techniques has been a routine clinical practice, which may guide selection of target agents and help to improve the clinical outcomes of lung cancer patients.	('lung cancer', 'Disease', 'MESH:D008175', (204, 215))	('improve', 'PosReg', (171, 178))	('patients', 'Species', '9606', (216, 224))	('mutations', 'Var', (32, 41))	('lung cancer', 'Disease', (204, 215))	('lung cancer', 'Phenotype', 'HP:0100526', (204, 215))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
153062	31205520	In addition, variants with no less than 20% prevalence among a larger real-life patient sample population, which contains more than 5,000 samples in different cancer types, as tested by Genecast, Beijing, China on a Novaseq 6000 sequencer, were considered as sequencing-specific errors, and were also excluded from further analysis.	('cancer', 'Disease', (159, 165))	('variants', 'Var', (13, 21))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('patient', 'Species', '9606', (80, 87))
153064	31205520	The thresholds of copy number >=3 and <=1.2 were used to categorize altered regions as CNV gains (amplification) and copy number losses (deletions).	('CNV gains', 'Disease', (87, 96))	('copy number', 'Var', (117, 128))	('CNV gains', 'Disease', 'MESH:D015430', (87, 96))	('losses', 'NegReg', (129, 135))
153068	31205520	Somatic variants that can be detected in the LN metastasis, but not in the primary tumor, were termed as LME-SMs.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('primary tumor', 'Disease', 'MESH:D009369', (75, 88))	('primary tumor', 'Disease', (75, 88))	('variants', 'Var', (8, 16))
153069	31205520	In 23 patients with LUAD, a total of 116 and 84 mutations were discovered in the primary lesion and LN metastasis lesion, respectively.	('LUAD', 'Disease', (20, 24))	('LN metastasis lesion', 'Disease', (100, 120))	('patients', 'Species', '9606', (6, 14))	('LN metastasis lesion', 'Disease', 'MESH:D009362', (100, 120))	('discovered', 'Reg', (63, 73))	('mutations', 'Var', (48, 57))
153070	31205520	Among these, a total of 45 mutations were concordant, which could be both detected in the primary and metastasis lesions (Fig.	('mutations', 'Var', (27, 36))	('metastasis lesions', 'Disease', (102, 120))	('metastasis lesions', 'Disease', 'MESH:D009362', (102, 120))
153072	31205520	In 14 patients with LUSC, a total of 74 and 37 mutations were discovered in the primary lesion and LN metastasis lesion respectively.	('LN metastasis lesion', 'Disease', (99, 119))	('mutations', 'Var', (47, 56))	('LN metastasis lesion', 'Disease', 'MESH:D009362', (99, 119))	('patients', 'Species', '9606', (6, 14))	('discovered', 'Reg', (62, 72))
153073	31205520	Among these, a total of 17 mutations were concordant, which could be both detected in the primary and metastasis lesions (Fig.	('mutations', 'Var', (27, 36))	('metastasis lesions', 'Disease', (102, 120))	('metastasis lesions', 'Disease', 'MESH:D009362', (102, 120))
153075	31205520	In conclusion, LUAD (29.0%) showed higher concordance rate in mutations between the primary and metastasis lesions than LUSC (18.1%).	('metastasis lesions', 'Disease', (96, 114))	('mutations', 'Var', (62, 71))	('metastasis lesions', 'Disease', 'MESH:D009362', (96, 114))
153076	31205520	Besides, more mutations were discovered in the primary lesion than LN metastasis lesion in both LUAD and LUSC, indicating that tumor mutation burden is higher in the primary lesion than that in LN metastasis lesion.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('higher', 'PosReg', (152, 158))	('LN metastasis lesion', 'Disease', 'MESH:D009362', (67, 87))	('tumor', 'Disease', (127, 132))	('LN metastasis lesion', 'Disease', 'MESH:D009362', (194, 214))	('LN metastasis lesion', 'Disease', (67, 87))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('LN metastasis lesion', 'Disease', (194, 214))	('mutations', 'Var', (14, 23))
153082	31205520	Regarding the mutational context, a strong enrichment of C > T transitions was observed in the primary tumor and LN metastasis in bolt LUAD and LUSC, especially at the CpG dinucleotides, which is denoted as signature 1 documented in the COSMIC Mutational Signature Framework (Fig.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('primary tumor', 'Disease', 'MESH:D009369', (95, 108))	('LN metastasis', 'CPA', (113, 126))	('C > T transitions', 'Var', (57, 74))	('primary tumor', 'Disease', (95, 108))
153083	31205520	The signature 1 is more dominant in LN metastasis than primary tumor, suggesting that the spontaneous deamination of cytosine contributes to the accumulation of mutations during tumor development and migration in both LUAD and LUSC(Fig.	('tumor', 'Disease', (63, 68))	('tumor', 'Disease', (178, 183))	('primary tumor', 'Disease', (55, 68))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('mutations', 'Var', (161, 170))	('primary tumor', 'Disease', 'MESH:D009369', (55, 68))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('cytosine', 'Chemical', 'MESH:D003596', (117, 125))
153088	31205520	Mutations in genes related to cell migration and metastasis may explain the process of progression in NSCLC.	('NSCLC', 'Disease', 'MESH:D002289', (102, 107))	('Mutations', 'Var', (0, 9))	('NSCLC', 'Disease', (102, 107))
153092	31205520	All these results suggest that the spontaneous deamination of cytosine may contribute to the accumulation of mutations during tumorigenesis and metastasis.	('contribute', 'Reg', (75, 85))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('mutations', 'Var', (109, 118))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('cytosine', 'Chemical', 'MESH:D003596', (62, 70))	('spontaneous deamination', 'MPA', (35, 58))	('tumor', 'Disease', (126, 131))
153094	31205520	EGFR mutation, as a targetable mutation, is of great significance in clinical practice in LUAD.	('mutation', 'Var', (5, 13))	('LUAD', 'Disease', (90, 94))	('EGFR', 'Gene', '1956', (0, 4))	('EGFR', 'Gene', (0, 4))
153095	31205520	Among the 23 LUAD patients enrolled in the present study, seven patients had EGFR targetable hotspot mutations (including L858R, 19del, and T790M) in the tumor sample, while six patients had EGFR mutations in LN samples.	('L858R', 'Var', (122, 127))	('19del', 'Var', (129, 134))	('patients', 'Species', '9606', (64, 72))	('L858R', 'Mutation', 'rs121434568', (122, 127))	('T790M', 'Mutation', 'rs121434569', (140, 145))	('patients', 'Species', '9606', (178, 186))	('EGFR', 'Gene', '1956', (191, 195))	('EGFR', 'Gene', (191, 195))	('19del', 'Mutation', 'c.19del', (129, 134))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('EGFR', 'Gene', '1956', (77, 81))	('T790M', 'Var', (140, 145))	('patients', 'Species', '9606', (18, 26))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('EGFR', 'Gene', (77, 81))	('tumor', 'Disease', (154, 159))
153096	31205520	The discordance rate in mutations between tumor and LN samples was 13.0% (3/23).	('mutations', 'Var', (24, 33))	('tumor', 'Disease', (42, 47))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
153097	31205520	For patient P7870, a sensitive EGFR mutation L858R was detected in the metastasis LN tissue, but not in the primary tumor, which implies that mutational profiling in metastatic samples would be of more value.	('EGFR', 'Gene', '1956', (31, 35))	('P7870', 'Var', (12, 17))	('EGFR', 'Gene', (31, 35))	('L858R', 'Var', (45, 50))	('primary tumor', 'Disease', (108, 121))	('patient', 'Species', '9606', (4, 11))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('primary tumor', 'Disease', 'MESH:D009369', (108, 121))	('L858R', 'Mutation', 'rs121434568', (45, 50))
153098	31205520	For patient P5082 and P5249, EGFR T790M mutations and EGFR 21del were only detected in primary tumors, respectively.	('P5249', 'Var', (22, 27))	('primary tumors', 'Disease', (87, 101))	('patient', 'Species', '9606', (4, 11))	('primary tumors', 'Disease', 'MESH:D009369', (87, 101))	('T790M', 'Mutation', 'rs121434569', (34, 39))	('EGFR', 'Gene', '1956', (29, 33))	('EGFR', 'Gene', '1956', (54, 58))	('EGFR', 'Gene', (29, 33))	('T790M mutations', 'Var', (34, 49))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('P5082', 'Var', (12, 17))	('EGFR', 'Gene', (54, 58))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('EGFR 21del', 'Mutation', 'c.21delEGFR', (54, 64))
153099	31205520	[20]and Wang et al., in which a considerable discrepancy(11.9% and 14.5%, respectively) in EGFR mutations generates between primary tumors and metastatic LN, suggesting that genetic heterogeneity originates at the molecular level during the process of metastasis.	('EGFR', 'Gene', (91, 95))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('primary tumors', 'Disease', (124, 138))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('primary tumors', 'Disease', 'MESH:D009369', (124, 138))	('EGFR', 'Gene', '1956', (91, 95))	('mutations', 'Var', (96, 105))
153100	31205520	Furthermore, a considerable proportion of mutations were found to be different between primary tumors and metastatic lesions, which is in agreement with the observation reported by Um et al., in which a considerable proportion of NSCLCs exhibited unique mutations in metastatic LN, supporting that clonal evolution occurs at the molecular level during the process of metastasis.	('NSCLC', 'Disease', 'MESH:D002289', (230, 235))	('primary tumors', 'Disease', (87, 101))	('metastatic LN', 'Gene', (267, 280))	('primary tumors', 'Disease', 'MESH:D009369', (87, 101))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('NSCLC', 'Disease', (230, 235))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('mutations', 'Var', (254, 263))
153102	31205520	It is noteworthy that more mutations were found in the primary tumor in both LUAD and LUSC, when compared to the paired LN metastasis, indicating that tumor mutation burden is higher in primary lesion than that in LN metastasis lesion.	('mutations', 'Var', (27, 36))	('tumor', 'Disease', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('LN metastasis lesion', 'Disease', 'MESH:D009362', (214, 234))	('tumor', 'Disease', (151, 156))	('primary tumor', 'Disease', (55, 68))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('primary tumor', 'Disease', 'MESH:D009369', (55, 68))	('higher', 'PosReg', (176, 182))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('LN metastasis lesion', 'Disease', (214, 234))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
153103	31205520	This was also observed by Kim et al., in which there was a higher chance of non-synonymous mutation in primary tumors than in metastatic LNs.	('primary tumors', 'Disease', (103, 117))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('primary tumors', 'Disease', 'MESH:D009369', (103, 117))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('non-synonymous mutation', 'Var', (76, 99))
153107	31205520	These results imply that LN metastasis may be associated with the PI3K-Akt, MAPK and Ras signaling pathway in NSCLC.	('LN metastasis', 'CPA', (25, 38))	('MAPK', 'Pathway', (76, 80))	('NSCLC', 'Disease', (110, 115))	('PI3K-Akt', 'Var', (66, 74))	('NSCLC', 'Disease', 'MESH:D002289', (110, 115))	('Ras signaling pathway', 'Pathway', (85, 106))	('associated', 'Reg', (46, 56))
153113	31205520	NSCLC non-small cell lung cancer LME-SMs lymphatic metastasis exclusive somatic mutations LN lymph nodes CNV Copy number variation GO Gene Ontology KEGG Kyoto Encyclopedia of Gene and Genomes BP biological process CC cellular component MF molecular function	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (6, 32))	('NSCLC', 'Disease', 'MESH:D002289', (0, 5))	('Copy number variation', 'Var', (109, 130))	('mutations', 'Var', (80, 89))	('lung cancer', 'Phenotype', 'HP:0100526', (21, 32))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (6, 32))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('non-small cell lung cancer', 'Disease', (6, 32))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (10, 32))	('NSCLC', 'Disease', (0, 5))
153143	31058031	The immunohistochemistry profile revealed the following: CK AE1/AE3 (+), CK 7 (+), CK 20 (-), p63 (+), CK 5/6 (+), renal cell carcinoma marker (RCC) (-), cell membrane metallopeptidase 10 (CD10) (-), p16 (+), transcription factor protein 3 (guanine - adenine - thymine) (GATA 3): non-contributory (Figures 4A-4C).	('RCC', 'Disease', 'MESH:C538614', (144, 147))	('CD10', 'Gene', (189, 193))	('CK 20', 'Gene', (83, 88))	('AE3', 'Gene', '6508', (64, 67))	('CK 5', 'Gene', '3852', (103, 107))	('CK 20', 'Gene', '54474', (83, 88))	('AE1', 'Gene', (60, 63))	('renal cell carcinoma', 'Disease', (115, 135))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (115, 135))	('p63', 'Gene', (94, 97))	('CK 7 (+', 'Var', (73, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('p63', 'Gene', '8626', (94, 97))	('p16', 'Gene', (200, 203))	('CK 5', 'Gene', (103, 107))	('p16', 'Gene', '1029', (200, 203))	('RCC', 'Disease', (144, 147))	('AE3', 'Gene', (64, 67))	('CD10', 'Gene', '4311', (189, 193))	('transcription factor protein 3 (guanine - adenine - thymine) (GATA 3', 'Gene', '2625', (209, 277))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (115, 135))	('AE1', 'Gene', '6521', (60, 63))
153173	30157900	Compared with other EGFR blockers, the second-generation EGFR-TKI afatinib exerted superior antitumor effects in ESCC, and EGFR copy number gain (CNG) or overexpression was proposed to be predictive biomarkers.	('gain', 'PosReg', (140, 144))	('ESCC', 'Disease', (113, 117))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('afatinib', 'Chemical', 'MESH:D000077716', (66, 74))	('tumor', 'Disease', (96, 101))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('superior', 'PosReg', (83, 91))	('copy number', 'Var', (128, 139))
153185	30157900	Despite the failure of some EGFR blockers in ESCC such as EGFR monoclonal antibodies (mAbs) cetuximab and tyrosine kinase inhibitors (TKIs) gefitinib as confirmed by several clinical trials, subsequent stratified analysis of these trials suggested that patients with squamous histopathological type, EGFR copy number gain (CNG), or overexpression might benefit from EGFR-targeted therapy, which motivated us greatly to initiate the deeper exploration.	('tyrosine kinase', 'Gene', '7294', (106, 121))	('mAbs', 'Gene', (86, 90))	('gefitinib', 'Chemical', 'MESH:D000077156', (140, 149))	('copy number', 'Var', (305, 316))	('overexpression', 'PosReg', (332, 346))	('gain', 'PosReg', (317, 321))	('mAbs', 'Gene', '72935', (86, 90))	('patients', 'Species', '9606', (253, 261))	('EGFR', 'Gene', (300, 304))	('cetuximab', 'Chemical', 'MESH:D000068818', (92, 101))	('tyrosine kinase', 'Gene', (106, 121))	('squamous', 'Disease', (267, 275))
153188	30157900	Gefitinib (#S1025), osimertinib (#S7297), dasatinib hydrochloride (#HY-10181A), and crizotinib hydrochloride (#HY-50878A) were purchased from Selleck Chemicals or MedChem Express.	('crizotinib hydrochloride', 'Chemical', '-', (84, 108))	('#S7297', 'Var', (33, 39))	('Gefitinib', 'Chemical', 'MESH:D000077156', (0, 9))	('#S1025', 'Var', (11, 17))	('#HY-50878A', 'Var', (110, 120))	('osimertinib', 'Chemical', 'MESH:C000603933', (20, 31))	('dasatinib hydrochloride', 'Chemical', '-', (42, 65))	('#HY-10181A', 'Var', (67, 77))
153195	30157900	Cells were treated with afatinib or vehicle for 48 h. Apoptosis was measured by PE Annexin V Apoptosis Detection Kit I (#559763, BD Pharmingen), and cell cycle distribution was performed using PI/RNase staining buffer solution (#550825, BD Pharmingen) according to manufacturer's instructions.	('Annexin V', 'Gene', '308', (83, 92))	('Annexin V', 'Gene', (83, 92))	('Apoptosis', 'CPA', (54, 63))	('afatinib', 'Chemical', 'MESH:D000077716', (24, 32))	('#550825', 'Var', (228, 235))
153222	30157900	Meanwhile, these three afatinib-sensitive cell lines had an EGFR copy number gain, with copy numbers of 3.05, 8.10, and 4.81, respectively (Fig.	('gain', 'PosReg', (77, 81))	('copy number', 'Var', (65, 76))	('EGFR', 'Gene', (60, 64))	('afatinib', 'Chemical', 'MESH:D000077716', (23, 31))
153223	30157900	A significant reverse correlation was found between EGFR expression or copy number and afatinib sensitivity as indicated by IC50 (Fig.	('afatinib', 'Chemical', 'MESH:D000077716', (87, 95))	('EGFR', 'Gene', (52, 56))	('sensitivity', 'MPA', (96, 107))	('copy number', 'Var', (71, 82))
153225	30157900	Also, a very good correlation was presented between EGFR copy number and inhibitory effects of afatinib in PDXs (Fig.	('copy number', 'Var', (57, 68))	('EGFR', 'Gene', (52, 56))	('PDXs', 'Disease', (107, 111))	('afatinib', 'Chemical', 'MESH:D000077716', (95, 103))	('inhibitory effects', 'MPA', (73, 91))
153227	30157900	Panel sequencing of these cell lines and PDXs showed that KYSE450 harbored an activating EGFR mutation (S7681), TE-1 harbored an activating BRAF mutation at codon 326 (I326V), and KYSE510 and PDX06 harbored an activating PIK3CA mutation (E545K and H1047L, respectively), which partially provided rationale for the sensitivity and resistance of these models to afatinib (Fig.	('PIK3CA', 'Gene', '5290', (221, 227))	('afatinib', 'Chemical', 'MESH:D000077716', (360, 368))	('activating', 'PosReg', (78, 88))	('EGFR', 'Gene', (89, 93))	('BRAF', 'Gene', '673', (140, 144))	('activating', 'PosReg', (210, 220))	('H1047L', 'Mutation', 'rs121913279', (248, 254))	('S7681', 'Var', (104, 109))	('H1047L', 'Var', (248, 254))	('BRAF', 'Gene', (140, 144))	('PIK3CA', 'Gene', (221, 227))	('E545K', 'Mutation', 'rs104886003', (238, 243))	('I326V', 'Mutation', 'rs775040765', (168, 173))	('E545K', 'Var', (238, 243))	('activating', 'PosReg', (129, 139))
153230	30157900	S6 and ERK phosphorylation (pS6 and pERK) were significantly inhibited by 100 nM afatinib in the afatinib-sensitive lines EC109, KYSE450, and KYSE140, but 100 nM afatinib did not inhibit pS6 in KYSE510 or pERK in TE-1 cells possibly due to the abovementioned PIK3CA and BRAF mutations, respectively (Fig.	('afatinib', 'Chemical', 'MESH:D000077716', (81, 89))	('BRAF', 'Gene', (270, 274))	('inhibited', 'NegReg', (61, 70))	('BRAF', 'Gene', '673', (270, 274))	('ERK', 'Gene', (37, 40))	('pS6', 'Gene', (187, 190))	('ERK', 'Gene', '5594', (7, 10))	('ERK', 'Gene', '5594', (206, 209))	('PIK3CA', 'Gene', '5290', (259, 265))	('pS6', 'Gene', (28, 31))	('afatinib', 'Chemical', 'MESH:D000077716', (162, 170))	('pERK', 'Gene', (205, 209))	('pERK', 'Gene', '9451', (205, 209))	('pS6', 'Gene', '338413', (187, 190))	('ERK', 'Gene', (7, 10))	('ERK', 'Gene', (206, 209))	('mutations', 'Var', (275, 284))	('afatinib', 'Chemical', 'MESH:D000077716', (97, 105))	('ERK', 'Gene', '5594', (37, 40))	('pS6', 'Gene', '338413', (28, 31))	('PIK3CA', 'Gene', (259, 265))	('pERK', 'Gene', (36, 40))	('pERK', 'Gene', '9451', (36, 40))
153234	30157900	In addition, afatinib could induce obvious G1 phase arrest and apoptosis in a dose-dependent manner in afatinib-sensitive KYSE450, KYSE140, and EC109 cells, but not in afatinib-insensitive KYSE510 cells (Fig.	('afatinib', 'Chemical', 'MESH:D000077716', (168, 176))	('arrest', 'Disease', (52, 58))	('afatinib', 'Chemical', 'MESH:D000077716', (103, 111))	('apoptosis', 'CPA', (63, 72))	('arrest', 'Disease', 'MESH:D006323', (52, 58))	('afatinib-sensitive', 'Var', (103, 121))	('afatinib', 'Chemical', 'MESH:D000077716', (13, 21))
153244	30157900	In addition, variant analysis did not reveal any new mutations within the EGFR kinase domain or mutations in the downstream effectors like PIK3CA, KRAS, or BRAF after afatinib-acquired resistance (data not shown).	('PIK3CA', 'Gene', '5290', (139, 145))	('afatinib', 'Chemical', 'MESH:D000077716', (167, 175))	('BRAF', 'Gene', (156, 160))	('BRAF', 'Gene', '673', (156, 160))	('mutations', 'Var', (53, 62))	('PIK3CA', 'Gene', (139, 145))	('KRAS', 'Gene', (147, 151))	('EGFR', 'Gene', (74, 78))	('KRAS', 'Gene', '3845', (147, 151))
153249	30157900	An alternative strategy was employed by MET knockdown, and results also confirmed that MET downregulation could not re-sensitize the resistant cells to afatinib (Fig.	('afatinib', 'Chemical', 'MESH:D000077716', (152, 160))	('downregulation', 'NegReg', (91, 105))	('MET', 'Var', (87, 90))
153250	30157900	Deep-going analysis demonstrated that neither combining crizotinib with afatinib nor MET knockdown had effects on phosphorylated S6 and ERK (Fig.	('afatinib', 'Chemical', 'MESH:D000077716', (72, 80))	('phosphorylated', 'MPA', (114, 128))	('ERK', 'Gene', '5594', (136, 139))	('knockdown', 'Var', (89, 98))	('ERK', 'Gene', (136, 139))	('crizotinib', 'Chemical', 'MESH:D000077547', (56, 66))
153264	30157900	Previous clinical trials of gefitinib (the COG study) and icotinib (first-generation EGFR-TKIs) demonstrated that EGFR-TKIs exhibited favorable efficacy in ESCC patients with EGFR amplification as detected by fluorescence in situ hybridization (FISH) method.	('gefitinib', 'Chemical', 'MESH:D000077156', (28, 37))	('EGFR-TKIs', 'Var', (114, 123))	('icotinib', 'Chemical', 'MESH:C531470', (58, 66))	('patients', 'Species', '9606', (161, 169))	('ESCC', 'Disease', (156, 160))
153268	30157900	Besides, KYSE510 harbored a non-activating EGFR mutation (A702D) in the juxtamembrane region and showed no correlations with sensitivity to EGFR-TKIs according to previous studies; KYSE450 harbored an activating EGFR mutation (S768I) in tyrosine kinase domain, and this mutation was reported to be sensitive to afatinib.	('tyrosine kinase', 'Gene', '7294', (237, 252))	('activating EGFR', 'PosReg', (201, 216))	('tyrosine kinase', 'Gene', (237, 252))	('S768I', 'Var', (227, 232))	('A702D', 'Mutation', 'p.A702D', (58, 63))	('S768I', 'Mutation', 'rs121913465', (227, 232))	('afatinib', 'Chemical', 'MESH:D000077716', (311, 319))
153270	30157900	Above all, EGFR CNG or amplification may be a promising predictive biomarker for EGFR-targeted therapy in ESCC patients, but patients with mutations in EGFR downstream effectors such as PIK3CA or BRAF may exhibit de novo resistance to afatinib.	('patients', 'Species', '9606', (125, 133))	('mutations', 'Var', (139, 148))	('resistance', 'MPA', (221, 231))	('ESCC', 'Disease', (106, 110))	('BRAF', 'Gene', '673', (196, 200))	('patients', 'Species', '9606', (111, 119))	('BRAF', 'Gene', (196, 200))	('PIK3CA', 'Gene', (186, 192))	('EGFR', 'Gene', (152, 156))	('afatinib', 'Chemical', 'MESH:D000077716', (235, 243))	('PIK3CA', 'Gene', '5290', (186, 192))
153273	30157900	After excluding the emergence of mutations in EGFR and downstream effectors such as PIK3CA, KRAS, and BRAF, we speculated that bypass signaling pathways might result in the resistance.	('PIK3CA', 'Gene', '5290', (84, 90))	('BRAF', 'Gene', '673', (102, 106))	('KRAS', 'Gene', (92, 96))	('BRAF', 'Gene', (102, 106))	('mutations', 'Var', (33, 42))	('EGFR', 'Gene', (46, 50))	('PIK3CA', 'Gene', (84, 90))	('KRAS', 'Gene', '3845', (92, 96))	('result', 'Reg', (159, 165))
153278	30157900	Dual EGFR and SFKs blockade could abolish the downstream phosphorylation of S6 and ERK and therefore overcome the resistance.	('downstream phosphorylation', 'MPA', (46, 72))	('resistance', 'MPA', (114, 124))	('blockade', 'Var', (19, 27))	('abolish', 'NegReg', (34, 41))	('ERK', 'Gene', (83, 86))	('SFKs', 'Gene', (14, 18))	('overcome', 'NegReg', (101, 109))	('ERK', 'Gene', '5594', (83, 86))
153279	30157900	In Eiki's study, they found that increased pSFKs levels were caused by amplification of YES1, one member of the SFKs, and further led to EGFR-TKIs resistance.	('pSFKs levels', 'MPA', (43, 55))	('EGFR-TKIs resistance', 'CPA', (137, 157))	('caused by', 'Reg', (61, 70))	('amplification', 'Var', (71, 84))	('increased', 'PosReg', (33, 42))	('YES1', 'Gene', (88, 92))	('led to', 'Reg', (130, 136))	('YES1', 'Gene', '7525', (88, 92))
153305	28841699	Proposed prognostic biomarkers have included p16, Ki67, p53, and laminin-5 expression.	('p16', 'Gene', '1029', (45, 48))	('p53', 'Gene', (56, 59))	('p53', 'Gene', '7157', (56, 59))	('p16', 'Gene', (45, 48))	('Ki67', 'Var', (50, 54))	('laminin-5', 'Protein', (65, 74))	('expression', 'MPA', (75, 85))
153311	28841699	In cervical cancer, the variation in the number of LRIG1 gene copies and promoter methylation patterns are associated with patient survival.	('LRIG1', 'Gene', (51, 56))	('LRIG1', 'Gene', '26018', (51, 56))	('patient', 'Species', '9606', (123, 130))	('variation', 'Var', (24, 33))	('associated', 'Reg', (107, 117))	('cervical cancer', 'Disease', 'MESH:D002583', (3, 18))	('cervical cancer', 'Disease', (3, 18))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))
153313	28841699	In general, high expression of LRIG1 and LRIG3 in tumours is associated with improved survival in cancer patients, whereas high expression of LRIG2 is associated with poor survival even in early-stage cervical cancer patients.	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('LRIG2', 'Gene', (142, 147))	('tumours', 'Disease', (50, 57))	('cancer', 'Disease', (98, 104))	('LRIG1', 'Gene', (31, 36))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('tumours', 'Phenotype', 'HP:0002664', (50, 57))	('LRIG1', 'Gene', '26018', (31, 36))	('tumours', 'Disease', 'MESH:D009369', (50, 57))	('LRIG2', 'Gene', '9860', (142, 147))	('cancer', 'Disease', 'MESH:D009369', (210, 216))	('tumour', 'Phenotype', 'HP:0002664', (50, 56))	('patients', 'Species', '9606', (105, 113))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('patients', 'Species', '9606', (217, 225))	('cervical cancer', 'Disease', (201, 216))	('improved', 'PosReg', (77, 85))	('cervical cancer', 'Disease', 'MESH:D002583', (201, 216))	('LRIG3', 'Gene', (41, 46))	('high', 'Var', (12, 16))	('survival', 'MPA', (86, 94))	('LRIG3', 'Gene', '121227', (41, 46))	('cancer', 'Disease', (210, 216))
153345	28841699	Intriguingly, high LRIG1 expression was associated with superior cancer-specific survival in the PVC patients in our study.	('patients', 'Species', '9606', (101, 109))	('expression', 'MPA', (25, 35))	('LRIG1', 'Gene', (19, 24))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('LRIG1', 'Gene', '26018', (19, 24))	('high', 'Var', (14, 18))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('PVC', 'Disease', (97, 100))	('superior', 'PosReg', (56, 64))
153347	28841699	In accordance with the present study, Lindstrom et al showed that LRIG1 expression might be a predictor of improved survival in early-stage cervical carcinoma.	('LRIG1', 'Gene', '26018', (66, 71))	('LRIG1', 'Gene', (66, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (149, 158))	('improved', 'PosReg', (107, 115))	('cervical carcinoma', 'Disease', 'MESH:D002575', (140, 158))	('cervical carcinoma', 'Disease', (140, 158))	('survival', 'MPA', (116, 124))	('expression', 'Var', (72, 82))
153365	28841699	In addition, Lindquist et al demonstrated that HPV-positive tumours with high LRIG1 expression correlated with a very good prognosis in terms of disease-free survival and overall survival.	('HPV-positive tumours', 'Disease', 'MESH:D030361', (47, 67))	('HPV-positive tumours', 'Disease', (47, 67))	('LRIG1', 'Gene', '26018', (78, 83))	('LRIG1', 'Gene', (78, 83))	('tumours', 'Phenotype', 'HP:0002664', (60, 67))	('disease-free survival', 'CPA', (145, 166))	('high', 'Var', (73, 77))	('overall survival', 'CPA', (171, 187))	('tumour', 'Phenotype', 'HP:0002664', (60, 66))	('expression', 'MPA', (84, 94))
153367	28841699	In the study by Lindstrom and Hellberg, high LRIG3 expression was correlated with HPV positivity in both normal cervical epithelium and precancerous cervical lesions.	('high', 'Var', (40, 44))	('LRIG3', 'Gene', (45, 50))	('correlated', 'Reg', (66, 76))	('precancerous cervical lesions', 'Disease', 'MESH:D011230', (136, 165))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('expression', 'MPA', (51, 61))	('LRIG3', 'Gene', '121227', (45, 50))	('precancerous cervical lesions', 'Disease', (136, 165))	('HPV', 'Species', '10566', (82, 85))	('HPV', 'Gene', (82, 85))
153370	28841699	In agreement with our results, previous studies on squamous cell carcinomas of the cervix and oropharynx, breast, skin, and non-small cell lung cancer showed that high LRIG1 expression is associated with improved prognosis.	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('non-small cell lung cancer', 'Disease', (124, 150))	('lung cancer', 'Phenotype', 'HP:0100526', (139, 150))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('carcinomas of the cervix', 'Phenotype', 'HP:0030079', (65, 89))	('carcinomas', 'Phenotype', 'HP:0030731', (65, 75))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (124, 150))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (51, 75))	('expression', 'MPA', (174, 184))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (51, 75))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (128, 150))	('improved', 'PosReg', (204, 212))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (51, 74))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (124, 150))	('high', 'Var', (163, 167))	('squamous cell carcinomas', 'Disease', (51, 75))	('prognosis', 'CPA', (213, 222))	('LRIG1', 'Gene', (168, 173))	('LRIG1', 'Gene', '26018', (168, 173))
153373	28841699	Additionally, we found that non-keratinising tumours correlated to HPV positivity.	('tumour', 'Phenotype', 'HP:0002664', (45, 51))	('tumours', 'Phenotype', 'HP:0002664', (45, 52))	('HPV', 'Species', '10566', (67, 70))	('tumours', 'Disease', 'MESH:D009369', (45, 52))	('HPV', 'Gene', (67, 70))	('positivity', 'Var', (71, 81))	('tumours', 'Disease', (45, 52))
153375	28841699	Furthermore, it has been shown that high LRIG1 expression correlates with increased sensitivity to platinum-based chemotherapy, thus LRIG might be of interest as a potential predictor and target for treatment in PVC patients to minimise the risk of overtreatment.	('sensitivity to platinum-based chemotherapy', 'MPA', (84, 126))	('LRIG1', 'Gene', '26018', (41, 46))	('LRIG1', 'Gene', (41, 46))	('expression', 'MPA', (47, 57))	('increased', 'PosReg', (74, 83))	('patients', 'Species', '9606', (216, 224))	('platinum', 'Chemical', 'MESH:D010984', (99, 107))	('high', 'Var', (36, 40))
153388	28603423	Moreover, EVI1 high expression was identified as an independent prognostic factor of SCC, predicting the unfavorable prognosis (P=0.013).	('high expression', 'Var', (15, 30))	('SCC', 'Gene', '6317', (85, 88))	('EVI1', 'Gene', '2122', (10, 14))	('EVI1', 'Gene', (10, 14))	('SCC', 'Gene', (85, 88))
153389	28603423	High expression of EVI1 was significantly associated with a poorer prognosis and it was identified as an independent prognostic factor of SCC.	('EVI1', 'Gene', (19, 23))	('High', 'Var', (0, 4))	('SCC', 'Gene', (138, 141))	('SCC', 'Gene', '6317', (138, 141))	('EVI1', 'Gene', '2122', (19, 23))
153398	28603423	Frequent activation of EVI gene could be observed for intrachromosomal or interchromosomal rearrangements in patients with AML or MDS.	('activation', 'PosReg', (9, 19))	('patients', 'Species', '9606', (109, 117))	('AML', 'Disease', 'MESH:D015470', (123, 126))	('MDS', 'Disease', 'MESH:D009190', (130, 133))	('interchromosomal rearrangements', 'Var', (74, 105))	('EVI', 'Gene', '79971', (23, 26))	('AML', 'Disease', (123, 126))	('MDS', 'Disease', (130, 133))	('EVI', 'Gene', (23, 26))
153434	28603423	It was suspected that EVI1 expression might affect the prognosis of SCC and therefore its prognostic significance was evaluated with univariate and multivariate analyses (Table 3).	('EVI1', 'Gene', '2122', (22, 26))	('SCC', 'Gene', '6317', (68, 71))	('EVI1', 'Gene', (22, 26))	('SCC', 'Gene', (68, 71))	('expression', 'Var', (27, 37))	('affect', 'Reg', (44, 50))
153437	28603423	Notably, the high expression of EVI1 could also predict the unfavorable prognosis of SCC (P=0.021, 18.5 vs 26.6 months) (Figure 2C).	('EVI1', 'Gene', (32, 36))	('SCC', 'Gene', '6317', (85, 88))	('high', 'Var', (13, 17))	('predict', 'Reg', (48, 55))	('EVI1', 'Gene', '2122', (32, 36))	('SCC', 'Gene', (85, 88))
153439	28603423	In the multivariate analysis, the high expression of EVI1 was identified as an independent prognostic factor of SCC (hazard ratio [HR] =1.66, 95% confidence interval [CI] =1.11-2.47, P=0.013), indicating that the high expression of EVI1 alone was enough to predict the poorer prognosis of SCC.	('EVI1', 'Gene', (53, 57))	('EVI1', 'Gene', (232, 236))	('SCC', 'Gene', (289, 292))	('SCC', 'Gene', '6317', (112, 115))	('high', 'Var', (34, 38))	('SCC', 'Gene', '6317', (289, 292))	('EVI1', 'Gene', '2122', (53, 57))	('EVI1', 'Gene', '2122', (232, 236))	('SCC', 'Gene', (112, 115))
153449	28603423	For example, Nanjundan et al pointed out that amplification of EVI1 is associated with a favorable prognosis in ovarian cancer.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('ovarian cancer', 'Disease', 'MESH:D010051', (112, 126))	('amplification', 'Var', (46, 59))	('ovarian cancer', 'Disease', (112, 126))	('EVI1', 'Gene', '2122', (63, 67))	('EVI1', 'Gene', (63, 67))	('ovarian cancer', 'Phenotype', 'HP:0100615', (112, 126))
153459	28603423	The finding of this study that the high expression of EVI1 is an independent prognostic factor could help more specifically stratify SCC high-risk and low-risk patients and help them get different treating therapies.	('EVI1', 'Gene', '2122', (54, 58))	('EVI1', 'Gene', (54, 58))	('patients', 'Species', '9606', (160, 168))	('SCC', 'Gene', '6317', (133, 136))	('high', 'Var', (35, 39))	('SCC', 'Gene', (133, 136))
153463	28603423	Furthermore, it was demonstrated that the high expression of EVI1 was significantly associated with the unfavorable prognosis of SCC and that EVI1 was an independent prognostic factor of SCC.	('SCC', 'Gene', '6317', (129, 132))	('EVI1', 'Gene', '2122', (61, 65))	('EVI1', 'Gene', (142, 146))	('SCC', 'Gene', (187, 190))	('EVI1', 'Gene', (61, 65))	('EVI1', 'Gene', '2122', (142, 146))	('associated', 'Reg', (84, 94))	('SCC', 'Gene', '6317', (187, 190))	('high', 'Var', (42, 46))	('SCC', 'Gene', (129, 132))
153471	33380808	Therefore, targeting BRD9 to study its biological roles will be an attractive tool for cancer diagnosis and treatment, but it remains a great challenge.	('cancer', 'Disease', (87, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('targeting', 'Var', (11, 20))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('BRD9', 'Gene', (21, 25))
153477	33380808	For example, in malignant rhabdoid tumors (MRT), biallelic inactivation of SMARCB1 was first reported, and thereafter, in myoepithelial tumors and hepatoblastomas, repeated mutations were reported.	('hepatoblastomas', 'Disease', (147, 162))	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('myoepithelial tumors', 'Disease', 'MESH:D009208', (122, 142))	('malignant rhabdoid tumors', 'Disease', 'MESH:D018335', (16, 41))	('SMARCB1', 'Gene', '6598', (75, 82))	('biallelic inactivation', 'Var', (49, 71))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('hepatoblastomas', 'Disease', 'MESH:D018197', (147, 162))	('myoepithelial tumors', 'Disease', (122, 142))	('SMARCB1', 'Gene', (75, 82))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('malignant rhabdoid tumors', 'Disease', (16, 41))
153479	33380808	Several studies have revealed that SMARCA4 undergoes mutations at different frequencies in Burkitt's lymphoma, lung adenocarcinoma, esophageal adenocarcinoma, and medulloblastoma.	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('adenocarcinoma', 'Disease', (143, 157))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (111, 130))	("Burkitt's lymphoma", 'Phenotype', 'HP:0030080', (91, 109))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (111, 130))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (132, 157))	('adenocarcinoma', 'Disease', (116, 130))	("Burkitt's lymphoma", 'Disease', 'MESH:D002051', (91, 109))	("Burkitt's lymphoma", 'Disease', (91, 109))	('SMARCA4', 'Gene', '6597', (35, 42))	('adenocarcinoma', 'Disease', 'MESH:D000230', (143, 157))	('medulloblastoma', 'Disease', 'MESH:D008527', (163, 178))	('medulloblastoma', 'Phenotype', 'HP:0002885', (163, 178))	('carcinoma', 'Phenotype', 'HP:0030731', (148, 157))	('medulloblastoma', 'Disease', (163, 178))	('adenocarcinoma', 'Disease', 'MESH:D000230', (116, 130))	('mutations', 'Var', (53, 62))	('lymphoma', 'Phenotype', 'HP:0002665', (101, 109))	('lung adenocarcinoma', 'Disease', (111, 130))	('SMARCA4', 'Gene', (35, 42))
153480	33380808	Moreover, researchers have found that the mutation frequency of ARID1A, which encodes the BAF250a subunit, is high in hepatocellular carcinoma, gastric cancer, bladder cancer, colorectal cancer, pancreatic cancer, Burkitt's lymphoma, and cholangiocarcinoma.	('colorectal cancer', 'Disease', 'MESH:D015179', (176, 193))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (118, 142))	('BAF250a', 'Gene', '8289', (90, 97))	('gastric cancer', 'Disease', 'MESH:D013274', (144, 158))	('colorectal cancer', 'Disease', (176, 193))	('lymphoma', 'Phenotype', 'HP:0002665', (224, 232))	('carcinoma', 'Phenotype', 'HP:0030731', (247, 256))	('high', 'Reg', (110, 114))	('pancreatic cancer', 'Disease', 'MESH:D010190', (195, 212))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('bladder cancer', 'Disease', 'MESH:D001749', (160, 174))	('bladder cancer', 'Disease', (160, 174))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('hepatocellular carcinoma', 'Disease', (118, 142))	('mutation', 'Var', (42, 50))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('bladder cancer', 'Phenotype', 'HP:0009725', (160, 174))	('pancreatic cancer', 'Disease', (195, 212))	('gastric cancer', 'Phenotype', 'HP:0012126', (144, 158))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (238, 256))	('ARID1A', 'Gene', (64, 70))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('BAF250a', 'Gene', (90, 97))	('colorectal cancer', 'Phenotype', 'HP:0003003', (176, 193))	('cholangiocarcinoma', 'Disease', (238, 256))	("Burkitt's lymphoma", 'Phenotype', 'HP:0030080', (214, 232))	("Burkitt's lymphoma", 'Disease', 'MESH:D002051', (214, 232))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (238, 256))	("Burkitt's lymphoma", 'Disease', (214, 232))	('ARID1A', 'Gene', '8289', (64, 70))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (118, 142))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (195, 212))	('gastric cancer', 'Disease', (144, 158))
153486	33380808	A study reported that prostate cancer cell line (PC3) proliferation and colony formation was dependent on GLTSCR1 expression, and knocking out GLTSCR1 could decreased PC3 cell proliferation and colony formation.	('rat', 'Species', '10116', (183, 186))	('colony formation', 'CPA', (72, 88))	('prostate cancer', 'Disease', (22, 37))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('colony formation', 'CPA', (194, 210))	('PC3', 'CellLine', 'CVCL:0035', (167, 170))	('rat', 'Species', '10116', (61, 64))	('prostate cancer', 'Disease', 'MESH:D011471', (22, 37))	('knocking out', 'Var', (130, 142))	('GLTSCR1', 'Gene', (143, 150))	('PC3', 'CellLine', 'CVCL:0035', (49, 52))	('PC3 cell proliferation', 'CPA', (167, 189))	('prostate cancer', 'Phenotype', 'HP:0012125', (22, 37))	('GLTSCR1', 'Gene', (106, 113))	('decreased', 'NegReg', (157, 166))
153489	33380808	Kang et al confirmed the presence of BRD9 amplification on chromosome 5p in patients with non-small cell lung cancer (NSCLC) through high-resolution array comparative genomic hybridization analysis.	('lung cancer', 'Phenotype', 'HP:0100526', (105, 116))	('patients', 'Species', '9606', (76, 84))	('non-small cell lung cancer', 'Disease', (90, 116))	('NSCLC', 'Phenotype', 'HP:0030358', (118, 123))	('rat', 'Species', '10116', (160, 163))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (94, 116))	('BRD9', 'Gene', (37, 41))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (90, 116))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('NSCLC', 'Disease', (118, 123))	('SCLC', 'Phenotype', 'HP:0030359', (119, 123))	('amplification', 'Var', (42, 55))	('NSCLC', 'Disease', 'MESH:D002289', (118, 123))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (90, 116))
153495	33380808	Wei et al confirmed that BRD9 inhibitors could restore beta-cell function and reduce inflammation to a certain extent.	('beta-cell function', 'CPA', (55, 73))	('reduce', 'NegReg', (78, 84))	('restore', 'PosReg', (47, 54))	('inhibitors', 'Var', (30, 40))	('inflammation', 'Disease', 'MESH:D007249', (85, 97))	('BRD9', 'Gene', (25, 29))	('inflammation', 'Disease', (85, 97))
153499	33380808	Inoue et al suggested that mutant SF3B1 recognized BRD9 introns and induced mis-splicing of BRD9, which ultimately led to the degradation of BRD9, and thus, promoted melanomagenesis.	('melanoma', 'Phenotype', 'HP:0002861', (166, 174))	('melanoma', 'Disease', (166, 174))	('BRD9', 'Gene', (141, 145))	('led to', 'Reg', (115, 121))	('mutant', 'Var', (27, 33))	('melanoma', 'Disease', 'MESH:D008545', (166, 174))	('induced', 'Reg', (68, 75))	('mis-splicing', 'MPA', (76, 88))	('SF3B1', 'Gene', (34, 39))	('promoted', 'PosReg', (157, 165))	('BRD9', 'Gene', (92, 96))	('SF3B1', 'Gene', '23451', (34, 39))	('degradation', 'MPA', (126, 137))	('BRD9', 'Gene', (51, 55))
153505	33380808	BRD9 contains a bromodomain and a DUF3512 domain.	('DUF3512', 'Chemical', '-', (34, 41))	('DUF3512 domain', 'Var', (34, 48))	('bromodomain', 'Gene', '679713', (16, 27))	('BRD9', 'Gene', (0, 4))	('bromodomain', 'Gene', (16, 27))
153513	33380808	The BRPF1 protein is a component of the MOZ/HAT complex, and its bromodomain recognizes H2AK5ac, H4K12ac, H3K14ac, H4K8ac, and H4K5ac.	('H4K5ac', 'Var', (127, 133))	('H4K8ac', 'Var', (115, 121))	('bromodomain', 'Gene', (65, 76))	('H2AK5ac', 'Chemical', '-', (88, 95))	('bromodomain', 'Gene', '679713', (65, 76))	('H2AK5ac', 'Var', (88, 95))	('H4K12ac', 'Var', (97, 104))	('BRPF1', 'Gene', (4, 9))	('H3K14ac', 'Var', (106, 113))
153516	33380808	ATAD2 is mainly located in reproductive tissues, and its bromodomain can recognize H4K5ac, H4K12ac, and H4K5acK12ac; ATAD2B is expressed in neural tissues, and its bromodomain and histone ligand have not been fully studied.	('bromodomain', 'Gene', '679713', (164, 175))	('bromodomain', 'Gene', (164, 175))	('H4K5acK12ac', 'Var', (104, 115))	('H4K5ac', 'Var', (83, 89))	('ATAD2B', 'Gene', (117, 123))	('bromodomain', 'Gene', '679713', (57, 68))	('bromodomain', 'Gene', (57, 68))	('H4K12ac', 'Var', (91, 98))
153517	33380808	BRD7 and BRD9 are the subunits of the PBAF and ncBAF complexes, respectively.	('BRD9', 'Var', (9, 13))	('BAF', 'Gene', '12016', (39, 42))	('BAF', 'Gene', (49, 52))	('cBAF', 'Chemical', '-', (48, 52))	('BAF', 'Gene', '12016', (49, 52))	('BAF', 'Gene', (39, 42))	('BRD7', 'Var', (0, 4))
153521	33380808	Although few biological ligands for the BRD9 bromodomain are known, BRD9 has been demonstrated to bind to diacetylated H4K5acK8ac and dipropionylated H4K5prK8pr.	('H4K5prK8pr', 'Var', (150, 160))	('H4K5acK8ac', 'Protein', (119, 129))	('bromodomain', 'Gene', '679713', (45, 56))	('bromodomain', 'Gene', (45, 56))	('rat', 'Species', '10116', (89, 92))	('H4K5acK8ac', 'Chemical', '-', (119, 129))	('bind', 'Interaction', (98, 102))	('BRD9', 'Gene', (68, 72))
153528	33380808	In leukemia, BRD9 is overexpressed, and induces the activation of the signal transducer and activator of transcription 5 (STAT5) pathway.	('leukemia', 'Phenotype', 'HP:0001909', (3, 11))	('leukemia', 'Disease', 'MESH:D007938', (3, 11))	('BRD9', 'Var', (13, 17))	('leukemia', 'Disease', (3, 11))	('activation', 'PosReg', (52, 62))
153529	33380808	The activation of STAT5 is known to promote the proliferation and survival of AML cells and the occurrence of inflammation.	('STAT5', 'Gene', (18, 23))	('inflammation', 'Disease', (110, 122))	('promote', 'PosReg', (36, 43))	('AML', 'Disease', 'MESH:D015470', (78, 81))	('proliferation', 'CPA', (48, 61))	('activation', 'Var', (4, 14))	('survival', 'CPA', (66, 74))	('AML', 'Phenotype', 'HP:0004808', (78, 81))	('AML', 'Disease', (78, 81))	('rat', 'Species', '10116', (55, 58))	('inflammation', 'Disease', 'MESH:D007249', (110, 122))
153531	33380808	Therefore, knocking down BRD9 to decrease the activation of STAT5 and induce apoptosis through the Caspase8 signaling cascade may be a possible therapeutic strategy.	('knocking down', 'Var', (11, 24))	('decrease', 'NegReg', (33, 41))	('STAT5', 'MPA', (60, 65))	('apoptosis', 'CPA', (77, 86))	('Caspase8', 'Gene', '841', (99, 107))	('Caspase8', 'Gene', (99, 107))	('induce', 'PosReg', (70, 76))	('rat', 'Species', '10116', (158, 161))	('BRD9', 'Gene', (25, 29))	('activation', 'MPA', (46, 56))
153538	33380808	For example, in lung cancer, miR-342-3p and miR-30d-5p are inhibited in lung cancer, whereas miR-29b, hsa-miR-3180, and miR-14,081 are highly expressed.	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('miR-29b', 'Gene', '407024', (93, 100))	('lung cancer', 'Disease', 'MESH:D008175', (16, 27))	('inhibited', 'NegReg', (59, 68))	('miR-342-3p', 'Var', (29, 39))	('miR-30d', 'Gene', (44, 51))	('lung cancer', 'Disease', (72, 83))	('lung cancer', 'Phenotype', 'HP:0100526', (72, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('miR-30d', 'Gene', '407033', (44, 51))	('lung cancer', 'Phenotype', 'HP:0100526', (16, 27))	('miR-29b', 'Gene', (93, 100))	('lung cancer', 'Disease', 'MESH:D008175', (72, 83))	('lung cancer', 'Disease', (16, 27))
153539	33380808	Huang et al demonstrated that miR-140-3p was downregulated in NSCLC cells and tissues, and regulated the process of NSCLC by directly targeting BRD9.	('BRD9', 'Gene', (144, 148))	('NSCLC', 'Disease', 'MESH:D002289', (116, 121))	('SCLC', 'Phenotype', 'HP:0030359', (117, 121))	('targeting', 'Reg', (134, 143))	('NSCLC', 'Disease', (62, 67))	('NSCLC', 'Disease', 'MESH:D002289', (62, 67))	('NSCLC', 'Phenotype', 'HP:0030358', (116, 121))	('rat', 'Species', '10116', (19, 22))	('regulated', 'Reg', (91, 100))	('downregulated', 'NegReg', (45, 58))	('miR-140-3p', 'Var', (30, 40))	('NSCLC', 'Phenotype', 'HP:0030358', (62, 67))	('miR-140-3p', 'Chemical', '-', (30, 40))	('NSCLC', 'Disease', (116, 121))	('process', 'MPA', (105, 112))	('SCLC', 'Phenotype', 'HP:0030359', (63, 67))
153541	33380808	miR-140-3p directly targets BRD9 mRNA, inhibiting its protein translation and consequently downregulating the expression level of C-myc, and suppressing the proliferation of SCLC.	('expression level', 'MPA', (110, 126))	('miR-140-3p', 'Chemical', '-', (0, 10))	('BRD9', 'Gene', (28, 32))	('protein translation', 'MPA', (54, 73))	('C-myc', 'Gene', '4609', (130, 135))	('C-myc', 'Gene', (130, 135))	('downregulating', 'NegReg', (91, 105))	('suppressing', 'NegReg', (141, 152))	('SCLC', 'Disease', (174, 178))	('SCLC', 'Disease', 'MESH:D018288', (174, 178))	('rat', 'Species', '10116', (164, 167))	('SCLC', 'Phenotype', 'HP:0030359', (174, 178))	('miR-140-3p', 'Var', (0, 10))	('inhibiting', 'NegReg', (39, 49))
153552	33380808	For example, small-molecule inhibitors of the BRD9 bromodomain selectively suppress tumor cell proliferation and survival and induce apoptosis.	('survival', 'CPA', (113, 121))	('induce', 'Reg', (126, 132))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('apoptosis', 'CPA', (133, 142))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('BRD9', 'Gene', (46, 50))	('bromodomain', 'Gene', '679713', (51, 62))	('tumor', 'Disease', (84, 89))	('suppress', 'NegReg', (75, 83))	('bromodomain', 'Gene', (51, 62))	('inhibitors', 'Var', (28, 38))	('rat', 'Species', '10116', (102, 105))
153554	33380808	LP99 is the first reported selective BRD7/9 inhibitor that effectively inhibits the binding of BRD7/9 to acetylated histones in vivo and in vitro; Moreover, LP99 inhibits the secretion of proinflammatory cytokine IL-6.	('IL-6', 'Gene', '3569', (213, 217))	('acetylated', 'MPA', (105, 115))	('inhibits', 'NegReg', (162, 170))	('BRD7/9', 'Gene', '29117;65980', (37, 43))	('LP99', 'Var', (157, 161))	('LP99', 'Chemical', '-', (157, 161))	('BRD7/9', 'Gene', '29117;65980', (95, 101))	('IL-6', 'Gene', (213, 217))	('LP99', 'Chemical', '-', (0, 4))	('BRD7/9', 'Gene', (37, 43))	('binding', 'Interaction', (84, 91))	('inhibits', 'NegReg', (71, 79))	('BRD7/9', 'Gene', (95, 101))
153557	33380808	BRD9 inhibitors, BI-7273 and BI-9564, used to investigate the biological functions of BRD9 in vivo and in vitro were proven to be non-toxic by fragment-based screening.	('BI-7273', 'Chemical', '-', (17, 24))	('BRD9', 'Gene', (86, 90))	('BI-7273', 'Var', (17, 24))	('BI-9564', 'Var', (29, 36))	('BI-9564', 'Chemical', 'MESH:C000619421', (29, 36))
153559	33380808	Studies on the selection mechanism of I-BRD9 for the BRD9 bromodomain have demonstrated that several residues in the ZA and ZB loops of the bromodomain, such as Asp144, Ile53, Lys91, Thr104, Pro82, Asn140, Asn100, and Phe44, can be used as important references for designing BRD9 inhibitors.	('bromodomain', 'Gene', (140, 151))	('bromodomain', 'Gene', '679713', (140, 151))	('Asn100', 'Var', (206, 212))	('Ile53', 'Var', (169, 174))	('Asp144', 'Var', (161, 167))	('Phe44', 'Var', (218, 223))	('Asn100', 'Chemical', '-', (206, 212))	('bromodomain', 'Gene', '679713', (58, 69))	('bromodomain', 'Gene', (58, 69))	('Pro82', 'Var', (191, 196))	('Asp144', 'Chemical', '-', (161, 167))	('Asn140', 'Chemical', '-', (198, 204))	('Thr104', 'Chemical', '-', (183, 189))	('Lys91', 'Chemical', '-', (176, 181))	('Asn140', 'Var', (198, 204))	('Ile53', 'Chemical', '-', (169, 174))	('Thr104', 'Var', (183, 189))	('Phe44', 'Chemical', '-', (218, 223))	('rat', 'Species', '10116', (82, 85))	('Pro82', 'Chemical', '-', (191, 196))	('Lys91', 'Var', (176, 181))
153567	33380808	Repeated mutations in the subunits of the SWI/SNF complex in cancer make it a promising therapeutic target.	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('SWI/SNF', 'Gene', (42, 49))	('mutations', 'Var', (9, 18))	('cancer', 'Disease', (61, 67))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))
153575	33380808	It consists of a bromodomain and a DUF3512 domain.	('DUF3512', 'Chemical', '-', (35, 42))	('DUF3512', 'Var', (35, 42))	('bromodomain', 'Gene', (17, 28))	('bromodomain', 'Gene', '679713', (17, 28))
153576	33380808	The deletion of the DUF3512 domain affects the assembly of the ncBAF complex.	('DUF3512', 'Chemical', '-', (20, 27))	('assembly', 'MPA', (47, 55))	('DUF3512', 'Gene', (20, 27))	('affects', 'Reg', (35, 42))	('deletion', 'Var', (4, 12))	('cBAF', 'Chemical', '-', (64, 68))
153598	32399208	Gene mutations may also cause cancer development in the pharynx and oral cavity; however, no specific gene has been identified in OSCCs .	('cancer', 'Disease', (30, 36))	('cause', 'Reg', (24, 29))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('mutations', 'Var', (5, 14))	('men', 'Species', '9606', (44, 47))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
153615	32399208	Positive regional lymph node involvement, extracapsular invasion of tumor cells, and human papilloma virus negativity are key factors that increase the risk of primary tumor cell dissemination to distant organs .	('tumor', 'Disease', (68, 73))	('tumor', 'Disease', (168, 173))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('human papilloma virus', 'Species', '10566', (85, 106))	('papilloma', 'Phenotype', 'HP:0012740', (91, 100))	('men', 'Species', '9606', (36, 39))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('negativity', 'Var', (107, 117))	('human', 'Gene', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
153724	30005633	To show the genes' relatedness to cancer, we confirmed that all select genes have at least one pathogenic mutation (Additional file 1: Figure S2A), and they undergo fusion (F), mutation (M), overexpression (O) or underexpression (U) in different diseases (Additional file 1: Figure S2B), according to COSMIC v80.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('mutation', 'Var', (177, 185))	('overexpression', 'PosReg', (191, 205))	('undergo', 'Reg', (157, 164))	('fusion', 'MPA', (165, 171))	('mutation', 'Var', (106, 114))	('underexpression', 'MPA', (213, 228))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('cancer', 'Disease', (34, 40))
153754	30005633	Since it is a negative-strand gene, an increment in the index indicates a decrease in 3' UTR length, for CSs that share the same stop codon (R1, R2, and R3).	('R1', 'Var', (141, 143))	("3' UTR length", 'CPA', (86, 99))	('decrease', 'NegReg', (74, 82))	('CSs', 'Chemical', '-', (105, 108))
153767	30005633	Ignoring CSs that were mapped either to a separate stop codon (P5, P6, and P7), or to multiple stop codons (P2), we are left with three CSs.	('P5', 'Var', (63, 65))	('CSs', 'Chemical', '-', (9, 12))	('CSs', 'Chemical', '-', (136, 139))	('P7', 'Var', (75, 77))
153770	30005633	The current paradigm of APA characterization revolves around analyzing two CSs at a time, namely proximal and distal CSs, and emphasizes 3' UTR length change, namely shortening or lengthening.	('shortening', 'Var', (166, 176))	('CSs', 'Chemical', '-', (117, 120))	('CSs', 'Chemical', '-', (75, 78))	('lengthening', 'Var', (180, 191))
153822	30005633	One of the two strongest PAS hexamers AATAAA and ATTAAA were required to be within a 50 bp window, and at least one of the following conditions of polyadenylation evidence was satisfied: length_of_tail_in_contig >=4, number_of_bridge_reads >=2, or max_bridge_read_tail_length >= 4.	('length_of_tail_in_contig', 'Var', (187, 211))	('number_of_bridge_reads >=2', 'Var', (217, 243))	('max_bridge_read_tail_length', 'Var', (248, 275))	('PAS', 'Chemical', '-', (25, 28))
153871	27472392	A large body of evidence points to MET as a key oncogenic driver of several human cancers, including small cell (SCLC) and non-small cell lung cancers (NSCLC).	('non-small cell lung cancers', 'Disease', 'MESH:D002289', (123, 150))	('MET', 'Var', (35, 38))	('SCLC', 'Disease', 'MESH:D018288', (153, 157))	('cancers', 'Phenotype', 'HP:0002664', (82, 89))	('cancers', 'Disease', (82, 89))	('lung cancer', 'Phenotype', 'HP:0100526', (138, 149))	('lung cancers', 'Phenotype', 'HP:0100526', (138, 150))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('SCLC', 'Disease', (113, 117))	('cancers', 'Phenotype', 'HP:0002664', (143, 150))	('non-small cell lung cancers', 'Disease', (123, 150))	('cancers', 'Disease', (143, 150))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('non-small cell lung cancers', 'Phenotype', 'HP:0030358', (123, 150))	('SCLC', 'Disease', (153, 157))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (123, 149))	('small cell', 'Disease', (101, 111))	('cancers', 'Disease', 'MESH:D009369', (82, 89))	('NSCLC', 'Disease', 'MESH:D002289', (152, 157))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (127, 149))	('SCLC', 'Disease', 'MESH:D018288', (113, 117))	('small cell lung cancers', 'Phenotype', 'HP:0030357', (127, 150))	('NSCLC', 'Disease', (152, 157))	('human', 'Species', '9606', (76, 81))	('cancers', 'Disease', 'MESH:D009369', (143, 150))
153875	27472392	Recent molecular characterization of patient samples demonstrates that NSCLC arises from alteration of a relatively small subset of genes, including MET copy number (CN) gain and exon 14 skipping, which together account for ~6.5% and 3.6% of driver mutations in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) cases, respectively.	('lung adenocarcinoma', 'Disease', (262, 281))	('patient', 'Species', '9606', (37, 44))	('skipping', 'Var', (187, 195))	('mutations', 'Var', (249, 258))	('carcinoma', 'Phenotype', 'HP:0030731', (272, 281))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (262, 281))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (293, 321))	('carcinoma', 'Phenotype', 'HP:0030731', (312, 321))	('gain', 'PosReg', (170, 174))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (262, 281))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (293, 321))	('NSCLC', 'Disease', (71, 76))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (298, 321))	('lung squamous cell carcinoma', 'Disease', (293, 321))	('NSCLC', 'Disease', 'MESH:D002289', (71, 76))
153877	27472392	Given the prevalence of MET aberrations across multiple cancer types, it is not surprising that MET has been a target of significant clinical interest and drug discovery efforts for several years.	('MET aberrations', 'Var', (24, 39))	('aberrations', 'Var', (28, 39))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('clinical', 'Species', '191496', (133, 141))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))
153884	27472392	The MET-binding antibodies ABT-700, LY2875358 and onartuzumab (MetMab) are in Phase I, I/II and I/II/III trials, respectively.	('MET-binding', 'Protein', (4, 15))	('onartuzumab', 'Gene', (50, 61))	('MetMab', 'Chemical', 'MESH:C584058', (63, 69))	('LY2875358', 'Chemical', 'MESH:C000599789', (36, 45))	('LY2875358', 'Var', (36, 45))	('ABT-700', 'Gene', (27, 34))	('ABT', 'Chemical', 'MESH:C002502', (27, 30))	('onartuzumab', 'Chemical', 'MESH:C584058', (50, 61))
153887	27472392	Several small-molecule MET inhibitors, including savolitinib, INC280, AMG337, LY2801653, SAR125844, MSC2156119J (EMD 1214063), JNJ-38877605 and PHA-665752 have progressed through Phase I and II trials in multiple cancer types; however, JNJ-38877605 trials were terminated due to renal toxicity/lack of a pharmacodynamic response, and development of PHA-665752 was stopped for undisclosed reasons.	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('renal toxicity', 'Disease', (279, 293))	('MSC2156119J', 'Var', (100, 111))	('savolitinib', 'Chemical', 'MESH:C000593259', (49, 60))	('LY2801653', 'Var', (78, 87))	('LY2801653', 'Chemical', 'MESH:C586252', (78, 87))	('cancer', 'Disease', 'MESH:D009369', (213, 219))	('renal toxicity', 'Disease', 'MESH:D007674', (279, 293))	('cancer', 'Disease', (213, 219))
153895	27472392	Lastly, we uncover a novel role for PIM kinases in acquired savolitinib resistance and show that PIM inhibition restores savolitinib sensitivity both in vitro and in vivo.	('inhibition', 'Var', (101, 111))	('savolitinib', 'Chemical', 'MESH:C000593259', (121, 132))	('restores', 'PosReg', (112, 120))	('savolitinib resistance', 'MPA', (60, 82))	('PIM', 'Gene', (97, 100))	('PIM', 'Gene', '5292', (36, 39))	('savolitinib', 'Chemical', 'MESH:C000593259', (60, 71))	('savolitinib sensitivity', 'MPA', (121, 144))	('PIM', 'Gene', '5292', (97, 100))	('PIM', 'Gene', (36, 39))
153915	27472392	Savolitinib treatment led to marked decreases in tumor growth relative to vehicle controls in both models over the full dose ranges tested (Figure 2A, 2B), with savolitinib achieving a maximal response at doses as low as 0.3 mg/kg and 2.5 mg/kg in H1993 and EBC-1 tumors, respectively.	('EBC-1 tumors', 'Disease', (258, 270))	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('savolitinib', 'Chemical', 'MESH:C000593259', (161, 172))	('H1993', 'CellLine', 'CVCL:1512', (248, 253))	('Savolitinib', 'Chemical', 'MESH:C000593259', (0, 11))	('tumor', 'Phenotype', 'HP:0002664', (264, 269))	('EBC-1 tumors', 'Disease', 'MESH:D009369', (258, 270))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor', 'Disease', (264, 269))	('tumor', 'Disease', (49, 54))	('H1993', 'Var', (248, 253))	('tumors', 'Phenotype', 'HP:0002664', (264, 270))	('tumor', 'Disease', 'MESH:D009369', (264, 269))	('decreases', 'NegReg', (36, 45))
153924	27472392	Lastly, we tested savolitinib in vivo activity in HLXF-036LN, a patient-derived xenograft (PDX) derived from a NSCLC lymph-node metastasis.	('patient', 'Species', '9606', (64, 71))	('NSCLC', 'Disease', (111, 116))	('savolitinib', 'Chemical', 'MESH:C000593259', (18, 29))	('NSCLC', 'Disease', 'MESH:D002289', (111, 116))	('tested', 'Reg', (11, 17))	('HLXF-036LN', 'Var', (50, 60))
153932	27472392	Surprisingly, phospho-MET inhibition by savolitinib was indistinguishable between parental cells and clones (Figure 3A), suggesting the absence of activating MET mutations or MET CN gains, which we confirmed by exome sequencing (Supplementary Figure S3B, C and NCBI Sequence Read Archive SubmissionID SUB1084746).	('savolitinib', 'Chemical', 'MESH:C000593259', (40, 51))	('MET mutations', 'Var', (158, 171))	('MET', 'MPA', (175, 178))	('mutations', 'Var', (162, 171))
153940	27472392	To determine whether deregulated MYC expression functionally promotes savolitinib resistance, we first used siRNA to knock down MYC in parental and resistant H1993 cells and treated with vehicle or 100 nM savolitinib for three days followed by cell viability measurements.	('knock down', 'Var', (117, 127))	('H1993', 'CellLine', 'CVCL:1512', (158, 163))	('MYC', 'Gene', (128, 131))	('MYC', 'Gene', '4609', (33, 36))	('promotes', 'PosReg', (61, 69))	('savolitinib', 'Chemical', 'MESH:C000593259', (70, 81))	('deregulated', 'Var', (21, 32))	('savolitinib', 'Chemical', 'MESH:C000593259', (205, 216))	('savolitinib', 'MPA', (70, 81))	('MYC', 'Gene', (33, 36))	('MYC', 'Gene', '4609', (128, 131))
153948	27472392	Attenuation of MYC expression strongly inhibited resistant EBC-1 cell viability proportional to the degree of MYC knockdown (Supplementary Figure S4C, D), suggesting that MYC is also required for savolitinib resistance in a LUSC model.	('resistant EBC-1 cell viability', 'CPA', (49, 79))	('inhibited', 'NegReg', (39, 48))	('MYC', 'Gene', '4609', (15, 18))	('Attenuation', 'NegReg', (0, 11))	('knockdown', 'Var', (114, 123))	('MYC', 'Gene', (110, 113))	('MYC', 'Gene', (15, 18))	('MYC', 'Gene', '4609', (171, 174))	('savolitinib', 'Chemical', 'MESH:C000593259', (196, 207))	('MYC', 'Gene', '4609', (110, 113))	('MYC', 'Gene', (171, 174))
153963	27472392	Together, these data demonstrate that a switch to EGFR signaling maintains MYC levels and confers savolitinib resistance in a clone-specific manner.	('MYC', 'Gene', '4609', (75, 78))	('EGFR', 'Gene', '1956', (50, 54))	('savolitinib resistance', 'MPA', (98, 120))	('MYC', 'Gene', (75, 78))	('switch', 'Var', (40, 46))	('EGFR', 'Gene', (50, 54))	('savolitinib', 'Chemical', 'MESH:C000593259', (98, 109))	('maintains', 'PosReg', (65, 74))
153970	27472392	However, three dual mTORC1/2 inhibitors : AZD2014, AZD8055 and the less-selective, dual mTOR/PI3K inhibitor PF-04691502 : reduced the viability of all four cell lines (Figure 6A).	('mTORC1/2', 'Gene', '74343;382056', (20, 28))	('AZD2014', 'Var', (42, 49))	('AZD2014', 'Chemical', 'MESH:C585537', (42, 49))	('AZD8055', 'Var', (51, 58))	('AZD8055', 'Chemical', 'MESH:C546624', (51, 58))	('mTOR', 'Gene', (88, 92))	('mTORC1/2', 'Gene', (20, 28))	('mTOR', 'Gene', '2475', (88, 92))	('PF-04691502', 'Chemical', 'MESH:C570662', (108, 119))	('mTOR', 'Gene', '2475', (20, 24))	('reduced', 'NegReg', (122, 129))	('viability', 'CPA', (134, 143))	('mTOR', 'Gene', (20, 24))
153971	27472392	Screen results were confirmed by treating resistant clones with a nine-point dose response curve of AZD2014, AZD8055 or PF-04691502, ranging from ~11.1 muM to ~1.7nM, in the presence or absence of 100 nM savolitinib, followed by viability measurements.	('PF-04691502', 'Chemical', 'MESH:C570662', (120, 131))	('AZD8055', 'Chemical', 'MESH:C546624', (109, 116))	('AZD2014', 'Chemical', 'MESH:C585537', (100, 107))	('AZD2014', 'Gene', (100, 107))	('savolitinib', 'Chemical', 'MESH:C000593259', (204, 215))	('muM', 'Gene', '56925', (152, 155))	('PF-04691502', 'Var', (120, 131))	('muM', 'Gene', (152, 155))	('AZD8055', 'Var', (109, 116))
153975	27472392	Combination of mTORC1/2 inhibitors with savolitinib further reduced viability of clone 3 and clone 6.	('viability', 'CPA', (68, 77))	('savolitinib', 'Chemical', 'MESH:C000593259', (40, 51))	('inhibitors', 'Var', (24, 34))	('mTORC1/2', 'Gene', '74343;382056', (15, 23))	('reduced', 'NegReg', (60, 67))	('mTORC1/2', 'Gene', (15, 23))
153977	27472392	Furthermore, combination of savolitinib (100 nM) with either AZD8055, AZD2014 or PF-04691502 resulted in synergistic induction of growth arrest or cell death at mTORC1/2 inhibitor concentrations above ~400 nM (Supplementary Figure S6A-D).	('AZD8055', 'Var', (61, 68))	('AZD8055', 'Chemical', 'MESH:C546624', (61, 68))	('AZD2014', 'Var', (70, 77))	('AZD2014', 'Chemical', 'MESH:C585537', (70, 77))	('savolitinib', 'Chemical', 'MESH:C000593259', (28, 39))	('growth arrest', 'Disease', 'MESH:D006323', (130, 143))	('growth arrest', 'Disease', (130, 143))	('mTORC1/2', 'Gene', (161, 169))	('combination', 'Interaction', (13, 24))	('induction', 'Reg', (117, 126))	('growth arrest', 'Phenotype', 'HP:0001510', (130, 143))	('cell death', 'CPA', (147, 157))	('PF-04691502', 'Var', (81, 92))	('100', 'Var', (41, 44))	('mTORC1/2', 'Gene', '74343;382056', (161, 169))	('PF-04691502', 'Chemical', 'MESH:C570662', (81, 92))
153989	27472392	Resistant clones were treated with a nine-point dose response curve of AZD5363 (AKT inhibitor) or SCH772984 (ERK inhibitor) for five days in the presence or absence of 100 nM savolitinib and assessed for viability.	('savolitinib', 'Chemical', 'MESH:C000593259', (175, 186))	('AKT', 'Gene', '207', (80, 83))	('SCH772984', 'Chemical', 'MESH:C587178', (98, 107))	('ERK', 'Gene', '5594', (109, 112))	('AZD5363', 'Chemical', 'MESH:C575618', (71, 78))	('AZD5363', 'Var', (71, 78))	('AKT', 'Gene', (80, 83))	('ERK', 'Gene', (109, 112))	('SCH772984', 'Var', (98, 107))
153994	27472392	Savolitinib-resistant cells were treated with two unique pan-PIM inhibitors : a picolinamide pan-PIM inhibitor related to LGB-321 : and AZD1208 over the standard nine-point dose response range in the presence or absence of 100 nM savolitinib.	('PIM', 'Gene', '5292', (61, 64))	('Savolitinib', 'Chemical', 'MESH:C000593259', (0, 11))	('savolitinib', 'Chemical', 'MESH:C000593259', (230, 241))	('AZD1208', 'Chemical', 'MESH:C587575', (136, 143))	('PIM', 'Gene', (61, 64))	('PIM', 'Gene', (97, 100))	('PIM', 'Gene', '5292', (97, 100))	('AZD1208', 'Var', (136, 143))	('picolinamide', 'Chemical', 'MESH:C003142', (80, 92))
153997	27472392	Furthermore, PIM inhibition reversed savolitinib-induced pEGFR and MYC upregulation and downregulated total and phospho-S6 levels in clone 11 (Figure 7C).	('PIM', 'Gene', '5292', (13, 16))	('EGFR', 'Gene', '1956', (58, 62))	('MYC', 'Gene', '4609', (67, 70))	('PIM', 'Gene', (13, 16))	('EGFR', 'Gene', (58, 62))	('inhibition', 'Var', (17, 27))	('MYC', 'Gene', (67, 70))	('upregulation', 'PosReg', (71, 83))	('savolitinib', 'Chemical', 'MESH:C000593259', (37, 48))	('downregulated', 'NegReg', (88, 101))
154003	27472392	Indeed, H1993 clone 11 tumors are insensitive to savolitinib over a 100-fold range of doses, including the clinically-relevant dose of 30 mg/kg (Supplementary Figure S9A).	('tumors', 'Disease', 'MESH:D009369', (23, 29))	('tumors', 'Disease', (23, 29))	('clinical', 'Species', '191496', (107, 115))	('savolitinib', 'Chemical', 'MESH:C000593259', (49, 60))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('H1993', 'CellLine', 'CVCL:1512', (8, 13))	('H1993', 'Var', (8, 13))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))
154007	27472392	We also quantified levels of phospho-EGFR (pY1068; pEGFR), phospho-ribosomal protein S6 (pS235/236; pS6) and MYC proteins.	('pS6', 'Gene', (100, 103))	('EGFR', 'Gene', '1956', (52, 56))	('ribosomal protein S6', 'Gene', (67, 87))	('EGFR', 'Gene', (52, 56))	('MYC', 'Gene', '4609', (109, 112))	('ribosomal protein S6', 'Gene', '6194', (67, 87))	('EGFR', 'Gene', '1956', (37, 41))	('pS6', 'Gene', '338413', (100, 103))	('pY1068;', 'Var', (43, 50))	('EGFR', 'Gene', (37, 41))	('MYC', 'Gene', (109, 112))
154015	27472392	Taken together, these results demonstrate that H1993 clone 11 tumors maintain savolitinib resistance in vivo, and that patterns of signaling and savolitinib-induced pharmacodynamic changes observed in vitro are also observed in vivo.	('H1993', 'Var', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('savolitinib', 'Chemical', 'MESH:C000593259', (145, 156))	('tumors', 'Disease', (62, 68))	('tumors', 'Disease', 'MESH:D009369', (62, 68))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('savolitinib resistance', 'MPA', (78, 100))	('savolitinib', 'Chemical', 'MESH:C000593259', (78, 89))	('H1993', 'CellLine', 'CVCL:1512', (47, 52))
154016	27472392	Having established that the H1993 clone 11 model retains its core characteristics in vivo, we next tested whether our in vitro findings could be extended in vivo by testing the effects of AZD1208 and AZD2014 treatment, alone or in combination with savolitinib, on the growth of H1993 clone 11 tumors.	('H1993', 'CellLine', 'CVCL:1512', (28, 33))	('tumors', 'Phenotype', 'HP:0002664', (293, 299))	('savolitinib', 'Chemical', 'MESH:C000593259', (248, 259))	('H1993', 'CellLine', 'CVCL:1512', (278, 283))	('tumor', 'Phenotype', 'HP:0002664', (293, 298))	('tested', 'Reg', (99, 105))	('AZD1208', 'Chemical', 'MESH:C587575', (188, 195))	('AZD2014', 'Var', (200, 207))	('tumors', 'Disease', 'MESH:D009369', (293, 299))	('AZD2014', 'Chemical', 'MESH:C585537', (200, 207))	('tumors', 'Disease', (293, 299))	('H1993', 'Gene', (278, 283))	('testing', 'Reg', (165, 172))
154018	27472392	Treatment began the following day with each drug : AZD1208 (30 mg/kg, BID), AZD2014 (20 mg/kg, BID, 2on/5off) and savolitinib (30 mg/kg, QD) : given alone or in combination with savolitinib.	('savolitinib', 'Chemical', 'MESH:C000593259', (178, 189))	('BID', 'Gene', '637', (95, 98))	('AZD1208', 'Var', (51, 58))	('BID', 'Gene', (70, 73))	('savolitinib', 'Chemical', 'MESH:C000593259', (114, 125))	('AZD2014', 'Chemical', 'MESH:C585537', (76, 83))	('BID', 'Gene', (95, 98))	('AZD1208', 'Chemical', 'MESH:C587575', (51, 58))	('BID', 'Gene', '637', (70, 73))
154020	27472392	However, combination of savolitinib and AZD1208 resulted in a TGI of 51% +- 8.7% s.e.m.	('AZD1208', 'Chemical', 'MESH:C587575', (40, 47))	('AZD1208', 'Var', (40, 47))	('combination', 'Interaction', (9, 20))	('savolitinib', 'Chemical', 'MESH:C000593259', (24, 35))
154026	27472392	In contrast, in vivo we found that AZD2014 alone reduced H1993 clone 11 tumor growth by ~41% +- 8.9% s.e.m.	('AZD2014', 'Var', (35, 42))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('AZD2014', 'Chemical', 'MESH:C585537', (35, 42))	('reduced', 'NegReg', (49, 56))	('tumor', 'Disease', (72, 77))	('H1993', 'CellLine', 'CVCL:1512', (57, 62))	('tumor', 'Disease', 'MESH:D009369', (72, 77))
154028	27472392	Combination of AZD2014 with savolitinib generated a small supra-additive effect, increasing the TGI to ~59% +- 6.6% s.e.m.	('increasing', 'PosReg', (81, 91))	('savolitinib', 'Chemical', 'MESH:C000593259', (28, 39))	('AZD2014', 'Var', (15, 22))	('AZD2014', 'Chemical', 'MESH:C585537', (15, 22))	('TGI', 'MPA', (96, 99))
154039	27472392	It is tempting to speculate that aberrant HER2 activity acts as a bypass mechanism to render OE33 cells innately resistant to savolitinib.	('HER2', 'Gene', '2064', (42, 46))	('savolitinib', 'Chemical', 'MESH:C000593259', (126, 137))	('resistant', 'MPA', (113, 122))	('activity', 'MPA', (47, 55))	('aberrant', 'Var', (33, 41))	('HER2', 'Gene', (42, 46))
154046	27472392	TKI resistance can arise through aberrant activation of the PI3K/AKT/mTOR axis in several cancer types, including NSCLC, often through PTEN deletion or activating PIK3CA mutations; however, such mechanisms were elucidated primarily in the context of EGFR inhibitors.	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('PTEN', 'Gene', '5728', (135, 139))	('PIK3CA', 'Gene', (163, 169))	('activation', 'PosReg', (42, 52))	('AKT', 'Gene', '207', (65, 68))	('activating', 'PosReg', (152, 162))	('EGFR', 'Gene', (250, 254))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('deletion', 'Var', (140, 148))	('EGFR', 'Gene', '1956', (250, 254))	('NSCLC', 'Disease', 'MESH:D002289', (114, 119))	('PIK3CA', 'Gene', '5290', (163, 169))	('mTOR', 'Gene', (69, 73))	('AKT', 'Gene', (65, 68))	('PTEN', 'Gene', (135, 139))	('mutations', 'Var', (170, 179))	('NSCLC', 'Disease', (114, 119))	('cancer', 'Disease', (90, 96))	('mTOR', 'Gene', '2475', (69, 73))
154047	27472392	Here, we demonstrate that deregulated PI3K/AKT/mTOR activity also confers MET inhibitor resistance in NSCLC, but without PTEN loss or PIK3CA mutation, suggesting that an uncommon or novel mTOR activation mechanism may underlie savolitinib resistance.	('PTEN loss', 'Disease', 'MESH:D006223', (121, 130))	('deregulated', 'Var', (26, 37))	('MET inhibitor resistance', 'MPA', (74, 98))	('PIK3CA', 'Gene', (134, 140))	('NSCLC', 'Disease', 'MESH:D002289', (102, 107))	('savolitinib', 'Chemical', 'MESH:C000593259', (227, 238))	('activity', 'MPA', (52, 60))	('AKT', 'Gene', '207', (43, 46))	('PTEN loss', 'Disease', (121, 130))	('PIK3CA', 'Gene', '5290', (134, 140))	('mTOR', 'Gene', '2475', (47, 51))	('mTOR', 'Gene', (188, 192))	('AKT', 'Gene', (43, 46))	('mTOR', 'Gene', (47, 51))	('mTOR', 'Gene', '2475', (188, 192))	('NSCLC', 'Disease', (102, 107))
154048	27472392	Additionally, we observe MYC upregulation in all resistant H1993 clones and in a resistant EBC-1 population, suggesting that MYC may be a critical node upon which more diverse mechanisms converge.	('MYC', 'Gene', (25, 28))	('MYC', 'Gene', '4609', (125, 128))	('H1993', 'CellLine', 'CVCL:1512', (59, 64))	('H1993', 'Var', (59, 64))	('MYC', 'Gene', (125, 128))	('upregulation', 'PosReg', (29, 41))	('MYC', 'Gene', '4609', (25, 28))
154056	27472392	Indeed, we observe a clone-specific reversible switch to EGFR dependence demonstrated by synthetic lethality of combined MET/EGFR inhibition; furthermore, our data suggest that EGFR and/or HER2 signal to MET in resistant, but not parental, H1993 cells while MET appears to partially activate EGFR in a clone-specific manner.	('EGFR', 'Gene', '1956', (292, 296))	('H1993', 'CellLine', 'CVCL:1512', (240, 245))	('EGFR', 'Gene', '1956', (125, 129))	('EGFR', 'Gene', (292, 296))	('EGFR', 'Gene', (125, 129))	('EGFR', 'Gene', '1956', (57, 61))	('EGFR', 'Gene', '1956', (177, 181))	('MET', 'Var', (204, 207))	('HER2', 'Gene', (189, 193))	('EGFR', 'Gene', (57, 61))	('EGFR', 'Gene', (177, 181))	('HER2', 'Gene', '2064', (189, 193))
154062	27472392	This demonstrates that inhibition of PIM concurrent with MET inhibition resensitizes savolitinib-resistant tumors in vivo as well.	('PIM', 'Gene', (37, 40))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('inhibition', 'Var', (23, 33))	('tumors', 'Disease', (107, 113))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('tumors', 'Disease', 'MESH:D009369', (107, 113))	('savolitinib', 'Chemical', 'MESH:C000593259', (85, 96))	('PIM', 'Gene', '5292', (37, 40))
154064	27472392	In support of this notion, Siu and colleagues previously demonstrated in prostate cancer models that PIM-1 inhibition upregulates MIG6, a negative regulator of EGFR signaling, thereby inhibiting EGFR/MAPK activation.	('prostate cancer', 'Disease', (73, 88))	('MIG6', 'Gene', (130, 134))	('upregulates', 'PosReg', (118, 129))	('inhibition', 'Var', (107, 117))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('EGFR', 'Gene', (195, 199))	('MIG6', 'Gene', '54206', (130, 134))	('EGFR', 'Gene', '1956', (160, 164))	('prostate cancer', 'Disease', 'MESH:D011471', (73, 88))	('prostate cancer', 'Phenotype', 'HP:0012125', (73, 88))	('PIM-1', 'Gene', (101, 106))	('EGFR', 'Gene', (160, 164))	('inhibiting', 'NegReg', (184, 194))	('activation', 'MPA', (205, 215))	('PIM-1', 'Gene', '5292', (101, 106))	('EGFR', 'Gene', '1956', (195, 199))
154082	27472392	Ambion Silencer Select siRNAs (human MYC: s9130 and s9129; non-targeting control #4390843) were reverse-transfected at 5 nM final concentration with Lipofectamine RNAimax (Life Technologies).	('Lipofectamine', 'Chemical', 'MESH:C086724', (149, 162))	('MYC', 'Gene', '4609', (37, 40))	('human', 'Species', '9606', (31, 36))	('s9129', 'Var', (52, 57))	('MYC', 'Gene', (37, 40))
154083	27472392	MYC transcript levels were measured 72 hours later by qRT-PCR (normalized to GAPDH) - Taqman probes: GAPDH #1404051, MYC Hs00153408_m1 (Life Technologies).	('MYC', 'Gene', (0, 3))	('Hs00153408_m1', 'Var', (121, 134))	('GAPDH', 'Gene', '2597', (101, 106))	('MYC', 'Gene', (117, 120))	('GAPDH', 'Gene', (101, 106))	('GAPDH', 'Gene', '2597', (77, 82))	('MYC', 'Gene', '4609', (0, 3))	('MYC', 'Gene', '4609', (117, 120))	('GAPDH', 'Gene', (77, 82))
154094	27174913	DLC1 expression was higher in TCGA LAD patients who remained cancer-free, while low DLC1 had a poorer prognosis than low DLC2 or low DLC3 in a more completely annotated database.	('expression', 'MPA', (5, 15))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('patients', 'Species', '9606', (39, 47))	('low DLC', 'Phenotype', 'HP:0045051', (80, 87))	('low DLC', 'Phenotype', 'HP:0045051', (117, 124))	('LAD', 'Disease', (35, 38))	('TCGA', 'Disease', (30, 34))	('higher', 'PosReg', (20, 26))	('DLC2', 'Gene', '90627', (121, 125))	('DLC2', 'Gene', (121, 125))	('DLC1', 'Gene', '10395', (0, 4))	('cancer', 'Disease', (61, 67))	('low DLC', 'Phenotype', 'HP:0045051', (129, 136))	('DLC1', 'Gene', (0, 4))	('LAD', 'Disease', 'MESH:C535887', (35, 38))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('DLC3', 'Gene', (133, 137))	('DLC3', 'Gene', '9754', (133, 137))	('low', 'Var', (80, 83))	('DLC1', 'Gene', '10395', (84, 88))	('LAD', 'Phenotype', 'HP:0030078', (35, 38))	('DLC1', 'Gene', (84, 88))
154099	27174913	Although the RAS GTPases are frequently activated by mutation in tumors, such changes are less common among the RHO family GTPases.	('GTP', 'Chemical', 'MESH:D006160', (17, 20))	('mutation', 'Var', (53, 61))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('activated', 'PosReg', (40, 49))	('tumors', 'Disease', (65, 71))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('RAS GTPases', 'Enzyme', (13, 24))	('GTP', 'Chemical', 'MESH:D006160', (123, 126))
154108	27174913	Overexpression of DLC1 inhibits several biological parameters of neoplastic growth, and inactivation of endogenous DLC1 can, in conjunction with other genetic and/or epigenetic changes, lead to cell transformation and tumor formation.	('lead to', 'Reg', (186, 193))	('biological parameters of neoplastic growth', 'CPA', (40, 82))	('DLC1', 'Gene', '10395', (18, 22))	('tumor', 'Disease', 'MESH:D009369', (218, 223))	('DLC1', 'Gene', '10395', (115, 119))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('DLC1', 'Gene', (18, 22))	('cell transformation', 'CPA', (194, 213))	('DLC1', 'Gene', (115, 119))	('tumor', 'Disease', (218, 223))	('inhibits', 'NegReg', (23, 31))	('inactivation', 'Var', (88, 100))
154137	27174913	We have previously used this dataset to determine that low DLC1 expression is associated with a poor prognosis.	('low DLC', 'Phenotype', 'HP:0045051', (55, 62))	('expression', 'MPA', (64, 74))	('DLC1', 'Gene', (59, 63))	('low', 'Var', (55, 58))	('DLC1', 'Gene', '10395', (59, 63))
154140	27174913	The combination of low DLC1 and low DLC2 (Figure 3G) or low DLC1 and low DLC3 (Figure 3H) was not a better predictor of outcome than that of low DLC1 by itself (P = 8E-06 for DLC1/DLC2 and P = 7E-05 for DLC1/DLC3).	('DLC1', 'Gene', (60, 64))	('DLC1', 'Gene', '10395', (203, 207))	('low DLC', 'Phenotype', 'HP:0045051', (56, 63))	('low', 'NegReg', (19, 22))	('DLC1', 'Gene', (203, 207))	('low', 'NegReg', (32, 35))	('DLC3', 'Gene', (73, 77))	('low DLC', 'Phenotype', 'HP:0045051', (69, 76))	('DLC3', 'Gene', '9754', (73, 77))	('DLC3', 'Gene', (208, 212))	('DLC1', 'Gene', '10395', (145, 149))	('DLC3', 'Gene', '9754', (208, 212))	('DLC1', 'Gene', (145, 149))	('DLC1', 'Gene', '10395', (175, 179))	('DLC1', 'Gene', (175, 179))	('low DLC', 'Phenotype', 'HP:0045051', (19, 26))	('DLC1', 'Gene', '10395', (23, 27))	('low', 'Var', (56, 59))	('DLC1', 'Gene', (23, 27))	('low DLC', 'Phenotype', 'HP:0045051', (32, 39))	('DLC2', 'Gene', '90627', (180, 184))	('DLC2', 'Gene', '90627', (36, 40))	('DLC2', 'Gene', (180, 184))	('DLC1', 'Gene', '10395', (60, 64))	('low DLC', 'Phenotype', 'HP:0045051', (141, 148))	('DLC2', 'Gene', (36, 40))
154142	27174913	In addition to deletion of DLC1, reduced expression of DLC1 in cancer has also been linked to promoter hypermethylation.	('DLC1', 'Gene', '10395', (27, 31))	('deletion', 'Var', (15, 23))	('expression', 'MPA', (41, 51))	('DLC1', 'Gene', '10395', (55, 59))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('DLC1', 'Gene', (27, 31))	('reduced', 'NegReg', (33, 40))	('DLC1', 'Gene', (55, 59))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('promoter hypermethylation', 'MPA', (94, 119))	('cancer', 'Disease', (63, 69))
154143	27174913	In the TCGA HCC dataset, close to one-half (48%) of the tumors had DLC1 copy number loss, while just under one-quarter (22%) of them had copy number loss for DLC2 (Figure 4A).	('DLC2', 'Gene', '90627', (158, 162))	('copy number loss', 'Var', (72, 88))	('DLC1', 'Gene', (67, 71))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('HCC', 'Phenotype', 'HP:0001402', (12, 15))	('DLC2', 'Gene', (158, 162))	('tumors', 'Disease', (56, 62))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('copy number loss', 'Var', (137, 153))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('DLC1', 'Gene', '10395', (67, 71))
154144	27174913	Expression of DLC1 and DLC2 was two-fold lower in the groups with copy number loss than in those without it.	('DLC2', 'Gene', (23, 27))	('copy number loss', 'Var', (66, 82))	('DLC1', 'Gene', '10395', (14, 18))	('Expression', 'MPA', (0, 10))	('lower', 'NegReg', (41, 46))	('DLC1', 'Gene', (14, 18))	('DLC2', 'Gene', '90627', (23, 27))
154145	27174913	Compared with HCC, copy number loss of DLC1 was less frequent in LAD (20%) and LSC (25%) (Figure 4B and 4C), and, as expected, was not present in control tissue (Figure 4D).	('LAD', 'Disease', (65, 68))	('DLC1', 'Gene', (39, 43))	('copy number loss', 'Var', (19, 35))	('LAD', 'Disease', 'MESH:C535887', (65, 68))	('LSC', 'Phenotype', 'HP:0030359', (79, 82))	('LAD', 'Phenotype', 'HP:0030078', (65, 68))	('DLC1', 'Gene', '10395', (39, 43))	('LSC', 'Disease', (79, 82))	('less', 'NegReg', (48, 52))	('HCC', 'Phenotype', 'HP:0001402', (14, 17))
154146	27174913	DLC2 copy number loss was also less frequent for LAD (9%) and LSC (16%).	('DLC2', 'Gene', '90627', (0, 4))	('LAD', 'Disease', (49, 52))	('LSC', 'Phenotype', 'HP:0030359', (62, 65))	('copy number loss', 'Var', (5, 21))	('DLC2', 'Gene', (0, 4))	('LSC', 'Disease', (62, 65))	('LAD', 'Disease', 'MESH:C535887', (49, 52))	('LAD', 'Phenotype', 'HP:0030078', (49, 52))
154159	27174913	We evaluated whether altered expression of any of the three DLC genes in the cancers might be associated with mutations in TP53, one of the most commonly mutated genes in cancer.	('mutations', 'Var', (110, 119))	('cancers', 'Disease', 'MESH:D009369', (77, 84))	('cancers', 'Phenotype', 'HP:0002664', (77, 84))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('cancer', 'Disease', (77, 83))	('cancers', 'Disease', (77, 84))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('cancer', 'Disease', (171, 177))	('associated', 'Reg', (94, 104))	('TP53', 'Gene', '7157', (123, 127))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('expression', 'MPA', (29, 39))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('altered', 'Reg', (21, 28))	('TP53', 'Gene', (123, 127))
154160	27174913	Among 520 and 178 TCGA patients with LAD and LSC, there were 276 (53%) and 141 cases (79%), respectively, with at least one TP53 mutation (including frame shift deletions, frame shift insertions, in-frame deletions, missense mutations, nonsense mutations, and splice site mutations).	('frame shift insertions', 'Var', (172, 194))	('LAD', 'Disease', 'MESH:C535887', (37, 40))	('TP53', 'Gene', '7157', (124, 128))	('frame shift deletions', 'Var', (149, 170))	('patients', 'Species', '9606', (23, 31))	('LAD', 'Phenotype', 'HP:0030078', (37, 40))	('splice site mutations', 'Var', (260, 281))	('TP53', 'Gene', (124, 128))	('LSC', 'Phenotype', 'HP:0030359', (45, 48))	('nonsense mutations', 'Var', (236, 254))	('LAD', 'Disease', (37, 40))	('missense mutations', 'Var', (216, 234))	('in-frame deletions', 'Var', (196, 214))
154161	27174913	DLC1 expression was lower in patients with TP53 mutations than in patients with wild TP53 (Figure 6) in LAD and LSC.	('TP53', 'Gene', (85, 89))	('patients', 'Species', '9606', (29, 37))	('expression', 'MPA', (5, 15))	('lower', 'NegReg', (20, 25))	('DLC1', 'Gene', '10395', (0, 4))	('LSC', 'Phenotype', 'HP:0030359', (112, 115))	('LAD', 'Disease', (104, 107))	('LSC', 'Disease', (112, 115))	('DLC1', 'Gene', (0, 4))	('TP53', 'Gene', '7157', (85, 89))	('LAD', 'Disease', 'MESH:C535887', (104, 107))	('LAD', 'Phenotype', 'HP:0030078', (104, 107))	('TP53', 'Gene', '7157', (43, 47))	('TP53', 'Gene', (43, 47))	('mutations', 'Var', (48, 57))	('patients', 'Species', '9606', (66, 74))
154162	27174913	Expression of DLC2 and DLC3 was also lower in patients with mutant TP53, although not to the same degree as with DLC1.	('DLC1', 'Gene', (113, 117))	('DLC2', 'Gene', '90627', (14, 18))	('patients', 'Species', '9606', (46, 54))	('TP53', 'Gene', (67, 71))	('DLC2', 'Gene', (14, 18))	('DLC3', 'Gene', '9754', (23, 27))	('TP53', 'Gene', '7157', (67, 71))	('DLC3', 'Gene', (23, 27))	('lower', 'NegReg', (37, 42))	('DLC1', 'Gene', '10395', (113, 117))	('mutant', 'Var', (60, 66))
154163	27174913	Further analysis of the TCGA dataset showed that DLC1 down-regulation and TP53 mutation were found more frequently in current smokers with LAD.	('LAD', 'Disease', 'MESH:C535887', (139, 142))	('LAD', 'Phenotype', 'HP:0030078', (139, 142))	('DLC1', 'Gene', '10395', (49, 53))	('down-regulation', 'NegReg', (54, 69))	('TP53', 'Gene', '7157', (74, 78))	('LAD', 'Disease', (139, 142))	('DLC1', 'Gene', (49, 53))	('mutation', 'Var', (79, 87))	('TP53', 'Gene', (74, 78))
154164	27174913	Fifty-five percent of current smokers had low DLC1 expression and TP53 mutations, while only 29% of former smokers and 20% never smokers had this phenotype.	('TP53', 'Gene', '7157', (66, 70))	('TP53', 'Gene', (66, 70))	('DLC1', 'Gene', '10395', (46, 50))	('mutations', 'Var', (71, 80))	('low', 'NegReg', (42, 45))	('DLC1', 'Gene', (46, 50))	('low DLC', 'Phenotype', 'HP:0045051', (42, 49))
154165	27174913	The combination of low DLC1 and TP53 mutation in current smokers was more frequent than that of low DLC2 or DLC3 and TP53 mutation (Figure S5A).	('DLC1', 'Gene', (23, 27))	('DLC3', 'Gene', (108, 112))	('mutation', 'Var', (37, 45))	('DLC2', 'Gene', '90627', (100, 104))	('TP53', 'Gene', '7157', (117, 121))	('TP53', 'Gene', (117, 121))	('TP53', 'Gene', '7157', (32, 36))	('low', 'Var', (19, 22))	('DLC3', 'Gene', '9754', (108, 112))	('low DLC', 'Phenotype', 'HP:0045051', (96, 103))	('low DLC', 'Phenotype', 'HP:0045051', (19, 26))	('DLC2', 'Gene', (100, 104))	('TP53', 'Gene', (32, 36))	('DLC1', 'Gene', '10395', (23, 27))
154170	27174913	In addition, compared to the control cells, the migration rate of the cells expressing the each DLC gene was slowed to a similar degree (Figure 7B and 7D), as was the anchorage-independent cell growth in soft agar (Figure 7E).	('slowed', 'NegReg', (109, 115))	('agar', 'Chemical', 'MESH:D000362', (209, 213))	('gene', 'Var', (100, 104))	('DLC', 'Gene', (96, 99))	('anchorage-independent cell growth in soft agar', 'CPA', (167, 213))	('migration rate', 'CPA', (48, 62))
154174	27174913	Third, the reduced expression of DLC1 in LSC and LAD was frequently associated with promoter methylation, while this reduction was frequently associated with DLC1 copy number loss in HCC.	('copy number loss', 'Var', (163, 179))	('expression', 'MPA', (19, 29))	('LAD', 'Disease', (49, 52))	('reduced', 'NegReg', (11, 18))	('DLC1', 'Gene', '10395', (158, 162))	('HCC', 'Phenotype', 'HP:0001402', (183, 186))	('LSC', 'Phenotype', 'HP:0030359', (41, 44))	('DLC1', 'Gene', (158, 162))	('promoter methylation', 'MPA', (84, 104))	('DLC1', 'Gene', '10395', (33, 37))	('LAD', 'Disease', 'MESH:C535887', (49, 52))	('LAD', 'Phenotype', 'HP:0030078', (49, 52))	('DLC1', 'Gene', (33, 37))
154187	27174913	Given our experimental in vitro findings that the biological activities of DLC1, DLC2, and DLC3 appear to be similar, we conclude that the biology of changes in DLC1 expression are more relevant to the lung tumors than are those in the other two family members.	('DLC3', 'Gene', '9754', (91, 95))	('lung tumors', 'Disease', 'MESH:D008175', (202, 213))	('DLC2', 'Gene', (81, 85))	('changes', 'Var', (150, 157))	('DLC1', 'Gene', (75, 79))	('DLC1', 'Gene', (161, 165))	('lung tumors', 'Phenotype', 'HP:0100526', (202, 213))	('lung tumors', 'Disease', (202, 213))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('tumors', 'Phenotype', 'HP:0002664', (207, 213))	('DLC3', 'Gene', (91, 95))	('DLC2', 'Gene', '90627', (81, 85))	('DLC1', 'Gene', '10395', (161, 165))	('DLC1', 'Gene', '10395', (75, 79))
154192	27174913	Prior to the molecular identification of DLC1, cytogenetic analysis had indicated that chromosome 8p22, where DLC1 is located, was frequently deleted in HCC.	('DLC1', 'Gene', '10395', (41, 45))	('DLC1', 'Gene', '10395', (110, 114))	('HCC', 'Phenotype', 'HP:0001402', (153, 156))	('DLC1', 'Gene', (41, 45))	('deleted', 'Var', (142, 149))	('DLC1', 'Gene', (110, 114))
154193	27174913	Our results indicate that copy number loss of DLC1 occurred about twice as frequently in HCC (48%) as in LSC (25%) or LAD (20%).	('LAD', 'Phenotype', 'HP:0030078', (118, 121))	('copy number loss', 'Var', (26, 42))	('DLC1', 'Gene', '10395', (46, 50))	('HCC', 'Disease', (89, 92))	('LAD', 'Disease', (118, 121))	('HCC', 'Phenotype', 'HP:0001402', (89, 92))	('DLC1', 'Gene', (46, 50))	('LAD', 'Disease', 'MESH:C535887', (118, 121))	('LSC', 'Phenotype', 'HP:0030359', (105, 108))
154194	27174913	Compared with DLC1, copy number loss of DLC2 was less common in HCC (22%), LSC (16%) and LAD (9%).	('LSC', 'Disease', (75, 78))	('DLC1', 'Gene', '10395', (14, 18))	('LAD', 'Disease', 'MESH:C535887', (89, 92))	('HCC', 'Disease', (64, 67))	('LAD', 'Phenotype', 'HP:0030078', (89, 92))	('DLC1', 'Gene', (14, 18))	('DLC2', 'Gene', '90627', (40, 44))	('HCC', 'Phenotype', 'HP:0001402', (64, 67))	('copy number loss', 'Var', (20, 36))	('LSC', 'Phenotype', 'HP:0030359', (75, 78))	('LAD', 'Disease', (89, 92))	('DLC2', 'Gene', (40, 44))
154195	27174913	DLC1 and DLC2 copy number loss percentages in the TCGA breast carcinoma dataset were 33% and 18% respectively (data not shown).	('breast carcinoma', 'Phenotype', 'HP:0003002', (55, 71))	('DLC1', 'Gene', '10395', (0, 4))	('breast carcinoma', 'Disease', (55, 71))	('DLC1', 'Gene', (0, 4))	('DLC2', 'Gene', '90627', (9, 13))	('breast carcinoma', 'Disease', 'MESH:D001943', (55, 71))	('copy number', 'Var', (14, 25))	('DLC2', 'Gene', (9, 13))	('carcinoma', 'Phenotype', 'HP:0030731', (62, 71))
154197	27174913	As expected, copy number loss of DLC1 was found to be associated with its reduced expression.	('expression', 'MPA', (82, 92))	('DLC1', 'Gene', '10395', (33, 37))	('copy number loss', 'Var', (13, 29))	('reduced', 'NegReg', (74, 81))	('DLC1', 'Gene', (33, 37))
154198	27174913	Since almost one-half of the HCC cases had DLC1 copy number changes, this mechanism may be a major factor driving the reduced expression of DLC1 in this tumor type.	('DLC1', 'Gene', '10395', (140, 144))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('DLC1', 'Gene', (43, 47))	('changes', 'Reg', (60, 67))	('HCC', 'Disease', (29, 32))	('DLC1', 'Gene', (140, 144))	('HCC', 'Phenotype', 'HP:0001402', (29, 32))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('copy number', 'Var', (48, 59))	('DLC1', 'Gene', '10395', (43, 47))
154199	27174913	The less frequent DLC1 copy number losses in LSC and LAD suggest that other mechanisms contribute to the decreased DLC1 expression in these tumors.	('LAD', 'Disease', 'MESH:C535887', (53, 56))	('tumors', 'Disease', (140, 146))	('expression', 'MPA', (120, 130))	('tumors', 'Disease', 'MESH:D009369', (140, 146))	('LAD', 'Phenotype', 'HP:0030078', (53, 56))	('DLC1', 'Gene', '10395', (18, 22))	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('copy number losses', 'Var', (23, 41))	('DLC1', 'Gene', '10395', (115, 119))	('LSC', 'Phenotype', 'HP:0030359', (45, 48))	('LAD', 'Disease', (53, 56))	('DLC1', 'Gene', (18, 22))	('LSC', 'Disease', (45, 48))	('DLC1', 'Gene', (115, 119))	('decreased', 'NegReg', (105, 114))
154203	27174913	Thus, HCC tumors are more likely to present with DLC1 copy number loss than with promoter hypermethylation, while the situation is reversed in LSC and LAD.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('LAD', 'Disease', (151, 154))	('HCC tumors', 'Disease', (6, 16))	('copy number', 'Var', (54, 65))	('DLC1', 'Gene', '10395', (49, 53))	('LSC', 'Phenotype', 'HP:0030359', (143, 146))	('tumors', 'Phenotype', 'HP:0002664', (10, 16))	('LAD', 'Disease', 'MESH:C535887', (151, 154))	('HCC tumors', 'Disease', 'MESH:D006528', (6, 16))	('DLC1', 'Gene', (49, 53))	('LAD', 'Phenotype', 'HP:0030078', (151, 154))	('HCC', 'Phenotype', 'HP:0001402', (6, 9))
154206	27174913	Our results show an association of low DLC1 levels with TP53 mutations in the lung tumors, and the combination of low DLC1 expression and TP53 mutation was more prevalent in current smokers.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('DLC1', 'Gene', (39, 43))	('low DLC', 'Phenotype', 'HP:0045051', (114, 121))	('TP53', 'Gene', '7157', (138, 142))	('lung tumors', 'Disease', (78, 89))	('TP53', 'Gene', '7157', (56, 60))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('mutations', 'Var', (61, 70))	('TP53', 'Gene', (138, 142))	('lung tumors', 'Phenotype', 'HP:0100526', (78, 89))	('TP53', 'Gene', (56, 60))	('low', 'NegReg', (35, 38))	('DLC1', 'Gene', '10395', (118, 122))	('DLC1', 'Gene', '10395', (39, 43))	('low DLC', 'Phenotype', 'HP:0045051', (35, 42))	('lung tumors', 'Disease', 'MESH:D008175', (78, 89))	('DLC1', 'Gene', (118, 122))
154207	27174913	An association between TP53 mutations and expression of the other DLC family members is not striking.	('TP53', 'Gene', (23, 27))	('mutations', 'Var', (28, 37))	('TP53', 'Gene', '7157', (23, 27))
154208	27174913	Mutations in TP53 are common in smoking-related cancers and occur more frequently in lung tumors from smokers.	('cancers', 'Disease', (48, 55))	('TP53', 'Gene', (13, 17))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('cancers', 'Phenotype', 'HP:0002664', (48, 55))	('lung tumors', 'Phenotype', 'HP:0100526', (85, 96))	('lung tumors', 'Disease', (85, 96))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('Mutations', 'Var', (0, 9))	('common', 'Reg', (22, 28))	('TP53', 'Gene', '7157', (13, 17))	('lung tumors', 'Disease', 'MESH:D008175', (85, 96))	('cancers', 'Disease', 'MESH:D009369', (48, 55))
154209	27174913	Inactivation or mutation of TP53 is reported to lead to increased Rho GTPase signaling and to the acquisition of a more aggressive, invasive phenotype in tumor cells.	('Rho', 'MPA', (66, 69))	('TP53', 'Gene', '7157', (28, 32))	('mutation', 'Var', (16, 24))	('increased', 'PosReg', (56, 65))	('TP53', 'Gene', (28, 32))	('GTP', 'Chemical', 'MESH:D006160', (70, 73))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('aggressive', 'CPA', (120, 130))	('Inactivation', 'Var', (0, 12))	('tumor', 'Disease', (154, 159))
154210	27174913	Further analysis of the links between TP53 and DLC1 expression in cancer may help to elucidate how dysregulation of the p53 and RhoA pathways might cooperate to promote oncogenesis.	('RhoA', 'Gene', (128, 132))	('DLC1', 'Gene', (47, 51))	('p53', 'Gene', '7157', (120, 123))	('TP53', 'Gene', (38, 42))	('RhoA', 'Gene', '387', (128, 132))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('dysregulation', 'Var', (99, 112))	('promote', 'PosReg', (161, 168))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('cooperate', 'Reg', (148, 157))	('DLC1', 'Gene', '10395', (47, 51))	('oncogenesis', 'CPA', (169, 180))	('p53', 'Gene', (120, 123))	('cancer', 'Disease', (66, 72))	('TP53', 'Gene', '7157', (38, 42))
154217	27174913	TCGA uses results generated with the Illumina HumanMethylation450 BeadChip to report the methylation status of the promoter regions of the DLC1 variant 2, DLC2 alpha, variant 1, and DLC3 beta, variant 3 transcripts, which are analogous to the variant 2 transcript of DLC1.	('DLC1', 'Gene', (267, 271))	('DLC3', 'Gene', (182, 186))	('DLC3', 'Gene', '9754', (182, 186))	('DLC2', 'Gene', '90627', (155, 159))	('methylation', 'MPA', (89, 100))	('DLC1', 'Gene', '10395', (139, 143))	('DLC2', 'Gene', (155, 159))	('DLC1', 'Gene', '10395', (267, 271))	('variant', 'Var', (144, 151))	('DLC1', 'Gene', (139, 143))
154224	27174913	Anti-RhoA antibody (EMD Millipore) was used for immunobloting to detect RhoGTP, and anti-GFP antibody was used to detect GFP-tagged DLCs and the GFP control.	('RhoGTP', 'Chemical', '-', (72, 78))	('RhoA', 'Gene', '387', (5, 9))	('RhoA', 'Gene', (5, 9))	('GFP-tagged', 'Var', (121, 131))
154287	31461552	Lesions include EGFR mutation, and ALK and ROS1 receptor fusion, which if present significantly improves targeted treatment outcomes of cancer patients.	('ROS1', 'Gene', '6098', (43, 47))	('ALK', 'Gene', '238', (35, 38))	('ROS1', 'Gene', (43, 47))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('mutation', 'Var', (21, 29))	('patients', 'Species', '9606', (143, 151))	('improves', 'PosReg', (96, 104))	('cancer', 'Disease', (136, 142))	('EGFR', 'Gene', '1956', (16, 20))	('ALK', 'Gene', (35, 38))	('EGFR', 'Gene', (16, 20))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
154288	31461552	Besides these molecular mutations, abnormal cellular metabolism is also a hallmark of lung cancer (Hanahan and Weinberg, 2011).	('hallmark of lung cancer', 'Disease', 'MESH:D008175', (74, 97))	('abnormal cellular metabolism', 'Phenotype', 'HP:0011017', (35, 63))	('lung cancer', 'Phenotype', 'HP:0100526', (86, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('hallmark of lung cancer', 'Disease', (74, 97))	('cellular metabolism', 'MPA', (44, 63))	('mutations', 'Var', (24, 33))
154319	31461552	The panel focuses on the exonic regions of 52 genes that have been found recurrently mutated in NSCLC (Table S2).	('NSCLC', 'Phenotype', 'HP:0030358', (96, 101))	('NSCLC', 'Disease', 'MESH:D002289', (96, 101))	('mutated', 'Var', (85, 92))	('NSCLC', 'Disease', (96, 101))
154322	31461552	Variants were selected when they were observed at >= 1% frequency in tumour, when they had no associated frequencies in the dbSNP, 1000 Genomes, NHBLI ESP, Exome Aggregation Consortium and Genome Aggregation Database or when, if the variant was known already in population-level databases, its observed incidence was < 0.001.	('tumour', 'Disease', (69, 75))	('tumour', 'Phenotype', 'HP:0002664', (69, 75))	('Variants', 'Var', (0, 8))	('tumour', 'Disease', 'MESH:D009369', (69, 75))
154323	31461552	In addition, CADD score >= 15 was used and correlated with SIFT and PolyPhen prediction scores to predict potential protein-damaging effects of missense variants.	('protein-damaging', 'MPA', (116, 132))	('PolyPhen', 'Chemical', 'MESH:C037153', (68, 76))	('missense variants', 'Var', (144, 161))
154353	31461552	The turquoise (2696 genes), blue (n = 1821) and green (n = 214) modules were significantly correlated with the level of ADP, glutamate, histamine, GDP-fructose, 3'-AMP and 5'-AMP.	('histamine', 'Chemical', 'MESH:D006632', (136, 145))	("3'-AMP", 'MPA', (161, 167))	('GDP-fructose', 'Chemical', 'MESH:D005632', (147, 159))	("3'-AMP", 'Chemical', 'MESH:D000249', (161, 167))	('GDP-fructose', 'MPA', (147, 159))	("5'-AMP", 'Chemical', 'MESH:D000249', (172, 178))	('ADP', 'Chemical', 'MESH:D000244', (120, 123))	('correlated', 'Reg', (91, 101))	('histamine', 'MPA', (136, 145))	('level', 'MPA', (111, 116))	('glutamate', 'Chemical', 'None', (125, 134))	('ADP', 'MPA', (120, 123))	('2696 genes', 'Var', (15, 25))	('glutamate', 'MPA', (125, 134))
154360	31461552	Genes of cell cycle progression such as CDKN2A and RB1 were more frequently mutated in LUSC tumours.	('tumours', 'Phenotype', 'HP:0002664', (92, 99))	('RB1', 'Gene', (51, 54))	('tumour', 'Disease', 'MESH:D009369', (92, 98))	('tumour', 'Disease', (92, 98))	('mutated', 'Var', (76, 83))	('CDKN2A', 'Gene', (40, 46))	('RB1', 'Gene', '5925', (51, 54))	('CDKN2A', 'Gene', '1029', (40, 46))	('tumour', 'Phenotype', 'HP:0002664', (92, 98))	('LUSC', 'Phenotype', 'HP:0030359', (87, 91))
154366	31461552	The higher mutation frequency of TP53 in LUSC suggests interaction between these factors in this lung cancer subtype.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('lung cancer', 'Disease', 'MESH:D008175', (97, 108))	('interaction', 'Interaction', (55, 66))	('TP53', 'Gene', '7157', (33, 37))	('TP53', 'Gene', (33, 37))	('mutation', 'Var', (11, 19))	('lung cancer', 'Disease', (97, 108))	('lung cancer', 'Phenotype', 'HP:0100526', (97, 108))	('LUSC', 'Phenotype', 'HP:0030359', (41, 45))
154374	31461552	P2YR12 represents a potential target for an anticancer therapy due to its involvement in platelet-cancer cell crosstalk, and P2YR12-mediated platelet activation has been demonstrated to promote metastasis in mouse model of melanoma (Zhu et al., 2017 ).	('melanoma', 'Disease', (223, 231))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('promote', 'PosReg', (186, 193))	('melanoma', 'Disease', 'MESH:D008545', (223, 231))	('platelet-cancer', 'Disease', 'MESH:D009369', (89, 104))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('metastasis', 'CPA', (194, 204))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('P2YR12-mediated', 'Var', (125, 140))	('cancer', 'Disease', (98, 104))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('mouse', 'Species', '10090', (208, 213))	('platelet-cancer', 'Disease', (89, 104))	('melanoma', 'Phenotype', 'HP:0002861', (223, 231))
154375	31461552	It has been previously speculated that manipulation of ADP and/or its receptor could limit cancer-associated thrombosis (Murugappa and Kunapuli, 2006).	('ADP', 'Chemical', 'MESH:D000244', (55, 58))	('limit', 'NegReg', (85, 90))	('thrombosis', 'Disease', 'MESH:D013927', (109, 119))	('cancer', 'Disease', (91, 97))	('manipulation', 'Var', (39, 51))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('ADP', 'Protein', (55, 58))	('thrombosis', 'Disease', (109, 119))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('Murugappa', 'Disease', 'None', (121, 130))	('Murugappa', 'Disease', (121, 130))
154390	31461552	The effects of mutations in TP53 are complex, and gain-of-function effects are common (Schulz-Heddergott and Moll, 2018).	('gain-of-function', 'PosReg', (50, 66))	('mutations', 'Var', (15, 24))	('TP53', 'Gene', '7157', (28, 32))	('TP53', 'Gene', (28, 32))
154393	31461552	Although we observed higher mutation rates of TP53 in patients with LUSC, due to the scope of our study, we was unable to validate the effect of these mutations on the expression of p53 signalling pathway in the cohort.	('patients', 'Species', '9606', (54, 62))	('p53', 'Gene', '7157', (182, 185))	('TP53', 'Gene', '7157', (46, 50))	('mutation', 'Var', (28, 36))	('TP53', 'Gene', (46, 50))	('higher', 'PosReg', (21, 27))	('LUSC', 'Disease', (68, 72))	('LUSC', 'Phenotype', 'HP:0030359', (68, 72))	('p53', 'Gene', (182, 185))
154414	29843604	Alternative splicing of a gene produces splicing variants, and accumulating evidence has revealed its essential role in cancer-related processes, implying the urgent need to discover tumor-specific isoforms and uncover their potential functions in tumorigenesis.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('tumor', 'Disease', (248, 253))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('tumor', 'Disease', (183, 188))	('tumor', 'Disease', 'MESH:D009369', (248, 253))	('Alternative splicing', 'Var', (0, 20))	('tumor', 'Phenotype', 'HP:0002664', (248, 253))	('splicing variants', 'MPA', (40, 57))
154420	29843604	Aberrant splicing patterns are closely related to tumor progression.	('Aberrant splicing patterns', 'Var', (0, 26))	('related', 'Reg', (39, 46))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Disease', (50, 55))
154421	29843604	For example, misregulation of splicing caused by splicing factor Serine And Arginine Rich Splicing Factor 1 (SRSF1) can lead to the malignant transformation of normal mammary cells; we also reported that Serine And Arginine Rich Splicing Factor 6 (SRSF6) promotes tumor progression by regulating AS and might be a potential therapeutic target.	('splicing factor', 'Gene', (49, 64))	('tumor', 'Phenotype', 'HP:0002664', (264, 269))	('misregulation', 'Var', (13, 26))	('Serine And Arginine Rich Splicing Factor 1', 'Gene', '6426', (65, 107))	('SRSF6', 'Gene', (248, 253))	('tumor', 'Disease', (264, 269))	('lead to', 'Reg', (120, 127))	('Serine And Arginine Rich Splicing Factor 1', 'Gene', (65, 107))	('malignant transformation', 'CPA', (132, 156))	('promotes', 'PosReg', (255, 263))	('Serine And Arginine Rich Splicing Factor 6', 'Gene', (204, 246))	('SRSF6', 'Gene', '6431', (248, 253))	('splicing factor', 'Gene', '10569', (49, 64))	('SRSF1', 'Gene', (109, 114))	('regulating', 'Reg', (285, 295))	('tumor', 'Disease', 'MESH:D009369', (264, 269))	('Serine And Arginine Rich Splicing Factor 6', 'Gene', '6431', (204, 246))	('SRSF1', 'Gene', '6426', (109, 114))
154422	29843604	Thus, splicing variants could be potential biomarkers and therapeutic targets in cancer studies.	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('cancer', 'Disease', (81, 87))	('splicing variants', 'Var', (6, 23))	('cancer', 'Disease', 'MESH:D009369', (81, 87))
154450	29843604	Additionally, the KM-plots showed the correlation between uc003spw.3 and uc003spx.3 with the overall survival of colon cancer patients (Fig.	('uc003spw.3', 'Var', (58, 68))	('colon cancer', 'Phenotype', 'HP:0003003', (113, 125))	('correlation', 'Interaction', (38, 49))	('colon cancer', 'Disease', 'MESH:D015179', (113, 125))	('uc003spx.3', 'Var', (73, 83))	('colon cancer', 'Disease', (113, 125))	('patients', 'Species', '9606', (126, 134))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
154465	33466597	Furthermore, available data indicate a much more frequent mutation of the tumor suppressor gene-p53 in non-small cell lung cancer (NSCLC) female patients compared to males.	('patients', 'Species', '9606', (145, 153))	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('p53', 'Gene', (96, 99))	('p53', 'Gene', '7157', (96, 99))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('NSCLC', 'Disease', (131, 136))	('SCLC', 'Phenotype', 'HP:0030357', (132, 136))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (103, 129))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('NSCLC', 'Disease', 'MESH:D002289', (131, 136))	('mutation', 'Var', (58, 66))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (103, 129))	('tumor', 'Disease', (74, 79))	('lung cancer', 'Phenotype', 'HP:0100526', (118, 129))	('non-small cell lung cancer', 'Disease', (103, 129))	('NSCLC', 'Phenotype', 'HP:0030358', (131, 136))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (107, 129))
154500	33466597	Chronic and too frequent adduct formation might cause gene mutations that could lead to the development of lung cancer.	('adduct', 'Interaction', (25, 31))	('lead to', 'Reg', (80, 87))	('lung cancer', 'Disease', 'MESH:D008175', (107, 118))	('cause', 'Reg', (48, 53))	('men', 'Species', '9606', (99, 102))	('lung cancer', 'Disease', (107, 118))	('mutations', 'Var', (59, 68))	('lung cancer', 'Phenotype', 'HP:0100526', (107, 118))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))
154505	33466597	Gene mutations, which result in changes of protein expression, such as Bax, p53 or Bcl-2, have a significant impact on the prognosis of lung cancer patients.	('changes', 'Reg', (32, 39))	('Bcl-2', 'Gene', '596', (83, 88))	('patients', 'Species', '9606', (148, 156))	('lung cancer', 'Phenotype', 'HP:0100526', (136, 147))	('Bcl-2', 'Gene', (83, 88))	('impact', 'Reg', (109, 115))	('p53', 'Gene', (76, 79))	('Bax', 'Gene', (71, 74))	('p53', 'Gene', '7157', (76, 79))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('mutations', 'Var', (5, 14))	('lung cancer', 'Disease', 'MESH:D008175', (136, 147))	('Bax', 'Gene', '581', (71, 74))	('protein expression', 'MPA', (43, 61))	('lung cancer', 'Disease', (136, 147))
154515	33466597	Interestingly, a meta-analysis evaluating the effectiveness of anti-PD1 inhibitors and standard chemotherapy in female patients did not show a clear benefit from immune checkpoint inhibitors.	('inhibitors', 'Var', (72, 82))	('patients', 'Species', '9606', (119, 127))	('PD1', 'Gene', (68, 71))	('PD1', 'Gene', '6622', (68, 71))
154519	33466597	Patients diagnosed with adenocarcinoma harboring druggable mutations are currently offered molecularly targeted medications directed against EGFR, ALK, ROS, Her2 new, MET, TRK or any other even less frequent alterations.	('ROS', 'Gene', (152, 155))	('MET', 'Gene', '79811', (167, 170))	('MET', 'Gene', (167, 170))	('EGFR', 'Gene', '1956', (141, 145))	('TRK', 'Gene', '4914', (172, 175))	('carcinoma', 'Phenotype', 'HP:0030731', (29, 38))	('adenocarcinoma', 'Disease', (24, 38))	('ALK', 'Gene', (147, 150))	('ROS', 'Chemical', '-', (152, 155))	('EGFR', 'Gene', (141, 145))	('Patients', 'Species', '9606', (0, 8))	('Her2', 'Gene', (157, 161))	('TRK', 'Gene', (172, 175))	('mutations', 'Var', (59, 68))	('adenocarcinoma', 'Disease', 'MESH:D000230', (24, 38))	('Her2', 'Gene', '2064', (157, 161))	('ALK', 'Gene', '238', (147, 150))
154529	33466597	Female patients with lung adenocarcinoma harboring ALK that was rearranged and treated with ALK inhibitors such as crizotinib or ceritinib obtain similar benefits as men.	('ALK', 'Gene', '238', (51, 54))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (21, 40))	('ALK', 'Gene', (92, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (31, 40))	('men', 'Species', '9606', (166, 169))	('rearranged', 'Var', (64, 74))	('ceritinib', 'Chemical', 'MESH:C586847', (129, 138))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (21, 40))	('ALK', 'Gene', (51, 54))	('benefits', 'PosReg', (154, 162))	('ALK', 'Gene', '238', (92, 95))	('lung adenocarcinoma', 'Disease', (21, 40))	('patients', 'Species', '9606', (7, 15))	('crizotinib', 'Chemical', 'MESH:D000077547', (115, 125))
154538	33466597	In addition, high ERbeta expression is associated with a poor prognosis of advanced NSCLC.	('NSCLC', 'Phenotype', 'HP:0030358', (84, 89))	('ERbeta', 'Gene', (18, 24))	('high', 'Var', (13, 17))	('expression', 'MPA', (25, 35))	('NSCLC', 'Disease', (84, 89))	('ERbeta', 'Gene', '2099', (18, 24))	('NSCLC', 'Disease', 'MESH:D002289', (84, 89))	('SCLC', 'Phenotype', 'HP:0030357', (85, 89))
154540	33466597	Tumors exhibiting high ERbeta expression have been characterized as signalers via fibroblast growth factors, which are the autocrine signaling loop and contribute to the progression of lung cancer and pluripotency of human embryonic stem cells.	('lung cancer', 'Disease', 'MESH:D008175', (185, 196))	('ERbeta', 'Gene', '2099', (23, 29))	('pluripotency of human embryonic', 'Disease', 'MESH:D003333', (201, 232))	('lung cancer', 'Disease', (185, 196))	('pluripotency of human embryonic', 'Disease', (201, 232))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('high', 'Var', (18, 22))	('lung cancer', 'Phenotype', 'HP:0100526', (185, 196))	('ERbeta', 'Gene', (23, 29))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))
154584	33466597	The impact of estrogens is noted in female cancers, for example breast cancer, or in the case of modulation of genetic mutations.	('breast cancer', 'Phenotype', 'HP:0003002', (64, 77))	('cancers', 'Phenotype', 'HP:0002664', (43, 50))	('cancers', 'Disease', (43, 50))	('cancers', 'Disease', 'MESH:D009369', (43, 50))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('breast cancer', 'Disease', 'MESH:D001943', (64, 77))	('genetic mutations', 'Var', (111, 128))	('breast cancer', 'Disease', (64, 77))
154593	33466597	It has also been shown in vitro that 2ME inhibits several stages of the andiogenic cascade, thereby inhibiting proliferation and inducing tumor cell apoptosis.	('inhibits', 'NegReg', (41, 49))	('tumor', 'Disease', (138, 143))	('2ME', 'Chemical', 'MESH:D008623', (37, 40))	('proliferation', 'CPA', (111, 124))	('inhibiting', 'NegReg', (100, 110))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('2ME', 'Var', (37, 40))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('inducing', 'NegReg', (129, 137))	('andiogenic cascade', 'Pathway', (72, 90))
154606	33466597	It has been hypothesized that the 4-OH-E metabolite affects oncogene mutation in the lungs and also activates ER signaling, which increases the risk of lung cancer.	('activates', 'PosReg', (100, 109))	('4-OH-E', 'Chemical', '-', (34, 40))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('4-OH-E', 'Var', (34, 40))	('lung cancer', 'Disease', 'MESH:D008175', (152, 163))	('oncogene', 'Gene', (60, 68))	('mutation', 'Var', (69, 77))	('ER', 'Gene', '2069', (110, 112))	('lung cancer', 'Phenotype', 'HP:0100526', (152, 163))	('affects', 'Reg', (52, 59))	('increases', 'PosReg', (130, 139))	('lung cancer', 'Disease', (152, 163))
154634	33466597	In addition, molecular tests for mutations are performed to diagnose NSCLC activators in the EGFR gene.	('EGFR', 'Gene', '1956', (93, 97))	('NSCLC', 'Disease', (69, 74))	('SCLC', 'Phenotype', 'HP:0030357', (70, 74))	('mutations', 'Var', (33, 42))	('EGFR', 'Gene', (93, 97))	('NSCLC', 'Disease', 'MESH:D002289', (69, 74))	('NSCLC', 'Phenotype', 'HP:0030358', (69, 74))
154659	33466597	According to the data, fulvestrant causes greater sensitization of the NSCLC tumor to chemotherapy and reduces the mesinochemical features.	('NSCLC', 'Phenotype', 'HP:0030358', (71, 76))	('sensitization', 'MPA', (50, 63))	('fulvestrant', 'Var', (23, 34))	('NSCLC tumor', 'Disease', 'MESH:D009369', (71, 82))	('SCLC', 'Phenotype', 'HP:0030357', (72, 76))	('reduces', 'NegReg', (103, 110))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('NSCLC tumor', 'Disease', (71, 82))	('mesinochemical features', 'MPA', (115, 138))
154669	33466597	HR + = positive estrogen or progesterone receptor, both SCLC and NSCLC patients received 50 mg of MLN8237 orally twice daily for 7 days, consecutively 14 days off.	('SCLC', 'Disease', 'MESH:D018288', (56, 60))	('MLN8237', 'Chemical', 'MESH:C550258', (98, 105))	('SCLC', 'Phenotype', 'HP:0030357', (66, 70))	('patients', 'Species', '9606', (71, 79))	('NSCLC', 'Disease', 'MESH:D002289', (65, 70))	('MLN8237', 'Var', (98, 105))	('progesterone receptor', 'Gene', '5241', (28, 49))	('SCLC', 'Phenotype', 'HP:0030357', (56, 60))	('NSCLC', 'Disease', (65, 70))	('NSCLC', 'Phenotype', 'HP:0030358', (65, 70))	('SCLC', 'Disease', (66, 70))	('SCLC', 'Disease', 'MESH:D018288', (66, 70))	('SCLC', 'Disease', (56, 60))	('progesterone receptor', 'Gene', (28, 49))
154674	33466597	Compared to men, a much more common tumor suppressor p53 mutation was observed in women with NSCLC.	('mutation', 'Var', (57, 65))	('NSCLC', 'Disease', (93, 98))	('C', 'Chemical', 'MESH:D002244', (97, 98))	('NSCLC', 'Disease', 'MESH:D002289', (93, 98))	('women', 'Species', '9606', (82, 87))	('men', 'Species', '9606', (12, 15))	('SCLC', 'Phenotype', 'HP:0030357', (94, 98))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('men', 'Species', '9606', (84, 87))	('p53', 'Gene', (53, 56))	('p53', 'Gene', '7157', (53, 56))	('C', 'Chemical', 'MESH:D002244', (95, 96))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('NSCLC', 'Phenotype', 'HP:0030358', (93, 98))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('tumor', 'Disease', (36, 41))
154694	32518413	trained a deep learning model to classify and predict mutations from non-small cell lung cancer histopathology.	('lung cancer', 'Disease', (84, 95))	('lung cancer', 'Phenotype', 'HP:0100526', (84, 95))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (73, 95))	('mutations', 'Var', (54, 63))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (69, 95))	('lung cancer', 'Disease', 'MESH:D008175', (84, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
154852	27347096	In addition, CYP11B1 and CYP11B2 exhibited the highest number of mutations among endogenous CYPs in all samples.	('CYP', 'Gene', '9360', (13, 16))	('CYP', 'Gene', (13, 16))	('CYP', 'Gene', '9360', (92, 95))	('CYP', 'Gene', (92, 95))	('CYP11B2', 'Gene', (25, 32))	('CYP11B2', 'Gene', '1585', (25, 32))	('CYP', 'Gene', '9360', (25, 28))	('CYP', 'Gene', (25, 28))	('CYP11B1', 'Gene', (13, 20))	('CYP11B1', 'Gene', '1584', (13, 20))	('mutations', 'Var', (65, 74))
154872	27347096	PolyPhen-2 is a tool that predicts the possible impact of an amino acid substitution on the structure and function of a human protein using physical and comparative considerations.	('human', 'Species', '9606', (120, 125))	('function', 'MPA', (106, 114))	('PolyPhen-2', 'Chemical', '-', (0, 10))	('amino acid substitution', 'Var', (61, 84))	('structure', 'MPA', (92, 101))
154894	27347096	As the structure of CYP11B2 may be indicated in RCSB PDB, PyMOL was used to visualize somatic mutations in the structure of CYP11B2 (Fig.	('mutations', 'Var', (94, 103))	('CYP11B2', 'Gene', (20, 27))	('CYP11B2', 'Gene', (124, 131))	('CYP11B2', 'Gene', '1585', (20, 27))	('CYP11B2', 'Gene', '1585', (124, 131))
154898	27347096	Furthermore, mutations in CYP11B1 and CYP11B2 may affect cortisol and aldosterone levels.	('cortisol', 'Chemical', 'MESH:D006854', (57, 65))	('CYP11B1', 'Gene', (26, 33))	('CYP11B2', 'Gene', (38, 45))	('CYP11B1', 'Gene', '1584', (26, 33))	('affect', 'Reg', (50, 56))	('CYP11B2', 'Gene', '1585', (38, 45))	('mutations', 'Var', (13, 22))	('aldosterone', 'Chemical', 'MESH:D000450', (70, 81))
154908	27347096	Approximately 80% of these mutations may alter the function of the CYP11B1 and CYP11B2 proteins.	('mutations', 'Var', (27, 36))	('CYP11B1', 'Gene', (67, 74))	('proteins', 'Protein', (87, 95))	('function', 'MPA', (51, 59))	('CYP11B1', 'Gene', '1584', (67, 74))	('CYP11B2', 'Gene', (79, 86))	('alter', 'Reg', (41, 46))	('CYP11B2', 'Gene', '1585', (79, 86))
154910	27347096	Decreased expression and mutations of the CYP11 family may influence the biosynthesis of steroid hormones.	('mutations', 'Var', (25, 34))	('Decreased', 'NegReg', (0, 9))	('expression', 'MPA', (10, 20))	('biosynthesis of steroid hormones', 'MPA', (73, 105))	('influence', 'Reg', (59, 68))	('steroid hormones', 'Chemical', 'MESH:D013256', (89, 105))	('CYP', 'Gene', '9360', (42, 45))	('CYP', 'Gene', (42, 45))
154969	25214794	The MDR1 G2677 A/T gene was heterozygous mutant with reduced transportation activity, and might have been sensitive to antimicrotubule medicine.	('MDR1', 'Gene', (4, 8))	('G2677 A/T', 'Var', (9, 18))	('reduced', 'NegReg', (53, 60))	('G2677 A/T', 'Mutation', 'c.2677G>A,T', (9, 18))	('transportation activity', 'MPA', (61, 84))	('MDR1', 'Gene', '5243', (4, 8))
155049	33541291	That is to say, patients with protein degradation, RNA degradation and splicing effects were more inclined to a poor prognosis (Fig.	('protein', 'MPA', (30, 37))	('splicing effects', 'Var', (71, 87))	('patients', 'Species', '9606', (16, 24))	('RNA', 'MPA', (51, 54))
155073	33541291	The splice variant of oncostatin M receptor beta is overexpressed in human esophageal squamous cell carcinoma.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (86, 109))	('esophageal squamous cell carcinoma', 'Disease', (75, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('overexpressed', 'PosReg', (52, 65))	('splice variant', 'Var', (4, 18))	('human', 'Species', '9606', (69, 74))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (75, 109))
155079	33541291	Mutations in genes encoding splice proteins are frequently found in cancer.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('Mutations', 'Var', (0, 9))	('found', 'Reg', (59, 64))	('cancer', 'Disease', (68, 74))
155120	33419290	On the contrary to these normal cells, various malignancies take advantage by dysregulation of this cell adhesion component for the development of their tumor microenvironment.	('malignancies', 'Disease', 'MESH:D009369', (47, 59))	('dysregulation', 'Var', (78, 91))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('malignancies', 'Disease', (47, 59))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))
155130	33419290	Overexpressed-CADM1 in human epidermal keratinocytes increases adhesion of cytotoxic T cells and enhances their cytotoxic function.	('adhesion', 'CPA', (63, 71))	('cytotoxic function', 'CPA', (112, 130))	('Overexpressed-CADM1', 'Var', (0, 19))	('human', 'Species', '9606', (23, 28))	('increases', 'PosReg', (53, 62))	('enhances', 'PosReg', (97, 105))
155131	33419290	Epidermal overexpressed-CADM1 transgenic mice had an enhanced autoimmune alopecia reaction, suggesting that CADM1 supports adhesion ability of lymphocytes and acts as a scaffolding molecule for other cells to promote inflammation in the epidermis.	('inflammation', 'Disease', (217, 229))	('promote', 'PosReg', (209, 216))	('inflammation', 'Disease', 'MESH:D007249', (217, 229))	('transgenic', 'Var', (30, 40))	('autoimmune alopecia reaction', 'CPA', (62, 90))	('CADM1', 'Gene', (108, 113))	('transgenic mice', 'Species', '10090', (30, 45))	('alopecia', 'Phenotype', 'HP:0001596', (73, 81))	('adhesion', 'CPA', (123, 131))	('supports', 'PosReg', (114, 122))	('enhanced', 'PosReg', (53, 61))
155145	33419290	As one of the mechanisms, the expression of CADM1 on ATLL cells contributes to infiltration and the adhesion ability to vessels and the skin to form nodules and tumors.	('contributes', 'Reg', (64, 75))	('tumors', 'Disease', (161, 167))	('tumors', 'Phenotype', 'HP:0002664', (161, 167))	('expression', 'Var', (30, 40))	('tumors', 'Disease', 'MESH:D009369', (161, 167))	('adhesion ability', 'CPA', (100, 116))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('infiltration', 'CPA', (79, 91))	('CADM1', 'Gene', (44, 49))
155164	33419290	The survival of melanoma is significantly decreased in reduced expression of CADM1 patients with melanoma or harboring methylated CADM1, indicating that the epigenetic modification of CADM1 by hypermethylation is also an important factor in the pathogenesis of melanoma.	('melanoma', 'Disease', 'MESH:D008545', (97, 105))	('melanoma', 'Phenotype', 'HP:0002861', (97, 105))	('melanoma', 'Disease', (97, 105))	('decreased', 'NegReg', (42, 51))	('reduced', 'NegReg', (55, 62))	('hypermethylation', 'Var', (193, 209))	('epigenetic modification', 'Var', (157, 180))	('survival', 'CPA', (4, 12))	('expression', 'MPA', (63, 73))	('melanoma', 'Disease', 'MESH:D008545', (16, 24))	('melanoma', 'Phenotype', 'HP:0002861', (16, 24))	('melanoma', 'Disease', (16, 24))	('patients', 'Species', '9606', (83, 91))	('melanoma', 'Disease', 'MESH:D008545', (261, 269))	('CADM1', 'Gene', (77, 82))	('melanoma', 'Phenotype', 'HP:0002861', (261, 269))	('melanoma', 'Disease', (261, 269))
155169	33419290	The frequency of CADM1+ T cells positively correlates with abnormal lymphocytes in the peripheral blood of ATLL patients.	('CADM1+ T cells', 'Var', (17, 31))	('abnormal lymphocytes in the peripheral blood', 'CPA', (59, 103))	('abnormal lymphocytes', 'Phenotype', 'HP:0004332', (59, 79))	('patients', 'Species', '9606', (112, 120))
155172	33419290	The insertion of CADM1 promotes ATLL cells to cause aggregation and adhesion to vascular endothelial cells, suggesting that CADM1 is a biomarker for acute ATLL and its involvement in tumor invasion.	('CADM1', 'Gene', (17, 22))	('promotes', 'PosReg', (23, 31))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('aggregation', 'CPA', (52, 63))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('insertion', 'Var', (4, 13))	('ATLL cells', 'CPA', (32, 42))	('tumor', 'Disease', (183, 188))	('adhesion', 'CPA', (68, 76))
155178	33419290	Regarding the contribution of CADM1 on the pathogenesis of mycosis fungoides, our study has revealed that the survival rate in mycosis fungoides is significantly lower in patients with high CADM1-expressed groups.	('mycosis fungoides', 'Disease', (127, 144))	('high CADM1-expressed', 'Var', (185, 205))	('patients', 'Species', '9606', (171, 179))	('lower', 'NegReg', (162, 167))	('survival rate', 'CPA', (110, 123))
155196	33419290	Overexpression of CADM1 shows an increased Claudin-1 expression, while the silencing CADM1 improves the intestinal barrier function.	('CADM1', 'Gene', (85, 90))	('intestinal barrier function', 'CPA', (104, 131))	('improves', 'PosReg', (91, 99))	('Claudin-1', 'Gene', '9076', (43, 52))	('increased', 'PosReg', (33, 42))	('silencing', 'Var', (75, 84))	('Claudin-1', 'Gene', (43, 52))	('expression', 'MPA', (53, 63))
155197	33419290	Claudin-1 is responsible for barrier function in the skin, therefore CADM1 in keratinocytes is expected to exhibit a positive regulation in the skin barrier and have a beneficial impact on skin barrier-related diseases.	('positive regulation', 'PosReg', (117, 136))	('CADM1', 'Var', (69, 74))	('Claudin-1', 'Gene', '9076', (0, 9))	('Claudin-1', 'Gene', (0, 9))	('beneficial impact', 'PosReg', (168, 185))
155203	33419290	PI3K inhibitors, Wortmannin and LY294002, inhibit cell spread in HEK293, although there are no inhibitory effects by JAK, MAPK, and NF-KB inhibitors.	('Wortmannin', 'Chemical', 'MESH:D000077191', (17, 27))	('cell spread', 'CPA', (50, 61))	('LY294002', 'Var', (32, 40))	('HEK293', 'CellLine', 'CVCL:0045', (65, 71))	('inhibit', 'NegReg', (42, 49))	('LY294002', 'Chemical', 'MESH:C085911', (32, 40))
155208	33419290	Although soluble interleukin-2 receptor alpha (sIL-2Ralpha) is known to predict the progression of ATLL, plasma-soluble CADM1 was reported as a biomarker for aggressive ATLL.	('plasma-soluble', 'Var', (105, 119))	('aggressive ATLL', 'Disease', 'MESH:D015459', (158, 173))	('ATLL', 'Disease', (99, 103))	('interleukin-2 receptor alpha', 'Gene', (17, 45))	('aggressive ATLL', 'Disease', (158, 173))	('interleukin-2 receptor alpha', 'Gene', '3559', (17, 45))
155213	33419290	The usefulness of plasma CADM1 methylation as a metastasis biomarker in cervical cancer has been reported.	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('CADM1', 'Gene', (25, 30))	('cancer', 'Disease', (81, 87))	('methylation', 'Var', (31, 42))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))
155214	33419290	Plasma levels of methylated CADM1 are increased in patients with advanced cervical cancer.	('CADM1', 'Gene', (28, 33))	('methylated', 'Var', (17, 27))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('patients', 'Species', '9606', (51, 59))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('Plasma levels', 'MPA', (0, 13))	('increased', 'PosReg', (38, 47))	('cancer', 'Disease', (83, 89))
155221	33419290	Epigenetic changes are involved in numerous cellular processes, such as differentiation, immune responses, and tumor development.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('immune responses', 'CPA', (89, 105))	('differentiation', 'CPA', (72, 87))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumor', 'Disease', (111, 116))	('Epigenetic changes', 'Var', (0, 18))	('involved', 'Reg', (23, 31))
155222	33419290	DNA methylation is known to regulate CADM1 in various tumors, such as ATLL, cervical cancer, epithelial ovarian cancer, oral squamous cell carcinoma, and breast cancer, and this epigenetic modification-targeted treatment exhibits therapeutic potential against malignancy.	('ATLL', 'Disease', (70, 74))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('cancer', 'Disease', (161, 167))	('CADM1', 'Gene', (37, 42))	('malignancy', 'Disease', 'MESH:D009369', (260, 270))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (125, 148))	('epithelial ovarian cancer', 'Phenotype', 'HP:0025318', (93, 118))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (120, 148))	('oral squamous cell carcinoma', 'Disease', (120, 148))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('regulate', 'Reg', (28, 36))	('tumors', 'Disease', (54, 60))	('malignancy', 'Disease', (260, 270))	('epithelial ovarian cancer', 'Disease', (93, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('breast cancer', 'Phenotype', 'HP:0003002', (154, 167))	('methylation', 'Var', (4, 15))	('cancer', 'Disease', (85, 91))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('epithelial ovarian cancer', 'Disease', 'MESH:D000077216', (93, 118))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('tumors', 'Disease', 'MESH:D009369', (54, 60))	('breast cancer', 'Disease', 'MESH:D001943', (154, 167))	('breast cancer', 'Disease', (154, 167))	('carcinoma', 'Phenotype', 'HP:0030731', (139, 148))	('ovarian cancer', 'Phenotype', 'HP:0100615', (104, 118))
155223	33419290	In cutaneous solid tumors, the CADM1 promoter is highly methylated in cutaneous melanoma and is also associated with the advance of the tumor stage and disease-related survival methylation, suggesting that CADM1 is an indicator for poor prognoses of melanoma.	('tumors', 'Disease', (19, 25))	('CADM1', 'Gene', (31, 36))	('tumor', 'Disease', (19, 24))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (70, 88))	('melanoma', 'Phenotype', 'HP:0002861', (80, 88))	('melanoma', 'Disease', (80, 88))	('melanoma', 'Disease', 'MESH:D008545', (250, 258))	('tumor', 'Disease', (136, 141))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('associated', 'Reg', (101, 111))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('methylation', 'Var', (177, 188))	('melanoma', 'Disease', 'MESH:D008545', (80, 88))	('melanoma', 'Phenotype', 'HP:0002861', (250, 258))	('melanoma', 'Disease', (250, 258))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('highly', 'PosReg', (49, 55))
155224	33419290	In addition, long non-coding RNA lymph node metastasis associated transcript 1 (LNMAT1) epigenetically impairs the expression of CADM1 in melanoma by EZH2 recruitment, which is the key enzyme of trimethylation of histone H3 at lysine 27 (H3K27me3) and promotes hypermethylation of the CADM1 promoter, resulting in the transcriptional inhibition of CADM1.	('melanoma', 'Disease', 'MESH:D008545', (138, 146))	('melanoma', 'Phenotype', 'HP:0002861', (138, 146))	('melanoma', 'Disease', (138, 146))	('EZH2', 'Gene', '2146', (150, 154))	('impairs', 'NegReg', (103, 110))	('promotes', 'PosReg', (252, 260))	('EZH2', 'Gene', (150, 154))	('transcriptional', 'MPA', (318, 333))	('expression', 'MPA', (115, 125))	('LNMAT1', 'Gene', (80, 86))	('CADM1', 'Gene', (348, 353))	('hypermethylation', 'MPA', (261, 277))	('CADM1', 'Gene', (129, 134))	('lysine', 'Chemical', 'MESH:D008239', (227, 233))	('epigenetically', 'Var', (88, 102))
155226	33419290	CADM1 promoter methylation is associated with unfavorable survival rates in patients with oral squamous cell carcinoma.	('methylation', 'Var', (15, 26))	('patients', 'Species', '9606', (76, 84))	('CADM1', 'Gene', (0, 5))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (90, 118))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (95, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('oral squamous cell carcinoma', 'Disease', (90, 118))
155230	33419290	In mice experiments of the transplantation of lymphoma cells expressing CADM1, anti-CADM1 antibodies suppress the organ invasion of lymphoma cells, resulting in improved survival rates.	('anti-CADM1', 'Var', (79, 89))	('lymphoma', 'Phenotype', 'HP:0002665', (132, 140))	('lymphoma', 'Phenotype', 'HP:0002665', (46, 54))	('survival rates', 'CPA', (170, 184))	('suppress', 'NegReg', (101, 109))	('mice', 'Species', '10090', (3, 7))	('CADM1', 'Var', (72, 77))	('lymphoma', 'Disease', (46, 54))	('lymphoma', 'Disease', (132, 140))	('lymphoma', 'Disease', 'MESH:D008223', (132, 140))	('lymphoma', 'Disease', 'MESH:D008223', (46, 54))	('improved', 'PosReg', (161, 169))
155238	33419290	Therefore, miR-194 might be useful to aid the suppression of CADM1 in the tumor cells.	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('miR-194', 'Var', (11, 18))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('CADM1', 'Gene', (61, 66))	('tumor', 'Disease', (74, 79))	('miR-194', 'Chemical', '-', (11, 18))	('suppression', 'MPA', (46, 57))
155265	31511502	The new protein variants translated by these novel spliced mRNA isoforms may play essential roles in tumorigenesis.	('roles', 'Reg', (92, 97))	('play', 'Reg', (77, 81))	('tumor', 'Disease', (101, 106))	('protein', 'Protein', (8, 15))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('variants', 'Var', (16, 24))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
155270	31511502	These mutations in SNRPB are the main cause of cerebro-costo-mandibular syndrome.	('cerebro-costo-mandibular syndrome', 'Disease', 'MESH:D008336', (47, 80))	('cause', 'Reg', (38, 43))	('SNRPB', 'Gene', (19, 24))	('cerebro-costo-mandibular syndrome', 'Disease', (47, 80))	('mutations', 'Var', (6, 15))	('-mandibular', 'Phenotype', 'HP:0000303', (60, 71))
155272	31511502	A recent study has reported that SNRPB depletion could inhibit glioblastoma cell growth.	('depletion', 'Var', (39, 48))	('glioblastoma', 'Disease', (63, 75))	('glioblastoma', 'Disease', 'MESH:D005909', (63, 75))	('SNRPB', 'Protein', (33, 38))	('glioblastoma', 'Phenotype', 'HP:0012174', (63, 75))	('inhibit', 'NegReg', (55, 62))
155287	31511502	SNRPB (16807-1-AP) and RAB26 (14284-1-AP) were obtained from Proteintech for IHC studies.	('14284-1-AP', 'Var', (30, 40))	('RAB26', 'Gene', (23, 28))	('RAB26', 'Gene', '25837', (23, 28))
155315	31511502	To examine whether SNRPB promotes the growth of NSCLC cells, we designed two different small interfering RNAs (siRNAs) to knockdown SNRPB.	('NSCLC', 'Disease', (48, 53))	('NSCLC', 'Disease', 'MESH:D002289', (48, 53))	('knockdown', 'Var', (122, 131))	('SNRPB', 'Gene', (132, 137))	('NSCLC', 'Phenotype', 'HP:0030358', (48, 53))
155316	31511502	2b, c, knockdown of SNRPB significantly decreased the growth of H1299 and A549 cells.	('H1299', 'CellLine', 'CVCL:0060', (64, 69))	('A549', 'CellLine', 'CVCL:0023', (74, 78))	('knockdown', 'Var', (7, 16))	('decreased', 'NegReg', (40, 49))	('SNRPB', 'Gene', (20, 25))
155317	31511502	In contrast, ectopic expression of SNRPB in H460 cells markedly promotes cell growth (Fig.	('cell growth', 'CPA', (73, 84))	('promotes', 'PosReg', (64, 72))	('SNRPB', 'Gene', (35, 40))	('ectopic expression', 'Var', (13, 31))	('H460', 'CellLine', 'CVCL:0459', (44, 48))
155318	31511502	In addition, knockdown of SNRPB inhibits colony formation in H1299 and A549 cells (Fig.	('H1299', 'CellLine', 'CVCL:0060', (61, 66))	('knockdown', 'Var', (13, 22))	('inhibits', 'NegReg', (32, 40))	('colony formation', 'CPA', (41, 57))	('A549', 'CellLine', 'CVCL:0023', (71, 75))	('SNRPB', 'Gene', (26, 31))
155328	31511502	Western blot assays showed that knockdown of SNRPB reduced epithelial-to-mesenchymal transition (EMT) markers expression, such as vimentin, MMP2, and MMP9 in H1299 and A549 cells (Fig.	('MMP9', 'Gene', (150, 154))	('MMP2', 'Gene', (140, 144))	('reduced', 'NegReg', (51, 58))	('A549', 'CellLine', 'CVCL:0023', (168, 172))	('SNRPB', 'Gene', (45, 50))	('knockdown', 'Var', (32, 41))	('MMP2', 'Gene', '4313', (140, 144))	('expression', 'MPA', (110, 120))	('H1299', 'CellLine', 'CVCL:0060', (158, 163))	('vimentin', 'Gene', '7431', (130, 138))	('vimentin', 'Gene', (130, 138))	('MMP9', 'Gene', '4318', (150, 154))
155336	31511502	Knockout of SNRPB decreased the tumor growth rate, tumor size and tumor weight (Fig.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor', 'Disease', (66, 71))	('decreased', 'NegReg', (18, 27))	('tumor', 'Disease', (51, 56))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('SNRPB', 'Gene', (12, 17))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('Knockout', 'Var', (0, 8))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('tumor', 'Disease', (32, 37))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
155339	31511502	Ki67 staining of xenografts derived from H1299-SNRPB-null cells indicated that cell proliferation was dramatically decreased (Fig.	('Ki67', 'Gene', '17345', (0, 4))	('cell proliferation', 'CPA', (79, 97))	('decreased', 'NegReg', (115, 124))	('H1299-SNRPB-null', 'Var', (41, 57))	('Ki67', 'Gene', (0, 4))	('H1299-SNRPB', 'CellLine', 'CVCL:0060', (41, 52))
155343	31511502	Bioluminescence imaging results showed that knockout of endogenous SNRPB in H1299 cells significantly inhibited lung metastasis (Fig.	('knockout', 'Var', (44, 52))	('inhibited', 'NegReg', (102, 111))	('H1299', 'CellLine', 'CVCL:0060', (76, 81))	('lung metastasis', 'CPA', (112, 127))	('SNRPB', 'Gene', (67, 72))
155345	31511502	Histological analysis confirmed that mice injected with cells with SNRPB knockout had fewer and smaller metastatic tumors in the lung (Fig.	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('smaller', 'NegReg', (96, 103))	('tumors', 'Disease', (115, 121))	('tumors', 'Disease', 'MESH:D009369', (115, 121))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('SNRPB', 'Gene', (67, 72))	('knockout', 'Var', (73, 81))	('mice', 'Species', '10090', (37, 41))
155348	31511502	Q-PCR analysis confirmed that the decreased expression of RAB26 upon SNRPB knockdown was most consistent with the results from the RNA-seq data (Fig.	('expression', 'MPA', (44, 54))	('decreased', 'NegReg', (34, 43))	('SNRPB', 'Gene', (69, 74))	('RAB26', 'Gene', (58, 63))	('knockdown', 'Var', (75, 84))	('RAB26', 'Gene', '25837', (58, 63))
155353	31511502	We also observed a reduction of RAB26 expression in SNRPB-knockout H1299 cells compared with control cells (Fig.	('reduction', 'NegReg', (19, 28))	('expression', 'MPA', (38, 48))	('SNRPB-knockout', 'Var', (52, 66))	('SNRPB-knockout', 'Gene', (52, 66))	('RAB26', 'Gene', '25837', (32, 37))	('H1299', 'CellLine', 'CVCL:0060', (67, 72))	('RAB26', 'Gene', (32, 37))
155363	31511502	To validate the involvement of RAB26 in SNRPB-mediated NSCLC cell proliferation, migration, and invasion, we stably introduced RAB26 or empty-vector controls into SNRPB knockout H1299 cells.	('knockout', 'Var', (169, 177))	('NSCLC', 'Disease', (55, 60))	('H1299', 'CellLine', 'CVCL:0060', (178, 183))	('SNRPB', 'Gene', (163, 168))	('RAB26', 'Gene', (127, 132))	('NSCLC', 'Disease', 'MESH:D002289', (55, 60))	('RAB26', 'Gene', (31, 36))	('RAB26', 'Gene', '25837', (127, 132))	('RAB26', 'Gene', '25837', (31, 36))	('NSCLC', 'Phenotype', 'HP:0030358', (55, 60))
155366	31511502	To further prove that RAB26 mediates SNRPB function in NSCLC, we knocked out RAB26 in SNRPB-overexpressing H460 (Fig.	('knocked out', 'Var', (65, 76))	('RAB26', 'Gene', (22, 27))	('RAB26', 'Gene', '25837', (22, 27))	('RAB26', 'Gene', (77, 82))	('NSCLC', 'Disease', (55, 60))	('RAB26', 'Gene', '25837', (77, 82))	('SNRPB-overexpressing', 'Gene', (86, 106))	('NSCLC', 'Disease', 'MESH:D002289', (55, 60))	('H460', 'CellLine', 'CVCL:0459', (107, 111))	('NSCLC', 'Phenotype', 'HP:0030358', (55, 60))
155367	31511502	Overexpression of SNRPB in H460 cells markedly facilitate xenograft tumor growth and metastasis, however, knockout of RAB6 attenuated SNRPB-induced tumor growth and metastasis (Fig.	('tumor', 'Disease', (68, 73))	('SNRPB-induced', 'Gene', (134, 147))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('H460', 'CellLine', 'CVCL:0459', (27, 31))	('tumor', 'Disease', (148, 153))	('RAB6', 'Gene', (118, 122))	('knockout', 'Var', (106, 114))	('RAB6', 'Gene', '5870', (118, 122))	('xenograft tumor', 'Disease', (58, 73))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('facilitate', 'PosReg', (47, 57))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('xenograft tumor', 'Disease', 'MESH:D009369', (58, 73))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('attenuated', 'NegReg', (123, 133))
155370	31511502	There is an intron (intron 7) retained between exons 7 and 8 in the noncoding RAB26-204 transcript variant compared with protein-coding transcript variant RAB26-201 (Fig.	('RAB26', 'Gene', (78, 83))	('RAB26', 'Gene', '25837', (78, 83))	('variant', 'Var', (99, 106))	('RAB26', 'Gene', (155, 160))	('RAB26', 'Gene', '25837', (155, 160))
155372	31511502	Interestingly, when we performed RT-PCR using primers from within exons 7 and 8 that span the intron, we found the noncoding RAB26-204 transcript was remarkably increased whereas the protein-coding transcript variant RAB26-201was decreased in SNRPB knockdown cells compared with control cells, suggesting that SNRPB is responsible for splicing the intron 7 of RAB26 (Fig.	('decreased', 'NegReg', (230, 239))	('knockdown', 'Var', (249, 258))	('RAB26', 'Gene', (360, 365))	('RAB26', 'Gene', (217, 222))	('RAB26', 'Gene', '25837', (217, 222))	('RAB26', 'Gene', (125, 130))	('RAB26', 'Gene', '25837', (360, 365))	('increased', 'PosReg', (161, 170))	('transcript', 'MPA', (135, 145))	('RAB26', 'Gene', '25837', (125, 130))
155374	31511502	To validate this hypothesis, we knocked down the essential core protein of the NMD machinery UPF1 with siRNA in H1299 cells (Fig.	('UPF1', 'Gene', (93, 97))	('H1299', 'CellLine', 'CVCL:0060', (112, 117))	('UPF1', 'Gene', '5976', (93, 97))	('knocked', 'Var', (32, 39))
155378	31511502	These data indicate that SNRPB depletion resulted in RAB26 pre-mRNA spliced into a noncoding transcript variant that was degraded by NMD.	('RAB26', 'Gene', (53, 58))	('RAB26', 'Gene', '25837', (53, 58))	('SNRPB', 'Gene', (25, 30))	('resulted in', 'Reg', (41, 52))	('depletion', 'Var', (31, 40))
155382	31511502	Dysregulation of alternative splicing is considered to be one of the hallmarks of cancer.	('Dysregulation', 'Var', (0, 13))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('cancer', 'Disease', (82, 88))
155383	31511502	A recent study also revealed that alternative splicing of many genes is significantly associated with patient survival in NSCLC.	('NSCLC', 'Disease', 'MESH:D002289', (122, 127))	('patient', 'Species', '9606', (102, 109))	('associated with', 'Reg', (86, 101))	('NSCLC', 'Phenotype', 'HP:0030358', (122, 127))	('alternative splicing', 'Var', (34, 54))	('NSCLC', 'Disease', (122, 127))
155386	31511502	Previous studies have revealed that in MYC-driven cancers, MYC directly upregulates the transcription of several genes encoding splicing factors, as well as genes encoding factors involved in snRNP assembly, including SNRPB.	('cancers', 'Disease', 'MESH:D009369', (50, 57))	('cancers', 'Phenotype', 'HP:0002664', (50, 57))	('MYC', 'Var', (59, 62))	('cancers', 'Disease', (50, 57))	('snRNP', 'Gene', (192, 197))	('snRNP', 'Gene', '57819', (192, 197))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('transcription', 'MPA', (88, 101))	('upregulates', 'PosReg', (72, 83))
155388	31511502	Indeed, our analysis of SNRPB expression in clinical samples as well as from open-access online databases both supported that that SNRPB is significantly upregulated in lung cancer and high level of SNRPB in cancer patients is associated with lower probability of overall survival.	('patients', 'Species', '9606', (215, 223))	('overall survival', 'CPA', (264, 280))	('upregulated', 'PosReg', (154, 165))	('lower', 'NegReg', (243, 248))	('cancer', 'Disease', (208, 214))	('lung cancer', 'Disease', 'MESH:D008175', (169, 180))	('SNRPB', 'Gene', (131, 136))	('cancer', 'Disease', (174, 180))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('clinical samples', 'Species', '191496', (44, 60))	('lung cancer', 'Phenotype', 'HP:0100526', (169, 180))	('lung cancer', 'Disease', (169, 180))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('high level', 'Var', (185, 195))	('cancer', 'Disease', 'MESH:D009369', (208, 214))	('SNRPB', 'Gene', (24, 29))
155392	31511502	Though the role of RBA26 in cancer is relatively unclear now, a lot of studies have revealed that the aberrant expression of Rab GTPases is closely associated with tumor suppression or tumorigenesis.	('tumor', 'Disease', (185, 190))	('tumor', 'Disease', (164, 169))	('Rab', 'Gene', (125, 128))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('Rab', 'Gene', '25837;5873;5874;326624;115827;5870', (125, 128))	('expression', 'MPA', (111, 121))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('associated', 'Reg', (148, 158))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('cancer', 'Disease', (28, 34))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('aberrant', 'Var', (102, 110))
155393	31511502	For example, RAB37 is identified as a tumor suppressor and frequently downregulated by promoter hypermethylation in lung cancer and nasopharyngeal cancer.	('promoter hypermethylation', 'Var', (87, 112))	('tumor', 'Disease', (38, 43))	('nasopharyngeal cancer', 'Disease', 'MESH:D009303', (132, 153))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('lung cancer', 'Disease', (116, 127))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('nasopharyngeal cancer', 'Disease', (132, 153))	('lung cancer', 'Phenotype', 'HP:0100526', (116, 127))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('RAB37', 'Gene', (13, 18))	('RAB37', 'Gene', '326624', (13, 18))	('downregulated', 'NegReg', (70, 83))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('lung cancer', 'Disease', 'MESH:D008175', (116, 127))	('nasopharyngeal cancer', 'Phenotype', 'HP:0100630', (132, 153))
155488	31217745	The fourth edition of the World Health Organization Classification of Tumours of the Head and Neck described a highly significant difference in the risk of malignant progression between low- and high-grade dysplasia, and high-grade dysplasia and CIS are associated with a higher risk of invasion.	('malignant progression', 'CPA', (156, 177))	('dysplasia', 'Disease', (206, 215))	('CIS', 'Phenotype', 'HP:0030075', (246, 249))	('invasion', 'CPA', (287, 295))	('dysplasia', 'Disease', 'MESH:D004476', (206, 215))	('low-', 'Var', (186, 190))	('dysplasia', 'Disease', (232, 241))	('Tumours of the Head and Neck', 'Phenotype', 'HP:0012288', (70, 98))	('dysplasia', 'Disease', 'MESH:D004476', (232, 241))	('Tumours', 'Phenotype', 'HP:0002664', (70, 77))
155491	31217745	found that high DeltaNp63 expression was involved in malignant transformation in oral OED.	('expression', 'MPA', (26, 36))	('p63', 'Gene', '8626', (22, 25))	('involved', 'Reg', (41, 49))	('p63', 'Gene', (22, 25))	('malignant transformation', 'CPA', (53, 77))	('high', 'Var', (11, 15))	('oral OED', 'Disease', (81, 89))
155511	31217745	We suggest that an overabundance of YAP results from gene amplification or increased transcription, subsequently causing YAP nuclear or cytoplasmic expression in dysplastic and malignant cells.	('transcription', 'MPA', (85, 98))	('YAP', 'Gene', '10413', (36, 39))	('YAP', 'Gene', (121, 124))	('dysplastic', 'Disease', 'MESH:D004416', (162, 172))	('dysplastic', 'Disease', (162, 172))	('YAP', 'Gene', (36, 39))	('nuclear', 'MPA', (125, 132))	('gene amplification', 'Var', (53, 71))	('increased', 'PosReg', (75, 84))	('causing', 'Reg', (113, 120))	('YAP', 'Gene', '10413', (121, 124))
155520	30834052	This retrospective and single institutional study collected 185 adenocarcinomas without active EGFR mutation, 115 squamous cell carcinomas treated with first-line cytotoxic chemotherapy, and 140 NSCLCs with mutant EGFR treated with first- or second-generation EGFR-TKI monotherapy.	('EGFR', 'Gene', (260, 264))	('EGFR', 'Gene', '1956', (214, 218))	('EGFR', 'Gene', '1956', (95, 99))	('NSCLC', 'Disease', 'MESH:D002289', (195, 200))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('carcinomas', 'Phenotype', 'HP:0030731', (128, 138))	('mutant', 'Var', (207, 213))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (114, 138))	('EGFR', 'Gene', '1956', (260, 264))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))	('NSCLC', 'Disease', (195, 200))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (114, 138))	('EGFR', 'Gene', (214, 218))	('adenocarcinomas', 'Disease', 'MESH:D000230', (64, 79))	('adenocarcinomas', 'Disease', (64, 79))	('EGFR', 'Gene', (95, 99))	('carcinomas', 'Phenotype', 'HP:0030731', (69, 79))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (114, 137))	('mutation', 'Var', (100, 108))	('squamous cell carcinomas', 'Disease', (114, 138))
155531	30834052	Our previous study suggested that the LIPI is a useful prognostic biomarker of cytotoxic chemotherapy for pulmonary adenocarcinoma with wild-type epidermal growth factor receptor (EGFR), and of EGFR-tyrosine kinase inhibitors (TKIs) for NSCLC harboring activated EGFR mutation.	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('pulmonary adenocarcinoma', 'Disease', (106, 130))	('NSCLC', 'Disease', (237, 242))	('LIPI', 'Gene', '149998', (38, 42))	('NSCLC', 'Disease', 'MESH:D002289', (237, 242))	('pulmonary adenocarcinoma', 'Disease', 'MESH:D008175', (106, 130))	('EGFR', 'Gene', '1956', (180, 184))	('pulmonary adenocarcinoma', 'Phenotype', 'HP:0030078', (106, 130))	('EGFR', 'Gene', (180, 184))	('EGFR', 'Gene', '1956', (263, 267))	('mutation', 'Var', (268, 276))	('EGFR', 'Gene', '1956', (194, 198))	('epidermal growth factor receptor', 'Gene', (146, 178))	('EGFR', 'Gene', (194, 198))	('LIPI', 'Gene', (38, 42))	('EGFR', 'Gene', (263, 267))	('epidermal growth factor receptor', 'Gene', '1956', (146, 178))
155532	30834052	As independent prognostic factors of overall survival (OS), our multivariate analyses also detected serum albumin concentration < 3.5 g/dL for wild-type EGFR adenocarcinoma treated with chemotherapy and the number of metastatic sites >= 2 for NSCLC with positive EGFR mutation treated with EGFR-TKI (in submission).	('NSCLC', 'Disease', 'MESH:D002289', (243, 248))	('carcinoma', 'Phenotype', 'HP:0030731', (163, 172))	('adenocarcinoma', 'Disease', (158, 172))	('EGFR', 'Gene', '1956', (153, 157))	('serum albumin concentration', 'MPA', (100, 127))	('adenocarcinoma', 'Disease', 'MESH:D000230', (158, 172))	('EGFR', 'Gene', '1956', (290, 294))	('mutation', 'Var', (268, 276))	('EGFR', 'Gene', '1956', (263, 267))	('EGFR', 'Gene', (153, 157))	('EGFR', 'Gene', (290, 294))	('EGFR', 'Gene', (263, 267))	('NSCLC', 'Disease', (243, 248))
155536	30834052	These patients with pathologically confirmed diagnosis of NSCLC were categorized into the following three groups according to histological and genetic characteristics: 1) wild-type EGFR adenocarcinoma; 2) NSCLC with activated EGFR mutation; and 3) Squamous cell carcinoma.	('NSCLC', 'Disease', (58, 63))	('adenocarcinoma', 'Disease', 'MESH:D000230', (186, 200))	('EGFR', 'Gene', (181, 185))	('Squamous cell carcinoma', 'Disease', 'MESH:D002294', (248, 271))	('NSCLC', 'Disease', 'MESH:D002289', (58, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (191, 200))	('activated', 'PosReg', (216, 225))	('NSCLC', 'Disease', (205, 210))	('patients', 'Species', '9606', (6, 14))	('EGFR', 'Gene', '1956', (226, 230))	('Squamous cell carcinoma', 'Phenotype', 'HP:0002860', (248, 271))	('adenocarcinoma', 'Disease', (186, 200))	('NSCLC', 'Disease', 'MESH:D002289', (205, 210))	('carcinoma', 'Phenotype', 'HP:0030731', (262, 271))	('EGFR', 'Gene', '1956', (181, 185))	('Squamous cell carcinoma', 'Disease', (248, 271))	('mutation', 'Var', (231, 239))	('EGFR', 'Gene', (226, 230))
155537	30834052	EGFR mutation status was examined by the peptide nucleic acid-locked nucleic acid polymerase chain reaction (PCR) clamp method or cobas EGFR Mutation Test v2 by LSI Medience Cooperation (Tokyo, Japan).	('EGFR', 'Gene', (136, 140))	('EGFR', 'Gene', (0, 4))	('EGFR', 'Gene', '1956', (136, 140))	('EGFR', 'Gene', '1956', (0, 4))	('Mutation', 'Var', (141, 149))
155546	30834052	This study collected 185 patients with wild-type EGFR adenocarcinoma, 140 patients with activated EGFR mutation, and 115 patients with squamous cell carcinoma.	('EGFR', 'Gene', (98, 102))	('EGFR', 'Gene', '1956', (49, 53))	('adenocarcinoma', 'Disease', (54, 68))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (135, 158))	('adenocarcinoma', 'Disease', 'MESH:D000230', (54, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (149, 158))	('EGFR', 'Gene', (49, 53))	('patients', 'Species', '9606', (74, 82))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (135, 158))	('carcinoma', 'Phenotype', 'HP:0030731', (59, 68))	('squamous cell carcinoma', 'Disease', (135, 158))	('patients', 'Species', '9606', (25, 33))	('EGFR', 'Gene', '1956', (98, 102))	('mutation', 'Var', (103, 111))	('patients', 'Species', '9606', (121, 129))
155549	30834052	At the time of data cut-off, the numbers of dead patients and patients who had experienced confirmed PD or death after the first-line chemotherapy were 144 and 166 in wild-type EGFR adenocarcinoma, 71 and 107 in NSCLC harboring positive EGFR mutation, and 82 and 94 in squamous cell carcinoma, respectively.	('EGFR', 'Gene', '1956', (237, 241))	('NSCLC', 'Disease', 'MESH:D002289', (212, 217))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (269, 292))	('squamous cell carcinoma', 'Disease', (269, 292))	('carcinoma', 'Phenotype', 'HP:0030731', (187, 196))	('EGFR', 'Gene', (237, 241))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (269, 292))	('carcinoma', 'Phenotype', 'HP:0030731', (283, 292))	('adenocarcinoma', 'Disease', (182, 196))	('death', 'Disease', 'MESH:D003643', (107, 112))	('EGFR', 'Gene', '1956', (177, 181))	('adenocarcinoma', 'Disease', 'MESH:D000230', (182, 196))	('patients', 'Species', '9606', (49, 57))	('death', 'Disease', (107, 112))	('patients', 'Species', '9606', (62, 70))	('EGFR', 'Gene', (177, 181))	('NSCLC', 'Disease', (212, 217))	('mutation', 'Var', (242, 250))
155550	30834052	The OS and PFS of low-score groups were significantly longer than those of high-score groups in wild-type EGFR adenocarcinoma (low vs. high; median OS, 18.4 vs. 5.1 months, P < 0.01, and median PFS, 5.8 vs. 3.7 months, P = 0.01) (Figs.	('low-score', 'Var', (18, 27))	('longer', 'PosReg', (54, 60))	('adenocarcinoma', 'Disease', (111, 125))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('EGFR', 'Gene', '1956', (106, 110))	('adenocarcinoma', 'Disease', 'MESH:D000230', (111, 125))	('EGFR', 'Gene', (106, 110))
155576	30145807	Depletion of the p65 subunit of NF-kappaB abolished the TNFalpha-induced expression of TNFAIP2.	('TNFalpha-induced', 'Gene', (56, 72))	('p65', 'Gene', '5970', (17, 20))	('abolished', 'NegReg', (42, 51))	('Depletion', 'Var', (0, 9))	('p65', 'Gene', (17, 20))	('expression', 'MPA', (73, 83))	('TNFAIP2', 'Gene', (87, 94))	('p65 subunit of NF-kappaB', 'Gene', '5970', (17, 41))	('p65 subunit of NF-kappaB', 'Gene', (17, 41))
155578	30145807	The study revealed that NF-kappaB inhibitor (BAY11-7082) or depletion of p65 largely reduced the LMP1-induced TNFAIP2 expression, whereas ectopic expression of p65 is sufficient to induce TNFAIP2 expression.	('BAY11-7082', 'Var', (45, 55))	('TNFAIP2', 'Gene', (110, 117))	('BAY11-7082', 'Chemical', 'MESH:C434003', (45, 55))	('LMP1-induced TNFAIP2', 'Gene', (97, 117))	('reduced', 'NegReg', (85, 92))	('depletion', 'MPA', (60, 69))	('expression', 'MPA', (118, 128))
155590	30145807	The silencing of TNFAIP2 in activated endothelial cells decreased the transendothelial migration of effector T lymphocytes by reducing the preferential secretion of endothelial-produced CCL2, IL-6 and GM-CSF.31  We reported that KLF5 induces TNFAIP2 to promote triple-negative breast cancer cell proliferation.	('promote', 'PosReg', (253, 260))	('CCL2', 'Gene', '6347', (186, 190))	('breast cancer', 'Phenotype', 'HP:0003002', (277, 290))	('TNFAIP2', 'Gene', (17, 24))	('reducing', 'NegReg', (126, 134))	('decreased', 'NegReg', (56, 65))	('triple-negative breast cancer', 'Disease', (261, 290))	('IL-6', 'Gene', (192, 196))	('CCL2', 'Gene', (186, 190))	('IL-6', 'Gene', '3569', (192, 196))	('cancer', 'Phenotype', 'HP:0002664', (284, 290))	('TNFAIP2', 'Gene', (242, 249))	('GM-CSF', 'Gene', (201, 207))	('silencing', 'Var', (4, 13))	('transendothelial migration of', 'CPA', (70, 99))	('GM-CSF', 'Gene', '1437', (201, 207))
155593	30145807	Knockdown of TNFAIP2 in nasopharyngeal carcinoma HK1 cells dramatically reduced cell migration and invasion but had no significant impact on cell growth.30  Additionally, TNFAIP2 was found to promote cell migration and invasion via the activation of the Wnt/beta-catenin signalling pathway in oesophageal squamous cell carcinoma.32 Knockdown of TNFAIP2 inhibits the expression of beta-catenin and its downstream targets, including C-Myc, Cyclin D1, MMP-7 and Snail, and upregulates the expression of E-cadherin and p-GSK-3beta.	('Cyclin D1', 'Gene', '595', (438, 447))	('Knockdown', 'Var', (332, 341))	('MMP-7', 'Gene', (449, 454))	('Cyclin D1', 'Gene', (438, 447))	('carcinoma', 'Phenotype', 'HP:0030731', (319, 328))	('upregulates', 'PosReg', (470, 481))	('Snail', 'Gene', '6615', (459, 464))	('expression', 'MPA', (366, 376))	('expression', 'MPA', (486, 496))	('MMP-7', 'Gene', '4316', (449, 454))	('carcinoma', 'Phenotype', 'HP:0030731', (39, 48))	('beta-catenin', 'Gene', (380, 392))	('inhibits', 'NegReg', (353, 361))	('beta-catenin', 'Gene', '1499', (380, 392))	('HK1', 'CellLine', 'CVCL:7047', (49, 52))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (305, 328))	('p-GSK-3beta', 'Protein', (515, 526))	('TNFAIP2', 'Gene', (345, 352))	('Snail', 'Gene', (459, 464))	('beta-catenin', 'Gene', (258, 270))	('C-Myc', 'Gene', (431, 436))	('E-cadherin', 'Gene', (500, 510))	('E-cadherin', 'Gene', '999', (500, 510))	('beta-catenin', 'Gene', '1499', (258, 270))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (24, 48))	('C-Myc', 'Gene', '4609', (431, 436))
155594	30145807	TNT structures mediate the intercellular transport of various components, including calcium, proteins, organelles and HIV virus, in a variety of cell types, such as B cells,33 T cells,34 macrophages,35 mast cells,36 NK cells37 and dendritic cells.38  TNFAIP2 is recognized as a TNT marker and central factor for TNT formation.39 Depletion of TNFAIP2 drastically reduces endogenous TNT formation as well as intercellular calcium flux in Raw264.7 macrophages.	('intercellular calcium flux', 'MPA', (406, 432))	('TNFAIP2', 'Gene', (342, 349))	('Raw264.7', 'CellLine', 'CVCL:0493', (436, 444))	('Depletion', 'Var', (329, 338))	('calcium', 'Chemical', 'MESH:D002118', (420, 427))	('calcium', 'Chemical', 'MESH:D002118', (84, 91))	('reduces', 'NegReg', (362, 369))	('endogenous TNT formation', 'MPA', (370, 394))	('HIV virus', 'Disease', 'MESH:D015658', (118, 127))	('HIV virus', 'Disease', (118, 127))
155596	30145807	In squamous cell carcinoma of the head and neck, the rs8126 variant C allele greatly reduced luciferase activity and mRNA expression of TNFAIP2 and increased cancer risk in an allele dose-response manner compared with the rs8126 TT genotype.9 In another study, the rs8126 CC genotype was significantly associated with an increased risk of gastric cancer compared with the combined rs8126 TT+TC genotypes.42 In normal oesophagus tissues, carriers of the rs8126 CC and CT genotypes had significantly lower TNFAIP2 mRNA levels than those with the TT genotypes.43 Furthermore, the SNP at the 3' UTR of TNFAIP2 (rs8126 T > C) is the binding site of miR-184.	('rs8126', 'Mutation', 'rs8126', (607, 613))	('rs8126', 'Mutation', 'rs8126', (265, 271))	('gastric cancer', 'Phenotype', 'HP:0012126', (339, 353))	('rs8126', 'Var', (607, 613))	('rs8126', 'Var', (265, 271))	('miR-184', 'Gene', '406960', (644, 651))	('carcinoma', 'Phenotype', 'HP:0030731', (17, 26))	('rs8126', 'Mutation', 'rs8126', (453, 459))	('rs8126', 'Var', (453, 459))	('rs8126', 'DBSNP_MENTION', 'None', (607, 613))	('rs8126', 'Mutation', 'rs8126', (222, 228))	('gastric cancer', 'Disease', (339, 353))	('carcinoma of the head and neck', 'Phenotype', 'HP:0012288', (17, 47))	('rs8126', 'DBSNP_MENTION', 'None', (265, 271))	('rs8126', 'Var', (222, 228))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('rs8126', 'Mutation', 'rs8126', (381, 387))	('binding', 'Interaction', (628, 635))	('cancer', 'Phenotype', 'HP:0002664', (347, 353))	('rs8126', 'Var', (381, 387))	('rs8126', 'Mutation', 'rs8126', (53, 59))	('rs8126', 'DBSNP_MENTION', 'None', (453, 459))	('rs8126', 'Var', (53, 59))	('miR-184', 'Gene', (644, 651))	('TNFAIP2', 'Gene', (598, 605))	('gastric cancer', 'Disease', 'MESH:D013274', (339, 353))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (3, 26))	('rs8126', 'DBSNP_MENTION', 'None', (222, 228))	('rs8126', 'DBSNP_MENTION', 'None', (381, 387))	('increased risk of gastric cancer', 'Phenotype', 'HP:0006753', (321, 353))	('rs8126', 'DBSNP_MENTION', 'None', (53, 59))
155597	30145807	miR-184 is inversely correlated with TNFAIP2 mRNA and protein expression levels in glioma.44 In septic shock patients, the 3'UTR SNP (rs8126) of TNFAIP2 is associated with the higher mortality of septic shock patients.	('glioma', 'Disease', (83, 89))	('septic shock', 'Disease', 'MESH:D012772', (196, 208))	('septic shock', 'Disease', (96, 108))	('rs8126', 'DBSNP_MENTION', 'None', (134, 140))	('septic shock', 'Disease', 'MESH:D012772', (96, 108))	('shock', 'Phenotype', 'HP:0031273', (103, 108))	('TNFAIP2', 'Gene', (145, 152))	('glioma', 'Disease', 'MESH:D005910', (83, 89))	('glioma', 'Phenotype', 'HP:0009733', (83, 89))	('septic shock', 'Phenotype', 'HP:0100806', (196, 208))	('associated', 'Reg', (156, 166))	('septic shock', 'Disease', (196, 208))	('septic shock', 'Phenotype', 'HP:0100806', (96, 108))	('shock', 'Phenotype', 'HP:0031273', (203, 208))	('rs8126', 'Var', (134, 140))
155598	30145807	Compared with the A allele, the G allele of TNFAIP2 rs8126 enhanced TNFAIP2 expression, decreased IL-8 production, reduced the survival and increased organ dysfunction in patients experiencing septic shock.45  Expression of TNFAIP2 was found to be abnormal in cancers, bacteria and virus infectious diseases.	('septic shock', 'Phenotype', 'HP:0100806', (193, 205))	('shock', 'Phenotype', 'HP:0031273', (200, 205))	('rs8126', 'DBSNP_MENTION', 'None', (52, 58))	('IL-8', 'Gene', (98, 102))	('decreased', 'NegReg', (88, 97))	('virus infectious diseases', 'Disease', 'MESH:D003141', (282, 307))	('organ dysfunction', 'Disease', 'MESH:D019965', (150, 167))	('IL-8', 'Gene', '3576', (98, 102))	('TNFAIP2', 'Gene', (68, 75))	('organ dysfunction', 'Disease', (150, 167))	('cancers', 'Phenotype', 'HP:0002664', (260, 267))	('cancers', 'Disease', (260, 267))	('cancer', 'Phenotype', 'HP:0002664', (260, 266))	('virus infectious diseases', 'Disease', (282, 307))	('rs8126', 'Var', (52, 58))	('enhanced', 'PosReg', (59, 67))	('TNFAIP2', 'Gene', (224, 231))	('abnormal', 'Reg', (248, 256))	('expression', 'MPA', (76, 86))	('bacteria', 'Disease', (269, 277))
155603	30145807	A high TNFAIP2 mRNA level is significantly associated with a short survival in several cancer types, including kidney renal clear cell carcinoma, brain lower grade glioma and thymoma (Figure 2B).	('glioma', 'Phenotype', 'HP:0009733', (164, 170))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('high', 'Var', (2, 6))	('kidney renal clear cell carcinoma', 'Disease', 'MESH:C538614', (111, 144))	('TNFAIP2', 'Gene', (7, 14))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('kidney renal clear cell carcinoma', 'Disease', (111, 144))	('mRNA level', 'MPA', (15, 25))	('thymoma', 'Phenotype', 'HP:0100522', (175, 182))	('glioma and thymoma', 'Disease', 'MESH:D013945', (164, 182))
155604	30145807	On the contrary, a high TNFAIP2 mRNA level is significantly associated with a long survival in several cancers, including bladder urothelial carcinoma, sarcoma and skin cutaneous melanoma (Figure 2C).	('bladder urothelial carcinoma', 'Disease', (122, 150))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (164, 187))	('sarcoma', 'Disease', 'MESH:D012509', (152, 159))	('high', 'Var', (19, 23))	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('skin cutaneous melanoma', 'Disease', (164, 187))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (169, 187))	('sarcoma', 'Disease', (152, 159))	('sarcoma', 'Phenotype', 'HP:0100242', (152, 159))	('TNFAIP2', 'Gene', (24, 31))	('mRNA level', 'MPA', (32, 42))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (122, 150))	('melanoma', 'Phenotype', 'HP:0002861', (179, 187))	('cancers', 'Phenotype', 'HP:0002664', (103, 110))	('associated with', 'Reg', (60, 75))
155608	28000771	The pan-cancer pathological regulatory landscape Dysregulation of the normal gene expression program is the cause of a broad range of diseases, including cancer.	('cancer', 'Disease', (8, 14))	('cancer', 'Disease', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('Dysregulation', 'Var', (49, 62))	('cause', 'Reg', (108, 113))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (8, 14))
155614	28000771	In fact, a broad range of diseases and syndromes, including cancer, are caused by mutations that affect TFs either directly or indirectly, by affecting cofactors, regulatory sequences, chromatin regulators, and noncoding RNAs that interact with these regions.	('noncoding', 'Protein', (211, 220))	('TFs', 'Gene', (104, 107))	('regulatory sequences', 'MPA', (163, 183))	('chromatin', 'MPA', (185, 194))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('cancer', 'Disease', (60, 66))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('mutations', 'Var', (82, 91))	('diseases', 'Disease', (26, 34))	('RNAs', 'Protein', (221, 225))	('affecting', 'Reg', (142, 151))	('cofactors', 'MPA', (152, 161))	('caused by', 'Reg', (72, 81))
155615	28000771	Specifically, dysregulations or changes in the activation status of distinct TFs are known to be linked to a number of cancers.	('changes', 'Reg', (32, 39))	('activation', 'MPA', (47, 57))	('cancers', 'Disease', 'MESH:D009369', (119, 126))	('cancers', 'Phenotype', 'HP:0002664', (119, 126))	('linked', 'Reg', (97, 103))	('cancers', 'Disease', (119, 126))	('TFs', 'Gene', (77, 80))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('dysregulations', 'Var', (14, 28))
155621	28000771	Alterations in the transcriptional regulatory network due to perturbed TF activity cause the dysregulation of gene expression observed during cancer progression.	('perturbed', 'Var', (61, 70))	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('dysregulation of gene expression', 'MPA', (93, 125))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('transcriptional regulatory network', 'Pathway', (19, 53))	('activity', 'MPA', (74, 82))	('Alterations', 'Reg', (0, 11))	('cancer', 'Disease', (142, 148))
155634	28000771	Actually, high levels of SP1 protein are considered a negative prognostic factor for several cancers.	('cancers', 'Disease', (93, 100))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('cancers', 'Disease', 'MESH:D009369', (93, 100))	('SP1 protein', 'Protein', (25, 36))	('high', 'Var', (10, 14))	('cancers', 'Phenotype', 'HP:0002664', (93, 100))
155663	28000771	Supplementary Table 1 contains the complete list of p-values obtained for all the TFs in all the cancers studied.	('cancers', 'Disease', 'MESH:D009369', (97, 104))	('cancers', 'Phenotype', 'HP:0002664', (97, 104))	('cancers', 'Disease', (97, 104))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('p-values', 'Var', (52, 60))
155748	27686732	Studies also suggest that lncRNA aberrant expression is associated with numerous diseases including cancer.	('lncRNA', 'Protein', (26, 32))	('numerous diseases', 'Disease', (72, 89))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('associated', 'Reg', (56, 66))	('numerous diseases', 'Disease', 'MESH:D004194', (72, 89))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('aberrant expression', 'Var', (33, 52))
155758	27686732	However, recent studies have linked specific lncRNA gene mutations with cancer, raising the possibility of lncRNA-based cancer diagnostics and therapy.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('mutations', 'Var', (57, 66))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('lncRNA gene', 'Gene', (45, 56))	('cancer', 'Disease', (72, 78))
155774	27686732	HOTAIR knockdown efficiently inhibits cell proliferation and matrix invasiveness in gastric cancer cells in vitro.	('cell proliferation', 'CPA', (38, 56))	('gastric cancer', 'Disease', (84, 98))	('gastric cancer', 'Disease', 'MESH:D013274', (84, 98))	('gastric cancer', 'Phenotype', 'HP:0012126', (84, 98))	('matrix invasiveness', 'CPA', (61, 80))	('inhibits', 'NegReg', (29, 37))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('knockdown', 'Var', (7, 16))
155776	27686732	The five-year survival rate of patients with positive HOTAIR expression was greatly reduced compared with patients with negative expression.	('reduced', 'NegReg', (84, 91))	('patients', 'Species', '9606', (106, 114))	('patients', 'Species', '9606', (31, 39))	('HOTAIR expression', 'Var', (54, 71))
155777	27686732	In vitro, HOTAIR facilitates ESCC cell proliferation, colony formation, and migration, while silencing of HOTAIR in ESCC KYSE30 cells reduced cell invasion and migration but enhances apoptosis rate.	('apoptosis rate', 'CPA', (183, 197))	('silencing', 'Var', (93, 102))	('facilitates', 'PosReg', (17, 28))	('colony formation', 'CPA', (54, 70))	('migration', 'CPA', (76, 85))	('migration', 'CPA', (160, 169))	('KYSE30', 'CellLine', 'CVCL:1351', (121, 127))	('cell invasion', 'CPA', (142, 155))	('enhances', 'PosReg', (174, 182))	('ESCC cell proliferation', 'CPA', (29, 52))	('reduced', 'NegReg', (134, 141))	('HOTAIR', 'Gene', (106, 112))
155778	27686732	In nude mice ESCC models, HOTAIR promoted cell proliferation and tumor metastasis, while knockout reduced the metastasis of ESCC cells.	('HOTAIR', 'Var', (26, 32))	('promoted', 'PosReg', (33, 41))	('ESCC', 'Disease', (13, 17))	('metastasis', 'CPA', (110, 120))	('cell proliferation', 'CPA', (42, 60))	('tumor metastasis', 'Disease', 'MESH:D009362', (65, 81))	('nude mice', 'Species', '10090', (3, 12))	('tumor metastasis', 'Disease', (65, 81))	('reduced', 'NegReg', (98, 105))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
155782	27686732	Additionally, HOTAIR impedes RNA binding motif 38 (RBM38) protein expression and initiates HCC cell invasion and migration.	('RBM38', 'Gene', (51, 56))	('protein', 'Protein', (58, 65))	('RBM38', 'Gene', '55544', (51, 56))	('HCC', 'Gene', '619501', (91, 94))	('HCC', 'Phenotype', 'HP:0001402', (91, 94))	('impedes', 'NegReg', (21, 28))	('expression', 'MPA', (66, 76))	('RNA binding motif 38', 'Gene', '55544', (29, 49))	('HOTAIR', 'Var', (14, 20))	('initiates', 'PosReg', (81, 90))	('RNA binding motif 38', 'Gene', (29, 49))	('HCC', 'Gene', (91, 94))
155788	27686732	Facilitation of matrix invasion and migration has been ascribed to HOTAIR-mediated activation of VEGF, MMP-9, and genes associated with epithelial-to-mesenchymal transition (EMT) as well as inhibition of p21.	('MMP-9', 'Gene', '4318', (103, 108))	('VEGF', 'Gene', (97, 101))	('MMP-9', 'Gene', (103, 108))	('matrix invasion', 'CPA', (16, 31))	('p21', 'Gene', (204, 207))	('epithelial-to-mesenchymal transition', 'CPA', (136, 172))	('VEGF', 'Gene', '7422', (97, 101))	('inhibition', 'Var', (190, 200))	('p21', 'Gene', '644914', (204, 207))	('genes', 'Gene', (114, 119))	('activation', 'PosReg', (83, 93))
155793	27686732	Ip1, HO8910-PM, and HEY-A8) in vitro depresses cell migration and invasion.	('depresses', 'NegReg', (37, 46))	('Ip1', 'Gene', '8517', (0, 3))	('HO8910-PM', 'Var', (5, 14))	('HO8910', 'CellLine', 'CVCL:6868', (5, 11))	('Ip1', 'Gene', (0, 3))
155803	27686732	MALAT1 is associated with EMT, which confers invasive capacity to malignant cells, and the depletion of MALAT1 can reduce the migration of glioblastoma cells.	('glioblastoma', 'Disease', 'MESH:D005909', (139, 151))	('glioblastoma', 'Phenotype', 'HP:0012174', (139, 151))	('depletion', 'Var', (91, 100))	('MALAT1', 'Gene', (104, 110))	('glioblastoma', 'Disease', (139, 151))	('reduce', 'NegReg', (115, 121))
155813	27686732	Post-transcriptional silencing of MALAT1 can reduce ESCC cell proliferation through cell cycle block, and this may relate to suppression of MALAT1-mediated upregulation of p21 and p27 as well as inhibition of the cell cycle-associated transcription factor B-MYB.	('MALAT1', 'Gene', (34, 40))	('p21', 'Gene', (172, 175))	('p21', 'Gene', '644914', (172, 175))	('upregulation', 'PosReg', (156, 168))	('suppression', 'NegReg', (125, 136))	('MALAT1-mediated', 'Gene', (140, 155))	('p27', 'Gene', '3429', (180, 183))	('inhibition', 'NegReg', (195, 205))	('B-MYB', 'Gene', (256, 261))	('reduce', 'NegReg', (45, 51))	('Post-transcriptional', 'Var', (0, 20))	('ESCC', 'Disease', (52, 56))	('B-MYB', 'Gene', '4605', (256, 261))	('p27', 'Gene', (180, 183))	('cell cycle block', 'CPA', (84, 100))
155815	27686732	Stable knockout of MALAT1 prevents cell proliferation and motility, which is associated with G2/M arrest, enhanced apoptosis, disrupted EMT, and weakened cancer stem-like properties in vitro, consistent with a putative oncogenic role for MALAT1 in this usually fatal disease.	('enhanced', 'PosReg', (106, 114))	('prevents', 'NegReg', (26, 34))	('cancer', 'Disease', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('cell proliferation', 'CPA', (35, 53))	('disrupted', 'NegReg', (126, 135))	('knockout', 'Var', (7, 15))	('apoptosis', 'CPA', (115, 124))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('weakened', 'NegReg', (145, 153))	('MALAT1', 'Gene', (19, 25))	('EMT', 'CPA', (136, 139))
155822	27686732	In castrated male nude mice, siRNA-mediated silencing of MALAT1 delayed tumor growth and inhibited PCa cell metastasis.	('delayed', 'NegReg', (64, 71))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('PCa cell metastasis', 'CPA', (99, 118))	('PCa', 'Phenotype', 'HP:0012125', (99, 102))	('tumor', 'Disease', (72, 77))	('inhibited', 'NegReg', (89, 98))	('nude mice', 'Species', '10090', (18, 27))	('silencing', 'Var', (44, 53))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('MALAT1', 'Gene', (57, 63))
155831	27686732	Furthermore, high expression of MALAT1 was found exclusively in metastatic tissues developed in lymph node, and knockout of MALAT1 inhibits melanoma cell migration in vitro.	('knockout', 'Var', (112, 120))	('MALAT1', 'Gene', (124, 130))	('melanoma', 'Phenotype', 'HP:0002861', (140, 148))	('inhibits', 'NegReg', (131, 139))	('melanoma', 'Disease', (140, 148))	('melanoma', 'Disease', 'MESH:D008545', (140, 148))
155833	27686732	Ectopic expression of MALAT2 enhanced the motility of the human GC cell line SGC-7901 in vitro, whereas silencing of MALAT2 impairs tumor metastasis.	('impairs tumor metastasis', 'Disease', 'MESH:D009362', (124, 148))	('human', 'Species', '9606', (58, 63))	('motility', 'CPA', (42, 50))	('silencing', 'Var', (104, 113))	('GC', 'Phenotype', 'HP:0012126', (78, 80))	('MALAT2', 'Gene', (22, 28))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('GC', 'Phenotype', 'HP:0012126', (64, 66))	('SGC-7901', 'CellLine', 'CVCL:0520', (77, 85))	('MALAT2', 'Gene', (117, 123))	('enhanced', 'PosReg', (29, 37))	('impairs tumor metastasis', 'Disease', (124, 148))
155838	27686732	The oncogenic properties of H19 were strongly associated with antagonism of the tumor suppressor miRNA let-7 and forced EMT mediated by the non-histone chromosomal transcriptional regulator HMGA2.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('H19', 'Gene', '283120', (28, 31))	('oncogenic properties', 'CPA', (4, 24))	('HMGA2', 'Gene', (190, 195))	('H19', 'Gene', (28, 31))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumor', 'Disease', (80, 85))	('antagonism', 'Var', (62, 72))	('associated', 'Reg', (46, 56))	('HMGA2', 'Gene', '8091', (190, 195))	('miR', 'Gene', '220972', (97, 100))	('miR', 'Gene', (97, 100))	('forced EMT mediated', 'CPA', (113, 132))
155848	27686732	In retinoblastoma tissues, high BANCR expression was correlated with tumor size and invasion of choroid and optic nerve.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor', 'Disease', (69, 74))	('correlated', 'Reg', (53, 63))	('BANCR', 'Gene', '100885775', (32, 37))	('retinoblastoma', 'Phenotype', 'HP:0009919', (3, 17))	('high', 'Var', (27, 31))	('BANCR', 'Gene', (32, 37))	('retinoblastoma', 'Disease', 'MESH:D012175', (3, 17))	('retinoblastoma', 'Disease', (3, 17))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
155865	27686732	As expected, the ectopic expression of UCA1 induced a marked increase in lymph node metastasis.	('UCA1', 'Gene', '652995', (39, 43))	('UCA1', 'Gene', (39, 43))	('ectopic expression', 'Var', (17, 35))	('increase', 'PosReg', (61, 69))	('lymph node metastasis', 'CPA', (73, 94))
155872	27686732	UCA1 upregulation was correlated with poor differentiation, advanced lymph node classification, and metastasis of melanoma cells, while invasive and migratory capacities were remarkably diminished by UCA1 knockdown.	('metastasis of melanoma cells', 'Disease', 'MESH:D009362', (100, 128))	('advanced lymph node classification', 'CPA', (60, 94))	('UCA1', 'Gene', '652995', (200, 204))	('UCA1', 'Gene', (200, 204))	('knockdown', 'Var', (205, 214))	('upregulation', 'PosReg', (5, 17))	('melanoma', 'Phenotype', 'HP:0002861', (114, 122))	('UCA1', 'Gene', '652995', (0, 4))	('UCA1', 'Gene', (0, 4))	('diminished', 'NegReg', (186, 196))	('metastasis of melanoma cells', 'Disease', (100, 128))	('poor differentiation', 'CPA', (38, 58))
155876	27686732	Conversely, inhibition of FOXCUT impaired the invasion and migration capabilities of the breast cancer cell lines MDA-MB-231 and MDA-MB-468.	('FOXCUT', 'Gene', '101927703', (26, 32))	('inhibition', 'Var', (12, 22))	('breast cancer', 'Disease', 'MESH:D001943', (89, 102))	('MDA-MB-468', 'CellLine', 'CVCL:0419', (129, 139))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('impaired', 'NegReg', (33, 41))	('breast cancer', 'Disease', (89, 102))	('breast cancer', 'Phenotype', 'HP:0003002', (89, 102))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (114, 124))	('FOXCUT', 'Gene', (26, 32))
155882	27686732	On the contrary, knockdown of these lncRNAs lead to diminished cell viability and increased anoikis in EAC EC9706 and KYSE150 cells compared to cells transfected with empty vector.	('KYSE150', 'CellLine', 'CVCL:1348', (118, 125))	('cell viability', 'CPA', (63, 77))	('EC9706', 'CellLine', 'CVCL:E307', (107, 113))	('diminished', 'NegReg', (52, 62))	('increased', 'PosReg', (82, 91))	('knockdown', 'Var', (17, 26))	('anoikis', 'CPA', (92, 99))
155886	27686732	found that local infiltration depth of neuroblastoma was correlated with dysregulated expression of SPRY4-IT1, leading to repressed proliferation and extensive apoptosis.	('apoptosis', 'CPA', (160, 169))	('dysregulated', 'Var', (73, 85))	('neuroblastoma', 'Disease', 'MESH:D009447', (39, 52))	('expression', 'MPA', (86, 96))	('neuroblastoma', 'Disease', (39, 52))	('neuroblastoma', 'Phenotype', 'HP:0003006', (39, 52))	('SPRY4-IT1', 'Gene', (100, 109))	('repressed proliferation', 'CPA', (122, 145))	('SPRY4-IT1', 'Gene', '100642175;81848;79441', (100, 109))
155895	27686732	In one study, patients with high ATB expression had strikingly shorter overall survivals than those with low expression.	('shorter', 'NegReg', (63, 70))	('ATB', 'Protein', (33, 36))	('overall survivals', 'MPA', (71, 88))	('ATB', 'Chemical', 'MESH:C042207', (33, 36))	('high', 'Var', (28, 32))	('expression', 'MPA', (37, 47))	('patients', 'Species', '9606', (14, 22))
155902	27686732	In vitro, knockdown of ZXF1 by siRNA depressed the invasion and migration of A549 cells, whereas no remarkable effect was observed on cell growth.	('depressed', 'NegReg', (37, 46))	('ZXF1', 'Gene', (23, 27))	('ZXF1', 'Gene', '100132116', (23, 27))	('knockdown', 'Var', (10, 19))	('A549', 'CellLine', 'CVCL:0023', (77, 81))
155908	27686732	In vitro experiment, knockdown of CARLo-5 inhibited the proliferative activity, infiltration, and migration of NSCLC cell lines.	('infiltration', 'CPA', (80, 92))	('NSCLC', 'Disease', (111, 116))	('men', 'Species', '9606', (15, 18))	('NSCLC', 'Disease', 'MESH:D002289', (111, 116))	('inhibited', 'NegReg', (42, 51))	('NSCLC', 'Phenotype', 'HP:0030358', (111, 116))	('CARLo-5', 'Gene', (34, 41))	('CARLo-5', 'Gene', '100507056', (34, 41))	('knockdown', 'Var', (21, 30))	('proliferative activity', 'CPA', (56, 78))
155909	27686732	Additionally, inhibition of CARLo-5 could reverse EMT in a NSCLC cell line.	('NSCLC', 'Disease', 'MESH:D002289', (59, 64))	('NSCLC', 'Phenotype', 'HP:0030358', (59, 64))	('EMT', 'CPA', (50, 53))	('CARLo-5', 'Gene', (28, 35))	('CARLo-5', 'Gene', '100507056', (28, 35))	('inhibition', 'Var', (14, 24))	('NSCLC', 'Disease', (59, 64))
155915	27686732	XIST expression is upregulated in glioma tissues and human glioblastoma stem cells (GSCs), while knockdown of XIST reduced cell proliferation, migration, and invasion, and induced apoptosis.	('upregulated', 'PosReg', (19, 30))	('glioma', 'Phenotype', 'HP:0009733', (34, 40))	('knockdown', 'Var', (97, 106))	('glioma tissues', 'Disease', (34, 48))	('glioma tissues', 'Disease', 'MESH:D005910', (34, 48))	('cell proliferation', 'CPA', (123, 141))	('reduced', 'NegReg', (115, 122))	('glioblastoma', 'Disease', (59, 71))	('glioblastoma', 'Disease', 'MESH:D005909', (59, 71))	('invasion', 'CPA', (158, 166))	('XIST', 'Gene', (0, 4))	('induced', 'Reg', (172, 179))	('human', 'Species', '9606', (53, 58))	('XIST', 'Gene', (110, 114))	('glioblastoma', 'Phenotype', 'HP:0012174', (59, 71))	('migration', 'CPA', (143, 152))	('apoptosis', 'CPA', (180, 189))
155916	27686732	In vivo knockdown of XIST restrained tumor growth and produced higher survival in nude mice.	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('knockdown', 'Var', (8, 17))	('nude mice', 'Species', '10090', (82, 91))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('XIST', 'Gene', (21, 25))	('tumor', 'Disease', (37, 42))	('restrained', 'NegReg', (26, 36))	('survival', 'CPA', (70, 78))	('higher', 'PosReg', (63, 69))
155920	27686732	HIT expression is dramatically increased in the highly metastatic 4 T1 cell line, and knockout of HIT in 4 T1 cells resulted in decreased cell migration and invasion.	('knockout', 'Var', (86, 94))	('HIT', 'Disease', 'MESH:D013921', (0, 3))	('HIT', 'Disease', (0, 3))	('increased', 'PosReg', (31, 40))	('4 T1', 'CellLine', 'CVCL:0125', (105, 109))	('decreased', 'NegReg', (128, 137))	('HIT', 'Disease', 'MESH:D013921', (98, 101))	('4 T1', 'CellLine', 'CVCL:0125', (66, 70))	('HIT', 'Disease', (98, 101))
155928	27686732	Loc554202 is expressed at markedly higher levels in breast cancer tissues than in normal controls and is associated with advanced pathologic stage and greater tumor size.	('breast cancer', 'Disease', 'MESH:D001943', (52, 65))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('breast cancer', 'Disease', (52, 65))	('tumor', 'Disease', (159, 164))	('breast cancer', 'Phenotype', 'HP:0003002', (52, 65))	('Loc554202', 'Var', (0, 9))	('higher', 'PosReg', (35, 41))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('associated', 'Reg', (105, 115))
155931	27686732	Increased BCAR4 level was correlated with progressive mammary cancer, and targeting BCAR4 based on knockout of specific gene intensively suppressed breast cancer spread in an animal model.	('targeting', 'Var', (74, 83))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('suppressed', 'NegReg', (137, 147))	('BCAR4', 'Gene', (10, 15))	('breast cancer', 'Disease', 'MESH:D001943', (148, 161))	('BCAR4', 'Gene', '400500', (10, 15))	('breast cancer', 'Disease', (148, 161))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('breast cancer', 'Phenotype', 'HP:0003002', (148, 161))	('BCAR4', 'Gene', (84, 89))	('cancer', 'Disease', (155, 161))	('BCAR4', 'Gene', '400500', (84, 89))	('cancer', 'Disease', 'MESH:D009369', (155, 161))
155933	27686732	Furthermore, siRNA-induced depletion of RCCRT1 expression diminished migration and invasion in ACHN and A498 RCC cell lines.	('A498', 'CellLine', 'CVCL:1056', (104, 108))	('ACHN', 'Gene', '55323', (95, 99))	('RCC', 'Disease', (40, 43))	('diminished', 'NegReg', (58, 68))	('RCC', 'Phenotype', 'HP:0005584', (40, 43))	('RCC', 'Disease', 'MESH:C538614', (109, 112))	('RCC', 'Disease', (109, 112))	('RCC', 'Disease', 'MESH:C538614', (40, 43))	('RCC', 'Phenotype', 'HP:0005584', (109, 112))	('depletion', 'Var', (27, 36))	('ACHN', 'Gene', (95, 99))
155944	27686732	PCGEM1 polymorphisms may contribute to PCa risk in Chinese men.	('PCGEM1', 'Gene', '64002', (0, 6))	('PCa', 'Phenotype', 'HP:0012125', (39, 42))	('contribute', 'Reg', (25, 35))	('polymorphisms', 'Var', (7, 20))	('PCGEM1', 'Gene', (0, 6))	('PCa', 'Disease', (39, 42))	('men', 'Species', '9606', (59, 62))
155945	27686732	LncRNA PCAT18 is specifically expressed in PCa, and PCAT18 silencing significantly inhibited PCa cell proliferation, migration, and invasion, and triggered caspase 3/7 activation with no effect on non-neoplastic cells.	('migration', 'CPA', (117, 126))	('PCa', 'Phenotype', 'HP:0012125', (43, 46))	('caspase 3', 'Gene', (156, 165))	('PCAT18', 'Gene', '728606', (7, 13))	('PCAT18', 'Gene', '728606', (52, 58))	('inhibited', 'NegReg', (83, 92))	('caspase 3', 'Gene', '836', (156, 165))	('PCa', 'Disease', (93, 96))	('activation', 'PosReg', (168, 178))	('PCa', 'Phenotype', 'HP:0012125', (93, 96))	('silencing', 'Var', (59, 68))	('PCAT18', 'Gene', (7, 13))	('PCAT18', 'Gene', (52, 58))	('invasion', 'CPA', (132, 140))
155952	27686732	In particular, the antitumor effects of targeted knockdown highlight the potential of lncRNA-based cancer therapies for patients at high risk for metastasis, an outcome currently lacking effective chemotherapeutic options.	('knockdown', 'Var', (49, 58))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('cancer', 'Disease', (99, 105))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('patients', 'Species', '9606', (120, 128))	('targeted knockdown', 'Var', (40, 58))	('tumor', 'Disease', (23, 28))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
155983	27686732	The lncRNA FENDRR controls the expression of target genes epigenetically by binding to PRC2.	('FENDRR', 'Gene', '400550', (11, 17))	('PRC2', 'Gene', (87, 91))	('epigenetically', 'Var', (58, 72))	('expression', 'MPA', (31, 41))	('FENDRR', 'Gene', (11, 17))	('binding', 'Interaction', (76, 83))
155987	27686732	ENST00000480739 level was negatively related to tumor node metastasis stage and lymph node metastasis, indicating that it could be an independent prognostic factor of survival time in PDAC patients following surgery.	('lymph node metastasis', 'CPA', (80, 101))	('tumor node metastasis', 'Disease', 'MESH:D009362', (48, 69))	('PDAC', 'Chemical', '-', (184, 188))	('negatively', 'NegReg', (26, 36))	('tumor node metastasis', 'Disease', (48, 69))	('patients', 'Species', '9606', (189, 197))	('ENST00000480739', 'Var', (0, 15))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('PDAC', 'Phenotype', 'HP:0006725', (184, 188))
155991	27686732	Microarray studies have found that upregulated expression of Meg3 in MIN6 cells can attenuate the level of the proto-oncogene c-Met and reduce cell migration and invasion.	('Meg3', 'Gene', (61, 65))	('reduce', 'NegReg', (136, 142))	('expression', 'Var', (47, 57))	('proto-oncogene c-Met', 'Gene', '17295', (111, 131))	('upregulated', 'PosReg', (35, 46))	('attenuate', 'NegReg', (84, 93))	('MIN6', 'CellLine', 'CVCL:0431', (69, 73))	('level of the', 'MPA', (98, 110))	('proto-oncogene c-Met', 'Gene', (111, 131))
155995	27686732	Moreover, the aberrant expression of BANCR was positively associated with clinical stage, tumor depth, lymph node metastasis, and distant metastasis, and was an independent prognostic factor for GC/NSCLC in survival analysis.	('lymph node metastasis', 'CPA', (103, 124))	('clinical stage', 'CPA', (74, 88))	('NSCLC', 'Phenotype', 'HP:0030358', (198, 203))	('associated', 'Reg', (58, 68))	('BANCR', 'Gene', '100885775', (37, 42))	('distant metastasis', 'CPA', (130, 148))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('aberrant expression', 'Var', (14, 33))	('NSCLC', 'Disease', (198, 203))	('BANCR', 'Gene', (37, 42))	('GC', 'Phenotype', 'HP:0012126', (195, 197))	('NSCLC', 'Disease', 'MESH:D002289', (198, 203))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
156113	26554648	It was unclear if CDKN3 overexpression is linked to alternative splicing variants or mutations that produce dominant-negative CDKN3.	('CDKN3', 'Gene', (18, 23))	('CDKN3', 'Gene', '1033', (126, 131))	('CDKN3', 'Gene', '1033', (18, 23))	('overexpression', 'PosReg', (24, 38))	('mutations', 'Var', (85, 94))	('CDKN3', 'Gene', (126, 131))
156115	26554648	We also examined CDKN3 mutations in the Cancer Genome Atlas (TCGA) and the Moffitt Cancer Center's Total Cancer Care (TCC) projects.	('Cancer Genome Atlas', 'Disease', (40, 59))	('CDKN3', 'Gene', (17, 22))	('Cancer', 'Phenotype', 'HP:0002664', (40, 46))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (40, 59))	("Moffitt Cancer Center's Total Cancer", 'Disease', (75, 111))	('Cancer', 'Phenotype', 'HP:0002664', (105, 111))	("Moffitt Cancer Center's Total Cancer", 'Disease', 'MESH:D009369', (75, 111))	('mutations', 'Var', (23, 32))	('CDKN3', 'Gene', '1033', (17, 22))	('Cancer', 'Phenotype', 'HP:0002664', (83, 89))
156119	26554648	High CDKN3 expression is associated with poor overall survival in lung adenocarcinoma.	('lung adenocarcinoma', 'Disease', (66, 85))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (66, 85))	('High', 'Var', (0, 4))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('expression', 'MPA', (11, 21))	('CDKN3', 'Gene', (5, 10))	('poor', 'NegReg', (41, 45))	('overall', 'MPA', (46, 53))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (66, 85))	('CDKN3', 'Gene', '1033', (5, 10))
156122	26554648	CDKN3 mutations were found to be very rare.	('CDKN3', 'Gene', '1033', (0, 5))	('CDKN3', 'Gene', (0, 5))	('mutations', 'Var', (6, 15))
156133	26554648	Inhibition of CDKN3 expression by antisense CDKN3 suppressed anchorage-independent colony formation in vitro and tumour xenograft growth in vivo, suggesting that increased CDKN3 expression in cancer cells plays a positive role in the transformed phenotypes.	('CDKN3', 'Gene', (172, 177))	('suppressed', 'NegReg', (50, 60))	('anchorage-independent colony formation', 'CPA', (61, 99))	('CDKN3', 'Gene', (14, 19))	('tumour', 'Disease', 'MESH:D009369', (113, 119))	('tumour', 'Phenotype', 'HP:0002664', (113, 119))	('CDKN3', 'Gene', '1033', (44, 49))	('tumour', 'Disease', (113, 119))	('cancer', 'Disease', (192, 198))	('CDKN3', 'Gene', '1033', (172, 177))	('cancer', 'Disease', 'MESH:D009369', (192, 198))	('CDKN3', 'Gene', '1033', (14, 19))	('antisense', 'Var', (34, 43))	('CDKN3', 'Gene', (44, 49))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))
156137	26554648	However, based on the perception that CDKN3 is a potential tumour suppressor, a possible explanation of CDKN3 mRNA overexpression in cancer is the presence of dominant-negative CDKN3 mutations, which could not be distinguished from the normal CDKN3-encoding mRNA in the gene expression data.	('CDKN3', 'Gene', (38, 43))	('CDKN3', 'Gene', '1033', (104, 109))	('CDKN3', 'Gene', '1033', (177, 182))	('mutations', 'Var', (183, 192))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('CDKN3', 'Gene', (104, 109))	('tumour', 'Phenotype', 'HP:0002664', (59, 65))	('CDKN3', 'Gene', '1033', (243, 248))	('cancer', 'Disease', (133, 139))	('CDKN3', 'Gene', '1033', (38, 43))	('CDKN3', 'Gene', (177, 182))	('tumour', 'Disease', 'MESH:D009369', (59, 65))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('tumour', 'Disease', (59, 65))	('overexpression', 'PosReg', (115, 129))	('CDKN3', 'Gene', (243, 248))
156138	26554648	Hence, CDKN3 overexpression may actually result in overexpression of dominant-negative CDKN3 mutants.	('CDKN3', 'Gene', (7, 12))	('overexpression', 'MPA', (51, 65))	('CDKN3', 'Gene', (87, 92))	('mutants', 'Var', (93, 100))	('CDKN3', 'Gene', '1033', (7, 12))	('CDKN3', 'Gene', '1033', (87, 92))	('result in', 'Reg', (41, 50))
156139	26554648	It was reported that aberrant CDKN3 transcripts from alternated splicing, insertion/deletion and nonsense mutations were found in hepatocellular carcinoma.	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (130, 154))	('carcinoma', 'Phenotype', 'HP:0030731', (145, 154))	('CDKN3', 'Gene', '1033', (30, 35))	('insertion/deletion', 'Var', (74, 92))	('nonsense mutations', 'Var', (97, 115))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (130, 154))	('CDKN3', 'Gene', (30, 35))	('found', 'Reg', (121, 126))	('hepatocellular carcinoma', 'Disease', (130, 154))
156142	26554648	Variant c is an exon 2 skip transcript that results in a short 23-amino acid peptide with little sequence homology to CDKN3.	('CDKN3', 'Gene', '1033', (118, 123))	('results in', 'Reg', (44, 54))	('CDKN3', 'Gene', (118, 123))	('amino acid peptide', 'Chemical', '-', (66, 84))	('Variant', 'Var', (0, 7))
156149	26554648	Consistent with this notion, knockdown of CDKN3 leads to mitotic failure.	('CDKN3', 'Gene', (42, 47))	('knockdown', 'Var', (29, 38))	('leads to', 'Reg', (48, 56))	('CDKN3', 'Gene', '1033', (42, 47))	('mitotic failure', 'Disease', (57, 72))	('mitotic failure', 'Disease', 'MESH:C536987', (57, 72))
156153	26554648	Furthermore, CDKN3 mutations are rare in TCGA tumours and in the TCC data set of 3383 tumours.	('TCGA tumours', 'Disease', (41, 53))	('CDKN3', 'Gene', (13, 18))	('tumours', 'Disease', 'MESH:D009369', (46, 53))	('tumour', 'Phenotype', 'HP:0002664', (46, 52))	('CDKN3', 'Gene', '1033', (13, 18))	('tumour', 'Phenotype', 'HP:0002664', (86, 92))	('tumours', 'Disease', (46, 53))	('mutations', 'Var', (19, 28))	('tumours', 'Phenotype', 'HP:0002664', (86, 93))	('TCGA tumours', 'Disease', 'MESH:D009369', (41, 53))	('tumours', 'Disease', 'MESH:D009369', (86, 93))	('tumours', 'Disease', (86, 93))	('tumours', 'Phenotype', 'HP:0002664', (46, 53))
156171	26554648	pLKO.1-based CDKN3 shRNA lentiviral vectors TRCN0000002525 and TRCN0000002527, and a non-target shRNA were obtained from Sigma.	('CDKN3', 'Gene', (13, 18))	('CDKN3', 'Gene', '1033', (13, 18))	('TRCN0000002525', 'Var', (44, 58))	('TRCN0000002527', 'Var', (63, 77))
156173	26554648	RT-PCR was performed using SuperScript One-Step RT-PCR Platinum Taq system (Life Technologies) with 50 ng RNA and one of the following primer pairs CK1/CK1R, CK2/CK2R, CK3/CK3R or CK1/CK3R (See Supplementary Information).	('CK1/CK1R', 'Var', (148, 156))	('CK2/CK2R', 'Var', (158, 166))	('CK3/CK3R', 'Var', (168, 176))	('CK1', 'Species', '2498238', (180, 183))	('CK1', 'Species', '2498238', (152, 155))	('CK1', 'Species', '2498238', (148, 151))	('CK1/CK3R', 'Var', (180, 188))
156188	26554648	), 7.048+-1.104 (adenocarcinoma), 7.617+-1.461 (large cell carcinoma) and 8.000+-0.683 (squamous cell carcinoma).	('7.048+-1.104', 'Var', (3, 15))	('cell carcinoma', 'Disease', (54, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (59, 68))	('large cell carcinoma', 'Phenotype', 'HP:0030360', (48, 68))	('cell carcinoma', 'Disease', 'MESH:C538614', (97, 111))	('adenocarcinoma', 'Disease', (17, 31))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (88, 111))	('adenocarcinoma', 'Disease', 'MESH:D000230', (17, 31))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('cell carcinoma', 'Disease', 'MESH:C538614', (54, 68))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (88, 111))	('squamous cell carcinoma', 'Disease', (88, 111))
156200	26554648	Additional evidence to support the identification of the 27-kDa band as CDKN3 was obtained by knocking down endogenous CDKN3 in cell lines with shRNAs (see below).	('CDKN3', 'Gene', (72, 77))	('CDKN3', 'Gene', '1033', (119, 124))	('endogenous', 'MPA', (108, 118))	('knocking', 'Var', (94, 102))	('CDKN3', 'Gene', '1033', (72, 77))	('CDKN3', 'Gene', (119, 124))
156213	26554648	Figure 3D shows that the Lung SPORE422 patients with high CDKN3 levels had significantly shorter overall survival than those with lower CDKN3 levels (P<0.0006).	('CDKN3', 'Gene', (58, 63))	('high', 'Var', (53, 57))	('shorter', 'NegReg', (89, 96))	('patients', 'Species', '9606', (39, 47))	('overall survival', 'MPA', (97, 113))	('CDKN3', 'Gene', '1033', (136, 141))	('CDKN3', 'Gene', '1033', (58, 63))	('CDKN3', 'Gene', (136, 141))
156216	26554648	Again, among stage I patients, those with high CDKN3 levels had a shorter survival probability (Supplementary Fig.	('CDKN3', 'Gene', '1033', (47, 52))	('shorter', 'NegReg', (66, 73))	('survival probability', 'CPA', (74, 94))	('patients', 'Species', '9606', (21, 29))	('CDKN3', 'Gene', (47, 52))	('high', 'Var', (42, 46))
156217	26554648	Taken together, these data indicate that high CDKN3 levels are associated with poor overall survival in lung adenocarcinoma patients.	('lung adenocarcinoma', 'Disease', (104, 123))	('patients', 'Species', '9606', (124, 132))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (104, 123))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('CDKN3', 'Gene', (46, 51))	('high', 'Var', (41, 45))	('overall', 'MPA', (84, 91))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (104, 123))	('poor', 'NegReg', (79, 83))	('CDKN3', 'Gene', '1033', (46, 51))
156218	26554648	We designed RT-PCR primer pairs CK1/CK1R located in exons 1 and 5 (Figure 4) that allowed us to detect both the full length CDKN3 transcript and splicing variants between exons 2-5 reported previously by other investigators.	('CDKN3', 'Gene', (124, 129))	('splicing variants', 'Var', (145, 162))	('CK1', 'Species', '2498238', (36, 39))	('CK1', 'Species', '2498238', (32, 35))	('CDKN3', 'Gene', '1033', (124, 129))
156222	26554648	The short RT-PCR product from the CK1/CK1R primer pairs yields a 284-bp fragment resulting from exon 2 skip (equivalent to variant c reported in the study by, Figure 4).	('CK1/CK1R', 'Gene', (34, 42))	('CK1', 'Species', '2498238', (34, 37))	('CK1', 'Species', '2498238', (38, 41))	('exon 2 skip', 'Var', (96, 107))
156223	26554648	This Exon 2 skip variant results in a frameshift that is predicted to encode a 23-amino acid peptide with little sequence homology to CDKN3 (Figure 4 and Supplementary Figure 5).	('CDKN3', 'Gene', '1033', (134, 139))	('amino acid peptide', 'Chemical', '-', (82, 100))	('results in', 'Reg', (25, 35))	('variant', 'Var', (17, 24))	('CDKN3', 'Gene', (134, 139))	('frameshift', 'Var', (38, 48))
156226	26554648	To explore the possibility of point mutation in regions not covered by CK1/CK3 primers, we performed RT-PCR using primer pairs CK2/CK2R and CK3/CK3R (Figure 4), both of them yield a single, predicted PCR product in all samples.	('CK3/CK3R', 'Var', (140, 148))	('yield', 'Reg', (174, 179))	('CK1', 'Species', '2498238', (71, 74))	('CK2/CK2R', 'Var', (127, 135))	('PCR', 'MPA', (200, 203))
156231	26554648	To further assess the possibility of CDKN3 mutations in human cancer, we examined the massively parallel sequencing data set of 3383 tumour tissues from 48 tumour types in the TCC project.	('CDKN3', 'Gene', '1033', (37, 42))	('tumour', 'Phenotype', 'HP:0002664', (133, 139))	('tumour', 'Disease', 'MESH:D009369', (133, 139))	('tumour', 'Disease', (156, 162))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('human', 'Species', '9606', (56, 61))	('CDKN3', 'Gene', (37, 42))	('tumour', 'Disease', (133, 139))	('cancer', 'Disease', (62, 68))	('mutations', 'Var', (43, 52))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('tumour', 'Phenotype', 'HP:0002664', (156, 162))	('tumour', 'Disease', 'MESH:D009369', (156, 162))
156232	26554648	Twenty-three CDKN3 mutation cases were found in 11 tumour types (Table 2).	('CDKN3', 'Gene', (13, 18))	('mutation', 'Var', (19, 27))	('CDKN3', 'Gene', '1033', (13, 18))	('tumour', 'Phenotype', 'HP:0002664', (51, 57))	('tumour', 'Disease', 'MESH:D009369', (51, 57))	('tumour', 'Disease', (51, 57))
156233	26554648	Of these 23 mutations, 13 mutations at 3 unique positions of Q8R, I108V and T127I were observed in either 1000 Genomes or Exome Sequencing Project (Exome Variant Server, http://evs.gs.washington.edu/EVS/, accessed February 2015) of healthy people, and are likely inherited variants.	('T127I', 'Mutation', 'rs141698864', (76, 81))	('people', 'Species', '9606', (240, 246))	('T127I', 'Var', (76, 81))	('I108V', 'Mutation', 'rs144479038', (66, 71))	('Q8R', 'Var', (61, 64))	('I108V', 'Var', (66, 71))
156253	26554648	Supplementary Figure 6 shows that we were able to knockdown CDKN3 in A549 and HeLa cells.	('knockdown', 'Var', (50, 59))	('A549', 'CellLine', 'CVCL:0023', (69, 73))	('CDKN3', 'Gene', '1033', (60, 65))	('HeLa', 'CellLine', 'CVCL:0030', (78, 82))	('CDKN3', 'Gene', (60, 65))
156254	26554648	CDKN3 knockdown in A549 and HeLa cells resulted in significantly reduced cell proliferation of these cells (Supplementary Figure 6).	('reduced', 'NegReg', (65, 72))	('CDKN3', 'Gene', '1033', (0, 5))	('cell proliferation of these cells', 'CPA', (73, 106))	('A549', 'CellLine', 'CVCL:0023', (19, 23))	('knockdown', 'Var', (6, 15))	('HeLa', 'CellLine', 'CVCL:0030', (28, 32))	('CDKN3', 'Gene', (0, 5))
156257	26554648	Three cohorts of lung adenocarcinoma consisted of 1328 patients and used either mRNA microarray or RNA-seq method to measure CDKN3 expression; high CDKN3 expression is consistently associated with significantly shorter overall survival of these patients.	('overall survival', 'MPA', (219, 235))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (17, 36))	('carcinoma', 'Phenotype', 'HP:0030731', (27, 36))	('patients', 'Species', '9606', (245, 253))	('CDKN3', 'Gene', (125, 130))	('CDKN3', 'Gene', (148, 153))	('high', 'Var', (143, 147))	('Thr', 'Chemical', 'MESH:D013912', (0, 3))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (17, 36))	('shorter', 'NegReg', (211, 218))	('patients', 'Species', '9606', (55, 63))	('CDKN3', 'Gene', '1033', (125, 130))	('CDKN3', 'Gene', '1033', (148, 153))	('lung adenocarcinoma', 'Disease', (17, 36))
156263	26554648	Furthermore, the high CDKN3 levels are associated with poor survival in lung adenocarcinoma but not in lung squamous cell carcinoma.	('lung adenocarcinoma', 'Disease', (72, 91))	('CDKN3', 'Gene', '1033', (22, 27))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (72, 91))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (108, 131))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (103, 131))	('high', 'Var', (17, 21))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (103, 131))	('lung squamous cell carcinoma', 'Disease', (103, 131))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (72, 91))	('CDKN3', 'Gene', (22, 27))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('poor', 'NegReg', (55, 59))
156264	26554648	Based on the perception of CDKN3 as a potential tumour suppressor, a possible mechanistic explanation of CDKN3 overexpression in the tumours is alternative splicing or mutations that produce dominant-negative products of CDKN3.	('CDKN3', 'Gene', (27, 32))	('tumour', 'Phenotype', 'HP:0002664', (133, 139))	('CDKN3', 'Gene', '1033', (105, 110))	('tumour', 'Phenotype', 'HP:0002664', (48, 54))	('tumour', 'Disease', 'MESH:D009369', (133, 139))	('tumours', 'Phenotype', 'HP:0002664', (133, 140))	('CDKN3', 'Gene', (221, 226))	('CDKN3', 'Gene', '1033', (27, 32))	('tumour', 'Disease', 'MESH:D009369', (48, 54))	('tumour', 'Disease', (133, 139))	('tumours', 'Disease', (133, 140))	('CDKN3', 'Gene', (105, 110))	('tumour', 'Disease', (48, 54))	('tumours', 'Disease', 'MESH:D009369', (133, 140))	('alternative splicing', 'Var', (144, 164))	('overexpression', 'PosReg', (111, 125))	('CDKN3', 'Gene', '1033', (221, 226))	('mutations', 'Var', (168, 177))
156266	26554648	We detected no aberrant splice variant or point mutation in the CDKN3 transcripts.	('point mutation', 'Var', (42, 56))	('CDKN3', 'Gene', (64, 69))	('CDKN3', 'Gene', '1033', (64, 69))
156269	26554648	Similar to the results of, our experiments showed that knockdown of CDKN3 inhibited cell proliferation, suggesting that CDKN3 has a positive role in cell proliferation.	('CDKN3', 'Gene', (68, 73))	('inhibited', 'NegReg', (74, 83))	('knockdown', 'Var', (55, 64))	('CDKN3', 'Gene', '1033', (120, 125))	('CDKN3', 'Gene', '1033', (68, 73))	('CDKN3', 'Gene', (120, 125))	('cell proliferation', 'CPA', (84, 102))
156271	26554648	Recurrent missense Q8R, I108V and T127I mutations were found in TCC tumours.	('found', 'Reg', (55, 60))	('tumour', 'Phenotype', 'HP:0002664', (68, 74))	('tumours', 'Phenotype', 'HP:0002664', (68, 75))	('I108V', 'Mutation', 'rs144479038', (24, 29))	('TCC tumours', 'Disease', (64, 75))	('missense Q8R', 'Var', (10, 22))	('I108V', 'Var', (24, 29))	('T127I', 'Var', (34, 39))	('T127I', 'Mutation', 'rs141698864', (34, 39))	('TCC tumours', 'Disease', 'MESH:C536943', (64, 75))
156273	26554648	Nevertheless, the only two cases of T127I change found in lung tumours cannot account for the poor survival of high CDKN3 expression patients in approximately one-half of 1328 lung adenocarcinoma cases.	('lung tumours', 'Disease', 'MESH:D008175', (58, 70))	('lung adenocarcinoma', 'Disease', (176, 195))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (176, 195))	('carcinoma', 'Phenotype', 'HP:0030731', (186, 195))	('T127I', 'Mutation', 'rs141698864', (36, 41))	('CDKN3', 'Gene', '1033', (116, 121))	('patients', 'Species', '9606', (133, 141))	('T127I', 'Var', (36, 41))	('tumour', 'Phenotype', 'HP:0002664', (63, 69))	('lung tumours', 'Disease', (58, 70))	('tumours', 'Phenotype', 'HP:0002664', (63, 70))	('lung tumour', 'Phenotype', 'HP:0100526', (58, 69))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (176, 195))	('CDKN3', 'Gene', (116, 121))	('high', 'Var', (111, 115))
156328	33679809	DNA methylation is a form of DNA chemical modification, and as an essential regulator of gene transcription, can be carcinogenic.	('carcinogenic', 'Disease', (116, 128))	('carcinogenic', 'Disease', 'MESH:D063646', (116, 128))	('methylation', 'Var', (4, 15))
156351	33679809	Kaplan-Meier survival analysis also demonstrated that among patients with CESC (Figure 3D; p = 0.021), DLBC (Figure 3E; p = 0.009), LUAD (Figure 3H; p = 0.020), THCA (Figure 3I; p = 0.013), and SKCM (Figure 3G, p = 0.029), those with high levels of TREM2 had longer survival times, while in patients with LGG (Figure 3B; P = 0.003), LIHC (Figure 3C; p = 0.006), and KIRC (Figure 3F; p = 0.014), high TREM2 expression was associated with poor OS.	('LUAD', 'Phenotype', 'HP:0030078', (132, 136))	('patients', 'Species', '9606', (60, 68))	('THCA', 'Phenotype', 'HP:0002890', (161, 165))	('high', 'Var', (395, 399))	('patients', 'Species', '9606', (291, 299))	('poor OS', 'Disease', (437, 444))	('survival times', 'CPA', (266, 280))	('longer', 'PosReg', (259, 265))	('expression', 'MPA', (406, 416))	('TREM2', 'Gene', (400, 405))
156356	33679809	KM analysis showed that individuals with in CESC (Figure 5B; p = 0.001) and DLBC (Figure 5E; p = 0.003) and high levels of TREM2 expression had longer survival times, while patients with LGG (Figure 5C; p = 0.005) and PRAD (Figure 5D; p < 0.001) and high TREM2 expression had poor PFI.	('survival times', 'CPA', (151, 165))	('patients', 'Species', '9606', (173, 181))	('longer', 'PosReg', (144, 150))	('expression', 'MPA', (261, 271))	('TREM2', 'Gene', (123, 128))	('high', 'Var', (108, 112))	('TREM2', 'Gene', (255, 260))
156386	33679809	TREM2 methylation level was a protective factor in patients with mesothelioma, uveal melanoma, and liver cancer, in terms of OS (Figure 12B).	('methylation level', 'Var', (6, 23))	('liver cancer', 'Disease', (99, 111))	('mesothelioma', 'Disease', (65, 77))	('TREM2', 'Gene', (0, 5))	('mesothelioma', 'Disease', 'MESH:D008654', (65, 77))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('uveal melanoma', 'Disease', 'MESH:C536494', (79, 93))	('patients', 'Species', '9606', (51, 59))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('liver cancer', 'Phenotype', 'HP:0002896', (99, 111))	('liver cancer', 'Disease', 'MESH:D006528', (99, 111))	('uveal melanoma', 'Phenotype', 'HP:0007716', (79, 93))	('uveal melanoma', 'Disease', (79, 93))
156396	33679809	The results demonstrate that TREM2 expression is positively associated with several immune cell-related pathways, including B, CD4 T, and CD8 T cells, and immune factor-related pathways such as TNF, cell migration, and synaptic pruning.	('cell migration', 'CPA', (199, 213))	('immune cell-related pathways', 'Pathway', (84, 112))	('TREM2', 'Gene', (29, 34))	('CD4', 'Gene', '920', (127, 130))	('synaptic pruning', 'CPA', (219, 235))	('associated', 'Reg', (60, 70))	('CD8', 'Gene', (138, 141))	('TNF', 'Gene', (194, 197))	('CD8', 'Gene', '925', (138, 141))	('TNF', 'Gene', '7124', (194, 197))	('CD4', 'Gene', (127, 130))	('expression', 'Var', (35, 45))
156405	33679809	Similarly, TREM2 expression was previously reported as associated with shorter survival time in patients with gastric cancer.	('gastric cancer', 'Disease', (110, 124))	('gastric cancer', 'Disease', 'MESH:D013274', (110, 124))	('survival time', 'CPA', (79, 92))	('gastric cancer', 'Phenotype', 'HP:0012126', (110, 124))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('TREM2', 'Gene', (11, 16))	('expression', 'Var', (17, 27))	('patients', 'Species', '9606', (96, 104))	('shorter', 'NegReg', (71, 78))
156408	33679809	In contrast, high TREM2 expression is associated with good prognosis in patients with CESC, LUAD, and THCA.	('CESC', 'Disease', (86, 90))	('THCA', 'Phenotype', 'HP:0002890', (102, 106))	('expression', 'MPA', (24, 34))	('high', 'Var', (13, 17))	('THCA', 'Disease', (102, 106))	('LUAD', 'Disease', (92, 96))	('TREM2', 'Gene', (18, 23))	('LUAD', 'Phenotype', 'HP:0030078', (92, 96))	('patients', 'Species', '9606', (72, 80))
156420	33679809	High-frequency MSI in colorectal cancer is an independent predictor of clinical characteristics and prognosis.	('colorectal cancer', 'Disease', (22, 39))	('colorectal cancer', 'Disease', 'MESH:D015179', (22, 39))	('High-frequency MSI', 'Var', (0, 18))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('colorectal cancer', 'Phenotype', 'HP:0003003', (22, 39))
156432	33679809	These results all indicate that expression of TREM2 is closely related to immune infiltration of tumor cells, affects patient prognosis, and proposes new targets for the development of immunosuppressants.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('expression', 'Var', (32, 42))	('tumor', 'Disease', (97, 102))	('affects', 'Reg', (110, 117))	('patient prognosis', 'CPA', (118, 135))	('patient', 'Species', '9606', (118, 125))	('TREM2', 'Gene', (46, 51))	('related', 'Reg', (63, 70))
156549	27561985	Several microRNAs have been functionally classified as oncogenes or tumor suppressors, and the aberrant expression of microRNA has been observed in almost all cancer types including OTSCC.	('cancer', 'Disease', (159, 165))	('tumor', 'Disease', (68, 73))	('microRNA', 'Gene', (118, 126))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('OTSCC', 'Disease', (182, 187))	('expression', 'MPA', (104, 114))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('observed', 'Reg', (136, 144))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('aberrant', 'Var', (95, 103))
156550	27561985	Deregulation of these cancer-associated microRNAs can significantly impact tumor initiation and progression by activating pathways promoting uncontrolled proliferation, favoring survival, inhibiting differentiation, and promoting invasion.	('differentiation', 'CPA', (199, 214))	('inhibiting', 'NegReg', (188, 198))	('Deregulation', 'Var', (0, 12))	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('survival', 'CPA', (178, 186))	('uncontrolled', 'MPA', (141, 153))	('cancer', 'Disease', (22, 28))	('promoting', 'PosReg', (131, 140))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('progression', 'CPA', (96, 107))	('impact', 'Reg', (68, 74))	('favoring', 'PosReg', (169, 177))	('invasion', 'CPA', (230, 238))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('tumor', 'Disease', (75, 80))	('promoting', 'PosReg', (220, 229))
156558	27561985	The human HNSCC cell lines (1386Ln, 1386Tu, 686Ln, 686Tu, CAL27, SCC2, SCC4, SCC9, SCC15, SCC25, Tca8113, UM1, UM2) were maintained in DMEM/F12 medium (Gibco) supplemented with 10% FBS, 100 units/ml penicillin, and 100 mug/ml streptomycin (Invitrogen).	('streptomycin', 'Chemical', 'MESH:D013307', (226, 238))	('SCC4', 'Gene', (71, 75))	('human', 'Species', '9606', (4, 9))	('UM1', 'CellLine', 'CVCL:W392', (106, 109))	('SCC9', 'CellLine', 'CVCL:1685', (77, 81))	('1386Ln', 'Var', (28, 34))	('FBS', 'Disease', 'MESH:D005198', (181, 184))	('SCC4', 'Gene', '23383', (71, 75))	('penicillin', 'Chemical', 'MESH:D010406', (199, 209))	('SCC2', 'Gene', (65, 69))	('SCC2', 'Gene', '25836', (65, 69))	('SCC2', 'Gene', (90, 94))	('SCC2', 'Gene', '25836', (90, 94))	('FBS', 'Disease', (181, 184))
156575	27561985	The luciferase reporter gene constructs (pGL-E1 and pGL-E2E3) were created by cloning a 55-bp fragment from the 3'-UTR (position 2625-2680 of the HPGD mRNA sequence NM_000860, containing the miR-21 site E1) and a 61-bp fragment from the 3'-UTR (position 2860-2921 of the HPGD mRNA sequence NM_000860, containing the miR-21 targeting sites E2 and E3) into the Xba I site of the pGL3-Control firefly luciferase reporter vector (Promega) as described previously.	('HPGD', 'Gene', (271, 275))	('pGL-E1', 'Gene', (41, 47))	('pGL3', 'Gene', '6391', (377, 381))	('miR-21', 'Gene', '406991', (191, 197))	('pGL-E1', 'Gene', '6080', (41, 47))	('HPGD', 'Gene', '3248', (271, 275))	('HPGD', 'Gene', (146, 150))	('E3', 'Gene', '223', (346, 348))	('HPGD', 'Gene', '3248', (146, 150))	('miR-21', 'Gene', (316, 322))	('NM_000860', 'Var', (290, 299))	('E1', 'Gene', '6080', (203, 205))	('E1', 'Gene', '6080', (45, 47))	('miR-21', 'Gene', (191, 197))	('E3', 'Gene', '223', (58, 60))	('pGL3', 'Gene', (377, 381))	('miR-21', 'Gene', '406991', (316, 322))
156593	27561985	Interestingly, when the seed region of E2 was mutated (pGL-E2mE3), the miR-21-mediated down-regulation of the luciferase activity was observed.	('down-regulation', 'NegReg', (87, 102))	('luciferase', 'Enzyme', (110, 120))	('activity', 'MPA', (121, 129))	('miR-21', 'Gene', '406991', (71, 77))	('mutated', 'Var', (46, 53))	('miR-21', 'Gene', (71, 77))	('E3', 'Gene', '223', (62, 64))
156594	27561985	MiR-21 has no effect on constructs with E3 mutation (pGL-E2E3m) or mutations of both E2 and E3 (pGL-E2mE3m).	('MiR-21', 'Gene', (0, 6))	('E3', 'Gene', '223', (59, 61))	('E3', 'Gene', '223', (40, 42))	('mutations', 'Var', (67, 76))	('E3', 'Gene', '223', (92, 94))	('MiR-21', 'Gene', '406991', (0, 6))	('pGL-E2mE3m', 'Gene', '223', (96, 106))	('pGL-E2mE3m', 'Gene', (96, 106))	('E3', 'Gene', '223', (103, 105))
156595	27561985	4a and b, both siRNA-mediated knockdown of COX2 and treatment with COX2 inhibitor (CelecoxiB) led to down-regulation of miR-21 in UM1 cells.	('miR-21', 'Gene', (120, 126))	('COX2', 'Gene', (67, 71))	('COX2', 'Gene', (43, 47))	('down-regulation', 'NegReg', (101, 116))	('COX2', 'Gene', '4513', (67, 71))	('UM1', 'CellLine', 'CVCL:W392', (130, 133))	('COX2', 'Gene', '4513', (43, 47))	('miR-21', 'Gene', '406991', (120, 126))	('CelecoxiB', 'Chemical', 'MESH:D000068579', (83, 92))	('knockdown', 'Var', (30, 39))
156596	27561985	4c, directly apply PGE2 to the UM1 cells led to the up-regulation of miR-21, and knockdown of HPGD (Fig.	('up-regulation', 'PosReg', (52, 65))	('UM1', 'CellLine', 'CVCL:W392', (31, 34))	('HPGD', 'Gene', '3248', (94, 98))	('miR-21', 'Gene', (69, 75))	('HPGD', 'Gene', (94, 98))	('knockdown', 'Var', (81, 90))	('PGE2', 'Chemical', 'MESH:D015232', (19, 23))	('miR-21', 'Gene', '406991', (69, 75))
156602	27561985	Deregulations of miR-21 and miR-130b, as well as deregulation of GPD1L, HLF, HPGD and MGLL have been reported either in HNOC or other cancer types, and these MRMs represent significant functional relevance in OTSCC.	('miR-130b', 'Gene', '406920', (28, 36))	('miR-130b', 'Gene', (28, 36))	('HPGD', 'Gene', (77, 81))	('MGLL', 'Gene', (86, 90))	('GPD1L', 'Gene', '23171', (65, 70))	('cancer', 'Disease', (134, 140))	('HNOC', 'Disease', (120, 124))	('miR-21', 'Gene', '406991', (17, 23))	('GPD1L', 'Gene', (65, 70))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('MGLL', 'Gene', '11343', (86, 90))	('Deregulations', 'Var', (0, 13))	('HLF', 'Gene', (72, 75))	('OTSCC', 'Disease', (209, 214))	('HLF', 'Gene', '3131', (72, 75))	('HPGD', 'Gene', '3248', (77, 81))	('miR-21', 'Gene', (17, 23))	('deregulation', 'Var', (49, 61))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('reported', 'Reg', (101, 109))
156619	27561985	The elimination of E2 may partially restore the capability of E3 (which has a stronger binding affinity among the two sites) to binding to the RISC complex.	('capability', 'MPA', (48, 58))	('elimination', 'Var', (4, 15))	('binding', 'Interaction', (87, 94))	('binding', 'Interaction', (128, 135))	('E3', 'Gene', '223', (62, 64))
156621	27561985	The HPGD gene has 6 known transcript variants (NCBI accession: NM_000860, NM_001145816, NM_001256301, NM_001256305, NM_001256306, NM_001256307), and all 6 variants have the same 3'-UTR.	('HPGD', 'Gene', (4, 8))	('NM_001145816', 'Var', (74, 86))	('HPGD', 'Gene', '3248', (4, 8))	('NM_001256306', 'Var', (116, 128))	('NM_001256301', 'Var', (88, 100))	('NM_000860', 'Var', (63, 72))	('NM_001256305', 'Var', (102, 114))	('NM_001256307', 'Var', (130, 142))
156715	32899735	Also, the high levels of IL-13 were associates with several tumor types such as head and neck carcinoma, Kaposi's sarcoma, renal carcinoma, and ovarian cancer.	('high levels', 'Var', (10, 21))	('head and neck carcinoma', 'Phenotype', 'HP:0012288', (80, 103))	('tumor', 'Disease', (60, 65))	('renal carcinoma', 'Disease', 'MESH:C538614', (123, 138))	('renal carcinoma', 'Disease', (123, 138))	('ovarian cancer', 'Disease', 'MESH:D010051', (144, 158))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('IL-13', 'Gene', '3596', (25, 30))	('renal carcinoma', 'Phenotype', 'HP:0005584', (123, 138))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('head and neck carcinoma', 'Disease', 'MESH:D006258', (80, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	("Kaposi's sarcoma", 'Disease', 'MESH:D012514', (105, 121))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('ovarian cancer', 'Disease', (144, 158))	('ovarian cancer', 'Phenotype', 'HP:0100615', (144, 158))	('IL-13', 'Gene', (25, 30))	("Kaposi's sarcoma", 'Phenotype', 'HP:0100726', (105, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('sarcoma', 'Phenotype', 'HP:0100242', (114, 121))	("Kaposi's sarcoma", 'Disease', (105, 121))	('associates', 'Reg', (36, 46))
156730	32899735	Studies have outlined that IL-6, IL-8, VEGF, IL-1b, and TNF-alpha are involved in the initial process of OSCC and that the present antibodies against IL-6 and p53 can be potential salivary biomarkers.	('IL-8', 'Gene', '3576', (33, 37))	('TNF-alpha', 'Gene', '7124', (56, 65))	('IL-8', 'Gene', (33, 37))	('p53', 'Gene', (159, 162))	('TNF-alpha', 'Gene', (56, 65))	('IL-1b', 'Gene', (45, 50))	('OSCC', 'Disease', (105, 109))	('p53', 'Gene', '7157', (159, 162))	('VEGF', 'Gene', (39, 43))	('IL-6', 'Gene', '3569', (150, 154))	('IL-6', 'Gene', (150, 154))	('involved', 'Reg', (70, 78))	('IL-6', 'Gene', (27, 31))	('antibodies', 'Var', (131, 141))	('IL-1b', 'Gene', '3553', (45, 50))	('IL-6', 'Gene', '3569', (27, 31))	('VEGF', 'Gene', '7422', (39, 43))
156796	31921388	According to the study, upregulated genes categories were identified, in which hydrolase (PC00121), enzyme modulator (PC00095), nucleic acid binding (PC00171), receptor (PC00197), transcription factor (PC00218), transporter (PC00227), and signaling molecule (PC00207) are the top seven most abundant protein classes.	('PC00227', 'Var', (225, 232))	('PC00207', 'Chemical', 'MESH:C075359', (259, 266))	('PC00207', 'Var', (259, 266))	('PC00197', 'Var', (170, 177))	('PC00218', 'Var', (202, 209))	('upregulated', 'PosReg', (24, 35))	('PC00171', 'Var', (150, 157))
156818	31921388	Whereas there was a positive correlation between methylation and Gap43 gene expression in LUSC samples (Supplementary Figures 3-24).	('LUSC', 'Phenotype', 'HP:0030359', (90, 94))	('Gap43', 'Gene', '2596', (65, 70))	('LUSC', 'Disease', 'MESH:D002294', (90, 94))	('LUSC', 'Disease', (90, 94))	('expression', 'MPA', (76, 86))	('Gap43', 'Gene', (65, 70))	('methylation', 'Var', (49, 60))
156819	31921388	Copy number alteration data demonstrated that Cdh1, Cdh2, Gfap, Perp, and Robo2 had a higher mRNA expression than normal tissues; increased expression was associated with gain or amplification alterations in LUAD samples (Supplementary Figure 25).	('mRNA expression', 'MPA', (93, 108))	('gain', 'PosReg', (171, 175))	('higher', 'PosReg', (86, 92))	('LUAD', 'Phenotype', 'HP:0030078', (208, 212))	('Cdh1', 'Gene', '999', (46, 50))	('Robo2', 'Gene', (74, 79))	('LUAD', 'Disease', (208, 212))	('increased', 'PosReg', (130, 139))	('amplification alterations', 'Var', (179, 204))	('Cdh2', 'Gene', (52, 56))	('Perp', 'Gene', '64065', (64, 68))	('Robo2', 'Gene', '6092', (74, 79))	('Gfap', 'Gene', '2670', (58, 62))	('LUAD', 'Disease', 'MESH:C538231', (208, 212))	('Perp', 'Gene', (64, 68))	('expression', 'MPA', (140, 150))	('Gfap', 'Gene', (58, 62))	('Cdh2', 'Gene', '1000', (52, 56))	('Cdh1', 'Gene', (46, 50))
156826	31921388	In order to analyze the pathway by which Schwann cells induce neoplastic and their own cell proliferation and migration, we evaluated the expression of MEK1 (MEK1 and MEK1_pS217S221), ERK2, AKT (PRAS40_pT246, AKT_pT308 and AKT_pS473), RAF (CRAF and CRAF_pS338), and GSK3Beta (GSK3_pS9 and GSK3ALPHABETA_pS21S9) proteins.	('MEK1', 'Gene', (152, 156))	('RAF', 'Gene', (241, 244))	('PRAS40_pT246', 'Var', (195, 207))	('AKT', 'Gene', (223, 226))	('MEK1', 'Gene', (167, 171))	('RAF', 'Gene', (235, 238))	('AKT', 'Gene', (190, 193))	('neoplastic', 'CPA', (62, 72))	('ERK2', 'Gene', '5594', (184, 188))	('cell proliferation', 'CPA', (87, 105))	('MEK1', 'Gene', (158, 162))	('CRAF', 'Gene', (249, 253))	('AKT', 'Gene', (209, 212))	('AKT', 'Gene', '207', (223, 226))	('MEK1', 'Gene', '5604', (152, 156))	('ERK2', 'Gene', (184, 188))	('GSK3Beta', 'Gene', '2932', (266, 274))	('CRAF', 'Gene', (240, 244))	('MEK1', 'Gene', '5604', (167, 171))	('AKT', 'Gene', '207', (190, 193))	('RAF', 'Gene', '22882', (250, 253))	('RAF', 'Gene', '22882', (235, 238))	('CRAF', 'Gene', '5894', (249, 253))	('RAF', 'Gene', '22882', (241, 244))	('CRAF', 'Gene', '5894', (240, 244))	('AKT', 'Gene', '207', (209, 212))	('MEK1', 'Gene', '5604', (158, 162))	('RAF', 'Gene', (250, 253))	('GSK3Beta', 'Gene', (266, 274))
156858	31921388	Copy number alteration analysis also showed that amplification and gain are associated with E-cadherin and N-cadherin mRNA levels in both cancers.	('amplification', 'Var', (49, 62))	('E-cadherin', 'Gene', (92, 102))	('E-cadherin', 'Gene', '999', (92, 102))	('N-cadherin', 'Gene', (107, 117))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('N-cadherin', 'Gene', '1000', (107, 117))	('cancers', 'Phenotype', 'HP:0002664', (138, 145))	('gain', 'PosReg', (67, 71))	('cancers', 'Disease', (138, 145))	('cancers', 'Disease', 'MESH:D009369', (138, 145))
156864	31921388	The maintenance of the myelinating phenotype therefore requires the continuous expression of KROX-20 and SOX-10, considering that inactivation of both proteins results in dedifferentiation of Schwann cells.	('KROX-20', 'Gene', (93, 100))	('inactivation', 'Var', (130, 142))	('SOX-10', 'Gene', '6663', (105, 111))	('results in', 'Reg', (160, 170))	('dedifferentiation', 'CPA', (171, 188))	('KROX-20', 'Gene', '1959', (93, 100))	('SOX-10', 'Gene', (105, 111))
156882	31921388	Meanwhile, upregulated miRNAs inactivate the "axon guidance" pathway, targeting Robo2 and Slit2 genes.	('Robo2', 'Gene', '6092', (80, 85))	('Slit2', 'Gene', (90, 95))	('inactivate', 'NegReg', (30, 40))	('miRNAs', 'Var', (23, 29))	('upregulated', 'PosReg', (11, 22))	('Slit2', 'Gene', '9353', (90, 95))	('Robo2', 'Gene', (80, 85))
156894	30408569	Co-expression analysis reveals mechanisms underlying the varied roles of NOTCH1 in non-small cell lung cancer Notch receptor family dysregulation can be tumor promoting or suppressing depending on cellular context.	('small cell lung cancer', 'Phenotype', 'HP:0030357', (87, 109))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('lung cancer', 'Phenotype', 'HP:0100526', (98, 109))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (83, 109))	('suppressing', 'NegReg', (172, 183))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (83, 109))	('non-small cell lung cancer', 'Disease', (83, 109))	('dysregulation', 'Var', (132, 145))	('NOTCH1', 'Gene', '4851', (73, 79))	('NOTCH1', 'Gene', (73, 79))
156898	30408569	Tissue culture and xenograft studies of lung adenocarcinoma and lung squamous models with NOTCH1 knockdown demonstrated growth differences and opposing effects on these pathways.	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (40, 59))	('knockdown', 'Var', (97, 106))	('lung adenocarcinoma and lung squamous', 'Disease', 'MESH:C538231', (40, 77))	('carcinoma', 'Phenotype', 'HP:0030731', (50, 59))	('NOTCH1', 'Gene', (90, 96))
156906	30408569	In contrast, a tumor suppressive role of Notch has been claimed across different squamous cell carcinoma (SCC) tumors based on the loss of function mutations commonly found in cutaneous SCC.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('mutations', 'Var', (148, 157))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('SCC', 'Phenotype', 'HP:0002860', (106, 109))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('SCC', 'Disease', (106, 109))	('SCC', 'Disease', 'MESH:D002294', (186, 189))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('squamous cell carcinoma (SCC) tumors', 'Disease', 'MESH:D002294', (81, 117))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('tumor', 'Disease', (111, 116))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('tumor', 'Disease', (15, 20))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (81, 104))	('SCC', 'Phenotype', 'HP:0002860', (186, 189))	('loss of function', 'NegReg', (131, 147))	('SCC', 'Disease', 'MESH:D002294', (106, 109))	('SCC', 'Disease', (186, 189))
156908	30408569	Notch mutations have been identified in less than 10% of lung tumors, but aberrant Notch signaling has been reported in 33% of non-small cell lung cancers (NSCLCs).	('small cell lung cancer', 'Phenotype', 'HP:0030357', (131, 153))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (127, 153))	('lung tumors', 'Phenotype', 'HP:0100526', (57, 68))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('non-small cell lung cancers', 'Phenotype', 'HP:0030358', (127, 154))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('small cell lung cancers', 'Phenotype', 'HP:0030357', (131, 154))	('NSCLCs', 'Disease', 'MESH:D002289', (156, 162))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('lung tumors', 'Disease', (57, 68))	('non-small cell lung cancers', 'Disease', 'MESH:D002289', (127, 154))	('lung cancer', 'Phenotype', 'HP:0100526', (142, 153))	('NSCLCs', 'Phenotype', 'HP:0030358', (156, 162))	('lung cancers', 'Phenotype', 'HP:0100526', (142, 154))	('reported', 'Reg', (108, 116))	('NSCLCs', 'Disease', (156, 162))	('cancers', 'Phenotype', 'HP:0002664', (147, 154))	('lung tumors', 'Disease', 'MESH:D008175', (57, 68))	('Notch signaling', 'MPA', (83, 98))	('non-small cell lung cancers', 'Disease', (127, 154))	('aberrant', 'Var', (74, 82))
156939	30408569	RNA from flash frozen tissue from paired NTC and NOTCH1 knockdown xenograft tumor sections lung AD model (A549) and in the lung SCC model (HCC15) were sequenced.	('lung AD', 'Disease', (91, 98))	('lung SCC', 'Disease', (123, 131))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('lung SCC', 'Disease', 'MESH:D002294', (123, 131))	('SCC', 'Phenotype', 'HP:0002860', (128, 131))	('lung AD', 'Disease', 'MESH:C538231', (91, 98))	('HCC15', 'CellLine', 'CVCL:2057', (139, 144))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('NOTCH1', 'Gene', (49, 55))	('knockdown', 'Var', (56, 65))	('A549', 'CellLine', 'CVCL:0023', (106, 110))
156976	30408569	In contrast, NOTCH1 knockdown resulted in decreased NOTCH1 expression but increased cell proliferation in lung SCC cell lines.	('SCC', 'Phenotype', 'HP:0002860', (111, 114))	('lung SCC cell lines', 'Disease', (106, 125))	('decreased', 'NegReg', (42, 51))	('NOTCH1', 'Gene', (13, 19))	('increased', 'PosReg', (74, 83))	('expression', 'MPA', (59, 69))	('NOTCH1', 'Gene', (52, 58))	('knockdown', 'Var', (20, 29))	('lung SCC cell lines', 'Disease', 'MESH:D002294', (106, 125))
156977	30408569	These results demonstrate an opposing phenotypic response to NOTCH1 knockdown in NSCLC.	('NOTCH1', 'Gene', (61, 67))	('knockdown', 'Var', (68, 77))	('NSCLC', 'Disease', 'MESH:D002289', (81, 86))	('NSCLC', 'Disease', (81, 86))
156981	30408569	In contrast, knockdown of NOTCH1 in lung SCC models resulted in significant increase in tumor growth, supporting a tumor suppressive role of NOTCH1 in SCC (Figure 3C,D).	('lung SCC', 'Disease', (36, 44))	('SCC', 'Phenotype', 'HP:0002860', (41, 44))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('increase', 'PosReg', (76, 84))	('NOTCH1', 'Gene', (26, 32))	('lung SCC', 'Disease', 'MESH:D002294', (36, 44))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('SCC', 'Phenotype', 'HP:0002860', (151, 154))	('SCC', 'Disease', (151, 154))	('tumor', 'Disease', (115, 120))	('SCC', 'Disease', (41, 44))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor', 'Disease', (88, 93))	('SCC', 'Disease', 'MESH:D002294', (41, 44))	('knockdown', 'Var', (13, 22))	('SCC', 'Disease', 'MESH:D002294', (151, 154))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
156982	30408569	Unlike prior studies that have extrapolated a tumor suppressor function for NOTCH1 in lung SCC from the existence of loss of function mutations, these experiments show the pro-growth and tumor suppressive role of NOTCH1 in vitro and in vivo in controlled lung models.	('lung SCC', 'Disease', 'MESH:D002294', (86, 94))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('tumor', 'Disease', (46, 51))	('tumor', 'Disease', (187, 192))	('NOTCH1', 'Gene', (213, 219))	('pro-growth', 'CPA', (172, 182))	('mutations', 'Var', (134, 143))	('lung SCC', 'Disease', (86, 94))	('SCC', 'Phenotype', 'HP:0002860', (91, 94))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
156983	30408569	To explore how NOTCH1 knockdown experimentally correlates with changes in mitotic, vasculature, and immune process predicted by our in silico studies, we performed immunohistochemistry (IHC) staining and RNA-sequencing on the human lung AD and SCC xenograft tumors collected at the end of the study.	('tumor', 'Phenotype', 'HP:0002664', (258, 263))	('human', 'Species', '9606', (226, 231))	('tumors', 'Disease', (258, 264))	('NOTCH1', 'Gene', (15, 21))	('lung AD', 'Disease', (232, 239))	('tumors', 'Phenotype', 'HP:0002664', (258, 264))	('tumors', 'Disease', 'MESH:D009369', (258, 264))	('knockdown', 'Var', (22, 31))	('lung AD', 'Disease', 'MESH:C538231', (232, 239))	('SCC', 'Phenotype', 'HP:0002860', (244, 247))	('SCC', 'Disease', (244, 247))	('SCC', 'Disease', 'MESH:D002294', (244, 247))
156985	30408569	Flash frozen tumor xenografts were evaluated for changes in human and mouse mRNA following NOTCH1 knockdown in two of the lung AD model (A549) and lung SCC model (HCC15) xenografts.	('tumor', 'Disease', (13, 18))	('lung AD', 'Disease', 'MESH:C538231', (122, 129))	('mRNA', 'MPA', (76, 80))	('NOTCH1', 'Gene', (91, 97))	('knockdown', 'Var', (98, 107))	('mouse', 'Species', '10090', (70, 75))	('lung SCC', 'Disease', (147, 155))	('HCC15', 'CellLine', 'CVCL:2057', (163, 168))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('lung SCC', 'Disease', 'MESH:D002294', (147, 155))	('lung AD', 'Disease', (122, 129))	('SCC', 'Phenotype', 'HP:0002860', (152, 155))	('A549', 'CellLine', 'CVCL:0023', (137, 141))	('human', 'Species', '9606', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
156987	30408569	NOTCH1 knockdown corresponded with a significant increase in pHH3 expression in tumors generated from the lung SCC but no significant change in pHH3 expression in the lung AD cell lines (Figure 3G) as predicted by our in silico analysis.	('increase', 'PosReg', (49, 57))	('H3', 'Chemical', 'MESH:C006633', (63, 65))	('pHH3', 'Gene', (61, 65))	('H3', 'Chemical', 'MESH:C006633', (146, 148))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('expression', 'MPA', (66, 76))	('lung AD', 'Disease', (167, 174))	('lung SCC', 'Disease', (106, 114))	('tumors', 'Disease', (80, 86))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('lung SCC', 'Disease', 'MESH:D002294', (106, 114))	('NOTCH1', 'Gene', (0, 6))	('SCC', 'Phenotype', 'HP:0002860', (111, 114))	('knockdown', 'Var', (7, 16))	('lung AD', 'Disease', 'MESH:C538231', (167, 174))
156988	30408569	Furthermore, pathway analysis of the RNA sequencing data supported our IHC results and predicted activation of the G2 phase of cell cycle progression in the SCC model (HCC15) but decreased function in the lung AD model (A549) with NOTCH1 knockdown (Supplemental Table 6).	('decreased', 'NegReg', (179, 188))	('HCC15', 'CellLine', 'CVCL:2057', (168, 173))	('SCC', 'Phenotype', 'HP:0002860', (157, 160))	('A549', 'CellLine', 'CVCL:0023', (220, 224))	('activation', 'PosReg', (97, 107))	('knockdown', 'Var', (238, 247))	('lung AD', 'Disease', (205, 212))	('decreased function in the lung', 'Phenotype', 'HP:0005952', (179, 209))	('NOTCH1', 'Gene', (231, 237))	('G2 phase', 'CPA', (115, 123))	('function', 'MPA', (189, 197))	('SCC', 'Disease', (157, 160))	('lung AD', 'Disease', 'MESH:C538231', (205, 212))	('SCC', 'Disease', 'MESH:D002294', (157, 160))
156990	30408569	Our hypothesis is supported by the findings of Ye and collaborators who reported that a specific inhibitor of CDC7 (LY3177833), which plays a role in cell cycle, centromere cohesion, and chromosome segregation, resulted in tumor stasis or regression in the majority of lung SCC cancer patient derived tumor models.	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('tumor stasis', 'Disease', 'MESH:D018589', (223, 235))	('tumor', 'Phenotype', 'HP:0002664', (301, 306))	('cancer', 'Disease', (278, 284))	('CDC7', 'Gene', (110, 114))	('cancer', 'Phenotype', 'HP:0002664', (278, 284))	('LY3177833', 'Var', (116, 125))	('patient', 'Species', '9606', (285, 292))	('tumor', 'Disease', (223, 228))	('lung SCC', 'Disease', 'MESH:D002294', (269, 277))	('CDC7', 'Gene', '8317', (110, 114))	('LY3177833', 'Chemical', 'MESH:C430423', (116, 125))	('cancer', 'Disease', 'MESH:D009369', (278, 284))	('tumor', 'Disease', 'MESH:D009369', (223, 228))	('tumor', 'Disease', (301, 306))	('SCC', 'Phenotype', 'HP:0002860', (274, 277))	('lung SCC', 'Disease', (269, 277))	('tumor', 'Disease', 'MESH:D009369', (301, 306))	('regression', 'CPA', (239, 249))	('tumor stasis', 'Disease', (223, 235))
156992	30408569	In lung AD tumors NOTCH1 knockdown resulted in a significant increase in CD31 expression, but was unchanged or decreased in lung SCC tumors (Figure 3H).	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('NOTCH1', 'Gene', (18, 24))	('SCC', 'Phenotype', 'HP:0002860', (129, 132))	('lung AD', 'Disease', 'MESH:C538231', (3, 10))	('expression', 'MPA', (78, 88))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('tumors', 'Disease', (133, 139))	('tumors', 'Disease', 'MESH:D009369', (133, 139))	('tumors', 'Phenotype', 'HP:0002664', (11, 17))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumors', 'Disease', (11, 17))	('tumors', 'Disease', 'MESH:D009369', (11, 17))	('CD31', 'Protein', (73, 77))	('lung AD', 'Disease', (3, 10))	('increase', 'PosReg', (61, 69))	('lung SCC', 'Disease', (124, 132))	('knockdown', 'Var', (25, 34))	('lung SCC', 'Disease', 'MESH:D002294', (124, 132))
156993	30408569	Studies have also shown that the expression of NOTCH1 and VEGFA in lung AD have a significant negative prognostic impact in the lung AD cohort.	('VEGFA', 'Gene', (58, 63))	('lung AD', 'Disease', (128, 135))	('expression', 'Var', (33, 43))	('NOTCH1', 'Gene', (47, 53))	('lung AD', 'Disease', (67, 74))	('lung AD', 'Disease', 'MESH:C538231', (67, 74))	('lung AD', 'Disease', 'MESH:C538231', (128, 135))	('VEGFA', 'Gene', '7422', (58, 63))	('negative', 'NegReg', (94, 102))
156995	30408569	Our RNA sequencing pathway analysis of in vivo NOTCH1 knockdown tumors in lung AD (A549) predicted an increase in the recruitment of the innate immune and inflammatory system components and a decrease in lung SCC (HCC15) (Supplemental Table 7).	('tumors', 'Disease', (64, 70))	('lung SCC', 'Disease', (204, 212))	('recruitment', 'MPA', (118, 129))	('decrease', 'NegReg', (192, 200))	('knockdown', 'Var', (54, 63))	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('NOTCH1', 'Gene', (47, 53))	('lung SCC', 'Disease', 'MESH:D002294', (204, 212))	('A549', 'CellLine', 'CVCL:0023', (83, 87))	('lung AD', 'Disease', (74, 81))	('HCC15', 'CellLine', 'CVCL:2057', (214, 219))	('increase', 'PosReg', (102, 110))	('lung AD', 'Disease', 'MESH:C538231', (74, 81))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('SCC', 'Phenotype', 'HP:0002860', (209, 212))
156997	30408569	Our studies were carried out using human cell lines with NOTCH1 knockdown that were implanted in NSG mice.	('human', 'Species', '9606', (35, 40))	('mice', 'Species', '10090', (101, 105))	('knockdown', 'Var', (64, 73))	('NOTCH1', 'Gene', (57, 63))
157006	30408569	NOTCH1 interactions were specific; we detected NOTCH1 interaction with the positive control RBPJ-MYC or RBPJ-FLAG and NOTCH1-ICD V5 (Figure 4C,D) but not in our negative control experiment with GFP-FLAG (Figure 4E).	('RBPJ', 'Gene', (104, 108))	('RBPJ', 'Gene', '3516', (104, 108))	('NOTCH1', 'Var', (47, 53))	('MYC', 'Gene', (97, 100))	('RBPJ', 'Gene', (92, 96))	('RBPJ', 'Gene', '3516', (92, 96))	('interaction', 'Interaction', (54, 65))	('MYC', 'Gene', '4609', (97, 100))
157009	30408569	IDH2 is a very interesting link given that the genetic variant rs11540478 is a risk factor for lung cancer.	('lung cancer', 'Disease', (95, 106))	('lung cancer', 'Phenotype', 'HP:0100526', (95, 106))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('rs11540478', 'Var', (63, 73))	('lung cancer', 'Disease', 'MESH:D008175', (95, 106))	('IDH2', 'Gene', (0, 4))	('risk', 'Reg', (79, 83))	('rs11540478', 'Mutation', 'rs11540478', (63, 73))	('IDH2', 'Gene', '3418', (0, 4))
157078	27879376	Notably, at an early time point of TSL-1 treatment, 0.1, 0.15, and 0.2 mg/mL TSL-1 significantly induces apoptosis but not necrosis in Saos-2 (Figure 3C).	('0.1', 'Var', (52, 55))	('necrosis', 'Disease', 'MESH:D009336', (123, 131))	('apoptosis', 'CPA', (105, 114))	('TSL-1', 'Gene', (77, 82))	('induces', 'Reg', (97, 104))	('necrosis', 'Disease', (123, 131))	('0.15', 'Var', (57, 61))
157086	27879376	We found TSL-1, TSL-2, and TSL-1-5-7 decrease cell viability in a dose-dependent manner in 3 human osteosarcoma cell lines, MG-63, Saos-2, and U2OS.	('osteosarcoma', 'Disease', 'MESH:D012516', (99, 111))	('decrease', 'NegReg', (37, 45))	('MG', 'Chemical', 'MESH:D008274', (124, 126))	('sarcoma', 'Phenotype', 'HP:0100242', (104, 111))	('TSL-1', 'Var', (9, 14))	('human', 'Species', '9606', (93, 98))	('TSL-1-5-7', 'Var', (27, 36))	('cell viability', 'CPA', (46, 60))	('osteosarcoma', 'Phenotype', 'HP:0002669', (99, 111))	('U2OS', 'CellLine', 'CVCL:0042', (143, 147))	('osteosarcoma', 'Disease', (99, 111))
157128	29262640	Furthermore, this modification enhances the burden of esophageal cancer and do not increase the incidence of gastric cancer, thus providing a false perception of better gastric cancer control.	('gastric cancer', 'Disease', (169, 183))	('gastric cancer', 'Disease', 'MESH:D013274', (169, 183))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('gastric cancer', 'Disease', (109, 123))	('burden', 'MPA', (44, 50))	('increase the incidence of gastric cancer', 'Phenotype', 'HP:0006753', (83, 123))	('gastric cancer', 'Disease', 'MESH:D013274', (109, 123))	('gastric cancer', 'Phenotype', 'HP:0012126', (169, 183))	('esophageal cancer', 'Disease', (54, 71))	('enhances', 'PosReg', (31, 39))	('modification', 'Var', (18, 30))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('gastric cancer', 'Phenotype', 'HP:0012126', (109, 123))	('esophageal cancer', 'Disease', 'MESH:D004938', (54, 71))
157196	33692861	Compared with in the non-hypermutant cohort, the proportion of squamous cell carcinoma cases and small cell lung cancer cases was higher in the hypermutant cohort (22.4 vs. 13.1% and 6.0 vs. 2.6%, respectively).	('small cell lung cancer', 'Disease', 'MESH:D055752', (97, 119))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (97, 119))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (63, 86))	('higher', 'PosReg', (130, 136))	('squamous cell carcinoma', 'Disease', (63, 86))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (63, 86))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('small cell lung cancer', 'Disease', (97, 119))	('lung cancer', 'Phenotype', 'HP:0100526', (108, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('hypermutant', 'Var', (144, 155))
157197	33692861	In addition, compared with in the non-hypermutant cohort, mutations in the low-density lipoprotein receptor-related protein 1B were more frequently observed in the hypermutant cohort (67.2 vs. 14.3%; P<0.0001).	('mutations', 'Var', (58, 67))	('low-density lipoprotein receptor-related protein 1B', 'Gene', '53353', (75, 126))	('observed', 'Reg', (148, 156))
157199	33692861	The mutation frequency in DNA damage response (DDR) genes was notably higher in the hypermutant cohort, where several DDR-associated genes were enriched, compared with in the non-hypermutant cohort.	('mutation', 'Var', (4, 12))	('DDR', 'Chemical', '-', (118, 121))	('DDR) genes', 'Gene', (47, 57))	('higher', 'PosReg', (70, 76))	('DDR', 'Chemical', '-', (47, 50))
157200	33692861	The enrichment analysis revealed a strong association between mutations in Notch signaling and high TMB.	('men', 'Species', '9606', (10, 13))	('TMB', 'Chemical', '-', (100, 103))	('high TMB', 'Disease', (95, 103))	('Notch signaling', 'Gene', (75, 90))	('mutations', 'Var', (62, 71))
157212	33692861	For example, the retrospective analysis of the Checkmate-032 study suggested that the efficacy of nivolumab combined with ipilimumab was improved in patients with high TMB compared with in those with low TMB (ORR, 46.2 vs. 22.2%).	('patients', 'Species', '9606', (149, 157))	('TMB', 'Chemical', '-', (168, 171))	('nivolumab', 'Chemical', 'MESH:D000077594', (98, 107))	('high TMB', 'Var', (163, 171))	('ipilimumab', 'Chemical', 'MESH:D000074324', (122, 132))	('TMB', 'Chemical', '-', (204, 207))	('improved', 'PosReg', (137, 145))	('efficacy', 'MPA', (86, 94))
157214	33692861	Several studies have demonstrated that single gene mutations, such as driver mutations in polymerase epsilon catalytic subunit A (POLE)/polymerase delta catalytic subunit gene 1 (POLD1) genes and pathogenetic mutations in mismatch repair genes, are associated with high TMB, which may provide an economical, simple and complementary method for predicting TMB and response to immunotherapy.	('TMB', 'Disease', (355, 358))	('men', 'Species', '9606', (325, 328))	('TMB', 'Chemical', '-', (355, 358))	('mutations', 'Var', (77, 86))	('POLD1', 'Gene', '5424', (179, 184))	('POLE', 'Gene', (130, 134))	('POLD1', 'Gene', (179, 184))	('TMB', 'Chemical', '-', (270, 273))	('high TMB', 'Disease', (265, 273))	('associated', 'Reg', (249, 259))
157220	33692861	Additionally, alterations in DNA damage response (DDR) genes may be associated with high TMB and improved clinical benefits from immunotherapy in patients with NSCLC.	('alterations', 'Var', (14, 25))	('SCLC', 'Phenotype', 'HP:0030357', (161, 165))	('associated', 'Reg', (68, 78))	('clinical benefits', 'CPA', (106, 123))	('improved', 'PosReg', (97, 105))	('NSCLC', 'Phenotype', 'HP:0030358', (160, 165))	('high TMB', 'Disease', (84, 92))	('DDR) genes', 'Gene', (50, 60))	('DDR', 'Chemical', '-', (50, 53))	('NSCLC', 'Disease', (160, 165))	('TMB', 'Chemical', '-', (89, 92))	('patients', 'Species', '9606', (146, 154))	('NSCLC', 'Disease', 'MESH:D002289', (160, 165))
157221	33692861	Tumors with co-occurring TP53/KRAS gene mutations exhibited remarkable clinical benefit from immunotherapy with PD-1 inhibitors.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('TP53', 'Gene', (25, 29))	('Tumors', 'Disease', (0, 6))	('benefit', 'PosReg', (80, 87))	('mutations', 'Var', (40, 49))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('KRAS', 'Gene', (30, 34))	('TP53', 'Gene', '7157', (25, 29))	('KRAS', 'Gene', '3845', (30, 34))
157222	33692861	However, some driver mutations in NSCLC tend to predict a poorer response to immunotherapy, such as EGFR sensitive mutations and ALK fusions.	('EGFR', 'Gene', '1956', (100, 104))	('NSCLC', 'Disease', (34, 39))	('ALK', 'Gene', (129, 132))	('poorer', 'NegReg', (58, 64))	('NSCLC', 'Disease', 'MESH:D002289', (34, 39))	('EGFR', 'Gene', (100, 104))	('SCLC', 'Phenotype', 'HP:0030357', (35, 39))	('NSCLC', 'Phenotype', 'HP:0030358', (34, 39))	('ALK', 'Gene', '238', (129, 132))	('mutations', 'Var', (21, 30))
157223	33692861	Somatic mutations in PTEN, beta-2 microglobulin (B2M), serine-threonine kinase 11 (STK11), Kelch-like ECH-associated protein 1 (KEAP1), murine double minute 2 (MDM2) and 11q13 amplification have also been negatively associated with immunotherapy response.	('murine double minute 2', 'Gene', '17246', (136, 158))	('serine-threonine kinase 11', 'Gene', (55, 81))	('Kelch-like ECH-associated protein 1', 'Gene', (91, 126))	('Kelch-like ECH-associated protein 1', 'Gene', '50868', (91, 126))	('serine-threonine kinase 11', 'Gene', '20869', (55, 81))	('beta-2 microglobulin', 'Gene', (27, 47))	('beta-2 microglobulin', 'Gene', '12010', (27, 47))	('associated', 'Reg', (216, 226))	('murine double minute 2', 'Gene', (136, 158))	('mutations', 'Var', (8, 17))	('negatively', 'NegReg', (205, 215))	('PTEN', 'Gene', (21, 25))	('immunotherapy response', 'CPA', (232, 254))	('11q13', 'Gene', (170, 175))
157232	33692861	TMB was calculated as the number of somatic non-synonymous SNVs and InDels per Mb in the coding region, with a variant allele fraction of >=0.03.	('TMB', 'Chemical', '-', (0, 3))	('SNVs', 'Var', (59, 63))	('InDels', 'Var', (68, 74))
157236	33692861	Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis was performed using the Web-based Gene Set Analysis Toolkit (WebGestalt; ) to explore whether the DMGs that were more frequently mutated in the hypermutant cohort were enriched in certain signaling pathways.	('mutated', 'Var', (185, 192))	('enriched', 'Reg', (224, 232))	('signaling pathways', 'Pathway', (244, 262))	('DMGs', 'Chemical', '-', (154, 158))
157247	33692861	Additionally, compared with in the non-hypermutant cohort, the proportion of patients with squamous cell carcinoma and SCLC was higher in the hypermutant cohort (22.4 vs. 13.1% and 6.0 vs. 2.6%, respectively; P=0.0215).	('hypermutant', 'Var', (142, 153))	('patients', 'Species', '9606', (77, 85))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (91, 114))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('squamous cell carcinoma', 'Disease', (91, 114))	('SCLC', 'Gene', '7864', (119, 123))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (91, 114))	('SCLC', 'Phenotype', 'HP:0030357', (119, 123))	('SCLC', 'Gene', (119, 123))	('higher', 'PosReg', (128, 134))
157251	33692861	Low-density lipoprotein receptor-related protein 1B (LRP1B) exerted the most significant difference on mutation rate between the hypermutant and non-hypermutant cohorts (67.2 vs. 14.3%; P<0.001).	('mutation', 'Var', (103, 111))	('LRP1B', 'Gene', (53, 58))	('Low-density lipoprotein receptor-related protein 1B', 'Gene', '53353', (0, 51))	('LRP1B', 'Gene', '53353', (53, 58))
157252	33692861	In addition, 51.1% of cases with LRP1B mutations in the hypermutant cohort harbored >2 mutations, which was significantly higher compared with in the non-hypermutant cohort (21.8%; P=0.0002) (data not shown).	('LRP1B', 'Gene', (33, 38))	('higher', 'PosReg', (122, 128))	('LRP1B', 'Gene', '53353', (33, 38))	('mutations', 'Var', (39, 48))
157253	33692861	Only EGFR mutations were more frequently observed in the non-hypermutant cohort compared with in the hypermutant cohort (48.9 vs. 22.4%; P<0.001).	('mutations', 'Var', (10, 19))	('observed', 'Reg', (41, 49))	('EGFR', 'Gene', '1956', (5, 9))	('EGFR', 'Gene', (5, 9))
157256	33692861	EGFR sensitive mutations (exon 19 deletions, Leu858Arg and other missense mutations that are sensitive to first- and second-generation EGFR tyrosine kinase inhibitors) and amplification were identified in only 7.5 and 9% of hypermutant patients, respectively.	('Leu858Arg', 'Var', (45, 54))	('EGFR', 'Gene', (0, 4))	('Leu858Arg', 'Mutation', 'rs121434568', (45, 54))	('patients', 'Species', '9606', (236, 244))	('EGFR', 'Gene', '1956', (135, 139))	('EGFR', 'Gene', (135, 139))	('EGFR', 'Gene', '1956', (0, 4))
157257	33692861	BRAF non-V600E mutations were found in 4 cases in the hypermutant cohort.	('BRAF', 'Gene', (0, 4))	('BRAF', 'Gene', '673', (0, 4))	('V600E', 'Mutation', 'rs113488022', (9, 14))	('non-V600E', 'Var', (5, 14))
157258	33692861	3B), EGFR mutations were detected in 48% of cases.	('mutations', 'Var', (10, 19))	('EGFR', 'Gene', '1956', (5, 9))	('EGFR', 'Gene', (5, 9))
157259	33692861	Furthermore, EGFR sensitive mutations were identified in 43.2% of non-hypermutant patients, and among them, 45 cases harbored EGFR secondary resistance mutations.	('EGFR', 'Gene', (13, 17))	('EGFR', 'Gene', (126, 130))	('patients', 'Species', '9606', (82, 90))	('harbored', 'Reg', (117, 125))	('EGFR', 'Gene', '1956', (13, 17))	('mutations', 'Var', (28, 37))	('EGFR', 'Gene', '1956', (126, 130))
157260	33692861	EGFR amplification was found in 12.2% of non-hypermutant patients, with 76.3% of cases accompanied with EGFR sensitive mutations.	('EGFR', 'Gene', (0, 4))	('EGFR', 'Gene', (104, 108))	('amplification', 'Var', (5, 18))	('patients', 'Species', '9606', (57, 65))	('EGFR', 'Gene', '1956', (0, 4))	('EGFR', 'Gene', '1956', (104, 108))
157261	33692861	Compared with in the hypermutant cohort, fewer patients in the non-hypermutant cohort harbored KRAS mutations (10%).	('KRAS', 'Gene', '3845', (95, 99))	('mutations', 'Var', (100, 109))	('patients', 'Species', '9606', (47, 55))	('KRAS', 'Gene', (95, 99))
157263	33692861	Finally, BRAF mutations were detected in 23 cases, including 11 V600E and 12 non-V600E mutations, representing 2.5% of all patients in the non-hypermutant cohort.	('BRAF', 'Gene', (9, 13))	('V600E', 'Mutation', 'rs113488022', (81, 86))	('detected', 'Reg', (29, 37))	('patients', 'Species', '9606', (123, 131))	('V600E', 'Mutation', 'rs113488022', (64, 69))	('mutations', 'Var', (14, 23))	('V600E', 'Var', (64, 69))	('BRAF', 'Gene', '673', (9, 13))
157265	33692861	Subsequently, the prevalence of DDR variants (Table SVII) between the hypermutant and non-hypermutant cohorts was compared.	('DDR', 'Chemical', '-', (32, 35))	('DDR', 'Gene', (32, 35))	('variants', 'Var', (36, 44))
157266	33692861	A total of 105 mutations were identified in DDR genes in 70.1% of patients in the hypermutant cohort, while 321 mutations in DDR genes were detected in 27.0% of patients in the non-hypermutant cohort (data not shown).	('DDR genes', 'Gene', (44, 53))	('mutations', 'Var', (15, 24))	('patients', 'Species', '9606', (161, 169))	('DDR', 'Chemical', '-', (125, 128))	('DDR', 'Chemical', '-', (44, 47))	('patients', 'Species', '9606', (66, 74))
157267	33692861	Mutations in multiple DDR genes were enriched in the hypermutant cohort, including mutations in ATM, POLE/POLD1 and BRCA1/2 genes (Fig.	('mutations', 'Var', (83, 92))	('DDR genes', 'Gene', (22, 31))	('BRCA1/2', 'Gene', '672;675', (116, 123))	('ATM', 'Gene', '472', (96, 99))	('Mutations', 'Var', (0, 9))	('POLD1', 'Gene', '5424', (106, 111))	('ATM', 'Gene', (96, 99))	('DDR', 'Chemical', '-', (22, 25))	('POLD1', 'Gene', (106, 111))	('BRCA1/2', 'Gene', (116, 123))
157270	33692861	In addition, several mutations in POLD1 (E795Q and S816C) and POLE (A1528T and P1205L) genes were considered as non-driver mutations, according to the POLE/POLD1 variants and associated mutation burden referred by Campbell et al.	('E795Q', 'Mutation', 'p.E795Q', (41, 46))	('S816C', 'Var', (51, 56))	('A1528T', 'Var', (68, 74))	('P1205L', 'Var', (79, 85))	('E795Q', 'Var', (41, 46))	('POLD1', 'Gene', '5424', (156, 161))	('P1205L', 'Mutation', 'p.P1205L', (79, 85))	('POLD1', 'Gene', (156, 161))	('POLD1', 'Gene', (34, 39))	('POLD1', 'Gene', '5424', (34, 39))	('A1528T', 'Mutation', 'c.1528A>T', (68, 74))	('S816C', 'Mutation', 'p.S816C', (51, 56))
157272	33692861	Furthermore, several genetic alterations were negatively associated with response to immunotherapy, including three PTEN loss-of-function (LOF) mutations, two B2M LOF mutations, five EGFR sensitive mutations, three STK11 LOF mutations, one KEAP1 LOF mutation, two cases with 11q13 amplification (CCND1, FGF3, FGF4 and FGF19) and one case with MDM2 amplification (data not shown).	('LOF', 'NegReg', (163, 166))	('CCND1', 'Gene', '595', (296, 301))	('mutations', 'Var', (167, 176))	('B2M', 'Gene', (159, 162))	('PTEN', 'Gene', (116, 120))	('mutations', 'Var', (144, 153))	('FGF3', 'Gene', (303, 307))	('CCND1', 'Gene', (296, 301))	('FGF4', 'Gene', '2249', (309, 313))	('FGF3', 'Gene', '2248', (303, 307))	('EGFR', 'Gene', (183, 187))	('loss-of-function', 'NegReg', (121, 137))	('LOF', 'NegReg', (246, 249))	('FGF19', 'Gene', (318, 323))	('FGF19', 'Gene', '9965', (318, 323))	('STK11', 'Gene', (215, 220))	('mutations', 'Var', (225, 234))	('EGFR', 'Gene', '1956', (183, 187))	('LOF', 'NegReg', (221, 224))	('negatively', 'NegReg', (46, 56))	('FGF4', 'Gene', (309, 313))
157275	33692861	Mutations in the Notch signaling pathway were enriched in the hypermutant cohort, with an enrichment ratio of 3.49.	('men', 'Species', '9606', (96, 99))	('Mutations', 'Var', (0, 9))	('Notch signaling pathway', 'Pathway', (17, 40))
157277	33692861	To validate the enrichment of mutations in the Notch signaling pathway in the hypermutant cohort, lung adenocarcinoma and squamous cell carcinoma data from TCGA database were analyzed (n=1,031).	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('Notch signaling pathway', 'Pathway', (47, 70))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (98, 117))	('men', 'Species', '9606', (22, 25))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (122, 145))	('mutations', 'Var', (30, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('squamous cell carcinoma', 'Disease', (122, 145))	('lung adenocarcinoma', 'Disease', (98, 117))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (122, 145))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (98, 117))
157278	33692861	Patients with mutations in these nine genes exhibited more non-synonymous mutations in the coding regions compared with those without these mutations (median, 310 vs. 183.5; P<0.0001; Fig.	('Patients', 'Species', '9606', (0, 8))	('non-synonymous mutations', 'MPA', (59, 83))	('mutations', 'Var', (14, 23))
157280	33692861	It has been reported that hypermutation is frequently found in melanoma, lung and bladder cancer.	('melanoma', 'Disease', 'MESH:D008545', (63, 71))	('bladder cancer', 'Phenotype', 'HP:0009725', (82, 96))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('lung', 'Disease', (73, 77))	('hypermutation', 'Var', (26, 39))	('found', 'Reg', (54, 59))	('bladder cancer', 'Disease', 'MESH:D001749', (82, 96))	('bladder cancer', 'Disease', (82, 96))	('melanoma', 'Phenotype', 'HP:0002861', (63, 71))	('melanoma', 'Disease', (63, 71))
157284	33692861	First, the clinical characteristics between cohorts were compared, and the results revealed that hypermutation was more frequently observed in certain groups of patients, including males, smokers and specific histological subtypes.	('patients', 'Species', '9606', (161, 169))	('observed', 'Reg', (131, 139))	('hypermutation', 'Var', (97, 110))
157288	33692861	LRP1B was more frequently mutated in the hypermutant cohort.	('mutated', 'Var', (26, 33))	('LRP1B', 'Gene', '53353', (0, 5))	('LRP1B', 'Gene', (0, 5))
157291	33692861	Several studies have demonstrated an association between LRP1B mutations and a high level of TMB in patients with NSCLC and melanoma; these studies suggested that in patients with LRP1B mutations, immune response and cell cycle regulation circuits were among the top enriched pathways.	('mutations', 'Var', (63, 72))	('melanoma', 'Disease', 'MESH:D008545', (124, 132))	('NSCLC', 'Phenotype', 'HP:0030358', (114, 119))	('melanoma', 'Disease', (124, 132))	('LRP1B', 'Gene', (57, 62))	('immune response', 'CPA', (197, 212))	('LRP1B', 'Gene', '53353', (180, 185))	('mutations', 'Var', (186, 195))	('melanoma', 'Phenotype', 'HP:0002861', (124, 132))	('NSCLC', 'Disease', (114, 119))	('TMB', 'Chemical', '-', (93, 96))	('cell cycle regulation', 'CPA', (217, 238))	('patients', 'Species', '9606', (100, 108))	('LRP1B', 'Gene', '53353', (57, 62))	('NSCLC', 'Disease', 'MESH:D002289', (114, 119))	('SCLC', 'Phenotype', 'HP:0030357', (115, 119))	('LRP1B', 'Gene', (180, 185))	('patients', 'Species', '9606', (166, 174))
157293	33692861	The distribution of KRAS and EGFR mutations identified in the present study was also consistent with previous studies, suggesting the positive effect of KRAS mutations and negative effect of EGFR mutations on immunotherapy response.	('KRAS', 'Gene', '3845', (20, 24))	('positive', 'PosReg', (134, 142))	('EGFR', 'Gene', '1956', (191, 195))	('KRAS', 'Gene', (153, 157))	('EGFR', 'Gene', (191, 195))	('negative', 'NegReg', (172, 180))	('EGFR', 'Gene', '1956', (29, 33))	('KRAS', 'Gene', '3845', (153, 157))	('EGFR', 'Gene', (29, 33))	('mutations', 'Var', (158, 167))	('KRAS', 'Gene', (20, 24))
157294	33692861	ALK, ROS1 and RET rearrangements were only found in the non-hypermutant cohort, which may suggest a negative association with hypermutation, thereby affecting the response to immunotherapy.	('negative', 'NegReg', (100, 108))	('RET', 'Gene', '5979', (14, 17))	('ALK', 'Gene', '238', (0, 3))	('ALK', 'Gene', (0, 3))	('hypermutation', 'Var', (126, 139))	('RET', 'Gene', (14, 17))	('association', 'Interaction', (109, 120))	('affecting', 'Reg', (149, 158))	('men', 'Species', '9606', (27, 30))	('ROS1', 'Gene', '6098', (5, 9))	('ROS1', 'Gene', (5, 9))
157297	33692861	The enrichment of DDR gene mutations in the hypermutant cohort suggested that mutations in DDR genes may serve as biomarkers for predicting TMB and patient response to immunotherapy.	('mutations', 'Var', (27, 36))	('DDR gene', 'Gene', (18, 26))	('men', 'Species', '9606', (10, 13))	('TMB', 'Chemical', '-', (140, 143))	('DDR genes', 'Gene', (91, 100))	('DDR', 'Chemical', '-', (18, 21))	('mutations', 'Var', (78, 87))	('DDR', 'Chemical', '-', (91, 94))	('patient', 'Species', '9606', (148, 155))	('TMB', 'Disease', (140, 143))
157298	33692861	A previous study has confirmed elevated TMB and improved efficacy of immunotherapy in patients with pathogenic DDR alterations.	('DDR', 'Disease', (111, 114))	('efficacy of immunotherapy', 'CPA', (57, 82))	('improved', 'PosReg', (48, 56))	('TMB', 'MPA', (40, 43))	('alterations', 'Var', (115, 126))	('DDR', 'Chemical', '-', (111, 114))	('elevated', 'PosReg', (31, 39))	('TMB', 'Chemical', '-', (40, 43))	('patients', 'Species', '9606', (86, 94))
157300	33692861	In addition, several negative biomarkers, such as PTEN mutations and MDM2/4 amplification, in the hypermutant cohort were identified, suggesting hyper-progressive disease or disease resistant to immunotherapy, which should raise concern.	('amplification', 'Var', (76, 89))	('hyper-progressive disease or disease', 'Disease', 'MESH:D003141', (145, 181))	('mutations', 'Var', (55, 64))	('MDM2/4', 'Gene', (69, 75))	('PTEN', 'Gene', (50, 54))	('suggesting', 'Reg', (134, 144))	('hyper-progressive disease or disease', 'Disease', (145, 181))
157302	33692861	The results suggested that mutations in the Notch signaling pathway were associated with high TMB, which was confirmed using molecular profiles of lung cancer in TCGA database.	('mutations', 'Var', (27, 36))	('Notch signaling pathway', 'Pathway', (44, 67))	('lung cancer', 'Disease', (147, 158))	('TMB', 'Chemical', '-', (94, 97))	('lung cancer', 'Phenotype', 'HP:0100526', (147, 158))	('associated', 'Reg', (73, 83))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('high TMB', 'Disease', (89, 97))	('lung cancer', 'Disease', 'MESH:D008175', (147, 158))
157305	33692861	Targeting NOTCH1 may therefore affect cell proliferation and survival, and provide an immune-responsive tumor microenvironment, thus improving the efficacy of immunotherapy.	('affect', 'Reg', (31, 37))	('cell proliferation', 'CPA', (38, 56))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('survival', 'CPA', (61, 69))	('improving', 'PosReg', (133, 142))	('tumor', 'Disease', (104, 109))	('NOTCH1', 'Gene', (10, 16))	('efficacy of immunotherapy', 'CPA', (147, 172))	('NOTCH1', 'Gene', '4851', (10, 16))	('Targeting', 'Var', (0, 9))	('men', 'Species', '9606', (122, 125))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
157306	33692861	Another study uncovered a marked association between mutations in NOTCH1/2/3 and improved outcomes in EGFR- and ALK-wild-type patients with NSCLC treated with immune checkpoint inhibitors.	('improved', 'PosReg', (81, 89))	('NSCLC', 'Disease', 'MESH:D002289', (140, 145))	('NOTCH1/2/3', 'Gene', '4851;4853;4854', (66, 76))	('ALK', 'Gene', (112, 115))	('EGFR', 'Gene', '1956', (102, 106))	('SCLC', 'Phenotype', 'HP:0030357', (141, 145))	('NOTCH1/2/3', 'Gene', (66, 76))	('EGFR', 'Gene', (102, 106))	('mutations', 'Var', (53, 62))	('NSCLC', 'Phenotype', 'HP:0030358', (140, 145))	('patients', 'Species', '9606', (126, 134))	('ALK', 'Gene', '238', (112, 115))	('outcomes', 'MPA', (90, 98))	('NSCLC', 'Disease', (140, 145))
157307	33692861	Previous studies found that tumors with Notch family gene (NOTCH1/2/3/4) mutations exerted higher TMBs in multiple types of cancer, including hepatocellular carcinoma, esophageal carcinoma, breast cancer, SCLC, head and neck cancer and cutaneous carcinoma, which may explain the predictive value of NOTCH mutations to immunotherapy response.	('NOTCH1/2/3/4', 'Gene', '4851;4853;4854;4855', (59, 71))	('cancer', 'Disease', 'MESH:D009369', (197, 203))	('esophageal carcinoma', 'Disease', (168, 188))	('cancer', 'Disease', (225, 231))	('SCLC', 'Gene', '7864', (205, 209))	('SCLC', 'Gene', (205, 209))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (142, 166))	('head and neck cancer', 'Phenotype', 'HP:0012288', (211, 231))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('neck cancer', 'Disease', 'MESH:D006258', (220, 231))	('breast cancer', 'Disease', (190, 203))	('cutaneous carcinoma', 'Disease', (236, 255))	('breast cancer', 'Disease', 'MESH:D001943', (190, 203))	('cancer', 'Disease', 'MESH:D009369', (124, 130))	('TMBs', 'MPA', (98, 102))	('neck cancer', 'Disease', (220, 231))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('carcinoma', 'Phenotype', 'HP:0030731', (246, 255))	('hepatocellular carcinoma', 'Disease', (142, 166))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (168, 188))	('carcinoma', 'Phenotype', 'HP:0030731', (157, 166))	('cutaneous carcinoma', 'Disease', 'MESH:D009369', (236, 255))	('TMB', 'Chemical', '-', (98, 101))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('cancer', 'Disease', 'MESH:D009369', (225, 231))	('higher', 'PosReg', (91, 97))	('tumors', 'Disease', (28, 34))	('cancer', 'Disease', (197, 203))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('carcinoma', 'Phenotype', 'HP:0030731', (179, 188))	('cancer', 'Disease', (124, 130))	('NOTCH1/2/3/4', 'Gene', (59, 71))	('tumors', 'Disease', 'MESH:D009369', (28, 34))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (142, 166))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (168, 188))	('SCLC', 'Phenotype', 'HP:0030357', (205, 209))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('breast cancer', 'Phenotype', 'HP:0003002', (190, 203))	('mutations', 'Var', (73, 82))
157308	33692861	In the present study, the strong association between NOTCH gene mutations and high TMB indicated a potential strategy for immunotherapy in patients with lung cancer with mutations in the Notch signaling pathway.	('lung cancer', 'Disease', 'MESH:D008175', (153, 164))	('patients', 'Species', '9606', (139, 147))	('mutations', 'Var', (170, 179))	('TMB', 'Chemical', '-', (83, 86))	('high TMB', 'Disease', (78, 86))	('lung cancer', 'Disease', (153, 164))	('mutations', 'Var', (64, 73))	('lung cancer', 'Phenotype', 'HP:0100526', (153, 164))	('NOTCH gene', 'Gene', (53, 63))	('Notch signaling pathway', 'Pathway', (187, 210))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
157319	33692861	In conclusion, the present cohort study suggested that hypermutant lung cancer exhibited distinctive genetic profiles, including high occurrence of MSI-high, high frequency of mutations in DDR genes and genes involved in the Notch signaling pathway, which may be associated with high levels of TMB.	('mutations', 'Var', (176, 185))	('DDR', 'Chemical', '-', (189, 192))	('hypermutant', 'Var', (55, 66))	('lung cancer', 'Disease', 'MESH:D008175', (67, 78))	('MSI-high', 'Gene', (148, 156))	('DDR genes', 'Gene', (189, 198))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('lung cancer', 'Disease', (67, 78))	('lung cancer', 'Phenotype', 'HP:0100526', (67, 78))	('TMB', 'Chemical', '-', (294, 297))
157320	33692861	In addition, patients with hypermutant lung cancer may be more likely to have a history of tobacco use and exhibit the histological subtypes of squamous carcinoma and SCLC.	('tobacco', 'Species', '4097', (91, 98))	('lung cancer', 'Phenotype', 'HP:0100526', (39, 50))	('hypermutant', 'Var', (27, 38))	('squamous carcinoma', 'Disease', 'MESH:D002294', (144, 162))	('lung cancer', 'Disease', (39, 50))	('squamous carcinoma', 'Disease', (144, 162))	('patients', 'Species', '9606', (13, 21))	('carcinoma', 'Phenotype', 'HP:0030731', (153, 162))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (144, 162))	('lung cancer', 'Disease', 'MESH:D008175', (39, 50))	('SCLC', 'Gene', (167, 171))	('SCLC', 'Gene', '7864', (167, 171))	('SCLC', 'Phenotype', 'HP:0030357', (167, 171))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
157326	33692861	NSCLC non-small cell lung cancer SCLC small cell lung cancer ORR objective response rate TMB tumor mutation burden NGS next-generation sequencing MSI microsatellite instability DDR DNA damage response FFPE formalin-fixed, paraffin-embedded SNV single nucleotide variant InDel insertions and deletions DMG differentially mutated gene	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (6, 32))	('deletions', 'Var', (291, 300))	('NSCLC', 'Phenotype', 'HP:0030358', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('small cell lung cancer', 'Disease', 'MESH:D055752', (38, 60))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (10, 32))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('small cell lung cancer', 'Disease', (38, 60))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (6, 32))	('lung cancer', 'Phenotype', 'HP:0100526', (49, 60))	('formalin', 'Chemical', 'MESH:D005557', (206, 214))	('TMB', 'Chemical', '-', (89, 92))	('DDR', 'Chemical', '-', (177, 180))	('SCLC', 'Phenotype', 'HP:0030357', (1, 5))	('SCLC', 'Phenotype', 'HP:0030357', (33, 37))	('non-small cell lung cancer', 'Disease', (6, 32))	('small cell lung cancer', 'Disease', 'MESH:D055752', (10, 32))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (38, 60))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('NSCLC', 'Disease', 'MESH:D002289', (0, 5))	('single nucleotide variant InDel insertions', 'Var', (244, 286))	('DMG', 'Chemical', '-', (301, 304))	('tumor', 'Disease', (93, 98))	('SCLC', 'Gene', (33, 37))	('lung cancer', 'Phenotype', 'HP:0100526', (21, 32))	('SCLC', 'Gene', '7864', (1, 5))	('SCLC', 'Gene', (1, 5))	('SCLC', 'Gene', '7864', (33, 37))	('paraffin', 'Chemical', 'MESH:D010232', (222, 230))	('NSCLC', 'Disease', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
157354	32245901	We report the biodistribution and radiation dosimetry, and describe the tumor uptake of 18F-PARPi compared to 18F-FDG.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Disease', (72, 77))	('18F-FDG', 'Chemical', 'MESH:D019788', (110, 117))	('18F-PARPi', 'Var', (88, 97))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('18F-PARPi', 'Chemical', '-', (88, 97))
157419	32245901	A smaller decrease in SUVmax values was found for 18F-PARPi (66% and 15% for 18F-PARPi and 18F-FDG, respectively, when grouping primary/level 1 lymph nodes and level 2/level 3 lymph nodes; Fig.	('18F-PARPi', 'Var', (77, 86))	('18F-PARPi', 'Chemical', '-', (77, 86))	('SUVmax values', 'MPA', (22, 35))	('18F-PARPi', 'Chemical', '-', (50, 59))	('18F-FDG', 'Chemical', 'MESH:D019788', (91, 98))
157420	32245901	Uptake ratios (SUVmax(lesion)/SUVmax(trapezius muscle)) for 18F-FDG were higher than for 18F-PARPi (median = 10.4 versus 4.5, p < 0.0001, Fig.	('18F-FDG', 'Chemical', 'MESH:D019788', (60, 67))	('18F-PARPi', 'Chemical', '-', (89, 98))	('Uptake ratios', 'MPA', (0, 13))	('18F-FDG', 'Var', (60, 67))	('higher', 'PosReg', (73, 79))
157449	32245901	The number of PET avid lymph nodes is higher for 18F-PARPi than for 18F-FDG, and a subset of 18F-PARPi positive and 18F-FDG negative lymph nodes resolved after chemoradiation.	('18F-FDG', 'Chemical', 'MESH:D019788', (68, 75))	('18F-FDG', 'Chemical', 'MESH:D019788', (116, 123))	('PET avid lymph nodes', 'CPA', (14, 34))	('18F-PARPi', 'Var', (49, 58))	('higher', 'PosReg', (38, 44))	('18F-PARPi', 'Chemical', '-', (49, 58))	('18F-PARPi', 'Chemical', '-', (93, 102))
157454	32756609	The goal of this study was to identify the frequency of causal genetic mutations across a variety of lung cancer subtypes in the earlier stages.	('c', 'Chemical', 'MESH:D002244', (106, 107))	('lung cancer', 'Disease', 'MESH:D008175', (101, 112))	('c', 'Chemical', 'MESH:D002244', (69, 70))	('c', 'Chemical', 'MESH:D002244', (56, 57))	('genetic mutations', 'Var', (63, 80))	('lung cancer', 'Phenotype', 'HP:0100526', (101, 112))	('c', 'Chemical', 'MESH:D002244', (50, 51))	('c', 'Chemical', 'MESH:D002244', (109, 110))	('lung cancer', 'Disease', (101, 112))	('c', 'Chemical', 'MESH:D002244', (82, 83))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
157455	32756609	833 samples of non-small cell lung cancer from 799 patients who received resection of their lung cancer, were selected for molecular analysis of six known mutations, including EGFR, KRAS, BRAF, PIK3CA, HER2 and ALK.	('BRAF', 'Disease', (188, 192))	('c', 'Chemical', 'MESH:D002244', (168, 169))	('lung cancer', 'Phenotype', 'HP:0100526', (92, 103))	('c', 'Chemical', 'MESH:D002244', (25, 26))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('ALK', 'Disease', (211, 214))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (19, 41))	('HER2', 'Gene', (202, 206))	('PIK3CA', 'Var', (194, 200))	('c', 'Chemical', 'MESH:D002244', (38, 39))	('lung cancer', 'Disease', (30, 41))	('c', 'Chemical', 'MESH:D002244', (127, 128))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('EGFR', 'Gene', (176, 180))	('patients', 'Species', '9606', (51, 59))	('c', 'Chemical', 'MESH:D002244', (77, 78))	('lung cancer', 'Disease', (92, 103))	('c', 'Chemical', 'MESH:D002244', (100, 101))	('lung cancer', 'Disease', 'MESH:D008175', (30, 41))	('KRAS', 'Disease', (182, 186))	('lung cancer', 'Phenotype', 'HP:0100526', (30, 41))	('c', 'Chemical', 'MESH:D002244', (35, 36))	('c', 'Chemical', 'MESH:D002244', (66, 67))	('c', 'Chemical', 'MESH:D002244', (97, 98))	('lung cancer', 'Disease', 'MESH:D008175', (92, 103))	('c', 'Chemical', 'MESH:D002244', (114, 115))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (15, 41))
157459	32756609	The observed frequencies among the total samples vs. only the adenocarcinoma cases were notable different, with the highest frequency being the KRAS mutation (24.49% vs. 35.55%), followed by EGFR (6.96% vs. 10.23%), PIK3CA (1.20% vs. 0.9%), BRAF (1.08% vs. 1.62%), ALK (0.12% vs. 0.18%), while the lowest was the HER2 mutation (0% for both).	('c', 'Chemical', 'MESH:D002244', (20, 21))	('c', 'Chemical', 'MESH:D002244', (131, 132))	('adenocarcinoma', 'Disease', (62, 76))	('c', 'Chemical', 'MESH:D002244', (70, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('c', 'Chemical', 'MESH:D002244', (67, 68))	('KRAS', 'Gene', (144, 148))	('adenocarcinoma', 'Disease', 'MESH:D000230', (62, 76))	('mutation', 'Var', (149, 157))	('c', 'Chemical', 'MESH:D002244', (77, 78))
157467	32756609	The mutations most frequently reported in adenocarcinoma occur in the KRAS and EGFR genes.	('EGFR', 'Gene', (79, 83))	('KRAS', 'Gene', (70, 74))	('adenocarcinoma', 'Disease', (42, 56))	('carcinoma', 'Phenotype', 'HP:0030731', (47, 56))	('adenocarcinoma', 'Disease', 'MESH:D000230', (42, 56))	('mutations', 'Var', (4, 13))
157474	32756609	For tumours identified to not carry a mutation leading to drug responsiveness, early identification could lead to earlier surgical resection, however other treatments such as adjuvant chemotherapy would often be required either immediately following resection or in later stages of the disease when surgery was no longer an option.	('c', 'Chemical', 'MESH:D002244', (30, 31))	('c', 'Chemical', 'MESH:D002244', (127, 128))	('tumour', 'Phenotype', 'HP:0002664', (4, 10))	('c', 'Chemical', 'MESH:D002244', (254, 255))	('c', 'Chemical', 'MESH:D002244', (93, 94))	('c', 'Chemical', 'MESH:D002244', (100, 101))	('lead to', 'Reg', (106, 113))	('c', 'Chemical', 'MESH:D002244', (135, 136))	('c', 'Chemical', 'MESH:D002244', (169, 170))	('tumours', 'Phenotype', 'HP:0002664', (4, 11))	('c', 'Chemical', 'MESH:D002244', (184, 185))	('mutation', 'Var', (38, 46))	('tumours', 'Disease', 'MESH:D009369', (4, 11))	('men', 'Species', '9606', (161, 164))	('tumours', 'Disease', (4, 11))
157476	32756609	The most common driver mutations are found in KRAS (V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog; 25%), EGFR (epidermal growth factor receptor; 23%), ALK (anaplastic lymphoma kinase; 6%), PIK3CA (phosphoinositide-3-kinase, catalytic, alpha polypeptide; 3%), BRAF (v-Raf murine sarcoma viral oncogene homolog B1; 3%), and HER2 (human epidermal growth factor receptor 2; 1%).	('c', 'Chemical', 'MESH:D002244', (137, 138))	('c', 'Chemical', 'MESH:D002244', (144, 145))	('sarcoma', 'Disease', (285, 292))	('c', 'Chemical', 'MESH:D002244', (367, 368))	('PIK3CA', 'Gene', (196, 202))	('epidermal growth factor receptor', 'Gene', (118, 150))	('v-Raf murine sarcoma viral oncogene homolog B1', 'Gene', (272, 318))	('c', 'Chemical', 'MESH:D002244', (301, 302))	('anaplastic lymphoma kinase', 'Gene', (163, 189))	('c', 'Chemical', 'MESH:D002244', (239, 240))	('human', 'Species', '9606', (335, 340))	('sarcoma', 'Phenotype', 'HP:0100242', (285, 292))	('sarcoma', 'Phenotype', 'HP:0100242', (74, 81))	('HER2', 'Gene', (329, 333))	('lymphoma', 'Phenotype', 'HP:0002665', (174, 182))	('mutations', 'Var', (23, 32))	('epidermal growth factor receptor 2', 'Gene', '2064', (341, 375))	('c', 'Chemical', 'MESH:D002244', (77, 78))	('EGFR', 'Gene', (112, 116))	('v-Raf murine sarcoma viral oncogene homolog B1', 'Gene', '114486', (272, 318))	('rat', 'Species', '10116', (70, 73))	('anaplastic lymphoma kinase', 'Gene', '266802', (163, 189))	('c', 'Chemical', 'MESH:D002244', (172, 173))	('BRAF', 'Gene', (266, 270))	('sarcoma', 'Disease', 'MESH:D012509', (74, 81))	('epidermal growth factor receptor 2', 'Gene', (341, 375))	('sarcoma', 'Disease', (74, 81))	('c', 'Chemical', 'MESH:D002244', (360, 361))	('ALK', 'Gene', (158, 161))	('KRAS', 'Gene', (46, 50))	('c', 'Chemical', 'MESH:D002244', (9, 10))	('c', 'Chemical', 'MESH:D002244', (90, 91))	('epidermal growth factor receptor', 'Gene', '24329', (341, 373))	('epidermal growth factor receptor', 'Gene', '24329', (118, 150))	('c', 'Chemical', 'MESH:D002244', (231, 232))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (163, 182))	('c', 'Chemical', 'MESH:D002244', (288, 289))	('sarcoma', 'Disease', 'MESH:D012509', (285, 292))
157477	32756609	The resulting aberrant gene products are involved in signalling pathways associated with cell proliferation and cell survival.	('c', 'Chemical', 'MESH:D002244', (89, 90))	('rat', 'Species', '10116', (101, 104))	('involved', 'Reg', (41, 49))	('aberrant gene products', 'Var', (14, 36))	('c', 'Chemical', 'MESH:D002244', (33, 34))	('c', 'Chemical', 'MESH:D002244', (112, 113))	('signalling pathways', 'Pathway', (53, 72))	('c', 'Chemical', 'MESH:D002244', (77, 78))
157478	32756609	The development of therapies that target specific mutations in lung cancer has revolutionized the therapy for patients who harbour a targetable mutation.	('c', 'Chemical', 'MESH:D002244', (44, 45))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('lung cancer', 'Disease', 'MESH:D008175', (63, 74))	('c', 'Chemical', 'MESH:D002244', (68, 69))	('mutations', 'Var', (50, 59))	('c', 'Chemical', 'MESH:D002244', (48, 49))	('lung cancer', 'Disease', (63, 74))	('lung cancer', 'Phenotype', 'HP:0100526', (63, 74))	('c', 'Chemical', 'MESH:D002244', (71, 72))	('patients', 'Species', '9606', (110, 118))	('men', 'Species', '9606', (11, 14))
157479	32756609	Treating most patients with EGFR and ALK mutations with targeted tyrosine kinase inhibitors (TKIs) is standard of care and has been proven to be better tolerated and more efficacious than cytotoxic chemotherapy as initial therapy.	('mutations', 'Var', (41, 50))	('c', 'Chemical', 'MESH:D002244', (175, 176))	('rat', 'Species', '10116', (156, 159))	('c', 'Chemical', 'MESH:D002244', (188, 189))	('c', 'Chemical', 'MESH:D002244', (196, 197))	('ALK', 'Gene', (37, 40))	('EGFR', 'Gene', (28, 32))	('c', 'Chemical', 'MESH:D002244', (114, 115))	('c', 'Chemical', 'MESH:D002244', (198, 199))	('c', 'Chemical', 'MESH:D002244', (177, 178))	('patients', 'Species', '9606', (14, 22))
157480	32756609	There are now multiple drugs available for patients with targetable EGFR and ALK mutations, and better understanding of how tumours become resistant to initial lines of therapy has allowed for new drug development that circumvents resistance such that many patients can be treated with multiple TKIs in sequence before requiring chemotherapy.	('c', 'Chemical', 'MESH:D002244', (239, 240))	('c', 'Chemical', 'MESH:D002244', (134, 135))	('ALK', 'Gene', (77, 80))	('c', 'Chemical', 'MESH:D002244', (329, 330))	('c', 'Chemical', 'MESH:D002244', (219, 220))	('c', 'Chemical', 'MESH:D002244', (244, 245))	('c', 'Chemical', 'MESH:D002244', (309, 310))	('patients', 'Species', '9606', (43, 51))	('tumour', 'Phenotype', 'HP:0002664', (124, 130))	('tumours', 'Phenotype', 'HP:0002664', (124, 131))	('patients', 'Species', '9606', (257, 265))	('mutations', 'Var', (81, 90))	('c', 'Chemical', 'MESH:D002244', (266, 267))	('men', 'Species', '9606', (209, 212))	('c', 'Chemical', 'MESH:D002244', (222, 223))	('EGFR', 'Gene', (68, 72))	('tumours', 'Disease', 'MESH:D009369', (124, 131))	('tumours', 'Disease', (124, 131))
157481	32756609	For example, more than half of patients with a targetable EGFR mutation who receive initial therapy with a first- or second-generation EGFR TKI (gefitinib, erlotinib or afatinib) will become resistant by developing a new T790M point mutation.	('T790M', 'Var', (221, 226))	('erlotinib', 'Chemical', 'MESH:D000069347', (156, 165))	('EGFR', 'Gene', (58, 62))	('T790M', 'SUBSTITUTION', 'None', (221, 226))	('c', 'Chemical', 'MESH:D002244', (186, 187))	('gefitinib', 'Chemical', 'MESH:D000077156', (145, 154))	('mutation', 'Var', (63, 71))	('resistant', 'MPA', (191, 200))	('patients', 'Species', '9606', (31, 39))	('afatinib', 'Chemical', 'MESH:D000077716', (169, 177))	('c', 'Chemical', 'MESH:D002244', (78, 79))	('rat', 'Species', '10116', (128, 131))	('c', 'Chemical', 'MESH:D002244', (119, 120))
157482	32756609	The third generation EGFR TKI osimertinib has activity in this patient group and has been established as the standard second line therapy for a patient with an acquired T790M mutation.	('c', 'Chemical', 'MESH:D002244', (161, 162))	('c', 'Chemical', 'MESH:D002244', (120, 121))	('T790M', 'Var', (169, 174))	('TKI osimertinib', 'Disease', (26, 41))	('TKI osimertinib', 'Disease', 'None', (26, 41))	('patient', 'Species', '9606', (144, 151))	('activity', 'MPA', (46, 54))	('patient', 'Species', '9606', (63, 70))	('c', 'Chemical', 'MESH:D002244', (47, 48))	('rat', 'Species', '10116', (14, 17))	('T790M', 'SUBSTITUTION', 'None', (169, 174))
157488	32756609	There are multiple other driver mutations that have been identified in lung cancer that have effective targeted therapies, including ROS1, BRAF, and NTRK mutations to name a few.	('c', 'Chemical', 'MESH:D002244', (79, 80))	('BRAF', 'Gene', (139, 143))	('ROS1', 'Gene', '6098', (133, 137))	('NTRK', 'Gene', (149, 153))	('lung cancer', 'Phenotype', 'HP:0100526', (71, 82))	('lung cancer', 'Disease', 'MESH:D008175', (71, 82))	('c', 'Chemical', 'MESH:D002244', (97, 98))	('c', 'Chemical', 'MESH:D002244', (125, 126))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('c', 'Chemical', 'MESH:D002244', (76, 77))	('mutations', 'Var', (32, 41))	('mutations', 'Var', (154, 163))	('lung cancer', 'Disease', (71, 82))	('ROS1', 'Gene', (133, 137))
157498	32756609	Diagnosis of lung cancer subtype for each case was achieved by morphology assessment and immunohistochemistry (TTF-1, Napsin A, P40/P63, CH5/6, CK7, CK20).	('TTF-1', 'Gene', (111, 116))	('c', 'Chemical', 'MESH:D002244', (39, 40))	('lung cancer', 'Disease', (13, 24))	('Napsin A', 'Gene', '9476', (118, 126))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('CK7', 'Gene', (144, 147))	('c', 'Chemical', 'MESH:D002244', (21, 22))	('c', 'Chemical', 'MESH:D002244', (52, 53))	('c', 'Chemical', 'MESH:D002244', (100, 101))	('CK20', 'Gene', (149, 153))	('men', 'Species', '9606', (80, 83))	('TTF-1', 'Gene', '7270', (111, 116))	('lung cancer', 'Disease', 'MESH:D008175', (13, 24))	('Napsin A', 'Gene', (118, 126))	('CK7', 'Gene', '3855', (144, 147))	('lung cancer', 'Phenotype', 'HP:0100526', (13, 24))	('c', 'Chemical', 'MESH:D002244', (42, 43))	('c', 'Chemical', 'MESH:D002244', (18, 19))	('P40/P63', 'Var', (128, 135))	('CH5/6', 'Var', (137, 142))	('CK20', 'Gene', '54474', (149, 153))
157503	32756609	ALK mutations reported in NSCLC are primarily chromosomal inversions or translocations that result in an ALK-EML4 fusion gene and elevated expression of abnormal ALK fusion protein.	('c', 'Chemical', 'MESH:D002244', (79, 80))	('c', 'Chemical', 'MESH:D002244', (46, 47))	('EML4', 'Gene', '27436', (109, 113))	('NSCLC', 'Disease', (26, 31))	('ALK', 'Gene', (0, 3))	('elevated', 'PosReg', (130, 138))	('expression', 'MPA', (139, 149))	('mutations', 'Var', (4, 13))	('ALK fusion protein', 'Protein', (162, 180))	('EML4', 'Gene', (109, 113))	('NSCLC', 'Disease', 'MESH:D002289', (26, 31))
157506	32756609	These include the c.2573T>G (p.Leu858Arg, or L858R) and c.2369C>T (p.Thr790Met, or T790M) mutations in EGFR (NM_005228.4), the c.34G>T (p.Gly12Cys) and c.35G>T (p.Gly12Val) mutations in KRAS (NM_004985.4), the c.1624G>A (p.Glu542Lys, or E542K) and c.1633G>A (p.Glu545Lys, or E545K) mutations in PIK3CA (NM_006218.3), and the c.1799T>A (p.Val600Glu, or V600E) mutation in BRAF (NM_004333.5).	('E542K', 'SUBSTITUTION', 'None', (237, 242))	('p.Leu858Arg', 'Var', (29, 40))	('c', 'Chemical', 'MESH:D002244', (56, 57))	('c', 'Chemical', 'MESH:D002244', (8, 9))	('p.Glu542Lys', 'Var', (221, 232))	('V600E', 'SUBSTITUTION', 'None', (352, 357))	('c', 'Chemical', 'MESH:D002244', (152, 153))	('p.Thr790Met', 'Var', (67, 78))	('E542K', 'Var', (237, 242))	('c.2573T>G', 'SUBSTITUTION', 'None', (18, 27))	('c', 'Chemical', 'MESH:D002244', (325, 326))	('p.Gly12Cys', 'SUBSTITUTION', 'None', (136, 146))	('E545K', 'SUBSTITUTION', 'None', (275, 280))	('c', 'Chemical', 'MESH:D002244', (127, 128))	('c.1624G>A', 'SUBSTITUTION', 'None', (210, 219))	('c.1633G>A', 'Var', (248, 257))	('p.Gly12Val', 'Var', (161, 171))	('p.Thr790Met', 'SUBSTITUTION', 'None', (67, 78))	('c.34G>T', 'SUBSTITUTION', 'None', (127, 134))	('BRAF', 'Gene', (371, 375))	('c.1624G>A', 'Var', (210, 219))	('c.1799T>A', 'SUBSTITUTION', 'None', (325, 334))	('c.1633G>A', 'SUBSTITUTION', 'None', (248, 257))	('p.Glu542Lys', 'SUBSTITUTION', 'None', (221, 232))	('T790M', 'Var', (83, 88))	('c.2369C>T', 'SUBSTITUTION', 'None', (56, 65))	('c.1799T>A', 'Var', (325, 334))	('PIK3CA', 'Gene', (295, 301))	('c.34G>T', 'Var', (127, 134))	('p.Leu858Arg', 'SUBSTITUTION', 'None', (29, 40))	('L858R', 'SUBSTITUTION', 'None', (45, 50))	('p.Val600Glu', 'Var', (336, 347))	('EGFR', 'Gene', (103, 107))	('L858R', 'Var', (45, 50))	('E545K', 'Var', (275, 280))	('p.Gly12Cys', 'Var', (136, 146))	('c.2573T>G', 'Var', (18, 27))	('p.Glu545Lys', 'SUBSTITUTION', 'None', (259, 270))	('p.Gly12Val', 'SUBSTITUTION', 'None', (161, 171))	('c.2369C>T', 'Var', (56, 65))	('c', 'Chemical', 'MESH:D002244', (248, 249))	('c.35G>T', 'SUBSTITUTION', 'None', (152, 159))	('c', 'Chemical', 'MESH:D002244', (210, 211))	('c', 'Chemical', 'MESH:D002244', (18, 19))	('p.Glu545Lys', 'Var', (259, 270))	('T790M', 'SUBSTITUTION', 'None', (83, 88))	('c.35G>T', 'Var', (152, 159))	('V600E', 'Var', (352, 357))	('p.Val600Glu', 'SUBSTITUTION', 'None', (336, 347))
157514	32756609	This assay requires 20 ng of input DNA and is sensitive enough to detect the mutant alleles in tumour cells that comprise as low as 1% to 10% of total nucleated cells.	('c', 'Chemical', 'MESH:D002244', (161, 162))	('tumour', 'Disease', 'MESH:D009369', (95, 101))	('tumour', 'Phenotype', 'HP:0002664', (95, 101))	('c', 'Chemical', 'MESH:D002244', (70, 71))	('tumour', 'Disease', (95, 101))	('c', 'Chemical', 'MESH:D002244', (153, 154))	('mutant', 'Var', (77, 83))	('c', 'Chemical', 'MESH:D002244', (113, 114))	('c', 'Chemical', 'MESH:D002244', (102, 103))
157515	32756609	A fragment analysis sizing assay was used to detect small recurring deletions in exon 19 of EGFR and insertions in exon 20 of EGFR and exon 20 of HER2.	('EGFR', 'Gene', (126, 130))	('c', 'Chemical', 'MESH:D002244', (49, 50))	('deletions in', 'Var', (68, 80))	('EGFR', 'Gene', (92, 96))	('insertions', 'Var', (101, 111))	('HER2', 'Gene', (146, 150))	('c', 'Chemical', 'MESH:D002244', (60, 61))	('men', 'Species', '9606', (6, 9))
157525	32756609	Cox proportional hazards analysis was used to investigate if overall patient survival, not just 5-year survival, was related to mutation.	('mutation', 'Var', (128, 136))	('related', 'Reg', (117, 124))	('patient', 'Species', '9606', (69, 76))
157531	32756609	Among 58 cases with EGFR mutations 30 had an exon 19 deletion (3.6% of total), 25 had an exon 21 L858R mutation (3.0%), and 3 had an exon 20 insertion (0.36%).	('mutations', 'Var', (25, 34))	('EGFR', 'Gene', (20, 24))	('L858R', 'SUBSTITUTION', 'None', (97, 102))	('c', 'Chemical', 'MESH:D002244', (9, 10))	('L858R', 'Var', (97, 102))
157532	32756609	In 10 cases with PIK3CA mutations, 4 were PIK3CA E452K (0.48% of total) and 6 were PIK3CA E545K (0.72%).	('c', 'Chemical', 'MESH:D002244', (6, 7))	('E452K', 'Var', (49, 54))	('E452K', 'SUBSTITUTION', 'None', (49, 54))	('E545K', 'SUBSTITUTION', 'None', (90, 95))	('PIK3CA', 'Gene', (17, 23))	('PIK3CA', 'Gene', (42, 48))	('E545K', 'Var', (90, 95))	('mutations', 'Var', (24, 33))
157533	32756609	There was also one case which exhibited both a KRAS and PIK3CA mutation.	('PIK3CA', 'Gene', (56, 62))	('c', 'Chemical', 'MESH:D002244', (19, 20))	('c', 'Chemical', 'MESH:D002244', (27, 28))	('KRAS', 'Var', (47, 51))
157535	32756609	It was followed by the EGFR mutation (10.23%), BRAF mutation (1.62%), PIK3CA mutation (0.9%), and ALK gene rearrangement (0.18%).	('BRAF', 'Gene', (47, 51))	('PIK3CA', 'Gene', (70, 76))	('mutation', 'Var', (28, 36))	('EGFR', 'Gene', (23, 27))	('men', 'Species', '9606', (116, 119))
157542	32756609	There was no evidence that different mutations are associated with differing cancer stages (p-value of 0.446).	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('c', 'Chemical', 'MESH:D002244', (55, 56))	('associated', 'Reg', (51, 61))	('mutations', 'Var', (37, 46))	('c', 'Chemical', 'MESH:D002244', (80, 81))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('c', 'Chemical', 'MESH:D002244', (19, 20))	('c', 'Chemical', 'MESH:D002244', (77, 78))
157545	32756609	A higher than expected number of KRAS and EGFR mutations were observed among adenocarcinoma cases, with fewer than expected among squamous cell and other cancer types (p-value of <0.0001) (Table 2).	('c', 'Chemical', 'MESH:D002244', (154, 155))	('adenocarcinoma', 'Disease', 'MESH:D000230', (77, 91))	('c', 'Chemical', 'MESH:D002244', (18, 19))	('EGFR', 'Gene', (42, 46))	('KRAS', 'Gene', (33, 37))	('cancer', 'Disease', (154, 160))	('mutations', 'Var', (47, 56))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('c', 'Chemical', 'MESH:D002244', (139, 140))	('c', 'Chemical', 'MESH:D002244', (85, 86))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('c', 'Chemical', 'MESH:D002244', (157, 158))	('c', 'Chemical', 'MESH:D002244', (92, 93))	('adenocarcinoma', 'Disease', (77, 91))	('c', 'Chemical', 'MESH:D002244', (82, 83))	('c', 'Chemical', 'MESH:D002244', (119, 120))
157546	32756609	A reasonable effect of gender was observed, with more females and fewer males exhibiting the EGFR mutation than expected (p-value of 0.00563) (Table 3).	('mutation', 'Var', (98, 106))	('c', 'Chemical', 'MESH:D002244', (17, 18))	('EGFR', 'Gene', (93, 97))	('exhibiting', 'Reg', (78, 88))	('c', 'Chemical', 'MESH:D002244', (116, 117))
157548	32756609	Investigation of the type of mutation in relation to smoking history identified strong evidence of an association between individuals with the EGFR mutation and those who had never smoked (p-value of <0.001) (Table 4).	('EGFR', 'Gene', (143, 147))	('mutation', 'Var', (148, 156))	('c', 'Chemical', 'MESH:D002244', (106, 107))	('c', 'Chemical', 'MESH:D002244', (93, 94))
157551	32756609	The mutation status was reasonably associated with vascular, potentially with pleural, but not with lymphatic invasion (p-values of 0.00164, 0.0482, and 0.313, respectively).	('c', 'Chemical', 'MESH:D002244', (165, 166))	('pleural', 'Disease', (78, 85))	('associated', 'Reg', (35, 45))	('mutation', 'Var', (4, 12))	('vascular', 'CPA', (51, 59))	('c', 'Chemical', 'MESH:D002244', (108, 109))	('pleural', 'Disease', 'MESH:D010995', (78, 85))	('c', 'Chemical', 'MESH:D002244', (39, 40))	('c', 'Chemical', 'MESH:D002244', (54, 55))
157552	32756609	In terms of vascular invasion effect, fewer individuals were observed with the EGFR mutation than expected.	('c', 'Chemical', 'MESH:D002244', (34, 35))	('mutation', 'Var', (84, 92))	('EGFR', 'Gene', (79, 83))	('vascular invasion', 'CPA', (12, 29))	('c', 'Chemical', 'MESH:D002244', (15, 16))	('c', 'Chemical', 'MESH:D002244', (102, 103))
157558	32756609	Due to the small number of cases exhibiting the ALK, BRAF, PIK3CA and HER2 mutations, these cases were combined under 'Others'.	('HER2', 'Gene', (70, 74))	('c', 'Chemical', 'MESH:D002244', (27, 28))	('c', 'Chemical', 'MESH:D002244', (103, 104))	('PIK3CA', 'Gene', (59, 65))	('ALK', 'Gene', (48, 51))	('mutations', 'Var', (75, 84))	('c', 'Chemical', 'MESH:D002244', (92, 93))
157563	32756609	Examining presence of a mutation against 5-year survival yielded a p-value of 0.2701 indicating that the data provided no evidence of the mutations affecting 5-year survival.	('c', 'Chemical', 'MESH:D002244', (89, 90))	('c', 'Chemical', 'MESH:D002244', (128, 129))	('mutation', 'Var', (24, 32))	('c', 'Chemical', 'MESH:D002244', (152, 153))	('c', 'Chemical', 'MESH:D002244', (16, 17))	('mutations', 'Var', (138, 147))
157566	32756609	The frequencies of mutations in NSCLC, especially EGFR and ALK, in the data are lower than those found in other studies, while KRAS is similar to those published by Sequist et al..	('c', 'Chemical', 'MESH:D002244', (11, 12))	('mutations', 'Var', (19, 28))	('NSCLC', 'Disease', 'MESH:D002289', (32, 37))	('NSCLC', 'Disease', (32, 37))	('ALK', 'Gene', (59, 62))	('lower', 'NegReg', (80, 85))	('c', 'Chemical', 'MESH:D002244', (43, 44))	('EGFR', 'Gene', (50, 54))
157571	32756609	Although the statistical analysis of mutations in different cancer stages in this cohort produced non-significant results, it may be related to the sample size since most of the cases were at a relatively early stage of the disease.	('c', 'Chemical', 'MESH:D002244', (63, 64))	('c', 'Chemical', 'MESH:D002244', (178, 179))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('c', 'Chemical', 'MESH:D002244', (21, 22))	('c', 'Chemical', 'MESH:D002244', (60, 61))	('cancer', 'Disease', (60, 66))	('mutations', 'Var', (37, 46))	('c', 'Chemical', 'MESH:D002244', (163, 164))	('c', 'Chemical', 'MESH:D002244', (94, 95))	('c', 'Chemical', 'MESH:D002244', (109, 110))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('c', 'Chemical', 'MESH:D002244', (82, 83))
157580	32756609	(2013) has suggested the KRAS mutation predicts a shorter survival for patients with advanced lung adenocarcinoma, however Bauml et al.	('c', 'Chemical', 'MESH:D002244', (44, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('lung adenocarcinoma', 'Disease', (94, 113))	('mutation', 'Var', (30, 38))	('c', 'Chemical', 'MESH:D002244', (107, 108))	('patients', 'Species', '9606', (71, 79))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (94, 113))	('c', 'Chemical', 'MESH:D002244', (104, 105))	('c', 'Chemical', 'MESH:D002244', (90, 91))	('shorter', 'NegReg', (50, 57))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (94, 113))	('KRAS', 'Gene', (25, 29))	('survival', 'MPA', (58, 66))
157586	32756609	This could indicate that, for instance, the KRAS mutation is not associated with any one cancer stage but could affect mortality in those with later stages, in particular adenocarcinoma, based on previous studies.	('c', 'Chemical', 'MESH:D002244', (89, 90))	('c', 'Chemical', 'MESH:D002244', (15, 16))	('cancer', 'Disease', (89, 95))	('KRAS', 'Gene', (44, 48))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('adenocarcinoma', 'Disease', (171, 185))	('c', 'Chemical', 'MESH:D002244', (165, 166))	('mortality', 'Disease', 'MESH:D003643', (119, 128))	('mutation', 'Var', (49, 57))	('c', 'Chemical', 'MESH:D002244', (116, 117))	('c', 'Chemical', 'MESH:D002244', (92, 93))	('c', 'Chemical', 'MESH:D002244', (179, 180))	('adenocarcinoma', 'Disease', 'MESH:D000230', (171, 185))	('c', 'Chemical', 'MESH:D002244', (69, 70))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('affect', 'Reg', (112, 118))	('c', 'Chemical', 'MESH:D002244', (5, 6))	('c', 'Chemical', 'MESH:D002244', (36, 37))	('c', 'Chemical', 'MESH:D002244', (106, 107))	('c', 'Chemical', 'MESH:D002244', (176, 177))	('mortality', 'Disease', (119, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (176, 185))
157587	32756609	As expected based on the literature, only a small percentage of the squamous cell carcinoma exhibited any of the mutations screened for in this study (approximately 5%).	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (68, 91))	('c', 'Chemical', 'MESH:D002244', (7, 8))	('rat', 'Species', '10116', (29, 32))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('c', 'Chemical', 'MESH:D002244', (124, 125))	('mutations', 'Var', (113, 122))	('c', 'Chemical', 'MESH:D002244', (85, 86))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (68, 91))	('c', 'Chemical', 'MESH:D002244', (53, 54))	('squamous cell carcinoma', 'Disease', (68, 91))	('c', 'Chemical', 'MESH:D002244', (82, 83))	('c', 'Chemical', 'MESH:D002244', (77, 78))
157588	32756609	Further to this, for the cases exhibiting a PIK3CA mutation, five were squamous cell carcinoma and the remaining five were adenocarcinoma.	('PIK3CA', 'Gene', (44, 50))	('c', 'Chemical', 'MESH:D002244', (25, 26))	('adenocarcinoma', 'Disease', (123, 137))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (71, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('c', 'Chemical', 'MESH:D002244', (131, 132))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (71, 94))	('adenocarcinoma', 'Disease', 'MESH:D000230', (123, 137))	('mutation', 'Var', (51, 59))	('squamous cell carcinoma', 'Disease', (71, 94))	('c', 'Chemical', 'MESH:D002244', (80, 81))	('c', 'Chemical', 'MESH:D002244', (128, 129))	('c', 'Chemical', 'MESH:D002244', (88, 89))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('c', 'Chemical', 'MESH:D002244', (85, 86))
157590	32756609	This specific mutation has more commonly been observed in oral squamous cell carcinoma, involved the oral cavity, pharynx, and larynx, although typically in advanced stages.	('c', 'Chemical', 'MESH:D002244', (106, 107))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (63, 86))	('observed', 'Reg', (46, 54))	('squamous cell carcinoma', 'Disease', (63, 86))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (63, 86))	('c', 'Chemical', 'MESH:D002244', (72, 73))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('c', 'Chemical', 'MESH:D002244', (162, 163))	('mutation', 'Var', (14, 22))	('c', 'Chemical', 'MESH:D002244', (8, 9))	('c', 'Chemical', 'MESH:D002244', (80, 81))	('c', 'Chemical', 'MESH:D002244', (148, 149))	('c', 'Chemical', 'MESH:D002244', (12, 13))	('c', 'Chemical', 'MESH:D002244', (32, 33))	('c', 'Chemical', 'MESH:D002244', (77, 78))
157591	32756609	This would suggest the mutation has a larger role in tumour progression as opposed to its initiation.	('tumour', 'Disease', (53, 59))	('tumour', 'Phenotype', 'HP:0002664', (53, 59))	('tumour', 'Disease', 'MESH:D009369', (53, 59))	('mutation', 'Var', (23, 31))
157593	32756609	Studies have shown relationships between smoking and the mutations, with a significant correlation between cigarette smoking and the KRAS mutation, and a higher association between females and the KRAS mutation.	('c', 'Chemical', 'MESH:D002244', (165, 166))	('KRAS', 'Disease', (133, 137))	('c', 'Chemical', 'MESH:D002244', (87, 88))	('c', 'Chemical', 'MESH:D002244', (107, 108))	('correlation', 'Interaction', (87, 98))	('mutation', 'Var', (138, 146))	('c', 'Chemical', 'MESH:D002244', (82, 83))
157595	32756609	However, the opposite trend for smoking history was observed with the EGFR mutation, in that if the individual harbored mutations in this receptor, there was a higher likelihood that they had never smoked.	('c', 'Chemical', 'MESH:D002244', (140, 141))	('EGFR', 'Gene', (70, 74))	('mutations', 'Var', (120, 129))
157599	32756609	For instance, while this study analyzed for the EGFR L858R and T790M point mutations, and exon 19 deletion and exon 20 insertion, there are other types of EGFR mutations not included in this study.	('c', 'Chemical', 'MESH:D002244', (10, 11))	('EGFR', 'Gene', (48, 52))	('c', 'Chemical', 'MESH:D002244', (176, 177))	('T790M', 'SUBSTITUTION', 'None', (63, 68))	('L858R', 'SUBSTITUTION', 'None', (53, 58))	('T790M', 'Var', (63, 68))	('L858R', 'Var', (53, 58))
157600	32756609	These include point mutations G719C/S/A in exon 18, V765A AND T783A in exon 20, and L861Q in exon 21, to name a few.	('T783A', 'Var', (62, 67))	('G719C', 'SUBSTITUTION', 'None', (30, 35))	('L861Q', 'SUBSTITUTION', 'None', (84, 89))	('L861Q', 'Var', (84, 89))	('T783A', 'SUBSTITUTION', 'None', (62, 67))	('c', 'Chemical', 'MESH:D002244', (8, 9))	('G719C', 'Var', (30, 35))	('V765A', 'Var', (52, 57))	('V765A', 'SUBSTITUTION', 'None', (52, 57))
157605	32756609	This study provides clinically relevant data on individual mutations that will aid guiding future research in personalized medicines that will ultimately improve lung cancer survivorship and quality of life.	('c', 'Chemical', 'MESH:D002244', (167, 168))	('c', 'Chemical', 'MESH:D002244', (20, 21))	('improve', 'PosReg', (154, 161))	('c', 'Chemical', 'MESH:D002244', (127, 128))	('lung cancer', 'Disease', 'MESH:D008175', (162, 173))	('c', 'Chemical', 'MESH:D002244', (25, 26))	('c', 'Chemical', 'MESH:D002244', (170, 171))	('c', 'Chemical', 'MESH:D002244', (104, 105))	('lung cancer', 'Disease', (162, 173))	('mutations', 'Var', (59, 68))	('lung cancer', 'Phenotype', 'HP:0100526', (162, 173))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))
157609	29793508	Western blots were used to quantitate changes in autophagy-related protein expression after A549 cells were treated with GSK-3beta inhibitors and after H460 cells were transfected with GSK-3beta mutants with different activities and X-ray irradiated.	('autophagy-related', 'MPA', (49, 66))	('GSK-3beta', 'Gene', '2932', (121, 130))	('GSK-3beta', 'Gene', (121, 130))	('changes', 'Reg', (38, 45))	('H460', 'CellLine', 'CVCL:0459', (152, 156))	('A549', 'CellLine', 'CVCL:0023', (92, 96))	('inhibitors', 'Var', (131, 141))	('GSK-3beta', 'Gene', '2932', (185, 194))	('GSK-3beta', 'Gene', (185, 194))
157610	29793508	GSK-3beta expression positively correlated with NSCLC differentiation (P < 0.05), and GSK-3beta negativity was associated with a better prognosis in 89 NSCLC patients.	('NSCLC', 'Disease', (48, 53))	('NSCLC', 'Phenotype', 'HP:0030358', (152, 157))	('GSK-3beta', 'Gene', (86, 95))	('NSCLC', 'Disease', 'MESH:D002289', (48, 53))	('GSK-3beta', 'Gene', '2932', (86, 95))	('correlated', 'Reg', (32, 42))	('NSCLC', 'Disease', (152, 157))	('expression', 'MPA', (10, 20))	('NSCLC', 'Disease', 'MESH:D002289', (152, 157))	('patients', 'Species', '9606', (158, 166))	('NSCLC', 'Phenotype', 'HP:0030358', (48, 53))	('negativity', 'Var', (96, 106))	('GSK-3beta', 'Gene', '2932', (0, 9))	('GSK-3beta', 'Gene', (0, 9))
157613	29793508	After transfecting H460 cells with different GSK-3beta mutants [wild type GSK-3beta (GSK-3beta-WT), constitutively active GSK-3beta (GSK-3beta-S9A), and catalytically inactive GSK-3beta (GSK-3beta-K85R)] and subjecting these cells to X-ray irradiation, AMPK and LC3 expression levels decreased, and p62 expression levels increased.	('GSK-3beta', 'Gene', '2932', (45, 54))	('LC3', 'Gene', (262, 265))	('K85R', 'Mutation', 'p.K85R', (197, 201))	('GSK-3beta', 'Gene', '2932', (74, 83))	('GSK-3beta', 'Gene', '2932', (187, 196))	('GSK-3beta', 'Gene', (85, 94))	('GSK-3beta', 'Gene', '2932', (122, 131))	('p62', 'Gene', '23636', (299, 302))	('GSK-3beta', 'Gene', '2932', (176, 185))	('GSK-3beta', 'Gene', (45, 54))	('p62', 'Gene', (299, 302))	('GSK-3beta', 'Gene', (187, 196))	('GSK-3beta', 'Gene', (74, 83))	('increased', 'PosReg', (321, 330))	('H460', 'CellLine', 'CVCL:0459', (19, 23))	('GSK-3beta', 'Gene', (122, 131))	('decreased', 'NegReg', (284, 293))	('LC3', 'Gene', '84557', (262, 265))	('GSK-3beta', 'Gene', (176, 185))	('GSK-3beta', 'Gene', '2932', (133, 142))	('mutants', 'Var', (55, 62))	('AMPK', 'Gene', (253, 257))	('AMPK', 'Gene', '5564', (253, 257))	('GSK-3beta', 'Gene', (133, 142))	('GSK-3beta', 'Gene', '2932', (85, 94))
157620	29793508	Tyr216 phosphorylation can enhance kinase activity, whereas Ser9 phosphorylation can inhibit kinase activity.	('Tyr216', 'Chemical', '-', (0, 6))	('kinase activity', 'MPA', (93, 108))	('Ser9', 'Chemical', '-', (60, 64))	('enhance', 'PosReg', (27, 34))	('inhibit', 'NegReg', (85, 92))	('kinase activity', 'MPA', (35, 50))	('Tyr216 phosphorylation', 'Var', (0, 22))
157625	29793508	Radiotherapy is one of the most common and effective treatment methods for cancer, and radioresistance due to hypoxia or drug resistance has marked effects on therapeutic efficacy.	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('drug resistance', 'Phenotype', 'HP:0020174', (121, 136))	('cancer', 'Disease', (75, 81))	('radioresistance', 'Disease', (87, 102))	('effects', 'Reg', (148, 155))	('drug resistance', 'Var', (121, 136))	('hypoxia', 'Disease', (110, 117))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('hypoxia', 'Disease', 'MESH:D000860', (110, 117))
157645	29793508	The sections were incubated with GSK-3beta (1:200, Santa Cruz, CA, USA), p-GSK-3betaSer9 (1:200, Bioss, China), p-GSK-3betaTyr216 (1:200, Bioss, China), LC3 (1:200, Wanleibio, China), AMPK (1:200, Wanleibio, China), and p62 (1:200, Wanleibio, China) primary antibodies at 4  C overnight, followed by incubation with a biotinylated goat anti-rabbit IgG secondary antibody.	('1:200', 'Var', (190, 195))	('AMPK', 'Gene', '5564', (184, 188))	('p62', 'Gene', '23636', (220, 223))	('AMPK', 'Gene', (184, 188))	('1:200', 'Var', (90, 95))	('p62', 'Gene', (220, 223))	('GSK-3beta', 'Gene', (33, 42))	('GSK-3beta', 'Gene', (114, 123))	('goat', 'Species', '9925', (331, 335))	('GSK-3beta', 'Gene', '2932', (114, 123))	('GSK-3beta', 'Gene', '2932', (33, 42))	('LC3', 'Gene', '84557', (153, 156))	('LC3', 'Gene', (153, 156))	('biotin', 'Chemical', 'MESH:D001710', (318, 324))	('GSK-3beta', 'Gene', '2932', (75, 84))	('GSK-3beta', 'Gene', (75, 84))	('rabbit', 'Species', '9986', (341, 347))	('1:200', 'Var', (225, 230))
157651	29793508	Tumor samples with scores between 1 and 2 were categorized as showing weak expression, whereas those with scores of 0 were defined as negative for GSK-3beta expression.	('scores', 'Var', (19, 25))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('GSK-3beta', 'Gene', '2932', (147, 156))	('GSK-3beta', 'Gene', (147, 156))	('weak', 'NegReg', (70, 74))	('expression', 'MPA', (75, 85))
157656	29793508	The membranes were incubated overnight at 4  C with primary antibodies against GSK-3beta (1:1000, Santa Cruz Biotechnology), GAPDH (1:5000, Sigma, St. Louis, MO, USA), LC3 (1:1000, Wanleibio, China), AMPK (1:1000, Wanleibio, China), and p62 (1:1000, Wanleibio, China).	('AMPK', 'Gene', (200, 204))	('GSK-3beta', 'Gene', (79, 88))	('GSK-3beta', 'Gene', '2932', (79, 88))	('p62', 'Gene', (237, 240))	('1:1000', 'Var', (206, 212))	('LC3', 'Gene', (168, 171))	('1:1000', 'Var', (90, 96))	('AMPK', 'Gene', '5564', (200, 204))	('1:1000', 'Var', (242, 248))	('GAPDH', 'Gene', (125, 130))	('1:1000', 'Var', (173, 179))	('1:5000', 'Var', (132, 138))	('LC3', 'Gene', '84557', (168, 171))	('p62', 'Gene', '23636', (237, 240))
157672	29793508	Conversely, GSK-3beta inhibition increased AMPK and LC3 protein expression levels, and these changes are indicative of autophagy.	('inhibition', 'Var', (22, 32))	('AMPK', 'Gene', '5564', (43, 47))	('LC3', 'Gene', '84557', (52, 55))	('AMPK', 'Gene', (43, 47))	('GSK-3beta', 'Gene', '2932', (12, 21))	('GSK-3beta', 'Gene', (12, 21))	('increased', 'PosReg', (33, 42))	('LC3', 'Gene', (52, 55))	('autophagy', 'CPA', (119, 128))
157674	29793508	After GSK-3beta transfection and X-ray irradiation, AMPK and LC3 protein expression levels decreased, and p62 protein expression levels increased.	('LC3', 'Gene', '84557', (61, 64))	('GSK-3beta', 'Gene', '2932', (6, 15))	('GSK-3beta', 'Gene', (6, 15))	('LC3', 'Gene', (61, 64))	('p62', 'Gene', (106, 109))	('p62', 'Gene', '23636', (106, 109))	('transfection', 'Var', (16, 28))	('increased', 'PosReg', (136, 145))	('AMPK', 'Gene', (52, 56))	('decreased', 'NegReg', (91, 100))	('AMPK', 'Gene', '5564', (52, 56))
157675	29793508	Of the GSK-3beta mutants, GSK-3beta-S9A yielded greater effects than GSK-3beta-WT and the catalytically inactive GSK-3beta-K85R.	('GSK-3beta', 'Gene', '2932', (7, 16))	('GSK-3beta', 'Gene', (7, 16))	('GSK-3beta', 'Gene', '2932', (69, 78))	('GSK-3beta', 'Gene', (69, 78))	('K85R', 'Mutation', 'p.K85R', (123, 127))	('GSK-3beta', 'Gene', '2932', (26, 35))	('GSK-3beta', 'Gene', (26, 35))	('effects', 'MPA', (56, 63))	('GSK-3beta', 'Gene', (113, 122))	('GSK-3beta', 'Gene', '2932', (113, 122))	('mutants', 'Var', (17, 24))
157677	29793508	The results showed that after transfection with GSK-3beta-S9A, clonogenic ability and cell survival were decreased.	('GSK-3beta', 'Gene', '2932', (48, 57))	('GSK-3beta', 'Gene', (48, 57))	('transfection', 'Var', (30, 42))	('cell survival', 'CPA', (86, 99))	('clonogenic ability', 'CPA', (63, 81))	('decreased', 'NegReg', (105, 114))
157687	29793508	Tyr216 phosphorylation can increase kinase activity, whereas Ser9 phosphorylation can inhibit kinase activity.	('Tyr216', 'Chemical', '-', (0, 6))	('kinase activity', 'MPA', (94, 109))	('kinase activity', 'MPA', (36, 51))	('Ser9', 'MPA', (61, 65))	('Ser9', 'Chemical', '-', (61, 65))	('inhibit', 'NegReg', (86, 93))	('increase', 'PosReg', (27, 35))	('Tyr216 phosphorylation', 'Var', (0, 22))
157696	29793508	In the early phases of tumor growth, inhibiting autophagy can increase anabolism and cancer cell proliferation and decrease protein degradation.	('anabolism', 'CPA', (71, 80))	('autophagy', 'CPA', (48, 57))	('protein degradation', 'MPA', (124, 143))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('cancer', 'Disease', (85, 91))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('inhibiting', 'Var', (37, 47))	('tumor', 'Disease', (23, 28))	('decrease', 'NegReg', (115, 123))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('increase', 'PosReg', (62, 70))
157725	27802187	lncRNAs have been reported to participate in a broad scope of biological processes, and lncRNA dysregulation leads to diverse human diseases, including cancer.	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('human', 'Species', '9606', (126, 131))	('dysregulation', 'Var', (95, 108))	('human diseases', 'Disease', (126, 140))	('lncRNA', 'Gene', (88, 94))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('leads to', 'Reg', (109, 117))
157733	27802187	Anomalous lncRNAs are suggested to be closely associated with multiple human diseases, including cancer.	('Anomalous', 'Var', (0, 9))	('cancer', 'Disease', (97, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('associated', 'Reg', (46, 56))	('human', 'Species', '9606', (71, 76))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
157747	27802187	HOTAIR interacts with EZH2 or LSD1, leading to gene silencing via H3K27-methylation or H3K4-demethylation, respectively.	('HOTAIR', 'Gene', '100124700', (0, 6))	('EZH2', 'Gene', (22, 26))	('H3K4-demethylation', 'Var', (87, 105))	('H3K27-methylation', 'Protein', (66, 83))	('gene', 'MPA', (47, 51))	('HOTAIR', 'Gene', (0, 6))	('LSD1', 'Gene', (30, 34))	('EZH2', 'Gene', '2146', (22, 26))	('LSD1', 'Gene', '23028', (30, 34))
157750	27802187	HOTAIR knockdown reduces cell invasion and increases cell apoptosis in vitro and inhibits LSCC xenograft growth in vivo.	('inhibits', 'NegReg', (81, 89))	('HOTAIR', 'Gene', '100124700', (0, 6))	('reduces', 'NegReg', (17, 24))	('cell apoptosis', 'CPA', (53, 67))	('cell invasion', 'CPA', (25, 38))	('LSCC xenograft growth in vivo', 'CPA', (90, 119))	('increases', 'PosReg', (43, 52))	('HOTAIR', 'Gene', (0, 6))	('knockdown', 'Var', (7, 16))
157768	27802187	LOI at H19 leads to the transcription of H19 from the maternal and paternal alleles, and LOH at H19 inhibits the expression of H19.	('H19', 'Gene', '283120', (7, 10))	('expression', 'MPA', (113, 123))	('H19', 'Gene', '283120', (41, 44))	('H19', 'Gene', (127, 130))	('inhibits', 'NegReg', (100, 108))	('H19', 'Gene', (7, 10))	('H19', 'Gene', (96, 99))	('transcription', 'MPA', (24, 37))	('LOI at', 'Var', (0, 6))	('leads to', 'Reg', (11, 19))	('H19', 'Gene', '283120', (96, 99))	('H19', 'Gene', '283120', (127, 130))	('H19', 'Gene', (41, 44))
157769	27802187	Hypomethylation in the H19 promoter region may be the main cause of H19 LOI.	('Hypomethylation', 'Var', (0, 15))	('LOI', 'NegReg', (72, 75))	('cause', 'Reg', (59, 64))	('H19', 'Gene', (23, 26))	('H19', 'Gene', '283120', (23, 26))	('H19', 'Gene', '283120', (68, 71))	('H19', 'Gene', (68, 71))
157771	27802187	Mutation leads to H19 LOH, and the expression of H19 in cancer is down-regulated by p53.	('H19', 'Gene', '283120', (49, 52))	('LOH', 'NegReg', (22, 25))	('H19', 'Gene', (49, 52))	('H19', 'Gene', '283120', (18, 21))	('H19', 'Gene', (18, 21))	('Mutation', 'Var', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('down-regulated', 'NegReg', (66, 80))	('expression', 'MPA', (35, 45))	('p53', 'Gene', (84, 87))	('p53', 'Gene', '7157', (84, 87))	('leads to', 'Reg', (9, 17))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))
157772	27802187	Both LOI and LOH of H19 are associated with cancer carcinogenesis and progression.	('H19', 'Gene', (20, 23))	('LOH', 'Var', (13, 16))	('associated', 'Reg', (28, 38))	('cancer carcinogenesis', 'Disease', (44, 65))	('LOI', 'Var', (5, 8))	('cancer carcinogenesis', 'Disease', 'MESH:D063646', (44, 65))	('progression', 'CPA', (70, 81))	('H19', 'Gene', '283120', (20, 23))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
157775	27802187	LOI at the IGF2-H19 locus and aberrant H19 expression have been observed in HNC and may be related to HNC oncogenesis and progression.	('HNC', 'Phenotype', 'HP:0012288', (76, 79))	('aberrant', 'Var', (30, 38))	('IGF2', 'Gene', (11, 15))	('related', 'Reg', (91, 98))	('observed', 'Reg', (64, 72))	('HNC oncogenesis', 'Disease', 'MESH:D063646', (102, 117))	('HNC oncogenesis', 'Disease', (102, 117))	('HNC', 'Disease', (76, 79))	('H19', 'Gene', '283120', (16, 19))	('HNC', 'Phenotype', 'HP:0012288', (102, 105))	('H19', 'Gene', (16, 19))	('H19', 'Gene', '283120', (39, 42))	('IGF2', 'Gene', '3481', (11, 15))	('expression', 'MPA', (43, 53))	('H19', 'Gene', (39, 42))	('LOI', 'Var', (0, 3))
157779	27802187	Among patients showing H19 expression, 6 had T2-grade tumors and 5 eventually presented recurrence and/or metastasis.	('tumors', 'Disease', 'MESH:D009369', (54, 60))	('T2-grade', 'Disease', (45, 53))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('patients', 'Species', '9606', (6, 14))	('H19', 'Gene', (23, 26))	('H19', 'Gene', '283120', (23, 26))	('expression', 'Var', (27, 37))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('tumors', 'Disease', (54, 60))
157782	27802187	Hypomethylation of CpG dinucleotides in the H19 promoter region may be the main epigenetic event that induces H19 transcription.	('H19', 'Gene', '283120', (110, 113))	('Hypomethylation', 'Var', (0, 15))	('H19', 'Gene', (110, 113))	('H19', 'Gene', '283120', (44, 47))	('transcription', 'MPA', (114, 127))	('CpG dinucleotides', 'Chemical', 'MESH:C015772', (19, 36))	('H19', 'Gene', (44, 47))	('induces', 'PosReg', (102, 109))
157789	27802187	One of the main mechanisms of MEG3 silencing is hypermethylation of the MEG3 promoter region.	('silencing', 'NegReg', (35, 44))	('MEG3', 'Gene', (72, 76))	('MEG3', 'Gene', '55384', (72, 76))	('hypermethylation', 'Var', (48, 64))	('MEG3', 'Gene', (30, 34))	('MEG3', 'Gene', '55384', (30, 34))
157790	27802187	The loss of MEG3 expression promotes tumor progression through specific molecular mechanisms, and re-expression of MEG3 in tumor cells inhibits proliferation and induces apoptosis.	('MEG3', 'Gene', (115, 119))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('tumor', 'Disease', (123, 128))	('MEG3', 'Gene', (12, 16))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('MEG3', 'Gene', '55384', (115, 119))	('re-expression', 'Var', (98, 111))	('promotes', 'PosReg', (28, 36))	('MEG3', 'Gene', '55384', (12, 16))	('tumor', 'Disease', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('proliferation', 'CPA', (144, 157))	('inhibits', 'NegReg', (135, 143))	('induces', 'Reg', (162, 169))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('apoptosis', 'CPA', (170, 179))	('loss', 'Var', (4, 8))
157797	27802187	Over-expression of MEG3 in SCC-15 and CAL27 cell lines inhibits cell proliferation, arrests the cell cycle and induces apoptosis.	('MEG3', 'Gene', (19, 23))	('cell proliferation', 'CPA', (64, 82))	('arrests', 'NegReg', (84, 91))	('cell cycle', 'CPA', (96, 106))	('inhibits', 'NegReg', (55, 63))	('MEG3', 'Gene', '55384', (19, 23))	('apoptosis', 'CPA', (119, 128))	('Over-expression', 'Var', (0, 15))	('induces', 'Reg', (111, 118))	('CAL27', 'CellLine', 'CVCL:1107', (38, 43))
157826	27802187	The levels of the FOXC1 mRNA are positively associated with the levels of the FOXCUT transcript, and FOXCUT silencing substantially reduces FOXC1 expression at both the mRNA and protein levels.	('levels', 'MPA', (4, 10))	('FOXC1', 'Gene', (18, 23))	('FOXCUT', 'Gene', (78, 84))	('silencing', 'Var', (108, 117))	('FOXCUT', 'Gene', '101927703', (78, 84))	('FOXC1', 'Gene', '2296', (140, 145))	('FOXC1', 'Gene', '2296', (18, 23))	('reduces', 'NegReg', (132, 139))	('FOXCUT', 'Gene', (101, 107))	('FOXCUT', 'Gene', '101927703', (101, 107))	('expression', 'MPA', (146, 156))	('FOXC1', 'Gene', (140, 145))
157828	27802187	High NEAT1 expression is closely related to LSCC tumorigenesis, and patients with neck nodal metastasis exhibit high NEAT1 expression.	('NEAT1', 'Gene', (5, 10))	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('expression', 'MPA', (123, 133))	('High', 'Var', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('related', 'Reg', (33, 40))	('expression', 'MPA', (11, 21))	('NEAT1', 'Gene', '283131', (117, 122))	('tumor', 'Disease', (49, 54))	('patients', 'Species', '9606', (68, 76))	('NEAT1', 'Gene', (117, 122))	('NEAT1', 'Gene', '283131', (5, 10))
157829	27802187	NEAT1 knockdown in LSCC suppresses tumor growth, increases cell apoptosis and arrests the cell cycle.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('NEAT1', 'Gene', (0, 5))	('NEAT1', 'Gene', '283131', (0, 5))	('arrests', 'NegReg', (78, 85))	('cell cycle', 'CPA', (90, 100))	('increases', 'PosReg', (49, 58))	('tumor', 'Disease', (35, 40))	('suppresses', 'NegReg', (24, 34))	('knockdown', 'Var', (6, 15))	('cell apoptosis', 'CPA', (59, 73))
157835	27802187	AFAP1-AS1 knockdown represses NPC cell invasion and migration in vitro and inhibits NPC lung metastasis in nude mice.	('represses', 'NegReg', (20, 29))	('migration', 'CPA', (52, 61))	('NPC', 'Gene', (84, 87))	('AFAP1-AS1', 'Gene', '84740;60312;5729', (0, 9))	('NPC lung metastasis', 'Disease', 'MESH:D052556', (84, 103))	('NPC', 'Phenotype', 'HP:0100630', (84, 87))	('NPC', 'Phenotype', 'HP:0100630', (30, 33))	('NPC', 'Gene', (30, 33))	('AFAP1-AS1', 'Gene', (0, 9))	('NPC', 'Gene', '4864', (30, 33))	('NPC', 'Gene', '4864', (84, 87))	('nude mice', 'Species', '10090', (107, 116))	('knockdown', 'Var', (10, 19))	('NPC lung metastasis', 'Disease', (84, 103))	('inhibits', 'NegReg', (75, 83))
157846	27802187	High lncRNA-ROR expression increase the ability of NPC cells to resist chemotherapy.	('NPC', 'Gene', (51, 54))	('High', 'Var', (0, 4))	('NPC', 'Gene', '4864', (51, 54))	('ROR', 'Gene', (12, 15))	('resist chemotherapy', 'CPA', (64, 83))	('NPC', 'Phenotype', 'HP:0100630', (51, 54))	('ROR', 'Gene', '100885779', (12, 15))	('increase', 'PosReg', (27, 35))
157853	27802187	Further research suggests that low levels of LET expression are induced by EZH2-mediated H3K27 histone methylation in the LET promoter region.	('EZH2', 'Gene', (75, 79))	('histone', 'Reg', (95, 102))	('H3K27', 'Protein', (89, 94))	('methylation', 'Var', (103, 114))	('EZH2', 'Gene', '2146', (75, 79))	('LET', 'MPA', (45, 48))
157857	27802187	Furthermore, GAS8-AS1 mutations in PTC are associated with an advanced clinical stage, and the wild-type lncRNA GAS8-AS1 is a stronger suppressor of tumor growth than mutated lncRNA GAS8-AS1.	('GAS8', 'Gene', '2622', (112, 116))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('GAS8', 'Gene', '2622', (13, 17))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('GAS8', 'Gene', (112, 116))	('PTC', 'Gene', '8030', (35, 38))	('tumor', 'Disease', (149, 154))	('mutations', 'Var', (22, 31))	('GAS8', 'Gene', (13, 17))	('associated', 'Reg', (43, 53))	('GAS8', 'Gene', '2622', (182, 186))	('PTC', 'Gene', (35, 38))	('TC', 'Phenotype', 'HP:0002890', (36, 38))	('PTC', 'Phenotype', 'HP:0002895', (35, 38))	('GAS8', 'Gene', (182, 186))
157859	27802187	As revealed in functional studies, LOC401317 is a tumor suppressor and LOC401317 transfection in NPC cells represses tumor cell proliferation, arrests the cell cycle and increases cell apoptosis.	('transfection', 'Var', (81, 93))	('increases', 'PosReg', (170, 179))	('NPC', 'Gene', '4864', (97, 100))	('LOC401317', 'Gene', (35, 44))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('represses', 'NegReg', (107, 116))	('LOC401317', 'Gene', '401317', (35, 44))	('tumor', 'Disease', (50, 55))	('NPC', 'Phenotype', 'HP:0100630', (97, 100))	('LOC401317', 'Gene', (71, 80))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('LOC401317', 'Gene', '401317', (71, 80))	('cell apoptosis', 'CPA', (180, 194))	('NPC', 'Gene', (97, 100))	('tumor', 'Disease', (117, 122))	('cell cycle', 'CPA', (155, 165))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('arrests', 'NegReg', (143, 150))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
157863	27802187	PVT1 silencing in TC cell lines obviously inhibits cell proliferation and arrests the cell cycle at the G0/G1 phase.	('cell cycle at the G0/G1 phase', 'CPA', (86, 115))	('inhibits', 'NegReg', (42, 50))	('silencing', 'Var', (5, 14))	('PVT1', 'Gene', (0, 4))	('arrests', 'NegReg', (74, 81))	('TC', 'Phenotype', 'HP:0002890', (18, 20))	('cell proliferation', 'CPA', (51, 69))	('PVT1', 'Gene', '5820', (0, 4))
157871	27802187	NAMA expression is induced by BRAF knockdown, suppression of the MAP kinase pathway, growth arrest and DNA damage.	('knockdown', 'Var', (35, 44))	('induced', 'Reg', (19, 26))	('growth arrest', 'Disease', (85, 98))	('NAMA', 'Gene', '100996569', (0, 4))	('MAP kinase pathway', 'Pathway', (65, 83))	('growth arrest', 'Disease', 'MESH:D006323', (85, 98))	('suppression', 'NegReg', (46, 57))	('BRAF', 'Gene', (30, 34))	('BRAF', 'Gene', '673', (30, 34))	('DNA', 'CPA', (103, 106))	('growth arrest', 'Phenotype', 'HP:0001510', (85, 98))	('NAMA', 'Gene', (0, 4))
157877	27802187	Re-expression of PTCSC3 in TC cells represses tumor growth and influences the transcription of some genes associated with DNA replication, recombination, repair, cellular movement, tumor morphology, and cell death.	('tumor', 'Disease', (181, 186))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('TC', 'Phenotype', 'HP:0002890', (27, 29))	('tumor', 'Disease', (46, 51))	('influences', 'Reg', (63, 73))	('Re-expression', 'Var', (0, 13))	('cellular movement', 'CPA', (162, 179))	('TC', 'Phenotype', 'HP:0002890', (18, 20))	('PTC', 'Phenotype', 'HP:0002895', (17, 20))	('represses', 'NegReg', (36, 45))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('genes', 'Gene', (100, 105))	('PTCSC3', 'Gene', '100886964', (17, 23))	('PTCSC3', 'Gene', (17, 23))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('transcription', 'MPA', (78, 91))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
157880	27802187	The polymorphisms rs965513 and rs944289 are related to PTC and TC risk via PTCSC2 and PTCSC3, respectively.	('TC', 'Phenotype', 'HP:0002890', (56, 58))	('rs944289', 'Var', (31, 39))	('PTC', 'Gene', '8030', (86, 89))	('PTC', 'Gene', '8030', (55, 58))	('rs965513', 'Mutation', 'rs965513', (18, 26))	('related', 'Reg', (44, 51))	('TC', 'Phenotype', 'HP:0002890', (63, 65))	('TC', 'Phenotype', 'HP:0002890', (87, 89))	('PTC', 'Gene', (55, 58))	('PTC', 'Gene', (86, 89))	('PTC', 'Phenotype', 'HP:0002895', (86, 89))	('PTC', 'Phenotype', 'HP:0002895', (55, 58))	('PTC', 'Gene', '8030', (75, 78))	('PTCSC3', 'Gene', (86, 92))	('TC', 'Phenotype', 'HP:0002890', (76, 78))	('PTCSC2', 'Gene', (75, 81))	('PTC', 'Gene', (75, 78))	('PTCSC2', 'Gene', '101928337', (75, 81))	('rs965513', 'Var', (18, 26))	('PTC', 'Phenotype', 'HP:0002895', (75, 78))	('rs944289', 'Mutation', 'rs944289', (31, 39))	('PTCSC3', 'Gene', '100886964', (86, 92))
157881	27802187	The risk allele (A) of rs965513 is significantly associated with down-regulation of PTCSC2 in normal thyroid tissues.	('TC', 'Phenotype', 'HP:0002890', (85, 87))	('PTCSC2', 'Gene', '101928337', (84, 90))	('PTCSC2', 'Gene', (84, 90))	('PTC', 'Phenotype', 'HP:0002895', (84, 87))	('rs965513', 'Var', (23, 31))	('down-regulation', 'NegReg', (65, 80))	('rs965513', 'Mutation', 'rs965513', (23, 31))
157882	27802187	The risk allele (T) of rs944289 is strongly related to the down-regulation of PTCSC3 in TC tumor tissues.	('rs944289', 'Var', (23, 31))	('PTCSC3', 'Gene', (78, 84))	('TC', 'Phenotype', 'HP:0002890', (88, 90))	('rs944289', 'Mutation', 'rs944289', (23, 31))	('TC', 'Phenotype', 'HP:0002890', (79, 81))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('PTCSC3', 'Gene', '100886964', (78, 84))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('PTC', 'Phenotype', 'HP:0002895', (78, 81))	('down-regulation', 'NegReg', (59, 74))	('tumor', 'Disease', (91, 96))
157886	27802187	ENST00000438550 is strongly associated with the progression of NPC patients, and ENST00000438550 might be a prognostic biomarker and a potential treatment target in NPC.	('ENST00000438550', 'Var', (81, 96))	('NPC', 'Gene', '4864', (165, 168))	('associated', 'Reg', (28, 38))	('NPC', 'Gene', '4864', (63, 66))	('patients', 'Species', '9606', (67, 75))	('NPC', 'Phenotype', 'HP:0100630', (165, 168))	('ENST00000438550', 'Var', (0, 15))	('NPC', 'Gene', (165, 168))	('NPC', 'Gene', (63, 66))	('NPC', 'Phenotype', 'HP:0100630', (63, 66))
157889	27802187	The lncRNA AB209630 may be a tumor suppressor in hypopharyngeal squamous cell carcinoma (HSCC).	('HSCC', 'Phenotype', 'HP:0012182', (89, 93))	('hypopharyngeal squamous cell carcinoma', 'Disease', 'MESH:D002294', (49, 87))	('hypopharyngeal squamous cell carcinoma', 'Phenotype', 'HP:0012182', (49, 87))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('HSCC', 'Chemical', '-', (89, 93))	('tumor', 'Disease', (29, 34))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (64, 87))	('AB209630', 'Var', (11, 19))	('hypopharyngeal squamous cell carcinoma', 'Disease', (49, 87))
157891	27802187	HSCC patients with high AB209630 levels have a better prognosis than patients with low AB209630 levels.	('HSCC', 'Phenotype', 'HP:0012182', (0, 4))	('patients', 'Species', '9606', (5, 13))	('HSCC', 'Disease', (0, 4))	('HSCC', 'Chemical', '-', (0, 4))	('high AB209630', 'Var', (19, 32))	('AB209630', 'Var', (24, 32))	('patients', 'Species', '9606', (69, 77))
157892	27802187	AB209630 may be a valuable target in HSCC therapy.	('HSCC', 'Disease', (37, 41))	('AB209630', 'Var', (0, 8))	('HSCC', 'Chemical', '-', (37, 41))	('HSCC', 'Phenotype', 'HP:0012182', (37, 41))
157906	27802187	The dysregulation of lncRNAs in HNC may be a promising indicator for use in providing an exact and early cancer diagnosis.	('HNC', 'Phenotype', 'HP:0012288', (32, 35))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('dysregulation', 'Var', (4, 17))	('HNC', 'Disease', (32, 35))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))
157917	27802187	The ENST00000438550 expression level is positively correlated with NPC progression, and high levels of ENST00000438550 are an indicator of NPC progression.	('NPC', 'Phenotype', 'HP:0100630', (67, 70))	('ENST00000438550', 'Gene', (4, 19))	('NPC', 'Gene', (67, 70))	('NPC', 'Phenotype', 'HP:0100630', (139, 142))	('NPC', 'Gene', '4864', (67, 70))	('NPC', 'Gene', (139, 142))	('NPC', 'Gene', '4864', (139, 142))	('ENST00000438550', 'Var', (103, 118))	('expression level', 'MPA', (20, 36))	('correlated', 'Reg', (51, 61))
157925	27802187	Low expression levels of AC026166.2-001 and RP11-169D4.1-001 are statistically linked to OS in LSCC patients and are independent indicators of a poor prognosis.	('expression levels', 'MPA', (4, 21))	('RP11-169D4.1-001', 'Var', (44, 60))	('linked', 'Reg', (79, 85))	('AC026166.2-001', 'Var', (25, 39))	('LSCC', 'Disease', (95, 99))	('patients', 'Species', '9606', (100, 108))	('OS', 'Chemical', '-', (89, 91))	('Low', 'NegReg', (0, 3))
157943	27802187	MALAT1 knockdown in NPC sensitizes the tumor cells to ionizing radiation and reduces the percentage of ALDH1-postive cells displaying properties associated with CSCs.	('ALDH1', 'Gene', (103, 108))	('MALAT1', 'Gene', '378938', (0, 6))	('NPC', 'Gene', '4864', (20, 23))	('ALDH1', 'Gene', '216', (103, 108))	('sensitizes', 'Reg', (24, 34))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('MALAT1', 'Gene', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('CSCs', 'Disease', (161, 165))	('tumor', 'Disease', (39, 44))	('NPC', 'Gene', (20, 23))	('knockdown', 'Var', (7, 16))	('NPC', 'Phenotype', 'HP:0100630', (20, 23))	('reduces', 'NegReg', (77, 84))
157949	27802187	Dysregulated lncRNAs are significantly correlated with cancer development and progression in HNC.	('HNC', 'Phenotype', 'HP:0012288', (93, 96))	('correlated', 'Reg', (39, 49))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('HNC', 'Disease', (93, 96))	('lncRNAs', 'Protein', (13, 20))	('Dysregulated', 'Var', (0, 12))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('cancer', 'Disease', (55, 61))
157963	27802187	For example, knockdown of HOTAIR or MALAT1 with siRNAs inhibits cancer-cell proliferation and increases apoptosis.	('inhibits', 'NegReg', (55, 63))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('HOTAIR', 'Gene', (26, 32))	('MALAT1', 'Gene', '378938', (36, 42))	('increases', 'PosReg', (94, 103))	('HOTAIR', 'Gene', '100124700', (26, 32))	('MALAT1', 'Gene', (36, 42))	('apoptosis', 'CPA', (104, 113))	('knockdown', 'Var', (13, 22))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
157970	26804163	We show that ECS cell-produced vascular endothelial growth factor (VEGF)-A is required for the maintenance of this phenotype, as knockdown of VEGF-A gene expression or treatment with VEGF-A-inactivating antibody reduces these responses.	('reduces', 'NegReg', (212, 219))	('knockdown', 'Var', (129, 138))	('vascular endothelial growth factor', 'Gene', (31, 65))	('VEGF-A', 'Gene', (142, 148))	('vascular endothelial growth factor', 'Gene', '34127', (31, 65))
158011	26804163	Figure 2c shows that junction, segment and node formation is reduced by treating the ECS cell-derived extracts with anti-VEGF-A, suggesting that VEGF-A is a key angiogenic factor in ECS cell-derived tumors.	('tumors', 'Disease', (199, 205))	('tumors', 'Disease', 'MESH:D009369', (199, 205))	('tumors', 'Phenotype', 'HP:0002664', (199, 205))	('junction', 'CPA', (21, 29))	('anti-VEGF-A', 'Var', (116, 127))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('reduced', 'NegReg', (61, 68))
158032	26804163	Figures 3f and g show that treatment with VEGF-A- or NRP-1-siRNA attenuates ECS cell spheroid formation and migration, but that VEGFR1- or VEGFR2-siRNA have no impact.	('VEGFR2', 'Gene', '3791', (139, 145))	('attenuates', 'NegReg', (65, 75))	('VEGF-A-', 'Var', (42, 49))	('VEGFR1', 'Gene', '2321', (128, 134))	('ECS cell spheroid formation', 'CPA', (76, 103))	('VEGFR1', 'Gene', (128, 134))	('VEGFR2', 'Gene', (139, 145))	('NRP-1-siRNA', 'Gene', (53, 64))
158036	26804163	Figure 4a shows that treatment with EG00229 reduces spheroid size.	('EG00229', 'Chemical', '-', (36, 43))	('spheroid size', 'CPA', (52, 65))	('EG00229', 'Var', (36, 43))	('reduces', 'NegReg', (44, 51))
158038	26804163	Figure 4b shows that EG00229 reduces invasion by 25%.	('reduces', 'NegReg', (29, 36))	('EG00229', 'Chemical', '-', (21, 28))	('invasion', 'CPA', (37, 45))	('EG00229', 'Var', (21, 28))
158044	26804163	Figure 4h shows that CD31 staining is reduced in EG00229-treated cultures.	('reduced', 'NegReg', (38, 45))	('CD31', 'Gene', '18613', (21, 25))	('EG00229-treated', 'Var', (49, 64))	('CD31', 'Gene', (21, 25))	('EG00229', 'Chemical', '-', (49, 56))
158058	26804163	Our studies show that more VEGF-A is produced by ECS cell-derived tumors as compared with non-stem cancer cell-derived tumors.	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('more', 'PosReg', (22, 26))	('tumors', 'Disease', (119, 125))	('tumors', 'Disease', 'MESH:D009369', (119, 125))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('tumors', 'Disease', (66, 72))	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('cancer', 'Disease', (99, 105))	('VEGF-A', 'Gene', (27, 33))	('ECS', 'Var', (49, 52))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
158060	26804163	Again, VEGF-A appears to be a key stimulator of this process, as treating the extracts with anti-VEGF-A redues HUVEC cell vessel formation.	('HUVEC cell vessel formation', 'CPA', (111, 138))	('HUVEC', 'CellLine', 'CVCL:2959', (111, 116))	('redues', 'NegReg', (104, 110))	('anti-VEGF-A', 'Var', (92, 103))
158068	26804163	Consistent with this role, NRP-1 overexpression increases blood vessel formation, and inactivation causes abnormal vasculature formation leading to embryonic lethality.	('blood vessel formation', 'CPA', (58, 80))	('abnormal vasculature', 'Phenotype', 'HP:0002597', (106, 126))	('causes', 'Reg', (99, 105))	('vasculature formation', 'CPA', (115, 136))	('NRP-1', 'Gene', (27, 32))	('inactivation', 'Var', (86, 98))	('embryonic lethality', 'Disease', 'MESH:D020964', (148, 167))	('embryonic lethality', 'Disease', (148, 167))	('overexpression increases', 'PosReg', (33, 57))
158070	26804163	In some model systems, NRP-1 expression increases angiogenesis and tumor formation; however, how NRP-1 regulates tumor formation is not well understood.	('tumor', 'Disease', (113, 118))	('expression', 'Var', (29, 39))	('angiogenesis', 'CPA', (50, 62))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Disease', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('increases', 'PosReg', (40, 49))	('NRP-1', 'Gene', (23, 28))
158074	26804163	In this cell type, VEGF-mediated stimulation of proliferation requires NRP-1, In addition, restoration of NRP-1 in NRP-1-negative pancreatic cancer cells altered cell survival, and VEGF can operate via NRP-1 to stimulate malignant progression in metastatic renal cell carcinoma.	('NRP-1', 'Gene', (106, 111))	('stimulate', 'PosReg', (211, 220))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('metastatic renal cell carcinoma', 'Disease', (246, 277))	('metastatic renal cell carcinoma', 'Disease', 'MESH:C538445', (246, 277))	('cell survival', 'CPA', (162, 175))	('NRP-1-negative', 'Gene', (115, 129))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (130, 147))	('restoration', 'Var', (91, 102))	('carcinoma', 'Phenotype', 'HP:0030731', (268, 277))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (257, 277))	('malignant progression', 'CPA', (221, 242))	('altered', 'Reg', (154, 161))	('pancreatic cancer', 'Disease', (130, 147))	('pancreatic cancer', 'Disease', 'MESH:D010190', (130, 147))
158079	26804163	Antibodies to CD31 (ab28364), Bmi-1 (ab14389), NRP-1 (ab81321), VEGFR2 (ab2349) were from Abcam (Cambridge, MA, USA).	('VEGFR2', 'Gene', (64, 70))	('ab2349', 'Var', (72, 78))	('VEGFR2', 'Gene', '3791', (64, 70))	('ab28364', 'Var', (20, 27))	('Bmi-1', 'Gene', (30, 35))	('CD31', 'Gene', '18613', (14, 18))	('ab81321', 'Var', (54, 61))	('CD31', 'Gene', (14, 18))	('NRP-1', 'Gene', (47, 52))
158096	26804163	EG00229 is a small molecular inhibitor of VEGF-A interaction with NRP-1.	('EG00229', 'Chemical', '-', (0, 7))	('NRP-1', 'Gene', (66, 71))	('interaction', 'Interaction', (49, 60))	('EG00229', 'Var', (0, 7))
158184	33953569	Genetic Analysis and Targeted Therapy Using Buparlisib and MK2206 in a Patient with Triple Metachronous Cancers of the Kidney, Prostate, and Squamous Cell Carcinoma of the Lung: A Case Report Multiple primary cancers (MPC) occurring in the same individual is considered rare but being increasingly recognized owing to the longer cancer survival nowadays.	('cancer', 'Phenotype', 'HP:0002664', (329, 335))	('Cancers of the Kidney', 'Phenotype', 'HP:0009726', (104, 125))	('Triple Metachronous Cancers of the Kidney', 'Disease', 'MESH:D007680', (84, 125))	('Buparlisib', 'Chemical', 'MESH:C571178', (44, 54))	('Triple Metachronous Cancers of the Kidney', 'Disease', (84, 125))	('cancer', 'Disease', 'MESH:D009369', (329, 335))	('MK2206', 'Chemical', 'MESH:C548887', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (209, 215))	('cancers', 'Disease', 'MESH:D009369', (209, 216))	('Squamous Cell Carcinoma', 'Disease', 'MESH:D002294', (141, 164))	('Carcinoma', 'Phenotype', 'HP:0030731', (155, 164))	('Cancer', 'Phenotype', 'HP:0002664', (104, 110))	('Squamous Cell Carcinoma of the Lung', 'Phenotype', 'HP:0030359', (141, 176))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (141, 164))	('Carcinoma of the Lung', 'Phenotype', 'HP:0100526', (155, 176))	('MK2206', 'Var', (59, 65))	('Squamous Cell Carcinoma', 'Disease', (141, 164))	('cancer', 'Disease', (329, 335))	('cancers', 'Phenotype', 'HP:0002664', (209, 216))	('Patient', 'Species', '9606', (71, 78))	('MPC', 'Chemical', '-', (218, 221))	('cancers', 'Disease', (209, 216))	('cancer', 'Disease', (209, 215))	('Cancers', 'Phenotype', 'HP:0002664', (104, 111))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
158191	33953569	Briefly, the results identified VHL, EGFR, PIK3CA, TP53, and AKT1 mutations in lung cancer, AKT1, FGFR2, and TP53 mutations in renal cancer, and FGFR2 mutations in prostate cancer.	('mutations', 'Var', (66, 75))	('mutations', 'Var', (114, 123))	('VHL', 'Gene', '7428', (32, 35))	('renal cancer', 'Disease', 'MESH:D007680', (127, 139))	('lung cancer', 'Disease', (79, 90))	('FGFR2', 'Gene', (98, 103))	('AKT1', 'Gene', '207', (92, 96))	('AKT1', 'Gene', '207', (61, 65))	('PIK3CA', 'Gene', (43, 49))	('FGFR2', 'Gene', (145, 150))	('TP53', 'Gene', (51, 55))	('TP53', 'Gene', '7157', (109, 113))	('EGFR', 'Gene', '1956', (37, 41))	('FGFR2', 'Gene', '2263', (98, 103))	('mutations', 'Var', (151, 160))	('AKT1', 'Gene', (92, 96))	('lung cancer', 'Disease', 'MESH:D008175', (79, 90))	('AKT1', 'Gene', (61, 65))	('FGFR2', 'Gene', '2263', (145, 150))	('lung cancer', 'Phenotype', 'HP:0100526', (79, 90))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('prostate cancer', 'Disease', 'MESH:D011471', (164, 179))	('TP53', 'Gene', '7157', (51, 55))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('renal cancer', 'Disease', (127, 139))	('prostate cancer', 'Phenotype', 'HP:0012125', (164, 179))	('VHL', 'Gene', (32, 35))	('PIK3CA', 'Gene', '5290', (43, 49))	('renal cancer', 'Phenotype', 'HP:0009726', (127, 139))	('prostate cancer', 'Disease', (164, 179))	('TP53', 'Gene', (109, 113))	('EGFR', 'Gene', (37, 41))
158192	33953569	A combined medication targeting PIK3CA and AKT1 signaling was recommended and the patient was given BKM120 (PIK3CA, Phase III clinical trial) and MK2206 (AKT, phase III clinical trial).	('MK2206', 'Var', (146, 152))	('BKM120', 'Var', (100, 106))	('AKT1', 'Gene', (43, 47))	('PIK3CA', 'Gene', '5290', (32, 38))	('patient', 'Species', '9606', (82, 89))	('AKT', 'Gene', '207', (154, 157))	('AKT', 'Gene', '207', (43, 46))	('PIK3CA', 'Gene', (108, 114))	('AKT', 'Gene', (154, 157))	('AKT', 'Gene', (43, 46))	('MK2206', 'Chemical', 'MESH:C548887', (146, 152))	('AKT1', 'Gene', '207', (43, 47))	('BKM120', 'Chemical', 'MESH:C571178', (100, 106))	('PIK3CA', 'Gene', '5290', (108, 114))	('PIK3CA', 'Gene', (32, 38))
158223	33953569	Lung SQCC was found to have mutations in VHL, PIK3CA, EGFR, HRAS, TP53, BRAF, CDH1, and AKT1.	('VHL', 'Gene', '7428', (41, 44))	('PIK3CA', 'Gene', '5290', (46, 52))	('BRAF', 'Gene', (72, 76))	('TP53', 'Gene', '7157', (66, 70))	('TP53', 'Gene', (66, 70))	('CDH1', 'Gene', '999', (78, 82))	('BRAF', 'Gene', '673', (72, 76))	('EGFR', 'Gene', '1956', (54, 58))	('HRAS', 'Gene', '3265', (60, 64))	('VHL', 'Gene', (41, 44))	('CDH1', 'Gene', (78, 82))	('AKT1', 'Gene', '207', (88, 92))	('HRAS', 'Gene', (60, 64))	('EGFR', 'Gene', (54, 58))	('mutations', 'Var', (28, 37))	('AKT1', 'Gene', (88, 92))	('PIK3CA', 'Gene', (46, 52))
158224	33953569	CCRCC harbored mutations in VHL, FGFR2 and AKT1, and TP53.	('AKT1', 'Gene', (43, 47))	('CCRCC', 'Disease', (0, 5))	('mutations', 'Var', (15, 24))	('FGFR2', 'Gene', (33, 38))	('FGFR2', 'Gene', '2263', (33, 38))	('TP53', 'Gene', '7157', (53, 57))	('AKT1', 'Gene', '207', (43, 47))	('VHL', 'Gene', (28, 31))	('TP53', 'Gene', (53, 57))	('VHL', 'Gene', '7428', (28, 31))
158226	33953569	The metastatic bone tumor of CCRCC origin showed mutations in VHL, FGFR2, and TP53.	('bone tumor', 'Disease', (15, 25))	('bone tumor', 'Disease', 'MESH:D001859', (15, 25))	('mutations', 'Var', (49, 58))	('bone tumor', 'Phenotype', 'HP:0010622', (15, 25))	('CCRCC', 'Disease', (29, 34))	('FGFR2', 'Gene', (67, 72))	('VHL', 'Gene', (62, 65))	('metastatic', 'Disease', (4, 14))	('TP53', 'Gene', (78, 82))	('FGFR2', 'Gene', '2263', (67, 72))	('TP53', 'Gene', '7157', (78, 82))	('VHL', 'Gene', '7428', (62, 65))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))
158227	33953569	The VHL, FGFR2, and TP53 mutations were the most common ones, with the VHL mutations in lung, renal and bone tumors, and the FGFR2 mutations in renal and metastatic bone tumors.	('bone tumors', 'Disease', (165, 176))	('FGFR2', 'Gene', '2263', (125, 130))	('bone tumors', 'Phenotype', 'HP:0010622', (165, 176))	('VHL', 'Gene', '7428', (71, 74))	('lung', 'Disease', (88, 92))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('mutations', 'Var', (25, 34))	('TP53', 'Gene', (20, 24))	('bone tumors', 'Disease', 'MESH:D001859', (165, 176))	('FGFR2', 'Gene', (9, 14))	('renal and', 'Disease', (144, 153))	('bone tumor', 'Phenotype', 'HP:0010622', (165, 175))	('VHL', 'Gene', (4, 7))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('bone tumors', 'Disease', (104, 115))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('FGFR2', 'Gene', '2263', (9, 14))	('bone tumors', 'Phenotype', 'HP:0010622', (104, 115))	('tumors', 'Phenotype', 'HP:0002664', (170, 176))	('VHL', 'Gene', '7428', (4, 7))	('TP53', 'Gene', '7157', (20, 24))	('mutations', 'Var', (131, 140))	('FGFR2', 'Gene', (125, 130))	('common', 'Reg', (49, 55))	('VHL', 'Gene', (71, 74))	('bone tumors', 'Disease', 'MESH:D001859', (104, 115))	('mutations', 'Var', (75, 84))	('bone tumor', 'Phenotype', 'HP:0010622', (104, 114))
158228	33953569	Several PIK3CA and AKT1 mutations are canonical and had been reported in various cancers according to COSMIC and Clinvar database, including PIK3CA c.3142C>T p.His1048Tyr (COSM249875), AKT1 c.68G>A p.Arg23Gln (COSM3770600), and c.49G>A p.Glu17Lys (COSM33765).	('c.68G>A', 'SUBSTITUTION', 'None', (190, 197))	('cancers', 'Phenotype', 'HP:0002664', (81, 88))	('COSM33765', 'Chemical', '-', (248, 257))	('cancers', 'Disease', (81, 88))	('p.His1048Tyr', 'Var', (158, 170))	('c.49G>A', 'Var', (228, 235))	('mutations', 'Var', (24, 33))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('PIK3CA', 'Gene', '5290', (8, 14))	('p.Arg23Gln', 'SUBSTITUTION', 'None', (198, 208))	('p.Glu17Lys', 'SUBSTITUTION', 'None', (236, 246))	('AKT1', 'Gene', '207', (19, 23))	('PIK3CA', 'Gene', '5290', (141, 147))	('AKT1', 'Gene', '207', (185, 189))	('cancers', 'Disease', 'MESH:D009369', (81, 88))	('AKT1', 'Gene', (19, 23))	('c.68G>A', 'Var', (190, 197))	('PIK3CA', 'Gene', (8, 14))	('c.49G>A', 'SUBSTITUTION', 'None', (228, 235))	('c.3142C>T', 'Var', (148, 157))	('c.3142C>T', 'SUBSTITUTION', 'None', (148, 157))	('p.Glu17Lys', 'Var', (236, 246))	('AKT1', 'Gene', (185, 189))	('p.Arg23Gln', 'Var', (198, 208))	('PIK3CA', 'Gene', (141, 147))	('COSM3770600', 'Chemical', '-', (210, 221))	('COSM249875', 'Chemical', '-', (172, 182))	('p.His1048Tyr', 'SUBSTITUTION', 'None', (158, 170))	('reported', 'Reg', (61, 69))
158231	33953569	A combination of PIK3CA inhibitor BKM120 (80mg PO QD) and AKT1 inhibitor MK2206 (45mg PO QOD) on a 28-day cycle was initiated starting from February, 2015.	('MK2206', 'Var', (73, 79))	('AKT1', 'Gene', '207', (58, 62))	('PIK3CA', 'Gene', (17, 23))	('BKM120', 'Chemical', 'MESH:C571178', (34, 40))	('PIK3CA', 'Gene', '5290', (17, 23))	('AKT1', 'Gene', (58, 62))	('MK2206', 'Chemical', 'MESH:C548887', (73, 79))	('BKM120', 'Var', (34, 40))
158232	33953569	The combination of BKM120 and MK2206 was expected to suppress growth of both CCRCC and lung SQCC.	('BKM120', 'Chemical', 'MESH:C571178', (19, 25))	('MK2206', 'Var', (30, 36))	('lung SQCC', 'Disease', (87, 96))	('growth', 'MPA', (62, 68))	('suppress', 'NegReg', (53, 61))	('BKM120', 'Var', (19, 25))	('CCRCC', 'Disease', (77, 82))	('MK2206', 'Chemical', 'MESH:C548887', (30, 36))
158249	33953569	According to the Cancer Genome Atlas (TCGA), the hot- spot mutations reported in SQCC are TP53, CDKN2A, PTEN, PIK3CA, KEAP1, MLL2, AKT1, NFE2L2, NOTCH1, and RB1.	('TP53', 'Gene', '7157', (90, 94))	('RB1', 'Gene', (157, 160))	('SQCC', 'Gene', (81, 85))	('AKT1', 'Gene', '207', (131, 135))	('Cancer', 'Phenotype', 'HP:0002664', (17, 23))	('MLL2', 'Gene', '8085', (125, 129))	('CDKN2A', 'Gene', (96, 102))	('PTEN', 'Gene', (104, 108))	('PIK3CA', 'Gene', '5290', (110, 116))	('NFE2L2', 'Gene', '4780', (137, 143))	('RB1', 'Gene', '5925', (157, 160))	('MLL2', 'Gene', (125, 129))	('Cancer', 'Disease', (17, 23))	('KEAP1', 'Gene', '9817', (118, 123))	('TP53', 'Gene', (90, 94))	('mutations', 'Var', (59, 68))	('AKT1', 'Gene', (131, 135))	('KEAP1', 'Gene', (118, 123))	('NOTCH1', 'Gene', (145, 151))	('PTEN', 'Gene', '5728', (104, 108))	('CDKN2A', 'Gene', '1029', (96, 102))	('Cancer', 'Disease', 'MESH:D009369', (17, 23))	('NFE2L2', 'Gene', (137, 143))	('PIK3CA', 'Gene', (110, 116))	('NOTCH1', 'Gene', '4851', (145, 151))
158250	33953569	Our findings are consistent with the TCGA reports, with PIK3CA and AKT1 mutations being identified and employed as drug targets, along with the other mutations on EGFR, BRAF, CDH1, HRAS, and TP53 (Table 1).	('AKT1', 'Gene', (67, 71))	('mutations', 'Var', (72, 81))	('BRAF', 'Gene', (169, 173))	('HRAS', 'Gene', (181, 185))	('CDH1', 'Gene', '999', (175, 179))	('BRAF', 'Gene', '673', (169, 173))	('EGFR', 'Gene', '1956', (163, 167))	('TP53', 'Gene', '7157', (191, 195))	('TP53', 'Gene', (191, 195))	('HRAS', 'Gene', '3265', (181, 185))	('PIK3CA', 'Gene', (56, 62))	('EGFR', 'Gene', (163, 167))	('AKT1', 'Gene', '207', (67, 71))	('PIK3CA', 'Gene', '5290', (56, 62))	('CDH1', 'Gene', (175, 179))
158251	33953569	A combination of PIK3CA inhibitor Buparlisib (BKM120) and AKT inhibitor MK2206 was used to treat the lung SQCC of our patient presented here.	('BKM120', 'Chemical', 'MESH:C571178', (46, 52))	('PIK3CA', 'Gene', (17, 23))	('Buparlisib', 'Chemical', 'MESH:C571178', (34, 44))	('MK2206', 'Chemical', 'MESH:C548887', (72, 78))	('MK2206', 'Var', (72, 78))	('PIK3CA', 'Gene', '5290', (17, 23))	('AKT', 'Gene', '207', (58, 61))	('lung SQCC', 'Disease', (101, 110))	('patient', 'Species', '9606', (118, 125))	('AKT', 'Gene', (58, 61))
158252	33953569	BKM120 and MK2206, as newer targeted drugs inhibiting the PI3K-Akt signaling pathway, are currently on clinical trials for NSCLC.	('inhibiting', 'NegReg', (43, 53))	('NSCLC', 'Disease', (123, 128))	('BKM120', 'Var', (0, 6))	('NSCLC', 'Disease', 'MESH:D002289', (123, 128))	('MK2206', 'Chemical', 'MESH:C548887', (11, 17))	('BKM120', 'Chemical', 'MESH:C571178', (0, 6))	('Akt', 'Gene', '207', (63, 66))	('MK2206', 'Var', (11, 17))	('Akt', 'Gene', (63, 66))
158255	33953569	The phase-II BASALT-1 study failed to show increased PFS in receiving BKM120.	('BKM120', 'Chemical', 'MESH:C571178', (70, 76))	('PFS', 'MPA', (53, 56))	('BKM120', 'Var', (70, 76))
158256	33953569	The NCT01911325 Phase II trial showed only a marginal anti-tumor activity by BKM120 plus docetaxel.	('BKM120', 'Chemical', 'MESH:C571178', (77, 83))	('tumor', 'Disease', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('BKM120', 'Var', (77, 83))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('docetaxel', 'Chemical', 'MESH:D000077143', (89, 98))
158258	33953569	Similarly, in a study of Erlotinib-resistant NSCLC, the AKT inhibitor MK2206 seemed unable to potentiate the efficacy of Erlotinib.	('AKT', 'Gene', '207', (56, 59))	('NSCLC', 'Disease', (45, 50))	('Erlotinib', 'Chemical', 'MESH:D000069347', (25, 34))	('MK2206', 'Chemical', 'MESH:C548887', (70, 76))	('AKT', 'Gene', (56, 59))	('Erlotinib', 'Chemical', 'MESH:D000069347', (121, 130))	('NSCLC', 'Disease', 'MESH:D002289', (45, 50))	('potentiate', 'PosReg', (94, 104))	('MK2206', 'Var', (70, 76))
158259	33953569	The BATTLE-2 trial aimed to compare the efficacy of MK2206 in NSCLC with mutant or wild type KRAS and the study remained ongoing.	('KRAS', 'Gene', (93, 97))	('NSCLC', 'Disease', (62, 67))	('MK2206', 'Chemical', 'MESH:C548887', (52, 58))	('NSCLC', 'Disease', 'MESH:D002289', (62, 67))	('KRAS', 'Gene', '3845', (93, 97))	('MK2206', 'Var', (52, 58))
158260	33953569	Currently there have been no studies using combined MK2206 and BKM120 in NSCLC/SQCC treatment.	('BKM120', 'Var', (63, 69))	('MK2206', 'Var', (52, 58))	('MK2206', 'Chemical', 'MESH:C548887', (52, 58))	('NSCLC', 'Disease', (73, 78))	('BKM120', 'Chemical', 'MESH:C571178', (63, 69))	('NSCLC', 'Disease', 'MESH:D002289', (73, 78))
158261	33953569	Our case demonstrated a good combination of BKM120 and MK2206 to combat lung SQCC and possibly CCRCC with actionable AKT1 mutation, which is worth further clinical investigations.	('BKM120', 'Chemical', 'MESH:C571178', (44, 50))	('MK2206', 'Var', (55, 61))	('AKT1', 'Gene', '207', (117, 121))	('mutation', 'Var', (122, 130))	('combat lung SQCC', 'Disease', (65, 81))	('MK2206', 'Chemical', 'MESH:C548887', (55, 61))	('AKT1', 'Gene', (117, 121))	('BKM120', 'Var', (44, 50))	('CCRCC', 'Disease', (95, 100))
158264	33953569	Smoking is the major risk factor for CCRCC and gene mutation including VHL gene and genes on the PI3K-Akt-mTOR axis is another known risk factor.	('Akt', 'Gene', (102, 105))	('Akt', 'Gene', '207', (102, 105))	('VHL', 'Gene', (71, 74))	('gene mutation', 'Var', (47, 60))	('VHL', 'Gene', '7428', (71, 74))	('mTOR', 'Gene', (106, 110))	('CCRCC', 'Disease', (37, 42))	('mTOR', 'Gene', '2475', (106, 110))
158266	33953569	While clinical interest in PI3K-Akt inhibitors is rising rapidly, certain phase I/II trials demonstrated a great potential of BKM120 and MK2206 in CCRCC treatment.	('MK2206', 'Chemical', 'MESH:C548887', (137, 143))	('Akt', 'Gene', '207', (32, 35))	('BKM120', 'Chemical', 'MESH:C571178', (126, 132))	('CCRCC', 'Disease', (147, 152))	('Akt', 'Gene', (32, 35))	('MK2206', 'Var', (137, 143))	('BKM120', 'Var', (126, 132))
158267	33953569	A Phase I study of BKM120 plus bevacizumab showed partial response in 13% metastatic CCRCC patients, with increased efficacy in those harboring activating PI3K mutations.	('metastatic CCRCC', 'Disease', (74, 90))	('BKM120', 'Chemical', 'MESH:C571178', (19, 25))	('patients', 'Species', '9606', (91, 99))	('activating', 'PosReg', (144, 154))	('BKM120', 'Var', (19, 25))	('bevacizumab', 'Chemical', 'MESH:D000068258', (31, 42))	('increased', 'PosReg', (106, 115))	('PI3K mutations', 'Var', (155, 169))
158269	33953569	Although in our case, the patient's renal cancer could have been cured by Sorafenib and no further bone metastasis had been reported for years, our decision to use BKM120 combined with MK2206 may exert certain protective function against the CCRCC in overt stage.	('patient', 'Species', '9606', (26, 33))	('renal cancer', 'Disease', 'MESH:D007680', (36, 48))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('MK2206', 'Chemical', 'MESH:C548887', (185, 191))	('BKM120', 'Chemical', 'MESH:C571178', (164, 170))	('Sorafenib', 'Chemical', 'MESH:D000077157', (74, 83))	('renal cancer', 'Disease', (36, 48))	('CCRCC', 'Disease', (242, 247))	('renal cancer', 'Phenotype', 'HP:0009726', (36, 48))	('MK2206', 'Var', (185, 191))	('BKM120', 'Var', (164, 170))
158271	33953569	Genome-guided targeted therapy identified mutations aberrantly affecting the PI3K-Akt pathway across different tumors and a combination of PI3K inhibitor BKM120 and AKT inhibitor MK2206 achieved good efficacy prolonging the patient's survival for more than a year.	('AKT', 'Gene', (165, 168))	('BKM120', 'Chemical', 'MESH:C571178', (154, 160))	('MK2206', 'Chemical', 'MESH:C548887', (179, 185))	('Akt', 'Gene', '207', (82, 85))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('patient', 'Species', '9606', (224, 231))	('affecting', 'Reg', (63, 72))	('tumors', 'Disease', (111, 117))	('tumors', 'Disease', 'MESH:D009369', (111, 117))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('AKT', 'Gene', '207', (165, 168))	('Akt', 'Gene', (82, 85))	('prolonging', 'PosReg', (209, 219))	('mutations', 'Var', (42, 51))
158275	32833992	Expression, intracellular localization, and mutation of EGFR in conjunctival squamous cell carcinoma and the association with prognosis and treatment Conjunctival squamous cell carcinoma (SCC) is primarily treated with surgical resection.	('mutation', 'Var', (44, 52))	('SCC', 'Gene', '6317', (188, 191))	('Conjunctival squamous cell carcinoma', 'Disease', 'MESH:D002294', (150, 186))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (163, 186))	('conjunctival squamous cell carcinoma', 'Disease', (64, 100))	('EGFR', 'Gene', '1956', (56, 60))	('conjunctival squamous cell carcinoma', 'Disease', 'MESH:D002294', (64, 100))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (77, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (177, 186))	('EGFR', 'Gene', (56, 60))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('Conjunctival squamous cell carcinoma', 'Disease', (150, 186))	('SCC', 'Gene', (188, 191))
158278	32833992	In this retrospective study, we performed immunohistochemistry to evaluate EGFR expression and localization in tumor cells, EGFR mutation-specific expression (E746-A750del and L858R), and human papillomavirus expression in a series of 29 conjunctival SCCs.	('conjunctival SCCs', 'Disease', (238, 255))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('EGFR', 'Gene', '1956', (124, 128))	('human papillomavirus', 'Species', '10566', (188, 208))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('L858R', 'Var', (176, 181))	('EGFR', 'Gene', (124, 128))	('E746-A750del', 'Var', (159, 171))	('tumor', 'Disease', (111, 116))	('EGFR', 'Gene', '1956', (75, 79))	('L858R', 'Mutation', 'rs121434568', (176, 181))	('conjunctival SCCs', 'Disease', 'MESH:D003229', (238, 255))	('EGFR', 'Gene', (75, 79))	('E746-A750del', 'Mutation', 'p.746,750delA', (159, 171))
158281	32833992	In addition, we calculated the percentages of the two most important mutations in EGFR (exon 19 746-A750del (8/29, 27.5%), exon 21 (L858R mutant (2/29, 6.8%)) in conjunctival SCCs.	('EGFR', 'Gene', (82, 86))	('A750del', 'Mutation', 'c.750delA', (100, 107))	('746-A750del', 'Var', (96, 107))	('L858R', 'Var', (132, 137))	('conjunctival SCCs', 'Disease', 'MESH:D003229', (162, 179))	('EGFR', 'Gene', '1956', (82, 86))	('conjunctival SCCs', 'Disease', (162, 179))	('exon', 'Var', (123, 127))	('L858R', 'Mutation', 'rs121434568', (132, 137))
158284	32833992	Increased understanding of EGFR mutations may have important implications for future treatment options.	('EGFR', 'Gene', '1956', (27, 31))	('mutations', 'Var', (32, 41))	('EGFR', 'Gene', (27, 31))	('men', 'Species', '9606', (90, 93))
158302	32833992	As primary antibodies, we used EGFR E746-A750del (#2085, Cell Signaling Technologies, Danvers, MA, USA) and EGFR L858R (#3197, Cell Signaling Technologies), which were manually applied to the slides.	('EGFR', 'Gene', '1956', (31, 35))	('EGFR', 'Gene', '1956', (108, 112))	('EGFR', 'Gene', (108, 112))	('E746-A750del', 'Mutation', 'p.746,750delA', (36, 48))	('EGFR', 'Gene', (31, 35))	('L858R', 'Mutation', 'rs121434568', (113, 118))	('E746-A750del', 'Var', (36, 48))
158304	32833992	Slides immunostained for EGFR, EGFR mutations, and HPV were evaluated in a blinded manner by two specialists (MT and AK).	('EGFR', 'Gene', '1956', (31, 35))	('EGFR', 'Gene', (25, 29))	('HPV', 'Species', '10566', (51, 54))	('EGFR', 'Gene', (31, 35))	('mutations', 'Var', (36, 45))	('EGFR', 'Gene', '1956', (25, 29))
158332	32833992	EGFR E746-A750 del and EGFR L858R expression were assessed with immunohistochemistry in all 29 patients (Fig 3).	('E746-A750 del', 'Var', (5, 18))	('L858R', 'Var', (28, 33))	('EGFR', 'Gene', (0, 4))	('patients', 'Species', '9606', (95, 103))	('L858R', 'Mutation', 'rs121434568', (28, 33))	('EGFR', 'Gene', '1956', (23, 27))	('EGFR', 'Gene', (23, 27))	('EGFR', 'Gene', '1956', (0, 4))	('E746-A750 del', 'Mutation', 'p.746,750delA', (5, 18))
158333	32833992	The mutation at exon 19, EGFR E7446-A750 del, was confirmed in 8/29 (27.5%) cases, and that at exon 21, EGFR L858R point mutation, was confirmed in 2/29 (6.8%) cases with IHC (Table 4).	('EGFR', 'Gene', (25, 29))	('EGFR', 'Gene', (104, 108))	('L858R', 'Mutation', 'rs121434568', (109, 114))	('E7446-A750 del', 'Var', (30, 44))	('IHC', 'Disease', (171, 174))	('E7446-A750 del', 'Mutation', 'p.7446,750delA', (30, 44))	('EGFR', 'Gene', '1956', (25, 29))	('EGFR', 'Gene', '1956', (104, 108))
158334	32833992	The relationship between EGFR mutation and EGFR staining (focal or diffuse) was determined using univariate linear regression analysis with correction for age (P = 0.559).	('EGFR', 'Gene', (25, 29))	('mutation', 'Var', (30, 38))	('EGFR', 'Gene', '1956', (43, 47))	('EGFR', 'Gene', (43, 47))	('EGFR', 'Gene', '1956', (25, 29))
158338	32833992	The Cox regression model was used to examine and analyze the relationship between long-term prognosis including orbital exenteration and PFS and the clinicopathological status, EGFR staining pattern, and EGFR mutation.	('EGFR', 'Gene', '1956', (204, 208))	('mutation', 'Var', (209, 217))	('EGFR', 'Gene', '1956', (177, 181))	('orbital exenteration', 'Disease', (112, 132))	('PFS', 'Disease', (137, 140))	('EGFR', 'Gene', (204, 208))	('EGFR', 'Gene', (177, 181))
158341	32833992	In addition, the EGFR mutation was not significantly correlated with final orbital exenteration or PFS (Tables 5 and 6).	('mutation', 'Var', (22, 30))	('PFS', 'Disease', (99, 102))	('EGFR', 'Gene', '1956', (17, 21))	('EGFR', 'Gene', (17, 21))
158342	32833992	To the best of our knowledge, this is one of the first studies to survey the prevalence of EGFR mutations and intracellular localization in conjunctival SCC and to evaluate the prognostic significance of tumor cells that express EGFR in conjunctival SCC.	('SCC', 'Gene', '6317', (250, 253))	('SCC', 'Gene', '6317', (153, 156))	('EGFR', 'Gene', (91, 95))	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('EGFR', 'Gene', '1956', (229, 233))	('tumor', 'Disease', (204, 209))	('EGFR', 'Gene', (229, 233))	('SCC', 'Gene', (250, 253))	('SCC', 'Gene', (153, 156))	('EGFR', 'Gene', '1956', (91, 95))	('mutations', 'Var', (96, 105))
158344	32833992	In addition, we determined the percentages of the two most important mutations in EGFR (exon 19 746-A750del (8/29, 27.5%), exon 21 (L858R Mutant (2/29, 6.8%)) in conjunctival SCCs.	('EGFR', 'Gene', (82, 86))	('A750del', 'Mutation', 'c.750delA', (100, 107))	('746-A750del', 'Var', (96, 107))	('L858R', 'Var', (132, 137))	('conjunctival SCCs', 'Disease', 'MESH:D003229', (162, 179))	('EGFR', 'Gene', '1956', (82, 86))	('conjunctival SCCs', 'Disease', (162, 179))	('exon', 'Var', (123, 127))	('L858R', 'Mutation', 'rs121434568', (132, 137))
158352	32833992	Other previous studies reported that post-translational modification can promote EGFR endocytosis and lysosomal degradation of EGFR, thereby ensuring termination of receptor signaling.	('lysosomal degradation', 'MPA', (102, 123))	('EGFR', 'Gene', '1956', (81, 85))	('EGFR', 'Gene', '1956', (127, 131))	('post-translational modification', 'Var', (37, 68))	('promote', 'PosReg', (73, 80))	('EGFR', 'Gene', (127, 131))	('termination', 'MPA', (150, 161))	('EGFR', 'Gene', (81, 85))
158358	32833992	EGFR mutations in OSSN including invasive SCCs have not been examined in Asian patients.	('EGFR', 'Gene', (0, 4))	('invasive SCCs', 'Disease', 'MESH:D009361', (33, 46))	('mutations', 'Var', (5, 14))	('patients', 'Species', '9606', (79, 87))	('invasive SCCs', 'Disease', (33, 46))	('EGFR', 'Gene', '1956', (0, 4))
158359	32833992	Since 2016, approximately 16,000 EGFR mutations in lung cancer had been registered in the COSMIC (the catalog of somatic mutations in cancer) database.	('lung cancer', 'Disease', 'MESH:D008175', (51, 62))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('lung cancer', 'Disease', (51, 62))	('EGFR', 'Gene', '1956', (33, 37))	('lung cancer', 'Phenotype', 'HP:0100526', (51, 62))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('EGFR', 'Gene', (33, 37))	('mutations', 'Var', (38, 47))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
158361	32833992	in 2007 reported that EGFR mutations are common in Asians, females, non-smokers, and adenocarcinomas in lung cancer.	('mutations', 'Var', (27, 36))	('adenocarcinomas', 'Disease', 'MESH:D000230', (85, 100))	('lung cancer', 'Disease', 'MESH:D008175', (104, 115))	('adenocarcinomas', 'Disease', (85, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('carcinomas', 'Phenotype', 'HP:0030731', (90, 100))	('lung cancer', 'Disease', (104, 115))	('lung cancer', 'Phenotype', 'HP:0100526', (104, 115))	('EGFR', 'Gene', '1956', (22, 26))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('EGFR', 'Gene', (22, 26))	('common', 'Reg', (41, 47))
158362	32833992	Generally, when EGFR mutation occurs, the tyrosine kinase activity of EGFR at the ATP binding site is constantly active, even without growth factor.	('ATP', 'Gene', (82, 85))	('ATP', 'Gene', '51761', (82, 85))	('EGFR', 'Gene', '1956', (70, 74))	('mutation', 'Var', (21, 29))	('EGFR', 'Gene', (70, 74))	('EGFR', 'Gene', '1956', (16, 20))	('active', 'MPA', (113, 119))	('EGFR', 'Gene', (16, 20))	('tyrosine kinase activity', 'MPA', (42, 66))
158365	32833992	Blockade of signal transmission has antitumor effects.	('signal', 'Protein', (12, 18))	('Blockade', 'Var', (0, 8))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))
158366	32833992	Previous reports of EGFR activating mutations (common mutations) described the frequency of exon 19 deletion mutations as 44.8% (2573/5741) and 39.8% for L858R mutations (2283/5731) in lung cancer.	('lung cancer', 'Disease', 'MESH:D008175', (185, 196))	('deletion mutations', 'Var', (100, 118))	('EGFR', 'Gene', (20, 24))	('activating', 'PosReg', (25, 35))	('2283/5731', 'Var', (171, 180))	('L858R', 'Mutation', 'rs121434568', (154, 159))	('mutations', 'Var', (36, 45))	('lung cancer', 'Disease', (185, 196))	('lung cancer', 'Phenotype', 'HP:0100526', (185, 196))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('L858R mutations (2283/5731', 'Var', (154, 180))	('EGFR', 'Gene', '1956', (20, 24))
158367	32833992	EGFR mutations were examined to verify the effect of gefitinib on positive non-small cell lung carcinoma in two Phase III clinical trials from Japan.	('lung carcinoma', 'Disease', (90, 104))	('lung carcinoma', 'Disease', 'MESH:D008175', (90, 104))	('EGFR', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('small cell lung carcinoma', 'Phenotype', 'HP:0030357', (79, 104))	('non-small cell lung carcinoma', 'Phenotype', 'HP:0030358', (75, 104))	('gefitinib', 'Chemical', 'MESH:D000077156', (53, 62))	('EGFR', 'Gene', '1956', (0, 4))
158370	32833992	In view of these findings in lung cancer in Asians, our findings regarding EGFR expression and mutations will provide further options for potential treatment of OSSN for pre- and post-surgical treatment.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('lung cancer', 'Disease', 'MESH:D008175', (29, 40))	('men', 'Species', '9606', (153, 156))	('EGFR', 'Gene', '1956', (75, 79))	('mutations', 'Var', (95, 104))	('men', 'Species', '9606', (198, 201))	('lung cancer', 'Phenotype', 'HP:0100526', (29, 40))	('lung cancer', 'Disease', (29, 40))	('EGFR', 'Gene', (75, 79))
158372	32833992	Ours is the first report to show that differences in the expression form and mutations in EGFR in OSSN are associated with prognosis and treatment.	('expression', 'MPA', (57, 67))	('men', 'Species', '9606', (142, 145))	('associated', 'Reg', (107, 117))	('EGFR', 'Gene', '1956', (90, 94))	('mutations', 'Var', (77, 86))	('EGFR', 'Gene', (90, 94))
158380	32833992	In addition, the method we used for identification of EGFR mutations was not general genotyping, but was a judgment of immunohistochemically stained sections.	('men', 'Species', '9606', (111, 114))	('EGFR', 'Gene', '1956', (54, 58))	('EGFR', 'Gene', (54, 58))	('mutations', 'Var', (59, 68))
158382	32833992	Our study found that EGFR mutations were also present in conjunctival SCC in east Asians.	('EGFR', 'Gene', '1956', (21, 25))	('EGFR', 'Gene', (21, 25))	('SCC', 'Gene', (70, 73))	('mutations', 'Var', (26, 35))	('SCC', 'Gene', '6317', (70, 73))
158383	32833992	Another limitation is that double testing of formalin-fixed paraffin-embedded specimens and plasma with real-time PCR for detection of EGFR mutations is more common than IHC in actual clinical practice.	('men', 'Species', '9606', (83, 86))	('EGFR', 'Gene', '1956', (135, 139))	('paraffin', 'Chemical', 'MESH:D010232', (60, 68))	('EGFR', 'Gene', (135, 139))	('mutations', 'Var', (140, 149))	('formalin', 'Chemical', 'MESH:D005557', (45, 53))
158387	32833992	20 May 2020  PONE-D-20-09283 Expression, intracellular localization, and mutation of EGFR in conjunctival squamous cell carcinoma associated with prognosis and treatment PLOS ONE Dear Dr. Tagami, Thank you for submitting your manuscript to PLOS ONE.	('men', 'Species', '9606', (165, 168))	('EGFR', 'Gene', (85, 89))	('EGFR', 'Gene', '1956', (85, 89))	('Tagami', 'Chemical', '-', (188, 194))	('PONE-D-20-09283', 'Chemical', '-', (13, 28))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('conjunctival squamous cell carcinoma', 'Disease', (93, 129))	('conjunctival squamous cell carcinoma', 'Disease', 'MESH:D002294', (93, 129))	('mutation', 'Var', (73, 81))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (106, 129))	('associated', 'Reg', (130, 140))
158414	32833992	The authors claim that this is the first report to show that mutations in EGFR are associated with prognosis and treatment.	('men', 'Species', '9606', (118, 121))	('mutations', 'Var', (61, 70))	('EGFR', 'Gene', '1956', (74, 78))	('associated', 'Reg', (83, 93))	('EGFR', 'Gene', (74, 78))
158415	32833992	They allude to the EGFR mutations in lung cancer and they show in table 3 the results of the 2 investigated mutations but there is no correlation of the 2 mutations with prognosis and treatment in ocular neoplasia.	('lung cancer', 'Disease', (37, 48))	('ocular neoplasia', 'Disease', (197, 213))	('men', 'Species', '9606', (189, 192))	('lung cancer', 'Phenotype', 'HP:0100526', (37, 48))	('mutations', 'Var', (108, 117))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('neoplasia', 'Phenotype', 'HP:0002664', (204, 213))	('EGFR', 'Gene', '1956', (19, 23))	('ocular neoplasia', 'Disease', 'MESH:D009369', (197, 213))	('lung cancer', 'Disease', 'MESH:D008175', (37, 48))	('EGFR', 'Gene', (19, 23))	('mutations', 'Var', (24, 33))	('ocular neoplasia', 'Phenotype', 'HP:0100012', (197, 213))
158417	32833992	However, the authors conclude that IHC can be used to identify EGFR mutations.	('mutations', 'Var', (68, 77))	('EGFR', 'Gene', (63, 67))	('EGFR', 'Gene', '1956', (63, 67))
158428	32833992	In present manuscript authors also evaluated EGFR mutation using immunohistochemistry.	('EGFR', 'Gene', '1956', (45, 49))	('EGFR', 'Gene', (45, 49))	('mutation', 'Var', (50, 58))
158429	32833992	They observed EGFR E746-A750 del and EGFR L858R expression in patients.	('EGFR', 'Gene', '1956', (14, 18))	('L858R', 'Var', (42, 47))	('EGFR', 'Gene', (14, 18))	('E746-A750 del', 'Var', (19, 32))	('L858R', 'Mutation', 'rs121434568', (42, 47))	('EGFR', 'Gene', '1956', (37, 41))	('EGFR', 'Gene', (37, 41))	('patients', 'Species', '9606', (62, 70))	('E746-A750 del', 'Mutation', 'p.746,750delA', (19, 32))
158432	32833992	Reviewer #3: In the submitted manuscript, Sakai et al evaluated the expression, localization, and mutation of EGFR in conjunctival squamous cell carcinoma.	('conjunctival squamous cell carcinoma', 'Disease', 'MESH:D002294', (118, 154))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (131, 154))	('carcinoma', 'Phenotype', 'HP:0030731', (145, 154))	('mutation', 'Var', (98, 106))	('EGFR', 'Gene', '1956', (110, 114))	('EGFR', 'Gene', (110, 114))	('conjunctival squamous cell carcinoma', 'Disease', (118, 154))
158434	32833992	Eight samples presented the E746-A750 del mutation while 2 samples the L858R point mutation.	('E746-A750 del', 'Mutation', 'p.746,750delA', (28, 41))	('E746-A750 del', 'Var', (28, 41))	('L858R', 'Var', (71, 76))	('L858R', 'Mutation', 'rs121434568', (71, 76))
158443	32833992	Line 159: Include more information regarding EGFR E746-A750 del and EGFR L858R expression like diffuse/focal staining, membrane/cytoplasmic score.	('E746-A750 del', 'Var', (50, 63))	('EGFR', 'Gene', (45, 49))	('EGFR', 'Gene', '1956', (68, 72))	('E746-A750 del', 'Mutation', 'p.746,750delA', (50, 63))	('EGFR', 'Gene', (68, 72))	('EGFR', 'Gene', '1956', (45, 49))	('L858R', 'Mutation', 'rs121434568', (73, 78))
158444	32833992	Is there any correlation between EGFR mutation and clinical data (orbital exenteration/PFS)?	('EGFR', 'Gene', '1956', (33, 37))	('mutation', 'Var', (38, 46))	('EGFR', 'Gene', (33, 37))
158458	32833992	The Cox regression model was used to examine the relationship between EGFR mutations and long-term prognosis including orbital exenteration and PFS.	('PFS', 'Disease', (144, 147))	('EGFR', 'Gene', '1956', (70, 74))	('orbital exenteration', 'Disease', (119, 139))	('EGFR', 'Gene', (70, 74))	('mutations', 'Var', (75, 84))
158459	32833992	EGFR mutations were not significantly correlated with final orbital exenteration or PFS (Tables 4 and 5).	('PFS', 'Disease', (84, 87))	('EGFR', 'Gene', '1956', (0, 4))	('EGFR', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))
158460	32833992	Examination of these cases suggested that mutation-positive cases also tended to have slightly advanced cancer, but no statistically significant difference was found.	('mutation-positive', 'Var', (42, 59))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))
158461	32833992	L264 Our study found that EGFR mutations were also found in the conjunctival Scc, but we could not obtain the results that would correlate with the final prognosis.	('EGFR', 'Gene', (26, 30))	('mutations', 'Var', (31, 40))	('Scc', 'Gene', (77, 80))	('Scc', 'Gene', '6317', (77, 80))	('EGFR', 'Gene', '1956', (26, 30))	('found', 'Reg', (51, 56))
158462	32833992	Certainly, double testing of formalin-fixed paraffin-embedded tissue and plasma with real-time PCR for detection of EGFR mutations is more common than IHC in the actual clinical setting.	('mutations', 'Var', (121, 130))	('formalin', 'Chemical', 'MESH:D005557', (29, 37))	('paraffin', 'Chemical', 'MESH:D010232', (44, 52))	('EGFR', 'Gene', '1956', (116, 120))	('EGFR', 'Gene', (116, 120))
158463	32833992	Kane S, Wu J, Benedettini E, Li D, Reeves C, Innocenti G, Wetzel R, Crosby K, Becker A, Ferrante M, Cheung WC, Hong X, Chirieac LR, Sholl LM, Haack H, Smith BL, Polakiewicz RD, Tan Y, Gu TL, Loda M, Zhou X, Comb MJ.. Mutation-specific antibodies for the detection of EGFR mutations in non -small-cell lung cancer.	('mutations', 'Var', (272, 281))	('Comb MJ', 'Disease', (207, 214))	('Comb MJ', 'Disease', 'MESH:D009207', (207, 214))	('cancer', 'Phenotype', 'HP:0002664', (306, 312))	('lung cancer', 'Disease', 'MESH:D008175', (301, 312))	('EGFR', 'Gene', '1956', (267, 271))	('lung cancer', 'Disease', (301, 312))	('lung cancer', 'Phenotype', 'HP:0100526', (301, 312))	('EGFR', 'Gene', (267, 271))
158472	32833992	L173 The relationship between EGFR mutation and EGFR stating (focal or diffuse) was determined using univariate linear regression analysis with making corrections based on age(p=0.559) 2.	('EGFR', 'Gene', '1956', (48, 52))	('EGFR', 'Gene', (30, 34))	('EGFR', 'Gene', (48, 52))	('mutation', 'Var', (35, 43))	('EGFR', 'Gene', '1956', (30, 34))
158474	32833992	L180 The Cox regression model was used to examine and analyze the relationship between long-term prognosis including orbital exenteration and PFS and the clinicopathological status, EGFR staining pattern, and EGFR mutation.	('PFS', 'Disease', (142, 145))	('mutation', 'Var', (214, 222))	('EGFR', 'Gene', (209, 213))	('EGFR', 'Gene', '1956', (182, 186))	('EGFR', 'Gene', (182, 186))	('orbital exenteration', 'Disease', (117, 137))	('EGFR', 'Gene', '1956', (209, 213))
158475	32833992	L187 The EGFR mutation was not significantly correlated with final orbital exenteration or PFS (Tables 4 and 5).	('EGFR', 'Gene', '1956', (9, 13))	('L187', 'Var', (0, 4))	('EGFR', 'Gene', (9, 13))	('PFS', 'Disease', (91, 94))
158477	32833992	L156- No significant difference was found between carcinoma in situ (Tis) and invasive carcinoma (Tadv) (Table 2).	('carcinoma', 'Disease', (87, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (50, 59))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))	('invasive carcinoma', 'Disease', 'MESH:D009361', (78, 96))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (50, 67))	('carcinoma', 'Disease', (50, 59))	('carcinoma', 'Disease', 'MESH:D009369', (87, 96))	('L156-', 'Chemical', '-', (0, 5))	('invasive carcinoma', 'Disease', (78, 96))	('L156-', 'Var', (0, 5))	('carcinoma', 'Disease', 'MESH:D009369', (50, 59))
158482	32833992	L170 The mutation at exon 19, EGFR E7446-A750 del, was confirmed in 8/29 (27.5%) cases, and that at exon 21, EGFR L858R point mutation, was confirmed in 2/29 (6.8%) cases with IHC (Table 3).	('E7446-A750 del', 'Mutation', 'p.7446,750delA', (35, 49))	('EGFR', 'Gene', (30, 34))	('IHC', 'Disease', (176, 179))	('EGFR', 'Gene', '1956', (109, 113))	('EGFR', 'Gene', (109, 113))	('EGFR', 'Gene', '1956', (30, 34))	('L858R', 'Mutation', 'rs121434568', (114, 119))	('E7446-A750 del', 'Var', (35, 49))
158483	32833992	L180 COX regression model was used to examine and analysis among clinicopathological status, EGFR staining pattern, and EGFR mutation for long-term prognosis.	('EGFR', 'Gene', '1956', (93, 97))	('EGFR', 'Gene', (93, 97))	('EGFR', 'Gene', '1956', (120, 124))	('mutation', 'Var', (125, 133))	('EGFR', 'Gene', (120, 124))
158484	32833992	L187 In addition, the EGFR mutation was not significantly correlation with final orbital exenteration and PFS(Table 5).	('EGFR', 'Gene', (22, 26))	('L187', 'Var', (0, 4))	('mutation', 'Var', (27, 35))	('EGFR', 'Gene', '1956', (22, 26))	('PFS', 'Disease', (106, 109))
158491	32833992	The EGFR mutation was not significantly correlated with final orbital exenteration or PFS (Tables 4 and 5).	('EGFR', 'Gene', (4, 8))	('mutation', 'Var', (9, 17))	('PFS', 'Disease', (86, 89))	('EGFR', 'Gene', '1956', (4, 8))
158492	32833992	15 Jul 2020  PONE-D-20-09283R1 Expression, intracellular localization, and mutation of EGFR in conjunctival squamous cell carcinoma and the association with prognosis and treatment PLOS ONE Dear Dr.Tagami, Thank you for submitting your manuscript to PLOS ONE.	('conjunctival squamous cell carcinoma', 'Disease', (95, 131))	('EGFR', 'Gene', '1956', (87, 91))	('conjunctival squamous cell carcinoma', 'Disease', 'MESH:D002294', (95, 131))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (108, 131))	('mutation', 'Var', (75, 83))	('men', 'Species', '9606', (176, 179))	('EGFR', 'Gene', (87, 91))	('PONE-D-20-09283', 'Chemical', '-', (13, 28))	('Tagami', 'Chemical', '-', (198, 204))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))
158499	32833992	Line 188 - In addition, the EGFR 188 mutation was not significantly correlation with final orbital exenteration and PFS(Table 4 and 5).	('PFS', 'Disease', (116, 119))	('EGFR', 'Gene', (28, 32))	('EGFR', 'Gene', '1956', (28, 32))	('mutation', 'Var', (37, 45))
158511	32833992	Summary of EGFR E746-A750 del and EGFR L858R point mutations  Mutation N = 29 (%) Age (y) Sex (M/F) T stage EGFR staining patterns (diffuse/focal) EGFR localization score (membrane/cytoplasmic) Exon 19 EGFR E746-A750 del (N=8) 8/29 (27.5%) 75.8 3/5 T3: 4 T2: 2 Tis: 2 2/6 1.6/1.5 Exon 21 EGFR L858R point mutation (N=3) 2/29 (6.8%) 73.0 1/1 T3: 1 Tis: 1 1/2 1/3 M: Male, F: Female 6.	('EGFR', 'Gene', (202, 206))	('E746-A750 del', 'Var', (207, 220))	('EGFR', 'Gene', (147, 151))	('L858R', 'Mutation', 'rs121434568', (39, 44))	('EGFR', 'Gene', (34, 38))	('E746-A750 del', 'Mutation', 'p.746,750delA', (16, 29))	('EGFR', 'Gene', '1956', (108, 112))	('EGFR', 'Gene', '1956', (11, 15))	('EGFR', 'Gene', (108, 112))	('EGFR', 'Gene', (11, 15))	('E746-A750 del', 'Var', (16, 29))	('EGFR', 'Gene', '1956', (147, 151))	('EGFR', 'Gene', '1956', (288, 292))	('E746-A750 del', 'Mutation', 'p.746,750delA', (207, 220))	('EGFR', 'Gene', '1956', (202, 206))	('EGFR', 'Gene', (288, 292))	('EGFR', 'Gene', '1956', (34, 38))	('L858R', 'Mutation', 'rs121434568', (293, 298))
158518	32833992	11 Aug 2020  Expression, intracellular localization, and mutation of EGFR in conjunctival squamous cell carcinoma and the association with prognosis and treatment PONE-D-20-09283R2 Dear Dr. Tagami, We're pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.	('mutation', 'Var', (57, 65))	('EGFR', 'Gene', '1956', (69, 73))	('PONE-D-20-09283', 'Chemical', '-', (163, 178))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (90, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('conjunctival squamous cell carcinoma', 'Disease', 'MESH:D002294', (77, 113))	('EGFR', 'Gene', (69, 73))	('men', 'Species', '9606', (396, 399))	('Tagami', 'Chemical', '-', (190, 196))	('men', 'Species', '9606', (158, 161))	('conjunctival squamous cell carcinoma', 'Disease', (77, 113))
158523	32833992	13 Aug 2020  PONE-D-20-09283R2   Expression, intracellular localization, and mutation of EGFR in conjunctival squamous cell carcinoma and the association with prognosis and treatment  Dear Dr. Tagami: I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE.	('conjunctival squamous cell carcinoma', 'Disease', 'MESH:D002294', (97, 133))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (110, 133))	('EGFR', 'Gene', (89, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('mutation', 'Var', (77, 85))	('PONE-D-20-09283', 'Chemical', '-', (13, 28))	('Tagami', 'Chemical', '-', (193, 199))	('conjunctival squamous cell carcinoma', 'Disease', (97, 133))	('EGFR', 'Gene', '1956', (89, 93))	('men', 'Species', '9606', (178, 181))
158592	31548347	Role of KEAP1/NFE2L2 mutations in the chemotherapeutic response of non-small cell lung cancer patients Activation of NFE2L2 has been linked to chemoresistance in cell line models.	('KEAP1', 'Gene', (8, 13))	('cancer', 'Disease', (87, 93))	('lung cancer', 'Phenotype', 'HP:0100526', (82, 93))	('NFE2L2', 'Gene', '4780', (117, 123))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (71, 93))	('NFE2L2', 'Gene', '4780', (14, 20))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (67, 93))	('KEAP1', 'Gene', '9817', (8, 13))	('NFE2L2', 'Gene', (117, 123))	('chemoresistance', 'CPA', (143, 158))	('Activation', 'PosReg', (103, 113))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('NFE2L2', 'Gene', (14, 20))	('mutations', 'Var', (21, 30))
158593	31548347	Recently, somatic mutations which activate NFE2L2, including mutations in NFE2L2, KEAP1, or CUL3, have been found to be associated with poor outcomes in patients with non-small cell lung cancer (NSCLC).	('associated', 'Reg', (120, 130))	('NSCLC', 'Disease', 'MESH:D002289', (195, 200))	('activate', 'PosReg', (34, 42))	('NFE2L2', 'Gene', (43, 49))	('patients', 'Species', '9606', (153, 161))	('CUL3', 'Gene', (92, 96))	('CUL3', 'Gene', '8452', (92, 96))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (167, 193))	('lung cancer', 'Phenotype', 'HP:0100526', (182, 193))	('NFE2L2', 'Gene', (74, 80))	('mutations', 'Var', (61, 70))	('non-small cell lung cancer', 'Disease', (167, 193))	('NSCLC', 'Phenotype', 'HP:0030358', (195, 200))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (171, 193))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('NSCLC', 'Disease', (195, 200))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (167, 193))
158594	31548347	We investigated the effect of Keap1 deletion on chemoresistance in cell lines from Trp53-based mouse models of lung squamous cell carcinoma (LSCC) and lung adenocarcinoma (LUAD).	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (151, 170))	('LUAD', 'Phenotype', 'HP:0030078', (172, 176))	('deletion', 'Var', (36, 44))	('mouse', 'Species', '10090', (95, 100))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (111, 139))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (111, 139))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (116, 139))	('LSCC', 'Phenotype', 'HP:0030359', (141, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('lung adenocarcinoma', 'Disease', (151, 170))	('carcinoma', 'Phenotype', 'HP:0030731', (161, 170))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (151, 170))	('lung squamous cell carcinoma', 'Disease', (111, 139))	('Keap1', 'Gene', (30, 35))
158595	31548347	Separately, we identified 51 stage IV NSCLC patients with KEAP1, NFE2L2, or CUL3 mutations and a matched cohort of 52 wildtype patients.	('NSCLC', 'Disease', (38, 43))	('patients', 'Species', '9606', (44, 52))	('NSCLC', 'Disease', 'MESH:D002289', (38, 43))	('KEAP1', 'Gene', (58, 63))	('patients', 'Species', '9606', (127, 135))	('NSCLC', 'Phenotype', 'HP:0030358', (38, 43))	('mutations', 'Var', (81, 90))	('NFE2L2', 'Gene', (65, 71))	('CUL3', 'Gene', '8452', (76, 80))	('CUL3', 'Gene', (76, 80))
158597	31548347	Deletion of Keap1 in Trp53-null murine LUAD and LSCC resulted in increased clonogenic survival upon treatment with diverse cytotoxic chemotherapies.	('increased', 'PosReg', (65, 74))	('murine', 'Species', '10090', (32, 38))	('Trp53-null', 'Gene', (21, 31))	('Keap1', 'Gene', (12, 17))	('clonogenic survival', 'CPA', (75, 94))	('LSCC', 'Phenotype', 'HP:0030359', (48, 52))	('LUAD', 'Phenotype', 'HP:0030078', (39, 43))	('Deletion', 'Var', (0, 8))
158600	31548347	Keap1 deletion confers chemoresistance in murine lung cancer cells.	('Keap1', 'Gene', (0, 5))	('lung cancer', 'Disease', 'MESH:D008175', (49, 60))	('lung cancer', 'Disease', (49, 60))	('chemoresistance', 'CPA', (23, 38))	('deletion', 'Var', (6, 14))	('murine', 'Species', '10090', (42, 48))	('lung cancer', 'Phenotype', 'HP:0100526', (49, 60))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
158601	31548347	Patients with metastatic NSCLC with mutations in KEAP1, NFE2L2, or CUL3 have shorter time to treatment failure and overall survival after first line platinum doublet chemotherapy compared with matched controls.	('CUL3', 'Gene', '8452', (67, 71))	('CUL3', 'Gene', (67, 71))	('NSCLC', 'Disease', (25, 30))	('platinum', 'Chemical', 'MESH:D010984', (149, 157))	('mutations', 'Var', (36, 45))	('NSCLC', 'Disease', 'MESH:D002289', (25, 30))	('KEAP1', 'Gene', (49, 54))	('Patients', 'Species', '9606', (0, 8))	('time', 'MPA', (85, 89))	('NFE2L2', 'Gene', (56, 62))	('shorter', 'NegReg', (77, 84))	('NSCLC', 'Phenotype', 'HP:0030358', (25, 30))
158608	31548347	Recently, large-scale genomic analyses have revealed that genes in the KEAP1-NFE2L2 pathway are mutated in ~33% of lung squamous cell carcinoma and ~22% of lung adenocarcinoma.	('mutated', 'Var', (96, 103))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (156, 175))	('carcinoma', 'Phenotype', 'HP:0030731', (166, 175))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (115, 143))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (120, 143))	('lung adenocarcinoma', 'Disease', (156, 175))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (156, 175))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (115, 143))	('lung squamous cell carcinoma', 'Disease', (115, 143))
158609	31548347	Genetically engineered mouse model studies have indicated that KEAP1 deletion and NFE2L2 mutations confer a pro-survival phenotype and promote the development and aggressiveness of NSCLCs, suggesting a potential mechanism for selection of mutations in these genes during tumorigenesis.	('promote', 'PosReg', (135, 142))	('tumor', 'Phenotype', 'HP:0002664', (271, 276))	('tumor', 'Disease', 'MESH:D009369', (271, 276))	('aggressiveness', 'Phenotype', 'HP:0000718', (163, 177))	('KEAP1', 'Gene', (63, 68))	('tumor', 'Disease', (271, 276))	('NFE2L2', 'Gene', (82, 88))	('aggressiveness of NSCLCs', 'Disease', 'MESH:D001523', (163, 187))	('development', 'CPA', (147, 158))	('NSCLC', 'Phenotype', 'HP:0030358', (181, 186))	('pro-survival phenotype', 'CPA', (108, 130))	('mouse', 'Species', '10090', (23, 28))	('mutations', 'Var', (89, 98))	('deletion', 'Var', (69, 77))	('aggressiveness of NSCLCs', 'Disease', (163, 187))
158611	31548347	For example, prior work from our group demonstrated that Keap1 deletion in a Trp53-based mouse model of lung squamous cell carcinoma confers radioresistance by interfering with reactive oxygen species (ROS) generation and that early stage NSCLC patients with KEAP1 or NFE2L2 mutations are at high risk for local recurrence after radiotherapy.	('patients', 'Species', '9606', (245, 253))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (104, 132))	('NSCLC', 'Phenotype', 'HP:0030358', (239, 244))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (177, 200))	('deletion', 'Var', (63, 71))	('local recurrence', 'CPA', (306, 322))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (109, 132))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (104, 132))	('lung squamous cell carcinoma', 'Disease', (104, 132))	('radioresistance', 'CPA', (141, 156))	('NFE2L2', 'Gene', (268, 274))	('KEAP1', 'Gene', (259, 264))	('NSCLC', 'Disease', 'MESH:D002289', (239, 244))	('mutations', 'Var', (275, 284))	('ROS', 'Chemical', 'MESH:D017382', (202, 205))	('NSCLC', 'Disease', (239, 244))	('interfering', 'NegReg', (160, 171))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('Keap1', 'Gene', (57, 62))	('mouse', 'Species', '10090', (89, 94))
158613	31548347	However, these studies were limited to NSCLC patients with KRAS mutations or stratified NSCLC patients based on protein levels of NRF2 rather than KEAP1/NFE2L2 mutations.	('KRAS', 'Gene', '3845', (59, 63))	('NSCLC', 'Phenotype', 'HP:0030358', (39, 44))	('NSCLC', 'Disease', 'MESH:D002289', (39, 44))	('patients', 'Species', '9606', (94, 102))	('NSCLC', 'Phenotype', 'HP:0030358', (88, 93))	('NRF2', 'Gene', '4780', (130, 134))	('NSCLC', 'Disease', (88, 93))	('patients', 'Species', '9606', (45, 53))	('mutations', 'Var', (64, 73))	('NSCLC', 'Disease', (39, 44))	('NSCLC', 'Disease', 'MESH:D002289', (88, 93))	('NRF2', 'Gene', (130, 134))	('KRAS', 'Gene', (59, 63))
158614	31548347	We therefore set out to explore the impact of KEAP1/NFE2L2 mutations on chemoresistance and prognosis after chemotherapy in NSCLC regardless of KRAS mutational status.	('KRAS', 'Gene', '3845', (144, 148))	('NSCLC', 'Disease', (124, 129))	('KEAP1/NFE2L2', 'Gene', (46, 58))	('NSCLC', 'Disease', 'MESH:D002289', (124, 129))	('mutations', 'Var', (59, 68))	('KRAS', 'Gene', (144, 148))	('chemoresistance', 'CPA', (72, 87))	('NSCLC', 'Phenotype', 'HP:0030358', (124, 129))
158615	31548347	To this end, we employed NSCLC cells from Trp53-deletion based lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LSCC) mouse models without Kras mutations and found that Keap1 deletion confers resistance to diverse anticancer drugs including platinum reagents.	('resistance', 'MPA', (204, 214))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (63, 82))	('NSCLC', 'Disease', (25, 30))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (63, 82))	('NSCLC', 'Phenotype', 'HP:0030358', (25, 30))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (94, 122))	('Kras', 'Gene', (151, 155))	('cancer', 'Disease', (230, 236))	('LSCC', 'Phenotype', 'HP:0030359', (124, 128))	('deletion', 'Var', (187, 195))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('Kras', 'Gene', '16653', (151, 155))	('platinum', 'Chemical', 'MESH:D010984', (253, 261))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (94, 122))	('lung squamous cell carcinoma', 'Disease', (94, 122))	('Trp53-deletion', 'Gene', (42, 56))	('LUAD', 'Phenotype', 'HP:0030078', (84, 88))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (99, 122))	('mouse', 'Species', '10090', (130, 135))	('lung adenocarcinoma', 'Disease', (63, 82))	('Trp53-deletion', 'Var', (42, 56))	('NSCLC', 'Disease', 'MESH:D002289', (25, 30))	('cancer', 'Disease', 'MESH:D009369', (230, 236))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
158616	31548347	We further demonstrate that KEAP1/NFE2L2 mutations are predictive of worse response to platinum doublet chemotherapy.	('mutations', 'Var', (41, 50))	('KEAP1/NFE2L2', 'Gene', (28, 40))	('platinum', 'Chemical', 'MESH:D010984', (87, 95))
158630	31548347	We identified a total of 1021 NSCLC patients with STAMP results and found 178 patients with KEAP1, NFE2L2 or CUL3 mutations.	('KEAP1', 'Gene', (92, 97))	('CUL3', 'Gene', (109, 113))	('NSCLC', 'Disease', 'MESH:D002289', (30, 35))	('NFE2L2', 'Gene', (99, 105))	('patients', 'Species', '9606', (36, 44))	('mutations', 'Var', (114, 123))	('patients', 'Species', '9606', (78, 86))	('NSCLC', 'Phenotype', 'HP:0030358', (30, 35))	('NSCLC', 'Disease', (30, 35))	('CUL3', 'Gene', '8452', (109, 113))
158634	31548347	For the control cohort, 843 patients with available STAMP testing who were wildtype (WT) for KEAP1/NFE2L2/CUL3 mutations were abstracted.	('CUL3', 'Gene', (106, 110))	('mutations', 'Var', (111, 120))	('patients', 'Species', '9606', (28, 36))	('CUL3', 'Gene', '8452', (106, 110))
158645	31548347	Additionally, we found that deletion of Keap1 confers radioresistance in mouse NSCLC and that KEAP1/NFE2L2 mutations are predictive of local failure and recurrence of NSCLC after radiotherapy in human patients.	('NSCLC', 'Disease', (167, 172))	('patients', 'Species', '9606', (201, 209))	('NSCLC', 'Disease', 'MESH:D002289', (167, 172))	('human', 'Species', '9606', (195, 200))	('NSCLC', 'Disease', 'MESH:D002289', (79, 84))	('mutations', 'Var', (107, 116))	('radioresistance', 'CPA', (54, 69))	('NSCLC', 'Phenotype', 'HP:0030358', (167, 172))	('local failure', 'Disease', 'MESH:D006333', (135, 148))	('KEAP1/NFE2L2', 'Gene', (94, 106))	('NSCLC', 'Phenotype', 'HP:0030358', (79, 84))	('mouse', 'Species', '10090', (73, 78))	('deletion', 'Var', (28, 36))	('Keap1', 'Gene', (40, 45))	('NSCLC', 'Disease', (79, 84))	('local failure', 'Disease', (135, 148))
158648	31548347	To test this hypothesis, we treated cancer cells from Trp53-deletion based Keap1-WT (Keap1WT;Trp53-/-, "P-") and Keap1-deleted (Keap1-/-;Trp53-/-, "K/P-") LUADs with several anti-cancer drugs including cisplatin, carboplatin, paclitaxel, and etoposide.	('Trp53-deletion', 'Var', (54, 68))	('cisplatin', 'Chemical', 'MESH:D002945', (202, 211))	('carboplatin', 'Chemical', 'MESH:D016190', (213, 224))	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('LUAD', 'Phenotype', 'HP:0030078', (155, 159))	('cancer', 'Disease', (36, 42))	('etoposide', 'Chemical', 'MESH:D005047', (242, 251))	('Trp53-deletion', 'Gene', (54, 68))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('cancer', 'Disease', (179, 185))	('paclitaxel', 'Chemical', 'MESH:D017239', (226, 236))
158649	31548347	In in vitro tumorsphere assays, K/P-LUAD cells were significantly more resistant than P-LUAD cells to all drugs tested, suggesting that Keap1 deletion confers resistance to anticancer drugs (Fig.	('resistance', 'MPA', (159, 169))	('cancer', 'Disease', (177, 183))	('cancer', 'Disease', 'MESH:D009369', (177, 183))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('LUAD', 'Phenotype', 'HP:0030078', (36, 40))	('LUAD', 'Phenotype', 'HP:0030078', (88, 92))	('tumors', 'Disease', (12, 18))	('deletion', 'Var', (142, 150))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('tumors', 'Disease', 'MESH:D009369', (12, 18))	('Keap1', 'Gene', (136, 141))
158651	31548347	These data demonstrate that Keap1 deletion, which mimics KEAP1/NFE2L2 mutations found in human tumors, leads to in vitro chemoresistance in NSCLC models.	('human', 'Species', '9606', (89, 94))	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('NSCLC', 'Disease', 'MESH:D002289', (140, 145))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('leads to', 'Reg', (103, 111))	('NSCLC', 'Phenotype', 'HP:0030358', (140, 145))	('deletion', 'Var', (34, 42))	('KEAP1/NFE2L2', 'Gene', (57, 69))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('chemoresistance', 'CPA', (121, 136))	('tumors', 'Disease', (95, 101))	('NSCLC', 'Disease', (140, 145))
158652	31548347	Based on these preclinical data, we hypothesized that patients with KEAP1, NFE2L2, and CUL3 mutant metastatic NSCLC will have worse prognosis after first-line platinum doublet chemotherapy than their wild type counterparts.	('NFE2L2', 'Gene', (75, 81))	('KEAP1', 'Gene', (68, 73))	('patients', 'Species', '9606', (54, 62))	('NSCLC', 'Disease', (110, 115))	('NSCLC', 'Phenotype', 'HP:0030358', (110, 115))	('NSCLC', 'Disease', 'MESH:D002289', (110, 115))	('CUL3', 'Gene', '8452', (87, 91))	('CUL3', 'Gene', (87, 91))	('mutant', 'Var', (92, 98))	('platinum', 'Chemical', 'MESH:D010984', (159, 167))
158653	31548347	To test this hypothesis, we identified a cohort of 178 NSCLC patients with KEAP1/NFE2L2/CUL3 mutations on the Stanford Solid Tumor Actionable Mutation Panel.	('CUL3', 'Gene', '8452', (88, 92))	('CUL3', 'Gene', (88, 92))	('mutations', 'Var', (93, 102))	('NSCLC', 'Disease', (55, 60))	('patients', 'Species', '9606', (61, 69))	('NSCLC', 'Disease', 'MESH:D002289', (55, 60))	('Tumor', 'Phenotype', 'HP:0002664', (125, 130))	('NSCLC', 'Phenotype', 'HP:0030358', (55, 60))
158656	31548347	Of the 51 patients with KEAP1/NFE2L2/CUL3 mutations, 35 had somatic mutations in KEAP1, 12 patients in NFE2L2, and 4 patients in CUL3.	('CUL3', 'Gene', '8452', (129, 133))	('KEAP1', 'Gene', (81, 86))	('CUL3', 'Gene', '8452', (37, 41))	('CUL3', 'Gene', (129, 133))	('CUL3', 'Gene', (37, 41))	('patients', 'Species', '9606', (91, 99))	('patients', 'Species', '9606', (10, 18))	('mutations', 'Var', (68, 77))	('patients', 'Species', '9606', (117, 125))	('mutations', 'Var', (42, 51))
158662	31548347	Similarly, the most common mutations in the control group were found in TP53 (N=29 (55%)), KRAS (N=14 (26%)) and EGFR (N=8 (15%)).	('mutations', 'Var', (27, 36))	('TP53', 'Gene', '7157', (72, 76))	('TP53', 'Gene', (72, 76))	('EGFR', 'Gene', '1956', (113, 117))	('EGFR', 'Gene', (113, 117))	('KRAS', 'Gene', (91, 95))	('KRAS', 'Gene', '3845', (91, 95))
158665	31548347	MET (8% vs 0%, unadjusted p = 0.01) and NRAS (6% vs 0%, unadjusted p = 0.03) mutations were slightly more common in the control group and APC mutations were more common in the KEAP1/NFE2L2/CUL3 cohort (8% vs 0%, unadjusted p = 0.01), although these differences were not significant upon multi-hypothesis testing correction.	('mutations', 'Var', (142, 151))	('NRAS', 'Gene', (40, 44))	('MET', 'Gene', (0, 3))	('APC', 'Gene', (138, 141))	('NRAS', 'Gene', '4893', (40, 44))	('mutations', 'Var', (77, 86))	('CUL3', 'Gene', (189, 193))	('APC', 'Gene', '324', (138, 141))	('CUL3', 'Gene', '8452', (189, 193))
158667	31548347	Next, we compared treatment outcomes in patients with or without KEAP1, NFE2L2, or CUL3 mutations.	('patients', 'Species', '9606', (40, 48))	('KEAP1', 'Gene', (65, 70))	('mutations', 'Var', (88, 97))	('CUL3', 'Gene', '8452', (83, 87))	('CUL3', 'Gene', (83, 87))	('NFE2L2', 'Gene', (72, 78))
158672	31548347	In KRAS wild type patients, KEAP1/NFE2L2/CUL3 mutations were associated with shorter time on treatment (2.6 vs 8.5 months, p = 0.0001) and shorter OS (11.2 vs 38.1 months, p = 0.0039) compared with KEAP1/NFE2L2/CUL3 wildtype patients, suggesting that the association between KEAP1/NFE2L2/CUL3 mutations and worse prognosis is not limited to patients with KRAS mutations (Fig.	('CUL3', 'Gene', (211, 215))	('CUL3', 'Gene', '8452', (288, 292))	('patients', 'Species', '9606', (341, 349))	('KRAS', 'Gene', (355, 359))	('mutations', 'Var', (46, 55))	('CUL3', 'Gene', (288, 292))	('KRAS', 'Gene', '3845', (3, 7))	('patients', 'Species', '9606', (225, 233))	('CUL3', 'Gene', '8452', (41, 45))	('KRAS', 'Gene', '3845', (355, 359))	('CUL3', 'Gene', (41, 45))	('patients', 'Species', '9606', (18, 26))	('shorter', 'NegReg', (77, 84))	('KRAS', 'Gene', (3, 7))	('CUL3', 'Gene', '8452', (211, 215))
158673	31548347	In addition, as patients with Epidermal Growth Factor Receptor (EGFR) mutations on average have superior outcomes compared to EGFR wildtype patients, we additionally performed a subset analysis in which EGFR-mutant patients were removed from both cohorts (5 from the KEAP1/NFE2L2/CUL3 mutant cohort and 8 from the KEAP1/NFE2L2/CUL3 wildtype cohort).	('patients', 'Species', '9606', (215, 223))	('EGFR', 'Gene', '1956', (203, 207))	('mutations', 'Var', (70, 79))	('EGFR', 'Gene', (126, 130))	('EGFR', 'Gene', (203, 207))	('patients', 'Species', '9606', (16, 24))	('patients', 'Species', '9606', (140, 148))	('EGFR', 'Gene', '1956', (64, 68))	('CUL3', 'Gene', (280, 284))	('EGFR', 'Gene', (64, 68))	('Epidermal Growth Factor Receptor', 'Gene', (30, 62))	('CUL3', 'Gene', '8452', (280, 284))	('CUL3', 'Gene', '8452', (327, 331))	('Epidermal Growth Factor Receptor', 'Gene', '1956', (30, 62))	('CUL3', 'Gene', (327, 331))	('EGFR', 'Gene', '1956', (126, 130))
158674	31548347	TTF remained shorter in KEAP1/NFE2L2/CUL3 mutant patients compared with KEAP1/NFE2L2/CUL3 wildtype patients (2.7 vs 8.2 months, p=0.0003).	('shorter', 'NegReg', (13, 20))	('TTF', 'MPA', (0, 3))	('CUL3', 'Gene', '8452', (37, 41))	('mutant', 'Var', (42, 48))	('CUL3', 'Gene', (37, 41))	('CUL3', 'Gene', '8452', (85, 89))	('CUL3', 'Gene', (85, 89))	('patients', 'Species', '9606', (99, 107))	('patients', 'Species', '9606', (49, 57))
158675	31548347	Similarly, KEAP1/NFE2L2/CUL3 mutant patients continued to display shorter OS than KEAP1/NFE2L2/CUL3 wildtype patients (10.1 months vs 34.1 months; p=0.02; Supplemental Fig.	('CUL3', 'Gene', '8452', (95, 99))	('patients', 'Species', '9606', (36, 44))	('patients', 'Species', '9606', (109, 117))	('shorter', 'NegReg', (66, 73))	('mutant', 'Var', (29, 35))	('CUL3', 'Gene', (95, 99))	('CUL3', 'Gene', '8452', (24, 28))	('CUL3', 'Gene', (24, 28))
158677	31548347	STK11 mutations were negatively associated with TTF on UVA (HR 2.36 95% CI 1.09 - 5.08, p = 0.03) but not significant in MVA with KEAP1/NFE2L2/CUL3 (HR 2.07 95% CI 0.48-0.89 p=0.09).	('negatively', 'NegReg', (21, 31))	('STK11', 'Gene', (0, 5))	('CUL3', 'Gene', '8452', (143, 147))	('CUL3', 'Gene', (143, 147))	('STK11', 'Gene', '6794', (0, 5))	('TTF', 'Disease', (48, 51))	('mutations', 'Var', (6, 15))
158678	31548347	KEAP1/NFE2L2/CUL3 mutations were significant predictors of TTF (HR 2.19, 95% CI 1.42-3.38, p=0.00036) and overall survival (HR 2.17, 95% CI 1.34-3.52, p=0.0016).	('CUL3', 'Gene', '8452', (13, 17))	('CUL3', 'Gene', (13, 17))	('TTF', 'Disease', (59, 62))	('overall survival', 'CPA', (106, 122))	('mutations', 'Var', (18, 27))
158679	31548347	Thus, KEAP1-NFE2L2 pathway mutations are strongly associated with poor outcomes to first-line chemotherapy in advanced NSCLC.	('mutations', 'Var', (27, 36))	('NSCLC', 'Disease', 'MESH:D002289', (119, 124))	('NSCLC', 'Phenotype', 'HP:0030358', (119, 124))	('associated', 'Reg', (50, 60))	('NSCLC', 'Disease', (119, 124))	('KEAP1-NFE2L2 pathway', 'Gene', (6, 26))
158680	31548347	In this study, we demonstrated that deletion of KEAP1 confers chemoresistance in preclinical models of LUAD and LSCC and that patients with metastatic NSCLC with KEAP1/NFE2L2/CUL3 mutations have significantly shorter time to treatment failure and overall survival when treated with front line platinum doublet chemotherapy.	('time to treatment failure', 'CPA', (217, 242))	('NSCLC', 'Disease', (151, 156))	('deletion', 'Var', (36, 44))	('LUAD', 'Phenotype', 'HP:0030078', (103, 107))	('overall survival', 'CPA', (247, 263))	('platinum', 'Chemical', 'MESH:D010984', (293, 301))	('LUAD', 'Disease', (103, 107))	('NSCLC', 'Disease', 'MESH:D002289', (151, 156))	('CUL3', 'Gene', '8452', (175, 179))	('LSCC', 'Phenotype', 'HP:0030359', (112, 116))	('CUL3', 'Gene', (175, 179))	('KEAP1', 'Gene', (48, 53))	('patients', 'Species', '9606', (126, 134))	('NSCLC', 'Phenotype', 'HP:0030358', (151, 156))	('chemoresistance', 'CPA', (62, 77))	('shorter', 'NegReg', (209, 216))
158681	31548347	Our prior work demonstrated that KEAP1 deletion also confers NSCLC resistance to ionizing radiation and that KEAP1 and NFE2L2 mutations are associated with worse prognosis after radiotherapy.	('KEAP1', 'Gene', (109, 114))	('NSCLC', 'Phenotype', 'HP:0030358', (61, 66))	('deletion', 'Var', (39, 47))	('NFE2L2', 'Gene', (119, 125))	('NSCLC', 'Disease', (61, 66))	('mutations', 'Var', (126, 135))	('KEAP1', 'Gene', (33, 38))	('NSCLC', 'Disease', 'MESH:D002289', (61, 66))
158682	31548347	Together our findings indicate that KEAP1/NFE2L2/CUL3 mutations induce resistance to conventional cancer therapies and could serve as a biomarker to predict therapeutic responses for both localized and metastatic NSCLC patients.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('NSCLC', 'Disease', 'MESH:D002289', (213, 218))	('mutations', 'Var', (54, 63))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('CUL3', 'Gene', '8452', (49, 53))	('CUL3', 'Gene', (49, 53))	('NSCLC', 'Phenotype', 'HP:0030358', (213, 218))	('cancer', 'Disease', (98, 104))	('patients', 'Species', '9606', (219, 227))	('resistance', 'CPA', (71, 81))	('NSCLC', 'Disease', (213, 218))
158683	31548347	Prior studies have mostly focused on immunohistochemical NFE2L2 and/or KEAP1, and some have shown association of expression with outcomes in early or advanced stage NSCLC patients.	('association', 'Interaction', (98, 109))	('NSCLC', 'Disease', 'MESH:D002289', (165, 170))	('patients', 'Species', '9606', (171, 179))	('NSCLC', 'Phenotype', 'HP:0030358', (165, 170))	('NFE2L2', 'Var', (57, 63))	('NSCLC', 'Disease', (165, 170))
158684	31548347	Given the rapid adoption of next generation sequencing-based tumor genotyping, our demonstration that mutations in KEAP1/NFE2L2/CUL3 are associated with worse outcomes after first line chemotherapy has immediate clinical relevance.	('associated', 'Reg', (137, 147))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('mutations', 'Var', (102, 111))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('CUL3', 'Gene', '8452', (128, 132))	('CUL3', 'Gene', (128, 132))	('tumor', 'Disease', (61, 66))
158685	31548347	In line with previous studies reporting the frequency of KEAP1/NFE2L2/CUL3 mutations in 15-30% of NSCLCs, we identified mutations in these genes in 178 out of 1021 patients (17%).	('NSCLCs', 'Disease', 'MESH:D002289', (98, 104))	('NSCLC', 'Phenotype', 'HP:0030358', (98, 103))	('CUL3', 'Gene', '8452', (70, 74))	('mutations', 'Var', (75, 84))	('mutations', 'Var', (120, 129))	('patients', 'Species', '9606', (164, 172))	('NSCLCs', 'Disease', (98, 104))	('CUL3', 'Gene', (70, 74))
158687	31548347	Our results are also consistent with a recent study reporting that KEAP1/NFE2L2 mutations are associated with worse outcomes after platinum doublet chemotherapy in NSCLC patients with KRAS mutations.	('patients', 'Species', '9606', (170, 178))	('NSCLC', 'Disease', (164, 169))	('platinum', 'Chemical', 'MESH:D010984', (131, 139))	('mutations', 'Var', (80, 89))	('KRAS', 'Gene', (184, 188))	('NSCLC', 'Disease', 'MESH:D002289', (164, 169))	('KRAS', 'Gene', '3845', (184, 188))	('NSCLC', 'Phenotype', 'HP:0030358', (164, 169))	('KEAP1/NFE2L2 mutations', 'Var', (67, 89))
158688	31548347	This study found that at a median follow up of 1.5 years, advanced NSCLC patients with mutations in KRAS and KEAP1/NFE2L2 had shorter overall survival and duration of platinum-based therapy than patients with only mutations in KRAS.	('KRAS', 'Gene', (100, 104))	('shorter', 'NegReg', (126, 133))	('KRAS', 'Gene', (227, 231))	('KRAS', 'Gene', '3845', (100, 104))	('KRAS', 'Gene', '3845', (227, 231))	('NSCLC', 'Phenotype', 'HP:0030358', (67, 72))	('KEAP1/NFE2L2', 'Gene', (109, 121))	('patients', 'Species', '9606', (195, 203))	('overall', 'MPA', (134, 141))	('NSCLC', 'Disease', (67, 72))	('platinum', 'Chemical', 'MESH:D010984', (167, 175))	('patients', 'Species', '9606', (73, 81))	('NSCLC', 'Disease', 'MESH:D002289', (67, 72))	('mutations', 'Var', (87, 96))
158690	31548347	Due to the small number of NSCLC patients with KRAS mutations in our cohort, we were not powered to detect differences in outcomes within the KRAS mutant cohort.	('mutations', 'Var', (52, 61))	('KRAS', 'Gene', (142, 146))	('patients', 'Species', '9606', (33, 41))	('NSCLC', 'Disease', (27, 32))	('KRAS', 'Gene', '3845', (142, 146))	('NSCLC', 'Disease', 'MESH:D002289', (27, 32))	('NSCLC', 'Phenotype', 'HP:0030358', (27, 32))	('KRAS', 'Gene', (47, 51))	('KRAS', 'Gene', '3845', (47, 51))
158695	31548347	Furthermore, there were not enough patients in our cohort who received immunotherapy to explore the potential effect of KEAP1, NFE2L2 and CUL3 mutations on treatment with such agents, which is a significant limitation given that chemo-immunotherapy combinations are now standard of care for front line treatment of advanced NSCLC.	('NSCLC', 'Phenotype', 'HP:0030358', (324, 329))	('KEAP1', 'Gene', (120, 125))	('NSCLC', 'Disease', (324, 329))	('NSCLC', 'Disease', 'MESH:D002289', (324, 329))	('NFE2L2', 'Gene', (127, 133))	('CUL3', 'Gene', '8452', (138, 142))	('patients', 'Species', '9606', (35, 43))	('CUL3', 'Gene', (138, 142))	('mutations', 'Var', (143, 152))
158696	31548347	However, prior work on KRAS and KEAP1/NFE2L2 mutated adenocarcinoma showed shorter progression free survival after frontline immunotherapy.	('adenocarcinoma', 'Disease', (53, 67))	('adenocarcinoma', 'Disease', 'MESH:D000230', (53, 67))	('KRAS', 'Gene', (23, 27))	('shorter', 'NegReg', (75, 82))	('KRAS', 'Gene', '3845', (23, 27))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))	('mutated', 'Var', (45, 52))	('progression free', 'MPA', (83, 99))
158697	31548347	Additionally, due to their low frequency of occurrence, we had insufficient power to test if NFE2L2 or CUL3 mutations are individually associated with outcome.	('mutations', 'Var', (108, 117))	('associated', 'Reg', (135, 145))	('CUL3', 'Gene', '8452', (103, 107))	('CUL3', 'Gene', (103, 107))	('NFE2L2', 'Gene', (93, 99))
158698	31548347	In conclusion, we show that Keap1 deletion results in chemoresistance in isogenic mouse models of LUAD and LSCC and that patients with mutations in the KEAP1-NEF2L2 pathway have significantly worse outcomes after front line platinum-based chemotherapy.	('KEAP1-NEF2L2 pathway', 'Pathway', (152, 172))	('worse', 'NegReg', (192, 197))	('mouse', 'Species', '10090', (82, 87))	('Keap1', 'Gene', (28, 33))	('chemoresistance', 'CPA', (54, 69))	('mutations', 'Var', (135, 144))	('deletion', 'Var', (34, 42))	('LSCC', 'Phenotype', 'HP:0030359', (107, 111))	('LUAD', 'Phenotype', 'HP:0030078', (98, 102))	('platinum', 'Chemical', 'MESH:D010984', (224, 232))	('patients', 'Species', '9606', (121, 129))	('LUAD', 'Disease', (98, 102))
158699	31548347	Our findings add to the growing body of evidence that these mutations identify a particularly resistant subtype of NSCLC and have potential clinical implications.	('mutations', 'Var', (60, 69))	('NSCLC', 'Disease', (115, 120))	('NSCLC', 'Disease', 'MESH:D002289', (115, 120))	('NSCLC', 'Phenotype', 'HP:0030358', (115, 120))
158700	31548347	Future work should endeavor to understand if patients with KEAP1/NFE2L2/CUL3 mutations could benefit from more aggressive up-front therapy.	('CUL3', 'Gene', (72, 76))	('mutations', 'Var', (77, 86))	('patients', 'Species', '9606', (45, 53))	('CUL3', 'Gene', '8452', (72, 76))
158701	31548347	Additionally, our work supports the importance of developing novel strategies to overcome treatment resistance conferred by KEAP1/NFE2L2/CUL3 mutations.	('CUL3', 'Gene', (137, 141))	('mutations', 'Var', (142, 151))	('CUL3', 'Gene', '8452', (137, 141))
158703	31548347	The KEAP1-NFE2L2 pathway plays an important role in management of reactive oxygen species and mutations in this pathway lead to tumor aggressiveness and enhanced tumor survival.	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('mutations', 'Var', (94, 103))	('lead to', 'Reg', (120, 127))	('tumor', 'Disease', (162, 167))	('tumor aggressiveness', 'Disease', (128, 148))	('aggressiveness', 'Phenotype', 'HP:0000718', (134, 148))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (66, 89))	('tumor', 'Disease', (128, 133))	('enhanced', 'PosReg', (153, 161))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (128, 148))	('tumor', 'Disease', 'MESH:D009369', (162, 167))
158704	31548347	To do this we first exposed lung cancer cells from murine lung cancer models with Keap1 deletion to cytotoxic chemotherapies and showed that this led to increased clonogenic survival.	('lung cancer', 'Disease', 'MESH:D008175', (28, 39))	('deletion', 'Var', (88, 96))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('lung cancer', 'Disease', (58, 69))	('increased', 'PosReg', (153, 162))	('clonogenic survival', 'CPA', (163, 182))	('lung cancer', 'Phenotype', 'HP:0100526', (58, 69))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('lung cancer', 'Disease', (28, 39))	('lung cancer', 'Phenotype', 'HP:0100526', (28, 39))	('murine', 'Species', '10090', (51, 57))	('Keap1', 'Gene', (82, 87))	('lung cancer', 'Disease', 'MESH:D008175', (58, 69))
158705	31548347	We then retrospectively evaluated patients with mutations in KEAP1-NFE2L2 pathway that received upfront chemotherapy and compared their outcomes to patients without mutations.	('KEAP1-NFE2L2', 'Gene', (61, 73))	('patients', 'Species', '9606', (148, 156))	('patients', 'Species', '9606', (34, 42))	('mutations', 'Var', (48, 57))
158706	31548347	We found that patients with mutations in the KEAP1-NFE2L2 pathway have inferior time on therapy and overall survival suggesting that these mutations confer chemoresistance.	('KEAP1-NFE2L2 pathway', 'Gene', (45, 65))	('mutations', 'Var', (139, 148))	('inferior', 'NegReg', (71, 79))	('chemoresistance', 'CPA', (156, 171))	('patients', 'Species', '9606', (14, 22))	('mutations', 'Var', (28, 37))	('time on therapy', 'CPA', (80, 95))
158719	29896280	The great example is deimination of histone arginines which can lead to the creation neoantigens trigger for autoimmunity.	('deimination', 'Var', (21, 32))	('autoimmunity', 'Phenotype', 'HP:0002960', (109, 121))	('lead to', 'Reg', (64, 71))	('arginines', 'Chemical', 'MESH:D001120', (44, 53))	('autoimmunity', 'Disease', (109, 121))	('neoantigens', 'MPA', (85, 96))	('autoimmunity', 'Disease', 'MESH:D001327', (109, 121))
158746	29896280	Neutrophils were incubated in the presence of rhIL-17 at a concentration of 50 ng/mL (Bender MedSystem) or LPS - 10 mug/mL (Sigma-Aldrich, Merck).	('IL-17', 'Gene', (48, 53))	('IL-17', 'Gene', '3605', (48, 53))	('LPS', 'Chemical', 'MESH:D008070', (107, 110))	('LPS - 10 mug/mL', 'Var', (107, 122))
158813	26134262	Predictive biomarkers in precision medicine and drug development against lung cancer The molecular characterization of various cancers has shown that cancers with the same origins, histopathologic diagnoses, and clinical stages can be highly heterogeneous in their genetic and epigenetic alterations that cause tumorigenesis.	('lung cancer', 'Disease', 'MESH:D008175', (73, 84))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('cancers', 'Phenotype', 'HP:0002664', (150, 157))	('cancers', 'Disease', (150, 157))	('epigenetic alterations', 'Var', (277, 299))	('cancers', 'Disease', 'MESH:D009369', (150, 157))	('tumor', 'Disease', 'MESH:D009369', (311, 316))	('cancers', 'Disease', 'MESH:D009369', (127, 134))	('cancers', 'Phenotype', 'HP:0002664', (127, 134))	('tumor', 'Phenotype', 'HP:0002664', (311, 316))	('lung cancer', 'Disease', (73, 84))	('cancers', 'Disease', (127, 134))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('tumor', 'Disease', (311, 316))	('rat', 'Species', '10116', (292, 295))	('lung cancer', 'Phenotype', 'HP:0100526', (73, 84))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
158840	26134262	It is now clear that mutations in cancer driver genes and alterations in gene expression and/or posttranscriptional modifications can all drastically affect treatment responses or clinical outcomes.	('treatment responses', 'CPA', (157, 176))	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('rat', 'Species', '10116', (62, 65))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('cancer', 'Disease', (34, 40))	('affect', 'Reg', (150, 156))	('alterations', 'Reg', (58, 69))	('clinical outcomes', 'CPA', (180, 197))	('mutations', 'Var', (21, 30))
158841	26134262	Moreover, the success of targeted anticancer therapy largely depends on biomarkers that can identify patient subgroups that may respond to specific therapeutic agents because alterations in a particular cancer driver usually exist in only a small subset of patients.	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('patient', 'Species', '9606', (257, 264))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('cancer', 'Disease', (203, 209))	('cancer', 'Disease', 'MESH:D009369', (203, 209))	('patients', 'Species', '9606', (257, 265))	('cancer', 'Disease', (38, 44))	('rat', 'Species', '10116', (179, 182))	('patient', 'Species', '9606', (101, 108))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('alterations', 'Var', (175, 186))
158843	26134262	Genome-wide gene sequencing analyses have found that each lung cancer may have an average of approximately 150 somatic mutations that are expected to alter their protein products; this number is much higher than the average of 30-60 mutations observed in other solid tumors.	('alter', 'Reg', (150, 155))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('solid tumors', 'Disease', (261, 273))	('lung cancer', 'Disease', (58, 69))	('protein products', 'MPA', (162, 178))	('lung cancer', 'Phenotype', 'HP:0100526', (58, 69))	('tumor', 'Phenotype', 'HP:0002664', (267, 272))	('tumors', 'Phenotype', 'HP:0002664', (267, 273))	('mutations', 'Var', (119, 128))	('solid tumors', 'Disease', 'MESH:D009369', (261, 273))	('lung cancer', 'Disease', 'MESH:D008175', (58, 69))
158845	26134262	Indeed, the total number of point mutations in coding regions identified in lung cancer is approximately 10 times higher in smokers than in non-smokers.	('lung cancer', 'Disease', 'MESH:D008175', (76, 87))	('lung cancer', 'Disease', (76, 87))	('lung cancer', 'Phenotype', 'HP:0100526', (76, 87))	('point mutations', 'Var', (28, 43))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('higher', 'PosReg', (114, 120))
158850	26134262	Figure 1 shows the frequencies of cancer driver genes that are frequently mutated (including copy number changes) in lung adenocarcinoma, squamous cell cancer, and SCLC.	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (117, 136))	('SCLC', 'Gene', '7864', (164, 168))	('SCLC', 'Gene', (164, 168))	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (138, 158))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('squamous cell cancer', 'Disease', 'MESH:D002294', (138, 158))	('cancer', 'Disease', (34, 40))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (117, 136))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('copy', 'Var', (93, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('lung adenocarcinoma', 'Disease', (117, 136))	('squamous cell cancer', 'Disease', (138, 158))
158853	26134262	Phosphatidylinositol-4,5-biphosphate 3-kinase, catalytic subunit alpha (PIK3CA), sex-determining region Y-related gene family 2 (SOX2), CDKN2A, TP63, fibroblast growth factor receptor 1(FGFR1), and MLL2 are the top mutant genes in squamous cell cancer; retinoblastoma 1 (RB1), E1A-binding protein p300 (EP300), MLL2, smoothened (SMO), and PIK3CA are the top mutant genes in SCLC.	('PIK3CA', 'Gene', (339, 345))	('squamous cell cancer', 'Disease', (231, 251))	('RB1', 'Gene', '5925', (271, 274))	('fibroblast growth factor receptor 1', 'Gene', (150, 185))	('SOX2', 'Gene', '6657', (129, 133))	('SOX2', 'Gene', (129, 133))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (231, 251))	('retinoblastoma', 'Disease', (253, 267))	('MLL2', 'Gene', (311, 315))	('SMO', 'Gene', '6608', (329, 332))	('TP63', 'Gene', (144, 148))	('PIK3CA', 'Gene', '5290', (72, 78))	('FGFR1', 'Gene', '2260', (186, 191))	('squamous cell cancer', 'Disease', 'MESH:D002294', (231, 251))	('MLL2', 'Gene', (198, 202))	('TP63', 'Gene', '8626', (144, 148))	('smoothened', 'Gene', (317, 327))	('mutant', 'Var', (215, 221))	('SMO', 'Gene', (329, 332))	('E1A-binding protein p300', 'Gene', '2033', (277, 301))	('PIK3CA', 'Gene', (72, 78))	('PIK3CA', 'Gene', '5290', (339, 345))	('retinoblastoma', 'Disease', 'MESH:D012175', (253, 267))	('smoothened', 'Gene', '6608', (317, 327))	('cancer', 'Phenotype', 'HP:0002664', (245, 251))	('RB1', 'Gene', (271, 274))	('FGFR1', 'Gene', (186, 191))	('E1A-binding protein p300', 'Gene', (277, 301))	('MLL2', 'Gene', '9757', (311, 315))	('fibroblast growth factor receptor 1', 'Gene', '2260', (150, 185))	('SCLC', 'Gene', '7864', (374, 378))	('retinoblastoma', 'Phenotype', 'HP:0009919', (253, 267))	('SCLC', 'Gene', (374, 378))	('MLL2', 'Gene', '9757', (198, 202))
158854	26134262	Our recent sequencing analysis of the exomes of 200 cancer-related genes found that mutations in TP53, KRAS, MLL3, SET domain-containing 2 (SETD2), AT rich interactive domain 1A (ARID1A), PIK3CA, and ALK were frequently detected in primary tumors and corresponding patient-derived xenografts of NSCLC.	('PIK3CA', 'Gene', (188, 194))	('SETD2', 'Gene', '29072', (140, 145))	('TP53', 'Gene', '7157', (97, 101))	('AT rich interactive domain 1A', 'Gene', '8289', (148, 177))	('ARID1A', 'Gene', (179, 185))	('primary tumors', 'Disease', (232, 246))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('AT rich interactive domain 1A', 'Gene', (148, 177))	('MLL3', 'Gene', (109, 113))	('ARID1A', 'Gene', '8289', (179, 185))	('SET domain-containing 2', 'Gene', '29072', (115, 138))	('primary tumors', 'Disease', 'MESH:D009369', (232, 246))	('mutations', 'Var', (84, 93))	('TP53', 'Gene', (97, 101))	('ALK', 'Gene', '238', (200, 203))	('PIK3CA', 'Gene', '5290', (188, 194))	('cancer', 'Disease', (52, 58))	('SET domain-containing 2', 'Gene', (115, 138))	('ALK', 'Gene', (200, 203))	('tumor', 'Phenotype', 'HP:0002664', (240, 245))	('KRAS', 'Gene', (103, 107))	('NSCLC', 'Disease', 'MESH:D002289', (295, 300))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('tumors', 'Phenotype', 'HP:0002664', (240, 246))	('SETD2', 'Gene', (140, 145))	('MLL3', 'Gene', '58508', (109, 113))	('patient', 'Species', '9606', (265, 272))	('NSCLC', 'Disease', (295, 300))	('detected', 'Reg', (220, 228))
158855	26134262	Most of the mutations (93%) detected in the primary tumors were also detected in their corresponding patient-derived xenografts.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('detected', 'Reg', (69, 77))	('primary tumors', 'Disease', 'MESH:D009369', (44, 58))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('mutations', 'Var', (12, 21))	('patient', 'Species', '9606', (101, 108))	('primary tumors', 'Disease', (44, 58))
158856	26134262	Nevertheless, the numbers of mutations detected in each primary tumor varied greatly, and most tumors had mutations in more than two genes.	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('tumor', 'Disease', (64, 69))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('mutations', 'Var', (106, 115))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumors', 'Disease', (95, 101))	('tumor', 'Disease', (95, 100))
158859	26134262	Moreover, mutations in those genes, particularly for tumor suppressor genes such as TP53 (Figure 2b), are often widely distributed in the entire coding region.	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('TP53', 'Gene', '7157', (84, 88))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Disease', (53, 58))	('TP53', 'Gene', (84, 88))	('mutations', 'Var', (10, 19))
158860	26134262	Evidence has shown that mutations in TP53 can lead to either loss or gain of functions, and both may promote tumorigenesis through different mechanisms.	('promote', 'PosReg', (101, 108))	('TP53', 'Gene', (37, 41))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('gain of functions', 'PosReg', (69, 86))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('TP53', 'Gene', '7157', (37, 41))	('loss', 'NegReg', (61, 65))	('mutations', 'Var', (24, 33))	('tumor', 'Disease', (109, 114))
158861	26134262	Similarly, different mutations in KRAS, even if in the same codon such as G12C, G12V, and G12D mutations in the KRAS gene, may lead to different conformational changes in KRAS and have different effects on clinical outcomes and molecular pathway activation.	('G12V', 'Var', (80, 84))	('effects', 'Reg', (195, 202))	('G12D', 'Var', (90, 94))	('G12V', 'Mutation', 'rs121913529', (80, 84))	('G12D', 'Mutation', 'rs121913529', (90, 94))	('activation', 'PosReg', (246, 256))	('lead to', 'Reg', (127, 134))	('G12C', 'Var', (74, 78))	('KRAS', 'Protein', (171, 175))	('G12C', 'Mutation', 'rs121913530', (74, 78))	('KRAS', 'Gene', (112, 116))	('conformational changes', 'MPA', (145, 167))	('molecular pathway', 'Pathway', (228, 245))	('KRAS', 'Gene', (34, 38))
158863	26134262	For example, activated EGFR mutations are detected in approximately 10-17% of lung adenocarcinoma patients in the United States and Europe but in approximately 30-65% of lung adenocarcinoma patients in Asia.	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (170, 189))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (78, 97))	('patients', 'Species', '9606', (190, 198))	('carcinoma', 'Phenotype', 'HP:0030731', (180, 189))	('patients', 'Species', '9606', (98, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('lung adenocarcinoma', 'Disease', (170, 189))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (170, 189))	('activated', 'PosReg', (13, 22))	('EGFR', 'Gene', (23, 27))	('mutations', 'Var', (28, 37))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (78, 97))	('lung adenocarcinoma', 'Disease', (78, 97))
158864	26134262	In contrast, KRAS mutations were detected in 35-50% of lung adenocarcinomas in Caucasian patients but in less than 5% of lung adenocarcinomas in Chinese patients.	('lung adenocarcinomas', 'Disease', (55, 75))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (55, 75))	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('lung adenocarcinomas', 'Disease', (121, 141))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (121, 141))	('patients', 'Species', '9606', (153, 161))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (55, 75))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (121, 141))	('detected', 'Reg', (33, 41))	('patients', 'Species', '9606', (89, 97))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (121, 140))	('KRAS', 'Gene', (13, 17))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (55, 74))	('mutations', 'Var', (18, 27))
158868	26134262	As noted above, activating EGFR mutations are detected in substantial numbers of lung cancer patients and are more commonly observed in women and non-smokers.	('lung cancer', 'Disease', (81, 92))	('EGFR', 'Gene', (27, 31))	('lung cancer', 'Phenotype', 'HP:0100526', (81, 92))	('patients', 'Species', '9606', (93, 101))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('women', 'Species', '9606', (136, 141))	('mutations', 'Var', (32, 41))	('lung cancer', 'Disease', 'MESH:D008175', (81, 92))	('activating', 'PosReg', (16, 26))
158869	26134262	The finding that EGFR mutations in primary lung cancer are associated with sensitivity to EGFR inhibitors gefitinib and erlotinib contributed greatly to the final approval of these therapeutics for the treatment of lung cancer.	('lung cancer', 'Disease', (215, 226))	('lung cancer', 'Disease', (43, 54))	('lung cancer', 'Phenotype', 'HP:0100526', (43, 54))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('lung cancer', 'Disease', 'MESH:D008175', (215, 226))	('associated', 'Reg', (59, 69))	('erlotinib', 'Chemical', 'MESH:D000069347', (120, 129))	('mutations', 'Var', (22, 31))	('lung cancer', 'Disease', 'MESH:D008175', (43, 54))	('sensitivity', 'MPA', (75, 86))	('gefitinib', 'Chemical', 'MESH:D000077156', (106, 115))	('lung cancer', 'Phenotype', 'HP:0100526', (215, 226))	('EGFR', 'Gene', (17, 21))
158870	26134262	Both gefitinib and erlotinib (Figure 3) are the first choice for therapy in lung cancer patients whose tumors harbor EGFR mutations and are reported to significantly prolong progression-free survival (PFS) in patients with EGFR-mutant lung cancer.	('progression-free survival', 'CPA', (174, 199))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('erlotinib', 'Chemical', 'MESH:D000069347', (19, 28))	('tumors', 'Disease', (103, 109))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('lung cancer', 'Disease', (76, 87))	('tumors', 'Disease', 'MESH:D009369', (103, 109))	('gefitinib', 'Chemical', 'MESH:D000077156', (5, 14))	('lung cancer', 'Disease', (235, 246))	('prolong', 'PosReg', (166, 173))	('patients', 'Species', '9606', (209, 217))	('lung cancer', 'Disease', 'MESH:D008175', (76, 87))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('patients', 'Species', '9606', (88, 96))	('EGFR', 'Gene', (117, 121))	('lung cancer', 'Disease', 'MESH:D008175', (235, 246))	('lung cancer', 'Phenotype', 'HP:0100526', (76, 87))	('mutations', 'Var', (122, 131))	('lung cancer', 'Phenotype', 'HP:0100526', (235, 246))
158872	26134262	The most common EGFR mutations are in-frame deletions in exon 19 and L858R point mutations in exon 21.	('in-frame deletions', 'Var', (35, 53))	('L858R point mutations', 'Var', (69, 90))	('L858R', 'Mutation', 'rs121434568', (69, 74))	('EGFR', 'Gene', (16, 20))	('mutations', 'Var', (21, 30))
158873	26134262	Together, these mutations account for approximately 85% of the EGFR mutations observed in lung cancer; tumors with these mutations are highly sensitive to treatment with erlotinib, gefitinib, and the second-generation EGFR inhibitor afatinib.	('gefitinib', 'Chemical', 'MESH:D000077156', (181, 190))	('lung cancer', 'Disease', 'MESH:D008175', (90, 101))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('afatinib', 'Chemical', 'MESH:D000077716', (233, 241))	('mutations', 'Var', (121, 130))	('erlotinib', 'Chemical', 'MESH:D000069347', (170, 179))	('rat', 'Species', '10116', (211, 214))	('EGFR', 'Gene', (63, 67))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('lung cancer', 'Disease', (90, 101))	('tumors', 'Disease', (103, 109))	('tumors', 'Disease', 'MESH:D009369', (103, 109))	('sensitive', 'Reg', (142, 151))	('lung cancer', 'Phenotype', 'HP:0100526', (90, 101))	('mutations', 'Var', (68, 77))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))
158874	26134262	Tumors with other less common mutations, such as exon 18 mutations at G719 and exon 21 mutation L861Q, are also susceptible to treatment with EGFR inhibitors.	('L861Q', 'Var', (96, 101))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('L861Q', 'Mutation', 'rs121913444', (96, 101))
158875	26134262	Nevertheless, tumors with exon 20 in-frame insertions, which account for approximately 4-10% of all EGFR mutations, usually do not respond to treatment with EGFR inhibitors.	('EGFR', 'Gene', (100, 104))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('tumors', 'Disease', (14, 20))	('mutations', 'Var', (105, 114))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
158877	26134262	A number of mechanisms for this acquired resistance have been identified, including a secondary T790M mutation at exon 20 of the EGFR gene, amplification of the MET proto-oncogene (MET) or HER2 gene, mutations of the KRAS gene, activation of AXL receptor tyrosine kinase (AXL), V-Srcavian sarcoma (Schmidt-Ruppin A-2) viral oncogene homolog (SRC) kinases, and extracellular signal-regulated kinase (ERK), loss of phosphatase and tensin homolog (PTEN), and activation of the nuclear factor-kappaB (NF-kappaB) or interleukin-6 receptor (IL-6R)/signal transducer and activator of transcription 3 (STAT3) pathway.	('mutations', 'Var', (200, 209))	('SRC', 'Gene', '6714', (342, 345))	('IL-6R', 'Gene', '3570', (535, 540))	('STAT3', 'Gene', (594, 599))	('activation', 'PosReg', (456, 466))	('phosphatase', 'Gene', (413, 424))	('ERK', 'Gene', (399, 402))	('SRC', 'Gene', (342, 345))	('AXL', 'Gene', (242, 245))	('STAT3', 'Gene', '6774', (594, 599))	('AXL', 'Gene', '558', (272, 275))	('AXL', 'Gene', '558', (242, 245))	('sarcoma', 'Disease', 'MESH:D012509', (289, 296))	('IL-6R', 'Gene', (535, 540))	('HER2', 'Gene', '2064', (189, 193))	('KRAS', 'Gene', (217, 221))	('extracellular signal-regulated kinase', 'Gene', (360, 397))	('sarcoma', 'Disease', (289, 296))	('PTEN', 'Gene', (445, 449))	('T790M', 'Mutation', 'rs121434569', (96, 101))	('extracellular signal-regulated kinase', 'Gene', '5594', (360, 397))	('loss', 'NegReg', (405, 409))	('EGFR gene', 'Gene', (129, 138))	('interleukin-6 receptor', 'Gene', '3570', (511, 533))	('AXL', 'Gene', (272, 275))	('activation', 'PosReg', (228, 238))	('mutation', 'Var', (102, 110))	('sarcoma', 'Phenotype', 'HP:0100242', (289, 296))	('signal transducer and activator of transcription 3', 'Gene', '6774', (542, 592))	('interleukin-6 receptor', 'Gene', (511, 533))	('PTEN', 'Gene', '5728', (445, 449))	('HER2', 'Gene', (189, 193))	('T790M', 'Gene', (96, 101))	('ERK', 'Gene', '5594', (399, 402))
158879	26134262	A number of second-generation EGFR inhibitors, most of which are irreversible, inhibit two or more receptors in the EGFR family, and may have some activity in T790M-mutant cancers, have been evaluated in clinical trials.	('inhibit', 'NegReg', (79, 86))	('T790M-mutant', 'Var', (159, 171))	('EGFR', 'Gene', (30, 34))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('rat', 'Species', '10116', (23, 26))	('cancers', 'Disease', 'MESH:D009369', (172, 179))	('cancers', 'Phenotype', 'HP:0002664', (172, 179))	('cancers', 'Disease', (172, 179))	('T790M', 'Mutation', 'rs121434569', (159, 164))	('activity', 'MPA', (147, 155))
158880	26134262	Among those evaluated in clinical trials, only afatinib has been approved (in July 2013) by the United States Food and Drug Administration (FDA) for the treatment of metastatic NSCLC with EGFR mutations.	('afatinib', 'Chemical', 'MESH:D000077716', (47, 55))	('rat', 'Species', '10116', (132, 135))	('mutations', 'Var', (193, 202))	('NSCLC', 'Disease', (177, 182))	('NSCLC', 'Disease', 'MESH:D002289', (177, 182))	('EGFR', 'Gene', (188, 192))
158881	26134262	Unfortunately, diarrhea and rash, the two most common adverse effects associated with a good response to the therapy, appear to be more severe in patients treated with afatinib than those treated with erlotinib or gefitinib.	('afatinib', 'Var', (168, 176))	('afatinib', 'Chemical', 'MESH:D000077716', (168, 176))	('diarrhea', 'Disease', (15, 23))	('gefitinib', 'Chemical', 'MESH:D000077156', (214, 223))	('rash', 'Disease', 'MESH:D005076', (28, 32))	('diarrhea', 'Phenotype', 'HP:0002014', (15, 23))	('rash', 'Disease', (28, 32))	('diarrhea', 'Disease', 'MESH:D003967', (15, 23))	('rash', 'Phenotype', 'HP:0000988', (28, 32))	('patients', 'Species', '9606', (146, 154))	('erlotinib', 'Chemical', 'MESH:D000069347', (201, 210))
158882	26134262	More recently, the third-generation EGFR inhibitors AZD9291 and CO-1686 have shown promising anticancer activity in T790M-mutant tumors.	('CO-1686', 'Chemical', 'MESH:C000589977', (64, 71))	('tumors', 'Disease', (129, 135))	('cancer', 'Disease', (97, 103))	('tumors', 'Disease', 'MESH:D009369', (129, 135))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('EGFR', 'Gene', (36, 40))	('T790M', 'Mutation', 'rs121434569', (116, 121))	('rat', 'Species', '10116', (29, 32))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('AZD9291', 'Chemical', 'MESH:C000596361', (52, 59))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('T790M-mutant', 'Var', (116, 128))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
158883	26134262	Our recent studies have revealed that ibrutinib, an irreversible inhibitor of Bruton tyrosine kinase (BTK) that was recently approved by the FDA for the treatment of mantle cell lymphoma and chronic lymphocytic leukemia, can function as an EGFR inhibitor to selectively inhibit growth and induce apoptosis in EGFR-mutant NSCLC cells in vitro and in vivo, including erlotinib-resistant cells that harbor a T790M mutation.	('inhibit', 'NegReg', (270, 277))	('chronic lymphocytic leukemia', 'Disease', 'MESH:D015451', (191, 219))	('cell lymphoma', 'Phenotype', 'HP:0012191', (173, 186))	('induce', 'PosReg', (289, 295))	('chronic lymphocytic leukemia', 'Disease', (191, 219))	('growth', 'CPA', (278, 284))	('EGFR-mutant', 'Gene', (309, 320))	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (191, 219))	('Bruton tyrosine kinase', 'Gene', (78, 100))	('leukemia', 'Phenotype', 'HP:0001909', (211, 219))	('EGFR-mutant', 'Var', (309, 320))	('NSCLC', 'Disease', 'MESH:D002289', (321, 326))	('erlotinib', 'Chemical', 'MESH:D000069347', (365, 374))	('BTK', 'Gene', (102, 105))	('T790M', 'Mutation', 'rs121434569', (405, 410))	('mantle cell lymphoma', 'Disease', (166, 186))	('BTK', 'Gene', '695', (102, 105))	('NSCLC', 'Disease', (321, 326))	('mantle cell lymphoma', 'Disease', 'MESH:D020522', (166, 186))	('apoptosis', 'CPA', (296, 305))	('ibrutinib', 'Chemical', 'MESH:C551803', (38, 47))	('lymphoma', 'Phenotype', 'HP:0002665', (178, 186))	('T790M', 'Var', (405, 410))	('Bruton tyrosine kinase', 'Gene', '695', (78, 100))
158885	26134262	The discovery of gene rearrangements between the echinoderm microtubule-associated protein-like 4 (EML4) gene and the ALK gene that lead to constitutive activation of ALK in NSCLC greatly contributed to the subsequent development and approval of crizotinib, a small-molecule inhibitor of ALK, c-ros oncogene 1 receptor tyrosine kinase (ROS1), and MET.	('NSCLC', 'Disease', 'MESH:D002289', (174, 179))	('contributed', 'Reg', (188, 199))	('NSCLC', 'Disease', (174, 179))	('activation', 'PosReg', (153, 163))	('echinoderm microtubule-associated protein-like 4', 'Gene', '27436', (49, 97))	('ROS1', 'Gene', '6098', (336, 340))	('ALK', 'Gene', '238', (288, 291))	('rearrangements', 'Var', (22, 36))	('ALK', 'Gene', (288, 291))	('EML4', 'Gene', (99, 103))	('EML4', 'Gene', '27436', (99, 103))	('echinoderm microtubule-associated protein-like 4', 'Gene', (49, 97))	('ALK', 'Gene', '238', (167, 170))	('c-ros oncogene 1 receptor tyrosine kinase', 'Gene', (293, 334))	('crizotinib', 'Chemical', 'MESH:D000077547', (246, 256))	('ROS1', 'Gene', (336, 340))	('c-ros oncogene 1 receptor tyrosine kinase', 'Gene', '6098', (293, 334))	('ALK', 'Gene', (167, 170))	('ALK', 'Gene', '238', (118, 121))	('ALK', 'Gene', (118, 121))
158886	26134262	EML4/ALK rearrangements are detected in approximately 4-5% of patients with NSCLC, mostly in young patients with adenocarcinoma who are non-smokers or light smokers.	('adenocarcinoma', 'Disease', (113, 127))	('ALK', 'Gene', (5, 8))	('EML4', 'Gene', (0, 4))	('NSCLC', 'Disease', (76, 81))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('adenocarcinoma', 'Disease', 'MESH:D000230', (113, 127))	('patients', 'Species', '9606', (99, 107))	('ALK', 'Gene', '238', (5, 8))	('EML4', 'Gene', '27436', (0, 4))	('NSCLC', 'Disease', 'MESH:D002289', (76, 81))	('rearrangements', 'Var', (9, 23))	('patients', 'Species', '9606', (62, 70))
158887	26134262	ALK rearrangements were found to be mutually exclusive with EGFR and KRAS mutations, although they share common downstream signaling pathways with EGFR such as the RAS/RAF/MEK/ERK, PI3K/AKT/mTOR, and JAK/STAT pathways.	('KRAS', 'Gene', (69, 73))	('RAF', 'Gene', (168, 171))	('AKT', 'Gene', '207', (186, 189))	('MEK', 'Gene', (172, 175))	('rearrangements', 'Var', (4, 18))	('ERK', 'Gene', (176, 179))	('mTOR', 'Gene', '2475', (190, 194))	('JAK/STAT pathways', 'Pathway', (200, 217))	('mTOR', 'Gene', (190, 194))	('mutations', 'Var', (74, 83))	('MEK', 'Gene', '5609', (172, 175))	('ALK', 'Gene', (0, 3))	('AKT', 'Gene', (186, 189))	('EGFR', 'Gene', (60, 64))	('RAF', 'Gene', '22882', (168, 171))	('ERK', 'Gene', '5594', (176, 179))	('ALK', 'Gene', '238', (0, 3))
158888	26134262	Crizotinib (Figure 4) was originally developed as an MET inhibitor; however, crizotinib also inhibits ALK and ROS1.	('crizotinib', 'Chemical', 'MESH:D000077547', (77, 87))	('Crizotinib', 'Chemical', 'MESH:D000077547', (0, 10))	('ALK', 'Gene', (102, 105))	('inhibits', 'NegReg', (93, 101))	('ROS1', 'Gene', (110, 114))	('ROS1', 'Gene', '6098', (110, 114))	('crizotinib', 'Var', (77, 87))	('ALK', 'Gene', '238', (102, 105))
158889	26134262	Soon after the first reports of EML4/ALK rearrangement and its role in lung cancer oncogenesis, a diagnostic method for detecting EML4/ALK rearrangement by fluorescence in situ hybridization (FISH) was developed, and patients with EML4/ALK rearrangement-positive lung cancer were enrolled in clinical trials with crizotinib.	('ALK', 'Gene', (135, 138))	('lung cancer', 'Disease', (263, 274))	('ALK', 'Gene', '238', (37, 40))	('rearrangement', 'Var', (41, 54))	('ALK', 'Gene', (37, 40))	('lung cancer', 'Disease', 'MESH:D008175', (71, 82))	('lung cancer', 'Disease', 'MESH:D008175', (263, 274))	('crizotinib', 'Chemical', 'MESH:D000077547', (313, 323))	('lung cancer', 'Phenotype', 'HP:0100526', (71, 82))	('lung cancer', 'Phenotype', 'HP:0100526', (263, 274))	('EML4', 'Gene', (130, 134))	('EML4', 'Gene', '27436', (130, 134))	('patients', 'Species', '9606', (217, 225))	('EML4', 'Gene', (32, 36))	('EML4', 'Gene', (231, 235))	('EML4', 'Gene', '27436', (32, 36))	('lung cancer oncogenesis', 'Disease', (71, 94))	('EML4', 'Gene', '27436', (231, 235))	('cancer', 'Phenotype', 'HP:0002664', (268, 274))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('ALK', 'Gene', '238', (135, 138))	('lung cancer oncogenesis', 'Disease', 'MESH:D063646', (71, 94))	('ALK', 'Gene', '238', (236, 239))	('ALK', 'Gene', (236, 239))
158894	26134262	ROS1 gene rearrangement and activation are detected in approximately 1-1.5% of NSCLC, predominantly in adenocarcinoma and in non-smokers, as is observed with ALK rearrangement.	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('NSCLC', 'Disease', 'MESH:D002289', (79, 84))	('ROS1', 'Gene', (0, 4))	('rearrangement', 'Var', (10, 23))	('ALK', 'Gene', (158, 161))	('adenocarcinoma', 'Disease', (103, 117))	('ROS1', 'Gene', '6098', (0, 4))	('activation', 'PosReg', (28, 38))	('ALK', 'Gene', '238', (158, 161))	('adenocarcinoma', 'Disease', 'MESH:D000230', (103, 117))	('NSCLC', 'Disease', (79, 84))
158896	26134262	Because the kinase domains of ALK and ROS1 share 77% homology at the protein sequence level and crizotinib is highly active for both ALK and ROS1, clinical investigation into the treatment of NSCLC patients with ROS1 rearrangement has been pursued.	('NSCLC', 'Disease', (192, 197))	('ALK', 'Gene', (30, 33))	('patients', 'Species', '9606', (198, 206))	('ROS1', 'Gene', (212, 216))	('NSCLC', 'Disease', 'MESH:D002289', (192, 197))	('rearrangement', 'Var', (217, 230))	('ROS1', 'Gene', (38, 42))	('ALK', 'Gene', (133, 136))	('ROS1', 'Gene', '6098', (212, 216))	('ROS1', 'Gene', '6098', (38, 42))	('ROS1', 'Gene', (141, 145))	('ALK', 'Gene', '238', (30, 33))	('ROS1', 'Gene', '6098', (141, 145))	('ALK', 'Gene', '238', (133, 136))	('crizotinib', 'Chemical', 'MESH:D000077547', (96, 106))
158898	26134262	The response duration in ROS1 rearrangement-positive patients appears to be longer than that in ALK-positive patients (10-11 months).	('ALK', 'Gene', '238', (96, 99))	('rat', 'Species', '10116', (15, 18))	('patients', 'Species', '9606', (53, 61))	('ROS1', 'Gene', (25, 29))	('patients', 'Species', '9606', (109, 117))	('ROS1', 'Gene', '6098', (25, 29))	('ALK', 'Gene', (96, 99))	('rearrangement-positive', 'Var', (30, 52))
158899	26134262	Similar to the diagnosis of ALK rearrangement, FISH and/or reverse transcription-polymerase chain reaction (RT-PCR) are used to identify patients with ROS1 rearrangement.	('ALK', 'Gene', '238', (28, 31))	('ROS1', 'Gene', (151, 155))	('patients', 'Species', '9606', (137, 145))	('ROS1', 'Gene', '6098', (151, 155))	('rearrangement', 'Var', (156, 169))	('ALK', 'Gene', (28, 31))
158901	26134262	Among the patients with ALK-positive NSCLC who acquired resistance to crizotinib, one-third had various secondary mutations in the ALK kinase domain and/or had ALK gene amplification.	('NSCLC', 'Disease', 'MESH:D002289', (37, 42))	('ALK', 'Gene', (160, 163))	('had', 'Reg', (92, 95))	('ALK', 'Gene', '238', (24, 27))	('mutations', 'Var', (114, 123))	('ALK', 'Gene', '238', (131, 134))	('ALK', 'Gene', '238', (160, 163))	('NSCLC', 'Disease', (37, 42))	('ALK', 'Gene', (24, 27))	('crizotinib', 'Chemical', 'MESH:D000077547', (70, 80))	('patients', 'Species', '9606', (10, 18))	('ALK', 'Gene', (131, 134))
158902	26134262	Resistance can also be caused by aberrant activation of alternative or bypass pathways, such as marked v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (KIT) amplification and EGFR activation.	('alternative', 'Pathway', (56, 67))	('activation', 'PosReg', (194, 204))	('sarcoma viral', 'Disease', (134, 147))	('KIT', 'Gene', (166, 169))	('EGFR', 'Gene', (189, 193))	('amplification', 'Var', (171, 184))	('activation', 'PosReg', (42, 52))	('bypass pathways', 'Pathway', (71, 86))	('sarcoma', 'Phenotype', 'HP:0100242', (134, 141))	('sarcoma viral', 'Disease', 'MESH:D001102', (134, 147))
158904	26134262	Second-generation ALK inhibitors have been developed to overcome crizotinib resistance caused by mutations in the ALK kinase domain.	('mutations', 'Var', (97, 106))	('ALK', 'Gene', '238', (18, 21))	('ALK', 'Gene', '238', (114, 117))	('crizotinib', 'MPA', (65, 75))	('ALK', 'Gene', (18, 21))	('rat', 'Species', '10116', (11, 14))	('ALK', 'Gene', (114, 117))	('crizotinib', 'Chemical', 'MESH:D000077547', (65, 75))
158911	26134262	The presence of tumor antigens derived from mutant proteins, dysregulated or overexpressed proteins, and viral oncogenic proteins has inspired intensive investigation into anticancer immunotherapy through various approaches.	('mutant', 'Var', (44, 50))	('proteins', 'Protein', (51, 59))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('tumor', 'Disease', (16, 21))	('cancer', 'Disease', (176, 182))	('cancer', 'Disease', 'MESH:D009369', (176, 182))
158912	26134262	The high mutation rates observed in lung cancers suggest that lung cancer cells may possess high levels of tumor antigens from mutant proteins and may therefore be vulnerable to immunotherapy.	('mutant', 'Var', (127, 133))	('rat', 'Species', '10116', (18, 21))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('lung cancers', 'Disease', 'MESH:D008175', (36, 48))	('tumor', 'Disease', (107, 112))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('lung cancers', 'Phenotype', 'HP:0100526', (36, 48))	('lung cancer', 'Phenotype', 'HP:0100526', (62, 73))	('lung cancer', 'Disease', 'MESH:D008175', (36, 47))	('lung cancer', 'Disease', (62, 73))	('cancers', 'Phenotype', 'HP:0002664', (41, 48))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('lung cancers', 'Disease', (36, 48))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('lung cancer', 'Disease', 'MESH:D008175', (62, 73))	('lung cancer', 'Phenotype', 'HP:0100526', (36, 47))	('proteins', 'Protein', (134, 142))
158925	26134262	The expression of PD-L1 in lung cancer is detected in 25-50% of NSCLC cases, depending on the assays used to detect its protein or mRNA, and is associated with the presence of EGFR mutations in NSCLC.	('NSCLC', 'Disease', 'MESH:D002289', (64, 69))	('mRNA', 'MPA', (131, 135))	('associated', 'Reg', (144, 154))	('lung cancer', 'Disease', (27, 38))	('NSCLC', 'Disease', (194, 199))	('expression', 'MPA', (4, 14))	('lung cancer', 'Phenotype', 'HP:0100526', (27, 38))	('EGFR', 'Gene', (176, 180))	('NSCLC', 'Disease', 'MESH:D002289', (194, 199))	('mutations', 'Var', (181, 190))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('PD-L1', 'Gene', (18, 23))	('NSCLC', 'Disease', (64, 69))	('lung cancer', 'Disease', 'MESH:D008175', (27, 38))	('PD-L1', 'Gene', '29126', (18, 23))	('detected', 'Reg', (42, 50))
158930	26134262	Monoclonal antibodies for PD-L1 are also under intensive clinical evaluation for the treatment of NSCLC and other solid tumors.	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('Monoclonal', 'Var', (0, 10))	('PD-L1', 'Gene', '29126', (26, 31))	('PD-L1', 'Gene', (26, 31))	('solid tumors', 'Disease', (114, 126))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('NSCLC', 'Disease', (98, 103))	('solid tumors', 'Disease', 'MESH:D009369', (114, 126))	('NSCLC', 'Disease', 'MESH:D002289', (98, 103))
158950	26134262	In this case, loss-of-function mutations in the BRCA1 and BRCA2 genes or other functional deficiencies in the DNA repair pathways will serve as predictive biomarkers for response to olaparib and other PARP inhibitors.	('BRCA1', 'Gene', '672', (48, 53))	('mutations', 'Var', (31, 40))	('BRCA2', 'Gene', '675', (58, 63))	('functional deficiencies', 'Disease', 'OMIM:608852', (79, 102))	('olaparib', 'Chemical', 'MESH:C531550', (182, 190))	('DNA repair pathways', 'Pathway', (110, 129))	('loss-of-function', 'NegReg', (14, 30))	('functional deficiencies', 'Disease', (79, 102))	('BRCA1', 'Gene', (48, 53))	('BRCA2', 'Gene', (58, 63))
158952	26134262	This approach could be useful for the indirect targeting of cancer drivers such as genetic changes in TP53, STK11, RB1, and RAS genes that are nondruggable or difficult to target using small molecules.	('TP53', 'Gene', (102, 106))	('genetic changes', 'Var', (83, 98))	('RB1', 'Gene', (115, 118))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('RAS', 'Gene', (124, 127))	('cancer', 'Disease', (60, 66))	('RB1', 'Gene', '5925', (115, 118))	('STK11', 'Gene', (108, 113))	('TP53', 'Gene', '7157', (102, 106))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
158954	26134262	The molecular pathology of RAS-mediated oncogenesis is further complicated by the fact that cancer cells with different mutations in KRAS, even if in the same codon (such as G12C, G12V, and G12D mutations), may lead to different conformational changes in KRAS, have different effects on clinical outcomes, and activate different molecular and metabolic pathways.	('G12V', 'Var', (180, 184))	('lead to', 'Reg', (211, 218))	('cancer', 'Disease', (92, 98))	('G12V', 'Mutation', 'rs121913529', (180, 184))	('G12D', 'Mutation', 'rs121913529', (190, 194))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('G12C', 'Mutation', 'rs121913530', (174, 178))	('KRAS', 'Protein', (255, 259))	('KRAS', 'Gene', (133, 137))	('effects', 'Reg', (276, 283))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('activate', 'PosReg', (310, 318))	('G12C', 'Var', (174, 178))	('G12D mutations', 'Var', (190, 204))	('conformational changes', 'MPA', (229, 251))
158956	26134262	Studies in transgenic mice have found that activating mutations in KRAS predispose mice to early-onset lung adenocarcinoma.	('predispose', 'Reg', (72, 82))	('lung adenocarcinoma', 'Disease', (103, 122))	('activating mutations', 'Var', (43, 63))	('KRAS', 'Gene', (67, 71))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (103, 122))	('mice', 'Species', '10090', (83, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('transgenic mice', 'Species', '10090', (11, 26))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (103, 122))	('mice', 'Species', '10090', (22, 26))
158958	26134262	Metastasis will occur only when additional genetic changes, such as Tp53 mutations or Stk11 deletion, are introduced.	('Tp53', 'Gene', '7157', (68, 72))	('Metastasis', 'Disease', 'MESH:D009362', (0, 10))	('Metastasis', 'Disease', (0, 10))	('Stk11', 'Gene', '6794', (86, 91))	('deletion', 'Var', (92, 100))	('occur', 'Reg', (16, 21))	('Stk11', 'Gene', (86, 91))	('Tp53', 'Gene', (68, 72))
158960	26134262	Through synthetic lethality screening using a chemical library for isogenic cell lines with and without oncogenic KRAS, we previously reported a small molecule, designated oncrasin-1, that induces apoptosis in several KRAS-mutant lung cancer cell lines.	('apoptosis', 'CPA', (197, 206))	('induces', 'PosReg', (189, 196))	('oncrasin', 'Chemical', '-', (172, 180))	('lung cancer', 'Disease', (230, 241))	('lung cancer', 'Phenotype', 'HP:0100526', (230, 241))	('KRAS-mutant', 'Var', (218, 229))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))	('lung cancer', 'Disease', 'MESH:D008175', (230, 241))
158966	26134262	Statistical analysis of associations between the activity of NSC-743380 (oncrasin-72) and the gene expression profile in the NCI-60 cell line panel led to the identification of a number of candidate genes, and subsequent molecular characterizations demonstrated the causal relationship between the expression of SULT1A1 and the anticancer activity of NSC-743380, validating the feasibility of using SULT1A1 as a predictive marker for those compounds.	('cancer', 'Phenotype', 'HP:0002664', (332, 338))	('NCI-60', 'CellLine', 'CVCL:A592', (125, 131))	('SULT1A1', 'Gene', (312, 319))	('SULT1A1', 'Gene', '6817', (312, 319))	('oncrasin', 'Chemical', '-', (73, 81))	('rat', 'Species', '10116', (256, 259))	('cancer', 'Disease', 'MESH:D009369', (332, 338))	('NSC-743380', 'Gene', (61, 71))	('cancer', 'Disease', (332, 338))	('SULT1A1', 'Gene', (399, 406))	('NSC-743380', 'Var', (351, 361))	('SULT1A1', 'Gene', '6817', (399, 406))
158981	32485800	PDT of squamous cell carcinoma cells treated with Ce6 ethosomes triggered increased mitochondrial superoxide levels and increased caspase 3/7 activity, resulting in concentration- and light-dose-dependent cytotoxicity.	('Ce6 ethosomes', 'Var', (50, 63))	('squamous cell carcinoma', 'Disease', (7, 30))	('mitochondrial superoxide levels', 'MPA', (84, 115))	('activity', 'MPA', (142, 150))	('caspase 3/7', 'Gene', '836;840', (130, 141))	('carcinoma', 'Phenotype', 'HP:0030731', (21, 30))	('caspase 3/7', 'Gene', (130, 141))	('cytotoxicity', 'Disease', 'MESH:D064420', (205, 217))	('Ce6 ethosomes', 'Chemical', '-', (50, 63))	('superoxide', 'Chemical', 'MESH:D013481', (98, 108))	('increased', 'PosReg', (74, 83))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (7, 30))	('increased mitochondrial superoxide', 'Phenotype', 'HP:0025464', (74, 108))	('increased', 'PosReg', (120, 129))	('cytotoxicity', 'Disease', (205, 217))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (7, 30))
158982	32485800	Ce6 ethosomes showed good penetration into 3D squamous cell carcinoma spheroids, which upon laser light irradiation exhibited reduced size, proliferation, and viability.	('squamous cell carcinoma spheroids', 'Disease', 'MESH:D002294', (46, 79))	('Ce6', 'Var', (0, 3))	('proliferation', 'CPA', (140, 153))	('Ce6 ethosomes', 'Chemical', '-', (0, 13))	('penetration', 'CPA', (26, 37))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (46, 69))	('squamous cell carcinoma spheroids', 'Disease', (46, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (60, 69))	('squamous cell carcinoma spheroids', 'Phenotype', 'HP:0025014', (46, 79))	('reduced', 'NegReg', (126, 133))
158983	32485800	The PDT effect of Ce6 ethosomes was specific and showed higher cytotoxicity against squamous cell carcinoma spheroids compared to normal skin fibroblast spheroids.	('Ce6', 'Var', (18, 21))	('Ce6 ethosomes', 'Chemical', '-', (18, 31))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('squamous cell carcinoma spheroids', 'Disease', (84, 117))	('cytotoxicity', 'Disease', (63, 75))	('squamous cell carcinoma spheroids', 'Disease', 'MESH:D002294', (84, 117))	('squamous cell carcinoma spheroids', 'Phenotype', 'HP:0025014', (84, 117))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (84, 107))	('higher', 'PosReg', (56, 62))	('cytotoxicity', 'Disease', 'MESH:D064420', (63, 75))
158997	32485800	In addition, due to the strong fluorescence emission of Ce6 in the red region, it can serve as an imaging agent for theranostic approaches.	('Ce6', 'Var', (56, 59))	('Ce6', 'Chemical', 'MESH:C062985', (56, 59))	('fluorescence emission', 'MPA', (31, 52))
159017	32485800	The mixture was then sonicated in a water bath (UC-20500B Chrom Tech, Taipei, Taiwan) at maximum power for 30 min.	('water', 'Chemical', 'MESH:D014867', (36, 41))	('mum', 'Gene', '56925', (93, 96))	('UC-20500B', 'Var', (48, 57))	('mum', 'Gene', (93, 96))
159060	32485800	Ce6 loaded into ethosomes shows the characteristic lambdamax for Ce6 at about 405 nm and another smaller slightly shifted peak at about 667 nm.	('lambdamax', 'MPA', (51, 60))	('Ce6', 'Var', (65, 68))	('Ce6', 'Chemical', 'MESH:C062985', (65, 68))	('ethosomes', 'Chemical', '-', (16, 25))	('Ce6', 'Chemical', 'MESH:C062985', (0, 3))
159070	32485800	The above controls showed minimal photobleaching of the ADPA sensor compared to PDT samples containing either Ce6 or Ce6 ethosomes and exposed to the same light doses (12-60 J/cm2).	('Ce6', 'Var', (110, 113))	('Ce6', 'Chemical', 'MESH:C062985', (110, 113))	('Ce6', 'Var', (117, 120))	('Ce6 ethosomes', 'Chemical', '-', (117, 130))	('Ce6', 'Chemical', 'MESH:C062985', (117, 120))	('ADPA', 'Protein', (56, 60))	('ADPA', 'Chemical', '-', (56, 60))
159078	32485800	In order to examine if Ce6 ethosomes induce apoptosis in squamous cell carcinoma cells, activation of the executioner caspase 3/7 was analyzed.	('caspase 3/7', 'Gene', (118, 129))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (57, 80))	('Ce6 ethosomes', 'Var', (23, 36))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (57, 80))	('squamous cell carcinoma', 'Disease', (57, 80))	('Ce6 ethosomes', 'Chemical', '-', (23, 36))	('caspase 3/7', 'Gene', '836;840', (118, 129))
159079	32485800	The caspase 3/7 activity in squamous cell carcinoma cells after PDT was significantly increased in comparison to control samples, suggesting activation of the intrinsic apoptotic pathway (Figure 3B).	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (28, 51))	('PDT', 'Var', (64, 67))	('increased', 'PosReg', (86, 95))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (28, 51))	('squamous cell carcinoma', 'Disease', (28, 51))	('carcinoma', 'Phenotype', 'HP:0030731', (42, 51))	('caspase 3/7', 'Gene', (4, 15))	('caspase 3/7', 'Gene', '836;840', (4, 15))	('activity', 'MPA', (16, 24))	('intrinsic apoptotic pathway', 'Pathway', (159, 186))	('activation', 'PosReg', (141, 151))
159085	32485800	PDT of spheroids treated for 24 h with Ce6 ethosomes induced a significant decrease in the spheroid diameter to 240 +- 6 mum compared to control (382 +- 20 mum) (*** p < 0.001) and loss of spheroid structural integrity.	('loss', 'NegReg', (181, 185))	('mum', 'Gene', '56925', (156, 159))	('mum', 'Gene', (121, 124))	('decrease', 'NegReg', (75, 83))	('Ce6 ethosomes', 'Var', (39, 52))	('mum', 'Gene', (156, 159))	('spheroid diameter', 'CPA', (91, 108))	('Ce6 ethosomes', 'Chemical', '-', (39, 52))	('spheroid structural integrity', 'CPA', (189, 218))	('mum', 'Gene', '56925', (121, 124))
159093	32485800	Histopathological analysis showed a reduction in tumor size post PDT and little or no effect on tumors either exposed to laser only (light control) or incubated with Ce6 ethosomes only (dark control) in comparison to untreated control tumors.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Disease', 'MESH:D009369', (235, 240))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('PDT', 'Var', (65, 68))	('tumors', 'Disease', (96, 102))	('Ce6 ethosomes', 'Chemical', '-', (166, 179))	('tumor', 'Disease', (96, 101))	('reduction', 'NegReg', (36, 45))	('tumor', 'Disease', (49, 54))	('tumors', 'Phenotype', 'HP:0002664', (235, 241))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('tumor', 'Disease', (235, 240))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('tumors', 'Disease', 'MESH:D009369', (235, 241))	('tumors', 'Disease', (235, 241))
159094	32485800	Light microscopic images taken from the chorioallantoic membrane beneath the tumors showed reduced angiogenesis after PDT (Figure 6A).	('tumors', 'Disease', 'MESH:D009369', (77, 83))	('tumors', 'Disease', (77, 83))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('angiogenesis', 'CPA', (99, 111))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('reduced', 'NegReg', (91, 98))	('PDT', 'Var', (118, 121))
159100	32485800	Moreover, Ce6 accumulates more effectively in tumors compared to healthy tissue, penetrates through cell membranes, and can be cleared rapidly from an organism.	('Ce6', 'Chemical', 'MESH:C062985', (10, 13))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('tumors', 'Disease', (46, 52))	('Ce6', 'Var', (10, 13))	('tumors', 'Disease', 'MESH:D009369', (46, 52))
159104	32485800	Thus, confocal microscopy revealed that Ce6 ethosomes reached the core of a large tumor spheroid measuring 350 nm after 24 h of treatment.	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('Ce6', 'Var', (40, 43))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumor', 'Disease', (82, 87))	('Ce6 ethosomes', 'Chemical', '-', (40, 53))
159112	32485800	Indeed, squamous cell carcinoma treated with Ce6 ethosomes followed by light exposure exhibited increased mitochondrial ROS production.	('increased', 'PosReg', (96, 105))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (8, 31))	('ROS', 'Chemical', 'MESH:D017382', (120, 123))	('Ce6 ethosomes', 'Chemical', '-', (45, 58))	('increased mitochondrial ROS production', 'Phenotype', 'HP:0025464', (96, 134))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (8, 31))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('squamous cell carcinoma', 'Disease', (8, 31))	('mitochondrial ROS production', 'MPA', (106, 134))	('Ce6 ethosomes', 'Var', (45, 58))
159113	32485800	Exuberant ROS production might exceed the capacities of the cellular antioxidant system and affect the mitochondrial membrane integrity.	('Exuberant ROS production', 'Phenotype', 'HP:0025464', (0, 24))	('ROS', 'Chemical', 'MESH:D017382', (10, 13))	('Exuberant', 'Var', (0, 9))	('exceed', 'PosReg', (31, 37))	('mitochondrial membrane integrity', 'MPA', (103, 135))	('affect', 'Reg', (92, 98))	('cellular antioxidant system', 'MPA', (60, 87))
159116	32485800	Importantly, Ce6 ethosomes show selectivity towards skin carcinoma cells compared to normal skin cells.	('skin carcinoma', 'Disease', (52, 66))	('skin carcinoma', 'Disease', 'MESH:D012878', (52, 66))	('carcinoma', 'Phenotype', 'HP:0030731', (57, 66))	('Ce6', 'Var', (13, 16))	('Ce6 ethosomes', 'Chemical', '-', (13, 26))
159117	32485800	Thus, after PDT, squamous cell carcinoma spheroids exhibited lower proliferation and reduced viability compared to normal skin fibroblasts.	('squamous cell carcinoma spheroids', 'Phenotype', 'HP:0025014', (17, 50))	('lower', 'NegReg', (61, 66))	('squamous cell carcinoma spheroids', 'Disease', 'MESH:D002294', (17, 50))	('squamous cell carcinoma spheroids', 'Disease', (17, 50))	('viability', 'CPA', (93, 102))	('PDT', 'Var', (12, 15))	('reduced', 'NegReg', (85, 92))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (17, 40))	('carcinoma', 'Phenotype', 'HP:0030731', (31, 40))
159124	32485800	PDT using Ce6 ethosomes induced a visible decrease in the number and diameter of blood vessels beneath squamous cell carcinomas, reducing the oxygen and nutrient supply to tumor tissue.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('carcinomas', 'Phenotype', 'HP:0030731', (117, 127))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (103, 126))	('tumor', 'Disease', (172, 177))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (103, 127))	('Ce6 ethosomes', 'Chemical', '-', (10, 23))	('decrease', 'NegReg', (42, 50))	('squamous cell carcinomas', 'Disease', (103, 127))	('oxygen', 'Chemical', 'MESH:D010100', (142, 148))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (103, 127))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('reducing', 'NegReg', (129, 137))	('Ce6', 'Var', (10, 13))
159125	32485800	In addition, PDT reduced cancer cell proliferation and induced apoptosis.	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('cancer', 'Disease', 'MESH:D009369', (25, 31))	('apoptosis', 'CPA', (63, 72))	('cancer', 'Disease', (25, 31))	('induced', 'Reg', (55, 62))	('reduced', 'NegReg', (17, 24))	('PDT', 'Var', (13, 16))
159127	32485800	Thus, the increased apoptotic population of tumor cells proved that Ce6-mediated PDT is efficient in the reduction of the vascular network around squamous cell carcinomas and in reducing tumor viability.	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (146, 170))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('reducing', 'NegReg', (178, 186))	('carcinoma', 'Phenotype', 'HP:0030731', (160, 169))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (146, 169))	('vascular network', 'CPA', (122, 138))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (146, 170))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('tumor', 'Disease', (187, 192))	('reduction', 'NegReg', (105, 114))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('carcinomas', 'Phenotype', 'HP:0030731', (160, 170))	('squamous cell carcinomas', 'Disease', (146, 170))	('Ce6', 'Chemical', 'MESH:C062985', (68, 71))	('tumor', 'Disease', (44, 49))	('Ce6-mediated', 'Var', (68, 80))
159136	32622267	Pleiotropic SH2B3 variants are associated with breast cancer risk in BRCA1/2 mutation carriers.	('BRCA1/2', 'Gene', (69, 76))	('BRCA', 'Phenotype', 'HP:0003002', (69, 73))	('breast cancer', 'Disease', (47, 60))	('breast cancer', 'Phenotype', 'HP:0003002', (47, 60))	('variants', 'Var', (18, 26))	('associated with', 'Reg', (31, 46))	('SH2B3', 'Gene', (12, 17))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('breast cancer', 'Disease', 'MESH:D001943', (47, 60))
159139	32622267	Cancer risk genetic variants linked to immune/stromal cell tissue content SH2B3 associated with BRCA1/2 cancer risk and immune cell counts Peripheral immune cell types linked to breast cancer age at diagnosis Immunology; Cancer Systems Biology; Cancer The immune system maintains organismal integrity and function by continuously protecting itself from exogenous and endogenous assaults.	('Cancer', 'Disease', (245, 251))	('variants', 'Var', (20, 28))	('BRCA1/2 cancer', 'Disease', 'OMIM:612555', (96, 110))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('Cancer', 'Disease', 'MESH:D009369', (221, 227))	('BRCA', 'Phenotype', 'HP:0003002', (96, 100))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('Cancer', 'Disease', 'MESH:D009369', (245, 251))	('SH2B3', 'Gene', (74, 79))	('breast cancer', 'Phenotype', 'HP:0003002', (178, 191))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('BRCA1/2 cancer', 'Disease', (96, 110))	('Cancer', 'Phenotype', 'HP:0002664', (221, 227))	('Cancer', 'Phenotype', 'HP:0002664', (245, 251))	('breast cancer', 'Disease', 'MESH:D001943', (178, 191))	('Cancer', 'Disease', (0, 6))	('breast cancer', 'Disease', (178, 191))	('Cancer', 'Disease', (221, 227))
159144	32622267	In parallel, studies of mouse models with defined genetic alterations have demonstrated the relevance of immunosurveillance; for example, loss of Nkg2d, which encodes the activating receptor of natural killer (NK) and T cells, increases the risk of spontaneous neoplasms.	('mouse', 'Species', '10090', (24, 29))	('Nkg2d', 'Gene', '27007', (146, 151))	('loss', 'Var', (138, 142))	('increases', 'PosReg', (227, 236))	('neoplasms', 'Disease', 'MESH:D009369', (261, 270))	('Nkg2d', 'Gene', (146, 151))	('neoplasms', 'Disease', (261, 270))	('neoplasms', 'Phenotype', 'HP:0002664', (261, 270))
159145	32622267	Results from genome-wide association studies (GWASs) have identified risk-associated variants in loci coding for immune regulatory factors, such as NKG2D for cervical cancer risk.	('NKG2D', 'Gene', '22914', (148, 153))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('variants', 'Var', (85, 93))	('cancer', 'Disease', (167, 173))	('NKG2D', 'Gene', (148, 153))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('risk-associated', 'Reg', (69, 84))
159147	32622267	In parallel, many germline genetic variants can influence immune cell infiltration in tumors.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('variants', 'Var', (35, 43))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('tumors', 'Disease', (86, 92))	('influence', 'Reg', (48, 57))
159149	32622267	However, whether common genetic variants linked to cancer risk alter immune cell contents in the corresponding cancer target tissue, and/or at the systemic level, remains largely undetermined.	('immune cell contents', 'MPA', (69, 89))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('alter', 'Reg', (63, 68))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('variants', 'Var', (32, 40))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))
159153	32622267	We identify the lymphocyte SH2B adaptor 3 (LNK/SH2B3) locus as linking immune cell counts and breast cancer risk, including that from BRCA1/2 mutation carriers.	('LNK', 'Gene', (43, 46))	('BRCA', 'Phenotype', 'HP:0003002', (134, 138))	('BRCA1/2', 'Gene', (134, 141))	('LNK', 'Gene', '16923', (43, 46))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('breast cancer', 'Disease', 'MESH:D001943', (94, 107))	('mutation', 'Var', (142, 150))	('breast cancer', 'Phenotype', 'HP:0003002', (94, 107))	('breast cancer', 'Disease', (94, 107))	('linking', 'Interaction', (63, 70))
159157	32622267	In parallel, many successful GWASs have identified hundreds of germline genetic variants associated with the risk of common cancer types.	('associated', 'Reg', (89, 99))	('cancer', 'Disease', (124, 130))	('germline genetic variants', 'Var', (63, 88))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('cancer', 'Disease', 'MESH:D009369', (124, 130))
159158	32622267	By compiling GWAS results, we assigned cancer risk variants to 17 TCGA projects based on tissue of origin correspondences (Figure 1A lists the cancer study acronyms, and Table S1 lists the cancer risk variants).	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('cancer', 'Disease', (39, 45))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('variants', 'Var', (51, 59))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('cancer', 'Disease', (189, 195))
159159	32622267	As deconvolution analyses of bulk gene expression enable robust inference of cell type content in heterogeneous samples, deduced cell content in normal tissue and tumors can be assessed for associations with cancer risk variants in multivariate analyses (Figure 1B).	('variants', 'Var', (220, 228))	('cancer', 'Disease', (208, 214))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('associations', 'Interaction', (190, 202))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('tumors', 'Disease', (163, 169))	('tumors', 'Disease', 'MESH:D009369', (163, 169))	('tumors', 'Phenotype', 'HP:0002664', (163, 169))	('cancer', 'Disease', 'MESH:D009369', (208, 214))
159160	32622267	Moreover, as differences in cancer risk are more accurately defined by combinations of key variants in PRSs, it might be possible to better define the relevance of the immune/stromal cells by analyzing associations between PRSs and their corresponding signatures (Figure 1C; Table S2 summarizes the number of normal tissue and primary tumor samples available for each subsequent analysis).	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('PRSs', 'Gene', (103, 107))	('associations', 'Interaction', (202, 214))	('tumor', 'Disease', 'MESH:D009369', (335, 340))	('variants', 'Var', (91, 99))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('tumor', 'Phenotype', 'HP:0002664', (335, 340))	('cancer', 'Disease', (28, 34))	('tumor', 'Disease', (335, 340))
159166	32622267	A total of 1,453 cancer risk variants were compiled from various sources; 214 of these were directly genotyped in TCGA, and the rest were imputed.	('variants', 'Var', (29, 37))	('cancer', 'Disease', (17, 23))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
159170	32622267	Several of the identified isQTLs involved differences in endothelial and fibroblast cell content (Table S5), and these signals may also indicate links with immune cell differences: for instance, rs4072037 is associated with endothelial cell content in normal esophageal tissue, and this variant corresponds to a cis-expression (cis-e) QTL in several normal tissue types of genes whose products are functionally relevant in the immune system and biology of endothelial cells, including GBA, GBAP1, TSP3/THSB3, and MUC1, which are locus-mapped genes.	('rs4072037', 'Mutation', 'rs4072037', (195, 204))	('TSP3', 'Gene', (497, 501))	('GBA', 'Gene', (490, 493))	('GBA', 'Gene', '2629', (485, 488))	('GBA', 'Gene', '2629', (490, 493))	('associated', 'Reg', (208, 218))	('GBA', 'Gene', (485, 488))	('rs4072037', 'Var', (195, 204))	('MUC1', 'Gene', (513, 517))	('MUC1', 'Gene', '4582', (513, 517))	('TSP3', 'Gene', '7059', (497, 501))	('GBAP1', 'Gene', (490, 495))	('GBAP1', 'Gene', '2630', (490, 495))
159171	32622267	In addition, the cancer pleiotropy rs11168936 variant is associated with differences in fibroblast content in normal lung tissue corresponding to LUSC, and this variant is a cis-eQTL for C1QL4 in several normal tissue types.	('rs11168936', 'Var', (35, 45))	('LUSC', 'Phenotype', 'HP:0030359', (146, 150))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('C1QL4', 'Gene', (187, 192))	('rs11168936', 'Mutation', 'rs11168936', (35, 45))	('cancer', 'Disease', (17, 23))	('eQTL', 'Gene', '67753', (178, 182))	('fibroblast content', 'MPA', (88, 106))	('eQTL', 'Gene', (178, 182))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))	('C1QL4', 'Gene', '338761', (187, 192))
159172	32622267	Intriguingly, C1q is a regulator of dendritic cell maturation, and we found this variant also to be associated with dendritic cell content (Figure 2B).	('C1q', 'Gene', (14, 17))	('associated', 'Reg', (100, 110))	('variant', 'Var', (81, 88))	('C1q', 'Gene', '712', (14, 17))	('dendritic cell content', 'MPA', (116, 138))
159173	32622267	In normal lung tissue corresponding to LUAD, rs17078110 is associated with B cells, and this locus codes for SASH1, a regulator of TLR4 signaling and cytokine production.	('SASH1', 'Gene', '23328', (109, 114))	('rs17078110', 'Var', (45, 55))	('rs17078110', 'Mutation', 'rs17078110', (45, 55))	('TLR4', 'Gene', '7099', (131, 135))	('TLR4', 'Gene', (131, 135))	('SASH1', 'Gene', (109, 114))	('LUAD', 'Phenotype', 'HP:0030078', (39, 43))
159174	32622267	Among the isQTLs identified in tumors, rs3764419 is associated with cytotoxic cell content in OV.	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumors', 'Disease', (31, 37))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('cytotoxic cell content', 'MPA', (68, 90))	('associated', 'Reg', (52, 62))	('tumors', 'Disease', 'MESH:D009369', (31, 37))	('rs3764419', 'Var', (39, 48))	('OV', 'Phenotype', 'HP:0012887', (94, 96))	('rs3764419', 'Mutation', 'rs3764419', (39, 48))
159176	32622267	Overall, these data suggest that some cancer risk variants are associated with immune/stromal cell tissue content, and that this link is mediated by alterations in genes of functional importance to the immune system.	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('alterations', 'Reg', (149, 160))	('associated', 'Reg', (63, 73))	('immune/stromal', 'MPA', (79, 93))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('variants', 'Var', (50, 58))	('cancer', 'Disease', (38, 44))
159179	32622267	Of the 57 unique variants identified from all isQTLs, five were linked to tumor suppressor genes with recognized roles in the immune system: CDKN2A/B, DCC, MUC1, and SASH1.	('CDKN2A/B', 'Gene', '1029;1030', (141, 149))	('SASH1', 'Gene', (166, 171))	('variants', 'Var', (17, 25))	('MUC1', 'Gene', (156, 160))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('MUC1', 'Gene', '4582', (156, 160))	('SASH1', 'Gene', '23328', (166, 171))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('CDKN2A/B', 'Gene', (141, 149))	('tumor', 'Disease', (74, 79))	('DCC', 'Gene', (151, 154))	('linked', 'Reg', (64, 70))	('DCC', 'Gene', '1630', (151, 154))
159180	32622267	In addition, genomic enhancers identified in T helper, regulatory, effector, memory, and mononuclear cells were significantly over-represented in this unique variant set relative to all human variants: > 2-fold enrichments, binomial test p values <0.05.	('human', 'Species', '9606', (186, 191))	('variant', 'Var', (158, 165))	('over-represented', 'PosReg', (126, 142))
159181	32622267	Consistent with this observation, 8 (14%) variants corresponded to expression (e) QTLs from 18 immune-related genes in normal human tissue and 13 (25%) corresponded to eQTLs identified in CD4+ and/or CD8+ T cells (Tables S5 and S6).	('human', 'Species', '9606', (126, 131))	('CD8', 'Gene', '925', (200, 203))	('CD4', 'Gene', '920', (188, 191))	('variants', 'Var', (42, 50))	('eQTL', 'Gene', '67753', (168, 172))	('expression', 'MPA', (67, 77))	('CD8', 'Gene', (200, 203))	('CD4', 'Gene', (188, 191))	('eQTL', 'Gene', (168, 172))
159185	32622267	Finally, variants correlated (r2 > 0.8) with each isQTL were intersected with various functional genomic data from B cells, monocytes, and CD4+ and CD8+ T cells, and for potential effects on protein coding sequences (Methods).	('CD8', 'Gene', '925', (148, 151))	('CD4', 'Gene', (139, 142))	('effects', 'Reg', (180, 187))	('CD8', 'Gene', (148, 151))	('variants', 'Var', (9, 17))	('CD4', 'Gene', '920', (139, 142))
159187	32622267	The effects of individual cancer risk variants are generally small, but their combinations within PRSs can potentially identify individuals who are at substantially higher risk than average for the population.	('cancer', 'Disease', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('variants', 'Var', (38, 46))
159198	32622267	Combined analyses of normal tissue and primary tumor data further suggested common protective effects for high immune cell content in breast and colorectal tissue, and also potentially in brain and a few other settings (Figure 3C).	('high', 'Var', (106, 110))	('tumor', 'Disease', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor', 'Disease', 'MESH:D009369', (47, 52))
159199	32622267	In contrast, high immune cell content might principally increase the risk of lung, bladder, and pancreatic cancer (Figure 3C), although, as already noted, smoking may influence these associations.	('bladder', 'Disease', (83, 90))	('increase', 'PosReg', (56, 64))	('pancreatic cancer', 'Disease', (96, 113))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('influence', 'Reg', (167, 176))	('pancreatic cancer', 'Disease', 'MESH:D010190', (96, 113))	('high immune', 'Var', (13, 24))	('lung', 'Disease', (77, 81))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (96, 113))
159200	32622267	Then, analyses of COAD subtypes (Methods) suggested protective effects for high immune cell content in genomic stable tumors (Figure 3D, left panel), but this association might be biased due to PRS development in overall incident cases.	('high', 'Var', (75, 79))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('tumors', 'Disease', (118, 124))	('tumors', 'Disease', 'MESH:D009369', (118, 124))
159206	32622267	Examination of GWAS results for blood cell traits revealed that the tumor COAD isQTL rs12412391 in chromosome 10 (Table S6) is in linkage disequilibrium (r2 = 0.93) with rs11190133, which is associated with differences in platelets in the UK Biobank study.	('rs12412391', 'Mutation', 'rs12412391', (85, 95))	('rs11190133', 'Mutation', 'rs11190133', (170, 180))	('tumor COAD isQTL', 'Disease', 'MESH:D029424', (68, 84))	('rs12412391', 'Var', (85, 95))	('rs11190133', 'Var', (170, 180))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('tumor COAD isQTL', 'Disease', (68, 84))
159207	32622267	These variants constitute an eQTL of NKX2-3, and, remarkably, loss of the mouse ortholog causes developmental alterations in the spleen, colonic crypts, and lymphocyte tissue homing.	('lymphocyte tissue homing', 'CPA', (157, 181))	('eQTL', 'Gene', '67753', (29, 33))	('loss', 'Var', (62, 66))	('developmental alterations in', 'CPA', (96, 124))	('colonic crypts', 'Disease', 'MESH:D003110', (137, 151))	('eQTL', 'Gene', (29, 33))	('NKX2-3', 'Gene', '18089', (37, 43))	('mouse', 'Species', '10090', (74, 79))	('colonic crypts', 'Disease', (137, 151))	('NKX2-3', 'Gene', (37, 43))
159208	32622267	In addition to this locus, the tumor BRCA isQTL rs11065979 in chromosome 12 (Table S5) was associated with blood count differences in basophils, erythrocytes, eosinophils, leukocytes, monocytes, and neutrophils in the UK Biobank study (Table S8).	('tumor BRCA isQTL', 'Disease', (31, 47))	('rs11065979', 'Mutation', 'rs11065979', (48, 58))	('rs11065979', 'Var', (48, 58))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('blood count differences', 'MPA', (107, 130))	('BRCA', 'Phenotype', 'HP:0003002', (37, 41))	('tumor BRCA isQTL', 'Disease', 'MESH:D009369', (31, 47))	('associated', 'Reg', (91, 101))
159210	32622267	This variant has also been linked to cancer pleiotropy and psoriasis, among other traits (GWAS Catalog).	('linked', 'Reg', (27, 33))	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('cancer', 'Disease', (37, 43))	('psoriasis', 'Disease', 'MESH:D011565', (59, 68))	('variant', 'Var', (5, 12))	('psoriasis', 'Phenotype', 'HP:0003765', (59, 68))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('psoriasis', 'Disease', (59, 68))
159211	32622267	A variant in linkage disequilibrium, rs3184504 (r2 = 0.89), had also been associated with breast cancer risk, serum IgA levels, and various autoimmune diseases, among other traits (GWAS Catalog).	('autoimmune diseases', 'Disease', (140, 159))	('autoimmune diseases', 'Phenotype', 'HP:0002960', (140, 159))	('rs3184504', 'Var', (37, 46))	('IgA', 'Gene', (116, 119))	('IgA', 'Gene', '973', (116, 119))	('breast cancer', 'Disease', 'MESH:D001943', (90, 103))	('rs3184504', 'Mutation', 'rs3184504', (37, 46))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('breast cancer', 'Disease', (90, 103))	('breast cancer', 'Phenotype', 'HP:0003002', (90, 103))	('autoimmune diseases', 'Disease', 'MESH:D001327', (140, 159))	('associated', 'Reg', (74, 84))
159212	32622267	To investigate further the role of the isQTL identified in chromosome 12 and linked to breast cancer risk, we analyzed association results from BRCA1/2 mutation carriers.	('BRCA1/2', 'Gene', (144, 151))	('breast cancer', 'Disease', 'MESH:D001943', (87, 100))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('breast cancer', 'Disease', (87, 100))	('linked', 'Reg', (77, 83))	('breast cancer', 'Phenotype', 'HP:0003002', (87, 100))	('BRCA', 'Phenotype', 'HP:0003002', (144, 148))	('mutation', 'Var', (152, 160))
159213	32622267	Both depicted variants showed nominal associations with breast cancer risk in women carriers of germline BRCA1 or BRCA2 mutations: BRCA1 mutation carriers, rs11065979 hazard ratio (HR) = 0.96, 95% confidence interval (CI) 0.92-0.99, p = 0.018; rs3184504 HR = 0.95, 95% CI 0.92-0.99, p = 0.006; BRCA2 mutation carriers, rs11065979 HR = 0.94, 95% CI 0.90-0.99, p = 0.019; and rs3184504 HR = 0.93, 95% CI 0.89-0.98, p = 0.003.	('BRCA2', 'Gene', (114, 119))	('BRCA', 'Phenotype', 'HP:0003002', (131, 135))	('BRCA1', 'Gene', '672', (131, 136))	('BRCA', 'Phenotype', 'HP:0003002', (105, 109))	('breast cancer', 'Disease', 'MESH:D001943', (56, 69))	('rs11065979', 'Mutation', 'rs11065979', (156, 166))	('mutations', 'Var', (120, 129))	('BRCA1', 'Gene', (131, 136))	('rs11065979', 'Var', (319, 329))	('breast cancer', 'Disease', (56, 69))	('rs3184504', 'Mutation', 'rs3184504', (374, 383))	('women', 'Species', '9606', (78, 83))	('BRCA2', 'Gene', '675', (114, 119))	('BRCA', 'Phenotype', 'HP:0003002', (114, 118))	('BRCA2', 'Gene', (294, 299))	('BRCA', 'Phenotype', 'HP:0003002', (294, 298))	('BRCA1', 'Gene', '672', (105, 110))	('rs3184504', 'Mutation', 'rs3184504', (244, 253))	('rs11065979', 'Mutation', 'rs11065979', (319, 329))	('BRCA1', 'Gene', (105, 110))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('BRCA2', 'Gene', '675', (294, 299))	('associations', 'Interaction', (38, 50))	('rs11065979', 'Var', (156, 166))	('breast cancer', 'Phenotype', 'HP:0003002', (56, 69))	('rs3184504 HR', 'Var', (374, 386))
159237	32622267	Common genetic variation at this locus has been linked to cancer pleiotropy, including breast cancer susceptibility.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('breast cancer', 'Disease', 'MESH:D001943', (87, 100))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('breast cancer', 'Disease', (87, 100))	('Common genetic variation', 'Var', (0, 24))	('breast cancer', 'Phenotype', 'HP:0003002', (87, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))	('cancer', 'Disease', (58, 64))	('cancer', 'Disease', (94, 100))	('linked', 'Reg', (48, 54))
159238	32622267	We extend these observations by identifying potential associations with breast and ovarian cancer risk in BRCA1/2 mutation carriers.	('ovarian cancer', 'Phenotype', 'HP:0100615', (83, 97))	('associations', 'Interaction', (54, 66))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('BRCA', 'Phenotype', 'HP:0003002', (106, 110))	('mutation', 'Var', (114, 122))	('BRCA1/2', 'Gene', (106, 113))	('breast and ovarian cancer', 'Disease', 'MESH:D001943', (72, 97))
159239	32622267	Thus, pharmacological enhancement of SH2B3 function might reduce cancer risk in individuals with high PRSs and/or carriers of BRCA1/2 mutations.	('function', 'MPA', (43, 51))	('carriers', 'Reg', (114, 122))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('SH2B3', 'Gene', (37, 42))	('enhancement', 'PosReg', (22, 33))	('reduce', 'NegReg', (58, 64))	('mutations', 'Var', (134, 143))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('BRCA1/2', 'Gene', (126, 133))	('BRCA', 'Phenotype', 'HP:0003002', (126, 130))
159243	32622267	However, high baseline leukocyte counts in a prospective study of postmenopausal women were found to be associated with increased breast cancer incidence.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('breast cancer', 'Disease', (130, 143))	('breast cancer', 'Phenotype', 'HP:0003002', (130, 143))	('women', 'Species', '9606', (81, 86))	('leukocyte counts', 'Var', (23, 39))	('increased', 'PosReg', (120, 129))	('breast cancer', 'Disease', 'MESH:D001943', (130, 143))
159246	32622267	The present report identifies cancer-associated genetic variants and polygenic risk scores linked to the alteration of immune and/or stromal cell systemic and/or tissue contents.	('variants', 'Var', (56, 64))	('cancer', 'Disease', (30, 36))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
159255	32201313	ERO1 dysfunction critically affects several diseases states.	('diseases', 'Disease', (44, 52))	('ERO1', 'Gene', '854909', (0, 4))	('ERO1', 'Gene', (0, 4))	('affects', 'Reg', (28, 35))	('dysfunction', 'Var', (5, 16))
159273	32201313	Furthermore, complex II (succinate dehydrogenase) also plays a role in ROS generation, and mutation or dysfunction of complex II can enhance ROS production.	('enhance', 'PosReg', (133, 140))	('mutation', 'Var', (91, 99))	('ROS', 'MPA', (71, 74))	('ROS', 'Chemical', 'MESH:D017382', (141, 144))	('complex II', 'Gene', (118, 128))	('dysfunction', 'Var', (103, 114))	('ROS production', 'MPA', (141, 155))	('enhance ROS production', 'Phenotype', 'HP:0025464', (133, 155))	('ROS', 'Chemical', 'MESH:D017382', (71, 74))
159309	32201313	For example, ROS induces the release of cytochrome c to the cytoplasm, inhibiting complex III activity and further inducing ROS in the form of a ubisemiquinone radical intermediate.	('inhibiting', 'NegReg', (71, 81))	('ROS', 'Var', (13, 16))	('ROS', 'MPA', (124, 127))	('complex', 'Enzyme', (82, 89))	('ubisemiquinone', 'Chemical', 'MESH:C024989', (145, 159))	('inducing', 'NegReg', (115, 123))	('cytochrome c', 'Gene', (40, 52))	('ROS', 'Chemical', 'MESH:D017382', (124, 127))	('cytochrome c', 'Gene', '54205', (40, 52))	('ROS', 'Chemical', 'MESH:D017382', (13, 16))
159312	32201313	ERO1 silencing or pharmacological inhibition (EN460) blocks calcium re-uptake by mitochondria but not by the ER.	('ER', 'Gene', '2069', (109, 111))	('calcium', 'Chemical', 'MESH:D002118', (60, 67))	('silencing', 'Var', (5, 14))	('mitochondria', 'MPA', (81, 93))	('ERO1', 'Gene', '854909', (0, 4))	('calcium re-uptake', 'CPA', (60, 77))	('ERO1', 'Gene', (0, 4))	('EN460', 'Chemical', '-', (46, 51))	('ER', 'Gene', '2069', (0, 2))	('blocks', 'NegReg', (53, 59))
159321	32201313	ERO1beta is more active than ERO1alpha in vitro, and is highly expressed in the pancreas, emphasizing its importance in insulin biogenesis and glucose homeostasis.	('glucose homeostasis', 'Disease', 'MESH:D044882', (143, 162))	('insulin', 'Gene', (120, 127))	('insulin', 'Gene', '3630', (120, 127))	('ERO1beta', 'Var', (0, 8))	('glucose homeostasis', 'Disease', (143, 162))	('active', 'MPA', (17, 23))
159324	32201313	Furthermore, ERO1alpha contains two sites for N-glycosylation, Asp280 and Asp384.	('N', 'Chemical', 'MESH:D009584', (46, 47))	('Asp384', 'Chemical', '-', (74, 80))	('N-glycosylation', 'MPA', (46, 61))	('Asp384', 'Var', (74, 80))	('Asp280', 'Var', (63, 69))	('ERO1alpha', 'Gene', (13, 22))	('Asp280', 'Chemical', '-', (63, 69))
159332	32201313	ERO1alpha is inactivated when those cysteines form bonds with other cysteines in the protein, to form two disulfide bond pairs (OX2): Cys94-Cys131 and Cys99-Cys104 (Fig.	('OX2', 'Gene', '4345', (128, 131))	('Cys99-Cys104', 'Var', (151, 163))	('Cys104', 'Chemical', '-', (157, 163))	('Cys131', 'Chemical', '-', (140, 146))	('Cys94-Cys131', 'Var', (134, 146))	('cysteines', 'Chemical', 'MESH:D003545', (36, 45))	('OX2', 'Gene', (128, 131))	('cysteines', 'Chemical', 'MESH:D003545', (68, 77))	('Cys94', 'Chemical', '-', (134, 139))	('ERO1alpha', 'Gene', (0, 9))	('Cys99', 'Chemical', '-', (151, 156))	('disulfide', 'Chemical', 'MESH:D004220', (106, 115))
159335	32201313	A Cys81-Cys390 disulfide stabilizes ERO1beta by linking the "loop cap" and "helical core."	('Cys390', 'Chemical', '-', (8, 14))	('Cys81', 'Chemical', '-', (2, 7))	('disulfide', 'Chemical', 'MESH:D004220', (15, 24))	('Cys81-Cys390', 'Var', (2, 14))	('stabilizes', 'Reg', (25, 35))	('helical', 'MPA', (76, 83))	('ERO1beta', 'Protein', (36, 44))
159346	32201313	ERO1p knockdown in yeast (S. cerevisiae) impairs the redox environment of the ER and disrupts protein folding.	('yeast', 'Species', '4932', (19, 24))	('ERO1p', 'Gene', (0, 5))	('ERO1p', 'Gene', '854909', (0, 5))	('disrupts', 'NegReg', (85, 93))	('ER', 'Gene', '2069', (78, 80))	('impairs', 'NegReg', (41, 48))	('S. cerevisiae', 'Species', '4932', (26, 39))	('redox environment of', 'MPA', (53, 73))	('ER', 'Gene', '2069', (0, 2))	('protein folding', 'MPA', (94, 109))	('knockdown', 'Var', (6, 15))
159347	32201313	ERO1beta knockdown in mice hinders proinsulin folding, while double knockdown of ERO1alpha and ERO1beta in immunoglobulin-producing cells does not affect disulfide bond formation or secretion of immunoglobulin.	('disulfide', 'Chemical', 'MESH:D004220', (154, 163))	('proinsulin folding', 'MPA', (35, 53))	('knockdown', 'Var', (9, 18))	('ERO1beta', 'Gene', (0, 8))	('hinders', 'NegReg', (27, 34))	('ERO1alpha', 'Gene', (81, 90))	('mice', 'Species', '10090', (22, 26))
159351	32201313	Knockout of ERO1alpha, ERO1beta, and the antioxidant enzyme peroxiredoxin 4 (PRDX4) leads to a deficiency in procollagen maturation, depletion of ascorbic acid, and scurvy in mice.	('deficiency', 'Disease', 'MESH:D007153', (95, 105))	('mice', 'Species', '10090', (175, 179))	('PRDX4', 'Gene', (77, 82))	('ERO1beta', 'Var', (23, 31))	('ERO1alpha', 'Gene', (12, 21))	('procollagen maturation', 'MPA', (109, 131))	('deficiency', 'Disease', (95, 105))	('Knockout', 'Var', (0, 8))	('scurvy', 'Disease', (165, 171))	('ascorbic acid', 'Chemical', 'MESH:D001205', (146, 159))	('depletion of ascorbic acid', 'MPA', (133, 159))
159352	32201313	In cervical cancer cells, knockdown of ERO1 impaired tumorigenesis.	('ERO1', 'Gene', '854909', (39, 43))	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('cancer', 'Disease', (12, 18))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('ERO1', 'Gene', (39, 43))	('impaired', 'NegReg', (44, 52))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('knockdown', 'Var', (26, 35))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('tumor', 'Disease', (53, 58))
159353	32201313	Whole body knockout of ERO1beta specifically impairs pancreatic beta cell function because ERO1beta is expressed in the pancreas; in addition to the pancreas, ERO1beta is selectively expressed in the testis, liver, appendix, thyroid, and pituitary gland.	('impairs pancreatic beta', 'Disease', (45, 68))	('ERO1beta', 'Var', (159, 167))	('ERO1beta', 'Gene', (91, 99))	('impairs pancreatic beta', 'Disease', 'MESH:D010195', (45, 68))
159360	32201313	However, because ERO1beta plays such a significant role in insulin signaling, ERO1beta inhibitors may cause side effects such as glucose intolerance.	('glucose intolerance', 'Phenotype', 'HP:0001952', (129, 148))	('cause', 'Reg', (102, 107))	('glucose intolerance', 'Disease', (129, 148))	('ERO1beta', 'Gene', (78, 86))	('glucose', 'Chemical', 'MESH:D005947', (129, 136))	('insulin', 'Gene', (59, 66))	('insulin', 'Gene', '3630', (59, 66))	('inhibitors', 'Var', (87, 97))
159375	32201313	Specifically, Phe240, Phe249, and Phe304 in the b' domain likely form non-covalent interactions with the beta-hairpin region of ERO1alpha.	('Phe304', 'Var', (34, 40))	('form', 'Reg', (65, 69))	('Phe240', 'Chemical', '-', (14, 20))	('Phe240', 'Var', (14, 20))	('non-covalent', 'MPA', (70, 82))	('Phe304', 'Chemical', '-', (34, 40))	('Phe249', 'Chemical', '-', (22, 28))	('beta-hairpin', 'Protein', (105, 117))	('Phe249', 'Var', (22, 28))
159376	32201313	Furthermore, Val101 and Trp272 of ERO1alpha are necessary for PDI-ERO1 complex formation.	('Trp272', 'Chemical', '-', (24, 30))	('Val101', 'Chemical', '-', (13, 19))	('ERO1', 'Gene', '854909', (34, 38))	('ERO1', 'Gene', (34, 38))	('ERO1', 'Gene', '854909', (66, 70))	('Trp272', 'Protein', (24, 30))	('Val101', 'Var', (13, 19))	('PDI', 'Gene', (62, 65))	('PDI', 'Gene', '5034', (62, 65))	('ERO1', 'Gene', (66, 70))
159377	32201313	These interactions position Cys397 and Cys400 in the a' domain active site of PDIA1 near the disulfide-bonded cysteines in the shuttle loop of ERO1alpha and allow ERO1alpha to perform the disulfide exchange.	('cysteines', 'Chemical', 'MESH:D003545', (110, 119))	('allow', 'Reg', (157, 162))	('Cys397', 'Var', (28, 34))	('disulfide', 'Chemical', 'MESH:D004220', (93, 102))	('PDIA1', 'Gene', '5034', (78, 83))	('interactions', 'Var', (6, 18))	('perform', 'MPA', (176, 183))	('disulfide', 'Chemical', 'MESH:D004220', (188, 197))	('Cys400', 'Chemical', '-', (39, 45))	('disulfide exchange', 'MPA', (188, 206))	('Cys397', 'Chemical', '-', (28, 34))	('Cys400', 'Var', (39, 45))	('PDIA1', 'Gene', (78, 83))
159384	32201313	Inhibition of ERO1 may prevent or slow reoxidation of PDIA1 and impair protein folding in tumor cells.	('PDIA1', 'Gene', (54, 59))	('protein folding', 'MPA', (71, 86))	('reoxidation', 'MPA', (39, 50))	('PDIA1', 'Gene', '5034', (54, 59))	('tumor', 'Disease', (90, 95))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('slow', 'NegReg', (34, 38))	('ERO1', 'Gene', '854909', (14, 18))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('Inhibition', 'Var', (0, 10))	('ERO1', 'Gene', (14, 18))	('impair', 'NegReg', (64, 70))
159386	32201313	Furthermore, S-nitrosylation of PDIA1 can lead to sulfinic acid (-SO2H) modification.	('sulfinic acid', 'Chemical', 'MESH:D013441', (50, 63))	('PDIA1', 'Gene', '5034', (32, 37))	('SO2H', 'Chemical', '-', (66, 70))	('lead to', 'Reg', (42, 49))	('S-nitrosylation', 'Var', (13, 28))	('PDIA1', 'Gene', (32, 37))
159395	32201313	Thus, S-glutathionylation of PDIA1 halts protein folding until cell homeostasis is restored.	('PDIA1', 'Gene', '5034', (29, 34))	('S-glutathionylation', 'Var', (6, 25))	('protein folding', 'MPA', (41, 56))	('halts', 'NegReg', (35, 40))	('PDIA1', 'Gene', (29, 34))
159408	32201313	PDIA1 regulates integrin-mediated platelet function, thus, inhibition of PDIA1 has shown promise as a potential thrombosis inhibitor.	('thrombosis', 'Disease', 'MESH:D013927', (112, 122))	('PDIA1', 'Gene', '5034', (73, 78))	('PDIA1', 'Gene', (0, 5))	('PDIA1', 'Gene', '5034', (0, 5))	('regulates', 'Reg', (6, 15))	('PDIA1', 'Gene', (73, 78))	('thrombosis', 'Disease', (112, 122))	('inhibition', 'Var', (59, 69))	('integrin-mediated platelet function', 'MPA', (16, 51))
159409	32201313	In neurodegenerative diseases, PDIA1 is overexpressed and causes apoptosis, and modulation of PDIA1 with small molecule inhibitors is neuroprotective in Huntington's disease models.	("Huntington's disease", 'Disease', (153, 173))	('PDIA1', 'Gene', '5034', (94, 99))	("Huntington's disease", 'Disease', 'MESH:D006816', (153, 173))	('causes', 'Reg', (58, 64))	('modulation', 'Var', (80, 90))	('neurodegenerative diseases', 'Disease', 'MESH:D019636', (3, 29))	('apoptosis', 'CPA', (65, 74))	('PDIA1', 'Gene', (31, 36))	('PDIA1', 'Gene', (94, 99))	('neurodegenerative diseases', 'Phenotype', 'HP:0002180', (3, 29))	('overexpressed', 'PosReg', (40, 53))	('PDIA1', 'Gene', '5034', (31, 36))	('neurodegenerative diseases', 'Disease', (3, 29))
159410	32201313	In diabetes, PDIA1 knockdown promotes proinsulin export and overexpression of PDIA1 leads to proinsulin retention in the organelle.	('PDIA1', 'Gene', (13, 18))	('proinsulin retention in the organelle', 'MPA', (93, 130))	('diabetes', 'Disease', (3, 11))	('PDIA1', 'Gene', '5034', (78, 83))	('knockdown', 'Var', (19, 28))	('diabetes', 'Disease', 'MESH:D003920', (3, 11))	('proinsulin export', 'MPA', (38, 55))	('PDIA1', 'Gene', '5034', (13, 18))	('promotes', 'PosReg', (29, 37))	('PDIA1', 'Gene', (78, 83))
159416	32201313	ER stress, or an imbalance between the newly synthesized proteins and machinery expressed and ready to fold and secrete them, triggers the UPR via three major arms: protein kinase RNA-like ER kinase (PERK), inositol-requiring protein 1alpha (IRE1alpha), and activating transcription factor 6 (ATF6).	('inositol-requiring protein 1', 'Gene', '2081', (207, 235))	('ER', 'Gene', '2069', (201, 203))	('protein kinase RNA-like ER kinase', 'Gene', (165, 198))	('IRE1alpha', 'Gene', (242, 251))	('inositol-requiring protein 1', 'Gene', (207, 235))	('imbalance', 'Phenotype', 'HP:0002172', (17, 26))	('ATF6', 'Gene', (293, 297))	('PERK', 'Gene', (200, 204))	('activating transcription factor 6', 'Gene', (258, 291))	('activating transcription factor 6', 'Gene', '22926', (258, 291))	('PERK', 'Gene', '9451', (200, 204))	('ER', 'Gene', '2069', (0, 2))	('protein kinase RNA-like ER kinase', 'Gene', '9451', (165, 198))	('imbalance', 'Var', (17, 26))	('IRE1alpha', 'Gene', '2081', (242, 251))	('ER', 'Gene', '2069', (189, 191))	('ATF6', 'Gene', '22926', (293, 297))
159421	32201313	Increased protein synthesis leads to an increase in ROS and ERO1alpha knockdown actually rescues cell death when CHOP and ATF4 are activated.	('ROS', 'MPA', (52, 55))	('knockdown', 'Var', (70, 79))	('increase', 'PosReg', (40, 48))	('ATF4', 'Gene', (122, 126))	('ROS', 'Chemical', 'MESH:D017382', (52, 55))	('Increased', 'PosReg', (0, 9))	('ATF4', 'Gene', '468', (122, 126))	('protein synthesis', 'MPA', (10, 27))	('ERO1alpha', 'Protein', (60, 69))	('cell death', 'CPA', (97, 107))
159423	32201313	It has been suggested that ERO1-mediated generation of H2O2 during ER stress leads to apoptosis; however, the origin of ROS may actually be the mitochondria.	('H2O2', 'Chemical', 'MESH:D006861', (55, 59))	('H2O2', 'Var', (55, 59))	('ROS', 'Chemical', 'MESH:D017382', (120, 123))	('ER', 'Gene', '2069', (67, 69))	('ERO1', 'Gene', '854909', (27, 31))	('ERO1', 'Gene', (27, 31))	('ER', 'Gene', '2069', (27, 29))	('apoptosis', 'CPA', (86, 95))	('leads to', 'Reg', (77, 85))
159434	32201313	Increased ROS can increase sarco/endoplasmic-reticulum Ca2+ ATPase activity, in turn increasing calcium levels in the ER.	('calcium levels', 'MPA', (96, 110))	('increase', 'PosReg', (18, 26))	('ATP', 'Chemical', 'MESH:D000255', (60, 63))	('ER', 'Gene', '2069', (118, 120))	('ROS', 'Var', (10, 13))	('increasing', 'PosReg', (85, 95))	('ROS', 'Chemical', 'MESH:D017382', (10, 13))	('Ca2+', 'Chemical', 'MESH:D000069285', (55, 59))	('calcium', 'Chemical', 'MESH:D002118', (96, 103))	('sarco/endoplasmic-reticulum Ca2+ ATPase activity', 'MPA', (27, 75))
159445	32201313	ERO1 knockout in mammals is not as lethal as it is in yeast, suggesting that mammalian systems have evolved redundant pathways to compensate for ERO1 loss.	('ERO1', 'Gene', (145, 149))	('knockout', 'Var', (5, 13))	('yeast', 'Species', '4932', (54, 59))	('ERO1', 'Gene', '854909', (0, 4))	('mammalian', 'Species', '9606', (77, 86))	('ERO1', 'Gene', (0, 4))	('loss', 'NegReg', (150, 154))	('ERO1', 'Gene', '854909', (145, 149))
159447	32201313	Abnormalities associated with dysfunctional ERO1 include cardiac conduction irregularities in ERO1alpha mutant mice and problems with insulin folding and secretion.	('ERO1', 'Gene', '854909', (44, 48))	('ERO1', 'Gene', (94, 98))	('insulin', 'Gene', (134, 141))	('problems', 'Reg', (120, 128))	('ERO1', 'Gene', (44, 48))	('mutant', 'Var', (104, 110))	('secretion', 'MPA', (154, 163))	('insulin', 'Gene', '3630', (134, 141))	('mice', 'Species', '10090', (111, 115))	('cardiac conduction irregularities', 'Phenotype', 'HP:0011675', (57, 90))	('dysfunctional', 'Disease', 'MESH:D009461', (30, 43))	('ERO1', 'Gene', '854909', (94, 98))	('cardiac', 'MPA', (57, 64))	('dysfunctional', 'Disease', (30, 43))
159449	32201313	Although the knockout phenotype is mild, ERO1 dysfunction may stimulate ER stress and lead to diseases related to oxidative stress and ER malfunction.	('diseases', 'Disease', (94, 102))	('ERO1', 'Gene', '854909', (41, 45))	('ERO1', 'Gene', (41, 45))	('stimulate', 'PosReg', (62, 71))	('lead to', 'Reg', (86, 93))	('ER', 'Gene', '2069', (41, 43))	('dysfunction', 'Var', (46, 57))	('ER', 'Gene', '2069', (72, 74))	('oxidative stress', 'Phenotype', 'HP:0025464', (114, 130))	('ER', 'Gene', '2069', (135, 137))
159451	32201313	ERO1alpha overexpression decreases mutant proinsulin-G(B32)V misfolding in a model of mutant Ins-gene-induced diabetes of youth.	('mutant', 'Var', (86, 92))	('decreases', 'NegReg', (25, 34))	('diabetes', 'Disease', (110, 118))	('mutant', 'Var', (35, 41))	('diabetes', 'Disease', 'MESH:D003920', (110, 118))	('ERO1alpha', 'Gene', (0, 9))
159455	32201313	ERp44 forms a covalent bond with adiponectin to promote its retention in the secretory pathway, and ERO1alpha can release adiponectin, likely because it is a competitive binder of ERp44.	('ERp44', 'Gene', (180, 185))	('adiponectin', 'Gene', '9370', (33, 44))	('secretory pathway', 'MPA', (77, 94))	('retention', 'MPA', (60, 69))	('adiponectin', 'Gene', (33, 44))	('adiponectin', 'Gene', '9370', (122, 133))	('ERp44', 'Gene', (0, 5))	('ERp44', 'Gene', '23071', (0, 5))	('promote', 'PosReg', (48, 55))	('ERp44', 'Gene', '23071', (180, 185))	('ERO1alpha', 'Var', (100, 109))	('adiponectin', 'Gene', (122, 133))
159456	32201313	Thus, in this context, knockout or inhibition of ERO1alpha could lead to potential side effects caused by improper folding and release of functional adiponectin.	('adiponectin', 'Gene', '9370', (149, 160))	('folding', 'MPA', (115, 122))	('ERO1alpha', 'Gene', (49, 58))	('knockout', 'Var', (23, 31))	('adiponectin', 'Gene', (149, 160))	('lead to', 'Reg', (65, 72))	('inhibition', 'NegReg', (35, 45))
159463	32201313	In other mouse models of diabetes, in addition to promoting cell survival and decreasing oxidative damage, CHOP deletion decreased ERO1alpha expression, reflecting the role of ERO1alpha as a target of CHOP.	('diabetes', 'Disease', (25, 33))	('ERO1alpha', 'Gene', (131, 140))	('diabetes', 'Disease', 'MESH:D003920', (25, 33))	('mouse', 'Species', '10090', (9, 14))	('deletion', 'Var', (112, 120))	('decreasing', 'NegReg', (78, 88))	('decreased', 'NegReg', (121, 130))	('promoting', 'PosReg', (50, 59))	('expression', 'MPA', (141, 151))	('cell survival', 'CPA', (60, 73))	('CHOP', 'Gene', (107, 111))	('oxidative damage', 'MPA', (89, 105))
159470	32201313	Furthermore, ERO1alpha overexpression is associated with poor prognosis of cervical, gastric, breast, lung, hepatocellular, and multiple myeloma cancers, and knockdown of ERO1alpha in mice inhibited tumor growth.	('tumor', 'Disease', (199, 204))	('lung', 'Disease', (102, 106))	('overexpression', 'PosReg', (23, 37))	('cervical', 'Disease', (75, 83))	('multiple myeloma', 'Phenotype', 'HP:0006775', (128, 144))	('multiple myeloma cancers', 'Disease', (128, 152))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('breast', 'Disease', (94, 100))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('multiple myeloma cancers', 'Disease', 'MESH:D009369', (128, 152))	('hepatocellular', 'Disease', (108, 122))	('knockdown', 'Var', (158, 167))	('mice', 'Species', '10090', (184, 188))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('cancers', 'Phenotype', 'HP:0002664', (145, 152))	('ERO1alpha', 'Gene', (13, 22))	('gastric', 'Disease', (85, 92))
159489	32201313	Additionally, inhibition of ERO1 activity may prevent tumor growth in hypoxic tumors as ERO1alpha was identified as an adaptive response element in VEGF-mediated angiogenesis.	('prevent', 'NegReg', (46, 53))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('VEGF', 'Gene', (148, 152))	('ERO1', 'Gene', (88, 92))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor', 'Disease', (78, 83))	('ERO1', 'Gene', '854909', (28, 32))	('VEGF', 'Gene', '7422', (148, 152))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('ERO1', 'Gene', (28, 32))	('tumor', 'Disease', (54, 59))	('inhibition', 'Var', (14, 24))	('hypoxic tumors', 'Disease', (70, 84))	('ERO1', 'Gene', '854909', (88, 92))	('hypoxic tumors', 'Disease', 'MESH:D009369', (70, 84))
159508	32201313	Furthermore, inhibitors of P4H sensitize breast cancer cells to docetaxel and doxorubicin.	('breast cancer', 'Disease', 'MESH:D001943', (41, 54))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('breast cancer', 'Disease', (41, 54))	('inhibitors', 'Var', (13, 23))	('P4H', 'Protein', (27, 30))	('doxorubicin', 'Chemical', 'MESH:D004317', (78, 89))	('breast cancer', 'Phenotype', 'HP:0003002', (41, 54))	('sensitize', 'Reg', (31, 40))	('docetaxel', 'Chemical', 'MESH:D000077143', (64, 73))
159509	32201313	Similarly, knockdown of P4HA1 prevented collagen synthesis and neovascularization in glioma, and its expression could serve as a prognostic biomarker for high grade glioma.	('glioma', 'Disease', 'MESH:D005910', (85, 91))	('prevented', 'NegReg', (30, 39))	('glioma', 'Disease', 'MESH:D005910', (165, 171))	('glioma', 'Phenotype', 'HP:0009733', (165, 171))	('collagen synthesis', 'MPA', (40, 58))	('glioma', 'Disease', (165, 171))	('neovascularization', 'CPA', (63, 81))	('glioma', 'Phenotype', 'HP:0009733', (85, 91))	('glioma', 'Disease', (85, 91))	('P4HA1', 'Gene', (24, 29))	('expression', 'MPA', (101, 111))	('knockdown', 'Var', (11, 20))	('P4HA1', 'Gene', '5033', (24, 29))
159512	32201313	In ovarian cancer, an upstream repressor of P4HA1, miR-122, is typically downregulated, and overexpression can prevent epithelial to mesenchymal transition.	('miR-122', 'Gene', '406906', (51, 58))	('miR-122', 'Gene', (51, 58))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('P4HA1', 'Gene', (44, 49))	('ovarian cancer', 'Phenotype', 'HP:0100615', (3, 17))	('epithelial to mesenchymal transition', 'CPA', (119, 155))	('ovarian cancer', 'Disease', 'MESH:D010051', (3, 17))	('downregulated', 'NegReg', (73, 86))	('ovarian cancer', 'Disease', (3, 17))	('overexpression', 'Var', (92, 106))	('P4HA1', 'Gene', '5033', (44, 49))	('prevent', 'NegReg', (111, 118))
159517	32201313	Co-expression of ERO1alpha with proteins involved in COPII vesicle coating points to its role in lipid trafficking and biosynthesis, although this relationship has yet to be explored in detail.	('lipid', 'Chemical', 'MESH:D008055', (97, 102))	('Co-expression', 'Var', (0, 13))	('ERO1alpha', 'Gene', (17, 26))
159518	32201313	In HCC, ERO1alpha was demonstrated to trigger angiogenesis via the S1PR1/STAT3/VEGF-A signaling pathway.	('ERO1alpha', 'Var', (8, 17))	('trigger', 'PosReg', (38, 45))	('HCC', 'Gene', (3, 6))	('S1PR1', 'Gene', '1901', (67, 72))	('VEGF-A', 'Gene', '7422', (79, 85))	('STAT3', 'Gene', (73, 78))	('HCC', 'Gene', '619501', (3, 6))	('VEGF-A', 'Gene', (79, 85))	('S1PR1', 'Gene', (67, 72))	('STAT3', 'Gene', '6774', (73, 78))	('angiogenesis', 'CPA', (46, 58))
159520	32201313	We focused on lung cancer cell lines because ERO1alpha expression is associated with reduced LUAD patient survival.	('patient', 'Species', '9606', (98, 105))	('LUAD', 'Disease', (93, 97))	('lung cancer', 'Disease', (14, 25))	('lung cancer', 'Phenotype', 'HP:0100526', (14, 25))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('ERO1alpha', 'Var', (45, 54))	('reduced', 'NegReg', (85, 92))	('lung cancer', 'Disease', 'MESH:D008175', (14, 25))
159523	32201313	This also suggests that ERO1alpha knockdown may affect kinase signaling, such as JAK, p38, and other protein kinases.	('p38', 'Gene', (86, 89))	('affect', 'Reg', (48, 54))	('ERO1alpha', 'Protein', (24, 33))	('kinase signaling', 'MPA', (55, 71))	('protein', 'Enzyme', (101, 108))	('JAK', 'Disease', (81, 84))	('p38', 'Gene', '1432', (86, 89))	('knockdown', 'Var', (34, 43))
159525	32201313	ERO1alpha inhibition or knockdown may be lethal to cancer cells when combined with EGFR inhibitors, JAK inhibitors, or other kinase inhibitors.	('ERO1alpha', 'Protein', (0, 9))	('EGFR', 'Gene', '1956', (83, 87))	('combined', 'Interaction', (69, 77))	('EGFR', 'Gene', (83, 87))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('cancer', 'Disease', (51, 57))	('inhibition', 'Var', (10, 20))	('knockdown', 'Var', (24, 33))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('inhibitors', 'Var', (88, 98))
159526	32201313	We also identified genes that, when knocked down, have a similar signature as ERO1alpha knockdown in two lung cancer cell lines.	('lung cancer', 'Phenotype', 'HP:0100526', (105, 116))	('knockdown', 'Var', (88, 97))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('lung cancer', 'Disease', 'MESH:D008175', (105, 116))	('ERO1alpha', 'Gene', (78, 87))	('lung cancer', 'Disease', (105, 116))
159536	32201313	Furthermore, HEXIM1 is downregulated during cancer progression, and expression sensitizes prostate cancer cells to anti-androgens.	('downregulated', 'NegReg', (23, 36))	('prostate cancer', 'Disease', 'MESH:D011471', (90, 105))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('prostate cancer', 'Phenotype', 'HP:0012125', (90, 105))	('cancer', 'Disease', (99, 105))	('expression', 'Var', (68, 78))	('HEXIM1', 'Gene', (13, 19))	('HEXIM1', 'Gene', '10614', (13, 19))	('sensitizes', 'Reg', (79, 89))	('prostate cancer', 'Disease', (90, 105))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
159539	32201313	In addition to the three significantly connected perturbagens in CMap, P4HB overexpression is positively correlated with ERO1alpha knockdown in HCC515 cells (ranked 127 out of the 215 hits with a connectivity score > +90), suggesting there may be a compensatory expression mechanism (Table S4, Fig.	('ERO1alpha', 'Gene', (121, 130))	('knockdown', 'Var', (131, 140))	('P4HB', 'Gene', '5034', (71, 75))	('HCC515', 'CellLine', 'CVCL:5136', (144, 150))	('P4HB', 'Gene', (71, 75))	('overexpression', 'PosReg', (76, 90))
159546	32201313	Probe molecules EN460 and QM295 were identified from a biochemical high throughput screen to inhibit ERO1alpha-mediated reduction of thioredoxin A with IC50 values around 1.9 muM.	('inhibit', 'NegReg', (93, 100))	('EN460', 'Var', (16, 21))	('EN460', 'Chemical', '-', (16, 21))	('thioredoxin', 'Gene', (133, 144))	('QM295', 'Var', (26, 31))	('ERO1alpha-mediated', 'Enzyme', (101, 119))	('thioredoxin', 'Gene', '7295', (133, 144))
159547	32201313	EN460 interacts reversibly with the reduced, active form of ERO1alpha, displacing the FAD moiety.	('EN460', 'Chemical', '-', (0, 5))	('EN460', 'Var', (0, 5))	('displacing', 'NegReg', (71, 81))	('FAD moiety', 'MPA', (86, 96))	('FAD', 'Chemical', 'MESH:D005182', (86, 89))
159548	32201313	EN460 inhibition of ERO1alpha prevents H2O2 production when ERO1alpha function is stimulated.	('EN460', 'Chemical', '-', (0, 5))	('H2O2 production', 'MPA', (39, 54))	('EN460 inhibition', 'Var', (0, 16))	('prevents', 'NegReg', (30, 38))	('H2O2', 'Chemical', 'MESH:D006861', (39, 43))
159549	32201313	EN460 also prevents replication of the chikunguya virus.	('EN460', 'Chemical', '-', (0, 5))	('EN460', 'Var', (0, 5))	('replication', 'MPA', (20, 31))	('chikunguya virus', 'Disease', (39, 55))	('prevents', 'NegReg', (11, 19))
159550	32201313	However, EN460 is not selective for ERO1 and also inhibits other FAD-containing enzymes including monoamine oxidase A, monoamine oxidase B, and LSD-1.	('FAD', 'Chemical', 'MESH:D005182', (65, 68))	('ERO1', 'Gene', (36, 40))	('LSD-1', 'Gene', '23028', (144, 149))	('LSD-1', 'Gene', (144, 149))	('monoamine oxidase B', 'Gene', '4129', (119, 138))	('EN460', 'Chemical', '-', (9, 14))	('monoamine oxidase A', 'Gene', (98, 117))	('monoamine oxidase A', 'Gene', '4128', (98, 117))	('inhibits', 'NegReg', (50, 58))	('ERO1', 'Gene', '854909', (36, 40))	('EN460', 'Var', (9, 14))	('FAD-containing enzymes', 'Enzyme', (65, 87))	('monoamine oxidase B', 'Gene', (119, 138))
159551	32201313	Recently, the interaction between ERO1alpha and PDIA1 was demonstrated to depend on Val101 of ERO1alpha; thus, inhibition of the ERO1alpha-PDIA1 interaction around Val101 may be a potential anti-cancer strategy.	('PDIA1', 'Gene', '5034', (139, 144))	('Val101', 'Chemical', '-', (84, 90))	('interaction', 'Interaction', (14, 25))	('cancer', 'Disease', (195, 201))	('PDIA1', 'Gene', (48, 53))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('interaction', 'Interaction', (145, 156))	('Val101', 'Chemical', '-', (164, 170))	('Val101', 'Var', (164, 170))	('PDIA1', 'Gene', '5034', (48, 53))	('PDIA1', 'Gene', (139, 144))	('inhibition', 'Var', (111, 121))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
159552	32201313	One hypothesis may be that ERO1alpha inhibition would block PDIA1 re-oxidation, and thus be another strategy for selective PDIA1 inhibition.	('PDIA1', 'Gene', (60, 65))	('inhibition', 'Var', (37, 47))	('PDIA1', 'Gene', (123, 128))	('PDIA1', 'Gene', '5034', (60, 65))	('ERO1alpha', 'Protein', (27, 36))	('PDIA1', 'Gene', '5034', (123, 128))	('block', 'NegReg', (54, 59))
159555	32201313	Thus, inhibiting this interaction may have a broader application to cancers other than cervical cancer.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('inhibiting', 'Var', (6, 16))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('cancers', 'Phenotype', 'HP:0002664', (68, 75))	('cancers', 'Disease', (68, 75))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('cancers', 'Disease', 'MESH:D009369', (68, 75))	('interaction', 'Interaction', (22, 33))	('cancer', 'Disease', (68, 74))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Disease', (96, 102))
159557	32201313	Inhibition of PDIA1 has been linked to many diseases and a number of inhibitors have been discovered.	('diseases', 'Disease', (44, 52))	('PDIA1', 'Gene', (14, 19))	('linked', 'Reg', (29, 35))	('Inhibition', 'Var', (0, 10))	('PDIA1', 'Gene', '5034', (14, 19))
159559	32201313	Polymorphisms in P4HB have been linked to Cole Carpenter syndrome.	('Polymorphisms', 'Var', (0, 13))	('P4HB', 'Gene', '5034', (17, 21))	('linked', 'Reg', (32, 38))	('Cole Carpenter syndrome', 'Disease', (42, 65))	('P4HB', 'Gene', (17, 21))
159568	32201313	CRISPR/Cas9-mediated PDIA1 knockout prevents ROS production induced by lipopolysaccharide (LPS) and inactivates the NF-kappaB pathway.	('inactivates', 'NegReg', (100, 111))	('lipopolysaccharide', 'Chemical', 'MESH:D008070', (71, 89))	('prevents', 'NegReg', (36, 44))	('NF-kappaB', 'Gene', '4790', (116, 125))	('ROS', 'Chemical', 'MESH:D017382', (45, 48))	('PDIA1', 'Gene', (21, 26))	('NF-kappaB', 'Gene', (116, 125))	('ROS production', 'MPA', (45, 59))	('knockout', 'Var', (27, 35))	('PDIA1', 'Gene', '5034', (21, 26))
159569	32201313	PDIA1 has been linked to a major source of ROS, Nox, and PDIA1 overexpression leads to an increase in ROS levels via increased Nox activity.	('ROS', 'Chemical', 'MESH:D017382', (102, 105))	('PDIA1', 'Gene', (0, 5))	('increase', 'PosReg', (90, 98))	('increased', 'PosReg', (117, 126))	('PDIA1', 'Gene', '5034', (57, 62))	('overexpression', 'Var', (63, 77))	('PDIA1', 'Gene', '5034', (0, 5))	('N', 'Chemical', 'MESH:D009584', (127, 128))	('Nox activity', 'MPA', (127, 139))	('N', 'Chemical', 'MESH:D009584', (48, 49))	('ROS levels', 'MPA', (102, 112))	('PDIA1', 'Gene', (57, 62))	('ROS', 'Chemical', 'MESH:D017382', (43, 46))
159570	32201313	Furthermore, ROS production by PDIA1 in leukocytes was found to be redox-dependent; oxidized PDIA1 stimulated ROS production, whereas reduced PDIA1 did not.	('oxidized', 'Var', (84, 92))	('PDIA1', 'Gene', (93, 98))	('ROS', 'MPA', (13, 16))	('ROS', 'Chemical', 'MESH:D017382', (110, 113))	('PDIA1', 'Gene', (142, 147))	('PDIA1', 'Gene', (31, 36))	('ROS production', 'MPA', (110, 124))	('PDIA1', 'Gene', '5034', (142, 147))	('PDIA1', 'Gene', '5034', (31, 36))	('ROS', 'Chemical', 'MESH:D017382', (13, 16))	('PDIA1', 'Gene', '5034', (93, 98))
159579	32201313	ERO1 function is essential in yeast systems; however, mammalian cells can survive ERO1 knockout, indicating redundant pathways for disulfide formation.	('ERO1', 'Gene', '854909', (82, 86))	('yeast', 'Species', '4932', (30, 35))	('disulfide', 'Chemical', 'MESH:D004220', (131, 140))	('ERO1', 'Gene', (82, 86))	('ERO1', 'Gene', '854909', (0, 4))	('mammalian', 'Species', '9606', (54, 63))	('ERO1', 'Gene', (0, 4))	('knockout', 'Var', (87, 95))
159586	32201313	Furthermore, our bioinformatics analysis demonstrated that ERO1 inhibitors may be effective in lung cancer, uncovering a potential avenue of therapeutic value to be explored.	('lung cancer', 'Disease', (95, 106))	('lung cancer', 'Phenotype', 'HP:0100526', (95, 106))	('ERO1', 'Gene', '854909', (59, 63))	('effective', 'Reg', (82, 91))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('inhibitors', 'Var', (64, 74))	('ERO1', 'Gene', (59, 63))	('lung cancer', 'Disease', 'MESH:D008175', (95, 106))
159643	27613525	In addition, high expression of DUSP6 or ACTN4 identified patients with worse prognosis in the Kaplan-Meier analysis of the Japan and NCI-MD/Norway cohorts (Fig.	('high', 'Var', (13, 17))	('DUSP6', 'Gene', (32, 37))	('ACTN4', 'Gene', (41, 46))	('DUSP6', 'Gene', '1848', (32, 37))	('patients', 'Species', '9606', (58, 66))	('ACTN4', 'Gene', '81', (41, 46))
159645	27613525	The resulting coefficients were incorporated into a classifier score as follows: (0.590 x DUSP6) + (0.550 x ACTN4).	('DUSP6', 'Gene', (90, 95))	('DUSP6', 'Gene', '1848', (90, 95))	('ACTN4', 'Gene', (108, 113))	('0.590', 'Var', (82, 87))	('ACTN4', 'Gene', '81', (108, 113))
159679	27613525	In addition, silencing of DUSP6 resulted in increased sensitivity to cytotoxic drugs and reduced cancer cell proliferation.	('cancer', 'Disease', (97, 103))	('sensitivity to cytotoxic drugs', 'MPA', (54, 84))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('DUSP6', 'Gene', (26, 31))	('reduced', 'NegReg', (89, 96))	('increased', 'PosReg', (44, 53))	('DUSP6', 'Gene', '1848', (26, 31))	('silencing', 'Var', (13, 22))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
159681	27613525	Gene expression profiles in tumors with high DUSP6 were associated with a family of serine/threonine protein kinases and receptor tyrosine kinases, including ErbB family and downstream signaling mediators, which may promote cancer cell invasion and oppose apoptotic programs.	('high', 'Var', (40, 44))	('DUSP6', 'Gene', (45, 50))	('DUSP6', 'Gene', '1848', (45, 50))	('apoptotic programs', 'CPA', (256, 274))	('tumors', 'Disease', (28, 34))	('tumors', 'Disease', 'MESH:D009369', (28, 34))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('promote', 'PosReg', (216, 223))	('associated', 'Reg', (56, 66))	('ErbB', 'Gene', '1956', (158, 162))	('cancer', 'Disease', 'MESH:D009369', (224, 230))	('ErbB', 'Gene', (158, 162))	('cancer', 'Disease', (224, 230))
159683	27613525	ACTN4 amplification and high expression are frequently observed in patients with carcinomas of the pancreas, ovary, lung, and salivary gland, and patients with ACTN4 amplifications and high ACTN4 expression have worse outcomes than patients without amplification, which is consistent with our observations.	('carcinomas of the pancreas', 'Disease', (81, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('carcinomas', 'Phenotype', 'HP:0030731', (81, 91))	('amplifications', 'Var', (166, 180))	('observed', 'Reg', (55, 63))	('patients', 'Species', '9606', (146, 154))	('ACTN4', 'Gene', (0, 5))	('patients', 'Species', '9606', (67, 75))	('ACTN4', 'Gene', '81', (0, 5))	('ACTN4', 'Gene', (190, 195))	('expression', 'MPA', (29, 39))	('ACTN4', 'Gene', (160, 165))	('ovary', 'Disease', (109, 114))	('ACTN4', 'Gene', '81', (190, 195))	('ACTN4', 'Gene', '81', (160, 165))	('ovary', 'Disease', 'MESH:D010051', (109, 114))	('patients', 'Species', '9606', (232, 240))	('expression', 'MPA', (196, 206))	('carcinomas of the pancreas', 'Disease', 'MESH:D010190', (81, 107))	('amplification', 'Var', (6, 19))
159684	27613525	Gene expression profiles in tumors with high ACTN4 were associated with epithelial adherens junction and protein tyrosine kinase 2, which may lead cell migration and invasion through tissue remodeling and cell motility.	('high', 'Var', (40, 44))	('invasion', 'CPA', (166, 174))	('cell migration', 'CPA', (147, 161))	('protein tyrosine kinase 2', 'Gene', (105, 130))	('lead', 'PosReg', (142, 146))	('protein tyrosine kinase 2', 'Gene', '5747', (105, 130))	('tumors', 'Disease', (28, 34))	('tumors', 'Disease', 'MESH:D009369', (28, 34))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('ACTN4', 'Gene', (45, 50))	('associated', 'Reg', (56, 66))	('cell motility', 'CPA', (205, 218))	('epithelial adherens junction', 'Protein', (72, 100))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('ACTN4', 'Gene', '81', (45, 50))
159753	30547768	The primary antibodies of p53 (ab131442), p16 (ab118459), Cyclin D1 (ab134175), Bcl-2 (ab32124), Bax (ab32503), cleaved-Caspase-3 (ab32042) cleaved-Caspase-9 (ab2324), metalloproteinase-9 (MMP-9, ab73734), Vimentin (ab8978), Wnt3a (ab28472), beta-catenin (ab32572), p-p70S6K (ab2571, phospho T389), p70S6K (ab9366), p-mTOR (ab84400, phospho S2448), mTOR (ab2732), and beta-actin (ab8226) as well as the appropriate secondary antibodites were all obtained from Abcam Biotechnology.	('MMP-9', 'Gene', (189, 194))	('Vimentin', 'Gene', '7431', (206, 214))	('Bcl-2', 'Gene', '596', (80, 85))	('p53', 'Gene', (26, 29))	('p70S6K', 'Gene', '6198', (299, 305))	('p70S6K', 'Gene', '6198', (268, 274))	('Bax', 'Gene', (97, 100))	('Vimentin', 'Gene', (206, 214))	('Caspase-9', 'Gene', '842', (148, 157))	('p16', 'Gene', (42, 45))	('mTOR', 'Gene', (318, 322))	('mTOR', 'Gene', (349, 353))	('Bax', 'Gene', '581', (97, 100))	('Caspase-9', 'Gene', (148, 157))	('ab84400', 'Var', (324, 331))	('beta-actin', 'Gene', (368, 378))	('p16', 'Gene', '1029', (42, 45))	('MMP-9', 'Gene', '4318', (189, 194))	('beta-catenin', 'Gene', (242, 254))	('mTOR', 'Gene', '2475', (318, 322))	('beta-catenin', 'Gene', '1499', (242, 254))	('mTOR', 'Gene', '2475', (349, 353))	('p70S6K', 'Gene', (268, 274))	('p70S6K', 'Gene', (299, 305))	('Bcl-2', 'Gene', (80, 85))	('Wnt3a', 'Gene', '89780', (225, 230))	('p53', 'Gene', '7157', (26, 29))	('Cyclin D1', 'Gene', '595', (58, 67))	('Wnt3a', 'Gene', (225, 230))	('beta-actin', 'Gene', '728378', (368, 378))	('Cyclin D1', 'Gene', (58, 67))
159772	30547768	To analyze the roles of miR-372 in propofol-induced A549 cell proliferation inhibition and cell apoptosis, miR-372 mimic or miR-372 inhibitor was transfected into A549 cells to overexpress or knockdown miR-372.	('inhibition', 'NegReg', (76, 86))	('miR-372', 'Gene', '442917', (107, 114))	('miR-372', 'Gene', (202, 209))	('A549', 'CellLine', 'CVCL:0023', (52, 56))	('propofol', 'Chemical', 'MESH:D015742', (35, 43))	('miR-372', 'Gene', (24, 31))	('miR-372', 'Gene', '442917', (24, 31))	('miR-372', 'Gene', (124, 131))	('A549', 'CellLine', 'CVCL:0023', (163, 167))	('overexpress', 'PosReg', (177, 188))	('miR-372', 'Gene', '442917', (202, 209))	('miR-372', 'Gene', (107, 114))	('rat', 'Species', '10116', (69, 72))	('knockdown', 'Var', (192, 201))	('miR-372', 'Gene', '442917', (124, 131))
159774	30547768	Figure 4b displayed that miR-372 overexpression reversed the anti-proliferative effect of propofol on A549 cells (P < 0.01), while miR-372 knockdown enhanced the anti-proliferative effect of propofol on A549 cells (P < 0.05).	('miR-372', 'Gene', '442917', (131, 138))	('A549', 'CellLine', 'CVCL:0023', (203, 207))	('miR-372', 'Gene', '442917', (25, 32))	('knockdown', 'Var', (139, 148))	('miR-372', 'Gene', (25, 32))	('propofol', 'Chemical', 'MESH:D015742', (191, 199))	('anti-proliferative effect', 'MPA', (61, 86))	('rat', 'Species', '10116', (174, 177))	('enhanced', 'PosReg', (149, 157))	('anti-proliferative', 'MPA', (162, 180))	('miR-372', 'Gene', (131, 138))	('propofol', 'Chemical', 'MESH:D015742', (90, 98))	('A549', 'CellLine', 'CVCL:0023', (102, 106))	('rat', 'Species', '10116', (73, 76))
159782	30547768	Figure 5a and b showed that miR-372 overexpression weakened the propofol-induced A549 cell migration and invasion inhibition, while miR-372 knockdown promoted the propofol-induced A549 cell migration and invasion inhibition (P < 0.05 or P < 0.01).	('propofol', 'Chemical', 'MESH:D015742', (64, 72))	('rat', 'Species', '10116', (94, 97))	('miR-372', 'Gene', '442917', (132, 139))	('rat', 'Species', '10116', (193, 196))	('propofol-induced', 'Disease', (64, 80))	('invasion inhibition', 'CPA', (105, 124))	('A549', 'CellLine', 'CVCL:0023', (180, 184))	('promoted', 'PosReg', (150, 158))	('miR-372', 'Gene', (28, 35))	('miR-372', 'Gene', (132, 139))	('propofol', 'Chemical', 'MESH:D015742', (163, 171))	('weakened', 'NegReg', (51, 59))	('knockdown', 'Var', (140, 149))	('miR-372', 'Gene', '442917', (28, 35))	('invasion inhibition', 'CPA', (204, 223))	('A549', 'CellLine', 'CVCL:0023', (81, 85))
159838	30479696	Despite recent advances in the understanding of the tumor biology and mutations in lung cancer, outcomes remain poor, particularly for patients with advanced-stage disease or disease that persists after multiple lines of therapy.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('mutations', 'Var', (70, 79))	('lung cancer', 'Disease', 'MESH:D008175', (83, 94))	('patients', 'Species', '9606', (135, 143))	('tumor', 'Disease', (52, 57))	('advanced-stage disease', 'Disease', 'MESH:D020178', (149, 171))	('lung cancer', 'Disease', (83, 94))	('advanced-stage disease', 'Disease', (149, 171))	('lung cancer', 'Phenotype', 'HP:0100526', (83, 94))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('tumor', 'Disease', 'MESH:D009369', (52, 57))
159849	30479696	A previously published study found that gastric cancer cell lines that were transfected with MUC1 demonstrated increased invasiveness.	('MUC1', 'Gene', (93, 97))	('MUC1', 'Gene', '4582', (93, 97))	('invasiveness', 'CPA', (121, 133))	('increased', 'PosReg', (111, 120))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('gastric cancer', 'Disease', (40, 54))	('transfected', 'Var', (76, 87))	('gastric cancer', 'Disease', 'MESH:D013274', (40, 54))	('gastric cancer', 'Phenotype', 'HP:0012126', (40, 54))
159852	30479696	MUC1 has been shown to be overexpressed or aberrantly expressed in both adenocarcinoma and squamous carcinoma NSCLC, as well as in premalignant lesions, including squamous metaplasia and squamous dysplasia.	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('adenocarcinoma and squamous carcinoma NSCLC', 'Disease', 'MESH:D002294', (72, 115))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (91, 109))	('aberrantly expressed', 'Var', (43, 63))	('squamous metaplasia and squamous dysplasia', 'Disease', 'MESH:D002294', (163, 205))	('squamous dysplasia', 'Phenotype', 'HP:0002860', (187, 205))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('MUC1', 'Gene', (0, 4))	('MUC1', 'Gene', '4582', (0, 4))	('overexpressed', 'PosReg', (26, 39))	('squamous metaplasia', 'Phenotype', 'HP:0002860', (163, 182))	('NSCLC', 'Phenotype', 'HP:0030358', (110, 115))
159864	30479696	Figure 2 shows the association between MUC1 expression score and overall survival for squamous lesions, with corresponding results for adenocarcinoma lesions shown in Figure 3.	('overall', 'MPA', (65, 72))	('expression score', 'Var', (44, 60))	('MUC1', 'Gene', (39, 43))	('MUC1', 'Gene', '4582', (39, 43))	('squamous lesions', 'Disease', 'MESH:D002294', (86, 102))	('adenocarcinoma lesions', 'Disease', (135, 157))	('squamous lesions', 'Disease', (86, 102))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))	('adenocarcinoma lesions', 'Disease', 'MESH:C538614', (135, 157))	('association', 'Interaction', (19, 30))
159875	30479696	It seems plausible that increased aberrant MUC1 cell surface expression may render a tumor more immunogenic; however, whether this increased expression actually translates into improved response to immunotherapeutic approaches remains unknown.	('tumor', 'Disease', (85, 90))	('more', 'PosReg', (91, 95))	('aberrant', 'Var', (34, 42))	('MUC1', 'Gene', (43, 47))	('MUC1', 'Gene', '4582', (43, 47))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('render', 'Reg', (76, 82))	('immunogenic', 'MPA', (96, 107))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('increased', 'PosReg', (24, 33))
159891	30479696	Two clinical trials investigating the combination of these vaccinations with the checkpoint inhibitor nivolumab in advanced NSCLC are ongoing: one with TG4010 (https://clinicaltrials.gov/ NCT02823990) and one with CV301 (NCT02840994), a vaccine targeting both MUC1 and carcinoembryonic antigen.	('clinical', 'Species', '191496', (4, 12))	('TG4010', 'Var', (152, 158))	('nivolumab', 'Chemical', 'MESH:D000077594', (102, 111))	('NSCLC', 'Disease', (124, 129))	('NSCLC', 'Phenotype', 'HP:0030358', (124, 129))	('NSCLC', 'Disease', 'MESH:D002289', (124, 129))	('MUC1', 'Gene', (260, 264))	('MUC1', 'Gene', '4582', (260, 264))	('NCT02840994', 'Var', (221, 232))	('clinical', 'Species', '191496', (168, 176))
159951	30122949	In patients with squamous cell carcinoma, there was no difference in OS (HR: 1.01 [95% CI: 0.85-1.21]; P=0.8907) in the primary analysis; however, adjustment for SLD resulted in a notable decrease in the HR to 0.92 (95% CI: 0.77-1.10; P=0.365).	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (17, 40))	('carcinoma', 'Phenotype', 'HP:0030731', (31, 40))	('OS', 'Chemical', '-', (69, 71))	('decrease', 'NegReg', (188, 196))	('adjustment', 'Var', (147, 157))	('SLD', 'Disease', (162, 165))	('patients', 'Species', '9606', (3, 11))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (17, 40))	('SLD', 'Disease', 'None', (162, 165))	('squamous cell carcinoma', 'Disease', (17, 40))
159986	30122949	In the overall adenocarcinoma population, disease control was achieved in 60.2% of patients in the nintedanib arm and 44.0% in the placebo arm.	('adenocarcinoma', 'Disease', 'MESH:D000230', (15, 29))	('carcinoma', 'Phenotype', 'HP:0030731', (20, 29))	('nintedanib', 'Var', (99, 109))	('patients', 'Species', '9606', (83, 91))	('nintedanib', 'Chemical', 'MESH:C530716', (99, 109))	('adenocarcinoma', 'Disease', (15, 29))
159990	30122949	In all adenocarcinoma patient populations, treatment with nintedanib/docetaxel produced a significant reduction in tumor size over time compared with placebo/docetaxel in the likelihood ratio test of the treatment effect (P<0.0001 for the overall adenocarcinoma population).	('nintedanib/docetaxel', 'Var', (58, 78))	('docetaxel', 'Chemical', 'MESH:D000077143', (69, 78))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('adenocarcinoma', 'Disease', (7, 21))	('adenocarcinoma', 'Disease', (247, 261))	('tumor', 'Disease', (115, 120))	('carcinoma', 'Phenotype', 'HP:0030731', (12, 21))	('carcinoma', 'Phenotype', 'HP:0030731', (252, 261))	('reduction', 'NegReg', (102, 111))	('adenocarcinoma', 'Disease', 'MESH:D000230', (7, 21))	('adenocarcinoma', 'Disease', 'MESH:D000230', (247, 261))	('docetaxel', 'Chemical', 'MESH:D000077143', (158, 167))	('nintedanib', 'Chemical', 'MESH:C530716', (58, 68))	('patient', 'Species', '9606', (22, 29))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
159992	30122949	Disease stabilization was greater in patients receiving nintedanib than in patients receiving placebo (Table S2).	('nintedanib', 'Chemical', 'MESH:C530716', (56, 66))	('Disease stabilization', 'CPA', (0, 21))	('patients', 'Species', '9606', (37, 45))	('patients', 'Species', '9606', (75, 83))	('nintedanib', 'Var', (56, 66))
159996	30122949	The analysis of the time to occurrence of new lesions favored the nintedanib arm and in the second sensitivity analysis was significantly longer with nintedanib in the TSFLT <9 and PD-FLT populations (Table 3).	('nintedanib', 'Chemical', 'MESH:C530716', (66, 76))	('nintedanib', 'Var', (150, 160))	('FLT', 'Gene', '2321', (184, 187))	('FLT', 'Gene', (170, 173))	('FLT', 'Gene', (184, 187))	('FLT', 'Gene', '2321', (170, 173))	('nintedanib', 'Chemical', 'MESH:C530716', (150, 160))
160002	30122949	Corresponding well with the OS findings of LUME-Lung 1, the analyses of data on the impact of the change in target lesion size over time as a treatment effect showed that nintedanib/docetaxel significantly decreased tumor burden and decelerated tumor size compared with placebo/docetaxel in all patients with adenocarcinoma and squamous histology.	('tumor', 'Disease', (216, 221))	('docetaxel', 'Chemical', 'MESH:D000077143', (278, 287))	('OS', 'Chemical', '-', (28, 30))	('docetaxel', 'Chemical', 'MESH:D000077143', (182, 191))	('tumor', 'Disease', 'MESH:D009369', (245, 250))	('carcinoma', 'Phenotype', 'HP:0030731', (314, 323))	('adenocarcinoma', 'Disease', (309, 323))	('decelerated', 'NegReg', (233, 244))	('decreased', 'NegReg', (206, 215))	('patients', 'Species', '9606', (295, 303))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('tumor', 'Disease', 'MESH:D009369', (216, 221))	('nintedanib', 'Chemical', 'MESH:C530716', (171, 181))	('tumor', 'Disease', (245, 250))	('adenocarcinoma', 'Disease', 'MESH:D000230', (309, 323))	('nintedanib/docetaxel', 'Var', (171, 191))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))
160021	29390380	Apatinib is highly selective tyrosine kinase inhibitor of vascular endothelial growth factor receptor-2, studies have revealed that apatinib inhibit the growth of solid tumors including NSCLC.	('solid tumors', 'Disease', 'MESH:D009369', (163, 175))	('apatinib', 'Var', (132, 140))	('NSCLC', 'Phenotype', 'HP:0030358', (186, 191))	('apatinib', 'Chemical', 'MESH:C553458', (132, 140))	('Apatinib', 'Chemical', 'MESH:C553458', (0, 8))	('vascular endothelial growth factor receptor-2', 'Gene', (58, 103))	('NSCLC', 'Disease', (186, 191))	('vascular endothelial growth factor receptor-2', 'Gene', '3791', (58, 103))	('solid tumors', 'Disease', (163, 175))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('tumors', 'Phenotype', 'HP:0002664', (169, 175))	('NSCLC', 'Disease', 'MESH:D002289', (186, 191))	('inhibit', 'NegReg', (141, 148))	('growth', 'MPA', (153, 159))
160066	29390380	In recent years, researchers have been trying to restrict the growth of tumor by restraining the combination between VEGF and VEGFR to stop the activation of the downstream pathway.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('VEGF', 'Gene', (117, 121))	('combination', 'Interaction', (97, 108))	('VEGFR', 'Gene', '3791', (126, 131))	('restraining', 'Var', (81, 92))	('tumor', 'Disease', (72, 77))	('VEGF', 'Gene', '7422', (126, 130))	('VEGF', 'Gene', '7422', (117, 121))	('VEGFR', 'Gene', (126, 131))	('VEGF', 'Gene', (126, 130))	('tumor', 'Disease', 'MESH:D009369', (72, 77))
160082	29390380	The results showed that median PFS, response rate, and disease control rate in the apatinib group were all better than the placebo group (4.7 months vs 1.9 months, P < .0001; 12.2% vs 0%, P < .0158; 68.9% vs 24.4%, P < 0.0001, respectively).	('response', 'CPA', (36, 44))	('better', 'PosReg', (107, 113))	('disease control', 'CPA', (55, 70))	('PFS', 'CPA', (31, 34))	('apatinib', 'Var', (83, 91))	('apatinib', 'Chemical', 'MESH:C553458', (83, 91))
160084	29390380	Zhu and Li have reported that Apatinib, a new small molecular VEGFR2 inhibitor suppresses the activity of lung cancer stem cells in the 2016 WCLC meeting, provide an important molecular basis for the application of Apatinib in lung cancer patients.	('VEGFR2', 'Gene', '3791', (62, 68))	('Apatinib', 'Chemical', 'MESH:C553458', (215, 223))	('lung cancer', 'Disease', (106, 117))	('lung cancer', 'Phenotype', 'HP:0100526', (106, 117))	('lung cancer', 'Disease', (227, 238))	('Apatinib', 'Chemical', 'MESH:C553458', (30, 38))	('VEGFR2', 'Gene', (62, 68))	('inhibitor', 'Var', (69, 78))	('patients', 'Species', '9606', (239, 247))	('activity', 'CPA', (94, 102))	('lung cancer', 'Phenotype', 'HP:0100526', (227, 238))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('suppresses', 'NegReg', (79, 89))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('lung cancer', 'Disease', 'MESH:D008175', (106, 117))	('lung cancer', 'Disease', 'MESH:D008175', (227, 238))
160096	29207124	Inhibiting proliferation and migration of lung cancer using small interfering RNA targeting on Aldo-keto reductase family 1 member B10 Lung cancer is the leading cause of global cancer-associated mortality.	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('migration of lung cancer', 'Disease', 'MESH:D008175', (29, 53))	('Lung cancer', 'Disease', 'MESH:D008175', (135, 146))	('cancer', 'Disease', (47, 53))	('migration of lung cancer', 'Disease', (29, 53))	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('lung cancer', 'Phenotype', 'HP:0100526', (42, 53))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('Lung cancer', 'Phenotype', 'HP:0100526', (135, 146))	('Lung cancer', 'Disease', (135, 146))	('small interfering', 'Var', (60, 77))	('Inhibiting', 'NegReg', (0, 10))	('cancer', 'Disease', (140, 146))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('proliferation', 'CPA', (11, 24))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('cancer', 'Disease', (178, 184))	('Aldo-keto reductase family 1 member B', 'Gene', '231', (95, 132))	('Aldo-keto reductase family 1 member B', 'Gene', (95, 132))
160119	29207124	Silencing of AKR1B10 was demonstrated to inhibit proliferation and increase apoptosis of lung cancer cell lines.	('AKR1B10', 'Gene', (13, 20))	('AKR1B10', 'Gene', '57016', (13, 20))	('lung cancer', 'Phenotype', 'HP:0100526', (89, 100))	('proliferation', 'CPA', (49, 62))	('increase apoptosis of lung cancer', 'Disease', (67, 100))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('increase apoptosis of lung cancer', 'Disease', 'MESH:D008175', (67, 100))	('inhibit', 'NegReg', (41, 48))	('Silencing', 'Var', (0, 9))
160125	29207124	The GSE43580 and GSE40588 datasets include 60 noncancerous lung tissues adjacent to lung squamous cell carcinoma (SCC) tissues, 77 lung adenocarcinoma and 73 lung SCC tissues.	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (84, 112))	('lung squamous cell carcinoma', 'Disease', (84, 112))	('cancer', 'Disease', (49, 55))	('lung adenocarcinoma', 'Disease', (131, 150))	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (131, 150))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('SCC', 'Gene', (114, 117))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (84, 112))	('SCC', 'Gene', (163, 166))	('SCC', 'Gene', '6317', (114, 117))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (89, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('SCC', 'Gene', '6317', (163, 166))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (131, 150))	('GSE40588', 'Var', (17, 25))
160139	29207124	To normalize the transfection efficiency, cells were digested by trypsin and frozen in liquid nitrogen for the follow-up AKR1B10 silencing experiment.	('AKR1B10', 'Gene', (121, 128))	('nitrogen', 'Chemical', 'MESH:D009584', (94, 102))	('AKR1B10', 'Gene', '57016', (121, 128))	('silencing', 'Var', (129, 138))
160165	29207124	Furthermore, CDK2 and Cyclin E protein levels were down-regulated in the interference group, while P21 was upregulated (Fig.	('CDK2', 'Gene', (13, 17))	('P21', 'Gene', '1026', (99, 102))	('CDK2', 'Gene', '1017', (13, 17))	('Cyclin', 'Gene', (22, 28))	('down-regulated', 'NegReg', (51, 65))	('P21', 'Gene', (99, 102))	('upregulated', 'PosReg', (107, 118))	('interference', 'Var', (73, 85))	('Cyclin', 'Gene', '5111', (22, 28))
160168	29207124	Proteins of the ERK/MAPK signaling pathway were determined by western blotting and results demonstrated that the expression of P-ERK and MAPK decreased after AKR1B10 gene silencing (Fig.	('expression', 'MPA', (113, 123))	('ERK', 'Gene', '5594', (16, 19))	('MAPK', 'Gene', (137, 141))	('P-ERK', 'Gene', (127, 132))	('AKR1B10', 'Gene', '57016', (158, 165))	('ERK', 'Gene', (16, 19))	('decreased', 'NegReg', (142, 151))	('ERK', 'Gene', '5594', (129, 132))	('ERK', 'Gene', (129, 132))	('P-ERK', 'Gene', '9451', (127, 132))	('gene silencing', 'Var', (166, 180))	('AKR1B10', 'Gene', (158, 165))
160170	29207124	P-NF-kappaB was also tested, and was also down-regulated after the AKR1B10 gene silencing.	('gene silencing', 'Var', (75, 89))	('down-regulated', 'NegReg', (42, 56))	('AKR1B10', 'Gene', (67, 74))	('AKR1B10', 'Gene', '57016', (67, 74))
160171	29207124	12, silencing of AKR1B10 by shRNA led to down-regulation of Snail, Twist, Vimentin, and MMP9, and upregulation of E-cadherin, which may indicate that AKR1B10 gene silencing may inhibit the invasion and metastasis of tumor cells.	('AKR1B10', 'Gene', '57016', (17, 24))	('tumor', 'Disease', (216, 221))	('Twist', 'Gene', (67, 72))	('Snail', 'Gene', (60, 65))	('tumor', 'Disease', 'MESH:D009369', (216, 221))	('AKR1B10', 'Gene', '57016', (150, 157))	('silencing', 'Var', (4, 13))	('MMP9', 'Gene', '4318', (88, 92))	('AKR1B10', 'Gene', (17, 24))	('E-cadherin', 'Gene', (114, 124))	('E-cadherin', 'Gene', '999', (114, 124))	('AKR1B10', 'Gene', (150, 157))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('Vimentin', 'Gene', '7431', (74, 82))	('Twist', 'Gene', '7291', (67, 72))	('inhibit', 'NegReg', (177, 184))	('Snail', 'Gene', '6615', (60, 65))	('gene silencing', 'Var', (158, 172))	('Vimentin', 'Gene', (74, 82))	('upregulation', 'PosReg', (98, 110))	('MMP9', 'Gene', (88, 92))	('down-regulation', 'NegReg', (41, 56))
160183	29207124	The present study investigated and identified inhibition of the cell cycle, cell proliferation, and cell adhesion and migration of A549 lung carcinoma cells following AKR1B10 RNA interference.	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('AKR1B10', 'Gene', (167, 174))	('inhibition', 'NegReg', (46, 56))	('migration of A549 lung carcinoma', 'Disease', 'MESH:D014085', (118, 150))	('cell proliferation', 'CPA', (76, 94))	('cell adhesion', 'CPA', (100, 113))	('RNA interference', 'Var', (175, 191))	('AKR1B10', 'Gene', '57016', (167, 174))	('migration of A549 lung carcinoma', 'Disease', (118, 150))	('cell cycle', 'CPA', (64, 74))
160185	29207124	Western blot analysis results demonstrated that transmembrane proteins TMEM33 and TMEM208 were down regulated in the interference group, probably due to the autophagy at the condition of endoplasmic reticulum stress.	('TMEM33', 'Gene', '55161', (71, 77))	('TMEM33', 'Gene', (71, 77))	('TMEM208', 'Gene', '29100', (82, 89))	('TMEM208', 'Gene', (82, 89))	('autophagy', 'CPA', (157, 166))	('interference', 'Var', (117, 129))	('transmembrane proteins', 'Protein', (48, 70))	('down regulated', 'NegReg', (95, 109))
160186	29207124	It was also demonstrated that the epithelial-mesenchymal transition-associated proteins, such as Snail, Twist, Vimentin and MMP9 were down-regulated after AKR1B10 gene silencing, whereas the expression of E-cadherin was upregulated, indicating that AKR1B10 gene silencing effectively inhibits the invasion and metastasis of tumor cells.	('epithelial-mesenchymal', 'Protein', (34, 56))	('E-cadherin', 'Gene', (205, 215))	('E-cadherin', 'Gene', '999', (205, 215))	('AKR1B10', 'Gene', (155, 162))	('upregulated', 'PosReg', (220, 231))	('Vimentin', 'Gene', '7431', (111, 119))	('Twist', 'Gene', '7291', (104, 109))	('gene silencing', 'Var', (163, 177))	('inhibits', 'NegReg', (284, 292))	('AKR1B10', 'Gene', '57016', (249, 256))	('down-regulated', 'NegReg', (134, 148))	('Vimentin', 'Gene', (111, 119))	('MMP9', 'Gene', '4318', (124, 128))	('tumor', 'Phenotype', 'HP:0002664', (324, 329))	('MMP9', 'Gene', (124, 128))	('Snail', 'Gene', (97, 102))	('AKR1B10', 'Gene', (249, 256))	('Twist', 'Gene', (104, 109))	('AKR1B10', 'Gene', '57016', (155, 162))	('tumor', 'Disease', (324, 329))	('Snail', 'Gene', '6615', (97, 102))	('tumor', 'Disease', 'MESH:D009369', (324, 329))
160193	29207124	The eukaryotic cell division cycle is mainly regulated by the cyclin/CDK complex; inhibition of this complex results in down regulation of the cell cycle.	('down regulation', 'NegReg', (120, 135))	('cell cycle', 'CPA', (143, 153))	('inhibition', 'Var', (82, 92))	('cyclin', 'Gene', '5111', (62, 68))	('CDK', 'Gene', '1017', (69, 72))	('CDK', 'Gene', (69, 72))	('cyclin', 'Gene', (62, 68))
160194	29207124	The AKR1B10 gene silencing of the A549 cell line caused a delay of the cell cycle at the G0 to G1 phase.	('A549', 'CellLine', 'CVCL:0023', (34, 38))	('AKR1B10', 'Gene', (4, 11))	('AKR1B10', 'Gene', '57016', (4, 11))	('delay', 'NegReg', (58, 63))	('gene', 'Var', (12, 16))	('cell cycle at the G0 to G1 phase', 'CPA', (71, 103))
160200	29207124	In this study, the expression of P-ERK and MAPK were observed to decrease after AKR1B10 gene silencing which is consistent with previous studies.	('gene silencing', 'Var', (88, 102))	('expression', 'MPA', (19, 29))	('P-ERK', 'Gene', '9451', (33, 38))	('AKR1B10', 'Gene', '57016', (80, 87))	('P-ERK', 'Gene', (33, 38))	('decrease', 'NegReg', (65, 73))	('AKR1B10', 'Gene', (80, 87))	('MAPK', 'Gene', (43, 47))
160212	28008744	FGFR1 amplification is more prevalent in late stage SQC patients but does not predict chemotherapy response.	('patients', 'Species', '9606', (56, 64))	('SQC', 'Phenotype', 'HP:0002860', (52, 55))	('FGFR1', 'Gene', (0, 5))	('SQC', 'Disease', (52, 55))	('amplification', 'Var', (6, 19))	('prevalent', 'Reg', (28, 37))
160214	28008744	Molecularly targeted drugs, such as erlotinib and crizotinib, have greatly improved the clinical outcome for NSCLC patients with sensitizing epidermal growth factor receptor (EGFR) gene mutations or anaplastic lymphoma kinase (ALK) gene translocations, respectively.	('improved', 'PosReg', (75, 83))	('patients', 'Species', '9606', (115, 123))	('NSCLC', 'Disease', 'MESH:D002289', (109, 114))	('EGFR', 'Gene', (175, 179))	('anaplastic lymphoma kinase', 'Gene', '238', (199, 225))	('mutations', 'Var', (186, 195))	('crizotinib', 'Chemical', 'MESH:D000077547', (50, 60))	('epidermal growth factor receptor', 'Gene', (141, 173))	('ALK', 'Gene', '238', (227, 230))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (199, 218))	('NSCLC', 'Phenotype', 'HP:0030358', (109, 114))	('erlotinib', 'Chemical', 'MESH:D000069347', (36, 45))	('anaplastic lymphoma kinase', 'Gene', (199, 225))	('ALK', 'Gene', (227, 230))	('lymphoma', 'Phenotype', 'HP:0002665', (210, 218))	('epidermal growth factor receptor', 'Gene', '1956', (141, 173))	('EGFR', 'Gene', '1956', (175, 179))	('NSCLC', 'Disease', (109, 114))
160217	28008744	Particularly, checkpoint inhibitors, such as anti-programmed cell death-1 (PD-1)/programmed cell death-ligand-1 (PD-L1) monoclonal antibodies, have brought survival benefit for advanced lung cancer patients.	('benefit', 'PosReg', (165, 172))	('PD-1', 'Gene', (75, 79))	('patients', 'Species', '9606', (198, 206))	('PD-1', 'Gene', '5133', (75, 79))	('lung cancer', 'Disease', 'MESH:D008175', (186, 197))	('lung cancer', 'Phenotype', 'HP:0100526', (186, 197))	('monoclonal', 'Var', (120, 130))	('programmed cell death-ligand-1', 'Gene', '29126', (81, 111))	('survival', 'CPA', (156, 164))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('lung cancer', 'Disease', (186, 197))	('anti-programmed', 'Var', (45, 60))	('programmed cell death-ligand-1', 'Gene', (81, 111))
160239	28008744	Cox proportional hazard models were used for multivariate analysis to assess the variables, including degree of differentiation, lymph node metastasis, PD-L1 expression, FGFR1 amplification, and efficacy of treatment with gemcitabine plus cisplatinum (GP) therapy, and to predict the hazard rates for progression-free survival (PFS) and OS.	('FGFR1', 'Gene', (170, 175))	('gemcitabine', 'Chemical', 'MESH:C056507', (222, 233))	('Cox', 'Gene', '1351', (0, 3))	('Cox', 'Gene', (0, 3))	('cisplatinum', 'Chemical', 'MESH:D002945', (239, 250))	('PD-L1', 'Gene', (152, 157))	('amplification', 'Var', (176, 189))	('men', 'Species', '9606', (212, 215))
160245	28008744	According to FISH results, 32 of the 128 patients (25.0%) displayed FGFR1 amplification.	('patients', 'Species', '9606', (41, 49))	('FGFR1', 'Gene', (68, 73))	('amplification', 'Var', (74, 87))
160248	28008744	Among 79 patients with PD-L1 positive expression, FGFR1 positive and negative rates were 25.3% (20/79) and 74.7% (59/79), respectively.	('positive expression', 'Var', (29, 48))	('patients', 'Species', '9606', (9, 17))	('PD-L1', 'Gene', (23, 28))	('FGFR1', 'Gene', (50, 55))
160252	28008744	Of these 77 cases, patients with PD-L1 positive expression presented an ORR of 36.2% (17/47) and DCR of 78.7.7% (37/47; P = 0.840), while those with negative PD-L1 expression presented an ORR of 43.3% (13/30) and DCR of 80.0% (24/30; P = 0.434) after GP regimen treatment.	('PD-L1', 'Gene', (33, 38))	('men', 'Species', '9606', (258, 261))	('patients', 'Species', '9606', (19, 27))	('positive expression', 'Var', (39, 58))	('men', 'Species', '9606', (267, 270))
160256	28008744	In multivariate Cox regression analysis where the smoking status, degree of differentiation, clinical stage, and lymph node metastasis were included as covariates together with PD-L1 expression, PD-L1 expression (OR 2.38, 95% CI 1.35:4.17; P = 0.003) was an independent predictor of OS.	('PD-L1 expression', 'Var', (195, 211))	('Cox', 'Gene', '1351', (16, 19))	('Cox', 'Gene', (16, 19))
160270	28008744	conducted a study of 226 Caucasian patients and implied that there was no correlation between FGFR1 amplification and prognosis.12, 23 Our results and those of previous studies demonstrated no significant difference in OS by FGFR1 amplification status.	('FGFR1', 'Gene', (225, 230))	('amplification status', 'Var', (231, 251))	('patients', 'Species', '9606', (35, 43))
160271	28008744	These experiments revealed that there is no evidence to indicate that FGFRl amplification is a prognostic factor for lung SQC.	('men', 'Species', '9606', (12, 15))	('lung SQC', 'Disease', (117, 125))	('SQC', 'Phenotype', 'HP:0002860', (122, 125))	('FGFRl', 'Gene', (70, 75))	('amplification', 'Var', (76, 89))
160278	33122723	Supporting this, modulation of SASH1 levels in a panel of lung cancer cell lines mediated changes in cellular proliferation and sensitivity to cisplatin.	('SASH1', 'Gene', (31, 36))	('cisplatin', 'Chemical', 'MESH:D002945', (143, 152))	('modulation', 'Var', (17, 27))	('cellular proliferation', 'CPA', (101, 123))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('lung cancer', 'Disease', (58, 69))	('sensitivity to cisplatin', 'MPA', (128, 152))	('SASH1', 'Gene', '23328', (31, 36))	('lung cancer', 'Phenotype', 'HP:0100526', (58, 69))	('changes', 'Reg', (90, 97))	('lung cancer', 'Disease', 'MESH:D008175', (58, 69))
160280	33122723	In summary, compounds that increase SASH1 protein levels could represent a novel approach to treat NSCLC and warrant further study.	('compounds', 'Var', (12, 21))	('NSCLC', 'Disease', (99, 104))	('SASH1', 'Gene', (36, 41))	('SASH1', 'Gene', '23328', (36, 41))	('increase', 'PosReg', (27, 35))	('NSCLC', 'Disease', 'MESH:D002289', (99, 104))
160294	33122723	Highlighting this, mutations in SASH1 resulting in hyperpigmentation.	('resulting in', 'Reg', (38, 50))	('mutations', 'Var', (19, 28))	('SASH1', 'Gene', (32, 37))	('SASH1', 'Gene', '23328', (32, 37))	('hyperpigmentation', 'Disease', (51, 68))	('hyperpigmentation', 'Disease', 'MESH:D017495', (51, 68))
160295	33122723	Our previous data have shown that chloropyramine, a known competitive reversible H1-receptor antagonist (also known as an H1 inverse agonist), can increase SASH1 protein levels in breast cancer cells.	('chloropyramine', 'Var', (34, 48))	('breast cancer', 'Disease', 'MESH:D001943', (180, 193))	('SASH1', 'Gene', (156, 161))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('chloropyramine', 'Chemical', 'MESH:C004664', (34, 48))	('breast cancer', 'Disease', (180, 193))	('increase', 'PosReg', (147, 155))	('breast cancer', 'Phenotype', 'HP:0003002', (180, 193))	('SASH1', 'Gene', '23328', (156, 161))
160297	33122723	Chloropyramine has also been shown to inhibit VEGFR-3 and FAK, showing anti-cancer activity in several tumor types, with a decrease in cell proliferation.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('decrease', 'NegReg', (123, 131))	('Chloropyramine', 'Chemical', 'MESH:C004664', (0, 14))	('tumor', 'Disease', (103, 108))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('FAK', 'Gene', (58, 61))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('EGFR', 'Gene', '1956', (47, 51))	('cancer', 'Disease', (76, 82))	('cell proliferation', 'CPA', (135, 153))	('inhibit', 'NegReg', (38, 45))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('EGFR', 'Gene', (47, 51))	('Chloropyramine', 'Var', (0, 14))
160298	33122723	The backbone of first-line treatment for most lung cancer patients, without identified mutations in genes such as EGFR, comprises combinational therapies using cytotoxic chemotherapeutic agents such as cisplatin, which cause an overwhelming level of irreparable DNA damage.	('cisplatin', 'Chemical', 'MESH:D002945', (202, 211))	('patients', 'Species', '9606', (58, 66))	('mutations', 'Var', (87, 96))	('lung cancer', 'Disease', 'MESH:D008175', (46, 57))	('EGFR', 'Gene', '1956', (114, 118))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('EGFR', 'Gene', (114, 118))	('lung cancer', 'Disease', (46, 57))	('lung cancer', 'Phenotype', 'HP:0100526', (46, 57))
160305	33122723	Kaplan-Meier survival analysis was performed for all 1145 patients stratified using medium SASH1 expression as the cut-off.	('expression', 'Species', '120121', (97, 107))	('SASH1', 'Gene', (91, 96))	('patients', 'Species', '9606', (58, 66))	('medium', 'Var', (84, 90))	('SASH1', 'Gene', '23328', (91, 96))
160306	33122723	Evaluation of all NSCLC cases in the cohort indicated there was a significant difference in survival based on SASH1 expression, with high SASH1 showing improved survival (Fig.	('NSCLC', 'Disease', (18, 23))	('SASH1', 'Gene', (110, 115))	('high', 'Var', (133, 137))	('SASH1', 'Gene', '23328', (138, 143))	('NSCLC', 'Disease', 'MESH:D002289', (18, 23))	('SASH1', 'Gene', '23328', (110, 115))	('improved', 'PosReg', (152, 160))	('expression', 'Species', '120121', (116, 126))	('survival', 'MPA', (161, 169))	('SASH1', 'Gene', (138, 143))
160307	33122723	1E; HR (95% CI): 1.74 (1.49-2.06), p = 6.3 x 10-11 for low SASH1 versus high SASH1, log-rank p < 0.0001)).	('SASH1', 'Gene', '23328', (59, 64))	('SASH1', 'Gene', (77, 82))	('low', 'Var', (55, 58))	('SASH1', 'Gene', (59, 64))	('SASH1', 'Gene', '23328', (77, 82))
160310	33122723	In contrast, overall survival for patients with SASH1 high expressing adenocarcinomas was associated with improved outcomes (Fig.	('improved', 'PosReg', (106, 114))	('SASH1', 'Gene', '23328', (48, 53))	('adenocarcinomas', 'Disease', 'MESH:D000230', (70, 85))	('high expressing', 'Var', (54, 69))	('adenocarcinomas', 'Disease', (70, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('carcinomas', 'Phenotype', 'HP:0030731', (75, 85))	('patients', 'Species', '9606', (34, 42))	('SASH1', 'Gene', (48, 53))	('outcomes', 'MPA', (115, 123))
160311	33122723	1G; HR (95% CI): 2.03 (1.47-2.8), p = 2.0 x 10-5 for low SASH1 versus high SASH1, log-rank p < 0.0001).	('low', 'Var', (53, 56))	('SASH1', 'Gene', (57, 62))	('SASH1', 'Gene', (75, 80))	('SASH1', 'Gene', '23328', (75, 80))	('SASH1', 'Gene', '23328', (57, 62))
160318	33122723	SASH1 depletion in the A549, H460 and H1299 NSCLC cell lines significantly increased cellular proliferation.	('SASH1', 'Gene', '23328', (0, 5))	('NSCLC', 'Disease', 'MESH:D002289', (44, 49))	('H460', 'CellLine', 'CVCL:0459', (29, 33))	('cellular proliferation', 'CPA', (85, 107))	('depletion', 'Var', (6, 15))	('SASH1', 'Gene', (0, 5))	('increased', 'PosReg', (75, 84))	('A549', 'CellLine', 'CVCL:0023', (23, 27))	('NSCLC', 'Disease', (44, 49))	('H1299', 'CellLine', 'CVCL:0060', (38, 43))
160321	33122723	This is consistent with other studies that have shown that depletion of SASH1 results in increased cellular proliferation in breast, lung, colon and ovarian cell lines.	('colon and ovarian', 'Disease', 'MESH:D010051', (139, 156))	('SASH1', 'Gene', '23328', (72, 77))	('lung', 'CPA', (133, 137))	('cellular proliferation', 'CPA', (99, 121))	('depletion', 'Var', (59, 68))	('increased', 'PosReg', (89, 98))	('SASH1', 'Gene', (72, 77))
160323	33122723	3A-F, the depletion of SASH1 led to increased cell survival suggesting that SASH1 may mediate cisplatin resistance.	('SASH1', 'Gene', (76, 81))	('mediate', 'Reg', (86, 93))	('cisplatin', 'Chemical', 'MESH:D002945', (94, 103))	('SASH1', 'Gene', (23, 28))	('depletion', 'Var', (10, 19))	('SASH1', 'Gene', '23328', (76, 81))	('cell survival', 'CPA', (46, 59))	('increased', 'PosReg', (36, 45))	('SASH1', 'Gene', '23328', (23, 28))
160324	33122723	SASH1 depletion in HBEC cells did not affect sensitivity to cisplatin, indicating this effect may be specifc to tumour cells.	('SASH1', 'Gene', '23328', (0, 5))	('tumour', 'Disease', 'MESH:D009369', (112, 118))	('sensitivity', 'MPA', (45, 56))	('tumour', 'Disease', (112, 118))	('HBEC', 'CellLine', 'CVCL:X489', (19, 23))	('depletion', 'Var', (6, 15))	('tumour', 'Phenotype', 'HP:0002664', (112, 118))	('SASH1', 'Gene', (0, 5))	('cisplatin', 'Chemical', 'MESH:D002945', (60, 69))
160328	33122723	Ectopic expression of SASH1 also yielded a decrease in cell survival of NSCLC cells treated with cisplatin.	('decrease', 'NegReg', (43, 51))	('expression', 'Species', '120121', (8, 18))	('NSCLC', 'Disease', (72, 77))	('SASH1', 'Gene', (22, 27))	('cell survival', 'CPA', (55, 68))	('Ectopic expression', 'Var', (0, 18))	('cisplatin', 'Chemical', 'MESH:D002945', (97, 106))	('NSCLC', 'Disease', 'MESH:D002289', (72, 77))	('SASH1', 'Gene', '23328', (22, 27))
160333	33122723	Our earlier work in breast cancer indicated that chloropyramine can induce cell death via a SASH1-dependent mechanism.	('chloropyramine', 'Var', (49, 63))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('cell death', 'CPA', (75, 85))	('breast cancer', 'Disease', 'MESH:D001943', (20, 33))	('SASH1', 'Gene', (92, 97))	('breast cancer', 'Disease', (20, 33))	('breast cancer', 'Phenotype', 'HP:0003002', (20, 33))	('SASH1', 'Gene', '23328', (92, 97))	('chloropyramine', 'Chemical', 'MESH:C004664', (49, 63))
160342	33122723	Taken together, these data suggest that chloropyramine is effective at inducing cell death in lung cancer cells.	('lung cancer', 'Disease', 'MESH:D008175', (94, 105))	('chloropyramine', 'Chemical', 'MESH:C004664', (40, 54))	('lung cancer', 'Disease', (94, 105))	('chloropyramine', 'Var', (40, 54))	('lung cancer', 'Phenotype', 'HP:0100526', (94, 105))	('inducing', 'PosReg', (71, 79))	('cell death', 'CPA', (80, 90))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
160344	33122723	This demonstrated that SASH1 depletion partially rescued the cell death response in these cell lines, suggesting chloropyramine-induced cell death is at least in part dependent upon the function of SASH1.	('depletion', 'Var', (29, 38))	('SASH1', 'Gene', (198, 203))	('SASH1', 'Gene', (23, 28))	('chloropyramine', 'Chemical', 'MESH:C004664', (113, 127))	('SASH1', 'Gene', '23328', (198, 203))	('SASH1', 'Gene', '23328', (23, 28))
160345	33122723	SASH1 has been proposed as a tumor suppressor, based on the correlation of the presence of SASH1 mRNA expression with beneficial prognosis in several human cancers and the observation that loss or depletion of SASH1 enhances tumor cell line survival and invasiveness in vitro.	('depletion', 'Var', (197, 206))	('invasiveness in vitro', 'CPA', (254, 275))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('tumor', 'Disease', (225, 230))	('enhances', 'PosReg', (216, 224))	('expression', 'Species', '120121', (102, 112))	('SASH1', 'Gene', '23328', (91, 96))	('tumor', 'Disease', 'MESH:D009369', (225, 230))	('loss', 'Var', (189, 193))	('cancers', 'Disease', 'MESH:D009369', (156, 163))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('SASH1', 'Gene', (91, 96))	('SASH1', 'Gene', '23328', (210, 215))	('human', 'Species', '9606', (150, 155))	('SASH1', 'Gene', '23328', (0, 5))	('SASH1', 'Gene', (210, 215))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('SASH1', 'Gene', (0, 5))	('cancers', 'Phenotype', 'HP:0002664', (156, 163))	('cancers', 'Disease', (156, 163))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('tumor', 'Disease', (29, 34))
160347	33122723	However, in contrast to what we have observed here, our recently published work in breast cancer showed a strong association between high nuclear SASH1 protein expression and favorable outcome in ER + cases, suggesting that the prognostic impact may be context dependent.	('expression', 'MPA', (160, 170))	('SASH1', 'Gene', (146, 151))	('high nuclear', 'Var', (133, 145))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('ER +', 'Var', (196, 200))	('breast cancer', 'Disease', 'MESH:D001943', (83, 96))	('breast cancer', 'Disease', (83, 96))	('SASH1', 'Gene', '23328', (146, 151))	('protein', 'Protein', (152, 159))	('expression', 'Species', '120121', (160, 170))	('breast cancer', 'Phenotype', 'HP:0003002', (83, 96))
160354	33122723	As a novel observation we identified that low SASH1 expression is associated with resistance to cisplatin, whilst high SASH1 expression induces sensitivity to the chemotherapeutic agent.	('expression', 'Species', '120121', (52, 62))	('expression', 'Species', '120121', (125, 135))	('SASH1', 'Gene', (46, 51))	('cisplatin', 'Chemical', 'MESH:D002945', (96, 105))	('high', 'Var', (114, 118))	('SASH1', 'Gene', (119, 124))	('associated', 'Reg', (66, 76))	('expression', 'MPA', (52, 62))	('SASH1', 'Gene', '23328', (46, 51))	('sensitivity to the chemotherapeutic agent', 'MPA', (144, 185))	('low', 'NegReg', (42, 45))	('resistance to cisplatin', 'MPA', (82, 105))	('induces', 'Reg', (136, 143))	('SASH1', 'Gene', '23328', (119, 124))
160363	33122723	Although changes to SASH1 expression have been linked with several other diseases, these associations need further investigation to cement the role of SASH1 as a tumor suppressor relevant to cancer prognoses, particularly within the context of apoptosis, cell cycle and proliferation.	('SASH1', 'Gene', (151, 156))	('SASH1', 'Gene', '23328', (20, 25))	('cancer', 'Disease', (191, 197))	('changes', 'Var', (9, 16))	('cancer', 'Disease', 'MESH:D009369', (191, 197))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('SASH1', 'Gene', '23328', (151, 156))	('tumor', 'Disease', (162, 167))	('expression', 'Species', '120121', (26, 36))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('linked', 'Reg', (47, 53))	('SASH1', 'Gene', (20, 25))	('tumor', 'Disease', 'MESH:D009369', (162, 167))
160378	33122723	Chloropyramine was identified as an agent associated with upregulation of SASH1 expression as previously described in breast cancer.	('expression', 'Species', '120121', (80, 90))	('SASH1', 'Gene', (74, 79))	('Chloropyramine', 'Chemical', 'MESH:C004664', (0, 14))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('SASH1', 'Gene', '23328', (74, 79))	('breast cancer', 'Disease', 'MESH:D001943', (118, 131))	('expression', 'MPA', (80, 90))	('Chloropyramine', 'Var', (0, 14))	('breast cancer', 'Disease', (118, 131))	('upregulation', 'PosReg', (58, 70))	('breast cancer', 'Phenotype', 'HP:0003002', (118, 131))
160453	29246019	For the 16 non-LCCs, not only TP53 and KRAS but also EGFR, KIT, PIK3CA, PTEN, IDH1, APC, ATM and BRAF mutations were also observed.	('PTEN', 'Gene', '5728', (72, 76))	('ATM', 'Gene', (89, 92))	('LCCs', 'Gene', '2733', (15, 19))	('KIT', 'Gene', (59, 62))	('LCC', 'Phenotype', 'HP:0030360', (15, 18))	('TP53', 'Gene', (30, 34))	('IDH1', 'Gene', (78, 82))	('PIK3CA', 'Gene', '5290', (64, 70))	('mutations', 'Var', (102, 111))	('EGFR', 'Gene', '1956', (53, 57))	('BRAF', 'Gene', (97, 101))	('APC', 'Disease', 'MESH:D011125', (84, 87))	('APC', 'Disease', (84, 87))	('IDH1', 'Gene', '3417', (78, 82))	('ATM', 'Gene', '472', (89, 92))	('KRAS', 'Gene', '3845', (39, 43))	('TP53', 'Gene', '7157', (30, 34))	('PIK3CA', 'Gene', (64, 70))	('PTEN', 'Gene', (72, 76))	('LCCs', 'Gene', (15, 19))	('KRAS', 'Gene', (39, 43))	('EGFR', 'Gene', (53, 57))	('BRAF', 'Gene', '673', (97, 101))
160454	29246019	In addition, LCCs without TP53 mutations did not present any gene mutations under the 2004 or 2015 WHO criteria.	('TP53', 'Gene', (26, 30))	('mutations', 'Var', (31, 40))	('LCC', 'Phenotype', 'HP:0030360', (13, 16))	('LCCs', 'Gene', (13, 17))	('LCCs', 'Gene', '2733', (13, 17))	('TP53', 'Gene', '7157', (26, 30))
160455	29246019	Importantly, the patients with TP53 mutation exhibited a trend with a worse survival outcome at the time of follow-up.	('TP53', 'Gene', '7157', (31, 35))	('TP53', 'Gene', (31, 35))	('patients', 'Species', '9606', (17, 25))	('mutation', 'Var', (36, 44))
160465	29246019	Driver gene profiling of Asian lung adenocarcinoma patients is markedly different from the Caucasian patients, particularly with respect to EGFR mutation status.	('patients', 'Species', '9606', (101, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (41, 50))	('lung adenocarcinoma', 'Disease', (31, 50))	('EGFR', 'Gene', (140, 144))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (31, 50))	('patients', 'Species', '9606', (51, 59))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (31, 50))	('EGFR', 'Gene', '1956', (140, 144))	('mutation', 'Var', (145, 153))
160472	29246019	Representative samples with positivity for each marker and typical HE staining of LCCs were shown in Figure 1, and the details of the IHC results for each specimen are shown in Table 2.	('LCC', 'Phenotype', 'HP:0030360', (82, 85))	('positivity', 'Var', (28, 38))	('LCCs', 'Gene', (82, 86))	('HE', 'Chemical', 'MESH:D006371', (67, 69))	('LCCs', 'Gene', '2733', (82, 86))
160474	29246019	Ten of the 46 candidate genes, including EGFR, KRAS, TP53, KIT, PIK3CA, PTEN, IDH1, APC, ATM and BRAF, were mutated in this cohort (Figure 2A).	('PTEN', 'Gene', '5728', (72, 76))	('ATM', 'Gene', (89, 92))	('KIT', 'Gene', (59, 62))	('TP53', 'Gene', (53, 57))	('mutated', 'Var', (108, 115))	('EGFR', 'Gene', (41, 45))	('IDH1', 'Gene', (78, 82))	('PIK3CA', 'Gene', '5290', (64, 70))	('BRAF', 'Gene', (97, 101))	('APC', 'Disease', 'MESH:D011125', (84, 87))	('APC', 'Disease', (84, 87))	('IDH1', 'Gene', '3417', (78, 82))	('TP53', 'Gene', '7157', (53, 57))	('KRAS', 'Gene', '3845', (47, 51))	('ATM', 'Gene', '472', (89, 92))	('EGFR', 'Gene', '1956', (41, 45))	('PIK3CA', 'Gene', (64, 70))	('PTEN', 'Gene', (72, 76))	('KRAS', 'Gene', (47, 51))	('BRAF', 'Gene', '673', (97, 101))
160476	29246019	Among the eight LCC patients under the 2015 WHO criteria, four LCC patients presented TP53 (50%) mutations, and two patients presented concurrent TP53 and KRAS mutations.	('mutations', 'Var', (97, 106))	('TP53', 'Gene', '7157', (146, 150))	('KRAS', 'Gene', (155, 159))	('patients', 'Species', '9606', (67, 75))	('TP53', 'Gene', '7157', (86, 90))	('KRAS', 'Gene', '3845', (155, 159))	('patients', 'Species', '9606', (116, 124))	('TP53', 'Gene', (146, 150))	('TP53', 'Gene', (86, 90))	('patients', 'Species', '9606', (20, 28))	('LCC', 'Phenotype', 'HP:0030360', (63, 66))	('LCC', 'Phenotype', 'HP:0030360', (16, 19))
160479	29246019	Six non-LCC patients presented single TP53 mutations, and nine non-LCC patients presented concurrent mutations in TP53 and other genes (Figure 2A).	('LCC', 'Phenotype', 'HP:0030360', (67, 70))	('patients', 'Species', '9606', (12, 20))	('LCC', 'Phenotype', 'HP:0030360', (8, 11))	('TP53', 'Gene', (38, 42))	('patients', 'Species', '9606', (71, 79))	('TP53', 'Gene', '7157', (114, 118))	('mutations', 'Var', (43, 52))	('TP53', 'Gene', (114, 118))	('TP53', 'Gene', '7157', (38, 42))
160480	29246019	LCCs under the 2015 WHO criteria showed lower heterogeneity among the detected mutations of LCCs vs the rest = 2/46 vs 10/46, respectively, P = 0.030.	('LCCs', 'Gene', (92, 96))	('mutations', 'Var', (79, 88))	('LCC', 'Phenotype', 'HP:0030360', (92, 95))	('LCCs', 'Gene', '2733', (92, 96))	('LCCs', 'Gene', (0, 4))	('LCC', 'Phenotype', 'HP:0030360', (0, 3))	('heterogeneity', 'MPA', (46, 59))	('lower', 'NegReg', (40, 45))	('LCCs', 'Gene', '2733', (0, 4))
160491	29246019	In addition, we investigated the correlation between survival and TP53 mutation in LCC patients defined according to the 2004 or 2015 WHO classification criteria (Figure 4B).	('TP53', 'Gene', '7157', (66, 70))	('LCC', 'Disease', (83, 86))	('TP53', 'Gene', (66, 70))	('mutation', 'Var', (71, 79))	('investigated', 'Reg', (16, 28))	('LCC', 'Phenotype', 'HP:0030360', (83, 86))	('patients', 'Species', '9606', (87, 95))
160492	29246019	Five patients without TP53 mutations, including four patients reclassified as LCCs and one non-LCC patient according to the 2015 WHO criteria, were absent of any other mutation (Figure 2A) and were alive at the time of follow-up.	('mutations', 'Var', (27, 36))	('patient', 'Species', '9606', (99, 106))	('patient', 'Species', '9606', (5, 12))	('patients', 'Species', '9606', (5, 13))	('LCCs', 'Gene', (78, 82))	('patients', 'Species', '9606', (53, 61))	('LCC', 'Phenotype', 'HP:0030360', (95, 98))	('LCC', 'Phenotype', 'HP:0030360', (78, 81))	('LCCs', 'Gene', '2733', (78, 82))	('TP53', 'Gene', '7157', (22, 26))	('TP53', 'Gene', (22, 26))	('patient', 'Species', '9606', (53, 60))
160493	29246019	The patients with TP53 mutations, under both the 2004 and 2015 WHO criteria, showed shorter survival, although without significant difference, probably due to the limited patient number.	('TP53', 'Gene', '7157', (18, 22))	('patient', 'Species', '9606', (171, 178))	('patient', 'Species', '9606', (4, 11))	('TP53', 'Gene', (18, 22))	('mutations', 'Var', (23, 32))	('survival', 'MPA', (92, 100))	('shorter', 'NegReg', (84, 91))	('patients', 'Species', '9606', (4, 12))
160507	29246019	Under the 2004 WHO criteria, the most frequent mutations in LCCs occurred in TP53 and KRAS genes, consistent with our findings.	('LCC', 'Phenotype', 'HP:0030360', (60, 63))	('KRAS', 'Gene', (86, 90))	('LCCs', 'Gene', (60, 64))	('KRAS', 'Gene', '3845', (86, 90))	('mutations', 'Var', (47, 56))	('LCCs', 'Gene', '2733', (60, 64))	('TP53', 'Gene', '7157', (77, 81))	('TP53', 'Gene', (77, 81))
160508	29246019	LCCs with IHC marker-null phenotypes were also associated with a high incidence of TP53 and KRAS mutations.	('TP53', 'Gene', '7157', (83, 87))	('mutations', 'Var', (97, 106))	('TP53', 'Gene', (83, 87))	('KRAS', 'Gene', (92, 96))	('LCCs', 'Gene', (0, 4))	('LCC', 'Phenotype', 'HP:0030360', (0, 3))	('KRAS', 'Gene', '3845', (92, 96))	('LCCs', 'Gene', '2733', (0, 4))
160509	29246019	The high incidence of TP53 mutations in many pulmonary tumors and the correlation of KRAS mutations with smoking status have been reported.	('mutations', 'Var', (27, 36))	('TP53', 'Gene', (22, 26))	('pulmonary tumors', 'Phenotype', 'HP:0100526', (45, 61))	('pulmonary tumors', 'Disease', 'MESH:D008175', (45, 61))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('TP53', 'Gene', '7157', (22, 26))	('KRAS', 'Gene', (85, 89))	('KRAS', 'Gene', '3845', (85, 89))	('pulmonary tumors', 'Disease', (45, 61))
160510	29246019	In the present study, both LCC and non-LCC patients under the 2015 WHO criteria presented a high incidence of TP53 (50% vs 93.75%, respectively) and KRAS (25% vs 43.75%, respectively) mutations (Figure 2).	('TP53', 'Gene', '7157', (110, 114))	('LCC', 'Phenotype', 'HP:0030360', (39, 42))	('TP53', 'Gene', (110, 114))	('mutations', 'Var', (184, 193))	('patients', 'Species', '9606', (43, 51))	('KRAS', 'Gene', (149, 153))	('KRAS', 'Gene', '3845', (149, 153))	('LCC', 'Phenotype', 'HP:0030360', (27, 30))
160511	29246019	Under the 2015 WHO criteria, we also observed that LCC patients only presented TP53 and KRAS mutations in the 46 gene panel, while non-LCC patients showed 8 additional mutations in genes other than TP53 and KRAS (LCC vs non-LCC = 2/46 vs 10/46, respectively).	('LCC', 'Phenotype', 'HP:0030360', (135, 138))	('TP53', 'Gene', '7157', (79, 83))	('mutations', 'Var', (93, 102))	('TP53', 'Gene', (79, 83))	('patients', 'Species', '9606', (139, 147))	('LCC', 'Phenotype', 'HP:0030360', (213, 216))	('KRAS', 'Gene', (207, 211))	('KRAS', 'Gene', '3845', (207, 211))	('TP53', 'Gene', '7157', (198, 202))	('patients', 'Species', '9606', (55, 63))	('KRAS', 'Gene', (88, 92))	('LCC', 'Phenotype', 'HP:0030360', (51, 54))	('KRAS', 'Gene', '3845', (88, 92))	('LCC', 'Phenotype', 'HP:0030360', (224, 227))	('TP53', 'Gene', (198, 202))
160513	29246019	Furthermore, although there was no significant difference, all four LCC patients under the 2015 WHO criteria who did not harbor TP53 mutations were alive at the time of follow-up and might present better prognoses compared with the other patients in this cohort.	('TP53', 'Gene', '7157', (128, 132))	('LCC', 'Phenotype', 'HP:0030360', (68, 71))	('TP53', 'Gene', (128, 132))	('mutations', 'Var', (133, 142))	('patients', 'Species', '9606', (238, 246))	('patients', 'Species', '9606', (72, 80))
160519	29246019	The two ADC-S and one NK-SQCC patients also presented concurrent mutations, while no concurrent mutations were detected in large cell carcinoma with null immunohistochemical features (LCC-N).	('LCC', 'Phenotype', 'HP:0030360', (184, 187))	('cell carcinoma', 'Disease', (129, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('patients', 'Species', '9606', (30, 38))	('cell carcinoma', 'Disease', 'MESH:C538614', (129, 143))	('large cell carcinoma', 'Phenotype', 'HP:0030360', (123, 143))	('mutations', 'Var', (65, 74))
160521	29246019	In addition, although the statistical analysis was not provided, the previous study reported that the incidence of TP53 mutations of LCC-N was lower than ADC-S and NK-SQCC (LCC-N vs ADC-S + NK-SQCC = 0/2 vs 7/15, respectively), consistent with the results of our study.	('TP53', 'Gene', '7157', (115, 119))	('lower', 'NegReg', (143, 148))	('LCC', 'Phenotype', 'HP:0030360', (133, 136))	('TP53', 'Gene', (115, 119))	('mutations', 'Var', (120, 129))	('LCC-N', 'Gene', (133, 138))	('LCC', 'Phenotype', 'HP:0030360', (173, 176))
160523	29246019	Previous studies have demonstrated that EGFR mutations are strongly correlated with clinical features, including Asian, female, non-smokers and adenocarcinoma.	('mutations', 'Var', (45, 54))	('female', 'Disease', (120, 126))	('carcinoma', 'Phenotype', 'HP:0030731', (149, 158))	('adenocarcinoma', 'Disease', (144, 158))	('adenocarcinoma', 'Disease', 'MESH:D000230', (144, 158))	('non-smokers', 'Disease', (128, 139))	('EGFR', 'Gene', '1956', (40, 44))	('EGFR', 'Gene', (40, 44))	('Asian', 'Disease', (113, 118))	('correlated', 'Reg', (68, 78))
160524	29246019	The rare incidence of EGFR mutations was reported in LCCs under the 2004 WHO criteria and LCCs with IHC marker-null phenotypes.	('mutations', 'Var', (27, 36))	('LCCs', 'Gene', (90, 94))	('LCC', 'Phenotype', 'HP:0030360', (53, 56))	('LCCs', 'Gene', '2733', (90, 94))	('LCCs', 'Gene', (53, 57))	('LCCs', 'Gene', '2733', (53, 57))	('EGFR', 'Gene', '1956', (22, 26))	('LCC', 'Phenotype', 'HP:0030360', (90, 93))	('EGFR', 'Gene', (22, 26))
160525	29246019	In our study, no EGFR mutations were observed under the 2015 WHO classification, while four of the sixteen excluded tumors harbored EGFR mutations (Figure 2).	('tumors', 'Disease', 'MESH:D009369', (116, 122))	('tumors', 'Disease', (116, 122))	('EGFR', 'Gene', '1956', (132, 136))	('EGFR', 'Gene', (132, 136))	('mutations', 'Var', (137, 146))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('EGFR', 'Gene', '1956', (17, 21))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))	('EGFR', 'Gene', (17, 21))
160536	29246019	Surgically resected LCCs with TP53 mutations showed a worse survival tendency, while LCCs without any detected mutations might indicate a better prognosis.	('LCCs', 'Gene', '2733', (20, 24))	('TP53', 'Gene', (30, 34))	('LCC', 'Phenotype', 'HP:0030360', (85, 88))	('LCCs', 'Gene', (85, 89))	('LCCs', 'Gene', (20, 24))	('LCC', 'Phenotype', 'HP:0030360', (20, 23))	('TP53', 'Gene', '7157', (30, 34))	('LCCs', 'Gene', '2733', (85, 89))	('mutations', 'Var', (35, 44))
160546	29246019	Forty-six mutations, including EGFR, BRAF, TP53, ALK and other cancer-related gene mutations, were targeted in this study (Table 3).	('mutations', 'Var', (83, 92))	('EGFR', 'Gene', '1956', (31, 35))	('ALK', 'Gene', '238', (49, 52))	('BRAF', 'Gene', '673', (37, 41))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('EGFR', 'Gene', (31, 35))	('BRAF', 'Gene', (37, 41))	('ALK', 'Gene', (49, 52))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('TP53', 'Gene', '7157', (43, 47))	('TP53', 'Gene', (43, 47))	('cancer', 'Disease', (63, 69))
160611	25424871	Patients with T1/2 disease had a better 3-year OS than stage T3 and T4 tumors (36.1% vs. 30.4% vs. 12.5% p =0.001).	('Patients', 'Species', '9606', (0, 8))	('T1/2', 'Var', (14, 18))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('tumors', 'Disease', (71, 77))	('OS', 'Chemical', '-', (47, 49))	('tumors', 'Disease', 'MESH:D009369', (71, 77))
160612	25424871	The 3-year PFS of patients with T1/T2 disease was significantly better than that of patients with T3 and T4 disease (30.7% vs. 21.3% vs. 6.3%; p =0.002).	('better', 'PosReg', (64, 70))	('patients', 'Species', '9606', (84, 92))	('PFS', 'MPA', (11, 14))	('patients', 'Species', '9606', (18, 26))	('T1/T2 disease', 'Var', (32, 45))
160615	25424871	The 3-year OS and PFS of patients who received cisplatin and 5-FU were 14.5% and 13.1%, respectively (p =0.003), while the 3-year OS and PFS rates of patients who received other regimens were 13.3% and 11.0%, respectively (p =0.034).	('OS', 'Chemical', '-', (11, 13))	('5-FU', 'Chemical', 'MESH:D005472', (61, 65))	('cisplatin', 'Var', (47, 56))	('patients', 'Species', '9606', (150, 158))	('patients', 'Species', '9606', (25, 33))	('PFS', 'CPA', (18, 21))	('OS', 'Chemical', '-', (130, 132))	('cisplatin', 'Chemical', 'MESH:D002945', (47, 56))	('5-FU', 'Var', (61, 65))
160636	25424871	In our study, the survival of patients with T1/2 disease is better than that of those with a T3 lesion, and the prognosis of patients with T3 disease is better than that of those with T4 lesions.	('better', 'PosReg', (60, 66))	('T1/2', 'Var', (44, 48))	('T3 disease', 'Disease', (139, 149))	('T3 disease', 'Disease', 'MESH:C537047', (139, 149))	('patients', 'Species', '9606', (30, 38))	('survival', 'CPA', (18, 26))	('patients', 'Species', '9606', (125, 133))
160683	33670576	similarly found SVs impacting oncogenic and tumor-suppressing genes not identified by NGS or WGS alone in prostate cancer.	('prostate cancer', 'Phenotype', 'HP:0012125', (106, 121))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('impacting', 'Reg', (20, 29))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('prostate cancer', 'Disease', (106, 121))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('SVs', 'Var', (16, 19))	('tumor', 'Disease', (44, 49))	('prostate cancer', 'Disease', 'MESH:D011471', (106, 121))
160722	33670576	Those SVs inaccurately identified as somatic were rare germline variants, predominantly insertions or deletions, essentially private to the patient's genome.	('deletions', 'Var', (102, 111))	('patient', 'Species', '9606', (140, 147))	('insertions', 'Var', (88, 98))
160733	33670576	However, it is noteworthy that the SNV mutational burden in thyroid cancers is among the lowest among all tumor types and that measure of genome instability is mirrored in the low number of somatic SVs in all four of the samples examined.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('cancers', 'Phenotype', 'HP:0002664', (68, 75))	('thyroid cancers', 'Disease', 'MESH:D013964', (60, 75))	('lowest', 'NegReg', (89, 95))	('mutational', 'Var', (39, 49))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('thyroid cancer', 'Phenotype', 'HP:0002890', (60, 74))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('SNV', 'MPA', (35, 38))	('thyroid cancers', 'Disease', (60, 75))	('tumor', 'Disease', (106, 111))
160734	33670576	Similarly, the SNV mutational burden in lung cancers is among the highest across all tumor types and both of the lung tumors examined here also carry a high level of somatic SV.	('tumor', 'Disease', (85, 90))	('lung cancers', 'Disease', 'MESH:D008175', (40, 52))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('lung cancers', 'Phenotype', 'HP:0100526', (40, 52))	('lung tumors', 'Phenotype', 'HP:0100526', (113, 124))	('lung tumors', 'Disease', (113, 124))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('mutational', 'Var', (19, 29))	('tumor', 'Disease', (118, 123))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('cancers', 'Phenotype', 'HP:0002664', (45, 52))	('lung cancers', 'Disease', (40, 52))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('lung tumors', 'Disease', 'MESH:D008175', (113, 124))	('lung tumor', 'Phenotype', 'HP:0100526', (113, 123))
160738	33670576	Identification of Cancer Gene Mutations.	('Mutations', 'Var', (30, 39))	('Cancer', 'Disease', (18, 24))	('Cancer', 'Disease', 'MESH:D009369', (18, 24))	('Cancer', 'Phenotype', 'HP:0002664', (18, 24))
160739	33670576	While, as noted above, we cannot generalize regarding the role of structural variants in onset and progression of different tumor types, our results indicate that we can extract from the structural variant list clinically relevant data on individual tumors that might inform prognosis or treatment options.	('inform', 'Reg', (268, 274))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('variant', 'Var', (198, 205))	('tumor', 'Disease', (124, 129))	('tumor', 'Disease', 'MESH:D009369', (250, 255))	('tumors', 'Phenotype', 'HP:0002664', (250, 256))	('tumor', 'Phenotype', 'HP:0002664', (250, 255))	('tumors', 'Disease', 'MESH:D009369', (250, 256))	('tumors', 'Disease', (250, 256))	('tumor', 'Disease', (250, 255))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
160741	33670576	In particular, we annotated those genes altered by a structural variant, either by disruption, duplication, deletion or fusion, and intersected that list with the set of cancer-related genes in the Cosmic database (v92).	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('duplication', 'Var', (95, 106))	('fusion', 'Var', (120, 126))	('cancer', 'Disease', (170, 176))	('structural', 'Var', (53, 63))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('altered', 'Reg', (40, 47))	('disruption', 'Var', (83, 93))	('deletion', 'Var', (108, 116))
160743	33670576	We included only those oncogenes that were potentially activated by duplication or gene fusion and only those tumor suppressor genes that were potentially inactivated by deletion, insertion or fusion.	('duplication', 'Var', (68, 79))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('oncogenes', 'Gene', (23, 32))	('gene fusion', 'Var', (83, 94))	('activated', 'PosReg', (55, 64))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
160744	33670576	As evident, every tumor sample carried at least one such cancer gene mutation and most contained multiple hits.	('carried', 'Reg', (31, 38))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('tumor', 'Disease', (18, 23))	('cancer', 'Disease', (57, 63))	('mutation', 'Var', (69, 77))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
160749	33670576	For instance, we observed a fusion of CDK6 in one of the tongue tumors while it has previously been associated predominantly only with ALL.	('tumors', 'Disease', (64, 70))	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('tongue tumors', 'Phenotype', 'HP:0100648', (57, 70))	('fusion', 'Var', (28, 34))	('CDK6', 'Gene', (38, 42))	('CDK6', 'Gene', '1021', (38, 42))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('tongue tumor', 'Phenotype', 'HP:0100648', (57, 69))
160750	33670576	Similarly, LRP1B is often inactivated in CLL or ovarian cancer, while we find it inactivated by deletion in one of the lung tumors.	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('lung tumors', 'Phenotype', 'HP:0100526', (119, 130))	('LRP1B', 'Gene', (11, 16))	('lung tumors', 'Disease', (119, 130))	('inactivated', 'Reg', (26, 37))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('ovarian cancer', 'Phenotype', 'HP:0100615', (48, 62))	('CLL or ovarian cancer', 'Disease', 'MESH:D015451', (41, 62))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('deletion', 'Var', (96, 104))	('LRP1B', 'Gene', '53353', (11, 16))	('lung tumors', 'Disease', 'MESH:D008175', (119, 130))	('CLL or ovarian cancer', 'Disease', (41, 62))	('lung tumor', 'Phenotype', 'HP:0100526', (119, 129))
160751	33670576	Diagrams of somatic structural variants in all the solid tumor genomes, filtered to remove known polymorphisms, showing translocations and inversions in the center, copy number on the inner ring and insertions (green), deletions (orange) inversions (light blue) and duplications (violet) on the next to most outer ring.	('duplications', 'Var', (266, 278))	('variants', 'Var', (31, 39))	('insertions', 'Var', (199, 209))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('deletions', 'Var', (219, 228))	('translocations', 'Var', (120, 134))	('copy number', 'Var', (165, 176))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Disease', (57, 62))
160754	33670576	Such images present an integrated picture of the aneuploidies, translocations, inversions, deletions and insertions, which offers a readily digestible impression of the extent of genetic instability underlying a tumor.	('translocations', 'Var', (63, 77))	('deletions', 'Var', (91, 100))	('inversions', 'Var', (79, 89))	('tumor', 'Disease', 'MESH:D009369', (212, 217))	('aneuploidies', 'Disease', (49, 61))	('aneuploidies', 'Disease', 'MESH:D000782', (49, 61))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('insertions', 'Var', (105, 115))	('tumor', 'Disease', (212, 217))
160760	33670576	Somatic driver events in a tumor:point mutations and structural variants (SVs) including insertions, deletions, inversions, translocations and copy number changes:are currently identified in solid tumors by some combinations of RNA sequencing and genome sequencing of either targeted gene panels, whole exomes or whole genomes.	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('insertions', 'Var', (89, 99))	('solid tumors', 'Disease', 'MESH:D009369', (191, 203))	('tumor', 'Disease', (27, 32))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('tumors', 'Phenotype', 'HP:0002664', (197, 203))	('copy number changes', 'Var', (143, 162))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('solid tumors', 'Disease', (191, 203))	('deletions', 'Var', (101, 110))	('tumor', 'Disease', (197, 202))
160777	33670576	The system can be used to accurately detect genetic mutation hallmarks in cancer tissue samples, including rearrangements such as translocations, gene fusions and copy number alterations.	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('copy number alterations', 'Var', (163, 186))	('gene fusions', 'Var', (146, 158))	('cancer', 'Disease', (74, 80))	('translocations', 'Var', (130, 144))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
160783	33191645	Here, we showed that CX3CL1 can further invasion and migration of lung adenocarcinoma A549 and lung squamous cell carcinoma H520.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (100, 123))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (95, 123))	('lung squamous cell carcinoma', 'Disease', (95, 123))	('lung adenocarcinoma A549', 'Disease', (66, 90))	('invasion', 'CPA', (40, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('CX3CL1', 'Var', (21, 27))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (66, 85))	('migration', 'CPA', (53, 62))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (95, 123))	('lung adenocarcinoma A549', 'Disease', 'MESH:D000077192', (66, 90))
160785	33191645	Nevertheless, the src/abl inhibitor bosutinib and mutations of cortactin phosphorylation site could inhibit the promotion effect of CX3CL1 on invasion and migration of A549 and H520.	('A549', 'CellLine', 'CVCL:0023', (168, 172))	('mutations', 'Var', (50, 59))	('src', 'Gene', '6714', (18, 21))	('bosutinib', 'Chemical', 'MESH:C471992', (36, 45))	('abl', 'Gene', '25', (22, 25))	('cortactin', 'Gene', (63, 72))	('abl', 'Gene', (22, 25))	('src', 'Gene', (18, 21))	('inhibit', 'NegReg', (100, 107))
160786	33191645	Moreover, these results of MTT, Hoechst staining and Western blot suggested that CX3CL1 had no effect on the proliferation and apoptosis of A549 and H520 in vitro.	('CX3CL1', 'Var', (81, 87))	('MTT', 'Chemical', '-', (27, 30))	('Hoechst', 'Chemical', '-', (32, 39))	('A549', 'CellLine', 'CVCL:0023', (140, 144))	('apoptosis', 'CPA', (127, 136))
160788	33191645	In summary, our results indicated that CX3CL1 furthered invasion and migration in lung cancer cells partly via activating cortactin, and CX3CL1 may be a potential molecule in regulating the migration and invasion of lung cancer.	('CX3CL1', 'Var', (137, 143))	('lung cancer', 'Phenotype', 'HP:0100526', (82, 93))	('lung cancer', 'Disease', (216, 227))	('cortactin', 'MPA', (122, 131))	('lung cancer', 'Disease', (82, 93))	('lung cancer', 'Phenotype', 'HP:0100526', (216, 227))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('activating', 'PosReg', (111, 121))	('furthered', 'PosReg', (46, 55))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('lung cancer', 'Disease', 'MESH:D008175', (82, 93))	('CX3CL1', 'Var', (39, 45))	('lung cancer', 'Disease', 'MESH:D008175', (216, 227))	('invasion', 'CPA', (56, 64))
160804	33191645	30  Phosphorylation of cortactin tyrosine residues is the key for its conformational transformation, recruitment of the Arp2/3 complex and regulation of MMPs.	('MMPs', 'Gene', '4314;17392;4318', (153, 157))	('cortactin', 'Gene', (23, 32))	('Phosphorylation', 'MPA', (4, 19))	('conformational', 'MPA', (70, 84))	('tyrosine', 'Chemical', 'MESH:D014443', (33, 41))	('tyrosine', 'Var', (33, 41))	('MMPs', 'Gene', (153, 157))	('Arp2/3 complex', 'Protein', (120, 134))
160815	33191645	The following target sequences of siRNA are used: siCX3CR1#1: AGACGCTTAAGCTCTATGA siCX3CR1#2: CCGCAATGTGGAAACAAAT The mixture of 100 muL/mL medium without FBS and penicillin-streptomycin, 1mul/ml Lipo2000 and 1 mug/mL cortactin wild-type plasmid (cortactin WT) or 1 mug/mL cortactin Y421, Y470 and Y486 mutant plasmid (cortactin 3YF) was put at room temperature for 30 minutes before adding into the culture dish evenly.	('FBS', 'Disease', (155, 158))	('CX3CR1', 'Gene', '1524', (52, 58))	('CX3CR1', 'Gene', (52, 58))	('CX3CR1', 'Gene', '1524', (84, 90))	('FBS', 'Disease', 'MESH:D005198', (155, 158))	('streptomycin', 'Chemical', 'MESH:D013307', (174, 186))	('CX3CR1', 'Gene', (84, 90))	('penicillin', 'Chemical', 'MESH:D010406', (163, 173))	('Y486', 'Var', (298, 302))
160855	33191645	It revealed that the transmembrane numbers of A549 and H520 cells in CX3CL1 group were higher than that in control group (Figure 2C,D).	('CX3CL1', 'Var', (69, 75))	('A549', 'CellLine', 'CVCL:0023', (46, 50))	('transmembrane numbers', 'CPA', (21, 42))	('higher', 'PosReg', (87, 93))
160857	33191645	The results showed that the transmembrane numbers of A549 and H520 cells in CX3CL1 group were higher than that in control group (Figure 2C,D).	('A549', 'CellLine', 'CVCL:0023', (53, 57))	('transmembrane numbers', 'CPA', (28, 49))	('higher', 'PosReg', (94, 100))	('CX3CL1', 'Var', (76, 82))
160860	33191645	Transwell test without matrix revealed that the transmembrane numbers of A549 and H520 cells were lower in CX3CR1 knockdown group than that in control group (Figure 3C,D).	('CX3CR1', 'Gene', '1524', (107, 113))	('A549', 'CellLine', 'CVCL:0023', (73, 77))	('knockdown', 'Var', (114, 123))	('CX3CR1', 'Gene', (107, 113))	('transmembrane numbers', 'CPA', (48, 69))	('lower', 'NegReg', (98, 103))
160861	33191645	Meanwhile, transwell test with matrix indicated that the transmembrane numbers of A549 and H520 cells were lower in CX3CR1 knockdown group than that in control group (Figure 3C,D), and the protein level of MMP-3 was down-regulated in A549 and H520 cells by transfecting siCX3CR1 (Figure 3E,F).	('protein level', 'MPA', (189, 202))	('A549', 'CellLine', 'CVCL:0023', (234, 238))	('CX3CR1', 'Gene', '1524', (272, 278))	('CX3CR1', 'Gene', (272, 278))	('lower', 'NegReg', (107, 112))	('down-regulated', 'NegReg', (216, 230))	('transmembrane numbers', 'CPA', (57, 78))	('CX3CR1', 'Gene', '1524', (116, 122))	('A549', 'CellLine', 'CVCL:0023', (82, 86))	('CX3CR1', 'Gene', (116, 122))	('transfecting', 'Var', (257, 269))	('MMP-3', 'Gene', (206, 211))
160863	33191645	It is observed in the in vivo experiments that the tumour formation and growth was increased by adding with CX3CL1 compared to control mice (Figure 4A-C), and immunohistochemistry results showed that p-cortactin 421 and MMP-3 were up-regulated in CX3CL1 group (Figure 4D).	('CX3CL1', 'Var', (247, 253))	('increased', 'PosReg', (83, 92))	('growth', 'CPA', (72, 78))	('tumour', 'Phenotype', 'HP:0002664', (51, 57))	('up-regulated', 'PosReg', (231, 243))	('CX3CL1', 'Var', (108, 114))	('mice', 'Species', '10090', (135, 139))	('p-cortactin 421', 'Protein', (200, 215))	('tumour', 'Disease', 'MESH:D009369', (51, 57))	('tumour', 'Disease', (51, 57))	('MMP-3', 'Gene', (220, 225))
160864	33191645	In addition, immunohistochemistry results showed that PCNA was up-regulated in CX3CL1 group (Figure S1).	('PCNA', 'Gene', '5111', (54, 58))	('PCNA', 'Gene', (54, 58))	('CX3CL1', 'Var', (79, 85))	('up-regulated', 'PosReg', (63, 75))
160870	33191645	In addition, it is observed in the immunofluorescence experiments that CX3CL1 promoted the expression of p-cortactin 421 in A549 and H520 cells, whereas it had no effect on the expression of cortactin (Figure 6D).	('p-cortactin 421', 'Var', (105, 120))	('expression', 'MPA', (91, 101))	('A549', 'CellLine', 'CVCL:0023', (124, 128))	('promoted', 'PosReg', (78, 86))	('CX3CL1', 'Var', (71, 77))
160871	33191645	To explore the role of cortactin in the regulation of migration and invasion in A549 and H520 by CX3CL1, we selected the WT and mutant plasmids of cortactin.	('A549', 'CellLine', 'CVCL:0023', (80, 84))	('invasion', 'CPA', (68, 76))	('mutant', 'Var', (128, 134))
160873	33191645	19  Western blot showed that the protein levels of p-c-Src and p-c-Abl were up-regulated in CX3CL1 group compared with control (Figure 7A,B).	('c-Abl', 'Gene', '25', (65, 70))	('up-regulated', 'PosReg', (76, 88))	('c-Src', 'Gene', (53, 58))	('protein levels', 'MPA', (33, 47))	('c-Src', 'Gene', '6714', (53, 58))	('c-Abl', 'Gene', (65, 70))	('CX3CL1', 'Var', (92, 98))
160877	33191645	The result showed that the number of transmembrane cell in the bosutinib group was significantly lower than that in the control group after CX3CL1 treatment (Figure 7F,G).	('bosutinib', 'Var', (63, 72))	('number of transmembrane cell', 'CPA', (27, 55))	('lower', 'NegReg', (97, 102))	('bosutinib', 'Chemical', 'MESH:C471992', (63, 72))
160891	33191645	16  Our group has confirmed that 100ng/ml of CX3CL1 can up-regulate migrated and invasive abilities of lung cancer A549 cells and H520 cells.	('lung cancer', 'Disease', 'MESH:D008175', (103, 114))	('CX3CL1', 'Var', (45, 51))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('lung cancer', 'Disease', (103, 114))	('A549', 'CellLine', 'CVCL:0023', (115, 119))	('up-regulate', 'PosReg', (56, 67))	('lung cancer', 'Phenotype', 'HP:0100526', (103, 114))
160892	33191645	After knocking down the unique receptor of CX3CL1, that is CX3CR1, the ability of CX3CL1 to promote A549 and H520 cells was inhibited.	('A549', 'CellLine', 'CVCL:0023', (100, 104))	('CX3CR1', 'Gene', '1524', (59, 65))	('promote', 'PosReg', (92, 99))	('CX3CR1', 'Gene', (59, 65))	('inhibited', 'NegReg', (124, 133))	('knocking down', 'Var', (6, 19))
160899	33191645	Phosphorylated Y421 and Y466 interact with SH2 and SH3 domain-rich proteins, like Src, N-WASP, Nck1 and FAK.	('Nck1', 'Gene', (95, 99))	('N-WASP', 'Gene', '8976', (87, 93))	('Y421', 'Var', (15, 19))	('interact', 'Interaction', (29, 37))	('Nck1', 'Gene', '4690', (95, 99))	('N-WASP', 'Gene', (87, 93))	('Y466', 'Var', (24, 28))
160901	33191645	20 ,  21 ,  43 ,  44  Furthermore, a high expression of p-cortactin 421 in lung adenocarcinoma and lung squamous cell carcinoma compared with adjacent tissues was observed in the experiment.	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (75, 94))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (104, 127))	('lung squamous cell carcinoma', 'Disease', (99, 127))	('expression', 'MPA', (42, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('lung adenocarcinoma', 'Disease', (75, 94))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (75, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (99, 127))	('p-cortactin', 'Var', (56, 67))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (99, 127))
160911	33191645	16 ,  40  Therefore, in the next experiment, we will further investigate the regulation mechanism of the metastasis of lung cancer by verifying whether CX3CL1 regulates the phosphorylation of cortactin through MAPK/ERK and PI3K/AKT signalling pathways.	('metastasis of lung cancer', 'Disease', 'MESH:D008175', (105, 130))	('AKT', 'Gene', '207', (228, 231))	('lung cancer', 'Phenotype', 'HP:0100526', (119, 130))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('metastasis of lung cancer', 'Disease', (105, 130))	('AKT', 'Gene', (228, 231))	('cortactin', 'Protein', (192, 201))	('CX3CL1', 'Var', (152, 158))	('phosphorylation', 'MPA', (173, 188))	('regulates', 'Reg', (159, 168))
160918	33191645	However, in vitro experiments, the same concentration of CX3CL1 had no effect on proliferation or apoptosis of A549 and H520, but furthered migration and invasion of A549 and H520.	('apoptosis', 'CPA', (98, 107))	('furthered', 'PosReg', (130, 139))	('A549', 'CellLine', 'CVCL:0023', (166, 170))	('invasion', 'CPA', (154, 162))	('A549', 'CellLine', 'CVCL:0023', (111, 115))	('CX3CL1', 'Var', (57, 63))	('migration', 'CPA', (140, 149))
160923	33191645	49 ,  50 ,  51 ,  52  Therefore, we speculate that besides promoting the invasion directly by affecting on tumour cells, in vivo injection of CX3CL1 may also be involved in the recruitment of M2 macrophages with high expression of CX3CR1.	('promoting', 'PosReg', (59, 68))	('involved', 'Reg', (161, 169))	('CX3CR1', 'Gene', (231, 237))	('tumour', 'Phenotype', 'HP:0002664', (107, 113))	('CX3CR1', 'Gene', '1524', (231, 237))	('CX3CL1', 'Var', (142, 148))	('tumour', 'Disease', 'MESH:D009369', (107, 113))	('affecting', 'Reg', (94, 103))	('invasion', 'CPA', (73, 81))	('tumour', 'Disease', (107, 113))
160925	33191645	In addition, some studies have confirmed that CX3CL1 significantly enhances NK cell cytotoxicity, IFN-gamma expression and secretion to inhibit neuroblastoma proliferation and metastasis.	('cytotoxicity', 'Disease', (84, 96))	('inhibit', 'NegReg', (136, 143))	('enhances', 'PosReg', (67, 75))	('secretion', 'MPA', (123, 132))	('cytotoxicity', 'Disease', 'MESH:D064420', (84, 96))	('neuroblastoma', 'Disease', 'MESH:D009447', (144, 157))	('IFN-gamma', 'Gene', '3458', (98, 107))	('CX3CL1', 'Var', (46, 52))	('neuroblastoma', 'Disease', (144, 157))	('IFN-gamma', 'Gene', (98, 107))	('expression', 'MPA', (108, 118))	('neuroblastoma', 'Phenotype', 'HP:0003006', (144, 157))
160927	33191645	To sum up, our research suggested that CX3CL1 could promote invasion and migration of lung cancer A549 and H520 cells by up-regulating the phosphorylation of cortactin, which might be a potential target of clinical diagnosis and therapy.	('A549', 'CellLine', 'CVCL:0023', (98, 102))	('migration', 'CPA', (73, 82))	('phosphorylation', 'MPA', (139, 154))	('invasion', 'CPA', (60, 68))	('cortactin', 'Protein', (158, 167))	('lung cancer', 'Phenotype', 'HP:0100526', (86, 97))	('lung cancer', 'Disease', (86, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('lung cancer', 'Disease', 'MESH:D008175', (86, 97))	('CX3CL1', 'Var', (39, 45))	('promote', 'PosReg', (52, 59))	('up-regulating', 'PosReg', (121, 134))
160928	33191645	The current study demonstrates that CX3CL1 promotes the phosphorylation of cortactin via c-Src and c-Abl signalling pathways, and further promotes the migration and invasion of lung adenocarcinoma A549 cells and lung squamous cell carcinoma H520 cells.	('carcinoma', 'Phenotype', 'HP:0030731', (231, 240))	('c-Abl', 'Gene', (99, 104))	('migration', 'CPA', (151, 160))	('c-Src', 'Gene', (89, 94))	('promotes', 'PosReg', (138, 146))	('phosphorylation', 'MPA', (56, 71))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (212, 240))	('promotes', 'PosReg', (43, 51))	('c-Src', 'Gene', '6714', (89, 94))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (217, 240))	('c-Abl', 'Gene', '25', (99, 104))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (177, 196))	('lung adenocarcinoma A549', 'Disease', 'MESH:D000077192', (177, 201))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (212, 240))	('lung adenocarcinoma A549', 'Disease', (177, 201))	('carcinoma', 'Phenotype', 'HP:0030731', (187, 196))	('lung squamous cell carcinoma', 'Disease', (212, 240))	('invasion', 'CPA', (165, 173))	('cortactin', 'Gene', (75, 84))	('CX3CL1', 'Var', (36, 42))
160936	32857918	Of the 41 candidate genes with high-frequency mutation rates, six genes were significantly associated with OS: TP53, LPP, MAP3K13, FGF12, BCL6, and TP63.	('TP63', 'Gene', (148, 152))	('FGF12', 'Gene', '2257', (131, 136))	('BCL6', 'Gene', (138, 142))	('LPP', 'Gene', (117, 120))	('TP53', 'Gene', '7157', (111, 115))	('TP53', 'Gene', (111, 115))	('MAP3K13', 'Gene', (122, 129))	('TP63', 'Gene', '8626', (148, 152))	('LPP', 'Gene', '4026', (117, 120))	('BCL6', 'Gene', '604', (138, 142))	('FGF12', 'Gene', (131, 136))	('mutation', 'Var', (46, 54))	('MAP3K13', 'Gene', '9175', (122, 129))	('associated', 'Reg', (91, 101))
160938	32857918	TP53 mutations are potentially markers of poor prognosis for stage I lung adenocarcinoma patients.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('lung adenocarcinoma', 'Disease', (69, 88))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (69, 88))	('mutations', 'Var', (5, 14))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('patients', 'Species', '9606', (89, 97))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (69, 88))
160939	32857918	The mutation status of this gene may contribute to clinical decision-making with respect to selecting patients who may benefit from adjuvant therapy.	('contribute', 'Reg', (37, 47))	('patients', 'Species', '9606', (102, 110))	('mutation', 'Var', (4, 12))
160950	32857918	Some studies have demonstrated that EGFR and KRAS mutations were correlated with prognosis in early-stage NSCLC, 6 ,  7 ,  8  and numerous other oncogenic and tumor suppressor genes have been identified in the initiation and pathogenesis of NSCLC.	('KRAS', 'Gene', '3845', (45, 49))	('NSCLC', 'Disease', 'MESH:D002289', (106, 111))	('NSCLC', 'Disease', (241, 246))	('mutations', 'Var', (50, 59))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('NSCLC', 'Disease', 'MESH:D002289', (241, 246))	('EGFR', 'Gene', '1956', (36, 40))	('NSCLC', 'Phenotype', 'HP:0030358', (106, 111))	('tumor', 'Disease', (159, 164))	('EGFR', 'Gene', (36, 40))	('NSCLC', 'Phenotype', 'HP:0030358', (241, 246))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('KRAS', 'Gene', (45, 49))	('NSCLC', 'Disease', (106, 111))	('correlated', 'Reg', (65, 75))
160957	32857918	Clinicopathology, treatment details, and survival status were extracted, including sex, age, smoking status, tumor dimension, histology, total mutation count, surgical margin, prior cancer diagnosis, gene mutation and copy-number alterations (CNA) type, disease-free survival (DFS), and overall survival (OS).	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('disease-free survival', 'CPA', (254, 275))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('copy-number alterations', 'Var', (218, 241))	('cancer', 'Disease', (182, 188))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('overall survival', 'CPA', (287, 303))	('gene mutation', 'Var', (200, 213))	('tumor', 'Disease', (109, 114))
160961	32857918	From the 408 patients with stage IA or IB NSCLC from the PLC dataset, we retrieved 41 candidate cancer genes with high (>10%) frequency rate (Table S1): 15 somatic mutations (Table S2) and 26 CNAs (Table S3).	('NSCLC', 'Disease', (42, 47))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('NSCLC', 'Disease', 'MESH:D002289', (42, 47))	('patients', 'Species', '9606', (13, 21))	('somatic mutations', 'Var', (156, 173))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('NSCLC', 'Phenotype', 'HP:0030358', (42, 47))	('CNAs', 'Var', (192, 196))	('cancer', 'Disease', (96, 102))
160962	32857918	Alterations in six genes (TP53, LPP, MAP3K13, FGF12, BCL6, and TP63) were significantly associated with the OS of patients with stage I NSCLC (Figure 2).	('TP53', 'Gene', (26, 30))	('NSCLC', 'Disease', 'MESH:D002289', (136, 141))	('TP53', 'Gene', '7157', (26, 30))	('FGF12', 'Gene', '2257', (46, 51))	('BCL6', 'Gene', '604', (53, 57))	('Alterations', 'Var', (0, 11))	('MAP3K13', 'Gene', (37, 44))	('NSCLC', 'Phenotype', 'HP:0030358', (136, 141))	('LPP', 'Gene', (32, 35))	('MAP3K13', 'Gene', '9175', (37, 44))	('FGF12', 'Gene', (46, 51))	('BCL6', 'Gene', (53, 57))	('TP63', 'Gene', '8626', (63, 67))	('patients', 'Species', '9606', (114, 122))	('LPP', 'Gene', '4026', (32, 35))	('NSCLC', 'Disease', (136, 141))	('associated with', 'Reg', (88, 103))	('TP63', 'Gene', (63, 67))
160968	32857918	Interestingly, TP53 mutations were associated with a worse OS in patients with stage I lung ADC, but they were not associated with OS in patients with lung SqCC (Figure 4).	('patients', 'Species', '9606', (137, 145))	('TP53', 'Gene', '7157', (15, 19))	('TP53', 'Gene', (15, 19))	('SqCC', 'Phenotype', 'HP:0002860', (156, 160))	('patients', 'Species', '9606', (65, 73))	('mutations', 'Var', (20, 29))
160970	32857918	In the 1093 patients from the LUAD and LUSC datasets, 50 patients with stage IA NSCLC who have mutation data available had undergone definite R0 surgical resection without prior cancer diagnosis occurence, and the clinicopathologic characteristics of the TP53 mutations are shown in Table 1.	('TP53', 'Gene', (255, 259))	('patients', 'Species', '9606', (12, 20))	('NSCLC', 'Phenotype', 'HP:0030358', (80, 85))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('patients', 'Species', '9606', (57, 65))	('NSCLC', 'Disease', (80, 85))	('LUSC', 'Phenotype', 'HP:0030359', (39, 43))	('cancer', 'Disease', (178, 184))	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('NSCLC', 'Disease', 'MESH:D002289', (80, 85))	('mutations', 'Var', (260, 269))	('LUAD', 'Phenotype', 'HP:0030078', (30, 34))	('TP53', 'Gene', '7157', (255, 259))
160971	32857918	The number of patients with mutated vs wild-type TP53 was comparable in this study cohort (n = 28 vs n = 22, respectively).	('TP53', 'Gene', (49, 53))	('patients', 'Species', '9606', (14, 22))	('mutated', 'Var', (28, 35))	('TP53', 'Gene', '7157', (49, 53))
160972	32857918	However, the distribution of TP53 mutation differed among patients with lung ADC vs SqCC, with the mutation being more common in lung SqCC.	('SqCC', 'Phenotype', 'HP:0002860', (134, 138))	('mutation', 'Var', (34, 42))	('lung', 'Disease', (72, 76))	('TP53', 'Gene', '7157', (29, 33))	('TP53', 'Gene', (29, 33))	('patients', 'Species', '9606', (58, 66))	('common', 'Reg', (119, 125))	('SqCC', 'Phenotype', 'HP:0002860', (84, 88))
160973	32857918	In addition, patients with the TP53 mutation were more commonly heavy smokers and had a higher mutation burden (Table 1 ).	('higher', 'PosReg', (88, 94))	('TP53', 'Gene', '7157', (31, 35))	('patients', 'Species', '9606', (13, 21))	('TP53', 'Gene', (31, 35))	('mutation burden', 'MPA', (95, 110))	('mutation', 'Var', (36, 44))
160974	32857918	And it was found that TP53 mutation was an independent risk factor for the poor prognosis (Table S5).	('mutation', 'Var', (27, 35))	('TP53', 'Gene', '7157', (22, 26))	('TP53', 'Gene', (22, 26))
160976	32857918	It was demonstrated that TP53 mutations were not significantly associated with DFS in either lung ADC or lung SqCC (Figure 5A).	('TP53', 'Gene', (25, 29))	('SqCC', 'Phenotype', 'HP:0002860', (110, 114))	('associated', 'Reg', (63, 73))	('lung SqCC', 'Disease', (105, 114))	('DFS', 'Disease', (79, 82))	('mutations', 'Var', (30, 39))	('lung ADC', 'Disease', (93, 101))	('TP53', 'Gene', '7157', (25, 29))
160977	32857918	However, consistent with the findings of total stage I NSCLC from the PLC dataset, TP53 mutations were significantly associated with OS, but only for patients with lung ADC and not lung SqCC (Figure 5B).	('TP53', 'Gene', '7157', (83, 87))	('NSCLC', 'Disease', (55, 60))	('TP53', 'Gene', (83, 87))	('lung ADC', 'Disease', (164, 172))	('associated with', 'Reg', (117, 132))	('mutations', 'Var', (88, 97))	('NSCLC', 'Disease', 'MESH:D002289', (55, 60))	('patients', 'Species', '9606', (150, 158))	('SqCC', 'Phenotype', 'HP:0002860', (186, 190))	('NSCLC', 'Phenotype', 'HP:0030358', (55, 60))
160979	32857918	Lung SqCC had more TP53 genetic alterations compared with lung ADC (Figure 6A), and the mutation sites (Figure 6B) of TP53 were markedly different between lung ADC and SqCC (Table 2).	('different', 'Reg', (137, 146))	('genetic alterations', 'Var', (24, 43))	('Lung SqCC', 'Disease', (0, 9))	('SqCC', 'Phenotype', 'HP:0002860', (168, 172))	('TP53', 'Gene', '7157', (118, 122))	('TP53', 'Gene', (118, 122))	('TP53', 'Gene', '7157', (19, 23))	('TP53', 'Gene', (19, 23))	('SqCC', 'Phenotype', 'HP:0002860', (5, 9))
160986	32857918	In the present study, we explored the role of TP53 mutations on the prognosis of patients with stage I NSCLC by analyzing three public datasets from TCGA, in particular those patients with surgically resected stage IA disease.	('stage IA disease', 'Disease', (209, 225))	('mutations', 'Var', (51, 60))	('stage IA disease', 'Disease', 'MESH:D058625', (209, 225))	('NSCLC', 'Disease', (103, 108))	('TP53', 'Gene', '7157', (46, 50))	('patients', 'Species', '9606', (81, 89))	('NSCLC', 'Disease', 'MESH:D002289', (103, 108))	('patients', 'Species', '9606', (175, 183))	('TP53', 'Gene', (46, 50))	('NSCLC', 'Phenotype', 'HP:0030358', (103, 108))
160990	32857918	Only the TP53 mutation was associated with worse OS, and this association was restricted to patients with lung ADC which was consistent with the findings in stage I NSCLC of PLC dataset.	('NSCLC', 'Disease', 'MESH:D002289', (165, 170))	('lung ADC', 'Disease', (106, 114))	('patients', 'Species', '9606', (92, 100))	('TP53', 'Gene', '7157', (9, 13))	('NSCLC', 'Phenotype', 'HP:0030358', (165, 170))	('mutation', 'Var', (14, 22))	('TP53', 'Gene', (9, 13))	('NSCLC', 'Disease', (165, 170))
160991	32857918	We noticed that there was a trend of lung ADC and SqCC patients with TP53 mutation having a worse DFS, however, without significance, which is probably due to the limited sample number in each group.	('mutation', 'Var', (74, 82))	('lung ADC', 'Disease', (37, 45))	('SqCC', 'Disease', (50, 54))	('TP53', 'Gene', '7157', (69, 73))	('TP53', 'Gene', (69, 73))	('patients', 'Species', '9606', (55, 63))	('SqCC', 'Phenotype', 'HP:0002860', (50, 54))
160992	32857918	In addition, we identified 183 TP53 mutation sites, with five mutation types, in 408 patients with stage I NSCLC in the PLC dataset.	('NSCLC', 'Disease', (107, 112))	('TP53', 'Gene', '7157', (31, 35))	('NSCLC', 'Disease', 'MESH:D002289', (107, 112))	('TP53', 'Gene', (31, 35))	('patients', 'Species', '9606', (85, 93))	('NSCLC', 'Phenotype', 'HP:0030358', (107, 112))	('mutation', 'Var', (36, 44))
160994	32857918	These differences might explain the discrepant impact of TP53 mutation on lung ADC and SqCC.	('SqCC', 'Phenotype', 'HP:0002860', (87, 91))	('mutation', 'Var', (62, 70))	('TP53', 'Gene', '7157', (57, 61))	('SqCC', 'Disease', (87, 91))	('TP53', 'Gene', (57, 61))	('lung ADC', 'Disease', (74, 82))
160996	32857918	Szymanowska et al 16  showed that the TP53 Arg72Pro polymorphism was associated with an increased risk of NSCLC.	('NSCLC', 'Disease', 'MESH:D002289', (106, 111))	('TP53', 'Gene', (38, 42))	('Arg72Pro', 'Var', (43, 51))	('NSCLC', 'Phenotype', 'HP:0030358', (106, 111))	('Arg72Pro', 'SUBSTITUTION', 'None', (43, 51))	('NSCLC', 'Disease', (106, 111))	('TP53', 'Gene', '7157', (38, 42))
160997	32857918	According to a pooled analysis of data from the International Adjuvant Lung Cancer Trial and three other randomized trials, the LACE-Bio Collaborative Group reported that TP53 mutations had no significant predictive value on the outcome of platinum-based adjuvant chemotherapy.	('TP53', 'Gene', (171, 175))	('mutations', 'Var', (176, 185))	('Lung Cancer', 'Disease', (71, 82))	('Lung Cancer', 'Phenotype', 'HP:0100526', (71, 82))	('Lung Cancer', 'Disease', 'MESH:D008175', (71, 82))	('Cancer', 'Phenotype', 'HP:0002664', (76, 82))	('platinum', 'Chemical', 'MESH:D010984', (240, 248))	('TP53', 'Gene', '7157', (171, 175))
160998	32857918	However, in patients who received adjuvant chemotherapy, TP53 mutation was associated with shorter survival than wild-type TP53.	('patients', 'Species', '9606', (12, 20))	('mutation', 'Var', (62, 70))	('TP53', 'Gene', '7157', (123, 127))	('survival', 'MPA', (99, 107))	('TP53', 'Gene', '7157', (57, 61))	('TP53', 'Gene', (57, 61))	('TP53', 'Gene', (123, 127))	('shorter', 'NegReg', (91, 98))
161001	32857918	19  Consistent with the findings from our study, that meta-analysis also indicated that TP53 gene alterations suggested a poor prognosis in patients with early-stage lung ADC.	('alterations', 'Var', (98, 109))	('early-stage lung ADC', 'Disease', (154, 174))	('TP53', 'Gene', '7157', (88, 92))	('patients', 'Species', '9606', (140, 148))	('TP53', 'Gene', (88, 92))
161003	32857918	In 120 patients with NSCLC who underwent surgery, Mitsudomi et al 20  found that a p53 mutation was a significant prognostic factor for worse survival in the patients with advanced disease (stages IIIA-IV) but not early disease (stages I-II).	('worse', 'NegReg', (136, 141))	('p53', 'Gene', (83, 86))	('NSCLC', 'Disease', (21, 26))	('p53', 'Gene', '7157', (83, 86))	('NSCLC', 'Disease', 'MESH:D002289', (21, 26))	('NSCLC', 'Phenotype', 'HP:0030358', (21, 26))	('patients', 'Species', '9606', (158, 166))	('mutation', 'Var', (87, 95))	('patients', 'Species', '9606', (7, 15))
161004	32857918	However, Ahrendt et al 21  reported the opposite results; after analyzing 188 patients with operable NSCLC, they showed that the risk of death was significantly higher in patients with p53 mutations than wild-type patients.	('p53', 'Gene', (185, 188))	('p53', 'Gene', '7157', (185, 188))	('patients', 'Species', '9606', (214, 222))	('NSCLC', 'Disease', (101, 106))	('patients', 'Species', '9606', (78, 86))	('death', 'Disease', 'MESH:D003643', (137, 142))	('patients', 'Species', '9606', (171, 179))	('death', 'Disease', (137, 142))	('NSCLC', 'Disease', 'MESH:D002289', (101, 106))	('higher', 'Reg', (161, 167))	('mutations', 'Var', (189, 198))	('NSCLC', 'Phenotype', 'HP:0030358', (101, 106))
161005	32857918	Furthermore, a stratified analysis showed that the statistically significant prognostic effect (predicting worse survival) of p53 mutations was limited to patients with stage I NSCLC.	('stage', 'Disease', (169, 174))	('p53', 'Gene', '7157', (126, 129))	('NSCLC', 'Phenotype', 'HP:0030358', (177, 182))	('NSCLC', 'Disease', (177, 182))	('mutations', 'Var', (130, 139))	('patients', 'Species', '9606', (155, 163))	('NSCLC', 'Disease', 'MESH:D002289', (177, 182))	('p53', 'Gene', (126, 129))	('significant', 'Reg', (65, 76))
161006	32857918	21  Molina-Vila et al 22  reported that a TP53 mutation was an independent predictor of shorter survival in patients with advanced NSCLC (stage IIIB-IV), but they did not provide the data for patients with surgically resected early-stage NSCLC.	('shorter', 'NegReg', (88, 95))	('TP53', 'Gene', '7157', (42, 46))	('patients', 'Species', '9606', (108, 116))	('NSCLC', 'Phenotype', 'HP:0030358', (238, 243))	('NSCLC', 'Disease', (131, 136))	('TP53', 'Gene', (42, 46))	('mutation', 'Var', (47, 55))	('patients', 'Species', '9606', (192, 200))	('NSCLC', 'Disease', 'MESH:D002289', (131, 136))	('NSCLC', 'Disease', (238, 243))	('NSCLC', 'Disease', 'MESH:D002289', (238, 243))	('NSCLC', 'Phenotype', 'HP:0030358', (131, 136))	('survival', 'MPA', (96, 104))
161008	32857918	Lee et al 23  did not find that patients with NSCLC and TP53 mutations had a significantly worse survival compared to the wild-type group, but a subgroup analysis showed that TP53 variants with a high mutation frequency were associated with a significantly worse survival compared with wild type.	('TP53', 'Gene', (175, 179))	('patients', 'Species', '9606', (32, 40))	('TP53', 'Gene', '7157', (56, 60))	('worse', 'NegReg', (257, 262))	('NSCLC', 'Disease', (46, 51))	('mutations', 'Var', (61, 70))	('survival', 'MPA', (263, 271))	('TP53', 'Gene', (56, 60))	('NSCLC', 'Disease', 'MESH:D002289', (46, 51))	('variants', 'Var', (180, 188))	('TP53', 'Gene', '7157', (175, 179))	('NSCLC', 'Phenotype', 'HP:0030358', (46, 51))
161009	32857918	From a multiregion sequencing study, Zhang et al 24  identified a universal spatial heterogeneity of TP53 mutation in NSCLC; therefore, the sites and timing of tumor acquisition may cause a marked difference in the positivity and frequency of TP53 mutation.	('NSCLC', 'Phenotype', 'HP:0030358', (118, 123))	('TP53', 'Gene', '7157', (101, 105))	('mutation', 'Var', (106, 114))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('cause', 'Reg', (182, 187))	('NSCLC', 'Disease', (118, 123))	('TP53', 'Gene', (101, 105))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('TP53', 'Gene', '7157', (243, 247))	('NSCLC', 'Disease', 'MESH:D002289', (118, 123))	('TP53', 'Gene', (243, 247))	('tumor', 'Disease', (160, 165))
161010	32857918	Moreover, Deben et al 25  recently showed that the Pro allele of the TP53 R72P polymorphism was predictive of worse OS in stage I NSCLC and that the R213R polymorphism was significantly associated with TP53 mutations in patients with NSCLC ADC.	('NSCLC', 'Disease', 'MESH:D002289', (130, 135))	('TP53', 'Gene', (202, 206))	('R72P', 'Var', (74, 78))	('NSCLC', 'Disease', (234, 239))	('R72P', 'Mutation', 'rs1042522', (74, 78))	('TP53', 'Gene', '7157', (69, 73))	('TP53', 'Gene', (69, 73))	('worse OS', 'Disease', (110, 118))	('NSCLC', 'Disease', 'MESH:D002289', (234, 239))	('NSCLC', 'Phenotype', 'HP:0030358', (130, 135))	('TP53', 'Gene', '7157', (202, 206))	('R213R', 'Mutation', 'rs1800372', (149, 154))	('mutations', 'Var', (207, 216))	('associated', 'Reg', (186, 196))	('patients', 'Species', '9606', (220, 228))	('NSCLC', 'Phenotype', 'HP:0030358', (234, 239))	('NSCLC', 'Disease', (130, 135))	('R213R', 'Var', (149, 154))
161012	32857918	These factors likely complicate the predictive power of TP53 mutations on the prognosis of patients with NSCLC.	('NSCLC', 'Disease', 'MESH:D002289', (105, 110))	('patients', 'Species', '9606', (91, 99))	('complicate', 'NegReg', (21, 31))	('NSCLC', 'Phenotype', 'HP:0030358', (105, 110))	('TP53', 'Gene', '7157', (56, 60))	('mutations', 'Var', (61, 70))	('TP53', 'Gene', (56, 60))	('NSCLC', 'Disease', (105, 110))
161013	32857918	In addition, from the enrichment analysis from cBioPortal, co-occurrence of TP53 alterations was significantly associated with the amplification of MAP3K13, FGF12, BCL6, LPP, and TP63 (Table S6).	('MAP3K13', 'Gene', (148, 155))	('BCL6', 'Gene', (164, 168))	('MAP3K13', 'Gene', '9175', (148, 155))	('FGF12', 'Gene', (157, 162))	('TP53', 'Gene', '7157', (76, 80))	('associated', 'Reg', (111, 121))	('TP63', 'Gene', '8626', (179, 183))	('TP53', 'Gene', (76, 80))	('alterations', 'Var', (81, 92))	('TP63', 'Gene', (179, 183))	('LPP', 'Gene', (170, 173))	('BCL6', 'Gene', '604', (164, 168))	('FGF12', 'Gene', '2257', (157, 162))	('amplification', 'MPA', (131, 144))	('LPP', 'Gene', '4026', (170, 173))
161016	32857918	Some previous studies showed that genetic variants in TP63 were associated with an increased risk of lung adenocarcinoma, 26 ,  27 ,  28  but genomic amplification of p63 is paradoxically associated with prolonged survival in NSCLC.	('p63', 'Gene', (167, 170))	('associated', 'Reg', (64, 74))	('NSCLC', 'Disease', 'MESH:D002289', (226, 231))	('associated', 'Reg', (188, 198))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (101, 120))	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('genomic amplification', 'Var', (142, 163))	('TP63', 'Gene', (54, 58))	('TP63', 'Gene', '8626', (54, 58))	('genetic variants', 'Var', (34, 50))	('lung adenocarcinoma', 'Disease', (101, 120))	('p63', 'Gene', '8626', (167, 170))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (101, 120))	('NSCLC', 'Phenotype', 'HP:0030358', (226, 231))	('NSCLC', 'Disease', (226, 231))
161022	32857918	In conclusion, our study shows that for patients with stage I ADC, TP53 mutations confer an OS disadvantage compared with wild-type TP53.	('mutations', 'Var', (72, 81))	('ADC', 'Disease', (62, 65))	('patients', 'Species', '9606', (40, 48))	('TP53', 'Gene', '7157', (132, 136))	('TP53', 'Gene', (132, 136))	('TP53', 'Gene', '7157', (67, 71))	('TP53', 'Gene', (67, 71))	('disadvantage', 'NegReg', (95, 107))
161023	32857918	For patients with stage I surgically resected ADC, a TP53 mutation might be a potential molecular biomarker of prognosis that can be used with other histologic markers to guide decision-making about adjuvant therapy.	('mutation', 'Var', (58, 66))	('TP53', 'Gene', '7157', (53, 57))	('patients', 'Species', '9606', (4, 12))	('ADC', 'Disease', (46, 49))	('TP53', 'Gene', (53, 57))
161132	33029111	The sensitivity of dabrafenib, a selective inhibitor of mutated forms of BRAF kinase for BRAF-mutated melanoma, thyroid cancer, and non-small-cell lung cancer, was found to be positively associated with PPARGC1A (correlation coefficient = 0.448, p < 0.001) and PPARGC1B (correlation coefficient = 0.377, p = 0.003).	('PPARGC1B', 'Gene', (261, 269))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (136, 158))	('sensitivity', 'MPA', (4, 15))	('mutated', 'Var', (56, 63))	('dabrafenib', 'Chemical', 'MESH:C561627', (19, 29))	('lung cancer', 'Phenotype', 'HP:0100526', (147, 158))	('BRAF', 'Gene', '673', (89, 93))	('PPARGC1A', 'Gene', (203, 211))	('BRAF', 'Gene', (89, 93))	('associated', 'Interaction', (187, 197))	('BRAF', 'Gene', (73, 77))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('PPARGC1A', 'Gene', '10891', (203, 211))	('thyroid cancer', 'Disease', (112, 126))	('melanoma', 'Phenotype', 'HP:0002861', (102, 110))	('melanoma', 'Disease', (102, 110))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (132, 158))	('PPARGC1B', 'Gene', '133522', (261, 269))	('thyroid cancer', 'Disease', 'MESH:D013964', (112, 126))	('thyroid cancer', 'Phenotype', 'HP:0002890', (112, 126))	('non-small-cell lung cancer', 'Disease', 'MESH:D002289', (132, 158))	('melanoma', 'Disease', 'MESH:D008545', (102, 110))	('non-small-cell lung cancer', 'Disease', (132, 158))	('BRAF', 'Gene', '673', (73, 77))
161137	33029111	Statistically significant survival differences were observed between high and low PPAR-expressed patients in some types of cancers, suggesting that PPARs might become potential prognostic indicators for clinical applications.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('PPAR', 'Gene', (148, 152))	('PPAR', 'Gene', '5465', (82, 86))	('cancers', 'Disease', 'MESH:D009369', (123, 130))	('cancers', 'Phenotype', 'HP:0002664', (123, 130))	('cancers', 'Disease', (123, 130))	('PPAR', 'Gene', (82, 86))	('high', 'Var', (69, 73))	('PPAR', 'Gene', '5465', (148, 152))	('patients', 'Species', '9606', (97, 105))
161174	32598517	Downregulation of miRNA-126-3p is associated with progression of and poor prognosis for lung squamous cell carcinoma Here, we show that miRNA-126-3p is significantly underexpressed in 685 cases of lung squamous cell carcinoma (LUSC) as compared to 298 nontumor lung tissues, by combining various methods including in-house RT-qPCR, miRNA-sequencing, and miRNA microarrays.	('tumor', 'Phenotype', 'HP:0002664', (255, 260))	('Downregulation', 'NegReg', (0, 14))	('miRNA-126-3p', 'Var', (136, 148))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (88, 116))	('underexpressed', 'NegReg', (166, 180))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (197, 225))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (88, 116))	('lung squamous cell carcinoma', 'Disease', (88, 116))	('tumor', 'Disease', (255, 260))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (93, 116))	('miRNA-126-3p', 'Chemical', '-', (18, 30))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (197, 225))	('tumor', 'Disease', 'MESH:D009369', (255, 260))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (202, 225))	('lung squamous cell carcinoma', 'Disease', (197, 225))	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('LUSC', 'Phenotype', 'HP:0030359', (227, 231))	('miRNA-126-3p', 'Chemical', '-', (136, 148))	('carcinoma', 'Phenotype', 'HP:0030731', (216, 225))
161177	32598517	We previously reported that low expression of miRNA-126-3p is associated with the occurrence and progression of lung adenocarcinoma (LUAD).	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (112, 131))	('miRNA-126-3p', 'Var', (46, 58))	('associated', 'Reg', (62, 72))	('LUAD', 'Phenotype', 'HP:0030078', (133, 137))	('lung adenocarcinoma', 'Disease', (112, 131))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (112, 131))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('low', 'NegReg', (28, 31))	('miRNA-126-3p', 'Chemical', '-', (46, 58))
161178	32598517	Here, we examined expression of miRNA-126-3p in 23 samples from patients with LUSCs and 23 normal control specimens by quantitative real-time PCR (RT-qPCR).	('miRNA-126-3p', 'Var', (32, 44))	('patients', 'Species', '9606', (64, 72))	('men', 'Species', '9606', (111, 114))	('LUSCs', 'Disease', (78, 83))	('LUSC', 'Phenotype', 'HP:0030359', (78, 82))	('miRNA-126-3p', 'Chemical', '-', (32, 44))	('examined', 'Reg', (9, 17))
161181	32598517	GEO microarray analysis, TCGA data mining, RT-qPCR, and integration analysis consistently reported low expression of miRNA-126-3p in LUSC.	('low', 'NegReg', (99, 102))	('expression', 'MPA', (103, 113))	('miRNA-126-3p', 'Chemical', '-', (117, 129))	('LUSC', 'Phenotype', 'HP:0030359', (133, 137))	('miRNA-126-3p', 'Var', (117, 129))
161183	32598517	SOX2, E2F2, and E2F3 were selected as hub genes from the PPI network for further analysis.	('SOX2', 'Gene', '6657', (0, 4))	('E2F2', 'Gene', '1870', (6, 10))	('E2F3', 'Var', (16, 20))	('hub', 'Gene', '1993', (38, 41))	('E2F2', 'Gene', (6, 10))	('hub', 'Gene', (38, 41))	('SOX2', 'Gene', (0, 4))
161184	32598517	In summary, our results suggest that the low expression of miRNA-126-3p may play a role in promoting the development of LUSC and miRNA-126-3p may be a biomarker for LUSC early diagnosis and prognosis.	('LUSC', 'Disease', (165, 169))	('development of LUSC', 'CPA', (105, 124))	('miRNA-126-3p', 'Chemical', '-', (129, 141))	('miRNA-126-3p', 'Var', (129, 141))	('low', 'NegReg', (41, 44))	('miRNA-126-3p', 'Chemical', '-', (59, 71))	('expression', 'MPA', (45, 55))	('miRNA-126-3p', 'Gene', (59, 71))	('LUSC', 'Phenotype', 'HP:0030359', (120, 124))	('men', 'Species', '9606', (112, 115))	('promoting', 'PosReg', (91, 100))	('LUSC', 'Phenotype', 'HP:0030359', (165, 169))
161191	32598517	[11] found that seven highly expressed miRNAs (miRNA-301b, miRNA-383, miRNA-512, miRNA-515, miRNA-525, miRNA577, and miRNA5682) and five underexpressed miRNAs (miRNA-448, miRNA-486, miRNA-4732, miRNA-516, and miRNA-1911) are associated with improved prognosis of patients with LUSC.	('miRNA-1911', 'Var', (209, 219))	('miRNA-4732', 'Var', (182, 192))	('miRNA-525', 'Var', (92, 101))	('miRNA-486', 'Var', (171, 180))	('miRNA-448', 'Gene', (160, 169))	('LUSC', 'Disease', (277, 281))	('patients', 'Species', '9606', (263, 271))	('improved', 'PosReg', (241, 249))	('miRNA-516', 'Var', (194, 203))	('miRNA-301b', 'Var', (47, 57))	('miRNA-383', 'Var', (59, 68))	('LUSC', 'Phenotype', 'HP:0030359', (277, 281))	('miRNA5682', 'Var', (117, 126))	('miRNA577', 'Var', (103, 111))	('miRNA-448', 'Gene', '554212', (160, 169))	('miRNA-512', 'Var', (70, 79))	('miRNA-515', 'Var', (81, 90))
161192	32598517	In previous studies, we reported that miRNA-136-5p [12], miRNA-182-5p [13], miRNA-198-5p [14], miRNA-452-5p [15], and miRNA-375 [16] are all correlated with the development and prognosis of LUSC.	('miRNA-136-5p [', 'Var', (38, 52))	('miRNA-375', 'Gene', (118, 127))	('LUSC', 'Disease', (190, 194))	('LUSC', 'Phenotype', 'HP:0030359', (190, 194))	('correlated with', 'Reg', (141, 156))	('miRNA-375', 'Gene', '494324', (118, 127))	('miRNA-182-5p [', 'Var', (57, 71))	('men', 'Species', '9606', (168, 171))	('miRNA-198-5p [', 'Var', (76, 90))	('miRNA-452-5p [', 'Var', (95, 109))
161193	32598517	MiRNA-126-3p is located on human chromosome 9, and it is associated with thyroid cancer [17] and pancreatic cancer [18].	('thyroid cancer', 'Phenotype', 'HP:0002890', (73, 87))	('thyroid cancer', 'Disease', (73, 87))	('MiRNA-126-3p', 'Chemical', '-', (0, 12))	('human', 'Species', '9606', (27, 32))	('pancreatic cancer', 'Disease', 'MESH:D010190', (97, 114))	('pancreatic cancer', 'Disease', (97, 114))	('thyroid cancer', 'Disease', 'MESH:D013964', (73, 87))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('MiRNA-126-3p', 'Var', (0, 12))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('associated', 'Reg', (57, 67))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (97, 114))
161194	32598517	Our previous findings indicate that low expression of miRNA-126-3p is associated with the occurrence and progression of lung adenocarcinoma (LUAD) [19].	('expression', 'MPA', (40, 50))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (120, 139))	('low', 'NegReg', (36, 39))	('miRNA-126-3p', 'Var', (54, 66))	('LUAD', 'Phenotype', 'HP:0030078', (141, 145))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (120, 139))	('associated', 'Reg', (70, 80))	('miRNA-126-3p', 'Chemical', '-', (54, 66))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('lung adenocarcinoma', 'Disease', (120, 139))
161195	32598517	However, there are few reports on the specific mechanism of the role of miRNA-126-3p in LUSC.	('miRNA-126-3p', 'Chemical', '-', (72, 84))	('LUSC', 'Disease', (88, 92))	('LUSC', 'Phenotype', 'HP:0030359', (88, 92))	('miRNA-126-3p', 'Var', (72, 84))
161196	32598517	Here, we aimed to elucidate the specific molecular action of miRNA-126-3p in LUSC to help provide a new direction for the early detection and treatment of LUSC.	('LUSC', 'Disease', (155, 159))	('miRNA-126-3p', 'Chemical', '-', (61, 73))	('LUSC', 'Phenotype', 'HP:0030359', (155, 159))	('miRNA-126-3p', 'Var', (61, 73))	('LUSC', 'Disease', (77, 81))	('LUSC', 'Phenotype', 'HP:0030359', (77, 81))	('men', 'Species', '9606', (147, 150))
161197	32598517	In this study, the expression pattern and clinical role of miRNA-126-3p in LUSC were determined by quantitative real-time PCR (RT-qPCR).	('miRNA-126-3p', 'Chemical', '-', (59, 71))	('miRNA-126-3p', 'Var', (59, 71))	('LUSC', 'Disease', (75, 79))	('LUSC', 'Phenotype', 'HP:0030359', (75, 79))
161199	32598517	Subsequently, 12 online analyses were performed to identify candidate target genes of miRNA-126-3p, and the potential mechanism of miRNA-126-3p in LUSC was studied by examination of key genes, such as SOX2, E2F2, and E2F3.	('miRNA-126-3p', 'Var', (131, 143))	('E2F3', 'Gene', (217, 221))	('E2F2', 'Gene', (207, 211))	('SOX2', 'Gene', '6657', (201, 205))	('SOX2', 'Gene', (201, 205))	('E2F2', 'Gene', '1870', (207, 211))	('miRNA-126-3p', 'Chemical', '-', (86, 98))	('miRNA-126-3p', 'Chemical', '-', (131, 143))	('LUSC', 'Phenotype', 'HP:0030359', (147, 151))
161217	32598517	The sequences of RNU6B and miRNA-126-3p were CGCAAGGAUGACACGCAAAUUCGUGAAGCGUUCCAUAUUUUU and UCGUACCGUGAGUAAUAAUGCG, respectively.	('miRNA-126-3p', 'Var', (27, 39))	('RNU6B', 'Gene', (17, 22))	('miRNA-126-3p', 'Chemical', '-', (27, 39))	('RNU6B', 'Gene', '26826', (17, 22))
161221	32598517	We used the intermediate expression level of miRNA-126-3p to construct a Kaplan-Meier curve to describe the relationship between the aberrant expression of miRNA-126-3p and the overall survival (OS) rate of LUSC patients.	('aberrant', 'Var', (133, 141))	('miRNA-126-3p', 'Gene', (156, 168))	('LUSC', 'Phenotype', 'HP:0030359', (207, 211))	('overall survival', 'MPA', (177, 193))	('patients', 'Species', '9606', (212, 220))	('miRNA-126-3p', 'Chemical', '-', (45, 57))	('miRNA-126-3p', 'Chemical', '-', (156, 168))
161225	32598517	The selection criteria for microarrays were as follows: (a) The microarray involved LUSC and adjacent tissue specimens, and (b) the study provided data on the miRNA-126-3p original expression profile in LUSC and noncancerous tissues.	('cancer', 'Disease', (215, 221))	('cancer', 'Disease', 'MESH:D009369', (215, 221))	('men', 'Species', '9606', (114, 117))	('miRNA-126-3p', 'Chemical', '-', (159, 171))	('LUSC', 'Phenotype', 'HP:0030359', (84, 88))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('miRNA-126-3p', 'Var', (159, 171))	('LUSC', 'Phenotype', 'HP:0030359', (203, 207))
161242	32598517	In total, 478 tumor tissues and 45 noncancerous tissues were obtained for the expression data and clinical information of miRNA-126-3p from TCGA.	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('tumor', 'Disease', (14, 19))	('miRNA-126-3p', 'Chemical', '-', (122, 134))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('miRNA-126-3p', 'Var', (122, 134))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('cancer', 'Disease', (38, 44))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
161248	32598517	It was clear that LUSC patients with a high expression of miRNA-126-3p had significantly better OS than patients with a low expression (P = 0.0004).	('LUSC', 'Phenotype', 'HP:0030359', (18, 22))	('better', 'PosReg', (89, 95))	('patients', 'Species', '9606', (23, 31))	('high expression', 'Var', (39, 54))	('miRNA-126-3p', 'Chemical', '-', (58, 70))	('miRNA-126-3p', 'Var', (58, 70))	('patients', 'Species', '9606', (104, 112))
161249	32598517	The relative expression and clinicopathological features of miRNA-126-3p were analyzed by univariate and multivariate Cox analyses, and miRNA-126-3p was found to be significantly different in the univariate and multivariate Cox analyses compared with other clinicopathological characteristics (Fig.	('different', 'Reg', (179, 188))	('miRNA-126-3p', 'Chemical', '-', (136, 148))	('miRNA-126-3p', 'Var', (136, 148))	('miRNA-126-3p', 'Chemical', '-', (60, 72))
161250	32598517	These results indicate that miRNA-126-3p might act as a tumor inhibitor in LUSC, and it might suppress the proliferation of LUSC cells.	('LUSC', 'Phenotype', 'HP:0030359', (124, 128))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('suppress', 'NegReg', (94, 102))	('tumor', 'Disease', (56, 61))	('miRNA-126-3p', 'Chemical', '-', (28, 40))	('proliferation of LUSC cells', 'CPA', (107, 134))	('LUSC', 'Phenotype', 'HP:0030359', (75, 79))	('miRNA-126-3p', 'Var', (28, 40))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('LUSC', 'Disease', (75, 79))
161256	32598517	According to the random effect model, the combined SMD of miRNA-126-3p was -6.56 (95% CI was -6.95 to -6.18), and the I 2 value was 0.989, P < 0.001, which indicated considerable heterogeneity in the study.	('miRNA-126-3p', 'Var', (58, 70))	('SMD', 'Disease', 'MESH:C537501', (51, 54))	('SMD', 'Disease', (51, 54))	('miRNA-126-3p', 'Chemical', '-', (58, 70))
161258	32598517	We analyzed the integrative sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, and diagnostic ratio of miRNA-126-3p in LUSC (Fig.	('miRNA-126-3p', 'Chemical', '-', (132, 144))	('miRNA-126-3p', 'Var', (132, 144))	('LUSC', 'Disease', (148, 152))	('LUSC', 'Phenotype', 'HP:0030359', (148, 152))
161259	32598517	All of these implied that miRNA-126-3p showed high diagnostic efficiency in LUSC.	('miRNA-126-3p', 'Chemical', '-', (26, 38))	('LUSC', 'Disease', (76, 80))	('LUSC', 'Phenotype', 'HP:0030359', (76, 80))	('miRNA-126-3p', 'Var', (26, 38))
161261	32598517	After overlapping these upregulated genes with the 578 candidate targets of miRNA-126-3p, 42 genes were obtained as predicted target genes of miRNA-126-3p (Fig.	('miRNA-126-3p', 'Var', (142, 154))	('upregulated', 'PosReg', (24, 35))	('miRNA-126-3p', 'Chemical', '-', (142, 154))	('miRNA-126-3p', 'Chemical', '-', (76, 88))
161265	32598517	Among the 42 target genes, SOX2, E2F2, and E2F3 had more connections in the PPI network.	('E2F2', 'Gene', (33, 37))	('E2F3', 'Var', (43, 47))	('E2F2', 'Gene', '1870', (33, 37))	('SOX2', 'Gene', (27, 31))	('connections', 'Reg', (57, 68))	('SOX2', 'Gene', '6657', (27, 31))
161267	32598517	The expressions of SOX2, E2F2, and E2F3 in LUSC and noncancerous cases are shown in Fig.	('E2F2', 'Gene', '1870', (25, 29))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('SOX2', 'Gene', (19, 23))	('SOX2', 'Gene', '6657', (19, 23))	('LUSC', 'Disease', (43, 47))	('E2F2', 'Gene', (25, 29))	('LUSC', 'Phenotype', 'HP:0030359', (43, 47))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('cancer', 'Disease', (55, 61))	('E2F3', 'Var', (35, 39))
161270	32598517	The three core gene expressions were significantly negatively correlated with the expression of miRNA-126-3p in LUSC.	('negatively', 'NegReg', (51, 61))	('expression', 'MPA', (82, 92))	('miRNA-126-3p', 'Chemical', '-', (96, 108))	('miRNA-126-3p', 'Var', (96, 108))	('LUSC', 'Phenotype', 'HP:0030359', (112, 116))
161271	32598517	[26] discovered 15 abnormally expressed miRNAs in lung malignancies, including a low expression of miRNA-126-3p.	('lung malignancies', 'Disease', (50, 67))	('miRNA-126-3p', 'Var', (99, 111))	('lung malignancies', 'Phenotype', 'HP:0100526', (50, 67))	('lung malignancies', 'Disease', 'MESH:D008175', (50, 67))	('miRNA-126-3p', 'Chemical', '-', (99, 111))
161273	32598517	To date, there have been many studies about miRNA-126-3p in the field of malignant lung tumors.	('miRNA-126-3p', 'Chemical', '-', (44, 56))	('miRNA-126-3p', 'Var', (44, 56))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('malignant lung tumors', 'Disease', (73, 94))	('lung tumors', 'Phenotype', 'HP:0100526', (83, 94))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('malignant lung tumors', 'Disease', 'MESH:D009369', (73, 94))
161275	32598517	In this study, a GEO integration analysis, TCGA data mining, RT-qPCR, and an integration analysis consistently indicated that in contrast to the noncancerous tissues, the miRNA-126-3p expression is significantly downregulated in LUSC tissues.	('cancer', 'Disease', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('miRNA-126-3p', 'Chemical', '-', (171, 183))	('downregulated', 'NegReg', (212, 225))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('LUSC', 'Phenotype', 'HP:0030359', (229, 233))	('miRNA-126-3p', 'Var', (171, 183))	('LUSC', 'Disease', (229, 233))	('expression', 'MPA', (184, 194))
161277	32598517	Based on previous findings [27], we confirmed that miRNA-126-3p was underexpressed in both LUAD and LUSC, and it played a role in tumor suppressor in LUAD and LUSC.	('LUAD', 'Disease', (150, 154))	('LUSC', 'Phenotype', 'HP:0030359', (100, 104))	('LUSC', 'Phenotype', 'HP:0030359', (159, 163))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('miRNA-126-3p', 'Chemical', '-', (51, 63))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('miRNA-126-3p', 'Var', (51, 63))	('tumor', 'Disease', (130, 135))	('LUAD', 'Phenotype', 'HP:0030078', (91, 95))	('LUAD', 'Phenotype', 'HP:0030078', (150, 154))
161278	32598517	The difference in the expression of miRNA-126-3p between T stages in the TCGA data suggests that the underexpression of miRNA-126-3p might stimulate the proliferation of LUSC tumor cells.	('stimulate', 'PosReg', (139, 148))	('miRNA-126-3p', 'Chemical', '-', (36, 48))	('tumor', 'Disease', (175, 180))	('miRNA-126-3p', 'Chemical', '-', (120, 132))	('LUSC', 'Phenotype', 'HP:0030359', (170, 174))	('proliferation', 'CPA', (153, 166))	('miRNA-126-3p', 'Var', (120, 132))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))
161279	32598517	Univariate and multivariate Cox analyses of TCGA data illustrate that miRNA-126-3p could be an independent prognostic factor in LUSC compared with other clinicopathological characteristics.	('miRNA-126-3p', 'Var', (70, 82))	('LUSC', 'Disease', (128, 132))	('LUSC', 'Phenotype', 'HP:0030359', (128, 132))	('miRNA-126-3p', 'Chemical', '-', (70, 82))
161280	32598517	A Kaplan-Meier survival curve analysis from TCGA data shows that the total survival time and median survival time of low-expression miRNA-126-3p were greater than were those of high-expression miRNA-126-3p.	('miRNA-126-3p', 'Var', (132, 144))	('miRNA-126-3p', 'Chemical', '-', (132, 144))	('low-expression', 'NegReg', (117, 131))	('greater', 'PosReg', (150, 157))	('miRNA-126-3p', 'Chemical', '-', (193, 205))
161281	32598517	From this, we can infer that miRNA-126-3p has potential as a prognostic marker of LUSC.	('miRNA-126-3p', 'Var', (29, 41))	('LUSC', 'Disease', (82, 86))	('LUSC', 'Phenotype', 'HP:0030359', (82, 86))	('miRNA-126-3p', 'Chemical', '-', (29, 41))
161282	32598517	[28], wherein the miRNA-126-3p expression in LUSC was shown to be related to OS, as well as its potential as an independent prognostic factor for LUSC.	('miRNA-126-3p expression', 'Var', (18, 41))	('LUSC', 'Disease', (146, 150))	('LUSC', 'Phenotype', 'HP:0030359', (146, 150))	('miRNA-126-3p', 'Chemical', '-', (18, 30))	('related', 'Reg', (66, 73))	('LUSC', 'Phenotype', 'HP:0030359', (45, 49))
161284	32598517	Three functional analyses of GO showed that SOX2, E2F2, and E2F3 were mainly enriched in GO-BP (regulation of transcription), GO-CC [transcription factor (TF) complex], and GO-MF (transcriptional activator and factor activity).	('E2F3', 'Var', (60, 64))	('E2F2', 'Gene', (50, 54))	('SOX2', 'Gene', '6657', (44, 48))	('E2F2', 'Gene', '1870', (50, 54))	('SOX2', 'Gene', (44, 48))	('GO-BP', 'Disease', (89, 94))
161286	32598517	Therefore, we can infer that SOX2, E2F2, and E2F3 act as TFs and can affect the biological process of LUSC through mutual regulation with miRNA126-3p.	('affect', 'Reg', (69, 75))	('biological process of', 'CPA', (80, 101))	('mutual', 'Interaction', (115, 121))	('SOX2', 'Gene', (29, 33))	('SOX2', 'Gene', '6657', (29, 33))	('E2F2', 'Gene', '1870', (35, 39))	('LUSC', 'Phenotype', 'HP:0030359', (102, 106))	('E2F3', 'Var', (45, 49))	('E2F2', 'Gene', (35, 39))
161292	32598517	We assume miRNA-126-3p may suppress the proliferation and infiltration of LUSC cells through cell cycle apoptosis and cell cycle arrest.	('arrest', 'Disease', (129, 135))	('cell cycle apoptosis', 'CPA', (93, 113))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (118, 135))	('LUSC', 'Phenotype', 'HP:0030359', (74, 78))	('miRNA-126-3p', 'Var', (10, 22))	('arrest', 'Disease', 'MESH:D006323', (129, 135))	('miRNA-126-3p', 'Chemical', '-', (10, 22))	('suppress', 'NegReg', (27, 35))
161294	32598517	Interestingly, the two hub genes, E2F2 and E2F3, were all involved in these cancer-related pathways.	('hub', 'Gene', '1993', (23, 26))	('E2F2', 'Gene', '1870', (34, 38))	('E2F3', 'Var', (43, 47))	('involved', 'Reg', (58, 66))	('hub', 'Gene', (23, 26))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('E2F2', 'Gene', (34, 38))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))
161295	32598517	Hence, we hypothesized that miRNA-126-3p regulated the biological function of LUSC by targeting E2F2 and E2F3.	('biological function', 'MPA', (55, 74))	('E2F2', 'Gene', '1870', (96, 100))	('miRNA-126-3p', 'Chemical', '-', (28, 40))	('LUSC', 'Phenotype', 'HP:0030359', (78, 82))	('E2F3', 'Gene', (105, 109))	('targeting', 'Reg', (86, 95))	('E2F2', 'Gene', (96, 100))	('miRNA-126-3p', 'Var', (28, 40))	('regulated', 'Reg', (41, 50))
161296	32598517	We selected three genes with the highest frequency as the hub genes from the PPI network: SOX2, E2F2, and E2F3.	('E2F2', 'Gene', '1870', (96, 100))	('SOX2', 'Gene', '6657', (90, 94))	('hub', 'Gene', '1993', (58, 61))	('SOX2', 'Gene', (90, 94))	('E2F3', 'Var', (106, 110))	('E2F2', 'Gene', (96, 100))	('hub', 'Gene', (58, 61))
161298	32598517	Based on the miRNA-126-3p downregulated in tumor tissues, these overlapping and most frequently occurring genes can be used as target genes of miRNA-126-3p.	('downregulated', 'NegReg', (26, 39))	('miRNA-126-3p', 'Chemical', '-', (13, 25))	('miRNA-126-3p', 'Chemical', '-', (143, 155))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('miRNA-126-3p', 'Var', (143, 155))	('miRNA-126-3p', 'Gene', (13, 25))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Disease', (43, 48))
161301	32598517	[39] identified that the aberrant expression of SOX2 can inhibit esophageal squamous cell carcinoma development.	('SOX2', 'Gene', '6657', (48, 52))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (76, 99))	('SOX2', 'Gene', (48, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('men', 'Species', '9606', (107, 110))	('esophageal squamous cell carcinoma', 'Disease', (65, 99))	('aberrant expression', 'Var', (25, 44))	('inhibit', 'NegReg', (57, 64))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (65, 99))
161305	32598517	TFs E2F2 and E2F3 are two members of E2F family, and E2F1-3, a subfamily of the E2F family, serves as a transcriptional activator [43].	('E2F1-3', 'Gene', '1869;1870;1871', (53, 59))	('E2F1-3', 'Gene', (53, 59))	('E2F2', 'Gene', '1870', (4, 8))	('E2F3', 'Var', (13, 17))	('E2F2', 'Gene', (4, 8))
161306	32598517	Current studies indicate that E2F2 and E2F3 may act as vital regulators in several cancers.	('cancers', 'Disease', 'MESH:D009369', (83, 90))	('E2F2', 'Gene', '1870', (30, 34))	('E2F3', 'Var', (39, 43))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('E2F2', 'Gene', (30, 34))	('cancers', 'Phenotype', 'HP:0002664', (83, 90))	('cancers', 'Disease', (83, 90))
161311	32598517	The mechanisms of interaction of E2F2-3 and miRNA-126-3p in LUSC have not yet been reported.	('miRNA-126-3p', 'Chemical', '-', (44, 56))	('miRNA-126-3p', 'Var', (44, 56))	('LUSC', 'Phenotype', 'HP:0030359', (60, 64))	('E2F2-3', 'Gene', '1870;1871', (33, 39))	('E2F2-3', 'Gene', (33, 39))
161312	32598517	We speculate that miRNA-126-3p may target E2F2 and E2F3 to restrain the cell proliferation and cancer progression of LUSC.	('restrain', 'NegReg', (59, 67))	('LUSC', 'Phenotype', 'HP:0030359', (117, 121))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('E2F2', 'Gene', '1870', (42, 46))	('miRNA-126-3p', 'Var', (18, 30))	('cancer', 'Disease', (95, 101))	('cell proliferation', 'CPA', (72, 90))	('miRNA-126-3p', 'Chemical', '-', (18, 30))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('E2F2', 'Gene', (42, 46))	('E2F3', 'Gene', (51, 55))
161313	32598517	We consider that miRNA-126-3p regulates the elevated expressions of core genes, SOX2, E2F2, and E2F3, and it may help elucidate the carcinostatic functions of miRNA-126-3p in LUSC.	('E2F2', 'Gene', (86, 90))	('carcinostatic', 'Disease', 'None', (132, 145))	('elevated', 'PosReg', (44, 52))	('SOX2', 'Gene', (80, 84))	('miRNA-126-3p', 'Chemical', '-', (17, 29))	('SOX2', 'Gene', '6657', (80, 84))	('E2F2', 'Gene', '1870', (86, 90))	('miRNA-126-3p', 'Chemical', '-', (159, 171))	('miRNA-126-3p', 'Var', (17, 29))	('LUSC', 'Phenotype', 'HP:0030359', (175, 179))	('expressions', 'MPA', (53, 64))	('miRNA-126-3p', 'Var', (159, 171))	('carcinostatic', 'Disease', (132, 145))	('E2F3', 'Gene', (96, 100))
161316	32598517	By combining RT-qPCR, bioinformatics, and an integrated analysis, we confirmed that the downregulation of miRNA-126-3p in LUSC was involved in several biological processes that promote the occurrence, progression, and poor prognosis of LUSC.	('downregulation', 'NegReg', (88, 102))	('promote', 'PosReg', (177, 184))	('miRNA-126-3p', 'Chemical', '-', (106, 118))	('miRNA-126-3p', 'Var', (106, 118))	('LUSC', 'Disease', (236, 240))	('LUSC', 'Phenotype', 'HP:0030359', (122, 126))	('LUSC', 'Phenotype', 'HP:0030359', (236, 240))	('involved', 'Reg', (131, 139))
161324	32598517	However, the clinical implication of miRNA-126-3p in the early diagnosis of LUSC patients must be confirmed in future.	('miRNA-126-3p', 'Chemical', '-', (37, 49))	('LUSC', 'Phenotype', 'HP:0030359', (76, 80))	('miRNA-126-3p', 'Var', (37, 49))	('patients', 'Species', '9606', (81, 89))	('LUSC', 'Disease', (76, 80))
161326	32598517	A low expression of miRNA-126-3p suppressed the development of LUSC, whereas a high expression of miRNA-126-3p was associated with a better LUSC prognosis.	('LUSC', 'Phenotype', 'HP:0030359', (63, 67))	('miRNA-126-3p', 'Chemical', '-', (98, 110))	('men', 'Species', '9606', (55, 58))	('miRNA-126-3p', 'Chemical', '-', (20, 32))	('development of LUSC', 'CPA', (48, 67))	('miRNA-126-3p', 'Var', (98, 110))	('miRNA-126-3p', 'Var', (20, 32))	('LUSC', 'Phenotype', 'HP:0030359', (140, 144))	('suppressed', 'NegReg', (33, 43))
161327	32598517	MiRNA-126-3p may act as a tumor inhibitor in LUSC, and it suppresses the proliferation of LUSC cells.	('MiRNA-126-3p', 'Chemical', '-', (0, 12))	('LUSC', 'Phenotype', 'HP:0030359', (90, 94))	('LUSC', 'Phenotype', 'HP:0030359', (45, 49))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('MiRNA-126-3p', 'Var', (0, 12))	('suppresses', 'NegReg', (58, 68))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('proliferation of LUSC cells', 'CPA', (73, 100))
161328	32598517	In summary, miRNA-126-3p may be a promising biomarker for LUSC diagnosis and prognosis.	('LUSC', 'Phenotype', 'HP:0030359', (58, 62))	('miRNA-126-3p', 'Var', (12, 24))	('LUSC', 'Disease', (58, 62))	('miRNA-126-3p', 'Chemical', '-', (12, 24))
161338	27956804	FGFR1 and MYC amplifications were observed in 21.4% (37/173) and 54.2% (91/168) of patients, respectively, while MYC expression was observed in 58.9% (106/180) of patients.	('patients', 'Species', '9606', (163, 171))	('MYC', 'Gene', (10, 13))	('patients', 'Species', '9606', (83, 91))	('FGFR1', 'Gene', (0, 5))	('MYC', 'Gene', '4609', (113, 116))	('FGFR1', 'Gene', '2260', (0, 5))	('amplifications', 'Var', (14, 28))	('MYC', 'Gene', '4609', (10, 13))	('observed', 'Reg', (34, 42))	('MYC', 'Gene', (113, 116))
161340	27956804	Although FGFR1 amplification was not associated with MYC amplification or expression, 12.3% (20/163) of patients exhibited both FGFR1 amplification and MYC expression.	('FGFR1', 'Gene', (128, 133))	('FGFR1', 'Gene', '2260', (128, 133))	('MYC', 'Gene', '4609', (152, 155))	('FGFR1', 'Gene', '2260', (9, 14))	('MYC', 'Gene', '4609', (53, 56))	('FGFR1', 'Gene', (9, 14))	('amplification', 'Var', (134, 147))	('MYC', 'Gene', (152, 155))	('exhibited', 'Reg', (113, 122))	('MYC', 'Gene', (53, 56))	('patients', 'Species', '9606', (104, 112))
161341	27956804	There was also a correlation in FGFR1 amplification status between matched primary tumors and metastatic lymph nodes (P < 0.001).	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('FGFR1', 'Gene', (32, 37))	('FGFR1', 'Gene', '2260', (32, 37))	('tumors', 'Disease', (83, 89))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('correlation', 'Reg', (17, 28))	('amplification status', 'Var', (38, 58))	('tumors', 'Disease', 'MESH:D009369', (83, 89))
161344	27956804	FGFR1 amplification was an independent predictor for prolonged OS in all patients (P = 0.029) and in those who did not receive adjuvant therapy (P = 0.013).	('OS', 'Chemical', '-', (63, 65))	('FGFR1', 'Gene', (0, 5))	('FGFR1', 'Gene', '2260', (0, 5))	('prolonged OS', 'Disease', (53, 65))	('amplification', 'Var', (6, 19))	('patients', 'Species', '9606', (73, 81))
161345	27956804	Combined FGFR1 amplification and MYC expression predicted better OS in patients who did not receive adjuvant therapy (P = 0.034) but not in those who did receive adjuvant therapy.	('FGFR1', 'Gene', '2260', (9, 14))	('OS', 'Chemical', '-', (65, 67))	('amplification', 'Var', (15, 28))	('better', 'PosReg', (58, 64))	('MYC', 'Gene', '4609', (33, 36))	('patients', 'Species', '9606', (71, 79))	('MYC', 'Gene', (33, 36))	('FGFR1', 'Gene', (9, 14))
161346	27956804	FGFR1 amplification and MYC expression have prognostic implications in resected ESCCs with respect to adjuvant therapy.	('implications', 'Reg', (55, 67))	('SCC', 'Gene', '6317', (81, 84))	('MYC', 'Gene', (24, 27))	('SCC', 'Gene', (81, 84))	('FGFR1', 'Gene', (0, 5))	('FGFR1', 'Gene', '2260', (0, 5))	('amplification', 'Var', (6, 19))	('SCC', 'Phenotype', 'HP:0002860', (81, 84))	('MYC', 'Gene', '4609', (24, 27))
161350	27956804	FGFR1 and MYC amplifications were observed in 21.4% and 54.2% of patients with ESCC, respectively, while 12.3% exhibited both FGFR1 amplification and MYC expression.	('SCC', 'Gene', '6317', (80, 83))	('SCC', 'Phenotype', 'HP:0002860', (80, 83))	('MYC', 'Gene', (10, 13))	('FGFR1', 'Gene', (126, 131))	('MYC', 'Gene', '4609', (150, 153))	('FGFR1', 'Gene', (0, 5))	('FGFR1', 'Gene', '2260', (0, 5))	('amplifications', 'Var', (14, 28))	('FGFR1', 'Gene', '2260', (126, 131))	('MYC', 'Gene', '4609', (10, 13))	('patients', 'Species', '9606', (65, 73))	('SCC', 'Gene', (80, 83))	('observed', 'Reg', (34, 42))	('MYC', 'Gene', (150, 153))
161351	27956804	MYC expression and FGFR1 amplification were significantly associated with prolonged survival.	('MYC', 'Gene', (0, 3))	('associated', 'Reg', (58, 68))	('FGFR1', 'Gene', '2260', (19, 24))	('MYC', 'Gene', '4609', (0, 3))	('prolonged', 'PosReg', (74, 83))	('amplification', 'Var', (25, 38))	('FGFR1', 'Gene', (19, 24))
161352	27956804	Combined FGFR1 amplification and MYC expression was a predictor of better survival in patients who did not receive adjuvant therapy, but not in those who did.	('FGFR1', 'Gene', '2260', (9, 14))	('amplification', 'Var', (15, 28))	('MYC', 'Gene', '4609', (33, 36))	('expression', 'MPA', (37, 47))	('MYC', 'Gene', (33, 36))	('FGFR1', 'Gene', (9, 14))	('better', 'PosReg', (67, 73))	('patients', 'Species', '9606', (86, 94))
161356	27956804	Recently, genomic and molecular alterations have been discovered in ESCC, including activation of the receptor tyrosine kinase (RTK) pathway, cell cycle dysregulation, activation of Wnt and Notch signaling pathways and epigenetic modifications.	('RTK', 'Gene', (128, 131))	('receptor tyrosine kinase', 'Gene', '5979', (102, 126))	('cell cycle dysregulation', 'Phenotype', 'HP:0011018', (142, 166))	('activation', 'PosReg', (84, 94))	('SCC', 'Gene', (69, 72))	('SCC', 'Phenotype', 'HP:0002860', (69, 72))	('epigenetic modifications', 'Var', (219, 243))	('SCC', 'Gene', '6317', (69, 72))	('RTK', 'Gene', '5979', (128, 131))	('activation', 'PosReg', (168, 178))	('cell cycle dysregulation', 'CPA', (142, 166))	('receptor tyrosine kinase', 'Gene', (102, 126))
161363	27956804	However, the prognostic significance of FGFR1 amplification in patients with ESCC remains controversial.	('amplification', 'Var', (46, 59))	('SCC', 'Gene', '6317', (78, 81))	('FGFR1', 'Gene', (40, 45))	('FGFR1', 'Gene', '2260', (40, 45))	('patients', 'Species', '9606', (63, 71))	('SCC', 'Gene', (78, 81))	('SCC', 'Phenotype', 'HP:0002860', (78, 81))
161364	27956804	Pulmonary squamous cell carcinoma (SCC) is another cancer frequently showing FGFR1 amplification.	('FGFR1', 'Gene', (77, 82))	('SCC', 'Gene', (35, 38))	('SCC', 'Phenotype', 'HP:0002860', (35, 38))	('FGFR1', 'Gene', '2260', (77, 82))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (24, 33))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('SCC', 'Gene', '6317', (35, 38))	('Pulmonary squamous cell carcinoma', 'Phenotype', 'HP:0030359', (0, 33))	('Pulmonary squamous cell carcinoma', 'Disease', (0, 33))	('cancer', 'Disease', (51, 57))	('amplification', 'Var', (83, 96))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (10, 33))	('Pulmonary squamous cell carcinoma', 'Disease', 'MESH:D002294', (0, 33))
161378	27956804	The entire tumor area was scanned for hot spots representing increased FGFR1 copy numbers.	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('FGFR1', 'Gene', (71, 76))	('increased FGFR1', 'Phenotype', 'HP:0030269', (61, 76))	('tumor', 'Disease', (11, 16))	('copy numbers', 'Var', (77, 89))	('FGFR1', 'Gene', '2260', (71, 76))	('increased', 'PosReg', (61, 70))	('tumor', 'Disease', 'MESH:D009369', (11, 16))
161393	27956804	In ESCCs, FGFR1 amplification was detected in 21.4% (37/173) of patients (high amplification in 19.7%, n = 34 and low amplification in 1.7%, n = 3; Figure 1A and B).	('detected', 'Reg', (34, 42))	('SCC', 'Gene', (4, 7))	('patients', 'Species', '9606', (64, 72))	('SCC', 'Phenotype', 'HP:0002860', (4, 7))	('SCC', 'Gene', '6317', (4, 7))	('amplification', 'Var', (16, 29))	('FGFR1', 'Gene', (10, 15))	('FGFR1', 'Gene', '2260', (10, 15))
161397	27956804	FGFR1 amplification status was not associated with MYC amplification or protein expression.	('MYC', 'Gene', (51, 54))	('protein expression', 'MPA', (72, 90))	('FGFR1', 'Gene', (0, 5))	('FGFR1', 'Gene', '2260', (0, 5))	('amplification', 'Var', (6, 19))	('MYC', 'Gene', '4609', (51, 54))
161399	27956804	ESCC patients with FGFR1 amplification were younger than those without FGFR1 amplification (mean +- SD, 62.3 +- 8.4 years versus 65.6 +- 7.4 years, P = 0.022).	('FGFR1', 'Gene', (71, 76))	('patients', 'Species', '9606', (5, 13))	('FGFR1', 'Gene', '2260', (19, 24))	('FGFR1', 'Gene', '2260', (71, 76))	('SCC', 'Gene', (1, 4))	('SCC', 'Gene', '6317', (1, 4))	('SCC', 'Phenotype', 'HP:0002860', (1, 4))	('amplification', 'Var', (25, 38))	('FGFR1', 'Gene', (19, 24))
161400	27956804	Other clinicopathological parameters including sex, histological differentiation, smoking status and TNM stage were not significantly correlated with FGFR1 amplification.	('amplification', 'Var', (156, 169))	('FGFR1', 'Gene', (150, 155))	('FGFR1', 'Gene', '2260', (150, 155))
161404	27956804	Briefly, FGFR1 amplification in the primary tumor was observed in 11 of 56 cases, and 7 (63.6%) patients also showed FGFR1 amplification in metastatic tumors of the regional lymph nodes.	('FGFR1', 'Gene', '2260', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('amplification', 'Var', (15, 28))	('tumors', 'Disease', (151, 157))	('tumors', 'Disease', 'MESH:D009369', (151, 157))	('tumor', 'Disease', (151, 156))	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('FGFR1', 'Gene', (117, 122))	('FGFR1', 'Gene', '2260', (117, 122))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('patients', 'Species', '9606', (96, 104))	('amplification', 'Var', (123, 136))	('FGFR1', 'Gene', (9, 14))	('tumor', 'Disease', (44, 49))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
161405	27956804	In contrast, only 3 (6.7%) of the 45 cases who did not have FGFR1 amplification in the primary tumor exhibited FGFR1 amplification in metastatic tumors of the lymph nodes.	('FGFR1', 'Gene', '2260', (111, 116))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('FGFR1', 'Gene', (60, 65))	('FGFR1', 'Gene', '2260', (60, 65))	('tumors of the lymph nodes', 'Disease', 'MESH:D000072717', (145, 170))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Disease', (145, 150))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('FGFR1', 'Gene', (111, 116))	('amplification', 'Var', (117, 130))	('tumor', 'Disease', (95, 100))	('tumors of the lymph nodes', 'Disease', (145, 170))
161409	27956804	Kaplan-Meier analysis revealed that DFS of ESCC patients with FGFR1 amplification was significantly prolonged compared with those without FGFR1 amplification (P = 0.021; Figure 2A).	('SCC', 'Gene', '6317', (44, 47))	('FGFR1', 'Gene', (138, 143))	('prolonged', 'PosReg', (100, 109))	('FGFR1', 'Gene', (62, 67))	('SCC', 'Gene', (44, 47))	('FGFR1', 'Gene', '2260', (138, 143))	('amplification', 'Var', (68, 81))	('patients', 'Species', '9606', (48, 56))	('FGFR1', 'Gene', '2260', (62, 67))	('SCC', 'Phenotype', 'HP:0002860', (44, 47))	('DFS', 'MPA', (36, 39))
161410	27956804	OS also tended to be longer in patients with FGFR1 amplification compared with those without FGFR1 amplification (P = 0.081; Figure 2B).	('OS', 'Chemical', '-', (0, 2))	('longer', 'PosReg', (21, 27))	('patients', 'Species', '9606', (31, 39))	('FGFR1', 'Gene', (45, 50))	('FGFR1', 'Gene', (93, 98))	('FGFR1', 'Gene', '2260', (45, 50))	('FGFR1', 'Gene', '2260', (93, 98))	('amplification', 'Var', (51, 64))
161418	27956804	In patients without adjuvant therapy, FGFR1 amplification and MYC expression were significantly associated with prolonged OS (P = 0.024 and 0.031, respectively; Figure 2E and F), but not in patients who received adjuvant chemo- and/or radiotherapy (Figure 2G and H).	('MYC', 'Gene', (62, 65))	('patients', 'Species', '9606', (190, 198))	('associated', 'Reg', (96, 106))	('amplification', 'Var', (44, 57))	('FGFR1', 'Gene', (38, 43))	('FGFR1', 'Gene', '2260', (38, 43))	('patients', 'Species', '9606', (3, 11))	('MYC', 'Gene', '4609', (62, 65))	('OS', 'Chemical', '-', (122, 124))	('prolonged OS', 'Disease', (112, 124))
161420	27956804	In contrast, FGFR1 amplification was found to be an independent favorable prognostic factor in all patients (HR = 0.532 with 95%CI: 0.302-0.937, P = 0.029) and in patients without adjuvant therapy (HR = 0.301 with 95%CI: 0.117-0.774, P = 0.013), but not in patients with adjuvant therapy (Table 4).	('patients', 'Species', '9606', (163, 171))	('amplification', 'Var', (19, 32))	('FGFR1', 'Gene', (13, 18))	('patients', 'Species', '9606', (99, 107))	('favorable', 'PosReg', (64, 73))	('FGFR1', 'Gene', '2260', (13, 18))	('patients', 'Species', '9606', (257, 265))
161422	27956804	ESCC patients (25/173) with both FGFR1 amplification and MYC expression (hereafter referred to as combined positivity) exhibited prolonged DFS (P = 0.023; data not shown) and OS (P = 0.066) in Kaplan-Meier analysis (Figure 2I).	('DFS', 'MPA', (139, 142))	('OS', 'Chemical', '-', (175, 177))	('patients', 'Species', '9606', (5, 13))	('FGFR1', 'Gene', '2260', (33, 38))	('amplification', 'Var', (39, 52))	('MYC', 'Gene', '4609', (57, 60))	('SCC', 'Gene', (1, 4))	('prolonged', 'PosReg', (129, 138))	('SCC', 'Phenotype', 'HP:0002860', (1, 4))	('SCC', 'Gene', '6317', (1, 4))	('MYC', 'Gene', (57, 60))	('FGFR1', 'Gene', (33, 38))
161426	27956804	Several previous studies reported the prognostic implication of FGFR1 amplification in ESCC, but the results were controversial.	('amplification', 'Var', (70, 83))	('FGFR1', 'Gene', (64, 69))	('SCC', 'Gene', (88, 91))	('FGFR1', 'Gene', '2260', (64, 69))	('SCC', 'Phenotype', 'HP:0002860', (88, 91))	('SCC', 'Gene', '6317', (88, 91))
161427	27956804	FGFR1 amplification was associated with poor prognosis or had no prognostic significance in ESCC; however, the FISH criteria for FGFR1 amplification were not identical.	('FGFR1', 'Gene', (129, 134))	('FGFR1', 'Gene', '2260', (129, 134))	('SCC', 'Gene', (93, 96))	('FGFR1', 'Gene', (0, 5))	('FGFR1', 'Gene', '2260', (0, 5))	('SCC', 'Phenotype', 'HP:0002860', (93, 96))	('SCC', 'Gene', '6317', (93, 96))	('amplification', 'Var', (6, 19))
161428	27956804	In the present study, FGFR1 amplification was a favorable prognostic indicator in patients with resected ESCC, which was in conflict with a previous report using the same FISH criteria.	('SCC', 'Phenotype', 'HP:0002860', (106, 109))	('FGFR1', 'Gene', '2260', (22, 27))	('SCC', 'Gene', '6317', (106, 109))	('patients', 'Species', '9606', (82, 90))	('SCC', 'Gene', (106, 109))	('amplification', 'Var', (28, 41))	('FGFR1', 'Gene', (22, 27))
161429	27956804	In a study using FISH and different criteria, FGFR1 amplification was not associated with clinical outcomes in patients with ESCC.	('SCC', 'Phenotype', 'HP:0002860', (126, 129))	('SCC', 'Gene', '6317', (126, 129))	('SCC', 'Gene', (126, 129))	('FGFR1', 'Gene', (46, 51))	('amplification', 'Var', (52, 65))	('FGFR1', 'Gene', '2260', (46, 51))	('patients', 'Species', '9606', (111, 119))
161431	27956804	One study demonstrated that FGFR1 amplification was an independent favorable prognostic factor in pulmonary SCC and large cell carcinoma, which contrasted with another study showing that FGFR1 amplification was an independent negative prognostic factor in resected pulmonary SCC.	('FGFR1', 'Gene', (187, 192))	('FGFR1', 'Gene', '2260', (187, 192))	('cell carcinoma', 'Disease', (122, 136))	('SCC', 'Gene', (275, 278))	('SCC', 'Gene', (108, 111))	('SCC', 'Phenotype', 'HP:0002860', (275, 278))	('FGFR1', 'Gene', (28, 33))	('SCC', 'Phenotype', 'HP:0002860', (108, 111))	('SCC', 'Gene', '6317', (275, 278))	('SCC', 'Gene', '6317', (108, 111))	('FGFR1', 'Gene', '2260', (28, 33))	('amplification', 'Var', (34, 47))	('cell carcinoma', 'Disease', 'MESH:C538614', (122, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('large cell carcinoma', 'Phenotype', 'HP:0030360', (116, 136))
161432	27956804	Consequently, a recent meta-analysis concluded that FGFR1 amplification had no influence on the survival of patients with pulmonary SCC.	('patients', 'Species', '9606', (108, 116))	('SCC', 'Gene', (132, 135))	('SCC', 'Phenotype', 'HP:0002860', (132, 135))	('SCC', 'Gene', '6317', (132, 135))	('FGFR1', 'Gene', (52, 57))	('FGFR1', 'Gene', '2260', (52, 57))	('amplification', 'Var', (58, 71))
161433	27956804	Notably, in this study, the association of FGFR1 amplification with clinical outcome of resected ESCC patients was dependent on the status of adjuvant therapy; i.e., FGFR1 amplification was a favorable prognostic factor in patients with ESCC who did not receive adjuvant therapy.	('SCC', 'Phenotype', 'HP:0002860', (98, 101))	('amplification', 'Var', (49, 62))	('FGFR1', 'Gene', (43, 48))	('SCC', 'Gene', '6317', (98, 101))	('patients', 'Species', '9606', (102, 110))	('FGFR1', 'Gene', '2260', (43, 48))	('SCC', 'Gene', (238, 241))	('SCC', 'Phenotype', 'HP:0002860', (238, 241))	('FGFR1', 'Gene', '2260', (166, 171))	('FGFR1', 'Gene', (166, 171))	('patients', 'Species', '9606', (223, 231))	('amplification', 'Var', (172, 185))	('SCC', 'Gene', '6317', (238, 241))	('SCC', 'Gene', (98, 101))
161434	27956804	Adjuvant therapy after surgery for patients with stage III-IV or lymph node metastasis prolonged survival compared with surgery alone in ESCC.	('survival', 'MPA', (97, 105))	('SCC', 'Gene', (138, 141))	('prolonged', 'PosReg', (87, 96))	('SCC', 'Phenotype', 'HP:0002860', (138, 141))	('SCC', 'Gene', '6317', (138, 141))	('lymph node metastasis', 'Var', (65, 86))	('patients', 'Species', '9606', (35, 43))
161438	27956804	Otherwise, it could be possible that ESCC with FGFR1 amplification represents a biologically less aggressive group among ESCCs having variable genetic alterations.	('SCC', 'Gene', (122, 125))	('SCC', 'Phenotype', 'HP:0002860', (122, 125))	('FGFR1', 'Gene', (47, 52))	('SCC', 'Gene', (38, 41))	('SCC', 'Phenotype', 'HP:0002860', (38, 41))	('amplification', 'Var', (53, 66))	('SCC', 'Gene', '6317', (122, 125))	('FGFR1', 'Gene', '2260', (47, 52))	('SCC', 'Gene', '6317', (38, 41))
161445	27956804	Thus, the favorable prognosis of patients with ESCC who showed combined FGFR1 amplification and MYC expression in the group without adjuvant therapy might be due to the association of FGFR1 amplification with prognosis.	('FGFR1', 'Gene', '2260', (184, 189))	('MYC', 'Gene', (96, 99))	('patients', 'Species', '9606', (33, 41))	('amplification', 'Var', (78, 91))	('SCC', 'Gene', (48, 51))	('SCC', 'Phenotype', 'HP:0002860', (48, 51))	('association', 'Interaction', (169, 180))	('MYC', 'Gene', '4609', (96, 99))	('FGFR1', 'Gene', '2260', (72, 77))	('SCC', 'Gene', '6317', (48, 51))	('FGFR1', 'Gene', (72, 77))	('FGFR1', 'Gene', (184, 189))
161451	27956804	Thus, another study using large prospective cohorts is required to validate the prognostic role of FGFR1 amplification in ESCC according to adjuvant therapy status.	('SCC', 'Phenotype', 'HP:0002860', (123, 126))	('amplification', 'Var', (105, 118))	('SCC', 'Gene', '6317', (123, 126))	('FGFR1', 'Gene', (99, 104))	('FGFR1', 'Gene', '2260', (99, 104))	('SCC', 'Gene', (123, 126))
161458	27956804	Among the all patients with resected ESCC, 12.3% (20/163) exhibited both FGFR1 amplification and MYC expression.	('exhibited', 'Reg', (58, 67))	('FGFR1', 'Gene', '2260', (73, 78))	('SCC', 'Gene', (38, 41))	('SCC', 'Phenotype', 'HP:0002860', (38, 41))	('MYC', 'Gene', (97, 100))	('SCC', 'Gene', '6317', (38, 41))	('MYC', 'Gene', '4609', (97, 100))	('amplification', 'Var', (79, 92))	('patients', 'Species', '9606', (14, 22))	('FGFR1', 'Gene', (73, 78))
161461	27956804	In conclusion, FGFR1 amplifications were observed in 21.4% of patients and combined FGFR1 amplification and MYC expression was observed in 12.3% of patients with resected ESCC.	('MYC', 'Gene', '4609', (108, 111))	('FGFR1', 'Gene', (84, 89))	('FGFR1', 'Gene', '2260', (84, 89))	('SCC', 'Gene', (172, 175))	('FGFR1', 'Gene', '2260', (15, 20))	('patients', 'Species', '9606', (148, 156))	('SCC', 'Phenotype', 'HP:0002860', (172, 175))	('amplifications', 'Var', (21, 35))	('MYC', 'Gene', (108, 111))	('SCC', 'Gene', '6317', (172, 175))	('observed', 'Reg', (41, 49))	('patients', 'Species', '9606', (62, 70))	('FGFR1', 'Gene', (15, 20))
161462	27956804	FGFR1 amplification had prognostic implications in patients with resected ESCC with respect to adjuvant therapy.	('SCC', 'Gene', '6317', (75, 78))	('SCC', 'Phenotype', 'HP:0002860', (75, 78))	('FGFR1', 'Gene', (0, 5))	('FGFR1', 'Gene', '2260', (0, 5))	('patients', 'Species', '9606', (51, 59))	('SCC', 'Gene', (75, 78))	('amplification', 'Var', (6, 19))	('implications', 'Reg', (35, 47))
161470	27956804	In this study, FGFR1 amplifications were observed in 21.4% of patients and combined FGFR1 amplification and MYC expression was observed in 12.3% of patients with resected ESCC.	('MYC', 'Gene', '4609', (108, 111))	('FGFR1', 'Gene', (84, 89))	('FGFR1', 'Gene', '2260', (84, 89))	('SCC', 'Gene', (172, 175))	('FGFR1', 'Gene', '2260', (15, 20))	('patients', 'Species', '9606', (148, 156))	('SCC', 'Phenotype', 'HP:0002860', (172, 175))	('amplifications', 'Var', (21, 35))	('MYC', 'Gene', (108, 111))	('SCC', 'Gene', '6317', (172, 175))	('observed', 'Reg', (41, 49))	('patients', 'Species', '9606', (62, 70))	('FGFR1', 'Gene', (15, 20))
161471	27956804	This study suggests that patients with ESCC harboring combined FGFR1 amplification and MYC expression might benefit from therapies targeting FGFR1 and/or MYC, especially those with advanced disease requiring adjuvant therapies.	('SCC', 'Gene', '6317', (40, 43))	('MYC', 'Gene', (87, 90))	('MYC', 'Gene', '4609', (154, 157))	('benefit', 'PosReg', (108, 115))	('FGFR1', 'Gene', (63, 68))	('FGFR1', 'Gene', '2260', (63, 68))	('patients', 'Species', '9606', (25, 33))	('MYC', 'Gene', (154, 157))	('FGFR1', 'Gene', (141, 146))	('SCC', 'Gene', (40, 43))	('SCC', 'Phenotype', 'HP:0002860', (40, 43))	('amplification', 'Var', (69, 82))	('MYC', 'Gene', '4609', (87, 90))	('FGFR1', 'Gene', '2260', (141, 146))
161501	24264641	The rat tongue carcinoma induced by water-soluble 4NQO closely mimics all carcinogenesis stages of their human counterparts from various degrees of epithelial dysplasia to carcinoma, which provides an ideal model for understanding how neoplasm develops.	('water', 'Chemical', 'MESH:D014867', (36, 41))	('tongue carcinoma', 'Phenotype', 'HP:0030415', (8, 24))	('4NQO', 'Var', (50, 54))	('epithelial dysplasia to carcinoma', 'Disease', (148, 181))	('human', 'Species', '9606', (105, 110))	('neoplasm', 'Phenotype', 'HP:0002664', (235, 243))	('carcinoma', 'Disease', 'MESH:D002277', (172, 181))	('carcinoma', 'Phenotype', 'HP:0030731', (15, 24))	('carcinoma', 'Disease', (15, 24))	('4NQO', 'Chemical', 'MESH:D015112', (50, 54))	('carcinogenesis', 'Disease', (74, 88))	('rat', 'Species', '10116', (4, 7))	('neoplasm', 'Disease', 'MESH:D009369', (235, 243))	('carcinoma', 'Phenotype', 'HP:0030731', (172, 181))	('carcinogenesis', 'Disease', 'MESH:D063646', (74, 88))	('carcinoma', 'Disease', 'MESH:D002277', (15, 24))	('carcinoma', 'Disease', (172, 181))	('neoplasm', 'Disease', (235, 243))	('epithelial dysplasia to carcinoma', 'Disease', 'MESH:D002277', (148, 181))
161502	24264641	In the current study, we investigated the distribution of CD4+ CD25+ Foxp3+ Tregs in the peripheral blood and regional lymph node lymphocytes during 4NQO-induced rat tongue carcinogenesis and determined their relationships with tumor progression.	('Tregs', 'Chemical', '-', (76, 81))	('rat', 'Species', '10116', (162, 165))	('tumor', 'Disease', 'MESH:D009369', (228, 233))	('Foxp3', 'Gene', (69, 74))	('tongue carcinogenesis', 'Disease', 'MESH:D063646', (166, 187))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('tumor', 'Disease', (228, 233))	('tongue carcinogenesis', 'Disease', (166, 187))	('4NQO', 'Chemical', 'MESH:D015112', (149, 153))	('CD4+ CD25+', 'Var', (58, 68))	('Foxp3', 'Gene', '317382', (69, 74))
161545	24264641	In the present study, we have described the sequential analysis of CD4+ CD25+ FoxP3+ Tregs frequency in the peripheral blood as well as lymph nodes of 4NQO-induced rat tongue carcinogenesis.	('tongue carcinogenesis', 'Disease', 'MESH:D063646', (168, 189))	('CD4+ CD25+', 'Var', (67, 77))	('4NQO', 'Chemical', 'MESH:D015112', (151, 155))	('Tregs', 'Chemical', '-', (85, 90))	('FoxP3+', 'Gene', (78, 84))	('tongue carcinogenesis', 'Disease', (168, 189))	('rat', 'Species', '10116', (164, 167))
161548	24264641	Increasing evidence demonstrated that the frequency and activity of CD4+ CD25+ FoxP3+ Tregs increased in the circulation and tumor microenvironment in patients with various types of cancer.	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('CD4+ CD25+ FoxP3+', 'Var', (68, 85))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('activity', 'MPA', (56, 64))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('patients', 'Species', '9606', (151, 159))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('tumor', 'Disease', (125, 130))	('increased', 'PosReg', (92, 101))	('rat', 'Species', '10116', (27, 30))	('cancer', 'Disease', (182, 188))	('Tregs', 'Chemical', '-', (86, 91))
161561	24264641	A number of studies have identified CD4+ CD25+ Treg cells infiltration of draining lymph node in mouse models and human cancer.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('CD4+ CD25+', 'Var', (36, 46))	('rat', 'Species', '10116', (64, 67))	('mouse', 'Species', '10090', (97, 102))	('human', 'Species', '9606', (114, 119))
161564	24264641	In addition, depletion of Tregs enhanced effector T cell responses in tumor-draining lymph nodes.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', (70, 75))	('Tregs', 'Chemical', '-', (26, 31))	('depletion', 'Var', (13, 22))	('enhanced', 'PosReg', (32, 40))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('Tregs', 'Protein', (26, 31))
161567	24264641	Our study showed that the percentage of CD4+ CD25+ Treg cells in lymph nodes was significantly higher from OSCC rat than in controls.	('CD4+ CD25+ Treg cells', 'CPA', (40, 61))	('higher', 'PosReg', (95, 101))	('OSCC rat', 'Var', (107, 115))	('SCC', 'Phenotype', 'HP:0002860', (108, 111))	('rat', 'Species', '10116', (112, 115))
161591	24564251	Numerous studies have utilized different "-omics"-based approaches to identify molecular signatures in lung cancer with diagnostic or prognostic value while using minimally invasive processes.	('lung cancer', 'Disease', 'MESH:D008175', (103, 114))	('molecular', 'Var', (79, 88))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('lung cancer', 'Disease', (103, 114))	('lung cancer', 'Phenotype', 'HP:0100526', (103, 114))
161592	24564251	Some of these are as follows: 34 miRNA signatures, expression profiles of 11 miRNAs (miR-106a, miR-15b, miR-27b, miR-142-3p, miR-26b, miR-182, miR-126, let7g, let-7i and miR-30e-5p) from serum, 7 miRNA signatures, overexpression of six snoRNAs, and expression of 3 miRs (miR-205, miR-210 and miR-708) in sputum.	('miR-182', 'Gene', (134, 141))	('miR-126', 'Gene', '406913', (143, 150))	('miR-182', 'Gene', '406958', (134, 141))	('expression', 'MPA', (51, 61))	('miR-106a', 'Gene', (85, 93))	('miR-205', 'Gene', (271, 278))	('let-7i', 'Gene', (159, 165))	('expression', 'MPA', (249, 259))	('let7g', 'Gene', '406890', (152, 157))	('miR-210', 'Gene', '406992', (280, 287))	('miR-708', 'Gene', (292, 299))	('miR-210', 'Gene', (280, 287))	('miR-26b', 'Gene', '407017', (125, 132))	('miR-126', 'Gene', (143, 150))	('miR-106a', 'Gene', '406899', (85, 93))	('miR-142-3p', 'Var', (113, 123))	('let7g', 'Gene', (152, 157))	('miR-205', 'Gene', '406988', (271, 278))	('miR-27b', 'Gene', (104, 111))	('miR-15b', 'Gene', '406949', (95, 102))	('miR-26b', 'Gene', (125, 132))	('overexpression', 'PosReg', (214, 228))	('let-7i', 'Gene', '406891', (159, 165))	('miR-27b', 'Gene', '407019', (104, 111))	('miR-15b', 'Gene', (95, 102))	('miR-708', 'Gene', '100126333', (292, 299))
161598	24564251	Extensive literature and text mining was carried out to collect deregulated miRNAs in lung cancers (NSCLC and SCLC) using databases such as PubMed, Sirus, and Elsevier as well as search engines such as Google and Google Scholar.	('SCLC', 'Gene', '7864', (110, 114))	('deregulated', 'Var', (64, 75))	('SCLC', 'Gene', (110, 114))	('SCLC', 'Phenotype', 'HP:0030357', (110, 114))	('NSCLC', 'Disease', (100, 105))	('SCLC', 'Gene', '7864', (101, 105))	('SCLC', 'Phenotype', 'HP:0030357', (101, 105))	('SCLC', 'Gene', (101, 105))	('cancers', 'Phenotype', 'HP:0002664', (91, 98))	('lung cancers', 'Disease', (86, 98))	('NSCLC', 'Disease', 'MESH:D002289', (100, 105))	('lung cancer', 'Phenotype', 'HP:0100526', (86, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('lung cancers', 'Disease', 'MESH:D008175', (86, 98))	('NSCLC', 'Phenotype', 'HP:0030358', (100, 105))	('lung cancers', 'Phenotype', 'HP:0100526', (86, 98))
161681	24564251	E2F6 (E2F transcription factor 6) inhibits entry into S phase of cells stimulated to exit G0 and inhibits apoptosis through E2F1.	('inhibits', 'NegReg', (34, 42))	('inhibits', 'NegReg', (97, 105))	('apoptosis', 'CPA', (106, 115))	('E2F transcription factor 6', 'Gene', '100037157', (6, 32))	('E2F transcription factor 6', 'Gene', (6, 32))	('entry into S phase of cells', 'CPA', (43, 70))	('E2F6', 'Var', (0, 4))	('E2F1', 'Var', (124, 128))
161686	24564251	SUV39H1 inhibits the expression of CCND1 and may thereby negatively regulate cell proliferation.	('inhibits', 'NegReg', (8, 16))	('expression', 'MPA', (21, 31))	('CCND1', 'Gene', '595', (35, 40))	('SUV39H1', 'Var', (0, 7))	('negatively regulate', 'NegReg', (57, 76))	('cell proliferation', 'CPA', (77, 95))	('CCND1', 'Gene', (35, 40))
161701	24564251	The interactions show that the tumor suppressor miRNAs (miR-29a, miR-16, miR-125, and let-7) that could target the oncogene HMGA1 are downregulated.	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('downregulated', 'NegReg', (134, 147))	('interactions', 'Interaction', (4, 16))	('miR-125', 'Chemical', '-', (73, 80))	('tumor', 'Disease', (31, 36))	('miR-16', 'Gene', (65, 71))	('miR-29a', 'Gene', '407021', (56, 63))	('HMGA1', 'Gene', (124, 129))	('miR-16', 'Gene', '51573', (65, 71))	('miR-29a', 'Gene', (56, 63))	('miR-125', 'Var', (73, 80))	('let-7', 'Gene', (86, 91))	('HMGA1', 'Gene', '3159', (124, 129))
161716	24564251	While two pro-oncogenic miRNAs, miR-28 and miR-193, are upregulated the putative tumor-suppressor, miR-137, is downregulated in lung cancers.	('miR-193', 'Var', (43, 50))	('miR-28', 'Gene', (32, 38))	('miR-137', 'Gene', '406928', (99, 106))	('lung cancers', 'Phenotype', 'HP:0100526', (128, 140))	('tumor-suppressor', 'Gene', '7248', (81, 97))	('cancers', 'Phenotype', 'HP:0002664', (133, 140))	('lung cancers', 'Disease', (128, 140))	('downregulated', 'NegReg', (111, 124))	('lung cancer', 'Phenotype', 'HP:0100526', (128, 139))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('lung cancers', 'Disease', 'MESH:D008175', (128, 140))	('miR-137', 'Gene', (99, 106))	('tumor-suppressor', 'Gene', (81, 97))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('upregulated', 'PosReg', (56, 67))	('miR-28', 'Gene', '407020', (32, 38))
161717	24564251	Furthermore, E2F6 putatively upregulates TFDP1 and is downregulated by RB1.	('TFDP1', 'Gene', '7027', (41, 46))	('upregulates', 'PosReg', (29, 40))	('TFDP1', 'Gene', (41, 46))	('RB1', 'Gene', (71, 74))	('E2F6', 'Var', (13, 17))	('RB1', 'Gene', '5925', (71, 74))	('downregulated', 'NegReg', (54, 67))
161718	24564251	It is also found from the interaction map that E2F6 inhibition by two upregulated pro-oncomiRs (miR-28 and miR-193) is not sufficient, as the E2F6 was found to be upregulated in lung cancer.	('E2F6', 'Var', (142, 146))	('lung cancer', 'Disease', (178, 189))	('lung cancer', 'Phenotype', 'HP:0100526', (178, 189))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('miR-28', 'Gene', '407020', (96, 102))	('miR-28', 'Gene', (96, 102))	('miR-193', 'Var', (107, 114))	('lung cancer', 'Disease', 'MESH:D008175', (178, 189))	('upregulated', 'PosReg', (163, 174))
161719	24564251	Further, E2F6 has been reported to upregulate oncogene TFDP1 and to positively regulate cell proliferation and cell survival through E2F1.	('E2F6', 'Var', (9, 13))	('E2F1', 'Var', (133, 137))	('cell survival', 'CPA', (111, 124))	('TFDP1', 'Gene', (55, 60))	('TFDP1', 'Gene', '7027', (55, 60))	('regulate', 'Reg', (79, 87))	('cell proliferation', 'CPA', (88, 106))	('upregulate', 'PosReg', (35, 45))
161727	32878000	Decoding the Role of CD271 in Melanoma The evolution of melanoma, the most aggressive type of skin cancer, is triggered by driver mutations that are acquired in the coding regions of particularly BRAF (rat fibrosarcoma serine/threonine kinase, isoform B) or NRAS (neuroblastoma-type ras sarcoma virus) in melanocytes.	('serine', 'Chemical', 'MESH:D012694', (219, 225))	('neuroblastoma', 'Phenotype', 'HP:0003006', (264, 277))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (206, 218))	('sarcoma', 'Phenotype', 'HP:0100242', (287, 294))	('skin cancer', 'Disease', 'MESH:D012878', (94, 105))	('neuroblastoma-type ras sarcoma virus', 'Disease', (264, 300))	('melanoma', 'Phenotype', 'HP:0002861', (56, 64))	('melanoma', 'Disease', (56, 64))	('CD271', 'Gene', '4804', (21, 26))	('triggered by', 'Reg', (110, 122))	('BRAF', 'Gene', (196, 200))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('neuroblastoma-type ras sarcoma virus', 'Disease', 'MESH:D009447', (264, 300))	('fibrosarcoma', 'Disease', 'MESH:D005354', (206, 218))	('Melanoma', 'Disease', 'MESH:D008545', (30, 38))	('NRAS', 'Gene', '24605', (258, 262))	('fibrosarcoma', 'Disease', (206, 218))	('skin cancer', 'Disease', (94, 105))	('CD271', 'Gene', (21, 26))	('sarcoma', 'Phenotype', 'HP:0100242', (211, 218))	('rat', 'Species', '10116', (202, 205))	('melanoma', 'Disease', 'MESH:D008545', (56, 64))	('Melanoma', 'Disease', (30, 38))	('skin cancer', 'Phenotype', 'HP:0008069', (94, 105))	('mutations', 'Var', (130, 139))	('NRAS', 'Gene', (258, 262))	('Melanoma', 'Phenotype', 'HP:0002861', (30, 38))
161728	32878000	Although driver mutations strongly determine tumor progression, additional factors are likely required and prerequisite for melanoma formation.	('melanoma', 'Disease', 'MESH:D008545', (124, 132))	('melanoma', 'Phenotype', 'HP:0002861', (124, 132))	('melanoma', 'Disease', (124, 132))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumor', 'Disease', (45, 50))	('mutations', 'Var', (16, 25))	('determine', 'Reg', (35, 44))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
161747	32878000	MICs that exhibit expression of CD271 are capable of renewing the tumor mass and give rise to differentiated progeny that feature typical melanocyte/melanoma antigens.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('CD271', 'Gene', (32, 37))	('melanoma', 'Disease', 'MESH:D008545', (149, 157))	('melanoma', 'Phenotype', 'HP:0002861', (149, 157))	('tumor', 'Disease', (66, 71))	('melanoma', 'Disease', (149, 157))	('give rise', 'Reg', (81, 90))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('CD271', 'Gene', '4804', (32, 37))	('expression', 'Var', (18, 28))
161749	32878000	The expression profiling of melanoma cells with a stable knockdown of CD271 demonstrated for the first time that cellular properties of a subset of melanoma cells is regulated in a CD271-dependent fashion.	('melanoma', 'Disease', (28, 36))	('rat', 'Species', '10116', (83, 86))	('regulated', 'Reg', (166, 175))	('melanoma', 'Disease', 'MESH:D008545', (148, 156))	('melanoma', 'Phenotype', 'HP:0002861', (148, 156))	('CD271', 'Gene', '4804', (181, 186))	('melanoma', 'Disease', (148, 156))	('knockdown', 'Var', (57, 66))	('CD271', 'Gene', '4804', (70, 75))	('CD271', 'Gene', (181, 186))	('cellular properties of', 'CPA', (113, 135))	('CD271', 'Gene', (70, 75))	('melanoma', 'Disease', 'MESH:D008545', (28, 36))	('melanoma', 'Phenotype', 'HP:0002861', (28, 36))
161761	32878000	The EMT that in turn is mediating the delamination of NCSCs from the NC (Figure 1a) is mediated by binding of the transcriptional repressors SNAI1 (Snail), SNAI2 (Slug), and ZEB1 to the E-cadherin/CDH1 promoter, reviewed by Barrallo-Gimeno et al.. First insight into the functional role of CD271 in cell migration was provided by murine models, which enabled the conditional knockout of CD271 in NC cells.	('SNAI2', 'Gene', '6591', (156, 161))	('Slug', 'Gene', '6591', (163, 167))	('ZEB1', 'Gene', (174, 178))	('CDH1', 'Gene', '999', (197, 201))	('E-cadherin', 'Gene', (186, 196))	('E-cadherin', 'Gene', '999', (186, 196))	('CD271', 'Gene', (387, 392))	('Snail', 'Gene', '6615', (148, 153))	('CDH1', 'Gene', (197, 201))	('murine', 'Species', '10090', (330, 336))	('rat', 'Species', '10116', (307, 310))	('knockout', 'Var', (375, 383))	('CD271', 'Gene', '4804', (290, 295))	('ZEB1', 'Gene', '6935', (174, 178))	('SNAI2', 'Gene', (156, 161))	('SNAI1', 'Gene', '6615', (141, 146))	('Slug', 'Gene', (163, 167))	('SNAI1', 'Gene', (141, 146))	('CD271', 'Gene', (290, 295))	('Snail', 'Gene', (148, 153))	('CD271', 'Gene', '4804', (387, 392))
161773	32878000	The formation of melanocytic nevi is the consequence of a hyper-activation of the MAPK pathway, triggered by acquired mutations in BRAF, most prevalently BRAFV600E/K (~15-20% and ~40-50%).	('BRAF', 'Gene', (131, 135))	('nevi', 'Phenotype', 'HP:0003764', (29, 33))	('melanocytic nevi', 'Disease', (17, 33))	('melanocytic nevi', 'Phenotype', 'HP:0000995', (17, 33))	('MAPK pathway', 'Pathway', (82, 94))	('BRAFV600E', 'Mutation', 'rs113488022', (154, 163))	('BRAFV600E/K', 'Var', (154, 165))
161775	32878000	Hence, the loss of tumor suppressor genes, e.g., p16INK4a, PTEN, or TP53, is prerequisite for the transformation of BRAF-mutated melanocytes and formation of melanoma.	('loss', 'NegReg', (11, 15))	('PTEN', 'Gene', '5728', (59, 63))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('BRAF-mutated', 'Var', (116, 128))	('melanoma', 'Disease', 'MESH:D008545', (158, 166))	('tumor', 'Disease', (19, 24))	('p16INK4a', 'Gene', (49, 57))	('TP53', 'Gene', '7157', (68, 72))	('TP53', 'Gene', (68, 72))	('PTEN', 'Gene', (59, 63))	('melanoma', 'Phenotype', 'HP:0002861', (158, 166))	('melanoma', 'Disease', (158, 166))	('p16INK4a', 'Gene', '1029', (49, 57))
161778	32878000	Whereas the distinct expression of BrafV600E triggered oncogene-induced senescence, the genetic loss of Pten mediated melanoma formation with a high efficacy.	('melanoma', 'Phenotype', 'HP:0002861', (118, 126))	('melanoma', 'Disease', (118, 126))	('melanoma', 'Disease', 'MESH:D008545', (118, 126))	('Pten', 'Gene', '5728', (104, 108))	('Pten', 'Gene', (104, 108))	('BrafV600E', 'Mutation', 'rs113488022', (35, 44))	('BrafV600E', 'Var', (35, 44))	('oncogene-induced senescence', 'MPA', (55, 82))	('triggered', 'PosReg', (45, 54))
161779	32878000	Besides Braf, mutated Nras, Kras, or Hras were shown to effectively induce melanoma formation in combination with a genetic ablation of p16Ink4a, p53 and Cdkn2a among other, reviewed by Perez-Guijarro et al..	('induce', 'PosReg', (68, 74))	('p53', 'Gene', (146, 149))	('Nras', 'Gene', '4893', (22, 26))	('p16Ink4a', 'Gene', (136, 144))	('mutated', 'Var', (14, 21))	('Braf', 'Gene', (8, 12))	('melanoma', 'Disease', 'MESH:D008545', (75, 83))	('Hras', 'Gene', (37, 41))	('Cdkn2a', 'Gene', (154, 160))	('Hras', 'Gene', '3265', (37, 41))	('Cdkn2a', 'Gene', '1029', (154, 160))	('Kras', 'Gene', '3845', (28, 32))	('Nras', 'Gene', (22, 26))	('p16Ink4a', 'Gene', '1029', (136, 144))	('p53', 'Gene', '7157', (146, 149))	('Braf', 'Gene', '673', (8, 12))	('melanoma', 'Phenotype', 'HP:0002861', (75, 83))	('melanoma', 'Disease', (75, 83))	('Kras', 'Gene', (28, 32))
161780	32878000	In addition, activated AKT3 cooperates with BRAFV600E to promote melanocyte transformation, which in turn is associated with a growth factor independent proliferation and enhanced anchorage-independent growth.	('enhanced', 'PosReg', (171, 179))	('rat', 'Species', '10116', (160, 163))	('promote', 'PosReg', (57, 64))	('melanocyte transformation', 'CPA', (65, 90))	('rat', 'Species', '10116', (33, 36))	('AKT3', 'Gene', (23, 27))	('AKT3', 'Gene', '10000', (23, 27))	('anchorage-independent growth', 'CPA', (180, 208))	('BRAFV600E', 'Var', (44, 53))	('BRAFV600E', 'Mutation', 'rs113488022', (44, 53))
161781	32878000	Although the AKT signaling pathway is frequently activated in melanoma progression, the loss of PTEN predominantly precedes the activation of AKT3.	('PTEN', 'Gene', '5728', (96, 100))	('melanoma', 'Disease', (62, 70))	('AKT3', 'Gene', (142, 146))	('AKT3', 'Gene', '10000', (142, 146))	('melanoma', 'Disease', 'MESH:D008545', (62, 70))	('AKT', 'Gene', (142, 145))	('AKT', 'Gene', '207', (13, 16))	('loss', 'Var', (88, 92))	('AKT', 'Gene', '207', (142, 145))	('PTEN', 'Gene', (96, 100))	('AKT', 'Gene', (13, 16))	('melanoma', 'Phenotype', 'HP:0002861', (62, 70))
161792	32878000	Consequentially, CD271 regulates key features of melanoma cells; particularly, a stem-like/NCSC-like phenotype and cell migration and plasticity abrogated in melanoma cells with a stable knockdown of CD271 (see Section 5).	('CD271', 'Gene', (200, 205))	('melanoma', 'Disease', 'MESH:D008545', (49, 57))	('regulates', 'Reg', (23, 32))	('CD271', 'Gene', '4804', (17, 22))	('abrogated', 'NegReg', (145, 154))	('knockdown', 'Var', (187, 196))	('melanoma', 'Phenotype', 'HP:0002861', (49, 57))	('rat', 'Species', '10116', (123, 126))	('CD271', 'Gene', '4804', (200, 205))	('CD271', 'Gene', (17, 22))	('melanoma', 'Disease', 'MESH:D008545', (158, 166))	('melanoma', 'Phenotype', 'HP:0002861', (158, 166))	('melanoma', 'Disease', (49, 57))	('melanoma', 'Disease', (158, 166))
161796	32878000	Consistently, the stable shRNA-mediated knockdown of CD271 decreased the expression of AKT3, suggesting that the concerted action of CD271 and AKT3 may promote the melanocyte transformation and maintenance of early established melanoma cells.	('AKT3', 'Gene', (87, 91))	('melanoma', 'Disease', 'MESH:D008545', (227, 235))	('CD271', 'Gene', (53, 58))	('melanoma', 'Disease', (227, 235))	('AKT3', 'Gene', '10000', (87, 91))	('melanoma', 'Phenotype', 'HP:0002861', (227, 235))	('decreased', 'NegReg', (59, 68))	('CD271', 'Gene', (133, 138))	('melanocyte transformation', 'CPA', (164, 189))	('knockdown', 'Var', (40, 49))	('expression', 'MPA', (73, 83))	('AKT3', 'Gene', (143, 147))	('CD271', 'Gene', '4804', (133, 138))	('AKT3', 'Gene', '10000', (143, 147))	('CD271', 'Gene', '4804', (53, 58))	('promote', 'PosReg', (152, 159))
161803	32878000	The loss of CD271 consequentially induced a severe impairment of cell survival and proliferation, most likely caused by a loss of genomic integrity that in turn was associated with a reduced expression of DNA-repair genes and revealed a mutually exclusive expression with inhibitors of metastasis, KISS1, and DMBT1 (Figure 2).	('rat', 'Species', '10116', (90, 93))	('cell survival', 'CPA', (65, 78))	('impairment', 'NegReg', (51, 61))	('CD271', 'Gene', (12, 17))	('CD271', 'Gene', '4804', (12, 17))	('reduced', 'NegReg', (183, 190))	('DMBT1', 'Gene', (309, 314))	('KISS1', 'Gene', (298, 303))	('loss', 'NegReg', (122, 126))	('KISS1', 'Gene', '3814', (298, 303))	('expression', 'MPA', (191, 201))	('DMBT1', 'Gene', '1755', (309, 314))	('loss', 'Var', (4, 8))
161806	32878000	These experiments strongly suggest a more comprehensive role of CD271, serving as determinant of melanoma cell properties independent from the presence of a BRAFV600E-mutation.	('melanoma', 'Disease', 'MESH:D008545', (97, 105))	('melanoma', 'Phenotype', 'HP:0002861', (97, 105))	('melanoma', 'Disease', (97, 105))	('CD271', 'Gene', '4804', (64, 69))	('CD271', 'Gene', (64, 69))	('BRAFV600E-mutation', 'Var', (157, 175))	('BRAFV600E', 'Mutation', 'rs113488022', (157, 166))
161807	32878000	The presence of the latter was not sufficient to prevent melanoma cells from apoptosis induced by the loss of CD271 expression.	('melanoma', 'Phenotype', 'HP:0002861', (57, 65))	('melanoma', 'Disease', (57, 65))	('melanoma', 'Disease', 'MESH:D008545', (57, 65))	('CD271', 'Gene', '4804', (110, 115))	('loss', 'Var', (102, 106))	('CD271', 'Gene', (110, 115))
161810	32878000	Interestingly, the loss of SOX10 reduced the level of CD271, suggesting a mutual dependency.	('CD271', 'Gene', (54, 59))	('level', 'MPA', (45, 50))	('loss', 'Var', (19, 23))	('reduced', 'NegReg', (33, 40))	('SOX10', 'Gene', (27, 32))	('CD271', 'Gene', '4804', (54, 59))
161830	32878000	Mutant BRAFV600 serves as yet another driver of metastasis as mutant melanoma cells featured a higher endogenous migration capacity in vitro than wild type (wt) cells.	('endogenous', 'MPA', (102, 112))	('melanoma', 'Disease', 'MESH:D008545', (69, 77))	('mutant', 'Var', (62, 68))	('BRAFV600', 'Gene', (7, 15))	('higher', 'PosReg', (95, 101))	('rat', 'Species', '10116', (116, 119))	('Mutant', 'Var', (0, 6))	('melanoma', 'Phenotype', 'HP:0002861', (69, 77))	('melanoma', 'Disease', (69, 77))
161838	32878000	Concordantly, the selective inhibitor of oncogenic BRAFV600E/K vemurafenib mediated resistance via increased expression of CD271.	('resistance', 'MPA', (84, 94))	('expression', 'MPA', (109, 119))	('CD271', 'Gene', '4804', (123, 128))	('vemurafenib', 'Chemical', 'MESH:D000077484', (63, 74))	('mediated', 'Reg', (75, 83))	('BRAFV600E', 'Mutation', 'rs113488022', (51, 60))	('BRAFV600E/K', 'Var', (51, 62))	('CD271', 'Gene', (123, 128))	('increased', 'PosReg', (99, 108))	('vemurafenib', 'Gene', (63, 74))
161839	32878000	In summary, therapeutic interventions select for highly migratory and metastatic melanoma cells, likely via the modification of levels of CD271.	('melanoma', 'Disease', 'MESH:D008545', (81, 89))	('CD271', 'Gene', '4804', (138, 143))	('modification', 'Var', (112, 124))	('melanoma', 'Phenotype', 'HP:0002861', (81, 89))	('CD271', 'Gene', (138, 143))	('melanoma', 'Disease', (81, 89))	('rat', 'Species', '10116', (59, 62))
161852	32878000	demonstrated that the modulation of the hypoxia-inducible factor 1alpha (HIF1alpha) was sufficient to induce the dedifferentiation and phenotype switching of proliferative into invasive melanoma cells, referring to the AXL/MITF axis.	('melanoma', 'Phenotype', 'HP:0002861', (186, 194))	('induce', 'Reg', (102, 108))	('phenotype switching', 'CPA', (135, 154))	('dedifferentiation', 'CPA', (113, 130))	('hypoxia-inducible factor 1alpha', 'Gene', (40, 71))	('invasive melanoma', 'Disease', (177, 194))	('HIF1alpha', 'Gene', (73, 82))	('AXL', 'Gene', '558', (219, 222))	('HIF1alpha', 'Gene', '3091', (73, 82))	('rat', 'Species', '10116', (7, 10))	('modulation', 'Var', (22, 32))	('hypoxia-inducible factor 1alpha', 'Gene', '3091', (40, 71))	('rat', 'Species', '10116', (165, 168))	('invasive melanoma', 'Disease', 'MESH:D008545', (177, 194))	('AXL', 'Gene', (219, 222))
161902	32878000	The phosphorylation of CD271 at S303/S304 by protein kinase a (PKA) in turn promoted glioblastoma invasiveness and the translocation of CD271 to lipid rafts in neurons and potentially in glioblastoma.	('glioblastoma', 'Phenotype', 'HP:0012174', (187, 199))	('CD271', 'Gene', (23, 28))	('phosphorylation', 'MPA', (4, 19))	('glioblastoma', 'Disease', (85, 97))	('CD271', 'Gene', (136, 141))	('translocation', 'MPA', (119, 132))	('at S303/S304', 'Var', (29, 41))	('glioblastoma invasiveness', 'Disease', (85, 110))	('glioblastoma', 'Disease', 'MESH:D005909', (187, 199))	('lipid', 'Chemical', 'MESH:D008055', (145, 150))	('glioblastoma', 'Disease', 'MESH:D005909', (85, 97))	('glioblastoma invasiveness', 'Disease', 'MESH:D005909', (85, 110))	('glioblastoma', 'Phenotype', 'HP:0012174', (85, 97))	('glioblastoma', 'Disease', (187, 199))	('promoted', 'PosReg', (76, 84))	('CD271', 'Gene', '4804', (23, 28))	('CD271', 'Gene', '4804', (136, 141))
161903	32878000	In addition, the expression of CD271 was associated with increased migration/invasion and metastasis of head and neck cancer, hypopharyngeal cancer, and oral squamous cell carcinoma and was associated with poor prognosis of LSCC and urothelial carcinoma (TCGA, human protein atlas, Figure S7b).	('migration/invasion', 'CPA', (67, 85))	('CD271', 'Gene', '4804', (31, 36))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (158, 181))	('associated', 'Reg', (190, 200))	('hypopharyngeal cancer', 'Disease', 'MESH:D007012', (126, 147))	('LSCC', 'Disease', (224, 228))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (233, 253))	('carcinoma', 'Phenotype', 'HP:0030731', (244, 253))	('CD271', 'Gene', (31, 36))	('rat', 'Species', '10116', (70, 73))	('head and neck cancer', 'Phenotype', 'HP:0012288', (104, 124))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('human', 'Species', '9606', (261, 266))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('neck cancer', 'Disease', 'MESH:D006258', (113, 124))	('urothelial carcinoma', 'Disease', (233, 253))	('expression', 'Var', (17, 27))	('increased', 'PosReg', (57, 66))	('neck cancer', 'Disease', (113, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (172, 181))	('metastasis', 'CPA', (90, 100))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (153, 181))	('hypopharyngeal cancer', 'Disease', (126, 147))	('oral squamous cell carcinoma', 'Disease', (153, 181))
161910	32878000	Nevertheless, commercially available small molecule drugs like non-peptide inhibitors preventing NGF from binding to CD271; PD90780, Ro 08-2750, and peptide inhibitor NTR368 have not yet been tested in vivo.	('NGF', 'Gene', (97, 100))	('binding', 'Interaction', (106, 113))	('PD90780', 'Var', (124, 131))	('PD90780', 'Chemical', 'MESH:C096822', (124, 131))	('CD271', 'Gene', '4804', (117, 122))	('NTR368', 'Chemical', '-', (167, 173))	('CD271', 'Gene', (117, 122))	('Ro 08-2750', 'Chemical', 'MESH:C412503', (133, 143))	('NGF', 'Gene', '4803', (97, 100))
161936	33364071	In patients with metastatic pancreatic cancer and germline mutations in BRCA1 or BRCA2, maintenance therapy with olaparib doubled the time to disease progression and the proportion of patients who were progression-free at 2 years, in the phase III POLO trial (Kindler et al., 2019).	('pancreatic cancer', 'Disease', (28, 45))	('BRCA1', 'Gene', '672', (72, 77))	('doubled', 'PosReg', (122, 129))	('patients', 'Species', '9606', (184, 192))	('pancreatic cancer', 'Disease', 'MESH:D010190', (28, 45))	('germline mutations', 'Var', (50, 68))	('BRCA1', 'Gene', (72, 77))	('BRCA2', 'Gene', (81, 86))	('BRCA2', 'Gene', '675', (81, 86))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('patients', 'Species', '9606', (3, 11))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (28, 45))	('time', 'MPA', (134, 138))	('olaparib', 'Chemical', 'MESH:C531550', (113, 121))
161942	33364071	Dr. Cole continued: "Now that we have a targeted medicine that can benefit patients with BRCA mutations, it is our duty to search for this mutation to identify those who will benefit from a treatment that could extend their life."	('patients', 'Species', '9606', (75, 83))	('BRCA', 'Gene', '672', (89, 93))	('BRCA', 'Gene', (89, 93))	('mutations', 'Var', (94, 103))
161945	33364071	Some 4% to 7% of patients with metastatic pancreatic cancer harbor a germline BRCA mutation.	('pancreatic cancer', 'Disease', (42, 59))	('pancreatic cancer', 'Disease', 'MESH:D010190', (42, 59))	('mutation', 'Var', (83, 91))	('BRCA', 'Gene', '672', (78, 82))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('patients', 'Species', '9606', (17, 25))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (42, 59))	('BRCA', 'Gene', (78, 82))
161949	33364071	Of 3,315 patients with pancreatic cancer screened, 247, or 7.5%, had germline BRCA mutations, and 154 were enrolled after not experiencing disease progression during 16 weeks or more of platinum-based chemotherapy.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('mutations', 'Var', (83, 92))	('patients', 'Species', '9606', (9, 17))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (23, 40))	('platinum', 'Chemical', 'MESH:D010984', (186, 194))	('germline', 'Var', (69, 77))	('pancreatic cancer', 'Disease', (23, 40))	('BRCA', 'Gene', '672', (78, 82))	('pancreatic cancer', 'Disease', 'MESH:D010190', (23, 40))	('BRCA', 'Gene', (78, 82))
161959	33364071	"We conclude that a strategic approach of first-line platinum-based chemotherapy followed by maintenance olaparib treatment should become a new standard of care for patients with metastatic pancreatic cancer who have a germline BRCA mutation," said Dr. Kindler.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (190, 207))	('germline', 'Var', (219, 227))	('olaparib', 'Chemical', 'MESH:C531550', (105, 113))	('pancreatic cancer', 'Disease', (190, 207))	('platinum', 'Chemical', 'MESH:D010984', (53, 61))	('BRCA', 'Gene', '672', (228, 232))	('patients', 'Species', '9606', (165, 173))	('pancreatic cancer', 'Disease', 'MESH:D010190', (190, 207))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('BRCA', 'Gene', (228, 232))
161963	33364071	Olaparib as maintenance treatment following first-line platinum-based chemotherapy in patients with a germline BRCA mutation and metastatic pancreatic cancer: Phase III POLO trial [Abstract LBA4].	('pancreatic cancer', 'Disease', 'MESH:D010190', (140, 157))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('patients', 'Species', '9606', (86, 94))	('mutation', 'Var', (116, 124))	('BRCA', 'Gene', '672', (111, 115))	('Olaparib', 'Chemical', 'MESH:C531550', (0, 8))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (140, 157))	('BRCA', 'Gene', (111, 115))	('platinum', 'Chemical', 'MESH:D010984', (55, 63))	('pancreatic cancer', 'Disease', (140, 157))
161965	33364071	However, many patients do not always understand trial details and the fact that benefits may only be applicable to a certain group, like this study was in patients with BRCA mutations (which only occurs in about 4% to 7% of patients).	('BRCA', 'Gene', '672', (169, 173))	('patients', 'Species', '9606', (224, 232))	('patients', 'Species', '9606', (155, 163))	('mutations', 'Var', (174, 183))	('patients', 'Species', '9606', (14, 22))	('BRCA', 'Gene', (169, 173))
161979	33364071	After the launch of the APACT trial, gemcitabine plus capecitabine and modified FOLFIRINOX demonstrated survival benefits in the adjuvant ESPAC-4 (Neoptolemos et al., 2017) and PRODIGE 24 trials (Conroy et al., 2018) and so became preferred treatments.	('modified', 'Var', (71, 79))	('survival benefits', 'CPA', (104, 121))	('ESPAC-4', 'Chemical', '-', (138, 145))	('capecitabine', 'Chemical', 'MESH:D000069287', (54, 66))	('gemcitabine', 'Chemical', 'MESH:C056507', (37, 48))	('FOLFIRINOX', 'Chemical', 'MESH:C000627770', (80, 90))
161985	33364071	The most common grade >= 3 hematologic and nonhematologic toxicities were for nab-paclitaxel/gemcitabine vs gemcitabine, neutropenia (49% vs 43%) and fatigue (10% vs 3%).	('nab-paclitaxel/gemcitabine', 'Var', (78, 104))	('toxicities', 'Disease', 'MESH:D064420', (58, 68))	('neutropenia', 'Phenotype', 'HP:0001875', (121, 132))	('gemcitabine', 'Chemical', 'MESH:C056507', (108, 119))	('nab', 'Chemical', '-', (78, 81))	('neutropenia', 'Disease', 'MESH:D009503', (121, 132))	('gemcitabine', 'Chemical', 'MESH:C056507', (93, 104))	('fatigue', 'Disease', 'MESH:D005221', (150, 157))	('fatigue', 'Disease', (150, 157))	('paclitaxel', 'Chemical', 'MESH:D017239', (82, 92))	('toxicities', 'Disease', (58, 68))	('neutropenia', 'Disease', (121, 132))	('fatigue', 'Phenotype', 'HP:0012378', (150, 157))
162028	33364071	This study found improved overall survival in patients in the pembrolizumab plus chemotherapy arm, regardless of PD-L1 expression, although survival rates were higher in groups with enhanced PD-L1 expression (CPS >= 1) and high PD-L1 expression (CPS > 20).	('improved', 'PosReg', (17, 25))	('patients', 'Species', '9606', (46, 54))	('higher', 'PosReg', (160, 166))	('expression', 'MPA', (234, 244))	('PD-L1', 'Gene', (113, 118))	('high', 'Var', (223, 227))	('CPS >= 1', 'Gene', '1373', (209, 217))	('overall', 'MPA', (26, 33))	('PD-L1', 'Gene', '29126', (113, 118))	('PD-L1', 'Gene', (191, 196))	('PD-L1', 'Gene', '29126', (191, 196))	('CPS', 'Chemical', '-', (209, 212))	('CPS > 20', 'Var', (246, 254))	('pembrolizumab', 'Chemical', 'MESH:C582435', (62, 75))	('PD-L1', 'Gene', (228, 233))	('enhanced', 'PosReg', (182, 190))	('PD-L1', 'Gene', '29126', (228, 233))	('CPS >= 1', 'Gene', (209, 217))	('expression', 'MPA', (197, 207))	('CPS', 'Chemical', '-', (246, 249))	('survival', 'MPA', (140, 148))
162050	33364071	Second, antibody titers of patients receiving SurVaxM produced an increase in SurVaxM.	('increase', 'PosReg', (66, 74))	('antibody', 'Var', (8, 16))	('SurVaxM', 'Chemical', '-', (46, 53))	('SurVaxM', 'MPA', (78, 85))	('SurVaxM', 'Chemical', '-', (78, 85))	('patients', 'Species', '9606', (27, 35))
162056	33364071	Arecent, updated predictive analysis of the three World Health Organization (WHO)-defined molecular subgroups based on IDH mutation status and 1p/19q codeletion status represented in the high-risk treatment arms of a phase III trial found that both IDH-mutant subgroups may derive benefit from the addition of PCV (procarbazine, lomustine, and vincristine) chemotherapy to radiotherapy.	('benefit', 'PosReg', (281, 288))	('IDH', 'Gene', '3417', (119, 122))	('mutation', 'Var', (123, 131))	('lomustine', 'Chemical', 'MESH:D008130', (329, 338))	('procarbazine', 'Chemical', 'MESH:D011344', (315, 327))	('IDH', 'Gene', '3417', (249, 252))	('vincristine', 'Chemical', 'MESH:D014750', (344, 355))	('IDH', 'Gene', (249, 252))	('IDH', 'Gene', (119, 122))
162061	33364071	Of these specimens, 41% were categorized as IDH-mutated, 1p/19q noncodeleted, 35% were IDH-mutated, 1p/19q codeleted, and 24% were IDH wild-type.	('1p/19q', 'Var', (100, 106))	('IDH', 'Gene', (87, 90))	('IDH', 'Gene', (131, 134))	('IDH', 'Gene', '3417', (87, 90))	('IDH', 'Gene', (44, 47))	('IDH', 'Gene', '3417', (131, 134))	('1p/19q noncodeleted', 'Var', (57, 76))	('IDH', 'Gene', '3417', (44, 47))
162065	33364071	https://doi.org/10.1200/JCO.2019.37.15_suppl.2002 Nanette Fong, RN, MSN Ronald Reagan UCLA Medical Center Since the completion of the NRG-RTOG 9802 trial, clinical practice at the UCLA Neuro-Oncology Program has changed in the treatment of low-grade IDH mutated, 1p/19q co-deleted and 1p/19q noncodeleted patients.	('Oncology', 'Phenotype', 'HP:0002664', (191, 199))	('low-grade', 'Var', (240, 249))	('Fong', 'Gene', '348751', (58, 62))	('1p/19q noncodeleted', 'Var', (285, 304))	('MSN', 'Gene', '4478', (68, 71))	('MSN', 'Gene', (68, 71))	('patients', 'Species', '9606', (305, 313))	('Fong', 'Gene', (58, 62))	('1p/19q co-deleted', 'Var', (263, 280))	('IDH', 'Gene', (250, 253))	('IDH', 'Gene', '3417', (250, 253))
162081	33364071	A weighted analysis of both patient groups, which controlled for other factors that may have led to differences between the patient groups, found that the relative risk of a severe toxicity was two-thirds lower for patients treated with proton therapy vs patients treated with photon therapy.	('patients', 'Species', '9606', (215, 223))	('proton therapy', 'Var', (237, 251))	('toxicity', 'Disease', 'MESH:D064420', (181, 189))	('toxicity', 'Disease', (181, 189))	('patient', 'Species', '9606', (255, 262))	('patients', 'Species', '9606', (255, 263))	('patient', 'Species', '9606', (28, 35))	('patient', 'Species', '9606', (124, 131))	('lower', 'NegReg', (205, 210))	('patient', 'Species', '9606', (215, 222))
162108	31226960	Third, several population-based studies have reported a higher re-intervention rate in patients who underwent MIE, while no evident reduction in postoperative complications or overall morbidity was observed.	('MIE', 'Chemical', '-', (110, 113))	('MIE', 'Var', (110, 113))	('postoperative complications', 'Disease', (145, 172))	('postoperative complications', 'Disease', 'MESH:D011183', (145, 172))	('higher', 'PosReg', (56, 62))	('re-intervention', 'MPA', (63, 78))	('patients', 'Species', '9606', (87, 95))
162146	31226960	Quality of life (QOL): QOL is assessed among patients by using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C-30 (EORTC QLQ-C30) and EORTC QLQ-OES18 at randomization, and 3 month, 6 month, 9 month and yearly till 3 years after surgery respectively.	('Cancer', 'Disease', (119, 125))	('EORTC', 'Chemical', '-', (181, 186))	('Cancer', 'Disease', 'MESH:D009369', (119, 125))	('EORTC', 'Var', (181, 186))	('Cancer', 'Phenotype', 'HP:0002664', (119, 125))	('patients', 'Species', '9606', (45, 53))	('EORTC', 'Chemical', '-', (162, 167))
162182	29969465	Slug is highly expressed in these cells, and Slug siRNA effectively represses anti-tumor drug resistance and invasive properties.	('Slug', 'Var', (45, 49))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('invasive properties', 'CPA', (109, 128))	('tumor', 'Disease', (83, 88))	('drug resistance', 'Phenotype', 'HP:0020174', (89, 104))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('represses', 'NegReg', (68, 77))
162206	29969465	Indeed, mice that lack TGF-beta3, a TGF-beta family member, exhibit a high frequency of cleft palate formation, probably due to absence of apoptosis and EMT in the medial edge epithelium during fusion of both upper jaws.	('cleft palate', 'Phenotype', 'HP:0000175', (88, 100))	('TGF-beta3', 'Gene', (23, 32))	('TGF-beta3', 'Gene', '21809', (23, 32))	('cleft palate', 'Disease', (88, 100))	('lack', 'Var', (18, 22))	('absence', 'NegReg', (128, 135))	('cleft palate', 'Disease', 'MESH:D002972', (88, 100))	('mice', 'Species', '10090', (8, 12))	('apoptosis', 'CPA', (139, 148))
162214	29969465	Thus, the knockdown of Slug and Snail in tandem, but not either alone, efficiently suppresses invasive properties and chemo-resistance against anti-tumor drugs induced by TGF-beta.	('knockdown', 'Var', (10, 19))	('Slug', 'Gene', (23, 27))	('chemo-resistance', 'CPA', (118, 134))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('tumor', 'Disease', (148, 153))	('invasive properties', 'CPA', (94, 113))	('TGF-beta', 'Gene', (171, 179))	('suppresses', 'NegReg', (83, 93))	('tumor', 'Disease', 'MESH:D009369', (148, 153))
162245	29969465	Similar to invasion assays, Slug knockdown significantly reduced chemo-resistance against docetaxel (DTX), a chemotherapeutic agent widely used in oral cancer patients, whereas combination of Snail siRNAs did not further affect it (Fig 1E).	('chemo-resistance against docetaxel', 'MPA', (65, 99))	('oral cancer', 'Disease', 'MESH:D009062', (147, 158))	('knockdown', 'Var', (33, 42))	('docetaxel', 'Chemical', 'MESH:D000077143', (90, 99))	('DTX', 'Chemical', 'MESH:D000077143', (101, 104))	('oral cancer', 'Disease', (147, 158))	('Slug', 'Gene', (28, 32))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('reduced', 'NegReg', (57, 64))	('patients', 'Species', '9606', (159, 167))
162246	29969465	These findings suggested that, under normal culture conditions, Slug regulates invasiveness and chemo-resistance against anti-tumor drugs in HSC4 cells, and the increase in Snail levels following Slug knockdown may only negligibly affect these cellular phenomena.	('knockdown', 'Var', (201, 210))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('Snail levels', 'MPA', (173, 185))	('regulates', 'Reg', (69, 78))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('HSC4', 'CellLine', 'CVCL:1289', (141, 145))	('invasiveness', 'CPA', (79, 91))	('tumor', 'Disease', (126, 131))
162253	29969465	In addition, chemo-resistance to DTX induced by TGF-beta was not significantly affected by either siRNA alone, but dramatically reduced by combined transfections with both siRNAs in HSC4 cells (Fig 2I) and SAS cells (S2 Fig).	('chemo-resistance', 'MPA', (13, 29))	('TGF-beta', 'Gene', (48, 56))	('reduced', 'NegReg', (128, 135))	('siRNAs', 'Gene', (172, 178))	('transfections', 'Var', (148, 161))	('combined', 'Interaction', (139, 147))	('DTX', 'Chemical', 'MESH:D000077143', (33, 36))	('HSC4', 'CellLine', 'CVCL:1289', (182, 186))
162254	29969465	Thus, these findings indicate that aggressive cellular phenotypes, particularly chemo-resistance, induced by TGF-beta are ameliorated by the knockdown of Snail and Slug in tandem, but not of either alone.	('knockdown', 'Var', (141, 150))	('chemo-resistance', 'CPA', (80, 96))	('ameliorated', 'PosReg', (122, 133))	('TGF-beta', 'Gene', (109, 117))	('rat', 'Species', '10116', (128, 131))
162262	29969465	STAT3 phosphorylation is inhibited by inhibitory molecules for STAT3, PIAS3, and SOCS3, but their expression levels were not significantly changed by both siRNAs (data not shown).	('inhibitory molecules', 'Var', (38, 58))	('SOCS3', 'Gene', (81, 86))	('STAT3', 'Gene', '6774', (0, 5))	('PIAS3', 'Gene', (70, 75))	('STAT3', 'Gene', '6774', (63, 68))	('inhibited', 'NegReg', (25, 34))	('STAT3', 'Gene', (0, 5))	('SOCS3', 'Gene', '9021', (81, 86))	('PIAS3', 'Gene', '10401', (70, 75))	('STAT3', 'Gene', (63, 68))
162263	29969465	Among them, IL-6 was increased by Slug siRNA in the absence or presence of TGF-beta in HSC4 and SAS cells (Fig 4C, 4D, 4F and 4G).	('presence', 'Var', (63, 71))	('increased', 'PosReg', (21, 30))	('IL-6', 'Gene', (12, 16))	('IL-6', 'Gene', '3569', (12, 16))	('HSC4', 'CellLine', 'CVCL:1289', (87, 91))	('TGF-beta', 'Gene', (75, 83))
162264	29969465	In addition, Snail siRNA also upregulated IL-8 expression in both cells treated with TGF-beta, but not in cells that were not treated with TGF-beta (Fig 4E and 4H, and data not shown).	('TGF-beta', 'Var', (85, 93))	('upregulated', 'PosReg', (30, 41))	('IL-8', 'Gene', '3576', (42, 46))	('IL-8', 'Gene', (42, 46))	('expression', 'MPA', (47, 57))
162279	29969465	Taken together, our findings suggest that, in terms of nucleic acid medicine, silencing only one of the two genes is not sufficient for chemo-resistance against anti-tumor drugs and invasiveness in OSCC cells.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('tumor', 'Disease', (166, 171))	('OSCC', 'CellLine', 'CVCL:L894', (198, 202))	('silencing', 'Var', (78, 87))
162289	29969465	As in the case of beta-catenin, GSK-3beta-mediated phosphorylation in Snail provokes its cytoplasmic export and subsequent ubiquitin-mediated proteasome degradation by beta-TrCP.	('ubiquitin-mediated proteasome degradation', 'MPA', (123, 164))	('cytoplasmic export', 'MPA', (89, 107))	('beta-catenin', 'Gene', (18, 30))	('beta-catenin', 'Gene', '1499', (18, 30))	('provokes', 'PosReg', (76, 84))	('GSK-3beta', 'Gene', '2932', (32, 41))	('GSK-3beta', 'Gene', (32, 41))	('phosphorylation', 'Var', (51, 66))
162296	29969465	Because ZEB1 and ZEB2 are reportedly to be reciprocally controlled by TGF-beta in endothelial cells, the simultaneous knockdown of ZEB1 and ZEB2, rather than knockdown of either alone, would be useful for potential therapeutic strategy, as previous report.	('ZEB2', 'Gene', '9839', (17, 21))	('ZEB1', 'Gene', '6935', (131, 135))	('knockdown', 'Var', (118, 127))	('ZEB1', 'Gene', (8, 12))	('rat', 'Species', '10116', (146, 149))	('ZEB1', 'Gene', (131, 135))	('ZEB1', 'Gene', '6935', (8, 12))	('rat', 'Species', '10116', (229, 232))	('ZEB2', 'Gene', '9839', (140, 144))	('TGF-beta', 'Gene', (70, 78))	('ZEB2', 'Gene', (17, 21))	('ZEB2', 'Gene', (140, 144))
162300	32437477	Aberrant expression of CPSF1 promotes head and neck squamous cell carcinoma via regulating alternative splicing Alternative mRNA splicing increases protein diversity, and alternative splicing events (ASEs) drive oncogenesis in multiple tumor types.	('carcinoma', 'Phenotype', 'HP:0030731', (66, 75))	('increases', 'PosReg', (138, 147))	('protein diversity', 'MPA', (148, 165))	('oncogenesis', 'CPA', (212, 223))	('tumor', 'Disease', 'MESH:D009369', (236, 241))	('promotes', 'PosReg', (29, 37))	('Aberrant', 'Var', (0, 8))	('alternative splicing events', 'MPA', (171, 198))	('tumor', 'Phenotype', 'HP:0002664', (236, 241))	('neck squamous cell carcinoma', 'Disease', (47, 75))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (52, 75))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (47, 75))	('alternative splicing', 'MPA', (91, 111))	('expression', 'Species', '29278', (9, 19))	('drive', 'Reg', (206, 211))	('CPSF1', 'Gene', (23, 28))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (38, 75))	('CPSF1', 'Gene', '29894', (23, 28))	('tumor', 'Disease', (236, 241))
162301	32437477	Using head and neck squamous cell carcinoma (HNSCC) as a model, we hypothesized that the genomic alteration of genes associated with the spliceosome may broadly induce ASEs across a broad range of target genes, driving an oncogenic phenotype.	('alteration', 'Var', (97, 107))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (20, 43))	('induce', 'Reg', (161, 167))	('ASEs', 'MPA', (168, 172))	('driving', 'Reg', (211, 218))	('carcinoma', 'Phenotype', 'HP:0030731', (34, 43))	('neck squamous cell carcinoma', 'Disease', (15, 43))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (6, 43))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (15, 43))
162303	32437477	We employed knockdown and overexpression assays followed by identification of ASEs regulated by CPSF1 overexpression to identify changes in ASEs, and the expression of these ASEs was validated using RNA from cell line models.	('expression', 'Species', '29278', (154, 164))	('ASEs', 'MPA', (140, 144))	('expression', 'Species', '29278', (106, 116))	('CPSF1', 'Gene', (96, 101))	('overexpression', 'Var', (102, 116))	('expression', 'Species', '29278', (30, 40))
162304	32437477	Alterations in expression of spliceosome genes, including CPSF1, may contribute to HNSCC by mediating aberrant ASE expression.	('HNSCC', 'Disease', (83, 88))	('mediating', 'Reg', (92, 101))	('ASE expression', 'MPA', (111, 125))	('Alterations', 'Var', (0, 11))	('expression', 'Species', '29278', (15, 25))	('CPSF1', 'Gene', (58, 63))	('expression', 'Species', '29278', (115, 125))	('contribute', 'Reg', (69, 79))
162308	32437477	The Cancer Genome Atlas (TCGA) study also reported differences in genetic alterations between HPV-negative and -positive cancers, underscoring that HPV-positive HNSCC are a distinct tumor type from HPV-negative HNSCC.	('cancers', 'Disease', (121, 128))	('cancers', 'Disease', 'MESH:D009369', (121, 128))	('HPV-positive', 'Var', (148, 160))	('tumor', 'Disease', (182, 187))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('HPV', 'Species', '10566', (94, 97))	('HPV', 'Species', '10566', (148, 151))	('Cancer', 'Phenotype', 'HP:0002664', (4, 10))	('Cancer', 'Disease', (4, 10))	('HPV', 'Species', '10566', (198, 201))	('HNSCC', 'Disease', (161, 166))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('Cancer', 'Disease', 'MESH:D009369', (4, 10))	('cancers', 'Phenotype', 'HP:0002664', (121, 128))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
162311	32437477	Alternative splicing has been demonstrated to have a key role in cancer development, and data indicate that alternative splicing of key genes such as BCL2L1, RON and FOX2 can drive a cancer phenotype.	('cancer', 'Disease', (183, 189))	('drive', 'Reg', (175, 180))	('FOX2', 'Gene', (166, 170))	('BCL2L1', 'Gene', (150, 156))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('RON', 'Gene', (158, 161))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (183, 189))	('alternative splicing', 'Var', (108, 128))
162312	32437477	reported that the dysregulated expression of SRSF1 could cause oncogenic transformation of cells.	('dysregulated', 'Var', (18, 30))	('SRSF1', 'Gene', (45, 50))	('cause', 'Reg', (57, 62))	('expression', 'Species', '29278', (31, 41))	('oncogenic transformation of cells', 'CPA', (63, 96))	('expression', 'MPA', (31, 41))
162313	32437477	We defined an alternative splicing event phenotype and showed that alternative splicing could represent an important contributor to HPV-related oropharyngeal cancer.	('alternative splicing', 'Var', (67, 87))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('HPV', 'Species', '10566', (132, 135))	('contributor', 'Reg', (117, 128))	('cancer', 'Disease', (158, 164))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
162314	32437477	We assumed that the oncogenesis driven by alternative splicing could be associated not only with HPV-positive tumors but also HPV-negative tumors.	('HPV-positive tumors', 'Disease', 'MESH:D030361', (97, 116))	('HPV-positive tumors', 'Disease', (97, 116))	('HPV', 'Species', '10566', (97, 100))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('associated', 'Reg', (72, 82))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumors', 'Disease', (110, 116))	('tumors', 'Disease', 'MESH:D009369', (110, 116))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('tumors', 'Disease', (139, 145))	('tumors', 'Disease', 'MESH:D009369', (139, 145))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('alternative splicing', 'Var', (42, 62))	('HPV', 'Species', '10566', (126, 129))
162315	32437477	Thus, we hypothesized that a contributor to HNSCC development may be spliceosome gene mutations and/or overexpression, which could induce aberrant splicing in HNSCC.	('mutations', 'Var', (86, 95))	('expression', 'Species', '29278', (107, 117))	('spliceosome gene', 'Gene', (69, 85))	('induce', 'Reg', (131, 137))	('aberrant splicing', 'MPA', (138, 155))	('HNSCC', 'Gene', (159, 164))
162319	32437477	From these results, the list was sorted by frequency of mutations, as well as frequency of copy number variation and expression alterations.	('expression', 'MPA', (117, 127))	('copy number variation', 'Var', (91, 112))	('expression', 'Species', '29278', (117, 127))
162320	32437477	13 genes were selected based on high number of mutations and/or CNV, with accompanying expression alterations.	('CNV', 'Var', (64, 67))	('expression', 'Species', '29278', (87, 97))	('mutations', 'Var', (47, 56))	('expression', 'MPA', (87, 97))	('alterations', 'Reg', (98, 109))
162321	32437477	Genes selected for analysis were based on a 1) mutation threshold of 3 or greater tumors 2) high frequency of upregulation and/or downregulation and 3) concordance of amplification with upregulation or deletion with downregulation, 3) consistent direction of amplification/upregulation or deletion/downregulation, 4) high total frequency of these alterations, and 5) consistency of these alterations with biologic activity reported in the literature.	('upregulation', 'PosReg', (110, 122))	('tumors', 'Disease', (82, 88))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('amplification/upregulation', 'Var', (259, 285))	('downregulation', 'NegReg', (130, 144))	('upregulation', 'PosReg', (186, 198))	('deletion/downregulation', 'NegReg', (289, 312))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('downregulation', 'NegReg', (216, 230))	('deletion', 'Var', (202, 210))	('amplification/upregulation', 'PosReg', (259, 285))
162330	32437477	ON-TARGETplus SMARTpool was used for PRPF6 (L-012821-01), DBR1 (L-008290-00), PSIP1 (L-015209-00), SNRPN (L-011776-02), SRPK2 (L-004839-00), DHX9 (L-009950-00), TRA2B (L-007278-00), RSRC1 (L-020548-01), CPSF1 (L-020395-00), RBM4 (L-019588-00), HNRNPL (L-011293-01), YTHDC1 (L-015332-02), and CPSF7 (L-015842-02), and the scrambled ON-TARGETplus non-targeting siRNA pool (D-001810-10) was used as a control.	('SNRPN', 'Gene', (99, 104))	('L-019588-00', 'Var', (230, 241))	('L-011293-01', 'CellLine', 'CVCL:0462', (252, 263))	('PSIP1', 'Gene', '101739', (78, 83))	('DHX9', 'Gene', (141, 145))	('DBR1', 'Gene', (58, 62))	('SNRPN', 'Gene', '20646', (99, 104))	('RSRC1', 'Gene', (182, 187))	('SRPK2', 'Gene', '20817', (120, 125))	('DHX9', 'Gene', '13211', (141, 145))	('L-020395-00', 'Var', (210, 221))	('TRA2B', 'Gene', (161, 166))	('L-015332-02', 'Var', (274, 285))	('PSIP1', 'Gene', (78, 83))	('L-011293-01', 'Var', (252, 263))	('TRA2B', 'Gene', '20462', (161, 166))	('SRPK2', 'Gene', (120, 125))	('CPSF7', 'Gene', '269061', (292, 297))	('DBR1', 'Gene', '83703', (58, 62))	('RBM4', 'Gene', (224, 228))	('CPSF7', 'Gene', (292, 297))	('RBM4', 'Gene', '19653', (224, 228))	('RSRC1', 'Gene', '66880', (182, 187))
162336	32437477	to identify significant splice variants within the HPV-positive and -negative TCGA tumors (407 HPV-negative tumors and 90 HPV-positive tumors) compared with 44 normal samples.	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('tumors', 'Disease', (135, 141))	('tumors', 'Disease', 'MESH:D009369', (83, 89))	('HPV', 'Species', '10566', (51, 54))	('TCGA', 'Gene', (78, 82))	('tumors', 'Disease', 'MESH:D009369', (135, 141))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('HPV-positive tumors', 'Disease', (122, 141))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('HPV', 'Species', '10566', (122, 125))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('HPV-positive tumors', 'Disease', 'MESH:D030361', (122, 141))	('splice variants', 'Var', (24, 39))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('tumors', 'Disease', (108, 114))	('HPV', 'Species', '10566', (95, 98))	('tumors', 'Disease', (83, 89))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))	('tumors', 'Disease', 'MESH:D009369', (108, 114))
162340	32437477	Inducible shRNA expression vectors (SMARTvector Inducible Human CPSF1 hEF1a-TurboGFP shRNA (V3SH11255-02EG91746, V3SH11252-226572495, V3SH11252-227528901, and V3SH11252-227628825) and SMARTvector Inducible Non-targeting hEF1a-TurboGFP (VSC11653) were purchased from Dharmacon (GE Healthcare Dharmacon, Inc., Chicago, IL, USA).	('V3SH11252-227628825', 'Var', (159, 178))	('hEF1a', 'Gene', (220, 225))	('V3SH11252-227528901', 'Var', (134, 153))	('hEF1a', 'Gene', '1917', (220, 225))	('expression vectors', 'Species', '29278', (16, 34))	('hEF1a', 'Gene', '1917', (70, 75))	('hEF1a', 'Gene', (70, 75))	('Human', 'Species', '9606', (58, 63))	('V3SH11255-02EG91746', 'Var', (92, 111))	('V3SH11252-226572495', 'Var', (113, 132))
162369	32437477	Of note, variation of cutoff thresholds yielded similar results (median, and median + 1.0SD (S1 Fig), We used these data to support a hypothesis that aberrant expression of spliceosome genes is associated with ASE expression in HNSCC, and infer that expression of these genes may also drive a malignant phenotype.	('aberrant', 'Var', (150, 158))	('expression', 'Species', '29278', (159, 169))	('HNSCC', 'Disease', (228, 233))	('ASE', 'Disease', (210, 213))	('associated', 'Reg', (194, 204))	('drive', 'Reg', (285, 290))	('expression', 'Species', '29278', (250, 260))	('expression', 'Species', '29278', (214, 224))	('spliceosome genes', 'Gene', (173, 190))
162371	32437477	We selected 13 genes (PRPF6, DBR1, PSIP1, HNRNPL, SNRPN, SRPK2, DHX9, YTHDC1, TRA2B, RSRC1, CPSF7, CPSF1, and RBM4) for further analysis based on high number of mutations and/or CNV, with accompanying expression alterations (Table 1).	('TRA2B', 'Gene', (78, 83))	('PRPF6', 'Gene', (22, 27))	('RBM4', 'Gene', (110, 114))	('DHX9', 'Gene', '13211', (64, 68))	('RBM4', 'Gene', '19653', (110, 114))	('TRA2B', 'Gene', '20462', (78, 83))	('expression', 'MPA', (201, 211))	('RSRC1', 'Gene', '66880', (85, 90))	('alterations', 'Reg', (212, 223))	('SNRPN', 'Gene', (50, 55))	('CPSF1', 'Gene', (99, 104))	('PSIP1', 'Gene', (35, 40))	('SNRPN', 'Gene', '20646', (50, 55))	('DBR1', 'Gene', '83703', (29, 33))	('RSRC1', 'Gene', (85, 90))	('SRPK2', 'Gene', '20817', (57, 62))	('HNRNPL', 'Gene', (42, 48))	('expression', 'Species', '29278', (201, 211))	('SRPK2', 'Gene', (57, 62))	('DHX9', 'Gene', (64, 68))	('YTHDC1', 'Gene', (70, 76))	('DBR1', 'Gene', (29, 33))	('PSIP1', 'Gene', '101739', (35, 40))	('CPSF7', 'Gene', '269061', (92, 97))	('mutations', 'Var', (161, 170))	('CPSF7', 'Gene', (92, 97))
162373	32437477	These genes were determined based on high levels of mutation, copy number variation and expression in 279 head and neck cancer samples in TCGA.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('head and neck cancer', 'Phenotype', 'HP:0012288', (106, 126))	('head and neck cancer', 'Disease', 'MESH:D006258', (106, 126))	('copy number variation', 'Var', (62, 83))	('expression', 'Species', '29278', (88, 98))	('expression', 'MPA', (88, 98))
162383	32437477	Similarly, the proliferation of sh-CPSF1 cells in the presence of doxycycline was limited compared with that of the other cells (Fig 2B), and apoptosis in the sh-CPSF1 cells was significantly increased compared with that in the sh-control cells (Fig 2C).	('doxycycline', 'Var', (66, 77))	('proliferation', 'CPA', (15, 28))	('apoptosis', 'CPA', (142, 151))	('limited', 'NegReg', (82, 89))	('doxycycline', 'Chemical', 'MESH:D004318', (66, 77))	('increased', 'PosReg', (192, 201))
162386	32437477	We examined growth curves to investigate the effect of overexpression on proliferation (Fig 3A) The proliferation of SCC090 cells overexpressing CPSF1 significantly increased compared with that of the empty vector cells but the proliferation increase in SCC17B cells was not significant.	('SCC090', 'CellLine', 'CVCL:1899', (117, 123))	('proliferation', 'CPA', (100, 113))	('overexpressing', 'Var', (130, 144))	('expression', 'Species', '29278', (59, 69))	('CPSF1', 'Gene', (145, 150))	('increased', 'PosReg', (165, 174))
162388	32437477	Tumor growth in the nude mice injected with cells overexpressing CPSF1 was increased compared to empty vector-containing cells (Fig 3B).	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('CPSF1', 'Var', (65, 70))	('nude mice', 'Species', '10090', (20, 29))	('increased', 'PosReg', (75, 84))	('Tumor growth', 'CPA', (0, 12))
162389	32437477	We also found that the tumor volumes in the CPSF1 group were significantly larger than those in the empty vector group (p<0.05) at all time points (Fig 3B).	('CPSF1', 'Var', (44, 49))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('larger', 'PosReg', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('tumor', 'Disease', (23, 28))
162398	32437477	We also investigated the overlapping genes that significantly changed in both knockdown and overexpression of CPSF1 and found that two genes, UBE2C and SZT2 were overlapped (S7 Fig).	('expression', 'Species', '29278', (96, 106))	('overexpression', 'PosReg', (92, 106))	('knockdown', 'Var', (78, 87))	('SZT2', 'Gene', (152, 156))	('UBE2C', 'Gene', '11065', (142, 147))	('UBE2C', 'Gene', (142, 147))	('SZT2', 'Gene', '23334', (152, 156))	('CPSF1', 'Gene', (110, 115))
162399	32437477	We were able to define a specific SZT2 splice junction that were decreased in the CPSF1 knockdown dataset with a reciprocal increase in expression in the CPSF1 overexpression dataset as well as SZT2 splice junctions that were increased in the CPSF1 knockdown dataset and decreased in the CPSF1 overexpression dataset.	('increase', 'PosReg', (124, 132))	('expression', 'MPA', (136, 146))	('expression', 'Species', '29278', (164, 174))	('CPSF1', 'Gene', (82, 87))	('decreased', 'NegReg', (65, 74))	('SZT2', 'Gene', '23334', (34, 38))	('SZT2', 'Gene', (194, 198))	('CPSF1', 'Gene', (154, 159))	('knockdown', 'Var', (88, 97))	('SZT2', 'Gene', '23334', (194, 198))	('SZT2', 'Gene', (34, 38))	('expression', 'Species', '29278', (136, 146))	('expression', 'Species', '29278', (298, 308))
162401	32437477	We validated junctions from the cancer-associated genes UBE2C (chr20:44443109-44444493), and TGFBI (chr5:135390550-135390958) which were confirmed by the Integrative Genomics Viewer (IGV) using raw RNA-Seq data (S8 Fig).	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('cancer', 'Disease', (32, 38))	('chr20:44443109-44444493', 'STRUCTURAL_ABNORMALITY', 'None', (63, 86))	('UBE2C', 'Gene', '11065', (56, 61))	('chr5:135390550-135390958', 'STRUCTURAL_ABNORMALITY', 'None', (100, 124))	('UBE2C', 'Gene', (56, 61))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('TGFBI', 'Gene', '7045', (93, 98))	('chr5:135390550-135390958', 'Var', (100, 124))	('TGFBI', 'Gene', (93, 98))
162404	32437477	The junction expression of UBE2C and TGFBI in RNA-seq were decreased after knockdown of CPSF1.	('CPSF1', 'Gene', (88, 93))	('junction expression', 'MPA', (4, 23))	('expression', 'Species', '29278', (13, 23))	('TGFBI', 'Gene', '7045', (37, 42))	('decreased', 'NegReg', (59, 68))	('TGFBI', 'Gene', (37, 42))	('UBE2C', 'Gene', '11065', (27, 32))	('UBE2C', 'Gene', (27, 32))	('knockdown', 'Var', (75, 84))
162405	32437477	Moreover, to validate the junction expression, several other junctions (MICAL2 (chr11:12248678-12260983), WNK1 (chr12:1006847-1017013), ZMYM2 (chr13:20635364-20638591), ADRM1 (chr20:60879541-60881253) and MAPKAPK5 (chr12:112304035-112306557)) were also selected for RT-PCR.	('chr13:20635364-20638591', 'STRUCTURAL_ABNORMALITY', 'None', (143, 166))	('chr12:112304035-112306557', 'STRUCTURAL_ABNORMALITY', 'None', (215, 240))	('expression', 'Species', '29278', (35, 45))	('chr13:20635364-20638591', 'Var', (143, 166))	('chr12:1006847-1017013', 'STRUCTURAL_ABNORMALITY', 'None', (112, 133))	('chr12:1006847-1017013', 'Var', (112, 133))	('chr20:60879541-60881253', 'STRUCTURAL_ABNORMALITY', 'None', (176, 199))	('chr11:12248678-12260983', 'STRUCTURAL_ABNORMALITY', 'None', (80, 103))	('chr20:60879541-60881253', 'Var', (176, 199))
162414	32437477	In the CPSF1 knockdown dataset, the junction expressions of UBE2C and TGFBI were decreased by knockdown of CPSF1 as expected.	('UBE2C', 'Gene', (60, 65))	('decreased', 'NegReg', (81, 90))	('knockdown', 'Var', (94, 103))	('junction expressions', 'MPA', (36, 56))	('expression', 'Species', '29278', (45, 55))	('CPSF1', 'Gene', (107, 112))	('TGFBI', 'Gene', '7045', (70, 75))	('TGFBI', 'Gene', (70, 75))	('UBE2C', 'Gene', '11065', (60, 65))
162416	32437477	Six significant cancer-related gene sets were found in the CSFI knockdown dataset including two well-known pathways, metastasis and RAS activation (S11A Fig).	('cancer', 'Disease', 'MESH:D009369', (16, 22))	('cancer', 'Disease', (16, 22))	('S11A', 'Var', (148, 152))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('S11A', 'SUBSTITUTION', 'None', (148, 152))	('metastasis', 'CPA', (117, 127))
162417	32437477	Twelve cancer-associated gene sets were identified in the CPSF1 overexpression dataset, including MISHRA_CARCINOMA_ASSOCIATED_FIBROBLAST_UP, RICKMAN HEAD_AND_NECK_CANCER_D, and SMID_BREAST_CANCER_RELAPSE_IN_LUNG_UP (S11B Fig).	('S11B', 'Var', (216, 220))	('expression', 'Species', '29278', (68, 78))	('cancer', 'Disease', 'MESH:D009369', (7, 13))	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('S11B', 'SUBSTITUTION', 'None', (216, 220))	('CPSF1', 'Gene', (58, 63))	('cancer', 'Disease', (7, 13))	('HEAD', 'Disease', (149, 153))	('HEAD', 'Disease', 'MESH:D005271', (149, 153))
162418	32437477	These data confirm that the net effect of CPSF1 dysregulation results in downstream alterations in target gene sets associated with carcinogenesis.	('carcinogenesis', 'Disease', (132, 146))	('target gene sets', 'MPA', (99, 115))	('alterations', 'Reg', (84, 95))	('dysregulation', 'Var', (48, 61))	('CPSF1', 'Gene', (42, 47))	('carcinogenesis', 'Disease', 'MESH:D063646', (132, 146))
162421	32437477	Ron has an isoform called dRON, which is generated by alternative splicing through the skipping of exon 11 and is expressed in breast and colon cancer.	('breast and colon cancer', 'Disease', 'MESH:D001943', (127, 150))	('skipping', 'Var', (87, 95))	('expressed', 'Reg', (114, 123))	('colon cancer', 'Phenotype', 'HP:0003003', (138, 150))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
162430	32437477	We hypothesized that the aberrant expression of CPSF1 changed the ASEs, thereby conveying the ability to induce oncogenesis.	('oncogenesis', 'CPA', (112, 123))	('ASEs', 'MPA', (66, 70))	('aberrant expression', 'Var', (25, 44))	('CPSF1', 'Gene', (48, 53))	('changed', 'Reg', (54, 61))	('induce', 'Reg', (105, 111))	('expression', 'Species', '29278', (34, 44))
162433	32437477	In particular, genes known to be associated with cancer such as LAMC2, UBE2C, AKT2, AKT2, BOK, MAP4, and FANCD2 were noted to be aberrantly spliced, indicating that the aberrant expression of CPSF1 significantly altered the ASEs of oncogenes in each dataset.	('UBE2C', 'Gene', (71, 76))	('altered', 'Reg', (212, 219))	('expression', 'Species', '29278', (178, 188))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('ASEs of', 'MPA', (224, 231))	('CPSF1', 'Gene', (192, 197))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('aberrant expression', 'Var', (169, 188))	('UBE2C', 'Gene', '11065', (71, 76))	('cancer', 'Disease', (49, 55))
162437	32437477	Exon analysis showed that the junctions of TGFBI (chr5:135390550-135390958) is novel and likely change protein function.	('TGFBI', 'Gene', '7045', (43, 48))	('junctions', 'Var', (30, 39))	('protein function', 'MPA', (103, 119))	('TGFBI', 'Gene', (43, 48))	('change', 'Reg', (96, 102))	('chr5:135390550-135390958', 'STRUCTURAL_ABNORMALITY', 'None', (50, 74))
162440	32437477	Here we demonstrated that aberrant expression of CPSF1 induces ASE, but the correlation between activation of CPSF1 and mutation or epigenetic changes including methylation has not been investigated.	('aberrant expression', 'Var', (26, 45))	('expression', 'Species', '29278', (35, 45))	('induces', 'Reg', (55, 62))	('ASE', 'Disease', (63, 66))	('CPSF1', 'Gene', (49, 54))	('CPSF1', 'Gene', (110, 115))
162441	32437477	Further consideration will be needed to explore additiona findings related mutation or epigenetic alterations driving CPSF1 expression.	('epigenetic alterations', 'Var', (87, 109))	('expression', 'Species', '29278', (124, 134))	('CPSF1', 'Gene', (118, 123))
162442	32437477	Finally, we performed ssGSEA analysis in each dataset to determine the gene sets altered by aberrant CPSF1 expression, and defined multiple cancer-associated gene sets in association with CPSF1 dysregulation.	('aberrant', 'Var', (92, 100))	('expression', 'Species', '29278', (107, 117))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('CPSF1', 'Gene', (101, 106))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))
162443	32437477	Therefore, there is a possibility that gene expression changes caused by aberrant CPSF1 are associated with splicing.	('gene expression', 'MPA', (39, 54))	('CPSF1', 'Gene', (82, 87))	('splicing', 'Disease', (108, 116))	('aberrant', 'Var', (73, 81))	('associated', 'Reg', (92, 102))	('expression', 'Species', '29278', (44, 54))
162446	31308744	Silencing of LINC01116 suppresses the development of oral squamous cell carcinoma by up-regulating microRNA-136 to inhibit FN1 Oral squamous cell carcinoma (OSCC), one of the most common cancers worldwide with a high mortality rate, is accompanied by poor prognosis, highlighting the significance of early diagnosis and effective treatment.	('LINC01116', 'Gene', (13, 22))	('microRNA-136', 'Gene', '406927', (99, 111))	('Oral squamous cell carcinoma', 'Disease', (127, 155))	('LINC01116', 'Gene', '375295', (13, 22))	('Silencing', 'Var', (0, 9))	('cancers', 'Disease', 'MESH:D009369', (187, 194))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('microRNA-136', 'Gene', (99, 111))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (132, 155))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (58, 81))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (53, 81))	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('cancers', 'Phenotype', 'HP:0002664', (187, 194))	('inhibit', 'NegReg', (115, 122))	('cancers', 'Disease', (187, 194))	('Oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (127, 155))	('FN1', 'Gene', (123, 126))	('suppresses', 'NegReg', (23, 33))	('oral squamous cell carcinoma', 'Disease', (53, 81))	('up-regulating', 'PosReg', (85, 98))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))
162455	31308744	Moreover, in response to LINC01116 silencing or miR-136 over-expression, OSCC cells exhibited diminished EMT process and inhibited cell viability, invasion, and migration in vitro, coupling with impaired tumorigenicity and LNM in vivo.	('silencing', 'Var', (35, 44))	('miR-136', 'Gene', (48, 55))	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('LINC01116', 'Gene', (25, 34))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('cell viability', 'CPA', (131, 145))	('invasion', 'CPA', (147, 155))	('over-expression', 'PosReg', (56, 71))	('tumor', 'Disease', (204, 209))	('LINC01116', 'Gene', '375295', (25, 34))	('diminished EMT', 'Phenotype', 'HP:0032198', (94, 108))	('impaired', 'NegReg', (195, 203))	('diminished', 'NegReg', (94, 104))	('inhibited', 'NegReg', (121, 130))	('EMT process', 'CPA', (105, 116))
162490	31308744	Tca8113 was cultured in an incubator in F12K medium (21127022, Gibco, Grand Island, NY, USA) in an incubator (thromo3111, Shandong Biobase Chemdrug Co., Ltd., Jinan, Shandong, China) with 5% CO2 in air at 37 C. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) was performed to determine the expression of LINC01116 to select cell lines for subsequent experimentation.	('thromo3111', 'Chemical', '-', (110, 120))	('LINC01116', 'Gene', (327, 336))	('F12K', 'SUBSTITUTION', 'None', (40, 44))	('F12K', 'Var', (40, 44))	('LINC01116', 'Gene', '375295', (327, 336))	('CO2', 'Chemical', 'MESH:D002245', (191, 194))
162506	31308744	The antibodies used in RIP were AGO2 (dilution ratio of 1:50, ab32381, Abcam, Cambridge, MA, USA), which was mixed at room temperature for 30 mins, and IgG (dilution ratio of 1:100, ab109489, Abcam, Cambridge, MA, USA), which was used as a negative control.	('AGO2', 'Gene', '27161', (32, 36))	('ab32381', 'Var', (62, 69))	('RIP', 'Gene', (23, 26))	('RIP', 'Gene', '84268', (23, 26))	('AGO2', 'Gene', (32, 36))
162552	31308744	Kaplan-Meier analysis showed a poor overall survival rate of OSCC patients with high expression of FN1 or LINC01116 (p<0.05) (Figure 1J and K).	('high expression', 'Var', (80, 95))	('FN1', 'Gene', '2335', (99, 102))	('FN1', 'Gene', (99, 102))	('LINC01116', 'Gene', '375295', (106, 115))	('OSCC', 'Disease', (61, 65))	('poor', 'NegReg', (31, 35))	('LINC01116', 'Gene', (106, 115))	('patients', 'Species', '9606', (66, 74))
162560	31308744	As the results of bioinformatics and dual-luciferase reporter gene assay indicated (Figure 3), the presence of a binding relationship between LINC01116 and miR-136 was evident, and miR-136 targeted FN1.	('FN1', 'Gene', '2335', (198, 201))	('targeted', 'Reg', (189, 197))	('LINC01116', 'Gene', (142, 151))	('FN1', 'Gene', (198, 201))	('miR-136', 'Gene', (156, 163))	('LINC01116', 'Gene', '375295', (142, 151))	('miR-136', 'Var', (181, 188))	('binding', 'Interaction', (113, 120))
162571	31308744	Furthermore, CCK-8 assay was utilized to detect changes in cell proliferation brought about by LINC01116 and miR-136.	('LINC01116', 'Gene', '375295', (95, 104))	('cell proliferation', 'CPA', (59, 77))	('miR-136', 'Var', (109, 116))	('LINC01116', 'Gene', (95, 104))
162580	31308744	In comparison to the blank and NC groups, higher expression of miR-136 and E-cadherin while lower expression of LINC01116, FN1, Vimentin, N-cadherin and MMP-9 were noted in the siRNA-LINC01116 and miR-136 mimic groups (p<0.05).	('Vimentin', 'Gene', (128, 136))	('miR-136', 'Protein', (63, 70))	('E-cadherin', 'Gene', (75, 85))	('expression', 'MPA', (49, 59))	('E-cadherin', 'Gene', '999', (75, 85))	('N-cadherin', 'Gene', (138, 148))	('LINC01116', 'Gene', (112, 121))	('N-cadherin', 'Gene', '1000', (138, 148))	('FN1', 'Gene', '2335', (123, 126))	('miR-136', 'Var', (197, 204))	('LINC01116', 'Gene', '375295', (112, 121))	('MMP-9', 'Gene', '4318', (153, 158))	('LINC01116', 'Gene', (183, 192))	('higher', 'PosReg', (42, 48))	('MMP-9', 'Gene', (153, 158))	('LINC01116', 'Gene', '375295', (183, 192))	('FN1', 'Gene', (123, 126))	('Vimentin', 'Gene', '7431', (128, 136))	('lower', 'NegReg', (92, 97))	('expression', 'MPA', (98, 108))
162582	31308744	The aforementioned findings suggested that silencing of LINC01116 or miR-136 over-expression could exert inhibitory effects on EMT in OSCC.	('miR-136', 'Gene', (69, 76))	('LINC01116', 'Gene', (56, 65))	('silencing', 'Var', (43, 52))	('OSCC', 'Disease', (134, 138))	('LINC01116', 'Gene', '375295', (56, 65))	('over-expression', 'PosReg', (77, 92))	('EMT', 'CPA', (127, 130))
162583	31308744	Tumor xenograft experimentation was performed in nude mice to measure cell tumorigenicity and LNM affected by LINC01116 and miR-136.	('nude mice', 'Species', '10090', (49, 58))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('LINC01116', 'Gene', (110, 119))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('LINC01116', 'Gene', '375295', (110, 119))	('miR-136', 'Var', (124, 131))	('tumor', 'Disease', (75, 80))
162598	31308744	Consistent with our results, miR-136 was reported to be significantly under-expressed in OSCC when compared to healthy individuals and patients in remission.	('under-expressed', 'NegReg', (70, 85))	('OSCC', 'Disease', (89, 93))	('patients', 'Species', '9606', (135, 143))	('miR-136', 'Var', (29, 36))
162599	31308744	A study concerning lung adenocarcinoma verified that miR-136 might serve as a tumor-suppressor to EMT as well as prometastatic traits through Smad2 and Smad3, indicating a novel perspective for potential therapeutic approaches.	('miR-136', 'Var', (53, 60))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (19, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (29, 38))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('Smad3', 'Gene', '4088', (152, 157))	('lung adenocarcinoma', 'Disease', (19, 38))	('tumor', 'Disease', (78, 83))	('Smad2', 'Gene', '4087', (142, 147))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (19, 38))	('Smad2', 'Gene', (142, 147))	('Smad3', 'Gene', (152, 157))
162609	31308744	In conclusion, LINC01116 silencing or miR-136 over-expression was demonstrated to inhibit OSCC cell proliferation, migration and invasion, EMT, and LNM via modulation of the LINC01116/miR-136/FN1 axis (Figure 10).	('silencing', 'Var', (25, 34))	('miR-136', 'Gene', (38, 45))	('modulation', 'Reg', (156, 166))	('FN1', 'Gene', '2335', (192, 195))	('FN1', 'Gene', (192, 195))	('LNM', 'CPA', (148, 151))	('LINC01116', 'Gene', '375295', (174, 183))	('inhibit', 'NegReg', (82, 89))	('over-expression', 'PosReg', (46, 61))	('LINC01116', 'Gene', (15, 24))	('EMT', 'CPA', (139, 142))	('LINC01116', 'Gene', '375295', (15, 24))	('OSCC cell proliferation', 'CPA', (90, 113))	('LINC01116', 'Gene', (174, 183))
162656	30281878	The results showed that PIG3 knockdown significantly inhibited the migration and invasion ability of NSCLC cells, and decreased paxillin, phospho-focal adhesion kinase (FAK) and phospho-Src kinase expression, while its overexpression resulted in the opposite effects.	('Src', 'Gene', (186, 189))	('Src', 'Gene', '6714', (186, 189))	('FAK', 'Gene', '5747', (169, 172))	('expression', 'MPA', (197, 207))	('paxillin', 'Gene', '5829', (128, 136))	('inhibited', 'NegReg', (53, 62))	('knockdown', 'Var', (29, 38))	('paxillin', 'Gene', (128, 136))	('phospho-focal adhesion kinase', 'Gene', (138, 167))	('NSCLC', 'Disease', (101, 106))	('PIG3', 'Gene', (24, 28))	('PIG3', 'Gene', '9540', (24, 28))	('NSCLC', 'Disease', 'MESH:D002289', (101, 106))	('phospho-focal adhesion kinase', 'Gene', '5747', (138, 167))	('decreased', 'NegReg', (118, 127))	('FAK', 'Gene', (169, 172))	('NSCLC', 'Phenotype', 'HP:0030358', (101, 106))
162658	30281878	Furthermore, PIG3 silencing sensitized NSCLC cells to FAK inhibitor.	('NSCLC', 'Phenotype', 'HP:0030358', (39, 44))	('sensitized', 'Reg', (28, 38))	('silencing', 'Var', (18, 27))	('PIG3', 'Gene', '9540', (13, 17))	('PIG3', 'Gene', (13, 17))	('FAK', 'Gene', (54, 57))	('FAK', 'Gene', '5747', (54, 57))	('NSCLC', 'Disease', (39, 44))	('NSCLC', 'Disease', 'MESH:D002289', (39, 44))
162674	30281878	To determine the role of PIG3 on NSCLC metastasis, gain and loss of function experiments were performed, showing that PIG3 knockdown significantly inhibited the migration and invasion ability of NSCLC cells, while its overexpression increased the above mentioned abilities.	('NSCLC', 'Phenotype', 'HP:0030358', (33, 38))	('NSCLC', 'Disease', 'MESH:D002289', (195, 200))	('PIG3', 'Gene', '9540', (25, 29))	('men', 'Species', '9606', (83, 86))	('men', 'Species', '9606', (253, 256))	('PIG3', 'Gene', (25, 29))	('NSCLC', 'Phenotype', 'HP:0030358', (195, 200))	('PIG3', 'Gene', (118, 122))	('NSCLC', 'Disease', (33, 38))	('inhibited', 'NegReg', (147, 156))	('knockdown', 'Var', (123, 132))	('NSCLC', 'Disease', 'MESH:D002289', (33, 38))	('NSCLC', 'Disease', (195, 200))	('PIG3', 'Gene', '9540', (118, 122))	('NSCLC metastasis', 'Disease', (33, 49))	('NSCLC metastasis', 'Disease', 'MESH:D009362', (33, 49))
162677	30281878	Moreover, suppression of PIG3 increased the sensitivity of NSCLC cells to the FAK inhibitors PF-573228 and PF-562271.	('sensitivity', 'MPA', (44, 55))	('NSCLC', 'Disease', 'MESH:D002289', (59, 64))	('PF-573228', 'Var', (93, 102))	('suppression', 'NegReg', (10, 21))	('PIG3', 'Gene', '9540', (25, 29))	('FAK', 'Gene', (78, 81))	('FAK', 'Gene', '5747', (78, 81))	('PIG3', 'Gene', (25, 29))	('NSCLC', 'Phenotype', 'HP:0030358', (59, 64))	('PF-573228', 'Chemical', 'MESH:C521108', (93, 102))	('PF-562271', 'Var', (107, 116))	('increased', 'PosReg', (30, 39))	('NSCLC', 'Disease', (59, 64))
162695	30281878	To evaluate if FAK pathway is involved in the mechanism of PIG3-mediated metastasis, FAK inhibitors such as PF-573228 and PF-562271 (Selleckchem, Houston, TX, USA) were used.	('FAK', 'Gene', '5747', (15, 18))	('PF-573228', 'Var', (108, 117))	('FAK', 'Gene', (15, 18))	('FAK', 'Gene', (85, 88))	('PIG3', 'Gene', (59, 63))	('PIG3', 'Gene', '9540', (59, 63))	('FAK', 'Gene', '5747', (85, 88))	('PF-562271', 'Var', (122, 131))	('PF-573228', 'Chemical', 'MESH:C521108', (108, 117))
162715	30281878	Cells were then treated with different concentrations (0, 1.25, 2.5, 5, 10 and 20 mumol/L) of FAK inhibitors PF-573228 or PF-562271.	('PF-573228', 'Chemical', 'MESH:C521108', (109, 118))	('PF-562271', 'Var', (122, 131))	('PF-573228', 'Var', (109, 118))	('FAK', 'Gene', '5747', (94, 97))	('FAK', 'Gene', (94, 97))
162720	30281878	Consistent with our previous study, NSCLC patients with lymph node metastasis had higher PIG3 mRNA expression in comparison with those without (P = .039, Figure 1B).	('NSCLC', 'Phenotype', 'HP:0030358', (36, 41))	('higher', 'PosReg', (82, 88))	('PIG3', 'Gene', '9540', (89, 93))	('PIG3', 'Gene', (89, 93))	('NSCLC', 'Disease', (36, 41))	('patients', 'Species', '9606', (42, 50))	('lymph node metastasis', 'Var', (56, 77))	('NSCLC', 'Disease', 'MESH:D002289', (36, 41))
162723	30281878	In other words, LUAD patients with high PIG3 expression had a higher metastatic risk in comparison with those with low PIG3 expression (P = .001), suggesting that PIG3 might represent an auxiliary diagnostic element for lymph node metastasis in LUAD.	('LUAD', 'Phenotype', 'HP:0030078', (16, 20))	('metastatic', 'CPA', (69, 79))	('PIG3', 'Gene', (119, 123))	('PIG3', 'Gene', '9540', (119, 123))	('patients', 'Species', '9606', (21, 29))	('men', 'Species', '9606', (211, 214))	('LUAD', 'Phenotype', 'HP:0030078', (245, 249))	('LUAD', 'Disease', (245, 249))	('PIG3', 'Gene', '9540', (163, 167))	('PIG3', 'Gene', (163, 167))	('expression', 'Var', (45, 55))	('PIG3', 'Gene', '9540', (40, 44))	('PIG3', 'Gene', (40, 44))
162732	30281878	PIG3 silencing significantly suppressed A549 cell migration to the scratched zone, showing 44% and 28% reduction in relative migration distance by siPIG3 #1 and siPIG3 #2 transfected cells, respectively, compared to corresponding siNC-transfected cells (P < .05, Figure 2B and C).	('transfected', 'Var', (171, 182))	('A549 cell migration to the scratched zone', 'CPA', (40, 81))	('relative migration distance', 'CPA', (116, 143))	('silencing', 'Var', (5, 14))	('PIG3', 'Gene', (0, 4))	('PIG3', 'Gene', '9540', (0, 4))	('PIG3', 'Gene', (149, 153))	('A549', 'CellLine', 'CVCL:0023', (40, 44))	('PIG3', 'Gene', '9540', (163, 167))	('PIG3', 'Gene', (163, 167))	('PIG3', 'Gene', '9540', (149, 153))	('reduction', 'NegReg', (103, 112))	('suppressed', 'NegReg', (29, 39))
162750	30281878	PIG3 silencing reduced the number of these foci as compared with siNC-transfected A549 cells (P < .001, Figure 4A and B).	('silencing', 'Var', (5, 14))	('PIG3', 'Gene', '9540', (0, 4))	('PIG3', 'Gene', (0, 4))	('reduced', 'NegReg', (15, 22))	('A549', 'CellLine', 'CVCL:0023', (82, 86))
162757	30281878	In contrast, PIG3 knockdown suppressed the expression of phosphorylated FAK and phosphorylated Src.	('knockdown', 'Var', (18, 27))	('Src', 'Gene', (95, 98))	('Src', 'Gene', '6714', (95, 98))	('PIG3', 'Gene', '9540', (13, 17))	('PIG3', 'Gene', (13, 17))	('suppressed', 'NegReg', (28, 38))	('phosphorylated', 'Var', (80, 94))	('FAK', 'Gene', '5747', (72, 75))	('phosphorylated', 'MPA', (57, 71))	('expression', 'MPA', (43, 53))	('FAK', 'Gene', (72, 75))
162759	30281878	H1299 cells transfected with PIG3 constructs and treated with the FAK inhibitor PF-573228 at different concentrations (0, 5, and 10 mumol/L) for 24 hours resulted in effective dose-dependent inhibition of FAK phosphorylation (Figure 6A).	('FAK', 'Gene', (205, 208))	('FAK', 'Gene', '5747', (205, 208))	('PF-573228', 'Var', (80, 89))	('inhibition', 'NegReg', (191, 201))	('FAK', 'Gene', (66, 69))	('FAK', 'Gene', '5747', (66, 69))	('PF-573228', 'Chemical', 'MESH:C521108', (80, 89))	('H1299', 'CellLine', 'CVCL:0060', (0, 5))	('PIG3', 'Gene', '9540', (29, 33))	('PIG3', 'Gene', (29, 33))
162762	30281878	Furthermore, we evaluated whether PIG3 silencing might modulate the sensitivity of NSCLC cells to PF-573228 and PF-562271.	('modulate', 'Reg', (55, 63))	('PF-573228', 'Chemical', 'MESH:C521108', (98, 107))	('PF-562271', 'Var', (112, 121))	('NSCLC', 'Disease', (83, 88))	('PIG3', 'Gene', '9540', (34, 38))	('NSCLC', 'Disease', 'MESH:D002289', (83, 88))	('PIG3', 'Gene', (34, 38))	('silencing', 'Var', (39, 48))	('NSCLC', 'Phenotype', 'HP:0030358', (83, 88))
162763	30281878	The cell viability of siPIG3 and siNC-transfected A549 cells was measured by CCK8 assay at 72 hours after PF-573228 and PF-562271 treatment.	('PF-573228', 'Chemical', 'MESH:C521108', (106, 115))	('cell viability', 'CPA', (4, 18))	('PF-562271', 'Var', (120, 129))	('PIG3', 'Gene', '9540', (24, 28))	('PIG3', 'Gene', (24, 28))	('men', 'Species', '9606', (135, 138))	('A549', 'CellLine', 'CVCL:0023', (50, 54))	('PF-573228', 'Var', (106, 115))
162764	30281878	PIG3 silenced cells were more sensitive to PF-573228 and PF-562271 treatment compared with siNC-transfected cells (Figure 6F and Figure S1).	('PF-573228', 'Chemical', 'MESH:C521108', (43, 52))	('PF-562271', 'Var', (57, 66))	('men', 'Species', '9606', (72, 75))	('sensitive', 'MPA', (30, 39))	('PIG3', 'Gene', '9540', (0, 4))	('PIG3', 'Gene', (0, 4))	('PF-573228', 'Var', (43, 52))
162770	30281878	Our previous research showed that PIG3 expression is significantly and negatively correlated with smoking history (P < .05),13 indicating that non-smokers are associated with high PIG3 expression while smokers are associated with low PIG3 expression.	('expression', 'MPA', (185, 195))	('PIG3', 'Gene', '9540', (34, 38))	('PIG3', 'Gene', '9540', (234, 238))	('PIG3', 'Gene', (234, 238))	('high', 'Var', (175, 179))	('PIG3', 'Gene', (34, 38))	('negatively', 'NegReg', (71, 81))	('PIG3', 'Gene', '9540', (180, 184))	('PIG3', 'Gene', (180, 184))
162772	30281878	Because LUAD is typically found in young women who are mostly non-smokers, metastasis can occur in early-stage LUAD due to high PIG3 expression.	('LUAD', 'Phenotype', 'HP:0030078', (111, 115))	('high', 'Var', (123, 127))	('LUAD', 'Phenotype', 'HP:0030078', (8, 12))	('metastasis', 'CPA', (75, 85))	('PIG3', 'Gene', '9540', (128, 132))	('PIG3', 'Gene', (128, 132))	('LUAD', 'Disease', (8, 12))	('women', 'Species', '9606', (41, 46))
162778	30281878	The PIG3 promoter contains tandem repeats of pentanucleotides (TGYCC)n that is known as a p53 binding site.23 The induction of PIG3 by p53 is affected by mutation and post-translational modification of p53.	('p53', 'Gene', (90, 93))	('PIG3', 'Gene', '9540', (127, 131))	('PIG3', 'Gene', (127, 131))	('p53', 'Gene', '7157', (90, 93))	('PIG3', 'Gene', '9540', (4, 8))	('PIG3', 'Gene', (4, 8))	('mutation', 'Var', (154, 162))	('affected', 'Reg', (142, 150))	('p53', 'Gene', (135, 138))	('p53', 'Gene', '7157', (135, 138))	('p53', 'Gene', '7157', (202, 205))	('induction', 'MPA', (114, 123))	('p53', 'Gene', (202, 205))
162779	30281878	p53 mutations are present in many tumors, but different p53 mutants have different regulatory effects on PIG3.	('PIG3', 'Gene', (105, 109))	('p53', 'Gene', (0, 3))	('p53', 'Gene', '7157', (0, 3))	('tumors', 'Disease', (34, 40))	('tumors', 'Disease', 'MESH:D009369', (34, 40))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('p53', 'Gene', (56, 59))	('p53', 'Gene', '7157', (56, 59))	('mutants', 'Var', (60, 67))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('regulatory', 'MPA', (83, 93))	('PIG3', 'Gene', '9540', (105, 109))
162780	30281878	p53 point mutations mostly do not cause loss of transcriptional regulatory function.	('p53', 'Gene', (0, 3))	('point mutations', 'Var', (4, 19))	('transcriptional regulatory function', 'MPA', (48, 83))	('p53', 'Gene', '7157', (0, 3))
162781	30281878	For example, the transcriptional activity of the p53 mutant C277Y isolated from a Ewing's sarcoma did not decrease but increased, and it is accompanied by high constitutive PIG3 expression.24 In contrast, Campomenosi et al.	('men', 'Species', '9606', (210, 213))	('PIG3', 'Gene', '9540', (173, 177))	('PIG3', 'Gene', (173, 177))	('p53', 'Gene', (49, 52))	('mutant C277Y', 'Var', (53, 65))	('p53', 'Gene', '7157', (49, 52))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (82, 97))	('sarcoma', 'Phenotype', 'HP:0100242', (90, 97))	('C277Y', 'Mutation', 'rs763098116', (60, 65))	('C277Y', 'Var', (60, 65))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (82, 97))	("Ewing's sarcoma", 'Disease', (82, 97))
162783	30281878	show that 36% of NSCLC patients have one or more mutations in TP53.26 Eighty-two percent of these mutations were found in the DNA binding region.	('TP53', 'Gene', '7157', (62, 66))	('NSCLC', 'Disease', (17, 22))	('mutations', 'Var', (49, 58))	('patients', 'Species', '9606', (23, 31))	('NSCLC', 'Disease', 'MESH:D002289', (17, 22))	('TP53', 'Gene', (62, 66))	('mutations', 'Var', (98, 107))	('NSCLC', 'Phenotype', 'HP:0030358', (17, 22))
162784	30281878	The 2 most common mutations were V157 and R158 in their patient population.	('patient', 'Species', '9606', (56, 63))	('V157', 'Var', (33, 37))	('R158', 'Var', (42, 46))
162785	30281878	Therefore, regulation of PIG3 expression by p53 mutants in the context of NSCLC is still unclear.	('NSCLC', 'Phenotype', 'HP:0030358', (74, 79))	('PIG3', 'Gene', '9540', (25, 29))	('mutants', 'Var', (48, 55))	('PIG3', 'Gene', (25, 29))	('p53', 'Gene', (44, 47))	('NSCLC', 'Disease', (74, 79))	('p53', 'Gene', '7157', (44, 47))	('NSCLC', 'Disease', 'MESH:D002289', (74, 79))
162792	30281878	found that FAK promoter contains p53 binding sites, and that p53 negatively regulates FAK transcription both in vitro 30 and in vivo.31 FAK conversely inhibits p53-induced apoptotic signaling by interacting with p53 itself32 and suppresses the transcriptional activity of p53 through its interaction with Mdm2, which mediates p53 ubiquitination and degradation.33 There is a feedback loop in FAK-p53 regulation.29 In addition, p53 mutations that are frequently found in cancers can lead to upregulation and overexpression of FAK.34 p53 is inactivated in a significant number of NSCLC patients and contributes to metastatic spread.35 Thus, further investigation is needed to evaluate whether p53 mutation-induced FAK upregulation is mediated by PIG3 in NSCLC.	('p53', 'Gene', '7157', (272, 275))	('NSCLC', 'Disease', 'MESH:D002289', (752, 757))	('p53', 'Gene', '7157', (160, 163))	('upregulation', 'PosReg', (716, 728))	('FAK', 'Gene', (11, 14))	('p53', 'Gene', '7157', (33, 36))	('NSCLC', 'Disease', 'MESH:D002289', (578, 583))	('p53', 'Gene', '7157', (532, 535))	('p53', 'Gene', '7157', (326, 329))	('FAK', 'Gene', (392, 395))	('FAK', 'Gene', '5747', (712, 715))	('cancers', 'Disease', (470, 477))	('cancers', 'Phenotype', 'HP:0002664', (470, 477))	('p53', 'Gene', (272, 275))	('mutation-induced', 'Var', (695, 711))	('NSCLC', 'Disease', (752, 757))	('cancer', 'Phenotype', 'HP:0002664', (470, 476))	('Mdm2', 'Gene', (305, 309))	('p53', 'Gene', '7157', (396, 399))	('p53', 'Gene', '7157', (691, 694))	('p53', 'Gene', (160, 163))	('PIG3', 'Gene', (744, 748))	('p53', 'Gene', (33, 36))	('p53', 'Gene', (326, 329))	('NSCLC', 'Disease', (578, 583))	('patients', 'Species', '9606', (584, 592))	('p53', 'Gene', '7157', (427, 430))	('FAK', 'Gene', '5747', (11, 14))	('NSCLC', 'Phenotype', 'HP:0030358', (752, 757))	('p53', 'Gene', (532, 535))	('FAK', 'Gene', '5747', (392, 395))	('p53', 'Gene', '7157', (212, 215))	('NSCLC', 'Phenotype', 'HP:0030358', (578, 583))	('p53', 'Gene', (396, 399))	('p53', 'Gene', (691, 694))	('FAK', 'Gene', (525, 528))	('p53', 'Gene', (427, 430))	('FAK', 'Gene', (136, 139))	('PIG3', 'Gene', '9540', (744, 748))	('FAK', 'Gene', (86, 89))	('cancers', 'Disease', 'MESH:D009369', (470, 477))	('p53', 'Gene', (212, 215))	('p53', 'Gene', '7157', (61, 64))	('FAK', 'Gene', '5747', (525, 528))	('FAK', 'Gene', '5747', (136, 139))	('Mdm2', 'Gene', '4193', (305, 309))	('FAK', 'Gene', '5747', (86, 89))	('p53', 'Gene', (61, 64))	('FAK', 'Gene', (712, 715))
162797	30281878	PF-04554878 efficacy in NSCLC with KRAS gene mutation is currently under phase II clinical trials.44 In the present study, we demonstrated that a lack of PIG3 significantly sensitized NSCLC cells to PF-573228 and PF-562271, suggesting that both of them might be considered as an effective targeted therapy against PIG3-low expressing NSCLC.	('NSCLC', 'Disease', (24, 29))	('NSCLC', 'Phenotype', 'HP:0030358', (184, 189))	('NSCLC', 'Disease', (334, 339))	('PF-562271', 'Var', (213, 222))	('NSCLC', 'Phenotype', 'HP:0030358', (24, 29))	('NSCLC', 'Phenotype', 'HP:0030358', (334, 339))	('PF-573228', 'Chemical', 'MESH:C521108', (199, 208))	('KRAS', 'Gene', '3845', (35, 39))	('PIG3', 'Gene', (314, 318))	('KRAS', 'Gene', (35, 39))	('PIG3', 'Gene', (154, 158))	('NSCLC', 'Disease', 'MESH:D002289', (184, 189))	('sensitized', 'Reg', (173, 183))	('PIG3', 'Gene', '9540', (314, 318))	('lack', 'Var', (146, 150))	('NSCLC', 'Disease', 'MESH:D002289', (24, 29))	('PIG3', 'Gene', '9540', (154, 158))	('NSCLC', 'Disease', (184, 189))	('NSCLC', 'Disease', 'MESH:D002289', (334, 339))	('PF-573228', 'Var', (199, 208))
162803	30143678	In addition, we showed that niclosamide inhibits the epithelial-to-mesenchymal transition (EMT), migration and colony formation of the OSCC cells, by dose-dependently upregulating E-cadherin and the tissue inhibitor of metalloproteinases 2 (TIMP2) mRNA levels, while reducing the expression levels of vimentin, snail, MMP2 and MMP9 mRNA.	('E-cadherin', 'Gene', '999', (180, 190))	('tissue inhibitor of metalloproteinases 2', 'Gene', '7077', (199, 239))	('tissue inhibitor of metalloproteinases 2', 'Gene', (199, 239))	('TIMP2', 'Gene', '7077', (241, 246))	('niclosamide', 'Chemical', 'MESH:D009534', (28, 39))	('mRNA levels', 'MPA', (248, 259))	('MMP2', 'Gene', (318, 322))	('snail', 'Gene', '6615', (311, 316))	('upregulating', 'PosReg', (167, 179))	('colon', 'Disease', 'MESH:D015179', (111, 116))	('expression levels', 'MPA', (280, 297))	('niclosamide', 'Var', (28, 39))	('colon', 'Disease', (111, 116))	('vimentin', 'Gene', '7431', (301, 309))	('vimentin', 'Gene', (301, 309))	('reducing', 'NegReg', (267, 275))	('migration', 'CPA', (97, 106))	('MMP2', 'Gene', '4313', (318, 322))	('TIMP2', 'Gene', (241, 246))	('MMP9', 'Gene', (327, 331))	('MMP9', 'Gene', '4318', (327, 331))	('snail', 'Gene', (311, 316))	('inhibits', 'NegReg', (40, 48))	('E-cadherin', 'Gene', (180, 190))
162814	30143678	The aberrant activation of the Wnt/beta-catenin signaling is a common theme across several cancer types, including OSCC; more importantly, aberrantly increased Wnt/beta-catenin expression or activity has been implicated in CSCs biology, making it a potential molecular target and promising approach for regulation of the CSCs and prevention of oral CSC - facilitated metastasis and recurrence.	('aberrantly', 'Var', (139, 149))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('activity', 'MPA', (191, 199))	('implicated', 'Reg', (209, 219))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))
162822	30143678	Additionally, we demonstrated that niclosamide inhibits cisplatin-induced oral cancer stem cell enrichment and enhances sensitivity of the ALDH+ OSCC cells to cisplatin treatment.	('oral cancer', 'Disease', 'MESH:D009062', (74, 85))	('sensitivity', 'MPA', (120, 131))	('ALDH', 'Gene', (139, 143))	('oral cancer', 'Disease', (74, 85))	('cisplatin', 'Chemical', 'MESH:D002945', (56, 65))	('niclosamide', 'Chemical', 'MESH:D009534', (35, 46))	('ALDH', 'Gene', '216', (139, 143))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('cisplatin', 'Chemical', 'MESH:D002945', (159, 168))	('niclosamide', 'Var', (35, 46))	('cisplatin-induced', 'CPA', (56, 73))	('enhances', 'PosReg', (111, 119))	('inhibits', 'NegReg', (47, 55))
162859	30143678	Our data showed that the number of tumorspheres formed by the ADLH+ cells were significantly more in number and much larger in size than those by the ALDH- cells (both cell lines: p < 0.01) (Fig.	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('ALDH', 'Gene', (150, 154))	('ADLH+', 'Var', (62, 67))	('tumors', 'Disease', (35, 41))	('ALDH', 'Gene', '216', (150, 154))	('tumors', 'Disease', 'MESH:D009369', (35, 41))	('more', 'PosReg', (93, 97))
162864	30143678	Kaplan-Meier curves for TGCA database, suggested worse overall survival in patients with high versus low WNT/CTNNB1 expression (Supplementary Fig.	('expression', 'MPA', (116, 126))	('overall survival', 'MPA', (55, 71))	('CTNNB1', 'Gene', (109, 115))	('worse', 'NegReg', (49, 54))	('patients', 'Species', '9606', (75, 83))	('high', 'Var', (89, 93))	('CTNNB1', 'Gene', '1499', (109, 115))
162869	30143678	Additionally, we noted that this inhibitory effect of niclosamide was not restricted to the primary tumorspheres alone, but also in the secondary generation; as we recorded a 83.3% (p < 0.01) and 85.8% (p < 0.01) decrease in the number of primary and secondary tumorspheres formed, respectively, in the niclosamide-treated SCC4 cells, compared with the untreated control cells, while for the niclosamide-treated SCC25 cells, the number of primary and secondary tumorspheres formed were reduced by 83.6% (p < 0.01) and 83.3% (p < 0.01), respectively, compared with the untreated control cells (Fig.	('tumor', 'Phenotype', 'HP:0002664', (461, 466))	('tumors', 'Disease', (461, 467))	('tumors', 'Phenotype', 'HP:0002664', (261, 267))	('decrease', 'NegReg', (213, 221))	('reduced', 'NegReg', (486, 493))	('tumor', 'Phenotype', 'HP:0002664', (261, 266))	('tumors', 'Disease', 'MESH:D009369', (461, 467))	('tumors', 'Disease', (261, 267))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('niclosamide', 'Chemical', 'MESH:D009534', (392, 403))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('niclosamide-treated', 'Var', (392, 411))	('niclosamide', 'Chemical', 'MESH:D009534', (303, 314))	('tumors', 'Disease', 'MESH:D009369', (261, 267))	('tumors', 'Disease', (100, 106))	('SCC4', 'Gene', '23383', (323, 327))	('SCC4', 'Gene', (323, 327))	('tumors', 'Phenotype', 'HP:0002664', (461, 467))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('niclosamide', 'Chemical', 'MESH:D009534', (54, 65))
162878	30143678	In addition, our results indicate that the expression levels of vimentin and snail mRNAs were markedly inhibited in SCC4 cells after niclosamide treatment, while conversely, E-cadherin mRNA expression level was enhanced (Fig.	('SCC4', 'Gene', (116, 120))	('niclosamide', 'Var', (133, 144))	('vimentin', 'Gene', '7431', (64, 72))	('E-cadherin', 'Gene', (174, 184))	('inhibited', 'NegReg', (103, 112))	('vimentin', 'Gene', (64, 72))	('snail', 'Gene', (77, 82))	('E-cadherin', 'Gene', '999', (174, 184))	('enhanced', 'PosReg', (211, 219))	('expression levels', 'MPA', (43, 60))	('niclosamide', 'Chemical', 'MESH:D009534', (133, 144))	('SCC4', 'Gene', '23383', (116, 120))	('snail', 'Gene', '6615', (77, 82))
162892	30143678	This data suggests an association between the observed concurrent dowregulation of beta-catenin, reduced expression of beta-catenin downstream target genes and stemness markers, suppressed migration, invasion and colony formation, as well as loss of tumorsphere formation potential in the ALDH+ SCC cells.	('beta-catenin', 'Protein', (83, 95))	('ALDH', 'Gene', '216', (289, 293))	('suppressed', 'NegReg', (178, 188))	('ALDH', 'Gene', (289, 293))	('colon', 'Disease', (213, 218))	('tumors', 'Disease', 'MESH:D009369', (250, 256))	('reduced', 'NegReg', (97, 104))	('tumors', 'Phenotype', 'HP:0002664', (250, 256))	('loss', 'NegReg', (242, 246))	('tumor', 'Phenotype', 'HP:0002664', (250, 255))	('colon', 'Disease', 'MESH:D015179', (213, 218))	('dowregulation', 'Var', (66, 79))	('tumors', 'Disease', (250, 256))	('expression', 'MPA', (105, 115))	('migration', 'CPA', (189, 198))
162918	30143678	For the first time, to the best of our knowledge, we demonstrated that niclosamide potently suppresses the CSCs-like trait, including the migration, invasion, EMT, and colony formation potentials of ALDH -rich OSCC cell lines (Figs 2 and 3).	('migration', 'CPA', (138, 147))	('suppresses', 'NegReg', (92, 102))	('CSCs-like trait', 'CPA', (107, 122))	('EMT', 'CPA', (159, 162))	('colon', 'Disease', (168, 173))	('niclosamide', 'Chemical', 'MESH:D009534', (71, 82))	('ALDH', 'Gene', (199, 203))	('ALDH', 'Gene', '216', (199, 203))	('colon', 'Disease', 'MESH:D015179', (168, 173))	('niclosamide', 'Var', (71, 82))	('invasion', 'CPA', (149, 157))
162920	30143678	However, in this present study, we demonstrated that unlike in the TNBC cells, the anticancer activity of niclosamide against ALDH+ OSCC cells is mediated by the dysregulation of the Wnt/beta-Catenin signaling pathway (Fig.	('beta-Catenin', 'Gene', '1499', (187, 199))	('cancer', 'Disease', (87, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('TNBC', 'Disease', 'None', (67, 71))	('ALDH', 'Gene', (126, 130))	('TNBC', 'Disease', (67, 71))	('niclosamide', 'Chemical', 'MESH:D009534', (106, 117))	('dysregulation', 'Var', (162, 175))	('ALDH', 'Gene', '216', (126, 130))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('beta-Catenin', 'Gene', (187, 199))
162930	30143678	Our data showing that the cells treated with cisplatin alone generated more and larger tumorspheres compared to the untreated control group is corroborated by the findings of Wang and his team, showing that cisplatin enriches the CSCs in non-small cell lung cancer (NSCLC) and that TRIB1/HDAC activity enhances the multidrug resistance of this lung CSCs.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('TRIB1', 'Gene', '10221', (282, 287))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (242, 264))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('multidrug resistance', 'MPA', (315, 335))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (238, 264))	('cisplatin', 'Var', (207, 216))	('cisplatin', 'Chemical', 'MESH:D002945', (207, 216))	('tumors', 'Disease', (87, 93))	('NSCLC', 'Disease', 'MESH:D002289', (266, 271))	('enhances', 'PosReg', (302, 310))	('non-small cell lung cancer', 'Disease', (238, 264))	('TRIB1', 'Gene', (282, 287))	('tumors', 'Disease', 'MESH:D009369', (87, 93))	('NSCLC', 'Disease', (266, 271))	('lung cancer', 'Phenotype', 'HP:0100526', (253, 264))	('cancer', 'Phenotype', 'HP:0002664', (258, 264))	('cisplatin', 'Chemical', 'MESH:D002945', (45, 54))	('NSCLC', 'Phenotype', 'HP:0030358', (266, 271))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (238, 264))
162932	30143678	7), we have provided evidence that the antihelminthic niclosamide inhibits cancer stemness, extracellular matrix remodeling, and metastasis through dysregulation of the Wnt/beta-catenin signaling in OSCC.	('cancer stemness', 'Disease', 'MESH:D009369', (75, 90))	('inhibits', 'NegReg', (66, 74))	('cancer stemness', 'Disease', (75, 90))	('niclosamide', 'Chemical', 'MESH:D009534', (54, 65))	('metastasis', 'CPA', (129, 139))	('dysregulation', 'Var', (148, 161))	('OSCC', 'Disease', (199, 203))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('extracellular matrix remodeling', 'CPA', (92, 123))
162933	30143678	In essence, we showed that niclosamide through the dysregulation of the Wnt/beta-catenin signaling pathway, inhibits the stemness of OSCC cells via the downregulation of pluripotency transcription factors, suppress oral CSC -associated EMT and metastasis by upregulating vimentin and snail, while downregulating E-cadherin, as well as limit EMT-related ECM remodeling by modulation of TIMP2, MMP2 and MMP9.	('snail', 'Gene', '6615', (284, 289))	('downregulation', 'NegReg', (152, 166))	('MMP2', 'Gene', (392, 396))	('upregulating', 'PosReg', (258, 270))	('vimentin', 'Gene', '7431', (271, 279))	('pluripotency transcription factors', 'Protein', (170, 204))	('vimentin', 'Gene', (271, 279))	('niclosamide', 'Chemical', 'MESH:D009534', (27, 38))	('TIMP2', 'Gene', '7077', (385, 390))	('inhibits', 'NegReg', (108, 116))	('snail', 'Gene', (284, 289))	('downregulating', 'NegReg', (297, 311))	('dysregulation', 'Var', (51, 64))	('suppress', 'NegReg', (206, 214))	('stemness of OSCC cells', 'CPA', (121, 143))	('EMT-related ECM remodeling', 'CPA', (341, 367))	('MMP9', 'Gene', (401, 405))	('MMP2', 'Gene', '4313', (392, 396))	('MMP9', 'Gene', '4318', (401, 405))	('limit', 'NegReg', (335, 340))	('Wnt/beta-catenin signaling pathway', 'Pathway', (72, 106))	('E-cadherin', 'Gene', (312, 322))	('E-cadherin', 'Gene', '999', (312, 322))	('TIMP2', 'Gene', (385, 390))
162934	30143678	Similarly, niclosamide suppresses the cisplatin-induced oral CSCs enrichment and enhances the sensitivity of the ALDH+ OSCC cells to cisplatin.	('niclosamide', 'Chemical', 'MESH:D009534', (11, 22))	('ALDH', 'Gene', (113, 117))	('oral CSCs enrichment', 'CPA', (56, 76))	('sensitivity', 'MPA', (94, 105))	('suppresses', 'NegReg', (23, 33))	('niclosamide', 'Var', (11, 22))	('ALDH', 'Gene', '216', (113, 117))	('cisplatin-induced', 'CPA', (38, 55))	('enhances', 'PosReg', (81, 89))	('cisplatin', 'Chemical', 'MESH:D002945', (133, 142))	('cisplatin', 'Chemical', 'MESH:D002945', (38, 47))
162945	34036015	Conclusions A high OX40 level is associated with advanced-stage disease and a poor prognosis, possibly reflecting the immune-exhausted status against OSCC.	('high', 'Var', (14, 18))	('advanced-stage disease', 'Disease', (49, 71))	('associated', 'Reg', (33, 43))	('OX40', 'Gene', '7293', (19, 23))	('OX40', 'Gene', (19, 23))	('advanced-stage disease', 'Disease', 'MESH:D006223', (49, 71))
163015	34036015	Based on the findings, the present study revealed that a high OX40 level is associated with advanced-stage disease and a poor prognosis possibly reflecting the immune-exhausted status against OSCC, especially in the male gender, and buccal mucosa tumors.	('tumor', 'Phenotype', 'HP:0002664', (247, 252))	('buccal mucosa tumors', 'Disease', (233, 253))	('high', 'Var', (57, 61))	('advanced-stage disease', 'Disease', 'MESH:D006223', (92, 114))	('tumors', 'Phenotype', 'HP:0002664', (247, 253))	('OX40', 'Gene', '7293', (62, 66))	('OX40', 'Gene', (62, 66))	('advanced-stage disease', 'Disease', (92, 114))	('buccal mucosa tumors', 'Disease', 'MESH:C565008', (233, 253))
163059	33287876	Proteins with fold change > 2 and adjusted p value < 0.05 were considered to be cancer-associated proteins.	('fold', 'Var', (14, 18))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('Proteins', 'Protein', (0, 8))	('cancer', 'Disease', (80, 86))
163153	33287876	Moreover, we discovered the drugs targeting cyclin-dependent kinases (CDKs), such as CKD2, CKD4 and CKD6, which were overexpressed in several cancer types.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('cyclin', 'Gene', '5111', (44, 50))	('CKD6', 'Var', (100, 104))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('cyclin', 'Gene', (44, 50))	('CDKs', 'Gene', (70, 74))	('CDKs', 'Gene', '1017;1019;1021;51755', (70, 74))	('CKD2', 'Var', (85, 89))	('CKD4', 'Var', (91, 95))	('cancer', 'Disease', (142, 148))
163210	31408573	Gene and miRNA expression profiles of the prostate cancer, which were detected on GPL5188 and GPL8227 platforms (GSE21034 and GSE21036), contained sample-matched information on 28 normal controls and 111 cancer samples (Table S1, Data source).	('cancer', 'Disease', (204, 210))	('cancer', 'Disease', 'MESH:D009369', (204, 210))	('prostate cancer', 'Phenotype', 'HP:0012125', (42, 57))	('miRNA expression', 'MPA', (9, 25))	('GSE21036', 'Var', (126, 134))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('prostate cancer', 'Disease', (42, 57))	('prostate cancer', 'Disease', 'MESH:D011471', (42, 57))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('GSE21034', 'Var', (113, 121))
163291	30417500	In addition, the disruption of FGFR2 in the NF2-KO cell clone suppressed cell proliferation as well as the phosphorylation levels of JNK, c-Jun, and Rb.	('NF2', 'Gene', '4771', (44, 47))	('FGFR2', 'Gene', (31, 36))	('FGFR2', 'Gene', '2263', (31, 36))	('suppressed', 'NegReg', (62, 72))	('phosphorylation levels of JNK', 'MPA', (107, 136))	('cell proliferation', 'CPA', (73, 91))	('NF2', 'Gene', (44, 47))	('c-Jun', 'MPA', (138, 143))	('disruption', 'Var', (17, 27))	('Rb', 'Phenotype', 'HP:0009919', (149, 151))
163296	30417500	Homozygous CDKN2A deletions are a poor prognostic indicator for patients with MPM.14, 15, 16 Deletion of NF2 is associated with increased cell proliferation, invasiveness, spreading, and migration.17, 18 However, the molecular mechanism by which normal mesothelial cells acquire a carcinogenic phenotype in humans is not well understood.	('invasiveness', 'CPA', (158, 170))	('humans', 'Species', '9606', (307, 313))	('patients', 'Species', '9606', (64, 72))	('carcinogenic', 'Disease', 'MESH:D063646', (281, 293))	('Deletion', 'Var', (93, 101))	('carcinogenic', 'Disease', (281, 293))	('NF2', 'Gene', (105, 108))	('deletions', 'Var', (18, 27))	('cell proliferation', 'CPA', (138, 156))	('CDKN2A', 'Gene', (11, 17))	('migration.17', 'CPA', (187, 199))	('CDKN2A', 'Gene', '1029', (11, 17))	('NF2', 'Gene', '4771', (105, 108))
163308	30417500	Two sh oligonucleotides were designed for the target sequence of the hairpin loop of YAP (sh1, 5'-TTCTATGTTCATTCCATCTCC-3'; sh2, 5'-GAGTTCTGACATCCTTAAT-3').	('sh2', 'Var', (124, 127))	('YAP', 'Gene', '10413', (85, 88))	('oligonucleotides', 'Chemical', 'MESH:D009841', (7, 23))	('sh1', 'Var', (90, 93))	('YAP', 'Gene', (85, 88))
163323	30417500	DNA sequencing analysis showed that the NF2-KO cell clones possessed frameshift mutations, which harbored either 200-bp (NF2-KO #1) or 22-bp (NF2-KO #2) deletions in the NF2 gene (Figure 1A).	('NF2', 'Gene', '4771', (170, 173))	('NF2', 'Gene', '4771', (40, 43))	('frameshift mutations', 'Var', (69, 89))	('NF2', 'Gene', (142, 145))	('NF2', 'Gene', (121, 124))	('NF2', 'Gene', (170, 173))	('NF2', 'Gene', (40, 43))	('NF2', 'Gene', '4771', (142, 145))	('NF2', 'Gene', '4771', (121, 124))	('deletions', 'Var', (153, 162))
163330	30417500	We found that rescuing NF2 in the NF2-KO cells significantly suppressed the cell proliferation, colony formation, migration, and wound-healing activities induced by NF2 mutation (Figure 2).	('wound-healing activities', 'CPA', (129, 153))	('suppressed', 'NegReg', (61, 71))	('mutation', 'Var', (169, 177))	('NF2', 'Gene', (34, 37))	('NF2', 'Gene', (165, 168))	('NF2', 'Gene', '4771', (23, 26))	('migration', 'CPA', (114, 123))	('cell proliferation', 'CPA', (76, 94))	('NF2', 'Gene', '4771', (34, 37))	('NF2', 'Gene', '4771', (165, 168))	('colony formation', 'CPA', (96, 112))	('NF2', 'Gene', (23, 26))
163331	30417500	These results suggest that NF2 inactivation enhances the proliferation, clonogenicity, and migration of normal mesothelial cells.	('NF2', 'Gene', (27, 30))	('inactivation', 'Var', (31, 43))	('enhances', 'PosReg', (44, 52))	('NF2', 'Gene', '4771', (27, 30))	('migration of normal mesothelial cells', 'CPA', (91, 128))	('clonogenicity', 'CPA', (72, 85))	('proliferation', 'CPA', (57, 70))
163353	30417500	Additionally, knockout of NF2 in other normal mesothelial cell lines, HOMC-A4, and HOMC-D4 substantially increased the FGFR2 protein levels (Figure 5C).	('NF2', 'Gene', '4771', (26, 29))	('FGFR2', 'Gene', '2263', (119, 124))	('HOMC-A4', 'CellLine', 'CVCL:Z622', (70, 77))	('increased', 'PosReg', (105, 114))	('HOMC-D4', 'Chemical', '-', (83, 90))	('NF2', 'Gene', (26, 29))	('knockout', 'Var', (14, 22))	('FGFR2', 'Gene', (119, 124))
163360	30417500	In addition, disruption of FGFR2 in NF2-KO cells suppressed the NF2 knockout-induced migration and wound healing activities of NF2/FGFR2-DKO cells (Figures 6C,D).	('NF2', 'Gene', (127, 130))	('NF2', 'Gene', '4771', (36, 39))	('FGFR2', 'Gene', (27, 32))	('FGFR2', 'Gene', '2263', (27, 32))	('FGFR2', 'Gene', (131, 136))	('NF2', 'Gene', '4771', (64, 67))	('disruption', 'Var', (13, 23))	('wound healing activities', 'CPA', (99, 123))	('NF2', 'Gene', '4771', (127, 130))	('FGFR2', 'Gene', '2263', (131, 136))	('NF2', 'Gene', (36, 39))	('suppressed', 'NegReg', (49, 59))	('migration', 'CPA', (85, 94))	('NF2', 'Gene', (64, 67))
163363	30417500	These results indicate the possibility that FGFR2 could play important role in the proliferation of mesothelioma cells with NF2 mutation.	('NF2', 'Gene', (124, 127))	('mutation', 'Var', (128, 136))	('mesothelioma', 'Disease', (100, 112))	('mesothelioma', 'Disease', 'MESH:D008654', (100, 112))	('FGFR2', 'Gene', '2263', (44, 49))	('FGFR2', 'Gene', (44, 49))	('NF2', 'Gene', '4771', (124, 127))
163368	30417500	We also found that the phosphorylation level of c-Jun increased after exogenous YAP expression, whereas it decreased following YAP knockdown (Figure S3).	('phosphorylation level', 'MPA', (23, 44))	('YAP', 'Gene', (127, 130))	('exogenous', 'Var', (70, 79))	('YAP', 'Gene', '10413', (80, 83))	('increased', 'PosReg', (54, 63))	('YAP', 'Gene', '10413', (127, 130))	('expression', 'Species', '29278', (84, 94))	('-Jun increased', 'Phenotype', 'HP:0003138', (49, 63))	('YAP', 'Gene', (80, 83))
163371	30417500	Interestingly, the rate of positivity for FGFR2 signals in the NF2-negative MPM tissues (11 of 12 tissues, 91.7%) was significantly higher than that in the NF2-positive MPM tissues (2 of 11 tissues, 18.2%; Figure 8).	('higher', 'PosReg', (132, 138))	('FGFR2', 'Gene', (42, 47))	('FGFR2', 'Gene', '2263', (42, 47))	('positivity', 'Var', (27, 37))	('NF2', 'Gene', (63, 66))	('NF2', 'Gene', (156, 159))	('NF2', 'Gene', '4771', (63, 66))	('NF2', 'Gene', '4771', (156, 159))
163373	30417500	Notably, overall survival in the MPM patients with high FGFR2 expression was shorter than in those with low FGFR2 expression in both datasets (Figure S4B).	('expression', 'Species', '29278', (62, 72))	('FGFR2', 'Gene', (56, 61))	('FGFR2', 'Gene', '2263', (56, 61))	('patients', 'Species', '9606', (37, 45))	('FGFR2', 'Gene', (108, 113))	('overall survival', 'MPA', (9, 25))	('MPM', 'Disease', (33, 36))	('FGFR2', 'Gene', '2263', (108, 113))	('expression', 'Species', '29278', (114, 124))	('high', 'Var', (51, 55))	('shorter', 'NegReg', (77, 84))	('expression', 'Var', (62, 72))
163376	30417500	In this study, we generated NF2 knockout isogenic cell clones using a human immortalized normal mesothelial cell line, MeT-5A, and showed that the loss of NF2 enhances cell proliferation with global gene expression changes.	('NF2', 'Gene', (155, 158))	('cell proliferation', 'CPA', (168, 186))	('NF2', 'Gene', (28, 31))	('human', 'Species', '9606', (70, 75))	('NF2', 'Gene', '4771', (155, 158))	('expression', 'Species', '29278', (204, 214))	('NF2', 'Gene', '4771', (28, 31))	('enhances', 'PosReg', (159, 167))	('loss', 'Var', (147, 151))
163378	30417500	Furthermore, we showed that the loss of FGFR2 attenuates the proliferation of NF2-KO MeT-5A cells.	('NF2', 'Gene', '4771', (78, 81))	('loss', 'Var', (32, 36))	('attenuates', 'NegReg', (46, 56))	('FGFR2', 'Gene', (40, 45))	('FGFR2', 'Gene', '2263', (40, 45))	('proliferation', 'CPA', (61, 74))	('NF2', 'Gene', (78, 81))
163379	30417500	Our cellular model presented here is the first to reveal the gene expression profile under complete disruption of NF2 in human normal mesothelial cells.	('NF2', 'Gene', (114, 117))	('expression', 'Species', '29278', (66, 76))	('human', 'Species', '9606', (121, 126))	('disruption', 'Var', (100, 110))	('NF2', 'Gene', '4771', (114, 117))
163386	30417500	In other normal mesothelial cell lines HOMC-A4 and HOMC-D4, we also found that knockout of NF2 causes a substantial increase in FGFR2 protein level.	('HOMC-A4', 'CellLine', 'CVCL:Z622', (39, 46))	('FGFR2', 'Gene', (128, 133))	('FGFR2', 'Gene', '2263', (128, 133))	('NF2', 'Gene', (91, 94))	('increase', 'PosReg', (116, 124))	('HOMC-D4', 'Chemical', '-', (51, 58))	('knockout', 'Var', (79, 87))	('NF2', 'Gene', '4771', (91, 94))
163389	30417500	Furthermore, knockout of FGFR2 in NF2-KO cells led to retardation of cell growth, accompanied by decreases in the phosphorylation of JNK, c-Jun, and Rb, as well as the expression of CDK2.	('expression', 'Species', '29278', (168, 178))	('NF2', 'Gene', (34, 37))	('expression', 'MPA', (168, 178))	('FGFR2', 'Gene', (25, 30))	('FGFR2', 'Gene', '2263', (25, 30))	('knockout', 'Var', (13, 21))	('retardation', 'Disease', (54, 65))	('decreases', 'NegReg', (97, 106))	('NF2', 'Gene', '4771', (34, 37))	('retardation', 'Disease', 'MESH:D008607', (54, 65))	('CDK2', 'Protein', (182, 186))	('c-Jun', 'MPA', (138, 143))	('phosphorylation', 'MPA', (114, 129))	('Rb', 'Phenotype', 'HP:0009919', (149, 151))	('JNK', 'MPA', (133, 136))	('cell growth', 'CPA', (69, 80))
163391	30417500	A transcription factor in the downstream of NF2 signaling, YAP/TAZ, was reported to be critical for the carcinogenesis of mesothelial cells with NF2 loss.30, 31 Our previous study reported c-Jun amplification in a panel of MPM tumors.42 In this study, we observed that overexpression of constitutively active YAP mutant does not alter the FGFR2 protein level in the NF2-KO clone, whereas it increases the phosphorylation levels of c-Jun and cyclin D1.	('YAP', 'Gene', (309, 312))	('NF2', 'Gene', '4771', (366, 369))	('mutant', 'Var', (313, 319))	('FGFR2', 'Gene', '2263', (339, 344))	('NF2', 'Gene', (366, 369))	('increases', 'PosReg', (391, 400))	('MPM tumors', 'Disease', 'MESH:D009369', (223, 233))	('expression', 'Species', '29278', (273, 283))	('YAP', 'Gene', '10413', (309, 312))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))	('NF2', 'Gene', '4771', (44, 47))	('YAP', 'Gene', (59, 62))	('MPM tumors', 'Disease', (223, 233))	('NF2', 'Gene', (44, 47))	('NF2', 'Gene', '4771', (145, 148))	('carcinogenesis', 'Disease', (104, 118))	('NF2', 'Gene', (145, 148))	('carcinogenesis', 'Disease', 'MESH:D063646', (104, 118))	('YAP', 'Gene', '10413', (59, 62))	('FGFR2', 'Gene', (339, 344))
163394	30417500	Further studies are necessary to clarify the molecular mechanism by which loss of NF2 increases FGFR2 expression in mesothelial cells.	('FGFR2', 'Gene', (96, 101))	('expression', 'Species', '29278', (102, 112))	('NF2', 'Gene', '4771', (82, 85))	('expression', 'MPA', (102, 112))	('FGFR2', 'Gene', '2263', (96, 101))	('increases', 'PosReg', (86, 95))	('loss', 'Var', (74, 78))	('NF2', 'Gene', (82, 85))
163396	30417500	The CRISPR/Cas9-mediated loss of NF2 enhanced the proliferation of cells and the expression of FGFR2, the subsequent disruption of which significantly suppressed the phosphorylation of cell cycle-related molecules as well as enhanced the proliferation of the cells.	('NF2', 'Gene', '4771', (33, 36))	('cell', 'Protein', (185, 189))	('FGFR2', 'Gene', '2263', (95, 100))	('loss', 'Var', (25, 29))	('expression', 'Species', '29278', (81, 91))	('suppressed', 'NegReg', (151, 161))	('proliferation of cells', 'CPA', (50, 72))	('NF2', 'Gene', (33, 36))	('disruption', 'Var', (117, 127))	('enhanced', 'PosReg', (225, 233))	('phosphorylation', 'MPA', (166, 181))	('enhanced', 'PosReg', (37, 45))	('FGFR2', 'Gene', (95, 100))	('expression', 'MPA', (81, 91))	('proliferation of the cells', 'CPA', (238, 264))
163405	29358879	Core tip: Competing endogenous RNAs (ceRNAs) may play a critical role in tumourigenesis, and perturbations to ceRNA networks would result in the progression of oesophageal squamous cell carcinoma (ESCC).	('result in', 'Reg', (131, 140))	('oesophageal squamous cell carcinoma', 'Disease', 'MESH:D002294', (160, 195))	('carcinoma', 'Phenotype', 'HP:0030731', (186, 195))	('oesophageal squamous cell carcinoma', 'Disease', (160, 195))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (172, 195))	('perturbations', 'Var', (93, 106))
163412	29358879	Tumourigenesis and cancer development have been closely associated with the aberrant expression of protein coding mRNAs and non-coding RNAs.	('cancer', 'Disease', 'MESH:D009369', (19, 25))	('mRNAs', 'Gene', (114, 119))	('cancer', 'Disease', (19, 25))	('associated', 'Reg', (56, 66))	('aberrant', 'Var', (76, 84))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('Tumourigenesis', 'CPA', (0, 14))
163413	29358879	Approximately 98% of the human genome are non-coding RNAs, suggesting their promising effects on physiological and pathological processes.	('effects', 'Reg', (86, 93))	('non-coding RNAs', 'Var', (42, 57))	('human', 'Species', '9606', (25, 30))
163416	29358879	With these information, a synthetic analysis could be performed on the association between molecular alterations and certain cancer type.	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('molecular alterations', 'Var', (91, 112))	('association', 'Interaction', (71, 82))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))
163418	29358879	The expression data of miRNAs and mRNAs in 101 oesophageal cancer patients were collected from the National Center for Biotechnology Information Gene Expression Omnibus (NCBI) with login numbers of GSE45670 (38 patients, =GSE45670), GSE26886 (28 patients, =GSE26886), GSE17351 (10 samples, =GSE17351), GSE55856 (216 patients, =GSE55856), and GSE66274 (60 patients, =GSE66274).	('oesophageal cancer', 'Disease', 'MESH:D009369', (47, 65))	('GSE45670', 'Var', (198, 206))	('patients', 'Species', '9606', (355, 363))	('patients', 'Species', '9606', (211, 219))	('patients', 'Species', '9606', (246, 254))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('GSE66274', 'Var', (342, 350))	('patients', 'Species', '9606', (316, 324))	('oesophageal cancer', 'Disease', (47, 65))	('patients', 'Species', '9606', (66, 74))
163432	29358879	However, the expression levels were down-regulated for has-miR-30a-3p, has-miR-150-5p, and has-miR-133a-3p.	('expression levels', 'MPA', (13, 30))	('miR-150', 'Gene', (75, 82))	('miR-150', 'Gene', '406942', (75, 82))	('has-miR-30a-3p', 'Var', (55, 69))	('has-miR-133a-3p', 'Var', (91, 106))	('down-regulated', 'NegReg', (36, 50))
163435	29358879	Among the six significant mRNAs, the overall survival was negatively related to five mRNA transcripts (STC2, SLC6A1, MMP12, EPCAM, and EPB411L4B) (P < 0.05) while positively associated with the remaining mRNA transcript (LAMC2) (P < 0.05) (Figure 7A-F).	('positively', 'PosReg', (163, 173))	('STC2', 'Gene', (103, 107))	('EPCAM', 'Gene', '4072', (124, 129))	('MMP12', 'Gene', (117, 122))	('LAMC2', 'Gene', (221, 226))	('LAMC2', 'Gene', '3918', (221, 226))	('EPB411L4B', 'Var', (135, 144))	('MMP12', 'Gene', '4321', (117, 122))	('SLC6A1', 'Gene', '6529', (109, 115))	('SLC6A1', 'Gene', (109, 115))	('STC2', 'Gene', '8614', (103, 107))	('negatively', 'NegReg', (58, 68))	('EPCAM', 'Gene', (124, 129))
163463	29358879	However, the levels of has-miR-30a-3p, has-miR-150-5p, and has-miR-133a-3p were down-regulated.	('has-miR-133a-3p', 'Var', (59, 74))	('miR-150', 'Gene', (43, 50))	('has-miR-30a-3p', 'Var', (23, 37))	('miR-150', 'Gene', '406942', (43, 50))	('down-regulated', 'NegReg', (80, 94))	('levels', 'MPA', (13, 19))
163472	27693541	The cumulative incidence of any, distant, and locoregional recurrence as well as lung cancer-specific death were significantly higher in patients with STAS compared to those without STAS, whereas there was no statistically significant difference in OS.	('lung cancer', 'Disease', (81, 92))	('locoregional recurrence', 'CPA', (46, 69))	('distant', 'CPA', (33, 40))	('death', 'Disease', 'MESH:D003643', (102, 107))	('death', 'Disease', (102, 107))	('lung cancer', 'Phenotype', 'HP:0100526', (81, 92))	('STAS', 'Var', (151, 155))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('patients', 'Species', '9606', (137, 145))	('lung cancer', 'Disease', 'MESH:D008175', (81, 92))	('higher', 'PosReg', (127, 133))	('any', 'CPA', (28, 31))
163486	27693541	Warth A. et al examined tumors of all stages and showed STAS was associated with both significantly reduced overall survival (OS) and disease-free survival (DFS) for all stages of adenocarcinoma.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('disease-free survival', 'CPA', (134, 155))	('tumors', 'Disease', (24, 30))	('overall', 'MPA', (108, 115))	('tumors', 'Disease', 'MESH:D009369', (24, 30))	('reduced', 'NegReg', (100, 107))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('adenocarcinoma', 'Disease', (180, 194))	('STAS', 'Var', (56, 60))	('carcinoma', 'Phenotype', 'HP:0030731', (185, 194))	('adenocarcinoma', 'Disease', 'MESH:D000230', (180, 194))
163488	27693541	STAS-like "aerogenous spread" was also described by Jin Y, et al in ROS1 rearranged lung adenocarcinomas associated with decreased E-cadherin expression and poor disease free survival.	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (84, 103))	('ROS1', 'Gene', '6098', (68, 72))	('E-cadherin', 'Gene', '999', (131, 141))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('STAS-like', 'Disease', (0, 9))	('carcinomas', 'Phenotype', 'HP:0030731', (94, 104))	('lung adenocarcinomas', 'Disease', (84, 104))	('decreased', 'NegReg', (121, 130))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (84, 104))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (84, 104))	('expression', 'MPA', (142, 152))	('E-cadherin', 'Gene', (131, 141))	('ROS1', 'Gene', (68, 72))	('rearranged', 'Var', (73, 83))
163547	27693541	In stage II-III (Figure 2), patients with STAS had higher incidence of any and distant recurrence and lung cancer-specific death compared to those without STAS (p=0.021, p=0.014, and p=0.011, respectively) but there was no statistically significant difference in CIR for locoregional recurrence.	('lung cancer', 'Phenotype', 'HP:0100526', (102, 113))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('lung cancer', 'Disease', (102, 113))	('death', 'Disease', 'MESH:D003643', (123, 128))	('death', 'Disease', (123, 128))	('STAS', 'Var', (42, 46))	('lung cancer', 'Disease', 'MESH:D008175', (102, 113))	('higher', 'PosReg', (51, 57))	('patients', 'Species', '9606', (28, 36))
163548	27693541	In stage I (Supplementary Figure 2), patients with STAS had higher incidence of locoregional recurrence and lung cancer-specific death compared to those without STAS (p=0.028 and p=0.027, respectively) but there were no statistically significant differences in CIR for any recurrence and distant recurrence.	('death', 'Disease', 'MESH:D003643', (129, 134))	('death', 'Disease', (129, 134))	('lung cancer', 'Disease', 'MESH:D008175', (108, 119))	('higher', 'PosReg', (60, 66))	('patients', 'Species', '9606', (37, 45))	('STAS', 'Var', (51, 55))	('lung cancer', 'Disease', (108, 119))	('lung cancer', 'Phenotype', 'HP:0100526', (108, 119))	('locoregional recurrence', 'CPA', (80, 103))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
163550	27693541	In multivariable Cox model for OS, higher age, Ki-67 >=20%, and presence of single cell invasion were independent risk factors for worse OS (p<0.001, p=0.040, and p=0.016) but STAS was not (p=0.4).	('Cox', 'Gene', '1351', (17, 20))	('Ki', 'Chemical', 'MESH:C066186', (47, 49))	('Cox', 'Gene', (17, 20))	('worse OS', 'Disease', (131, 139))	('>=20', 'Var', (53, 57))	('Ki-67', 'Var', (47, 52))
163554	27693541	We found STAS in lung SCC was associated with p-stage, lymphatic and vascular invasion, necrosis, larger nuclear diameter, increased mitoses and high Ki-67 labeling index.	('associated', 'Reg', (30, 40))	('increased', 'PosReg', (123, 132))	('necrosis', 'Disease', 'MESH:D009336', (88, 96))	('p-stage', 'CPA', (46, 53))	('SCC', 'Gene', (22, 25))	('mitoses', 'CPA', (133, 140))	('larger nuclear diameter', 'CPA', (98, 121))	('necrosis', 'Disease', (88, 96))	('SCC', 'Gene', '6317', (22, 25))	('Ki', 'Chemical', 'MESH:C066186', (150, 152))	('STAS', 'Var', (9, 13))
163593	33846775	A minority of oesophageal cancers belong to the spectrum of Lynch syndrome-associated cancers and are characterized by microsatellite instability (MSI).	('Lynch syndrome-associated cancers', 'Disease', (60, 93))	('cancers', 'Phenotype', 'HP:0002664', (26, 33))	('cancers', 'Disease', 'MESH:D009369', (26, 33))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('cancers', 'Disease', (26, 33))	('oesophageal cancer', 'Disease', (14, 32))	('cancers', 'Phenotype', 'HP:0002664', (86, 93))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('oesophageal cancer', 'Disease', 'MESH:D009369', (14, 32))	('cancers', 'Disease', (86, 93))	('microsatellite instability', 'Var', (119, 145))	('cancers', 'Disease', 'MESH:D009369', (86, 93))	('Lynch syndrome-associated cancers', 'Disease', 'MESH:D009369', (60, 93))
163615	33846775	The identification and selection of robust biomarkers predicting clinical benefit are also mandatory before commencing immunotherapy treatment, as even though generally well-tolerated compared to standard therapies, immunotherapy is associated occasionally with severe toxic side-effects, such as cutaneous, gastrointestinal, endocrine and hepatic toxicity.	('cutaneous', 'Disease', (297, 306))	('gastrointestinal', 'Disease', (308, 324))	('hepatic toxicity', 'Disease', 'MESH:D056486', (340, 356))	('endocrine', 'Disease', (326, 335))	('hepatic toxicity', 'Disease', (340, 356))	('immunotherapy', 'Var', (216, 229))
163618	33846775	In general, tumours with MSI have a higher mutation rate, which increases the probability for the immune system to recognize tumour cells.	('tumours', 'Disease', 'MESH:D009369', (12, 19))	('tumour', 'Disease', 'MESH:D009369', (12, 18))	('tumour', 'Disease', (12, 18))	('tumours', 'Disease', (12, 19))	('mutation rate', 'MPA', (43, 56))	('tumour', 'Phenotype', 'HP:0002664', (125, 131))	('tumour', 'Phenotype', 'HP:0002664', (12, 18))	('tumour', 'Disease', 'MESH:D009369', (125, 131))	('MSI', 'Var', (25, 28))	('tumours', 'Phenotype', 'HP:0002664', (12, 19))	('tumour', 'Disease', (125, 131))	('increases', 'PosReg', (64, 73))
163659	33846775	Currently, combination therapies with anti-PD1 and anti-CTLA-4 antibodies are forthcoming.	('CTLA-4', 'Gene', '1493', (56, 62))	('anti-PD1', 'Var', (38, 46))	('CTLA-4', 'Gene', (56, 62))
163668	33846775	In all cases, the expanded or modified T-cells exert an improved tumour-specific immunity.	('tumour', 'Phenotype', 'HP:0002664', (65, 71))	('improved', 'PosReg', (56, 64))	('modified', 'Var', (30, 38))	('tumour', 'Disease', 'MESH:D009369', (65, 71))	('tumour', 'Disease', (65, 71))
163699	33846775	In a previous study, the 5-year relapse-free survival of oesophageal cancer patients was 44.6% in patients that received the vaccination compared to the ones that did not receive the vaccination (31.6% relapse-free survival).	('oesophageal cancer', 'Disease', (57, 75))	('patients', 'Species', '9606', (76, 84))	('vaccination', 'Var', (125, 136))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('patients', 'Species', '9606', (98, 106))	('oesophageal cancer', 'Disease', 'MESH:D009369', (57, 75))
163703	33846775	In an exploratory study based on 15 patients with oesophageal tumours, an increased immune response in tumour tissue was observed following vaccination with S-588410.	('S-588410', 'Var', (157, 165))	('oesophageal tumours', 'Disease', (50, 69))	('patients', 'Species', '9606', (36, 44))	('tumour', 'Phenotype', 'HP:0002664', (62, 68))	('immune response', 'MPA', (84, 99))	('oesophageal tumours', 'Disease', 'MESH:D009369', (50, 69))	('tumour', 'Phenotype', 'HP:0002664', (103, 109))	('tumour', 'Disease', 'MESH:D009369', (103, 109))	('increased', 'PosReg', (74, 83))	('tumour', 'Disease', 'MESH:D009369', (62, 68))	('tumours', 'Phenotype', 'HP:0002664', (62, 69))	('tumour', 'Disease', (62, 68))	('tumour', 'Disease', (103, 109))	('S-588410', 'Chemical', '-', (157, 165))
163704	33846775	Following a median of 5 injections of S-588410, peptide-specific CD8+ T-cells for all peptides included in this vaccination were induced in all patients.	('S-588410', 'Chemical', '-', (38, 46))	('S-588410', 'Var', (38, 46))	('CD8', 'Gene', (65, 68))	('patients', 'Species', '9606', (144, 152))	('CD8', 'Gene', '925', (65, 68))
163722	33846775	Furthermore, it is well-established that immunotherapies are resulting in an increased tumour burden and/or emergence of new tumour lesions in the short-term.	('tumour', 'Disease', (87, 93))	('tumour', 'Phenotype', 'HP:0002664', (125, 131))	('tumour', 'Disease', 'MESH:D009369', (87, 93))	('tumour lesions', 'Disease', (125, 139))	('tumour lesions', 'Disease', 'MESH:D009369', (125, 139))	('tumour', 'Phenotype', 'HP:0002664', (87, 93))	('tumour', 'Disease', 'MESH:D009369', (125, 131))	('increased', 'PosReg', (77, 86))	('tumour', 'Disease', (125, 131))	('immunotherapies', 'Var', (41, 56))
163827	32648580	In breast invasive carcinoma (BRCA) and liver hepatocellular carcinoma (LIHC), high YIF1B expression correlated with a poor disease-free interval (DFI), indicating a role in malignancy progression.	('liver hepatocellular carcinoma', 'Disease', 'MESH:D006528', (40, 70))	('malignancy', 'Disease', 'MESH:D009369', (174, 184))	('BRCA', 'Gene', (30, 34))	('malignancy', 'Disease', (174, 184))	('YIF1B', 'Gene', '90522', (84, 89))	('breast invasive carcinoma', 'Phenotype', 'HP:0003002', (3, 28))	('carcinoma', 'Phenotype', 'HP:0030731', (19, 28))	('breast invasive carcinoma', 'Disease', (3, 28))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (46, 70))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('YIF1B', 'Gene', (84, 89))	('expression', 'MPA', (90, 100))	('high', 'Var', (79, 83))	('disease-free', 'MPA', (124, 136))	('liver hepatocellular carcinoma', 'Disease', (40, 70))	('breast invasive carcinoma', 'Disease', 'MESH:D001943', (3, 28))	('BRCA', 'Phenotype', 'HP:0003002', (30, 34))	('BRCA', 'Gene', '672', (30, 34))
163867	32648580	The following survival analyses, using patient data dichotomized for the median expression value in each cancer type (Figure 3), show that survival differences were all significant in OS-related cancer types, and that patients with high expression of YIF1B had worse outcomes (Figure 3).	('significant', 'Reg', (169, 180))	('patient', 'Species', '9606', (39, 46))	('YIF1B', 'Gene', (251, 256))	('patient', 'Species', '9606', (218, 225))	('patients', 'Species', '9606', (218, 226))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('cancer', 'Disease', (195, 201))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('YIF1B', 'Gene', '90522', (251, 256))	('high expression', 'Var', (232, 247))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
163871	32648580	In the following survival analysis, cancer types with high YIF1B expression again exhibited a worse prognosis in comparison with the low expression groups (Figure 5).	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('YIF1B', 'Gene', (59, 64))	('high', 'Var', (54, 58))	('cancer', 'Disease', (36, 42))	('YIF1B', 'Gene', '90522', (59, 64))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))
163881	32648580	Their corresponding linear regression graphs show that high YIF1B expression is linked to a possible increased infiltration level by immune cells.	('infiltration level by immune cells', 'MPA', (111, 145))	('increased', 'PosReg', (101, 110))	('expression', 'MPA', (66, 76))	('YIF1B', 'Gene', '90522', (60, 65))	('high', 'Var', (55, 59))	('YIF1B', 'Gene', (60, 65))
163891	32648580	The coefficient values would indicate that YIF1B expression positively correlates with high mutation status in COAD, BLCA and LIHC, but low mutation in THYM, LAML and ESCA (particularly THYM).	('COAD', 'Disease', 'MESH:D029424', (111, 115))	('THYM', 'Phenotype', 'HP:0100522', (152, 156))	('YIF1B', 'Gene', '90522', (43, 48))	('COAD', 'Disease', (111, 115))	('high mutation status', 'Var', (87, 107))	('THYM', 'Phenotype', 'HP:0100522', (186, 190))	('YIF1B', 'Gene', (43, 48))	('ESCA', 'Phenotype', 'HP:0011459', (167, 171))
163897	32648580	Having established a correlation between YIF1B expression and the mutation indicators, TMB and MSI, further investigation of links between YIF1B expression and tumorigenesis mechanisms was warranted, in particular a relationship with MMR defects and methylation of specific tumor suppression genes.	('MMR defects', 'Disease', (234, 245))	('MMR defects', 'Disease', 'MESH:C536928', (234, 245))	('YIF1B', 'Gene', '90522', (139, 144))	('YIF1B', 'Gene', (41, 46))	('tumor', 'Disease', 'MESH:D009369', (274, 279))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('TMB', 'Chemical', '-', (87, 90))	('YIF1B', 'Gene', (139, 144))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('tumor', 'Phenotype', 'HP:0002664', (274, 279))	('tumor', 'Disease', (274, 279))	('tumor', 'Disease', (160, 165))	('methylation', 'Var', (250, 261))	('YIF1B', 'Gene', '90522', (41, 46))
163907	32648580	In follow-on survival analysis, after dichotomizing patients according to their mean YIF1B expression value, patients in the high expression group had worse OS, which is consistent with in the results obtained using TCGA data (Supplementary Figure S1).	('YIF1B', 'Gene', (85, 90))	('patients', 'Species', '9606', (109, 117))	('YIF1B', 'Gene', '90522', (85, 90))	('high', 'Var', (125, 129))	('patients', 'Species', '9606', (52, 60))
163912	32648580	A correlation with disease progression rates was identified for LIHC and BRCA, for which patients with high YIF1B expression suffered from early recurrence of tumor.	('BRCA', 'Phenotype', 'HP:0003002', (73, 77))	('BRCA', 'Gene', '672', (73, 77))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('BRCA', 'Gene', (73, 77))	('LIHC', 'Disease', (64, 68))	('tumor', 'Disease', (159, 164))	('YIF1B', 'Gene', (108, 113))	('patients', 'Species', '9606', (89, 97))	('high', 'Var', (103, 107))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('expression', 'MPA', (114, 124))	('YIF1B', 'Gene', '90522', (108, 113))
163914	32648580	Previous research has shown that YIF1B is involved in anterograde vesicle traffic in cells, transporting 'cargo' proteins (including the serotonin receptor HTR1A) from the endoplasmic reticulum to the cell membrane via the Golgi apparatus; such cell membrane localization being accelerated upon knocking out YIF1B in HeLa cells.	('YIF1B', 'Gene', '90522', (33, 38))	('YIF1B', 'Gene', '90522', (308, 313))	("transporting 'cargo' proteins", 'MPA', (92, 121))	('serotonin', 'Chemical', 'MESH:D012701', (137, 146))	('knocking out', 'Var', (295, 307))	('YIF1B', 'Gene', (33, 38))	('HTR1A', 'Gene', '3350', (156, 161))	('YIF1B', 'Gene', (308, 313))	('accelerated', 'PosReg', (278, 289))	('HeLa', 'CellLine', 'CVCL:0030', (317, 321))	('HTR1A', 'Gene', (156, 161))
163917	32648580	A link to signaling pathways via HTR receptors is the likely reason for association of YIF1B mutations with functional changes to specific proteins in neuronal cells, causing encephalopathy, epilepsy and movement disorder.	('HTR', 'Gene', (33, 36))	('movement disorder', 'Phenotype', 'HP:0100022', (204, 221))	('mutations', 'Var', (93, 102))	('specific proteins', 'MPA', (130, 147))	('YIF1B', 'Gene', (87, 92))	('link', 'Reg', (2, 6))	('association', 'Interaction', (72, 83))	('epilepsy and movement disorder', 'Disease', 'MESH:D004827', (191, 221))	('encephalopathy', 'Disease', 'MESH:D001927', (175, 189))	('epilepsy', 'Phenotype', 'HP:0001250', (191, 199))	('HTR', 'Gene', '7012', (33, 36))	('encephalopathy', 'Phenotype', 'HP:0001298', (175, 189))	('YIF1B', 'Gene', '90522', (87, 92))	('causing', 'Reg', (167, 174))	('encephalopathy', 'Disease', (175, 189))
163932	32648580	Furthermore, COAD patients with high MSI have demonstrated better checkpoint inhibitor responses and survival in both low and high clinical stages.	('COAD', 'Disease', (13, 17))	('high MSI', 'Var', (32, 40))	('better', 'PosReg', (59, 65))	('COAD', 'Disease', 'MESH:D029424', (13, 17))	('checkpoint inhibitor responses', 'MPA', (66, 96))	('patients', 'Species', '9606', (18, 26))	('survival', 'CPA', (101, 109))
163944	32648580	For example, protein activity might be affected in normal or cancer cells by post-transcription modification and/or regulated proteolysis.	('regulated proteolysis', 'MPA', (116, 137))	('affected', 'Reg', (39, 47))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('post-transcription modification', 'Var', (77, 108))	('cancer', 'Disease', (61, 67))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('activity', 'MPA', (21, 29))	('protein', 'Protein', (13, 20))
163956	32149133	Two datasets (GSE70880 and GSE113852) were downloaded from the Gene Expression Omnibus (GEO) database and used to identify the differentially expressed genes (DEGs) between lung cancer tissues and normal tissues.	('GSE113852', 'Var', (27, 36))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('lung cancer', 'Disease', 'MESH:D008175', (173, 184))	('lung cancer', 'Disease', (173, 184))	('GSE70880', 'Var', (14, 22))	('lung cancer', 'Phenotype', 'HP:0100526', (173, 184))
164014	30872331	When provided with a collection of PSNs, GeneMANIA takes a query of patients as input ("+" nodes) and solves a constrained regression problem on the network to maximize edges that connect query patients, that is, enriched for (+,+) interactions, relative to other edges in the network.	('patients', 'Species', '9606', (68, 76))	('interactions', 'Var', (232, 244))	('patients', 'Species', '9606', (194, 202))	('maximize', 'PosReg', (160, 168))
164034	30872331	For all tumor types, netDx demonstrates performance consistently better than, or at par with, other machine-learning methods (Fig 2B; Dataset EV1).	('EV1', 'Gene', '11322', (142, 145))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('EV1', 'Gene', (142, 145))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('netDx', 'Chemical', '-', (21, 26))	('better', 'PosReg', (65, 71))	('tumor', 'Disease', (8, 13))	('netDx', 'Var', (21, 26))
164056	30872331	Similar to the breast cancer example, pathway-level features result in significantly improved classification performance, relative to a predictor design where gene expression is provided as a single feature (100 train/test splits; mean AUROC = 0.56, AUPR = 0.54; one-sided WMW for greater performance of pathway-based design, P < 2e-16).	('expression', 'Species', '29278', (164, 174))	('improved', 'PosReg', (85, 93))	('breast cancer', 'Disease', 'MESH:D001943', (15, 28))	('classification', 'MPA', (94, 108))	('breast cancer', 'Disease', (15, 28))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('breast cancer', 'Phenotype', 'HP:0003002', (15, 28))	('features', 'Var', (52, 60))
164085	30872331	DIABLO identified a range of features correlated with outcome, such as the known link of mir-30a overexpression with improved survival in both luminal and basal tumors (Kawaguchi et al, 2017).	('DIABLO', 'Gene', (0, 6))	('basal tumors', 'Disease', (155, 167))	('DIABLO', 'Gene', '56616', (0, 6))	('tumors', 'Phenotype', 'HP:0002664', (161, 167))	('mir-30a', 'Gene', '407029', (89, 96))	('improved', 'PosReg', (117, 125))	('expression', 'Species', '29278', (101, 111))	('overexpression', 'Var', (97, 111))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('basal tumors', 'Phenotype', 'HP:0002671', (155, 167))	('basal tumors', 'Disease', 'MESH:D002280', (155, 167))	('mir-30a', 'Gene', (89, 96))
164150	29069744	The four downregulated DEGs had similar areas under the curve (AUC): 0.9188 for DSG3, 0.9386 for KRT5, 0.9333 for KRT6A, and 0.9229 for KRT6B (Figure 5A).	('0.9333', 'Var', (103, 109))	('KRT5', 'Gene', '3852', (97, 101))	('KRT6A', 'Gene', (114, 119))	('KRT6B', 'Gene', '3854', (136, 141))	('0.9386', 'Var', (86, 92))	('0.9229', 'Var', (125, 131))	('KRT6B', 'Gene', (136, 141))	('DSG3', 'Gene', '1830', (80, 84))	('KRT5', 'Gene', (97, 101))	('KRT6A', 'Gene', '3853', (114, 119))	('DSG3', 'Gene', (80, 84))
164151	29069744	The four upregulated DEGs also had similar AUCs: 0.8723 for NKX2-1, 0.8559 for SFTA2, 0.8108 for SFTA3, and 0.8442 for TMC5 (Figure 5B).	('0.8442', 'Var', (108, 114))	('NKX2-1', 'Gene', '7080', (60, 66))	('SFTA3', 'Gene', '253970', (97, 102))	('TMC5', 'Gene', (119, 123))	('SFTA2', 'Gene', (79, 84))	('0.8108', 'Var', (86, 92))	('SFTA3', 'Gene', (97, 102))	('SFTA2', 'Gene', '389376', (79, 84))	('0.8723', 'Var', (49, 55))	('NKX2-1', 'Gene', (60, 66))	('TMC5', 'Gene', '79838', (119, 123))	('0.8559', 'Var', (68, 74))
164155	29069744	However, only low NKX2-1 expression was associated with unfavorable prognosis in LSCC patients (Table 6).	('LSCC', 'Disease', (81, 85))	('expression', 'MPA', (25, 35))	('NKX2-1', 'Gene', (18, 24))	('NKX2-1', 'Gene', '7080', (18, 24))	('low', 'Var', (14, 17))	('patients', 'Species', '9606', (86, 94))
164189	29069744	These datasets contained 361 LADC (50 in GSE28571, 106 in GSE37745, 77 in GSE43580, and 128 in GS50081) and 210 LSCC (28 in GSE28571, 66 in GSE37745, 73 in GSE43580, and 43 in GSE50081) fresh-frozen specimens (Tables S11-S14).	('GSE28571', 'Var', (124, 132))	('GSE28571', 'Var', (41, 49))	('GSE37745', 'Var', (140, 148))	('GS50081', 'Chemical', '-', (95, 102))
164206	27216254	In general, miRs negatively regulate gene expression by base pairing with sequences in the 3'-untranslated region of mRNAs, which either inhibits their translation or triggers their cleavage.	('miR', 'Gene', (12, 15))	('translation', 'MPA', (152, 163))	('mRNAs', 'Gene', (117, 122))	('gene expression', 'MPA', (37, 52))	('miR', 'Gene', '442893', (12, 15))	('triggers', 'Reg', (167, 175))	('cleavage', 'MPA', (182, 190))	('negatively', 'NegReg', (17, 27))	('regulate', 'Reg', (28, 36))	('inhibits', 'NegReg', (137, 145))	('base pairing', 'Var', (56, 68))
164243	27216254	Examples of miR aspects include expression level and state (e.g., hyper-methylated or mutated); examples of disease aspects include outcome/stage, biomarker, or therapy.	('mutated', 'Var', (86, 93))	('miR', 'Gene', '442893', (12, 15))	('expression', 'MPA', (32, 42))	('hyper-methylated', 'Var', (66, 82))	('miR', 'Gene', (12, 15))
164245	27216254	mir-9, overexpressed mir-9, hypermethylation of mir-9) and likewise refer to a disease or its aspects as a disease entity (e.g.	('hypermethylation', 'Var', (28, 44))	('overexpressed', 'PosReg', (7, 20))	('mir', 'Gene', '442893', (21, 24))	('mir', 'Gene', '442893', (0, 3))	('mir', 'Gene', '442893', (48, 51))	('refer to', 'Reg', (68, 76))	('mir', 'Gene', (21, 24))	('mir', 'Gene', (0, 3))	('mir', 'Gene', (48, 51))
164332	27216254	For miR aspects we use trigger words such as methylation, expression, silencing, and knockdown while for disease aspects we use words/phrases such as level, biomarker, or disease free survival.	('expression', 'MPA', (58, 68))	('miR', 'Gene', (4, 7))	('silencing', 'MPA', (70, 79))	('methylation', 'Var', (45, 56))	('knockdown', 'Var', (85, 94))	('miR', 'Gene', '442893', (4, 7))
164347	27216254	Some example sentences in this category include: "miR-23b is epigenetically down-regulated and restoration of miR-23b can effectively suppress cell growth in glioma stem cells" or "miR-139-5p is a potential biomarker for early diagnosis and prognosis and is a therapeutic target for esophageal squamous cell carcinoma (ESCC)".	('esophageal squamous cell carcinoma', 'Disease', (283, 317))	('miR-23b', 'Gene', (50, 57))	('glioma', 'Disease', 'MESH:D005910', (158, 164))	('glioma', 'Phenotype', 'HP:0009733', (158, 164))	('miR-1', 'Gene', '79187', (181, 186))	('carcinoma', 'Phenotype', 'HP:0030731', (308, 317))	('miR-23b', 'Gene', '407011', (110, 117))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (294, 317))	('down-regulated', 'NegReg', (76, 90))	('glioma', 'Disease', (158, 164))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (283, 317))	('restoration', 'Var', (95, 106))	('miR-23b', 'Gene', (110, 117))	('suppress', 'NegReg', (134, 142))	('miR-1', 'Gene', (181, 186))	('miR-23b', 'Gene', '407011', (50, 57))
164391	27216254	For example, the following sentence contains a temporal relation, which is triggered by the word "after": "These data indicate for the first time a mechanism involving STAT1/2 upregulation under the transcriptional control of INF-alpha signaling after knockdown of miR-221/222 cluster in U251 glioma cells" (PMID 20428775).	('miR-221', 'Gene', (265, 272))	('upregulation', 'PosReg', (176, 188))	('INF-alpha', 'Gene', '3451', (226, 235))	('glioma', 'Disease', (293, 299))	('INF-alpha', 'Gene', (226, 235))	('STAT1/2', 'Gene', '6772;6773', (168, 175))	('knockdown', 'Var', (252, 261))	('STAT1/2', 'Gene', (168, 175))	('glioma', 'Disease', 'MESH:D005910', (293, 299))	('miR-221', 'Gene', '407006', (265, 272))	('U251', 'CellLine', 'CVCL:0021', (288, 292))	('glioma', 'Phenotype', 'HP:0009733', (293, 299))
164416	27216254	Variations in miR-9 expression related to miR-9 promoter hypermethylation have also been observed in the disease.	('miR', 'Gene', '442893', (14, 17))	('promoter', 'MPA', (48, 56))	('expression', 'MPA', (20, 30))	('disease', 'Disease', (105, 112))	('miR', 'Gene', (42, 45))	('Variations', 'Var', (0, 10))	('observed', 'Reg', (89, 97))	('miR', 'Gene', (14, 17))	('miR', 'Gene', '442893', (42, 45))
164442	30704458	Using per-cancer and pan-cancer settings, the model predicted both known, including EGFR inhibitors in non-small cell lung cancer and tamoxifen in ER+ breast cancer, and novel drug targets, such as vinorelbine for TTN-mutated tumors.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('tumors', 'Disease', 'MESH:D009369', (226, 232))	('inhibitors', 'Var', (89, 99))	('breast cancer', 'Phenotype', 'HP:0003002', (151, 164))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (103, 129))	('vinorelbine', 'Chemical', 'MESH:D000077235', (198, 209))	('cancer', 'Disease', (25, 31))	('cancer', 'Disease', (10, 16))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('tamoxifen', 'Chemical', 'MESH:D013629', (134, 143))	('TTN', 'Gene', '7273', (214, 217))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('breast cancer', 'Disease', 'MESH:D001943', (151, 164))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('cancer', 'Disease', (158, 164))	('breast cancer', 'Disease', (151, 164))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('non-small cell lung cancer', 'Disease', (103, 129))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('tumors', 'Phenotype', 'HP:0002664', (226, 232))	('TTN', 'Gene', (214, 217))	('cancer', 'Disease', 'MESH:D009369', (25, 31))	('cancer', 'Disease', 'MESH:D009369', (10, 16))	('lung cancer', 'Phenotype', 'HP:0100526', (118, 129))	('ER', 'Gene', '2099', (147, 149))	('tumors', 'Disease', (226, 232))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (103, 129))	('cancer', 'Disease', (123, 129))	('EGFR', 'Gene', (84, 88))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (107, 129))
164446	30704458	For instance, recent reports identified mutation profiles associated with drug response both in tumor type-specific and pan-cancer manners.	('mutation', 'Var', (40, 48))	('cancer', 'Disease', (124, 130))	('drug response', 'Disease', (74, 87))	('associated', 'Reg', (58, 68))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumor', 'Disease', (96, 101))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('cancer', 'Disease', 'MESH:D009369', (124, 130))
164460	30704458	In this study, we analyzed 622 cell lines with available expression, mutation, and IC50 data and 9059 tumors with expression and mutation profiles.	('tumors', 'Disease', 'MESH:D009369', (102, 108))	('tumors', 'Disease', (102, 108))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('IC50', 'Gene', (83, 87))	('mutation', 'Var', (69, 77))	('expression', 'Species', '29278', (114, 124))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('expression', 'Species', '29278', (57, 67))
164467	30704458	We pre-trained an autoencoder on each of the TCGA mutation and expression datasets to optimize the capability to capture high-order features.	('TCGA', 'Gene', (45, 49))	('expression', 'Species', '29278', (63, 73))	('mutation', 'Var', (50, 58))
164473	30704458	For each method, top 64 principal components of mutations and gene expression were merged to predict IC50 values of all (using linear regression) or individual drugs (SVM).	('expression', 'Species', '29278', (67, 77))	('mutations', 'Var', (48, 57))	('IC50', 'MPA', (101, 105))
164487	30704458	Also, two EGFR inhibitors, afatinib and gefitinib, achieved better performance in non-small cell lung cancers (NSCLC) with mutated EGFR (P = 2.0 x 10- 7 and 6.6 x 10- 3).	('small cell lung cancer', 'Phenotype', 'HP:0030357', (86, 108))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('non-small cell lung cancers', 'Phenotype', 'HP:0030358', (82, 109))	('afatinib', 'Chemical', 'MESH:D000077716', (27, 35))	('NSCLC', 'Disease', (111, 116))	('EGFR', 'Gene', (10, 14))	('NSCLC', 'Disease', 'MESH:D002289', (111, 116))	('EGFR', 'Gene', (131, 135))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))	('non-small cell lung cancers', 'Disease', (82, 109))	('gefitinib', 'Chemical', 'MESH:D000077156', (40, 49))	('mutated', 'Var', (123, 130))	('small cell lung cancers', 'Phenotype', 'HP:0030357', (86, 109))	('lung cancer', 'Phenotype', 'HP:0100526', (97, 108))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (82, 108))	('non-small cell lung cancers', 'Disease', 'MESH:D002289', (82, 109))	('lung cancers', 'Phenotype', 'HP:0100526', (97, 109))
164492	30704458	The top three combinations were TP53 mutations in lung adenocarcinoma (LUAD; modulating response to 235 drugs), lung squamous cell carcinoma (LUSC; 228 drugs), and stomach adenocarcinoma (STAD; 224 drugs) (Table 2).	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (112, 140))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (117, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (50, 69))	('lung squamous cell carcinoma', 'Disease', (112, 140))	('TP53', 'Gene', '7157', (32, 36))	('carcinoma', 'Phenotype', 'HP:0030731', (177, 186))	('lung adenocarcinoma', 'Disease', (50, 69))	('mutations', 'Var', (37, 46))	('stomach adenocarcinoma', 'Disease', 'MESH:D013274', (164, 186))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (50, 69))	('TP53', 'Gene', (32, 36))	('carcinoma', 'Phenotype', 'HP:0030731', (60, 69))	('stomach adenocarcinoma', 'Disease', (164, 186))
164494	30704458	The mutation has been shown to be associated with cancer stem cells and resistance functions and thus regulates drug resistance.	('drug resistance', 'Phenotype', 'HP:0020174', (112, 127))	('associated', 'Reg', (34, 44))	('regulates', 'Reg', (102, 111))	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('mutation', 'Var', (4, 12))	('resistance functions', 'CPA', (72, 92))	('drug resistance', 'MPA', (112, 127))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))
164498	30704458	We also identified gene mutations that sensitized tumors to a large number of drugs, such as IDH1 (138 drugs; Table 2).	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('sensitized', 'Reg', (39, 49))	('tumors', 'Disease', (50, 56))	('mutations', 'Var', (24, 33))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))
164500	30704458	Our finding agreed with the report and showed that IDH1 mutation dramatically reduced IC50 of chemotherapeutic agents, e.g., doxorubicin in LGG (DeltaIC50 = - 0.85; P = 3.6 x 10- 71; Fig.	('IC50 of', 'MPA', (86, 93))	('doxorubicin', 'MPA', (125, 136))	('reduced', 'NegReg', (78, 85))	('mutation', 'Var', (56, 64))	('IDH1', 'Gene', (51, 55))	('doxorubicin', 'Chemical', 'MESH:D004317', (125, 136))
164501	30704458	We also carried out a study to explore how gene mutations affect drug response in a pan-cancer setting.	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('gene mutations', 'Var', (43, 57))	('drug response', 'MPA', (65, 78))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('affect', 'Reg', (58, 64))
164503	30704458	Among them, TP53 (9 sensitive and 242 resistant drugs) and TTN mutations (44 and 162) were associated with the largest numbers of resistant and sensitive drugs, respectively (Table 3).	('mutations', 'Var', (63, 72))	('TTN', 'Gene', (59, 62))	('TP53', 'Gene', '7157', (12, 16))	('TTN', 'Gene', '7273', (59, 62))	('TP53', 'Gene', (12, 16))
164504	30704458	Many of the drugs with large TP53 mutations-modulated changes in DeltaIC50 ( DeltaIC50  >= 0.7; Fig.	('changes', 'Reg', (54, 61))	('DeltaIC50', 'MPA', (65, 74))	('TP53', 'Gene', '7157', (29, 33))	('mutations-modulated', 'Var', (34, 53))	('TP53', 'Gene', (29, 33))
164514	30704458	For each drug, pan-cancer patients predicted to be very sensitive and resistant (with IC50 in bottom and top 1%, n = 91 in each group; Fig.	('cancer', 'Disease', 'MESH:D009369', (19, 25))	('cancer', 'Disease', (19, 25))	('IC50', 'Var', (86, 90))	('patients', 'Species', '9606', (26, 34))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))
164519	30704458	On average, each sensitive tumor harbored 2.7 mutations among these genes, much higher than 0.51 observed in the resistant group (Fig.	('tumor', 'Disease', (27, 32))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('mutations', 'Var', (46, 55))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))
164528	30704458	Nine of the top 10 differentially mutated genes were enriched in the resistant group and led by TP53 mutations (mutation rate, 95.6% in resistant vs. 13.2% in sensitive patients; Fig.	('patients', 'Species', '9606', (169, 177))	('mutations', 'Var', (101, 110))	('TP53', 'Gene', '7157', (96, 100))	('TP53', 'Gene', (96, 100))
164534	30704458	Furthermore, DeepDR may incorporate additional genomic mutation information, such as copy number alterations, into data matrices MTCGA and MCCLE, to enrich the complexity of tumor mutation for model training and further reduce the training MSE.	('tumor', 'Disease', (174, 179))	('copy number alterations', 'Var', (85, 108))	('CCLE', 'Chemical', '-', (140, 144))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))
164535	30704458	In this study, by integrating genomics profiles to the predictions, we systematically investigated how single gene mutations, as well as the interplay between cancer type, mutations, and biological functions, were associated with the predicted drug response.	('cancer', 'Disease', (159, 165))	('mutations', 'Var', (115, 124))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('drug response', 'MPA', (244, 257))	('associated', 'Reg', (214, 224))
164545	26970127	The pathophysiology of EA is complex and involves diverse factors, including gastroesophageal reflux, gastric acid secretion, dysfunction of the antireflux barrier, gastric emptying disturbances, and abnormalities in esophageal defense mechanisms.	('gastric acid secretion', 'MPA', (102, 124))	('abnormalities', 'Var', (200, 213))	('gastroesophageal reflux', 'Phenotype', 'HP:0002020', (77, 100))	('esophageal reflux', 'Phenotype', 'HP:0002020', (83, 100))	('gastric emptying', 'Phenotype', 'HP:0002578', (165, 181))	('gastroesophageal reflux', 'Disease', 'MESH:D005764', (77, 100))	('gastroesophageal reflux', 'Disease', (77, 100))	('gastric emptying disturbances', 'Disease', (165, 194))	('dysfunction', 'Disease', (126, 137))
164548	26970127	If changes in the proposed factors alter the stepwise progression (RE-BE-dysplasia- EA), they may represent potential targets for chemoprevention.	('changes', 'Var', (3, 10))	('stepwise progression', 'CPA', (45, 65))	('alter', 'Reg', (35, 40))	('RE-BE-dysplasia- EA', 'Disease', 'MESH:C535499', (67, 86))	('RE-BE-dysplasia- EA', 'Disease', (67, 86))
164561	26970127	Dysbiosis is a term that describes such microbial alterations that disrupt the symbiotic relationship between the host and the microbiome.	('alterations', 'Var', (50, 61))	('disrupt', 'NegReg', (67, 74))	('Dysbiosis', 'Disease', (0, 9))	('Dysbiosis', 'Disease', 'MESH:D064806', (0, 9))	('symbiotic relationship', 'CPA', (79, 101))
164607	26970127	Furthermore, S. bovis has also been associated with hematopoietic malignancy.	('hematopoietic malignancy', 'Disease', (52, 76))	('S. bovis', 'Species', '1335', (13, 21))	('hematopoietic malignancy', 'Disease', 'MESH:D019337', (52, 76))	('associated', 'Reg', (36, 46))	('hematopoietic malignancy', 'Phenotype', 'HP:0004377', (52, 76))	('S. bovis', 'Var', (13, 21))
164613	26970127	Alterations in MAMPs trigger pattern receptors of innate immunity, including Toll-like receptors (TLR) and/or nucleotide-binding-oligomerization-domain (NOD)-like receptors.	('Alterations', 'Var', (0, 11))	('trigger', 'Reg', (21, 28))	('TLR', 'Gene', (98, 101))	('TLR', 'Gene', '7099', (98, 101))	('MAMPs', 'Gene', (15, 20))
164614	26970127	Stimulating the receptors activates the NF-kappaB pathway and causes expression of cytokines and interleukins.	('NF-kappaB', 'Gene', '4790', (40, 49))	('Stimulating', 'Var', (0, 11))	('NF-kappaB', 'Gene', (40, 49))	('causes', 'Reg', (62, 68))	('activates', 'PosReg', (26, 35))	('expression of cytokines', 'MPA', (69, 92))
164620	26970127	nitrosamine and acetaldehyde), activation of dietary phytochemicals, metabolism of hormones, xenobiotics, and modification of tumor promoting bile acids.	('metabolism', 'MPA', (69, 79))	('nitrosamine', 'Chemical', 'MESH:D009602', (0, 11))	('acetaldehyde', 'Chemical', 'MESH:D000079', (16, 28))	('bile acids', 'Chemical', 'MESH:D001647', (142, 152))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('modification', 'Var', (110, 122))	('activation', 'PosReg', (31, 41))	('tumor', 'Disease', (126, 131))
164641	26970127	Other studies suggest that H. pylori may act as a significant protective factor against EA via a mechanism involving ghrelin, a hormone that stimulates appetite and contributes to the development of obesity.	('H. pylori', 'Var', (27, 36))	('ghrelin', 'Chemical', 'MESH:D054439', (117, 124))	('obesity', 'Phenotype', 'HP:0001513', (199, 206))	('appetite', 'MPA', (152, 160))	('obesity', 'Disease', 'MESH:D009765', (199, 206))	('H. pylori', 'Species', '210', (27, 36))	('stimulates appetite', 'Phenotype', 'HP:0002591', (141, 160))	('obesity', 'Disease', (199, 206))	('ghrelin', 'Protein', (117, 124))	('stimulates', 'PosReg', (141, 151))
164642	26970127	Studies suggest that eradication of H. pylori may result in increased serum levels of ghrelin, which may in turn lead to obesity.	('H. pylori', 'Species', '210', (36, 45))	('obesity', 'Disease', (121, 128))	('lead to', 'Reg', (113, 120))	('eradication', 'Var', (21, 32))	('ghrelin', 'Protein', (86, 93))	('obesity', 'Phenotype', 'HP:0001513', (121, 128))	('serum levels of', 'MPA', (70, 85))	('obesity', 'Disease', 'MESH:D009765', (121, 128))	('H. pylori', 'Gene', (36, 45))	('increased', 'PosReg', (60, 69))	('ghrelin', 'Chemical', 'MESH:D054439', (86, 93))
164644	26970127	There is also evidence that suggests that H. pylori stimulates apoptosis in Barrett's derived EA cells via the Fas-caspase cascade, providing yet another potential mechanism that may account for the possible protective effects of H. pylori.	('H. pylori', 'Species', '210', (230, 239))	('H. pylori', 'Species', '210', (42, 51))	('stimulates', 'PosReg', (52, 62))	('apoptosis', 'CPA', (63, 72))	('H. pylori', 'Var', (42, 51))
164651	26970127	Second, in mice, sub-therapeutic antibiotics consistently increase the relative abundance of Firmicutes at the cost of decreasing the abundance of Bacteroidetes.	('increase', 'PosReg', (58, 66))	('mice', 'Species', '10090', (11, 15))	('Bacteroidetes', 'MPA', (147, 160))	('Firmicutes', 'MPA', (93, 103))	('sub-therapeutic', 'Var', (17, 32))
164684	26970127	In a mouse model, LPS caused a dose-dependent fall in the basal tone.	('basal tone', 'MPA', (58, 68))	('LPS', 'Chemical', 'MESH:D008070', (18, 21))	('LPS', 'Var', (18, 21))	('fall', 'NegReg', (46, 50))	('mouse', 'Species', '10090', (5, 10))	('fall', 'Phenotype', 'HP:0002527', (46, 50))
164709	26970127	Detailed analyses suggest that H. pylori eradication increases the risk for development of RE in patients who have existing risks for BE and EA, such as male gender and hiatal hernia.	('development', 'Disease', (76, 87))	('eradication', 'Var', (41, 52))	('H. pylori', 'Gene', (31, 40))	('hiatal hernia', 'Disease', 'MESH:D006551', (169, 182))	('hernia', 'Phenotype', 'HP:0100790', (176, 182))	('hiatal hernia', 'Disease', (169, 182))	('H. pylori', 'Species', '210', (31, 40))	('hiatal hernia', 'Phenotype', 'HP:0002036', (169, 182))	('BE', 'Chemical', 'MESH:D001608', (134, 136))	('patients', 'Species', '9606', (97, 105))
164769	26970127	Nevertheless, erythromycin has been shown to significantly increase the lower esophageal sphincter (LES) pressure, without affecting the postdeglutition relaxation of LES.	('erythromycin', 'Chemical', 'MESH:D004917', (14, 26))	('erythromycin', 'Var', (14, 26))	('esophageal sphincter', 'Disease', (78, 98))	('esophageal sphincter', 'Disease', 'MESH:D009122', (78, 98))	('increase', 'PosReg', (59, 67))
164785	33279803	Because the esophagus and trachea are closely adjacent and P. gingivalis can instantly enter and colonize in cells, we speculate that P. gingivalis may be colonized in lung cancer cells through oral or blood, promoting the malignant progression of lung cancer.	('P. gingivalis', 'Var', (134, 147))	('lung cancer', 'Disease', 'MESH:D008175', (248, 259))	('P. gingivalis', 'Species', '837', (59, 72))	('lung cancer', 'Disease', (168, 179))	('P. gingivalis', 'Species', '837', (134, 147))	('lung cancer', 'Phenotype', 'HP:0100526', (168, 179))	('trachea', 'Disease', (26, 33))	('malignant progression', 'CPA', (223, 244))	('lung cancer', 'Disease', (248, 259))	('trachea', 'Disease', 'MESH:C557675', (26, 33))	('lung cancer', 'Phenotype', 'HP:0100526', (248, 259))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('lung cancer', 'Disease', 'MESH:D008175', (168, 179))	('cancer', 'Phenotype', 'HP:0002664', (253, 259))	('promoting', 'PosReg', (209, 218))
164786	33279803	In this study, we investigated P. gingivalis infection in lung carcinoma tissues and adjacent lung tissues, and found that the colonization rate of P. gingivalis in carcinoma tissues was significantly higher than that in adjacent lung tissues.	('carcinoma', 'Disease', (165, 174))	('gingivalis in carcinoma', 'Phenotype', 'HP:0000169', (151, 174))	('gingivalis infection', 'Disease', (34, 54))	('colonization', 'CPA', (127, 139))	('gingivalis infection', 'Disease', 'MESH:D007239', (34, 54))	('lung carcinoma', 'Disease', 'MESH:D008175', (58, 72))	('carcinoma', 'Disease', (63, 72))	('P. gingivalis', 'Species', '837', (31, 44))	('P. gingivalis', 'Var', (148, 161))	('P. gingivalis', 'Species', '837', (148, 161))	('carcinoma', 'Disease', 'MESH:D009369', (165, 174))	('carcinoma', 'Disease', 'MESH:D009369', (63, 72))	('lung carcinoma', 'Disease', (58, 72))	('carcinoma', 'Phenotype', 'HP:0030731', (165, 174))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))	('higher', 'PosReg', (201, 207))
164798	33279803	The main risk factors include smoking, occupational and environmental exposure, past chronic lung infection, genetic susceptibility and decreased immune function.	('immune function', 'CPA', (146, 161))	('decreased immune function', 'Phenotype', 'HP:0002721', (136, 161))	('chronic lung infection', 'Phenotype', 'HP:0002783', (85, 107))	('genetic susceptibility', 'Var', (109, 131))	('lung infection', 'Phenotype', 'HP:0006532', (93, 107))	('lung infection', 'Disease', 'MESH:D012141', (93, 107))	('lung infection', 'Disease', (93, 107))	('decreased', 'NegReg', (136, 145))
164799	33279803	With the continuous development and progress of medical research, genetic changes and environmental exposure constitute the etiology of lung cancer.	('lung cancer', 'Phenotype', 'HP:0100526', (136, 147))	('genetic changes', 'Var', (66, 81))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('lung cancer', 'Disease', 'MESH:D008175', (136, 147))	('lung cancer', 'Disease', (136, 147))
164806	33279803	We had found that the detection rate of P. gingivalis in cancer tissues of patients with esophageal cancer was as high as 42%.	('esophageal cancer', 'Disease', (89, 106))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('P. gingivalis', 'Var', (40, 53))	('P. gingivalis', 'Species', '837', (40, 53))	('cancer', 'Disease', (57, 63))	('esophageal cancer', 'Disease', 'MESH:D004938', (89, 106))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('patients', 'Species', '9606', (75, 83))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))
164808	33279803	Therefore, P. gingivalis is closely related to the occurrence and development of esophageal cancer.	('related', 'Reg', (36, 43))	('esophageal cancer', 'Disease', 'MESH:D004938', (81, 98))	('P. gingivalis', 'Species', '837', (11, 24))	('P. gingivalis', 'Var', (11, 24))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('esophageal cancer', 'Disease', (81, 98))
164809	33279803	Because the esophagus and trachea are closely adjacent to each other, and the process of P. gingivalis entering the cells is instantaneous and can be colonized in the cells for a long time, we speculate that P. gingivalis may be colonized in lung cancer cells through oral or blood, promoting the malignant progression of lung cancer.	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('lung cancer', 'Disease', (322, 333))	('lung cancer', 'Phenotype', 'HP:0100526', (322, 333))	('P. gingivalis', 'Species', '837', (89, 102))	('malignant progression', 'CPA', (297, 318))	('lung cancer', 'Disease', 'MESH:D008175', (242, 253))	('cancer', 'Phenotype', 'HP:0002664', (327, 333))	('trachea', 'Disease', (26, 33))	('trachea', 'Disease', 'MESH:C557675', (26, 33))	('promoting', 'PosReg', (283, 292))	('lung cancer', 'Disease', (242, 253))	('P. gingivalis', 'Species', '837', (208, 221))	('P. gingivalis', 'Var', (208, 221))	('lung cancer', 'Disease', 'MESH:D008175', (322, 333))	('lung cancer', 'Phenotype', 'HP:0100526', (242, 253))
164839	33279803	Moreover, it was found that the positive rates of P. gingivalis staining in carcinoma tissues of patients with small cell lung cancer, lung adenocarcinoma and lung squamous cell carcinoma were 35.00%, 26.89% and 39.00%, respectively, which were significantly higher than those in the adjacent lung tissues, as presented in Table 2 and Fig.	('small cell lung cancer', 'Disease', 'MESH:D055752', (111, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (145, 154))	('carcinoma', 'Disease', (178, 187))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (159, 187))	('small cell lung cancer', 'Disease', (111, 133))	('carcinoma', 'Disease', (145, 154))	('carcinoma', 'Disease', 'MESH:D009369', (76, 85))	('higher', 'PosReg', (259, 265))	('lung cancer', 'Phenotype', 'HP:0100526', (122, 133))	('carcinoma', 'Disease', 'MESH:D009369', (178, 187))	('P. gingivalis', 'Var', (50, 63))	('lung squamous cell carcinoma', 'Disease', (159, 187))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (159, 187))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (164, 187))	('carcinoma', 'Disease', 'MESH:D009369', (145, 154))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (111, 133))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('lung adenocarcinoma', 'Disease', (135, 154))	('P. gingivalis', 'Species', '837', (50, 63))	('patients', 'Species', '9606', (97, 105))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (135, 154))	('carcinoma', 'Disease', (76, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (178, 187))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (135, 154))
164840	33279803	P. gingivalis was associated with smoking, alcohol, lymph node metastasis and clinical stages in patients with small cell lung cancer, lung adenocarcinoma and lung squamous cell carcinoma (P <0.05), but not with sex, age and degree of differentiation, as presented in Table 3.	('small cell lung cancer', 'Disease', 'MESH:D055752', (111, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (145, 154))	('P. gingivalis', 'Species', '837', (0, 13))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (159, 187))	('small cell lung cancer', 'Disease', (111, 133))	('lymph', 'Disease', (52, 57))	('lung cancer', 'Phenotype', 'HP:0100526', (122, 133))	('alcohol', 'Disease', (43, 50))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (159, 187))	('lung squamous cell carcinoma', 'Disease', (159, 187))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (164, 187))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (111, 133))	('age', 'Gene', (89, 92))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('lung adenocarcinoma', 'Disease', (135, 154))	('age', 'Gene', (217, 220))	('associated', 'Interaction', (18, 28))	('patients', 'Species', '9606', (97, 105))	('P. gingivalis', 'Var', (0, 13))	('alcohol', 'Chemical', 'MESH:D000438', (43, 50))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (135, 154))	('age', 'Gene', '5973', (89, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (178, 187))	('age', 'Gene', '5973', (217, 220))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (135, 154))
164847	33279803	In patients with these three types of lung cancer, the 5-year survival rate and median survival time in P. gingivalis positive group were significantly lower than those in P. gingivalis negative group, as presented in Table 4 and Fig.	('lung cancer', 'Disease', (38, 49))	('lung cancer', 'Phenotype', 'HP:0100526', (38, 49))	('P. gingivalis', 'Species', '837', (172, 185))	('P. gingivalis', 'Species', '837', (104, 117))	('P. gingivalis', 'Var', (104, 117))	('survival', 'CPA', (87, 95))	('lower', 'NegReg', (152, 157))	('patients', 'Species', '9606', (3, 11))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('lung cancer', 'Disease', 'MESH:D008175', (38, 49))
164862	33279803	Meanwhile, P. gingivalis infection could cause the overexpression of lysine demethylase 5B in esophageal cancer cells, while the overexpression of KDM5B can "hypnotize" T-cells in the tumor by inhibiting the attraction and aggregation of lymphocytes in the tumor bed, thus inhibiting the immune system and assisting tumor cells to evade immune surveillance.	('esophageal cancer', 'Disease', (94, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('lysine', 'Chemical', 'MESH:D008239', (69, 75))	('inhibiting', 'NegReg', (273, 283))	('tumor', 'Disease', (257, 262))	('tumor', 'Phenotype', 'HP:0002664', (316, 321))	('gingivalis infection', 'Disease', 'MESH:D007239', (14, 34))	('tumor', 'Disease', (184, 189))	('tumor', 'Disease', 'MESH:D009369', (257, 262))	('assisting', 'PosReg', (306, 315))	('KDM5B', 'Var', (147, 152))	('overexpression', 'PosReg', (51, 65))	('inhibiting', 'NegReg', (193, 203))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('evade immune surveillance', 'CPA', (331, 356))	('tumor', 'Phenotype', 'HP:0002664', (257, 262))	('immune system', 'CPA', (288, 301))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('gingivalis infection', 'Disease', (14, 34))	('tumor', 'Disease', (316, 321))	('P. gingivalis', 'Species', '837', (11, 24))	('esophageal cancer', 'Disease', 'MESH:D004938', (94, 111))	('tumor', 'Disease', 'MESH:D009369', (316, 321))
164863	33279803	Therefore, P. gingivalis can indeed promote the occurrence and development of malignant tumors by remodeling the host immune microenvironment.	('malignant tumors', 'Disease', (78, 94))	('promote', 'PosReg', (36, 43))	('malignant tumors', 'Disease', 'MESH:D009369', (78, 94))	('P. gingivalis', 'Species', '837', (11, 24))	('P. gingivalis', 'Var', (11, 24))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))
164865	33279803	We found that, the positive rates of P. gingivalis staining in carcinoma tissues of patients with small cell lung cancer, lung adenocarcinoma and lung squamous cell carcinoma were 35.00%, 26.89% and 39.00%, respectively, and the intensity and frequency of the sections stained with P. gingivalis were significantly enhanced in cancerous tissues of these three types of lung cancer compared to those in adjacent lung tissues, as presented in Table 2 and Fig.	('lung cancer', 'Disease', 'MESH:D008175', (369, 380))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (98, 120))	('cancerous', 'Disease', 'MESH:D009369', (327, 336))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (146, 174))	('lung squamous cell carcinoma', 'Disease', (146, 174))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (151, 174))	('lung cancer', 'Phenotype', 'HP:0100526', (369, 380))	('cancer', 'Phenotype', 'HP:0002664', (374, 380))	('carcinoma', 'Disease', 'MESH:D009369', (132, 141))	('patients', 'Species', '9606', (84, 92))	('carcinoma', 'Disease', (63, 72))	('cancer', 'Phenotype', 'HP:0002664', (327, 333))	('P. gingivalis', 'Var', (282, 295))	('carcinoma', 'Phenotype', 'HP:0030731', (165, 174))	('lung adenocarcinoma', 'Disease', (122, 141))	('P. gingivalis', 'Species', '837', (37, 50))	('cancerous', 'Disease', (327, 336))	('carcinoma', 'Disease', (165, 174))	('P. gingivalis', 'Species', '837', (282, 295))	('small cell lung cancer', 'Disease', 'MESH:D055752', (98, 120))	('carcinoma', 'Disease', 'MESH:D009369', (63, 72))	('lung cancer', 'Disease', 'MESH:D008175', (109, 120))	('lung cancer', 'Disease', (369, 380))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (122, 141))	('small cell lung cancer', 'Disease', (98, 120))	('lung cancer', 'Phenotype', 'HP:0100526', (109, 120))	('enhanced', 'PosReg', (315, 323))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (122, 141))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (146, 174))	('carcinoma', 'Disease', 'MESH:D009369', (165, 174))	('carcinoma', 'Disease', (132, 141))
164871	33279803	Since long term heavy smoking can severely damage the immune function of the body, P. gingivalis may be more likely to sneak in.	('age', 'Gene', '5973', (46, 49))	('P. gingivalis', 'Species', '837', (83, 96))	('immune function of the body', 'CPA', (54, 81))	('P. gingivalis', 'Var', (83, 96))	('age', 'Gene', (46, 49))
164874	33279803	It was suggested that long term smoking and alcohol could lead to worse immune microenvironment, creating a better "hotbed" for P. gingivalis, and P. gingivalis was more likely to be infected and colonized in this environment.	('P. gingivalis', 'Var', (147, 160))	('alcohol', 'Chemical', 'MESH:D000438', (44, 51))	('P. gingivalis', 'Species', '837', (147, 160))	('infected', 'Disease', 'MESH:D007239', (183, 191))	('infected', 'Disease', (183, 191))	('P. gingivalis', 'Species', '837', (128, 141))
164875	33279803	In this case, P. gingivalis may further induce host immunosuppression and assist the immune escape of tumor cells, thus promoting the invasion, proliferation and metastasis of lung cancer cells.	('assist', 'PosReg', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('P. gingivalis', 'Var', (14, 27))	('host immunosuppression', 'CPA', (47, 69))	('P. gingivalis', 'Species', '837', (14, 27))	('metastasis of lung cancer', 'Disease', (162, 187))	('invasion', 'CPA', (134, 142))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('metastasis of lung cancer', 'Disease', 'MESH:D008175', (162, 187))	('promoting', 'PosReg', (120, 129))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('lung cancer', 'Phenotype', 'HP:0100526', (176, 187))	('proliferation', 'CPA', (144, 157))	('induce', 'PosReg', (40, 46))
164876	33279803	In this study we also found that the 5-year survival rate and median survival time of these three types of lung cancer patients in the P. gingivalis positive group were significantly lower than those in the P. gingivalis negative group, as presented in Table 2 and Fig.	('P. gingivalis', 'Species', '837', (135, 148))	('lung cancer', 'Disease', 'MESH:D008175', (107, 118))	('patients', 'Species', '9606', (119, 127))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('P. gingivalis', 'Var', (135, 148))	('P. gingivalis', 'Species', '837', (207, 220))	('lung cancer', 'Disease', (107, 118))	('lung cancer', 'Phenotype', 'HP:0100526', (107, 118))	('lower', 'NegReg', (183, 188))	('positive', 'Var', (149, 157))
164881	33279803	In summary, P. gingivalis could promote the metastasis and malignant progression of lung cancer through long term colonization of lung cancer cells.	('lung cancer', 'Phenotype', 'HP:0100526', (130, 141))	('lung cancer', 'Disease', (84, 95))	('lung cancer', 'Phenotype', 'HP:0100526', (84, 95))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('lung cancer', 'Disease', 'MESH:D008175', (130, 141))	('metastasis', 'CPA', (44, 54))	('lung cancer', 'Disease', 'MESH:D008175', (84, 95))	('malignant progression', 'CPA', (59, 80))	('promote', 'PosReg', (32, 39))	('P. gingivalis', 'Species', '837', (12, 25))	('P. gingivalis', 'Var', (12, 25))	('lung cancer', 'Disease', (130, 141))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
164911	31529338	Later, it was reported that prostasin is GPI anchored to the cell surface and is released from the cell upon GPI-anchor cleavage by phospholipase C (Fig.	('GPI-anchor', 'Disease', 'MESH:C537277', (109, 119))	('GPI-anchor', 'Disease', (109, 119))	('cleavage', 'Var', (120, 128))
164919	31529338	Furthermore, after exposure to a single topical dose of the chemical carcinogen 7,12-dimethylbenzanthracene (DMBA), nearly all the matriptase transgenic mice developed SCC within 40 weeks.	('SCC', 'Gene', (168, 171))	('transgenic mice', 'Species', '10090', (142, 157))	('7,12-dimethylbenzanthracene', 'Chemical', 'MESH:D015127', (80, 107))	('transgenic', 'Var', (142, 152))	('SCC', 'Gene', '6317', (168, 171))	('matriptase', 'Gene', '19143', (131, 141))	('matriptase', 'Gene', (131, 141))	('developed', 'PosReg', (158, 167))	('DMBA', 'Chemical', 'MESH:D015127', (109, 113))
164920	31529338	Importantly, when the cognate matriptase inhibitor HAI-1 was simultaneously overexpressed with matriptase in the epidermis, development of SCC following DMBA exposure was abrogated, indicating that HAI-1 expression is sufficient to protect mice from matriptase-induced SCC.	('SCC', 'Gene', '6317', (139, 142))	('HAI-1', 'Var', (198, 203))	('matriptase', 'Gene', (95, 105))	('SCC', 'Gene', (269, 272))	('mice', 'Species', '10090', (240, 244))	('matriptase', 'Gene', (250, 260))	('matriptase', 'Gene', (30, 40))	('DMBA', 'Chemical', 'MESH:D015127', (153, 157))	('SCC', 'Gene', '6317', (269, 272))	('matriptase', 'Gene', '19143', (250, 260))	('SCC', 'Gene', (139, 142))	('abrogated', 'NegReg', (171, 180))	('development', 'CPA', (124, 135))	('matriptase', 'Gene', '19143', (30, 40))	('matriptase', 'Gene', '19143', (95, 105))
164923	31529338	This indicates that continued dysregulation of matriptase activity is necessary for SCC progression, and that inhibition of matriptase activity in established tumors may be an avenue for therapeutic intervention.	('SCC', 'Gene', '6317', (84, 87))	('activity', 'MPA', (58, 66))	('dysregulation', 'Var', (30, 43))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('matriptase', 'Gene', (47, 57))	('tumors', 'Disease', (159, 165))	('matriptase', 'Gene', '19143', (124, 134))	('tumors', 'Phenotype', 'HP:0002664', (159, 165))	('tumors', 'Disease', 'MESH:D009369', (159, 165))	('matriptase', 'Gene', '19143', (47, 57))	('SCC', 'Gene', (84, 87))	('matriptase', 'Gene', (124, 134))
164927	31529338	K5-matriptase transgenic mice crossed to PAR-2 null mice were protected against development of epidermal hyperplasia or dysplasia that is normally associated with matriptase overexpression in the epidermis, indicating that pre-malignant transformation into SCC is dependent on PAR-2 expression.	('epidermal hyperplasia or dysplasia', 'Disease', (95, 129))	('mice', 'Species', '10090', (25, 29))	('transgenic', 'Var', (14, 24))	('matriptase', 'Gene', (163, 173))	('matriptase', 'Gene', '19143', (3, 13))	('PAR-2', 'Gene', '2150', (41, 46))	('SCC', 'Gene', '6317', (257, 260))	('PAR-2', 'Gene', (277, 282))	('mice', 'Species', '10090', (52, 56))	('PAR-2', 'Gene', '2150', (277, 282))	('overexpression', 'PosReg', (174, 188))	('matriptase', 'Gene', '19143', (163, 173))	('epidermal hyperplasia or dysplasia', 'Disease', 'MESH:D006965', (95, 129))	('matriptase', 'Gene', (3, 13))	('PAR-2', 'Gene', (41, 46))	('transgenic mice', 'Species', '10090', (14, 29))	('SCC', 'Gene', (257, 260))
164928	31529338	This was further confirmed by the inability of transgenic matriptase to potentiate DMBA-induced tumors in the absence of PAR-2.	('inability', 'Disease', 'MESH:D007319', (34, 43))	('PAR-2', 'Gene', (121, 126))	('PAR-2', 'Gene', '2150', (121, 126))	('matriptase', 'Gene', '19143', (58, 68))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumors', 'Disease', (96, 102))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('DMBA-induced', 'Disease', (83, 95))	('DMBA', 'Chemical', 'MESH:D015127', (83, 87))	('transgenic', 'Var', (47, 57))	('potentiate', 'PosReg', (72, 82))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('matriptase', 'Gene', (58, 68))	('inability', 'Disease', (34, 43))
164933	31529338	Loss of c-Met impaired matriptase-induced SCC formation, demonstrating an essential role for c-Met signaling for the pro-oncogenic properties of matriptase.	('matriptase', 'Gene', (145, 155))	('SCC', 'Gene', (42, 45))	('matriptase', 'Gene', '19143', (145, 155))	('matriptase', 'Gene', '19143', (23, 33))	('matriptase', 'Gene', (23, 33))	('rat', 'Species', '10116', (64, 67))	('SCC', 'Gene', '6317', (42, 45))	('c-Met', 'Protein', (8, 13))	('Loss', 'Var', (0, 4))	('impaired', 'NegReg', (14, 22))
164934	31529338	Another study specifically investigating the role of HAI-1 in oral SCC (OSCC) cell lines, including those of the gingiva and tongue, found that silencing of HAI-1 enhanced migration and tumorigenicity.	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('SCC', 'Gene', (73, 76))	('tumor', 'Disease', (186, 191))	('SCC', 'Gene', '6317', (67, 70))	('SCC', 'Gene', (67, 70))	('enhanced', 'PosReg', (163, 171))	('rat', 'Species', '10116', (175, 178))	('SCC', 'Gene', '6317', (73, 76))	('silencing', 'Var', (144, 153))	('HAI-1', 'Gene', (157, 162))	('migration', 'CPA', (172, 181))
164939	31529338	It was previously demonstrated that a matriptase-prostasin reciprocal zymogen activation complex exists, which could cause dysregulation of both matriptase and prostasin activity upon HAI-2 KO.	('matriptase', 'Gene', '19143', (38, 48))	('prostasin activity', 'MPA', (160, 178))	('HAI-2', 'Var', (184, 189))	('matriptase', 'Gene', '19143', (145, 155))	('KO', 'Gene', '3856', (190, 192))	('dysregulation', 'MPA', (123, 136))	('matriptase', 'Gene', (38, 48))	('cause', 'Reg', (117, 122))	('rat', 'Species', '10116', (25, 28))	('matriptase', 'Gene', (145, 155))
164942	31529338	HAI-1 silencing in SAS cells further enhanced the migratory CAF phenotype, due to an increase in active matriptase produced by the cancer cells.	('cancer', 'Disease', (131, 137))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('CAF', 'Gene', (60, 63))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('CAF', 'Gene', '8850', (60, 63))	('matriptase', 'Gene', '19143', (104, 114))	('rat', 'Species', '10116', (53, 56))	('SAS', 'CellLine', 'CVCL:1675', (19, 22))	('increase', 'PosReg', (85, 93))	('HAI-1', 'Gene', (0, 5))	('enhanced', 'PosReg', (37, 45))	('silencing', 'Var', (6, 15))	('matriptase', 'Gene', (104, 114))
164947	31529338	In some cases, DESC1 is undetectable in HNSCC, which suggests that loss of the protease may be important for the development of SCC.	('SCC', 'Gene', (128, 131))	('SCC', 'Gene', (42, 45))	('SCC', 'Gene', '6317', (128, 131))	('SCC', 'Gene', '6317', (42, 45))	('loss', 'Var', (67, 71))
164965	31529338	Stable knock-down (KD) of TMPRSS3 in NPC cells reduced the proliferation and invasive phenotype of the cells in vitro by inhibition of the PI3K/Akt oncogenic signaling pathway.	('NPC', 'Gene', '4864', (37, 40))	('TMPRSS3', 'Gene', (26, 33))	('TMPRSS3', 'Gene', '64699', (26, 33))	('knock-down', 'Var', (7, 17))	('rat', 'Species', '10116', (66, 69))	('PI3K/Akt oncogenic signaling pathway', 'Pathway', (139, 175))	('NPC', 'Gene', (37, 40))	('invasive phenotype of the cells in vitro', 'CPA', (77, 117))	('inhibition', 'NegReg', (121, 131))	('reduced', 'NegReg', (47, 54))
164969	31529338	In ESCC tissues and cell lines with low or undetectable expression of prostasin, the CpG island-containing region of the PRSS8 gene promoter was hypermethylated.	('SCC', 'Gene', (4, 7))	('PRSS8', 'Gene', (121, 126))	('PRSS8', 'Gene', '5652', (121, 126))	('SCC', 'Gene', '6317', (4, 7))	('hypermethylated', 'Var', (145, 160))
164970	31529338	This CpG island hypermethylation silenced prostasin expression and could be reversed by treatment of cells with the demethylating agent decitabine.	('prostasin', 'Protein', (42, 51))	('hypermethylation', 'Var', (16, 32))	('expression', 'MPA', (52, 62))	('silenced', 'NegReg', (33, 41))	('decitabine', 'Chemical', 'MESH:D000077209', (136, 146))
164979	31529338	For mechanistic studies, primary mammary carcinoma cells with genetic disruption of the matriptase encoding gene by tamoxifen-inducible Cre-loxP recombination were generated.	('carcinoma', 'Phenotype', 'HP:0030731', (41, 50))	('matriptase', 'Gene', (88, 98))	('carcinoma', 'Disease', (41, 50))	('tamoxifen', 'Chemical', 'MESH:D013629', (116, 125))	('matriptase', 'Gene', '19143', (88, 98))	('rat', 'Species', '10116', (168, 171))	('mammary carcinoma', 'Phenotype', 'HP:0003002', (33, 50))	('carcinoma', 'Disease', 'MESH:D009369', (41, 50))	('genetic disruption', 'Var', (62, 80))
164991	31529338	Thirteen single nucleotide polymorphisms (SNPs) in the TMPRSS6 gene were investigated in triple-negative breast cancer and four variants were associated with reduced matriptase-2 expression and poor survival.	('matriptase-2 expression', 'MPA', (166, 189))	('TMPRSS6', 'Gene', '164656', (55, 62))	('single nucleotide polymorphisms', 'Var', (9, 40))	('breast cancer', 'Disease', 'MESH:D001943', (105, 118))	('TMPRSS6', 'Gene', (55, 62))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('reduced', 'NegReg', (158, 165))	('breast cancer', 'Disease', (105, 118))	('breast cancer', 'Phenotype', 'HP:0003002', (105, 118))
164995	31529338	Hepsin facilitates the invasive potential of breast cancer cells through remodeling of the basement membrane by cleavage of laminin-332, a component of the hemidesmosome at cell-cell junctions.	('cleavage', 'Var', (112, 120))	('Hepsin', 'Protein', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('laminin-332', 'Protein', (124, 135))	('remodeling of the basement membrane', 'CPA', (73, 108))	('facilitates', 'PosReg', (7, 18))	('breast cancer', 'Disease', 'MESH:D001943', (45, 58))	('breast cancer', 'Disease', (45, 58))	('breast cancer', 'Phenotype', 'HP:0003002', (45, 58))	('invasive potential', 'CPA', (23, 41))
164996	31529338	Decreasing hepsin activity with a selective inhibitor or its expression with siRNA-mediated silencing reduced desmosome cleavage and impaired the proliferation and invasiveness of cultured breast cancer cells.	('invasiveness', 'CPA', (164, 176))	('activity', 'MPA', (18, 26))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('Decreasing', 'NegReg', (0, 10))	('hepsin', 'Protein', (11, 17))	('proliferation', 'CPA', (146, 159))	('rat', 'Species', '10116', (153, 156))	('breast cancer', 'Disease', 'MESH:D001943', (189, 202))	('expression', 'MPA', (61, 71))	('silencing', 'Var', (92, 101))	('breast cancer', 'Phenotype', 'HP:0003002', (189, 202))	('impaired', 'NegReg', (133, 141))	('breast cancer', 'Disease', (189, 202))	('reduced', 'NegReg', (102, 109))	('desmosome cleavage', 'MPA', (110, 128))
165005	31529338	Prostasin expression may be lost in breast cancer cells lines due to methylation of its promoter region, as treatment of breast cancer cell lines with a DNA methyltransferase inhibitor was able to reactivate prostasin expression.	('breast cancer', 'Phenotype', 'HP:0003002', (36, 49))	('breast cancer', 'Disease', (36, 49))	('expression', 'MPA', (10, 20))	('breast cancer', 'Disease', 'MESH:D001943', (121, 134))	('lost', 'NegReg', (28, 32))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('breast cancer', 'Disease', (121, 134))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('methylation', 'Var', (69, 80))	('breast cancer', 'Phenotype', 'HP:0003002', (121, 134))	('breast cancer', 'Disease', 'MESH:D001943', (36, 49))
165010	31529338	Silencing of matriptase expression with siRNA or inhibition of matriptase activity using small-molecule inhibitors in the CRC cell line DLD-1 led to decreased activation of pro-HGF and decreased cell invasion through an extracellular matrix in vitro.	('activation', 'PosReg', (159, 169))	('decreased', 'NegReg', (185, 194))	('matriptase', 'Gene', '19143', (13, 23))	('matriptase', 'Gene', '19143', (63, 73))	('pro-HGF', 'Protein', (173, 180))	('matriptase', 'Gene', (13, 23))	('decreased', 'NegReg', (149, 158))	('matriptase', 'Gene', (63, 73))	('Silencing', 'Var', (0, 9))	('inhibition', 'NegReg', (49, 59))
165011	31529338	Similarly to matriptase null mice, which have severe epidermal barrier defects, mice with matriptase ablation specifically in the intestinal epithelium (villin-Cre+/0;St14LoxP/-) display intestinal epithelial barrier defects due to decreased tight junction formation.	('matriptase', 'Gene', '19143', (13, 23))	('ablation', 'Var', (101, 109))	('tight junction formation', 'CPA', (242, 266))	('matriptase', 'Gene', '19143', (90, 100))	('matriptase', 'Gene', (13, 23))	('intestinal epithelial barrier defects', 'CPA', (187, 224))	('mice', 'Species', '10090', (80, 84))	('mice', 'Species', '10090', (29, 33))	('decreased', 'NegReg', (232, 241))	('matriptase', 'Gene', (90, 100))
165018	31529338	RNAi-mediated silencing of TMPRSS4 in the CRC cell line HCT116 demonstrated decreased cell proliferation, invasion and migration, as well as a reduction in the cancer stem cell (CSC) markers CD44 and CD133.	('silencing', 'Var', (14, 23))	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('rat', 'Species', '10116', (70, 73))	('cancer', 'Disease', (160, 166))	('CD133', 'Gene', (200, 205))	('TMPRSS4', 'Gene', (27, 34))	('CD133', 'Gene', '8842', (200, 205))	('decreased', 'NegReg', (76, 85))	('invasion', 'CPA', (106, 114))	('HCT116', 'CellLine', 'CVCL:0291', (56, 62))	('cell proliferation', 'CPA', (86, 104))	('rat', 'Species', '10116', (98, 101))	('rat', 'Species', '10116', (122, 125))	('reduction', 'NegReg', (143, 152))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('CD44', 'Gene', '960', (191, 195))	('TMPRSS4', 'Gene', '56649', (27, 34))	('CD44', 'Gene', (191, 195))
165030	31529338	Since epidermal ablation of either prostasin or matriptase leads to identical epidermal barrier phenotypes, it is plausible that the conditional prostasin KO mice have impaired intestinal barrier function which could promote inflammation and carcinogenesis as a secondary effect.	('inflammation', 'Disease', 'MESH:D007249', (225, 237))	('carcinogenesis', 'Disease', (242, 256))	('matriptase', 'Gene', '19143', (48, 58))	('KO', 'Gene', '3856', (155, 157))	('mice', 'Species', '10090', (158, 162))	('promote', 'PosReg', (217, 224))	('inflammation', 'Disease', (225, 237))	('intestinal barrier function', 'CPA', (177, 204))	('ablation', 'Var', (16, 24))	('matriptase', 'Gene', (48, 58))	('impaired', 'NegReg', (168, 176))	('carcinogenesis', 'Disease', 'MESH:D063646', (242, 256))
165045	31529338	In a later study, genome-profiling was performed in epithelial ovarian cancer (EOC) cell lines following treatment with S-adenosyl-l-methionine (SAM, a compound that stimulates DNA methylation).	('epithelial ovarian cancer', 'Disease', (52, 77))	('epithelial ovarian cancer', 'Phenotype', 'HP:0025318', (52, 77))	('S-adenosyl-l-methionine', 'Chemical', 'MESH:D012436', (120, 143))	('SAM', 'Chemical', 'MESH:D012436', (145, 148))	('ovarian cancer', 'Phenotype', 'HP:0100615', (63, 77))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('S-adenosyl-l-methionine', 'Var', (120, 143))	('DNA methylation', 'MPA', (177, 192))	('epithelial ovarian cancer', 'Disease', 'MESH:D000077216', (52, 77))
165049	31529338	TMPRSS3 overexpression in the ovarian cancer cell line A2780 increased proliferation, invasion, and migration of the cells, and conversely, silencing of TMPRSS3 in HO8910 cells had the opposite effect further suggesting a role of TMPRSS3 as a pro-oncogenic protease in ovarian cancer.	('ovarian cancer', 'Disease', (30, 44))	('ovarian cancer', 'Phenotype', 'HP:0100615', (269, 283))	('increased', 'PosReg', (61, 70))	('proliferation', 'CPA', (71, 84))	('ovarian cancer', 'Phenotype', 'HP:0100615', (30, 44))	('rat', 'Species', '10116', (103, 106))	('TMPRSS3', 'Gene', (230, 237))	('rat', 'Species', '10116', (78, 81))	('TMPRSS3', 'Gene', (0, 7))	('HO8910', 'CellLine', 'CVCL:6868', (164, 170))	('silencing', 'Var', (140, 149))	('cancer', 'Phenotype', 'HP:0002664', (277, 283))	('TMPRSS3', 'Gene', '64699', (153, 160))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('A2780', 'CellLine', 'CVCL:0134', (55, 60))	('ovarian cancer', 'Disease', 'MESH:D010051', (269, 283))	('overexpression', 'PosReg', (8, 22))	('migration of the cells', 'CPA', (100, 122))	('ovarian cancer', 'Disease', 'MESH:D010051', (30, 44))	('TMPRSS3', 'Gene', '64699', (0, 7))	('TMPRSS3', 'Gene', '64699', (230, 237))	('invasion', 'CPA', (86, 94))	('TMPRSS3', 'Gene', (153, 160))	('ovarian cancer', 'Disease', (269, 283))
165062	31529338	When matriptase expression was reduced in these cells using hammerhead ribozyme transgenes, the cells exhibited slower growth, reduced invasion and migration, and increased cell-cell adhesion.	('slower', 'NegReg', (112, 118))	('reduced', 'NegReg', (31, 38))	('increased', 'PosReg', (163, 172))	('matriptase', 'Gene', (5, 15))	('hammerhead ribozyme', 'Var', (60, 79))	('cell-cell adhesion', 'CPA', (173, 191))	('rat', 'Species', '10116', (151, 154))	('reduced', 'NegReg', (127, 134))	('expression', 'MPA', (16, 26))	('matriptase', 'Gene', '19143', (5, 15))
165068	31529338	This lends credence to the idea that dysregulation of HAI-1 expression, under some conditions, can lead to a more aggressive prostate cancer phenotype.	('dysregulation', 'Var', (37, 50))	('lead to', 'Reg', (99, 106))	('aggressive prostate cancer', 'Disease', 'MESH:D011471', (114, 140))	('prostate cancer', 'Phenotype', 'HP:0012125', (125, 140))	('aggressive prostate cancer', 'Disease', (114, 140))	('HAI-1', 'Gene', (54, 59))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('more', 'PosReg', (109, 113))
165071	31529338	Furthermore, shRNA-mediated silencing of HAI-2 in CWR22Rv1 prostate cancer cells demonstrated increased levels of active matriptase and increased prostate cancer invasiveness, while overexpression of HAI-2 in N2 cells showed co-localization with matriptase on the cell surface, reduced matriptase activity, and reduced invasive capability.	('levels', 'MPA', (104, 110))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('matriptase', 'Gene', (246, 256))	('prostate cancer', 'Disease', 'MESH:D011471', (59, 74))	('prostate cancer', 'Phenotype', 'HP:0012125', (59, 74))	('increased', 'PosReg', (94, 103))	('rat', 'Species', '10116', (88, 91))	('prostate cancer', 'Disease', 'MESH:D011471', (146, 161))	('invasive capability', 'CPA', (319, 338))	('prostate cancer', 'Phenotype', 'HP:0012125', (146, 161))	('reduced', 'NegReg', (311, 318))	('prostate cancer', 'Disease', (59, 74))	('matriptase', 'Gene', '19143', (121, 131))	('increased prostate cancer invasiveness', 'Disease', 'MESH:D011471', (136, 174))	('silencing', 'Var', (28, 37))	('reduced', 'NegReg', (278, 285))	('matriptase', 'Gene', '19143', (286, 296))	('CWR22Rv1', 'CellLine', 'CVCL:1045', (50, 58))	('HAI-2', 'Gene', (41, 46))	('increased prostate cancer invasiveness', 'Disease', (136, 174))	('matriptase', 'Gene', '19143', (246, 256))	('matriptase', 'Gene', (121, 131))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('N2', 'CellLine', 'CVCL:H592', (209, 211))	('matriptase', 'Gene', (286, 296))
165072	31529338	Silencing of matriptase reduced the invasive potential induced by HAI-2 silencing in CWR22Rv1 cells.	('matriptase', 'Gene', '19143', (13, 23))	('silencing', 'Var', (72, 81))	('reduced', 'NegReg', (24, 31))	('HAI-2', 'Gene', (66, 71))	('matriptase', 'Gene', (13, 23))	('Silencing', 'Var', (0, 9))	('CWR22Rv1', 'CellLine', 'CVCL:1045', (85, 93))	('invasive potential', 'CPA', (36, 54))
165074	31529338	These results suggest that matriptase activity is primarily controlled by HAI-2 in prostate cancer and that an imbalance between HAI-2 and matriptase expression leads to matriptase-mediated cell migration, invasion, and metastasis.	('leads to', 'Reg', (161, 169))	('matriptase', 'Gene', (139, 149))	('matriptase', 'Gene', '19143', (27, 37))	('imbalance', 'Var', (111, 120))	('activity', 'MPA', (38, 46))	('imbalance', 'Phenotype', 'HP:0002172', (111, 120))	('matriptase', 'Gene', (170, 180))	('prostate cancer', 'Disease', 'MESH:D011471', (83, 98))	('prostate cancer', 'Phenotype', 'HP:0012125', (83, 98))	('invasion', 'CPA', (206, 214))	('matriptase', 'Gene', '19143', (139, 149))	('rat', 'Species', '10116', (198, 201))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('prostate cancer', 'Disease', (83, 98))	('matriptase', 'Gene', '19143', (170, 180))	('matriptase', 'Gene', (27, 37))	('HAI-2', 'Gene', (129, 134))	('metastasis', 'CPA', (220, 230))
165085	31529338	Dysregulated ErbB-2 signaling is associated with cancer cell proliferation and invasion, and this signaling can be ligand-dependent as well as ligand-independent.	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('associated', 'Reg', (33, 43))	('Dysregulated', 'Var', (0, 12))	('ErbB-2', 'Gene', (13, 19))	('rat', 'Species', '10116', (68, 71))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('invasion', 'CPA', (79, 87))	('cancer', 'Disease', (49, 55))
165091	31529338	Matriptase was identified as a TMPRSS2 substrate in prostate cancer cell lines, where TMPRSS2 can proteolytically activate matriptase and enhance its shedding.	('Matriptase', 'Gene', (0, 10))	('Matriptase', 'Gene', '19143', (0, 10))	('enhance', 'PosReg', (138, 145))	('TMPRSS2', 'Var', (86, 93))	('matriptase', 'Gene', (123, 133))	('prostate cancer', 'Disease', 'MESH:D011471', (52, 67))	('activate', 'PosReg', (114, 122))	('rat', 'Species', '10116', (44, 47))	('shedding', 'MPA', (150, 158))	('prostate cancer', 'Phenotype', 'HP:0012125', (52, 67))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('prostate cancer', 'Disease', (52, 67))	('proteolytically', 'MPA', (98, 113))	('matriptase', 'Gene', '19143', (123, 133))
165094	31529338	This matriptase activation mechanism is dependent on activation of Src tyrosine kinase by androgen binding to androgen receptor (AR), and silencing of matriptase with siRNA significantly decreases the AR-dependent invasiveness of the PC-3 cells.	('androgen receptor', 'Gene', '367', (110, 127))	('silencing', 'Var', (138, 147))	('matriptase', 'Gene', '19143', (151, 161))	('androgen receptor', 'Gene', (110, 127))	('AR', 'Gene', '367', (201, 203))	('matriptase', 'Gene', (5, 15))	('Src tyrosine kinase', 'Enzyme', (67, 86))	('AR', 'Gene', '367', (129, 131))	('matriptase', 'Gene', '19143', (5, 15))	('decreases', 'NegReg', (187, 196))	('PC-3', 'CellLine', 'CVCL:0035', (234, 238))	('binding', 'Interaction', (99, 106))	('matriptase', 'Gene', (151, 161))
165096	31529338	COX-2 silencing in PC-3 cells leads to a 90% decrease in levels of activated matriptase.	('PC-3', 'CellLine', 'CVCL:0035', (19, 23))	('matriptase', 'Gene', (77, 87))	('decrease', 'NegReg', (45, 53))	('matriptase', 'Gene', '19143', (77, 87))	('COX-2', 'Gene', (0, 5))	('COX-2', 'Gene', '5743', (0, 5))	('silencing', 'Var', (6, 15))
165103	31529338	Furthermore, a major 11-locus haplotype was significantly associated with prostate cancer susceptibility and one of the SNPs correlated with Gleason score.	('associated', 'Reg', (58, 68))	('prostate cancer', 'Disease', (74, 89))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('haplotype', 'Var', (30, 39))	('prostate cancer', 'Disease', 'MESH:D011471', (74, 89))	('prostate cancer', 'Phenotype', 'HP:0012125', (74, 89))
165119	31529338	In a different study, a mouse model was generated in which PB-Hepsin transgenic mice were crossed with mice in which adenomatous polyposis coli (APC, a tumor suppressor that inhibits Wnt signaling), was knocked out in the prostate (ApcPBKOHepsin mice).	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('adenomatous polyposis coli', 'Phenotype', 'HP:0005227', (117, 143))	('mouse', 'Species', '10090', (24, 29))	('adenomatous polyposis coli', 'Gene', (117, 143))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('mice', 'Species', '10090', (103, 107))	('tumor', 'Disease', (152, 157))	('rat', 'Species', '10116', (44, 47))	('APC', 'Disease', 'MESH:D011125', (145, 148))	('PB', 'Gene', '54192', (235, 237))	('mice', 'Species', '10090', (80, 84))	('mice', 'Species', '10090', (246, 250))	('APC', 'Disease', (145, 148))	('transgenic mice', 'Species', '10090', (69, 84))	('knocked out', 'Var', (203, 214))	('PB', 'Gene', '54192', (59, 61))
165124	31529338	Around 50% of prostate cancers harbor a gene rearrangement between TMPRSS2 and estrogen-regulated gene (ERG), a member of the erythroblast transformation specific (ETS) family of transcription factors.	('prostate cancers', 'Disease', 'MESH:D011471', (14, 30))	('cancers', 'Phenotype', 'HP:0002664', (23, 30))	('ERG', 'Gene', (104, 107))	('prostate cancer', 'Phenotype', 'HP:0012125', (14, 29))	('prostate cancers', 'Phenotype', 'HP:0012125', (14, 30))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('prostate cancers', 'Disease', (14, 30))	('TMPRSS2', 'Gene', (67, 74))	('gene rearrangement', 'Var', (40, 58))
165136	31529338	Thus, the mRNA expression of uPA, uPAR, COX-2, and the inducible nitric oxide synthase (iNOS) was decreased by WT and active-site mutant prostasin in PC-3 cells.	('uPA', 'Gene', (29, 32))	('decreased', 'NegReg', (98, 107))	('uPAR', 'Gene', (34, 38))	('iNOS', 'Gene', (88, 92))	('uPA', 'Gene', '5328', (29, 32))	('inducible nitric oxide synthase', 'Gene', (55, 86))	('uPA', 'Gene', (34, 37))	('iNOS', 'Gene', '4843', (88, 92))	('COX-2', 'Gene', (40, 45))	('mRNA expression', 'MPA', (10, 25))	('COX-2', 'Gene', '5743', (40, 45))	('inducible nitric oxide synthase', 'Gene', '4843', (55, 86))	('PC-3', 'CellLine', 'CVCL:0035', (150, 154))	('uPA', 'Gene', '5328', (34, 37))	('active-site mutant', 'Var', (118, 136))	('uPAR', 'Gene', '5329', (34, 38))
165137	31529338	Mutant prostasin reduced the protein level of EGFR upon treatment of the cells with EGF but did not affect the mRNA expression of EGFR or the expression of activated Erk2, a kinase downstream of EGFR signaling.	('Erk2', 'Gene', (166, 170))	('EGFR', 'Gene', (195, 199))	('EGFR', 'Gene', '1956', (46, 50))	('EGF', 'Gene', '1950', (84, 87))	('EGF', 'Gene', (46, 49))	('EGFR', 'Gene', (130, 134))	('reduced', 'NegReg', (17, 24))	('EGF', 'Gene', '1950', (195, 198))	('protein level', 'MPA', (29, 42))	('prostasin', 'Gene', (7, 16))	('EGF', 'Gene', '1950', (130, 133))	('EGFR', 'Gene', '1956', (195, 199))	('EGF', 'Gene', (84, 87))	('EGF', 'Gene', (195, 198))	('EGFR', 'Gene', (46, 50))	('Mutant', 'Var', (0, 6))	('EGFR', 'Gene', '1956', (130, 134))	('EGF', 'Gene', '1950', (46, 49))	('EGF', 'Gene', (130, 133))	('Erk2', 'Gene', '5594', (166, 170))
165140	31529338	Furthermore, the mutant prostasin significantly upregulated the mRNA and protein expression of matriptase in PC-3 cells, indicating that both proteolytically active and inactive prostasin play a role in matriptase-mediated oncogenic signaling.	('matriptase', 'Gene', '19143', (203, 213))	('matriptase', 'Gene', (95, 105))	('prostasin', 'Gene', (24, 33))	('PC-3', 'CellLine', 'CVCL:0035', (109, 113))	('matriptase', 'Gene', (203, 213))	('upregulated', 'PosReg', (48, 59))	('matriptase', 'Gene', '19143', (95, 105))	('mutant', 'Var', (17, 23))
165143	31529338	Furthermore, high matriptase expression is significantly associated with poor progression-free and overall survival in patients with endometrial cancer.	('progression-free', 'CPA', (78, 94))	('endometrial cancer', 'Phenotype', 'HP:0012114', (133, 151))	('high', 'Var', (13, 17))	('endometrial cancer', 'Disease', 'MESH:D016889', (133, 151))	('patients', 'Species', '9606', (119, 127))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('matriptase', 'Gene', '19143', (18, 28))	('overall survival', 'CPA', (99, 115))	('endometrial cancer', 'Disease', (133, 151))	('expression', 'MPA', (29, 39))	('poor', 'NegReg', (73, 77))	('matriptase', 'Gene', (18, 28))
165147	31529338	These improved patient outcomes are likely due to HAI-1/HAI-2 inhibition of their oncogenic protease targets, including matriptase.	('patient', 'Species', '9606', (15, 22))	('improved', 'PosReg', (6, 14))	('HAI-1/HAI-2', 'Var', (50, 61))	('matriptase', 'Gene', (120, 130))	('matriptase', 'Gene', '19143', (120, 130))	('inhibition', 'NegReg', (62, 72))
165156	31529338	Hepsin is another target for inhibition by HAI-1 and HAI-2, and overexpression of HAI-1 and HAI-2 in HeLa and SiHa cervical cancer cell lines reduced hepsin protein expression and induced apoptosis.	('induced', 'Reg', (180, 187))	('HeLa', 'CellLine', 'CVCL:0030', (101, 105))	('HAI-1', 'Var', (82, 87))	('reduced', 'NegReg', (142, 149))	('SiHa cervical cancer', 'Disease', (110, 130))	('apoptosis', 'CPA', (188, 197))	('overexpression', 'PosReg', (64, 78))	('HAI-2', 'Var', (92, 97))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('SiHa cervical cancer', 'Disease', 'MESH:D002583', (110, 130))	('hepsin protein', 'Protein', (150, 164))
165165	31529338	Thus, HAI-1 stable knock-down in the SUIT-2 pancreatic cancer cell line caused the cells to adopt an EMT-like phenotype, including reduced levels of the epithelial marker E-cadherin and increased expression of matrix metalloprotease-9 (MMP-9), a protease associated with ECM cleavage.	('SUIT-2 pancreatic cancer', 'Disease', (37, 61))	('SUIT-2 pancreatic cancer', 'Disease', 'MESH:D010190', (37, 61))	('EMT-like', 'CPA', (101, 109))	('E-cadherin', 'Gene', (171, 181))	('increased', 'PosReg', (186, 195))	('expression', 'MPA', (196, 206))	('matrix metalloprotease-9', 'Gene', (210, 234))	('E-cadherin', 'Gene', '999', (171, 181))	('reduced', 'NegReg', (131, 138))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (44, 61))	('MMP-9', 'Gene', '4318', (236, 241))	('matrix metalloprotease-9', 'Gene', '4318', (210, 234))	('HAI-1', 'Gene', (6, 11))	('MMP-9', 'Gene', (236, 241))	('knock-down', 'Var', (19, 29))
165166	31529338	Stable knock-down of matriptase in HAI-1 knockdown SUIT-2 cells partially reversed the EMT-like phenotype of the cells, suggesting that matriptase may be acting alongside other HAI-1 targets like TMPRSS4 to enhance invasiveness of pancreatic cancer cells.	('matriptase', 'Gene', '19143', (21, 31))	('cancer', 'Phenotype', 'HP:0002664', (242, 248))	('knock-down', 'Var', (7, 17))	('TMPRSS4', 'Gene', (196, 203))	('invasiveness of pancreatic cancer', 'Disease', (215, 248))	('matriptase', 'Gene', (136, 146))	('invasiveness of pancreatic cancer', 'Disease', 'MESH:D010190', (215, 248))	('TMPRSS4', 'Gene', '56649', (196, 203))	('enhance', 'PosReg', (207, 214))	('matriptase', 'Gene', (21, 31))	('matriptase', 'Gene', '19143', (136, 146))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (231, 248))
165167	31529338	In vivo models using SUIT-2 and S2-CP8 pancreatic cancer cell xenografts showed that loss of HAI-1 in these cells increased the number of lung metastases, while forced overexpression of HAI-1 in S2-CP8 cells decreased the number of metastatic lesions.	('loss', 'Var', (85, 89))	('lung metastases', 'Disease', (138, 153))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (39, 56))	('HAI-1', 'Gene', (93, 98))	('lung metastases', 'Disease', 'MESH:D009362', (138, 153))	('increased', 'PosReg', (114, 123))	('pancreatic cancer', 'Disease', (39, 56))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('pancreatic cancer', 'Disease', 'MESH:D010190', (39, 56))
165168	31529338	These studies demonstrate an important role for HAI-1 regulation of metastatic spreading in pancreatic cancer, mediated in part by dysregulation of matriptase expression.	('HAI-1', 'Gene', (48, 53))	('matriptase', 'Gene', (148, 158))	('metastatic spreading', 'CPA', (68, 88))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (92, 109))	('pancreatic cancer', 'Disease', 'MESH:D010190', (92, 109))	('expression', 'MPA', (159, 169))	('matriptase', 'Gene', '19143', (148, 158))	('rat', 'Species', '10116', (21, 24))	('pancreatic cancer', 'Disease', (92, 109))	('dysregulation', 'Var', (131, 144))
165175	31529338	It was found that, in cell lines that do not express testisin like the embryonal carcinoma line Tera-2, the promoter CpG rich region of the testisin gene is hypermethylated, leading to silencing of the gene.	('testisin', 'Gene', (140, 148))	('embryonal carcinoma', 'Disease', 'MESH:D018236', (71, 90))	('Tera-2', 'CellLine', 'CVCL:2777', (96, 102))	('hypermethylated', 'Var', (157, 172))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('embryonal carcinoma', 'Phenotype', 'HP:0002898', (71, 90))	('embryonal carcinoma', 'Disease', (71, 90))	('silencing', 'MPA', (185, 194))
165176	31529338	Hypermethylation was also observed in primary testicular tumors, while adjacent normal testis tissue harbored mainly unmethylated testisin promoters.	('testicular tumors', 'Disease', 'MESH:D013736', (46, 63))	('testicular tumors', 'Phenotype', 'HP:0010788', (46, 63))	('Hypermethylation', 'Var', (0, 16))	('observed', 'Reg', (26, 34))	('testicular tumors', 'Disease', (46, 63))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))
165179	31529338	Interestingly, the cleavage of PAR-2 induces its internalization and intracellular signaling and may contribute to its degradation.	('induces', 'Reg', (37, 44))	('contribute', 'Reg', (101, 111))	('PAR-2', 'Gene', '2150', (31, 36))	('intracellular signaling', 'MPA', (69, 92))	('internalization', 'MPA', (49, 64))	('cleavage', 'Var', (19, 27))	('degradation', 'MPA', (119, 130))	('PAR-2', 'Gene', (31, 36))
165183	31529338	Silencing of matriptase in B-cell Burkitt's lymphoma Namalwa cells caused a significant reduction in cell invasion through reconstituted basement membrane matrix, but the proliferation of the cells was unaffected.	('matriptase', 'Gene', '19143', (13, 23))	("Burkitt's lymphoma", 'Phenotype', 'HP:0030080', (34, 52))	('lymphoma', 'Phenotype', 'HP:0002665', (44, 52))	("Burkitt's lymphoma", 'Disease', 'MESH:D002051', (34, 52))	('reduction', 'NegReg', (88, 97))	("Burkitt's lymphoma", 'Disease', (34, 52))	('matriptase', 'Gene', (13, 23))	('rat', 'Species', '10116', (178, 181))	('Silencing', 'Var', (0, 9))
165193	31529338	RNAi-mediated silencing of HATL-4 in the THP-1 AML cell line significantly reduced cell invasion, mediated by reduced activation of MMP-2 and ECM cleavage.	('silencing', 'Var', (14, 23))	('activation', 'PosReg', (118, 128))	('MMP-2', 'Gene', '4313', (132, 137))	('reduced', 'NegReg', (110, 117))	('HATL-4', 'Gene', (27, 33))	('cell invasion', 'CPA', (83, 96))	('THP-1', 'Gene', (41, 46))	('AML', 'Disease', 'MESH:D015470', (47, 50))	('HATL-4', 'Gene', '389208', (27, 33))	('reduced', 'NegReg', (75, 82))	('THP-1', 'Gene', '2736', (41, 46))	('ECM cleavage', 'CPA', (142, 154))	('AML', 'Disease', (47, 50))	('MMP-2', 'Gene', (132, 137))
165209	31529338	A significant reduction in final mean tumor volume was observed in CVS-3983 treated compared to vehicle-treated mice.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('CVS-3983', 'Var', (67, 75))	('reduction', 'NegReg', (14, 23))	('mice', 'Species', '10090', (112, 116))
165210	31529338	Additionally, in a cell culture assay CVS-3983 reduced the invasion of prostate cancer cell lines through reconstituted ECM.	('invasion of prostate cancer', 'Disease', (59, 86))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('CVS-3983', 'Var', (38, 46))	('prostate cancer', 'Phenotype', 'HP:0012125', (71, 86))	('reduced', 'NegReg', (47, 54))	('invasion of prostate cancer', 'Disease', 'MESH:D011471', (59, 86))
165216	31529338	Although CVS-3983 and analogs 8 and 59 are highly selective towards matriptase when compared to the tested secreted serine proteases, it cannot be ruled out that the inhibition of additional proteases including TTSP family members plays a role in the cell culture and in vivo models used.	('matriptase', 'Gene', '19143', (68, 78))	('TTSP', 'Gene', '243084', (211, 215))	('matriptase', 'Gene', (68, 78))	('TTSP', 'Gene', (211, 215))	('CVS-3983', 'Var', (9, 17))
165223	31529338	One scFv was shown to detect denatured matriptase by western blot analysis with no cross reactivity to other family members in HeLa or PC-3 cell lysates.	('scFv', 'Gene', '652070', (4, 8))	('matriptase', 'Gene', (39, 49))	('scFv', 'Gene', (4, 8))	('PC-3', 'CellLine', 'CVCL:0035', (135, 139))	('HeLa', 'CellLine', 'CVCL:0030', (127, 131))	('matriptase', 'Gene', '19143', (39, 49))	('denatured', 'Var', (29, 38))
165235	31529338	MAbs were generated in mice immunized with a mutated variant of human matriptase in which the serine protease domain is locked in the zymogen conformation (R614A).	('human', 'Species', '9606', (64, 69))	('matriptase', 'Gene', '19143', (70, 80))	('R614A', 'Var', (156, 161))	('R614A', 'Mutation', 'p.R614A', (156, 161))	('matriptase', 'Gene', (70, 80))	('rat', 'Species', '10116', (14, 17))	('mutated', 'Var', (45, 52))	('mice', 'Species', '10090', (23, 27))
165243	31529338	M69 has previously been shown to bind active matriptase and matriptase in complex with HAI-1 with no cross-activity with epithin.	('matriptase', 'Gene', (60, 70))	('epithin', 'Gene', (121, 128))	('matriptase', 'Gene', '19143', (45, 55))	('bind', 'Interaction', (33, 37))	('epithin', 'Gene', '19143', (121, 128))	('M69', 'Var', (0, 3))	('matriptase', 'Gene', '19143', (60, 70))	('matriptase', 'Gene', (45, 55))
165244	31529338	M69-MMAE displayed IC50 equivalent values ranging from 30-322 pM in cell lines expressing high levels of matriptase versus 758-838 pM in cell lines with low expression.	('matriptase', 'Gene', '19143', (105, 115))	('matriptase', 'Gene', (105, 115))	('IC50 equivalent', 'MPA', (19, 34))	('M69-MMAE', 'Var', (0, 8))
165249	31529338	Anti-tumor activity of M69-MMAE against TNBC-PDX tumors was also observed.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('M69-MMAE', 'Var', (23, 31))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('TNBC-PDX tumors', 'Disease', (40, 55))	('TNBC-PDX tumors', 'Disease', 'MESH:D009369', (40, 55))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('tumor', 'Disease', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('tumor', 'Disease', (5, 10))
165250	31529338	Furthermore, the ADC enhanced the anti-tumor response of cisplatin in MDA-MB-468 xenografts, which suggests that targeted therapy against matriptase in combination with conventional chemotherapy may provide treatment benefits for breast cancer patients.	('breast cancer', 'Disease', 'MESH:D001943', (230, 243))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('breast cancer', 'Disease', (230, 243))	('enhanced', 'PosReg', (21, 29))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('breast cancer', 'Phenotype', 'HP:0003002', (230, 243))	('matriptase', 'Gene', '19143', (138, 148))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('ADC', 'Var', (17, 20))	('MDA-MB-468', 'CellLine', 'CVCL:0419', (70, 80))	('cisplatin', 'Chemical', 'MESH:D002945', (57, 66))	('tumor', 'Disease', (39, 44))	('patients', 'Species', '9606', (244, 252))	('matriptase', 'Gene', (138, 148))
165255	31529338	In humans with mutations in the matriptase encoding ST14 gene rendering the protease inactive or retaining very low activity, no gastrointestinal symptoms were reported Therefore, it still remains of high priority to assess the safety of matriptase targeting in clinical settings.	('matriptase', 'Gene', (238, 248))	('matriptase', 'Gene', (32, 42))	('ST14', 'Gene', '6768', (52, 56))	('mutations', 'Var', (15, 24))	('gastrointestinal symptoms', 'Disease', 'MESH:D012817', (129, 154))	('humans', 'Species', '9606', (3, 9))	('ST14', 'Gene', (52, 56))	('matriptase', 'Gene', '19143', (32, 42))	('activity', 'MPA', (116, 124))	('matriptase', 'Gene', '19143', (238, 248))	('protease', 'Enzyme', (76, 84))	('gastrointestinal symptoms', 'Disease', (129, 154))
165259	31529338	Studies of peptidomimetics/semi-peptidic TTSP inhibitors revealed that removal of the N-terminal amino group (desamino) yielded more biologically stable compounds.	('TTSP', 'Gene', (41, 45))	('removal', 'Var', (71, 78))	('biologically stable compounds', 'MPA', (133, 162))	('desamino', 'Chemical', '-', (110, 118))	('TTSP', 'Gene', '243084', (41, 45))
165262	31529338	It was demonstrated that MCoTI-II is a significantly more potent matriptase inhibitor than SFTI-1 and that all alanine mutants of both peptides, generated using positional scanning mutagenesis, had decreased trypsin affinity, whereas several mutations resulted in enhanced matriptase inhibitory activity - the most potent with a Ki of 290 pM.	('rat', 'Species', '10116', (149, 152))	('decreased trypsin', 'Phenotype', 'HP:0032493', (198, 215))	('matriptase', 'Gene', '19143', (65, 75))	('alanine mutants', 'Var', (111, 126))	('matriptase', 'Gene', (273, 283))	('trypsin affinity', 'MPA', (208, 224))	('SFTI-1', 'Gene', '110928012', (91, 97))	('SFTI-1', 'Gene', (91, 97))	('rat', 'Species', '10116', (14, 17))	('enhanced', 'PosReg', (264, 272))	('alanine', 'Chemical', 'MESH:D000409', (111, 118))	('MCoTI-II', 'Chemical', '-', (25, 33))	('matriptase', 'Gene', '19143', (273, 283))	('decreased', 'NegReg', (198, 207))	('Ki', 'Gene', '21941', (329, 331))	('matriptase', 'Gene', (65, 75))
165269	31529338	Macromolecular matriptase inhibitors include ecotin and variants (described above in 3.1), eglin C, and KD1-KD2/1-Fc (engineered HAI-1).	('variants', 'Var', (56, 64))	('matriptase', 'Gene', (15, 25))	('matriptase', 'Gene', '19143', (15, 25))
165270	31529338	In order to identify potent matriptase inhibitors, a cDNA library expressing variants of the protease inhibitor eglin C was screened.	('variants', 'Var', (77, 85))	('matriptase', 'Gene', '19143', (28, 38))	('eglin C', 'Gene', (112, 119))	('matriptase', 'Gene', (28, 38))
165271	31529338	The most potent of these, R1K4'-eglin, which had the wild-type Pro45 (P1 position) and Tyr49 (P4' position) residues replaced with arginine and lysine, respectively, led to the production of a selective, high affinity (Ki of 4 nM), and proteolytically stable inhibitor of matriptase.	('matriptase', 'Gene', '19143', (272, 282))	('Ki', 'Gene', '21941', (219, 221))	('Tyr49', 'Chemical', '-', (87, 92))	("R1K4'-eglin", 'Var', (26, 37))	('matriptase', 'Gene', (272, 282))	('lysine', 'Chemical', 'MESH:D008239', (144, 150))	('Pro45', 'Chemical', '-', (63, 68))	('Tyr49', 'Var', (87, 92))	('arginine', 'Chemical', 'MESH:D001120', (131, 139))
165281	31529338	Additionally, SRI31215 reduced primary resistance to cetuximab and gefitinib in pro-HGF-producing colon cancer cells, blocked crosstalk between c-MET-amplified non-small cell lung cancer (NSCLC) cells and pro-HGF-secreting fibroblasts, and perturbed fibroblast-mediated resistance to c-Met kinase inhibition in NSCLC cells.	('blocked', 'NegReg', (118, 125))	('perturbed', 'NegReg', (240, 249))	('colon cancer', 'Phenotype', 'HP:0003003', (98, 110))	('c-MET', 'Gene', '4233', (144, 149))	('lung cancer', 'Disease', (175, 186))	('c-MET', 'Gene', (144, 149))	('crosstalk', 'MPA', (126, 135))	('NSCLC', 'Disease', 'MESH:D002289', (188, 193))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('colon cancer', 'Disease', 'MESH:D015179', (98, 110))	('cetuximab', 'Chemical', 'MESH:D000068818', (53, 62))	('SRI31215', 'Var', (14, 22))	('lung cancer', 'Disease', 'MESH:D008175', (175, 186))	('primary resistance', 'MPA', (31, 49))	('NSCLC', 'Disease', (188, 193))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('lung cancer', 'Phenotype', 'HP:0100526', (175, 186))	('colon cancer', 'Disease', (98, 110))	('gefitinib', 'Chemical', 'MESH:D000077156', (67, 76))	('reduced', 'NegReg', (23, 30))	('NSCLC', 'Disease', 'MESH:D002289', (311, 316))	('SRI31215', 'Chemical', 'MESH:C000625563', (14, 22))	('NSCLC', 'Disease', (311, 316))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (164, 186))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (160, 186))
165289	31529338	It was demonstrated that the dipeptide analog Ac-LR-kbt (15) exhibited strong inhibition of hepsin activity with Ki values of 3.38 nM and 2.91 nM for the (S)-epimer and the (R)-epimer, respectively.	('hepsin activity', 'MPA', (92, 107))	('Ac-LR-kbt', 'Chemical', '-', (46, 55))	('Ac-LR-kbt', 'Var', (46, 55))	('dipeptide', 'Chemical', 'MESH:D004151', (29, 38))	('inhibition', 'NegReg', (78, 88))	('rat', 'Species', '10116', (14, 17))	('Ki', 'Gene', '21941', (113, 115))
165293	31529338	The Leu-Arg dipeptides attached to borondipyrromethene (BODIPY) or SulfoCy7 exhibited strong hepsin binding affinities with Ki values of 21 and 22nM, respectively and high selectivity over matriptase.	('Leu-Arg', 'Chemical', 'MESH:C078789', (4, 11))	('BODIPY', 'Chemical', '-', (56, 62))	('dipeptides', 'Chemical', 'MESH:D004151', (12, 22))	('SulfoCy7', 'Chemical', '-', (67, 75))	('borondipyrromethene', 'Chemical', '-', (35, 54))	('matriptase', 'Gene', '19143', (189, 199))	('Ki', 'Gene', '21941', (124, 126))	('hepsin', 'Protein', (93, 99))	('SulfoCy7', 'Var', (67, 75))	('Leu-Arg dipeptides', 'Var', (4, 22))	('matriptase', 'Gene', (189, 199))	('affinities', 'MPA', (108, 118))
165294	31529338	In cell uptake studies, SulfoCy7-conjugated inhibitor exhibited selective targeting and retention in hepsin-overexpressing prostate cancer cells.	('prostate cancer', 'Phenotype', 'HP:0012125', (123, 138))	('prostate cancer', 'Disease', (123, 138))	('retention', 'MPA', (88, 97))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('prostate cancer', 'Disease', 'MESH:D011471', (123, 138))	('SulfoCy7', 'Chemical', '-', (24, 32))	('SulfoCy7-conjugated', 'Var', (24, 43))
165329	31529338	The native activation sequence of PrAG was mutated to a sequence derived from protein C inhibitor (PCI), that can be cleaved by membrane-anchored serine proteases, to generate the mutant protein PrAg-PCIS.	('PCI', 'Gene', '5104', (99, 102))	('PCI', 'Gene', (200, 203))	('PrAg', 'Chemical', '-', (195, 199))	('PCI', 'Gene', (99, 102))	('PrAG', 'Gene', (34, 38))	('mutant', 'Var', (180, 186))	('protein C inhibitor', 'Gene', '5104', (78, 97))	('rat', 'Species', '10116', (171, 174))	('PCI', 'Gene', '5104', (200, 203))	('protein C inhibitor', 'Gene', (78, 97))
165424	30996568	Defining risk levels in locally advanced head and neck cancers: a comparative analysis of concurrent postoperative radiation plus chemotherapy trials of the EORTC (#22931) and RTOG (# 9501).	('head and neck cancer', 'Phenotype', 'HP:0012288', (41, 61))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('head and neck cancers', 'Phenotype', 'HP:0012288', (41, 62))	('neck cancers', 'Disease', (50, 62))	('# 9501', 'Var', (182, 188))	('cancers', 'Phenotype', 'HP:0002664', (55, 62))	('#22931', 'Var', (164, 170))	('neck cancers', 'Disease', 'MESH:D006258', (50, 62))
165481	30996568	In addition, patients with a unresectable large tumor volume or stage T4 or N2c-N3 cancer may also consider sequential therapy with induction chemotherapy combined with follow-up radiation therapy.	('tumor', 'Disease', (48, 53))	('patients', 'Species', '9606', (13, 21))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('N2c-N3', 'Var', (76, 82))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('cancer', 'Disease', (83, 89))
165511	30996568	In addition, patients with unresectable big tumor burden or staging T4 or N2c-N3, sequential therapy may be considered with induction chemotherapy followed by radiation therapy.	('N2c-N3', 'Var', (74, 80))	('patients', 'Species', '9606', (13, 21))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumor', 'Disease', (44, 49))
165535	30996568	Thus, clinical trials containing anti-PD-1/programmed death ligand 1 (PD-L1) antibodies may be benefiting as second-line therapy after failure of first-line platinum-based chemotherapy.	('PD-L1', 'Gene', '29126', (70, 75))	('antibodies', 'Var', (77, 87))	('anti-PD-1/programmed death ligand 1', 'Gene', (33, 68))	('anti-PD-1/programmed death ligand 1', 'Gene', '29126', (33, 68))	('platinum', 'Chemical', 'MESH:D010984', (157, 165))	('PD-L1', 'Gene', (70, 75))
165564	28531216	Impact of mutations in Toll-like receptor pathway genes on esophageal carcinogenesis Esophageal adenocarcinoma (EAC) develops in an inflammatory microenvironment with reduced microbial diversity, but mechanisms for these influences remain poorly characterized.	('Esophageal adenocarcinoma', 'Disease', (85, 110))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (59, 84))	('Esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (85, 110))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('EAC', 'Phenotype', 'HP:0011459', (112, 115))	('Esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (85, 110))	('esophageal carcinogenesis', 'Disease', (59, 84))	('mutations', 'Var', (10, 19))
165565	28531216	We hypothesized that mutations targeting the Toll-like receptor (TLR) pathway could disrupt innate immune signaling and promote a microenvironment that favors tumorigenesis.	('microenvironment', 'MPA', (130, 146))	('innate immune signaling', 'MPA', (92, 115))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('favors', 'PosReg', (152, 158))	('promote', 'PosReg', (120, 127))	('tumor', 'Disease', (159, 164))	('disrupt', 'NegReg', (84, 91))	('TLR', 'Gene', '7096;7097;7098;7099;21898;7100;51284;51311;54106;81793', (65, 68))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('TLR', 'Gene', (65, 68))	('mutations', 'Var', (21, 30))
165566	28531216	Through interrogating whole genome sequencing data from 171 EAC patients, we showed that non-synonymous mutations collectively affect the TLR pathway in 25/171 (14.6%, PathScan p = 8.7x10-5) tumors.	('tumors', 'Phenotype', 'HP:0002664', (191, 197))	('non-synonymous mutations', 'Var', (89, 113))	('EAC', 'Phenotype', 'HP:0011459', (60, 63))	('patients', 'Species', '9606', (64, 72))	('TLR', 'Gene', (138, 141))	('tumors', 'Disease', 'MESH:D009369', (191, 197))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('tumors', 'Disease', (191, 197))	('TLR', 'Gene', '7096;7097;7098;7099;21898;7100;51284;51311;54106;81793', (138, 141))	('affect', 'Reg', (127, 133))
165567	28531216	TLR mutant cases were associated with more proximal tumors and metastatic disease, indicating possible clinical significance of these mutations.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('mutant', 'Var', (4, 10))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('tumors', 'Disease', (52, 58))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('more', 'PosReg', (38, 42))	('TLR', 'Gene', '7096;7097;7098;7099;21898;7100;51284;51311;54106;81793', (0, 3))	('metastatic disease', 'CPA', (63, 81))	('TLR', 'Gene', (0, 3))
165569	28531216	We validated our findings in an external EAC dataset with non-synonymous TLR pathway mutations in 33/149 (22.1%, PathScan p = 0.05) tumors, and in other solid tumor types exposed to microbiomes in the COSMIC database (10,318 samples), including uterine endometrioid carcinoma (188/320, 58.8%), cutaneous melanoma (377/988, 38.2%), colorectal adenocarcinoma (402/1519, 26.5%), and stomach adenocarcinoma (151/579, 26.1%).	('TLR', 'Gene', (73, 76))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('tumor', 'Disease', (132, 137))	('stomach adenocarcinoma', 'Disease', (380, 402))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (253, 275))	('cutaneous melanoma', 'Disease', (294, 312))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (294, 312))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (294, 312))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('colorectal adenocarcinoma', 'Disease', (331, 356))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('endometrioid carcinoma', 'Disease', 'MESH:D016889', (253, 275))	('carcinoma', 'Phenotype', 'HP:0030731', (347, 356))	('stomach adenocarcinoma', 'Disease', 'MESH:D013274', (380, 402))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumor', 'Disease', (159, 164))	('mutations', 'Var', (85, 94))	('tumors', 'Disease', (132, 138))	('TLR', 'Gene', '7096;7097;7098;7099;21898;7100;51284;51311;54106;81793', (73, 76))	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (331, 356))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('endometrioid carcinoma', 'Disease', (253, 275))	('carcinoma', 'Phenotype', 'HP:0030731', (393, 402))	('EAC', 'Phenotype', 'HP:0011459', (41, 44))	('melanoma', 'Phenotype', 'HP:0002861', (304, 312))	('carcinoma', 'Phenotype', 'HP:0030731', (266, 275))	('tumors', 'Disease', 'MESH:D009369', (132, 138))
165570	28531216	TLR4 was the most frequently mutated gene with eleven mutations in 10/171 (5.8%) of EAC tumors.	('EAC', 'Phenotype', 'HP:0011459', (84, 87))	('TLR4', 'Gene', (0, 4))	('mutations', 'Var', (54, 63))	('EAC tumors', 'Disease', (84, 94))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('EAC tumors', 'Disease', 'MESH:C536611', (84, 94))
165571	28531216	The TLR4 mutants E439G, S570I, F703C and R787H were confirmed to have impaired reactivity to bacterial lipopolysaccharide with marked reductions in signaling by luciferase reporter assays.	('R787H', 'Var', (41, 46))	('S570I', 'Var', (24, 29))	('F703C', 'Var', (31, 36))	('S570I', 'Mutation', 'p.S570I', (24, 29))	('TLR4', 'Gene', (4, 8))	('lipopolysaccharide', 'Chemical', 'MESH:D008070', (103, 121))	('impaired reactivity to bacterial lipopolysaccharide', 'Phenotype', 'HP:0002848', (70, 121))	('signaling', 'MPA', (148, 157))	('reductions', 'NegReg', (134, 144))	('F703C', 'Mutation', 'rs141844350', (31, 36))	('E439G', 'Var', (17, 22))	('reactivity to bacterial lipopolysaccharide', 'MPA', (79, 121))	('E439G', 'Mutation', 'p.E439G', (17, 22))	('R787H', 'Mutation', 'rs200905500', (41, 46))	('impaired', 'NegReg', (70, 78))
165572	28531216	Overall, our findings show that TLR pathway genes are recurrently mutated in EAC, and TLR4 mutations have decreased responsiveness to bacterial lipopolysaccharide and may play a role in disease pathogenesis in a subset of patients.	('decreased', 'NegReg', (106, 115))	('TLR', 'Gene', (86, 89))	('TLR', 'Gene', '7096;7097;7098;7099;21898;7100;51284;51311;54106;81793', (32, 35))	('EAC', 'Phenotype', 'HP:0011459', (77, 80))	('patients', 'Species', '9606', (222, 230))	('TLR', 'Gene', (32, 35))	('EAC', 'Disease', (77, 80))	('play', 'Reg', (171, 175))	('lipopolysaccharide', 'Chemical', 'MESH:D008070', (144, 162))	('responsiveness to bacterial lipopolysaccharide', 'MPA', (116, 162))	('mutations', 'Var', (91, 100))	('TLR', 'Gene', '7096;7097;7098;7099;21898;7100;51284;51311;54106;81793', (86, 89))	('role', 'Reg', (178, 182))
165575	28531216	The Toll-like receptor (TLR) signalling pathway is critical for host-microbe interaction, and therefore mutations in these pathways could be important in the pathogenesis of EAC.	('TLR', 'Gene', (24, 27))	('mutations', 'Var', (104, 113))	('important', 'Reg', (141, 150))	('EAC', 'Phenotype', 'HP:0011459', (174, 177))	('EAC', 'Disease', (174, 177))	('TLR', 'Gene', '7096;7097;7098;7099;21898;7100;51284;51311;54106;81793', (24, 27))
165576	28531216	Here we show that TLR pathway genes are recurrently mutated in 15% of EAC tumours and other solid tumour types exposed to microbial communities, including uterine endometrioid carcinoma (59%), cutaneous melanoma (38%), colorectal adenocarcinoma (27%), and stomach adenocarcinoma (26%).	('TLR', 'Gene', (18, 21))	('endometrioid carcinoma', 'Disease', (163, 185))	('tumours', 'Phenotype', 'HP:0002664', (74, 81))	('stomach adenocarcinoma', 'Disease', 'MESH:D013274', (256, 278))	('EAC tumours', 'Disease', (70, 81))	('EAC tumours', 'Disease', 'MESH:C536611', (70, 81))	('EAC', 'Phenotype', 'HP:0011459', (70, 73))	('tumour', 'Phenotype', 'HP:0002664', (74, 80))	('tumour', 'Disease', 'MESH:D009369', (74, 80))	('tumour', 'Phenotype', 'HP:0002664', (98, 104))	('mutated', 'Var', (52, 59))	('colorectal adenocarcinoma', 'Disease', (219, 244))	('tumour', 'Disease', 'MESH:D009369', (98, 104))	('tumour', 'Disease', (74, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (269, 278))	('carcinoma', 'Phenotype', 'HP:0030731', (235, 244))	('tumour', 'Disease', (98, 104))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (163, 185))	('melanoma', 'Phenotype', 'HP:0002861', (203, 211))	('TLR', 'Gene', '7096;7097;7098;7099;21898;7100;51284;51311;54106;81793', (18, 21))	('cutaneous melanoma', 'Disease', (193, 211))	('stomach adenocarcinoma', 'Disease', (256, 278))	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (219, 244))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (193, 211))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (193, 211))	('endometrioid carcinoma', 'Disease', 'MESH:D016889', (163, 185))	('carcinoma', 'Phenotype', 'HP:0030731', (176, 185))
165577	28531216	TLR mutant cases were associated with more proximal tumours and metastatic disease, indicating possible clinical significance of these mutations.	('mutant', 'Var', (4, 10))	('tumours', 'Disease', (52, 59))	('tumour', 'Phenotype', 'HP:0002664', (52, 58))	('metastatic disease', 'CPA', (64, 82))	('more', 'PosReg', (38, 42))	('TLR', 'Gene', '7096;7097;7098;7099;21898;7100;51284;51311;54106;81793', (0, 3))	('tumours', 'Phenotype', 'HP:0002664', (52, 59))	('TLR', 'Gene', (0, 3))	('tumours', 'Disease', 'MESH:D009369', (52, 59))
165578	28531216	A better understanding of how altered TLR signalling contributes to the inflammatory tumour microenvironment in EAC could help inform cancer prevention strategies.	('TLR', 'Gene', (38, 41))	('EAC', 'Phenotype', 'HP:0011459', (112, 115))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('EAC', 'Disease', (112, 115))	('inflammatory tumour', 'Disease', 'MESH:D058922', (72, 91))	('TLR', 'Gene', '7096;7097;7098;7099;21898;7100;51284;51311;54106;81793', (38, 41))	('altered', 'Var', (30, 37))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('tumour', 'Phenotype', 'HP:0002664', (85, 91))	('inflammatory tumour', 'Disease', (72, 91))
165582	28531216	The combination of exposure to noxious substances and defects in DNA damage repair enable cancer cells to accumulate mutations, evidenced by characteristic mutational signatures.	('mutations', 'Var', (117, 126))	('accumulate', 'PosReg', (106, 116))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('defects', 'Var', (54, 61))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))
165586	28531216	An example is the SWI/SNF nucleosome remodeling complex (ARID1A, SMARCA4 and ARID2), for which gene members are mutated collectively in 20% of EAC tumors.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('EAC tumors', 'Disease', (143, 153))	('tumors', 'Phenotype', 'HP:0002664', (147, 153))	('EAC', 'Phenotype', 'HP:0011459', (143, 146))	('SMARCA4', 'Gene', (65, 72))	('EAC tumors', 'Disease', 'MESH:C536611', (143, 153))	('SMARCA4', 'Gene', '6597', (65, 72))	('ARID2', 'Gene', '196528', (77, 82))	('mutated', 'Var', (112, 119))	('ARID1A', 'Gene', (57, 63))	('ARID1A', 'Gene', '8289', (57, 63))	('ARID2', 'Gene', (77, 82))
165593	28531216	Genome-wide association studies and next-generation sequencing studies have identified TLR4 gene mutations in solid tumors including EAC.	('solid tumors', 'Disease', 'MESH:D009369', (110, 122))	('mutations', 'Var', (97, 106))	('EAC', 'Phenotype', 'HP:0011459', (133, 136))	('TLR4', 'Gene', (87, 91))	('solid tumors', 'Disease', (110, 122))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('EAC', 'Disease', (133, 136))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))
165595	28531216	We aimed to interrogate TLR pathway mutations and expression in a cohort of EAC and Barrett's esophagus patients with clinical outcome data.	('TLR', 'Gene', (24, 27))	("Barrett's esophagus", 'Disease', 'MESH:D001471', (84, 103))	("Barrett's esophagus", 'Disease', (84, 103))	('EAC', 'Disease', (76, 79))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (84, 103))	('mutations', 'Var', (36, 45))	('TLR', 'Gene', '7096;7097;7098;7099;21898;7100;51284;51311;54106;81793', (24, 27))	('EAC', 'Phenotype', 'HP:0011459', (76, 79))	('patients', 'Species', '9606', (104, 112))
165596	28531216	Finally, we aimed to determine the broader relevance of TLR pathway mutations in other cancers using TCGA data and the COSMIC database.	('TLR', 'Gene', '7096;7097;7098;7099;21898;7100;51284;51311;54106;81793', (56, 59))	('cancers', 'Disease', (87, 94))	('TLR', 'Gene', (56, 59))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cancers', 'Phenotype', 'HP:0002664', (87, 94))	('mutations', 'Var', (68, 77))	('cancers', 'Disease', 'MESH:D009369', (87, 94))
165597	28531216	To determine whether the TLR signaling pathway is dysregulated through somatic mutations in EAC, we interrogated the mutational profiles of 171 EAC tumors and matched germline controls that were sequenced as part of the International Cancer Genome Consortium (ICGC) esophageal study.	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('dysregulated', 'Reg', (50, 62))	('EAC', 'Phenotype', 'HP:0011459', (92, 95))	('EAC tumors', 'Disease', 'MESH:C536611', (144, 154))	('EAC', 'Phenotype', 'HP:0011459', (144, 147))	('TLR', 'Gene', '7096;7097;7098;7099;21898;7100;51284;51311;54106;81793', (25, 28))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('Cancer', 'Phenotype', 'HP:0002664', (234, 240))	('EAC', 'Gene', (92, 95))	('TLR', 'Gene', (25, 28))	('mutations', 'Var', (79, 88))	('EAC tumors', 'Disease', (144, 154))
165598	28531216	Missense mutations (and two splice variants) were identified in TLR4 (5.8%), TRAF6 (1.8%), TLR7 (1.8%), TLR9 (1.2%), MYD88 (1.2%), IRAK4 (1.2%), LBP (0.6%), TRAF3 (0.6%), TLR5 (0.6%), and TLR2 (0.6%, Fig 1A, S1 Table).	('LBP', 'Gene', '3929', (145, 148))	('TLR5', 'Gene', '7100', (171, 175))	('TLR7', 'Gene', (91, 95))	('TLR7', 'Gene', '51284', (91, 95))	('TRAF6', 'Gene', (77, 82))	('TLR9', 'Gene', (104, 108))	('TRAF3', 'Gene', '7187', (157, 162))	('TLR9', 'Gene', '54106', (104, 108))	('MYD88', 'Gene', '4615', (117, 122))	('LBP', 'Gene', (145, 148))	('MYD88', 'Gene', (117, 122))	('IRAK4', 'Gene', (131, 136))	('TRAF3', 'Gene', (157, 162))	('IRAK4', 'Gene', '51135', (131, 136))	('TLR2', 'Gene', '7097', (188, 192))	('TLR2', 'Gene', (188, 192))	('TLR5', 'Gene', (171, 175))	('TRAF6', 'Gene', '7189', (77, 82))	('Missense mutations', 'Var', (0, 18))
165599	28531216	Applying the PathScan tool showed that genes in the TLR signaling pathway were significantly enriched for mutations (p = 8.7x10-5).	('TLR', 'Gene', '7096;7097;7098;7099;21898;7100;51284;51311;54106;81793', (52, 55))	('mutations', 'Var', (106, 115))	('TLR', 'Gene', (52, 55))
165600	28531216	Fig 1A presents the mutation and copy number status for known recurrent alterations in EAC in the context of TLR pathway mutated samples, and these events are compared with the remainder of the ICGC cohort in S1 Fig.	('alterations', 'Var', (72, 83))	('EAC', 'Gene', (87, 90))	('TLR', 'Gene', '7096;7097;7098;7099;21898;7100;51284;51311;54106;81793', (109, 112))	('mutated', 'Var', (121, 128))	('TLR', 'Gene', (109, 112))	('EAC', 'Phenotype', 'HP:0011459', (87, 90))
165601	28531216	As expected in EAC, most samples showed mutations in TP53, independent of whether or not they contain TLR pathway mutations.	('EAC', 'Phenotype', 'HP:0011459', (15, 18))	('TLR', 'Gene', '7096;7097;7098;7099;21898;7100;51284;51311;54106;81793', (102, 105))	('mutations', 'Var', (40, 49))	('TP53', 'Gene', '7157', (53, 57))	('TLR', 'Gene', (102, 105))	('TP53', 'Gene', (53, 57))
165602	28531216	There was no significant enrichment of other known driver mutations in the TLR pathway mutated samples (S1 Fig).	('TLR', 'Gene', '7096;7097;7098;7099;21898;7100;51284;51311;54106;81793', (75, 78))	('mutated', 'Var', (87, 94))	('TLR', 'Gene', (75, 78))
165603	28531216	TLR pathway mutated tumors did not show significant differences in the numbers of total SNVs (Welch's t-test, p = 0.134) or non-synonymous SNVs (p = 0.147) compared to wild-type tumors and did not show significant enrichment of any of the molecular subtypes recently defined on the basis of their dominant molecular signature (Fisher's exact test, p = 0.57, S1 Fig).	('tumors', 'Disease', (20, 26))	('tumors', 'Disease', 'MESH:D009369', (20, 26))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('tumors', 'Disease', (178, 184))	('tumors', 'Disease', 'MESH:D009369', (178, 184))	('tumors', 'Phenotype', 'HP:0002664', (178, 184))	('mutated', 'Var', (12, 19))	('TLR', 'Gene', '7096;7097;7098;7099;21898;7100;51284;51311;54106;81793', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('TLR', 'Gene', (0, 3))
165604	28531216	To investigate other potential sources of altered function of the TLR pathway genes, we investigated copy number and structural variants potentially affecting the TLR pathway in the ICGC cohort.	('TLR', 'Gene', (66, 69))	('TLR', 'Gene', (163, 166))	('variants', 'Var', (128, 136))	('TLR', 'Gene', '7096;7097;7098;7099;21898;7100;51284;51311;54106;81793', (66, 69))	('affecting', 'Reg', (149, 158))	('TLR', 'Gene', '7096;7097;7098;7099;21898;7100;51284;51311;54106;81793', (163, 166))
165606	28531216	Three samples showed homozygous deletions in TLR pathway genes: MYD88 in ICGC-30, IRAK1 in ICGC-24, and TLR7, TLR8 and IRAK1 in ICGC-10.	('deletions', 'Var', (32, 41))	('TLR', 'Gene', (45, 48))	('TLR', 'Gene', (104, 107))	('TLR', 'Gene', (110, 113))	('TLR8', 'Gene', (110, 114))	('IRAK1', 'Gene', (119, 124))	('TLR8', 'Gene', '51311', (110, 114))	('IRAK1', 'Gene', '3654', (82, 87))	('TLR7', 'Gene', (104, 108))	('IRAK1', 'Gene', (82, 87))	('IRAK1', 'Gene', '3654', (119, 124))	('TLR7', 'Gene', '51284', (104, 108))	('TLR', 'Gene', '7096;7097;7098;7099;21898;7100;51284;51311;54106;81793', (45, 48))	('TLR', 'Gene', '7096;7097;7098;7099;21898;7100;51284;51311;54106;81793', (104, 107))	('TLR', 'Gene', '7096;7097;7098;7099;21898;7100;51284;51311;54106;81793', (110, 113))	('MYD88', 'Gene', '4615', (64, 69))	('MYD88', 'Gene', (64, 69))
165607	28531216	Interestingly, several TLR pathway genes were affected by loss of heterozygosity.	('TLR', 'Gene', (23, 26))	('affected', 'Reg', (46, 54))	('loss of heterozygosity', 'Var', (58, 80))	('TLR', 'Gene', '7096;7097;7098;7099;21898;7100;51284;51311;54106;81793', (23, 26))
165609	28531216	Eleven out of 171 samples showed structural variants whose breakpoints overlap with TLR pathway genes or lead to a potential fusion with a TLR pathway gene (S2 Table).	('TLR', 'Gene', '7096;7097;7098;7099;21898;7100;51284;51311;54106;81793', (139, 142))	('TLR', 'Gene', '7096;7097;7098;7099;21898;7100;51284;51311;54106;81793', (84, 87))	('lead to', 'Reg', (105, 112))	('TLR', 'Gene', (139, 142))	('TLR', 'Gene', (84, 87))	('fusion', 'Interaction', (125, 131))	('variants', 'Var', (44, 52))
165613	28531216	We verified 11/11 TLR4 mutations and 2/2 TLR9 mutations from the ICGC cohort using PCR and Sanger sequencing (S3 Fig).	('TLR4', 'Gene', (18, 22))	('mutations', 'Var', (23, 32))	('TLR9', 'Gene', (41, 45))	('TLR9', 'Gene', '54106', (41, 45))
165614	28531216	We also examined the COSMIC database for 20 different cancer types (as defined in S3 Table), comprising a total of 10,318 samples, and found a high proportion of mutations in TLR pathway genes in endometrial carcinoma (188/320, 58.8%), cutaneous melanoma (377/988, 38.2%), colorectal adenocarcinoma (402/1519, 26.5%), stomach adenocarcinoma (151/579, 26.1%), lung adenocarcinoma (81/477, 17%), lung squamous cell carcinoma (81/497, 16.3%), head and neck squamous cell carcinoma (41/330, 12.4%), and esophageal carcinoma (combined adenocarcinoma and squamous cell carcinoma: 99/869, 11.4%, Fig 2A).	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (273, 298))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (454, 477))	('esophageal carcinoma', 'Disease', (499, 519))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('carcinoma', 'Phenotype', 'HP:0030731', (208, 217))	('adenocarcinoma', 'Disease', (364, 378))	('adenocarcinoma', 'Disease', 'MESH:D000230', (326, 340))	('carcinoma', 'Phenotype', 'HP:0030731', (289, 298))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (196, 217))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (399, 422))	('adenocarcinoma', 'Disease', (530, 544))	('TLR', 'Gene', (175, 178))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (549, 572))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (440, 477))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (196, 217))	('adenocarcinoma', 'Disease', (284, 298))	('lung adenocarcinoma', 'Disease', (359, 378))	('stomach adenocarcinoma', 'Disease', 'MESH:D013274', (318, 340))	('carcinoma', 'Phenotype', 'HP:0030731', (413, 422))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (454, 477))	('melanoma', 'Phenotype', 'HP:0002861', (246, 254))	('cutaneous melanoma', 'Disease', (236, 254))	('adenocarcinoma', 'Disease', 'MESH:D000230', (364, 378))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (499, 519))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (236, 254))	('adenocarcinoma', 'Disease', 'MESH:D000230', (530, 544))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (236, 254))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (394, 422))	('squamous cell carcinoma', 'Disease', (549, 572))	('carcinoma', 'Phenotype', 'HP:0030731', (331, 340))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (359, 378))	('adenocarcinoma', 'Disease', 'MESH:D000230', (284, 298))	('cancer', 'Disease', (54, 60))	('neck squamous cell carcinoma', 'Disease', (449, 477))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (359, 378))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('colorectal adenocarcinoma', 'Disease', (273, 298))	('endometrial carcinoma', 'Disease', (196, 217))	('adenocarcinoma', 'Disease', (326, 340))	('mutations', 'Var', (162, 171))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (394, 422))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (449, 477))	('carcinoma', 'Phenotype', 'HP:0030731', (369, 378))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (399, 422))	('lung squamous cell carcinoma', 'Disease', (394, 422))	('stomach adenocarcinoma', 'Disease', (318, 340))	('TLR', 'Gene', '7096;7097;7098;7099;21898;7100;51284;51311;54106;81793', (175, 178))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (499, 519))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (549, 572))
165615	28531216	The COSMIC database further showed a high proportion of TLR4 non-synonymous mutations in cutaneous melanoma (60/988, 6.1%), lung adenocarcinoma (22/477, 4.6%), stomach adenocarcinoma (26/579, 4.5%) and lung squamous cell carcinoma (17/497, 3.4%, Fig 2A and S4 Table).	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (89, 107))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (89, 107))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (202, 230))	('carcinoma', 'Phenotype', 'HP:0030731', (221, 230))	('lung adenocarcinoma', 'Disease', (124, 143))	('stomach adenocarcinoma', 'Disease', 'MESH:D013274', (160, 182))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (207, 230))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (124, 143))	('lung squamous cell carcinoma', 'Disease', (202, 230))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (202, 230))	('carcinoma', 'Phenotype', 'HP:0030731', (173, 182))	('stomach adenocarcinoma', 'Disease', (160, 182))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('TLR4', 'Gene', (56, 60))	('melanoma', 'Phenotype', 'HP:0002861', (99, 107))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (124, 143))	('non-synonymous mutations', 'Var', (61, 85))	('cutaneous melanoma', 'Disease', (89, 107))
165617	28531216	There was an increase in the frequency of TLR pathway mutations in cancer types that are highly exposed to microbes (p = 0.019, Wilcoxon rank-sum test, S4 Fig).	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('TLR', 'Gene', (42, 45))	('cancer', 'Disease', (67, 73))	('mutations', 'Var', (54, 63))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('increase', 'PosReg', (13, 21))	('TLR', 'Gene', '7096;7097;7098;7099;21898;7100;51284;51311;54106;81793', (42, 45))
165618	28531216	This trend was also present when looking only at the fraction of TLR4 mutant tumors (p = 0.028).	('tumors', 'Disease', (77, 83))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('tumors', 'Disease', 'MESH:D009369', (77, 83))	('TLR4', 'Gene', (65, 69))	('mutant', 'Var', (70, 76))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))
165619	28531216	Next we investigated the clinical relevance of TLR pathway mutations through correlation with clinical outcome data.	('TLR', 'Gene', '7096;7097;7098;7099;21898;7100;51284;51311;54106;81793', (47, 50))	('TLR', 'Gene', (47, 50))	('mutations', 'Var', (59, 68))	('investigated', 'Reg', (8, 20))
165620	28531216	In the ICGC EAC cohort, patients with TLR pathway mutations (n = 25) tended to have more advanced disease with metastases (Fisher's exact test, p = 0.036, Table 1).	('TLR', 'Gene', (38, 41))	('metastases', 'Disease', (111, 121))	('mutations', 'Var', (50, 59))	('metastases', 'Disease', 'MESH:D009362', (111, 121))	('TLR', 'Gene', '7096;7097;7098;7099;21898;7100;51284;51311;54106;81793', (38, 41))	('patients', 'Species', '9606', (24, 32))	('EAC', 'Phenotype', 'HP:0011459', (12, 15))
165621	28531216	TLR mutant tumors originated more proximally at the level of the gastro-esophageal junction or above (Siewert Type 1-2 or esophageal, Fisher's exact test, p = 0.012).	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('mutant', 'Var', (4, 10))	('tumors', 'Phenotype', 'HP:0002664', (11, 17))	('tumors', 'Disease', (11, 17))	('gastro-esophageal junction', 'Disease', (65, 91))	('tumors', 'Disease', 'MESH:D009369', (11, 17))	('gastro-esophageal junction', 'Disease', 'MESH:D005764', (65, 91))	('TLR', 'Gene', '7096;7097;7098;7099;21898;7100;51284;51311;54106;81793', (0, 3))	('TLR', 'Gene', (0, 3))
165622	28531216	There was a trend towards decreased survival in patients with TLR mutations in comparison to wild-type although this did not reach statistical significance, possibly due to the limited number of TLR mutant cases and length of follow-up (S5 Fig).	('mutations', 'Var', (66, 75))	('survival', 'MPA', (36, 44))	('TLR', 'Gene', '7096;7097;7098;7099;21898;7100;51284;51311;54106;81793', (195, 198))	('patients', 'Species', '9606', (48, 56))	('TLR', 'Gene', '7096;7097;7098;7099;21898;7100;51284;51311;54106;81793', (62, 65))	('decreased', 'NegReg', (26, 35))	('TLR', 'Gene', (195, 198))	('TLR', 'Gene', (62, 65))
165623	28531216	This trend was also seen when comparing patients with TLR pathway mutations to wild-type patients in the EAC cohort from the TCGA database, although again the clinical data is limited.	('mutations', 'Var', (66, 75))	('TLR', 'Gene', '7096;7097;7098;7099;21898;7100;51284;51311;54106;81793', (54, 57))	('patients', 'Species', '9606', (40, 48))	('TLR', 'Gene', (54, 57))	('patients', 'Species', '9606', (89, 97))	('EAC', 'Phenotype', 'HP:0011459', (105, 108))
165625	28531216	To investigate the timing of TLR pathway mutations in disease pathogenesis, we examined samples from patients with Barrett's esophagus adjacent to tumor (n = 24).	('mutations', 'Var', (41, 50))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('patients', 'Species', '9606', (101, 109))	('TLR', 'Gene', '7096;7097;7098;7099;21898;7100;51284;51311;54106;81793', (29, 32))	('TLR', 'Gene', (29, 32))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	("Barrett's esophagus", 'Disease', 'MESH:D001471', (115, 134))	("Barrett's esophagus", 'Disease', (115, 134))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (115, 134))
165627	28531216	Only 2/24 Barrett's samples showed mutations in the TLR pathway.	('TLR', 'Gene', (52, 55))	('TLR', 'Gene', '7096;7097;7098;7099;21898;7100;51284;51311;54106;81793', (52, 55))	('mutations', 'Var', (35, 44))
165628	28531216	A TRAF6 mutation was present in tumor and adjacent Barrett's, indicating that the mutation had occurred early in carcinogenesis.	('carcinogenesis', 'Disease', 'MESH:D063646', (113, 127))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('TRAF6', 'Gene', (2, 7))	('carcinogenesis', 'Disease', (113, 127))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('TRAF6', 'Gene', '7189', (2, 7))	('mutation', 'Var', (8, 16))	('tumor', 'Disease', (32, 37))
165629	28531216	In another patient, a TLR9 mutation was detected in Barrett's but not the adjacent tumor.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumor', 'Disease', (83, 88))	('TLR9', 'Gene', (22, 26))	('detected', 'Reg', (40, 48))	('mutation', 'Var', (27, 35))	('patient', 'Species', '9606', (11, 18))	('TLR9', 'Gene', '54106', (22, 26))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
165631	28531216	Since TLR4 was frequently mutated in both EAC cohorts and other solid tumor types in the COSMIC database, we decided to characterize these mutations in greater detail.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('TLR4', 'Gene', (6, 10))	('tumor', 'Disease', (70, 75))	('mutated', 'Var', (26, 33))	('EAC', 'Phenotype', 'HP:0011459', (42, 45))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
165632	28531216	Both EAC cohorts identified missense mutations at amino acid position E439 (substitution to glycine) and F487 (substitution to leucine or valine, Fig 2B).	('valine', 'Chemical', 'MESH:D014633', (138, 144))	('leucine', 'Chemical', 'MESH:D007930', (127, 134))	('EAC', 'Phenotype', 'HP:0011459', (5, 8))	('E439', 'Var', (70, 74))	('missense mutations', 'Var', (28, 46))	('glycine', 'Chemical', 'MESH:D005998', (92, 99))
165633	28531216	The COSMIC database showed additional missense mutations at position E439 (two in stomach adenocarcinoma and one in cutaneous melanoma) and position F487 (two in stomach adenocarcinoma and one in esophageal carcinoma, Fig 2C).	('esophageal carcinoma', 'Disease', (196, 216))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (196, 216))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (116, 134))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (196, 216))	('carcinoma', 'Phenotype', 'HP:0030731', (207, 216))	('stomach adenocarcinoma', 'Disease', 'MESH:D013274', (82, 104))	('position F487', 'Var', (140, 153))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('melanoma', 'Phenotype', 'HP:0002861', (126, 134))	('stomach adenocarcinoma', 'Disease', (82, 104))	('cutaneous melanoma', 'Disease', (116, 134))	('carcinoma', 'Phenotype', 'HP:0030731', (175, 184))	('stomach adenocarcinoma', 'Disease', 'MESH:D013274', (162, 184))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (116, 134))	('stomach adenocarcinoma', 'Disease', (162, 184))
165634	28531216	Seven tumors with TLR4 mutations had paraffin-embedded tissue available to evaluate mutant TLR4 protein expression using immunohistochemistry for TLR4 monoclonal antibody.	('protein', 'Protein', (96, 103))	('TLR4', 'Gene', (18, 22))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('tumors', 'Disease', (6, 12))	('mutations', 'Var', (23, 32))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('paraffin', 'Chemical', 'MESH:D010232', (37, 45))	('TLR4', 'Gene', (91, 95))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))
165635	28531216	Similar to wild-type tumors, the TLR4 mutant tumors showed combined membranous and cytoplasmic staining of TLR4 protein, with staining intensity ranging from weak to strongly positive (S6 Fig).	('mutant', 'Var', (38, 44))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumors', 'Disease', (45, 51))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('tumors', 'Disease', (21, 27))	('tumors', 'Disease', 'MESH:D009369', (21, 27))	('TLR4', 'Gene', (107, 111))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('tumors', 'Disease', 'MESH:D009369', (45, 51))	('TLR4', 'Gene', (33, 37))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
165636	28531216	None of the mutant tumors showed complete loss of TLR4 expression, which was anticipated since the missense mutations did not cause truncation of the protein.	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('tumors', 'Disease', (19, 25))	('missense mutations', 'Var', (99, 117))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('expression', 'MPA', (55, 65))	('TLR4', 'Gene', (50, 54))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))
165637	28531216	We hypothesized that the mutations could have a functional effect on TLR4 signaling, and this was supported by computational modeling using a published crystal structure for dimerized human TLR4 ectodomain with associated MD2 co-receptor (LY96 gene product) with LPS bound (PDB ID 4G8A) and a hypothetical structure for the dimerized TIR domain based on TLR10 (PDB ID 2J67, S7 Fig).	('mutations', 'Var', (25, 34))	('TLR10', 'Gene', (354, 359))	('LY96', 'Gene', '23643', (239, 243))	('PDB ID', 'Disease', 'MESH:C537985', (361, 367))	('PDB ID', 'Disease', (274, 280))	('TLR10', 'Gene', '81793', (354, 359))	('effect', 'Reg', (59, 65))	('LY96', 'Gene', (239, 243))	('LPS', 'Disease', (263, 266))	('PDB ID', 'Disease', 'MESH:C537985', (274, 280))	('TLR4 signaling', 'MPA', (69, 83))	('human', 'Species', '9606', (184, 189))	('MD2', 'Gene', '23643', (222, 225))	('PDB ID', 'Disease', (361, 367))	('LPS', 'Disease', 'MESH:C536528', (263, 266))	('MD2', 'Gene', (222, 225))
165638	28531216	Two structurally significant mutations affected the TIR domain (F703C and R787H), which is involved in downstream signaling and interaction with the adaptor molecule MyD88.	('F703C', 'Mutation', 'rs141844350', (64, 69))	('affected', 'Reg', (39, 47))	('R787H', 'Var', (74, 79))	('R787H', 'Mutation', 'rs200905500', (74, 79))	('MyD88', 'Gene', (166, 171))	('MyD88', 'Gene', '4615', (166, 171))	('F703C', 'Var', (64, 69))
165639	28531216	The E439G mutation is also critically located at the TLR4 dimerization interface and may disrupt hydrogen bonds in the binding site of LPS and MD2 (Fig 2D).	('MD2', 'Gene', (143, 146))	('hydrogen bonds', 'MPA', (97, 111))	('LPS', 'Disease', (135, 138))	('E439G', 'Var', (4, 9))	('E439G', 'Mutation', 'p.E439G', (4, 9))	('LPS', 'Disease', 'MESH:C536528', (135, 138))	('hydrogen', 'Chemical', 'MESH:D006859', (97, 105))	('disrupt', 'NegReg', (89, 96))	('MD2', 'Gene', '23643', (143, 146))	('binding', 'Interaction', (119, 126))
165640	28531216	Further, amino acid sequence alignment against seven non-human species showed that the positions of the TIR domain mutations (F703 and R787) are evolutionarily conserved, along with amino acids L80, L498 and S570, and E439 is semi-conserved (S8 Fig).	('R787', 'Var', (135, 139))	('L498', 'Var', (199, 203))	('F703', 'Var', (126, 130))	('L80', 'Var', (194, 197))	('S570', 'Var', (208, 212))	('human', 'Species', '9606', (57, 62))
165641	28531216	Overall the combination of crystal structure modeling, sequence alignment, and SNP prediction algorithms (SIFT and Polyphen) suggested that six of the verified TLR4 mutations could have a functional consequence: L80M, E439G, L498V, S570I, F703C and R787H (S5 Table).	('R787H', 'Var', (249, 254))	('SIFT', 'Disease', 'None', (106, 110))	('R787H', 'Mutation', 'rs200905500', (249, 254))	('E439G', 'Mutation', 'p.E439G', (218, 223))	('E439G', 'Var', (218, 223))	('F703C', 'Var', (239, 244))	('L80M', 'Mutation', 'p.L80M', (212, 216))	('S570I', 'Var', (232, 237))	('TLR4', 'Gene', (160, 164))	('SIFT', 'Disease', (106, 110))	('L80M', 'Var', (212, 216))	('S570I', 'Mutation', 'p.S570I', (232, 237))	('L498V', 'Mutation', 'rs1481925827', (225, 230))	('F703C', 'Mutation', 'rs141844350', (239, 244))	('L498V', 'Var', (225, 230))
165642	28531216	To test our functional predictions for the TLR4 mutants, we performed site-directed mutagenesis and NF-kappaB luciferase reporter assays in HEK293 cells, a common model for measuring TLR signaling.	('TLR', 'Gene', (183, 186))	('HEK293', 'CellLine', 'CVCL:0045', (140, 146))	('TLR', 'Gene', '7096;7097;7098;7099;21898;7100;51284;51311;54106;81793', (43, 46))	('mutants', 'Var', (48, 55))	('TLR', 'Gene', (43, 46))	('NF-kappaB', 'Gene', '4790', (100, 109))	('TLR', 'Gene', '7096;7097;7098;7099;21898;7100;51284;51311;54106;81793', (183, 186))	('NF-kappaB', 'Gene', (100, 109))
165643	28531216	The TLR4 mutants were stimulated first using the weak agonist synthetic monophosphoryl Lipid A (MPLA).	('TLR4', 'Gene', (4, 8))	('mutants', 'Var', (9, 16))	('MPLA', 'Chemical', 'MESH:C048436', (96, 100))	('monophosphoryl Lipid A', 'Chemical', 'MESH:C048436', (72, 94))
165644	28531216	There was a significant decrease in ligand-dependent signaling for 7/9 of the TLR4 mutations stimulated with synthetic MPLA (S9 Fig).	('mutations', 'Var', (83, 92))	('ligand-dependent signaling', 'MPA', (36, 62))	('decrease', 'NegReg', (24, 32))	('MPLA', 'Chemical', 'MESH:C048436', (119, 123))	('TLR4', 'Gene', (78, 82))
165645	28531216	A double mutation of E439G with F703C, representing a tumor with two TLR4 mutations, showed a further decrease in TLR4 signaling compared to F703C (p = 0.0052) but not E439G (p = 0.099).	('F703C', 'Mutation', 'rs141844350', (32, 37))	('decrease', 'NegReg', (102, 110))	('TLR4', 'Gene', (69, 73))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor', 'Disease', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('F703C', 'Var', (32, 37))	('F703C', 'Mutation', 'rs141844350', (141, 146))	('E439G', 'Mutation', 'p.E439G', (168, 173))	('E439G', 'Var', (21, 26))	('E439G', 'Mutation', 'p.E439G', (21, 26))	('TLR4 signaling', 'MPA', (114, 128))
165646	28531216	Stimulation with stronger TLR4 agonists, synthetic Lipid A and lipopolysaccharide (LPS), showed a significant decrease in signaling for four single mutants (E439G, S570I, F703C and R787H) and the double mutation E439G + F703C (Fig 3A).	('lipopolysaccharide', 'Chemical', 'MESH:D008070', (63, 81))	('signaling', 'MPA', (122, 131))	('LPS', 'Disease', (83, 86))	('S570I', 'Mutation', 'p.S570I', (164, 169))	('F703C', 'Mutation', 'rs141844350', (220, 225))	('TLR4', 'Gene', (26, 30))	('E439G', 'Mutation', 'p.E439G', (157, 162))	('E439G', 'Var', (157, 162))	('F703C', 'Var', (171, 176))	('E439G', 'Mutation', 'p.E439G', (212, 217))	('LPS', 'Disease', 'MESH:C536528', (83, 86))	('decrease', 'NegReg', (110, 118))	('R787H', 'Var', (181, 186))	('R787H', 'Mutation', 'rs200905500', (181, 186))	('E439G + F703C', 'Var', (212, 225))	('S570I', 'Var', (164, 169))	('Lipid A', 'Chemical', 'MESH:D008050', (51, 58))	('F703C', 'Mutation', 'rs141844350', (171, 176))
165647	28531216	We also visualized recombinant TLR4-FLAG protein expression in HEK293 cells using confocal microscopy for mutants E439G and R787H, and there was no difference in expression or localization of TLR4-FLAG for either of the mutants in comparison to wild-type, suggesting that the decreased signaling was due to altered protein function rather than mis-folding and failure to reach the cell surface (Fig 3C).	('R787H', 'Mutation', 'rs200905500', (124, 129))	('E439G', 'Var', (114, 119))	('E439G', 'Mutation', 'p.E439G', (114, 119))	('altered', 'Reg', (307, 314))	('decreased', 'NegReg', (276, 285))	('signaling', 'MPA', (286, 295))	('HEK293', 'CellLine', 'CVCL:0045', (63, 69))	('TLR4-FLAG', 'Gene', (31, 40))	('protein', 'Protein', (315, 322))	('R787H', 'Var', (124, 129))
165648	28531216	Next, TLR4 mutants E439G, R787H and E439G+F703C were transfected into EAC cell lines stimulated with LPS for 24 hours, and secretion of the NF-kappaB dependent cytokine IL-8 was measured.	('TLR4', 'Gene', (6, 10))	('IL-8', 'Gene', (169, 173))	('E439G', 'Var', (19, 24))	('NF-kappaB', 'Gene', '4790', (140, 149))	('F703C', 'Mutation', 'rs141844350', (42, 47))	('E439G+F703C', 'Var', (36, 47))	('secretion', 'MPA', (123, 132))	('NF-kappaB', 'Gene', (140, 149))	('LPS', 'Disease', (101, 104))	('E439G', 'Mutation', 'p.E439G', (19, 24))	('E439G', 'Mutation', 'p.E439G', (36, 41))	('R787H', 'Var', (26, 31))	('R787H', 'Mutation', 'rs200905500', (26, 31))	('LPS', 'Disease', 'MESH:C536528', (101, 104))	('IL-8', 'Gene', '3576', (169, 173))	('EAC', 'Phenotype', 'HP:0011459', (70, 73))
165650	28531216	The fold change of IL-8 secretion was significantly lower for mutants R787H and E439G+F703C in comparison to wild-type TLR4 (Fig 3D).	('IL-8', 'Gene', '3576', (19, 23))	('E439G', 'Mutation', 'p.E439G', (80, 85))	('E439G+F703C', 'Var', (80, 91))	('IL-8', 'Gene', (19, 23))	('lower', 'NegReg', (52, 57))	('secretion', 'MPA', (24, 33))	('F703C', 'Mutation', 'rs141844350', (86, 91))	('R787H', 'Var', (70, 75))	('R787H', 'Mutation', 'rs200905500', (70, 75))
165651	28531216	In contrast to HEK293 cells, no significant decrease in TLR4 signaling was observed for mutant E439G stimulated with LPS in the EAC cell lines, suggesting that the strong agonist LPS was still able to trigger TLR signaling despite mutation of the ligand binding site.	('TLR', 'Gene', '7096;7097;7098;7099;21898;7100;51284;51311;54106;81793', (56, 59))	('HEK293', 'CellLine', 'CVCL:0045', (15, 21))	('LPS', 'Disease', (117, 120))	('LPS', 'Disease', 'MESH:C536528', (179, 182))	('mutant E439G', 'Var', (88, 100))	('TLR', 'Gene', (56, 59))	('TLR', 'Gene', '7096;7097;7098;7099;21898;7100;51284;51311;54106;81793', (209, 212))	('binding', 'Interaction', (254, 261))	('E439G', 'Var', (95, 100))	('E439G', 'Mutation', 'p.E439G', (95, 100))	('LPS', 'Disease', 'MESH:C536528', (117, 120))	('TLR', 'Gene', (209, 212))	('EAC', 'Phenotype', 'HP:0011459', (128, 131))	('LPS', 'Disease', (179, 182))
165652	28531216	Our experiments in cell lines suggest that TLR4 mutations impair TLR signaling and NF-kappaB activation in HEK293 cells and IL-8 secretion by EAC cell lines.	('TLR', 'Gene', '7096;7097;7098;7099;21898;7100;51284;51311;54106;81793', (43, 46))	('impair', 'NegReg', (58, 64))	('NF-kappaB', 'Gene', '4790', (83, 92))	('TLR', 'Gene', (43, 46))	('IL-8', 'Gene', '3576', (124, 128))	('HEK293', 'CellLine', 'CVCL:0045', (107, 113))	('activation', 'MPA', (93, 103))	('NF-kappaB', 'Gene', (83, 92))	('EAC', 'Phenotype', 'HP:0011459', (142, 145))	('TLR', 'Gene', '7096;7097;7098;7099;21898;7100;51284;51311;54106;81793', (65, 68))	('mutations', 'Var', (48, 57))	('TLR', 'Gene', (65, 68))	('IL-8', 'Gene', (124, 128))
165654	28531216	Out of 89 samples with RNA-Seq data available, 17 samples had TLR pathway mutations and four had TLR4 mutations.	('TLR', 'Gene', (97, 100))	('TLR', 'Gene', (62, 65))	('mutations', 'Var', (74, 83))	('TLR', 'Gene', '7096;7097;7098;7099;21898;7100;51284;51311;54106;81793', (62, 65))	('TLR', 'Gene', '7096;7097;7098;7099;21898;7100;51284;51311;54106;81793', (97, 100))
165655	28531216	Our analysis using DESeq2 shows that expression of IL-8, NFKB2 and RELB was significantly elevated in the tumors compared to normal samples (n = 10), but no significant difference was observed when comparing tumors with mutations in the TLR pathway and wild-type tumors, possibly related to the small sample size (Fig 4A).	('NFKB2', 'Gene', (57, 62))	('tumors', 'Disease', (106, 112))	('RELB', 'Gene', (67, 71))	('tumors', 'Disease', 'MESH:D009369', (263, 269))	('tumors', 'Disease', 'MESH:D009369', (208, 214))	('TLR', 'Gene', (237, 240))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('IL-8', 'Gene', '3576', (51, 55))	('mutations', 'Var', (220, 229))	('elevated', 'PosReg', (90, 98))	('RELB', 'Gene', '5971', (67, 71))	('tumors', 'Phenotype', 'HP:0002664', (208, 214))	('NFKB2', 'Gene', '4791', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumors', 'Phenotype', 'HP:0002664', (263, 269))	('expression', 'MPA', (37, 47))	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('tumor', 'Phenotype', 'HP:0002664', (263, 268))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('tumors', 'Disease', (208, 214))	('TLR', 'Gene', '7096;7097;7098;7099;21898;7100;51284;51311;54106;81793', (237, 240))	('IL-8', 'Gene', (51, 55))	('tumors', 'Disease', (263, 269))
165656	28531216	Similarly, there was no significant difference in gene expression between TLR4 mutant and wild-type tumors.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('mutant', 'Var', (79, 85))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('tumors', 'Disease', (100, 106))	('TLR4', 'Gene', (74, 78))
165657	28531216	We next searched for alternative genes whose expression could be affected by TLR mutations in vivo.	('expression', 'MPA', (45, 55))	('TLR', 'Gene', '7096;7097;7098;7099;21898;7100;51284;51311;54106;81793', (77, 80))	('TLR', 'Gene', (77, 80))	('mutations', 'Var', (81, 90))
165658	28531216	Tumors with TLR pathway mutations showed significant upregulation of NLRP6, GAST, TTC29 and C19orf69, and down-regulation of SFRP5, MYO18B, NAT8L, SHISA9 and IGFALS (Fig 4B).	('TTC29', 'Gene', (82, 87))	('C19orf69', 'Gene', (92, 100))	('NLRP6', 'Gene', (69, 74))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('mutations', 'Var', (24, 33))	('TLR', 'Gene', '7096;7097;7098;7099;21898;7100;51284;51311;54106;81793', (12, 15))	('SHISA9', 'Gene', (147, 153))	('IGFALS', 'Gene', '3483', (158, 164))	('Tumors', 'Disease', (0, 6))	('SHISA9', 'Gene', '729993', (147, 153))	('SFRP5', 'Gene', '6425', (125, 130))	('TLR', 'Gene', (12, 15))	('NAT8L', 'Gene', '339983', (140, 145))	('upregulation', 'PosReg', (53, 65))	('SFRP5', 'Gene', (125, 130))	('MYO18B', 'Gene', '84700', (132, 138))	('MYO18B', 'Gene', (132, 138))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('NAT8L', 'Gene', (140, 145))	('C19orf69', 'Gene', '100170765', (92, 100))	('NLRP6', 'Gene', '171389', (69, 74))	('IGFALS', 'Gene', (158, 164))	('down-regulation', 'NegReg', (106, 121))	('GAST', 'Gene', (76, 80))	('TTC29', 'Gene', '83894', (82, 87))
165659	28531216	We validated our findings using RNA-Seq data from 23 independent tumors of which 2 were mutated in the TLR pathway, and significant upregulation was found only for NLRP6 (p = 0.004).	('NLRP6', 'Gene', '171389', (164, 169))	('NLRP6', 'Gene', (164, 169))	('upregulation', 'PosReg', (132, 144))	('TLR', 'Gene', (103, 106))	('tumors', 'Disease', (65, 71))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('mutated', 'Var', (88, 95))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('TLR', 'Gene', '7096;7097;7098;7099;21898;7100;51284;51311;54106;81793', (103, 106))
165661	28531216	Additionally, quantitative RT-PCR was performed in 22 tumor samples with available RNA (11 of which contained TLR pathway mutations, including 5 TLR4 mutations).	('TLR', 'Gene', (145, 148))	('TLR', 'Gene', '7096;7097;7098;7099;21898;7100;51284;51311;54106;81793', (145, 148))	('TLR', 'Gene', (110, 113))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('mutations', 'Var', (122, 131))	('mutations', 'Var', (150, 159))	('tumor', 'Disease', (54, 59))	('TLR', 'Gene', '7096;7097;7098;7099;21898;7100;51284;51311;54106;81793', (110, 113))
165662	28531216	The results showed a similar trend, with upregulation of NLRP6 in TLR pathway mutated samples in comparison to wild-type tumors; however, this did not reach significance likely due to the small sample size (p = 0.172, S11 Fig).	('TLR', 'Gene', (66, 69))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumors', 'Disease', (121, 127))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('tumors', 'Disease', 'MESH:D009369', (121, 127))	('mutated', 'Var', (78, 85))	('NLRP6', 'Gene', '171389', (57, 62))	('NLRP6', 'Gene', (57, 62))	('upregulation', 'PosReg', (41, 53))	('TLR', 'Gene', '7096;7097;7098;7099;21898;7100;51284;51311;54106;81793', (66, 69))
165663	28531216	Of the samples with TLR4 mutations, R787H (relative expression 6.8) and L80M (relative expression 3.7) showed upregulation of NLRP6 compared to mean expression in wild-type tumors (relative expression 0.87, S6 Table).	('NLRP6', 'Gene', (126, 131))	('upregulation', 'PosReg', (110, 122))	('mutations', 'Var', (25, 34))	('TLR4', 'Gene', (20, 24))	('L80M', 'Var', (72, 76))	('R787H', 'Var', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('R787H', 'Mutation', 'rs200905500', (36, 41))	('tumors', 'Disease', (173, 179))	('tumors', 'Disease', 'MESH:D009369', (173, 179))	('tumors', 'Phenotype', 'HP:0002664', (173, 179))	('L80M', 'Mutation', 'p.L80M', (72, 76))	('NLRP6', 'Gene', '171389', (126, 131))
165667	28531216	TLR4 mutations have been previously reported in high grade dysplasia, which implies that this mutation may be acquired later during disease progression.	('TLR4', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))	('reported', 'Reg', (36, 44))	('dysplasia', 'Disease', (59, 68))	('dysplasia', 'Disease', 'MESH:D004476', (59, 68))
165670	28531216	In addition to EAC, TLR pathway mutations were frequently observed in solid tumors arising in body sites exposed to microbiota including the oral and gastrointestinal tract (colorectal adenocarcinoma, stomach adenocarcinoma and head and neck squamous cell carcinoma), skin (melanoma), urogenital tract (endometrial carcinoma) and respiratory tract (lung adenocarcinoma and squamous cell carcinoma).	('carcinoma', 'Phenotype', 'HP:0030731', (359, 368))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (349, 368))	('melanoma', 'Disease', 'MESH:D008545', (274, 282))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (228, 265))	('carcinoma', 'Phenotype', 'HP:0030731', (256, 265))	('solid tumors', 'Disease', (70, 82))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (373, 396))	('respiratory tract', 'Disease', 'MESH:D012140', (330, 347))	('EAC', 'Phenotype', 'HP:0011459', (15, 18))	('neck squamous cell carcinoma', 'Disease', (237, 265))	('carcinoma', 'Phenotype', 'HP:0030731', (190, 199))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (237, 265))	('carcinoma', 'Phenotype', 'HP:0030731', (214, 223))	('endometrial carcinoma', 'Disease', (303, 324))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('mutations', 'Var', (32, 41))	('lung adenocarcinoma and squamous cell carcinoma', 'Disease', 'MESH:D002294', (349, 396))	('TLR', 'Gene', '7096;7097;7098;7099;21898;7100;51284;51311;54106;81793', (20, 23))	('solid tumors', 'Disease', 'MESH:D009369', (70, 82))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (242, 265))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('melanoma', 'Phenotype', 'HP:0002861', (274, 282))	('gastrointestinal tract', 'Disease', (150, 172))	('melanoma', 'Disease', (274, 282))	('carcinoma', 'Phenotype', 'HP:0030731', (315, 324))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (303, 324))	('gastrointestinal tract', 'Disease', 'MESH:D004067', (150, 172))	('colorectal adenocarcinoma, stomach adenocarcinoma', 'Disease', 'MESH:D000230', (174, 223))	('TLR', 'Gene', (20, 23))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (303, 324))	('respiratory tract', 'Disease', (330, 347))	('observed', 'Reg', (58, 66))
165673	28531216	However, only one of the tumors from that study had a TLR4 mutation so it was not possible to further correlate the findings with our current study, and additional research is needed to investigate the link between TLR mutations and the microbiome in EAC.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('TLR', 'Gene', '7096;7097;7098;7099;21898;7100;51284;51311;54106;81793', (215, 218))	('tumors', 'Disease', (25, 31))	('TLR', 'Gene', '7096;7097;7098;7099;21898;7100;51284;51311;54106;81793', (54, 57))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('EAC', 'Phenotype', 'HP:0011459', (251, 254))	('tumors', 'Disease', 'MESH:D009369', (25, 31))	('TLR', 'Gene', (215, 218))	('TLR', 'Gene', (54, 57))	('mutation', 'Var', (59, 67))	('EAC', 'Disease', (251, 254))	('mutations', 'Var', (219, 228))
165674	28531216	This suggests that the mutations differentially affected signaling with weak versus strong agonists, which may be relevant to the different microbial antigens present in the tumor environment.	('signaling', 'MPA', (57, 66))	('tumor', 'Disease', (174, 179))	('mutations', 'Var', (23, 32))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('affected', 'Reg', (48, 56))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))
165675	28531216	The model system was also a contributing factor; for instance E439G was hyporesponsive to LPS in HEK293 cells but not EAC cell lines.	('E439G', 'Var', (62, 67))	('LPS', 'Disease', (90, 93))	('LPS', 'Disease', 'MESH:C536528', (90, 93))	('E439G', 'Mutation', 'p.E439G', (62, 67))	('EAC', 'Phenotype', 'HP:0011459', (118, 121))	('HEK293', 'CellLine', 'CVCL:0045', (97, 103))
165676	28531216	In EAC cell lines, addition of the second mutation F703C was required to significantly reduce TLR4 signaling activity.	('TLR4 signaling activity', 'MPA', (94, 117))	('F703C', 'Var', (51, 56))	('EAC', 'Phenotype', 'HP:0011459', (3, 6))	('F703C', 'Mutation', 'rs141844350', (51, 56))	('reduce', 'NegReg', (87, 93))
165677	28531216	Further, loss of heterozygosity events overlapped with four TLR4 mutations, R787H, E603D, T193K, and L498V.	('T193K', 'Mutation', 'rs752866944', (90, 95))	('R787H', 'Var', (76, 81))	('L498V', 'Var', (101, 106))	('R787H', 'Mutation', 'rs200905500', (76, 81))	('E603D', 'Mutation', 'p.E603D', (83, 88))	('T193K', 'Var', (90, 95))	('E603D', 'Var', (83, 88))	('L498V', 'Mutation', 'rs1481925827', (101, 106))	('TLR4', 'Gene', (60, 64))
165678	28531216	Of these, R787H showed decreased signaling in response to strong and weak agonists, L498V showed decreased signaling in response to weak agonist only, and E603D and T193K showed no significant change.	('L498V', 'Var', (84, 89))	('E603D', 'Var', (155, 160))	('T193K', 'Var', (165, 170))	('decreased', 'NegReg', (97, 106))	('signaling', 'MPA', (107, 116))	('T193K', 'Mutation', 'rs752866944', (165, 170))	('E603D', 'Mutation', 'p.E603D', (155, 160))	('R787H', 'Var', (10, 15))	('decreased', 'NegReg', (23, 32))	('signaling', 'MPA', (33, 42))	('L498V', 'Mutation', 'rs1481925827', (84, 89))	('R787H', 'Mutation', 'rs200905500', (10, 15))
165679	28531216	A possible mechanism is that defective TLR4 signaling may negatively impact epithelial cell repair, which is in part dependent on TLR4 stimulation, and potentially enable microbes to breach the epithelial barrier in the tumor microenvironment.	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('tumor', 'Disease', (220, 225))	('negatively impact', 'NegReg', (58, 75))	('enable', 'Reg', (164, 170))	('defective', 'Var', (29, 38))	('epithelial cell repair', 'CPA', (76, 98))	('TLR4', 'Gene', (39, 43))	('tumor', 'Disease', 'MESH:D009369', (220, 225))
165680	28531216	found that the single nucleotide polymorphism c.896A>G (p.D299G) was associated with an increased risk of gastric cancer in two patient populations, and cells with this mutation have been shown to be hypo-responsive to lipopolysaccharide.	('c.896A>G', 'Mutation', 'rs4986790', (46, 54))	('gastric cancer', 'Disease', 'MESH:D013274', (106, 120))	('c.896A>G', 'Var', (46, 54))	('gastric cancer', 'Disease', (106, 120))	('lipopolysaccharide', 'Chemical', 'MESH:D008070', (219, 237))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('patient', 'Species', '9606', (128, 135))	('gastric cancer', 'Phenotype', 'HP:0012126', (106, 120))	('p.D299G', 'Mutation', 'rs4986790', (56, 63))
165681	28531216	found no significant increased risk for EAC or esophageal squamous cell carcinoma with this germline polymorphism, and the D299G polymorphism was not identified in either of the ICGC or TCGA cohorts.	('EAC', 'Phenotype', 'HP:0011459', (40, 43))	('esophageal squamous cell carcinoma', 'Disease', (47, 81))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('EAC', 'Disease', (40, 43))	('D299G', 'Var', (123, 128))	('D299G', 'Mutation', 'rs4986790', (123, 128))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (47, 81))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (58, 81))
165682	28531216	The relationship between TLR4 signaling and tumorigenesis is complex and involves both innate and adaptive immunity, with evidence showing that TLR4 signaling can enhance or suppress cancer development, depending on the model system.	('cancer', 'Disease', (183, 189))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('enhance', 'PosReg', (163, 170))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('suppress', 'NegReg', (174, 182))	('tumor', 'Disease', (44, 49))	('TLR4', 'Var', (144, 148))	('cancer', 'Disease', 'MESH:D009369', (183, 189))
165685	28531216	Additionally, analysis of TCGA expression data suggested that NLRP6 is upregulated in TLR mutant tumors, which may reflect cross-talk between the TLR pathway and NOD-like receptor signaling pathway.	('TLR', 'Gene', (86, 89))	('TLR', 'Gene', '7096;7097;7098;7099;21898;7100;51284;51311;54106;81793', (146, 149))	('NLRP6', 'Gene', '171389', (62, 67))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('mutant', 'Var', (90, 96))	('TLR', 'Gene', (146, 149))	('NLRP6', 'Gene', (62, 67))	('tumors', 'Disease', (97, 103))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('TLR', 'Gene', '7096;7097;7098;7099;21898;7100;51284;51311;54106;81793', (86, 89))	('tumors', 'Disease', 'MESH:D009369', (97, 103))	('upregulated', 'PosReg', (71, 82))
165687	28531216	Further understanding of how altered TLR signaling may contribute to the inflammatory tumor microenvironment in Barrett's carcinogenesis could be helpful in cancer prevention strategies.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('TLR', 'Gene', '7096;7097;7098;7099;21898;7100;51284;51311;54106;81793', (37, 40))	('tumor', 'Disease', (86, 91))	("Barrett's carcinogenesis", 'Disease', (112, 136))	("Barrett's carcinogenesis", 'Disease', 'MESH:D001471', (112, 136))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('TLR', 'Gene', (37, 40))	('altered', 'Var', (29, 36))	('cancer', 'Disease', (157, 163))	('contribute', 'Reg', (55, 65))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
165696	28531216	PathScan was used to assess whether mutations affecting the TLR pathway were significantly enriched in the ICGC cohort or the Dulak et al.	('TLR', 'Gene', '7096;7097;7098;7099;21898;7100;51284;51311;54106;81793', (60, 63))	('TLR', 'Gene', (60, 63))	('ICGC', 'Disease', (107, 111))	('mutations', 'Var', (36, 45))
165699	28531216	The COSMIC database v78 (http://cancer.sanger.ac.uk/cosmic) was downloaded and interrogated for TLR4 and TLR pathway mutations.	('mutations', 'Var', (117, 126))	('TLR', 'Gene', '7096;7097;7098;7099;21898;7100;51284;51311;54106;81793', (105, 108))	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('cancer', 'Disease', (32, 38))	('TLR', 'Gene', (105, 108))	('TLR', 'Gene', '7096;7097;7098;7099;21898;7100;51284;51311;54106;81793', (96, 99))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('TLR', 'Gene', (96, 99))
165700	28531216	Mutations were counted by cancer type as defined by the filters for tissue type and histology described in S3 Table.	('cancer', 'Disease', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('Mutations', 'Var', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))
165701	28531216	The ICGC TLR4 mutations were modeled using mutation functions in COOT (Crystallographic Object-Oriented Toolkit) applied to the crystal structure for dimerized TLR4 ectodomain (PDB ID: 4G8A) bound to MD2 and lipopolysaccharide (LPS) and a hypothetical structure for the Toll/interleukin-1 receptor (TIR) domain based on the TLR10 dimer (PDB ID: 2J67).	('PDB ID', 'Disease', (177, 183))	('lipopolysaccharide', 'Chemical', 'MESH:D008070', (208, 226))	('PDB ID', 'Disease', 'MESH:C537985', (177, 183))	('LPS', 'Disease', (228, 231))	('TLR10', 'Gene', '81793', (324, 329))	('MD2', 'Gene', '23643', (200, 203))	('TLR4', 'Gene', (9, 13))	('PDB ID', 'Disease', 'MESH:C537985', (337, 343))	('bound', 'Interaction', (191, 196))	('PDB ID', 'Disease', (337, 343))	('MD2', 'Gene', (200, 203))	('LPS', 'Disease', 'MESH:C536528', (228, 231))	('mutations', 'Var', (14, 23))	('TLR10', 'Gene', (324, 329))
165702	28531216	The starting ectodomain PDB structure 4G8A was the common human variant (D299G and T399I), which was initially mutated back to D299 T399 before modeling the observed ICGC mutations.	('D299 T399', 'Var', (127, 136))	('human variant', 'Species', '9606', (58, 71))	('T399I', 'Mutation', 'rs4986791', (83, 88))	('T399I', 'Var', (83, 88))	('D299G', 'Var', (73, 78))	('D299G', 'Mutation', 'rs4986790', (73, 78))
165734	28531216	RNA-Seq read counts per gene and variant calls for esophageal cancer were downloaded from the TCGA data portal (https://gdc.cancer.gov/).	('cancer', 'Disease', (124, 130))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('esophageal cancer', 'Disease', (51, 68))	('variant', 'Var', (33, 40))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('esophageal cancer', 'Disease', 'MESH:D004938', (51, 68))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (124, 130))
165736	28531216	Differential expression analysis between TLR pathway mutated vs. wild-type, TLR pathway vs. control and wild-type vs. control samples was performed using DESeq2.	('TLR', 'Gene', '7096;7097;7098;7099;21898;7100;51284;51311;54106;81793', (76, 79))	('TLR', 'Gene', (76, 79))	('TLR', 'Gene', '7096;7097;7098;7099;21898;7100;51284;51311;54106;81793', (41, 44))	('mutated', 'Var', (53, 60))	('TLR', 'Gene', (41, 44))
165737	28531216	The Wilcoxon rank-sum test was used to compare the frequency of TLR mutant samples for microbiome exposed versus rarely exposed tumors in the COSMIC database.	('TLR', 'Gene', '7096;7097;7098;7099;21898;7100;51284;51311;54106;81793', (64, 67))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumors', 'Disease', 'MESH:D009369', (128, 134))	('tumors', 'Disease', (128, 134))	('TLR', 'Gene', (64, 67))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('mutant', 'Var', (68, 74))
165741	28260029	Ly2-3 was associated with tumor size (P=0.028), lymph node metastasis (P<0.001), venous invasion (P=0.001) and histological differentiation (P=0.047).	('lymph node metastasis', 'CPA', (48, 69))	('associated', 'Reg', (10, 20))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('venous invasion', 'CPA', (81, 96))	('histological differentiation', 'CPA', (111, 139))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('Ly2-3', 'Var', (0, 5))
165742	28260029	Statistical analysis using the Kaplan-Meier method and the log-rank test indicated that overall survival was significantly reduced in patients with ly2-3 compared with those with ly0-1 (P<0.001).	('ly2', 'Chemical', '-', (148, 151))	('patients', 'Species', '9606', (134, 142))	('ly2-3', 'Var', (148, 153))	('overall survival', 'CPA', (88, 104))	('reduced', 'NegReg', (123, 130))
165762	28260029	The degree of lymphatic invasion was classified as follows: Ly0, no lymphatic invasion; ly1, mild lymphatic invasion; ly2, moderate lymphatic invasion; or ly3, severe lymphatic invasion (Fig.	('ly3', 'Gene', '926', (155, 158))	('ly3', 'Gene', (155, 158))	('ly1', 'Var', (88, 91))	('ly1', 'Chemical', '-', (88, 91))	('ly2', 'Var', (118, 121))	('ly2', 'Chemical', '-', (118, 121))	('Ly0', 'Chemical', '-', (60, 63))	('Ly0', 'Var', (60, 63))
165764	28260029	Since some specimens included two INF patterns, the patients were divided into seven INF categories: INFa, INFa>b, INFa<b, INFb, INFb>c, INFb<c, and INFc.	('INFa', 'Gene', '3451', (107, 111))	('INFa', 'Gene', '3451', (115, 119))	('INFa', 'Gene', '3451', (101, 105))	('INFb>c', 'Var', (129, 135))	('INFa', 'Gene', (115, 119))	('INFa', 'Gene', (107, 111))	('patients', 'Species', '9606', (52, 60))	('INFa', 'Gene', (101, 105))
165769	28260029	The degree of lymphatic invasion was classified into four groups: Ly0 in 43 cases (41.7%), ly1 in 41 cases (39.8%), ly2 in 12 cases (11.7%) and ly3 in 7 cases (6.8%).	('ly2', 'Var', (116, 119))	('ly3', 'Gene', '926', (144, 147))	('Ly0', 'Chemical', '-', (66, 69))	('Ly0', 'Var', (66, 69))	('ly1', 'Chemical', '-', (91, 94))	('ly2', 'Chemical', '-', (116, 119))	('ly3', 'Gene', (144, 147))	('ly1', 'Var', (91, 94))
165771	28260029	Analysis using the Kaplan-Meier method and the log-rank test indicated that patients with ly2 exhibited poorer survival compared with patients with ly1 (P=0.048; Fig.	('patients', 'Species', '9606', (76, 84))	('ly1', 'Chemical', '-', (148, 151))	('survival', 'MPA', (111, 119))	('ly2', 'Var', (90, 93))	('ly2', 'Chemical', '-', (90, 93))	('poorer', 'NegReg', (104, 110))	('patients', 'Species', '9606', (134, 142))
165772	28260029	However, overall survival was not significantly different between patients with ly0 and ly1 (P=0.237), or between patients with ly2 and ly3 (P=0.138).	('ly1', 'Var', (88, 91))	('ly2', 'Chemical', '-', (128, 131))	('ly1', 'Chemical', '-', (88, 91))	('patients', 'Species', '9606', (66, 74))	('ly0', 'Var', (80, 83))	('ly3', 'Gene', (136, 139))	('patients', 'Species', '9606', (114, 122))	('ly3', 'Gene', '926', (136, 139))
165773	28260029	A more statistically significant difference was detected between patients with ly0-1 and ly2-3 (P<0.001), compared with between patients with ly0 and ly1-3 (P=0.018, Fig.	('ly0-1', 'Var', (79, 84))	('ly2-3', 'Var', (89, 94))	('ly1', 'Chemical', '-', (150, 153))	('patients', 'Species', '9606', (65, 73))	('patients', 'Species', '9606', (128, 136))	('ly2', 'Chemical', '-', (89, 92))
165775	28260029	Ly2-3 was significantly associated with larger tumor size (P=0.028), lymph node metastasis (P<0.001), venous invasion (P=0.001) and poor differentiation (P=0.047), as compared with ly0-1.	('poor differentiation', 'CPA', (132, 152))	('tumor', 'Disease', (47, 52))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('larger', 'PosReg', (40, 46))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('venous invasion', 'CPA', (102, 117))	('Ly2-3', 'Var', (0, 5))	('lymph node metastasis', 'CPA', (69, 90))
165777	28260029	In addition, multivariate analysis identified ly2-3 as an independent predictor of mortality (HR, 2.580; 95% CI, 1.376-4.839; Table IV).	('ly2-3', 'Var', (46, 51))	('mortality', 'Disease', (83, 92))	('ly2', 'Chemical', '-', (46, 49))
165778	28260029	The present study investigated the degree of lymphatic invasion and other clinicopathological features of lung SqCC, and demonstrated that ly2-3 was associated with higher malignant potential compared with ly0-1.	('ly2-3', 'Var', (139, 144))	('malignant potential', 'CPA', (172, 191))	('lung SqCC', 'Disease', (106, 115))	('higher', 'PosReg', (165, 171))	('ly2', 'Chemical', '-', (139, 142))	('SqCC', 'Phenotype', 'HP:0002860', (111, 115))
165779	28260029	A total of 18% of patients with lung SqCC had ly2-3, and exhibited higher rates of lymph node metastasis and poorer overall survival compared with those with ly0-1.	('higher', 'PosReg', (67, 73))	('lung SqCC', 'Disease', (32, 41))	('ly2', 'Chemical', '-', (46, 49))	('ly2-3', 'Var', (46, 51))	('patients', 'Species', '9606', (18, 26))	('SqCC', 'Phenotype', 'HP:0002860', (37, 41))	('poorer', 'NegReg', (109, 115))	('lymph node metastasis', 'CPA', (83, 104))
165798	28260029	However, there was a more statistically significant difference in survival between patients with ly0-1 and ly2-3.	('survival', 'MPA', (66, 74))	('ly2', 'Chemical', '-', (107, 110))	('significant', 'Reg', (40, 51))	('ly0-1', 'Var', (97, 102))	('ly2-3', 'Var', (107, 112))	('patients', 'Species', '9606', (83, 91))
165799	28260029	Univariate analysis indicated a significant difference in survival between patients with ly1-3 and ly0; however, the HR was 1.854, which was lower than the HR of 3.298 for the comparison of survival between patients with ly0-1 and ly2-3.	('patients', 'Species', '9606', (207, 215))	('patients', 'Species', '9606', (75, 83))	('ly1', 'Chemical', '-', (89, 92))	('ly2', 'Chemical', '-', (231, 234))	('ly1-3', 'Var', (89, 94))	('ly0', 'Var', (99, 102))
165801	28260029	In the present study, patients with ly2-3 exhibited a significantly higher rate of lymph node metastasis compared with those with ly0-1 (P<0.001).	('ly2-3', 'Var', (36, 41))	('patients', 'Species', '9606', (22, 30))	('higher', 'PosReg', (68, 74))	('ly2', 'Chemical', '-', (36, 39))	('lymph node metastasis', 'CPA', (83, 104))
165813	32508443	Disruption in the mechanisms that regulate cell cycle checkpoints and DNA repair mechanism results in genomic instability; these alterations might contribute to carcinoma.	('genomic', 'MPA', (102, 109))	('carcinoma', 'Disease', 'MESH:D009369', (161, 170))	('results in', 'Reg', (91, 101))	('contribute', 'Reg', (147, 157))	('carcinoma', 'Phenotype', 'HP:0030731', (161, 170))	('carcinoma', 'Disease', (161, 170))	('Disruption', 'Var', (0, 10))
165823	32508443	The genetic variation in the population of genes involved in NER pathway may cause variations in DNA repair capacity leading to extreme photosensitivity and increased susceptibility to both oral epithelial dysplastic lesions and cancer.	('cause', 'Reg', (77, 82))	('photosensitivity', 'Phenotype', 'HP:0000992', (136, 152))	('cancer', 'Disease', (229, 235))	('cancer', 'Disease', 'MESH:D009369', (229, 235))	('extreme photosensitivity', 'Phenotype', 'HP:0007537', (128, 152))	('epithelial dysplastic lesions', 'Phenotype', 'HP:0031492', (195, 224))	('oral epithelial dysplastic lesions', 'Disease', (190, 224))	('variations', 'Var', (83, 93))	('oral epithelial dysplastic lesions', 'Disease', 'MESH:D004416', (190, 224))	('DNA repair capacity', 'MPA', (97, 116))	('genetic variation', 'Var', (4, 21))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('susceptibility', 'Reg', (167, 181))
165850	32508443	The germline mutations in several genes of the NER are associated with cerebro-oculofacial syndrome and trichothiodystrophy and can cause Xeroderma pigmentosum, a disorder characterized by extreme sensitivity to sunlight with propensity to develop skin cancer and other malignancies.	('Xeroderma pigmentosum', 'Disease', 'MESH:D014983', (138, 159))	('cerebro-oculofacial syndrome', 'Disease', 'MESH:D020331', (71, 99))	('malignancies', 'Disease', (270, 282))	('trichothiodystrophy', 'Disease', 'MESH:D054463', (104, 123))	('associated', 'Reg', (55, 65))	('sensitivity to sunlight', 'Phenotype', 'HP:0000992', (197, 220))	('cerebro-oculofacial syndrome', 'Disease', (71, 99))	('skin cancer', 'Disease', (248, 259))	('germline mutations', 'Var', (4, 22))	('skin cancer', 'Phenotype', 'HP:0008069', (248, 259))	('NER', 'Gene', (47, 50))	('Xeroderma pigmentosum', 'Disease', (138, 159))	('malignancies', 'Disease', 'MESH:D009369', (270, 282))	('trichothiodystrophy', 'Disease', (104, 123))	('skin cancer', 'Disease', 'MESH:D012878', (248, 259))	('cause', 'Reg', (132, 137))	('cancer', 'Phenotype', 'HP:0002664', (253, 259))
165854	32508443	The expression of ERCC2 has been proved in premalignant lesions, and the polymorphism associated with this gene has been associated with high risk of oral cancer.	('oral cancer', 'Disease', (150, 161))	('malignant lesions', 'Disease', 'MESH:D009369', (46, 63))	('ERCC2', 'Gene', (18, 23))	('polymorphism', 'Var', (73, 85))	('associated', 'Reg', (121, 131))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('oral cancer', 'Disease', 'MESH:D009369', (150, 161))	('malignant lesions', 'Disease', (46, 63))	('ERCC2', 'Gene', '2068', (18, 23))
165858	32508443	There were few cases which did not take up the stain; the reason could be polymorphism that has occurred in few of the cells, degradation of the proteins by reactive oxygen species or due to epigenetic change.	('proteins', 'Protein', (145, 153))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (157, 180))	('polymorphism', 'Var', (74, 86))	('degradation', 'MPA', (126, 137))	('epigenetic change', 'Var', (191, 208))
165859	32508443	All these molecular changes can lead to deficiency of ERCC1 that results in poor repair capability as well as gradual loss of transcription process which decrease the proportion of cells to express ERCC1.	('poor', 'NegReg', (76, 80))	('deficiency', 'Disease', 'MESH:D007153', (40, 50))	('decrease', 'NegReg', (154, 162))	('loss', 'NegReg', (118, 122))	('repair', 'MPA', (81, 87))	('transcription process', 'MPA', (126, 147))	('deficiency', 'Disease', (40, 50))	('ERCC1', 'Gene', (198, 203))	('changes', 'Var', (20, 27))	('ERCC1', 'Gene', '2067', (198, 203))	('ERCC1', 'Gene', '2067', (54, 59))	('ERCC1', 'Gene', (54, 59))	('lead', 'Reg', (32, 36))
165861	32508443	Their study concluded that patients with dysplasia were prone to cancer due to deficiency of NER pathway and polymorphism in NER genes that lead to genetic instability.	('deficiency', 'Disease', (79, 89))	('dysplasia', 'Disease', (41, 50))	('NER pathway', 'Pathway', (93, 104))	('NER genes', 'Gene', (125, 134))	('deficiency', 'Disease', 'MESH:D007153', (79, 89))	('lead to', 'Reg', (140, 147))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('patients', 'Species', '9606', (27, 35))	('polymorphism', 'Var', (109, 121))	('dysplasia', 'Disease', 'MESH:C536170', (41, 50))	('genetic instability', 'MPA', (148, 167))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))
165876	32508443	Thus, the combination of EGFR and ERCC1 helps in the repair of DNA double-stranded breaks.	('ERCC1', 'Gene', (34, 39))	('EGFR', 'Gene', (25, 29))	('ERCC1', 'Gene', '2067', (34, 39))	('repair', 'MPA', (53, 59))	('DNA', 'Var', (63, 66))	('EGFR', 'Gene', '1956', (25, 29))	('helps', 'Reg', (40, 45))
165881	32508443	Mutations and inherited polymorphism of the DNA repair genes alter the expression of ERCC1.	('expression', 'MPA', (71, 81))	('ERCC1', 'Gene', '2067', (85, 90))	('polymorphism', 'Var', (24, 36))	('alter', 'Reg', (61, 66))	('ERCC1', 'Gene', (85, 90))
165885	29168599	Moreover, knockdown of HOXC13 inhibited proliferation and induced apoptosis of ESCC through upregulating CASP3.	('CASP3', 'Gene', (105, 110))	('inhibited', 'NegReg', (30, 39))	('induced', 'Reg', (58, 65))	('HOXC13', 'Gene', '3229', (23, 29))	('HOXC13', 'Gene', (23, 29))	('apoptosis', 'CPA', (66, 75))	('CASP3', 'Gene', '836', (105, 110))	('knockdown', 'Var', (10, 19))	('proliferation', 'CPA', (40, 53))	('upregulating', 'PosReg', (92, 104))
165912	29168599	Transfection of shRNA and miR-503 mimics was performed according to the Lipofectamine 3000 Reagent (Invitrogen, Carlsbad, CA, USA) protocol; nonsense shRNA (sh-nc) and negative control mimic (miR-nc) were used as the respective controls.	('nonsense', 'Var', (141, 149))	('miR', 'Gene', '220972', (26, 29))	('miR-503', 'Gene', (26, 33))	('miR', 'Gene', (26, 29))	('miR', 'Gene', '220972', (192, 195))	('miR', 'Gene', (192, 195))	('miR-503', 'Gene', '574506', (26, 33))	('Lipofectamine', 'Chemical', 'MESH:C086724', (72, 85))
165939	29168599	To further investigate the biological function of HOXC13 in ESCC, we conducted two shRNA (sh1 and sh2) to knockdown HOXC13 in ECA109 and TE13 cells.	('HOXC13', 'Gene', '3229', (50, 56))	('HOXC13', 'Gene', (50, 56))	('HOXC13', 'Gene', '3229', (116, 122))	('HOXC13', 'Gene', (116, 122))	('knockdown', 'Var', (106, 115))	('sh2', 'Gene', '100125854', (98, 101))	('sh2', 'Gene', (98, 101))
165940	29168599	Cell Counting Kit-8 (CCK-8) assay, colony formation test and xCELLigence System assay all revealed that knockdown of HOXC13 inhibited proliferation of ECA109 and TE13 cells (Figure 2C-E).	('inhibited', 'NegReg', (124, 133))	('HOXC13', 'Gene', '3229', (117, 123))	('proliferation', 'CPA', (134, 147))	('HOXC13', 'Gene', (117, 123))	('knockdown', 'Var', (104, 113))
165942	29168599	Results indicated that knockdown of HOXC13 significantly induced apoptosis in ECA109 and TE13 cells (Figure 2F).	('HOXC13', 'Gene', (36, 42))	('knockdown', 'Var', (23, 32))	('HOXC13', 'Gene', '3229', (36, 42))	('induced', 'Reg', (57, 64))	('apoptosis', 'CPA', (65, 74))
165946	29168599	Using qRT-PCR and western blot analysis, we found that expression of CASP3 was significantly upregulated by knockdown of HOXC13 (Figure 3B,C).	('knockdown', 'Var', (108, 117))	('CASP3', 'Gene', '836', (69, 74))	('expression', 'Species', '29278', (55, 65))	('expression', 'MPA', (55, 65))	('CASP3', 'Gene', (69, 74))	('HOXC13', 'Gene', (121, 127))	('upregulated', 'PosReg', (93, 104))	('HOXC13', 'Gene', '3229', (121, 127))
165950	29168599	Moreover, ectopic expression of HOXC13 promotes proliferation of TE3 cells (Figure 4A-C) and inhibits apoptosis (Figure 4D).	('promotes', 'PosReg', (39, 47))	('HOXC13', 'Gene', (32, 38))	('apoptosis', 'CPA', (102, 111))	('proliferation', 'CPA', (48, 61))	('HOXC13', 'Gene', '3229', (32, 38))	('expression', 'Species', '29278', (18, 28))	('inhibits', 'NegReg', (93, 101))	('ectopic expression', 'Var', (10, 28))
165955	29168599	Immunohistochemistry (IHC) analysis revealed that tumors derived from sh-HOXC13 transfected cells showed thicker staining of CASP3 than those in the sh-nc group (Figure 5E).	('HOXC13', 'Gene', '3229', (73, 79))	('HOXC13', 'Gene', (73, 79))	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('staining', 'MPA', (113, 121))	('transfected', 'Var', (80, 91))	('thicker', 'PosReg', (105, 112))	('CASP3', 'Gene', '836', (125, 130))	('CASP3', 'Gene', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('tumors', 'Disease', (50, 56))
165986	28978144	Dual PI3K/mTOR inhibition enhanced the effect of radiation by inhibiting AKT/mTOR signaling pathways and caused G1 phase arrest, which is associated with downregulation of cyclin D1/CDK4 activity, leading to growth inhibition.	('enhanced', 'PosReg', (26, 34))	('growth inhibition', 'CPA', (208, 225))	('effect', 'MPA', (39, 45))	('G1 phase arrest', 'CPA', (112, 127))	('AKT', 'Gene', (73, 76))	('cyclin D1', 'Gene', (172, 181))	('downregulation', 'NegReg', (154, 168))	('activity', 'MPA', (187, 195))	('inhibiting', 'NegReg', (62, 72))	('CDK4', 'Gene', (182, 186))	('CDK4', 'Gene', '1019', (182, 186))	('cyclin D1', 'Gene', '595', (172, 181))	('AKT', 'Gene', '207', (73, 76))	('inhibition', 'Var', (15, 25))
166000	28978144	Recent findings suggest that dual targeting of PI3K and mTOR has the ability to overcome resistance to IR and improve the anticancer efficacy of the treatment in various cancer cell types in vitro and in in vivo xenograft models of cancer.	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (232, 238))	('resistance to IR', 'MPA', (89, 105))	('mTOR', 'Gene', (56, 60))	('cancer', 'Disease', (170, 176))	('cancer', 'Disease', (232, 238))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('improve', 'PosReg', (110, 117))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('PI3K', 'Var', (47, 51))
166007	28978144	We also analyzed the expression profiles of AKT/mTOR signaling pathway-related proteins; both p110 and p85 PI3K showed high expression levels in OML1-R cells.	('expression levels', 'MPA', (124, 141))	('p110', 'Gene', '100616443', (94, 98))	('AKT', 'Gene', '207', (44, 47))	('p110', 'Gene', (94, 98))	('p85 PI3K', 'Var', (103, 111))	('AKT', 'Gene', (44, 47))
166010	28978144	Thus, our findings suggest that the PI3K/Akt/mTOR signaling pathway is actively involved in OSCC radioresistance and that disruption of the PI3K/AKT/mTOR signaling pathway using the dual PI3K/mTOR inhibitor sensitizes cells to RT and overcomes OSCC radioresistance.	('sensitizes', 'PosReg', (207, 217))	('AKT', 'Gene', (145, 148))	('overcomes', 'PosReg', (234, 243))	('OSCC', 'Disease', (92, 96))	('disruption', 'Var', (122, 132))	('Akt', 'Gene', '207', (41, 44))	('OSCC', 'Disease', (244, 248))	('Akt', 'Gene', (41, 44))	('involved', 'Reg', (80, 88))	('AKT', 'Gene', '207', (145, 148))
166013	28978144	The combination of NVP-BEZ235 and IR clearly reduced proliferation of OSCC and radioresistant OSCC cell lines (Figure 2A).	('reduced', 'NegReg', (45, 52))	('BEZ235', 'Chemical', 'MESH:C531198', (23, 29))	('proliferation', 'CPA', (53, 66))	('radioresistant OSCC cell lines', 'CPA', (79, 109))	('NVP-BEZ235', 'Var', (19, 29))
166014	28978144	To confirm the clinical effectiveness of the dual PI3K/mTOR inhibitor, we isolated and expanded four primary tumor cells from OSCC patients and then treated them with NVP-BEZ235 with and without IR.	('patients', 'Species', '9606', (131, 139))	('BEZ235', 'Chemical', 'MESH:C531198', (171, 177))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('OSCC', 'Disease', (126, 130))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('NVP-BEZ235', 'Var', (167, 177))	('tumor', 'Disease', (109, 114))
166017	28978144	Consistently, the combination treatment of BEZ235 and IR significantly reduced colony formation in all primary OSCC cells (Figure 2B and Table 1).	('BEZ235', 'Var', (43, 49))	('colony formation in', 'CPA', (79, 98))	('reduced', 'NegReg', (71, 78))	('BEZ235', 'Chemical', 'MESH:C531198', (43, 49))
166018	28978144	Thus, inhibition of the PI3K/AKT/mTOR signaling pathway enhances radiosensitivity in OSCC cells by repressing their colony formation ability.	('colony formation ability', 'CPA', (116, 140))	('radiosensitivity', 'CPA', (65, 81))	('AKT', 'Gene', '207', (29, 32))	('repressing', 'NegReg', (99, 109))	('inhibition', 'Var', (6, 16))	('AKT', 'Gene', (29, 32))	('enhances', 'PosReg', (56, 64))
166020	28978144	The combination treatment of BEZ235 and 4-Gy IR consistently showed a significant reduction in colony formation compared with that by each single PI3K or mTOR inhibitor (BKM120 or AZD2014) with or without IR.	('4-Gy IR', 'Var', (40, 47))	('reduction', 'NegReg', (82, 91))	('colony formation', 'CPA', (95, 111))	('AZD2014', 'Chemical', 'MESH:C585537', (180, 187))	('BEZ235', 'Var', (29, 35))	('BEZ235', 'Chemical', 'MESH:C531198', (29, 35))	('BKM120', 'Chemical', 'MESH:C571178', (170, 176))
166022	28978144	In addition, we also found that AZD2014 was more effective than BKM120 in reducing clonogenic survival of SCC25 and primary OSCC cells.	('AZD2014', 'Chemical', 'MESH:C585537', (32, 39))	('BKM120', 'Chemical', 'MESH:C571178', (64, 70))	('AZD2014', 'Var', (32, 39))	('reducing', 'NegReg', (74, 82))
166025	28978144	BEZ235 in combination with IR increased cell growth inhibition rates of 2.4 to 6.3 fold when compared with BEZ235 alone (Figure 3B).	('BEZ235', 'Var', (0, 6))	('cell growth inhibition rates', 'CPA', (40, 68))	('BEZ235', 'Chemical', 'MESH:C531198', (0, 6))	('BEZ235', 'Chemical', 'MESH:C531198', (107, 113))	('increased', 'PosReg', (30, 39))
166026	28978144	On the other hand, the addition of cisplatin obviously decreased the cell viability of OML1-R, SCC25 cells, and primary OSCC cells by 23.1%, 28.0% and 21.1%, and significantly reduced cell growth by 19.6%, 8.7% and 6.9% when combined with IR, respectively.	('cell growth', 'CPA', (184, 195))	('reduced', 'NegReg', (176, 183))	('cisplatin', 'Chemical', 'MESH:D002945', (35, 44))	('cell viability', 'CPA', (69, 83))	('decreased', 'NegReg', (55, 64))	('cisplatin', 'Var', (35, 44))
166028	28978144	The above results showed that BEZ235 had a lower toxicity than cisplatin.	('BEZ235', 'Chemical', 'MESH:C531198', (30, 36))	('cisplatin', 'Chemical', 'MESH:D002945', (63, 72))	('toxicity', 'Disease', 'MESH:D064420', (49, 57))	('toxicity', 'Disease', (49, 57))	('BEZ235', 'Var', (30, 36))
166029	28978144	More notably, when the cell lines were exposed to BEZ235 in conjunction with IR, cytotoxicity was obviously augmented.	('cytotoxicity', 'Disease', (81, 93))	('augmented', 'PosReg', (108, 117))	('cytotoxicity', 'Disease', 'MESH:D064420', (81, 93))	('BEZ235', 'Var', (50, 56))	('BEZ235', 'Chemical', 'MESH:C531198', (50, 56))
166030	28978144	The tumor-killing effects of radiation were enhanced by adding BEZ235 in both radiosensitive and radioresistant OSCC cells.	('tumor', 'Disease', (4, 9))	('BEZ235', 'Var', (63, 69))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('BEZ235', 'Chemical', 'MESH:C531198', (63, 69))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('enhanced', 'PosReg', (44, 52))
166031	28978144	Our results suggested that inhibiting the PI3K/AKT/mTOR signaling pathway acts additively with IR, decreases proliferation of OSCC cells, and re-sensitizes resistant cells to IR obviously.	('decreases', 'NegReg', (99, 108))	('AKT', 'Gene', (47, 50))	('inhibiting', 'Var', (27, 37))	('AKT', 'Gene', '207', (47, 50))	('proliferation', 'CPA', (109, 122))
166037	28978144	LC3 expression levels were increased after the combination treatment of BEZ235 and IR; however, neither apoptosis markers (Caspase 3, Bax, Bak) nor gamma-H2AX, a sensitive marker of DNA damage response, showed significant differences after combination treatment (Figure 4B).	('expression levels', 'MPA', (4, 21))	('LC3', 'Gene', '84557', (0, 3))	('increased', 'PosReg', (27, 36))	('Bak', 'Gene', (139, 142))	('LC3', 'Gene', (0, 3))	('BEZ235', 'Var', (72, 78))	('BEZ235', 'Chemical', 'MESH:C531198', (72, 78))	('Caspase 3', 'Gene', (123, 132))	('Bak', 'Gene', '578', (139, 142))	('Bax', 'Gene', (134, 137))	('Caspase 3', 'Gene', '836', (123, 132))	('gamma-H2AX', 'Chemical', '-', (148, 158))	('Bax', 'Gene', '581', (134, 137))
166038	28978144	Thus, these findings indicate that BEZ235 may be effective as a radiosensitizing agent against OSCC cell growth through enhanced inhibition of the AKT/mTORC axis and induction of autophagy activity.	('enhanced', 'PosReg', (120, 128))	('BEZ235', 'Var', (35, 41))	('induction', 'Reg', (166, 175))	('OSCC', 'Disease', (95, 99))	('inhibition', 'NegReg', (129, 139))	('AKT', 'Gene', '207', (147, 150))	('BEZ235', 'Chemical', 'MESH:C531198', (35, 41))	('autophagy activity', 'CPA', (179, 197))	('AKT', 'Gene', (147, 150))
166041	28978144	Based on these findings, we demonstrated that BEZ235 significantly increased the proportion of OSCC cells (SCC4 and SCC25) and IR-resistant cells (OML1-R) in the G1 phase.	('SCC4', 'Gene', '23383', (107, 111))	('increased', 'PosReg', (67, 76))	('OSCC', 'Disease', (95, 99))	('SCC4', 'Gene', (107, 111))	('BEZ235', 'Var', (46, 52))	('BEZ235', 'Chemical', 'MESH:C531198', (46, 52))
166042	28978144	Similar results were observed for three primary OSCC cell lines, which had a higher ratio of cells in the G1 phase after treatment with BEZ235.	('higher', 'PosReg', (77, 83))	('BEZ235', 'Var', (136, 142))	('BEZ235', 'Chemical', 'MESH:C531198', (136, 142))
166043	28978144	In order to understand the molecular basis of the BEZ235-induced G1 arrest in cell growth inhibition, we investigated the probability of changes in expression levels of diverse regulators of the cell cycle, particularly those associated with G1 checkpoints such as cyclin D1, and CDK4.	('BEZ235-induced', 'Var', (50, 64))	('CDK4', 'Gene', (280, 284))	('cyclin D1', 'Gene', (265, 274))	('CDK4', 'Gene', '1019', (280, 284))	('expression', 'MPA', (148, 158))	('cyclin D1', 'Gene', '595', (265, 274))	('BEZ235', 'Chemical', 'MESH:C531198', (50, 56))
166044	28978144	In the presence of BEZ235, cyclin D1 and CDK4 were significantly decreased; however, there were no obvious changes in the expression levels of these molecules in neither control nor IR-treated cells (Figure 5B).	('BEZ235', 'Chemical', 'MESH:C531198', (19, 25))	('cyclin D1', 'Gene', (27, 36))	('decreased', 'NegReg', (65, 74))	('CDK4', 'Gene', (41, 45))	('CDK4', 'Gene', '1019', (41, 45))	('BEZ235', 'Var', (19, 25))	('cyclin D1', 'Gene', '595', (27, 36))
166045	28978144	In agreement with the cell-cycle distribution analysis, inhibition of the PI3K/mTOR signaling pathway significantly reduced the expression of cyclin D1 and CDK4, causing cell cycle G1 arrest, thus contributing to the growth-inhibitory effects in all OSCC cells.	('PI3K/mTOR signaling pathway', 'Pathway', (74, 101))	('CDK4', 'Gene', (156, 160))	('cyclin D1', 'Gene', (142, 151))	('CDK4', 'Gene', '1019', (156, 160))	('growth-inhibitory effects', 'CPA', (217, 242))	('OSCC', 'Disease', (250, 254))	('inhibition', 'Var', (56, 66))	('expression', 'MPA', (128, 138))	('reduced', 'NegReg', (116, 123))	('cell cycle G1 arrest', 'CPA', (170, 190))	('cyclin D1', 'Gene', '595', (142, 151))
166052	28978144	Immunohistochemistry analysis revealed a significant reduction in phospho-S6 and eIF4E levels in tumor-bearing radioresistant OML1-R mice treated with BEZ235 compared with that by either IR or control treatments (Figure 6C).	('mice', 'Species', '10090', (133, 137))	('BEZ235', 'Var', (151, 157))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('BEZ235', 'Chemical', 'MESH:C531198', (151, 157))	('phospho-S6', 'MPA', (66, 76))	('reduction', 'NegReg', (53, 62))	('tumor', 'Disease', (97, 102))	('eIF4E', 'Protein', (81, 86))
166068	28978144	BKM120 is a highly specific, orally available pan-Class I PI3K inhibitor that exhibits potent antiproliferative and synergistic radiosensitization in tumor cell lines.	('BKM120', 'Var', (0, 6))	('antiproliferative', 'CPA', (94, 111))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('BKM120', 'Chemical', 'MESH:C571178', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('PI3K', 'Gene', (58, 62))	('tumor', 'Disease', (150, 155))
166083	28978144	It was also reported that inhibition of mTOR can cause G1 arrest in a manner that could be suppressed through 4EBP1 phosphorylation; however, mTOR inhibition is not sufficient to suppress eIF4E in most cells.	('4EBP1', 'Gene', '1978', (110, 115))	('4EBP1', 'Gene', (110, 115))	('inhibition', 'Var', (26, 36))	('cause', 'Reg', (49, 54))	('G1 arrest', 'CPA', (55, 64))
166087	28978144	Treatment with BEZ235 in combination with IR caused a slight induction of autophagy, whereas it had no relevant effect in apoptosis of OSCC cells for any of the treatments.	('autophagy', 'CPA', (74, 83))	('BEZ235', 'Chemical', 'MESH:C531198', (15, 21))	('BEZ235', 'Var', (15, 21))
166090	28978144	BEZ235 displayed a statistically significant anti-tumor activity and synergy with IR against OML1-R xenografts and an attenuation effect of eIF4E and S6K phosphorylation.	('phosphorylation', 'MPA', (154, 169))	('BEZ235', 'Var', (0, 6))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('BEZ235', 'Chemical', 'MESH:C531198', (0, 6))	('S6K', 'Protein', (150, 153))	('eIF4E', 'Protein', (140, 145))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('attenuation', 'NegReg', (118, 129))	('tumor', 'Disease', (50, 55))
166092	28978144	Furthermore, combination treatment of BEZ235 and IR in vivo is a safe and effective treatment that offered a greater therapeutic gain than that of RT alone.	('gain', 'PosReg', (129, 133))	('BEZ235', 'Chemical', 'MESH:C531198', (38, 44))	('BEZ235', 'Var', (38, 44))
166094	28978144	More notably, the present study declared that combining a novel agent of BEZ235 to inhibit the PI3K/mTOR signaling pathway is a potential therapeutic strategy for irradiating OSCC, including patient-derived cells, OSCC radioresistant cell lines, and xenografts.	('BEZ235', 'Var', (73, 79))	('OSCC', 'Disease', (175, 179))	('BEZ235', 'Chemical', 'MESH:C531198', (73, 79))	('patient', 'Species', '9606', (191, 198))	('inhibit', 'NegReg', (83, 90))	('PI3K/mTOR signaling pathway', 'Pathway', (95, 122))
166095	28978144	The radiosensitization efficiency of BEZ235 is achieved by impairing S6K1 and 4EBP1/eIF4E signaling pathways, inducing cell-cycle arrest, and inducing autophagic cell death that causes cell proliferation or cell growth inhibition.	('inducing', 'PosReg', (110, 118))	('autophagic cell death', 'CPA', (151, 172))	('cell growth inhibition', 'CPA', (207, 229))	('inducing', 'Reg', (142, 150))	('cell proliferation', 'CPA', (185, 203))	('S6K1 and 4EBP1', 'Gene', '6198', (69, 83))	('cell-cycle arrest', 'CPA', (119, 136))	('BEZ235', 'Var', (37, 43))	('impairing', 'NegReg', (59, 68))	('BEZ235', 'Chemical', 'MESH:C531198', (37, 43))
166116	28978144	When tumors reached a size of approximately 100 mm3, mice were randomized into three groups: Vehicle control, RT, and BEZ235+RT.	('tumors', 'Disease', (5, 11))	('tumors', 'Disease', 'MESH:D009369', (5, 11))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('BEZ235', 'Chemical', 'MESH:C531198', (118, 124))	('tumors', 'Phenotype', 'HP:0002664', (5, 11))	('BEZ235+RT', 'Var', (118, 127))	('mice', 'Species', '10090', (53, 57))
166124	26715988	In this study, the effect of rs11549465 (1772 C/T) and rs11549467 (1790 G/A) polymorphisms of HIF1A gene and its association with cancers were investigated through meta-analysis.	('1772 C/T', 'Mutation', 'rs11549465', (41, 49))	('1790 G/A', 'Mutation', 'rs11549467', (67, 75))	('cancers', 'Phenotype', 'HP:0002664', (130, 137))	('cancers', 'Disease', (130, 137))	('cancers', 'Disease', 'MESH:D009369', (130, 137))	('rs11549465 (1772 C/T', 'Var', (29, 49))	('rs11549467', 'Mutation', 'rs11549467', (55, 65))	('HIF1A', 'Gene', (94, 99))	('rs11549465', 'Mutation', 'rs11549465', (29, 39))	('HIF1A', 'Gene', '3091', (94, 99))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('rs11549467 (1790 G/A', 'Var', (55, 75))
166125	26715988	Meta-analysis of genome wide association studies of HIF1A 1772 C/T polymorphism were conducted on 22 case-control studies of sample size 19024 and for 1790 G/A polymorphism 19 case-control studies were included with sample size 10654.	('1772 C/T', 'Mutation', 'rs11549465', (58, 66))	('1790 G/A', 'Mutation', 'rs11549467', (151, 159))	('HIF1A', 'Gene', '3091', (52, 57))	('HIF1A', 'Gene', (52, 57))	('polymorphism', 'Var', (67, 79))
166127	26715988	Meta-analysis from this study indicated that HIF1A 1772 C/T polymorphism is significantly associated with overall cancer risk.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('1772 C/T', 'Mutation', 'rs11549465', (51, 59))	('associated', 'Reg', (90, 100))	('HIF1A', 'Gene', (45, 50))	('HIF1A', 'Gene', '3091', (45, 50))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('1772 C/T polymorphism', 'Var', (51, 72))	('cancer', 'Disease', (114, 120))
166130	26715988	In detail meta-analysis indicated that both the polymorphisms 1772 C/T and 1790 G/A are significantly associated with overall cancer risk.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('1790 G/A', 'Mutation', 'rs11549467', (75, 83))	('1790 G/A', 'Var', (75, 83))	('associated', 'Reg', (102, 112))	('1772 C/T', 'Mutation', 'rs11549465', (62, 70))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))
166143	26715988	In the scientific community, HIF1A has been a research focus and a number of SNPs within HIF1A gene have been identified in association with cancers, with the most widely studied polymorphisms are C1772T (rs11549465) and G1790A (rs11549467) polymorphisms.	('HIF1A', 'Gene', (89, 94))	('G1790A (rs11549467', 'Var', (221, 239))	('HIF1A', 'Gene', '3091', (89, 94))	('rs11549465', 'Var', (205, 215))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('G1790A', 'Mutation', 'rs11549467', (221, 227))	('association', 'Interaction', (124, 135))	('rs11549467', 'Mutation', 'rs11549467', (229, 239))	('C1772T (rs11549465', 'Var', (197, 215))	('C1772T', 'Mutation', 'rs11549465', (197, 203))	('HIF1A', 'Gene', '3091', (29, 34))	('cancers', 'Phenotype', 'HP:0002664', (141, 148))	('cancers', 'Disease', 'MESH:D009369', (141, 148))	('HIF1A', 'Gene', (29, 34))	('rs11549467', 'Var', (229, 239))	('cancers', 'Disease', (141, 148))	('rs11549465', 'Mutation', 'rs11549465', (205, 215))
166146	26715988	A number of studies have suggested that these two nonsynonymous mutations might alter the transcriptional activity of HIF1A gene by causing structural changes with varied stability, which in turn, might influence the downstream target genes expression and regulation.	('stability', 'MPA', (171, 180))	('HIF1A', 'Gene', '3091', (118, 123))	('transcriptional activity', 'MPA', (90, 114))	('causing', 'Reg', (132, 139))	('expression', 'MPA', (241, 251))	('influence', 'Reg', (203, 212))	('regulation', 'MPA', (256, 266))	('mutations', 'Var', (64, 73))	('structural changes', 'MPA', (140, 158))	('HIF1A', 'Gene', (118, 123))	('alter', 'Reg', (80, 85))
166147	26715988	In the recent years, a good number of studies have investigated the impact of HIF1A polymorphisms on cancer risk in different populations; however reported results varied across studies and remain inconclusive.	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('HIF1A', 'Gene', (78, 83))	('cancer', 'Disease', (101, 107))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('HIF1A', 'Gene', '3091', (78, 83))	('polymorphisms', 'Var', (84, 97))
166148	26715988	In this study, the effect of rs11549465 (1772 C/T) and rs11549467 (1790 G/A) polymorphisms of HIF1A gene and its association with cancers were investigated systematically through meta-analysis.	('1772 C/T', 'Mutation', 'rs11549465', (41, 49))	('1790 G/A', 'Mutation', 'rs11549467', (67, 75))	('cancers', 'Phenotype', 'HP:0002664', (130, 137))	('cancers', 'Disease', (130, 137))	('cancers', 'Disease', 'MESH:D009369', (130, 137))	('rs11549465 (1772 C/T', 'Var', (29, 49))	('rs11549467', 'Mutation', 'rs11549467', (55, 65))	('HIF1A', 'Gene', (94, 99))	('rs11549465', 'Mutation', 'rs11549465', (29, 39))	('HIF1A', 'Gene', '3091', (94, 99))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('rs11549467 (1790 G/A', 'Var', (55, 75))
166149	26715988	The search terms included were (1) HIF1A, (2) GWAS, (3) SNPs, (4) polymorphisms, (5) C1772T/ P582S, (6) A1790G/ A588T, (7) case-control study, and (8) cancer.	('SNPs', 'Disease', (56, 60))	('GWAS', 'Disease', (46, 50))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('A1790G/ A588T', 'Var', (104, 117))	('A1790G', 'Mutation', 'c.1790A>G', (104, 110))	('A588T', 'Mutation', 'rs11549467', (112, 117))	('P582S', 'Mutation', 'rs11549465', (93, 98))	('cancer', 'Disease', (151, 157))	('HIF1A', 'Gene', (35, 40))	('polymorphisms', 'Var', (66, 79))	('C1772T/ P582S', 'Var', (85, 98))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('HIF1A', 'Gene', '3091', (35, 40))	('C1772T', 'Mutation', 'rs11549465', (85, 91))
166153	26715988	Following information were extracted from each study: (1) authors name, (2) year of study, (3) ethnicity of the study subjects, (4) cancer type and (5) allelic frequency (Fig.	('allelic frequency', 'Var', (152, 169))	('cancer', 'Disease', (132, 138))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))
166155	26715988	Meta-analysis of genome wide association studies (GWAS) of HIF1A were conducted for two polymorphisms, 1772 C/T and 1790 G/A using odds ratios (ORs).	('1772 C/T', 'Var', (103, 111))	('1790 G/A', 'Var', (116, 124))	('1790 G/A', 'Mutation', 'rs11549467', (116, 124))	('1772 C/T', 'Mutation', 'rs11549465', (103, 111))	('HIF1A', 'Gene', (59, 64))	('HIF1A', 'Gene', '3091', (59, 64))
166162	26715988	In the meta-analysis of the HIF1A 1772 C/T polymorphism, ten different types of cancers consisted of 22 studies with 8149 cancer cases and 10,875 controls were included.	('1772 C/T', 'Mutation', 'rs11549465', (34, 42))	('cancers', 'Disease', 'MESH:D009369', (80, 87))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('HIF1A', 'Gene', (28, 33))	('cancer', 'Disease', (122, 128))	('cancers', 'Disease', (80, 87))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('HIF1A', 'Gene', '3091', (28, 33))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('polymorphism', 'Var', (43, 55))	('cancer', 'Disease', (80, 86))	('cancers', 'Phenotype', 'HP:0002664', (80, 87))
166166	26715988	For the meta-analysis of HIF1A 1790 G/A polymorphism, 19 studies with eleven different cancer types consisted of 4681 cancer cases and 5973 controls were included.	('cancer', 'Disease', (87, 93))	('cancer', 'Disease', (118, 124))	('1790 G/A', 'Mutation', 'rs11549467', (31, 39))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('HIF1A', 'Gene', (25, 30))	('polymorphism', 'Var', (40, 52))	('HIF1A', 'Gene', '3091', (25, 30))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('cancer', 'Disease', 'MESH:D009369', (118, 124))
166171	26715988	The subgroup analyses of prostate cancer, colorectal cancer, breast cancer and oral squamous-cell carcinoma suggested no significant association of the HIF1A 1772 C/T polymorphism.	('1772 C/T', 'Mutation', 'rs11549465', (158, 166))	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('colorectal cancer', 'Disease', (42, 59))	('prostate cancer', 'Disease', 'MESH:D011471', (25, 40))	('breast cancer', 'Phenotype', 'HP:0003002', (61, 74))	('prostate cancer', 'Phenotype', 'HP:0012125', (25, 40))	('prostate cancer', 'Disease', (25, 40))	('HIF1A', 'Gene', '3091', (152, 157))	('breast cancer', 'Disease', 'MESH:D001943', (61, 74))	('colorectal cancer', 'Phenotype', 'HP:0003003', (42, 59))	('breast cancer', 'Disease', (61, 74))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('oral squamous-cell carcinoma', 'Disease', (79, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('HIF1A', 'Gene', (152, 157))	('oral squamous-cell carcinoma', 'Disease', 'MESH:D002294', (79, 107))	('1772 C/T', 'Var', (158, 166))	('colorectal cancer', 'Disease', 'MESH:D015179', (42, 59))
166172	26715988	However, the subgroup analyses of renal cell carcinoma suggested that the HIF1A 1772 C/T polymorphism is significantly associated with lowering renal cell carcinoma risk in homozygote comparison [TT vs. CC: OR 0.27, 95 % CI (0.08-0.90), p-value:0.0335].	('carcinoma', 'Phenotype', 'HP:0030731', (155, 164))	('polymorphism', 'Var', (89, 101))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (144, 164))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (34, 54))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (144, 164))	('renal cell carcinoma', 'Disease', (34, 54))	('HIF1A', 'Gene', '3091', (74, 79))	('1772 C/T', 'Mutation', 'rs11549465', (80, 88))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (34, 54))	('renal cell carcinoma', 'Disease', (144, 164))	('HIF1A', 'Gene', (74, 79))	('lowering', 'NegReg', (135, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (45, 54))
166173	26715988	Interestingly, the results of subgroup analyses of lung cancer suggested that the HIF1A 1772 C/T polymorphism is highly associated with increasing lung cancer risk in homozygote comparison [TT vs. CC: OR 4.88, 95 % CI (2.42-9.84), p-value: <0.0001], recessive model [TT vs. CT + CC: OR 4.04, 95 % CI (2.02-8.08), p-value:<0.0001].	('HIF1A', 'Gene', (82, 87))	('lung cancer', 'Disease', 'MESH:D008175', (51, 62))	('HIF1A', 'Gene', '3091', (82, 87))	('increasing', 'PosReg', (136, 146))	('lung cancer', 'Disease', (147, 158))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('polymorphism', 'Var', (97, 109))	('lung cancer', 'Disease', (51, 62))	('lung cancer', 'Phenotype', 'HP:0100526', (147, 158))	('lung cancer', 'Phenotype', 'HP:0100526', (51, 62))	('1772 C/T', 'Mutation', 'rs11549465', (88, 96))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('lung cancer', 'Disease', 'MESH:D008175', (147, 158))
166174	26715988	The subgroup analyses of Other Cancers suggested that the HIF1A 1772 C/T polymorphism is highly associated with increasing Other Cancer risk in homozygote comparison [TT vs. CC: OR 27.20, 95 % CI (5.04-146.78), p-value: 0.0001], heterozygote comparison [CT vs. CC: OR 2.16, 95 % CI (1.46-3.18), p-value: 0.0056], dominant model [TT + CT vs. CC: OR 1.92, 95 % CI (1.17-3.14), p-value: 0.0093], recessive model [TT vs. CT + CC: OR 17.5, 95 % CI (3.49-87.70), p-value: 0.0005] and [T vs. C allele: OR 2.42, 95 % CI (1.55-3.77), p-value: <0.0001] (Table 3).	('HIF1A', 'Gene', '3091', (58, 63))	('HIF1A', 'Gene', (58, 63))	('polymorphism', 'Var', (73, 85))	('Cancer', 'Phenotype', 'HP:0002664', (129, 135))	('Cancers', 'Disease', (31, 38))	('Cancer', 'Phenotype', 'HP:0002664', (31, 37))	('Cancers', 'Disease', 'MESH:D009369', (31, 38))	('Other Cancer', 'Disease', (123, 135))	('TT + CT', 'Chemical', '-', (329, 336))	('1772 C/T', 'Mutation', 'rs11549465', (64, 72))	('Cancers', 'Phenotype', 'HP:0002664', (31, 38))
166175	26715988	The analyses data for the HIF1A 1772 C/T polymorphism suggested that there was no significant effect on the Caucasian population.	('polymorphism', 'Var', (41, 53))	('1772 C/T', 'Mutation', 'rs11549465', (32, 40))	('HIF1A', 'Gene', '3091', (26, 31))	('HIF1A', 'Gene', (26, 31))
166176	26715988	However, the subgroup analyses of the Asian population suggested that the HIF1A 1772 C/T polymorphism was significantly associated with increasing cancer risk in homozygote comparison [TT vs. CC: OR 4.98, 95 % CI (2.66-9.31), p-value: <0.0001], heterozygote comparison [CT vs. CC: OR 1.30, 95 % CI (1.01-1.69), p-value: 0.0455], dominant model [TT + CT vs. CC: OR 1.41, 95 % CI (1.08-1.84), p-value: 0.0109], recessive model [TT vs. CT + CC: OR 4.28, 95 % CI (2.31-7.95), p-value:<0.0001] and [T vs. C allele: OR 1.43, 95 % CI (1.07-1.90), p-value: 0.0156] (Table 3).	('polymorphism', 'Var', (89, 101))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('TT + CT', 'Chemical', '-', (345, 352))	('increasing', 'PosReg', (136, 146))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('1772 C/T', 'Mutation', 'rs11549465', (80, 88))	('HIF1A', 'Gene', '3091', (74, 79))	('cancer', 'Disease', (147, 153))	('HIF1A', 'Gene', (74, 79))
166178	26715988	There were significant heterogeneity observed in the analyses of HIF1A 1772 C/T polymorphism for overall cancer heterozygote comparison [CT vs. CC: Q = 69.67, d.f = 18, p-value 0.0001, I^2 = 74.2 % (59.5 %-83.5 %)], dominant model [TT + CT vs. CC: Q = 90.25, d.f = 21, p <0.0001, I^2 = 76.7 % (65.1 %-84.5 %)], and [T vs. C allele: Q = 96.87, d.f = 18, p <0.0001, I^2 = 81.4 % (71.9 %-87.7 %).	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('polymorphism', 'Var', (80, 92))	('HIF1A', 'Gene', (65, 70))	('TT + CT', 'Chemical', '-', (232, 239))	('HIF1A', 'Gene', '3091', (65, 70))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('1772 C/T', 'Mutation', 'rs11549465', (71, 79))
166182	26715988	The pooled ORs for overall cancer suggested that the HIF1A 1790 G/A polymorphism was significantly associated with increasing cancer risk for homozygote comparison [AA vs. GG: OR 5.10, 95 % CI (3.12-8.33), p-value: <0.0001, heterozygote comparison [GA vs. GG: OR 1.74, 95 % CI (1.20-2.52), p-value: 0.0033, dominant model [AA + GA vs. GG: OR 1.82, 95 % CI (1.26-2.62), p-value: 0.0014], recessive model [AA vs. GA + GG: OR 3.79, 95 % CI (2.34-6.15), p-value: <0.0001] and [A vs. G allele: OR 1.82, 95 % CI (1.31-2.52), p-value: 0.0003] (Fig.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('GA', 'Chemical', 'MESH:D005708', (411, 413))	('HIF1A', 'Gene', '3091', (53, 58))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('1790 G/A', 'Mutation', 'rs11549467', (59, 67))	('cancer', 'Disease', (27, 33))	('polymorphism', 'Var', (68, 80))	('cancer', 'Disease', 'MESH:D009369', (27, 33))	('GA', 'Chemical', 'MESH:D005708', (249, 251))	('HIF1A', 'Gene', (53, 58))	('GA', 'Chemical', 'MESH:D005708', (328, 330))
166185	26715988	The subgroup analyses of lung cancer suggested that the HIF1A 1790 G/A polymorphism was significantly associated with increasing cancer risk for homozygote comparison [AA vs. GG: OR 5.41, 95 % CI (2.74-10.69), p-value: <0.0001], heterozygote comparison [GA vs. GG: OR 1.76, 95 % CI (1.25-2.49), p-value: 0.0013], dominant model [AA + GA vs. GG: OR 2.20, 95 % CI (1.60-3.03), p-value:<0.0001], recessive model [AA vs. GA + GG: OR 4.51, 95 % CI (2.31-8.81), p-value:<0.0001] and [A vs. G allele: OR 2.31, 95 % CI (1.77-3.02), p-value: <0.0001].	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('cancer', 'Disease', (30, 36))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('lung cancer', 'Disease', (25, 36))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('GA', 'Chemical', 'MESH:D005708', (254, 256))	('GA', 'Chemical', 'MESH:D005708', (334, 336))	('HIF1A', 'Gene', (56, 61))	('HIF1A', 'Gene', '3091', (56, 61))	('1790 G/A', 'Mutation', 'rs11549467', (62, 70))	('lung cancer', 'Phenotype', 'HP:0100526', (25, 36))	('polymorphism', 'Var', (71, 83))	('GA', 'Chemical', 'MESH:D005708', (417, 419))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('lung cancer', 'Disease', 'MESH:D008175', (25, 36))
166186	26715988	Also, the subgroup analyses of oral squamous cell carcinoma (OSCC) suggested that the HIF1A 1790 G/A polymorphism was significantly associated with increasing cancer risk for homozygote comparison [AA vs. GG: OR 12.68, 95 % CI (1.43-112.64), p-value: 0.0227], heterozygote comparison [GA vs. GG: OR 4.69, 95 % CI (1.96-11.21), p-value: 0.0005], dominant model [AA + GA vs. GG: OR 5.17, 95 % CI (1.99-13.43), p-value: 0.0008], recessive model [AA vs. GA + GG: OR 10.12, 95 % CI (1.14-89.72), p-value: 0.0376] and [A vs. G allele: OR 5.00, 95 % CI (2.10-11.97), p-value: 0.0003] (Table 4).	('cancer', 'Disease', (159, 165))	('1790 G/A', 'Mutation', 'rs11549467', (92, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (50, 59))	('GA', 'Chemical', 'MESH:D005708', (450, 452))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (31, 59))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (36, 59))	('HIF1A', 'Gene', (86, 91))	('polymorphism', 'Var', (101, 113))	('HIF1A', 'Gene', '3091', (86, 91))	('oral squamous cell carcinoma', 'Disease', (31, 59))	('GA', 'Chemical', 'MESH:D005708', (285, 287))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('GA', 'Chemical', 'MESH:D005708', (366, 368))
166187	26715988	The subgroup analyses of Other Cancers suggested that the HIF1A 1790 G/A polymorphism is highly associated with increasing Other Cancer risk heterozygote comparison [GA vs. GG: OR 1.96, 95 % CI (1.05-3.65), p-value: 0.0336], dominant model [AA + GA vs. GG: OR 1.96, 95 % CI (1.05-3.67), p-value: 0.0341], and [A vs. G allele: OR 1.91, 95 % CI (1.06-3.44), p-value: 0.0306] (Table 4).	('1790 G/A', 'Mutation', 'rs11549467', (64, 72))	('HIF1A', 'Gene', '3091', (58, 63))	('HIF1A', 'Gene', (58, 63))	('polymorphism', 'Var', (73, 85))	('Cancer', 'Phenotype', 'HP:0002664', (129, 135))	('Cancers', 'Disease', (31, 38))	('Cancer', 'Phenotype', 'HP:0002664', (31, 37))	('Cancers', 'Disease', 'MESH:D009369', (31, 38))	('Cancers', 'Phenotype', 'HP:0002664', (31, 38))	('GA', 'Chemical', 'MESH:D005708', (166, 168))	('GA', 'Chemical', 'MESH:D005708', (246, 248))
166188	26715988	For Caucasian population, the analyzed data suggested that the HIF1A 1790 G/A polymorphism was highly associated with increasing cancer risk for homozygote comparison [AA vs. GG: OR 5.68, 95 % CI (2.57-12.58), p-value: <0.0001], recessive model [AA vs. GA + GG: OR 3.42, 95 % CI (1.57-7.45), p-value: 0.002].	('GA', 'Chemical', 'MESH:D005708', (253, 255))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('increasing', 'PosReg', (118, 128))	('HIF1A', 'Gene', (63, 68))	('HIF1A', 'Gene', '3091', (63, 68))	('cancer', 'Disease', (129, 135))	('1790 G/A', 'Mutation', 'rs11549467', (69, 77))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('polymorphism', 'Var', (78, 90))
166189	26715988	For the Asian population, the subgroup analyses of ethnicity group suggested that the HIF1A 1790 G/A polymorphism was highly associated with increasing cancer risk for homozygote comparison [AA vs. GG: OR 4.76, 95 % CI (2.55-8.91), p-value: <0.0001], heterozygote comparison [GA vs. GG: OR 1.94, 95 % CI (1.38-2.72), p-value: 0.0001], dominant model [AA + GA vs. GG: OR 2.04, 95 % CI (1.44-2.87), p-value: <0.0001], recessive model [AA vs. GA + GG: OR 4.05, 95 % CI (2.18-7.51), p-value: <0.0001] and [A vs. G allele: OR 2.03, 95 % CI (1.46-2.81), p-value: <0.0001] (Table 4).	('GA', 'Chemical', 'MESH:D005708', (356, 358))	('cancer', 'Disease', (152, 158))	('1790 G/A', 'Mutation', 'rs11549467', (92, 100))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('GA', 'Chemical', 'MESH:D005708', (440, 442))	('HIF1A', 'Gene', (86, 91))	('polymorphism', 'Var', (101, 113))	('HIF1A', 'Gene', '3091', (86, 91))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('GA', 'Chemical', 'MESH:D005708', (276, 278))
166193	26715988	The conventionally constructed funnel plot (log odds ratio [log(OR] vs 1/standard error, 1/se) of HIF1A polymorphism 1772 C/T for T vs. C allele suggested that there was evidence of publication bias (Fig.	('1772 C/T', 'Mutation', 'rs11549465', (117, 125))	('polymorphism', 'Var', (104, 116))	('HIF1A', 'Gene', '3091', (98, 103))	('HIF1A', 'Gene', (98, 103))
166194	26715988	Also the funnel plot of HIF1A polymorphism 1790 G/A for A vs. G allele suggested that there was evidence of publication bias (Fig.	('HIF1A', 'Gene', (24, 29))	('HIF1A', 'Gene', '3091', (24, 29))	('polymorphism 1790 G/A', 'Var', (30, 51))	('1790 G/A', 'Mutation', 'rs11549467', (43, 51))
166195	26715988	However, the Egger's linear regression analyses suggested no evidence of significant publication bias in [T vs C allele: t = 1.83, d.f = 17, p-value 0.0847] for HIF1A 1772 C/T polymorphism.	('HIF1A', 'Gene', '3091', (161, 166))	('1772 C/T', 'Mutation', 'rs11549465', (167, 175))	('HIF1A', 'Gene', (161, 166))	('1772 C/T', 'Var', (167, 175))
166196	26715988	Also, for HIF1A 1790 G/A polymorphism results showed no significant evidence of publication bias in [A vs G allele: t = -1.87, d.f = 17, p-value 0.0787] (Additional file 3).	('1790 G/A', 'Mutation', 'rs11549467', (16, 24))	('polymorphism', 'Var', (25, 37))	('G/A polymorphism', 'Var', (21, 37))	('HIF1A', 'Gene', '3091', (10, 15))	('HIF1A', 'Gene', (10, 15))
166197	26715988	Results generated from this meta-analysis indicated that both 1772 C/T and 1790 G/A polymorphisms are significantly associated with increasing overall cancer risk.	('increasing', 'PosReg', (132, 142))	('1790 G/A', 'Var', (75, 83))	('1790 G/A', 'Mutation', 'rs11549467', (75, 83))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('1772 C/T', 'Mutation', 'rs11549465', (62, 70))	('cancer', 'Disease', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('1772 C/T', 'Var', (62, 70))
166198	26715988	The subgroup analyses by cancer type showed that both 1772 C/T and 1790 G/A polymorphisms have significant association with lung cancer, whereas these two polymorphisms showed no significant association with prostate cancer.	('cancer', 'Disease', (129, 135))	('prostate cancer', 'Disease', 'MESH:D011471', (208, 223))	('prostate cancer', 'Phenotype', 'HP:0012125', (208, 223))	('cancer', 'Disease', (25, 31))	('prostate cancer', 'Disease', (208, 223))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('1790 G/A', 'Mutation', 'rs11549467', (67, 75))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('cancer', 'Disease', 'MESH:D009369', (217, 223))	('lung cancer', 'Disease', (124, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (25, 31))	('association', 'Interaction', (107, 118))	('lung cancer', 'Disease', 'MESH:D008175', (124, 135))	('1772 C/T', 'Var', (54, 62))	('1772 C/T', 'Mutation', 'rs11549465', (54, 62))	('cancer', 'Disease', (217, 223))	('lung cancer', 'Phenotype', 'HP:0100526', (124, 135))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))
166201	26715988	Also, 1790 G/A polymorphism has increased the cancer risk significantly in both Caucasian and Asian ethnicity.	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('1790 G/A', 'Var', (6, 14))	('cancer', 'Disease', (46, 52))	('1790 G/A', 'Mutation', 'rs11549467', (6, 14))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('increased', 'PosReg', (32, 41))
166208	24954188	Non-smokers had fewer TP53 mutations (P=0.02) than smokers.	('mutations', 'Var', (27, 36))	('fewer', 'NegReg', (16, 21))	('TP53', 'Gene', '7157', (22, 26))	('TP53', 'Gene', (22, 26))
166210	24954188	The young age of non-smoker oral tongue cancer patients, and fewer TP53 mutations suggest a viral role in this disease.	('mutations', 'Var', (72, 81))	('oral tongue cancer', 'Disease', (28, 46))	('patients', 'Species', '9606', (47, 55))	('fewer', 'NegReg', (61, 66))	('TP53', 'Gene', '7157', (67, 71))	('TP53', 'Gene', (67, 71))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('oral tongue cancer', 'Disease', 'MESH:D014062', (28, 46))
166258	24954188	Human reads were subtracted by first mapping reads to a database of human database sequences using BWA (Release 0.6.1, default settings), Megablast (Release 2.2.25, cut-off E-value 10-7, word size 16) and Blastn (Release 2.2.25, cut-off E-value 10-7, word size 7, nucleotide match reward 1, nucleotide mismatch -3, gap open cost 5, gap extension cost 2) .	('Human', 'Species', '9606', (0, 5))	('human', 'Species', '9606', (68, 73))	('nucleotide match reward 1', 'Var', (264, 289))	('nucleotide mismatch -3', 'Var', (291, 313))	('gap open cost', 'Var', (315, 328))
166282	24954188	In the cancers from smokers, the recurrent mutations were in CD101, LAMA1, NCAPD3, RIMBP2, SI, SYNE, and TP53.	('LAMA1', 'Gene', (68, 73))	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('RIMBP2', 'Gene', (83, 89))	('CD101', 'Gene', (61, 66))	('RIMBP2', 'Gene', '23504', (83, 89))	('NCAPD3', 'Gene', '23310', (75, 81))	('LAMA1', 'Gene', '284217', (68, 73))	('NCAPD3', 'Gene', (75, 81))	('mutations', 'Var', (43, 52))	('TP53', 'Gene', '7157', (105, 109))	('cancers', 'Disease', 'MESH:D009369', (7, 14))	('TP53', 'Gene', (105, 109))	('cancers', 'Disease', (7, 14))	('CD101', 'Gene', '9398', (61, 66))	('cancers', 'Phenotype', 'HP:0002664', (7, 14))	('SI', 'Disease', 'None', (91, 93))
166283	24954188	All 5 tumors from smokers had TP53 mutations (5 of 5), whereas only one cancer from a non-smoker had a TP53 mutation (1 of 6, P=0.02, Fisher's exact test).	('TP53', 'Gene', '7157', (103, 107))	('TP53', 'Gene', (30, 34))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('TP53', 'Gene', (103, 107))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('tumors', 'Disease', (6, 12))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('mutations', 'Var', (35, 44))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('TP53', 'Gene', '7157', (30, 34))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('cancer', 'Disease', (72, 78))
166285	24954188	In a previous study, we also detected telomerase reverse transcriptase (TERT) promoter mutations in 5 of 11 (45%) tumors sequenced .	('telomerase reverse transcriptase', 'Gene', (38, 70))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('telomerase reverse transcriptase', 'Gene', '7015', (38, 70))	('detected', 'Reg', (29, 37))	('tumors', 'Disease', (114, 120))	('tumors', 'Disease', 'MESH:D009369', (114, 120))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('TERT', 'Gene', '7015', (72, 76))	('TERT', 'Gene', (72, 76))	('mutations', 'Var', (87, 96))
166287	24954188	The mutational spectrum for the two groups was significantly different although the most common substitution in cancers from both non-smokers and smokers was C:G>T:A (Table 3).	('cancers', 'Phenotype', 'HP:0002664', (112, 119))	('C:G>T:A', 'Var', (158, 165))	('cancers', 'Disease', 'MESH:D009369', (112, 119))	('cancers', 'Disease', (112, 119))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))
166288	24954188	Compared to cancers from non-smokers, a greater proportion of mutations in cancers from smokers were either A:T>G:C (P<0.0001) or A:T>T:A substitutions (P<0.0001).	('cancers', 'Disease', 'MESH:D009369', (12, 19))	('A:T>T', 'Var', (130, 135))	('cancers', 'Phenotype', 'HP:0002664', (12, 19))	('cancers', 'Disease', 'MESH:D009369', (75, 82))	('A:T>G:C', 'Var', (108, 115))	('cancers', 'Disease', (12, 19))	('cancers', 'Phenotype', 'HP:0002664', (75, 82))	('cancers', 'Disease', (75, 82))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('mutations', 'Var', (62, 71))
166289	24954188	Conversely:compared to cancers from smokers, a greater proportion of mutations in cancers from non-smokers were C:G>G:C transversions (P<0.0001).	('mutations', 'Var', (69, 78))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('cancers', 'Disease', 'MESH:D009369', (23, 30))	('cancers', 'Phenotype', 'HP:0002664', (23, 30))	('cancers', 'Phenotype', 'HP:0002664', (82, 89))	('cancers', 'Disease', (23, 30))	('cancers', 'Disease', (82, 89))	('cancers', 'Disease', 'MESH:D009369', (82, 89))	('C:G>G:C transversions', 'Var', (112, 133))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))
166300	24954188	In concordance with the exome sequencing data, 1 of 10 (10%) of the cancers from non-smoking patients had a deleterious TP53 mutation while 2 out of 5 (40%) of the cancers from patients who smoked had deleterious TP53 mutations (Table S3).	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('patients', 'Species', '9606', (93, 101))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('TP53', 'Gene', (213, 217))	('patients', 'Species', '9606', (177, 185))	('cancers', 'Phenotype', 'HP:0002664', (68, 75))	('cancers', 'Phenotype', 'HP:0002664', (164, 171))	('cancers', 'Disease', (68, 75))	('cancers', 'Disease', 'MESH:D009369', (68, 75))	('cancers', 'Disease', (164, 171))	('cancers', 'Disease', 'MESH:D009369', (164, 171))	('TP53', 'Gene', (120, 124))	('TP53', 'Gene', '7157', (213, 217))	('TP53', 'Gene', '7157', (120, 124))	('mutation', 'Var', (125, 133))
166305	24954188	Next-generation exomic sequencing and Sanger Sequencing data suggest that cancers from non-smokers have a lower prevalence of TP53 mutations.	('mutations', 'Var', (131, 140))	('TP53', 'Gene', (126, 130))	('cancers', 'Disease', 'MESH:D009369', (74, 81))	('cancers', 'Phenotype', 'HP:0002664', (74, 81))	('cancers', 'Disease', (74, 81))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('TP53', 'Gene', '7157', (126, 130))
166319	24954188	The most striking differences in mutation patterns between cancers from non-smokers and smokers were seen in the prevalence of TP53 mutations.	('mutations', 'Var', (132, 141))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('cancers', 'Disease', 'MESH:D009369', (59, 66))	('cancers', 'Phenotype', 'HP:0002664', (59, 66))	('TP53', 'Gene', '7157', (127, 131))	('cancers', 'Disease', (59, 66))	('TP53', 'Gene', (127, 131))
166321	24954188	The majority of tumors reported by Agrawal et al and Stransky et al harbored TP53 mutations or TP53 inactivation through HPV .	('harbored', 'Reg', (68, 76))	('inactivation', 'NegReg', (100, 112))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('HPV', 'Species', '10566', (121, 124))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('tumors', 'Disease', 'MESH:D009369', (16, 22))	('mutations', 'Var', (82, 91))	('TP53', 'Gene', '7157', (77, 81))	('tumors', 'Disease', (16, 22))	('TP53', 'Gene', (77, 81))	('TP53', 'Gene', '7157', (95, 99))	('TP53', 'Gene', (95, 99))
166322	24954188	In our study only 2 of 16 cancers from non-smokers had a TP53 mutation, whereas 7 of 10 cancers from smokers had TP53 mutations.	('cancers', 'Phenotype', 'HP:0002664', (26, 33))	('cancers', 'Disease', 'MESH:D009369', (26, 33))	('cancers', 'Disease', 'MESH:D009369', (88, 95))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('cancers', 'Disease', (26, 33))	('cancers', 'Disease', (88, 95))	('TP53', 'Gene', '7157', (113, 117))	('mutation', 'Var', (62, 70))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('TP53', 'Gene', '7157', (57, 61))	('TP53', 'Gene', (57, 61))	('TP53', 'Gene', (113, 117))
166326	24954188	The young age of the patients, lack of carcinogen exposure and lack of TP53 mutations raises the possibility that a known or novel virus could be driving tumor development.	('mutations', 'Var', (76, 85))	('lack', 'NegReg', (63, 67))	('patients', 'Species', '9606', (21, 29))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('TP53', 'Gene', '7157', (71, 75))	('TP53', 'Gene', (71, 75))	('tumor', 'Disease', (154, 159))
166333	24954188	Future directions may utilize methods to detect epigenetic signatures of previous viral infection at a point when viral DNA has been lost from cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('viral infection', 'Disease', (82, 97))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('epigenetic', 'Var', (48, 58))	('viral infection', 'Disease', 'MESH:D001102', (82, 97))
166334	24954188	Two landmark studies independently demonstrated that non-smokers with HNSCC harbored fewer mutations compared to smokers , .	('SCC', 'Gene', (72, 75))	('SCC', 'Gene', '6317', (72, 75))	('mutations', 'Var', (91, 100))	('fewer', 'NegReg', (85, 90))
166338	24954188	Surprisingly, the mutational spectrum in cancers from smokers was not enriched in the C:G>A:T transversions that are typically associated with smoking.	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('C:G>A:T', 'Var', (86, 93))	('cancers', 'Phenotype', 'HP:0002664', (41, 48))	('cancers', 'Disease', 'MESH:D009369', (41, 48))	('cancers', 'Disease', (41, 48))
166339	24954188	Cancers from smokers demonstrated more A:T>T:A and A:T>G:C transitions, whereas cancers from non-smokers showed higher rates of C:G>G:C transversions.	('A:T>T', 'Var', (39, 44))	('A:T>G:C', 'Var', (51, 58))	('cancers', 'Disease', 'MESH:D009369', (80, 87))	('Cancers', 'Disease', (0, 7))	('Cancers', 'Phenotype', 'HP:0002664', (0, 7))	('cancers', 'Disease', (80, 87))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('Cancers', 'Disease', 'MESH:D009369', (0, 7))	('cancers', 'Phenotype', 'HP:0002664', (80, 87))
166341	24954188	This study did not investigate the role of other genomic alterations including chromosomal rearrangements and copy number variations in oral tongue SCC, nor did we characterize the potential epigenetic changes that may contribute to oncogenesis in this tumor type.	('tumor', 'Disease', 'MESH:D009369', (253, 258))	('tumor', 'Phenotype', 'HP:0002664', (253, 258))	('epigenetic', 'Var', (191, 201))	('contribute', 'Reg', (219, 229))	('SCC', 'Gene', (148, 151))	('tumor', 'Disease', (253, 258))	('SCC', 'Gene', '6317', (148, 151))
166582	27322149	Anti-PD-1 or anti-PD-L1 antibodies have clinically benefitted patients with some solid cancers in early clinical trials.	('anti-PD-L1', 'Gene', (13, 23))	('solid cancers', 'Disease', (81, 94))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cancers', 'Phenotype', 'HP:0002664', (87, 94))	('antibodies', 'Var', (24, 34))	('solid cancers', 'Disease', 'MESH:D009369', (81, 94))	('benefitted', 'PosReg', (51, 61))	('PD-1', 'Gene', (5, 9))	('patients', 'Species', '9606', (62, 70))	('PD-1', 'Gene', '5133', (5, 9))
166587	27322149	Recently, high mutation burdens in tumors were reported to be associated with a clinical benefit of PD-1 blockade.	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('PD-1', 'Gene', (100, 104))	('PD-1', 'Gene', '5133', (100, 104))	('tumors', 'Disease', (35, 41))	('tumors', 'Disease', 'MESH:D009369', (35, 41))	('mutation burdens', 'Var', (15, 31))	('benefit', 'PosReg', (89, 96))
166608	27322149	Patients with PD-L1 positive in TIICs had significantly better OS than those with PD-L1 negative in TIICs (P = 0.041).	('OS', 'Chemical', '-', (63, 65))	('positive', 'Var', (20, 28))	('better', 'PosReg', (56, 62))	('Patients', 'Species', '9606', (0, 8))	('PD-L1', 'Gene', (14, 19))
166629	27322149	In addition, marked infiltrations of immune suppressor cells such as regulatory T cells (FOXP3+) and M2 macrophages (CD204+) were also associated with PD-L1 expression in both TCs and TIICs.	('TCs', 'Chemical', '-', (176, 179))	('PD-L1', 'Gene', (151, 156))	('associated', 'Reg', (135, 145))	('expression', 'Var', (157, 167))	('CD204', 'Gene', '4481', (117, 122))	('CD204', 'Gene', (117, 122))
166631	27322149	In contrast, significant associations of positivity for PD-L1 expression with the CD8+/FOXP3+ and CD8+/CD204+ ratios, as well as a trend for an inverse association of PD-L1 expression with the FOXP3+/CD4+ ratio, were observed, suggesting PD- L1 expression to be associated with the balance between infiltrating effector cells and immune suppressor cells.	('associations', 'Interaction', (25, 37))	('CD8', 'Gene', (98, 101))	('CD8', 'Gene', (82, 85))	('positivity', 'Var', (41, 51))	('CD8', 'Gene', '925', (82, 85))	('PD-L1', 'Gene', (167, 172))	('CD8', 'Gene', '925', (98, 101))	('CD4', 'Gene', (200, 203))	('inverse', 'NegReg', (144, 151))	('CD204', 'Gene', '4481', (103, 108))	('CD204', 'Gene', (103, 108))	('CD4', 'Gene', '920', (200, 203))	('PD-L1', 'Gene', (56, 61))
166640	27322149	The number of tumor infiltrating FOXP3+ regulatory T cells, especially as reflected by a decreased CD8+/FOXP3+ ratio, is reportedly associated with a poor prognosis for several cancer types.	('cancer', 'Disease', (177, 183))	('tumor', 'Disease', (14, 19))	('cancer', 'Disease', 'MESH:D009369', (177, 183))	('CD8', 'Gene', (99, 102))	('CD8', 'Gene', '925', (99, 102))	('FOXP3+', 'Var', (33, 39))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('decreased', 'NegReg', (89, 98))
166680	32300299	The purpose of this study was to identify aberrantly expressed genes across various cancer types, analyze prospective mechanisms and their correlation with survival outcomes.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('aberrantly expressed', 'Var', (42, 62))	('cancer', 'Disease', (84, 90))
166683	32300299	Importantly, high NCAPG level was significantly associated with unfavorable survival in various cancer types such as hepatocellular carcinoma (HCC), breast, lung or ovarian cancer.	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (117, 141))	('associated', 'Reg', (48, 58))	('breast', 'Disease', (149, 155))	('HCC', 'Phenotype', 'HP:0001402', (143, 146))	('cancer', 'Disease', (96, 102))	('high', 'Var', (13, 17))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (117, 141))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('ovarian cancer', 'Phenotype', 'HP:0100615', (165, 179))	('cancer', 'Disease', (173, 179))	('lung or ovarian cancer', 'Disease', (157, 179))	('hepatocellular carcinoma', 'Disease', (117, 141))	('NCAPG', 'Gene', '64151', (18, 23))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('NCAPG', 'Gene', (18, 23))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('lung or ovarian cancer', 'Disease', 'MESH:D055370', (157, 179))
166741	32300299	These data suggest that high expression of NCAPG correlated with shorter survival in patients with several types of cancer, including HCC, breast cancer, lung cancer, and ovarian cancer.	('cancer', 'Disease', (146, 152))	('lung cancer', 'Phenotype', 'HP:0100526', (154, 165))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('ovarian cancer', 'Disease', (171, 185))	('high', 'Var', (24, 28))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('ovarian cancer', 'Phenotype', 'HP:0100615', (171, 185))	('cancer', 'Disease', (159, 165))	('survival', 'MPA', (73, 81))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('HCC', 'Disease', (134, 137))	('patients', 'Species', '9606', (85, 93))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('HCC', 'Phenotype', 'HP:0001402', (134, 137))	('breast cancer', 'Phenotype', 'HP:0003002', (139, 152))	('NCAPG', 'Gene', '64151', (43, 48))	('lung cancer', 'Disease', (154, 165))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('cancer', 'Disease', (116, 122))	('shorter', 'NegReg', (65, 72))	('NCAPG', 'Gene', (43, 48))	('breast cancer', 'Disease', 'MESH:D001943', (139, 152))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('breast cancer', 'Disease', (139, 152))	('expression', 'MPA', (29, 39))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('ovarian cancer', 'Disease', 'MESH:D010051', (171, 185))	('lung cancer', 'Disease', 'MESH:D008175', (154, 165))	('cancer', 'Disease', (179, 185))
166767	32300299	qPCR was used to detect the inhibition efficiency of siNCAPG1 and siNCAPG2.The results showed that NCAPG was greatly decreased by the siRNAs of NCAPG ( Figure 8C ).	('NCAPG', 'Gene', '64151', (68, 73))	('NCAPG', 'Gene', '64151', (144, 149))	('NCAPG', 'Gene', '64151', (55, 60))	('decreased', 'NegReg', (117, 126))	('NCAPG', 'Gene', (68, 73))	('NCAPG', 'Gene', (99, 104))	('NCAPG', 'Gene', (144, 149))	('siRNAs', 'Var', (134, 140))	('NCAPG', 'Gene', '64151', (99, 104))	('NCAPG', 'Gene', (55, 60))
166769	32300299	Moreover, EdU assay showed that inhibiting NCAPG could significantly reduce MDA-MB-231 cells proliferation ( Figure 8E ).	('NCAPG', 'Gene', (43, 48))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (76, 86))	('MDA-MB-231 cells proliferation', 'CPA', (76, 106))	('inhibiting', 'Var', (32, 42))	('reduce', 'NegReg', (69, 75))	('NCAPG', 'Gene', '64151', (43, 48))
166770	32300299	Furthermore, knockdown of NCAPG increased cleaved-PARP protein level but decreased phosphorylated levels of retinoblastoma protein (pRb) and cyclin B1 protein ( Figure 8F ).	('retinoblastoma', 'Disease', 'MESH:D012175', (108, 122))	('pRb', 'Gene', (132, 135))	('decreased', 'NegReg', (73, 82))	('retinoblastoma', 'Disease', (108, 122))	('cyclin B1', 'Gene', (141, 150))	('pRb', 'Gene', '5925', (132, 135))	('cyclin B1', 'Gene', '891', (141, 150))	('NCAPG', 'Gene', (26, 31))	('PARP', 'Gene', (50, 54))	('PARP', 'Gene', '1302', (50, 54))	('increased', 'PosReg', (32, 41))	('retinoblastoma', 'Phenotype', 'HP:0009919', (108, 122))	('NCAPG', 'Gene', '64151', (26, 31))	('knockdown', 'Var', (13, 22))
166778	32300299	Furthermore, knockdown of NCAPG by siRNA significantly decreased cell proliferation in breast cancer cell line MDA-MB-231.	('MDA-MB-231', 'CellLine', 'CVCL:0062', (111, 121))	('breast cancer', 'Disease', 'MESH:D001943', (87, 100))	('NCAPG', 'Gene', (26, 31))	('decreased', 'NegReg', (55, 64))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('breast cancer', 'Disease', (87, 100))	('breast cancer', 'Phenotype', 'HP:0003002', (87, 100))	('NCAPG', 'Gene', '64151', (26, 31))	('knockdown', 'Var', (13, 22))
166788	32300299	For the first time, the US Food and Drug Administration approved a cancer drug for treatment based on a tumor biomarker and not the tumor's original location: pembrolizumab, indicated for treatment of mismatch repair deficient, or microsatellite instability-high advanced solid tumors.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('tumor', 'Phenotype', 'HP:0002664', (278, 283))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('cancer', 'Disease', (67, 73))	('tumors', 'Disease', (278, 284))	('pembrolizumab', 'Chemical', 'MESH:C582435', (159, 172))	('tumor', 'Disease', (278, 283))	('tumors', 'Phenotype', 'HP:0002664', (278, 284))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumor', 'Disease', (104, 109))	('tumors', 'Disease', 'MESH:D009369', (278, 284))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('tumor', 'Disease', (132, 137))	('microsatellite instability-high', 'Var', (231, 262))	('tumor', 'Disease', 'MESH:D009369', (278, 283))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
166789	32300299	It has been reported that the knockdown of NCAPG expression could not only reduce HCC cell viability, but also induce apoptosis and arrest the cells at the S phase of the cell cycle by regulating the expression of Bax, cleaved caspase-3, E-cadherin, cyclin A1, CDK2, Bcl-2, N-cadherin, and HOXB9.	('arrest', 'CPA', (132, 138))	('cyclin A1', 'Gene', '8900', (250, 259))	('Bcl-2', 'Gene', (267, 272))	('expression', 'MPA', (200, 210))	('cyclin A1', 'Gene', (250, 259))	('knockdown', 'Var', (30, 39))	('apoptosis', 'CPA', (118, 127))	('N-cadherin', 'Gene', (274, 284))	('cleaved', 'Protein', (219, 226))	('N-cadherin', 'Gene', '1000', (274, 284))	('induce', 'Reg', (111, 117))	('Bcl-2', 'Gene', '596', (267, 272))	('HOXB9', 'Gene', '3219', (290, 295))	('NCAPG', 'Gene', '64151', (43, 48))	('reduce', 'NegReg', (75, 81))	('cells at the S phase of the cell cycle', 'CPA', (143, 181))	('regulating', 'Reg', (185, 195))	('Bax', 'Gene', (214, 217))	('NCAPG', 'Gene', (43, 48))	('caspase-3', 'Gene', '836', (227, 236))	('CDK2', 'Gene', '1017', (261, 265))	('Bax', 'Gene', '581', (214, 217))	('caspase-3', 'Gene', (227, 236))	('E-cadherin', 'Gene', (238, 248))	('E-cadherin', 'Gene', '999', (238, 248))	('HCC', 'Disease', (82, 85))	('CDK2', 'Gene', (261, 265))	('HCC', 'Phenotype', 'HP:0001402', (82, 85))	('HOXB9', 'Gene', (290, 295))
166790	32300299	Downregulation of NCAPG by miR-99a-3p inhibits cancer cell aggressiveness via decreasing cell proliferation, migration, and invasion in castration-resistant prostate cancer.	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('Downregulation', 'NegReg', (0, 14))	('decreasing', 'NegReg', (78, 88))	('aggressiveness', 'Disease', (59, 73))	('aggressiveness', 'Phenotype', 'HP:0000718', (59, 73))	('cell proliferation', 'CPA', (89, 107))	('miR-99a-3p', 'Chemical', '-', (27, 37))	('aggressiveness', 'Disease', 'MESH:D001523', (59, 73))	('inhibits', 'NegReg', (38, 46))	('cancer', 'Disease', (47, 53))	('migration', 'CPA', (109, 118))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('cancer', 'Disease', (166, 172))	('NCAPG', 'Gene', '64151', (18, 23))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('NCAPG', 'Gene', (18, 23))	('prostate cancer', 'Disease', 'MESH:D011471', (157, 172))	('prostate cancer', 'Phenotype', 'HP:0012125', (157, 172))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('miR-99a-3p', 'Var', (27, 37))	('prostate cancer', 'Disease', (157, 172))	('invasion', 'CPA', (124, 132))
166802	32300299	In conclusion, this study represents a comprehensive RNA-Seq analysis of several types of tumor revealing NCAPG as a promising molecular target and NCAPG overexpression may play important roles in carcinogenesis and progression of tumors through regulating tumor-related pathways, including cell cycle, cellular senescence, and mismatch repair.	('mismatch repair', 'CPA', (328, 343))	('regulating', 'Reg', (246, 256))	('NCAPG', 'Gene', '64151', (148, 153))	('tumors', 'Disease', (231, 237))	('NCAPG', 'Gene', (148, 153))	('overexpression', 'Var', (154, 168))	('tumor', 'Disease', (257, 262))	('tumor', 'Disease', (90, 95))	('tumor', 'Disease', (231, 236))	('tumor', 'Disease', 'MESH:D009369', (257, 262))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('NCAPG', 'Gene', '64151', (106, 111))	('tumors', 'Disease', 'MESH:D009369', (231, 237))	('tumor', 'Disease', 'MESH:D009369', (231, 236))	('play', 'Reg', (173, 177))	('NCAPG', 'Gene', (106, 111))	('cellular senescence', 'CPA', (303, 322))	('cell cycle', 'CPA', (291, 301))	('tumor', 'Phenotype', 'HP:0002664', (257, 262))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumors', 'Phenotype', 'HP:0002664', (231, 237))
166803	32300299	Moreover, high NCAPG level significantly correlated with poor survival in patients with several types of cancer, including HCC, breast cancer, lung cancer, and ovarian cancer.	('NCAPG', 'Gene', (15, 20))	('lung cancer', 'Disease', (143, 154))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', (168, 174))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('breast cancer', 'Disease', (128, 141))	('breast cancer', 'Disease', 'MESH:D001943', (128, 141))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('cancer', 'Disease', (135, 141))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('lung cancer', 'Disease', 'MESH:D008175', (143, 154))	('ovarian cancer', 'Disease', 'MESH:D010051', (160, 174))	('poor', 'NegReg', (57, 61))	('patients', 'Species', '9606', (74, 82))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('lung cancer', 'Phenotype', 'HP:0100526', (143, 154))	('HCC', 'Disease', (123, 126))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('HCC', 'Phenotype', 'HP:0001402', (123, 126))	('cancer', 'Disease', 'MESH:D009369', (135, 141))	('cancer', 'Disease', (148, 154))	('survival', 'MPA', (62, 70))	('ovarian cancer', 'Disease', (160, 174))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('NCAPG', 'Gene', '64151', (15, 20))	('high', 'Var', (10, 14))	('breast cancer', 'Phenotype', 'HP:0003002', (128, 141))	('ovarian cancer', 'Phenotype', 'HP:0100615', (160, 174))
166857	31533862	Before matching, there were significant differences in the distribution of age and the pathological T stage between patients with high preoperative CRP levels (> 5.0 mg/mL) and those with low preoperative CRP levels (<= 5.0 mg/mL).	('differences', 'Reg', (40, 51))	('CRP', 'Gene', '1401', (148, 151))	('CRP', 'Gene', (148, 151))	('CRP', 'Gene', (205, 208))	('CRP', 'Gene', '1401', (205, 208))	('patients', 'Species', '9606', (116, 124))	('> 5.0', 'Var', (160, 165))
166861	31533862	In the matched cohort, the differences in survival between the low- and high-CRP group remained significant (p = 0.044, Fig.	('CRP', 'Gene', (77, 80))	('low-', 'Var', (63, 67))	('CRP', 'Gene', '1401', (77, 80))
166870	31533862	It has been reported that some factors may affect the prognosis of patients with EC, such as patient status; tumor biological behavior, including the number of cancer-positive lymph nodes; histopathological cell type; histological grade; cancer location, including the esophagogastric junction; genetic mutations; and surgery type.	('cancer', 'Disease', (238, 244))	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('cancer', 'Disease', 'MESH:D009369', (238, 244))	('patient', 'Species', '9606', (67, 74))	('patients', 'Species', '9606', (67, 75))	('cancer', 'Disease', (160, 166))	('genetic mutations', 'Var', (295, 312))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('affect', 'Reg', (43, 49))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('EC', 'Disease', 'MESH:D004938', (81, 83))	('patient', 'Species', '9606', (93, 100))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumor', 'Disease', (109, 114))
166887	31533862	showed significantly better survival in patients with normal CRP compared to that in patients with raised CRP levels among those who received neoadjuvant therapy that comprised 2 cycles of 5-fluorouracil (5-FU) and cisplatin in combination with 45-54 Gy of radiotherapy.	('normal', 'Var', (54, 60))	('patients', 'Species', '9606', (40, 48))	('better', 'PosReg', (21, 27))	('CRP', 'Gene', (61, 64))	('patients', 'Species', '9606', (85, 93))	('raised CRP', 'Phenotype', 'HP:0011227', (99, 109))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (189, 203))	('cisplatin', 'Chemical', 'MESH:D002945', (215, 224))	('CRP', 'Gene', '1401', (106, 109))	('5-FU', 'Chemical', 'MESH:D005472', (205, 209))	('CRP', 'Gene', '1401', (61, 64))	('CRP', 'Gene', (106, 109))
166975	30384176	We found 81 significantly differentially expressed miRNAs (SDEmiRNAs) in a single cancer.	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('miRNAs', 'Var', (51, 57))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('cancer', 'Disease', (82, 88))
166981	30384176	discovered the deletion or down-regulation of miR15/miR16 in chronic lymphocytic leukemia, Takamizawa et al.	('leukemia', 'Phenotype', 'HP:0001909', (81, 89))	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (61, 89))	('lymphocytic leukemia', 'Disease', 'MESH:D007945', (69, 89))	('lymphocytic leukemia', 'Disease', (69, 89))	('deletion', 'Var', (15, 23))	('miR16', 'Gene', '51573', (52, 57))	('down-regulation', 'NegReg', (27, 42))	('miR16', 'Gene', (52, 57))
166982	30384176	showed under-expressed hsa-let-7 is related to a lower survival rate in lung cancer, Chan et al.	('hsa', 'Gene', (23, 26))	('hsa', 'Gene', '213', (23, 26))	('lung cancer', 'Disease', (72, 83))	('survival rate', 'CPA', (55, 68))	('lower', 'NegReg', (49, 54))	('lung cancer', 'Phenotype', 'HP:0100526', (72, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('under-expressed', 'Var', (7, 22))	('lung cancer', 'Disease', 'MESH:D008175', (72, 83))
167018	30384176	Most of these miRNAs have been previously reported in at least one publication to be associated with cancer, some of which are well-studied tumor suppressors, including hasmir-133b, and hsa-mir-139, or contribute to cell invasion, such as hsa-mir-301b.	('cell invasion', 'CPA', (216, 229))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('hsa', 'Gene', '213', (186, 189))	('tumor', 'Disease', (140, 145))	('cancer', 'Disease', (101, 107))	('hsa', 'Gene', (186, 189))	('hsa', 'Gene', '213', (239, 242))	('hsa-mir-139', 'Gene', '406931', (186, 197))	('hsa', 'Gene', (239, 242))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('contribute', 'Reg', (202, 212))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('hsa-mir-139', 'Gene', (186, 197))	('associated', 'Reg', (85, 95))	('miRNAs', 'Var', (14, 20))
167066	30384176	have recently found a single-nucleotide variation in hsa-mir-1269a that could contribute to the occurrence of hepatocellular carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('hsa-mir-1269a', 'Gene', '100302177', (53, 66))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (110, 134))	('hepatocellular carcinoma', 'Disease', (110, 134))	('contribute to', 'Reg', (78, 91))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (110, 134))	('occurrence', 'Reg', (96, 106))	('single-nucleotide variation', 'Var', (22, 49))	('hsa-mir-1269a', 'Gene', (53, 66))
167073	30384176	Newly identified miRNAs hsa-mir-4746, hsa-mir-3648, hsamir-3687, and hsa-mir-1269a could also be important factors in multiple cancer types, although their relations to cancer were rarely reported by previous studies due to their low expression levels compared to others.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('cancer', 'Disease', (169, 175))	('hsamir-3687', 'Chemical', 'None', (52, 63))	('multiple cancer', 'Disease', 'MESH:D009369', (118, 133))	('hsa-mir-3648', 'Gene', '100500862', (38, 50))	('hsa-mir-1269a', 'Gene', (69, 82))	('hsamir-3687', 'Var', (52, 63))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('hsa-mir-1269a', 'Gene', '100302177', (69, 82))	('miRNAs', 'Var', (17, 23))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('multiple cancer', 'Disease', (118, 133))	('hsa-mir-4746', 'Gene', '100616371', (24, 36))	('factors', 'Reg', (107, 114))	('cancer', 'Disease', (127, 133))	('hsa-mir-4746', 'Gene', (24, 36))	('cancer', 'Disease', 'MESH:D009369', (169, 175))	('hsa-mir-3648', 'Gene', (38, 50))
167094	30384176	The most common molecular functions in which these miRNAs and their targets participate in cancer are negative regulation of ERK1 and ERK2 cascade (GO:0070373), canonical Wnt signaling pathway (GO:0060070), and positive regulation of sequence-specific DNA binding transcription factor activity (GO:0051091).	('activity', 'MPA', (285, 293))	('negative regulation', 'NegReg', (102, 121))	('ERK2', 'Gene', (134, 138))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('sequence-specific', 'Pathway', (234, 251))	('ERK1', 'Gene', (125, 129))	('positive regulation', 'PosReg', (211, 230))	('ERK1', 'Gene', '5595', (125, 129))	('GO:0060070', 'Var', (194, 204))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('ERK2', 'Gene', '5594', (134, 138))	('participate', 'Reg', (76, 87))	('canonical Wnt signaling pathway', 'Pathway', (161, 192))
167216	25348067	MSEA: detection and quantification of mutation hotspots through mutation set enrichment analysis Many cancer genes form mutation hotspots that disrupt their functional domains or active sites, leading to gain- or loss-of-function.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('active sites', 'MPA', (179, 191))	('mutation', 'Var', (120, 128))	('functional domains', 'MPA', (157, 175))	('loss-of-function', 'NegReg', (213, 229))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('gain-', 'PosReg', (204, 209))	('disrupt', 'NegReg', (143, 150))
167221	25348067	Single nucleotide variants (SNVs) and short insertions and deletions (indels) are the most abundant somatic mutations in cancer genomes.	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('S', 'Chemical', 'MESH:D013455', (28, 29))	('Single nucleotide variants', 'Var', (0, 26))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('cancer', 'Disease', (121, 127))	('S', 'Chemical', 'MESH:D013455', (0, 1))
167222	25348067	Next-generation sequencing (NGS) studies have revealed that tens of thousands of SNVs and indels may exist in a cancer genome, yet many of them do not play important roles in tumorigenesis.	('tumor', 'Disease', (175, 180))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('SNVs', 'Var', (81, 85))	('S', 'Chemical', 'MESH:D013455', (30, 31))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('S', 'Chemical', 'MESH:D013455', (81, 82))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('indels', 'Var', (90, 96))
167223	25348067	Currently, one major challenge is to distinguish mutations that confer a selective advantage (so-called 'driver mutations') to cancer cells from those that do not offer such advantages ('passenger mutations').	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('mutations', 'Var', (49, 58))	('advantage', 'PosReg', (83, 92))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('cancer', 'Disease', (127, 133))
167230	25348067	In practice, each of the above groups of methods has its own advantages and shortcomings in detecting cancer genes or mutations with unique features.	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('mutations', 'Var', (118, 127))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))
167231	25348067	For example, mutations residing in the loops responsible for nucleotide binding (codons 12, 13, and 61) occur with high frequency in the RAS gene family (KRAS, HRAS, and NRAS); mutations at codons 154, 157, 158, 245, 248, and 273 of TP53 fall in the DNA binding domain of its protein product; and mutations in PIK3CA form two clusters in the helical (E542K and E545K in exon 9) and catalytic (H1047R in exon 20) domains, respectively.	('NRAS', 'Gene', (170, 174))	('S', 'Chemical', 'MESH:D013455', (173, 174))	('PIK3CA', 'Gene', '5290', (310, 316))	('fall', 'Phenotype', 'HP:0002527', (238, 242))	('H1047R', 'Var', (393, 399))	('KRAS', 'Gene', '3845', (154, 158))	('S', 'Chemical', 'MESH:D013455', (163, 164))	('S', 'Chemical', 'MESH:D013455', (139, 140))	('H1047R', 'Mutation', 'rs121913279', (393, 399))	('E545K', 'Mutation', 'rs104886003', (361, 366))	('KRAS', 'Gene', (154, 158))	('TP53', 'Gene', (233, 237))	('HRAS', 'Gene', '3265', (160, 164))	('E542K', 'Mutation', 'rs121913273', (351, 356))	('NRAS', 'Gene', '4893', (170, 174))	('HRAS', 'Gene', (160, 164))	('PIK3CA', 'Gene', (310, 316))	('E545K', 'Var', (361, 366))	('E542K', 'Var', (351, 356))	('binding', 'Interaction', (254, 261))	('S', 'Chemical', 'MESH:D013455', (157, 158))	('TP53', 'Gene', '7157', (233, 237))
167232	25348067	In extreme cases, many oncogenes are observed with highly recurrent substitutions that change the same amino acid, such as in the case of the substitution of arginine at codon 132 in isocitrate dehydrogenase 1 (IDH1) protein and the V600 mutation in BRAF.	('isocitrate dehydrogenase 1', 'Gene', (183, 209))	('BRAF', 'Gene', '673', (250, 254))	('IDH1', 'Gene', (211, 215))	('arginine', 'Chemical', 'MESH:D001120', (158, 166))	('BRAF', 'Gene', (250, 254))	('IDH1', 'Gene', '3417', (211, 215))	('V600', 'Var', (233, 237))	('isocitrate dehydrogenase 1', 'Gene', '3417', (183, 209))	('arginine at', 'Var', (158, 169))
167240	25348067	In particular, we investigated known cancer genes from the Cancer Gene Census (CGC) collection and found that among the 183 CGC genes that had been detected through SNV/indel analyses in previous studies, approximately 51% can be detected through mutation hotspot analysis, while the remaining approximately 49% of genes do not show a clear pattern of mutation hotspots.	('Cancer', 'Phenotype', 'HP:0002664', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('cancer', 'Disease', (37, 43))	('mutation', 'Var', (247, 255))	('Cancer', 'Disease', (59, 65))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('Cancer', 'Disease', 'MESH:D009369', (59, 65))	('S', 'Chemical', 'MESH:D013455', (165, 166))
167242	25348067	Specifically, we applied these methods to eight cancer types using The Cancer Genome Atlas (TCGA) mutation data for cancer gene prioritization (Table S1 in Additional file 1).	('Cancer', 'Disease', (71, 77))	('mutation', 'Var', (98, 106))	('Cancer', 'Disease', 'MESH:D009369', (71, 77))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('S', 'Chemical', 'MESH:D013455', (150, 151))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('S', 'Chemical', 'MESH:D013455', (0, 1))	('Cancer', 'Phenotype', 'HP:0002664', (71, 77))
167252	25348067	These results demonstrate that MSEA-clust has the capability to detect genes with more mutations occurring in converged gene regions, a feature that resembles the observed mutation hotspots in known cancer genes.	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('S', 'Chemical', 'MESH:D013455', (32, 33))	('cancer', 'Disease', (199, 205))	('mutations', 'Var', (87, 96))
167256	25348067	As shown in Table S3 in Additional file 1, the statistical power of MSEA-domain increases with more mutations or smaller domain length but is not influenced by the mutations' locations within the domains.	('mutations', 'Var', (100, 109))	('S', 'Chemical', 'MESH:D013455', (18, 19))	('smaller', 'NegReg', (113, 120))	('domain length', 'MPA', (121, 134))	('S', 'Chemical', 'MESH:D013455', (69, 70))	('increases', 'PosReg', (80, 89))
167259	25348067	Because the P-values in the MSEA-domain model describe whether mutations are significantly associated with the domain distribution (that is, whether the alternative model h1 improves model fitting compared to h0), recurrent mutations did not provide an advantage in this test.	('mutations', 'Var', (63, 72))	('domain distribution', 'Disease', (111, 130))	('improves', 'PosReg', (174, 182))	('model fitting', 'MPA', (183, 196))	('S', 'Chemical', 'MESH:D013455', (29, 30))	('associated', 'Reg', (91, 101))
167260	25348067	These results indicate that MSEA-domain may not be powerful when detecting highly recurrent mutations, for example, the R132H mutation in IDH1.	('IDH1', 'Gene', '3417', (138, 142))	('S', 'Chemical', 'MESH:D013455', (29, 30))	('R132H', 'Var', (120, 125))	('IDH1', 'Gene', (138, 142))	('R132H', 'Mutation', 'rs121913500', (120, 125))
167264	25348067	Here, we refer to Mis-CGC genes as those that have one or more of the following mutation types: missense (SNVs), nonsense (SNVs), splice site (SNVs and indels), or frameshift (indels), and thus, they are eligible for mutation hotspot analysis (see Materials and methods for details).	('S', 'Chemical', 'MESH:D013455', (143, 144))	('Mis', 'Gene', (18, 21))	('missense', 'Var', (96, 104))	('nonsense', 'Var', (113, 121))	('S', 'Chemical', 'MESH:D013455', (123, 124))	('Mis', 'Gene', '268', (18, 21))	('S', 'Chemical', 'MESH:D013455', (106, 107))	('splice', 'MPA', (130, 136))
167271	25348067	Due to study biases, the mutation data are highly inflated towards those intensively studied mutations (for example, codons 12, 13, and 61 in KRAS).	('KRAS', 'Gene', (142, 146))	('KRAS', 'Gene', '3845', (142, 146))	('codons 12', 'Var', (117, 126))
167273	25348067	For each cancer, we obtained six sets of empirical P-values using six mutation sets (see Materials and methods), which are 1) all non-silent SNVs, 2) deleterious non-silent SNVs, 3) all non-silent SNVs plus indels, 4) deleterious non-silent SNVs plus indels, 5) all silent (synonymous) SNVs, and 6) all silent SNVs plus benign non-silent SNVs, respectively.	('cancer', 'Disease', (9, 15))	('S', 'Chemical', 'MESH:D013455', (241, 242))	('S', 'Chemical', 'MESH:D013455', (141, 142))	('S', 'Chemical', 'MESH:D013455', (286, 287))	('silent', 'Var', (266, 272))	('S', 'Chemical', 'MESH:D013455', (338, 339))	('S', 'Chemical', 'MESH:D013455', (310, 311))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('S', 'Chemical', 'MESH:D013455', (173, 174))	('non-silent SNVs', 'Var', (230, 245))	('indels', 'Var', (251, 257))	('S', 'Chemical', 'MESH:D013455', (197, 198))	('cancer', 'Disease', 'MESH:D009369', (9, 15))
167278	25348067	To further assess the P-value distributions and to identify potential reasons for the slight inflation, we examined several factors that may impact the distributions, for example, non-silent versus silent mutations (Figures S1 to S4 in Additional file 1) and gene expression levels (Figures S5 to S8 in Additional file 1).	('non-silent', 'Var', (180, 190))	('gene expression levels', 'MPA', (259, 281))	('S', 'Chemical', 'MESH:D013455', (224, 225))	('S', 'Chemical', 'MESH:D013455', (297, 298))	('S', 'Chemical', 'MESH:D013455', (291, 292))	('impact', 'Reg', (141, 147))	('S', 'Chemical', 'MESH:D013455', (230, 231))
167280	25348067	In our results, the P-value distributions obtained using silent SNVs are much closer to the expected distribution.	('silent', 'Var', (57, 63))	('P-value', 'MPA', (20, 27))	('S', 'Chemical', 'MESH:D013455', (64, 65))
167281	25348067	Especially for cancer types where a slight inflation was observed using non-silent mutations by MSEA-clust, for example, GBM, COADREAD, and LUSC, the P-value distributions obtained using silent SNVs are close to normal (Figures S1 in Additional file 1).	('mutations', 'Var', (83, 92))	('non-silent mutations', 'Var', (72, 92))	('S', 'Chemical', 'MESH:D013455', (97, 98))	('S', 'Chemical', 'MESH:D013455', (142, 143))	('COAD', 'Disease', (126, 130))	('cancer', 'Disease', (15, 21))	('cancer', 'Disease', 'MESH:D009369', (15, 21))	('S', 'Chemical', 'MESH:D013455', (194, 195))	('S', 'Chemical', 'MESH:D013455', (228, 229))	('COAD', 'Disease', 'MESH:D029424', (126, 130))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))
167282	25348067	However, in BRCA and UCEC, both non-silent and silent mutation sets showed skewed P-value distributions towards 0.	('BRCA', 'Gene', (12, 16))	('BRCA', 'Gene', '672', (12, 16))	('non-silent', 'Var', (32, 42))	('silent mutation sets', 'Var', (47, 67))
167301	25348067	For example, the gene IDH1 has mutations almost exclusively occurring in the 132nd amino acid (c.G395A, p.R132H); seven of eight mutations occurring in U2 small nuclear RNA auxiliary factor 1 (U2AF1) in LAML were substitutions at c.C101 (p.S34).	('c.C101', 'Var', (230, 236))	('c.G395A', 'Mutation', 'rs121913500', (95, 102))	('IDH1', 'Gene', (22, 26))	('U2AF1', 'Gene', (193, 198))	('U2AF1', 'Gene', '7307', (193, 198))	('IDH1', 'Gene', '3417', (22, 26))	('p.R132H', 'Mutation', 'rs121913500', (104, 111))	('S', 'Chemical', 'MESH:D013455', (240, 241))
167315	25348067	Examples include the mutations at S34 in U2AF1 (LAML), R132 in IDH1 (LAML, GBM), E17K in AKT1 (BRCA), and a four-amino-acid deletion at residues 125 to 128 in TGFBR2 (NM_003242, COADREAD).	('BRCA', 'Gene', (95, 99))	('E17K', 'Mutation', 'rs121434592', (81, 85))	('U2AF1', 'Gene', (41, 46))	('E17K', 'Var', (81, 85))	('U2AF1', 'Gene', '7307', (41, 46))	('IDH1', 'Gene', '3417', (63, 67))	('AKT1', 'Gene', '207', (89, 93))	('mutations at S34', 'Var', (21, 37))	('COAD', 'Disease', (178, 182))	('AKT1', 'Gene', (89, 93))	('TGFBR2', 'Gene', (159, 165))	('S', 'Chemical', 'MESH:D013455', (34, 35))	('BRCA', 'Gene', '672', (95, 99))	('COAD', 'Disease', 'MESH:D029424', (178, 182))	('IDH1', 'Gene', (63, 67))	('TGFBR2', 'Gene', '7048', (159, 165))	('R132', 'Var', (55, 59))
167319	25348067	However, many have nominally significant P-values by MSEA-clust, even though they failed multiple testing corrections, for example, TP53 in LAML (nominal pclust =0.02, pdomain =5.12 x 10-3), SMAD4 (SMAD family member 4) in COADREAD (nominal pclust =0.016, pdomain =1.43 x 10-5), and CDK12 (cyclin-dependent kinase 12) in OvCa (nominal pclust =8.31 x 10-3, pdomain =9.08 x 10-4), among others.	('cyclin-dependent kinase 12', 'Gene', '51755', (290, 316))	('SMAD4', 'Gene', '4089', (191, 196))	('CDK12', 'Gene', (283, 288))	('P-values', 'Var', (41, 49))	('CDK12', 'Gene', '51755', (283, 288))	('COAD', 'Disease', (223, 227))	('SMAD4', 'Gene', (191, 196))	('TP53', 'Gene', '7157', (132, 136))	('SMAD family member 4', 'Gene', (198, 218))	('TP53', 'Gene', (132, 136))	('S', 'Chemical', 'MESH:D013455', (191, 192))	('S', 'Chemical', 'MESH:D013455', (198, 199))	('S', 'Chemical', 'MESH:D013455', (54, 55))	('SMAD family member 4', 'Gene', '4089', (198, 218))	('OvCa', 'Disease', (321, 325))	('COAD', 'Disease', 'MESH:D029424', (223, 227))	('cyclin-dependent kinase 12', 'Gene', (290, 316))
167320	25348067	In addition to using all non-silent SNVs, we also tested mutation hotspots using three sets of mutations: only deleterious SNVs (deleterious missense SNVs and nonsense SNVs), all non-silent SNVs plus indels, and deleterious SNVs plus indels.	('S', 'Chemical', 'MESH:D013455', (168, 169))	('tested', 'Reg', (50, 56))	('S', 'Chemical', 'MESH:D013455', (224, 225))	('SNVs', 'Var', (190, 194))	('missense SNVs', 'Var', (141, 154))	('nonsense SNVs', 'Var', (159, 172))	('S', 'Chemical', 'MESH:D013455', (190, 191))	('S', 'Chemical', 'MESH:D013455', (36, 37))	('S', 'Chemical', 'MESH:D013455', (150, 151))	('S', 'Chemical', 'MESH:D013455', (123, 124))
167323	25348067	For MSEA-domain, four scenarios were created for testing: non-silent SNVs (NS), deleterious non-silent SNVs (del NS), non-silent SNVs plus indels (NS + I), and deleterious non-silent SNVs plus indels (del NS + I).	('SNVs', 'Var', (103, 107))	('del NS', 'Mutation', 'c.delNS', (109, 115))	('S', 'Chemical', 'MESH:D013455', (206, 207))	('S', 'Chemical', 'MESH:D013455', (76, 77))	('S', 'Chemical', 'MESH:D013455', (69, 70))	('NS', 'Chemical', '-', (205, 207))	('S', 'Chemical', 'MESH:D013455', (148, 149))	('del NS', 'Mutation', 'c.delNS', (201, 207))	('non-silent SNVs', 'Var', (172, 187))	('S', 'Chemical', 'MESH:D013455', (5, 6))	('non-silent SNVs', 'Disease', (58, 73))	('S', 'Chemical', 'MESH:D013455', (114, 115))	('NS', 'Chemical', '-', (75, 77))	('non-silent SNVs', 'Var', (92, 107))	('S', 'Chemical', 'MESH:D013455', (129, 130))	('NS', 'Chemical', '-', (147, 149))	('SNVs', 'Var', (183, 187))	('S', 'Chemical', 'MESH:D013455', (103, 104))	('S', 'Chemical', 'MESH:D013455', (183, 184))	('SNVs plus indels', 'Var', (129, 145))	('NS', 'Chemical', '-', (113, 115))
167326	25348067	The inclusion of indels contributed to a noticeable increase of significant genes, especially for BRCA, COADREAD, and UCEC.	('BRCA', 'Gene', (98, 102))	('UCEC', 'Disease', (118, 122))	('increase', 'PosReg', (52, 60))	('COAD', 'Disease', (104, 108))	('inclusion', 'Var', (4, 13))	('indels', 'Var', (17, 23))	('COAD', 'Disease', 'MESH:D029424', (104, 108))	('BRCA', 'Gene', '672', (98, 102))
167331	25348067	For example, we found that gene GIGYF2 (encoding GRB10 interacting GYF protein 2) has a 3-bp deletion (c.3693_3695del, p.1231_1232del) in 11 (6.3%) BRCA samples (Figure S3 in Additional file 1).	('GRB10 interacting GYF protein 2', 'Gene', (49, 80))	('p.1231_1232del', 'Mutation', 'p.1231_1232del', (119, 133))	('BRCA', 'Gene', '672', (148, 152))	('GIGYF2', 'Gene', '26058', (32, 38))	('BRCA', 'Gene', (148, 152))	('S', 'Chemical', 'MESH:D013455', (169, 170))	('p.1231_1232del', 'Var', (119, 133))	('c.3693_3695del', 'Mutation', 'c.3693_3695del', (103, 117))	('GRB10 interacting GYF protein 2', 'Gene', '26058', (49, 80))	('GIGYF2', 'Gene', (32, 38))	('c.3693_3695del', 'Var', (103, 117))
167333	25348067	Previous studies have shown that knockdown of GIGYF2 resulted in a significant reduction of the phosphorylation of AKT in breast cancer cell lines.	('GIGYF2', 'Gene', '26058', (46, 52))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('breast cancer', 'Disease', (122, 135))	('AKT', 'Gene', '207', (115, 118))	('breast cancer', 'Phenotype', 'HP:0003002', (122, 135))	('breast cancer', 'Disease', 'MESH:D001943', (122, 135))	('knockdown', 'Var', (33, 42))	('phosphorylation', 'MPA', (96, 111))	('AKT', 'Gene', (115, 118))	('GIGYF2', 'Gene', (46, 52))	('reduction', 'NegReg', (79, 88))
167334	25348067	Another gene of high interest is MAP3K4, which has a 3-bp deletion (c.3566_3568del, p.1189_1190del) occurring in 13 (7.5%) BRCA samples.	('BRCA', 'Gene', (123, 127))	('p.1189_1190del', 'Mutation', 'p.1189_1190del', (84, 98))	('c.3566_3568del', 'Mutation', 'c.3566_3568del', (68, 82))	('c.3566_3568del', 'Var', (68, 82))	('MAP3K4', 'Gene', '4216', (33, 39))	('p.1189_1190del', 'Var', (84, 98))	('MAP3K4', 'Gene', (33, 39))	('BRCA', 'Gene', '672', (123, 127))
167349	25348067	We also found that FZD6, a critical gene in the WNT pathway, had mutations clustered in its Frizzled domain in UCEC (Figure 5).	('FZD6', 'Gene', (19, 23))	('FZD6', 'Gene', '8323', (19, 23))	('mutations', 'Var', (65, 74))
167359	25348067	We applied OncodriveCLUST to the same dataset of eight cancer types with consideration of mutation patterns, as previously used for MSEA; for example, all non-silent SNVs versus silent SNVs and all non-silent SNVs plus indels versus silent SNVs.	('S', 'Chemical', 'MESH:D013455', (185, 186))	('S', 'Chemical', 'MESH:D013455', (209, 210))	('S', 'Chemical', 'MESH:D013455', (166, 167))	('non-silent SNVs', 'Var', (198, 213))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('indels', 'Var', (219, 225))	('S', 'Chemical', 'MESH:D013455', (23, 24))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('non-silent SNVs', 'Var', (155, 170))	('S', 'Chemical', 'MESH:D013455', (133, 134))	('cancer', 'Disease', (55, 61))	('S', 'Chemical', 'MESH:D013455', (240, 241))
167367	25348067	The explosive growth in the number of somatic mutations reported in cancer genomes has placed a high demand on the development of computational tools that can help researchers and clinicians extract and interpret information about the candidate mutations and genes underlying tumorigenesis.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('tumor', 'Disease', 'MESH:D009369', (276, 281))	('mutations', 'Var', (46, 55))	('tumor', 'Phenotype', 'HP:0002664', (276, 281))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('tumor', 'Disease', (276, 281))	('cancer', 'Disease', (68, 74))
167368	25348067	In this study, we leveraged the observation of mutation hotspots in known cancer genes to prioritize candidate cancer genes.	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('mutation', 'Var', (47, 55))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('cancer', 'Disease', (74, 80))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
167376	25348067	MSEA-clust also has better coverage on proteins that lack domain annotations or proteins in which the substitutions occurred outside of domain regions (for example, MAP3K4 and MEF2A (Myocyte enhancer factor 2A) in BRCA).	('Myocyte enhancer factor 2A', 'Gene', (183, 209))	('MAP3K4', 'Gene', '4216', (165, 171))	('MEF2A', 'Gene', '4205', (176, 181))	('MAP3K4', 'Gene', (165, 171))	('MEF2A', 'Gene', (176, 181))	('S', 'Chemical', 'MESH:D013455', (1, 2))	('BRCA', 'Gene', '672', (214, 218))	('substitutions', 'Var', (102, 115))	('BRCA', 'Gene', (214, 218))	('Myocyte enhancer factor 2A', 'Gene', '4205', (183, 209))
167383	25348067	For example, the 3-bp deletions in GIGYF2 and MAP3K4 in BRCA were not validated.	('deletions', 'Var', (22, 31))	('GIGYF2', 'Gene', (35, 41))	('BRCA', 'Gene', '672', (56, 60))	('BRCA', 'Gene', (56, 60))	('MAP3K4', 'Gene', '4216', (46, 52))	('MAP3K4', 'Gene', (46, 52))	('GIGYF2', 'Gene', '26058', (35, 41))
167394	25348067	For example, many known cancer genes tend to have an overrepresentation of functionally deleterious mutations or positive selection pressure (for example, a high ratio of non-synonymous versus synonymous SNVs).	('mutations', 'Var', (100, 109))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('overrepresentation', 'PosReg', (53, 71))	('S', 'Chemical', 'MESH:D013455', (204, 205))	('cancer', 'Disease', (24, 30))	('cancer', 'Disease', 'MESH:D009369', (24, 30))	('non-synonymous', 'Var', (171, 185))
167395	25348067	In addition, the inclusion of other types of somatic mutations, such as somatic copy number variations and translocations, will also nominate candidate cancer genes.	('translocations', 'Var', (107, 121))	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))
167396	25348067	Furthermore, tumor suppressor genes are often interrupted by nonsense mutations that could occur anywhere across the gene, and these mutations typically do not form hotspots.	('tumor', 'Disease', (13, 18))	('interrupted', 'Reg', (46, 57))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('nonsense mutations', 'Var', (61, 79))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
167398	25348067	Finally, the prioritized candidate genes and their mutations in no way guarantee a 'driver' role of the gene in cancer.	('mutations', 'Var', (51, 60))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	("'driver'", 'PosReg', (83, 91))
167399	25348067	Follow-up experimental validation is required to verify the functional impact of the mutations or genes in the corresponding cancer(s).	('genes', 'Var', (98, 103))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('mutations', 'Var', (85, 94))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))
167408	25348067	A mutation (for example, T790M in EGFR) could appear in multiple mutation records corresponding to multiple samples.	('T790M', 'Var', (25, 30))	('T790M', 'Mutation', 'rs121434569', (25, 30))	('EGFR', 'Gene', '1956', (34, 38))	('EGFR', 'Gene', (34, 38))
167412	25348067	The CGC database catalogues genes with causally implicated mutations in cancer.	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('mutations', 'Var', (59, 68))	('cancer', 'Disease', (72, 78))
167413	25348067	As we focus on SNVs and indels in this study, we selected those genes that have one or more of the following mutation types: missense (SNVs), nonsense (SNVs), splice site (SNVs and indels), or frameshift (indels).	('S', 'Chemical', 'MESH:D013455', (172, 173))	('S', 'Chemical', 'MESH:D013455', (135, 136))	('splice site', 'Var', (159, 170))	('S', 'Chemical', 'MESH:D013455', (15, 16))	('S', 'Chemical', 'MESH:D013455', (152, 153))	('missense', 'Var', (125, 133))	('nonsense', 'Var', (142, 150))
167422	25348067	Silent SNVs are synonymous SNVs; non-silent SNVs include missense and nonsense SNVs.	('S', 'Chemical', 'MESH:D013455', (79, 80))	('S', 'Chemical', 'MESH:D013455', (7, 8))	('S', 'Chemical', 'MESH:D013455', (27, 28))	('nonsense SNVs', 'Var', (70, 83))	('S', 'Chemical', 'MESH:D013455', (44, 45))	('missense', 'Var', (57, 65))	('S', 'Chemical', 'MESH:D013455', (0, 1))
167423	25348067	For missense SNVs, we used SIFT, PolyPhen-2, and MutationAssessor to predict their functional impacts.	('S', 'Chemical', 'MESH:D013455', (27, 28))	('SIFT', 'Disease', 'None', (27, 31))	('SIFT', 'Disease', (27, 31))	('S', 'Chemical', 'MESH:D013455', (13, 14))	('missense SNVs', 'Var', (4, 17))
167437	25348067	MAS increases when we encounter a mutation and decreases at non-mutated positions.	('S', 'Chemical', 'MESH:D013455', (2, 3))	('mutation', 'Var', (34, 42))	('MAS', 'MPA', (0, 3))
167452	25348067	In contrast, missense SNVs, nonsense SNVs, and indels are considered non-silent mutations and are used for hotspot detection.	('S', 'Chemical', 'MESH:D013455', (22, 23))	('S', 'Chemical', 'MESH:D013455', (37, 38))	('missense SNVs', 'Var', (13, 26))	('nonsense SNVs', 'Var', (28, 41))
167453	25348067	The second background set includes all silent SNVs plus benign missense SNVs (see 'Cancer somatic mutation data from eight TCGA cancers' section).	('cancers', 'Disease', 'MESH:D009369', (128, 135))	('cancers', 'Phenotype', 'HP:0002664', (128, 135))	('S', 'Chemical', 'MESH:D013455', (72, 73))	('cancers', 'Disease', (128, 135))	('missense', 'Var', (63, 71))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('S', 'Chemical', 'MESH:D013455', (46, 47))	('Cancer', 'Disease', (83, 89))	('Cancer', 'Phenotype', 'HP:0002664', (83, 89))	('Cancer', 'Disease', 'MESH:D009369', (83, 89))
167454	25348067	Accordingly, deleterious missense SNVs, nonsense SNVs, and indels are considered non-silent mutations for hotspot detection.	('S', 'Chemical', 'MESH:D013455', (34, 35))	('nonsense SNVs', 'Var', (40, 53))	('S', 'Chemical', 'MESH:D013455', (49, 50))	('missense SNVs', 'Var', (25, 38))
167456	25348067	Specifically, the following steps are implemented: 1) NES values obtained using background mutations are median-centered and used for the estimation of the mean and standard deviation of the null distribution f0 using maximum likelihood iteration; 2) NES values obtained using non-silent mutations, which are also median-centered, are then adjusted using the mean and standard deviation of f0 from step 1, resulting in normalized z-scores; and 3) nominal P-values are computed based on the normalized z -scores.	('S', 'Chemical', 'MESH:D013455', (56, 57))	('NES', 'Gene', (251, 254))	('S', 'Chemical', 'MESH:D013455', (253, 254))	('mutations', 'Var', (91, 100))	('NES', 'Gene', '10763', (54, 57))	('mutations', 'Var', (288, 297))	('NES', 'Gene', (54, 57))	('S', 'Chemical', 'MESH:D013455', (0, 1))	('NES', 'Gene', '10763', (251, 254))
167459	25348067	BRCA breast adenocarcinoma CGC Cancer Gene Census COAD colon carcinoma COADREAD colon and rectal carcinoma COSMIC Catalog of Somatic Mutations in Cancer FDR false discovery rate GBM glioblastoma multiforme LAML acute myeloid leukemia LUSC lung squamous cell carcinoma MAS mutation accumulation score MES mutation enrichment score MSEA mutation set enrichment analysis NES normalized mutation enrichment score NGS next-generation sequencing OvCa ovarian serous carcinoma READ rectal carcinoma RMA robust multi array SNV single nucleotide variant TCGA The Cancer Genome Atlas UCEC uterine corpus endometrial carcinoma	('RMA', 'Chemical', '-', (492, 495))	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('NES', 'Gene', '10763', (368, 371))	('BRCA', 'Gene', (0, 4))	('COAD', 'Disease', 'MESH:D029424', (71, 75))	('S', 'Chemical', 'MESH:D013455', (270, 271))	('S', 'Chemical', 'MESH:D013455', (515, 516))	('glioblastoma multiforme', 'Disease', (182, 205))	('breast adenocarcinoma', 'Disease', (5, 26))	('carcinoma', 'Disease', 'MESH:D002277', (61, 70))	('single nucleotide variant', 'Var', (519, 544))	('carcinoma', 'Disease', 'MESH:D002277', (482, 491))	('corpus endometrial carcinoma', 'Disease', (587, 615))	('carcinoma', 'Disease', (97, 106))	('MES', 'Chemical', '-', (300, 303))	('rectal carcinoma COSMIC', 'Phenotype', 'HP:0100743', (90, 113))	('S', 'Chemical', 'MESH:D013455', (236, 237))	('S', 'Chemical', 'MESH:D013455', (370, 371))	('S', 'Chemical', 'MESH:D013455', (109, 110))	('Cancer', 'Disease', 'MESH:D009369', (31, 37))	('carcinoma', 'Disease', 'MESH:D002277', (258, 267))	('S', 'Chemical', 'MESH:D013455', (331, 332))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (182, 205))	('Cancer', 'Disease', 'MESH:D009369', (554, 560))	('corpus endometrial carcinoma', 'Disease', 'MESH:D016889', (587, 615))	('carcinoma', 'Phenotype', 'HP:0030731', (17, 26))	('carcinoma', 'Disease', (460, 469))	('carcinoma', 'Disease', 'MESH:D002277', (606, 615))	('breast adenocarcinoma', 'Phenotype', 'HP:0003002', (5, 26))	('carcinoma', 'Phenotype', 'HP:0030731', (460, 469))	('Cancer', 'Phenotype', 'HP:0002664', (146, 152))	('carcinoma', 'Disease', (17, 26))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (594, 615))	('S', 'Chemical', 'MESH:D013455', (125, 126))	('colon carcinoma', 'Disease', (55, 70))	('colon and rectal carcinoma', 'Disease', 'MESH:D012004', (80, 106))	('COAD', 'Disease', (71, 75))	('Cancer', 'Disease', (146, 152))	('rectal carcinoma', 'Phenotype', 'HP:0100743', (475, 491))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (244, 267))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (239, 267))	('lung squamous cell carcinoma', 'Disease', (239, 267))	('carcinoma', 'Disease', 'MESH:D002277', (97, 106))	('COAD', 'Disease', 'MESH:D029424', (50, 54))	('myeloid leukemia', 'Disease', (217, 233))	('NES', 'Gene', (368, 371))	('colon carcinoma', 'Disease', 'MESH:D015179', (55, 70))	('UCEC uterine corpus', 'Phenotype', 'HP:0000139', (574, 593))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('Cancer', 'Phenotype', 'HP:0002664', (31, 37))	('TCGA', 'Gene', (545, 549))	('carcinoma', 'Disease', 'MESH:D002277', (17, 26))	('carcinoma', 'Disease', 'MESH:D002277', (460, 469))	('carcinoma', 'Disease', (61, 70))	('carcinoma', 'Disease', (482, 491))	('leukemia', 'Phenotype', 'HP:0001909', (225, 233))	('carcinoma', 'Phenotype', 'HP:0030731', (258, 267))	('rectal carcinoma', 'Phenotype', 'HP:0100743', (90, 106))	('Cancer', 'Phenotype', 'HP:0002664', (554, 560))	('BRCA', 'Gene', '672', (0, 4))	('Cancer', 'Disease', 'MESH:D009369', (146, 152))	('S', 'Chemical', 'MESH:D013455', (302, 303))	('carcinoma', 'Disease', (606, 615))	('carcinoma', 'Disease', (258, 267))	('ovarian serous carcinoma', 'Disease', (445, 469))	('Cancer', 'Disease', (31, 37))	('myeloid leukemia', 'Disease', 'MESH:D007951', (217, 233))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (217, 233))	('glioblastoma', 'Phenotype', 'HP:0012174', (182, 194))	('Cancer', 'Disease', (554, 560))	('COAD', 'Disease', (50, 54))	('breast adenocarcinoma', 'Disease', 'MESH:D000230', (5, 26))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (239, 267))	('S', 'Chemical', 'MESH:D013455', (411, 412))	('ovarian serous carcinoma', 'Disease', 'MESH:D010051', (445, 469))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (211, 233))
167463	31423230	The results of the present study indicate that pterostilbene significantly reduced cell viability and induced S phase arrest, and that treatment with pterostilbene was associated with the downregulation of cyclin A and cyclin E, as with the upregulation of p21 and p27 expression in H520 cells.	('cyclin', 'Protein', (219, 225))	('upregulation', 'PosReg', (241, 253))	('arrest', 'Disease', 'MESH:D006323', (118, 124))	('cell viability', 'CPA', (83, 97))	('pterostilbene', 'Var', (150, 163))	('pterostilbene', 'Var', (47, 60))	('induced', 'Reg', (102, 109))	('downregulation', 'NegReg', (188, 202))	('cyclin A', 'Gene', (206, 214))	('reduced', 'NegReg', (75, 82))	('H520', 'CellLine', 'CVCL:1566', (283, 287))	('pterostilbene', 'Chemical', 'MESH:C107773', (47, 60))	('cyclin A', 'Gene', '890', (206, 214))	('arrest', 'Disease', (118, 124))	('pterostilbene', 'Chemical', 'MESH:C107773', (150, 163))
167464	31423230	In the apoptosis analysis, pterostilbene induced S phase accumulation and the activation of caspase-3, -8 and -9 in H520 cells, potentially through the activation of extrinsic and intrinsic apoptotic pathways.	('extrinsic', 'Pathway', (166, 175))	('pterostilbene', 'Chemical', 'MESH:C107773', (27, 40))	('H520', 'CellLine', 'CVCL:1566', (116, 120))	('activation', 'PosReg', (78, 88))	('pterostilbene', 'Var', (27, 40))	('caspase-3, -8 and -9', 'Gene', '836;841;842', (92, 112))
167481	31423230	Although epidermal growth factor receptor (EGFR) mutations serve an important therapeutic role in patients with NSCLC, EGFR mutations are rarely (0-14.6%) identified in lung SqCC.	('epidermal growth factor receptor', 'Gene', '1956', (9, 41))	('lung SqCC', 'Disease', (169, 178))	('mutations', 'Var', (124, 133))	('mutations', 'Var', (49, 58))	('NSCLC', 'Phenotype', 'HP:0030358', (112, 117))	('SqCC', 'Phenotype', 'HP:0002860', (174, 178))	('patients', 'Species', '9606', (98, 106))	('NSCLC', 'Disease', 'MESH:D002289', (112, 117))	('EGFR', 'Gene', '1956', (43, 47))	('EGFR', 'Gene', '1956', (119, 123))	('NSCLC', 'Disease', (112, 117))	('epidermal growth factor receptor', 'Gene', (9, 41))	('EGFR', 'Gene', (43, 47))	('EGFR', 'Gene', (119, 123))
167536	31423230	The Cip/Kip family members, p21 (Cip1) and p27 (Kip1), can inhibit the activity of cyclin E-CDK2 and cyclin A-CDK2 complexes.	('Cip', 'Gene', '90523', (33, 36))	('Kip1', 'Gene', '1027', (48, 52))	('Cip1', 'Gene', '1026', (33, 37))	('cyclin A', 'Gene', '890', (101, 109))	('p27', 'Var', (43, 46))	('Cip1', 'Gene', (33, 37))	('Cip', 'Gene', (33, 36))	('cyclin', 'Protein', (83, 89))	('Cip', 'Gene', '90523', (4, 7))	('Cip', 'Gene', (4, 7))	('activity', 'MPA', (71, 79))	('inhibit', 'NegReg', (59, 66))	('Kip1', 'Gene', (48, 52))	('cyclin A', 'Gene', (101, 109))
167544	31423230	5A, following treatment with pterostilbene, a dose-dependent increase in the green fluorescence was observed in H520 cells, suggesting that pterostilbene produced significant mitochondrial depolarization.	('pterostilbene', 'Chemical', 'MESH:C107773', (140, 153))	('pterostilbene', 'Chemical', 'MESH:C107773', (29, 42))	('mitochondrial', 'MPA', (175, 188))	('pterostilbene', 'Var', (140, 153))	('H520', 'CellLine', 'CVCL:1566', (112, 116))	('increase', 'PosReg', (61, 69))	('depolarization', 'NegReg', (189, 203))	('green fluorescence', 'MPA', (77, 95))
167553	31423230	6C) (day 38), indicating that pterostilbene also inhibited the growth of SqCC cells in vivo.	('growth of SqCC cells', 'CPA', (63, 83))	('pterostilbene', 'Var', (30, 43))	('SqCC', 'Phenotype', 'HP:0002860', (73, 77))	('pterostilbene', 'Chemical', 'MESH:C107773', (30, 43))	('inhibited', 'NegReg', (49, 58))
167569	31423230	In agreement with recent research reporting the antitumor effect of pterostilbene on various malignant cancers, the results of the present study demonstrated that pterostilbene inhibited lung SqCC tumor growth.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('inhibited', 'NegReg', (177, 186))	('lung SqCC', 'Disease', (187, 196))	('cancers', 'Phenotype', 'HP:0002664', (103, 110))	('pterostilbene', 'Chemical', 'MESH:C107773', (163, 176))	('tumor', 'Disease', (52, 57))	('rat', 'Species', '10116', (152, 155))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('SqCC', 'Phenotype', 'HP:0002860', (192, 196))	('pterostilbene', 'Chemical', 'MESH:C107773', (68, 81))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('malignant cancers', 'Disease', (93, 110))	('tumor', 'Disease', (197, 202))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('pterostilbene', 'Var', (163, 176))	('malignant cancers', 'Disease', 'MESH:D009369', (93, 110))
167571	31423230	It has been reported that pterostilbene could induce cell cycle arrest and apoptosis in numerous types of cancer cells, including gastric, lung, and pancreatic cancer cells.	('arrest', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (149, 166))	('induce', 'PosReg', (46, 52))	('pterostilbene', 'Var', (26, 39))	('apoptosis', 'CPA', (75, 84))	('cancer', 'Disease', (160, 166))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('pancreatic cancer', 'Disease', 'MESH:D010190', (149, 166))	('cancer', 'Disease', (106, 112))	('pancreatic cancer', 'Disease', (149, 166))	('pterostilbene', 'Chemical', 'MESH:C107773', (26, 39))	('lung', 'Disease', (139, 143))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('arrest', 'Disease', 'MESH:D006323', (64, 70))	('gastric', 'Disease', (130, 137))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
167573	31423230	Western blot analysis revealed that pterostilbene increased the expression of p21 and p27, and decreased the expression of cyclin A and E. The cyclin A- and E-CDK2 complexes are the most important proteins in S phase that regulate progression to the G2/M phase.	('decreased', 'NegReg', (95, 104))	('cyclin A', 'Gene', (123, 131))	('expression', 'MPA', (64, 74))	('expression', 'MPA', (109, 119))	('pterostilbene', 'Var', (36, 49))	('p27', 'Protein', (86, 89))	('cyclin A', 'Gene', '890', (123, 131))	('cyclin A', 'Gene', (143, 151))	('increased', 'PosReg', (50, 59))	('pterostilbene', 'Chemical', 'MESH:C107773', (36, 49))	('cyclin A', 'Gene', '890', (143, 151))	('p21', 'Protein', (78, 81))
167575	31423230	The results of the present study also indicated that the expression levels of p21 and p27, which are CDK inhibitors that can inhibit the majority of cyclin-CDK complexes, were increased by pterostilbene.	('inhibit', 'NegReg', (125, 132))	('increased', 'PosReg', (176, 185))	('p27', 'Var', (86, 89))	('p21', 'Var', (78, 81))	('expression levels', 'MPA', (57, 74))	('pterostilbene', 'Chemical', 'MESH:C107773', (189, 202))
167583	31423230	The results of the present study indicated that pterostilbene increased the expression of caspase-3, -8, and -9, suggesting that pterostilbene induced the apoptosis of lung SqCC cells in a caspase-dependent manner, potentially through the activation of the extrinsic and intrinsic apoptotic pathways.	('pterostilbene', 'Var', (129, 142))	('pterostilbene', 'Chemical', 'MESH:C107773', (129, 142))	('SqCC', 'Phenotype', 'HP:0002860', (173, 177))	('caspase-3, -8, and -9', 'Gene', '836;841;842', (90, 111))	('apoptosis', 'CPA', (155, 164))	('pterostilbene', 'Chemical', 'MESH:C107773', (48, 61))
167585	31423230	In addition, Pan et al also reported that pterostilbene promoted apoptosis and induced cell cycle arrest in gastric cancer AGS cells, by activating the caspase cascade and inducing changes in several cell cycle-regulating proteins, which is in agreement with the results of the current study.	('inducing changes', 'Reg', (172, 188))	('arrest', 'Disease', (98, 104))	('pterostilbene', 'Chemical', 'MESH:C107773', (42, 55))	('activating', 'PosReg', (137, 147))	('cell', 'Protein', (200, 204))	('gastric cancer', 'Phenotype', 'HP:0012126', (108, 122))	('pterostilbene', 'Var', (42, 55))	('apoptosis', 'CPA', (65, 74))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('promoted', 'PosReg', (56, 64))	('arrest', 'Disease', 'MESH:D006323', (98, 104))	('gastric cancer', 'Disease', (108, 122))	('caspase cascade', 'Pathway', (152, 167))	('gastric cancer', 'Disease', 'MESH:D013274', (108, 122))
167586	31423230	To summarize, the present study demonstrated the antitumor effect of pterostilbene in lung SqCC, and revealed that pterostilbene could cause cell cycle arrest, induce apoptosis in lung SqCC cell lines in vitro, and inhibit tumor growth in vivo in a mouse xenograft model.	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('SqCC', 'Phenotype', 'HP:0002860', (91, 95))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('SqCC', 'Phenotype', 'HP:0002860', (185, 189))	('inhibit', 'NegReg', (215, 222))	('tumor', 'Disease', (53, 58))	('cause', 'Reg', (135, 140))	('pterostilbene', 'Var', (115, 128))	('pterostilbene', 'Chemical', 'MESH:C107773', (115, 128))	('arrest', 'Disease', 'MESH:D006323', (152, 158))	('rat', 'Species', '10116', (39, 42))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('induce', 'PosReg', (160, 166))	('tumor', 'Disease', (223, 228))	('mouse', 'Species', '10090', (249, 254))	('tumor', 'Disease', 'MESH:D009369', (223, 228))	('apoptosis', 'CPA', (167, 176))	('arrest', 'Disease', (152, 158))	('pterostilbene', 'Chemical', 'MESH:C107773', (69, 82))
167597	31117164	First, we quantified the tumor growth rate and changes in serum cytokine profiles of mice administered Porphyromonas gingivalis, a major pathogen of chronic periodontitis.	('mice', 'Species', '10090', (85, 89))	('serum cytokine profiles', 'MPA', (58, 81))	('Porphyromonas gingivalis', 'Var', (103, 127))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('changes', 'Reg', (47, 54))	('tumor', 'Disease', (25, 30))	('chronic periodontitis', 'Disease', 'MESH:D055113', (149, 170))	('periodontitis', 'Phenotype', 'HP:0000704', (157, 170))	('chronic periodontitis', 'Disease', (149, 170))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('Porphyromonas gingivalis', 'Species', '837', (103, 127))
167599	31117164	In addition, P. gingivalis-treated mice exhibited higher serum levels of interleukin-6 (IL-6) than uninfected mice.	('higher', 'PosReg', (50, 56))	('IL-6', 'Gene', (88, 92))	('IL-6', 'Gene', '16193', (88, 92))	('P. gingivalis', 'Species', '837', (13, 26))	('interleukin-6', 'Gene', '16193', (73, 86))	('mice', 'Species', '10090', (110, 114))	('interleukin-6', 'Gene', (73, 86))	('higher serum levels of interleukin-6', 'Phenotype', 'HP:0030783', (50, 86))	('mice', 'Species', '10090', (35, 39))	('P. gingivalis-treated', 'Var', (13, 34))
167619	31117164	First, though periodontitis is a multifactorial and polymicrobial disease, studies have reported that P. gingivalis is strongly involved in the etiology of chronic periodontitis.	('chronic periodontitis', 'Disease', 'MESH:D055113', (156, 177))	('periodontitis', 'Disease', 'MESH:D010518', (164, 177))	('periodontitis', 'Disease', 'MESH:D010518', (14, 27))	('periodontitis', 'Phenotype', 'HP:0000704', (164, 177))	('periodontitis', 'Disease', (164, 177))	('periodontitis', 'Disease', (14, 27))	('involved', 'Reg', (128, 136))	('chronic periodontitis', 'Disease', (156, 177))	('periodontitis', 'Phenotype', 'HP:0000704', (14, 27))	('P. gingivalis', 'Species', '837', (102, 115))	('P. gingivalis', 'Var', (102, 115))
167620	31117164	Second, it has been reported that oral administration of P. gingivalis could induce experimental periodontitis in mice.	('P. gingivalis', 'Var', (57, 70))	('periodontitis', 'Phenotype', 'HP:0000704', (97, 110))	('mice', 'Species', '10090', (114, 118))	('periodontitis', 'Disease', 'MESH:D010518', (97, 110))	('periodontitis', 'Disease', (97, 110))	('P. gingivalis', 'Species', '837', (57, 70))	('induce', 'Reg', (77, 83))
167621	31117164	Third, among numerous periodontal pathogens, P. gingivalis has been reported to be intimately associated with cancer progression.	('cancer', 'Disease', (110, 116))	('P. gingivalis', 'Species', '837', (45, 58))	('P. gingivalis', 'Var', (45, 58))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('associated', 'Reg', (94, 104))	('cancer', 'Disease', 'MESH:D009369', (110, 116))
167623	31117164	To further clarify whether the presence of P. gingivalis in the tumor microenvironment also contributes to the retarded growth of OSCC, tumor xenografts were established using the OSCC line OSC-20 on the backs of mice.	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('tumor', 'Disease', (64, 69))	('mice', 'Species', '10090', (213, 217))	('growth', 'MPA', (120, 126))	('retarded growth', 'Phenotype', 'HP:0001510', (111, 126))	('retarded', 'Disease', (111, 119))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Disease', (136, 141))	('P. gingivalis', 'Species', '837', (43, 56))	('P. gingivalis', 'Var', (43, 56))	('retarded', 'Disease', 'MESH:D008607', (111, 119))
167629	31117164	The tumor volumes of the P. gingivalis-treated mice were slightly larger than those of untreated control mice, but this difference was not significant (Figure 1B).	('tumor', 'Disease', (4, 9))	('larger', 'PosReg', (66, 72))	('P. gingivalis-treated', 'Var', (25, 46))	('P. gingivalis', 'Species', '837', (25, 38))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('mice', 'Species', '10090', (105, 109))	('mice', 'Species', '10090', (47, 51))
167635	31117164	The serum level of IL-6 was significantly different between the control mice and P. gingivalis-treated and/or paclitaxel-treated mice, whereas the other inflammatory factors showed no significant differences among the groups.	('P. gingivalis', 'Species', '837', (81, 94))	('IL-6', 'Gene', (19, 23))	('IL-6', 'Gene', '16193', (19, 23))	('paclitaxel', 'Chemical', 'MESH:D017239', (110, 120))	('serum level', 'MPA', (4, 15))	('different', 'Reg', (42, 51))	('mice', 'Species', '10090', (72, 76))	('mice', 'Species', '10090', (129, 133))	('P. gingivalis-treated', 'Var', (81, 102))
167636	31117164	In particular, the mice administered both P. gingivalis and paclitaxel exhibited the highest level of serum IL-6, although the difference in serum IL-6 was insignificant as determined by post hoc analysis (Figure 2).	('P. gingivalis', 'Var', (42, 55))	('level', 'MPA', (93, 98))	('P. gingivalis', 'Species', '837', (42, 55))	('highest level of serum IL-6', 'Phenotype', 'HP:0030783', (85, 112))	('IL-6', 'Gene', (147, 151))	('IL-6', 'Gene', '16193', (147, 151))	('paclitaxel', 'Chemical', 'MESH:D017239', (60, 70))	('mice', 'Species', '10090', (19, 23))	('IL-6', 'Gene', (108, 112))	('IL-6', 'Gene', '16193', (108, 112))
167655	31117164	The level of MCP-1/CCL2, a potent chemotactic factor in monocytes, was distinctly decreased with ibuprofen administration, while the other mediators did not prominently decrease in response to ibuprofen.	('ibuprofen', 'Var', (97, 106))	('MCP-1', 'Gene', (13, 18))	('ibuprofen', 'Chemical', 'MESH:D007052', (97, 106))	('ibuprofen', 'Chemical', 'MESH:D007052', (193, 202))	('CCL2', 'Gene', (19, 23))	('CCL2', 'Gene', '20296', (19, 23))	('MCP-1', 'Gene', '20296', (13, 18))	('decreased', 'NegReg', (82, 91))
167659	31117164	It is known that cancer is caused by genetic and epigenetic changes and that inflammation promotes tumor growth by accelerating factors that are related to angiogenesis, cell motility, and cell survival.	('tumor', 'Disease', (99, 104))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('inflammation', 'Disease', 'MESH:D007249', (77, 89))	('inflammation', 'Disease', (77, 89))	('cancer', 'Disease', (17, 23))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('epigenetic changes', 'Var', (49, 67))	('promotes', 'PosReg', (90, 98))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('accelerating', 'PosReg', (115, 127))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
167673	31117164	Our experiment also suggested that IL-6 may be the most important factor for the development of chronic periodontitis-induced chemoresistance by showing that the serum level of only IL-6 was significantly impacted by P. gingivalis administration and/or paclitaxel treatment and that ibuprofen reduced paclitaxel resistance and the differences in the serum IL-6 levels among groups.	('IL-6', 'Gene', (35, 39))	('IL-6', 'Gene', '16193', (35, 39))	('chronic periodontitis', 'Disease', (96, 117))	('P. gingivalis', 'Var', (217, 230))	('P. gingivalis', 'Species', '837', (217, 230))	('serum level of', 'MPA', (162, 176))	('reduced', 'NegReg', (293, 300))	('paclitaxel resistance', 'MPA', (301, 322))	('IL-6', 'Gene', (356, 360))	('IL-6', 'Gene', '16193', (356, 360))	('paclitaxel', 'Chemical', 'MESH:D017239', (301, 311))	('impacted', 'Reg', (205, 213))	('paclitaxel', 'Chemical', 'MESH:D017239', (253, 263))	('ibuprofen', 'Chemical', 'MESH:D007052', (283, 292))	('chronic periodontitis', 'Disease', 'MESH:D055113', (96, 117))	('periodontitis', 'Phenotype', 'HP:0000704', (104, 117))	('IL-6', 'Gene', (182, 186))	('IL-6', 'Gene', '16193', (182, 186))
167680	31117164	We previously reported that P. gingivalis, a major pathogen in chronic periodontitis, induced cell cycle arrest of OSCC cells by enhancing the autophagic response, and in this study, we observed that the growth of tumor xenografts was retarded in P. gingivalis-treated mice.	('chronic periodontitis', 'Disease', 'MESH:D055113', (63, 84))	('periodontitis', 'Phenotype', 'HP:0000704', (71, 84))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (94, 111))	('P. gingivalis', 'Var', (28, 41))	('retarded', 'Disease', 'MESH:D008607', (235, 243))	('autophagic response', 'CPA', (143, 162))	('tumor', 'Disease', 'MESH:D009369', (214, 219))	('P. gingivalis', 'Species', '837', (247, 260))	('chronic periodontitis', 'Disease', (63, 84))	('P. gingivalis', 'Species', '837', (28, 41))	('arrest', 'Disease', 'MESH:D006323', (105, 111))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('mice', 'Species', '10090', (269, 273))	('tumor', 'Disease', (214, 219))	('retarded', 'Disease', (235, 243))	('enhancing', 'PosReg', (129, 138))	('arrest', 'Disease', (105, 111))
167682	31117164	In summary, we demonstrated that the administration of P. gingivalis delayed tumor growth and provoked resistance to paclitaxel, which supports the close correlation between chronic periodontitis and oral cancer.	('paclitaxel', 'Chemical', 'MESH:D017239', (117, 127))	('chronic periodontitis', 'Disease', (174, 195))	('resistance to paclitaxel', 'MPA', (103, 127))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('oral cancer', 'Disease', 'MESH:D009062', (200, 211))	('P. gingivalis', 'Species', '837', (55, 68))	('P. gingivalis', 'Var', (55, 68))	('delayed', 'NegReg', (69, 76))	('periodontitis', 'Phenotype', 'HP:0000704', (182, 195))	('oral cancer', 'Disease', (200, 211))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('chronic periodontitis', 'Disease', 'MESH:D055113', (174, 195))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Disease', (77, 82))	('provoked', 'Reg', (94, 102))
167727	30296485	Patients with an identified PD-L1 expression may be treated with pembrolizumab based on PD-L1 expression equal to or greater than 1% in second-line treatment or where PD-L1 expression is equal to or greater than 50% in first-line treatment.	('PD-L1', 'Gene', (88, 93))	('expression', 'Var', (34, 44))	('Patients', 'Species', '9606', (0, 8))	('PD-L1', 'Gene', (28, 33))	('pembrolizumab', 'Chemical', 'MESH:C582435', (65, 78))
167733	30296485	The reflex testing (in adenocarcinoma) included PD-L1 protein overexpression, ALK receptor tyrosine kinase (ALK) IHC, and EGFR mutational status.	('mutational status', 'Var', (127, 144))	('adenocarcinoma', 'Disease', 'MESH:D000230', (23, 37))	('reflex testing', 'MPA', (4, 18))	('PD-L1 protein', 'Protein', (48, 61))	('overexpression', 'PosReg', (62, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (28, 37))	('adenocarcinoma', 'Disease', (23, 37))	('EGFR', 'Gene', (122, 126))
167747	30296485	Sections from a small internal TMA consisting of four cores (representing PD-L1 expression levels of more than 50%, 1% to 49%, and less than1%, as well as tonsil) were used in each test run to assess specificity and sensitivity and intra-run reproducibility.	('TMA', 'Chemical', '-', (31, 34))	('less than1%', 'Var', (131, 142))	('PD-L1', 'Gene', (74, 79))
167787	30296485	Our clinical validation confirms the equivalence of the 22C3 and SP263 PD-L1 antibody clones, perhaps highlighting that when other variables are corrected for (same interpretative team, same rules of interpretation, and same samples) the reported antibody equivalence should be obvious.	('clinical', 'Species', '191496', (4, 12))	('SP263', 'Var', (65, 70))	('PD-L1', 'Gene', (71, 76))
167824	29916308	The mTOR is phosphorylated by Akt1 at Ser2448 to yield phospho-mTOR (p-mTOR), which regulates ribosome biogenesis and protein synthesis, and is also present in the cytoplasm and nucleus, with high p-mTOR expression indicating reduced response to tumor treatment.	('Akt1', 'Gene', (30, 34))	('regulates ribosome biogenesis', 'MPA', (84, 113))	('protein synthesis', 'MPA', (118, 135))	('tumor', 'Disease', 'MESH:D009369', (246, 251))	('expression', 'MPA', (204, 214))	('Akt1', 'Gene', '207', (30, 34))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('Ser2448', 'Var', (38, 45))	('Ser2448', 'Chemical', '-', (38, 45))	('tumor', 'Disease', (246, 251))
167827	29916308	The loss or mutation of these genes leads to a wide variety of human sporadic and inherited cancer.	('human', 'Species', '9606', (63, 68))	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('leads to', 'Reg', (36, 44))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('mutation', 'Var', (12, 20))	('loss', 'NegReg', (4, 8))
167828	29916308	We have observed increased activity of the mTOR pathway after silencing PTEN.	('increased', 'PosReg', (17, 26))	('silencing', 'Var', (62, 71))	('mTOR pathway', 'Pathway', (43, 55))	('PTEN', 'Gene', (72, 76))	('PTEN', 'Gene', '5728', (72, 76))	('activity', 'MPA', (27, 35))
167829	29916308	In the present study, we knocked down PTEN to activate the mTOR pathway.	('PTEN', 'Gene', '5728', (38, 42))	('knocked down', 'Var', (25, 37))	('mTOR pathway', 'Pathway', (59, 71))	('activate', 'PosReg', (46, 54))	('PTEN', 'Gene', (38, 42))
167832	29916308	These alterations increase tumor cell proliferation (Warburg effect).	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('increase', 'PosReg', (18, 26))	('alterations', 'Var', (6, 17))	('tumor', 'Disease', (27, 32))	('tumor', 'Disease', 'MESH:D009369', (27, 32))
167833	29916308	Moreover, knocking down HIF-1alpha inhibits lactate production and pyruvate kinase M2 isoform (PKM2) expression in pancreatic cancer.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('knocking down', 'Var', (10, 23))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (115, 132))	('lactate', 'Chemical', 'MESH:D019344', (44, 51))	('inhibits', 'NegReg', (35, 43))	('pancreatic cancer', 'Disease', (115, 132))	('pancreatic cancer', 'Disease', 'MESH:D010190', (115, 132))	('lactate production', 'MPA', (44, 62))	('pyruvate kinase M2 isoform', 'Gene', (67, 93))	('expression', 'MPA', (101, 111))	('HIF-1alpha', 'Gene', (24, 34))	('pyruvate kinase M2 isoform', 'Gene', '5315', (67, 93))
167839	29916308	We hypothesized that knocking down PTEN will affect mTOR and thus regulate PKM2, inducing cancer cells to convert glucose into lactic acid to produce energy, which may be the major pathway for cellular energy metabolism in ESCC.	('affect', 'Reg', (45, 51))	('convert glucose into lactic acid to produce energy', 'MPA', (106, 156))	('knocking down', 'Var', (21, 34))	('PKM2', 'Enzyme', (75, 79))	('glucose', 'Chemical', 'MESH:D005947', (114, 121))	('PTEN', 'Gene', (35, 39))	('mTOR', 'MPA', (52, 56))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('PTEN', 'Gene', '5728', (35, 39))	('lactic acid', 'Chemical', 'MESH:D019344', (127, 138))	('cancer', 'Disease', (90, 96))	('regulate', 'Reg', (66, 74))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('inducing', 'Reg', (81, 89))
167863	29916308	Immunoblot analysis was performed using secondary antibodies conjugated to horseradish peroxidase, and the primary antibodies included anti-mTOR, anti-p-mTOR, anti-PKM2, and anti-GAPDH (Sangon Biotech, D110016, China).	('GAPDH', 'Gene', (179, 184))	('anti-p-mTOR', 'Var', (146, 157))	('horseradish', 'Species', '3704', (75, 86))	('GAPDH', 'Gene', '2597', (179, 184))	('anti-mTOR', 'Var', (135, 144))	('anti-PKM2', 'Var', (159, 168))
167871	29916308	The remaining glucose in the medium showed that the PKM2-up and PKM2-down groups consumed more and less glucose, respectively, than the control group (Figure 2B).	('less', 'NegReg', (99, 103))	('PKM2-up', 'Var', (52, 59))	('glucose', 'MPA', (104, 111))	('PKM2-down', 'Var', (64, 73))	('glucose', 'Chemical', 'MESH:D005947', (14, 21))	('glucose', 'Chemical', 'MESH:D005947', (104, 111))
167872	29916308	Lactate assays showed that modifying PKM2 expression also affected lactate production.	('lactate', 'Chemical', 'MESH:D019344', (67, 74))	('Lactate', 'Chemical', 'MESH:D019344', (0, 7))	('lactate production', 'MPA', (67, 85))	('affected', 'Reg', (58, 66))	('modifying', 'Var', (27, 36))	('PKM2', 'Gene', (37, 41))
167873	29916308	The PKM2-up group produced more lactate and the PKM2-down group produced less lactate than the control group (Figure 2C).	('lactate', 'Chemical', 'MESH:D019344', (32, 39))	('lactate', 'Chemical', 'MESH:D019344', (78, 85))	('lactate', 'MPA', (32, 39))	('PKM2-up', 'Var', (4, 11))	('more', 'PosReg', (27, 31))
167878	29916308	Measurement of the remaining glucose in the medium showed that the rapamycin group consumed less glucose than did the control group (Figure 3C).	('glucose', 'Chemical', 'MESH:D005947', (97, 104))	('less', 'NegReg', (92, 96))	('glucose', 'Chemical', 'MESH:D005947', (29, 36))	('rapamycin', 'Chemical', 'MESH:D020123', (67, 76))	('glucose', 'MPA', (97, 104))	('rapamycin', 'Var', (67, 76))
167879	29916308	Furthermore, in the lactate assay, the rapamycin group produced less lactate than did the control group (Figure 3D).	('lactate', 'MPA', (69, 76))	('less', 'NegReg', (64, 68))	('rapamycin', 'Chemical', 'MESH:D020123', (39, 48))	('lactate assay', 'MPA', (20, 33))	('lactate', 'Chemical', 'MESH:D019344', (20, 27))	('lactate', 'Chemical', 'MESH:D019344', (69, 76))	('rapamycin', 'Var', (39, 48))
167882	29916308	However, the PTEN gene is a key suppressor gene in the mTOR pathway, as mentioned earlier; therefore, we knocked down PTEN to activate mTOR.	('activate', 'PosReg', (126, 134))	('PTEN', 'Gene', '5728', (118, 122))	('PTEN', 'Gene', (118, 122))	('PTEN', 'Gene', (13, 17))	('PTEN', 'Gene', '5728', (13, 17))	('knocked down', 'Var', (105, 117))
167884	29916308	Western blotting showed that knocking down PTEN was associated with increased p-mTOR expression (Figure 3B).	('knocking down', 'Var', (29, 42))	('PTEN', 'Gene', (43, 47))	('p-mTOR expression', 'MPA', (78, 95))	('PTEN', 'Gene', '5728', (43, 47))	('increased', 'PosReg', (68, 77))
167889	29916308	We knocked down both PTEN and PKM2 in the same group (PTEN-down + PKM2-down group) to activate mTOR and inhibit PKM2.	('mTOR', 'MPA', (95, 99))	('PKM2', 'Enzyme', (112, 116))	('activate', 'PosReg', (86, 94))	('PTEN', 'Gene', (54, 58))	('knocked', 'Var', (3, 10))	('PTEN', 'Gene', '5728', (54, 58))	('PTEN', 'Gene', (21, 25))	('inhibit', 'NegReg', (104, 111))	('PTEN', 'Gene', '5728', (21, 25))
167892	29916308	Inhibitors of mTOR (including rapamycin derivatives) and PKM2 are thus potential drugs that could serve as new therapeutic options for cancer treatment (Figure 4B).	('cancer', 'Disease', (135, 141))	('Inhibitors', 'Var', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('rapamycin', 'Chemical', 'MESH:D020123', (30, 39))	('cancer', 'Disease', 'MESH:D009369', (135, 141))	('mTOR', 'Gene', (14, 18))	('PKM2', 'Gene', (57, 61))
167897	29916308	mTOR is phosphorylated by Akt1 at Ser2448, leading to downstream signaling by p-mTOR.	('leading to', 'Reg', (43, 53))	('Akt1', 'Gene', '207', (26, 30))	('Ser2448', 'Var', (34, 41))	('Ser2448', 'Chemical', '-', (34, 41))	('downstream signaling', 'MPA', (54, 74))	('Akt1', 'Gene', (26, 30))
167901	29916308	The consumption of glucose and the production of lactic acid by ESCC cells changed following the modification of PKM2 expression.	('production of lactic acid', 'MPA', (35, 60))	('glucose', 'Chemical', 'MESH:D005947', (19, 26))	('changed', 'Reg', (75, 82))	('consumption of glucose', 'MPA', (4, 26))	('lactic acid', 'Chemical', 'MESH:D019344', (49, 60))	('PKM2', 'Gene', (113, 117))	('modification', 'Var', (97, 109))
167906	29916308	We thus knocked down PTEN to activate mTOR and inhibited mTOR with rapamycin.	('inhibited', 'NegReg', (47, 56))	('mTOR', 'MPA', (38, 42))	('PTEN', 'Gene', '5728', (21, 25))	('PTEN', 'Gene', (21, 25))	('rapamycin', 'Chemical', 'MESH:D020123', (67, 76))	('knocked down', 'Var', (8, 20))	('activate', 'PosReg', (29, 37))
167916	33888679	Therefore, a comprehensive understanding of ECM dysregulation in the TME would contribute to the discovery of promising therapeutic targets for cancer treatment.	('C', 'Chemical', 'MESH:D002244', (45, 46))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('dysregulation', 'Var', (48, 61))	('cancer', 'Disease', (144, 150))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
167954	33888679	alpha Chains vary greatly in size (ranging from 662 up to 3152 amino acids for the human alpha1 (collagen type X) and alpha3 (collagen type VI) chains, respectively) as well as the frequencies of imperfections and interruptions of Gly-X-Y repeats, resulting in differences in plasticity, flexibility and recognition patterns among various types of collagens.	('flexibility', 'MPA', (288, 299))	('imperfections', 'Var', (196, 209))	('human', 'Species', '9606', (83, 88))	('differences', 'Reg', (261, 272))	('recognition patterns', 'MPA', (304, 324))	('Gly-X-Y', 'Protein', (231, 238))	('plasticity', 'MPA', (276, 286))	('C', 'Chemical', 'MESH:D002244', (6, 7))
167967	33888679	In the ECM, fibronectin connects various structural proteins to form an integrated matrix, such as collagens, fibrillin, and tenascin-C. For example, the antibody targeting the collagen-binding site in fibronectin could suppress the fibrillogenesis of collagen, suggesting that type I collagen cannot assemble without fibronectin.	('fibrillogenesis', 'MPA', (233, 248))	('C', 'Chemical', 'MESH:D002244', (134, 135))	('tenascin-C', 'Gene', '3371', (125, 135))	('C', 'Chemical', 'MESH:D002244', (8, 9))	('tenascin-C', 'Gene', (125, 135))	('suppress', 'NegReg', (220, 228))	('antibody', 'Var', (154, 162))
167979	33888679	The beta-turn in the polypeptide chain is produced based on the interaction of Gly4 (N-H) and Gly1 (C = O) or Leu5 (N-H) and Val2 (C = O), resulting in the resilience of elastin.	('N', 'Chemical', 'MESH:D009584', (116, 117))	('C', 'Chemical', 'MESH:D002244', (100, 101))	('C', 'Chemical', 'MESH:D002244', (131, 132))	('Leu5', 'Chemical', '-', (110, 114))	('N', 'Chemical', 'MESH:D009584', (85, 86))	('Gly4', 'Var', (79, 83))	('Gly1', 'Gene', '390816', (94, 98))	('Leu5', 'Var', (110, 114))	('Val2', 'Chemical', '-', (125, 129))	('elastin', 'Gene', '2006', (170, 177))	('Gly4', 'Chemical', 'MESH:C046274', (79, 83))	('resilience', 'MPA', (156, 166))	('interaction', 'Interaction', (64, 75))	('elastin', 'Gene', (170, 177))	('Gly1', 'Gene', (94, 98))
168000	33888679	O-sulfation modification of heparan sulfate mainly occurs at C-2 of iduronic acid (IdoA) and C-6 of glucosamine, and sometimes at C-2 of GlcA and C-3 of glucosamine.	('C', 'Chemical', 'MESH:D002244', (93, 94))	('C-6', 'Var', (93, 96))	('iduronic acid', 'Chemical', 'MESH:D007067', (68, 81))	('heparan sulfate', 'Protein', (28, 43))	('C', 'Chemical', 'MESH:D002244', (146, 147))	('GlcA', 'Chemical', '-', (137, 141))	('O-sulfation modification', 'MPA', (0, 24))	('IdoA', 'Chemical', 'MESH:D007067', (83, 87))	('heparan sulfate', 'Chemical', 'MESH:D006497', (28, 43))	('C', 'Chemical', 'MESH:D002244', (130, 131))	('C', 'Chemical', 'MESH:D002244', (61, 62))	('glucosamine', 'Chemical', 'MESH:D005944', (100, 111))	('occurs', 'Reg', (51, 57))	('glucosamine', 'Chemical', 'MESH:D005944', (153, 164))
168086	33888679	reported that Ras suppressor-1 (RSU-1), a cell-ECM protein, is overexpressed in breast cancer cells embedded in stiffer 3D collagen I gels, and silencing RSU-1 led to the inhibition of urokinase plasminogen activator (UPA) and MMP-13, resulting in reduced invasion activity in breast cancer cells.	('breast cancer', 'Phenotype', 'HP:0003002', (277, 290))	('breast cancer', 'Disease', 'MESH:D001943', (80, 93))	('breast cancer', 'Disease', (80, 93))	('RSU-1', 'Gene', (154, 159))	('UPA', 'Gene', (218, 221))	('MMP-13', 'Gene', '4322', (227, 233))	('RSU-1', 'Gene', '6251', (154, 159))	('breast cancer', 'Disease', 'MESH:D001943', (277, 290))	('breast cancer', 'Disease', (277, 290))	('reduced', 'NegReg', (248, 255))	('inhibition', 'NegReg', (171, 181))	('urokinase plasminogen activator', 'Gene', '5328', (185, 216))	('urokinase plasminogen activator', 'Gene', (185, 216))	('Ras suppressor-1', 'Gene', (14, 30))	('C', 'Chemical', 'MESH:D002244', (48, 49))	('MMP-13', 'Gene', (227, 233))	('UPA', 'Gene', '5328', (218, 221))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('RSU-1', 'Gene', (32, 37))	('cancer', 'Phenotype', 'HP:0002664', (284, 290))	('RSU-1', 'Gene', '6251', (32, 37))	('invasion activity', 'CPA', (256, 273))	('silencing', 'Var', (144, 153))	('breast cancer', 'Phenotype', 'HP:0003002', (80, 93))	('Ras suppressor-1', 'Gene', '6251', (14, 30))
168092	33888679	Overgrowth of cancer cells, as well as a structural and functional abnormality of ECM both, contributes to the hypoxia of solid tumor.	('hypoxia', 'Disease', (111, 118))	('cancer', 'Disease', (14, 20))	('contributes', 'Reg', (92, 103))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('ECM', 'Gene', (82, 85))	('Overgrowth', 'Phenotype', 'HP:0001548', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumor', 'Disease', (128, 133))	('hypoxia', 'Disease', 'MESH:D000860', (111, 118))	('cancer', 'Disease', 'MESH:D009369', (14, 20))	('abnormality', 'Var', (67, 78))	('C', 'Chemical', 'MESH:D002244', (83, 84))
168099	33888679	Third, ECM stiffness induces hypoxia in the tumor microenvironment, further inducing neovascular chaos, resulting in disorganized and perforated intratumoral microvessels.	('hypoxia', 'Disease', (29, 36))	('hypoxia', 'Disease', 'MESH:D000860', (29, 36))	('induces', 'Reg', (21, 28))	('C', 'Chemical', 'MESH:D002244', (8, 9))	('ECM', 'Var', (7, 10))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('resulting in', 'Reg', (104, 116))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('inducing', 'Reg', (76, 84))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('neovascular chaos', 'CPA', (85, 102))	('tumor', 'Disease', (150, 155))	('tumor', 'Disease', (44, 49))
168104	33888679	Mechanically, the downstream signals of beta1 integrins would be activated in response of radiation, such as ILK, FAK, paxillin, c-Jun N2-terminal kinase (JNK), PI3K, and AKT/protein kinase B (PKB).	('PI3K', 'Var', (161, 165))	('JNK', 'Gene', '5599', (155, 158))	('ILK', 'Gene', (109, 112))	('FAK', 'Gene', '5747', (114, 117))	('paxillin', 'Gene', '5829', (119, 127))	('PKB', 'Gene', '207', (193, 196))	('AKT/protein kinase B', 'Gene', '207', (171, 191))	('c-Jun N2-terminal kinase', 'Gene', (129, 153))	('ILK', 'Gene', '3611', (109, 112))	('beta1 integrins', 'Gene', '3688', (40, 55))	('c-Jun N2-terminal kinase', 'Gene', '5599', (129, 153))	('PKB', 'Gene', (193, 196))	('AKT/protein kinase B', 'Gene', (171, 191))	('beta1 integrins', 'Gene', (40, 55))	('activated', 'PosReg', (65, 74))	('paxillin', 'Gene', (119, 127))	('JNK', 'Gene', (155, 158))	('FAK', 'Gene', (114, 117))
168105	33888679	The activation of PI3K/AKT leads to the radiation resistance, and inhibition of integrin signaling attenuates the insensitivity of cancer cells exposed to radiation.	('cancer', 'Disease', (131, 137))	('radiation resistance', 'CPA', (40, 60))	('insensitivity', 'MPA', (114, 127))	('leads to', 'Reg', (27, 35))	('AKT', 'Gene', '207', (23, 26))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('inhibition', 'Var', (66, 76))	('AKT', 'Gene', (23, 26))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('attenuates', 'NegReg', (99, 109))	('activation', 'PosReg', (4, 14))
168111	33888679	Such squeezing movement would isolate some mobilizable nuclear proteins away from DNA, such as DNA repair proteins (e.g., BRCA1), thus increasing the possibility of GIN.	('BRCA1', 'Gene', (122, 127))	('N', 'Chemical', 'MESH:D009584', (167, 168))	('N', 'Chemical', 'MESH:D009584', (83, 84))	('N', 'Chemical', 'MESH:D009584', (96, 97))	('BRCA1', 'Gene', '672', (122, 127))	('isolate', 'Var', (30, 37))	('mobilizable nuclear proteins', 'MPA', (43, 71))	('increasing', 'PosReg', (135, 145))
168114	33888679	These cells are constantly influenced by the physical, chemical, and biological signals emitted by ECM in TME.	('influenced', 'Reg', (27, 37))	('ECM', 'Var', (99, 102))	('C', 'Chemical', 'MESH:D002244', (100, 101))
168139	33888679	reported that the adhesion of prostatic cancer cells could be attenuated by silencing CUB domain-containing protein-1 (CDCP1) due to the reduction of inside-out signaling mediated by integrin beta1 subunit.	('integrin beta1', 'Gene', (183, 197))	('prostatic cancer', 'Disease', (30, 46))	('inside-out signaling', 'MPA', (150, 170))	('attenuated', 'NegReg', (62, 72))	('adhesion', 'CPA', (18, 26))	('silencing', 'Var', (76, 85))	('integrin beta1', 'Gene', '3688', (183, 197))	('CUB domain-containing protein-1', 'Gene', '64866', (86, 117))	('CDCP1', 'Gene', '64866', (119, 124))	('CDCP1', 'Gene', (119, 124))	('reduction', 'NegReg', (137, 146))	('prostatic cancer', 'Disease', 'MESH:D011471', (30, 46))	('prostatic cancer', 'Phenotype', 'HP:0012125', (30, 46))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('CUB domain-containing protein-1', 'Gene', (86, 117))
168152	33888679	However, ECM cell signal transduction mediated by DDRs is unidirectional, while the one mediated by integrin is bidirectional.	('DDRs', 'Var', (50, 54))	('C', 'Chemical', 'MESH:D002244', (10, 11))	('ECM cell signal transduction', 'MPA', (9, 37))
168159	33888679	HA-CD44 interaction activates multiple cell receptors, such as c-MET, EGF receptor (EGFR), erb-b2 receptor tyrosine kinase 2 (ErbB2), and TGF-beta, which then promotes oncogenic pathways.	('HA', 'Chemical', 'MESH:D006820', (0, 2))	('interaction', 'Var', (8, 19))	('c-MET', 'Gene', '4233', (63, 68))	('TGF-beta', 'Gene', '7039', (138, 146))	('oncogenic pathways', 'CPA', (168, 186))	('c-MET', 'Gene', (63, 68))	('TGF-beta', 'Gene', (138, 146))	('CD4', 'Gene', '920', (3, 6))	('erb-b2', 'Gene', '2064', (91, 97))	('EGFR', 'Gene', '1956', (84, 88))	('EGFR', 'Gene', (84, 88))	('activates', 'PosReg', (20, 29))	('CD4', 'Gene', (3, 6))	('tyrosine', 'Chemical', 'MESH:D014443', (107, 115))	('promotes', 'PosReg', (159, 167))	('EGF receptor', 'Gene', '1956', (70, 82))	('ErbB2', 'Gene', (126, 131))	('erb-b2', 'Gene', (91, 97))	('EGF receptor', 'Gene', (70, 82))
168160	33888679	In addition to membrane receptors, the HA-CD44 interaction also activates intracellular signal transducers, such as Grb2, Gab-1, Src, and Rac GTPase families.	('Gab-1', 'Gene', '2549', (122, 127))	('Src', 'Gene', (129, 132))	('Src', 'Gene', '6714', (129, 132))	('CD4', 'Gene', (42, 45))	('Gab-1', 'Gene', (122, 127))	('Grb2', 'Gene', '2885', (116, 120))	('CD4', 'Gene', '920', (42, 45))	('HA', 'Chemical', 'MESH:D006820', (39, 41))	('activates', 'PosReg', (64, 73))	('interaction', 'Var', (47, 58))	('Rac GTPase families', 'Enzyme', (138, 157))	('intracellular signal transducers', 'MPA', (74, 106))	('Grb2', 'Gene', (116, 120))
168196	33888679	In addition to collagenases, a few studies showed that strategies aimed at regulating the quantity or activity of MMPs could also be helpful for cancer treatment, such as marimastat (BB-2516), prinomastat (AG3340), tanomastat (BAY 12-9566), and neovastat.	('cancer', 'Disease', (145, 151))	('BAY 12-9566', 'Chemical', 'MESH:C113281', (227, 238))	('BB-2516', 'Chemical', 'MESH:C100342', (183, 190))	('AG3340', 'Var', (206, 212))	('AG3340', 'Chemical', 'MESH:C113282', (206, 212))	('tanomastat', 'Chemical', 'MESH:C113281', (215, 225))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('prinomastat', 'Chemical', 'MESH:C113282', (193, 204))	('activity', 'MPA', (102, 110))	('marimastat', 'Chemical', 'MESH:C100342', (171, 181))	('cancer', 'Disease', 'MESH:D009369', (145, 151))
168203	33888679	Inhibition of LOXs has been shown to enhance chemotherapeutic drug delivery in mouse models of pancreatic cancer and breast cancer.	('mouse', 'Species', '10090', (79, 84))	('LOX', 'Gene', '4015', (14, 17))	('chemotherapeutic drug delivery', 'MPA', (45, 75))	('LOX', 'Gene', (14, 17))	('breast cancer', 'Disease', 'MESH:D001943', (117, 130))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (95, 112))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('breast cancer', 'Disease', (117, 130))	('breast cancer', 'Phenotype', 'HP:0003002', (117, 130))	('Inhibition', 'Var', (0, 10))	('pancreatic cancer', 'Disease', (95, 112))	('pancreatic cancer', 'Disease', 'MESH:D010190', (95, 112))	('enhance', 'PosReg', (37, 44))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
168211	33888679	Mechanically, the direct effect when TGF-beta binds to TGFbetaR is proapoptotic, so TGFbetaR is downregulated or mutant in various types of cancer.	('TGF-beta', 'Gene', '7039', (37, 45))	('proapoptotic', 'MPA', (67, 79))	('binds', 'Interaction', (46, 51))	('TGFbetaR', 'Gene', (55, 63))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('TGF-beta', 'Gene', (37, 45))	('downregulated', 'NegReg', (96, 109))	('mutant', 'Var', (113, 119))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('TGFbetaR', 'Gene', (84, 92))
168216	33888679	SB-431542 and SB-505124 have been shown to suppress proliferation, motility, and vascularization in mice models of glioma and renal carcinoma.	('SB-431542', 'Var', (0, 9))	('proliferation', 'CPA', (52, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('SB-505124', 'Chemical', 'MESH:C519132', (14, 23))	('mice', 'Species', '10090', (100, 104))	('SB-505124', 'Var', (14, 23))	('suppress', 'NegReg', (43, 51))	('glioma', 'Phenotype', 'HP:0009733', (115, 121))	('SB-431542', 'Chemical', 'MESH:C459179', (0, 9))	('glioma and renal carcinoma', 'Disease', 'MESH:D005910', (115, 141))	('motility', 'CPA', (67, 75))	('vascularization', 'CPA', (81, 96))	('renal carcinoma', 'Phenotype', 'HP:0005584', (126, 141))
168217	33888679	SB-431542 also enhances the activity of DC and CD8+ T cells.	('SB-431542', 'Var', (0, 9))	('activity', 'CPA', (28, 36))	('C', 'Chemical', 'MESH:D002244', (41, 42))	('enhances', 'PosReg', (15, 23))	('CD8', 'Gene', (47, 50))	('CD8', 'Gene', '925', (47, 50))	('SB-431542', 'Chemical', 'MESH:C459179', (0, 9))	('C', 'Chemical', 'MESH:D002244', (47, 48))
168219	33888679	Ki26894 has been reported to suppress bone metastasis in mice models of breast cancer and gastric cancer.	('mice', 'Species', '10090', (57, 61))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('gastric cancer', 'Disease', 'MESH:D013274', (90, 104))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('suppress', 'NegReg', (29, 37))	('bone metastasis', 'CPA', (38, 53))	('gastric cancer', 'Phenotype', 'HP:0012126', (90, 104))	('Ki26894', 'Var', (0, 7))	('breast cancer', 'Disease', 'MESH:D001943', (72, 85))	('breast cancer', 'Disease', (72, 85))	('breast cancer', 'Phenotype', 'HP:0003002', (72, 85))	('gastric cancer', 'Disease', (90, 104))
168220	33888679	Other small molecules that inhibit TGFbetaR, such as LY-2109761, SD-093, SD-208, and LY-580276, have also been tested in various kinds of cancer.	('cancer', 'Disease', (138, 144))	('SD-093', 'Var', (65, 71))	('SD-093', 'CellLine', 'CVCL:V432', (65, 71))	('TGFbetaR', 'Gene', (35, 43))	('LY-580276', 'Var', (85, 94))	('LY', 'Chemical', 'MESH:D008239', (53, 55))	('LY-2109761', 'Var', (53, 63))	('LY', 'Chemical', 'MESH:D008239', (85, 87))	('LY-2109761', 'CellLine', 'CVCL:2097', (53, 63))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('SD-208', 'Var', (73, 79))	('tested', 'Reg', (111, 117))	('inhibit', 'NegReg', (27, 34))	('cancer', 'Disease', 'MESH:D009369', (138, 144))
168223	33888679	As for advanced tumors, inhibition of TGFbetaR suppresses the metastasis and invasion of tumor.	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('suppresses', 'NegReg', (47, 57))	('TGFbetaR', 'Gene', (38, 46))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('tumors', 'Disease', 'MESH:D009369', (16, 22))	('inhibition', 'Var', (24, 34))	('tumor', 'Disease', (16, 21))	('tumors', 'Disease', (16, 22))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
168233	33888679	Dysregulations of AT1R and AT2R has been reported in the breast in situ carcinoma, invasive breast carcinoma, skin squamous cell carcinoma, cervical cancer, ovarian cancer, and prostate cancer.	('prostate cancer', 'Disease', 'MESH:D011471', (177, 192))	('breast carcinoma', 'Phenotype', 'HP:0003002', (92, 108))	('prostate cancer', 'Phenotype', 'HP:0012125', (177, 192))	('AT2R', 'Gene', (27, 31))	('ovarian cancer', 'Disease', (157, 171))	('prostate cancer', 'Disease', (177, 192))	('reported', 'Reg', (41, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('ovarian cancer', 'Phenotype', 'HP:0100615', (157, 171))	('cervical cancer', 'Disease', (140, 155))	('cervical cancer', 'Disease', 'MESH:D002583', (140, 155))	('invasive breast carcinoma', 'Disease', (83, 108))	('AT1R', 'Gene', '185', (18, 22))	('situ carcinoma', 'Disease', 'MESH:D002278', (67, 81))	('invasive breast carcinoma', 'Disease', 'MESH:D001943', (83, 108))	('AT1R', 'Gene', (18, 22))	('skin squamous cell carcinoma', 'Disease', 'MESH:D002294', (110, 138))	('Dysregulations', 'Var', (0, 14))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('situ carcinoma', 'Disease', (67, 81))	('AT2R', 'Gene', '186', (27, 31))	('skin squamous cell carcinoma', 'Disease', (110, 138))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('ovarian cancer', 'Disease', 'MESH:D010051', (157, 171))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (115, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))
168240	33888679	4-MU has been shown to suppress the activation of CSCs and attenuate chemoresistance in animal models of ovarian cancer.	('activation', 'MPA', (36, 46))	('chemoresistance', 'CPA', (69, 84))	('attenuate', 'NegReg', (59, 68))	('ovarian cancer', 'Disease', 'MESH:D010051', (105, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('ovarian cancer', 'Disease', (105, 119))	('suppress', 'NegReg', (23, 31))	('4-MU', 'Chemical', 'MESH:D006923', (0, 4))	('CSCs', 'Protein', (50, 54))	('4-MU', 'Var', (0, 4))	('ovarian cancer', 'Phenotype', 'HP:0100615', (105, 119))
168241	33888679	demonstrated that liposomes containing 4-MU could potently suppress HA synthesis, eventually facilitating the penetration of more liposome drugs into breast cancer xenografts.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('HA', 'Chemical', 'MESH:D006820', (68, 70))	('HA synthesis', 'MPA', (68, 80))	('breast cancer', 'Disease', 'MESH:D001943', (150, 163))	('4-MU', 'Chemical', 'MESH:D006923', (39, 43))	('breast cancer', 'Phenotype', 'HP:0003002', (150, 163))	('breast cancer', 'Disease', (150, 163))	('4-MU', 'Var', (39, 43))	('suppress', 'NegReg', (59, 67))
168258	33888679	Similarly, APTEDB-decorated nanoparticles encapsulating paclitaxel has been applied for the inhibition of neovasculature in a mice model of glioma tumor, and such modification significantly enhanced the intratumoral accumulation of paclitaxel and prolonged the survival time.	('glioma tumor', 'Disease', 'MESH:D005910', (140, 152))	('tumor', 'Disease', (147, 152))	('glioma', 'Phenotype', 'HP:0009733', (140, 146))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('paclitaxel', 'Chemical', 'MESH:D017239', (56, 66))	('mice', 'Species', '10090', (126, 130))	('tumor', 'Disease', 'MESH:D009369', (208, 213))	('prolonged', 'PosReg', (247, 256))	('EDB', 'Gene', (14, 17))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('glioma tumor', 'Disease', (140, 152))	('survival time', 'CPA', (261, 274))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('tumor', 'Disease', (208, 213))	('paclitaxel', 'Chemical', 'MESH:D017239', (232, 242))	('EDB', 'Gene', '2335', (14, 17))	('modification', 'Var', (163, 175))	('enhanced', 'PosReg', (190, 198))
168266	33888679	knocked down DDR1 by siRNA and found that migration was inhibited in pancreatic ductal adenocarcinoma cells.	('migration', 'CPA', (42, 51))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('knocked down', 'Var', (0, 12))	('N', 'Chemical', 'MESH:D009584', (24, 25))	('DDR1', 'Gene', (13, 17))	('inhibited', 'NegReg', (56, 65))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (69, 101))	('pancreatic ductal adenocarcinoma', 'Disease', (69, 101))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (69, 101))
168267	33888679	The combination of DDR1 inhibitors and classical chemotherapeutic drugs has been reported to reduce the tumor burden in both orthotopic xenografts and autochthonous pancreatic cancer models.	('pancreatic cancer', 'Disease', 'MESH:D010190', (165, 182))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('DDR1', 'Gene', (19, 23))	('tumor', 'Disease', (104, 109))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('inhibitors', 'Var', (24, 34))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (165, 182))	('combination', 'Interaction', (4, 15))	('reduce', 'NegReg', (93, 99))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('pancreatic cancer', 'Disease', (165, 182))
168268	33888679	Moreover, an in vivo study showed that the knockdown of DDR1 suppressed tumor growth and multiorgan metastasis in breast cancer mouse models.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('suppressed', 'NegReg', (61, 71))	('DDR1', 'Gene', (56, 60))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('tumor', 'Disease', (72, 77))	('knockdown', 'Var', (43, 52))	('mouse', 'Species', '10090', (128, 133))	('multiorgan metastasis', 'CPA', (89, 110))	('breast cancer', 'Disease', 'MESH:D001943', (114, 127))	('breast cancer', 'Phenotype', 'HP:0003002', (114, 127))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('breast cancer', 'Disease', (114, 127))
168269	33888679	Similarly, in a KRAS-mutant lung adenocarcinoma mouse model, inhibition of DDR1 attenuated tumor aggression.	('aggression', 'Phenotype', 'HP:0000718', (97, 107))	('lung adenocarcinoma', 'Disease', (28, 47))	('attenuated tumor aggression', 'Disease', (80, 107))	('inhibition', 'Var', (61, 71))	('mouse', 'Species', '10090', (48, 53))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (28, 47))	('attenuated tumor aggression', 'Disease', 'MESH:C538265', (80, 107))	('KRAS', 'Gene', '16653', (16, 20))	('KRAS', 'Gene', (16, 20))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (28, 47))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('DDR1', 'Gene', (75, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (38, 47))
168270	33888679	The signal transduction triggered by DDRs could be blocked by tyrosine kinase inhibitors (TKIs), such as imatinib, nilotinib, and dasatinib, some of which have been applied as a cancer treatment for more than a decade.	('tyrosine', 'Chemical', 'MESH:D014443', (62, 70))	('signal transduction', 'MPA', (4, 23))	('dasatinib', 'Chemical', 'MESH:D000069439', (130, 139))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('imatinib', 'Chemical', 'MESH:D000068877', (105, 113))	('cancer', 'Disease', (178, 184))	('nilotinib', 'Chemical', 'MESH:C498826', (115, 124))	('DDRs', 'Var', (37, 41))	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('blocked', 'NegReg', (51, 58))
168272	33888679	Moreover, lung squamous cell carcinoma patients with a DDR2 mutation were more sensitive to dasatinib than those with wild-type DDR2.	('DDR2', 'Gene', (128, 132))	('dasatinib', 'Chemical', 'MESH:D000069439', (92, 101))	('mutation', 'Var', (60, 68))	('patients', 'Species', '9606', (39, 47))	('carcinoma', 'Phenotype', 'HP:0030731', (29, 38))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (10, 38))	('sensitive to dasatinib', 'MPA', (79, 101))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (15, 38))	('lung squamous cell carcinoma', 'Disease', (10, 38))	('DDR2', 'Gene', '4921', (55, 59))	('DDR2', 'Gene', '4921', (128, 132))	('DDR2', 'Gene', (55, 59))
168276	33888679	For example, bivatuzumab (e.g., the first humanized monoclonal antibody against CD44v6 underwent clinical trials), displayed a moderate antitumor effect in patients with advanced squamous cell carcinoma of the head and neck or esophagus.	('patients', 'Species', '9606', (156, 164))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (179, 202))	('squamous cell carcinoma', 'Disease', (179, 202))	('human', 'Species', '9606', (42, 47))	('esophagus', 'Disease', (227, 236))	('bivatuzumab', 'Var', (13, 24))	('carcinoma', 'Phenotype', 'HP:0030731', (193, 202))	('CD4', 'Gene', (80, 83))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('bivatuzumab', 'Chemical', 'MESH:C479239', (13, 24))	('CD4', 'Gene', '920', (80, 83))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (179, 202))	('tumor', 'Disease', (140, 145))
168277	33888679	Subsequently, more CD44 antibodies entered clinical trials, such as RO5429083 (clinicaltrials.gov identifier: NCT01358903 and NCT01641250).	('CD4', 'Gene', (19, 22))	('NCT01641250', 'Var', (126, 137))	('CD4', 'Gene', '920', (19, 22))	('RO5429083', 'Chemical', '-', (68, 77))
168279	33888679	However, due to the lack of a comprehensive understanding of all CD44 isoforms and the consequences of knocking down a mixture of CD44 isoforms, some challenges persist for the clinical applications of a siRNA-based strategy targeting CD44.	('N', 'Chemical', 'MESH:D009584', (207, 208))	('CD4', 'Gene', '920', (130, 133))	('CD4', 'Gene', (65, 68))	('CD4', 'Gene', '920', (65, 68))	('knocking', 'Var', (103, 111))	('CD4', 'Gene', (235, 238))	('CD4', 'Gene', (130, 133))	('CD4', 'Gene', '920', (235, 238))
168283	33888679	For example, small interfering RNA-mediated suppression of RHAMM has been shown to sensitize lung adenocarcinoma A549 cells to radiotherapy.	('N', 'Chemical', 'MESH:D009584', (32, 33))	('RHAMM', 'Gene', '3161', (59, 64))	('lung adenocarcinoma', 'Disease', (93, 112))	('RHAMM', 'Gene', (59, 64))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (93, 112))	('small interfering', 'Var', (13, 30))	('A549', 'CellLine', 'CVCL:0023', (113, 117))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('radiotherapy', 'CPA', (127, 139))	('suppression', 'NegReg', (44, 55))	('sensitize', 'Reg', (83, 92))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (93, 112))
168311	33888679	On the other hand, the N-linked glycosylated CD44 variant (CD44v6) forms high-avidity interaction with HA under the stimulation of the CD40 ligand, thus producing an adhesive force to stop CLL mobility, thus retaining CLL cells in specialized compartments of lymph node where they would encounter intensive survival and proliferation-inducing signals.	('CLL', 'Phenotype', 'HP:0005550', (189, 192))	('interaction', 'Interaction', (86, 97))	('variant', 'Var', (50, 57))	('C', 'Chemical', 'MESH:D002244', (45, 46))	('CD4', 'Gene', '920', (45, 48))	('adhesive force', 'MPA', (166, 180))	('CD4', 'Gene', (135, 138))	('C', 'Chemical', 'MESH:D002244', (218, 219))	('stop', 'NegReg', (184, 188))	('CD4', 'Gene', (45, 48))	('CD4', 'Gene', '920', (59, 62))	('high-avidity', 'MPA', (73, 85))	('CLL', 'Phenotype', 'HP:0005550', (218, 221))	('CLL', 'Protein', (189, 192))	('CD4', 'Gene', (59, 62))	('C', 'Chemical', 'MESH:D002244', (135, 136))	('C', 'Chemical', 'MESH:D002244', (189, 190))	('N', 'Chemical', 'MESH:D009584', (23, 24))	('HA', 'Chemical', 'MESH:D006820', (103, 105))	('CD4', 'Gene', '920', (135, 138))	('C', 'Chemical', 'MESH:D002244', (59, 60))
168312	33888679	Moreover, engagement of CD44 would activate the intercellular PI3K/AKT and MAPK/ERK pathways, and increase the expression level of myeloid cell leukemia sequence 1 protein to suppress spontaneous and drug-induced apoptosis in CLL cells.	('AKT', 'Gene', '207', (67, 70))	('ERK', 'Gene', '5594', (80, 83))	('CLL', 'Phenotype', 'HP:0005550', (226, 229))	('leukemia', 'Phenotype', 'HP:0001909', (144, 152))	('engagement', 'Var', (10, 20))	('expression level', 'MPA', (111, 127))	('CD4', 'Gene', (24, 27))	('ERK', 'Gene', (80, 83))	('CD4', 'Gene', '920', (24, 27))	('AKT', 'Gene', (67, 70))	('myeloid cell leukemia', 'Disease', (131, 152))	('activate', 'PosReg', (35, 43))	('myeloid cell leukemia', 'Phenotype', 'HP:0012324', (131, 152))	('increase', 'PosReg', (98, 106))	('C', 'Chemical', 'MESH:D002244', (226, 227))	('suppress', 'NegReg', (175, 183))	('myeloid cell leukemia', 'Disease', 'MESH:D007951', (131, 152))	('C', 'Chemical', 'MESH:D002244', (24, 25))
168314	33888679	reported that a humanized monoclonal antibody specific for CD44 (RG7356) was directly cytotoxic for CLL cells both in vitro and in vivo, but had little effects on normal B cells.	('C', 'Chemical', 'MESH:D002244', (100, 101))	('CLL', 'Phenotype', 'HP:0005550', (100, 103))	('CD4', 'Gene', (59, 62))	('CD4', 'Gene', '920', (59, 62))	('RG7356', 'Chemical', 'MESH:C576196', (65, 71))	('RG7356', 'Var', (65, 71))	('human', 'Species', '9606', (16, 21))	('C', 'Chemical', 'MESH:D002244', (59, 60))
168316	33888679	Several CD44 antibodies have been shown to suppress AML cells, such as RG7356, HI44a, A3D8, and ARH460-16-2.	('AML', 'Phenotype', 'HP:0004808', (52, 55))	('antibodies', 'Var', (13, 23))	('AML', 'Disease', (52, 55))	('CD4', 'Gene', (8, 11))	('suppress', 'NegReg', (43, 51))	('CD4', 'Gene', '920', (8, 11))	('RG7356', 'Chemical', 'MESH:C576196', (71, 77))	('AML', 'Disease', 'MESH:D015470', (52, 55))
168317	33888679	In the Phase I clinical study of RG7356 in AML patients, one complete response (CR) with incomplete platelet recovery (CRp) and one partial response (PR) were recorded, suggesting its potential as an effective therapy for AML.	('CR', 'Gene', '1401', (80, 82))	('RG7356', 'Var', (33, 39))	('CRp', 'Gene', (119, 122))	('AML', 'Disease', 'MESH:D015470', (43, 46))	('AML', 'Disease', 'MESH:D015470', (222, 225))	('patients', 'Species', '9606', (47, 55))	('CRp', 'Gene', '1401', (119, 122))	('AML', 'Phenotype', 'HP:0004808', (43, 46))	('AML', 'Phenotype', 'HP:0004808', (222, 225))	('AML', 'Disease', (43, 46))	('RG7356', 'Chemical', 'MESH:C576196', (33, 39))	('AML', 'Disease', (222, 225))	('CR', 'Gene', '1401', (119, 121))
168319	33888679	The success of Ibrutinib and RG7356 in hematological malignancies suggests that cell-ECM interactions, as well as the signaling network involved in the tissue homing process, are highly workable and druggable targets for combating hematological malignancies.	('hematological malignancies', 'Disease', 'MESH:D019337', (39, 65))	('hematological malignancies', 'Disease', 'MESH:D019337', (231, 257))	('hematological malignancies', 'Disease', (231, 257))	('C', 'Chemical', 'MESH:D002244', (86, 87))	('hematological malignancies', 'Phenotype', 'HP:0004377', (231, 257))	('hematological malignancies', 'Phenotype', 'HP:0004377', (39, 65))	('Ibrutinib', 'Chemical', 'MESH:C551803', (15, 24))	('RG7356', 'Chemical', 'MESH:C576196', (29, 35))	('RG7356', 'Var', (29, 35))	('hematological malignancies', 'Disease', (39, 65))
168323	33888679	One of the most successful cases is the application of TKIs in non-small cell lung cancer with EGFR mutation and chronic myeloid leukemia, which is partially mediated by the blockage of the signal transduction stimulated by DDRs.	('lung cancer', 'Disease', (78, 89))	('lung cancer', 'Phenotype', 'HP:0100526', (78, 89))	('chronic myeloid leukemia', 'Phenotype', 'HP:0005506', (113, 137))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (67, 89))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (63, 89))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('myeloid leukemia', 'Disease', (121, 137))	('mutation', 'Var', (100, 108))	('lung cancer', 'Disease', 'MESH:D008175', (78, 89))	('myeloid leukemia', 'Disease', 'MESH:D007951', (121, 137))	('EGFR', 'Gene', '1956', (95, 99))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (121, 137))	('leukemia', 'Phenotype', 'HP:0001909', (129, 137))	('EGFR', 'Gene', (95, 99))
168357	33888679	Overall, ECM components contribute greatly to the microenvironment of almost every single cell in the human body, and its dysregulation is closely related to the development and progression of many diseases such as cancer.	('dysregulation', 'Var', (122, 135))	('cancer', 'Disease', (215, 221))	('cancer', 'Disease', 'MESH:D009369', (215, 221))	('related', 'Reg', (147, 154))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('microenvironment', 'MPA', (50, 66))	('C', 'Chemical', 'MESH:D002244', (10, 11))	('human', 'Species', '9606', (102, 107))
168429	32235715	(2003) compared HPV types present in women with squamous cell cervical carcinoma versus control women and found that HPV73 was associated with cancer, with an odds ratio >45.	('squamous cell cervical carcinoma', 'Disease', 'MESH:D002294', (48, 80))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('associated with', 'Reg', (127, 142))	('women', 'Species', '9606', (37, 42))	('HPV', 'Species', '10566', (117, 120))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('HPV', 'Species', '10566', (16, 19))	('squamous cell cervical carcinoma', 'Disease', (48, 80))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('women', 'Species', '9606', (96, 101))	('HPV73', 'Var', (117, 122))
168443	32235715	Furthermore, their study demonstrated that within an individual subject, HPV tropism and persistence at specific anatomical sites may be associated with particular intra-genotypic HPV variants.	('associated', 'Reg', (137, 147))	('persistence', 'MPA', (89, 100))	('HPV', 'Species', '10566', (73, 76))	('HPV', 'Species', '10566', (180, 183))	('HPV', 'Gene', (180, 183))	('variants', 'Var', (184, 192))
168455	30243489	In xenograft experiments, miR-34a-5p overexpression in CAFs could inhibit the tumorigenesis of OSCC cells.	('overexpression', 'PosReg', (37, 51))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('miR-34a-5p', 'Var', (26, 36))	('34a', 'Chemical', '-', (30, 33))	('OS', 'Phenotype', 'HP:0002669', (95, 97))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('si', 'Chemical', 'MESH:D012825', (88, 90))	('si', 'Chemical', 'MESH:D012825', (47, 49))	('inhibit', 'NegReg', (66, 73))	('tumor', 'Disease', (78, 83))
168456	30243489	We further revealed that miR-34a-5p binds to its direct downstream target AXL to suppress OSCC cell proliferation and metastasis.	('OSCC', 'Disease', (90, 94))	('AXL', 'Gene', '558', (74, 77))	('34a', 'Chemical', '-', (29, 32))	('AXL', 'Gene', (74, 77))	('suppress', 'NegReg', (81, 89))	('miR-34a-5p', 'Var', (25, 35))	('OS', 'Phenotype', 'HP:0002669', (90, 92))	('si', 'Chemical', 'MESH:D012825', (125, 127))
168457	30243489	Stable ectopic expression of AXL in OSCC cells overexpressing miR-34a-5p restored proliferation and motility abolished by the miRNA.	('AXL', 'Gene', '558', (29, 32))	('motility', 'CPA', (100, 108))	('OS', 'Phenotype', 'HP:0002669', (36, 38))	('si', 'Chemical', 'MESH:D012825', (57, 59))	('AXL', 'Gene', (29, 32))	('restored', 'PosReg', (73, 81))	('proliferation', 'CPA', (82, 95))	('si', 'Chemical', 'MESH:D012825', (21, 23))	('miR-34a-5p', 'Var', (62, 72))	('34a', 'Chemical', '-', (66, 69))
168467	30243489	Moreover, miR-34a-5p binds to its direct downstream target AXL to suppress OSCC cell proliferation and metastasis.	('AXL', 'Gene', (59, 62))	('si', 'Chemical', 'MESH:D012825', (110, 112))	('suppress', 'NegReg', (66, 74))	('OS', 'Phenotype', 'HP:0002669', (75, 77))	('AXL', 'Gene', '558', (59, 62))	('OSCC', 'Disease', (75, 79))	('miR-34a-5p', 'Var', (10, 20))	('34a', 'Chemical', '-', (14, 17))
168484	30243489	MiRNAs can negatively regulate gene expression at the posttranscriptional level by binding to their target mRNAs through base pairing to the 3'-untranslated region (UTR), causing translational repression of the mRNA.	('base pairing', 'Var', (121, 133))	('MiR', 'Gene', (0, 3))	('MiR', 'Gene', '220972', (0, 3))	('negatively', 'NegReg', (11, 21))	('binding', 'Interaction', (83, 90))	('si', 'Chemical', 'MESH:D012825', (174, 176))	('gene expression', 'MPA', (31, 46))	('si', 'Chemical', 'MESH:D012825', (199, 201))	('si', 'Chemical', 'MESH:D012825', (42, 44))	('translational repression', 'MPA', (179, 203))
168485	30243489	Several mechanisms leading to abnormal expression of miRNAs in cancer have been reported, such as chromosome rearrangements and epigenetic modifications.	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('epigenetic modifications', 'Var', (128, 152))	('chromosome rearrangements', 'CPA', (98, 123))	('expression', 'MPA', (39, 49))	('si', 'Chemical', 'MESH:D012825', (45, 47))	('cancer', 'Disease', (63, 69))	('miRNAs', 'Protein', (53, 59))
168486	30243489	Chou et al., showed that dysregulated miRNAs in the stromal compartment could reprogram normal fibroblasts into tumor-promoting CAFs, which could enhance ovarian cancer cells metastasis.	('ovarian cancer', 'Phenotype', 'HP:0100615', (154, 168))	('ovarian cancer', 'Disease', 'MESH:D010051', (154, 168))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('enhance', 'PosReg', (146, 153))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('si', 'Chemical', 'MESH:D012825', (182, 184))	('ovarian cancer', 'Disease', (154, 168))	('tumor', 'Disease', (112, 117))	('dysregulated', 'Var', (25, 37))
168503	30243489	Lentiviral plasmids encoding miR-34a-5p, or a negative control, and plasmids encoding wild-type (WT) or mutant (Mut) 3'-UTR AXL (encoding AXL receptor tyrosine kinase) were purchased from Genechem (Shanghai, China).	('AXL', 'Gene', (124, 127))	('AXL', 'Gene', (138, 141))	('mutant', 'Var', (104, 110))	('34a', 'Chemical', '-', (33, 36))	('AXL', 'Gene', '558', (124, 127))	('AXL', 'Gene', '558', (138, 141))	('si', 'Chemical', 'MESH:D012825', (155, 157))	('miR-34a-5p', 'Var', (29, 39))
168504	30243489	MiR-34a-5p mimic and miR-34a-5p mimic-control were produced by GenePharma (Shanghai, China).	('MiR', 'Gene', (0, 3))	('MiR', 'Gene', '220972', (0, 3))	('miR-34a-5p', 'Var', (21, 31))	('34a', 'Chemical', '-', (25, 28))	('34a', 'Chemical', '-', (4, 7))
168508	30243489	AXL, SNAIL, and CTNNB1 (encoding beta-catenin) knockdown was achieved by transfection using Lipofectamine RNAiMax (Thermo Scientifc, Lafayette, CO, USA) according to the manufacturer's instructions.	('CTNNB1', 'Gene', (16, 22))	('si', 'Chemical', 'MESH:D012825', (87, 89))	('beta-catenin', 'Gene', '1499', (33, 45))	('SNAIL', 'Gene', '6615', (5, 10))	('SNAIL', 'Gene', (5, 10))	('CTNNB1', 'Gene', '1499', (16, 22))	('Lipofectamine', 'Chemical', 'MESH:C086724', (92, 105))	('AXL', 'Gene', '558', (0, 3))	('knockdown', 'Var', (47, 56))	('beta-catenin', 'Gene', (33, 45))	('AXL', 'Gene', (0, 3))
168510	30243489	The cells were then assessed for the overexpression or knockdown of AXL, Snail, and beta-catenin using western blotting analysis.	('knockdown', 'Var', (55, 64))	('AXL', 'Gene', '558', (68, 71))	('beta-catenin', 'Gene', (84, 96))	('si', 'Chemical', 'MESH:D012825', (47, 49))	('si', 'Chemical', 'MESH:D012825', (98, 100))	('AXL', 'Gene', (68, 71))	('Snail', 'Gene', '6615', (73, 78))	('Snail', 'Gene', (73, 78))	('beta-catenin', 'Gene', '1499', (84, 96))	('si', 'Chemical', 'MESH:D012825', (125, 127))
168526	30243489	A luciferase reporter gene assay was used to verify whether AXL was the direct target gene of miR-34a-5p.	('AXL', 'Gene', (60, 63))	('miR-34a-5p', 'Var', (94, 104))	('AXL', 'Gene', '558', (60, 63))	('34a', 'Chemical', '-', (98, 101))
168527	30243489	Luciferase reporter constructs encoding the wild-type 3' untranslated regions of AXL (AXL-3'UTR-WT) or mutant 3' UTRs of AXL (AXL-3'UTR-MUT) were synthesized by Genechem (Shanghai, China).	('AXL', 'Gene', (86, 89))	('AXL', 'Gene', (121, 124))	('si', 'Chemical', 'MESH:D012825', (152, 154))	('AXL', 'Gene', '558', (81, 84))	('mutant', 'Var', (103, 109))	('AXL', 'Gene', (81, 84))	('AXL', 'Gene', '558', (126, 129))	('AXL', 'Gene', (126, 129))	("AXL-3'UTR-MUT", 'Gene', '558', (126, 139))	('AXL', 'Gene', '558', (86, 89))	('AXL', 'Gene', '558', (121, 124))	("AXL-3'UTR-MUT", 'Gene', (126, 139))
168528	30243489	The 3'-UTR luciferase vector (150 ng) was cotransfected into OSCC cells co-transfected with either miR-34a-5p mimic or miR-34a-5p mimic-control using Lipofectamine 2000 (Invitrogen).	('si', 'Chemical', 'MESH:D012825', (145, 147))	('34a', 'Chemical', '-', (103, 106))	('miR-34a-5p mimic', 'Var', (99, 115))	('OS', 'Phenotype', 'HP:0002669', (61, 63))	('Lipofectamine 2000', 'Chemical', 'MESH:C086724', (150, 168))	('miR-34a-5p', 'Var', (119, 129))	('34a', 'Chemical', '-', (123, 126))
168554	30243489	Among the 31 significantly downregulated and 12 significantly upregulated miRNAs in the CAF-derived exosomes, miR-34a-5p has been reported to be downregulated in primary colorectal cancer (CRC) tissue and inhibits the recurrence of CRC in a p53-dependent manner.	('miR-34a-5p', 'Var', (110, 120))	('34a', 'Chemical', '-', (114, 117))	('downregulated', 'NegReg', (145, 158))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('recurrence', 'CPA', (218, 228))	('CRC', 'Disease', (232, 235))	('colorectal cancer', 'Disease', 'MESH:D015179', (170, 187))	('CRC', 'Phenotype', 'HP:0003003', (189, 192))	('colorectal cancer', 'Phenotype', 'HP:0003003', (170, 187))	('inhibits', 'NegReg', (205, 213))	('upregulated', 'PosReg', (62, 73))	('downregulated', 'NegReg', (27, 40))	('CRC', 'Phenotype', 'HP:0003003', (232, 235))	('si', 'Chemical', 'MESH:D012825', (13, 15))	('p53', 'Gene', '7157', (241, 244))	('colorectal cancer', 'Disease', (170, 187))	('si', 'Chemical', 'MESH:D012825', (48, 50))	('p53', 'Gene', (241, 244))
168555	30243489	In osteosarcoma (OS), miR-34a-5p promoted OS multi-chemoresistance via downregulating the Deltalike ligand 1 (DLL1) gene, the ligand of the Notch pathway, and thus negatively correlates with OS chemoresistance.	('Deltalike ligand 1', 'Gene', (90, 108))	('promoted', 'PosReg', (33, 41))	('OS', 'Phenotype', 'HP:0002669', (191, 193))	('Deltalike ligand 1', 'Gene', '28514', (90, 108))	('si', 'Chemical', 'MESH:D012825', (201, 203))	('osteosarcoma', 'Disease', (3, 15))	('DLL1', 'Gene', (110, 114))	('miR-34a-5p', 'Var', (22, 32))	('34a', 'Chemical', '-', (26, 29))	('osteosarcoma', 'Phenotype', 'HP:0002669', (3, 15))	('osteosarcoma', 'Disease', 'MESH:D012516', (3, 15))	('downregulating', 'NegReg', (71, 85))	('OS', 'Phenotype', 'HP:0002669', (42, 44))	('OS', 'Phenotype', 'HP:0002669', (17, 19))	('si', 'Chemical', 'MESH:D012825', (58, 60))	('DLL1', 'Gene', '28514', (110, 114))
168561	30243489	Therefore, we used 5 ng/ml TGF-beta1 to stimulated NFs and CAFs for 48 h and measured the expression of miR-34a-5p in TGF-beta1-treated fibroblasts.	('34a', 'Chemical', '-', (108, 111))	('TGF-beta1', 'Gene', '7040', (27, 36))	('TGF-beta1', 'Gene', (27, 36))	('stimulated', 'PosReg', (40, 50))	('CAFs', 'CPA', (59, 63))	('TGF-beta1', 'Gene', '7040', (118, 127))	('expression', 'MPA', (90, 100))	('TGF-beta1', 'Gene', (118, 127))	('si', 'Chemical', 'MESH:D012825', (96, 98))	('NFs', 'CPA', (51, 54))	('miR-34a-5p', 'Var', (104, 114))
168563	30243489	We then measured the expression of miR-34a-5p in human OSCC cell lines, CAL27 and SCC15, and in human oral keratinocytes (HOK).	('CAL27', 'CellLine', 'CVCL:1107', (72, 77))	('human', 'Species', '9606', (96, 101))	('human', 'Species', '9606', (49, 54))	('34a', 'Chemical', '-', (39, 42))	('SCC15', 'Gene', '100034867', (82, 87))	('SCC15', 'Gene', (82, 87))	('miR-34a-5p', 'Var', (35, 45))	('si', 'Chemical', 'MESH:D012825', (27, 29))	('OS', 'Phenotype', 'HP:0002669', (55, 57))
168565	30243489	To examine whether CAF-derived exosomes could be transferred to OSCC cells, we cultured OSCC cells in cell culture medium supplemented with exosome-depleted serum for 3 days, and then co-cultured OSCC cells with CAFs transfected with cy3-tagged miR-34a-5p indirectly.	('34a', 'Chemical', '-', (249, 252))	('OS', 'Phenotype', 'HP:0002669', (88, 90))	('OS', 'Phenotype', 'HP:0002669', (64, 66))	('OS', 'Phenotype', 'HP:0002669', (196, 198))	('cy3-tagged', 'Var', (234, 244))	('miR-34a-5p', 'Var', (245, 255))	('cy3', 'Chemical', '-', (234, 237))
168567	30243489	We found that OSCC cells took up cy3-tagged miR-34a-5p, and the red fluorescence of cy3 was abolished when CAFs were treated with GW4869, an exosome inhibitor (Fig.	('GW4869', 'Var', (130, 136))	('cy3-tagged', 'Var', (33, 43))	('red fluorescence', 'MPA', (64, 80))	('cy3', 'Chemical', '-', (33, 36))	('cy3', 'Chemical', '-', (84, 87))	('GW4869', 'Chemical', 'MESH:C468773', (130, 136))	('abolished', 'NegReg', (92, 101))	('OS', 'Phenotype', 'HP:0002669', (14, 16))	('34a', 'Chemical', '-', (48, 51))
168568	30243489	Exosomes were then isolated from the CAFs transfected with cy3-tagged miR-34a-5p.	('cy3-tagged', 'Var', (59, 69))	('34a', 'Chemical', '-', (74, 77))	('cy3', 'Chemical', '-', (59, 62))	('miR-34a-5p', 'Gene', (70, 80))
168575	30243489	The CCK-8 assays revealed that miR-34a-5p significantly reduced the rate of cell proliferation in CAL27 and SCC15 cells compared with that in the miR-control transfected group (Fig.	('SCC15', 'Gene', '100034867', (108, 113))	('reduced', 'NegReg', (56, 63))	('SCC15', 'Gene', (108, 113))	('CAL27', 'CellLine', 'CVCL:1107', (98, 103))	('miR-34a-5p', 'Var', (31, 41))	('34a', 'Chemical', '-', (35, 38))	('si', 'Chemical', 'MESH:D012825', (42, 44))
168576	30243489	Using a colony formation assay, we also found that miR-34a-5p overexpression could significantly reduce the colony counts of both CAL27 and SCC15 cells (Fig.	('colon', 'Disease', 'MESH:D015179', (108, 113))	('colon', 'Disease', 'MESH:D015179', (8, 13))	('si', 'Chemical', 'MESH:D012825', (1, 3))	('si', 'Chemical', 'MESH:D012825', (72, 74))	('colon', 'Disease', (108, 113))	('CAL27', 'CellLine', 'CVCL:1107', (130, 135))	('SCC15', 'Gene', '100034867', (140, 145))	('miR-34a-5p', 'Var', (51, 61))	('34a', 'Chemical', '-', (55, 58))	('colon', 'Disease', (8, 13))	('SCC15', 'Gene', (140, 145))	('si', 'Chemical', 'MESH:D012825', (83, 85))	('reduce', 'NegReg', (97, 103))
168578	30243489	We used a Transwell assay to determine the impact of miR-34a-5p on OSCC cell mobility.	('34a', 'Chemical', '-', (57, 60))	('miR-34a-5p', 'Var', (53, 63))	('OSCC', 'Disease', (67, 71))	('OS', 'Phenotype', 'HP:0002669', (67, 69))
168579	30243489	We found that miR-34a-5p overexpression could suppress the migration of both CAL27 and SCC15 cells (Fig.	('SCC15', 'Gene', (87, 92))	('SCC15', 'Gene', '100034867', (87, 92))	('suppress', 'NegReg', (46, 54))	('CAL27', 'CellLine', 'CVCL:1107', (77, 82))	('si', 'Chemical', 'MESH:D012825', (35, 37))	('overexpression', 'PosReg', (25, 39))	('migration of', 'CPA', (59, 71))	('miR-34a-5p', 'Var', (14, 24))	('34a', 'Chemical', '-', (18, 21))
168581	30243489	Using an immunodeficient BALB/c mice subcutaneous tumor model to determine the tumorigenesis of miR-34a-5p transfected OSCC cells, we found that the mean weight of tumor nodules in the SCC15 miR-34a-5p overexpression group was lower than in the miR-control group (Fig.	('tumor', 'Disease', (164, 169))	('lower', 'NegReg', (227, 232))	('si', 'Chemical', 'MESH:D012825', (89, 91))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('si', 'Chemical', 'MESH:D012825', (1, 3))	('overexpression', 'PosReg', (202, 216))	('34a', 'Chemical', '-', (100, 103))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('tumor', 'Disease', (50, 55))	('tumor', 'Disease', (79, 84))	('subcutaneous tumor', 'Phenotype', 'HP:0001482', (37, 55))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('mice', 'Species', '10090', (32, 36))	('34a', 'Chemical', '-', (195, 198))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('si', 'Chemical', 'MESH:D012825', (212, 214))	('SCC15', 'Gene', (185, 190))	('miR-34a-5p', 'Var', (191, 201))	('OS', 'Phenotype', 'HP:0002669', (119, 121))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('SCC15', 'Gene', '100034867', (185, 190))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
168583	30243489	We found that NFs did not promote the tumorigenicity of CAL27 cells, and that the tumorigenicity of CAL27 cells in CAFs-miR-34a-5p group was lower than that in the CAFs-miR-control group (Fig.	('CAFs-miR-34a-5p', 'Var', (115, 130))	('tumor', 'Disease', (38, 43))	('CAL27', 'CellLine', 'CVCL:1107', (100, 105))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('lower', 'NegReg', (141, 146))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('tumor', 'Disease', (82, 87))	('CAL27', 'CellLine', 'CVCL:1107', (56, 61))	('34a', 'Chemical', '-', (124, 127))
168585	30243489	These results indicated that CAFs-miR-34a-5p suppressed the tumorigenicity of cancer cells through the transfer of exosomal miR-34a-5p to OSCC cells.	('miR-34a-5p', 'Var', (124, 134))	('34a', 'Chemical', '-', (128, 131))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('cancer', 'Disease', (78, 84))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('suppressed', 'NegReg', (45, 55))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('34a', 'Chemical', '-', (38, 41))	('tumor', 'Disease', (60, 65))	('OS', 'Phenotype', 'HP:0002669', (138, 140))
168588	30243489	Western blotting showed that the expression of AXL was significantly lower in CAL27 and SCC15 cells transfected with a lentiviral plasmid expressing miR-34a-5p than in the miR-control group (Fig.	('si', 'Chemical', 'MESH:D012825', (39, 41))	('34a', 'Chemical', '-', (153, 156))	('AXL', 'Gene', '558', (47, 50))	('lower', 'NegReg', (69, 74))	('CAL27', 'CellLine', 'CVCL:1107', (78, 83))	('si', 'Chemical', 'MESH:D012825', (144, 146))	('SCC15', 'Gene', (88, 93))	('SCC15', 'Gene', '100034867', (88, 93))	('expression', 'MPA', (33, 43))	('miR-34a-5p', 'Var', (149, 159))	('AXL', 'Gene', (47, 50))	('si', 'Chemical', 'MESH:D012825', (55, 57))
168589	30243489	After incubation with CAFs-exo (CAFs-derived exosomes), CAFs-miR-control-exo (exosomes from CAFs transfected with miR-control), or CAFs-miR-34a-5p-exo (exosomes from CAFs overexpressing miR-34a-5p), we found that the mRNA level of AXL in the CAFs-miR-34a-5p-exo treated CAL27 and SCC15 cells groups was significantly lower than that in the CAFs-exo group and CAFs-miR-control-exo group (Fig.	('AXL', 'Gene', '558', (231, 234))	('CAFs-miR-34a-5p-exo', 'Var', (242, 261))	('34a', 'Chemical', '-', (190, 193))	('AXL', 'Gene', (231, 234))	('lower', 'NegReg', (317, 322))	('CAL27', 'CellLine', 'CVCL:1107', (270, 275))	('SCC15', 'Gene', '100034867', (280, 285))	('34a', 'Chemical', '-', (251, 254))	('34a', 'Chemical', '-', (140, 143))	('SCC15', 'Gene', (280, 285))	('si', 'Chemical', 'MESH:D012825', (181, 183))	('si', 'Chemical', 'MESH:D012825', (303, 305))
168591	30243489	We used a luciferase reporter assay to determine whether miR-34a-5p could target the 3' UTR of AXL directly.	('AXL', 'Gene', (95, 98))	('AXL', 'Gene', '558', (95, 98))	('34a', 'Chemical', '-', (61, 64))	('miR-34a-5p', 'Var', (57, 67))
168592	30243489	We cloned the 3' UTR fragment (WT-AXL) of AXL containing a miR-34a-5p binding site and mutant fragments (MUT-AXL) into luciferase reporter vectors.	('AXL', 'Gene', (42, 45))	('AXL', 'Gene', '558', (109, 112))	('AXL', 'Gene', '558', (34, 37))	('mutant', 'Var', (87, 93))	('si', 'Chemical', 'MESH:D012825', (78, 80))	('AXL', 'Gene', (109, 112))	('AXL', 'Gene', '558', (42, 45))	('34a', 'Chemical', '-', (63, 66))	('AXL', 'Gene', (34, 37))
168593	30243489	We found that miR-34a-5p could significantly reduce WT-AXL luciferase activity in both CAL27 and SCC15 cells, and that miR-34a-5p had no effect on the luciferase activity of MUT-AXL group (Fig.	('si', 'Chemical', 'MESH:D012825', (31, 33))	('activity', 'MPA', (70, 78))	('AXL', 'Gene', '558', (178, 181))	('SCC15', 'Gene', '100034867', (97, 102))	('SCC15', 'Gene', (97, 102))	('miR-34a-5p', 'Var', (119, 129))	('34a', 'Chemical', '-', (123, 126))	('reduce', 'NegReg', (45, 51))	('AXL', 'Gene', '558', (55, 58))	('CAL27', 'CellLine', 'CVCL:1107', (87, 92))	('AXL', 'Gene', (178, 181))	('miR-34a-5p', 'Var', (14, 24))	('34a', 'Chemical', '-', (18, 21))	('AXL', 'Gene', (55, 58))
168598	30243489	The colony formation, proliferation, and mobility of SCC15 cells decreased significantly after AXL knockdown, and AXL overexpression increased the colony formation, proliferation, and mobility of CAL27 cells (Figs.	('colon', 'Disease', (4, 9))	('decreased', 'NegReg', (65, 74))	('AXL', 'Gene', '558', (114, 117))	('proliferation', 'CPA', (165, 178))	('colon', 'Disease', 'MESH:D015179', (147, 152))	('si', 'Chemical', 'MESH:D012825', (128, 130))	('colon', 'Disease', (147, 152))	('knockdown', 'Var', (99, 108))	('SCC15', 'Gene', (53, 58))	('proliferation', 'CPA', (22, 35))	('AXL', 'Gene', '558', (95, 98))	('AXL', 'Gene', (114, 117))	('SCC15', 'Gene', '100034867', (53, 58))	('CAL27', 'CellLine', 'CVCL:1107', (196, 201))	('mobility', 'CPA', (41, 49))	('si', 'Chemical', 'MESH:D012825', (75, 77))	('AXL', 'Gene', (95, 98))	('mobility', 'CPA', (184, 192))	('colon', 'Disease', 'MESH:D015179', (4, 9))	('increased', 'PosReg', (133, 142))
168599	30243489	Next, we transfected both a lentiviral plasmid containing pre-miR-34a-5p and a plasmid containing full-length AXL.	('34a', 'Chemical', '-', (66, 69))	('pre-miR-34a-5p', 'Var', (58, 72))	('AXL', 'Gene', '558', (110, 113))	('AXL', 'Gene', (110, 113))
168600	30243489	AXL overexpression counteracted the effects of miR-34a-5p in CAL27 cells (Figs.	('si', 'Chemical', 'MESH:D012825', (14, 16))	('miR-34a-5p', 'Var', (47, 57))	('AXL', 'Gene', '558', (0, 3))	('CAL27', 'CellLine', 'CVCL:1107', (61, 66))	('overexpression', 'PosReg', (4, 18))	('AXL', 'Gene', (0, 3))	('34a', 'Chemical', '-', (51, 54))
168603	30243489	Overexpression of miR-34a-5p in CAL27 cells could decrease the amount of active beta-catenin in the nucleus (Fig.	('34a', 'Chemical', '-', (22, 25))	('CAL27', 'CellLine', 'CVCL:1107', (32, 37))	('beta-catenin', 'Gene', (80, 92))	('beta-catenin', 'Gene', '1499', (80, 92))	('miR-34a-5p', 'Var', (18, 28))	('si', 'Chemical', 'MESH:D012825', (10, 12))	('decrease', 'NegReg', (50, 58))
168604	30243489	Moreover, these effects of overexpressing miR-34a-5p could be rescued by upregulating AXL expression ectopically (Fig.	('AXL', 'Gene', (86, 89))	('34a', 'Chemical', '-', (46, 49))	('si', 'Chemical', 'MESH:D012825', (37, 39))	('miR-34a-5p', 'Var', (42, 52))	('upregulating', 'PosReg', (73, 85))	('AXL', 'Gene', '558', (86, 89))	('si', 'Chemical', 'MESH:D012825', (96, 98))
168605	30243489	Meanwhile, immunofluorescence staining showed that miR-34a-5p overexpression markedly decreased the activation of beta-catenin in the nucleus, and that AXL overexpression could upregulate the activation of beta-catenin (Fig.	('AXL', 'Gene', '558', (152, 155))	('beta-catenin', 'Gene', (114, 126))	('upregulate', 'PosReg', (177, 187))	('beta-catenin', 'Gene', '1499', (206, 218))	('si', 'Chemical', 'MESH:D012825', (166, 168))	('AXL', 'Gene', (152, 155))	('activation', 'MPA', (100, 110))	('beta-catenin', 'Gene', '1499', (114, 126))	('si', 'Chemical', 'MESH:D012825', (72, 74))	('decreased', 'NegReg', (86, 95))	('miR-34a-5p', 'Var', (51, 61))	('34a', 'Chemical', '-', (55, 58))	('beta-catenin', 'Gene', (206, 218))
168607	30243489	We found that overexpression of miR-34a-5p markedly suppressed the phosphorylation of GSK-3beta and AKT in CAL27 cells, consequently causing a decrease in vimentin levels and an increase in the expression of E-cadherin (Fig.	('GSK-3beta', 'Gene', (86, 95))	('si', 'Chemical', 'MESH:D012825', (136, 138))	('AKT', 'Gene', (100, 103))	('increase', 'PosReg', (178, 186))	('si', 'Chemical', 'MESH:D012825', (24, 26))	('E-cadherin', 'Gene', (208, 218))	('34a', 'Chemical', '-', (36, 39))	('E-cadherin', 'Gene', '999', (208, 218))	('suppressed', 'NegReg', (52, 62))	('AKT', 'Gene', '207', (100, 103))	('phosphorylation', 'MPA', (67, 82))	('vimentin', 'Gene', '7431', (155, 163))	('CAL27', 'CellLine', 'CVCL:1107', (107, 112))	('vimentin', 'Gene', (155, 163))	('miR-34a-5p', 'Var', (32, 42))	('decrease', 'NegReg', (143, 151))	('GSK-3beta', 'Gene', '2932', (86, 95))	('expression', 'MPA', (194, 204))	('si', 'Chemical', 'MESH:D012825', (200, 202))
168608	30243489	However, AXL overexpression in miR-34a-5p transfected CAL27 cells antogonized the effect of miR-34a-5p on the phosphorylation of GSK-3beta and AKT (Fig.	('miR-34a-5p', 'Var', (92, 102))	('si', 'Chemical', 'MESH:D012825', (23, 25))	('GSK-3beta', 'Gene', (129, 138))	('AXL', 'Gene', (9, 12))	('34a', 'Chemical', '-', (96, 99))	('overexpression', 'PosReg', (13, 27))	('phosphorylation', 'MPA', (110, 125))	('antogonized', 'NegReg', (66, 77))	('CAL27', 'CellLine', 'CVCL:1107', (54, 59))	('AKT', 'Gene', '207', (143, 146))	('miR-34a-5p', 'Var', (31, 41))	('34a', 'Chemical', '-', (35, 38))	('GSK-3beta', 'Gene', '2932', (129, 138))	('AKT', 'Gene', (143, 146))	('AXL', 'Gene', '558', (9, 12))
168610	30243489	A marked decrease in active GSK-3beta, active beta-catenin, active AKT, and vimentin, and upregulation of E-cadherin was observed after AXL knockdown.	('GSK-3beta', 'Gene', '2932', (28, 37))	('GSK-3beta', 'Gene', (28, 37))	('AKT', 'Gene', '207', (67, 70))	('vimentin', 'Gene', '7431', (76, 84))	('AXL', 'Gene', (136, 139))	('upregulation', 'PosReg', (90, 102))	('beta-catenin', 'Gene', (46, 58))	('AKT', 'Gene', (67, 70))	('AXL', 'Gene', '558', (136, 139))	('vimentin', 'Gene', (76, 84))	('beta-catenin', 'Gene', '1499', (46, 58))	('E-cadherin', 'Gene', (106, 116))	('E-cadherin', 'Gene', '999', (106, 116))	('knockdown', 'Var', (140, 149))	('decrease', 'NegReg', (9, 17))
168619	30243489	We found that the expression levels of AXL, beta-catenin, Snail, vimentin, MMP-2, and MMP-9 were decreased in the miR-34a-5p overexpressing group, and the expression of E-cadherin was elevated at the same time.	('MMP-9', 'Gene', '4318', (86, 91))	('MMP-9', 'Gene', (86, 91))	('decreased', 'NegReg', (97, 106))	('AXL', 'Gene', (39, 42))	('si', 'Chemical', 'MESH:D012825', (161, 163))	('vimentin', 'Gene', '7431', (65, 73))	('overexpressing', 'PosReg', (125, 139))	('vimentin', 'Gene', (65, 73))	('si', 'Chemical', 'MESH:D012825', (135, 137))	('34a', 'Chemical', '-', (118, 121))	('Snail', 'Gene', (58, 63))	('MMP-2', 'Gene', '4313', (75, 80))	('miR-34a-5p', 'Var', (114, 124))	('si', 'Chemical', 'MESH:D012825', (24, 26))	('E-cadherin', 'Gene', (169, 179))	('E-cadherin', 'Gene', '999', (169, 179))	('elevated', 'PosReg', (184, 192))	('beta-catenin', 'Gene', (44, 56))	('beta-catenin', 'Gene', '1499', (44, 56))	('MMP-2', 'Gene', (75, 80))	('AXL', 'Gene', '558', (39, 42))	('expression levels', 'MPA', (18, 35))	('expression', 'MPA', (155, 165))	('Snail', 'Gene', '6615', (58, 63))
168626	30243489	Furthermore, we found that miR-34a-5p could suppress OSCC cell proliferation and motility by targeting AXL.	('targeting', 'Reg', (93, 102))	('AXL', 'Gene', (103, 106))	('OS', 'Phenotype', 'HP:0002669', (53, 55))	('OSCC', 'Disease', (53, 57))	('suppress', 'NegReg', (44, 52))	('miR-34a-5p', 'Var', (27, 37))	('AXL', 'Gene', '558', (103, 106))	('motility', 'CPA', (81, 89))	('34a', 'Chemical', '-', (31, 34))
168637	30243489	Our results showed that the expression of miR-34a-5p in NFs was downregulated when they were treated with TGF-beta1.	('34a', 'Chemical', '-', (46, 49))	('expression', 'MPA', (28, 38))	('miR-34a-5p', 'Var', (42, 52))	('si', 'Chemical', 'MESH:D012825', (34, 36))	('TGF-beta1', 'Gene', '7040', (106, 115))	('TGF-beta1', 'Gene', (106, 115))	('downregulated', 'NegReg', (64, 77))
168638	30243489	We also found that overexpression of cy3-labeled miR-34a-5p in CAFs leads to an increase of exosomal miR-34a-5p in the OSCC cells, suggesting that oral cancer cells absorb CAFs-derived miR-34a-5p via exosomes.	('overexpression', 'PosReg', (19, 33))	('exosomal miR-34a-5p', 'MPA', (92, 111))	('si', 'Chemical', 'MESH:D012825', (29, 31))	('34a', 'Chemical', '-', (105, 108))	('34a', 'Chemical', '-', (189, 192))	('increase', 'PosReg', (80, 88))	('cy3-labeled miR-34a-5p', 'Var', (37, 59))	('oral cancer', 'Disease', 'MESH:D009062', (147, 158))	('34a', 'Chemical', '-', (53, 56))	('oral cancer', 'Disease', (147, 158))	('cy3', 'Chemical', '-', (37, 40))	('OS', 'Phenotype', 'HP:0002669', (119, 121))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('miR-34a-5p', 'Var', (49, 59))
168642	30243489	Although studies have shown the effect of dysregulated miR-34a-5p in colorectal cancer and osteosarcoma, the underlying mechanisms of miR-34a-5p in OSCC progression have not been elucidated.	('OS', 'Phenotype', 'HP:0002669', (148, 150))	('colorectal cancer', 'Disease', 'MESH:D015179', (69, 86))	('colorectal cancer', 'Phenotype', 'HP:0003003', (69, 86))	('si', 'Chemical', 'MESH:D012825', (160, 162))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('miR-34a-5p', 'Gene', (55, 65))	('effect', 'Reg', (32, 38))	('colorectal cancer', 'Disease', (69, 86))	('osteosarcoma', 'Phenotype', 'HP:0002669', (91, 103))	('osteosarcoma', 'Disease', (91, 103))	('osteosarcoma', 'Disease', 'MESH:D012516', (91, 103))	('34a', 'Chemical', '-', (59, 62))	('34a', 'Chemical', '-', (138, 141))	('dysregulated', 'Var', (42, 54))
168643	30243489	Our study provides evidence that miR-34a-5p overexpression could inhibit the proliferation and motility of OSCC cells in vitro and in vivo.	('miR-34a-5p', 'Var', (33, 43))	('si', 'Chemical', 'MESH:D012825', (54, 56))	('34a', 'Chemical', '-', (37, 40))	('motility of OSCC cells', 'CPA', (95, 117))	('overexpression', 'PosReg', (44, 58))	('inhibit', 'NegReg', (65, 72))	('OS', 'Phenotype', 'HP:0002669', (107, 109))	('proliferation', 'CPA', (77, 90))
168644	30243489	To confirm the effects of CAFs-derived miR-34a-5p-devoid exosomes on tumorigenicity of OSCC cells, we co-injected CAL27 cells with CAFs overexpressing miR-34a-5p into nude mice.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('CAL27', 'CellLine', 'CVCL:1107', (114, 119))	('si', 'Chemical', 'MESH:D012825', (146, 148))	('tumor', 'Disease', (69, 74))	('34a', 'Chemical', '-', (43, 46))	('nude mice', 'Species', '10090', (167, 176))	('OS', 'Phenotype', 'HP:0002669', (87, 89))	('miR-34a-5p', 'Var', (151, 161))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('34a', 'Chemical', '-', (155, 158))
168645	30243489	We found that CAFs-miR-34a-5p significantly inhibited tumor growth in vivo.	('34a', 'Chemical', '-', (23, 26))	('inhibited', 'NegReg', (44, 53))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('si', 'Chemical', 'MESH:D012825', (30, 32))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('CAFs-miR-34a-5p', 'Var', (14, 29))	('tumor', 'Disease', (54, 59))
168647	30243489	In our search for a direct target for miR-34a-5p, we performed bioinformatics analysis and identified a sequence complementary to miR-34a-5p in the 3' UTR region of the AXL mRNA.	('AXL', 'Gene', (169, 172))	('miR-34a-5p', 'Var', (130, 140))	('34a', 'Chemical', '-', (134, 137))	('AXL', 'Gene', '558', (169, 172))	('34a', 'Chemical', '-', (42, 45))	('si', 'Chemical', 'MESH:D012825', (83, 85))
168648	30243489	Furthermore, we found that ectopic expression of miR-34a-5p significantly downregulated the expression of AXL in OSCC cells.	('OS', 'Phenotype', 'HP:0002669', (113, 115))	('34a', 'Chemical', '-', (53, 56))	('AXL', 'Gene', '558', (106, 109))	('si', 'Chemical', 'MESH:D012825', (60, 62))	('si', 'Chemical', 'MESH:D012825', (98, 100))	('si', 'Chemical', 'MESH:D012825', (41, 43))	('miR-34a-5p', 'Var', (49, 59))	('AXL', 'Gene', (106, 109))	('downregulated', 'NegReg', (74, 87))	('expression', 'MPA', (92, 102))
168651	30243489	In the present study, we found that reintroduction of AXL in miR-34a-5p-overexpressing OSCC cells antagonized the effect of miR-34a-5p on the proliferation and motility of OSCC cells, suggesting that the miR-34a-5p/AXL axis plays an important role in OSCC progression.	('34a', 'Chemical', '-', (128, 131))	('si', 'Chemical', 'MESH:D012825', (263, 265))	('34a', 'Chemical', '-', (208, 211))	('proliferation', 'CPA', (142, 155))	('AXL', 'Gene', '558', (215, 218))	('AXL', 'Gene', '558', (54, 57))	('AXL', 'Gene', (215, 218))	('motility', 'CPA', (160, 168))	('AXL', 'Gene', (54, 57))	('reintroduction', 'Var', (36, 50))	('si', 'Chemical', 'MESH:D012825', (82, 84))	('OSCC', 'Disease', (251, 255))	('OS', 'Phenotype', 'HP:0002669', (172, 174))	('OS', 'Phenotype', 'HP:0002669', (87, 89))	('miR-34a-5p-overexpressing', 'Gene', (61, 86))	('OS', 'Phenotype', 'HP:0002669', (251, 253))	('34a', 'Chemical', '-', (65, 68))	('antagonized', 'NegReg', (98, 109))
168656	30243489	We further validated that EMT in miR-34a-5p and AXL-transfected OSCC cells was associated with the activation of the AKT/GSK-3beta/beta-catenin signaling pathway.	('AKT', 'Gene', '207', (117, 120))	('miR-34a-5p', 'Var', (33, 43))	('AXL', 'Gene', (48, 51))	('beta-catenin', 'Gene', (131, 143))	('GSK-3beta', 'Gene', (121, 130))	('GSK-3beta', 'Gene', '2932', (121, 130))	('34a', 'Chemical', '-', (37, 40))	('AKT', 'Gene', (117, 120))	('OS', 'Phenotype', 'HP:0002669', (64, 66))	('activation', 'PosReg', (99, 109))	('si', 'Chemical', 'MESH:D012825', (144, 146))	('beta-catenin', 'Gene', '1499', (131, 143))	('EMT', 'CPA', (26, 29))	('AXL', 'Gene', '558', (48, 51))
168657	30243489	Interestingly, AXL and beta-catenin knockdown decreased the expression of Snail, a canonical EMT-inducing transcription factor.	('expression', 'MPA', (60, 70))	('knockdown', 'Var', (36, 45))	('beta-catenin', 'Gene', (23, 35))	('AXL', 'Gene', (15, 18))	('beta-catenin', 'Gene', '1499', (23, 35))	('decreased', 'NegReg', (46, 55))	('si', 'Chemical', 'MESH:D012825', (66, 68))	('Snail', 'Gene', '6615', (74, 79))	('Snail', 'Gene', (74, 79))	('AXL', 'Gene', '558', (15, 18))
168661	30243489	Accumulating evidence indicates that high expression of Snail in patients with OSCC or hepatocellular carcinoma (HCC) is a predictor for shorter survival and poor prognosis.	('high expression', 'Var', (37, 52))	('shorter', 'NegReg', (137, 144))	('si', 'Chemical', 'MESH:D012825', (169, 171))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (87, 111))	('OSCC or hepatocellular carcinoma', 'Disease', 'MESH:D006528', (79, 111))	('HCC', 'Phenotype', 'HP:0001402', (113, 116))	('Snail', 'Gene', '6615', (56, 61))	('Snail', 'Gene', (56, 61))	('patients', 'Species', '9606', (65, 73))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('OSCC or hepatocellular carcinoma', 'Disease', (79, 111))	('si', 'Chemical', 'MESH:D012825', (48, 50))	('OS', 'Phenotype', 'HP:0002669', (79, 81))
168667	30243489	In conclusion, our findings showed that OSCC cells gain a more aggressive phenotype in the tumor microenvironment by taking up miR-34a-5p-devoid exosomes derived from CAFs.	('miR-34a-5p-devoid', 'Var', (127, 144))	('34a', 'Chemical', '-', (131, 134))	('aggressive', 'CPA', (63, 73))	('OS', 'Phenotype', 'HP:0002669', (40, 42))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('si', 'Chemical', 'MESH:D012825', (9, 11))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor', 'Disease', (91, 96))	('si', 'Chemical', 'MESH:D012825', (69, 71))
168668	30243489	In addition, the transfer of miR-34a-5p could affect the proliferation and motility of OSCC cells through the AKT/GSK-3beta/beta-catenin/Snail signaling cascade (Fig.	('beta-catenin', 'Gene', (124, 136))	('AKT', 'Gene', (110, 113))	('beta-catenin', 'Gene', '1499', (124, 136))	('GSK-3beta', 'Gene', '2932', (114, 123))	('GSK-3beta', 'Gene', (114, 123))	('Snail', 'Gene', (137, 142))	('affect', 'Reg', (46, 52))	('Snail', 'Gene', '6615', (137, 142))	('34a', 'Chemical', '-', (33, 36))	('transfer', 'Var', (17, 25))	('si', 'Chemical', 'MESH:D012825', (143, 145))	('proliferation', 'CPA', (57, 70))	('motility', 'CPA', (75, 83))	('OS', 'Phenotype', 'HP:0002669', (87, 89))	('AKT', 'Gene', '207', (110, 113))	('miR-34a-5p', 'Var', (29, 39))
168690	28881780	We observed a strong correlation between expression of PD-L1 and reduced overall survival time.	('expression', 'Var', (41, 51))	('reduced', 'NegReg', (65, 72))	('PD-L1', 'Gene', '29126', (55, 60))	('overall survival time', 'CPA', (73, 94))	('PD-L1', 'Gene', (55, 60))
168691	28881780	Furthermore, high PD-L1 expression was identified as a strong prognostic factor of patient's outcome when verified together with recognized prognostic factors.	('expression', 'MPA', (24, 34))	('high', 'Var', (13, 17))	('patient', 'Species', '9606', (83, 90))	('PD-L1', 'Gene', (18, 23))	('PD-L1', 'Gene', '29126', (18, 23))
168701	28881780	Co-expression of PD-L1 and its receptor PD-1 (programmed death 1) causes inhibition of lymphocyte proliferation and cytokine secretion mediated by T-cell receptor.	('cytokine secretion mediated by', 'MPA', (116, 146))	('PD-1', 'Gene', '5133', (40, 44))	('PD-L1', 'Gene', '29126', (17, 22))	('inhibition', 'NegReg', (73, 83))	('lymphocyte proliferation', 'CPA', (87, 111))	('Co-expression', 'Var', (0, 13))	('PD-L1', 'Gene', (17, 22))	('PD-1', 'Gene', (40, 44))
168707	28881780	Brahmer and colleagues demonstrated that inhibition of PD-1 using an anti-PD-1-antibody enhanced objective response rates of 6% to 17% and prolonged disease stabilization in patients with metastatic non-small-cell lung cancer, melanoma, renal-cell-carcinoma and ovarian cancer.	('enhanced', 'PosReg', (88, 96))	('disease stabilization', 'CPA', (149, 170))	('PD-1', 'Gene', (74, 78))	('lung cancer', 'Disease', (214, 225))	('melanoma', 'Disease', 'MESH:D008545', (227, 235))	('PD-1', 'Gene', '5133', (74, 78))	('inhibition', 'Var', (41, 51))	('cancer', 'Phenotype', 'HP:0002664', (270, 276))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (203, 225))	('renal-cell-carcinoma', 'Phenotype', 'HP:0005584', (237, 257))	('PD-1', 'Gene', (55, 59))	('PD-1', 'Gene', '5133', (55, 59))	('lung cancer', 'Disease', 'MESH:D008175', (214, 225))	('lung cancer', 'Phenotype', 'HP:0100526', (214, 225))	('melanoma', 'Phenotype', 'HP:0002861', (227, 235))	('melanoma', 'Disease', (227, 235))	('renal-cell-carcinoma and ovarian cancer', 'Disease', 'MESH:C538614', (237, 276))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('ovarian cancer', 'Phenotype', 'HP:0100615', (262, 276))	('patients', 'Species', '9606', (174, 182))	('objective response', 'CPA', (97, 115))	('carcinoma', 'Phenotype', 'HP:0030731', (248, 257))
168712	28881780	Multivariate analysis identified high PD-L1 expression as an independent risk factor in males and smokers.	('high', 'Var', (33, 37))	('expression', 'MPA', (44, 54))	('PD-L1', 'Gene', (38, 43))	('PD-L1', 'Gene', '29126', (38, 43))
168730	28881780	Interestingly, there was an association between high PD-L2 expression and the occurrence of hemangiosis carcinomatosis in both cohorts (first cohort: p=0.030; second cohort: p=0.044).	('hemangiosis carcinomatosis', 'Disease', 'MESH:D002277', (92, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('PD-L2', 'Gene', (53, 58))	('PD-L2', 'Gene', '80380', (53, 58))	('hemangiosis carcinomatosis', 'Disease', (92, 118))	('expression', 'MPA', (59, 69))	('high', 'Var', (48, 52))
168734	28881780	Mean survival time in HNSCC showing low and high PD-L1 expression was 1452 days vs. 735 days in the first cohort, and 2045 days vs. 989 days in the second cohort, respectively.	('PD-L1', 'Gene', (49, 54))	('high', 'Var', (44, 48))	('PD-L1', 'Gene', '29126', (49, 54))	('HNSCC', 'Phenotype', 'HP:0012288', (22, 27))
168735	28881780	In both cohorts staining intensity of PD-L1 proved to be a prognostic factor for overall survival time in univariate proportional hazards model analysis (first cohort: p=0.002, HR=4.269 [95%Cl=1.733 - 10.514]; second cohort: p<0.0001, HR=2.845 [95%CI=1.808 - 4.479]).	('staining', 'Var', (16, 24))	('PD-L1', 'Gene', (38, 43))	('PD-L1', 'Gene', '29126', (38, 43))
168736	28881780	In a multivariate cox proportional hazards model, high expression of PD-L1 prevailed to be an independent and in fact the strongest prognostic factor of patient's outcome, even when verified together with recognized prognostic factors like tumor size, lymph node involvement, distant metastases, surgical margin status, lymphatic invasion, vascular invasion, grading, and extracapsular expansion (p=0.02; HR=2.926 [95%CI=1.183 - 7.235]; Table 3).	('cox', 'Gene', (18, 21))	('high expression', 'Var', (50, 65))	('metastases', 'Disease', 'MESH:D009362', (284, 294))	('PD-L1', 'Gene', '29126', (69, 74))	('tumor', 'Disease', (240, 245))	('metastases', 'Disease', (284, 294))	('cox', 'Gene', '1351', (18, 21))	('patient', 'Species', '9606', (153, 160))	('tumor', 'Disease', 'MESH:D009369', (240, 245))	('extracapsular expansion', 'CPA', (372, 395))	('PD-L1', 'Gene', (69, 74))	('tumor', 'Phenotype', 'HP:0002664', (240, 245))
168748	28881780	Remarkably, in both the univariate and multivariate analysis, PD-L1 expression was a strong predictor for poor outcome, even leaving tumor stage and distant metastasis behind.	('distant metastasis', 'CPA', (149, 167))	('PD-L1', 'Gene', '29126', (62, 67))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('leaving', 'Reg', (125, 132))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('expression', 'Var', (68, 78))	('tumor', 'Disease', (133, 138))	('PD-L1', 'Gene', (62, 67))
168749	28881780	We did also demonstrate an association between distant metastases and high PD-L1 expression in the primary tumor, suggesting that metastases might be supported by a disrupted antitumor immune response.	('metastases', 'Disease', (55, 65))	('metastases', 'Disease', 'MESH:D009362', (130, 140))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('PD-L1', 'Gene', (75, 80))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('metastases', 'Disease', 'MESH:D009362', (55, 65))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('metastases', 'Disease', (130, 140))	('PD-L1', 'Gene', '29126', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('high', 'Var', (70, 74))	('expression', 'MPA', (81, 91))	('tumor', 'Disease', (179, 184))
168750	28881780	Lin et al., who investigated the influence of PD-L1 expression on oral HNSCC in an Asian cohort, further described a correlation between high PD-L1 expression in smokers and overall survival time.	('PD-L1', 'Gene', (46, 51))	('PD-L1', 'Gene', '29126', (142, 147))	('PD-L1', 'Gene', '29126', (46, 51))	('high', 'Var', (137, 141))	('overall survival time', 'CPA', (174, 195))	('HNSCC', 'Phenotype', 'HP:0012288', (71, 76))	('expression', 'MPA', (148, 158))	('PD-L1', 'Gene', (142, 147))
168752	28881780	Interestingly, in a minor subset of oral HNSCC, PD-L1 amplifications seem to be responsible for PD-L1 overexpression, as demonstrated by Straub et al.	('PD-L1', 'Gene', '29126', (48, 53))	('PD-L1', 'Gene', '29126', (96, 101))	('HNSCC', 'Phenotype', 'HP:0012288', (41, 46))	('overexpression', 'PosReg', (102, 116))	('PD-L1', 'Gene', (48, 53))	('PD-L1', 'Gene', (96, 101))	('responsible', 'Reg', (80, 91))	('amplifications', 'Var', (54, 68))
168753	28881780	In spite of that, PD-L1 amplification was not associated with unfavorable prognostic factors or outcome.	('PD-L1', 'Gene', (18, 23))	('amplification', 'Var', (24, 37))	('PD-L1', 'Gene', '29126', (18, 23))
168757	28881780	In contrast, we found an association of high PD-L2 expression and hemangiosis carcinomatosa as well as advanced tumor stage.	('high', 'Var', (40, 44))	('hemangiosis carcinomatosa', 'Disease', 'None', (66, 91))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('association', 'Interaction', (25, 36))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('expression', 'MPA', (51, 61))	('tumor', 'Disease', (112, 117))	('hemangiosis carcinomatosa', 'Disease', (66, 91))	('PD-L2', 'Gene', (45, 50))	('PD-L2', 'Gene', '80380', (45, 50))
168767	28881780	Lastly, our results indicate that even small and localized HNSCC with high PD-L1 expression potentially follow an unfavorable clinical course, and thus might benefit from early treatment with check-point inhibitors and provide the rationale for the use of these approaches in the adjuvant setting.	('follow', 'Reg', (104, 110))	('PD-L1', 'Gene', (75, 80))	('benefit', 'Reg', (158, 165))	('PD-L1', 'Gene', '29126', (75, 80))	('high', 'Var', (70, 74))	('HNSCC', 'Phenotype', 'HP:0012288', (59, 64))	('expression', 'MPA', (81, 91))	('HNSCC', 'Disease', (59, 64))
168795	24205020	Association of X-ray Repair Cross Complementing Group 1 Arg399Gln Polymorphisms with the Risk of Squamous Cell Carcinoma of the Head and Neck: Evidence from an Updated Meta-Analysis Epidemiologic studies have reported the association of X-ray repair cross-complementary group 1 (XRCC1) Arg399Gln polymorphisms with susceptibility to squamous cell carcinoma of the head and neck (HNSCC).	('Arg399Gln', 'SUBSTITUTION', 'None', (56, 65))	('Arg399Gln', 'SUBSTITUTION', 'None', (286, 295))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (333, 356))	('Squamous Cell Carcinoma', 'Disease', 'MESH:D002294', (97, 120))	('X-ray repair cross-complementary group 1', 'Gene', (237, 277))	('association', 'Interaction', (222, 233))	('X-ray repair cross-complementary group 1', 'Gene', '7515', (237, 277))	('XRCC1', 'Gene', '7515', (279, 284))	('Arg399Gln', 'Var', (56, 65))	('Arg399Gln', 'Var', (286, 295))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (97, 120))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (333, 356))	('carcinoma', 'Phenotype', 'HP:0030731', (347, 356))	('Squamous Cell Carcinoma', 'Disease', (97, 120))	('X-ray Repair Cross Complementing Group 1', 'Gene', '7515', (15, 55))	('carcinoma of the head and neck', 'Phenotype', 'HP:0012288', (347, 377))	('squamous cell carcinoma', 'Disease', (333, 356))	('X-ray Repair Cross Complementing Group 1', 'Gene', (15, 55))	('Carcinoma of the Head and Neck', 'Phenotype', 'HP:0012288', (111, 141))	('XRCC1', 'Gene', (279, 284))	('Carcinoma', 'Phenotype', 'HP:0030731', (111, 120))
168796	24205020	The purpose of this study was to clarify the association of XRCC1 Arg399Gln variants with HNSCC risk.	('association', 'Interaction', (45, 56))	('HNSCC', 'Disease', (90, 95))	('XRCC1', 'Gene', (60, 65))	('Arg399Gln', 'SUBSTITUTION', 'None', (66, 75))	('Arg399Gln', 'Var', (66, 75))	('XRCC1', 'Gene', '7515', (60, 65))
168797	24205020	Overall, we did not observe any association of XRCC1 Arg399Gln polymorphisms with HNSCC risk in total population (OR = 0.95, 95% CI: 0.76-1.19 for Gln/Gln vs. Arg/Arg, OR = 1.05, 95% CI: 0.92-1.20 for Arg/Gln vs. Arg/Arg, and OR = 1.03, 95% CI: 0.90-1.18 for Gln/Gln+Arg/Gln vs. Arg/Arg) based on 18 studies including 3917 cases and 4560 controls.	('Arg', 'Chemical', 'MESH:D001120', (201, 204))	('XRCC1', 'Gene', (47, 52))	('Gln', 'Chemical', 'MESH:D005973', (263, 266))	('Gln', 'Chemical', 'MESH:D005973', (151, 154))	('Arg', 'Chemical', 'MESH:D001120', (159, 162))	('Arg', 'Chemical', 'MESH:D001120', (279, 282))	('Arg', 'Chemical', 'MESH:D001120', (217, 220))	('Gln', 'Chemical', 'MESH:D005973', (205, 208))	('Arg', 'Chemical', 'MESH:D001120', (213, 216))	('Arg399Gln', 'SUBSTITUTION', 'None', (53, 62))	('XRCC1', 'Gene', '7515', (47, 52))	('Arg/Gln', 'Var', (201, 208))	('Gln/Gln+Arg/Gln', 'Var', (259, 274))	('Gln', 'Chemical', 'MESH:D005973', (259, 262))	('Arg399Gln', 'Var', (53, 62))	('Gln', 'Chemical', 'MESH:D005973', (147, 150))	('Gln', 'Chemical', 'MESH:D005973', (59, 62))	('Arg', 'Chemical', 'MESH:D001120', (163, 166))	('Arg', 'Chemical', 'MESH:D001120', (283, 286))	('Arg', 'Chemical', 'MESH:D001120', (267, 270))	('HNSCC', 'Disease', (82, 87))	('Arg', 'Chemical', 'MESH:D001120', (53, 56))	('Gln', 'Chemical', 'MESH:D005973', (271, 274))
168798	24205020	In subgroup analyses, we observed an increased risk of XRCC1 399 Arg/Gln genotype for HNSCC in Caucasians (OR = 1.20, 95% CI: 1.00-1.44) and Gln/Gln genotype for larynx squamous cell carcinoma (OR = 1.63, 95% CI: 1.10-2.40).	('Gln/Gln', 'Var', (141, 148))	('Gln', 'Chemical', 'MESH:D005973', (141, 144))	('Gln', 'Chemical', 'MESH:D005973', (69, 72))	('HNSCC', 'Disease', (86, 91))	('399 Arg/Gln', 'SUBSTITUTION', 'None', (61, 72))	('Gln', 'Chemical', 'MESH:D005973', (145, 148))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (169, 192))	('carcinoma', 'Phenotype', 'HP:0030731', (183, 192))	('399 Arg/Gln', 'Var', (61, 72))	('XRCC1', 'Gene', '7515', (55, 60))	('larynx squamous cell carcinoma', 'Disease', (162, 192))	('larynx squamous cell carcinoma', 'Disease', 'MESH:D002294', (162, 192))	('XRCC1', 'Gene', (55, 60))
168799	24205020	We did not observe any association between XRCC1 Arg399Gln variants and HNSCC risk in additional subgroup analyses.	('HNSCC', 'Disease', (72, 77))	('XRCC1', 'Gene', (43, 48))	('Arg399Gln', 'Var', (49, 58))	('Arg399Gln', 'SUBSTITUTION', 'None', (49, 58))	('XRCC1', 'Gene', '7515', (43, 48))
168800	24205020	The results from this present meta-analysis suggest that XRCC1 Arg399Gln variants may contribute to HNSCC risk among Caucasians and to the risk of larynx squamous cell carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (168, 177))	('HNSCC', 'Disease', (100, 105))	('XRCC1', 'Gene', (57, 62))	('Arg399Gln', 'Var', (63, 72))	('Arg399Gln', 'SUBSTITUTION', 'None', (63, 72))	('larynx squamous cell carcinoma', 'Disease', (147, 177))	('larynx squamous cell carcinoma', 'Disease', 'MESH:D002294', (147, 177))	('XRCC1', 'Gene', '7515', (57, 62))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (154, 177))	('contribute', 'Reg', (86, 96))
168808	24205020	Several single nucleotide polymorphisms (SNP) have been identified in the XRCC1 gene, three of which (Arg194Trp, Arg280His and Arg399Gln) occur within conserved sequences, as described by Shen et al.	('Arg194Trp', 'Var', (102, 111))	('XRCC1', 'Gene', (74, 79))	('Arg399Gln', 'Var', (127, 136))	('Arg280His', 'Var', (113, 122))	('Arg399Gln', 'SUBSTITUTION', 'None', (127, 136))	('Arg194Trp', 'SUBSTITUTION', 'None', (102, 111))	('XRCC1', 'Gene', '7515', (74, 79))	('Arg280His', 'SUBSTITUTION', 'None', (113, 122))
168809	24205020	A polymorphism Arg399Gln (rs25487) leads to amino acid substitutions (exon 10, G-A).	('rs25487', 'Mutation', 'rs25487', (26, 33))	('substitutions', 'Var', (55, 68))	('leads to', 'Reg', (35, 43))	('Arg399Gln', 'Var', (15, 24))	('Arg399Gln', 'SUBSTITUTION', 'None', (15, 24))
168810	24205020	This mutation could alter XRCC1 function, diminish repair kinetics, and influence susceptibility to adverse health effect, such as cancer.	('cancer', 'Disease', (131, 137))	('XRCC1', 'Gene', (26, 31))	('repair kinetics', 'MPA', (51, 66))	('alter', 'Reg', (20, 25))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('influence', 'Reg', (72, 81))	('XRCC1', 'Gene', '7515', (26, 31))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('function', 'MPA', (32, 40))	('mutation', 'Var', (5, 13))	('diminish', 'NegReg', (42, 50))
168811	24205020	To date, a number of studies have investigated the association between XRCC1 Arg399Gln polymorphisms and HNSCC risk.	('XRCC1', 'Gene', (71, 76))	('association', 'Interaction', (51, 62))	('HNSCC', 'Disease', (105, 110))	('XRCC1', 'Gene', '7515', (71, 76))	('Arg399Gln', 'Var', (77, 86))	('Arg399Gln', 'SUBSTITUTION', 'None', (77, 86))
168812	24205020	Moreover, Li et al conducted a meta-analysis on the association of XRCC1 Arg399Gln polymorphisms with HNSCC risk in 2007 and did not observe any significant association based on 7 published studies.	('XRCC1', 'Gene', (67, 72))	('Arg399Gln', 'Var', (73, 82))	('Arg399Gln', 'SUBSTITUTION', 'None', (73, 82))	('association', 'Interaction', (52, 63))	('polymorphisms', 'Var', (83, 96))	('XRCC1', 'Gene', '7515', (67, 72))	('HNSCC', 'Disease', (102, 107))
168813	24205020	Ever since, several new studies have provided additional data on the association between XRCC1 Arg399Gln polymorphisms and HNSCC risk.	('Arg399Gln', 'SUBSTITUTION', 'None', (95, 104))	('XRCC1', 'Gene', (89, 94))	('association', 'Interaction', (69, 80))	('XRCC1', 'Gene', '7515', (89, 94))	('Arg399Gln', 'Var', (95, 104))	('HNSCC', 'Disease', (123, 128))
168814	24205020	In order to address a more precise estimation of this relationship, a meta-analysis including a total of 18 studies was performed, which may provide the more comprehensive evidence for the association of XRCC1 Arg399Gln variants with HNSCC risk.	('association', 'Interaction', (189, 200))	('Arg399Gln', 'Var', (210, 219))	('Arg399Gln', 'SUBSTITUTION', 'None', (210, 219))	('XRCC1', 'Gene', '7515', (204, 209))	('HNSCC', 'Disease', (234, 239))	('XRCC1', 'Gene', (204, 209))
168816	24205020	The following criteria were used for study selection: (1) The papers should evaluate the association between XRCC1 Arg399Gln polymorphisms and HNSCC risk; (2) Case-control studies or cohort studies; (3) Sufficient data were used for estimating OR with 95% CI; (4) When more than one article was identified for the same study population, we included the publication containing more information.	('HNSCC', 'Disease', (143, 148))	('XRCC1', 'Gene', (109, 114))	('Arg399Gln', 'Var', (115, 124))	('Arg399Gln', 'SUBSTITUTION', 'None', (115, 124))	('polymorphisms', 'Var', (125, 138))	('XRCC1', 'Gene', '7515', (109, 114))	('association', 'Interaction', (89, 100))
168818	24205020	In total, 30 published articles were identified with the association between XRCC1 Arg399Gln polymorphisms and head and neck cancer risk.	('XRCC1', 'Gene', (77, 82))	('Arg399Gln', 'Var', (83, 92))	('Arg399Gln', 'SUBSTITUTION', 'None', (83, 92))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('head and neck cancer', 'Phenotype', 'HP:0012288', (111, 131))	('neck cancer', 'Disease', 'MESH:D006258', (120, 131))	('association', 'Interaction', (57, 68))	('XRCC1', 'Gene', '7515', (77, 82))	('neck cancer', 'Disease', (120, 131))
168819	24205020	At last, 18 original articles that reported the association between XRCC1 Arg399Gln polymorphisms and HNSCC risk were determined to be eligible to enter our study (Figure S1 Flow diagram).	('XRCC1', 'Gene', (68, 73))	('association', 'Interaction', (48, 59))	('HNSCC', 'Disease', (102, 107))	('Arg399Gln', 'SUBSTITUTION', 'None', (74, 83))	('Arg399Gln', 'Var', (74, 83))	('XRCC1', 'Gene', '7515', (68, 73))
168820	24205020	The strength of association between XRCC1 Arg399Gln polymorphisms and HNSCC risk was measured by OR with 95% CI.	('HNSCC', 'Disease', (70, 75))	('XRCC1', 'Gene', (36, 41))	('Arg399Gln', 'Var', (42, 51))	('Arg399Gln', 'SUBSTITUTION', 'None', (42, 51))	('XRCC1', 'Gene', '7515', (36, 41))
168821	24205020	There were a total of 18 studies with 3917 cases and 4560 controls concerning the XRCC1 Arg399Gln polymorphisms related to HNSCC risk.	('XRCC1', 'Gene', (82, 87))	('related', 'Reg', (112, 119))	('Arg399Gln', 'Var', (88, 97))	('XRCC1', 'Gene', '7515', (82, 87))	('Arg399Gln', 'SUBSTITUTION', 'None', (88, 97))	('HNSCC', 'Disease', (123, 128))
168822	24205020	The heterogeneity of XRCC1 codon 399 Gln/Gln vs. Arg/Arg, Arg/Gln vs. Arg/Arg and Gln/Gln+Arg/Gln vs. Arg/Arg was analyzed for 18 identified studies.	('Arg', 'Chemical', 'MESH:D001120', (90, 93))	('Arg', 'Chemical', 'MESH:D001120', (74, 77))	('Gln', 'Chemical', 'MESH:D005973', (62, 65))	('Arg', 'Chemical', 'MESH:D001120', (106, 109))	('Gln', 'Chemical', 'MESH:D005973', (94, 97))	('Gln', 'Chemical', 'MESH:D005973', (86, 89))	('Arg', 'Chemical', 'MESH:D001120', (49, 52))	('XRCC1', 'Gene', (21, 26))	('Arg/Gln vs. Arg/Arg', 'Var', (58, 77))	('Gln/Gln', 'Var', (37, 44))	('Gln', 'Chemical', 'MESH:D005973', (37, 40))	('Arg', 'Chemical', 'MESH:D001120', (102, 105))	('XRCC1', 'Gene', '7515', (21, 26))	('Arg', 'Chemical', 'MESH:D001120', (70, 73))	('Gln/Gln+Arg/Gln', 'Var', (82, 97))	('Arg', 'Chemical', 'MESH:D001120', (53, 56))	('Arg', 'Chemical', 'MESH:D001120', (58, 61))	('Gln', 'Chemical', 'MESH:D005973', (82, 85))	('Gln', 'Chemical', 'MESH:D005973', (41, 44))
168823	24205020	The results showed that XRCC1 codon 399 Gln/Gln vs. Arg/Arg, Arg/Gln vs. Arg/Arg and Gln/Gln+Arg/Gln vs. Arg/Arg for Caucasians and oral squamous cell carcinoma, Gln/Gln vs. Arg/Arg for healthy population-based control and larynx squamous cell carcinoma, and Arg/Gln vs. Arg/Arg for hospital-based control and healthy population-based control had no heterogeneity with a P value >=0.05, therefore, we analyzed the summary odds ratios for them with a fixed-effects model.	('Gln', 'Chemical', 'MESH:D005973', (97, 100))	('Gln/Gln', 'Var', (40, 47))	('Arg', 'Chemical', 'MESH:D001120', (52, 55))	('Arg', 'Chemical', 'MESH:D001120', (105, 108))	('Gln', 'Chemical', 'MESH:D005973', (263, 266))	('Gln', 'Chemical', 'MESH:D005973', (40, 43))	('Arg', 'Chemical', 'MESH:D001120', (271, 274))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (230, 253))	('XRCC1', 'Gene', '7515', (24, 29))	('Gln', 'Chemical', 'MESH:D005973', (166, 169))	('Gln/Gln+Arg/Gln', 'Var', (85, 100))	('Arg', 'Chemical', 'MESH:D001120', (73, 76))	('Arg/Gln', 'Var', (61, 68))	('Gln', 'Chemical', 'MESH:D005973', (85, 88))	('Arg', 'Chemical', 'MESH:D001120', (174, 177))	('carcinoma', 'Phenotype', 'HP:0030731', (244, 253))	('carcinoma', 'Phenotype', 'HP:0030731', (151, 160))	('Arg', 'Chemical', 'MESH:D001120', (61, 64))	('Arg', 'Chemical', 'MESH:D001120', (56, 59))	('Gln', 'Chemical', 'MESH:D005973', (44, 47))	('Arg', 'Chemical', 'MESH:D001120', (77, 80))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (132, 160))	('Arg', 'Chemical', 'MESH:D001120', (109, 112))	('oral squamous cell carcinoma', 'Disease', (132, 160))	('Arg', 'Chemical', 'MESH:D001120', (275, 278))	('larynx squamous cell carcinoma', 'Disease', (223, 253))	('Arg', 'Chemical', 'MESH:D001120', (93, 96))	('Gln', 'Chemical', 'MESH:D005973', (162, 165))	('XRCC1', 'Gene', (24, 29))	('larynx squamous cell carcinoma', 'Disease', 'MESH:D002294', (223, 253))	('Arg', 'Chemical', 'MESH:D001120', (259, 262))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (137, 160))	('Gln', 'Chemical', 'MESH:D005973', (89, 92))	('Arg', 'Chemical', 'MESH:D001120', (178, 181))	('Gln', 'Chemical', 'MESH:D005973', (65, 68))
168824	24205020	Table 2 listed the summary ORs of XRCC1 Arg399Gln polymorphisms related to HNSCC risk on the basis of 3917 cases and 4560 controls.	('XRCC1', 'Gene', '7515', (34, 39))	('HNSCC', 'Disease', (75, 80))	('XRCC1', 'Gene', (34, 39))	('Arg399Gln', 'Var', (40, 49))	('Arg399Gln', 'SUBSTITUTION', 'None', (40, 49))
168825	24205020	We did not observe any association of XRCC1 Arg399Gln polymorphisms with HNSCC risk in the total population (OR = 0.95, 95% CI: 0.76-1.19 for Gln/Gln vs. Arg/Arg (Fig.	('Arg399Gln', 'Var', (44, 53))	('Gln', 'Chemical', 'MESH:D005973', (142, 145))	('Arg399Gln', 'SUBSTITUTION', 'None', (44, 53))	('Gln', 'Chemical', 'MESH:D005973', (146, 149))	('HNSCC', 'Disease', (73, 78))	('XRCC1', 'Gene', (38, 43))	('Gln', 'Chemical', 'MESH:D005973', (50, 53))	('Arg', 'Chemical', 'MESH:D001120', (44, 47))	('Arg', 'Chemical', 'MESH:D001120', (158, 161))	('Arg', 'Chemical', 'MESH:D001120', (154, 157))	('Gln/Gln vs.', 'Var', (142, 153))	('XRCC1', 'Gene', '7515', (38, 43))
168826	24205020	1), OR = 1.05, 95% CI: 0.92-1.20 for Arg/Gln vs. Arg/Arg (Fig.	('Arg', 'Chemical', 'MESH:D001120', (49, 52))	('Arg/Arg', 'Var', (49, 56))	('Arg', 'Chemical', 'MESH:D001120', (53, 56))	('Arg/Gln vs.', 'Var', (37, 48))	('Arg', 'Chemical', 'MESH:D001120', (37, 40))	('Gln', 'Chemical', 'MESH:D005973', (41, 44))
168828	24205020	In subgroup analysis, we observed an increased risk of XRCC1 codon 399 Arg/Gln genotype for HNSCC in Caucasians (OR = 1.20, 95% CI: 1.00-1.44) and Gln/Gln genotype for larynx squamous cell carcinoma (OR = 1.63, 95% CI: 1.10-2.40).	('399 Arg/Gln', 'Var', (67, 78))	('larynx squamous cell carcinoma', 'Disease', (168, 198))	('XRCC1', 'Gene', '7515', (55, 60))	('carcinoma', 'Phenotype', 'HP:0030731', (189, 198))	('Gln', 'Chemical', 'MESH:D005973', (75, 78))	('HNSCC', 'Disease', (92, 97))	('Gln/Gln', 'Var', (147, 154))	('larynx squamous cell carcinoma', 'Disease', 'MESH:D002294', (168, 198))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (175, 198))	('XRCC1', 'Gene', (55, 60))	('Gln', 'Chemical', 'MESH:D005973', (147, 150))	('399 Arg/Gln', 'SUBSTITUTION', 'None', (67, 78))	('Gln', 'Chemical', 'MESH:D005973', (151, 154))
168829	24205020	We did not observe any association between XRCC1 Arg399Gln variants and HNSCC risk in additional subgroup analyses (Table 2).	('HNSCC', 'Disease', (72, 77))	('XRCC1', 'Gene', (43, 48))	('Arg399Gln', 'Var', (49, 58))	('Arg399Gln', 'SUBSTITUTION', 'None', (49, 58))	('XRCC1', 'Gene', '7515', (43, 48))
168830	24205020	The overall effects were not altered when the studies were homogenous for Gln/Gln vs. Arg/Arg, Arg/Gln vs. Arg/Arg and Gln/Gln+Arg/Gln vs. Arg/Arg among total population by removing some eligible studies (Fig.	('Arg', 'Chemical', 'MESH:D001120', (86, 89))	('Arg', 'Chemical', 'MESH:D001120', (90, 93))	('Arg/Gln', 'Var', (95, 102))	('Gln/Gln+Arg/Gln', 'Var', (119, 134))	('Gln', 'Chemical', 'MESH:D005973', (131, 134))	('Gln', 'Chemical', 'MESH:D005973', (123, 126))	('Arg', 'Chemical', 'MESH:D001120', (107, 110))	('Gln', 'Chemical', 'MESH:D005973', (78, 81))	('Arg', 'Chemical', 'MESH:D001120', (95, 98))	('Arg', 'Chemical', 'MESH:D001120', (111, 114))	('Gln/Gln', 'Var', (74, 81))	('Arg', 'Chemical', 'MESH:D001120', (139, 142))	('Gln', 'Chemical', 'MESH:D005973', (74, 77))	('Gln', 'Chemical', 'MESH:D005973', (99, 102))	('Gln', 'Chemical', 'MESH:D005973', (119, 122))	('Arg', 'Chemical', 'MESH:D001120', (127, 130))	('Arg', 'Chemical', 'MESH:D001120', (143, 146))
168831	24205020	XRCC1 is an important component of the base excision repair system, which is the predominant DNA repair pathway for small base lesions resulting from oxidation and alkylation damage.	('alkylation damage', 'Disease', (164, 181))	('alkylation damage', 'Disease', 'MESH:D004194', (164, 181))	('oxidation', 'Var', (150, 159))	('XRCC1', 'Gene', (0, 5))	('XRCC1', 'Gene', '7515', (0, 5))
168833	24205020	More than 300 validated single nucleotide polymorphisms in the XRCC1 gene were reported in the dbSNP database (http://www.ncbi.nlm.nih.gov/SNP), among them, rs25487 in XRCC1 codon 399 of exon 10 was the most extensively studied polymorphic site.	('XRCC1', 'Gene', '7515', (168, 173))	('XRCC1', 'Gene', (63, 68))	('rs25487 in', 'Var', (157, 167))	('rs25487', 'Mutation', 'rs25487', (157, 164))	('XRCC1', 'Gene', (168, 173))	('XRCC1', 'Gene', '7515', (63, 68))
168834	24205020	Recently, meta-analysis studies have reported that XRCC1 Arg399Gln variant was associated with the risk of certain cancers, such as breast cancer, nasopharyngeal carcinoma, cervical carcinoma and glioma.	('associated', 'Reg', (79, 89))	('cancers', 'Phenotype', 'HP:0002664', (115, 122))	('cancers', 'Disease', (115, 122))	('XRCC1', 'Gene', '7515', (51, 56))	('Arg399Gln', 'Var', (57, 66))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (147, 171))	('glioma', 'Phenotype', 'HP:0009733', (196, 202))	('carcinoma', 'Phenotype', 'HP:0030731', (182, 191))	('breast cancer', 'Phenotype', 'HP:0003002', (132, 145))	('cancers', 'Disease', 'MESH:D009369', (115, 122))	('breast cancer', 'Disease', 'MESH:D001943', (132, 145))	('XRCC1', 'Gene', (51, 56))	('breast cancer', 'Disease', (132, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (162, 171))	('nasopharyngeal carcinoma', 'Disease', (147, 171))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('carcinoma and glioma', 'Disease', 'MESH:D005910', (182, 202))	('Arg399Gln', 'SUBSTITUTION', 'None', (57, 66))	('nasopharyngeal carcinoma', 'Disease', 'MESH:D000077274', (147, 171))
168835	24205020	In this paper, we performed a systematic literature review to comprehensively evaluate the association between sequence variants in XRCC1 Arg399Gln and the risk of squamous cell carcinoma of the head and neck.	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (164, 187))	('Arg399Gln', 'Var', (138, 147))	('Arg399Gln', 'SUBSTITUTION', 'None', (138, 147))	('XRCC1', 'Gene', '7515', (132, 137))	('carcinoma of the head and neck', 'Phenotype', 'HP:0012288', (178, 208))	('carcinoma', 'Phenotype', 'HP:0030731', (178, 187))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (164, 187))	('squamous cell carcinoma', 'Disease', (164, 187))	('XRCC1', 'Gene', (132, 137))
168837	24205020	In summary, we did not observe an association of XRCC1 Arg399Gln polymorphisms with HNSCC risk in the total population.	('XRCC1', 'Gene', '7515', (49, 54))	('HNSCC', 'Disease', (84, 89))	('Arg399Gln', 'Var', (55, 64))	('Arg399Gln', 'SUBSTITUTION', 'None', (55, 64))	('XRCC1', 'Gene', (49, 54))
168843	24205020	When subgroup analyses were conducted by tumor site, the subjects carrying Gln/Gln genotype had an increased risk in larynx squamous cell carcinoma subgroup.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (124, 147))	('Gln/Gln', 'Var', (75, 82))	('tumor', 'Disease', (41, 46))	('larynx squamous cell carcinoma', 'Disease', (117, 147))	('Gln', 'Chemical', 'MESH:D005973', (75, 78))	('larynx squamous cell carcinoma', 'Disease', 'MESH:D002294', (117, 147))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('Gln', 'Chemical', 'MESH:D005973', (79, 82))
168844	24205020	There was no association of XRCC1 Arg399Gln polymorphisms with oral squamous cell carcinoma.	('XRCC1', 'Gene', '7515', (28, 33))	('Arg399Gln', 'Var', (34, 43))	('association', 'Interaction', (13, 24))	('Arg399Gln', 'SUBSTITUTION', 'None', (34, 43))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (63, 91))	('XRCC1', 'Gene', (28, 33))	('oral squamous cell carcinoma', 'Disease', (63, 91))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (68, 91))
168846	24205020	Considering that the frequency of the XRCC1 399 Gln allele variant is significantly different among different ethnic population.	('399 Gln', 'Var', (44, 51))	('XRCC1', 'Gene', '7515', (38, 43))	('XRCC1', 'Gene', (38, 43))	('Gln', 'Chemical', 'MESH:D005973', (48, 51))
168847	24205020	Allele frequency patterns of XRCC1 Arg399Gln polymorphism vary greatly among major ethnic groups.	('Arg399Gln', 'SUBSTITUTION', 'None', (35, 44))	('Arg399Gln', 'Var', (35, 44))	('XRCC1', 'Gene', '7515', (29, 34))	('XRCC1', 'Gene', (29, 34))
168849	24205020	When stratified by ethnicity, we observed an association of XRCC1 Arg399Gln polymorphisms with HNSCC risk among Caucasians, but not among Asian population.	('association', 'Interaction', (45, 56))	('XRCC1', 'Gene', (60, 65))	('Arg399Gln', 'Var', (66, 75))	('Arg399Gln', 'SUBSTITUTION', 'None', (66, 75))	('XRCC1', 'Gene', '7515', (60, 65))	('HNSCC', 'Disease', (95, 100))
168850	24205020	Different ethnicities cancer susceptibility associated with the XRCC1 Arg399Gln polymorphisms was also observed in previous meta-analyses of lung cancer and breast cancer.	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('XRCC1', 'Gene', (64, 69))	('breast cancer', 'Phenotype', 'HP:0003002', (157, 170))	('lung cancer', 'Disease', (141, 152))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('breast cancer', 'Disease', 'MESH:D001943', (157, 170))	('breast cancer', 'Disease', (157, 170))	('Arg399Gln', 'SUBSTITUTION', 'None', (70, 79))	('lung cancer', 'Disease', 'MESH:D008175', (141, 152))	('XRCC1', 'Gene', '7515', (64, 69))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('Arg399Gln', 'Var', (70, 79))	('cancer', 'Disease', (22, 28))	('cancer', 'Disease', (164, 170))	('lung cancer', 'Phenotype', 'HP:0100526', (141, 152))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))
168852	24205020	When subgroup analysis was performed by source of control, we observed any association between XRCC1 Arg399Gln polymorphisms and HNSCC risk neither in hospital-based control nor in healthy population-based control.	('Arg399Gln', 'Var', (101, 110))	('XRCC1', 'Gene', (95, 100))	('Arg399Gln', 'SUBSTITUTION', 'None', (101, 110))	('HNSCC', 'Disease', (129, 134))	('XRCC1', 'Gene', '7515', (95, 100))
168854	24205020	In conclusion, this systematic review demonstrates that XRCC1 Arg399Gln variants appear not to be a risk factor of HNSCC in the total population.	('HNSCC', 'Disease', (115, 120))	('XRCC1', 'Gene', '7515', (56, 61))	('Arg399Gln', 'Var', (62, 71))	('Arg399Gln', 'SUBSTITUTION', 'None', (62, 71))	('XRCC1', 'Gene', (56, 61))
168855	24205020	However, XRCC1 Arg399Gln variants might be a potential risk factor for HNSCC among Caucasians and for larynx squamous cell carcinoma.	('larynx squamous cell carcinoma', 'Disease', (102, 132))	('risk', 'Reg', (55, 59))	('larynx squamous cell carcinoma', 'Disease', 'MESH:D002294', (102, 132))	('XRCC1', 'Gene', '7515', (9, 14))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (109, 132))	('Arg399Gln', 'Var', (15, 24))	('HNSCC', 'Disease', (71, 76))	('Arg399Gln', 'SUBSTITUTION', 'None', (15, 24))	('XRCC1', 'Gene', (9, 14))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))
168893	31831737	In particular, proteome-based versus mRNA-based subtyping associations, respectively, included (proteome-based) k1 to (mRNA-based) c1, k2 to both c3 and c10, k3 to c3, k4 to c5, k5 to c6, k6 to c7, and k7 to c8.	('k4 to c5', 'Var', (168, 176))	('k3 to c3', 'Var', (158, 166))	('c10', 'Gene', (153, 156))	('k5 to c6', 'Var', (178, 186))	('c10', 'Gene', '3226', (153, 156))
168908	31831737	2e), other tumors that were not breast could also manifest a k4-associated signature pattern.	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('k4-associated', 'Var', (61, 74))	('tumors', 'Phenotype', 'HP:0002664', (11, 17))	('tumors', 'Disease', 'MESH:D009369', (11, 17))	('tumors', 'Disease', (11, 17))
169078	29675106	There is substantial evidence that aging-related changes can influence stromal-epithelial interactions leading to a microenvironment permissive for tumor growth.	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('stromal-epithelial interactions', 'CPA', (71, 102))	('microenvironment permissive for', 'MPA', (116, 147))	('influence', 'Reg', (61, 70))	('tumor', 'Disease', (148, 153))	('changes', 'Var', (49, 56))	('tumor', 'Disease', 'MESH:D009369', (148, 153))
169124	29675106	The results showed that expression levels of IL-6 and IL-8 in both H2O2- and bleomycin-induced groups are significant higher than normal control groups (Fig.	('higher', 'PosReg', (118, 124))	('expression levels', 'MPA', (24, 41))	('IL-8', 'Gene', (54, 58))	('H2O2', 'Chemical', 'MESH:D006861', (67, 71))	('IL-6', 'Gene', (45, 49))	('H2O2-', 'Var', (67, 72))	('bleomycin', 'Chemical', 'MESH:D001761', (77, 86))	('IL-8', 'Gene', '3576', (54, 58))
169130	29675106	We found that phosphorylation levels of STAT3 are much higher in senescent HELF groups than that of normal HELF groups (Fig.	('senescent', 'Var', (65, 74))	('STAT3', 'Gene', '6774', (40, 45))	('STAT3', 'Gene', (40, 45))	('phosphorylation levels', 'MPA', (14, 36))	('higher', 'PosReg', (55, 61))
169136	29675106	This is a website which can assess the survival effect of gene or gene combination in lung, breast, ovarian and gastric cancer.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('gene combination', 'Var', (66, 82))	('lung', 'Disease', (86, 90))	('breast', 'Disease', (92, 98))	('gastric cancer', 'Phenotype', 'HP:0012126', (112, 126))	('ovarian and gastric cancer', 'Disease', 'MESH:D013274', (100, 126))
169138	29675106	The corresponding valid Affymetrix IDs of KL, IL-6 and IL-8 are 205978_at, 205207_at and 202859_x_at.	('205207_at', 'Var', (75, 84))	('202859_x_at', 'Var', (89, 100))	('KL', 'Chemical', '-', (42, 44))	('IL-8', 'Gene', '3576', (55, 59))	('205978_at', 'Var', (64, 73))	('IL-8', 'Gene', (55, 59))
169141	29675106	Studies reported that senescence-associated changes in extracellular protein could affect cancer viability, so we follow-up evaluated whether oxidative stress and DNA damage-induced senescence-associated changes in extracellular protein can influence viability of human lung adenocarcinoma cell line A549, and also explored whether Klotho can regulate this biological process.	('affect', 'Reg', (83, 89))	('human', 'Species', '9606', (264, 269))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (270, 289))	('changes', 'Var', (44, 51))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (280, 289))	('viability', 'CPA', (251, 260))	('lung adenocarcinoma', 'Disease', (270, 289))	('A549', 'CellLine', 'CVCL:0023', (300, 304))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (270, 289))	('oxidative stress', 'Phenotype', 'HP:0025464', (142, 158))	('influence', 'Reg', (241, 250))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))
169143	29675106	The results indicated that CM from H2O2- or bleomycin-induced senescent HELF cells can obviously promote proliferation of A549 cells, while CM from KL-transfected senescent HELF cells can effectively inhibit proliferation of A549 cells when compared with that from NC-transfected cells (Fig.	('inhibit', 'NegReg', (200, 207))	('H2O2-', 'Var', (35, 40))	('H2O2', 'Chemical', 'MESH:D006861', (35, 39))	('bleomycin', 'Chemical', 'MESH:D001761', (44, 53))	('proliferation', 'CPA', (105, 118))	('proliferation', 'CPA', (208, 221))	('A549', 'CellLine', 'CVCL:0023', (225, 229))	('A549', 'CellLine', 'CVCL:0023', (122, 126))	('promote', 'PosReg', (97, 104))	('KL', 'Chemical', '-', (148, 150))
169147	29675106	And we found that phosphorylation levels of STAT3 of A549 cells are much higher using CM from senescent HELF cells groups than that from normal CM groups (Fig.	('A549', 'CellLine', 'CVCL:0023', (53, 57))	('STAT3', 'Gene', '6774', (44, 49))	('phosphorylation levels', 'MPA', (18, 40))	('STAT3', 'Gene', (44, 49))	('senescent HELF cells', 'Var', (94, 114))	('higher', 'PosReg', (73, 79))
169151	29675106	We found that CM from H2O2- or bleomycin-induced senescent HELF cells can promote migration of A549 cells, while CM from KL-transfected senescent HELF cells can effectively inhibit migration of A549 cells when compared with that from NC-transfected cells (Fig.	('promote', 'PosReg', (74, 81))	('bleomycin', 'Chemical', 'MESH:D001761', (31, 40))	('migration', 'CPA', (82, 91))	('H2O2', 'Chemical', 'MESH:D006861', (22, 26))	('KL', 'Chemical', '-', (121, 123))	('A549', 'CellLine', 'CVCL:0023', (194, 198))	('migration', 'CPA', (181, 190))	('H2O2-', 'Var', (22, 27))	('inhibit', 'NegReg', (173, 180))	('A549', 'CellLine', 'CVCL:0023', (95, 99))
169176	29675106	that modulating the activity of a key member of the senescence-messaging secretome (SMS) can also normalize the levels of other SMS factors.	('activity', 'MPA', (20, 28))	('levels of', 'MPA', (112, 121))	('SMS', 'Chemical', '-', (128, 131))	('normalize', 'MPA', (98, 107))	('modulating', 'Var', (5, 15))	('SMS', 'Chemical', '-', (84, 87))
169246	28388649	Also, patients treated initially with radiotherapy or chemotherapy were more likely to have a longer mean time interval from diagnosis to treatment, when compared with that of those who were treated initially with surgery.	('chemotherapy', 'Var', (54, 66))	('patients', 'Species', '9606', (6, 14))	('radiotherapy', 'Var', (38, 50))
169291	28388649	In addition, patients receiving MDT management within 180 days also had a better survival rate when compared with those who did not.	('better', 'PosReg', (74, 80))	('patients', 'Species', '9606', (13, 21))	('MDT', 'Chemical', '-', (32, 35))	('survival rate', 'CPA', (81, 94))	('MDT', 'Var', (32, 35))
169303	28388649	In conclusion, although the causal relationship between time interval from diagnosis to treatment and survival requires further investigation, our results imply that shortening the time interval from diagnosis to treatment may improve the survival of OCSCC patients.	('OCSCC', 'Disease', (251, 256))	('survival', 'CPA', (239, 247))	('shortening', 'Var', (166, 176))	('improve', 'PosReg', (227, 234))	('patients', 'Species', '9606', (257, 265))
169306	32548300	Univariate and multivariate analyses were performed sequentially to predict EGFR mutation status using each individual feature extractor.	('EGFR', 'Gene', (76, 80))	('EGFR', 'Gene', '1956', (76, 80))	('mutation', 'Var', (81, 89))
169317	32548300	Univariate and multivariate analyses were performed sequentially on predicting epidermal growth factor receptor (EGFR) mutant status by using each individual extractor, and performance was compared between the 3.	('epidermal growth factor receptor', 'Gene', (79, 111))	('EGFR', 'Gene', '1956', (113, 117))	('epidermal growth factor receptor', 'Gene', '1956', (79, 111))	('mutant status', 'Var', (119, 132))	('EGFR', 'Gene', (113, 117))
169320	32548300	The NSCLC Radiogenomics data set included 211 cases with 129 EGFR wildtypes, 43 EGFR mutants, and 39 unknowns.	('NSCLC', 'Disease', 'MESH:D002289', (4, 9))	('EGFR', 'Gene', '1956', (80, 84))	('EGFR', 'Gene', (80, 84))	('NSCLC', 'Phenotype', 'HP:0030358', (4, 9))	('mutants', 'Var', (85, 92))	('EGFR', 'Gene', '1956', (61, 65))	('EGFR', 'Gene', (61, 65))	('NSCLC', 'Disease', (4, 9))
169321	32548300	TCGA-LUAD data set included 69 cases with 52 EGFR wildtypes, 11 EGFR mutants, and 6 unknowns.	('EGFR', 'Gene', (45, 49))	('mutants', 'Var', (69, 76))	('EGFR', 'Gene', '1956', (64, 68))	('EGFR', 'Gene', (64, 68))	('EGFR', 'Gene', '1956', (45, 49))
169323	32548300	We included all patients that had a chest CT scan and a known EGFR mutation status.	('patients', 'Species', '9606', (16, 24))	('EGFR', 'Gene', '1956', (62, 66))	('EGFR', 'Gene', (62, 66))	('mutation', 'Var', (67, 75))
169326	32548300	The training and validation cohorts were split by data set and adjusted in order to maintain a balance of EGFR mutants and wildtypes in each cohort.	('mutants', 'Var', (111, 118))	('EGFR', 'Gene', '1956', (106, 110))	('EGFR', 'Gene', (106, 110))
169327	32548300	The training cohort consisted of a random subset of the NSCLC Radiogenomics-included cases, totaling 105, with 27 mutant and 78 wildtype cases.	('NSCLC', 'Disease', 'MESH:D002289', (56, 61))	('NSCLC', 'Disease', (56, 61))	('NSCLC', 'Phenotype', 'HP:0030358', (56, 61))	('mutant', 'Var', (114, 120))
169328	32548300	The validation cohort included the remaining 44 cases from NSCLC Radiogenomics and the cases from TCGA-LUAD and TGCA-LUSC, totaling 123, with 18 mutant and 105 wildtype cases.	('NSCLC', 'Phenotype', 'HP:0030358', (59, 64))	('mutant', 'Var', (145, 151))	('NSCLC', 'Disease', 'MESH:D002289', (59, 64))	('NSCLC', 'Disease', (59, 64))
169329	32548300	The NSCLC Radiogenomics subgroup had 44 cases with 33 EGFR wildtypes and 11 EGFR mutants.	('NSCLC', 'Disease', 'MESH:D002289', (4, 9))	('EGFR', 'Gene', '1956', (76, 80))	('EGFR', 'Gene', '1956', (54, 58))	('NSCLC', 'Phenotype', 'HP:0030358', (4, 9))	('EGFR', 'Gene', (76, 80))	('mutants', 'Var', (81, 88))	('EGFR', 'Gene', (54, 58))	('NSCLC', 'Disease', (4, 9))
169330	32548300	The TCGA-LUAD subgroup had 46 cases with 39 EGFR wildtypes and 7 EGFR mutants.	('mutants', 'Var', (70, 77))	('EGFR', 'Gene', '1956', (65, 69))	('EGFR', 'Gene', (65, 69))	('EGFR', 'Gene', '1956', (44, 48))	('EGFR', 'Gene', (44, 48))
169343	32548300	Although not statistically significant, there is a trend toward a difference between the training and validation cohorts in terms of proportion of EGFR mutants and wildtypes (P = .54) owing to the increased number of EGFR wildtypes in the validation cohort.	('EGFR', 'Gene', '1956', (217, 221))	('EGFR', 'Gene', (147, 151))	('EGFR', 'Gene', (217, 221))	('mutants', 'Var', (152, 159))	('EGFR', 'Gene', '1956', (147, 151))
169346	32548300	Moreover, we performed nonparametric Wilcoxon rank sum test to test the significance of feature distribution between EGFR wildtype and mutant for each individual candidate feature, and the results are shown in the online supplemental Figures S2-S4.	('EGFR', 'Gene', '1956', (117, 121))	('EGFR', 'Gene', (117, 121))	('mutant', 'Var', (135, 141))
169348	32548300	Only CIFE: intensity skewness had a significant difference between wildtype and mutant subsets of both the training and validation cohorts (P = .0072, P = .014) (see online supplemental Figure S4.4).	('CIFE', 'Chemical', '-', (5, 9))	('intensity', 'MPA', (11, 20))	('mutant', 'Var', (80, 86))
169356	32548300	have found skewness to be predictive of EGFR mutation status and subtypes.	('EGFR', 'Gene', '1956', (40, 44))	('mutation', 'Var', (45, 53))	('EGFR', 'Gene', (40, 44))
169357	32548300	also used the Pyradiomics feature extractor and similarly found that Size Zone NonUniformity Normalized was a predictor for EGFR mutation status.	('Pyradiomics', 'Chemical', '-', (14, 25))	('mutation', 'Var', (129, 137))	('EGFR', 'Gene', '1956', (124, 128))	('EGFR', 'Gene', (124, 128))
169362	32548300	In addition, the trend toward a difference in proportion of EGFR wildtype and mutant cases between the training and validation cohorts may have also affected the performance.	('EGFR', 'Gene', (60, 64))	('affected', 'Reg', (149, 157))	('mutant', 'Var', (78, 84))	('EGFR', 'Gene', '1956', (60, 64))
169366	32548300	Different radiomics features were selected from different feature extractors to predict EGFR mutation status in patients with NSCLC, which resulted in varying prediction performance.	('NSCLC', 'Disease', 'MESH:D002289', (126, 131))	('predict', 'Reg', (80, 87))	('patients', 'Species', '9606', (112, 120))	('NSCLC', 'Phenotype', 'HP:0030358', (126, 131))	('EGFR', 'Gene', '1956', (88, 92))	('mutation', 'Var', (93, 101))	('EGFR', 'Gene', (88, 92))	('NSCLC', 'Disease', (126, 131))
169375	26208906	Emerging evidence has indicated that lncRNAs contribute to tumor initiation and progression through diverse mechanisms ranging from epigenetic regulation of key cancer genes and enhancer-associated activity to post-transcriptional processing of mRNAs.	('tumor initiation', 'Disease', 'MESH:D009369', (59, 75))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('tumor initiation', 'Disease', (59, 75))	('epigenetic', 'Var', (132, 142))	('enhancer-associated', 'PosReg', (178, 197))	('lncRNAs', 'Protein', (37, 44))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('cancer', 'Disease', (161, 167))	('progression', 'CPA', (80, 91))	('contribute', 'Reg', (45, 55))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
169445	25409149	IAPP driven metabolic reprogramming induces regression of p53 - deficient tumours in vivo TP53 is commonly altered in human cancer, and Tp53 reactivation suppresses tumours in-vivo .	('p53', 'Gene', '22060', (58, 61))	('tumour', 'Phenotype', 'HP:0002664', (165, 171))	('TP53', 'Gene', '7157', (90, 94))	('suppresses', 'NegReg', (154, 164))	('deficient tumours', 'Disease', (64, 81))	('IAPP', 'Gene', (0, 4))	('tumours', 'Disease', (74, 81))	('p53', 'Gene', (137, 140))	('cancer', 'Disease', 'MESH:D009369', (124, 130))	('Tp53', 'Gene', (136, 140))	('reactivation', 'Var', (141, 153))	('tumours', 'Phenotype', 'HP:0002664', (74, 81))	('p53', 'Gene', '22060', (137, 140))	('tumours', 'Disease', 'MESH:D009369', (74, 81))	('deficient tumours', 'Disease', 'MESH:D009369', (64, 81))	('regression', 'CPA', (44, 54))	('tumour', 'Phenotype', 'HP:0002664', (74, 80))	('Tp53', 'Gene', '7157', (136, 140))	('TP53', 'Gene', (90, 94))	('human', 'Species', '9606', (118, 123))	('tumours', 'Disease', (165, 172))	('cancer', 'Disease', (124, 130))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('tumours', 'Phenotype', 'HP:0002664', (165, 172))	('tumours', 'Disease', 'MESH:D009369', (165, 172))	('p53', 'Gene', (58, 61))	('IAPP', 'Gene', '15874', (0, 4))
169446	25409149	This strategy has proven difficult to implement therapeutically, and here we have examined an alternative strategy by manipulating the p53 family members, p63 and p73.	('manipulating', 'Reg', (118, 130))	('p63', 'Gene', (155, 158))	('p73', 'Var', (163, 166))	('p63', 'Gene', '22061', (155, 158))
169448	25409149	The p53 family interacts extensively in cellular processes that promote tumour suppression, such as apoptosis and autophagy, thus a clear understanding of this interplay in cancer is needed to treat tumours with alterations in the p53 pathway.	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('tumour suppression', 'Disease', 'OMIM:146850', (72, 90))	('tumour', 'Phenotype', 'HP:0002664', (199, 205))	('promote', 'PosReg', (64, 71))	('cancer', 'Disease', (173, 179))	('tumour', 'Phenotype', 'HP:0002664', (72, 78))	('tumours', 'Phenotype', 'HP:0002664', (199, 206))	('autophagy', 'CPA', (114, 123))	('tumour suppression', 'Disease', (72, 90))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('tumours', 'Disease', 'MESH:D009369', (199, 206))	('tumours', 'Disease', (199, 206))	('alterations', 'Var', (212, 223))	('apoptosis', 'CPA', (100, 109))
169449	25409149	Here, we show that deletion of the DeltaN isoforms of p63 or p73 leads to metabolic reprogramming and regression of p53 deficient tumours through upregulation of IAPP, the gene that encodes amylin, a 37 amino acid peptide cosecreted with insulin from the beta cells of the pancreas.	('regression', 'CPA', (102, 112))	('IAPP', 'Gene', (162, 166))	('tumours', 'Phenotype', 'HP:0002664', (130, 137))	('upregulation', 'PosReg', (146, 158))	('tumour', 'Phenotype', 'HP:0002664', (130, 136))	('metabolic reprogramming', 'CPA', (74, 97))	('deletion', 'Var', (19, 27))	('deficient tumours', 'Disease', (120, 137))	('p63', 'Gene', '22061', (54, 57))	('deficient tumours', 'Disease', 'MESH:D009369', (120, 137))	('p73', 'Var', (61, 64))	('p63', 'Gene', (54, 57))	('p53', 'Gene', (116, 119))
169452	25409149	Using DeltaNp63 and DeltaNp73 conditional knock out mice (Extended Data Figure 1a & b), we generated DeltaNp63+/- and DeltaNp73-/- mice (Extended Data Figure 1c-f).	('generated', 'Var', (91, 100))	('DeltaNp73', 'Gene', (20, 29))	('p63', 'Gene', '22061', (107, 110))	('p63', 'Gene', '22061', (12, 15))	('mice', 'Species', '10090', (52, 56))	('p63', 'Gene', (107, 110))	('mice', 'Species', '10090', (131, 135))	('DeltaNp73', 'Gene', '22062', (20, 29))	('DeltaNp73', 'Gene', (118, 127))	('p63', 'Gene', (12, 15))	('and', 'Var', (114, 117))	('DeltaNp73', 'Gene', '22062', (118, 127))
169453	25409149	To ask whether the DeltaN isoforms of p63 and p73 act as oncogenes in vivo by interacting with p53, DeltaNp63+/-;p53-/- and DeltaNp73-/-;p53-/- mice were aged for the development of thymic lymphomas, which form in nearly all p53-/- mice.	('p63', 'Gene', '22061', (38, 41))	('p63', 'Gene', (106, 109))	('thymic lymphomas', 'Disease', (182, 198))	('p53-/-', 'Var', (113, 119))	('mice', 'Species', '10090', (144, 148))	('lymphomas', 'Phenotype', 'HP:0002665', (189, 198))	('p63', 'Gene', (38, 41))	('DeltaNp73', 'Gene', (124, 133))	('interacting', 'Interaction', (78, 89))	('lymphoma', 'Phenotype', 'HP:0002665', (189, 197))	('DeltaNp73', 'Gene', '22062', (124, 133))	('thymic lymphomas', 'Disease', 'MESH:D013953', (182, 198))	('p63', 'Gene', '22061', (106, 109))	('mice', 'Species', '10090', (232, 236))
169455	25409149	We found that TAp63 and TAp73 were upregulated in thymic lymphomas from DeltaNp63+/-;p53-/- and DeltaNp73-/-;p53-/- mice (Extended Data Figure 2d & e) along with an upregulation of apoptosis (Extended Data Figure 2f-j) and senescence (Extended Data 2k-o).	('p53-/-', 'Var', (85, 91))	('p63', 'Gene', (78, 81))	('mice', 'Species', '10090', (116, 120))	('and', 'CPA', (219, 222))	('lymphomas', 'Phenotype', 'HP:0002665', (57, 66))	('lymphoma', 'Phenotype', 'HP:0002665', (57, 65))	('thymic lymphomas', 'Disease', 'MESH:D013953', (50, 66))	('DeltaNp73', 'Gene', (96, 105))	('p63', 'Gene', '22061', (16, 19))	('TAp73', 'Gene', '22062', (24, 29))	('DeltaNp73', 'Gene', '22062', (96, 105))	('p63', 'Gene', (16, 19))	('upregulated', 'PosReg', (35, 46))	('p63', 'Gene', '22061', (78, 81))	('thymic lymphomas', 'Disease', (50, 66))	('TAp73', 'Gene', (24, 29))
169458	25409149	Mice deficient for either DeltaNp63 or DeltaNp73 and p53 showed marked decreases in tumour burden (Figure 1h & i).	('DeltaNp73', 'Gene', '22062', (39, 48))	('p53', 'Var', (53, 56))	('p63', 'Gene', '22061', (32, 35))	('tumour', 'Phenotype', 'HP:0002664', (84, 90))	('Mice', 'Species', '10090', (0, 4))	('DeltaNp73', 'Gene', (39, 48))	('p63', 'Gene', (32, 35))	('decreases in tumour burden', 'Disease', (71, 97))	('decreases in tumour burden', 'Disease', 'MESH:D009369', (71, 97))
169462	25409149	Indeed, we found that p53-/- thymic lymphomas are composed primarily of CD4/CD8 double positive thymocytes while the DeltaNp63Delta/Delta;p53-/- and DeltaNp73Delta/Delta;p53-/- lymphomas contain very few CD4/CD8 double positive thymocytes (Extended Data Figure 4q-t).	('CD4', 'Gene', (72, 75))	('lymphomas', 'Disease', (177, 186))	('DeltaNp73', 'Gene', '22062', (149, 158))	('lymphoma', 'Phenotype', 'HP:0002665', (177, 185))	('CD4', 'Gene', (204, 207))	('CD4', 'Gene', '12504', (72, 75))	('lymphomas', 'Disease', 'MESH:D008223', (36, 45))	('lymphomas', 'Phenotype', 'HP:0002665', (36, 45))	('p53-/-', 'Var', (22, 28))	('thymic lymphomas', 'Disease', 'MESH:D013953', (29, 45))	('lymphomas', 'Disease', 'MESH:D008223', (177, 186))	('DeltaNp73', 'Gene', (149, 158))	('CD4', 'Gene', '12504', (204, 207))	('lymphomas', 'Phenotype', 'HP:0002665', (177, 186))	('p63', 'Gene', (123, 126))	('lymphoma', 'Phenotype', 'HP:0002665', (36, 44))	('lymphomas', 'Disease', (36, 45))	('p63', 'Gene', '22061', (123, 126))	('thymic lymphomas', 'Disease', (29, 45))
169464	25409149	We sorted CD45 positive cells to select for T-lymphocytes in p53-/-, DeltaNp63fl/fl;p53-/- and DeltaNp73fl/fl;p53-/- mice and infected them with adenovirus-cre (Extended Data Figure 4u).	('p53-/-', 'Var', (61, 67))	('CD4', 'Gene', (10, 13))	('DeltaNp73', 'Gene', '22062', (95, 104))	('CD4', 'Gene', '12504', (10, 13))	('p63', 'Gene', '22061', (75, 78))	('p53-/-', 'Var', (84, 90))	('mice', 'Species', '10090', (117, 121))	('p63', 'Gene', (75, 78))	('DeltaNp73', 'Gene', (95, 104))
169467	25409149	We found that the DeltaN isoforms of p63 and p73 bind to the promoters of the TA isoforms of p63 and p73 suggesting that the DeltaN isoforms of p63 and p73 can transcriptionally repress TAp63 and TAp73 transcription (Extended Data Figure 5a-i).	('p63', 'Gene', '22061', (144, 147))	('p63', 'Gene', '22061', (93, 96))	('transcription', 'MPA', (202, 215))	('p63', 'Gene', (144, 147))	('p73', 'Var', (152, 155))	('p63', 'Gene', (93, 96))	('p63', 'Gene', '22061', (37, 40))	('TAp73', 'Gene', (196, 201))	('TAp73', 'Gene', '22062', (196, 201))	('p63', 'Gene', '22061', (188, 191))	('p63', 'Gene', (37, 40))	('p63', 'Gene', (188, 191))	('repress', 'NegReg', (178, 185))
169469	25409149	We performed RNA sequencing of lymphomas after infection with Ad-mCherry (DeltaNp63fl/fl;p53-/- and DeltaNp73fl/fl;p53-/-) and Ad-Cre-mCherry (DeltaNp63Delta/Delta;p53-/- and DeltaNp73Delta/Delta;p53-/-) and found that thymic lymphomas from mice deficient for p53 and DeltaNp63 clustered with those from mice deficient for p53 and DeltaNp73 (Extended Data Figure 6a).	('deficient', 'Var', (246, 255))	('lymphomas', 'Disease', 'MESH:D008223', (31, 40))	('thymic lymphomas', 'Disease', (219, 235))	('lymphomas', 'Phenotype', 'HP:0002665', (31, 40))	('lymphomas', 'Disease', 'MESH:D008223', (226, 235))	('DeltaNp73', 'Gene', '22062', (331, 340))	('DeltaNp73', 'Gene', (175, 184))	('lymphomas', 'Phenotype', 'HP:0002665', (226, 235))	('p63', 'Gene', (149, 152))	('lymphoma', 'Phenotype', 'HP:0002665', (31, 39))	('p63', 'Gene', (80, 83))	('DeltaNp73', 'Gene', '22062', (100, 109))	('mice', 'Species', '10090', (304, 308))	('lymphomas', 'Disease', (31, 40))	('p63', 'Gene', '22061', (149, 152))	('mice', 'Species', '10090', (241, 245))	('p63', 'Gene', '22061', (80, 83))	('DeltaNp73', 'Gene', (331, 340))	('lymphomas', 'Disease', (226, 235))	('thymic lymphomas', 'Disease', 'MESH:D013953', (219, 235))	('p63', 'Gene', (274, 277))	('p53', 'Var', (260, 263))	('DeltaNp73', 'Gene', '22062', (175, 184))	('DeltaNp73', 'Gene', (100, 109))	('p63', 'Gene', '22061', (274, 277))	('lymphoma', 'Phenotype', 'HP:0002665', (226, 234))
169476	25409149	Because a greater binding affinity of TAp63 and TAp73 was detected in the promoter region (site 1) of IAPP, we cloned this site into a luciferase reporter gene and also mutated this site (Extended Data Figure 6h-k).	('mutated', 'Var', (169, 176))	('IAPP', 'Gene', (102, 106))	('p63', 'Gene', '22061', (40, 43))	('TAp73', 'Gene', '22062', (48, 53))	('TAp73', 'Gene', (48, 53))	('p63', 'Gene', (40, 43))	('binding affinity', 'Interaction', (18, 34))
169479	25409149	Expression of IAPP in p53-/- MEFs resulted in low levels of glycolysis comparable to that in DeltaNp63-/-;p53-/- and DeltaNp73-/-;p53-/- MEFs (Extended Data Figure 6l-m & Figure 1u).	('low', 'NegReg', (46, 49))	('MEFs', 'CellLine', 'CVCL:9115', (29, 33))	('MEFs', 'CellLine', 'CVCL:9115', (137, 141))	('DeltaNp73', 'Gene', (117, 126))	('p53-/- MEFs', 'Var', (22, 33))	('p63', 'Gene', '22061', (99, 102))	('DeltaNp73', 'Gene', '22062', (117, 126))	('IAPP', 'Gene', (14, 18))	('levels of glycolysis', 'MPA', (50, 70))	('p63', 'Gene', (99, 102))
169480	25409149	Conversely, when we knocked down IAPP in DeltaNp63-/-;p53-/- and DeltaNp73-/-;p53-/- MEFs, the levels of glycolysis were similar to that of p53-/- MEFs (Figure 1u) indicating that IAPP inhibits glycolysis.	('p63', 'Gene', (47, 50))	('IAPP', 'Gene', (33, 37))	('p53-/-', 'Var', (54, 60))	('DeltaNp73', 'Gene', (65, 74))	('glycolysis', 'MPA', (194, 204))	('inhibits', 'NegReg', (185, 193))	('MEFs', 'CellLine', 'CVCL:9115', (85, 89))	('MEFs', 'CellLine', 'CVCL:9115', (147, 151))	('glycolysis', 'MPA', (105, 115))	('knocked down', 'NegReg', (20, 32))	('DeltaNp73', 'Gene', '22062', (65, 74))	('p63', 'Gene', '22061', (47, 50))
169481	25409149	In vivo, we detected massive tumour regression in DeltaNp63fl/fl;p53-/- or DeltaNp73fl/fl;p53-/- thymic lymphomas treated with IAPP (Extended Data Figure 7a and Figure 2a, b, h, i, o & p), p<0.05.	('thymic lymphomas', 'Disease', 'MESH:D013953', (97, 113))	('tumour', 'Disease', (29, 35))	('DeltaNp73', 'Gene', '22062', (75, 84))	('p63', 'Gene', '22061', (56, 59))	('p63', 'Gene', (56, 59))	('p53-/-', 'Var', (65, 71))	('thymic lymphomas', 'Disease', (97, 113))	('lymphomas', 'Phenotype', 'HP:0002665', (104, 113))	('tumour', 'Phenotype', 'HP:0002664', (29, 35))	('tumour', 'Disease', 'MESH:D009369', (29, 35))	('lymphoma', 'Phenotype', 'HP:0002665', (104, 112))	('DeltaNp73', 'Gene', (75, 84))
169483	25409149	Additionally, p53-/- mice treated with Ad-IAPP had an extended tumour free survival compared to p53-/- mice or DeltaNp63Delta/Delta;p53-/- and DeltaNp73Delta/Delta;p53-/- mice treated intratumourally with Ad-shIAPP-mCherry (Extended Data Figure 7a & b) indicating that IAPP is a tumour suppressor gene and is causally involved in the in vivo effects seen upon inactivation of DeltaNp63 or DeltaNp73.	('upon', 'Var', (355, 359))	('Ad-IAPP', 'Var', (39, 46))	('mice', 'Species', '10090', (21, 25))	('tumour', 'Phenotype', 'HP:0002664', (189, 195))	('DeltaNp73', 'Gene', '22062', (143, 152))	('p63', 'Gene', (382, 385))	('tumour', 'Disease', 'MESH:D009369', (189, 195))	('tumour', 'Disease', (189, 195))	('mice', 'Species', '10090', (171, 175))	('p63', 'Gene', '22061', (382, 385))	('DeltaNp73', 'Gene', (389, 398))	('DeltaNp73', 'Gene', (143, 152))	('tumour', 'Phenotype', 'HP:0002664', (279, 285))	('p63', 'Gene', (117, 120))	('tumour', 'Disease', 'MESH:D009369', (279, 285))	('tumour', 'Disease', (279, 285))	('mice', 'Species', '10090', (103, 107))	('p63', 'Gene', '22061', (117, 120))	('tumour', 'Phenotype', 'HP:0002664', (63, 69))	('tumour', 'Disease', 'MESH:D009369', (63, 69))	('DeltaNp73', 'Gene', '22062', (389, 398))	('tumour', 'Disease', (63, 69))
169490	25409149	Pramlinitide also inhibits glycolysis in tumours (Figure 2v).	('Pramlinitide', 'Chemical', '-', (0, 12))	('inhibits', 'NegReg', (18, 26))	('tumour', 'Phenotype', 'HP:0002664', (41, 47))	('tumours', 'Phenotype', 'HP:0002664', (41, 48))	('Pramlinitide', 'Var', (0, 12))	('tumours', 'Disease', 'MESH:D009369', (41, 48))	('glycolysis', 'MPA', (27, 37))	('tumours', 'Disease', (41, 48))
169491	25409149	IAPP has been shown to induce ROS and activate apoptosis .	('ROS', 'Protein', (30, 33))	('induce', 'PosReg', (23, 29))	('apoptosis', 'CPA', (47, 56))	('IAPP', 'Var', (0, 4))	('activate', 'PosReg', (38, 46))	('ROS', 'Chemical', 'MESH:D017382', (30, 33))
169494	25409149	Additionally, cancer cells tightly regulate ROS by acquiring additional mutations and compensatory mechanisms often ensue and may be at play in the thymic lymphoma cells that acutely downregulate glycolysis by IAPP.	('cancer', 'Disease', (14, 20))	('mutations', 'Var', (72, 81))	('ROS', 'Gene', (44, 47))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('thymic lymphoma', 'Disease', (148, 163))	('regulate', 'Reg', (35, 43))	('thymic lymphoma', 'Disease', 'MESH:D013953', (148, 163))	('glycolysis', 'MPA', (196, 206))	('ROS', 'Chemical', 'MESH:D017382', (44, 47))	('lymphoma', 'Phenotype', 'HP:0002665', (155, 163))	('cancer', 'Disease', 'MESH:D009369', (14, 20))	('downregulate', 'NegReg', (183, 195))
169495	25409149	To extend our findings to human cancer where p53 is altered in the majority of cases, we analyzed human cancer cell lines containing p53 deletions or mutations.	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('deletions', 'Var', (137, 146))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('cancer', 'Disease', (32, 38))	('mutations', 'Var', (150, 159))	('human', 'Species', '9606', (98, 103))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('p53', 'Gene', (133, 136))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('human', 'Species', '9606', (26, 31))
169501	25409149	Previous studies have indicated that IAPP inhibits glycolysis by increasing intracellular glucose-6-phosphate (G-6-P) in turn leading to an inhibition of hexokinase .	('IAPP', 'Var', (37, 41))	('inhibits', 'NegReg', (42, 50))	('G-6-P', 'Chemical', 'MESH:D019298', (111, 116))	('hexokinase', 'MPA', (154, 164))	('glucose-6-phosphate', 'Chemical', 'MESH:D019298', (90, 109))	('increasing', 'PosReg', (65, 75))	('inhibition', 'NegReg', (140, 150))	('glycolysis', 'MPA', (51, 61))
169502	25409149	We measured the levels of intracellular G-6-P in H1299 cells and found that cells expressing high levels of IAPP (H1299-siDeltaNp63, H1299-siDeltaNp73, or H1299+IAPP) also had high levels of G-6-P while knock down of IAPP resulted in a diminution in G-6-P (Extended Data Figure 8f & g).	('knock down', 'Var', (203, 213))	('H1299', 'CellLine', 'CVCL:0060', (155, 160))	('H1299', 'CellLine', 'CVCL:0060', (49, 54))	('H1299', 'CellLine', 'CVCL:0060', (114, 119))	('H1299+IAPP', 'Var', (155, 165))	('p63', 'Gene', '22061', (128, 131))	('p63', 'Gene', (128, 131))	('DeltaNp73', 'Gene', (141, 150))	('diminution', 'NegReg', (236, 246))	('G-6-P', 'Chemical', 'MESH:D019298', (191, 196))	('H1299', 'CellLine', 'CVCL:0060', (133, 138))	('G-6-P', 'MPA', (191, 196))	('DeltaNp73', 'Gene', '22062', (141, 150))	('G-6-P', 'Chemical', 'MESH:D019298', (250, 255))	('G-6-P', 'Chemical', 'MESH:D019298', (40, 45))
169507	25409149	In contrast, when these media were used to treat H1299 cells with knock down of CALCR or RAMP3, glycolysis was not inhibited and ROS and apoptosis were not induced (Figure 4b-d) indicating that the CALCR and RAMP3 receptors are critical for IAPP function.	('H1299', 'CellLine', 'CVCL:0060', (49, 54))	('knock down', 'Var', (66, 76))	('glycolysis', 'MPA', (96, 106))	('ROS', 'Chemical', 'MESH:D017382', (129, 132))	('CALCR', 'Gene', (80, 85))	('RAMP3', 'Gene', (89, 94))
169510	25409149	IAPP causes activation of the NLRP3 inflammasome , which has been shown to be anti-tumourigenic in certain cancers via IL-18 processing.	('tumour', 'Disease', (83, 89))	('cancers', 'Disease', (107, 114))	('cancers', 'Disease', 'MESH:D009369', (107, 114))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('NLRP3', 'Gene', (30, 35))	('activation', 'PosReg', (12, 22))	('NLRP3', 'Gene', '216799', (30, 35))	('IAPP', 'Var', (0, 4))	('IL-18', 'Gene', '16173', (119, 124))	('tumour', 'Phenotype', 'HP:0002664', (83, 89))	('tumour', 'Disease', 'MESH:D009369', (83, 89))	('cancers', 'Phenotype', 'HP:0002664', (107, 114))	('IL-18', 'Gene', (119, 124))
169513	25409149	To further determine the anti-tumourigenic efficacy of pramlintide in cells with p53 deletions or mutations, we treated additional human cancer cell lines  with pramlintide and a calcitonin receptor inhibitor resulting in increased glycolysis, decreased ROS and apoptosis (Extended Data Figure 9d-i).	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('ROS', 'MPA', (254, 257))	('decreased', 'NegReg', (244, 253))	('deletions', 'Var', (85, 94))	('tumour', 'Disease', 'MESH:D009369', (30, 36))	('glycolysis', 'MPA', (232, 242))	('tumour', 'Disease', (30, 36))	('ROS', 'Chemical', 'MESH:D017382', (254, 257))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('mutations', 'Var', (98, 107))	('increased', 'PosReg', (222, 231))	('human', 'Species', '9606', (131, 136))	('cancer', 'Disease', (137, 143))	('p53', 'Gene', (81, 84))	('apoptosis', 'CPA', (262, 271))	('tumour', 'Phenotype', 'HP:0002664', (30, 36))
169514	25409149	We assessed patient survival using data from the Cancer Genome Atlas (TCGA) of patients with p53 mutations and found that co-expression of IAPP, CALCR and RAMP3 correlated with better patient survival in basal breast cancer (Figure 4o), and colorectal cancer and lung squamous cell carcinoma (Extended Data Figure 9j & k).	('mutations', 'Var', (97, 106))	('colorectal cancer', 'Disease', (241, 258))	('Cancer Genome Atlas', 'Disease', (49, 68))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (263, 291))	('patient', 'Species', '9606', (184, 191))	('patient', 'Species', '9606', (79, 86))	('better', 'PosReg', (177, 183))	('Cancer', 'Phenotype', 'HP:0002664', (49, 55))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (263, 291))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (268, 291))	('lung squamous cell carcinoma', 'Disease', (263, 291))	('colorectal cancer', 'Phenotype', 'HP:0003003', (241, 258))	('basal breast cancer', 'Disease', 'MESH:D001943', (204, 223))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('breast cancer', 'Phenotype', 'HP:0003002', (210, 223))	('CALCR', 'Gene', (145, 150))	('patient', 'Species', '9606', (12, 19))	('carcinoma', 'Phenotype', 'HP:0030731', (282, 291))	('basal breast cancer', 'Disease', (204, 223))	('IAPP', 'Gene', (139, 143))	('RAMP3', 'Gene', (155, 160))	('p53', 'Gene', (93, 96))	('patients', 'Species', '9606', (79, 87))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (49, 68))	('colorectal cancer', 'Disease', 'MESH:D015179', (241, 258))
169515	25409149	Reactivation of p53 activity in tumours results in tumour suppression.	('activity', 'MPA', (20, 28))	('tumours', 'Disease', 'MESH:D009369', (32, 39))	('tumours', 'Disease', (32, 39))	('p53', 'Protein', (16, 19))	('tumour', 'Phenotype', 'HP:0002664', (51, 57))	('tumour suppression', 'Disease', (51, 69))	('Reactivation', 'Var', (0, 12))	('tumour suppression', 'Disease', 'OMIM:146850', (51, 69))	('tumours', 'Phenotype', 'HP:0002664', (32, 39))	('tumour', 'Phenotype', 'HP:0002664', (32, 38))
169516	25409149	We have focused on interactions between the three p53 family members and have revealed a novel strategy to target p53-deficient and mutant cancers through amylin based therapies like pramlintide.	('cancers', 'Disease', 'MESH:D009369', (139, 146))	('cancers', 'Phenotype', 'HP:0002664', (139, 146))	('mutant', 'Var', (132, 138))	('cancers', 'Disease', (139, 146))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('p53-deficient', 'Gene', (114, 127))	('interactions', 'Interaction', (19, 31))
169527	25409149	Genomic DNA from tail biopsies was genotyped by Southern blot analysis by digesting genomic DNA with AflII and HindIII or by PCR using the following primers and annealing temperatures: 1) for wild-type: wt-F, 5'-ACAGTCCTCTGCTTTCAGC-3' and wt-R (fl-R), 5'-CACACAGCA CTGGCCTTGC -3', annealing temp: 58 C, 2) for DeltaNp73flox: fl-F, 5' - CATAGCCATGGGCTCTCCT - 3' and fl-R (wt-R), 5'-TGTCCTGCTGCTGGTTGTAT- 3', annealing temp: 63 C, 3) DeltaNp73floxneo: flneo-F, 5'-GGGAGGATTGGGAAGACAAT-3' and flneo-R, 5'-TGTCCTGCTGCTGGTTGTAT-3' annealing temp:60 C and 4) for DeltaNp73KO: ko-F, 5'-CCTAGCCCAAGCATACTGGT-3' and wt-R, 5'-TGTCCTGCTGCTGGTTGTAT-3' annealing temp: 58 C. Primers used to genotype for the Cre gene are as follows: Cre-F, 5'-TGGGCGGCATGGTGCAAGTT-3' and Cre-R, 5'-CGGTGCTAACCAGCGTTTTC-3', annealing temp: 60  C. The primers for DeltaNp63WT, DeltaNp63KO, DeltaNp63flox and p53 were previously described.	('p63', 'Gene', '22061', (851, 854))	('p63', 'Gene', '22061', (838, 841))	('p63', 'Gene', (851, 854))	('p63', 'Gene', (838, 841))	('DeltaNp73', 'Gene', (432, 441))	('p53', 'Var', (876, 879))	('DeltaNp73', 'Gene', (557, 566))	('p63', 'Gene', '22061', (864, 867))	('DeltaNp73', 'Gene', (310, 319))	('p63', 'Gene', (864, 867))	('DeltaNp73', 'Gene', '22062', (432, 441))	('DeltaNp73', 'Gene', '22062', (557, 566))	('DeltaNp73', 'Gene', '22062', (310, 319))
169535	25409149	Antigens were unmasked in citrate buffer unmasking solution (Vector Laboratory) followed by incubation with blocking solution, and 18 hour incubation at 4 C with the following antibodies: cleaved caspase 3 (1:200)(Cell Signaling), PCNA (1:500)(Cell Signaling), malondialdehyde (1:50)(Abcam).	('1:200', 'Var', (207, 212))	('malondialdehyde', 'Chemical', 'MESH:D008315', (261, 276))	('caspase 3', 'Protein', (196, 205))	('PCNA', 'Gene', '18538', (231, 235))	('citrate', 'Chemical', 'MESH:D019343', (26, 33))	('PCNA', 'Gene', (231, 235))
169553	25409149	qRT-PCR was performed by using the primers specific for the indicated regions on the TAp63 promoter: Site 1 (-41) -forward 5'-CAGGAGCTCTCAAATCAAGTCAGA-3' and (+37) -reverse 5'-ATCACAGAAGCCAGGACTTGTCAC-3', and non-specific site (-3030) - forward 5'-GCTATAAATGTTTCCATGTGATGGATTGC-3' and (-2973) - reverse 5'-TGCAGACTTAGCTATGGTCTCTTG-3'.	('-3030', 'Var', (228, 233))	('p63', 'Gene', '22061', (87, 90))	('-41', 'Var', (109, 112))	('p63', 'Gene', (87, 90))	('-2973) - reverse', 'Var', (286, 302))
169554	25409149	Similarly, qRT-PCR was performed using the primers specific for the indicated regions on the TAp73 promoter: Site 1 (-1103) -forward 5'-CTAGCACACCAATCCAAGGAAAGA and (-1059) -reverse 5'-GCCTGCAGTCCGGGTTT-3' and non-specific site (-2488)-forward 5'ACTAGACCTCTGTACTTGTGAACATACATTT-3' and (-2382) -reverse 5'-GCACTCTCAFFATCCTGTAACAAAA-3'.	('TAp73', 'Gene', (93, 98))	('-1103', 'Var', (117, 122))	('-2488', 'Var', (229, 234))	('-1059) -reverse', 'Var', (166, 181))	('TAp73', 'Gene', '22062', (93, 98))	('-2382) -reverse', 'Var', (286, 301))
169555	25409149	Luciferase assays were performed using p53-/-;p63-/- and p53-/-;p73-/- MEFs as described previously.	('MEFs', 'CellLine', 'CVCL:9115', (71, 75))	('p53-/-;p73-/- MEFs', 'Var', (57, 75))	('p63', 'Gene', '22061', (46, 49))	('p63', 'Gene', (46, 49))	('Luciferase', 'Enzyme', (0, 10))
169556	25409149	To generate the luciferase reporter gene (pGL3-IAPP), the DNA fragment containing the TAp63/TAp73-binding site identified by ChIP was amplified from C57BL/6 genomic DNA by PCR with the following primers containing 5' XhoI and 3' HindIII cloning restriction enzyme sites: IAPP 5'-ATACTCGAGGTGTTCAGGGAACCTTCGGT-3' (forward) and 5'-ATAAAGCTTCACCTGACCTCCAAACTCCC-3' (reverse).	('TAp73', 'Gene', '22062', (92, 97))	('IAPP', 'Var', (271, 275))	('TAp73', 'Gene', (92, 97))	('p63', 'Gene', '22061', (88, 91))	('p63', 'Gene', (88, 91))
169557	25409149	Cells were transfected with 50 nM siDeltaNp63 (SASI_Hs02 00328367)(Mission siRNA, Sigma), siDeltaNp73 (SASI_Hs02_00326884)(Mission siRNA, Sigma), siTAp63 (SASI_Hs01_00246771) (Mission siRNA, Sigma), siTAp73 (SASI_Hs02_00339573) (Mission siRNA, Sigma), siRAMP3 (SASI_Hs01_00199036)(Mission siRNA, Sigma), siCalcitonin receptor (SASI_Hs01_00077738)(Mission siRNA, Sigma), siIAPP (SASI_Hs01_00183962) (Mission siRNA, Sigma) or siNT(SIC_001)(Mission siRNA, Sigma) using Lipofectamine RNAiMAX (Invitrogen).	('SIC_001', 'Disease', 'MESH:D015431', (429, 436))	('p63', 'Gene', '22061', (42, 45))	('DeltaNp73', 'Gene', '22062', (92, 101))	('Calcitonin receptor', 'Gene', '12311', (306, 325))	('Calcitonin receptor', 'Gene', (306, 325))	('TAp73', 'Gene', '22062', (201, 206))	('p63', 'Gene', (42, 45))	('TAp73', 'Gene', (201, 206))	('SIC_001', 'Disease', (429, 436))	('Lipofectamine', 'Chemical', 'MESH:C086724', (466, 479))	('p63', 'Gene', '22061', (150, 153))	('DeltaNp73', 'Gene', (92, 101))	('p63', 'Gene', (150, 153))	('SASI_Hs01_00077738', 'Var', (327, 345))
169560	25409149	Cells were selected with G418, MEFs (350mug/mul) and human cancer cells (500mug/mul) for a period of 9 days.	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('350mug/mul', 'Var', (37, 47))	('MEFs', 'CellLine', 'CVCL:9115', (31, 35))	('human', 'Species', '9606', (53, 58))	('G418', 'Var', (25, 29))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))
169564	25409149	Hierarchical clustering of samples was executed by first computing the symmetrical sample distance matrix using the Pearson correlation between mRNA profiles as a metric, supervised sample analysis was performed using the t-test statistics, and heatmaps were generated using the heatmap.2 package in R. For gene signatures and pathway analysis gene list from the RNA-Seq comparing DeltaNfl/fl;p53-/- versus DeltaNp63Delta/Delta;p53-/- and DeltaNp73Delta/Delta;p53-/- were obtained at a p-value <0.01.	('DeltaNp73', 'Gene', (439, 448))	('p63', 'Gene', '22061', (413, 416))	('DeltaNp73', 'Gene', '22062', (439, 448))	('p63', 'Gene', (413, 416))	('DeltaNfl/fl;p53-/-', 'Var', (381, 399))
169615	25409149	We considered four major cancer types with high p53 mutation rates, which include lung squamous cell carcinoma, head & neck squamous cell cancer, basal breast cancer, and colon cancer.	('cancer', 'Disease', (177, 183))	('cancer', 'Disease', (138, 144))	('basal breast cancer', 'Disease', 'MESH:D001943', (146, 165))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('colon cancer', 'Disease', 'MESH:D015179', (171, 183))	('mutation', 'Var', (52, 60))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('cancer', 'Disease', (25, 31))	('cancer', 'Disease', (159, 165))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (87, 110))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (82, 110))	('lung squamous cell carcinoma', 'Disease', (82, 110))	('basal breast cancer', 'Disease', (146, 165))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('colon cancer', 'Disease', (171, 183))	('cancer', 'Disease', 'MESH:D009369', (138, 144))	('squamous cell cancer', 'Disease', (124, 144))	('p53', 'Gene', (48, 51))	('cancer', 'Disease', 'MESH:D009369', (177, 183))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (124, 144))	('cancer', 'Disease', 'MESH:D009369', (25, 31))	('breast cancer', 'Phenotype', 'HP:0003002', (152, 165))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('squamous cell cancer', 'Disease', 'MESH:D002294', (124, 144))	('colon cancer', 'Phenotype', 'HP:0003003', (171, 183))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (82, 110))
169622	33833226	In this study, we demonstrate that E47 plays the distinctive and opposite roles on cell proliferation in adenocarcinoma and squamous cell carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (124, 147))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('cell proliferation', 'CPA', (83, 101))	('adenocarcinoma and squamous cell carcinoma', 'Disease', 'MESH:D002294', (105, 147))	('E47', 'Var', (35, 38))
169623	33833226	While E47 suppresses cell proliferation in adenocarcinoma cells, it functions as a oncoprotein to promote cell proliferation and tumor growth of squamous cell carcinoma.	('cell proliferation', 'CPA', (106, 124))	('adenocarcinoma', 'Disease', (43, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (159, 168))	('E47', 'Var', (6, 9))	('promote', 'PosReg', (98, 105))	('adenocarcinoma', 'Disease', 'MESH:D000230', (43, 57))	('cell proliferation', 'CPA', (21, 39))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (145, 168))	('tumor growth of squamous cell carcinoma', 'Disease', (129, 168))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('tumor growth of squamous cell carcinoma', 'Disease', 'MESH:D002294', (129, 168))	('suppresses', 'NegReg', (10, 20))	('carcinoma', 'Phenotype', 'HP:0030731', (48, 57))
169624	33833226	Mechanistically, we show that E47 can directly bind to the promoter and transactivate DeltaNp63 gene expression in squamous cell carcinoma cells, resulting in upregulation of cyclins D1/E1 and downregulation of p21, and thereby promoting cell proliferation and tumor growth.	('p21', 'Gene', '1026', (211, 214))	('promoting', 'PosReg', (228, 237))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (115, 138))	('tumor', 'Phenotype', 'HP:0002664', (261, 266))	('E47', 'Var', (30, 33))	('squamous cell carcinoma', 'Disease', (115, 138))	('cell proliferation', 'CPA', (238, 256))	('cyclins D1/E1', 'Gene', '595;898', (175, 188))	('p21', 'Gene', (211, 214))	('cyclins D1/E1', 'Gene', (175, 188))	('downregulation', 'NegReg', (193, 207))	('tumor', 'Disease', (261, 266))	('transactivate', 'Reg', (72, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('DeltaNp63', 'Gene', (86, 95))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (115, 138))	('expression', 'MPA', (101, 111))	('tumor', 'Disease', 'MESH:D009369', (261, 266))	('upregulation', 'PosReg', (159, 171))
169626	33833226	These results highlight that the E47-DeltaNp63alpha axis may be potential therapeutic targets for treatment of squamous cell carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (111, 134))	('DeltaNp63alpha', 'Chemical', '-', (37, 51))	('E47-DeltaNp63alpha', 'Var', (33, 51))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (111, 134))	('squamous cell carcinoma', 'Disease', (111, 134))
169629	33833226	Activating mutations in epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) rearrangement are the major driving force for lung adenocarcinoma while most squamous cell carcinomas display somatic mutation of p53.	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (68, 87))	('epidermal growth factor receptor', 'Gene', (24, 56))	('p53', 'Gene', '7157', (231, 234))	('epidermal growth factor receptor', 'Gene', '1956', (24, 56))	('lung adenocarcinoma', 'Disease', (147, 166))	('carcinoma', 'Phenotype', 'HP:0030731', (192, 201))	('carcinomas', 'Phenotype', 'HP:0030731', (192, 202))	('anaplastic lymphoma kinase', 'Gene', '238', (68, 94))	('EGFR', 'Gene', (58, 62))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (178, 202))	('p53', 'Gene', (231, 234))	('anaplastic lymphoma kinase', 'Gene', (68, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (157, 166))	('lymphoma', 'Phenotype', 'HP:0002665', (79, 87))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (147, 166))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (178, 202))	('ALK', 'Gene', '238', (96, 99))	('Activating mutations', 'Var', (0, 20))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (147, 166))	('ALK', 'Gene', (96, 99))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (178, 201))	('EGFR', 'Gene', '1956', (58, 62))	('squamous cell carcinomas', 'Disease', (178, 202))
169636	33833226	DeltaNp63alpha can function as a proto-oncogene in promoting cancer cell proliferation and survival.	('survival', 'CPA', (91, 99))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('promoting', 'PosReg', (51, 60))	('cancer', 'Disease', (61, 67))	('DeltaNp63alpha', 'Chemical', '-', (0, 14))	('DeltaNp63alpha', 'Var', (0, 14))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))
169637	33833226	It has been well documented that DeltaNp63alpha can directly bind to the promoter of CDKNIA (also known as p21CIP1) to inhibit its transcription, thereby promoting cell cycle progression and suppression of cell apoptosis.	('promoting', 'PosReg', (154, 163))	('DeltaNp63alpha', 'Chemical', '-', (33, 47))	('DeltaNp63alpha', 'Var', (33, 47))	('CDKNIA', 'Gene', (85, 91))	('inhibit', 'NegReg', (119, 126))	('transcription', 'MPA', (131, 144))	('suppression', 'NegReg', (191, 202))	('cell apoptosis', 'CPA', (206, 220))	('p21CIP1', 'Gene', (107, 114))	('cell cycle progression', 'CPA', (164, 186))	('p21CIP1', 'Gene', '1026', (107, 114))
169638	33833226	DeltaNp63alpha can also promote tumor growth by downregulation expression of growth-suppressing genes including PUMA and MIC-1, and upregulation expression of growth-promoting genes including cyclins D1 and E1 (CCND1, CCNE1).	('MIC-1', 'Gene', (121, 126))	('cyclins D1 and E1', 'Gene', '595;898', (192, 209))	('CCND1', 'Gene', (211, 216))	('expression', 'MPA', (145, 155))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('PUMA', 'Gene', (112, 116))	('promote', 'PosReg', (24, 31))	('CCNE1', 'Gene', (218, 223))	('upregulation', 'PosReg', (132, 144))	('MIC-1', 'Gene', '9518', (121, 126))	('expression', 'MPA', (63, 73))	('tumor', 'Disease', (32, 37))	('CCNE1', 'Gene', '898', (218, 223))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('DeltaNp63alpha', 'Chemical', '-', (0, 14))	('downregulation', 'NegReg', (48, 62))	('DeltaNp63alpha', 'Var', (0, 14))	('CCND1', 'Gene', '595', (211, 216))	('PUMA', 'Gene', '27113', (112, 116))
169639	33833226	In addition, p63 can form hetero oligomers with p53 and inhibits its transcription function.	('p53', 'Gene', (48, 51))	('p53', 'Gene', '7157', (48, 51))	('transcription', 'MPA', (69, 82))	('inhibits', 'NegReg', (56, 64))	('p63', 'Var', (13, 16))	('hetero oligomers', 'MPA', (26, 42))
169640	33833226	The TCF3 gene, also called E2A, encodes two alternative splicing variants, E47 and E12, both of which are members of basic helix-loop-helix (bHLH) transcription factor.	('E2A', 'Gene', (27, 30))	('TCF3', 'Gene', (4, 8))	('E12', 'Gene', '26767', (83, 86))	('E47', 'Var', (75, 78))	('E2A', 'Gene', '6929', (27, 30))	('E12', 'Gene', (83, 86))	('TCF3', 'Gene', '6929', (4, 8))
169641	33833226	On the other hand, it has been reported that E47 can function as a growth suppresser in adenocarcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('E47', 'Var', (45, 48))	('adenocarcinoma', 'Disease', 'MESH:D000230', (88, 102))	('growth', 'CPA', (67, 73))	('adenocarcinoma', 'Disease', (88, 102))
169642	33833226	Under that circumstances, E47 can downregulate Myc protein expression and upregulate expression of p27 or p21 protein to inhibit cell-cycle progression and promote senescence.	('inhibit', 'NegReg', (121, 128))	('expression', 'MPA', (85, 95))	('Myc', 'Gene', '4609', (47, 50))	('p27', 'Gene', (99, 102))	('Myc', 'Gene', (47, 50))	('cell-cycle progression', 'CPA', (129, 151))	('upregulate', 'PosReg', (74, 84))	('E47', 'Var', (26, 29))	('downregulate', 'NegReg', (34, 46))	('senescence', 'CPA', (164, 174))	('p21', 'Gene', '1026', (106, 109))	('p27', 'Gene', '3429', (99, 102))	('p21', 'Gene', (106, 109))	('promote', 'PosReg', (156, 163))
169644	33833226	In this study, we demonstrate that E47 plays the inhibitory role on cell proliferation in adenocarcinoma.	('cell proliferation', 'CPA', (68, 86))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('adenocarcinoma', 'Disease', (90, 104))	('adenocarcinoma', 'Disease', 'MESH:D000230', (90, 104))	('E47', 'Var', (35, 38))
169645	33833226	By sharp contrast, E47 functions as a oncoprotein to promote growth of squamous cell carcinoma through directly transactivating DeltaNp63alpha expression.	('DeltaNp63alpha', 'Protein', (128, 142))	('growth', 'MPA', (61, 67))	('DeltaNp63alpha', 'Chemical', '-', (128, 142))	('expression', 'MPA', (143, 153))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (71, 94))	('transactivating', 'Reg', (112, 127))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (71, 94))	('E47', 'Var', (19, 22))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('squamous cell carcinoma', 'Disease', (71, 94))	('promote', 'PosReg', (53, 60))
169646	33833226	It has been reported that E47 inhibits cell proliferation in adenocarcinoma, while its roles in SCC are largely unknown.	('carcinoma', 'Phenotype', 'HP:0030731', (66, 75))	('SCC', 'Phenotype', 'HP:0002860', (96, 99))	('adenocarcinoma', 'Disease', 'MESH:D000230', (61, 75))	('E47', 'Var', (26, 29))	('cell proliferation', 'CPA', (39, 57))	('inhibits', 'NegReg', (30, 38))	('adenocarcinoma', 'Disease', (61, 75))
169649	33833226	1A, B, E47 was lowly expressed in adenocarcinoma of lung and esophagus, whereas E47 was highly expressed in SCC of lung and esophagus.	('E47', 'Var', (80, 83))	('carcinoma', 'Phenotype', 'HP:0030731', (39, 48))	('SCC', 'Phenotype', 'HP:0002860', (108, 111))	('adenocarcinoma of lung', 'Disease', (34, 56))	('esophagus', 'Disease', (61, 70))	('adenocarcinoma of lung', 'Disease', 'MESH:D000077192', (34, 56))	('E47', 'Var', (7, 10))
169650	33833226	Consistently, the expression of E47 in adenocarcinoma A549 cells was lower than that in SCC FaDu and H292 cells (Fig.	('adenocarcinoma', 'Disease', 'MESH:D000230', (39, 53))	('E47', 'Var', (32, 35))	('lower', 'NegReg', (69, 74))	('H292', 'CellLine', 'CVCL:0455', (101, 105))	('A549', 'CellLine', 'CVCL:0023', (54, 58))	('expression', 'MPA', (18, 28))	('carcinoma', 'Phenotype', 'HP:0030731', (44, 53))	('adenocarcinoma', 'Disease', (39, 53))	('SCC', 'Phenotype', 'HP:0002860', (88, 91))
169651	33833226	Moreover, ectopic expression of E47 inhibited cell proliferation in adenocarcinoma A549 and H1299 cells, as evidenced by MTS assays and colony formation assays (Fig.	('inhibited', 'NegReg', (36, 45))	('adenocarcinoma', 'Disease', (68, 82))	('E47', 'Gene', (32, 35))	('A549', 'CellLine', 'CVCL:0023', (83, 87))	('H1299', 'CellLine', 'CVCL:0060', (92, 97))	('adenocarcinoma', 'Disease', 'MESH:D000230', (68, 82))	('ectopic expression', 'Var', (10, 28))	('cell proliferation', 'CPA', (46, 64))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
169653	33833226	Unlike wild-type E47, E47A592N/I596D mutant (E47DM) defective in its transcriptional activity, had little effects on cell proliferation (Fig.	('I596D', 'Mutation', 'p.I596D', (31, 36))	('cell proliferation', 'CPA', (117, 135))	('E47A592N/I596D', 'Var', (22, 36))	('transcriptional activity', 'MPA', (69, 93))
169654	33833226	These data indicate that E47 plays the opposite roles on cell proliferation in adenocarcinoma and SCC and that E47 functions as a oncoprotein in SCC, which is dependent on its transcriptional activity.	('SCC', 'Phenotype', 'HP:0002860', (98, 101))	('SCC', 'Disease', (98, 101))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('SCC', 'Phenotype', 'HP:0002860', (145, 148))	('E47', 'Var', (111, 114))	('adenocarcinoma', 'Disease', (79, 93))	('SCC', 'Disease', (145, 148))	('adenocarcinoma', 'Disease', 'MESH:D000230', (79, 93))	('E47', 'Gene', (25, 28))	('cell proliferation', 'CPA', (57, 75))
169655	33833226	In keeping with this notion, E47 inhibited expression of Cyclin E1 and Cyclin D1 and upregulated expression of cell-cycle inhibitor p21 in adenocarcinoma A549 and H1299 cells (Fig.	('A549', 'CellLine', 'CVCL:0023', (154, 158))	('expression', 'MPA', (97, 107))	('Cyclin E1', 'Gene', '898', (57, 66))	('adenocarcinoma', 'Disease', 'MESH:D000230', (139, 153))	('upregulated', 'PosReg', (85, 96))	('Cyclin D1', 'Gene', '595', (71, 80))	('Cyclin E1', 'Gene', (57, 66))	('H1299', 'CellLine', 'CVCL:0060', (163, 168))	('p21', 'Gene', '1026', (132, 135))	('cell-cycle', 'Gene', (111, 121))	('p21', 'Gene', (132, 135))	('Cyclin D1', 'Gene', (71, 80))	('E47', 'Var', (29, 32))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('adenocarcinoma', 'Disease', (139, 153))	('expression', 'MPA', (43, 53))	('inhibited', 'NegReg', (33, 42))
169656	33833226	By sharp contrast, E47 significantly upregulated expression of Cyclin E1 and Cyclin D1 and suppressed expression of p21 in SCC H292 and FaDu cells (Fig.	('suppressed', 'NegReg', (91, 101))	('SCC', 'Phenotype', 'HP:0002860', (123, 126))	('p21', 'Gene', (116, 119))	('upregulated', 'PosReg', (37, 48))	('expression', 'MPA', (102, 112))	('Cyclin D1', 'Gene', '595', (77, 86))	('SCC H292', 'CellLine', 'CVCL:0455', (123, 131))	('expression', 'MPA', (49, 59))	('Cyclin D1', 'Gene', (77, 86))	('Cyclin E1', 'Gene', '898', (63, 72))	('E47', 'Var', (19, 22))	('Cyclin E1', 'Gene', (63, 72))	('p21', 'Gene', '1026', (116, 119))
169657	33833226	We therefore asked whether DeltaNp63alpha plays a role in E47-mediated stimulation of SCC cell proliferation.	('SCC', 'Disease', (86, 89))	('SCC', 'Phenotype', 'HP:0002860', (86, 89))	('DeltaNp63alpha', 'Chemical', '-', (27, 41))	('DeltaNp63alpha', 'Var', (27, 41))
169658	33833226	S1C, ectopic expression of E47 significantly upregulated DeltaNp63alpha expression, concomitant with increased Cyclins D1/E1 expression and decreased p21 expression in H292, FaDu, and KYSE150 cells, while ectopic expression of E47DM mutant was unable to do so.	('decreased', 'NegReg', (140, 149))	('Cyclins D1/E1', 'Gene', '595;898', (111, 124))	('H292', 'CellLine', 'CVCL:0455', (168, 172))	('increased', 'PosReg', (101, 110))	('DeltaNp63alpha', 'Chemical', '-', (57, 71))	('expression', 'MPA', (72, 82))	('expression', 'MPA', (125, 135))	('upregulated', 'PosReg', (45, 56))	('KYSE150', 'CellLine', 'CVCL:1348', (184, 191))	('p21', 'Gene', '1026', (150, 153))	('p21', 'Gene', (150, 153))	('E47', 'Var', (27, 30))	('Cyclins D1/E1', 'Gene', (111, 124))	('DeltaNp63alpha', 'Gene', (57, 71))	('expression', 'MPA', (154, 164))
169659	33833226	We then used shRNAs specific for E2A (E12/E47) to knockdown of E47 in H292, FaDu, and KYSE150 cells.	('KYSE150', 'CellLine', 'CVCL:1348', (86, 93))	('knockdown', 'Var', (50, 59))	('H292', 'CellLine', 'CVCL:0455', (70, 74))	('E2A (E12/E47)', 'Gene', '6929', (33, 46))	('E2A (E12/E47', 'Gene', (33, 45))	('E47', 'Gene', (63, 66))
169660	33833226	S1D, E, silencing of E47 significantly reduced expression of DeltaNp63alpha, concomitant with decreased Cyclins E1/D1 expression, increased p21 expression, and suppression of cell proliferation.	('increased', 'PosReg', (130, 139))	('cell proliferation', 'CPA', (175, 193))	('DeltaNp63alpha', 'Protein', (61, 75))	('expression', 'MPA', (144, 154))	('DeltaNp63alpha', 'Chemical', '-', (61, 75))	('silencing', 'Var', (8, 17))	('suppression', 'NegReg', (160, 171))	('decreased', 'NegReg', (94, 103))	('reduced', 'NegReg', (39, 46))	('E47', 'Gene', (21, 24))	('Cyclins E1/D1', 'Protein', (104, 117))	('expression', 'MPA', (118, 128))	('p21', 'Gene', '1026', (140, 143))	('expression', 'MPA', (47, 57))	('p21', 'Gene', (140, 143))
169661	33833226	Together, these results indicate that E47 significantly upregulates DeltaNp63alpha protein expression and promotes cell proliferation in SCC cells.	('SCC', 'Phenotype', 'HP:0002860', (137, 140))	('expression', 'MPA', (91, 101))	('upregulates', 'PosReg', (56, 67))	('DeltaNp63alpha protein', 'Protein', (68, 90))	('promotes', 'PosReg', (106, 114))	('cell proliferation', 'CPA', (115, 133))	('DeltaNp63alpha', 'Chemical', '-', (68, 82))	('E47', 'Var', (38, 41))
169663	33833226	2A, silencing of DeltaNp63alpha completely reversed E47-induced changes expression of Cyclin E1, Cyclin D1, and p21, all of which are downstream effectors of DeltaNp63alpha.	('DeltaNp63alpha', 'Gene', (17, 31))	('Cyclin D1', 'Gene', (97, 106))	('Cyclin E1', 'Gene', (86, 95))	('DeltaNp63alpha', 'Chemical', '-', (158, 172))	('p21', 'Gene', '1026', (112, 115))	('E47-induced', 'Gene', (52, 63))	('DeltaNp63alpha', 'Chemical', '-', (17, 31))	('Cyclin E1', 'Gene', '898', (86, 95))	('silencing', 'Var', (4, 13))	('Cyclin D1', 'Gene', '595', (97, 106))	('p21', 'Gene', (112, 115))
169664	33833226	Consistently, silencing of DeltaNp63alpha significantly rescued E47-mediated cell proliferation in H292 and FaDu cells, as evidenced by MTS assays and colony formation assays (Fig.	('H292', 'CellLine', 'CVCL:0455', (99, 103))	('silencing', 'Var', (14, 23))	('DeltaNp63alpha', 'Gene', (27, 41))	('DeltaNp63alpha', 'Chemical', '-', (27, 41))	('E47-mediated cell proliferation', 'CPA', (64, 95))	('rescued', 'NegReg', (56, 63))
169665	33833226	In addition, ectopic expression of wild-type E47, but not E47DM, led to increased BrdU+ cell and S-phase population in SCC H292 cells, both of which were rescued by simultaneous silencing of  Np63 (Fig.	('E47', 'Var', (45, 48))	('BrdU', 'Chemical', 'MESH:D001973', (82, 86))	('increased', 'PosReg', (72, 81))	('Np63', 'Gene', (192, 196))	('E47DM', 'Var', (58, 63))	('SCC H292', 'CellLine', 'CVCL:0455', (119, 127))	('SCC', 'Phenotype', 'HP:0002860', (119, 122))
169666	33833226	By contrast, silencing of E47 led to an increase of the BrdU+ cells in H1299 cells (Fig.	('increase', 'PosReg', (40, 48))	('E47', 'Gene', (26, 29))	('H1299', 'CellLine', 'CVCL:0060', (71, 76))	('BrdU', 'Chemical', 'MESH:D001973', (56, 60))	('BrdU+ cells in H1299 cells', 'CPA', (56, 82))	('silencing', 'Var', (13, 22))
169667	33833226	These results indicate that DeltaNp63alpha plays a causative role in E47-induced cell proliferation of SCC.	('cell proliferation', 'CPA', (81, 99))	('SCC', 'Phenotype', 'HP:0002860', (103, 106))	('DeltaNp63alpha', 'Var', (28, 42))	('DeltaNp63alpha', 'Chemical', '-', (28, 42))	('E47-induced', 'Var', (69, 80))
169668	33833226	To further substantiate this conclusion, we examined the role of E47-DeltaNp63alpha in tumor growth in vivo.	('E47-DeltaNp63alpha', 'Var', (65, 83))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Disease', (87, 92))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('DeltaNp63alpha', 'Chemical', '-', (69, 83))
169669	33833226	2G, H, ectopic expression of E47, but not E47DM, dramatically promoted tumor growth in H292 xenograft mouse model.	('H292', 'CellLine', 'CVCL:0455', (87, 91))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('E47', 'Var', (29, 32))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('promoted', 'PosReg', (62, 70))	('tumor', 'Disease', (71, 76))	('mouse', 'Species', '10090', (102, 107))
169670	33833226	Notably, silencing of DeltaNp63alpha completely rescued E47-induced tumor growth (Fig.	('tumor', 'Disease', (68, 73))	('DeltaNp63alpha', 'Protein', (22, 36))	('silencing', 'Var', (9, 18))	('DeltaNp63alpha', 'Chemical', '-', (22, 36))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('E47-induced', 'Gene', (56, 67))	('rescued', 'NegReg', (48, 55))
169671	33833226	Furthermore, Flag-E47-expressing tumors exhibited significant increased Ki67+ cells and decreased cleaved caspase-3 + (CC3 + ) cells, all of which were rescued by silencing of DeltaNp63alpha (Fig.	('increased', 'PosReg', (62, 71))	('silencing', 'Var', (163, 172))	('caspase-3', 'Gene', '836', (106, 115))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('caspase-3', 'Gene', (106, 115))	('DeltaNp63alpha', 'Protein', (176, 190))	('tumors', 'Disease', 'MESH:D009369', (33, 39))	('decreased', 'NegReg', (88, 97))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('DeltaNp63alpha', 'Chemical', '-', (176, 190))	('tumors', 'Disease', (33, 39))	('Ki67+ cells', 'CPA', (72, 83))
169672	33833226	2I), indicating that E47-mediated upregulation of DeltaNp63alpha consequently facilitates tumor growth through increased cell proliferation and reduced apoptotic cell death.	('reduced', 'NegReg', (144, 151))	('increased', 'PosReg', (111, 120))	('death', 'Disease', 'MESH:D003643', (167, 172))	('death', 'Disease', (167, 172))	('DeltaNp63alpha', 'Chemical', '-', (50, 64))	('tumor', 'Disease', (90, 95))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('cell proliferation', 'CPA', (121, 139))	('DeltaNp63alpha', 'Gene', (50, 64))	('E47-mediated', 'Var', (21, 33))	('facilitates', 'PosReg', (78, 89))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('upregulation', 'PosReg', (34, 46))
169673	33833226	Together, these results demonstrate that DeltaNp63alpha is an essential downstream effector of E47 in promoting cell proliferation and tumor growth in SCC.	('cell proliferation', 'CPA', (112, 130))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('SCC', 'Phenotype', 'HP:0002860', (151, 154))	('SCC', 'Disease', (151, 154))	('tumor', 'Disease', (135, 140))	('tumor', 'Disease', 'MESH:D009369', (135, 140))	('promoting', 'PosReg', (102, 111))	('DeltaNp63alpha', 'Chemical', '-', (41, 55))	('DeltaNp63alpha', 'Var', (41, 55))
169675	33833226	3A, silencing of E2A significantly reduced steady-state DeltaNp63 mRNA levels, concomitant with upregulation of steady-state p21 (CDKN1A) mRNA levels and downregulation of steady-state mRNA levels of Cyclin E1 (CCNE1) and Cyclin D1 (CCND1).	('CDKN1A', 'Gene', (130, 136))	('CCND1', 'Gene', '595', (233, 238))	('p21', 'Gene', '1026', (125, 128))	('reduced', 'NegReg', (35, 42))	('CDKN1A', 'Gene', '1026', (130, 136))	('CCND1', 'Gene', (233, 238))	('Cyclin E1', 'Gene', '898', (200, 209))	('mRNA levels', 'MPA', (185, 196))	('Cyclin D1', 'Gene', '595', (222, 231))	('Cyclin D1', 'Gene', (222, 231))	('E2A', 'Gene', '6929', (17, 20))	('silencing', 'Var', (4, 13))	('E2A', 'Gene', (17, 20))	('CCNE1', 'Gene', (211, 216))	('downregulation', 'NegReg', (154, 168))	('p21', 'Gene', (125, 128))	('CCNE1', 'Gene', '898', (211, 216))	('DeltaNp63 mRNA levels', 'MPA', (56, 77))	('upregulation', 'PosReg', (96, 108))	('Cyclin E1', 'Gene', (200, 209))
169676	33833226	Conversely, ectopic expression of E47 dramatically upregulated steady-state DeltaNp63 mRNA levels, concomitant with the changes of steady-state mRNA levels of Cyclin E1, Cyclin D1, and p21 in H292 and FaDu cells (Fig.	('Cyclin E1', 'Gene', (159, 168))	('Cyclin D1', 'Gene', (170, 179))	('p21', 'Gene', (185, 188))	('DeltaNp63 mRNA levels', 'MPA', (76, 97))	('changes', 'Reg', (120, 127))	('Cyclin E1', 'Gene', '898', (159, 168))	('mRNA levels', 'MPA', (144, 155))	('upregulated', 'PosReg', (51, 62))	('E47', 'Var', (34, 37))	('H292', 'CellLine', 'CVCL:0455', (192, 196))	('p21', 'Gene', '1026', (185, 188))	('Cyclin D1', 'Gene', '595', (170, 179))
169677	33833226	Furthermore, silencing of DeltaNp63alpha significantly rescued E47-mediated changes of steady-state mRNA levels of Cyclin E1, Cyclin D1 and p21 in H292 and FaDu cells (Fig.	('H292', 'CellLine', 'CVCL:0455', (147, 151))	('Cyclin E1', 'Gene', (115, 124))	('steady-state', 'MPA', (87, 99))	('DeltaNp63alpha', 'Chemical', '-', (26, 40))	('rescued', 'NegReg', (55, 62))	('E47-mediated', 'Gene', (63, 75))	('Cyclin D1', 'Gene', '595', (126, 135))	('changes', 'MPA', (76, 83))	('DeltaNp63alpha', 'Gene', (26, 40))	('Cyclin E1', 'Gene', '898', (115, 124))	('Cyclin D1', 'Gene', (126, 135))	('p21', 'Gene', '1026', (140, 143))	('silencing', 'Var', (13, 22))	('p21', 'Gene', (140, 143))
169678	33833226	Together, these results indicate that E47 upregulates DeltaNp63 gene transcription, which, in turn, regulates transcription of cyclins D1/E1 and p21.	('cyclins D1/E1', 'Gene', (127, 140))	('p21', 'Gene', '1026', (145, 148))	('transcription', 'MPA', (69, 82))	('p21', 'Gene', (145, 148))	('DeltaNp63', 'Gene', (54, 63))	('transcription', 'MPA', (110, 123))	('cyclins D1/E1', 'Gene', '595;898', (127, 140))	('regulates', 'Reg', (100, 109))	('E47', 'Var', (38, 41))	('upregulates', 'PosReg', (42, 53))
169680	33833226	Data from ChIP experiments showed that E47 directly bound P1 and P2 but not P3 sites in H292 cells (Fig.	('H292', 'CellLine', 'CVCL:0455', (88, 92))	('bound', 'Interaction', (52, 57))	('E47', 'Var', (39, 42))
169684	33833226	3H, ectopic expression of E47 was unable to upregulate steady-state DeltaNp63 mRNA levels in A549 cells.	('E47', 'Var', (26, 29))	('DeltaNp63 mRNA levels', 'MPA', (68, 89))	('A549', 'CellLine', 'CVCL:0023', (93, 97))
169686	33833226	These results indicate that DeltaNp63alpha is a direct E47 transcriptional target in SCC cells, but not in adenocarcinoma cells.	('SCC', 'Disease', (85, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('DeltaNp63alpha', 'Var', (28, 42))	('adenocarcinoma', 'Disease', (107, 121))	('DeltaNp63alpha', 'Chemical', '-', (28, 42))	('adenocarcinoma', 'Disease', 'MESH:D000230', (107, 121))	('SCC', 'Phenotype', 'HP:0002860', (85, 88))
169687	33833226	Our results prompted us to verify the clinical relevance of the E47-p63 axis in squamous cell carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('E47-p63 axis', 'Var', (64, 76))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (80, 103))	('squamous cell carcinoma', 'Disease', (80, 103))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (80, 103))
169690	33833226	4C, D, a significant positive correlation was observed between p63 and E2A protein expression (R = 0.908; p < 0.0001).	('E2A', 'Gene', (71, 74))	('E2A', 'Gene', '6929', (71, 74))	('p63', 'Var', (63, 66))
169692	33833226	Together, these results indicate that E47 is positively correlated with p63 in SCC and that increased E47 expression is associated with poor clinical outcomes of SCC patients.	('associated', 'Reg', (120, 130))	('p63', 'Var', (72, 75))	('correlated', 'Reg', (56, 66))	('expression', 'MPA', (106, 116))	('SCC', 'Phenotype', 'HP:0002860', (79, 82))	('increased', 'PosReg', (92, 101))	('SCC', 'Disease', (79, 82))	('SCC', 'Phenotype', 'HP:0002860', (162, 165))	('E47', 'Gene', (102, 105))	('SCC', 'Disease', (162, 165))	('patients', 'Species', '9606', (166, 174))	('E47', 'Var', (38, 41))
169696	33833226	p63 is often overexpressed in SCC and is a well-known marker of squamous differentiation, whereas p63 is little expressed in advanced adenocarcinoma.	('adenocarcinoma', 'Disease', (134, 148))	('overexpressed', 'PosReg', (13, 26))	('SCC', 'Disease', (30, 33))	('carcinoma', 'Phenotype', 'HP:0030731', (139, 148))	('adenocarcinoma', 'Disease', 'MESH:D000230', (134, 148))	('p63', 'Var', (0, 3))	('SCC', 'Phenotype', 'HP:0002860', (30, 33))
169701	33833226	Therefore, we propose that the expression of DeltaNp63alpha is a critical intrinsic link between ADC and SCC.	('SCC', 'Disease', (105, 108))	('ADC', 'Disease', (97, 100))	('SCC', 'Phenotype', 'HP:0002860', (105, 108))	('DeltaNp63alpha', 'Chemical', '-', (45, 59))	('DeltaNp63alpha', 'Var', (45, 59))
169702	33833226	It would be worthwhile to further investigate how the expression of DeltaNp63alpha is lost during the development of ADC or expression of DeltaNp63alpha is established during SCC development and whether E47 plays a role in transdifferentiation of lung ADC to SCC.	('DeltaNp63alpha', 'Chemical', '-', (138, 152))	('SCC', 'Phenotype', 'HP:0002860', (175, 178))	('DeltaNp63alpha', 'Chemical', '-', (68, 82))	('SCC', 'Phenotype', 'HP:0002860', (259, 262))	('DeltaNp63alpha', 'Var', (138, 152))	('DeltaNp63alpha', 'Gene', (68, 82))
169709	33833226	We demonstrate that DeltaNp63alpha protein is a critical target of E47 in promoting cell proliferation and tumor growth in squamous cell carcinoma.	('squamous cell carcinoma', 'Disease', (123, 146))	('DeltaNp63alpha protein', 'Protein', (20, 42))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('E47', 'Var', (67, 70))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('DeltaNp63alpha', 'Chemical', '-', (20, 34))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (123, 146))	('promoting', 'PosReg', (74, 83))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('cell proliferation', 'CPA', (84, 102))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (123, 146))
169710	33833226	Importantly, clinical validation of human lung SCC and esophagus SCC samples reveals a significant and positive correlation between p63 and E47, and that lung SCC patients with high E47 expression show poor overall survival.	('correlation', 'Interaction', (112, 123))	('patients', 'Species', '9606', (163, 171))	('SCC', 'Phenotype', 'HP:0002860', (47, 50))	('p63', 'Var', (132, 135))	('SCC', 'Phenotype', 'HP:0002860', (159, 162))	('overall survival', 'CPA', (207, 223))	('SCC', 'Phenotype', 'HP:0002860', (65, 68))	('lung SCC', 'Disease', (154, 162))	('poor', 'NegReg', (202, 206))	('E47', 'Var', (182, 185))	('human', 'Species', '9606', (36, 41))	('E47', 'Var', (140, 143))
169711	33833226	Therefore, targeting E47-DeltaNp63alpha axis may be a potential therapeutic strategy for treatment of squamous cell carcinoma.	('squamous cell carcinoma', 'Disease', (102, 125))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('DeltaNp63alpha', 'Chemical', '-', (25, 39))	('E47-DeltaNp63alpha', 'Var', (21, 39))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (102, 125))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (102, 125))
169718	33833226	E47A592N/I596D and  Np63 promotor deletion P2 site (Delta-1665~-1656) were generated by KOD-Plus-Mutagenesis kit (SMK-101, Toyobo Osaka).	('Np63', 'Gene', (20, 24))	('Delta-1665~-1656', 'Var', (52, 68))	('E47A592N/I596D', 'Var', (0, 14))	('I596D', 'Mutation', 'p.I596D', (9, 14))
169719	33833226	A pLKO.1-puromysci lentiviral vector was used to generate short hairpin RNAs (shRNAs) targeting GFP, E2A, or p63.	('E2A', 'Gene', (101, 104))	('E2A', 'Gene', '6929', (101, 104))	('p63', 'Var', (109, 112))	('GFP', 'Gene', (96, 99))
169724	33833226	Antibodies specific for p63 (CY5659), p21 (CY5543), and GAPDH (AB0037) were purchased from Abways (Shanghai, China).	('CY5659', 'Var', (29, 35))	('CY5543', 'Chemical', '-', (43, 49))	('p21', 'Gene', (38, 41))	('GAPDH', 'Gene', '2597', (56, 61))	('GAPDH', 'Gene', (56, 61))	('p21', 'Gene', '1026', (38, 41))
169725	33833226	Antibodies specific for CyclinE1 (3327) and CyclinD1 (2261) were purchased from Epitomics (Burlingame CA, USA).	('CyclinE1', 'Gene', '898', (24, 32))	('CyclinE1', 'Gene', (24, 32))	('CyclinD1', 'Gene', (44, 52))	('CyclinD1', 'Gene', '595', (44, 52))	('3327', 'Var', (34, 38))
169848	33061803	First, we found that dioscin not only inhibited cell proliferation and cell migration and induced cell apoptosis in lung SCC cells but also suppressed tumour growth in tumour-bearing mice.	('suppressed', 'NegReg', (140, 150))	('cell apoptosis', 'CPA', (98, 112))	('dioscin', 'Var', (21, 28))	('tumour', 'Phenotype', 'HP:0002664', (151, 157))	('tumour', 'Phenotype', 'HP:0002664', (168, 174))	('tumour', 'Disease', 'MESH:D009369', (168, 174))	('dioscin', 'Chemical', 'MESH:C019357', (21, 28))	('SCC', 'Gene', (121, 124))	('cell proliferation', 'CPA', (48, 66))	('inhibited', 'NegReg', (38, 47))	('mice', 'Species', '10090', (183, 187))	('tumour', 'Disease', 'MESH:D009369', (151, 157))	('SCC', 'Phenotype', 'HP:0002860', (121, 124))	('tumour', 'Disease', (151, 157))	('tumour', 'Disease', (168, 174))	('induced', 'Reg', (90, 97))	('SCC', 'Gene', '6317', (121, 124))	('cell migration', 'CPA', (71, 85))
169862	33061803	Moreover, dioscin has been confirmed to induce DNA damage and cell apoptosis and to inhibit cell proliferation and cell invasion in human lung cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('lung cancer', 'Disease', 'MESH:D008175', (138, 149))	('inhibit', 'NegReg', (84, 91))	('human', 'Species', '9606', (132, 137))	('dioscin', 'Var', (10, 17))	('DNA damage', 'MPA', (47, 57))	('cell apoptosis', 'CPA', (62, 76))	('dioscin', 'Chemical', 'MESH:C019357', (10, 17))	('lung cancer', 'Disease', (138, 149))	('lung cancer', 'Phenotype', 'HP:0100526', (138, 149))	('induce', 'PosReg', (40, 46))
169867	33061803	Moreover, dioscin upregulates ROS levels to accelerate DNA damage, mitochondrial dysfunction and subsequent cell apoptosis in other cancers.	('cancers', 'Disease', (132, 139))	('upregulates', 'PosReg', (18, 29))	('DNA damage', 'MPA', (55, 65))	('cancers', 'Disease', 'MESH:D009369', (132, 139))	('upregulates ROS levels', 'Phenotype', 'HP:0025464', (18, 40))	('ROS', 'Chemical', 'MESH:D017382', (30, 33))	('dioscin', 'Var', (10, 17))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('mitochondrial dysfunction', 'Disease', 'MESH:D028361', (67, 92))	('dioscin', 'Chemical', 'MESH:C019357', (10, 17))	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (67, 92))	('ROS levels', 'MPA', (30, 40))	('mitochondrial dysfunction', 'Disease', (67, 92))	('cancers', 'Phenotype', 'HP:0002664', (132, 139))	('accelerate', 'PosReg', (44, 54))
169874	33061803	Although some previous studies have indicated that HSP27 phosphorylation contributes to p38-MAPK-induced apoptosis, it may play a cytoprotective role under certain conditions.	('p38-MAPK', 'Gene', (88, 96))	('HSP27', 'Gene', (51, 56))	('p38-MAPK', 'Gene', '1432', (88, 96))	('apoptosis', 'CPA', (105, 114))	('phosphorylation', 'Var', (57, 72))	('HSP27', 'Gene', '3315', (51, 56))	('contributes', 'Reg', (73, 84))
169876	33061803	We hypothesized that dioscin could induce cell apoptosis through the ROS-mediated p38-MAPK/HSP27 signalling pathway in lung SCC cells.	('dioscin', 'Var', (21, 28))	('p38-MAPK', 'Gene', (82, 90))	('ROS', 'Chemical', 'MESH:D017382', (69, 72))	('dioscin', 'Chemical', 'MESH:C019357', (21, 28))	('p38-MAPK', 'Gene', '1432', (82, 90))	('SCC', 'Gene', (124, 127))	('SCC', 'Phenotype', 'HP:0002860', (124, 127))	('cell apoptosis', 'CPA', (42, 56))	('induce', 'PosReg', (35, 41))	('HSP27', 'Gene', (91, 96))	('HSP27', 'Gene', '3315', (91, 96))	('SCC', 'Gene', '6317', (124, 127))	('lung', 'Disease', (119, 123))
169883	33061803	The p38 inhibitor SB203580 and the p38 activator Anisomycin were purchased from Selleck Chemicals (Houston, TX, USA), while reactive oxygen species inhibitor antioxidant N-Acetyl-L-cysteine (NAC) was purchased from Sigma-Aldrich (St. Louis, MO, USA).	('NAC', 'Chemical', 'MESH:D000111', (191, 194))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (124, 147))	('SB203580', 'Chemical', 'MESH:C093642', (18, 26))	('p38', 'Gene', '1432', (4, 7))	('p38', 'Gene', '1432', (35, 38))	('Anisomycin', 'Chemical', 'MESH:D000841', (49, 59))	('N-Acetyl-L-cysteine', 'Chemical', 'MESH:D000111', (170, 189))	('SB203580', 'Var', (18, 26))	('p38', 'Gene', (4, 7))	('p38', 'Gene', (35, 38))
169902	33061803	Antibodies against Bcl2, Bax, cleaved caspase-3, cleaved PARP, p38, p-p38 (Thr180/Tyr182), E-cadherin, N-cadherin and Vimentin were purchased from Cell Signalling Technology (Danvers, MA, USA).	('p38', 'Gene', (70, 73))	('Vimentin', 'Gene', '7431', (118, 126))	('p38', 'Gene', '1432', (63, 66))	('Bax', 'Gene', (25, 28))	('cleaved', 'Var', (49, 56))	('caspase-3', 'Gene', '836', (38, 47))	('Bax', 'Gene', '581', (25, 28))	('Vimentin', 'Gene', (118, 126))	('E-cadherin', 'Gene', (91, 101))	('E-cadherin', 'Gene', '999', (91, 101))	('Bcl2', 'Gene', (19, 23))	('p38', 'Gene', '1432', (70, 73))	('PARP', 'Gene', '1302', (57, 61))	('caspase-3', 'Gene', (38, 47))	('Bcl2', 'Gene', '596', (19, 23))	('N-cadherin', 'Gene', (103, 113))	('N-cadherin', 'Gene', '1000', (103, 113))	('Tyr182', 'Chemical', '-', (82, 88))	('p38', 'Gene', (63, 66))	('PARP', 'Gene', (57, 61))	('Thr180', 'Chemical', '-', (75, 81))
169931	33061803	4A, we found that dioscin clearly increased the levels of p-p38 and p-HSP27, while the levels of total p38 and HSP27 were not obviously changes in NCI-H520 and SK-MES-1 cells.	('p38', 'Gene', '1432', (60, 63))	('HSP27', 'Gene', (70, 75))	('p38', 'Gene', (103, 106))	('HSP27', 'Gene', '3315', (111, 116))	('HSP27', 'Gene', (111, 116))	('HSP27', 'Gene', '3315', (70, 75))	('SK-MES-1', 'CellLine', 'CVCL:0630', (160, 168))	('p38', 'Gene', '1432', (103, 106))	('p38', 'Gene', (60, 63))	('dioscin', 'Var', (18, 25))	('dioscin', 'Chemical', 'MESH:C019357', (18, 25))	('increased', 'PosReg', (34, 43))
169943	33061803	6A, there was a significant reduction in tumour volume in dioscin-treated mice compared with vehicle-treated control mice at day 12.	('dioscin-treated', 'Var', (58, 73))	('dioscin', 'Chemical', 'MESH:C019357', (58, 65))	('tumour', 'Phenotype', 'HP:0002664', (41, 47))	('tumour', 'Disease', 'MESH:D009369', (41, 47))	('mice', 'Species', '10090', (117, 121))	('tumour', 'Disease', (41, 47))	('mice', 'Species', '10090', (74, 78))	('reduction', 'NegReg', (28, 37))
169946	33061803	The weight of NCI-H520 tumours in dioscin-treated mice was lower than that in control mice (Fig.	('tumour', 'Phenotype', 'HP:0002664', (23, 29))	('dioscin-treated', 'Var', (34, 49))	('tumours', 'Phenotype', 'HP:0002664', (23, 30))	('lower', 'NegReg', (59, 64))	('NCI-H520 tumours', 'Disease', (14, 30))	('weight', 'CPA', (4, 10))	('NCI-H520 tumours', 'Disease', 'MESH:D009369', (14, 30))	('mice', 'Species', '10090', (86, 90))	('dioscin', 'Chemical', 'MESH:C019357', (34, 41))	('mice', 'Species', '10090', (50, 54))
169970	33061803	Fluctuations in intracellular ROS levels induced by dioscin cause damage to cellular structures, which accelerating apoptosis.	('apoptosis', 'CPA', (116, 125))	('intracellular ROS levels', 'MPA', (16, 40))	('cellular structures', 'CPA', (76, 95))	('dioscin', 'Var', (52, 59))	('accelerating', 'PosReg', (103, 115))	('dioscin', 'Chemical', 'MESH:C019357', (52, 59))	('Fluctuations', 'MPA', (0, 12))	('ROS', 'Chemical', 'MESH:D017382', (30, 33))
169977	33061803	However, some controversial evidence has proven that inactivation of p38-MAPK inhibits tumorigenesis.	('p38-MAPK', 'Gene', (69, 77))	('p38-MAPK', 'Gene', '1432', (69, 77))	('inhibits', 'NegReg', (78, 86))	('inactivation', 'Var', (53, 65))	('tumorigenesis', 'CPA', (87, 100))
170009	31595151	Many studies have shown that the abnormal expression of FZD2 is significantly associated with the development of many tumors, such as gastric cancer, hepatocellular carcinoma and endometrial cancer, in which FZD2 plays oncogenic roles.	('gastric cancer', 'Disease', (134, 148))	('expression', 'MPA', (42, 52))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('hepatocellular carcinoma', 'Disease', (150, 174))	('endometrial cancer', 'Phenotype', 'HP:0012114', (179, 197))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('gastric cancer', 'Disease', 'MESH:D013274', (134, 148))	('endometrial cancer', 'Disease', (179, 197))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('tumors', 'Disease', (118, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (165, 174))	('associated', 'Reg', (78, 88))	('endometrial cancer', 'Disease', 'MESH:D016889', (179, 197))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('FZD2', 'Gene', (56, 60))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (150, 174))	('gastric cancer', 'Phenotype', 'HP:0012126', (134, 148))	('tumors', 'Disease', 'MESH:D009369', (118, 124))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (150, 174))	('abnormal', 'Var', (33, 41))
170020	31595151	We further analyzed the data and determined that FZD2 was significantly increased in head and neck squamous cell carcinoma and tongue cancer compared with normal tissues (Fig 1B); moreover, the overall survival of patients with head and neck squamous carcinoma with high FZD2 expression (n=194, FPKM>means) was significantly decreased (Fig 1C, P=0.02) when compared FZD2 low expression (n=307, FPKM<means).	('head and neck squamous cell carcinoma', 'Disease', 'MESH:C535575', (85, 122))	('high', 'Var', (266, 270))	('patients', 'Species', '9606', (214, 222))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (242, 260))	('FZD2', 'Gene', (271, 275))	('tongue cancer', 'Disease', (127, 140))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (99, 122))	('head and neck squamous carcinoma', 'Phenotype', 'HP:0012288', (228, 260))	('carcinoma', 'Phenotype', 'HP:0030731', (251, 260))	('tongue cancer', 'Disease', 'MESH:D014062', (127, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (85, 122))	('head and neck squamous carcinoma', 'Disease', 'MESH:C535575', (228, 260))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('decreased', 'NegReg', (325, 334))	('expression', 'MPA', (276, 286))
170027	31595151	The CCK8 (Fig 2C and Fig S1B) and colony formation assays (Fig 2D and Fig S1C) indicated that the siRNA-mediated knockdown of FZD2 significantly inhibited the growth of tongue cancer cells.	('tongue cancer', 'Disease', 'MESH:D014062', (169, 182))	('FZD2', 'Gene', (126, 130))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('knockdown', 'Var', (113, 122))	('tongue cancer', 'Disease', (169, 182))	('inhibited', 'NegReg', (145, 154))
170036	31595151	As seen from the tumor weight (Fig 4A) and tumor sizes (Fig 4B), the tumor growth rate of the siRNA-605 group and siRNA-931 group was significantly lower than that of NC group.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor', 'Disease', (17, 22))	('tumor', 'Disease', (69, 74))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('siRNA-605', 'Var', (94, 103))	('lower', 'NegReg', (148, 153))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('tumor', 'Disease', (43, 48))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
170037	31595151	Furthermore, the FZD2 protein level and proliferation index (Ki-67) of xenograft tumors of the siRNA transfection group were decreased compared with the negative control, while the apoptotic cells (as indicated as Caspase-9 level) were increased (Fig 4C, P<0.001).	('Caspase-9', 'Gene', (214, 223))	('tumors', 'Disease', (81, 87))	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('Ki-67', 'Chemical', 'MESH:D019394', (61, 66))	('apoptotic cells', 'CPA', (181, 196))	('decreased', 'NegReg', (125, 134))	('Caspase-9', 'Gene', '842', (214, 223))	('transfection', 'Var', (101, 113))	('FZD2 protein level', 'MPA', (17, 35))	('increased', 'PosReg', (236, 245))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('proliferation index', 'CPA', (40, 59))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))
170040	31595151	The transwell assay (Fig 5B and Fig S1D), which used transwell inserts that were uncoated or were coated Matrigel, demonstrated that the invasion and migration of tongue cancer cells were decreased in the siRNA-605 group and siRNA-931 group compared to the NC group.	('decreased', 'NegReg', (188, 197))	('invasion', 'CPA', (137, 145))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('siRNA-605', 'Var', (205, 214))	('tongue cancer', 'Disease', (163, 176))	('migration', 'CPA', (150, 159))	('tongue cancer', 'Disease', 'MESH:D014062', (163, 176))
170045	31595151	When the 501 samples were divided into two groups according to the expression level of FZD2, the expression of WNT3A, WNT5B and WNT2 was significantly higher and that of WNT4 was significantly lower (Fig 6B) in the FZD2-high group (n=194) compared with the FZD2-low group (n=307).	('WNT2', 'Gene', (128, 132))	('WNT3A', 'Gene', (111, 116))	('WNT4', 'Gene', (170, 174))	('WNT4', 'Gene', '54361', (170, 174))	('WNT2', 'Gene', '7472', (128, 132))	('FZD2', 'Gene', (87, 91))	('lower', 'NegReg', (193, 198))	('higher', 'PosReg', (151, 157))	('WNT3A', 'Gene', '89780', (111, 116))	('WNT5B', 'Gene', '81029', (118, 123))	('WNT5B', 'Gene', (118, 123))	('expression', 'MPA', (97, 107))	('FZD2-high', 'Var', (215, 224))
170059	31595151	When the WNT/Frizzled signaling pathway is abnormally expressed, tumor proliferation, invasion, immunity, chemoresistance and stemness are frequently dysregulated.	('tumor', 'Disease', (65, 70))	('immunity', 'CPA', (96, 104))	('dysregulated', 'Reg', (150, 162))	('abnormally', 'Var', (43, 53))	('stemness', 'Disease', 'MESH:D020295', (126, 134))	('stemness', 'Disease', (126, 134))	('chemoresistance', 'CPA', (106, 121))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('invasion', 'CPA', (86, 94))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
170061	31595151	explored the function of miR-30a-3p/5p in esophageal squamous cell carcinoma and determined that the downregulation of miR-30a-3p/5p promotes esophageal squamous cell carcinoma cell proliferation by activating the expression of WNT2 and FZD2.	('promotes', 'PosReg', (133, 141))	('activating', 'PosReg', (199, 209))	('WNT2', 'Gene', (228, 232))	('carcinoma', 'Phenotype', 'HP:0030731', (167, 176))	('esophageal squamous cell carcinoma', 'Disease', (42, 76))	('miR-30a', 'Gene', '407029', (25, 32))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (53, 76))	('esophageal squamous cell carcinoma', 'Disease', (142, 176))	('miR-30a', 'Gene', '407029', (119, 126))	('expression', 'MPA', (214, 224))	('miR-30a', 'Gene', (25, 32))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:C562729', (42, 76))	('miR-30a', 'Gene', (119, 126))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (153, 176))	('FZD2', 'Gene', (237, 241))	('WNT2', 'Gene', '7472', (228, 232))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('downregulation', 'Var', (101, 115))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:C562729', (142, 176))
170064	31595151	Another study showed that FZD2 was expressed in tumorous HCC tissue but not in the surrounding nontumorous tissue and that the proliferative capacity of hepatocellular carcinoma cells was decreased after transfection with FZD2-targeting shRNA.	('carcinoma', 'Phenotype', 'HP:0030731', (168, 177))	('tumorous HCC', 'Disease', 'MESH:D006528', (48, 60))	('decreased', 'NegReg', (188, 197))	('tumor', 'Disease', (48, 53))	('FZD2-targeting', 'Var', (222, 236))	('tumorous HCC', 'Disease', (48, 60))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (153, 177))	('proliferative capacity', 'CPA', (127, 149))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('hepatocellular carcinoma', 'Disease', (153, 177))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (153, 177))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Disease', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
170224	30419062	Association of specific gene mutations derived from machine learning with survival in lung adenocarcinoma Lung cancer is the second most common cancer in the United States and the leading cause of mortality in cancer patients.	('Lung cancer', 'Phenotype', 'HP:0100526', (106, 117))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (86, 105))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('Lung cancer', 'Disease', (106, 117))	('cancer', 'Disease', (144, 150))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (86, 105))	('cancer', 'Disease', (111, 117))	('Association', 'Interaction', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (210, 216))	('mutations', 'Var', (29, 38))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('patients', 'Species', '9606', (217, 225))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('lung adenocarcinoma', 'Disease', (86, 105))	('Lung cancer', 'Disease', 'MESH:D008175', (106, 117))	('cancer', 'Disease', (210, 216))
170227	30419062	The objective of this study was to perform machine learning with data from The Cancer Genome Atlas of patients with lung adenocarcinoma (LUAD) to find survival-specific gene mutations that could be used as survival-predicting biomarkers.	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (116, 135))	('patients', 'Species', '9606', (102, 110))	('lung adenocarcinoma', 'Disease', (116, 135))	('Cancer', 'Phenotype', 'HP:0002664', (79, 85))	('mutations', 'Var', (174, 183))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('LUAD', 'Phenotype', 'HP:0030078', (137, 141))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (116, 135))
170228	30419062	Mutations in MMRN2 and GMPPA were significantly associated with patient mortality while those in ZNF560 and SETX were associated with patient survival.	('GMPPA', 'Chemical', '-', (23, 28))	('patient', 'Species', '9606', (64, 71))	('SETX', 'Gene', (108, 112))	('GMPPA', 'Gene', (23, 28))	('ZNF560', 'Gene', (97, 103))	('associated with', 'Reg', (48, 63))	('SETX', 'Gene', '23064', (108, 112))	('ZNF560', 'Gene', '147741', (97, 103))	('MMRN2', 'Gene', '79812', (13, 18))	('Mutations', 'Var', (0, 9))	('associated', 'Reg', (118, 128))	('MMRN2', 'Gene', (13, 18))	('patient', 'Species', '9606', (134, 141))
170229	30419062	Mutations in DNAJC2 and MMRN2 showed significant negative association with overall survival while mutations in ZNF560 showed significant positive association with overall survival.	('ZNF560', 'Gene', '147741', (111, 117))	('ZNF560', 'Gene', (111, 117))	('positive', 'PosReg', (137, 145))	('negative', 'NegReg', (49, 57))	('MMRN2', 'Gene', '79812', (24, 29))	('mutations', 'Var', (98, 107))	('Mutations', 'Var', (0, 9))	('DNAJC2', 'Gene', (13, 19))	('overall survival', 'MPA', (75, 91))	('DNAJC2', 'Gene', '27000', (13, 19))	('MMRN2', 'Gene', (24, 29))
170230	30419062	Mutations in MMRN2 showed significant negative association with disease-free survival while mutations in DRD3 and ZNF560 showed positive associated with disease-free survival.	('DRD3', 'Gene', '1814', (105, 109))	('ZNF560', 'Gene', '147741', (114, 120))	('ZNF560', 'Gene', (114, 120))	('negative', 'NegReg', (38, 46))	('MMRN2', 'Gene', '79812', (13, 18))	('DRD3', 'Gene', (105, 109))	('mutations', 'Var', (92, 101))	('Mutations', 'Var', (0, 9))	('MMRN2', 'Gene', (13, 18))	('disease-free survival', 'CPA', (64, 85))
170231	30419062	Mutations in DRD3, SETX, and ZNF560 showed significant positive association with survival in patients with LUAD while the opposite was true for mutations in DNAJC2, GMPPA, and MMRN2.	('MMRN2', 'Gene', (176, 181))	('ZNF560', 'Gene', (29, 35))	('LUAD', 'Phenotype', 'HP:0030078', (107, 111))	('GMPPA', 'Chemical', '-', (165, 170))	('DRD3', 'Gene', '1814', (13, 17))	('LUAD', 'Disease', (107, 111))	('SETX', 'Gene', (19, 23))	('ZNF560', 'Gene', '147741', (29, 35))	('Mutations', 'Var', (0, 9))	('survival', 'MPA', (81, 89))	('DRD3', 'Gene', (13, 17))	('positive', 'PosReg', (55, 63))	('DNAJC2', 'Gene', (157, 163))	('MMRN2', 'Gene', '79812', (176, 181))	('DNAJC2', 'Gene', '27000', (157, 163))	('SETX', 'Gene', '23064', (19, 23))	('patients', 'Species', '9606', (93, 101))
170232	30419062	These gene mutations were also found in other cohorts of LUAD, lung squamous cell carcinoma, and small cell lung cancer.	('small cell lung cancer', 'Disease', 'MESH:D055752', (97, 119))	('mutations', 'Var', (11, 20))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (97, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (63, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('small cell lung cancer', 'Disease', (97, 119))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (63, 91))	('lung squamous cell carcinoma', 'Disease', (63, 91))	('lung cancer', 'Phenotype', 'HP:0100526', (108, 119))	('LUAD', 'Phenotype', 'HP:0030078', (57, 61))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (68, 91))	('LUAD', 'Disease', (57, 61))	('found', 'Reg', (31, 36))
170233	30419062	In LUAD of Pan-Lung Cancer cohort, mutations in GMPPA, DNAJC2, and MMRN2 showed significant negative associations with survival of patients while mutations in DRD3 and SETX showed significant positive association with survival.	('DRD3', 'Gene', (159, 163))	('MMRN2', 'Gene', '79812', (67, 72))	('LUAD', 'Phenotype', 'HP:0030078', (3, 7))	('MMRN2', 'Gene', (67, 72))	('negative', 'NegReg', (92, 100))	('Pan-Lung Cancer', 'Disease', 'MESH:D008175', (11, 26))	('Lung Cancer', 'Phenotype', 'HP:0100526', (15, 26))	('survival', 'MPA', (119, 127))	('Pan-Lung Cancer', 'Disease', (11, 26))	('DNAJC2', 'Gene', '27000', (55, 61))	('patients', 'Species', '9606', (131, 139))	('DRD3', 'Gene', '1814', (159, 163))	('SETX', 'Gene', (168, 172))	('GMPPA', 'Chemical', '-', (48, 53))	('GMPPA', 'Gene', (48, 53))	('DNAJC2', 'Gene', (55, 61))	('Cancer', 'Phenotype', 'HP:0002664', (20, 26))	('SETX', 'Gene', '23064', (168, 172))	('associations', 'Interaction', (101, 113))	('mutations', 'Var', (35, 44))
170234	30419062	In this study, machine learning was conducted to obtain information necessary to discover specific gene mutations associated with the survival of patients with LUAD.	('mutations', 'Var', (104, 113))	('LUAD', 'Phenotype', 'HP:0030078', (160, 164))	('LUAD', 'Disease', (160, 164))	('associated', 'Reg', (114, 124))	('patients', 'Species', '9606', (146, 154))
170235	30419062	Mutations in the above six genes could predict survival rate and disease-free survival rate in patients with LUAD.	('survival rate', 'CPA', (47, 60))	('patients', 'Species', '9606', (95, 103))	('disease-free survival', 'CPA', (65, 86))	('Mutations', 'Var', (0, 9))	('LUAD', 'Phenotype', 'HP:0030078', (109, 113))	('predict', 'Reg', (39, 46))	('LUAD', 'Disease', (109, 113))
170243	30419062	These methods can be used to identify breast cancer patients by genetic mutations as a result of applying gene learning methods to breast cancer samples.	('mutations', 'Var', (72, 81))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('breast cancer', 'Disease', 'MESH:D001943', (38, 51))	('breast cancer', 'Disease', (38, 51))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('breast cancer', 'Disease', 'MESH:D001943', (131, 144))	('breast cancer', 'Phenotype', 'HP:0003002', (38, 51))	('breast cancer', 'Disease', (131, 144))	('breast cancer', 'Phenotype', 'HP:0003002', (131, 144))	('patients', 'Species', '9606', (52, 60))
170244	30419062	One prostate cancer study has combined machine learning methods with National Institute for Health and Care Excellence features to observe the association between the prognosis of prostate cancer and genetic mutation profile.	('prostate cancer', 'Disease', 'MESH:D011471', (4, 19))	('prostate cancer', 'Disease', (180, 195))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('prostate cancer', 'Phenotype', 'HP:0012125', (4, 19))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('genetic mutation profile', 'Var', (200, 224))	('prostate cancer', 'Disease', 'MESH:D011471', (180, 195))	('prostate cancer', 'Phenotype', 'HP:0012125', (180, 195))	('prostate cancer', 'Disease', (4, 19))
170246	30419062	In this study, machine learning methods with data from The Cancer Genome Atlas (TCGA) of patients with lung adenocarcinoma (LUAD) were utilized to discover gene mutations associated with patient survival.	('patient', 'Species', '9606', (89, 96))	('LUAD', 'Phenotype', 'HP:0030078', (124, 128))	('lung adenocarcinoma', 'Disease', (103, 122))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (103, 122))	('patients', 'Species', '9606', (89, 97))	('mutations', 'Var', (161, 170))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('Cancer', 'Phenotype', 'HP:0002664', (59, 65))	('patient', 'Species', '9606', (187, 194))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (103, 122))	('associated', 'Reg', (171, 181))
170247	30419062	Results suggested that mutations in six genes, DRD3, SETX, ZNF560, DNAJC2, GMPPA, and MMRN2, were significantly associated with survival and overall survival time of patients with LUAD.	('MMRN2', 'Gene', (86, 91))	('associated with', 'Reg', (112, 127))	('ZNF560', 'Gene', '147741', (59, 65))	('DNAJC2', 'Gene', '27000', (67, 73))	('DNAJC2', 'Gene', (67, 73))	('GMPPA', 'Chemical', '-', (75, 80))	('GMPPA', 'Gene', (75, 80))	('LUAD', 'Disease', (180, 184))	('DRD3', 'Gene', '1814', (47, 51))	('DRD3', 'Gene', (47, 51))	('mutations', 'Var', (23, 32))	('LUAD', 'Phenotype', 'HP:0030078', (180, 184))	('SETX', 'Gene', (53, 57))	('survival', 'CPA', (128, 136))	('MMRN2', 'Gene', '79812', (86, 91))	('SETX', 'Gene', '23064', (53, 57))	('patients', 'Species', '9606', (166, 174))	('ZNF560', 'Gene', (59, 65))
170259	30419062	Results suggested that specific gene mutations were associated with patient survival.	('mutations', 'Var', (37, 46))	('associated', 'Reg', (52, 62))	('patient survival', 'CPA', (68, 84))	('patient', 'Species', '9606', (68, 75))
170260	30419062	Among mutations in 19 genes, mutations in GMPPA and MMRN2 were significantly associated with patient mortality while mutations in ZNF560 and SETX were significantly associated with patient survival (Fig 1 and Table 1).	('MMRN2', 'Gene', (52, 57))	('mutations', 'Var', (117, 126))	('SETX', 'Gene', (141, 145))	('patient', 'Species', '9606', (181, 188))	('mutations', 'Var', (29, 38))	('patient mortality', 'CPA', (93, 110))	('associated with', 'Reg', (165, 180))	('ZNF560', 'Gene', (130, 136))	('GMPPA', 'Chemical', '-', (42, 47))	('GMPPA', 'Gene', (42, 47))	('SETX', 'Gene', '23064', (141, 145))	('patient', 'Species', '9606', (93, 100))	('MMRN2', 'Gene', '79812', (52, 57))	('ZNF560', 'Gene', '147741', (130, 136))	('patient', 'MPA', (181, 188))	('associated', 'Reg', (77, 87))
170262	30419062	However, the median survival time in patients with mutations in MMRN2 was about 11 months.	('patients', 'Species', '9606', (37, 45))	('MMRN2', 'Gene', '79812', (64, 69))	('mutations', 'Var', (51, 60))	('MMRN2', 'Gene', (64, 69))
170263	30419062	Mutations in MMRN2 were significantly and negatively associated with disease-free survival while mutations in DRD3 and ZNF560 were significantly and positively associated with disease-free survival.	('DRD3', 'Gene', (110, 114))	('mutations', 'Var', (97, 106))	('MMRN2', 'Gene', '79812', (13, 18))	('disease-free survival', 'CPA', (69, 90))	('Mutations', 'Var', (0, 9))	('associated', 'Reg', (53, 63))	('ZNF560', 'Gene', (119, 125))	('DRD3', 'Gene', '1814', (110, 114))	('MMRN2', 'Gene', (13, 18))	('ZNF560', 'Gene', '147741', (119, 125))	('associated', 'Reg', (160, 170))	('negatively', 'NegReg', (42, 52))
170264	30419062	The median disease-free survival time in patients with LUAD was about 36 months while that in patients with mutations in MMRN2 was about 5 months.	('LUAD', 'Phenotype', 'HP:0030078', (55, 59))	('MMRN2', 'Gene', (121, 126))	('patients', 'Species', '9606', (94, 102))	('mutations', 'Var', (108, 117))	('LUAD', 'Disease', (55, 59))	('disease-free survival', 'CPA', (11, 32))	('patients', 'Species', '9606', (41, 49))	('MMRN2', 'Gene', '79812', (121, 126))
170265	30419062	Mutations in DNAJC2, GMPPA, MMRN2, DRD3, SETX, and ZNF560 were associated with survival in patients with LUAD.	('patients', 'Species', '9606', (91, 99))	('ZNF560', 'Gene', '147741', (51, 57))	('ZNF560', 'Gene', (51, 57))	('DRD3', 'Gene', (35, 39))	('SETX', 'Gene', '23064', (41, 45))	('associated with', 'Reg', (63, 78))	('DNAJC2', 'Gene', (13, 19))	('Mutations', 'Var', (0, 9))	('LUAD', 'Disease', (105, 109))	('GMPPA', 'Gene', (21, 26))	('GMPPA', 'Chemical', '-', (21, 26))	('MMRN2', 'Gene', '79812', (28, 33))	('DNAJC2', 'Gene', '27000', (13, 19))	('SETX', 'Gene', (41, 45))	('LUAD', 'Phenotype', 'HP:0030078', (105, 109))	('MMRN2', 'Gene', (28, 33))	('DRD3', 'Gene', '1814', (35, 39))
170267	30419062	About 42% of patients with LUAD lacking a mutation in MMRN2 relapsed with a median disease-free time of about 33 months while those with mutations in MMRN2 all relapsed within 10 months.	('LUAD', 'Disease', (27, 31))	('LUAD', 'Phenotype', 'HP:0030078', (27, 31))	('MMRN2', 'Gene', '79812', (54, 59))	('MMRN2', 'Gene', '79812', (150, 155))	('patients', 'Species', '9606', (13, 21))	('LUAD lacking', 'Phenotype', 'HP:0009788', (27, 39))	('MMRN2', 'Gene', (54, 59))	('mutation', 'Var', (42, 50))	('MMRN2', 'Gene', (150, 155))	('lacking', 'NegReg', (32, 39))
170268	30419062	Therefore, mutations in DNAJC2 and/or MMRN2 are considered to be predictors of survival or relapse of patients with LUAD since the probability of death or recurrence due to LUAD might be higher in the presence of mutations in DNAJC2 or MMRN2.	('mutations', 'Var', (11, 20))	('MMRN2', 'Gene', '79812', (236, 241))	('patients', 'Species', '9606', (102, 110))	('MMRN2', 'Gene', (236, 241))	('DNAJC2', 'Gene', '27000', (24, 30))	('MMRN2', 'Gene', '79812', (38, 43))	('DNAJC2', 'Gene', (24, 30))	('LUAD', 'Phenotype', 'HP:0030078', (173, 177))	('presence', 'Reg', (201, 209))	('DNAJC2', 'Gene', (226, 232))	('DNAJC2', 'Gene', '27000', (226, 232))	('LUAD', 'Disease', (173, 177))	('mutations', 'Var', (213, 222))	('MMRN2', 'Gene', (38, 43))	('death', 'Disease', 'MESH:D003643', (146, 151))	('LUAD', 'Phenotype', 'HP:0030078', (116, 120))	('higher', 'PosReg', (187, 193))	('death', 'Disease', (146, 151))
170269	30419062	In contrast, patients with LUAD without a mutation in ZNF560 had shorter survival than other patients, with a median survival time of about 45 months while those with mutations in ZNF560 all survived.	('LUAD', 'Disease', (27, 31))	('survival', 'MPA', (73, 81))	('ZNF560', 'Gene', (180, 186))	('LUAD', 'Phenotype', 'HP:0030078', (27, 31))	('ZNF560', 'Gene', '147741', (180, 186))	('patients', 'Species', '9606', (13, 21))	('shorter', 'NegReg', (65, 72))	('mutation', 'Var', (42, 50))	('ZNF560', 'Gene', '147741', (54, 60))	('ZNF560', 'Gene', (54, 60))	('patients', 'Species', '9606', (93, 101))
170270	30419062	Additionally, about 42% of patients with LUAD without a mutation in ZNF560 or DRD3 relapsed with a median disease-free time of about 30 months.	('LUAD', 'Disease', (41, 45))	('LUAD', 'Phenotype', 'HP:0030078', (41, 45))	('DRD3', 'Gene', '1814', (78, 82))	('DRD3', 'Gene', (78, 82))	('patients', 'Species', '9606', (27, 35))	('mutation', 'Var', (56, 64))	('ZNF560', 'Gene', '147741', (68, 74))	('ZNF560', 'Gene', (68, 74))
170271	30419062	However, those with mutations in ZNF560 or DRD3 relapsed at a rate of about 11% or 0%, respectively.	('ZNF560', 'Gene', (33, 39))	('DRD3', 'Gene', '1814', (43, 47))	('DRD3', 'Gene', (43, 47))	('ZNF560', 'Gene', '147741', (33, 39))	('mutations', 'Var', (20, 29))
170272	30419062	Because the probability of death or relapse due to LUAD might be lower when the ZNF560 or DRD3 was mutated, mutations in ZNF560 or DRD3 were considered to be predictors of survival or relapse in patients with LUAD.	('ZNF560', 'Gene', (121, 127))	('DRD3', 'Gene', '1814', (131, 135))	('ZNF560', 'Gene', (80, 86))	('LUAD', 'Phenotype', 'HP:0030078', (51, 55))	('LUAD', 'Disease', (51, 55))	('DRD3', 'Gene', (90, 94))	('mutations', 'Var', (108, 117))	('ZNF560', 'Gene', '147741', (80, 86))	('lower', 'NegReg', (65, 70))	('DRD3', 'Gene', (131, 135))	('LUAD', 'Phenotype', 'HP:0030078', (209, 213))	('death', 'Disease', 'MESH:D003643', (27, 32))	('death', 'Disease', (27, 32))	('mutated', 'Var', (99, 106))	('patients', 'Species', '9606', (195, 203))	('DRD3', 'Gene', '1814', (90, 94))	('ZNF560', 'Gene', '147741', (121, 127))
170273	30419062	Mutations in DNAJC2 or MMRN2 were negatively associated with survival.	('survival', 'CPA', (61, 69))	('MMRN2', 'Gene', (23, 28))	('associated', 'Reg', (45, 55))	('Mutations', 'Var', (0, 9))	('DNAJC2', 'Gene', (13, 19))	('DNAJC2', 'Gene', '27000', (13, 19))	('negatively', 'NegReg', (34, 44))	('MMRN2', 'Gene', '79812', (23, 28))
170275	30419062	However, mutations in DRD3 or ZNF560 were positively associated with survival.	('mutations', 'Var', (9, 18))	('DRD3', 'Gene', '1814', (22, 26))	('survival', 'CPA', (69, 77))	('DRD3', 'Gene', (22, 26))	('ZNF560', 'Gene', '147741', (30, 36))	('ZNF560', 'Gene', (30, 36))	('associated with', 'Reg', (53, 68))
170276	30419062	Furthermore, mutations in DNAJC2, GMPPA, or MMRN2 significantly decreased median survival time to 11.27 months and the median disease-free survival time to 6.87 months (Fig 3).	('disease-free survival', 'CPA', (126, 147))	('DNAJC2', 'Gene', '27000', (26, 32))	('DNAJC2', 'Gene', (26, 32))	('MMRN2', 'Gene', '79812', (44, 49))	('GMPPA', 'Chemical', '-', (34, 39))	('GMPPA', 'Gene', (34, 39))	('MMRN2', 'Gene', (44, 49))	('median survival time', 'CPA', (74, 94))	('mutations', 'Var', (13, 22))	('decreased', 'NegReg', (64, 73))
170277	30419062	Mutations in DRD3, SETX, or ZNF560 significantly increased both survival time and disease-free survival time.	('survival time', 'CPA', (64, 77))	('increased', 'PosReg', (49, 58))	('DRD3', 'Gene', '1814', (13, 17))	('SETX', 'Gene', (19, 23))	('Mutations', 'Var', (0, 9))	('DRD3', 'Gene', (13, 17))	('disease-free survival time', 'CPA', (82, 108))	('SETX', 'Gene', '23064', (19, 23))	('ZNF560', 'Gene', '147741', (28, 34))	('ZNF560', 'Gene', (28, 34))
170278	30419062	Patients with LUAD who had mutations in DNAJC2, GMPPA, or MMRN2 exhibited significantly shorter survival and earlier recurrence than those without mutations.	('mutations', 'Var', (27, 36))	('shorter', 'NegReg', (88, 95))	('LUAD', 'Disease', (14, 18))	('LUAD', 'Phenotype', 'HP:0030078', (14, 18))	('survival', 'CPA', (96, 104))	('MMRN2', 'Gene', '79812', (58, 63))	('DNAJC2', 'Gene', '27000', (40, 46))	('DNAJC2', 'Gene', (40, 46))	('Patients', 'Species', '9606', (0, 8))	('GMPPA', 'Gene', (48, 53))	('GMPPA', 'Chemical', '-', (48, 53))	('MMRN2', 'Gene', (58, 63))
170279	30419062	However, patients with mutations in DRD3, SETX, or ZNF560 exhibited longer survival and later recurrence than those without these mutations.	('DRD3', 'Gene', '1814', (36, 40))	('patients', 'Species', '9606', (9, 17))	('SETX', 'Gene', (42, 46))	('ZNF560', 'Gene', '147741', (51, 57))	('longer', 'PosReg', (68, 74))	('ZNF560', 'Gene', (51, 57))	('DRD3', 'Gene', (36, 40))	('SETX', 'Gene', '23064', (42, 46))	('mutations', 'Var', (23, 32))
170280	30419062	The frequency of mutations in six gene associated with survival was further analyzed in other lung cancer types such as lung squamous cell carcinoma, small cell lung cancer, and another two data sets of LUAD (Table 3 and S3 Fig).	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (125, 148))	('small cell lung cancer', 'Disease', (150, 172))	('lung cancer', 'Disease', 'MESH:D008175', (94, 105))	('LUAD', 'Phenotype', 'HP:0030078', (203, 207))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (120, 148))	('lung squamous cell carcinoma', 'Disease', (120, 148))	('carcinoma', 'Phenotype', 'HP:0030731', (139, 148))	('lung cancer', 'Phenotype', 'HP:0100526', (161, 172))	('lung cancer', 'Disease', (94, 105))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (120, 148))	('small cell lung cancer', 'Disease', 'MESH:D055752', (150, 172))	('lung cancer', 'Phenotype', 'HP:0100526', (94, 105))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (150, 172))	('mutations', 'Var', (17, 26))	('lung cancer', 'Disease', 'MESH:D008175', (161, 172))
170281	30419062	Mutations in these six genes were found not only in another two LUAD data sets (n = 21 and n = 4), but also in lung squamous cell carcinoma (n = 28), small cell lung cancer (n = 12), and Pan-lung cancer (n = 146).	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('small cell lung cancer', 'Disease', (150, 172))	('LUAD', 'Phenotype', 'HP:0030078', (64, 68))	('lung cancer', 'Phenotype', 'HP:0100526', (161, 172))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (111, 139))	('Pan-lung cancer', 'Disease', 'MESH:D008175', (187, 202))	('Mutations', 'Var', (0, 9))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (111, 139))	('Pan-lung cancer', 'Disease', (187, 202))	('small cell lung cancer', 'Disease', 'MESH:D055752', (150, 172))	('found', 'Reg', (34, 39))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (116, 139))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('lung cancer', 'Phenotype', 'HP:0100526', (191, 202))	('lung squamous cell carcinoma', 'Disease', (111, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (150, 172))
170282	30419062	Associations of mutations in six genes with survival were analyzed using three data sets of lung cancer cohorts with survival information (Table 4).	('lung cancer', 'Disease', (92, 103))	('lung cancer', 'Phenotype', 'HP:0100526', (92, 103))	('Associations', 'Interaction', (0, 12))	('mutations', 'Var', (16, 25))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('lung cancer', 'Disease', 'MESH:D008175', (92, 103))
170283	30419062	Mutations in GMPPA, DNAJC2, and MMRN2 were significantly associated with patient mortality in lung adenocarcinoma of Pan-Lung Cancer cohort.	('MMRN2', 'Gene', '79812', (32, 37))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('MMRN2', 'Gene', (32, 37))	('GMPPA', 'Chemical', '-', (13, 18))	('lung adenocarcinoma of Pan-Lung Cancer', 'Disease', 'MESH:D008175', (94, 132))	('Cancer', 'Phenotype', 'HP:0002664', (126, 132))	('GMPPA', 'Gene', (13, 18))	('lung adenocarcinoma of Pan-Lung Cancer', 'Disease', (94, 132))	('Mutations', 'Var', (0, 9))	('patient', 'Species', '9606', (73, 80))	('DNAJC2', 'Gene', '27000', (20, 26))	('DNAJC2', 'Gene', (20, 26))	('associated with', 'Reg', (57, 72))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (94, 113))	('Lung Cancer', 'Phenotype', 'HP:0100526', (121, 132))
170284	30419062	Mutations in DNAJC2 and MMRN2 were significantly associated with shortened overall survival (median survival of 10 and 21.9 months, respectively) (S4 Fig).	('MMRN2', 'Gene', '79812', (24, 29))	('shortened', 'NegReg', (65, 74))	('Mutations', 'Var', (0, 9))	('DNAJC2', 'Gene', (13, 19))	('overall survival', 'MPA', (75, 91))	('DNAJC2', 'Gene', '27000', (13, 19))	('MMRN2', 'Gene', (24, 29))
170285	30419062	Mutations in DRD3 and SETX were significantly associated with patient survival, and mutations in SETX extended overall survival.	('SETX', 'Gene', '23064', (22, 26))	('SETX', 'Gene', (97, 101))	('patient survival', 'CPA', (62, 78))	('DRD3', 'Gene', '1814', (13, 17))	('patient', 'Species', '9606', (62, 69))	('overall', 'MPA', (111, 118))	('extended', 'PosReg', (102, 110))	('mutations', 'Var', (84, 93))	('Mutations', 'Var', (0, 9))	('SETX', 'Gene', (22, 26))	('DRD3', 'Gene', (13, 17))	('SETX', 'Gene', '23064', (97, 101))	('associated', 'Reg', (46, 56))
170286	30419062	These gene mutations were not associated with mortality or overall survival in other types of lung cancer.	('associated', 'Reg', (30, 40))	('mutations', 'Var', (11, 20))	('lung cancer', 'Disease', 'MESH:D008175', (94, 105))	('lung cancer', 'Disease', (94, 105))	('lung cancer', 'Phenotype', 'HP:0100526', (94, 105))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
170287	30419062	These results suggested that mutations in DNAJC2, GMPPA, MMRN2, DRD3, and SETX could be significantly associated with survival in patients with LUAD.	('MMRN2', 'Gene', '79812', (57, 62))	('LUAD', 'Disease', (144, 148))	('associated with', 'Reg', (102, 117))	('LUAD', 'Phenotype', 'HP:0030078', (144, 148))	('DRD3', 'Gene', '1814', (64, 68))	('GMPPA', 'Chemical', '-', (50, 55))	('GMPPA', 'Gene', (50, 55))	('mutations', 'Var', (29, 38))	('DRD3', 'Gene', (64, 68))	('SETX', 'Gene', (74, 78))	('MMRN2', 'Gene', (57, 62))	('patients', 'Species', '9606', (130, 138))	('SETX', 'Gene', '23064', (74, 78))	('DNAJC2', 'Gene', '27000', (42, 48))	('DNAJC2', 'Gene', (42, 48))
170292	30419062	Patients with LUAD were divided into surviving and non-surviving groups and machine learning was performed with four feature selection methods to identify gene mutations associated with survival of patients with LUAD from mutations in about 40,000 genes.	('LUAD', 'Phenotype', 'HP:0030078', (212, 216))	('mutations', 'Var', (160, 169))	('LUAD', 'Phenotype', 'HP:0030078', (14, 18))	('patients', 'Species', '9606', (198, 206))	('Patients', 'Species', '9606', (0, 8))	('mutations', 'Var', (222, 231))	('associated', 'Reg', (170, 180))	('LUAD', 'Disease', (212, 216))
170293	30419062	The most frequently observed mutations determined by machine learning were in SETX and ZNF560 genes.	('ZNF560', 'Gene', (87, 93))	('ZNF560', 'Gene', '147741', (87, 93))	('mutations', 'Var', (29, 38))	('SETX', 'Gene', (78, 82))	('SETX', 'Gene', '23064', (78, 82))
170295	30419062	Mutations in MMRN2 and DNAJC2 were significantly and negatively associated with patient survival while those in ZNF560 and DRD3 were positively associated with patient survival.	('associated', 'Reg', (64, 74))	('associated', 'Reg', (144, 154))	('MMRN2', 'Gene', '79812', (13, 18))	('DRD3', 'Gene', '1814', (123, 127))	('DNAJC2', 'Gene', (23, 29))	('ZNF560', 'Gene', '147741', (112, 118))	('DRD3', 'Gene', (123, 127))	('ZNF560', 'Gene', (112, 118))	('Mutations', 'Var', (0, 9))	('patient survival', 'CPA', (80, 96))	('negatively', 'NegReg', (53, 63))	('DNAJC2', 'Gene', '27000', (23, 29))	('MMRN2', 'Gene', (13, 18))	('patient', 'Species', '9606', (160, 167))	('patient', 'Species', '9606', (80, 87))
170296	30419062	Because of the relatively small number of mutations in LUAD cohort, mutations in six genes were applied to other data sets of lung cancer cohorts to analyze mutation frequencies and association with survivals such as Lung Adenocarcinoma (Broad and MSKCC) cohorts, Lung Squamous Cell Carcinoma TCGA cohort, Pan-Lung Cancer cohort, and Small Cell Lung Cancer cohort.	('Small Cell Lung Cancer', 'Phenotype', 'HP:0030357', (334, 356))	('Pan-Lung Cancer', 'Disease', 'MESH:D008175', (306, 321))	('Small Cell Lung Cancer', 'Disease', (334, 356))	('Lung Squamous Cell Carcinoma', 'Phenotype', 'HP:0030359', (264, 292))	('mutations', 'Var', (42, 51))	('Lung Adenocarcinoma', 'Phenotype', 'HP:0030078', (217, 236))	('Lung Squamous Cell Carcinoma', 'Disease', (264, 292))	('Pan-Lung Cancer', 'Disease', (306, 321))	('Carcinoma', 'Phenotype', 'HP:0030731', (283, 292))	('LUAD', 'Phenotype', 'HP:0030078', (55, 59))	('Cancer', 'Phenotype', 'HP:0002664', (350, 356))	('lung cancer', 'Disease', (126, 137))	('Small Cell Lung Cancer', 'Disease', 'MESH:D055752', (334, 356))	('Lung Adenocarcinoma', 'Disease', (217, 236))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (269, 292))	('Lung Squamous Cell Carcinoma', 'Disease', 'MESH:D002294', (264, 292))	('lung cancer', 'Disease', 'MESH:D008175', (126, 137))	('carcinoma', 'Phenotype', 'HP:0030731', (227, 236))	('Cancer', 'Phenotype', 'HP:0002664', (315, 321))	('Lung Cancer', 'Phenotype', 'HP:0100526', (345, 356))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('lung cancer', 'Phenotype', 'HP:0100526', (126, 137))	('Lung Adenocarcinoma', 'Disease', 'MESH:D000077192', (217, 236))	('mutations', 'Var', (68, 77))	('Lung Cancer', 'Phenotype', 'HP:0100526', (310, 321))
170297	30419062	The average frequency of mutations in six genes was 0.81% ~ 3.30% and their associations with survival were similar between LUAD cohort and Pan-Lung Cancer cohort.	('mutations', 'Var', (25, 34))	('LUAD', 'Phenotype', 'HP:0030078', (124, 128))	('Pan-Lung Cancer', 'Disease', (140, 155))	('Lung Cancer', 'Phenotype', 'HP:0100526', (144, 155))	('Pan-Lung Cancer', 'Disease', 'MESH:D008175', (140, 155))	('Cancer', 'Phenotype', 'HP:0002664', (149, 155))
170299	30419062	In LUAD of Pan-Lung Cancer cohort, mutations in DNAJC2, GMPPA, MMRN2, DRD3, and SETX were significantly associated with survival status, and those in DNAJC2, MMRN2, and SETX were significantly associated with overall survival.	('LUAD', 'Phenotype', 'HP:0030078', (3, 7))	('DNAJC2', 'Gene', '27000', (48, 54))	('Pan-Lung Cancer', 'Disease', 'MESH:D008175', (11, 26))	('DRD3', 'Gene', (70, 74))	('Lung Cancer', 'Phenotype', 'HP:0100526', (15, 26))	('SETX', 'Gene', (169, 173))	('MMRN2', 'Gene', '79812', (63, 68))	('associated with', 'Reg', (104, 119))	('DNAJC2', 'Gene', '27000', (150, 156))	('Pan-Lung Cancer', 'Disease', (11, 26))	('MMRN2', 'Gene', (63, 68))	('DNAJC2', 'Gene', (48, 54))	('SETX', 'Gene', (80, 84))	('survival', 'Disease', (120, 128))	('MMRN2', 'Gene', '79812', (158, 163))	('DNAJC2', 'Gene', (150, 156))	('GMPPA', 'Chemical', '-', (56, 61))	('GMPPA', 'Gene', (56, 61))	('SETX', 'Gene', '23064', (169, 173))	('DRD3', 'Gene', '1814', (70, 74))	('MMRN2', 'Gene', (158, 163))	('Cancer', 'Phenotype', 'HP:0002664', (20, 26))	('SETX', 'Gene', '23064', (80, 84))	('overall', 'MPA', (209, 216))	('associated', 'Reg', (193, 203))	('mutations', 'Var', (35, 44))
170300	30419062	This result supports that mutations in these six genes can predict the survival of patients with LUAD and overall survival time.	('predict', 'Reg', (59, 66))	('LUAD', 'Phenotype', 'HP:0030078', (97, 101))	('LUAD', 'Disease', (97, 101))	('mutations', 'Var', (26, 35))	('patients', 'Species', '9606', (83, 91))
170301	30419062	Mutations in MMRN2 and DNAJC2 were observed to be important for predicting the survival and prognosis negatively.	('MMRN2', 'Gene', '79812', (13, 18))	('DNAJC2', 'Gene', '27000', (23, 29))	('DNAJC2', 'Gene', (23, 29))	('Mutations', 'Var', (0, 9))	('MMRN2', 'Gene', (13, 18))
170313	30419062	Mutations in ZNF560 and SETX were observed to be important for predicting the survival and prognosis positively.	('SETX', 'Gene', '23064', (24, 28))	('Mutations', 'Var', (0, 9))	('ZNF560', 'Gene', '147741', (13, 19))	('ZNF560', 'Gene', (13, 19))	('SETX', 'Gene', (24, 28))
170319	30419062	Mutations in SETX are linked to neurodegenerative disorders, ataxia oculomotor apraxia type 2, and amyotrophic lateral sclerosis type 4.	('SETX', 'Gene', '23064', (13, 17))	('amyotrophic lateral sclerosis', 'Disease', 'MESH:D000690', (99, 128))	('amyotrophic lateral sclerosis', 'Disease', (99, 128))	('ataxia oculomotor apraxia type 2', 'Disease', 'MESH:C537308', (61, 93))	('neurodegenerative disorders', 'Disease', 'MESH:D019636', (32, 59))	('apraxia', 'Phenotype', 'HP:0002186', (79, 86))	('Mutations', 'Var', (0, 9))	('ataxia oculomotor apraxia type 2', 'Disease', (61, 93))	('neurodegenerative disorders', 'Phenotype', 'HP:0002180', (32, 59))	('amyotrophic lateral sclerosis', 'Phenotype', 'HP:0007354', (99, 128))	('neurodegenerative disorders', 'Disease', (32, 59))	('linked', 'Reg', (22, 28))	('oculomotor apraxia', 'Phenotype', 'HP:0000657', (68, 86))	('SETX', 'Gene', (13, 17))	('ataxia', 'Phenotype', 'HP:0001251', (61, 67))
170323	30419062	It is important to apply the optimal feature selection method that classifies human cancer genetic mutations according to specific factors among various feature selection methods.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('cancer', 'Disease', (84, 90))	('mutations', 'Var', (99, 108))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('human', 'Species', '9606', (78, 83))
170325	30419062	In summary, machine learning was conducted to obtain information necessary to select mutations in genes associated with survival of patients with LUAD.	('LUAD', 'Phenotype', 'HP:0030078', (146, 150))	('mutations', 'Var', (85, 94))	('LUAD', 'Disease', (146, 150))	('patients', 'Species', '9606', (132, 140))
170327	30419062	Mutations in DNAJC2, GMPPA, and MMRN2 can be used as biomarkers of negative prognosis for patient's overall survival and disease-free survival while mutations in DRD3, SETX, and ZNF560 can be used as biomarkers of positive prognosis.	('MMRN2', 'Gene', '79812', (32, 37))	('SETX', 'Gene', (168, 172))	('DRD3', 'Gene', (162, 166))	('MMRN2', 'Gene', (32, 37))	('SETX', 'Gene', '23064', (168, 172))	('GMPPA', 'Chemical', '-', (21, 26))	('DNAJC2', 'Gene', (13, 19))	('Mutations', 'Var', (0, 9))	('patient', 'Species', '9606', (90, 97))	('GMPPA', 'Gene', (21, 26))	('DNAJC2', 'Gene', '27000', (13, 19))	('DRD3', 'Gene', '1814', (162, 166))	('negative', 'NegReg', (67, 75))	('ZNF560', 'Gene', (178, 184))	('ZNF560', 'Gene', '147741', (178, 184))
170363	29977775	BRAF V600E and ALK protein were negative.	('ALK', 'Gene', (15, 18))	('V600E', 'Mutation', 'rs113488022', (5, 10))	('ALK', 'Gene', '238', (15, 18))	('V600E', 'Var', (5, 10))	('BRAF', 'Gene', '673', (0, 4))	('BRAF', 'Gene', (0, 4))
170386	29977775	Because BRAF, EGFR, KRAS and AKT1 mutations, and ALK rearrangements were recently identified in CMPTs, molecular genetic analyses of MSCGP and CMPT for the specific alterations may provide valuable information in understanding their pathogenesis.	('KRAS', 'Gene', '3845', (20, 24))	('KRAS', 'Gene', (20, 24))	('men', 'Species', '9606', (62, 65))	('BRAF', 'Gene', '673', (8, 12))	('ALK', 'Gene', '238', (49, 52))	('EGFR', 'Gene', (14, 18))	('EGFR', 'Gene', '1956', (14, 18))	('BRAF', 'Gene', (8, 12))	('AKT1', 'Gene', '207', (29, 33))	('ALK', 'Gene', (49, 52))	('AKT1', 'Gene', (29, 33))	('mutations', 'Var', (34, 43))
170387	29977775	The characteristics of the present case, such as large tumor size, unusual pattern of extension, and lack of immunohistochemical detection of BRAF V600E and ALK protein, are not aligned with the characteristics of CMPT.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('V600E', 'Var', (147, 152))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('ALK', 'Gene', (157, 160))	('tumor', 'Disease', (55, 60))	('BRAF', 'Gene', '673', (142, 146))	('V600E', 'Mutation', 'rs113488022', (147, 152))	('ALK', 'Gene', '238', (157, 160))	('BRAF', 'Gene', (142, 146))
170404	28977863	SFTA1P, LINC01272, GATA6-AS1 and MIR3945HG were closely related to the survival time of LUSC.	('GATA6-AS1', 'Var', (19, 28))	('SFTA1P', 'Gene', '207107', (0, 6))	('MIR3945HG', 'Gene', (33, 42))	('SFTA1P', 'Gene', (0, 6))	('LUSC', 'Phenotype', 'HP:0030359', (88, 92))	('MIR3945HG', 'Gene', '731424', (33, 42))	('LINC01272', 'Gene', (8, 17))	('LINC01272', 'Gene', '100506115', (8, 17))	('survival time of LUSC', 'CPA', (71, 92))	('related', 'Reg', (56, 63))
170421	28977863	Survival analyses showed that SFTA1P, LINC01272, GATA6-AS1 and MIR3945HG were significantly related to the survival time of LUSC (Figure 4).	('GATA6-AS1', 'Var', (49, 58))	('LUSC', 'Phenotype', 'HP:0030359', (124, 128))	('LINC01272', 'Gene', '100506115', (38, 47))	('MIR3945HG', 'Gene', '731424', (63, 72))	('related', 'Reg', (92, 99))	('LINC01272', 'Gene', (38, 47))	('survival time of LUSC', 'CPA', (107, 128))	('SFTA1P', 'Gene', '207107', (30, 36))	('MIR3945HG', 'Gene', (63, 72))	('SFTA1P', 'Gene', (30, 36))
170429	28977863	The OncoPrint from cBioPortal showed that 14% (69/501) cases with genetic alterations could be obtained (Figure 8A), except RP1-78O14.1, whose data were not available in cBioPortal.	('RP1', 'Gene', '6101', (124, 127))	('genetic alterations', 'Var', (66, 85))	('RP1', 'Gene', (124, 127))
170430	28977863	And only SFTA1P, LINC00968, LINC00961, and FENDRR had genetic alterations, including amplification, deep deletion and mRNA upregulation.	('LINC00968', 'Gene', (17, 26))	('deep deletion', 'Var', (100, 113))	('LINC00968', 'Gene', '100507632', (17, 26))	('mRNA', 'MPA', (118, 122))	('LINC00961', 'Gene', '158376', (28, 37))	('SFTA1P', 'Gene', '207107', (9, 15))	('LINC00961', 'Gene', (28, 37))	('upregulation', 'PosReg', (123, 135))	('amplification', 'Var', (85, 98))	('SFTA1P', 'Gene', (9, 15))
170448	28977863	In the support of the result, GATA6-AS1 might act as a tumor suppressor in the several cancers including BLCA, CESC, ESCA, LUAD, pheochromocytoma and paraganglioma (PCPG) and UCEC.	('CESC', 'Disease', (111, 115))	('cancers', 'Disease', (87, 94))	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('paraganglioma', 'Phenotype', 'HP:0002668', (150, 163))	('BLCA', 'Disease', (105, 109))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('ESCA', 'Phenotype', 'HP:0011459', (117, 121))	('pheochromocytoma and paraganglioma', 'Disease', 'MESH:D010673', (129, 163))	('cancers', 'Phenotype', 'HP:0002664', (87, 94))	('tumor', 'Disease', (55, 60))	('GATA6-AS1', 'Var', (30, 39))	('ESCA', 'Disease', (117, 121))	('UCEC', 'Disease', (175, 179))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (129, 145))	('LUAD', 'Phenotype', 'HP:0030078', (123, 127))	('cancers', 'Disease', 'MESH:D009369', (87, 94))	('LUAD', 'Disease', (123, 127))
170452	28977863	In LUAD patients, EGFR-activating somatic mutations in exons 18/19/20/21 modify the sensitivity (namely exon 21 L858R, exon 19 deletion) or resistance (namely exon 20 T790M and/or insertion) to tyrosine kinase inhibitor (TKI) mediated targeted therapeutic strategies.	('modify', 'Reg', (73, 79))	('exon 19 deletion', 'Var', (119, 135))	('L858R', 'Mutation', 'rs121434568', (112, 117))	('EGFR', 'Gene', '1956', (18, 22))	('T790M', 'Mutation', 'rs121434569', (167, 172))	('LUAD', 'Phenotype', 'HP:0030078', (3, 7))	('T790M', 'Var', (167, 172))	('EGFR', 'Gene', (18, 22))	('resistance', 'MPA', (140, 150))	('deletion', 'Var', (127, 135))	('L858R', 'Var', (112, 117))	('sensitivity', 'MPA', (84, 95))	('insertion', 'Var', (180, 189))	('patients', 'Species', '9606', (8, 16))
170454	28977863	Ten lncRNAs with the highest diagnostic value (SFTA1P, LINC00968, LINC00961, LINC01572, RP1-78O14.1, FENDRR, LINC01314, LINC01272, GATA6-AS1, and MIR3945HG) were selected for further investigation of their clinical roles in LUSC.	('LUSC', 'Phenotype', 'HP:0030359', (224, 228))	('MIR3945HG', 'Gene', '731424', (146, 155))	('LINC01572', 'Gene', (77, 86))	('LINC01572', 'Gene', '101927957', (77, 86))	('LINC00968', 'Gene', '100507632', (55, 64))	('clinical', 'Species', '191496', (206, 214))	('SFTA1P', 'Gene', (47, 53))	('LINC01272', 'Gene', '100506115', (120, 129))	('LINC00961', 'Gene', '158376', (66, 75))	('LINC01314', 'Gene', (109, 118))	('LINC01272', 'Gene', (120, 129))	('FENDRR', 'Var', (101, 107))	('LINC00961', 'Gene', (66, 75))	('RP1', 'Gene', (88, 91))	('MIR3945HG', 'Gene', (146, 155))	('LINC00968', 'Gene', (55, 64))	('RP1', 'Gene', '6101', (88, 91))	('SFTA1P', 'Gene', '207107', (47, 53))	('LINC01314', 'Gene', '100996492', (109, 118))
170455	28977863	EGFR mutations are extremely rare (<5%) in LUSC; nonetheless, other genetic alterations, like overexpression and gene amplification are much common in LUSC, which play pivotal roles in the biological process and disease development of LUSC.	('LUSC', 'Disease', (151, 155))	('gene amplification', 'Var', (113, 131))	('EGFR', 'Gene', (0, 4))	('common', 'Reg', (141, 147))	('LUSC', 'Phenotype', 'HP:0030359', (235, 239))	('mutations', 'Var', (5, 14))	('LUSC', 'Phenotype', 'HP:0030359', (43, 47))	('LUSC', 'Phenotype', 'HP:0030359', (151, 155))	('EGFR', 'Gene', '1956', (0, 4))
170460	28977863	The top 10 lncRNAs (SFTA1P, LINC00968, LINC00961, LINC01572, RP1-78O14.1, FENDRR, LINC01314, LINC01272, GATA6-AS1, and MIR3945HG) had extremely high diagnostic values for LUSC, since the AUCs were all over 0.99.	('LINC00968', 'Gene', (28, 37))	('LINC00961', 'Gene', (39, 48))	('LINC01314', 'Gene', '100996492', (82, 91))	('SFTA1P', 'Gene', '207107', (20, 26))	('LINC01572', 'Gene', (50, 59))	('RP1', 'Gene', (61, 64))	('LINC00968', 'Gene', '100507632', (28, 37))	('LINC01572', 'Gene', '101927957', (50, 59))	('RP1', 'Gene', '6101', (61, 64))	('LUSC', 'Disease', (171, 175))	('MIR3945HG', 'Gene', (119, 128))	('SFTA1P', 'Gene', (20, 26))	('LINC01272', 'Gene', '100506115', (93, 102))	('LINC01314', 'Gene', (82, 91))	('LUSC', 'Phenotype', 'HP:0030359', (171, 175))	('LINC00961', 'Gene', '158376', (39, 48))	('MIR3945HG', 'Gene', '731424', (119, 128))	('LINC01272', 'Gene', (93, 102))	('FENDRR', 'Var', (74, 80))
170468	28977863	Down-regulation of FENDRR was found in gastric cancer and moreover, FENDRR was closely related to the poor prognosis in gastric cancer.	('FENDRR', 'Var', (68, 74))	('gastric cancer', 'Disease', (39, 53))	('FENDRR', 'Gene', (19, 25))	('gastric cancer', 'Disease', 'MESH:D013274', (39, 53))	('gastric cancer', 'Disease', (120, 134))	('gastric cancer', 'Disease', 'MESH:D013274', (120, 134))	('Down-regulation', 'NegReg', (0, 15))	('gastric cancer', 'Phenotype', 'HP:0012126', (39, 53))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('gastric cancer', 'Phenotype', 'HP:0012126', (120, 134))
170473	28977863	SNP rs11256676 in Phenotypes DMFS5mand of Chr.	('Chr', 'Disease', (42, 45))	('rs11256676', 'Mutation', 'rs11256676', (4, 14))	('DMFS5mand', 'Var', (29, 38))
170480	28977863	Furthermore, the genetic alterations can also regulate the function of certain lncRNA, and thus influence the clinical outcome.	('regulate', 'Reg', (46, 54))	('clinical', 'Species', '191496', (110, 118))	('function', 'MPA', (59, 67))	('genetic alterations', 'Var', (17, 36))	('influence', 'Reg', (96, 105))
170481	28977863	Only several studies explored single lncRNAs and their genetic variants in lung cancer.	('lung cancer', 'Disease', (75, 86))	('lung cancer', 'Phenotype', 'HP:0100526', (75, 86))	('variants', 'Var', (63, 71))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('lung cancer', 'Disease', 'MESH:D008175', (75, 86))
170482	28977863	For instance, among the advanced lung cancer patients, cases with rs3200401 CT and CT + TT genotypes in MALAT1 had clearly better prognosis than those with the MALAT1 rs3200401 CC genotype.	('lung cancer', 'Phenotype', 'HP:0100526', (33, 44))	('rs3200401', 'Mutation', 'rs3200401', (66, 75))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('better', 'PosReg', (123, 129))	('rs3200401', 'Var', (66, 75))	('MALAT1', 'Gene', '378938', (104, 110))	('MALAT1', 'Gene', '378938', (160, 166))	('MALAT1', 'Gene', (104, 110))	('lung cancer', 'Disease', 'MESH:D008175', (33, 44))	('patients', 'Species', '9606', (45, 53))	('rs3200401', 'Mutation', 'rs3200401', (167, 176))	('MALAT1', 'Gene', (160, 166))	('lung cancer', 'Disease', (33, 44))
170483	28977863	SNP rs114020893 of NEXN-AS1 at 1p31.1 might also contribute to lung cancer susceptibility.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('lung cancer', 'Disease', 'MESH:D008175', (63, 74))	('NEXN-AS1', 'Gene', '374987', (19, 27))	('NEXN-AS1', 'Gene', (19, 27))	('rs114020893', 'Mutation', 'rs114020893', (4, 15))	('lung cancer', 'Disease', (63, 74))	('lung cancer', 'Phenotype', 'HP:0100526', (63, 74))	('contribute', 'Reg', (49, 59))	('SNP', 'Var', (0, 3))
170484	28977863	In the current study, gene amplification, deep deletion and mRNA upregulation were detected in SFTA1P, LINC00968, LINC00961 and FENDRR and these genetic alterations of the lncRNAs showed a close correlation with survival of LUSC.	('SFTA1P', 'Gene', (95, 101))	('LUSC', 'Phenotype', 'HP:0030359', (224, 228))	('LINC00968', 'Gene', (103, 112))	('LINC00968', 'Gene', '100507632', (103, 112))	('mRNA', 'MPA', (60, 64))	('LINC00961', 'Gene', '158376', (114, 123))	('gene amplification', 'Var', (22, 40))	('SFTA1P', 'Gene', '207107', (95, 101))	('upregulation', 'PosReg', (65, 77))	('deep deletion', 'Var', (42, 55))	('LINC00961', 'Gene', (114, 123))
170486	28977863	Overall, we show a signature of aberrantly expressed lncRNAs in LUSC tissues and the top 10 of them have great clinical value to act as diagnostic biomarkers, and indicators to evaluate the survival and progression of LUSC.	('aberrantly expressed', 'Var', (32, 52))	('clinical', 'Species', '191496', (111, 119))	('lncRNAs', 'Gene', (53, 60))	('LUSC', 'Phenotype', 'HP:0030359', (64, 68))	('LUSC', 'Phenotype', 'HP:0030359', (218, 222))
170516	32218836	Mutations in phosphatidylethanolamine-binding protein 4 (PEBP4) have frequently been reported in numerous types of cancer, and PEBP4 has been suggested as an important treatment target for ovarian, prostate and rectal tumors.	('reported', 'Reg', (85, 93))	('cancer', 'Disease', (115, 121))	('phosphatidylethanolamine-binding protein 4', 'Gene', '157310', (13, 55))	('prostate', 'Disease', (198, 206))	('ovarian', 'Disease', (189, 196))	('PEBP4', 'Gene', '157310', (57, 62))	('PEBP4', 'Gene', (57, 62))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('PEBP4', 'Gene', '157310', (127, 132))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('Mutations', 'Var', (0, 9))	('rectal tumors', 'Disease', 'MESH:D012004', (211, 224))	('rectal tumors', 'Phenotype', 'HP:0100743', (211, 224))	('rectal tumors', 'Disease', (211, 224))	('phosphatidylethanolamine-binding protein 4', 'Gene', (13, 55))	('tumors', 'Phenotype', 'HP:0002664', (218, 224))	('PEBP4', 'Gene', (127, 132))
170529	32218836	However, there were significant between-study variances (P<1x10-324; see LSCC_PEBP4  Ref for pathway analysis), with three studies exhibiting increased expression levels, including LFC=2.13, 0.080 and 0.072, calculated from datasets GSE67061 , GSE84784  and GSE12428 , respectively; this variability in results requires an analysis to study the influence of potential factors affecting the results.	('GSE67061', 'Var', (233, 241))	('PEBP4', 'Gene', '157310', (78, 83))	('GSE84784', 'Var', (244, 252))	('PEBP4', 'Gene', (78, 83))	('GSE12428', 'Var', (258, 266))
170547	32218836	One possible reason may lie in the data generation of different studies, as they used different platforms, including GPL570 for GSE30219 and GPL6884 for GSE32036, and sample sources, including lung samples in GSE67061 and bronchial biopsy samples in GSE33479 (LSCC_PEBP4  Data).	('GSE33479', 'Var', (250, 258))	('GSE67061', 'Var', (209, 217))	('PEBP4', 'Gene', '157310', (265, 270))	('PEBP4', 'Gene', (265, 270))
170579	30280186	Notably, CYC1 silencing markedly eliminated the effects of lncRNA C5orf66-AS1 downregulation on OSCC cells.	('eliminated', 'NegReg', (33, 43))	('silencing', 'Var', (14, 23))	('C5orf66-AS1', 'Gene', '101927953;100996485;5729', (66, 77))	('CYC1', 'Gene', '1537', (9, 13))	('downregulation', 'NegReg', (78, 92))	('C5orf66-AS1', 'Gene', (66, 77))	('CYC1', 'Gene', (9, 13))	('OSCC', 'Disease', (96, 100))
170589	30280186	In addition, a large number of abnormally expressed lncRNAs are involved in tumor metabolism, occurrence and development.	('involved', 'Reg', (64, 72))	('lncRNAs', 'Gene', (52, 59))	('abnormally', 'Var', (31, 41))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('men', 'Species', '9606', (116, 119))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
170626	30280186	9502; 1:1,000 dilution; Cell Signaling Technology, Inc.), anti-cleaved Caspase-3 (no.	('anti-cleaved', 'Var', (58, 70))	('Caspase-3', 'Gene', '836', (71, 80))	('Caspase-3', 'Gene', (71, 80))
170627	30280186	9664; 1:1,000 dilution; Cell Signaling Technology, Inc.), anti-cleaved Caspase-7 (no.	('anti-cleaved', 'Var', (58, 70))	('Caspase-7', 'Gene', (71, 80))	('Caspase-7', 'Gene', '840', (71, 80))
170628	30280186	9491; 1:1,000 dilution; Cell Signaling Technology, Inc.), anti-cleaved Caspase-9 (no.	('anti-cleaved', 'Var', (58, 70))	('Caspase-9', 'Gene', '842', (71, 80))	('Caspase-9', 'Gene', (71, 80))
170645	30280186	By contrast, in the lncRNA C5orf66-AS1-siRNA transfection group, the cell migration and invasion abilities were increased and there was no statistically significant changes between the control group and the NC group (Fig.	('transfection', 'Var', (45, 57))	('C5orf66-AS1', 'Gene', '101927953;100996485;5729', (27, 38))	('increased', 'PosReg', (112, 121))	('C5orf66-AS1', 'Gene', (27, 38))
170652	30280186	As expected, overexpression of lncRNA C5orf66-AS1 downregulated the protein level of CYC1 in SCC9 cells, while silencing of lncRNA C5orf66-AS1 significantly enhanced the protein level of CYC1, as compared with the corresponding control groups (Fig.	('CYC1', 'Gene', '1537', (187, 191))	('CYC1', 'Gene', (85, 89))	('silencing', 'Var', (111, 120))	('C5orf66-AS1', 'Gene', (38, 49))	('enhanced', 'PosReg', (157, 165))	('CYC1', 'Gene', (187, 191))	('C5orf66-AS1', 'Gene', '101927953;100996485;5729', (131, 142))	('CYC1', 'Gene', '1537', (85, 89))	('downregulated', 'NegReg', (50, 63))	('C5orf66-AS1', 'Gene', '101927953;100996485;5729', (38, 49))	('SCC9', 'CellLine', 'CVCL:1685', (93, 97))	('C5orf66-AS1', 'Gene', (131, 142))
170654	30280186	The results demonstrated that lncRNA C5orf66-AS1-plasmid transfection significantly reduced the protein levels of Bcl-2 and MMP9, while the expression levels of Bax, cleaved Caspase-3/Caspase-3, cleaved Caspase-7/Caspase-7 and cleaved Caspase-9/Caspase-9 were significantly increased (Fig.	('Caspase-3', 'Gene', '836', (174, 183))	('C5orf66-AS1', 'Gene', (37, 48))	('transfection', 'Var', (57, 69))	('Caspase-3', 'Gene', (184, 193))	('Bax', 'Gene', (161, 164))	('Caspase-9', 'Gene', '842', (245, 254))	('Caspase-9', 'Gene', (245, 254))	('cleaved', 'MPA', (166, 173))	('Caspase-7', 'Gene', '840', (213, 222))	('Bax', 'Gene', '581', (161, 164))	('MMP9', 'Gene', '4318', (124, 128))	('MMP9', 'Gene', (124, 128))	('Caspase-9', 'Gene', '842', (235, 244))	('increased', 'PosReg', (274, 283))	('expression levels', 'MPA', (140, 157))	('Caspase-9', 'Gene', (235, 244))	('Caspase-3', 'Gene', (174, 183))	('Caspase-7', 'Gene', '840', (203, 212))	('Bcl-2', 'Gene', (114, 119))	('Caspase-3', 'Gene', '836', (184, 193))	('cleaved', 'MPA', (195, 202))	('cleaved', 'MPA', (227, 234))	('Caspase-7', 'Gene', (213, 222))	('C5orf66-AS1', 'Gene', '101927953;100996485;5729', (37, 48))	('Bcl-2', 'Gene', '596', (114, 119))	('reduced', 'NegReg', (84, 91))	('protein levels', 'MPA', (96, 110))	('Caspase-7', 'Gene', (203, 212))
170656	30280186	However, lncRNA C5orf66-AS1-siRNA transfection significantly increased the protein levels of Bcl-2 and MMP9, while it markedly decreased the expression levels of Bax, cleaved Caspase-3/Caspase-3, cleaved Caspase-7/Caspase-7, and cleaved Caspase-9/Caspase-9 (Fig.	('Bax', 'Gene', (162, 165))	('Bcl-2', 'Gene', (93, 98))	('Caspase-9', 'Gene', '842', (247, 256))	('Caspase-3', 'Gene', (185, 194))	('MMP9', 'Gene', '4318', (103, 107))	('MMP9', 'Gene', (103, 107))	('Caspase-9', 'Gene', (247, 256))	('C5orf66-AS1', 'Gene', '101927953;100996485;5729', (16, 27))	('Caspase-7', 'Gene', '840', (214, 223))	('increased', 'PosReg', (61, 70))	('Bax', 'Gene', '581', (162, 165))	('Caspase-3', 'Gene', (175, 184))	('Bcl-2', 'Gene', '596', (93, 98))	('Caspase-9', 'Gene', '842', (237, 246))	('cleaved', 'MPA', (229, 236))	('Caspase-7', 'Gene', '840', (204, 213))	('expression levels', 'MPA', (141, 158))	('Caspase-9', 'Gene', (237, 246))	('cleaved', 'MPA', (196, 203))	('C5orf66-AS1', 'Gene', (16, 27))	('Caspase-3', 'Gene', '836', (185, 194))	('decreased', 'NegReg', (127, 136))	('protein levels', 'MPA', (75, 89))	('Caspase-7', 'Gene', (214, 223))	('Caspase-7', 'Gene', (204, 213))	('Caspase-3', 'Gene', '836', (175, 184))	('transfection', 'Var', (34, 46))
170659	30280186	The findings suggested that lncRNA C5orf66-AS1-siRNA transfection significantly enhanced the proliferation, migration and invasion ability of SCC9 cells, and inhibited cell apoptosis.	('transfection', 'Var', (53, 65))	('invasion ability', 'CPA', (122, 138))	('migration', 'CPA', (108, 117))	('tosis', 'Disease', (177, 182))	('proliferation', 'CPA', (93, 106))	('C5orf66-AS1', 'Gene', '101927953;100996485;5729', (35, 46))	('inhibited', 'NegReg', (158, 167))	('C5orf66-AS1', 'Gene', (35, 46))	('tosis', 'Disease', 'None', (177, 182))	('enhanced', 'PosReg', (80, 88))	('SCC9', 'CellLine', 'CVCL:1685', (142, 146))
170663	30280186	Previous studies have demonstrated that dysregulation of oncogenes and tumor suppressor genes is an important factor in tumorigenesis and development.	('men', 'Species', '9606', (145, 148))	('dysregulation', 'Var', (40, 53))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('oncogenes', 'Protein', (57, 66))	('tumor', 'Disease', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('development', 'CPA', (138, 149))	('tumor', 'Disease', (120, 125))
170678	30280186	Furthermore, it was observed that CYC1 silencing partially offset the promotion of lncRNA C5orf66-AS1 silencing on OSCC cells.	('promotion', 'MPA', (70, 79))	('C5orf66-AS1', 'Gene', '101927953;100996485;5729', (90, 101))	('CYC1', 'Gene', (34, 38))	('offset', 'NegReg', (59, 65))	('C5orf66-AS1', 'Gene', (90, 101))	('silencing', 'NegReg', (102, 111))	('silencing', 'Var', (39, 48))	('CYC1', 'Gene', '1537', (34, 38))
170684	28210137	Prevalence of driver mutations in non-small-cell lung cancers in the People's Republic of China Lung cancer is a leading cause of cancer-related mortality worldwide and in the People's Republic of China.	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('Lung cancer', 'Phenotype', 'HP:0100526', (96, 107))	('Lung cancer', 'Disease', (96, 107))	('lung cancers', 'Disease', 'MESH:D008175', (49, 61))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('lung cancers', 'Disease', (49, 61))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (38, 60))	('lung cancer', 'Phenotype', 'HP:0100526', (49, 60))	('lung cancers', 'Phenotype', 'HP:0100526', (49, 61))	('cancers', 'Phenotype', 'HP:0002664', (54, 61))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (34, 60))	('cancer', 'Disease', (54, 60))	('People', 'Species', '9606', (69, 75))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('mutations', 'Var', (21, 30))	('cancer', 'Disease', (101, 107))	('cancer', 'Disease', (130, 136))	('People', 'Species', '9606', (176, 182))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('Lung cancer', 'Disease', 'MESH:D008175', (96, 107))
170688	28210137	It is essential to further understand mutations that drive cancer development (driver mutations) in relevant genes and their effects on cancer cell proliferation and survival.	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('cancer', 'Disease', (136, 142))	('mutations', 'Var', (38, 47))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
170701	28210137	In lung adenocarcinomas, such mutations occur in the EGFR, EML4-ALK, KRAS, ROS1, PIK3CA, BRAF, RET, and HER2 genes.	('KRAS', 'Gene', (69, 73))	('PIK3CA', 'Gene', '5290', (81, 87))	('BRAF', 'Gene', '673', (89, 93))	('RET', 'Gene', '5979', (95, 98))	('BRAF', 'Gene', (89, 93))	('EML4', 'Gene', (59, 63))	('ROS1', 'Gene', '6098', (75, 79))	('EML4', 'Gene', '27436', (59, 63))	('HER2', 'Gene', (104, 108))	('EGFR', 'Gene', '1956', (53, 57))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (3, 23))	('occur', 'Reg', (40, 45))	('RET', 'Gene', (95, 98))	('PIK3CA', 'Gene', (81, 87))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (3, 22))	('mutations', 'Var', (30, 39))	('ALK', 'Gene', '238', (64, 67))	('carcinoma', 'Phenotype', 'HP:0030731', (13, 22))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (3, 23))	('KRAS', 'Gene', '3845', (69, 73))	('ROS1', 'Gene', (75, 79))	('ALK', 'Gene', (64, 67))	('lung adenocarcinomas', 'Disease', (3, 23))	('EGFR', 'Gene', (53, 57))	('HER2', 'Gene', '2064', (104, 108))
170705	28210137	In recent years, many studies have shown that EGFR, EML4-ALK, HER2, KRAS, and BRAF mutations are mainly found in non-smoking-related adenocarcinoma.	('mutations', 'Var', (83, 92))	('HER2', 'Gene', '2064', (62, 66))	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('found', 'Reg', (104, 109))	('BRAF', 'Gene', '673', (78, 82))	('ALK', 'Gene', (57, 60))	('BRAF', 'Gene', (78, 82))	('adenocarcinoma', 'Disease', (133, 147))	('EGFR', 'Gene', '1956', (46, 50))	('adenocarcinoma', 'Disease', 'MESH:D000230', (133, 147))	('KRAS', 'Gene', (68, 72))	('EML4', 'Gene', (52, 56))	('EGFR', 'Gene', (46, 50))	('KRAS', 'Gene', '3845', (68, 72))	('ALK', 'Gene', '238', (57, 60))	('HER2', 'Gene', (62, 66))	('EML4', 'Gene', '27436', (52, 56))
170708	28210137	Consequently, we herein review the prevalence of driver mutations and the epidemiology of resistance mechanisms in Chinese patients with NSCLC.	('mutations', 'Var', (56, 65))	('NSCLC', 'Disease', (137, 142))	('NSCLC', 'Disease', 'MESH:D002289', (137, 142))	('patients', 'Species', '9606', (123, 131))	('NSCLC', 'Phenotype', 'HP:0030358', (137, 142))
170709	28210137	Currently, a promising treatment strategy for advanced NSCLC features small molecules targeting epidermal growth factor receptor (EGFR) mutations.	('NSCLC', 'Disease', (55, 60))	('epidermal growth factor receptor', 'Gene', (96, 128))	('NSCLC', 'Disease', 'MESH:D002289', (55, 60))	('mutations', 'Var', (136, 145))	('epidermal growth factor receptor', 'Gene', '1956', (96, 128))	('NSCLC', 'Phenotype', 'HP:0030358', (55, 60))	('EGFR', 'Gene', '1956', (130, 134))	('EGFR', 'Gene', (130, 134))
170710	28210137	The prevalence of EGFR mutations in pulmonary adenocarcinoma among female non-smoking Asian patients was first revealed by a subgroup analysis of the Iressa Survival Evaluation in Lung Cancer trial.	('pulmonary adenocarcinoma', 'Phenotype', 'HP:0030078', (36, 60))	('Lung Cancer', 'Disease', (180, 191))	('pulmonary adenocarcinoma', 'Disease', 'MESH:D008175', (36, 60))	('Lung Cancer', 'Phenotype', 'HP:0100526', (180, 191))	('EGFR', 'Gene', '1956', (18, 22))	('patients', 'Species', '9606', (92, 100))	('EGFR', 'Gene', (18, 22))	('mutations', 'Var', (23, 32))	('Cancer', 'Phenotype', 'HP:0002664', (185, 191))	('Lung Cancer', 'Disease', 'MESH:D008175', (180, 191))	('pulmonary adenocarcinoma', 'Disease', (36, 60))	('carcinoma', 'Phenotype', 'HP:0030731', (51, 60))
170711	28210137	Further, several Phase III studies have compared first-line EGFR TKIs such as gefitinib and erlotinib with double platinum-based chemotherapy, used to treat NSCLC patients harboring activating EGFR mutations.	('patients', 'Species', '9606', (163, 171))	('platinum', 'Chemical', 'MESH:D010984', (114, 122))	('activating', 'PosReg', (182, 192))	('erlotinib', 'Chemical', 'MESH:D000069347', (92, 101))	('EGFR', 'Gene', '1956', (193, 197))	('NSCLC', 'Phenotype', 'HP:0030358', (157, 162))	('mutations', 'Var', (198, 207))	('EGFR', 'Gene', '1956', (60, 64))	('EGFR', 'Gene', (193, 197))	('gefitinib', 'Chemical', 'MESH:D000077156', (78, 87))	('NSCLC', 'Disease', (157, 162))	('EGFR', 'Gene', (60, 64))	('NSCLC', 'Disease', 'MESH:D002289', (157, 162))
170713	28210137	Currently, adenocarcinoma of the lung in non-smokers is recognized as a distinct disease entity because of its peculiar epidemiological, clinical, and biological characteristics; many studies have comprehensively analyzed the major known driver mutations in female non-smoking Asian patients with pulmonary adenocarcinoma.	('mutations', 'Var', (245, 254))	('patients', 'Species', '9606', (283, 291))	('carcinoma', 'Phenotype', 'HP:0030731', (16, 25))	('carcinoma', 'Phenotype', 'HP:0030731', (312, 321))	('pulmonary adenocarcinoma', 'Disease', (297, 321))	('adenocarcinoma of the lung', 'Disease', (11, 37))	('pulmonary adenocarcinoma', 'Disease', 'MESH:D008175', (297, 321))	('adenocarcinoma of the lung', 'Disease', 'MESH:D000077192', (11, 37))	('pulmonary adenocarcinoma', 'Phenotype', 'HP:0030078', (297, 321))
170714	28210137	EGFR mutations are associated with smoking status and particular histological subtypes of disease.	('associated', 'Reg', (19, 29))	('EGFR', 'Gene', '1956', (0, 4))	('EGFR', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))
170716	28210137	Of 506 patients with NSCLC, the EGFR mutation rate in smokers was 15.1%, and lower than in non-smokers (45.5%; P<0.00001).	('lower', 'NegReg', (77, 82))	('NSCLC', 'Disease', (21, 26))	('mutation', 'Var', (37, 45))	('EGFR', 'Gene', '1956', (32, 36))	('NSCLC', 'Disease', 'MESH:D002289', (21, 26))	('NSCLC', 'Phenotype', 'HP:0030358', (21, 26))	('EGFR', 'Gene', (32, 36))	('patients', 'Species', '9606', (7, 15))
170720	28210137	The mutation rates of EGFR in patients with adenocarcinoma and squamous cell cancer were 40.3% (140/347) and 4.4% (6/144), respectively.	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (63, 83))	('adenocarcinoma and squamous cell cancer', 'Disease', 'MESH:D002294', (44, 83))	('mutation', 'Var', (4, 12))	('patients', 'Species', '9606', (30, 38))	('EGFR', 'Gene', '1956', (22, 26))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('EGFR', 'Gene', (22, 26))
170721	28210137	In summary, EGFR mutations occur at high frequencies in female patients, non-smokers, those of Asian ethnicity, and patients with adenocarcinoma.	('adenocarcinoma', 'Disease', (130, 144))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('adenocarcinoma', 'Disease', 'MESH:D000230', (130, 144))	('patients', 'Species', '9606', (116, 124))	('EGFR', 'Gene', '1956', (12, 16))	('patients', 'Species', '9606', (63, 71))	('EGFR', 'Gene', (12, 16))	('mutations', 'Var', (17, 26))
170722	28210137	Earlier Chinese studies recorded the frequencies of EGFR mutations in patients with NSCLC, adenocarcinoma, and squamous cell cancer (Table 2).	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('squamous cell cancer', 'Disease', (111, 131))	('patients', 'Species', '9606', (70, 78))	('squamous cell cancer', 'Disease', 'MESH:D002294', (111, 131))	('NSCLC', 'Phenotype', 'HP:0030358', (84, 89))	('EGFR', 'Gene', '1956', (52, 56))	('EGFR', 'Gene', (52, 56))	('adenocarcinoma', 'Disease', 'MESH:D000230', (91, 105))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (111, 131))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('NSCLC', 'Disease', (84, 89))	('mutations', 'Var', (57, 66))	('NSCLC', 'Disease', 'MESH:D002289', (84, 89))	('adenocarcinoma', 'Disease', (91, 105))
170723	28210137	Such mutations include exon 18 G719A, G719V, and G719D; exon 19 E746-A750 del, E746-S752 del, and L747-A750 (751, 753) del; exon 20 T790M and R776H; and exon 21 L858R, L858M, and L861R.	('G719A', 'Mutation', 'rs121913428', (31, 36))	('R776H', 'Mutation', 'rs483352806', (142, 147))	('A750 del', 'Mutation', 'c.750delA', (69, 77))	('L858M', 'Var', (168, 173))	('E746-S752 del', 'Mutation', 'p.746,752delS', (79, 92))	('T790M', 'Mutation', 'rs121434569', (132, 137))	('L858R', 'Mutation', 'rs121434568', (161, 166))	('G719A', 'Var', (31, 36))	('E746-A750 del', 'Var', (64, 77))	('L861R', 'Var', (179, 184))	('L747-A750 (751, 753) del', 'Var', (98, 122))	('L861R', 'Mutation', 'rs121913444', (179, 184))	('T790M', 'Var', (132, 137))	('E746-S752 del', 'Var', (79, 92))	('G719V', 'Mutation', 'p.G719V', (38, 43))	('G719D', 'Mutation', 'rs121913428', (49, 54))	('L858R', 'Var', (161, 166))	('G719V', 'Var', (38, 43))	('G719D', 'Var', (49, 54))	('L858M', 'Mutation', 'rs121913443', (168, 173))	('R776H', 'Var', (142, 147))
170724	28210137	As reported earlier, most EGFR mutations occur in exons 19 and 21.	('EGFR', 'Gene', '1956', (26, 30))	('EGFR', 'Gene', (26, 30))	('mutations', 'Var', (31, 40))	('occur', 'Reg', (41, 46))
170726	28210137	Many reports have linked KRAS mutations to lung cancer.	('lung cancer', 'Disease', (43, 54))	('lung cancer', 'Phenotype', 'HP:0100526', (43, 54))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('linked', 'Reg', (18, 24))	('mutations', 'Var', (30, 39))	('lung cancer', 'Disease', 'MESH:D008175', (43, 54))	('KRAS', 'Gene', (25, 29))	('KRAS', 'Gene', '3845', (25, 29))
170727	28210137	However, the frequency of KRAS mutations is lower in Eastern Asia than in the West.	('mutations', 'Var', (31, 40))	('KRAS', 'Gene', '3845', (26, 30))	('KRAS', 'Gene', (26, 30))
170728	28210137	The KRAS mutation frequency is 30% or over in NSCLC patients from the USA and some other Western countries, but less than 10% in patients from Japan, Korea, Taiwan, and Hong Kong (Table 2).	('mutation', 'Var', (9, 17))	('KRAS', 'Gene', '3845', (4, 8))	('patients', 'Species', '9606', (129, 137))	('NSCLC', 'Disease', (46, 51))	('NSCLC', 'Disease', 'MESH:D002289', (46, 51))	('patients', 'Species', '9606', (52, 60))	('KRAS', 'Gene', (4, 8))	('NSCLC', 'Phenotype', 'HP:0030358', (46, 51))
170729	28210137	Other research showed that KRAS mutations occurred more often in males than females, in patients with adenocarcinoma compared with other forms of lung cancer, and in smokers compared with non-smokers.	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('occurred', 'Reg', (42, 50))	('adenocarcinoma', 'Disease', (102, 116))	('KRAS', 'Gene', '3845', (27, 31))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('lung cancer', 'Disease', 'MESH:D008175', (146, 157))	('adenocarcinoma', 'Disease', 'MESH:D000230', (102, 116))	('patients', 'Species', '9606', (88, 96))	('mutations', 'Var', (32, 41))	('lung cancer', 'Disease', (146, 157))	('lung cancer', 'Phenotype', 'HP:0100526', (146, 157))	('KRAS', 'Gene', (27, 31))
170731	28210137	Codon 12 mutations include G12A, G12C, G12D, G12R, G12S, G12V, G12V/C, and G12V/D.	('G12A', 'Var', (27, 31))	('G12S', 'Mutation', 'rs121913530', (51, 55))	('G12C', 'Var', (33, 37))	('G12V', 'Mutation', 'rs121913529', (75, 79))	('G12A', 'Mutation', 'rs121913529', (27, 31))	('G12S', 'Var', (51, 55))	('G12D', 'Var', (39, 43))	('G12V', 'Var', (75, 79))	('G12R', 'Mutation', 'rs121913530', (45, 49))	('G12V', 'SUBSTITUTION', 'None', (75, 79))	('G12V', 'Mutation', 'rs121913529', (57, 61))	('G12D', 'Mutation', 'rs121913529', (39, 43))	('G12V', 'Mutation', 'rs121913529', (63, 67))	('G12V', 'SUBSTITUTION', 'None', (57, 61))	('G12V', 'Var', (57, 61))	('G12V', 'SUBSTITUTION', 'None', (63, 67))	('G12C', 'Mutation', 'rs121913530', (33, 37))	('G12V', 'Var', (63, 67))	('G12R', 'Var', (45, 49))
170732	28210137	Codon 13 mutations include G13C and G13D.	('G13D', 'Var', (36, 40))	('G13C', 'Var', (27, 31))	('G13C', 'Mutation', 'rs121913535', (27, 31))	('G13D', 'Mutation', 'rs112445441', (36, 40))
170733	28210137	Guan et al found KRAS mutations in codons 12 (81.32%, 74/1,935), 13 (5.49%, 5/1,935), 59 (1.10%, 1/1,935), 60 (3.30%, 3/1,935), and both 12 and 13 (5.49%, 5/1,935).	('KRAS', 'Gene', '3845', (17, 21))	('KRAS', 'Gene', (17, 21))	('mutations', 'Var', (22, 31))
170734	28210137	The codon 60 mutations were Q60H and Q60L.	('Q60H', 'Var', (28, 32))	('Q60H', 'Mutation', 'rs374403513', (28, 32))	('Q60L', 'Mutation', 'p.Q60L', (37, 41))	('Q60L', 'Var', (37, 41))
170735	28210137	Mutations in both codons 12 and 13 consisted of G12D/G13D (n=3), G12C/G13C (n=1), and G12V/G13C (n=1).	('G12C', 'Var', (65, 69))	('G12V', 'Mutation', 'rs121913529', (86, 90))	('G13C', 'Mutation', 'rs121913535', (70, 74))	('G12D', 'Mutation', 'rs121913529', (48, 52))	('G12D/G13D', 'Var', (48, 57))	('G13C', 'Mutation', 'rs121913535', (91, 95))	('G13D', 'Mutation', 'rs112445441', (53, 57))	('G12V/G13C', 'Var', (86, 95))	('G12C', 'SUBSTITUTION', 'None', (65, 69))
170736	28210137	An et al enrolled 524 patients and found that 27 had KRAS mutations, all in codon 12, including G12C (44.4%, 12/27), G12V (18.5%, 5/27), G12D (18.5%, 5/27) and others (18.5%, 5/27).	('G12C', 'Var', (96, 100))	('G12V', 'Mutation', 'rs121913529', (117, 121))	('G12C', 'Mutation', 'rs121913530', (96, 100))	('patients', 'Species', '9606', (22, 30))	('G12D', 'Var', (137, 141))	('G12D', 'Mutation', 'rs121913529', (137, 141))	('KRAS', 'Gene', (53, 57))	('KRAS', 'Gene', '3845', (53, 57))	('G12V', 'Var', (117, 121))
170737	28210137	In summary, most studies support the idea that KRAS mutations occur in Chinese smokers with adenocarcinoma.	('adenocarcinoma', 'Disease', (92, 106))	('mutations', 'Var', (52, 61))	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('adenocarcinoma', 'Disease', 'MESH:D000230', (92, 106))	('KRAS', 'Gene', (47, 51))	('KRAS', 'Gene', '3845', (47, 51))
170738	28210137	We analyzed studies performed in Chinese patients with lung cancer to identify the subtypes and frequencies of KRAS mutations, and found that most occurred in codons 12, 13, 59, and 60, especially codon 12 (88%; Figure 1F).	('codons 12', 'Var', (159, 168))	('lung cancer', 'Disease', 'MESH:D008175', (55, 66))	('KRAS', 'Gene', (111, 115))	('KRAS', 'Gene', '3845', (111, 115))	('patients', 'Species', '9606', (41, 49))	('lung cancer', 'Disease', (55, 66))	('mutations', 'Var', (116, 125))	('lung cancer', 'Phenotype', 'HP:0100526', (55, 66))	('occurred', 'Reg', (147, 155))	('codon 12', 'Var', (197, 205))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
170739	28210137	Further, EGFR mutations were never found in tumors with KRAS mutations, suggesting that these mutations are mutually exclusive.	('tumors', 'Disease', (44, 50))	('tumors', 'Disease', 'MESH:D009369', (44, 50))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('KRAS', 'Gene', (56, 60))	('KRAS', 'Gene', '3845', (56, 60))	('EGFR', 'Gene', '1956', (9, 13))	('EGFR', 'Gene', (9, 13))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('mutations', 'Var', (14, 23))
170741	28210137	Fusions of ALK with an upstream gene, EML4, were found in NSCLC patients in 2007.	('NSCLC', 'Disease', (58, 63))	('Fusions', 'Var', (0, 7))	('patients', 'Species', '9606', (64, 72))	('NSCLC', 'Disease', 'MESH:D002289', (58, 63))	('EML4', 'Gene', (38, 42))	('ALK', 'Gene', (11, 14))	('ALK', 'Gene', '238', (11, 14))	('NSCLC', 'Phenotype', 'HP:0030358', (58, 63))	('EML4', 'Gene', '27436', (38, 42))	('found', 'Reg', (49, 54))
170742	28210137	The frequency of EML4-ALK translocations ranges from 3% to 7% in unselected patients with NSCLC.	('patients', 'Species', '9606', (76, 84))	('EML4', 'Gene', (17, 21))	('NSCLC', 'Disease', (90, 95))	('EML4', 'Gene', '27436', (17, 21))	('NSCLC', 'Disease', 'MESH:D002289', (90, 95))	('ALK', 'Gene', '238', (22, 25))	('translocations', 'Var', (26, 40))	('to 7', 'Species', '1214577', (56, 60))	('NSCLC', 'Phenotype', 'HP:0030358', (90, 95))	('ALK', 'Gene', (22, 25))
170743	28210137	As with EGFR mutations, the frequency of EML4-ALK fusions is elevated in patients with adenocarcinoma, in younger adult patients, and in those who have never smoked (<100 cigarettes in a lifetime) or who are light smokers (<=15 pack-years).	('EML4', 'Gene', (41, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('fusions', 'Var', (50, 57))	('adenocarcinoma', 'Disease', (87, 101))	('elevated', 'PosReg', (61, 69))	('EGFR', 'Gene', '1956', (8, 12))	('patients', 'Species', '9606', (73, 81))	('EML4', 'Gene', '27436', (41, 45))	('ALK', 'Gene', '238', (46, 49))	('patients', 'Species', '9606', (120, 128))	('EGFR', 'Gene', (8, 12))	('mutations', 'Var', (13, 22))	('adenocarcinoma', 'Disease', 'MESH:D000230', (87, 101))	('ALK', 'Gene', (46, 49))
170744	28210137	EML4-ALK translocations are generally found in tumors wild-type for EGFR and KRAS.	('tumors', 'Disease', (47, 53))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('ALK', 'Gene', (5, 8))	('translocations', 'Var', (9, 23))	('EML4', 'Gene', (0, 4))	('ALK', 'Gene', '238', (5, 8))	('KRAS', 'Gene', (77, 81))	('EML4', 'Gene', '27436', (0, 4))	('EGFR', 'Gene', '1956', (68, 72))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))	('KRAS', 'Gene', '3845', (77, 81))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('found', 'Reg', (38, 43))	('EGFR', 'Gene', (68, 72))
170750	28210137	Patients with EML4-ALK fusions are always wild-type for EGFR and KRAS.	('ALK', 'Gene', (19, 22))	('KRAS', 'Gene', '3845', (65, 69))	('EGFR', 'Gene', '1956', (56, 60))	('fusions', 'Var', (23, 30))	('EML4', 'Gene', (14, 18))	('ALK', 'Gene', '238', (19, 22))	('Patients', 'Species', '9606', (0, 8))	('EGFR', 'Gene', (56, 60))	('EML4', 'Gene', '27436', (14, 18))	('KRAS', 'Gene', (65, 69))
170751	28210137	EML4-ALK fusions are caused by various small inversions within the short arm of chromosome 2.	('ALK', 'Gene', (5, 8))	('fusions', 'Var', (9, 16))	('EML4', 'Gene', (0, 4))	('short arm', 'Phenotype', 'HP:0009824', (67, 76))	('ALK', 'Gene', '238', (5, 8))	('EML4', 'Gene', '27436', (0, 4))	('caused by', 'Reg', (21, 30))
170758	28210137	ROS1 rearrangements were initially identified in a human glioblastoma cell line.	('glioblastoma', 'Disease', (57, 69))	('ROS1', 'Gene', (0, 4))	('glioblastoma', 'Disease', 'MESH:D005909', (57, 69))	('ROS1', 'Gene', '6098', (0, 4))	('glioblastoma', 'Phenotype', 'HP:0012174', (57, 69))	('human', 'Species', '9606', (51, 56))	('rearrangements', 'Var', (5, 19))
170760	28210137	Several recent studies used whole-transcriptome and whole-genome sequencing to detect ROS1 rearrangements, and several novel fusion partners were identified.	('ROS1', 'Gene', '6098', (86, 90))	('ROS1', 'Gene', (86, 90))	('rearrangements', 'Var', (91, 105))
170765	28210137	Recently, many studies have analyzed the spectra of well known driver mutations in non-smokers with adenocarcinoma of the lung.	('adenocarcinoma of the lung', 'Disease', 'MESH:D000077192', (100, 126))	('mutations', 'Var', (70, 79))	('adenocarcinoma of the lung', 'Disease', (100, 126))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))
170766	28210137	Table 3 shows the oncogenic driver mutations in the ROS1, BRAF, PIK3CA, RET, and HER2 genes of such highly selected Chinese patients.	('PIK3CA', 'Gene', (64, 70))	('patients', 'Species', '9606', (124, 132))	('RET', 'Gene', '5979', (72, 75))	('HER2', 'Gene', (81, 85))	('PIK3CA', 'Gene', '5290', (64, 70))	('ROS1', 'Gene', (52, 56))	('HER2', 'Gene', '2064', (81, 85))	('BRAF', 'Gene', '673', (58, 62))	('ROS1', 'Gene', '6098', (52, 56))	('RET', 'Gene', (72, 75))	('BRAF', 'Gene', (58, 62))	('mutations', 'Var', (35, 44))
170771	28210137	Xu et al and others have shown that the frequency of the PIK3CA mutation in NSCLC patients is 2%-4%, and the mutation occurs less often in those with adenocarcinomas compared with other forms of lung cancer.	('carcinoma', 'Phenotype', 'HP:0030731', (155, 164))	('PIK3CA', 'Gene', '5290', (57, 63))	('adenocarcinomas', 'Disease', (150, 165))	('mutation', 'Var', (64, 72))	('patients', 'Species', '9606', (82, 90))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('NSCLC', 'Disease', (76, 81))	('lung cancer', 'Disease', (195, 206))	('lung cancer', 'Phenotype', 'HP:0100526', (195, 206))	('NSCLC', 'Disease', 'MESH:D002289', (76, 81))	('lung cancer', 'Disease', 'MESH:D008175', (195, 206))	('adenocarcinomas', 'Disease', 'MESH:D000230', (150, 165))	('NSCLC', 'Phenotype', 'HP:0030358', (76, 81))	('PIK3CA', 'Gene', (57, 63))
170772	28210137	We have summarized the data from the Chinese studies, and describe the general spectrum of mutations in EGFR, ALK, KRAS, PIK3CA, BRAF, RET, and HER2 in patients with NSCLC, adenocarcinoma, and squamous cell cancer, respectively (Figure 1A-C).	('squamous cell cancer', 'Disease', 'MESH:D002294', (193, 213))	('NSCLC', 'Disease', (166, 171))	('KRAS', 'Gene', '3845', (115, 119))	('HER2', 'Gene', '2064', (144, 148))	('NSCLC', 'Phenotype', 'HP:0030358', (166, 171))	('adenocarcinoma', 'Disease', (173, 187))	('EGFR', 'Gene', (104, 108))	('KRAS', 'Gene', (115, 119))	('RET', 'Gene', '5979', (135, 138))	('PIK3CA', 'Gene', (121, 127))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('adenocarcinoma', 'Disease', 'MESH:D000230', (173, 187))	('HER2', 'Gene', (144, 148))	('patients', 'Species', '9606', (152, 160))	('EGFR', 'Gene', '1956', (104, 108))	('RET', 'Gene', (135, 138))	('squamous cell cancer', 'Disease', (193, 213))	('BRAF', 'Gene', (129, 133))	('BRAF', 'Gene', '673', (129, 133))	('ALK', 'Gene', '238', (110, 113))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (193, 213))	('mutations', 'Var', (91, 100))	('NSCLC', 'Disease', 'MESH:D002289', (166, 171))	('ALK', 'Gene', (110, 113))	('PIK3CA', 'Gene', '5290', (121, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (178, 187))
170773	28210137	Most advanced NSCLCs with activating EGFR mutations initially respond to the TKIs gefitinib or erlotinib.	('activating', 'PosReg', (26, 36))	('NSCLC', 'Disease', (14, 19))	('erlotinib', 'MPA', (95, 104))	('respond', 'Reg', (62, 69))	('NSCLC', 'Disease', 'MESH:D002289', (14, 19))	('EGFR', 'Gene', '1956', (37, 41))	('TKIs gefitinib', 'MPA', (77, 91))	('erlotinib', 'Chemical', 'MESH:D000069347', (95, 104))	('NSCLC', 'Phenotype', 'HP:0030358', (14, 19))	('gefitinib', 'Chemical', 'MESH:D000077156', (82, 91))	('EGFR', 'Gene', (37, 41))	('mutations', 'Var', (42, 51))
170775	28210137	T790M mutation, MET amplification, overexpression of hepatocyte growth factor, and activation of the insulin-like growth factor 1 receptor (IGF1R) and other factors have been reported to be associated with acquired resistance to EGFR TKIs.	('MET', 'MPA', (16, 19))	('T790M mutation', 'Var', (0, 14))	('IGF1R', 'Gene', (140, 145))	('insulin-like growth factor 1 receptor', 'Gene', '3480', (101, 138))	('T790M', 'Mutation', 'rs121434569', (0, 5))	('acquired resistance', 'Disease', (206, 225))	('EGFR', 'Gene', '1956', (229, 233))	('EGFR', 'Gene', (229, 233))	('insulin-like growth factor 1 receptor', 'Gene', (101, 138))	('associated', 'Reg', (190, 200))	('IGF1R', 'Gene', '3480', (140, 145))	('overexpression', 'PosReg', (35, 49))	('activation', 'PosReg', (83, 93))
170784	28210137	The increasing amount of preclinical data on EGFR-mutated NSCLCs that have acquired resistance to TKIs has enhanced interest in the development of novel drugs inhibiting the effects of T790M, MET, or IGF-1R mutations, to be used in combination with EGFR TKIs.	('IGF-1R', 'Gene', (200, 206))	('NSCLC', 'Disease', (58, 63))	('EGFR', 'Gene', (45, 49))	('NSCLC', 'Disease', 'MESH:D002289', (58, 63))	('T790M', 'Mutation', 'rs121434569', (185, 190))	('EGFR', 'Gene', '1956', (249, 253))	('EGFR', 'Gene', (249, 253))	('NSCLC', 'Phenotype', 'HP:0030358', (58, 63))	('T790M', 'Var', (185, 190))	('MET', 'Var', (192, 195))	('IGF-1R', 'Gene', '3480', (200, 206))	('EGFR', 'Gene', '1956', (45, 49))
170785	28210137	A pan-HER TKI, PF00299804, to which resistance does not develop, has been tested in xenograft models and shows promise for use in humans to overcome T790M-mediated TKI resistance.	('humans', 'Species', '9606', (130, 136))	('T790M-mediated', 'Var', (149, 163))	('PF00299804', 'Var', (15, 25))	('T790M', 'Mutation', 'rs121434569', (149, 154))
170786	28210137	Ongoing clinical research on EGFR-mutated NSCLCs will improve the survival of patients with somatic mutations such as T790M, MET, or IGF-1R.	('NSCLC', 'Disease', (42, 47))	('T790M', 'Mutation', 'rs121434569', (118, 123))	('T790M', 'Var', (118, 123))	('NSCLC', 'Disease', 'MESH:D002289', (42, 47))	('MET', 'Var', (125, 128))	('patients', 'Species', '9606', (78, 86))	('IGF-1R', 'Gene', '3480', (133, 139))	('EGFR', 'Gene', '1956', (29, 33))	('IGF-1R', 'Gene', (133, 139))	('survival', 'CPA', (66, 74))	('EGFR', 'Gene', (29, 33))	('NSCLC', 'Phenotype', 'HP:0030358', (42, 47))	('improve', 'PosReg', (54, 61))
170788	28210137	The frequency of EGFR mutations ranges from 28.0% in unselected Chinese patients with NSCLC to 48.5% in those with lung adenocarcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('NSCLC', 'Disease', (86, 91))	('lung adenocarcinoma', 'Disease', (115, 134))	('NSCLC', 'Disease', 'MESH:D002289', (86, 91))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (115, 134))	('EGFR', 'Gene', (17, 21))	('mutations', 'Var', (22, 31))	('EGFR', 'Gene', '1956', (17, 21))	('NSCLC', 'Phenotype', 'HP:0030358', (86, 91))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (115, 134))	('patients', 'Species', '9606', (72, 80))
170789	28210137	The KRAS mutation frequency is lower in the People's Republic of China than in Western countries.	('mutation', 'Var', (9, 17))	('People', 'Species', '9606', (44, 50))	('KRAS', 'Gene', '3845', (4, 8))	('lower', 'NegReg', (31, 36))	('KRAS', 'Gene', (4, 8))
170792	28210137	First, EGFR mutation status should be tested; almost 70% of adenocarcinoma tumors have such a mutation.	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('adenocarcinoma tumors', 'Disease', 'MESH:D000230', (60, 81))	('EGFR', 'Gene', (7, 11))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('adenocarcinoma tumors', 'Disease', (60, 81))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('mutation', 'Var', (94, 102))	('EGFR', 'Gene', '1956', (7, 11))
170793	28210137	Treatment options include EGFR TKIs such as gefitinib or erlotinib or irreversible TKIs such as afatinib (if the T790M mutation is detected).	('gefitinib', 'Chemical', 'MESH:D000077156', (44, 53))	('EGFR', 'Gene', (26, 30))	('afatinib', 'Chemical', 'MESH:D000077716', (96, 104))	('T790M', 'Mutation', 'rs121434569', (113, 118))	('erlotinib', 'Chemical', 'MESH:D000069347', (57, 66))	('T790M', 'Var', (113, 118))	('erlotinib', 'Disease', (57, 66))	('EGFR', 'Gene', '1956', (26, 30))
170820	26460192	Mouse anti-human LC3A/B monoclonal antibody (66139-1-Ig), rabbit anti-human Beclin 1 polyclonal antibody (11306-1-AP), rabbit anti-human B-cell lymphoma 2 (Bcl-2) polyclonal antibody (12789-1-AP) and rabbit anti-human p53 polyclonal antibody (10442-1-AP) were purchased from ProteinTech Group, Inc (ProteinTech, Chicago, IL, USA).	('LC3A', 'Gene', '84557', (17, 21))	('human', 'Species', '9606', (11, 16))	('10442-1-AP', 'Var', (243, 253))	('p53', 'Gene', (218, 221))	('rabbit', 'Species', '9986', (58, 64))	('rabbit', 'Species', '9986', (200, 206))	('B-cell lymphoma 2', 'Gene', '596', (137, 154))	('lymphoma', 'Phenotype', 'HP:0002665', (144, 152))	('Bcl-2', 'Gene', (156, 161))	('LC3A', 'Gene', (17, 21))	('human', 'Species', '9606', (212, 217))	('human', 'Species', '9606', (70, 75))	('B-cell lymphoma 2', 'Gene', (137, 154))	('Bcl-2', 'Gene', '596', (156, 161))	('rabbit', 'Species', '9986', (119, 125))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (137, 152))	('Beclin 1', 'Gene', (76, 84))	('human', 'Species', '9606', (131, 136))	('Beclin 1', 'Gene', '8678', (76, 84))	('p53', 'Gene', '7157', (218, 221))	('Mouse', 'Species', '10090', (0, 5))
170868	26460192	Annexin V-PI staining indicated that no apoptosis was occurring following PAB treatment for 12 h, and the early apoptotic ratio increased from 0 to 1.95% in the PAB-treated cells compared with the control group (Fig.	('Annexin V', 'Gene', '308', (0, 9))	('Annexin V', 'Gene', (0, 9))	('PAB-treated', 'Var', (161, 172))	('increased', 'PosReg', (128, 137))	('PAB', 'Chemical', 'MESH:C058391', (74, 77))	('PAB', 'Chemical', 'MESH:C058391', (161, 164))
170892	26460192	Inhibition of autophagy using the autophagy inhibitor, 3-MA, increased cell death, indicating that during cytostasis autophagy sustains cell survival.	('autophagy', 'CPA', (14, 23))	('3-MA', 'Chemical', 'MESH:C025946', (55, 59))	('cell death', 'CPA', (71, 81))	('Inhibition', 'Var', (0, 10))
170904	25631659	Yet, few algorithms exist that exploit this vast dataset to identify hypo- and hypermethylated genes in cancer.	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('hypermethylated', 'Var', (79, 94))
170906	25631659	We discover pancancer hypo- and hypermethylated genes and identify novel methylation-driven subgroups with clinical implications.	('cancer', 'Disease', (15, 21))	('cancer', 'Disease', 'MESH:D009369', (15, 21))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('hypermethylated genes', 'Var', (32, 53))
170908	25631659	Besides genetic mutations and copy number alterations, differential methylation is an alternative mechanism that is capable of altering the normal state and driving a wide range of cancers.	('altering', 'Reg', (127, 135))	('differential methylation', 'Var', (55, 79))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('normal state', 'MPA', (140, 152))	('cancers', 'Disease', 'MESH:D009369', (181, 188))	('cancers', 'Phenotype', 'HP:0002664', (181, 188))	('driving', 'Reg', (157, 164))	('cancers', 'Disease', (181, 188))
170912	25631659	showed that extensive hypomethylation is present in intergenic regions in breast cancer and is mutually exclusive with repressive histone methylation (that is, H27K3me3 and H3K9me3).	('breast cancer', 'Disease', (74, 87))	('H27K3me3', 'Var', (160, 168))	('hypomethylation', 'Var', (22, 37))	('H3K9me3', 'Var', (173, 180))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('breast cancer', 'Disease', 'MESH:D001943', (74, 87))	('breast cancer', 'Phenotype', 'HP:0003002', (74, 87))
170913	25631659	identified focal regions of hypermethylation within long-range regions of hypomethylation using sequencing in colorectal cancer.	('hypermethylation', 'Var', (28, 44))	('rectal cancer', 'Phenotype', 'HP:0100743', (114, 127))	('colorectal cancer', 'Disease', 'MESH:D015179', (110, 127))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('colorectal cancer', 'Phenotype', 'HP:0003003', (110, 127))	('colorectal cancer', 'Disease', (110, 127))
170915	25631659	Many prior studies have identified hypo- or hypermethylation of cancer based on heuristic measures (reviewed in).	('hypo-', 'Var', (35, 40))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('hypermethylation', 'Var', (44, 60))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
170918	25631659	Finally, the identification of genes that are hypo- and hypermethylated in cancer and likely drivers should be selected as having a significant predictive effect on gene expression, thereby implying that their methylation is predictive of transcription and thus functionally relevant.	('hypermethylated', 'Var', (56, 71))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('cancer', 'Disease', (75, 81))	('gene', 'MPA', (165, 169))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))
170920	25631659	MethylMix is an algorithm that produces transcriptionally predictive and differentially methylated genes in cancer that serve as potential epigenetic driver genes of malignancy and, in this manner, provides a complement to the mutation spectra being derived from DNA sequencing efforts.	('differentially methylated', 'Var', (73, 98))	('malignancy', 'Disease', 'MESH:D009369', (166, 176))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('malignancy', 'Disease', (166, 176))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
170924	25631659	Since the normal state of DNA methylation is tissue specific, MethylMix incorporates the DNA methylation of normal tissue obtained from a subset of cancer patients in the same tissue to determine if a specific gene is hyper- or hypomethylated in that specific tissue type.	('cancer', 'Disease', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('hypomethylated', 'Var', (228, 242))	('patients', 'Species', '9606', (155, 163))
170927	25631659	Using MethylMix we identified hyper- and hypomethylated genes, and dual genes - genes with two methylation statuses, hypermethylated in one subgroup and hypomethylated in another subgroup of patients - in a particular cancer.	('cancer', 'Disease', 'MESH:D009369', (218, 224))	('patients', 'Species', '9606', (191, 199))	('hypomethylated', 'Var', (153, 167))	('cancer', 'Disease', (218, 224))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('hypermethylated', 'Var', (117, 132))
170928	25631659	This resulted in between 408 and 1,133 genes called differentially and transcriptionally predictive methylated by MethylMix in each cancer (Table 1).	('cancer', 'Disease', (132, 138))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('methylated', 'Var', (100, 110))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))
170929	25631659	For all cancers we identified more hypermethylated genes than hypomethylated genes.	('cancers', 'Disease', 'MESH:D009369', (8, 15))	('cancers', 'Phenotype', 'HP:0002664', (8, 15))	('cancers', 'Disease', (8, 15))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('hypermethylated genes', 'Var', (35, 56))
170930	25631659	For each cancer we also found a significant number of dual genes, suggesting a dependence on the genomic context as these genes can switch from a tumor suppressor role, through hypermethylation, to an oncogene role via hypomethylation, depending on the context.	('cancer', 'Disease', (9, 15))	('hypomethylation', 'Var', (219, 234))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('tumor', 'Disease', (146, 151))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('switch', 'Reg', (132, 138))	('hypermethylation', 'Var', (177, 193))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
170939	25631659	For four cancer sites we were able to identify a sufficient number of cancer stage driver genes and showed that genes identified by MethylMix are more enriched with cancer stage driver genes compared with those identified by IMA, COHCAP and minfi (Table S3 in Additional file 2).	('cancer', 'Disease', (9, 15))	('COHCAP', 'Chemical', '-', (230, 236))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('MethylMix', 'Var', (132, 141))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('cancer', 'Disease', (165, 171))	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('cancer', 'Disease', 'MESH:D009369', (70, 76))
170946	25631659	We investigated the enrichment of molecular pathways in the hyper- and hypomethylated genes in all 12 cancer sites using enrichment analysis.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('hyper-', 'Var', (60, 66))	('hypomethylated', 'Var', (71, 85))	('investigated', 'Reg', (3, 15))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))
170948	25631659	These genes sets are related to suppression of genes involved in differentiation, such as genes repressed by co-binding of POU5F1 (also known as OCT4), SOX2 and NANOG; genes affected by knockdown of TCL1A (also known as TCL1); a polycomb target module and targets of SMAD1 and ZNF281, and genes differentially expressed after RNA interference knockdown of NANOG.	('SMAD1', 'Gene', (267, 272))	('TCL1A', 'Gene', '8115', (199, 204))	('OCT4', 'Gene', (145, 149))	('POU5F1', 'Gene', (123, 129))	('TCL1', 'Gene', '8115', (199, 203))	('TCL1A', 'Gene', (199, 204))	('knockdown', 'Var', (186, 195))	('NANOG', 'Gene', '79923', (161, 166))	('SOX2', 'Gene', '6657', (152, 156))	('NANOG', 'Gene', (161, 166))	('SOX2', 'Gene', (152, 156))	('SMAD1', 'Gene', '4086', (267, 272))	('TCL1', 'Gene', '8115', (220, 224))	('ZNF281', 'Gene', '23528', (277, 283))	('TCL1', 'Gene', (199, 203))	('POU5F1', 'Gene', '5460', (123, 129))	('NANOG', 'Gene', '79923', (356, 361))	('OCT4', 'Gene', '5460', (145, 149))	('NANOG', 'Gene', (356, 361))	('ZNF281', 'Gene', (277, 283))	('TCL1', 'Gene', (220, 224))
170954	25631659	Next, we confirmed the hypermethylated phenotype in GBM, also known as G-CIMP, and the hypermethylated phenotype in LAML, also known as L-CIMP characterized by IDH1 or IDH2 mutations (Figure 1B,C; Figures S2, S3 and S4 in Additional file 1).	('IDH2', 'Gene', '3418', (168, 172))	('AML', 'Disease', (117, 120))	('IDH1', 'Gene', (160, 164))	('L-CIMP', 'Chemical', '-', (136, 142))	('IDH1', 'Gene', '3417', (160, 164))	('mutations', 'Var', (173, 182))	('G-CIMP', 'Chemical', '-', (71, 77))	('IDH2', 'Gene', (168, 172))	('GBM', 'Phenotype', 'HP:0012174', (52, 55))	('AML', 'Disease', 'MESH:D015470', (117, 120))
170964	25631659	The good prognosis cluster, cluster 3, is characterized by hypermethylation of CYTIP, with 65% of all hypermethylated cases in cluster 3 (Figure 2C) and virtually all samples in cluster 3 are CYTIP hypermethylated (n = 192/204).	('hypermethylated', 'Var', (102, 117))	('CYTIP', 'Gene', '9595', (192, 197))	('CYTIP', 'Gene', '9595', (79, 84))	('CYTIP', 'Gene', (192, 197))	('CYTIP', 'Gene', (79, 84))
170966	25631659	Interestingly, cluster 2 was significantly associated with mutations in NSD1 (P-value <0.001); more than half of the cluster 2 samples carry a mutation.	('NSD1', 'Gene', '64324', (72, 76))	('NSD1', 'Gene', (72, 76))	('mutations', 'Var', (59, 68))
170967	25631659	Next, cluster 4 is enriched with CASP8 and NOTCH1 mutations (P-value <0.001 and <0.001, respectively), both of which have been strongly implicated in HNSC.	('HNSC', 'Disease', (150, 154))	('NOTCH1', 'Gene', '4851', (43, 49))	('NOTCH1', 'Gene', (43, 49))	('mutations', 'Var', (50, 59))	('implicated', 'Reg', (136, 146))	('CASP8', 'Gene', (33, 38))	('CASP8', 'Gene', '841', (33, 38))
170968	25631659	This group is also characterized by hypermethylation of BCL2, with more than 50% of the hyper-methylated cases being in cluster 4 (Figure 3C), and virtually all cases in cluster 4 having BCL2 hypermethylated (that is, 75 out of 77 cases).	('hyper-methylated', 'Var', (88, 104))	('BCL2', 'Gene', '596', (56, 60))	('BCL2', 'Gene', '596', (187, 191))	('BCL2', 'Gene', (56, 60))	('BCL2', 'Gene', (187, 191))
170973	25631659	Although this CIMP group is associated with MLH1 hypermethylation, MethylMix identified other hypermethylated genes that characterize this group, such as hypermethylation of ELOVL4 and EPM2AIP1, a gene sharing a promoter with MLH1 (Figure 4B).	('MLH1', 'Gene', (44, 48))	('MLH1', 'Gene', '4292', (44, 48))	('hypermethylation', 'Var', (49, 65))	('MLH1', 'Gene', '4292', (226, 230))	('MLH1', 'Gene', (226, 230))	('ELOVL4', 'Gene', (174, 180))	('EPM2AIP1', 'Gene', '9852', (185, 193))	('ELOVL4', 'Gene', '6785', (174, 180))	('OV', 'Phenotype', 'HP:0100615', (176, 178))	('EPM2AIP1', 'Gene', (185, 193))	('CIMP', 'Chemical', '-', (14, 18))	('hypermethylation', 'Var', (154, 170))
170979	25631659	We found 10 pancancer clusters showing significant tissue-specific enrichment (Table S13 in Additional file 2), corresponding tissue-specific correlations with mutations (Figure S10 in Additional file 1) and survival (Figure S11 in Additional file 1).	('S10', 'Gene', (178, 181))	('mutations', 'Var', (160, 169))	('cancer', 'Disease', (15, 21))	('cancer', 'Disease', 'MESH:D009369', (15, 21))	('S10', 'Gene', '6204', (178, 181))	('S11', 'Gene', '6267', (225, 228))	('S11', 'Gene', (225, 228))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))
170994	25631659	We also observed a significant correlation between mutations in the lincRNA ADAM6 and pancancer cluster 8 (P-value <0.001; Figure S10 in Additional file 1).	('S10', 'Gene', (130, 133))	('mutations', 'Var', (51, 60))	('ADAM6', 'Gene', (76, 81))	('ADAM6', 'Gene', '8755', (76, 81))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('correlation', 'Interaction', (31, 42))	('S10', 'Gene', '6204', (130, 133))	('cancer', 'Disease', (89, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
170995	25631659	ADAM6 mutations appear across tissue in pancancer cluster 8, including in HNSC, LUSC and BLCA cases.	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('cancer', 'Disease', (43, 49))	('LUSC', 'Phenotype', 'HP:0030359', (80, 84))	('BLCA', 'Phenotype', 'HP:0009725', (89, 93))	('ADAM6', 'Gene', '8755', (0, 5))	('LUSC', 'Disease', (80, 84))	('BLCA cases', 'Disease', (89, 99))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('ADAM6', 'Gene', (0, 5))	('HNSC', 'Disease', (74, 78))	('mutations', 'Var', (6, 15))
171007	25631659	Therefore, DNA methylation is increasingly being recognized as a critical mechanism responsible for the transition from a normal to a malignant cellular phenotype and a possible driver of therapeutic resistance, and we have shown that differentially methylated genes are potential cancer driver genes.	('differentially methylated genes', 'Var', (235, 266))	('cancer', 'Phenotype', 'HP:0002664', (281, 287))	('cancer', 'Disease', (281, 287))	('cancer', 'Disease', 'MESH:D009369', (281, 287))
171013	25631659	Applying MethylMix to the combined pancancer data set identified 10 methylation subgroups, including four clusters with significant presence of multiple tissues.	('methylation', 'Var', (68, 79))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('cancer', 'Disease', (38, 44))
171014	25631659	Our findings emphasize the importance of studying aberrant DNA methylation in cancer and we identified surprising commonalities across cancers arising from different tissues.	('cancer', 'Disease', (135, 141))	('cancers', 'Phenotype', 'HP:0002664', (135, 142))	('cancers', 'Disease', (135, 142))	('cancers', 'Disease', 'MESH:D009369', (135, 142))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('aberrant', 'Var', (50, 58))	('cancer', 'Disease', 'MESH:D009369', (135, 141))
171020	25631659	MAGEA4 is also a therapeutic target in breast cancer where we observed hypomethylation in 18% of BRCA cases.	('breast cancer', 'Phenotype', 'HP:0003002', (39, 52))	('BRCA', 'Phenotype', 'HP:0003002', (97, 101))	('MAGEA4', 'Gene', (0, 6))	('BRCA', 'Gene', '672', (97, 101))	('MAGEA4', 'Gene', '4103', (0, 6))	('BRCA', 'Gene', (97, 101))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('breast cancer', 'Disease', 'MESH:D001943', (39, 52))	('hypomethylation', 'Var', (71, 86))	('breast cancer', 'Disease', (39, 52))
171022	25631659	This identifies aberrant methylation of MAGEA4 as a cause of its widespread upregulation and as a potential target for immunotherapy in multiple cancers.	('aberrant', 'Var', (16, 24))	('MAGEA4', 'Gene', (40, 46))	('methylation', 'MPA', (25, 36))	('multiple cancers', 'Disease', 'MESH:D009369', (136, 152))	('MAGEA4', 'Gene', '4103', (40, 46))	('upregulation', 'PosReg', (76, 88))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('multiple cancers', 'Disease', (136, 152))	('cancers', 'Phenotype', 'HP:0002664', (145, 152))
171023	25631659	Previous studies on DNA methylation have focused almost exclusively on hypermethylation leading to the identification of the CIMP subgroups in at least three cancer sites, colorectal, LAML and glioma.	('AML', 'Disease', (185, 188))	('CIMP', 'Chemical', '-', (125, 129))	('glioma', 'Disease', (193, 199))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('cancer', 'Disease', (158, 164))	('glioma', 'Phenotype', 'HP:0009733', (193, 199))	('AML', 'Disease', 'MESH:D015470', (185, 188))	('hypermethylation', 'Var', (71, 87))	('glioma', 'Disease', 'MESH:D005910', (193, 199))	('colorectal', 'Disease', (172, 182))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
171028	25631659	Moreover, we identified a subtype of HNSC that is potentially caused by NSD1 mutations.	('NSD1', 'Gene', '64324', (72, 76))	('NSD1', 'Gene', (72, 76))	('mutations', 'Var', (77, 86))	('HNSC', 'Disease', (37, 41))	('caused by', 'Reg', (62, 71))
171030	25631659	Its mutational pattern suggests a loss of function creating aberrant histone methylation, also affecting DNA methylation processes through DNA-histone methylation crosstalk, and thereby potentially defining the NSD1 HNSC subtype.	('affecting', 'Reg', (95, 104))	('NSD1', 'Gene', '64324', (211, 215))	('NSD1', 'Gene', (211, 215))	('histone methylation', 'MPA', (69, 88))	('DNA methylation processes', 'MPA', (105, 130))	('aberrant', 'Var', (60, 68))
171033	25631659	Our map revealed six pancancer clusters that are heavily enriched in one tissue, illustrating that, due to DNA methylation being a tissue mark, aberrant DNA methylation heavily reflects the tissue of origin.	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('aberrant', 'Var', (144, 152))	('cancer', 'Disease', (24, 30))	('cancer', 'Disease', 'MESH:D009369', (24, 30))	('reflects', 'Reg', (177, 185))
171076	25631659	We used consensus clustering to identify robust clusters defined by DM-values within each tissue and across all cancers (see the 'Pancancer MethylMix analysis' section above).	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('cancers', 'Phenotype', 'HP:0002664', (112, 119))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('cancers', 'Disease', 'MESH:D009369', (112, 119))	('cancer', 'Disease', (133, 139))	('cancers', 'Disease', (112, 119))	('DM-values', 'Var', (68, 77))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
171085	25631659	BIC Bayesian Information Criterion BLCA bladder cancer BRCA breast cancer COAD colon cancer DM differential methylation FDR false discovery rate GBM glioblastoma HNSC head and neck squamous carcinoma KIRC clear cell renal carcinoma LAML acute myeloid leukemia LUAD lung adeno carcinoma LUSC lung squamous carcinoma MSI microsatellite instability OV serous ovarian cancer READ rectal cancer TCGA The Cancer Genome Atlas UCEC endometrial carcinoma	('colon cancer', 'Disease', (79, 91))	('glioblastoma', 'Disease', 'MESH:D005909', (149, 161))	('MSI', 'Disease', (315, 318))	('BRCA', 'Gene', (55, 59))	('cancer', 'Phenotype', 'HP:0002664', (383, 389))	('neck squamous carcinoma', 'Disease', 'MESH:D000077195', (176, 199))	('rectal cancer', 'Disease', 'MESH:D012004', (376, 389))	('acute myeloid leukemia', 'Disease', (237, 259))	('serous ovarian cancer', 'Disease', (349, 370))	('BIC', 'Chemical', '-', (0, 3))	('endometrial carcinoma', 'Disease', (424, 445))	('breast cancer', 'Phenotype', 'HP:0003002', (60, 73))	('Cancer', 'Phenotype', 'HP:0002664', (399, 405))	('glioblastoma', 'Disease', (149, 161))	('clear cell renal carcinoma', 'Disease', (205, 231))	('carcinoma', 'Phenotype', 'HP:0030731', (276, 285))	('lung adeno carcinoma', 'Disease', 'MESH:D008175', (265, 285))	('carcinoma', 'Phenotype', 'HP:0030731', (190, 199))	('leukemia', 'Phenotype', 'HP:0001909', (251, 259))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('glioblastoma', 'Phenotype', 'HP:0012174', (149, 161))	('lung squamous carcinoma', 'Phenotype', 'HP:0030359', (291, 314))	('LUSC', 'Phenotype', 'HP:0030359', (286, 290))	('bladder cancer', 'Disease', 'MESH:D001749', (40, 54))	('bladder cancer', 'Disease', (40, 54))	('clear cell renal carcinoma', 'Disease', 'MESH:C538614', (205, 231))	('colon cancer', 'Phenotype', 'HP:0003003', (79, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (222, 231))	('GBM', 'Phenotype', 'HP:0012174', (145, 148))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (296, 314))	('breast cancer', 'Disease', 'MESH:D001943', (60, 73))	('BLCA', 'Phenotype', 'HP:0009725', (35, 39))	('OV', 'Phenotype', 'HP:0100615', (346, 348))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (237, 259))	('bladder cancer', 'Phenotype', 'HP:0009725', (40, 54))	('breast cancer', 'Disease', (60, 73))	('carcinoma', 'Phenotype', 'HP:0030731', (436, 445))	('cancer', 'Phenotype', 'HP:0002664', (364, 370))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (424, 445))	('BRCA', 'Phenotype', 'HP:0003002', (55, 59))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (243, 259))	('COAD', 'Disease', 'MESH:D029424', (74, 78))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (237, 259))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (424, 445))	('lung squamous carcinoma', 'Disease', (291, 314))	('rectal cancer', 'Disease', (376, 389))	('colon cancer', 'Disease', 'MESH:D015179', (79, 91))	('microsatellite instability', 'Var', (319, 345))	('lung adeno carcinoma', 'Disease', (265, 285))	('renal carcinoma', 'Phenotype', 'HP:0005584', (216, 231))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('serous ovarian cancer', 'Disease', 'MESH:D010051', (349, 370))	('rectal cancer', 'Phenotype', 'HP:0100743', (376, 389))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (399, 418))	('LUAD', 'Phenotype', 'HP:0030078', (260, 264))	('BRCA', 'Gene', '672', (55, 59))	('lung squamous carcinoma', 'Disease', 'MESH:D002294', (291, 314))	('lung adeno carcinoma', 'Phenotype', 'HP:0030078', (265, 285))	('clear cell renal carcinoma', 'Phenotype', 'HP:0006770', (205, 231))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (181, 199))	('AML', 'Disease', 'MESH:D015470', (233, 236))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('carcinoma', 'Phenotype', 'HP:0030731', (305, 314))	('neck squamous carcinoma', 'Disease', (176, 199))	('AML', 'Disease', (233, 236))	('COAD', 'Disease', (74, 78))	('MSI', 'Disease', 'None', (315, 318))	('Cancer Genome Atlas', 'Disease', (399, 418))	('ovarian cancer', 'Phenotype', 'HP:0100615', (356, 370))
171087	31508486	We and others have shown that miR-195 regulates the sensitivity of NSCLC to microtubule-targeting agents (MTAs) in vitro and in vivo and that miR-195 represses the migration and invasion of NSCLC cells in vitro.	('miR-195', 'Var', (142, 149))	('NSCLC', 'Phenotype', 'HP:0030358', (190, 195))	('NSCLC', 'Phenotype', 'HP:0030358', (67, 72))	('regulates', 'Reg', (38, 47))	('NSCLC', 'Disease', 'MESH:D002289', (190, 195))	('NSCLC', 'Disease', (190, 195))	('NSCLC', 'Disease', (67, 72))	('miR-195', 'Gene', (30, 37))	('represses', 'NegReg', (150, 159))	('NSCLC', 'Disease', 'MESH:D002289', (67, 72))	('migration', 'CPA', (164, 173))
171090	31508486	We found that miR-195 directly targets TUBB; knockdown of TUBB sensitizes cells to MTAs, while overexpression confers resistance; high expression of TUBB is correlated with worse survival of lung adenocarcinoma; TUBB is also regulated by CHEK1, which has been shown to regulate chemoresistance; and miR-195 targets BIRC5 to repress migration and invasion in vitro and metastasis in vivo.	('BIRC5', 'Gene', '332', (315, 320))	('CHEK1', 'Gene', '1111', (238, 243))	('BIRC5', 'Gene', (315, 320))	('miR-195', 'Var', (299, 306))	('TUBB', 'Gene', (39, 43))	('TUBB', 'Gene', '203068', (58, 62))	('TUBB', 'Gene', (212, 216))	('TUBB', 'Gene', (149, 153))	('CHEK1', 'Gene', (238, 243))	('lung adenocarcinoma', 'Disease', (191, 210))	('TUBB', 'Gene', '203068', (39, 43))	('TUBB', 'Gene', '203068', (212, 216))	('metastasis', 'CPA', (368, 378))	('carcinoma', 'Phenotype', 'HP:0030731', (201, 210))	('repress', 'NegReg', (324, 331))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (191, 210))	('TUBB', 'Gene', '203068', (149, 153))	('TUBB', 'Gene', (58, 62))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (191, 210))
171099	31508486	TUBB mutations were first reported to correlate with paclitaxel resistance in NSCLC patients.	('TUBB', 'Gene', '203068', (0, 4))	('patients', 'Species', '9606', (84, 92))	('NSCLC', 'Phenotype', 'HP:0030358', (78, 83))	('mutations', 'Var', (5, 14))	('correlate', 'Reg', (38, 47))	('paclitaxel resistance', 'MPA', (53, 74))	('paclitaxel', 'Chemical', 'MESH:D017239', (53, 63))	('TUBB', 'Gene', (0, 4))	('NSCLC', 'Disease', (78, 83))	('NSCLC', 'Disease', 'MESH:D002289', (78, 83))
171100	31508486	It was later argued, however, that TUBB mutations are not common in NSCLC and that the reported TUBB mutations likely occur in TUBB pseudogenes.	('TUBB', 'Gene', '203068', (127, 131))	('mutations', 'Var', (101, 110))	('NSCLC', 'Disease', 'MESH:D002289', (68, 73))	('TUBB', 'Gene', '203068', (96, 100))	('TUBB', 'Gene', (127, 131))	('TUBB', 'Gene', (96, 100))	('mutations', 'Var', (40, 49))	('NSCLC', 'Phenotype', 'HP:0030358', (68, 73))	('TUBB', 'Gene', '203068', (35, 39))	('TUBB', 'Gene', (35, 39))	('NSCLC', 'Disease', (68, 73))
171110	31508486	Specifically, miR-195 increases chemosensitivity of colon cancer and cervical cancer, but correlates with acquired chemoresistance in glioblastoma.	('colon cancer', 'Disease', (52, 64))	('chemosensitivity', 'MPA', (32, 48))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('glioblastoma', 'Disease', (134, 146))	('glioblastoma', 'Disease', 'MESH:D005909', (134, 146))	('glioblastoma', 'Phenotype', 'HP:0012174', (134, 146))	('colon cancer', 'Phenotype', 'HP:0003003', (52, 64))	('cervical cancer', 'Disease', 'MESH:D002583', (69, 84))	('increases', 'PosReg', (22, 31))	('colon cancer', 'Disease', 'MESH:D015179', (52, 64))	('cervical cancer', 'Disease', (69, 84))	('miR-195', 'Var', (14, 21))
171115	31508486	Our investigation of the function of miR-195 in NSCLC revealed that TUBB is a direct target of miR-195, regulating the response of NSCLC cells to MTAs and that expression of TUBB correlates with the prognosis of NSCLC patients.	('NSCLC', 'Disease', 'MESH:D002289', (212, 217))	('NSCLC', 'Disease', (48, 53))	('NSCLC', 'Phenotype', 'HP:0030358', (48, 53))	('NSCLC', 'Disease', (212, 217))	('response', 'MPA', (119, 127))	('TUBB', 'Gene', (174, 178))	('NSCLC', 'Disease', 'MESH:D002289', (131, 136))	('NSCLC', 'Phenotype', 'HP:0030358', (212, 217))	('patients', 'Species', '9606', (218, 226))	('TUBB', 'Gene', (68, 72))	('NSCLC', 'Disease', (131, 136))	('correlates with', 'Reg', (179, 194))	('miR-195', 'Gene', (95, 102))	('NSCLC', 'Phenotype', 'HP:0030358', (131, 136))	('TUBB', 'Gene', '203068', (174, 178))	('expression', 'Var', (160, 170))	('NSCLC', 'Disease', 'MESH:D002289', (48, 53))	('regulating', 'Reg', (104, 114))	('TUBB', 'Gene', '203068', (68, 72))
171116	31508486	We also found that miR-195 and TUBB had no effect on microtubule structure.	('miR-195', 'Var', (19, 26))	('TUBB', 'Gene', (31, 35))	('TUBB', 'Gene', '203068', (31, 35))	('microtubule structure', 'MPA', (53, 74))
171117	31508486	Interestingly, we show that TUBB expression can be regulated by another target of miR-195, CHEK1, which had previously been shown to regulate chemoresistance in NSCLC.	('NSCLC', 'Disease', 'MESH:D002289', (161, 166))	('CHEK1', 'Gene', (91, 96))	('chemoresistance', 'CPA', (142, 157))	('regulate', 'Reg', (133, 141))	('TUBB', 'Gene', '203068', (28, 32))	('CHEK1', 'Gene', '1111', (91, 96))	('NSCLC', 'Phenotype', 'HP:0030358', (161, 166))	('TUBB', 'Gene', (28, 32))	('miR-195', 'Var', (82, 89))	('expression', 'MPA', (33, 43))	('regulated', 'Reg', (51, 60))	('NSCLC', 'Disease', (161, 166))
171123	31508486	We found that high expression of TUBB, TUBA3D, or TUBB4B is correlated with worse overall survival and worse chemotherapy response in lung adenocarcinoma patients (Figures 1A and 1B; Figure S1), as assessed by Kaplan-Meier survival analysis and log-rank test.	('TUBB4B', 'Gene', (50, 56))	('TUBB4B', 'Gene', '10383', (50, 56))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (134, 153))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (134, 153))	('TUBA3D', 'Gene', (39, 45))	('patients', 'Species', '9606', (154, 162))	('high', 'Var', (14, 18))	('worse', 'NegReg', (76, 81))	('lung adenocarcinoma', 'Disease', (134, 153))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('TUBB', 'Gene', '203068', (33, 37))	('TUBB', 'Gene', '203068', (50, 54))	('overall survival', 'CPA', (82, 98))	('TUBA3D', 'Gene', '113457', (39, 45))	('TUBB', 'Gene', (33, 37))	('TUBB', 'Gene', (50, 54))
171126	31508486	In similar analysis of data from The Cancer Genome Atlas (TCGA), we found that high expression of TUBB is correlated with worse overall survival and recurrence-free survival of lung adenocarcinoma, but not squamous cell carcinoma (Figures 1E-1H).	('recurrence-free survival', 'CPA', (149, 173))	('worse', 'NegReg', (122, 127))	('Cancer Genome Atlas', 'Disease', (37, 56))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (206, 229))	('squamous cell carcinoma', 'Disease', (206, 229))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (37, 56))	('TUBB', 'Gene', (98, 102))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (206, 229))	('overall survival', 'CPA', (128, 144))	('carcinoma', 'Phenotype', 'HP:0030731', (187, 196))	('lung adenocarcinoma', 'Disease', (177, 196))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (177, 196))	('Cancer', 'Phenotype', 'HP:0002664', (37, 43))	('high expression', 'Var', (79, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (220, 229))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (177, 196))	('TUBB', 'Gene', '203068', (98, 102))
171130	31508486	We demonstrated that this relationship is causal:miR-195 inhibits both the mRNA and protein levels of TUBB (Figures 2E and 2F):and confirmed the direct and specific binding of miR-195 to the 3' UTR of TUBB by luciferase assay (Figure 2G).	('TUBB', 'Gene', '203068', (102, 106))	('binding', 'Interaction', (165, 172))	('TUBB', 'Gene', (102, 106))	('miR-195', 'Gene', (176, 183))	('TUBB', 'Gene', '203068', (201, 205))	('TUBB', 'Gene', (201, 205))	('miR-195', 'Var', (49, 56))	('inhibits', 'NegReg', (57, 65))
171131	31508486	To functionally validate that TUBB regulates the response of lung adenocarcinoma cells to MTAs, we knocked down TUBB with a validated siRNA pool designed against TUBB (siTUBB) (Figure 3A).	('TUBB', 'Gene', (170, 174))	('TUBB', 'Gene', '203068', (30, 34))	('TUBB', 'Gene', (112, 116))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (61, 80))	('TUBB', 'Gene', (30, 34))	('knocked', 'Var', (99, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('lung adenocarcinoma', 'Disease', (61, 80))	('TUBB', 'Gene', '203068', (162, 166))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (61, 80))	('TUBB', 'Gene', '203068', (170, 174))	('TUBB', 'Gene', (162, 166))	('TUBB', 'Gene', '203068', (112, 116))
171132	31508486	We found that knockdown of TUBB sensitizes H1299 cells to eribulin, but not paclitaxel, and sensitizes H1993 and A549 cells to both paclitaxel and eribulin (Figures 3B and 3C).	('paclitaxel', 'Chemical', 'MESH:D017239', (76, 86))	('sensitizes', 'Reg', (32, 42))	('H1993', 'CellLine', 'CVCL:1512', (103, 108))	('TUBB', 'Gene', '203068', (27, 31))	('sensitizes', 'Reg', (92, 102))	('paclitaxel', 'Chemical', 'MESH:D017239', (132, 142))	('H1299', 'CellLine', 'CVCL:0060', (43, 48))	('TUBB', 'Gene', (27, 31))	('A549', 'CellLine', 'CVCL:0023', (113, 117))	('knockdown', 'Var', (14, 23))
171137	31508486	We confirmed that TUBB is regulated by CHEK1: knockdown of CHEK1 represses TUBB protein levels in H1299 cells, while overexpression of CHEK1 increases TUBB protein levels (Figure 5B).	('TUBB', 'Gene', '203068', (75, 79))	('represses', 'NegReg', (65, 74))	('TUBB', 'Gene', '203068', (151, 155))	('knockdown', 'Var', (46, 55))	('CHEK1', 'Gene', (59, 64))	('TUBB', 'Gene', (75, 79))	('TUBB', 'Gene', (151, 155))	('H1299', 'CellLine', 'CVCL:0060', (98, 103))	('TUBB', 'Gene', '203068', (18, 22))	('CHEK1', 'Gene', '1111', (135, 140))	('TUBB', 'Gene', (18, 22))	('CHEK1', 'Gene', '1111', (39, 44))	('CHEK1', 'Gene', '1111', (59, 64))	('CHEK1', 'Gene', (135, 140))	('CHEK1', 'Gene', (39, 44))
171138	31508486	To assess whether miR-195 regulation of TUBB affects microtubule structures, we visualized microtubule structures though immunofluorescence staining.	('TUBB', 'Gene', '203068', (40, 44))	('miR-195', 'Var', (18, 25))	('TUBB', 'Gene', (40, 44))	('microtubule', 'MPA', (53, 64))
171142	31508486	We were unable, however, to demonstrate whether miR-195 or siTUBB enhance the effects of paclitaxel and eribulin on microtubule disruption.	('effects', 'MPA', (78, 85))	('TUBB', 'Gene', '203068', (61, 65))	('enhance', 'PosReg', (66, 73))	('miR-195', 'Var', (48, 55))	('microtubule disruption', 'MPA', (116, 138))	('TUBB', 'Gene', (61, 65))	('paclitaxel', 'Chemical', 'MESH:D017239', (89, 99))
171146	31508486	The results confirmed that miR-195 inhibits the migration and invasion of lung adenocarcinoma cells independent of its effect on cell viability and that miR-195 inhibitors promote migration and invasion of cancer cells, albeit slightly (Figures 7A-7D; Figure S4).	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('invasion', 'CPA', (194, 202))	('inhibits', 'NegReg', (35, 43))	('migration', 'CPA', (180, 189))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (74, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('promote', 'PosReg', (172, 179))	('inhibitors', 'Var', (161, 171))	('miR-195', 'Gene', (153, 160))	('lung adenocarcinoma', 'Disease', (74, 93))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (74, 93))	('cancer', 'Disease', (206, 212))	('cancer', 'Disease', 'MESH:D009369', (206, 212))	('miR-195', 'Var', (27, 34))
171147	31508486	In addition, we exploited a chemotaxis assay designed for real-time visualization and automated analysis of cell migration and invasion to show that miR-195 inhibits the migration and invasion of cancer cells (Figures 8A and 8B).	('miR-195', 'Var', (149, 156))	('inhibits', 'NegReg', (157, 165))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('cancer', 'Disease', 'MESH:D009369', (196, 202))	('cancer', 'Disease', (196, 202))
171148	31508486	We generated cells stably overexpressing miR-195 (H1299/luc-miR-195 #116 and #126) and demonstrated that constitutive overexpression of miR-195 inhibits cancer cell migration and invasion in vitro (Figures S5A-S5E).	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('inhibits', 'NegReg', (144, 152))	('overexpression', 'PosReg', (118, 132))	('cancer', 'Disease', (153, 159))	('miR-195', 'Var', (136, 143))	('invasion', 'CPA', (179, 187))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('H1299', 'CellLine', 'CVCL:0060', (50, 55))
171153	31508486	Leveraging an experimental model of lung metastasis, mouse lung adenocarcinoma cell line 344SQ, which has been demonstrated to form lung metastases when inoculated subcutaneously into syngeneic mice, we subcutaneously injected 344SQ/control cells and 344SQ cells overexpressing miR-195 (344SQ/miR-195) into syngeneic mice (4 mice in the control group and 5 mice in the miR-195 group) (Figure S6A).	('mice', 'Species', '10090', (325, 329))	('miR-195', 'Var', (278, 285))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (59, 78))	('mice', 'Species', '10090', (357, 361))	('lung metastases', 'Disease', (132, 147))	('mice', 'Species', '10090', (194, 198))	('lung metastases', 'Disease', 'MESH:D009362', (132, 147))	('mice', 'Species', '10090', (317, 321))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (59, 78))	('mouse', 'Species', '10090', (53, 58))	('344SQ/miR-195', 'Var', (287, 300))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))	('lung adenocarcinoma', 'Disease', (59, 78))
171154	31508486	Due to the small number of mice and large variance in tumor size, tumor weight and size in the miR-195 group were not significantly smaller than those in the control group (Figures S6B-S6E).	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Disease', (66, 71))	('mice', 'Species', '10090', (27, 31))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('miR-195', 'Var', (95, 102))	('smaller', 'NegReg', (132, 139))	('tumor', 'Disease', (54, 59))	('tumor', 'Disease', 'MESH:D009369', (66, 71))
171157	31508486	Quantification of lung metastasis demonstrated that the number of metastases is significantly smaller in the miR-195 group than in the control group, implying that miR-195 represses lung metastasis in vivo (Figures 7F-7H).	('metastases', 'Disease', (66, 76))	('metastases', 'Disease', 'MESH:D009362', (66, 76))	('represses', 'NegReg', (172, 181))	('smaller', 'NegReg', (94, 101))	('miR-195', 'Var', (109, 116))	('miR-195', 'Var', (164, 171))	('lung metastasis', 'CPA', (182, 197))
171161	31508486	We found that overexpression of BIRC5 indeed reverses the effects of miR-195 and that knockdown of BIRC5 inhibits the migration and invasion of cancer cells, confirming that miR-195 targets BIRC5 to regulate the migration and invasion of lung cancer cells (Figures 8A-8D).	('knockdown', 'Var', (86, 95))	('invasion', 'CPA', (226, 234))	('cancer', 'Disease', (144, 150))	('migration', 'CPA', (212, 221))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('lung cancer', 'Disease', 'MESH:D008175', (238, 249))	('BIRC5', 'Gene', '332', (99, 104))	('cancer', 'Disease', 'MESH:D009369', (243, 249))	('BIRC5', 'Gene', (99, 104))	('lung cancer', 'Phenotype', 'HP:0100526', (238, 249))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('inhibits', 'NegReg', (105, 113))	('BIRC5', 'Gene', '332', (190, 195))	('BIRC5', 'Gene', '332', (32, 37))	('BIRC5', 'Gene', (190, 195))	('BIRC5', 'Gene', (32, 37))	('cancer', 'Disease', (243, 249))	('regulate', 'Reg', (199, 207))	('lung cancer', 'Disease', (238, 249))	('cancer', 'Phenotype', 'HP:0002664', (243, 249))
171164	31508486	Collectively, our data indicate that miR-195/BIRC5 dysregulation is not a driver of lung metastasis, but a contributing factor.	('BIRC5', 'Gene', (45, 50))	('BIRC5', 'Gene', '332', (45, 50))	('dysregulation', 'Var', (51, 64))
171169	31508486	Interestingly, although TUBB is the most abundant among tubulin proteins, miR-195 regulation of TUBB does not alter microtubule structure.	('TUBB', 'Gene', '203068', (96, 100))	('TUBB', 'Gene', '203068', (24, 28))	('miR-195', 'Var', (74, 81))	('TUBB', 'Gene', (96, 100))	('TUBB', 'Gene', (24, 28))
171171	31508486	The correlation between TUBB mutations and paclitaxel resistance in NSCLC was debated almost two decades ago.	('NSCLC', 'Disease', 'MESH:D002289', (68, 73))	('TUBB', 'Gene', '203068', (24, 28))	('mutations', 'Var', (29, 38))	('paclitaxel', 'Chemical', 'MESH:D017239', (43, 53))	('TUBB', 'Gene', (24, 28))	('NSCLC', 'Phenotype', 'HP:0030358', (68, 73))	('NSCLC', 'Disease', (68, 73))
171173	31508486	However, neither TUBB mutations nor expression were found to correlate with NSCLC resistance to paclitaxel, and the role of TUBB in chemoresistance has never been experimentally validated.	('paclitaxel', 'Chemical', 'MESH:D017239', (96, 106))	('TUBB', 'Gene', '203068', (17, 21))	('NSCLC', 'Disease', (76, 81))	('TUBB', 'Gene', (17, 21))	('TUBB', 'Gene', '203068', (124, 128))	('NSCLC', 'Disease', 'MESH:D002289', (76, 81))	('mutations', 'Var', (22, 31))	('TUBB', 'Gene', (124, 128))	('NSCLC', 'Phenotype', 'HP:0030358', (76, 81))
171175	31508486	Importantly, overexpression of TUBB confers resistance to MTAs, while knockdown of TUBB sensitizes NSCLC cells to MTAs.	('knockdown', 'Var', (70, 79))	('TUBB', 'Gene', '203068', (83, 87))	('sensitizes', 'Reg', (88, 98))	('NSCLC', 'Phenotype', 'HP:0030358', (99, 104))	('resistance', 'MPA', (44, 54))	('TUBB', 'Gene', (83, 87))	('overexpression', 'PosReg', (13, 27))	('TUBB', 'Gene', '203068', (31, 35))	('NSCLC', 'Disease', (99, 104))	('TUBB', 'Gene', (31, 35))	('NSCLC', 'Disease', 'MESH:D002289', (99, 104))
171177	31508486	Additionally, we show that TUBB is a direct target of miR-195 and can be regulated by another target of miR-195, CHEK1.	('miR-195', 'Var', (104, 111))	('CHEK1', 'Gene', (113, 118))	('TUBB', 'Gene', '203068', (27, 31))	('miR-195', 'Var', (54, 61))	('TUBB', 'Gene', (27, 31))	('CHEK1', 'Gene', '1111', (113, 118))
171183	31508486	In conclusion, this report demonstrates that miR-195 targets TUBB to regulate the response of NSCLC cells to MTAs and that the expression of TUBB can be a prognostic factor in lung adenocarcinoma.	('NSCLC', 'Phenotype', 'HP:0030358', (94, 99))	('TUBB', 'Gene', '203068', (61, 65))	('miR-195', 'Gene', (45, 52))	('lung adenocarcinoma', 'Disease', (176, 195))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (176, 195))	('carcinoma', 'Phenotype', 'HP:0030731', (186, 195))	('TUBB', 'Gene', (61, 65))	('NSCLC', 'Disease', (94, 99))	('TUBB', 'Gene', '203068', (141, 145))	('NSCLC', 'Disease', 'MESH:D002289', (94, 99))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (176, 195))	('expression', 'Var', (127, 137))	('TUBB', 'Gene', (141, 145))
171191	31508486	H1299/control, H1299/miR-195, 344SQ/control, and 344SQ/miR-195 cells were generated using luciferase-pcDNA3, which was a gift from William Kaelin (Addgene plasmid #18964).	('H1299/control', 'Var', (0, 13))	('H1299', 'CellLine', 'CVCL:0060', (15, 20))	('344SQ/miR-195', 'Var', (49, 62))	('H1299/miR-195', 'Var', (15, 28))	('H1299', 'CellLine', 'CVCL:0060', (0, 5))
171198	31508486	Primers used for TUBB 3' UTR with mutations in the binding site of miR-195: forward-5'-GTTGAACTTGAGAGTTTTTTTCATATTGAAAAGATGACATCGCC-3' and reverse-5'-AAAAACTCTCAAGTTCAACATAAAATAGAAATCTCAAATGTAGGATAGAA-3'.	('miR-195', 'Gene', (67, 74))	('TUBB 3', 'Gene', (17, 23))	('mutations', 'Var', (34, 43))	('TUBB 3', 'Gene', '10381', (17, 23))
171200	31508486	Anti-Chk1 (A300-161A-T) was purchased from Bethyl Laboratories (TX, USA).	('Chk1', 'Gene', (5, 9))	('A300-161A-T', 'Var', (11, 22))	('A300-161A-T', 'Mutation', 'c.300-161A,A>T', (11, 22))	('Chk1', 'Gene', '1111', (5, 9))
88106	31508486	Antibodies to calnexin (sc-11397) and GAPDH (sc-25778) were purchased from Santa Cruz Biotechnology (TX, USA).	('GAPDH', 'Gene', '2597', (38, 43))	('GAPDH', 'Gene', (38, 43))	('calnexin', 'Gene', (14, 22))	('sc-25778', 'Var', (45, 53))	('calnexin', 'Gene', '821', (14, 22))
171201	31508486	Anti-TUBB (T7816-100UL) was purchase from Sigma (MO, USA).	('T7816-100UL', 'Var', (11, 22))	('TUBB', 'Gene', (5, 9))	('TUBB', 'Gene', '203068', (5, 9))
171210	30568465	High expression of uPA related to p38MAPK in esophageal cancer indicates poor prognosis The aim of the study was to investigate the relationship between urokinase-type plasminogen activator (uPA) and mitogen-activated protein kinase 38 (p38MAPK), and preliminarily analyze their relationship with clinical characteristics of esophageal cancer.	('uPA', 'Gene', (191, 194))	('esophageal cancer', 'Disease', (45, 62))	('cancer', 'Phenotype', 'HP:0002664', (336, 342))	('uPA', 'Gene', '5328', (191, 194))	('uPA', 'Gene', (19, 22))	('esophageal cancer', 'Disease', 'MESH:D004938', (325, 342))	('p38MAPK', 'Var', (34, 41))	('esophageal cancer', 'Disease', 'MESH:D004938', (45, 62))	('uPA', 'Gene', '5328', (19, 22))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('urokinase-type plasminogen activator', 'Gene', '5328', (153, 189))	('urokinase-type plasminogen activator', 'Gene', (153, 189))	('esophageal cancer', 'Disease', (325, 342))
171211	30568465	Immunohistochemistry and Western blot were used to detect the expressions of uPA and p38MAPK in patients with esophageal cancer.	('p38MAPK', 'Var', (85, 92))	('uPA', 'Gene', (77, 80))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('uPA', 'Gene', '5328', (77, 80))	('esophageal cancer', 'Disease', (110, 127))	('patients', 'Species', '9606', (96, 104))	('esophageal cancer', 'Disease', 'MESH:D004938', (110, 127))
171213	30568465	The expressions of uPA and p38MAPK proteins were significantly higher in esophageal squamous cell carcinoma or adenocarcinoma than in normal esophageal mucosa tissue (both P<0.0001).	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (73, 107))	('uPA', 'Gene', (19, 22))	('p38MAPK', 'Var', (27, 34))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('expressions', 'MPA', (4, 15))	('uPA', 'Gene', '5328', (19, 22))	('esophageal squamous cell carcinoma', 'Disease', (73, 107))	('adenocarcinoma', 'Disease', (111, 125))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (84, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('higher', 'PosReg', (63, 69))	('adenocarcinoma', 'Disease', 'MESH:D000230', (111, 125))
171214	30568465	The expression of uPA was significantly correlated with the depth of invasion of esophageal cancer (P=0.0067), tumor size (P=0.0364), and pathological stage (P<0.0001); p38MAPK expression vs esophageal cancer tissue type (P=0.0043), esophageal cancer infiltration depth (P=0.0097), tumor size (P=0.0015), and pathological stage (P<0.0001).	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumor', 'Disease', (282, 287))	('tumor', 'Disease', 'MESH:D009369', (282, 287))	('esophageal cancer', 'Disease', 'MESH:D004938', (233, 250))	('p38MAPK', 'Var', (169, 176))	('esophageal cancer infiltration depth', 'Disease', (233, 269))	('uPA', 'Gene', (18, 21))	('esophageal cancer', 'Disease', 'MESH:D004938', (81, 98))	('tumor', 'Phenotype', 'HP:0002664', (282, 287))	('tumor', 'Disease', (111, 116))	('correlated', 'Reg', (40, 50))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('esophageal cancer', 'Disease', (81, 98))	('esophageal cancer', 'Disease', 'MESH:D004938', (191, 208))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('esophageal cancer', 'Disease', (191, 208))	('esophageal cancer infiltration depth', 'Disease', 'MESH:D017254', (233, 269))	('uPA', 'Gene', '5328', (18, 21))
171216	30568465	There was a positive correlation between uPA and p38MAPK expressions (r=0.7301, P=0.0104).	('uPA', 'Gene', '5328', (41, 44))	('uPA', 'Gene', (41, 44))	('p38MAPK expressions', 'Var', (49, 68))
171217	30568465	Kaplan-Meier analysis showed that the overall survival time of patients with positive expression of uPA or p38MAPK protein was significantly shorter, and the time of recurrence or metastasis of esophageal cancer was significantly earlier in patients with uPA-positive expression.	('metastasis of esophageal cancer', 'Disease', (180, 211))	('earlier', 'PosReg', (230, 237))	('shorter', 'NegReg', (141, 148))	('uPA', 'Gene', (255, 258))	('p38MAPK', 'Var', (107, 114))	('uPA', 'Gene', (100, 103))	('metastasis of esophageal cancer', 'Disease', 'MESH:D009362', (180, 211))	('patients', 'Species', '9606', (63, 71))	('uPA', 'Gene', '5328', (255, 258))	('survival', 'CPA', (46, 54))	('uPA', 'Gene', '5328', (100, 103))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('patients', 'Species', '9606', (241, 249))
171218	30568465	Multivariate analysis of Cox model showed that uPA, p38MAPK, and pathological staging were independent factors influencing survival.	('Cox', 'Gene', '1351', (25, 28))	('Cox', 'Gene', (25, 28))	('p38MAPK', 'Var', (52, 59))	('uPA', 'Gene', (47, 50))	('uPA', 'Gene', '5328', (47, 50))
171219	30568465	The expressions of uPA and p38MAPK may play an important role in the progression of esophageal cancer, and there is a close relationship between the two proteins, which may be one of the prognostic indicators.	('relationship', 'Interaction', (124, 136))	('uPA', 'Gene', (19, 22))	('p38MAPK', 'Var', (27, 34))	('uPA', 'Gene', '5328', (19, 22))	('play', 'Reg', (39, 43))	('esophageal cancer', 'Disease', (84, 101))	('esophageal cancer', 'Disease', 'MESH:D004938', (84, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))
171231	30568465	Although some progress has been made on this research, there are few more detailed studies on them, such as whether p38MAPK participates in the formation of uPA/uPAR/PAI-1 and affects the degradation of the outer matrix (ECM), or their relationship in the esophagus carcinoma progression.	('p38MAPK', 'Var', (116, 123))	('uPA', 'Gene', '5328', (157, 160))	('uPAR', 'Gene', (161, 165))	('esophagus carcinoma', 'Phenotype', 'HP:0011459', (256, 275))	('carcinoma', 'Phenotype', 'HP:0030731', (266, 275))	('uPA', 'Gene', (161, 164))	('uPA', 'Gene', (157, 160))	('uPA', 'Gene', '5328', (161, 164))	('esophagus carcinoma', 'Disease', 'MESH:D004938', (256, 275))	('PAI-1', 'Gene', (166, 171))	('degradation', 'MPA', (188, 199))	('PAI-1', 'Gene', '5054', (166, 171))	('uPAR', 'Gene', '5329', (161, 165))	('participates', 'Reg', (124, 136))	('affects', 'Reg', (176, 183))	('esophagus carcinoma', 'Disease', (256, 275))
171234	30568465	p38MAPK is known to be involved in a variety of different biological processes, including promoting apoptosis, participating in inflammatory reactions, malignant tumor development, and regulating transcription and translation of many different proteins, but its research in esophageal cancer is relatively rare.	('p38MAPK', 'Var', (0, 7))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('transcription', 'MPA', (196, 209))	('esophageal cancer', 'Disease', 'MESH:D004938', (274, 291))	('regulating', 'Reg', (185, 195))	('malignant tumor', 'Disease', (152, 167))	('promoting', 'PosReg', (90, 99))	('cancer', 'Phenotype', 'HP:0002664', (285, 291))	('esophageal cancer', 'Disease', (274, 291))	('participating', 'Reg', (111, 124))	('malignant tumor', 'Disease', 'MESH:D018198', (152, 167))	('apoptosis', 'CPA', (100, 109))
171235	30568465	In our previous study, we found that uPA and p38MAPK may be closely related to esophageal cancer.	('esophageal cancer', 'Disease', (79, 96))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('uPA', 'Gene', '5328', (37, 40))	('p38MAPK', 'Var', (45, 52))	('uPA', 'Gene', (37, 40))	('related', 'Reg', (68, 75))	('esophageal cancer', 'Disease', 'MESH:D004938', (79, 96))
171254	30568465	After blocking with 5% nonfat dry milk for 2 hours, added anti-uPA (1:600), anti-p38MAPK (1:500), and mouse anti-beta-actin (clone AC-15; 1:10,000, Sigma-Aldrich).	('uPA', 'Gene', '5328', (63, 66))	('uPA', 'Gene', (63, 66))	('mouse', 'Species', '10090', (102, 107))	('anti-p38MAPK', 'Var', (76, 88))
171257	30568465	After immunohistochemistry test, according to the above methods, the expressions of uPA and p38MAPK in esophageal squamous cell carcinoma and adenocarcinoma were found to be higher than those in normal esophageal tissues (both P<0.0001): uPA (squamous cell carcinoma: 89/112, adenocarcinoma: 61/72, and normal tissue: 15/62) and p38MAPK (squamous cell carcinoma: 92/112, adenocarcinoma: 61/72, normal tissue: 20/62).	('uPA', 'Gene', '5328', (238, 241))	('higher', 'PosReg', (174, 180))	('squamous cell carcinoma', 'Disease', (338, 361))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (114, 137))	('carcinoma', 'Phenotype', 'HP:0030731', (352, 361))	('adenocarcinoma', 'Disease', (142, 156))	('squamous cell carcinoma', 'Disease', (243, 266))	('p38MAPK', 'Var', (329, 336))	('adenocarcinoma', 'Disease', (276, 290))	('adenocarcinoma', 'Disease', (371, 385))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('esophageal squamous cell carcinoma', 'Disease', (103, 137))	('adenocarcinoma', 'Disease', 'MESH:D000230', (142, 156))	('uPA', 'Gene', (84, 87))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (338, 361))	('adenocarcinoma', 'Disease', 'MESH:D000230', (276, 290))	('uPA', 'Gene', '5328', (84, 87))	('adenocarcinoma', 'Disease', 'MESH:D000230', (371, 385))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (243, 266))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (103, 137))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (114, 137))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (338, 361))	('carcinoma', 'Phenotype', 'HP:0030731', (257, 266))	('carcinoma', 'Phenotype', 'HP:0030731', (281, 290))	('carcinoma', 'Phenotype', 'HP:0030731', (147, 156))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (243, 266))	('uPA', 'Gene', (238, 241))
171258	30568465	Further detection by Western blot found similar results, compared with normal esophageal tissue; the expression of uPA or p38MAPK protein in esophageal squamous cell carcinoma or adenocarcinoma was higher than that of normal esophageal tissue, and all P-value < 0.0001 (Table 1 and Figure 1).	('p38MAPK', 'Var', (122, 129))	('uPA', 'Gene', '5328', (115, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (184, 193))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (141, 175))	('adenocarcinoma', 'Disease', (179, 193))	('carcinoma', 'Phenotype', 'HP:0030731', (166, 175))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (152, 175))	('adenocarcinoma', 'Disease', 'MESH:D000230', (179, 193))	('expression', 'MPA', (101, 111))	('higher', 'PosReg', (198, 204))	('esophageal squamous cell carcinoma', 'Disease', (141, 175))	('uPA', 'Gene', (115, 118))
171259	30568465	After further analysis, it was found that there was a close correlation between the expressions of uPA and p38MAPK in esophageal cancer tissues (r=0.7301, P=0.0104, Table 1).	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('uPA', 'Gene', '5328', (99, 102))	('uPA', 'Gene', (99, 102))	('p38MAPK', 'Var', (107, 114))	('esophageal cancer', 'Disease', (118, 135))	('esophageal cancer', 'Disease', 'MESH:D004938', (118, 135))
171261	30568465	p38MAPK expression was correlated with esophageal cancer infiltration depth (T stage, P=0.0097), tumor length (P=0.0015), pTNM stage (P<0.0001), and tissue type (P=0.0043), but it was also not significantly associated with morphologic type, age, gender, and lymph node staging (Table 2).	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('p38MAPK', 'Var', (0, 7))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('TNM', 'Gene', (123, 126))	('esophageal cancer infiltration depth', 'Disease', 'MESH:D017254', (39, 75))	('esophageal cancer infiltration depth', 'Disease', (39, 75))	('tumor', 'Disease', (97, 102))	('correlated', 'Reg', (23, 33))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('TNM', 'Gene', '10178', (123, 126))
171262	30568465	After Kaplan-Meier analysis, the survival time of uPA- and p38MAPK-positive expression patients was found to be significantly shorter than that of negative patients (former, median survival: 42 vs 96 months, P<0.0001; latter, median survival: 45 vs 78 months, P=0.0121).	('patients', 'Species', '9606', (156, 164))	('survival time', 'CPA', (33, 46))	('shorter', 'NegReg', (126, 133))	('uPA', 'Gene', '5328', (50, 53))	('uPA', 'Gene', (50, 53))	('patients', 'Species', '9606', (87, 95))	('p38MAPK-positive expression', 'Var', (59, 86))
171264	30568465	Cox multivariate regression analysis was performed based on patient age, gender, depth of tumor invasion, lymph node metastasis, lesion length, pTNM, uPA, and p38MAPK protein expressions.	('patient', 'Species', '9606', (60, 67))	('uPA', 'Gene', (150, 153))	('Cox', 'Gene', (0, 3))	('TNM', 'Gene', '10178', (145, 148))	('Cox', 'Gene', '1351', (0, 3))	('tumor', 'Disease', (90, 95))	('uPA', 'Gene', '5328', (150, 153))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('p38MAPK', 'Var', (159, 166))	('TNM', 'Gene', (145, 148))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
171265	30568465	The results showed that uPA, p38MAPK protein expressions, and pTNM staging were independent prognostic factors (Table 3).	('TNM', 'Gene', '10178', (63, 66))	('TNM', 'Gene', (63, 66))	('p38MAPK', 'Var', (29, 36))	('uPA', 'Gene', (24, 27))	('uPA', 'Gene', '5328', (24, 27))
171268	30568465	This study explored the relationship between uPA, p38MAPK, and esophageal cancer, explored its possible mechanism, and provided a preliminary scientific basis for expanding the new diagnosis and treatment of esophageal cancer.	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('esophageal cancer', 'Disease', (63, 80))	('esophageal cancer', 'Disease', 'MESH:D004938', (63, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('esophageal cancer', 'Disease', (208, 225))	('uPA', 'Gene', (45, 48))	('esophageal cancer', 'Disease', 'MESH:D004938', (208, 225))	('uPA', 'Gene', '5328', (45, 48))	('p38MAPK', 'Var', (50, 57))
171277	30568465	Kim et al found that inhibition of p38MAPK activity can reduce the ability of cancer cells to exercise and reduce invasion and metastasis.	('ability', 'CPA', (67, 74))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('inhibition', 'Var', (21, 31))	('reduce', 'NegReg', (56, 62))	('reduce', 'NegReg', (107, 113))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('p38MAPK activity', 'Protein', (35, 51))
171278	30568465	Studies on human choriocarcinoma have shown that activated p38 enhances the invasive behavior of human trophoblast cells and plays an important role in the formation of choriocarcinoma.	('p38', 'Gene', (59, 62))	('choriocarcinoma', 'Disease', 'MESH:D002822', (169, 184))	('choriocarcinoma', 'Disease', (17, 32))	('choriocarcinoma', 'Phenotype', 'HP:0100768', (17, 32))	('human', 'Species', '9606', (11, 16))	('carcinoma', 'Phenotype', 'HP:0030731', (23, 32))	('human', 'Species', '9606', (97, 102))	('choriocarcinoma', 'Disease', (169, 184))	('p38', 'Gene', '5594', (59, 62))	('activated', 'Var', (49, 58))	('choriocarcinoma', 'Disease', 'MESH:D002822', (17, 32))	('choriocarcinoma', 'Phenotype', 'HP:0100768', (169, 184))	('enhances', 'PosReg', (63, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (175, 184))	('invasive behavior of human trophoblast cells', 'CPA', (76, 120))
171279	30568465	This study showed that the expressions of uPA and p38MAPK in esophageal cancer tissues were much higher than those in adjacent normal esophageal tissues, suggesting that both proteins may play an important role in the progression of esophageal cancer.	('higher', 'PosReg', (97, 103))	('esophageal cancer', 'Disease', 'MESH:D004938', (61, 78))	('esophageal cancer', 'Disease', (233, 250))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('play', 'Reg', (188, 192))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('esophageal cancer', 'Disease', 'MESH:D004938', (233, 250))	('expressions', 'MPA', (27, 38))	('uPA', 'Gene', (42, 45))	('esophageal cancer', 'Disease', (61, 78))	('uPA', 'Gene', '5328', (42, 45))	('p38MAPK', 'Var', (50, 57))
171280	30568465	These data suggest an important possibility: do not rule out the role of uPA and p38MAPK in promoting the progression of esophageal cancer in the same pathway.	('uPA', 'Gene', '5328', (73, 76))	('esophageal cancer', 'Disease', (121, 138))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('esophageal cancer', 'Disease', 'MESH:D004938', (121, 138))	('uPA', 'Gene', (73, 76))	('p38MAPK', 'Var', (81, 88))
171284	30568465	We found that the positive expressions of uPA and p38MAPK are closely related to the cancer size, depth of invasion, and pathological stage of esophageal cancer.	('esophageal cancer', 'Disease', 'MESH:D004938', (143, 160))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('cancer', 'Disease', (154, 160))	('p38MAPK', 'Var', (50, 57))	('cancer', 'Disease', (85, 91))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('positive', 'PosReg', (18, 26))	('uPA', 'Gene', (42, 45))	('related', 'Reg', (70, 77))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('uPA', 'Gene', '5328', (42, 45))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('esophageal cancer', 'Disease', (143, 160))
171286	30568465	In these studies, uPA or p38MAPK was also observed to be closely related to esophageal cancer size and pTNM staging.	('esophageal cancer', 'Disease', (76, 93))	('p38MAPK', 'Var', (25, 32))	('TNM', 'Gene', '10178', (104, 107))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('esophageal cancer', 'Disease', 'MESH:D004938', (76, 93))	('related', 'Reg', (65, 72))	('TNM', 'Gene', (104, 107))	('uPA', 'Gene', (18, 21))	('uPA', 'Gene', '5328', (18, 21))
171287	30568465	In this study, we also found that uPA has no significant relationship with esophageal cancer tissue type, and p38MAPK is relatively high in adenocarcinoma.	('high', 'Reg', (132, 136))	('esophageal cancer', 'Disease', 'MESH:D004938', (75, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (145, 154))	('adenocarcinoma', 'Disease', (140, 154))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('p38MAPK', 'Var', (110, 117))	('adenocarcinoma', 'Disease', 'MESH:D000230', (140, 154))	('uPA', 'Gene', (34, 37))	('uPA', 'Gene', '5328', (34, 37))	('esophageal cancer', 'Disease', (75, 92))
171291	30568465	We found that the median survival time of patients with positive protein expression was significantly shortened, which is consistent with the above data and also with most of research on their relationship between single uPA or p38MAPK and esophageal cancer.	('esophageal cancer', 'Disease', (240, 257))	('uPA', 'Gene', '5328', (221, 224))	('shortened', 'NegReg', (102, 111))	('uPA', 'Gene', (221, 224))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('protein', 'Protein', (65, 72))	('esophageal cancer', 'Disease', 'MESH:D004938', (240, 257))	('positive', 'Var', (56, 64))	('p38MAPK', 'Var', (228, 235))	('patients', 'Species', '9606', (42, 50))
171294	30568465	In this study, we found that uPA and p38MAPK proteins may play important roles in the progression of esophageal cancer, and there may be synergistic effects in this process, which provide a new perspective for us to further explore the mechanism of esophageal cancer progression.	('esophageal cancer', 'Disease', 'MESH:D004938', (249, 266))	('uPA', 'Gene', (29, 32))	('proteins', 'Protein', (45, 53))	('uPA', 'Gene', '5328', (29, 32))	('esophageal cancer', 'Disease', (101, 118))	('esophageal cancer', 'Disease', (249, 266))	('esophageal cancer', 'Disease', 'MESH:D004938', (101, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('cancer', 'Phenotype', 'HP:0002664', (260, 266))	('p38MAPK', 'Var', (37, 44))
171296	30568465	The role of uPA and p38MAPK in the progression of esophageal cancer may provide a scientific basis for exploring the feasibility of biologically targeted therapy for esophageal cancer.	('uPA', 'Gene', '5328', (12, 15))	('esophageal cancer', 'Disease', (166, 183))	('p38MAPK', 'Var', (20, 27))	('esophageal cancer', 'Disease', (50, 67))	('esophageal cancer', 'Disease', 'MESH:D004938', (166, 183))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('esophageal cancer', 'Disease', 'MESH:D004938', (50, 67))	('uPA', 'Gene', (12, 15))
171302	30466474	Alterations in several histone marks are associated with different types of cancers, and these alterations are distinct from marks found in original normal tissues.	('cancers', 'Disease', 'MESH:D009369', (76, 83))	('cancers', 'Phenotype', 'HP:0002664', (76, 83))	('mark', 'Gene', (125, 129))	('associated', 'Reg', (41, 51))	('mark', 'Gene', (31, 35))	('cancers', 'Disease', (76, 83))	('Alterations', 'Var', (0, 11))	('mark', 'Gene', '4139', (125, 129))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('mark', 'Gene', '4139', (31, 35))
171308	30466474	However, histone methylation may have both repressive (H3K9, H3K27) or enhancing (H3K4) effects on transcription, depending on the residue that is modified.	('H3', 'Gene', '126961', (61, 63))	('histone', 'Protein', (9, 16))	('H3', 'Gene', '126961', (82, 84))	('transcription', 'MPA', (99, 112))	('methylation', 'Var', (17, 28))	('H3', 'Gene', '126961', (55, 57))	('H3K27', 'Gene', '126961', (61, 66))	('H3K27', 'Gene', (61, 66))	('enhancing', 'PosReg', (71, 80))
171309	30466474	Histone methylation can occur on lysine and/or arginine residues.	('occur', 'Reg', (24, 29))	('lysine', 'Chemical', 'MESH:D008239', (33, 39))	('arginine', 'Chemical', 'MESH:D001120', (47, 55))	('lysine', 'Var', (33, 39))	('Histone methylation', 'MPA', (0, 19))
171314	30466474	Epigenetic changes along with genetic alterations can determine cell fate, either to maintain cell homeostasis or to promote tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('cell homeostasis', 'MPA', (94, 110))	('tumor', 'Disease', (125, 130))	('maintain', 'Reg', (85, 93))	('determine', 'Reg', (54, 63))	('promote', 'PosReg', (117, 124))	('Epigenetic changes', 'Var', (0, 18))
171315	30466474	Several histone methylation alterations are known to play a role in the transition of melanocytes to melanoma cells.	('melanoma', 'Phenotype', 'HP:0002861', (101, 109))	('alterations', 'Var', (28, 39))	('melanoma', 'Disease', (101, 109))	('melanoma', 'Disease', 'MESH:D008545', (101, 109))	('role', 'Reg', (60, 64))	('play', 'Reg', (53, 57))	('histone', 'Protein', (8, 15))
171328	30466474	Treatment of melanoma tumors with MAPK inhibitors increases the H3K4 demethylase JARID1B-positive subpopulation of melanoma cells.	('inhibitors', 'Var', (39, 49))	('JARID1B', 'Gene', '10765', (81, 88))	('melanoma tumors', 'Disease', 'MESH:D008545', (13, 28))	('JARID1B', 'Gene', (81, 88))	('H3', 'Gene', '126961', (64, 66))	('melanoma', 'Disease', (115, 123))	('melanoma', 'Phenotype', 'HP:0002861', (115, 123))	('MAPK', 'Gene', (34, 38))	('demethylase', 'Gene', '8932', (69, 80))	('melanoma', 'Disease', 'MESH:D008545', (115, 123))	('melanoma', 'Phenotype', 'HP:0002861', (13, 21))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('melanoma', 'Disease', (13, 21))	('increases', 'PosReg', (50, 59))	('melanoma', 'Disease', 'MESH:D008545', (13, 21))	('melanoma tumors', 'Disease', (13, 28))	('demethylase', 'Gene', (69, 80))	('tumors', 'Phenotype', 'HP:0002664', (22, 28))
171331	30466474	KDM5-C70 inhibits myeloma cells, increasing levels of H3K4me3 at the whole genome level.	('levels of', 'MPA', (44, 53))	('myeloma', 'Disease', 'MESH:D009101', (18, 25))	('inhibits', 'NegReg', (9, 17))	('KDM5-C70', 'Var', (0, 8))	('myeloma', 'Disease', (18, 25))	('H3', 'Gene', '126961', (54, 56))	('increasing', 'PosReg', (33, 43))
171338	30466474	Monomethylation of H3K4 is a histone modification that marks enhancers throughout the genome.	('H3', 'Gene', '126961', (19, 21))	('Monomethylation', 'Var', (0, 15))	('mark', 'Gene', '4139', (55, 59))	('mark', 'Gene', (55, 59))
171344	30466474	Trimethylated H3K9 is a well-known heterochromatin mark, which often highlights closed chromatin regions and is present on distal regions of genes.	('mark', 'Gene', (51, 55))	('mark', 'Gene', '4139', (51, 55))	('Trimethylated', 'Var', (0, 13))	('closed chromatin regions', 'MPA', (80, 104))	('H3', 'Gene', '126961', (14, 16))
171347	30466474	showed that enforced LSD1 expression in vivo can promote BRAFV600E-driven melanomagenesis.	('melanoma', 'Disease', 'MESH:D008545', (74, 82))	('BRAFV600E-driven', 'Var', (57, 73))	('melanoma', 'Phenotype', 'HP:0002861', (74, 82))	('melanoma', 'Disease', (74, 82))	('BRAFV600E', 'Mutation', 'rs113488022', (57, 66))	('promote', 'PosReg', (49, 56))	('LSD1', 'Gene', '23028', (21, 25))	('LSD1', 'Gene', (21, 25))
171349	30466474	The presence of this repressive histone mark at the promoter region of pluripotency marks (e.g., SOX2) can inhibit expression that is essential to maintaining self-renewal and tumorigenicity.	('inhibit', 'NegReg', (107, 114))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('SOX2', 'Gene', '6657', (97, 101))	('SOX2', 'Gene', (97, 101))	('tumor', 'Disease', (176, 181))	('mark', 'Gene', (40, 44))	('expression', 'MPA', (115, 125))	('pluripotency', 'Disease', (71, 83))	('mark', 'Gene', (84, 88))	('mark', 'Gene', '4139', (84, 88))	('mark', 'Gene', '4139', (40, 44))	('presence', 'Var', (4, 12))	('pluripotency', 'Disease', 'None', (71, 83))	('tumor', 'Disease', 'MESH:D009369', (176, 181))
171350	30466474	The H3K9 demethylase activity of LSD1 can epigenetically control SOX2 transcription and thus maintain cancer stem cell pluripotency (Fig.	('SOX2', 'Gene', '6657', (65, 69))	('demethylase', 'Gene', (9, 20))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('SOX2', 'Gene', (65, 69))	('demethylase', 'Gene', '8932', (9, 20))	('LSD1', 'Gene', (33, 37))	('control', 'Reg', (57, 64))	('epigenetically', 'Var', (42, 56))	('H3', 'Gene', '126961', (4, 6))	('cancer stem cell pluripotency', 'Disease', (102, 131))	('LSD1', 'Gene', '23028', (33, 37))	('maintain', 'PosReg', (93, 101))	('cancer stem cell pluripotency', 'Disease', 'MESH:D020295', (102, 131))
171351	30466474	Depletion of histone demethylase LSD1 in cancer cells increases repetitive element expression that can stimulate anti-tumor T cell immunity and inhibit tumor growth.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('LSD1', 'Gene', (33, 37))	('tumor', 'Disease', (152, 157))	('Depletion', 'Var', (0, 9))	('repetitive element expression', 'MPA', (64, 93))	('demethylase', 'Gene', (21, 32))	('stimulate', 'PosReg', (103, 112))	('increases', 'PosReg', (54, 63))	('inhibit', 'NegReg', (144, 151))	('tumor', 'Disease', (118, 123))	('cancer', 'Disease', (41, 47))	('demethylase', 'Gene', '8932', (21, 32))	('LSD1', 'Gene', '23028', (33, 37))	('cancer', 'Disease', 'MESH:D009369', (41, 47))
171358	30466474	In acute myeloblastic leukemia (AML) cell lines, GSK2879552 treatment inhibited proliferation.	('acute myeloblastic leukemia', 'Disease', 'MESH:D015470', (3, 30))	('AML', 'Disease', 'MESH:D015470', (32, 35))	('GSK2879552', 'Chemical', 'MESH:C000602008', (49, 59))	('GSK2879552', 'Var', (49, 59))	('acute myeloblastic leukemia', 'Phenotype', 'HP:0004808', (3, 30))	('proliferation', 'CPA', (80, 93))	('AML', 'Phenotype', 'HP:0004808', (32, 35))	('AML', 'Disease', (32, 35))	('myeloblastic leukemia', 'Phenotype', 'HP:0012324', (9, 30))	('inhibited', 'NegReg', (70, 79))	('acute myeloblastic leukemia', 'Disease', (3, 30))	('leukemia', 'Phenotype', 'HP:0001909', (22, 30))
171362	30466474	Recently, compound S2101, a new LSD1 inhibitor, is shown to have a greater effect than TCPs.	('S2101', 'CellLine', 'CVCL:K863', (19, 24))	('compound S2101', 'Var', (10, 24))	('LSD1', 'Gene', (32, 36))	('LSD1', 'Gene', '23028', (32, 36))	('TCPs', 'Chemical', 'MESH:C049563', (87, 91))
171363	30466474	Several other LSD1 inhibitors including T-3775440, NCD38, and RN1 are in pre-clinical stages of investigation.	('T-3775440', 'Chemical', 'MESH:C000624318', (40, 49))	('LSD1', 'Gene', (14, 18))	('T-3775440', 'Var', (40, 49))	('LSD1', 'Gene', '23028', (14, 18))
171365	30466474	JMJD2A-amplified tumors demonstrate copy gains for these regions.	('copy gains', 'Var', (36, 46))	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('tumors', 'Disease', (17, 23))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('JMJD2A', 'Gene', '9682', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('JMJD2A', 'Gene', (0, 6))
171375	30466474	Complexes of JMJD3 and proteins involved in transcriptional elongation, demethylate H3K27me3 on their target genes.	('Complexes', 'Interaction', (0, 9))	('H3K27', 'Gene', (84, 89))	('H3K27', 'Gene', '126961', (84, 89))	('demethylate', 'Var', (72, 83))	('JMJD3', 'Gene', (13, 18))	('JMJD3', 'Gene', '23135', (13, 18))
171383	30466474	Mutations in histone methyltransferase MLL3 (a subunit of the COMPASS complex with H3K4me1 methyltransferase activity) or BAP1 (a tumor suppressor) in cancer cells can inhibit H3K27 demethylase UTX and MLL3 recruitment to gene enhancers.	('BAP1', 'Gene', (122, 126))	('H3K27', 'Gene', (176, 181))	('H3K27', 'Gene', '126961', (176, 181))	('MLL3', 'Gene', '58508', (202, 206))	('tumor', 'Disease', (130, 135))	('MLL3', 'Gene', (39, 43))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('histone', 'Protein', (13, 20))	('Mutations', 'Var', (0, 9))	('cancer', 'Disease', (151, 157))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('MLL3', 'Gene', (202, 206))	('UTX', 'Gene', (194, 197))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('BAP1', 'Gene', '8314', (122, 126))	('UTX', 'Gene', '7403', (194, 197))	('recruitment', 'MPA', (207, 218))	('H3', 'Gene', '126961', (176, 178))	('demethylase', 'Gene', (182, 193))	('demethylase', 'Gene', '8932', (182, 193))	('inhibit', 'NegReg', (168, 175))	('H3', 'Gene', '126961', (83, 85))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('MLL3', 'Gene', '58508', (39, 43))
171384	30466474	Thus, inhibition of H3K27 methyltransferase PRC2 in these cells can restore normal transcription patterns.	('transcription patterns', 'MPA', (83, 105))	('restore', 'PosReg', (68, 75))	('PRC', 'Gene', (44, 47))	('inhibition', 'Var', (6, 16))	('H3K27', 'Gene', (20, 25))	('PRC', 'Gene', '23082', (44, 47))	('H3K27', 'Gene', '126961', (20, 25))
171386	30466474	H3K27-demethylase UTX activates gene transcription in melanoma at sites with poised promoters that are marked with trimethylated H3K27.	('UTX', 'Gene', (18, 21))	('mark', 'Gene', (103, 107))	('H3K27', 'Gene', '126961', (0, 5))	('mark', 'Gene', '4139', (103, 107))	('UTX', 'Gene', '7403', (18, 21))	('melanoma', 'Disease', 'MESH:D008545', (54, 62))	('melanoma', 'Phenotype', 'HP:0002861', (54, 62))	('melanoma', 'Disease', (54, 62))	('trimethylated', 'Var', (115, 128))	('H3K27', 'Gene', (129, 134))	('activates', 'PosReg', (22, 31))	('demethylase', 'Gene', (6, 17))	('H3K27', 'Gene', '126961', (129, 134))	('H3K27', 'Gene', (0, 5))	('demethylase', 'Gene', '8932', (6, 17))	('gene transcription', 'MPA', (32, 50))
171402	30466474	The Cancer Genome Atlas (TCGA) data reveal that KMT2D is mutated in 15% of melanoma patients.	('patients', 'Species', '9606', (84, 92))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (4, 23))	('melanoma', 'Phenotype', 'HP:0002861', (75, 83))	('melanoma', 'Disease', (75, 83))	('Cancer', 'Phenotype', 'HP:0002664', (4, 10))	('KMT2D', 'Gene', '8085', (48, 53))	('melanoma', 'Disease', 'MESH:D008545', (75, 83))	('Cancer Genome Atlas', 'Disease', (4, 23))	('mutated', 'Var', (57, 64))	('KMT2D', 'Gene', (48, 53))
171404	30466474	KMT2D is encoded by genes with the highest number of UVB signature mutations (Fig.	('KMT2D', 'Gene', '8085', (0, 5))	('UVB', 'Gene', (53, 56))	('KMT2D', 'Gene', (0, 5))	('mutations', 'Var', (67, 76))
171421	30466474	WDR5 is an essential part of the KMT2 (MLL) complex that trimethylates H3K4.	('MLL', 'Gene', (39, 42))	('WDR5', 'Gene', '11091', (0, 4))	('MLL', 'Gene', '4297', (39, 42))	('WDR5', 'Gene', (0, 4))	('trimethylates', 'Var', (57, 70))	('H3', 'Gene', '126961', (71, 73))
171428	30466474	Dimethylated H3K9 has a higher global level in melanoma samples compared to the normal skin tissue.	('Dimethylated', 'Var', (0, 12))	('H3', 'Gene', '126961', (13, 15))	('higher', 'PosReg', (24, 30))	('melanoma', 'Phenotype', 'HP:0002861', (47, 55))	('melanoma', 'Disease', (47, 55))	('global level', 'MPA', (31, 43))	('melanoma', 'Disease', 'MESH:D008545', (47, 55))
171429	30466474	EHMT2 (G9A) mono- and dimethylates H3K9.	('mono-', 'Var', (12, 17))	('G9A', 'Gene', (7, 10))	('EHMT2', 'Gene', (0, 5))	('G9A', 'Gene', '10919', (7, 10))	('H3', 'Gene', '126961', (35, 37))	('EHMT2', 'Gene', '10919', (0, 5))	('dimethylates', 'Var', (22, 34))
171430	30466474	Methylated H3K9 recruits HP1 proteins that cause transcriptional repression.	('H3', 'Gene', '126961', (11, 13))	('HP1', 'Gene', '23468', (25, 28))	('Methylated', 'Var', (0, 10))	('HP1', 'Gene', (25, 28))	('transcriptional repression', 'MPA', (49, 75))
171431	30466474	HP1 proteins harbor a methyl lysine binding chromodomain that binds to methylated H3K9.	('proteins', 'Protein', (4, 12))	('binds', 'Interaction', (62, 67))	('H3', 'Gene', '126961', (82, 84))	('lysine', 'Chemical', 'MESH:D008239', (29, 35))	('HP1', 'Gene', '23468', (0, 3))	('HP1', 'Gene', (0, 3))	('methylated', 'Var', (71, 81))
171433	30466474	Interestingly, in several cancer types (not including melanoma), inhibition of EHMT2 resulted in the arrest of cancer cell proliferation and a decrease in cell survival.	('arrest of cancer', 'Disease', 'MESH:D006323', (101, 117))	('cancer', 'Disease', (26, 32))	('decrease', 'NegReg', (143, 151))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('melanoma', 'Disease', 'MESH:D008545', (54, 62))	('arrest of cancer', 'Disease', (101, 117))	('melanoma', 'Phenotype', 'HP:0002861', (54, 62))	('melanoma', 'Disease', (54, 62))	('EHMT2', 'Gene', (79, 84))	('cell survival', 'CPA', (155, 168))	('EHMT2', 'Gene', '10919', (79, 84))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('inhibition', 'Var', (65, 75))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))
171437	30466474	Formation of various cancer types including rhabdomyosarcoma and melanoma are sensitive to the loss of SUV39H1.	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('SUV39H1', 'Gene', (103, 110))	('SUV39H1', 'Gene', '6839', (103, 110))	('rhabdomyosarcoma', 'Disease', (44, 60))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (44, 60))	('sarcoma', 'Phenotype', 'HP:0100242', (53, 60))	('cancer', 'Disease', (21, 27))	('cancer', 'Disease', 'MESH:D009369', (21, 27))	('melanoma', 'Phenotype', 'HP:0002861', (65, 73))	('melanoma', 'Disease', (65, 73))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (44, 60))	('loss', 'Var', (95, 99))	('melanoma', 'Disease', 'MESH:D008545', (65, 73))
171438	30466474	In differentiated melanoma cells, silencing SUV39H1 or the other H3K9 methyltransferase, G9A, can elevate their self-renewal capabilities.	('melanoma', 'Disease', 'MESH:D008545', (18, 26))	('elevate', 'PosReg', (98, 105))	('G9A', 'Gene', '10919', (89, 92))	('self-renewal capabilities', 'CPA', (112, 137))	('SUV39H1', 'Gene', (44, 51))	('H3', 'Gene', '126961', (65, 67))	('SUV39H1', 'Gene', '6839', (44, 51))	('G9A', 'Gene', (89, 92))	('melanoma', 'Phenotype', 'HP:0002861', (18, 26))	('silencing', 'Var', (34, 43))	('melanoma', 'Disease', (18, 26))
171441	30466474	SUV39H2 trimethylates histone lysine demethylase LSD1 and prevents degradation of this protein due to polyubiquitination, thus stabilizing its structure in the cell.	('LSD1', 'Gene', '23028', (49, 53))	('structure', 'MPA', (143, 152))	('trimethylates', 'Var', (8, 21))	('demethylase', 'Gene', (37, 48))	('demethylase', 'Gene', '8932', (37, 48))	('polyubiquitination', 'MPA', (102, 120))	('degradation', 'MPA', (67, 78))	('lysine', 'Chemical', 'MESH:D008239', (30, 36))	('SUV39H2', 'Gene', (0, 7))	('prevents', 'NegReg', (58, 66))	('SUV39H2', 'Gene', '79723', (0, 7))	('LSD1', 'Gene', (49, 53))
171444	30466474	SUV39 proteins, unlike the HP1 chromodomain of the EHMT complex that shows high affinity for dimethyl, prefer the trimethyl state.	('trimethyl state', 'MPA', (114, 129))	('HP1', 'Gene', '23468', (27, 30))	('HP1', 'Gene', (27, 30))	('SUV39', 'Var', (0, 5))	('proteins', 'Protein', (6, 14))
171450	30466474	BIX01294 is an inhibitor of GLP and G9A methyltransferase.	('BIX01294', 'Chemical', 'MESH:C518299', (0, 8))	('BIX01294', 'Var', (0, 8))	('G9A', 'Gene', '10919', (36, 39))	('G9A', 'Gene', (36, 39))	('GLP', 'Gene', (28, 31))	('GLP', 'Gene', '79813', (28, 31))
171453	30466474	UNC0321 is a newer modification of BIX12094 with a greater potency against G9A and GLP.	('G9A', 'Gene', '10919', (75, 78))	('BIX12094', 'Chemical', '-', (35, 43))	('potency', 'MPA', (59, 66))	('G9A', 'Gene', (75, 78))	('UNC0321', 'Var', (0, 7))	('BIX12094', 'Var', (35, 43))	('GLP', 'Gene', (83, 86))	('GLP', 'Gene', '79813', (83, 86))
171454	30466474	Unlike monomethylated H3K27, which is associated with gene activation, di-/trimethylated H3K27 act as repressive marks.	('mark', 'Gene', '4139', (113, 117))	('di-/trimethylated', 'Var', (71, 88))	('mark', 'Gene', (113, 117))	('H3K27', 'Gene', (22, 27))	('H3K27', 'Gene', '126961', (22, 27))	('H3K27', 'Gene', (89, 94))	('H3K27', 'Gene', '126961', (89, 94))
171458	30466474	PRC2 mediates gene repression through chromatin reorganization by methylating H3K27.	('methylating', 'Var', (66, 77))	('gene repression', 'MPA', (14, 29))	('PRC', 'Gene', '23082', (0, 3))	('mediates', 'Reg', (5, 13))	('H3K27', 'Gene', (78, 83))	('H3K27', 'Gene', '126961', (78, 83))	('PRC', 'Gene', (0, 3))
171460	30466474	Mutations in EZH2 could result from the replacement of a tyrosine in its SET domain (Tyr641).	('EZH2', 'Gene', (13, 17))	('Mutations', 'Var', (0, 9))	('tyrosine', 'Chemical', 'MESH:D014443', (57, 65))	('result from', 'Reg', (24, 35))	('Tyr641', 'Chemical', '-', (85, 91))	('replacement', 'Var', (40, 51))	('Tyr641', 'Var', (85, 91))
171462	30466474	In addition, in various melanoma cell lines, Tyr641 mutations of EZH2 have shown to alter the substrate specificity of EZH2 to H3K27me2, causing an increase in H3K27me3 and depletion of H3K27me2.	('substrate specificity', 'MPA', (94, 115))	('melanoma', 'Disease', 'MESH:D008545', (24, 32))	('H3K27', 'Gene', (127, 132))	('increase', 'PosReg', (148, 156))	('Tyr641 mutations', 'Var', (45, 61))	('Tyr641', 'Chemical', '-', (45, 51))	('H3K27', 'Gene', (186, 191))	('EZH2', 'Gene', (65, 69))	('H3K27', 'Gene', '126961', (186, 191))	('depletion', 'MPA', (173, 182))	('H3K27', 'Gene', (160, 165))	('melanoma', 'Disease', (24, 32))	('H3K27', 'Gene', '126961', (160, 165))	('melanoma', 'Phenotype', 'HP:0002861', (24, 32))	('alter', 'Reg', (84, 89))	('H3K27', 'Gene', '126961', (127, 132))
171463	30466474	H3K27me1/me2 produced by wild-type EZH2 could be methylated by Tyr641-mutant EZH2 to generate elevated levels of H3K27me3 that can promote tumorigenesis.	('EZH2', 'Gene', (77, 81))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('elevated', 'PosReg', (94, 102))	('Tyr641-mutant', 'Var', (63, 76))	('Tyr641', 'Chemical', '-', (63, 69))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('H3K27', 'Gene', '126961', (113, 118))	('H3K27', 'Gene', (0, 5))	('H3K27', 'Gene', '126961', (0, 5))	('H3K27', 'Gene', (113, 118))	('promote', 'PosReg', (131, 138))
171471	30466474	EPZ011989 is a potent and orally bioavailable EZH2 inhibitor.	('EZH2', 'Gene', (46, 50))	('EPZ011989', 'Chemical', '-', (0, 9))	('EPZ011989', 'Var', (0, 9))
171479	30466474	In cancers with genetic alteration in EZH2, such as various forms of lymphoma, EPZ005687 reduces H3K27 methylation.	('genetic alteration', 'Var', (16, 34))	('lymphoma', 'Disease', (69, 77))	('H3K27', 'Gene', (97, 102))	('H3K27', 'Gene', '126961', (97, 102))	('EZH2', 'Gene', (38, 42))	('methylation', 'MPA', (103, 114))	('cancers', 'Phenotype', 'HP:0002664', (3, 10))	('cancers', 'Disease', (3, 10))	('lymphoma', 'Disease', 'MESH:D008223', (69, 77))	('EPZ005687', 'Var', (79, 88))	('cancers', 'Disease', 'MESH:D009369', (3, 10))	('lymphoma', 'Phenotype', 'HP:0002665', (69, 77))	('reduces', 'NegReg', (89, 96))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
171480	30466474	Mutations in EZH2 result in a dependency on its enzymatic activity for proliferation that could make EPZ005687 a treatment for cancers in which EZH2 is genetically altered.	('enzymatic activity', 'MPA', (48, 66))	('EZH2', 'Gene', (13, 17))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('Mutations', 'Var', (0, 9))	('cancers', 'Disease', 'MESH:D009369', (127, 134))	('cancers', 'Phenotype', 'HP:0002664', (127, 134))	('cancers', 'Disease', (127, 134))	('dependency', 'MPA', (30, 40))
171485	30466474	Di-/trimethylation of H3K36 is usually associated with transcriptional activation and double-strand break repair.	('H3', 'Gene', '126961', (22, 24))	('double-strand break repair', 'CPA', (86, 112))	('transcriptional activation', 'MPA', (55, 81))	('Di-/trimethylation', 'Var', (0, 18))	('associated', 'Reg', (39, 49))
171489	30466474	Nucleosomes are more frequent in areas with this particular histone mark.	('Nucleosomes', 'Var', (0, 11))	('frequent', 'Reg', (21, 29))	('mark', 'Gene', '4139', (68, 72))	('mark', 'Gene', (68, 72))
171490	30466474	H3K36 trimethylation is also shown to play a role in homologous recombination (HR) repair in human cells.	('homologous', 'CPA', (53, 63))	('human', 'Species', '9606', (93, 98))	('H3', 'Gene', '126961', (0, 2))	('trimethylation', 'Var', (6, 20))
171492	30466474	Also, H3K36 methylation antagonizes PRC2-mediated H3K27 methylation.	('H3', 'Gene', '126961', (50, 52))	('antagonizes', 'NegReg', (24, 35))	('PRC', 'Gene', (36, 39))	('H3', 'Gene', '126961', (6, 8))	('methylation', 'MPA', (56, 67))	('H3K27', 'Gene', '126961', (50, 55))	('PRC', 'Gene', '23082', (36, 39))	('H3K27', 'Gene', (50, 55))	('methylation', 'Var', (12, 23))
171497	30466474	A TCGA study also suggests crosstalk between H3K36 methylation and DNA methylation.	('methylation', 'Var', (51, 62))	('DNA methylation', 'MPA', (67, 82))	('H3', 'Gene', '126961', (45, 47))	('crosstalk', 'Reg', (27, 36))
171498	30466474	Renal clear cell carcinoma tumors with SETD2 mutations had DNA hypomethylation at non-promoter regions that are marked by H3K36me3.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('mutations', 'Var', (45, 54))	('Renal clear cell carcinoma tumors', 'Disease', 'MESH:C538614', (0, 33))	('SETD2', 'Gene', (39, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (17, 26))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('mark', 'Gene', (112, 116))	('DNA hypomethylation', 'MPA', (59, 78))	('Renal clear cell carcinoma tumors', 'Disease', (0, 33))	('mark', 'Gene', '4139', (112, 116))	('SETD2', 'Gene', '29072', (39, 44))	('H3', 'Gene', '126961', (122, 124))
171499	30466474	A similar pattern is found in sarcoma where H3K36 mutation prevents methylation as well as mesenchymal progenitor cell differentiation and induces sarcoma.	('mesenchymal progenitor cell differentiation', 'CPA', (91, 134))	('H3', 'Gene', '126961', (44, 46))	('sarcoma', 'Phenotype', 'HP:0100242', (30, 37))	('sarcoma', 'Disease', 'MESH:D012509', (30, 37))	('induces', 'Reg', (139, 146))	('prevents', 'NegReg', (59, 67))	('sarcoma', 'Disease', (30, 37))	('sarcoma', 'Disease', 'MESH:D012509', (147, 154))	('methylation', 'MPA', (68, 79))	('sarcoma', 'Phenotype', 'HP:0100242', (147, 154))	('sarcoma', 'Disease', (147, 154))	('mutation', 'Var', (50, 58))
171505	30466474	NSD1 inactivating mutations define a hypomethylated subtype in different cancer types such as head and neck squamous cell carcinoma (HNSC) and lung squamous cell carcinoma (LUSC).	('cancer', 'Disease', (73, 79))	('NSD1', 'Gene', (0, 4))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (108, 131))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (148, 171))	('neck squamous cell carcinoma (HNSC) and lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (103, 171))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('NSD1', 'Gene', '64324', (0, 4))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('inactivating mutations', 'Var', (5, 27))	('carcinoma', 'Phenotype', 'HP:0030731', (162, 171))
171507	30466474	NSD1 inactivation along with SETD2 mutation that causes a distorted H3K36 is a key feature of clear cell renal cell carcinoma.	('SETD2', 'Gene', '29072', (29, 34))	('NSD1', 'Gene', (0, 4))	('H3', 'Gene', '126961', (68, 70))	('clear cell renal cell carcinoma', 'Disease', (94, 125))	('SETD2', 'Gene', (29, 34))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (94, 125))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (105, 125))	('inactivation', 'NegReg', (5, 17))	('mutation', 'Var', (35, 43))	('NSD1', 'Gene', '64324', (0, 4))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (94, 125))
171508	30466474	NSD1 mutations may have a genome-wide impact on DNA methylation.	('NSD1', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))	('impact', 'Reg', (38, 44))	('NSD1', 'Gene', '64324', (0, 4))	('DNA methylation', 'MPA', (48, 63))
171512	30466474	Due to the high similarity of the SET domain of NSDs to that of GLP and G9A, BIX01294 would be capable of inhibiting H3K36 methyltransferase NSD1/2/3.	('NSD1', 'Gene', '64324', (141, 145))	('inhibiting', 'NegReg', (106, 116))	('G9A', 'Gene', (72, 75))	('GLP', 'Gene', (64, 67))	('NSD1', 'Gene', (141, 145))	('H3', 'Gene', '126961', (117, 119))	('NSD', 'Disease', 'MESH:D029461', (141, 144))	('NSD', 'Disease', 'MESH:D029461', (48, 51))	('GLP', 'Gene', '79813', (64, 67))	('BIX01294', 'Chemical', 'MESH:C518299', (77, 85))	('BIX01294', 'Var', (77, 85))	('NSD', 'Disease', (141, 144))	('G9A', 'Gene', '10919', (72, 75))	('NSD', 'Disease', (48, 51))
171519	30466474	H3K79 methylation has a crucial role in heterochromatin formation and chromosome integrity.	('methylation', 'Var', (6, 17))	('heterochromatin formation', 'CPA', (40, 65))	('chromosome integrity', 'CPA', (70, 90))	('H3', 'Gene', '126961', (0, 2))
171523	30466474	DOT1L depletion will cause UV-induced DNA damage not to be efficiently repaired, thus encouraging progression of melanoma (Fig.	('encouraging progression', 'PosReg', (86, 109))	('DOT1L', 'Gene', (0, 5))	('melanoma', 'Phenotype', 'HP:0002861', (113, 121))	('melanoma', 'Disease', (113, 121))	('depletion', 'Var', (6, 15))	('melanoma', 'Disease', 'MESH:D008545', (113, 121))	('DNA damage', 'MPA', (38, 48))	('DOT1L', 'Gene', '84444', (0, 5))
171526	30466474	EPZ004777 is a specific, SAM-competitive inhibitor of DOT1L.	('SAM', 'Chemical', 'MESH:D012436', (25, 28))	('EPZ004777', 'Var', (0, 9))	('DOT1L', 'Gene', '84444', (54, 59))	('DOT1L', 'Gene', (54, 59))
171531	30466474	Loss of SET8 could cause cell cycle defects and promote DNA damage.	('cause', 'Reg', (19, 24))	('DNA damage', 'CPA', (56, 66))	('SET8', 'Gene', (8, 12))	('SET8', 'Gene', '387893', (8, 12))	('promote', 'PosReg', (48, 55))	('Loss', 'Var', (0, 4))	('cell cycle defects', 'CPA', (25, 43))
171535	30466474	H4K20me2 plays a role in cell cycle control and DNA damage response whereas H4K20me3 takes part in transcriptional repression and is a hallmark of silenced heterochromatin regions.	('cell cycle', 'CPA', (25, 35))	('mark', 'Gene', (139, 143))	('transcriptional repression', 'MPA', (99, 125))	('H4K20me2', 'Var', (0, 8))	('mark', 'Gene', '4139', (139, 143))	('DNA damage', 'MPA', (48, 58))	('H4K20me3', 'Var', (76, 84))
171538	30466474	SUV420H1 and SUV420H2 play roles in NHEJ-directed DNA repair by di- and trimethylation of H4K20.	('SUV420H2', 'Gene', (13, 21))	('trimethylation', 'Var', (72, 86))	('NHEJ-directed DNA repair', 'Disease', (36, 60))	('SUV420H1', 'Gene', '51111', (0, 8))	('SUV420H2', 'Gene', '84787', (13, 21))	('di-', 'MPA', (64, 67))	('SUV420H1', 'Gene', (0, 8))	('H4K20', 'Protein', (90, 95))
171545	30466474	Various compounds that target the epigenome, such as HDAC inhibitors (e.g., the entinostat, NCT00185302) or DNMT inhibitors (e.g., the decitabine, NCT00030615), have been used in clinical trials to treat melanoma patients, but the use of histone methylating/demethylating agents requires substantial additional investigation.	('DNMT', 'Gene', (108, 112))	('melanoma', 'Phenotype', 'HP:0002861', (204, 212))	('melanoma', 'Disease', (204, 212))	('decitabine', 'Chemical', 'MESH:D000077209', (135, 145))	('NCT00185302', 'Var', (92, 103))	('melanoma', 'Disease', 'MESH:D008545', (204, 212))	('HDAC', 'Gene', (53, 57))	('patients', 'Species', '9606', (213, 221))	('HDAC', 'Gene', '9734', (53, 57))	('DNMT', 'Gene', '1786', (108, 112))
171557	31326317	Risk loci identification and polygenic risk score in prediction of lung cancer: a large-scale prospective cohort study in Chinese Genetic variation plays an important role in the development of non-small cell lung cancer (NSCLC).	('NSCLC', 'Phenotype', 'HP:0030358', (222, 227))	('lung cancer', 'Phenotype', 'HP:0100526', (209, 220))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (198, 220))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('non-small cell lung cancer', 'Disease', (194, 220))	('lung cancer', 'Disease', 'MESH:D008175', (67, 78))	('variation', 'Var', (138, 147))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('NSCLC', 'Disease', (222, 227))	('NSCLC', 'Disease', 'MESH:D002289', (222, 227))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (194, 220))	('lung cancer', 'Disease', 'MESH:D008175', (209, 220))	('lung cancer', 'Disease', (67, 78))	('lung cancer', 'Phenotype', 'HP:0100526', (67, 78))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (194, 220))
171559	31326317	To systematically identify genetic variants for NSCLC risk, we newly genotyped 19,546 samples and conducted a meta-analysis of genome-wide association studies (GWASs) of 27,120 cases and 27,355 controls.	('NSCLC', 'Disease', 'MESH:D002289', (48, 53))	('NSCLC', 'Disease', (48, 53))	('NSCLC', 'Phenotype', 'HP:0030358', (48, 53))	('variants', 'Var', (35, 43))
171567	31326317	smoking) contribute the most to risk of NSCLC,  genetic variants can explain approximately 12% ~ 21% of the heritability of lung cancer.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('lung cancer', 'Disease', 'MESH:D008175', (124, 135))	('NSCLC', 'Phenotype', 'HP:0030358', (40, 45))	('genetic variants', 'Var', (48, 64))	('lung cancer', 'Disease', (124, 135))	('NSCLC', 'Disease', (40, 45))	('lung cancer', 'Phenotype', 'HP:0100526', (124, 135))	('NSCLC', 'Disease', 'MESH:D002289', (40, 45))
171582	31326317	We derived a PRS specific for Chinese populations from all reported SNPs (i.e., 81 SNPs in 40 loci) that have been reported to be associated with lung cancer risk at genome-wide significance level in both current and previous studies.	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('lung cancer', 'Disease', 'MESH:D008175', (146, 157))	('SNPs', 'Var', (83, 87))	('lung cancer', 'Disease', (146, 157))	('lung cancer', 'Phenotype', 'HP:0100526', (146, 157))	('associated', 'Reg', (130, 140))
171583	31326317	To ensure the efficiency of the model, several criteria were applied to filter out redundant variants: (1) MAF < 0 01 in Chinese populations; (2) SNPs in linkage disequilibrium (LD, r2 >=0 1); (3) P value >= 0 00125 (after multiple comparison at 0 05/40, 40 independent loci remained according to the above two criteria) in Chinese populations included in the present study.	('SNPs', 'Var', (146, 150))	('P value >= 0 00125', 'Var', (197, 215))	('MAF', 'Gene', '4094', (107, 110))	('MAF', 'Gene', (107, 110))
171584	31326317	Effect sizes for all variants were derived from the association of NSCLC patients of Chinese descent in the present study, which were all flipped into risk alleles, where appropriate.	('variants', 'Var', (21, 29))	('NSCLC', 'Phenotype', 'HP:0030358', (67, 72))	('NSCLC', 'Disease', (67, 72))	('patients', 'Species', '9606', (73, 81))	('NSCLC', 'Disease', 'MESH:D002289', (67, 72))
171591	31326317	Among the 19 loci, six were novel ones, including three loci for overall NSCLC: 2q33.1 (rs3769821: odds ratios (OR) = 1 08, P = 4 45x10-8), 3q26.2 (rs2293607: OR = 1 10, P = 1 82x10-10), 14q13.1 (rs1200399: OR = 1 11, P = 3 05x10-9); two for LUAD: 2p14 (rs17038564: OR = 1 15, P = 1 87x10-8), 9p13.3 (rs35201538: OR = 1 10, P = 1 99x10-8); and one for LUSC: 9q33.2 (rs4573350: OR = 1 13, P = 3 23x10-9) (Figure 1, Table 1).	('rs3769821:', 'Var', (88, 98))	('rs3769821', 'Mutation', 'rs3769821', (88, 97))	('rs2293607', 'Mutation', 'rs2293607', (148, 157))	('rs4573350: OR', 'Var', (366, 379))	('NSCLC', 'Disease', (73, 78))	('rs4573350', 'Mutation', 'rs4573350', (366, 375))	('rs1200399: OR', 'Var', (196, 209))	('LUAD', 'Disease', (242, 246))	('rs17038564: OR', 'Var', (254, 268))	('LUSC', 'Disease', 'MESH:D002294', (352, 356))	('LUSC', 'Phenotype', 'HP:0030359', (352, 356))	('NSCLC', 'Phenotype', 'HP:0030358', (73, 78))	('rs35201538:', 'Var', (301, 312))	('rs1200399', 'Mutation', 'rs1200399', (196, 205))	('rs2293607: OR', 'Var', (148, 161))	('LUAD', 'Disease', 'MESH:C538231', (242, 246))	('rs17038564', 'Mutation', 'rs17038564', (254, 264))	('rs35201538', 'Mutation', 'rs35201538', (301, 311))	('LUAD', 'Phenotype', 'HP:0030078', (242, 246))	('LUSC', 'Disease', (352, 356))	('NSCLC', 'Disease', 'MESH:D002289', (73, 78))
171592	31326317	We also replicated 13 previously reported loci at the GWAS-significant level, including 12 loci for overall NSCLC: 3q28, 5p15.33, 6p22.1, etc.	('NSCLC', 'Phenotype', 'HP:0030358', (108, 113))	('NSCLC', 'Disease', 'MESH:D002289', (108, 113))	('NSCLC', 'Disease', (108, 113))	('5p15.33', 'Var', (121, 128))
171594	31326317	It is noteworthy that three risk loci (8p12: rs4236709; 9p21.3: rs10429489 and 11q23.3: rs55768116) previously reported in European populations were also identified in Chinese populations for the first time.	('rs4236709', 'Var', (45, 54))	('rs55768116', 'Var', (88, 98))	('rs55768116', 'Mutation', 'rs55768116', (88, 98))	('rs4236709', 'Mutation', 'rs4236709', (45, 54))	('rs10429489', 'Mutation', 'rs10429489', (64, 74))
171595	31326317	As shown in Figure 1 A and 1 B, we identified four novel loci for LUAD: 2p14 and 9p13.3 were specifically significant in LUAD subgroup, while 3q26.2 and 14q13.1 were detected in both overall NSCLC and LUAD.	('NSCLC', 'Phenotype', 'HP:0030358', (191, 196))	('LUAD', 'Disease', (66, 70))	('LUAD', 'Phenotype', 'HP:0030078', (121, 125))	('LUAD', 'Disease', 'MESH:C538231', (66, 70))	('LUAD', 'Phenotype', 'HP:0030078', (66, 70))	('LUAD', 'Disease', (121, 125))	('LUAD', 'Phenotype', 'HP:0030078', (201, 205))	('LUAD', 'Disease', 'MESH:C538231', (121, 125))	('significant', 'Reg', (106, 117))	('LUAD', 'Disease', (201, 205))	('9p13.3', 'Var', (81, 87))	('NSCLC', 'Disease', (191, 196))	('LUAD', 'Disease', 'MESH:C538231', (201, 205))	('2p14', 'Var', (72, 76))	('NSCLC', 'Disease', 'MESH:D002289', (191, 196))
171605	31326317	Figure 3 C showed that the cancer risk in light smokers (pack-year, PY<30) at low genetic risk was similar to nonsmokers (HR=1 17, 95% CI: 0 64-2 15), while a gradually increased cancer risk was observed for light smokers (pack-year, PY<30) at intermediate genetic risk (HR=1 79, 95% CI: 1 49-2 14), heavy smokers (PY>=30) at low genetic risk (HR=2 08, 95% CI: 1 18-3 67), light smokers at high genetic risk (HR=2 93, 95%CI: 1 92-4 49), heavy smokers at intermediate genetic risk (HR=3 27, 95% CI: 2 71-3 94), and heavy smokers at high genetic risk (HR=3 98, 95% CI: 2 64-5 99) after adjustment for age, sex, and region (Figure 3 C).	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('PY>=30', 'Var', (315, 321))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('cancer', 'Disease', (27, 33))	('cancer', 'Disease', 'MESH:D009369', (27, 33))	('cancer', 'Disease', (179, 185))
171611	31326317	In the present study, we performed a large-scale GWAS of lung cancer, and we found six novel variants and confirmed 13 previously reported variants that were associated with NSCLC risk.	('NSCLC', 'Disease', 'MESH:D002289', (174, 179))	('associated', 'Reg', (158, 168))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('lung cancer', 'Phenotype', 'HP:0100526', (57, 68))	('variants', 'Var', (93, 101))	('lung cancer', 'Disease', 'MESH:D008175', (57, 68))	('NSCLC', 'Phenotype', 'HP:0030358', (174, 179))	('variants', 'Var', (139, 147))	('lung cancer', 'Disease', (57, 68))	('NSCLC', 'Disease', (174, 179))
171615	31326317	Among the 19 loci we identified,  loci (e.g., 2p14, 3q26.2, 9p13.3 14q13.1, and 15q21.1) were significant in the LUAD subgroup, while only one signal was specific for LUSC (9q33.2).	('LUSC', 'Phenotype', 'HP:0030359', (167, 171))	('3q26.2', 'Var', (52, 58))	('9p13.3 14q13.1', 'Var', (60, 74))	('14q13.1', 'Var', (67, 74))	('LUAD', 'Disease', (113, 117))	('LUAD', 'Disease', 'MESH:C538231', (113, 117))	('LUSC', 'Disease', 'MESH:D002294', (167, 171))	('LUSC', 'Disease', (167, 171))	('LUAD', 'Phenotype', 'HP:0030078', (113, 117))	('15q21.1', 'Var', (80, 87))
171624	31326317	In the present study, we observed that GWAS-based PRS was a potential predictor for lung cancer risk beyond age and pack-years of smoking, the main screening eligibility criteria used in the current guidelines by the United States Preventive Services Task Force and the NCCN Clinical Practice Guidelines.	('lung cancer', 'Disease', (84, 95))	('lung cancer', 'Phenotype', 'HP:0100526', (84, 95))	('GWAS-based', 'Var', (39, 49))	('lung cancer', 'Disease', 'MESH:D008175', (84, 95))	('predictor', 'Reg', (70, 79))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
171629	31326317	Similar to recent studies on coronary disease,  the population with a genetic score of the top one-twentieth, even the top one-tenth, has the ability to offset much of this risk by sticking to not smoking throughout their lifetime, leading to reduction of their overall risk of lung cancer by nearly 60%.	('coronary disease', 'Disease', (29, 45))	('lung cancer', 'Disease', 'MESH:D008175', (278, 289))	('coronary disease', 'Phenotype', 'HP:0001677', (29, 45))	('genetic', 'Var', (70, 77))	('reduction', 'NegReg', (243, 252))	('lung cancer', 'Disease', (278, 289))	('coronary disease', 'Disease', 'MESH:D003327', (29, 45))	('lung cancer', 'Phenotype', 'HP:0100526', (278, 289))	('cancer', 'Phenotype', 'HP:0002664', (283, 289))
171660	31612030	Previous studies have indicated that the dysregulation of certain lncRNAs has been identified in NSCLC and serves an important role in the tumorigenesis and progression of NSCLC, providing a novel potential therapeutic target for NSCLC.	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('NSCLC', 'Disease', 'MESH:D002289', (230, 235))	('NSCLC', 'Disease', (172, 177))	('NSCLC', 'Disease', (97, 102))	('identified', 'Reg', (83, 93))	('dysregulation', 'Var', (41, 54))	('NSCLC', 'Phenotype', 'HP:0030358', (230, 235))	('NSCLC', 'Disease', 'MESH:D002289', (172, 177))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('NSCLC', 'Phenotype', 'HP:0030358', (172, 177))	('NSCLC', 'Disease', 'MESH:D002289', (97, 102))	('lncRNAs', 'Protein', (66, 73))	('NSCLC', 'Disease', (230, 235))	('NSCLC', 'Phenotype', 'HP:0030358', (97, 102))
171661	31612030	For example, HOX transcript antisense RNA is overexpressed in NSCLC and promotes tumorigenesis and metastasis by regulating microRNA (miR)-613.	('NSCLC', 'Disease', (62, 67))	('NSCLC', 'Disease', 'MESH:D002289', (62, 67))	('regulating', 'Reg', (113, 123))	('overexpressed', 'PosReg', (45, 58))	('microRNA (miR)-613', 'Gene', (124, 142))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('promotes', 'PosReg', (72, 80))	('antisense', 'Var', (28, 37))	('NSCLC', 'Phenotype', 'HP:0030358', (62, 67))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Disease', (81, 86))	('microRNA (miR)-613', 'Gene', '693198', (124, 142))
171711	31612030	The RT-qPCR results demonstrated that DLX6-AS1 expression was significantly reduced following transfection (Fig.	('DLX6-AS1', 'Gene', (38, 46))	('reduced', 'NegReg', (76, 83))	('DLX6-AS1', 'Gene', '285987;1750;5729', (38, 46))	('transfection', 'Var', (94, 106))	('expression', 'MPA', (47, 57))
171716	31612030	The data indicated that the serum expression levels of DLX6-AS1 were significantly higher in patients with advanced disease stage, positive lymph node metastasis and poor tumor differentiation compared with in patients with earlier disease stage, negative lymph node metastasis and well/moderate tumor differentiation, respectively (Fig.	('tumor', 'Phenotype', 'HP:0002664', (296, 301))	('patients', 'Species', '9606', (93, 101))	('DLX6-AS1', 'Gene', '285987;1750;5729', (55, 63))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('tumor', 'Disease', (296, 301))	('tumor', 'Disease', (171, 176))	('poor', 'Var', (166, 170))	('DLX6-AS1', 'Gene', (55, 63))	('serum expression levels', 'MPA', (28, 51))	('patients', 'Species', '9606', (210, 218))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('positive', 'Var', (131, 139))	('higher', 'PosReg', (83, 89))	('tumor', 'Disease', 'MESH:D009369', (296, 301))
171746	31612030	However, further investigation is required to determine the underlying mechanisms of circulating DLX6-AS1 on NSCLC progression.	('NSCLC', 'Disease', 'MESH:D002289', (109, 114))	('NSCLC', 'Phenotype', 'HP:0030358', (109, 114))	('DLX6-AS1', 'Gene', (97, 105))	('circulating', 'Var', (85, 96))	('NSCLC', 'Disease', (109, 114))	('DLX6-AS1', 'Gene', '285987;1750;5729', (97, 105))
171752	30824826	Mutations in DNA repair genes are associated with increased neoantigen burden and a distinct immunophenotype in lung squamous cell carcinoma Deficiencies in DNA repair pathways, including mismatch repair (MMR), have been linked to higher tumor mutation burden and improved response to immune checkpoint inhibitors.	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (112, 140))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (117, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('tumor', 'Disease', 'MESH:D009369', (238, 243))	('DNA repair genes', 'Gene', (13, 29))	('neoantigen burden', 'MPA', (60, 77))	('higher', 'PosReg', (231, 237))	('lung squamous cell carcinoma', 'Disease', (112, 140))	('increased', 'PosReg', (50, 59))	('tumor', 'Phenotype', 'HP:0002664', (238, 243))	('mismatch repair', 'Disease', (188, 203))	('Mutations', 'Var', (0, 9))	('tumor', 'Disease', (238, 243))	('Deficiencies', 'NegReg', (141, 153))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (112, 140))	('DNA repair pathways', 'Pathway', (157, 176))
171753	30824826	However, the significance of MMR mutations in lung cancer has not been well characterized, and the relevance of other processes, including homologous recombination (HR) and polymerase epsilon (POLE) activity, remains unclear.	('mutations', 'Var', (33, 42))	('lung cancer', 'Disease', 'MESH:D008175', (46, 57))	('MMR', 'Gene', (29, 32))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('lung cancer', 'Disease', (46, 57))	('lung cancer', 'Phenotype', 'HP:0100526', (46, 57))
171755	30824826	Variants in DNA repair genes were associated with increased tumor mutation and neoantigen burden, which in turn were linked with greater tumor infiltration by activated T cells.	('increased tumor', 'Disease', (50, 65))	('Variants', 'Var', (0, 8))	('tumor', 'Disease', (137, 142))	('tumor', 'Disease', (60, 65))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('DNA repair genes', 'Gene', (12, 28))	('neoantigen burden', 'MPA', (79, 96))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('increased tumor', 'Disease', 'MESH:D009369', (50, 65))
171756	30824826	The subset of tumors with DNA repair gene variants but without T cell infiltration exhibited upregulation of TGF-beta and Wnt pathway genes, and a combined score incorporating these genes and DNA repair status accurately predicted immune cell infiltration.	('upregulation', 'PosReg', (93, 105))	('immune cell infiltration', 'CPA', (231, 255))	('DNA repair gene', 'Gene', (26, 41))	('TGF-beta', 'Gene', '7040', (109, 117))	('variants', 'Var', (42, 50))	('tumors', 'Disease', (14, 20))	('Wnt', 'Gene', (122, 125))	('predicted', 'Reg', (221, 230))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('TGF-beta', 'Gene', (109, 117))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('Wnt', 'Gene', '7471;7472;89780;7474;7476', (122, 125))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
171757	30824826	These findings provide evidence that DNA repair pathway defects and immunomodulatory genes together lead to specific immunophenotypes in lung squamous cell carcinoma and could potentially serve as biomarkers for immunotherapy.	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (137, 165))	('carcinoma', 'Phenotype', 'HP:0030731', (156, 165))	('DNA repair pathway', 'Pathway', (37, 55))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (142, 165))	('defects', 'Var', (56, 63))	('lung squamous cell carcinoma', 'Disease', (137, 165))	('lead to', 'Reg', (100, 107))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (137, 165))
171765	30824826	In many solid tumors, deleterious mutations in DNA repair genes can drive a substantial increase in the number of neoantigens.	('solid tumors', 'Disease', 'MESH:D009369', (8, 20))	('DNA repair genes', 'Gene', (47, 63))	('increase', 'PosReg', (88, 96))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('solid tumors', 'Disease', (8, 20))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('mutations', 'Var', (34, 43))
171766	30824826	Deficient DNA repair has accordingly been associated with improved clinical responses to PD-1 blockade.	('Deficient', 'Var', (0, 9))	('improved', 'PosReg', (58, 66))	('PD-1', 'Gene', (89, 93))	('PD-1', 'Gene', '5133', (89, 93))	('clinical responses', 'MPA', (67, 85))
171768	30824826	These results have now led to the landmark FDA approval for PD-1 inhibitors in MMR-deficient tumors, which represents a paradigm-altering shift towards oncologic treatments centered on molecular profile.	('PD-1', 'Gene', '5133', (60, 64))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('MMR-deficient tumors', 'Disease', 'MESH:C536928', (79, 99))	('MMR-deficient tumors', 'Disease', (79, 99))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('inhibitors', 'Var', (65, 75))	('PD-1', 'Gene', (60, 64))
171769	30824826	In an analysis of NSCLC patients, mutations in POLD1, POLE, and MSH2 were identified in tumors with the highest neoantigen burden, which in turn correlated with improved response to PD-1 inhibitors.	('response', 'MPA', (170, 178))	('MSH2', 'Gene', (64, 68))	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('MSH2', 'Gene', '4436', (64, 68))	('NSCLC', 'Disease', (18, 23))	('neoantigen burden', 'MPA', (112, 129))	('NSCLC', 'Disease', 'MESH:D002289', (18, 23))	('POLD1', 'Gene', (47, 52))	('PD-1', 'Gene', (182, 186))	('POLD1', 'Gene', '5424', (47, 52))	('PD-1', 'Gene', '5133', (182, 186))	('NSCLC', 'Phenotype', 'HP:0030358', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('patients', 'Species', '9606', (24, 32))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('tumors', 'Disease', (88, 94))	('mutations', 'Var', (34, 43))	('improved', 'PosReg', (161, 169))
171770	30824826	Further, endometrial cancers with polymerase epsilon (POLE) mutations contained increased neoantigen burden and PD-L1 expression, and cases of exceptional responders to immunotherapy have been reported with these mutations.	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('neoantigen burden', 'MPA', (90, 107))	('PD-L1', 'Gene', (112, 117))	('increased', 'PosReg', (80, 89))	('cancers', 'Phenotype', 'HP:0002664', (21, 28))	('POLE', 'Gene', (54, 58))	('PD-L1', 'Gene', '29126', (112, 117))	('mutations', 'Var', (60, 69))	('expression', 'MPA', (118, 128))	('endometrial cancers', 'Disease', 'MESH:D016889', (9, 28))	('endometrial cancers', 'Disease', (9, 28))
171771	30824826	Similarly, alterations in the homologous recombination (HR) apparatus, such as BRCA1 and BRCA2 mutations, were associated with higher neoantigen load and increased overall survival after anti-PD-1 treatment.	('alterations', 'Var', (11, 22))	('BRCA2', 'Gene', '675', (89, 94))	('BRCA1', 'Gene', '672', (79, 84))	('neoantigen load', 'MPA', (134, 149))	('PD-1', 'Gene', (192, 196))	('PD-1', 'Gene', '5133', (192, 196))	('BRCA1', 'Gene', (79, 84))	('BRCA2', 'Gene', (89, 94))	('mutations', 'Var', (95, 104))	('higher', 'PosReg', (127, 133))	('increased', 'PosReg', (154, 163))	('overall survival', 'CPA', (164, 180))
171772	30824826	Though DNA repair mutations have been shown to be relevant to immunotherapy response in a variety of solid tumors, limited data exists detailing the importance of these pathways in lung cancer.	('solid tumors', 'Disease', 'MESH:D009369', (101, 113))	('DNA repair', 'Gene', (7, 17))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('lung cancer', 'Disease', 'MESH:D008175', (181, 192))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('lung cancer', 'Disease', (181, 192))	('lung cancer', 'Phenotype', 'HP:0100526', (181, 192))	('solid tumors', 'Disease', (101, 113))	('mutations', 'Var', (18, 27))
171774	30824826	We hypothesized that a comparable relationship would be elucidated in squamous cell carcinoma (SqCC) of the lung, and that mutations in DNA repair pathways could thus function as biomarkers predictive of response to immune checkpoint blockade.	('SqCC', 'Phenotype', 'HP:0002860', (95, 99))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (70, 93))	('DNA', 'Gene', (136, 139))	('squamous cell carcinoma', 'Disease', (70, 93))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (70, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('mutations', 'Var', (123, 132))
171776	30824826	We evaluated tumors for somatic variants in genes related to MMR, HR, or in POLE, and identified changes predicted to be deleterious by the SIFT and CADD v1.4 scoring systems.	('CADD', 'Disease', (149, 153))	('tumors', 'Disease', (13, 19))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('v1.4', 'Gene', (154, 158))	('SIFT', 'Disease', 'None', (140, 144))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('CADD', 'Disease', 'None', (149, 153))	('v1.4', 'Gene', '28815', (154, 158))	('variants', 'Var', (32, 40))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('SIFT', 'Disease', (140, 144))	('MMR', 'Disease', (61, 64))
171777	30824826	Tumors with defects in MMR and HR had a significantly higher number of overall mutations (Student's t-test, p < 0.0001 for both; Fig.	('higher', 'PosReg', (54, 60))	('defects', 'Var', (12, 19))	('MMR', 'Gene', (23, 26))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('mutations', 'Var', (79, 88))
171779	30824826	Tumors with multiple DNA repair gene variants had corresponding increases in TMB.	('DNA repair', 'Gene', (21, 31))	('TMB', 'MPA', (77, 80))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('variants', 'Var', (37, 45))	('TMB', 'Chemical', '-', (77, 80))	('increases', 'PosReg', (64, 73))
171780	30824826	For example, tumors with 1 affected gene had an average of 293.8 +- 27.0 tumor mutations, while those with 3-5 affected genes had 815.8 +- 248.6 mutations (Fig.	('tumor', 'Disease', (13, 18))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Disease', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Disease', (73, 78))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('mutations', 'Var', (79, 88))
171781	30824826	POLE variants were rare (n = 8) but were also associated with increased TMB (Student's t-test, p = 0.010).	('increased', 'PosReg', (62, 71))	('TMB', 'Chemical', '-', (72, 75))	('variants', 'Var', (5, 13))	('TMB', 'Disease', (72, 75))
171782	30824826	There was no difference in smoking history between tumors with low and high TMB (Supplementary Fig.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('TMB', 'Chemical', '-', (76, 79))	('tumors', 'Disease', (51, 57))	('tumors', 'Disease', 'MESH:D009369', (51, 57))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('low', 'Var', (63, 66))	('high TMB', 'Var', (71, 79))
171783	30824826	This total predicted neoantigen burden was significantly greater in tumors with somatic variants in HR (Student's t-test, p = 0.0003) and MMR (p < 0.0001), but not POLE (p = 0.538) (Fig.	('MMR', 'Gene', (138, 141))	('tumors', 'Disease', (68, 74))	('tumors', 'Disease', 'MESH:D009369', (68, 74))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('variants', 'Var', (88, 96))	('neoantigen burden', 'MPA', (21, 38))	('greater', 'PosReg', (57, 64))
171785	30824826	Tumors with high TMB were more likely to be infiltrated by activated CD4+ (proportion Z-score, p = 0.013) and activated CD8+ (p = 0.036) T cells (Fig.	('TMB', 'Chemical', '-', (17, 20))	('CD4', 'Gene', (69, 72))	('high', 'Var', (12, 16))	('CD8', 'Gene', (120, 123))	('CD8', 'Gene', '925', (120, 123))	('CD4', 'Gene', '920', (69, 72))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))
171787	30824826	Presence of variants in HR, MMR, and POLE did not predict infiltration by CD4+, CD8+, or total activated T cells (Fig.	('CD8', 'Gene', '925', (80, 83))	('variants', 'Var', (12, 20))	('CD4', 'Gene', (74, 77))	('CD8', 'Gene', (80, 83))	('CD4', 'Gene', '920', (74, 77))
171788	30824826	This grouping delineated four types of tumor: DNA repair variant absent without T cell infiltration (group I), DNA repair variant present without T cell infiltration (group II), DNA repair variant absent with infiltration (group III), and DNA repair variant present with infiltration (group IV).	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('variant', 'Var', (57, 64))	('tumor', 'Disease', (39, 44))	('absent', 'NegReg', (197, 203))	('DNA repair', 'Gene', (46, 56))	('variant', 'Var', (189, 196))
171795	30824826	Variants in the beta-catenin/Wnt pathway were similarly not associated with tumor groups (Supplementary Fig.	('Variants', 'Var', (0, 8))	('Wnt', 'Gene', (29, 32))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('beta-catenin', 'Gene', (16, 28))	('Wnt', 'Gene', '7471;7472;89780;7474;7476', (29, 32))	('beta-catenin', 'Gene', '1499', (16, 28))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
171797	30824826	Thus, a score of 3 indicates intact DNA repair pathways and high TGF-beta/Wnt2, while a score of 0 indicates presence of DNA repair pathway variants and low TGF-beta/Wnt2.	('Wnt2', 'Gene', (166, 170))	('TGF-beta', 'Gene', (65, 73))	('variants', 'Var', (140, 148))	('Wnt2', 'Gene', (74, 78))	('Wnt2', 'Gene', '7472', (74, 78))	('TGF-beta', 'Gene', '7040', (157, 165))	('DNA repair pathways', 'Pathway', (36, 55))	('Wnt2', 'Gene', '7472', (166, 170))	('TGF-beta', 'Gene', (157, 165))	('TGF-beta', 'Gene', '7040', (65, 73))	('DNA repair pathway', 'Pathway', (121, 139))
171798	30824826	Using a threshold of <=1, tumors with low scores indeed demonstrated a significantly increased likelihood of CD4+ (false discovery rate-adjusted proportion Z-score, p < 0.0003) and CD8+ (p = 0.012) activated T cell infiltration (Fig.	('activated', 'PosReg', (198, 207))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('CD8', 'Gene', (181, 184))	('CD8', 'Gene', '925', (181, 184))	('increased', 'PosReg', (85, 94))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('low scores', 'Var', (38, 48))	('CD4', 'Gene', (109, 112))	('T cell infiltration', 'CPA', (208, 227))	('CD4', 'Gene', '920', (109, 112))	('tumors', 'Disease', (26, 32))
171810	30824826	High-neoantigen tumors exhibited increased gene expression of the pro-inflammatory markers GZMA, GZMB, PRF1, CD8A, EOMES, CXCL9, and IFNG, as well as the immune checkpoint marker LAG3 (Fig.	('GZMB', 'Gene', (97, 101))	('PRF1', 'Gene', '5551', (103, 107))	('CD8A', 'Gene', '925', (109, 113))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('PRF1', 'Gene', (103, 107))	('IFNG', 'Gene', (133, 137))	('LAG3', 'Gene', '3902', (179, 183))	('tumors', 'Disease', (16, 22))	('GZMA', 'Gene', '3001', (91, 95))	('High-neoantigen', 'Var', (0, 15))	('GZMA', 'Gene', (91, 95))	('CD8A', 'Gene', (109, 113))	('LAG3', 'Gene', (179, 183))	('EOMES', 'Gene', '8320', (115, 120))	('tumors', 'Disease', 'MESH:D009369', (16, 22))	('CXCL9', 'Gene', (122, 127))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('IFNG', 'Gene', '3458', (133, 137))	('increased', 'PosReg', (33, 42))	('CXCL9', 'Gene', '4283', (122, 127))	('GZMB', 'Gene', '3002', (97, 101))	('gene expression', 'MPA', (43, 58))	('EOMES', 'Gene', (115, 120))
171816	30824826	Mutation burden has been shown to affect both treatment response as well as intrinsic survival in multiple cancer types.	('treatment response', 'CPA', (46, 64))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('intrinsic survival', 'CPA', (76, 94))	('Mutation burden', 'Var', (0, 15))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('affect', 'Reg', (34, 40))	('cancer', 'Disease', (107, 113))
171818	30824826	Defects in DNA repair pathways have been shown to strongly affect the tumor immune profile and consequently the clinical response to immunotherapy.	('affect', 'Reg', (59, 65))	('DNA repair pathways', 'Pathway', (11, 30))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', (70, 75))	('Defects', 'Var', (0, 7))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
171819	30824826	We here sought to characterize the role of DNA repair gene mutations in shaping immunological characteristics in lung squamous cell carcinoma.	('lung squamous cell carcinoma', 'Disease', (113, 141))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('DNA repair gene', 'Gene', (43, 58))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (118, 141))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (113, 141))	('mutations', 'Var', (59, 68))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (113, 141))
171820	30824826	Our results overall support findings seen in other cancer types, and demonstrate that mutations in DNA repair pathways are associated with high tumor mutation burden (TMB).	('mutations', 'Var', (86, 95))	('associated', 'Reg', (123, 133))	('TMB', 'Chemical', '-', (167, 170))	('high tumor', 'Disease', (139, 149))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('high tumor', 'Disease', 'MESH:D009369', (139, 149))	('DNA repair pathways', 'Pathway', (99, 118))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))
171821	30824826	We also used mutation data to predict presence of tumor-specific neoantigens, which may be more relevant to anti-tumor immunity, and showed that presence of DNA repair gene variants was associated with high neoantigen load.	('tumor', 'Disease', (113, 118))	('high neoantigen load', 'MPA', (202, 222))	('DNA repair', 'Gene', (157, 167))	('presence', 'Var', (145, 153))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('associated', 'Reg', (186, 196))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('variants', 'Var', (173, 181))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('tumor', 'Disease', (50, 55))
171825	30824826	An effective immune response requires not only the immunogenic impetus provided by tumor mutations, but also the ability of immune cells to infiltrate the tumor parenchyma.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('tumor', 'Disease', (83, 88))	('tumor', 'Disease', (155, 160))	('mutations', 'Var', (89, 98))	('tumor parenchyma', 'Disease', 'MESH:D010195', (155, 171))	('tumor parenchyma', 'Disease', (155, 171))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
171827	30824826	In tumors with greater mutation load, there was a higher percentage of tumors infiltrated by activated CD4 + and CD8 + T cells.	('mutation load', 'Var', (23, 36))	('tumors', 'Phenotype', 'HP:0002664', (3, 9))	('CD8', 'Gene', (113, 116))	('tumors', 'Disease', (3, 9))	('CD8', 'Gene', '925', (113, 116))	('tumors', 'Disease', 'MESH:D009369', (3, 9))	('CD4', 'Gene', (103, 106))	('CD4', 'Gene', '920', (103, 106))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('tumors', 'Disease', (71, 77))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))	('tumors', 'Disease', 'MESH:D009369', (71, 77))
171829	30824826	High-mutation and high-neoantigen tumors also had significantly elevated expression of IFN-gamma-inducible chemokines such as CXCL9, which promotes trafficking of activated T cells.	('high-neoantigen', 'Var', (18, 33))	('tumors', 'Disease', (34, 40))	('trafficking', 'MPA', (148, 159))	('IFN-gamma', 'Gene', (87, 96))	('elevated', 'PosReg', (64, 72))	('IFN-gamma', 'Gene', '3458', (87, 96))	('tumors', 'Disease', 'MESH:D009369', (34, 40))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('High-mutation', 'Var', (0, 13))	('expression', 'MPA', (73, 83))	('CXCL9', 'Gene', '4283', (126, 131))	('promotes', 'PosReg', (139, 147))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('CXCL9', 'Gene', (126, 131))
171831	30824826	Despite the relationship between mutation load and T cell infiltration, we did not find a direct association between DNA repair gene variants and tumor immunophenotype.	('mutation', 'Var', (33, 41))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('tumor', 'Disease', (146, 151))	('variants', 'Var', (133, 141))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
171832	30824826	Notably, there was a sizeable sub-group of tumors with repair gene variants (many with high mutation burden) that nonetheless did not exhibit T cell infiltration.	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumors', 'Disease', (43, 49))	('repair gene', 'Gene', (55, 66))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('variants', 'Var', (67, 75))	('tumors', 'Disease', 'MESH:D009369', (43, 49))
171834	30824826	Our group of DNA repair gene-variant tumors without infiltrated T cells (i.e.	('DNA repair', 'Gene', (13, 23))	('gene-variant', 'Var', (24, 36))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('tumors', 'Disease', (37, 43))	('tumors', 'Disease', 'MESH:D009369', (37, 43))
171840	30824826	Deficiencies in the antigen presenting apparatus have been linked to low anti-tumor immune activity, but mutations in relevant genes (including HLA molecules and beta-2-microglobulin) were not predictive of immunophenotypic groups.	('beta-2-microglobulin', 'Gene', '567', (162, 182))	('HLA molecules', 'Protein', (144, 157))	('Deficiencies', 'Var', (0, 12))	('beta-2-microglobulin', 'Gene', (162, 182))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('low', 'NegReg', (69, 72))	('tumor', 'Disease', (78, 83))
171841	30824826	HLA defects have been linked specifically to escape mechanisms in the context of acquired resistance to immunotherapy, and they thus may not have relevance in a broader set of tumors.	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('escape', 'Disease', (45, 51))	('tumors', 'Disease', (176, 182))	('tumors', 'Disease', 'MESH:D009369', (176, 182))	('tumors', 'Phenotype', 'HP:0002664', (176, 182))	('HLA', 'Gene', (0, 3))	('linked', 'Reg', (22, 28))	('defects', 'Var', (4, 11))
171843	30824826	This score is a crude measure but serves as a proof of concept demonstrating that DNA repair gene aberrations, when adjusted for tumor microenvironment factors, can help identify inflamed tumors.	('tumor', 'Disease', (188, 193))	('inflamed tumors', 'Disease', (179, 194))	('tumors', 'Phenotype', 'HP:0002664', (188, 194))	('DNA repair gene', 'Gene', (82, 97))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('inflamed tumors', 'Disease', 'MESH:C531841', (179, 194))	('tumor', 'Disease', (129, 134))	('aberrations', 'Var', (98, 109))
171845	30824826	In contrast to the results in SqCC, our prior study in lung adenocarcinoma did observe a direct relationship between DNA repair gene variants and activated T cell infiltration.	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('SqCC', 'Phenotype', 'HP:0002860', (30, 34))	('lung adenocarcinoma', 'Disease', (55, 74))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (55, 74))	('activated T cell infiltration', 'CPA', (146, 175))	('DNA repair gene', 'Gene', (117, 132))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (55, 74))	('variants', 'Var', (133, 141))
171848	30824826	In this dataset, we found significant differences between low- and high-mutation tumors in regards to immune-related gene expression, including in genes related to cytolytic activity and IFN-gamma-inducible pro-inflammatory factors.	('expression', 'MPA', (122, 132))	('tumors', 'Disease', (81, 87))	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('differences', 'Reg', (38, 49))	('low-', 'Var', (58, 62))	('immune-related gene', 'Gene', (102, 121))	('IFN-gamma', 'Gene', (187, 196))	('IFN-gamma', 'Gene', '3458', (187, 196))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('high-mutation', 'Var', (67, 80))
171849	30824826	Increased mutation burden did not affect survival outcomes, but high neoantigen burden was associated with worse disease-free survival, possibly due to greater clinical relevance of tumor-specific neoantigens.	('high', 'Var', (64, 68))	('tumor', 'Disease', (182, 187))	('worse', 'NegReg', (107, 112))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('disease-free survival', 'CPA', (113, 134))	('neoantigen burden', 'MPA', (69, 86))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
171850	30824826	Meanwhile, presence of DNA repair gene variants did not relate to patient survival.	('variants', 'Var', (39, 47))	('DNA repair gene', 'Gene', (23, 38))	('patient', 'Species', '9606', (66, 73))
171851	30824826	Similarly, high neoantigen load would be expected to lead to improved survival in those patients, while in these tumors, an increased number of neoantigens may represent more aggressive disease.	('improved', 'PosReg', (61, 69))	('tumors', 'Disease', (113, 119))	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('survival', 'MPA', (70, 78))	('neoantigen', 'Protein', (16, 26))	('aggressive disease', 'Disease', 'MESH:D001523', (175, 193))	('patients', 'Species', '9606', (88, 96))	('aggressive disease', 'Disease', (175, 193))	('high', 'Var', (11, 15))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
171854	30824826	Our data overall provide evidence that DNA repair pathway variants are closely associated with mutation and neoantigen burden in lung SqCC, and together with other immune-related signals are important factors in determining the tumor immunophenotype.	('neoantigen burden', 'MPA', (108, 125))	('associated', 'Reg', (79, 89))	('lung SqCC', 'Disease', (129, 138))	('variants', 'Var', (58, 66))	('mutation', 'MPA', (95, 103))	('tumor', 'Disease', 'MESH:D009369', (228, 233))	('SqCC', 'Phenotype', 'HP:0002860', (134, 138))	('DNA repair pathway', 'Pathway', (39, 57))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('tumor', 'Disease', (228, 233))
171856	30824826	To identify mutations in homologous recombination, samples were assessed for mutations in the following genes: ATR, ATM, CHEK1, CHEK2, BRCA1, BRCA2, BAP1, BARD1, FANCD2, FANCE, FANCC, FANCA, RAD50, RAD51, and PALB2.	('FANCC', 'Gene', (177, 182))	('FANCE', 'Gene', (170, 175))	('FANCE', 'Gene', '2178', (170, 175))	('CHEK1', 'Gene', (121, 126))	('ATR', 'Gene', (111, 114))	('BRCA2', 'Gene', (142, 147))	('FANCA', 'Gene', (184, 189))	('BAP1', 'Gene', '8314', (149, 153))	('FANCD2', 'Gene', (162, 168))	('RAD51', 'Gene', (198, 203))	('RAD51', 'Gene', '5888', (198, 203))	('RAD50', 'Gene', (191, 196))	('ATM', 'Gene', '472', (116, 119))	('BRCA1', 'Gene', '672', (135, 140))	('FANCD2', 'Gene', '2177', (162, 168))	('BRCA2', 'Gene', '675', (142, 147))	('PALB2', 'Gene', (209, 214))	('CHEK2', 'Gene', (128, 133))	('BRCA1', 'Gene', (135, 140))	('BAP1', 'Gene', (149, 153))	('mutations', 'Var', (77, 86))	('RAD50', 'Gene', '10111', (191, 196))	('ATR', 'Gene', '545', (111, 114))	('BARD1', 'Gene', '580', (155, 160))	('BARD1', 'Gene', (155, 160))	('FANCC', 'Gene', '2176', (177, 182))	('mutations', 'Var', (12, 21))	('PALB2', 'Gene', '79728', (209, 214))	('CHEK1', 'Gene', '1111', (121, 126))	('ATM', 'Gene', (116, 119))	('CHEK2', 'Gene', '11200', (128, 133))	('FANCA', 'Gene', '2175', (184, 189))
171868	29107330	Using LOHHLA, we find that HLA LOH occurs in 40% of non-small-cell lung cancers (NSCLCs) and is associated with a high subclonal neoantigen burden, APOBEC-mediated mutagenesis, upregulation of cytolytic activity, and PD-L1 positivity.	('PD-L1', 'Gene', '29126', (217, 222))	('lung cancers', 'Disease', 'MESH:D008175', (67, 79))	('cytolytic activity', 'CPA', (193, 211))	('NSCLC', 'Phenotype', 'HP:0030358', (81, 86))	('upregulation', 'PosReg', (177, 189))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (56, 78))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('mutagenesis', 'Var', (164, 175))	('lung cancers', 'Disease', (67, 79))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('lung cancers', 'Phenotype', 'HP:0100526', (67, 79))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (52, 78))	('LOHHLA', 'Chemical', '-', (6, 12))	('HLA', 'Gene', (27, 30))	('NSCLC', 'Disease', 'MESH:D002289', (81, 86))	('PD-L1', 'Gene', (217, 222))	('NSCLC', 'Disease', (81, 86))	('LOH', 'NegReg', (31, 34))	('lung cancer', 'Phenotype', 'HP:0100526', (67, 78))
171869	29107330	The focal nature of HLA LOH alterations, their subclonal frequencies, enrichment in metastatic sites, and occurrence as parallel events suggests that HLA LOH is an immune escape mechanism that is subject to strong microenvironmental selection pressures later in tumor evolution.	('tumor', 'Phenotype', 'HP:0002664', (262, 267))	('alterations', 'Var', (28, 39))	('tumor', 'Disease', (262, 267))	('HLA LOH', 'Gene', (20, 27))	('tumor', 'Disease', 'MESH:D009369', (262, 267))
171885	29107330	In order to determine allele-specific copy number, the majority of copy-number tools rely on the relative coverage and variant allele frequency of single nucleotide polymorphisms (SNPs) in the tumor and matched normal across the genome or exome.	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('tumor', 'Disease', (193, 198))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('single nucleotide polymorphisms', 'Var', (147, 178))
171895	29107330	We therefore used ASCAT to estimate the frequency of allelic imbalance and LOH in the genomic regions surrounding the HLA locus in 288 TRACERx non-small-cell lung cancer (NSCLC) exomes from 96 patients and compared these to LOHHLA copy-number estimation.	('patients', 'Species', '9606', (193, 201))	('lung cancer', 'Disease', (158, 169))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (143, 169))	('lung cancer', 'Phenotype', 'HP:0100526', (158, 169))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (147, 169))	('NSCLC', 'Phenotype', 'HP:0030358', (171, 176))	('non-small-cell', 'Disease', (143, 157))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('imbalance', 'Phenotype', 'HP:0002172', (61, 70))	('lung cancer', 'Disease', 'MESH:D008175', (158, 169))	('LOHHLA', 'Chemical', '-', (224, 230))	('NSCLC', 'Disease', (171, 176))	('LOH', 'Var', (75, 78))	('NSCLC', 'Disease', 'MESH:D002289', (171, 176))
171899	29107330	Thirty-four additional allelic imbalance events in tumor regions were uncovered using LOHHLA while only 8 tumor regions exhibited evidence of allelic imbalance using ASCAT and not LOHHLA.	('imbalance', 'Phenotype', 'HP:0002172', (31, 40))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor', 'Disease', (51, 56))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('LOHHLA', 'Var', (86, 92))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('LOHHLA', 'Chemical', '-', (180, 186))	('imbalance', 'Phenotype', 'HP:0002172', (150, 159))	('LOHHLA', 'Chemical', '-', (86, 92))	('tumor', 'Disease', (106, 111))
171906	29107330	Taken together, these data suggest that LOHHLA is able to accurately infer both allelic imbalance and LOH in tumor samples.	('LOHHLA', 'Chemical', '-', (40, 46))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('imbalance', 'Phenotype', 'HP:0002172', (88, 97))	('allelic imbalance', 'Var', (80, 97))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('infer', 'Reg', (69, 74))	('LOH', 'MPA', (102, 105))	('tumor', 'Disease', (109, 114))
171909	29107330	HLA mutations, which have the ability to disrupt neoantigen-MHC binding, have been previously described in many cancer types, including NSCLC.	('binding', 'Interaction', (64, 71))	('NSCLC', 'Disease', 'MESH:D002289', (136, 141))	('disrupt', 'NegReg', (41, 48))	('cancer', 'Disease', (112, 118))	('described', 'Reg', (94, 103))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('MHC', 'Gene', (60, 63))	('NSCLC', 'Phenotype', 'HP:0030358', (136, 141))	('HLA', 'Gene', (0, 3))	('mutations', 'Var', (4, 13))	('MHC', 'Gene', '3107', (60, 63))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('NSCLC', 'Disease', (136, 141))
171911	29107330	In our cohort of 90 lung adenocarcinoma or lung squamous cell carcinoma TRACERx patients, only tumors from three patients were found to harbor nonsynonymous mutations in HLA genes using Polysolver (Figure 2A).	('nonsynonymous mutations', 'Var', (143, 166))	('lung adenocarcinoma or lung squamous cell carcinoma', 'Disease', 'MESH:D000077192', (20, 71))	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('patients', 'Species', '9606', (80, 88))	('patients', 'Species', '9606', (113, 121))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('HLA genes', 'Gene', (170, 179))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (48, 71))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (20, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (30, 39))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (43, 71))	('tumors', 'Disease', (95, 101))	('carcinoma', 'Phenotype', 'HP:0030731', (62, 71))
171912	29107330	One lung adenocarcinoma tumor had also acquired a mutation in beta-2 microglobulin (B2m), which is vital for MHC class I expression and peptide binding stability.	('B2m', 'Gene', '567', (84, 87))	('lung adenocarcinoma tumor', 'Disease', (4, 29))	('carcinoma', 'Phenotype', 'HP:0030731', (14, 23))	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('MHC', 'Gene', (109, 112))	('B2m', 'Gene', (84, 87))	('lung adenocarcinoma tumor', 'Disease', 'MESH:D000077192', (4, 29))	('MHC', 'Gene', '3107', (109, 112))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (4, 23))	('mutation', 'Var', (50, 58))
171913	29107330	No further mutations predicted to disrupt antigen presentation or the MHC class I complex were identified in this cohort.	('MHC', 'Gene', '3107', (70, 73))	('mutations', 'Var', (11, 20))	('MHC', 'Gene', (70, 73))	('antigen', 'MPA', (42, 49))
171914	29107330	Likewise, a broader study of 174 lung squamous cell and 223 lung adenocarcinoma patients from TCGA only classified 8% and 5% of tumors as harboring HLA mutations, respectively.	('HLA', 'Gene', (148, 151))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (60, 79))	('patients', 'Species', '9606', (80, 88))	('mutations', 'Var', (152, 161))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('lung adenocarcinoma', 'Disease', (60, 79))	('tumors', 'Disease', (128, 134))	('tumors', 'Disease', 'MESH:D009369', (128, 134))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (60, 79))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))
171916	29107330	Just as HLA mutations occur more frequently in lung squamous cell carcinomas, we also observed an enrichment for HLA LOH in this histological subtype (p = 0.004, 19/31 [61%] of lung squamous cell carcinomas versus 17/59 [29%] of lung adenocarcinomas) (Figures 2A and 2B).	('HLA', 'Gene', (8, 11))	('lung squamous cell carcinomas', 'Disease', 'MESH:D002294', (47, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (66, 75))	('carcinomas', 'Phenotype', 'HP:0030731', (66, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (239, 248))	('lung squamous cell carcinomas', 'Disease', (177, 206))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (229, 249))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (182, 205))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (229, 248))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (229, 249))	('lung squamous cell carcinomas', 'Disease', (47, 76))	('carcinomas', 'Phenotype', 'HP:0030731', (239, 249))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (52, 76))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (47, 75))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (52, 75))	('lung adenocarcinomas', 'Disease', (229, 249))	('carcinoma', 'Phenotype', 'HP:0030731', (196, 205))	('lung squamous cell carcinomas', 'Disease', 'MESH:D002294', (177, 206))	('carcinomas', 'Phenotype', 'HP:0030731', (196, 206))	('mutations', 'Var', (12, 21))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (177, 205))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (182, 206))
171928	29107330	Thus, while chromosomal instability may lead to LOH at the HLA locus, facilitating immune escape, the high prevalence of HLA LOH, beyond that expected by chance, suggests it is subject to significant positive selection in tumor evolution.	('lead to', 'Reg', (40, 47))	('tumor', 'Disease', 'MESH:D009369', (222, 227))	('LOH', 'Var', (48, 51))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('tumor', 'Disease', (222, 227))	('chromosomal instability', 'Phenotype', 'HP:0040012', (12, 35))	('HLA', 'Gene', (121, 124))
171935	29107330	Conceivably, if one of the homologous chromosomes harboring the HLA haplotypes were subject to copy-number loss, the number of putative neoantigens presented to T cells would be reduced.	('HLA haplotype', 'Gene', (64, 77))	('loss', 'NegReg', (107, 111))	('HLA haplotype', 'Gene', '3105', (64, 77))	('copy-number', 'Var', (95, 106))	('reduced', 'NegReg', (178, 185))
171938	29107330	While overall, we observed a significant increase in the number of non-synonymous mutations (Figure 4A) and neoantigens (Figure S4A) in tumor samples exhibiting any HLA LOH, this did not remain significant when the subtypes were considered separately (NSCLC p = 0.016; lung adenocarcinoma p = 0.07; lung squamous cell carcinoma p = 0.82, Wilcoxon test).	('carcinoma', 'Phenotype', 'HP:0030731', (279, 288))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (299, 327))	('increase', 'PosReg', (41, 49))	('lung adenocarcinoma', 'Disease', (269, 288))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (269, 288))	('NSCLC', 'Phenotype', 'HP:0030358', (252, 257))	('carcinoma', 'Phenotype', 'HP:0030731', (318, 327))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('non-synonymous mutations', 'Var', (67, 91))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (299, 327))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (304, 327))	('lung squamous cell carcinoma', 'Disease', (299, 327))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (269, 288))	('NSCLC', 'Disease', (252, 257))	('tumor', 'Disease', (136, 141))	('NSCLC', 'Disease', 'MESH:D002289', (252, 257))
171943	29107330	When we considered HLA LOH events at the region-level, we also observed a significant increase in subclonal mutations between tumor regions exhibiting HLA loss compared to tumor regions from patients without any evidence for HLA LOH (Figure S4D; NSCLC p = 1.9e-05; lung adenocarcinoma p = 0.009; lung squamous cell carcinoma p = 0.07).	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (296, 324))	('tumor', 'Disease', (172, 177))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (301, 324))	('lung squamous cell carcinoma', 'Disease', (296, 324))	('NSCLC', 'Disease', (246, 251))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('loss', 'NegReg', (155, 159))	('increase', 'PosReg', (86, 94))	('NSCLC', 'Phenotype', 'HP:0030358', (246, 251))	('lung adenocarcinoma', 'Disease', (265, 284))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (265, 284))	('carcinoma', 'Phenotype', 'HP:0030731', (315, 324))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (265, 284))	('tumor', 'Disease', (126, 131))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (296, 324))	('carcinoma', 'Phenotype', 'HP:0030731', (275, 284))	('patients', 'Species', '9606', (191, 199))	('subclonal mutations', 'Var', (98, 117))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('NSCLC', 'Disease', 'MESH:D002289', (246, 251))
171944	29107330	Interestingly, even in tumor regions without HLA LOH, but evidence for HLA LOH in other regions from the same tumor, we observed a significantly higher burden of subclonal mutations compared to tumor regions derived from tumors without any evidence for HLA LOH (Figure S4D).	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('tumors', 'Phenotype', 'HP:0002664', (221, 227))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('tumor', 'Disease', (221, 226))	('tumor', 'Disease', (110, 115))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', 'MESH:D009369', (221, 226))	('tumors', 'Disease', 'MESH:D009369', (221, 227))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('tumor', 'Disease', (194, 199))	('tumors', 'Disease', (221, 227))	('tumor', 'Disease', (23, 28))	('subclonal mutations', 'Var', (162, 181))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
171958	29107330	In one extreme example, tumor CRUK0020, a lung adenocarcinoma, we observed a total of 1,220 mutations predicted to yield neoantigens, of which 92% were predicted to bind to lost HLA alleles.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (42, 61))	('carcinoma', 'Phenotype', 'HP:0030731', (52, 61))	('tumor', 'Disease', (24, 29))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (42, 61))	('mutations', 'Var', (92, 101))	('yield', 'Reg', (115, 120))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('neoantigens', 'MPA', (121, 132))	('lung adenocarcinoma', 'Disease', (42, 61))
171963	29107330	We found tumors exhibiting clonal HLA LOH were characterized by significantly elevated PD-L1 staining of immune cells compared to tumors without any HLA LOH (p = 0.029, Cochrane Armitage test), and a trend was observed for elevated PD-L1 staining on tumor cells (p = 0.14, Cochrane Armitage test).	('tumors', 'Disease', 'MESH:D009369', (130, 136))	('PD-L1', 'Gene', (232, 237))	('clonal HLA LOH', 'Var', (27, 41))	('PD-L1', 'Gene', '29126', (232, 237))	('tumors', 'Disease', 'MESH:D009369', (9, 15))	('PD-L1', 'Gene', (87, 92))	('tumor', 'Disease', (130, 135))	('tumor', 'Disease', (250, 255))	('PD-L1', 'Gene', '29126', (87, 92))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('tumor', 'Disease', 'MESH:D009369', (250, 255))	('tumor', 'Disease', (9, 14))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('ran', 'Gene', (173, 176))	('tumor', 'Phenotype', 'HP:0002664', (250, 255))	('ran', 'Gene', '5901', (173, 176))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('elevated', 'PosReg', (223, 231))	('tumors', 'Disease', (130, 136))	('ran', 'Gene', (277, 280))	('ran', 'Gene', '5901', (277, 280))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('elevated', 'PosReg', (78, 86))	('tumors', 'Disease', (9, 15))
171977	29107330	Importantly, LOHHLA is able to determine which specific HLA haplotype is subject to copy-number loss, which is not possible using conventional copy-number tools.	('HLA haplotype', 'Gene', '3105', (56, 69))	('LOHHLA', 'Chemical', '-', (13, 19))	('loss', 'NegReg', (96, 100))	('HLA haplotype', 'Gene', (56, 69))	('copy-number', 'Var', (84, 95))
171981	29107330	In keeping with these results, in four early stage tumors, we observed evidence for parallel evolution of HLA allele-specific loss, and in a cohort of primary NSCLC tumors with matched brain metastasis, we detected HLA LOH in 47% of cases, occurring subclonally in the majority of cases (11/17) and preferentially at the metastatic sites (Figure 3H).	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('NSCLC tumors', 'Disease', 'MESH:D009369', (159, 171))	('tumors', 'Disease', (165, 171))	('NSCLC tumors', 'Disease', (159, 171))	('tumors', 'Disease', 'MESH:D009369', (165, 171))	('tumors', 'Phenotype', 'HP:0002664', (165, 171))	('tumors', 'Disease', (51, 57))	('tumors', 'Disease', 'MESH:D009369', (51, 57))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('HLA', 'Gene', (106, 109))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('loss', 'NegReg', (126, 130))	('NSCLC', 'Phenotype', 'HP:0030358', (159, 164))	('HLA', 'Var', (215, 218))
171984	29107330	In both lung adenocarcinomas and lung squamous cell carcinomas, subclones harboring HLA LOH were associated with a significantly elevated non-synonymous mutation/neoantigen burden compared to subclones descended from the same ancestral cancer cell but without HLA LOH.	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (8, 27))	('carcinoma', 'Phenotype', 'HP:0030731', (18, 27))	('carcinoma', 'Phenotype', 'HP:0030731', (52, 61))	('carcinomas', 'Phenotype', 'HP:0030731', (52, 62))	('cancer', 'Disease', 'MESH:D009369', (236, 242))	('elevated', 'PosReg', (129, 137))	('carcinomas', 'Phenotype', 'HP:0030731', (18, 28))	('cancer', 'Disease', (236, 242))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (8, 28))	('lung adenocarcinomas and lung squamous cell carcinomas', 'Disease', 'MESH:D000077192', (8, 62))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (38, 62))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (33, 61))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (38, 61))	('non-synonymous mutation/neoantigen burden', 'MPA', (138, 179))	('LOH', 'Var', (88, 91))
171986	29107330	The high mutational load and low levels of HLA expression in lung squamous cell tumors, even in tumors without HLA LOH suggests alternative mechanisms of immune evasion and/or disruption of neoantigen presentation through other mechanisms (e.g., mutations to B2M or NLRC5).	('B2M', 'Gene', '567', (259, 262))	('NLRC5', 'Gene', '84166', (266, 271))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('immune evasion', 'MPA', (154, 168))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumors', 'Disease', (96, 102))	('tumors', 'Disease', (80, 86))	('lung squamous cell tumors', 'Disease', (61, 86))	('neoantigen presentation', 'MPA', (190, 213))	('lung squamous cell tumors', 'Disease', 'MESH:D002294', (61, 86))	('mutational', 'Var', (9, 19))	('disruption', 'MPA', (176, 186))	('mutations', 'Var', (246, 255))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('NLRC5', 'Gene', (266, 271))	('squamous cell tumors', 'Phenotype', 'HP:0002860', (66, 86))	('B2M', 'Gene', (259, 262))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))
172029	29107330	Patients CRUK0013, CRUK0061, CRUK0082, and CRUK0084 had HLA LOH events that did not fit the current phylogentic tree, so additional nodes (indicated in gray) were included to contain the HLA LOH event.	('CRUK0082', 'Var', (29, 37))	('CRUK0084', 'Var', (43, 51))	('Patients', 'Species', '9606', (0, 8))	('CRUK0013', 'Var', (9, 17))	('CRUK0061', 'Var', (19, 27))
172030	29107330	Patients CRUK003, CRUK0032, CRUK0051, and CRUK0062 had multiple independent HLA LOH events which were manually mapped.	('CRUK0032', 'Var', (18, 26))	('CRUK003', 'Var', (9, 16))	('Patients', 'Species', '9606', (0, 8))	('CRUK0062', 'Var', (42, 50))	('CRUK0051', 'Var', (28, 36))
172043	29107330	Previously defined measures of immune infiltration and activity were used to compare the immune microenvironment between tumors exhibiting HLA LOH at all HLA loci and those without any evidence for HLA LOH.	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('HLA', 'Gene', (139, 142))	('LOH', 'Var', (143, 146))	('tumors', 'Disease', (121, 127))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('tumors', 'Disease', 'MESH:D009369', (121, 127))
172057	28723786	Group analysis of the 74 peripheral lung SCC showed that those with the tumor long axis <=2 cm had a lower rate of lymph node metastasis (7.9% vs 27.8%, P = .025).	('peripheral lung SCC', 'Phenotype', 'HP:0004969', (25, 44))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('lymph node metastasis', 'CPA', (115, 136))	('SCC', 'Gene', (41, 44))	('SCC', 'Phenotype', 'HP:0002860', (41, 44))	('<=2', 'Var', (88, 91))	('tumor long axis', 'Disease', (72, 87))	('tumor long axis', 'Disease', 'MESH:C566610', (72, 87))	('SCC', 'Gene', '6317', (41, 44))	('lower', 'NegReg', (101, 106))	('lower rate of lymph node', 'Phenotype', 'HP:0002732', (101, 125))
172107	28723786	Among tumor size, SUV in PET, serum levels of CEA, and CYFRA21-1, no factor showed a significant risk value in Tsutani et al's study.	('CEA', 'Gene', '1048', (46, 49))	('CEA', 'Gene', (46, 49))	('CYFRA21-1', 'Var', (55, 64))	('tumor', 'Disease', 'MESH:D009369', (6, 11))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('serum', 'MPA', (30, 35))	('tumor', 'Disease', (6, 11))
172122	28723786	However, even in the group of the 38 peripheral lung SCC with tumor long axis <=2 cm, there were 3 exceptions with nodal involvement (7.9%, pN1 in 1 patient and pN2 in 2), and the long axis of the smallest one was only 0.7 cm.	('pN2', 'Gene', (161, 164))	('SCC', 'Gene', '6317', (53, 56))	('nodal', 'Gene', (115, 120))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor long axis', 'Disease', (62, 77))	('pN2', 'Gene', '351', (161, 164))	('<=2', 'Var', (78, 81))	('pN1', 'Gene', '5270', (140, 143))	('nodal', 'Gene', '4838', (115, 120))	('SCC', 'Phenotype', 'HP:0002860', (53, 56))	('patient', 'Species', '9606', (149, 156))	('peripheral lung SCC', 'Phenotype', 'HP:0004969', (37, 56))	('SCC', 'Gene', (53, 56))	('pN1', 'Gene', (140, 143))	('tumor long axis', 'Disease', 'MESH:C566610', (62, 77))
172124	28723786	Moreover, Cho et al found that CYFRA21-1 was associated with N1 metastasis, but not with N2 metastasis in NSCLC, whereas SCC-Ag was not found to be associated with either N1 or N2 metastasis.	('NSCLC', 'Disease', 'MESH:D002289', (106, 111))	('CYFRA21-1', 'Var', (31, 40))	('SCC', 'Gene', (121, 124))	('SCC', 'Phenotype', 'HP:0002860', (121, 124))	('associated', 'Reg', (45, 55))	('NSCLC', 'Phenotype', 'HP:0030358', (106, 111))	('SCC', 'Gene', '6317', (121, 124))	('NSCLC', 'Disease', (106, 111))
172134	28723786	In addition, the level of CYFRA21-1 might also be used as a predictive factor of lymph node metastasis in lung SCC.	('SCC', 'Gene', (111, 114))	('lymph node metastasis', 'CPA', (81, 102))	('SCC', 'Phenotype', 'HP:0002860', (111, 114))	('CYFRA21-1', 'Var', (26, 35))	('SCC', 'Gene', '6317', (111, 114))
172135	28723786	Lymph node dissection or sampling is still recommended in peripheral lung SCC with tumor long axis <=2 cm, yet this needs to be further verified in prospective studies with larger study groups.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('<=2', 'Var', (99, 102))	('tumor long axis', 'Disease', 'MESH:C566610', (83, 98))	('tumor long axis', 'Disease', (83, 98))	('SCC', 'Gene', (74, 77))	('SCC', 'Phenotype', 'HP:0002860', (74, 77))	('SCC', 'Gene', '6317', (74, 77))	('peripheral lung SCC', 'Phenotype', 'HP:0004969', (58, 77))
172143	33413565	There were two methylation sites including cg01399317 and cg20519035 located at FAM83H-AS1.	('FAM83H-AS1', 'Gene', (80, 90))	('cg20519035', 'Var', (58, 68))	('cg01399317', 'Chemical', '-', (43, 53))	('FAM83H-AS1', 'Gene', '100128338', (80, 90))	('cg01399317', 'Var', (43, 53))	('cg20519035', 'Chemical', '-', (58, 68))
172144	33413565	The methylation level of cg01399317 was correlated with gene expression of FAM83H-AS1.	('methylation level', 'MPA', (4, 21))	('cg01399317', 'Var', (25, 35))	('FAM83H-AS1', 'Gene', '100128338', (75, 85))	('FAM83H-AS1', 'Gene', (75, 85))	('correlated', 'Reg', (40, 50))	('gene expression', 'MPA', (56, 71))	('cg01399317', 'Chemical', '-', (25, 35))
172198	33413565	TP53 was a ceRNA of FAM83H-AS1 and mutations in the TP53 gene are still by far the most frequent genomic event in cancer genomes.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('TP53', 'Gene', '7157', (52, 56))	('FAM83H-AS1', 'Gene', '100128338', (20, 30))	('FAM83H-AS1', 'Gene', (20, 30))	('TP53', 'Gene', (52, 56))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('mutations', 'Var', (35, 44))	('cancer', 'Disease', (114, 120))
172200	33413565	We found there were two methylation sites including cg01399317 and cg20519035 located at FAM83H-AS1 (Fig.	('cg01399317', 'Chemical', '-', (52, 62))	('FAM83H-AS1', 'Gene', '100128338', (89, 99))	('cg01399317', 'Var', (52, 62))	('FAM83H-AS1', 'Gene', (89, 99))	('cg20519035', 'Chemical', '-', (67, 77))	('cg20519035', 'Var', (67, 77))
172201	33413565	The methylation level of cg01399317 was correlated with gene expression of FAM83H-AS1 (P = 0.011, Fig.	('methylation level', 'MPA', (4, 21))	('cg01399317', 'Var', (25, 35))	('FAM83H-AS1', 'Gene', '100128338', (75, 85))	('FAM83H-AS1', 'Gene', (75, 85))	('correlated', 'Reg', (40, 50))	('gene expression', 'MPA', (56, 71))	('cg01399317', 'Chemical', '-', (25, 35))
172245	33413565	Kaplan-Meier method and log-rank test were used to evaluate the survival difference in patients with high and low expression of FER1L4.	('FER1L4', 'Gene', (128, 134))	('FER1L4', 'Gene', '80307', (128, 134))	('high', 'Var', (101, 105))	('low', 'NegReg', (110, 113))	('patients', 'Species', '9606', (87, 95))
172261	30607139	Speckle-type POZ protein functions as a tumor suppressor in non-small cell lung cancer due to DNA methylation Tumor suppressor epigenetic silencing plays an important role in non-small cell lung cancer (NSCLC) development and progression.	('epigenetic silencing', 'Var', (127, 147))	('lung cancer', 'Phenotype', 'HP:0100526', (75, 86))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (175, 201))	('non-small cell lung cancer', 'Disease', (60, 86))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('NSCLC', 'Disease', 'MESH:D002289', (203, 208))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('Tumor', 'Phenotype', 'HP:0002664', (110, 115))	('non-small cell lung cancer', 'Disease', (175, 201))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (60, 86))	('NSCLC', 'Disease', (203, 208))	('Speckle-type POZ protein', 'Gene', '8405', (0, 24))	('NSCLC', 'Phenotype', 'HP:0030358', (203, 208))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (64, 86))	('tumor', 'Disease', (40, 45))	('lung cancer', 'Phenotype', 'HP:0100526', (190, 201))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (175, 201))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (60, 86))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (179, 201))	('Speckle-type POZ protein', 'Gene', (0, 24))
172263	30607139	Our research aimed to investigate the molecular mechanisms, clinical significance and epigenetic alteration of SPOP in NSCLC.	('NSCLC', 'Disease', 'MESH:D002289', (119, 124))	('epigenetic alteration', 'Var', (86, 107))	('rat', 'Species', '10116', (101, 104))	('NSCLC', 'Phenotype', 'HP:0030358', (119, 124))	('SPOP', 'Gene', (111, 115))	('NSCLC', 'Disease', (119, 124))
172265	30607139	Furthermore, we evaluated the effects of C/EBPalpha siRNA on SPOP expression, tumor cell migration and proliferation via MTT and Transwell assays in vitro and tumor growth in vivo.	('rat', 'Species', '10116', (110, 113))	('SPOP expression', 'MPA', (61, 76))	('proliferation', 'CPA', (103, 116))	('C/EBPalpha', 'Var', (41, 51))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('rat', 'Species', '10116', (92, 95))	('tumor', 'Disease', (159, 164))	('MTT', 'Chemical', 'MESH:C070243', (121, 124))	('tumor', 'Disease', (78, 83))	('evaluated', 'Reg', (16, 25))	('tumor', 'Disease', 'MESH:D009369', (159, 164))
172266	30607139	Hypermethylation was found in the CpG island of the SPOP gene promoter in NSCLC tissues, and this methylation was found to be correlated with SPOP expression.	('SPOP', 'Disease', (142, 146))	('NSCLC', 'Phenotype', 'HP:0030358', (74, 79))	('Hypermethylation', 'Var', (0, 16))	('correlated', 'Reg', (126, 136))	('NSCLC', 'Disease', (74, 79))	('NSCLC', 'Disease', 'MESH:D002289', (74, 79))	('SPOP gene', 'Gene', (52, 61))
172267	30607139	The transcriptional activities were significantly inhibited by the hypermethylation of specific CpG sites within the SPOP gene promoter, while 5-aza-2'-deoxycytidine significantly increased SPOP gene expression.	('SPOP gene', 'Gene', (190, 199))	('transcriptional activities', 'MPA', (4, 30))	('increased', 'PosReg', (180, 189))	('inhibited', 'NegReg', (50, 59))	('hypermethylation', 'Var', (67, 83))	("5-aza-2'-deoxycytidine", 'Chemical', 'MESH:D000077209', (143, 165))	('expression', 'MPA', (200, 210))	('SPOP gene', 'Gene', (117, 126))
172275	30607139	As one of the most common epigenetic modifications in mammalian genomes, DNA methylation plays critical roles in tumorigenesis.	('tumor', 'Disease', (113, 118))	('methylation', 'Var', (77, 88))	('mammalian', 'Species', '9606', (54, 63))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('roles', 'Reg', (104, 109))
172277	30607139	Specifically, the inactivation of tumor-suppressor genes caused by hypermethylation of promoter regions has been shown to be important for the onset and progression of cancer.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('tumor', 'Disease', (34, 39))	('inactivation', 'NegReg', (18, 30))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('hypermethylation', 'Var', (67, 83))	('cancer', 'Disease', (168, 174))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
172280	30607139	Cumulative evidence indicates that ubiquitin-proteasome system dysregulation is involved in the pathogenesis of cancer.	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('dysregulation', 'Var', (63, 76))	('ubiquitin-proteasome system', 'MPA', (35, 62))	('involved', 'Reg', (80, 88))
172284	30607139	Somatic mutation analyses of cancer genomes have indicated that the SPOP gene is always mutated in several human cancers; for example, approximately 10% of prostate cancers, 8% of endometrial carcinoma and 2.2% of colorectal cancer reveal SPOP gene mutations.	('prostate cancers', 'Disease', (156, 172))	('cancer', 'Disease', (225, 231))	('cancers', 'Phenotype', 'HP:0002664', (113, 120))	('cancers', 'Disease', (113, 120))	('cancer', 'Disease', (113, 119))	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('cancers', 'Disease', 'MESH:D009369', (165, 172))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (180, 201))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (192, 201))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (180, 201))	('colorectal cancer', 'Disease', 'MESH:D015179', (214, 231))	('colorectal cancer', 'Disease', (214, 231))	('cancer', 'Disease', (29, 35))	('cancer', 'Disease', 'MESH:D009369', (225, 231))	('SPOP gene', 'Gene', (239, 248))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('cancers', 'Disease', 'MESH:D009369', (113, 120))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('prostate cancers', 'Disease', 'MESH:D011471', (156, 172))	('cancer', 'Disease', (165, 171))	('cancers', 'Phenotype', 'HP:0002664', (165, 172))	('cancers', 'Disease', (165, 172))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('human', 'Species', '9606', (107, 112))	('mutations', 'Var', (249, 258))	('colorectal cancer', 'Phenotype', 'HP:0003003', (214, 231))	('endometrial carcinoma', 'Disease', (180, 201))	('prostate cancer', 'Phenotype', 'HP:0012125', (156, 171))	('cancer', 'Disease', 'MESH:D009369', (29, 35))	('prostate cancers', 'Phenotype', 'HP:0012125', (156, 172))
172288	30607139	As mentioned above, aberrant TSG DNA hypermethylation is a hallmark of many human cancers.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('aberrant', 'Var', (20, 28))	('cancers', 'Phenotype', 'HP:0002664', (82, 89))	('TSG', 'Gene', (29, 32))	('cancers', 'Disease', (82, 89))	('human', 'Species', '9606', (76, 81))	('cancers', 'Disease', 'MESH:D009369', (82, 89))	('TSG', 'Gene', '57045', (29, 32))
172289	30607139	Taken together, we speculated that SPOP gene hypermethylation could be associated with lung cancer pathogenesis.	('SPOP gene', 'Gene', (35, 44))	('hypermethylation', 'Var', (45, 61))	('lung cancer', 'Disease', 'MESH:D008175', (87, 98))	('lung cancer', 'Disease', (87, 98))	('lung cancer', 'Phenotype', 'HP:0100526', (87, 98))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('associated', 'Reg', (71, 81))
172291	30607139	As a well-known transcription factor, C/EBPalpha induces the transcription of several lineage-specific genes, such as G-CSF-R and PPARgamma.	('induces', 'PosReg', (49, 56))	('G-CSF-R', 'Gene', (118, 125))	('C/EBPalpha', 'Var', (38, 48))	('PPARgamma', 'Gene', (130, 139))	('PPARgamma', 'Gene', '5468', (130, 139))	('transcription', 'MPA', (61, 74))	('G-CSF-R', 'Gene', '1441', (118, 125))
172293	30607139	However, the mechanism how C/EBPalpha inhibits tumor progression is still unclear.	('C/EBPalpha', 'Var', (27, 37))	('inhibits', 'NegReg', (38, 46))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor', 'Disease', (47, 52))
172295	30607139	Furthermore, we demonstrated that SPOP is transcriptionally activated by C/EBPalpha, while CpG island methylation in the promoter region of SPOP leads to C/EBPalpha binding abrogation.	('SPOP', 'Gene', (34, 38))	('binding', 'Interaction', (165, 172))	('methylation', 'Var', (102, 113))	('rat', 'Species', '10116', (23, 26))	('activated', 'PosReg', (60, 69))	('abrogation', 'NegReg', (173, 183))	('C/EBPalpha', 'Var', (73, 83))
172311	30607139	This modification converted unmethylated cytosine to thymine, while methylated cytosine remained unchanged.	('modification', 'Var', (5, 17))	('thymine', 'Chemical', 'MESH:D013941', (53, 60))	('converted', 'Reg', (18, 27))	('cytosine', 'Chemical', 'MESH:D003596', (41, 49))	('cytosine', 'Chemical', 'MESH:D003596', (79, 87))	('thymine', 'MPA', (53, 60))
172334	30607139	The fragment was cloned into plasmid pGL3-Basic vectors named pGL-C5 (- 1208/+ 110), pGL-C4 (- 932/+ 73), pGL-C3 (- 720/+ 73), and pGL-C2 (- 312/+ 73), which were created by PCR.	('- 720/+ 73', 'Var', (114, 124))	('pGL-C2', 'Disease', (131, 137))	('pGL3', 'Gene', (37, 41))	('pGL-C2', 'Disease', 'OMIM:217000', (131, 137))	('pGL3', 'Gene', '6391', (37, 41))	('- 932/+ 73', 'Var', (93, 103))
172365	30607139	The MSP of NSCLC showed that SPOP promoter methylation was found in 61 of the 82 NSCLC patients and was associated with the pathology grade, while no correlation was found between the SPOP promoter methylation extent and age, gender, histologic type, smoking status, staging, and lymph node metastasis (Table 1).	('NSCLC', 'Disease', (11, 16))	('SPOP promoter', 'Gene', (29, 42))	('methylation', 'Var', (43, 54))	('NSCLC', 'Disease', 'MESH:D002289', (11, 16))	('NSCLC', 'Phenotype', 'HP:0030358', (81, 86))	('associated', 'Reg', (104, 114))	('NSCLC', 'Phenotype', 'HP:0030358', (11, 16))	('found', 'Reg', (59, 64))	('NSCLC', 'Disease', (81, 86))	('lymph node metastasis', 'Disease', (280, 301))	('lymph node metastasis', 'Disease', 'MESH:D009362', (280, 301))	('patients', 'Species', '9606', (87, 95))	('NSCLC', 'Disease', 'MESH:D002289', (81, 86))
172375	30607139	These results indicate that SPOP promoter region methylation leads to SPOP suppression in lung cancer cell lines.	('lung cancer', 'Disease', 'MESH:D008175', (90, 101))	('lung cancer', 'Disease', (90, 101))	('lung cancer', 'Phenotype', 'HP:0100526', (90, 101))	('methylation', 'Var', (49, 60))	('SPOP suppression', 'CPA', (70, 86))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))
172382	30607139	The deletion of the region containing only the - 312 to + 110 site (pGL3-C2) also caused a significant decrease in SPOP gene promoter activity with C/EBPalpha inhibition.	('SPOP gene', 'Gene', (115, 124))	('deletion', 'Var', (4, 12))	('pGL3', 'Gene', (68, 72))	('decrease', 'NegReg', (103, 111))	('pGL3', 'Gene', '6391', (68, 72))
172383	30607139	The deletion constructs pGL3-C3 and pGL3-C4 in the siC/EBPalpha-transfected cells also revealed lower promoter activity at levels similar to those observed in the control cells, which expressed endogenous C/EBPalpha (Fig.	('lower', 'NegReg', (96, 101))	('pGL3', 'Gene', (36, 40))	('promoter activity', 'MPA', (102, 119))	('pGL3', 'Gene', '6391', (24, 28))	('pGL3', 'Gene', '6391', (36, 40))	('deletion', 'Var', (4, 12))	('pGL3', 'Gene', (24, 28))
172384	30607139	To determine whether the three identified C/EBPalpha binding sites play a role in the transcriptional activation of SPOP, we individually generated substitution mutations of the sites (pGL3-MT1, pGL3-MT2, and pGL3-MT5).	('SPOP', 'Gene', (116, 120))	('MT2', 'Gene', '4502', (200, 203))	('MT2', 'Gene', (200, 203))	('substitution mutations', 'Var', (148, 170))	('pGL3', 'Gene', '6391', (195, 199))	('pGL3', 'Gene', '6391', (209, 213))	('pGL3', 'Gene', '6391', (185, 189))	('rat', 'Species', '10116', (142, 145))	('MT1', 'Gene', (190, 193))	('MT1', 'Gene', '644314', (190, 193))	('pGL3', 'Gene', (195, 199))	('pGL3', 'Gene', (209, 213))	('pGL3', 'Gene', (185, 189))
172391	30607139	Conversely, when the H1299 cells were cotransfected with siC/EBPalpha and the SPOP expression plasmid or vector control, the increased cell proliferation by the C/EBPalpha depletion was reversed by the SPOP expression plasmid transfection (Fig.	('increased', 'PosReg', (125, 134))	('C/EBPalpha', 'Var', (161, 171))	('depletion', 'NegReg', (172, 181))	('rat', 'Species', '10116', (147, 150))	('cell proliferation', 'CPA', (135, 153))	('H1299', 'CellLine', 'CVCL:0060', (21, 26))
172392	30607139	The C/EBPalpha depletion also inhibited SPOP expression in the H1299 cells (Fig.	('depletion', 'Var', (15, 24))	('inhibited', 'NegReg', (30, 39))	('SPOP expression', 'CPA', (40, 55))	('H1299', 'CellLine', 'CVCL:0060', (63, 68))
172399	30607139	The results demonstrated that the C/EBPalpha depletion significantly promoted xenograft tumor growth.	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('C/EBPalpha', 'Gene', (34, 44))	('rat', 'Species', '10116', (19, 22))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('promoted', 'PosReg', (69, 77))	('depletion', 'Var', (45, 54))	('tumor', 'Disease', (88, 93))
172400	30607139	These data also show that SPOP is essential for the C/EBPalpha-regulated suppression of tumor growth in vivo.	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('suppression', 'NegReg', (73, 84))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('C/EBPalpha-regulated', 'Var', (52, 72))	('tumor', 'Disease', (88, 93))
172407	30607139	This tumor suppressor effect is abrogated by prostate cancer associated SPOP mutations.	('prostate cancer', 'Disease', 'MESH:D011471', (45, 60))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('prostate cancer', 'Phenotype', 'HP:0012125', (45, 60))	('SPOP', 'Gene', (72, 76))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('abrogated', 'NegReg', (32, 41))	('mutations', 'Var', (77, 86))	('tumor', 'Disease', (5, 10))	('prostate cancer', 'Disease', (45, 60))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
172413	30607139	Numerous studies suggest that the hypermethylation of specific genes, mainly tumor suppressor genes, is associated with the onset and progression of lung cancer.	('lung cancer', 'Disease', 'MESH:D008175', (149, 160))	('hypermethylation', 'Var', (34, 50))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('associated with', 'Reg', (104, 119))	('lung cancer', 'Phenotype', 'HP:0100526', (149, 160))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('lung cancer', 'Disease', (149, 160))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('tumor', 'Disease', (77, 82))
172418	30607139	The methylation of the SPOP gene was only associated with the pathology grade of NSCLC, suggesting that the SPOP gene could play a more significant role in NSCLC tissue differentiation.	('associated', 'Reg', (42, 52))	('NSCLC', 'Phenotype', 'HP:0030358', (156, 161))	('NSCLC', 'Phenotype', 'HP:0030358', (81, 86))	('SPOP gene', 'Gene', (23, 32))	('methylation', 'Var', (4, 15))	('NSCLC', 'Disease', 'MESH:D002289', (81, 86))	('NSCLC', 'Disease', (81, 86))	('NSCLC', 'Disease', (156, 161))	('NSCLC', 'Disease', 'MESH:D002289', (156, 161))	('play', 'Reg', (124, 128))
172419	30607139	However, gender, age, histologic type, smoking status, staging and lymph node metastasis were not significantly associated with SPOP gene methylation in NSCLC tissues.	('NSCLC', 'Phenotype', 'HP:0030358', (153, 158))	('SPOP gene', 'Gene', (128, 137))	('lymph node metastasis', 'Disease', 'MESH:D009362', (67, 88))	('NSCLC', 'Disease', (153, 158))	('methylation', 'Var', (138, 149))	('NSCLC', 'Disease', 'MESH:D002289', (153, 158))	('lymph node metastasis', 'Disease', (67, 88))
172421	30607139	Therefore, SPOP gene methylation may be associated with poor NSCLC patient outcomes and can be a potential predictive biomarker for prognosis.	('patient', 'Species', '9606', (67, 74))	('NSCLC', 'Phenotype', 'HP:0030358', (61, 66))	('methylation', 'Var', (21, 32))	('NSCLC', 'Disease', (61, 66))	('NSCLC', 'Disease', 'MESH:D002289', (61, 66))	('associated', 'Reg', (40, 50))	('SPOP gene', 'Gene', (11, 20))
172422	30607139	We treated hypermethylated cell lines (A427 and H-1299 cells) with AZA, which is a well-known DNMT inhibitor, to confirm that CpG island methylation was indeed responsible for the decreased SPOP expression.	('SPOP expression', 'CPA', (190, 205))	('DNMT', 'Gene', '1786', (94, 98))	('methylation', 'Var', (137, 148))	('DNMT', 'Gene', (94, 98))	('decreased', 'NegReg', (180, 189))	('H-1299', 'CellLine', 'CVCL:0060', (48, 54))	('AZA', 'Chemical', 'MESH:D000077209', (67, 70))
172425	30607139	Subsequently, we found that epigenetically silenced SPOP mRNA and protein expression gradually reactivates after treatment with AZA at an increasing concentration.	('rat', 'Species', '10116', (156, 159))	('reactivates', 'NegReg', (95, 106))	('SPOP', 'Gene', (52, 56))	('AZA', 'Chemical', 'MESH:D000077209', (128, 131))	('epigenetically silenced', 'Var', (28, 51))
172426	30607139	These results demonstrate that the hypermethylation of the SPOP gene promoter directly contributes to SPOP silencing in NSCLC cells.	('SPOP', 'Gene', (102, 106))	('hypermethylation', 'Var', (35, 51))	('NSCLC', 'Disease', 'MESH:D002289', (120, 125))	('NSCLC', 'Phenotype', 'HP:0030358', (120, 125))	('rat', 'Species', '10116', (21, 24))	('SPOP gene', 'Gene', (59, 68))	('NSCLC', 'Disease', (120, 125))	('silencing', 'NegReg', (107, 116))
172429	30607139	Second, methylated cytosine residues can prevent transcription factors from binding their binding elements in the promoter region.	('cytosine', 'Chemical', 'MESH:D003596', (19, 27))	('prevent', 'NegReg', (41, 48))	('binding', 'Interaction', (90, 97))	('binding', 'Interaction', (76, 83))	('methylated', 'Var', (8, 18))
172430	30607139	We demonstrated that C/EBPalpha is an important SPOP transcriptional regulator and that CpG site methylation within the C/EBPalpha binding element interfered with the binding affinity.	('methylation', 'Var', (97, 108))	('interfered', 'NegReg', (147, 157))	('rat', 'Species', '10116', (10, 13))	('binding affinity', 'Interaction', (167, 183))
172431	30607139	The ChIP results demonstrated that C/EBPalpha clearly binds the SPOP gene promoter, and the sequential deletion and substitution mutation analyses demonstrated that three sites (- 1144 to - 1135, - 815 to - 806 and + 55 to + 64) are essential for C/EBPalpha-regulated SPOP gene promoter activity.	('SPOP', 'Gene', (268, 272))	('rat', 'Species', '10116', (154, 157))	('- 1144 to - 1135', 'Var', (178, 194))	('rat', 'Species', '10116', (24, 27))	('SPOP', 'Gene', (64, 68))
172433	30607139	Our study is the first to show that the CpG island in the SPOP gene promoter in NSCLC is hypermethylated and that abnormal methylation is only associated with the pathology state of NSCLC.	('NSCLC', 'Phenotype', 'HP:0030358', (80, 85))	('associated', 'Reg', (143, 153))	('NSCLC', 'Disease', (182, 187))	('NSCLC', 'Disease', 'MESH:D002289', (182, 187))	('NSCLC', 'Disease', (80, 85))	('hypermethylated', 'Var', (89, 104))	('NSCLC', 'Disease', 'MESH:D002289', (80, 85))	('NSCLC', 'Phenotype', 'HP:0030358', (182, 187))	('SPOP gene', 'Gene', (58, 67))
172503	29473326	For example, consider a 62-year-old T2N1MX HNSCC patient with MiR score equal to 0.8 who received radiotherapy, the total points for this patient is 0 + 9 + 14 + 45 = 65.	('MiR', 'Gene', (62, 65))	('T2N1MX', 'Var', (36, 42))	('MiR', 'Gene', '220972', (62, 65))	('patient', 'Species', '9606', (49, 56))	('patient', 'Species', '9606', (138, 145))	('HNSCC', 'Phenotype', 'HP:0012288', (43, 48))
172510	29473326	For the radioresistant subset of patients, radiotherapy has no benefit and may also introduce undesirable side effects and compromises their quality of life.	('radiotherapy', 'Var', (43, 55))	('quality of life', 'CPA', (141, 156))	('patients', 'Species', '9606', (33, 41))	('compromises', 'NegReg', (123, 134))
172546	26529033	A single HPV16 DNA+ tumor additionally harbored HPV16 E6*I mRNA but was p16INK4a negative (HPV16 E1 seropositive patient).	('patient', 'Species', '9606', (113, 120))	('HPV16', 'Species', '333760', (91, 96))	('p16INK4a', 'Gene', '1029', (72, 80))	('HPV16 E6*I', 'Var', (48, 58))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('HPV16', 'Species', '333760', (9, 14))	('HPV16', 'Species', '333760', (48, 53))	('sero', 'Chemical', '-', (100, 104))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('p16INK4a', 'Gene', (72, 80))	('HPV16', 'Gene', (9, 14))	('tumor', 'Disease', (20, 25))
172568	26529033	In addition to HPV functional markers that can be assessed in tumor tissues, antibodies to HPV early proteins, especially E6 and E7, have been demonstrated to be markers for HPV-driven SCC of the cervix, penis, and oropharynx.	('antibodies', 'Var', (77, 87))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', (62, 67))	('SCC', 'Disease', (185, 188))	('HPV early', 'Gene', (91, 100))	('HPV', 'Species', '10566', (15, 18))	('markers', 'Reg', (162, 169))	('HPV', 'Species', '10566', (91, 94))	('HPV', 'Species', '10566', (174, 177))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
172575	26529033	Of these 1,561 ESCC patients, 357 were seropositive to at least one of the sixteen HPV early proteins from the eight most prevalent HR-HPV types: HPV16 (E1, E2, E6, E7); HPV18 (E6, E7); HPV31, 33, 35, 45, 52, and 58 (E6); or LR-HPV types 6 and 11 (E6, E7).	('ESCC', 'Disease', (15, 19))	('HR-HPV', 'Disease', (132, 138))	('sero', 'Chemical', '-', (39, 43))	('HPV', 'Species', '10566', (83, 86))	('HPV', 'Species', '10566', (146, 149))	('HPV', 'Species', '10566', (228, 231))	('HPV', 'Species', '10566', (170, 173))	('patients', 'Species', '9606', (20, 28))	('HPV', 'Species', '10566', (135, 138))	('HPV', 'Species', '10566', (186, 189))	('HPV31', 'Var', (186, 191))	('HPV16', 'Species', '333760', (146, 151))	('HR-HPV', 'Disease', 'MESH:D030361', (132, 138))
172604	26529033	All 133 ESCC patients' tissues were analyzed for the presence of: (i) HPV16 E6*I mRNA, (ii) ubC mRNA as a cellular mRNA positive control, and (iii) mRNA of the non-HPV16 types determined by genotyping and/or serological assays.	('E6*I', 'Var', (76, 80))	('ESCC', 'Disease', (8, 12))	('ubC', 'Chemical', '-', (92, 95))	('patients', 'Species', '9606', (13, 21))	('HPV16', 'Species', '333760', (164, 169))	('HPV16', 'Gene', (70, 75))	('HPV16', 'Species', '333760', (70, 75))	('sero', 'Chemical', '-', (208, 212))
172609	26529033	Each staining batch included tissue sections for HPV16 DNA+/RNA+ cervical cancer, and HPV DNA-negative (HPV DNA-) normal oral epithelium, which served to control for intra- and inter-day staining reproducibility and protocol performance.	('HPV', 'Species', '10566', (86, 89))	('HPV', 'Species', '10566', (104, 107))	('HPV', 'Species', '10566', (49, 52))	('cervical cancer', 'Disease', (65, 80))	('HPV16 DNA+/RNA+', 'Var', (49, 64))	('cervical cancer', 'Disease', 'MESH:D002583', (65, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('HPV16', 'Species', '333760', (49, 54))
172624	26529033	BSGP5+6+-PCR/MPG yielded 74/118 (63%), TS-E7-PCR/MPG 115/118 (97%), and HPV16/18 qRT-PCR 106/118 (90%) DNA valid samples (Table 1, Supplementary Table S1).	('MPG', 'Gene', (13, 16))	('MPG', 'Gene', '4350', (49, 52))	('HPV16/18', 'Var', (72, 80))	('MPG', 'Gene', (49, 52))	('HPV16', 'Species', '333760', (72, 77))	('men', 'Species', '9606', (137, 140))	('MPG', 'Gene', '4350', (13, 16))
172628	26529033	HPV types identified were: HPV16 (four tumors); HPV33, 35, 45 (one tumor each), HPV11 (two tumors); and HPV16, 70 double infection (one tumor) (Table 2).	('tumors', 'Disease', 'MESH:D009369', (91, 97))	('HPV11', 'Species', '10580', (80, 85))	('infection', 'Disease', (121, 130))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('infection', 'Disease', 'MESH:D007239', (121, 130))	('tumor', 'Disease', (67, 72))	('tumor', 'Disease', (91, 96))	('tumors', 'Disease', (39, 45))	('HPV16', 'Var', (104, 109))	('HPV', 'Species', '10566', (27, 30))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('HPV16', 'Species', '333760', (27, 32))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('tumor', 'Disease', (136, 141))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('HPV', 'Species', '10566', (104, 107))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor', 'Disease', (39, 44))	('HPV11', 'Var', (80, 85))	('HPV16', 'Species', '333760', (104, 109))	('tumors', 'Disease', (91, 97))	('HPV', 'Species', '10566', (0, 3))	('HPV', 'Species', '10566', (48, 51))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('HPV', 'Species', '10566', (80, 83))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('HPV16', 'Var', (27, 32))	('HPV33', 'Var', (48, 53))
172629	26529033	Of the 118 tissues analyzed in a total of 170 RNA reactions (118 reactions for HPV16 and ubC and 52 additional reactions performed for a non-HPV16 type determined by genotyping or serological assays), a single tissue positive for HPV16 DNA exclusively by TS-E7-PCR/MPG also expressed HPV16 E6*I mRNA (Table 2).	('MPG', 'Gene', '4350', (265, 268))	('E6*I mRNA', 'Var', (290, 299))	('HPV16', 'Gene', (284, 289))	('ubC', 'Chemical', '-', (89, 92))	('HPV16', 'Species', '333760', (284, 289))	('MPG', 'Gene', (265, 268))	('HPV16', 'Gene', (230, 235))	('HPV16', 'Species', '333760', (230, 235))	('HPV16', 'Species', '333760', (79, 84))	('sero', 'Chemical', '-', (180, 184))	('HPV16', 'Species', '333760', (141, 146))
172639	26529033	Interestingly, only 33% of patients with HPV DNA- tumors were female, in contrast to the 70% females among patients with HPV DNA+ tumors (p=0.019).	('tumors', 'Disease', (130, 136))	('tumors', 'Disease', 'MESH:D009369', (130, 136))	('HPV', 'Species', '10566', (41, 44))	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('HPV', 'Var', (41, 44))	('HPV', 'Species', '10566', (121, 124))	('patients', 'Species', '9606', (27, 35))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('tumors', 'Disease', (50, 56))	('patients', 'Species', '9606', (107, 115))
172648	26529033	None of the tumors that were positive for other HPV DNA types (HPV33, 35, 45, 70, or 11) showed type-concordant E6*I or E6 fl mRNA.	('HPV', 'Species', '10566', (48, 51))	('HPV', 'Species', '10566', (63, 66))	('E6 fl mRNA', 'Var', (120, 130))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('E6*I', 'Var', (112, 116))	('tumors', 'Disease', (12, 18))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('tumors', 'Disease', 'MESH:D009369', (12, 18))
172651	26529033	(i) viral load 1 copy per cell, (ii) presence of HPV type-concordant E6*I mRNA, and (iii) up-regulation of the cellular surrogate marker p16INK4a), none was positive for all three or even two functional markers.	('E6*I', 'Var', (69, 73))	('up-regulation', 'PosReg', (90, 103))	('p16INK4a', 'Gene', (137, 145))	('HPV', 'Species', '10566', (49, 52))	('viral load', 'MPA', (4, 14))	('p16INK4a', 'Gene', '1029', (137, 145))	('presence', 'Reg', (37, 45))
172652	26529033	Of the two HPV16 DNA+ tissues that displayed at least one functional marker, one harbored HPV16 mRNA but without p16INK4a up-regulation and the other showed up-regulated p16INK4a in the absence of HPV16 transcription.	('HPV16', 'Gene', (90, 95))	('HPV16', 'Species', '333760', (197, 202))	('p16INK4a', 'Gene', (113, 121))	('p16INK4a', 'Gene', '1029', (170, 178))	('p16INK4a', 'Gene', '1029', (113, 121))	('mRNA', 'Var', (96, 100))	('HPV16', 'Species', '333760', (11, 16))	('up-regulated', 'PosReg', (157, 169))	('HPV16', 'Species', '333760', (90, 95))	('p16INK4a', 'Gene', (170, 178))
172676	26529033	We found a single HPV16 DNA+ ESCC tumor that expressed HPV16 mRNA, however, without p16INK4a up-regulation.	('tumor', 'Disease', (34, 39))	('p16INK4a', 'Gene', (84, 92))	('p16INK4a', 'Gene', '1029', (84, 92))	('HPV16', 'Species', '333760', (18, 23))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('HPV16', 'Species', '333760', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('HPV16 mRNA', 'Var', (55, 65))
172677	26529033	HPV16 E6*I transcripts can be abundantly expressed in the cervix in the absence of malignant transformation, as well as in some non-HPV-driven oropharyngeal and laryngeal cancers.	('HPV', 'Species', '10566', (0, 3))	('HPV16', 'Species', '333760', (0, 5))	('HPV', 'Species', '10566', (132, 135))	('laryngeal cancers', 'Disease', 'MESH:D007822', (161, 178))	('laryngeal cancers', 'Phenotype', 'HP:0012118', (161, 178))	('HPV16', 'Gene', (0, 5))	('cancers', 'Phenotype', 'HP:0002664', (171, 178))	('laryngeal cancers', 'Disease', (161, 178))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('E6*I', 'Var', (6, 10))
172678	26529033	The E6*I transcripts are, therefore, markers of active viral infection but are not transformation-specific; thus we did not consider this single low viral load HPV DNA+/RNA+ ESCC an HPV-driven tumor.	('HPV', 'Species', '10566', (182, 185))	('active viral infection', 'Disease', (48, 70))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('active viral infection', 'Disease', 'MESH:D001102', (48, 70))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('HPV', 'Species', '10566', (160, 163))	('tumor', 'Disease', (193, 198))	('E6*I', 'Var', (4, 8))
172687	26529033	Lack of CDKN2a mutations in combination with p16INK4a up-regulation was demonstrated for HPV RNA+ cervical cancers and cervical cancer cell lines, as well as for the HPV RNA+ tumors of the head-and-neck including oral, oropharyngeal and laryngeal tumors.	('tumor', 'Phenotype', 'HP:0002664', (247, 252))	('tumors', 'Disease', (175, 181))	('cervical cancers', 'Disease', (98, 114))	('tumors', 'Disease', (247, 253))	('cervical cancer', 'Disease', 'MESH:D002583', (119, 134))	('laryngeal tumors', 'Disease', 'MESH:D007822', (237, 253))	('oropharyngeal and laryngeal tumors', 'Phenotype', 'HP:0100638', (219, 253))	('cervical cancers', 'Disease', 'MESH:D002583', (98, 114))	('cervical cancer', 'Disease', (119, 134))	('p16INK4a', 'Gene', (45, 53))	('oral', 'Disease', (213, 217))	('tumors', 'Disease', 'MESH:D009369', (175, 181))	('laryngeal tumors', 'Disease', (237, 253))	('tumors', 'Disease', 'MESH:D009369', (247, 253))	('laryngeal tumors', 'Phenotype', 'HP:0012118', (237, 253))	('mutations', 'Var', (15, 24))	('up-regulation', 'PosReg', (54, 67))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('HPV', 'Species', '10566', (89, 92))	('p16INK4a', 'Gene', '1029', (45, 53))	('CDKN2a', 'Gene', (8, 14))	('tumors', 'Phenotype', 'HP:0002664', (175, 181))	('tumors', 'Phenotype', 'HP:0002664', (247, 253))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('tumors of the head-and-neck', 'Phenotype', 'HP:0012288', (175, 202))	('cervical cancer', 'Disease', 'MESH:D002583', (98, 113))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('HPV', 'Species', '10566', (166, 169))	('oropharyngeal', 'Disease', (219, 232))	('cancers', 'Phenotype', 'HP:0002664', (107, 114))
172691	26529033	For the one case with HPV16 DNA+ ESCC with p16INK4a up-regulation in our study, the low viral load and absence of HPV16 E6*I mRNA do not support classification of this case as HPV16-driven.	('up-regulation', 'PosReg', (52, 65))	('HPV16', 'Species', '333760', (22, 27))	('HPV16', 'Gene', (114, 119))	('p16INK4a', 'Gene', (43, 51))	('p16INK4a', 'Gene', '1029', (43, 51))	('E6*I', 'Var', (120, 124))	('HPV16', 'Species', '333760', (176, 181))	('HPV16', 'Species', '333760', (114, 119))	('viral load', 'MPA', (88, 98))
172693	26529033	Two studies found p16INK4a positivity statistically significantly associated with HPV DNA+ ESCC.	('p16INK4a', 'Gene', '1029', (18, 26))	('positivity', 'Var', (27, 37))	('associated', 'Reg', (66, 76))	('p16INK4a', 'Gene', (18, 26))	('HPV DNA+ ESCC', 'Disease', (82, 95))	('HPV', 'Species', '10566', (82, 85))
172695	26529033	Castillo and colleagues used 10% as a cut-off to define p16INK4a positivity and reported high p16INK4a positivity in both HPV DNA+ (56%) and HPV DNA- tissues (33%).	('positivity', 'MPA', (103, 113))	('HPV', 'Species', '10566', (122, 125))	('HPV', 'Species', '10566', (141, 144))	('p16INK4a', 'Gene', '1029', (56, 64))	('positivity', 'Var', (65, 75))	('p16INK4a', 'Gene', '1029', (94, 102))	('p16INK4a', 'Gene', (56, 64))	('p16INK4a', 'Gene', (94, 102))
172707	26529033	More precisely, HPV16 E6 seropositivity was present in prediagnostic samples of 35% of OPSCC patients and 0.6% controls (OR, 274; 95% CI 110 to 681) but was not associated with cancer at other sites including esophagus.	('esophagus', 'Disease', (209, 218))	('HPV16', 'Species', '333760', (16, 21))	('cancer', 'Disease', (177, 183))	('cancer', 'Disease', 'MESH:D009369', (177, 183))	('E6 seropositivity', 'Var', (22, 39))	('associated', 'Reg', (161, 171))	('OPSCC', 'Phenotype', 'HP:0012182', (87, 92))	('HPV16', 'Gene', (16, 21))	('OPSCC', 'Disease', (87, 92))	('sero', 'Chemical', '-', (25, 29))	('seropositivity', 'Var', (25, 39))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('patients', 'Species', '9606', (93, 101))
172716	28123547	CEP55 overexpression predicts poor prognosis in patients with locally advanced esophageal squamous cell carcinoma Development of esophageal squamous cell carcinoma (ESCC) involves alterations in multiple genes with corresponding proteins.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (90, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('men', 'Species', '9606', (121, 124))	('alterations', 'Var', (180, 191))	('CEP55', 'Gene', '55165', (0, 5))	('esophageal squamous cell carcinoma', 'Disease', (79, 113))	('CEP55', 'Gene', (0, 5))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (129, 163))	('proteins', 'Protein', (229, 237))	('overexpression', 'PosReg', (6, 20))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (140, 163))	('carcinoma', 'Phenotype', 'HP:0030731', (154, 163))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (79, 113))	('patients', 'Species', '9606', (48, 56))	('esophageal squamous cell carcinoma', 'Disease', (129, 163))
172723	28123547	Overexpression of CEP55 was significantly associated with differentiation degree (P=0.022), T stage (P=0.019), lymph node metastasis (P=0.033), clinicopathological staging (P=0.002) and tumor recurrence (P=0.021) in locally advanced ESCC patients.	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('T stage', 'CPA', (92, 99))	('lymph node metastasis', 'CPA', (111, 132))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('associated', 'Reg', (42, 52))	('tumor', 'Disease', (186, 191))	('locally advanced ESCC', 'Disease', (216, 237))	('CEP55', 'Gene', '55165', (18, 23))	('Overexpression', 'Var', (0, 14))	('CEP55', 'Gene', (18, 23))	('ESCC', 'Disease', (233, 237))	('differentiation degree', 'CPA', (58, 80))	('patients', 'Species', '9606', (238, 246))
172733	28123547	In our previous study, some molecular indicators (including C-C chemokine receptor type 7 and vascular endothelial growth factor-C) were identified that may be useful to predict lymphatic metastatic recurrence in pN0 esophageal squamous cell carcinoma.	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (217, 251))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (228, 251))	('carcinoma', 'Phenotype', 'HP:0030731', (242, 251))	('lymphatic metastatic recurrence', 'CPA', (178, 209))	('esophageal squamous cell carcinoma', 'Disease', (217, 251))	('C-C chemokine receptor type 7 and vascular endothelial growth factor-C', 'Gene', '1236;7424', (60, 130))	('pN0', 'Var', (213, 216))
172737	28123547	Overexpression of CEP55 leads to cytokinesis defects and multinucleated cells increase, which may cause tumorigenesis.	('cause', 'Reg', (98, 103))	('cytokinesis defects', 'CPA', (33, 52))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumor', 'Disease', (104, 109))	('increase', 'PosReg', (78, 86))	('CEP55', 'Gene', '55165', (18, 23))	('Overexpression', 'Var', (0, 14))	('CEP55', 'Gene', (18, 23))	('multinucleated cells', 'CPA', (57, 77))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
172739	28123547	Overexpression of CEP55 in mammalian cells correlates with increased cell migration and invasion.	('mammalian', 'Species', '9606', (27, 36))	('invasion', 'CPA', (88, 96))	('cell migration', 'CPA', (69, 83))	('CEP55', 'Gene', '55165', (18, 23))	('Overexpression', 'Var', (0, 14))	('CEP55', 'Gene', (18, 23))	('increased', 'PosReg', (59, 68))
172779	28123547	Typically, patients with pT3-4 are advised to receive radiotherapy and those with pN1 should receive chemotherapy as a minimum.	('patients', 'Species', '9606', (11, 19))	('pN1', 'Gene', (82, 85))	('pN1', 'Gene', '5270', (82, 85))	('pT3-4', 'Var', (25, 30))
172826	28123547	Failure of cytokinesis results in tetraploid cells, which are chromosomally unstable and hence more prone to tumorigenesis.	('prone', 'Reg', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('results in', 'Reg', (23, 33))	('tetraploid cells', 'Var', (34, 50))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumor', 'Disease', (109, 114))
172827	28123547	Overexpression of CEP55 causes cytokinesis defects via an increase of chromosomally unstable binucleated cells, suggesting CEP55 overexpression is associated with tumorigenesis.	('increase', 'PosReg', (58, 66))	('associated', 'Reg', (147, 157))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('overexpression', 'PosReg', (129, 143))	('chromosomally unstable binucleated cells', 'CPA', (70, 110))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('cytokinesis defects', 'CPA', (31, 50))	('CEP55', 'Gene', '55165', (123, 128))	('CEP55', 'Gene', (123, 128))	('Overexpression', 'Var', (0, 14))	('CEP55', 'Gene', (18, 23))	('tumor', 'Disease', (163, 168))	('CEP55', 'Gene', '55165', (18, 23))
172837	28123547	Further research should be performed to identify whether knockdown of the CEP55 gene can retard the invasiveness of ESCC cells.	('CEP55', 'Gene', '55165', (74, 79))	('CEP55', 'Gene', (74, 79))	('retard', 'NegReg', (89, 95))	('invasiveness of ESCC cells', 'CPA', (100, 126))	('knockdown', 'Var', (57, 66))
172853	33912192	Drugs targeting this negative immune regulatory pathway, including the anti-PD-1 monoclonal antibodies (mAbs) nivolumab, pembrolizumab, and cemiplimab and the anti-PD-L1 mAbs atezolizumab, avelumab, and durvalumab have been approved for the treatment of various cancer types.	('cancer', 'Disease', (262, 268))	('PD-L1 mAbs atezolizumab', 'Disease', (164, 187))	('pembrolizumab', 'Chemical', 'MESH:C582435', (121, 134))	('avelumab', 'Chemical', 'MESH:C000609138', (189, 197))	('cemiplimab', 'Chemical', 'MESH:C000627974', (140, 150))	('cancer', 'Phenotype', 'HP:0002664', (262, 268))	('durvalumab', 'Chemical', 'MESH:C000613593', (203, 213))	('negative immune regulatory pathway', 'Pathway', (21, 55))	('cancer', 'Disease', 'MESH:D009369', (262, 268))	('PD-L1 mAbs atezolizumab', 'Disease', 'MESH:D010300', (164, 187))	('nivolumab', 'Chemical', 'MESH:D000077594', (110, 119))	('anti-PD-1', 'Var', (71, 80))
172859	33912192	Microsatellite instability has been considered a common response biomarker to monitor a variety of solid tumors treated with pembrolizumab, which was approved by the FDA.	('Microsatellite', 'Var', (0, 14))	('pembrolizumab', 'Chemical', 'MESH:C582435', (125, 138))	('solid tumors', 'Disease', 'MESH:D009369', (99, 111))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('solid tumors', 'Disease', (99, 111))
172894	33912192	The stepwise Akaike's information criterion regression analysis revealed that cytokine combinations I and II were the most predictive of the S0+S1 and S0+S1+S2 samples in the R/NR ( Supplementary Table 3 ) and CB/NCB groups ( Supplementary Table 4 ), respectively.	('S0+S1', 'Var', (141, 146))	('S0+S1+S2', 'Var', (151, 159))	('NCB', 'Chemical', '-', (213, 216))
172980	31923345	Although these advances resulted in more refined diagnoses and classifications of glioma tumors, integrating histological and molecular information (e.g., IDH1/2 mutations and 1p/19q codeletion) (Louis et al., 2016), significant improvements in therapies that truly impact on patient outcomes are still lacking.	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('mutations', 'Var', (162, 171))	('glioma', 'Phenotype', 'HP:0009733', (82, 88))	('patient', 'Species', '9606', (276, 283))	('IDH1/2', 'Gene', '3417;3418', (155, 161))	('glioma tumors', 'Disease', (82, 95))	('glioma tumors', 'Disease', 'MESH:D005910', (82, 95))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('IDH1/2', 'Gene', (155, 161))
172982	31923345	Functionally, WNT6 expression was associated with increased GBM cell viability, proliferation, invasion, migration, resistance to TMZ, and stemness capacity (Goncalves et al., 2018).	('resistance to TMZ', 'CPA', (116, 133))	('invasion', 'CPA', (95, 103))	('stemness capacity', 'CPA', (139, 156))	('GBM', 'Phenotype', 'HP:0012174', (60, 63))	('GBM cell viability', 'CPA', (60, 78))	('increased', 'PosReg', (50, 59))	('expression', 'Var', (19, 29))	('proliferation', 'CPA', (80, 93))	('migration', 'CPA', (105, 114))	('TMZ', 'Chemical', 'MESH:D000077204', (130, 133))	('WNT6', 'Gene', (14, 18))
172983	31923345	In vivo, WNT6 accelerated GBM-associated death in mice.	('GBM', 'Phenotype', 'HP:0012174', (26, 29))	('WNT6', 'Var', (9, 13))	('death', 'Disease', 'MESH:D003643', (41, 46))	('death', 'Disease', (41, 46))	('mice', 'Species', '10090', (50, 54))	('accelerated', 'PosReg', (14, 25))
172987	31923345	Agilent G4502A 244K data were used for LGG and GBM (WNT6 and HOXA9-high expression was considered when TCGA level 3 value >= 0 [GBM median value] or 3, respectively), while RNAseq data (Illumina HiSeq 2000 Sequencing System) were downloaded for all cancers (WNT6-high expression was considered when TCGA FPKM-UQ value >= 6800 [GBM median value]) (The Cancer Genome Atlas Research Network, 2008).	('G4502A', 'Var', (8, 14))	('cancers', 'Disease', 'MESH:D009369', (249, 256))	('cancers', 'Phenotype', 'HP:0002664', (249, 256))	('GBM', 'Phenotype', 'HP:0012174', (47, 50))	('cancers', 'Disease', (249, 256))	('Cancer', 'Disease', (351, 357))	('G4502A', 'SUBSTITUTION', 'None', (8, 14))	('Cancer', 'Disease', 'MESH:D009369', (351, 357))	('Cancer', 'Phenotype', 'HP:0002664', (351, 357))	('GBM', 'Phenotype', 'HP:0012174', (128, 131))	('cancer', 'Phenotype', 'HP:0002664', (249, 255))	('GBM', 'Phenotype', 'HP:0012174', (327, 330))
173022	31923345	For beta-catenin IF (610153; BD Transduction Laboratories, San Jose, CA, USA, 1 : 200), U87-MSCV and U87-HOXA9 cells plated on coverslips were fixed in 95% EtOH and 5% acetic acid (v/v), followed by incubation in 1% BSA in PBS-0.1% Tween for 1 h, and overnight at 4  C with the primary antibody.	('Tween', 'Chemical', 'MESH:D011136', (232, 237))	('610153;', 'Var', (21, 28))	('EtOH', 'Chemical', 'MESH:D000431', (156, 160))	('acetic acid', 'Chemical', 'MESH:D019342', (168, 179))	('PBS', 'Chemical', 'MESH:D007854', (223, 226))	('MSCV', 'Species', '258023', (92, 96))	('beta-catenin', 'Protein', (4, 16))
173042	31923345	Together, these results show that high WNT6 expression associates with higher glioma grades independently of IDH mutation and 1p/19q codeletion status.	('higher', 'PosReg', (71, 77))	('IDH', 'Gene', '3417', (109, 112))	('glioma', 'Phenotype', 'HP:0009733', (78, 84))	('WNT6', 'Gene', (39, 43))	('high', 'Var', (34, 38))	('glioma', 'Disease', (78, 84))	('IDH', 'Gene', (109, 112))	('glioma', 'Disease', 'MESH:D005910', (78, 84))
173043	31923345	To understand the mechanisms responsible for WNT6 overexpression in glioma, we started by investigating copy number alterations of the WNT6 locus in LGG (n = 509) and GBM (n = 565) patients from TCGA (Fig.	('glioma', 'Disease', 'MESH:D005910', (68, 74))	('glioma', 'Phenotype', 'HP:0009733', (68, 74))	('WNT6', 'Gene', (135, 139))	('GBM', 'Phenotype', 'HP:0012174', (167, 170))	('copy number alterations', 'Var', (104, 127))	('patients', 'Species', '9606', (181, 189))	('glioma', 'Disease', (68, 74))
173051	31923345	Interestingly, looking for the 28 DNA methylation sites within the WNT6 locus, in 516 LGG and 141 GBM patients, we identified regions that are consistently hypomethylated (e.g., from the 4th probe [cg16256504] to the 8th probe [cg02175741]) or hypermethylated (e.g., 16th probe [cg05618201]) both in LGG and in GBM (Figs 2A and S2), showing a remarkable homogeneity of DNA methylation levels of these particular regions across very heterogeneous glioma samples of different grades.	('GBM', 'Phenotype', 'HP:0012174', (311, 314))	('GBM', 'Phenotype', 'HP:0012174', (98, 101))	('patients', 'Species', '9606', (102, 110))	('glioma', 'Disease', 'MESH:D005910', (446, 452))	('glioma', 'Phenotype', 'HP:0009733', (446, 452))	('[cg16256504]', 'Var', (197, 209))	('[cg02175741]', 'Var', (227, 239))	('glioma', 'Disease', (446, 452))
173055	31923345	MSP analyses showed that five of the seven cell lines presented 5-Aza-mediated demethylation (A172, SNB19, KNS42, SW1783, and Res186; Fig.	('5-Aza', 'Chemical', 'MESH:D000077209', (64, 69))	('A172', 'Var', (94, 98))	('SW1783', 'CellLine', 'CVCL:1722', (114, 120))	('SNB19', 'Var', (100, 105))	('SW1783', 'Var', (114, 120))	('5-Aza-mediated demethylation', 'MPA', (64, 92))
173056	31923345	Interestingly, 5-Aza treatment successfully increased WNT6 expression in four of these five cell lines (fold changes between 1.7 and 3.15; for KNS42, SW1783, A172, and Res186).	('WNT6 expression', 'MPA', (54, 69))	('increased', 'PosReg', (44, 53))	('5-Aza', 'Chemical', 'MESH:D000077209', (15, 20))	('SW1783', 'CellLine', 'CVCL:1722', (150, 156))	('SW1783', 'Var', (150, 156))
173065	31923345	Interestingly, when performing GSEA to identify transcriptomic signatures reminiscent of WNT6-associated genes in GBM patients (Goncalves et al., 2018), we found that WNT6-negatively correlated genes were enriched for genes upregulated in LAML cells upon HOXA9 knockdown [enrichment score (ES) = -0.26 and false discovery rate, FDR = 0.18; Fig.	('knockdown', 'Var', (261, 270))	('GSEA', 'Chemical', '-', (31, 35))	('upregulated', 'PosReg', (224, 235))	('GBM', 'Phenotype', 'HP:0012174', (114, 117))	('patients', 'Species', '9606', (118, 126))
173067	31923345	This association was not only observed in vitro but also in vivo, as U87+/-HOXA9 tumors grown subcutaneously in nude mice also showed significantly higher expression of WNT6 and beta-catenin (mainly in the nucleus) in HOXA9-positive tumors when compared to HOXA9-negative tumors (Fig.	('tumors', 'Disease', (81, 87))	('tumors', 'Disease', 'MESH:D009369', (233, 239))	('tumors', 'Disease', 'MESH:D009369', (272, 278))	('nude mice', 'Species', '10090', (112, 121))	('WNT6', 'Protein', (169, 173))	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('beta-catenin', 'Protein', (178, 190))	('higher', 'PosReg', (148, 154))	('U87+/-HOXA9', 'Var', (69, 80))	('tumors', 'Phenotype', 'HP:0002664', (233, 239))	('tumors', 'Phenotype', 'HP:0002664', (272, 278))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('tumor', 'Phenotype', 'HP:0002664', (272, 277))	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('tumors', 'Disease', (233, 239))	('HOXA9-positive', 'Var', (218, 232))	('tumors', 'Disease', (272, 278))	('expression', 'MPA', (155, 165))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))
173068	31923345	In addition, cyclin D1, a known transcriptional target of the canonical WNT/beta-catenin pathway, was also upregulated in HOXA9-positive tumors when compared to negative tumors (Fig.	('tumors', 'Disease', (137, 143))	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('cyclin D1', 'Gene', (13, 22))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('HOXA9-positive', 'Var', (122, 136))	('tumors', 'Disease', 'MESH:D009369', (170, 176))	('tumors', 'Phenotype', 'HP:0002664', (170, 176))	('cyclin D1', 'Gene', '595', (13, 22))	('upregulated', 'PosReg', (107, 118))	('tumors', 'Disease', (170, 176))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
173072	31923345	Thus, the clinical impact of WNT6 in GBM was evaluated using a multivariable Cox model to adjust to potential confounding effects of other putative prognostic factors, namely patient age, KPS, gender, therapy, IDH mutation status, and HOXA9 expression (Tables 2 and S2).	('GBM', 'Phenotype', 'HP:0012174', (37, 40))	('mutation', 'Var', (214, 222))	('IDH', 'Gene', '3417', (210, 213))	('patient', 'Species', '9606', (175, 182))	('IDH', 'Gene', (210, 213))
173074	31923345	Importantly, IDHwt GBM patients with both WNT6-high and HOXA9-high expression presented a shorter OS (median OS = 290 days) when compared to all other patients (median OS = 425; log-rank P = 0.002; Fig.	('IDH', 'Gene', '3417', (13, 16))	('GBM', 'Phenotype', 'HP:0012174', (19, 22))	('patients', 'Species', '9606', (23, 31))	('shorter', 'NegReg', (90, 97))	('patients', 'Species', '9606', (151, 159))	('HOXA9-high expression', 'Var', (56, 77))	('IDH', 'Gene', (13, 16))
173085	31923345	In contrast, our findings demonstrated that DNA methylation, a critical epigenetic mechanism, associates with WNT6 expression levels in glioma (Figs 2, S2 and S3), similarly to what was observed for other WNT ligands in other cancer types (Carmona et al., 2013; Jung et al., 2015; Kim et al., 2015a; Liu et al., 2016; Xu et al., 2005).	('WNT6', 'Gene', (110, 114))	('DNA', 'MPA', (44, 47))	('glioma', 'Disease', 'MESH:D005910', (136, 142))	('glioma', 'Phenotype', 'HP:0009733', (136, 142))	('cancer', 'Disease', (226, 232))	('glioma', 'Disease', (136, 142))	('cancer', 'Disease', 'MESH:D009369', (226, 232))	('methylation', 'Var', (48, 59))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
173087	31923345	Interestingly, most of the CpG sites are more frequently methylated in LGG than GBM patients (19 out of 28; Fig.	('GBM', 'Phenotype', 'HP:0012174', (80, 83))	('LGG', 'Disease', (71, 74))	('methylated', 'Var', (57, 67))	('patients', 'Species', '9606', (84, 92))
173089	31923345	Although DNA methylation was clearly associated with WNT6 expression in glioma, this association was not universal.	('glioma', 'Disease', (72, 78))	('methylation', 'Var', (13, 24))	('glioma', 'Phenotype', 'HP:0009733', (72, 78))	('WNT6', 'Gene', (53, 57))	('glioma', 'Disease', 'MESH:D005910', (72, 78))	('associated', 'Reg', (37, 47))	('DNA', 'MPA', (9, 12))
173099	31923345	Interestingly, WNT6 was also shown to be associated with shorter survival in LGG patients (Dao Trong et al., 2018), where HOXA9 overexpression is not frequent (Pojo et al., 2015).	('patients', 'Species', '9606', (81, 89))	('WNT6', 'Var', (15, 19))	('LGG', 'Disease', (77, 80))	('survival', 'MPA', (65, 73))	('shorter', 'NegReg', (57, 64))
173124	32195358	Epigenetic modifiers, such as long noncoding RNAs (lncRNAs), have important roles in the development and progression of NSCLC.	('NSCLC', 'Disease', 'MESH:D002289', (120, 125))	('long noncoding RNAs', 'Var', (30, 49))	('NSCLC', 'Phenotype', 'HP:0030358', (120, 125))	('roles', 'Reg', (76, 81))	('NSCLC', 'Disease', (120, 125))
173145	32195358	These observations consistently showed that LINC00263 deregulation was a comment event in lung cancer and thus encouraged us to further study the significance of LINC00263 overexpression in lung cancer.	('lung cancer', 'Disease', 'MESH:D008175', (90, 101))	('LINC00263', 'Gene', (162, 171))	('LINC00263', 'Gene', '90271', (162, 171))	('lung cancer', 'Disease', 'MESH:D008175', (190, 201))	('lung cancer', 'Disease', (90, 101))	('lung cancer', 'Phenotype', 'HP:0100526', (90, 101))	('deregulation', 'Var', (54, 66))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('lung cancer', 'Disease', (190, 201))	('lung cancer', 'Phenotype', 'HP:0100526', (190, 201))	('LINC00263', 'Gene', (44, 53))	('LINC00263', 'Gene', '90271', (44, 53))
173164	32195358	The injection of A549-LINC00263 showed that LINC00263 overexpression significantly increased tumor sizes, volumes, and weights after 35 days of growth compared with A549-Vector cells.	('LINC00263', 'Gene', '90271', (44, 53))	('increased', 'PosReg', (83, 92))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Disease', (93, 98))	('volumes', 'CPA', (106, 113))	('LINC00263', 'Gene', '90271', (22, 31))	('overexpression', 'Var', (54, 68))	('LINC00263', 'Gene', (22, 31))	('weights', 'CPA', (119, 126))	('LINC00263', 'Gene', (44, 53))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
173168	32195358	Moreover, the knockdown of LINC00263 significantly inhibited invasion and migration (Fig.	('F', 'Chemical', 'MESH:D005461', (85, 86))	('LINC00263', 'Gene', (27, 36))	('LINC00263', 'Gene', '90271', (27, 36))	('knockdown', 'Var', (14, 23))	('inhibited', 'NegReg', (51, 60))
173178	32195358	Nuclear factor kappa-B (NF-kappaB) is a family of transcription-related factors that includes five genes: NF-kappaB1(P50/P105), NF-kappaB2 (P52/P100), RelA (P65), c-Rel, and RelB.	('NF-kappaB', 'Gene', '4790', (106, 115))	('P105', 'Gene', '4790', (121, 125))	('c-Rel', 'Gene', '5966', (163, 168))	('P50', 'Gene', (117, 120))	('NF-kappaB', 'Gene', (24, 33))	('RelB', 'Gene', '5971', (174, 178))	('NF-kappaB', 'Gene', (128, 137))	('P52', 'Gene', '4791', (140, 143))	('NF-kappaB', 'Gene', '4790', (24, 33))	('NF-kappaB', 'Gene', '4790', (128, 137))	('c-Rel', 'Gene', (163, 168))	('RelB', 'Gene', (174, 178))	('P105', 'Gene', (121, 125))	('P52', 'Gene', (140, 143))	('RelA', 'Gene', (151, 155))	('P50', 'Gene', '4790', (117, 120))	('Nuclear factor kappa-B', 'Gene', '4790', (0, 22))	('NF-kappaB', 'Gene', (106, 115))	('RelA', 'Gene', '5970', (151, 155))	('Nuclear factor kappa-B', 'Gene', (0, 22))	('P65', 'Var', (157, 160))
173191	32195358	Furthermore, the quantitative reverse transcription PCR (RT-qPCR) analysis confirmed that the trend of related genes with A549 and H1299 and tumors obtained from nude mice were consistent with RNA-Seq (Fig.	('A549', 'Var', (122, 126))	('F', 'Chemical', 'MESH:D005461', (0, 1))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumors', 'Disease', (141, 147))	('tumors', 'Disease', 'MESH:D009369', (141, 147))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('F', 'Chemical', 'MESH:D005461', (202, 203))	('H1299', 'Var', (131, 136))	('nude mice', 'Species', '10090', (162, 171))
173193	32195358	We analyzed the target genes of miRNAs that interact with LINC00263 and found that LINC00263 could act on AKT2, DHX58, NOD2, WNT16, TNFSF15, MAP4K1, and CSF1, which were involved in the NF-KB pathway by modulating has-let-7a-5p, has-miR-106a-5p, has-miR-135a-5p, has-miR-98-5p, and other miRNAs (Fig.	('LINC00263', 'Gene', '90271', (83, 92))	('F', 'Chemical', 'MESH:D005461', (136, 137))	('MAP4K1', 'Gene', (141, 147))	('WNT16', 'Gene', '51384', (125, 130))	('TNFSF15', 'Gene', (132, 139))	('NOD2', 'Gene', '64127', (119, 123))	('AKT2', 'Gene', '208', (106, 110))	('LINC00263', 'Gene', '90271', (58, 67))	('F', 'Chemical', 'MESH:D005461', (134, 135))	('MAP4K1', 'Gene', '11184', (141, 147))	('AKT2', 'Gene', (106, 110))	('has-let-7a-5p', 'MPA', (214, 227))	('DHX58', 'Gene', (112, 117))	('LINC00263', 'Gene', (83, 92))	('has-miR-135a-5p', 'Var', (246, 261))	('has-miR-106a-5p', 'Var', (229, 244))	('act', 'Reg', (99, 102))	('F', 'Chemical', 'MESH:D005461', (155, 156))	('F', 'Chemical', 'MESH:D005461', (187, 188))	('has-miR-98-5p', 'MPA', (263, 276))	('TNFSF15', 'Gene', '9966', (132, 139))	('CSF1', 'Gene', (153, 157))	('LINC00263', 'Gene', (58, 67))	('modulating', 'Reg', (203, 213))	('WNT16', 'Gene', (125, 130))	('DHX58', 'Gene', '79132', (112, 117))	('F', 'Chemical', 'MESH:D005461', (296, 297))	('NOD2', 'Gene', (119, 123))	('CSF1', 'Gene', '1435', (153, 157))
173199	32195358	There was no significant difference between male patients and female patients and the high expression of LINC00263 had no significant effect on the survival prognosis (Supplementary Fig.	('F', 'Chemical', 'MESH:D005461', (182, 183))	('LINC00263', 'Gene', '90271', (105, 114))	('high expression', 'Var', (86, 101))	('patients', 'Species', '9606', (49, 57))	('patients', 'Species', '9606', (69, 77))	('LINC00263', 'Gene', (105, 114))
173228	32195358	LNCaP cells are androgen-sensitive; however, with AR knockdown, the expression of LINC00263 did not change (Fig.	('knockdown', 'Var', (53, 62))	('LINC00263', 'Gene', (82, 91))	('LINC00263', 'Gene', '90271', (82, 91))	('F', 'Chemical', 'MESH:D005461', (108, 109))	('LNCaP', 'CellLine', 'CVCL:0395;0.06850841560717028', (0, 5))
173241	32195358	At the same time, we analyzed the difference in patients with breast cancer and ovarian cancer mutated in BRCA1 or BRCA2 or who were wild-type.	('ovarian cancer', 'Disease', (80, 94))	('BRCA2', 'Gene', (115, 120))	('BRCA1', 'Gene', (106, 111))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('breast cancer', 'Disease', 'MESH:D001943', (62, 75))	('BRCA2', 'Gene', '675', (115, 120))	('breast cancer', 'Phenotype', 'HP:0003002', (62, 75))	('mutated', 'Var', (95, 102))	('ovarian cancer', 'Phenotype', 'HP:0100615', (80, 94))	('breast cancer', 'Disease', (62, 75))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('ovarian cancer', 'Disease', 'MESH:D010051', (80, 94))	('BRCA1', 'Gene', '672', (106, 111))	('patients', 'Species', '9606', (48, 56))
173243	32195358	The mechanism of LINC00263 in breast cancer was related to estrogen receptors and might be associated with BRCA gene mutations in ovarian cancer.	('LINC00263', 'Gene', '90271', (17, 26))	('mutations', 'Var', (117, 126))	('breast cancer', 'Disease', 'MESH:D001943', (30, 43))	('ovarian cancer', 'Disease', 'MESH:D010051', (130, 144))	('LINC00263', 'Gene', (17, 26))	('estrogen receptor', 'Gene', (59, 76))	('BRCA', 'Gene', '672', (107, 111))	('breast cancer', 'Phenotype', 'HP:0003002', (30, 43))	('breast cancer', 'Disease', (30, 43))	('estrogen receptor', 'Gene', '2099', (59, 76))	('ovarian cancer', 'Disease', (130, 144))	('related', 'Reg', (48, 55))	('BRCA', 'Gene', (107, 111))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('ovarian cancer', 'Phenotype', 'HP:0100615', (130, 144))	('associated', 'Reg', (91, 101))
173249	32195358	In the classification of breast cancer, ~30% of breast cancer patients had genetic alterations in the HER-2 gene.	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('breast cancer', 'Disease', 'MESH:D001943', (25, 38))	('breast cancer', 'Disease', 'MESH:D001943', (48, 61))	('breast cancer', 'Phenotype', 'HP:0003002', (48, 61))	('HER-2', 'Gene', (102, 107))	('breast cancer', 'Disease', (25, 38))	('genetic alterations', 'Var', (75, 94))	('breast cancer', 'Disease', (48, 61))	('HER-2', 'Gene', '2064', (102, 107))	('breast cancer', 'Phenotype', 'HP:0003002', (25, 38))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('patients', 'Species', '9606', (62, 70))
173250	32195358	HER-2 positive cancers have been associated with poor overall survival and have been shown preclinically to enhance malignancy and the metastatic phenotype.	('malignancy', 'Disease', (116, 126))	('poor', 'NegReg', (49, 53))	('cancers', 'Disease', 'MESH:D009369', (15, 22))	('metastatic', 'CPA', (135, 145))	('cancers', 'Phenotype', 'HP:0002664', (15, 22))	('positive', 'Var', (6, 14))	('enhance', 'PosReg', (108, 115))	('cancers', 'Disease', (15, 22))	('clinical', 'Species', '191496', (94, 102))	('HER-2', 'Gene', (0, 5))	('HER-2', 'Gene', '2064', (0, 5))	('malignancy', 'Disease', 'MESH:D009369', (116, 126))	('overall', 'MPA', (54, 61))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))
173268	32195358	A recent analytic approach based on the propensity score revealed molecular differences in sex-specific cancers due to mutations, DNA methylation, transcripts, and protein expression.	('transcripts', 'MPA', (147, 158))	('protein', 'Protein', (164, 171))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('cancers', 'Phenotype', 'HP:0002664', (104, 111))	('mutations', 'Var', (119, 128))	('cancers', 'Disease', (104, 111))	('cancers', 'Disease', 'MESH:D009369', (104, 111))
173275	32195358	High expression of LINC00263 was a disadvantage in the survival prognosis of lung adenocarcinoma, renal and clear cell carcinomas, colorectal cancer and hepatic carcinoma, but it was a favorable factor in ovarian cancer and had no significant effect in prostate cancer and breast cancer.	('hepatic carcinoma', 'Disease', 'MESH:D056486', (153, 170))	('ovarian cancer', 'Disease', (205, 219))	('LINC00263', 'Gene', '90271', (19, 28))	('cancer', 'Phenotype', 'HP:0002664', (280, 286))	('ovarian cancer', 'Phenotype', 'HP:0100615', (205, 219))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (77, 96))	('High', 'Var', (0, 4))	('colorectal cancer', 'Phenotype', 'HP:0003003', (131, 148))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('carcinomas', 'Phenotype', 'HP:0030731', (119, 129))	('breast cancer', 'Phenotype', 'HP:0003002', (273, 286))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('disadvantage', 'NegReg', (35, 47))	('cancer', 'Phenotype', 'HP:0002664', (262, 268))	('LINC00263', 'Gene', (19, 28))	('prostate cancer', 'Disease', 'MESH:D011471', (253, 268))	('breast cancer', 'Disease', 'MESH:D001943', (273, 286))	('prostate cancer', 'Phenotype', 'HP:0012125', (253, 268))	('ovarian cancer', 'Disease', 'MESH:D010051', (205, 219))	('breast cancer', 'Disease', (273, 286))	('hepatic carcinoma', 'Disease', (153, 170))	('lung adenocarcinoma, renal and clear cell carcinomas', 'Disease', 'MESH:D008649', (77, 129))	('hepatic carcinoma', 'Phenotype', 'HP:0001402', (153, 170))	('colorectal cancer', 'Disease', 'MESH:D015179', (131, 148))	('prostate cancer', 'Disease', (253, 268))	('carcinoma', 'Phenotype', 'HP:0030731', (161, 170))	('colorectal cancer', 'Disease', (131, 148))
173305	32195358	The sex of A549, PC9, and H1299 was male.	('H1299', 'Var', (26, 31))	('PC9', 'Gene', '255738', (17, 20))	('PC9', 'Gene', (17, 20))
173337	32195358	We used beta-E2 (Sigma, E2758-250MG).	('E2758-250MG', 'Var', (24, 35))	('beta-E2', 'Gene', (8, 15))	('beta-E2', 'Gene', '6522', (8, 15))
173359	31565549	Luciferase reporter assay and Western blotting results suggested that AC026166.2-001 could act as a sponge of miR-24-3p and regulate the expression of p27 and cyclin D1.	('cyclin D1', 'Gene', (159, 168))	('expression', 'MPA', (137, 147))	('p27', 'Gene', '3429', (151, 154))	('p27', 'Gene', (151, 154))	('AC026166.2-001', 'Var', (70, 84))	('regulate', 'Reg', (124, 132))	('cyclin D1', 'Gene', '595', (159, 168))
173365	31565549	For example, hyper-methylation of the promoter region was observed to lead to a loss of expression of lncRNA maternally expressed gene 3 (MEG3).	('maternally expressed gene 3', 'Gene', (109, 136))	('MEG3', 'Gene', '55384', (138, 142))	('maternally expressed gene 3', 'Gene', '55384', (109, 136))	('loss of', 'NegReg', (80, 87))	('hyper-methylation', 'Var', (13, 30))	('expression', 'MPA', (88, 98))	('MEG3', 'Gene', (138, 142))
173366	31565549	Downregulated MEG3 was insufficient to sponge miR-9 and block its inhibition effects on the expressions of E-cadherin and FOXO1, consequentially resulting in poor prognosis in patients with esophageal squamous cell carcinoma.	('E-cadherin', 'Gene', '999', (107, 117))	('Downregulated', 'Var', (0, 13))	('patients', 'Species', '9606', (176, 184))	('MEG3', 'Gene', '55384', (14, 18))	('expressions', 'MPA', (92, 103))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:C562729', (190, 224))	('FOXO1', 'Gene', (122, 127))	('resulting', 'Reg', (145, 154))	('FOXO1', 'Gene', '2308', (122, 127))	('inhibition', 'MPA', (66, 76))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (201, 224))	('carcinoma', 'Phenotype', 'HP:0030731', (215, 224))	('E-cadherin', 'Gene', (107, 117))	('MEG3', 'Gene', (14, 18))	('esophageal squamous cell carcinoma', 'Disease', (190, 224))
173370	31565549	found that the loci of three miRNAs (namely miR-199a-2, miR-124a-2 and miR-184) were linked to hyper-methylated differentially methylated regions (DMRs) in human testicular cancer.	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('hyper-methylated differentially methylated regions', 'MPA', (95, 145))	('miR-124a-2', 'Var', (56, 66))	('human', 'Species', '9606', (156, 161))	('cancer', 'Disease', (173, 179))	('miR-199a-2', 'Gene', (44, 54))	('miR-184', 'Gene', '406960', (71, 78))	('miR-184', 'Gene', (71, 78))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('miR-199a-2', 'Gene', '406977', (44, 54))	('linked', 'Reg', (85, 91))	('testicular cancer', 'Phenotype', 'HP:0010788', (162, 179))
173395	31565549	2E) (Supplemental Information 9); and 4,567 DMRs were identified in the LSCC genome of  dataset, including 1616 hypomethylated and 2,951 hypermethylated (Fig.	('hypermethylated', 'Var', (137, 152))	('LSCC', 'Disease', (72, 76))	('LSCC', 'Disease', 'MESH:D002294', (72, 76))	('hypomethylated', 'Var', (112, 126))
173401	31565549	The results showed that 17 significant GO BP terms were enriched, including GO:0042981 ~ regulation of apoptosis (PAWR), GO:0015031 ~ protein transport (SNX21; SCG5), cell cycle (PRDM5) and GO:0043407 ~ negative regulation of MAP kinase activity 4 (SPRY4).	('SPRY4', 'Gene', '81848', (249, 254))	('PAWR', 'Gene', (114, 118))	('PAWR', 'Gene', '5074', (114, 118))	('GO:0043407 ~', 'Var', (190, 202))	('negative regulation', 'NegReg', (203, 222))	('SCG5', 'Gene', '6447', (160, 164))	('PRDM5', 'Gene', '11107', (179, 184))	('cell cycle', 'CPA', (167, 177))	('SNX21', 'Gene', (153, 158))	('SNX21', 'Gene', '90203', (153, 158))	('apoptosis', 'CPA', (103, 112))	('MAP kinase activity 4', 'Pathway', (226, 247))	('SPRY4', 'Gene', (249, 254))	('SCG5', 'Gene', (160, 164))	('protein transport', 'MPA', (134, 151))	('GO:0015031 ~', 'Var', (121, 133))	('GO:0042981 ~', 'Var', (76, 88))	('PRDM5', 'Gene', (179, 184))
173415	31565549	Although epigenetics modification has been shown to trigger silencing or overexpression of lncRNAs in cancer, the aberrant methylation-mediated expression changes of lncRNAs remain unclear in LSCC.	('silencing', 'MPA', (60, 69))	('lncRNAs', 'Protein', (91, 98))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('LSCC', 'Disease', (192, 196))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('LSCC', 'Disease', 'MESH:D002294', (192, 196))	('epigenetics modification', 'Var', (9, 33))	('overexpression', 'PosReg', (73, 87))
173423	31565549	Consistent with this hypothesis, our study showed that SNX21 was less expressed in LSCC tissues and patients with high expression of SNX21 had a higher OS rate.	('SNX21', 'Gene', '90203', (133, 138))	('LSCC', 'Disease', 'MESH:D002294', (83, 87))	('LSCC', 'Disease', (83, 87))	('OS rate', 'CPA', (152, 159))	('less', 'NegReg', (65, 69))	('patients', 'Species', '9606', (100, 108))	('SNX21', 'Gene', (55, 60))	('SNX21', 'Gene', '90203', (55, 60))	('SNX21', 'Gene', (133, 138))	('high expression', 'Var', (114, 129))	('higher', 'PosReg', (145, 151))
173425	31565549	The tumor inhibition effects of TRAPPC10 may be related to its potential to activate GTPase RAB11 and the Rab coupling protein, the targeted deletion of which led to accelerated tumor onset.	('tumor', 'Disease', (4, 9))	('accelerated', 'PosReg', (166, 177))	('tumor', 'Disease', (178, 183))	('deletion', 'Var', (141, 149))	('TRAPPC10', 'Gene', '7109', (32, 40))	('TRAPPC10', 'Gene', (32, 40))	('RAB11', 'Gene', '8766', (92, 97))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('activate', 'PosReg', (76, 84))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('RAB11', 'Gene', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))
173456	32071317	Among them, long noncoding RNAs (lncRNAs) refer to non-protein coding transcripts longer than 200 nucleotides, a broad definition that includes different types of RNAs.	('ncRNA', 'Gene', '220202', (34, 39))	('ncRNA', 'Gene', (34, 39))	('long noncoding', 'Var', (12, 26))
173462	32071317	The concomitant gene expression changes aimed at activating this tumor suppressor program are often driven by the cooperative action of different epigenetic complexes, including SWI/SNF.	('tumor', 'Disease', (65, 70))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('SWI/SNF', 'Disease', (178, 185))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('changes', 'Var', (32, 39))
173463	32071317	Consistently, genes encoding for components of SWI/SNF are mutated in more than 20% of human cancers, being among the most prominent tumor suppressors in humans.	('cancers', 'Disease', (93, 100))	('human', 'Species', '9606', (154, 159))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('cancers', 'Phenotype', 'HP:0002664', (93, 100))	('human', 'Species', '9606', (87, 92))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('humans', 'Species', '9606', (154, 160))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('tumor', 'Disease', (133, 138))	('SWI/SNF', 'Gene', (47, 54))	('cancers', 'Disease', 'MESH:D009369', (93, 100))	('mutated', 'Var', (59, 66))
173464	32071317	The clearest demonstration of SWI/SNF tumor suppressor role are the malignant rhabdoid tumors (MRTs), specifically driven by the biallelic inactivation of the gene encoding for SMARCB1 SWI/SNF core subunit.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('SMARCB1', 'Gene', '6598', (177, 184))	('biallelic', 'Var', (129, 138))	('rhabdoid tumors', 'Disease', (78, 93))	('SMARCB1', 'Gene', (177, 184))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('driven by', 'Reg', (115, 124))	('rhabdoid tumors', 'Disease', 'MESH:D018335', (78, 93))	('SNF tumor', 'Disease', (34, 43))	('SNF tumor', 'Disease', 'MESH:D009369', (34, 43))
173475	32071317	We then performed high-throughput sequencing of the total (Poly A+ and Poly A-) RNA molecules interacting with SMARCB1, which identified hundreds of enriched RNAs compared to the correspondent Input (Fig.	('SMARCB1', 'Gene', '6598', (111, 118))	('interacting', 'Interaction', (94, 105))	('Poly A-', 'Var', (71, 78))	('SMARCB1', 'Gene', (111, 118))
173481	32071317	We selected a subset of both annotated and uncharacterized lncRNAs, confirming their specific enrichment by RIP-qPCR in proliferating and/or senescence conditions (Fig.	('ncRNA', 'Gene', (60, 65))	('RIP-qPCR', 'Var', (108, 116))	('ncRNA', 'Gene', '220202', (60, 65))
173492	32071317	We found that SMARCB1 is enriched at genomic loci marked as promoters (high H3K4me3/H3K4me2 ratio) or enhancers (low H3K4me3/H3K4me2 ratio) (Fig.	('SMARCB1', 'Gene', (14, 21))	('SMARCB1', 'Gene', '6598', (14, 21))	('enhancers', 'PosReg', (102, 111))	('high H3K4me3/H3K4me2', 'Var', (71, 91))
173523	32071317	To further confirm the functional co-dependency between SMARCB1 and SWINGN transcript, we used as control a highly aggressive type of pediatric cancer driven by the biallelic deletion of SMARCB1 gene.	('biallelic deletion', 'Var', (165, 183))	('SMARCB1', 'Gene', (56, 63))	('SMARCB1', 'Gene', '6598', (56, 63))	('SMARCB1', 'Gene', '6598', (187, 194))	('SMARCB1', 'Gene', (187, 194))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('driven by', 'Reg', (151, 160))	('cancer', 'Disease', (144, 150))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
173535	32071317	Consistently, the knockdown of SWINGN in BJ fibroblasts impairs their proliferation and increases apoptosis levels (Supplementary Fig.	('knockdown', 'Var', (18, 27))	('apoptosis levels', 'MPA', (98, 114))	('proliferation', 'CPA', (70, 83))	('SWINGN', 'Gene', (31, 37))	('BJ', 'CellLine', 'CVCL:6573', (41, 43))	('increases', 'PosReg', (88, 97))	('impairs', 'NegReg', (56, 63))
173543	32071317	As consequence of SWINGN knockdown, H226 cell proliferation and colony formation capacity were affected concomitantly with an increase in the percentage of apoptotic cells (Fig.	('H226', 'CellLine', 'CVCL:J621', (36, 40))	('H226 cell proliferation', 'CPA', (36, 59))	('colony formation capacity', 'CPA', (64, 89))	('SWINGN', 'Gene', (18, 24))	('increase', 'PosReg', (126, 134))	('knockdown', 'Var', (25, 34))	('affected', 'Reg', (95, 103))
173552	32071317	7A-C), and GAS6 overexpression only partially recovered the effect of SWINGN knockdown (Supplementary Fig.	('GAS6', 'Gene', '2621', (11, 15))	('GAS6', 'Gene', (11, 15))	('knockdown', 'Var', (77, 86))	('SWINGN', 'Gene', (70, 76))
173560	32071317	To assess the relationship between the decrease in SMARCB1 binding and the H3K27ac reduction caused by SWINGN depletion, we analyzed H2K27ac signal at the 4791 SMARCB1 differentially bound sites upon SWINGN knockdown (Fig.	('SMARCB1', 'Gene', '6598', (160, 167))	('H3K27ac', 'Protein', (75, 82))	('SMARCB1', 'Gene', (160, 167))	('knockdown', 'Var', (207, 216))	('SWINGN', 'Gene', (200, 206))	('SMARCB1', 'Gene', '6598', (51, 58))	('bound', 'Interaction', (183, 188))	('reduction', 'NegReg', (83, 92))	('SMARCB1', 'Gene', (51, 58))
173562	32071317	These data demonstrate that the changes in H3K27ac are mainly associated with the decreased binding of SMARCB1 at specific loci caused by SWINGN knockdown.	('changes', 'Reg', (32, 39))	('SMARCB1', 'Gene', (103, 110))	('binding', 'Interaction', (92, 99))	('knockdown', 'Var', (145, 154))	('H3K27ac', 'Protein', (43, 50))	('SWINGN', 'Gene', (138, 144))	('SMARCB1', 'Gene', '6598', (103, 110))	('decreased', 'NegReg', (82, 91))
173563	32071317	Next, since it has been shown that the ablation of SMARCB1 can decrease acetylation at enhancers, we analyzed H3K27ac changes upon SWINGN knockdown separately at distal enhancer sites and proximal promoter regions.	('ablation', 'Var', (39, 47))	('decrease', 'NegReg', (63, 71))	('SMARCB1', 'Gene', '6598', (51, 58))	('H3K27ac', 'Protein', (110, 117))	('SMARCB1', 'Gene', (51, 58))	('acetylation at enhancers', 'MPA', (72, 96))
173574	32071317	This gene, recently found altered in AT/RT and elected as a novel therapeutic target for these tumor types, showed similar chromatin changes upon SWINGN knockdown, corroborating the hypothesis of a regulation orchestrated by SMARCB1 and SWINGN (Fig.	('knockdown', 'Var', (153, 162))	('AT', 'Disease', 'None', (37, 39))	('SMARCB1', 'Gene', '6598', (225, 232))	('SMARCB1', 'Gene', (225, 232))	('changes', 'Reg', (133, 140))	('chromatin', 'MPA', (123, 132))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Disease', (95, 100))
173607	32071317	The unveiled role of SWINGN in the establishment of its regulatory network provides an epigenetic signature for tumor progression linked to SMARCB1 alterations.	('alterations', 'Var', (148, 159))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('SMARCB1', 'Gene', (140, 147))	('SMARCB1', 'Gene', '6598', (140, 147))	('tumor', 'Disease', (112, 117))
173660	32071317	ASO_LINC#3 was used to knockdown SWINGN expression.	('SWINGN expression', 'Gene', (33, 50))	('LINC', 'Gene', (4, 8))	('knockdown', 'Var', (23, 32))	('LINC', 'Gene', '378805', (4, 8))
173686	32071317	For differential binding analysis of CTRL and SWINGN-knockdown ChIP-seq data, SMARCB1 and H3K27ac BAMs from two different replicates were merged and MACS2 was used to identify enriched peaks with the following cut offs: for H3K27ac ChIP, FDR < 0.001; for SMARCB1 ChIP, FDR < 0.0001.	('CTRL', 'Gene', (37, 41))	('H3K27ac', 'Var', (224, 231))	('SMARCB1', 'Gene', '6598', (78, 85))	('SMARCB1', 'Gene', (78, 85))	('CTRL', 'Gene', '1506', (37, 41))	('SMARCB1', 'Gene', '6598', (255, 262))	('SMARCB1', 'Gene', (255, 262))
173719	32038720	Although these articles established the critical role of lncRNA SOX2-OT expression in some cancers, the prognostic value of SOX2-OT expression in numerous other cancers remained uncharacterized.	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('cancers', 'Disease', 'MESH:D009369', (91, 98))	('cancers', 'Phenotype', 'HP:0002664', (91, 98))	('cancers', 'Disease', (91, 98))	('lncRNA', 'Var', (57, 63))	('cancers', 'Disease', 'MESH:D009369', (161, 168))	('cancers', 'Phenotype', 'HP:0002664', (161, 168))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('cancers', 'Disease', (161, 168))
173736	32038720	This subgroup analysis showed a significantly lower heterogeneity in the above 60 months follow-up group, the tissue group, or the Cholangiocarcinoma group, which suggested that the relationship between high SOX2-OT expression and TNM stage has stronger efficacy in these groups.	('TNM stage', 'CPA', (231, 240))	('SOX2-OT', 'Protein', (208, 215))	('Cholangiocarcinoma', 'Disease', (131, 149))	('high', 'Var', (203, 207))	('Cholangiocarcinoma', 'Disease', 'MESH:D018281', (131, 149))	('Cholangiocarcinoma', 'Phenotype', 'HP:0030153', (131, 149))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))
173746	32038720	Regarding the clinicopathological characteristics of patients with cancers, our research suggested that high SOX2-OT expression was significantly associated with the invasion of cancers, as reveal by the tumor stage (RR = 1.468, 95% CI: 1.106-1.949), lymphatic metastasis (RR = 1.554, 95% CI: 1.211-1.994), distant metastasis (RR = 3.054, 95% CI: 1.866-4.999), tumor size (RR = 1.264, 95% CI: 1.019-1.566), and depth of tumor invasion (RR = 1.552, 95% CI: 1.274-1.890), but couldn't predict histological differentiation, age, or gender.	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('tumor', 'Phenotype', 'HP:0002664', (420, 425))	('tumor invasion', 'Disease', (420, 434))	('tumor', 'Disease', (361, 366))	('tumor invasion', 'Disease', 'MESH:D009361', (420, 434))	('tumor', 'Disease', 'MESH:D009369', (361, 366))	('cancers', 'Disease', 'MESH:D009369', (67, 74))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('cancers', 'Disease', 'MESH:D009369', (178, 185))	('depth of tumor', 'Disease', 'MESH:D007222', (411, 425))	('depth of tumor', 'Disease', (411, 425))	('tumor', 'Phenotype', 'HP:0002664', (361, 366))	('tumor', 'Disease', (420, 425))	('lymphatic metastasis', 'CPA', (251, 271))	('tumor', 'Disease', 'MESH:D009369', (420, 425))	('cancers', 'Phenotype', 'HP:0002664', (67, 74))	('cancers', 'Disease', (67, 74))	('distant metastasis', 'CPA', (307, 325))	('cancers', 'Phenotype', 'HP:0002664', (178, 185))	('cancers', 'Disease', (178, 185))	('high', 'Var', (104, 108))	('tumor', 'Disease', (204, 209))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('associated', 'Reg', (146, 156))
173750	32038720	Kaplan-Meier analysis initially suggested that SOX2-OT overexpression was associated with a bad OS in adrenocortical cancer (ACC), cervical cancer (CESC), mesothelioma (MESO), and glioma (LGG), and associated with a worse OS in breast cancer (BRCA), kidney renal clear cell carcinoma (KIRC), thymoma (THYM), thyroid cancer (THCA), uterine carcinosarcoma (UCS), and endometrioid cancer (UCEC) according to the TCGA datasets ( Table 7  and  Supplementary Figures 3  and  4 ).	('THCA', 'Disease', (324, 328))	('MESO', 'Disease', (169, 173))	('endometrioid cancer', 'Phenotype', 'HP:0012114', (365, 384))	('carcinosarcoma', 'Disease', (339, 353))	('THYM', 'Disease', (301, 305))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('glioma', 'Phenotype', 'HP:0009733', (180, 186))	('cancer', 'Disease', 'MESH:D009369', (378, 384))	('THCA', 'Phenotype', 'HP:0002890', (324, 328))	('kidney renal clear cell carcinoma', 'Disease', (250, 283))	('thyroid cancer', 'Disease', 'MESH:D013964', (308, 322))	('breast cancer', 'Phenotype', 'HP:0003002', (228, 241))	('carcinosarcoma', 'Disease', 'MESH:D002296', (339, 353))	('BRCA', 'Disease', (243, 247))	('cancer', 'Disease', 'MESH:D009369', (235, 241))	('thymoma', 'Disease', 'MESH:D013945', (292, 299))	('UCS', 'Phenotype', 'HP:0002891', (355, 358))	('adrenocortical cancer', 'Disease', (102, 123))	('BRCA', 'Disease', 'MESH:D001943', (243, 247))	('THYM', 'Disease', 'MESH:D013945', (301, 305))	('thyroid cancer', 'Phenotype', 'HP:0002890', (308, 322))	('breast cancer', 'Disease', 'MESH:D001943', (228, 241))	('cancer', 'Disease', (117, 123))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (331, 353))	('cancer', 'Disease', (316, 322))	('breast cancer', 'Disease', (228, 241))	('endometrioid cancer', 'Disease', 'MESH:D009369', (365, 384))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('cancer', 'Phenotype', 'HP:0002664', (316, 322))	('cancer', 'Disease', (140, 146))	('thymoma', 'Disease', (292, 299))	('cancer', 'Disease', (378, 384))	('thymoma', 'Phenotype', 'HP:0100522', (292, 299))	('KIRC', 'Disease', (285, 289))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('glioma', 'Disease', (180, 186))	('sarcoma', 'Phenotype', 'HP:0100242', (346, 353))	('THYM', 'Phenotype', 'HP:0100522', (301, 305))	('cancer', 'Phenotype', 'HP:0002664', (378, 384))	('kidney renal clear cell carcinoma', 'Disease', 'MESH:D002292', (250, 283))	('cancer', 'Disease', (235, 241))	('mesothelioma', 'Disease', (155, 167))	('ACC', 'Disease', (125, 128))	('SOX2-OT', 'Var', (47, 54))	('ACC', 'Disease', 'MESH:D000306', (125, 128))	('MESO', 'Disease', 'MESH:D008654', (169, 173))	('glioma', 'Disease', 'MESH:D005910', (180, 186))	('endometrioid cancer', 'Disease', (365, 384))	('BRCA', 'Phenotype', 'HP:0003002', (243, 247))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('thyroid cancer', 'Disease', (308, 322))	('KIRC', 'Disease', 'MESH:D002292', (285, 289))	('cancer', 'Disease', 'MESH:D009369', (316, 322))	('THCA', 'Disease', 'MESH:D013964', (324, 328))	('mesothelioma', 'Disease', 'MESH:D008654', (155, 167))	('carcinoma', 'Phenotype', 'HP:0030731', (274, 283))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))	('adrenocortical cancer', 'Disease', 'MESH:D000306', (102, 123))
173754	32038720	proposed that SOX2-OT was highly expressed in gastric cancer cells, which promoted the expression of AKT2 by targeting miR-194-5p, thus elevating cell proliferation and metastasis.	('promoted', 'PosReg', (74, 82))	('AKT2', 'Gene', (101, 105))	('gastric cancer', 'Disease', (46, 60))	('gastric cancer', 'Disease', 'MESH:D013274', (46, 60))	('expression', 'MPA', (87, 97))	('gastric cancer', 'Phenotype', 'HP:0012126', (46, 60))	('targeting miR-194-5p', 'Var', (109, 129))	('miR-194-5p', 'Var', (119, 129))	('elevating', 'PosReg', (136, 145))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('cell proliferation', 'CPA', (146, 164))
173759	32038720	showed that high SOX2-OT expression predicted poor OS and more advanced tumor progression, but failed to predict distant metastasis and lymph node metastasis in Chinese cancer patients.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('cancer', 'Disease', (169, 175))	('high', 'Var', (12, 16))	('tumor', 'Disease', (72, 77))	('expression', 'MPA', (25, 35))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('SOX2-OT', 'Protein', (17, 24))	('poor OS', 'CPA', (46, 53))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('cancer', 'Disease', 'MESH:D009369', (169, 175))
173770	32038720	This research was supported by the National Natural Science Foundation of China (81902498), Natural Science Foundation of Hubei Province of China (2019CFB177), Natural Science Foundation of Hubei Provincial Department of Education (Q20182105), Chen Xiao-ping Foundation for the development of science and technology of Hubei Provincial (CXPJJH11800001-2018333), Natural Science Foundation of Hubei Province of China (2016CFB530) and Faculty Development Foundation of Hubei University of Medicine (2014QDJZR01), and National Students' platform for innovation and entrepreneurship training program (201810929005, 201810929009, 201810929068, and 201813249010).	('201810929068', 'Var', (625, 637))	('201810929009', 'Var', (611, 623))	('201810929005', 'Var', (597, 609))	('201813249010', 'Var', (643, 655))	('2019CFB177', 'Chemical', 'MESH:C045346', (147, 157))
173803	29938858	For Runx1 deletion, mice were injected at PD17 intraperitoneally with 225microg Tamoxifen (Sigma) per gram of body weight dissolved in corn oil and sacrificed at PD20.	('Tamoxifen', 'Chemical', 'MESH:D013629', (80, 89))	('corn', 'Species', '4577', (135, 139))	('Runx1', 'Gene', (4, 9))	('mice', 'Species', '10090', (20, 24))	('deletion', 'Var', (10, 18))
173837	29938858	Primary keratinocytes were isolated from the newborn skin epithelium of Runx1 TG and Runx1 iKO mice.	('iKO', 'Var', (91, 94))	('mice', 'Species', '10090', (95, 99))	('Runx1', 'Gene', (72, 77))	('Runx1', 'Gene', (85, 90))
173858	29938858	Previously we have shown that iKO of Runx1 during DMBA/TPA tumor initiation stage in mouse skin impairs tumor formation while iKO post-tumor formation results in tumor shrinkage.	('skin impairs tumor', 'Disease', 'MESH:D012878', (91, 109))	('Runx1', 'Gene', (37, 42))	('tumor', 'Disease', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumor', 'Disease', (162, 167))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor initiation', 'Disease', 'MESH:D009369', (59, 75))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('tumor initiation', 'Disease', (59, 75))	('skin impairs tumor', 'Disease', (91, 109))	('iKO', 'Var', (30, 33))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('mouse', 'Species', '10090', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('tumor', 'Disease', (104, 109))	('tumor', 'Disease', (135, 140))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('tumor', 'Disease', 'MESH:D009369', (135, 140))	('DMBA', 'Chemical', 'MESH:D015127', (50, 54))
173869	29938858	Next, we inhibited expression of Scd1 and Soat1 using well-established small molecule chemical inhibitors (A939572) and TMP-153, respectively.	('inhibited', 'NegReg', (9, 18))	('expression', 'MPA', (19, 29))	('A939572', 'Var', (107, 114))	('Soat1', 'Gene', (42, 47))	('(A939572)', 'Chemical', 'None', (106, 115))	('Scd1', 'Gene', (33, 37))	('TMP-153', 'Chemical', 'MESH:C088280', (120, 127))
173870	29938858	A939572 inhibits both mouse and human Scd1respectively.	('inhibits', 'NegReg', (8, 16))	('A939572', 'Chemical', 'None', (0, 7))	('A939572', 'Var', (0, 7))	('human', 'Species', '9606', (32, 37))	('mouse', 'Species', '10090', (22, 27))
173871	29938858	A939572 has no inhibitory activity to the co-enzymes of Scd1, cytochrome b5 and cytochrome b5 reductase, and interact directly and specifically with Scd1.	('interact', 'Reg', (109, 117))	('cytochrome b5', 'Gene', (62, 75))	('cytochrome b5', 'Gene', (80, 93))	('cytochrome b5', 'Gene', '109672', (62, 75))	('A939572', 'Chemical', 'None', (0, 7))	('A939572', 'Var', (0, 7))	('Scd1', 'Gene', (56, 60))	('cytochrome b5', 'Gene', '109672', (80, 93))	('inhibitory activity', 'MPA', (15, 34))
173872	29938858	Furthermore, Scd1 shRNAs and A939572 have similar effects on renal carcinoma cell proliferation attesting to the specificity of this inhibitor.	('A939572', 'Chemical', 'None', (29, 36))	('A939572', 'Var', (29, 36))	('renal carcinoma', 'Disease', (61, 76))	('renal carcinoma', 'Disease', 'MESH:D002292', (61, 76))	('renal carcinoma', 'Phenotype', 'HP:0005584', (61, 76))	('Scd1 shRNAs', 'Var', (13, 24))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('effects', 'Reg', (50, 57))
173875	29938858	We found that A939572 and TMP-153 individually and synergistically reduce proliferation of both WT and Runx1 TG keratinocytes (Fig.	('reduce', 'NegReg', (67, 73))	('proliferation', 'CPA', (74, 87))	('TMP-153', 'Gene', (26, 33))	('TMP-153', 'Chemical', 'MESH:C088280', (26, 33))	('A939572', 'Chemical', 'None', (14, 21))	('A939572', 'Var', (14, 21))
173877	29938858	Inhibition of Scd1 is known to result in depletion of its end-product oleate, which is needed for cell proliferation.	('oleate', 'Chemical', 'MESH:D019301', (70, 76))	('depletion of', 'MPA', (41, 53))	('Scd1', 'Gene', (14, 18))	('Inhibition', 'Var', (0, 10))
173881	29938858	Next, we tested whether inhibition of Scd1 and Soat1 also affects proliferation of human SCC cell lines.	('SCC', 'Gene', '6317', (89, 92))	('Scd1', 'Gene', (38, 42))	('proliferation', 'CPA', (66, 79))	('human', 'Species', '9606', (83, 88))	('affects', 'Reg', (58, 65))	('inhibition', 'Var', (24, 34))	('SCC', 'Phenotype', 'HP:0002860', (89, 92))	('tested', 'Reg', (9, 15))	('SCC', 'Gene', (89, 92))	('Soat1', 'Gene', (47, 52))
173882	29938858	4C) where either A939572 or TMP-153 alone was sufficient to significantly reduce proliferation, SCCs required both inhibitors to produce a significant effect, as shown by percentage of EdU+ cells.	('SCC', 'Gene', (96, 99))	('TMP-153', 'Gene', (28, 35))	('TMP-153', 'Chemical', 'MESH:C088280', (28, 35))	('reduce', 'NegReg', (74, 80))	('SCC', 'Phenotype', 'HP:0002860', (96, 99))	('4C', 'Chemical', 'MESH:C060809', (0, 2))	('SCC', 'Gene', '6317', (96, 99))	('A939572', 'Chemical', 'None', (17, 24))	('A939572', 'Var', (17, 24))	('proliferation', 'CPA', (81, 94))
173886	29938858	GC-MS- based lipidome analysis from total skin of Runx1 TG, Runx1 iKO and their WT littermate controls shows that fatty acids in different classes of lipids were changed in response to Runx1 levels (Fig.	('Runx1', 'Gene', (50, 55))	('changed', 'Reg', (162, 169))	('Runx1', 'Gene', (60, 65))	('fatty acids', 'Chemical', 'MESH:D005227', (114, 125))	('fatty acids in different classes of lipids', 'MPA', (114, 156))	('iKO', 'Var', (66, 69))
173890	29938858	Ratios of iso-16:0/16:0, iso-21:0/20:0 and iso-23:0/24:0 are significantly increased in the Runx1 knockout mice skin compared to controls (Fig.	('Runx1', 'Gene', (92, 97))	('iso-16:0/16:0', 'Var', (10, 23))	('iso-23:0/24:0', 'Var', (43, 56))	('knockout', 'Var', (98, 106))	('mice', 'Species', '10090', (107, 111))	('iso-21:0/20:0', 'Var', (25, 38))	('increased', 'PosReg', (75, 84))
173896	29938858	oleate) cause kinks in the long hydrocarbon tail resulting in poor packing within the membrane and hence a less ordered state (fluid or liquid phase).	('less ordered state', 'MPA', (107, 125))	('kinks', 'Var', (14, 19))	('long hydrocarbon tail', 'Phenotype', 'HP:0002831', (27, 48))	('packing', 'MPA', (67, 74))	('long hydrocarbon tail', 'Protein', (27, 48))	('hydrocarbon', 'Chemical', 'MESH:D006838', (32, 43))	('poor', 'NegReg', (62, 66))	('oleate', 'Chemical', 'MESH:D019301', (0, 6))
173905	29938858	These data suggest that varying the expression of Runx1 changes plasma membrane organization and this is partly mediated by Scd1 and likely by the concentration of its product, oleate, within the lipid bilayer.	('oleate', 'Chemical', 'MESH:D019301', (177, 183))	('Runx1', 'Gene', (50, 55))	('varying', 'Var', (24, 31))	('expression', 'Var', (36, 46))	('plasma membrane organization', 'MPA', (64, 92))	('changes', 'Reg', (56, 63))
173907	29938858	We measured the strength of Wnt signaling using a TOPflash Wnt reporter assay in the presence of oleate, and chemical inhibitors A939572 or TMP-153 (Fig.	('TOPflash Wnt reporter assay', 'MPA', (50, 77))	('TMP-153', 'Gene', (140, 147))	('A939572', 'Chemical', 'None', (129, 136))	('A939572', 'Var', (129, 136))	('oleate', 'Chemical', 'MESH:D019301', (97, 103))	('Wnt signaling', 'MPA', (28, 41))	('TMP-153', 'Chemical', 'MESH:C088280', (140, 147))
173909	29938858	TOPflash activity relative to Wnt3a alone was significantly decreased by addition of A939572 (Fig.	('decreased', 'NegReg', (60, 69))	('Wnt3a', 'Gene', (30, 35))	('A939572', 'Chemical', 'None', (85, 92))	('A939572', 'Var', (85, 92))	('TOPflash activity', 'CPA', (0, 17))	('Wnt3a', 'Gene', '22416', (30, 35))
173918	29938858	Inhibiting the Scd1 and Soat1 enzymes has synergistic negative effects on cellular proliferation of mouse keratinocytes and of our previously demonstrated Runx1-dependent human epithelial cancer cell lines from skin and oral epithelium.	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('Inhibiting', 'Var', (0, 10))	('cellular proliferation', 'CPA', (74, 96))	('mouse', 'Species', '10090', (100, 105))	('epithelial cancer', 'Phenotype', 'HP:0031492', (177, 194))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('cancer', 'Disease', (188, 194))	('Scd1', 'Gene', (15, 19))	('human', 'Species', '9606', (171, 176))	('Soat1 enzymes', 'Gene', (24, 37))	('negative', 'NegReg', (54, 62))
173920	29938858	The Scd1-product oleate was decreased in the Runx1 knockout mice in the phospholipid fraction, which predominates in the plasma membrane.	('decreased', 'NegReg', (28, 37))	('Runx1', 'Gene', (45, 50))	('knockout', 'Var', (51, 59))	('oleate', 'Chemical', 'MESH:D019301', (17, 23))	('mice', 'Species', '10090', (60, 64))	('oleate', 'MPA', (17, 23))
173921	29938858	Because oleate is an unsaturated fatty acid its double bond would generate a kink in the hydrocarbon chain that may increase membrane fluidity, and possibly enhance membrane protein movement and signal transduction strength through the plasma membrane.	('membrane protein movement', 'MPA', (165, 190))	('enhance', 'PosReg', (157, 164))	('hydrocarbon', 'Chemical', 'MESH:D006838', (89, 100))	('oleate', 'Chemical', 'MESH:D019301', (8, 14))	('signal transduction strength', 'MPA', (195, 223))	('unsaturated fatty acid', 'Chemical', 'MESH:D005231', (21, 43))	('increase', 'PosReg', (116, 124))	('double bond', 'Var', (48, 59))	('kink in the hydrocarbon chain', 'MPA', (77, 106))	('membrane fluidity', 'MPA', (125, 142))
173927	29938858	Whereas Soat1 and Scd1 mutations have been associated with defects in sebaceous glands and with scarring alopecia, their potential roles in controlling hair cycle through directly promoting stem cell activation and proliferation have not been yet explored.	('sebaceous glands', 'Phenotype', 'HP:0032227', (70, 86))	('scarring alopecia', 'Disease', (96, 113))	('promoting', 'PosReg', (180, 189))	('scarring', 'Phenotype', 'HP:0100699', (96, 104))	('Scd1', 'Gene', (18, 22))	('sebaceous gland', 'Phenotype', 'HP:0032227', (70, 85))	('mutations', 'Var', (23, 32))	('associated', 'Reg', (43, 53))	('Soat1', 'Gene', (8, 13))	('alopecia', 'Phenotype', 'HP:0001596', (105, 113))	('proliferation', 'CPA', (215, 228))	('scarring alopecia', 'Disease', 'MESH:D002921', (96, 113))	('sebaceous glands', 'Disease', (70, 86))	('scarring alopecia', 'Phenotype', 'HP:0004552', (96, 113))
173932	29938858	This is particularly appealing, since spontaneous mutations in the Scd1 gene in the Asebia mice cause all growth phases of the hair cycle, anagen, catagen, and telogen to last longer than those of the controls.	('mice', 'Species', '10090', (91, 95))	('mutations', 'Var', (50, 59))	('telogen', 'CPA', (160, 167))	('anagen', 'CPA', (139, 145))	('growth phases of the hair cycle', 'CPA', (106, 137))	('catagen', 'CPA', (147, 154))	('Scd1', 'Gene', (67, 71))
173946	29938858	Evidences from cancer preclinical and clinical trials suggest that chemical inhibition of lipid metabolism enzymes may be a potentially promissing approach to block cancer.	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('cancer', 'Disease', (15, 21))	('block cancer', 'Disease', (159, 171))	('cancer', 'Disease', 'MESH:D009369', (15, 21))	('chemical inhibition', 'Var', (67, 86))	('block cancer', 'Disease', 'MESH:D009369', (159, 171))	('lipid', 'Enzyme', (90, 95))	('cancer', 'Disease', (165, 171))	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))
173948	29938858	Soat1 and Soat2) and aberrant cholesterol ester accumulation along with accumulation of oncogenic events promote prostate cancer aggressiveness.	('promote', 'PosReg', (105, 112))	('aberrant', 'Var', (21, 29))	('prostate cancer aggressiveness', 'Disease', 'MESH:D011471', (113, 143))	('prostate cancer aggressiveness', 'Disease', (113, 143))	('aggressiveness', 'Phenotype', 'HP:0000718', (129, 143))	('Soat2', 'Gene', (10, 15))	('Soat2', 'Gene', '223920', (10, 15))	('cholesterol ester', 'Chemical', 'MESH:D002788', (30, 47))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('cholesterol ester accumulation', 'MPA', (30, 60))	('cholesterol ester accumulation', 'Phenotype', 'HP:0031211', (30, 60))	('prostate cancer', 'Phenotype', 'HP:0012125', (113, 128))
173949	29938858	It is worth noting that our combination of A939572 and TMP-153 drugs to target Scd1 and Soat1 results in synergistic decrease in the proliferation of keratinocytes and of two of three human SCC cell lines.	('TMP-153', 'Chemical', 'MESH:C088280', (55, 62))	('TMP-153', 'Gene', (55, 62))	('Scd1', 'Gene', (79, 83))	('A939572', 'Chemical', 'None', (43, 50))	('A939572', 'Var', (43, 50))	('SCC', 'Gene', (190, 193))	('human', 'Species', '9606', (184, 189))	('Soat1', 'Gene', (88, 93))	('proliferation', 'CPA', (133, 146))	('decrease', 'NegReg', (117, 125))	('SCC', 'Phenotype', 'HP:0002860', (190, 193))	('SCC', 'Gene', '6317', (190, 193))
173954	29938858	6B), we need lipidome analysis from sorted hair germ and bulge stem cells at different hair cycle stages and in Runx1 mutants, and direct genetic targeting of Scd1, Soat1 and the other lipid enzymes in the HFSCs in vivo.	('HFSC', 'CellLine', 'None', (206, 210))	('Runx1', 'Gene', (112, 117))	('mutants', 'Var', (118, 125))
173966	29618619	Further analysis of the whole exomes of 109 melanoma patients demonstrated that the homozygous deletion of interferon (P = 0.0029, OR = 11.8) and defensin (P = 0.06, OR = 2.79) genes are significantly associated with resistance to anti-CTLA-4 (Cytotoxic T-Lymphocyte Associated protein 4) immunotherapy.	('interferon', 'Gene', (107, 117))	('CTLA-4', 'Gene', '1493', (236, 242))	('deletion', 'Var', (95, 103))	('patients', 'Species', '9606', (53, 61))	('melanoma', 'Phenotype', 'HP:0002861', (44, 52))	('melanoma', 'Disease', (44, 52))	('melanoma', 'Disease', 'MESH:D008545', (44, 52))	('CTLA-4', 'Gene', (236, 242))	('Cytotoxic T-Lymphocyte Associated protein 4', 'Gene', '1493', (244, 287))	('interferon', 'Gene', '3439', (107, 117))	('associated with', 'Reg', (201, 216))	('Cytotoxic T-Lymphocyte Associated protein 4', 'Gene', (244, 287))	('defensin', 'Gene', (146, 154))	('resistance to', 'CPA', (217, 230))
173969	29618619	Previous studies estimate that 25% of the cancer genome is affected by arm-level SCNAs and 10% by focal SCNAs with 2% overlap.	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('affected', 'Reg', (59, 67))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('cancer', 'Disease', (42, 48))	('SCNAs', 'Var', (81, 86))
173972	29618619	Another study exploring the copy number profiles of 3131 tumor genomes across 26 cancer types identified 158 recurrent focal SCNAs including 76 amplification affecting 1566 genes and 82 deletions affecting 2001 genes.	('amplification affecting', 'Var', (144, 167))	('focal SCNAs', 'Disease', (119, 130))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('cancer', 'Disease', (81, 87))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('tumor', 'Disease', (57, 62))	('deletions', 'Var', (186, 195))
173978	29618619	Survival analyses of different tumor types indicated that patients with homozygous deletion of interferon or defensin genes exhibit much worse overall or disease-free survival.	('worse', 'NegReg', (137, 142))	('interferon', 'Gene', '3439', (95, 105))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('disease-free survival', 'CPA', (154, 175))	('tumor', 'Disease', (31, 36))	('overall', 'CPA', (143, 150))	('homozygous deletion', 'Var', (72, 91))	('interferon', 'Gene', (95, 105))	('patients', 'Species', '9606', (58, 66))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('defensin genes', 'Gene', (109, 123))
173979	29618619	RNA-seq gene expression analyses between patients with and without IFN/DEF deletion in 19 cancer types indicate that homozygous deletions of IFN and DEF activate oncogenic and cell cycle pathways but repress immune response pathways.	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('IFN', 'Gene', '3439', (141, 144))	('repress immune response', 'Phenotype', 'HP:0002721', (200, 223))	('patients', 'Species', '9606', (41, 49))	('DEF', 'Gene', (149, 152))	('immune response pathways', 'Pathway', (208, 232))	('IFN', 'Gene', '3439', (67, 70))	('activate', 'PosReg', (153, 161))	('repress', 'NegReg', (200, 207))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('IFN', 'Gene', (141, 144))	('deletions', 'Var', (128, 137))	('IFN', 'Gene', (67, 70))
173981	29618619	Since a large body of evidence suggest that interferons and defensins play major roles in tumor immunity by recognizing tumor cells and serve as a bridge to spontaneous adaptive T cell response, our findings suggest a common molecular mechanism mediated by the deletion of interferon and defensin genes, through which tumor cells escape immune detection and destruction.	('defensin genes', 'Gene', (288, 302))	('interferon', 'Gene', '3439', (273, 283))	('interferon', 'Gene', '3439', (44, 54))	('tumor', 'Disease', 'MESH:D009369', (318, 323))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('tumor', 'Phenotype', 'HP:0002664', (318, 323))	('interferon', 'Gene', (44, 54))	('interferon', 'Gene', (273, 283))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('deletion', 'Var', (261, 269))	('tumor', 'Disease', (318, 323))	('tumor', 'Disease', (120, 125))
173994	29618619	beta = 0.2), the minimum number of required events (K) is calculated as: where Zalpha/2 = 1.96, Zbeta = 0.84, pi1 and pi2 are the proportions to be allocated into two groups and were determined by the HDI/HDD frequencies in each cancer type.	('cancer', 'Disease', (229, 235))	('pi1', 'Var', (110, 113))	('cancer', 'Disease', 'MESH:D009369', (229, 235))	('Zalpha/2 = 1.96', 'Var', (79, 94))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('pi2', 'Var', (118, 121))	('HDD', 'Disease', (205, 208))	('pi2', 'Species', '1214577', (118, 121))	('HDD', 'Disease', 'None', (205, 208))
174026	29618619	Since both interferons and defensins are involved in innate immune response and play important roles in recognizing tumor cells and inducing an anti-tumor immune response, the widespread, homozygous deletion of these genes suggests a common molecular mechanism through which tumor cells escape immune destruction.	('interferon', 'Gene', (11, 21))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('tumor', 'Phenotype', 'HP:0002664', (275, 280))	('tumor', 'Disease', (275, 280))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('interferon', 'Gene', '3439', (11, 21))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumor', 'Disease', (149, 154))	('deletion', 'Var', (199, 207))	('tumor', 'Disease', 'MESH:D009369', (275, 280))	('tumor', 'Disease', (116, 121))
174051	29618619	We asked the question whether homozygous deletions of interferon genes are passive hitchhiking events due to the nearby CDKN2A deletion, or they play an active role in tumorigenesis and affect the patient survival.	('play', 'Reg', (145, 149))	('affect', 'Reg', (186, 192))	('interferon', 'Gene', '3439', (54, 64))	('tumor', 'Disease', (168, 173))	('CDKN2A', 'Gene', (120, 126))	('interferon', 'Gene', (54, 64))	('deletion', 'Var', (127, 135))	('CDKN2A', 'Gene', '1029', (120, 126))	('patient survival', 'CPA', (197, 213))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('patient', 'Species', '9606', (197, 204))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
174053	29618619	We performed the survival analyses on three patient groups: (I) patients only have CDKN2A deletion (CDKN2A-/IFN+); (II) patients have CDKN2A deletion and additional IFN gene deletions (CDKN2A-/IFN-); and (III) patients have neither CDKN2A nor IFN gene deletions (CDKN2A+/IFN+).	('deletion', 'Var', (90, 98))	('IFN', 'Gene', '3439', (271, 274))	('IFN', 'Gene', (243, 246))	('CDKN2A nor IFN', 'Gene', '1029;3439', (232, 246))	('CDKN2A', 'Gene', (83, 89))	('CDKN2A', 'Gene', '1029', (100, 106))	('CDKN2A', 'Gene', (263, 269))	('IFN', 'Gene', (193, 196))	('patient', 'Species', '9606', (64, 71))	('CDKN2A', 'Gene', (232, 238))	('patient', 'Species', '9606', (120, 127))	('CDKN2A-/IFN+);', 'Gene', '1029;3439', (100, 114))	('IFN', 'Gene', (271, 274))	('patients', 'Species', '9606', (210, 218))	('CDKN2A', 'Gene', (185, 191))	('deletion', 'Var', (141, 149))	('CDKN2A', 'Gene', '1029', (83, 89))	('CDKN2A', 'Gene', '1029', (263, 269))	('CDKN2A', 'Gene', (134, 140))	('IFN', 'Gene', '3439', (165, 168))	('CDKN2A', 'Gene', '1029', (232, 238))	('IFN', 'Gene', '3439', (108, 111))	('CDKN2A-/IFN-', 'Gene', (185, 197))	('CDKN2A nor IFN', 'Gene', (232, 246))	('CDKN2A+/IFN+', 'Gene', '3439', (263, 275))	('IFN', 'Gene', '3439', (243, 246))	('CDKN2A', 'Gene', '1029', (185, 191))	('CDKN2A-/IFN+)', 'Gene', (100, 113))	('patient', 'Species', '9606', (44, 51))	('CDKN2A-/IFN-)', 'Gene', '1029;3439', (185, 198))	('patients', 'Species', '9606', (64, 72))	('CDKN2A+/IFN+', 'Gene', (263, 275))	('CDKN2A', 'Gene', '1029', (134, 140))	('IFN', 'Gene', (165, 168))	('patient', 'Species', '9606', (210, 217))	('CDKN2A', 'Gene', (100, 106))	('patients', 'Species', '9606', (120, 128))	('IFN', 'Gene', '3439', (193, 196))	('IFN', 'Gene', (108, 111))
174060	29618619	It could be also due to other confounding factors such as PTEN and RB1 deletions, which tend to be mutually exclusive with HDIs and HDDs (Supplementary Figure 7).	('deletions', 'Var', (71, 80))	('PTEN', 'Gene', '5728', (58, 62))	('RB1', 'Gene', (67, 70))	('RB1', 'Gene', '5925', (67, 70))	('HDIs and HDDs', 'Disease', 'None', (123, 136))	('PTEN', 'Gene', (58, 62))
174061	29618619	To identify gene expression signatures associated with the deletion of IFN and DEF genes, we performed gene expression analysis on each of the 19 cancer types (or 17 cancer types when COAD and READ are combined as colorectal cancer, LUSC and LUAD are combined as lung cancer) having high frequencies of HDI and HDD.	('cancer', 'Disease', (146, 152))	('lung cancer', 'Disease', (263, 274))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('cancer', 'Disease', (225, 231))	('COAD', 'Disease', (184, 188))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('IFN', 'Gene', '3439', (71, 74))	('cancer', 'Disease', 'MESH:D009369', (268, 274))	('HDD', 'Disease', 'None', (311, 314))	('colorectal cancer', 'Disease', 'MESH:D015179', (214, 231))	('lung cancer', 'Disease', 'MESH:D008175', (263, 274))	('colorectal cancer', 'Disease', (214, 231))	('HDD', 'Disease', (311, 314))	('cancer', 'Disease', (166, 172))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (225, 231))	('lung cancer', 'Phenotype', 'HP:0100526', (263, 274))	('IFN', 'Gene', (71, 74))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('deletion', 'Var', (59, 67))	('cancer', 'Disease', (268, 274))	('COAD', 'Disease', 'MESH:D029424', (184, 188))	('cancer', 'Phenotype', 'HP:0002664', (268, 274))	('colorectal cancer', 'Phenotype', 'HP:0003003', (214, 231))
174075	29618619	In a recent report, copy loss of type I interferon genes are found in 6 out of 12 melanoma patients that resist to anti-CTLA-4 treatment, but in none of the 4 responders (P = 0.23, two-tailed Fisher exact test).	('copy loss', 'Var', (20, 29))	('patients', 'Species', '9606', (91, 99))	('interferon', 'Gene', '3439', (40, 50))	('CTLA-4', 'Gene', '1493', (120, 126))	('melanoma', 'Phenotype', 'HP:0002861', (82, 90))	('melanoma', 'Disease', (82, 90))	('interferon', 'Gene', (40, 50))	('melanoma', 'Disease', 'MESH:D008545', (82, 90))	('CTLA-4', 'Gene', (120, 126))
174080	29618619	As a comparison, deletions of two tumor suppressor genes CDKN2A (P = 0.63) and PTEN (P = 0.55) are not associated with responders or non-responders (Fig.	('tumor', 'Disease', (34, 39))	('CDKN2A', 'Gene', (57, 63))	('deletions', 'Var', (17, 26))	('CDKN2A', 'Gene', '1029', (57, 63))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('PTEN', 'Gene', (79, 83))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('PTEN', 'Gene', '5728', (79, 83))
174081	29618619	Taken together, our meta-analyses of two independent melanoma cohorts suggest the deletion of interferon and defensin genes is significantly associated anti-CTLA-4 treatment resistance, and might be a potential prognostic biomarker to predict resistance to other immunotherapies.	('CTLA-4', 'Gene', (157, 163))	('interferon', 'Gene', (94, 104))	('melanoma', 'Phenotype', 'HP:0002861', (53, 61))	('melanoma', 'Disease', (53, 61))	('CTLA-4', 'Gene', '1493', (157, 163))	('deletion', 'Var', (82, 90))	('melanoma', 'Disease', 'MESH:D008545', (53, 61))	('associated', 'Reg', (141, 151))	('interferon', 'Gene', '3439', (94, 104))
174083	29618619	In this study, we analyzed the copy number profiles of 10,759 primary cancer tissues and found the homozygous deletions of type I interferon and defensin genes are pervasive in 19 TCGA cancer types, and the alteration frequency is much higher than those of well-known tumor suppressors PTEN and RB1 in the same cancer type (Supplementary Figure 7).	('interferon', 'Gene', '3439', (130, 140))	('PTEN', 'Gene', '5728', (286, 290))	('cancer', 'Disease', (311, 317))	('defensin', 'Gene', (145, 153))	('cancer', 'Disease', (185, 191))	('cancer', 'Phenotype', 'HP:0002664', (311, 317))	('tumor', 'Phenotype', 'HP:0002664', (268, 273))	('RB1', 'Gene', '5925', (295, 298))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (311, 317))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('PTEN', 'Gene', (286, 290))	('tumor', 'Disease', (268, 273))	('interferon', 'Gene', (130, 140))	('RB1', 'Gene', (295, 298))	('deletions', 'Var', (110, 119))	('tumor', 'Disease', 'MESH:D009369', (268, 273))
174084	29618619	More importantly, homozygous deletions of interferon and defensin genes associate with worse overall or disease-free survival, and the resistance to anti-CTLA4 treatment in melanoma patients.	('defensin', 'Gene', (57, 65))	('CTLA4', 'Gene', (154, 159))	('worse', 'NegReg', (87, 92))	('melanoma', 'Phenotype', 'HP:0002861', (173, 181))	('melanoma', 'Disease', (173, 181))	('interferon', 'Gene', '3439', (42, 52))	('melanoma', 'Disease', 'MESH:D008545', (173, 181))	('disease-free survival', 'CPA', (104, 125))	('resistance', 'CPA', (135, 145))	('patients', 'Species', '9606', (182, 190))	('overall', 'CPA', (93, 100))	('interferon', 'Gene', (42, 52))	('CTLA4', 'Gene', '1493', (154, 159))	('homozygous deletions', 'Var', (18, 38))
174085	29618619	Defects in the type I interferon signaling pathway have been proposed as a potential mechanism of cancer escape (insensitivity) to immunotherapy in mice and prostate cancer cell line.	('prostate cancer', 'Disease', 'MESH:D011471', (157, 172))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('interferon', 'Gene', '3439', (22, 32))	('cancer', 'Disease', (166, 172))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('prostate cancer', 'Phenotype', 'HP:0012125', (157, 172))	('Defects', 'Var', (0, 7))	('interferon', 'Gene', (22, 32))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('mice', 'Species', '10090', (148, 152))	('cancer', 'Disease', (98, 104))	('prostate cancer', 'Disease', (157, 172))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))
174090	29618619	By analyzing the genomes of 10,759 cancer patients across 31 cancer types, we found interferon and defensin genes are homozygously deleted with high frequencies in 19 cancer types, and the surviving time of patients with these deletions are significantly reduced.	('reduced', 'NegReg', (255, 262))	('patients', 'Species', '9606', (207, 215))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('interferon', 'Gene', (84, 94))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('surviving time', 'CPA', (189, 203))	('cancer', 'Disease', (167, 173))	('cancer', 'Disease', (61, 67))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('interferon', 'Gene', '3439', (84, 94))	('deletions', 'Var', (227, 236))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('patients', 'Species', '9606', (42, 50))	('defensin genes', 'Gene', (99, 113))	('cancer', 'Disease', (35, 41))
174101	29899458	The 2-year cumulative recurrence rate of patients with higher lambdaHU values was significantly higher than that of patients with lower lambdaHU values (P < 0.05), while the 2-year survival rate of those patients was not significantly different (P > 0.05).	('lambdaHU values', 'Var', (62, 77))	('patients', 'Species', '9606', (204, 212))	('patients', 'Species', '9606', (116, 124))	('patients', 'Species', '9606', (41, 49))	('higher', 'PosReg', (96, 102))	('cumulative recurrence', 'CPA', (11, 32))
174153	29899458	The 2-year follow-up also confirmed that patients with a higher lambdaHU values were more prone to have early local recurrence (41.67% VS 61.54%, P < 0.05).	('patients', 'Species', '9606', (41, 49))	('lambdaHU', 'Gene', (64, 72))	('higher', 'Var', (57, 63))
174155	29899458	A previous study suggested that after treatment, the advanced LHSCC patients with NCR had higher localized control failure rates than the CR patients, and other studies showed that the main factors affecting the prognosis of advanced LHSCC patients were local recurrence and metastasis.	('metastasis', 'CPA', (275, 285))	('CR', 'Chemical', '-', (83, 85))	('patients', 'Species', '9606', (141, 149))	('LHSCC', 'Chemical', '-', (234, 239))	('CR', 'Chemical', '-', (138, 140))	('patients', 'Species', '9606', (68, 76))	('LHSCC', 'Chemical', '-', (62, 67))	('patients', 'Species', '9606', (240, 248))	('localized control failure', 'CPA', (97, 122))	('higher', 'PosReg', (90, 96))	('NCR', 'Var', (82, 85))
174240	27246533	In squamous cell carcinoma (SCC), as the rs2228000, rs2228001 (XPC), rs2273953 (TP73), rs2279744 (MDM2), rs2299939 (PTEN) and rs8178085, rs12334811 (DNA-PKcs) affected the sensitivity to chemotherapy, so did the rs8178085, rs12334811 to radiotherapy.	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (3, 26))	('rs2228000', 'Mutation', 'rs2228000', (41, 50))	('SCC', 'Gene', '6317', (28, 31))	('carcinoma', 'Phenotype', 'HP:0030731', (17, 26))	('PTEN', 'Gene', (116, 120))	('rs8178085', 'Var', (212, 221))	('rs8178085', 'Var', (126, 135))	('squamous cell carcinoma', 'Disease', (3, 26))	('rs12334811', 'Mutation', 'rs12334811', (137, 147))	('DNA-PKcs', 'Gene', '5591', (149, 157))	('rs12334811', 'Mutation', 'rs12334811', (223, 233))	('MDM2', 'Gene', (98, 102))	('SCC', 'Gene', (28, 31))	('P73', 'Gene', (81, 84))	('rs12334811', 'Var', (137, 147))	('rs12334811', 'Var', (223, 233))	('PTEN', 'Gene', '5728', (116, 120))	('rs2279744', 'Var', (87, 96))	('rs2273953', 'Var', (69, 78))	('MDM2', 'Gene', '4193', (98, 102))	('sensitivity to chemotherapy', 'MPA', (172, 199))	('rs2299939', 'Var', (105, 114))	('rs8178085', 'Mutation', 'rs8178085', (212, 221))	('rs8178085', 'Mutation', 'rs8178085', (126, 135))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (3, 26))	('rs2228000', 'Var', (41, 50))	('rs2299939', 'Mutation', 'rs2299939', (105, 114))	('rs2228001', 'Mutation', 'rs2228001', (52, 61))	('XPC', 'Gene', '7508', (63, 66))	('DNA-PKcs', 'Gene', (149, 157))	('rs2228001', 'Var', (52, 61))	('rs2273953', 'Mutation', 'rs2273953', (69, 78))	('affected', 'Reg', (159, 167))	('P73', 'Gene', '7161', (81, 84))	('rs2279744', 'Mutation', 'rs2279744', (87, 96))	('XPC', 'Gene', (63, 66))
174241	27246533	Moreover rs344781, rs2273953 and rs12334811 were related with the survival time of SCC.	('rs344781', 'Var', (9, 17))	('rs344781', 'Mutation', 'rs344781', (9, 17))	('SCC', 'Gene', (83, 86))	('rs12334811', 'Mutation', 'rs12334811', (33, 43))	('rs2273953', 'Var', (19, 28))	('SCC', 'Gene', '6317', (83, 86))	('related', 'Reg', (49, 56))	('rs2273953', 'Mutation', 'rs2273953', (19, 28))	('rs12334811', 'Var', (33, 43))
174242	27246533	In general, the "good" genotype GG (rs12334811) showed greater efficacy of radio-chemotherapy and MSF (24 months) on SCC.	('rs12334811', 'Var', (36, 46))	('greater efficacy', 'PosReg', (55, 71))	('SCC', 'Gene', (117, 120))	('SCC', 'Gene', '6317', (117, 120))	('radio-chemotherapy', 'CPA', (75, 93))	('rs12334811', 'Mutation', 'rs12334811', (36, 46))
174243	27246533	In adenocarcinoma, as the rs2699887 (PIK3), rs12334811 (DNA-PKcs) influenced the sensitivity to chemotherapy, so did the rs2299939, rs2735343 (PTEN) to radiotherapy.	('rs12334811', 'Var', (44, 54))	('PIK3', 'Gene', (37, 41))	('PIK3', 'Gene', '5294', (37, 41))	('rs2735343', 'Var', (132, 141))	('carcinoma', 'Phenotype', 'HP:0030731', (8, 17))	('rs2299939', 'Var', (121, 130))	('rs2699887', 'Var', (26, 35))	('rs2699887', 'Mutation', 'rs2699887', (26, 35))	('DNA-PKcs', 'Gene', (56, 64))	('adenocarcinoma', 'Disease', (3, 17))	('PTEN', 'Gene', (143, 147))	('rs2299939', 'Mutation', 'rs2299939', (121, 130))	('adenocarcinoma', 'Disease', 'MESH:D000230', (3, 17))	('rs12334811', 'Mutation', 'rs12334811', (44, 54))	('rs2735343', 'Mutation', 'rs2735343', (132, 141))	('PTEN', 'Gene', '5728', (143, 147))	('influenced', 'Reg', (66, 76))	('DNA-PKcs', 'Gene', '5591', (56, 64))	('sensitivity to chemotherapy', 'MPA', (81, 108))
174244	27246533	And rs402710, rs80270, rs2279744 and rs2909430 impacted the survival time of the adenocarcinoma patients.	('rs402710', 'Mutation', 'rs402710', (4, 12))	('rs402710', 'Var', (4, 12))	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('adenocarcinoma', 'Disease', (81, 95))	('rs80270', 'Mutation', 'rs80270', (14, 21))	('rs2909430', 'Mutation', 'rs2909430', (37, 46))	('adenocarcinoma', 'Disease', 'MESH:D000230', (81, 95))	('rs2909430', 'Var', (37, 46))	('rs2279744', 'Mutation', 'rs2279744', (23, 32))	('patients', 'Species', '9606', (96, 104))	('rs2279744', 'Var', (23, 32))	('rs80270', 'Var', (14, 21))	('impacted', 'Reg', (47, 55))	('survival time', 'CPA', (60, 73))
174245	27246533	Both GG (rs2279744) and AG (rs2909430) showed a shorter survival time (MFS = 6).	('rs2909430', 'Mutation', 'rs2909430', (28, 37))	('rs2279744', 'Mutation', 'rs2279744', (9, 18))	('shorter', 'NegReg', (48, 55))	('rs2279744', 'Var', (9, 18))	('survival time', 'CPA', (56, 69))	('rs2909430', 'Var', (28, 37))
174246	27246533	Additionally, some SNPs such as rs2228000, rs2228001 and rs344781 were found to regulate the expression of DNA repair pathway genes through eQTLs dataset analysis.	('rs2228001', 'Var', (43, 52))	('regulate', 'Reg', (80, 88))	('rs344781', 'Var', (57, 65))	('rs344781', 'Mutation', 'rs344781', (57, 65))	('rs2228000', 'Var', (32, 41))	('rs2228000', 'Mutation', 'rs2228000', (32, 41))	('expression', 'MPA', (93, 103))	('rs2228001', 'Mutation', 'rs2228001', (43, 52))	('DNA repair pathway', 'Pathway', (107, 125))
174247	27246533	These results indicate that SNPs in DNA repair pathway genes might regulate the expression and affect the DNA damage repair, and thereby impact the efficacy of radio-chemotherapy and the survival time of NSCLC.	('regulate', 'Reg', (67, 75))	('DNA damage repair', 'MPA', (106, 123))	('impact', 'NegReg', (137, 143))	('NSCLC', 'Disease', (204, 209))	('NSCLC', 'Disease', 'MESH:D002289', (204, 209))	('DNA repair pathway genes', 'Gene', (36, 60))	('affect', 'Reg', (95, 101))	('expression', 'MPA', (80, 90))	('SNPs', 'Var', (28, 32))	('efficacy of radio-chemotherapy', 'CPA', (148, 178))
174266	27246533	Now, it has been widely used to study the biomarkers for the survival, advanced, and susceptibility of the NSCLC by using high-throughput genotyping technology and selecting tagging SNPs across the whole genome.	('tagging SNPs', 'Var', (174, 186))	('NSCLC', 'Disease', 'MESH:D002289', (107, 112))	('NSCLC', 'Disease', (107, 112))
174269	27246533	Genetic variation in DNA damage repair genes is a universal phenomenon in living organisms, which can change the repair capacities of individuals to DNA damages and then affect the survival status of tumor patients.	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('Genetic variation', 'Var', (0, 17))	('change', 'Reg', (102, 108))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('affect', 'Reg', (170, 176))	('tumor', 'Disease', (200, 205))	('survival status', 'CPA', (181, 196))	('repair capacities', 'MPA', (113, 130))	('patients', 'Species', '9606', (206, 214))
174271	27246533	Therefore, based on the assumption that SNPs of genes in multiple related pathways affect DNA repair, this study sought to analyze the correlation between SNPs and the outcomes of radio-chemotherapy, discuss the differential treatment efficacy of non-small cell lung cancers based on different genotypes of SNPs in DNA damage repair pathway genes and provide reliable support for clinical treatment regimens.	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (247, 273))	('affect', 'Reg', (83, 89))	('non-small cell lung cancers', 'Disease', 'MESH:D002289', (247, 274))	('SNPs', 'Var', (40, 44))	('non-small cell lung cancers', 'Disease', (247, 274))	('non-small cell lung cancers', 'Phenotype', 'HP:0030358', (247, 274))	('cancers', 'Phenotype', 'HP:0002664', (267, 274))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (251, 273))	('cancer', 'Phenotype', 'HP:0002664', (267, 273))	('small cell lung cancers', 'Phenotype', 'HP:0030357', (251, 274))	('lung cancer', 'Phenotype', 'HP:0100526', (262, 273))	('lung cancers', 'Phenotype', 'HP:0100526', (262, 274))	('DNA', 'Gene', (315, 318))	('DNA repair', 'MPA', (90, 100))	('SNPs', 'Var', (307, 311))
174272	27246533	To extensively explore the relation between DNA damage repair and the efficacy of radio-chemotherapy of lung cancers, this study analyzed the SNPs in DNA damage repair-related genes.	('cancers', 'Phenotype', 'HP:0002664', (109, 116))	('lung cancers', 'Disease', (104, 116))	('lung cancer', 'Phenotype', 'HP:0100526', (104, 115))	('lung cancers', 'Disease', 'MESH:D008175', (104, 116))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('lung cancers', 'Phenotype', 'HP:0100526', (104, 116))	('SNPs', 'Var', (142, 146))
174281	27246533	Table 2 showed the correlation analysis results about the radio-chemotherapy treatment efficacy of 90 squamous cell carcinoma patients and 26 SNPs in DNA damage repair-related genes.	('squamous cell carcinoma', 'Disease', (102, 125))	('patients', 'Species', '9606', (126, 134))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (102, 125))	('SNPs', 'Var', (142, 146))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (102, 125))
174282	27246533	The results showed that the SNPs in XPC (rs2228000 and rs2228001), TP73 (rs2273953), MDM2 (rs2279744), PTEN (rs2299939) and DNA-PKcs (rs8178085 and rs12334811) genes significantly affected the sensitivity of lung squamous cell carcinoma to chemotherapy.	('rs2273953', 'Var', (73, 82))	('rs12334811', 'Var', (148, 158))	('PTEN', 'Gene', '5728', (103, 107))	('rs2228000', 'Mutation', 'rs2228000', (41, 50))	('MDM2', 'Gene', (85, 89))	('rs2299939', 'Var', (109, 118))	('XPC', 'Gene', '7508', (36, 39))	('P73', 'Gene', (68, 71))	('rs8178085', 'Var', (134, 143))	('sensitivity', 'MPA', (193, 204))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (213, 236))	('DNA-PKcs', 'Gene', '5591', (124, 132))	('rs2279744', 'Var', (91, 100))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (208, 236))	('XPC', 'Gene', (36, 39))	('MDM2', 'Gene', '4193', (85, 89))	('rs2299939', 'Mutation', 'rs2299939', (109, 118))	('rs2273953', 'Mutation', 'rs2273953', (73, 82))	('affected', 'Reg', (180, 188))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (208, 236))	('lung squamous cell carcinoma', 'Disease', (208, 236))	('rs8178085', 'Mutation', 'rs8178085', (134, 143))	('rs2228001', 'Mutation', 'rs2228001', (55, 64))	('rs2279744', 'Mutation', 'rs2279744', (91, 100))	('rs2228001', 'Var', (55, 64))	('P73', 'Gene', '7161', (68, 71))	('PTEN', 'Gene', (103, 107))	('rs2228000', 'Var', (41, 50))	('carcinoma', 'Phenotype', 'HP:0030731', (227, 236))	('DNA-PKcs', 'Gene', (124, 132))	('rs12334811', 'Mutation', 'rs12334811', (148, 158))
174283	27246533	With the chemotherapy treatment of squamous cell carcinoma, among patients of the same age and clinical stage, patients with non-CC homozygous genotypes of the SNP rs2228000 (XPC) showed higher chemotherapy efficacy (OR = 3.94) compared with the CC homozygous genotype patients.	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (35, 58))	('squamous cell carcinoma', 'Disease', (35, 58))	('XPC', 'Gene', '7508', (175, 178))	('chemotherapy efficacy', 'CPA', (194, 215))	('patients', 'Species', '9606', (66, 74))	('rs2228000', 'Var', (164, 173))	('SNP', 'Var', (160, 163))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (35, 58))	('rs2228000', 'Mutation', 'rs2228000', (164, 173))	('XPC', 'Gene', (175, 178))	('patients', 'Species', '9606', (269, 277))	('higher', 'PosReg', (187, 193))	('patients', 'Species', '9606', (111, 119))
174284	27246533	Patients with the AC heterozygous genotype of the SNP rs2228001 (XPC) showed better chemotherapy efficacy than patients with a CC homozygous genotype (OR = 6.17).	('better', 'PosReg', (77, 83))	('XPC', 'Gene', '7508', (65, 68))	('chemotherapy efficacy', 'CPA', (84, 105))	('Patients', 'Species', '9606', (0, 8))	('rs2228001', 'Mutation', 'rs2228001', (54, 63))	('rs2228001', 'Var', (54, 63))	('XPC', 'Gene', (65, 68))	('patients', 'Species', '9606', (111, 119))
174285	27246533	Patients with a CC homozygous genotype of the SNP rs2273953 (TP73) demonstrated curve effect than patients with a CC homozygous genotype (OR = 17.67).	('P73', 'Gene', '7161', (62, 65))	('rs2273953', 'Var', (50, 59))	('patients', 'Species', '9606', (98, 106))	('rs2273953', 'Mutation', 'rs2273953', (50, 59))	('Patients', 'Species', '9606', (0, 8))	('P73', 'Gene', (62, 65))	('curve effect', 'MPA', (80, 92))
174286	27246533	Patients with non-TT homozygous genotypes of the SNP rs2279744 (MDM2) showed higher chemotherapy efficacy than patients with a TT homozygous genotype (OR = 4.54).	('SNP', 'Gene', (49, 52))	('MDM2', 'Gene', '4193', (64, 68))	('MDM2', 'Gene', (64, 68))	('higher', 'PosReg', (77, 83))	('chemotherapy efficacy', 'CPA', (84, 105))	('rs2279744', 'Mutation', 'rs2279744', (53, 62))	('Patients', 'Species', '9606', (0, 8))	('rs2279744', 'Var', (53, 62))	('patients', 'Species', '9606', (111, 119))
174287	27246533	Patients with a CC homozygous genotype of the SNP rs2299939 (PTEN) is better than patients with a non-CC homozygous genotype (OR = 4.29).	('rs2299939', 'Var', (50, 59))	('patients', 'Species', '9606', (82, 90))	('better', 'PosReg', (70, 76))	('Patients', 'Species', '9606', (0, 8))	('PTEN', 'Gene', (61, 65))	('PTEN', 'Gene', '5728', (61, 65))	('rs2299939', 'Mutation', 'rs2299939', (50, 59))
174288	27246533	Patients with a GG homozygous genotype of the SNP rs12334811 (DNA-PKcs) (in the non-AG heterozygous genotypes, only one case of an AA homozygote was detected) revealed better impact than patients with an AG heterozygous genotype (OR = 4.22).	('patients', 'Species', '9606', (187, 195))	('DNA-PKcs', 'Gene', (62, 70))	('rs12334811', 'Var', (50, 60))	('better', 'PosReg', (168, 174))	('Patients', 'Species', '9606', (0, 8))	('impact', 'MPA', (175, 181))	('rs12334811', 'Mutation', 'rs12334811', (50, 60))	('DNA-PKcs', 'Gene', '5591', (62, 70))
174289	27246533	Additionally, patients with a CA heterozygous genotype of SNP rs8178085 (DNA-PKcs) were completely insensitive to chemotherapy.	('rs8178085', 'Var', (62, 71))	('DNA-PKcs', 'Gene', (73, 81))	('rs8178085', 'Mutation', 'rs8178085', (62, 71))	('patients', 'Species', '9606', (14, 22))	('SNP', 'Gene', (58, 61))	('DNA-PKcs', 'Gene', '5591', (73, 81))
174290	27246533	With the radiotherapy treatment of squamous cell carcinoma, we found that the rs12334811 and rs8178085 were sensitive to radiotherapy.	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (35, 58))	('rs8178085', 'Var', (93, 102))	('squamous cell carcinoma', 'Disease', (35, 58))	('rs12334811', 'Var', (78, 88))	('rs8178085', 'Mutation', 'rs8178085', (93, 102))	('rs12334811', 'Mutation', 'rs12334811', (78, 88))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (35, 58))
174291	27246533	Patients with a GG homozygous genotype of rs12334811 (DNA-PKcs) showed higher radiotherapy efficacy than patients with an AG heterozygous genotype (OR = 4.97).	('higher', 'PosReg', (71, 77))	('rs12334811', 'Mutation', 'rs12334811', (42, 52))	('patients', 'Species', '9606', (105, 113))	('DNA-PKcs', 'Gene', '5591', (54, 62))	('Patients', 'Species', '9606', (0, 8))	('DNA-PKcs', 'Gene', (54, 62))	('rs12334811', 'Var', (42, 52))	('radiotherapy efficacy', 'CPA', (78, 99))
174292	27246533	Patients with an AA homozygous genotype of rs8178085 (DNA-PKcs) is better effect than patients with non-CA heterozygous genotypes (OR = 9.49).	('DNA-PKcs', 'Gene', '5591', (54, 62))	('rs8178085', 'Mutation', 'rs8178085', (43, 52))	('Patients', 'Species', '9606', (0, 8))	('rs8178085', 'Var', (43, 52))	('DNA-PKcs', 'Gene', (54, 62))	('patients', 'Species', '9606', (86, 94))
174293	27246533	We found that many SNPs in DNA damage-repair genes were correlated with squamous cell carcinoma sensitivity to radio-chemotherapy.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (72, 95))	('SNPs', 'Var', (19, 23))	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (72, 95))	('squamous cell carcinoma', 'Disease', (72, 95))	('DNA damage-repair genes', 'Gene', (27, 50))	('correlated', 'Reg', (56, 66))
174294	27246533	Among them, the GG homozygous genotype of rs12334811 and the AA homozygous genotype of rs8178085 of the DNA-PKcs gene belong to "good" genotypes, which demonstrate significant sensitivity to radio-chemotherapy.	('rs12334811', 'Mutation', 'rs12334811', (42, 52))	('rs8178085', 'Var', (87, 96))	('DNA-PKcs', 'Gene', (104, 112))	('rs12334811', 'Var', (42, 52))	('DNA-PKcs', 'Gene', '5591', (104, 112))	('rs8178085', 'Mutation', 'rs8178085', (87, 96))
174296	27246533	Through the correlation analysis of radio-chemotherapy treatment efficacy in 63 adenocarcinoma patients and SNP sites on DNA repair-related genes, we found that in chemotherapy treatment of adenocarcinoma, SNPs in PIK3 (rs2699887) and DNA-PKcs (rs12334811) significantly affected the sensitivity to chemotherapy.	('adenocarcinoma', 'Disease', 'MESH:D000230', (190, 204))	('rs2699887', 'Var', (220, 229))	('DNA-PKcs', 'Gene', '5591', (235, 243))	('patients', 'Species', '9606', (95, 103))	('adenocarcinoma', 'Disease', 'MESH:D000230', (80, 94))	('rs2699887', 'Mutation', 'rs2699887', (220, 229))	('affected', 'Reg', (271, 279))	('rs12334811', 'Mutation', 'rs12334811', (245, 255))	('PIK3', 'Gene', (214, 218))	('DNA-PKcs', 'Gene', (235, 243))	('adenocarcinoma', 'Disease', (190, 204))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (195, 204))	('adenocarcinoma', 'Disease', (80, 94))	('PIK3', 'Gene', '5294', (214, 218))	('sensitivity to chemotherapy', 'MPA', (284, 311))	('rs12334811', 'Var', (245, 255))
174297	27246533	Patients with an AG heterozygous genotype of rs2699887 (PIK3) showed higher chemotherapy efficacy than GG homozygous genotype (OR = 14.98).	('chemotherapy efficacy', 'CPA', (76, 97))	('rs2699887', 'Var', (45, 54))	('PIK3', 'Gene', (56, 60))	('Patients', 'Species', '9606', (0, 8))	('rs2699887', 'Mutation', 'rs2699887', (45, 54))	('PIK3', 'Gene', '5294', (56, 60))	('higher', 'PosReg', (69, 75))
174298	27246533	Patients with an AG heterozygous genotype of rs12334811 (DNA-PKcs) is better than GG homozygous genotype (OR = 4.63).	('rs12334811', 'Mutation', 'rs12334811', (45, 55))	('DNA-PKcs', 'Gene', '5591', (57, 65))	('Patients', 'Species', '9606', (0, 8))	('DNA-PKcs', 'Gene', (57, 65))	('rs12334811', 'Var', (45, 55))
174299	27246533	In radiotherapy treatment of adenocarcinoma, we found that rs2299939 and rs2735343 in PTEN gene were sensitive to radiotherapy of adenocarcinoma.	('adenocarcinoma', 'Disease', 'MESH:D000230', (29, 43))	('adenocarcinoma', 'Disease', (130, 144))	('PTEN', 'Gene', (86, 90))	('rs2735343', 'Mutation', 'rs2735343', (73, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('PTEN', 'Gene', '5728', (86, 90))	('adenocarcinoma', 'Disease', 'MESH:D000230', (130, 144))	('rs2299939', 'Mutation', 'rs2299939', (59, 68))	('rs2299939', 'Var', (59, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (34, 43))	('adenocarcinoma', 'Disease', (29, 43))	('rs2735343', 'Var', (73, 82))
174300	27246533	Patients with a non-CC homozygous genotype of rs2299939 (PTEN) showed higher radiotherapy efficacy than CC homozygote genotype (OR = 15.64).	('radiotherapy efficacy', 'CPA', (77, 98))	('rs2299939', 'Var', (46, 55))	('PTEN', 'Gene', (57, 61))	('Patients', 'Species', '9606', (0, 8))	('PTEN', 'Gene', '5728', (57, 61))	('higher', 'PosReg', (70, 76))	('rs2299939', 'Mutation', 'rs2299939', (46, 55))
174301	27246533	Patients with a non-CC homozygous genotype of rs2735343 (PTEN) is better than CC homozygous genotype (OR = 6.13).	('rs2735343', 'Var', (46, 55))	('rs2735343', 'Mutation', 'rs2735343', (46, 55))	('PTEN', 'Gene', (57, 61))	('Patients', 'Species', '9606', (0, 8))	('PTEN', 'Gene', '5728', (57, 61))
174304	27246533	Three SNPs (rs344781, rs2273953 and rs12334811) have a significant effect on the survival of patients with squamous cell carcinoma (Table 4).	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('rs344781', 'Var', (12, 20))	('rs344781', 'Mutation', 'rs344781', (12, 20))	('rs12334811', 'Var', (36, 46))	('rs2273953', 'Mutation', 'rs2273953', (22, 31))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (107, 130))	('effect', 'Reg', (67, 73))	('squamous cell carcinoma', 'Disease', (107, 130))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (107, 130))	('rs12334811', 'Mutation', 'rs12334811', (36, 46))	('rs2273953', 'Var', (22, 31))	('patients', 'Species', '9606', (93, 101))
174305	27246533	Among patients of the same age and clinical stage, patients with a CC homozygous genotype of rs2273953 had longer OS than TT homozygous genotype (P < 0.05) and longer PFS than CT heterozygous genotype (P < 0.05).	('longer', 'PosReg', (160, 166))	('rs2273953', 'Var', (93, 102))	('PFS', 'MPA', (167, 170))	('longer', 'PosReg', (107, 113))	('patients', 'Species', '9606', (6, 14))	('patients', 'Species', '9606', (51, 59))	('rs2273953', 'Mutation', 'rs2273953', (93, 102))
174306	27246533	Patients with a GG homozygous genotype of rs12334811 had longer OS than AG heterozygous genotype (P < 0.01).	('longer', 'PosReg', (57, 63))	('rs12334811', 'Var', (42, 52))	('rs12334811', 'Mutation', 'rs12334811', (42, 52))	('Patients', 'Species', '9606', (0, 8))
174307	27246533	Patients with a TT homozygous genotype of rs344781 had longer PFS than CC homozygous genotype (P < 0.05).	('PFS', 'CPA', (62, 65))	('Patients', 'Species', '9606', (0, 8))	('rs344781', 'Var', (42, 50))	('longer', 'PosReg', (55, 61))	('rs344781', 'Mutation', 'rs344781', (42, 50))
174308	27246533	Meanwhile, we found that patients with a GG homozygous genotype of rs2273953 (DNA-PKcs) had significant sensitivity to radio-chemotherapy of squamous cell carcinoma, and patients with a CC homozygous genotype of rs12334811 (TP73) showed significant sensitivity to chemotherapy of squamous cell carcinoma.	('DNA-PKcs', 'Gene', '5591', (78, 86))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (280, 303))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (141, 164))	('rs2273953', 'Mutation', 'rs2273953', (67, 76))	('P73', 'Gene', (225, 228))	('sensitivity', 'MPA', (104, 115))	('carcinoma', 'Phenotype', 'HP:0030731', (294, 303))	('squamous cell carcinoma', 'Disease', (280, 303))	('patients', 'Species', '9606', (170, 178))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (141, 164))	('patients', 'Species', '9606', (25, 33))	('DNA-PKcs', 'Gene', (78, 86))	('carcinoma', 'Phenotype', 'HP:0030731', (155, 164))	('rs12334811', 'Mutation', 'rs12334811', (212, 222))	('squamous cell carcinoma', 'Disease', (141, 164))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (280, 303))	('rs2273953', 'Var', (67, 76))	('rs12334811', 'Var', (212, 222))	('P73', 'Gene', '7161', (225, 228))
174309	27246533	The results indicate that the SNPs in these two genes may have important implications for the treatment and prognosis of squamous cell carcinoma.	('implications', 'Reg', (73, 85))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (121, 144))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('squamous cell carcinoma', 'Disease', (121, 144))	('SNPs', 'Var', (30, 34))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (121, 144))
174310	27246533	The correlation analysis of SNPs and the survival time of all adenocarcinoma patients revealed that among patients of the same age and clinical stage, patients with a CC homozygous genotype of rs402710 (CLPTM1L) had longer PFS compared with CT heterozygous genotype (P < 0.05).Patients with an AA homozygous genotype of rs80270 (CDKN1A) prolong PFS compared with patients with a CC homozygous genotype (P < 0.05).	('rs80270', 'Mutation', 'rs80270', (320, 327))	('prolong', 'PosReg', (337, 344))	('patients', 'Species', '9606', (363, 371))	('rs402710', 'Mutation', 'rs402710', (193, 201))	('CDKN1A', 'Gene', (329, 335))	('adenocarcinoma', 'Disease', (62, 76))	('patients', 'Species', '9606', (151, 159))	('Patients', 'Species', '9606', (277, 285))	('CLPTM1L', 'Gene', '81037', (203, 210))	('CDKN1A', 'Gene', '1026', (329, 335))	('CLPTM1L', 'Gene', (203, 210))	('patients', 'Species', '9606', (106, 114))	('PFS', 'MPA', (345, 348))	('patients', 'Species', '9606', (77, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('adenocarcinoma', 'Disease', 'MESH:D000230', (62, 76))	('rs80270', 'Var', (320, 327))
174311	27246533	Patients with a GT heterozygous genotype of rs2279744 (MDM2) had longer PFS and OS (P < 0.05).	('Patients', 'Species', '9606', (0, 8))	('longer', 'PosReg', (65, 71))	('rs2279744', 'Mutation', 'rs2279744', (44, 53))	('MDM2', 'Gene', '4193', (55, 59))	('MDM2', 'Gene', (55, 59))	('rs2279744', 'Var', (44, 53))
174312	27246533	Patients with an AA homozygous genotype of rs2909430 (TP53) had better OS compared with patients with an AG heterozygous genotype (P = 0.016), as shown in Table 4.	('better', 'PosReg', (64, 70))	('patients', 'Species', '9606', (88, 96))	('Patients', 'Species', '9606', (0, 8))	('rs2909430', 'Var', (43, 52))	('TP53', 'Gene', '7157', (54, 58))	('TP53', 'Gene', (54, 58))	('rs2909430', 'Mutation', 'rs2909430', (43, 52))
174314	27246533	Together with earlier results showing that PIK3 had sensitivity to chemotherapy in adenocarcinoma and PTEN had sensitivity to radiotherapy in adenocarcinoma, these findings suggest that the polymorphisms in PTEN, PI3K, Mdm2 and p53 genes, which belong to a functionally related network, may function cooperatively in the radio-chemotherapy and survival time of adenocarcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (366, 375))	('Mdm2', 'Gene', (219, 223))	('adenocarcinoma', 'Disease', (142, 156))	('function', 'Reg', (291, 299))	('PTEN', 'Gene', '5728', (102, 106))	('adenocarcinoma', 'Disease', (83, 97))	('p53', 'Gene', '7157', (228, 231))	('adenocarcinoma', 'Disease', (361, 375))	('PIK3', 'Gene', (43, 47))	('adenocarcinoma', 'Disease', 'MESH:D000230', (142, 156))	('polymorphisms', 'Var', (190, 203))	('PIK3', 'Gene', '5294', (43, 47))	('PTEN', 'Gene', (207, 211))	('p53', 'Gene', (228, 231))	('PI3K', 'Gene', (213, 217))	('adenocarcinoma', 'Disease', 'MESH:D000230', (83, 97))	('adenocarcinoma', 'Disease', 'MESH:D000230', (361, 375))	('Mdm2', 'Gene', '4193', (219, 223))	('PTEN', 'Gene', '5728', (207, 211))	('PTEN', 'Gene', (102, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (147, 156))
174316	27246533	In the analysis of squamous cell carcinoma, we chose three SNPs with longer survival time, rs344781 (PLAUR, TT homozygote), rs2273953 (TP73, CC homozygote) and rs12334811 (DNPK1, GG homozygote), to do stepwise regression analysis, and the results are shown in Fig.	('P73', 'Gene', '7161', (136, 139))	('rs12334811', 'Var', (160, 170))	('DNPK1', 'Gene', '5591', (172, 177))	('rs344781', 'Var', (91, 99))	('rs344781', 'Mutation', 'rs344781', (91, 99))	('rs2273953', 'Var', (124, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (33, 42))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (19, 42))	('DNPK1', 'Gene', (172, 177))	('PLAUR', 'Gene', (101, 106))	('rs12334811', 'Mutation', 'rs12334811', (160, 170))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (19, 42))	('squamous cell carcinoma', 'Disease', (19, 42))	('P73', 'Gene', (136, 139))	('rs2273953', 'Mutation', 'rs2273953', (124, 133))	('PLAUR', 'Gene', '5329', (101, 106))
174317	27246533	Patients with both rs2273953 (TP73) CC and rs12334811 (DNPK1) GG SNPs, compared with a single SNP, could be better distinguished by survival time (P = 0.018), although the median survival time did not change (MSF = 24).	('rs12334811', 'Var', (43, 53))	('P73', 'Gene', '7161', (31, 34))	('DNPK1', 'Gene', '5591', (55, 60))	('rs2273953', 'Var', (19, 28))	('Patients', 'Species', '9606', (0, 8))	('rs12334811', 'Mutation', 'rs12334811', (43, 53))	('P73', 'Gene', (31, 34))	('rs2273953', 'Mutation', 'rs2273953', (19, 28))	('DNPK1', 'Gene', (55, 60))
174318	27246533	In the analysis of adenocarcinoma, we performed stepwise regression analysis on four SNPs showing significant correlation with OS: rs402710 (CLPTM1L), rs1801270 (CDKN1A), rs2279744 (MDM2) and rs2909430 (TP53).	('rs1801270', 'Var', (151, 160))	('CLPTM1L', 'Gene', '81037', (141, 148))	('rs402710', 'Var', (131, 139))	('MDM2', 'Gene', '4193', (182, 186))	('carcinoma', 'Phenotype', 'HP:0030731', (24, 33))	('CDKN1A', 'Gene', (162, 168))	('CDKN1A', 'Gene', '1026', (162, 168))	('TP53', 'Gene', (203, 207))	('rs1801270', 'Mutation', 'rs1801270', (151, 160))	('rs2909430', 'Mutation', 'rs2909430', (192, 201))	('rs402710', 'Mutation', 'rs402710', (131, 139))	('CLPTM1L', 'Gene', (141, 148))	('rs2279744', 'Mutation', 'rs2279744', (171, 180))	('adenocarcinoma', 'Disease', (19, 33))	('rs2909430', 'Var', (192, 201))	('TP53', 'Gene', '7157', (203, 207))	('adenocarcinoma', 'Disease', 'MESH:D000230', (19, 33))	('MDM2', 'Gene', (182, 186))	('rs2279744', 'Var', (171, 180))
174319	27246533	We found that the combination of the two "worst" genotypes, rs2279744 (MDM2, GG homozygote) and rs2909430 (TP53, AG heterozygote), showed significant differences in their effects on survival time (Fig.	('rs2279744', 'Var', (60, 69))	('MDM2', 'Gene', '4193', (71, 75))	('survival time', 'CPA', (182, 195))	('MDM2', 'Gene', (71, 75))	('TP53', 'Gene', '7157', (107, 111))	('TP53', 'Gene', (107, 111))	('rs2909430', 'Mutation', 'rs2909430', (96, 105))	('rs2279744', 'Mutation', 'rs2279744', (60, 69))	('rs2909430', 'Var', (96, 105))
174321	27246533	The above results indicate that in non-small cell lung cancers, rs2273953 (TP73), rs12334811(DNPK1), rs2279744 (MDM2) and rs2909430 (TP53) can be used as biological markers for clinical treatment and prognosis.	('rs2909430', 'Mutation', 'rs2909430', (122, 131))	('DNPK1', 'Gene', '5591', (93, 98))	('non-small cell lung cancers', 'Disease', 'MESH:D002289', (35, 62))	('rs2909430', 'Var', (122, 131))	('lung cancer', 'Phenotype', 'HP:0100526', (50, 61))	('DNPK1', 'Gene', (93, 98))	('rs12334811', 'Mutation', 'rs12334811', (82, 92))	('rs2279744', 'Mutation', 'rs2279744', (101, 110))	('lung cancers', 'Phenotype', 'HP:0100526', (50, 62))	('P73', 'Gene', (76, 79))	('rs12334811', 'Var', (82, 92))	('rs2273953', 'Var', (64, 73))	('cancers', 'Phenotype', 'HP:0002664', (55, 62))	('TP53', 'Gene', '7157', (133, 137))	('non-small cell lung cancers', 'Disease', (35, 62))	('MDM2', 'Gene', (112, 116))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('non-small cell lung cancers', 'Phenotype', 'HP:0030358', (35, 62))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (39, 61))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (35, 61))	('small cell lung cancers', 'Phenotype', 'HP:0030357', (39, 62))	('MDM2', 'Gene', '4193', (112, 116))	('rs2273953', 'Mutation', 'rs2273953', (64, 73))	('rs2279744', 'Var', (101, 110))	('P73', 'Gene', '7161', (76, 79))	('TP53', 'Gene', (133, 137))
174322	27246533	Among the 10 SNPs, 8 SNPs including rs2228001, rs2228000 and rs344781 are associated with the expression of DNA damage repair-related genes.	('DNA damage repair-related genes', 'Gene', (108, 139))	('rs344781', 'Var', (61, 69))	('rs344781', 'Mutation', 'rs344781', (61, 69))	('rs2228000', 'Var', (47, 56))	('rs2228000', 'Mutation', 'rs2228000', (47, 56))	('rs2228001', 'Mutation', 'rs2228001', (36, 45))	('rs2228001', 'Var', (36, 45))	('associated', 'Reg', (74, 84))
174323	27246533	We also discovered that the rs2228001 (XPC) and rs2228000 (XPC) were relevant to the sensitivity of chemotherapy, and rs344781 (PLAUR) was related to the survival of patients of lung squamous cell carcinoma through the above research (Tables 2 and 4).	('rs2228000', 'Mutation', 'rs2228000', (48, 57))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (183, 206))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (178, 206))	('lung squamous cell carcinoma', 'Disease', (178, 206))	('XPC', 'Gene', (39, 42))	('PLAUR', 'Gene', '5329', (128, 133))	('XPC', 'Gene', '7508', (59, 62))	('XPC', 'Gene', (59, 62))	('rs344781', 'Var', (118, 126))	('related', 'Reg', (139, 146))	('carcinoma', 'Phenotype', 'HP:0030731', (197, 206))	('PLAUR', 'Gene', (128, 133))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (178, 206))	('rs344781', 'Mutation', 'rs344781', (118, 126))	('rs2228000', 'Var', (48, 57))	('rs2228001', 'Mutation', 'rs2228001', (28, 37))	('rs2228001', 'Var', (28, 37))	('XPC', 'Gene', '7508', (39, 42))	('patients', 'Species', '9606', (166, 174))
174324	27246533	The results showed the reason for the sensitivity of radio-chemotherapy is probably that the rs2228000, rs2228001 and rs344781 induced the variation of gene expression of XPC and PLAUR.	('PLAUR', 'Gene', (179, 184))	('XPC', 'Gene', '7508', (171, 174))	('rs2228000', 'Mutation', 'rs2228000', (93, 102))	('rs2228001', 'Mutation', 'rs2228001', (104, 113))	('induced', 'Reg', (127, 134))	('PLAUR', 'Gene', '5329', (179, 184))	('rs2228001', 'Var', (104, 113))	('XPC', 'Gene', (171, 174))	('gene expression', 'MPA', (152, 167))	('rs344781', 'Var', (118, 126))	('rs344781', 'Mutation', 'rs344781', (118, 126))	('rs2228000', 'Var', (93, 102))
174325	27246533	Furthermore, rs1130214, rs11615, rs159153 and rs2132572 can regulate the expression of AKT, ERCC1, OGG1 although they have no relation with chemo-radiotherapy.	('rs159153', 'Mutation', 'rs159153', (33, 41))	('rs159153', 'Var', (33, 41))	('regulate', 'Reg', (60, 68))	('AKT', 'Gene', (87, 90))	('rs1130214', 'Var', (13, 22))	('rs1130214', 'Mutation', 'rs1130214', (13, 22))	('rs2132572', 'Mutation', 'rs2132572', (46, 55))	('OGG1', 'Gene', (99, 103))	('rs11615', 'Var', (24, 31))	('rs11615', 'Mutation', 'rs11615', (24, 31))	('expression', 'MPA', (73, 83))	('OGG1', 'Gene', '4968', (99, 103))	('rs2132572', 'Var', (46, 55))	('ERCC1', 'Gene', '2067', (92, 97))	('ERCC1', 'Gene', (92, 97))	('AKT', 'Gene', '207', (87, 90))
174326	27246533	Using the eQTLs dataset from lymphoblastoid cell lines, we identified three significant associations between three SNPs (rs2228001, rs25406 and rs8073069) and the expression of XPC, C20orf30 and BIRC5 as described in Table 6.	('C20orf30', 'Gene', (182, 190))	('XPC', 'Gene', (177, 180))	('rs2228001', 'Mutation', 'rs2228001', (121, 130))	('BIRC5', 'Gene', '332', (195, 200))	('XPC', 'Gene', '7508', (177, 180))	('rs25406', 'Var', (132, 139))	('BIRC5', 'Gene', (195, 200))	('rs2228001', 'Var', (121, 130))	('C20orf30', 'Gene', '29058', (182, 190))	('rs8073069', 'Mutation', 'rs8073069', (144, 153))	('rs25406', 'Mutation', 'rs25406', (132, 139))	('rs8073069', 'Var', (144, 153))
174327	27246533	Using the GTEx samples in human lung tissue, we identified two SNPs including rs25487 and rs25406, which could significantly regulate ZNF575 (P = 1.50E-07 and effect size = 0.30) and TMEM230 (P = 9.40E-11 and effect size = 0.18), respectively.	('rs25487', 'Var', (78, 85))	('TMEM230', 'Gene', (183, 190))	('ZNF575', 'Gene', '284346', (134, 140))	('rs25487', 'Mutation', 'rs25487', (78, 85))	('rs25406', 'Var', (90, 97))	('ZNF575', 'Gene', (134, 140))	('rs25406', 'Mutation', 'rs25406', (90, 97))	('TMEM230', 'Gene', '29058', (183, 190))	('regulate', 'Reg', (125, 133))	('human', 'Species', '9606', (26, 31))
174330	27246533	Therefore, we performed regression analysis to investigate the potential association of SNPs in DNA damage repair-related genes with patient survival time and sensitivity to radio-chemotherapy separately.	('patient', 'Species', '9606', (133, 140))	('DNA damage repair-related genes', 'Gene', (96, 127))	('SNPs', 'Var', (88, 92))
174331	27246533	We found that a large number of SNPs in DNA damage repair-related genes were associated with the sensitivity to radio-chemotherapy, some SNPs also affected the survival time of patients, and the joint actions of multiple sites could further enhance the effect on survival time.	('SNPs', 'Var', (32, 36))	('affected', 'Reg', (147, 155))	('patients', 'Species', '9606', (177, 185))	('survival time', 'CPA', (160, 173))	('DNA damage repair-related genes', 'Gene', (40, 71))	('sensitivity to radio-chemotherapy', 'MPA', (97, 130))	('associated', 'Reg', (77, 87))
174332	27246533	In squamous cell carcinoma, we found that the GG genotype of rs12334811 in the DNA-PKcs gene had a significant effect on sensitivity to radio-chemotherapy and longer OS.	('DNA-PKcs', 'Gene', (79, 87))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (3, 26))	('rs12334811', 'Var', (61, 71))	('effect', 'Reg', (111, 117))	('rs12334811', 'Mutation', 'rs12334811', (61, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (17, 26))	('DNA-PKcs', 'Gene', '5591', (79, 87))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (3, 26))	('sensitivity to radio-chemotherapy', 'MPA', (121, 154))	('squamous cell carcinoma', 'Disease', (3, 26))
174334	27246533	found that rs12334811 was associated with sensitivity to treatments of lung cancer.	('rs12334811', 'Mutation', 'rs12334811', (11, 21))	('lung cancer', 'Disease', 'MESH:D008175', (71, 82))	('associated', 'Reg', (26, 36))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('rs12334811', 'Var', (11, 21))	('lung cancer', 'Disease', (71, 82))	('lung cancer', 'Phenotype', 'HP:0100526', (71, 82))
174335	27246533	We also found that the GG genotype of rs12334811 in the DNA-PKcs gene had significant importance on radio-chemotherapy treatments and survival time in squamous cell carcinoma, showing a median survival time of 24 months.	('rs12334811', 'Mutation', 'rs12334811', (38, 48))	('importance', 'Reg', (86, 96))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (151, 174))	('squamous cell carcinoma', 'Disease', (151, 174))	('DNA-PKcs', 'Gene', (56, 64))	('rs12334811', 'Var', (38, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (165, 174))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (151, 174))	('DNA-PKcs', 'Gene', '5591', (56, 64))
174336	27246533	Mutations of this gene may affect DNA repair ability, thereby affecting the efficacy of radio-chemotherapy, and eventually affecting the survival time of patients.	('survival time', 'CPA', (137, 150))	('affecting', 'Reg', (123, 132))	('patients', 'Species', '9606', (154, 162))	('DNA', 'MPA', (34, 37))	('affecting', 'Reg', (62, 71))	('Mutations', 'Var', (0, 9))	('affect', 'Reg', (27, 33))
174341	27246533	further indicated that patients with a low expression level of DNA-PKcs could benefit more from radiotherapy.	('DNA-PKcs', 'Gene', (63, 71))	('low expression level', 'Var', (39, 59))	('patients', 'Species', '9606', (23, 31))	('DNA-PKcs', 'Gene', '5591', (63, 71))	('benefit', 'PosReg', (78, 85))	('radiotherapy', 'CPA', (96, 108))
174344	27246533	In this study, the SNP site rs12334811of the DNA-PKcs gene was closely related with squamous cell carcinoma sensitivity to radio-chemotherapy.	('rs12334811', 'Mutation', 'rs12334811', (28, 38))	('related', 'Reg', (71, 78))	('rs12334811of', 'Var', (28, 40))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (84, 107))	('DNA-PKcs', 'Gene', '5591', (45, 53))	('squamous cell carcinoma', 'Disease', (84, 107))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (84, 107))	('DNA-PKcs', 'Gene', (45, 53))
174346	27246533	We also found that the CC homozygous genotype of the rs2273953 in the TP73 gene had significant importance in chemotherapy and survival time of squamous cell carcinoma.	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (144, 167))	('rs2273953', 'Mutation', 'rs2273953', (53, 62))	('squamous cell carcinoma', 'Disease', (144, 167))	('P73', 'Gene', (71, 74))	('rs2273953', 'Var', (53, 62))	('carcinoma', 'Phenotype', 'HP:0030731', (158, 167))	('P73', 'Gene', '7161', (71, 74))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (144, 167))	('importance', 'Reg', (96, 106))
174349	27246533	revealed that the polymorphisms G4C14-to-A4T14 of p73 (rs2273953, rs1801173) had a positive correlation with triple-negative breast cancer (TNBC) and then found that it could be used in the treatment of TNBC.We found that the CC homozygous genotype of the rs2273953 in the TP73 gene was sensitivity toward chemotherapy in squamous cell carcinoma and had a median survival time of 26 months compared with other genotypes (P < 0.05).	('P73', 'Gene', (274, 277))	('TNBC', 'Disease', 'None', (140, 144))	('rs2273953', 'Var', (256, 265))	('breast cancer', 'Phenotype', 'HP:0003002', (125, 138))	('TNBC', 'Disease', 'None', (203, 207))	('squamous cell carcinoma', 'Disease', (322, 345))	('p73', 'Gene', '7161', (50, 53))	('breast cancer', 'Disease', 'MESH:D001943', (125, 138))	('p73', 'Gene', (50, 53))	('breast cancer', 'Disease', (125, 138))	('TNBC', 'Disease', (140, 144))	('TNBC', 'Disease', (203, 207))	('rs2273953', 'Mutation', 'rs2273953', (256, 265))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (322, 345))	('P73', 'Gene', '7161', (274, 277))	('rs1801173', 'Mutation', 'rs1801173', (66, 75))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (336, 345))	('sensitivity', 'Reg', (287, 298))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (322, 345))	('rs2273953', 'Mutation', 'rs2273953', (55, 64))
174350	27246533	This indicates that rs2273953 may affect DNA damage-repair ability to some extent, which may induce sensitivity to chemotherapy and then prolong the survival time of the patients.	('rs2273953', 'Var', (20, 29))	('patients', 'Species', '9606', (170, 178))	('rs2273953', 'Mutation', 'rs2273953', (20, 29))	('DNA damage-repair', 'MPA', (41, 58))	('sensitivity to chemotherapy', 'MPA', (100, 127))	('survival time', 'CPA', (149, 162))	('induce', 'PosReg', (93, 99))	('affect', 'Reg', (34, 40))	('prolong', 'PosReg', (137, 144))
174351	27246533	In adenocarcinoma, we found that the rs2699887 in PI3K had a great effect on the chemotherapy of adenocarcinoma.	('rs2699887', 'Mutation', 'rs2699887', (37, 46))	('adenocarcinoma', 'Disease', 'MESH:D000230', (97, 111))	('carcinoma', 'Phenotype', 'HP:0030731', (8, 17))	('adenocarcinoma', 'Disease', (3, 17))	('effect', 'Reg', (67, 73))	('adenocarcinoma', 'Disease', 'MESH:D000230', (3, 17))	('chemotherapy', 'CPA', (81, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('adenocarcinoma', 'Disease', (97, 111))	('rs2699887', 'Var', (37, 46))
174352	27246533	Two SNPs rs2299939 and rs2735343 in PTEN gene had significant importance in the radiotherapy of adenocarcinoma (P < 0.05).	('adenocarcinoma', 'Disease', 'MESH:D000230', (96, 110))	('rs2299939', 'Var', (9, 18))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('rs2735343', 'Var', (23, 32))	('PTEN', 'Gene', (36, 40))	('adenocarcinoma', 'Disease', (96, 110))	('PTEN', 'Gene', '5728', (36, 40))	('rs2735343', 'Mutation', 'rs2735343', (23, 32))	('rs2299939', 'Mutation', 'rs2299939', (9, 18))
174353	27246533	The rs1801270 in CDKN1A gene, rs2279744 in MDM2 gene and rs2909430 in TP53 gene were related with the survival time of adenocarcinoma patients (P < 0.05).	('rs1801270', 'Var', (4, 13))	('adenocarcinoma', 'Disease', (119, 133))	('survival time', 'CPA', (102, 115))	('related', 'Reg', (85, 92))	('MDM2', 'Gene', '4193', (43, 47))	('TP53', 'Gene', '7157', (70, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('CDKN1A', 'Gene', (17, 23))	('MDM2', 'Gene', (43, 47))	('patients', 'Species', '9606', (134, 142))	('adenocarcinoma', 'Disease', 'MESH:D000230', (119, 133))	('CDKN1A', 'Gene', '1026', (17, 23))	('TP53', 'Gene', (70, 74))	('rs2909430', 'Var', (57, 66))	('rs2279744', 'Mutation', 'rs2279744', (30, 39))	('rs2279744', 'Var', (30, 39))	('rs2909430', 'Mutation', 'rs2909430', (57, 66))	('rs1801270', 'Mutation', 'rs1801270', (4, 13))
174354	27246533	The effects of these polymorphisms suggested a close relationship between PI3K, PTEN, Mdm2 and p53 and the efficacy of radio-chemotherapy treatment of adenocarcinoma and the survival time of patients.	('patients', 'Species', '9606', (191, 199))	('PTEN', 'Gene', (80, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (156, 165))	('PTEN', 'Gene', '5728', (80, 84))	('Mdm2', 'Gene', '4193', (86, 90))	('adenocarcinoma', 'Disease', (151, 165))	('p53', 'Gene', (95, 98))	('p53', 'Gene', '7157', (95, 98))	('adenocarcinoma', 'Disease', 'MESH:D000230', (151, 165))	('PI3K', 'Var', (74, 78))	('Mdm2', 'Gene', (86, 90))
174355	27246533	PTEN, PI3K, Mdm2 and p53 belong to a network of oncogenes and antioncogenes and are related to many important physiological functions of the cell.	('PI3K', 'Var', (6, 10))	('related', 'Reg', (84, 91))	('Mdm2', 'Gene', (12, 16))	('Mdm2', 'Gene', '4193', (12, 16))	('p53', 'Gene', '7157', (21, 24))	('PTEN', 'Gene', '5728', (0, 4))	('PTEN', 'Gene', (0, 4))	('p53', 'Gene', (21, 24))
174356	27246533	observed SNPs in P53 (rs1042522) and MDM2 (rs2279744) in 199 patients with stage III - IV non-small cell lung cancer who were undergoing cisplatin-based chemotherapy.	('lung cancer', 'Phenotype', 'HP:0100526', (105, 116))	('non-small cell lung cancer', 'Disease', (90, 116))	('MDM2', 'Gene', '4193', (37, 41))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (94, 116))	('MDM2', 'Gene', (37, 41))	('rs1042522', 'Mutation', 'rs1042522', (22, 31))	('P53', 'Gene', (17, 20))	('rs2279744', 'Mutation', 'rs2279744', (43, 52))	('patients', 'Species', '9606', (61, 69))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (90, 116))	('P53', 'Gene', '7157', (17, 20))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('cisplatin', 'Chemical', 'MESH:D002945', (137, 146))	('rs1042522', 'Var', (22, 31))	('rs2279744', 'Var', (43, 52))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (90, 116))	('SNPs', 'Reg', (9, 13))
174357	27246533	The results showed patients with Pro/Pro genotype of P53 (rs1042522) combined with the GG genotype of MDM2 (rs2279744) had a survival time only half that of the patients with the wild-type genotype.	('rs2279744', 'Mutation', 'rs2279744', (108, 117))	('P53', 'Gene', (53, 56))	('patients', 'Species', '9606', (19, 27))	('Pro', 'Chemical', 'MESH:D011392', (33, 36))	('P53', 'Gene', '7157', (53, 56))	('MDM2', 'Gene', '4193', (102, 106))	('rs1042522', 'Var', (58, 67))	('MDM2', 'Gene', (102, 106))	('Pro', 'Chemical', 'MESH:D011392', (37, 40))	('rs2279744', 'Var', (108, 117))	('patients', 'Species', '9606', (161, 169))	('survival time', 'CPA', (125, 138))	('rs1042522', 'Mutation', 'rs1042522', (58, 67))
174359	27246533	found that SNPs in this pathway were closely correlated with brain metastasis of NSCLC.	('brain metastasis', 'Disease', 'MESH:D009362', (61, 77))	('SNPs', 'Var', (11, 15))	('NSCLC', 'Disease', (81, 86))	('NSCLC', 'Disease', 'MESH:D002289', (81, 86))	('brain metastasis', 'Disease', (61, 77))	('correlated', 'Reg', (45, 55))
174361	27246533	The absence of PTEN inhibits the expression of XPC, a GG-NER pathway key factor.	('inhibits', 'NegReg', (20, 28))	('PTEN', 'Gene', (15, 19))	('PTEN', 'Gene', '5728', (15, 19))	('XPC', 'Gene', (47, 50))	('expression', 'MPA', (33, 43))	('absence', 'Var', (4, 11))	('XPC', 'Gene', '7508', (47, 50))
174364	27246533	found that the SNP site rs2699887 of PIK3 could increase the toxicity of treatments, whereas the SNP sites of PTEN could alleviate the toxicity of chemotherapy.	('PIK3', 'Gene', '5294', (37, 41))	('PTEN', 'Gene', '5728', (110, 114))	('toxicity', 'Disease', 'MESH:D064420', (61, 69))	('toxicity', 'Disease', (61, 69))	('rs2699887', 'Var', (24, 33))	('rs2699887', 'Mutation', 'rs2699887', (24, 33))	('toxicity', 'Disease', 'MESH:D064420', (135, 143))	('PIK3', 'Gene', (37, 41))	('alleviate', 'NegReg', (121, 130))	('toxicity', 'Disease', (135, 143))	('PTEN', 'Gene', (110, 114))	('increase', 'PosReg', (48, 56))
174365	27246533	In our study, PTEN (rs2299939, rs2735343), PI3K (s2699887), MDM2 (rs2279744) and P53 (rs1042522) significantly affected the chemotherapy sensitivity and survival time of lung adenocarcinoma patients, suggesting that the related genes of this pathway and the combined effects of these genes changed the tumor sensitivity to radio-chemotherapy, and then changed the survival time after treatment of NSCLC.	('PTEN', 'Gene', (14, 18))	('MDM2', 'Gene', (60, 64))	('tumor', 'Phenotype', 'HP:0002664', (302, 307))	('patients', 'Species', '9606', (190, 198))	('P53', 'Gene', '7157', (81, 84))	('NSCLC', 'Disease', (397, 402))	('rs2299939', 'Var', (20, 29))	('affected', 'Reg', (111, 119))	('changed', 'Reg', (290, 297))	('s2699887', 'Var', (49, 57))	('MDM2', 'Gene', '4193', (60, 64))	('PTEN', 'Gene', '5728', (14, 18))	('rs2279744', 'Var', (66, 75))	('changed', 'Reg', (352, 359))	('rs2299939', 'Mutation', 'rs2299939', (20, 29))	('lung adenocarcinoma', 'Disease', (170, 189))	('carcinoma', 'Phenotype', 'HP:0030731', (180, 189))	('tumor', 'Disease', (302, 307))	('rs2735343', 'Mutation', 'rs2735343', (31, 40))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (170, 189))	('survival', 'MPA', (364, 372))	('rs2279744', 'Mutation', 'rs2279744', (66, 75))	('chemotherapy', 'MPA', (124, 136))	('tumor', 'Disease', 'MESH:D009369', (302, 307))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (170, 189))	('P53', 'Gene', (81, 84))	('rs1042522', 'Var', (86, 95))	('NSCLC', 'Disease', 'MESH:D002289', (397, 402))	('rs2735343', 'Var', (31, 40))	('rs1042522', 'Mutation', 'rs1042522', (86, 95))
174366	27246533	We found that, in patients with squamous cell carcinoma, the survival time of patients with the GG genotype of rs12334811 and CC genotype of rs2273953 was significantly different compared to other groups (P = 0.018).	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (32, 55))	('carcinoma', 'Phenotype', 'HP:0030731', (46, 55))	('rs12334811', 'Mutation', 'rs12334811', (111, 121))	('rs2273953', 'Var', (141, 150))	('patients', 'Species', '9606', (78, 86))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (32, 55))	('rs2273953', 'Mutation', 'rs2273953', (141, 150))	('squamous cell carcinoma', 'Disease', (32, 55))	('different', 'Reg', (169, 178))	('patients', 'Species', '9606', (18, 26))	('rs12334811', 'Var', (111, 121))
174367	27246533	In patients with adenocarcinoma, the median survival time of patients with the GG genotype of rs2279744 and the AG genotype of rs2909430 was only 6 months (P = 0.018), indicating that the combination of these two genotypes predicts poor prognosis.	('rs2279744', 'Mutation', 'rs2279744', (94, 103))	('rs2909430', 'Mutation', 'rs2909430', (127, 136))	('patients', 'Species', '9606', (61, 69))	('adenocarcinoma', 'Disease', (17, 31))	('rs2279744', 'Var', (94, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('adenocarcinoma', 'Disease', 'MESH:D000230', (17, 31))	('patients', 'Species', '9606', (3, 11))	('rs2909430', 'Var', (127, 136))
174368	27246533	Although there are only a few of cases (rs2279744 homozygote and rs2909430 AG heterozygote), it shows great value in prognostic effects.	('rs2279744', 'Var', (40, 49))	('rs2279744', 'Mutation', 'rs2279744', (40, 49))	('rs2909430 AG', 'Var', (65, 77))	('rs2909430', 'Mutation', 'rs2909430', (65, 74))
174374	27246533	Additionally we found that the rs2228001 (XPC) and rs2228000 (XPC) were related with the sensitivity of chemotherapy and rs344781 (PLAUR) was related with the survival of patients of lung squamous cell carcinoma by eQTLs analysis.	('related with', 'Reg', (142, 154))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (183, 211))	('PLAUR', 'Gene', (131, 136))	('rs344781', 'Var', (121, 129))	('patients', 'Species', '9606', (171, 179))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (183, 211))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (188, 211))	('lung squamous cell carcinoma', 'Disease', (183, 211))	('rs344781', 'Mutation', 'rs344781', (121, 129))	('rs2228000', 'Var', (51, 60))	('XPC', 'Gene', '7508', (42, 45))	('rs2228001', 'Mutation', 'rs2228001', (31, 40))	('rs2228001', 'Var', (31, 40))	('related', 'Reg', (72, 79))	('PLAUR', 'Gene', '5329', (131, 136))	('XPC', 'Gene', '7508', (62, 65))	('XPC', 'Gene', (42, 45))	('rs2228000', 'Mutation', 'rs2228000', (51, 60))	('XPC', 'Gene', (62, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (202, 211))
174376	27246533	In the present study, SNPs in DNA damage repair-related genes showed a significant impact on the efficacy of radio-chemotherapy treatment of non-small cell lung cancer.	('small cell lung cancer', 'Phenotype', 'HP:0030357', (145, 167))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('SNPs', 'Var', (22, 26))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (141, 167))	('DNA damage repair-related genes', 'Gene', (30, 61))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (141, 167))	('impact', 'Reg', (83, 89))	('lung cancer', 'Phenotype', 'HP:0100526', (156, 167))	('non-small cell lung cancer', 'Disease', (141, 167))
174377	27246533	The GG genotype of rs12334811 in the DNA-PKcs gene had a significant effect on radio-chemotherapy and survival time of lung squamous cell carcinoma, and the CC genotype of rs2273953 in the TP73 gene had a significant effect on chemotherapy and the survival time in patients with lung squamous cell carcinoma.	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (279, 307))	('survival time', 'CPA', (102, 115))	('rs2273953', 'Mutation', 'rs2273953', (172, 181))	('rs12334811', 'Mutation', 'rs12334811', (19, 29))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (119, 147))	('effect', 'Reg', (69, 75))	('rs12334811', 'Var', (19, 29))	('DNA-PKcs', 'Gene', '5591', (37, 45))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (279, 307))	('patients', 'Species', '9606', (265, 273))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (284, 307))	('lung squamous cell carcinoma', 'Disease', (279, 307))	('P73', 'Gene', '7161', (190, 193))	('radio-chemotherapy', 'CPA', (79, 97))	('chemotherapy', 'CPA', (227, 239))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (124, 147))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (119, 147))	('lung squamous cell carcinoma', 'Disease', (119, 147))	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('rs2273953', 'Var', (172, 181))	('P73', 'Gene', (190, 193))	('DNA-PKcs', 'Gene', (37, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (298, 307))
174378	27246533	Polymorphisms in the PTEN (rs2299939, rs2735343), PI3K (rs2699887), MDM2 (rs2279744), and P53 (rs1042522) genes influence the efficacy of radio-chemotherapy and survival time of lung adenocarcinoma.	('influence', 'Reg', (112, 121))	('MDM2', 'Gene', (68, 72))	('rs2279744', 'Var', (74, 83))	('lung adenocarcinoma', 'Disease', (178, 197))	('PTEN', 'Gene', '5728', (21, 25))	('MDM2', 'Gene', '4193', (68, 72))	('Polymorphisms', 'Var', (0, 13))	('rs2299939', 'Var', (27, 36))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (178, 197))	('rs2735343', 'Mutation', 'rs2735343', (38, 47))	('survival time', 'CPA', (161, 174))	('rs2699887', 'Var', (56, 65))	('efficacy of radio-chemotherapy', 'CPA', (126, 156))	('rs2279744', 'Mutation', 'rs2279744', (74, 83))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (178, 197))	('rs2699887', 'Mutation', 'rs2699887', (56, 65))	('rs2299939', 'Mutation', 'rs2299939', (27, 36))	('P53', 'Gene', (90, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (188, 197))	('rs1042522', 'Var', (95, 104))	('rs1042522', 'Mutation', 'rs1042522', (95, 104))	('PTEN', 'Gene', (21, 25))	('rs2735343', 'Var', (38, 47))	('P53', 'Gene', '7157', (90, 93))
174379	27246533	The combination of rs2279744 (MDM2) and rs2909430 (TP53) showed poor survival time.	('rs2909430', 'Mutation', 'rs2909430', (40, 49))	('TP53', 'Gene', (51, 55))	('rs2279744', 'Mutation', 'rs2279744', (19, 28))	('MDM2', 'Gene', '4193', (30, 34))	('MDM2', 'Gene', (30, 34))	('poor', 'NegReg', (64, 68))	('survival time', 'CPA', (69, 82))	('rs2909430', 'Var', (40, 49))	('rs2279744', 'Var', (19, 28))	('TP53', 'Gene', '7157', (51, 55))
174505	26272389	Further immunohistochemical analysis on 42 breast carcinoma specimens showed that MHG1152 and MGD785 had intensive staining mainly in membrane, while CHH11617, CHH995 and MJF656 had more intensive staining within the cytoplasm.	('breast carcinoma', 'Disease', 'MESH:D001943', (43, 59))	('breast carcinoma', 'Disease', (43, 59))	('carcinoma', 'Phenotype', 'HP:0030731', (50, 59))	('breast carcinoma', 'Phenotype', 'HP:0003002', (43, 59))	('MHG1152', 'Var', (82, 89))	('CHH995', 'Chemical', '-', (160, 166))	('MJF656', 'Chemical', '-', (171, 177))	('staining', 'MPA', (115, 123))
174506	26272389	MGA scoring results showed that MJF656 had the highest rate (92.8%) of positive staining among five mAbs, including higher staining intensity when compared with that of MHG1152 (p < 0.01) and CHH995 (p < 0.05) and the highest the mean percentage of cells stained among mAbs.	('mAbs', 'Gene', '72935', (100, 104))	('MGA', 'Gene', (0, 3))	('mAbs', 'Gene', (269, 273))	('higher', 'PosReg', (116, 122))	('MJF656', 'Var', (32, 38))	('CHH995', 'Chemical', '-', (192, 198))	('mAbs', 'Gene', '72935', (269, 273))	('MGA', 'Gene', '4250', (0, 3))	('MJF656', 'Chemical', '-', (32, 38))	('mAbs', 'Gene', (100, 104))	('staining intensity', 'MPA', (123, 141))
174536	26272389	3A, anti-MGA immunostaining of MHG1152 and MGD785 mAbs was patchy and occurred in both cytoplasm and cell membrane, mainly in cell membrane, whereas anti-MGA immunostaining of CHH11617, CHH995 and MJF656 was more extensive within the cytoplasm (Fig.	('MGA', 'Gene', '4250', (9, 12))	('mAbs', 'Gene', (50, 54))	('MGA', 'Gene', '4250', (154, 157))	('mAbs', 'Gene', '72935', (50, 54))	('MGA', 'Gene', (9, 12))	('CHH995', 'Chemical', '-', (186, 192))	('MJF656', 'Chemical', '-', (197, 203))	('MGA', 'Gene', (154, 157))	('MHG1152', 'Var', (31, 38))
174543	26272389	The difference in intensity between MJF656 and MHG1152 was statistically significant (p < 0.01), and the difference between MJF656 and CHH995 is also significant (p < 0.05) (Fig.	('MJF656', 'Var', (124, 130))	('MJF656', 'Var', (36, 42))	('intensity', 'MPA', (18, 27))	('MJF656', 'Chemical', '-', (124, 130))	('CHH995', 'Chemical', '-', (135, 141))	('MHG1152', 'Var', (47, 54))	('MJF656', 'Chemical', '-', (36, 42))
174545	26272389	4B, the mean percentage of stained cells with MJF656 was the highest among all five mAbs.	('MJF656', 'Var', (46, 52))	('mAbs', 'Gene', (84, 88))	('mAbs', 'Gene', '72935', (84, 88))	('MJF656', 'Chemical', '-', (46, 52))
174546	26272389	The above data suggests that MJF 656 is the best of the five mAbs for MGA immunostaining in breast carcinoma tissues.	('breast carcinoma', 'Disease', 'MESH:D001943', (92, 108))	('breast carcinoma', 'Disease', (92, 108))	('MJF', 'Var', (29, 32))	('breast carcinoma', 'Phenotype', 'HP:0003002', (92, 108))	('MGA', 'Gene', (70, 73))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('mAbs', 'Gene', (61, 65))	('mAbs', 'Gene', '72935', (61, 65))	('MGA', 'Gene', '4250', (70, 73))
174549	26272389	It was clear that MJF656 has a higher diagnostic sensitivity compared with other MGA mAbs, p value is <0.001 in all cases except for comparison with CHH11617.	('MGA', 'Gene', '4250', (81, 84))	('mAbs', 'Gene', '72935', (85, 89))	('MJF656', 'Chemical', '-', (18, 24))	('mAbs', 'Gene', (85, 89))	('higher', 'PosReg', (31, 37))	('MGA', 'Gene', (81, 84))	('MJF656', 'Var', (18, 24))	('diagnostic sensitivity', 'MPA', (38, 60))
174551	26272389	But the staining with MHG1152, MGD785, CHH11617, CHH995 and commercially available MGA mAb were seen in lung squamous cell carcinoma and cervical polyp (Fig.	('cervical polyp', 'Phenotype', 'HP:0030159', (137, 151))	('CHH995', 'Var', (49, 55))	('CHH11617', 'Var', (39, 47))	('MGA', 'Gene', (83, 86))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (109, 132))	('lung squamous cell carcinoma and cervical polyp', 'Disease', 'MESH:D011127', (104, 151))	('MHG1152', 'Var', (22, 29))	('CHH995', 'Chemical', '-', (49, 55))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('MGA', 'Gene', '4250', (83, 86))
174556	26272389	MJF656 had the significantly highest positive staining rate (88%) in the infiltrating ductal carcinoma (IDC) as compared with the other antibodies (p < 0.05 in all cases, except for CHH11617).	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('MJF656', 'Chemical', '-', (0, 6))	('ductal carcinoma', 'Disease', 'MESH:D044584', (86, 102))	('ductal carcinoma', 'Disease', (86, 102))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (86, 102))	('MJF656', 'Var', (0, 6))
174559	26272389	6B, all of the 14 cases of Stage 1 breast carcinoma showed staining with MJF656; p value is less than 0.01 in all cases as compared with MGD785, CHH995 and MHG1152.	('MJF656', 'Var', (73, 79))	('breast carcinoma', 'Disease', (35, 51))	('MJF656', 'Chemical', '-', (73, 79))	('breast carcinoma', 'Disease', 'MESH:D001943', (35, 51))	('CHH995', 'Chemical', '-', (145, 151))	('staining', 'MPA', (59, 67))	('breast carcinoma', 'Phenotype', 'HP:0003002', (35, 51))	('carcinoma', 'Phenotype', 'HP:0030731', (42, 51))
174560	26272389	As to Stage 2 breast carcinoma, the positive staining rate of MJF656 is higher than MHG1152 (p < 0.05) (Supplementary Table 3).	('MJF656', 'Chemical', '-', (62, 68))	('breast carcinoma', 'Disease', 'MESH:D001943', (14, 30))	('breast carcinoma', 'Disease', (14, 30))	('MJF656', 'Var', (62, 68))	('higher', 'PosReg', (72, 78))	('carcinoma', 'Phenotype', 'HP:0030731', (21, 30))	('breast carcinoma', 'Phenotype', 'HP:0003002', (14, 30))	('positive staining', 'MPA', (36, 53))
174562	26272389	The reactivity of MJF656 in G1 breast carcinoma is better than MHG1152 (p = 0.05) (Supplementary Table 3).	('reactivity', 'MPA', (4, 14))	('breast carcinoma', 'Disease', (31, 47))	('breast carcinoma', 'Disease', 'MESH:D001943', (31, 47))	('MJF656', 'Chemical', '-', (18, 24))	('better', 'PosReg', (51, 57))	('breast carcinoma', 'Phenotype', 'HP:0003002', (31, 47))	('carcinoma', 'Phenotype', 'HP:0030731', (38, 47))	('MJF656', 'Var', (18, 24))
174564	26272389	The positive staining rate of MJF656 in lymph node metastasis-negative breast cancer samples is significantly higher than that of MGD785, CHH995 or MHG1152 (p < 0.01 in all cases) (Supplementary Table 3).	('breast cancer', 'Disease', (71, 84))	('breast cancer', 'Phenotype', 'HP:0003002', (71, 84))	('positive staining', 'MPA', (4, 21))	('MJF656', 'Var', (30, 36))	('CHH995', 'Chemical', '-', (138, 144))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('higher', 'PosReg', (110, 116))	('breast cancer', 'Disease', 'MESH:D001943', (71, 84))	('MJF656', 'Chemical', '-', (30, 36))
174565	26272389	Overall, MJF656 might be the best candidate for MGA detection in early stage, low clinical grade and lymph node metastasis-negative breast cancer patients.	('MJF656', 'Var', (9, 15))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('MGA', 'Gene', (48, 51))	('MJF656', 'Chemical', '-', (9, 15))	('clinical', 'Species', '191496', (82, 90))	('breast cancer', 'Disease', 'MESH:D001943', (132, 145))	('MGA', 'Gene', '4250', (48, 51))	('breast cancer', 'Disease', (132, 145))	('patients', 'Species', '9606', (146, 154))	('breast cancer', 'Phenotype', 'HP:0003002', (132, 145))
174566	26272389	Whereas CHH11617 may be more appropriate for late stage, high grade and lymph node metastasis-positive breast cancer cases as compared with MGD785 or CHH995 (Fig.	('CHH995', 'Chemical', '-', (150, 156))	('high grade', 'Disease', (57, 67))	('breast cancer', 'Disease', 'MESH:D001943', (103, 116))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('breast cancer', 'Disease', (103, 116))	('breast cancer', 'Phenotype', 'HP:0003002', (103, 116))	('CHH11617', 'Var', (8, 16))
174573	26272389	These studies showed that MJF656 is the most appropriate mAb for detecting MGA protein by immunohistochemistry in early stage, low grade breast carcinoma.	('breast carcinoma', 'Disease', (137, 153))	('early stage', 'Disease', (114, 125))	('MJF656', 'Var', (26, 32))	('MGA', 'Gene', '4250', (75, 78))	('breast carcinoma', 'Disease', 'MESH:D001943', (137, 153))	('breast carcinoma', 'Phenotype', 'HP:0003002', (137, 153))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('MGA', 'Gene', (75, 78))	('MJF656', 'Chemical', '-', (26, 32))
174575	26272389	In this study, we also found membrane staining of MGA using MHG1152 and MGD785, but not with the other three mAbs.	('MGA', 'Gene', '4250', (50, 53))	('mAbs', 'Gene', (109, 113))	('MHG1152', 'Var', (60, 67))	('mAbs', 'Gene', '72935', (109, 113))	('MGA', 'Gene', (50, 53))	('MGD785', 'Var', (72, 78))
174576	26272389	The hydrophobic analysis showed that peptide A-D regions against which MHG1152, MGD785, CHH11617 and CHH995 were generated are hydrophobic, while peptide E region against which MJF656 was generated is hydrophilic, which might give good explanations for the best cytoplasm staining by MJF656.	('CHH11617', 'Var', (88, 96))	('MHG1152', 'Var', (71, 78))	('MJF656', 'Chemical', '-', (177, 183))	('MJF656', 'Chemical', '-', (284, 290))	('CHH995', 'Chemical', '-', (101, 107))
174580	26272389	In particular, MJF656 might be a good candidate antibody for identification of breast cancer origin cells that was captured by CTC detection system (CELLSEARCH  Circulating Tumor Cell (CTC) Test) as specific staining in the exfoliated cells.	('breast cancer', 'Disease', 'MESH:D001943', (79, 92))	('MJF656', 'Var', (15, 21))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('breast cancer', 'Disease', (79, 92))	('breast cancer', 'Phenotype', 'HP:0003002', (79, 92))	('Tumor', 'Phenotype', 'HP:0002664', (173, 178))	('MJF656', 'Chemical', '-', (15, 21))
174621	31878324	The blockage of extracellular signal-regulated kinase (ERK) activation suppressed cell migration and reduced stemness characteristics in NHRI-HN1 cells, similar to human OSCC cell lines.	('cell migration', 'CPA', (82, 96))	('NHRI-HN1', 'CellLine', 'CVCL:8123', (137, 145))	('human', 'Species', '9606', (164, 169))	('extracellular signal-regulated kinase', 'Gene', '5594', (16, 53))	('reduced', 'NegReg', (101, 108))	('extracellular signal-regulated kinase', 'Gene', (16, 53))	('stemness characteristics', 'CPA', (109, 133))	('blockage', 'Var', (4, 12))	('ERK', 'Gene', (55, 58))	('suppressed', 'NegReg', (71, 81))
174650	31878324	We also demonstrated that NHRI-HN1 is highly tumorigenic in vivo and it can produce syngeneic tumors by orthotopic injection into immunocompetent hosts.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('NHRI-HN1', 'CellLine', 'CVCL:8123', (26, 34))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('NHRI-HN1', 'Var', (26, 34))	('tumor', 'Disease', (45, 50))	('tumor', 'Disease', (94, 99))	('produce', 'PosReg', (76, 83))	('tumors', 'Disease', (94, 100))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
174653	31878324	As in human OSCC cell lines, MAPK kinase inhibitors suppressed NHRI-HN1's enhanced migration and cancer stemness, which suggests an essential role for extracellular signal-regulated kinase (ERK) activation in modulating cell motility and stemness in NHRI-HN1 cells and human oral cancer cells.	('cancer stemness', 'Disease', (97, 112))	('cancer', 'Disease', (280, 286))	('cell motility', 'CPA', (220, 233))	('MAPK', 'Gene', (29, 33))	('inhibitors', 'Var', (41, 51))	('cancer', 'Phenotype', 'HP:0002664', (280, 286))	('cancer', 'Disease', (97, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('migration', 'CPA', (83, 92))	('NHRI-HN1', 'CellLine', 'CVCL:8123', (250, 258))	('human', 'Species', '9606', (6, 11))	('cancer', 'Disease', 'MESH:D009369', (280, 286))	('NHRI-HN1', 'Gene', (63, 71))	('human', 'Species', '9606', (269, 274))	('suppressed', 'NegReg', (52, 62))	('cancer stemness', 'Disease', 'MESH:D009369', (97, 112))	('cancer', 'Disease', 'MESH:D009369', (97, 103))	('extracellular signal-regulated kinase', 'Gene', (151, 188))	('NHRI-HN1', 'CellLine', 'CVCL:8123', (63, 71))	('stemness', 'CPA', (238, 246))	('extracellular signal-regulated kinase', 'Gene', '5594', (151, 188))	('enhanced', 'PosReg', (74, 82))
174665	31878324	The subcutaneous tumor weights were 0.11 g (n = 1) and 0.575 +- 0.145 g (n = 2) for mice receiving M1-2 and M2-3 cells, respectively (Figure 2A and Figure S3A).	('tumor', 'Disease', (17, 22))	('M1-2', 'Var', (99, 103))	('subcutaneous tumor', 'Phenotype', 'HP:0001482', (4, 22))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('M2-3 cells', 'Var', (108, 118))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('mice', 'Species', '10090', (84, 88))
174673	31878324	In another set of experiments, NHRI-HN1 cells developed into orthotopic tumors with an average weight of 0.4614 +- 0.0688 g (n = 7) and 0.2184 +- 0.075 g (n = 7) in nude mice and B6 mice, respectively (Figure 2E and Figure S3D-E).	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('NHRI-HN1', 'Gene', (31, 39))	('NHRI-HN1', 'CellLine', 'CVCL:8123', (31, 39))	('orthotopic tumors', 'Disease', (61, 78))	('mice', 'Species', '10090', (182, 186))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('nude mice', 'Species', '10090', (165, 174))	('0.2184 +- 0.075 g', 'Var', (136, 153))	('mice', 'Species', '10090', (170, 174))	('orthotopic tumors', 'Disease', 'MESH:D009369', (61, 78))
174680	31878324	The weight and volume of orthotopic tumors in mice receiving CpG-ODN injection were markedly reduced as compared to those injected with phosphate buffered saline (PBS) following the scheme that is shown in Figure 3A (n = 6, p < 0.001; Figure 3B and Figure S3F).	('PBS', 'Chemical', '-', (163, 166))	('orthotopic tumors', 'Disease', 'MESH:D009369', (25, 42))	('reduced', 'NegReg', (93, 100))	('CpG-ODN', 'Var', (61, 68))	('phosphate buffered saline', 'Chemical', '-', (136, 161))	('mice', 'Species', '10090', (46, 50))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('orthotopic tumors', 'Disease', (25, 42))	('CpG-ODN', 'Chemical', 'MESH:C408982', (61, 68))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))
174681	31878324	Histological examination of tumors that were treated with CpG-ODN revealed a significant increase in the number of tumor-infiltrating CD8+ T cells (Figure 3C,D).	('tumor', 'Disease', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumors', 'Disease', (28, 34))	('tumors', 'Disease', 'MESH:D009369', (28, 34))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('tumor', 'Disease', (115, 120))	('CpG-ODN', 'Var', (58, 65))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('CpG-ODN', 'Chemical', 'MESH:C408982', (58, 65))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('increase', 'PosReg', (89, 97))
174682	31878324	No substantial difference in the numbers of infiltrating CD4+ cells was found between CpG-ODN-treated and control tumors (Figure 3C,D).	('CpG-ODN', 'Chemical', 'MESH:C408982', (86, 93))	('CpG-ODN-treated', 'Var', (86, 101))	('CD4', 'Gene', '12504', (57, 60))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumors', 'Disease', (114, 120))	('tumors', 'Disease', 'MESH:D009369', (114, 120))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('CD4', 'Gene', (57, 60))
174698	31878324	NHRI-HN1 cells have a higher growth rate than M1-2 cells (Figure 5A).	('NHRI-HN1', 'CellLine', 'CVCL:8123', (0, 8))	('higher', 'PosReg', (22, 28))	('NHRI-HN1', 'Var', (0, 8))	('growth rate', 'CPA', (29, 40))
174701	31878324	Prominin-1 (CD133) and CD44 are stemness-related markers found in a variety of human tumors, including oral cancer, and the expression of these markers has been associated with the survival and prognosis of OSCC patients.	('OSCC', 'Disease', (207, 211))	('human', 'Species', '9606', (79, 84))	('associated with', 'Reg', (161, 176))	('tumors', 'Disease', 'MESH:D009369', (85, 91))	('CD44', 'Gene', (23, 27))	('CD133', 'Gene', (12, 17))	('patients', 'Species', '9606', (212, 220))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))	('CD133', 'Gene', '8842', (12, 17))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('expression', 'Var', (124, 134))	('cancer', 'Disease', (108, 114))	('tumors', 'Disease', (85, 91))
174708	31878324	We sequenced EGFR cDNA synthesized from NHRI-HN1 cells to determine whether EGFR mutation was associated with constitutive dephosphorylation.	('mutation', 'Var', (81, 89))	('constitutive dephosphorylation', 'MPA', (110, 140))	('associated', 'Reg', (94, 104))	('EGFR', 'Gene', (76, 80))	('NHRI-HN1', 'CellLine', 'CVCL:8123', (40, 48))
174711	31878324	Additionally, the basal level of ERK phosphorylation was higher in NHRI-HN1 cells than in M1-2 cells under serum starvation (Figure 6A), which indicated constitutively active ERK in NHRI-HN1 cells.	('higher', 'PosReg', (57, 63))	('NHRI-HN1', 'CellLine', 'CVCL:8123', (182, 190))	('ERK', 'Protein', (33, 36))	('NHRI-HN1', 'CellLine', 'CVCL:8123', (67, 75))	('NHRI-HN1', 'Var', (67, 75))
174713	31878324	The mitogen-activated protein kinase (MAPK) kinase inhibitor PD98059 suppressed ERK phosphorylation in NHRI-HN1 cells (Figure S5C) and it had slight inhibitory effects on cell growth of NHRI-HN1 cells on day 3 (Figure 6B), while PD98059 treatment inhibited the number of NHRI-HN1 cell spheres (Figure 6C).	('PD98059', 'Chemical', 'MESH:C093973', (229, 236))	('PD98059', 'Var', (61, 68))	('ERK phosphorylation', 'MPA', (80, 99))	('NHRI-HN1', 'CellLine', 'CVCL:8123', (271, 279))	('PD98059', 'Chemical', 'MESH:C093973', (61, 68))	('inhibited', 'NegReg', (247, 256))	('NHRI-HN1', 'CellLine', 'CVCL:8123', (103, 111))	('inhibitory', 'NegReg', (149, 159))	('suppressed', 'NegReg', (69, 79))	('NHRI-HN1', 'CellLine', 'CVCL:8123', (186, 194))	('cell growth', 'CPA', (171, 182))
174714	31878324	The relative amounts of Prominin-1+/CD44+ cells were significantly suppressed in PD98059-treated NHRI-HN1 cells (Figure 6D), and the migration activity of NHRI-HN1 cells was markedly diminished by PD98059 treatment in a dose-dependent manner (Figure 6E).	('diminished', 'NegReg', (183, 193))	('PD98059', 'Chemical', 'MESH:C093973', (81, 88))	('NHRI-HN1', 'CellLine', 'CVCL:8123', (155, 163))	('PD98059', 'Var', (197, 204))	('NHRI-HN1', 'CellLine', 'CVCL:8123', (97, 105))	('suppressed', 'NegReg', (67, 77))	('migration activity', 'CPA', (133, 151))	('PD98059-treated', 'Var', (81, 96))	('PD98059', 'Chemical', 'MESH:C093973', (197, 204))
174716	31878324	Immunoblot analysis showed decreased Nanog expression in PD98059-treated NHRI-HN1 cells as compared to the untreated cells, but no differences in the expression of the other stemness- and EMT-related proteins assessed (Figure 6G).	('Nanog', 'Protein', (37, 42))	('decreased', 'NegReg', (27, 36))	('PD98059', 'Chemical', 'MESH:C093973', (57, 64))	('NHRI-HN1', 'CellLine', 'CVCL:8123', (73, 81))	('PD98059-treated', 'Var', (57, 72))
174724	31878324	Nude mice that were injected with either M1-2 or M2-3 cells developed tumors, but tumors were not developed after cell injection in immunocompetent B6 mice (Table 1), which suggests tumor cell elimination by the host immunity.	('tumors', 'Disease', (82, 88))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('tumor', 'Disease', (82, 87))	('mice', 'Species', '10090', (5, 9))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumors', 'Disease', (70, 76))	('M1-2', 'Var', (41, 45))	('tumors', 'Disease', 'MESH:D009369', (70, 76))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('Nude mice', 'Species', '10090', (0, 9))	('mice', 'Species', '10090', (151, 155))	('tumor', 'Disease', (182, 187))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('tumor', 'Disease', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('M2-3 cells', 'Var', (49, 59))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
174726	31878324	Two known mechanisms for cancer immune evasion are the selection of mutant cells resistant to immune effectors, and the progressive formation of an immunosuppressive environment within the tumor.	('tumor', 'Disease', (189, 194))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('cancer', 'Disease', 'MESH:D009369', (25, 31))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('cancer', 'Disease', (25, 31))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('mutant', 'Var', (68, 74))
174753	31878324	Additionally, we observed reduced Nanog expression in NHRI-HN1 cells after PD98059 treatment (Figure 6G), which suggested that Nanog plays a role in cancer stemness and the migration of NHRI-HN1 cells.	('expression', 'MPA', (40, 50))	('PD98059', 'Chemical', 'MESH:C093973', (75, 82))	('cancer stemness', 'Disease', (149, 164))	('role', 'Reg', (141, 145))	('migration', 'CPA', (173, 182))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('reduced', 'NegReg', (26, 33))	('NHRI-HN1', 'CellLine', 'CVCL:8123', (186, 194))	('cancer stemness', 'Disease', 'MESH:D009369', (149, 164))	('Nanog', 'Protein', (34, 39))	('PD98059', 'Var', (75, 82))	('NHRI-HN1', 'CellLine', 'CVCL:8123', (54, 62))
174754	31878324	reported that human cancer cells with high Nanog expression exhibit stem-like, anti-apoptotic properties, and they are resistant to immune attack.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('anti-apoptotic properties', 'CPA', (79, 104))	('human', 'Species', '9606', (14, 19))	('cancer', 'Disease', 'MESH:D009369', (20, 26))	('cancer', 'Disease', (20, 26))	('high Nanog expression', 'Var', (38, 59))
174767	31878324	All of the mouse oral cancer cell lines were established before November 2016, authenticated by amplification of Cox I and short tandem repeat analysis in June, 2017, and then kept free of mycoplasma contamination.	('mouse', 'Species', '10090', (11, 16))	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('cancer', 'Disease', (22, 28))	('short tandem repeat analysis', 'Var', (123, 151))	('Cox I', 'Gene', (113, 118))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('Cox I', 'Gene', '17708', (113, 118))
174818	31878324	Table S1: Short tandem repeat (STR) genotyping of mouse cell lines, Figure S1: Establishment and genetic identification of mouse OSCC cells, Figure S2: Characterization of mouse OSCC cells, Figure S3: Tumor growth of mouse OSCC cells in nude mice and B6 mice, Figure S4: Gene expression analysis of 4 mouse OSCC cell lines and 40 pairs of OSCC and their corresponding adjacent nontumor tissues, Figure S5: ERK activation in NHRI-HN1 cells, Figure S6: Blockage of ERK activation by PD98059 inhibited cell migration and stemness of human OSCC cells.	('tumor', 'Disease', (380, 385))	('inhibited', 'NegReg', (489, 498))	('mouse', 'Species', '10090', (217, 222))	('mouse', 'Species', '10090', (123, 128))	('human', 'Species', '9606', (530, 535))	('mouse', 'Species', '10090', (172, 177))	('mice', 'Species', '10090', (254, 258))	('tumor', 'Phenotype', 'HP:0002664', (380, 385))	('PD98059', 'Var', (481, 488))	('PD98059', 'Chemical', 'MESH:C093973', (481, 488))	('tumor', 'Disease', 'MESH:D009369', (380, 385))	('nude mice', 'Species', '10090', (237, 246))	('mouse', 'Species', '10090', (50, 55))	('mouse', 'Species', '10090', (301, 306))	('Tumor', 'Phenotype', 'HP:0002664', (201, 206))	('mice', 'Species', '10090', (242, 246))	('NHRI-HN1', 'CellLine', 'CVCL:8123', (424, 432))
174824	31138778	Conversely, knockdown of ZCCHC10 exerts opposite effects in the normal lung cell Beas-2b.	('ZCCHC10', 'Gene', (25, 32))	('knockdown', 'Var', (12, 21))	('Beas-2', 'CellLine', 'CVCL:0168', (81, 87))
174833	31138778	A common feature of all human cancers is the loss of p53 function, either via mutation or inactivation.	('function', 'MPA', (57, 65))	('mutation', 'Var', (78, 86))	('human', 'Species', '9606', (24, 29))	('cancers', 'Phenotype', 'HP:0002664', (30, 37))	('cancers', 'Disease', (30, 37))	('cancers', 'Disease', 'MESH:D009369', (30, 37))	('p53', 'Gene', (53, 56))	('p53', 'Gene', '7157', (53, 56))	('inactivation', 'Var', (90, 102))	('loss', 'NegReg', (45, 49))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
174834	31138778	Mutations in the TP53 gene, which encodes the p53 protein, occur in approximately half of all cancer specimens.	('occur', 'Reg', (59, 64))	('p53', 'Gene', (46, 49))	('TP53', 'Gene', (17, 21))	('p53', 'Gene', '7157', (46, 49))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('Mutations', 'Var', (0, 9))	('TP53', 'Gene', '7157', (17, 21))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
174840	31138778	ZCCHC10 (zinc finger CCHC-type containing 10) gene is located on chromosome 5q31.1, a region that is frequently deleted or silenced by hypermethylation in lung cancer, gastric cancer, and acute myeloid leukemia.	('gastric cancer', 'Phenotype', 'HP:0012126', (168, 182))	('zinc finger CCHC-type containing 10', 'Gene', (9, 44))	('leukemia', 'Phenotype', 'HP:0001909', (202, 210))	('ZCCHC10', 'Gene', (0, 7))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (188, 210))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('lung cancer', 'Disease', (155, 166))	('acute myeloid leukemia', 'Disease', (188, 210))	('hypermethylation', 'Var', (135, 151))	('lung cancer', 'Phenotype', 'HP:0100526', (155, 166))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('gastric cancer', 'Disease', (168, 182))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (188, 210))	('lung cancer', 'Disease', 'MESH:D008175', (155, 166))	('gastric cancer', 'Disease', 'MESH:D013274', (168, 182))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (194, 210))	('zinc finger CCHC-type containing 10', 'Gene', '54819', (9, 44))
174850	31138778	The Myc-Zh10 was used a template of PCR to construct a Myc-mtZh10 plasmid, in which the first two Cys residues of the CCHC-type zinc finger (C45QKCLEFGHWTYEC58) were substituted with Ala.	('C45QKCLEFGHWTYEC58', 'Var', (141, 159))	('Zh10', 'Gene', (8, 12))	('Myc', 'Gene', '4609', (4, 7))	('Myc', 'Gene', (4, 7))	('Zh10', 'Gene', (61, 65))	('Myc', 'Gene', '4609', (55, 58))	('Zh10', 'Gene', '54819', (8, 12))	('Myc', 'Gene', (55, 58))	('Zh10', 'Gene', '54819', (61, 65))
174882	31138778	Likewise, ZCCHC10 knockdown also promoted cell proliferation and migration in Hek293 cells (Supplementary Fig.	('knockdown', 'Var', (18, 27))	('migration', 'CPA', (65, 74))	('promoted', 'PosReg', (33, 41))	('cell proliferation', 'CPA', (42, 60))	('ZCCHC10', 'Gene', (10, 17))	('Hek293', 'CellLine', 'CVCL:0045', (78, 84))
174888	31138778	Moreover, tumors derived from A549-ZCCHC10 cells had higher levels of p53 and Bax proteins than control tumors (Fig.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('higher', 'PosReg', (53, 59))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('p53', 'Gene', (70, 73))	('p53', 'Gene', '7157', (70, 73))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('A549-ZCCHC10', 'Var', (30, 42))	('Bax', 'Gene', (78, 81))	('tumors', 'Disease', (10, 16))	('tumors', 'Disease', 'MESH:D009369', (10, 16))	('tumors', 'Phenotype', 'HP:0002664', (10, 16))	('tumors', 'Disease', (104, 110))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('A549-ZCCHC10', 'CellLine', 'CVCL:0023', (30, 42))	('Bax', 'Gene', '581', (78, 81))
174889	31138778	These results suggested that ZCCHC10 inhibited tumor growth possibly through p53 pathway.	('inhibited', 'NegReg', (37, 46))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('p53', 'Gene', (77, 80))	('p53', 'Gene', '7157', (77, 80))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('ZCCHC10', 'Var', (29, 36))	('tumor', 'Disease', (47, 52))
174895	31138778	To examine the effects of ZCCHC10 on the cisplatin sensitivity, IC50 (half inhibitory concentration) values were calculated based on the cell viability after exposure in different concentrations of cisplatin for 48 h. Based on the IC50 values, ZCCHC10 overexpression enhanced the cisplatin sensitivity in A549 and H460 cells, whereas knockdown of ZCCHC10 inhibited cisplatin sensitivity in Beas-2b cells (Fig.	('overexpression enhanced', 'PosReg', (252, 275))	('knockdown', 'Var', (334, 343))	('cisplatin', 'Chemical', 'MESH:D002945', (41, 50))	('Beas-2', 'CellLine', 'CVCL:0168', (390, 396))	('cisplatin', 'Chemical', 'MESH:D002945', (365, 374))	('cisplatin', 'Chemical', 'MESH:D002945', (280, 289))	('cisplatin', 'Chemical', 'MESH:D002945', (198, 207))	('ZCCHC10', 'Gene', (347, 354))	('ZCCHC10', 'Gene', (244, 251))	('cisplatin sensitivity', 'MPA', (280, 301))	('H460', 'CellLine', 'CVCL:0459', (314, 318))	('A549', 'CellLine', 'CVCL:0023', (305, 309))
174905	31138778	Co-IP assay showed that mutation of the CCHC zinc finger in the ZCCHC10 protein reduced its interaction between with p53 (Fig.	('ZCCHC10', 'Gene', (64, 71))	('p53', 'Gene', (117, 120))	('p53', 'Gene', '7157', (117, 120))	('reduced', 'NegReg', (80, 87))	('mutation', 'Var', (24, 32))	('interaction', 'Interaction', (92, 103))
174911	31138778	The results showed that overexpression of ZCCHC10 increased p53 level whereas knockdown of ZCCHC10 decreased p53 level (Fig.	('ZCCHC10', 'Gene', (91, 98))	('decreased', 'NegReg', (99, 108))	('knockdown', 'Var', (78, 87))	('increased', 'PosReg', (50, 59))	('p53', 'Gene', (60, 63))	('ZCCHC10', 'Gene', (42, 49))	('p53', 'Gene', (109, 112))	('p53', 'Gene', '7157', (109, 112))	('p53', 'Gene', '7157', (60, 63))
174913	31138778	The in vivo ubiquitination assay showed that the amount of ubiquitinated p53 in the A549 cells and H460 cells stably over-expressing ZCCHC10 were much lower than that in the corresponding control cells, whereas knockdown of ZCCHC10 promoted p53 ubiquitination in Beas-2B cells (Fig.	('ubiquitinated', 'MPA', (59, 72))	('H460', 'CellLine', 'CVCL:0459', (99, 103))	('p53', 'Gene', (241, 244))	('promoted', 'PosReg', (232, 240))	('amount', 'MPA', (49, 55))	('p53', 'Gene', (73, 76))	('p53', 'Gene', '7157', (73, 76))	('Beas-2B', 'CellLine', 'CVCL:0168', (263, 270))	('lower', 'NegReg', (151, 156))	('ubiquitination', 'MPA', (245, 259))	('ZCCHC10', 'Gene', (224, 231))	('over-expressing', 'PosReg', (117, 132))	('p53', 'Gene', '7157', (241, 244))	('A549', 'CellLine', 'CVCL:0023', (84, 88))	('ZCCHC10', 'Var', (133, 140))
174917	31138778	To eliminate the influence of MDM2-mediated p53 degradation on the interaction between p53 and MDM2, the ligase-inactive C464A mutant Myc-MDM2C464A was used in the co-IP experiment.	('Myc', 'Gene', '4609', (134, 137))	('p53', 'Gene', (87, 90))	('p53', 'Gene', '7157', (87, 90))	('Myc', 'Gene', (134, 137))	('MDM2', 'Gene', '4193', (30, 34))	('MDM2', 'Gene', '4193', (95, 99))	('MDM2', 'Gene', (30, 34))	('MDM2', 'Gene', (95, 99))	('p53', 'Gene', (44, 47))	('p53', 'Gene', '7157', (44, 47))	('interaction', 'Interaction', (67, 78))	('C464A', 'Var', (121, 126))	('MDM2', 'Gene', '4193', (138, 142))	('MDM2', 'Gene', (138, 142))	('C464A', 'Mutation', 'rs542860790', (142, 147))	('C464A', 'Mutation', 'rs542860790', (121, 126))
174918	31138778	6g, the amount of p53-binding MDM2 decreased with the increase of ZCCHC10 expression, indicating that ZCCHC10 suppressed the interaction of p53 with MDM2.	('MDM2', 'Gene', '4193', (149, 153))	('expression', 'MPA', (74, 84))	('ZCCHC10', 'Var', (102, 109))	('p53', 'Gene', (18, 21))	('p53', 'Gene', '7157', (18, 21))	('MDM2', 'Gene', '4193', (30, 34))	('increase', 'PosReg', (54, 62))	('interaction', 'Interaction', (125, 136))	('MDM2', 'Gene', (30, 34))	('amount', 'MPA', (8, 14))	('ZCCHC10', 'Gene', (66, 73))	('decreased', 'NegReg', (35, 44))	('suppressed', 'NegReg', (110, 120))	('p53', 'Gene', (140, 143))	('p53', 'Gene', '7157', (140, 143))	('MDM2', 'Gene', (149, 153))
174919	31138778	These results suggested that ZCCHC10 suppressed MDM2-mediated ubiquitination of p53 through disrupting the interaction between p53 and MDM2.	('MDM2', 'Gene', '4193', (135, 139))	('MDM2', 'Gene', (135, 139))	('p53', 'Gene', '7157', (127, 130))	('disrupting', 'NegReg', (92, 102))	('p53', 'Gene', (127, 130))	('p53', 'Gene', (80, 83))	('interaction', 'Interaction', (107, 118))	('p53', 'Gene', '7157', (80, 83))	('MDM2', 'Gene', '4193', (48, 52))	('MDM2', 'Gene', (48, 52))	('ZCCHC10', 'Var', (29, 36))	('suppressed', 'NegReg', (37, 47))
174924	31138778	Moreover, mutation of CCHC domain of ZCCHC10 protein resulted in the decline of its influence on p53 activity (Supplementary Fig.	('p53', 'Gene', (97, 100))	('ZCCHC10', 'Gene', (37, 44))	('decline', 'NegReg', (69, 76))	('protein', 'Protein', (45, 52))	('p53', 'Gene', '7157', (97, 100))	('mutation', 'Var', (10, 18))	('influence', 'MPA', (84, 93))
174927	31138778	Additionally, ZCCHC10 enhanced the level of cleaved Caspase 3, but suppressed the expression of Cyclin D1 (CCND1) in the cells with wtp53 (Fig.	('Cyclin D1', 'Gene', (96, 105))	('Caspase 3', 'Gene', (52, 61))	('p53', 'Gene', '7157', (134, 137))	('expression', 'MPA', (82, 92))	('CCND1', 'Gene', '595', (107, 112))	('ZCCHC10', 'Var', (14, 21))	('level', 'MPA', (35, 40))	('p53', 'Gene', (134, 137))	('Cyclin D1', 'Gene', '595', (96, 105))	('suppressed', 'NegReg', (67, 77))	('CCND1', 'Gene', (107, 112))	('enhanced', 'PosReg', (22, 30))	('Caspase 3', 'Gene', '836', (52, 61))
174939	31138778	It suggested ZCCHC10 downregulation and p53 mutation were mutually exclusive.	('mutation', 'Var', (44, 52))	('ZCCHC10', 'Gene', (13, 20))	('downregulation', 'NegReg', (21, 35))	('p53', 'Gene', (40, 43))	('p53', 'Gene', '7157', (40, 43))
174947	31138778	Mechanistically, we demonstrated that ZCCHC10 stabilizes p53 protein by interfering with the MDM2-mediated ubiquitination of p53, and enhances the regulatory roles of p53 on the expression of the genes involved in cell cycle (p21), apoptosis (Bax, Bcl2) and EMT (E-cadherin, Snail and Slug).	('Bax', 'Gene', '581', (243, 246))	('expression', 'MPA', (178, 188))	('Slug', 'Gene', (285, 289))	('Snail', 'Gene', (275, 280))	('p53', 'Gene', '7157', (167, 170))	('p21', 'Gene', '1026', (226, 229))	('MDM2', 'Gene', '4193', (93, 97))	('p53', 'Gene', '7157', (57, 60))	('ZCCHC10', 'Var', (38, 45))	('p53', 'Gene', (57, 60))	('p53', 'Gene', (167, 170))	('stabilizes', 'PosReg', (46, 56))	('E-cadherin', 'Gene', (263, 273))	('E-cadherin', 'Gene', '999', (263, 273))	('Bcl2', 'Gene', (248, 252))	('Slug', 'Gene', '6591', (285, 289))	('p53', 'Gene', '7157', (125, 128))	('enhances', 'PosReg', (134, 142))	('Bcl2', 'Gene', '596', (248, 252))	('Snail', 'Gene', '6615', (275, 280))	('protein', 'Protein', (61, 68))	('p21', 'Gene', (226, 229))	('interfering', 'NegReg', (72, 83))	('p53', 'Gene', (125, 128))	('Bax', 'Gene', (243, 246))	('regulatory', 'MPA', (147, 157))	('MDM2', 'Gene', (93, 97))	('cell', 'CPA', (214, 218))
174954	31138778	Moreover, ZCCHC10 expression has a greater benefit for non-smokers than smokers among patients with lung cancer.	('lung cancer', 'Phenotype', 'HP:0100526', (100, 111))	('lung cancer', 'Disease', (100, 111))	('benefit', 'PosReg', (43, 50))	('ZCCHC10', 'Gene', (10, 17))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('expression', 'Var', (18, 28))	('lung cancer', 'Disease', 'MESH:D008175', (100, 111))	('patients', 'Species', '9606', (86, 94))
174956	31138778	TP53 mutation is more prevalent among patients with LUSC than patients with LUAD (57-65% versus 40-41%), and the frequency of TP53 mutation in the lungs of patients with cancer who smoke is also higher than in never smokers (48% versus 36%).	('patients', 'Species', '9606', (156, 164))	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('TP53', 'Gene', (126, 130))	('cancer', 'Disease', (170, 176))	('LUSC', 'Disease', (52, 56))	('TP53', 'Gene', '7157', (126, 130))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('prevalent', 'Reg', (22, 31))	('patients', 'Species', '9606', (38, 46))	('patients', 'Species', '9606', (62, 70))	('mutation', 'Var', (5, 13))	('mutation', 'Var', (131, 139))
174961	30310408	Successful development of squamous cell carcinoma and hyperplasia in RGEN-mediated p27 KO mice after the treatment of DMBA and TPA To evaluate the carcinogenicity of p27 knockout (KO) mice with RNA-guided endonuclease (RGENs)-mediated p27 mutant exon I gene (IDelta), alterations in the carcinogenic phenotypes including tumor spectrum, tumor suppressor proteins, apoptotic proteins and cell cycle regulators were observed in p27 (IDelta) KO mice after treatment with 7,12-Dimethylbenz[a]anthracene (DMBA) and 12-O-tetradecanoylphorbol-13-acetate (TPA)(DT) for 5 months.	('tumor', 'Disease', (337, 342))	('carcinogenic', 'Disease', (147, 159))	('DT', 'Chemical', 'MESH:D013936', (553, 555))	('p27', 'Gene', (166, 169))	('tumor', 'Disease', (321, 326))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (26, 49))	('mice', 'Species', '10090', (442, 446))	('tumor', 'Disease', 'MESH:D009369', (337, 342))	('DMBA', 'Chemical', 'MESH:D015127', (500, 504))	('carcinogenic', 'Disease', 'MESH:D063646', (147, 159))	('p27', 'Gene', (426, 429))	('tumor', 'Disease', 'MESH:D009369', (321, 326))	('hyperplasia', 'Disease', (54, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (40, 49))	('squamous cell carcinoma', 'Disease', (26, 49))	('mutant', 'Var', (239, 245))	('hyperplasia', 'Disease', 'MESH:D006965', (54, 65))	('p27', 'Gene', '12576', (166, 169))	('tumor', 'Phenotype', 'HP:0002664', (337, 342))	('p27', 'Gene', (235, 238))	('carcinogenic', 'Disease', (287, 299))	('tumor', 'Phenotype', 'HP:0002664', (321, 326))	('mice', 'Species', '10090', (90, 94))	('p27', 'Gene', (83, 86))	('p27', 'Gene', '12576', (426, 429))	('mice', 'Species', '10090', (184, 188))	('DMBA', 'Chemical', 'MESH:D015127', (118, 122))	('carcinogenic', 'Disease', 'MESH:D063646', (287, 299))	('TPA', 'Chemical', 'MESH:D013755', (127, 130))	('TPA', 'Chemical', 'MESH:D013755', (548, 551))	('p27', 'Gene', '12576', (235, 238))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (26, 49))	('p27', 'Gene', '12576', (83, 86))
174970	30310408	Several studies have been accomplished on the organ sensitivity in chemically induced carcinogenesis during p27 deficiency.	('carcinogenesis', 'Disease', (86, 100))	('deficiency', 'Var', (112, 122))	('carcinogenesis', 'Disease', 'MESH:D063646', (86, 100))	('p27', 'Gene', (108, 111))	('p27', 'Gene', '12576', (108, 111))
174971	30310408	Intestinal and lung adenocarcinoma and pituitary tumors were found in p27 KO mice with exon I and II deletion (I/IIDelta) challenged with gamma-irradiation and N-ethyl-N-nitrosourea (ENU) injection, while skin tumor and intestinal adenoma were significantly increased in p27 (I/IIDelta) KO mice after DMBA and TPA treatment.	('skin tumor', 'Phenotype', 'HP:0008069', (205, 215))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('N-ethyl-N-nitrosourea', 'Chemical', 'MESH:D005038', (160, 181))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (15, 34))	('p27', 'Gene', '12576', (271, 274))	('pituitary tumors', 'Disease', 'MESH:D010911', (39, 55))	('carcinoma', 'Phenotype', 'HP:0030731', (25, 34))	('mice', 'Species', '10090', (290, 294))	('mice', 'Species', '10090', (77, 81))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (15, 34))	('increased', 'PosReg', (258, 267))	('adenoma', 'Disease', (231, 238))	('skin tumor', 'Disease', 'MESH:D012878', (205, 215))	('p27', 'Gene', (70, 73))	('adenoma', 'Disease', 'MESH:D000236', (231, 238))	('deletion', 'Var', (101, 109))	('pituitary tumors', 'Disease', (39, 55))	('DMBA', 'Chemical', 'MESH:D015127', (301, 305))	('skin tumor', 'Disease', (205, 215))	('p27', 'Gene', '12576', (70, 73))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('p27', 'Gene', (271, 274))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('lung adenocarcinoma', 'Disease', (15, 34))	('exon', 'Gene', (87, 91))	('TPA', 'Chemical', 'MESH:D013755', (310, 313))
174972	30310408	Also, dimethylhydrazine (DMH)-treated germline deletion p27 (exon I and II) mice presented only gastrointestinal adenocarcinoma malignancies, but N-methyl-N-nitrosourea (MNU) treatment induced hyperplasia and carcinoma in various organs.	('MNU', 'Chemical', '-', (170, 173))	('p27', 'Gene', '12576', (56, 59))	('carcinoma', 'Disease', 'MESH:D002277', (118, 127))	('hyperplasia', 'Disease', (193, 204))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('DMH', 'Chemical', 'MESH:D004127', (25, 28))	('deletion', 'Var', (47, 55))	('mice', 'Species', '10090', (76, 80))	('N-methyl-N-nitrosourea', 'Chemical', 'MESH:D008770', (146, 168))	('p27', 'Gene', (56, 59))	('carcinoma', 'Disease', (118, 127))	('gastrointestinal adenocarcinoma malignancies', 'Disease', 'MESH:D004067', (96, 140))	('hyperplasia', 'Disease', 'MESH:D006965', (193, 204))	('dimethylhydrazine', 'Chemical', 'MESH:D004127', (6, 23))	('carcinoma', 'Disease', 'MESH:D002277', (209, 218))	('carcinoma', 'Phenotype', 'HP:0030731', (209, 218))	('gastrointestinal adenocarcinoma malignancies', 'Disease', (96, 140))	('carcinoma', 'Disease', (209, 218))
174973	30310408	Carcinoma of the urinary bladder and esophageal cancer were significantly higher in p27 (I/IIDelta) KO mice treated with N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) and methylbenzylnitrosamine (MBN).	('p27', 'Gene', (84, 87))	('Carcinoma', 'Phenotype', 'HP:0030731', (0, 9))	('BBN', 'Chemical', 'MESH:D002085', (160, 163))	('Carcinoma of the urinary bladder', 'Disease', (0, 32))	('higher', 'PosReg', (74, 80))	('mice', 'Species', '10090', (103, 107))	('methylbenzylnitrosamine', 'Var', (169, 192))	('N-butyl-N-(4-hydroxybutyl)nitrosamine', 'Chemical', 'MESH:D002085', (121, 158))	('p27', 'Gene', '12576', (84, 87))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('MBN', 'Chemical', 'MESH:C014707', (194, 197))	('Carcinoma of the urinary bladder', 'Disease', 'MESH:D001749', (0, 32))	('esophageal cancer', 'Disease', (37, 54))	('methylbenzylnitrosamine', 'Chemical', 'MESH:C014707', (169, 192))	('esophageal cancer', 'Disease', 'MESH:D004938', (37, 54))
174975	30310408	However, all above studies used only the p27 (I/IIDelta) KO mice with targeted disruption of exon I and II using the homologous recombination technique.	('p27', 'Gene', (41, 44))	('disruption', 'Var', (79, 89))	('p27', 'Gene', '12576', (41, 44))	('exon', 'Gene', (93, 97))	('mice', 'Species', '10090', (60, 64))
174980	30310408	After assessing their efficacy for small deletion at the target site in mouse NIH3T3 cells, each RGEN mRNA was injected into the cytoplasm of mouse pronuclear-stage embryos to produce mutant FVB/N founders (F0) with mutations in p27.	('p27', 'Gene', '12576', (229, 232))	('mouse', 'Species', '10090', (72, 77))	('mouse', 'Species', '10090', (142, 147))	('mutations', 'Var', (216, 225))	('p27', 'Gene', (229, 232))	('NIH3T3', 'CellLine', 'CVCL:0594', (78, 84))
174981	30310408	The resultant p27 (IDelta) KO mice have a 28 bp deletion in exon 1 of the p27 gene (Figure 1A).	('mice', 'Species', '10090', (30, 34))	('p27', 'Gene', '12576', (74, 77))	('p27', 'Gene', (14, 17))	('deletion in', 'Var', (48, 59))	('p27', 'Gene', '12576', (14, 17))	('p27', 'Gene', (74, 77))
174983	30310408	The RGEN-mediated p27 mutant genes in FVB/N background strains were amplified using two primer sets.	('p27', 'Gene', '12576', (18, 21))	('p27', 'Gene', (18, 21))	('mutant', 'Var', (22, 28))
175000	30310408	Proteins prepared from the skin tissue of mice were separated by 4-20% sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) for 2 h, after which the resolved proteins were transferred to nitrocellulose membranes for 2 h at 40 V. Each membrane was then incubated separately, overnight at 4C, with the following primary antibodies: anti-p27 (1:1,000, Sigma-Aldrich Co.), anti-p53 (1:1,000, Sigma-Aldrich Co.), anti-Bax (1:1,000, Abcam, Cambridge, UK), anti-Bcl-2 (1:1,000, Thermo Fisher Scientific, Waltham, MA, USA), anti-Caspase-3 (1:1,000, Cell Signaling Technology, Danvers, MA, USA), anti-Cyclin D1 (1:1,000, Cell Signaling Technology), anti-CDK2 (1:1,000, Santa Cruz Biotechnology, Santa Cruz, CA, USA), anti-CDK4 (1:1,000, Santa Cruz Biotechnology) and anti-beta-actin (1:1,000, Sigma-Aldrich Co.).	('CDK4', 'Gene', (729, 733))	('p53', 'Gene', '22060', (390, 393))	('CDK4', 'Gene', '12567', (729, 733))	('Bcl-2', 'Gene', '12043', (471, 476))	('Bcl-2', 'Gene', (471, 476))	('Bax', 'Gene', '12028', (429, 432))	('mice', 'Species', '10090', (42, 46))	('Caspase-3', 'Gene', (537, 546))	('p53', 'Gene', (390, 393))	('Cyclin D1', 'Gene', '12443', (608, 617))	('p27', 'Gene', (351, 354))	('Caspase-3', 'Gene', '12367', (537, 546))	('CDK2', 'Gene', '12566', (661, 665))	('Bax', 'Gene', (429, 432))	('Cyclin D1', 'Gene', (608, 617))	('p27', 'Gene', '12576', (351, 354))	('anti-beta-actin', 'Var', (774, 789))	('CDK2', 'Gene', (661, 665))
175010	30310408	Furthermore, squamous cell hyperplasia with chronic inflammation was detected in the dermis region of DT-treated p27 (IDelta) KO mice, as compared to the WT and Vehicle-treated p27 (IDelta) KO mice (Figure 2Bc and d).	('p27', 'Gene', '12576', (177, 180))	('squamous cell hyperplasia', 'Disease', (13, 38))	('inflammation', 'Disease', (52, 64))	('p27', 'Gene', (113, 116))	('DT', 'Chemical', 'MESH:D013936', (102, 104))	('DT-treated', 'Var', (102, 112))	('mice', 'Species', '10090', (129, 133))	('p27', 'Gene', '12576', (113, 116))	('squamous cell hyperplasia', 'Phenotype', 'HP:0002860', (13, 38))	('mice', 'Species', '10090', (193, 197))	('squamous cell hyperplasia', 'Disease', 'MESH:D002294', (13, 38))	('p27', 'Gene', (177, 180))	('inflammation', 'Disease', 'MESH:D007249', (52, 64))
175026	30310408	In the present study, we used p27 (IDelta) KO mice with RGEN specific deletion of exon I in p27 gene.	('p27', 'Gene', (30, 33))	('p27', 'Gene', (92, 95))	('deletion of', 'Var', (70, 81))	('p27', 'Gene', '12576', (30, 33))	('p27', 'Gene', '12576', (92, 95))	('mice', 'Species', '10090', (46, 50))
175038	30310408	One reason for these differences might be that the two classes of KO mice have different deletion sites for the p27 gene.	('p27', 'Gene', '12576', (112, 115))	('deletion', 'Var', (89, 97))	('mice', 'Species', '10090', (69, 73))	('p27', 'Gene', (112, 115))
175041	30310408	Therefore, we believe that RGENs-mediated p27 (IDelta) KO mice can be considered a novel animal model for chemical carcinogenesis.	('p27', 'Gene', (42, 45))	('RGENs-mediated', 'Var', (27, 41))	('mice', 'Species', '10090', (58, 62))	('carcinogenesis', 'Disease', 'MESH:D063646', (115, 129))	('carcinogenesis', 'Disease', (115, 129))	('p27', 'Gene', '12576', (42, 45))
175047	29452120	Recently, genome-wide association studies among non-Hispanic whites have identified variants in 21 genetic loci that have are associated with cutaneous squamous cell carcinoma (cSCC) risk.	('associated', 'Reg', (126, 136))	('cSCC', 'Phenotype', 'HP:0006739', (177, 181))	('cutaneous squamous cell carcinoma', 'Disease', (142, 175))	('carcinoma', 'Phenotype', 'HP:0030731', (166, 175))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (152, 175))	('cutaneous squamous cell carcinoma', 'Phenotype', 'HP:0006739', (142, 175))	('cutaneous squamous cell carcinoma', 'Disease', 'MESH:D002294', (142, 175))	('variants', 'Var', (84, 92))
175052	29452120	Prevalent SNPs with moderate to high odds ratios contributed the most the multi-locus PAR, and included SNPs in the genes SLC45A2, SRC, HERC2, DEF8 and HLADQA1.	('SRC', 'Gene', (131, 134))	('HLADQA1', 'Gene', (152, 159))	('DEF8', 'Gene', '54849', (143, 147))	('HERC2', 'Gene', (136, 141))	('SLC45A2', 'Gene', '51151', (122, 129))	('DEF8', 'Gene', (143, 147))	('HERC2', 'Gene', '8924', (136, 141))	('SRC', 'Gene', '6714', (131, 134))	('SNPs', 'Var', (104, 108))	('HLADQA1', 'Gene', '3117', (152, 159))	('SLC45A2', 'Gene', (122, 129))
175056	29452120	Activation of AHR during UV radiation exposure may decrease apoptosis in keratinocytes with potential consequences for enhancing cancer risk.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('enhancing', 'PosReg', (119, 128))	('cancer', 'Disease', (129, 135))	('apoptosis', 'CPA', (60, 69))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('Activation', 'Var', (0, 10))	('decrease', 'NegReg', (51, 59))	('AHR', 'Gene', '196', (14, 17))	('AHR', 'Gene', (14, 17))
175059	29452120	While the multi-locus PAR allows quantification of the joint impact of these variants on cSCC risk, this one statistic is of limited utility for screening purposes, as it does not consider known environmental risk factors, such as sun exposure and smoking.	('variants', 'Var', (77, 85))	('men', 'Species', '9606', (202, 205))	('impact', 'Reg', (61, 67))	('cSCC', 'Phenotype', 'HP:0006739', (89, 93))	('cSCC', 'Disease', (89, 93))
175064	25568334	Inactivation of GSK3beta and activation of NF-kappaB pathway via Axl represents an important mediator of tumorigenesis in esophageal squamous cell carcinoma Deregulation of Axl in esophageal squamous cell carcinoma (OSCC) with potential therapeutic implications is described for the first time.	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (180, 214))	('esophageal squamous cell carcinoma', 'Disease', (122, 156))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (191, 214))	('Axl', 'Gene', '558', (173, 176))	('GSK3beta', 'Gene', '2932', (16, 24))	('Axl', 'Gene', (173, 176))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (133, 156))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (122, 156))	('Inactivation', 'Var', (0, 12))	('carcinoma', 'Phenotype', 'HP:0030731', (205, 214))	('GSK3beta', 'Gene', (16, 24))	('esophageal squamous cell carcinoma', 'Disease', (180, 214))	('activation', 'PosReg', (29, 39))	('NF-kappaB', 'Gene', (43, 52))	('Axl', 'Gene', '558', (65, 68))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('NF-kappaB', 'Gene', '4790', (43, 52))	('Axl', 'Gene', (65, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (147, 156))
175070	25568334	Blockage of Axl gene expression by small interfering RNA inhibits cell survival, proliferation, migration, and invasion in vitro and esophageal tumor growth in vivo.	('migration', 'CPA', (96, 105))	('esophageal tumor', 'Disease', 'MESH:D004938', (133, 149))	('esophageal tumor', 'Disease', (133, 149))	('cell survival', 'CPA', (66, 79))	('Axl gene', 'Gene', (12, 20))	('esophageal tumor', 'Phenotype', 'HP:0100751', (133, 149))	('small interfering', 'Var', (35, 52))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('invasion', 'CPA', (111, 119))	('inhibits', 'NegReg', (57, 65))	('Blockage', 'NegReg', (0, 8))
175084	25568334	Axl phosphorylation and consequent activation have been linked to signaling pathways such as the phosphatidylinositol 3-OH kinase (PI3K) pathway, including its downstream targets S6K and Akt; the mitogen-activated protein kinases (MAPK) pathway; and the Jak/Stat and NF-kappaB signal transduction pathway cascades, which are closely related to progression and development of tumors and inhibition of apoptosis.	('phosphatidylinositol 3-OH kinase', 'Gene', (97, 129))	('NF-kappaB', 'Gene', (267, 276))	('tumor', 'Phenotype', 'HP:0002664', (375, 380))	('S6K', 'Gene', (179, 182))	('Akt', 'Gene', (187, 190))	('PI3', 'Gene', (131, 134))	('S6K', 'Gene', '6198', (179, 182))	('men', 'Species', '9606', (367, 370))	('tumors', 'Disease', (375, 381))	('tumors', 'Disease', 'MESH:D009369', (375, 381))	('tumors', 'Phenotype', 'HP:0002664', (375, 381))	('Akt', 'Gene', '207', (187, 190))	('PI3', 'Gene', '5266', (131, 134))	('phosphorylation', 'Var', (4, 19))	('phosphatidylinositol 3-OH kinase', 'Gene', '5294', (97, 129))	('activation', 'PosReg', (35, 45))	('NF-kappaB', 'Gene', '4790', (267, 276))
175089	25568334	Moreover, inhibition of Axl leads to restoration of sensitivity to erlotinib, indicating that Axl may represent a promising therapeutic target whose inhibition could prevent or overcome acquired resistance to certain drugs.	('inhibition', 'Var', (10, 20))	('sensitivity to erlotinib', 'MPA', (52, 76))	('erlotinib', 'Chemical', 'MESH:D000069347', (67, 76))	('Axl', 'Enzyme', (24, 27))
175092	25568334	Furthermore, we reveal that blockage of Axl protein expression inhibits proliferation, invasion, and migration of OSCC cells and tumor formation in vivo.	('blockage', 'Var', (28, 36))	('migration of OSCC cells', 'CPA', (101, 124))	('inhibits', 'NegReg', (63, 71))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('proliferation', 'CPA', (72, 85))	('OSCC cells', 'CellLine', 'CVCL:L894', (114, 124))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('invasion', 'CPA', (87, 95))	('tumor', 'Disease', (129, 134))	('Axl protein expression', 'Protein', (40, 62))
175093	25568334	Interestingly, inhibition of Axl expression strikingly leads to reduction of Akt activation, leading to inhibition of IkappaBalpha phosphorylation and consequent blockage of NF-kappaB transcriptional activity.	('inhibition', 'NegReg', (104, 114))	('Akt', 'Gene', '207', (77, 80))	('IkappaBalpha', 'Gene', '4792', (118, 130))	('blockage', 'NegReg', (162, 170))	('IkappaBalpha', 'Gene', (118, 130))	('NF-kappaB', 'Gene', '4790', (174, 183))	('Akt', 'Gene', (77, 80))	('activation', 'PosReg', (81, 91))	('NF-kappaB', 'Gene', (174, 183))	('Axl', 'Protein', (29, 32))	('reduction', 'NegReg', (64, 73))	('transcriptional activity', 'MPA', (184, 208))	('inhibition', 'Var', (15, 25))
175110	25568334	For determining the effect of Axl blockage on tumor formation in vivo, Kyse450 cells infected either with LV-siRNA GFP (control) or LV-siRNA Axl were subcutaneously injected into MF-1 nude mice.	('nude mice', 'Species', '10090', (184, 193))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('LV-siRNA', 'Var', (132, 140))	('tumor', 'Disease', (46, 51))	('LV-siRNA', 'Var', (106, 114))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
175112	25568334	Mice implanted with Kyse450 siSRNA Axl cells developed tumors 60% lower in mass when compared with mice implanted with Kyse450 siRNA GFP control cells (Figure 3).	('mice', 'Species', '10090', (99, 103))	('mass', 'MPA', (75, 79))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('Kyse450 siSRNA', 'Var', (20, 34))	('lower', 'NegReg', (66, 71))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('tumors', 'Disease', (55, 61))	('tumors', 'Disease', 'MESH:D009369', (55, 61))	('Mice', 'Species', '10090', (0, 4))
175113	25568334	Additionally, we observed lymph node metastasis only in mice implanted with Kyse450 siRNA GFP cells, while no metastases were observed in mice implanted with Kyse450 siRNA Axl (unpublished data), indicating that Axl expression plays an important role for tumor growth in vivo.	('metastases', 'Disease', (110, 120))	('tumor', 'Phenotype', 'HP:0002664', (255, 260))	('tumor', 'Disease', (255, 260))	('metastases', 'Disease', 'MESH:D009362', (110, 120))	('mice', 'Species', '10090', (138, 142))	('lymph node metastasis', 'CPA', (26, 47))	('Kyse450 siRNA GFP', 'Var', (76, 93))	('mice', 'Species', '10090', (56, 60))	('tumor', 'Disease', 'MESH:D009369', (255, 260))
175120	25568334	Western blot analysis of whole-cell extracts comparing Kyse450 and WHCO5 cells with Axl knockdown to the GFP knockdown cells revealed that inhibition of Axl leads to reduction of both Akt and IKKalpha phosphorylation and activity, which should result in inhibition of NF-kappaB (Figure 4A).	('inhibition', 'Var', (139, 149))	('reduction', 'NegReg', (166, 175))	('activity', 'MPA', (221, 229))	('Akt', 'Gene', (184, 187))	('Axl', 'Protein', (153, 156))	('IKKalpha', 'Gene', (192, 200))	('IKKalpha', 'Gene', '1147', (192, 200))	('NF-kappaB', 'Gene', '4790', (268, 277))	('inhibition', 'NegReg', (254, 264))	('NF-kappaB', 'Gene', (268, 277))	('Akt', 'Gene', '207', (184, 187))
175126	25568334	GSK3beta activity is regulated by site-specific phosphorylation of the Ser-9 residue, and deregulated phosphorylation has been linked to pathological conditions such as cancer.	('linked', 'Reg', (127, 133))	('cancer', 'Disease', (169, 175))	('phosphorylation', 'MPA', (102, 117))	('activity', 'MPA', (9, 17))	('cancer', 'Disease', 'MESH:D009369', (169, 175))	('phosphorylation', 'MPA', (48, 63))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('deregulated', 'Var', (90, 101))	('Ser', 'Chemical', 'MESH:D012694', (71, 74))	('GSK3beta', 'Gene', (0, 8))	('GSK3beta', 'Gene', '2932', (0, 8))
175128	25568334	Indeed, Akt phosphorylates the Ser-9 residue in GSK3beta, leading to its inactivation.	('GSK3beta', 'Gene', (48, 56))	('GSK3beta', 'Gene', '2932', (48, 56))	('inactivation', 'MPA', (73, 85))	('Akt', 'Gene', (8, 11))	('Ser', 'Chemical', 'MESH:D012694', (31, 34))	('Ser-9', 'Var', (31, 36))	('Akt', 'Gene', '207', (8, 11))
175131	25568334	As observed in Figure 5A, knockdown of Axl in both Kyse450 and WHCO5 cells inhibits the GSK3beta Ser-9 phosphorylation, indicating that Axl leads to inactivation of GSK3beta in OSSC.	('GSK3beta', 'Gene', '2932', (165, 173))	('GSK3beta', 'Gene', (88, 96))	('Ser', 'Chemical', 'MESH:D012694', (97, 100))	('inactivation', 'NegReg', (149, 161))	('knockdown', 'Var', (26, 35))	('GSK3beta', 'Gene', '2932', (88, 96))	('GSK3beta', 'Gene', (165, 173))	('inhibits', 'NegReg', (75, 83))
175135	25568334	Figure 5B demonstrates that GSK3beta is activated after treatment of esophageal cancer cells with wortmannin, because wortmannin reduces its phosphorylation.	('wortmannin', 'Chemical', 'MESH:D000077191', (98, 108))	('GSK3beta', 'Gene', '2932', (28, 36))	('esophageal cancer', 'Disease', (69, 86))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('esophageal cancer', 'Disease', 'MESH:D004938', (69, 86))	('phosphorylation', 'MPA', (141, 156))	('men', 'Species', '9606', (61, 64))	('GSK3beta', 'Gene', (28, 36))	('wortmannin', 'Var', (118, 128))	('wortmannin', 'Chemical', 'MESH:D000077191', (118, 128))	('reduces', 'NegReg', (129, 136))
175142	25568334	As shown in Supplemental Figure 1, inactivation of GSK3beta is more pronounced in Kyse450 siRNA Axl transfected with pcDNA Flag-Axl vector and treated with GSK3beta inhibitor II.	('inactivation', 'NegReg', (35, 47))	('Kyse450 siRNA Axl', 'Enzyme', (82, 99))	('transfected', 'Var', (100, 111))	('GSK3beta', 'Gene', (156, 164))	('GSK3beta', 'Gene', '2932', (51, 59))	('men', 'Species', '9606', (18, 21))	('GSK3beta', 'Gene', '2932', (156, 164))	('GSK3beta', 'Gene', (51, 59))
175145	25568334	Treatment of cells with wortmannin or GSK3beta inhibitor II reveals that wortmannin reduces proliferation of OSCC cells and knockdown cells transfected with pcDNA Flag-Axl vector, but it does not significantly affect proliferation of cells lacking Axl (Figure 5D).	('GSK3beta', 'Gene', '2932', (38, 46))	('wortmannin', 'Chemical', 'MESH:D000077191', (24, 34))	('wortmannin', 'Var', (73, 83))	('reduces', 'NegReg', (84, 91))	('men', 'Species', '9606', (5, 8))	('OSCC cells', 'CellLine', 'CVCL:L894', (109, 119))	('proliferation', 'CPA', (92, 105))	('wortmannin', 'Chemical', 'MESH:D000077191', (73, 83))	('GSK3beta', 'Gene', (38, 46))
175146	25568334	On the other hand, the GSK3beta inhibitor II induces proliferation in Axl knockdown cells but not in parental cells (Kyse450) or Axl knockdown cells transfected with pcDNA Flag-Axl.	('induces', 'Reg', (45, 52))	('knockdown', 'Var', (74, 83))	('GSK3beta', 'Gene', (23, 31))	('proliferation', 'CPA', (53, 66))	('GSK3beta', 'Gene', '2932', (23, 31))
175154	25568334	In addition, analysis of E-cadherin mRNA levels, an epithelial marker, demonstrates that cells lacking Axl and, consequently, expressing lower levels of Snail, have higher levels of E-cadherin mRNA when compared with control, and transfection of Axl knockdown cells with pcDNA Flag-Axl reduces E-cadherin expression (Figure 6B).	('lower', 'NegReg', (137, 142))	('transfection', 'Var', (230, 242))	('reduces', 'NegReg', (286, 293))	('E-cadherin', 'Gene', (182, 192))	('E-cadherin', 'Gene', (294, 304))	('higher', 'PosReg', (165, 171))	('E-cadherin', 'Gene', (25, 35))	('E-cadherin', 'Gene', '999', (294, 304))	('E-cadherin', 'Gene', '999', (182, 192))	('Snail', 'Gene', (153, 158))	('E-cadherin', 'Gene', '999', (25, 35))	('levels', 'MPA', (172, 178))	('Snail', 'Gene', '6615', (153, 158))
175169	25568334	Our findings demonstrate that blockage of Axl expression significantly reduces migration, invasion, and proliferation of OSCC cells and inhibits tumor growth.	('migration', 'CPA', (79, 88))	('reduces', 'NegReg', (71, 78))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('OSCC cells', 'CellLine', 'CVCL:L894', (121, 131))	('proliferation', 'CPA', (104, 117))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumor', 'Disease', (145, 150))	('invasion', 'CPA', (90, 98))	('blockage', 'Var', (30, 38))	('inhibits', 'NegReg', (136, 144))	('Axl expression', 'Protein', (42, 56))
175173	25568334	Furthermore, inhibition of NF-kappaB induces apoptosis and blocks tumor growth.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('blocks tumor', 'Disease', 'MESH:D006327', (59, 71))	('inhibition', 'Var', (13, 23))	('NF-kappaB', 'Gene', '4790', (27, 36))	('NF-kappaB', 'Gene', (27, 36))	('apoptosis', 'CPA', (45, 54))	('blocks tumor', 'Disease', (59, 71))
175174	25568334	Here we demonstrate that knockdown of Axl expression leads to the inactivation of NF-kappaB by inhibition of Akt and IKKalpha activity.	('Akt', 'Gene', '207', (109, 112))	('NF-kappaB', 'Gene', (82, 91))	('inhibition', 'NegReg', (95, 105))	('inactivation', 'NegReg', (66, 78))	('Akt', 'Gene', (109, 112))	('Axl', 'Gene', (38, 41))	('IKKalpha', 'Gene', '1147', (117, 125))	('NF-kappaB', 'Gene', '4790', (82, 91))	('knockdown', 'Var', (25, 34))	('IKKalpha', 'Gene', (117, 125))
175185	25568334	We demonstrate now that inhibition of Axl expression has a pivotal effect on GSK3beta activation.	('Axl expression', 'Protein', (38, 52))	('GSK3beta', 'Gene', (77, 85))	('inhibition', 'Var', (24, 34))	('activation', 'PosReg', (86, 96))	('GSK3beta', 'Gene', '2932', (77, 85))
175189	25568334	In OSCC cells, expression of Axl activates Akt and leads to GSK3beta inactivation via phosphorylation of its Ser-9.	('expression', 'Var', (15, 25))	('OSCC cells', 'CellLine', 'CVCL:L894', (3, 13))	('Akt', 'Gene', '207', (43, 46))	('inactivation', 'NegReg', (69, 81))	('GSK3beta', 'Gene', (60, 68))	('activates', 'PosReg', (33, 42))	('Ser-9', 'Protein', (109, 114))	('phosphorylation', 'MPA', (86, 101))	('Akt', 'Gene', (43, 46))	('GSK3beta', 'Gene', '2932', (60, 68))	('Ser', 'Chemical', 'MESH:D012694', (109, 112))
175192	25568334	Accordingly, the treatment of Axl knockdown cells with an inhibitor of GSK3beta leads to increased cell proliferation.	('cell proliferation', 'CPA', (99, 117))	('inhibitor', 'Var', (58, 67))	('GSK3beta', 'Gene', (71, 79))	('men', 'Species', '9606', (22, 25))	('increased', 'PosReg', (89, 98))	('GSK3beta', 'Gene', '2932', (71, 79))
175195	25568334	These observations strongly support the notion that Axl may represent an underexplored therapeutic target for OSCC and may induce EMT in OSCC via GSK3beta inactivation.	('GSK3beta', 'Gene', (146, 154))	('induce', 'PosReg', (123, 129))	('inactivation', 'Var', (155, 167))	('OSCC', 'Disease', (137, 141))	('GSK3beta', 'Gene', '2932', (146, 154))	('OSCC', 'Disease', (110, 114))	('EMT', 'CPA', (130, 133))
175225	33636047	However, the majority of COVID-19-related genetic and epigenetic variants still remain uninvestigated.	('COVID-19', 'Disease', (25, 33))	('COVID-19', 'Disease', 'MESH:C000657245', (25, 33))	('epigenetic variants', 'Var', (54, 73))
175227	33636047	To decipher the potential mechanisms, we first identified COVID-19-susceptible single nucleotide polymorphisms (COVID-19-SNPs) and then assessed genetic-epigenetic links between COVID-19 and cancer using COVID-19-SNPs and (1) CpG methylation or (2) gene transcription/translation data (Figure  1  a).	('COVID-19', 'Disease', 'MESH:C000657245', (204, 212))	('cancer', 'Disease', (191, 197))	('COVID-19-SNPs', 'Disease', (204, 217))	('cancer', 'Disease', 'MESH:D009369', (191, 197))	('COVID-19', 'Disease', 'MESH:C000657245', (58, 66))	('COVID-19', 'Disease', 'MESH:C000657245', (112, 120))	('COVID-19-SNPs', 'Disease', (112, 125))	('COVID-19-SNPs', 'Disease', 'MESH:C000657245', (204, 217))	('COVID-19', 'Disease', 'MESH:C000657245', (178, 186))	('COVID-19', 'Disease', (204, 212))	('single', 'Var', (79, 85))	('COVID-19', 'Disease', (112, 120))	('COVID-19-SNPs', 'Disease', 'MESH:C000657245', (112, 125))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('COVID-19', 'Disease', (178, 186))	('COVID-19', 'Disease', (58, 66))
175233	33636047	Amongst them, three mQTL-CpGs (cg21620969, cg18089519, and cg01741372) were positively correlated with COVID-19-SNP risk alleles in multiple cancers, whereas the remaining mQTL-CpGs were negatively correlated.	('cg21620969', 'Var', (31, 41))	('multiple cancers', 'Disease', (132, 148))	('correlated', 'Reg', (87, 97))	('COVID-19', 'Disease', (103, 111))	('cg01741372', 'Var', (59, 69))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('multiple cancers', 'Disease', 'MESH:D009369', (132, 148))	('cg18089519', 'Var', (43, 53))	('cancers', 'Phenotype', 'HP:0002664', (141, 148))	('cg01741372', 'Chemical', '-', (59, 69))	('COVID-19', 'Disease', 'MESH:C000657245', (103, 111))	('cg18089519', 'Chemical', '-', (43, 53))
175236	33636047	Based on this approach, we yielded three mQTL-CpGs: cg01741372 in breast invasive carcinoma (BRCA), esophageal carcinoma (ESCA), head and neck squamous cell carcinoma (HNSC), kidney renal papillary cell carcinoma (KIRP), lung squamous cell carcinoma (LUSC), and uterine corpus endometrial carcinoma (UCEC); cg16320329 in kidney renal clear cell carcinoma (KIRC); and cg18089519 in KIRC (Figure  1  d, Supplementary Table  S3 ).	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (277, 298))	('BRCA', 'Gene', '672', (93, 97))	('cg16320329', 'Var', (307, 317))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (100, 120))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (143, 166))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (277, 298))	('cg01741372', 'Chemical', '-', (52, 62))	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('esophageal carcinoma', 'Disease', (100, 120))	('renal papillary cell carcinoma', 'Phenotype', 'HP:0006766', (182, 212))	('breast invasive carcinoma', 'Phenotype', 'HP:0003002', (66, 91))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (221, 249))	('BRCA', 'Gene', (93, 97))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (129, 166))	('carcinoma', 'Phenotype', 'HP:0030731', (157, 166))	('LUSC', 'Phenotype', 'HP:0030359', (251, 255))	('ESCA', 'Phenotype', 'HP:0011459', (122, 126))	('neck squamous cell carcinoma (HNSC), kidney renal papillary cell carcinoma', 'Disease', 'MESH:C538614', (138, 212))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (100, 120))	('cg16320329', 'Chemical', '-', (307, 317))	('kidney renal clear cell carcinoma', 'Disease', 'MESH:C538614', (321, 354))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (221, 249))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (226, 249))	('HNSC', 'Phenotype', 'HP:0012288', (168, 172))	('lung squamous cell carcinoma', 'Disease', (221, 249))	('carcinoma', 'Phenotype', 'HP:0030731', (203, 212))	('endometrial carcinoma', 'Disease', (277, 298))	('cg18089519', 'Var', (367, 377))	('cg01741372', 'Var', (52, 62))	('BRCA', 'Phenotype', 'HP:0003002', (93, 97))	('cg18089519', 'Chemical', '-', (367, 377))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('breast invasive carcinoma', 'Disease', (66, 91))	('kidney renal clear cell carcinoma', 'Disease', (321, 354))	('carcinoma', 'Phenotype', 'HP:0030731', (240, 249))	('breast invasive carcinoma', 'Disease', 'MESH:D001943', (66, 91))
175237	33636047	cg01741372 and cg18089519 had higher methylation levels while cg16320329 had lower methylation levels in tumors versus normal tissues.	('lower', 'NegReg', (77, 82))	('tumors', 'Disease', (105, 111))	('tumors', 'Disease', 'MESH:D009369', (105, 111))	('cg01741372', 'Var', (0, 10))	('cg16320329', 'Var', (62, 72))	('higher', 'PosReg', (30, 36))	('cg16320329', 'Chemical', '-', (62, 72))	('cg18089519', 'Var', (15, 25))	('methylation levels', 'MPA', (83, 101))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('cg18089519', 'Chemical', '-', (15, 25))	('cg01741372', 'Chemical', '-', (0, 10))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('methylation levels', 'MPA', (37, 55))
175238	33636047	Collectively, based on the directions of correlations demonstrated above, the positive correlation between COVID-19-SNP risk alleles and multiple cancer pathogenesis might be mediated by CpG methylation (Figure  1  e).	('COVID-19', 'Disease', (107, 115))	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('COVID-19', 'Disease', 'MESH:C000657245', (107, 115))	('mediated', 'Reg', (175, 183))	('CpG methylation', 'Var', (187, 202))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('methylation', 'Var', (191, 202))
175248	33636047	Collectively, methylation changes in these genes might be associated with specific biological functions and suggested as a mediator linking COVID-19 and RCC.	('associated', 'Reg', (58, 68))	('RCC', 'Phenotype', 'HP:0005584', (153, 156))	('RCC', 'Disease', 'MESH:C538614', (153, 156))	('COVID-19', 'Disease', 'MESH:C000657245', (140, 148))	('RCC', 'Disease', (153, 156))	('methylation changes', 'Var', (14, 33))	('COVID-19', 'Disease', (140, 148))
175281	31906958	A number of previous studies demonstrated that miRNAs played essential roles in various cancers, including LC, via their effects on various biological events, such as differentiation, apoptosis, and proliferation, at the post-transcriptional level.	('differentiation', 'CPA', (167, 182))	('proliferation', 'CPA', (199, 212))	('effects', 'Reg', (121, 128))	('miRNAs', 'Var', (47, 53))	('roles', 'Reg', (71, 76))	('cancers', 'Disease', 'MESH:D009369', (88, 95))	('LC', 'Phenotype', 'HP:0100526', (107, 109))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('cancers', 'Disease', (88, 95))	('LC', 'Disease', 'MESH:D008175', (107, 109))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('apoptosis', 'CPA', (184, 193))
175320	31906958	Kaplan-Meier survival curves revealed insignificant difference in the survival outcomes of LUAD and NSCLC patients with low or high miR-182-5p expression (data not shown).	('LC', 'Phenotype', 'HP:0100526', (103, 105))	('NSCLC', 'Disease', (100, 105))	('NSCLC', 'Disease', 'MESH:D002289', (100, 105))	('patients', 'Species', '9606', (106, 114))	('low', 'Var', (120, 123))	('miR-182-5p', 'Gene', '100302183', (132, 142))	('miR-182-5p', 'Gene', (132, 142))	('NSCLC', 'Phenotype', 'HP:0030358', (100, 105))
175328	31906958	Several of the datasets that contained information on miR-182-5p expression in LUSC (GSE29248, GSE47525, GSE19945, GSE51853, and GSE74190) have been mined in previous work.	('GSE47525', 'Var', (95, 103))	('GSE19945', 'Var', (105, 113))	('GSE29248', 'Var', (85, 93))	('GSE74190', 'Var', (129, 137))	('GSE51853', 'Var', (115, 123))	('miR-182-5p', 'Gene', '100302183', (54, 64))	('miR-182-5p', 'Gene', (54, 64))
175343	31906958	Recent studies reported that dysregulation of the expression of multiple miRNAs, including miR-182-5p, was significantly correlated with tumorigenesis of LC.	('LC', 'Phenotype', 'HP:0100526', (154, 156))	('expression', 'MPA', (50, 60))	('tumor', 'Disease', (137, 142))	('LC', 'Disease', 'MESH:D008175', (154, 156))	('correlated with', 'Reg', (121, 136))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('miR-182-5p', 'Gene', (91, 101))	('dysregulation', 'Var', (29, 42))	('miR-182-5p', 'Gene', '100302183', (91, 101))
175368	31906958	Alterations in the expression of various genes, such as EGFR, ALK, ROS1, KRAS, and BRAF, play essential roles in NSCLC, and these genes serve as targets of chemotherapy.	('ROS1', 'Gene', (67, 71))	('LC', 'Phenotype', 'HP:0100526', (116, 118))	('expression', 'MPA', (19, 29))	('KRAS', 'Gene', (73, 77))	('ROS1', 'Gene', '6098', (67, 71))	('KRAS', 'Gene', '3845', (73, 77))	('Alterations', 'Var', (0, 11))	('EGFR', 'Gene', '1956', (56, 60))	('NSCLC', 'Phenotype', 'HP:0030358', (113, 118))	('ALK', 'Gene', (62, 65))	('EGFR', 'Gene', (56, 60))	('BRAF', 'Gene', '673', (83, 87))	('NSCLC', 'Disease', (113, 118))	('ALK', 'Gene', '238', (62, 65))	('roles', 'Reg', (104, 109))	('BRAF', 'Gene', (83, 87))	('NSCLC', 'Disease', 'MESH:D002289', (113, 118))
175387	30343534	The FGFR3 inhibitor PD173074 prevented MAPK rebound and sensitized the response of HNSCC cells to selumetinib.	('MAPK rebound', 'MPA', (39, 51))	('HNSCC', 'Phenotype', 'HP:0012288', (83, 88))	('PD173074', 'Var', (20, 28))	('sensitized', 'Reg', (56, 66))	('PD173074', 'Chemical', 'MESH:C115711', (20, 28))	('FGFR3', 'Gene', (4, 9))	('response', 'MPA', (71, 79))	('selumetinib', 'Chemical', 'MESH:C517975', (98, 109))	('FGFR3', 'Gene', '2261', (4, 9))	('prevented', 'NegReg', (29, 38))
175402	30343534	MEK inhibition promoted an ERK rebound during early phase treatment, which was due to feedback-induced, ligand-dependent activation of FGFR3 signaling.	('MEK', 'Gene', (0, 3))	('FGFR3', 'Gene', '2261', (135, 140))	('inhibition', 'Var', (4, 14))	('ERK', 'Gene', '5594', (27, 30))	('FGFR3', 'Gene', (135, 140))	('activation', 'PosReg', (121, 131))	('ERK', 'Gene', (27, 30))
175404	30343534	The current study was designed to explore whether feedback activation of FGFR3 occurs after MEK inhibition and whether combined inhibition of FGFR3 and MEK is a promising treatment strategy for HNSCC.	('rat', 'Species', '10116', (183, 186))	('HNSCC', 'Phenotype', 'HP:0012288', (194, 199))	('FGFR3', 'Gene', '2261', (142, 147))	('FGFR3', 'Gene', '2261', (73, 78))	('HNSCC', 'Disease', (194, 199))	('inhibition', 'Var', (96, 106))	('FGFR3', 'Gene', (142, 147))	('FGFR3', 'Gene', (73, 78))	('activation', 'PosReg', (59, 69))	('MEK', 'Protein', (92, 95))
175433	30343534	injection with DMSO (vehicle control), 20 mg/(kg day) AZD6244, 10 mg/(kg day) PD173074, or 10 mg/(kg day) PD173074 at 1 day post-injection of 20 mg/(kg day) AZD6244.	('PD173074', 'Var', (78, 86))	('PD173074', 'Chemical', 'MESH:C115711', (78, 86))	('DMSO', 'Chemical', 'MESH:D004121', (15, 19))	('PD173074', 'Var', (106, 114))	('PD173074', 'Chemical', 'MESH:C115711', (106, 114))	('AZD6244', 'Chemical', 'MESH:C517975', (54, 61))	('AZD6244', 'Gene', (54, 61))	('AZD6244', 'Chemical', 'MESH:C517975', (157, 164))
175441	30343534	Therefore, we investigated whether the ERK pathway is related to resistance in HNSCC using AZD6244 as a selective MEK inhibitor to inhibit the ERK pathway.	('inhibit', 'NegReg', (131, 138))	('AZD6244', 'Var', (91, 98))	('ERK', 'Gene', '5594', (39, 42))	('AZD6244', 'Chemical', 'MESH:C517975', (91, 98))	('ERK', 'Gene', '5594', (143, 146))	('ERK', 'Gene', (39, 42))	('HNSCC', 'Phenotype', 'HP:0012288', (79, 84))	('ERK', 'Gene', (143, 146))
175444	30343534	Results showed that ERK activation rebounded transiently within a few hours after AZD6244 treatment in HNSCC cell lines.	('HNSCC', 'Phenotype', 'HP:0012288', (103, 108))	('ERK', 'Gene', '5594', (20, 23))	('AZD6244', 'Var', (82, 89))	('AZD6244', 'Chemical', 'MESH:C517975', (82, 89))	('activation', 'PosReg', (24, 34))	('ERK', 'Gene', (20, 23))
175448	30343534	In cells treated with AZD6244, FGFR3 expression was elevated among RTK and some factors involved in downstream signal-transduction pathways.	('FGFR3', 'Gene', '2261', (31, 36))	('AZD6244', 'Var', (22, 29))	('AZD6244', 'Chemical', 'MESH:C517975', (22, 29))	('expression', 'MPA', (37, 47))	('FGFR3', 'Gene', (31, 36))	('elevated', 'PosReg', (52, 60))
175450	30343534	Using PD173074 as an FGFR3 inhibitor, we evaluated the effect of FGFR3 activity on cell proliferation when cells were exposed to the MEK inhibitor.	('FGFR3', 'Gene', '2261', (65, 70))	('FGFR3', 'Gene', '2261', (21, 26))	('PD173074', 'Var', (6, 14))	('rat', 'Species', '10116', (95, 98))	('PD173074', 'Chemical', 'MESH:C115711', (6, 14))	('FGFR3', 'Gene', (65, 70))	('FGFR3', 'Gene', (21, 26))
175451	30343534	Combined treatment with AZD6244 and PD173074 attenuated cell proliferation significantly more than treatment with AZD6244 or PD173074 alone (P < .05).	('AZD6244', 'Chemical', 'MESH:C517975', (24, 31))	('AZD6244', 'Chemical', 'MESH:C517975', (114, 121))	('attenuated', 'NegReg', (45, 55))	('rat', 'Species', '10116', (68, 71))	('cell proliferation', 'CPA', (56, 74))	('PD173074', 'Chemical', 'MESH:C115711', (125, 133))	('AZD6244', 'Var', (24, 31))	('PD173074', 'Var', (36, 44))	('PD173074', 'Chemical', 'MESH:C115711', (36, 44))
175452	30343534	Treatment with AZD6244 or PD173074 alone did not influence cell growth itself (Figure 1D).	('PD173074', 'Chemical', 'MESH:C115711', (26, 34))	('AZD6244', 'Var', (15, 22))	('PD173074', 'Var', (26, 34))	('AZD6244', 'Chemical', 'MESH:C517975', (15, 22))
175453	30343534	After a dose gradient exposure to AZD6244, combination treatment with PD173074 clearly reduced the number of colonies more so than did AZD6244 treatment alone (Figure 1E).	('AZD6244', 'Chemical', 'MESH:C517975', (34, 41))	('reduced', 'NegReg', (87, 94))	('AZD6244', 'Chemical', 'MESH:C517975', (135, 142))	('PD173074', 'Var', (70, 78))	('PD173074', 'Chemical', 'MESH:C115711', (70, 78))
175454	30343534	These results showed that coinhibition of MEK and FGFR3 may synergistically increase the sensitivity of HNSCC cells to AZD6244.	('sensitivity', 'MPA', (89, 100))	('FGFR3', 'Gene', (50, 55))	('increase', 'PosReg', (76, 84))	('HNSCC', 'Phenotype', 'HP:0012288', (104, 109))	('MEK', 'Gene', (42, 45))	('coinhibition', 'Var', (26, 38))	('AZD6244', 'Chemical', 'MESH:C517975', (119, 126))	('FGFR3', 'Gene', '2261', (50, 55))
175455	30343534	To further investigate whether FGFR3 activation is effective against the AZD6244-induced ERK-activity rebound, siRNA against FGFR3 was used in Cal27 cells.	('FGFR3', 'Gene', '2261', (31, 36))	('AZD6244', 'Chemical', 'MESH:C517975', (73, 80))	('ERK', 'Gene', '5594', (89, 92))	('FGFR3', 'Gene', '2261', (125, 130))	('AZD6244-induced', 'Var', (73, 88))	('ERK', 'Gene', (89, 92))	('FGFR3', 'Gene', (125, 130))	('Cal27', 'CellLine', 'CVCL:1107', (143, 148))	('FGFR3', 'Gene', (31, 36))
175458	30343534	As a result of the AZD6244 half-maximal inhibitory concentration (IC50) in HNSCC cells, Cal27 cells (AZD6244 IC50, 1.33 mumol/L) showed a higher IC50 than observed in HN6 cells (AZD6244 IC50, 0.58 mumol/L) or FADU cells (AZD6244 IC50, 1.16 mumol/L), but these differences were not significant (Figure 2B).	('half-maximal', 'MPA', (27, 39))	('FADU', 'Chemical', '-', (209, 213))	('AZD6244', 'Var', (19, 26))	('AZD6244', 'Chemical', 'MESH:C517975', (101, 108))	('IC50', 'MPA', (145, 149))	('Cal27', 'CellLine', 'CVCL:1107', (88, 93))	('AZD6244', 'Chemical', 'MESH:C517975', (221, 228))	('AZD6244', 'Chemical', 'MESH:C517975', (19, 26))	('HN6', 'Gene', (167, 170))	('HNSCC', 'Phenotype', 'HP:0012288', (75, 80))	('rat', 'Species', '10116', (58, 61))	('AZD6244', 'Chemical', 'MESH:C517975', (178, 185))	('higher', 'PosReg', (138, 144))	('HN6', 'Gene', '100463482', (167, 170))
175459	30343534	After siFGFR3 transfection, proliferation of Cal27 cells was significantly reduced compared to that of control transfectants treated with scrambled siRNA (Figure 2C).	('Cal27', 'CellLine', 'CVCL:1107', (45, 50))	('proliferation', 'CPA', (28, 41))	('reduced', 'NegReg', (75, 82))	('transfection', 'Var', (14, 26))	('FGFR3', 'Gene', '2261', (8, 13))	('rat', 'Species', '10116', (35, 38))	('FGFR3', 'Gene', (8, 13))
175462	30343534	In Cal27 cells, FGF2 level in the media increased time-dependently after treatment with AZD6244 (Figure 2D).	('FGF2', 'Gene', (16, 20))	('AZD6244', 'Var', (88, 95))	('FGF2', 'Gene', '2247', (16, 20))	('increased', 'PosReg', (40, 49))	('AZD6244', 'Chemical', 'MESH:C517975', (88, 95))	('Cal27', 'CellLine', 'CVCL:1107', (3, 8))
175463	30343534	In FGF2 siRNA transfectants, the p-FGFR3 level decreased and the ERK rebound also reduced, suggesting that FGF2 mediated FGFR3 feedback activation during MEK inhibition (Figure 2E).	('ERK', 'Gene', (65, 68))	('FGF2', 'Gene', '2247', (107, 111))	('FGFR3', 'Gene', '2261', (121, 126))	('FGFR3', 'Gene', '2261', (35, 40))	('FGF2', 'Gene', (3, 7))	('transfectants', 'Var', (14, 27))	('FGF2', 'Gene', (107, 111))	('FGFR3', 'Gene', (121, 126))	('FGFR3', 'Gene', (35, 40))	('ERK', 'Gene', '5594', (65, 68))	('reduced', 'NegReg', (82, 89))	('FGF2', 'Gene', '2247', (3, 7))	('decreased', 'NegReg', (47, 56))
175466	30343534	Sub-G1 distribution following combination treatment with AZD6244 and PD173074 increased, which represented delayed cell proliferation due to apoptotic cell death (Figure 3A, histogram can be seen in Figure S4).	('distribution', 'MPA', (7, 19))	('PD173074', 'Var', (69, 77))	('PD173074', 'Chemical', 'MESH:C115711', (69, 77))	('AZD6244', 'Var', (57, 64))	('increased', 'PosReg', (78, 87))	('rat', 'Species', '10116', (127, 130))	('cell proliferation', 'CPA', (115, 133))	('AZD6244', 'Chemical', 'MESH:C517975', (57, 64))
175468	30343534	After treatment with AZD6244 alone, the p-FGFR3 level increased and the ERK rebound was evoked, but not after treatment with both AZD6244 and PD173074.	('ERK', 'Gene', (72, 75))	('FGFR3', 'Gene', '2261', (42, 47))	('evoked', 'PosReg', (88, 94))	('increased', 'PosReg', (54, 63))	('AZD6244', 'Chemical', 'MESH:C517975', (130, 137))	('FGFR3', 'Gene', (42, 47))	('AZD6244', 'Var', (21, 28))	('PD173074', 'Chemical', 'MESH:C115711', (142, 150))	('ERK', 'Gene', '5594', (72, 75))	('AZD6244', 'Chemical', 'MESH:C517975', (21, 28))
175469	30343534	Treatment with PD173074 and AZD6244 attenuated the ERK rebound in Cal27 cells.	('Cal27', 'CellLine', 'CVCL:1107', (66, 71))	('AZD6244', 'Chemical', 'MESH:C517975', (28, 35))	('ERK', 'Gene', (51, 54))	('PD173074', 'Chemical', 'MESH:C115711', (15, 23))	('attenuated', 'NegReg', (36, 46))	('ERK', 'Gene', '5594', (51, 54))	('AZD6244', 'Var', (28, 35))	('PD173074', 'Var', (15, 23))
175475	30343534	However, the proportion of apoptotic cells after combined treatment with AZD6244 and PD173074 was 21.2 +- 2.4% (Cal27 cells), suggesting that an additive effect was observed with AZD6244 and PD173074 (Figure 3C).	('AZD6244', 'Chemical', 'MESH:C517975', (73, 80))	('PD173074', 'Chemical', 'MESH:C115711', (191, 199))	('PD173074', 'Var', (85, 93))	('Cal27', 'CellLine', 'CVCL:1107', (112, 117))	('PD173074', 'Chemical', 'MESH:C115711', (85, 93))	('AZD6244', 'Var', (179, 186))	('PD173074', 'Var', (191, 199))	('AZD6244', 'Chemical', 'MESH:C517975', (179, 186))	('AZD6244', 'Var', (73, 80))
175483	30343534	AZD6244 treatment alone did not show a significant effect on tumor growth, whereas cotreatment with AZD6244 and PD173074 led to tumor regression.	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('PD173074', 'Var', (112, 120))	('PD173074', 'Chemical', 'MESH:C115711', (112, 120))	('cotreatment', 'Var', (83, 94))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Disease', (128, 133))	('AZD6244', 'Chemical', 'MESH:C517975', (0, 7))	('AZD6244', 'Var', (100, 107))	('tumor', 'Disease', (61, 66))	('AZD6244', 'Chemical', 'MESH:C517975', (100, 107))
175484	30343534	H&E staining showed that vehicle and AZD6244-treated tumors showed significantly greater tumor cellularities and sizes versus mice given combination treatment (Figure 4D).	('and', 'Var', (33, 36))	('mice', 'Species', '10090', (126, 130))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('significantly', 'PosReg', (67, 80))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('H&E', 'Chemical', 'MESH:D006371', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('AZD6244', 'Chemical', 'MESH:C517975', (37, 44))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('tumor', 'Disease', (53, 58))	('tumors', 'Disease', (53, 59))	('tumor', 'Disease', (89, 94))
175485	30343534	Enhanced levels of Ki67 and p-FGFR3 were found in tumors of the vehicle-control and AZD6244 groups, indicating strong cell proliferation in the tumor masses (Figure 4E, magnified images and Allred scores can be seen in Figure S6 and Table S2).	('tumor', 'Disease', (144, 149))	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('FGFR3', 'Gene', '2261', (30, 35))	('AZD6244', 'Var', (84, 91))	('FGFR3', 'Gene', (30, 35))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('AZD6244', 'Chemical', 'MESH:C517975', (84, 91))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('cell proliferation', 'CPA', (118, 136))	('rat', 'Species', '10116', (130, 133))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('tumors', 'Disease', (50, 56))	('tumor', 'Disease', (50, 55))	('Ki67', 'Var', (19, 23))	('Enhanced', 'PosReg', (0, 8))
175486	30343534	In contrast, combination treatment with AZD6244 and PD173074 resulted in a significant decline in the levels of Ki67 and p-FGFR3, which was the result of inhibited tumor cell proliferation.	('FGFR3', 'Gene', '2261', (123, 128))	('tumor', 'Disease', (164, 169))	('Ki67', 'MPA', (112, 116))	('decline', 'NegReg', (87, 94))	('AZD6244', 'Var', (40, 47))	('FGFR3', 'Gene', (123, 128))	('inhibited', 'NegReg', (154, 163))	('AZD6244', 'Chemical', 'MESH:C517975', (40, 47))	('rat', 'Species', '10116', (182, 185))	('PD173074', 'Var', (52, 60))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('PD173074', 'Chemical', 'MESH:C115711', (52, 60))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('levels', 'MPA', (102, 108))
175488	30343534	Treatment of mice with PD173074 only showed no effect on histology or apoptosis in a group of four treated mice.	('mice', 'Species', '10090', (13, 17))	('PD173074', 'Chemical', 'MESH:C115711', (23, 31))	('PD173074', 'Var', (23, 31))	('mice', 'Species', '10090', (107, 111))	('apoptosis', 'CPA', (70, 79))
175490	30343534	The relative insensitivity of BRAF V600E-mutated melanoma to BRAF inhibition emerges through an enhanced level of cyclin D1.18 Cyclin E overexpression confers insensitivity of trastuzumab in Her2+ breast cancer cells.19 The lack of responsiveness of BRAFV600E-positive colorectal cancer cells to BRAF inhibition is associated with the feedback activation of EGFR.20 ERK 1/2-pathway reactivation during acquired resistance has led to the identification of gatekeeper mutations in oncogenic kinases promoting the use of the alternative MEK pathway.	('Her2', 'Gene', (191, 195))	('BRAF', 'Gene', (296, 300))	('cyclin D1', 'Gene', (114, 123))	('colorectal cancer', 'Phenotype', 'HP:0003003', (269, 286))	('promoting', 'PosReg', (497, 506))	('cancer', 'Phenotype', 'HP:0002664', (280, 286))	('cyclin D1', 'Gene', '595', (114, 123))	('breast cancer', 'Phenotype', 'HP:0003002', (197, 210))	('ERK 1/2', 'Gene', (366, 373))	('EGFR', 'Gene', (358, 362))	('alternative MEK pathway', 'Pathway', (522, 545))	('breast cancer', 'Disease', 'MESH:D001943', (197, 210))	('V600E', 'Mutation', 'rs113488022', (35, 40))	('melanoma', 'Disease', 'MESH:D008545', (49, 57))	('breast cancer', 'Disease', (197, 210))	('gatekeeper', 'Species', '111938', (455, 465))	('colorectal cancer', 'Disease', 'MESH:D015179', (269, 286))	('BRAF', 'Gene', '673', (61, 65))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('BRAF', 'Gene', (30, 34))	('BRAF', 'Gene', (61, 65))	('mutations', 'Var', (466, 475))	('BRAF', 'Gene', '673', (30, 34))	('V600E', 'Mutation', 'rs113488022', (254, 259))	('colorectal cancer', 'Disease', (269, 286))	('EGFR', 'Gene', '1956', (358, 362))	('ERK 1/2', 'Gene', '5595;5594', (366, 373))	('BRAF', 'Gene', '673', (250, 254))	('Her2', 'Gene', '2064', (191, 195))	('BRAF', 'Gene', (250, 254))	('BRAF', 'Gene', '673', (296, 300))	('melanoma', 'Phenotype', 'HP:0002861', (49, 57))	('melanoma', 'Disease', (49, 57))
175491	30343534	Shi et al21 reported that the acquired resistance of melanoma cells to BRAF inhibition can result in amplification of V600E BRAF expression.	('expression', 'MPA', (129, 139))	('BRAF', 'Gene', '673', (71, 75))	('V600E', 'Mutation', 'rs113488022', (118, 123))	('melanoma', 'Phenotype', 'HP:0002861', (53, 61))	('melanoma', 'Disease', (53, 61))	('BRAF', 'Gene', '673', (124, 128))	('BRAF', 'Gene', (71, 75))	('melanoma', 'Disease', 'MESH:D008545', (53, 61))	('V600E', 'Var', (118, 123))	('amplification', 'MPA', (101, 114))	('BRAF', 'Gene', (124, 128))
175494	30343534	We used AZD6244 as a selective MEK inhibitor and observed an ERK-activity rebound in AZD6244-treated HNSCC cell lines.	('HNSCC', 'Phenotype', 'HP:0012288', (101, 106))	('AZD6244', 'Chemical', 'MESH:C517975', (8, 15))	('AZD6244-treated', 'Var', (85, 100))	('ERK', 'Gene', '5594', (61, 64))	('AZD6244', 'Chemical', 'MESH:C517975', (85, 92))	('ERK', 'Gene', (61, 64))
175499	30343534	When FGFR3 activation was suppressed by FGFR siRNA or PD173074, these results were not observed.	('PD173074', 'Chemical', 'MESH:C115711', (54, 62))	('suppressed', 'NegReg', (26, 36))	('activation', 'MPA', (11, 21))	('FGFR3', 'Gene', '2261', (5, 10))	('FGFR3', 'Gene', (5, 10))	('PD173074', 'Var', (54, 62))
175500	30343534	Recently, it was reported that ERK reactivation in tumors induced extensive and complex feedback activation of RTK.	('ERK', 'Gene', (31, 34))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('feedback activation', 'MPA', (88, 107))	('tumors', 'Disease', (51, 57))	('tumors', 'Disease', 'MESH:D009369', (51, 57))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('ERK', 'Gene', '5594', (31, 34))	('reactivation', 'Var', (35, 47))	('RTK', 'MPA', (111, 114))
175502	30343534	These data also indicated that combined treatment with a BRAF inhibitor and cetuximab synergistically inhibited tumor growth in vivo.20  Recent findings showed that FGFR dysregulation plays an important role in many cancers.	('cetuximab', 'Chemical', 'MESH:D000068818', (76, 85))	('BRAF', 'Gene', '673', (57, 61))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('FGFR', 'Gene', (165, 169))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('BRAF', 'Gene', (57, 61))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('cancers', 'Phenotype', 'HP:0002664', (216, 223))	('cancers', 'Disease', (216, 223))	('tumor', 'Disease', (112, 117))	('dysregulation', 'Var', (170, 183))	('cancers', 'Disease', 'MESH:D009369', (216, 223))
175514	29625048	These integrated subtypes shared mutations, copy-number alterations, pathway commonalities, and micro-environment characteristics that appeared influential in the new molecular taxonomy, beyond any phenotypic contributions from tumor stage or tissue of origin.	('tumor', 'Disease', 'MESH:D009369', (228, 233))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('tumor', 'Disease', (228, 233))	('copy-number alterations', 'Var', (44, 67))
175528	29625048	Using aneuploidy (AN), CpG hypermethylation (METH), mRNA (MRNA), miRNA (MIR), and protein (P), the resultant number of groups ranged from 10 to 25 (Figure 1).	('hypermethylation', 'Var', (27, 43))	('METH', 'Chemical', '-', (45, 49))	('miRNA', 'MPA', (65, 70))	('mRNA', 'MPA', (52, 56))	('aneuploidy', 'Var', (6, 16))
175532	29625048	Over one-third of the samples displayed relatively sparse aneuploidy in AN7; these were enriched for THCA, LAML, PRAD, and THYM.	('AN7', 'Gene', (72, 75))	('amp', 'Chemical', 'MESH:D000249', (23, 26))	('aneuploidy', 'Var', (58, 68))	('THCA', 'Disease', (101, 105))
175535	29625048	Consistent with previous results, squamous (lung, head and neck, and esophageal) tumors clustered together by aneuploidy patterns, particularly 3p loss and 3q gain (AN3).	('3p loss', 'Var', (144, 151))	('3q gain', 'Var', (156, 163))	('esophageal) tumors clustered', 'Disease', 'MESH:D004938', (69, 97))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))
175537	29625048	Despite the exclusion of loci known to be involved in tissue-specific DNA methylation, tumors originating from the same organ often aggregated by cancer-type-specific hypermethylation (Figure 1B; Table S2).	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('tumors', 'Disease', (87, 93))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('tumors', 'Disease', 'MESH:D009369', (87, 93))	('hypermethylation', 'Var', (167, 183))
175541	29625048	Gastrointestinal adenocarcinomas (ESCA, STAD, COAD and READ) were represented in a branch containing METH10 through METH13.	('COAD', 'Disease', 'MESH:D029424', (46, 50))	('Gastrointestinal adenocarcinomas', 'Disease', 'MESH:D004067', (0, 32))	('METH13', 'Chemical', '-', (116, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('carcinomas', 'Phenotype', 'HP:0030731', (22, 32))	('COAD', 'Disease', (46, 50))	('STAD', 'Disease', (40, 44))	('METH10', 'Var', (101, 107))	('Gastrointestinal adenocarcinomas', 'Disease', (0, 32))	('METH10', 'Chemical', '-', (101, 107))
175553	29625048	We used clustering of cluster assignments (COCA) algorithm to assess the overlap of platform-specific memberships from each of the five molecular platforms (aneuploidy, mRNA, miRNA, DNA methylation, and RPPA) (Figure 2A).	('COCA', 'Species', '289672', (43, 47))	('miRNA', 'MPA', (175, 180))	('mRNA', 'MPA', (169, 173))	('DNA', 'MPA', (182, 185))	('aneuploidy', 'Var', (157, 167))
175564	29625048	Eight iClusters were dominated by a single tumor type (C24:LAML, C11:LGG [IDH1 mut], C6:OV, C8:UCEC, C12:THCA, C16:PRAD, C26:LIHC, C14:LUAD).	('C26', 'CellLine', 'CVCL:0240', (121, 124))	('IDH1', 'Gene', (74, 78))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('C11', 'Gene', '51728', (65, 68))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('C24:', 'Var', (55, 59))	('IDH1', 'Gene', '3417', (74, 78))	('C12:THCA', 'Var', (101, 109))	('tumor', 'Disease', (43, 48))	('C11', 'Gene', (65, 68))
175565	29625048	Others contained tumors from similar or related cells or tissues: C28:pan-kidney (KIRC, KIRP), C15:SKCM/UVM-melanoma of the skin (SKCM) and eye (UVM), C23:GBM/LGG (IDH1wt), and C5:CNS/ endocrine.	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('C15', 'Gene', '51316', (95, 98))	('C23:GBM/LGG', 'Gene', '4691', (151, 162))	('UVM-melanoma of the skin', 'Disease', (104, 128))	('tumors', 'Disease', (17, 23))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('C15', 'Gene', (95, 98))	('C28', 'Var', (66, 69))	('IDH1', 'Gene', '3417', (164, 168))	('IDH1', 'Gene', (164, 168))	('UVM-melanoma of the skin', 'Disease', 'MESH:D008545', (104, 128))	('melanoma', 'Phenotype', 'HP:0002861', (108, 116))	('C23:GBM/LGG', 'Gene', (151, 162))
175569	29625048	C4:pan-GI (CRC) was predominantly COAD and READ with chromosomal instability (CIN) and a distinct aneuploidy profile (Figure 2B).	('CIN', 'Disease', (78, 81))	('COAD', 'Disease', (34, 38))	('pan-GI', 'Var', (3, 9))	('CIN', 'Disease', 'MESH:D007674', (78, 81))	('COAD', 'Disease', 'MESH:D029424', (34, 38))	('chromosomal instability', 'Phenotype', 'HP:0040012', (53, 76))	('chromosomal instability', 'Disease', (53, 76))
175570	29625048	The pan-squamous cohort formed three iClusters (C10, C25, and C27).	('C10', 'Gene', '3226', (48, 51))	('C10', 'Gene', (48, 51))	('C25', 'Var', (53, 56))	('C27', 'Var', (62, 65))
175572	29625048	Even though all squamous iClusters were characterized by chromosome 3q amplification, unique features defined C10:pan-SCC (9p deletion) and C25:pan-SCC (Chr11 amp) (Figure 2B).	('amp', 'Chemical', 'MESH:D000249', (71, 74))	('SCC', 'Gene', (118, 121))	('C10', 'Gene', (110, 113))	('SCC', 'Gene', (148, 151))	('C10', 'Gene', '3226', (110, 113))	('SCC', 'Gene', '6317', (118, 121))	('SCC', 'Gene', '6317', (148, 151))	('amp', 'Chemical', 'MESH:D000249', (159, 162))	('9p deletion', 'Var', (123, 134))
175573	29625048	Among mixed tumor type iClusters, three were defined by copy-number alterations.	('tumor', 'Disease', (12, 17))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('copy-number alterations', 'Var', (56, 79))
175574	29625048	C7:mixed was characterized by chr9 deletion, C2:BRCA (HER2 amp) mainly consisted of ERBB2-amplified tumors (BRCA, BLCA, and STAD), and C13:mixed (Chr8 del) contained highly aneuploid tumors, including a mixture of BRCA-Basal, UCEC (CN-high subtype), UCS, and BLCA.	('BRCA', 'Gene', '672', (108, 112))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('BRCA', 'Gene', (48, 52))	('amp', 'Chemical', 'MESH:D000249', (59, 62))	('amp', 'Chemical', 'MESH:D000249', (90, 93))	('BRCA', 'Gene', (214, 218))	('tumors', 'Disease', (183, 189))	('BLCA', 'Disease', (259, 263))	('aneuploid tumors', 'Disease', 'MESH:D000782', (173, 189))	('BRCA', 'Gene', (108, 112))	('UCEC', 'Disease', (226, 230))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('HER2', 'Gene', '2064', (54, 58))	('tumors', 'Disease', 'MESH:D009369', (183, 189))	('ERBB2', 'Gene', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('C13', 'Gene', (135, 138))	('tumors', 'Disease', (100, 106))	('deletion', 'Var', (35, 43))	('ERBB2', 'Gene', '2064', (84, 89))	('UCS', 'Disease', (250, 253))	('C13', 'Gene', '3229', (135, 138))	('BRCA', 'Gene', '672', (48, 52))	('HER2', 'Gene', (54, 58))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('BRCA', 'Gene', '672', (214, 218))	('tumors', 'Phenotype', 'HP:0002664', (183, 189))	('aneuploid tumors', 'Disease', (173, 189))
175582	29625048	The silhouette widths ranged from -0.05 to 0.59, with the highest silhouette widths belonging to single-cancer-type-dominant iClusters (C11:LGG [IDH1 mut], C12:THCA, C16:PRAD, and C24:LAML).	('IDH1', 'Gene', (145, 149))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('IDH1', 'Gene', '3417', (145, 149))	('C11', 'Gene', '51728', (136, 139))	('C16:PRAD', 'Var', (166, 174))	('C24:LAML', 'Var', (180, 188))	('C11', 'Gene', (136, 139))	('C12:THCA', 'Var', (156, 164))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))
175583	29625048	Interestingly, 6 of the 7 pan-organ system iClusters (pan-GI: C1, C4, C18; pan-SCC: C25, C27, and pan-kidney: C28) had similar ranges of silhouette widths to those of single cancer-type dominant iClusters, suggesting that these were as robust as the cancer-type-dominant iClusters.	('cancer', 'Disease', 'MESH:D009369', (250, 256))	('SCC', 'Gene', (79, 82))	('C27', 'Var', (89, 92))	('C18', 'Gene', (70, 73))	('cancer', 'Disease', (250, 256))	('cancer', 'Disease', (174, 180))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('SCC', 'Gene', '6317', (79, 82))	('C18', 'Gene', '27241', (70, 73))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))
175584	29625048	iClusters driven by a shared specific chromosomal alteration (e.g., C13:mixed [chr8 del]) tended to compose multiple tumor types and appeared to have among the lowest silhouette widths, suggesting substantial molecular heterogeneity.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('mixed [chr8 del]', 'Var', (72, 88))	('tumor', 'Disease', (117, 122))	('C13', 'Gene', (68, 71))	('C13', 'Gene', '3229', (68, 71))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
175601	29625048	Melanomas and lung adenocarcinomas have been shown to have relatively high mutation rates, and we observed similar results with C15:SKCM/UVM and C14:LUAD.	('Melanomas', 'Phenotype', 'HP:0002861', (0, 9))	('C15', 'Gene', (128, 131))	('C14:LUAD', 'Var', (145, 153))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (14, 34))	('mutation', 'MPA', (75, 83))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (14, 33))	('Melanomas and lung adenocarcinomas', 'Disease', 'MESH:D000077192', (0, 34))	('carcinoma', 'Phenotype', 'HP:0030731', (24, 33))	('C15', 'Gene', '51316', (128, 131))	('carcinomas', 'Phenotype', 'HP:0030731', (24, 34))
175602	29625048	Mutation frequencies varied widely within the two iClusters with the most diverse tumor compositions: C3:mesenchymal (immune) and C20:mixed (stromal/immune).	('C20', 'Var', (130, 133))	('tumor', 'Disease', (82, 87))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))
175609	29625048	Despite having very different cancer type compositions, the pan-squamous iClusters C10:pan-SCC, C25:pan-SCC (chr11 amp), and C27:pan-SCC (HPV) shared many pathway characteristics.	('amp', 'Chemical', 'MESH:D000249', (115, 118))	('SCC', 'Gene', '6317', (133, 136))	('SCC', 'Gene', '6317', (91, 94))	('C10', 'Gene', (83, 86))	('HPV', 'Species', '10566', (138, 141))	('cancer', 'Disease', (30, 36))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('SCC', 'Gene', (104, 107))	('C10', 'Gene', '3226', (83, 86))	('C25', 'Var', (96, 99))	('SCC', 'Gene', (91, 94))	('SCC', 'Gene', '6317', (104, 107))	('SCC', 'Gene', (133, 136))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('C27', 'Var', (125, 128))
175613	29625048	In addition, C20:mixed (stromal/immune) contained 32% Pan-GI samples and also displayed strong immune-related signaling.	('amp', 'Chemical', 'MESH:D000249', (62, 65))	('C20:mixed', 'Var', (13, 22))	('Pan-GI', 'Protein', (54, 60))
175614	29625048	Beta-catenin/cell-cell adhesion signaling appeared high in C4:pan-GI (CRC), C18:pan-GI (MSI), and C20:mixed (stromal/immune), but not in the smaller C1:STAD (EBV-CIMP).	('SI', 'Disease', 'None', (89, 91))	('C18', 'Gene', (76, 79))	('C4:pan-GI', 'Var', (59, 68))	('Beta-catenin/cell-cell adhesion signaling', 'MPA', (0, 41))	('C20:mixed', 'Var', (98, 107))	('C18', 'Gene', '27241', (76, 79))	('EBV', 'Species', '10376', (158, 161))	('high', 'PosReg', (51, 55))
175632	29625048	Interrogation of individual iClusters for their differentiating PARADIGM pathway features, canonical pathways, and gene programs amenable to drug targeting identified strong immune-related signaling features for both C3:mesenchymal (immune) and C20:mixed (stromal/immune) tumors, suggesting that they may share potential susceptibility to immunotherapy.	('tumor', 'Phenotype', 'HP:0002664', (272, 277))	('tumors', 'Disease', (272, 278))	('C20', 'Var', (245, 248))	('tumors', 'Phenotype', 'HP:0002664', (272, 278))	('tumors', 'Disease', 'MESH:D009369', (272, 278))	('C3', 'Var', (217, 219))	('immune-related signaling', 'MPA', (174, 198))	('AR', 'Gene', '367', (65, 67))
175635	29625048	Compared to the seemingly discohesive groupings of the 17 heterogeneous iClusters, the 11 most homogeneous iClusters (C6:OV, C8:UCEC, C11:LGG [IDH1 mut], C12:THCA, C14:LUAD, C15:SKCM/UVM, C16:PRAD, C19:BRCA [luminal], C21:DLBC, C24:LAML, C26:LIHC) had higher silhouette widths, uniform tumor types, and histopathologies, but showed surprising degrees of spatial discohesion in the TumorMap.	('tumor', 'Phenotype', 'HP:0002664', (286, 291))	('C21', 'Gene', (218, 221))	('IDH1', 'Gene', (143, 147))	('C11', 'Gene', (134, 137))	('C24:LAML', 'Var', (228, 236))	('higher', 'PosReg', (252, 258))	('Tumor', 'Phenotype', 'HP:0002664', (381, 386))	('C16:PRAD', 'Var', (188, 196))	('C21', 'Gene', '79718', (218, 221))	('C19:BRCA', 'Gene', (198, 206))	('IDH1', 'Gene', '3417', (143, 147))	('tumor', 'Disease', (286, 291))	('C15', 'Gene', '51316', (174, 177))	('tumor', 'Disease', 'MESH:D009369', (286, 291))	('C15', 'Gene', (174, 177))	('C26', 'CellLine', 'CVCL:0240', (238, 241))	('silhouette widths', 'CPA', (259, 276))	('C11', 'Gene', '51728', (134, 137))	('C19:BRCA', 'Gene', '672', (198, 206))
175638	29625048	However, exceptions that challenge this concept have also become apparent from such notable examples as the unpredictable clinical responses to a potent BRAF inhibitor across diverse malignancies all expressing the same BRAF mutation.	('BRAF', 'Gene', '673', (153, 157))	('BRAF', 'Gene', (153, 157))	('BRAF', 'Gene', '673', (220, 224))	('malignancies', 'Disease', 'MESH:D009369', (183, 195))	('BRAF', 'Gene', (220, 224))	('amp', 'Chemical', 'MESH:D000249', (94, 97))	('mutation', 'Var', (225, 233))	('malignancies', 'Disease', (183, 195))
175656	29625048	Cervical squamous tumors clustered in high aneuploidy clusters AN1 and AN5.	('squamous tumors', 'Disease', (9, 24))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('squamous tumors', 'Disease', 'MESH:D002294', (9, 24))	('AN1', 'Var', (63, 66))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
175657	29625048	These clusters were also enriched for other Pan-gyn tumors, including ovarian, high-copy number endometrial, and uterine carcinosarcoma.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('high-copy number', 'Var', (79, 95))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('carcinosarcoma', 'Disease', 'MESH:D002296', (121, 135))	('ovarian', 'Disease', (70, 77))	('sarcoma', 'Phenotype', 'HP:0100242', (128, 135))	('tumors', 'Disease', (52, 58))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (113, 135))	('carcinosarcoma', 'Disease', (121, 135))
175658	29625048	Gynecologic tumors with fewer copy-number alterations including Luminal breast cancers and other endometrial tumors grouped separately in low aneuploidy clusters AN7 and AN8, respectively.	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('low aneuploidy clusters', 'Disease', 'MESH:D000782', (138, 161))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumors', 'Disease', (109, 115))	('copy-number alterations', 'Var', (30, 53))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('low aneuploidy clusters', 'Disease', (138, 161))	('Gynecologic', 'Disease', (0, 11))	('breast cancers', 'Disease', 'MESH:D001943', (72, 86))	('breast cancers', 'Disease', (72, 86))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('endometrial tumors', 'Disease', 'MESH:D016889', (97, 115))	('tumors', 'Disease', (12, 18))	('tumors', 'Disease', 'MESH:D009369', (109, 115))	('breast cancers', 'Phenotype', 'HP:0003002', (72, 86))	('AN7', 'Var', (162, 165))	('endometrial tumors', 'Disease', (97, 115))	('breast cancer', 'Phenotype', 'HP:0003002', (72, 85))	('tumors', 'Disease', 'MESH:D009369', (12, 18))
175669	29625048	To minimize the influence of variable tumor purity levels on a clustering result, we dichotomized the data using a beta-value of >= 0.3 to define positive DNA methylation and < 0.3 to specify lack of methylation.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('positive DNA methylation', 'Var', (146, 170))
175671	29625048	For clustering analysis of tumors, we selected 3,139 CpG sites that were methylated at a beta-value of >= 0.3 in more than 10% of tumors within any of the 33 cancer types.	('tumors', 'Disease', (130, 136))	('tumors', 'Disease', 'MESH:D009369', (130, 136))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('tumors', 'Disease', (27, 33))	('tumors', 'Disease', 'MESH:D009369', (27, 33))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('cancer', 'Disease', (158, 164))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('methylated', 'Var', (73, 83))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
175674	29625048	The heatmap was generated using the original beta-values for the top one-third (n = 1,035) of the most variability methylated CpGs across tumors (Figure 1B).	('CpGs', 'Gene', (126, 130))	('methylated', 'Var', (115, 125))	('tumors', 'Disease', (138, 144))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('tumors', 'Disease', 'MESH:D009369', (138, 144))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
175675	29625048	We noted that a fraction of ESCA and STAD was found in METH9 with LUAD and PAAD, a result that may be related to the low tumor cellularity of the cancers in this cluster.	('cancers', 'Disease', (146, 153))	('cancers', 'Disease', 'MESH:D009369', (146, 153))	('METH', 'Chemical', '-', (55, 59))	('low tumor', 'Disease', (117, 126))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('ESCA', 'Disease', (28, 32))	('METH9', 'Var', (55, 60))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('cancers', 'Phenotype', 'HP:0002664', (146, 153))	('low tumor', 'Disease', 'MESH:D009800', (117, 126))
175699	29625048	MIR5 contained OV, MIR8 BRCA, MIR12 LGG, MIR13 LIHC, MIR14 THCA, and MIR15 PRAD.	('MIR1', 'Gene', '79187', (69, 73))	('MIR1', 'Gene', (69, 73))	('BRCA', 'Gene', '672', (24, 28))	('MIR12', 'Gene', (30, 35))	('BRCA', 'Gene', (24, 28))	('MIR8', 'Var', (19, 23))	('MIR1', 'Gene', '79187', (53, 57))	('MIR12', 'Gene', '406905', (30, 35))	('MIR1', 'Gene', (53, 57))	('MIR1', 'Gene', '79187', (41, 45))	('MIR1', 'Gene', '79187', (30, 34))	('MIR1', 'Gene', (41, 45))	('MIR1', 'Gene', (30, 34))
175707	29625048	MIR6, the Pan-GI group, was largely COAD and STAD, but also had substantial PAAD, READ and ESCA, with smaller numbers of CHOL and LIHC.	('MIR6', 'Var', (0, 4))	('COAD', 'Disease', (36, 40))	('COAD', 'Disease', 'MESH:D029424', (36, 40))
175767	29204555	In blood samples of patients with oral squamous cell carcinoma, there was an association between the presence of mRNA for cytokeratin 20 and a reduced disease free survival and increased lymph node metastases.	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (34, 62))	('metastases', 'Disease', (198, 208))	('presence', 'Var', (101, 109))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (39, 62))	('mRNA for', 'Var', (113, 121))	('increased', 'PosReg', (177, 186))	('carcinoma', 'Phenotype', 'HP:0030731', (53, 62))	('oral squamous cell carcinoma', 'Disease', (34, 62))	('patients', 'Species', '9606', (20, 28))	('metastases', 'Disease', 'MESH:D009362', (198, 208))	('cytokeratin 20', 'Gene', (122, 136))	('cytokeratin 20', 'Gene', '54474', (122, 136))	('disease free survival', 'CPA', (151, 172))	('reduced', 'NegReg', (143, 150))
175795	29204555	Retrospective studies have associated the degree of PDPN expression with decreased survival in cutaneous squamous cell carcinoma and oral squamous cell carcinoma, although one study suggests no association.	('carcinoma', 'Phenotype', 'HP:0030731', (152, 161))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (138, 161))	('decreased', 'NegReg', (73, 82))	('PDPN', 'Gene', '10630', (52, 56))	('PDPN', 'Gene', (52, 56))	('expression', 'Var', (57, 67))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (105, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('cutaneous squamous cell carcinoma and oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (95, 161))	('survival', 'MPA', (83, 91))
175803	29204555	Interestingly, they found an improved short-term survival benefit with the presence of cytoplasmic PDL-1 on CTCs.	('PDL-1', 'Gene', '29126', (99, 104))	('cytoplasmic', 'Var', (87, 98))	('PDL-1', 'Gene', (99, 104))	('improved', 'PosReg', (29, 37))	('presence', 'Var', (75, 83))
175839	27633916	We also characterize 16 cancer type-specific subnetwork signatures which show diverse implications to somatic mutations, somatic copy number aberrations, DNA methylation alterations and clinical outcomes.	('cancer', 'Disease', (24, 30))	('cancer', 'Disease', 'MESH:D009369', (24, 30))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('mutations', 'Var', (110, 119))
175847	27633916	conducted a multiplatform pan-cancer analysis across twelve cancer types and found a subtype consisting of lung squamous, head and neck, and a subset of bladder cancers, which are characterized by TP53 alterations, TP63 amplifications, and deregulation of immune and proliferation genes.	('TP63', 'Gene', (215, 219))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('bladder cancers', 'Phenotype', 'HP:0009725', (153, 168))	('cancers', 'Phenotype', 'HP:0002664', (161, 168))	('cancer', 'Disease', (161, 167))	('bladder cancer', 'Phenotype', 'HP:0009725', (153, 167))	('TP53', 'Gene', (197, 201))	('alterations', 'Var', (202, 213))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('TP63', 'Gene', '8626', (215, 219))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('lung squamous', 'Disease', (107, 120))	('bladder cancers', 'Disease', 'MESH:D001749', (153, 168))	('bladder cancers', 'Disease', (153, 168))	('cancer', 'Disease', (30, 36))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('TP53', 'Gene', '7157', (197, 201))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('deregulation', 'Var', (240, 252))	('cancer', 'Disease', (60, 66))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
175849	27633916	also employed a pan-cancer study to demonstrate universal patterns of epigenomic deregulation and distinct processes controlling genome-wide DNA hypo- and hyper-methylation across tumor lineages.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('hyper-methylation', 'Var', (155, 172))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('tumor', 'Disease', (180, 185))	('cancer', 'Disease', 'MESH:D009369', (20, 26))	('cancer', 'Disease', (20, 26))
175872	27633916	Generally, dysregulation of these cell cycle genes with defects of proteins RB and TP53 will permit persistent cell proliferation of cancer cells and promote tumor progression in the long term.	('defects of proteins RB', 'Disease', 'MESH:D012175', (56, 78))	('TP53', 'Gene', '7157', (83, 87))	('tumor', 'Disease', (158, 163))	('promote', 'PosReg', (150, 157))	('TP53', 'Gene', (83, 87))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('cancer', 'Disease', (133, 139))	('cell proliferation', 'CPA', (111, 129))	('dysregulation', 'Var', (11, 24))	('permit', 'PosReg', (93, 99))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('defects of proteins RB', 'Disease', (56, 78))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('cell cycle genes', 'Gene', (34, 50))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
175873	27633916	From another perspective, alterations in cyclin-dependent kinase (CDK) activity often induce and regulate cell cycle defects in tumors.	('cyclin-dependent', 'Protein', (41, 57))	('induce', 'Reg', (86, 92))	('alterations', 'Var', (26, 37))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('cell cycle defects', 'CPA', (106, 124))	('activity', 'MPA', (71, 79))	('tumors', 'Disease', (128, 134))	('tumors', 'Disease', 'MESH:D009369', (128, 134))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('regulate', 'Reg', (97, 105))	('cell cycle defects', 'Phenotype', 'HP:0011018', (106, 124))
175891	27633916	The deregulation of these functions remind us of the metastasizing features across different cancer types while the specific signatures of these subnetworks imply the distinct mechanisms of metastases.	('deregulation', 'Var', (4, 16))	('cancer', 'Disease', (93, 99))	('metastases', 'Disease', (190, 200))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('metastases', 'Disease', 'MESH:D009362', (190, 200))
175904	27633916	4A) tend to be ER, PR and HER2 negative ones and they have high frequency of TP53 mutations (Fig.	('HER2', 'Gene', (26, 30))	('mutations', 'Var', (82, 91))	('HER2', 'Gene', '2064', (26, 30))	('TP53', 'Gene', '7157', (77, 81))	('TP53', 'Gene', (77, 81))
175913	27633916	Dysregulation of this gene may influence the remaining genes of this subnetwork, and further accelerates cell differentiation in basal-like tumors (Fig.	('tumors', 'Disease', (140, 146))	('tumors', 'Disease', 'MESH:D009369', (140, 146))	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('Dysregulation', 'Var', (0, 13))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('cell differentiation', 'CPA', (105, 125))	('influence', 'Reg', (31, 40))	('accelerates', 'PosReg', (93, 104))
175914	27633916	Previous studies have shown that malignant renal papillary cell carcinoma are marked by the trisomy of chromosomes 7, 16, 17 and the loss of Y chromosome.	('malignant renal papillary cell carcinoma', 'Disease', 'MESH:C538614', (33, 73))	('loss', 'NegReg', (133, 137))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))	('trisomy', 'Var', (92, 99))	('malignant renal papillary cell carcinoma', 'Disease', (33, 73))	('renal papillary cell carcinoma', 'Phenotype', 'HP:0006766', (43, 73))
175925	27633916	We find that the ME scores of the THCA-specific subnetwork are strongly associated with the mutation status of BRAF, NRAS and HRAS, which have relatively high mutation frequency (Fig.	('ME', 'Chemical', '-', (17, 19))	('NRAS', 'Gene', (117, 121))	('HRAS', 'Gene', (126, 130))	('NRAS', 'Gene', '4893', (117, 121))	('THCA', 'Phenotype', 'HP:0002890', (34, 38))	('associated', 'Reg', (72, 82))	('HRAS', 'Gene', '3265', (126, 130))	('BRAF', 'Gene', '673', (111, 115))	('mutation status', 'Var', (92, 107))	('BRAF', 'Gene', (111, 115))
175930	27633916	This subnetwork is associated with FGFR3 mutations (Supplementary Figure S6B), which is a key marker of Ta pathway and therapeutic target of bladder cancer.	('associated', 'Reg', (19, 29))	('mutations', 'Var', (41, 50))	('bladder cancer', 'Disease', (141, 155))	('FGFR3', 'Gene', '2261', (35, 40))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('bladder cancer', 'Phenotype', 'HP:0009725', (141, 155))	('FGFR3', 'Gene', (35, 40))	('bladder cancer', 'Disease', 'MESH:D001749', (141, 155))
175932	27633916	A recent study revealed a biological component relating to both Ta pathway and carcinoma in situ pathway, of which one biomarker is early TP53 mutation.	('TP53', 'Gene', '7157', (138, 142))	('carcinoma', 'Disease', (79, 88))	('mutation', 'Var', (143, 151))	('TP53', 'Gene', (138, 142))	('Ta pathway', 'Pathway', (64, 74))	('carcinoma', 'Disease', 'MESH:D002277', (79, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (79, 96))
175936	27633916	We also find 16 cancer type-specific subnetworks which demonstrate strong implications to somatic mutations, SCNAs, DNA methylation alterations and clinical outcomes in some specific cancers.	('cancer', 'Disease', (183, 189))	('cancers', 'Disease', (183, 190))	('cancer', 'Disease', 'MESH:D009369', (16, 22))	('cancer', 'Disease', (16, 22))	('mutations', 'Var', (98, 107))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('implications', 'Reg', (74, 86))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('cancers', 'Phenotype', 'HP:0002664', (183, 190))	('cancer', 'Disease', 'MESH:D009369', (183, 189))	('cancers', 'Disease', 'MESH:D009369', (183, 190))
175938	27633916	Not surprisingly, different cancer-specific subnetworks show very diverse implications to mutation status, SCNAs and others.	('cancer', 'Disease', (28, 34))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('mutation status', 'Var', (90, 105))
175947	27633916	With the deepening of understanding of cancer, the nosogenesis is not only restricted to somatic mutations but also to SCNAs, some epigenomic deregulations and so on.	('cancer', 'Disease', (39, 45))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('epigenomic deregulations', 'Var', (131, 155))	('cancer', 'Disease', 'MESH:D009369', (39, 45))
175968	27633916	We download the mutation annotation files (MAF) of all 16 cancer types and the output of mutsig2cv which gives if a gene is significantly mutated or not from Broad Institute on July 24, 2015 (Supplementary Table S1).	('cancer', 'Disease', (58, 64))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('mutated', 'Var', (138, 145))
175981	27633916	For each cancer, we use LIMMA to detect DEGs relative to normal samples with the TMM normalized data as input.	('DEGs', 'Var', (40, 44))	('cancer', 'Disease', (9, 15))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))
176045	33372710	In contrast to J591 (Wang et al, 2015), an established PSMA antibody that has been reported to recognize a linear epitope on the native PSMA molecule located at its apical domain (Bander et al, 2003b) (Fig 1A), 10B3 is not suitable for the detection of PSMA by Western blot analysis (Fig EV1A).	('PSMA', 'Gene', '2346', (55, 59))	('PSMA', 'Gene', (253, 257))	('PSMA', 'Gene', (136, 140))	('PSMA', 'Gene', '2346', (253, 257))	('PSMA', 'Gene', '2346', (136, 140))	('10B3', 'Var', (211, 215))	('PSMA', 'Gene', (55, 59))
176075	33372710	Since this difference was larger than expected when considering the molecular weight of the two molecules (7 vs 16 Ig domains), it appears that the CH3 domains, capable of binding to the FcRn receptor, largely influence the serum half-life of the IgGsc molecule.	('FcRn', 'Gene', (187, 191))	('binding', 'Interaction', (172, 179))	('serum half-life', 'MPA', (224, 239))	('CH3', 'Var', (148, 151))	('FcRn', 'Gene', '2217', (187, 191))	('influence', 'Reg', (210, 219))
176109	33372710	Taken together, binding of 10B3 is markedly superior to that of J591, with regard to both, neovascular cells in prostate carcinoma and tumor cells in lung SCC samples.	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('superior', 'PosReg', (44, 52))	('prostate carcinoma', 'Disease', 'MESH:D011471', (112, 130))	('10B3', 'Var', (27, 31))	('tumor', 'Disease', (135, 140))	('neovascular cells', 'CPA', (91, 108))	('prostate carcinoma', 'Phenotype', 'HP:0012125', (112, 130))	('prostate carcinoma', 'Disease', (112, 130))	('binding', 'Interaction', (16, 23))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
176123	33372710	In both, a metastasis prevention model and in a second model where mice were bearing large established tumors, the IgGsc molecule achieved a marked and prolonged antitumor effect, whereas the Fabsc bsAb was clearly less efficient and ineffective, respectively.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('IgGsc', 'Var', (115, 120))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('tumor', 'Disease', (103, 108))	('Fab', 'Gene', '2187', (192, 195))	('tumor', 'Disease', (166, 171))	('tumors', 'Disease', (103, 109))	('prolonged', 'PosReg', (152, 161))	('tumors', 'Disease', 'MESH:D009369', (103, 109))	('Fab', 'Gene', (192, 195))	('bsAb', 'Chemical', 'MESH:D018033', (198, 202))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('mice', 'Species', '10090', (67, 71))	('metastasis', 'CPA', (11, 21))
176156	33372710	To this end, 27 ZZ probes were designed to target the Hs-FOLH1 mRNA nucleotide sequences [85-397] and [2,666-3,960] (GenBank no.	('[85-397]', 'Var', (89, 97))	('FOLH1', 'Gene', '2346', (57, 62))	('FOLH1', 'Gene', (57, 62))
176161	33372710	AAD15290.1 and AAA39002.1), and humanized UCHT1 (anti-CD3; GenBank no.	('CD3', 'Gene', (54, 57))	('CD3', 'Gene', '12501', (54, 57))	('human', 'Species', '9606', (32, 37))	('AAA39002.1', 'Var', (15, 25))
176166	33372710	The IgGsc construct is based on the format originally described by Coloma and Morrison (Coloma & Morrison, 1997) with modifications in the CH2 domain consisting of the amino acid substitutions and deletions E233P; L234V; L235A; DeltaG236; D265G; A327Q; A330S (EU index) which abrogate FcR binding and complement fixation.	('DeltaG236', 'Mutation', 'c.236delG', (228, 237))	('and complement', 'CPA', (297, 311))	('A330S', 'Mutation', 'p.A330S', (253, 258))	('D265G', 'Mutation', 'p.D265G', (239, 244))	('abrogate FcR', 'Interaction', (276, 288))	('L235A', 'Mutation', 'p.L235A', (221, 226))	('L234V', 'Mutation', 'p.L234V', (214, 219))	('A327Q', 'Mutation', 'p.A327Q', (246, 251))	('deletions E233P; L234V; L235A; DeltaG236; D265G; A327Q', 'Var', (197, 251))	('Coloma and Morrison (Coloma', 'Disease', 'MESH:D003969', (67, 94))	('E233P', 'Mutation', 'p.E233P', (207, 212))	('which', 'NegReg', (270, 275))
176170	33372710	Surface Plasmon Resonance (SPR) experiments with recombinant, His-tagged PSMA produced by transfected CHO cells were performed using 10B3 and J591 antibodies immobilized to a sensor Chip coated with Protein A (GE Healthcare, Chicago, USA).	('J591', 'Var', (142, 146))	('CHO', 'CellLine', 'CVCL:0213', (102, 105))	('PSMA', 'Gene', (73, 77))	('PSMA', 'Gene', '2346', (73, 77))
176208	33372710	GJ, HS, FV, and LatZ are listed as inventors on the patent application "Novel PSMA binding antibody and uses thereof," EP16151281, applicant German Cancer Research Center, Heidelberg, Germany.	('EP16151281', 'Var', (119, 129))	('PSMA', 'Gene', (78, 82))	('Cancer', 'Phenotype', 'HP:0002664', (148, 154))	('PSMA', 'Gene', '2346', (78, 82))	('Cancer', 'Disease', (148, 154))	('Cancer', 'Disease', 'MESH:D009369', (148, 154))
176217	32899896	High UBE2C expression was also correlated with shorter disease-specific survival in TSCC patients having poor cell differentiation, advanced pathological stages, lymph node metastasis as well as receiving radiation therapy.	('shorter', 'NegReg', (47, 54))	('High', 'Var', (0, 4))	('expression', 'MPA', (11, 21))	('disease-specific survival', 'CPA', (55, 80))	('patients', 'Species', '9606', (89, 97))	('TSCC', 'Disease', (84, 88))	('UBE2C', 'Gene', '11065', (5, 10))	('UBE2C', 'Gene', (5, 10))
176233	32899896	Herein, we found that high expression level of UBE2C was associated with the tumorigenesis, poor clinicopathological outcomes and poor prognosis in OSCC patients.	('OSCC', 'Disease', (148, 152))	('UBE2C', 'Gene', (47, 52))	('patients', 'Species', '9606', (153, 161))	('high', 'Var', (22, 26))	('tumor', 'Disease', (77, 82))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('expression level', 'MPA', (27, 43))	('associated', 'Reg', (57, 67))	('UBE2C', 'Gene', '11065', (47, 52))
176273	32899896	Taken together, our results indicated that UBE2C expression was significantly associated with tumorigenesis, clinicopathological outcomes and prognosis in OSCC patients, especially in TSCC patients.	('UBE2C', 'Gene', (43, 48))	('associated', 'Reg', (78, 88))	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('patients', 'Species', '9606', (160, 168))	('OSCC', 'Disease', (155, 159))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Disease', (94, 99))	('TSCC', 'Disease', (184, 188))	('patients', 'Species', '9606', (189, 197))	('UBE2C', 'Gene', '11065', (43, 48))	('expression', 'Var', (49, 59))
176275	32899896	To further investigate the role of UBE2C in the tumorigenesis of TSCC, UBE2C was knocked down in two OSCC cell lines, SAS and Ca9-22 cells, for 48, 72 and 96 h and the knockdown efficiency was verified by western blot (Figure 2A).	('UBE2C', 'Gene', (71, 76))	('tumor', 'Disease', (48, 53))	('knocked', 'Var', (81, 88))	('UBE2C', 'Gene', '11065', (35, 40))	('Ca9-22', 'CellLine', 'CVCL:1102', (126, 132))	('UBE2C', 'Gene', (35, 40))	('SAS', 'Phenotype', 'HP:0002860', (118, 121))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('UBE2C', 'Gene', '11065', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
176289	32899896	Overexpression of UBE2C is associated with tumorigenesis and tumor progression in various types of cancer.	('UBE2C', 'Gene', '11065', (18, 23))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('associated with', 'Reg', (27, 42))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('UBE2C', 'Gene', (18, 23))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('cancer', 'Disease', (99, 105))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('Overexpression', 'Var', (0, 14))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Disease', (43, 48))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('tumor', 'Disease', (61, 66))
176294	32899896	High expression of UBE2C is associated with the tumor progression and unfavorable outcome in patients with malignant glioma.	('malignant glioma', 'Disease', (107, 123))	('High expression', 'Var', (0, 15))	('tumor', 'Disease', (48, 53))	('malignant glioma', 'Disease', 'MESH:D005910', (107, 123))	('patients', 'Species', '9606', (93, 101))	('associated', 'Reg', (28, 38))	('glioma', 'Phenotype', 'HP:0009733', (117, 123))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('UBE2C', 'Gene', '11065', (19, 24))	('UBE2C', 'Gene', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
176299	32899896	Silencing UBE2C arrests cell cycle progression at the G1/S phases, inhibits cell proliferation in pancreatic ductal adenocarcinoma and blocks the G2/M transition in melanoma.	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('cell cycle progression', 'CPA', (24, 46))	('UBE2C', 'Gene', '11065', (10, 15))	('arrests', 'NegReg', (16, 23))	('UBE2C', 'Gene', (10, 15))	('melanoma', 'Phenotype', 'HP:0002861', (165, 173))	('pancreatic ductal adenocarcinoma', 'Disease', (98, 130))	('cell proliferation', 'CPA', (76, 94))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (98, 130))	('G2/M transition', 'CPA', (146, 161))	('blocks', 'NegReg', (135, 141))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (98, 130))	('inhibits', 'NegReg', (67, 75))	('Silencing', 'Var', (0, 9))	('melanoma', 'Disease', (165, 173))	('melanoma', 'Disease', 'MESH:D008545', (165, 173))
176302	32899896	On the other hand, knockdown of UBE2C arrests G2/M phase of cell cycle and enhances cell apoptosis through induction of Bax/p53 and downregulation of Bcl-2.	('downregulation', 'NegReg', (132, 146))	('p53', 'Gene', (124, 127))	('knockdown', 'Var', (19, 28))	('Bax', 'Gene', '581', (120, 123))	('p53', 'Gene', '7157', (124, 127))	('enhances', 'PosReg', (75, 83))	('Bax', 'Gene', (120, 123))	('Bcl-2', 'Gene', '596', (150, 155))	('G2/M phase of cell cycle', 'CPA', (46, 70))	('induction', 'PosReg', (107, 116))	('cell apoptosis', 'CPA', (84, 98))	('Bcl-2', 'Gene', (150, 155))	('UBE2C', 'Gene', (32, 37))	('UBE2C', 'Gene', '11065', (32, 37))	('arrests', 'NegReg', (38, 45))
176303	32899896	Our results indicated that silencing UBE2C decreased the viability of OSCC cells (Figure 2) but further verification is needed to determine whether UBE2C is involved in cell proliferation or apoptosis.	('silencing', 'Var', (27, 36))	('UBE2C', 'Gene', '11065', (148, 153))	('UBE2C', 'Gene', (148, 153))	('UBE2C', 'Gene', '11065', (37, 42))	('UBE2C', 'Gene', (37, 42))	('viability', 'CPA', (57, 66))	('decreased', 'NegReg', (43, 52))
176310	32899896	Knockdown of UBE2C sensitizes epirubicin- and docetaxel-resistant breast cancer cells to chemotherapeutic agents.	('UBE2C', 'Gene', '11065', (13, 18))	('Knockdown', 'Var', (0, 9))	('UBE2C', 'Gene', (13, 18))	('docetaxel', 'Chemical', 'MESH:D000077143', (46, 55))	('epirubicin-', 'MPA', (30, 41))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('breast cancer', 'Disease', 'MESH:D001943', (66, 79))	('epirubicin', 'Chemical', 'MESH:D015251', (30, 40))	('sensitizes', 'Reg', (19, 29))	('breast cancer', 'Disease', (66, 79))	('breast cancer', 'Phenotype', 'HP:0003002', (66, 79))
176317	32899896	Our results indicated that knockdown of UBE2C decreased the expression levels of these cancer stemness markers including ALDH1A2, CD44, CD166 and EpCAM in both Ca9-22 and SAS cells (Figure 4).	('SAS', 'Phenotype', 'HP:0002860', (171, 174))	('knockdown', 'Var', (27, 36))	('EpCAM', 'Gene', (146, 151))	('Ca9-22', 'CellLine', 'CVCL:1102', (160, 166))	('cancer stemness', 'Disease', (87, 102))	('CD44', 'Gene', (130, 134))	('ALDH1A2', 'Gene', '8854', (121, 128))	('EpCAM', 'Gene', '4072', (146, 151))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('CD166', 'Gene', (136, 141))	('expression levels', 'MPA', (60, 77))	('cancer stemness', 'Disease', 'MESH:D009369', (87, 102))	('decreased', 'NegReg', (46, 55))	('CD166', 'Gene', '214', (136, 141))	('ALDH1A2', 'Gene', (121, 128))	('UBE2C', 'Gene', '11065', (40, 45))	('UBE2C', 'Gene', (40, 45))
176321	32899896	Indeed, UBE2C expression is associated in worse survival in several cancer types except oral cancer , suggesting low discrimination of UBE2C expression between different forms of cancers.	('expression', 'Var', (14, 24))	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('worse', 'NegReg', (42, 47))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('UBE2C', 'Gene', '11065', (135, 140))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('UBE2C', 'Gene', (135, 140))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('cancer', 'Disease', (68, 74))	('cancers', 'Disease', (179, 186))	('UBE2C', 'Gene', '11065', (8, 13))	('cancers', 'Disease', 'MESH:D009369', (179, 186))	('cancers', 'Phenotype', 'HP:0002664', (179, 186))	('cancer', 'Disease', (179, 185))	('UBE2C', 'Gene', (8, 13))
176322	32899896	Nevertheless, we further found that high co-expression of UBE2C and cancer stemness markers, including CD44, D166 and EpCAM, have even worse poor prognosis in TSCC patients, which provided potential diagnostic and prognostic markers in oral cancer patients.	('high', 'PosReg', (36, 40))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('UBE2C', 'Gene', '11065', (58, 63))	('UBE2C', 'Gene', (58, 63))	('D166', 'Var', (109, 113))	('EpCAM', 'Gene', (118, 123))	('cancer stemness', 'Disease', 'MESH:D009369', (68, 83))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('cancer', 'Disease', 'MESH:D009369', (241, 247))	('TSCC', 'Disease', (159, 163))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('cancer', 'Disease', (241, 247))	('cancer', 'Disease', (68, 74))	('cancer stemness', 'Disease', (68, 83))	('patients', 'Species', '9606', (164, 172))	('patients', 'Species', '9606', (248, 256))	('CD44', 'Gene', (103, 107))	('EpCAM', 'Gene', '4072', (118, 123))
176332	32899896	This work was supported by the Ministry of Science and Technology (MOST 108-2320-B-037-038, MOST 109-2320-B-037 -015 -MY3), Kaohsiung Medical University Research Foundation (KMU-Q109008), NSYSU-KMU Joint Research Project (NSYSUKMU 109-I007) and Kaohsiung Veterans General Hospital (VGHKS107-134).	('Kaohsiung Veterans', 'Disease', (245, 263))	('109-2320-B-037 -015 -MY3', 'Var', (97, 121))	('Kaohsiung Veterans', 'Disease', 'None', (245, 263))
176338	30420903	DNA amplification was common in LUAD patients (88/551, 16.0%) and was associated with significantly upregulated UBE2D1 RNA expression.	('UBE2D1', 'Gene', (112, 118))	('DNA amplification', 'Var', (0, 17))	('patients', 'Species', '9606', (37, 45))	('LUAD', 'Disease', (32, 36))	('upregulated', 'PosReg', (100, 111))	('UBE2D1', 'Gene', '7321', (112, 118))
176342	30420903	Previous studies found that UBE2D dysregulation is involved in some important pathways in carcinogenesis.	('UBE2', 'Gene', '7318', (28, 32))	('dysregulation', 'Var', (34, 47))	('UBE2', 'Gene', (28, 32))	('involved', 'Reg', (51, 59))	('carcinogenesis', 'Disease', 'MESH:D063646', (90, 104))	('carcinogenesis', 'Disease', (90, 104))
176347	30420903	Interruption of this complex by siRNA reduces the clonogenic survival in vitro and increases tumor latency in vivo in cancer cells including mutant KRAS-driven tumors.	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('KRAS', 'Gene', (148, 152))	('cancer', 'Disease', (118, 124))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('reduces', 'NegReg', (38, 45))	('mutant', 'Var', (141, 147))	('KRAS', 'Gene', '3845', (148, 152))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('increases tumor', 'Disease', 'MESH:D009369', (83, 98))	('clonogenic survival', 'CPA', (50, 69))	('tumors', 'Disease', (160, 166))	('increases tumor', 'Disease', (83, 98))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('tumors', 'Disease', 'MESH:D009369', (160, 166))
176356	30420903	Kaplan-Meier curves of OS and RFS were generated to examine the survival difference in patients with high/low UBE2D1 RNA expression.	('high/low', 'Var', (101, 109))	('OS', 'Chemical', 'MESH:D009992', (23, 25))	('UBE2D1', 'Gene', '7321', (110, 116))	('patients', 'Species', '9606', (87, 95))	('UBE2D1', 'Gene', (110, 116))
176373	30420903	Results showed that in LUAD patients, the group with high UBE2D1 RNA expression had inferior OS (p = 0.0033) and RFS (p = 0.0011) compared to the group with low expression (Figures 4(a) and 4(b)).	('high', 'Var', (53, 57))	('OS', 'Chemical', 'MESH:D009992', (93, 95))	('UBE2D1', 'Gene', '7321', (58, 64))	('UBE2D1', 'Gene', (58, 64))	('RFS', 'CPA', (113, 116))	('LUAD', 'Disease', (23, 27))	('patients', 'Species', '9606', (28, 36))
176380	30420903	Among 551 cases with both UBE2D1 CNAs and RNA-seq data, 88 cases had amplification (+1/+2) CNA, 295 had copy neutral (0) CNA, and 128 had deletion (-1/-2) CNA (Figure 5).	('amplification (+1/+2) CNA', 'Var', (69, 94))	('UBE2D1', 'Gene', (26, 32))	('deletion (-1/-2) CNA', 'Var', (138, 158))	('UBE2D1', 'Gene', '7321', (26, 32))
176388	30420903	P53 inactivation is closely associated with lung adenocarcinoma initiation, progression, and metastasis via multiple signaling pathways.	('lung adenocarcinoma initiation', 'Disease', (44, 74))	('inactivation', 'Var', (4, 16))	('carcinoma', 'Phenotype', 'HP:0030731', (54, 63))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (44, 63))	('associated', 'Reg', (28, 38))	('metastasis', 'CPA', (93, 103))	('P53', 'Gene', (0, 3))	('P53', 'Gene', '7157', (0, 3))	('lung adenocarcinoma initiation', 'Disease', 'MESH:D000077192', (44, 74))
176390	30420903	P53 inactivation can lead to DDX3 loss, which subsequently results in Slug-suppressed E-cadherin expression via decreased MDM2-mediated Slug degradation.	('Slug', 'Gene', '6591', (136, 140))	('inactivation', 'Var', (4, 16))	('Slug', 'Gene', (136, 140))	('E-cadherin', 'Gene', (86, 96))	('MDM2', 'Gene', '4193', (122, 126))	('MDM2', 'Gene', (122, 126))	('DDX3', 'Gene', '1654', (29, 33))	('DDX3', 'Gene', (29, 33))	('Slug', 'Gene', '6591', (70, 74))	('P53', 'Gene', (0, 3))	('E-cadherin', 'Gene', '999', (86, 96))	('P53', 'Gene', '7157', (0, 3))	('loss', 'NegReg', (34, 38))	('decreased', 'NegReg', (112, 121))	('Slug', 'Gene', (70, 74))
176392	30420903	P53 degradation directly lowers the p53-dependent transcription of the tumor suppressors RAD51 and p21 and the upregulation of the oncogene SOX2 in LUAD.	('RAD51', 'Gene', '5888', (89, 94))	('upregulation', 'PosReg', (111, 123))	('SOX2', 'Gene', '6657', (140, 144))	('lowers', 'NegReg', (25, 31))	('p53', 'Gene', (36, 39))	('degradation', 'Var', (4, 15))	('p53', 'Gene', '7157', (36, 39))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('P53', 'Gene', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('P53', 'Gene', '7157', (0, 3))	('tumor', 'Disease', (71, 76))	('p21', 'Gene', (99, 102))	('RAD51', 'Gene', (89, 94))	('p21', 'Gene', '644914', (99, 102))	('SOX2', 'Gene', (140, 144))
176398	30420903	In this study, we examined the association between UBE2D1 RNA expression and the CNAs of its DNA, and the results showed that DNA amplification was common in LUAD patients (88/551, 16.0%) and was associated with significantly upregulated UBE2D1 RNA expression, compared to the copy neutral patients.	('expression', 'MPA', (249, 259))	('patients', 'Species', '9606', (163, 171))	('patients', 'Species', '9606', (290, 298))	('upregulated', 'PosReg', (226, 237))	('amplification', 'Var', (130, 143))	('UBE2D1', 'Gene', '7321', (51, 57))	('UBE2D1', 'Gene', (51, 57))	('UBE2D1', 'Gene', '7321', (238, 244))	('UBE2D1', 'Gene', (238, 244))	('DNA amplification', 'Var', (126, 143))
176399	30420903	These findings suggest that DNA amplification might be an essential cause of upregulated UBE2D1 in LUAD.	('LUAD', 'Disease', (99, 103))	('DNA amplification', 'Var', (28, 45))	('upregulated', 'PosReg', (77, 88))	('UBE2D1', 'Gene', '7321', (89, 95))	('UBE2D1', 'Gene', (89, 95))
176542	30228817	Finally, we cannot exclude the presence of proto-oncogene mutations which may predispose the bronchial NET patients to an additional oncological risk, though at the moment there are no literature data supporting such hypothesis.	('mutations', 'Var', (58, 67))	('NET', 'Phenotype', 'HP:0100634', (103, 106))	('patients', 'Species', '9606', (107, 115))	('bronchial NET', 'Disease', (93, 106))
176567	25871623	Lastly, the recently recognized anaplastic lymphoma kinase (ALK) rearrangement predicted sensitivity to the targeted agent, Crizotinib, and it also specifically occurred in adenocarcinoma.	('sensitivity', 'MPA', (89, 100))	('ALK', 'Gene', (60, 63))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (32, 51))	('predicted', 'Reg', (79, 88))	('anaplastic lymphoma kinase', 'Gene', (32, 58))	('lymphoma', 'Phenotype', 'HP:0002665', (43, 51))	('rearrangement', 'Var', (65, 78))	('Crizotinib', 'Chemical', 'MESH:D000077547', (124, 134))	('anaplastic lymphoma kinase', 'Gene', '238', (32, 58))	('ALK', 'Gene', '238', (60, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (178, 187))	('occurred', 'Reg', (161, 169))	('adenocarcinoma', 'Disease', (173, 187))	('adenocarcinoma', 'Disease', 'MESH:D000230', (173, 187))
176577	25871623	When differentiating adenocarcinoma and squamous cell carcinoma, 8G7G3/1 was more specific to but less sensitive while SPT24 was less specific to but more sensitive for lung adenocarcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (54, 63))	('lung adenocarcinoma', 'Disease', (169, 188))	('adenocarcinoma and squamous cell carcinoma', 'Disease', 'MESH:D002294', (21, 63))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (169, 188))	('less', 'NegReg', (98, 102))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (40, 63))	('8G7G3/1', 'Var', (65, 72))	('carcinoma', 'Phenotype', 'HP:0030731', (26, 35))	('carcinoma', 'Phenotype', 'HP:0030731', (179, 188))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (169, 188))
176657	25871623	Among tumors positive for both TTF-1 SPT 24 and 8G7G3/1 (n = 13), most cases (n = 12) were also positive for Napsin A.	('Napsin A', 'Gene', (109, 117))	('TTF-1', 'Gene', (31, 36))	('TTF-1', 'Gene', '7080', (31, 36))	('positive', 'Reg', (96, 104))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('tumors', 'Disease', (6, 12))	('8G7G3/1', 'Var', (48, 55))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('Napsin A', 'Gene', '9476', (109, 117))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))
176672	25871623	In support of immunophenotypic re-classification, it was found that some of these tumors harbor mutations typical of adenocarcinoma (EGFR, KRAS) rather than squamous cell carcinoma.	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (157, 180))	('squamous cell carcinoma', 'Disease', (157, 180))	('tumors', 'Disease', (82, 88))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('adenocarcinoma', 'Disease', (117, 131))	('KRAS', 'Gene', (139, 143))	('KRAS', 'Gene', '3845', (139, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (171, 180))	('EGFR', 'Gene', '1956', (133, 137))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (157, 180))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('adenocarcinoma', 'Disease', 'MESH:D000230', (117, 131))	('EGFR', 'Gene', (133, 137))	('mutations', 'Var', (96, 105))
176746	33002094	P. gingivalis is frequently detected in patients with periodontitis and it plays a major role in the pathophysiology of the disease.	('periodontitis', 'Disease', 'MESH:D010518', (54, 67))	('periodontitis', 'Phenotype', 'HP:0000704', (54, 67))	('periodontitis', 'Disease', (54, 67))	('P. gingivalis', 'Species', '837', (0, 13))	('P. gingivalis', 'Var', (0, 13))	('patients', 'Species', '9606', (40, 48))
176747	33002094	P. gingivalis colonizes the subgingival crevice, where it mediates its invasive and replicative potential within various cell types including oral cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('P. gingivalis', 'Species', '837', (0, 13))	('P. gingivalis', 'Var', (0, 13))	('invasive', 'CPA', (71, 79))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('cancer', 'Disease', (147, 153))
176774	33002094	We further demonstrated the translational potential of a highly pure form of nisin (nisin ZP, 95% purity), which reduced oral tumorigenesis in vivo, and long-term treatment with nisin ZP extended the lifespan of tumor-bearing mice.	('nisin ZP', 'Chemical', '-', (84, 92))	('mice', 'Species', '10090', (226, 230))	('lifespan', 'CPA', (200, 208))	('nisin ZP', 'Chemical', '-', (178, 186))	('tumor', 'Disease', (126, 131))	('tumor', 'Disease', 'MESH:D009369', (212, 217))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('reduced', 'NegReg', (113, 120))	('nisin ZP', 'Var', (178, 186))	('tumor', 'Disease', (212, 217))	('extended', 'PosReg', (187, 195))
176778	33002094	This study demonstrates that key periodontal pathogens, T. denticola, P. gingivalis and F. nucleatum, enhance OSCC cell migration, invasion, stemness, and tumor aggressivity via crosstalk between integrin/FAK and TLR/MyDD88 signaling pathways, which can be abrogated by bacteriocin/nisin treatment.	('FAK', 'Gene', (205, 208))	('invasion', 'CPA', (131, 139))	('F. nucleatum', 'Species', '851', (88, 100))	('FAK', 'Gene', '5747', (205, 208))	('enhance', 'PosReg', (102, 109))	('OSCC cell migration', 'CPA', (110, 129))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('crosstalk', 'Reg', (178, 187))	('P. gingivalis', 'Var', (70, 83))	('tumor aggressivity', 'Disease', (155, 173))	('T. denticola', 'Species', '158', (56, 68))	('P. gingivalis', 'Species', '837', (70, 83))	('TLR/MyDD88 signaling pathways', 'Pathway', (213, 242))	('stemness', 'CPA', (141, 149))	('tumor aggressivity', 'Disease', 'MESH:D001523', (155, 173))
176783	33002094	However, P. gingivalis at high concentrations (100 MOI) induced apoptotic effects on OSCC cells (S2 Fig), whereas T. denticola and F. nucleatum had minimal effects on OSCC proliferation and apoptosis (S1 and S2 Figs).	('F. nucleatum', 'Species', '851', (131, 143))	('T. denticola', 'Species', '158', (114, 126))	('P. gingivalis', 'Species', '837', (9, 22))	('P. gingivalis', 'Var', (9, 22))	('apoptotic effects', 'CPA', (64, 81))	('apoptosis', 'CPA', (190, 199))
176820	33002094	Epidemiological data supports an association between alterations in microbial communities and numerous diseases processes, including cancer.	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('alterations', 'Var', (53, 64))	('cancer', 'Disease', (133, 139))	('diseases', 'Disease', (103, 111))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
176821	33002094	Several lines of evidence have emerged implicating bacteria in the etiology of some cancers, such as H. pylori in gastric cancer, C. trachomatis in cervical cancer, S. typhi in gall bladder cancer, both B. fragilis and F. nucleatum in colon cancer, and P. gingivalis in pancreatic cancer.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('pancreatic cancer', 'Disease', 'MESH:D010190', (270, 287))	('colon cancer', 'Disease', 'MESH:D015179', (235, 247))	('gall bladder cancer', 'Disease', (177, 196))	('gastric cancer', 'Disease', 'MESH:D013274', (114, 128))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('H. pylori', 'Disease', (101, 110))	('C. trachomatis', 'Species', '813', (130, 144))	('pancreatic cancer', 'Disease', (270, 287))	('P. gingivalis', 'Species', '837', (253, 266))	('cancer', 'Disease', (190, 196))	('cancer', 'Disease', 'MESH:D009369', (281, 287))	('cancers', 'Disease', 'MESH:D009369', (84, 91))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('colon cancer', 'Disease', (235, 247))	('S. typhi', 'Var', (165, 173))	('F. nucleatum', 'Species', '851', (219, 231))	('gastric cancer', 'Phenotype', 'HP:0012126', (114, 128))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('H. pylori', 'Species', '210', (101, 110))	('cancer', 'Disease', 'MESH:D009369', (241, 247))	('cancer', 'Disease', (84, 90))	('bladder cancer', 'Phenotype', 'HP:0009725', (182, 196))	('C. trachomatis', 'Var', (130, 144))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (270, 287))	('gall bladder cancer', 'Disease', 'MESH:D005706', (177, 196))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('cancer', 'Disease', (157, 163))	('B. fragilis', 'Species', '817', (203, 214))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('cancer', 'Disease', 'MESH:D009369', (190, 196))	('gastric cancer', 'Disease', (114, 128))	('colon cancer', 'Phenotype', 'HP:0003003', (235, 247))	('cancers', 'Phenotype', 'HP:0002664', (84, 91))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', (281, 287))	('cancers', 'Disease', (84, 91))	('S. typhi', 'Species', '90370', (165, 173))	('cancer', 'Disease', (241, 247))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))
176834	33002094	P. gingivalis can increase cell proliferation by accelerating the cell cycle via modulation of apoptosis.	('increase', 'PosReg', (18, 26))	('P. gingivalis', 'Species', '837', (0, 13))	('P. gingivalis', 'Var', (0, 13))	('cell proliferation', 'CPA', (27, 45))	('apoptosis', 'CPA', (95, 104))	('modulation', 'Reg', (81, 91))	('cell cycle', 'CPA', (66, 76))	('gingivalis can increase', 'Phenotype', 'HP:0000212', (3, 26))	('accelerating', 'PosReg', (49, 61))
176835	33002094	P. gingivalis can also induce G1 cell cycle arrest and increase autophagy without affecting apoptosis.	('increase', 'PosReg', (55, 63))	('P. gingivalis', 'Species', '837', (0, 13))	('P. gingivalis', 'Var', (0, 13))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (33, 50))	('arrest', 'Disease', 'MESH:D006323', (44, 50))	('autophagy', 'CPA', (64, 73))	('induce', 'Reg', (23, 29))	('arrest', 'Disease', (44, 50))
176837	33002094	Thus, an autophagy mechanism mediated by P. gingivalis in infected cells may have contributed to the apoptosis.	('P. gingivalis', 'Species', '837', (41, 54))	('P. gingivalis', 'Var', (41, 54))	('autophagy mechanism', 'CPA', (9, 28))	('infected', 'Disease', 'MESH:D007239', (58, 66))	('infected', 'Disease', (58, 66))	('apoptosis', 'CPA', (101, 110))	('contributed', 'Reg', (82, 93))
176840	33002094	Although P. gingivalis and F. nucleatum can promote migration and invasion of OSCC cells by triggering an epithelial to mesenchymal transition and acquisition of stemness properties, specific bacterial molecules or their structural features have not been specifically linked with migration effects.	('triggering', 'Reg', (92, 102))	('promote', 'PosReg', (44, 51))	('F. nucleatum', 'Species', '851', (27, 39))	('epithelial to mesenchymal transition', 'CPA', (106, 142))	('P. gingivalis', 'Species', '837', (9, 22))	('P. gingivalis', 'Var', (9, 22))	('invasion', 'CPA', (66, 74))	('stemness properties', 'CPA', (162, 181))
176848	33002094	P. gingivalis can also promote invasion in OSCC and esophageal cancer.	('promote', 'PosReg', (23, 30))	('P. gingivalis', 'Var', (0, 13))	('P. gingivalis', 'Species', '837', (0, 13))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('OSCC', 'Disease', (43, 47))	('invasion', 'CPA', (31, 39))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('cancer', 'Disease', (63, 69))
176854	33002094	Under pathological states, defective integrin signaling can result in abnormal cell division, migration and adhesion, which are hallmarks of cancer and metastasis.	('adhesion', 'CPA', (108, 116))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('migration', 'CPA', (94, 103))	('defective', 'Var', (27, 36))	('result in', 'Reg', (60, 69))	('integrin', 'Protein', (37, 45))	('cell division', 'CPA', (79, 92))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('cancer', 'Disease', (141, 147))
176863	33002094	Growth factor-mediated FAK phosphorylation promotes cellular adhesion, migration, and survival; all key factors in carcinogenesis.	('cellular adhesion', 'CPA', (52, 69))	('promotes', 'PosReg', (43, 51))	('FAK', 'Gene', (23, 26))	('FAK', 'Gene', '5747', (23, 26))	('migration', 'CPA', (71, 80))	('survival', 'CPA', (86, 94))	('carcinogenesis', 'Disease', 'MESH:D063646', (115, 129))	('phosphorylation', 'Var', (27, 42))	('carcinogenesis', 'Disease', (115, 129))
176864	33002094	Furthermore, increased expression of phosphorylated FAK (phosphorylation at Tyr 576) enabled identification of HNSCC tumors with a more aggressive phenotype.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('FAK', 'Gene', '5747', (52, 55))	('HNSCC tumors', 'Disease', 'MESH:D000077195', (111, 123))	('HNSCC', 'Phenotype', 'HP:0012288', (111, 116))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('Tyr', 'Chemical', 'MESH:D014443', (76, 79))	('HNSCC tumors', 'Disease', (111, 123))	('FAK', 'Gene', (52, 55))	('increased', 'PosReg', (13, 22))	('phosphorylated', 'Var', (37, 51))	('expression', 'MPA', (23, 33))
176865	33002094	In addition, increased FAK mRNA levels and dysregulation of integrin-FAK signaling in HNSCC led to enhanced cancer cell migration and invasion.	('dysregulation', 'Var', (43, 56))	('FAK', 'Gene', (23, 26))	('FAK', 'Gene', '5747', (23, 26))	('HNSCC', 'Phenotype', 'HP:0012288', (86, 91))	('enhanced', 'PosReg', (99, 107))	('invasion', 'CPA', (134, 142))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('FAK', 'Gene', (69, 72))	('FAK', 'Gene', '5747', (69, 72))	('increased', 'PosReg', (13, 22))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
176872	33002094	Taken together, T. denticola promotes OSCC carcinogenesis properties, such as migration, via crosstalk between TLR/MyD88 and integrin/FAK signaling pathways, and thereby contributes to a more aggressive oral cancer phenotype.	('contributes to', 'Reg', (170, 184))	('aggressive oral cancer', 'Disease', (192, 214))	('OSCC carcinogenesis', 'Disease', (38, 57))	('FAK', 'Gene', '5747', (134, 137))	('TLR/MyD88', 'Gene', (111, 120))	('MyD88', 'Chemical', '-', (115, 120))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('FAK', 'Gene', (134, 137))	('migration', 'CPA', (78, 87))	('crosstalk', 'Reg', (93, 102))	('aggressive oral cancer', 'Disease', 'MESH:D009369', (192, 214))	('T. denticola', 'Var', (16, 28))	('T. denticola', 'Species', '158', (16, 28))	('OSCC carcinogenesis', 'Disease', 'MESH:D063646', (38, 57))	('promotes', 'PosReg', (29, 37))
176931	27683113	The nerve growth factor receptor (NGFR) has been observed to be expressed on a subset of cells in OSCC, and NGFR+ cells have greater tumor-initiating capacity in vivo.	('nerve growth factor receptor', 'Gene', '18053', (4, 32))	('NGFR+', 'Var', (108, 113))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('nerve growth factor receptor', 'Gene', (4, 32))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumor', 'Disease', (133, 138))	('greater', 'PosReg', (125, 132))
176932	27683113	Further, inhibition of NGFR reduces tumor growth, indicating a functional role of this receptor; however, the mechanisms by which NGFR confers enhanced tumor formation are not known.	('NGFR', 'Gene', (23, 27))	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('enhanced', 'PosReg', (143, 151))	('reduces', 'NegReg', (28, 35))	('tumor', 'Disease', (152, 157))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('inhibition', 'Var', (9, 19))	('tumor', 'Disease', (36, 41))
176936	27683113	Importantly, ESM1 overexpression conferred an enhanced migratory, invasive, and metastatic phenotype, similar to what has been correlated with NGFR expression.	('migratory', 'CPA', (55, 64))	('invasive', 'CPA', (66, 74))	('overexpression', 'Var', (18, 32))	('ESM1', 'Gene', (13, 17))	('enhanced', 'PosReg', (46, 54))	('rat', 'Species', '10116', (58, 61))
176937	27683113	Conversely, shRNA knockdown of ESM1 in NGFR overexpressing OSCC cells abrogated the tumor growth kinetics and the invasive and metastatic properties associated with NGFR.	('knockdown', 'Var', (18, 27))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('abrogated', 'NegReg', (70, 79))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumor', 'Disease', (84, 89))	('ESM1', 'Gene', (31, 35))
176941	27683113	In normal oral mucosa epithelium, a sub population of basal cells with stem cell-like properties has been shown to express the nerve growth factor receptor (NGFR), and recent reports indicate that NGFR contributes to the tumor-initiating capacity of a number of malignancies.	('nerve growth factor receptor', 'Gene', (127, 155))	('contributes', 'Reg', (202, 213))	('nerve growth factor receptor', 'Gene', '18053', (127, 155))	('tumor', 'Disease', (221, 226))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('malignancies', 'Disease', 'MESH:D009369', (262, 274))	('NGFR', 'Var', (197, 201))	('malignancies', 'Disease', (262, 274))	('tumor', 'Disease', 'MESH:D009369', (221, 226))
176946	27683113	Activation of TrkA can inhibit angiogenesis, induce differentiation and growth arrest and mediate apoptosis.	('apoptosis', 'CPA', (98, 107))	('growth arrest', 'Phenotype', 'HP:0001510', (72, 85))	('TrkA', 'Gene', '18211', (14, 18))	('induce', 'PosReg', (45, 51))	('differentiation', 'CPA', (52, 67))	('inhibit', 'NegReg', (23, 30))	('Activation', 'Var', (0, 10))	('TrkA', 'Gene', (14, 18))	('mediate', 'Reg', (90, 97))	('growth arrest', 'Disease', (72, 85))	('angiogenesis', 'CPA', (31, 43))	('growth arrest', 'Disease', 'MESH:D006323', (72, 85))
176965	27683113	To examine the functional role of ESM1 in MOC cells, shRNA targeting ESM1 was stably transduced into MOC2 cells (ESM1-SH) to knockdown expression of ESM1, and an ESM1 expression construct was also transduced into MOC2 cell line (ESM1-OVER) to overexpress ESM1.	('ESM1-OVER', 'Gene', '71690', (229, 238))	('knockdown', 'Var', (125, 134))	('ESM1', 'Gene', (149, 153))	('ESM1-OVER', 'Gene', (229, 238))	('ESM1', 'Gene', (69, 73))
176967	27683113	Using transwell chamber assays, we assessed the ability of ESM1-SH and ESM1-OVER for their ability to invade and migrate through a Matrigel matrix.	('ESM1-OVER', 'Gene', '71690', (71, 80))	('invade', 'CPA', (102, 108))	('ESM1-SH', 'Var', (59, 66))	('ESM1-OVER', 'Gene', (71, 80))	('rat', 'Species', '10116', (116, 119))	('migrate', 'CPA', (113, 120))
176968	27683113	To assess the effect of ESM1 on tumor growth in vivo, MOC2 cells, in which ESM1 was knocked down (ESM1-SH), and control MOC2 cells were implanted subcutaneously into the flanks of mice, and the growth of the resultant primary tumors was monitored.	('tumors', 'Phenotype', 'HP:0002664', (226, 232))	('tumors', 'Disease', (226, 232))	('tumors', 'Disease', 'MESH:D009369', (226, 232))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('ESM1', 'Gene', (75, 79))	('tumor', 'Disease', 'MESH:D009369', (226, 231))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('mice', 'Species', '10090', (180, 184))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('tumor', 'Disease', (32, 37))	('tumor', 'Disease', (226, 231))	('knocked down', 'Var', (84, 96))
176969	27683113	A significant reduction in tumor growth kinetics and tumor volume was observed in the ESM1 knockdown cells (Figure 5A).	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('ESM1', 'Gene', (86, 90))	('tumor', 'Disease', (27, 32))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('knockdown', 'Var', (91, 100))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Disease', (53, 58))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('reduction', 'NegReg', (14, 23))
176971	27683113	These data demonstrated that ESM1 knockdown effectively suppressed MOC2 tumor growth, despite only modest changes in cell proliferation/viability measured in vitro (Figure 4D).	('rat', 'Species', '10116', (18, 21))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Disease', (72, 77))	('ESM1', 'Gene', (29, 33))	('rat', 'Species', '10116', (129, 132))	('suppressed', 'NegReg', (56, 66))	('knockdown', 'Var', (34, 43))	('tumor', 'Disease', 'MESH:D009369', (72, 77))
176972	27683113	The number of pulmonary metastases resulting from MOC2 primary tumors was significantly higher than that induced by ESM1 knockdown MOC2 cells (p<0.05).	('higher', 'PosReg', (88, 94))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('pulmonary metastases', 'Disease', 'MESH:D009362', (14, 34))	('pulmonary metastases', 'Disease', (14, 34))	('tumors', 'Disease', (63, 69))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('MOC2', 'Var', (50, 54))
176974	27683113	To assess whether ESM1 may participate in angiogenesis, VEGF expression was assessed in the tumor sections (Figure 5C), and VEGF expression was observed to be reduced in the ESM1 knockdown MOC2 tumors.	('MOC2 tumors', 'Disease', (189, 200))	('MOC2 tumors', 'Disease', 'MESH:D009369', (189, 200))	('VEGF', 'Gene', (56, 60))	('VEGF', 'Gene', '22339', (56, 60))	('expression', 'MPA', (129, 139))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('reduced', 'NegReg', (159, 166))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('knockdown', 'Var', (179, 188))	('tumors', 'Phenotype', 'HP:0002664', (194, 200))	('VEGF', 'Gene', '22339', (124, 128))	('tumor', 'Disease', (194, 199))	('tumor', 'Disease', (92, 97))	('ESM1', 'Gene', (174, 178))	('VEGF', 'Gene', (124, 128))
176979	27683113	However, ESM1 knockdown had a significant negative effect on the invasive/migratory capacity of MOC2T cells (Figure 6C).	('rat', 'Species', '10116', (77, 80))	('ESM1', 'Gene', (9, 13))	('MOC2T', 'CellLine', 'CVCL:0042', (96, 101))	('negative', 'NegReg', (42, 50))	('knockdown', 'Var', (14, 23))	('invasive/migratory capacity of MOC2T cells', 'CPA', (65, 107))
176982	27683113	Consistent with the effect of altered ESM1 expression on migration and invasion of MOC2T cells in vitro, knockdown of ESM1 significantly inhibited tumor growth (Figure 6D) and reduced the number of lung metastases (Figure 6E) associated with MOC2T cells in vivo.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('inhibited', 'NegReg', (137, 146))	('reduced', 'NegReg', (176, 183))	('ESM1', 'Gene', (118, 122))	('rat', 'Species', '10116', (60, 63))	('knockdown', 'Var', (105, 114))	('MOC2T', 'CellLine', 'CVCL:0042', (83, 88))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('lung metastases', 'Disease', (198, 213))	('lung metastases', 'Disease', 'MESH:D009362', (198, 213))	('MOC2T', 'CellLine', 'CVCL:0042', (242, 247))
176998	27683113	In accordance with these studies, our in vivo and in vitro data both indicate that altered ESM1 expression plays an important role in tumor formation and metastasis of murine oral squamous carcinoma.	('squamous carcinoma', 'Phenotype', 'HP:0002860', (180, 198))	('altered', 'Var', (83, 90))	('expression', 'MPA', (96, 106))	('oral squamous carcinoma', 'Disease', 'MESH:D002294', (175, 198))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('ESM1', 'Gene', (91, 95))	('metastasis', 'CPA', (154, 164))	('oral squamous carcinoma', 'Disease', (175, 198))	('murine', 'Species', '10090', (168, 174))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (189, 198))	('tumor', 'Disease', (134, 139))
177004	27683113	Consistent with this, we found that ESM1 knockdown resulted in significantly lower VEGF expression.	('lower', 'NegReg', (77, 82))	('VEGF', 'Gene', (83, 87))	('ESM1', 'Gene', (36, 40))	('VEGF', 'Gene', '22339', (83, 87))	('knockdown', 'Var', (41, 50))
177006	27683113	We have demonstrated that ESM1 knockdown reduces the metastatic capacity of MOC2 cells in vivo, providing rationale to investigate the therapeutic potential of targeting NGFR and/or ESM1 in oral SCC.	('metastatic capacity of MOC2 cells in vivo', 'CPA', (53, 94))	('rat', 'Species', '10116', (15, 18))	('ESM1', 'Gene', (182, 186))	('reduces', 'NegReg', (41, 48))	('ESM1', 'Gene', (26, 30))	('rat', 'Species', '10116', (106, 109))	('NGFR', 'Gene', (170, 174))	('knockdown', 'Var', (31, 40))
177049	32319563	Subsequently, it was found that the levsel of PD-L1 expression decreased following the silencing of PKD3 and that the ability of interferon (IFN)-gamma to induce PD-L1 expression was also decreased in OSCC.	('PD-L1', 'Gene', (46, 51))	('OSCC', 'Disease', (201, 205))	('silencing', 'Var', (87, 96))	('decreased', 'NegReg', (188, 197))	('levsel', 'MPA', (36, 42))	('expression', 'MPA', (168, 178))	('PKD3', 'Gene', '23683', (100, 104))	('PD-L1', 'Gene', '29126', (162, 167))	('decreased', 'NegReg', (63, 72))	('PD-L1', 'Gene', '29126', (46, 51))	('interferon (IFN)-gamma', 'Gene', (129, 151))	('expression', 'MPA', (52, 62))	('OSCC', 'Disease', 'MESH:D002294', (201, 205))	('interferon (IFN)-gamma', 'Gene', '3458', (129, 151))	('PKD3', 'Gene', (100, 104))	('PD-L1', 'Gene', (162, 167))
177051	32319563	It was also found that the phosphorylation of signal transducer and activator of transcription (STAT)1/STAT3 was reduced by the knockdown of PKD3 in OSCC.	('OSCC', 'Disease', (149, 153))	('signal transducer and activator of transcription (STAT)1', 'Gene', '6772', (46, 102))	('STAT3', 'Gene', (103, 108))	('knockdown', 'Var', (128, 137))	('phosphorylation', 'MPA', (27, 42))	('OSCC', 'Disease', 'MESH:D002294', (149, 153))	('PKD3', 'Gene', '23683', (141, 145))	('STAT3', 'Gene', '6774', (103, 108))	('reduced', 'NegReg', (113, 120))	('PKD3', 'Gene', (141, 145))
177052	32319563	Moreover, the expression level of PD-L1 was decreased after the use of siRNA to knockdown STAT1 or STAT3.	('knockdown', 'Var', (80, 89))	('STAT1', 'Gene', (90, 95))	('STAT3', 'Gene', '6774', (99, 104))	('PD-L1', 'Gene', (34, 39))	('STAT3', 'Gene', (99, 104))	('STAT1', 'Gene', '6772', (90, 95))	('PD-L1', 'Gene', '29126', (34, 39))	('expression level', 'MPA', (14, 30))	('decreased', 'NegReg', (44, 53))
177101	32319563	STAT1 siRNA (5'-CAC GAG ACC AAU GGU GUG GdT dT-3'; 5'-CCA CAC CAU UGG UCU CGU GdT dT-3') was used to knockdown STAT1 expression, as previously described.	('STAT1', 'Gene', '6772', (0, 5))	('expression', 'MPA', (117, 127))	('STAT1', 'Gene', (111, 116))	('STAT1', 'Gene', '6772', (111, 116))	('STAT1', 'Gene', (0, 5))	('knockdown', 'Var', (101, 110))
177186	32319563	It was found that the knockdown of PKD3 significantly decreased the phosphorylation levels of STAT1 and STAT3 at Ser727 in OSCC cell lines (P<0.001, Fig.	('STAT3', 'Gene', '6774', (104, 109))	('PKD3', 'Gene', (35, 39))	('Ser727', 'Chemical', '-', (113, 119))	('STAT3', 'Gene', (104, 109))	('STAT1', 'Gene', (94, 99))	('OSCC', 'Disease', (123, 127))	('knockdown', 'Var', (22, 31))	('phosphorylation levels', 'MPA', (68, 90))	('PKD3', 'Gene', '23683', (35, 39))	('STAT1', 'Gene', '6772', (94, 99))	('decreased', 'NegReg', (54, 63))	('OSCC', 'Disease', 'MESH:D002294', (123, 127))
177190	32319563	The knockdown of STAT1 significantly abrogated the IFN-gamma-induced PD-L1 upregulation at the protein level (P<0.001, Fig.	('PD-L1', 'Gene', '29126', (69, 74))	('IFN-gamma', 'Gene', '3458', (51, 60))	('IFN-gamma', 'Gene', (51, 60))	('STAT1', 'Gene', (17, 22))	('STAT1', 'Gene', '6772', (17, 22))	('upregulation', 'PosReg', (75, 87))	('abrogated', 'NegReg', (37, 46))	('knockdown', 'Var', (4, 13))	('PD-L1', 'Gene', (69, 74))
177201	32319563	These results are consistent with those of previous studies in several types of cancer, which supports the conclusion obtained herein that abnormal PKD3 expression and localization promote cancer progression.	('localization', 'MPA', (168, 180))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('PKD3', 'Gene', '23683', (148, 152))	('promote', 'PosReg', (181, 188))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('abnormal', 'Var', (139, 147))	('expression', 'MPA', (153, 163))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('PKD3', 'Gene', (148, 152))	('cancer', 'Disease', (80, 86))	('cancer', 'Disease', (189, 195))
177227	32319563	However, the phosphorylation of STAT1/3 at Ser727 is essential for the optimal DNA binding and transcriptional activity of STAT1/3.	('STAT1/3', 'Gene', '6772;6774', (32, 39))	('STAT1/3', 'Gene', (32, 39))	('DNA binding', 'Interaction', (79, 90))	('STAT1/3', 'Gene', '6772;6774', (123, 130))	('Ser727', 'Var', (43, 49))	('STAT1/3', 'Gene', (123, 130))	('Ser727', 'Chemical', '-', (43, 49))	('transcriptional activity', 'MPA', (95, 119))
177228	32319563	Previous studies have demonstrated that the inhibition of AKT activation can lead to the downregulation of the IFN-gamma-mediated phosphorylation of STAT1 at Ser727, which not only downregulates the expression of the STAT1 target genes, CXCL9 and CXCL10, but also downregulates the expression of PD-L1.	('PD-L1', 'Gene', '29126', (296, 301))	('CXCL9', 'Gene', (237, 242))	('STAT1', 'Gene', (217, 222))	('IFN-gamma', 'Gene', '3458', (111, 120))	('IFN-gamma', 'Gene', (111, 120))	('CXCL9', 'Gene', '4283', (237, 242))	('STAT1', 'Gene', '6772', (217, 222))	('expression', 'MPA', (199, 209))	('CXCL10', 'Gene', '3627', (247, 253))	('downregulates', 'NegReg', (264, 277))	('AKT', 'Gene', (58, 61))	('Ser727', 'Chemical', '-', (158, 164))	('STAT1', 'Gene', (149, 154))	('inhibition', 'NegReg', (44, 54))	('CXCL10', 'Gene', (247, 253))	('downregulation', 'NegReg', (89, 103))	('expression', 'MPA', (282, 292))	('downregulates', 'NegReg', (181, 194))	('AKT', 'Gene', '207', (58, 61))	('STAT1', 'Gene', '6772', (149, 154))	('PD-L1', 'Gene', (296, 301))	('Ser727', 'Var', (158, 164))
177238	29593425	Lung squamous cell carcinoma associated with hypoparathyroidism with sensorineural deafness and renal dysplasia syndrome: a case report Hypoparathyroidism with sensorineural deafness and renal dysplasia (HDR) syndrome is an autosomal dominant condition caused by mutations of the gene encoding the dual zinc-finger transcription factor, GATA3.	('sensorineural deafness and renal dysplasia syndrome', 'Disease', 'MESH:C536586', (69, 120))	('deafness', 'Phenotype', 'HP:0000365', (83, 91))	('mutations', 'Var', (263, 272))	('autosomal dominant condition', 'Disease', 'MESH:D017827', (224, 252))	('squamous cell carcinoma', 'Disease', (5, 28))	('hypoparathyroidism', 'Disease', 'MESH:D007011', (45, 63))	('sensorineural deafness', 'Phenotype', 'HP:0000407', (69, 91))	('renal dysplasia', 'Phenotype', 'HP:0000110', (187, 202))	('hypoparathyroidism', 'Disease', (45, 63))	('Lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (0, 28))	('Hypoparathyroidism', 'Disease', (136, 154))	('deafness', 'Phenotype', 'HP:0000365', (174, 182))	('Hypoparathyroidism', 'Disease', 'MESH:D007011', (136, 154))	('GATA3', 'Gene', '2625', (337, 342))	('caused by', 'Reg', (253, 262))	('renal dysplasia', 'Phenotype', 'HP:0000110', (96, 111))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (5, 28))	('hypoparathyroidism', 'Phenotype', 'HP:0000829', (45, 63))	('GATA3', 'Gene', (337, 342))	('sensorineural deafness', 'Phenotype', 'HP:0000407', (160, 182))	('carcinoma', 'Phenotype', 'HP:0030731', (19, 28))	('sensorineural deafness and renal dysplasia (HDR) syndrome', 'Disease', 'MESH:C537907', (160, 217))	('autosomal dominant condition', 'Disease', (224, 252))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (5, 28))	('Hypoparathyroidism', 'Phenotype', 'HP:0000829', (136, 154))
177239	29593425	A previous study identified some patients with GATA3 gene variants and breast cancer, suggesting that GATA3 variants may contribute to tumorigenesis in estrogen receptor 1-positive breast tumors; however, these patients did not have HDR syndrome.	('tumor', 'Disease', (188, 193))	('breast cancer', 'Phenotype', 'HP:0003002', (71, 84))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('HDR syndrome', 'Disease', 'MESH:C537907', (233, 245))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('estrogen receptor 1', 'Gene', '2099', (152, 171))	('GATA3', 'Gene', '2625', (47, 52))	('breast cancer', 'Disease', 'MESH:D001943', (71, 84))	('GATA3', 'Gene', '2625', (102, 107))	('breast cancer', 'Disease', (71, 84))	('patients', 'Species', '9606', (211, 219))	('tumors', 'Phenotype', 'HP:0002664', (188, 194))	('GATA3', 'Gene', (47, 52))	('breast tumors', 'Disease', (181, 194))	('GATA3', 'Gene', (102, 107))	('contribute', 'Reg', (121, 131))	('breast tumors', 'Disease', 'MESH:D001943', (181, 194))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('breast tumors', 'Phenotype', 'HP:0100013', (181, 194))	('tumor', 'Disease', (135, 140))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('tumor', 'Disease', 'MESH:D009369', (135, 140))	('patients', 'Species', '9606', (33, 41))	('HDR syndrome', 'Disease', (233, 245))	('variants', 'Var', (108, 116))	('estrogen receptor 1', 'Gene', (152, 171))
177240	29593425	A 32-year-old nonsmoking Japanese woman was histologically diagnosed with lung squamous cell carcinoma associated with HDR syndrome and a c.C952T>C (p.C318R) germline mutation in GATA3.	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('HDR syndrome', 'Disease', (119, 131))	('GATA3', 'Gene', '2625', (179, 184))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (79, 102))	('lung squamous cell carcinoma', 'Disease', (74, 102))	('associated', 'Reg', (103, 113))	('c.C952T>C', 'Mutation', 'c.952C,T>C', (138, 147))	('woman', 'Species', '9606', (34, 39))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (74, 102))	('c.C952T>C (p.C318R', 'Var', (138, 156))	('GATA3', 'Gene', (179, 184))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (74, 102))	('p.C318R', 'Mutation', 'p.C318R', (149, 156))	('HDR syndrome', 'Disease', 'MESH:C537907', (119, 131))
177242	29593425	Our data indicates that GATA3 mutations may be a potential therapeutic target for lung cancer.	('GATA3', 'Gene', '2625', (24, 29))	('lung cancer', 'Phenotype', 'HP:0100526', (82, 93))	('lung cancer', 'Disease', (82, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('mutations', 'Var', (30, 39))	('lung cancer', 'Disease', 'MESH:D008175', (82, 93))	('GATA3', 'Gene', (24, 29))
177243	29593425	Hypoparathyroidism with sensorineural deafness and renal dysplasia (HDR) syndrome (OMIM: 146255) is an autosomal dominant condition characterized by incomplete penetrance and clinical heterogneity, and is caused by mutations of GATA3 (OMIM: 131320).	('autosomal dominant condition', 'Disease', (103, 131))	('sensorineural deafness and renal dysplasia (HDR) syndrome', 'Disease', 'MESH:C537907', (24, 81))	('Hypoparathyroidism', 'Phenotype', 'HP:0000829', (0, 18))	('caused by', 'Reg', (205, 214))	('deafness', 'Phenotype', 'HP:0000365', (38, 46))	('Hypoparathyroidism', 'Disease', 'MESH:D007011', (0, 18))	('autosomal dominant condition', 'Disease', 'MESH:D017827', (103, 131))	('GATA3', 'Gene', (228, 233))	('mutations', 'Var', (215, 224))	('GATA3', 'Gene', '2625', (228, 233))	('sensorineural deafness', 'Phenotype', 'HP:0000407', (24, 46))	('renal dysplasia', 'Phenotype', 'HP:0000110', (51, 66))	('Hypoparathyroidism', 'Disease', (0, 18))
177246	29593425	Many types of GATA3 mutations can cause HDR syndrome, including intragenic deletions, along with nonsense, acceptor splice site, and missense mutations.	('deletions', 'Var', (75, 84))	('GATA3', 'Gene', '2625', (14, 19))	('cause', 'Reg', (34, 39))	('HDR syndrome', 'Disease', (40, 52))	('mutations', 'Var', (20, 29))	('GATA3', 'Gene', (14, 19))	('HDR syndrome', 'Disease', 'MESH:C537907', (40, 52))
177247	29593425	The missense variants p.C318R and p.N320K are predicted to disrupt the C-terminal zinc finger of GATA3.	('GATA3', 'Gene', (97, 102))	('p.N320K', 'Mutation', 'rs764474372', (34, 41))	('p.C318R', 'Mutation', 'p.C318R', (22, 29))	('disrupt', 'NegReg', (59, 66))	('p.C318R', 'Var', (22, 29))	('GATA3', 'Gene', '2625', (97, 102))	('C-terminal zinc finger', 'MPA', (71, 93))	('p.N320K', 'Var', (34, 41))
177250	29593425	Recently, potentially oncogenic mutations have been recognized in approximately 60% of lung adenocarcinoma, and molecular targeting therapies have been shown to improve the clinical outcomes of patients with these mutations.	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('patients', 'Species', '9606', (194, 202))	('lung adenocarcinoma', 'Disease', (87, 106))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (87, 106))	('mutations', 'Var', (214, 223))	('mutations', 'Var', (32, 41))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (87, 106))
177251	29593425	Nevertheless, oncogenic mutations are rare in lung squamous cell carcinoma, and the majority of patients are treated with conventional chemotherapy.	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (46, 74))	('patients', 'Species', '9606', (96, 104))	('mutations', 'Var', (24, 33))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (51, 74))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (46, 74))	('lung squamous cell carcinoma', 'Disease', (46, 74))
177258	29593425	The results indicated that she carried the missense variant, c.C952T>C (p.C318R), in exon 5 of GATA3 (Figure 1).	('c.C952T>C (p.C318R', 'Var', (61, 79))	('c.C952T>C', 'Mutation', 'c.952C,T>C', (61, 70))	('GATA3', 'Gene', (95, 100))	('p.C318R', 'Mutation', 'p.C318R', (72, 79))	('GATA3', 'Gene', '2625', (95, 100))
177262	29593425	Her clinical stage of cancer progression was cT2aN0M1c, stage IVB, according to the TNM classification of the Union for International Cancer Control.	('Cancer', 'Disease', (134, 140))	('TNM', 'Gene', (84, 87))	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('Cancer', 'Disease', 'MESH:D009369', (134, 140))	('Cancer', 'Phenotype', 'HP:0002664', (134, 140))	('cancer', 'Disease', (22, 28))	('TNM', 'Gene', '10178', (84, 87))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('cT2aN0M1c', 'Var', (45, 54))
177263	29593425	Sequencing analysis of the tumor sample revealed no mutations of EGFR or EML4-ALK.	('mutations', 'Var', (52, 61))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('ALK', 'Gene', (78, 81))	('EGFR', 'Gene', '1956', (65, 69))	('EGFR', 'Gene', (65, 69))	('tumor', 'Disease', (27, 32))	('EML4', 'Gene', (73, 77))	('ALK', 'Gene', '238', (78, 81))	('EML4', 'Gene', '27436', (73, 77))
177279	29593425	A previous study identified 5 patients with GATA3 gene mutations among 111 individuals with breast cancer; however, none of them had HDR syndrome.	('breast cancer', 'Disease', 'MESH:D001943', (92, 105))	('HDR syndrome', 'Disease', (133, 145))	('breast cancer', 'Phenotype', 'HP:0003002', (92, 105))	('breast cancer', 'Disease', (92, 105))	('mutations', 'Var', (55, 64))	('patients', 'Species', '9606', (30, 38))	('GATA3', 'Gene', (44, 49))	('GATA3', 'Gene', '2625', (44, 49))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('HDR syndrome', 'Disease', 'MESH:C537907', (133, 145))
177280	29593425	To our knowledge, there have been no reports describing patients with lung squamous cell carcinoma associated with HDR syndrome, although it has previously been suggested that disruption of GATA3 is associated with cancer.	('patients', 'Species', '9606', (56, 64))	('associated', 'Reg', (199, 209))	('GATA3', 'Gene', (190, 195))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('cancer', 'Disease', (215, 221))	('cancer', 'Disease', 'MESH:D009369', (215, 221))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (70, 98))	('GATA3', 'Gene', '2625', (190, 195))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (70, 98))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (75, 98))	('disruption', 'Var', (176, 186))	('lung squamous cell carcinoma', 'Disease', (70, 98))	('HDR syndrome', 'Disease', 'MESH:C537907', (115, 127))	('HDR syndrome', 'Disease', (115, 127))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('associated', 'Reg', (99, 109))
177284	29593425	In addition, we were unable to determine the genetic status of other family members; therefore, we cannot conclude that the patient developed a de novo GATA3 p.C318R mutation.	('GATA3', 'Gene', (152, 157))	('GATA3', 'Gene', '2625', (152, 157))	('p.C318R', 'Mutation', 'p.C318R', (158, 165))	('p.C318R', 'Var', (158, 165))	('patient', 'Species', '9606', (124, 131))
177285	29593425	Indeed, Esch et al reported patients with a de novo 49 bp frameshift deletion mutation in family 26/99, and Ferraris et al also reported a de novo heterozygous deletion of the nucleotides GG in codons 36 and 37 of GATA3.	('deletion', 'Var', (160, 168))	('GATA3', 'Gene', (214, 219))	('GATA3', 'Gene', '2625', (214, 219))	('frameshift deletion mutation', 'Var', (58, 86))	('patients', 'Species', '9606', (28, 36))
177293	29593425	Indeed, recent studies have reported several genetic abnormalities that cause lung squamous cell carcinoma, including mutations in FGFR, PIL3CA, PTEN, AKT, DDR2, BRAF, PDGFRA, SOX2, EphA2, and IGF-1R.	('AKT', 'Gene', (151, 154))	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('IGF-1R', 'Gene', '3480', (193, 199))	('EphA2', 'Gene', '1969', (182, 187))	('IGF-1R', 'Gene', (193, 199))	('PIL3CA', 'Gene', (137, 143))	('cause', 'Reg', (72, 77))	('genetic abnormalities', 'Disease', 'MESH:D030342', (45, 66))	('SOX2', 'Gene', '6657', (176, 180))	('SOX2', 'Gene', (176, 180))	('genetic abnormalities', 'Disease', (45, 66))	('AKT', 'Gene', '207', (151, 154))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (78, 106))	('DDR2', 'Gene', '4921', (156, 160))	('PTEN', 'Gene', (145, 149))	('mutations', 'Var', (118, 127))	('BRAF', 'Gene', '673', (162, 166))	('FGFR', 'Gene', (131, 135))	('BRAF', 'Gene', (162, 166))	('PDGFRA', 'Gene', (168, 174))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (78, 106))	('PDGFRA', 'Gene', '5156', (168, 174))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (83, 106))	('DDR2', 'Gene', (156, 160))	('lung squamous cell carcinoma', 'Disease', (78, 106))	('PTEN', 'Gene', '5728', (145, 149))	('EphA2', 'Gene', (182, 187))
177297	29593425	These data support the hypothesis that the GATA3 mutation identified in the present case is associated with her development of lung squamous cell carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (127, 155))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (132, 155))	('lung squamous cell carcinoma', 'Disease', (127, 155))	('mutation', 'Var', (49, 57))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (127, 155))	('GATA3', 'Gene', (43, 48))	('GATA3', 'Gene', '2625', (43, 48))	('associated', 'Reg', (92, 102))
177298	29593425	Nakamura et al described another GATA3 missense variant in the same position (p.C318S; this patient carries p.C318R) without clinical history of cancer.	('cancer', 'Disease', (145, 151))	('patient', 'Species', '9606', (92, 99))	('GATA3', 'Gene', (33, 38))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('p.C318S', 'Mutation', 'p.C318S', (78, 85))	('GATA3', 'Gene', '2625', (33, 38))	('p.C318R', 'Mutation', 'p.C318R', (108, 115))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('p.C318R', 'Var', (108, 115))
177299	29593425	We analyzed a whole blood sample from the patient using polymerase chain reaction-direct sequencing and found that she was carrying the missense variant, p.C318R, in exon 5; however, we were unable to perform further analyses of genetic abnormalities, including of GATA3 in the lung tumor, because the patient refused to give consent.	('GATA3', 'Gene', (265, 270))	('genetic abnormalities', 'Disease', (229, 250))	('lung tumor', 'Phenotype', 'HP:0100526', (278, 288))	('GATA3', 'Gene', '2625', (265, 270))	('p.C318R', 'Var', (154, 161))	('patient', 'Species', '9606', (302, 309))	('tumor', 'Phenotype', 'HP:0002664', (283, 288))	('p.C318R', 'Mutation', 'p.C318R', (154, 161))	('patient', 'Species', '9606', (42, 49))	('lung tumor', 'Disease', (278, 288))	('genetic abnormalities', 'Disease', 'MESH:D030342', (229, 250))	('lung tumor', 'Disease', 'MESH:D008175', (278, 288))
177301	29593425	Our study may provide valuable information regarding the pathogenesis of lung squamous cell carcinoma and indicate that GATA3 mutations may be a potential therapeutic target for lung cancer.	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (73, 101))	('lung cancer', 'Disease', (178, 189))	('lung cancer', 'Phenotype', 'HP:0100526', (178, 189))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (73, 101))	('GATA3', 'Gene', (120, 125))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (78, 101))	('lung squamous cell carcinoma', 'Disease', (73, 101))	('mutations', 'Var', (126, 135))	('lung cancer', 'Disease', 'MESH:D008175', (178, 189))	('GATA3', 'Gene', '2625', (120, 125))
177308	26313362	Interestingly, PD-L1 expression on tumor cells was associated with improved overall survival in pulmonary squamous cell carcinomas (SCC, p = 0.042, log rank test), with adjuvant therapy (p = 0.017), with increased tumor size (pT2-4, p = 0.039) and with positive lymph node status (pN1-3, p = 0.010).	('pulmonary squamous cell carcinomas', 'Disease', (96, 130))	('SCC', 'Gene', (132, 135))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('expression', 'Var', (21, 31))	('carcinomas', 'Phenotype', 'HP:0030731', (120, 130))	('PD-L1', 'Gene', (15, 20))	('tumor', 'Disease', (35, 40))	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('pulmonary squamous cell carcinoma', 'Phenotype', 'HP:0030359', (96, 129))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (106, 130))	('tumor', 'Disease', (214, 219))	('overall survival', 'MPA', (76, 92))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumor', 'Disease', 'MESH:D009369', (214, 219))	('pulmonary squamous cell carcinomas', 'Disease', 'MESH:D002294', (96, 130))	('SCC', 'Gene', '6317', (132, 135))	('improved', 'PosReg', (67, 75))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (106, 129))
177314	26313362	Molecular based therapies targeting epidermal growth factor receptor (EGFR) mutants or ALK rearrangements were shown to improve the outcome within well-defined subgroups of non-squamous cell carcinoma patients.	('patients', 'Species', '9606', (201, 209))	('epidermal growth factor receptor', 'Gene', '1956', (36, 68))	('ALK', 'Gene', '238', (87, 90))	('improve', 'PosReg', (120, 127))	('EGFR', 'Gene', '1956', (70, 74))	('non-squamous cell carcinoma', 'Disease', 'MESH:D002294', (173, 200))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (177, 200))	('carcinoma', 'Phenotype', 'HP:0030731', (191, 200))	('mutants', 'Var', (76, 83))	('EGFR', 'Gene', (70, 74))	('epidermal growth factor receptor', 'Gene', (36, 68))	('ALK', 'Gene', (87, 90))	('non-squamous cell carcinoma', 'Disease', (173, 200))	('rearrangements', 'Var', (91, 105))
177331	26313362	Antibodies against the PD-1-pathway have been successfully applied to reverse T cell tolerance of malignant cells and induce tumor regression.	('reverse', 'NegReg', (70, 77))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('Antibodies', 'Var', (0, 10))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('PD-1-pathway', 'Pathway', (23, 35))	('induce', 'Reg', (118, 124))	('T cell tolerance of malignant cells', 'CPA', (78, 113))	('tumor', 'Disease', (125, 130))
177341	26313362	Patients with stage IV, R1 or R2 resection status or with non-specified tumor histology (e.g.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('R2 resection status', 'Var', (30, 49))	('tumor', 'Disease', (72, 77))	('Patients', 'Species', '9606', (0, 8))	('tumor', 'Disease', 'MESH:D009369', (72, 77))
177359	26313362	In brief, DNA was extracted from FFPE tumor tissues and analyzed for EGFR mutations by Sanger sequencing.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('EGFR', 'Gene', '1956', (69, 73))	('EGFR', 'Gene', (69, 73))	('mutations', 'Var', (74, 83))	('tumor', 'Disease', 'MESH:D009369', (38, 43))
177376	26313362	Subgroup analyses were performed for sex, age, smoking status, performance status, adjuvant therapy, tumor histology, tumor grading, tumor stage, tumor size, lymph node status, Bcl-2 expression, Bcl-xl expression, EGFR mutation status, PD-1 expression in tumor infiltrating lymphocytes and PD-L1 expression in tumor cells.	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('tumor', 'Phenotype', 'HP:0002664', (255, 260))	('tumor', 'Disease', (146, 151))	('expression', 'MPA', (241, 251))	('mutation', 'Var', (219, 227))	('EGFR', 'Gene', '1956', (214, 218))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumor', 'Disease', 'MESH:D009369', (146, 151))	('Bcl-xl', 'Gene', '598', (195, 201))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('Bcl-xl', 'Gene', (195, 201))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('tumor', 'Disease', (255, 260))	('Bcl-2', 'Gene', (177, 182))	('tumor', 'Disease', (310, 315))	('tumor', 'Disease', (133, 138))	('EGFR', 'Gene', (214, 218))	('tumor', 'Disease', 'MESH:D009369', (255, 260))	('tumor', 'Disease', 'MESH:D009369', (310, 315))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('PD-L1', 'Gene', (290, 295))	('tumor', 'Disease', (101, 106))	('Bcl-2', 'Gene', '596', (177, 182))	('tumor', 'Disease', (118, 123))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('PD-1', 'Gene', (236, 240))
177377	26313362	Here, stratified analysis identified PD-L1 expression in NSCLC tumor cells to be associated with improved prognosis for adjuvant therapy (p = 0.017;  Fig 2C ), tumor histology (pulmonary squamous cell carcinoma; p = 0.042;  Fig 2D ), increased tumor size (pT2-4; p = 0.039;  Fig 2E ) and lymph node status (pN1-3; p = 0.010;  Fig 2F ).	('pulmonary squamous cell carcinoma', 'Disease', (177, 210))	('pulmonary squamous cell carcinoma', 'Disease', 'MESH:D002294', (177, 210))	('improved', 'PosReg', (97, 105))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('increased', 'PosReg', (234, 243))	('tumor', 'Phenotype', 'HP:0002664', (244, 249))	('expression', 'Var', (43, 53))	('NSCLC tumor', 'Disease', (57, 68))	('tumor', 'Disease', (63, 68))	('lymph node status', 'CPA', (288, 305))	('PD-L1', 'Gene', (37, 42))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (187, 210))	('NSCLC tumor', 'Disease', 'MESH:D009369', (57, 68))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumor', 'Disease', (160, 165))	('pulmonary squamous cell carcinoma', 'Phenotype', 'HP:0030359', (177, 210))	('carcinoma', 'Phenotype', 'HP:0030731', (201, 210))	('tumor', 'Disease', (244, 249))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('tumor', 'Disease', 'MESH:D009369', (244, 249))
177390	26313362	Tumor infiltration by PD-1 positive lymphocytes was detected in 22% of the tumor samples and 24% of the tumors displayed positivity for PD-L1 with 16 samples (5%) showing synchronous positivity for both.	('PD-1', 'Gene', (22, 26))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('tumor', 'Disease', (104, 109))	('positivity', 'Var', (121, 131))	('PD-L1', 'Gene', (136, 141))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumors', 'Disease', (104, 110))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('Tumor infiltration', 'CPA', (0, 18))	('tumor', 'Disease', (75, 80))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
177399	26313362	While one study group reported PD-L1 expression to be associated with adenocarcinoma histology and another study reported it to be associated with squamous cell carcinoma histology, our correlation anaylsis (Fisher's exact test) supports the latter observation.	('expression', 'Var', (37, 47))	('squamous cell carcinoma', 'Disease', (147, 170))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (147, 170))	('associated', 'Reg', (131, 141))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (147, 170))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('adenocarcinoma', 'Disease', (70, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (161, 170))	('adenocarcinoma', 'Disease', 'MESH:D000230', (70, 84))	('associated', 'Reg', (54, 64))	('PD-L1', 'Gene', (31, 36))
177400	26313362	As shown before, we did not find any association between PD-L1 expression and presence of EGFR mutations.	('EGFR', 'Gene', '1956', (90, 94))	('EGFR', 'Gene', (90, 94))	('PD-L1', 'Gene', (57, 62))	('mutations', 'Var', (95, 104))
177408	26313362	An association between PD-L1 expression with an improved overall survival was found in metastasized malignant melanoma, colorectal cancer, and breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('breast cancer', 'Disease', 'MESH:D001943', (143, 156))	('expression', 'Var', (29, 39))	('PD-L1', 'Gene', (23, 28))	('colorectal cancer', 'Disease', (120, 137))	('breast cancer', 'Disease', (143, 156))	('improved', 'PosReg', (48, 56))	('malignant melanoma', 'Phenotype', 'HP:0002861', (100, 118))	('breast cancer', 'Phenotype', 'HP:0003002', (143, 156))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('malignant melanoma', 'Disease', 'MESH:D008545', (100, 118))	('malignant melanoma', 'Disease', (100, 118))	('colorectal cancer', 'Disease', 'MESH:D015179', (120, 137))	('colorectal cancer', 'Phenotype', 'HP:0003003', (120, 137))	('overall', 'MPA', (57, 64))
177413	26313362	With respect to therapeutic interventions, inhibition of PD-1/PD-L1 is expected to become a powerful therapeutic alternative for NSCLC.	('NSCLC', 'Disease', (129, 134))	('inhibition', 'Var', (43, 53))	('PD-1/PD-L1', 'Gene', (57, 67))	('NSCLC', 'Disease', 'MESH:D002289', (129, 134))
177415	26313362	The latter study argues in favour of the evaluation of PD-L1 expression as a selective biomarker, and the analysis of PD-L1 in NSCLC could serve as predictor for response to PD-1 pathway inhibition and additionally as a prognostic marker for improved clinical outcome.	('NSCLC', 'Disease', (127, 132))	('PD-L1', 'Gene', (118, 123))	('analysis', 'Var', (106, 114))	('NSCLC', 'Disease', 'MESH:D002289', (127, 132))	('PD-1 pathway', 'Pathway', (174, 186))	('PD-L1', 'Gene', (55, 60))
177441	26156524	This result implies that highly correlated BiTM regulations might result in a complete loss or gain during tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('loss or gain', 'Disease', (87, 99))	('loss or gain', 'Disease', 'MESH:D015430', (87, 99))	('BiTM regulations', 'Var', (43, 59))
177442	26156524	In other words, the gain or loss of BiTM regulations with biologically meaningful regulatory activity may be associated with cancer development.	('gain', 'PosReg', (20, 24))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('BiTM regulations', 'Var', (36, 52))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('loss', 'NegReg', (28, 32))
177450	26156524	Notably, the cancer-associated TFs used in this study are integrally involved in cancers through mutation.	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('cancers', 'Phenotype', 'HP:0002664', (81, 88))	('involved', 'Reg', (69, 77))	('cancer', 'Disease', (81, 87))	('cancers', 'Disease', (81, 88))	('cancer', 'Disease', (13, 19))	('cancer', 'Disease', 'MESH:D009369', (13, 19))	('cancers', 'Disease', 'MESH:D009369', (81, 88))	('mutation', 'Var', (97, 105))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))
177451	26156524	A reasonable scenario is that these cancer-associated TFs are involved in cancer development via their mutations rather than through differential regulatory activity.	('mutations', 'Var', (103, 112))	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Disease', (36, 42))	('cancer', 'Disease', (74, 80))	('involved', 'Reg', (62, 70))	('TFs', 'Gene', (54, 57))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
177455	26156524	This observation further indicates that the mutations of these cancer-associated TFs might also influence their regulatory activity in cancer development.	('cancer', 'Disease', (135, 141))	('cancer', 'Disease', 'MESH:D009369', (135, 141))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('mutations', 'Var', (44, 53))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('influence', 'Reg', (96, 105))	('TFs', 'Gene', (81, 84))	('cancer', 'Disease', (63, 69))
177461	26156524	We found that STAT1-miR-155-5p ranked the first in DC BiTM regulations across seven cancer types.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('STAT1-miR-155-5p', 'Var', (14, 30))	('cancer', 'Disease', (84, 90))
177462	26156524	That is, STAT1 and miR-155-5p are highly differentially co-expressed in all the seven cancer types.	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('STAT1', 'Gene', (9, 14))	('miR-155-5p', 'Var', (19, 29))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('cancer', 'Disease', (86, 92))
177469	26156524	As we mentioned, STAT1 significantly and positively correlated with miR-155-5p in tumor samples across the seven studied cancer types.	('correlated', 'Reg', (52, 62))	('STAT1', 'Gene', (17, 22))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('miR-155-5p', 'Var', (68, 78))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('tumor', 'Disease', (82, 87))	('cancer', 'Disease', (121, 127))
177471	26156524	To investigate if losing the equilibrium controlled by the feedback loop of STAT1 and miR-155-5p is involved in tumorigenesis, we explored the STAT1 regulatory functional modules in tumor samples (Supporting Information S4).	('miR-155-5p', 'Var', (86, 96))	('tumor', 'Disease', (182, 187))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('tumor', 'Disease', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
177473	26156524	That is, the selected target genes could be activated by STAT1 in a tumor.	('tumor', 'Disease', (68, 73))	('STAT1', 'Var', (57, 62))	('activated', 'PosReg', (44, 53))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))
177486	26156524	Based on the results above, we proposed a hypothesis on how the losing equilibrium of the regulatory feedback loop between STAT1 and miR-155-5p influences tumorigenesis (Fig.	('STAT1', 'Gene', (123, 128))	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('influences', 'Reg', (144, 154))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('tumor', 'Disease', (155, 160))	('miR-155-5p', 'Var', (133, 143))
177489	26156524	During tumorigenesis, tumor cells that are genetically unstable and mutated promptly produce abundant variants.	('variants', 'Var', (102, 110))	('tumor', 'Disease', (7, 12))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('tumor', 'Disease', (22, 27))	('tumor', 'Disease', 'MESH:D009369', (7, 12))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
177490	26156524	Under immune selection pressure, many tumor cells were destroyed, but new tumor variants with distinct mutations that increased tumor immune resistance could survive.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('mutations', 'Var', (103, 112))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('increased', 'PosReg', (118, 127))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('tumor', 'Disease', (74, 79))	('tumor', 'Disease', (128, 133))
177494	26156524	Collectively, our findings suggest that the disequilibrium of the regulatory feedback loop between STAT1 and miR-155-5p might trigger cancer immunoediting in order to allow tumor cells to escape from immunosurveillance and even to promote tumorigenesis.	('allow', 'Reg', (167, 172))	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('promote', 'PosReg', (231, 238))	('escape', 'CPA', (188, 194))	('tumor', 'Disease', 'MESH:D009369', (239, 244))	('disequilibrium', 'Var', (44, 58))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('tumor', 'Phenotype', 'HP:0002664', (239, 244))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumor', 'Disease', (173, 178))	('trigger', 'Reg', (126, 133))	('tumor', 'Disease', (239, 244))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('miR-155-5p', 'Var', (109, 119))	('STAT1', 'Gene', (99, 104))
177517	26156524	Regulation rewiring analysis reveals mutual regulation between STAT1 and miR-155-5p in tumor immunosurveillance in seven major cancers.	('STAT1', 'Gene', (63, 68))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('mutual regulation', 'Reg', (37, 54))	('tumor', 'Disease', (87, 92))	('miR-155-5p', 'Var', (73, 83))	('cancers', 'Disease', 'MESH:D009369', (127, 134))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('cancers', 'Phenotype', 'HP:0002664', (127, 134))	('cancers', 'Disease', (127, 134))
177527	33029471	Thus, inhibition of this interaction via anti-PD-1 or anti-PD-L1 monoclonal antibodies is an effective therapy for tumor regression.	('anti-PD-L1', 'Gene', (54, 64))	('anti-PD-1', 'Protein', (41, 50))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('interaction', 'Interaction', (25, 36))	('tumor', 'Disease', (115, 120))	('inhibition', 'Var', (6, 16))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
177565	32884341	ZFAS1 overexpression improved OSCC cell growth and inhibited OSCC cell susceptibility to DDP.	('DDP', 'Chemical', '-', (89, 92))	('improved', 'PosReg', (21, 29))	('overexpression', 'Var', (6, 20))	('OSCC', 'Disease', (30, 34))	('OSCC', 'Disease', (61, 65))	('ZFAS1', 'Gene', (0, 5))	('inhibited', 'NegReg', (51, 60))
177566	32884341	In addition, the silencing of ZFAS1 promoted DDP-induced apoptosis.	('DDP', 'Chemical', '-', (45, 48))	('DDP-induced', 'Disease', (45, 56))	('ZFAS1', 'Gene', (30, 35))	('silencing', 'Var', (17, 26))	('promoted', 'PosReg', (36, 44))
177567	32884341	Inhibition of miR-421 reversed the effect of si-ZFAS1, which promoted the cell viability and decreased the sensitivity of DDP in DDP-resistant cells.	('DDP', 'Chemical', '-', (122, 125))	('promoted', 'PosReg', (61, 69))	('decreased', 'NegReg', (93, 102))	('si-ZFAS1', 'Var', (45, 53))	('sensitivity of DDP', 'MPA', (107, 125))	('cell viability', 'CPA', (74, 88))	('DDP', 'Chemical', '-', (129, 132))
177579	32884341	In cervical cancer, silencing ZFAS1 inhibits cell migration, invasion and proliferation as well as enhances cisplatin chemosensitivity.	('cisplatin chemosensitivity', 'MPA', (108, 134))	('cell migration', 'CPA', (45, 59))	('cervical cancer', 'Disease', 'MESH:D002583', (3, 18))	('cisplatin', 'Chemical', 'MESH:D002945', (108, 117))	('invasion', 'CPA', (61, 69))	('cervical cancer', 'Disease', (3, 18))	('ZFAS1', 'Gene', (30, 35))	('inhibits', 'NegReg', (36, 44))	('enhances', 'PosReg', (99, 107))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('proliferation', 'CPA', (74, 87))	('silencing', 'Var', (20, 29))
177580	32884341	Meanwhile, ZFAS1 is corresponding to the Adriamycin-resistant phenotype of T-cell acute lymphoblastic leukemia cell lines.	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (88, 110))	('lymphoblastic leukemia', 'Disease', 'MESH:D054198', (88, 110))	('Adriamycin', 'Chemical', 'MESH:D004317', (41, 51))	('T-cell acute lymphoblastic leukemia', 'Phenotype', 'HP:0006727', (75, 110))	('ZFAS1', 'Var', (11, 16))	('lymphoblastic leukemia', 'Disease', (88, 110))	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (82, 110))	('leukemia', 'Phenotype', 'HP:0001909', (102, 110))
177584	32884341	Meanwhile, miR-421 was demonstrated to target to 3'UTR of MEIS2 and to promote OSCC apoptosis.	('OSCC apoptosis', 'CPA', (79, 93))	('promote', 'PosReg', (71, 78))	('miR-421', 'Var', (11, 18))	('MEIS2', 'Gene', (58, 63))	('UTR', 'Gene', '2837', (51, 54))	('UTR', 'Gene', (51, 54))
177613	32884341	CAL-27/DDP cells with sh-ZFAS1 knockdown were dispersed in 100 muL medium.	('sh-ZFAS1', 'Gene', (22, 30))	('DDP', 'Chemical', '-', (7, 10))	('knockdown', 'Var', (31, 40))
177625	32884341	We performed CCK-8 assays after transfecting cells with ZFAS1 over-expressing plasmid, and the results exhibited that OSCC cell growth was markedly improved by ZFAS1 overexpression (Figure 2E).	('overexpression', 'Var', (166, 180))	('improved', 'PosReg', (148, 156))	('ZFAS1', 'Gene', (160, 165))	('CCK-8', 'Chemical', 'MESH:D012844', (13, 18))	('OSCC cell growth', 'CPA', (118, 134))
177628	32884341	Regarding the above results, silencing of ZFAS1 dramatically enhanced OSCC cell susceptibility to DDP, we further verified the anti-apoptotic role of ZFAS1 in DDP-resistant OSCC cells.	('OSCC', 'Disease', (70, 74))	('DDP', 'Chemical', '-', (98, 101))	('enhanced', 'PosReg', (61, 69))	('silencing', 'Var', (29, 38))	('DDP', 'Chemical', '-', (159, 162))	('ZFAS1', 'Gene', (42, 47))	('susceptibility to DDP', 'MPA', (80, 101))
177629	32884341	Through the flow cytometry results, we discovered that apoptosis induced by DDP in DDP-resistant OSCC cells (Figure 2H) was markedly augmented by si-ZFAS1.	('DDP', 'Var', (76, 79))	('DDP', 'Chemical', '-', (83, 86))	('DDP', 'Chemical', '-', (76, 79))	('si-ZFAS1', 'Var', (146, 154))	('apoptosis', 'CPA', (55, 64))	('augmented', 'PosReg', (133, 142))
177631	32884341	After silencing ZFAS1, the activity of caspase-3 was significantly elevated, which mirrored the results of the increased apoptotic ratio (Figure 2I).	('elevated', 'PosReg', (67, 75))	('caspase-3', 'Gene', (39, 48))	('ZFAS1', 'Gene', (16, 21))	('silencing', 'Var', (6, 15))	('caspase-3', 'Gene', '836', (39, 48))	('activity', 'MPA', (27, 35))
177633	32884341	These results indicated that the silencing of ZFAS1 promoted DDP-induced apoptosis in DDP-resistant OSCC cells treated with DDP.	('DDP', 'Chemical', '-', (61, 64))	('ZFAS1', 'Gene', (46, 51))	('DDP-induced', 'Disease', (61, 72))	('DDP', 'Chemical', '-', (86, 89))	('DDP', 'Chemical', '-', (124, 127))	('silencing', 'Var', (33, 42))	('promoted', 'PosReg', (52, 60))
177639	32884341	The results revealed that the proliferation of DDP-resistant OSCC cells was significantly reduced by si-ZFAS1, and anti-miR-421 could abolish this effect (Figure 3E and F).	('DDP', 'Chemical', '-', (47, 50))	('si-ZFAS1', 'Var', (101, 109))	('proliferation of DDP-resistant OSCC cells', 'CPA', (30, 71))	('reduced', 'NegReg', (90, 97))
177640	32884341	Meanwhile, anti-miR-421 significantly promoted the cell viability of DDP-resistant cells with the treatment of DDP.	('anti-miR-421', 'Gene', (11, 23))	('cell viability of DDP-resistant cells', 'CPA', (51, 88))	('DDP', 'Chemical', '-', (69, 72))	('DDP', 'Var', (111, 114))	('DDP', 'Chemical', '-', (111, 114))	('promoted', 'PosReg', (38, 46))
177643	32884341	Additionally, we also found that the caspase-3 activity (Figure 3J) and Bax expression (Figure 3K) was decreased while BCL2 expression (Figure 3K) was increased by anti-miR-421 Base-pair matching with the 3' untranslated region (3'UTR) of target mRNA transcripts was used to regulate gene expression by miRNAs.	('UTR', 'Gene', '2837', (231, 234))	('increased', 'PosReg', (151, 160))	('BCL2', 'Gene', (119, 123))	('UTR', 'Gene', (231, 234))	('caspase-3', 'Gene', (37, 46))	('anti-miR-421', 'Var', (164, 176))	('decreased', 'NegReg', (103, 112))	('Bax', 'Gene', '581', (72, 75))	('expression', 'MPA', (76, 86))	('expression', 'MPA', (124, 134))	('caspase-3', 'Gene', '836', (37, 46))	('BCL2', 'Gene', '596', (119, 123))	('activity', 'MPA', (47, 55))	('Bax', 'Gene', (72, 75))
177645	32884341	We detected an elevation of MEIS2 after transfected with MEIS2 in DDP-resistant OSCC cells.	('elevation', 'PosReg', (15, 24))	('DDP', 'Chemical', '-', (66, 69))	('MEIS2', 'Gene', (57, 62))	('MEIS2', 'Gene', (28, 33))	('transfected', 'Var', (40, 51))
177648	32884341	DDP-resistant cell line with stable ZFAS1 deficiency was injected into mice to construct an animal model with ZFAS1 down-regulation.	('mice', 'Species', '10090', (71, 75))	('ZFAS1', 'Gene', (110, 115))	('DDP', 'Chemical', '-', (0, 3))	('deficiency', 'Var', (42, 52))	('down-regulation', 'NegReg', (116, 131))	('ZFAS1', 'Gene', (36, 41))
177649	32884341	The results showed that DDP significantly reduced the tumor volume and tumor weight, both of which were further inhibited by si-ZFAS1 (Figure 4D-F).	('reduced', 'NegReg', (42, 49))	('DDP', 'Var', (24, 27))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('DDP', 'Chemical', '-', (24, 27))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('si-ZFAS1', 'Var', (125, 133))	('tumor', 'Disease', (54, 59))	('tumor', 'Disease', (71, 76))
177650	32884341	To sum up, we demonstrated that inhibition of ZFAS1 enhanced the sensitivity to DDP in vivo.	('ZFAS1', 'Gene', (46, 51))	('inhibition', 'Var', (32, 42))	('enhanced', 'PosReg', (52, 60))	('DDP', 'Chemical', '-', (80, 83))	('sensitivity to DDP', 'MPA', (65, 83))
177666	32884341	Here in our study, we revealed that OSCC cell growth was markedly improved by ZFAS1 overexpression and caused higher cell viability in DDP-resistant cells.	('cell viability', 'CPA', (117, 131))	('OSCC', 'Disease', (36, 40))	('improved', 'PosReg', (66, 74))	('ZFAS1', 'Gene', (78, 83))	('overexpression', 'Var', (84, 98))	('DDP', 'Chemical', '-', (135, 138))	('higher', 'PosReg', (110, 116))
177671	32884341	In gastric cancer, miR-421 was reported to promote metastasis, inhibit apoptosis, and induce cisplatin resistance.	('metastasis', 'CPA', (51, 61))	('gastric cancer', 'Phenotype', 'HP:0012126', (3, 17))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('apoptosis', 'CPA', (71, 80))	('promote', 'PosReg', (43, 50))	('cisplatin', 'Chemical', 'MESH:D002945', (93, 102))	('miR-421', 'Var', (19, 26))	('induce', 'PosReg', (86, 92))	('gastric cancer', 'Disease', 'MESH:D013274', (3, 17))	('cisplatin resistance', 'MPA', (93, 113))	('gastric cancer', 'Disease', (3, 17))	('inhibit', 'NegReg', (63, 70))
177672	32884341	In accordance, we discovered that anti-miR-421 inhibited the sensitivity of DDP-resistant cells to DDP, which is characterized by enhanced proliferation and decreased apoptosis in DDP-resistant OSCC cells.	('enhanced', 'PosReg', (130, 138))	('inhibited', 'NegReg', (47, 56))	('apoptosis', 'CPA', (167, 176))	('anti-miR-421', 'Var', (34, 46))	('DDP', 'Chemical', '-', (76, 79))	('DDP', 'Chemical', '-', (180, 183))	('sensitivity', 'MPA', (61, 72))	('decreased', 'NegReg', (157, 166))	('DDP', 'Chemical', '-', (99, 102))
177677	32884341	In vivo experiments also showed inhibition of ZFAS1 enhanced the sensitivity to DDP, evidenced by decreased tumor volume and weight.	('ZFAS1', 'Gene', (46, 51))	('inhibition', 'Var', (32, 42))	('decreased tumor', 'Disease', 'MESH:D002303', (98, 113))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('enhanced', 'PosReg', (52, 60))	('DDP', 'Chemical', '-', (80, 83))	('sensitivity to DDP', 'MPA', (65, 83))	('decreased tumor', 'Disease', (98, 113))
177797	29625594	Loss of SMARCB1 protein expression has been reported to be associated with atypical teratoid/rhabdoid tumors and malignant rhabdoid tumors of the kidney and extrarenal tissues.	('rhabdoid tumors', 'Disease', 'MESH:D018335', (93, 108))	('SMARCB1', 'Gene', '6598', (8, 15))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('SMARCB1', 'Gene', (8, 15))	('malignant rhabdoid tumors of the kidney', 'Disease', (113, 152))	('rhabdoid tumors', 'Disease', 'MESH:D018335', (123, 138))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumors of the kidney', 'Phenotype', 'HP:0009726', (132, 152))	('associated', 'Reg', (59, 69))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('protein', 'Protein', (16, 23))	('malignant rhabdoid tumors of the kidney', 'Disease', 'MESH:D018335', (113, 152))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('Loss', 'Var', (0, 4))	('rhabdoid tumors', 'Disease', (93, 108))
177807	29625594	Loss of SMARCB1 expression has been reported to be associated with atypical teratoid / rhabdoid tumors (AT / RT) and malignant rhabdoid tumors (MRTs) of the kidney and extrarenal tissues.	('SMARCB1', 'Gene', '6598', (8, 15))	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('SMARCB1', 'Gene', (8, 15))	('rhabdoid tumors', 'Disease', 'MESH:D018335', (87, 102))	('malignant rhabdoid tumors', 'Disease', (117, 142))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('associated', 'Reg', (51, 61))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('rhabdoid tumors', 'Disease', 'MESH:D018335', (127, 142))	('rhabdoid tumors', 'Disease', (87, 102))	('Loss', 'Var', (0, 4))	('malignant rhabdoid tumors', 'Disease', 'MESH:D018335', (117, 142))	('AT', 'Disease', 'None', (104, 106))
177808	29625594	Furthermore sinonasal basaloid carcinomas and neoplasms arising from the gastrointestinal tract, pancreas and uterus with SMARCB1 deficiency have been reported.	('neoplasms', 'Phenotype', 'HP:0002664', (46, 55))	('pancreas', 'Disease', 'MESH:D010190', (97, 105))	('neoplasms arising from the gastrointestinal tract', 'Phenotype', 'HP:0007378', (46, 95))	('deficiency', 'Var', (130, 140))	('sinonasal basaloid carcinomas', 'Disease', (12, 41))	('carcinomas', 'Phenotype', 'HP:0030731', (31, 41))	('basaloid carcinomas', 'Phenotype', 'HP:0002671', (22, 41))	('gastrointestinal tract', 'Disease', 'MESH:D004067', (73, 95))	('neoplasms', 'Disease', 'MESH:D009369', (46, 55))	('neoplasms', 'Disease', (46, 55))	('sinonasal basaloid carcinomas', 'Disease', 'MESH:C537344', (12, 41))	('SMARCB1', 'Gene', '6598', (122, 129))	('pancreas', 'Disease', (97, 105))	('SMARCB1', 'Gene', (122, 129))	('gastrointestinal tract', 'Disease', (73, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (31, 40))
177824	29625594	The sequence result showed copy number loss of SMARCB1 gene in this tumor (Fig.	('tumor', 'Disease', (68, 73))	('SMARCB1', 'Gene', '6598', (47, 54))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('SMARCB1', 'Gene', (47, 54))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('copy number loss', 'Var', (27, 43))
177825	29625594	And another next-generation sequencing assay (Agilent SureSelect NCC oncopanel) revealed no other common oncogene mutations, such as epidermal growth factor receptor (EGFR) mutation, anaplastic lymphoma kinase (ALK), RET or ROS1 rearrangements.	('anaplastic lymphoma kinase', 'Gene', (183, 209))	('lymphoma', 'Phenotype', 'HP:0002665', (194, 202))	('RET', 'Gene', '5979', (217, 220))	('ROS1', 'Gene', (224, 228))	('epidermal growth factor receptor', 'Gene', '1956', (133, 165))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (183, 202))	('ROS1', 'Gene', '6098', (224, 228))	('ALK', 'Gene', '238', (211, 214))	('anaplastic lymphoma kinase', 'Gene', '238', (183, 209))	('rearrangements', 'Var', (229, 243))	('RET', 'Gene', (217, 220))	('EGFR', 'Gene', '1956', (167, 171))	('ALK', 'Gene', (211, 214))	('epidermal growth factor receptor', 'Gene', (133, 165))	('EGFR', 'Gene', (167, 171))	('mutation', 'Var', (173, 181))
177826	29625594	We demonstrated squamous cell carcinoma of that pleura which was characterized by SMARCB1 deficiency.	('SMARCB1', 'Gene', '6598', (82, 89))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (16, 39))	('SMARCB1', 'Gene', (82, 89))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (16, 39))	('deficiency', 'Var', (90, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (30, 39))	('squamous cell carcinoma', 'Disease', (16, 39))
177830	29625594	Specific SMARCB1 biallelic inactivating mutations were discovered in majority cases of malignant rhabdoid tumors (MRTs).	('biallelic inactivating mutations', 'Var', (17, 49))	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('SMARCB1', 'Gene', '6598', (9, 16))	('SMARCB1', 'Gene', (9, 16))	('malignant rhabdoid tumors', 'Disease', (87, 112))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('malignant rhabdoid tumors', 'Disease', 'MESH:D018335', (87, 112))
177831	29625594	Thereafter SMARCB1 gene alternations were identified in other malignant tumors, such as epithelioid sarcoma, myoepithelial carcinoma.	('identified', 'Reg', (42, 52))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('sarcoma', 'Phenotype', 'HP:0100242', (100, 107))	('myoepithelial carcinoma', 'Disease', 'MESH:D009208', (109, 132))	('myoepithelial carcinoma', 'Disease', (109, 132))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('epithelioid sarcoma', 'Disease', 'MESH:D012509', (88, 107))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('SMARCB1', 'Gene', '6598', (11, 18))	('malignant tumors', 'Disease', (62, 78))	('epithelioid sarcoma', 'Disease', (88, 107))	('alternations', 'Var', (24, 36))	('SMARCB1', 'Gene', (11, 18))	('malignant tumors', 'Disease', 'MESH:D018198', (62, 78))
177862	29625594	Recently, epigenetic approaches have been reported as a therapeutic potential for SMARCB1-deficient tumors.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('SMARCB1-deficient tumors', 'Disease', 'MESH:D009369', (82, 106))	('SMARCB1-deficient tumors', 'Disease', (82, 106))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('epigenetic approaches', 'Var', (10, 31))
177864	29625594	In vivo tumor models, inactivation of EZH2 blocked tumorigenesis driven by SMARCB1 loss, completely .	('inactivation', 'Var', (22, 34))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('EZH2', 'Gene', '2146', (38, 42))	('SMARCB1', 'Gene', '6598', (75, 82))	('tumor', 'Disease', (51, 56))	('blocked', 'NegReg', (43, 50))	('SMARCB1', 'Gene', (75, 82))	('EZH2', 'Gene', (38, 42))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('tumor', 'Disease', (8, 13))	('loss', 'NegReg', (83, 87))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
177865	29625594	And a preclinical study has reported that EZH2 inhibitors can inhibit MRT cell proliferation efficiently.	('MRT cell proliferation', 'CPA', (70, 92))	('inhibitors', 'Var', (47, 57))	('EZH2', 'Gene', '2146', (42, 46))	('EZH2', 'Gene', (42, 46))	('inhibit', 'NegReg', (62, 69))
177873	29422656	Importantly, we show that AK methylation patterns already display classical features of cancer methylomes and are highly similar to cSCC profiles.	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('cSCC', 'Disease', (132, 136))	('methylation patterns', 'Var', (29, 49))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('AK', 'Phenotype', 'HP:0025127', (26, 28))	('cSCC', 'Phenotype', 'HP:0006739', (132, 136))
177879	29422656	However, AK samples already harbor mutations in the same genes that are found mutated in metastatic and aggressive cSCC, such as TP53, NOTCH1-2, FAT1, or MLL2.	('NOTCH1', 'Gene', (135, 141))	('MLL2', 'Gene', '8085', (154, 158))	('NOTCH1', 'Gene', '4851', (135, 141))	('cSCC', 'Phenotype', 'HP:0006739', (115, 119))	('FAT1', 'Gene', '2195', (145, 149))	('FAT1', 'Gene', (145, 149))	('aggressive', 'CPA', (104, 114))	('TP53', 'Gene', '7157', (129, 133))	('metastatic', 'Disease', (89, 99))	('MLL2', 'Gene', (154, 158))	('TP53', 'Gene', (129, 133))	('AK', 'Phenotype', 'HP:0025127', (9, 11))	('mutations', 'Var', (35, 44))
177884	29422656	The deregulation of the normal methylome is a major hallmark of human cancers and frequently characterized by global hypomethylation of lamina-associated domains (LAD) as well as widespread CpG island promoter hypermethylation.	('deregulation', 'Var', (4, 16))	('hallmark of human cancers', 'Disease', (52, 77))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('hypomethylation', 'Var', (117, 132))	('hallmark of human cancers', 'Disease', 'MESH:D009369', (52, 77))	('cancers', 'Phenotype', 'HP:0002664', (70, 77))
177886	29422656	Our current knowledge about epigenetic changes associated with cSCC is very limited and mostly comprises a moderate number of cancer-associated genes that become silenced by CpG island promoter hypermethylation.	('cSCC', 'Disease', (63, 67))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('silenced', 'NegReg', (162, 170))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('hypermethylation', 'Var', (194, 210))	('cSCC', 'Phenotype', 'HP:0006739', (63, 67))
177888	29422656	Finally, with respect to the transition between AK and cSCC, it has been suggested that CDH1 promoter hypermethylation might increase from normal skin to AK and cSCC, and that the silencing of miR-204 might play a role in the progression from AK to cSCC.	('CDH1', 'Gene', '999', (88, 92))	('AK', 'Phenotype', 'HP:0025127', (154, 156))	('play', 'Reg', (207, 211))	('cSCC', 'Phenotype', 'HP:0006739', (249, 253))	('AK', 'Phenotype', 'HP:0025127', (243, 245))	('AK', 'Phenotype', 'HP:0025127', (48, 50))	('increase', 'PosReg', (125, 133))	('cSCC', 'Disease', (249, 253))	('silencing', 'Var', (180, 189))	('cSCC', 'Phenotype', 'HP:0006739', (161, 165))	('CDH1', 'Gene', (88, 92))	('miR-204', 'Gene', '406987', (193, 200))	('promoter hypermethylation', 'MPA', (93, 118))	('miR-204', 'Gene', (193, 200))	('cSCC', 'Phenotype', 'HP:0006739', (55, 59))
177892	29422656	Cancer methylomes are often characterized by specific features, such as hypomethylated lamina-associated domains (LADs) and hypermethylated CpG islands.	('hypomethylated', 'Var', (72, 86))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('hypermethylated', 'Var', (124, 139))
177896	29422656	Non-CpG methylation has been closely associated with the DNMT3B DNA methyltransferase, which also represents an important epidermal stem cell gene.	('DNMT3B', 'Gene', (57, 63))	('DNMT3B', 'Gene', '1789', (57, 63))	('Non-CpG methylation', 'Var', (0, 19))	('associated', 'Reg', (37, 47))	('methylation', 'Var', (8, 19))
177906	29422656	Altered DNA methylation patterns are considered a classical hallmark of cancer, but their precise significance and functional relevance for tumorigenesis are still not completely understood.	('cancer', 'Disease', (72, 78))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('Altered', 'Var', (0, 7))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('DNA methylation', 'MPA', (8, 23))	('tumor', 'Disease', (140, 145))
177908	29422656	Our observation that AK methylomes display typical cancer-related features, such as CpG island hypermethylation and LAD hypomethylation may indicate a significant malignant potential of AK.	('AK', 'Phenotype', 'HP:0025127', (21, 23))	('hypomethylation', 'Var', (120, 135))	('LAD', 'MPA', (116, 119))	('CpG', 'Protein', (84, 87))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('AK', 'Phenotype', 'HP:0025127', (186, 188))	('malignant potential', 'CPA', (163, 182))	('indicate', 'Reg', (140, 148))	('hypermethylation', 'Var', (95, 111))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))
177909	29422656	This is consistent with previous reports showing that both AK and cSCC share mutations in key genes associated with cancer development and progression.	('AK', 'Phenotype', 'HP:0025127', (59, 61))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('cSCC', 'Gene', (66, 70))	('mutations', 'Var', (77, 86))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cSCC', 'Phenotype', 'HP:0006739', (66, 70))
177919	29422656	Primary antibodies and dilutions used to detect the different markers were as follows: p63 (790-4509, Ventana Medical Systems; 0.140 microg mL-1), keratin K5 (790-4554, Ventana Medical Systems; 10.4 microg mL-1) and keratin K14 (760-4805, Ventana Medical Systems; 1-5 microg mL-1).	('K14', 'Gene', (224, 227))	('p63', 'Gene', '8626', (87, 90))	('790-4509', 'Var', (92, 100))	('p63', 'Gene', (87, 90))	('K14', 'Gene', '3861', (224, 227))	('790-4554', 'Var', (159, 167))	('760-4805', 'Var', (229, 237))
177927	29422656	Single-nucleotide variations (SNVs) and insertions/deletions (indels) were called using an in-house workflow, based on SAMtools/BCFtools 0.1.19 (for SNVs) and Platypus 0.8.1 (for indels).	('Platypus', 'Species', '9258', (159, 167))	('Single-nucleotide', 'Var', (0, 17))	('insertions/deletions', 'Var', (40, 60))
177953	32405341	On the other hand, Chr X has the least peak density of around 80 PPMB, likely due to the inactivation of X chromosome via DNA methylation.	('PPMB', 'Chemical', '-', (65, 69))	('X chromosome', 'Protein', (105, 117))	('inactivation', 'Var', (89, 101))
177989	32405341	Two known GWAS single nucleotide polymorphisms rs113692904 and rs75027116 were also found in this region.	('rs75027116', 'Mutation', 'rs75027116', (63, 73))	('rs113692904', 'Mutation', 'rs113692904', (47, 58))	('rs113692904', 'Var', (47, 58))	('rs75027116', 'Var', (63, 73))
178003	32405341	It is known that germline mutation of BRCA1 is a risk factor for ovarian and breast cancer and BRCA1 carrier is sensitive to drugs that targeted the DNA damage and repair pathway.	('DNA damage and', 'Pathway', (149, 163))	('BRCA1', 'Gene', (95, 100))	('breast cancer', 'Phenotype', 'HP:0003002', (77, 90))	('ovarian and breast cancer', 'Disease', 'MESH:D001943', (65, 90))	('BRCA1', 'Gene', (38, 43))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('risk', 'Reg', (49, 53))	('germline mutation', 'Var', (17, 34))	('BRCA1', 'Gene', '672', (95, 100))	('BRCA1', 'Gene', '672', (38, 43))
178008	32405341	Instead of copy-number amplification, KRAS is frequently mutated in a wide array of tumors including lung cancer and pancreatic cancer.	('KRAS', 'Gene', '3845', (38, 42))	('lung cancer', 'Disease', 'MESH:D008175', (101, 112))	('pancreatic cancer', 'Disease', 'MESH:D010190', (117, 134))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('pancreatic cancer', 'Disease', (117, 134))	('lung cancer', 'Phenotype', 'HP:0100526', (101, 112))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('tumors', 'Disease', (84, 90))	('tumors', 'Disease', 'MESH:D009369', (84, 90))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (117, 134))	('mutated', 'Var', (57, 64))	('lung cancer', 'Disease', (101, 112))	('KRAS', 'Gene', (38, 42))
178060	30127774	In silico metagenomic and pathway analyses show that presence of microcystin correlates with reduced CD36 and increased PARP1 levels.	('CD36', 'Gene', (101, 105))	('CD36', 'Gene', '948', (101, 105))	('increased', 'PosReg', (110, 119))	('microcystin', 'Chemical', 'MESH:C078588', (65, 76))	('reduced', 'NegReg', (93, 100))	('presence', 'Var', (53, 61))	('PARP1', 'Gene', '142', (120, 125))	('PARP1', 'Gene', (120, 125))	('microcystin', 'Gene', (65, 76))
178185	30127774	The best hits of all consensus sequences are 16S rRNA of "Uncultured cyanobacterium" (GQ502588.1, FJ024312.1, KU667126.1 and KM892905.1) with identity >92% and p-value < 1.57e-178.	('GQ502588.1', 'Var', (86, 96))	('FJ024312.1', 'Var', (98, 108))	('Uncultured cyanobacterium', 'Species', '1211', (58, 83))	('KM892905.1', 'Var', (125, 135))	('KU667126.1', 'Var', (110, 120))	('N', 'Chemical', 'MESH:D009584', (51, 52))
178236	30127774	Therefore, inhibition of PARP1 expression in combination with other therapeutic regimens should be considered in management and treatment of lung cancer and other forms of cancer (Wang et al.,).	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('PARP1', 'Gene', '142', (25, 30))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('PARP1', 'Gene', (25, 30))	('lung cancer', 'Disease', (141, 152))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('lung cancer', 'Phenotype', 'HP:0100526', (141, 152))	('inhibition', 'Var', (11, 21))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('cancer', 'Disease', (172, 178))	('lung cancer', 'Disease', 'MESH:D008175', (141, 152))
178251	30127774	These changes may alter the quality of water and air that may affect the health of Arkansans.	('affect', 'Reg', (62, 68))	('water', 'Chemical', 'MESH:D014867', (39, 44))	('changes', 'Var', (6, 13))	('alter', 'Reg', (18, 23))	('health', 'MPA', (73, 79))
178274	30127774	Additional homology studies showed the Cyanobacteria sequences identified in LUAD had 92% homology to "uncultured cyanobacterium" (GQ502588.1, FJ024312.1, KU667126.1, and KM892905.1) that are in the Cyanobacteria/Melainabacteria group, Taxonomy ID: 1211.	('GQ502588.1', 'Var', (131, 141))	('FJ024312.1', 'Var', (143, 153))	('C', 'Chemical', 'MESH:D002244', (39, 40))	('Cyanobacteria/Melainabacteria group', 'Species', '1798711', (199, 234))	('uncultured cyanobacterium', 'Species', '1211', (103, 128))	('C', 'Chemical', 'MESH:D002244', (199, 200))
178300	30127774	Chronic inflammation can contribute to carcinogenesis through induction of genomic instability, alterations in epigenetic events and subsequent aberrant gene expression, enhanced proliferation of initiated cells and resistance to apoptosis (due to smoking).	('proliferation', 'CPA', (179, 192))	('genomic instability', 'MPA', (75, 94))	('epigenetic', 'Protein', (111, 121))	('aberrant', 'Var', (144, 152))	('carcinogenesis', 'Disease', (39, 53))	('Chronic inflammation', 'Disease', (0, 20))	('Chronic inflammation', 'Disease', 'MESH:D007249', (0, 20))	('induction', 'Reg', (62, 71))	('contribute', 'Reg', (25, 35))	('enhanced', 'PosReg', (170, 178))	('carcinogenesis', 'Disease', 'MESH:D063646', (39, 53))	('resistance to apoptosis', 'CPA', (216, 239))	('alterations', 'Reg', (96, 107))
178301	30127774	We proposed that the aberrant CD36 expression in LUAD or the activation of the pro-inflammatory molecules like the cytokines or chemokines (i.e., IL-4) can turn on the angiogenic switches mainly controlled by vascular endothelial growth factor (EGF), thereby inducing inflammatory angiogenesis and tumor cell-stroma communication (Figure 8).	('tumor cell-stroma communication', 'Disease', (298, 329))	('IL-4', 'Gene', '3565', (146, 150))	('tumor cell-stroma communication', 'Disease', 'MESH:D003147', (298, 329))	('aberrant', 'Var', (21, 29))	('inducing', 'PosReg', (259, 267))	('EGF', 'Gene', '1950', (245, 248))	('inflammatory angiogenesis', 'CPA', (268, 293))	('CD36', 'Gene', (30, 34))	('IL-4', 'Gene', (146, 150))	('turn on', 'Reg', (156, 163))	('CD36', 'Gene', '948', (30, 34))	('angiogenic switches', 'MPA', (168, 187))	('tumor', 'Phenotype', 'HP:0002664', (298, 303))	('EGF', 'Gene', (245, 248))
178309	30127774	Aberrant expression of CD36 may prevent these processes from taking effect.	('CD36', 'Gene', '948', (23, 27))	('prevent', 'NegReg', (32, 39))	('Aberrant expression', 'Var', (0, 19))	('CD36', 'Gene', (23, 27))
178310	30127774	The aberrant CD36 expression in our samples may be due to microcystin from the Cyanobacteria, which increases the expression of ribosomal protein S27A (RPS27A).	('microcystin', 'Chemical', 'MESH:C078588', (58, 69))	('S27A', 'Mutation', 'p.S27A', (154, 158))	('RPS27A', 'Gene', '6233', (152, 158))	('increases', 'PosReg', (100, 109))	('aberrant', 'Var', (4, 12))	('RPS27A', 'Gene', (152, 158))	('expression', 'MPA', (18, 28))	('CD36', 'Gene', (13, 17))	('CD36', 'Gene', '948', (13, 17))	('expression', 'MPA', (114, 124))	('C', 'Chemical', 'MESH:D002244', (79, 80))	('C', 'Chemical', 'MESH:D002244', (13, 14))	('S27A', 'Mutation', 'p.S27A', (146, 150))
178320	30127774	Interestingly, our pathway analysis predicted that presence of microcystin initiates an inflammatory process from which pro-inflammatory cytokines: TNF, type alpha (TNFalpha), interleukin 1-beta (IL-1beta), oncostatin M (OSM), and interleukin-4 (IL-4).	('TNFalpha', 'Gene', (165, 173))	('IL-4', 'Gene', (246, 250))	('interleukin 1-beta', 'Gene', '3553', (176, 194))	('interleukin-4', 'Gene', (231, 244))	('interleukin-4', 'Gene', '3565', (231, 244))	('microcystin', 'Chemical', 'MESH:C078588', (63, 74))	('oncostatin M', 'Gene', '5008', (207, 219))	('oncostatin M', 'Gene', (207, 219))	('TNFalpha', 'Gene', '7124', (165, 173))	('IL-4', 'Gene', '3565', (246, 250))	('IL-1beta', 'Gene', (196, 204))	('IL-1beta', 'Gene', '3553', (196, 204))	('interleukin 1-beta', 'Gene', (176, 194))	('TNF, type alpha', 'Gene', '7124', (148, 163))	('initiates', 'Reg', (75, 84))	('presence', 'Var', (51, 59))
178329	30127774	It has been reported that that nitrogen (N) speciation and inorganic carbon (C) availability might be important drivers of population dynamics Cyanobacteria and that an imbalance in cellular C:N ratios may trigger microcystin production.	('trigger', 'PosReg', (206, 213))	('C', 'Chemical', 'MESH:D002244', (143, 144))	('N', 'Chemical', 'MESH:D009584', (193, 194))	('imbalance', 'Var', (169, 178))	('imbalance', 'Phenotype', 'HP:0002172', (169, 178))	('carbon', 'Chemical', 'MESH:D002244', (69, 75))	('C', 'Chemical', 'MESH:D002244', (191, 192))	('nitrogen', 'Chemical', 'MESH:D009584', (31, 39))	('microcystin', 'Chemical', 'MESH:C078588', (214, 225))	('microcystin production', 'MPA', (214, 236))	('N', 'Chemical', 'MESH:D009584', (41, 42))	('C', 'Chemical', 'MESH:D002244', (77, 78))
178352	29180609	Overexpression of survivin was significantly associated with lymph nodes metastatic status (p=0.025), worse overall survival (OS) and disease free survival (DFS) in patients receiving RT (n=65, OS: p=0.024, DFS: p=0.006) and in all patients with SCCHN (n=100, OS: p=0.002, DFS: p=0.003).	('worse', 'NegReg', (102, 107))	('survivin', 'Protein', (18, 26))	('patients', 'Species', '9606', (232, 240))	('overall survival', 'CPA', (108, 124))	('lymph nodes metastatic status', 'CPA', (61, 90))	('SCC', 'Gene', (246, 249))	('OS', 'Chemical', '-', (194, 196))	('Overexpression', 'Var', (0, 14))	('patients', 'Species', '9606', (165, 173))	('OS', 'Chemical', '-', (126, 128))	('OS', 'Chemical', '-', (260, 262))	('disease free survival', 'CPA', (134, 155))	('SCC', 'Gene', '6317', (246, 249))
178362	29180609	Inhibition of this crucial survival factor has been shown to trigger apoptosis and sensitize cancer cells to RT.	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('Inhibition', 'Var', (0, 10))	('apoptosis', 'CPA', (69, 78))	('sensitize', 'Reg', (83, 92))	('trigger', 'PosReg', (61, 68))
178367	29180609	Honokiol also activates sirt3 and increases mitochondrial fusion and respiration, thereby antagonizing the protective effect of survivin on cell survival.	('mitochondrial', 'CPA', (44, 57))	('respiration', 'MPA', (69, 80))	('Honokiol', 'Var', (0, 8))	('Honokiol', 'Chemical', 'MESH:C005499', (0, 8))	('sirt3', 'Gene', '23410', (24, 29))	('sirt3', 'Gene', (24, 29))	('antagonizing', 'NegReg', (90, 102))	('activates', 'PosReg', (14, 23))	('increases', 'PosReg', (34, 43))
178429	29180609	In contrast, PCI-15A cells treated with the combination of honokiol and RT showed a statistically significant increase in tail DNA (Figure 4f), suggesting that honokiol may affect the DNA DSB repair process in SCCHN cells and sensitize DNA to RT.	('increase', 'PosReg', (110, 118))	('honokiol', 'Var', (160, 168))	('honokiol', 'Chemical', 'MESH:C005499', (160, 168))	('SCC', 'Gene', (210, 213))	('DNA DSB', 'MPA', (184, 191))	('tail DNA', 'MPA', (122, 130))	('affect', 'Reg', (173, 179))	('SCC', 'Gene', '6317', (210, 213))	('honokiol', 'Chemical', 'MESH:C005499', (59, 67))
178433	29180609	Clonogenic assay confirmed that PCI-15A-RR had acquired increased resistance to RT (SF2: 0.79+-0.02), whereas the parental PCI-15A (PCI-15A-P) cell line maintained its sensitivity to RT (SF2:0.40+-0.09).	('SF2', 'Gene', (84, 87))	('PCI-15A-RR', 'Var', (32, 42))	('sensitivity', 'MPA', (168, 179))	('increased', 'PosReg', (56, 65))	('PCI-15A-P', 'Disease', (132, 141))	('PCI-15A-P', 'Disease', 'MESH:C000656865', (132, 141))	('SF2', 'Gene', '6426', (187, 190))	('SF2', 'Gene', '6426', (84, 87))	('SF2', 'Gene', (187, 190))	('resistance to RT', 'MPA', (66, 82))
178437	29180609	To examine the ability of honokiol to attenuate acquired radioresistance via the inhibition of survivin, PCI-15A-RR cells were treated with honokiol and Western blot analysis revealed a markedly reduced survivin expression level in honokiol-treated cells compared with the control cells (Figure 5c).	('reduced', 'NegReg', (195, 202))	('honokiol', 'Chemical', 'MESH:C005499', (232, 240))	('honokiol', 'Chemical', 'MESH:C005499', (26, 34))	('honokiol', 'Chemical', 'MESH:C005499', (140, 148))	('honokiol-treated', 'Var', (232, 248))	('survivin expression level', 'MPA', (203, 228))	('acquired radioresistance', 'CPA', (48, 72))
178443	29180609	In contrast, the combination treatment significantly inhibited the growth of Tu686 tumors, when compared with any other groups (vs. control: p=0.037; vs. honokiol: p=0.030; vs. RT: p=0.007).	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('inhibited', 'NegReg', (53, 62))	('growth', 'MPA', (67, 73))	('tumors', 'Disease', (83, 89))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('honokiol', 'Chemical', 'MESH:C005499', (154, 162))	('Tu686', 'Var', (77, 82))	('tumors', 'Disease', 'MESH:D009369', (83, 89))
178445	29180609	The average tumor volume and weight in each treatment group at the end point were 3267.2+-1316.7 mm3 and 2.26+-0.86g (control), 2597.9 +- 939.4 mm3 and 1.26+-0.42g (honokiol), 1169.7+-109.9 mm3 and 0.64+-0.07g (RT), and 487.9 +-164.0mm3 and 0.28+-0.11g (combination), respectively (Figure 6a, b).	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('honokiol', 'Chemical', 'MESH:C005499', (165, 173))	('1169.7+-109.9 mm3', 'Var', (176, 193))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('2597.9 +- 939.4 mm3', 'Var', (128, 147))	('tumor', 'Disease', (12, 17))
178449	29180609	IHC analysis revealed a markedly reduced survivin expression in tumors treated with honokiol, either alone or in combination with RT, compared with the control and radiation treated tumors.	('honokiol', 'Chemical', 'MESH:C005499', (84, 92))	('tumors', 'Disease', (64, 70))	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('tumors', 'Phenotype', 'HP:0002664', (182, 188))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('honokiol', 'Var', (84, 92))	('tumors', 'Disease', (182, 188))	('tumors', 'Disease', 'MESH:D009369', (182, 188))	('reduced', 'NegReg', (33, 40))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('expression', 'MPA', (50, 60))	('survivin', 'Protein', (41, 49))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
178453	29180609	Overexpression of survivin has been frequently associated with radioresistance, metastasis, and poor prognosis in many cancers including lung, colon, breast, prostate, gastric and pancreas.	('survivin', 'Protein', (18, 26))	('metastasis', 'CPA', (80, 90))	('gastric and pancreas', 'Disease', 'MESH:D013274', (168, 188))	('colon', 'Disease', (143, 148))	('cancers', 'Disease', 'MESH:D009369', (119, 126))	('cancers', 'Phenotype', 'HP:0002664', (119, 126))	('cancers', 'Disease', (119, 126))	('radioresistance', 'CPA', (63, 78))	('Overexpression', 'Var', (0, 14))	('prostate', 'Disease', (158, 166))	('associated', 'Reg', (47, 57))	('breast', 'Disease', (150, 156))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('lung', 'Disease', (137, 141))
178455	29180609	Overexpression of survivin has been reported as a negative prognostic factor in SCCHN.	('SCC', 'Gene', '6317', (80, 83))	('survivin', 'Protein', (18, 26))	('Overexpression', 'Var', (0, 14))	('SCC', 'Gene', (80, 83))
178457	29180609	For example, one study showed that high survivin was correlated with favorable overall survival in patients with oral SCC.	('overall', 'MPA', (79, 86))	('SCC', 'Gene', (118, 121))	('patients', 'Species', '9606', (99, 107))	('survivin', 'Protein', (40, 48))	('SCC', 'Gene', '6317', (118, 121))	('high', 'Var', (35, 39))
178467	29180609	DNA DSBs are mainly repaired by two mechanisms: homologous recombination (HR) and non-homologous end joining (NHEJ).	('homologous', 'Var', (48, 58))	('DSBs', 'Chemical', '-', (4, 8))	('non-homologous end', 'Var', (82, 100))
178471	29180609	Interestingly, H2AX depletion resulted in a reduction of survivin foci formation, whereas survivin siRNA transfection did not have a significant effect on H2AX foci formation (Supplementary Figure 2).	('H2AX', 'Gene', '3014', (155, 159))	('H2AX', 'Gene', (155, 159))	('H2AX', 'Gene', '3014', (15, 19))	('survivin foci formation', 'MPA', (57, 80))	('depletion', 'Var', (20, 29))	('reduction', 'NegReg', (44, 53))	('H2AX', 'Gene', (15, 19))
178474	29180609	Significant efforts have been made to develop strategies to target survivin therapeutically in a variety of cancers, and several agents have been shown to modulate the expression/activation of survivin, such as an antisense molecule (LY218130B) and transcriptional repressors (YM155and EM-1421).	('cancers', 'Phenotype', 'HP:0002664', (108, 115))	('survivin', 'Gene', (193, 201))	('expression/activation', 'PosReg', (168, 189))	('YM155and', 'Var', (277, 285))	('LY218130B', 'Chemical', '-', (234, 243))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('expression/activation', 'MPA', (168, 189))	('cancers', 'Disease', 'MESH:D009369', (108, 115))	('LY218130B', 'Var', (234, 243))	('cancers', 'Disease', (108, 115))	('modulate', 'Reg', (155, 163))
178493	29180609	We evaluated the potential of using honokiol to mitigate radioresistance, and found that in SCCHN models, honokiol effectively downregulated survivin expression to reduce radioresistance.	('honokiol', 'Chemical', 'MESH:C005499', (36, 44))	('expression', 'MPA', (150, 160))	('SCC', 'Gene', '6317', (92, 95))	('survivin', 'Protein', (141, 149))	('radioresistance', 'CPA', (171, 186))	('reduce', 'NegReg', (164, 170))	('honokiol', 'Chemical', 'MESH:C005499', (106, 114))	('downregulated', 'NegReg', (127, 140))	('honokiol', 'Var', (106, 114))	('SCC', 'Gene', (92, 95))
178509	31788059	It is hypothesized that LUAD originates from epithelial secretory cells, while LUSC originates from basal cells; furthermore, epidermal growth factor receptor, KRAS proto-oncogene GTPase and EMAP-like 4-ALK receptor tyrosine kinase mutations tend to occur more frequently in LUAD.	('LUSC', 'Phenotype', 'HP:0030359', (79, 83))	('LUAD', 'Disease', (275, 279))	('LUAD', 'Disease', 'MESH:C538231', (275, 279))	('LUAD', 'Phenotype', 'HP:0030078', (24, 28))	('LUAD', 'Phenotype', 'HP:0030078', (275, 279))	('LUAD', 'Disease', (24, 28))	('LUSC', 'Disease', (79, 83))	('epidermal growth factor receptor', 'Gene', (126, 158))	('LUAD', 'Disease', 'MESH:C538231', (24, 28))	('KRAS', 'Gene', (160, 164))	('KRAS', 'Gene', '3845', (160, 164))	('mutations', 'Var', (232, 241))	('tyrosine', 'Chemical', 'None', (216, 224))	('epidermal growth factor receptor', 'Gene', '1956', (126, 158))	('LUSC', 'Disease', 'MESH:D002294', (79, 83))
178519	31788059	In the present study, three gene expression profiles (GSE19188, GSE21933 and GSE74706) were downloaded from the GEO; GSE19188 contained 27 LUSC tissue samples and 65 normal lung tissue samples; GSE21933 contained 10 LUSC tissue samples and 10 matched normal lung tissue samples, and GSE74706 contained 8 LUSC tissue samples and 8 matched normal lung tissue samples.	('GSE19188', 'Var', (117, 125))	('GSE21933', 'Var', (194, 202))	('LUSC', 'Phenotype', 'HP:0030359', (139, 143))	('LUSC', 'Disease', 'MESH:D002294', (139, 143))	('LUSC', 'Disease', (139, 143))	('LUSC', 'Disease', (304, 308))	('LUSC', 'Disease', 'MESH:D002294', (304, 308))	('LUSC', 'Phenotype', 'HP:0030359', (304, 308))	('LUSC', 'Phenotype', 'HP:0030359', (216, 220))	('LUSC', 'Disease', 'MESH:D002294', (216, 220))	('LUSC', 'Disease', (216, 220))
178556	31788059	CCNB1 and TYMS shared let-7b-5p, and MKI67 and CEP55 shared miR-16-5p, miR-192-5p and miR-215-5p.	('miR', 'Gene', (71, 74))	('miR', 'Gene', '220972', (60, 63))	('miR', 'Gene', (60, 63))	('TYMS', 'Gene', (10, 14))	('let-7b-5p', 'Var', (22, 31))	('CEP55', 'Gene', '55165', (47, 52))	('CEP55', 'Gene', (47, 52))	('miR', 'Gene', '220972', (86, 89))	('miR', 'Gene', (86, 89))	('TYMS', 'Gene', '7298', (10, 14))	('CCNB1', 'Gene', (0, 5))	('miR-215', 'Gene', (86, 93))	('CCNB1', 'Gene', '891', (0, 5))	('MKI67', 'Gene', (37, 42))	('miR-215', 'Gene', '406997', (86, 93))	('miR', 'Gene', '220972', (71, 74))	('MKI67', 'Gene', '4288', (37, 42))
178571	31788059	Dysregulation of CCNB1 leads to cell hyperplasia and tumorigenesis, which has been reported in various cancers, including esophageal squamous cell carcinoma, breast cancer and gastric cancer.	('cancers', 'Disease', 'MESH:D009369', (103, 110))	('Dysregulation', 'Var', (0, 13))	('esophageal squamous cell carcinoma', 'Disease', (122, 156))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('breast cancer', 'Phenotype', 'HP:0003002', (158, 171))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('CCNB1', 'Gene', '891', (17, 22))	('breast cancer', 'Disease', 'MESH:D001943', (158, 171))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('breast cancer', 'Disease', (158, 171))	('gastric cancer', 'Phenotype', 'HP:0012126', (176, 190))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (133, 156))	('cancers', 'Phenotype', 'HP:0002664', (103, 110))	('leads to', 'Reg', (23, 31))	('cancers', 'Disease', (103, 110))	('hyperplasia', 'Disease', (37, 48))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:C562729', (122, 156))	('CCNB1', 'Gene', (17, 22))	('hyperplasia', 'Disease', 'MESH:D006965', (37, 48))	('gastric cancer', 'Disease', (176, 190))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('tumor', 'Disease', (53, 58))	('gastric cancer', 'Disease', 'MESH:D013274', (176, 190))	('carcinoma', 'Phenotype', 'HP:0030731', (147, 156))
178585	31788059	In NSCLC patients, elevated levels CEP55 promote migration and invasion via activation of the PI3K/AKT pathway, in addition to predicting unfavorable clinical outcomes.	('patients', 'Species', '9606', (9, 17))	('NSCLC', 'Disease', (3, 8))	('NSCLC', 'Disease', 'MESH:D002289', (3, 8))	('migration', 'CPA', (49, 58))	('elevated', 'Var', (19, 27))	('promote', 'PosReg', (41, 48))	('PI3K/AKT pathway', 'Pathway', (94, 110))	('invasion', 'CPA', (63, 71))	('NSCLC', 'Phenotype', 'HP:0030358', (3, 8))	('CEP55', 'Gene', '55165', (35, 40))	('activation', 'PosReg', (76, 86))	('CEP55', 'Gene', (35, 40))
178605	31788059	TYMS inhibition results in cell cycle arrest at the S phase, and high TYMS expression accelerates cell proliferation and leads to malignant behaviors in various types of solid tumor.	('cell proliferation', 'CPA', (98, 116))	('TYMS', 'Gene', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('tumor', 'Disease', (176, 181))	('leads to', 'Reg', (121, 129))	('inhibition', 'NegReg', (5, 15))	('accelerates', 'PosReg', (86, 97))	('high', 'Var', (65, 69))	('cell cycle arrest at the S phase', 'CPA', (27, 59))	('TYMS', 'Gene', (70, 74))	('TYMS', 'Gene', '7298', (0, 4))	('malignant behaviors', 'CPA', (130, 149))	('TYMS', 'Gene', '7298', (70, 74))	('tumor', 'Disease', 'MESH:D009369', (176, 181))
178622	31697689	Assessing reliability of intra-tumor heterogeneity estimates from single sample whole exome sequencing data Tumors are made of evolving and heterogeneous populations of cells which arise from successive appearance and expansion of subclonal populations, following acquisition of mutations conferring them a selective advantage.	('intra-tumor', 'Disease', (25, 36))	('mutations', 'Var', (279, 288))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('intra-tumor', 'Disease', 'MESH:D009369', (25, 36))	('Tumors', 'Disease', (108, 114))	('Tumors', 'Disease', 'MESH:D009369', (108, 114))	('Tumors', 'Phenotype', 'HP:0002664', (108, 114))	('ran', 'Gene', (208, 211))	('ran', 'Gene', '5901', (208, 211))
178632	31697689	A consequence of this progressive accumulation of mutations is intra-tumor heterogeneity.	('mutations', 'Var', (50, 59))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('intra-tumor', 'Disease', 'MESH:D009369', (63, 74))	('intra-tumor', 'Disease', (63, 74))
178633	31697689	Indeed, when a new mutation occurs in a tumor cell and provides an evolutionary advantage, this cell tends to have a higher probability to survive and divide, hence seeding a new clonal population.	('mutation', 'Var', (19, 27))	('survive', 'CPA', (139, 146))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('seeding', 'Reg', (165, 172))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))
178654	31697689	A coverage filter was added, and we kept SNVs with at least 6 reads at the position in the normal sample, of which 1 maximum reports the alternative nucleotide (or with a variant allele frequency (VAF) <0.01), and for the tumor sample, at least 8 reads covering the position, of which at least 3 reporting the variant, or a VAF>0.2.	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('variant', 'Var', (310, 317))	('tumor', 'Disease', (222, 227))	('tumor', 'Disease', 'MESH:D009369', (222, 227))
178669	31697689	The raw data for 7 normal-tumor WES samples analyzed jointly with matching single cell sequencing were downloaded from the NCBI SRA platform https://www.ncbi.nlm.nih.gov/sra and processed into fastq format using the tool fastq-dump for the two acute lymphoblastic leukemia (ALL) patients (accession numbers: SRR1517761, SRR1517762, SRR1517763, SRR1517764), or directly downloaded in the fastq format from the EBI ENA platform https://www.ebi.ac.uk/ena for the Triple Negative Breast Cancer patient (TNBC) (accession number: SRR1163508 and SRR1298936), and the two samples (primary tumor and liver metastasis) from the two colorectal cancer patients (CRC) (accession number: SRR3472566, SRR3472567, SRR3472569, SRR3472571, SRR3472796, SRR3472798, SRR3472799, SRR3472800).	('SRA', 'Gene', (128, 131))	('SRR3472799', 'Var', (746, 756))	('SRR1517763', 'Chemical', 'MESH:C105415', (332, 342))	('colorectal cancer', 'Disease', (622, 639))	('patient', 'Species', '9606', (279, 286))	('lymphoblastic leukemia', 'Disease', 'MESH:D054198', (250, 272))	('Breast Cancer', 'Phenotype', 'HP:0003002', (476, 489))	('sra', 'Gene', (170, 173))	('SRA', 'Gene', '10011', (128, 131))	('lymphoblastic leukemia', 'Disease', (250, 272))	('patients', 'Species', '9606', (640, 648))	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (244, 272))	('SRR1517764', 'Chemical', 'MESH:C105415', (344, 354))	('SRR3472571', 'Var', (710, 720))	('tumor', 'Disease', (581, 586))	('SRR1517762', 'Chemical', 'MESH:C105415', (320, 330))	('tumor', 'Disease', (26, 31))	('SRR3472567', 'Chemical', 'MESH:C105415', (686, 696))	('tumor', 'Disease', 'MESH:D009369', (581, 586))	('SRR3472569', 'Var', (698, 708))	('patient', 'Species', '9606', (490, 497))	('colorectal cancer', 'Phenotype', 'HP:0003003', (622, 639))	('Breast Cancer', 'Disease', 'MESH:D001943', (476, 489))	('SRR3472571', 'Chemical', 'MESH:C105415', (710, 720))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (250, 272))	('SRR3472800', 'Var', (758, 768))	('patients', 'Species', '9606', (279, 287))	('cancer', 'Phenotype', 'HP:0002664', (633, 639))	('SRR3472796', 'Var', (722, 732))	('Breast Cancer', 'Disease', (476, 489))	('patient', 'Species', '9606', (640, 647))	('SRR3472798', 'Var', (734, 744))	('SRR3472567', 'Var', (686, 696))	('ALL', 'Phenotype', 'HP:0006721', (274, 277))	('tumor', 'Phenotype', 'HP:0002664', (581, 586))	('Cancer', 'Phenotype', 'HP:0002664', (483, 489))	('leukemia', 'Phenotype', 'HP:0001909', (264, 272))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('colorectal cancer', 'Disease', 'MESH:D015179', (622, 639))	('sra', 'Gene', '10011', (170, 173))
178671	31697689	Those variants and the copy number profile were then passed to PyClone, SciClone, PhyloWGS and Expands for ITH deconvolution.	('WGS', 'Disease', 'None', (87, 90))	('variants', 'Var', (6, 14))	('WGS', 'Disease', (87, 90))
178677	31697689	We assess ITH in each sample using 6 representative computational methods: PyClone, SciClone, PhyloWGS EXPANDS, the mutant-allele tumor heterogeneity (MATH) score, and CSR, a method providing a consensus of all of the above results (except MATH which is not compatible, see Methods).	('tumor', 'Disease', (130, 135))	('WGS', 'Disease', 'None', (99, 102))	('WGS', 'Disease', (99, 102))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('mutant-allele', 'Var', (116, 129))
178685	31697689	PyClone and PhyloWGS runtime rises very quickly with the number of mutations in tumor sample, which can be a limitation for applications to heavily mutated tumors.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('WGS', 'Disease', 'None', (17, 20))	('mutations', 'Var', (67, 76))	('tumor', 'Disease', (80, 85))	('WGS', 'Disease', (17, 20))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumors', 'Disease', 'MESH:D009369', (156, 162))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('tumor', 'Disease', (156, 161))	('tumors', 'Disease', (156, 162))
178689	31697689	In addition, we add to the comparison 5 measures directly extracted from the NGS analysis, namely, the number of mutations in the protected and in the public sets, the percentage of non-diploid cells (estimated by ASCAT and ABSOLUTE), the purity (estimated by ASCAT and ABSOLUTE), and the inv_T_cell (estimated from gene expression signatures).	('inv', 'Gene', (289, 292))	('mutations', 'Var', (113, 122))	('inv', 'Gene', '27130', (289, 292))	('purity', 'CPA', (239, 245))
178693	31697689	SciClone is different from PyClone and PhyloWGS in two ways: it only relies on mutations that are in regions without copy number alterations; and it does not correct for tumor purity.	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('WGS', 'Disease', 'None', (44, 47))	('WGS', 'Disease', (44, 47))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('tumor', 'Disease', (170, 175))	('mutations', 'Var', (79, 88))
178699	31697689	Each group of ITH methods is highly correlated to distinct genomic metrics, mutation load and CNV abundance (perc_non_diploid) for the first group (MATH, Expands), and purity (and the opposite of immune cells infiltration (inv_T_cells)) for the latter (PyClone, SciClone, PhyloWGS CSR).	('inv', 'Gene', '27130', (223, 226))	('WGS', 'Disease', 'None', (277, 280))	('WGS', 'Disease', (277, 280))	('mutation', 'Var', (76, 84))	('inv', 'Gene', (223, 226))
178719	31697689	They obtain significant prognostic association for all variant calling results in only one cancer type: UCEC, and already report some lack of robustness in the results.	('variant', 'Var', (55, 62))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('UCEC', 'Disease', (104, 108))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))
178753	29348878	Different cancers usually share common hallmarks, such as evading growth suppressors, resisting cell death and inducing angiogenesis.	('growth suppressors', 'CPA', (66, 84))	('resisting cell death', 'CPA', (86, 106))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('evading', 'Var', (58, 65))	('inducing', 'Reg', (111, 119))	('angiogenesis', 'CPA', (120, 132))	('cancers', 'Phenotype', 'HP:0002664', (10, 17))	('cancers', 'Disease', 'MESH:D009369', (10, 17))	('cancers', 'Disease', (10, 17))
178804	29348878	The BPs in the M7 are associated with the negative regulation of extracellular matrix disassembly and endothelial cell migration.	('endothelial cell migration', 'CPA', (102, 128))	('BPs', 'Var', (4, 7))	('extracellular matrix disassembly', 'CPA', (65, 97))	('negative', 'NegReg', (42, 50))	('rat', 'Species', '10116', (122, 125))
178807	29348878	It has been reported that alterations in glycosylation impacted cell cycle and may support neoplastic progression.	('impacted', 'Reg', (55, 63))	('neoplastic progression', 'CPA', (91, 113))	('glycosylation', 'MPA', (41, 54))	('alterations', 'Var', (26, 37))	('rat', 'Species', '10116', (30, 33))	('support', 'PosReg', (83, 90))	('cell cycle', 'CPA', (64, 74))
178913	33680972	Especially, high CD96 expression was associated with poorer overall survival (OS) and disease-specific survival (DSS) in the TCGA lower grade glioma (LGG) cohort (OS, HR = 2.18, 95% CI = 1.79-2.66, P < 0.001).	('CD96', 'Gene', (17, 21))	('high', 'Var', (12, 16))	('glioma', 'Disease', (142, 148))	('glioma', 'Disease', 'MESH:D005910', (142, 148))	('disease-specific survival', 'CPA', (86, 111))	('glioma', 'Phenotype', 'HP:0009733', (142, 148))	('poorer', 'NegReg', (53, 59))	('overall', 'MPA', (60, 67))	('DSS', 'Chemical', '-', (113, 116))	('expression', 'MPA', (22, 32))
178915	33680972	Notably, SKCM samples demonstrated the highest CD96 mutation frequency among all cancer types.	('CD96', 'Gene', (47, 51))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('cancer', 'Disease', (81, 87))	('SKCM', 'Chemical', '-', (9, 13))	('mutation', 'Var', (52, 60))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))
178917	33680972	CD96 was identified as a risk factor, protective factor, and irrelevant variable in LGG, SKCM and adrenocortical carcinoma (ACC), respectively.	('SKCM', 'Chemical', '-', (89, 93))	('adrenocortical carcinoma', 'Disease', (98, 122))	('ACC', 'Phenotype', 'HP:0006744', (124, 127))	('CD96', 'Var', (0, 4))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('LGG', 'Disease', (84, 87))	('SKCM', 'Disease', (89, 93))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (98, 122))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (98, 122))
178932	33680972	Anti-CD96 monoclonal antibody (mAb) also demonstrates higher efficacy in combination with either anti-CTLA-4 or anti-PD-1 mAbs, depending on the activation of CD226 signaling in NK cells.	('CD226', 'Gene', (159, 164))	('higher', 'PosReg', (54, 60))	('Anti-CD96', 'Var', (0, 9))	('CD226', 'Gene', '10666', (159, 164))	('efficacy', 'MPA', (61, 69))	('combination', 'Interaction', (73, 84))
178948	33680972	Results based on eight cohorts [GSE5287, GSE13507, GSE19615, GSE2034, GSE17537, GSE8894, GSE17260, GSE19234 ] suggested that high expression of CD96 was significantly associated with better prognosis (COX P < 0.05;  Figures 3A-H ).	('GSE2034', 'Chemical', '-', (61, 68))	('CD96', 'Gene', (144, 148))	('GSE5287', 'Chemical', '-', (32, 39))	('high expression', 'Var', (125, 140))	('better', 'PosReg', (183, 189))	('GSE8894', 'Chemical', '-', (80, 87))
178956	33680972	We then employed cBioPortal to inspect the mutation frequency of CD96 in the TCGA database (10967 samples in 32 studies), and we found that LUSC and SKCM shared relatively high mutation level with the CD96 alteration frequency exceeding 8% ( Figures 4A, B ).	('mutation', 'MPA', (177, 185))	('SKCM', 'Chemical', '-', (149, 153))	('alteration', 'Var', (206, 216))	('CD96', 'Gene', (201, 205))	('LUSC', 'Phenotype', 'HP:0030359', (140, 144))
178957	33680972	Among them, E24K and E574K were the two most frequent mutation sites.	('E574K', 'Var', (21, 26))	('E574K', 'Mutation', 'p.E574K', (21, 26))	('E24K', 'Var', (12, 16))	('E24K', 'Mutation', 'rs758011865', (12, 16))
178958	33680972	COSMIC provided detailed information on the CD96 mutation types, including substitution missense, non-sense, and synonymous mutations in different cancers.	('CD96', 'Gene', (44, 48))	('synonymous mutations', 'Var', (113, 133))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('cancers', 'Disease', 'MESH:D009369', (147, 154))	('cancers', 'Phenotype', 'HP:0002664', (147, 154))	('substitution missense', 'Var', (75, 96))	('cancers', 'Disease', (147, 154))	('non-sense', 'Var', (98, 107))
178959	33680972	Non-sense substitutions were found in cervix cancer (25%), large intestine cancer (2.47%), lung cancer (4.90%), and skin cancer (0.58%), while missense substitutions were observed in biliary tract cancer (5.56%), breast cancer (8.94%), cervix cancer (25%), central nervous system (CNS) cancer (33.33%), endometrial cancer (41.67%), hematopoietic and lymphoid cancer (7.41%), kidney cancer (25%), large intestine cancer (35.80%), liver cancer (8.70%), lung cancer (34.31%), esophageal cancer (25.53%), ovary cancer (12.50%), pancreas cancer (6.25%), prostate cancer (3.28%), skin cancer (44.77%), stomach cancer (16.22%), thyroid cancer (100%), upper aerodigestive tract cancer (46.15%), and urinary tract cancer (53.33%).	('lung cancer', 'Phenotype', 'HP:0100526', (91, 102))	('endometrial cancer', 'Disease', (303, 321))	('cancer', 'Disease', (629, 635))	('cancer', 'Disease', (96, 102))	('cancer', 'Disease', (533, 539))	('cancer', 'Disease', (382, 388))	('breast cancer', 'Disease', 'MESH:D001943', (213, 226))	('kidney cancer', 'Disease', (375, 388))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('cancer', 'Disease', 'MESH:D009369', (456, 462))	('cancer', 'Disease', 'MESH:D009369', (558, 564))	('thyroid cancer', 'Disease', (621, 635))	('ovary cancer', 'Disease', (501, 513))	('cancer', 'Disease', (197, 203))	('cancer', 'Disease', (315, 321))	('cancer', 'Disease', (220, 226))	('large intestine cancer', 'Phenotype', 'HP:0100834', (59, 81))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('thyroid cancer', 'Disease', 'MESH:D013964', (621, 635))	('cancer', 'Disease', (75, 81))	('liver cancer', 'Disease', (429, 441))	('ovary cancer', 'Disease', 'MESH:D010051', (501, 513))	('cancer', 'Disease', (359, 365))	('large intestine cancer', 'Phenotype', 'HP:0100834', (396, 418))	('cancer', 'Disease', 'MESH:D009369', (435, 441))	('skin cancer', 'Disease', (116, 127))	('biliary tract cancer', 'Phenotype', 'HP:0100574', (183, 203))	('stomach cancer', 'Phenotype', 'HP:0012126', (596, 610))	('ovary cancer', 'Phenotype', 'HP:0100615', (501, 513))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('cervix cancer', 'Phenotype', 'HP:0030079', (236, 249))	('cancer', 'Disease', (507, 513))	('cancer', 'Disease', (579, 585))	('cancer', 'Disease', 'MESH:D009369', (604, 610))	('cancer', 'Disease', 'MESH:D009369', (484, 490))	('skin cancer', 'Disease', 'MESH:D012878', (116, 127))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('cancer', 'Disease', 'MESH:D009369', (286, 292))	('skin cancer', 'Disease', 'MESH:D012878', (574, 585))	('lymphoid cancer', 'Disease', (350, 365))	('endometrial cancer', 'Phenotype', 'HP:0012114', (303, 321))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('urinary tract cancer', 'Phenotype', 'HP:0010786', (691, 711))	('cancer', 'Disease', 'MESH:D009369', (705, 711))	('cancer', 'Disease', (121, 127))	('thyroid cancer', 'Phenotype', 'HP:0002890', (621, 635))	('cancer', 'Disease', (456, 462))	('cancer', 'Disease', (558, 564))	('breast cancer', 'Phenotype', 'HP:0003002', (213, 226))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('prostate cancer', 'Disease', 'MESH:D011471', (549, 564))	('skin cancer', 'Disease', (574, 585))	('prostate cancer', 'Phenotype', 'HP:0012125', (549, 564))	('skin cancer', 'Phenotype', 'HP:0008069', (116, 127))	('cancer', 'Disease', 'MESH:D009369', (243, 249))	('cancer', 'Disease', 'MESH:D009369', (670, 676))	('cancer', 'Disease', (705, 711))	('missense', 'Var', (143, 151))	('lung cancer', 'Disease', 'MESH:D008175', (451, 462))	('pancreas cancer', 'Disease', (524, 539))	('cancer', 'Disease', (435, 441))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Disease', 'MESH:D009369', (533, 539))	('cancer', 'Disease', 'MESH:D009369', (382, 388))	('cancer', 'Disease', (243, 249))	('lung cancer', 'Disease', 'MESH:D008175', (91, 102))	('cancer', 'Disease', 'MESH:D009369', (412, 418))	('cancer', 'Disease', 'MESH:D009369', (197, 203))	('cancer', 'Disease', 'MESH:D009369', (315, 321))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('kidney cancer', 'Disease', 'MESH:D007680', (375, 388))	('cancer', 'Disease', (604, 610))	('cancer', 'Disease', 'MESH:D009369', (220, 226))	('cervix cancer', 'Phenotype', 'HP:0030079', (38, 51))	('endometrial cancer', 'Disease', 'MESH:D016889', (303, 321))	('cancer', 'Disease', (484, 490))	('lung cancer', 'Disease', (451, 462))	('lymphoid cancer', 'Disease', 'MESH:D009369', (350, 365))	('cancer', 'Disease', (286, 292))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('prostate cancer', 'Disease', (549, 564))	('kidney cancer', 'Phenotype', 'HP:0009726', (375, 388))	('breast cancer', 'Disease', (213, 226))	('pancreas cancer', 'Disease', 'MESH:D010190', (524, 539))	('cancer', 'Disease', (412, 418))	('skin cancer', 'Phenotype', 'HP:0008069', (574, 585))	('cancer', 'Disease', 'MESH:D009369', (359, 365))	('central nervous system', 'Disease', (257, 279))	('lung cancer', 'Disease', (91, 102))	('pancreas cancer', 'Phenotype', 'HP:0002894', (524, 539))	('liver cancer', 'Disease', 'MESH:D006528', (429, 441))	('lymphoid cancer', 'Phenotype', 'HP:0002665', (350, 365))	('cancer', 'Disease', 'MESH:D009369', (629, 635))	('cancer', 'Disease', (45, 51))	('lung cancer', 'Phenotype', 'HP:0100526', (451, 462))	('liver cancer', 'Phenotype', 'HP:0002896', (429, 441))	('cancer', 'Disease', 'MESH:D009369', (507, 513))	('cancer', 'Disease', 'MESH:D009369', (579, 585))	('cancer', 'Disease', (670, 676))
178966	33680972	DNA mismatch repair deficiency and subsequent microsatellite instability (MSI), a hypermutator phenotype secondary to frequent polymorphism in short repetitive DNA sequences and single nucleotide substitution, lead to the accumulation of mutation loads in cancer-related genes and the aggravation of tumor mutation burden (TMB).	('polymorphism', 'Var', (127, 139))	('deficiency', 'Disease', 'MESH:D007153', (20, 30))	('tumor', 'Disease', 'MESH:D009369', (300, 305))	('tumor', 'Phenotype', 'HP:0002664', (300, 305))	('cancer', 'Disease', 'MESH:D009369', (256, 262))	('tumor', 'Disease', (300, 305))	('cancer', 'Disease', (256, 262))	('microsatellite instability', 'MPA', (46, 72))	('TMB', 'Chemical', '-', (323, 326))	('mutation loads', 'MPA', (238, 252))	('aggravation', 'PosReg', (285, 296))	('cancer', 'Phenotype', 'HP:0002664', (256, 262))	('deficiency', 'Disease', (20, 30))	('accumulation', 'PosReg', (222, 234))	('single nucleotide substitution', 'Var', (178, 208))
178972	33680972	Despite the significances of these correlations, the correlation coefficients between CD96 and TMB, as well as MSI, were below 0.6 in almost all cancers, suggesting that CD96 was rather unlikely to affect tumorigenesis by participating in the process of genetic alterations, and was not sufficient to independently predict the patient's response to ICBs either.	('cancers', 'Disease', (145, 152))	('cancers', 'Phenotype', 'HP:0002664', (145, 152))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('affect', 'Reg', (198, 204))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumor', 'Disease', (205, 210))	('patient', 'Species', '9606', (327, 334))	('cancers', 'Disease', 'MESH:D009369', (145, 152))	('TMB', 'Chemical', '-', (95, 98))	('CD96', 'Var', (170, 174))
178988	33680972	This intriguing difference suggested that CD96 mediated immunosuppressive effects in glioma patients, but participated in completely opposite immune processes in melanoma patients, highly indicating that CD96 impacted patient prognosis via an immune-related manner.	('glioma', 'Disease', 'MESH:D005910', (85, 91))	('impacted', 'Reg', (209, 217))	('melanoma', 'Disease', 'MESH:D008545', (162, 170))	('patient', 'Species', '9606', (92, 99))	('patient', 'Species', '9606', (171, 178))	('melanoma', 'Disease', (162, 170))	('patient', 'Species', '9606', (218, 225))	('melanoma', 'Phenotype', 'HP:0002861', (162, 170))	('patients', 'Species', '9606', (92, 100))	('immunosuppressive effects', 'MPA', (56, 81))	('CD96', 'Gene', (42, 46))	('patients', 'Species', '9606', (171, 179))	('glioma', 'Disease', (85, 91))	('glioma', 'Phenotype', 'HP:0009733', (85, 91))	('CD96', 'Var', (204, 208))
178999	33680972	On the one hand, it has an immunoreceptor tyrosine-based inhibition motif (ITIM) motif, which is conserved in inhibit receptors such as KIR2DL; On the other hand, similar to the activating receptor NKG2D, CD96 harbors a YXXM motif.	('YXXM', 'MPA', (220, 224))	('NKG2D', 'Gene', '22914', (198, 203))	('NKG2D', 'Gene', (198, 203))	('CD96', 'Var', (205, 209))	('tyrosine', 'Chemical', 'MESH:D014443', (42, 50))
179000	33680972	Therefore, whether CD96 activates NK cells to exert tumor cell killing effect or inhibits its activity is still inconclusive.	('inhibits', 'NegReg', (81, 89))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumor', 'Disease', (52, 57))	('activity', 'MPA', (94, 102))	('activates', 'PosReg', (24, 33))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('CD96', 'Var', (19, 23))
179010	33680972	This suggests that CD96 can affect patient prognosis by influencing cancer malignant characteristics.	('affect', 'Reg', (28, 34))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('patient', 'Species', '9606', (35, 42))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('influencing', 'Reg', (56, 67))	('cancer', 'Disease', (68, 74))	('CD96', 'Var', (19, 23))
179014	33680972	Notably, further analysis showed that CD96 in SKCM, but not in LGG, was positively associated with Th1 markers, again corroborating that CD96 participates in Th1 activation, thereby enhancing tumor inhibiting effects and prolonging patient survival time in SKCM, again suggesting CD96 impacted patient survival in an immunity-depended manner.	('patient', 'Species', '9606', (294, 301))	('patient survival time', 'CPA', (232, 253))	('tumor', 'Disease', (192, 197))	('CD96', 'Var', (137, 141))	('enhancing', 'PosReg', (182, 191))	('prolonging', 'PosReg', (221, 231))	('SKCM', 'Chemical', '-', (46, 50))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('patient', 'Species', '9606', (232, 239))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('SKCM', 'Chemical', '-', (257, 261))
179015	33680972	Although the unique infiltration of immune cells in different tumors may affect our analysis results, we have reason to speculate that CD96 can influence the fate of immune infiltrates in TME, and may alter their distribution and subsequent interactions with malignancy cells, leading to distinct survival outcomes for different cancer patients.	('cancer', 'Phenotype', 'HP:0002664', (329, 335))	('alter', 'Reg', (201, 206))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('leading to', 'Reg', (277, 287))	('tumors', 'Disease', (62, 68))	('tumors', 'Disease', 'MESH:D009369', (62, 68))	('cancer', 'Disease', (329, 335))	('influence', 'Reg', (144, 153))	('interactions', 'Interaction', (241, 253))	('cancer', 'Disease', 'MESH:D009369', (329, 335))	('malignancy', 'Disease', 'MESH:D009369', (259, 269))	('patients', 'Species', '9606', (336, 344))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('malignancy', 'Disease', (259, 269))	('CD96', 'Var', (135, 139))	('fate', 'MPA', (158, 162))	('distribution', 'MPA', (213, 225))
179017	33680972	Moreover, we mainly employed TCGA database to perform these analyses, the included studies did not cover all previous published literatures involved CD96 and certain cancers, for instance, CD96 did not significantly related to LGG patient survival in GEO datasets by Prognoscan site.	('cancers', 'Disease', (166, 173))	('cancers', 'Disease', 'MESH:D009369', (166, 173))	('LGG', 'Disease', (227, 230))	('CD96', 'Var', (189, 193))	('related', 'Reg', (216, 223))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('patient', 'Species', '9606', (231, 238))	('cancers', 'Phenotype', 'HP:0002664', (166, 173))
179018	33680972	In summary, we applied integrated bioinformatics approaches to suggest that CD96 expression may mediate immune infiltration and impact patient prognosis in pan-cancer, sharing the potential as a prognostic biomarker and providing a novel direction to explore the pathogenesis malignance of these prevailing cancers.	('impact', 'Reg', (128, 134))	('cancer', 'Disease', (307, 313))	('cancer', 'Disease', 'MESH:D009369', (307, 313))	('immune infiltration', 'CPA', (104, 123))	('patient', 'Species', '9606', (135, 142))	('cancers', 'Disease', 'MESH:D009369', (307, 314))	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('cancers', 'Disease', (307, 314))	('cancer', 'Disease', (160, 166))	('cancer', 'Phenotype', 'HP:0002664', (307, 313))	('expression', 'Var', (81, 91))	('mediate', 'Reg', (96, 103))	('cancers', 'Phenotype', 'HP:0002664', (307, 314))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('CD96', 'Gene', (76, 80))	('patient prognosis', 'CPA', (135, 152))
179042	33680972	We also employed TISIDB  to assess whether CD96 had a significant expression difference between responders and non-responders to immunotherapy (e.g., anti-PD-L1 and anti-PD-1).	('PD-L1', 'Gene', '29126', (155, 160))	('PD-L1', 'Gene', (155, 160))	('anti-PD-1', 'Var', (165, 174))	('CD96', 'Gene', (43, 47))
179072	32340320	In addition, we utilized patient clinical information from DEGs in the TCGA for univariate cox regression analysis, lasso regression analysis and multivariate cox regression analysis to identify prognostic-related key genes.	('patient', 'Species', '9606', (25, 32))	('DEGs', 'Var', (59, 63))	('TCGA', 'Gene', (71, 75))
179116	32340320	MYEOV expression was positively associated with the infiltration of CD4+ T cells (Cor = 0.147, p = 1.27e-03), neutrophil cells (Cor = 0.168, p = 2.35e-04) and dendritic cells (Cor = 0.195, p = 1.96e-05; Figure 7E).	('associated', 'Interaction', (32, 42))	('CD4', 'Gene', '920', (68, 71))	('dendritic cells', 'CPA', (159, 174))	('neutrophil cells', 'CPA', (110, 126))	('MYEOV', 'Gene', '26579', (0, 5))	('MYEOV', 'Gene', (0, 5))	('expression', 'Var', (6, 16))	('CD4', 'Gene', (68, 71))	('infiltration', 'CPA', (52, 64))
179124	32340320	used two lung adenocarcinoma cell lines to verify that miR-137 can induce G1/S cell cycle arrest and dysregulate mRNA expression in cell cycle associated proteins, including CCNA2.	('arrest', 'Disease', 'MESH:D006323', (90, 96))	('CCNA2', 'Gene', (174, 179))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (9, 28))	('miR-137', 'Gene', (55, 62))	('mRNA expression', 'MPA', (113, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (19, 28))	('lung adenocarcinoma', 'Disease', (9, 28))	('dysregulate', 'Var', (101, 112))	('miR-137', 'Gene', '406928', (55, 62))	('arrest', 'Disease', (90, 96))	('CCNA2', 'Gene', '890', (174, 179))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (9, 28))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (79, 96))	('induce', 'PosReg', (67, 73))
179139	32340320	The expression of OR2W3 can promote dysplasia and local aggressive growth of tumor cells.	('OR2W3', 'Gene', (18, 23))	('OR2W3', 'Gene', '343171', (18, 23))	('dysplasia', 'Disease', 'MESH:C536170', (36, 45))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('dysplasia', 'Disease', (36, 45))	('promote', 'PosReg', (28, 35))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('expression', 'Var', (4, 14))	('tumor', 'Disease', (77, 82))
179146	32340320	GAPs generally function as tumor suppressor genes and can promote hydrolysis of Ral GTPase activating protein to inhibit tumorigenesis and development.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('GAPs', 'Var', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumor', 'Disease', (27, 32))	('hydrolysis', 'MPA', (66, 76))	('promote', 'PosReg', (58, 65))	('Ral', 'Gene', '5898', (80, 83))	('tumor', 'Disease', (121, 126))	('inhibit', 'NegReg', (113, 120))	('men', 'Species', '9606', (146, 149))	('function', 'Reg', (15, 23))	('Ral', 'Gene', (80, 83))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
179160	32340320	Furthermore, radiotherapy also often reduces the number of white blood cells and platelets, and suppresses immune function, causing patients to be more vulnerable to infection.	('radiotherapy', 'Var', (13, 25))	('suppresses immune function', 'Phenotype', 'HP:0002721', (96, 122))	('infection', 'Disease', (166, 175))	('immune', 'MPA', (107, 113))	('infection', 'Disease', 'MESH:D007239', (166, 175))	('suppresses', 'NegReg', (96, 106))	('patients', 'Species', '9606', (132, 140))	('reduces', 'NegReg', (37, 44))
179192	26359694	In a retrospective study (n = 80), high expression of SERPINE1 was associated with poor progression-free (p = 0.022) and cancer-specific (p = 0.040) survival.	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('SERPINE1', 'Gene', '5054', (54, 62))	('SERPINE1', 'Gene', (54, 62))	('high expression', 'Var', (35, 50))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('poor', 'NegReg', (83, 87))	('cancer', 'Disease', (121, 127))
179193	26359694	In a prospective study (n = 190), high SERPINE1 expression was associated with poor local recurrence-free (p = 0.022), progression-free (p = 0.002) and cancer-specific (p = 0.006) survival.	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('expression', 'MPA', (48, 58))	('high', 'Var', (34, 38))	('SERPINE1', 'Gene', '5054', (39, 47))	('SERPINE1', 'Gene', (39, 47))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('poor', 'NegReg', (79, 83))
179195	26359694	In both patient cohorts, high SERPINE1 expression increased the risk of metastasis spread (p = 0.045; p = 0.029).	('expression', 'MPA', (39, 49))	('high', 'Var', (25, 29))	('patient', 'Species', '9606', (8, 15))	('metastasis spread', 'CPA', (72, 89))	('SERPINE1', 'Gene', '5054', (30, 38))	('SERPINE1', 'Gene', (30, 38))
179217	26359694	Although some studies have suggested an association between high SERPINE1 expression and poor prognosis, other authors have not found evidences of such an association.	('expression', 'MPA', (74, 84))	('SERPINE1', 'Gene', '5054', (65, 73))	('SERPINE1', 'Gene', (65, 73))	('high', 'Var', (60, 64))	('poor prognosis', 'CPA', (89, 103))
179228	26359694	The rate of metastatic recurrences after treatment in patients with high SERPINE1 staining was higher than in patients with moderate or low staining.	('high', 'Var', (68, 72))	('patients', 'Species', '9606', (54, 62))	('SERPINE1', 'Gene', '5054', (73, 81))	('higher', 'PosReg', (95, 101))	('SERPINE1', 'Gene', (73, 81))	('patients', 'Species', '9606', (110, 118))	('metastatic recurrences', 'CPA', (12, 34))
179229	26359694	SERPINE1 staining intensity was significantly associated with progression-free survival (PFS) (Figure 1C) and cancer-specific survival (CSS) (Figure 1D).	('SERPINE1', 'Gene', (0, 8))	('cancer', 'Disease', (110, 116))	('staining intensity', 'Var', (9, 27))	('progression-free survival', 'CPA', (62, 87))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('CSS', 'Gene', '55907', (136, 139))	('associated', 'Reg', (46, 56))	('CSS', 'Gene', (136, 139))	('SERPINE1', 'Gene', '5054', (0, 8))	('cancer', 'Disease', 'MESH:D009369', (110, 116))
179230	26359694	Patients bearing tumors with high SERPINE1 staining intensity (3) had a shorter progression-free (PFS) (p = 0.022) and cancer-specific survival (CSS) (p = 0.040) than patients with tumors showing intermediate (2) or low (1) staining.	('tumors', 'Disease', (17, 23))	('bearing tumors', 'Disease', (9, 23))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('SERPINE1', 'Gene', (34, 42))	('tumors', 'Phenotype', 'HP:0002664', (181, 187))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('cancer', 'Disease', (119, 125))	('Patients', 'Species', '9606', (0, 8))	('CSS', 'Gene', '55907', (145, 148))	('SERPINE1', 'Gene', '5054', (34, 42))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('high', 'Var', (29, 33))	('CSS', 'Gene', (145, 148))	('bearing tumors', 'Disease', 'MESH:C565129', (9, 23))	('tumors', 'Disease', (181, 187))	('shorter', 'NegReg', (72, 79))	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('tumors', 'Disease', 'MESH:D009369', (181, 187))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('patients', 'Species', '9606', (167, 175))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
179233	26359694	After performing an analysis that excluded this case we found that patients with high SERPINE1 expression continue having a significantly shorter progression-free survival than low expressing patients (p = 0.015) (Supplementary files, Figure S2).	('patients', 'Species', '9606', (67, 75))	('SERPINE1', 'Gene', '5054', (86, 94))	('SERPINE1', 'Gene', (86, 94))	('high', 'Var', (81, 85))	('shorter', 'NegReg', (138, 145))	('patients', 'Species', '9606', (192, 200))	('progression-free survival', 'CPA', (146, 171))
179239	26359694	The rate of metastatic recurrences was significantly higher in the group of patients with tumors expressing high levels of SERPINE1 (p = 0.029), thus confirming the results obtained in the IHC analysis (Table 2).	('patients', 'Species', '9606', (76, 84))	('higher', 'PosReg', (53, 59))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('high levels', 'Var', (108, 119))	('tumors', 'Disease', (90, 96))	('tumors', 'Disease', 'MESH:D009369', (90, 96))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('SERPINE1', 'Gene', '5054', (123, 131))	('SERPINE1', 'Gene', (123, 131))	('metastatic recurrences', 'CPA', (12, 34))
179241	26359694	Patients with high SERPINE1 tumor expression had shorter LRFS (p = 0.022), PFS (p = 0.002) and CSS (p = 0.006) than patients with low SERPINE1 expression (Figure 2).	('tumor', 'Disease', (28, 33))	('PFS', 'CPA', (75, 78))	('CSS', 'Gene', '55907', (95, 98))	('patients', 'Species', '9606', (116, 124))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('LRFS', 'CPA', (57, 61))	('shorter', 'NegReg', (49, 56))	('CSS', 'Gene', (95, 98))	('high', 'Var', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('SERPINE1', 'Gene', '5054', (19, 27))	('SERPINE1', 'Gene', (19, 27))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('SERPINE1', 'Gene', '5054', (134, 142))	('SERPINE1', 'Gene', (134, 142))
179244	26359694	There was a clear trend towards significance in the association between high SERPINE1 expression and poor patient survival (HR 1.78, 95%CI 0.98-3.23, p = 0.057), however the differences observed among groups, did not reach statistical significance in the multivariate analysis.	('patient', 'Species', '9606', (106, 113))	('poor patient survival', 'CPA', (101, 122))	('expression', 'MPA', (86, 96))	('SERPINE1', 'Gene', '5054', (77, 85))	('SERPINE1', 'Gene', (77, 85))	('high', 'Var', (72, 76))
179249	26359694	Patients with high SERPINE1 expression had a significantly progression-free survival than patients with low SERPINE1 expression (p = 0.015).	('progression-free survival', 'CPA', (59, 84))	('SERPINE1', 'Gene', (108, 116))	('SERPINE1', 'Gene', '5054', (108, 116))	('expression', 'MPA', (28, 38))	('high', 'Var', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('SERPINE1', 'Gene', '5054', (19, 27))	('SERPINE1', 'Gene', (19, 27))	('patients', 'Species', '9606', (90, 98))
179251	26359694	Again, SERPINE1 staining intensity was significantly associated with progression-free survival (PFS) (p = 0.016) and cancer-specific survival (CSS) (p = 0.028), confirming the results obtained by RT-PCR (Figure 2E-2H).	('SERPINE1', 'Gene', '5054', (7, 15))	('SERPINE1', 'Gene', (7, 15))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('progression-free survival', 'CPA', (69, 94))	('staining intensity', 'Var', (16, 34))	('CSS', 'Gene', '55907', (143, 146))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('associated', 'Reg', (53, 63))	('cancer', 'Disease', (117, 123))	('CSS', 'Gene', (143, 146))
179254	26359694	Kaplan -Meier curves showed that patients with high SERPINE1 tumor expression had shorter survival than patients with low SERPINE1 tumor expression (p < 0.001) (Figure 3B).	('SERPINE1', 'Gene', (122, 130))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('patients', 'Species', '9606', (33, 41))	('SERPINE1', 'Gene', '5054', (52, 60))	('survival', 'MPA', (90, 98))	('high', 'Var', (47, 51))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('SERPINE1', 'Gene', (52, 60))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Disease', (131, 136))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('SERPINE1', 'Gene', '5054', (122, 130))	('patients', 'Species', '9606', (104, 112))	('tumor', 'Disease', (61, 66))	('shorter', 'NegReg', (82, 89))
179255	26359694	Univariate Cox model analysis showed that overall survival was significantly lower in patients whose tumors expressed high level of SERPINE1 than in patients with low SERPINE1 expression (HR:2.03, 95%CI 1.32-3.10, p = 0.01).	('lower', 'NegReg', (77, 82))	('patients', 'Species', '9606', (149, 157))	('overall survival', 'CPA', (42, 58))	('tumors', 'Disease', 'MESH:D009369', (101, 107))	('Cox', 'Gene', '1351', (11, 14))	('Cox', 'Gene', (11, 14))	('SERPINE1', 'Gene', '5054', (132, 140))	('SERPINE1', 'Gene', (132, 140))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('high level', 'Var', (118, 128))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('SERPINE1', 'Gene', '5054', (167, 175))	('SERPINE1', 'Gene', (167, 175))	('tumors', 'Disease', (101, 107))	('patients', 'Species', '9606', (86, 94))
179259	26359694	Patients with tumors showing a high expression of SERPINE1 continue to have a significantly (p = 0.001) higher risk of death than patients with low expression (Supplementary files, Figure S2).	('death', 'Disease', 'MESH:D003643', (119, 124))	('death', 'Disease', (119, 124))	('SERPINE1', 'Gene', '5054', (50, 58))	('tumors', 'Disease', (14, 20))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('patients', 'Species', '9606', (130, 138))	('Patients', 'Species', '9606', (0, 8))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('SERPINE1', 'Gene', (50, 58))	('high expression', 'Var', (31, 46))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
179261	26359694	PNI-positive rate was higher in tumors with high SERPINE1 expression (54%) than in tumors expressing low levels (23.9%).	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('higher', 'PosReg', (22, 28))	('high', 'Var', (44, 48))	('SERPINE1', 'Gene', (49, 57))	('expression', 'MPA', (58, 68))	('tumors', 'Disease', (83, 89))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumors', 'Disease', 'MESH:D009369', (83, 89))	('tumors', 'Disease', (32, 38))	('SERPINE1', 'Gene', '5054', (49, 57))	('tumors', 'Disease', 'MESH:D009369', (32, 38))
179262	26359694	The rate of lymphovascular invasion-positive tumors was higher in tumors with a high SERPINE1 expression (37%) than in tumors with a low expression (28%), however, differences between groups for this variable did not reach statistical significance (p > 0.05).	('SERPINE1', 'Gene', (85, 93))	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumors', 'Disease', (119, 125))	('tumors', 'Disease', 'MESH:D009369', (119, 125))	('tumors', 'Disease', (45, 51))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('tumors', 'Disease', (66, 72))	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('tumors', 'Disease', 'MESH:D009369', (45, 51))	('expression', 'MPA', (94, 104))	('higher', 'PosReg', (56, 62))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('high', 'Var', (80, 84))	('SERPINE1', 'Gene', '5054', (85, 93))
179266	26359694	We next sought to determine whether the ectopic over-expression or inhibition of SERPINE1 could affect cell proliferation and migration.	('affect', 'Reg', (96, 102))	('inhibition', 'NegReg', (67, 77))	('cell proliferation', 'CPA', (103, 121))	('ectopic over-expression', 'Var', (40, 63))	('SERPINE1', 'Gene', '5054', (81, 89))	('SERPINE1', 'Gene', (81, 89))
179270	26359694	The SCC9 cell line was selected for SERPINE1 down-regulation using lentiviral transduction with two shRNA constructs (TRC2_331004, TRC2_370159).	('TRC2_331004', 'Var', (118, 129))	('SERPINE1', 'Gene', '5054', (36, 44))	('SERPINE1', 'Gene', (36, 44))	('TRC2_370159', 'Var', (131, 142))	('SCC9', 'CellLine', 'CVCL:1685', (4, 8))	('down-regulation', 'NegReg', (45, 60))
179273	26359694	After SERPINE1 inhibition, a partial loss of its characteristic fusiform shape was observed in the SCC9 cell line (Figure 5B).	('SERPINE1', 'Gene', (6, 14))	('SCC9', 'CellLine', 'CVCL:1685', (99, 103))	('loss', 'NegReg', (37, 41))	('SERPINE1', 'Gene', '5054', (6, 14))	('inhibition', 'Var', (15, 25))
179275	26359694	Cell proliferation was significantly higher in SCC9shRNA004 and SCC9shRNA159 cells than in the parental SCC9 cells at 48 hours, 72 hours and 96 hours after seeding (Figure 5D).	('SCC9', 'CellLine', 'CVCL:1685', (64, 68))	('higher', 'PosReg', (37, 43))	('SCC9', 'CellLine', 'CVCL:1685', (47, 51))	('SCC9shRNA004', 'Var', (47, 59))	('SCC9', 'CellLine', 'CVCL:1685', (104, 108))	('SCC9shRNA159', 'Var', (64, 76))	('Cell proliferation', 'CPA', (0, 18))
179281	26359694	After 48 hours of exposure to cisplatin, the IC50 increased from 10 muM to 20 muM by the ectopic expression of SERPINE1.	('IC50', 'MPA', (45, 49))	('muM', 'Gene', (78, 81))	('muM', 'Gene', (68, 71))	('SERPINE1', 'Gene', (111, 119))	('SERPINE1', 'Gene', '5054', (111, 119))	('ectopic expression', 'Var', (89, 107))	('cisplatin', 'Chemical', 'MESH:D002945', (30, 39))	('muM', 'Gene', '56925', (78, 81))	('muM', 'Gene', '56925', (68, 71))
179285	26359694	The number of apoptotic bodies after cisplatin exposure in the SCC9shRNA004 and SCC9shRNA159 transduced cells was higher than in SCC9 scramble cells (Figure 5E).	('higher', 'PosReg', (114, 120))	('apoptotic bodies', 'CPA', (14, 30))	('SCC9', 'CellLine', 'CVCL:1685', (129, 133))	('SCC9shRNA159', 'Var', (80, 92))	('transduced', 'Var', (93, 103))	('SCC9', 'CellLine', 'CVCL:1685', (63, 67))	('cisplatin', 'Chemical', 'MESH:D002945', (37, 46))	('SCC9', 'CellLine', 'CVCL:1685', (80, 84))
179288	26359694	The combination of cisplatin with the AKT inhibitor MK2206 completely reverts the resistance of 74BSerpE1 cells (overexpressing Serpine1) to cisplatin, since it induces apoptosis at a level similar to that achieved in UM-SCC-74B cells after their treatment with the same combination (Figure 5J).	('apoptosis', 'CPA', (169, 178))	('AKT', 'Gene', (38, 41))	('induces', 'Reg', (161, 168))	('MK2206', 'Chemical', 'MESH:C548887', (52, 58))	('cisplatin', 'Chemical', 'MESH:D002945', (141, 150))	('Serpine1', 'Gene', '5054', (128, 136))	('resistance', 'MPA', (82, 92))	('cisplatin', 'Chemical', 'MESH:D002945', (19, 28))	('MK2206', 'Var', (52, 58))	('AKT', 'Gene', '207', (38, 41))	('reverts', 'NegReg', (70, 77))	('combination', 'Interaction', (4, 15))	('Serpine1', 'Gene', (128, 136))
179290	26359694	A high expression of SERPINE1 increased the risk of metastasis and was associated with a poor clinical outcome.	('SERPINE1', 'Gene', (21, 29))	('metastasis', 'CPA', (52, 62))	('high', 'Var', (2, 6))	('increased', 'PosReg', (30, 39))	('associated', 'Reg', (71, 81))	('SERPINE1', 'Gene', '5054', (21, 29))
179293	26359694	Despite using different methods to detect SERPINE1 expression in pre-treatment tumor biopsies, we observed a positive association between high SERPINE1 expression and poor clinical outcome in three independent patient cohorts.	('SERPINE1', 'Gene', '5054', (42, 50))	('SERPINE1', 'Gene', (42, 50))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('tumor', 'Disease', (79, 84))	('expression', 'MPA', (152, 162))	('poor clinical outcome', 'CPA', (167, 188))	('patient', 'Species', '9606', (210, 217))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('high', 'Var', (138, 142))	('SERPINE1', 'Gene', '5054', (143, 151))	('SERPINE1', 'Gene', (143, 151))
179295	26359694	We also identified SERPINE1 expression as an independent risk factor for tumor progression in patients treated with radiotherapy or chemo-radiotherapy.	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('patients', 'Species', '9606', (94, 102))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Disease', (73, 78))	('SERPINE1', 'Gene', '5054', (19, 27))	('expression', 'Var', (28, 38))	('SERPINE1', 'Gene', (19, 27))
179300	26359694	In line with our results, Speleman and colleagues showed that high expression of SERPINE1 was associated with shorter disease-free survival in a univariate analysis performed in 46 HNSCC patients.	('patients', 'Species', '9606', (187, 195))	('shorter', 'NegReg', (110, 117))	('high expression', 'Var', (62, 77))	('disease-free survival', 'CPA', (118, 139))	('SERPINE1', 'Gene', '5054', (81, 89))	('SERPINE1', 'Gene', (81, 89))
179308	26359694	Similarly to our findings in HNSCC, a high expression of SERPINE1 was found to increase the risk of developing metastasis in patients with node negative breast cancer.	('increase', 'PosReg', (79, 87))	('breast cancer', 'Phenotype', 'HP:0003002', (153, 166))	('developing metastasis', 'CPA', (100, 121))	('high expression', 'Var', (38, 53))	('SERPINE1', 'Gene', '5054', (57, 65))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('breast cancer', 'Disease', 'MESH:D001943', (153, 166))	('SERPINE1', 'Gene', (57, 65))	('breast cancer', 'Disease', (153, 166))	('patients', 'Species', '9606', (125, 133))
179310	26359694	The observed association between high SERPINE1 expression and enhanced cell migration may seem counterintuitive regarding the notion that PA inhibition could reduce ECM degradation and cell invasion.	('high', 'Var', (33, 37))	('SERPINE1', 'Gene', (38, 46))	('cell invasion', 'CPA', (185, 198))	('ECM degradation', 'CPA', (165, 180))	('reduce', 'NegReg', (158, 164))	('enhanced', 'PosReg', (62, 70))	('cell migration', 'CPA', (71, 85))	('expression', 'MPA', (47, 57))	('SERPINE1', 'Gene', '5054', (38, 46))
179320	26359694	Although the inhibition of cell proliferation in cells displaying high SERPINE1 expression may at first glance seem inconsistent with its oncogenic role, previous studies have pointed out that the enhanced migration induced by SERPINE1 expression may also be accompanied by a decrease in cell proliferation.	('cell proliferation', 'CPA', (288, 306))	('expression', 'Var', (236, 246))	('SERPINE1', 'Gene', (227, 235))	('migration', 'CPA', (206, 215))	('SERPINE1', 'Gene', '5054', (227, 235))	('decrease', 'NegReg', (276, 284))	('enhanced', 'PosReg', (197, 205))	('SERPINE1', 'Gene', '5054', (71, 79))	('SERPINE1', 'Gene', (71, 79))
179330	26359694	In summary, a high expression of SERPINE1 is a poor prognostic marker in head and neck squamous cell carcinoma patients that increases the risk of metastatic recurrences after therapy, possibly due to an increase in tumor cell migration and in resistance to cisplatin.	('neck squamous cell carcinoma', 'Disease', (82, 110))	('tumor', 'Disease', (216, 221))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (87, 110))	('cisplatin', 'Chemical', 'MESH:D002945', (258, 267))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (82, 110))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('increases', 'PosReg', (125, 134))	('increase', 'PosReg', (204, 212))	('metastatic recurrences', 'CPA', (147, 169))	('tumor', 'Disease', 'MESH:D009369', (216, 221))	('SERPINE1', 'Gene', '5054', (33, 41))	('SERPINE1', 'Gene', (33, 41))	('high expression', 'Var', (14, 29))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (73, 110))	('patients', 'Species', '9606', (111, 119))
179354	26359694	HPRT1 amplification (Hs99999909_m1) was used as an endogenous control and RNA obtained from the UM-SCC-22A cell line was used as the calibration sample.	('HPRT1', 'Gene', '3251', (0, 5))	('HPRT1', 'Gene', (0, 5))	('Hs99999909_m1', 'Var', (21, 34))
179365	26359694	Lentiviral vectors (pLKO.1-puro) containing short hairpin RNA (shRNA) against human SERPINE1 (TRC2_331004, TRC2_370159) and non-mammalian shRNA control plasmid DNA (scramble) were purchased from Sigma-Aldrich (Sigma Aldrich, MO, USA).	('TRC2_370159', 'Var', (107, 118))	('mammalian', 'Species', '9606', (128, 137))	('SERPINE1', 'Gene', '5054', (84, 92))	('SERPINE1', 'Gene', (84, 92))	('human', 'Species', '9606', (78, 83))	('TRC2_331004', 'Var', (94, 105))
179377	26359694	Dilutions for the primary antibodies were: SERPINE1(1:1000, MAB10390, Abnova, USA), Phospho-Akt (Thr308)(1:1000, #9275, Cell Signalling), Akt (1:500, Mouse anti-Akt clone 55, BD Biosciences), ERK(1:2500, clone 16/ERK, BD Biosciences, USA), PI3K (1:2500, clone 4/PI3-Kinase, BD Biosciences) and GAPDH (1:10000, MAB374, Merck Millipore, Germany).	('1:2500', 'Var', (246, 252))	('Akt', 'Gene', (138, 141))	('1:10000', 'Var', (301, 308))	('Akt', 'Gene', '207', (92, 95))	('ERK', 'Gene', '2048', (213, 216))	('Akt', 'Gene', '207', (161, 164))	('ERK', 'Gene', '2048', (192, 195))	('Akt', 'Gene', '207', (138, 141))	('Akt', 'Gene', (92, 95))	('ERK', 'Gene', (213, 216))	('Mouse', 'Species', '10090', (150, 155))	('SERPINE1', 'Gene', '5054', (43, 51))	('SERPINE1', 'Gene', (43, 51))	('Akt', 'Gene', (161, 164))	('ERK', 'Gene', (192, 195))
179378	26359694	In the RT-PCR analysis and the TCGA database, the cut off to distinguish patients with high SERPINE1 expression and patients with low SERPINE1 expression was determined using Classification and Regression Tree Analysis (CART).	('patients', 'Species', '9606', (116, 124))	('high', 'Var', (87, 91))	('SERPINE1', 'Gene', '5054', (92, 100))	('SERPINE1', 'Gene', (92, 100))	('expression', 'MPA', (101, 111))	('patients', 'Species', '9606', (73, 81))	('SERPINE1', 'Gene', '5054', (134, 142))	('SERPINE1', 'Gene', (134, 142))
179412	32769880	The including criteria for carcinoma patients were as follows: esophageal squamous cell carcinoma patients with pT3N0-2M0 and the including criteria for control participates were normal healthy medical volunteers confirmed by gastroscopy.	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (63, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (27, 36))	('carcinoma', 'Disease', 'MESH:D009369', (88, 97))	('patients', 'Species', '9606', (37, 45))	('carcinoma', 'Disease', (27, 36))	('esophageal squamous cell carcinoma', 'Disease', (63, 97))	('patients', 'Species', '9606', (98, 106))	('pT3N0-2M0', 'Var', (112, 121))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (74, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('carcinoma', 'Disease', (88, 97))	('carcinoma', 'Disease', 'MESH:D009369', (27, 36))
179450	31496741	However, using an online database, we found that FAM163A may predict poor prognosis in lung squamous cell carcinomas (LUSC).	('carcinomas', 'Phenotype', 'HP:0030731', (106, 116))	('lung squamous cell carcinomas', 'Disease', (87, 116))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (87, 115))	('FAM163A', 'Var', (49, 56))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (92, 116))	('lung squamous cell carcinomas', 'Disease', 'MESH:D002294', (87, 116))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (92, 115))
179451	31496741	Co-immunoprecipitation and immunofluorescence were utilized to evaluate the interaction and co-localization of FAM163A with 14-3-3beta and ERK.	('interaction', 'Interaction', (76, 87))	('ERK', 'Gene', (139, 142))	('FAM163A', 'Var', (111, 118))	('ERK', 'Gene', '5594', (139, 142))
179452	31496741	In this study, our data revealed that FAM163A overexpression increased the levels of ERK and p90RSK phosphorylation and promoted the expression of cyclin D1.	('expression', 'MPA', (133, 143))	('p90RSK', 'Gene', '6195', (93, 99))	('p90RSK', 'Gene', (93, 99))	('FAM163A', 'Var', (38, 45))	('promoted', 'PosReg', (120, 128))	('ERK', 'Gene', '5594', (85, 88))	('ERK', 'Gene', (85, 88))	('levels', 'MPA', (75, 81))	('increased', 'PosReg', (61, 70))	('cyclin D1', 'Gene', '595', (147, 156))	('cyclin D1', 'Gene', (147, 156))
179454	31496741	FAM163A directly interacted with both 14-3-3beta and ERK and regulated the phosphorylation of ERK by upregulating the protein level of 14-3-3beta.	('interacted', 'Interaction', (17, 27))	('FAM163A', 'Var', (0, 7))	('ERK', 'Gene', (94, 97))	('protein level of 14-3-3beta', 'MPA', (118, 145))	('ERK', 'Gene', '5594', (53, 56))	('regulated', 'Reg', (61, 70))	('ERK', 'Gene', (53, 56))	('upregulating', 'PosReg', (101, 113))	('phosphorylation', 'MPA', (75, 90))	('ERK', 'Gene', '5594', (94, 97))
179456	31496741	Kaplan-Meier survival analysis implied the mean survival time of patients with positive FAM163A expression (49.72+-3.97 months) was much shorter than the patients with negative FAM163A expression (63.36+-3.14 months, P=0.011).	('shorter', 'NegReg', (137, 144))	('positive', 'Var', (79, 87))	('patients', 'Species', '9606', (154, 162))	('survival time', 'CPA', (48, 61))	('patients', 'Species', '9606', (65, 73))	('expression', 'Var', (96, 106))	('FAM163A', 'Gene', (88, 95))
179457	31496741	In summary, the present study identified a novel mechanism that FAM163A, through binding and upregulating 14-3-3beta, facilitated ERK phosphorylation that led to an increase of cellular proliferation of LUSC cells.	('14-3-3beta', 'Protein', (106, 116))	('increase', 'PosReg', (165, 173))	('cellular proliferation of LUSC cells', 'CPA', (177, 213))	('facilitated', 'PosReg', (118, 129))	('ERK', 'Gene', '5594', (130, 133))	('FAM163A', 'Var', (64, 71))	('upregulating', 'PosReg', (93, 105))	('ERK', 'Gene', (130, 133))	('binding', 'Interaction', (81, 88))
179458	31496741	FAM163A may be a useful marker to predict poor prognosis of patients with LUSC.	('FAM163A', 'Var', (0, 7))	('patients', 'Species', '9606', (60, 68))	('LUSC', 'Disease', (74, 78))
179465	31496741	Therefore, we speculated that FAM163A might activate ERK signaling pathway through its interaction with 14-3-3 family members.	('ERK', 'Gene', '5594', (53, 56))	('interaction', 'Interaction', (87, 98))	('ERK', 'Gene', (53, 56))	('FAM163A', 'Var', (30, 37))	('activate', 'PosReg', (44, 52))
179469	31496741	FAM163A was universal expressed in most of the NSCLC tissues.	('FAM163A', 'Var', (0, 7))	('NSCLC', 'Disease', 'MESH:D002289', (47, 52))	('NSCLC', 'Disease', (47, 52))
179470	31496741	However, overexpression of FAM163A was found predicting poor prognosis in squamous cell lung carcinomas (LUSC) but not in lung adenocarcinomas (Figure S1).	('FAM163A', 'Var', (27, 34))	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (122, 142))	('overexpression', 'PosReg', (9, 23))	('squamous cell lung carcinomas', 'Disease', 'MESH:D002294', (74, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('carcinomas', 'Phenotype', 'HP:0030731', (93, 103))	('carcinomas', 'Phenotype', 'HP:0030731', (132, 142))	('squamous cell lung carcinomas', 'Disease', (74, 103))	('lung adenocarcinomas', 'Disease', (122, 142))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (122, 142))	('squamous cell lung carcinomas', 'Phenotype', 'HP:0030359', (74, 103))	('squamous cell lung carcinoma', 'Phenotype', 'HP:0030359', (74, 102))
179471	31496741	We identified a novel mechanism that FAM163A, through binding and upregulating 14-3-3beta, facilitated ERK phosphorylation that led to the increase of cellular proliferation of LUSC cells.	('ERK', 'Gene', (103, 106))	('facilitated', 'PosReg', (91, 102))	('upregulating', 'PosReg', (66, 78))	('increase', 'PosReg', (139, 147))	('cellular proliferation of LUSC cells', 'CPA', (151, 187))	('FAM163A', 'Var', (37, 44))	('14-3-3beta', 'Protein', (79, 89))	('binding', 'Interaction', (54, 61))	('ERK', 'Gene', '5594', (103, 106))
179477	31496741	Single transgenic colonies were isolated by a micropipette, dissociated into small clumps of cells and transferred into 4-well plates coated with matrigel.The cells proliferated continuously in the presence of G418 and formed a large number of expanding undifferentiated colonies.	('G418', 'Var', (210, 214))	('G418', 'Chemical', 'MESH:C010680', (210, 214))	('expanding undifferentiated colonies', 'CPA', (244, 279))
179479	31496741	After blocking with 5% bovine serum albumin (BSA) for 2 hrs at room temperature, the membranes were incubated with the following primary antibodies overnight at 4 C: anti-FAM163A (1:100, sc-390936, Santa Cruz Biotechnology, Santa Cruz, CA, USA); anti-GAPDH (WH0002597M1, 1:5000, Sigma); anti-Myc-tag (#2276), anti- cyclin B1 (#4138), anti-cyclin D1 (#2978), anti-cyclin E1 (#4129), anti-cyclin H (#2927), anti-phosphorylated(p)-P38 ((Thr180/Tyr182#4511), P38 (#2308), anti-active-beta-catenin (Ser45, #19807), anti-beta-catenin (#2698), anti-p-JNK (Thr183/Tyr185, #4668), anti-JNK(#9252), anti-p-NF-kappaB (Ser536#13346), anti-NF-kappaB (#8242), anti-p-AKT (Ser473#12694), anti-AKT (#2920), anti-p-ERK (Thr202/Tyr204, #4370), anti-ERK (#4695) anti-p-p90RSK (Ser380, #11989), p90RSK (#9355), anti-p-GSK3beta (Ser9, #5558), anti-GSK3beta(#12456), anti-14-3-3beta (#9636), anti-14-3-3gamma (#5522), anti-14-3-3epsilon (#9635), 14-3-3zeta/delta (#7413), (1:500; Cell Signaling Technology, Danvers, MA, USA).	('AKT', 'Gene', '207', (678, 681))	('GSK3beta', 'Gene', (827, 835))	('#5522', 'Var', (888, 893))	('#9636', 'Var', (862, 867))	('p90RSK', 'Gene', (775, 781))	('cyclin B1', 'Gene', '891', (315, 324))	('P38', 'Gene', '1432', (455, 458))	('p90RSK', 'Gene', (750, 756))	('AKT', 'Gene', '207', (653, 656))	('cyclin B1', 'Gene', (315, 324))	('cyclin E1', 'Gene', '898', (363, 372))	('beta-catenin', 'Gene', (515, 527))	('NF-kappaB', 'Gene', (596, 605))	('NF-kappaB', 'Gene', (627, 636))	('GSK3beta', 'Gene', '2932', (798, 806))	('cyclin H', 'Gene', '902', (387, 395))	('ERK', 'Gene', '5594', (731, 734))	('beta-catenin', 'Gene', '1499', (515, 527))	('JNK', 'Gene', (577, 580))	('P38', 'Gene', (455, 458))	('NF-kappaB', 'Gene', '4790', (596, 605))	('NF-kappaB', 'Gene', '4790', (627, 636))	('ERK', 'Gene', '5594', (698, 701))	('JNK', 'Gene', '5599', (577, 580))	('p90RSK', 'Gene', '6195', (775, 781))	('cyclin E1', 'Gene', (363, 372))	('p-ERK', 'Gene', '9451', (696, 701))	('beta-catenin', 'Gene', (480, 492))	('ERK', 'Gene', (731, 734))	('AKT', 'Gene', (678, 681))	('beta-catenin', 'Gene', '1499', (480, 492))	('p-ERK', 'Gene', (696, 701))	('14-3-3zeta', 'Gene', '7534', (924, 934))	('p90RSK', 'Gene', '6195', (750, 756))	('cyclin D1', 'Gene', (339, 348))	('ERK', 'Gene', (698, 701))	('GSK3beta', 'Gene', (798, 806))	('bovine', 'Species', '9913', (23, 29))	('GSK3beta', 'Gene', '2932', (827, 835))	('P38', 'Gene', '1432', (428, 431))	('#9635', 'Var', (916, 921))	('JNK', 'Gene', (544, 547))	('AKT', 'Gene', (653, 656))	('14-3-3zeta', 'Gene', (924, 934))	('JNK', 'Gene', '5599', (544, 547))	('cyclin D1', 'Gene', '595', (339, 348))	('cyclin H', 'Gene', (387, 395))	('P38', 'Gene', (428, 431))
179484	31496741	LK2 and SK-MES-1 cells were stably transfected with pCMV6 or pCMV6-FAM163A plasmids, pretreated with U0126 or 14-3-3beta siRNA.	('pCMV6', 'Var', (52, 57))	('U0126', 'Chemical', 'MESH:C113580', (101, 106))	('SK-MES-1', 'CellLine', 'CVCL:0630', (8, 16))	('pCMV6-FAM163A', 'Var', (61, 74))
179492	31496741	After that, the lysates were immunoprecipitated overnight at 4 C with either anti-FAM163A (1:50, sc-390936, Santa Cruz Biotechnology) or anti-mouse IgG antibody bound to protein G PLUS-agarose (Santa Cruz Biotechnology).	('anti-FAM163A', 'Var', (77, 89))	('IgG antibody', 'Phenotype', 'HP:0003237', (148, 160))	('mouse', 'Species', '10090', (142, 147))	('protein G PLUS-agarose', 'Protein', (170, 192))	('IgG', 'Protein', (148, 151))	('agarose', 'Chemical', 'MESH:D012685', (185, 192))	('bound', 'Interaction', (161, 166))
179510	31496741	Subsequent cell viability assays indicated that cell transfected with FAM163A plasmid grew more rapidly than those transfected with the empty vector in LK2 and SK-MES-1 cell lines (P<0.05, respectively; Figure 1D).	('FAM163A', 'Var', (70, 77))	('grew', 'CPA', (86, 90))	('rapidly', 'PosReg', (96, 103))	('SK-MES-1', 'CellLine', 'CVCL:0630', (160, 168))
179511	31496741	In agreement with the results from in vitro analyses, our in vivo experiments revealed that the size and weight of the tumor xenografts were dramatically increased in mice injected with cells overexpressing FAM163A compared with those injected with cells transfected with empty vector (P<0.01, respectively; Figure 1G-I).	('tumor', 'Disease', (119, 124))	('FAM163A', 'Var', (207, 214))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('increased', 'PosReg', (154, 163))	('mice', 'Species', '10090', (167, 171))
179513	31496741	Subsequent cell viability assays (Figure 1K) and colony formation assays (Figure 1L and M) indicated that FAM163A RNAi inhibited the proliferation in both LK2 and SK-MES-1 cell lines (P<0.05, respectively).	('inhibited', 'NegReg', (119, 128))	('proliferation', 'CPA', (133, 146))	('SK-MES-1', 'CellLine', 'CVCL:0630', (163, 171))	('FAM163A RNAi', 'Var', (106, 118))
179516	31496741	By treated LK2 and SK-MES-1 cells with MEK inhibitor U0126, we found that the effects of FAM163A upregulating the phosphorylation of ERK and p90RSK, as well as the protein level of cyclin D1 were attenuated by U0126 incorporation (Figure 2B).	('cyclin D1', 'Gene', (181, 190))	('protein level', 'MPA', (164, 177))	('U0126', 'Chemical', 'MESH:C113580', (210, 215))	('SK-MES-1', 'CellLine', 'CVCL:0630', (19, 27))	('ERK', 'Gene', '5594', (133, 136))	('ERK', 'Gene', (133, 136))	('cyclin D1', 'Gene', '595', (181, 190))	('U0126', 'Chemical', 'MESH:C113580', (53, 58))	('FAM163A', 'Var', (89, 96))	('phosphorylation', 'MPA', (114, 129))	('upregulating', 'PosReg', (97, 109))	('MEK', 'Gene', (39, 42))	('MEK', 'Gene', '5609', (39, 42))	('p90RSK', 'Gene', '6195', (141, 147))	('p90RSK', 'Gene', (141, 147))
179518	31496741	The results indicated FAM163A directly interacted with ERK (Figure 2C).	('interacted', 'Reg', (39, 49))	('ERK', 'Gene', '5594', (55, 58))	('FAM163A', 'Var', (22, 29))	('ERK', 'Gene', (55, 58))
179519	31496741	The following immunofluorescence also found that FAM163A and ERK co-localized in the cytoplasm of LK2 cells (Figure 2D).	('ERK', 'Gene', '5594', (61, 64))	('ERK', 'Gene', (61, 64))	('FAM163A', 'Var', (49, 56))
179520	31496741	Besides, subsequent colony formation assays (Figure 2E and F) and MTT assays (Figure 2G) also revealed that the increase of cellular proliferation caused by FAM163A cDNA transfection was significantly reversed by U0126 incorporation.	('cellular proliferation', 'CPA', (124, 146))	('cDNA', 'Gene', (165, 169))	('increase', 'PosReg', (112, 120))	('MTT', 'Chemical', 'MESH:C070243', (66, 69))	('U0126', 'Chemical', 'MESH:C113580', (213, 218))	('FAM163A', 'Var', (157, 164))
179521	31496741	We first examined the expression of 14-3-3 family proteins after overexpressing FAM163A and interfering the expression of FAM163A in LK2 and SK-MES-1 cells.	('FAM163A', 'Var', (122, 129))	('overexpressing', 'PosReg', (65, 79))	('SK-MES-1', 'CellLine', 'CVCL:0630', (141, 149))	('examined', 'Reg', (9, 17))	('expression', 'MPA', (108, 118))	('interfering', 'NegReg', (92, 103))	('FAM163A', 'Gene', (80, 87))
179524	31496741	We found the upregulation of ERK and p90RSK phosphorylation resulted from overexpressing FAM163A was reversed by 14-3-3beta RNAi (Figure 3C).	('ERK', 'Gene', '5594', (29, 32))	('p90RSK', 'Gene', '6195', (37, 43))	('p90RSK', 'Gene', (37, 43))	('ERK', 'Gene', (29, 32))	('FAM163A', 'Var', (89, 96))	('upregulation', 'PosReg', (13, 25))
179525	31496741	The subsequent co-IP assays suggested that FAM163A interacted with 14-3-3beta (Figure 3D).	('FAM163A', 'Var', (43, 50))	('co-IP', 'Gene', '4512', (15, 20))	('interacted', 'Interaction', (51, 61))	('co-IP', 'Gene', (15, 20))
179526	31496741	Western blotting analysis showed that FAM163A protein level in 16 pairs of lung squamous cell carcinoma tissues and their corresponding normal tissues.	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (75, 103))	('lung squamous cell carcinoma', 'Disease', (75, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('FAM163A', 'Var', (38, 45))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (80, 103))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (75, 103))
179528	31496741	The mean protein level of FAM163A in lung squamous cell carcinoma tissues (mean +- SE, 0.76+-0.05) was significantly higher than that in the corresponding normal tissue (mean +- SE, 0.51+-0.07, P=0.0267, Figure 4B).	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (37, 65))	('lung squamous cell carcinoma', 'Disease', (37, 65))	('FAM163A', 'Var', (26, 33))	('protein level', 'MPA', (9, 22))	('higher', 'PosReg', (117, 123))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (37, 65))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (42, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (56, 65))
179538	31496741	Kaplan-Meier survival analysis implied the mean survival time of patients with positive FAM163A expression (49.72+-3.97 months) was much shorter than the patients with negative FAM163A expression (63.36+-3.14 months, P=0.011, Figure 4E).	('shorter', 'NegReg', (137, 144))	('positive', 'Var', (79, 87))	('patients', 'Species', '9606', (154, 162))	('survival time', 'CPA', (48, 61))	('patients', 'Species', '9606', (65, 73))	('expression', 'Var', (96, 106))	('FAM163A', 'Gene', (88, 95))
179539	31496741	In the present study, we identified that FAM163A interacted with 14-3-3beta and ERK, which thereby facilitating the phosphorylation of ERK by upregulating the protein level of 14-3-3beta.	('FAM163A', 'Var', (41, 48))	('ERK', 'Gene', '5594', (135, 138))	('ERK', 'Gene', '5594', (80, 83))	('interacted', 'Interaction', (49, 59))	('phosphorylation', 'MPA', (116, 131))	('ERK', 'Gene', (135, 138))	('facilitating', 'PosReg', (99, 111))	('ERK', 'Gene', (80, 83))	('protein level', 'MPA', (159, 172))	('upregulating', 'PosReg', (142, 154))
179540	31496741	Subsequently, FAM163A increased the levels of p90RSK phosphorylation and promoted the expression of cyclin D1, which were downstream molecules of ERK signaling, and upregulated proliferation of LUSC cells.	('ERK', 'Gene', '5594', (146, 149))	('FAM163A', 'Var', (14, 21))	('cyclin D1', 'Gene', (100, 109))	('ERK', 'Gene', (146, 149))	('p90RSK', 'Gene', '6195', (46, 52))	('p90RSK', 'Gene', (46, 52))	('expression', 'MPA', (86, 96))	('upregulated', 'PosReg', (165, 176))	('increased', 'PosReg', (22, 31))	('levels', 'MPA', (36, 42))	('promoted', 'PosReg', (73, 81))	('proliferation of LUSC cells', 'CPA', (177, 204))	('cyclin D1', 'Gene', '595', (100, 109))
179541	31496741	In clinical tissue samples, positive FAM163A expression significantly correlated with larger tumor sizes, advanced TNM staging, positive regional lymph node metastasis and poor overall survival.	('tumor', 'Disease', 'MESH:D009369', (93, 98))	('FAM163A', 'Gene', (37, 44))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Disease', (93, 98))	('expression', 'MPA', (45, 55))	('positive', 'Var', (28, 36))	('TNM', 'Gene', '10178', (115, 118))	('overall survival', 'CPA', (177, 193))	('correlated', 'Reg', (70, 80))	('TNM', 'Gene', (115, 118))
179542	31496741	The opinion of previous studies considered that FAM163A was specifically overexpressed in neuroblastoma at higher levels than other tissues including malignancies and normal tissues.	('neuroblastoma', 'Disease', (90, 103))	('neuroblastoma', 'Disease', 'MESH:D009447', (90, 103))	('neuroblastoma', 'Phenotype', 'HP:0003006', (90, 103))	('FAM163A', 'Var', (48, 55))	('malignancies', 'Disease', (150, 162))	('overexpressed', 'PosReg', (73, 86))	('malignancies', 'Disease', 'MESH:D009369', (150, 162))
179543	31496741	In the same study, they also revealed that FAM163A was a secreted protein in several neuroblastoma cell lines.	('FAM163A', 'Var', (43, 50))	('neuroblastoma', 'Disease', (85, 98))	('neuroblastoma', 'Disease', 'MESH:D009447', (85, 98))	('neuroblastoma', 'Phenotype', 'HP:0003006', (85, 98))
179545	31496741	Since FAM163A has been identified to be an oncogene in neuroblastoma, the expression of FAM163A in LUSC makes one wonder if it also plays an oncogenic role in the development of LUSC.	('FAM163A', 'Var', (88, 95))	('neuroblastoma', 'Disease', (55, 68))	('neuroblastoma', 'Disease', 'MESH:D009447', (55, 68))	('neuroblastoma', 'Phenotype', 'HP:0003006', (55, 68))
179546	31496741	Our data were consistent with previous studies that FAM163A facilitated cell proliferation in neuroblastoma.	('neuroblastoma', 'Disease', 'MESH:D009447', (94, 107))	('neuroblastoma', 'Disease', (94, 107))	('facilitated', 'PosReg', (60, 71))	('FAM163A', 'Var', (52, 59))	('cell proliferation', 'CPA', (72, 90))	('neuroblastoma', 'Phenotype', 'HP:0003006', (94, 107))
179547	31496741	In the same study, they addressed that FAM163A induced cell proliferation was mediated by ERK activation.	('ERK', 'Gene', (90, 93))	('cell proliferation', 'CPA', (55, 73))	('FAM163A', 'Var', (39, 46))	('ERK', 'Gene', '5594', (90, 93))	('activation', 'PosReg', (94, 104))
179549	31496741	Our results also showed that overexpression of FAM163A upregulated the phosphorylation of ERK, as well as its downstream molecule (p90RSK).	('phosphorylation', 'MPA', (71, 86))	('p90RSK', 'Gene', '6195', (131, 137))	('p90RSK', 'Gene', (131, 137))	('ERK', 'Gene', (90, 93))	('upregulated', 'PosReg', (55, 66))	('ERK', 'Gene', '5594', (90, 93))	('FAM163A', 'Var', (47, 54))
179552	31496741	As cyclin D1 was a downstream molecule of ERK signaling, we next incorporated ERK inhibitor to observe whether FAM163A promote cyclin D1 expression through ERK signaling.	('ERK', 'Gene', (42, 45))	('ERK', 'Gene', '5594', (156, 159))	('expression', 'MPA', (137, 147))	('ERK', 'Gene', (156, 159))	('promote', 'PosReg', (119, 126))	('ERK', 'Gene', '5594', (78, 81))	('FAM163A', 'Var', (111, 118))	('ERK', 'Gene', (78, 81))	('cyclin D1', 'Gene', '595', (127, 136))	('ERK', 'Gene', '5594', (42, 45))	('cyclin D1', 'Gene', '595', (3, 12))	('cyclin D1', 'Gene', (127, 136))	('cyclin D1', 'Gene', (3, 12))
179553	31496741	Our results showed that FAM163A promoted cell proliferation through interacting and activating ERK-cyclin D1 signaling.	('promoted', 'PosReg', (32, 40))	('ERK', 'Gene', '5594', (95, 98))	('FAM163A', 'Var', (24, 31))	('cell proliferation', 'CPA', (41, 59))	('ERK', 'Gene', (95, 98))	('interacting', 'Interaction', (68, 79))	('cyclin D1', 'Gene', '595', (99, 108))	('cyclin D1', 'Gene', (99, 108))	('activating', 'PosReg', (84, 94))
179554	31496741	Although previous studies have demonstrated that FAM163A regulated ERK signaling pathway, the results of the present study revealed that FAM163A directly interacted with ERK.	('ERK', 'Gene', '5594', (170, 173))	('ERK', 'Gene', '5594', (67, 70))	('ERK', 'Gene', (67, 70))	('ERK', 'Gene', (170, 173))	('interacted', 'Interaction', (154, 164))	('FAM163A', 'Var', (137, 144))
179556	31496741	Subsequent co-IP results suggested that FAM163A directly interacted with 14-3-3beta.	('interacted', 'Interaction', (57, 67))	('co-IP', 'Gene', '4512', (11, 16))	('FAM163A', 'Var', (40, 47))	('co-IP', 'Gene', (11, 16))
179558	31496741	Western blotting results showed that the increase of the levels of phosphorylated ERK and p90RSK induced by FAM163A overexpression were attenuated by 14-3-3beta RNAi, as well as the results of colony formation analysis and MTT analysis.	('p90RSK', 'Gene', (90, 96))	('colony formation analysis', 'CPA', (193, 218))	('p90RSK', 'Gene', '6195', (90, 96))	('ERK', 'Gene', '5594', (82, 85))	('levels', 'MPA', (57, 63))	('FAM163A', 'Gene', (108, 115))	('MTT', 'Chemical', 'MESH:C070243', (223, 226))	('ERK', 'Gene', (82, 85))	('overexpression', 'Var', (116, 130))	('increase', 'PosReg', (41, 49))	('attenuated', 'NegReg', (136, 146))
179559	31496741	These results suggested that FAM163A, 14-3-3beta and ERK were likely to form a complex and FAM163A might facilitate the phosphorylation of ERK signaling through interacting with 14-3-3beta which thereby mediated cell proliferation of LUSC cells.	('mediated', 'PosReg', (203, 211))	('phosphorylation', 'MPA', (120, 135))	('ERK', 'Gene', '5594', (53, 56))	('ERK', 'Gene', (139, 142))	('ERK', 'Gene', '5594', (139, 142))	('ERK', 'Gene', (53, 56))	('facilitate', 'PosReg', (105, 115))	('FAM163A', 'Var', (91, 98))	('interacting', 'Interaction', (161, 172))	('cell proliferation of LUSC cells', 'CPA', (212, 244))
179562	31496741	Our data were consistent with the results from an online database which indicated that FAM163A might have prognostic value in patients with LUSC.	('LUSC', 'Disease', (140, 144))	('FAM163A', 'Var', (87, 94))	('patients', 'Species', '9606', (126, 134))
179563	31496741	In summary, the present study identified a novel mechanism that FAM163A facilitates ERK phosphorylation through binding and upregulating 14-3-3beta, which led to an increase in cellular proliferation of LUSC cells.	('increase', 'PosReg', (165, 173))	('binding', 'Interaction', (112, 119))	('cellular proliferation of LUSC cells', 'CPA', (177, 213))	('ERK', 'Gene', '5594', (84, 87))	('facilitates', 'PosReg', (72, 83))	('14-3-3beta', 'MPA', (137, 147))	('ERK', 'Gene', (84, 87))	('upregulating', 'PosReg', (124, 136))	('FAM163A', 'Var', (64, 71))
179564	28719033	Identification of driver copy number alterations in diverse cancer types and application in drug repositioning Results from numerous studies suggest an important role for somatic copy number alterations (SCNAs) in cancer progression.	('cancer', 'Disease', (214, 220))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('copy number alterations', 'Var', (25, 48))	('cancer', 'Disease', (60, 66))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('cancer', 'Disease', 'MESH:D009369', (214, 220))
179611	28719033	a + b + c + d is the total number of genes in the expression profile, and a + b is the number of census cancer genes in the expression profile.	('a + b + c + d', 'Var', (0, 13))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('census cancer', 'Disease', (97, 110))	('census cancer', 'Disease', 'MESH:D009369', (97, 110))	('a + b', 'Var', (74, 79))
179624	28719033	Second, alterations, including SCNAs, that affect expression levels of other genes in the cancer genome have been used to identify key events for carcinogenesis (Masica and Karchin, 2011).	('carcinogenesis', 'Disease', (146, 160))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('alterations', 'Var', (8, 19))	('affect', 'Reg', (43, 49))	('expression levels', 'MPA', (50, 67))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('cancer', 'Disease', (90, 96))	('carcinogenesis', 'Disease', 'MESH:D063646', (146, 160))
179643	28719033	The drivers with deletions also significantly overlapped with tumor suppressor genes in the TSGene database in 11 of the 18 cancer types (Fig.	('overlapped', 'Reg', (46, 56))	('cancer', 'Disease', (124, 130))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('deletions', 'Var', (17, 26))	('tumor', 'Disease', (62, 67))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('cancer', 'Disease', 'MESH:D009369', (124, 130))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
179650	28719033	Many studies have reported aberrations in POU5F1B in cancer, such as in gastric and prostate cancer (Hayashi et al., 2015; Kastler et al., 2010).	('cancer', 'Disease', (93, 99))	('gastric and prostate cancer', 'Disease', 'MESH:D013274', (72, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('cancer', 'Disease', (53, 59))	('POU5F1B', 'Gene', (42, 49))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('POU5F1B', 'Gene', '5462', (42, 49))	('prostate cancer', 'Phenotype', 'HP:0012125', (84, 99))	('aberrations', 'Var', (27, 38))
179651	28719033	5C, a total of nine non-coding drivers (hsa-mir-106b, hsa-mir-218-2, hsa-mir-548k, AP006216.10, CAPN10-AS1, RP11-1191J2.4, RP11-191L9.4, RP11-443B7.1 and RP11-794P6.1) were shared by two cancer types, and three non-coding drivers (PVT1, SOX2-OT and hsa-mir-429) by three cancer types.	('AS1', 'Gene', (103, 106))	('RP11', 'Gene', (108, 112))	('RP11', 'Gene', '26121', (154, 158))	('PVT1', 'Gene', '5820', (231, 235))	('RP11', 'Gene', (123, 127))	('cancer', 'Disease', (271, 277))	('cancer', 'Disease', 'MESH:D009369', (187, 193))	('cancer', 'Phenotype', 'HP:0002664', (271, 277))	('RP11', 'Gene', (137, 141))	('RP11', 'Gene', (154, 158))	('SOX2-OT', 'Gene', (237, 244))	('AS1', 'Gene', '5729', (103, 106))	('CAPN10', 'Gene', (96, 102))	('SOX2-OT', 'Gene', '347689', (237, 244))	('RP11', 'Gene', '26121', (108, 112))	('CAPN10', 'Gene', '11132', (96, 102))	('cancer', 'Disease', 'MESH:D009369', (271, 277))	('hsa-mir-218-2', 'Gene', '407001', (54, 67))	('RP11', 'Gene', '26121', (123, 127))	('hsa-mir-218-2', 'Gene', (54, 67))	('cancer', 'Disease', (187, 193))	('AP006216.10', 'Var', (83, 94))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('hsa-mir-429', 'Gene', '554210', (249, 260))	('PVT1', 'Gene', (231, 235))	('RP11', 'Gene', '26121', (137, 141))	('hsa-mir-429', 'Gene', (249, 260))
179655	28719033	In total, seven drivers (MYC with amplification, PER2, HDAC4, PTPRG, PIK3R1, RAPGEF1 and PPP5C with deletion) were detected in both BRCA and OV.	('BRCA', 'Gene', '672', (132, 136))	('PIK3R1', 'Gene', (69, 75))	('MYC', 'Gene', (25, 28))	('HDAC4', 'Gene', '9759', (55, 60))	('RAPGEF1', 'Gene', '2889', (77, 84))	('PPP5C', 'Gene', (89, 94))	('PPP5C', 'Gene', '5536', (89, 94))	('BRCA', 'Gene', (132, 136))	('OV', 'Phenotype', 'HP:0100615', (141, 143))	('deletion', 'Var', (100, 108))	('amplification', 'Var', (34, 47))	('HDAC4', 'Gene', (55, 60))	('PIK3R1', 'Gene', '5295', (69, 75))	('MYC', 'Gene', '4609', (25, 28))	('PTPRG', 'Gene', (62, 67))	('PER2', 'Gene', (49, 53))	('BRCA', 'Phenotype', 'HP:0003002', (132, 136))	('RAPGEF1', 'Gene', (77, 84))	('PER2', 'Gene', '8864', (49, 53))	('PTPRG', 'Gene', '5793', (62, 67))
179666	28719033	Copy number alterations of non-coding RNAs play important roles in the progression of diverse types of cancer (Du et al., 2016).	('RNAs', 'Gene', (38, 42))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('Copy number alterations', 'Var', (0, 23))	('roles', 'Reg', (58, 63))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))
179669	28719033	For example, driver lncRNA GAS5 with amplification in liver hepatocellular carcinoma (LIHC) identified in our work has been reported with oncogenic roles in LIHC by Tao et al.	('GAS5', 'Gene', '60674', (27, 31))	('liver hepatocellular carcinoma', 'Disease', 'MESH:D006528', (54, 84))	('LIHC', 'Disease', (86, 90))	('LIHC', 'Disease', 'None', (86, 90))	('amplification', 'Var', (37, 50))	('GAS5', 'Gene', (27, 31))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('LIHC', 'Disease', (157, 161))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (60, 84))	('LIHC', 'Disease', 'None', (157, 161))	('liver hepatocellular carcinoma', 'Disease', (54, 84))
179670	28719033	Hsa-mir-134, a driver miRNA with a deletion in LUAD, was found to suppress NSCLC progression through down-regulation of CCND1 (Sun et al., 2016).	('LUAD', 'Gene', (47, 51))	('suppress', 'NegReg', (66, 74))	('down-regulation', 'NegReg', (101, 116))	('NSCLC', 'Phenotype', 'HP:0030358', (75, 80))	('Hsa-mir-134', 'Gene', '406924', (0, 11))	('CCND1', 'Gene', (120, 125))	('NSCLC', 'Disease', (75, 80))	('deletion', 'Var', (35, 43))	('LUAD', 'Phenotype', 'HP:0030078', (47, 51))	('Hsa-mir-134', 'Gene', (0, 11))	('NSCLC', 'Disease', 'MESH:D002289', (75, 80))	('CCND1', 'Gene', '595', (120, 125))
179694	28719033	Afatinib, another FDA approved drug, is used to treat late stage (metastatic) NSCLC with EGFR mutations (Dungo and Keating, 2013) (Fig.	('EGFR', 'Gene', '1956', (89, 93))	('EGFR', 'Gene', (89, 93))	('mutations', 'Var', (94, 103))	('NSCLC', 'Phenotype', 'HP:0030358', (78, 83))	('NSCLC', 'Disease', (78, 83))	('Afatinib', 'Chemical', 'MESH:D000077716', (0, 8))	('NSCLC', 'Disease', 'MESH:D002289', (78, 83))
179695	28719033	LUSC cell lines with amplification of EGFR show marginally significant sensitivity to lapatinib compared with those of LUSC cell lines with wild-type EGFR in the CCLE database (P = 0.049, Wilcoxon rank-sum test, Fig.	('EGFR', 'Gene', '1956', (38, 42))	('EGFR', 'Gene', (150, 154))	('EGFR', 'Gene', (38, 42))	('lapatinib', 'Chemical', 'MESH:D000077341', (86, 95))	('sensitivity to lapatinib', 'MPA', (71, 95))	('CCLE', 'Chemical', '-', (162, 166))	('LUSC', 'Phenotype', 'HP:0030359', (119, 123))	('amplification', 'Var', (21, 34))	('EGFR', 'Gene', '1956', (150, 154))	('LUSC', 'Phenotype', 'HP:0030359', (0, 4))
179696	28719033	LGG cell lines with amplification of EGFR show significant sensitivity to lapatinib compared with those of LGG cell lines with wild-type EGFR in the GDSC database (P = 6.1 x 10-3, Wilcoxon rank-sum test, Fig.	('EGFR', 'Gene', (137, 141))	('sensitivity to lapatinib', 'MPA', (59, 83))	('EGFR', 'Gene', '1956', (37, 41))	('lapatinib', 'Chemical', 'MESH:D000077341', (74, 83))	('EGFR', 'Gene', '1956', (137, 141))	('amplification', 'Var', (20, 33))	('EGFR', 'Gene', (37, 41))
179697	28719033	BRCA cell lines with amplification of ERBB2 show significantly lower IC50 levels of afatinib compared with those of BRCA cell lines with wild-type ERBB2 in the GDSC database (P = 6.1 x 10-3, Wilcoxon rank-sum test, Fig.	('IC50 levels of afatinib', 'MPA', (69, 92))	('BRCA', 'Gene', (0, 4))	('lower', 'NegReg', (63, 68))	('BRCA', 'Phenotype', 'HP:0003002', (0, 4))	('ERBB2', 'Gene', (38, 43))	('ERBB2', 'Gene', (147, 152))	('ERBB2', 'Gene', '2064', (38, 43))	('ERBB2', 'Gene', '2064', (147, 152))	('afatinib', 'Chemical', 'MESH:D000077716', (84, 92))	('BRCA', 'Phenotype', 'HP:0003002', (116, 120))	('amplification', 'Var', (21, 34))	('BRCA', 'Gene', (116, 120))	('BRCA', 'Gene', '672', (116, 120))	('BRCA', 'Gene', '672', (0, 4))
179709	28719033	Both CDKN2A and RB1 were reported to have deletions in BRCA and LGG (Bieche and Lidereau, 2000; Debniak et al., 2004).	('BRCA', 'Phenotype', 'HP:0003002', (55, 59))	('BRCA', 'Gene', '672', (55, 59))	('CDKN2A', 'Gene', (5, 11))	('BRCA', 'Gene', (55, 59))	('RB1', 'Gene', (16, 19))	('LGG', 'Gene', (64, 67))	('CDKN2A', 'Gene', '1029', (5, 11))	('deletions', 'Var', (42, 51))	('RB1', 'Gene', '5925', (16, 19))
179711	28719033	Notably, our work investigated the similarity and specificity of different cancer types from copy number alterations, which only represents one kind of molecular feature of cancer cells.	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('cancer', 'Disease', (173, 179))	('cancer', 'Disease', (75, 81))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('copy number alterations', 'Var', (93, 116))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))
179714	28719033	The drivers with amplifications in BRCA identified by our work significantly overlapped those detected by the Helios method (P = 9.46 x 10-10, hypergeometric test), including CCND1, MYC, ERBB2, ERLIN2, FOXA1, RAD52 and TOMM20.	('ERBB2', 'Gene', (187, 192))	('TOMM20', 'Gene', '9804', (219, 225))	('RAD52', 'Gene', '5893', (209, 214))	('BRCA', 'Phenotype', 'HP:0003002', (35, 39))	('ERLIN2', 'Gene', (194, 200))	('amplifications', 'Var', (17, 31))	('FOXA1', 'Gene', (202, 207))	('ERLIN2', 'Gene', '11160', (194, 200))	('BRCA', 'Gene', (35, 39))	('TOMM20', 'Gene', (219, 225))	('MYC', 'Gene', '4609', (182, 185))	('CCND1', 'Gene', (175, 180))	('BRCA', 'Gene', '672', (35, 39))	('FOXA1', 'Gene', '3169', (202, 207))	('RAD52', 'Gene', (209, 214))	('ERBB2', 'Gene', '2064', (187, 192))	('MYC', 'Gene', (182, 185))	('CCND1', 'Gene', '595', (175, 180))
179716	28719033	(2016) reported that gistic 2.0 tends to call larger deletion regions than amplification regions and identifies more drivers in deleted regions than in amplified regions for breast cancer.	('breast cancer', 'Disease', 'MESH:D001943', (174, 187))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('breast cancer', 'Disease', (174, 187))	('breast cancer', 'Phenotype', 'HP:0003002', (174, 187))	('deletion', 'Var', (53, 61))
179717	28719033	Generally, our methods identified more drivers with deletions than drivers with amplifications for each cancer type, except for LIHC, which has 77 amplified drivers and 41 deleted drivers (Table S2).	('LIHC', 'Disease', 'None', (128, 132))	('LIHC', 'Disease', (128, 132))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('deletions', 'Var', (52, 61))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))
179719	28719033	Some studies have also found that deletions or losses are more common than amplifications or gains in cancer (Cancer Genome Atlas Network, 2012; Schoch et al., 2002), which is an interesting phenomenon that warrants further exploration.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('deletions', 'Var', (34, 43))	('losses', 'NegReg', (47, 53))	('Cancer Genome Atlas', 'Disease', (110, 129))	('Cancer', 'Phenotype', 'HP:0002664', (110, 116))	('gains in cancer', 'Disease', (93, 108))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (110, 129))	('gains in cancer', 'Disease', 'MESH:D015430', (93, 108))
179724	28719033	The mutation status of known cancer genes may affect the expression of CDEGs.	('expression', 'MPA', (57, 67))	('cancer', 'Disease', (29, 35))	('CDEGs', 'Gene', (71, 76))	('mutation', 'Var', (4, 12))	('affect', 'Reg', (46, 52))	('CDEGs', 'Chemical', '-', (71, 76))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('cancer', 'Disease', 'MESH:D009369', (29, 35))
179735	32695668	In addition, high expression of CORO1C was found to be significantly correlated with tumor-infiltrating neutrophils (TINs), a negative regulatory component that facilitates tumor distant progression and induces poor clinical outcome.	('tumor', 'Disease', (85, 90))	('correlated', 'Reg', (69, 79))	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('TINs', 'Chemical', '-', (117, 121))	('CORO1C', 'Gene', (32, 38))	('high', 'Var', (13, 17))	('facilitates', 'PosReg', (161, 172))	('CORO1C', 'Gene', '23603', (32, 38))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('induces', 'Reg', (203, 210))	('tumor', 'Disease', (173, 178))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('expression', 'MPA', (18, 28))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))
179788	32695668	The two genes had almost identical mutational rates, both around 2%, but the major genetic changes in CORO1C are mutation and copy number amplification while deep depletion of TMPRSS4 gene is detectable in a small group of patients, which suggests a heterogeneous gene alteration pattern and exclusive molecular function of these two genes (Figures 8E,F).	('TMPRSS4', 'Gene', '56649', (176, 183))	('changes', 'Reg', (91, 98))	('mutation', 'Var', (113, 121))	('copy', 'MPA', (126, 130))	('CORO1C', 'Gene', (102, 108))	('CORO1C', 'Gene', '23603', (102, 108))	('TMPRSS4', 'Gene', (176, 183))	('patients', 'Species', '9606', (223, 231))
179801	32695668	In lung squamous cell carcinoma, overexpressed TMPRSS4 is associated with disease recurrence and poor survival by promoting invasion and metastasis.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (8, 31))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (3, 31))	('lung squamous cell carcinoma', 'Disease', (3, 31))	('TMPRSS4', 'Gene', (47, 54))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('promoting', 'PosReg', (114, 123))	('overexpressed', 'Var', (33, 46))	('TMPRSS4', 'Gene', '56649', (47, 54))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (3, 31))
179806	32695668	In pancreatic carcinoma, TMPRSS4 is identified as a candidate biomarker by affecting the clonability and invasiveness of pancreatic cancer cells, and overexpressed TMPRSS4 predicts poor prognosis.	('affecting', 'Reg', (75, 84))	('TMPRSS4', 'Gene', (164, 171))	('clonability', 'CPA', (89, 100))	('invasiveness of pancreatic cancer', 'Disease', (105, 138))	('TMPRSS4', 'Gene', (25, 32))	('invasiveness of pancreatic cancer', 'Disease', 'MESH:D010190', (105, 138))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('TMPRSS4', 'Gene', '56649', (164, 171))	('pancreatic carcinoma', 'Disease', (3, 23))	('overexpressed', 'Var', (150, 163))	('TMPRSS4', 'Gene', '56649', (25, 32))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (121, 138))	('pancreatic carcinoma', 'Disease', 'MESH:D010190', (3, 23))	('carcinoma', 'Phenotype', 'HP:0030731', (14, 23))
179807	32695668	In prostate cancer cells, overexpressed TMPRSS4 promotes migration via the progression of EMT.	('prostate cancer', 'Phenotype', 'HP:0012125', (3, 18))	('progression of EMT', 'CPA', (75, 93))	('migration', 'CPA', (57, 66))	('TMPRSS4', 'Gene', '56649', (40, 47))	('promotes', 'PosReg', (48, 56))	('prostate cancer', 'Disease', (3, 18))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('overexpressed', 'Var', (26, 39))	('TMPRSS4', 'Gene', (40, 47))	('prostate cancer', 'Disease', 'MESH:D011471', (3, 18))
179808	32695668	Interestingly, in contrast to most cancer types in published research, our study finds that high expression of TMPRSS4 predicts a better clinical outcome in bladder cancer, and this finding has been verified in three data sets (two online and one from our center).	('better', 'PosReg', (130, 136))	('TMPRSS4', 'Gene', (111, 118))	('high', 'Var', (92, 96))	('TMPRSS4', 'Gene', '56649', (111, 118))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('bladder cancer', 'Phenotype', 'HP:0009725', (157, 171))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('bladder cancer', 'Disease', 'MESH:D001749', (157, 171))	('cancer', 'Disease', (165, 171))	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('bladder cancer', 'Disease', (157, 171))	('cancer', 'Disease', (35, 41))
179813	32695668	In lung squamous cell carcinoma, CORO1C was identified as a target of the miR-1/133a cluster, and silencing CORO1C inhibited cancer cell proliferation, migration, and invasion.	('CORO1C', 'Gene', '23603', (108, 114))	('CORO1C', 'Gene', (33, 39))	('migration', 'CPA', (152, 161))	('miR-1', 'Gene', '79187', (74, 79))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (8, 31))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (3, 31))	('lung squamous cell carcinoma', 'Disease', (3, 31))	('CORO1C', 'Gene', '23603', (33, 39))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('miR-1', 'Gene', (74, 79))	('silencing', 'Var', (98, 107))	('invasion', 'CPA', (167, 175))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('inhibited', 'NegReg', (115, 124))	('CORO1C', 'Gene', (108, 114))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (3, 31))
179814	32695668	In gastric cancer, overexpressed CORO1C is associated with poor prognosis and could promote metastasis by regulating cyclin D1 and vimentin.	('CORO1C', 'Gene', (33, 39))	('cyclin D1', 'Gene', (117, 126))	('promote', 'PosReg', (84, 91))	('vimentin', 'Gene', '7431', (131, 139))	('CORO1C', 'Gene', '23603', (33, 39))	('gastric cancer', 'Phenotype', 'HP:0012126', (3, 17))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('metastasis', 'CPA', (92, 102))	('vimentin', 'Gene', (131, 139))	('regulating', 'Reg', (106, 116))	('overexpressed', 'Var', (19, 32))	('gastric cancer', 'Disease', (3, 17))	('gastric cancer', 'Disease', 'MESH:D013274', (3, 17))	('cyclin D1', 'Gene', '595', (117, 126))
179815	32695668	In our study, the high expression level of CORO1C also predicted poor survival outcomes in bladder cancer, which is consistent with other cancer types.	('survival outcomes', 'CPA', (70, 87))	('cancer', 'Disease', (138, 144))	('CORO1C', 'Gene', (43, 49))	('bladder cancer', 'Disease', 'MESH:D001749', (91, 105))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('CORO1C', 'Gene', '23603', (43, 49))	('bladder cancer', 'Disease', (91, 105))	('cancer', 'Disease', (99, 105))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('expression level', 'MPA', (23, 39))	('high', 'Var', (18, 22))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('bladder cancer', 'Phenotype', 'HP:0009725', (91, 105))	('poor', 'NegReg', (65, 69))	('cancer', 'Disease', 'MESH:D009369', (138, 144))
179818	32695668	Many studies have shown that TINs promote the adhesion of tumor cells to the epithelial monolayer and, thus, accelerate the metastasis of tumor cells.	('accelerate', 'PosReg', (109, 119))	('tumor', 'Disease', (58, 63))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (138, 143))	('TINs', 'Var', (29, 33))	('adhesion', 'CPA', (46, 54))	('TINs', 'Chemical', '-', (29, 33))	('promote', 'PosReg', (34, 41))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
179819	32695668	In pancreatic ductal adenocarcinoma, TINs promote the EMT process and the invasive growth of tumor cells.	('EMT process', 'CPA', (54, 65))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('TINs', 'Chemical', '-', (37, 41))	('tumor', 'Disease', (93, 98))	('TINs', 'Var', (37, 41))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (3, 35))	('promote', 'PosReg', (42, 49))	('pancreatic ductal adenocarcinoma', 'Disease', (3, 35))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (3, 35))	('carcinoma', 'Phenotype', 'HP:0030731', (26, 35))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
179874	32016477	Epigenetic abnormalities may serve as potential biomarkers and diagnostic and/or therapeutic targets, which may help to monitor and improve the prognosis of patients with cancer.	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('patients', 'Species', '9606', (157, 165))	('cancer', 'Disease', (171, 177))	('improve', 'PosReg', (132, 139))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('Epigenetic abnormalities', 'Var', (0, 24))
179888	32016477	At present, the pathogenesis and progressive mechanisms of LUSC remain unclear, though the two most important mechanisms of tumorigenesis are gene mutations and epigenetic alterations.	('LUSC', 'Disease', 'MESH:D018307', (59, 63))	('tumor', 'Disease', 'MESH:D009369', (124, 129))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('LUSC', 'Phenotype', 'HP:0030359', (59, 63))	('tumor', 'Disease', (124, 129))	('gene mutations', 'Var', (142, 156))	('epigenetic alterations', 'Var', (161, 183))	('LUSC', 'Disease', (59, 63))
179893	32016477	Even in solid tumors, methylated or epigenetic signatures have become an area of increasing interest, in such malignancies as breast cancer, esophageal carcinoma, epithelial ovarian and liver cancer.	('carcinoma', 'Phenotype', 'HP:0030731', (152, 161))	('solid tumors', 'Disease', 'MESH:D009369', (8, 20))	('epithelial ovarian and liver cancer', 'Disease', 'MESH:D010051', (163, 198))	('breast cancer', 'Phenotype', 'HP:0003002', (126, 139))	('epigenetic signatures', 'Var', (36, 57))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (141, 161))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('breast cancer', 'Disease', 'MESH:D001943', (126, 139))	('malignancies', 'Disease', 'MESH:D009369', (110, 122))	('breast cancer', 'Disease', (126, 139))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('esophageal carcinoma', 'Disease', (141, 161))	('liver cancer', 'Phenotype', 'HP:0002896', (186, 198))	('malignancies', 'Disease', (110, 122))	('methylated', 'Var', (22, 32))	('solid tumors', 'Disease', (8, 20))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (141, 161))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
179894	32016477	These studies indicated that the methylation of some specific genes may affect gene expression, and is closely associated with the diagnosis and prognosis of some types of cancer.	('methylation', 'Var', (33, 44))	('affect', 'Reg', (72, 78))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('gene expression', 'MPA', (79, 94))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('cancer', 'Disease', (172, 178))	('associated with', 'Reg', (111, 126))
179919	32016477	The present study focused on the correlation between the methylation of abnormal methylation sites and the corresponding gene expression of hub MDGs.	('MDG', 'Gene', (144, 147))	('MDG', 'Gene', '4350', (144, 147))	('methylation sites', 'Var', (81, 98))
179929	32016477	Of these 3 hub MDGs, PMPCAP1 and SOWAHC, characterized by hypomethylation and high expression levels, were associated with poor prognosis in patients with LUSC, whilst ZNF454, characterized by hypermethylation and low expression level, was associated with an improved prognosis.	('ZNF454', 'Gene', (168, 174))	('ZNF454', 'Gene', '285676', (168, 174))	('LUSC', 'Disease', (155, 159))	('expression levels', 'MPA', (83, 100))	('LUSC', 'Phenotype', 'HP:0030359', (155, 159))	('LUSC', 'Disease', 'MESH:D018307', (155, 159))	('SOWAHC', 'Gene', '65124', (33, 39))	('SOWAHC', 'Gene', (33, 39))	('PMPCAP1', 'Var', (21, 28))	('MDG', 'Gene', (15, 18))	('patients', 'Species', '9606', (141, 149))	('MDG', 'Gene', '4350', (15, 18))
179931	32016477	The results of correlation analysis revealed 5 key methylation sites of the PMPCAP1 gene (cg06551022, cg14777507, cg07794230, cg10697010 and cg16254375), 1 key methylation site of the SOWAHC gene (cg19399885) and 10 key methylation sites of the ZNF454 gene (cg17840719, cg16536329, cg23037403, cg20778451, cg24843380, cg03234732, cg02165355, cg10575261, cg10902717 and cg05461386; Fig.	('cg20778451', 'Var', (294, 304))	('SOWAHC', 'Gene', '65124', (184, 190))	('cg07794230', 'Var', (114, 124))	('cg10902717', 'Var', (354, 364))	('cg23037403', 'Var', (282, 292))	('ZNF454', 'Gene', (245, 251))	('cg24843380', 'Var', (306, 316))	('SOWAHC', 'Gene', (184, 190))	('cg10575261', 'Var', (342, 352))	('cg05461386', 'Var', (369, 379))	('cg02165355', 'Var', (330, 340))	('PMPCAP1', 'Gene', (76, 83))	('cg17840719', 'Var', (258, 268))	('cg03234732', 'Var', (318, 328))	('ZNF454', 'Gene', '285676', (245, 251))
179936	32016477	In addition to studies into gene mutations, the association between epigenetic changes (particularly DNA methylation) and LUSC has also attracted great attention.	('epigenetic changes', 'Var', (68, 86))	('LUSC', 'Disease', 'MESH:D018307', (122, 126))	('LUSC', 'Disease', (122, 126))	('LUSC', 'Phenotype', 'HP:0030359', (122, 126))
179937	32016477	Epigenetic studies have revealed that genome-scale epigenetic modifications, including DNA methylation, histone modification and microRNA interference, are involved in the pathogenic mechanisms of malignancy.	('DNA methylation', 'Var', (87, 102))	('histone modification', 'MPA', (104, 124))	('involved', 'Reg', (156, 164))	('malignancy', 'Disease', 'MESH:D009369', (197, 207))	('malignancy', 'Disease', (197, 207))	('microRNA interference', 'MPA', (129, 150))
179938	32016477	Due to its stability and ease of detection, accumulating evidence has demonstrated that aberrant gene methylation may serve as an effective, non-invasive diagnostic biomarker and therapeutic in carcinoma.	('aberrant gene methylation', 'Var', (88, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (194, 203))	('carcinoma', 'Disease', 'MESH:D002277', (194, 203))	('carcinoma', 'Disease', (194, 203))
179939	32016477	Reports have indicated that the abnormal methylation of certain genes, such as ZNF671, ADAMTS1 and CD36, may alter their functions, including the regulation of the cell cycle and signal transduction pathways, as well as transcriptional inhibition.	('ZNF671', 'Gene', '79891', (79, 85))	('CD36', 'Species', '42374', (99, 103))	('cell', 'Pathway', (164, 168))	('functions', 'MPA', (121, 130))	('regulation', 'MPA', (146, 156))	('alter', 'Reg', (109, 114))	('transcriptional', 'CPA', (220, 235))	('ZNF671', 'Gene', (79, 85))	('abnormal methylation', 'Var', (32, 52))	('methylation', 'Var', (41, 52))	('ADAMTS1', 'Gene', '9510', (87, 94))	('CD36', 'Gene', (99, 103))	('ADAMTS1', 'Gene', (87, 94))
179940	32016477	Kiyozumi et al demonstrated that indoleamine 2,3-dioygenase 1 promoter hypomethylation is associated with poor prognosis in esophageal cancer.	('esophageal cancer', 'Disease', (124, 141))	('esophageal cancer', 'Disease', 'MESH:D004938', (124, 141))	('indoleamine', 'Chemical', 'None', (33, 44))	('indoleamine', 'MPA', (33, 44))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('hypomethylation', 'Var', (71, 86))
179941	32016477	Therefore, the accurate detection of methylated genes is likely to improve the clinical management of LUSC.	('LUSC', 'Disease', 'MESH:D018307', (102, 106))	('LUSC', 'Disease', (102, 106))	('LUSC', 'Phenotype', 'HP:0030359', (102, 106))	('improve', 'PosReg', (67, 74))	('methylated', 'Var', (37, 47))
179948	32016477	In other words, differential methylation of specific MDGs is able affect their expression and transcription.	('methylation', 'Var', (29, 40))	('MDG', 'Gene', '4350', (53, 56))	('affect', 'Reg', (66, 72))	('expression', 'MPA', (79, 89))	('differential methylation', 'Var', (16, 40))	('transcription', 'MPA', (94, 107))	('MDG', 'Gene', (53, 56))
179951	32016477	The hub MDGs were determined by analyzing the association between hyper- or hypomethylation and survival, but also by integrating the degree of methylation and the expression of MDGs with survival.	('MDG', 'Gene', (178, 181))	('MDG', 'Gene', '4350', (178, 181))	('hypomethylation', 'Var', (76, 91))	('MDG', 'Gene', (8, 11))	('MDG', 'Gene', '4350', (8, 11))	('association', 'Interaction', (46, 57))	('hyper-', 'Var', (66, 72))
179953	32016477	The present study indicated that PMPCAP1 was hypomethylated in LUSC compared with normal tissues, which was associated with high expression levels, and ultimately, poor prognosis (P=0.041).	('LUSC', 'Disease', (63, 67))	('hypomethylated', 'Var', (45, 59))	('LUSC', 'Phenotype', 'HP:0030359', (63, 67))	('LUSC', 'Disease', 'MESH:D018307', (63, 67))	('high expression levels', 'MPA', (124, 146))	('PMPCAP1', 'Gene', (33, 40))
179954	32016477	Therefore, it may be speculated that the hypomethylation of PMPCAP1 in cancer tissue (and the subsequent increase in RNA expression) is an indicator of poor clinical outcome in patients with LUSC, though further investigation is required to confirm this hypothesis.	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('hypomethylation', 'Var', (41, 56))	('cancer', 'Disease', (71, 77))	('patients', 'Species', '9606', (177, 185))	('LUSC', 'Phenotype', 'HP:0030359', (191, 195))	('increase', 'PosReg', (105, 113))	('LUSC', 'Disease', (191, 195))	('LUSC', 'Disease', 'MESH:D018307', (191, 195))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('PMPCAP1', 'Gene', (60, 67))
179956	32016477	Takahashi et al identified that ANKRD1 was overexpressed in EGFR-TKIs-resistant NSCLC with EGFR mutation, and that by inhibiting ANKRD1 expression, resistant cells were re-sensitized to afatinib and osimertinib.	('NSCLC', 'Phenotype', 'HP:0030358', (80, 85))	('expression', 'MPA', (136, 146))	('EGFR', 'Gene', (91, 95))	('ANKRD1', 'Gene', '27063', (129, 135))	('ANKRD1', 'Gene', (32, 38))	('SCLC', 'Phenotype', 'HP:0030357', (81, 85))	('ANKRD1', 'Gene', (129, 135))	('afatinib', 'Chemical', 'MESH:C522924', (186, 194))	('NSCLC', 'Disease', (80, 85))	('mutation', 'Var', (96, 104))	('EGFR', 'Gene', '1956', (60, 64))	('NSCLC', 'Disease', 'MESH:D002289', (80, 85))	('inhibiting', 'NegReg', (118, 128))	('EGFR', 'Gene', '1956', (91, 95))	('overexpressed', 'PosReg', (43, 56))	('EGFR', 'Gene', (60, 64))	('osimertinib', 'Chemical', 'None', (199, 210))	('ANKRD1', 'Gene', '27063', (32, 38))
179960	32016477	Joint survival analysis revealed a significant association between the combined methylation and expression data and survival (P=0.028), suggesting that hypomethylation and high expression levels denoted improved prognosis in LUSC.	('improved', 'PosReg', (203, 211))	('LUSC', 'Disease', (225, 229))	('LUSC', 'Phenotype', 'HP:0030359', (225, 229))	('hypomethylation', 'Var', (152, 167))	('LUSC', 'Disease', 'MESH:D018307', (225, 229))	('high', 'Var', (172, 176))	('expression levels', 'MPA', (177, 194))
179970	32016477	A single methylation site was associated with SOWAHC expression (cg19399885) and the expression of ZNF454 was associated with 10 methylation sites, including 9 negatively related sites (cg17840719, cg16536329, cg23037403, cg20778451, cg24843380, cg03234732, cg02165355, cg10575261 and cg10902717) and 1 positive site (cg05461386).	('ZNF454', 'Gene', '285676', (99, 105))	('cg23037403', 'Var', (210, 220))	('cg17840719', 'Var', (186, 196))	('cg10902717', 'Var', (285, 295))	('SOWAHC', 'Gene', '65124', (46, 52))	('cg24843380', 'Var', (234, 244))	('cg02165355', 'Var', (258, 268))	('cg03234732', 'Var', (246, 256))	('cg10575261', 'Var', (270, 280))	('ZNF454', 'Gene', (99, 105))	('cg19399885', 'Var', (65, 75))	('cg16536329', 'Var', (198, 208))	('cg20778451', 'Var', (222, 232))	('SOWAHC', 'Gene', (46, 52))
179974	32016477	In patients with LUSC, PMPCAP1 and SOWAHC were hypomethylated and highly expressed, which was determined to be an indication of poor prognosis.	('LUSC', 'Phenotype', 'HP:0030359', (17, 21))	('SOWAHC', 'Gene', '65124', (35, 41))	('PMPCAP1', 'Gene', (23, 30))	('hypomethylated', 'Var', (47, 61))	('SOWAHC', 'Gene', (35, 41))	('patients', 'Species', '9606', (3, 11))	('LUSC', 'Disease', (17, 21))	('LUSC', 'Disease', 'MESH:D018307', (17, 21))	('highly', 'PosReg', (66, 72))
179978	24885028	Sequence artefacts in a prospective series of formalin-fixed tumours tested for mutations in hotspot regions by massively parallel sequencing Clinical specimens undergoing diagnostic molecular pathology testing are fixed in formalin due to the necessity for detailed morphological assessment.	('formalin', 'Chemical', 'MESH:D005557', (46, 54))	('mutations', 'Var', (80, 89))	('tumours', 'Phenotype', 'HP:0002664', (61, 68))	('tumours', 'Disease', 'MESH:D009369', (61, 68))	('formalin', 'Chemical', 'MESH:D005557', (224, 232))	('tumours', 'Disease', (61, 68))	('tumour', 'Phenotype', 'HP:0002664', (61, 67))
179990	24885028	In particular, a large number of genes can be screened for actionable changes using massively parallel sequencing (MPS) approaches .	('MPS', 'Disease', (115, 118))	('MPS', 'Disease', 'MESH:D009084', (115, 118))	('genes', 'Gene', (33, 38))	('changes', 'Var', (70, 77))
179995	24885028	low pH formalin over time increases the rate of apurinic/apyrimidinic site formation and eventually decomposition and fragmentation .	('increases', 'PosReg', (26, 35))	('low pH', 'Var', (0, 6))	('apurinic/apyrimidinic site formation', 'MPA', (48, 84))	('formalin', 'Chemical', 'MESH:D005557', (7, 15))
179999	24885028	Recently, we assessed an amplicon-based MPS technology and showed that C>T and G>A changes were the most prominent sequence errors in three formalin-fixed lung squamous cell carcinoma samples .	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (155, 183))	('G>A changes', 'Var', (79, 90))	('carcinoma', 'Phenotype', 'HP:0030731', (174, 183))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (155, 183))	('MPS', 'Disease', 'MESH:D009084', (40, 43))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (160, 183))	('lung squamous cell carcinoma', 'Disease', (155, 183))	('formalin', 'Chemical', 'MESH:D005557', (140, 148))	('MPS', 'Disease', (40, 43))	('C>T', 'Var', (71, 74))	('changes', 'Var', (83, 90))
180022	24885028	The Kruskal-Wallis one-way analysis of variance followed by the Dunn's post hoc test was used to test for associations between continuous variables (C>T/G>A changes, FTH1 results) versus anatomical pathology laboratory and tumour type.	('tumour', 'Phenotype', 'HP:0002664', (223, 229))	('FTH1', 'Gene', '2495', (166, 170))	('C>T/G>A changes', 'Var', (149, 164))	('tumour', 'Disease', 'MESH:D009369', (223, 229))	('tumour', 'Disease', (223, 229))	('associations', 'Interaction', (106, 118))	('FTH1', 'Gene', (166, 170))
180031	24885028	There were two outlier samples that displayed high amounts of amplifiable template as measured by the FTH1 assay but resulted in low coverage (samples Ca23 and Ca156).	('Ca156', 'Var', (160, 165))	('amplifiable', 'MPA', (62, 73))	('FTH1', 'Gene', (102, 106))	('FTH1', 'Gene', '2495', (102, 106))
180035	24885028	This is also in line with the fragmentation measurements with the 50 samples with the highest C>T/G>A levels strongly trending towards having lower estimated template numbers in the FTH1 assay (Figure  1).	('template numbers', 'MPA', (158, 174))	('C>T/G>A', 'Var', (94, 101))	('lower', 'NegReg', (142, 147))	('FTH1', 'Gene', (182, 186))	('FTH1', 'Gene', '2495', (182, 186))
180039	24885028	As shown in Figure  4, PIK3CA mutations in the two breast cancer cases (Ca309 and Ca285) were confirmed to be real mutations as the identical mutation of similar frequency was identified in each of these cases after UDG treatment.	('PIK3CA', 'Gene', (23, 29))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('PIK3CA', 'Gene', '5290', (23, 29))	('mutations', 'Var', (30, 39))	('breast cancer', 'Disease', 'MESH:D001943', (51, 64))	('breast cancer', 'Phenotype', 'HP:0003002', (51, 64))	('UDG', 'Gene', '7374', (216, 219))	('breast cancer', 'Disease', (51, 64))	('UDG', 'Gene', (216, 219))
180040	24885028	PIK3CA mutations are positive prognostic factors in breast cancer , supporting the clinical utility of MPS for the detection of clinically actionable mutations.	('MPS', 'Disease', (103, 106))	('breast cancer', 'Disease', 'MESH:D001943', (52, 65))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('PIK3CA', 'Gene', (0, 6))	('breast cancer', 'Disease', (52, 65))	('breast cancer', 'Phenotype', 'HP:0003002', (52, 65))	('PIK3CA', 'Gene', '5290', (0, 6))	('MPS', 'Disease', 'MESH:D009084', (103, 106))	('mutations', 'Var', (7, 16))
180041	24885028	In the case of a melanoma with an apparent NRAS c.35 G>A, p.G12D mutation (Ca97), resequencing (after UDG treatment) using the TSACP platform did not confirm the same mutation.	('p.G12D', 'Mutation', 'rs121913237', (58, 64))	('NRAS', 'Gene', (43, 47))	('UDG', 'Gene', '7374', (102, 105))	('melanoma', 'Phenotype', 'HP:0002861', (17, 25))	('melanoma', 'Disease', (17, 25))	('melanoma', 'Disease', 'MESH:D008545', (17, 25))	('p.G12D', 'Var', (58, 64))	('UDG', 'Gene', (102, 105))	('NRAS', 'Gene', '4893', (43, 47))	('TSACP', 'Chemical', '-', (127, 132))	('c.35 G>A', 'Mutation', 'rs121913237', (48, 56))
180048	24885028	There are a limited number of publications highlighting the ability of amplicon-based MPS to identify clinically relevant mutations or canonical mutations from DNA obtained from various tumour types .	('tumour', 'Disease', (186, 192))	('MPS', 'Disease', (86, 89))	('tumour', 'Phenotype', 'HP:0002664', (186, 192))	('mutations', 'Var', (122, 131))	('tumour', 'Disease', 'MESH:D009369', (186, 192))	('DNA', 'Gene', (160, 163))	('MPS', 'Disease', 'MESH:D009084', (86, 89))
180051	24885028	When DNA was then macro-dissected from the same tumour blocks, both sequencing and the TSACP analyses could now both detect the V600E mutation in seven cases (7/11).	('detect', 'Reg', (117, 123))	('tumour blocks', 'Disease', (48, 61))	('V600E', 'Mutation', 'rs113488022', (128, 133))	('tumour', 'Phenotype', 'HP:0002664', (48, 54))	('TSACP', 'Chemical', '-', (87, 92))	('V600E', 'Var', (128, 133))	('tumour blocks', 'Disease', 'MESH:D006327', (48, 61))
180063	24885028	Given the clinical context of these mutations in breast cancer, these mutations are of potential clinical benefit to the patient that may have implications for PIK3CA inhibitors that target the PI3K/AKT/mTOR pathway .	('mutations', 'Var', (70, 79))	('AKT', 'Gene', (199, 202))	('PIK3CA', 'Gene', '5290', (160, 166))	('mTOR', 'Gene', '2475', (203, 207))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('mutations', 'Var', (36, 45))	('breast cancer', 'Disease', 'MESH:D001943', (49, 62))	('breast cancer', 'Disease', (49, 62))	('AKT', 'Gene', '207', (199, 202))	('breast cancer', 'Phenotype', 'HP:0003002', (49, 62))	('patient', 'Species', '9606', (121, 128))	('mTOR', 'Gene', (203, 207))	('PIK3CA', 'Gene', (160, 166))
180064	24885028	In contrast, an activating NRAS G12D mutation discovered originally in our first screen but not confirmed in the same DNA specimen by subsequent UDG treatment or MPS has major implications for the patient.	('UDG', 'Gene', (145, 148))	('NRAS', 'Gene', '4893', (27, 31))	('G12D', 'Var', (32, 36))	('UDG', 'Gene', '7374', (145, 148))	('MPS', 'Disease', 'MESH:D009084', (162, 165))	('patient', 'Species', '9606', (197, 204))	('G12D', 'Mutation', 'rs121913237', (32, 36))	('MPS', 'Disease', (162, 165))	('NRAS', 'Gene', (27, 31))	('activating', 'PosReg', (16, 26))
180065	24885028	Activating mutations in NRAS have been reported in approximately 20% of all melanomas  and are potentially sensitive to therapeutics that target downstream signaling through mitogen-activated protein kinase kinase and phosphatidylinositol 3-OH kinase or AKT .	('NRAS', 'Gene', '4893', (24, 28))	('melanomas', 'Phenotype', 'HP:0002861', (76, 85))	('Activating', 'PosReg', (0, 10))	('mutations', 'Var', (11, 20))	('melanomas', 'Disease', 'MESH:D008545', (76, 85))	('AKT', 'Gene', (254, 257))	('melanomas', 'Disease', (76, 85))	('reported', 'Reg', (39, 47))	('NRAS', 'Gene', (24, 28))	('AKT', 'Gene', '207', (254, 257))	('melanoma', 'Phenotype', 'HP:0002861', (76, 84))
180068	24885028	We also propose that quality control measures be adopted prior to sequencing including the implementation of more efficient and accurate quality control assays that evaluate DNA concentration, fragmentation and the presence of uracil lesions.	('uracil', 'Chemical', 'MESH:D014498', (227, 233))	('uracil lesions', 'Var', (227, 241))	('DNA concentration', 'MPA', (174, 191))	('uracil lesions', 'Phenotype', 'HP:0012127', (227, 241))
180138	23715932	The Pearl Impulse Small Animal Imager (LI-COR Biosciences, Lincoln, NE) is specifically designed to image IRDye800CW and was used for in vitro (rEGFR and HNSCC cells) and in vivo imaging.	('rEGFR', 'Gene', '24329', (144, 149))	('rEGFR', 'Gene', (144, 149))	('IRDye800CW', 'Var', (106, 116))
180145	23715932	The mean dye-to-protein ratio was higher for cetuximab-IRDye800CW (1.44+-0.11) compared to panitumumab-IRDye800CW (0.80+-0.11).	('cetuximab', 'Chemical', 'MESH:D000068818', (45, 54))	('panitumumab', 'Chemical', 'MESH:D000077544', (91, 102))	('dye-to-protein ratio', 'MPA', (9, 29))	('higher', 'PosReg', (34, 40))	('cetuximab-IRDye800CW', 'Var', (45, 65))
180180	23715932	Though TBR values for IgG-IRDye800CW were quite low, we attribute values over 1 to the enhanced permeability and retention effect.	('permeability', 'MPA', (96, 108))	('retention', 'MPA', (113, 122))	('enhanced', 'PosReg', (87, 95))	('TBR', 'Chemical', '-', (7, 10))	('IgG-IRDye800CW', 'Var', (22, 36))
180193	23715932	demonstrated high fluorescence using IRDye800CW-labeled epidermal growth factor in both primary tongue tumors as well as associated cervical lymph node metastases.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tongue tumors', 'Disease', 'MESH:D014062', (96, 109))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('metastases', 'Disease', (152, 162))	('fluorescence', 'MPA', (18, 30))	('metastases', 'Disease', 'MESH:D009362', (152, 162))	('tongue tumors', 'Disease', (96, 109))	('tongue tumors', 'Phenotype', 'HP:0100648', (96, 109))	('IRDye800CW-labeled', 'Var', (37, 55))
180203	23715932	Both antibodies labeled to IRDye800CW demonstrated good contrast in this preclinical murine model for HNSCC.	('murine', 'Species', '10090', (85, 91))	('IRDye800CW', 'Var', (27, 37))	('HNSCC', 'Disease', (102, 107))
180381	33980137	This research and this article's publication costs were supported partially by the NCI Cancer Center Shared Resources (NIH-NCI P30CA54174 to YC), NIH (CTSA 1UL1RR025767-01 to YC, R01GM113245 to YH, and K99CA248944 to YCC), CPRIT (RP160732 to YC and MM, and RP190346 to YC and YH), San Antonio Life Sciences Institute (SALSI Innovation Challenge Award 2016 to YH and YC and SALSI Postdoctoral Research Fellowship to YCC), and the Fund for Innovation in Cancer Informatics (ICI Fund to YCC and YC).	('NCI Cancer', 'Disease', (83, 93))	('Cancer', 'Disease', 'MESH:D009369', (452, 458))	('Cancer', 'Phenotype', 'HP:0002664', (87, 93))	('RP160732', 'Var', (230, 238))	('Cancer', 'Phenotype', 'HP:0002664', (452, 458))	('K99CA248944', 'Var', (202, 213))	('P', 'Chemical', 'MESH:D010758', (258, 259))	('P', 'Chemical', 'MESH:D010758', (127, 128))	('P', 'Chemical', 'MESH:D010758', (224, 225))	('R01GM113245', 'Var', (179, 190))	('P', 'Chemical', 'MESH:D010758', (379, 380))	('NCI Cancer', 'Disease', 'MESH:D009369', (83, 93))	('Cancer', 'Disease', (87, 93))	('P', 'Chemical', 'MESH:D010758', (231, 232))	('RP190346 to', 'Var', (257, 268))	('Cancer', 'Disease', 'MESH:D009369', (87, 93))	('Cancer', 'Disease', (452, 458))
180424	31562292	Survival analysis demonstrated that OSCC patients with high expression of 6 hub genes (PLAU, SERPINE1, LAMC2, ITGA5, TGFBI, and FSCN1) had lower overall survival than those with low expression.	('overall survival', 'MPA', (145, 161))	('lower', 'NegReg', (139, 144))	('OSCC', 'Disease', 'MESH:D002294', (36, 40))	('ITGA5', 'Gene', (110, 115))	('TGFBI', 'Gene', '7045', (117, 122))	('FSCN1', 'Gene', '6624', (128, 133))	('ITGA5', 'Gene', '3678', (110, 115))	('TGFBI', 'Gene', (117, 122))	('LAMC2', 'Gene', (103, 108))	('OSCC', 'Disease', (36, 40))	('PLAU', 'Gene', '5328', (87, 91))	('patients', 'Species', '9606', (41, 49))	('high expression', 'Var', (55, 70))	('hub', 'Gene', (76, 79))	('LAMC2', 'Gene', '3918', (103, 108))	('SERPINE1', 'Gene', (93, 101))	('PLAU', 'Gene', (87, 91))	('FSCN1', 'Gene', (128, 133))	('hub', 'Gene', '1993', (76, 79))
180425	31562292	In contrast, patients with high expression of gene HLF displayed remarkably longer overall survival compared to those with low expression.	('HLF', 'Gene', (51, 54))	('patients', 'Species', '9606', (13, 21))	('high expression', 'Var', (27, 42))	('longer', 'PosReg', (76, 82))	('HLF', 'Gene', '3131', (51, 54))
180429	31562292	The transformative process of normal stratified squamous oral mucosa into squamous cell carcinoma contains several steps and factors in which accumulated genetic alterations intervene with the normal functions of oncogenes and tumor suppressor genes.	('tumor', 'Disease', (227, 232))	('intervene', 'Reg', (174, 183))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (74, 97))	('tumor', 'Disease', 'MESH:D009369', (227, 232))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (74, 97))	('genetic alterations', 'Var', (154, 173))	('squamous cell carcinoma', 'Disease', (74, 97))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))
180489	31562292	However, among the 5 datasets obtained from GEO, only GSE30784 contains normal mucosa, oral dysplasia, and OSCC samples.	('OSCC', 'Disease', (107, 111))	('oral dysplasia', 'Disease', 'MESH:D009062', (87, 101))	('OSCC', 'Disease', 'MESH:D002294', (107, 111))	('oral dysplasia', 'Disease', (87, 101))	('GSE30784', 'Var', (54, 62))
180492	31562292	Third, among the 5 datasets obtained from GEO, only GSE30784 consists of normal mucosa, oral dysplasia, and OSCC samples.	('OSCC', 'Disease', 'MESH:D002294', (108, 112))	('oral dysplasia', 'Disease', 'MESH:D009062', (88, 102))	('GSE30784', 'Var', (52, 60))	('OSCC', 'Disease', (108, 112))	('oral dysplasia', 'Disease', (88, 102))
180512	29530057	Esophageal cancer (EC) is the sixth most deadly cancer worldwide, which is caused by many factors, such as smoking, alcohol, lack of fruits and vegetables, and esophageal squamous cell carcinoma (ESCC) accounts for about 88% in EC.	('Esophageal cancer', 'Disease', 'MESH:D004938', (0, 17))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('alcohol', 'Chemical', 'MESH:D000438', (116, 123))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (160, 194))	('carcinoma', 'Phenotype', 'HP:0030731', (185, 194))	('cancer', 'Disease', 'MESH:D009369', (11, 17))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('Esophageal cancer', 'Disease', (0, 17))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (171, 194))	('cancer', 'Disease', (11, 17))	('esophageal squamous cell carcinoma', 'Disease', (160, 194))	('lack', 'Var', (125, 129))
180527	29530057	Low TUSC7 also decreased overall survival of patients with EC, and overexpression of TUSC7 inhibited colony formation in vitro and tumor volume and weight in vivo.	('colony formation', 'CPA', (101, 117))	('TUSC7', 'Gene', '285194', (85, 90))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('TUSC7', 'Gene', (4, 9))	('TUSC7', 'Gene', (85, 90))	('overexpression', 'PosReg', (67, 81))	('inhibited', 'NegReg', (91, 100))	('TUSC7', 'Gene', '285194', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumor', 'Disease', (131, 136))	('patients', 'Species', '9606', (45, 53))	('decreased', 'NegReg', (15, 24))	('overall survival', 'CPA', (25, 41))	('Low', 'Var', (0, 3))
180532	29530057	Combined chemotherapy for the treatment of ESCC was cisplatin, 5-Fu and adriamycin, or cisplatin, 5-Fu and paclitaxel.	('paclitaxel', 'Chemical', 'MESH:D017239', (107, 117))	('cisplatin', 'Chemical', 'MESH:D002945', (87, 96))	('5-Fu', 'Chemical', 'MESH:D005472', (63, 67))	('cisplatin', 'Chemical', 'MESH:D002945', (52, 61))	('ESCC', 'Disease', (43, 47))	('cisplatin', 'Var', (87, 96))	('adriamycin', 'Chemical', 'MESH:D004317', (72, 82))	('5-Fu', 'Chemical', 'MESH:D005472', (98, 102))
180536	29530057	si-TUSC7-1, si-TUSC7-2, pcDNA-TUSC7, miR-224 mimic, miR-224 inhibitor, si-DESC1, LV-TUSC7 and their non-specific control were synthesised by Invitrogen (Shanghai, China), and were transfected into cells using Lipofectamine 2000 (Invitrogen, USA).	('TUSC7', 'Gene', (30, 35))	('miR-224', 'Gene', '407009', (52, 59))	('TUSC7', 'Gene', '285194', (30, 35))	('TUSC7', 'Gene', (3, 8))	('TUSC7', 'Gene', '285194', (3, 8))	('miR-224', 'Gene', (37, 44))	('Lipofectamine 2000', 'Chemical', 'MESH:C086724', (209, 227))	('TUSC7', 'Gene', '285194', (15, 20))	('miR-224', 'Gene', '407009', (37, 44))	('TUSC7', 'Gene', (84, 89))	('TUSC7', 'Gene', (15, 20))	('TUSC7', 'Gene', '285194', (84, 89))	('si-DESC1', 'Var', (71, 79))	('miR-224', 'Gene', (52, 59))
180541	29530057	Luciferase report gene vectors containing DESC1 3'UTR WT or DESC1 3'UTR Mut (400 ng) was transfected into HEK293T cells with 40 ng pRL-TK vectors (Promega, USA).	('HEK293T', 'CellLine', 'CVCL:0063', (106, 113))	('DESC1', 'Gene', (60, 65))	("DESC1 3'UTR", 'Var', (42, 53))
180554	29530057	EC9706 or KYSE30 cells at the logarithmic phase were seeded into culture solution containing DDP with the low concentration started from 0.5 muM.	('EC9706', 'Var', (0, 6))	('muM', 'Gene', '56925', (141, 144))	('muM', 'Gene', (141, 144))	('EC9706', 'CellLine', 'CVCL:E307', (0, 6))
180555	29530057	After digestion, 1 muM DDP was added for the treatment for 48 h. With this procedure of changing solution and gradually increasing DDP concentration, cell lines that can resistent to 10 muM DDP were obtained, and named EC9706/DDP or KYSE30/DDP.	('muM', 'Gene', (19, 22))	('EC9706', 'CellLine', 'CVCL:E307', (219, 225))	('EC9706/DDP', 'Var', (219, 229))	('muM', 'Gene', '56925', (186, 189))	('muM', 'Gene', '56925', (19, 22))	('muM', 'Gene', (186, 189))
180557	29530057	Then, the membranes were probed with first primary antibody anti-DESC1 (1:1000, Signalway Antibody, USA), anti-EGFR (1:1000, Invitrogen, USA), anti-p-AKT (1:1000, Invitrogen, USA), anti-AKT (1:1000, Cell Signaling, USA) and anti-GAPDH (1:1000, Invitrogen, USA) and the secondary horseradish peroxidase-conjugated antibody (Invitrogen, USA).	('anti-DESC1', 'Var', (60, 70))	('AKT', 'Gene', '207', (186, 189))	('EGFR', 'Gene', '1956', (111, 115))	('AKT', 'Gene', '207', (150, 153))	('EGFR', 'Gene', (111, 115))	('AKT', 'Gene', (186, 189))	('GAPDH', 'Gene', '2597', (229, 234))	('GAPDH', 'Gene', (229, 234))	('AKT', 'Gene', (150, 153))	('horseradish', 'Species', '3704', (279, 290))
180586	29530057	We also detected TUSC7 level in EC9706 and drug-resistant EC9706/DDP cells or KYSE30 and drug-resistant KYSE30/DDP cells, and found TUSC7 level was downregulated in drug-resistant ESCC cells (Fig.	('TUSC7', 'Gene', (17, 22))	('detected', 'Reg', (8, 16))	('TUSC7', 'Gene', '285194', (17, 22))	('EC9706', 'CellLine', 'CVCL:E307', (58, 64))	('EC9706/DDP', 'Var', (58, 68))	('downregulated', 'NegReg', (148, 161))	('TUSC7', 'Gene', (132, 137))	('TUSC7', 'Gene', '285194', (132, 137))	('ESCC', 'Disease', (180, 184))	('EC9706', 'CellLine', 'CVCL:E307', (32, 38))
180603	29530057	To figure out whether DESC1 inhibited chemotherapy resistance of ESCC cells via EGFR/AKT, EC9706 or KYSE30 cells were transfected with si-NC, si-DESC1, si- DESC1 + DMSO, and si-DESC1 + AST1306 (EGFR inhibitor).	('chemotherapy resistance', 'CPA', (38, 61))	('DESC1', 'Gene', (22, 27))	('si-DESC1', 'Var', (142, 150))	('AKT', 'Gene', '207', (85, 88))	('EGFR', 'Gene', '1956', (80, 84))	('DMSO', 'Chemical', 'MESH:D004121', (164, 168))	('EGFR', 'Gene', (80, 84))	('EC9706', 'CellLine', 'CVCL:E307', (90, 96))	('si-NC', 'Var', (135, 140))	('inhibited', 'NegReg', (28, 37))	('EGFR', 'Gene', '1956', (194, 198))	('si- DESC1 + DMSO', 'Var', (152, 168))	('si-DESC1 + AST1306', 'Var', (174, 192))	('EGFR', 'Gene', (194, 198))	('AKT', 'Gene', (85, 88))	('AST1306', 'Chemical', 'MESH:C568037', (185, 192))
180604	29530057	7a and b, si-DESC1 promoted chemotherapy resistance of ESCC cells, while AST1306 reversed this effect.	('chemotherapy resistance', 'CPA', (28, 51))	('si-DESC1', 'Var', (10, 18))	('promoted', 'PosReg', (19, 27))	('AST1306', 'Chemical', 'MESH:C568037', (73, 80))
180605	29530057	Also, si-DESC1 upregulated expressions of EGFR and p-AKT, while AST1306 reversed this effect (Fig.	('EGFR', 'Gene', '1956', (42, 46))	('upregulated', 'PosReg', (15, 26))	('EGFR', 'Gene', (42, 46))	('AKT', 'Gene', '207', (53, 56))	('expressions', 'MPA', (27, 38))	('AST1306', 'Chemical', 'MESH:C568037', (64, 71))	('AKT', 'Gene', (53, 56))	('si-DESC1', 'Var', (6, 14))
180607	29530057	In order to confirm the regulatory role of TUSC7 in chemotherapy resistance in vivo, KYSE30 cells were transfected with LV-NC or LV-TUSC7 and subcutaneously injected into female nude mice.	('TUSC7', 'Gene', '285194', (43, 48))	('LV-NC', 'Var', (120, 125))	('nude mice', 'Species', '10090', (178, 187))	('TUSC7', 'Gene', (132, 137))	('TUSC7', 'Gene', '285194', (132, 137))	('TUSC7', 'Gene', (43, 48))
180614	29530057	Moreover, we also observed overexpression of TUSC7 inhibited tumor volume and weight.	('overexpression', 'Var', (27, 41))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('TUSC7', 'Gene', (45, 50))	('TUSC7', 'Gene', '285194', (45, 50))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('inhibited', 'NegReg', (51, 60))	('tumor', 'Disease', (61, 66))
180628	29530057	In conclusion, our data proved that TUSC7 was downregulated and miR-224 was upregulated in ESCC, and high level of TUSC7 indicated better overall survival.	('TUSC7', 'Gene', (36, 41))	('overall survival', 'CPA', (138, 154))	('ESCC', 'Disease', (91, 95))	('miR-224', 'Gene', (64, 71))	('high level', 'Var', (101, 111))	('TUSC7', 'Gene', (115, 120))	('miR-224', 'Gene', '407009', (64, 71))	('TUSC7', 'Gene', '285194', (115, 120))	('downregulated', 'NegReg', (46, 59))	('better', 'PosReg', (131, 137))	('upregulated', 'PosReg', (76, 87))	('TUSC7', 'Gene', '285194', (36, 41))
180637	28111536	When clinical findings need to be distinguished from pathological findings, descriptions such as "Although surgery was performed based on a preoperative finding of cT2,cN0, the pathological finding was pT3,pN1" are acceptable.	('cT2', 'Var', (164, 167))	('pT3', 'Gene', '7694', (202, 205))	('cN0', 'Var', (168, 171))	('pT3', 'Gene', (202, 205))
180744	26846300	In contrast to the recent discovery of targeted therapies for lung AC, including EGFR mutant or ALK fusions, there is no effective therapy for lung SCC other than chemotherapy.	('ALK', 'Gene', '238', (96, 99))	('mutant', 'Var', (86, 92))	('SCC', 'Gene', (148, 151))	('ALK', 'Gene', (96, 99))	('lung SCC', 'Phenotype', 'HP:0030359', (143, 151))	('lung AC', 'Phenotype', 'HP:0030078', (62, 69))	('SCC', 'Gene', '6317', (148, 151))	('EGFR', 'Gene', '1956', (81, 85))	('EGFR', 'Gene', (81, 85))
180745	26846300	In order to understand the molecular pathogenesis that leads to identifying potential therapeutic molecular targets for lung SCC, extensive genetic analysis, including next-generation sequencing, have been performed, which has revealed amplification of SOX2, PIK3CA, PDGFRA, BRF2 and FGFR1, deletion of CDKN2A/B, PTEN, TP53 and NF1, and mutations of PIK3CA, NRF2, DDR2, PTEN, EPHA2, LKB1 and AKT1 in lung SCC.	('PIK3CA', 'Gene', '5290', (350, 356))	('FGFR1', 'Gene', '2260', (284, 289))	('CDKN2A/B', 'Gene', (303, 311))	('PDGFRA', 'Gene', (267, 273))	('SCC', 'Gene', (125, 128))	('PDGFRA', 'Gene', '5156', (267, 273))	('LKB1', 'Gene', '6794', (383, 387))	('PTEN', 'Gene', (370, 374))	('TP53', 'Gene', '7157', (319, 323))	('NRF2', 'Gene', '4780', (358, 362))	('PTEN', 'Gene', (313, 317))	('lung SCC', 'Phenotype', 'HP:0030359', (400, 408))	('AKT1', 'Gene', '207', (392, 396))	('EPHA2', 'Gene', (376, 381))	('DDR2', 'Gene', '4921', (364, 368))	('PTEN', 'Gene', '5728', (370, 374))	('CDKN2A/B', 'Gene', '1029;1030', (303, 311))	('PIK3CA', 'Gene', '5290', (259, 265))	('FGFR1', 'Gene', (284, 289))	('PIK3CA', 'Gene', (350, 356))	('PTEN', 'Gene', '5728', (313, 317))	('SCC', 'Gene', '6317', (405, 408))	('NRF2', 'Gene', (358, 362))	('deletion', 'Var', (291, 299))	('AKT1', 'Gene', (392, 396))	('LKB1', 'Gene', (383, 387))	('NF1', 'Gene', '4763', (328, 331))	('DDR2', 'Gene', (364, 368))	('lung SCC', 'Phenotype', 'HP:0030359', (120, 128))	('SCC', 'Gene', (405, 408))	('mutations', 'Var', (337, 346))	('EPHA2', 'Gene', '1969', (376, 381))	('TP53', 'Gene', (319, 323))	('BRF2', 'Gene', '55290', (275, 279))	('NF1', 'Gene', (328, 331))	('PIK3CA', 'Gene', (259, 265))	('BRF2', 'Gene', (275, 279))	('SCC', 'Gene', '6317', (125, 128))
180811	26846300	Recent in vitro and in vivo studies using heterozygous or conditionally deleted Nkx2-1 mice also indicate that NKX2-1 directly suppresses the expression of mucous genes in asthma and lung cancer.	('Nkx2-1', 'Gene', '21869', (80, 86))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('mucous genes', 'Gene', (156, 168))	('mice', 'Species', '10090', (87, 91))	('asthma', 'Phenotype', 'HP:0002099', (172, 178))	('Nkx2-1', 'Gene', (80, 86))	('suppresses', 'NegReg', (127, 137))	('expression', 'MPA', (142, 152))	('NKX2-1', 'Var', (111, 117))	('lung cancer', 'Phenotype', 'HP:0100526', (183, 194))	('asthma and lung cancer', 'Disease', 'MESH:D008175', (172, 194))
180813	26846300	Conditional deletion of SOX2 in lung epithelium in mice recently revealed that SOX2 is required for proliferation/differentiation of airway epithelial cells.	('SOX2', 'Gene', (24, 28))	('Conditional deletion', 'Var', (0, 20))	('mice', 'Species', '10090', (51, 55))
180827	26846300	These results suggest a dual-role of SOX2, in which SOX2 suppresses lung SCC invasion and metastasis (tumor suppressor) while SOX2 also promotes lung SCC proliferation (oncogene).	('SCC', 'Gene', '6317', (150, 153))	('suppresses', 'NegReg', (57, 67))	('promotes', 'PosReg', (136, 144))	('SOX2', 'Var', (52, 56))	('metastasis', 'CPA', (90, 100))	('lung SCC', 'Phenotype', 'HP:0030359', (145, 153))	('SCC', 'Gene', (73, 76))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('lung SCC', 'Phenotype', 'HP:0030359', (68, 76))	('SCC', 'Gene', (150, 153))	('SCC', 'Gene', '6317', (73, 76))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))
180833	26846300	Our and others' data clearly indicate that inhibition of SOX2 suppresses lung SCC growth in vitro and in vivo.	('lung SCC', 'Phenotype', 'HP:0030359', (73, 81))	('inhibition', 'Var', (43, 53))	('SCC', 'Gene', '6317', (78, 81))	('SOX2', 'Gene', (57, 61))	('suppresses', 'NegReg', (62, 72))	('SCC', 'Gene', (78, 81))
180841	26846300	Further bioinformatical approaches, non-biased by previous reports, will make it possible to identify additional SOX2 downstream targets, which will lead to full understanding of the mechanisms of growth of lung SCC that harbors SOX2 amplification and/or highly expressed SOX2 and identify potential therapeutic molecular targets to eradicate lung SCC.	('SOX2', 'Gene', (272, 276))	('SCC', 'Gene', (212, 215))	('lung SCC', 'Phenotype', 'HP:0030359', (207, 215))	('SCC', 'Gene', '6317', (212, 215))	('SCC', 'Gene', (348, 351))	('SOX2', 'Gene', (229, 233))	('lung SCC', 'Phenotype', 'HP:0030359', (343, 351))	('amplification', 'Var', (234, 247))	('SCC', 'Gene', '6317', (348, 351))
180858	26846300	Cells were plated in a 6-well plate at a density of 3 x 105 per well and cultured overnight at 37  C. The following day 100 pmol of the different SOX2 siRNA (#1: D-011778-01, #2: D-011778-02), CDKN1A siRNA (#1: D-003471-01, #2: 003471-02) or nontargeting siRNA (siCtrl; Thermo Scientific) were transfected using 7.5 mul of Lipofectamine RNAi MAX reagent (Invitrogen, Life Technologies, Carlsbad, CA) according to the manufacturer's instructions.	('CDKN1A', 'Gene', (193, 199))	('#1: D-011778-01', 'Var', (158, 173))	('Lipofectamine', 'Chemical', 'MESH:C086724', (323, 336))	('CDKN1A', 'Gene', '1026', (193, 199))
180869	26846300	Specific probes for SOX2 (Hs01053049_s1), CDKN1A (Hs00355782_m1) and Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) (Hs03929097_g1) for TaqMan Gene Expression Assays were obtained from Applied Biosystems (Life Technologies, CA).	('GAPDH', 'Gene', '2597', (111, 116))	('Glyceraldehyde-3-phosphate dehydrogenase', 'Gene', '2597', (69, 109))	('CDKN1A', 'Gene', '1026', (42, 48))	('Hs03929097_g1', 'Var', (119, 132))	('CDKN1A', 'Gene', (42, 48))	('GAPDH', 'Gene', (111, 116))	('Hs01053049_s1', 'Var', (26, 39))	('Glyceraldehyde-3-phosphate dehydrogenase', 'Gene', (69, 109))	('Hs00355782_m1', 'Var', (50, 63))
180880	32509788	Beyond the Variants: Mutational Patterns in Next-Generation Sequencing Data for Cancer Precision Medicine Massively parallel sequencing, also referred to as "next-generation sequencing" (NGS) provides not only information about simple, single nucleotide alterations, but it can also provide information on complex variations, such as insertions and deletions, copy number alterations, and structural variants.	('provide', 'Reg', (283, 290))	('deletions', 'Var', (349, 358))	('copy number alterations', 'Var', (360, 383))	('insertions', 'Var', (334, 344))	('Cancer', 'Phenotype', 'HP:0002664', (80, 86))	('Cancer', 'Disease', (80, 86))	('Cancer', 'Disease', 'MESH:D009369', (80, 86))
180884	32509788	Since 1977 DNA sequencing technology has been one tool in the arsenal of scientists to detect these genetic alterations that lead to malignancy.	('malignancy', 'Disease', (133, 143))	('genetic alterations', 'Var', (100, 119))	('lead to', 'Reg', (125, 132))	('malignancy', 'Disease', 'MESH:D009369', (133, 143))
180906	32509788	This simple accounting of mutations across the genome in a tumor was termed TMB and is considered an emerging biomarker for the probability of effective treatment by immunotherapy on numerous tumor types.	('tumor', 'Disease', (192, 197))	('tumor', 'Disease', (59, 64))	('TMB', 'Chemical', '-', (76, 79))	('mutations', 'Var', (26, 35))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
180909	32509788	Tumors with the highest genomic mutational burden will translate more altered protein products which look unlike native peptides.	('altered', 'Reg', (70, 77))	('mutational', 'Var', (32, 42))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('protein products', 'MPA', (78, 94))
180917	32509788	Furthermore, there are many additional technical details for calculating TMB for targeted NGS panels that remain to be fully elucidated, such as the following: what types of variants should be included (missense, indels, etc.	('missense', 'Var', (203, 211))	('TMB', 'Chemical', '-', (73, 76))	('indels', 'Var', (213, 219))
180922	32509788	In particular, there is a lack of data supporting the association between a high TMB and an improved overall survival following ICI.	('overall survival', 'MPA', (101, 117))	('TMB', 'Gene', (81, 84))	('high', 'Var', (76, 80))	('improved', 'PosReg', (92, 100))	('TMB', 'Chemical', '-', (81, 84))
180925	32509788	Mathematical models can plot the total identified mutations seen in a particular tumor and compare to reference data.	('mutations', 'Var', (50, 59))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumor', 'Disease', (81, 86))
180926	32509788	Such mutational signatures can include both single base substitutions (SBS), doublet base substitutions (DBS), and small insertion and deletions and are detailed in the Catalogue of Somatic Mutations in Cancer (COSMIC).	('Cancer', 'Disease', (203, 209))	('Cancer', 'Disease', 'MESH:D009369', (203, 209))	('Cancer', 'Phenotype', 'HP:0002664', (203, 209))	('doublet base', 'MPA', (77, 89))	('single', 'Var', (44, 50))
180927	32509788	Some of these mutational signatures are attributed to carcinogens and environmental exposures including some with known mechanisms for carcinogenesis.	('attributed', 'Reg', (40, 50))	('carcinogenesis', 'Disease', (135, 149))	('carcinogenesis', 'Disease', 'MESH:D063646', (135, 149))	('mutational', 'Var', (14, 24))
180931	32509788	Of note, tumors with DNA polymerase epsilon mutations also display a high TMB.	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('TMB', 'MPA', (74, 77))	('tumors', 'Disease', (9, 15))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('mutations', 'Var', (44, 53))	('tumors', 'Disease', 'MESH:D009369', (9, 15))	('TMB', 'Chemical', '-', (74, 77))
180943	32509788	These loci included two mononucleotide repeats (BAT25 and BAT26) and three dinucleotide repeats (D2S123, D5S346, and D17S250).	('D2S123', 'Var', (97, 103))	('D5S346', 'Var', (105, 111))	('mononucleotide', 'Chemical', '-', (24, 38))	('BAT26', 'Gene', (58, 63))	('D17S250', 'Var', (117, 124))	('BAT25', 'Var', (48, 53))	('dinucleotide', 'Chemical', 'MESH:D015226', (75, 87))
180944	32509788	The selection was based on the reproducibility to discriminate between microsatellite stable (MSS) and microsatellite instable (MSI) colorectal tumors.	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('microsatellite', 'Var', (103, 117))	('microsatellite', 'Var', (71, 85))	('colorectal tumors', 'Disease', 'MESH:D015179', (133, 150))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('colorectal tumors', 'Disease', (133, 150))
180947	32509788	These hundreds of loci provide a global picture of microsatellite stability across the genome and therefore can be more sensitive for non-colorectal carcinomas with MSI.	('microsatellite', 'Var', (51, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (149, 158))	('carcinomas', 'Phenotype', 'HP:0030731', (149, 159))	('non-colorectal carcinomas', 'Disease', (134, 159))	('non-colorectal carcinomas', 'Disease', 'MESH:D015179', (134, 159))
180948	32509788	Higher infidelity at these microsatellites is seen in tumors with microsatellite instability.	('tumors', 'Disease', 'MESH:D009369', (54, 60))	('microsatellite instability', 'Var', (66, 92))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumors', 'Disease', (54, 60))	('infidelity', 'MPA', (7, 17))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))
180952	32509788	Finally, of note, tumors with MSI also have a high mutational burden (high TMB) and are more likely to express neoantigens that the immune system can identify as foreign and destroy.	('TMB', 'Chemical', '-', (75, 78))	('neoantigens', 'MPA', (111, 122))	('MSI', 'Var', (30, 33))	('tumors', 'Disease', (18, 24))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('express', 'Reg', (103, 110))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('mutational burden', 'MPA', (51, 68))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
180958	32509788	Poly ADP ribose polymerase inhibitors were initially discovered to elucidate exquisite sensitivity from BRCA1/2 mutated cells.	('Poly ADP ribose polymerase', 'Gene', (0, 26))	('BRCA1/2', 'Gene', (104, 111))	('BRCA1/2', 'Gene', '672;675', (104, 111))	('Poly ADP ribose polymerase', 'Gene', '142', (0, 26))	('mutated', 'Var', (112, 119))
180965	32509788	Sequencing of cancer specimens can identify whether there are mutations (either germline or somatic) in many of the genes involved in homologous recombination, such as a mutation in BRCA1.	('cancer', 'Disease', (14, 20))	('BRCA1', 'Gene', '672', (182, 187))	('BRCA1', 'Gene', (182, 187))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('cancer', 'Disease', 'MESH:D009369', (14, 20))	('mutation', 'Var', (170, 178))
180966	32509788	Additionally, mutational patterns exist that are also indicative of HRD, so-called "genomic scars".	('HRD', 'Disease', (68, 71))	('HRD', 'Disease', 'None', (68, 71))	('scars', 'Phenotype', 'HP:0100699', (92, 97))	('mutational', 'Var', (14, 24))
180967	32509788	3, HRDetect, deletions with microhomology, loss of heterozygosity (LOH), telomeric allelic imbalance (TAI), and large-scale state transitions (LST).	('microhomology', 'Var', (28, 41))	('HRD', 'Disease', 'None', (3, 6))	('deletions', 'Var', (13, 22))	('HRD', 'Disease', (3, 6))	('loss', 'NegReg', (43, 47))	('imbalance', 'Phenotype', 'HP:0002172', (91, 100))	('telomeric allelic', 'MPA', (73, 90))
180970	32509788	HRDetect has been shown to have utility in predicting "BRCA deficiency" as defined by either somatic or germline mutations in BRCA1 as well as promoter hypermethylation in several tumor types such as breast, ovarian, and pancreatic cancers.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('pancreatic cancers', 'Disease', (221, 239))	('cancers', 'Phenotype', 'HP:0002664', (232, 239))	('BRCA deficiency', 'Disease', 'MESH:C562694', (55, 70))	('BRCA1', 'Gene', (126, 131))	('BRCA deficiency', 'Disease', (55, 70))	('HRD', 'Disease', 'None', (0, 3))	('pancreatic cancers', 'Disease', 'MESH:D010190', (221, 239))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('tumor', 'Disease', (180, 185))	('breast', 'Disease', (200, 206))	('mutations', 'Var', (113, 122))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (221, 239))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('ovarian', 'Disease', (208, 215))	('HRD', 'Disease', (0, 3))	('BRCA1', 'Gene', '672', (126, 131))	('promoter', 'MPA', (143, 151))
180978	32509788	High HRD score (>42) and/or BRCA1/2 mutation is also associated with durable responses to olaparib (46).	('BRCA1/2', 'Gene', (28, 35))	('High HRD', 'Disease', (0, 8))	('BRCA1/2', 'Gene', '672;675', (28, 35))	('High HRD', 'Disease', 'MESH:D052456', (0, 8))	('olaparib', 'Chemical', 'MESH:C531550', (90, 98))	('mutation', 'Var', (36, 44))
180986	32509788	Somatic cancer sequencing as performed by NGS is an excellent, comprehensive test for identifying simple mutations, complex genetic alterations, quantifying TMB, determining MSI and HRD and recognizing potential mutational signatures.	('HRD', 'Disease', 'None', (182, 185))	('TMB', 'Chemical', '-', (157, 160))	('cancer', 'Disease', (8, 14))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('mutations', 'Var', (105, 114))	('HRD', 'Disease', (182, 185))	('TMB', 'MPA', (157, 160))	('MSI', 'MPA', (174, 177))	('cancer', 'Disease', 'MESH:D009369', (8, 14))
181037	27956436	Incidence rates for squamous cell carcinoma are also higher among AI/AN and API compared to white men (2.0 and 2.3 vs. 0.3, respectively).	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (20, 43))	('higher', 'PosReg', (53, 59))	('squamous cell carcinoma', 'Disease', (20, 43))	('AI/AN', 'Var', (66, 71))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (20, 43))	('carcinoma', 'Phenotype', 'HP:0030731', (34, 43))	('men', 'Species', '9606', (98, 101))
181066	27956436	AI/AN men had a higher rate of malignant neoplasms and unspecified carcinoma and a lower rate of adenocarcinoma compared to white men.	('neoplasm', 'Phenotype', 'HP:0002664', (41, 49))	('AI/AN', 'Var', (0, 5))	('adenocarcinoma', 'Disease', 'MESH:D000230', (97, 111))	('neoplasms', 'Phenotype', 'HP:0002664', (41, 50))	('carcinoma', 'Disease', 'MESH:D002277', (67, 76))	('unspecified', 'Species', '32644', (55, 66))	('carcinoma', 'Disease', 'MESH:D002277', (102, 111))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('malignant neoplasms', 'Disease', (31, 50))	('malignant neoplasms', 'Disease', 'MESH:D009369', (31, 50))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('adenocarcinoma', 'Disease', (97, 111))	('carcinoma', 'Disease', (67, 76))	('men', 'Species', '9606', (130, 133))	('carcinoma', 'Disease', (102, 111))	('men', 'Species', '9606', (6, 9))
181071	27956436	AI/AN and API women had lower rates for all subtypes compared to white women with the only exception of a higher rate of squamous cell carcinoma among AI/AN compared to white women.	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (121, 144))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('squamous cell carcinoma', 'Disease', (121, 144))	('AI/AN', 'Var', (151, 156))	('women', 'Species', '9606', (71, 76))	('women', 'Species', '9606', (175, 180))	('women', 'Species', '9606', (14, 19))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (121, 144))
181098	27956436	However, changes in tobacco blends and inhalation depth may be resulting in increasing peripheral adenocarcinomas of the lung.	('changes', 'Var', (9, 16))	('carcinomas', 'Phenotype', 'HP:0030731', (103, 113))	('adenocarcinomas of the lung', 'Disease', 'MESH:D000077192', (98, 125))	('tobacco', 'Species', '4097', (20, 27))	('increasing', 'PosReg', (76, 86))	('carcinomas of the lung', 'Phenotype', 'HP:0100526', (103, 125))	('adenocarcinomas of the lung', 'Disease', (98, 125))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))
181122	32393777	Protein-altering germline mutations implicate novel genes related to lung cancer development Few germline mutations are known to affect lung cancer risk.	('lung cancer', 'Phenotype', 'HP:0100526', (136, 147))	('lung cancer', 'Disease', 'MESH:D008175', (69, 80))	('implicate', 'Reg', (36, 45))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('mutations', 'Var', (26, 35))	('lung cancer', 'Disease', (69, 80))	('lung cancer', 'Disease', 'MESH:D008175', (136, 147))	('lung cancer', 'Phenotype', 'HP:0100526', (69, 80))	('genes', 'Gene', (52, 57))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('lung cancer', 'Disease', (136, 147))
181123	32393777	We find a large-effect association with an ATM L2307F (rs56009889) mutation in adenocarcinoma for discovery (adjusted Odds Ratio = 8.82, P = 1.18 x 10-15) and replication (adjusted OR = 2.93, P = 2.22 x 10-3) that is more pronounced in females (adjusted OR = 6.81 and 3.19 and for discovery and replication).	('ATM', 'Gene', (43, 46))	('rs56009889', 'Var', (55, 65))	('L2307F', 'Mutation', 'rs56009889', (47, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('adenocarcinoma', 'Disease', (79, 93))	('adenocarcinoma', 'Disease', 'MESH:D000230', (79, 93))	('ATM', 'Gene', '472', (43, 46))	('rs56009889', 'Mutation', 'rs56009889', (55, 65))
181124	32393777	We observe an excess loss of heterozygosity in lung tumors among ATM L2307F allele carriers.	('ATM', 'Gene', '472', (65, 68))	('L2307F', 'Var', (69, 75))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('L2307F', 'Mutation', 'rs56009889', (69, 75))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('lung tumors', 'Phenotype', 'HP:0100526', (47, 58))	('lung tumors', 'Disease', (47, 58))	('ATM', 'Gene', (65, 68))	('lung tumors', 'Disease', 'MESH:D008175', (47, 58))
181126	32393777	We also observe an association in discovery (adjusted OR = 2.61, P = 7.98 x 10-22) and replication datasets (adjusted OR = 1.55, P = 0.06) with a loss-of-function mutation, Q4X (rs150665432) of an uncharacterized gene, KIAA0930.	('Q4X', 'Mutation', 'rs150665432', (173, 176))	('rs150665432', 'Mutation', 'rs150665432', (178, 189))	('rs150665432', 'Var', (178, 189))	('loss-of-function', 'NegReg', (146, 162))	('KIAA0930', 'Gene', '23313', (219, 227))	('KIAA0930', 'Gene', (219, 227))
181127	32393777	Our findings implicate germline genetic variants in ATM with lung cancer susceptibility and suggest KIAA0930 as a novel candidate gene for lung cancer risk.	('lung cancer', 'Disease', (139, 150))	('lung cancer', 'Disease', (61, 72))	('lung cancer', 'Phenotype', 'HP:0100526', (61, 72))	('ATM', 'Gene', '472', (52, 55))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('lung cancer', 'Disease', 'MESH:D008175', (139, 150))	('KIAA0930', 'Gene', '23313', (100, 108))	('lung cancer', 'Disease', 'MESH:D008175', (61, 72))	('variants', 'Var', (40, 48))	('KIAA0930', 'Gene', (100, 108))	('lung cancer', 'Phenotype', 'HP:0100526', (139, 150))	('ATM', 'Gene', (52, 55))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
181129	32393777	Here the authors looked at rare variants in 39,146 individuals and find novel germline mutations associated with risk, as well as implicating ATM and a new candidate gene for lung cancer risk.	('ATM', 'Gene', '472', (142, 145))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('lung cancer', 'Disease', (175, 186))	('lung cancer', 'Phenotype', 'HP:0100526', (175, 186))	('variants', 'Var', (32, 40))	('lung cancer', 'Disease', 'MESH:D008175', (175, 186))	('associated', 'Reg', (97, 107))	('mutations', 'Var', (87, 96))	('ATM', 'Gene', (142, 145))
181132	32393777	The first wave of genome-wide association studies identified susceptibility regions and common variants for lung cancer risk but have been restricted to analysis of more common variants having allele frequencies of 1% or higher.	('lung cancer', 'Disease', 'MESH:D008175', (108, 119))	('lung cancer', 'Disease', (108, 119))	('lung cancer', 'Phenotype', 'HP:0100526', (108, 119))	('variants', 'Var', (95, 103))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
181134	32393777	Although <1% of most populations are carriers of a germline mutation that drives cancer, such mutations can confer as much as an 80% lifetime risk for developing cancer and influence between 3 and 10% of cancers diagnosed yearly.	('cancer', 'Disease', (204, 210))	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('cancer', 'Disease', 'MESH:D009369', (204, 210))	('influence', 'Reg', (173, 182))	('cancers', 'Phenotype', 'HP:0002664', (204, 211))	('cancers', 'Disease', (204, 211))	('mutations', 'Var', (94, 103))	('cancer', 'Disease', (162, 168))	('cancers', 'Disease', 'MESH:D009369', (204, 211))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('cancer', 'Disease', (81, 87))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))
181135	32393777	In addition, identification of cancer-related mutations has provided potential targets for cancer treatment and drug development.	('mutations', 'Var', (46, 55))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('cancer', 'Disease', (31, 37))
181136	32393777	For example, the rare inherited T790M mutation of EGFR is associated with greatly increased risk for lung cancer in nonsmokers.	('T790M', 'Mutation', 'rs121434569', (32, 37))	('lung cancer', 'Disease', 'MESH:D008175', (101, 112))	('T790M', 'Var', (32, 37))	('EGFR', 'Gene', '1956', (50, 54))	('lung cancer', 'Phenotype', 'HP:0100526', (101, 112))	('EGFR', 'Gene', (50, 54))	('lung cancer', 'Disease', (101, 112))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
181138	32393777	Similarly, identification of germline mutations in BRCA1 and BRCA2 led to the successful application of PARP inhibition therapy for breast and ovarian cancer.	('PARP', 'Gene', '1302', (104, 108))	('BRCA1', 'Gene', '672', (51, 56))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('ovarian cancer', 'Phenotype', 'HP:0100615', (143, 157))	('BRCA2', 'Gene', (61, 66))	('PARP', 'Gene', (104, 108))	('BRCA1', 'Gene', (51, 56))	('BRCA2', 'Gene', '675', (61, 66))	('breast and ovarian cancer', 'Disease', 'MESH:D001943', (132, 157))	('germline mutations', 'Var', (29, 47))
181140	32393777	The objective of this study was to identify reliable germline mutations that highly affect lung cancer risk and to discover novel genes that are involved in the etiology and development of lung cancer.	('lung cancer', 'Phenotype', 'HP:0100526', (91, 102))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('affect', 'Reg', (84, 90))	('lung cancer', 'Phenotype', 'HP:0100526', (189, 200))	('lung cancer', 'Disease', 'MESH:D008175', (91, 102))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('lung cancer', 'Disease', (189, 200))	('lung cancer', 'Disease', (91, 102))	('lung cancer', 'Disease', 'MESH:D008175', (189, 200))	('germline', 'Var', (53, 61))
181141	32393777	We analyzed two independent datasets comprising 39,146 individuals of European ancestry that have not been used previously for identifying low minor allele frequency (MAF) variants occurring in <1% of the population to discover and verify mutations having large effects increasing lung cancer risk.	('increasing', 'PosReg', (270, 280))	('lung cancer', 'Disease', (281, 292))	('variants', 'Var', (172, 180))	('lung cancer', 'Phenotype', 'HP:0100526', (281, 292))	('cancer', 'Phenotype', 'HP:0002664', (286, 292))	('mutations', 'Var', (239, 248))	('lung cancer', 'Disease', 'MESH:D008175', (281, 292))
181143	32393777	Altogether, our study identified and validated two novel mutations in genes that significantly affect lung cancer etiology, offering insights for understanding lung cancer mechanisms.	('lung cancer', 'Phenotype', 'HP:0100526', (102, 113))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('lung cancer', 'Disease', (102, 113))	('lung cancer', 'Disease', 'MESH:D008175', (160, 171))	('mutations', 'Var', (57, 66))	('affect', 'Reg', (95, 101))	('lung cancer', 'Disease', 'MESH:D008175', (102, 113))	('genes', 'Gene', (70, 75))	('lung cancer', 'Disease', (160, 171))	('lung cancer', 'Phenotype', 'HP:0100526', (160, 171))
181145	32393777	We used the availability of two datasets, of which 5742 individuals were genotyped on both platforms, to investigate germ-line mutations with large effects on lung cancer risk.	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('lung cancer', 'Disease', 'MESH:D008175', (159, 170))	('effects', 'Reg', (148, 155))	('lung cancer', 'Disease', (159, 170))	('lung cancer', 'Phenotype', 'HP:0100526', (159, 170))	('mutations', 'Var', (127, 136))
181146	32393777	We used the discovery dataset to identify potential rare variants linked with lung cancer susceptibility.	('lung cancer', 'Disease', (78, 89))	('lung cancer', 'Phenotype', 'HP:0100526', (78, 89))	('linked', 'Reg', (66, 72))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('lung cancer', 'Disease', 'MESH:D008175', (78, 89))	('variants', 'Var', (57, 65))
181149	32393777	Three mutations within the exome, including rs56009889, rs150665432, and rs61816761 had association with P values of <5.0 x 10-8 and OR values of more than 2.0 in the discovery dataset when crude association analysis were performed (Supplementary Table 2).	('rs150665432', 'Var', (56, 67))	('rs61816761', 'Var', (73, 83))	('rs56009889', 'Mutation', 'rs56009889', (44, 54))	('rs56009889', 'Var', (44, 54))	('rs150665432', 'Mutation', 'rs150665432', (56, 67))	('rs61816761', 'Mutation', 'rs61816761', (73, 83))
181150	32393777	The variants rs56009889 and rs150665432 had excellent concordances of 99.95% and 99.08% for overall genotypes and 89.66% and 92.31% for the rare alleles, respectively, which confirmed their genotyping fidelity in both datasets.	('rs150665432', 'Mutation', 'rs150665432', (28, 39))	('rs56009889', 'Var', (13, 23))	('rs150665432', 'Var', (28, 39))	('rs56009889', 'Mutation', 'rs56009889', (13, 23))
181152	32393777	Additionally, among unaffected individuals, the Minor Allele Frequencies (MAFs) of rs56009889 and rs150665432 in both datasets were comparable to the MAFs found for European populations in the Exome Aggregation Consortium, and were in agreement with MAFs in the NHLBI GO Exome Sequencing Project and the Trans-Omics for Precision Medicine Program (https://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=150665432, https://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=56009889) (Supplementary Table 4), which supported the reliability of the genotyping data of rs56009889 and rs150665432 in both datasets.	('rs56009889', 'Var', (566, 576))	('rs150665432', 'Mutation', 'rs150665432', (98, 109))	('rs56009889', 'Mutation', 'rs56009889', (83, 93))	('rs150665432', 'Mutation', 'rs150665432', (581, 592))	('rs150665432', 'Var', (581, 592))	('rs56009889', 'Mutation', 'rs56009889', (566, 576))
181153	32393777	In the independent replication series, rs56009889 (P = 0.34) did not significantly associate with overall lung cancer risk without adjustment (Table 1).	('rs56009889', 'Mutation', 'rs56009889', (39, 49))	('lung cancer', 'Disease', (106, 117))	('lung cancer', 'Phenotype', 'HP:0100526', (106, 117))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('rs56009889', 'Var', (39, 49))	('lung cancer', 'Disease', 'MESH:D008175', (106, 117))	('associate', 'Reg', (83, 92))
181154	32393777	However, strong evidence for association was noted in the replication data for lung adenocarcinoma (LUAD) (P = 9.8 x 10-4) and women (P = 0.01) for rs56009889.	('rs56009889', 'Mutation', 'rs56009889', (148, 158))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (79, 98))	('women', 'Species', '9606', (127, 132))	('rs56009889', 'Var', (148, 158))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (79, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('lung adenocarcinoma', 'Disease', (79, 98))
181157	32393777	rs56009889 maps within the ATM gene (Fig.	('rs56009889', 'Mutation', 'rs56009889', (0, 10))	('ATM', 'Gene', '472', (27, 30))	('rs56009889', 'Var', (0, 10))	('ATM', 'Gene', (27, 30))
181158	32393777	This mutation results in L2307F missense mutation in the FAT domain that regulates ATM activity, implying a putative functional role.	('ATM', 'Gene', '472', (83, 86))	('L2307F missense mutation', 'Var', (25, 49))	('regulates', 'Reg', (73, 82))	('L2307F', 'Mutation', 'rs56009889', (25, 31))	('ATM', 'Gene', (83, 86))
181159	32393777	Consistent with the location of this mutation in a highly conserved region that is critical for ATM function, in silico tools such as SNPeffect 4.0 PolyPhen-2 Fathmm-XF (http://fathmm.biocompute.org.uk/) and SIFT suggest a functional effect.	('ATM', 'Gene', '472', (96, 99))	('ATM', 'Gene', (96, 99))	('PolyPhen-2', 'Chemical', '-', (148, 158))	('mutation', 'Var', (37, 45))
181160	32393777	Compared to non-carriers (C/C), L2307F carriers (T/C + T/T) had statistically significant increased risk of lung cancer in the discovery dataset (adjusted odds ratios (ORs = 4.19, P = 3.56 x 10-7), though the increased risk did not reach significance in the replication dataset (Table 2).	('lung cancer', 'Disease', 'MESH:D008175', (108, 119))	('L2307F', 'Mutation', 'rs56009889', (32, 38))	('L2307F', 'Var', (32, 38))	('lung cancer', 'Disease', (108, 119))	('lung cancer', 'Phenotype', 'HP:0100526', (108, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
181161	32393777	Among females, L2307F was significantly associated with lung cancer risk with ORs being 7.76 (P = 0.0002) in the discovery dataset and 3.22 (P = 0.03) in the replication dataset.	('lung cancer', 'Phenotype', 'HP:0100526', (56, 67))	('lung cancer', 'Disease', 'MESH:D008175', (56, 67))	('L2307F', 'Var', (15, 21))	('L2307F', 'Mutation', 'rs56009889', (15, 21))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('lung cancer', 'Disease', (56, 67))	('associated', 'Reg', (40, 50))
181162	32393777	Among males, L2307F showed a weakly significant association with lung cancer risk in the discovery dataset and no association in the replication dataset (Fig.	('lung cancer', 'Disease', 'MESH:D008175', (65, 76))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('lung cancer', 'Disease', (65, 76))	('lung cancer', 'Phenotype', 'HP:0100526', (65, 76))	('L2307F', 'Var', (13, 19))	('L2307F', 'Mutation', 'rs56009889', (13, 19))
181163	32393777	Stratification analysis by histology indicated that L2307F carriers had a significant 5.23-fold increased risk for lung adenocarcinoma (LAD) in the discovery dataset (P = 6.47 x 10-9) and a 2.48-fold increased risk in the replication dataset (P = 0.01), and there was little evidence for association with the risk of lung squamous cell carcinoma (LSQ) or of small cell lung cancer (SCLC) in either dataset (Supplementary Table 5).	('small cell lung cancer', 'Disease', 'MESH:D055752', (358, 380))	('SCLC', 'Disease', 'MESH:D018288', (382, 386))	('LAD', 'Disease', 'MESH:C535887', (136, 139))	('small cell lung cancer', 'Disease', (358, 380))	('lung cancer', 'Phenotype', 'HP:0100526', (369, 380))	('cancer', 'Phenotype', 'HP:0002664', (374, 380))	('lung adenocarcinoma', 'Disease', (115, 134))	('L2307F', 'Mutation', 'rs56009889', (52, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('SCLC', 'Disease', (382, 386))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (358, 380))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (115, 134))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (322, 345))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (317, 345))	('lung squamous cell carcinoma', 'Disease', (317, 345))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (115, 134))	('LAD', 'Disease', (136, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (336, 345))	('L2307F', 'Var', (52, 58))
181164	32393777	Females carrying L2307F showed an 8.05-fold (P = 0.0001) and 4.69-fold (P = 0.004) greater risk of LAD in the discovery and replication datasets, respectively (Fig.	('LAD', 'Disease', 'MESH:C535887', (99, 102))	('greater', 'PosReg', (83, 90))	('L2307F', 'Mutation', 'rs56009889', (17, 23))	('L2307F', 'Var', (17, 23))	('LAD', 'Disease', (99, 102))
181165	32393777	Notably, all the L2307F homozygotes (N = 5), no matter what age, gender, and smoking status, had LAD in this study (P = 0.004) (Fig.	('LAD', 'Disease', 'MESH:C535887', (97, 100))	('L2307F', 'Mutation', 'rs56009889', (17, 23))	('LAD', 'Disease', (97, 100))	('L2307F', 'Var', (17, 23))
181166	32393777	Moreover, the association exhibited a dose-response relationship between the number of mutated alleles and the LAD risk in the discovery dataset (Ptrend = 5.44 x 10-9).	('LAD', 'Disease', 'MESH:C535887', (111, 114))	('LAD', 'Disease', (111, 114))	('mutated', 'Var', (87, 94))
181167	32393777	A more significant role for L2307F in LAD pathogenesis than in LSQ or SCLC is reflected in the low mutant allele frequency of LSQ and SCLC in both datasets.	('SCLC', 'Disease', 'MESH:D018288', (70, 74))	('LAD', 'Disease', (38, 41))	('LSQ', 'Disease', (126, 129))	('SCLC', 'Disease', (134, 138))	('LAD', 'Disease', 'MESH:C535887', (38, 41))	('SCLC', 'Disease', 'MESH:D018288', (134, 138))	('L2307F', 'Var', (28, 34))	('L2307F', 'Mutation', 'rs56009889', (28, 34))	('SCLC', 'Disease', (70, 74))
181168	32393777	These results suggested the association between rs56009889 and lung cancer risk was restricted to LAD and is especially prominent in women.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('lung cancer', 'Disease', 'MESH:D008175', (63, 74))	('rs56009889', 'Var', (48, 58))	('LAD', 'Disease', 'MESH:C535887', (98, 101))	('women', 'Species', '9606', (133, 138))	('lung cancer', 'Disease', (63, 74))	('lung cancer', 'Phenotype', 'HP:0100526', (63, 74))	('rs56009889', 'Mutation', 'rs56009889', (48, 58))	('LAD', 'Disease', (98, 101))
181171	32393777	We therefore investigated if the association of rs56009889 and lung cancer risk was affected by country of origin.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('lung cancer', 'Disease', 'MESH:D008175', (63, 74))	('rs56009889', 'Var', (48, 58))	('lung cancer', 'Disease', (63, 74))	('lung cancer', 'Phenotype', 'HP:0100526', (63, 74))	('rs56009889', 'Mutation', 'rs56009889', (48, 58))
181172	32393777	In both Israeli and North Americans, rs56009889 was significantly associated with the risk of lung cancer, of LAD in general and especially in women.	('lung cancer', 'Disease', 'MESH:D008175', (94, 105))	('rs56009889', 'Mutation', 'rs56009889', (37, 47))	('LAD', 'Disease', (110, 113))	('associated', 'Reg', (66, 76))	('lung cancer', 'Disease', (94, 105))	('rs56009889', 'Var', (37, 47))	('lung cancer', 'Phenotype', 'HP:0100526', (94, 105))	('LAD', 'Disease', 'MESH:C535887', (110, 113))	('women', 'Species', '9606', (143, 148))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
181173	32393777	As shown in Supplementary Table 7, the ORs for LAD risk among L2307F carriers were 3.36 in North Americans (P = 0.004) and 6.74 in the Israeli case control study (P = 3.38 x 10-6).	('LAD', 'Disease', (47, 50))	('L2307F', 'Mutation', 'rs56009889', (62, 68))	('LAD', 'Disease', 'MESH:C535887', (47, 50))	('L2307F', 'Var', (62, 68))
181174	32393777	The female carriage of L2307F conferred an increased LAD risk with an OR of 3.81 in North Americans (P = 0.04) and 17.15 for the Israeli (P = 0.006).	('LAD', 'Disease', 'MESH:C535887', (53, 56))	('L2307F', 'Var', (23, 29))	('LAD', 'Disease', (53, 56))	('L2307F', 'Mutation', 'rs56009889', (23, 29))
181176	32393777	Because populations in Israel mainly include Jews and Arabs, we then investigated whether L2307F had different prevalence and associations between the two ethnic groups as derived from genetic information (Supplementary Table 8).	('L2307F', 'Mutation', 'rs56009889', (90, 96))	('associations', 'Interaction', (126, 138))	('L2307F', 'Var', (90, 96))
181177	32393777	In addition, although L2307F had a significant association with the risk of lung cancer and of LAD for Jews wherever they lived, the association was more marked in the Israeli Jews than Jews in other countries (Supplementary Table 8).	('LAD', 'Disease', 'MESH:C535887', (95, 98))	('lung cancer', 'Disease', 'MESH:D008175', (76, 87))	('L2307F', 'Var', (22, 28))	('L2307F', 'Mutation', 'rs56009889', (22, 28))	('lung cancer', 'Disease', (76, 87))	('lung cancer', 'Phenotype', 'HP:0100526', (76, 87))	('LAD', 'Disease', (95, 98))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))
181178	32393777	Among L2307F carriers, the ORs for LAD risk were 7.86 in Israeli Jews (P = 2.12 x 10-6) and 3.40 for the Jews living in other countries (P = 0.005).	('LAD', 'Disease', (35, 38))	('Israeli Jews', 'Disease', (57, 69))	('LAD', 'Disease', 'MESH:C535887', (35, 38))	('L2307F', 'Mutation', 'rs56009889', (6, 12))	('L2307F', 'Var', (6, 12))
181179	32393777	Female Jews carrying L2307F had a 16.01-fold LAD risk (P = 0.008) in Israel and 4.23-fold risk in other countries (P = 0.03).	('LAD', 'Disease', (45, 48))	('LAD', 'Disease', 'MESH:C535887', (45, 48))	('Israel', 'Disease', (69, 75))	('L2307F', 'Var', (21, 27))	('L2307F', 'Mutation', 'rs56009889', (21, 27))
181181	32393777	The rs150665432 mutation codes for Q4X which results in the truncation of the full-length protein from 409 to 3 amino acids (https://www.ncbi.nlm.nih.gov/protein/NP_056079.1?report=graph).	('truncation', 'MPA', (60, 70))	('rs150665432', 'Var', (4, 15))	('rs150665432', 'Mutation', 'rs150665432', (4, 15))	('Q4X', 'Mutation', 'rs150665432', (35, 38))
181182	32393777	Compared to non-carriers (G/G), Q4X carriers (A/G + A/A) had an increased lung cancer risk in both the discovery (adjusted OR = 2.59; P = 1.15 x 10-18) and the replication datasets (adjusted OR = 1.69; P = 0.03) (Fig.	('lung cancer', 'Disease', (74, 85))	('lung cancer', 'Phenotype', 'HP:0100526', (74, 85))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('Q4X', 'Mutation', 'rs150665432', (32, 35))	('lung cancer', 'Disease', 'MESH:D008175', (74, 85))	('Q4X carriers', 'Var', (32, 44))
181183	32393777	Additionally, all Q4X homozygotes in the discovery set (N = 29) developed lung cancer (P = 2.29 x 10-8) (Fig.	('Q4X', 'Mutation', 'rs150665432', (18, 21))	('lung cancer', 'Disease', (74, 85))	('lung cancer', 'Phenotype', 'HP:0100526', (74, 85))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('Q4X', 'Var', (18, 21))	('lung cancer', 'Disease', 'MESH:D008175', (74, 85))	('developed', 'PosReg', (64, 73))
181184	32393777	3b), and the number of mutated alleles showed a dose-response relationship with lung cancer risk (Ptrend = 1.51 x 10-19) in the discovery dataset (Table 2).	('lung cancer', 'Disease', 'MESH:D008175', (80, 91))	('lung cancer', 'Disease', (80, 91))	('mutated', 'Var', (23, 30))	('lung cancer', 'Phenotype', 'HP:0100526', (80, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
181185	32393777	Stratification analysis showed that Q4X had a significant risk in all strata: among females, males, smokers, non-smokers (Supplementary Table 10), and of LAD, LSQ, and SCLC (Supplementary Table 11) in the discovery dataset.	('LAD', 'Disease', 'MESH:C535887', (154, 157))	('Q4X', 'Mutation', 'rs150665432', (36, 39))	('Q4X', 'Var', (36, 39))	('LAD', 'Disease', (154, 157))	('risk', 'Reg', (58, 62))	('SCLC', 'Disease', (168, 172))	('SCLC', 'Disease', 'MESH:D018288', (168, 172))
181186	32393777	Although the frequency of rs150665432 in controls varies non-significantly among geographic populations, ORs of the association between Q4X and lung cancer risk were higher in North American Countries (adjusted OR = 4.19; P = 3.27 x 10-16) than in European Countries (adjusted OR = 1.65; P = 0.0003, Supplementary Table 12).	('association', 'Interaction', (116, 127))	('Q4X', 'Var', (136, 139))	('lung cancer', 'Disease', (144, 155))	('rs150665432', 'Var', (26, 37))	('lung cancer', 'Phenotype', 'HP:0100526', (144, 155))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('lung cancer', 'Disease', 'MESH:D008175', (144, 155))	('Q4X', 'Mutation', 'rs150665432', (136, 139))	('rs150665432', 'Mutation', 'rs150665432', (26, 37))
181187	32393777	Carriers of L2307F tended to be significantly older at lung cancer onset overall and in all subsets except small-cell and squamous lung cancer in the discovery data.	('lung cancer', 'Disease', 'MESH:D008175', (55, 66))	('squamous lung cancer', 'Disease', 'MESH:D008175', (122, 142))	('L2307F', 'Mutation', 'rs56009889', (12, 18))	('L2307F', 'Var', (12, 18))	('lung cancer', 'Disease', 'MESH:D008175', (131, 142))	('small-cell', 'Disease', (107, 117))	('squamous lung cancer', 'Disease', (122, 142))	('older', 'PosReg', (46, 51))	('lung cancer', 'Disease', (55, 66))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('lung cancer', 'Phenotype', 'HP:0100526', (55, 66))	('lung cancer', 'Phenotype', 'HP:0100526', (131, 142))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
181192	32393777	The frequency of germline L2307F was higher in LADs (P = 0.0009), females vs male patients (P = 0.03), light-smokers (<=5 pack years) vs heavy smokers (>5 pack years, P = 0.003) and patients with EGFR oncogenic mutations vs cases without EGFR oncogenic mutations (P = 0.001).	('EGFR', 'Gene', (196, 200))	('higher', 'PosReg', (37, 43))	('germline', 'Var', (17, 25))	('patients', 'Species', '9606', (82, 90))	('L2307F', 'Var', (26, 32))	('L2307F', 'Mutation', 'rs56009889', (26, 32))	('EGFR', 'Gene', '1956', (238, 242))	('EGFR', 'Gene', (238, 242))	('patients', 'Species', '9606', (182, 190))	('LADs', 'Disease', 'None', (47, 51))	('EGFR', 'Gene', '1956', (196, 200))	('LADs', 'Disease', (47, 51))
181193	32393777	61 of 63 patients were L2307F heterozygotes, and of these 29.5% patients showed loss of heterozygosity (LOH) of the wild-type allele compared to 10% background LOH (P = 0.0026) (Fig.	('patients', 'Species', '9606', (9, 17))	('patients', 'Species', '9606', (64, 72))	('loss', 'NegReg', (80, 84))	('L2307F', 'Mutation', 'rs56009889', (23, 29))	('L2307F', 'Var', (23, 29))	('heterozygosity', 'MPA', (88, 102))
181196	32393777	To clarify whether rs56009889 and rs150665432 are included in the isoforms that are normally expressed in lung tissue and thereby may play a functional role in lung, we investigated the isoform expression of ATM and KIAA0930.	('ATM', 'Gene', (208, 211))	('rs150665432', 'Mutation', 'rs150665432', (34, 45))	('ATM', 'Gene', '472', (208, 211))	('rs150665432', 'Var', (34, 45))	('rs56009889', 'Mutation', 'rs56009889', (19, 29))	('play', 'Reg', (134, 138))	('KIAA0930', 'Gene', '23313', (216, 224))	('KIAA0930', 'Gene', (216, 224))	('rs56009889', 'Var', (19, 29))
181198	32393777	L2307F causes an amino acid (aa) change in the two isoforms ENST00000278616 and ENST00000452508, producing the full-length isoforms of ATM protein comprising 3056 aa long that include TAN, FAT, FATC, and Phosphoinositide 3-kinase related kinase (PIKK) domains (Fig.	('ATM', 'Gene', (135, 138))	('ATM', 'Gene', '472', (135, 138))	('amino', 'MPA', (17, 22))	('ENST00000452508', 'Var', (80, 95))	('L2307F', 'Mutation', 'rs56009889', (0, 6))	('L2307F', 'Var', (0, 6))
181200	32393777	rs150665432 truncates the protein length of ENST00000251993 from 409 to 3 amino acids (Fig.	('protein', 'MPA', (26, 33))	('rs150665432', 'Mutation', 'rs150665432', (0, 11))	('truncates', 'NegReg', (12, 21))	('ENST00000251993', 'Gene', (44, 59))	('rs150665432', 'Var', (0, 11))
181201	32393777	In addition, rs150665432 is included in 4 other isoforms, including ENST00000417906, ENST00000488038, ENST00000486640 and ENST0000049622, which are untranslated transcripts.	('ENST00000417906', 'Var', (68, 83))	('rs150665432', 'Mutation', 'rs150665432', (13, 24))	('ENST0000049622', 'Var', (122, 136))	('rs150665432', 'Var', (13, 24))	('ENST00000486640', 'Var', (102, 117))	('ENST00000488038', 'Var', (85, 100))
181202	32393777	The ENST00000251993 and ENST00000488038 transcripts, which include rs150665432, are the primary transcripts expressed in lung tissue in GTEx data (Supplementary Table 18 and Fig.	('ENST00000488038', 'Var', (24, 39))	('rs150665432', 'Mutation', 'rs150665432', (67, 78))	('rs150665432', 'Var', (67, 78))	('ENST00000251993', 'Var', (4, 19))
181208	32393777	Using this approach, we report large-effect associations with two variants; a rs56009889 germline mutation, where we observed a reproducible association in LAD and a suggestive association with the rs150665432.	('rs150665432', 'Var', (198, 209))	('LAD', 'Disease', (156, 159))	('rs56009889', 'Mutation', 'rs56009889', (78, 88))	('LAD', 'Disease', 'MESH:C535887', (156, 159))	('rs150665432', 'Mutation', 'rs150665432', (198, 209))	('rs56009889', 'Var', (78, 88))
181209	32393777	A case only analysis in the MSK-Impact study of rs56009889 reinforced the link between this polymorphism and LAD and particularly in females.	('LAD', 'Disease', 'MESH:C535887', (109, 112))	('link', 'Interaction', (74, 78))	('rs56009889', 'Var', (48, 58))	('LAD', 'Disease', (109, 112))	('rs56009889', 'Mutation', 'rs56009889', (48, 58))
181210	32393777	Both rs56009889 and rs150665432 are coding mutations, a missense variant in ATM-L2307F and a stop-gain variant KIAA0930-Q4X and both appear included in the full-length isoforms of genes.	('KIAA0930', 'Gene', (111, 119))	('ATM', 'Gene', (76, 79))	('rs150665432', 'Mutation', 'rs150665432', (20, 31))	('ATM', 'Gene', '472', (76, 79))	('rs56009889', 'Mutation', 'rs56009889', (5, 15))	('rs150665432', 'Var', (20, 31))	('Q4X', 'Mutation', 'rs150665432', (120, 123))	('L2307F', 'Mutation', 'rs56009889', (80, 86))	('rs56009889', 'Var', (5, 15))	('KIAA0930', 'Gene', '23313', (111, 119))
181212	32393777	The functional impact of ATM-L2307F remains ambiguous; in silico predictions suggest this variant may impact function, but it is reported by Clinvar as "likely benign" or "benign" (https://www.ncbi.nlm.nih.gov/clinvar/variation/127430/) and has not been associated with Ataxia Telangiectasia.	('L2307F', 'Mutation', 'rs56009889', (29, 35))	('Telangiectasia', 'Phenotype', 'HP:0001009', (277, 291))	('//www.ncbi.nlm.nih.gov/clinvar/variation/127430/', 'Var', (187, 235))	('Ataxia', 'Phenotype', 'HP:0001251', (270, 276))	('Ataxia Telangiectasia', 'Disease', (270, 291))	('impact', 'Reg', (102, 108))	('ATM', 'Gene', (25, 28))	('Ataxia Telangiectasia', 'Disease', 'MESH:D001260', (270, 291))	('function', 'MPA', (109, 117))	('ATM', 'Gene', '472', (25, 28))	('variant', 'Var', (90, 97))
181216	32393777	Mechanistically, L2307F is predicted to be deleterious by in silico analysis and defective ATM proteins are known permit the accumulation of new mutations.	('ATM', 'Gene', (91, 94))	('L2307F', 'Mutation', 'rs56009889', (17, 23))	('L2307F', 'Var', (17, 23))	('ATM', 'Gene', '472', (91, 94))
181218	32393777	It is noteworthy that all L2307F homozygotes had LAD and we observed an excess of LOH in tumors of allele carriers relative to non-carriers implying that biallelic loss might be important in this process.	('tumors', 'Disease', (89, 95))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('LAD', 'Disease', (49, 52))	('LOH', 'Disease', (82, 85))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('L2307F', 'Var', (26, 32))	('L2307F', 'Mutation', 'rs56009889', (26, 32))	('LAD', 'Disease', 'MESH:C535887', (49, 52))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))
181221	32393777	It remains to be tested if variants in other populations also contribute to lung cancer susceptibility, or if L2307F co-occurring with other clearly pathogenic ATM mutations increases lung cancer risk beyond that experienced by heterozygotes.	('variants', 'Var', (27, 35))	('increases', 'PosReg', (174, 183))	('L2307F', 'Mutation', 'rs56009889', (110, 116))	('lung cancer', 'Disease', 'MESH:D008175', (76, 87))	('L2307F', 'Var', (110, 116))	('ATM', 'Gene', (160, 163))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('lung cancer', 'Disease', 'MESH:D008175', (184, 195))	('ATM', 'Gene', '472', (160, 163))	('lung cancer', 'Disease', (76, 87))	('lung cancer', 'Phenotype', 'HP:0100526', (76, 87))	('contribute', 'Reg', (62, 72))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('lung cancer', 'Disease', (184, 195))	('mutations', 'Var', (164, 173))	('lung cancer', 'Phenotype', 'HP:0100526', (184, 195))
181224	32393777	The rs150665432 - Q4X mutation appears to comprise a loss of function allele, which is included in the full-length isoform of KIAA0930.	('Q4X', 'Mutation', 'rs150665432', (18, 21))	('rs150665432', 'Mutation', 'rs150665432', (4, 15))	('rs150665432 - Q4X', 'Var', (4, 21))	('KIAA0930', 'Gene', '23313', (126, 134))	('KIAA0930', 'Gene', (126, 134))
181227	32393777	Nevertheless, this association must be studied further to ensure its robustness and the mechanism by which the stop-gain mutation Q4X increases risk remains unclear.	('Q4X', 'Mutation', 'rs150665432', (130, 133))	('Q4X', 'Var', (130, 133))	('stop-gain', 'Gene', (111, 120))	('mutation Q4X', 'Var', (121, 133))
181229	32393777	The identification of the novel lung cancer-related germline mutations could greatly advance our understanding of lung cancer etiology.	('lung cancer', 'Disease', 'MESH:D008175', (114, 125))	('advance', 'PosReg', (85, 92))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('lung cancer', 'Disease', 'MESH:D008175', (32, 43))	('lung cancer', 'Disease', (114, 125))	('germline mutations', 'Var', (52, 70))	('lung cancer', 'Phenotype', 'HP:0100526', (114, 125))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('lung cancer', 'Disease', (32, 43))	('lung cancer', 'Phenotype', 'HP:0100526', (32, 43))
181241	32393777	Case-control association tests for genotyped data were conducted using 1-degree-of-freedom Cochran-Mantel-Haenszel tests with the application of PLINK version 1.9 to discover the germline mutations with large effects on lung cancer risk.	('germline mutations', 'Var', (179, 197))	('lung cancer', 'Disease', (220, 231))	('lung cancer', 'Phenotype', 'HP:0100526', (220, 231))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('effects', 'Reg', (209, 216))	('lung cancer', 'Disease', 'MESH:D008175', (220, 231))
181243	32393777	We estimated the association between the risk of lung cancer and the selected germline mutations by computing the ORs and 95% confidence intervals (CIs) in univariate and multivariate logistic regression analyses in both datasets.	('lung cancer', 'Disease', 'MESH:D008175', (49, 60))	('germline', 'Var', (78, 86))	('lung cancer', 'Disease', (49, 60))	('lung cancer', 'Phenotype', 'HP:0100526', (49, 60))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
181244	32393777	We further stratified the association of the selected germline mutations and lung cancer risk by gender and smoking status.	('lung cancer', 'Phenotype', 'HP:0100526', (77, 88))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('germline mutations', 'Var', (54, 72))	('lung cancer', 'Disease', 'MESH:D008175', (77, 88))	('association', 'Interaction', (26, 37))	('lung cancer', 'Disease', (77, 88))
181245	32393777	We also estimated the association between the selected SNP variants and the risk of LAD, lung squamous cell carcinoma or small cell lung cancer, respectively, in univariate and multivariate logistic regression analyses.	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (89, 117))	('LAD', 'Disease', 'MESH:C535887', (84, 87))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (94, 117))	('lung squamous cell carcinoma', 'Disease', (89, 117))	('variants', 'Var', (59, 67))	('lung cancer', 'Phenotype', 'HP:0100526', (132, 143))	('small cell lung cancer', 'Disease', (121, 143))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (121, 143))	('LAD', 'Disease', (84, 87))	('association', 'Interaction', (22, 33))	('small cell lung cancer', 'Disease', 'MESH:D055752', (121, 143))
181246	32393777	There were four mutations including rs17843743, 3:9970073, rs150665432, and rs61816761 with small cell lung cancer that reached the criteria of P values of less than 5.0 x 10-8 and OR values of more than 2.0 in the discovery dataset.	('rs150665432', 'Mutation', 'rs150665432', (59, 70))	('3:9970073', 'Var', (48, 57))	('rs61816761', 'Var', (76, 86))	('small cell lung cancer', 'Disease', 'MESH:D055752', (92, 114))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (92, 114))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('rs17843743', 'Mutation', 'rs17843743', (36, 46))	('lung cancer', 'Phenotype', 'HP:0100526', (103, 114))	('rs17843743', 'Var', (36, 46))	('rs150665432', 'Var', (59, 70))	('rs61816761', 'Mutation', 'rs61816761', (76, 86))	('small cell lung cancer', 'Disease', (92, 114))
181247	32393777	Based on the MAF of rs56009889 and the location of the study sites in the discovery dataset, we categorized all the studies to three subgroups, including Israeli among which rs56009889 had the highest MAF, population in other European countries, and North Americans.	('rs56009889', 'Var', (20, 30))	('rs56009889', 'Var', (174, 184))	('MAF', 'MPA', (201, 204))	('rs56009889', 'Mutation', 'rs56009889', (20, 30))	('rs56009889', 'Mutation', 'rs56009889', (174, 184))
181248	32393777	Since the frequency of rs150665432 in controls varies non-significantly between geographic populations, we categorized all the studies to two subgroups, including population in European countries and North American countries, to calculate the associations of rs150665432 and lung cancer risk in different geographic populations.	('rs150665432', 'Mutation', 'rs150665432', (23, 34))	('rs150665432', 'Var', (259, 270))	('lung cancer', 'Disease', (275, 286))	('rs150665432', 'Var', (23, 34))	('lung cancer', 'Phenotype', 'HP:0100526', (275, 286))	('cancer', 'Phenotype', 'HP:0002664', (280, 286))	('associations', 'Interaction', (243, 255))	('rs150665432', 'Mutation', 'rs150665432', (259, 270))	('lung cancer', 'Disease', 'MESH:D008175', (275, 286))
181250	32393777	In order to validate the reliability of genotyping data, we compared the MAFs of the selected germline mutations in unaffected individuals of the discovery and the replication datasets, respectively, to those in public sequencing projects or datasets including the Exome Aggregation Consortium (ExAC), the NHLBI GO Exome Sequencing Project (GO-ESP) and the Trans-Omics for Precision Medicine (TOPMed) Program.	('ESP', 'Gene', '148713', (344, 347))	('mutations', 'Var', (103, 112))	('ESP', 'Gene', (344, 347))
181257	32393777	Tumor and blood DNA from patients were sequenced by Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT).	('Tumor', 'Disease', 'MESH:D009369', (0, 5))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('Tumor', 'Disease', (0, 5))	('Mutation', 'Var', (63, 71))	('Cancer', 'Phenotype', 'HP:0002664', (96, 102))	('Cancer', 'Disease', (96, 102))	('patients', 'Species', '9606', (25, 33))	('Cancer', 'Disease', 'MESH:D009369', (96, 102))
181276	31059015	Deleted in liver cancer (DLC) proteins belong to the RhoGTPase-activating protein family and are considered to be tumor suppressor genes.	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('RhoGTPase-activating protein', 'Gene', '392', (53, 81))	('Deleted', 'Var', (0, 7))	('liver cancer', 'Phenotype', 'HP:0002896', (11, 23))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('liver cancer', 'Disease', 'MESH:D006528', (11, 23))	('tumor', 'Disease', (114, 119))	('RhoGTPase-activating protein', 'Gene', (53, 81))	('liver cancer', 'Disease', (11, 23))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
181293	31059015	Deleted in liver cancer (DLC) proteins are members of the RhoGTPase-activating protein (RhoGAP) family, and consist of DLC1-3.	('DLC1-3', 'Gene', (119, 125))	('Deleted', 'Var', (0, 7))	('liver cancer', 'Phenotype', 'HP:0002896', (11, 23))	('RhoGTPase-activating protein', 'Gene', '392', (58, 86))	('RhoGAP', 'Gene', '392', (88, 94))	('liver cancer', 'Disease', 'MESH:D006528', (11, 23))	('liver cancer', 'Disease', (11, 23))	('DLC1-3', 'Gene', '10395;90627;9754', (119, 125))	('RhoGAP', 'Gene', (88, 94))	('RhoGTPase-activating protein', 'Gene', (58, 86))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
181311	31059015	The Affymetrix ID corresponding to DLC1 used in the Kaplan Meier plotter was 210762_s_at, the Affymetrix ID corresponding to DLC2 was 213103_at and the Affymetrix ID corresponding to DLC3 was 206868_at.	('DLC3', 'Gene', (183, 187))	('DLC3', 'Gene', '9754', (183, 187))	('DLC2', 'Gene', '90627', (125, 129))	('DLC1', 'Gene', '10395', (35, 39))	('213103_at', 'Var', (134, 143))	('210762_s_at', 'Var', (77, 88))	('DLC2', 'Gene', (125, 129))	('DLC1', 'Gene', (35, 39))
181352	31059015	The valid Affymetrix IDs in the KM plotter dataset of DLC1, DLC2 and DLC3 are 210762_s_at, 213103_at and 206868_at, respectively.	('DLC2', 'Gene', (60, 64))	('DLC3', 'Gene', (69, 73))	('DLC3', 'Gene', '9754', (69, 73))	('DLC2', 'Gene', '90627', (60, 64))	('206868_at', 'Var', (105, 114))	('DLC1', 'Gene', '10395', (54, 58))	('213103_at', 'Var', (91, 100))	('210762_s_at', 'Var', (78, 89))	('DLC1', 'Gene', (54, 58))
181355	31059015	2, a high expression level of DLC1 was positively associated with survival duration in all NSCLCs (HR, 0.64; 95% CI, 0.56-0.73; P<0.0001).	('associated with', 'Reg', (50, 65))	('NSCLC', 'Disease', 'MESH:D002289', (91, 96))	('high', 'Var', (5, 9))	('DLC1', 'Gene', (30, 34))	('survival', 'Disease', (66, 74))	('NSCLC', 'Disease', (91, 96))	('DLC1', 'Gene', '10395', (30, 34))
181356	31059015	High expression level of DLC1 was also associated with prolonged survival in patients with LUAD (HR, 0.62; 95% CI, 0.49-0.78; P<0.0001), but not in patients with LUSC.	('patients', 'Species', '9606', (148, 156))	('High', 'Var', (0, 4))	('DLC1', 'Gene', (25, 29))	('patients', 'Species', '9606', (77, 85))	('survival', 'CPA', (65, 73))	('prolonged', 'PosReg', (55, 64))	('LUAD', 'Disease', (91, 95))	('DLC1', 'Gene', '10395', (25, 29))
181358	31059015	High mRNA expression of DLC2 was associated with improved survival time in all lung cancers (HR, 0.69; 95% CI, 0.6-0.78; P<0.0001).	('lung cancers', 'Disease', (79, 91))	('improved', 'PosReg', (49, 57))	('High', 'Var', (0, 4))	('DLC2', 'Gene', '90627', (24, 28))	('cancers', 'Phenotype', 'HP:0002664', (84, 91))	('mRNA expression', 'MPA', (5, 20))	('survival time', 'CPA', (58, 71))	('DLC2', 'Gene', (24, 28))	('lung cancer', 'Phenotype', 'HP:0100526', (79, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('lung cancers', 'Disease', 'MESH:D008175', (79, 91))	('lung cancers', 'Phenotype', 'HP:0100526', (79, 91))
181359	31059015	High mRNA expression of DLC2 was also associated with improved OS in patients with LUAD (HR, 0.52; 95% CI, 0.41-0.67; P<0.0001), but not in patients with LUSC.	('High', 'Var', (0, 4))	('DLC2', 'Gene', '90627', (24, 28))	('LUAD', 'Disease', (83, 87))	('mRNA expression', 'MPA', (5, 20))	('DLC2', 'Gene', (24, 28))	('patients', 'Species', '9606', (140, 148))	('improved', 'PosReg', (54, 62))	('patients', 'Species', '9606', (69, 77))
181362	31059015	A high mRNA expression level of DLC2 was associated with improved survival in patients with NSCLC who never smoked (HR, 0.49; 95% CI, 0.27-0.89; P=0.016).	('survival', 'MPA', (66, 74))	('high', 'Var', (2, 6))	('mRNA expression level', 'MPA', (7, 28))	('patients', 'Species', '9606', (78, 86))	('DLC2', 'Gene', '90627', (32, 36))	('improved', 'PosReg', (57, 65))	('NSCLC', 'Disease', (92, 97))	('NSCLC', 'Disease', 'MESH:D002289', (92, 97))	('DLC2', 'Gene', (32, 36))
181364	31059015	As seen in Table II, a high mRNA expression level of DLC1 was associated with improved prognosis in patients with stage 1 NSCLC (HR, 0.44, 95% CI, 0.33-0.58; P<0.0001).	('NSCLC', 'Disease', 'MESH:D002289', (122, 127))	('DLC1', 'Gene', (53, 57))	('high', 'Var', (23, 27))	('mRNA expression level', 'MPA', (28, 49))	('patients', 'Species', '9606', (100, 108))	('DLC1', 'Gene', '10395', (53, 57))	('improved', 'PosReg', (78, 86))	('NSCLC', 'Disease', (122, 127))
181390	31059015	The present study investigated the prognostic value of DLC1 in NSCLC, and the results obtained demonstrated that a high expression level of DLC1 indicated improved survival.	('high', 'Var', (115, 119))	('NSCLC', 'Disease', (63, 68))	('survival', 'MPA', (164, 172))	('DLC1', 'Gene', '10395', (140, 144))	('NSCLC', 'Disease', 'MESH:D002289', (63, 68))	('DLC1', 'Gene', '10395', (55, 59))	('improved', 'PosReg', (155, 163))	('DLC1', 'Gene', (140, 144))	('DLC1', 'Gene', (55, 59))
181403	31059015	Tang et al revealed that DLC2 mRNA is a direct target of microRNA (miR)-125b, and that the activation of DLC2 may be responsible for the metastasis induced by miR-125b in breast cancer cells.	('breast cancer', 'Disease', 'MESH:D001943', (171, 184))	('DLC2', 'Gene', '90627', (25, 29))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('breast cancer', 'Disease', (171, 184))	('breast cancer', 'Phenotype', 'HP:0003002', (171, 184))	('activation', 'PosReg', (91, 101))	('DLC2', 'Gene', (25, 29))	('miR-125b', 'Var', (159, 167))	('DLC2', 'Gene', '90627', (105, 109))	('metastasis', 'CPA', (137, 147))	('DLC2', 'Gene', (105, 109))	('miR-125b', 'Chemical', '-', (159, 167))
181409	31059015	DLC3 acts as a GAP for RhoA and Cdc42 in vitro; its GAP activity is responsible for the morphological changes observed in Hela cells, which become round following disruption of the actin fibers.	('DLC3', 'Gene', (0, 4))	('DLC3', 'Gene', '9754', (0, 4))	('GAP activity', 'MPA', (52, 64))	('Cdc42', 'Gene', '998', (32, 37))	('RhoA', 'Gene', (23, 27))	('Cdc42', 'Gene', (32, 37))	('RhoA', 'Gene', '387', (23, 27))	('Hela cells', 'CellLine', 'CVCL:0030', (122, 132))	('disruption', 'Var', (163, 173))
181412	31059015	Braun et al, reported that loss of DLC3 inhibited the degradation of epidermal growth factor receptor (EGFR), increasing the activity of the EGFR signaling pathway.	('loss', 'Var', (27, 31))	('EGFR', 'Gene', '1956', (103, 107))	('EGFR', 'Gene', '1956', (141, 145))	('inhibited', 'NegReg', (40, 49))	('epidermal growth factor receptor', 'Gene', (69, 101))	('activity', 'MPA', (125, 133))	('DLC3', 'Gene', (35, 39))	('EGFR', 'Gene', (103, 107))	('EGFR', 'Gene', (141, 145))	('degradation', 'MPA', (54, 65))	('DLC3', 'Gene', '9754', (35, 39))	('epidermal growth factor receptor', 'Gene', '1956', (69, 101))	('increasing', 'PosReg', (110, 120))
181413	31059015	Additionally, Braun et al, showed that knockdown of DLC3 decreased the expression level of N-cadherin on the cell surface and decreased cell aggregation.	('decreased', 'NegReg', (126, 135))	('N-cadherin', 'Gene', '1000', (91, 101))	('DLC3', 'Gene', (52, 56))	('cell aggregation', 'CPA', (136, 152))	('knockdown', 'Var', (39, 48))	('DLC3', 'Gene', '9754', (52, 56))	('N-cadherin', 'Gene', (91, 101))	('decreased', 'NegReg', (57, 66))
181414	31059015	In the current study, DLC3 was downregulated in patients with NSCLC, and a high expression level of DLC3 was associated with an improved prognosis in patients with stage 1 NSCLC.	('DLC3', 'Gene', (100, 104))	('NSCLC', 'Disease', (62, 67))	('NSCLC', 'Disease', (172, 177))	('DLC3', 'Gene', '9754', (100, 104))	('high', 'Var', (75, 79))	('DLC3', 'Gene', '9754', (22, 26))	('NSCLC', 'Disease', 'MESH:D002289', (62, 67))	('improved', 'PosReg', (128, 136))	('NSCLC', 'Disease', 'MESH:D002289', (172, 177))	('patients', 'Species', '9606', (150, 158))	('downregulated', 'NegReg', (31, 44))	('DLC3', 'Gene', (22, 26))	('patients', 'Species', '9606', (48, 56))
181424	29340043	We also assessed the correlation of YAP1 activation with genomic alterations such as copy number alteration, somatic mutation, and miRNA expression.	('miRNA expression', 'MPA', (131, 147))	('YAP1', 'Gene', (36, 40))	('YAP1', 'Gene', '10413', (36, 40))	('activation', 'PosReg', (41, 51))	('copy number alteration', 'Var', (85, 107))
181429	29340043	YI tumors were characterized by gain of PIK3CA, SOX2, and TP63; deletion of 11q23.1; and high mutation rates of NFE2L2, PTEN, SYNE1, and NSD1.	('deletion', 'Var', (64, 72))	('TP63', 'Gene', '8626', (58, 62))	('SYNE1', 'Gene', (126, 131))	('11q23.1', 'Gene', (76, 83))	('PIK3CA', 'Gene', '5290', (40, 46))	('gain', 'PosReg', (32, 36))	('SYNE1', 'Gene', '23345', (126, 131))	('NFE2L2', 'Gene', '4780', (112, 118))	('NSD1', 'Gene', (137, 141))	('YI tumors', 'Disease', (0, 9))	('SOX2', 'Gene', '6657', (48, 52))	('tumors', 'Phenotype', 'HP:0002664', (3, 9))	('SOX2', 'Gene', (48, 52))	('YI tumors', 'Disease', 'MESH:D009369', (0, 9))	('PTEN', 'Gene', (120, 124))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))	('NFE2L2', 'Gene', (112, 118))	('PIK3CA', 'Gene', (40, 46))	('mutation', 'MPA', (94, 102))	('NSD1', 'Gene', '64324', (137, 141))	('PTEN', 'Gene', '5728', (120, 124))	('TP63', 'Gene', (58, 62))
181438	29340043	Hyperactivation of YAP1 is widespread in cancers.	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('Hyperactivation', 'Var', (0, 15))	('cancers', 'Phenotype', 'HP:0002664', (41, 48))	('YAP1', 'Gene', '10413', (19, 23))	('YAP1', 'Gene', (19, 23))	('cancers', 'Disease', 'MESH:D009369', (41, 48))	('cancers', 'Disease', (41, 48))
181440	29340043	In a study of the mutational landscape across 12 major cancer types, significantly mutated genes of hippo signaling were found in several cancers included HNSCC.	('hippo signaling', 'Gene', (100, 115))	('mutated', 'Var', (83, 90))	('cancer', 'Disease', (138, 144))	('HNSCC', 'Phenotype', 'HP:0012288', (155, 160))	('HNSCC', 'Disease', (155, 160))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('cancers', 'Disease', 'MESH:D009369', (138, 145))	('cancers', 'Phenotype', 'HP:0002664', (138, 145))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('cancers', 'Disease', (138, 145))	('cancer', 'Disease', 'MESH:D009369', (138, 144))	('cancer', 'Disease', (55, 61))
181445	29340043	In HNSCC, amplification of the YAP1 gene was linked to cetuximab resistance in cell lines.	('cetuximab resistance', 'MPA', (55, 75))	('HNSCC', 'Phenotype', 'HP:0012288', (3, 8))	('linked', 'Reg', (45, 51))	('cetuximab', 'Chemical', 'MESH:D000068818', (55, 64))	('YAP1', 'Gene', (31, 35))	('YAP1', 'Gene', '10413', (31, 35))	('amplification', 'Var', (10, 23))
181453	29340043	Expression of YAP1 was significantly correlated with copy number alteration (Figure 1A, r = 0.781, P < 0.001), further supporting functional roles of YAP1 in the development of HNSCC.	('YAP1', 'Gene', '10413', (150, 154))	('YAP1', 'Gene', '10413', (14, 18))	('YAP1', 'Gene', (150, 154))	('YAP1', 'Gene', (14, 18))	('copy number alteration', 'Var', (53, 75))	('HNSCC', 'Phenotype', 'HP:0012288', (177, 182))
181455	29340043	Because the best-known molecular activity of YAP1 is transcription activation, we sought to identify potential downstream targets of YAP1 by finding genes with expression significantly correlated with copy number alterations (P < 0.001 and Pearson correlation coefficient > 0.2 or < -0.2), yielding 652 genes (copy number-associated genes).	('expression', 'MPA', (160, 170))	('YAP1', 'Gene', (45, 49))	('YAP1', 'Gene', '10413', (45, 49))	('transcription', 'MPA', (53, 66))	('copy number alterations', 'Var', (201, 224))	('correlated', 'Reg', (185, 195))	('YAP1', 'Gene', (133, 137))	('YAP1', 'Gene', '10413', (133, 137))
181457	29340043	Briefly, tumors were first divided into two groups according to copy number alterations: YAP1-high (GISTIC score >2) and YAP1-low (GISTIC score <2).	('YAP1', 'Gene', (89, 93))	('YAP1', 'Gene', '10413', (89, 93))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('copy number', 'Var', (64, 75))	('YAP1', 'Gene', '10413', (121, 125))	('YAP1', 'Gene', (121, 125))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('tumors', 'Disease', (9, 15))	('tumors', 'Disease', 'MESH:D009369', (9, 15))
181479	29340043	When frequency of significantly reoccurring alterations was compared using Fisher's exact test, the YA group had amplification of 7p11.2 (EGFR) and 8q11.21 (SNAI2).	('7p11.2', 'Var', (130, 136))	('SNAI2', 'Gene', '6591', (157, 162))	('SNAI2', 'Gene', (157, 162))	('EGFR', 'Gene', '1956', (138, 142))	('EGFR', 'Gene', (138, 142))	('8q11.21', 'Var', (148, 155))
181480	29340043	The YA group had deletion of 8p23 (CSMD1), 9p21.3 (CDKN2A), 9q34.3 (NOTCH1), and 18q21.2 (SMAD4).	('CSMD1', 'Gene', '64478', (35, 40))	('CDKN2A', 'Gene', '1029', (51, 57))	('NOTCH1', 'Gene', '4851', (68, 74))	('18q21.2', 'Var', (81, 88))	('SMAD4', 'Gene', '4089', (90, 95))	('9q34.3', 'Var', (60, 66))	('NOTCH1', 'Gene', (68, 74))	('deletion', 'Var', (17, 25))	('CDKN2A', 'Gene', (51, 57))	('9p21.3', 'Var', (43, 49))	('SMAD4', 'Gene', (90, 95))	('CSMD1', 'Gene', (35, 40))	('8p23', 'Gene', (29, 33))
181482	29340043	The YI group was distinguished by amplification of 3q26/28 (PIK3CA, SOX2, and TP63) and deletion of 11q23.1 (Supplementary Table 2).	('PIK3CA', 'Gene', (60, 66))	('TP63', 'Gene', '8626', (78, 82))	('PIK3CA', 'Gene', '5290', (60, 66))	('TP63', 'Gene', (78, 82))	('deletion of', 'Var', (88, 99))	('SOX2', 'Gene', (68, 72))	('11q23.1', 'Gene', (100, 107))	('SOX2', 'Gene', '6657', (68, 72))	('amplification', 'Var', (34, 47))
181486	29340043	The mutations of NFE2L2 (1.1% vs. 7.8%, P = 7.0 x 10-4), PTEN (0.5% vs. 4.2%, P = 0.022), SYNE1 (14.1% vs. 22.3%, P = 0.025), and NSD1 (8.2% vs. 14.9%, P = 0.033) were mutually exclusive for YAP1 activation.	('NSD1', 'Gene', (130, 134))	('SYNE1', 'Gene', '23345', (90, 95))	('NFE2L2', 'Gene', '4780', (17, 23))	('SYNE1', 'Gene', (90, 95))	('YAP1', 'Gene', (191, 195))	('NFE2L2', 'Gene', (17, 23))	('PTEN', 'Gene', (57, 61))	('PTEN', 'Gene', '5728', (57, 61))	('YAP1', 'Gene', '10413', (191, 195))	('activation', 'PosReg', (196, 206))	('NSD1', 'Gene', '64324', (130, 134))	('mutations', 'Var', (4, 13))
181491	29340043	miRNA-1-2, miRNA-133a, miRNA-133b, and miRNA-206 are known to be frequently downregulated in cancer.	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('miRNA-206', 'Gene', (39, 48))	('miRNA-133b', 'Gene', '442890', (23, 33))	('miRNA-1-2', 'Gene', (0, 9))	('miRNA-206', 'Gene', '406989', (39, 48))	('miRNA-1-2', 'Gene', '406905', (0, 9))	('miRNA-133b', 'Gene', (23, 33))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('downregulated', 'NegReg', (76, 89))	('miRNA-133a', 'Var', (11, 21))
181495	29340043	Of these miRNAs, only expressions of miRNA-187 and miRNA-675 were significantly higher in CNI-YA than in YI or in normal tissues (Supplementary Figure 4).	('miRNA-675', 'Var', (51, 60))	('miRNA-187', 'Gene', '406963', (37, 46))	('CNI-YA', 'Disease', (90, 96))	('miRNA-187', 'Gene', (37, 46))	('higher', 'PosReg', (80, 86))	('expressions', 'MPA', (22, 33))
181511	29340043	YI patients were characterized by gain of PIK3CA, SOX2, and TP63; deletion of 11q23.1; and high mutation rates of NFE2L2, PTEN, SYNE1, and NSD1.	('SOX2', 'Gene', '6657', (50, 54))	('SOX2', 'Gene', (50, 54))	('SYNE1', 'Gene', (128, 133))	('mutation', 'MPA', (96, 104))	('gain', 'PosReg', (34, 38))	('PIK3CA', 'Gene', (42, 48))	('SYNE1', 'Gene', '23345', (128, 133))	('NFE2L2', 'Gene', '4780', (114, 120))	('NSD1', 'Gene', (139, 143))	('PTEN', 'Gene', (122, 126))	('TP63', 'Gene', (60, 64))	('patients', 'Species', '9606', (3, 11))	('PTEN', 'Gene', '5728', (122, 126))	('NFE2L2', 'Gene', (114, 120))	('11q23.1', 'Gene', (78, 85))	('NSD1', 'Gene', '64324', (139, 143))	('TP63', 'Gene', '8626', (60, 64))	('PIK3CA', 'Gene', '5290', (42, 48))	('deletion', 'Var', (66, 74))
181519	29340043	A potential association of YAP1 with resistance to radiation therapy was also supported by previous studies, as amplification of YAP1 was correlated with cetuximab sensitivity in HNSCC and knockdown of YAP1 increased the sensitivity to cisplatin in vitro.	('YAP1', 'Gene', (202, 206))	('YAP1', 'Gene', (27, 31))	('YAP1', 'Gene', '10413', (202, 206))	('YAP1', 'Gene', '10413', (27, 31))	('correlated', 'Reg', (138, 148))	('amplification', 'Var', (112, 125))	('increased', 'PosReg', (207, 216))	('sensitivity to cisplatin', 'MPA', (221, 245))	('cisplatin', 'Chemical', 'MESH:D002945', (236, 245))	('cetuximab', 'Chemical', 'MESH:D000068818', (154, 163))	('cetuximab sensitivity', 'MPA', (154, 175))	('YAP1', 'Gene', (129, 133))	('HNSCC', 'Phenotype', 'HP:0012288', (179, 184))	('knockdown', 'Var', (189, 198))	('YAP1', 'Gene', '10413', (129, 133))
181521	29340043	In good agreement with a previous study demonstrating that deletion of CDKN2A and inactivating mutation were associated with HPV-negative tumors, the vast majority of tumors with the YA subtype were HPV-negative tumors, suggesting that YAP1 activation and inactivation of CDKN2A might be associated genetic events.	('tumors', 'Disease', 'MESH:D009369', (138, 144))	('CDKN2A', 'Gene', (272, 278))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('tumors', 'Disease', 'MESH:D009369', (167, 173))	('tumors', 'Phenotype', 'HP:0002664', (212, 218))	('CDKN2A', 'Gene', '1029', (272, 278))	('YAP1', 'Gene', '10413', (236, 240))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('associated', 'Reg', (109, 119))	('CDKN2A', 'Gene', (71, 77))	('tumors', 'Disease', (212, 218))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('deletion', 'Var', (59, 67))	('tumors', 'Phenotype', 'HP:0002664', (167, 173))	('YAP1', 'Gene', (236, 240))	('tumors', 'Disease', 'MESH:D009369', (212, 218))	('CDKN2A', 'Gene', '1029', (71, 77))	('tumors', 'Disease', (138, 144))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('tumors', 'Disease', (167, 173))
181527	29340043	SYNE1 mutation was associated with autosomal recessive cerebellar ataxia and is known to be associated with glioblastoma and lung, ovarian, colorectal, and head and neck cancers.	('associated', 'Reg', (19, 29))	('SYNE1', 'Gene', (0, 5))	('neck cancers', 'Disease', (165, 177))	('cancers', 'Phenotype', 'HP:0002664', (170, 177))	('glioblastoma and lung', 'Disease', 'MESH:D005909', (108, 129))	('colorectal', 'Disease', 'MESH:D015179', (140, 150))	('cerebellar ataxia', 'Phenotype', 'HP:0001251', (55, 72))	('autosomal recessive cerebellar ataxia', 'Disease', 'MESH:D002524', (35, 72))	('mutation', 'Var', (6, 14))	('autosomal recessive cerebellar ataxia', 'Disease', (35, 72))	('neck cancers', 'Disease', 'MESH:D006258', (165, 177))	('colorectal', 'Disease', (140, 150))	('ovarian', 'Disease', (131, 138))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('SYNE1', 'Gene', '23345', (0, 5))	('associated', 'Reg', (92, 102))	('head and neck cancers', 'Phenotype', 'HP:0012288', (156, 177))	('glioblastoma', 'Phenotype', 'HP:0012174', (108, 120))
181528	29340043	The nuclear receptor binding SET domain protein 1 (NSD1), a histone methyltransferase, was found to be frequently mutated in the clear cell variant of renal cell carcinoma and associated with DNA hypomethylation.	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (151, 171))	('NSD1', 'Gene', (51, 55))	('clear cell', 'Disease', (129, 139))	('DNA', 'MPA', (192, 195))	('mutated', 'Var', (114, 121))	('associated', 'Reg', (176, 186))	('renal cell carcinoma', 'Disease', (151, 171))	('NSD1', 'Gene', '64324', (51, 55))	('carcinoma', 'Phenotype', 'HP:0030731', (162, 171))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (151, 171))
181530	29340043	The basal subtype was characterized by inactivation of NOTCH1 and co-amplified 11q13/q22 (21) in which YAP1 resided.	('YAP1', 'Gene', '10413', (103, 107))	('YAP1', 'Gene', (103, 107))	('inactivation', 'Var', (39, 51))	('NOTCH1', 'Gene', '4851', (55, 61))	('NOTCH1', 'Gene', (55, 61))
181531	29340043	The atypical subtype was characterized by enrichment of HPV-positive tumor and activating mutations in exon 9 that contain PIK3CA (21).	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('mutations', 'Var', (90, 99))	('PIK3CA', 'Gene', (123, 129))	('PIK3CA', 'Gene', '5290', (123, 129))	('HPV-positive tumor', 'Disease', (56, 74))	('HPV-positive tumor', 'Disease', 'MESH:D030361', (56, 74))
181532	29340043	In good agreement with this, the YI subtype included most of the HPV-positive tumors and featured the amplification of copy number of PIK3CA.	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('PIK3CA', 'Gene', (134, 140))	('copy number', 'Var', (119, 130))	('amplification', 'Var', (102, 115))	('PIK3CA', 'Gene', '5290', (134, 140))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('HPV-positive tumors', 'Disease', 'MESH:D030361', (65, 84))	('HPV-positive tumors', 'Disease', (65, 84))
181545	29340043	These four cohorts consisted of data from the Institute for Medical Informatics, Statistics and Epidemiology (Leipzig cohort, GSE65858, n = 270), Aristotle University of Thessaloniki (Greek cohort, GSE27020, n = 109), MD Anderson Cancer Center (MD Anderson cohort, GSE42743, n = 74), and Fred Hutchinson Cancer Research Center (Seattle cohort, GSE41613, n = 97).	('Fred Hutchinson Cancer', 'Disease', 'MESH:D013590', (288, 310))	('Cancer', 'Phenotype', 'HP:0002664', (304, 310))	('Fred Hutchinson Cancer', 'Disease', (288, 310))	('Cancer', 'Phenotype', 'HP:0002664', (230, 236))	('Hutchinson Cancer', 'Phenotype', 'HP:0012413', (293, 310))	('MD Anderson Cancer', 'Disease', 'MESH:C535460', (218, 236))	('GSE65858', 'Var', (126, 134))	('MD Anderson Cancer', 'Disease', (218, 236))	('GSE27020', 'Var', (198, 206))
181551	29340043	We first identified YAP1-associated genes by using the correlation between copy number of YAP1 and mRNA expression of each gene (copy number-associated genes).	('copy number', 'Var', (75, 86))	('YAP1', 'Gene', '10413', (20, 24))	('mRNA expression', 'MPA', (99, 114))	('YAP1', 'Gene', (20, 24))	('YAP1', 'Gene', (90, 94))	('YAP1', 'Gene', '10413', (90, 94))
181575	31452819	Furthermore, one of our previous studies demonstrated that LGI3 attenuates adipogenesis through a disintegrin and metalloproteinase domain-containing protein (ADAM)23, which is one of the receptors for LGI3 (ADAM22 and ADAM23), and that LGI3 increases pro-inflammatory genes, including tumor necrosis factor-alpha (TNF-alpha) in macrophage cells.	('TNF-alpha', 'Gene', (315, 324))	('ADAM23', 'Gene', '8745', (219, 225))	('tumor', 'Phenotype', 'HP:0002664', (286, 291))	('ADAM)23', 'Gene', '8745', (159, 166))	('tumor necrosis factor-alpha', 'Gene', (286, 313))	('ADAM22', 'Gene', (208, 214))	('tumor necrosis factor-alpha', 'Gene', '7124', (286, 313))	('increases', 'PosReg', (242, 251))	('ADAM23', 'Gene', (219, 225))	('TNF-alpha', 'Gene', '7124', (315, 324))	('adipogenesis', 'MPA', (75, 87))	('LGI3', 'Var', (59, 63))	('LGI3', 'Var', (237, 241))	('ADAM22', 'Gene', '53616', (208, 214))	('attenuates', 'NegReg', (64, 74))
181580	31452819	Furthermore, the expression levels and genetic variations of LGI3 may have potential prognostic roles in various types of cancer.	('genetic variations', 'Var', (39, 57))	('expression', 'MPA', (17, 27))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('roles', 'Reg', (96, 101))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('LGI3', 'Gene', (61, 65))
181615	31452819	The somatic mutations of the LGI3 gene in NSCLC with amino acid alterations were identified in two major types of NSCLC, lung adenocarcinoma and lung squamous cell carcinoma (Table IV).	('NSCLC', 'Phenotype', 'HP:0030358', (114, 119))	('NSCLC', 'Disease', (42, 47))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('lung adenocarcinoma and lung squamous cell carcinoma', 'Disease', 'MESH:D000077192', (121, 173))	('NSCLC', 'Disease', 'MESH:D002289', (42, 47))	('mutations', 'Var', (12, 21))	('amino acid alterations', 'Var', (53, 75))	('NSCLC', 'Disease', (114, 119))	('LGI3', 'Gene', (29, 33))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (150, 173))	('NSCLC', 'Disease', 'MESH:D002289', (114, 119))	('NSCLC', 'Phenotype', 'HP:0030358', (42, 47))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (121, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (164, 173))	('identified', 'Reg', (81, 91))
181616	31452819	A total of seven mutations with amino acid alterations were found in each NSCLC type, none of which occurred in both types of cancer.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('NSCLC', 'Phenotype', 'HP:0030358', (74, 79))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('amino acid alterations', 'Var', (32, 54))	('found', 'Reg', (60, 65))	('NSCLC', 'Disease', (74, 79))	('NSCLC', 'Disease', 'MESH:D002289', (74, 79))
181617	31452819	Venn diagram analysis of the amino acid variations in the five categories [conserved residues, phylogenetically coevolved residues, SNPs and somatic mutations in two types of NSCLC] revealed that a subgroup of somatic mutation sites in NSCLC belonged to phylogenetically coevolved residues (Y293H in lung adenocarcinoma and A83V and L117F in lung squamous cell carcinoma) or SNP sites (S171stop and R430G in lung squamous cell carcinoma; Fig.	('R430G', 'Var', (399, 404))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (300, 319))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (413, 436))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (408, 436))	('lung squamous cell carcinoma', 'Disease', (408, 436))	('NSCLC', 'Phenotype', 'HP:0030358', (175, 180))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (300, 319))	('Y293H', 'Var', (291, 296))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (347, 370))	('L117F', 'Var', (333, 338))	('NSCLC', 'Disease', 'MESH:D002289', (236, 241))	('carcinoma', 'Phenotype', 'HP:0030731', (310, 319))	('R430G', 'Mutation', 'rs762086692', (399, 404))	('NSCLC', 'Disease', (236, 241))	('A83V', 'Mutation', 'rs763691960', (324, 328))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (342, 370))	('lung squamous cell carcinoma', 'Disease', (342, 370))	('NSCLC', 'Phenotype', 'HP:0030358', (236, 241))	('S171stop', 'Var', (386, 394))	('carcinoma', 'Phenotype', 'HP:0030731', (427, 436))	('NSCLC', 'Disease', 'MESH:D002289', (175, 180))	('lung adenocarcinoma', 'Disease', (300, 319))	('carcinoma', 'Phenotype', 'HP:0030731', (361, 370))	('Y293H', 'Mutation', 'rs1233908332', (291, 296))	('S171stop', 'Mutation', 'p.S171X', (386, 394))	('NSCLC', 'Disease', (175, 180))	('L117F', 'Mutation', 'rs1320616746', (333, 338))
181618	31452819	The amino acid alterations (S171stop and R430G) at SNP sites were different from the residues of the minor SNP alleles (Leu171, Cys430) and were not found in somatic mutations in NSCLC.	('S171stop', 'Var', (28, 36))	('Leu171', 'Var', (120, 126))	('NSCLC', 'Disease', 'MESH:D002289', (179, 184))	('S171stop', 'Mutation', 'p.S171X', (28, 36))	('R430G', 'Mutation', 'rs762086692', (41, 46))	('Cys430', 'Var', (128, 134))	('NSCLC', 'Phenotype', 'HP:0030358', (179, 184))	('Leu171', 'Chemical', '-', (120, 126))	('R430G', 'Var', (41, 46))	('Cys430', 'Chemical', '-', (128, 134))	('NSCLC', 'Disease', (179, 184))
181620	31452819	Our previous studies on LGI3 indicated that somatic mutations in various types of cancer were found in the LGI3 gene and subsets of the mutations affected SNP sites, phylogenetically coevolved amino acids and a conserved amino acid.	('mutations', 'Var', (52, 61))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('LGI3', 'Gene', (107, 111))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('mutations', 'Var', (136, 145))	('affected', 'Reg', (146, 154))
181630	31452819	These results suggested that dysregulation of LGI3 may account for perturbation of the cytokine network and cell-cell communication in the microenvironment of NSCLC.	('cell-cell communication', 'CPA', (108, 131))	('cytokine network', 'MPA', (87, 103))	('NSCLC', 'Disease', (159, 164))	('LGI3', 'Gene', (46, 50))	('NSCLC', 'Disease', 'MESH:D002289', (159, 164))	('NSCLC', 'Phenotype', 'HP:0030358', (159, 164))	('dysregulation', 'Var', (29, 42))	('account', 'Reg', (55, 62))
181634	31452819	All LGI3-regulated and NSCLC-altered genes were found in the previous literature on NSCLC that reported an association of genetic variations, expression and function of these genes with NSCLC.	('NSCLC', 'Phenotype', 'HP:0030358', (186, 191))	('NSCLC', 'Disease', 'MESH:D002289', (23, 28))	('NSCLC', 'Phenotype', 'HP:0030358', (23, 28))	('NSCLC', 'Phenotype', 'HP:0030358', (84, 89))	('function', 'MPA', (157, 165))	('NSCLC', 'Disease', (186, 191))	('genetic variations', 'Var', (122, 140))	('NSCLC', 'Disease', (84, 89))	('NSCLC', 'Disease', (23, 28))	('NSCLC', 'Disease', 'MESH:D002289', (186, 191))	('association', 'Interaction', (107, 118))	('NSCLC', 'Disease', 'MESH:D002289', (84, 89))	('expression', 'MPA', (142, 152))
181653	31452819	Cytokine perturbation in obesity may increase the risk of cancer in the digestive system, including the liver, pancreas and gastrointestinal tract.	('obesity', 'Phenotype', 'HP:0001513', (25, 32))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('perturbation', 'Var', (9, 21))	('Cytokine', 'MPA', (0, 8))	('increase', 'PosReg', (37, 45))	('obesity', 'Disease', 'MESH:D009765', (25, 32))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('cancer', 'Disease', (58, 64))	('obesity', 'Disease', (25, 32))	('pancreas and gastrointestinal tract', 'Disease', 'MESH:D004067', (111, 146))
181656	31452819	Our previous studies indicated that LGI3 increased M1-polarized macrophage markers (TNF-alpha, inducible nitric oxide synthase, CCL2/MCP-1, CD11c and IL-6).	('M1-polarized macrophage markers', 'MPA', (51, 82))	('increased', 'PosReg', (41, 50))	('CD11c', 'Gene', '3687', (140, 145))	('LGI3', 'Var', (36, 40))	('CD11c', 'Gene', (140, 145))	('MCP-1', 'Gene', '6347', (133, 138))	('TNF-alpha', 'Gene', '7124', (84, 93))	('CCL2', 'Gene', (128, 132))	('IL-6', 'Gene', (150, 154))	('inducible nitric oxide synthase', 'MPA', (95, 126))	('TNF-alpha', 'Gene', (84, 93))	('IL-6', 'Gene', '3569', (150, 154))	('MCP-1', 'Gene', (133, 138))	('CCL2', 'Gene', '6347', (128, 132))
181659	31452819	The somatic mutations of LGI3 in two major types of NSCLC suggested the potential prognostic value of the genetic variations of LGI3 in NSCLC.	('NSCLC', 'Disease', 'MESH:D002289', (136, 141))	('NSCLC', 'Disease', (52, 57))	('LGI3', 'Gene', (128, 132))	('NSCLC', 'Disease', 'MESH:D002289', (52, 57))	('NSCLC', 'Phenotype', 'HP:0030358', (136, 141))	('genetic variations', 'Var', (106, 124))	('NSCLC', 'Phenotype', 'HP:0030358', (52, 57))	('LGI3', 'Gene', (25, 29))	('NSCLC', 'Disease', (136, 141))
181660	31452819	The mutations were distributed throughout the LGI3 protein domains (leucine-rich repeats and EPTP domains) and the residue 248 was the only site with multiple mutations (A248V and A248P).	('A248P', 'Var', (180, 185))	('A248P', 'Mutation', 'p.A248P', (180, 185))	('A248V', 'Var', (170, 175))	('A248V', 'Mutation', 'p.A248V', (170, 175))
181661	31452819	It was noted that two somatic mutations in lung squamous cell carcinoma (S171stop and R430G) were found at SNP sites with rare variants (global minor allele frequency, 0.0002).	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (43, 71))	('lung squamous cell carcinoma', 'Disease', (43, 71))	('S171stop', 'Var', (73, 81))	('R430G', 'Mutation', 'rs762086692', (86, 91))	('S171stop', 'Mutation', 'p.S171X', (73, 81))	('R430G', 'Var', (86, 91))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (48, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (62, 71))
181662	31452819	These results warrant further studies on the prognostic and pathological roles of the genetic variations of LGI3 in NSCLC.	('NSCLC', 'Disease', 'MESH:D002289', (116, 121))	('genetic variations', 'Var', (86, 104))	('LGI3', 'Gene', (108, 112))	('NSCLC', 'Phenotype', 'HP:0030358', (116, 121))	('NSCLC', 'Disease', (116, 121))
181663	31452819	Studies with LGI3-deficient or variant LGI3-expressing animal models and cell lines may provide further insight into the prognostic and pathological mechanisms of LGI3 in NSCLC.	('NSCLC', 'Phenotype', 'HP:0030358', (171, 176))	('NSCLC', 'Disease', (171, 176))	('LGI3-deficient', 'Disease', (13, 27))	('LGI3-deficient', 'Disease', 'MESH:D007153', (13, 27))	('variant', 'Var', (31, 38))	('NSCLC', 'Disease', 'MESH:D002289', (171, 176))
181664	31452819	In conclusion, the present study provided an integrative insight into the prognostic value of LGI3 in NSCLC by revealing the regulatory network of NSCLC-altered and LGI3-regulated gene products, and the association of expression and genetic variations of LGI3 with NSCLC.	('NSCLC', 'Disease', 'MESH:D002289', (102, 107))	('NSCLC', 'Disease', (147, 152))	('NSCLC', 'Disease', 'MESH:D002289', (147, 152))	('NSCLC', 'Disease', (265, 270))	('association', 'Interaction', (203, 214))	('NSCLC', 'Phenotype', 'HP:0030358', (102, 107))	('genetic variations', 'Var', (233, 251))	('NSCLC', 'Disease', 'MESH:D002289', (265, 270))	('NSCLC', 'Phenotype', 'HP:0030358', (147, 152))	('NSCLC', 'Disease', (102, 107))	('NSCLC', 'Phenotype', 'HP:0030358', (265, 270))	('LGI3', 'Gene', (255, 259))
181666	31060750	Expression and prognostic value of NSD1 and SETD2 in pancreatic ductal adenocarcinoma and its precursor lesions Epigenetic regulation is emerging as a critical mechanism for pancreatic ductal adenocarcinoma (PDA) development.	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (53, 85))	('pancreatic ductal adenocarcinoma', 'Disease', (53, 85))	('NSD1', 'Gene', '64324', (35, 39))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (53, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('SETD2', 'Gene', '29072', (44, 49))	('pancreatic ductal adenocarcinoma', 'Disease', (174, 206))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (174, 206))	('SETD2', 'Gene', (44, 49))	('Epigenetic regulation', 'Var', (112, 133))	('NSD1', 'Gene', (35, 39))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (174, 206))	('carcinoma', 'Phenotype', 'HP:0030731', (197, 206))	('PDA', 'Phenotype', 'HP:0006725', (208, 211))
181667	31060750	NSD1 and SETD2 genes encoding two histone H3K36 methyltransferases, are mutated or altered in 8-10% of PDA cases.	('SETD2', 'Gene', (9, 14))	('NSD1', 'Gene', (0, 4))	('mutated', 'Var', (72, 79))	('altered', 'Reg', (83, 90))	('PDA', 'Phenotype', 'HP:0006725', (103, 106))	('NSD1', 'Gene', '64324', (0, 4))	('PDA', 'Disease', (103, 106))
181672	31060750	High NSD1 expression was associated with clinical stage III/IV disease (p=0.026), tumour grade 2 (p=0.022), use of neoadjuvant therapy (p=0.037), and overall higher clinical stage (p=0.022).	('tumour', 'Phenotype', 'HP:0002664', (82, 88))	('High', 'Var', (0, 4))	('NSD1', 'Gene', '64324', (5, 9))	('clinical stage III/IV disease', 'Disease', (41, 70))	('tumour', 'Disease', 'MESH:D009369', (82, 88))	('expression', 'MPA', (10, 20))	('higher', 'PosReg', (158, 164))	('tumour', 'Disease', (82, 88))	('NSD1', 'Gene', (5, 9))
181677	31060750	Examples of potentially important epigenetic alterations in PDA include mutations to the histone demethylase KDM6A, found in over 10% of cases in one whole-genome sequencing study, and the chromatin remodelling gene ARID1A that indicated poor prognosis in a whole-exome sequencing study.	('KDM6A', 'Gene', (109, 114))	('mutations', 'Var', (72, 81))	('PDA', 'Phenotype', 'HP:0006725', (60, 63))	('KDM6A', 'Gene', '7403', (109, 114))	('ARID1A', 'Gene', '8289', (216, 222))	('PDA', 'Disease', (60, 63))	('ARID1A', 'Gene', (216, 222))
181680	31060750	Mutations in NSD1, which functions as a mono- and dimethyltransferase targeting histone H3 at K36 (H3K36), have been implicated in the pathogenesis of acute myeloid leukaemia, HPV-negative head and neck squamous cell carcinoma, lung squamous cell carcinoma, urothelial carcinoma and colorectal carcinoma, and have been associated with increased sensitivity to cisplatin chemotherapy in head and neck squamous cell carcinoma cell lines.	('NSD1', 'Gene', (13, 17))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (386, 423))	('sensitivity to cisplatin chemotherapy', 'MPA', (345, 382))	('carcinoma', 'Phenotype', 'HP:0030731', (414, 423))	('myeloid leukaemia', 'Phenotype', 'HP:0012324', (157, 174))	('carcinoma', 'Phenotype', 'HP:0030731', (247, 256))	('colorectal carcinoma', 'Disease', (283, 303))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (228, 256))	('Mutations', 'Var', (0, 9))	('NSD1', 'Gene', '64324', (13, 17))	('carcinoma', 'Phenotype', 'HP:0030731', (294, 303))	('neck squamous cell carcinoma', 'Disease', (198, 226))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (283, 303))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (203, 226))	('acute myeloid leukaemia', 'Disease', 'MESH:D015470', (151, 174))	('neck squamous cell carcinoma', 'Disease', (395, 423))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (198, 226))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (258, 278))	('carcinoma', 'Phenotype', 'HP:0030731', (269, 278))	('acute myeloid leukaemia', 'Phenotype', 'HP:0004808', (151, 174))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (395, 423))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (233, 256))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (228, 256))	('implicated', 'Reg', (117, 127))	('lung squamous cell carcinoma', 'Disease', (228, 256))	('urothelial carcinoma', 'Disease', (258, 278))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (400, 423))	('acute myeloid leukaemia', 'Disease', (151, 174))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (189, 226))	('cisplatin', 'Chemical', 'MESH:D002945', (360, 369))	('carcinoma', 'Phenotype', 'HP:0030731', (217, 226))
181681	31060750	In addition, mutations or altered expression of SETD2, a trimethylase at H3K36, may have a major role in the pathogenesis of some leukaemias and lymphomas as well as solid organ cancers including malignant mesothelioma and thymic carcinoma.	('role', 'Reg', (97, 101))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (196, 218))	('expression', 'MPA', (34, 44))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('have', 'Reg', (84, 88))	('cancers', 'Disease', 'MESH:D009369', (178, 185))	('cancers', 'Phenotype', 'HP:0002664', (178, 185))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (196, 218))	('cancers', 'Disease', (178, 185))	('thymic carcinoma', 'Disease', (223, 239))	('carcinoma', 'Phenotype', 'HP:0030731', (230, 239))	('altered', 'Reg', (26, 33))	('lymphomas', 'Phenotype', 'HP:0002665', (145, 154))	('mutations', 'Var', (13, 22))	('SETD2', 'Gene', (48, 53))	('leukaemias and lymphomas', 'Disease', 'MESH:D008223', (130, 154))	('thymic carcinoma', 'Disease', 'MESH:D013953', (223, 239))	('malignant mesothelioma', 'Disease', (196, 218))
181682	31060750	Its inactivation or loss of expression has been linked to poor prognosis in chronic lymphocytic leukaemia and gastric and lung adenocarcinoma.	('inactivation', 'Var', (4, 16))	('loss of expression', 'NegReg', (20, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (122, 141))	('chronic lymphocytic leukaemia', 'Disease', (76, 105))	('chronic lymphocytic leukaemia', 'Disease', 'MESH:D007945', (76, 105))	('chronic lymphocytic leukaemia', 'Phenotype', 'HP:0005550', (76, 105))	('lung adenocarcinoma', 'Disease', (122, 141))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (122, 141))
181683	31060750	In addition, SETD2 inactivation has been linked with resistance to chemotherapy in some leukaemias.	('leukaemias', 'Disease', 'MESH:D007938', (88, 98))	('linked', 'Reg', (41, 47))	('leukaemias', 'Disease', (88, 98))	('SETD2', 'Gene', (13, 18))	('resistance to chemotherapy', 'MPA', (53, 79))	('inactivation', 'Var', (19, 31))
181684	31060750	Furthermore, alterations in both NSD1 and SETD2 have been recognised as potentially important in pathogenesis of clear cell renal cell carcinoma and gliomas.	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (124, 144))	('gliomas', 'Disease', (149, 156))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (113, 144))	('gliomas', 'Disease', 'MESH:D005910', (149, 156))	('gliomas', 'Phenotype', 'HP:0009733', (149, 156))	('NSD1', 'Gene', '64324', (33, 37))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('important', 'Reg', (84, 93))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (113, 144))	('clear cell renal cell carcinoma', 'Disease', (113, 144))	('NSD1', 'Gene', (33, 37))	('alterations', 'Var', (13, 24))	('SETD2', 'Gene', (42, 47))
181685	31060750	In pancreatic cancer, decreased histone methylation has been shown to be a poor prognostic factor, and one study of commonly mutated genes and loci in pancreatic cancer showed that all tumours had at least one mutation to an epigenetic regulator of histone modification.	('histone methylation', 'MPA', (32, 51))	('pancreatic cancer', 'Disease', 'MESH:D010190', (151, 168))	('pancreatic cancer', 'Disease', (3, 20))	('pancreatic cancer', 'Disease', 'MESH:D010190', (3, 20))	('tumours', 'Phenotype', 'HP:0002664', (185, 192))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('mutation', 'Var', (210, 218))	('tumour', 'Phenotype', 'HP:0002664', (185, 191))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (151, 168))	('tumours', 'Disease', 'MESH:D009369', (185, 192))	('tumours', 'Disease', (185, 192))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (3, 20))	('decreased', 'NegReg', (22, 31))	('pancreatic cancer', 'Disease', (151, 168))
181686	31060750	NSD1 is mutated or altered in 8.3% of PDA cases and SETD2 is altered or mutated in 10.7% of PDA cases according to The Cancer Genome Atlas (TCGA) PanCancer Atlas data (Fig.	('NSD1', 'Gene', (0, 4))	('mutated', 'Var', (72, 79))	('PDA', 'Phenotype', 'HP:0006725', (92, 95))	('Cancer', 'Disease', (119, 125))	('mutated', 'Var', (8, 15))	('Cancer', 'Disease', 'MESH:D009369', (149, 155))	('PDA', 'Phenotype', 'HP:0006725', (38, 41))	('PDA', 'Disease', (38, 41))	('Cancer', 'Disease', 'MESH:D009369', (119, 125))	('Cancer', 'Phenotype', 'HP:0002664', (149, 155))	('Cancer', 'Phenotype', 'HP:0002664', (119, 125))	('NSD1', 'Gene', '64324', (0, 4))	('altered', 'Reg', (19, 26))	('Cancer', 'Disease', (149, 155))	('SETD2', 'Gene', (52, 57))
181726	31060750	High NSD1 expression was significantly associated with stage III/IV disease compared to stage I/IIA disease (p=0.026), tumour grade G2 compared to G3 (p=0.022), and neoadjuvant therapy (p=0.037) (Table 4).	('tumour', 'Phenotype', 'HP:0002664', (119, 125))	('High', 'Var', (0, 4))	('tumour', 'Disease', 'MESH:D009369', (119, 125))	('NSD1', 'Gene', '64324', (5, 9))	('stage III/IV disease', 'Disease', (55, 75))	('expression', 'MPA', (10, 20))	('tumour', 'Disease', (119, 125))	('NSD1', 'Gene', (5, 9))	('associated', 'Reg', (39, 49))
181727	31060750	There was also a statistically significant association between overall higher pre-treatment clinical stage and high NSD1 expression (p=0.022).	('NSD1', 'Gene', (116, 120))	('higher', 'PosReg', (71, 77))	('expression', 'MPA', (121, 131))	('NSD1', 'Gene', '64324', (116, 120))	('high', 'Var', (111, 115))
181731	31060750	The difficulty in reaching statistical significance was possibly due to the variability of the protein levels in neoplastic lesions and the difficulty of establishing statistical significance in a cohort where only 8-10% of patients would be expected to have mutations or significantly altered mRNA expression based on prior data.	('mutations', 'Var', (259, 268))	('altered', 'Reg', (286, 293))	('mRNA expression', 'MPA', (294, 309))	('patients', 'Species', '9606', (224, 232))	('neoplastic lesions', 'Phenotype', 'HP:0002664', (113, 131))
181736	31060750	This finding is consistent with the mRNA expression and gene mutation data from the TCGA PanCancer Atlas where the majority of NSD1 mutations were amplifications and NSD1 mRNA level was frequently upregulated (Fig.	('NSD1', 'Gene', (127, 131))	('upregulated', 'PosReg', (197, 208))	('Cancer', 'Disease', 'MESH:D009369', (92, 98))	('Cancer', 'Disease', (92, 98))	('Cancer', 'Phenotype', 'HP:0002664', (92, 98))	('NSD1', 'Gene', '64324', (166, 170))	('mutations', 'Var', (132, 141))	('NSD1', 'Gene', (166, 170))	('NSD1', 'Gene', '64324', (127, 131))	('mRNA level', 'MPA', (171, 181))
181738	31060750	The lack of statistical significance is most likely due to the relatively low sample number, low frequency of NSD1 alteration in PDA, and the large range of scores.	('NSD1', 'Gene', '64324', (110, 114))	('PDA', 'Disease', (129, 132))	('NSD1', 'Gene', (110, 114))	('alteration', 'Var', (115, 125))	('PDA', 'Phenotype', 'HP:0006725', (129, 132))
181739	31060750	Compared to PDA, other solid organ cancers with frequent NSD1 alteration, including head and neck squamous cell carcinomas, clear cell renal cell carcinomas, and gliomas, more often showed inactivation and decreased expression of NSD1.	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (135, 156))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (84, 121))	('neck squamous cell carcinomas', 'Disease', (93, 122))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('NSD1', 'Gene', '64324', (57, 61))	('inactivation', 'Var', (189, 201))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (124, 155))	('carcinomas', 'Phenotype', 'HP:0030731', (146, 156))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('carcinomas', 'Phenotype', 'HP:0030731', (112, 122))	('NSD1', 'Gene', '64324', (230, 234))	('neck squamous cell carcinomas', 'Disease', 'MESH:D000077195', (93, 122))	('gliomas', 'Disease', (162, 169))	('expression', 'MPA', (216, 226))	('PDA', 'Phenotype', 'HP:0006725', (12, 15))	('cancers', 'Disease', 'MESH:D009369', (35, 42))	('clear cell renal cell carcinomas', 'Disease', 'MESH:C538614', (124, 156))	('gliomas', 'Disease', 'MESH:D005910', (162, 169))	('decreased', 'NegReg', (206, 215))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (98, 122))	('NSD1', 'Gene', (57, 61))	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('gliomas', 'Phenotype', 'HP:0009733', (162, 169))	('NSD1', 'Gene', (230, 234))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (135, 155))	('clear cell renal cell carcinomas', 'Phenotype', 'HP:0006770', (124, 156))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (98, 121))	('alteration', 'Var', (62, 72))	('clear cell renal cell carcinomas', 'Disease', (124, 156))	('cancers', 'Phenotype', 'HP:0002664', (35, 42))	('cancers', 'Disease', (35, 42))
181740	31060750	While NSD1 inactivating mutations have been associated with a good prognosis in laryngeal squamous cell carcinoma, our study did not show prognostic significance for the expression of NSD1 in PDA, again probably related to the relatively low sample number and variability of NSD1 protein expression.	('associated', 'Reg', (44, 54))	('PDA', 'Phenotype', 'HP:0006725', (192, 195))	('NSD1', 'Gene', (6, 10))	('inactivating mutations', 'Var', (11, 33))	('NSD1', 'Gene', '64324', (184, 188))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (90, 113))	('squamous cell carcinoma', 'Disease', (90, 113))	('NSD1', 'Gene', (275, 279))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (90, 113))	('NSD1', 'Gene', (184, 188))	('NSD1', 'Gene', '64324', (6, 10))	('NSD1', 'Gene', '64324', (275, 279))
181741	31060750	Similarly, the TCGA provisional data survival analysis based on mutation and mRNA data also failed to show prognostic significance for NSD1 alteration in PDA.	('NSD1', 'Gene', '64324', (135, 139))	('alteration', 'Var', (140, 150))	('PDA', 'Disease', (154, 157))	('NSD1', 'Gene', (135, 139))	('PDA', 'Phenotype', 'HP:0006725', (154, 157))
181743	31060750	This finding is consistent with the results from the TCGA PanCancer Atlas showing a predominance of mRNA downregulation and inactivating mutations in PDA patients (Fig.	('Cancer', 'Phenotype', 'HP:0002664', (61, 67))	('Cancer', 'Disease', (61, 67))	('PDA', 'Disease', (150, 153))	('downregulation', 'NegReg', (105, 119))	('Cancer', 'Disease', 'MESH:D009369', (61, 67))	('inactivating mutations', 'Var', (124, 146))	('patients', 'Species', '9606', (154, 162))	('mRNA', 'MPA', (100, 104))	('PDA', 'Phenotype', 'HP:0006725', (150, 153))
181745	31060750	SETD2 has also shown inactivation and/or decreased expression in other malignancies such as clear cell renal cell carcinomas, gastric cancers and acute leukaemias.	('clear cell renal cell carcinomas', 'Phenotype', 'HP:0006770', (92, 124))	('inactivation', 'Var', (21, 33))	('clear cell renal cell carcinomas', 'Disease', (92, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('carcinomas', 'Phenotype', 'HP:0030731', (114, 124))	('expression', 'MPA', (51, 61))	('acute leukaemias', 'Disease', 'MESH:D007938', (146, 162))	('cancers', 'Phenotype', 'HP:0002664', (134, 141))	('decreased', 'NegReg', (41, 50))	('SETD2', 'Gene', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('malignancies', 'Disease', 'MESH:D009369', (71, 83))	('acute leukaemias', 'Disease', (146, 162))	('acute leukaemias', 'Phenotype', 'HP:0002488', (146, 162))	('malignancies', 'Disease', (71, 83))	('clear cell renal cell carcinomas', 'Disease', 'MESH:C538614', (92, 124))	('gastric cancer', 'Phenotype', 'HP:0012126', (126, 140))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (103, 123))	('gastric cancers', 'Disease', 'MESH:D013274', (126, 141))	('gastric cancers', 'Disease', (126, 141))	('gastric cancers', 'Phenotype', 'HP:0012126', (126, 141))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (103, 124))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (92, 123))
181746	31060750	Low expression of SETD2 in gastric cancer and loss of function mutations to the gene in lung adenocarcinoma have been associated with poor survival, but the TCGA provisional data for pancreatic cancer does not identify a significant effect of altered SETD2 on prognosis.	('mutations', 'Var', (63, 72))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (183, 200))	('gastric cancer', 'Disease', (27, 41))	('gastric cancer', 'Phenotype', 'HP:0012126', (27, 41))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (88, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('expression', 'MPA', (4, 14))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('pancreatic cancer', 'Disease', 'MESH:D010190', (183, 200))	('lung adenocarcinoma', 'Disease', (88, 107))	('SETD2', 'Gene', (18, 23))	('pancreatic cancer', 'Disease', (183, 200))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (88, 107))	('Low', 'NegReg', (0, 3))	('loss of function', 'NegReg', (46, 62))	('gastric cancer', 'Disease', 'MESH:D013274', (27, 41))
181753	31060750	In addition, recent studies show potential therapeutic implications of NSD1 and SETD2 mutations or alterations in other neoplasms.	('mutations', 'Var', (86, 95))	('SETD2', 'Gene', (80, 85))	('neoplasm', 'Phenotype', 'HP:0002664', (120, 128))	('neoplasms', 'Phenotype', 'HP:0002664', (120, 129))	('NSD1', 'Gene', '64324', (71, 75))	('NSD1', 'Gene', (71, 75))	('neoplasms', 'Disease', 'MESH:D009369', (120, 129))	('neoplasms', 'Disease', (120, 129))
181754	31060750	In a study in cell lines of head and neck squamous cell carcinoma, loss of function mutations in NSD1 increase sensitivity to cisplatin.	('NSD1', 'Gene', '64324', (97, 101))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (37, 65))	('NSD1', 'Gene', (97, 101))	('mutations', 'Var', (84, 93))	('sensitivity to cisplatin', 'MPA', (111, 135))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (28, 65))	('increase', 'PosReg', (102, 110))	('loss of function', 'NegReg', (67, 83))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (42, 65))	('cisplatin', 'Chemical', 'MESH:D002945', (126, 135))	('carcinoma', 'Phenotype', 'HP:0030731', (56, 65))	('neck squamous cell carcinoma', 'Disease', (37, 65))
181756	31060750	In contrast to NSD1 inactivation, SETD2 inactivation has been associated with worsened response to therapy.	('NSD1', 'Gene', '64324', (15, 19))	('SETD2', 'Gene', (34, 39))	('response to therapy', 'MPA', (87, 106))	('NSD1', 'Gene', (15, 19))	('inactivation', 'Var', (40, 52))
181759	31060750	Limitations to our study include the relatively small cohort for survival analysis; given that only 8-10% of patients would be expected to have NSD1 and SETD2 alterations.	('SETD2', 'Gene', (153, 158))	('patients', 'Species', '9606', (109, 117))	('NSD1', 'Gene', (144, 148))	('alterations', 'Var', (159, 170))	('NSD1', 'Gene', '64324', (144, 148))
181766	31060750	Future objectives for investigating the role of NSD1 and SETD2 in PDA and its precursors include correlation of mutations with IHC staining, and investigating the biological impact of NSD1/SETD2 mutations on tumourigenesis, metastasis, and treatment resistance.	('metastasis', 'CPA', (224, 234))	('NSD1', 'Gene', '64324', (184, 188))	('tumour', 'Disease', (208, 214))	('PDA', 'Phenotype', 'HP:0006725', (66, 69))	('NSD1', 'Gene', (48, 52))	('NSD1', 'Gene', (184, 188))	('PDA', 'Disease', (66, 69))	('mutations', 'Var', (195, 204))	('treatment resistance', 'CPA', (240, 260))	('tumour', 'Phenotype', 'HP:0002664', (208, 214))	('tumour', 'Disease', 'MESH:D009369', (208, 214))	('NSD1', 'Gene', '64324', (48, 52))
181780	25573684	Signal Transducers and Activators of Transcription 3 (STAT3) is a cytoplasmic transcription factor that is activated by tyrosine phosphorylation, leading to dimerization and translocation into the nucleus.	('tyrosine phosphorylation', 'Var', (120, 144))	('STAT3', 'Gene', '6774', (54, 59))	('Signal Transducers and Activators of Transcription 3', 'Gene', '6774', (0, 52))	('translocation into the nucleus', 'MPA', (174, 204))	('dimerization', 'MPA', (157, 169))	('STAT3', 'Gene', (54, 59))	('tyrosine', 'Chemical', 'MESH:D014443', (120, 128))	('activated', 'PosReg', (107, 116))
181782	25573684	As a result, blockade of STAT3 appears to be an attractive target for cancer therapy, especially as it is activated by a number of upstream tyrosine kinases, including EGFR and FGFR1, and thereby serves as a central integration point for multiple oncogenic signaling pathways controlling cell cycle, apoptosis, angiogenesis, tumor invasion, and metastasis.	('FGFR1', 'Gene', (177, 182))	('tyrosine', 'Chemical', 'MESH:D014443', (140, 148))	('STAT3', 'Gene', (25, 30))	('EGFR', 'Gene', (168, 172))	('blockade', 'Var', (13, 21))	('EGFR', 'Gene', '1956', (168, 172))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('FGFR1', 'Gene', '2260', (177, 182))	('activated', 'PosReg', (106, 115))	('tumor', 'Disease', 'MESH:D009369', (325, 330))	('tumor', 'Phenotype', 'HP:0002664', (325, 330))	('cancer', 'Disease', (70, 76))	('tumor', 'Disease', (325, 330))	('STAT3', 'Gene', '6774', (25, 30))	('cancer', 'Disease', 'MESH:D009369', (70, 76))
181792	25573684	Antibodies used were PIAS3 (#4164; Cell Signaling Technology, Danvers, MA), STAT3 (#sc-7179, Santa Cruz Technology, Santa Cruz, CA), and beta-Actin (#A-5441, Sigma-Aldrich, St. Louis, MO).	('STAT3', 'Gene', '6774', (76, 81))	('#A-5441', 'Var', (149, 156))	('STAT3', 'Gene', (76, 81))	('PIAS3', 'Gene', (21, 26))	('#4164;', 'Var', (28, 34))	('#sc-7179', 'Var', (83, 91))	('PIAS3', 'Gene', '10401', (21, 26))	('beta-Actin', 'Gene', (137, 147))	('beta-Actin', 'Gene', '728378', (137, 147))
181804	25573684	After antigen retrieval, the slide was blocked using Background Sniper (#BS966M, Biocare, Concord, CA) for 20 min and stained overnight at 4 C with rabbit anti-human PIAS3 antibody (Cell Signaling Technology) at 1:400.	('rabbit', 'Species', '9986', (148, 154))	('#BS966M', 'Var', (72, 79))	('PIAS3', 'Gene', (166, 171))	('human', 'Species', '9606', (160, 165))	('PIAS3', 'Gene', '10401', (166, 171))
181812	25573684	The TCGA gene expression data for PIAS3 (203035_s_at) was extracted and merged with clinical outcome data for further analysis.	('203035_s_at', 'Var', (41, 52))	('PIAS3', 'Gene', '10401', (34, 39))	('PIAS3', 'Gene', (34, 39))
181819	25573684	Representative images of variable PIAS3 positivity in squamous lung cancer cores are depicted in Figure1B.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('squamous lung cancer', 'Disease', (54, 74))	('PIAS3', 'Gene', (34, 39))	('lung cancer', 'Phenotype', 'HP:0100526', (63, 74))	('PIAS3', 'Gene', '10401', (34, 39))	('squamous lung cancer', 'Disease', 'MESH:D008175', (54, 74))	('squamous lung cancer', 'Phenotype', 'HP:0030359', (54, 74))	('positivity', 'Var', (40, 50))
181827	25573684	The best survival was associated with PIAS3 expression >75% and the worst for PIAS3 expression <25% (P = 0.03).	('PIAS3', 'Gene', (78, 83))	('PIAS3', 'Gene', (38, 43))	('PIAS3', 'Gene', '10401', (78, 83))	('>75%', 'Var', (55, 59))	('PIAS3', 'Gene', '10401', (38, 43))
181836	25573684	Three squamous lung cancer cell lines (Calu-1, H520 and SW900) were treated with a concentration range of curcumin from 0.1 to 25 mumol/L for 24 h. Curcumin induced a dose-dependent increase in PIAS3 expression in Calu-1 and H520 cells (Fig.5A), but not SW900 cells (data not shown).	('increase', 'PosReg', (182, 190))	('SW900', 'CellLine', 'CVCL:1731', (254, 259))	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('PIAS3', 'Gene', '10401', (194, 199))	('SW900', 'CellLine', 'CVCL:1731', (56, 61))	('squamous lung cancer', 'Disease', 'MESH:D008175', (6, 26))	('squamous lung cancer', 'Phenotype', 'HP:0030359', (6, 26))	('H520', 'CellLine', 'CVCL:1566', (225, 229))	('Curcumin', 'Chemical', 'MESH:D003474', (148, 156))	('curcumin', 'Chemical', 'MESH:D003474', (106, 114))	('squamous lung cancer', 'Disease', (6, 26))	('H520', 'CellLine', 'CVCL:1566', (47, 51))	('Curcumin', 'Var', (148, 156))	('Calu-1', 'CellLine', 'CVCL:0608', (214, 220))	('expression', 'MPA', (200, 210))	('PIAS3', 'Gene', (194, 199))	('Calu-1', 'CellLine', 'CVCL:0608', (39, 45))	('lung cancer', 'Phenotype', 'HP:0100526', (15, 26))
181845	25573684	Squamous cell lung cancer was shown to be a complex disease entity, with a high rate of copy number alteration when compared to other malignancies such as ovarian, GBM, colorectal, breast, and renal cancer.	('GBM', 'Disease', (164, 167))	('malignancies', 'Disease', 'MESH:D009369', (134, 146))	('breast', 'Disease', (181, 187))	('Squamous cell lung cancer', 'Disease', (0, 25))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('colorectal', 'Disease', (169, 179))	('renal cancer', 'Phenotype', 'HP:0009726', (193, 205))	('ovarian', 'Disease', (155, 162))	('copy number alteration', 'Var', (88, 110))	('malignancies', 'Disease', (134, 146))	('ovarian', 'Disease', 'MESH:D010051', (155, 162))	('lung cancer', 'Phenotype', 'HP:0100526', (14, 25))	('Squamous cell lung cancer', 'Phenotype', 'HP:0030359', (0, 25))	('renal cancer', 'Disease', (193, 205))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('Squamous cell lung cancer', 'Disease', 'MESH:D002294', (0, 25))	('colorectal', 'Disease', 'MESH:D015179', (169, 179))	('renal cancer', 'Disease', 'MESH:D007680', (193, 205))
181875	24913332	Methylation of the promoter of CEBPalpha gene in CpG 5, CpG-14.15, CpG-19.20 were significantly higher in cervical cancer than in normal cervical tissues (P < 0.05, P < 0.01, P < 0.05, respectively).	('Methylation', 'MPA', (0, 11))	('CpG-19.20', 'Var', (67, 76))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('cervical cancer', 'Disease', (106, 121))	('cervical cancer', 'Disease', 'MESH:D002583', (106, 121))	('CEBPalpha', 'Gene', (31, 40))	('CEBPalpha', 'Gene', '1050', (31, 40))	('higher', 'PosReg', (96, 102))
181883	24913332	For instance, C/EBPalpha interacts with retinoblastoma (Rb) family proteins and inhibits cell growth .	('retinoblastoma', 'Phenotype', 'HP:0009919', (40, 54))	('retinoblastoma', 'Gene', '5925', (40, 54))	('C/EBPalpha', 'Var', (14, 24))	('inhibits', 'NegReg', (80, 88))	('Rb', 'Phenotype', 'HP:0009919', (56, 58))	('cell growth', 'CPA', (89, 100))	('interacts', 'Interaction', (25, 34))	('Rb', 'Gene', '5925', (56, 58))	('retinoblastoma', 'Gene', (40, 54))
181884	24913332	Studies showed that C/EBPalpha can form a complex with cyclin-dependent kinase 2 (cdk2) and cyclin-dependent kinase 4 (cdk4) proteins and block cyclin-cdk interactions and cell cycle progression .	('cyclin', 'Gene', (144, 150))	('cyclin', 'Gene', '5111', (55, 61))	('cyclin', 'Gene', '5111', (92, 98))	('C/EBPalpha', 'Var', (20, 30))	('block', 'NegReg', (138, 143))	('cell cycle progression', 'CPA', (172, 194))	('cdk2', 'Gene', '1017', (82, 86))	('cyclin-dependent kinase 4', 'Gene', (92, 117))	('cyclin', 'Gene', (55, 61))	('cyclin', 'Gene', (92, 98))	('cyclin-dependent kinase 4', 'Gene', '1019', (92, 117))	('cdk4', 'Gene', (119, 123))	('cyclin', 'Gene', '5111', (144, 150))	('interactions', 'Interaction', (155, 167))	('cyclin-dependent kinase 2', 'Gene', '1017', (55, 80))	('cdk2', 'Gene', (82, 86))	('cdk4', 'Gene', '1019', (119, 123))	('complex', 'Interaction', (42, 49))	('cyclin-dependent kinase 2', 'Gene', (55, 80))
181885	24913332	Aberrant expression of C/EBPalpha in Trib1-deficient bone marrow cells is responsible for the defects in macrophage differentiation .	('Aberrant', 'Var', (0, 8))	('macrophage differentiation', 'CPA', (105, 131))	('C/EBPalpha', 'Gene', (23, 33))	('Trib1', 'Gene', (37, 42))	('Trib1', 'Gene', '10221', (37, 42))	('deficient bone marrow', 'Phenotype', 'HP:0005528', (43, 64))	('defects', 'NegReg', (94, 101))
181887	24913332	C/EBPalpha gene as a lung tumor suppressor was demonstrated: loss of C/EBPalpha expression through p38alpha inactivation led to tumor promotion and progression .	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('lung tumor', 'Phenotype', 'HP:0100526', (21, 31))	('p38alpha', 'Gene', '1432', (99, 107))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('inactivation', 'Var', (108, 120))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('lung tumor', 'Disease', (21, 31))	('lung tumor', 'Disease', 'MESH:D008175', (21, 31))	('expression', 'MPA', (80, 90))	('tumor', 'Disease', (128, 133))	('loss', 'NegReg', (61, 65))	('tumor', 'Disease', (26, 31))	('progression', 'CPA', (148, 159))	('C/EBPalpha', 'Gene', (69, 79))	('p38alpha', 'Gene', (99, 107))
181936	24913332	The proliferation of HeLa cells transfected by C/EBPalpha pcDNA3.1 construct was inhibited significantly compared to those transfected by pcDNA3.1 plasmid and non-transfected HeLa cells using MTT assay (P < 0.001) (Figure  4A).	('pcDNA3.1', 'Gene', (58, 66))	('proliferation', 'CPA', (4, 17))	('MTT', 'Chemical', 'MESH:C070243', (192, 195))	('inhibited', 'NegReg', (81, 90))	('HeLa', 'CellLine', 'CVCL:0030', (175, 179))	('HeLa', 'CellLine', 'CVCL:0030', (21, 25))	('C/EBPalpha', 'Var', (47, 57))
181946	24913332	In gastric carcinoma, loss of C/EBPalpha is associated with the switch from cellular differentiation to cellular proliferation, presumably as a result of the activation of Ras/MAPK pathway .	('associated', 'Reg', (44, 54))	('Ras/MAPK pathway', 'Pathway', (172, 188))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (3, 20))	('cellular proliferation', 'CPA', (104, 126))	('C/EBPalpha', 'Gene', (30, 40))	('gastric carcinoma', 'Disease', 'MESH:D013274', (3, 20))	('cellular differentiation', 'CPA', (76, 100))	('activation', 'PosReg', (158, 168))	('gastric carcinoma', 'Disease', (3, 20))	('loss', 'Var', (22, 26))	('carcinoma', 'Phenotype', 'HP:0030731', (11, 20))
181947	24913332	In addition, methylation in the promoter of C/EBPalpha gene occurred at a rate of 24% in dedifferentiated liposarcoma (DLPS).	('C/EBPalpha', 'Gene', (44, 54))	('methylation', 'Var', (13, 24))	('liposarcoma', 'Disease', (106, 117))	('occurred', 'Reg', (60, 68))	('liposarcoma', 'Disease', 'MESH:D008080', (106, 117))	('liposarcoma', 'Phenotype', 'HP:0012034', (106, 117))
181953	24913332	There is evidence that C/EBPalpha exerts its effects, in part, by regulating specific micro RNAs, such as miR-223 .	('miR-223', 'Gene', (106, 113))	('micro', 'Protein', (86, 91))	('regulating', 'Reg', (66, 76))	('miR-223', 'Gene', '407008', (106, 113))	('C/EBPalpha', 'Var', (23, 33))
181956	24913332	In the mouse model of AML, C-terminal C/EBPalpha mutations increase the proliferation of long-term hematopoietic stem cells (LT-HSC) whereas N-terminal C/EBPalpha mutations allow formation of leukemia initiating cells .	('AML', 'Disease', 'MESH:D015470', (22, 25))	('leukemia', 'Disease', 'MESH:D007938', (192, 200))	('mutations', 'Var', (49, 58))	('leukemia', 'Disease', (192, 200))	('mouse', 'Species', '10090', (7, 12))	('proliferation', 'CPA', (72, 85))	('AML', 'Disease', (22, 25))	('C/EBPalpha', 'Gene', (38, 48))	('leukemia', 'Phenotype', 'HP:0001909', (192, 200))	('increase', 'PosReg', (59, 67))
181960	24913332	The ectopic expression of C/EBPalpha can induce the monocytic differentiation of myelomonocytic leukemic cells through the down-regulation of Myc gene .	('myelomonocytic leukemic', 'Disease', (81, 104))	('C/EBPalpha', 'Gene', (26, 36))	('Myc', 'Gene', '4609', (142, 145))	('induce', 'PosReg', (41, 47))	('down-regulation', 'NegReg', (123, 138))	('myelomonocytic leukemic', 'Disease', 'MESH:D007938', (81, 104))	('Myc', 'Gene', (142, 145))	('ectopic expression', 'Var', (4, 22))
181966	24913332	Thus, C/EBPalpha protein could potentially be a target for cervical cancer treatment and changes in the expression of C/EBPalpha protein could be of significance to the early diagnosis of cervical cancer.In addition, C/EBPalpha protein increased expression whereas Ki-67 protein decreased expression in chronic cervicitis tissues.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('cervicitis', 'Disease', (311, 321))	('cervicitis', 'Disease', 'MESH:D002575', (311, 321))	('C/EBPalpha', 'Var', (217, 227))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('cervical cancer', 'Disease', (188, 203))	('decreased', 'NegReg', (279, 288))	('cervical cancer', 'Disease', 'MESH:D002583', (188, 203))	('cervical cancer', 'Disease', 'MESH:D002583', (59, 74))	('expression', 'MPA', (289, 299))	('cervical cancer', 'Disease', (59, 74))	('increased', 'PosReg', (236, 245))	('expression', 'MPA', (246, 256))	('cervicitis', 'Phenotype', 'HP:0030160', (311, 321))
181967	24913332	However, C/EBPalpha protein decreased expression whereas Ki-67 protein increased expression in cancer tissues (Figure  2).	('decreased', 'NegReg', (28, 37))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('expression', 'MPA', (38, 48))	('cancer', 'Disease', (95, 101))	('C/EBPalpha', 'Var', (9, 19))	('increased', 'PosReg', (71, 80))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('expression', 'MPA', (81, 91))
181974	24913332	HeLa cells transfected by C/EBPalpha gene construct were significantly lower in growth than the HeLa cells transfected by pcDNA3.1 plasmid and the non-transfected HeLa cells by MTT assay.	('HeLa', 'CellLine', 'CVCL:0030', (163, 167))	('C/EBPalpha gene construct', 'Var', (26, 51))	('growth', 'MPA', (80, 86))	('MTT', 'Chemical', 'MESH:C070243', (177, 180))	('HeLa', 'CellLine', 'CVCL:0030', (0, 4))	('HeLa', 'CellLine', 'CVCL:0030', (96, 100))	('lower', 'NegReg', (71, 76))
181975	24913332	In addition, after being transfected by C/EBPalpha gene construct, the migration of HeLa cells was significantly reduced than those transfected by pcDNA3.1 plasmid and the non-transfected HeLa cells by matrigel-coated transwell migration assays.	('C/EBPalpha gene construct', 'Var', (40, 65))	('HeLa', 'CellLine', 'CVCL:0030', (84, 88))	('HeLa', 'CellLine', 'CVCL:0030', (188, 192))	('migration of HeLa cells', 'CPA', (71, 94))	('reduced', 'NegReg', (113, 120))
181978	24913332	In summary, the expression of C/EBPalpha gene and C/EBPalpha protein was down-regulated in cervical carcinoma tissues, possibly caused by methylation in the promoter region of this gene.	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('C/EBPalpha', 'Gene', (50, 60))	('methylation', 'Var', (138, 149))	('C/EBPalpha gene', 'Gene', (30, 45))	('expression', 'MPA', (16, 26))	('down-regulated', 'NegReg', (73, 87))	('protein', 'Protein', (61, 68))	('cervical carcinoma tissues', 'Disease', (91, 117))	('cervical carcinoma tissues', 'Disease', 'MESH:D002575', (91, 117))
181980	24913332	By gene transfection methods, we showed that C/EBPalpha gene could inhibit the growth of HeLa cells and reduce the invasion of HeLa cells.	('inhibit', 'NegReg', (67, 74))	('C/EBPalpha', 'Var', (45, 55))	('HeLa', 'CellLine', 'CVCL:0030', (127, 131))	('invasion of HeLa cells', 'CPA', (115, 137))	('reduce', 'NegReg', (104, 110))	('HeLa', 'CellLine', 'CVCL:0030', (89, 93))	('growth of HeLa cells', 'CPA', (79, 99))
181982	24913332	The pre-publication history for this paper can be accessed here: http://www.biomedcentral.com/1471-2407/14/417/prepub This work was supported by the National Natural Science Foundation of China (grant numbers 30860302 and 30660193), The Fund of Plan in the Year of 2011 for Promotion with the Region of Americas and Oceania Cooperation in Scientific Research and Cultivation of High Level Talent Project, The International Science and Technology Collaboration Projector of Xinjiang Production and Construction Corps (grant numbers 2013BC003), The Youth Scientific Innovation Special Grant of Xinjinag Production and Construction Corps (grant numbers 2012CB018) and an International Science and Technology of Collaboration and Exchange Special Grant (grant numbers 2010DFB34100).	('Oceania Cooperation', 'Disease', 'None', (316, 335))	('30660193', 'Var', (222, 230))	('Oceania Cooperation', 'Disease', (316, 335))
182003	33506873	Aidi injection (ADI) (Z52020236, China Food and Drug Administration), one of the multitarget anti-tumor Chinese patent medicines, is an adjuvant TCMP commonly used in the treatment of NSCLC in China.	('NSCLC', 'Phenotype', 'HP:0030358', (184, 189))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('men', 'Species', '9606', (176, 179))	('TCMP', 'Chemical', '-', (145, 149))	('NSCLC', 'Disease', (184, 189))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('NSCLC', 'Disease', 'MESH:D002289', (184, 189))	('ADI', 'Chemical', '-', (16, 19))	('tumor', 'Disease', (98, 103))	('Z52020236', 'Var', (22, 31))
182008	33506873	Modern pharmacological studies have shown that ADI possesses the ability to inhibit the proliferation of A549 cells, reduce hepatotoxicity and gastrointestinal toxicity, and improve immunity.	('ADI', 'Chemical', '-', (47, 50))	('improve', 'PosReg', (174, 181))	('inhibit', 'NegReg', (76, 83))	('gastrointestinal toxicity', 'Disease', (143, 168))	('immunity', 'CPA', (182, 190))	('hepatotoxicity', 'Disease', (124, 138))	('gastrointestinal toxicity', 'Disease', 'MESH:D005767', (143, 168))	('ADI', 'Var', (47, 50))	('reduce', 'NegReg', (117, 123))	('A549', 'CellLine', 'CVCL:0023', (105, 109))	('proliferation', 'CPA', (88, 101))	('hepatotoxicity', 'Disease', 'MESH:D056486', (124, 138))
182009	33506873	Besides, several meta-analyses report that ADI combined with chemotherapy make great improvements in clinical efficacy and quality of life (QoL) in patients with NSCLC and also reduce adverse events induced by chemotherapy.	('patients', 'Species', '9606', (148, 156))	('ADI', 'Var', (43, 46))	('NSCLC', 'Disease', (162, 167))	('NSCLC', 'Phenotype', 'HP:0030358', (162, 167))	('NSCLC', 'Disease', 'MESH:D002289', (162, 167))	('quality of life', 'CPA', (123, 138))	('improvements', 'PosReg', (85, 97))	('men', 'Species', '9606', (92, 95))	('ADI', 'Chemical', '-', (43, 46))	('adverse events', 'MPA', (184, 198))	('reduce', 'NegReg', (177, 183))	('clinical efficacy', 'CPA', (101, 118))
182061	33506873	Ultimately, 14 nodes proved to have degree value > 8 (double median value of degree), betweenness > 0.00198758 (above the median value), and closeness > 0.262279 (above the median value) were selected as hub nodes (the detailed information of 14 nodes in the PPI network is described in Table 1).	('> 0.00198758', 'Var', (98, 110))	('hub', 'Gene', '1993', (204, 207))	('hub', 'Gene', (204, 207))
182071	33506873	Higher level of EGFR expression was significantly associated with a poorer survival than compared with low expression in NSCLC patients (cutoff value of expression: 13.23; P-value: 0.017; HR: 1.3, 95% CI: 1.05-1.68), and this outcome resembled the ESR1 gene (cutoff value of expression: 7.71; P-value: 0.023; HR:1.3, 95% CI: 1.02-1.67) (Figure 7A,B).	('survival', 'CPA', (75, 83))	('poorer', 'NegReg', (68, 74))	('ESR1', 'Gene', (248, 252))	('NSCLC', 'Disease', (121, 126))	('patients', 'Species', '9606', (127, 135))	('NSCLC', 'Disease', 'MESH:D002289', (121, 126))	('EGFR', 'Gene', '1956', (16, 20))	('expression', 'Var', (21, 31))	('ESR1', 'Gene', '2099', (248, 252))	('EGFR', 'Gene', (16, 20))	('NSCLC', 'Phenotype', 'HP:0030358', (121, 126))
182101	33506873	A recent study finds that isorhamnetin is associated with anti-proliferation effects and cell apoptosis induction, and it could inhibit cancer cell growth and alters the expression of apoptosis-related genes involving Bcl-2, Bax, Caspase-3, and so on.	('Caspase-3', 'Gene', '836', (230, 239))	('cell apoptosis induction', 'CPA', (89, 113))	('inhibit', 'NegReg', (128, 135))	('Bax', 'Gene', (225, 228))	('anti-proliferation effects', 'CPA', (58, 84))	('Bax', 'Gene', '581', (225, 228))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('isorhamnetin', 'Chemical', 'MESH:C047368', (26, 38))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('isorhamnetin', 'Var', (26, 38))	('Bcl-2', 'Gene', (218, 223))	('Caspase-3', 'Gene', (230, 239))	('Bcl-2', 'Gene', '596', (218, 223))	('cancer', 'Disease', (136, 142))	('alters', 'Reg', (159, 165))	('apoptosis-related genes', 'Gene', (184, 207))	('expression', 'MPA', (170, 180))
182102	33506873	In addition, isorhamnetin increases protein levels of light chain 3-II when autophagy is initiated, up-regulates the expression of Beclin1, an activator of PI3K, and promotes accumulation of monodansylcadaverine, an in vivo marker for autophagic vacuoles, which confirm the effects of isorhamnetin on autophagy induction in NSCLC cells.	('isorhamnetin', 'Chemical', 'MESH:C047368', (13, 25))	('up-regulates', 'PosReg', (100, 112))	('autophagic vacuoles', 'Phenotype', 'HP:0003736', (235, 254))	('Beclin1', 'Gene', '8678', (131, 138))	('monodansylcadaverine', 'MPA', (191, 211))	('autophagy', 'CPA', (76, 85))	('accumulation', 'MPA', (175, 187))	('expression', 'MPA', (117, 127))	('NSCLC', 'Disease', (324, 329))	('protein levels', 'MPA', (36, 50))	('monodansylcadaverine', 'Chemical', 'MESH:C008542', (191, 211))	('isorhamnetin', 'Chemical', 'MESH:C047368', (285, 297))	('isorhamnetin', 'Var', (13, 25))	('NSCLC', 'Disease', 'MESH:D002289', (324, 329))	('Beclin1', 'Gene', (131, 138))	('promotes', 'PosReg', (166, 174))	('increases', 'PosReg', (26, 35))	('NSCLC', 'Phenotype', 'HP:0030358', (324, 329))
182107	33506873	High expression of ESR1 is regarded as an independent prognostic factor related to metastasis NSCLC, which is conducive to divide NSCLC patients into various prognosis groups, guiding the administration of chemotherapy.	('NSCLC', 'Disease', 'MESH:D002289', (130, 135))	('NSCLC', 'Phenotype', 'HP:0030358', (94, 99))	('High expression', 'Var', (0, 15))	('ESR1', 'Gene', '2099', (19, 23))	('NSCLC', 'Phenotype', 'HP:0030358', (130, 135))	('NSCLC', 'Disease', (94, 99))	('metastasis NSCLC', 'Disease', (83, 99))	('patients', 'Species', '9606', (136, 144))	('NSCLC', 'Disease', 'MESH:D002289', (94, 99))	('ESR1', 'Gene', (19, 23))	('related', 'Reg', (72, 79))	('NSCLC', 'Disease', (130, 135))	('metastasis NSCLC', 'Disease', 'MESH:D009362', (83, 99))
182117	33506873	According to Brueckl et al., the adjuvant treatment is associated with a reduced death risk in NSCLC patients with low ESR1 expression, but the same response did not appear in the patients with high ESR1 expression.	('death', 'Disease', 'MESH:D003643', (81, 86))	('patients', 'Species', '9606', (101, 109))	('low', 'Var', (115, 118))	('NSCLC', 'Disease', 'MESH:D002289', (95, 100))	('ESR1', 'Gene', (199, 203))	('death', 'Disease', (81, 86))	('reduced', 'NegReg', (73, 80))	('ESR1', 'Gene', '2099', (119, 123))	('patients', 'Species', '9606', (180, 188))	('NSCLC', 'Phenotype', 'HP:0030358', (95, 100))	('men', 'Species', '9606', (47, 50))	('ESR1', 'Gene', '2099', (199, 203))	('ESR1', 'Gene', (119, 123))	('NSCLC', 'Disease', (95, 100))
182119	33506873	In addition, a clinical trial includes 82 NSCLC patients who have received chemotherapy regimen previously or are considered not applicable for chemotherapy, indicating that high PIK3CA gain combined with high phosphatase and tensin homolog (PTEN) loss have shorter median overall survival compared with low PIK3CA gain and PTEN loss (4.93 vs 12.3 months, P-value <0.001).	('PIK3CA', 'Gene', (308, 314))	('PTEN', 'Gene', (324, 328))	('phosphatase and tensin homolog', 'Gene', '5728', (210, 240))	('gain', 'PosReg', (186, 190))	('PTEN loss', 'Disease', (324, 333))	('PTEN', 'Gene', (242, 246))	('high', 'Var', (174, 178))	('shorter', 'NegReg', (258, 265))	('PTEN', 'Gene', '5728', (324, 328))	('PIK3CA', 'Gene', (179, 185))	('loss', 'NegReg', (248, 252))	('NSCLC', 'Disease', 'MESH:D002289', (42, 47))	('PIK3CA', 'Gene', '5290', (308, 314))	('PTEN', 'Gene', '5728', (242, 246))	('NSCLC', 'Disease', (42, 47))	('high phosphatase', 'Phenotype', 'HP:0003155', (205, 221))	('PTEN loss', 'Disease', 'MESH:D006223', (324, 333))	('overall survival', 'MPA', (273, 289))	('PIK3CA', 'Gene', '5290', (179, 185))	('NSCLC', 'Phenotype', 'HP:0030358', (42, 47))	('men', 'Species', '9606', (92, 95))	('patients', 'Species', '9606', (48, 56))
182120	33506873	have reported that SMAD3 genetic variation rs4776342 is associated with poorer overall survival (HR = 1.25, 95% CI: 1.06-1.47, P-value <0.01), and multiple wild-type SMAD3 genotypes benefited the survival in both the chemo-radiation treatment group as well as the chemotherapy treatment group.	('rs4776342', 'Var', (43, 52))	('men', 'Species', '9606', (238, 241))	('rs4776342', 'Mutation', 'rs4776342', (43, 52))	('men', 'Species', '9606', (282, 285))	('SMAD3', 'Gene', '4088', (166, 171))	('poorer', 'NegReg', (72, 78))	('SMAD3', 'Gene', (166, 171))	('benefited', 'PosReg', (182, 191))	('survival', 'MPA', (196, 204))	('SMAD3', 'Gene', '4088', (19, 24))	('SMAD3', 'Gene', (19, 24))	('overall survival', 'MPA', (79, 95))
182121	33506873	recruited a total of 84 NSCLC patients to evaluate the importance of MYC, and their study showed that patients with expression of both MYC and PD-L1 had a poorer disease-free survival (7.1 vs 31.1 months, P-value: 0.011) than patients without double-positive expression pattern.	('NSCLC', 'Disease', (24, 29))	('MYC', 'Gene', (69, 72))	('NSCLC', 'Disease', 'MESH:D002289', (24, 29))	('patients', 'Species', '9606', (102, 110))	('expression', 'Var', (116, 126))	('poorer', 'NegReg', (155, 161))	('MYC', 'Gene', (135, 138))	('disease-free survival', 'CPA', (162, 183))	('PD-L1', 'Gene', (143, 148))	('patients', 'Species', '9606', (30, 38))	('patients', 'Species', '9606', (226, 234))	('NSCLC', 'Phenotype', 'HP:0030358', (24, 29))	('MYC', 'Gene', '4609', (69, 72))	('PD-L1', 'Gene', '29126', (143, 148))	('MYC', 'Gene', '4609', (135, 138))
182122	33506873	Besides, a retrospective cohort analysis including 285 lung cancer patients reveals that the EGFR mutations group has a better median overall survival of 20.0 months than that of 11.0 months in the non-mutated group (P-value: 0.007).	('better', 'PosReg', (120, 126))	('lung cancer', 'Disease', 'MESH:D008175', (55, 66))	('patients', 'Species', '9606', (67, 75))	('EGFR', 'Gene', '1956', (93, 97))	('EGFR', 'Gene', (93, 97))	('mutations', 'Var', (98, 107))	('lung cancer', 'Disease', (55, 66))	('lung cancer', 'Phenotype', 'HP:0100526', (55, 66))	('overall survival', 'MPA', (134, 150))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
182147	33506873	On one hand, our study predicted and verified the molecular mechanisms of ADI on lung cancer at a system level, while there was no sufficient experimental evidence to validate these results right now.	('lung cancer', 'Disease', (81, 92))	('lung cancer', 'Phenotype', 'HP:0100526', (81, 92))	('ADI', 'Var', (74, 77))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('men', 'Species', '9606', (148, 151))	('lung cancer', 'Disease', 'MESH:D008175', (81, 92))	('ADI', 'Chemical', '-', (74, 77))
182159	31757212	Transcriptome analysis can be applied to define biomarkers in precision medicine, to describe how observed alterations impact a patient's phenotype, or, more fundamentally, to infer causality among genes.	('phenotype', 'MPA', (138, 147))	('impact', 'Reg', (119, 125))	('patient', 'Species', '9606', (128, 135))	('alterations', 'Var', (107, 118))
182181	31757212	DS has been partially supported by the U.S. National Science Foundation under grants MCB-1412232, IOS-1339362, MCB-1355462, MCB-1158273, IOS-0922738, and MCB-0929339.	('IOS-0922738', 'Var', (137, 148))	('MCB-1158273', 'Var', (124, 135))	('IOS-1339362', 'Var', (98, 109))	('DS', 'Chemical', 'MESH:D003903', (0, 2))
182185	30210637	Results: The meta-analysis showed that high expression of CXCR7 predicted a high risk of LNM (pooled OR = 2.22, 95%CI: 1.41-3.50), high tumor grade (pooled OR = 1.94, 95%CI: 1.20-3.13), poor OS (pooled HR = 1.66, 95%CI: 1.30-2.03), and poor DFS/RFS (pooled HR = 1.82, 95%CI: 1.21-2.43).	('CXCR7', 'Gene', '57007', (58, 63))	('high tumor', 'Disease', (131, 141))	('high expression', 'Var', (39, 54))	('poor', 'NegReg', (236, 240))	('poor', 'Disease', (186, 190))	('OS', 'Chemical', '-', (191, 193))	('CXCR7', 'Gene', (58, 63))	('high tumor', 'Disease', 'MESH:D009369', (131, 141))	('LNM', 'Disease', (89, 92))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))
182188	30210637	As in OS group, we divided the data based on analysis method and it turned out that overexpressed CXCR7 predicted worse OS both in multivariate analysis (pooled HR =1.57, 95%CI: 1.12-2.01) and univariate analysis subgroup (pooled HR =1.86, 95%CI: 1.23-2.49).	('OS', 'Chemical', '-', (6, 8))	('CXCR7', 'Gene', (98, 103))	('worse OS', 'Disease', (114, 122))	('overexpressed', 'Var', (84, 97))	('OS', 'Chemical', '-', (120, 122))	('CXCR7', 'Gene', '57007', (98, 103))
182235	30210637	The results showed that high expression of CXCR7 was significantly associated with poor OS in patients with solid tumors (pooled HR =1.66, 95%CI: 1.30-2.03, Figure 4A).	('patients', 'Species', '9606', (94, 102))	('CXCR7', 'Gene', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('poor OS', 'Disease', (83, 90))	('solid tumors', 'Disease', (108, 120))	('high', 'Var', (24, 28))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('OS', 'Chemical', '-', (88, 90))	('solid tumors', 'Disease', 'MESH:D009369', (108, 120))	('CXCR7', 'Gene', '57007', (43, 48))
182236	30210637	The results revealed that high expression of CXCR7 predicted worse survival both in multivariate analysis subgroup (pooled HR =1.57, 95%CI: 1.12-2.01) and univariate analysis subgroup (pooled HR =1.86, 95%CI: 1.23-2.49) (Figure 4B).	('high', 'Var', (26, 30))	('CXCR7', 'Gene', '57007', (45, 50))	('survival', 'MPA', (67, 75))	('CXCR7', 'Gene', (45, 50))	('worse', 'NegReg', (61, 66))
182238	30210637	7 datasets with 667 patients included in our meta-analysis, the results showed that high expression of CXCR7 had a potent correlation with unfavorable DFS/RFS (pooled HR = 1.82, 95%CI: 1.21-2.43, Figure 5).	('high', 'Var', (84, 88))	('CXCR7', 'Gene', '57007', (103, 108))	('patients', 'Species', '9606', (20, 28))	('CXCR7', 'Gene', (103, 108))	('unfavorable DFS/RFS', 'MPA', (139, 158))
182246	30210637	There were several signaling mechanisms involved in these processes, including aberrated expression of PI3K/AKT, MAPK/ERK, Rho/ROCK and mTOR signaling pathway.	('AKT', 'Gene', '207', (108, 111))	('ERK', 'Gene', '5594', (118, 121))	('expression', 'MPA', (89, 99))	('aberrated', 'Var', (79, 88))	('Rho/ROCK', 'Gene', (123, 131))	('ERK', 'Gene', (118, 121))	('AKT', 'Gene', (108, 111))	('mTOR', 'Gene', (136, 140))	('mTOR', 'Gene', '2475', (136, 140))
182266	30210637	In conclusion, our meta-analysis suggested that high expression of CXCR7 could act as a common maker to predict a high risk of LNM, especially in adenocarcinoma, high tumor grade and poor OS or DFS/RFS in patients with the solid tumor.	('poor OS', 'Var', (183, 190))	('high tumor', 'Disease', (162, 172))	('adenocarcinoma', 'Disease', 'MESH:D000230', (146, 160))	('CXCR7', 'Gene', (67, 72))	('patients', 'Species', '9606', (205, 213))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('solid tumor', 'Disease', (223, 234))	('high tumor', 'Disease', 'MESH:D009369', (162, 172))	('carcinoma', 'Phenotype', 'HP:0030731', (151, 160))	('solid tumor', 'Disease', 'MESH:D009369', (223, 234))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('CXCR7', 'Gene', '57007', (67, 72))	('OS', 'Chemical', '-', (188, 190))	('adenocarcinoma', 'Disease', (146, 160))	('LNM', 'Disease', (127, 130))
182317	27528225	Compared to HPV-negative OPSCC, HPV-positive tumors are characterized by the absence of P53 mutation and a lower number of chromosomal abnormalities.	('absence', 'NegReg', (77, 84))	('P53', 'Gene', (88, 91))	('SCC', 'Gene', (27, 30))	('mutation', 'Var', (92, 100))	('chromosomal abnormalities', 'Disease', (123, 148))	('HPV-positive tumors', 'Disease', (32, 51))	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (123, 148))	('P53', 'Gene', '7157', (88, 91))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('SCC', 'Gene', '6317', (27, 30))	('HPV', 'Species', '10566', (12, 15))	('HPV', 'Species', '10566', (32, 35))	('HPV-positive tumors', 'Disease', 'MESH:D030361', (32, 51))
182318	27528225	Rb degradation also induces overexpression of P16, as a tumor suppressor protein, a hallmark of HPV-16-positive cancer of the oropharynx.	('degradation', 'Var', (3, 14))	('P16', 'Gene', '1029', (46, 49))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('HPV-16', 'Species', '333760', (96, 102))	('tumor', 'Disease', (56, 61))	('induces', 'Reg', (20, 27))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('cancer of the oropharynx', 'Phenotype', 'HP:0100638', (112, 136))	('overexpression', 'MPA', (28, 42))	('P16', 'Gene', (46, 49))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
182330	27528225	reported that the Mutational Landscape of HNSCC and reported that the mutation rate of HPV-positive tumors was approximately half of that found in HPV-negative HNSCC (2.28 mutations per megabase as compared with 4.83 mutations per megabase), and it's suggestive of biological differences between HPV-positive and -negative disease.	('SCC', 'Gene', '6317', (44, 47))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('HPV', 'Species', '10566', (296, 299))	('HPV', 'Species', '10566', (87, 90))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('SCC', 'Gene', (162, 165))	('HPV-positive tumors', 'Disease', 'MESH:D030361', (87, 106))	('SCC', 'Gene', (44, 47))	('mutation', 'Var', (70, 78))	('SCC', 'Gene', '6317', (162, 165))	('HPV', 'Species', '10566', (147, 150))	('HPV-positive tumors', 'Disease', (87, 106))
182331	27528225	Aberrant DNA hypermethylation within gene promoters is a hallmark in various human malignancies, including HNSCC.	('SCC', 'Gene', '6317', (109, 112))	('SCC', 'Gene', (109, 112))	('malignancies', 'Disease', 'MESH:D009369', (83, 95))	('Aberrant DNA hypermethylation', 'Var', (0, 29))	('malignancies', 'Disease', (83, 95))	('human', 'Species', '9606', (77, 82))
182345	27528225	The mechanisms underlying HPV interferes with immune surveillance include: 1) Hindering Langerhans cell migration and activation, 2)Suppressing the interferon (IFN) response, 3) Interfering with HLA class 1-mediated antigen presentation, 4) suppression of inhibitory signals by T regulatory cells (Treg) and immature myeloid cells.	('immune', 'MPA', (46, 52))	('suppression', 'NegReg', (241, 252))	('HLA class 1-mediated antigen presentation', 'MPA', (195, 236))	('activation', 'CPA', (118, 128))	('Interfering', 'NegReg', (178, 189))	('inhibitory signals', 'MPA', (256, 274))	('Hindering', 'NegReg', (78, 87))	('HPV', 'Species', '10566', (26, 29))	('Suppressing', 'NegReg', (132, 143))	('interferes', 'NegReg', (30, 40))	('HPV', 'Var', (26, 29))	('Langerhans cell migration', 'CPA', (88, 113))
182348	27528225	Genetic instability, as an important molecular mechanism in cancers of head and neck region, has been extensively studied .There exists a high consistency in relation to copy number gains and losses of specific patterns of DNA.	('cancers', 'Phenotype', 'HP:0002664', (60, 67))	('cancers', 'Disease', (60, 67))	('cancers', 'Disease', 'MESH:D009369', (60, 67))	('losses', 'NegReg', (192, 198))	('copy number gains', 'Var', (170, 187))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
182350	27528225	Loss of chromosome region 3p and 9p21 are common early genetic events in head and neck squamous neoplasia.	('neoplasia', 'Phenotype', 'HP:0002664', (96, 105))	('squamous neoplasia', 'Phenotype', 'HP:0002860', (87, 105))	('neck squamous neoplasia', 'Disease', 'MESH:D000077195', (82, 105))	('Loss of chromosome', 'Var', (0, 18))	('neck squamous neoplasia', 'Disease', (82, 105))
182355	27528225	Overexpression of EGFR, results from regulatory pathway changes, gene structure changes or gene amplification, which plays a rather important role in tumorigenesis.	('changes', 'Reg', (80, 87))	('EGFR', 'Gene', '1956', (18, 22))	('regulatory pathway', 'Pathway', (37, 55))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('EGFR', 'Gene', (18, 22))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('Overexpression', 'Var', (0, 14))	('tumor', 'Disease', (150, 155))	('gene amplification', 'Var', (91, 109))	('gene structure', 'CPA', (65, 79))	('changes', 'Reg', (56, 63))
182357	27528225	p53 gene alterations have been documented as the most frequent genetic event in HNSCC and cases with p53 alteration account for over 70% of the whole.	('p53', 'Gene', (0, 3))	('p53', 'Gene', '7157', (0, 3))	('men', 'Species', '9606', (35, 38))	('SCC', 'Gene', '6317', (82, 85))	('p53', 'Gene', '7157', (101, 104))	('p53', 'Gene', (101, 104))	('gene alterations', 'Var', (4, 20))	('SCC', 'Gene', (82, 85))
182358	27528225	Previous studies show that overexpression of p53 in HNSCC in young nonsmokers is not associated with the classic p53 mutations in exons 5-9.	('p53', 'Gene', (45, 48))	('mutations', 'Var', (117, 126))	('p53', 'Gene', '7157', (45, 48))	('SCC', 'Gene', '6317', (54, 57))	('p53', 'Gene', '7157', (113, 116))	('p53', 'Gene', (113, 116))	('overexpression', 'PosReg', (27, 41))	('SCC', 'Gene', (54, 57))
182361	27528225	In HNSCC patients, p16 is predominantly inactivated by methylation and deletion of the gene but not by mutation, and p16 methylation is a more common event in those patients under 40 years of age in contrast to p16 deletions, which are more generally seen in those older than 40 years.	('SCC', 'Gene', '6317', (5, 8))	('patients', 'Species', '9606', (9, 17))	('p16', 'Gene', (19, 22))	('p16', 'Gene', '1029', (117, 120))	('p16', 'Gene', (117, 120))	('methylation', 'Var', (55, 66))	('p16', 'Gene', '1029', (211, 214))	('deletion', 'Var', (71, 79))	('p16', 'Gene', '1029', (19, 22))	('patients', 'Species', '9606', (165, 173))	('SCC', 'Gene', (5, 8))	('inactivated', 'NegReg', (40, 51))	('p16', 'Gene', (211, 214))	('common', 'Reg', (143, 149))
182362	27528225	It appears that specific ways of inactivation of p16 in cancer of head and neck are related to specific patient risk profiles(p16INK4A genetic and epigenetic profiles differ in relation to age and site in head and neck squamous cell carcinomas).	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (205, 242))	('neck squamous cell carcinomas', 'Disease', 'MESH:D000077195', (214, 243))	('p16', 'Gene', (126, 129))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('p16', 'Gene', (49, 52))	('p16INK4A', 'Gene', (126, 134))	('neck squamous cell carcinomas', 'Disease', (214, 243))	('patient', 'Species', '9606', (104, 111))	('carcinoma', 'Phenotype', 'HP:0030731', (233, 242))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (219, 243))	('carcinomas', 'Phenotype', 'HP:0030731', (233, 243))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (219, 242))	('inactivation', 'Var', (33, 45))	('cancer', 'Disease', (56, 62))	('p16', 'Gene', '1029', (126, 129))	('p16INK4A', 'Gene', '1029', (126, 134))	('p16', 'Gene', '1029', (49, 52))
182365	27528225	For example, the recently identified single nucleotide polymorphism in the MDM2 promoter (SNP 309) may contribute to the early onset of in patients of HNSCC with defective p53.	('SCC', 'Gene', '6317', (153, 156))	('patients', 'Species', '9606', (139, 147))	('MDM2', 'Gene', '4193', (75, 79))	('p53', 'Gene', '7157', (172, 175))	('MDM2', 'Gene', (75, 79))	('defective', 'Var', (162, 171))	('SCC', 'Gene', (153, 156))	('contribute', 'Reg', (103, 113))	('single nucleotide polymorphism', 'Var', (37, 67))	('p53', 'Gene', (172, 175))
182370	27528225	It's worth noting that sporadic HNSCC that develop in the general population has relationship with inactivation of these genes (TP53, p16, FANCA-M) or aberrant expression of the members of these oncogenes (ras and myc gene family, int-2, hst-1, cyclin D1, epidermal growth factor receptor and Bcl-2).	('TP53', 'Gene', '7157', (128, 132))	('FANCA', 'Gene', (139, 144))	('int-2', 'Gene', (231, 236))	('Bcl-2', 'Gene', (293, 298))	('ras', 'Gene', (206, 209))	('inactivation', 'Var', (99, 111))	('cyclin D1', 'Gene', (245, 254))	('aberrant expression', 'Var', (151, 170))	('SCC', 'Gene', '6317', (34, 37))	('Bcl-2', 'Gene', '596', (293, 298))	('int-2', 'Gene', '2248', (231, 236))	('SCC', 'Gene', (34, 37))	('cyclin D1', 'Gene', '595', (245, 254))	('TP53', 'Gene', (128, 132))	('epidermal growth factor receptor', 'Gene', (256, 288))	('FANCA', 'Gene', '2175', (139, 144))	('epidermal growth factor receptor', 'Gene', '1956', (256, 288))	('myc', 'Gene', '4609', (214, 217))	('p16', 'Gene', (134, 137))	('hst-1', 'Gene', (238, 243))	('myc', 'Gene', (214, 217))	('hst-1', 'Gene', '2249', (238, 243))	('p16', 'Gene', '1029', (134, 137))
182500	31889247	The green fluorescence from coumarin-6 was showed in cytoplasm of the HSC3 cells, suggesting that coumarin-6 entered cytosol together with NPs.	('coumarin-6', 'Chemical', 'MESH:C517282', (98, 108))	('coumarin-6', 'Chemical', 'MESH:C517282', (28, 38))	('coumarin-6', 'Var', (98, 108))	('HSC3', 'Gene', '150353', (70, 74))	('HSC3', 'Gene', (70, 74))
182503	31889247	4a).The signal of tumor-to-background (TBR) ratio was calculated and used as a quantifiable indicator for evaluation using Omn-Nps compared with Omn.	('Omn', 'Chemical', 'MESH:C064925', (123, 126))	('tumor', 'Disease', (18, 23))	('Omn', 'Chemical', 'MESH:C064925', (145, 148))	('Omn-Nps', 'Var', (123, 130))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
182504	31889247	The results showed that maximum TBR for Omn-NPs was 2.23 +- 0.10 and 1.48 +- 0.01 for Omn, the time to peak was 30 min for Omn-NPs and 5 min for Omn, and the signal enhancement duration time was 180 min for Omn-NPs and 30 min for Omn (Fig.	('Omn', 'Chemical', 'MESH:C064925', (123, 126))	('Omn', 'Chemical', 'MESH:C064925', (230, 233))	('Omn-NPs', 'Var', (40, 47))	('Omn', 'Chemical', 'MESH:C064925', (86, 89))	('Omn', 'Chemical', 'MESH:C064925', (145, 148))	('Omn', 'Chemical', 'MESH:C064925', (207, 210))	('TBR', 'MPA', (32, 35))	('Omn', 'Chemical', 'MESH:C064925', (40, 43))
182514	31889247	The modification of polymer with hydrophilic mPEG could prolong the blood circulation and increase accumulation of NPs in tumors.	('accumulation', 'MPA', (99, 111))	('tumors', 'Disease', (122, 128))	('tumors', 'Disease', 'MESH:D009369', (122, 128))	('increase', 'PosReg', (90, 98))	('NPs', 'Protein', (115, 118))	('blood circulation', 'CPA', (68, 85))	('prolong', 'PosReg', (56, 63))	('mPEG', 'Chemical', 'MESH:C572057', (45, 49))	('modification', 'Var', (4, 16))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumors', 'Phenotype', 'HP:0002664', (122, 128))
182515	31889247	PEGylation could reduce serum protein adherence and create a stealth surface to prolong the circulating time through avoiding the uptake by the reticuloendothelial systems.	('serum protein', 'Protein', (24, 37))	('prolong', 'PosReg', (80, 87))	('reduce', 'NegReg', (17, 23))	('PEG', 'Chemical', 'MESH:C499599', (0, 3))	('circulating time', 'MPA', (92, 108))	('PEGylation', 'Var', (0, 10))
182517	31889247	Therefore, the peak point time of TBR was much later and the imaging latency period was much longer in Omn-NPs group than in Omn group.	('imaging', 'MPA', (61, 68))	('Omn', 'Chemical', 'MESH:C064925', (103, 106))	('Omn', 'Chemical', 'MESH:C064925', (125, 128))	('Omn-NPs', 'Var', (103, 110))	('longer', 'PosReg', (93, 99))
182527	31889247	The higher MRI T1 tumor-to-background ratio and prolonged blood circulation time were found for Omn-NPs than Omn in OSCC mice model.	('OSCC', 'Disease', 'MESH:D002294', (116, 120))	('blood circulation time', 'CPA', (58, 80))	('tumor', 'Disease', (18, 23))	('Omn', 'Chemical', 'MESH:C064925', (96, 99))	('prolonged', 'PosReg', (48, 57))	('OSCC', 'Disease', (116, 120))	('higher', 'PosReg', (4, 10))	('mice', 'Species', '10090', (121, 125))	('Omn-NPs', 'Var', (96, 103))	('MRI T1', 'MPA', (11, 17))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('Omn', 'Chemical', 'MESH:C064925', (109, 112))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
182562	31106047	After screening, we enrolled 425 patients with BSC of pure type and 90006, 6997 and 160638 patients with SCC, LCC and LAC, respectively.	('patients', 'Species', '9606', (91, 99))	('patients', 'Species', '9606', (33, 41))	('160638', 'Var', (84, 90))	('LAC', 'Phenotype', 'HP:0030078', (118, 121))	('SCC', 'Gene', (105, 108))	('SCC', 'Phenotype', 'HP:0002860', (105, 108))	('BSC', 'Chemical', '-', (47, 50))	('LCC', 'Phenotype', 'HP:0030360', (110, 113))	('SCC', 'Gene', '6317', (105, 108))
182605	31106047	The latest National Comprehensive Cancer Network recommends that EGFR mutations and other gene mutations should be considered as markers for lung squamous cell carcinoma, especially for non-smokers, small biopsy, or mixed squamous cell carcinoma  .	('mutations', 'Var', (70, 79))	('EGFR', 'Gene', '1956', (65, 69))	('EGFR', 'Gene', (65, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (160, 169))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (141, 169))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (141, 169))	('Cancer', 'Disease', (34, 40))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (222, 245))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (146, 169))	('Cancer', 'Phenotype', 'HP:0002664', (34, 40))	('carcinoma', 'Phenotype', 'HP:0030731', (236, 245))	('Cancer', 'Disease', 'MESH:D009369', (34, 40))	('lung squamous cell carcinoma', 'Disease', (141, 169))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (146, 169))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (222, 245))	('squamous cell carcinoma', 'Disease', (222, 245))
182619	31618441	Novel genetic variants in KIF16B and NEDD4L in the endosome-related genes are associated with non-small cell lung cancer survival The endosome is a membrane-bound organ inside most eukaryotic cells, playing an important role in adaptive immunity by delivering endocytosed antigens to both MHC class I and II pathways.	('associated with', 'Reg', (78, 93))	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('KIF16B', 'Gene', '55614', (26, 32))	('delivering endocytosed antigens', 'MPA', (249, 280))	('endosome-related genes', 'Gene', (51, 73))	('lung cancer', 'Phenotype', 'HP:0100526', (109, 120))	('NEDD4L', 'Gene', (37, 43))	('II pathways', 'Pathway', (305, 316))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (98, 120))	('NEDD4L', 'Gene', '23327', (37, 43))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (94, 120))	('genetic variants', 'Var', (6, 22))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('KIF16B', 'Gene', (26, 32))	('cancer', 'Disease', (114, 120))
182620	31618441	Here, by analyzing two published genome-wide association studies (GWASs), we evaluated associations between genetic variants in the endosome-related gene-set and survival of patients with non-small cell lung cancer (NSCLC).	('NSCLC', 'Disease', (216, 221))	('variants', 'Var', (116, 124))	('endosome-related gene-set', 'Gene', (132, 157))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (188, 214))	('NSCLC', 'Disease', 'MESH:D002289', (216, 221))	('associations', 'Interaction', (87, 99))	('NSCLC', 'Phenotype', 'HP:0030358', (216, 221))	('lung cancer', 'Phenotype', 'HP:0100526', (203, 214))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (188, 214))	('patients', 'Species', '9606', (174, 182))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('non-small cell lung cancer', 'Disease', (188, 214))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (192, 214))
182621	31618441	The discovery included 44,112 (3,478 genotyped and 40,634 imputed) single-nucleotide polymorphisms (SNPs) in 220 genes in a single locus analysis for their associations with survival of 1,185 NSCLC patients from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial.	('Cancer', 'Disease', (263, 269))	('NSCLC', 'Disease', (192, 197))	('Colorectal', 'Disease', (232, 242))	('patients', 'Species', '9606', (198, 206))	('NSCLC', 'Disease', 'MESH:D002289', (192, 197))	('Lung', 'Disease', (226, 230))	('single-nucleotide polymorphisms', 'Var', (67, 98))	('Colorectal', 'Disease', 'MESH:D015179', (232, 242))	('associations', 'Interaction', (156, 168))	('NSCLC', 'Phenotype', 'HP:0030358', (192, 197))	('Cancer', 'Phenotype', 'HP:0002664', (263, 269))	('Cancer', 'Disease', 'MESH:D009369', (263, 269))
182622	31618441	After validation of the 821 survival-associated significant SNPs in additional 984 NSCLC patients from the Harvard Lung Cancer Susceptibility study, 14 SNPs remained significant.	('Harvard Lung Cancer', 'Disease', 'MESH:D008175', (107, 126))	('Harvard Lung Cancer', 'Disease', (107, 126))	('SNPs', 'Var', (60, 64))	('NSCLC', 'Disease', (83, 88))	('Lung Cancer', 'Phenotype', 'HP:0100526', (115, 126))	('Cancer', 'Phenotype', 'HP:0002664', (120, 126))	('NSCLC', 'Disease', 'MESH:D002289', (83, 88))	('patients', 'Species', '9606', (89, 97))	('NSCLC', 'Phenotype', 'HP:0030358', (83, 88))
182623	31618441	The final multivariate stepwise Cox proportional hazards regression model in the PLCO datasets identified three potentially functional and independent SNPs (KIF16B rs1555195 C>T, NEDD4L rs11660748 A>G and rs73440898 A>G) with an adjusted hazards ratio (HR) of 0.86 [95% confidence interval (CI)=0.79-0.94, P=0.0007], 1.31 (1.16-1.47, P=6.0x10-5) and 1.27 (1.12-1.44, P=0.0001) for overall survival (OS), respectively.	('rs11660748', 'Mutation', 'rs11660748', (186, 196))	('rs11660748 A>G', 'Var', (186, 200))	('NEDD4L', 'Gene', '23327', (179, 185))	('rs1555195', 'Mutation', 'rs1555195', (164, 173))	('rs73440898', 'Mutation', 'rs73440898', (205, 215))	('rs1555195 C>T', 'Var', (164, 177))	('rs73440898 A>G', 'Var', (205, 219))	('overall survival', 'MPA', (381, 397))	('NEDD4L', 'Gene', (179, 185))
182624	31618441	Furthermore, the survival-associated KIF16B rs1555195T allele was significantly associated with decreased mRNA expression levels of KIF16B in both lung tissues and blood cells.	('decreased', 'NegReg', (96, 105))	('rs1555195T', 'Var', (44, 54))	('mRNA expression levels', 'MPA', (106, 128))	('KIF16B', 'Gene', (37, 43))	('rs1555195', 'Mutation', 'rs1555195', (44, 53))
182625	31618441	Therefore, genetic variants of the endosome-related genes may be biomarker for NSCLC survival, possibly through modulating the expression of corresponding genes.	('NSCLC', 'Disease', 'MESH:D002289', (79, 84))	('expression', 'MPA', (127, 137))	('biomarker', 'Reg', (65, 74))	('NSCLC', 'Phenotype', 'HP:0030358', (79, 84))	('genetic variants', 'Var', (11, 27))	('modulating', 'Reg', (112, 122))	('NSCLC', 'Disease', (79, 84))	('endosome-related genes', 'Gene', (35, 57))
182630	31618441	Moreover, genetic factors, such as single nucleotide polymorphisms (SNPs), have been shown to have an effect on prognosis of lung cancer patients .	('lung cancer', 'Disease', 'MESH:D008175', (125, 136))	('single nucleotide polymorphisms', 'Var', (35, 66))	('prognosis', 'CPA', (112, 121))	('patients', 'Species', '9606', (137, 145))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('lung cancer', 'Disease', (125, 136))	('lung cancer', 'Phenotype', 'HP:0100526', (125, 136))	('effect', 'Reg', (102, 108))
182632	31618441	To date, few novel and functional SNPs have been identified to be associated with prognosis of lung cancer patients in genome-wide association studies (GWASs).	('lung cancer', 'Disease', (95, 106))	('lung cancer', 'Phenotype', 'HP:0100526', (95, 106))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('associated', 'Reg', (66, 76))	('SNPs', 'Var', (34, 38))	('lung cancer', 'Disease', 'MESH:D008175', (95, 106))	('patients', 'Species', '9606', (107, 115))
182638	31618441	Immunotherapy alone in patients with a high level of PD-L1 expression or in combination with chemotherapy is now the standard first-line therapy for patients with metastatic NSCLC .	('PD-L1', 'Gene', (53, 58))	('patients', 'Species', '9606', (149, 157))	('NSCLC', 'Disease', 'MESH:D002289', (174, 179))	('patients', 'Species', '9606', (23, 31))	('high level', 'Var', (39, 49))	('PD-L1', 'Gene', '29126', (53, 58))	('NSCLC', 'Phenotype', 'HP:0030358', (174, 179))	('NSCLC', 'Disease', (174, 179))
182643	31618441	Therefore, we hypothesize that genetic variants of the genes involved in the endosome-related pathway in the process of anti-tumor immune response are associated with NSCLC survival.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('NSCLC', 'Disease', 'MESH:D002289', (167, 172))	('associated with', 'Reg', (151, 166))	('NSCLC', 'Phenotype', 'HP:0030358', (167, 172))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('genetic variants', 'Var', (31, 47))	('tumor', 'Disease', (125, 130))	('NSCLC', 'Disease', (167, 172))
182656	31618441	These genes were used for imputation with IMPUTE2 and the 1,000 Genomes Project data (phase 3), in which SNPs within their +-2kb flanking regions (SNPs located in the 2-kb upstream and downstream of a gene were considered having potential effects on gene transcription) were extracted with the following criteria: imputation info score >= 0.8 (Supplementary Figure 1), genotyping rate >= 95%, minor allelic frequency (MAF) >= 5%, and Hardy-Weinberg equilibrium (HWE) >= 1 x 10-5.	('Hardy-Weinberg equilibrium', 'Disease', (434, 460))	('minor allelic frequency', 'Var', (393, 416))	('men', 'Species', '9606', (350, 353))
182667	31618441	After multiple testing correction by BFDP <= 0.80, 821 SNPs were identified to be significantly associated with NSCLC OS (P<0.05).	('associated with', 'Reg', (96, 111))	('NSCLC', 'Phenotype', 'HP:0030358', (112, 117))	('NSCLC OS', 'Disease', 'MESH:C567932', (112, 120))	('SNPs', 'Var', (55, 59))	('NSCLC OS', 'Disease', (112, 120))
182668	31618441	Subsequently, we performed meta-analysis of these 14 newly identified SNPs in both PLCO and HLCS datasets and found that a better survival was associated with the KIF16B rs1555195 C>T (P=0.0007), but a poor survival was associated with the other 13 SNPs, without heterogeneity between the two studies (Table 1).	('KIF16B', 'Gene', (163, 169))	('better', 'PosReg', (123, 129))	('rs1555195', 'Mutation', 'rs1555195', (170, 179))	('rs1555195 C>T', 'Var', (170, 183))
182671	31618441	In the PLCO dataset with available covariates for complete adjustment, patients with the rs1555195T allele had a decreased risk of death [Ptrend=0.003 for OS and Ptrend=0.003 for disease-specific survival (DSS)], while patients with the rs11660748G allele and rs73440898G allele had an increased risk of death (Ptrend<0.0001 for OS and Ptrend=0.0003 for DSS; Ptrend=0.001 for OS and Ptrend=0.015 for DSS; respectively) (Table 3).	('patients', 'Species', '9606', (71, 79))	('death', 'Disease', 'MESH:D003643', (131, 136))	('decreased', 'NegReg', (113, 122))	('DSS', 'Gene', '5376', (354, 357))	('death', 'Disease', 'MESH:D003643', (304, 309))	('DSS', 'Gene', (400, 403))	('men', 'Species', '9606', (65, 68))	('rs73440898', 'Mutation', 'rs73440898', (260, 270))	('rs11660748G', 'Var', (237, 248))	('patients', 'Species', '9606', (219, 227))	('DSS', 'Gene', '5376', (400, 403))	('rs73440898G', 'Var', (260, 271))	('DSS', 'Gene', (206, 209))	('rs1555195T', 'Var', (89, 99))	('rs11660748', 'Mutation', 'rs11660748', (237, 247))	('death', 'Disease', (131, 136))	('rs1555195', 'Mutation', 'rs1555195', (89, 98))	('death', 'Disease', (304, 309))	('DSS', 'Gene', '5376', (206, 209))	('DSS', 'Gene', (354, 357))
182672	31618441	Compared with the reference genotype in a dominant genetic model, KIF16B rs1555195 CT+TT genotypes were associated with a better survival (HR=0.81, 95% CI=0.71-0.94, P=0.005 for OS and HR=0.80, 95% CI=0.69-0.94, P=0.005 for DSS), while NEDD4L rs11660748 AG+GG genotypes and rs73440898 AG+GG had a worse survival (HR=1.37, 95% CI=1.16-1.63 and P=0.0003 for OS and HR=1.37, 95% CI=1.14-1.65 and P=0.0006 for DSS; and HR=1.32, 95% CI=1.11-1.58, P=0.002 for OS and HR=1.25, 95% CI=1.03-1.51, P=0.022 for DSS; respectively) (Table 3).	('better', 'PosReg', (122, 128))	('DSS', 'Gene', (500, 503))	('DSS', 'Gene', (406, 409))	('rs11660748 AG+GG', 'Var', (243, 259))	('rs1555195', 'Mutation', 'rs1555195', (73, 82))	('DSS', 'Gene', '5376', (406, 409))	('KIF16B', 'Gene', (66, 72))	('DSS', 'Gene', '5376', (500, 503))	('NEDD4L', 'Gene', (236, 242))	('rs73440898', 'Mutation', 'rs73440898', (274, 284))	('rs11660748', 'Mutation', 'rs11660748', (243, 253))	('NEDD4L', 'Gene', '23327', (236, 242))	('DSS', 'Gene', (224, 227))	('rs73440898', 'Var', (274, 284))	('DSS', 'Gene', '5376', (224, 227))	('rs1555195', 'Var', (73, 82))
182673	31618441	Since rs73440898 and rs11660748 were both in NEDD4L, we performed haplotype analysis assess the relation between different haplotypes and survival.	('NEDD4L', 'Gene', '23327', (45, 51))	('rs73440898', 'Var', (6, 16))	('rs11660748', 'Var', (21, 31))	('rs11660748', 'Mutation', 'rs11660748', (21, 31))	('rs73440898', 'Mutation', 'rs73440898', (6, 16))	('NEDD4L', 'Gene', (45, 51))
182674	31618441	As shown in Table 4, there three SNPs is shown in Supplementary Figure 3. were four NEDD4L haplotypes (A-A, A-G, G-A and G-G) of the rs73440898 and rs11660748 loci, with a frequency of 82.40%, 8.18%, 7.16%, and 2.26%, respectively, and a significant NSCLC death-risk was associated with the G haplotypes (HR=1.32, 1.27 and 1.46 for OS, respectively; and HR=1.32.	('NSCLC death', 'Disease', 'MESH:D003643', (250, 261))	('rs11660748', 'Mutation', 'rs11660748', (148, 158))	('NSCLC death', 'Disease', (250, 261))	('NSCLC', 'Phenotype', 'HP:0030358', (250, 255))	('NEDD4L', 'Gene', (84, 90))	('men', 'Species', '9606', (56, 59))	('rs73440898', 'Mutation', 'rs73440898', (133, 143))	('NEDD4L', 'Gene', '23327', (84, 90))	('rs73440898', 'Var', (133, 143))	('rs11660748', 'Var', (148, 158))
182677	31618441	These results are consistent with the observed death-risk associated with the NEDD4L rs11660748G and rs73440898G alleles.	('rs73440898G', 'Var', (101, 112))	('death', 'Disease', 'MESH:D003643', (47, 52))	('rs73440898', 'Mutation', 'rs73440898', (101, 111))	('death', 'Disease', (47, 52))	('rs11660748G', 'Var', (85, 96))	('NEDD4L', 'Gene', (78, 84))	('rs11660748', 'Mutation', 'rs11660748', (85, 95))	('NEDD4L', 'Gene', '23327', (78, 84))
182679	31618441	First, we combined the unfavorable genotypes (i.e., KIF16B rs1555195 CC, NEDD4L rs73440898 AG+GG, NEDD4L rs11660748 AG+GG) into a genetic score as the number of unfavorable genotypes (NUGs).	('rs1555195', 'Mutation', 'rs1555195', (59, 68))	('rs11660748 AG+GG', 'Var', (105, 121))	('NEDD4L', 'Gene', (73, 79))	('NEDD4L', 'Gene', '23327', (73, 79))	('KIF16B', 'Gene', (52, 58))	('rs11660748', 'Mutation', 'rs11660748', (105, 115))	('rs73440898', 'Mutation', 'rs73440898', (80, 90))	('rs1555195 CC', 'Var', (59, 71))	('NEDD4L', 'Gene', (98, 104))	('NEDD4L', 'Gene', '23327', (98, 104))	('rs73440898 AG+GG', 'Var', (80, 96))
182680	31618441	As shown in Table 3, the increased genetic score of the NUGs was associated with a worse effect on death in the multivariate analysis in the PLCO dataset (Ptrend<0.0001 for OS and Ptrend<0.0001 for DSS).	('increased', 'PosReg', (25, 34))	('DSS', 'Gene', (198, 201))	('death', 'Disease', 'MESH:D003643', (99, 104))	('death', 'Disease', (99, 104))	('DSS', 'Gene', '5376', (198, 201))	('genetic score', 'Var', (35, 48))
182689	31618441	We found that the KIF16B rs1555195T allele was associated with lower expression levels of KIF16B in both lung normal tissues and whole blood cells (P=0.0009 and P=0.005, respectively; Figure 2g and 2h).	('expression levels', 'MPA', (69, 86))	('lower', 'NegReg', (63, 68))	('rs1555195', 'Mutation', 'rs1555195', (25, 34))	('KIF16B', 'Gene', (90, 96))	('KIF16B', 'Gene', (18, 24))	('rs1555195T', 'Var', (25, 35))
182690	31618441	For the NEDD4L rs11660748G and rs73440898G alleles, they were not significantly correlated with their corresponding mRNA expression levels (Supplementary Figure 6) .	('mRNA expression levels', 'MPA', (116, 138))	('rs11660748G', 'Var', (15, 26))	('NEDD4L', 'Gene', (8, 14))	('men', 'Species', '9606', (146, 149))	('NEDD4L', 'Gene', '23327', (8, 14))	('rs73440898', 'Mutation', 'rs73440898', (31, 41))	('rs73440898G', 'Var', (31, 42))	('rs11660748', 'Mutation', 'rs11660748', (15, 25))
182693	31618441	For examples rs1555195 has an effect on enhancer histone marks, DNAse and motifs while rs11660748 and rs73440898 have an effect on enhancer histone marks and motifs (Supplementary Table 5 and Supplementary Figure 7).	('rs73440898', 'Var', (102, 112))	('motifs', 'MPA', (74, 80))	('motifs', 'MPA', (158, 164))	('rs1555195', 'Mutation', 'rs1555195', (13, 22))	('DNAse', 'MPA', (64, 69))	('enhancer', 'PosReg', (131, 139))	('rs73440898', 'Mutation', 'rs73440898', (102, 112))	('enhancer', 'PosReg', (40, 48))	('rs11660748', 'Var', (87, 97))	('rs1555195', 'Var', (13, 22))	('men', 'Species', '9606', (198, 201))	('rs11660748', 'Mutation', 'rs11660748', (87, 97))	('men', 'Species', '9606', (172, 175))
182699	31618441	In the present study, we assessed associations between SNPs in the endosome-related gene-set and NSCLC survival by using available genotyping data from two published GWAS datasets.	('associations', 'Interaction', (34, 46))	('NSCLC', 'Disease', (97, 102))	('endosome-related gene-set', 'Gene', (67, 92))	('NSCLC', 'Disease', 'MESH:D002289', (97, 102))	('SNPs', 'Var', (55, 59))	('NSCLC', 'Phenotype', 'HP:0030358', (97, 102))
182700	31618441	We identified and validated three independent SNPs (i.e., KIF16B rs1555195, NEDD4L rs11660748 and rs73440898) that were significantly associated with NSCLC survival in Caucasian populations.	('rs11660748', 'Mutation', 'rs11660748', (83, 93))	('associated with', 'Reg', (134, 149))	('NSCLC', 'Disease', 'MESH:D002289', (150, 155))	('NEDD4L', 'Gene', '23327', (76, 82))	('KIF16B', 'Gene', (58, 64))	('rs73440898', 'Mutation', 'rs73440898', (98, 108))	('rs1555195', 'Mutation', 'rs1555195', (65, 74))	('NSCLC', 'Phenotype', 'HP:0030358', (150, 155))	('rs11660748', 'Var', (83, 93))	('rs73440898', 'Var', (98, 108))	('NSCLC', 'Disease', (150, 155))	('rs1555195', 'Var', (65, 74))	('NEDD4L', 'Gene', (76, 82))
182701	31618441	In subsequent eQTL analysis for functional genotype-mRNA expression correlation, we found that the KIF16B rs1555195T allele was associated with lower mRNA expression levels in normal lung tissues and whole blood cells.	('lower', 'NegReg', (144, 149))	('mRNA expression levels', 'MPA', (150, 172))	('rs1555195T', 'Var', (106, 116))	('rs1555195', 'Mutation', 'rs1555195', (106, 115))	('KIF16B', 'Gene', (99, 105))
182702	31618441	Based on the TCGA database, KIF16B appears to be a potential oncogene, and we also found that the rs1555195T allele was associated with a lower risk of death and a lower mRNA expression level of KIF16B.	('KIF16B', 'Gene', (195, 201))	('rs1555195T', 'Var', (98, 108))	('lower', 'NegReg', (164, 169))	('lower', 'NegReg', (138, 143))	('mRNA expression level', 'MPA', (170, 191))	('death', 'Disease', 'MESH:D003643', (152, 157))	('death', 'Disease', (152, 157))	('rs1555195', 'Mutation', 'rs1555195', (98, 107))
182704	31618441	Both rs11660748G and rs73440898G alleles in NEDD4L were found to be associated with a higher risk of death.	('associated', 'Reg', (68, 78))	('rs11660748G', 'Var', (5, 16))	('rs11660748', 'Mutation', 'rs11660748', (5, 15))	('NEDD4L', 'Gene', (44, 50))	('NEDD4L', 'Gene', '23327', (44, 50))	('death', 'Disease', 'MESH:D003643', (101, 106))	('rs73440898G', 'Var', (21, 32))	('death', 'Disease', (101, 106))	('rs73440898', 'Mutation', 'rs73440898', (21, 31))
182709	31618441	A key feature of KIF16B is the PX domain at the C terminus that could target the motor at early endosomes by binding to PI(3)P, and through that, KIF16B could transport early endosomes to the plus end of microtubules in a process regulated by the small GTPase Rab5 and its effector .	('Rab5', 'Gene', '5868', (260, 264))	('KIF16B', 'Var', (146, 152))	('Rab5', 'Gene', (260, 264))	('binding', 'Interaction', (109, 116))	('PI(3)P', 'Chemical', '-', (120, 126))
182717	31618441	It was found that miR-93 could promote TGF-beta-induced epithelial-to-mesenchymal transition through downregulation of NEDD4L in lung cancer cells  and that NEDD4L acted as a tumor suppressor gene in NSCLC and targeting EZH2 could upregulate NEDD4L expression .	('NSCLC', 'Phenotype', 'HP:0030358', (200, 205))	('upregulate', 'PosReg', (231, 241))	('miR-93', 'Gene', (18, 24))	('lung cancer', 'Disease', 'MESH:D008175', (129, 140))	('targeting', 'Var', (210, 219))	('NEDD4L', 'Gene', (157, 163))	('NEDD4L', 'Gene', '23327', (157, 163))	('expression', 'MPA', (249, 259))	('lung cancer', 'Phenotype', 'HP:0100526', (129, 140))	('NEDD4L', 'Gene', (242, 248))	('miR-93', 'Gene', '407051', (18, 24))	('NEDD4L', 'Gene', '23327', (242, 248))	('promote', 'PosReg', (31, 38))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('downregulation', 'NegReg', (101, 115))	('tumor', 'Disease', (175, 180))	('EZH2', 'Gene', '2146', (220, 224))	('EZH2', 'Gene', (220, 224))	('NSCLC', 'Disease', 'MESH:D002289', (200, 205))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('TGF-beta', 'Gene', '7039', (39, 47))	('lung cancer', 'Disease', (129, 140))	('epithelial-to-mesenchymal transition', 'CPA', (56, 92))	('NSCLC', 'Disease', (200, 205))	('NEDD4L', 'Gene', (119, 125))	('TGF-beta', 'Gene', (39, 47))	('NEDD4L', 'Gene', '23327', (119, 125))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))
182724	31618441	However, our findings provided new insights for additional functional studies to further support these genetic variants of endosome pathway genes as promising predictors of survival in NSCLC patients.	('patients', 'Species', '9606', (191, 199))	('NSCLC', 'Disease', 'MESH:D002289', (185, 190))	('genetic variants', 'Var', (103, 119))	('NSCLC', 'Phenotype', 'HP:0030358', (185, 190))	('endosome pathway genes', 'Gene', (123, 145))	('NSCLC', 'Disease', (185, 190))
182727	31618441	The survival-associated variant T genotypes of rs1555195 were also associated with mRNA expression levels of the KIF16B gene.	('rs1555195', 'Var', (47, 56))	('mRNA expression levels', 'MPA', (83, 105))	('associated', 'Reg', (67, 77))	('rs1555195', 'Mutation', 'rs1555195', (47, 56))	('KIF16B', 'Gene', (113, 119))
182728	31618441	These variants could be useful predictors of NSCLC survival, and further functional studies could uncover the roles of these genes in the development of lung cancer.	('variants', 'Var', (6, 14))	('men', 'Species', '9606', (145, 148))	('lung cancer', 'Disease', 'MESH:D008175', (153, 164))	('NSCLC', 'Phenotype', 'HP:0030358', (45, 50))	('NSCLC', 'Disease', (45, 50))	('NSCLC', 'Disease', 'MESH:D002289', (45, 50))	('lung cancer', 'Disease', (153, 164))	('lung cancer', 'Phenotype', 'HP:0100526', (153, 164))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
182736	32491253	Furthermore, modified miR-223 inhibitor effectively suppressed tumor growth in cell line-derived xenograft model, suggesting that miR-223 is a potential promising therapeutic target in CSCC.	('tumor', 'Disease', (63, 68))	('modified', 'Var', (13, 21))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('suppressed', 'NegReg', (52, 62))	('CSCC', 'Disease', (185, 189))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('miR-223', 'Gene', (22, 29))
182738	32491253	Human papillomaviruses (HPVs) produce early protein 6 of HPVs protein in infected female cervical tissue cells to enhance signal transducer and activator of transcription 3 (STAT3) activation, which promotes microRNA-223-3p (miR-223) transcription, leading to normal tissue to cervical squamous cancer transformation.	('Human', 'Species', '9606', (0, 5))	('transcription', 'MPA', (234, 247))	('microRNA-223-3p', 'Var', (208, 223))	('squamous cancer', 'Disease', (286, 301))	('infected', 'Disease', 'MESH:D007239', (73, 81))	('promotes', 'PosReg', (199, 207))	('squamous cancer', 'Disease', 'MESH:D002294', (286, 301))	('STAT3', 'Gene', '6774', (174, 179))	('miR-223', 'Gene', (225, 232))	('enhance', 'PosReg', (114, 121))	('signal transducer and activator of transcription 3', 'Gene', '6774', (122, 172))	('cancer', 'Phenotype', 'HP:0002664', (295, 301))	('infected', 'Disease', (73, 81))	('STAT3', 'Gene', (174, 179))	('squamous cancer', 'Phenotype', 'HP:0002860', (286, 301))
182756	32491253	A variety of miRNAs, including miR-19a/b, miR-125b, miR-21, and miR-7, have been reported to be dysregulated in cervical cancer (Fan et al., 2016; Liu et al., 2013a; Ribeiro et al., 2015; Wang et al., 2019; Xu et al., 2012).	('miR-7', 'Gene', '10859', (64, 69))	('miR-19a/b', 'Gene', (31, 40))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('miR-21', 'Gene', (52, 58))	('miR-125b', 'Var', (42, 50))	('cancer', 'Disease', (121, 127))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('miR-21', 'Gene', '406991', (52, 58))	('miR-7', 'Gene', (64, 69))	('miR-19a/b', 'Gene', '406979', (31, 40))
182757	32491253	microRNA-223-3p (miR-223) has been indicated to be overexpressed in cervical cancer or HPV-transformed raft tissue (Wang et al., 2008).	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('overexpressed', 'PosReg', (51, 64))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('microRNA-223-3p', 'Var', (0, 15))
182765	32491253	The knockdown of HMGCS1 results in more attenuated cell proliferation rates in BRAFV600D/E-expressing melanoma cells (Zhao et al., 2017).	('HMGCS1', 'Gene', (17, 23))	('attenuated', 'NegReg', (40, 50))	('melanoma', 'Phenotype', 'HP:0002861', (102, 110))	('melanoma', 'Disease', (102, 110))	('melanoma', 'Disease', 'MESH:D008545', (102, 110))	('knockdown', 'Var', (4, 13))	('cell proliferation rates', 'CPA', (51, 75))
182777	32491253	The antibodies used for IHC were as follows: anti-HMGCS1 (ab194971; Abcam), anti-TGFBR3 (#2519; CST, Danvers, MA, USA), anti-VEGFA (ab1316; Abcam), anti-CD34 (ab81289; Abcam), and anti-Ki67 (ab16667; Abcam).	('CD34', 'Gene', (153, 157))	('CD34', 'Gene', '947', (153, 157))	('VEGFA', 'Gene', (125, 130))	('CST', 'Gene', (96, 99))	('ab81289', 'Var', (159, 166))	('anti-Ki67', 'Var', (180, 189))	('anti-HMGCS1', 'Var', (45, 56))	('#2519', 'Var', (89, 94))	('VEGFA', 'Gene', '7422', (125, 130))	('CST', 'Gene', '106478911', (96, 99))
182806	32491253	For the 3'-UTR assay, miR-223 overexpression, knockdown plasmids, or control plasmids were cotransfected with pmir-GLO vector or mutant vectors into 293T cells.	('overexpression', 'PosReg', (30, 44))	('293T', 'CellLine', 'CVCL:0063', (149, 153))	('miR-223', 'Gene', (22, 29))	('mutant', 'Var', (129, 135))
182812	32491253	The antibodies were as follows: anti-STAT3 antibody (#9139; CST), anti-Flag antibody (#F1804; Sigma, St. Louis, MO, USA), anti-STAT3(705) antibody (#9145; CST), anti-STAT3(727) antibody (#9134; CST), anti-Actin antibody (#KM9001T, SUNGENE Biotech, Tianjin, China), anti-TGFBR3 antibody (#2519; CST), and anti-HMGCS1 antibody (Ab194971; Abcam).	('CST', 'Gene', (294, 297))	('STAT3', 'Gene', '6774', (37, 42))	('#9145;', 'Var', (148, 154))	('STAT3', 'Gene', (166, 171))	('#KM9001T', 'Var', (221, 229))	('CST', 'Gene', (155, 158))	('STAT3', 'Gene', (37, 42))	('CST', 'Gene', '106478911', (60, 63))	('CST', 'Gene', '106478911', (194, 197))	('#2519', 'Var', (287, 292))	('STAT3', 'Gene', '6774', (127, 132))	('#9134;', 'Var', (187, 193))	('CST', 'Gene', '106478911', (294, 297))	('CST', 'Gene', (194, 197))	('STAT3', 'Gene', '6774', (166, 171))	('CST', 'Gene', '106478911', (155, 158))	('STAT3', 'Gene', (127, 132))	('CST', 'Gene', (60, 63))
182815	32491253	After sonication, the chromatin was immunoprecipitated with 4 mug of anti-STAT3, anti-histone H3, or anti-IgG (Abcam) antibodies at 4  C overnight.	('STAT3', 'Gene', (74, 79))	('anti-histone', 'Var', (81, 93))	('STAT3', 'Gene', '6774', (74, 79))
182822	32491253	Additionally, we found that high expression of miR-223 was associated with worse outcomes in CSCC patients based on TCGA database (Fig.	('high', 'Var', (28, 32))	('patients', 'Species', '9606', (98, 106))	('miR-223', 'Gene', (47, 54))	('CSCC', 'Disease', (93, 97))
182825	32491253	To evaluate whether miR-223 affected the colony formation ability of CSCC cells, we seeded the same number of miR-223-OV, miR-223-KD, or control cells into 6-well plates coated with the indicated concentration of soft agar.	('miR-223-KD', 'Var', (122, 132))	('miR-223-OV', 'Var', (110, 120))	('agar', 'Chemical', 'MESH:D000362', (218, 222))
182827	32491253	Furthermore, to explore whether miR-223 was involved in tumor growth in vivo, a CDX model was established by injecting the modified cells into the flanks of nude mice.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('modified', 'Var', (123, 131))	('nude mice', 'Species', '10090', (157, 166))	('tumor', 'Disease', (56, 61))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('CDX', 'Chemical', '-', (80, 83))
182828	32491253	We found that miR-223 significantly promoted tumor growth in the nude mice, whereas the knockdown of miR-223 decreased tumor volume and weight (Fig.	('tumor', 'Disease', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('miR-223', 'Gene', (14, 21))	('tumor', 'Disease', (45, 50))	('knockdown', 'Var', (88, 97))	('miR-223', 'Gene', (101, 108))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('decreased tumor', 'Disease', (109, 124))	('decreased tumor', 'Disease', 'MESH:D002303', (109, 124))	('nude mice', 'Species', '10090', (65, 74))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('promoted', 'PosReg', (36, 44))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
182829	32491253	Similar results were obtained from the CDX model in which ME180 cells with miR-223 alterations were injected into nude mice (Fig.	('nude mice', 'Species', '10090', (114, 123))	('alterations', 'Var', (83, 94))	('miR-223', 'Gene', (75, 82))	('CDX', 'Chemical', '-', (39, 42))
182830	32491253	The IHC assays indicated that the levels of Ki67 and VEGFA were obviously increased in the miR-223-OV tumor tissues and were downregulated in the miR-223-KD tumors (Fig.	('tumor', 'Disease', (157, 162))	('VEGFA', 'Gene', '7422', (53, 58))	('miR-223-OV', 'Var', (91, 101))	('tumors', 'Phenotype', 'HP:0002664', (157, 163))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('miR-223-KD tumors', 'Disease', (146, 163))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('increased', 'PosReg', (74, 83))	('VEGFA', 'Gene', (53, 58))	('miR-223-KD tumors', 'Disease', 'MESH:C537017', (146, 163))	('Ki67', 'Protein', (44, 48))	('downregulated', 'NegReg', (125, 138))	('levels', 'MPA', (34, 40))	('tumor', 'Disease', (102, 107))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))
182840	32491253	Indeed, the activity of the promoter was upregulated in STAT3-overexpressing cells, whereas STAT3 silencing dramatically attenuated the promoter activity (Fig.	('STAT3', 'Gene', (56, 61))	('attenuated', 'NegReg', (121, 131))	('STAT3', 'Gene', '6774', (92, 97))	('upregulated', 'PosReg', (41, 52))	('silencing', 'Var', (98, 107))	('activity', 'MPA', (12, 20))	('STAT3', 'Gene', (92, 97))	('promoter activity', 'MPA', (136, 153))	('STAT3', 'Gene', '6774', (56, 61))
182847	32491253	Thus, we divided the patients (from the TCGA database) into several groups based on E6 expression or E7 expression, and the miR-223 levels were compared among these groups.	('E6 expression', 'Var', (84, 97))	('E7 expression', 'Var', (101, 114))	('E6', 'Chemical', '-', (84, 86))	('patients', 'Species', '9606', (21, 29))
182851	32491253	In contrast, silencing E6 markedly decreased miR-223 expression (Fig.	('decreased', 'NegReg', (35, 44))	('E6', 'Chemical', '-', (23, 25))	('miR-223 expression', 'MPA', (45, 63))	('silencing', 'Var', (13, 22))
182854	32491253	3K, after E6 knockdown, phospho-STAT3 was obviously decreased.	('STAT3', 'Gene', '6774', (32, 37))	('decreased', 'NegReg', (52, 61))	('STAT3', 'Gene', (32, 37))	('E6', 'Chemical', '-', (10, 12))	('knockdown', 'Var', (13, 22))
182868	32491253	These results suggested that miR-223 suppressed TGFBR3 and HMGCS1 expression in cervical cancer cells.	('TGFBR3', 'Gene', (48, 54))	('HMGCS1', 'Gene', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('expression', 'MPA', (66, 76))	('cancer', 'Disease', (89, 95))	('miR-223', 'Var', (29, 36))	('cervical', 'Disease', (80, 88))	('suppressed', 'NegReg', (37, 47))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
182872	32491253	To test this hypothesis, we first analyzed the integrated data from TCGA and found that TGFBR3 was expressed at low levels in high-grade tumor tissues and that high levels of TGFBR3 were associated with favorable prognosis (Fig.	('tumor', 'Disease', (137, 142))	('TGFBR3', 'Gene', (88, 94))	('favorable prognosis', 'CPA', (203, 222))	('high levels', 'Var', (160, 171))	('TGFBR3', 'Var', (175, 181))	('associated with', 'Reg', (187, 202))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
182874	32491253	6D, silencing TGFBR3 or HMGCS1 induced the accumulation of the beta-catenin and decreased the phosphorylation of p27 and CHK2.	('beta-catenin', 'Gene', (63, 75))	('HMGCS1', 'Gene', (24, 30))	('accumulation', 'PosReg', (43, 55))	('p27', 'Gene', (113, 116))	('beta-catenin', 'Gene', '1499', (63, 75))	('TGFBR3', 'Gene', (14, 20))	('decreased', 'NegReg', (80, 89))	('phosphorylation', 'MPA', (94, 109))	('p27', 'Gene', '10671', (113, 116))	('CHK2', 'Gene', (121, 125))	('silencing', 'Var', (4, 13))	('CHK2', 'Gene', '11200', (121, 125))
182879	32491253	Furthermore, pro-inflammatory IL-6 which has been reported to be a critical modulator of cancer progression was significantly upregulated in the miR-223-high group, whereas the IL-6R level was not different between miR-223-high and miR-223-low groups (Fig.	('IL-6', 'Gene', (177, 181))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('IL-6', 'Gene', '3569', (177, 181))	('IL-6R', 'Gene', '3570', (177, 182))	('upregulated', 'PosReg', (126, 137))	('IL-6', 'Gene', (30, 34))	('cancer', 'Disease', (89, 95))	('IL-6', 'Gene', '3569', (30, 34))	('IL-6R', 'Gene', (177, 182))	('miR-223-high', 'Var', (145, 157))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
182880	32491253	Although miR-223 enhanced IL-6 expression in CSCC cells to some extent, the difference in the IL-6 levels exhibited in the tumor tissues (TCGA cohort) was considered to be contributed by other cells (Fig.	('IL-6', 'Gene', (94, 98))	('tumor', 'Disease', (123, 128))	('enhanced', 'PosReg', (17, 25))	('IL-6', 'Gene', '3569', (94, 98))	('miR-223', 'Var', (9, 16))	('IL-6', 'Gene', (26, 30))	('expression', 'MPA', (31, 41))	('IL-6', 'Gene', '3569', (26, 30))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
182885	32491253	7E,F, IL-6 was obviously increased in exosome-treated cells, especially in miR-223-OV or STAT3-OV exosome-treated cells.	('increased', 'PosReg', (25, 34))	('STAT3', 'Gene', '6774', (89, 94))	('IL-6', 'Gene', (6, 10))	('IL-6', 'Gene', '3569', (6, 10))	('STAT3', 'Gene', (89, 94))	('miR-223-OV', 'Var', (75, 85))
182892	32491253	In addition, GW4869 (exosome inhibitor) inhibited IL-6 expression of THP-1 cells (Fig.	('IL-6', 'Gene', (50, 54))	('inhibited', 'NegReg', (40, 49))	('GW4869', 'Var', (13, 19))	('IL-6', 'Gene', '3569', (50, 54))	('THP-1', 'Gene', '2736', (69, 74))	('THP-1', 'Gene', (69, 74))	('expression', 'MPA', (55, 65))	('GW4869', 'Chemical', 'MESH:C468773', (13, 19))
182894	32491253	To investigate whether miR-223 could serve as therapeutic target for cervical cancer, cholesterol-conjugated miR-223 inhibitors or controls were delivered via the tail vein every 4 days for 16 days after implantation.	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('inhibitors', 'Var', (117, 127))	('cholesterol', 'Chemical', 'MESH:D002784', (86, 97))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('miR-223', 'Gene', (109, 116))
182904	32491253	In our previous work, we demonstrated that miR-223 promotes M2 polarization by targeting MOZ (Jiang et al., 2019).	('MOZ', 'Gene', '7994', (89, 92))	('promotes', 'PosReg', (51, 59))	('miR-223', 'Var', (43, 50))	('targeting', 'Reg', (79, 88))	('MOZ', 'Gene', (89, 92))	('M2 polarization', 'MPA', (60, 75))
182909	32491253	Particularly, loss of miR-223 is an early event during breast transformation (Citron et al., 2020), and stroma derived miR-223 inhibits tumor cell migration and invasion (Pinatel et al., 2014).	('loss', 'Var', (14, 18))	('inhibits', 'NegReg', (127, 135))	('Citron', 'Species', '171251', (78, 84))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('breast transformation', 'Disease', (55, 76))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('miR-223', 'Gene', (119, 126))	('tumor', 'Disease', (136, 141))	('miR-223', 'Gene', (22, 29))
182913	32491253	In hepatocellular carcinoma cells, miR-223 is found to target Rab1, which is critical for mTOR pathway, and to promote apoptosis (Dong et al., 2017).	('miR-223', 'Var', (35, 42))	('hepatocellular carcinoma', 'Disease', (3, 27))	('carcinoma', 'Phenotype', 'HP:0030731', (18, 27))	('mTOR', 'Gene', (90, 94))	('mTOR', 'Gene', '2475', (90, 94))	('Rab1', 'Gene', (62, 66))	('Rab1', 'Gene', '5861', (62, 66))	('apoptosis', 'CPA', (119, 128))	('target', 'Reg', (55, 61))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (3, 27))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (3, 27))	('promote', 'PosReg', (111, 118))
182914	32491253	Interestingly, a report indicates that miR-223 suppresses cell proliferation by targeting IGF-1R in HeLa cells, which models cervical adenocarcinoma (Jia et al., 2011).	('adenocarcinoma', 'Disease', (134, 148))	('suppresses', 'NegReg', (47, 57))	('cell proliferation', 'CPA', (58, 76))	('adenocarcinoma', 'Disease', 'MESH:D000230', (134, 148))	('carcinoma', 'Phenotype', 'HP:0030731', (139, 148))	('miR-223', 'Var', (39, 46))	('HeLa', 'CellLine', 'CVCL:0030', (100, 104))	('targeting', 'Reg', (80, 89))	('IGF-1R', 'Gene', (90, 96))	('IGF-1R', 'Gene', '3480', (90, 96))
182924	32491253	Over 70% of cancers are associated with hyperactivated STAT3.	('cancers', 'Disease', 'MESH:D009369', (12, 19))	('STAT3', 'Gene', (55, 60))	('associated', 'Reg', (24, 34))	('cancers', 'Phenotype', 'HP:0002664', (12, 19))	('cancers', 'Disease', (12, 19))	('hyperactivated', 'Var', (40, 54))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('STAT3', 'Gene', '6774', (55, 60))
182943	28210166	Factors predicting unlikely chemotherapy included age >=75 years, Eastern Cooperative Oncology Group (ECOG)-performance status (PS) >=2, Charlson comorbidity index >=2, hemoglobin <12.2 g/dL, red cell distribution width >=13.9%, and serum sodium <140 mEq/L.	('>=13.9', 'Var', (220, 226))	('>=2', 'Var', (164, 167))	('sodium', 'Chemical', 'MESH:D012964', (239, 245))	('serum sodium', 'MPA', (233, 245))	('>=2', 'Var', (132, 135))	('Oncology', 'Phenotype', 'HP:0002664', (86, 94))
182971	28210166	Regarding laboratory data, absolute lymphocyte count (1,803+-697 vs 1,478+-566 cells/muL, P<0.01), hemoglobin (13.0+-1.7 vs 11.8+-1.5 g/dL, P<0.01), and serum sodium concentration (139.6+-3.0 vs 137.8+-3.8 mEq/L, P<0.01) were significantly higher, while RDW (13.5%+-0.9% vs 14.1%+-1.2%, P<0.01) was lower in the chemotherapy group than in the non-chemotherapy group (Table S1).	('serum sodium concentration', 'MPA', (153, 179))	('muL', 'Gene', '4591', (85, 88))	('muL', 'Gene', (85, 88))	('lower', 'NegReg', (299, 304))	('absolute lymphocyte', 'MPA', (27, 46))	('RDW', 'MPA', (254, 257))	('higher', 'PosReg', (240, 246))	('hemoglobin', 'MPA', (99, 109))	('sodium', 'Chemical', 'MESH:D012964', (159, 165))	('chemotherapy', 'Var', (312, 324))
182997	28210166	Pretreatment low hemoglobin, increased RDW, and high LDH levels have also been shown to be independent poor prognostic indicators.	('men', 'Species', '9606', (8, 11))	('high LDH levels', 'MPA', (48, 63))	('increased', 'PosReg', (29, 38))	('low', 'Var', (13, 16))	('low hemoglobin', 'Phenotype', 'HP:0001903', (13, 27))	('RDW', 'MPA', (39, 42))
183011	33247687	NPC cases (1990-2014) were identified using the International Classification of Diseases for Oncology (ICD-O) code C11 from the Chiang Mai, Khon Kaen, Lampang, and Songkhla cancer registries and compared to Asian/Pacific Islanders (A/PI) from the US SEER program.	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('NPC', 'Gene', '4864', (0, 3))	('cancer', 'Disease', (173, 179))	('code C11', 'Var', (110, 118))	('Oncology', 'Phenotype', 'HP:0002664', (93, 101))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('NPC', 'Gene', (0, 3))	('NPC', 'Phenotype', 'HP:0100630', (0, 3))
183024	33247687	Several epidemiological studies have established the WHO histological classifications as independent prognostic factors for NPC survival (Burt et al., 1992; Levine et al., 1980), non-keratinizing carcinoma has been shown to have significant survival advantages when compared to keratinizing squamous cell carcinoma, with 5-year survival rates of 51% and 6%, respectively (Reddy et al., 1995).	('NPC', 'Gene', (124, 127))	('NPC', 'Phenotype', 'HP:0100630', (124, 127))	('carcinoma', 'Disease', (196, 205))	('squamous cell carcinoma', 'Disease', (291, 314))	('advantages', 'PosReg', (250, 260))	('carcinoma', 'Disease', 'MESH:D009369', (305, 314))	('NPC', 'Gene', '4864', (124, 127))	('non-keratinizing', 'Var', (179, 195))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (291, 314))	('survival', 'CPA', (241, 249))	('carcinoma', 'Phenotype', 'HP:0030731', (305, 314))	('carcinoma', 'Disease', 'MESH:D009369', (196, 205))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (291, 314))	('carcinoma', 'Phenotype', 'HP:0030731', (196, 205))	('carcinoma', 'Disease', (305, 314))
183101	31755426	A diagnostic biopsy is not usually necessary in cases of smaller tumors (<=4 clock hours limbal tumor or <=15 mm basal dimension) that appear benign.	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('tumor', 'Disease', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('<=15', 'Var', (105, 109))	('tumor', 'Disease', (96, 101))	('tumors', 'Disease', (65, 71))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('tumor', 'Disease', 'MESH:D009369', (65, 70))
183116	31755426	Primary excisional biopsy is appropriate for relatively smaller tumors (<=4 clock hours limbal tumor or <=15 mm basal dimension) that are symptomatic or suspected to be malignant.	('tumors', 'Disease', (64, 70))	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('tumor', 'Disease', (64, 69))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('<=15', 'Var', (104, 108))	('tumor', 'Disease', (95, 100))
183214	31755426	In the rare case of a very extensive lesion, where the lesion causes dense amblyopia with no hope for visual acuity, modified enucleation with ocular surface reconstruction may be necessary.	('amblyopia', 'Disease', (75, 84))	('amblyopia', 'Disease', 'MESH:D000550', (75, 84))	('causes', 'Reg', (62, 68))	('lesion', 'Var', (55, 61))	('amblyopia', 'Phenotype', 'HP:0000646', (75, 84))
183440	31506430	Kaplan-Meier survival analysis showed that patients with high CSC score have shorter overall survival (OS) in the entire cohort [37.7 vs. 60.4 months (mo), p = 0.001] and the adenocarcinoma subcohort [36.6 vs. 53.5 mo, p = 0.003], but not in the squamous cell carcinoma one.	('adenocarcinoma', 'Disease', (175, 189))	('overall survival', 'MPA', (85, 101))	('high', 'Var', (57, 61))	('carcinoma', 'Phenotype', 'HP:0030731', (180, 189))	('patients', 'Species', '9606', (43, 51))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (246, 269))	('adenocarcinoma', 'Disease', 'MESH:D000230', (175, 189))	('carcinoma', 'Phenotype', 'HP:0030731', (260, 269))	('squamous cell carcinoma', 'Disease', (246, 269))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (246, 269))	('shorter', 'NegReg', (77, 84))	('CSC score', 'Gene', (62, 71))
183454	31506430	For instance, CD133 and CD44 molecules have been successfully used to identify lung cancer cells with CSC properties in some studies, whereas other publications reported that CD133- or CD44- cell populations also possess the ability for self-renewal and enhanced tumor initiation capacity when transplanted into mice.	('lung cancer', 'Disease', 'MESH:D008175', (79, 90))	('tumor', 'Disease', 'MESH:D009369', (263, 268))	('CD133-', 'Var', (175, 181))	('tumor', 'Phenotype', 'HP:0002664', (263, 268))	('enhanced', 'PosReg', (254, 262))	('self-renewal', 'CPA', (237, 249))	('lung cancer', 'Disease', (79, 90))	('lung cancer', 'Phenotype', 'HP:0100526', (79, 90))	('tumor', 'Disease', (263, 268))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('mice', 'Species', '10090', (312, 316))
183462	31506430	KRAS gene mutations in codons 12, 13, and 61 were quantitatively detected by pyrosequencing using the theraScreen  KRAS Pyro  kit (Qiagen, Germany).	('KRAS', 'Gene', (115, 119))	('KRAS', 'Gene', '3845', (115, 119))	('mutations', 'Var', (10, 19))	('KRAS', 'Gene', (0, 4))	('KRAS', 'Gene', '3845', (0, 4))
183463	31506430	EGFR mutations were analyzed by quantitative real-time PCR (RTqPCR) using the theraScreen  EGFR RGQ PCR (Qiagen, Germany), whereas TP53 mutations were determined using standard PCR followed by Sanger sequencing.	('EGFR', 'Gene', (91, 95))	('EGFR', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))	('TP53', 'Gene', '7157', (131, 135))	('TP53', 'Gene', (131, 135))	('EGFR', 'Gene', '1956', (91, 95))	('EGFR', 'Gene', '1956', (0, 4))
183507	31506430	Cells from patients FIS299 and FIS301 grew as multilayers and formed cell colonies.	('FIS301', 'Var', (31, 37))	('cell colonies', 'CPA', (69, 82))	('formed', 'Reg', (62, 68))	('patients', 'Species', '9606', (11, 19))	('FIS299', 'Var', (20, 26))
183509	31506430	In contrast, cells from patients FIS302, FIS303, and FIS315 were more elongated, with brighter nuclei, fewer interactions, and a more isolated growth.	('FIS315', 'Var', (53, 59))	('interactions', 'Interaction', (109, 121))	('isolated growth', 'CPA', (134, 149))	('brighter', 'PosReg', (86, 94))	('more', 'PosReg', (65, 69))	('FIS303', 'Var', (41, 47))	('patients', 'Species', '9606', (24, 32))	('FIS302', 'Var', (33, 39))	('fewer', 'NegReg', (103, 108))
183511	31506430	Regarding tumorspheres, tight spheroids were formed by FIS299, FIS301, and FIS315 cultures, whereas FIS302, FIS303, FIS317, and FIS320 formed more loose and irregularly shaped spheres, and FIS343 showed a mixed behavior (Fig.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('FIS315', 'Var', (75, 81))	('loose', 'CPA', (147, 152))	('tumors', 'Disease', (10, 16))	('FIS299', 'Var', (55, 61))	('FIS302', 'Var', (100, 106))	('tumors', 'Disease', 'MESH:D009369', (10, 16))	('tumors', 'Phenotype', 'HP:0002664', (10, 16))
183538	31506430	When comparing the gene expression profiles, it was observed that expression of BMI1, CD166, CDKN2A, MDM2, HEY1, NUMB, ITGA6, and NOTCH3 was induced in tumorspheres from FIS343 and FIS320 patients, while tumorspheres from the rest of patients showed higher expression of EPCAM, NOTCH1, NOTCH2, CD44, CTNNB1, MMP9, and CDKN1A.	('CDKN2A', 'Gene', (93, 99))	('CD166', 'Gene', '214', (86, 91))	('ITGA6', 'Gene', (119, 124))	('FIS343', 'Var', (170, 176))	('expression', 'MPA', (257, 267))	('patients', 'Species', '9606', (188, 196))	('NOTCH1', 'Gene', '4851', (278, 284))	('MMP9', 'Gene', '4318', (308, 312))	('tumors', 'Phenotype', 'HP:0002664', (204, 210))	('MMP9', 'Gene', (308, 312))	('tumors', 'Disease', (152, 158))	('MDM2', 'Gene', '4193', (101, 105))	('NUMB', 'Gene', '8650', (113, 117))	('CDKN1A', 'Gene', (318, 324))	('BMI1', 'Gene', (80, 84))	('CDKN1A', 'Gene', '1026', (318, 324))	('CDKN2A', 'Gene', '1029', (93, 99))	('NOTCH3', 'Gene', '4854', (130, 136))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('induced', 'PosReg', (141, 148))	('patients', 'Species', '9606', (234, 242))	('NOTCH2', 'Gene', '4853', (286, 292))	('tumors', 'Disease', (204, 210))	('CD166', 'Gene', (86, 91))	('tumors', 'Disease', 'MESH:D009369', (152, 158))	('CTNNB1', 'Gene', '1499', (300, 306))	('NOTCH3', 'Gene', (130, 136))	('EPCAM', 'Gene', '4072', (271, 276))	('ITGA6', 'Gene', '3655', (119, 124))	('HEY1', 'Gene', (107, 111))	('HEY1', 'Gene', '23462', (107, 111))	('BMI1', 'Gene', '648', (80, 84))	('tumors', 'Disease', 'MESH:D009369', (204, 210))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('NOTCH2', 'Gene', (286, 292))	('NUMB', 'Gene', (113, 117))	('CTNNB1', 'Gene', (300, 306))	('NOTCH1', 'Gene', (278, 284))	('EPCAM', 'Gene', (271, 276))	('tumors', 'Phenotype', 'HP:0002664', (152, 158))	('MDM2', 'Gene', (101, 105))
183543	31506430	In addition, all cells forming tumorspheres expressed both CD44 and Nanog, although signals showed polarity, being higher on cell membranes of cells located in the periphery of the lung tumorspheres for CD44 and nuclear for Nanog.	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('lung tumorspheres', 'Disease', 'MESH:D008171', (181, 198))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('tumors', 'Disease', (31, 37))	('CD44', 'Var', (59, 63))	('Nanog', 'Gene', (224, 229))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('tumors', 'Phenotype', 'HP:0002664', (186, 192))	('CD44', 'Var', (203, 207))	('Nanog', 'Gene', '79923', (68, 73))	('tumors', 'Disease', 'MESH:D009369', (31, 37))	('tumors', 'Disease', (186, 192))	('lung tumorspheres', 'Disease', (181, 198))	('tumors', 'Disease', 'MESH:D009369', (186, 192))	('higher', 'PosReg', (115, 121))	('Nanog', 'Gene', (68, 73))	('Nanog', 'Gene', '79923', (224, 229))
183555	31506430	Cox regression and Kaplan-Meier analyses indicated that patients with high levels of THY1, SNAI1, ITGA6, and CDKN1A presented worse OS (Supplementary Table S4 and Supplementary Fig.	('patients', 'Species', '9606', (56, 64))	('ITGA6', 'Gene', '3655', (98, 103))	('CDKN1A', 'Gene', (109, 115))	('ITGA6', 'Gene', (98, 103))	('Cox', 'Gene', '1351', (0, 3))	('Cox', 'Gene', (0, 3))	('SNAI1', 'Gene', (91, 96))	('CDKN1A', 'Gene', '1026', (109, 115))	('THY1', 'Gene', '7070', (85, 89))	('SNAI1', 'Gene', '6615', (91, 96))	('THY1', 'Gene', (85, 89))	('high', 'Var', (70, 74))
183556	31506430	Survival analyses were also performed according to patient histology, associating high ITGA6 and JAG1 with worse prognosis in ADC patients.	('patient', 'Species', '9606', (130, 137))	('ADC', 'Disease', (126, 129))	('high', 'Var', (82, 86))	('JAG1', 'Gene', '182', (97, 101))	('ITGA6', 'Gene', '3655', (87, 92))	('patients', 'Species', '9606', (130, 138))	('JAG1', 'Gene', (97, 101))	('patient', 'Species', '9606', (51, 58))	('ITGA6', 'Gene', (87, 92))
183559	31506430	S14), and according to this ranking, the expression of CDKN1A, SNAI1, and ITGA6 were found to be associated with survival (Z-score >1.5), and therefore were selected to create a risk signature.	('survival', 'CPA', (113, 121))	('ITGA6', 'Gene', (74, 79))	('S14', 'Gene', (0, 3))	('SNAI1', 'Gene', '6615', (63, 68))	('S14', 'Gene', '6208', (0, 3))	('associated with', 'Reg', (97, 112))	('SNAI1', 'Gene', (63, 68))	('CDKN1A', 'Gene', (55, 61))	('expression', 'Var', (41, 51))	('CDKN1A', 'Gene', '1026', (55, 61))	('ITGA6', 'Gene', '3655', (74, 79))
183566	31506430	Cox regression and Kaplan-Meier analyses of individual genes indicated that patients with high expression levels of SNAI1 and ITGA6 presented worse OS (Supplementary Table S4 and Supplementary Fig.	('patients', 'Species', '9606', (76, 84))	('Cox', 'Gene', '1351', (0, 3))	('Cox', 'Gene', (0, 3))	('SNAI1', 'Gene', '6615', (116, 121))	('ITGA6', 'Gene', '3655', (126, 131))	('ITGA6', 'Gene', (126, 131))	('SNAI1', 'Gene', (116, 121))	('high', 'Var', (90, 94))	('expression', 'MPA', (95, 105))
183580	31506430	To reduce the dimensionality of our data, a mathematical algorithm was used, selecting CDKN1A, NOTCH3, CD44, ITGA6, NANOG, and SNAI1 to distinguish tumorspheres from adherent tumor cells.	('NANOG', 'Gene', '79923', (116, 121))	('NANOG', 'Gene', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('ITGA6', 'Gene', (109, 114))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('tumor', 'Disease', (175, 180))	('CD44', 'Var', (103, 107))	('SNAI1', 'Gene', '6615', (127, 132))	('SNAI1', 'Gene', (127, 132))	('tumors', 'Disease', (148, 154))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('CDKN1A', 'Gene', (87, 93))	('CDKN1A', 'Gene', '1026', (87, 93))	('ITGA6', 'Gene', '3655', (109, 114))	('tumor', 'Disease', (148, 153))	('NOTCH3', 'Gene', '4854', (95, 101))	('tumors', 'Disease', 'MESH:D009369', (148, 154))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('NOTCH3', 'Gene', (95, 101))
183584	31506430	In contrast, variability was greater for SCC patients, for whom no significant results were found for p21, CD44, and integrin alpha6, whereas the expression of Notch3, Nanog, and Snail seemed higher in adherent cells than in tumorspheres.	('Notch3', 'Gene', (160, 166))	('Nanog', 'Gene', (168, 173))	('SCC', 'Phenotype', 'HP:0002860', (41, 44))	('Snail', 'Gene', (179, 184))	('patients', 'Species', '9606', (45, 53))	('CD44', 'Var', (107, 111))	('tumors', 'Disease', 'MESH:D009369', (225, 231))	('expression', 'MPA', (146, 156))	('integrin alpha6', 'Gene', (117, 132))	('SCC', 'Gene', '6317', (41, 44))	('integrin alpha6', 'Gene', '3655', (117, 132))	('p21', 'Gene', (102, 105))	('SCC', 'Gene', (41, 44))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('Snail', 'Gene', '6615', (179, 184))	('tumors', 'Phenotype', 'HP:0002664', (225, 231))	('higher', 'PosReg', (192, 198))	('Nanog', 'Gene', '79923', (168, 173))	('p21', 'Gene', '1026', (102, 105))	('tumors', 'Disease', (225, 231))	('Notch3', 'Gene', '4854', (160, 166))
183659	31114327	Patients exhibiting high expression of the HLA-DQB1 had significantly lower recurrence rates than did subgroups with low HLA-DQB1 expression (17.19% vs 47.34% chi2 test P<0.001) (Figure 2B).	('HLA-DQB1', 'Gene', '3119', (43, 51))	('HLA-DQB1', 'Gene', (121, 129))	('high expression', 'Var', (20, 35))	('lower', 'NegReg', (70, 75))	('Patients', 'Species', '9606', (0, 8))	('HLA-DQB1', 'Gene', (43, 51))	('HLA-DQB1', 'Gene', '3119', (121, 129))	('recurrence rates', 'CPA', (76, 92))
183675	31114327	As shown in Figure 4, patients with high HLA-DQB1 levels also had a high lymphocyte infiltration rate and greater levels of CD4 and CD8 (P<0.0001).	('greater', 'PosReg', (106, 113))	('CD4', 'Gene', (124, 127))	('HLA-DQB1', 'Gene', (41, 49))	('patients', 'Species', '9606', (22, 30))	('HLA-DQB1', 'Gene', '3119', (41, 49))	('lymphocyte infiltration rate', 'CPA', (73, 101))	('CD4', 'Gene', '920', (124, 127))	('high lymphocyte', 'Phenotype', 'HP:0100827', (68, 83))	('CD8', 'Gene', (132, 135))	('CD8', 'Gene', '925', (132, 135))	('high', 'Var', (36, 40))
183680	31114327	According to the recent National Lung Screening Trial, low-dose spiral computed tomography screening can sharply increase the number of lung cancer cases diagnosed at an early stage, and thus, more patients will be eligible for curative surgery.	('lung cancer', 'Phenotype', 'HP:0100526', (136, 147))	('low-dose', 'Var', (55, 63))	('patients', 'Species', '9606', (198, 206))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('lung cancer', 'Disease', 'MESH:D008175', (136, 147))	('increase', 'PosReg', (113, 121))	('lung cancer', 'Disease', (136, 147))
183707	31114327	In conclusion, HLA-DQB1 protein expression on tumor cells is a robust predictive biomarker for RFS in early-stage LUAD, and the mechanism may be related to antitumor immunity.	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('RFS', 'Var', (95, 98))	('tumor', 'Disease', (46, 51))	('HLA-DQB1', 'Gene', (15, 23))	('early-stage LUAD', 'Disease', (102, 118))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('LUAD', 'Phenotype', 'HP:0030078', (114, 118))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('tumor', 'Disease', (160, 165))	('HLA-DQB1', 'Gene', '3119', (15, 23))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
183708	31114327	We speculate that early-stage LUAD tumors with high HLA-DQB1 protein expression may present high antigenic potential and trigger the immune system, especially T cells, with more efficient elimination of residual tumor cells after curative resection.	('high antigenic potential', 'MPA', (92, 116))	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('HLA-DQB1', 'Gene', (52, 60))	('high', 'Var', (47, 51))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('LUAD', 'Phenotype', 'HP:0030078', (30, 34))	('tumor', 'Disease', (35, 40))	('LUAD tumors', 'Disease', (30, 41))	('tumor', 'Disease', 'MESH:D009369', (212, 217))	('trigger', 'PosReg', (121, 128))	('LUAD tumors', 'Disease', 'MESH:D009369', (30, 41))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('protein', 'Protein', (61, 68))	('immune', 'CPA', (133, 139))	('HLA-DQB1', 'Gene', '3119', (52, 60))	('tumor', 'Disease', (212, 217))
183712	33473256	miR-708-5p enhances erlotinib/paclitaxel efficacy and overcomes chemoresistance in lung cancer cells Lung cancer is a collection of aggressive tumors generally not diagnosed until late-stage, resulting in high mortality rates.	('lung cancer', 'Disease', 'MESH:D008175', (83, 94))	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('aggressive tumors', 'Disease', (132, 149))	('lung cancer', 'Phenotype', 'HP:0100526', (83, 94))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('aggressive tumors', 'Disease', 'MESH:D001523', (132, 149))	('enhances', 'PosReg', (11, 19))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('miR-708-5p', 'Var', (0, 10))	('miR-708-5p', 'Chemical', '-', (0, 10))	('mortality', 'Disease', (210, 219))	('Lung cancer', 'Disease', 'MESH:D008175', (101, 112))	('lung cancer', 'Disease', (83, 94))	('Lung cancer', 'Phenotype', 'HP:0100526', (101, 112))	('erlotinib/paclitaxel', 'MPA', (20, 40))	('Lung cancer', 'Disease', (101, 112))	('mortality', 'Disease', 'MESH:D003643', (210, 219))	('paclitaxel', 'Chemical', 'MESH:D017239', (30, 40))	('erlotinib', 'Chemical', 'MESH:D000069347', (20, 29))
183719	33473256	Moreover, combination treatment of erlotinib (ERL) or paclitaxel (PAC) with miR-708-5p enhances COX-2 and mPGES-1 protein suppression.	('mPGES-1', 'Gene', '64292', (106, 113))	('miR-708-5p', 'Chemical', '-', (76, 86))	('erlotinib', 'Chemical', 'MESH:D000069347', (35, 44))	('mPGES-1', 'Gene', (106, 113))	('ERL', 'Chemical', 'MESH:D000069347', (46, 49))	('COX-2', 'Enzyme', (96, 101))	('PAC', 'Phenotype', 'HP:0006699', (66, 69))	('miR-708-5p', 'Var', (76, 86))	('paclitaxel', 'Chemical', 'MESH:D017239', (54, 64))	('enhances', 'PosReg', (87, 95))	('combination', 'Interaction', (10, 21))	('PAC', 'Chemical', 'MESH:D017239', (66, 69))	('suppression', 'NegReg', (122, 133))
183720	33473256	We also show that combination chemotherapeutic and miR-708-5p treatment intensifies the anti-proliferative and pro-apoptotic effects of ERL and PAC.	('miR-708-5p', 'Chemical', '-', (51, 61))	('intensifies', 'PosReg', (72, 83))	('anti-proliferative', 'CPA', (88, 106))	('PAC', 'Phenotype', 'HP:0006699', (144, 147))	('miR-708-5p', 'Var', (51, 61))	('ERL', 'Chemical', 'MESH:D000069347', (136, 139))	('pro-apoptotic effects', 'CPA', (111, 132))	('PAC', 'Chemical', 'MESH:D017239', (144, 147))
183722	33473256	While ERL and PAC treatments do not alter resistant cell phenotype alone, combination treatment with miR-708-5p partially restores the chemotherapies' anti-proliferative effects and fully restores their pro-apoptotic qualities.	('PAC', 'Chemical', 'MESH:D017239', (14, 17))	('pro-apoptotic', 'MPA', (203, 216))	('PAC', 'Phenotype', 'HP:0006699', (14, 17))	('ERL', 'Chemical', 'MESH:D000069347', (6, 9))	('miR-708-5p', 'Chemical', '-', (101, 111))	('combination', 'Interaction', (74, 85))	('miR-708-5p', 'Var', (101, 111))	('restores', 'PosReg', (188, 196))	('restores', 'PosReg', (122, 130))	('anti-proliferative effects', 'MPA', (151, 177))
183723	33473256	These data suggest miR-708-5p may have potential combinatory therapeutic value to more efficaciously treat lung tumors while overcoming chemoresistance.	('lung tumors', 'Disease', 'MESH:D008175', (107, 118))	('lung tumors', 'Phenotype', 'HP:0100526', (107, 118))	('chemoresistance', 'CPA', (136, 151))	('overcoming', 'PosReg', (125, 135))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('miR-708-5p', 'Chemical', '-', (19, 29))	('miR-708-5p', 'Var', (19, 29))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('lung tumors', 'Disease', (107, 118))
183731	33473256	While the COX-2/mPGES-1/PGE2 pathway has important homeostatic and immune-related functions, dysregulation of this signaling axis has been shown to have profound roles in cancer.	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('PGE2', 'Chemical', 'MESH:D015232', (24, 28))	('homeostatic', 'MPA', (51, 62))	('cancer', 'Disease', (171, 177))	('mPGES-1', 'Gene', '64292', (16, 23))	('mPGES-1', 'Gene', (16, 23))	('dysregulation', 'Var', (93, 106))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('roles', 'Reg', (162, 167))
183734	33473256	mPGES-1 has also been shown to be overexpressed in cancer, and knockdown of mPGES-1 prevented tumor growth in breast and lung cancer in vivo.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('prevented', 'NegReg', (84, 93))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('mPGES-1', 'Gene', (0, 7))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', (51, 57))	('tumor', 'Disease', (94, 99))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('mPGES-1', 'Gene', '64292', (76, 83))	('breast and lung cancer', 'Disease', 'MESH:D001943', (110, 132))	('lung cancer', 'Phenotype', 'HP:0100526', (121, 132))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('mPGES-1', 'Gene', (76, 83))	('knockdown', 'Var', (63, 72))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('mPGES-1', 'Gene', '64292', (0, 7))
183755	33473256	Here, we demonstrate that chemotherapies induce miR-708-5p expression, which may be through p53 and CHOP.	('miR-708-5p', 'Chemical', '-', (48, 58))	('miR-708-5p expression', 'Var', (48, 69))	('CHOP', 'Gene', '1649', (100, 104))	('p53', 'Gene', (92, 95))	('p53', 'Gene', '7157', (92, 95))	('CHOP', 'Gene', (100, 104))
183756	33473256	Moreover, combination treatment of ERL or PAC with miR-708-5p enhanced the reduction in COX-2 and mPGES-1 protein expression.	('miR-708-5p', 'Chemical', '-', (51, 61))	('PAC', 'Chemical', 'MESH:D017239', (42, 45))	('PAC', 'Phenotype', 'HP:0006699', (42, 45))	('COX-2', 'Protein', (88, 93))	('miR-708-5p', 'Var', (51, 61))	('enhanced', 'PosReg', (62, 70))	('ERL', 'Chemical', 'MESH:D000069347', (35, 38))	('reduction', 'NegReg', (75, 84))	('mPGES-1', 'Gene', '64292', (98, 105))	('combination', 'Interaction', (10, 21))	('mPGES-1', 'Gene', (98, 105))
183757	33473256	We also concluded that combination chemotherapeutic and miR-708-5p treatment intensified the anti-proliferative and pro-apoptotic effects greater than each therapy alone.	('pro-apoptotic effects', 'CPA', (116, 137))	('miR-708-5p', 'Var', (56, 66))	('anti-proliferative', 'CPA', (93, 111))	('intensified', 'PosReg', (77, 88))	('miR-708-5p', 'Chemical', '-', (56, 66))
183760	33473256	While ERL and PAC treatments did not alter cell phenotype alone, combination treatment with miR-708-5p partially restored the chemotherapies' anti-proliferative effects and fully restored their pro-apoptotic qualities.	('restored', 'PosReg', (113, 121))	('PAC', 'Chemical', 'MESH:D017239', (14, 17))	('PAC', 'Phenotype', 'HP:0006699', (14, 17))	('ERL', 'Chemical', 'MESH:D000069347', (6, 9))	('miR-708-5p', 'Chemical', '-', (92, 102))	('miR-708-5p', 'Var', (92, 102))	('pro-apoptotic', 'MPA', (194, 207))	('anti-proliferative effects', 'MPA', (142, 168))
183761	33473256	Researchers have previously described multiple functions for miR-708-5p in chemoresistance.	('chemoresistance', 'CPA', (75, 90))	('miR-708-5p', 'Chemical', '-', (61, 71))	('miR-708-5p', 'Var', (61, 71))
183775	33473256	More specifically, CHOP was significantly positively correlated with miR-708-5p expression in NSCLC (Table 1, p = 0.207, R2 = 0.0418, p = 2.18 x 10-11) and LUSC (Table 1, p = 0.188, R2 = 0.0333, p = 2.32 x 10-5) tumors.	('NSCLC', 'Phenotype', 'HP:0030358', (94, 99))	('miR-708-5p', 'Chemical', '-', (69, 79))	('CHOP', 'Gene', (19, 23))	('tumors', 'Disease', (212, 218))	('tumors', 'Disease', 'MESH:D009369', (212, 218))	('tumors', 'Phenotype', 'HP:0002664', (212, 218))	('LUSC', 'Phenotype', 'HP:0030359', (156, 160))	('NSCLC', 'Disease', (94, 99))	('miR-708-5p expression', 'Var', (69, 90))	('NSCLC', 'Disease', 'MESH:D002289', (94, 99))	('correlated', 'Interaction', (53, 63))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('positively', 'PosReg', (42, 52))	('CHOP', 'Gene', '1649', (19, 23))
183781	33473256	Moreover, high CHOP mRNA expression positively associated with increased survival rates in LUSC patients (Supplementary Figure 1, p = .014, n = 424), following similar patterns seen with miR-708-5p in NSCLC.	('high CHOP', 'Phenotype', 'HP:0007906', (10, 19))	('NSCLC', 'Phenotype', 'HP:0030358', (201, 206))	('increased', 'PosReg', (63, 72))	('survival rates', 'CPA', (73, 87))	('CHOP', 'Gene', (15, 19))	('miR-708-5p', 'Chemical', '-', (187, 197))	('NSCLC', 'Disease', (201, 206))	('high', 'Var', (10, 14))	('patients', 'Species', '9606', (96, 104))	('LUSC', 'Phenotype', 'HP:0030359', (91, 95))	('LUSC', 'Disease', (91, 95))	('NSCLC', 'Disease', 'MESH:D002289', (201, 206))	('CHOP', 'Gene', '1649', (15, 19))
183783	33473256	Next, we analyzed how miR-708-5p expression affected survival rates in p53 WT and mutant (MUT) tumors.	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('p53', 'Gene', (71, 74))	('p53', 'Gene', '7157', (71, 74))	('miR-708-5p', 'Chemical', '-', (22, 32))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumors', 'Disease', (95, 101))	('mutant', 'Var', (82, 88))
183784	33473256	miR-708-5p expression had no effect on survival in LUAD WT (Supplementary Figure 2A, p = 0.79, n = 240) or MUT (Supplementary Figure 2B, p = 0.45, n = 263) p53 tumors.	('miR-708-5p', 'Var', (0, 10))	('LUAD', 'Phenotype', 'HP:0030078', (51, 55))	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('p53', 'Gene', (156, 159))	('p53', 'Gene', '7157', (156, 159))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('tumors', 'Disease', (160, 166))	('miR-708-5p', 'Chemical', '-', (0, 10))	('tumors', 'Disease', 'MESH:D009369', (160, 166))
183785	33473256	While miR-708-5p levels in LUSC WT p53 tumors had no effect on survival (Supplementary Figure 2C, p = 0.91, n = 70), high miR-708-5p expression significantly enhanced survival in LUSC MUT p53 tumors (Supplementary Figure 2D, p = 0.041, n = 389).	('p53', 'Gene', (35, 38))	('tumors', 'Disease', (192, 198))	('high miR-708-5p', 'Var', (117, 132))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumors', 'Disease', (39, 45))	('tumors', 'Disease', 'MESH:D009369', (192, 198))	('survival', 'MPA', (167, 175))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('p53', 'Gene', '7157', (188, 191))	('enhanced', 'PosReg', (158, 166))	('p53', 'Gene', (188, 191))	('miR-708-5p', 'Var', (122, 132))	('LUSC', 'Phenotype', 'HP:0030359', (179, 183))	('LUSC', 'Phenotype', 'HP:0030359', (27, 31))	('miR-708-5p', 'Chemical', '-', (6, 16))	('p53', 'Gene', '7157', (35, 38))	('tumors', 'Phenotype', 'HP:0002664', (192, 198))	('miR-708-5p', 'Chemical', '-', (122, 132))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))
183786	33473256	Collectively, these data suggest that high miR-708-5p may improve survival rates in LUSC patients containing p53 mutations.	('survival rates', 'CPA', (66, 80))	('improve', 'PosReg', (58, 65))	('miR-708-5p', 'Chemical', '-', (43, 53))	('miR-708-5p', 'Var', (43, 53))	('LUSC', 'Disease', (84, 88))	('mutations', 'Var', (113, 122))	('p53', 'Gene', (109, 112))	('p53', 'Gene', '7157', (109, 112))	('patients', 'Species', '9606', (89, 97))	('LUSC', 'Phenotype', 'HP:0030359', (84, 88))
183789	33473256	We found that A549 cells transiently transfected with miR-708-5p induced p53 and CHOP protein expression while simultaneously reducing COX-2, mPGES-1, and Survivin protein levels (Figure 2B).	('A549', 'CellLine', 'CVCL:0023', (14, 18))	('p53', 'Gene', (73, 76))	('reducing', 'NegReg', (126, 134))	('induced', 'PosReg', (65, 72))	('CHOP', 'Gene', '1649', (81, 85))	('mPGES-1', 'Gene', '64292', (142, 149))	('p53', 'Gene', '7157', (73, 76))	('mPGES-1', 'Gene', (142, 149))	('COX-2', 'MPA', (135, 140))	('miR-708-5p', 'Chemical', '-', (54, 64))	('CHOP', 'Gene', (81, 85))	('miR-708-5p', 'Var', (54, 64))	('Survivin protein levels', 'MPA', (155, 178))
183790	33473256	Given miR-708-5p's ability to enhance p53 and CHOP protein expression, we examined the molecular and phenotypic consequences of combinatory miR-708-5p and chemotherapy treatments in lung cancer cells.	('miR-708-5p', 'Var', (6, 16))	('p53', 'Gene', (38, 41))	('CHOP', 'Gene', (46, 50))	('p53', 'Gene', '7157', (38, 41))	('lung cancer', 'Disease', (182, 193))	('lung cancer', 'Phenotype', 'HP:0100526', (182, 193))	('miR-708-5p', 'Chemical', '-', (140, 150))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('CHOP', 'Gene', '1649', (46, 50))	('enhance', 'PosReg', (30, 37))	('lung cancer', 'Disease', 'MESH:D008175', (182, 193))	('miR-708-5p', 'Chemical', '-', (6, 16))
183803	33473256	First, we examined whether ERL and miR-708-5p treatment enhanced anti-proliferative activities greater than either treatment alone.	('miR-708-5p', 'Chemical', '-', (35, 45))	('miR-708-5p', 'Var', (35, 45))	('anti-proliferative activities', 'CPA', (65, 94))	('ERL', 'Chemical', 'MESH:D000069347', (27, 30))	('enhanced', 'PosReg', (56, 64))
183808	33473256	Interestingly, ERL + miR-708-5p treatment further reduced the percent of A549 cells in G1 and G2/M phase to 43% and significantly reduced the number of cells in S phase by half (Figure 4, p < 0.01, n >= 3).	('A549', 'CellLine', 'CVCL:0023', (73, 77))	('ERL + miR-708-5p', 'Var', (15, 31))	('reduced', 'NegReg', (130, 137))	('reduced', 'NegReg', (50, 57))	('ERL', 'Chemical', 'MESH:D000069347', (15, 18))	('miR-708-5p', 'Chemical', '-', (21, 31))
183810	33473256	Collectively, these data reveal that ERL and miR-708-5p cooperate to enhance anti-proliferative activities in lung cancer cells.	('ERL', 'Chemical', 'MESH:D000069347', (37, 40))	('ERL', 'Gene', (37, 40))	('lung cancer', 'Disease', 'MESH:D008175', (110, 121))	('miR-708-5p', 'Var', (45, 55))	('enhance', 'PosReg', (69, 76))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('lung cancer', 'Disease', (110, 121))	('lung cancer', 'Phenotype', 'HP:0100526', (110, 121))	('anti-proliferative activities', 'CPA', (77, 106))	('miR-708-5p', 'Chemical', '-', (45, 55))
183811	33473256	While ERL and miR-708-5p have both been shown to induce apoptosis in lung cancer cells, researchers have not studied their combinatory potential.	('lung cancer', 'Disease', 'MESH:D008175', (69, 80))	('miR-708-5p', 'Chemical', '-', (14, 24))	('miR-708-5p', 'Var', (14, 24))	('ERL', 'Chemical', 'MESH:D000069347', (6, 9))	('ERL', 'Gene', (6, 9))	('lung cancer', 'Disease', (69, 80))	('induce', 'PosReg', (49, 55))	('lung cancer', 'Phenotype', 'HP:0100526', (69, 80))	('apoptosis', 'CPA', (56, 65))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
183813	33473256	We observed that ERL significantly increased PS+ cell number compared to vehicle treatment (Figure 5, p < 0.05, n >= 3).	('ERL', 'Var', (17, 20))	('increased', 'PosReg', (35, 44))	('ERL', 'Chemical', 'MESH:D000069347', (17, 20))	('PS', 'Chemical', 'MESH:D010718', (45, 47))	('PS+ cell number', 'CPA', (45, 60))
183816	33473256	Furthermore, ERL + miR-708-5p increased late apoptotic events while no other treatment was significantly different from our vehicle control (Figure 5F and 5H, p < 0.05, n >= 3).	('ERL', 'Chemical', 'MESH:D000069347', (13, 16))	('5H', 'Chemical', '-', (155, 157))	('ERL + miR-708-5p', 'Var', (13, 29))	('miR-708-5p', 'Chemical', '-', (19, 29))	('increased', 'PosReg', (30, 39))	('late apoptotic events', 'CPA', (40, 61))
183817	33473256	We conclude that while ERL induces apoptosis, ERL + miR-708-5p intensifies lung cancer cell death.	('intensifies', 'PosReg', (63, 74))	('lung cancer', 'Disease', (75, 86))	('death', 'Disease', (92, 97))	('ERL', 'Chemical', 'MESH:D000069347', (23, 26))	('death', 'Disease', 'MESH:D003643', (92, 97))	('ERL', 'Chemical', 'MESH:D000069347', (46, 49))	('miR-708-5p', 'Chemical', '-', (52, 62))	('lung cancer', 'Phenotype', 'HP:0100526', (75, 86))	('ERL + miR-708-5p', 'Var', (46, 62))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('lung cancer', 'Disease', 'MESH:D008175', (75, 86))	('apoptosis', 'CPA', (35, 44))
183818	33473256	These data, as well as the Ki-67 data, reveal an additive anti-tumor ERL and miR-708-5p combination therapy that reduces proliferation and survival greater than either treatment alone.	('tumor', 'Disease', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('Ki-67', 'Gene', (27, 32))	('proliferation', 'CPA', (121, 134))	('miR-708-5p', 'Chemical', '-', (77, 87))	('ERL', 'Chemical', 'MESH:D000069347', (69, 72))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('miR-708-5p', 'Var', (77, 87))	('reduces', 'NegReg', (113, 120))	('Ki-67', 'Gene', '17345', (27, 32))	('survival', 'CPA', (139, 147))
183823	33473256	Next, we examined how PAC and miR-708-5p were altering the cell cycle.	('PAC', 'Chemical', 'MESH:D017239', (22, 25))	('cell cycle', 'CPA', (59, 69))	('miR-708-5p', 'Chemical', '-', (30, 40))	('altering', 'Reg', (46, 54))	('PAC', 'Phenotype', 'HP:0006699', (22, 25))	('miR-708-5p', 'Var', (30, 40))
183824	33473256	We discovered that PAC + miR-708-5p treatment enhanced the percent of A549 cells in G0 to 20.6%, albeit significantly less than PAC (31%) and PAC + NC miR (35%) treatments (Figure 6, p < 0.01, n >= 3).	('PAC', 'Chemical', 'MESH:D017239', (142, 145))	('PAC', 'Chemical', 'MESH:D017239', (128, 131))	('less', 'NegReg', (118, 122))	('miR', 'Gene', '220972', (151, 154))	('miR', 'Gene', (151, 154))	('A549', 'CellLine', 'CVCL:0023', (70, 74))	('miR', 'Gene', '220972', (25, 28))	('PAC', 'Phenotype', 'HP:0006699', (142, 145))	('miR', 'Gene', (25, 28))	('PAC', 'Phenotype', 'HP:0006699', (128, 131))	('PAC', 'Chemical', 'MESH:D017239', (19, 22))	('enhanced', 'PosReg', (46, 54))	('PAC', 'Var', (19, 22))	('PAC', 'Phenotype', 'HP:0006699', (19, 22))	('miR-708-5p', 'Chemical', '-', (25, 35))
183826	33473256	Moreover, PAC + miR-708-5p further decreased the G1 population to 13%, while significantly increasing the percent of A549 cells in G2/M phase (Figure 6, p < 0.0001, n >= 3).	('increasing', 'PosReg', (91, 101))	('PAC', 'Phenotype', 'HP:0006699', (10, 13))	('G2/M phase', 'CPA', (131, 141))	('PAC + miR-708-5p', 'Var', (10, 26))	('A549', 'CellLine', 'CVCL:0023', (117, 121))	('decreased', 'NegReg', (35, 44))	('miR-708-5p', 'Chemical', '-', (16, 26))	('G1 population', 'CPA', (49, 62))	('PAC', 'Chemical', 'MESH:D017239', (10, 13))
183830	33473256	Therefore, miR-708-5p enhanced the anti-proliferative effects of PAC, as it further decreased the percent of G1 cells while also enhancing the PAC's G2/M-arresting effects (Figure 6, p < 0.0001, n >= 3).	('miR-708-5p', 'Var', (11, 21))	('PAC', 'Chemical', 'MESH:D017239', (65, 68))	('G2/M-arresting effects', 'CPA', (149, 171))	('PAC', 'Phenotype', 'HP:0006699', (143, 146))	('miR-708-5p', 'Chemical', '-', (11, 21))	('PAC', 'Phenotype', 'HP:0006699', (65, 68))	('decreased', 'NegReg', (84, 93))	('enhancing', 'PosReg', (129, 138))	('PAC', 'Chemical', 'MESH:D017239', (143, 146))	('enhanced', 'PosReg', (22, 30))	('anti-proliferative effects', 'MPA', (35, 61))
183832	33473256	Given PAC's anti-tumor characteristics, as well as miR-708-5p's pro-apoptotic functions, we studied the combinatory effects of these two treatments in lung cancer cells.	('miR-708-5p', 'Chemical', '-', (51, 61))	('tumor', 'Disease', (17, 22))	('miR-708-5p', 'Var', (51, 61))	('lung cancer', 'Phenotype', 'HP:0100526', (151, 162))	('PAC', 'Phenotype', 'HP:0006699', (6, 9))	('lung cancer', 'Disease', 'MESH:D008175', (151, 162))	('lung cancer', 'Disease', (151, 162))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('PAC', 'Chemical', 'MESH:D017239', (6, 9))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
183835	33473256	Conversely, combination PAC + miR-708-5p dramatically increased the percent of PS+ A549 cells from 11.5% to 39% (Figure 7, p < 0.0001, n >= 3).	('PAC', 'Chemical', 'MESH:D017239', (24, 27))	('PAC + miR-708-5p', 'Var', (24, 40))	('A549', 'CellLine', 'CVCL:0023', (83, 87))	('PS', 'Chemical', 'MESH:D010718', (79, 81))	('PAC', 'Phenotype', 'HP:0006699', (24, 27))	('increased', 'PosReg', (54, 63))	('miR-708-5p', 'Chemical', '-', (30, 40))	('miR-708-5p', 'Var', (30, 40))
183836	33473256	Moreover, PAC + miR-708-5p treatment increased the number of early and late apoptotic/dead cells compared to vehicle control (Figure 7, p < .05, n >= 3).	('PAC', 'Phenotype', 'HP:0006699', (10, 13))	('PAC + miR-708-5p', 'Var', (10, 26))	('miR-708-5p', 'Chemical', '-', (16, 26))	('increased', 'PosReg', (37, 46))	('PAC', 'Chemical', 'MESH:D017239', (10, 13))
183838	33473256	These data paired with our proliferation data form the basis for exploring the therapeutic combinatory potential of PAC and miR-708-5p in lung cancer.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('lung cancer', 'Disease', 'MESH:D008175', (138, 149))	('PAC', 'Phenotype', 'HP:0006699', (116, 119))	('miR-708-5p', 'Chemical', '-', (124, 134))	('miR-708-5p', 'Var', (124, 134))	('lung cancer', 'Disease', (138, 149))	('PAC', 'Chemical', 'MESH:D017239', (116, 119))	('lung cancer', 'Phenotype', 'HP:0100526', (138, 149))
183843	33473256	We found that COX-2 protein expression was higher in our A549-ER and A549-PR cells compared to A549-WT cells (Figure 8A).	('higher', 'PosReg', (43, 49))	('protein', 'Protein', (20, 27))	('A549', 'CellLine', 'CVCL:0023', (69, 73))	('A549', 'CellLine', 'CVCL:0023', (95, 99))	('A549-PR', 'Var', (69, 76))	('A549-ER', 'Var', (57, 64))	('A549', 'CellLine', 'CVCL:0023', (57, 61))	('COX-2', 'Gene', (14, 19))
183844	33473256	Next, we found that miR-708-5p expression was significantly lower at baseline in A549-ER (-69%) and A549-PR (-66%) cells compared to A549-WT cells (Figure 8B, p < .01, n = 3).	('A549', 'CellLine', 'CVCL:0023', (100, 104))	('A549-PR', 'Var', (100, 107))	('A549-ER', 'Var', (81, 88))	('A549', 'CellLine', 'CVCL:0023', (81, 85))	('miR-708-5p', 'Chemical', '-', (20, 30))	('miR-708-5p', 'Gene', (20, 30))	('A549', 'CellLine', 'CVCL:0023', (133, 137))	('lower', 'NegReg', (60, 65))
183848	33473256	Given enhanced AA signaling paired with decreased miR-708-5p expression in our resistant cell lines, we explored the ability of miR-708-5p to resensitize A549-ER and A549-PR cells to ERL and PAC treatments, respectively.	('A549', 'CellLine', 'CVCL:0023', (154, 158))	('miR-708-5p', 'Chemical', '-', (128, 138))	('enhanced', 'PosReg', (6, 14))	('PAC', 'Chemical', 'MESH:D017239', (191, 194))	('miR-708-5p', 'Var', (128, 138))	('A549', 'CellLine', 'CVCL:0023', (166, 170))	('miR-708-5p', 'Chemical', '-', (50, 60))	('PAC', 'Phenotype', 'HP:0006699', (191, 194))	('ERL', 'Chemical', 'MESH:D000069347', (183, 186))	('AA signaling', 'MPA', (15, 27))
183854	33473256	On the other hand, ERL + miR-708-5p significantly increased the number of PS+ cells from 12% in vehicle samples to 48% in ERL + miR-708-5p samples (Figure 10A and 10B, p < .0001, n >= 3).	('miR-708-5p', 'Chemical', '-', (128, 138))	('ERL', 'Chemical', 'MESH:D000069347', (122, 125))	('ERL + miR-708-5p', 'Var', (19, 35))	('increased', 'PosReg', (50, 59))	('PS', 'Chemical', 'MESH:D010718', (74, 76))	('ERL + miR-708-5p', 'Var', (122, 138))	('ERL', 'Chemical', 'MESH:D000069347', (19, 22))	('miR-708-5p', 'Chemical', '-', (25, 35))
183855	33473256	ERL + miR-708-5p treatment significantly elevated the percent of early apoptotic and late apoptotic/dead cells compared to vehicle, ERL, and ERL + NC miR treatments (Figure 10F-10H, p < .0001, n >= 3).	('miR', 'Gene', '220972', (150, 153))	('miR', 'Gene', (150, 153))	('ERL', 'Var', (0, 3))	('ERL', 'Chemical', 'MESH:D000069347', (0, 3))	('miR', 'Gene', '220972', (6, 9))	('ERL', 'Chemical', 'MESH:D000069347', (141, 144))	('miR', 'Gene', (6, 9))	('elevated', 'PosReg', (41, 49))	('ERL', 'Chemical', 'MESH:D000069347', (132, 135))	('miR-708-5p', 'Chemical', '-', (6, 16))
183856	33473256	Collectively, these data suggest that ERL + miR-708-5p represses proliferation and stimulates apoptosis in ERL resistant lung cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('proliferation', 'CPA', (65, 78))	('lung cancer', 'Disease', 'MESH:D008175', (121, 132))	('represses', 'NegReg', (55, 64))	('ERL', 'Chemical', 'MESH:D000069347', (38, 41))	('lung cancer', 'Disease', (121, 132))	('miR-708-5p', 'Chemical', '-', (44, 54))	('lung cancer', 'Phenotype', 'HP:0100526', (121, 132))	('ERL', 'Chemical', 'MESH:D000069347', (107, 110))	('stimulates', 'PosReg', (83, 93))	('apoptosis', 'CPA', (94, 103))	('ERL + miR-708-5p', 'Var', (38, 54))
183860	33473256	Conversely, combination treatment of PAC + miR-708-5p significantly reduced the percent of proliferating A549-PR cells from 95 to 82% (Figure 11A and 11B, p < .05, n >= 3).	('miR-708-5p', 'Chemical', '-', (43, 53))	('PAC', 'Chemical', 'MESH:D017239', (37, 40))	('PAC', 'Var', (37, 40))	('A549', 'CellLine', 'CVCL:0023', (105, 109))	('reduced', 'NegReg', (68, 75))	('PAC', 'Phenotype', 'HP:0006699', (37, 40))
183861	33473256	More specifically, it appears PAC + miR-708-5p is reducing proliferation by driving A549-PR cells into G0 phase, as well as reducing the percent of cells in S phase by 5.4% (Figure 11, p < .001, n >= 3).	('proliferation', 'CPA', (59, 72))	('PAC + miR-708-5p', 'Var', (30, 46))	('reducing', 'NegReg', (124, 132))	('miR-708-5p', 'Chemical', '-', (36, 46))	('PAC', 'Chemical', 'MESH:D017239', (30, 33))	('A549', 'CellLine', 'CVCL:0023', (84, 88))	('reducing', 'NegReg', (50, 58))	('PAC', 'Phenotype', 'HP:0006699', (30, 33))
183863	33473256	Lastly, PAC + miR-708-5p significantly increased the G2/M A549-PR population by 10-16% compared to other treatments (Figure 11, p < .0001, n >= 3).	('G2/M A549-PR population', 'CPA', (53, 76))	('PAC', 'Chemical', 'MESH:D017239', (8, 11))	('miR-708-5p', 'Chemical', '-', (14, 24))	('A549', 'CellLine', 'CVCL:0023', (58, 62))	('PAC', 'Phenotype', 'HP:0006699', (8, 11))	('PAC + miR-708-5p', 'Var', (8, 24))	('increased', 'PosReg', (39, 48))
183868	33473256	Moreover, it appears that PAC + miR-708-5p treatment is amplifying both early apoptotic and late apoptotic/dead events compared to other treatments in A549-PR cells (Figure 12, p < .01, n >= 3).	('A549', 'CellLine', 'CVCL:0023', (151, 155))	('miR-708-5p', 'Chemical', '-', (32, 42))	('PAC', 'Chemical', 'MESH:D017239', (26, 29))	('amplifying', 'PosReg', (56, 66))	('PAC + miR-708-5p', 'Var', (26, 42))	('PAC', 'Phenotype', 'HP:0006699', (26, 29))
183869	33473256	Together, these results suggest miR-708-5p may be an important component of PAC resistance in lung cancer cells.	('lung cancer', 'Disease', 'MESH:D008175', (94, 105))	('PAC', 'Chemical', 'MESH:D017239', (76, 79))	('miR-708-5p', 'Chemical', '-', (32, 42))	('miR-708-5p', 'Var', (32, 42))	('PAC', 'Phenotype', 'HP:0006699', (76, 79))	('lung cancer', 'Disease', (94, 105))	('lung cancer', 'Phenotype', 'HP:0100526', (94, 105))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
183870	33473256	Co-treatment of PAC + miR-708-5p helps to overcome resistance, highlighting the therapeutic potential of miR-708-5p in naive and chemotherapeutic-resistant lung tumors.	('lung tumors', 'Disease', (156, 167))	('tumors', 'Phenotype', 'HP:0002664', (161, 167))	('lung tumors', 'Phenotype', 'HP:0100526', (156, 167))	('PAC', 'Chemical', 'MESH:D017239', (16, 19))	('miR-708-5p', 'Chemical', '-', (105, 115))	('lung tumors', 'Disease', 'MESH:D008175', (156, 167))	('miR-708-5p', 'Var', (105, 115))	('miR-708-5p', 'Chemical', '-', (22, 32))	('PAC', 'Phenotype', 'HP:0006699', (16, 19))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))
183880	33473256	Moreover, combinatory treatments of chemotherapies and miR-708-5p suppress lung cancer cell proliferation and survival greater than either treatment alone (Figures 4-7).	('lung cancer', 'Disease', (75, 86))	('lung cancer', 'Phenotype', 'HP:0100526', (75, 86))	('miR-708-5p', 'Chemical', '-', (55, 65))	('suppress', 'NegReg', (66, 74))	('miR-708-5p', 'Var', (55, 65))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('lung cancer', 'Disease', 'MESH:D008175', (75, 86))	('survival', 'CPA', (110, 118))
183883	33473256	Interestingly, miR-708-5p also induced p53 and CHOP protein expression, suggesting a novel positive feedback loop (Figure 2).	('CHOP', 'Gene', '1649', (47, 51))	('miR-708-5p', 'Chemical', '-', (15, 25))	('induced', 'PosReg', (31, 38))	('miR-708-5p', 'Var', (15, 25))	('CHOP', 'Gene', (47, 51))	('p53', 'Gene', (39, 42))	('p53', 'Gene', '7157', (39, 42))
183885	33473256	We found that COX-2 expression was greater and miR-708-5p lower in our resistant cell lines compared with chemosensitive lung cancer cells (A549-WT, Figure 8).	('A549', 'CellLine', 'CVCL:0023', (140, 144))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('lung cancer', 'Disease', 'MESH:D008175', (121, 132))	('expression', 'MPA', (20, 30))	('greater', 'PosReg', (35, 42))	('lower', 'NegReg', (58, 63))	('lung cancer', 'Disease', (121, 132))	('miR-708-5p', 'Chemical', '-', (47, 57))	('lung cancer', 'Phenotype', 'HP:0100526', (121, 132))	('miR-708-5p', 'Var', (47, 57))	('COX-2', 'Gene', (14, 19))
183888	33473256	Addition of miR-708-5p did however restore chemosensitivity and anti-tumor effects to our ERL and PAC resistant cells (Figures 9-12).	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor', 'Disease', (69, 74))	('chemosensitivity', 'MPA', (43, 59))	('restore', 'PosReg', (35, 42))	('ERL', 'Chemical', 'MESH:D000069347', (90, 93))	('miR-708-5p', 'Chemical', '-', (12, 22))	('miR-708-5p', 'Var', (12, 22))	('PAC', 'Chemical', 'MESH:D017239', (98, 101))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('PAC', 'Phenotype', 'HP:0006699', (98, 101))
183889	33473256	Collectively, our data reveal a potent synergy between chemotherapies and miR-708-5p in suppressing lung cancer cell proliferation and survival.	('suppressing', 'NegReg', (88, 99))	('lung cancer', 'Phenotype', 'HP:0100526', (100, 111))	('lung cancer', 'Disease', (100, 111))	('miR-708-5p', 'Chemical', '-', (74, 84))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('miR-708-5p', 'Var', (74, 84))	('survival', 'CPA', (135, 143))	('lung cancer', 'Disease', 'MESH:D008175', (100, 111))
183890	33473256	This work provides the foundation for studying the therapeutic value of miR-708-5p in vivo in combination with frontline chemotherapies in lung cancer.	('lung cancer', 'Disease', (139, 150))	('miR-708-5p', 'Chemical', '-', (72, 82))	('miR-708-5p', 'Var', (72, 82))	('lung cancer', 'Disease', 'MESH:D008175', (139, 150))	('lung cancer', 'Phenotype', 'HP:0100526', (139, 150))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
183891	33473256	Although we present a novel enhancement in anti-tumor activity between chemotherapies and miR-708-5p, many questions remain.	('tumor', 'Disease', (48, 53))	('enhancement', 'PosReg', (28, 39))	('miR-708-5p', 'Chemical', '-', (90, 100))	('miR-708-5p', 'Var', (90, 100))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
183892	33473256	First, we must decipher the most efficacious combinatory cancer treatments with miR-708-5p.	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('cancer', 'Disease', (57, 63))	('miR-708-5p', 'Chemical', '-', (80, 90))	('miR-708-5p', 'Var', (80, 90))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))
183893	33473256	This should focus first on testing the ability of miR-708-5p to improve outcomes in combination with the standard of care in various lung cancer subtypes.	('improve', 'PosReg', (64, 71))	('lung cancer', 'Disease', (133, 144))	('lung cancer', 'Phenotype', 'HP:0100526', (133, 144))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('miR-708-5p', 'Chemical', '-', (50, 60))	('miR-708-5p', 'Var', (50, 60))	('lung cancer', 'Disease', 'MESH:D008175', (133, 144))	('outcomes', 'MPA', (72, 80))
183895	33473256	Therefore, miR-708-5p targeting of COX-2 may prevent and/or overcome ERL and PAC resistance.	('COX-2', 'Gene', (35, 40))	('PAC', 'Phenotype', 'HP:0006699', (77, 80))	('miR-708-5p targeting', 'Var', (11, 31))	('ERL', 'Chemical', 'MESH:D000069347', (69, 72))	('prevent', 'NegReg', (45, 52))	('PAC', 'Chemical', 'MESH:D017239', (77, 80))	('overcome', 'NegReg', (60, 68))	('miR-708-5p', 'Chemical', '-', (11, 21))
183899	33473256	One of the largest gaps in knowledge is identifying how miR-708-5p is adding to the anti-tumor activities of ERL and PAC.	('PAC', 'Chemical', 'MESH:D017239', (117, 120))	('miR-708-5p', 'Var', (56, 66))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('PAC', 'Phenotype', 'HP:0006699', (117, 120))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('miR-708-5p', 'Chemical', '-', (56, 66))	('adding', 'PosReg', (70, 76))	('tumor', 'Disease', (89, 94))	('ERL', 'Chemical', 'MESH:D000069347', (109, 112))
183900	33473256	Both chemotherapies have distinct tumor suppressive mechanisms, yet miR-708-5p is involved in both.	('tumor', 'Disease', (34, 39))	('miR-708-5p', 'Var', (68, 78))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('miR-708-5p', 'Chemical', '-', (68, 78))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
183901	33473256	Therefore, it is likely that miR-708-5p is targeting genes responsible for promoting resistance and survival.	('resistance', 'CPA', (85, 95))	('miR-708-5p', 'Chemical', '-', (29, 39))	('survival', 'CPA', (100, 108))	('miR-708-5p', 'Var', (29, 39))	('promoting', 'PosReg', (75, 84))
183902	33473256	We have identified several pro-survival genes involved in resistance that miR-708-5p is targeting in our lung cancer cells.	('lung cancer', 'Phenotype', 'HP:0100526', (105, 116))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('lung cancer', 'Disease', 'MESH:D008175', (105, 116))	('miR-708-5p', 'Chemical', '-', (74, 84))	('miR-708-5p', 'Var', (74, 84))	('lung cancer', 'Disease', (105, 116))
183903	33473256	First, we have previously shown that miR-708-5p targets COX-2 and mPGES-1 expression in lung cancer cells.	('expression', 'MPA', (74, 84))	('targets', 'Reg', (48, 55))	('lung cancer', 'Disease', (88, 99))	('mPGES-1', 'Gene', '64292', (66, 73))	('mPGES-1', 'Gene', (66, 73))	('lung cancer', 'Phenotype', 'HP:0100526', (88, 99))	('miR-708-5p', 'Chemical', '-', (37, 47))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('miR-708-5p', 'Var', (37, 47))	('lung cancer', 'Disease', 'MESH:D008175', (88, 99))	('COX-2', 'Gene', (56, 61))
183904	33473256	In this study, we show that while ERL and PAC can partially suppress COX-2 expression, miR-708-5p further represses COX-2 protein levels while also reducing mPGES-1 protein expression (Figure 3).	('PAC', 'Chemical', 'MESH:D017239', (42, 45))	('COX-2', 'Gene', (69, 74))	('mPGES-1', 'Gene', (157, 164))	('miR-708-5p', 'Var', (87, 97))	('miR-708-5p', 'Chemical', '-', (87, 97))	('PAC', 'Phenotype', 'HP:0006699', (42, 45))	('ERL', 'Chemical', 'MESH:D000069347', (34, 37))	('COX-2 protein levels', 'MPA', (116, 136))	('represses', 'NegReg', (106, 115))	('suppress', 'NegReg', (60, 68))	('reducing', 'NegReg', (148, 156))	('mPGES-1', 'Gene', '64292', (157, 164))	('expression', 'MPA', (75, 85))
183907	33473256	Interestingly, miR-708-5p co-treatment with either chemotherapy resulted in a pronounced reduction in Survivin protein levels (Figure 3).	('miR-708-5p', 'Var', (15, 25))	('reduction', 'NegReg', (89, 98))	('miR-708-5p', 'Chemical', '-', (15, 25))	('Survivin protein levels', 'MPA', (102, 125))
183908	33473256	This combinatory inhibition of primary oncogenic drivers with chemotherapies as well as compensatory signaling with miR-708-5p appears to be highly effective at reducing lung cancer cell proliferation while enhancing cell death.	('death', 'Disease', (222, 227))	('reducing', 'NegReg', (161, 169))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('lung cancer', 'Disease', 'MESH:D008175', (170, 181))	('miR-708-5p', 'Chemical', '-', (116, 126))	('miR-708-5p', 'Var', (116, 126))	('lung cancer', 'Disease', (170, 181))	('enhancing', 'PosReg', (207, 216))	('lung cancer', 'Phenotype', 'HP:0100526', (170, 181))	('death', 'Disease', 'MESH:D003643', (222, 227))
183910	33473256	Furthermore, miR-708-5p resensitized resistant cells to their respective chemotherapy (Figures 9-12).	('resensitized', 'PosReg', (24, 36))	('miR-708-5p', 'Chemical', '-', (13, 23))	('miR-708-5p', 'Var', (13, 23))
183911	33473256	Collectively, these data suggest that miR-708-5p may act dually in resistance by preventing as well as overcoming acquired resistance in lung cancer cells.	('acquired resistance', 'MPA', (114, 133))	('lung cancer', 'Disease', (137, 148))	('overcoming', 'PosReg', (103, 113))	('lung cancer', 'Phenotype', 'HP:0100526', (137, 148))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('lung cancer', 'Disease', 'MESH:D008175', (137, 148))	('miR-708-5p', 'Chemical', '-', (38, 48))	('miR-708-5p', 'Var', (38, 48))
183912	33473256	Given miR-708-5p's targeting of numerous pro-survival genes, it is likely COX-2, mPGES-1, and Survivin repression is only partly responsible for the tumor suppressive changes we have seen in lung cancer cells.	('miR-708-5p', 'Var', (6, 16))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('lung cancer', 'Disease', 'MESH:D008175', (191, 202))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('tumor', 'Disease', (149, 154))	('miR-708-5p', 'Chemical', '-', (6, 16))	('lung cancer', 'Disease', (191, 202))	('lung cancer', 'Phenotype', 'HP:0100526', (191, 202))	('mPGES-1', 'Gene', '64292', (81, 88))	('mPGES-1', 'Gene', (81, 88))
183913	33473256	While we have identified several miR-708-5p targets possibly involved in chemoresistance, we did have not investigated pro-apoptotic pathways miR-708-5p may be activating.	('involved', 'Reg', (61, 69))	('miR-708-5p', 'Chemical', '-', (33, 43))	('miR-708-5p', 'Chemical', '-', (142, 152))	('miR-708-5p', 'Var', (142, 152))	('activating', 'PosReg', (160, 170))
183915	33473256	Figure 2 reveals that miR-708-5p alone can induce both CHOP and p53 protein expression.	('p53', 'Gene', (64, 67))	('CHOP', 'Gene', '1649', (55, 59))	('miR-708-5p', 'Chemical', '-', (22, 32))	('miR-708-5p', 'Var', (22, 32))	('induce', 'PosReg', (43, 49))	('CHOP', 'Gene', (55, 59))	('p53', 'Gene', '7157', (64, 67))
183916	33473256	Additionally, combination treatment of ERL/PAC and miR-708-5p amplified CHOP and p53 protein expression greater than either treatment alone (Figure 3).	('miR-708-5p', 'Chemical', '-', (51, 61))	('CHOP', 'Gene', (72, 76))	('PAC', 'Phenotype', 'HP:0006699', (43, 46))	('miR-708-5p', 'Var', (51, 61))	('amplified', 'PosReg', (62, 71))	('p53', 'Gene', (81, 84))	('CHOP', 'Gene', '1649', (72, 76))	('p53', 'Gene', '7157', (81, 84))	('PAC', 'Chemical', 'MESH:D017239', (43, 46))	('ERL', 'Chemical', 'MESH:D000069347', (39, 42))
183917	33473256	How miR-708-5p is inducing CHOP and p53 expression remains enigmatic.	('expression', 'MPA', (40, 50))	('miR-708-5p', 'Chemical', '-', (4, 14))	('inducing', 'PosReg', (18, 26))	('miR-708-5p', 'Var', (4, 14))	('p53', 'Gene', (36, 39))	('p53', 'Gene', '7157', (36, 39))	('CHOP', 'Gene', '1649', (27, 31))	('CHOP', 'Gene', (27, 31))
183918	33473256	It is most likely that miR-708-5p is indirectly increasing their expression by repressing pro-survival signaling.	('pro-survival signaling', 'MPA', (90, 112))	('expression', 'MPA', (65, 75))	('increasing', 'PosReg', (48, 58))	('miR-708-5p', 'Var', (23, 33))	('miR-708-5p', 'Chemical', '-', (23, 33))	('repressing', 'NegReg', (79, 89))
183922	33473256	There also may be other stress-associated transcription factors promoting miR-708-5p expression.	('promoting', 'PosReg', (64, 73))	('miR-708-5p', 'Chemical', '-', (74, 84))	('miR-708-5p', 'Var', (74, 84))
183926	33473256	miR-708-5p and p53 mRNA expression were positively correlated in NSCLC tumors, yet there is no predicted p53 binding site within the ODZ4 promoter.	('miR-708-5p', 'Var', (0, 10))	('NSCLC tumors', 'Disease', (65, 77))	('mRNA expression', 'MPA', (19, 34))	('p53', 'Gene', (15, 18))	('p53', 'Gene', '7157', (15, 18))	('p53', 'Gene', (105, 108))	('p53', 'Gene', '7157', (105, 108))	('NSCLC', 'Phenotype', 'HP:0030358', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('NSCLC tumors', 'Disease', 'MESH:D009369', (65, 77))	('ODZ4', 'Gene', (133, 137))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('ODZ4', 'Gene', '26011', (133, 137))	('miR-708-5p', 'Chemical', '-', (0, 10))	('correlated', 'Reg', (51, 61))
183931	33473256	Regardless, we believe it is crucial to advance studies investigating the combinatory tumor suppressive effects of miR-708-5p and chemotherapies in vivo.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('miR-708-5p', 'Chemical', '-', (115, 125))	('tumor', 'Disease', (86, 91))	('miR-708-5p', 'Var', (115, 125))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
183942	33473256	Our data suggest that miR-708-5p can strongly enhance the anti-tumor effects of ERL and PAC.	('tumor', 'Disease', (63, 68))	('PAC', 'Chemical', 'MESH:D017239', (88, 91))	('miR-708-5p', 'Chemical', '-', (22, 32))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('miR-708-5p', 'Var', (22, 32))	('ERL', 'Chemical', 'MESH:D000069347', (80, 83))	('enhance', 'PosReg', (46, 53))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('PAC', 'Phenotype', 'HP:0006699', (88, 91))
183943	33473256	Additionally, while we demonstrate that miR-708-5p combination treatments profoundly regulate proliferation and apoptosis, there are many other hallmarks of cancer left to be studied.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('apoptosis', 'CPA', (112, 121))	('regulate', 'Reg', (85, 93))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('proliferation', 'CPA', (94, 107))	('miR-708-5p', 'Chemical', '-', (40, 50))	('cancer', 'Disease', (157, 163))	('miR-708-5p', 'Var', (40, 50))
183944	33473256	It is possible miR-708-5p is involved in immune evasion, as its targets COX-2 and mPGES-1 have notable immunosuppressive functions in cancer.	('mPGES-1', 'Gene', (82, 89))	('miR-708-5p', 'Chemical', '-', (15, 25))	('miR-708-5p', 'Var', (15, 25))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('immune evasion', 'MPA', (41, 55))	('immunosuppressive', 'CPA', (103, 120))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('mPGES-1', 'Gene', '64292', (82, 89))	('involved', 'Reg', (29, 37))
183945	33473256	Given these data, we believe there is significant promise in a therapeutic use of miR-708-5p for treating lung cancer.	('lung cancer', 'Disease', (106, 117))	('lung cancer', 'Phenotype', 'HP:0100526', (106, 117))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('miR-708-5p', 'Chemical', '-', (82, 92))	('lung cancer', 'Disease', 'MESH:D008175', (106, 117))	('miR-708-5p', 'Var', (82, 92))
183946	33473256	As researchers continue to discover novel targets and uncover new signaling mechanisms, miR-708-5p's role in lung cancer will be better defined.	('lung cancer', 'Disease', (109, 120))	('lung cancer', 'Phenotype', 'HP:0100526', (109, 120))	('miR-708-5p', 'Chemical', '-', (88, 98))	('miR-708-5p', 'Var', (88, 98))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('lung cancer', 'Disease', 'MESH:D008175', (109, 120))
183947	33473256	This will ultimately lead to in vivo studies that will better define the complete tumor suppressive function of miR-708-5p in lung cancer.	('lung cancer', 'Disease', 'MESH:D008175', (126, 137))	('miR-708-5p', 'Chemical', '-', (112, 122))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('lung cancer', 'Disease', (126, 137))	('lung cancer', 'Phenotype', 'HP:0100526', (126, 137))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('miR-708-5p', 'Var', (112, 122))	('tumor', 'Disease', (82, 87))
184030	32532008	The non-tumorigenic cell line MCF10A had the lowest HPRT1 expression, and it increased across the ER+/luminal A cell lines MCF-7 and T47D, and MDAMB453 (ER-, luminal) to the basal subtypes/triple-negative MDAMB468 and MDAMB231, and HCC1143 (Figure 3A).	('expression', 'MPA', (58, 68))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('HPRT1', 'Gene', '3251', (52, 57))	('increased', 'PosReg', (77, 86))	('T47D', 'CellLine', 'CVCL:0553', (133, 137))	('HCC1143', 'CellLine', 'CVCL:1245', (232, 239))	('lowest', 'NegReg', (45, 51))	('HPRT1', 'Gene', (52, 57))	('MDAMB468', 'CellLine', 'CVCL:0419', (205, 213))	('MCF10A', 'CellLine', 'CVCL:0598', (30, 36))	('tumor', 'Disease', (8, 13))	('luminal', 'Chemical', 'MESH:D010634', (158, 165))	('luminal', 'Chemical', 'MESH:D010634', (102, 109))	('MCF-7', 'CellLine', 'CVCL:0031', (123, 128))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('ER', 'Gene', '2099', (153, 155))	('MDAMB453', 'Var', (143, 151))	('MDAMB231', 'CellLine', 'CVCL:0062', (218, 226))	('ER', 'Gene', '2099', (98, 100))	('MDAMB453', 'CellLine', 'CVCL:0418', (143, 151))
184037	32532008	Interestingly, tumor suppressor gene CDH1 was upregulated upon HPRT1 knockdown, reiterating HPRT1's role in cancer biology.	('HPRT1', 'Gene', (92, 97))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('HPRT1', 'Gene', '3251', (63, 68))	('HPRT1', 'Gene', (63, 68))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('tumor', 'Disease', (15, 20))	('CDH1', 'Gene', (37, 41))	('cancer', 'Disease', 'MESH:D009369', (108, 114))	('CDH1', 'Gene', '999', (37, 41))	('HPRT1', 'Gene', '3251', (92, 97))	('knockdown', 'Var', (69, 78))	('cancer', 'Disease', (108, 114))	('upregulated', 'PosReg', (46, 57))
184041	32532008	Among genes downregulated by HPRT1 knockdown in MDAMB231, their expression was higher in ER- than ER+ breast tumors.	('knockdown', 'Var', (35, 44))	('downregulated', 'NegReg', (12, 25))	('HPRT1', 'Gene', (29, 34))	('expression', 'MPA', (64, 74))	('MDAMB231', 'CellLine', 'CVCL:0062', (48, 56))	('breast tumors', 'Phenotype', 'HP:0100013', (102, 115))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('breast tumor', 'Phenotype', 'HP:0100013', (102, 114))	('MDAMB231', 'Gene', (48, 56))	('breast tumors', 'Disease', 'MESH:D001943', (102, 115))	('breast tumors', 'Disease', (102, 115))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('higher', 'PosReg', (79, 85))	('ER', 'Gene', '2099', (89, 91))	('ER', 'Gene', '2099', (98, 100))	('HPRT1', 'Gene', '3251', (29, 34))
184044	32532008	In addition to basal cell type, we investigated the effect of HPRT1 knockdown in MCF10A (normal breast) and MCF-7 (ER+ breast cancer) cells (Figure S1C,D) using global transcriptomic profiling (Figure S1C).	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('breast cancer', 'Disease', 'MESH:D001943', (119, 132))	('breast cancer', 'Disease', (119, 132))	('breast cancer', 'Phenotype', 'HP:0003002', (119, 132))	('HPRT1', 'Gene', '3251', (62, 67))	('MCF-7', 'CellLine', 'CVCL:0031', (108, 113))	('ER', 'Gene', '2099', (115, 117))	('knockdown', 'Var', (68, 77))	('HPRT1', 'Gene', (62, 67))	('MCF10A', 'CellLine', 'CVCL:0598', (81, 87))
184045	32532008	Intriguingly, the impact of HPRT1 on gene regulation was not as dramatic in MCF10A and MCF-7 cells when compared to MDAMB231 cells, as evident in the Venn diagram, volcano plot, and heatmap of differentially expressed genes (Figure 3, Figures S2 and S3).	('MCF10A', 'CellLine', 'CVCL:0598', (76, 82))	('MCF-7', 'CellLine', 'CVCL:0031', (87, 92))	('HPRT1', 'Gene', '3251', (28, 33))	('HPRT1', 'Gene', (28, 33))	('MCF10A', 'Var', (76, 82))	('MDAMB231', 'CellLine', 'CVCL:0062', (116, 124))
184049	32532008	Further, to integrate the HPRT1-dependent transcriptome with the HPRT1-regulated proteome, we performed mass spectrometric analysis using a powerful TMT (tandem mass tag) technique upon HPRT1 knockdown using a siRNA (si_HPRT1-2) in MDAMB231 cells.	('HPRT1', 'Gene', '3251', (26, 31))	('tag', 'Gene', (166, 169))	('HPRT1', 'Gene', (26, 31))	('HPRT1', 'Gene', '3251', (65, 70))	('HPRT1-2', 'Gene', '3251', (220, 227))	('HPRT1', 'Gene', (65, 70))	('HPRT1', 'Gene', '3251', (220, 225))	('HPRT1', 'Gene', (220, 225))	('HPRT1-2', 'Gene', (220, 227))	('HPRT1', 'Gene', (186, 191))	('MDAMB231', 'CellLine', 'CVCL:0062', (232, 240))	('HPRT1', 'Gene', '3251', (186, 191))	('tag', 'Gene', '404663', (166, 169))	('knockdown', 'Var', (192, 201))
184062	32532008	Breast tumors with higher HPRT1 expression showed a worse clinical outcome, and its knockdown in the triple-negative basal-type MDAMB231 cells showed significant alteration in the expression of genes involved in Notch and ErbB signaling pathways (Figure 2 and Figure 3).	('Breast tumors', 'Disease', (0, 13))	('alteration', 'Reg', (162, 172))	('HPRT1', 'Gene', '3251', (26, 31))	('HPRT1', 'Gene', (26, 31))	('MDAMB231', 'CellLine', 'CVCL:0062', (128, 136))	('higher', 'PosReg', (19, 25))	('Breast tumors', 'Disease', 'MESH:D001943', (0, 13))	('knockdown', 'Var', (84, 93))	('Breast tumors', 'Phenotype', 'HP:0100013', (0, 13))	('ErbB', 'Gene', '1956', (222, 226))	('expression', 'MPA', (180, 190))	('tumors', 'Phenotype', 'HP:0002664', (7, 13))	('ErbB', 'Gene', (222, 226))	('expression', 'MPA', (32, 42))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
184075	32532008	Primers for RT-qPCR HPRT1 forward primer: 5'-AGAAGTTTTGTTCTGTCCTGGAA-3',  HPRT1 reverse primer: 5'-GGGAACTGCTGACAAAGATTCAC-3' RPL19 forward primer: 5'-ACATCCACAAGCTGAAGGCA-3'  RPL19 reverse primer: 5'-TGCGTGCTTCCTTGGTCTTA-3'  For RNA-seq analyses, two biological replicates were sequenced for each of the conditions (si-Ctrl, si-HPRT1-1, and si-HPRT1-2) in MCF10A, MCF-7, and MDAMB231 cells.	('HPRT1', 'Gene', (74, 79))	('HPRT1', 'Gene', '3251', (329, 334))	('MDAMB231', 'CellLine', 'CVCL:0062', (376, 384))	('HPRT1', 'Gene', '3251', (20, 25))	('si-Ctrl', 'Var', (317, 324))	('RPL19', 'Gene', (176, 181))	('HPRT1', 'Gene', (329, 334))	('HPRT1', 'Gene', (20, 25))	('RPL19', 'Gene', (126, 131))	('RPL19', 'Gene', '6143', (126, 131))	('MCF-7', 'CellLine', 'CVCL:0031', (365, 370))	('HPRT1', 'Gene', '3251', (345, 350))	('HPRT1-2', 'Gene', '3251', (345, 352))	('HPRT1', 'Gene', (345, 350))	('HPRT1', 'Gene', '3251', (74, 79))	('MCF10A', 'CellLine', 'CVCL:0598', (357, 363))	('RPL19', 'Gene', '6143', (176, 181))	('HPRT1-2', 'Gene', (345, 352))
184089	32532008	We used the TMT approach to detect proteins regulated upon HPRT1 knockdown using si-HPRT1-2 in MDAMB231 cells; replicate that showed HPRT1 depletion was selected for further analysis (n = 1).	('HPRT1', 'Gene', '3251', (133, 138))	('HPRT1', 'Gene', (133, 138))	('HPRT1-2', 'Gene', '3251', (84, 91))	('HPRT1-2', 'Gene', (84, 91))	('HPRT1', 'Gene', '3251', (59, 64))	('HPRT1', 'Gene', (59, 64))	('MDAMB231', 'CellLine', 'CVCL:0062', (95, 103))	('knockdown', 'Var', (65, 74))	('HPRT1', 'Gene', '3251', (84, 89))	('HPRT1', 'Gene', (84, 89))
184090	32532008	The proteins were identified, and peptides were quantified using Proteome Discoverer 2.2 (Table S3; TMT quantification of differentially regulated proteins upon HPRT1 knockdown).	('knockdown', 'Var', (167, 176))	('HPRT1', 'Gene', (161, 166))	('HPRT1', 'Gene', '3251', (161, 166))
184095	32532008	The following are available online at , Figure S1: HPRT1 knockdown in normal breast and breast cancer cells.	('knockdown', 'Var', (57, 66))	('HPRT1', 'Gene', '3251', (51, 56))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('HPRT1', 'Gene', (51, 56))	('breast cancer', 'Disease', (88, 101))	('breast cancer', 'Disease', 'MESH:D001943', (88, 101))	('breast cancer', 'Phenotype', 'HP:0003002', (88, 101))
184099	32532008	Heat map showing differential expression of genes upon HPRT1 knockdown in MCF10A and MCF-7 cells, Table S1: TCGA cancer types, Table S2: Overlapping set of downregulated genes at RNA and protein level upon HPRT1 knock down, Table S3: TMT quantification of differentially regulated proteins upon HPRT1 knock down.	('knock down', 'Var', (212, 222))	('MCF-7', 'CellLine', 'CVCL:0031', (85, 90))	('HPRT1', 'Gene', '3251', (295, 300))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('HPRT1', 'Gene', (295, 300))	('HPRT1', 'Gene', '3251', (206, 211))	('cancer', 'Disease', (113, 119))	('HPRT1', 'Gene', (206, 211))	('knockdown', 'Var', (61, 70))	('HPRT1', 'Gene', '3251', (55, 60))	('MCF10A', 'CellLine', 'CVCL:0598', (74, 80))	('HPRT1', 'Gene', (55, 60))	('downregulated', 'NegReg', (156, 169))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
184202	29142225	We find that mutated CSMD3 is associated with better prognosis in Asian patients.	('CSMD3', 'Gene', '114788', (21, 26))	('mutated', 'Var', (13, 20))	('patients', 'Species', '9606', (72, 80))	('CSMD3', 'Gene', (21, 26))
184205	29142225	Here, analysis of Chinese and TCGA ESCC patients reveals that Asian patients exhibit higher TP53, EP300 and NFE2L2 mutational frequencies, and mutated CSMD3 associates with better prognosis.	('EP300', 'Gene', (98, 103))	('better', 'PosReg', (173, 179))	('CSMD3', 'Gene', (151, 156))	('CSMD3', 'Gene', '114788', (151, 156))	('higher', 'PosReg', (85, 91))	('patients', 'Species', '9606', (40, 48))	('mutational', 'MPA', (115, 125))	('patients', 'Species', '9606', (68, 76))	('TP53', 'Gene', '7157', (92, 96))	('TP53', 'Gene', (92, 96))	('mutated', 'Var', (143, 150))	('NFE2L2', 'Gene', (108, 114))	('EP300', 'Gene', '2033', (98, 103))
184219	29142225	We therefore compared germline variations of two important alcohol metabolizing enzymes, ALDH2 (rs671) and ADH1B (rs1229984) in the three populations and found very similar patterns between Chinese and Vietnamese patients (Supplementary Fig.	('rs671', 'Var', (96, 101))	('ALDH2', 'Gene', (89, 94))	('rs671', 'Mutation', 'rs671', (96, 101))	('rs1229984', 'Mutation', 'rs1229984', (114, 123))	('rs1229984', 'Var', (114, 123))	('alcohol', 'Chemical', 'MESH:D000438', (59, 66))	('patients', 'Species', '9606', (213, 221))	('ADH1B', 'Gene', (107, 112))	('ALDH2', 'Gene', '217', (89, 94))	('ADH1B', 'Gene', '125', (107, 112))
184223	29142225	First, for TCGA patients, compared to the latest refined TCGA mutation data, 96.4% of our non-silent mutation (missense mutation, nonsense mutation and non-stop mutation) calls on the same patients were reported.	('TCGA', 'Disease', (11, 15))	('patients', 'Species', '9606', (189, 197))	('patients', 'Species', '9606', (16, 24))	('nonsense mutation', 'Var', (130, 147))
184229	29142225	We therefore examined the correlation of CSMD3 mutation status with patient survival times, which is orthogonal to the mutation rate analysis.	('examined', 'Reg', (13, 21))	('patient', 'Species', '9606', (68, 75))	('CSMD3', 'Gene', '114788', (41, 46))	('CSMD3', 'Gene', (41, 46))	('mutation', 'Var', (47, 55))
184230	29142225	We found that among Chinese patients with WES data (n = 78), patients with mutated CSMD3 showed significantly better survival time than those with the wild-type allele (Fig.	('CSMD3', 'Gene', (83, 88))	('CSMD3', 'Gene', '114788', (83, 88))	('patients', 'Species', '9606', (61, 69))	('mutated', 'Var', (75, 82))	('better', 'PosReg', (110, 116))	('survival time', 'CPA', (117, 130))	('patients', 'Species', '9606', (28, 36))
184234	29142225	These results suggest that the mutational status of CSMD3 is a prognostic marker for Asian populations.	('CSMD3', 'Gene', '114788', (52, 57))	('mutational status', 'Var', (31, 48))	('CSMD3', 'Gene', (52, 57))
184242	29142225	Specifically, TP53, NFE2L2, and EP300 showed a significantly higher mutation rate in Asian populations; while KRTAP9-1, LRFN5, and MAP2 showed the opposite patterns (Fig.	('TP53', 'Gene', '7157', (14, 18))	('TP53', 'Gene', (14, 18))	('NFE2L2', 'Var', (20, 26))	('LRFN5', 'Gene', (120, 125))	('higher', 'PosReg', (61, 67))	('KRTAP9-1', 'Gene', '728318', (110, 118))	('MAP2', 'Gene', (131, 135))	('MAP2', 'Gene', '4133', (131, 135))	('KRTAP9-1', 'Gene', (110, 118))	('LRFN5', 'Gene', '145581', (120, 125))	('mutation rate', 'MPA', (68, 81))	('EP300', 'Gene', (32, 37))	('EP300', 'Gene', '2033', (32, 37))
184244	29142225	Interestingly, the mutational status of these three genes showed marginally significant mutual exclusivity (CoMEt algorithm, Fig.	('CoMEt', 'Species', '302767', (108, 113))	('mutational', 'Var', (19, 29))	('mutual exclusivity', 'MPA', (88, 106))
184246	29142225	The TP53 mutations are widespread throughout the whole gene, while the mutations in EP300 are enriched in the domain of HAT_KAT11, as previously reported (Supplementary Fig.	('TP53', 'Gene', (4, 8))	('mutations', 'Var', (9, 18))	('EP300', 'Gene', (84, 89))	('EP300', 'Gene', '2033', (84, 89))	('TP53', 'Gene', '7157', (4, 8))
184247	29142225	NFE2L2 (also known as NRF2) is of particular interest: this gene is a transcription factor that regulates many proteins involved in response to injury and inflammation as well as cellular defense against oxidative stress; NFE2L2-knockout mice are more susceptible to esophageal carcinogenesis than wild-type mice; and its mutations have been recently reported to enrich in Vietnamese patients.	('esophageal carcinogenesis', 'Disease', (267, 292))	('susceptible', 'Reg', (252, 263))	('mutations', 'Var', (322, 331))	('oxidative stress', 'Phenotype', 'HP:0025464', (204, 220))	('mice', 'Species', '10090', (238, 242))	('patients', 'Species', '9606', (384, 392))	('NRF2', 'Gene', '18024', (22, 26))	('regulates', 'Reg', (96, 105))	('NFE2L2-knockout', 'Var', (222, 237))	('mice', 'Species', '10090', (308, 312))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (267, 292))	('NRF2', 'Gene', (22, 26))	('injury and inflammation', 'Disease', 'MESH:D007249', (144, 167))
184250	29142225	To further investigate the potential effects of this SNP on NFE2L2 expression, we integrated the SNP data from International Cancer Genome Consortium (ICGC) whole-genome sequencing and TCGA RNA-seq data to compare the mRNA expression level of NFE2L2 between cancer samples with and without this SNP and found that the presence of this SNP was associated with a significantly lower NFE2L2 expression across cancer types (paired Wilcoxon signed rank test, P = 4.9 x 10-4, Fig.	('cancer', 'Phenotype', 'HP:0002664', (258, 264))	('cancer', 'Disease', 'MESH:D009369', (406, 412))	('expression', 'MPA', (388, 398))	('cancer', 'Disease', (406, 412))	('cancer', 'Phenotype', 'HP:0002664', (406, 412))	('Cancer', 'Disease', (125, 131))	('presence', 'Var', (318, 326))	('cancer', 'Disease', 'MESH:D009369', (258, 264))	('lower', 'NegReg', (375, 380))	('NFE2L2', 'Gene', (381, 387))	('Cancer', 'Disease', 'MESH:D009369', (125, 131))	('cancer', 'Disease', (258, 264))	('Cancer', 'Phenotype', 'HP:0002664', (125, 131))	('SNP', 'Var', (335, 338))
184251	29142225	Interestingly, the mutational status for Asian patients was strongly associated with the allele status of this SNP (CoMEt, P = 1.7 x 10-2, Fig.	('patients', 'Species', '9606', (47, 55))	('mutational', 'Var', (19, 29))	('associated', 'Reg', (69, 79))	('CoMEt', 'Species', '302767', (116, 121))
184254	29142225	A key next step to implement precision cancer medicine is to identify race-specific mutated drivers, which will lay a critical foundation for developing novel therapeutic strategies that target different patient populations.	('cancer', 'Disease', (39, 45))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('mutated', 'Var', (84, 91))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('patient', 'Species', '9606', (204, 211))
184268	29142225	We then used several popular callers, including Muse, MuTect2, SomaticSniper, Radia, and VarScan2, to identify somatic point mutations.	('Muse', 'Gene', '399806', (48, 52))	('Muse', 'Gene', (48, 52))	('point mutations', 'Var', (119, 134))
184269	29142225	To assess the accuracy of our mutation calls, we obtained TCGA MC3 mutation data from Synapse (syn5917256, version 0.2.8) and calculated the (median) fraction of MC3 non-silent mutations (e.g., missense, nonsense, and nonstop) called in our mutation set across the same set of TCGA samples and vice versa.	('MC3', 'Gene', (63, 66))	('MC3', 'Gene', (162, 165))	('nonsense', 'Var', (204, 212))	('MC3', 'Gene', '4159', (162, 165))	('MC3', 'Gene', '4159', (63, 66))	('missense', 'Var', (194, 202))	('nonstop', 'Var', (218, 225))
184274	29142225	The SNP status of rs113671272 in Chinese and Vietnamese patients with WES was inferred from off-target reads with a minimum of 3 read coverage.	('patients', 'Species', '9606', (56, 64))	('rs113671272', 'Var', (18, 29))	('WES', 'Disease', (70, 73))	('rs113671272', 'Mutation', 'rs113671272', (18, 29))
184275	29142225	To examine the SNP effects on the gene expression, we obtained the genotypes of rs113671272 in TCGA samples from ICGC whole-genome sequencing data, and obtained the mRNA expression level of NFE2L2 (based on the longest transcript uc002uli.3) from Fire Browser (http://firebrowse.org, version 2016_01_28).	('rs113671272', 'Var', (80, 91))	('mRNA expression', 'MPA', (165, 180))	('rs113671272', 'Mutation', 'rs113671272', (80, 91))	('NFE2L2', 'Gene', (190, 196))
184284	29179482	Association of fibroblast growth factor receptor 1 gene amplification with poor survival in patients with esophageal squamous cell carcinoma To investigate whether FGFR1 gene amplification is associated with clinicopathologic characteristics and its potential impact on survival in patients with resected esophageal squamous cell carcinoma (ESCC).	('carcinoma', 'Phenotype', 'HP:0030731', (330, 339))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (117, 140))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (106, 140))	('fibroblast growth factor receptor 1', 'Gene', (15, 50))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (316, 339))	('esophageal squamous cell carcinoma', 'Disease', (305, 339))	('associated', 'Reg', (192, 202))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('esophageal squamous cell carcinoma', 'Disease', (106, 140))	('FGFR1', 'Gene', (164, 169))	('patients', 'Species', '9606', (92, 100))	('fibroblast growth factor receptor 1', 'Gene', '2260', (15, 50))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (305, 339))	('Association', 'Interaction', (0, 11))	('patients', 'Species', '9606', (282, 290))	('amplification', 'Var', (56, 69))
184288	29179482	FGFR1 amplification was identified in 67 (12.1%) patients; these patients had significantly shorter OS (50.0 vs 32.0 months; log rank; P<0.001) as well as shorter DFS (47.0 vs 28.0 months; log rank; P<0.001) than those without FGFR1 amplification.	('OS', 'Chemical', '-', (100, 102))	('shorter', 'NegReg', (155, 162))	('FGFR1', 'Gene', (0, 5))	('patients', 'Species', '9606', (65, 73))	('DFS', 'MPA', (163, 166))	('patients', 'Species', '9606', (49, 57))	('amplification', 'Var', (6, 19))	('shorter', 'NegReg', (92, 99))
184289	29179482	Under a Cox proportional hazard model, FGFR1 amplification was associated with significantly shorter OS (adjusted hazard ratio [AHR]=1.61; 95% CI, 1.10-2.43, P=0.004) and DFS (AHR=1.72; 95%CI, 1.15-2.48; P<0.001).	('FGFR1', 'Gene', (39, 44))	('shorter', 'NegReg', (93, 100))	('OS', 'Chemical', '-', (101, 103))	('DFS', 'CPA', (171, 174))	('amplification', 'Var', (45, 58))
184290	29179482	Moreover, cases with high intratumoral FGFR1 expression showed significantly shorter OS and DFS than those with low FGFR1 expression.	('FGFR1', 'Gene', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('OS', 'Chemical', '-', (85, 87))	('tumor', 'Disease', (31, 36))	('high', 'Var', (21, 25))	('DFS', 'CPA', (92, 95))	('shorter', 'NegReg', (77, 84))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
184297	29179482	Further delineation of genetic alterations may help uncover aberrant molecular pathways, novel biologic markers and tumorigenic pathways, and eventually allowing successful targeted therapy.	('alterations', 'Var', (31, 42))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('uncover', 'Reg', (52, 59))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('molecular pathways', 'Pathway', (69, 87))	('tumor', 'Disease', (116, 121))
184300	29179482	FGFR1 amplification has been identified in breast cancer, head and neck squamous cell carcinoma, ovarian cancer, ESCC, bladder cancer and lung cancer.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (72, 95))	('lung cancer', 'Disease', 'MESH:D008175', (138, 149))	('FGFR1', 'Gene', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('lung cancer', 'Phenotype', 'HP:0100526', (138, 149))	('ESCC', 'Disease', (113, 117))	('bladder cancer', 'Disease', 'MESH:D001749', (119, 133))	('bladder cancer', 'Disease', (119, 133))	('ovarian cancer', 'Disease', 'MESH:D010051', (97, 111))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (58, 95))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('breast cancer', 'Phenotype', 'HP:0003002', (43, 56))	('bladder cancer', 'Phenotype', 'HP:0009725', (119, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('identified', 'Reg', (29, 39))	('head and neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (58, 95))	('lung cancer', 'Disease', (138, 149))	('breast cancer', 'Disease', 'MESH:D001943', (43, 56))	('breast cancer', 'Disease', (43, 56))	('ovarian cancer', 'Disease', (97, 111))	('ovarian cancer', 'Phenotype', 'HP:0100615', (97, 111))	('amplification', 'Var', (6, 19))
184301	29179482	investigated the prevalence of FGFR1 amplification in a tissue microarray containing 346 esophageal adenocarcinomas and 254 ESCCs using dual-labeling fluorescent in situ hybridization (FISH) analysis and found that FGFR1 amplification correlated with the histologic subtype of ESCC (9.4% vs. esophageal adenocarcinoma 1.6%, P<0.001).	('FGFR1', 'Gene', (215, 220))	('amplification', 'Var', (221, 234))	('esophageal adenocarcinoma', 'Disease', (292, 317))	('ESCC', 'Disease', (277, 281))	('esophageal adenocarcinomas', 'Disease', 'MESH:D004938', (89, 115))	('carcinoma', 'Phenotype', 'HP:0030731', (308, 317))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (89, 114))	('correlated', 'Reg', (235, 245))	('FGFR1', 'Gene', (31, 36))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (89, 114))	('esophageal adenocarcinomas', 'Disease', (89, 115))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (292, 317))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (292, 317))
184302	29179482	studied 180 patients with resected ESCC and found FGFR1 amplification in 21.4% (37/173) patients; they observed that FGFR1 amplification was an independent predictor of prolonged OS in these patients.	('patients', 'Species', '9606', (12, 20))	('patients', 'Species', '9606', (191, 199))	('patients', 'Species', '9606', (88, 96))	('prolonged OS', 'Disease', (169, 181))	('FGFR1', 'Gene', (117, 122))	('amplification', 'Var', (123, 136))	('OS', 'Chemical', '-', (179, 181))
184304	29179482	FGFR1 inhibition in cell lines and mouse models with FGFR1-amplified engrafted tumors suppressed tumor cell growth and induced apoptosis, suggesting that FGFR inhibitors may be an effective therapeutic option in SCCs with FGFR1 amplification.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('tumor', 'Disease', (79, 84))	('induced', 'Reg', (119, 126))	('FGFR1-amplified', 'Gene', (53, 68))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('FGFR1', 'Gene', (0, 5))	('apoptosis', 'CPA', (127, 136))	('mouse', 'Species', '10090', (35, 40))	('tumor', 'Disease', (97, 102))	('tumors', 'Disease', (79, 85))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('suppressed', 'NegReg', (86, 96))	('inhibition', 'Var', (6, 16))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('SCCs', 'Disease', (212, 216))
184318	29179482	The median FGFR1 gene copy number was 10 (range, 6 to 17) in ESCC patients with FGFR1 amplification and 2 (range, 2 to 5) in those without FGFR1 amplification.	('amplification', 'Var', (86, 99))	('ESCC', 'Disease', (61, 65))	('FGFR1', 'Gene', (11, 16))	('FGFR1', 'Gene', (80, 85))	('patients', 'Species', '9606', (66, 74))
184320	29179482	ESCC patients with and without FGFR1 amplification were comparable in the demographic and baseline variables except that the percentage of heavy drinkers was significantly higher in patients with FGFR1 amplification than those without FGFR1 amplification (86.6% vs 43.1%, P<0.001) (Table 1).	('patients', 'Species', '9606', (5, 13))	('FGFR1', 'Gene', (196, 201))	('higher', 'PosReg', (172, 178))	('patients', 'Species', '9606', (182, 190))	('amplification', 'Var', (202, 215))
184322	29179482	Kaplan-Meier analysis showed that ESCC patients with FGFR1 amplification had significantly shorter OS (32.0 months; range, 11.0 to 116.0 months) than those without FGFR1 amplification (50.0 months; range, 9.0 to 137.0 months) (log rank; P<0.001) (Figure 2).	('FGFR1', 'Gene', (53, 58))	('patients', 'Species', '9606', (39, 47))	('ESCC', 'Disease', (34, 38))	('amplification', 'Var', (59, 72))	('OS', 'Chemical', '-', (99, 101))	('shorter', 'NegReg', (91, 98))
184323	29179482	After adjustment for sex, pathologic stage, diabetes, adjuvant chemotherapy and other factors, FGFR1 amplification remained associated with significantly shorter OS (adjusted hazard ratio [AHR], 1.61; 95% CI, 1.10-2.43, P=0.004) (Table 2).	('amplification', 'Var', (101, 114))	('FGFR1', 'Gene', (95, 100))	('OS', 'Chemical', '-', (162, 164))	('men', 'Species', '9606', (12, 15))	('diabetes', 'Disease', (44, 52))	('diabetes', 'Disease', 'MESH:D003920', (44, 52))	('shorter', 'NegReg', (154, 161))
184324	29179482	The median DFS was 28.0 months (range, 7.0 to 116.0 months) for ESCC patients with FGFR1 amplification and 47.0 (range, 5.0 to 137.0 months) months in those without FGFR1 amplification.	('patients', 'Species', '9606', (69, 77))	('FGFR1', 'Gene', (83, 88))	('ESCC', 'Disease', (64, 68))	('amplification', 'Var', (89, 102))
184325	29179482	Kaplan-Meier analysis revealed that patients with FGFR1 amplification had significantly shorter DFS (log rank; P<0.001) (Figure 2).	('shorter', 'NegReg', (88, 95))	('patients', 'Species', '9606', (36, 44))	('FGFR1', 'Gene', (50, 55))	('DFS', 'MPA', (96, 99))	('amplification', 'Var', (56, 69))
184326	29179482	After adjusting for sex, pathologic stage, diabetes, and other variables, FGFR1 amplification was associated with shorter DFS (AHR=1.72; 95%CI, 1.15-2.48; P<0.001) (Table 3).	('amplification', 'Var', (80, 93))	('diabetes', 'Disease', 'MESH:D003920', (43, 51))	('DFS', 'MPA', (122, 125))	('shorter', 'NegReg', (114, 121))	('diabetes', 'Disease', (43, 51))	('FGFR1', 'Gene', (74, 79))
184327	29179482	A cutoff IHC score of 62 was used to stratify ESCC patients into the high FGFR1 expression group (n=81) and the low FGFR1 expression group (n=475).	('ESCC', 'Disease', (46, 50))	('patients', 'Species', '9606', (51, 59))	('FGFR1', 'Gene', (74, 79))	('high', 'Var', (69, 73))
184328	29179482	ESCC patients with high FGFR1 expression and those with low FGFR1 expression were comparable in the demographic and baseline variables except that the percentage of heavy drinkers was significantly higher in patients with high FGFR1 expression than those with low FGFR1 expression (79.0% vs 43.2%, P<0.001) (Supplementary Table 1, Supplementary Figure 2).	('patients', 'Species', '9606', (208, 216))	('patients', 'Species', '9606', (5, 13))	('high', 'Var', (222, 226))	('men', 'Species', '9606', (337, 340))	('FGFR1', 'Gene', (227, 232))	('FGFR1', 'Gene', (24, 29))	('men', 'Species', '9606', (314, 317))	('higher', 'PosReg', (198, 204))
184329	29179482	Furthermore, ESCC patients with FGFR1 amplification had significantly higher IHC scores (mean 121.8 +- 36.8; range, 78 to 242) than those without FGFR1 amplification (mean 22.1 +- 19.9; range, 0 to 75) (P<0.001) (Figure 3) and all patients with FGFR1 amplification fell into the high FGFR1 expression group.	('patients', 'Species', '9606', (231, 239))	('IHC scores', 'CPA', (77, 87))	('FGFR1 amplification', 'Var', (32, 51))	('ESCC', 'Disease', (13, 17))	('fell', 'Reg', (265, 269))	('patients', 'Species', '9606', (18, 26))	('higher', 'PosReg', (70, 76))	('amplification', 'Var', (38, 51))
184330	29179482	Moreover, patients with high intratumoral FGFR1 expression had shorter OS (31.0 vs 52.0 months in subjects with low FGFR1 expression; P<0.001) and DFS (28.0 vs 48.0 months; P<0.001) (Figure 4).	('tumor', 'Disease', (34, 39))	('FGFR1', 'Gene', (42, 47))	('shorter', 'NegReg', (63, 70))	('OS', 'Chemical', '-', (71, 73))	('high', 'Var', (24, 28))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('DFS', 'CPA', (147, 150))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('patients', 'Species', '9606', (10, 18))
184335	29179482	Thirty-six patients with FGFR1 amplification received adjuvant therapy.	('patients', 'Species', '9606', (11, 19))	('FGFR1', 'Gene', (25, 30))	('amplification', 'Var', (31, 44))
184343	29179482	We demonstrated that FGFR1 amplification was an independent adverse prognostic predictor of OS and DFS of ESCC patients.	('DFS', 'Disease', (99, 102))	('FGFR1', 'Gene', (21, 26))	('OS', 'Chemical', '-', (92, 94))	('amplification', 'Var', (27, 40))	('patients', 'Species', '9606', (111, 119))
184347	29179482	In head and neck squamous cell carcinoma, FGFR1 amplification was significantly associated with poor prognostic factors such as higher T stage, and visceral metastasis.	('FGFR1', 'Gene', (42, 47))	('head and neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (3, 40))	('visceral metastasis', 'Disease', (148, 167))	('higher', 'Disease', (128, 134))	('associated', 'Reg', (80, 90))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (3, 40))	('visceral metastasis', 'Disease', 'MESH:D009362', (148, 167))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (17, 40))	('carcinoma', 'Phenotype', 'HP:0030731', (31, 40))	('amplification', 'Var', (48, 61))
184349	29179482	found no association between FGFR1 amplification and clinical outcome of ESCC patients while Kwon et al.	('amplification', 'Var', (35, 48))	('ESCC', 'Disease', (73, 77))	('FGFR1', 'Gene', (29, 34))	('patients', 'Species', '9606', (78, 86))
184350	29179482	showed that FGFR1 amplification was an independent predictor of prolonged OS of ESCC patients.	('FGFR1', 'Gene', (12, 17))	('predictor', 'Reg', (51, 60))	('patients', 'Species', '9606', (85, 93))	('amplification', 'Var', (18, 31))	('ESCC patients', 'Disease', (80, 93))	('prolonged OS', 'Disease', (64, 76))	('OS', 'Chemical', '-', (74, 76))
184351	29179482	investigated 526 curatively resected ESCC and showed that high FGFR1 amplification was associated with significantly shorter DFS and OS.	('DFS', 'CPA', (125, 128))	('shorter', 'NegReg', (117, 124))	('FGFR1', 'Gene', (63, 68))	('high', 'Var', (58, 62))	('OS', 'Chemical', '-', (133, 135))	('amplification', 'Var', (69, 82))
184352	29179482	Consistently, our study of 556 ESCC patients also showed that FGFR1 amplification was independently associated with worse OS and DFS.	('DFS', 'Disease', (129, 132))	('patients', 'Species', '9606', (36, 44))	('associated', 'Reg', (100, 110))	('FGFR1', 'Gene', (62, 67))	('OS', 'Chemical', '-', (122, 124))	('ESCC', 'Disease', (31, 35))	('amplification', 'Var', (68, 81))	('worse OS', 'Disease', (116, 124))
184354	29179482	Apart from genetic evidence, we further showed that high intratumoral FGFR1 expression was also associated with shorter OS and DFS, lending support to the proposition that FGFR1 amplification predicts poor clinical outcome of ESCC patients.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('patients', 'Species', '9606', (231, 239))	('DFS', 'MPA', (127, 130))	('ESCC', 'Disease', (226, 230))	('tumor', 'Disease', (62, 67))	('expression', 'MPA', (76, 86))	('FGFR1', 'Gene', (70, 75))	('high', 'Var', (52, 56))	('amplification', 'Var', (178, 191))	('OS', 'Chemical', '-', (120, 122))	('shorter', 'NegReg', (112, 119))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
184357	29179482	Our study has demonstrated that FGFR1 amplification is an independent adverse predictor of OS of ESCC patients, suggesting that FGFR1 may be a promising molecular therapeutic target.	('FGFR1', 'Gene', (32, 37))	('patients', 'Species', '9606', (102, 110))	('OS of ESCC patients', 'Disease', (91, 110))	('OS', 'Chemical', '-', (91, 93))	('amplification', 'Var', (38, 51))
184363	29179482	Patients with FGFR1 amplification benefitted from adjuvant chemotherapy while patients without FGFR1 amplification did not.	('benefitted', 'PosReg', (34, 44))	('patients', 'Species', '9606', (78, 86))	('FGFR1', 'Gene', (14, 19))	('Patients', 'Species', '9606', (0, 8))	('amplification', 'Var', (20, 33))
184366	29179482	A novel finding of the current study is significant association between FGFR1 amplification and alcohol intake.	('FGFR1', 'Gene', (72, 77))	('amplification', 'Var', (78, 91))	('alcohol intake', 'Disease', (96, 110))	('alcohol', 'Chemical', 'MESH:D000438', (96, 103))
184367	29179482	We also found that the incidence of FGFR1 amplification rose as the amount of alcohol intake increased.	('alcohol', 'Chemical', 'MESH:D000438', (78, 85))	('FGFR1', 'Gene', (36, 41))	('amplification', 'Var', (42, 55))
184368	29179482	Our findings suggest that FGFR1 amplification may be a major oncogenic aberration in ESCC that is induced by alcohol abuse.	('alcohol abuse', 'Phenotype', 'HP:0030955', (109, 122))	('FGFR1', 'Gene', (26, 31))	('amplification', 'Var', (32, 45))	('ESCC', 'Disease', (85, 89))	('alcohol abuse', 'Disease', (109, 122))	('alcohol abuse', 'Disease', 'MESH:D000437', (109, 122))
184369	29179482	On the basis of this finding, ESCC patients with alcohol consumption more than 100 g/day may be targeted for screening for FGFR1 amplification.	('amplification', 'Var', (129, 142))	('FGFR1', 'Gene', (123, 128))	('ESCC', 'Disease', (30, 34))	('alcohol', 'Chemical', 'MESH:D000438', (49, 56))	('patients', 'Species', '9606', (35, 43))
184371	29179482	FGFR1 amplification was positively associated with alcohol consumption, which strongly implies that FGFR1 amplification is an oncogenic aberration caused by alcohol abuse.	('alcohol abuse', 'Disease', 'MESH:D000437', (157, 170))	('alcohol abuse', 'Phenotype', 'HP:0030955', (157, 170))	('associated', 'Reg', (35, 45))	('FGFR1', 'Gene', (0, 5))	('alcohol', 'Chemical', 'MESH:D000438', (157, 164))	('amplification', 'Var', (106, 119))	('FGFR1', 'Gene', (100, 105))	('alcohol consumption', 'Disease', (51, 70))	('alcohol', 'Chemical', 'MESH:D000438', (51, 58))	('alcohol abuse', 'Disease', (157, 170))	('amplification', 'Var', (6, 19))
184397	25164541	Clinical study on postoperative recurrence in patients with pN0 esophageal squamous cell carcinoma Despite increasingly radical surgery for esophageal carcinoma, many patients still develop tumor recurrence after operation.	('esophageal carcinoma', 'Disease', (140, 160))	('patients', 'Species', '9606', (46, 54))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('develop', 'PosReg', (182, 189))	('esophageal squamous cell carcinoma', 'Disease', (64, 98))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (140, 160))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (140, 160))	('patients', 'Species', '9606', (167, 175))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('tumor', 'Disease', (190, 195))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (75, 98))	('pN0', 'Var', (60, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (64, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (151, 160))
184407	25164541	Locoregional recurrence was the most common recurrence pattern of patients with pN0 ESCC within 3 years after operation.	('pN0', 'Var', (80, 83))	('Locoregional recurrence', 'Disease', (0, 23))	('patients', 'Species', '9606', (66, 74))
184464	25164541	In summary, we have confirmed that locoregional recurrence was the most common recurrence pattern of patients with pN0 ESCC within 3 years after operation.	('patients', 'Species', '9606', (101, 109))	('locoregional recurrence', 'Disease', (35, 58))	('pN0', 'Var', (115, 118))
184484	33305308	Disruption of the cooperation between genes and regulatory factors in a GRN can give rise to abnormal gene expression, such as that which is present in diseases such as cancer.	('cancer', 'Disease', (169, 175))	('abnormal gene expression', 'MPA', (93, 117))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('give rise to', 'Reg', (80, 92))	('cooperation', 'Interaction', (18, 29))	('cancer', 'Disease', 'MESH:D009369', (169, 175))	('Disruption', 'Var', (0, 10))
184488	33305308	For example, dysregulations in the epidermal growth factor receptor EGFR, associated with sensitivity of lung cancers to the tyrosine kinase inhibitor gefitinib (Iressa), echinoderm microtubule-associated protein-like 4 (EML4) and anaplastic lymphoma kinase (ALK) are frequently involved in oncogenic transformation.	('EML4', 'Gene', '27436', (221, 225))	('lung cancers', 'Disease', 'MESH:D008175', (105, 117))	('ALK', 'Gene', '238', (259, 262))	('lung cancers', 'Disease', (105, 117))	('lung cancer', 'Phenotype', 'HP:0100526', (105, 116))	('lung cancers', 'Phenotype', 'HP:0100526', (105, 117))	('ALK', 'Gene', (259, 262))	('echinoderm microtubule-associated protein-like 4', 'Gene', (171, 219))	('gefitinib', 'Chemical', 'MESH:D000077156', (151, 160))	('EGFR', 'Gene', '1956', (68, 72))	('anaplastic lymphoma kinase', 'Gene', '238', (231, 257))	('cancers', 'Phenotype', 'HP:0002664', (110, 117))	('anaplastic lymphoma kinase', 'Gene', (231, 257))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (231, 250))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('lymphoma', 'Phenotype', 'HP:0002665', (242, 250))	('Iressa', 'Chemical', 'MESH:D000077156', (162, 168))	('dysregulations', 'Var', (13, 27))	('EML4', 'Gene', (221, 225))	('EGFR', 'Gene', (68, 72))	('associated', 'Reg', (74, 84))	('echinoderm microtubule-associated protein-like 4', 'Gene', '27436', (171, 219))
184511	33305308	Overall, we included 741 TCGA-LUAD patients (N = 409 and N = 332 in the early and late stages, respectively) and 758 TCGA-LUSC patients (N = 380 and N = 378 in the early and late stages, respectively) with (I + IA + IB) as the early stage and the rest as the late stage.	('patients', 'Species', '9606', (127, 135))	('TCGA-LUAD', 'Disease', (25, 34))	('I + IA', 'Var', (207, 213))	('patients', 'Species', '9606', (35, 43))
184568	33305308	the Type I RAF inhibitor:Dabrafenib and the Type II RAF inhibitor:AZ628 for the treatment of non-V600 BRAF mutant lung cancer in the late stage group, and YM155 for delaying the growth of NSCLC tumor xenografts is in the early stage group.	('AZ628', 'Chemical', 'MESH:C000592454', (66, 71))	('RAF', 'Gene', '22882', (11, 14))	('RAF', 'Gene', (11, 14))	('lung cancer', 'Disease', 'MESH:D008175', (114, 125))	('RAF', 'Gene', '22882', (103, 106))	('RAF', 'Gene', (103, 106))	('RAF', 'Gene', '22882', (52, 55))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('RAF', 'Gene', (52, 55))	('NSCLC tumor', 'Disease', 'MESH:D009369', (188, 199))	('lung cancer', 'Disease', (114, 125))	('lung cancer', 'Phenotype', 'HP:0100526', (114, 125))	('Dabrafenib', 'Chemical', 'MESH:C561627', (25, 35))	('YM155', 'Var', (155, 160))	('NSCLC tumor', 'Disease', (188, 199))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
184573	33305308	CI-1040 and PD-0325901 for advanced non-small cell lung, breast, colon or pancreatic cancers.	('colon or pancreatic cancers', 'Disease', 'MESH:D010190', (65, 92))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (74, 91))	('CI-1040', 'Chemical', 'MESH:C120227', (0, 7))	('PD-0325901', 'Chemical', 'MESH:C506614', (12, 22))	('cancers', 'Phenotype', 'HP:0002664', (85, 92))	('non-small cell lung', 'Disease', (36, 55))	('colon or pancreatic cancers', 'Disease', (65, 92))	('breast', 'Disease', (57, 63))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('CI-1040', 'Var', (0, 7))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (74, 92))	('PD-0325901', 'Var', (12, 22))
184685	32093372	In conclusion, in patients with multiple primary lung cancers, cancer-specific mutations can serve as clonal markers, affording a more accurate understanding of the pathology of multiple lung cancers and their lymphatic metastases and thus improving both the treatment selection and outcome.	('lung cancers', 'Phenotype', 'HP:0100526', (187, 199))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('cancers', 'Phenotype', 'HP:0002664', (192, 199))	('cancer', 'Disease', (192, 198))	('mutations', 'Var', (79, 88))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('improving', 'PosReg', (240, 249))	('lung cancer', 'Phenotype', 'HP:0100526', (49, 60))	('primary lung cancers', 'Disease', (41, 61))	('lung cancers', 'Phenotype', 'HP:0100526', (49, 61))	('cancer', 'Disease', (63, 69))	('multiple lung cancers', 'Disease', 'MESH:D008175', (178, 199))	('cancers', 'Phenotype', 'HP:0002664', (54, 61))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('primary lung cancers', 'Disease', 'MESH:D008175', (41, 61))	('cancer', 'Disease', (54, 60))	('cancer', 'Disease', 'MESH:D009369', (192, 198))	('patients', 'Species', '9606', (18, 26))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('metastases', 'Disease', 'MESH:D009362', (220, 230))	('multiple lung cancers', 'Disease', (178, 199))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('metastases', 'Disease', (220, 230))	('lung cancer', 'Phenotype', 'HP:0100526', (187, 198))
184696	32093372	Furthermore, we analyzed gene mutations in primary lung cancers as well as metastatic lymph nodes and genetically examined the pathology of the metastatic lymph nodes to accurately understand the pathology of lymphatic metastasis and thus enhance the postoperative treatment outcome.	('primary lung cancers', 'Disease', 'MESH:D008175', (43, 63))	('primary lung cancers', 'Disease', (43, 63))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('lung cancer', 'Phenotype', 'HP:0100526', (51, 62))	('mutations', 'Var', (30, 39))	('lung cancers', 'Phenotype', 'HP:0100526', (51, 63))	('enhance', 'PosReg', (239, 246))	('cancers', 'Phenotype', 'HP:0002664', (56, 63))
184714	32093372	Sequence analyses detected 314 somatic mutations with an allele fraction >=1% from 84 cancer lesions (1-54 mutations per tumor) (Supplementary Table S3).	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('tumor', 'Disease', (121, 126))	('mutations', 'Var', (39, 48))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('cancer', 'Disease', (86, 92))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
184715	32093372	In 29 patients, the gene, amino-acid substitution and nucleotide changes that were caused by these somatic mutations within individual tumors composing the multiple lung cancers lacked consistency (Figure 1, Supplementary Table S3).	('cancers', 'Phenotype', 'HP:0002664', (170, 177))	('mutations', 'Var', (107, 116))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('lung cancer', 'Phenotype', 'HP:0100526', (165, 176))	('nucleotide changes', 'Var', (54, 72))	('multiple lung cancers', 'Disease', 'MESH:D008175', (156, 177))	('tumors', 'Disease', (135, 141))	('tumors', 'Disease', 'MESH:D009369', (135, 141))	('patients', 'Species', '9606', (6, 14))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('multiple lung cancers', 'Disease', (156, 177))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))	('lung cancers', 'Phenotype', 'HP:0100526', (165, 177))
184724	32093372	Pathologically, the cancer stage was determined to be pT1cN2M0, stage IIIA.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('pT1cN2M0', 'Var', (54, 62))	('cancer', 'Disease', 'MESH:D009369', (20, 26))	('cancer', 'Disease', (20, 26))	('stage IIIA', 'Disease', (64, 74))
184726	32093372	Based on the genetic diagnosis, the cancer stage was ultimately upgraded to T3N2M0, stage IIIB.	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('cancer', 'Disease', (36, 42))	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('T3N2M0', 'Var', (76, 82))
184734	32093372	The patient was positive for a mutation in the epidermal growth factor receptor (EGFR) gene (exon 19 deletion); hence, oral administration of an EGFR-tyrosine kinase inhibitor (gefitinib) was continued.	('epidermal growth factor receptor', 'Gene', (47, 79))	('EGFR', 'Gene', '1956', (145, 149))	('mutation', 'Var', (31, 39))	('patient', 'Species', '9606', (4, 11))	('epidermal growth factor receptor', 'Gene', '1956', (47, 79))	('EGFR', 'Gene', (145, 149))	('gefitinib', 'Chemical', 'MESH:D000077156', (177, 186))	('EGFR', 'Gene', '1956', (81, 85))	('positive', 'Reg', (16, 24))	('EGFR', 'Gene', (81, 85))
184776	32093372	Therefore, we performed lung cancer mutation analysis through targeted deep sequencing and demonstrated that mutations of individual lung cancers are able to provide clonal markers, enabling discrimination of the clonal origin of multiple lung cancers and their metastases.	('multiple lung cancers', 'Disease', (230, 251))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('lung cancer', 'Disease', (24, 35))	('metastases', 'Disease', 'MESH:D009362', (262, 272))	('lung cancers', 'Disease', 'MESH:D008175', (239, 251))	('lung cancer', 'Disease', 'MESH:D008175', (239, 250))	('lung cancer', 'Disease', 'MESH:D008175', (24, 35))	('metastases', 'Disease', (262, 272))	('lung cancers', 'Disease', 'MESH:D008175', (133, 145))	('lung cancer', 'Phenotype', 'HP:0100526', (239, 250))	('lung cancers', 'Phenotype', 'HP:0100526', (239, 251))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('lung cancer', 'Phenotype', 'HP:0100526', (24, 35))	('multiple lung cancers', 'Disease', 'MESH:D008175', (230, 251))	('mutations', 'Var', (109, 118))	('lung cancer', 'Disease', 'MESH:D008175', (133, 144))	('cancers', 'Phenotype', 'HP:0002664', (244, 251))	('lung cancers', 'Disease', (133, 145))	('lung cancer', 'Phenotype', 'HP:0100526', (133, 144))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('lung cancers', 'Phenotype', 'HP:0100526', (133, 145))	('cancers', 'Phenotype', 'HP:0002664', (138, 145))
184777	32093372	Although discordance between two tumors was noted in mutations with an allele fraction <20%, this can be interpreted as tumor heterogeneity.	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('mutations', 'Var', (53, 62))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('tumors', 'Disease', 'MESH:D009369', (33, 39))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('tumor', 'Disease', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('tumors', 'Disease', (33, 39))	('tumor', 'Disease', (120, 125))
184780	32093372	Conversely, a driver mutation triggers clonal expansion and is retained ubiquitously within the tumors of the same clone.	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumors', 'Disease', (96, 102))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('mutation', 'Var', (21, 29))	('triggers', 'Reg', (30, 38))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('clonal', 'MPA', (39, 45))
184782	32093372	Such trunk somatic mutations to be found at the early stages of tumor development are ubiquitous events occurring at all sites of disease.	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Disease', (64, 69))	('mutations', 'Var', (19, 28))
184791	32093372	Using the method described, comprehensive mutation analysis is initially performed to identify the driver mutations in each cancer, which are subsequently compared to define their clonal origin.	('cancer', 'Disease', (124, 130))	('cancer', 'Disease', 'MESH:D009369', (124, 130))	('mutations', 'Var', (106, 115))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))
184801	32093372	Thus, in patients with multiple lung cancers, performing a mutation analysis helps select the medical treatment most likely to be effective.	('patients', 'Species', '9606', (9, 17))	('lung cancers', 'Phenotype', 'HP:0100526', (32, 44))	('cancers', 'Phenotype', 'HP:0002664', (37, 44))	('multiple lung cancers', 'Disease', 'MESH:D008175', (23, 44))	('mutation', 'Var', (59, 67))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('multiple lung cancers', 'Disease', (23, 44))	('lung cancer', 'Phenotype', 'HP:0100526', (32, 43))
184812	28123873	Weekly neo-epitope peptide vaccination was followed by a rapid and dramatic regression of multiple lung tumor nodules, while a much larger liver metastasis remained refractory to treatment.	('regression', 'NegReg', (76, 86))	('vaccination', 'Var', (27, 38))	('multiple lung tumor nodules', 'Disease', 'MESH:D055613', (90, 117))	('larger liver', 'Phenotype', 'HP:0002240', (132, 144))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('multiple lung tumor nodules', 'Disease', (90, 117))	('lung tumor', 'Phenotype', 'HP:0100526', (99, 109))
184813	28123873	Peripheral blood immune monitoring showed that specific cytotoxic T lymphocytes (CTLs) were induced primarily against peptide targets encompassing the widely shared EGFR L858R mutation, particularly one restricted to HLA-A*3101.	('EGFR', 'Gene', (165, 169))	('HLA-A', 'Gene', '3105', (217, 222))	('L858R', 'Var', (170, 175))	('HLA-A', 'Gene', (217, 222))	('L858R', 'Mutation', 'rs121434568', (170, 175))	('EGFR', 'Gene', '1956', (165, 169))
184814	28123873	Immunological targeting of this driver mutation may be of particular benefit to Asian lung cancer patients due to its relatively high prevalence within this patient population.	('patient', 'Species', '9606', (98, 105))	('mutation', 'Var', (39, 47))	('patient', 'Species', '9606', (157, 164))	('patients', 'Species', '9606', (98, 106))	('lung cancer', 'Phenotype', 'HP:0100526', (86, 97))	('lung cancer', 'Disease', (86, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('lung cancer', 'Disease', 'MESH:D008175', (86, 97))
184817	28123873	Although checkpoint-based approaches provide non-specific immune activation, this correlation suggests that the antitumor immune responses are mediated largely through the activation of T lymphocytes recognizing mutated peptides presented by HLA molecules at the tumor cell surface.	('tumor', 'Disease', 'MESH:D009369', (263, 268))	('tumor', 'Phenotype', 'HP:0002664', (263, 268))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor', 'Disease', (263, 268))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumor', 'Disease', (116, 121))	('mutated', 'Var', (212, 219))
184820	28123873	Recent vaccination approaches employing mutated peptides to stimulate antitumor immunity have shown success in generating specific cytotoxic T lymphocyte (CTL) responses in human melanoma patients, and similar approaches in murine models have resulted in substantial tumor regressions.	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Disease', 'MESH:D009369', (267, 272))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (267, 272))	('patients', 'Species', '9606', (188, 196))	('mutated', 'Var', (40, 47))	('tumor', 'Disease', (74, 79))	('human', 'Species', '9606', (173, 178))	('tumor', 'Disease', (267, 272))	('murine', 'Species', '10090', (224, 230))	('melanoma', 'Disease', 'MESH:D008545', (179, 187))	('melanoma', 'Phenotype', 'HP:0002861', (179, 187))	('melanoma', 'Disease', (179, 187))
184832	28123873	Genetic testing of a lung tumor needle biopsy specimen had revealed the presence of the common L858R driver mutation of the epidermal growth factor receptor (EGFR) gene.	('EGFR', 'Gene', (158, 162))	('lung tumor', 'Phenotype', 'HP:0100526', (21, 31))	('L858R', 'Mutation', 'rs121434568', (95, 100))	('epidermal growth factor receptor', 'Gene', (124, 156))	('lung tumor', 'Disease', (21, 31))	('lung tumor', 'Disease', 'MESH:D008175', (21, 31))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('EGFR', 'Gene', '1956', (158, 162))	('epidermal growth factor receptor', 'Gene', '1956', (124, 156))	('L858R', 'Var', (95, 100))
184836	28123873	Three months following initiation of the EGFR inhibitor, CT scans of the chest and abdomen revealed a dramatic increase in the number of tumors within the right lung (Fig.	('EGFR', 'Gene', (41, 45))	('increase', 'PosReg', (111, 119))	('tumors within the right lung', 'Disease', 'MESH:D001929', (137, 165))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('inhibitor', 'Var', (46, 55))	('tumors within the right lung', 'Disease', (137, 165))	('EGFR', 'Gene', '1956', (41, 45))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
184853	28123873	2A, IFNgamma ELISPOT analysis showed that antigen-specific T-cell frequencies were significantly increased (>3-fold) against 6 of the 11 mutated peptides compared to pre-vaccine levels.	('mutated', 'Var', (137, 144))	('IFNgamma', 'Gene', '3458', (4, 12))	('IFNgamma', 'Gene', (4, 12))	('increased', 'PosReg', (97, 106))
184854	28123873	Notably, three peptides eliciting the largest fold change were all derived from mutated EGFR-L858R (Fig.	('L858R', 'Mutation', 'rs121434568', (93, 98))	('EGFR', 'Gene', '1956', (88, 92))	('EGFR', 'Gene', (88, 92))	('mutated', 'Var', (80, 87))
184856	28123873	These results corroborated the ELISPOT results for two of the three mutated EGFR-derived peptides H9R9 (HVKITDFGR) and K9R7 (KITDFGRAK), in addition to one of the NAV3-derived peptides, V9L8 (VTIGPRLLL, Fig.	('EGFR', 'Gene', '1956', (76, 80))	('NAV3', 'Gene', (163, 167))	('EGFR', 'Gene', (76, 80))	('H9R9', 'Var', (98, 102))	('NAV3', 'Gene', '89795', (163, 167))	('K9R7', 'Var', (119, 123))
184857	28123873	To confirm antigen specificity, custom HLA-peptide tetramers were successfully generated for the two most reactive EGFR peptides, H9R9 (restricted to HLA*A3101) and K9R7 (restricted to HLA-A*1101).	('K9R7', 'Var', (165, 169))	('HLA-A', 'Gene', '3105', (185, 190))	('EGFR', 'Gene', '1956', (115, 119))	('HLA-A', 'Gene', (185, 190))	('EGFR', 'Gene', (115, 119))	('H9R9', 'Var', (130, 134))
184863	28123873	Although cancer vaccine trials have been ongoing for over two decades, objective clinical responses to vaccination have remained relatively rare, more typically resulting in modest benefits in progression-free survival.The squamous cell carcinoma patient reported here is notable in this regard, having experienced a rapid and dramatic regression of multiple lung tumors following neo-epitope peptide vaccination.	('multiple lung tumors', 'Disease', (350, 370))	('cancer', 'Disease', (9, 15))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (223, 246))	('tumors', 'Phenotype', 'HP:0002664', (364, 370))	('patient', 'Species', '9606', (247, 254))	('lung tumors', 'Phenotype', 'HP:0100526', (359, 370))	('lung tumor', 'Phenotype', 'HP:0100526', (359, 369))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (223, 246))	('multiple lung tumors', 'Disease', 'MESH:D008175', (350, 370))	('tumor', 'Phenotype', 'HP:0002664', (364, 369))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('neo-epitope peptide', 'Var', (381, 400))	('carcinoma', 'Phenotype', 'HP:0030731', (237, 246))	('squamous cell carcinoma', 'Disease', (223, 246))
184868	28123873	Mutated antigens are known to be substantially more immunogenic compared with non-mutated tumor antigens, therefore significantly increasing the chances of generating a productive tumor-specific T-cell response through vaccination.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('increasing', 'PosReg', (130, 140))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('tumor', 'Disease', (180, 185))	('Mutated', 'Var', (0, 7))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
184870	28123873	Of the 93 somatic mutations detected by WES, we chose to focus on targeting mutations from five known cancer-associated genes (EGFR, PTCH2, EPHB1, NAV3, and STK11), reasoning they would be most likely to be expressed at the protein level and least likely tolerated to be lost through immune selection and tumor escape.	('STK11', 'Gene', (157, 162))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('mutations', 'Var', (76, 85))	('NAV3', 'Gene', (147, 151))	('NAV3', 'Gene', '89795', (147, 151))	('PTCH2', 'Gene', '8643', (133, 138))	('tumor', 'Disease', 'MESH:D009369', (305, 310))	('EPHB1', 'Gene', (140, 145))	('EGFR', 'Gene', '1956', (127, 131))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('STK11', 'Gene', '6794', (157, 162))	('tumor', 'Phenotype', 'HP:0002664', (305, 310))	('EGFR', 'Gene', (127, 131))	('EPHB1', 'Gene', '2047', (140, 145))	('tumor', 'Disease', (305, 310))	('PTCH2', 'Gene', (133, 138))
184872	28123873	Of note, two of the three confirmed peptides (H9R9 and K9R7) were derived from the well-described shared EGFR-L858R mutation harbored by ~20% of Asian lung cancer patients, and less frequently (~5%) by non-Asian patients.	('patients', 'Species', '9606', (163, 171))	('lung cancer', 'Phenotype', 'HP:0100526', (151, 162))	('EGFR', 'Gene', '1956', (105, 109))	('patients', 'Species', '9606', (212, 220))	('lung cancer', 'Disease', (151, 162))	('K9R7', 'Var', (55, 59))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('EGFR', 'Gene', (105, 109))	('L858R', 'Mutation', 'rs121434568', (110, 115))	('lung cancer', 'Disease', 'MESH:D008175', (151, 162))
184874	28123873	Though we cannot exclude the contribution of multiple peptides to the clinical response observed (for example, the STK11 frameshift mutation), the dominant T-cell response seemed to be directed toward mutated EGFR, and specifically the H9R9 peptide.	('frameshift mutation', 'Var', (121, 140))	('EGFR', 'Gene', (209, 213))	('mutated', 'Var', (201, 208))	('STK11', 'Gene', (115, 120))	('EGFR', 'Gene', '1956', (209, 213))	('STK11', 'Gene', '6794', (115, 120))
184875	28123873	Interestingly, the L858R amino acid change has the potential to create true neo-epitope through alteration of a critical anchor residue in peptide position P9, which heavily favors binding to a number of HLA-A3 family members: HLA-A*3101, A*3301, A*3303, and A*6801, collectively expressed by ~12% of the worldwide population and ~20% of Asians (Table 3).	('alteration', 'Reg', (96, 106))	('HLA-A', 'Gene', (204, 209))	('L858R', 'Mutation', 'rs121434568', (19, 24))	('binding', 'Interaction', (181, 188))	('L858R amino acid change', 'Var', (19, 42))	('A*6801', 'Var', (259, 265))	('A*3303', 'Var', (247, 253))	('HLA-A', 'Gene', '3105', (227, 232))	('favors', 'PosReg', (174, 180))	('A*3301', 'Var', (239, 245))	('HLA-A', 'Gene', (227, 232))	('HLA-A', 'Gene', '3105', (204, 209))
184878	28123873	Being derived from a driver mutation, targeting mutated EGFR-derived peptides represents a particularly promising immunotherapeutic approach since the tumor very likely cannot lose the mutated EGFR protein.	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('mutated', 'Var', (48, 55))	('EGFR', 'Gene', '1956', (56, 60))	('EGFR', 'Gene', '1956', (193, 197))	('tumor', 'Disease', (151, 156))	('EGFR', 'Gene', (56, 60))	('EGFR', 'Gene', (193, 197))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
184879	28123873	However, further laboratory studies will be required to validate these L858R peptide targets as being naturally processed and presented by lung cancer cells.	('lung cancer', 'Disease', (139, 150))	('lung cancer', 'Phenotype', 'HP:0100526', (139, 150))	('L858R', 'Mutation', 'rs121434568', (71, 76))	('lung cancer', 'Disease', 'MESH:D008175', (139, 150))	('L858R', 'Var', (71, 76))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
184880	28123873	Currently, the most critical issue concerns target epitope identification: simply stated, there are substantially more (>100-fold) potential predicted mutated peptides than are actually presented by tumor cells.	('tumor', 'Disease', (199, 204))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('mutated', 'Var', (151, 158))
184898	28123873	Tumors were also analyzed by WES (GenomiCare Biotechnology Co. Ltd.), demonstrating 93 somatic mutations in total and providing confirmation of the five genetic lesions detected by the 508-gene panel.	('genetic lesions', 'Disease', (153, 168))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('mutations', 'Var', (95, 104))	('genetic lesions', 'Disease', 'MESH:D020022', (153, 168))
184912	28123873	For tetramer analysis, custom phycoerethrin(PE)-conjugated tetramers (Baylor College of Medicine, USA) were successfully generated for the H9R9 (HVKITDFGR) and K9R7 (KITDFGRAK) peptides restricted to HLA-A*3101 and HLA-A*1101, respectively.	('phycoerethrin', 'Chemical', '-', (30, 43))	('HLA-A', 'Gene', (215, 220))	('H9R9', 'Var', (139, 143))	('K9R7', 'Var', (160, 164))	('PE', 'Chemical', '-', (44, 46))	('HLA-A', 'Gene', '3105', (200, 205))	('HLA-A', 'Gene', '3105', (215, 220))	('HLA-A', 'Gene', (200, 205))
184914	25327479	Silencing of high-mobility group box 2 (HMGB2) modulates cisplatin and 5-fluorouracil sensitivity in head and neck squamous cell carcinoma Dysregulation of protein expression is associated with most diseases including cancer.	('HMGB2', 'Gene', (40, 45))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (101, 138))	('cisplatin', 'Chemical', 'MESH:D002945', (57, 66))	('Silencing', 'Var', (0, 9))	('modulates', 'Reg', (47, 56))	('cancer', 'Disease', 'MESH:D009369', (218, 224))	('neck squamous cell carcinoma', 'Disease', (110, 138))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (110, 138))	('high-mobility group box 2', 'Gene', (13, 38))	('high-mobility group box 2', 'Gene', '3148', (13, 38))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (71, 85))	('Dysregulation', 'Var', (139, 152))	('protein', 'Protein', (156, 163))	('HMGB2', 'Gene', '3148', (40, 45))	('associated', 'Reg', (178, 188))	('cancer', 'Disease', (218, 224))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (115, 138))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))
184919	25327479	Overexpression of HMGB2 has been reported in various cancers, yet its role in HNSCC remains unclear.	('cancers', 'Phenotype', 'HP:0002664', (53, 60))	('cancers', 'Disease', (53, 60))	('cancers', 'Disease', 'MESH:D009369', (53, 60))	('HMGB2', 'Gene', (18, 23))	('HMGB2', 'Gene', '3148', (18, 23))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('Overexpression', 'Var', (0, 14))	('reported', 'Reg', (33, 41))
184922	25327479	We observed that siRNA-mediated silencing of HMGB2 increased the sensitivity of the HNSCC cell lines to cisplatin and 5-FU.	('increased', 'PosReg', (51, 60))	('cisplatin', 'Chemical', 'MESH:D002945', (104, 113))	('HMGB2', 'Gene', '3148', (45, 50))	('sensitivity', 'MPA', (65, 76))	('silencing', 'Var', (32, 41))	('HMGB2', 'Gene', (45, 50))	('5-FU', 'Chemical', 'MESH:D005472', (118, 122))
184923	25327479	We hypothesize that targeting HMGB2 could enhance the efficacy of existing chemotherapeutic regimens for treatment of HNSCC.	('HMGB2', 'Gene', (30, 35))	('enhance', 'PosReg', (42, 49))	('HNSCC', 'Disease', (118, 123))	('targeting', 'Var', (20, 29))	('HMGB2', 'Gene', '3148', (30, 35))
184929	25327479	Additionally, as iTRAQ labeling involves isobaric tags it causes an increase in the precursor ion intensity resulting in improved MS/MS fragmentation and hence more confident peptide and protein identifications.	('more', 'PosReg', (160, 164))	('improved', 'PosReg', (121, 129))	('MS/MS fragmentation', 'MPA', (130, 149))	('precursor ion intensity', 'MPA', (84, 107))	('iTRAQ', 'Chemical', '-', (17, 22))	('increase', 'PosReg', (68, 76))	('isobaric', 'Var', (41, 49))
184990	25327479	Overexpression of SET and its association with tumorigenesis has been demonstrated in multiple cancers.	('multiple cancers', 'Disease', (86, 102))	('cancers', 'Phenotype', 'HP:0002664', (95, 102))	('multiple cancers', 'Disease', 'MESH:D009369', (86, 102))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('Overexpression', 'Var', (0, 14))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('SET', 'Gene', (18, 21))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('tumor', 'Disease', (47, 52))
185011	25327479	In glioblastoma, HMGB2 overexpression conferred resistance to temozolomide treatment and siRNA-mediated silencing of HMGB2 improved sensitivity to the drug.. Silencing of HMGB2 has been associated with increased sensitivity to ionizing radiation in colorectal cancer cells In hepatocellular carcinoma, overexpression of HMGB2 has been associated with decrease in cisplatin- and etoposide-induced cell death, aggressive tumor growth and poor prognosis  As mentioned previously, two of the common drugs used in the treatment of HNSCC are cisplatin and 5-FU.	('HMGB2', 'Gene', '3148', (171, 176))	('colorectal cancer', 'Disease', (249, 266))	('death', 'Disease', 'MESH:D003643', (401, 406))	('HMGB2', 'Gene', (117, 122))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (276, 300))	('tumor', 'Phenotype', 'HP:0002664', (419, 424))	('HMGB2', 'Gene', (171, 176))	('aggressive tumor', 'Disease', (408, 424))	('hepatocellular carcinoma', 'Disease', (276, 300))	('HMGB2', 'Gene', '3148', (320, 325))	('glioblastoma', 'Disease', 'MESH:D005909', (3, 15))	('5-FU', 'Chemical', 'MESH:D005472', (550, 554))	('cisplatin', 'Chemical', 'MESH:D002945', (363, 372))	('etoposide', 'Chemical', 'MESH:D005047', (378, 387))	('colorectal cancer', 'Phenotype', 'HP:0003003', (249, 266))	('Silencing', 'Var', (158, 167))	('HMGB2', 'Gene', '3148', (17, 22))	('death', 'Disease', (401, 406))	('carcinoma', 'Phenotype', 'HP:0030731', (291, 300))	('temozolomide', 'Chemical', 'MESH:D000077204', (62, 74))	('glioblastoma', 'Disease', (3, 15))	('HMGB2', 'Gene', (320, 325))	('glioblastoma', 'Phenotype', 'HP:0012174', (3, 15))	('cancer', 'Phenotype', 'HP:0002664', (260, 266))	('cisplatin', 'Chemical', 'MESH:D002945', (536, 545))	('colorectal cancer', 'Disease', 'MESH:D015179', (249, 266))	('HMGB2', 'Gene', '3148', (117, 122))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (276, 300))	('HMGB2', 'Gene', (17, 22))	('aggressive tumor', 'Disease', 'MESH:D001523', (408, 424))
185019	25327479	To investigate the role of HMGB2 in the sensitivity of HNSCC cells to cisplatin and 5-FU, we assessed the sensitivity of JHU-O22; JHU-O28 JHU-O29 and FaDu cells to cisplatin and 5-FU using siRNA-mediated silencing of HMGB2.	('HMGB2', 'Gene', '3148', (217, 222))	('cisplatin', 'Chemical', 'MESH:D002945', (70, 79))	('silencing', 'Var', (204, 213))	('HMGB2', 'Gene', '3148', (27, 32))	('HMGB2', 'Gene', (27, 32))	('cisplatin', 'Chemical', 'MESH:D002945', (164, 173))	('HMGB2', 'Gene', (217, 222))	('5-FU', 'Chemical', 'MESH:D005472', (178, 182))	('5-FU', 'Chemical', 'MESH:D005472', (84, 88))
185021	25327479	Silencing of HMGB2 in the HNSCC cells resulted in an increased sensitivity to both cisplatin and 5-FU (Fig.	('HMGB2', 'Gene', '3148', (13, 18))	('cisplatin', 'Chemical', 'MESH:D002945', (83, 92))	('HMGB2', 'Gene', (13, 18))	('sensitivity to', 'MPA', (63, 77))	('increased', 'PosReg', (53, 62))	('5-FU', 'Chemical', 'MESH:D005472', (97, 101))	('Silencing', 'Var', (0, 9))
185026	25327479	Dysregulation of various proteins drives drug resistance in cancer cells.	('drug resistance', 'Phenotype', 'HP:0020174', (41, 56))	('drug resistance', 'Disease', (41, 56))	('Dysregulation', 'Var', (0, 13))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('cancer', 'Disease', (60, 66))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('proteins', 'Protein', (25, 33))
185091	24972848	Then the membrane was washed three times with TBS-T and incubated overnight at 4 C with the primary antibody, mouse monoclonal anti-caspases-3 (1:1000, v/v), or rabbit monoclonal antibodies to poly (ADP-ribose) polymerase (PARP) (1:4000, v/v), Bcl-2-associated X protein (Bax) (1:8000, v/v) and beta-actin (1:2000, v/v), followed by 1 h incubation with a 1:10000 (v/v) dilution of the appropriate horseradish peroxidase (HRP)-conjugated secondary antibody.	('1:8000', 'Var', (278, 284))	('poly (ADP-ribose) polymerase', 'Gene', '142', (193, 221))	('horseradish', 'Species', '3704', (397, 408))	('beta-actin', 'Gene', '728378', (295, 305))	('Bax', 'Gene', '581', (272, 275))	('poly (ADP-ribose) polymerase', 'Gene', (193, 221))	('beta-actin', 'Gene', (295, 305))	('Bcl-2', 'Gene', (244, 249))	('mouse', 'Species', '10090', (110, 115))	('PARP', 'Gene', (223, 227))	('Bax', 'Gene', (272, 275))	('rabbit', 'Species', '9986', (161, 167))	('PARP', 'Gene', '142', (223, 227))	('1:2000', 'Var', (307, 313))	('Bcl-2', 'Gene', '596', (244, 249))
185149	31024953	Recently, various degrees of associations between P. gingivalis and digestive system cancers, including oral squamous cell carcinoma in the oral cavity, oesophageal squamous carcinoma in the digestive tract, and pancreatic cancer in pancreatic tissues, have been displayed in multiple clinical and experimental studies.	('pancreatic cancer', 'Disease', 'MESH:D010190', (212, 229))	('carcinoma in the oral cavity', 'Phenotype', 'HP:0100649', (123, 151))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (104, 132))	('pancreatic', 'Disease', 'MESH:D010195', (233, 243))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (165, 183))	('system cancers', 'Disease', 'MESH:D009369', (78, 92))	('oral squamous cell carcinoma', 'Disease', (104, 132))	('pancreatic', 'Disease', (212, 222))	('pancreatic cancer', 'Disease', (212, 229))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (109, 132))	('oesophageal squamous carcinoma', 'Disease', 'MESH:D002294', (153, 183))	('P. gingivalis', 'Var', (50, 63))	('system cancers', 'Disease', (78, 92))	('pancreatic', 'Disease', (233, 243))	('carcinoma', 'Phenotype', 'HP:0030731', (174, 183))	('cancers', 'Phenotype', 'HP:0002664', (85, 92))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (212, 229))	('oesophageal squamous carcinoma', 'Disease', (153, 183))	('P. gingivalis', 'Species', '837', (50, 63))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('carcinoma in the digestive tract', 'Phenotype', 'HP:0002672', (174, 206))	('associations', 'Interaction', (29, 41))	('pancreatic', 'Disease', 'MESH:D010195', (212, 222))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('squamous cell carcinoma in the oral cavity', 'Phenotype', 'HP:0030413', (109, 151))
185150	31024953	Since P. gingivalis has a strong association with periodontal diseases, not only the relationships between P. gingivalis and digestive system tumours but also the effects induced by periodontal diseases on cancers are well-illustrated in this review.	('periodontal disease', 'Phenotype', 'HP:0000704', (50, 69))	('P. gingivalis', 'Var', (6, 19))	('periodontal disease', 'Disease', 'MESH:D010510', (50, 69))	('periodontal diseases', 'Phenotype', 'HP:0000704', (50, 70))	('P. gingivalis', 'Species', '837', (6, 19))	('periodontal disease', 'Phenotype', 'HP:0000704', (182, 201))	('cancers', 'Phenotype', 'HP:0002664', (206, 213))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('periodontal disease', 'Disease', 'MESH:D010510', (182, 201))	('system tumours', 'Disease', 'MESH:D009369', (135, 149))	('P. gingivalis', 'Species', '837', (107, 120))	('periodontal diseases', 'Phenotype', 'HP:0000704', (182, 202))	('tumours', 'Phenotype', 'HP:0002664', (142, 149))	('periodontal disease', 'Disease', (50, 69))	('periodontal diseases on cancers', 'Disease', 'MESH:D010510', (182, 213))	('system tumours', 'Disease', (135, 149))	('periodontal diseases on cancers', 'Disease', (182, 213))	('tumour', 'Phenotype', 'HP:0002664', (142, 148))	('association', 'Interaction', (33, 44))
185153	31024953	One important carcinogenic effect of P. gingivalis is inhibiting the apoptosis of epithelial cells, which also plays an intrinsic role in protecting cancerous cells.	('cancerous', 'Disease', (149, 158))	('carcinogenic', 'Disease', 'MESH:D063646', (14, 26))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('carcinogenic', 'Disease', (14, 26))	('cancerous', 'Disease', 'MESH:D009369', (149, 158))	('apoptosis of epithelial cells', 'CPA', (69, 98))	('P. gingivalis', 'Species', '837', (37, 50))	('P. gingivalis', 'Var', (37, 50))	('inhibiting', 'NegReg', (54, 64))
185154	31024953	Some signalling pathways activated by P. gingivalis are involved in cell apoptosis, tumourigenesis, immune evasion and cell invasion of tumour cells.	('tumour', 'Disease', (84, 90))	('tumour', 'Disease', 'MESH:D009369', (136, 142))	('P. gingivalis', 'Species', '837', (38, 51))	('P. gingivalis', 'Var', (38, 51))	('tumour', 'Disease', (136, 142))	('tumour', 'Phenotype', 'HP:0002664', (136, 142))	('tumour', 'Phenotype', 'HP:0002664', (84, 90))	('tumour', 'Disease', 'MESH:D009369', (84, 90))
185155	31024953	In addition, metabolism of potentially carcinogenic substances caused by P. gingivalis is also one of the connections between this bacterium and cancers.	('cancers', 'Disease', (145, 152))	('carcinogenic substances', 'Disease', (39, 62))	('cancers', 'Phenotype', 'HP:0002664', (145, 152))	('connections', 'Reg', (106, 117))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('P. gingivalis', 'Species', '837', (73, 86))	('P. gingivalis', 'Var', (73, 86))	('metabolism of', 'MPA', (13, 26))	('cancers', 'Disease', 'MESH:D009369', (145, 152))	('carcinogenic substances', 'Disease', 'MESH:D019966', (39, 62))
185157	31024953	For the strong association between P. gingivalis and periodontal diseases, we also interpret how periodontal diseases push effects on digestive system tumours.	('periodontal disease', 'Phenotype', 'HP:0000704', (97, 116))	('periodontal disease', 'Phenotype', 'HP:0000704', (53, 72))	('tumour', 'Phenotype', 'HP:0002664', (151, 157))	('periodontal diseases', 'Phenotype', 'HP:0000704', (53, 73))	('P. gingivalis', 'Species', '837', (35, 48))	('P. gingivalis', 'Var', (35, 48))	('tumours', 'Phenotype', 'HP:0002664', (151, 158))	('periodontal disease', 'Disease', (97, 116))	('periodontal disease', 'Disease', (53, 72))	('periodontal disease', 'Disease', 'MESH:D010510', (97, 116))	('periodontal disease', 'Disease', 'MESH:D010510', (53, 72))	('system tumours', 'Disease', (144, 158))	('periodontal diseases', 'Phenotype', 'HP:0000704', (97, 117))	('effects', 'Reg', (123, 130))	('system tumours', 'Disease', 'MESH:D009369', (144, 158))
185159	31024953	In addition, the mechanisms by which P. gingivalis affects the occurrence and development of carcinomas are covered, including immune evasion, tumourigenesis, inhibition of apoptosis and invasion of tumour cells.	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('tumour', 'Phenotype', 'HP:0002664', (199, 205))	('apoptosis', 'CPA', (173, 182))	('tumour', 'Phenotype', 'HP:0002664', (143, 149))	('immune evasion', 'MPA', (127, 141))	('tumour', 'Disease', 'MESH:D009369', (143, 149))	('tumour', 'Disease', 'MESH:D009369', (199, 205))	('carcinomas', 'Phenotype', 'HP:0030731', (93, 103))	('carcinomas', 'Disease', (93, 103))	('tumour', 'Disease', (199, 205))	('carcinomas', 'Disease', 'MESH:D002277', (93, 103))	('tumour', 'Disease', (143, 149))	('affects', 'Reg', (51, 58))	('P. gingivalis', 'Species', '837', (37, 50))	('P. gingivalis', 'Var', (37, 50))
185169	31024953	Recently, an increasing number of investigations have focused on cancers related to P. gingivalis.	('cancers', 'Disease', (65, 72))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('cancers', 'Phenotype', 'HP:0002664', (65, 72))	('cancers', 'Disease', 'MESH:D009369', (65, 72))	('P. gingivalis', 'Species', '837', (84, 97))	('P. gingivalis', 'Var', (84, 97))
185176	31024953	Upon alcohol drinking, P. gingivalis would dehydrogenate ethanol to acetaldehyde, which is a carcinogenic derivative and capable of contributing to DNA damage, mutation and excessive proliferation of the epithelium.	('mutation', 'Var', (160, 168))	('acetaldehyde', 'Chemical', 'MESH:D000079', (68, 80))	('DNA damage', 'MPA', (148, 158))	('alcohol', 'Chemical', 'MESH:D000438', (5, 12))	('excessive proliferation', 'CPA', (173, 196))	('contributing', 'Reg', (132, 144))	('ethanol', 'Chemical', 'MESH:D000431', (57, 64))	('carcinogenic', 'Disease', 'MESH:D063646', (93, 105))	('carcinogenic', 'Disease', (93, 105))	('P. gingivalis', 'Species', '837', (23, 36))	('alcohol drinking', 'Phenotype', 'HP:0030955', (5, 21))
185178	31024953	Meanwhile, these authors suggested that P. gingivalis may lead to mouth cancer and the induction of epithelial cell transformation into a tumour.	('epithelial cell transformation', 'CPA', (100, 130))	('P. gingivalis', 'Var', (40, 53))	('P. gingivalis', 'Species', '837', (40, 53))	('mouth cancer', 'Disease', (66, 78))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('tumour', 'Phenotype', 'HP:0002664', (138, 144))	('lead to', 'Reg', (58, 65))	('mouth cancer', 'Phenotype', 'HP:0012290', (66, 78))	('mouth cancer', 'Disease', 'MESH:D009062', (66, 78))	('tumour', 'Disease', 'MESH:D009369', (138, 144))	('tumour', 'Disease', (138, 144))
185179	31024953	In a meta-analysis, the prevalence of P. gingivalis was 40.7%, and P. gingivalis made the chances of cancer and periodontal disease increasing 1.36 times.	('increasing', 'PosReg', (132, 142))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('periodontal disease', 'Phenotype', 'HP:0000704', (112, 131))	('cancer', 'Disease', (101, 107))	('P. gingivalis', 'Species', '837', (38, 51))	('periodontal disease', 'Disease', 'MESH:D010510', (112, 131))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('periodontal disease', 'Disease', (112, 131))	('P. gingivalis', 'Species', '837', (67, 80))	('P. gingivalis', 'Var', (67, 80))
185182	31024953	By activating ERK1/2-Ets1, p38/HSP27, and PAR2/NF-kB pathways, P. gingivalis increases pro-matrix metalloproteinase-9 (proMMP-9) levels and consequently promotes cellular invasion of OSCC cell lines when the proenzyme is stimulated by gingipains.	('p38/HSP27', 'Pathway', (27, 36))	('activating', 'PosReg', (3, 13))	('P. gingivalis', 'Var', (63, 76))	('P. gingivalis', 'Species', '837', (63, 76))	('gingivalis increases', 'Phenotype', 'HP:0000212', (66, 86))	('levels', 'MPA', (129, 135))	('increases', 'PosReg', (77, 86))	('cellular invasion of OSCC cell lines', 'CPA', (162, 198))	('promotes', 'PosReg', (153, 161))	('PAR2/NF-kB pathways', 'Pathway', (42, 61))	('ERK1/2-Ets1', 'Pathway', (14, 25))
185186	31024953	By establishing a long-term model in which human immortalized oral epithelial cells were chronically challenged with P. gingivalis for up to 23 wk, Geng et al found that long-term exposure to P. gingivalis accelerated the cell cycle and promoted cell migration as well as invasion abilities, both of which eventually induced metastatic proliferation in distant organs.	('metastatic proliferation in distant organs', 'CPA', (325, 367))	('invasion abilities', 'CPA', (272, 290))	('P. gingivalis', 'Var', (192, 205))	('P. gingivalis', 'Species', '837', (192, 205))	('P. gingivalis', 'Species', '837', (117, 130))	('promoted', 'PosReg', (237, 245))	('cell cycle', 'CPA', (222, 232))	('accelerated', 'PosReg', (206, 217))	('cell migration', 'CPA', (246, 260))	('induced', 'Reg', (317, 324))	('human', 'Species', '9606', (43, 48))
185193	31024953	The similarity in histology between oesophageal squamous cells and oral squamous cells is well-known, and it has been revealed that there is a high frequency of P. gingivalis (61%) in ESCC.	('P. gingivalis', 'Var', (161, 174))	('P. gingivalis', 'Species', '837', (161, 174))	('ESCC', 'Disease', (184, 188))
185194	31024953	In this study, the expression intensity of P. gingivalis antigen and the exclusive Lys-gingipain protease, as well as the detection of the P. gingivalis-specific 16S rDNA in ESCC patients, all of them were notably higher in tumour tissue than in ambient tissue or normal controls.	('higher', 'PosReg', (214, 220))	('tumour', 'Phenotype', 'HP:0002664', (224, 230))	('P. gingivalis', 'Species', '837', (139, 152))	('ESCC', 'Disease', (174, 178))	('expression intensity', 'MPA', (19, 39))	('tumour', 'Disease', 'MESH:D009369', (224, 230))	('patients', 'Species', '9606', (179, 187))	('tumour', 'Disease', (224, 230))	('P. gingivalis-specific', 'Var', (139, 161))	('P. gingivalis', 'Species', '837', (43, 56))
185196	31024953	Such conclusions not only firstly proved that infection with P. gingivalis would act as a new risk factor of ESCC, but also indicated that P. gingivalis could serve as a prognostic biomarker for ESCC.	('P. gingivalis', 'Species', '837', (61, 74))	('P. gingivalis', 'Var', (61, 74))	('ESCC', 'Disease', (109, 113))	('ESCC', 'Disease', (195, 199))	('P. gingivalis', 'Var', (139, 152))	('infection', 'Disease', (46, 55))	('infection', 'Disease', 'MESH:D007239', (46, 55))	('P. gingivalis', 'Species', '837', (139, 152))
185197	31024953	The inhibition of epithelial cell apoptosis, the promotion of tumour cell immune invasion and the metabolism of potentially carcinogenic substances induced by P. gingivalis all contribute to the occurrence and development of ESCC.	('epithelial cell apoptosis', 'CPA', (18, 43))	('ESCC', 'Disease', (225, 229))	('tumour', 'Phenotype', 'HP:0002664', (62, 68))	('promotion', 'PosReg', (49, 58))	('tumour', 'Disease', 'MESH:D009369', (62, 68))	('P. gingivalis', 'Species', '837', (159, 172))	('P. gingivalis', 'Var', (159, 172))	('tumour', 'Disease', (62, 68))	('carcinogenic substances', 'Disease', (124, 147))	('metabolism of', 'MPA', (98, 111))	('carcinogenic substances', 'Disease', 'MESH:D019966', (124, 147))	('inhibition', 'NegReg', (4, 14))
185200	31024953	Finally, interestingly, the rate of infection of P. gingivalis is much higher in oesophageal cancers than in cardiac cancers and is approximately as low as zero in gastric cancer, which is due to lack of acid adaptation.	('cardiac cancers', 'Disease', (109, 124))	('infection', 'Disease', 'MESH:D007239', (36, 45))	('gastric cancer', 'Phenotype', 'HP:0012126', (164, 178))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('cardiac cancers', 'Disease', 'MESH:D006338', (109, 124))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('cancers', 'Phenotype', 'HP:0002664', (93, 100))	('higher', 'Reg', (71, 77))	('oesophageal cancers', 'Disease', (81, 100))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('P. gingivalis', 'Species', '837', (49, 62))	('P. gingivalis', 'Var', (49, 62))	('gastric cancer', 'Disease', 'MESH:D013274', (164, 178))	('gastric cancer', 'Disease', (164, 178))	('cancers', 'Phenotype', 'HP:0002664', (117, 124))	('phageal cancer', 'Phenotype', 'HP:0100751', (85, 99))	('infection', 'Disease', (36, 45))	('oesophageal cancers', 'Disease', 'MESH:D009369', (81, 100))
185208	31024953	As Dr Miller recently demonstrated, P. gingivalis initiated the Toll-like receptor (TLR) signalling pathways, while TLR activation critically contributed to pancreatic carcinogenesis in animal models.	('P. gingivalis', 'Species', '837', (36, 49))	('pancreatic carcinogenesis', 'Disease', (157, 182))	('contributed', 'Reg', (142, 153))	('pancreatic carcinogenesis', 'Disease', 'MESH:D063646', (157, 182))	('activation', 'PosReg', (120, 130))	('P. gingivalis', 'Var', (36, 49))	('initiated', 'PosReg', (50, 59))
185210	31024953	Additionally, high rates of tumour suppressor gene p53 mutations were detected in pancreatic cancer patients, and it was concluded that abnormality of the p53 gene is a significant event in human pancreatic tumourigenesis.	('pancreatic tumourigenesis', 'Disease', (196, 221))	('p53', 'Gene', (51, 54))	('tumour', 'Phenotype', 'HP:0002664', (28, 34))	('detected', 'Reg', (70, 78))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (82, 99))	('tumour', 'Disease', 'MESH:D009369', (28, 34))	('patients', 'Species', '9606', (100, 108))	('pancreatic tumourigenesis', 'Disease', 'MESH:D010195', (196, 221))	('tumour', 'Disease', (28, 34))	('human', 'Species', '9606', (190, 195))	('pancreatic cancer', 'Disease', 'MESH:D010190', (82, 99))	('p53', 'Gene', '7157', (155, 158))	('mutations', 'Var', (55, 64))	('tumour', 'Phenotype', 'HP:0002664', (207, 213))	('pancreatic cancer', 'Disease', (82, 99))	('tumour', 'Disease', 'MESH:D009369', (207, 213))	('abnormality', 'Var', (136, 147))	('p53', 'Gene', '7157', (51, 54))	('tumour', 'Disease', (207, 213))	('p53', 'Gene', (155, 158))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))
185211	31024953	In addition, in the progression of P. gingivalis inhibiting epithelial cell apoptosis, p53 can be activated by P. gingivalis invasion.	('activated', 'PosReg', (98, 107))	('p53', 'Gene', (87, 90))	('p53', 'Gene', '7157', (87, 90))	('P. gingivalis', 'Var', (111, 124))	('P. gingivalis', 'Species', '837', (35, 48))	('P. gingivalis', 'Species', '837', (111, 124))	('inhibiting', 'NegReg', (49, 59))
185212	31024953	As a result, mutations in p53 can play a role as a bridge that links P. gingivalis with the development of pancreatic cancer, but further investigations are needed to enrich this link.	('pancreatic cancer', 'Disease', (107, 124))	('pancreatic cancer', 'Disease', 'MESH:D010190', (107, 124))	('P. gingivalis', 'Species', '837', (69, 82))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('p53', 'Gene', (26, 29))	('p53', 'Gene', '7157', (26, 29))	('mutations', 'Var', (13, 22))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (107, 124))
185213	31024953	In summary, P. gingivalis may be considered a biomarker in the occurrence and development of pancreatic cancer.	('pancreatic cancer', 'Disease', (93, 110))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('pancreatic cancer', 'Disease', 'MESH:D010190', (93, 110))	('P. gingivalis', 'Species', '837', (12, 25))	('P. gingivalis', 'Var', (12, 25))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (93, 110))
185214	31024953	It is urgent to conduct more research to explain the mechanism by which P. gingivalis acts on pancreatic cancer and to improve the prevention and treatment of pancreatic cancer.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (159, 176))	('pancreatic cancer', 'Disease', (159, 176))	('pancreatic cancer', 'Disease', 'MESH:D010190', (159, 176))	('acts', 'Reg', (86, 90))	('pancreatic cancer', 'Disease', (94, 111))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('pancreatic cancer', 'Disease', 'MESH:D010190', (94, 111))	('P. gingivalis', 'Var', (72, 85))	('P. gingivalis', 'Species', '837', (72, 85))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (94, 111))
185219	31024953	Among these bacterial species, P. gingivalis shows the strongest association with periodontitis.	('periodontitis', 'Disease', 'MESH:D010518', (82, 95))	('periodontitis', 'Phenotype', 'HP:0000704', (82, 95))	('periodontitis', 'Disease', (82, 95))	('P. gingivalis', 'Species', '837', (31, 44))	('association', 'Interaction', (65, 76))	('P. gingivalis', 'Var', (31, 44))
185220	31024953	Additionally, P. gingivalis acts as an independent risk factor for the above-mentioned cancers.	('cancers', 'Disease', (87, 94))	('P. gingivalis', 'Var', (14, 27))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('P. gingivalis', 'Species', '837', (14, 27))	('cancers', 'Disease', 'MESH:D009369', (87, 94))	('cancers', 'Phenotype', 'HP:0002664', (87, 94))
185242	31024953	The prevention and treatment to those digestive cancers are specific and complicated for the existence of P. gingivalis.	('cancers', 'Disease', (48, 55))	('P. gingivalis', 'Var', (106, 119))	('P. gingivalis', 'Species', '837', (106, 119))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('cancers', 'Disease', 'MESH:D009369', (48, 55))	('cancers', 'Phenotype', 'HP:0002664', (48, 55))
185244	31024953	For that P. gingivalis owns the characteristics of high genetic capability, this bacterium could resist any adverse environment that hindering its development; P. gingivalis could also be capable of resisting various antibiotics that in use currently.	('P. gingivalis', 'Var', (160, 173))	('resisting', 'MPA', (199, 208))	('P. gingivalis', 'Species', '837', (9, 22))	('P. gingivalis', 'Species', '837', (160, 173))
185246	31024953	Because of the specificity of this bacterium, the cancer treatment related to P. gingivalis is more directional and targeted.	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('P. gingivalis', 'Species', '837', (78, 91))	('P. gingivalis', 'Var', (78, 91))
185247	31024953	First, screening for P. gingivalis in dental plaques may identify susceptible subjects, which could help decrease the occurrence of cancers.	('cancers', 'Phenotype', 'HP:0002664', (132, 139))	('cancers', 'Disease', (132, 139))	('dental plaque', 'Phenotype', 'HP:0000670', (38, 51))	('cancers', 'Disease', 'MESH:D009369', (132, 139))	('P. gingivalis', 'Species', '837', (21, 34))	('P. gingivalis', 'Var', (21, 34))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('decrease', 'NegReg', (105, 113))	('dental plaques', 'Phenotype', 'HP:0000670', (38, 52))
185264	31024953	In summary, the combination of antimicrobial therapy against P. gingivalis and tumour clearance with surgery, radiotherapy or chemotherapy, and neoadjuvant therapy is a good treatment for these digestive system cancers caused by P. gingivalis.	('P. gingivalis', 'Species', '837', (61, 74))	('cancers', 'Phenotype', 'HP:0002664', (211, 218))	('system cancers', 'Disease', (204, 218))	('tumour', 'Phenotype', 'HP:0002664', (79, 85))	('system cancers', 'Disease', 'MESH:D009369', (204, 218))	('P. gingivalis', 'Species', '837', (229, 242))	('P. gingivalis', 'Var', (229, 242))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('tumour', 'Disease', 'MESH:D009369', (79, 85))	('tumour', 'Disease', (79, 85))	('caused', 'Reg', (219, 225))
185269	31024953	The correlation of orodigestive cancer mortality to P. gingivalis was first and directly illustrated in a cohort study from Ahn et al, who pinpointed that P. gingivalis would also act as a microbial marker full of value in such carcinomas.	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('cancer', 'Disease', (32, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (228, 237))	('P. gingivalis', 'Species', '837', (52, 65))	('P. gingivalis', 'Species', '837', (155, 168))	('P. gingivalis', 'Var', (155, 168))	('carcinomas', 'Phenotype', 'HP:0030731', (228, 238))	('carcinomas', 'Disease', (228, 238))	('carcinomas', 'Disease', 'MESH:D002277', (228, 238))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))
185270	31024953	In this study, non-parametric trend analysis for all subjects also showed an increase in orodigestive cancer mortality with the increase of anti-P. gingivalis IgG levels.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('increase', 'PosReg', (128, 136))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('anti-P.', 'Var', (140, 147))	('P. gingivalis', 'Species', '837', (145, 158))	('increase', 'PosReg', (77, 85))
185272	31024953	In addition to P. gingivalis inducing the invasion of tumour cells and activating TLR mentioned above, other possible mechanisms have also been identified.	('tumour', 'Disease', 'MESH:D009369', (54, 60))	('tumour', 'Disease', (54, 60))	('inducing', 'Reg', (29, 37))	('P. gingivalis', 'Species', '837', (15, 28))	('P. gingivalis', 'Var', (15, 28))	('TLR', 'Gene', (82, 85))	('tumour', 'Phenotype', 'HP:0002664', (54, 60))
185274	31024953	The NDK inhibits ATP activation of purinergic receptor (P2X7) receptors and consequently depress the production of IL-1beta in epithelium.	('P2X7) receptors', 'Protein', (56, 71))	('inhibits', 'NegReg', (8, 16))	('ATP', 'Chemical', 'MESH:D000255', (17, 20))	('NDK', 'Var', (4, 7))	('depress', 'NegReg', (89, 96))	('ATP activation', 'MPA', (17, 31))	('production of IL-1beta', 'MPA', (101, 123))
185278	31024953	Second, Yilmaz et al have noted that the inhibition of epithelial cell apoptosis is an important carcinogenic effect of P. gingivalis and is also an intrinsic protective mechanism of cancerous cells.	('P. gingivalis', 'Var', (120, 133))	('cancerous', 'Disease', (183, 192))	('P. gingivalis', 'Species', '837', (120, 133))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('epithelial cell apoptosis', 'CPA', (55, 80))	('cancerous', 'Disease', 'MESH:D009369', (183, 192))	('carcinogenic', 'Disease', 'MESH:D063646', (97, 109))	('inhibition', 'NegReg', (41, 51))	('carcinogenic', 'Disease', (97, 109))
185279	31024953	In addition, P. gingivalis modulates the expressing levels of microRNAs (miRNAs), and the upregulation of miR-203 caused by P. gingivalis results in the decreasing levels of negative regulator SOCS3 and subsequently suppressing apoptosis of epithelium.	('decreasing', 'NegReg', (153, 163))	('negative regulator SOCS3', 'MPA', (174, 198))	('expressing levels', 'MPA', (41, 58))	('upregulation', 'PosReg', (90, 102))	('P. gingivalis', 'Var', (124, 137))	('suppressing', 'NegReg', (216, 227))	('P. gingivalis', 'Species', '837', (13, 26))	('P. gingivalis', 'Species', '837', (124, 137))	('miR-203', 'Gene', (106, 113))	('apoptosis of epithelium', 'CPA', (228, 251))	('levels', 'MPA', (164, 170))
185282	31024953	Fourth, those carcinogenesis caused by P. gingivalis also contributes to metabolising potential carcinogen.	('P. gingivalis', 'Species', '837', (39, 52))	('metabolising potential carcinogen', 'MPA', (73, 106))	('carcinogenesis', 'Disease', 'MESH:D063646', (14, 28))	('carcinogenesis', 'Disease', (14, 28))	('P. gingivalis', 'Var', (39, 52))
185285	31024953	Lastly, P. gingivalis establishes chronic infections that involve intracellular persistence within epithelial cells.	('chronic infection', 'Phenotype', 'HP:0031035', (34, 51))	('chronic infections', 'Disease', (34, 52))	('chronic infections', 'Disease', 'MESH:D006505', (34, 52))	('chronic infections', 'Phenotype', 'HP:0031035', (34, 52))	('P. gingivalis', 'Species', '837', (8, 21))	('P. gingivalis', 'Var', (8, 21))
185287	31024953	All the above-mentioned possible mechanisms of cancers caused by P. gingivalis are shown in Figure 1.	('P. gingivalis', 'Species', '837', (65, 78))	('P. gingivalis', 'Var', (65, 78))	('caused', 'Reg', (55, 61))	('cancers', 'Disease', 'MESH:D009369', (47, 54))	('cancers', 'Phenotype', 'HP:0002664', (47, 54))	('cancers', 'Disease', (47, 54))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))
185288	31024953	P. gingivalis is involved in periodontal disease and several cancers.	('periodontal disease', 'Phenotype', 'HP:0000704', (29, 48))	('P. gingivalis', 'Species', '837', (0, 13))	('P. gingivalis', 'Var', (0, 13))	('involved', 'Reg', (17, 25))	('cancers', 'Disease', 'MESH:D009369', (61, 68))	('cancers', 'Phenotype', 'HP:0002664', (61, 68))	('cancers', 'Disease', (61, 68))	('periodontal disease', 'Disease', (29, 48))	('periodontal disease', 'Disease', 'MESH:D010510', (29, 48))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))
185290	31024953	One critical carcinogenesis caused by P. gingivalis is inhibiting the apoptotic effects of epithelium, which also function as the intrinsic protective mechanism of cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('carcinogenesis', 'Disease', 'MESH:D063646', (13, 27))	('P. gingivalis', 'Species', '837', (38, 51))	('P. gingivalis', 'Var', (38, 51))	('carcinogenesis', 'Disease', (13, 27))	('cancer', 'Disease', (164, 170))	('apoptotic effects of epithelium', 'CPA', (70, 101))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('inhibiting', 'NegReg', (55, 65))
185291	31024953	P. gingivalis has a strong association with oral cancer, and the treatment of oral cancer is abundant and has been improved in the clinic.	('oral cancer', 'Disease', (44, 55))	('oral cancer', 'Disease', (78, 89))	('P. gingivalis', 'Species', '837', (0, 13))	('P. gingivalis', 'Var', (0, 13))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('association', 'Interaction', (27, 38))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('oral cancer', 'Disease', 'MESH:D009062', (44, 55))	('oral cancer', 'Disease', 'MESH:D009062', (78, 89))
185293	31024953	For pancreatic cancer, the evidence concerning the role of P. gingivalis is still limited, while the relationship between periodontal diseases and pancreatic cancer is very large.	('pancreatic cancer', 'Disease', 'MESH:D010190', (147, 164))	('pancreatic cancer', 'Disease', (4, 21))	('pancreatic cancer', 'Disease', 'MESH:D010190', (4, 21))	('periodontal disease', 'Disease', (122, 141))	('P. gingivalis', 'Var', (59, 72))	('P. gingivalis', 'Species', '837', (59, 72))	('periodontal disease', 'Disease', 'MESH:D010510', (122, 141))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (4, 21))	('periodontal disease', 'Phenotype', 'HP:0000704', (122, 141))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (147, 164))	('periodontal diseases', 'Phenotype', 'HP:0000704', (122, 142))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('pancreatic cancer', 'Disease', (147, 164))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
185308	30501131	The regulation of miRNAs has been evaluated at different levels, including in studies of genetic mutations, epigenetic modifications, and alterations in the microprocessor components, such as DROSHA, DGCR8, and DICER1.	('DGCR8', 'Gene', (200, 205))	('mutations', 'Var', (97, 106))	('DROSHA', 'Gene', '29102', (192, 198))	('DROSHA', 'Gene', (192, 198))	('DGCR8', 'Gene', '54487', (200, 205))	('DICER1', 'Gene', (211, 217))	('DICER1', 'Gene', '23405', (211, 217))
185331	30501131	For each cancer type, we investigated whether miRNAs tend to be present in the SCNA regions because previous studies showed that miRNAs are more likely to be found in copy number-altered regions.	('cancer', 'Disease', (9, 15))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('copy number-altered', 'Var', (167, 186))
185334	30501131	Furthermore, we calculated the fractions of genomic regions with SCNAs across all genomes, which were shown to be higher than the fractions of miRNAs with SCNAs in all cancer types except for in KIRC samples.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('SCNAs', 'Var', (65, 70))	('cancer', 'Disease', (168, 174))	('cancer', 'Disease', 'MESH:D009369', (168, 174))
185360	30501131	investigated the co-deletion of mir-491 and CDKN2A in glioblastoma and demonstrated that the deletion of mir-491 was not just a passenger event and that mir-491 acts as a tumor suppressor.	('mir-491', 'Gene', (153, 160))	('glioblastoma', 'Disease', 'MESH:D005909', (54, 66))	('mir-491', 'Gene', (32, 39))	('glioblastoma', 'Phenotype', 'HP:0012174', (54, 66))	('CDKN2A', 'Gene', (44, 50))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('mir-491', 'Gene', (105, 112))	('mir-491', 'Gene', '574444', (153, 160))	('CDKN2A', 'Gene', '1029', (44, 50))	('mir-491', 'Gene', '574444', (32, 39))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', (171, 176))	('mir-491', 'Gene', '574444', (105, 112))	('deletion', 'Var', (93, 101))	('glioblastoma', 'Disease', (54, 66))
185362	30501131	These results suggest that co-deletion of hsa-mir-491 and CDKN2A plays an important role in BLCA, LUAD, and UCEC, and that co-deletion of mir-31 and CDKN2A is a crucial event in BLCA and LUSC.	('co-deletion', 'Var', (27, 38))	('CDKN2A', 'Gene', '1029', (149, 155))	('CDKN2A', 'Gene', (58, 64))	('LUAD', 'Disease', (98, 102))	('UCEC', 'Disease', (108, 112))	('hsa-mir-491', 'Gene', (42, 53))	('BLCA', 'Disease', (92, 96))	('role', 'Reg', (84, 88))	('BLCA', 'Phenotype', 'HP:0002862', (92, 96))	('mir-31', 'Gene', (138, 144))	('CDKN2A', 'Gene', '1029', (58, 64))	('LUSC', 'Phenotype', 'HP:0030359', (187, 191))	('BLCA', 'Disease', (178, 182))	('CDKN2A', 'Gene', (149, 155))	('hsa-mir-491', 'Gene', '574444', (42, 53))	('BLCA', 'Phenotype', 'HP:0002862', (178, 182))	('mir-31', 'Gene', '407035', (138, 144))	('LUAD', 'Phenotype', 'HP:0030078', (98, 102))	('co-deletion', 'Var', (123, 134))
185365	30501131	The survival of cancer patients was analyzed to determine whether copy number changes of 80 SCNA-miRNAs were associated with death by cancer (Figure 5).	('cancer', 'Disease', 'MESH:D009369', (16, 22))	('patients', 'Species', '9606', (23, 31))	('cancer', 'Disease', (16, 22))	('cancer', 'Disease', (134, 140))	('SCNA-miRNAs', 'Gene', (92, 103))	('death by cancer', 'Disease', 'MESH:D003643', (125, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('associated with', 'Reg', (109, 124))	('death by cancer', 'Disease', (125, 140))	('copy number changes', 'Var', (66, 85))
185373	30501131	For deleted miRNAs, for mir-31, the mean survival time of patients in the deletion group was shorter than that in the unchanged group of BRCA and KIRC patients (q = 0.0065 and 0.0024, respectively).	('BRCA', 'Gene', (137, 141))	('survival time', 'CPA', (41, 54))	('mir-31', 'Gene', '407035', (24, 30))	('deletion', 'Var', (74, 82))	('mir-31', 'Gene', (24, 30))	('patients', 'Species', '9606', (151, 159))	('shorter', 'NegReg', (93, 100))	('BRCA', 'Phenotype', 'HP:0003002', (137, 141))	('patients', 'Species', '9606', (58, 66))	('BRCA', 'Gene', '672', (137, 141))
185376	30501131	Mir-491 copy number alterations were shown to affect the survival of patients with BRCA and KIRC (q = 0.0071 and 0.023, respectively).	('BRCA', 'Phenotype', 'HP:0003002', (83, 87))	('BRCA', 'Gene', '672', (83, 87))	('Mir-491', 'Gene', '574444', (0, 7))	('Mir-491', 'Gene', (0, 7))	('BRCA', 'Gene', (83, 87))	('affect', 'Reg', (46, 52))	('copy number alterations', 'Var', (8, 31))	('patients', 'Species', '9606', (69, 77))	('survival', 'CPA', (57, 65))
185381	30501131	This suggests that alterations in these SCNA-miRNAs with a q-value < 0.05 affect patient survival by more than other miRNAs (p-value = 0.00254, Fisher's exact test).	('patient survival', 'CPA', (81, 97))	('alterations', 'Var', (19, 30))	('patient', 'Species', '9606', (81, 88))	('affect', 'Reg', (74, 80))
185413	30501131	Our results demonstrate that SCNA-miRNAs are more closely associated with cancer survival compared to other miRNAs.	('SCNA-miRNAs', 'Var', (29, 40))	('associated', 'Reg', (58, 68))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Disease', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
185462	30501131	Table S1: Analysis of patient survival according to copy numbers of the 84 pairs of SCNA-miRNAs and cancer types.	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('copy', 'Var', (52, 56))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('patient', 'Species', '9606', (22, 29))
185463	30501131	Table S3: miRNAs commonly correlated with SCNAs across seven cancer types.	('correlated with', 'Reg', (26, 41))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('cancer', 'Disease', (61, 67))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('SCNAs', 'Disease', (42, 47))	('miRNAs', 'Var', (10, 16))
185479	29590170	Multivariable analyses showed sarcopenia was independently associated with a male gender (odds ratio [OR], 11.13), elderly (OR, 2.02) and low BMI (OR, 6.28), stage IV (OR, 1.98), and high comorbidity (OR, 1.93).	('sarcopenia', 'Disease', 'MESH:D055948', (30, 40))	('sarcopenia', 'Disease', (30, 40))	('low BMI', 'Phenotype', 'HP:0045082', (138, 145))	('low', 'Var', (138, 141))
185481	29590170	Sarcopenia was found to be significantly associated with old age, male gender, an advanced stage, comorbidities, and low BMI in LCA.	('low BMI', 'Phenotype', 'HP:0045082', (117, 124))	('Sarcopenia', 'Disease', (0, 10))	('low BMI', 'Var', (117, 124))	('Sarcopenia', 'Disease', 'MESH:D055948', (0, 10))
185490	29590170	Many driver mutations found in adenocarcinoma, which facilitate individualized treatment and improve outcomes as compared with standard chemotherapy.	('mutations', 'Var', (12, 21))	('carcinoma', 'Phenotype', 'HP:0030731', (36, 45))	('men', 'Species', '9606', (84, 87))	('adenocarcinoma', 'Disease', (31, 45))	('improve', 'PosReg', (93, 100))	('adenocarcinoma', 'Disease', 'MESH:D000230', (31, 45))	('outcomes', 'MPA', (101, 109))
185505	29590170	Body mass index (BMI) was defined as weight divided by height squared (kg/m2), and BMI values were categorized as underweight (<18.5 kg/m2), normal (18.5-22.9 kg/m2), overweight (23.0-24.9 kg/m2), or obese (>=25 kg/m2).	('overweight', 'Phenotype', 'HP:0025502', (167, 177))	('obese', 'Disease', (200, 205))	('obese', 'Disease', 'MESH:D009765', (200, 205))	('<18.5 kg/m2', 'Var', (127, 138))
185517	29590170	The driver genetic abnormalities were investigated in non-small cell lung cancer (NSCLC); excluding patients whose information of EGFR (n = 62) and ALK (n = 54) was unavailable, epidermal growth factor receptor (EGFR) mutations was found in 32.6% and anaplastic lymphoma kinase (ALK) gene rearrangements was found in 4.7% in adenocarcinoma patients.	('adenocarcinoma', 'Disease', (325, 339))	('anaplastic lymphoma kinase', 'Gene', '238', (251, 277))	('ALK', 'Gene', '238', (148, 151))	('patients', 'Species', '9606', (100, 108))	('patients', 'Species', '9606', (340, 348))	('anaplastic lymphoma kinase', 'Gene', (251, 277))	('ALK', 'Gene', (148, 151))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (58, 80))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (54, 80))	('EGFR', 'Gene', (130, 134))	('EGFR', 'Gene', '1956', (212, 216))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('adenocarcinoma', 'Disease', 'MESH:D000230', (325, 339))	('found', 'Reg', (232, 237))	('lymphoma', 'Phenotype', 'HP:0002665', (262, 270))	('NSCLC', 'Disease', 'MESH:D002289', (82, 87))	('ALK', 'Gene', '238', (279, 282))	('epidermal growth factor receptor', 'Gene', (178, 210))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (54, 80))	('epidermal growth factor receptor', 'Gene', '1956', (178, 210))	('ALK', 'Gene', (279, 282))	('NSCLC', 'Disease', (82, 87))	('EGFR', 'Gene', '1956', (130, 134))	('EGFR', 'Gene', (212, 216))	('carcinoma', 'Phenotype', 'HP:0030731', (330, 339))	('mutations', 'Var', (218, 227))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (251, 270))	('non-small cell lung cancer', 'Disease', (54, 80))	('rearrangements', 'Var', (289, 303))	('genetic abnormalities', 'Disease', 'MESH:D030342', (11, 32))	('lung cancer', 'Phenotype', 'HP:0100526', (69, 80))	('men', 'Species', '9606', (298, 301))	('genetic abnormalities', 'Disease', (11, 32))
185525	29590170	Univariable analysis showed a non-adenocarcinoma histology, age (age >= 65 years), male gender, advanced stage (stage III or IV), high comorbidity (Charlson comorbidity index >= 3), low BMI (< 23 kg/m2), and a smoking history were associated with a higher prevalence of sarcopenia.	('non-adenocarcinoma', 'Disease', (30, 48))	('sarcopenia', 'Disease', 'MESH:D055948', (270, 280))	('low', 'Var', (182, 185))	('carcinoma', 'Phenotype', 'HP:0030731', (39, 48))	('low BMI', 'Phenotype', 'HP:0045082', (182, 189))	('sarcopenia', 'Disease', (270, 280))	('non-adenocarcinoma', 'Disease', 'MESH:D000230', (30, 48))
185540	29590170	On the other hand, in the advanced disease setting, the sub-classification of NSCLC is important for treatment decisions, because driver genetic abnormalities, such as, EGFR mutations and ALK gene rearrangements, have only been validated for a non-squamous histology.	('genetic abnormalities', 'Disease', 'MESH:D030342', (137, 158))	('ALK', 'Gene', (188, 191))	('genetic abnormalities', 'Disease', (137, 158))	('EGFR', 'Gene', '1956', (169, 173))	('ALK', 'Gene', '238', (188, 191))	('NSCLC', 'Disease', (78, 83))	('EGFR', 'Gene', (169, 173))	('mutations', 'Var', (174, 183))	('NSCLC', 'Disease', 'MESH:D002289', (78, 83))	('men', 'Species', '9606', (206, 209))	('men', 'Species', '9606', (106, 109))
185542	29590170	Multivariable analysis showed sarcopenia was significantly associated with a male gender, old age (>= 65 years), low BMI (< 23 kg/m2), and a high comorbidity score (Charlson comorbidity index >= 3).	('BMI', 'MPA', (117, 120))	('sarcopenia', 'Disease', 'MESH:D055948', (30, 40))	('low BMI', 'Phenotype', 'HP:0045082', (113, 120))	('low', 'Var', (113, 116))	('associated', 'Reg', (59, 69))	('sarcopenia', 'Disease', (30, 40))
185554	29590170	The prevalence of sarcopenia was found to be independently associated with age (>=65 years), male gender, high comorbidities Charlson comorbidity index >= 3), low BMI (< 23 kg/m2), and advanced stage (stage IV).	('low BMI', 'Phenotype', 'HP:0045082', (159, 166))	('sarcopenia', 'Disease', (18, 28))	('associated', 'Reg', (59, 69))	('sarcopenia', 'Disease', 'MESH:D055948', (18, 28))	('low', 'Var', (159, 162))
185556	29599978	Association between heme oxygenase-1 gene promoter polymorphisms and cancer susceptibility: A meta-analysis Numerous studies have focused on the association between heme oxygenase-1 (HO-1) gene promoter polymorphisms and susceptibility to cancer; however, results remain ambiguous.	('HO-1', 'Gene', (183, 187))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('heme oxygenase-1', 'Gene', '3162', (20, 36))	('HO-1', 'Gene', '3162', (183, 187))	('cancer', 'Disease', 'MESH:D009369', (239, 245))	('heme oxygenase-1', 'Gene', '3162', (165, 181))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('polymorphisms', 'Var', (203, 216))	('heme oxygenase-1', 'Gene', (165, 181))	('association', 'Interaction', (145, 156))	('cancer', 'Disease', (239, 245))	('heme oxygenase-1', 'Gene', (20, 36))	('cancer', 'Disease', (69, 75))
185558	29599978	A systematic search was used to assess the association of HO-1 gene polymorphisms with cancer susceptibility in the PubMed, Web of Science, Cochrane Library, Wanfang Data and China National Knowledge Infrastructure databases, with all reviewed studies published before April 10, 2017. Review Manager 5.3 and Stata 12.0 software were used to perform the meta-analysis.	('cancer', 'Disease', (87, 93))	('HO-1', 'Gene', (58, 62))	('HO-1', 'Gene', '3162', (58, 62))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('polymorphisms', 'Var', (68, 81))	('cancer', 'Disease', 'MESH:D009369', (87, 93))
185561	29599978	These findings indicated that there was no association of the HO-1 (GT)n and T(-413)A polymorphisms with cancer susceptibility, while the L-allele genotypes (LL and LS) of HO-1 (GT)n may be susceptibility factors for cancer in East Asian, digestive tract cancer in East Asian and squamous cell carcinoma populations.	('HO-1', 'Gene', (172, 176))	('digestive tract cancer', 'Phenotype', 'HP:0007378', (239, 261))	('T(-413)A', 'Gene', (77, 85))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', (255, 261))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (280, 303))	('cancer', 'Phenotype', 'HP:0002664', (255, 261))	('L-allele', 'Var', (138, 146))	('cancer', 'Disease', 'MESH:D009369', (217, 223))	('carcinoma', 'Phenotype', 'HP:0030731', (294, 303))	('squamous cell carcinoma', 'Disease', (280, 303))	('tract cancer', 'Disease', 'MESH:D014571', (249, 261))	('HO-1', 'Gene', '3162', (62, 66))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (255, 261))	('tract cancer', 'Disease', (249, 261))	('HO-1', 'Gene', (62, 66))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (280, 303))	('susceptibility factors', 'Reg', (190, 212))	('HO-1', 'Gene', '3162', (172, 176))	('cancer', 'Disease', (217, 223))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))
185567	29599978	Previous studies have indicated that the transition from normal to pre-cancer and cancer cells is a result of a multi-step accumulation of genetic and epigenetic modifications.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('cancer', 'Disease', (71, 77))	('epigenetic modifications', 'Var', (151, 175))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))
185568	29599978	Recent studies have focused on the interaction between heme oxygenase-1 (HO-1) gene polymorphisms and cancer.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('HO-1', 'Gene', '3162', (73, 77))	('interaction', 'Interaction', (35, 46))	('heme oxygenase-1', 'Gene', '3162', (55, 71))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('heme oxygenase-1', 'Gene', (55, 71))	('HO-1', 'Gene', (73, 77))	('polymorphisms', 'Var', (84, 97))
185571	29599978	In turn, ROS may modulate tumorigenesis by causing cell apoptosis/necrosis or an accumulation of DNA damage.	('DNA damage', 'MPA', (97, 107))	('necrosis', 'Disease', (66, 74))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('causing', 'Reg', (43, 50))	('necrosis', 'Disease', 'MESH:D009336', (66, 74))	('modulate', 'Reg', (17, 25))	('ROS', 'Chemical', 'MESH:D017382', (9, 12))	('ROS', 'Var', (9, 12))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))
185572	29599978	Two loci of the HO-1 gene have been focused on when regarding its potential association with cancer, namely the (GT)n repeat length polymorphism [which according to repeat length is divided into two classes: S (short) and L (long)] and T(-413)A (rs2071746); however, results so far are not conclusive.	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('association', 'Interaction', (76, 87))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('T(-413)A (rs2071746)', 'Var', (236, 256))	('HO-1', 'Gene', (16, 20))	('rs2071746);', 'Var', (246, 257))	('rs2071746', 'Mutation', 'rs2071746', (246, 255))	('HO-1', 'Gene', '3162', (16, 20))
185575	29599978	Based on previous observations, two previous meta-analyses focused on the association of HO-1 gene polymorphisms with cancer susceptibility, though again the data appears inconclusive.	('cancer', 'Disease', (118, 124))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('HO-1', 'Gene', '3162', (89, 93))	('polymorphisms', 'Var', (99, 112))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('association', 'Interaction', (74, 85))	('HO-1', 'Gene', (89, 93))
185577	29599978	The electronic databases PubMed , Web of Science , the Cochrane Library , Wanfang Data  and China National Knowledge Infrastructure  were searched for all studies published before April 10, 2017 that had examined the association between HO-1 gene polymorphisms and cancer.	('HO-1', 'Gene', (237, 241))	('cancer', 'Phenotype', 'HP:0002664', (265, 271))	('HO-1', 'Gene', '3162', (237, 241))	('polymorphisms', 'Var', (247, 260))	('cancer', 'Disease', (265, 271))	('cancer', 'Disease', 'MESH:D009369', (265, 271))
185580	29599978	Included studies met the following criteria: i) Case-control study or cohort study; ii) focus on the association of HO-1 (GT)n and T(-413)A polymorphisms with cancer; iii) provision of an odds ratio (OR) with 95% confidence intervals (CIs) or sufficient data for calculation of OR and 95% CIs.	('T(-413)A', 'Gene', (131, 139))	('cancer', 'Disease', (159, 165))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('polymorphisms', 'Var', (140, 153))	('HO-1', 'Gene', (116, 120))	('association', 'Interaction', (101, 112))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('HO-1', 'Gene', '3162', (116, 120))
185584	29599978	Thus, 14 studies were included in the meta-analysis, among which were 12 studies on (GT)n repeat length polymorphism and three studies on T(-413)A single nucleotide polymorphism (SNP) associations with cancer susceptibility (Table I).	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('single nucleotide polymorphism', 'Var', (147, 177))	('cancer', 'Disease', 'MESH:D009369', (202, 208))	('associations', 'Reg', (184, 196))	('cancer', 'Disease', (202, 208))
185586	29599978	No significant associations were identified between susceptibility to overall cancer and the SNP in any of the four genetic models screened (L vs. S, LL+LS vs. SS, LL vs. SS+SL, LL vs. SS).	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('L vs. S', 'Var', (141, 148))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('LL+LS vs. SS', 'Var', (150, 162))
185588	29599978	It was identified that the LL and L-allele (LL+LS) genotypes were associated with increased susceptibility to cancer compared with the SS+SL and SS genotypes in the East Asian subgroup (LL+LS vs. SS: OR=1.51, 95% CI=1.11-2.05, P=0.0003; LL vs. SS+SL: OR=1.44, 95% CI=1.04-2.01, P=0.03; LL vs. SS: OR=1.64, 95% CI=1.07-2.52, P=0.02).	('L-allele', 'Var', (34, 42))	('cancer', 'Disease', (110, 116))	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))
185597	29599978	The meta-analysis suggested that there were no significant associations between the HO-1 T(-413)A polymorphism and overall cancer susceptibility in any of the genetic models (Table II).	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('HO-1', 'Gene', (84, 88))	('cancer', 'Disease', (123, 129))	('polymorphism', 'Var', (98, 110))	('HO-1', 'Gene', '3162', (84, 88))
185605	29599978	However, the associations identified between the HO-1 polymorphisms and cancer susceptibility are inconsistent, and other studies have come to other conclusions.	('polymorphisms', 'Var', (54, 67))	('HO-1', 'Gene', (49, 53))	('HO-1', 'Gene', '3162', (49, 53))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('cancer', 'Disease', (72, 78))
185606	29599978	Therefore, the present study conducted an update meta-analysis following different inclusion criteria to that used previously to evaluate the association of HO-1 polymorphisms with cancer susceptibility.	('polymorphisms', 'Var', (162, 175))	('HO-1', 'Gene', '3162', (157, 161))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('HO-1', 'Gene', (157, 161))	('association', 'Interaction', (142, 153))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('cancer', 'Disease', (181, 187))
185608	29599978	However, on subgroup analysis, the LL and L-allele (LL+LS) genotypes of the HO-1(GT)n locus were associated with a higher susceptibility to squamous cell carcinoma, digestive tract cancer in East Asian carriers and overall cancer in East Asian carriers compared with the SS and/or SL genotype.	('L-allele', 'Var', (42, 50))	('susceptibility', 'Reg', (122, 136))	('HO-1', 'Gene', (76, 80))	('tract cancer', 'Disease', (175, 187))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('carcinoma', 'Phenotype', 'HP:0030731', (154, 163))	('HO-1', 'Gene', '3162', (76, 80))	('squamous cell carcinoma', 'Disease', (140, 163))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('cancer', 'Disease', 'MESH:D009369', (223, 229))	('digestive tract cancer', 'Phenotype', 'HP:0007378', (165, 187))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (140, 163))	('cancer', 'Disease', (181, 187))	('cancer', 'Disease', (223, 229))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (140, 163))	('tract cancer', 'Disease', 'MESH:D014571', (175, 187))
185610	29599978	The present study also identified no significant associations between the HO-1 T(-413)A SNP and overall cancer susceptibility.	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('T(-413)A', 'Var', (79, 87))	('HO-1', 'Gene', (74, 78))	('HO-1', 'Gene', '3162', (74, 78))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))
185612	29599978	Nevertheless, the current results indicated that there was no association of the HO-1 (GT)n and T(-413)A polymorphisms with overall cancer susceptibility.	('HO-1', 'Gene', '3162', (81, 85))	('cancer', 'Disease', (132, 138))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('association', 'Interaction', (62, 73))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('T(-413)A', 'Gene', (96, 104))	('HO-1', 'Gene', (81, 85))	('polymorphisms', 'Var', (105, 118))
185637	26835192	Clinical staging of this tumor, based on the American Joint Committee on Cancer (AJCC) :  TNM staging system for the nasal cavity and paranasal sinuses (7th edition, 2010), was T4N0M0.	('T4N0M0', 'Var', (177, 183))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('Cancer', 'Phenotype', 'HP:0002664', (73, 79))	('tumor', 'Disease', (25, 30))	('TNM', 'Gene', '10178', (90, 93))	('Cancer', 'Disease', (73, 79))	('TNM', 'Gene', (90, 93))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('Cancer', 'Disease', 'MESH:D009369', (73, 79))
185664	32194805	The results of survival analyses suggested that patients in the 4-gene combination low-risk group had better OS and RFS than those in the 4-gene combination high-risk group.	('better', 'PosReg', (102, 108))	('patients', 'Species', '9606', (48, 56))	('RFS', 'CPA', (116, 119))	('low-risk', 'NegReg', (83, 91))	('4-gene combination', 'Var', (64, 82))
185702	32194805	The Kaplan-Meier curve of OS and RFS, and univariate CPH model of OS and RFS results suggested that patients in the 4-gene combination low-risk group was associated with better OS and RFS compared with those in the 4-gene combination high-risk group in the training set (OS, hazards ratio (HR)=11.962, 95% CI: 6.232-22.961, P<0.001; RFS, HR=9.281, 95% CI: 4.064-21.193, P<0.001; figure 3 and supplementary table 4), test set (OS, HR=5.377, 95% CI: 1.736-16.657, P=0.003; RFS, HR=2.949, 95% CI: 0.800-10.867, P=0.104; figure 3 and supplementary table 4) and validation set (OS, HR=1.057, 95% CI: 1.016-1.079, P=0.002; RFS, HR=1.042, 95% CI: 1.018-1.066, P<0.001; figure 4 and Supplementary table 4).	('low-risk', 'Var', (135, 143))	('patients', 'Species', '9606', (100, 108))	('CPH', 'Chemical', '-', (53, 56))	('better', 'PosReg', (170, 176))
185705	32194805	As shown in figure 3, the Kaplan-Meier curve of OS and RFS, and univariate CPH model of OS and RFS (OS, HR=0.955, 95% CI: 1.016-1.079, P=0.002; RFS, (HR)=1.042, 95% CI: 1.018-1.066, P<0.001; Figure 3 and Supplementary table 4) in the 4-gene combination low-risk group were also significantly better than those in the 4-gene combination high-risk group.	('better', 'PosReg', (292, 298))	('4-gene combination', 'Var', (234, 252))	('CPH', 'Chemical', '-', (75, 78))	('low-risk', 'NegReg', (253, 261))
185712	32194805	DCA could determine a range of threshold probabilities for a prediction mode, as shown in Figure 7, the nomogram threshold probability based on 4-gene combinations was significantly better than the default strategies of treating all or none at a threshold probability more that 4%.	('combinations', 'Var', (151, 163))	('better', 'PosReg', (182, 188))	('DCA', 'Chemical', '-', (0, 3))
185717	32194805	The OS and RFS of LUAD patients in the 4-gene combination low-risk group significantly superior compared with those in the 4-gene combination high-risk group, and the 4-gene combination was shown to be an independently prognostic combination in LUAD.	('superior', 'PosReg', (87, 95))	('RFS', 'MPA', (11, 14))	('LUAD', 'Disease', 'MESH:D000077192', (245, 249))	('LUAD', 'Disease', (18, 22))	('patients', 'Species', '9606', (23, 31))	('LUAD', 'Phenotype', 'HP:0030078', (18, 22))	('4-gene combination', 'Var', (39, 57))	('LUAD', 'Phenotype', 'HP:0030078', (245, 249))	('LUAD', 'Disease', (245, 249))	('low-risk', 'NegReg', (58, 66))	('LUAD', 'Disease', 'MESH:D000077192', (18, 22))
185727	32194805	suggested that esophageal cancer patients with high USP4 expression had relative longer survival time.	('USP4', 'Gene', (52, 56))	('longer', 'PosReg', (81, 87))	('patients', 'Species', '9606', (33, 41))	('high', 'Var', (47, 51))	('esophageal cancer', 'Disease', (15, 32))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('esophageal cancer', 'Disease', 'MESH:D004938', (15, 32))	('survival time', 'CPA', (88, 101))
185729	32194805	suggested that USP4 had anti-cancer effect in breast cancer, and found that USP4 could inhibited the growth of tumors in a mouse tumor xenograft model.	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumors', 'Disease', (111, 117))	('breast cancer', 'Disease', 'MESH:D001943', (46, 59))	('USP4', 'Var', (76, 80))	('tumor', 'Disease', (129, 134))	('breast cancer', 'Disease', (46, 59))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('tumors', 'Disease', 'MESH:D009369', (111, 117))	('cancer', 'Disease', (29, 35))	('cancer', 'Disease', (53, 59))	('USP4', 'Gene', (15, 19))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('tumor', 'Disease', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('inhibited', 'NegReg', (87, 96))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('mouse', 'Species', '10090', (123, 128))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('breast cancer', 'Phenotype', 'HP:0003002', (46, 59))	('cancer', 'Disease', 'MESH:D009369', (29, 35))
185805	33227008	MAGE-A3 is a prognostic biomarker for poor clinical outcome in cutaneous squamous cell carcinoma with perineural invasion via modulation of cell proliferation Perineural invasion is a pathologic process of neoplastic dissemination along and invading into the nerves.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (73, 96))	('MAGE-A3', 'Gene', '17139', (0, 7))	('cutaneous squamous cell carcinoma', 'Disease', 'MESH:D002294', (63, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))	('cutaneous squamous cell carcinoma', 'Phenotype', 'HP:0006739', (63, 96))	('modulation', 'Var', (126, 136))	('MAGE-A3', 'Gene', (0, 7))	('cutaneous squamous cell carcinoma', 'Disease', (63, 96))
185813	33227008	However, knockout of MAGE-A3 expression caused a reduction in tumor growth (mean tumor volume 155.3 mm3 vs. 3.2 mm3) compared with parental cells.	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('knockout', 'Var', (9, 17))	('tumor growth', 'Disease', (62, 74))	('reduction', 'NegReg', (49, 58))	('tumor growth', 'Disease', 'MESH:D006130', (62, 74))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', (62, 67))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('MAGE-A3', 'Gene', (21, 28))	('tumor', 'Disease', (81, 86))
185820	33227008	We previously demonstrated that expression of MAGE-A3, a cancer testis antigen (CTA), in cSCC is associated with advanced tumor stage and poor prognosis.	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('cancer testis', 'Phenotype', 'HP:0010788', (57, 70))	('cSCC', 'Gene', '13070', (89, 93))	('cSCC', 'Gene', (89, 93))	('cancer', 'Disease', (57, 63))	('expression', 'Var', (32, 42))	('MAGE-A3', 'Gene', (46, 53))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('CTA', 'Chemical', '-', (80, 83))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('associated', 'Reg', (97, 107))	('tumor', 'Disease', (122, 127))
185860	33227008	The dual (366) targeting removes the splice-acceptor site of the coding exon, whereas the dual (1280) targeting removes the entire coding region of MAGE-A3 in a dox-dependent manner.	('MAGE-A3', 'Gene', (148, 155))	('removes', 'NegReg', (112, 119))	('dual (1280) targeting', 'Var', (90, 111))	('splice-acceptor site of the', 'MPA', (37, 64))	('removes', 'NegReg', (25, 32))	('dox', 'Chemical', 'MESH:D004317', (161, 164))
185872	33227008	Immunoblots were probed using the following antibodies where specified: MAGE-A3 IgG1-kappa monoclonal antibody (Proteintech 60054-1-Ig), MAGE-A4 (Cell Signaling (E7O1U) XP Rabbit mAb #82491), p53 (Cell Signaling (1C12) Mouse mAb #2524), Actin IgG1-kappa monoclonal antibody (Thermo Fisher #MA5-11869), GAPDH (Cell Signaling 14C10) and cyclin antibodies (Cell Signaling: Cyclin A2 (BF683), Cyclin B1 (4138), Cyclin D1 (92G2), Cyclin D2 (D52F9), Cyclin D3 (DCS22), and Cyclin E1 (HE12)).	('Cyclin D3', 'Gene', '896', (444, 453))	('Cyclin A2', 'Gene', (370, 379))	('Mouse', 'Species', '10090', (219, 224))	('Cyclin B1', 'Gene', '891', (389, 398))	('4138', 'Var', (400, 404))	('HE12', 'CellLine', 'CVCL:0T75', (478, 482))	('Cyclin A2', 'Gene', '890', (370, 379))	('IgG1', 'Gene', '16017', (243, 247))	('IgG1', 'Gene', (80, 84))	('p53', 'Gene', '22059', (192, 195))	('Cyclin E1', 'Gene', '898', (467, 476))	('Cyclin B1', 'Gene', (389, 398))	('Cyclin E1', 'Gene', (467, 476))	('p53', 'Gene', (192, 195))	('IgG1', 'Gene', (243, 247))	('IgG1', 'Gene', '16017', (80, 84))	('Cyclin D3', 'Gene', (444, 453))
185897	33227008	Reduced levels of S-phase A431 cSCC cells were observed upon treatment with MAGE-A3 antibody compared with antibody transport solution (ATS) alone and untreated groups (14.13+-2.8% vs. 24.33+-3.19% vs. 33.97+-1.1%, respectively; p < 0.05).	('antibody', 'Var', (84, 92))	('A431 cSCC', 'CellLine', 'CVCL:0037', (26, 35))	('MAGE-A3', 'Gene', (76, 83))	('Reduced', 'NegReg', (0, 7))
185906	33227008	The results showed that MAGE-A3 knockout reduced the growth of Pam 212 cells in a syngeneic model of SCC (Fig 5D and 5E).	('reduced', 'NegReg', (41, 48))	('MAGE-A3', 'Gene', (24, 31))	('knockout', 'Var', (32, 40))	('growth', 'MPA', (53, 59))	('Pam', 'Gene', '18484', (63, 66))	('SCC', 'Gene', (101, 104))	('Pam', 'Gene', (63, 66))	('SCC', 'Gene', '6317', (101, 104))
185928	33227008	This finding is consistent with previous studies given that MAGE-A3 is believed to inhibit p53 functions by blocking its interaction with chromatin and accelerating its denaturation and not at the transcription level.	('chromatin', 'Protein', (138, 147))	('blocking', 'NegReg', (108, 116))	('interaction', 'Interaction', (121, 132))	('MAGE-A3', 'Var', (60, 67))	('p53', 'Gene', (91, 94))	('denaturation', 'MPA', (169, 181))	('p53', 'Gene', '22059', (91, 94))	('accelerating', 'PosReg', (152, 164))	('functions', 'MPA', (95, 104))	('inhibit', 'NegReg', (83, 90))
185936	33227008	In our in vitro experiments with A431 cSCC cells, blockage of MAGE-A3 expression reduced the percentage of S-phase cells and reduced scratch closure after 72 hours.	('scratch closure', 'CPA', (133, 148))	('A431 cSCC', 'CellLine', 'CVCL:0037', (33, 42))	('blockage', 'Var', (50, 58))	('reduced', 'NegReg', (125, 132))	('reduced', 'NegReg', (81, 88))	('MAGE-A3', 'Gene', (62, 69))
185938	33227008	DMSO can induce water pores in dipalmitoylphosphatidylcholine bilayers, subsequently increasing the permeability of cell membranes and facilitating the entry of antibodies into cells.	('water', 'Chemical', 'MESH:D014867', (16, 21))	('water', 'MPA', (16, 21))	('dipalmitoylphosphatidylcholine', 'Chemical', 'MESH:D015060', (31, 61))	('increasing', 'PosReg', (85, 95))	('permeability of cell membranes', 'MPA', (100, 130))	('DMSO', 'Var', (0, 4))	('induce', 'Reg', (9, 15))	('DMSO', 'Chemical', 'MESH:D004121', (0, 4))	('entry', 'MPA', (152, 157))	('antibodies', 'Protein', (161, 171))
185948	33227008	We found that Pam 212 cells with MAGE-A3 knockout failed to grow in Balb/c mice, and total regression was observed in two cases.	('mice', 'Species', '10090', (75, 79))	('MAGE-A3', 'Gene', (33, 40))	('Pam', 'Gene', '18484', (14, 17))	('knockout', 'Var', (41, 49))	('Pam', 'Gene', (14, 17))
185960	33227008	revealed that knockout of collagen XI alpha I gene in a head and neck SCC cell line results in significant reductions in cancer proliferation, invasion and migration.	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('SCC', 'Gene', (70, 73))	('cancer', 'Disease', (121, 127))	('collagen XI alpha I', 'Gene', (26, 45))	('SCC', 'Gene', '6317', (70, 73))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('reductions', 'NegReg', (107, 117))	('knockout', 'Var', (14, 22))
185972	33227008	26 Feb 2020  PONE-D-19-34576 MAGE-A3 is a prognostic biomarker for poor clinical outcome in cutaneous squamous cell carcinoma with perineural invasion via modulation of cell proliferation PLOS ONE Dear Dr. Carucci, Thank you for submitting your manuscript to PLOS ONE.	('cutaneous squamous cell carcinoma', 'Disease', 'MESH:D002294', (92, 125))	('modulation', 'Var', (155, 165))	('PONE-D-19-34576', 'Chemical', '-', (13, 28))	('cutaneous squamous cell carcinoma', 'Disease', (92, 125))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('cell proliferation', 'CPA', (169, 187))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (102, 125))	('cutaneous squamous cell carcinoma', 'Phenotype', 'HP:0006739', (92, 125))
185981	33227008	3) The authors showed that not only MAGE-A3 but also MAGE-A4 mRNA expression was upregulated in poorly differentiated cSCC with PNI in Figure 1A.	('upregulated', 'PosReg', (81, 92))	('mRNA expression', 'MPA', (61, 76))	('cSCC', 'Gene', '13070', (118, 122))	('MAGE-A4', 'Var', (53, 60))	('cSCC', 'Gene', (118, 122))	('PNI', 'Gene', '51251', (128, 131))	('PNI', 'Gene', (128, 131))
185989	33227008	If the authors want to examine the role of MAGE-A3 in A431 SCC cells, it may be desirable to knockdown or knockout expression of MAGE-A3 using siRNA or CRISPR/Cas9.	('knockdown', 'Var', (93, 102))	('CRISPR', 'Gene', '70873', (152, 158))	('CRISPR', 'Gene', (152, 158))	('A431 SCC', 'CellLine', 'CVCL:0037', (54, 62))	('MAGE-A3', 'Gene', (129, 136))
186013	33227008	(Page 10 Line 18-20) DMSO can induce water pores in dipalmitoylphosphatidylcholine bilayers and cause cell membrane to become floppier, which increases permeability for the antibodies to enter cells.	('water', 'Chemical', 'MESH:D014867', (37, 42))	('dipalmitoylphosphatidylcholine', 'Chemical', 'MESH:D015060', (52, 82))	('DMSO', 'Var', (21, 25))	('increases', 'PosReg', (142, 151))	('DMSO', 'Chemical', 'MESH:D004121', (21, 25))	('cause', 'Reg', (96, 101))	('water pores', 'MPA', (37, 48))	('permeability', 'MPA', (152, 164))	('induce', 'Reg', (30, 36))
186040	33227008	This in vivo experiment reveals that knockout expression of MAGE-A3 results in significant tumor regression.	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('MAGE-A3', 'Gene', (60, 67))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('knockout expression', 'Var', (37, 56))	('tumor', 'Disease', (91, 96))
186047	33227008	J Biol Chem 2002 277(37): 34287-34294) (Page 24 Line 9) Dimethyl sulfoxide (DMSO) can induce water pores in dipalmitoyl phosphatidylcholine bilayers and cause cell membrane to become floppier, which increases permeability for the antibodies to enter cells.	('increases', 'PosReg', (199, 208))	('dipalmitoyl phosphatidylcholine', 'Chemical', 'MESH:D015060', (108, 139))	('Dimethyl', 'Var', (56, 64))	('induce', 'Reg', (86, 92))	('Dimethyl sulfoxide', 'Chemical', 'MESH:D004121', (56, 74))	('permeability', 'MPA', (209, 221))	('water', 'Chemical', 'MESH:D014867', (93, 98))	('cause', 'Reg', (153, 158))	('DMSO', 'Chemical', 'MESH:D004121', (76, 80))
186056	33227008	Fold changes in MAGE-A3 expression in KO Pam 212 by Guide 521 and 520 were 0.0049 +- 0.00198 and 0.000535 +- 0.000209, respectively.	('Pam', 'Gene', '18484', (41, 44))	('MAGE-A3', 'Gene', (16, 23))	('expression', 'MPA', (24, 34))	('0.000535 +- 0.000209', 'Var', (97, 117))	('Pam', 'Gene', (41, 44))	('0.0049 +- 0.00198', 'Var', (75, 92))
186060	33227008	23 Oct 2020  PONE-D-19-34576R1  MAGE-A3 is a prognostic biomarker for poor clinical outcome in cutaneous squamous cell carcinoma with perineural invasion via modulation of cell proliferation  Dear Dr. Carucci: I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE.	('Oct', 'Gene', '18845', (3, 6))	('PONE-D-19-34576', 'Chemical', '-', (13, 28))	('Oct', 'Gene', (3, 6))	('cutaneous squamous cell carcinoma', 'Disease', (95, 128))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (105, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('modulation', 'Var', (158, 168))	('cutaneous squamous cell carcinoma', 'Disease', 'MESH:D002294', (95, 128))	('cutaneous squamous cell carcinoma', 'Phenotype', 'HP:0006739', (95, 128))
186084	31976313	reported that the frequency of the PIK3CA mutation increased in parallel with COPD severity, and the PIK3CA mutation is a genetic feature of patients with non-small-cell lung cancer (NSCLC) with COPD, regardless of age, smoking, pathological stage, and histology.	('PIK3CA', 'Gene', '5290', (101, 107))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('non-small-cell lung cancer', 'Disease', (155, 181))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (155, 181))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (159, 181))	('mutation', 'Var', (42, 50))	('PIK3CA', 'Gene', (35, 41))	('mutation', 'Var', (108, 116))	('COPD', 'Phenotype', 'HP:0006510', (78, 82))	('PIK3CA', 'Gene', '5290', (35, 41))	('lung cancer', 'Phenotype', 'HP:0100526', (170, 181))	('PIK3CA', 'Gene', (101, 107))	('COPD', 'Phenotype', 'HP:0006510', (195, 199))
186085	31976313	reported that miR-181-5p, miR-30a-3p, miR-30e-3p, miR-361-5p, miR-10b-5p, miR-15b-5p, and miR-320b can be used to NSCLC with an AUC value of 0.899 for detecting NSCLC.	('miR-181-5p', 'Var', (14, 24))	('miR-30e-3p', 'Var', (38, 48))	('miR-10b-5p', 'Var', (62, 72))	('miR-15b', 'Gene', '406949', (74, 81))	('miR-361-5p', 'Gene', '100500847', (50, 60))	('miR-15b', 'Gene', (74, 81))	('miR-361-5p', 'Gene', (50, 60))	('NSCLC', 'Disease', (161, 166))	('miR-30a-3p', 'Var', (26, 36))	('miR-320b', 'Var', (90, 98))
186086	31976313	developed a signature containing 4 miRNAs, miR-23b, miR-221, miR-148b, and miR-423-3p, with an AUC of 0.885, and this signature may be considered as a biomarker for diagnosing lung cancer.	('miR-23b', 'Gene', '407011', (43, 50))	('lung cancer', 'Phenotype', 'HP:0100526', (176, 187))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('miR-423-3p', 'Var', (75, 85))	('miR-221', 'Gene', (52, 59))	('miR-23b', 'Gene', (43, 50))	('423-3p', 'Chemical', 'MESH:C072935', (79, 85))	('miR-148b', 'Gene', '442892', (61, 69))	('lung cancer', 'Disease', (176, 187))	('miR-221', 'Gene', '407006', (52, 59))	('miR-148b', 'Gene', (61, 69))
186093	31976313	In addition to lung cancer, miR-195 suppresses colon cancer proliferation and metastasis, inhibits tumour growth and angiogenesis in breast cancer, and is associated with the chemotherapy sensitivity of cisplatin and the clinical prognosis in gastric cancer.	('breast cancer', 'Phenotype', 'HP:0003002', (133, 146))	('suppresses', 'NegReg', (36, 46))	('colon cancer', 'Disease', (47, 59))	('tumour', 'Phenotype', 'HP:0002664', (99, 105))	('breast cancer', 'Disease', 'MESH:D001943', (133, 146))	('gastric cancer', 'Phenotype', 'HP:0012126', (243, 257))	('breast cancer', 'Disease', (133, 146))	('tumour', 'Disease', 'MESH:D009369', (99, 105))	('tumour', 'Disease', (99, 105))	('miR-195', 'Var', (28, 35))	('colon cancer', 'Phenotype', 'HP:0003003', (47, 59))	('associated', 'Reg', (155, 165))	('gastric cancer', 'Disease', (243, 257))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('lung cancer', 'Phenotype', 'HP:0100526', (15, 26))	('cisplatin', 'Chemical', 'MESH:D002945', (203, 212))	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('colon cancer', 'Disease', 'MESH:D015179', (47, 59))	('inhibits', 'NegReg', (90, 98))	('gastric cancer', 'Disease', 'MESH:D013274', (243, 257))
186102	29190900	64Cu-/177Lu-PCTA-cetuximab specifically accumulated in SNU-1066 tumor and those uptakes were peaked at 48 h and 7 day, respectively in biodistribution, PET and single-photon emission computed tomography/computed tomography (SPECT/CT) imaging.	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('64Cu', 'Chemical', 'MESH:C000615411', (0, 4))	('accumulated', 'PosReg', (40, 51))	('177Lu-PCTA-cetuximab', 'Chemical', '-', (6, 26))	('SNU-1066 tumor', 'Disease', (55, 69))	('SNU-1066 tumor', 'Disease', 'MESH:D009369', (55, 69))	('64Cu-/177Lu-PCTA-cetuximab', 'Var', (0, 26))
186103	29190900	RIT with single dose of 177Lu-PCTA-cetuximab exhibited significant tumor regression and markedly reduced 2-[18F]fluoro-2-deoxy-D-glucose (18F-FDG) uptake, compared to other groups.	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('2-[18F]fluoro-2-deoxy-D-glucose', 'Chemical', 'MESH:D019788', (105, 136))	('reduced', 'NegReg', (97, 104))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('177Lu-PCTA-cetuximab', 'Chemical', '-', (24, 44))	('tumor', 'Disease', (67, 72))	('18F-FDG', 'Chemical', 'MESH:D019788', (138, 145))	('177Lu-PCTA-cetuximab', 'Var', (24, 44))
186104	29190900	These results suggest that a diagnostic and therapeutic convergence radiopharmaceutical, 64Cu-/177Lu-PCTA-cetuximab has the potential of target selection using immuno-PET imaging and targeted therapy by RIT in EGFR expressing cetuximab-resistant HNSCC tumors.	('64Cu', 'Chemical', 'MESH:C000615411', (89, 93))	('cetuximab', 'Chemical', 'MESH:D000068818', (106, 115))	('177Lu-PCTA-cetuximab', 'Chemical', '-', (95, 115))	('HNSCC tumors', 'Disease', 'MESH:D000077195', (246, 258))	('EGFR', 'Gene', (210, 214))	('HNSCC', 'Phenotype', 'HP:0012288', (246, 251))	('tumor', 'Phenotype', 'HP:0002664', (252, 257))	('cetuximab', 'Chemical', 'MESH:D000068818', (226, 235))	('tumors', 'Phenotype', 'HP:0002664', (252, 258))	('HNSCC tumors', 'Disease', (246, 258))	('64Cu-/177Lu-PCTA-cetuximab', 'Var', (89, 115))
186125	29190900	89Zr has long half-life (78.4 h) comparable to physiological half-life of whole antibody, but 89Zr-labeled antibody showed higher radiation dose for immuno-PET imaging than 64Cu-labeled antibody.	('89Zr-labeled', 'Var', (94, 106))	('higher', 'PosReg', (123, 129))	('radiation dose', 'MPA', (130, 144))	('64Cu', 'Chemical', 'MESH:C000615411', (173, 177))
186139	29190900	64Cu- and 177Lu-PCTA-cetxuximab have favorable immunreactive index as 0.972 and 0.976, respectively.	('177Lu-PCTA', 'Chemical', '-', (10, 20))	('64Cu', 'Chemical', 'MESH:C000615411', (0, 4))	('177Lu-PCTA-cetxuximab', 'Var', (10, 31))	('PCTA-cetxuximab', 'Chemical', '-', (16, 31))	('64Cu-', 'Var', (0, 5))
186145	29190900	However, in the different radioactivity dose of 177Lu-PCTA-cetuximab-treated cells with same antibody concentration, the survival rate (%) was decreased as a radioactivity dose dependent manner and markedly decreased to 25.3 +- 1.2% at 1.48 MBq dose for 5 day incubation (P < 0.001).	('177Lu-PCTA-cetuximab-treated', 'Var', (48, 76))	('decreased', 'NegReg', (143, 152))	('survival rate', 'CPA', (121, 134))	('man', 'Species', '9606', (187, 190))	('177Lu-PCTA-cetuximab', 'Chemical', '-', (48, 68))	('decreased', 'NegReg', (207, 216))
186146	29190900	The cytotoxicity of 177Lu-PCTA-cetuximab also increased as incubation time-dependent manner.	('man', 'Species', '9606', (85, 88))	('increased', 'PosReg', (46, 55))	('cytotoxicity', 'Disease', (4, 16))	('177Lu-PCTA-cetuximab', 'Chemical', '-', (20, 40))	('177Lu-PCTA-cetuximab', 'Var', (20, 40))	('cytotoxicity', 'Disease', 'MESH:D064420', (4, 16))
186147	29190900	These results suggest that beta irradiation from 177Lu-PCTA-cetuximab could effectively kill in EGFR expressing and cetuximab-resistant HNSCC cells as a radiation dose dependent manner.	('EGFR', 'Gene', (96, 100))	('man', 'Species', '9606', (178, 181))	('cetuximab', 'Chemical', 'MESH:D000068818', (116, 125))	('177Lu-PCTA-cetuximab', 'Chemical', '-', (49, 69))	('HNSCC', 'Phenotype', 'HP:0012288', (136, 141))	('cetuximab', 'Chemical', 'MESH:D000068818', (60, 69))	('177Lu-PCTA-cetuximab', 'Var', (49, 69))
186157	29190900	The liver uptake of 64Cu-PCTA-cetuximab was the highest among normal organs.	('64Cu-PCTA-cetuximab', 'Chemical', '-', (20, 39))	('liver uptake', 'MPA', (4, 16))	('64Cu-PCTA-cetuximab', 'Var', (20, 39))
186158	29190900	The SNU-1066 tumor uptake of 64Cu-PCTA-cetuximab steadily increased and peaked at 48 h with 12.8 +- 1.7 %ID/g.	('increased', 'PosReg', (58, 67))	('64Cu-PCTA-cetuximab', 'Var', (29, 48))	('SNU-1066 tumor', 'Disease', (4, 18))	('64Cu-PCTA-cetuximab', 'Chemical', '-', (29, 48))	('SNU-1066 tumor', 'Disease', 'MESH:D009369', (4, 18))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
186160	29190900	In blocking study, the SNU-1066 tumor uptake of 64Cu-PCTA-cetuximab significantly reduced to 48.8% at 48 h post-injection, compared to that of 64Cu-PCTA-cetuximab without blocking (P < 0.01).	('64Cu-PCTA-cetuximab', 'Var', (48, 67))	('64Cu-PCTA-cetuximab', 'Chemical', '-', (143, 162))	('64Cu-PCTA-cetuximab', 'Chemical', '-', (48, 67))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('reduced', 'NegReg', (82, 89))	('SNU-1066 tumor', 'Disease', (23, 37))	('SNU-1066 tumor', 'Disease', 'MESH:D009369', (23, 37))
186164	29190900	The tumor-to-blood (T/B) and tumor-to-muscle (T/M) ratios of 177Lu-PCTA-cetuximab were 6.3 +- 3.8 and 21.9 +- 2.7 at 7 day and were highest with 7.7 +- 2.6 and 36.4 +- 13.1 at 14 day post-injection, respectively.	('tumor', 'Disease', (4, 9))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('177Lu-PCTA-cetuximab', 'Chemical', '-', (61, 81))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('177Lu-PCTA-cetuximab', 'Var', (61, 81))	('tumor', 'Disease', (29, 34))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))
186166	29190900	These results represent that 64Cu- and 177Lu-PCTA-cetuximab have good specificity in EGFR expressing HNSCC xenograft model.	('EGFR expressing', 'Gene', (85, 100))	('177Lu-PCTA-cetuximab', 'Chemical', '-', (39, 59))	('HNSCC', 'Phenotype', 'HP:0012288', (101, 106))	('177Lu-PCTA-cetuximab', 'Var', (39, 59))	('64Cu', 'Chemical', 'MESH:C000615411', (29, 33))	('64Cu-', 'Var', (29, 34))
186170	29190900	The tumor SUV of 64Cu-cetuximab was 0.9 +- 0.2, 1.9 +- 0.3 and 3.0 +- 0.7 at 2, 24 and 48 h post-injection, respectively.	('tumor', 'Disease', (4, 9))	('64Cu-cetuximab', 'Var', (17, 31))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('64Cu-cetuximab', 'Chemical', '-', (17, 31))
186174	29190900	177Lu-PCTA-cetuximab was selectively localized in SNU-1066 tumor and showed relatively low uptake in the liver.	('SNU-1066 tumor', 'Disease', (50, 64))	('SNU-1066 tumor', 'Disease', 'MESH:D009369', (50, 64))	('177Lu-PCTA-cetuximab', 'Chemical', '-', (0, 20))	('177Lu-PCTA-cetuximab', 'Var', (0, 20))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
186182	29190900	The tumor volume in 177Lu-PCTA-cetuximab-treated group showed a statistically significant difference compared with that in saline- and single dose of cetuximab-treated groups (P < 0.05).	('tumor', 'Disease', (4, 9))	('cetuximab', 'Chemical', 'MESH:D000068818', (31, 40))	('saline', 'Chemical', 'MESH:D012965', (123, 129))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('177Lu-PCTA-cetuximab', 'Chemical', '-', (20, 40))	('cetuximab', 'Chemical', 'MESH:D000068818', (150, 159))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('177Lu-PCTA-cetuximab-treated', 'Var', (20, 48))
186192	29190900	To determine the mechanism by which 177Lu-PCTA-cetuximab inhibited tumor growth in nude mice, we determined apoptosis and proliferation index using TUNEL and Ki-67 immunohistochemical staining on 14 day after treatment.	('177Lu-PCTA-cetuximab', 'Var', (36, 56))	('inhibited', 'NegReg', (57, 66))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('Ki-67', 'Gene', '17345', (158, 163))	('tumor', 'Disease', (67, 72))	('proliferation', 'CPA', (122, 135))	('nude mice', 'Species', '10090', (83, 92))	('177Lu-PCTA-cetuximab', 'Chemical', '-', (36, 56))	('Ki-67', 'Gene', (158, 163))
186193	29190900	There were statistically significant differences of apoptotic index in the 177Lu-PCTA-cetuximab (14.5 +- 7.0 cells per field) treated group compared to saline (0.7 +- 0.8) and cetuximab (0.5 +- 0.5) treated groups (P < 0.01; Figure 6c and 6d), suggesting that the reduction of tumor volume was caused by apoptosis.	('reduction', 'NegReg', (264, 273))	('cetuximab', 'Chemical', 'MESH:D000068818', (176, 185))	('177Lu-PCTA-cetuximab', 'Chemical', '-', (75, 95))	('cetuximab', 'Chemical', 'MESH:D000068818', (86, 95))	('177Lu-PCTA-cetuximab', 'Var', (75, 95))	('tumor', 'Disease', 'MESH:D009369', (277, 282))	('tumor', 'Phenotype', 'HP:0002664', (277, 282))	('apoptotic index', 'MPA', (52, 67))	('tumor', 'Disease', (277, 282))	('saline', 'Chemical', 'MESH:D012965', (152, 158))
186194	29190900	Ki-67 positive staining (%) were noticeably reduced in the 177Lu-PCTA-cetuximab treatment group.	('Ki-67', 'Gene', (0, 5))	('positive staining', 'MPA', (6, 23))	('Ki-67', 'Gene', '17345', (0, 5))	('177Lu-PCTA-cetuximab', 'Chemical', '-', (59, 79))	('reduced', 'NegReg', (44, 51))	('177Lu-PCTA-cetuximab', 'Var', (59, 79))
186205	29190900	However, single dose of radioimmunotherapy with 177Lu-PCTA-cetuximab showed greater therapeutic effect than cetuximab immunotherapy without significant toxicity (Figure 5 and supplementary Figure 2).	('177Lu-PCTA-cetuximab', 'Var', (48, 68))	('cetuximab', 'Chemical', 'MESH:D000068818', (108, 117))	('greater', 'PosReg', (76, 83))	('toxicity', 'Disease', 'MESH:D064420', (152, 160))	('toxicity', 'Disease', (152, 160))	('therapeutic', 'MPA', (84, 95))	('177Lu-PCTA-cetuximab', 'Chemical', '-', (48, 68))	('cetuximab', 'Chemical', 'MESH:D000068818', (59, 68))
186208	29190900	64Cu-PCTA-cetuximab was selectively accumulated in SNU-1066 HNSCC tumors and showed good tumor-to-background ratios in immuno-PET imaging and biodistribution study (Figure 2 and 3).	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('good tumor', 'Disease', (84, 94))	('64Cu-PCTA-cetuximab', 'Var', (0, 19))	('SNU-1066 HNSCC tumors', 'Disease', 'MESH:D000077195', (51, 72))	('good tumor', 'Disease', 'MESH:D009369', (84, 94))	('SNU-1066 HNSCC tumors', 'Disease', (51, 72))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('64Cu-PCTA-cetuximab', 'Chemical', '-', (0, 19))	('accumulated', 'PosReg', (36, 47))	('HNSCC', 'Phenotype', 'HP:0012288', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))
186209	29190900	In blocking study, the tumor uptake of 64Cu-PCTA-cetuximab was markedly reduced in SNU-1066 xenograft models, which represent the specificity of EGFR targeting of 64Cu-PCTA-cetuximab.	('reduced', 'NegReg', (72, 79))	('64Cu-PCTA-cetuximab', 'Chemical', '-', (39, 58))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('64Cu-PCTA-cetuximab', 'Chemical', '-', (163, 182))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('64Cu-PCTA-cetuximab', 'Var', (39, 58))	('tumor', 'Disease', (23, 28))	('SNU-1066', 'Chemical', '-', (83, 91))
186214	29190900	In dosimetry study, immuno-PET with 89Zr-labeled antibodies usually 8-times higher whole body effective dose (40 mSv/74 MBq in 89Zr vs. 5 mSv/130 MBq in 64Cu) than that with 64Cu-labeled antibodies in clinical patients.	('64Cu', 'Chemical', 'MESH:C000615411', (153, 157))	('89Zr-labeled', 'Var', (36, 48))	('patients', 'Species', '9606', (210, 218))	('higher', 'PosReg', (76, 82))	('whole body effective dose', 'MPA', (83, 108))	('64Cu', 'Chemical', 'MESH:C000615411', (174, 178))
186223	29190900	In a similar study, the tumor doses for 90Y-CC49 were found to be 1.8 to 30 Gy.	('tumor', 'Disease', (24, 29))	('90Y-CC49', 'Var', (40, 48))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('tumor', 'Phenotype', 'HP:0002664', (24, 29))
186227	29190900	We observed tumor regrowth over time in single-dose (100 mug) and multiple-dose (200 mug, 6 times/2 weeks) cetuximab treatments (Figure 1f and 5).	('cetuximab', 'Chemical', 'MESH:D000068818', (107, 116))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('100 mug', 'Var', (53, 60))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('tumor', 'Disease', (12, 17))
186228	29190900	However, there was no tumor regrowth or rebound phenomenon in 177Lu-PCTA-cetuximab treatment group.	('177Lu-PCTA-cetuximab', 'Var', (62, 82))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('tumor', 'Disease', (22, 27))	('177Lu-PCTA-cetuximab', 'Chemical', '-', (62, 82))
186238	29190900	Immuno-PET with 64Cu-PCTA-cetuximab exhibited good tumor targeting and target-to-background ratio.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('good tumor', 'Disease', (46, 56))	('good tumor', 'Disease', 'MESH:D009369', (46, 56))	('64Cu-PCTA-cetuximab', 'Var', (16, 35))	('64Cu-PCTA-cetuximab', 'Chemical', '-', (16, 35))
186272	29190900	Mice bearing SNU-1066 HNSCC tumors were intravenously injected with a 3.7 MBq (100 mug) of 64Cu-PCTA-cetuximab or 177Lu-PCTA-cetuximab (n = 4) and sacrificed at each time point.	('SNU-1066 HNSCC tumors', 'Disease', (13, 34))	('64Cu-PCTA-cetuximab', 'Chemical', '-', (91, 110))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('HNSCC', 'Phenotype', 'HP:0012288', (22, 27))	('64Cu-PCTA-cetuximab', 'Var', (91, 110))	('Mice', 'Species', '10090', (0, 4))	('177Lu-PCTA-cetuximab', 'Chemical', '-', (114, 134))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('SNU-1066 HNSCC tumors', 'Disease', 'MESH:D000077195', (13, 34))
186280	29190900	To evaluate the specificity of EGFR expressing tumor targeting of 177Lu-PCTA-cetuximab, excess cold cetuximab (2 mg/head) was intravenously injected for blocking experiments.	('177Lu-PCTA-cetuximab', 'Var', (66, 86))	('tumor', 'Disease', (47, 52))	('cetuximab', 'Chemical', 'MESH:D000068818', (100, 109))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('cetuximab', 'Chemical', 'MESH:D000068818', (77, 86))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('177Lu-PCTA-cetuximab', 'Chemical', '-', (66, 86))
186284	29190900	HNSCC tumor mice were intravenously administrated with saline (control), cetuximab (5 mg/kg, single dose) or 177Lu-PCTA-cetuximab (12.95 MBq, single dose, 5 mg/kg), respectively.	('cetuximab', 'Chemical', 'MESH:D000068818', (73, 82))	('177Lu-PCTA-cetuximab', 'Chemical', '-', (109, 129))	('177Lu-PCTA-cetuximab', 'Var', (109, 129))	('saline', 'Chemical', 'MESH:D012965', (55, 61))	('HNSCC tumor', 'Disease', 'MESH:D000077195', (0, 11))	('cetuximab', 'Chemical', 'MESH:D000068818', (120, 129))	('mice', 'Species', '10090', (12, 16))	('HNSCC', 'Phenotype', 'HP:0012288', (0, 5))	('HNSCC tumor', 'Disease', (0, 11))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))
186292	29190900	The excised tumors from the biodistribution of 177Lu-PCTA-cetuximab were round and mostly elliptical, and the assumption of the spherical volume for tumor dosimetry was not far from the actual geometrical shape.	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('177Lu-PCTA-cetuximab', 'Chemical', '-', (47, 67))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('177Lu-PCTA-cetuximab', 'Var', (47, 67))	('tumor', 'Disease', (149, 154))	('tumors', 'Disease', (12, 18))	('tumor', 'Disease', (12, 17))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('tumors', 'Disease', 'MESH:D009369', (12, 18))
186304	27551478	Lung squamous cell carcinoma represents 30% of lung cancers and only recently have possible drug-targetable mutations been identified in this disease, including fibroblast growth factor receptor 1 (FGFR1) gene amplification and genetic alterations in the phosphoinositide-3 kinase pathway.	('FGFR1', 'Gene', (198, 203))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('fibroblast growth factor receptor 1', 'Gene', '2260', (161, 196))	('lung cancer', 'Phenotype', 'HP:0100526', (47, 58))	('genetic alterations', 'Var', (228, 247))	('FGFR1', 'Gene', '2260', (198, 203))	('lung cancers', 'Disease', 'MESH:D008175', (47, 59))	('carcinoma', 'Phenotype', 'HP:0030731', (19, 28))	('lung cancers', 'Phenotype', 'HP:0100526', (47, 59))	('Lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (0, 28))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (5, 28))	('fibroblast growth factor receptor 1', 'Gene', (161, 196))	('gene amplification', 'Var', (205, 223))	('phosphoinositide-3 kinase pathway', 'Pathway', (255, 288))	('squamous cell carcinoma', 'Disease', (5, 28))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (5, 28))	('lung cancers', 'Disease', (47, 59))	('cancers', 'Phenotype', 'HP:0002664', (52, 59))
186308	27551478	FGFR1 is amplified in 20% of lung squamous cell carcinoma (SqCC).	('SqCC', 'Phenotype', 'HP:0002860', (59, 63))	('amplified', 'Var', (9, 18))	('FGFR1', 'Gene', (0, 5))	('FGFR1', 'Gene', '2260', (0, 5))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (29, 57))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (34, 57))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (29, 57))	('lung squamous cell carcinoma', 'Disease', (29, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (48, 57))
186313	27551478	Identification of genetic amplification in fibroblast growth factor receptor 1 (FGFR1) in lung SqCC has generated immense interest in the use of FGFR inhibitors in the clinic.	('lung SqCC', 'Disease', (90, 99))	('FGFR1', 'Gene', '2260', (80, 85))	('SqCC', 'Phenotype', 'HP:0002860', (95, 99))	('fibroblast growth factor receptor 1', 'Gene', (43, 78))	('genetic amplification', 'Var', (18, 39))	('fibroblast growth factor receptor 1', 'Gene', '2260', (43, 78))	('FGFR1', 'Gene', (80, 85))
186326	27551478	Using a more specific FGFR inhibitor (PD173074), Dutt et al.	('PD173074', 'Chemical', 'MESH:C115711', (38, 46))	('FGFR', 'Gene', (22, 26))	('PD173074', 'Var', (38, 46))
186334	27551478	They showed that cell lines overexpressing both MYC and FGFR1 were more sensitive to FGFR inhibition compared with cells expressing FGFR1 alone, suggesting that co-expression of MYC may increase sensitivity to FGFR inhibitors.	('MYC', 'Gene', (178, 181))	('FGFR1', 'Gene', '2260', (132, 137))	('co-expression', 'Var', (161, 174))	('increase', 'PosReg', (186, 194))	('MYC', 'Gene', (48, 51))	('FGFR1', 'Gene', '2260', (56, 61))	('MYC', 'Gene', '4609', (178, 181))	('FGFR1', 'Gene', (56, 61))	('increase sensitivity to FGFR', 'Phenotype', 'HP:0030269', (186, 214))	('sensitivity to FGFR inhibitors', 'MPA', (195, 225))	('MYC', 'Gene', '4609', (48, 51))	('sensitive', 'MPA', (72, 81))	('FGFR1', 'Gene', (132, 137))
186337	27551478	However, in FGFRamp/MYC-positive cell lines sensitive to FGFR inhibition, treatment with PD173074, a pan FGFR inhibitor, resulted in downregulation of MYC expression confounding the hypothesis that MYC expression could participate in cell death induced by FGFR inhibition.	('MYC', 'Gene', (20, 23))	('MYC', 'Gene', (151, 154))	('MYC', 'Gene', '4609', (198, 201))	('PD173074', 'Chemical', 'MESH:C115711', (89, 97))	('PD173074', 'Var', (89, 97))	('downregulation', 'NegReg', (133, 147))	('MYC', 'Gene', '4609', (151, 154))	('MYC', 'Gene', '4609', (20, 23))	('MYC', 'Gene', (198, 201))
186345	27551478	Another approach to enhance response to FGFR inhibition, prevent development of acquired resistance and limit the occurrence of adverse events would be to inhibit key components of the pathway downstream of FGFR, including phosphoinositide-3 kinase (PI3K) signaling, or to enhance cell death by combining FGFR inhibitors with pro-apoptotic therapies (Figure 2).	('enhance', 'PosReg', (273, 280))	('FGFR', 'Gene', (305, 309))	('cell death', 'CPA', (281, 291))	('enhance', 'PosReg', (20, 27))	('PI3', 'Gene', (250, 253))	('phosphoinositide-3', 'MPA', (223, 241))	('FGFR', 'Gene', (207, 211))	('inhibit', 'NegReg', (155, 162))	('inhibitors', 'Var', (310, 320))	('PI3', 'Gene', '5266', (250, 253))
186347	27551478	Ligand binding to FGFRs activates three downstream pathways: the Ras-MAP kinase pathway, the PI3K-Akt-mTOR pathway and PLCgamma-Ca2+ pathway to control cell proliferation, survival and differentiation (Figure 2).	('FGFRs', 'Gene', (18, 23))	('Ras-MAP kinase pathway', 'Pathway', (65, 87))	('PI3', 'Gene', (93, 96))	('Akt', 'Gene', '207', (98, 101))	('Ca2+', 'Chemical', 'MESH:D000069285', (128, 132))	('survival', 'CPA', (172, 180))	('PLCgamma-Ca2+ pathway', 'Pathway', (119, 140))	('control', 'PosReg', (144, 151))	('binding', 'Var', (7, 14))	('mTOR', 'Gene', (102, 106))	('Akt', 'Gene', (98, 101))	('mTOR', 'Gene', '2475', (102, 106))	('activates', 'PosReg', (24, 33))	('PI3', 'Gene', '5266', (93, 96))	('cell proliferation', 'CPA', (152, 170))
186348	27551478	Genetic alterations in the PI3 kinase pathway are frequent in lung SqCC with mutations in the catalytic subunit of PI3K encoded by PIK3CA present in 5-16% of lung SqCC, whereas loss of PTEN, a negative regulator of the PI3K pathway, is observed in 15% of tumors (Figure 1).	('SqCC', 'Phenotype', 'HP:0002860', (67, 71))	('tumor', 'Phenotype', 'HP:0002664', (255, 260))	('frequent', 'Reg', (50, 58))	('tumors', 'Disease', (255, 261))	('PIK3CA', 'Gene', (131, 137))	('PI3', 'Gene', (219, 222))	('PI3', 'Gene', (27, 30))	('PI3', 'Gene', (115, 118))	('tumors', 'Disease', 'MESH:D009369', (255, 261))	('lung SqCC', 'Disease', (158, 167))	('lung SqCC', 'Disease', (62, 71))	('PTEN', 'Gene', (185, 189))	('mutations', 'Var', (77, 86))	('PIK3CA', 'Gene', '5290', (131, 137))	('PTEN', 'Gene', '5728', (185, 189))	('PI3', 'Gene', '5266', (27, 30))	('tumors', 'Phenotype', 'HP:0002664', (255, 261))	('PI3', 'Gene', '5266', (219, 222))	('SqCC', 'Phenotype', 'HP:0002860', (163, 167))	('PI3', 'Gene', '5266', (115, 118))
186354	27551478	Inhibition of growth factor intracellular signaling pathways leads to decreased cell proliferation and/or initiation of apoptosis through induction of the expression of pro-apoptotic BH3-only proteins.	('BH3-only', 'Gene', (183, 191))	('apoptosis', 'CPA', (120, 129))	('induction', 'Reg', (138, 147))	('decreased', 'NegReg', (70, 79))	('expression', 'MPA', (155, 165))	('cell proliferation', 'CPA', (80, 98))	('Inhibition', 'Var', (0, 10))	('BH3', 'Chemical', 'MESH:C006008', (183, 186))	('growth factor intracellular signaling pathways', 'Pathway', (14, 60))
186356	27551478	showed that induction of BIM by EGFR TKI in EGFR-mutated NSCLC was necessary to induce cell death, and that combination of EGFR TKI with the BH3 mimetic ABT-737 potentiated cell death.	('cell death', 'CPA', (173, 183))	('ABT', 'Chemical', 'MESH:C002502', (153, 156))	('NSCLC', 'Phenotype', 'HP:0030358', (57, 62))	('BH3', 'Chemical', 'MESH:C006008', (141, 144))	('EGFR', 'Var', (123, 127))	('potentiated', 'PosReg', (161, 172))	('NSCLC', 'Disease', (57, 62))	('combination', 'Interaction', (108, 119))	('NSCLC', 'Disease', 'MESH:D002289', (57, 62))
186359	27551478	Analysis of somatic copy-number alterations in multiple cancer types demonstrated amplification of the MCL1 locus in 10.9% of cancers, with a higher prevalence in lung and breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('amplification', 'Var', (82, 95))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('MCL1', 'Gene', '4170', (103, 107))	('cancers', 'Phenotype', 'HP:0002664', (126, 133))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('breast cancer', 'Phenotype', 'HP:0003002', (172, 185))	('cancers', 'Disease', (126, 133))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('MCL1', 'Gene', (103, 107))	('cancers', 'Disease', 'MESH:D009369', (126, 133))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', (179, 185))	('lung and breast cancer', 'Disease', 'MESH:D001943', (163, 185))
186362	27551478	Further exploration of the downstream effect of FGFR1 inhibition on the activation of the intrinsic apoptotic pathway will help refine which BH3 mimetic may be the most appropriate for combination therapy with FGFR inhibitors.	('inhibition', 'Var', (54, 64))	('FGFR1', 'Gene', (48, 53))	('BH3', 'Chemical', 'MESH:C006008', (141, 144))	('intrinsic apoptotic pathway', 'Pathway', (90, 117))	('FGFR1', 'Gene', '2260', (48, 53))
186365	27551478	Oncogenes can alter the tumor microenvironment and the nature of immune infiltrates, suggesting that combination immunotherapy and targeted therapy may prove beneficial in oncogene-addicted tumors.	('Oncogenes', 'Var', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('oncogene-addicted tumors', 'Disease', (172, 196))	('tumor', 'Disease', (24, 29))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('oncogene-addicted tumors', 'Disease', 'MESH:D000074723', (172, 196))	('alter', 'Reg', (14, 19))	('tumor', 'Disease', (190, 195))	('tumors', 'Phenotype', 'HP:0002664', (190, 196))	('tumor', 'Disease', 'MESH:D009369', (24, 29))
186366	27551478	In syngenic mouse models of melanoma carrying a BRAFV600E driver mutation, B-RAF inhibitors have been shown to increase antigen presentation, antigen-specific T-cell recognition and improved T-cell effector function, suggesting that combination of targeted therapy with immunotherapy may improve patient outcome.	('melanoma', 'Disease', (28, 36))	('increase', 'PosReg', (111, 119))	('T-cell effector function', 'CPA', (191, 215))	('BRAFV600E', 'Var', (48, 57))	('inhibitors', 'Var', (81, 91))	('improved', 'PosReg', (182, 190))	('BRAFV600E', 'Mutation', 'rs113488022', (48, 57))	('antigen-specific T-cell recognition', 'MPA', (142, 177))	('antigen presentation', 'MPA', (120, 140))	('B-RAF', 'Gene', (75, 80))	('patient', 'Species', '9606', (296, 303))	('mouse', 'Species', '10090', (12, 17))	('melanoma', 'Disease', 'MESH:D008545', (28, 36))	('B-RAF', 'Gene', '109880', (75, 80))	('melanoma', 'Phenotype', 'HP:0002861', (28, 36))
186373	27551478	In the case of squamous cell cancer, in contrast to non-squamous NSCLC, mutation load but not PD-L1 expression may be predictive of outcome.	('squamous cell cancer', 'Disease', 'MESH:D002294', (15, 35))	('squamous cell cancer', 'Disease', (15, 35))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (15, 35))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('NSCLC', 'Phenotype', 'HP:0030358', (65, 70))	('mutation load', 'Var', (72, 85))	('squamous NSCLC', 'Disease', (56, 70))	('squamous NSCLC', 'Disease', 'MESH:D002294', (56, 70))
186380	27551478	Molecular profiling studies performed on patients' lung tumor and corresponding PDXs show that the transcriptome and genetic mutations are generally maintained in lung cancer PDXs, indicative of polyclonal engraftment.	('mutations', 'Var', (125, 134))	('lung cancer', 'Disease', 'MESH:D008175', (163, 174))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('lung tumor', 'Phenotype', 'HP:0100526', (51, 61))	('patients', 'Species', '9606', (41, 49))	('lung cancer', 'Phenotype', 'HP:0100526', (163, 174))	('lung cancer', 'Disease', (163, 174))	('lung tumor', 'Disease', 'MESH:D008175', (51, 61))	('lung tumor', 'Disease', (51, 61))
186391	27551478	However, it is becoming clear that tumors that respond best to immune checkpoint inhibitors, such as melanomas and lung cancers, have a high rate of mutations.	('melanomas', 'Phenotype', 'HP:0002861', (101, 110))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('lung cancers', 'Phenotype', 'HP:0100526', (115, 127))	('mutations', 'Var', (149, 158))	('melanoma', 'Phenotype', 'HP:0002861', (101, 109))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('melanomas and lung cancers', 'Disease', 'MESH:D008175', (101, 127))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('cancers', 'Phenotype', 'HP:0002664', (120, 127))	('tumors', 'Disease', (35, 41))	('tumors', 'Disease', 'MESH:D009369', (35, 41))	('lung cancer', 'Phenotype', 'HP:0100526', (115, 126))
186425	33939693	tumor initiation, clonal expansion (promotion) and transformation, have provided important insights into the stochastic dynamics and characteristic time-scales associated with the development of precursor lesions and their malignant successors.	('tumor initiation', 'Disease', (0, 16))	('men', 'Species', '9606', (187, 190))	('clonal', 'Var', (18, 24))	('tumor initiation', 'Disease', 'MESH:D009369', (0, 16))	('tumor', 'Phenotype', 'HP:0002664', (0, 5))
186430	33939693	Cells that comprise this field are assumed at equal risk to acquire 1 or more driver mutations (with rate mu1) that allow premalignant (or "cancerized") stem cells to proliferate and to form dysplastic foci.	('dysplastic foci', 'Disease', (191, 206))	('dysplastic foci', 'Disease', 'MESH:D004416', (191, 206))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('mutations', 'Var', (85, 94))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('proliferate', 'CPA', (167, 178))
186435	33939693	For a two-stage clonal expansion model (i.e., a single initiating mutational event is required to induce dysplastic cell proliferation), we have  with  and  with  Rather than fitting the model parameters p and q, we use the combinations g = -(p + q) = alpha - beta - mu2 (net cell proliferation) and pq = -alphamu2 (  malignant transformation).	('dysplastic', 'Disease', (105, 115))	('pq = -alphamu2', 'Var', (300, 314))	('dysplastic', 'Disease', 'MESH:D004416', (105, 115))
186459	33939693	Although environmental exposures, such as cigarette smoking, alcohol consumption may contribute to field formation later in life, the young-age signatures and time trends of the inferred premalignant field-defect suggest that other factors such as pediatric malnutrition and vitamin deficiencies may significantly influence ESCC incidence patterns in the US.	('ESCC', 'Disease', (324, 328))	('influence', 'Reg', (314, 323))	('alcohol', 'Chemical', 'MESH:D000438', (61, 68))	('malnutrition', 'Disease', (258, 270))	('contribute', 'Reg', (85, 95))	('malnutrition', 'Disease', 'MESH:D044342', (258, 270))	('men', 'Species', '9606', (16, 19))	('malnutrition', 'Phenotype', 'HP:0004395', (258, 270))	('deficiencies', 'Var', (283, 295))
186464	33939693	Importantly, the sporadic (independent) stem cell mutation scenario (Fig 3A) yields mutation rates that are implausible while the field-defect scenario yields estimates that are in line with the concept of an abnormal (defective) esophageal tissue in which rare (rate-limiting) mutations lead to the initiation of dysplasia.	('mutations', 'Var', (278, 287))	('lead to', 'Reg', (288, 295))	('initiation of dysplasia', 'Disease', 'MESH:D007319', (300, 323))	('mutation', 'Var', (50, 58))	('initiation of dysplasia', 'Disease', (300, 323))
186465	33939693	Since mutations in TP53 are found in virtually all ESCC and occur frequently in BE and EAC, it is plausible to assume that the first mutation in the field-defect involves TP53 LOH, associated with loss of TP53 tumor suppressor function, followed by a malignant transformation in response (or due) to the loss of TP53 control consistent with Knudson's two-hit model.	('TP53', 'Gene', (171, 175))	('mutation', 'Var', (133, 141))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('TP53', 'Gene', '7157', (205, 209))	('tumor', 'Disease', (210, 215))	('TP53', 'Gene', (205, 209))	('TP53', 'Gene', '7157', (171, 175))	('loss', 'NegReg', (197, 201))	('ESCC', 'Disease', (51, 55))	('LOH', 'Var', (176, 179))	('TP53', 'Gene', (19, 23))	('TP53', 'Gene', '7157', (19, 23))	('TP53', 'Gene', '7157', (312, 316))	('malignant transformation', 'CPA', (251, 275))	('mutations', 'Var', (6, 15))	('TP53', 'Gene', (312, 316))	('tumor', 'Disease', 'MESH:D009369', (210, 215))
186470	33939693	Environmental exposures, such as cigarette smoking, alcohol and industrial exposures may well contribute to field formation later in life (and increased promotion of precursor lesions), however the young-age signatures and time trends of the inferred premalignant field-defect suggest that other factors such as pediatric malnutrition, iron deficiency anemia (IDA) and deficiencies of some B vitamins (e.g.	('iron deficiency anemia', 'Phenotype', 'HP:0001891', (336, 358))	('malnutrition', 'Disease', (322, 334))	('malnutrition', 'Disease', 'MESH:D044342', (322, 334))	('iron deficiency anemia', 'Disease', (336, 358))	('malnutrition', 'Phenotype', 'HP:0004395', (322, 334))	('iron deficiency anemia', 'Disease', 'MESH:D018798', (336, 358))	('anemia', 'Phenotype', 'HP:0001903', (352, 358))	('deficiencies', 'Var', (369, 381))	('men', 'Species', '9606', (7, 10))	('alcohol', 'Chemical', 'MESH:D000438', (52, 59))
186496	33673690	Silencing DNA Polymerase beta Induces Aneuploidy as a Biomarker of Poor Prognosis in Oral Squamous Cell Cancer Most patients with oral squamous cell cancer (OSCC) have a locally advanced stage at diagnosis.	('oral squamous cell cancer', 'Disease', 'MESH:D002294', (130, 155))	('oral squamous cell cancer', 'Disease', (130, 155))	('Oral Squamous Cell Cancer', 'Disease', (85, 110))	('DNA Polymerase beta', 'Gene', (10, 29))	('Aneuploidy', 'Disease', 'MESH:D000782', (38, 48))	('patients', 'Species', '9606', (116, 124))	('Squamous Cell Cancer', 'Phenotype', 'HP:0002860', (90, 110))	('Oral Squamous Cell Cancer', 'Disease', 'MESH:D002294', (85, 110))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (135, 155))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('DNA Polymerase beta', 'Gene', '5423', (10, 29))	('Cancer', 'Phenotype', 'HP:0002664', (104, 110))	('Silencing', 'Var', (0, 9))	('Aneuploidy', 'Disease', (38, 48))
186497	33673690	DNA repair and genetic instability are highly associated with carcinogenesis and treatment outcomes in oral squamous cell cancer, affecting cell growth and proliferation.	('affecting', 'Reg', (130, 139))	('genetic instability', 'Var', (15, 34))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (108, 128))	('carcinogenesis', 'Disease', 'MESH:D063646', (62, 76))	('cell growth', 'CPA', (140, 151))	('oral squamous cell cancer', 'Disease', 'MESH:D002294', (103, 128))	('oral squamous cell cancer', 'Disease', (103, 128))	('associated', 'Reg', (46, 56))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('carcinogenesis', 'Disease', (62, 76))
186511	33673690	During the cancer development of OSCC, evidence indicates that malfunction of proteins promote tumorigenesis involving both enhancements of cancer cell proliferation and modulations of tumor microenvironment.	('malfunction', 'Var', (63, 74))	('tumor', 'Disease', (185, 190))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('cancer', 'Disease', 'MESH:D009369', (11, 17))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('proteins', 'Protein', (78, 86))	('cancer', 'Disease', (11, 17))	('promote', 'PosReg', (87, 94))	('enhancements', 'PosReg', (124, 136))	('tumor', 'Disease', (95, 100))
186520	33673690	The pathogenesis of CIN comprises diverse gene mutations, ploidy abnormalities and chromosomal damage caused by disturbance in the checkpoint and genomic surveillance genes.	('ploidy abnormalities and chromosomal damage', 'Disease', 'MESH:D025063', (58, 101))	('CIN', 'Disease', (20, 23))	('mutations', 'Var', (47, 56))	('checkpoint', 'Gene', (131, 141))	('CIN', 'Disease', 'MESH:D007674', (20, 23))	('CIN', 'Phenotype', 'HP:0040012', (20, 23))	('disturbance', 'Reg', (112, 123))
186524	33673690	In different cancer cell lines and cancer patients, the expression of POLB is associated with tumorigenesis.	('associated', 'Reg', (78, 88))	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('POLB', 'Gene', (70, 74))	('POLB', 'Gene', '5423', (70, 74))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('tumor', 'Disease', (94, 99))	('cancer', 'Disease', (13, 19))	('cancer', 'Disease', 'MESH:D009369', (13, 19))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('patients', 'Species', '9606', (42, 50))	('expression', 'Var', (56, 66))	('cancer', 'Disease', (35, 41))
186544	33673690	Patients with high POLB expression had significantly longer overall survival than patients with low POLB expression.	('POLB', 'Gene', '5423', (100, 104))	('patients', 'Species', '9606', (82, 90))	('POLB', 'Gene', '5423', (19, 23))	('high', 'Var', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('POLB', 'Gene', (100, 104))	('overall survival', 'MPA', (60, 76))	('expression', 'Var', (24, 34))	('longer', 'PosReg', (53, 59))	('POLB', 'Gene', (19, 23))
186546	33673690	Further analysis using a multivariate Cox regression model, which controlled for the effect of other clinical parameters, indicated that patients with high POLB expression were 0.475 times more likely to die of OSCC than those with low POLB expression (95% confidence interval (CI) of hazard ratio (HR) = 0.233-0.965), which also suggested that POLB expression had a protective effect on overall survival (p = 0.04).	('POLB', 'Gene', (236, 240))	('OSCC', 'Disease', (211, 215))	('high', 'Var', (151, 155))	('patients', 'Species', '9606', (137, 145))	('POLB', 'Gene', '5423', (345, 349))	('POLB', 'Gene', '5423', (156, 160))	('POLB', 'Gene', '5423', (236, 240))	('POLB', 'Gene', (345, 349))	('POLB', 'Gene', (156, 160))	('overall', 'MPA', (388, 395))
186557	33673690	The size of Ca9-22 cells with knockdown of POLB was larger than that of Ca9-22 cells.	('POLB', 'Gene', (43, 47))	('Ca9-22', 'CellLine', 'CVCL:1102', (12, 18))	('knockdown', 'Var', (30, 39))	('POLB', 'Gene', '5423', (43, 47))	('larger', 'PosReg', (52, 58))	('Ca9-22', 'CellLine', 'CVCL:1102', (72, 78))
186560	33673690	The shutdown of POLB in Ca9-22 cells resulted in a significant increase in the percentage of polyploid and aneuploid cells with >4 N compared with parental Ca9-22 cells (Figure 3C).	('increase', 'PosReg', (63, 71))	('Ca9-22', 'CellLine', 'CVCL:1102', (156, 162))	('POLB', 'Gene', (16, 20))	('aneuploid', 'Disease', 'MESH:D000782', (107, 116))	('shutdown', 'Var', (4, 12))	('POLB', 'Gene', '5423', (16, 20))	('Ca9-22', 'CellLine', 'CVCL:1102', (24, 30))	('aneuploid', 'Disease', (107, 116))
186563	33673690	After the shutdown of POLB expression, the levels of CDK inhibitors, including p21, p27 and p57, were decreased.	('p27', 'Gene', (84, 87))	('p57', 'Gene', (92, 95))	('POLB', 'Gene', (22, 26))	('p21', 'Gene', (79, 82))	('shutdown', 'Var', (10, 18))	('POLB', 'Gene', '5423', (22, 26))	('levels of CDK inhibitors', 'MPA', (43, 67))	('p27', 'Gene', '3429', (84, 87))	('p21', 'Gene', '1026', (79, 82))	('p57', 'Gene', '1028', (92, 95))	('decreased', 'NegReg', (102, 111))
186565	33673690	The results suggest that POLB silencing promoted polyploidy and aneuploidy through dysregulation of cyclin B and cyclin A2.	('polyploidy', 'Disease', (49, 59))	('cyclin', 'Gene', '5111', (113, 119))	('promoted', 'PosReg', (40, 48))	('aneuploidy', 'Disease', 'MESH:D000782', (64, 74))	('POLB', 'Gene', (25, 29))	('cyclin', 'Gene', (113, 119))	('aneuploidy', 'Disease', (64, 74))	('polyploidy', 'Disease', 'MESH:D011123', (49, 59))	('cyclin A2', 'Gene', '890', (113, 122))	('cyclin A2', 'Gene', (113, 122))	('dysregulation', 'MPA', (83, 96))	('cyclin', 'Gene', '5111', (100, 106))	('silencing', 'Var', (30, 39))	('POLB', 'Gene', '5423', (25, 29))	('cyclin', 'Gene', (100, 106))
186573	33673690	In the meta-analysis for OSCC, CD163+ M2 macrophages and CD57+ natural killer cells were the most promising predictors of survival among the tissue-infiltrating immune cells.	('CD57+', 'Var', (57, 62))	('CD163', 'Gene', (31, 36))	('CD163', 'Gene', '9332', (31, 36))
186586	33673690	Given that the functional properties and morphology of oral cancer cells are affected by the presence of POLB, we further examined whether these changes could be correlated to cell-cycle regulation and chromosomal instability.	('functional properties', 'CPA', (15, 36))	('presence', 'Var', (93, 101))	('affected', 'Reg', (77, 85))	('morphology', 'CPA', (41, 51))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('chromosomal instability', 'Phenotype', 'HP:0040012', (202, 225))	('cancer', 'Disease', (60, 66))	('POLB', 'Gene', '5423', (105, 109))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('POLB', 'Gene', (105, 109))
186589	33673690	In OSCC cells, depletion of POLB increased the proportion of polyploid and aneuploid cells with DNA content of 8N and >4N, revealing that the loss of POLB disrupts the normal cell-cycle progression, leading to aneuploidy and genetic instability in OSCC.	('aneuploidy', 'Disease', (210, 220))	('POLB', 'Gene', '5423', (28, 32))	('aneuploid', 'Disease', 'MESH:D000782', (210, 219))	('cell-cycle progression', 'CPA', (175, 197))	('aneuploid', 'Disease', (75, 84))	('loss', 'Var', (142, 146))	('genetic instability', 'CPA', (225, 244))	('POLB', 'Gene', (150, 154))	('leading to', 'Reg', (199, 209))	('disrupts', 'NegReg', (155, 163))	('aneuploidy', 'Disease', 'MESH:D000782', (210, 220))	('POLB', 'Gene', (28, 32))	('aneuploid', 'Disease', 'MESH:D000782', (75, 84))	('aneuploid', 'Disease', (210, 219))	('POLB', 'Gene', '5423', (150, 154))
186600	33673690	In vitro experiments demonstrated that silencing of POLB could induce chromosomal instability and numerical alterations.	('POLB', 'Gene', '5423', (52, 56))	('induce', 'Reg', (63, 69))	('chromosomal instability', 'Phenotype', 'HP:0040012', (70, 93))	('numerical alterations', 'CPA', (98, 119))	('silencing', 'Var', (39, 48))	('POLB', 'Gene', (52, 56))	('chromosomal instability', 'CPA', (70, 93))
186617	33673690	Cyclin B1 (#4138), cyclin A2 (#4656) and p21 (#2947) antibodies were purchased from Cell Signaling Technology (Danvers, MA, USA).	('p21', 'Gene', (41, 44))	('Cyclin B1', 'Gene', (0, 9))	('#4138', 'Var', (11, 16))	('cyclin A2', 'Gene', (19, 28))	('#4656', 'Var', (30, 35))	('Cyclin B1', 'Gene', '891', (0, 9))	('cyclin A2', 'Gene', '890', (19, 28))	('p21', 'Gene', '1026', (41, 44))
186619	33673690	POLB antibody (AP50642) was from Abgent (San Diego, CA, USA).	('POLB', 'Gene', '5423', (0, 4))	('POLB', 'Gene', (0, 4))	('AP50642', 'Var', (15, 22))
186622	33673690	For knockdown Pol beta, short hairpin (sh)RNA against Pol beta were purchased from the National RNAi Core Facility (Academia Sinica, Taipei City, Taiwan).	('Pol beta', 'Gene', (14, 22))	('knockdown', 'Var', (4, 13))	('Pol beta', 'Gene', '5422', (14, 22))	('Pol beta', 'Gene', (54, 62))	('Pol beta', 'Gene', '5422', (54, 62))
186641	29897167	Overexpression of wild type OIP5-AS1 led to strong CDK4 and CDK6 expression; however, these two proteins did not change when mutated OIP5-AS1 was upregulated.	('CDK6', 'Gene', (60, 64))	('CDK6', 'Gene', '1021', (60, 64))	('mutated', 'Var', (125, 132))	('expression', 'MPA', (65, 75))	('CDK4', 'Gene', (51, 55))	('CDK4', 'Gene', '1019', (51, 55))
186642	29897167	Finally, in vivo assay showed that the speed of tumor growth was increased and decreased when OIP5-AS1 was upregulated and downregulated, respectively.	('increased', 'PosReg', (65, 74))	('tumor', 'Disease', (48, 53))	('decreased', 'NegReg', (79, 88))	('OIP5-AS1', 'Var', (94, 102))	('downregulated', 'NegReg', (123, 136))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('upregulated', 'PosReg', (107, 118))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
186643	29897167	Our results revealed that OIP5-AS1 acts as a growth-promoting lncRNA in lung cancer by suppressing miR-378a-3p function.	('miR-378a-3p function', 'MPA', (99, 119))	('lung cancer', 'Disease', (72, 83))	('miR-378a', 'Chemical', '-', (99, 107))	('lung cancer', 'Phenotype', 'HP:0100526', (72, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('suppressing', 'NegReg', (87, 98))	('OIP5-AS1', 'Var', (26, 34))	('lung cancer', 'Disease', 'MESH:D008175', (72, 83))
186644	29897167	OIP5-AS1 and miR-378a-3p interaction may provide a potential target for lung cancer treatment.	('miR-378a', 'Chemical', '-', (13, 21))	('lung cancer', 'Disease', (72, 83))	('lung cancer', 'Phenotype', 'HP:0100526', (72, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('miR-378a-3p interaction', 'Var', (13, 36))	('lung cancer', 'Disease', 'MESH:D008175', (72, 83))
186646	29897167	Long non-coding RNAs (lncRNAs) are transcripts that are longer than 200 nucleotides and have no protein coding function.2 Some lncRNAs are known to be involved in complex mechanisms underlying the development of malignancies, including carcinogenesis, progression, and metastasis, but most of the underlying molecular events are unknown.3, 4, 5  The human lncRNA OIP5-AS1, which is transcribed in the antisense (AS) of OIP5, suppresses cell proliferation in multiple malignancies.6 OIP5-AS1 is reported to be associated with HuR in Hela cells, reducing its availability to target messenger RNAs of cyclins A and D1 (CCNA2 and CCND1) and SIRT1.	('CCNA2', 'Gene', '890', (616, 621))	('carcinogenesis', 'Disease', (236, 250))	('multiple malignancies', 'Disease', 'MESH:D009369', (458, 479))	('carcinogenesis', 'Disease', 'MESH:D063646', (236, 250))	('human', 'Species', '9606', (350, 355))	('SIRT1', 'Gene', '23411', (637, 642))	('CCND1', 'Gene', '595', (626, 631))	('multiple malignancies', 'Disease', (458, 479))	('cyclins A and D1', 'Gene', '890;595', (598, 614))	('availability', 'MPA', (557, 569))	('HuR', 'Gene', (525, 528))	('Hela cells', 'CellLine', 'CVCL:0030', (532, 542))	('CCND1', 'Gene', (626, 631))	('malignancies', 'Disease', 'MESH:D009369', (212, 224))	('SIRT1', 'Gene', (637, 642))	('malignancies', 'Disease', 'MESH:D009369', (467, 479))	('malignancies', 'Disease', (212, 224))	('OIP5-AS1', 'Var', (482, 490))	('CCNA2', 'Gene', (616, 621))	('malignancies', 'Disease', (467, 479))	('HuR', 'Gene', '1994', (525, 528))	('reducing', 'NegReg', (544, 552))
186688	29897167	Patients in the OIP5-AS1low group achieved higher total survival than in the OIP5-AS1high (hazard ratio [HR] 0.62, 95% confidence interval [CI] 0.51-0.69; P = 0.021) (Fig 1e).	('Patients', 'Species', '9606', (0, 8))	('total survival', 'MPA', (50, 64))	('OIP5-AS1low', 'Var', (16, 27))	('higher', 'PosReg', (43, 49))
186691	29897167	Both lymph node positive and negative patients showed higher total survival in the OIP5-AS1low than in the OIP5-AS1high group (positive: HR 0.72, 95% CI 0.612-0.920, P = 0.008; negative: HR 0.66, 95% CI 0.581-0.734, P = 0.012) (Fig 1f).	('total survival', 'CPA', (61, 75))	('patients', 'Species', '9606', (38, 46))	('higher', 'PosReg', (54, 60))	('OIP5-AS1low', 'Var', (83, 94))
186692	29897167	We analyzed lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) patient survival using the same method and the results showed that both LUAD and LUSC patients in the OIP5-AS1low group achieved higher total survival than the OIP5-AS1high (LUAD: HR 0.58, 95% CI 0.422-0.720, P = 0.032; LUSC: HR 0.61, 95% CI 0.525-0.716, P = 0.013) (Fig 1g).	('lung adenocarcinoma', 'Disease', (12, 31))	('LUSC', 'Phenotype', 'HP:0030359', (160, 164))	('LUAD', 'Phenotype', 'HP:0030078', (33, 37))	('patients', 'Species', '9606', (165, 173))	('LUAD', 'Phenotype', 'HP:0030078', (151, 155))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (43, 71))	('lung squamous cell carcinoma', 'Disease', (43, 71))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (12, 31))	('OIP5-AS1low', 'Var', (181, 192))	('patient', 'Species', '9606', (79, 86))	('LUAD', 'Phenotype', 'HP:0030078', (253, 257))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (12, 31))	('carcinoma', 'Phenotype', 'HP:0030731', (62, 71))	('LUSC', 'Phenotype', 'HP:0030359', (299, 303))	('patient', 'Species', '9606', (165, 172))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('higher', 'PosReg', (208, 214))	('total survival', 'CPA', (215, 229))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (43, 71))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (48, 71))	('LUSC', 'Phenotype', 'HP:0030359', (73, 77))
186696	29897167	Transfection of overexpression and silencing of OIP5-AS1 were performed in A549 and H520 lung cancer cells (Fig 2a,b).	('H520 lung cancer', 'Disease', 'MESH:D008175', (84, 100))	('silencing', 'Var', (35, 44))	('H520 lung cancer', 'Disease', (84, 100))	('lung cancer', 'Phenotype', 'HP:0100526', (89, 100))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('OIP5-AS1', 'Gene', (48, 56))	('A549', 'CellLine', 'CVCL:0023', (75, 79))
186700	29897167	These results confirmed that OIP5-AS1 functions as a proliferation-promoter in lung cancer cells.	('lung cancer', 'Disease', 'MESH:D008175', (79, 90))	('OIP5-AS1', 'Var', (29, 37))	('lung cancer', 'Disease', (79, 90))	('lung cancer', 'Phenotype', 'HP:0100526', (79, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))
186701	29897167	Among several miRNAs, we found that miR-378a-3p had the highest possibility of binding OIP5-AS1 (Fig 3a).	('miR-378a', 'Chemical', '-', (36, 44))	('OIP5-AS1', 'Protein', (87, 95))	('miR-378a-3p', 'Var', (36, 47))	('binding', 'Interaction', (79, 86))
186704	29897167	This result suggested that OIP5-AS1 and miR-378a-3p can both combine with AGO2 and format an RISC and that miR-378a-3p binds to OIP5-AS1 in lung cancer cells.	('binds', 'Interaction', (119, 124))	('AGO2', 'Gene', (74, 78))	('OIP5-AS1 in lung cancer', 'Disease', 'OMIM:607277', (128, 151))	('OIP5-AS1 in lung cancer', 'Disease', (128, 151))	('miR-378a', 'Chemical', '-', (40, 48))	('lung cancer', 'Phenotype', 'HP:0100526', (140, 151))	('combine', 'Interaction', (61, 68))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('AGO2', 'Gene', '27161', (74, 78))	('miR-378a-3p', 'Var', (107, 118))	('miR-378a', 'Chemical', '-', (107, 115))
186705	29897167	In addition, a luciferase assay was performed in A549 and H520 cells to test the binding site of miR-378a-3p in OIP5-AS1.	('A549', 'CellLine', 'CVCL:0023', (49, 53))	('binding', 'Interaction', (81, 88))	('miR-378a', 'Chemical', '-', (97, 105))	('miR-378a-3p', 'Var', (97, 108))
186706	29897167	The activity of luciferase reporters containing the theoretical binding site of OIP5-AS1 in miR-378a-3p was significantly decreased in OIP5-AS1-WT constructs, while there was no affect in OIP5-AS1-Mut constructs (Fig 3d,e).	('binding', 'Interaction', (64, 71))	('OIP5-AS1-WT', 'Var', (135, 146))	('luciferase', 'Enzyme', (16, 26))	('miR-378a', 'Chemical', '-', (92, 100))	('activity', 'MPA', (4, 12))	('decreased', 'NegReg', (122, 131))
186709	29897167	MTT assay and Ki67 expression showed that miR-378a-3p overexpression significantly inhibited the proliferation of lung cancer cells compared to untreated cells.	('lung cancer', 'Disease', 'MESH:D008175', (114, 125))	('miR-378a-3p', 'Var', (42, 53))	('proliferation', 'CPA', (97, 110))	('MTT', 'Chemical', 'MESH:C070243', (0, 3))	('inhibited', 'NegReg', (83, 92))	('lung cancer', 'Disease', (114, 125))	('lung cancer', 'Phenotype', 'HP:0100526', (114, 125))	('miR-378a', 'Chemical', '-', (42, 50))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
186710	29897167	The proliferation of lung cancer cells was significantly upregulated when miR-378a-3p was silenced (Fig 4b,c).	('proliferation', 'CPA', (4, 17))	('silenced', 'NegReg', (90, 98))	('miR-378a', 'Chemical', '-', (74, 82))	('lung cancer', 'Disease', (21, 32))	('lung cancer', 'Phenotype', 'HP:0100526', (21, 32))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('miR-378a-3p', 'Var', (74, 85))	('lung cancer', 'Disease', 'MESH:D008175', (21, 32))	('upregulated', 'PosReg', (57, 68))
186711	29897167	CDK4 and CDK6 have been reported as important proliferation-associated proteins in multiple human cancers.16 To confirm whether miR-378a-3p inhibited lung cancer cell proliferation, we examined changes in CDK4 and CDK6 expression in transfected A549 and H520 cells.	('CDK4', 'Gene', '1019', (205, 209))	('lung cancer', 'Disease', (150, 161))	('cancers', 'Phenotype', 'HP:0002664', (98, 105))	('inhibited', 'NegReg', (140, 149))	('cancers', 'Disease', (98, 105))	('CDK6', 'Gene', (9, 13))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('CDK6', 'Gene', '1021', (214, 218))	('lung cancer', 'Disease', 'MESH:D008175', (150, 161))	('A549', 'CellLine', 'CVCL:0023', (245, 249))	('CDK6', 'Gene', (214, 218))	('lung cancer', 'Phenotype', 'HP:0100526', (150, 161))	('cancers', 'Disease', 'MESH:D009369', (98, 105))	('CDK4', 'Gene', (0, 4))	('human', 'Species', '9606', (92, 97))	('CDK4', 'Gene', (205, 209))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('miR-378a-3p', 'Var', (128, 139))	('CDK4', 'Gene', '1019', (0, 4))	('miR-378a', 'Chemical', '-', (128, 136))	('CDK6', 'Gene', '1021', (9, 13))
186713	29897167	When A549 and H520 cells were transfected with miR-378a-3p mimics, CDK4 and CDK6 proteins were significantly reduced compared to cells that were not treated (Fig 4d).	('CDK4', 'Gene', (67, 71))	('A549', 'CellLine', 'CVCL:0023', (5, 9))	('CDK4', 'Gene', '1019', (67, 71))	('miR-378a', 'Chemical', '-', (47, 55))	('reduced', 'NegReg', (109, 116))	('miR-378a-3p', 'Var', (47, 58))	('CDK6', 'Gene', (76, 80))	('CDK6', 'Gene', '1021', (76, 80))
186714	29897167	These results showed that miR-378a-3p functions as an inhibitor of lung cancer proliferation and the underlying mechanisms are related to CDK4 and CDK6 proteins.	('inhibitor', 'NegReg', (54, 63))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('CDK6', 'Gene', (147, 151))	('lung cancer', 'Disease', 'MESH:D008175', (67, 78))	('CDK6', 'Gene', '1021', (147, 151))	('miR-378a', 'Chemical', '-', (26, 34))	('miR-378a-3p', 'Var', (26, 37))	('lung cancer', 'Disease', (67, 78))	('lung cancer', 'Phenotype', 'HP:0100526', (67, 78))	('CDK4', 'Gene', '1019', (138, 142))	('CDK4', 'Gene', (138, 142))
186715	29897167	Further experiments are required to confirm the relationship between OIP5-AS1, miR-378a-3p, and lung cancer proliferation.	('lung cancer', 'Disease', 'MESH:D008175', (96, 107))	('miR-378a-3p', 'Var', (79, 90))	('lung cancer', 'Disease', (96, 107))	('lung cancer', 'Phenotype', 'HP:0100526', (96, 107))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('miR-378a', 'Chemical', '-', (79, 87))
186716	29897167	To investigate whether the proliferation-inhibiting effects of miR-378a-3p were suppressed by OIP5-AS1, we co-transfected A549 and H520 cells with miR-378a-3p mimics and OIP5-AS1-WT expression vector.	('miR-378a-3p', 'Var', (63, 74))	('miR-378a', 'Chemical', '-', (147, 155))	('proliferation-inhibiting', 'CPA', (27, 51))	('miR-378a', 'Chemical', '-', (63, 71))	('A549', 'CellLine', 'CVCL:0023', (122, 126))
186718	29897167	When we co-transfected A549 cells with miR-378a-3p mimics and an OIP5-AS1-Mut expression vector, the proliferation-inhibiting function of miR-378a-3p barely differed from the control (Fig 5a).	('miR-378a', 'Chemical', '-', (39, 47))	('miR-378a-3p', 'Var', (138, 149))	('miR-378a', 'Chemical', '-', (138, 146))	('A549', 'CellLine', 'CVCL:0023', (23, 27))	('proliferation-inhibiting', 'CPA', (101, 125))
186719	29897167	Ki67, CDK4, and CDK6 expression were also increased after treatment with the OIP5-AS1-WT vector, while OIP5-AS1-Mut exerted no function in lung cancer cells (Fig 5b).	('lung cancer', 'Disease', (139, 150))	('increased', 'PosReg', (42, 51))	('OIP5-AS1-WT', 'Var', (77, 88))	('CDK6', 'Gene', (16, 20))	('CDK6', 'Gene', '1021', (16, 20))	('lung cancer', 'Disease', 'MESH:D008175', (139, 150))	('expression', 'MPA', (21, 31))	('Ki67', 'Gene', (0, 4))	('CDK4', 'Gene', (6, 10))	('lung cancer', 'Phenotype', 'HP:0100526', (139, 150))	('CDK4', 'Gene', '1019', (6, 10))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
186720	29897167	These observations suggest that OIP5-AS1 promoted tumor cell growth in part by competitively binding miR-378a-3p.	('miR-378a', 'Chemical', '-', (101, 109))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('binding', 'Interaction', (93, 100))	('miR-378a-3p', 'Var', (101, 112))	('promoted', 'PosReg', (41, 49))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Disease', (50, 55))
186737	29897167	The results show that miR-378a-3p could form complementary base pairing with OIP5-AS1 and reduce pGL3-OIP5-AS1 reporter gene expression.	('complementary base pairing', 'MPA', (45, 71))	('pGL3', 'Gene', (97, 101))	('miR-378a', 'Chemical', '-', (22, 30))	('pGL3', 'Gene', '6391', (97, 101))	('reduce', 'NegReg', (90, 96))	('miR-378a-3p', 'Var', (22, 33))
186738	29897167	In RIP assay, OIP5-AS1 expression immunoprecipitated with Ago2 was higher than when immunoprecipitated with immunoglobulin G, indicating the reciprocal repression of OIP5-AS1 and miR-378a-3p caused by RISC.	('Ago2', 'Gene', '27161', (58, 62))	('miR-378a-3p', 'Var', (179, 190))	('higher', 'PosReg', (67, 73))	('Ago2', 'Gene', (58, 62))	('miR-378a', 'Chemical', '-', (179, 187))	('OIP5-AS1', 'Gene', (14, 22))	('expression', 'MPA', (23, 33))
186739	29897167	We also show that miR-378a-3p overexpression arrested lung cancer cell growth and OIP5-AS1 can inhibit its function.	('lung cancer', 'Phenotype', 'HP:0100526', (54, 65))	('overexpression arrested lung cancer', 'Disease', (30, 65))	('miR-378a-3p', 'Var', (18, 29))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('miR-378a', 'Chemical', '-', (18, 26))	('overexpression arrested lung cancer', 'Disease', 'MESH:D008175', (30, 65))
186742	29897167	In addition, we found that miR-378a-3p negatively regulates the expression of proliferation-associated proteins, CDK4 and CDK6.16 These two proteins are significantly increased again by upregulating OIP5-AS1.	('OIP5-AS1', 'Protein', (199, 207))	('expression', 'MPA', (64, 74))	('miR-378a-3p', 'Var', (27, 38))	('CDK4', 'Gene', '1019', (113, 117))	('CDK4', 'Gene', (113, 117))	('CDK6', 'Gene', (122, 126))	('CDK6', 'Gene', '1021', (122, 126))	('increased', 'PosReg', (167, 176))	('negatively', 'NegReg', (39, 49))	('miR-378a', 'Chemical', '-', (27, 35))	('upregulating', 'PosReg', (186, 198))	('regulates', 'Reg', (50, 59))
186744	29897167	In summary, we showed that the lncRNA OIP5-AS1 promotes lung cancer cell proliferation by competitively binding miR-378a-3p.	('lung cancer', 'Phenotype', 'HP:0100526', (56, 67))	('lung cancer', 'Disease', 'MESH:D008175', (56, 67))	('promotes', 'PosReg', (47, 55))	('miR-378a', 'Chemical', '-', (112, 120))	('binding', 'Interaction', (104, 111))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('lung cancer', 'Disease', (56, 67))	('miR-378a-3p', 'Var', (112, 123))
186747	29897167	Our findings show that OIP5-AS1 may be a target for lung cancer therapy, with crosstalk between miR-378a-3p and OIP5-AS1 shedding new light on the potential treatment of lung cancer.	('lung cancer', 'Disease', 'MESH:D008175', (52, 63))	('miR-378a-3p', 'Var', (96, 107))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('lung cancer', 'Disease', 'MESH:D008175', (170, 181))	('lung cancer', 'Disease', (52, 63))	('OIP5-AS1', 'Gene', (112, 120))	('miR-378a', 'Chemical', '-', (96, 104))	('lung cancer', 'Phenotype', 'HP:0100526', (52, 63))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('lung cancer', 'Disease', (170, 181))	('lung cancer', 'Phenotype', 'HP:0100526', (170, 181))	('crosstalk', 'Reg', (78, 87))
186781	29642437	An in vitro maxillary sinus biofilm study demonstrated that APDT reduced the polymicrobial biofilm in chronic rhinosinusitis by >99.99% after a single treatment.	('reduced', 'NegReg', (65, 72))	('polymicrobial biofilm', 'MPA', (77, 98))	('chronic rhinosinusitis', 'Disease', 'MESH:D006505', (102, 124))	('APDT', 'Var', (60, 64))	('chronic rhinosinusitis', 'Disease', (102, 124))
186802	29642437	Cell survival of HepG2 and HFLF-PI4 cells were decreased following PDT in a concentration-dependent manner.	('HFLF-PI4', 'CellLine', 'CVCL:9V33', (27, 35))	('HepG2', 'CellLine', 'CVCL:0027', (17, 22))	('Cell survival', 'CPA', (0, 13))	('PDT', 'Var', (67, 70))	('decreased', 'NegReg', (47, 56))
186813	29642437	Furthermore, the SRB assay and light microscopy showed a significant decrease of cell numbers after LED light-activated MB treatment (100 muM, 32 J/cm2).	('SRB', 'Gene', '10575', (17, 20))	('SRB', 'Gene', (17, 20))	('LED', 'Gene', '399668', (100, 103))	('MB', 'Chemical', 'MESH:D008751', (120, 122))	('decrease', 'NegReg', (69, 77))	('100 muM', 'Var', (134, 141))	('cell numbers', 'CPA', (81, 93))	('LED', 'Gene', (100, 103))
186819	29642437	SCC-25 cells contain a deletion and a frame shift in the TP53 gene protein coding region and do not synthesize any p53 protein (own Sanger sequencing results).	('SCC', 'Gene', (0, 3))	('deletion', 'Var', (23, 31))	('SCC', 'Gene', '6317', (0, 3))	('p53', 'Gene', (115, 118))	('p53', 'Gene', '7157', (115, 118))	('frame shift', 'Var', (38, 49))	('TP53', 'Gene', '7157', (57, 61))	('TP53', 'Gene', (57, 61))
186823	29642437	A frequent gain of function mutation R175H of TP53 gene is contained in Detroit 562 cells, which has been confirmed by us utilizing Sanger sequencing.	('TP53', 'Gene', '7157', (46, 50))	('R175H', 'Mutation', 'rs28934578', (37, 42))	('R175H', 'Var', (37, 42))	('TP53', 'Gene', (46, 50))	('gain of function', 'PosReg', (11, 27))
186859	29642437	These modifications could prove effective in targeting cancer stem cells that are thought to be resistant to photodynamic therapy.	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('modifications', 'Var', (6, 19))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('cancer', 'Disease', (55, 61))
186871	29642437	In mice, MB-PDT showed a decrease of 99% in tumor volume and 75% in tumor weight compared with untreated mice (p < 0.05).	('tumor', 'Disease', (68, 73))	('MB', 'Chemical', 'MESH:D008751', (9, 11))	('mice', 'Species', '10090', (3, 7))	('decrease', 'NegReg', (25, 33))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('MB-PDT', 'Var', (9, 15))	('mice', 'Species', '10090', (105, 109))	('tumor', 'Disease', (44, 49))
186879	29642437	In conclusion, our study suggests a significant potential of combined MB-660 nm laser therapy in HNSCC, but MB alone has a remarkable toxicity in HNSCC tumor cell lines.	('MB', 'Chemical', 'MESH:D008751', (108, 110))	('toxicity', 'Disease', 'MESH:D064420', (134, 142))	('HNSCC tumor', 'Disease', (146, 157))	('toxicity', 'Disease', (134, 142))	('SCC', 'Gene', '6317', (99, 102))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('MB-660', 'Var', (70, 76))	('SCC', 'Gene', (148, 151))	('SCC', 'Gene', '6317', (148, 151))	('SCC', 'Gene', (99, 102))	('MB', 'Chemical', 'MESH:D008751', (70, 72))	('HNSCC tumor', 'Disease', 'MESH:D000077195', (146, 157))
186951	27903673	To assess the effects of miR-155 inhibition on chemoresistance, we used an in vivo orthotopic lung cancer model of athymic nude mice, which we treated with anti-miR-155 alone or in combination with chemotherapy.	('lung cancer', 'Disease', 'MESH:D008175', (94, 105))	('lung cancer', 'Disease', (94, 105))	('lung cancer', 'Phenotype', 'HP:0100526', (94, 105))	('nude mice', 'Species', '10090', (123, 132))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('anti-miR-155', 'Var', (156, 168))
186965	27903673	Overexpression of miR-155 has been associated with drug resistance in several human cancers, including breast cancer, B-cell lymphoma and colon cancer, but the molecular mechanisms through which miR-155 increases cancer cell resistance to treatment are not fully understood.	('breast cancer', 'Disease', 'MESH:D001943', (103, 116))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (118, 133))	('breast cancer', 'Disease', (103, 116))	('Overexpression', 'Var', (0, 14))	('drug resistance', 'MPA', (51, 66))	('colon cancer', 'Disease', 'MESH:D015179', (138, 150))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('cancers', 'Disease', 'MESH:D009369', (84, 91))	('B-cell lymphoma', 'Disease', (118, 133))	('drug resistance', 'Phenotype', 'HP:0020174', (51, 66))	('human', 'Species', '9606', (78, 83))	('colon cancer', 'Disease', (138, 150))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('increases cancer', 'Disease', (203, 219))	('lymphoma', 'Phenotype', 'HP:0002665', (125, 133))	('miR-155', 'Var', (195, 202))	('cancers', 'Phenotype', 'HP:0002664', (84, 91))	('associated', 'Reg', (35, 45))	('increases cancer', 'Disease', 'MESH:D009369', (203, 219))	('cancers', 'Disease', (84, 91))	('breast cancer', 'Phenotype', 'HP:0003002', (103, 116))	('miR-155', 'Gene', (18, 25))	('colon cancer', 'Phenotype', 'HP:0003003', (138, 150))
186981	27903673	Patients were grouped into percentiles according to miR-155 and TP53 expression.	('Patients', 'Species', '9606', (0, 8))	('miR-155', 'Var', (52, 59))	('TP53', 'Gene', (64, 68))
186984	27903673	For lung adenocarcinoma cases with miR-155 expression, TP53 mutational status and survival information available, we checked for a relationship between miR-155 expression, TP53 expression and overall survival in patients with wild-type TP53 and mutated TP53 in a similar manner as described above.	('lung adenocarcinoma', 'Disease', (4, 23))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (4, 23))	('patients', 'Species', '9606', (212, 220))	('mutated', 'Var', (245, 252))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (4, 23))	('checked', 'Reg', (117, 124))	('miR-155', 'Gene', (152, 159))	('carcinoma', 'Phenotype', 'HP:0030731', (14, 23))
186985	27903673	According to the TP53 mutational status, patients were divided into two groups: (i) those expressing wild-type TP53 (unmutated) or harboring TP53 mutations not affecting its protein function (according to the IARC TP53 database p53.iarc.fr), and (ii) those harboring TP53 mutations that affect TP53 protein function (according to the IARC TP53 database p53.iarc.fr).	('mutations', 'Var', (272, 281))	('TP53 protein', 'Protein', (294, 306))	('affect', 'Reg', (287, 293))	('p53', 'Gene', (228, 231))	('p53', 'Gene', '7157', (228, 231))	('patients', 'Species', '9606', (41, 49))	('p53', 'Gene', (353, 356))	('TP53', 'Gene', (267, 271))	('p53', 'Gene', '7157', (353, 356))
186987	27903673	As shown in Figure 2A-B, A549, REH and JM1 cells overexpresssing miR-155 grew significantly better and showed higher proliferation when undergoing treatment with CDDP or doxorubicin than cells expressing normal levels of miR-155.	('grew', 'CPA', (73, 77))	('doxorubicin', 'Chemical', 'MESH:D004317', (170, 181))	('A549', 'CellLine', 'CVCL:0023', (25, 29))	('proliferation', 'CPA', (117, 130))	('CDDP', 'Chemical', '-', (162, 166))	('miR-155', 'Var', (65, 72))	('JM1', 'CellLine', 'CVCL:3532', (39, 42))	('higher', 'PosReg', (110, 116))	('better', 'PosReg', (92, 98))
186988	27903673	In addition, we performed a clonogenic assay for A549 cells stably overexpressing miR-155 (A549-155LV) and treated with CDDP vs. control cells (A549-LVEV) treated with CDDP.	('CDDP', 'Chemical', '-', (168, 172))	('A549', 'CellLine', 'CVCL:0023', (144, 148))	('CDDP', 'Var', (120, 124))	('miR-155', 'Gene', (82, 89))	('A549', 'CellLine', 'CVCL:0023', (49, 53))	('A549-155LV', 'CellLine', 'CVCL:0023', (91, 101))	('CDDP', 'Chemical', '-', (120, 124))	('A549-LVEV', 'CellLine', 'CVCL:0023', (144, 153))	('A549', 'CellLine', 'CVCL:0023', (91, 95))
186990	27903673	Finally, no difference in proliferation and cell growth was observed after fludarabine treatment and miR-155 overexpression in MEC1 and MEC2 cell lines, both of which carry a deletion of the TP53 locus (Supplementary Figure S2).	('fludarabine', 'Chemical', 'MESH:C024352', (75, 86))	('TP53', 'Gene', (191, 195))	('deletion', 'Var', (175, 183))	('MEC2', 'CellLine', 'CVCL:1871', (136, 140))	('miR-155', 'Gene', (101, 108))
186992	27903673	To evaluate the in vivo involvement of miR-155 in therapy resistance, we established an orthotopic lung cancer mouse model by intrapulmonary injection of A549-LVEV (control) cells or with A549-155LV (miR-155 overexpressing) cells.	('A549-155LV', 'Var', (188, 198))	('lung cancer', 'Disease', (99, 110))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('mouse', 'Species', '10090', (111, 116))	('lung cancer', 'Disease', 'MESH:D008175', (99, 110))	('A549-155LV', 'CellLine', 'CVCL:0023', (188, 198))	('A549-LVEV', 'CellLine', 'CVCL:0023', (154, 163))	('lung cancer', 'Phenotype', 'HP:0100526', (99, 110))
186994	27903673	Mice injected with A549-LVEV cells and treated with CDDP and anti-miR-NC showed a decrease in number of tumors, reduced primary tumor size and a reduced aggregate mass of metastases when compared to untreated mice injected with A549-LVEV cells, although this decrease was not significant, indicating that these tumors are sensitive to CDDP, as was expected (Figure 1B-C and Supplementary Figure S1B-D).	('tumors', 'Disease', (311, 317))	('reduced', 'NegReg', (145, 152))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumors', 'Disease', (104, 110))	('CDDP', 'Var', (52, 56))	('Mice', 'Species', '10090', (0, 4))	('CDDP', 'Chemical', '-', (335, 339))	('tumors', 'Disease', 'MESH:D009369', (311, 317))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('reduced', 'NegReg', (112, 119))	('tumor', 'Disease', (311, 316))	('mice', 'Species', '10090', (209, 213))	('anti-miR-NC', 'Var', (61, 72))	('decrease', 'NegReg', (82, 90))	('tumor', 'Disease', (104, 109))	('A549-LVEV', 'CellLine', 'CVCL:0023', (228, 237))	('tumor', 'Disease', 'MESH:D009369', (311, 316))	('tumor', 'Disease', (128, 133))	('metastases', 'Disease', 'MESH:D009362', (171, 181))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('tumors', 'Phenotype', 'HP:0002664', (311, 317))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('CDDP', 'Chemical', '-', (52, 56))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('A549-LVEV', 'CellLine', 'CVCL:0023', (19, 28))	('metastases', 'Disease', (171, 181))	('tumor', 'Phenotype', 'HP:0002664', (311, 316))
186996	27903673	In addition, when anti-miR-155 was combined with CDDP treatment, the chemotherapy resistance was almost completely reversed (Figure 1B-C and Supplementary Figure S1B-D).	('CDDP', 'Chemical', '-', (49, 53))	('reversed', 'Reg', (115, 123))	('anti-miR-155', 'Var', (18, 30))	('chemotherapy resistance', 'CPA', (69, 92))
186998	27903673	Immunohistochemistry for Ki-67 (apoptosis), CD31 (angiogenesis) and the TUNEL (apoptosis) assay suggested that miR-155, even in the presence of CDDP, is able to induce cell proliferation and angiogenesis, and reduce apoptosis, effects that are completely abolished when miR-155 is inhibited (Figure 1E and Supplementary Figure S1F).	('angiogenesis', 'CPA', (191, 203))	('cell proliferation', 'CPA', (168, 186))	('induce', 'PosReg', (161, 167))	('CD31', 'Gene', (44, 48))	('reduce', 'NegReg', (209, 215))	('apoptosis', 'CPA', (216, 225))	('CD31', 'Gene', '5175', (44, 48))	('miR-155', 'Var', (111, 118))	('CDDP', 'Chemical', '-', (144, 148))
186999	27903673	Although treatment with anti-miR-155 alone resulted in a significant decrease in proliferation and angiogenesis, and increase in apoptosis, the effects are even more pronounced when anti-miR-155 is combined with CDDP therapy (Figure 1E).	('increase', 'PosReg', (117, 125))	('apoptosis', 'CPA', (129, 138))	('angiogenesis', 'CPA', (99, 111))	('anti-miR-155', 'Var', (182, 194))	('CDDP', 'Chemical', '-', (212, 216))	('decrease', 'NegReg', (69, 77))	('anti-miR-155', 'Var', (24, 36))	('proliferation', 'CPA', (81, 94))
187000	27903673	We performed a cytokine assay detecting 25 pro-inflammatory cytokines on serum of mice injected with either anti-NC-DOPC or anti-miR-155-DOPC.	('mice', 'Species', '10090', (82, 86))	('DOPC', 'Chemical', 'MESH:C017251', (116, 120))	('DOPC', 'Chemical', 'MESH:C017251', (137, 141))	('anti-NC-DOPC', 'Var', (108, 120))	('anti-miR-155-DOPC', 'Var', (124, 141))
187002	27903673	miR-155 is significantly overexpressed in patients with CLL and deletion of 17p, where the genomic TP53 locus resides, suggesting that TP53 might suppress the expression of miR-155.	('suppress', 'NegReg', (146, 154))	('CLL', 'Disease', (56, 59))	('overexpressed', 'PosReg', (25, 38))	('deletion', 'Var', (64, 72))	('miR-155', 'Gene', (0, 7))	('CLL', 'Phenotype', 'HP:0005550', (56, 59))	('expression', 'MPA', (159, 169))	('17p', 'Gene', (76, 79))	('patients', 'Species', '9606', (42, 50))	('miR-155', 'Gene', (173, 180))
187004	27903673	When downregulating miR-155 in the H2009 lung cancer cell line harboring a mutation in TP53 that does not affect the miR-155 binding sites, we observed increased TP53 and p21 protein expression (Figure 3E).	('p21', 'Gene', (171, 174))	('p21', 'Gene', '644914', (171, 174))	('H2009 lung cancer', 'Disease', 'MESH:D008175', (35, 52))	('H2009 lung cancer', 'Disease', (35, 52))	('increased', 'PosReg', (152, 161))	('mutation', 'Var', (75, 83))	('TP53', 'Gene', (87, 91))	('lung cancer', 'Phenotype', 'HP:0100526', (41, 52))	('TP53', 'Protein', (162, 166))	('miR-155', 'Gene', (20, 27))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('downregulating', 'NegReg', (5, 19))
187008	27903673	Treatment with anti-miR-155 alone did not significantly affect TP53 expression, but a combination of anti-miR-155 with CDDP resulted in a significant increase of TP53 expression (Figure 1G and Supplementary Figure S1G).	('anti-miR-155', 'Var', (101, 113))	('CDDP', 'Chemical', '-', (119, 123))	('CDDP', 'Gene', (119, 123))	('TP53', 'Protein', (162, 166))	('combination', 'Interaction', (86, 97))	('increase', 'PosReg', (150, 158))	('expression', 'MPA', (167, 177))
187014	27903673	We previously showed that a combination of miR-520d-3p and its target EphA2 is a better prognostic factor for ovarian cancer than each gene by itself.	('EphA2', 'Gene', (70, 75))	('ovarian cancer', 'Disease', (110, 124))	('EphA2', 'Gene', '1969', (70, 75))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('ovarian cancer', 'Phenotype', 'HP:0100615', (110, 124))	('miR-520d-3p', 'Var', (43, 54))	('ovarian cancer', 'Disease', 'MESH:D010051', (110, 124))
187017	27903673	Since all tumors in the NSCLC-Italy dataset were selected for having unmutated TP53, the same can be concluded for this dataset.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('unmutated', 'Var', (69, 78))	('TP53', 'Gene', (79, 83))	('tumors', 'Disease', 'MESH:D009369', (10, 16))	('tumors', 'Disease', (10, 16))	('tumors', 'Phenotype', 'HP:0002664', (10, 16))	('NSCLC-Italy', 'Disease', (24, 35))	('NSCLC', 'Phenotype', 'HP:0030358', (24, 29))	('NSCLC-Italy', 'Disease', 'MESH:D002289', (24, 35))
187024	27903673	In addition, a recent publication showed that knockdown of miR-155 in the doxorubicin-resistant cell line A549/dox reversed doxorubicin resistance and restored doxorubicin-induced apoptosis and cell cycle arrest, further supporting that miR-155 might be a good target in chemosensitization of tumors.	('doxorubicin', 'Chemical', 'MESH:D004317', (74, 85))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (194, 211))	('dox', 'Chemical', 'MESH:D004317', (111, 114))	('tumors', 'Phenotype', 'HP:0002664', (293, 299))	('doxorubicin', 'Chemical', 'MESH:D004317', (160, 171))	('restored', 'PosReg', (151, 159))	('dox', 'Chemical', 'MESH:D004317', (124, 127))	('tumor', 'Phenotype', 'HP:0002664', (293, 298))	('tumors', 'Disease', (293, 299))	('doxorubicin-induced apoptosis', 'MPA', (160, 189))	('miR-155', 'Gene', (59, 66))	('cell cycle arrest', 'CPA', (194, 211))	('doxorubicin resistance', 'MPA', (124, 146))	('tumors', 'Disease', 'MESH:D009369', (293, 299))	('dox', 'Chemical', 'MESH:D004317', (74, 77))	('doxorubicin', 'Chemical', 'MESH:D004317', (124, 135))	('knockdown', 'Var', (46, 55))	('dox', 'Chemical', 'MESH:D004317', (160, 163))	('A549', 'CellLine', 'CVCL:0023', (106, 110))
187025	27903673	When we took the TP53 mutational status into consideration for the survival analysis of the lung adenocarcinoma-TCGA cohort, we observed that miR-155 and the combination of miR-155 and TP53 are significantly associated with shorter OS, only in cases with unmutated TP53 or TP53 mutations not affecting its function.	('shorter OS', 'Disease', (224, 234))	('TP53', 'Gene', (185, 189))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (92, 111))	('miR-155', 'Var', (142, 149))	('miR-155', 'Var', (173, 180))	('associated with', 'Reg', (208, 223))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('lung adenocarcinoma', 'Disease', (92, 111))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (92, 111))
187027	27903673	In addition, we showed that overexpression of miR-155 in MEC1 and MEC2 cell lines (both carrying a deletion of the TP53 locus) does not induce chemoresistance to fludarabine treatment (Supplementary Figure S2), suggesting that there is a difference in response in the context of wild-type and mutant TP53 alleles.	('fludarabine', 'Chemical', 'MESH:C024352', (162, 173))	('MEC2', 'CellLine', 'CVCL:1871', (66, 70))	('mutant', 'Var', (293, 299))	('TP53', 'Gene', (115, 119))	('deletion', 'Var', (99, 107))	('miR-155', 'Var', (46, 53))	('chemoresistance', 'CPA', (143, 158))
187031	27903673	Actually, when combined, we found that high miR-155 and low TP53 expression significantly correlated with survival in 4 independent lung cancer datasets (Table 1), and that this combination remained independently associated with survival in the datasets analyzed in a multivariate analysis (Table 2 and Supplementary Table S4).	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('associated', 'Reg', (213, 223))	('lung cancer', 'Disease', 'MESH:D008175', (132, 143))	('correlated with', 'Reg', (90, 105))	('survival', 'Disease', (106, 114))	('high miR-155', 'Var', (39, 51))	('lung cancer', 'Disease', (132, 143))	('lung cancer', 'Phenotype', 'HP:0100526', (132, 143))	('TP53', 'Gene', (60, 64))	('low', 'NegReg', (56, 59))
187032	27903673	We recently demonstrated that a combination of miR-520d-3p and its target EphA2 is a better prognostic factor for ovarian cancer than each gene by itself, and that simultaneous targeting of miRNA/mRNA (miR-520d-3p/EphA2) results in a remarkable therapeutic synergy as compared to either monotherapy.	('ovarian cancer', 'Disease', (114, 128))	('EphA2', 'Gene', (74, 79))	('EphA2', 'Gene', (214, 219))	('therapeutic synergy', 'MPA', (245, 264))	('ovarian cancer', 'Phenotype', 'HP:0100615', (114, 128))	('miR-520d-3p', 'Var', (47, 58))	('EphA2', 'Gene', '1969', (74, 79))	('EphA2', 'Gene', '1969', (214, 219))	('ovarian cancer', 'Disease', 'MESH:D010051', (114, 128))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))
187038	27903673	The finding that treatment with anti-miR-155 can reverse chemoresistance in vivo supports a potential clinical use of anti-miR-155 therapy in human clinical trials of various cancer types as an addition to current chemotherapy regimens in order to overcome cancer-enacted resistance mechanisms.	('cancer', 'Phenotype', 'HP:0002664', (257, 263))	('cancer', 'Disease', (175, 181))	('cancer', 'Disease', (257, 263))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('human', 'Species', '9606', (142, 147))	('cancer', 'Disease', 'MESH:D009369', (257, 263))	('anti-miR-155', 'Var', (118, 130))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
187072	27980454	We designed this study to explore expression profile changes after HOXA11-AS knock-down and the possible molecular mechanisms of HOXA11-AS in NSCLC development and progression.	('NSCLC', 'Disease', (142, 147))	('NSCLC', 'Disease', 'MESH:D002289', (142, 147))	('HOXA11-AS', 'Gene', '221883', (67, 76))	('HOXA11-AS', 'Gene', '221883', (129, 138))	('HOXA11-AS', 'Gene', (67, 76))	('knock-down', 'Var', (77, 87))	('HOXA11-AS', 'Gene', (129, 138))
187090	27980454	Among these 9 aberrantly expressed genes, the expression of RSPO3 (NM_032784, fold change = 41.610487, P = 8.0502E-09) was dramatically upregulated and the expression of LOC100128054 (NR_033969, fold change = 4.6652225, P = 4.45517E-05) was significantly downregulated.	('LOC100128054', 'Var', (170, 182))	('upregulated', 'PosReg', (136, 147))	('downregulated', 'NegReg', (255, 268))	('NM_032784', 'Var', (67, 76))	('RSPO3', 'Gene', '84870', (60, 65))	('RSPO3', 'Gene', (60, 65))	('expression', 'MPA', (46, 56))
187094	27980454	DMBT1 was a candidate tumor suppressor gene; DMBT1 expression is often lost in lung cancer, indicating that DMBT1 inactivation may have a significant influence on lung tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('lung cancer', 'Disease', (79, 90))	('expression', 'MPA', (51, 61))	('DMBT1', 'Gene', '1755', (0, 5))	('DMBT1', 'Gene', (45, 50))	('DMBT1', 'Gene', (108, 113))	('lost', 'NegReg', (71, 75))	('influence', 'Reg', (150, 159))	('inactivation', 'Var', (114, 126))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('lung cancer', 'Disease', 'MESH:D008175', (79, 90))	('tumor', 'Disease', (168, 173))	('lung cancer', 'Phenotype', 'HP:0100526', (79, 90))	('DMBT1', 'Gene', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('DMBT1', 'Gene', '1755', (45, 50))	('DMBT1', 'Gene', '1755', (108, 113))	('lung', 'Disease', (163, 167))	('tumor', 'Disease', (22, 27))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
187104	27980454	And the ROC curve revealed that the area under curve (AUC) of HOXA11-AS was 0.727 (95% CI 0.663-0.790) for lung adenocarcinoma patients and 0.933 (95% CI 0.906-0.960) for squamous cell carcinoma patients (both P < 0.0001), which could gain high diagnostic value of HOXA11-AS level in NSCLC (Fig.	('squamous cell carcinoma', 'Disease', (171, 194))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (171, 194))	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('lung adenocarcinoma', 'Disease', (107, 126))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (107, 126))	('HOXA11-AS', 'Gene', (62, 71))	('HOXA11-AS', 'Gene', '221883', (62, 71))	('0.933', 'Var', (140, 145))	('HOXA11-AS', 'Gene', (265, 274))	('patients', 'Species', '9606', (195, 203))	('patients', 'Species', '9606', (127, 135))	('NSCLC', 'Disease', (284, 289))	('HOXA11-AS', 'Gene', '221883', (265, 274))	('carcinoma', 'Phenotype', 'HP:0030731', (185, 194))	('NSCLC', 'Disease', 'MESH:D002289', (284, 289))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (107, 126))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (171, 194))
187129	27980454	For example, lncRNA-TATDN1 is associated with NSCLC invasion and metastasis by influencing E-cadherin, HER2, beta-catenin and Ezrin expression, lncRNA-PVT1 promotes NSCLC cell proliferation by epigenetically regulating LATS2 expression and lncRNA-MALAT1 influences tumor invasion in NSCLC by regulating DNA methylation.	('TATDN1', 'Gene', '83940', (20, 26))	('epigenetically', 'Var', (193, 207))	('MALAT1', 'Gene', (247, 253))	('influences', 'Reg', (254, 264))	('NSCLC', 'Disease', 'MESH:D002289', (165, 170))	('Ezrin', 'Gene', (126, 131))	('PVT1', 'Gene', (151, 155))	('NSCLC', 'Disease', (46, 51))	('regulating', 'Reg', (292, 302))	('PVT1', 'Gene', '5820', (151, 155))	('NSCLC', 'Disease', 'MESH:D002289', (283, 288))	('MALAT1', 'Gene', '378938', (247, 253))	('expression', 'MPA', (225, 235))	('DNA methylation', 'MPA', (303, 318))	('promotes', 'PosReg', (156, 164))	('NSCLC', 'Disease', (165, 170))	('Ezrin', 'Gene', '7430', (126, 131))	('HER2', 'Gene', '2064', (103, 107))	('tumor', 'Disease', (265, 270))	('E-cadherin', 'Gene', (91, 101))	('E-cadherin', 'Gene', '999', (91, 101))	('beta-catenin', 'Gene', (109, 121))	('NSCLC', 'Disease', (283, 288))	('beta-catenin', 'Gene', '1499', (109, 121))	('tumor', 'Disease', 'MESH:D009369', (265, 270))	('TATDN1', 'Gene', (20, 26))	('LATS2', 'Gene', (219, 224))	('LATS2', 'Gene', '26524', (219, 224))	('regulating', 'Reg', (208, 218))	('HER2', 'Gene', (103, 107))	('tumor', 'Phenotype', 'HP:0002664', (265, 270))	('influencing', 'Reg', (79, 90))	('NSCLC', 'Disease', 'MESH:D002289', (46, 51))
187143	27980454	DOCK8 mutations and YAP activation were reported to be associated with neuroblastoma relapse in one study.	('YAP', 'Gene', (20, 23))	('neuroblastoma', 'Disease', 'MESH:D009447', (71, 84))	('DOCK8', 'Gene', (0, 5))	('associated', 'Reg', (55, 65))	('neuroblastoma', 'Disease', (71, 84))	('YAP', 'Gene', '10413', (20, 23))	('neuroblastoma', 'Phenotype', 'HP:0003006', (71, 84))	('DOCK8', 'Gene', '81704', (0, 5))	('mutations', 'Var', (6, 15))
187148	27980454	analyzed 22 lung squamous cell carcinoma cases and found that the loss of chromosome 9 p was specific for lung squamous cell carcinoma; thus, the DOCK8 gene might be a potential target for therapeutic measures against lung squamous cell carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (237, 246))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (218, 246))	('lung squamous cell carcinoma', 'Disease', (218, 246))	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (111, 134))	('loss', 'Var', (66, 70))	('lung squamous cell carcinoma', 'Disease', (106, 134))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (106, 134))	('DOCK8', 'Gene', '81704', (146, 151))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (12, 40))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (223, 246))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (12, 40))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (106, 134))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (218, 246))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (17, 40))	('DOCK8', 'Gene', (146, 151))	('lung squamous cell carcinoma', 'Disease', (12, 40))	('carcinoma', 'Phenotype', 'HP:0030731', (31, 40))
187149	27980454	found that genetic and epigenetic inactivation of DOCK8 was related to the development and/or progression of lung cancer using an array-CGH analysis.	('lung cancer', 'Disease', (109, 120))	('epigenetic inactivation', 'Var', (23, 46))	('lung cancer', 'Phenotype', 'HP:0100526', (109, 120))	('DOCK8', 'Gene', (50, 55))	('genetic', 'Var', (11, 18))	('progression', 'CPA', (94, 105))	('lung cancer', 'Disease', 'MESH:D008175', (109, 120))	('related to', 'Reg', (60, 70))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('DOCK8', 'Gene', '81704', (50, 55))
187151	27980454	Additionally, the deregulation of the Hippo signaling pathway induced tumors in model organisms and occurred in different human carcinomas, including lung, ovarian, colorectal and liver cancers.	('human', 'Species', '9606', (122, 127))	('lung', 'Disease', (150, 154))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('cancers', 'Phenotype', 'HP:0002664', (186, 193))	('deregulation', 'Var', (18, 30))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('carcinomas', 'Phenotype', 'HP:0030731', (128, 138))	('carcinomas', 'Disease', (128, 138))	('carcinomas', 'Disease', 'MESH:D002277', (128, 138))	('Hippo signaling pathway', 'Pathway', (38, 61))	('tumors', 'Disease', (70, 76))	('tumors', 'Disease', 'MESH:D009369', (70, 76))	('ovarian', 'Disease', (156, 163))	('colorectal and liver cancers', 'Disease', 'MESH:D015179', (165, 193))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('liver cancers', 'Phenotype', 'HP:0002896', (180, 193))	('occurred', 'Reg', (100, 108))
187162	27980454	In addition, we also further researched the relationships between the other 5 de-regulated genes (STMN2, SPINK6, TUSC3, LOC100128054, and C8orf22 and disease progression.	('SPINK6', 'Gene', (105, 111))	('C8orf22', 'Gene', '492307', (138, 145))	('LOC100128054', 'Var', (120, 132))	('C8orf22', 'Gene', (138, 145))	('TUSC3', 'Gene', '7991', (113, 118))	('STMN2', 'Gene', (98, 103))	('STMN2', 'Gene', '11075', (98, 103))	('SPINK6', 'Gene', '404203', (105, 111))	('TUSC3', 'Gene', (113, 118))
187180	33617877	Genome editing of endogenous genes to generate a cancer-associated PKC fusion resulted in cells with detectable levels of fusion transcript but no detectable protein.	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('PKC', 'Gene', (67, 70))	('PKC', 'Gene', '112476', (67, 70))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('fusion', 'Var', (71, 77))	('cancer', 'Disease', (49, 55))
187182	33617877	Overexpression of a PKC regulatory domain fusion suppressed both basal and agonist-induced endogenous PKC activity, acting in a dominant-negative manner by competing for diacylglycerol.	('PKC', 'Gene', '112476', (102, 105))	('PKC', 'Gene', (20, 23))	('diacylglycerol', 'MPA', (170, 184))	('agonist-induced endogenous', 'MPA', (75, 101))	('PKC', 'Gene', '112476', (20, 23))	('diacylglycerol', 'Chemical', 'MESH:D004075', (170, 184))	('fusion', 'Var', (42, 48))	('suppressed', 'NegReg', (49, 59))	('PKC', 'Gene', (102, 105))
187183	33617877	For both catalytic and regulatory domain fusions, the PKC component of the fusion proteins mediated the effects of the full-length fusions on the parameters examined, suggesting that the partner protein is dispensable in these contexts.	('fusions', 'Var', (41, 48))	('PKC', 'Gene', '112476', (54, 57))	('PKC', 'Gene', (54, 57))
187184	33617877	Taken together, our findings reveal that PKC gene fusions are distinct from oncogenic fusions and present a mechanism by which loss of PKC function occurs in cancer.	('PKC', 'Gene', '112476', (41, 44))	('loss of PKC function', 'Disease', (127, 147))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('fusions', 'Var', (50, 57))	('PKC', 'Gene', (135, 138))	('cancer', 'Disease', (158, 164))	('PKC', 'Gene', '112476', (135, 138))	('loss of PKC function', 'Disease', 'MESH:C537180', (127, 147))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('PKC', 'Gene', (41, 44))
187186	33617877	With its activity finely tuned, dysregulation of PKC has been implicated in a multitude of diseases, including metabolic disorders, neurodegeneration, and most notably, cancer.	('neurodegeneration', 'Phenotype', 'HP:0002180', (132, 149))	('dysregulation', 'Var', (32, 45))	('cancer', 'Disease', (169, 175))	('metabolic disorders', 'Disease', (111, 130))	('PKC', 'Gene', (49, 52))	('PKC', 'Gene', '112476', (49, 52))	('neurodegeneration', 'Disease', (132, 149))	('neurodegeneration', 'Disease', 'MESH:D019636', (132, 149))	('cancer', 'Disease', 'MESH:D009369', (169, 175))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('implicated', 'Reg', (62, 72))	('metabolic disorders', 'Disease', 'MESH:D008659', (111, 130))
187188	33617877	However, recent analysis of cancer-associated point mutations in PKC revealed that they are generally loss of function.	('PKC', 'Gene', (65, 68))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('PKC', 'Gene', '112476', (65, 68))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('loss', 'NegReg', (102, 106))	('cancer', 'Disease', (28, 34))	('point mutations', 'Var', (46, 61))
187189	33617877	Additionally, germline mutations in one isozyme, PKCdelta, are responsible for a lymphoproliferative disorder.	('PKCdelta', 'Gene', '5580', (49, 57))	('lymphoproliferative disorder', 'Disease', 'MESH:D008232', (81, 109))	('lymphoproliferative disorder', 'Disease', (81, 109))	('responsible for', 'Reg', (63, 78))	('germline mutations', 'Var', (14, 32))	('lymphoproliferative disorder', 'Phenotype', 'HP:0005523', (81, 109))	('PKCdelta', 'Gene', (49, 57))
187190	33617877	Furthermore, high protein levels of PKC are associated with improved survival in diverse cancers, including colon cancer, pancreatic cancer, and non-small-cell lung carcinoma, reframing PKC as providing a tumor suppressive function.	('protein levels', 'MPA', (18, 32))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('cancers', 'Phenotype', 'HP:0002664', (89, 96))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('cancers', 'Disease', (89, 96))	('PKC', 'Gene', (36, 39))	('PKC', 'Gene', '112476', (186, 189))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (122, 139))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('colon cancer', 'Disease', (108, 120))	('high', 'Var', (13, 17))	('non-small-cell lung carcinoma', 'Disease', (145, 174))	('non-small-cell lung carcinoma', 'Disease', 'MESH:D002289', (145, 174))	('PKC', 'Gene', (186, 189))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('carcinoma', 'Phenotype', 'HP:0030731', (165, 174))	('pancreatic cancer', 'Disease', 'MESH:D010190', (122, 139))	('cancers', 'Disease', 'MESH:D009369', (89, 96))	('colon cancer', 'Phenotype', 'HP:0003003', (108, 120))	('improved', 'PosReg', (60, 68))	('pancreatic cancer', 'Disease', (122, 139))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('small-cell lung carcinoma', 'Phenotype', 'HP:0030357', (149, 174))	('survival', 'MPA', (69, 77))	('tumor', 'Disease', (205, 210))	('PKC', 'Gene', '112476', (36, 39))	('non-small-cell lung carcinoma', 'Phenotype', 'HP:0030358', (145, 174))	('colon cancer', 'Disease', 'MESH:D015179', (108, 120))
187191	33617877	Gene fusions involving PKC have also been identified in cancer.	('identified', 'Reg', (42, 52))	('Gene fusions', 'Var', (0, 12))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('PKC', 'Gene', (23, 26))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('PKC', 'Gene', '112476', (23, 26))
187192	33617877	Analysis of RNA sequencing data from The Cancer Genome Atlas (TCGA) reveals that approximately 15% of in-frame kinase fusions belong to members of the AGC superfamily of serine/threonine kinases, second only to the tyrosine kinase family.	('kinase fusions', 'Var', (111, 125))	('fusions', 'Var', (118, 125))	('Cancer', 'Disease', (41, 47))	('Cancer', 'Disease', 'MESH:D009369', (41, 47))	('Cancer', 'Phenotype', 'HP:0002664', (41, 47))	('serine', 'Chemical', 'MESH:D012694', (170, 176))
187196	33617877	Before PKC is catalytically competent, it is matured by a series of ordered phosphorylations that are necessary for the enzyme to adopt an autoinhibited conformation; these are the activation loop (Thr500 in PKCbetaII), the turn motif (Thr641 in PKCbetaII), and the hydrophobic motif (Ser660 in PKCbetaII).	('PKCbeta', 'Gene', (246, 253))	('PKCbeta', 'Gene', (208, 215))	('Thr641', 'Chemical', '-', (236, 242))	('PKCbeta', 'Gene', (295, 302))	('Ser660', 'Var', (285, 291))	('PKC', 'Gene', '112476', (246, 249))	('PKC', 'Gene', '112476', (208, 211))	('PKC', 'Gene', '112476', (295, 298))	('PKC', 'Gene', '112476', (7, 10))	('PKC', 'Gene', (246, 249))	('Thr641', 'Var', (236, 242))	('PKC', 'Gene', (208, 211))	('Thr500', 'Chemical', '-', (198, 204))	('PKC', 'Gene', (295, 298))	('PKCbeta', 'Gene', '5578', (246, 253))	('PKCbeta', 'Gene', '5578', (208, 215))	('PKC', 'Gene', (7, 10))	('Thr500', 'Var', (198, 204))	('PKCbeta', 'Gene', '5578', (295, 302))	('Ser660', 'Chemical', '-', (285, 291))
187199	33617877	Aberrant PKC that is not properly autoinhibited is degraded, subject to PHLPP-mediated quality control of PKC.	('PKC', 'Gene', (106, 109))	('PKC', 'Gene', '112476', (106, 109))	('PHLPP', 'Gene', '23239', (72, 77))	('Aberrant', 'Var', (0, 8))	('PHLPP', 'Gene', (72, 77))	('PKC', 'Gene', (9, 12))	('PKC', 'Gene', '112476', (9, 12))
187201	33617877	Thus, cancer-associated mutations that disrupt autoinhibitory constraints are paradoxically loss of function because the constitutively active kinase is sensitive to degradation.	('sensitive', 'MPA', (153, 162))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('cancer', 'Disease', 'MESH:D009369', (6, 12))	('mutations', 'Var', (24, 33))	('cancer', 'Disease', (6, 12))
187203	33617877	Here, we investigated PKC gene fusions that yield proteins retaining the catalytic domain of PKC (3' PKC fusions) as well as fusions that yield proteins retaining the regulatory domain of PKC (5' PKC fusions).	('PKC', 'Gene', (196, 199))	('PKC', 'Gene', '112476', (196, 199))	('PKC', 'Gene', (93, 96))	('PKC', 'Gene', (101, 104))	('catalytic domain', 'MPA', (73, 89))	('PKC', 'Gene', '112476', (93, 96))	('PKC', 'Gene', '112476', (101, 104))	('PKC', 'Gene', (22, 25))	('PKC', 'Gene', '112476', (22, 25))	('fusions', 'Var', (31, 38))	('regulatory domain', 'MPA', (167, 184))	('PKC', 'Gene', (188, 191))	('PKC', 'Gene', '112476', (188, 191))
187206	33617877	Taken together, these results identify PKC fusions as a mechanism for loss of PKC function in cancer.	('loss of PKC function', 'Disease', 'MESH:C537180', (70, 90))	('fusions', 'Var', (43, 50))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('PKC', 'Gene', (39, 42))	('PKC', 'Gene', '112476', (39, 42))	('loss of PKC function', 'Disease', (70, 90))	('PKC', 'Gene', (78, 81))	('PKC', 'Gene', '112476', (78, 81))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
187214	33617877	Among these different cancer types, the greatest number of PKC gene fusions was identified in breast invasive carcinoma (BRCA) with 31 fusions detected and lung adenocarcinoma (LUAD) with nine fusions detected.	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (156, 175))	('PKC', 'Gene', (59, 62))	('breast invasive carcinoma', 'Disease', 'MESH:D001943', (94, 119))	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('carcinoma', 'Phenotype', 'HP:0030731', (166, 175))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('fusions', 'Var', (135, 142))	('PKC', 'Gene', '112476', (59, 62))	('cancer', 'Disease', (22, 28))	('BRCA', 'Phenotype', 'HP:0003002', (121, 125))	('fusions', 'Var', (68, 75))	('lung adenocarcinoma', 'Disease', (156, 175))	('breast invasive carcinoma', 'Phenotype', 'HP:0003002', (94, 119))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (156, 175))	('breast invasive carcinoma', 'Disease', (94, 119))	('LUAD', 'Phenotype', 'HP:0030078', (177, 181))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))
187216	33617877	Given that PKC is the most abundantly fused AGC kinase and the fusions were detected in a multitude of cancers, we sought to determine how these fusions might affect PKC signaling and contribute to tumorigenesis.	('PKC', 'Gene', (11, 14))	('cancers', 'Disease', 'MESH:D009369', (103, 110))	('PKC', 'Gene', '112476', (11, 14))	('cancers', 'Phenotype', 'HP:0002664', (103, 110))	('affect', 'Reg', (159, 165))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('PKC', 'Gene', (166, 169))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('PKC', 'Gene', '112476', (166, 169))	('tumor', 'Disease', (198, 203))	('fusions', 'Var', (145, 152))	('contribute to', 'Reg', (184, 197))	('cancers', 'Disease', (103, 110))
187218	33617877	3' PKC gene fusions yield proteins in which the N-terminal regulatory domain of PKC is truncated and replaced with the N-terminal domain of its gene partner.	('N-terminal regulatory domain', 'MPA', (48, 76))	('fusions', 'Var', (12, 19))	('PKC', 'Gene', (3, 6))	('PKC', 'Gene', '112476', (3, 6))	('PKC', 'Gene', (80, 83))	('PKC', 'Gene', '112476', (80, 83))
187227	33617877	Additionally, we analyzed a variant of the CTL1-PKCalpha fusion protein in which there was an internal deletion within CTL1.	('PKCalpha', 'Gene', '5578', (48, 56))	('PKCalpha', 'Gene', (48, 56))	('CTL1', 'Gene', '23446', (43, 47))	('CTL1', 'Gene', '23446', (119, 123))	('internal deletion', 'Var', (94, 111))	('CTL1', 'Gene', (43, 47))	('CTL1', 'Gene', (119, 123))
187231	33617877	We have previously reported that mutations that impair autoinhibition of PKC prevent retention of phosphate at the priming sites.	('prevent', 'NegReg', (77, 84))	('PKC', 'Gene', (73, 76))	('phosphate', 'Chemical', 'MESH:D010710', (98, 107))	('mutations', 'Var', (33, 42))	('PKC', 'Gene', '112476', (73, 76))	('retention of phosphate at the priming sites', 'MPA', (85, 128))
187235	33617877	Subsequent treatment with the phorbol ester PDBu resulted in maximal, sustained activity, which was abolished upon addition of PKC inhibitor, either Go6976 or Go6983 (Fig.	('PKC', 'Gene', '112476', (127, 130))	('Go6976', 'Chemical', 'MESH:C081021', (149, 155))	('Go6983', 'Chemical', 'MESH:C465664', (159, 165))	('Go6976', 'Var', (149, 155))	('PDBu', 'Chemical', 'MESH:D015240', (44, 48))	('Go6983', 'Var', (159, 165))	('phorbol ester', 'Chemical', 'MESH:D010703', (30, 43))	('maximal', 'MPA', (61, 68))	('PKC', 'Gene', (127, 130))
187237	33617877	Introduction of a mutation to render the PKC kinase domain catalytically dead (V353F in PKCalpha and V356F in PKCbeta, gray) abolished the constitutive activity of the full-length fusion proteins.	('V356F', 'Var', (101, 106))	('PKC', 'Gene', '112476', (41, 44))	('abolished', 'NegReg', (125, 134))	('PKC', 'Gene', (88, 91))	('PKC', 'Gene', (110, 113))	('PKC', 'Gene', '112476', (110, 113))	('V356F', 'Mutation', 'p.V356F', (101, 106))	('PKCbeta', 'Gene', '5578', (110, 117))	('PKCalpha', 'Gene', (88, 96))	('constitutive activity', 'MPA', (139, 160))	('PKCalpha', 'Gene', '5578', (88, 96))	('PKCbeta', 'Gene', (110, 117))	('V353F', 'Mutation', 'p.V353F', (79, 84))	('V353F', 'Var', (79, 84))	('PKC', 'Gene', '112476', (88, 91))	('PKC', 'Gene', (41, 44))
187241	33617877	In contrast, addition of inhibitor in cells overexpressing the full-length fusion proteins (red) or the PKC component of the fusions (yellow) resulted in a robust reduction in CKAR phosphorylation, indicating high basal activity.	('reduction', 'NegReg', (163, 172))	('fusions', 'Var', (125, 132))	('PKC', 'Gene', (104, 107))	('PKC', 'Gene', '112476', (104, 107))	('CKAR', 'Protein', (176, 180))	('CKAR', 'Chemical', '-', (176, 180))
187242	33617877	Thus, although the full-length fusion and N-deletion proteins were unphosphorylated at the PKC priming sites, they exhibited constitutive, agonist-independent activity.	('proteins', 'Protein', (53, 61))	('PKC', 'Gene', (91, 94))	('PKC', 'Gene', '112476', (91, 94))	('N-deletion', 'Var', (42, 52))
187244	33617877	Mutation of the hydrophobic motif Ser to Ala in TANC2-PKCalpha (S657A in wild-type PKCalpha, pink) or GGA2-PKCbetaII (S660A in wild-type PKCbetaII, pink) reduced basal activity to levels comparable with those of wild-type PKC (Fig.	('TANC2', 'Gene', (48, 53))	('S657A', 'Mutation', 'p.S657A', (64, 69))	('PKC', 'Gene', '112476', (107, 110))	('PKC', 'Gene', '112476', (83, 86))	('PKCalpha', 'Gene', (54, 62))	('S660A', 'Var', (118, 123))	('PKCalpha', 'Gene', '5578', (83, 91))	('basal activity', 'MPA', (162, 176))	('PKC', 'Gene', '112476', (137, 140))	('PKC', 'Gene', (83, 86))	('PKC', 'Gene', (107, 110))	('TANC2', 'Gene', '26115', (48, 53))	('PKCbeta', 'Gene', '5578', (107, 114))	('Ala', 'Chemical', 'MESH:D000409', (41, 44))	('PKC', 'Gene', (137, 140))	('S660A', 'Mutation', 'p.S660A', (118, 123))	('PKCalpha', 'Gene', (83, 91))	('PKCbeta', 'Gene', '5578', (137, 144))	('Ser', 'Chemical', 'MESH:D012694', (34, 37))	('PKC', 'Gene', '112476', (54, 57))	('GGA2', 'Gene', '23062', (102, 106))	('S657A', 'Var', (64, 69))	('GGA2', 'Gene', (102, 106))	('PKCbeta', 'Gene', (107, 114))	('PKC', 'Gene', '112476', (222, 225))	('PKCbeta', 'Gene', (137, 144))	('Mutation', 'Var', (0, 8))	('PKCalpha', 'Gene', '5578', (54, 62))	('PKC', 'Gene', (54, 57))	('reduced', 'NegReg', (154, 161))	('PKC', 'Gene', (222, 225))
187245	33617877	In contrast, mutation of the turn motif in either fusion protein to the phosphomimetic residue Glu (T638E in wild-type PKCalpha and T641E in wild-type PKCbetaII, green) resulted in expression of proteins with high basal activity.	('T641E', 'Mutation', 'p.T641E', (132, 137))	('expression', 'MPA', (181, 191))	('PKCbeta', 'Gene', '5578', (151, 158))	('mutation', 'Var', (13, 21))	('basal activity', 'MPA', (214, 228))	('resulted in', 'Reg', (169, 180))	('PKCbeta', 'Gene', (151, 158))	('T638E', 'Mutation', 'p.T638E', (100, 105))	('PKCalpha', 'Gene', '5578', (119, 127))	('Glu', 'Chemical', 'MESH:D018698', (95, 98))	('PKCalpha', 'Gene', (119, 127))	('T638E', 'Var', (100, 105))	('T641E', 'Var', (132, 137))	('proteins', 'Protein', (195, 203))
187246	33617877	Mutation of the hydrophobic motif in TANC2-PKCalpha to Glu (S657E in wild-type PKCalpha, orange) also resulted in protein with high basal activity.	('PKCalpha', 'Gene', '5578', (79, 87))	('basal activity', 'MPA', (132, 146))	('Glu', 'Chemical', 'MESH:D018698', (55, 58))	('Mutation', 'Var', (0, 8))	('TANC2', 'Gene', (37, 42))	('protein', 'Protein', (114, 121))	('PKCalpha', 'Gene', (43, 51))	('S657E', 'Mutation', 'p.S657E', (60, 65))	('resulted in', 'Reg', (102, 113))	('PKCalpha', 'Gene', '5578', (43, 51))	('TANC2', 'Gene', '26115', (37, 42))	('S657E', 'Var', (60, 65))	('PKCalpha', 'Gene', (79, 87))
187254	33617877	In contrast, the TANC2-PKCalpha and GGA2-PKCbetaII fusion proteins turned over more rapidly, with little to no protein detected at 24 h. Deletion of the pseudosubstrate (DeltaPS) in both PKCalpha and PKCbetaII resulted in rapid turnover, comparable with that observed for the fusion proteins.	('PKCbeta', 'Gene', (200, 207))	('PKCalpha', 'Gene', '5578', (187, 195))	('PKCalpha', 'Gene', (187, 195))	('PKCbeta', 'Gene', '5578', (41, 48))	('TANC2', 'Gene', '26115', (17, 22))	('PKCalpha', 'Gene', (23, 31))	('GGA2', 'Gene', (36, 40))	('PKCbeta', 'Gene', (41, 48))	('GGA2', 'Gene', '23062', (36, 40))	('Deletion', 'Var', (137, 145))	('PKCalpha', 'Gene', '5578', (23, 31))	('rapid turnover', 'MPA', (222, 236))	('PKCbeta', 'Gene', '5578', (200, 207))	('DeltaPS', 'Gene', (170, 177))	('TANC2', 'Gene', (17, 22))
187258	33617877	Thus, these data demonstrate that the fusion proteins are intrinsically unstable, consistent with our previous studies revealing that lack of phosphate at the hydrophobic motif targets PKC for degradation.	('phosphate', 'Chemical', 'MESH:D010710', (142, 151))	('PKC', 'Gene', (185, 188))	('PKC', 'Gene', '112476', (185, 188))	('targets', 'Reg', (177, 184))	('lack', 'Var', (134, 138))	('phosphate', 'MPA', (142, 151))
187278	33617877	Additionally, knockdown of RINCK, the E3 ligase that catalyzes ubiquitin-mediated degradation of wild-type PKC, as well as CHIP, a "quality control" E3 ligase that cooperates with molecular chaperones to ubiquitinate unfolded proteins, did not allow for accumulation of the protein in the CRISPR-edited cells (Fig.	('RINCK', 'Gene', (27, 32))	('PKC', 'Gene', (107, 110))	('PKC', 'Gene', '112476', (107, 110))	('knockdown', 'Var', (14, 23))	('RINCK', 'Gene', '90933', (27, 32))
187293	33617877	Previous studies investigating loss-of-function mutations in PKC demonstrated that kinase-dead mutants may act in a dominant-negative manner.	('mutations', 'Var', (48, 57))	('PKC', 'Gene', (61, 64))	('PKC', 'Gene', '112476', (61, 64))	('loss-of-function', 'NegReg', (31, 47))
187300	33617877	First, we determined the effect of the regulatory fusion and the C-deletion variant on endogenous PKC activity utilizing the genetically encoded FRET reporter CKAR.	('C-deletion variant', 'Var', (65, 83))	('PKC', 'Gene', '112476', (98, 101))	('PKC', 'Gene', (98, 101))	('CKAR', 'Chemical', '-', (159, 163))
187304	33617877	Although the response to a physiological stimulus (UTP) was significantly suppressed with expression of the regulatory domain fusion, there was no change in PDBu-induced activity.	('regulatory', 'Protein', (108, 118))	('suppressed', 'NegReg', (74, 84))	('UTP', 'Chemical', 'MESH:D014544', (51, 54))	('response to a physiological stimulus', 'MPA', (13, 49))	('PDBu', 'Chemical', 'MESH:D015240', (157, 161))	('expression', 'Var', (90, 100))
187308	33617877	Specifically, we mutated W58 and Y123 in the C1A and C1B domains of PKCbetaII, respectively, to Ala. Coexpression of a catalytically inactive PKC (S660F) with C kinase activity reporter 2 (CKAR2) resulted in suppression of endogenous PKC activity upon UTP stimulation (Fig.	('PKC', 'Gene', (234, 237))	('PKC', 'Gene', '112476', (234, 237))	('PKCbeta', 'Gene', '5578', (68, 75))	('endogenous', 'MPA', (223, 233))	('UTP', 'Chemical', 'MESH:D014544', (252, 255))	('PKC', 'Gene', (142, 145))	('PKCbeta', 'Gene', (68, 75))	('Ala', 'Chemical', 'MESH:D000409', (96, 99))	('PKC', 'Gene', '112476', (142, 145))	('suppression', 'NegReg', (208, 219))	('S660F', 'Var', (147, 152))	('CKAR', 'Chemical', '-', (189, 193))	('S660F', 'Mutation', 'p.S660F', (147, 152))	('PKC', 'Gene', (68, 71))	('PKC', 'Gene', '112476', (68, 71))
187309	33617877	However, mutation of the C1 domains to disrupt DAG binding abolished suppression of endogenous activity (Fig.	('mutation', 'Var', (9, 17))	('DAG', 'Chemical', 'MESH:D004075', (47, 50))	('abolished', 'NegReg', (59, 68))	('DAG', 'Protein', (47, 50))	('binding', 'Interaction', (51, 58))	('suppression', 'MPA', (69, 80))	('endogenous activity', 'MPA', (84, 103))
187310	33617877	Mutation of these residues also impeded UTP-induced translocation, a consequence of the mutant's inability to bind DAG (Fig.	('impeded', 'NegReg', (32, 39))	('inability', 'NegReg', (97, 106))	('UTP', 'Chemical', 'MESH:D014544', (40, 43))	('Mutation', 'Var', (0, 8))	('UTP-induced translocation', 'MPA', (40, 65))	('DAG', 'Chemical', 'MESH:D004075', (115, 118))	('bind', 'Interaction', (110, 114))
187312	33617877	To examine the effect of the fusion on basal activity, we treated cells expressing CKAR alone (white) or coexpressing the full-length fusion (red) or C-deletion protein (yellow) with the PKC inhibitor Go6983 (Fig.	('C-deletion protein', 'Var', (150, 168))	('Go6983', 'Chemical', 'MESH:C465664', (201, 207))	('CKAR', 'Gene', (83, 87))	('PKC', 'Gene', (187, 190))	('PKC', 'Gene', '112476', (187, 190))	('CKAR', 'Chemical', '-', (83, 87))
187313	33617877	Expression of either PKCalpha-CDH8 or the C-deletion variant suppressed endogenous PKC activity, indicated by the smaller reduction in CKAR phosphorylation compared with that of cells expressing the reporter alone.	('CDH8', 'Gene', (30, 34))	('CKAR', 'Chemical', '-', (135, 139))	('suppressed', 'NegReg', (61, 71))	('PKC', 'Gene', (83, 86))	('PKC', 'Gene', '112476', (21, 24))	('endogenous', 'MPA', (72, 82))	('CKAR phosphorylation', 'MPA', (135, 155))	('PKC', 'Gene', '112476', (83, 86))	('reduction', 'NegReg', (122, 131))	('CDH8', 'Gene', '1006', (30, 34))	('PKCalpha', 'Gene', (21, 29))	('PKCalpha', 'Gene', '5578', (21, 29))	('C-deletion', 'Var', (42, 52))	('PKC', 'Gene', (21, 24))
187314	33617877	Thus, these results show that the PKCalpha-CDH8 regulatory domain fusion and C-deletion variant are able to suppress not only agonist-induced PKC activity but also basal PKC activity.	('PKC', 'Gene', (34, 37))	('C-deletion variant', 'Var', (77, 95))	('PKC', 'Gene', '112476', (34, 37))	('PKC', 'Gene', (142, 145))	('basal', 'MPA', (164, 169))	('PKC', 'Gene', '112476', (142, 145))	('CDH8', 'Gene', '1006', (43, 47))	('PKC', 'Gene', (170, 173))	('PKC', 'Gene', '112476', (170, 173))	('CDH8', 'Gene', (43, 47))	('PKCalpha', 'Gene', '5578', (34, 42))	('PKCalpha', 'Gene', (34, 42))	('suppress', 'NegReg', (108, 116))
187316	33617877	We compared nontransfected (NT) COS7 cells to COS7 cells overexpressing YFP-tagged wild-type PKCalpha, PKCalpha-CDH8, or the C-deletion variant in PDBu-treated and vehicle (DMSO) conditions.	('PKCalpha', 'Gene', (93, 101))	('DMSO', 'Chemical', 'MESH:D004121', (173, 177))	('PKCalpha', 'Gene', '5578', (103, 111))	('PKCalpha', 'Gene', (103, 111))	('PKCalpha', 'Gene', '5578', (93, 101))	('C-deletion', 'Var', (125, 135))	('CDH8', 'Gene', '1006', (112, 116))	('COS7', 'CellLine', 'CVCL:0224', (46, 50))	('CDH8', 'Gene', (112, 116))	('PDBu', 'Chemical', 'MESH:D015240', (147, 151))	('COS7', 'CellLine', 'CVCL:0224', (32, 36))
187319	33617877	Importantly, there was significantly less PKC substrate phosphorylation in cells expressing either the regulatory fusion or the C-deletion protein compared with nontransfected cells.	('PKC', 'Gene', (42, 45))	('PKC', 'Gene', '112476', (42, 45))	('C-deletion protein', 'Var', (128, 146))	('less', 'NegReg', (37, 41))
187322	33617877	The unmasked regulatory domains of PKC have a propensity to bind the DAG-rich Golgi, leading us to address whether the fusions may have a more pronounced effect in suppressing PKC function at the Golgi.	('PKC', 'Gene', (35, 38))	('PKC', 'Gene', '112476', (35, 38))	('suppressing', 'NegReg', (164, 175))	('PKC', 'Gene', (176, 179))	('DAG', 'Chemical', 'MESH:D004075', (69, 72))	('PKC', 'Gene', '112476', (176, 179))	('fusions', 'Var', (119, 126))	('function', 'MPA', (180, 188))
187323	33617877	Analysis of the mCherry-tagged PKCalpha-CDH8 fusion in the imaging studies described above revealed that the fusion was more localized to the Golgi compared with wild-type PKCalpha (Fig.	('PKCalpha', 'Gene', '5578', (172, 180))	('CDH8', 'Gene', '1006', (40, 44))	('fusion', 'Var', (45, 51))	('CDH8', 'Gene', (40, 44))	('PKCalpha', 'Gene', '5578', (31, 39))	('PKCalpha', 'Gene', (31, 39))	('PKCalpha', 'Gene', (172, 180))
187326	33617877	These results corroborate the regulatory domain fusion sequestering DAG at the Golgi, effectively suppressing basal activity of wild-type PKC at this compartment as well as significantly reducing agonist-dependent activation.	('basal activity', 'MPA', (110, 124))	('DAG', 'Chemical', 'MESH:D004075', (68, 71))	('agonist-dependent activation', 'MPA', (196, 224))	('suppressing', 'NegReg', (98, 109))	('regulatory domain fusion', 'Var', (30, 54))	('PKC', 'Gene', (138, 141))	('PKC', 'Gene', '112476', (138, 141))	('reducing', 'NegReg', (187, 195))	('sequestering', 'NegReg', (55, 67))
187328	33617877	In this study, we show that PKC gene fusions result in proteins that are loss of function in cancer.	('cancer', 'Disease', (93, 99))	('proteins', 'Protein', (55, 63))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('PKC', 'Gene', (28, 31))	('PKC', 'Gene', '112476', (28, 31))	('loss of function', 'NegReg', (73, 89))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('fusions', 'Var', (37, 44))
187333	33617877	In addition to BCR-ABL, fusions of the kinase domain of PKA in DNAJB1-PRKACA and the kinase domain of various FGFR isozymes (e.g., FGFR3-TACC3, BCR-FGFR1) drive tumorigenesis because of their unregulated activity.	('PRKACA', 'Gene', (70, 76))	('FGFR', 'Gene', (110, 114))	('DNAJB1', 'Gene', '3337', (63, 69))	('FGFR', 'Gene', '2260;2263;2261', (110, 114))	('tumor', 'Disease', (161, 166))	('BCR-ABL', 'Gene', '25', (15, 22))	('DNAJB1', 'Gene', (63, 69))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('FGFR1', 'Gene', (148, 153))	('FGFR', 'Gene', (148, 152))	('FGFR3', 'Gene', (131, 136))	('FGFR', 'Gene', '2260;2263;2261', (148, 152))	('TACC3', 'Gene', '10460', (137, 142))	('TACC3', 'Gene', (137, 142))	('FGFR3', 'Gene', '2261', (131, 136))	('activity', 'MPA', (204, 212))	('PRKACA', 'Gene', '5566', (70, 76))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('PKA', 'Gene', (56, 59))	('FGFR', 'Gene', (131, 135))	('FGFR', 'Gene', '2260;2263;2261', (131, 135))	('BCR-ABL', 'Gene', (15, 22))	('drive', 'PosReg', (155, 160))	('FGFR1', 'Gene', '2260', (148, 153))	('fusions', 'Var', (24, 31))
187337	33617877	Thus, aberrant PKC that cannot be autoinhibited is subject to quality control degradation, facilitated by PHLPP.	('aberrant', 'Var', (6, 14))	('PKC', 'Gene', (15, 18))	('PHLPP', 'Gene', '23239', (106, 111))	('PKC', 'Gene', '112476', (15, 18))	('PHLPP', 'Gene', (106, 111))
187341	33617877	Although mRNA of the fusion was detected in CRISPR-edited cells engineered to express the TANC2-PRKCA fusion, we were unable to detect the fusion at the protein level.	('PRKCA', 'Gene', (96, 101))	('TANC2', 'Gene', (90, 95))	('fusion', 'Var', (102, 108))	('TANC2', 'Gene', '26115', (90, 95))	('PRKCA', 'Gene', '5578', (96, 101))
187343	33617877	Because 5' PKC fusions result in proteins with a truncated catalytic domain, they are intrinsically loss of function with respect to PKC activity.	('PKC', 'Gene', (11, 14))	('PKC', 'Gene', '112476', (11, 14))	('truncated catalytic domain', 'MPA', (49, 75))	('fusions', 'Var', (15, 22))	('result in', 'Reg', (23, 32))	('proteins', 'Protein', (33, 41))	('PKC', 'Gene', (133, 136))	('PKC', 'Gene', '112476', (133, 136))
187352	33617877	This enhanced affinity for DAG is likely what directs the regulatory domain fusions to the DAG-rich Golgi, overriding the intrinsic affinity of the C2 domain for plasma membrane.	('DAG', 'Chemical', 'MESH:D004075', (27, 30))	('fusions', 'Var', (76, 83))	('affinity', 'MPA', (14, 22))	('enhanced', 'PosReg', (5, 13))	('DAG', 'Chemical', 'MESH:D004075', (91, 94))
187354	33617877	This ability to suppress endogenous activity is consistent with previous studies showing that kinase-dead mutants also act in a dominant-negative manner, suppressing global PKC output.	('suppressing', 'NegReg', (154, 165))	('PKC', 'Gene', (173, 176))	('PKC', 'Gene', '112476', (173, 176))	('endogenous activity', 'MPA', (25, 44))	('mutants', 'Var', (106, 113))
187355	33617877	Functional studies revealed that basal levels of apoptosis are reduced in CRISPR-edited cells expressing the TANC2-PRKCA fusion compared with parental cells.	('TANC2', 'Gene', '26115', (109, 114))	('PRKCA', 'Gene', (115, 120))	('reduced', 'NegReg', (63, 70))	('fusion', 'Var', (121, 127))	('TANC2', 'Gene', (109, 114))	('PRKCA', 'Gene', '5578', (115, 120))
187356	33617877	This reduction in apoptosis was also observed in CRISPR-edited cells in which one allele of PRKCA was deleted.	('deleted', 'Var', (102, 109))	('reduction', 'NegReg', (5, 14))	('PRKCA', 'Gene', '5578', (92, 97))	('PRKCA', 'Gene', (92, 97))	('apoptosis', 'CPA', (18, 27))
187357	33617877	The similar effect on apoptosis resulting from either deletion of PRKCA or fusion of PRKCA with TANC2 corroborates loss of PKCalpha resulting in suppressed apoptosis.	('TANC2', 'Gene', (96, 101))	('PRKCA', 'Gene', (66, 71))	('fusion', 'Var', (75, 81))	('loss', 'NegReg', (115, 119))	('deletion', 'Var', (54, 62))	('apoptosis', 'CPA', (22, 31))	('TANC2', 'Gene', '26115', (96, 101))	('PRKCA', 'Gene', '5578', (85, 90))	('PKCalpha', 'Gene', (123, 131))	('PKCalpha', 'Gene', '5578', (123, 131))	('suppressed', 'NegReg', (145, 155))	('PRKCA', 'Gene', '5578', (66, 71))	('PRKCA', 'Gene', (85, 90))	('apoptosis', 'CPA', (156, 165))
187358	33617877	These results complement previous studies wherein a heterozygous loss-of-function mutation in PKCbeta was corrected to wild-type in DLD-1 colorectal cancer cells through CRISPR/Cas9 gene editing.	('DLD-1 colorectal cancer', 'Disease', 'MESH:D015179', (132, 155))	('colorectal cancer', 'Phenotype', 'HP:0003003', (138, 155))	('mutation', 'Var', (82, 90))	('loss-of-function', 'NegReg', (65, 81))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('PKCbeta', 'Gene', '5578', (94, 101))	('DLD-1 colorectal cancer', 'Disease', (132, 155))	('PKCbeta', 'Gene', (94, 101))
187360	33617877	Supporting a role of conventional PKC isozymes in promoting apoptosis, PKCalpha has been found to promote apoptosis in LNCaP cells, a model for androgen-dependent prostate cancer, through dephosphorylation and inactivation of Akt.	('prostate cancer', 'Disease', (163, 178))	('PKC', 'Gene', (34, 37))	('PKC', 'Gene', '112476', (34, 37))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('promote', 'PosReg', (98, 105))	('inactivation', 'Var', (210, 222))	('apoptosis', 'CPA', (106, 115))	('LNCaP', 'CellLine', 'CVCL:0395', (119, 124))	('prostate cancer', 'Disease', 'MESH:D011471', (163, 178))	('PKC', 'Gene', (71, 74))	('Akt', 'Gene', '207', (226, 229))	('prostate cancer', 'Phenotype', 'HP:0012125', (163, 178))	('dephosphorylation', 'Var', (188, 205))	('PKCalpha', 'Gene', '5578', (71, 79))	('PKCalpha', 'Gene', (71, 79))	('PKC', 'Gene', '112476', (71, 74))	('Akt', 'Gene', (226, 229))
187362	33617877	Our findings are thus consistent with expression of the PRKCA fusion resulting in increased survival due to loss of one allele of wild-type PRKCA.	('survival', 'CPA', (92, 100))	('loss', 'NegReg', (108, 112))	('PRKCA', 'Gene', (56, 61))	('fusion', 'Var', (62, 68))	('PRKCA', 'Gene', '5578', (140, 145))	('increased', 'PosReg', (82, 91))	('PRKCA', 'Gene', (140, 145))	('PRKCA', 'Gene', '5578', (56, 61))
187363	33617877	Although the vast majority of PKC gene fusions are not highly recurrent, they provide an additional general mechanism for loss of PKC function in cancer.	('PKC', 'Gene', '112476', (130, 133))	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('loss of PKC function', 'Disease', (122, 142))	('fusions', 'Var', (39, 46))	('PKC', 'Gene', (30, 33))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('PKC', 'Gene', '112476', (30, 33))	('loss of PKC function', 'Disease', 'MESH:C537180', (122, 142))	('PKC', 'Gene', (130, 133))
187364	33617877	The distribution of loss-of-function point mutations in the different domains of PKC revealed that there are no true mutational hotspots, indicating that there are a multitude of ways in which PKC can be inactivated.	('point mutations', 'Var', (37, 52))	('loss-of-function', 'NegReg', (20, 36))	('PKC', 'Gene', (193, 196))	('PKC', 'Gene', '112476', (193, 196))	('PKC', 'Gene', (81, 84))	('PKC', 'Gene', '112476', (81, 84))
187365	33617877	Similarly, although there are many different breakpoints among the PKC fusions, many of the truncation events would result in loss of PKC activity.	('PKC', 'Gene', (134, 137))	('PKC', 'Gene', '112476', (134, 137))	('fusions', 'Var', (71, 78))	('truncation', 'Var', (92, 102))	('PKC', 'Gene', (67, 70))	('PKC', 'Gene', '112476', (67, 70))	('loss', 'NegReg', (126, 130))
187368	33617877	Specifically, we showed that deletion of the pseudosubstrate in either PKCalpha or PKCbetaII resulted in lack of phosphorylation at the PKC priming sites, agonist-independent cellular activity, and sensitivity to degradation, as exhibited by the fusion proteins.	('PKC', 'Gene', (136, 139))	('deletion', 'Var', (29, 37))	('PKC', 'Gene', '112476', (136, 139))	('agonist-independent cellular activity', 'MPA', (155, 192))	('PKC', 'Gene', (83, 86))	('phosphorylation', 'MPA', (113, 128))	('PKC', 'Gene', '112476', (83, 86))	('PKC', 'Gene', (71, 74))	('PKCbeta', 'Gene', '5578', (83, 90))	('lack', 'NegReg', (105, 109))	('PKCalpha', 'Gene', '5578', (71, 79))	('PKCalpha', 'Gene', (71, 79))	('PKCbeta', 'Gene', (83, 90))	('PKC', 'Gene', '112476', (71, 74))	('sensitivity', 'MPA', (198, 209))
187369	33617877	Hence, for conventional isozymes of PKC, any fusion with a minimal truncation of the 5' end of the gene would constitute as loss of function.	('fusion', 'Var', (45, 51))	('PKC', 'Gene', (36, 39))	('PKC', 'Gene', '112476', (36, 39))	('loss of function', 'NegReg', (124, 140))
187370	33617877	Overall, due to the potential deletion of functionally relevant domains, PKC gene fusions have a high probability of impacting PKC activity.	('PKC', 'Gene', '112476', (127, 130))	('PKC', 'Gene', (73, 76))	('fusions', 'Var', (82, 89))	('deletion', 'Var', (30, 38))	('PKC', 'Gene', '112476', (73, 76))	('impacting', 'Reg', (117, 126))	('PKC', 'Gene', (127, 130))
187371	33617877	Our work underscores the importance of developing therapies that serve to stabilize or enhance PKC activity for cancers in which fusions or mutations of PKC have resulted in loss of PKC function.	('loss of PKC function', 'Disease', (174, 194))	('cancers', 'Phenotype', 'HP:0002664', (112, 119))	('fusions', 'Var', (129, 136))	('enhance', 'PosReg', (87, 94))	('cancers', 'Disease', 'MESH:D009369', (112, 119))	('loss of PKC function', 'Disease', 'MESH:C537180', (174, 194))	('PKC', 'Gene', (153, 156))	('PKC', 'Gene', (95, 98))	('cancers', 'Disease', (112, 119))	('mutations', 'Var', (140, 149))	('PKC', 'Gene', '112476', (153, 156))	('PKC', 'Gene', '112476', (95, 98))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('activity', 'MPA', (99, 107))	('PKC', 'Gene', (182, 185))	('PKC', 'Gene', '112476', (182, 185))
187372	33617877	This is an important consideration as the initial identification of catalytic domain fusions prompted discussion of PKC-targeted inhibitors.	('PKC', 'Gene', '112476', (116, 119))	('catalytic domain fusions', 'Var', (68, 92))	('PKC', 'Gene', (116, 119))
187373	33617877	In addition to informing the development of PKC-targeted therapeutics, PKC fusions may also serve another important role in cancer as biomarkers.	('cancer', 'Disease', (124, 130))	('fusions', 'Var', (75, 82))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('PKC', 'Gene', (71, 74))	('PKC', 'Gene', (44, 47))	('PKC', 'Gene', '112476', (71, 74))	('PKC', 'Gene', '112476', (44, 47))	('cancer', 'Disease', 'MESH:D009369', (124, 130))
187374	33617877	Recurrent fusions of PRKCB and PRKCD to membrane-associated proteins were identified in BFHs, one of the most common neoplasms in the skin.	('PRKCB', 'Gene', (21, 26))	('PRKCD', 'Gene', '5580', (31, 36))	('PRKCD', 'Gene', (31, 36))	('neoplasm', 'Phenotype', 'HP:0002664', (117, 125))	('BFHs', 'Disease', (88, 92))	('neoplasms', 'Disease', 'MESH:D009369', (117, 126))	('PRKCB', 'Gene', '5579', (21, 26))	('neoplasms', 'Disease', (117, 126))	('BFHs', 'Disease', 'None', (88, 92))	('neoplasms', 'Phenotype', 'HP:0002664', (117, 126))	('fusions', 'Var', (10, 17))
187378	33617877	Moreover, tumors containing rearrangements in PRKCB did not have rearrangements in ALK, previously shown to occur in the majority of the epithelial subtype of BFHs.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('BFHs', 'Disease', (159, 163))	('BFHs', 'Disease', 'None', (159, 163))	('ALK', 'Gene', '238', (83, 86))	('rearrangements', 'Var', (28, 42))	('tumors', 'Disease', (10, 16))	('tumors', 'Disease', 'MESH:D009369', (10, 16))	('tumors', 'Phenotype', 'HP:0002664', (10, 16))	('PRKCB', 'Gene', (46, 51))	('ALK', 'Gene', (83, 86))	('PRKCB', 'Gene', '5579', (46, 51))
187381	33617877	Furthermore, PGNTs harboring the PKC fusion lacked BRAF and FGFR1 mutations characteristic of histologically similar tumors.	('mutations', 'Var', (66, 75))	('lacked', 'NegReg', (44, 50))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('FGFR1', 'Gene', (60, 65))	('FGFR1', 'Gene', '2260', (60, 65))	('tumors', 'Disease', (117, 123))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('PKC', 'Gene', (33, 36))	('BRAF', 'Gene', '673', (51, 55))	('fusion', 'Var', (37, 43))	('BRAF', 'Gene', (51, 55))	('PKC', 'Gene', '112476', (33, 36))
187383	33617877	Taken together, the recurrent PKC fusions detected in BFHs and PGNTs and mutations and rearrangements in known drivers appear to be mutually exclusive, so these PKC fusions may serve as effective biomarkers.	('PKC', 'Gene', (161, 164))	('PKC', 'Gene', '112476', (161, 164))	('BFHs', 'Disease', (54, 58))	('PKC', 'Gene', '112476', (30, 33))	('BFHs', 'Disease', 'None', (54, 58))	('PKC', 'Gene', (30, 33))	('PGNTs', 'Gene', (63, 68))	('fusions', 'Var', (34, 41))
187394	33617877	The antibodies used in this study are as listed: PKCalpha (610108, BD Transduction), PKCbetaII (610128, BD Transduction), phospho-specific PKC turn motif (PKCalpha/beta pT638/641, 9375S, Cell Signaling), phospho-specific PKC hydrophobic motif (PKCbeta pS660, 9371S, Cell Signaling), HA (clone 16B12, 901515, BioLegend), Hsp90 (610418, BD Transduction), TANC2 (D-11, sc-515710, Santa Cruz), caspase-3 (9662S, Cell Signaling), cleaved caspase-3 (Asp175, 9661S, Cell Signaling), pSer PKC Substrate (2261S, Cell Signaling), GFP (2555S, Cell Signaling), beta-actin (A2228, Sigma-Aldrich), and alpha-tubulin (T6074, Sigma-Aldrich).	('PKCalpha', 'Gene', '5578', (155, 163))	('caspase-3', 'Gene', (390, 399))	('PKC', 'Gene', (155, 158))	('PKC', 'Gene', (481, 484))	('PKC', 'Gene', (244, 247))	('TANC2', 'Gene', '26115', (353, 358))	('Hsp90', 'Gene', (320, 325))	('PKCbeta', 'Gene', '5578', (244, 251))	('beta-actin', 'Gene', '728378', (549, 559))	('9375S', 'CellLine', 'CVCL:Z231', (180, 185))	('PKC', 'Gene', '112476', (139, 142))	('PKCalpha/beta', 'Gene', '5578', (155, 168))	('PKCalpha', 'Gene', (155, 163))	('PKCalpha/beta', 'Gene', (155, 168))	('PKCbeta', 'Gene', (85, 92))	('PKC', 'Gene', '112476', (49, 52))	('2261S', 'CellLine', 'CVCL:9J41', (496, 501))	('alpha-tubulin', 'Gene', (588, 601))	('PKC', 'Gene', (139, 142))	('PKCbeta', 'Gene', (244, 251))	('9371S', 'CellLine', 'CVCL:5G89', (259, 264))	('PKCalpha', 'Gene', '5578', (49, 57))	('caspase-3', 'Gene', '836', (433, 442))	('PKC', 'Gene', (49, 52))	('Ser', 'Chemical', 'MESH:D012694', (477, 480))	('PKC', 'Gene', '112476', (221, 224))	('beta-actin', 'Gene', (549, 559))	('PKC', 'Gene', '112476', (85, 88))	('caspase-3', 'Gene', (433, 442))	('TANC2', 'Gene', (353, 358))	('PKCalpha', 'Gene', (49, 57))	('PKC', 'Gene', '112476', (481, 484))	('PKC', 'Gene', '112476', (155, 158))	('PKC', 'Gene', '112476', (244, 247))	('Hsp90', 'Gene', '3320', (320, 325))	('PKC', 'Gene', (221, 224))	('alpha-tubulin', 'Gene', '10376', (588, 601))	('caspase-3', 'Gene', '836', (390, 399))	('PKC', 'Gene', (85, 88))	('2261S', 'Var', (496, 501))	('PKCbeta', 'Gene', '5578', (85, 92))
187396	33617877	The pharmacological reagents used in this study are as listed: UTP (6701, Calbiochem), PDBu (524390, Calbiochem), Go6976 (365253, Calbiochem), Go6983 (80,051-928, Calbiochem), BisIV (203297, Calbiochem), and etoposide (341205, Calbiochem).	('203297', 'Var', (183, 189))	('Go6976', 'Chemical', 'MESH:C081021', (114, 120))	('Go6983', 'Chemical', 'MESH:C465664', (143, 149))	('365253', 'Var', (122, 128))	('etoposide', 'Chemical', 'MESH:D005047', (208, 217))	('524390', 'Var', (93, 99))	('UTP', 'Chemical', 'MESH:D014544', (63, 66))	('341205', 'Var', (219, 225))	('PDBu', 'Chemical', 'MESH:D015240', (87, 91))
187425	30895747	Association between IL-1R2 polymorphisms and lung cancer risk in the Chinese Han population: A case-control study Interleukin-1 receptor 2 (IL-1R2), as an anti-inflammatory cytokine, is involved in the pathogenesis and progression of lung cancer.	('lung cancer', 'Disease', 'MESH:D008175', (45, 56))	('Interleukin-1', 'Gene', (114, 127))	('Interleukin-1', 'Gene', '3552', (114, 127))	('IL-1R2', 'Gene', (20, 26))	('IL-1R2', 'Gene', (140, 146))	('lung cancer', 'Disease', (234, 245))	('lung cancer', 'Disease', (45, 56))	('lung cancer', 'Phenotype', 'HP:0100526', (234, 245))	('lung cancer', 'Phenotype', 'HP:0100526', (45, 56))	('IL-1R2', 'Gene', '7850', (140, 146))	('polymorphisms', 'Var', (27, 40))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('Association', 'Interaction', (0, 11))	('involved', 'Reg', (186, 194))	('IL-1R2', 'Gene', '7850', (20, 26))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))	('lung cancer', 'Disease', 'MESH:D008175', (234, 245))
187426	30895747	However, the role of IL-1R2 polymorphisms in patients with lung cancer has yet to be fully elucidated.	('lung cancer', 'Disease', 'MESH:D008175', (59, 70))	('lung cancer', 'Disease', (59, 70))	('lung cancer', 'Phenotype', 'HP:0100526', (59, 70))	('polymorphisms', 'Var', (28, 41))	('patients', 'Species', '9606', (45, 53))	('IL-1R2', 'Gene', (21, 27))	('IL-1R2', 'Gene', '7850', (21, 27))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
187427	30895747	Six single-nucleotide polymorphisms (SNPs) in IL-1R2 were genotyped in 259 patients and 346 healthy controls.	('IL-1R2', 'Gene', (46, 52))	('patients', 'Species', '9606', (75, 83))	('single-nucleotide polymorphisms', 'Var', (4, 35))	('IL-1R2', 'Gene', '7850', (46, 52))
187428	30895747	We used the chi-squared test, genetic model analysis, Haploview analysis, and multifactor dimensionality reduction (MDR) to evaluate the potential association between IL-1R2 polymorphisms and lung cancer susceptibility.	('IL-1R2', 'Gene', (167, 173))	('lung cancer', 'Disease', (192, 203))	('lung cancer', 'Phenotype', 'HP:0100526', (192, 203))	('polymorphisms', 'Var', (174, 187))	('IL-1R2', 'Gene', '7850', (167, 173))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('lung cancer', 'Disease', 'MESH:D008175', (192, 203))
187430	30895747	Our results found that rs3218977-GG was associated with a decreased risk of lung cancer (odds ratio [OR] = 0.39; 95% confidence interval [CI]: 0.17-0.87; p = 0.023), and rs2072472 had a significant risk-increasing effect in the dominant model (AG + GG vs. AA: OR = 1.54; 95% CI: 1.09-2.20; p = 0.015).	('rs2072472', 'Mutation', 'rs2072472', (170, 179))	('rs3218977-GG', 'Var', (23, 35))	('lung cancer', 'Disease', 'MESH:D008175', (76, 87))	('decreased', 'NegReg', (58, 67))	('lung cancer', 'Disease', (76, 87))	('rs2072472', 'Var', (170, 179))	('rs3218977', 'Mutation', 'rs3218977', (23, 32))	('lung cancer', 'Phenotype', 'HP:0100526', (76, 87))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))
187431	30895747	The MDR model also revealed that rs2072472 is the most influential risk factor of lung cancer (testing accuracy = 0.543; cross-validation consistency = 10/10; p = 0.032).	('lung cancer', 'Phenotype', 'HP:0100526', (82, 93))	('rs2072472', 'Mutation', 'rs2072472', (33, 42))	('lung cancer', 'Disease', (82, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('lung cancer', 'Disease', 'MESH:D008175', (82, 93))	('rs2072472', 'Var', (33, 42))
187433	30895747	Our results suggest that genetic variants of IL-1R2 may play a role in lung cancer susceptibility.	('IL-1R2', 'Gene', '7850', (45, 51))	('play', 'Reg', (56, 60))	('role', 'Reg', (63, 67))	('lung cancer', 'Disease', 'MESH:D008175', (71, 82))	('genetic variants', 'Var', (25, 41))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('IL-1R2', 'Gene', (45, 51))	('lung cancer', 'Disease', (71, 82))	('lung cancer', 'Phenotype', 'HP:0100526', (71, 82))
187439	30895747	Additionally, individual variation, including age, sex, ethnicity, body weight, and especially single-nucleotide polymorphisms (SNPs) associated with genetic susceptibility, exerts an important role in the etiology of lung cancer (T. Wang et al., 2014; Zhang et al., 2015; Zhou et al., 2015).	('lung cancer', 'Disease', (218, 229))	('lung cancer', 'Phenotype', 'HP:0100526', (218, 229))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('single-nucleotide polymorphisms', 'Var', (95, 126))	('lung cancer', 'Disease', 'MESH:D008175', (218, 229))
187447	30895747	Epidemiological studies have confirmed that IL-1R2 polymorphisms were associated with cancer susceptibility (Jones et al., 2013; Oelmann, Stein, Berdel, & Herbst, 2015).	('IL-1R2', 'Gene', (44, 50))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('associated', 'Reg', (70, 80))	('IL-1R2', 'Gene', '7850', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('polymorphisms', 'Var', (51, 64))	('cancer', 'Disease', (86, 92))
187448	30895747	However, no previous study has investigated the association between lung cancer risk and IL-1R2 polymorphisms.	('lung cancer', 'Disease', (68, 79))	('lung cancer', 'Phenotype', 'HP:0100526', (68, 79))	('IL-1R2', 'Gene', (89, 95))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('polymorphisms', 'Var', (96, 109))	('lung cancer', 'Disease', 'MESH:D008175', (68, 79))	('IL-1R2', 'Gene', '7850', (89, 95))
187449	30895747	In the current study, we aimed to investigate IL-1R2 variants and their association with the susceptibility of lung cancer in a Chinese Han population using a case-control study.	('IL-1R2', 'Gene', (46, 52))	('lung cancer', 'Disease', 'MESH:D008175', (111, 122))	('association', 'Reg', (72, 83))	('IL-1R2', 'Gene', '7850', (46, 52))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('lung cancer', 'Disease', (111, 122))	('lung cancer', 'Phenotype', 'HP:0100526', (111, 122))	('variants', 'Var', (53, 61))
187457	30895747	Thus, six SNPs (rs11674595, rs4851527, rs719250, rs3218896, rs3218977, and rs2072472) were selected for further analysis.	('rs3218896', 'Mutation', 'rs3218896', (49, 58))	('rs2072472', 'Var', (75, 84))	('rs11674595', 'Mutation', 'rs11674595', (16, 26))	('rs2072472', 'Mutation', 'rs2072472', (75, 84))	('rs719250', 'Mutation', 'rs719250', (39, 47))	('rs3218977', 'Var', (60, 69))	('rs11674595', 'Var', (16, 26))	('rs3218896', 'Var', (49, 58))	('rs3218977', 'Mutation', 'rs3218977', (60, 69))	('rs719250', 'Var', (39, 47))	('rs4851527', 'Var', (28, 37))	('rs4851527', 'Mutation', 'rs4851527', (28, 37))
187458	30895747	Genotyping of IL-1R2 polymorphisms was conducted by the Agena MassARRAY RS1000 system (San Diego, CA, USA) according to previously published protocols (Gabriel, Ziaugra, & Tabbaa, 2009).	('IL-1R2', 'Gene', '7850', (14, 20))	('polymorphisms', 'Var', (21, 34))	('IL-1R2', 'Gene', (14, 20))
187472	30895747	There was no significant association of these SNPs in the IL-1R2 gene with lung cancer risk under the allelic model (Table 2).	('lung cancer', 'Disease', (75, 86))	('SNPs', 'Var', (46, 50))	('lung cancer', 'Phenotype', 'HP:0100526', (75, 86))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('IL-1R2', 'Gene', (58, 64))	('lung cancer', 'Disease', 'MESH:D008175', (75, 86))	('IL-1R2', 'Gene', '7850', (58, 64))
187473	30895747	The results of genetic models exhibited that rs3218977 and rs2072472 were associated with the risk of lung cancer.	('rs3218977', 'Mutation', 'rs3218977', (45, 54))	('rs2072472', 'Var', (59, 68))	('lung cancer', 'Phenotype', 'HP:0100526', (102, 113))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('lung cancer', 'Disease', (102, 113))	('rs2072472', 'Mutation', 'rs2072472', (59, 68))	('lung cancer', 'Disease', 'MESH:D008175', (102, 113))	('rs3218977', 'Var', (45, 54))	('associated', 'Reg', (74, 84))
187474	30895747	Rs3218977 moderately reduced lung cancer risk in the codominant (OR = 0.39; 95% CI: 0.17-0.87; p = 0.023) and recessive models (OR = 0.37; 95% CI: 0.17-0.81; p = 0.010).	('reduced', 'NegReg', (21, 28))	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('Rs3218977', 'Mutation', 'Rs3218977', (0, 9))	('lung cancer', 'Disease', 'MESH:D008175', (29, 40))	('Rs3218977', 'Var', (0, 9))	('lung cancer', 'Disease', (29, 40))	('lung cancer', 'Phenotype', 'HP:0100526', (29, 40))
187476	30895747	No significant associations were found between lung cancer risk and the remaining four SNPs (rs11674595, rs4851527, rs719250, and rs3218896; Table 3).	('rs3218896', 'Var', (130, 139))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('lung cancer', 'Disease', (47, 58))	('rs11674595', 'Mutation', 'rs11674595', (93, 103))	('lung cancer', 'Phenotype', 'HP:0100526', (47, 58))	('rs3218896', 'Mutation', 'rs3218896', (130, 139))	('rs4851527', 'Mutation', 'rs4851527', (105, 114))	('rs11674595', 'Var', (93, 103))	('rs4851527', 'Var', (105, 114))	('rs719250', 'Mutation', 'rs719250', (116, 124))	('lung cancer', 'Disease', 'MESH:D008175', (47, 58))	('rs719250', 'Var', (116, 124))
187478	30895747	We found a significant association between rs719250 polymorphism and lung small cell carcinoma (allele, OR = 1.97, 95% CI: 1.27-3.05, p = 0.002; codominant, OR = 2.64, 95% CI: 1.29-5.50, p = 0.007; dominant, OR = 2.84, 95% CI: 1.40-5.73, p = 0.002; additive model, OR = 1.97, 95% CI: 1.26-3.09, p = 0.003).	('lung small', 'Phenotype', 'HP:0002089', (69, 79))	('rs719250', 'Mutation', 'rs719250', (43, 51))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('lung small cell carcinoma', 'Disease', 'MESH:D055752', (69, 94))	('rs719250', 'Var', (43, 51))	('lung small cell carcinoma', 'Disease', (69, 94))
187479	30895747	Moreover, individuals carrying rs3218977-GG genotype showed a significant protective effect for lung squamous cell carcinoma (GG vs. AA, OR = 0.07, 95% CI: 0.01-0.58, p = 0.002; and GG vs. AA-GA, OR = 0.07, 95% CI: 0.01-0.54, p < 0.001).	('rs3218977', 'Mutation', 'rs3218977', (31, 40))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (101, 124))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (96, 124))	('lung squamous cell carcinoma', 'Disease', (96, 124))	('rs3218977-GG', 'Var', (31, 43))
187481	30895747	We found that rs11674595 C allele was highly represented in patients with III-IV tumor stage as compared to patients with I-II tumor stage (allele, OR = 1.77, 95% CI: 1.05-2.99, p = 0.029; additive, OR = 1.76, 95% CI: 1.04-2.98, p = 0.027; Table 5).	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('rs11674595', 'Mutation', 'rs11674595', (14, 24))	('patients', 'Species', '9606', (60, 68))	('III-IV tumor', 'Disease', (74, 86))	('rs11674595 C', 'Var', (14, 26))	('I-II tumor', 'Disease', (122, 132))	('I-II tumor', 'Disease', 'MESH:D009369', (122, 132))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('patients', 'Species', '9606', (108, 116))	('III-IV tumor', 'Disease', 'MESH:D009369', (74, 86))
187482	30895747	No significant association was observed between tumor metastasis and IL-1R2 variants.	('IL-1R2', 'Gene', '7850', (69, 75))	('tumor metastasis', 'Disease', 'MESH:D009362', (48, 64))	('variants', 'Var', (76, 84))	('tumor metastasis', 'Disease', (48, 64))	('IL-1R2', 'Gene', (69, 75))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
187484	30895747	The haplotype frequencies of four SNP haplotypes (rs11674595, rs4851527, rs719250, and rs3218896) and two SNP haplotypes (rs3218977 and rs2072472) in the case and control groups were shown in Table S1.	('rs2072472', 'Var', (136, 145))	('rs719250', 'Mutation', 'rs719250', (73, 81))	('rs3218896', 'Var', (87, 96))	('rs3218977', 'Var', (122, 131))	('rs719250', 'Var', (73, 81))	('rs11674595', 'Mutation', 'rs11674595', (50, 60))	('rs2072472', 'Mutation', 'rs2072472', (136, 145))	('rs3218977', 'Mutation', 'rs3218977', (122, 131))	('rs3218896', 'Mutation', 'rs3218896', (87, 96))	('rs4851527', 'Mutation', 'rs4851527', (62, 71))	('rs11674595', 'Var', (50, 60))	('rs4851527', 'Var', (62, 71))
187485	30895747	Haplotype-based logistic regression adjusted by age and gender was performed within the case-control cohort; however, the results revealed no significant association of the haplotypes with the risk of lung cancer (p > 0.05, Table S1).	('haplotypes', 'Var', (173, 183))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('lung cancer', 'Disease', 'MESH:D008175', (201, 212))	('lung cancer', 'Phenotype', 'HP:0100526', (201, 212))	('lung cancer', 'Disease', (201, 212))
187486	30895747	The results of MDR analysis were summarized in Table 6. rs2072472 was the most influential attributor for lung cancer risk in the single-locus model (testing accuracy = 0.5428, CVC = 10/10, p = 0.0321), a finding that is consistent with the results of previous studies.	('lung cancer', 'Disease', (106, 117))	('lung cancer', 'Phenotype', 'HP:0100526', (106, 117))	('rs2072472', 'Var', (56, 65))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('lung cancer', 'Disease', 'MESH:D008175', (106, 117))	('rs2072472', 'Mutation', 'rs2072472', (56, 65))
187487	30895747	Moreover, the three-locus interaction model (rs719250, rs3218977, and rs2072472) was found to be the best in the multilocus model (testing accuracy = 0.5409, CVC = 10/10, p = 0.0002).	('rs3218977', 'Var', (55, 64))	('rs2072472', 'Mutation', 'rs2072472', (70, 79))	('rs3218977', 'Mutation', 'rs3218977', (55, 64))	('rs719250', 'Var', (45, 53))	('rs2072472', 'Var', (70, 79))	('rs719250', 'Mutation', 'rs719250', (45, 53))
187492	30895747	In this case-control study, we successfully genotyped six SNPs in the IL1-R2 gene and found that rs2072472, rs719250, rs11674595, and rs3218977 were related to the risk of lung cancer.	('rs719250', 'Mutation', 'rs719250', (108, 116))	('IL1-R2', 'Gene', (70, 76))	('rs11674595', 'Mutation', 'rs11674595', (118, 128))	('lung cancer', 'Disease', (172, 183))	('rs719250', 'Var', (108, 116))	('lung cancer', 'Phenotype', 'HP:0100526', (172, 183))	('rs3218977', 'Var', (134, 143))	('rs2072472', 'Var', (97, 106))	('rs11674595', 'Var', (118, 128))	('rs3218977', 'Mutation', 'rs3218977', (134, 143))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('IL1-R2', 'Gene', '7850', (70, 76))	('related', 'Reg', (149, 156))	('lung cancer', 'Disease', 'MESH:D008175', (172, 183))	('rs2072472', 'Mutation', 'rs2072472', (97, 106))
187494	30895747	The findings further highlight that the polymorphisms in the IL1-R2 gene may contribute to lung cancer susceptibility in the Chinese Han population.	('lung cancer', 'Phenotype', 'HP:0100526', (91, 102))	('IL1-R2', 'Gene', '7850', (61, 67))	('polymorphisms', 'Var', (40, 53))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('contribute', 'Reg', (77, 87))	('lung cancer', 'Disease', 'MESH:D008175', (91, 102))	('IL1-R2', 'Gene', (61, 67))	('lung cancer', 'Disease', (91, 102))
187495	30895747	To the best of our knowledge, this is the first study to explore the relationship between IL1-R2 polymorphisms and lung cancer risk in the Chinese Han population.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('IL1-R2', 'Gene', (90, 96))	('lung cancer', 'Disease', 'MESH:D008175', (115, 126))	('polymorphisms', 'Var', (97, 110))	('IL1-R2', 'Gene', '7850', (90, 96))	('lung cancer', 'Disease', (115, 126))	('lung cancer', 'Phenotype', 'HP:0100526', (115, 126))
187496	30895747	Our study provides evidence about the potential role of the IL1-R2 variants in lung cancer risk.	('lung cancer', 'Disease', 'MESH:D008175', (79, 90))	('IL1-R2', 'Gene', '7850', (60, 66))	('lung cancer', 'Disease', (79, 90))	('lung cancer', 'Phenotype', 'HP:0100526', (79, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('IL1-R2', 'Gene', (60, 66))	('variants', 'Var', (67, 75))
187504	30895747	In silico, we found that IL-1R2 gene expression is downregulated in lung cancer, whereas high expression of IL-1R2 is associated with a poor overall survival for lung cancer.	('IL-1R2', 'Gene', '7850', (25, 31))	('lung cancer', 'Disease', (68, 79))	('IL-1R2', 'Gene', '7850', (108, 114))	('lung cancer', 'Disease', 'MESH:D008175', (162, 173))	('lung cancer', 'Phenotype', 'HP:0100526', (68, 79))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('IL-1R2', 'Gene', (25, 31))	('high', 'Var', (89, 93))	('lung cancer', 'Disease', (162, 173))	('downregulated', 'NegReg', (51, 64))	('lung cancer', 'Disease', 'MESH:D008175', (68, 79))	('associated', 'Reg', (118, 128))	('lung cancer', 'Phenotype', 'HP:0100526', (162, 173))	('expression', 'MPA', (37, 47))	('IL-1R2', 'Gene', (108, 114))
187506	30895747	Studies based on variants in the IL-1R2 gene are infrequent, and there is no finding of the association between the IL-1R2 SNPs and lung cancer risk in previous studies.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('IL-1R2', 'Gene', (33, 39))	('variants', 'Var', (17, 25))	('IL-1R2', 'Gene', (116, 122))	('lung cancer', 'Disease', 'MESH:D008175', (132, 143))	('IL-1R2', 'Gene', '7850', (33, 39))	('IL-1R2', 'Gene', '7850', (116, 122))	('lung cancer', 'Disease', (132, 143))	('lung cancer', 'Phenotype', 'HP:0100526', (132, 143))
187507	30895747	Given the expression and survival data of IL-1R2 in lung cancer, polymorphisms in the IL-1R2 gene might contribute to lung cancer risk.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('lung cancer', 'Disease', 'MESH:D008175', (52, 63))	('IL-1R2', 'Gene', '7850', (86, 92))	('lung cancer', 'Disease', 'MESH:D008175', (118, 129))	('polymorphisms', 'Var', (65, 78))	('lung cancer', 'Disease', (52, 63))	('IL-1R2', 'Gene', (42, 48))	('lung cancer', 'Phenotype', 'HP:0100526', (52, 63))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('lung cancer', 'Disease', (118, 129))	('IL-1R2', 'Gene', (86, 92))	('lung cancer', 'Phenotype', 'HP:0100526', (118, 129))	('IL-1R2', 'Gene', '7850', (42, 48))	('contribute', 'Reg', (104, 114))
187508	30895747	Our results found that rs3218977 in IL-1R2 was associated with a decreased risk of lung cancer, especially in patients with lung squamous cell carcinoma.	('IL-1R2', 'Gene', (36, 42))	('lung cancer', 'Disease', 'MESH:D008175', (83, 94))	('decreased', 'NegReg', (65, 74))	('rs3218977', 'Var', (23, 32))	('IL-1R2', 'Gene', '7850', (36, 42))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (129, 152))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (124, 152))	('lung squamous cell carcinoma', 'Disease', (124, 152))	('lung cancer', 'Disease', (83, 94))	('rs3218977', 'Mutation', 'rs3218977', (23, 32))	('lung cancer', 'Phenotype', 'HP:0100526', (83, 94))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (143, 152))	('patients', 'Species', '9606', (110, 118))
187509	30895747	rs2072472 polymorphism increased 1.77-fold risk of lung cancer, and rs719250 polymorphism increased 1.77-fold risk of lung small cell carcinoma.	('lung small cell carcinoma', 'Disease', 'MESH:D055752', (118, 143))	('lung cancer', 'Disease', 'MESH:D008175', (51, 62))	('lung small', 'Phenotype', 'HP:0002089', (118, 128))	('rs2072472', 'Var', (0, 9))	('lung small cell carcinoma', 'Disease', (118, 143))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('lung cancer', 'Disease', (51, 62))	('lung cancer', 'Phenotype', 'HP:0100526', (51, 62))	('rs719250', 'Mutation', 'rs719250', (68, 76))	('rs2072472', 'Mutation', 'rs2072472', (0, 9))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('rs719250', 'Var', (68, 76))
187510	30895747	Moreover, rs11674595 polymorphism was a significant risk factor for patients with III-IV stage.	('patients', 'Species', '9606', (68, 76))	('rs11674595', 'Mutation', 'rs11674595', (10, 20))	('rs11674595', 'Var', (10, 20))	('III-IV stage', 'Disease', (82, 94))
187514	30895747	However, the mechanisms on the biological function of these SNPs in IL1R2 are unknown and need more functional studies to explore.	('IL1R2', 'Gene', (68, 73))	('IL1R2', 'Gene', '7850', (68, 73))	('SNPs', 'Var', (60, 64))
187515	30895747	The expression analysis of IL-1R2 mRNA and annotation of the functional significance of the variants are needed to clarify the genetic mechanism underlying lung cancer in the future.	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('lung cancer', 'Disease', 'MESH:D008175', (156, 167))	('IL-1R2', 'Gene', (27, 33))	('lung cancer', 'Disease', (156, 167))	('lung cancer', 'Phenotype', 'HP:0100526', (156, 167))	('variants', 'Var', (92, 100))	('IL-1R2', 'Gene', '7850', (27, 33))
187516	30895747	In summary, this is an exploratory study concerning the association of IL-1R2 SNPs with the susceptibility of lung cancer.	('IL-1R2', 'Gene', (71, 77))	('lung cancer', 'Disease', 'MESH:D008175', (110, 121))	('SNPs', 'Var', (78, 82))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('lung cancer', 'Disease', (110, 121))	('IL-1R2', 'Gene', '7850', (71, 77))	('lung cancer', 'Phenotype', 'HP:0100526', (110, 121))	('association', 'Interaction', (56, 67))
187517	30895747	IL-1R2 rs2072472 polymorphism increased the risk of lung cancer; conversely, the rs3218977 polymorphism reduced the susceptibility of lung cancer.	('IL-1R2', 'Gene', '7850', (0, 6))	('lung cancer', 'Disease', (134, 145))	('lung cancer', 'Disease', 'MESH:D008175', (52, 63))	('lung cancer', 'Phenotype', 'HP:0100526', (134, 145))	('reduced', 'NegReg', (104, 111))	('rs2072472', 'Var', (7, 16))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('rs3218977', 'Var', (81, 90))	('IL-1R2', 'Gene', (0, 6))	('lung cancer', 'Disease', (52, 63))	('lung cancer', 'Disease', 'MESH:D008175', (134, 145))	('lung cancer', 'Phenotype', 'HP:0100526', (52, 63))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('rs3218977', 'Mutation', 'rs3218977', (81, 90))	('rs2072472', 'Mutation', 'rs2072472', (7, 16))	('increased', 'PosReg', (30, 39))
187518	30895747	Future studies are necessary to investigate the detailed mechanisms of the associated variants that affect the expression and function of the IL-1R2 gene.	('affect', 'Reg', (100, 106))	('function', 'MPA', (126, 134))	('IL-1R2', 'Gene', '7850', (142, 148))	('variants', 'Var', (86, 94))	('expression', 'MPA', (111, 121))	('IL-1R2', 'Gene', (142, 148))
187662	27225481	Multiplication of the 3q26.3 gene locus causes SOX2 amplification, which has been reported in glioblastoma, small-cell lung cancer and many squamous cell carcinomas.	('small-cell lung cancer', 'Disease', 'MESH:D055752', (108, 130))	('reported', 'Reg', (82, 90))	('glioblastoma', 'Disease', (94, 106))	('small-cell lung cancer', 'Disease', (108, 130))	('causes', 'Reg', (40, 46))	('glioblastoma', 'Phenotype', 'HP:0012174', (94, 106))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (140, 164))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (140, 163))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (140, 164))	('lung cancer', 'Phenotype', 'HP:0100526', (119, 130))	('Multiplication', 'Var', (0, 14))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (108, 130))	('SOX2', 'Gene', (47, 51))	('squamous cell carcinomas', 'Disease', (140, 164))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('amplification', 'MPA', (52, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (154, 163))	('carcinomas', 'Phenotype', 'HP:0030731', (154, 164))	('glioblastoma', 'Disease', 'MESH:D005909', (94, 106))
187663	27225481	Co-amplification of SOX2 and Protein Kinase CI (PRKCI) has been reported to be responsible for the CSC phenotype in lung squamous cell carcinoma.	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (116, 144))	('Protein Kinase CI', 'Gene', (29, 46))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('Protein Kinase CI', 'Gene', '5584', (29, 46))	('lung squamous cell carcinoma', 'Disease', (116, 144))	('CSC', 'Disease', (99, 102))	('PRKCI', 'Gene', '5584', (48, 53))	('PRKCI', 'Gene', (48, 53))	('responsible', 'Reg', (79, 90))	('SOX2', 'Gene', (20, 24))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (116, 144))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (121, 144))	('Co-amplification', 'Var', (0, 16))
187665	27225481	Subsequent SOX2 knockdown causes transcriptional induction of p21Cip1 and p27Kip1, resulting in cell cycle arrest and cell growth inhibition.	('cell cycle arrest', 'Phenotype', 'HP:0011018', (96, 113))	('arrest', 'Disease', 'MESH:D006323', (107, 113))	('p21Cip1', 'Gene', (62, 69))	('SOX2', 'Gene', (11, 15))	('p27Kip1', 'Gene', '1027', (74, 81))	('p27Kip1', 'Gene', (74, 81))	('arrest', 'Disease', (107, 113))	('knockdown', 'Var', (16, 25))	('p21Cip1', 'Gene', '1026', (62, 69))	('transcriptional', 'MPA', (33, 48))	('cell growth inhibition', 'CPA', (118, 140))
187666	27225481	Similarly, SOX2 silencing inhibits cellular proliferation in lung squamous cell carcinoma cells.	('inhibits', 'NegReg', (26, 34))	('SOX2', 'Gene', (11, 15))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('lung squamous cell carcinoma', 'Disease', (61, 89))	('silencing', 'Var', (16, 25))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (61, 89))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (61, 89))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (66, 89))	('cellular proliferation', 'CPA', (35, 57))
187668	27225481	SOX2 silencing causes a decrease in cell proliferation and loss of tumorigenicity in glioblastoma tumor-initiating cells in immunodeficient mice.	('mice', 'Species', '10090', (140, 144))	('glioblastoma tumor', 'Disease', (85, 103))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('silencing', 'Var', (5, 14))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('decrease', 'NegReg', (24, 32))	('glioblastoma tumor', 'Disease', 'MESH:D005909', (85, 103))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('glioblastoma', 'Phenotype', 'HP:0012174', (85, 97))	('tumor', 'Disease', (67, 72))	('tumor', 'Disease', (98, 103))	('loss', 'NegReg', (59, 63))	('SOX2', 'Gene', (0, 4))	('cell proliferation', 'CPA', (36, 54))
187676	27225481	The PI3K/Akt signaling pathway has been shown to be activated in prostate cancer cells overexpressing SOX2.	('prostate cancer', 'Disease', 'MESH:D011471', (65, 80))	('Akt', 'Gene', (9, 12))	('prostate cancer', 'Phenotype', 'HP:0012125', (65, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('PI3', 'Gene', '5266', (4, 7))	('activated', 'PosReg', (52, 61))	('PI3', 'Gene', (4, 7))	('prostate cancer', 'Disease', (65, 80))	('SOX2', 'Var', (102, 106))	('Akt', 'Gene', '207', (9, 12))
187681	27225481	High SOX2 expression is associated with higher histological grade in esophageal squamous cancer (p < 0.001).	('esophageal squamous cancer', 'Disease', 'MESH:D004938', (69, 95))	('High', 'Var', (0, 4))	('higher', 'PosReg', (40, 46))	('SOX2', 'Protein', (5, 9))	('esophageal squamous cancer', 'Disease', (69, 95))	('expression', 'MPA', (10, 20))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('squamous cancer', 'Phenotype', 'HP:0002860', (80, 95))
187682	27225481	A significant correlation (p < 0.001) between high SOX2 expression and decreasing patient survival was also established in the same study.	('high', 'Var', (46, 50))	('decreasing', 'NegReg', (71, 81))	('patient', 'Species', '9606', (82, 89))	('expression', 'MPA', (56, 66))	('SOX2', 'Protein', (51, 55))	('patient survival', 'CPA', (82, 98))
187700	27225481	Clinical implications Like high SOX2 expression, high OCT4 expression is associated with higher histological grade in esophageal squamous cancer (p < 0.001).	('esophageal squamous cancer', 'Disease', 'MESH:D004938', (118, 144))	('SOX2', 'Protein', (32, 36))	('esophageal squamous cancer', 'Disease', (118, 144))	('squamous cancer', 'Phenotype', 'HP:0002860', (129, 144))	('high SOX2', 'Protein', (27, 36))	('OCT4', 'Gene', '5460', (54, 58))	('expression', 'MPA', (59, 69))	('OCT4', 'Gene', (54, 58))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('high', 'Var', (49, 53))	('expression', 'MPA', (37, 47))
187701	27225481	Both NANOG and OCT4 overexpressions are associated with both advanced cancer stage and decreased survival in oral squamous cell and lung adenocarcinomas.	('lung adenocarcinomas', 'Disease', (132, 152))	('survival', 'MPA', (97, 105))	('decreased', 'NegReg', (87, 96))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('OCT4', 'Gene', '5460', (15, 19))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (132, 152))	('OCT4', 'Gene', (15, 19))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (132, 152))	('overexpressions', 'PosReg', (20, 35))	('oral squamous cell', 'Disease', (109, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (142, 151))	('carcinomas', 'Phenotype', 'HP:0030731', (142, 152))	('NANOG', 'Var', (5, 10))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (132, 151))
187704	27225481	NANOG functions NANOG is capable of maintaining embryonic stem cell pluripotency independently of the LIF-STAT3 pathway, which OCT4 is incapable of doing.	('NANOG', 'Var', (0, 5))	('LIF', 'Gene', (102, 105))	('LIF', 'Gene', '3976', (102, 105))	('OCT4', 'Gene', '5460', (127, 131))	('pluripotency', 'Disease', (68, 80))	('OCT4', 'Gene', (127, 131))	('pluripotency', 'Disease', 'None', (68, 80))	('embryonic stem cell', 'CPA', (48, 67))
187708	27225481	Furthermore, NANOG is capable of inducing CSC-like properties in primary p53-deficient mature mouse astrocytes; however, astrocytes with intact p53 could not be induced.	('mouse', 'Species', '10090', (94, 99))	('inducing', 'PosReg', (33, 41))	('CSC-like properties', 'MPA', (42, 61))	('NANOG', 'Var', (13, 18))
187714	27225481	In mouse embryonic stem cells, p53 was shown to suppress NANOG transcription in response to DNA damage.	('suppress', 'NegReg', (48, 56))	('NANOG', 'Gene', (57, 62))	('mouse', 'Species', '10090', (3, 8))	('p53', 'Var', (31, 34))	('response to DNA damage', 'MPA', (80, 102))
187727	27225481	In endometrial cancer cells, the loss of BMI1 results in the reduced expression of SOX2 and KLF4.	('KLF4', 'Gene', (92, 96))	('endometrial cancer', 'Phenotype', 'HP:0012114', (3, 21))	('SOX2', 'Protein', (83, 87))	('endometrial cancer', 'Disease', 'MESH:D016889', (3, 21))	('expression', 'MPA', (69, 79))	('BMI1', 'Gene', (41, 45))	('loss', 'Var', (33, 37))	('endometrial cancer', 'Disease', (3, 21))	('KLF4', 'Gene', '9314', (92, 96))	('reduced', 'NegReg', (61, 68))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))
187730	27225481	BMI1 overexpression correlates with NANOG overexpression, high-grade status and increased self-renewal in breast adenocarcinomas.	('NANOG', 'Var', (36, 41))	('increased', 'PosReg', (80, 89))	('overexpression', 'PosReg', (5, 19))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('carcinomas', 'Phenotype', 'HP:0030731', (118, 128))	('breast adenocarcinomas', 'Disease', 'MESH:D000230', (106, 128))	('BMI1', 'Gene', (0, 4))	('overexpression', 'PosReg', (42, 56))	('self-renewal', 'CPA', (90, 102))	('breast adenocarcinomas', 'Disease', (106, 128))
187738	27225481	In breast cancer, SOX2 silencing restores tamoxifen sensitivity.	('restores', 'PosReg', (33, 41))	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('SOX2', 'Gene', (18, 22))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('breast cancer', 'Disease', (3, 16))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('silencing', 'Var', (23, 32))	('tamoxifen', 'Chemical', 'MESH:D013629', (42, 51))	('tamoxifen sensitivity', 'MPA', (42, 63))
187739	27225481	NANOG overexpression, likewise, increases drug resistance in breast cancer cell lines.	('NANOG', 'Var', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('breast cancer', 'Disease', (61, 74))	('drug resistance', 'CPA', (42, 57))	('drug resistance', 'Phenotype', 'HP:0020174', (42, 57))	('breast cancer', 'Phenotype', 'HP:0003002', (61, 74))	('overexpression', 'PosReg', (6, 20))	('increases', 'PosReg', (32, 41))	('breast cancer', 'Disease', 'MESH:D001943', (61, 74))
187740	27225481	Lung adenocarcinoma cell lines are sensitized to erlotinib by shRNA-knockdown of SOX2.	('erlotinib', 'Chemical', 'MESH:D000069347', (49, 58))	('adenocarcinoma', 'Disease', (5, 19))	('adenocarcinoma', 'Disease', 'MESH:D000230', (5, 19))	('sensitized', 'Reg', (35, 45))	('shRNA-knockdown', 'Var', (62, 77))	('Lung adenocarcinoma', 'Phenotype', 'HP:0030078', (0, 19))	('SOX2', 'Gene', (81, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (10, 19))
187745	27225481	Docetaxel sensitivity is increased in prostate cancer cells by silencing BMI1.	('prostate cancer', 'Disease', 'MESH:D011471', (38, 53))	('increased', 'PosReg', (25, 34))	('Docetaxel sensitivity', 'MPA', (0, 21))	('prostate cancer', 'Phenotype', 'HP:0012125', (38, 53))	('prostate cancer', 'Disease', (38, 53))	('Docetaxel', 'Chemical', 'MESH:D000077143', (0, 9))	('BMI1', 'Gene', (73, 77))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('silencing', 'Var', (63, 72))
187746	27225481	Ovarian CSCs are more resistant to cisplatin and paclitaxel when BMI1 is overexpressed, and targeting BMI1 sensitizes ovarian cancer cells to cisplatin.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('targeting', 'Var', (92, 101))	('ovarian cancer', 'Disease', (118, 132))	('cisplatin', 'Chemical', 'MESH:D002945', (142, 151))	('paclitaxel', 'Chemical', 'MESH:D017239', (49, 59))	('cisplatin', 'Chemical', 'MESH:D002945', (35, 44))	('BMI1', 'Gene', (102, 106))	('ovarian cancer', 'Phenotype', 'HP:0100615', (118, 132))	('resistant', 'MPA', (22, 31))	('sensitizes', 'Reg', (107, 117))	('ovarian cancer', 'Disease', 'MESH:D010051', (118, 132))
187753	27225481	Additionally, YY1 upregulates NANOG in gastric cancer.	('upregulates', 'PosReg', (18, 29))	('gastric cancer', 'Disease', (39, 53))	('NANOG', 'Protein', (30, 35))	('gastric cancer', 'Disease', 'MESH:D013274', (39, 53))	('gastric cancer', 'Phenotype', 'HP:0012126', (39, 53))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('YY1', 'Var', (14, 17))
187769	27225481	NANOG antibody CAB019380 was never detected in breast cancer and had 0 % positive staining.	('breast cancer', 'Disease', (47, 60))	('breast cancer', 'Phenotype', 'HP:0003002', (47, 60))	('CAB019380', 'Var', (15, 24))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('breast cancer', 'Disease', 'MESH:D001943', (47, 60))
187770	27225481	By these same processes, it was determined that BMI1 antibody HPA030472 had 10/11 (91 %), BMI1 antibody CAB011120 had 8/10 (80 %), OCT4 antibody CAB025600 had 11/11 (100 %) and OCT4 antibody CAB026380 had 5/9 (55 %) positive staining.	('CAB025600', 'Var', (145, 154))	('HPA030472', 'Var', (62, 71))	('OCT4', 'Gene', '5460', (131, 135))	('OCT4', 'Gene', (131, 135))	('OCT4', 'Gene', '5460', (177, 181))	('OCT4', 'Gene', (177, 181))
187772	27225481	The final antibodies used were YY1 antibody HPA001119, SOX2 antibody CAB010648, NANOG antibody CAB019380, BMI1 antibody CAB011120 and OCT4 antibody CAB026380 (Table 1).	('CAB019380', 'Var', (95, 104))	('CAB026380', 'Var', (148, 157))	('CAB011120', 'Var', (120, 129))	('OCT4', 'Gene', '5460', (134, 138))	('CAB010648', 'Var', (69, 78))	('HPA001119', 'Var', (44, 53))	('OCT4', 'Gene', (134, 138))
187786	27225481	Tier two, characterized by high YY1 and low SOX2, is found in skin, testis and breast cancers.	('breast cancers', 'Phenotype', 'HP:0003002', (79, 93))	('low', 'NegReg', (40, 43))	('YY1', 'Var', (32, 35))	('SOX2', 'MPA', (44, 48))	('testis and breast cancers', 'Disease', 'MESH:D013736', (68, 93))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('breast cancer', 'Phenotype', 'HP:0003002', (79, 92))	('cancers', 'Phenotype', 'HP:0002664', (86, 93))	('skin', 'Disease', (62, 66))
187788	27225481	These findings show an overall pattern of high YY1, low SOX2, high BMI1 and high OCT4 (Fig.	('SOX2', 'MPA', (56, 60))	('BMI1', 'MPA', (67, 71))	('OCT4', 'Gene', '5460', (81, 85))	('OCT4', 'Gene', (81, 85))	('high', 'Var', (62, 66))	('low', 'NegReg', (52, 55))	('high YY1', 'Var', (42, 50))
187797	27225481	YY1 frequency of expression was associated with the SOX2, BMI1 and OCT4 frequency of expression across many cancers, though the type of association varied.	('cancers', 'Phenotype', 'HP:0002664', (108, 115))	('OCT4', 'Gene', '5460', (67, 71))	('OCT4', 'Gene', (67, 71))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('YY1', 'Gene', (0, 3))	('associated', 'Reg', (32, 42))	('cancers', 'Disease', 'MESH:D009369', (108, 115))	('frequency', 'Var', (4, 13))	('cancers', 'Disease', (108, 115))
187821	27029934	The dysregulation of miRNA expression has been identified in various cancers and suggests that miRNAs can function as classical oncogenes or tumor suppressor genes.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('cancers', 'Disease', 'MESH:D009369', (69, 76))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('dysregulation', 'Var', (4, 17))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('tumor', 'Disease', (141, 146))	('cancers', 'Phenotype', 'HP:0002664', (69, 76))	('cancers', 'Disease', (69, 76))	('miRNA', 'Protein', (21, 26))
187903	26792175	I identify the subset of targets of each TF most likely mediating the tumorigenic effect of their driver alterations in each tumor type, and explore their overlap.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumor', 'Disease', (70, 75))	('tumor', 'Disease', (125, 130))	('alterations', 'Var', (105, 116))	('mediating', 'Reg', (56, 65))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
187912	26792175	Second, uncovering the catalog of driver genes has revealed that at the level of genomic alterations, tumorigenesis possesses a very heterogeneous nature, with driver alterations in genes in the same pathway or in cross-talking pathways resulting in the same phenotype.	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('cross-talking', 'Reg', (214, 227))	('resulting in', 'Reg', (237, 249))	('alterations', 'Var', (167, 178))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))
187913	26792175	This is the case, for instance, of loss-of-function mutations of TP53, amplifications of MDM2 and MDM4, and deletions of CDKN2A, all leading to evading apoptosis and uncontrolled proliferation in malignancies such as glioblastoma.	('MDM4', 'Gene', (98, 102))	('TP53', 'Gene', '7157', (65, 69))	('loss-of-function', 'NegReg', (35, 51))	('deletions', 'Var', (108, 117))	('CDKN2A', 'Gene', (121, 127))	('amplifications', 'Var', (71, 85))	('glioblastoma', 'Disease', 'MESH:D005909', (217, 229))	('CDKN2A', 'Gene', '1029', (121, 127))	('malignancies', 'Disease', 'MESH:D009369', (196, 208))	('TP53', 'Gene', (65, 69))	('malignancies', 'Disease', (196, 208))	('glioblastoma', 'Disease', (217, 229))	('MDM2', 'Gene', (89, 93))	('glioblastoma', 'Phenotype', 'HP:0012174', (217, 229))	('mutations', 'Var', (52, 61))	('uncontrolled proliferation', 'CPA', (166, 192))	('evading apoptosis', 'CPA', (144, 161))	('MDM2', 'Gene', '4193', (89, 93))	('MDM4', 'Gene', '4194', (98, 102))
187915	26792175	The heterogeneity of driver alterations in a tumor type presents a major challenge to the efforts to develop a comprehensive toolbox of targeted therapies to extend personalized cancer medicine driven by genomics information.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('alterations', 'Var', (28, 39))	('tumor', 'Disease', (45, 50))	('cancer', 'Disease', (178, 184))	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
187921	26792175	Then, to investigate how their somatic alterations result in cancerogenesis across 15 tumor types, I explore the misregulated targets of 42 of them for which I was able to gather data.	('cancerogenesis across 15 tumor', 'Disease', (61, 91))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('alterations', 'Var', (39, 50))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('result in', 'Reg', (51, 60))	('cancerogenesis across 15 tumor', 'Disease', 'MESH:C567447', (61, 91))
187925	26792175	I inherited the list of mutational driver genes across 28 malignancies from our recent study, which identified them on the basis of three methods that exploit complementary signals of positive selection of the pattern of mutations in the genes in the tumorigenic process.	('tumor', 'Disease', (251, 256))	('mutations', 'Var', (221, 230))	('malignancies', 'Disease', 'MESH:D009369', (58, 70))	('tumor', 'Disease', 'MESH:D009369', (251, 256))	('malignancies', 'Disease', (58, 70))	('tumor', 'Phenotype', 'HP:0002664', (251, 256))
187928	26792175	I retrieved all mutations detected in driver TFs across almost 7,000 tumors sequenced in 48 cohorts representing the 28 aforementioned tumor types from the Integrative Oncogenomics (IntOGen) platform (www.intogen.org).	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('000 tumors', 'Disease', (65, 75))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('TFs', 'Gene', (45, 48))	('tumor', 'Disease', (69, 74))	('mutations', 'Var', (16, 25))	('tumor', 'Disease', (135, 140))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('000 tumors', 'Disease', 'MESH:D009369', (65, 75))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
187929	26792175	I then computed the enrichment/depletion of mutations in each driver TF in each cohort of tumors as the Fisher's test P value.	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('tumors', 'Disease', (90, 96))	('tumors', 'Disease', 'MESH:D009369', (90, 96))	('mutations', 'Var', (44, 53))
187931	26792175	To detect all putative driver alterations (mutations, amplifications, and deletions) across 15 TCGA cohorts of tumors (Additional file 5), I first downloaded CNA (continuous values per genomic segment) and expression data (processed RNAseq in the form of RPKMs) from synapse (syn300013).	('deletions', 'Var', (74, 83))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('tumors', 'Disease', 'MESH:D009369', (111, 117))	('tumors', 'Disease', (111, 117))
187932	26792175	Also from synapse, I retrieved the mutations detected in 34 pancreatic carcinoma samples, not included within the datasets of somatic mutations obtained from IntOGen.	('pancreatic carcinoma', 'Disease', (60, 80))	('pancreatic carcinoma', 'Disease', 'MESH:C562463', (60, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('mutations', 'Var', (35, 44))
187935	26792175	Both truncating - stop gained or lost, frame-shift, splice donor or splice acceptor - and missense mutations in LoF driver TFs were considered LoF driver mutations, while only missense mutations in Act driver TFs were considered Act driver mutations.	('frame-shift', 'Var', (39, 50))	('LoF', 'NegReg', (112, 115))	('LoF', 'NegReg', (143, 146))	('missense mutations', 'Var', (90, 108))	('donor', 'Species', '9606', (59, 64))	('driver TFs', 'Gene', (116, 126))
187937	26792175	These were merged with LoF and Act driver mutations, respectively, to produce the final matrices of samples with driver alterations of each driver TF in each tumor type.	('tumor', 'Disease', (158, 163))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('alterations', 'Var', (120, 131))	('mutations', 'Var', (42, 51))
187938	26792175	The expression of each target in the samples bearing driver alterations of the TF and unaltered samples were then compared using a Mann-Whitney test.	('TF a', 'Gene', (79, 83))	('TF a', 'Gene', '2152', (79, 83))	('alterations', 'Var', (60, 71))
187939	26792175	The aim of this differential expression test is - regardless of the high overlap observed between the targets of TFs and the top-ranking misregulated genes in response to their knock-down - to identify the subset of targets of each TF which are actually misregulated upon alterations of the TF within the context of the tumor type under analysis.	('tumor', 'Disease', (320, 325))	('tumor', 'Disease', 'MESH:D009369', (320, 325))	('alterations', 'Var', (272, 283))	('tumor', 'Phenotype', 'HP:0002664', (320, 325))
187943	26792175	To compare the effect of truncating and missense mutations of TP53 on the expression of its targets, I pooled the absolute fold-change values of all targets in the comparison between samples bearing truncating mutations - or missense-mutations - of the TF and non-altered samples.	('missense mutations', 'Var', (40, 58))	('missense-mutations -', 'Var', (225, 245))	('TP53', 'Gene', '7157', (62, 66))	('truncating mutations -', 'Var', (199, 221))	('TF a', 'Gene', '2152', (253, 257))	('TP53', 'Gene', (62, 66))	('TF a', 'Gene', (253, 257))
187945	26792175	For each TF-partner pair I assessed whether the alterations of the partner cause tumorigenesis through the same pathway as alterations in the connected TF.	('alterations', 'Var', (48, 59))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumor', 'Disease', (81, 86))
187946	26792175	As a proxy to the strength of the link between partner and TF in their causing tumorigenesis through alteration of the same cellular pathway, I computed the corrected (Benjamini-Hochberg) Fisher's q-value of the overlap between the significant targets of alterations of the TF and the significant targets of the alteration of the partner.	('tumor', 'Disease', (79, 84))	('TF a', 'Gene', '2152', (274, 278))	('TF a', 'Gene', (274, 278))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('alterations', 'Var', (255, 266))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
187953	26792175	We had previously carried out an exhaustive analysis of whole-exome mutations of 48 cohorts of tumors obtained from 28 different malignancies (approximately 7,000 tumors in total) employing three computational methods that exploit complementary signals of positive selection and identified 459 mutational driver genes.	('000 tumors', 'Disease', (159, 169))	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('malignancies', 'Disease', 'MESH:D009369', (129, 141))	('malignancies', 'Disease', (129, 141))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('tumors', 'Disease', (163, 169))	('tumors', 'Disease', 'MESH:D009369', (163, 169))	('tumors', 'Phenotype', 'HP:0002664', (163, 169))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('000 tumors', 'Disease', 'MESH:D009369', (159, 169))	('mutations', 'Var', (68, 77))	('tumors', 'Disease', (95, 101))
187957	26792175	For example, an activating driver TF (such as MYC) is expected to be more active than normal when affected by gain-of-function mutations or amplifications, and the opposite for a LoF TF driver, such as TP53 when affected by LoF mutations or deletions.	('TP53', 'Gene', (202, 206))	('active', 'MPA', (74, 80))	('more active than normal', 'Phenotype', 'HP:0000752', (69, 92))	('MYC', 'Gene', (46, 49))	('gain-of-function', 'PosReg', (110, 126))	('mutations', 'Var', (127, 136))	('MYC', 'Gene', '4609', (46, 49))	('activating', 'PosReg', (16, 26))	('TP53', 'Gene', '7157', (202, 206))
187961	26792175	For instance, while TP53 is significantly enriched for mutations in ovarian, colorectal, head and neck, or lung cancers, it is mutated below expectations - set by other driver TFs - in thyhroid and prostate carcinomas, as well as in melanomas and medulloblastomas.	('lung cancers', 'Disease', (107, 119))	('melanoma', 'Phenotype', 'HP:0002861', (233, 241))	('lung cancer', 'Phenotype', 'HP:0100526', (107, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('melanomas', 'Disease', 'MESH:D008545', (233, 242))	('ovarian', 'Disease', (68, 75))	('lung cancers', 'Phenotype', 'HP:0100526', (107, 119))	('TP53', 'Gene', (20, 24))	('medulloblastomas', 'Disease', (247, 263))	('cancers', 'Phenotype', 'HP:0002664', (112, 119))	('melanomas', 'Disease', (233, 242))	('carcinoma', 'Phenotype', 'HP:0030731', (207, 216))	('carcinomas', 'Phenotype', 'HP:0030731', (207, 217))	('thyhroid and prostate carcinomas', 'Disease', 'MESH:D011472', (185, 217))	('mutations', 'Var', (55, 64))	('mutated', 'Var', (127, 134))	('colorectal', 'Disease', (77, 87))	('melanomas', 'Phenotype', 'HP:0002861', (233, 242))	('TP53', 'Gene', '7157', (20, 24))	('medulloblastomas', 'Disease', 'MESH:D008527', (247, 263))	('lung cancers', 'Disease', 'MESH:D008175', (107, 119))
187966	26792175	In the case of somatic mutations detected across tumor samples, only those with consequence-types deemed to affect the protein sequence (that is, missense, stop-gain, stop-loss, splice-donor, splice-acceptor, frameshift) were included.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('splice-donor', 'MPA', (178, 190))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('stop-gain', 'MPA', (156, 165))	('tumor', 'Disease', (49, 54))	('splice-acceptor', 'MPA', (192, 207))	('missense', 'Var', (146, 154))	('frameshift', 'Var', (209, 219))	('donor', 'Species', '9606', (185, 190))	('stop-loss', 'MPA', (167, 176))
187967	26792175	In the case of the variants detected across non-cancer genomes of individuals, I included SNVs and short indels with all consequence types, but only those with allele frequency above 10-4, which ensures that they are likely to be common polymorphisms in the human population.	('human', 'Species', '9606', (258, 263))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('variants', 'Var', (19, 27))
187968	26792175	This analysis therefore aimed to rank higher domains with the greatest differences between the accumulation of somatic mutations in tumors that signals them as subjects of positive selection and the number of common germline variants that entail their baseline tolerance to variation.	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('tumors', 'Disease', (132, 138))	('mutations', 'Var', (119, 128))	('tumors', 'Disease', 'MESH:D009369', (132, 138))
187969	26792175	I thus computed the fraction of mutations occurring in every domain of a TF out of the total number of mutations observed in the gene across tumors and, similarly their share of common germline variants.	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('tumors', 'Disease', 'MESH:D009369', (141, 147))	('tumors', 'Disease', (141, 147))	('mutations', 'Var', (32, 41))
187970	26792175	All domains of TP53 (annotated at the right of panel A) accumulate a relatively low fraction of the variants observed in the gene, except the p53 tumor suppressor family, which encompasses most of the protein sequence.	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('p53', 'Gene', '7157', (142, 145))	('p53', 'Gene', (142, 145))	('variants', 'Var', (100, 108))	('tumor', 'Disease', (146, 151))	('TP53', 'Gene', '7157', (15, 19))	('TP53', 'Gene', (15, 19))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
187971	26792175	Whereas somatic mutations impairing the activity of TP53 tend to accumulate in the DNA-binding domain and the tetramerization domain of the TF, tolerated germline variants concentrate in the N-terminal and C-terminal portions of the protein, outside its most important structural and functional features.	('TP53', 'Gene', '7157', (52, 56))	('tetramerization', 'MPA', (110, 125))	('mutations', 'Var', (16, 25))	('TP53', 'Gene', (52, 56))	('variants', 'Var', (163, 171))	('activity', 'MPA', (40, 48))	('impairing', 'NegReg', (26, 35))
187974	26792175	Although many of the domains that appear at the top of the list of relative enrichment for somatic mutations correspond to the portions of the TF that directly bind the DNA (p53, DNA-binding domain, winged helix-turn-helix, zinc finger, homeodomain, and so on), other types of TFs domains are also tumorigenic.	('tumor', 'Disease', (298, 303))	('bind', 'Interaction', (160, 164))	('mutations', 'Var', (99, 108))	('p53', 'Gene', (174, 177))	('tumor', 'Disease', 'MESH:D009369', (298, 303))	('tumor', 'Phenotype', 'HP:0002664', (298, 303))	('p53', 'Gene', '7157', (174, 177))
187976	26792175	The rationale of this study - the hypothesis that driver alterations of TFs result in misregulation of their targets - assumes that driver TFs are expressed and carry out their functions in the tumor types where they are identified as drivers and where I probe this misregulation.	('misregulation', 'MPA', (86, 99))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('TFs', 'Gene', (72, 75))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('alterations', 'Var', (57, 68))	('tumor', 'Disease', (194, 199))	('result', 'Reg', (76, 82))
187977	26792175	The list of drivers employed in this study in each tumor type (and by extension the driver TFs) are known to be expressed in the tumors of the cohort where they act as drivers, because part of the process of detection of mutational drivers excludes non-expressed genes.	('tumors', 'Disease', (129, 135))	('tumors', 'Disease', 'MESH:D009369', (129, 135))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('tumor', 'Disease', (51, 56))	('mutational', 'Var', (221, 231))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('tumor', 'Disease', (129, 134))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
187979	26792175	(Note that in the latter case, the inactivation in tumors bearing LoF alterations presupposes that they are active in the other tumors of the cohort).	('alterations', 'Var', (70, 81))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumors', 'Disease', 'MESH:D009369', (51, 57))	('tumors', 'Disease', (51, 57))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('tumors', 'Disease', 'MESH:D009369', (128, 134))	('tumors', 'Disease', (128, 134))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))
187981	26792175	Finally, I compared the expression level of the target of each driver TF in the tumor samples bearing driver alterations with that of the samples where it was unaltered.	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('alterations', 'Var', (109, 120))	('tumor', 'Disease', (80, 85))
187987	26792175	S100A2, which also appears upregulated in samples bearing driver alterations of TP53 (Fig.	('alterations', 'Var', (65, 76))	('TP53', 'Gene', '7157', (80, 84))	('TP53', 'Gene', (80, 84))	('S100A2', 'Gene', '6273', (0, 6))	('S100A2', 'Gene', (0, 6))	('upregulated', 'PosReg', (27, 38))
187990	26792175	In both cases, truncating mutations of TP53 appear to cause larger upregulation of the targets, supporting the notion that they possess a higher driver potential, with some missense mutations actually acting as passengers.	('truncating mutations', 'Var', (15, 35))	('upregulation', 'PosReg', (67, 79))	('TP53', 'Gene', '7157', (39, 43))	('TP53', 'Gene', (39, 43))	('missense mutations', 'Var', (173, 191))
187991	26792175	Nevertheless, the pooled analysis of the misregulation of all targets of TP53 across all tumor types reveals that although in most cases truncating mutation of the TF do affect more the expression of its targets than missense mutations, the differences are clearly significant only in breast tumors, glioblastomas, and low grade gliomas (Additional file 1: Figure S4).	('TP53', 'Gene', '7157', (73, 77))	('tumors', 'Phenotype', 'HP:0002664', (292, 298))	('gliomas', 'Disease', (329, 336))	('glioblastoma', 'Phenotype', 'HP:0012174', (300, 312))	('tumor', 'Phenotype', 'HP:0002664', (292, 297))	('glioblastomas', 'Disease', (300, 313))	('gliomas', 'Disease', 'MESH:D005910', (329, 336))	('glioblastomas', 'Disease', 'MESH:D005909', (300, 313))	('tumor', 'Disease', (89, 94))	('glioma', 'Phenotype', 'HP:0009733', (329, 335))	('breast tumors', 'Disease', (285, 298))	('breast tumors', 'Disease', 'MESH:D001943', (285, 298))	('TP53', 'Gene', (73, 77))	('affect', 'Reg', (170, 176))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('gliomas', 'Phenotype', 'HP:0009733', (329, 336))	('breast tumors', 'Phenotype', 'HP:0100013', (285, 298))	('tumor', 'Disease', (292, 297))	('truncating mutation', 'Var', (137, 156))	('glioblastomas', 'Phenotype', 'HP:0012174', (300, 313))	('expression', 'MPA', (186, 196))	('tumor', 'Disease', 'MESH:D009369', (292, 297))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('significant', 'Reg', (265, 276))
187994	26792175	Finally, panels F and G illustrate the misregulation of TCF7L1 and DNAJC12, two significant targets of GATA3 linked to tumorigenesis.	('tumor', 'Disease', (119, 124))	('GATA3', 'Gene', '2625', (103, 108))	('DNAJC12', 'Gene', (67, 74))	('TCF7L1', 'Gene', '83439', (56, 62))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('DNAJC12', 'Gene', '56521', (67, 74))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('misregulation', 'Var', (39, 52))	('GATA3', 'Gene', (103, 108))	('TCF7L1', 'Gene', (56, 62))
187999	26792175	Nineteen genes are significantly over-expressed in samples of five tumor types driven by somatic alterations of NFE2L2.	('NFE2L2', 'Gene', (112, 118))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('alterations', 'Var', (97, 108))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('over-expressed', 'PosReg', (33, 47))	('tumor', 'Disease', (67, 72))	('NFE2L2', 'Gene', '4780', (112, 118))
188001	26792175	NFE2L2 thus probably causes the shift of the cellular metabolic program to promote tumorigenesis in cancer types driven by its alterations.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('promote', 'PosReg', (75, 82))	('tumor', 'Disease', (83, 88))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('NFE2L2', 'Gene', '4780', (0, 6))	('NFE2L2', 'Gene', (0, 6))	('alterations', 'Var', (127, 138))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
188002	26792175	This implies that tumors driven by alterations of NFE2L2, regardless of their tissue of origin are much more similar to each other than tumors driven by alterations of other driver TFs.	('tumors', 'Disease', (136, 142))	('NFE2L2', 'Gene', (50, 56))	('tumors', 'Disease', 'MESH:D009369', (136, 142))	('alterations', 'Var', (35, 46))	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('tumors', 'Disease', (18, 24))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('NFE2L2', 'Gene', '4780', (50, 56))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
188009	26792175	I then repeated the process of identifying significantly misregulated genes - within the set of targets of the TF - between the group of tumor samples bearing driver alterations of the partner and the tumors where neither the partner nor the driver TF were altered.	('tumor', 'Disease', (137, 142))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('alterations', 'Var', (166, 177))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('tumors', 'Disease', 'MESH:D009369', (201, 207))	('tumors', 'Disease', (201, 207))	('tumor', 'Disease', (201, 206))	('tumors', 'Phenotype', 'HP:0002664', (201, 207))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
188010	26792175	Next, I computed the significance of the overlap between the set of upregulated genes upon driver alteration of the TF and the set of upregulated genes upon driver alteration of the partner, and the same for the sets of downregulated genes.	('alteration', 'Var', (98, 108))	('upregulated', 'PosReg', (68, 79))	('TF a', 'Gene', (116, 120))	('TF a', 'Gene', '2152', (116, 120))
188012	26792175	I call these connections TF-partner 'driver circuits' - driver circuits in this paper, for simplicity - and understand them as common pathways towards tumorigenesis, with driver alterations of their two members resulting in convergent misregulation of the same cellular processes.	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('misregulation', 'MPA', (235, 248))	('tumor', 'Disease', (151, 156))	('alterations', 'Var', (178, 189))	('resulting in', 'Reg', (211, 223))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
188022	26792175	Driver alterations of KEAP1 in LUSC tumors result in the upregulation of the expression of a set of genes that very significantly (q-value = 1.42 x 10-26) overlap the upregulated targets of NFE2L2 (Fig.	('KEAP1', 'Gene', (22, 27))	('expression', 'MPA', (77, 87))	('tumors', 'Disease', 'MESH:D009369', (36, 42))	('upregulation', 'PosReg', (57, 69))	('NFE2L2', 'Gene', '4780', (190, 196))	('KEAP1', 'Gene', '9817', (22, 27))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumors', 'Disease', (36, 42))	('alterations', 'Var', (7, 18))	('NFE2L2', 'Gene', (190, 196))
188023	26792175	5e), corroborating that LoF mutations in the former cause tumorigenesis in lung squamous cells through the same pathway as gain-of-function mutations or amplifications of the latter.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('gain-of-function', 'PosReg', (123, 139))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('LoF', 'NegReg', (24, 27))	('mutations', 'Var', (28, 37))
188025	26792175	While the partnership in tumorigenesis of driver alterations of KEAP1 and NFE2L2 appears very prominent in LUSC tumors, CUL3 seems a more outstanding partner in head and neck squamous carcinomas (Fig.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('carcinoma', 'Phenotype', 'HP:0030731', (184, 193))	('CUL3', 'Gene', '8452', (120, 124))	('carcinomas', 'Phenotype', 'HP:0030731', (184, 194))	('neck squamous carcinomas', 'Disease', (170, 194))	('tumors', 'Disease', 'MESH:D009369', (112, 118))	('tumor', 'Disease', (112, 117))	('NFE2L2', 'Gene', '4780', (74, 80))	('KEAP1', 'Gene', '9817', (64, 69))	('alterations', 'Var', (49, 60))	('KEAP1', 'Gene', (64, 69))	('CUL3', 'Gene', (120, 124))	('neck squamous carcinomas', 'Disease', 'MESH:D000077195', (170, 194))	('tumor', 'Disease', (25, 30))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('NFE2L2', 'Gene', (74, 80))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumors', 'Disease', (112, 118))
188026	26792175	This work presents the first systematic characterization of the repertoire of mutational driver transcription factors in 28 human malignancies, as well as the collection of their targets most likely involved in tumorigenesis in 15 of these cancer types.	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('cancer', 'Disease', (240, 246))	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('malignancies', 'Disease', (130, 142))	('human', 'Species', '9606', (124, 129))	('cancer', 'Disease', 'MESH:D009369', (240, 246))	('tumor', 'Disease', (211, 216))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('mutational', 'Var', (78, 88))	('malignancies', 'Disease', 'MESH:D009369', (130, 142))
188033	26792175	Although previous works have identified cliques of drivers altered in a mutually exclusive manner across tumor samples - under the same rationale that this pattern signals convergent roads to tumorigenesis - no study to date has directly tested the hypothesis that alterations in connected drivers actually result in the misregulation of similar sets of targets.	('alterations', 'Var', (265, 276))	('tumor', 'Disease', (192, 197))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('misregulation', 'MPA', (321, 334))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('tumor', 'Disease', (105, 110))	('result in', 'Reg', (307, 316))
188036	26792175	It is reasonable to expect that tumors bearing alterations in driver genes connected in a circuit will follow similar evolution patterns, resulting in similar outcomes and exhibit similar response to a given therapeutic strategy.	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumors', 'Disease', (32, 38))	('alterations', 'Var', (47, 58))	('tumors', 'Disease', 'MESH:D009369', (32, 38))
188037	26792175	These circuits may thus represent a way of choosing therapies to indirectly target driver alterations in a tumor.	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('alterations', 'Var', (90, 101))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))
188040	26792175	With respect to the overlaps between the sets of significant targets of a TF in different tumor types, one can imagine the development of an 'index of similarity' between tumor types of different origin driven by alterations of the same gene, based on the overlap of their oncogenic signatures.	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('tumor', 'Disease', (90, 95))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('alterations', 'Var', (213, 224))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', (171, 176))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
188042	26792175	These driver circuits may provide clues to choosing therapies to indirectly target driver alterations in a tumor.	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('alterations', 'Var', (90, 101))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))
188083	24523806	Postoperative radiotherapy was effective in decreasing locoregional failure in patients with close surgical margins, tumor thicker than 10 mm, high-grade tumors, positive node, and bone invasion.	('high-grade', 'Var', (143, 153))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumors', 'Disease', (154, 160))	('locoregional failure', 'CPA', (55, 75))	('tumors', 'Disease', 'MESH:D009369', (154, 160))	('bone invasion', 'CPA', (181, 194))	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('tumor', 'Disease', (117, 122))	('decreasing', 'NegReg', (44, 54))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('patients', 'Species', '9606', (79, 87))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('tumor', 'Disease', (154, 159))
188140	24279398	For instance, EBV positivity in STAD has been reported to be higher in males, young subjects, non-antral subsites, diffuse-type histology, and in studies from the Americas.	('higher', 'PosReg', (61, 67))	('positivity', 'Var', (18, 28))	('EBV', 'Species', '10376', (14, 17))	('EBV', 'Gene', (14, 17))
188146	24279398	KSHV causes Kaposi's sarcoma and, to our knowledge, has not yet been associated with gastric adenocarcinomas.	("Kaposi's sarcoma", 'Phenotype', 'HP:0100726', (12, 28))	('KSHV', 'Var', (0, 4))	('gastric adenocarcinomas', 'Disease', 'MESH:D013274', (85, 108))	('sarcoma', 'Phenotype', 'HP:0100242', (21, 28))	('causes', 'Reg', (5, 11))	("Kaposi's sarcoma", 'Disease', 'MESH:D012514', (12, 28))	("Kaposi's sarcoma", 'Disease', (12, 28))	('gastric adenocarcinomas', 'Disease', (85, 108))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('carcinomas', 'Phenotype', 'HP:0030731', (98, 108))
188221	32948832	miR-34c-3p targets CDK1 a synthetic lethality partner of KRAS in non-small cell lung cancer Lung cancer is still the leading cause of death by cancer worldwide despite advances both in its detection and therapy.	('small cell lung cancer', 'Phenotype', 'HP:0030357', (69, 91))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('miR-34c-3p', 'Var', (0, 10))	('CDK1', 'Gene', (19, 23))	('cancer', 'Disease', (97, 103))	('CDK1', 'Gene', '983', (19, 23))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('lung cancer', 'Phenotype', 'HP:0100526', (80, 91))	('cancer', 'Disease', (143, 149))	('KRAS', 'Gene', '3845', (57, 61))	('miR-34c', 'Chemical', '-', (0, 7))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (65, 91))	('Lung cancer', 'Disease', 'MESH:D008175', (92, 103))	('cancer', 'Disease', (85, 91))	('KRAS', 'Gene', (57, 61))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('cancer', 'Disease', 'MESH:D009369', (97, 103))	('Lung cancer', 'Disease', (92, 103))	('cancer', 'Disease', 'MESH:D009369', (143, 149))
188222	32948832	Among them, KRAS mutations represent the most frequent oncogene aberrations in non-small cell lung cancer (NSCLC) patients with a negative prognostic impact, but effective therapies targeting KRAS are not well characterized yet.	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (79, 105))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (83, 105))	('NSCLC', 'Disease', (107, 112))	('NSCLC', 'Disease', 'MESH:D002289', (107, 112))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (79, 105))	('KRAS', 'Gene', (12, 16))	('KRAS', 'Gene', (192, 196))	('KRAS', 'Gene', '3845', (12, 16))	('non-small cell lung cancer', 'Disease', (79, 105))	('lung cancer', 'Phenotype', 'HP:0100526', (94, 105))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('patients', 'Species', '9606', (114, 122))	('mutations', 'Var', (17, 26))	('KRAS', 'Gene', '3845', (192, 196))
188223	32948832	Here, we demonstrate that the microRNA miR-34c-3p is a positive prognostic factor in KRAS-mutated NSCLC patients.	('miR-34c-3p', 'Chemical', '-', (39, 49))	('microRNA miR-34c-3p', 'Var', (30, 49))	('patients', 'Species', '9606', (104, 112))	('NSCLC', 'Disease', (98, 103))	('KRAS', 'Gene', (85, 89))	('KRAS', 'Gene', '3845', (85, 89))	('NSCLC', 'Disease', 'MESH:D002289', (98, 103))
188224	32948832	Firstly, looking at the TGCA dataset, we found that high miR-34c-3p expression correlated with longer survival of KRAS-mutated NSCLC patients.	('NSCLC', 'Disease', (127, 132))	('longer', 'PosReg', (95, 101))	('miR-34c-3p', 'Chemical', '-', (57, 67))	('NSCLC', 'Disease', 'MESH:D002289', (127, 132))	('patients', 'Species', '9606', (133, 141))	('KRAS', 'Gene', (114, 118))	('KRAS', 'Gene', '3845', (114, 118))	('high miR-34c-3p expression', 'Var', (52, 78))
188225	32948832	In vitro assays on immortalized and patient-derived primary NSCLC cells revealed that miR-34c-3p overexpression increased apoptosis and lowered proliferation rate in KRASmut cells.	('lowered', 'NegReg', (136, 143))	('apoptosis', 'CPA', (122, 131))	('KRAS', 'Gene', (166, 170))	('overexpression increased', 'PosReg', (97, 121))	('miR-34c-3p', 'Var', (86, 96))	('KRAS', 'Gene', '3845', (166, 170))	('miR-34c-3p', 'Chemical', '-', (86, 96))	('NSCLC', 'Disease', (60, 65))	('patient', 'Species', '9606', (36, 43))	('proliferation rate', 'CPA', (144, 162))	('NSCLC', 'Disease', 'MESH:D002289', (60, 65))
188226	32948832	Computational analysis and in vitro assays identified CDK1, one of the most promising lethal targets for KRAS-mutant cancer, as a target of miR-34c-3p.	('CDK1', 'Gene', '983', (54, 58))	('miR-34c-3p', 'Var', (140, 150))	('CDK1', 'Gene', (54, 58))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('miR-34c-3p', 'Chemical', '-', (140, 150))	('KRAS', 'Gene', (105, 109))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('KRAS', 'Gene', '3845', (105, 109))	('cancer', 'Disease', (117, 123))
188227	32948832	Moreover, the combination of CDK1 inhibition (mediated by RO3306) and miR-34c-3p overexpression resulted in an additive effect on the viability of KRASmut-expressing cells.	('CDK1', 'Gene', '983', (29, 33))	('CDK1', 'Gene', (29, 33))	('RO3306', 'Chemical', 'MESH:C512984', (58, 64))	('RO3306', 'Var', (58, 64))	('miR-34c-3p', 'Var', (70, 80))	('inhibition', 'NegReg', (34, 44))	('miR-34c-3p', 'Chemical', '-', (70, 80))	('KRAS', 'Gene', (147, 151))	('KRAS', 'Gene', '3845', (147, 151))
188228	32948832	Altogether, our findings demonstrate that miR-34c-3p is a novel biomarker that may allow tailored treatment for KRAS-mutated NSCLC patients.	('patients', 'Species', '9606', (131, 139))	('NSCLC', 'Disease', (125, 130))	('miR-34c-3p', 'Var', (42, 52))	('NSCLC', 'Disease', 'MESH:D002289', (125, 130))	('miR-34c-3p', 'Chemical', '-', (42, 52))	('KRAS', 'Gene', (112, 116))	('KRAS', 'Gene', '3845', (112, 116))
188233	32948832	Somatic KRAS mutations are prevalent in many cancers, such as colorectal and pancreatic cancer, and leukaemia.	('leukaemia', 'Disease', 'MESH:D007938', (100, 109))	('leukaemia', 'Disease', (100, 109))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (77, 94))	('KRAS', 'Gene', (8, 12))	('KRAS', 'Gene', '3845', (8, 12))	('cancers', 'Disease', 'MESH:D009369', (45, 52))	('cancers', 'Phenotype', 'HP:0002664', (45, 52))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('colorectal and pancreatic cancer', 'Disease', 'MESH:D015179', (62, 94))	('mutations', 'Var', (13, 22))	('cancers', 'Disease', (45, 52))	('prevalent', 'Reg', (27, 36))
188234	32948832	In NSCLC, activating mutations are generally limited to adenocarcinoma and are almost always mutually exclusive of EGFR and BRAF mutations.	('NSCLC', 'Disease', (3, 8))	('NSCLC', 'Disease', 'MESH:D002289', (3, 8))	('EGFR', 'Gene', '1956', (115, 119))	('BRAF', 'Gene', '673', (124, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('adenocarcinoma', 'Disease', (56, 70))	('EGFR', 'Gene', (115, 119))	('adenocarcinoma', 'Disease', 'MESH:D000230', (56, 70))	('BRAF', 'Gene', (124, 128))	('mutations', 'Var', (21, 30))
188235	32948832	In contrast to EGFR mutations, KRAS mutations are more frequent in males and smokers and are also less commonly identified in some NSCLC subtypes, such as squamous carcinomas and large cell carcinoma.	('large cell carcinoma', 'Phenotype', 'HP:0030360', (179, 199))	('squamous carcinomas', 'Disease', (155, 174))	('KRAS', 'Gene', (31, 35))	('carcinoma', 'Disease', (164, 173))	('squamous carcinomas', 'Disease', 'MESH:D002294', (155, 174))	('carcinoma', 'Phenotype', 'HP:0030731', (190, 199))	('NSCLC', 'Disease', (131, 136))	('KRAS', 'Gene', '3845', (31, 35))	('mutations', 'Var', (36, 45))	('NSCLC', 'Disease', 'MESH:D002289', (131, 136))	('EGFR', 'Gene', '1956', (15, 19))	('carcinoma', 'Disease', 'MESH:D009369', (164, 173))	('carcinoma', 'Disease', (190, 199))	('EGFR', 'Gene', (15, 19))	('carcinoma', 'Phenotype', 'HP:0030731', (164, 173))	('carcinoma', 'Disease', 'MESH:D009369', (190, 199))	('frequent', 'Reg', (55, 63))	('carcinomas', 'Phenotype', 'HP:0030731', (164, 174))
188236	32948832	The mutational status of KRAS appears, in general, to be associated with poor survival, prognosis, and response to most systemic therapies.	('mutational status', 'Var', (4, 21))	('poor', 'NegReg', (73, 77))	('KRAS', 'Gene', (25, 29))	('associated', 'Reg', (57, 67))	('KRAS', 'Gene', '3845', (25, 29))
188238	32948832	Despite KRAS mutation being one of the best candidates for the development of tailored anticancer molecules, until now all attempts have been unsuccessful.	('mutation', 'Var', (13, 21))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('KRAS', 'Gene', (8, 12))	('KRAS', 'Gene', '3845', (8, 12))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))
188243	32948832	In particular, low expression of the miR-34 family correlates with poor prognosis in NSCLCs, and miR-34a has just entered a phase I clinical trial in NSCLC patients with mutated KRAS.	('NSCLC', 'Disease', (85, 90))	('KRAS', 'Gene', (178, 182))	('NSCLC', 'Disease', 'MESH:D002289', (150, 155))	('expression', 'MPA', (19, 29))	('NSCLCs', 'Disease', 'MESH:D002289', (85, 91))	('miR-34a', 'Gene', '407040', (97, 104))	('NSCLC', 'Disease', 'MESH:D002289', (85, 90))	('KRAS', 'Gene', '3845', (178, 182))	('patients', 'Species', '9606', (156, 164))	('miR-34', 'Gene', (97, 103))	('miR-34', 'Gene', (37, 43))	('miR-34a', 'Gene', (97, 104))	('mutated', 'Var', (170, 177))	('miR-34', 'Gene', '407040', (97, 103))	('miR-34', 'Gene', '407040', (37, 43))	('NSCLCs', 'Disease', (85, 91))	('NSCLC', 'Disease', (150, 155))	('low', 'NegReg', (15, 18))
188245	32948832	Here, we show that miR-34c-3p expression correlates with better overall survival in NSCLC patients bearing KRAS mutations vs. no mutation.	('KRAS', 'Gene', (107, 111))	('miR-34c-3p', 'Chemical', '-', (19, 29))	('KRAS', 'Gene', '3845', (107, 111))	('NSCLC', 'Disease', (84, 89))	('overall survival', 'MPA', (64, 80))	('mutations', 'Var', (112, 121))	('NSCLC', 'Disease', 'MESH:D002289', (84, 89))	('better', 'PosReg', (57, 63))	('patients', 'Species', '9606', (90, 98))	('miR-34c-3p expression', 'Var', (19, 40))
188246	32948832	Moreover, in KRAS-mutated lung cancer cells, miR-34c-3p reduces cell proliferation and increases apoptosis to a greater extent compared to cells expressing wild-type RAS.	('KRAS', 'Gene', '3845', (13, 17))	('cell proliferation', 'CPA', (64, 82))	('increases', 'PosReg', (87, 96))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('lung cancer', 'Disease', 'MESH:D008175', (26, 37))	('reduces', 'NegReg', (56, 63))	('miR-34c-3p', 'Var', (45, 55))	('miR-34c-3p', 'Chemical', '-', (45, 55))	('KRAS', 'Gene', (13, 17))	('lung cancer', 'Disease', (26, 37))	('apoptosis', 'CPA', (97, 106))	('lung cancer', 'Phenotype', 'HP:0100526', (26, 37))
188247	32948832	In addition, for the first time, we show that miR-34c-3p targets CDK1, a synthetic lethality partner of the KRAS oncogene, and enhances the biological effects of RO3306, a CDK1 inhibitor.	('KRAS', 'Gene', (108, 112))	('KRAS', 'Gene', '3845', (108, 112))	('enhances', 'PosReg', (127, 135))	('targets', 'Reg', (57, 64))	('CDK1', 'Gene', (172, 176))	('miR-34c-3p', 'Var', (46, 56))	('CDK1', 'Gene', '983', (65, 69))	('CDK1', 'Gene', '983', (172, 176))	('CDK1', 'Gene', (65, 69))	('biological effects', 'MPA', (140, 158))	('RO3306', 'Chemical', 'MESH:C512984', (162, 168))	('miR-34c-3p', 'Chemical', '-', (46, 56))
188248	32948832	Finally, an aptamer-miR-34c-3p chimaera is able to specifically deliver miR-34c-3p to NSCLC cells and target CDK1.	('CDK1', 'Gene', (109, 113))	('CDK1', 'Gene', '983', (109, 113))	('NSCLC', 'Disease', (86, 91))	('miR-34c-3p', 'Chemical', '-', (20, 30))	('NSCLC', 'Disease', 'MESH:D002289', (86, 91))	('miR-34c-3p', 'Var', (72, 82))	('miR-34c-3p', 'Chemical', '-', (72, 82))
188253	32948832	Incidence of KRAS mutation in lung adenocarcinoma was frequent as already reported (Supplementary Table 1).	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (30, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (40, 49))	('mutation', 'Var', (18, 26))	('lung adenocarcinoma', 'Disease', (30, 49))	('KRAS', 'Gene', (13, 17))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (30, 49))	('KRAS', 'Gene', '3845', (13, 17))
188271	32948832	We analysed seven KRAS mutations in codon 12 (c.34G>A, p.Gly12Ser; c.35G>A, p.Gly12Asp; c.34G>C, p.Gly12Arg; c.34G>T, p.Gly12Cys; and c.35G>T, p.Gly12Val) and codon 13 (c.38G>A, p.Gly13Asp) of KRAS's exon 2,according to the assay design.	('c.35G>T', 'Mutation', 'rs121913529', (134, 141))	('p.Gly12Val', 'Mutation', 'rs121913529', (143, 153))	('c.34G>A', 'Var', (46, 53))	('KRAS', 'Gene', '3845', (193, 197))	('p.Gly13Asp', 'Mutation', 'rs112445441', (178, 188))	('p.Gly12Asp', 'Mutation', 'rs121913529', (76, 86))	('p.Gly12Arg', 'Mutation', 'rs121913530', (97, 107))	('c.34G>C', 'Var', (88, 95))	('c.34G>C', 'Mutation', 'rs121913530', (88, 95))	('KRAS', 'Gene', '3845', (18, 22))	('KRAS', 'Gene', (193, 197))	('c.34G>A', 'Mutation', 'rs121913530', (46, 53))	('p.Gly12Ser', 'Mutation', 'rs121913530', (55, 65))	('p.Gly12Cys', 'Mutation', 'rs121913530', (118, 128))	('KRAS', 'Gene', (18, 22))	('c.34G>T', 'Mutation', 'rs121913530', (109, 116))	('c.34G>T', 'Var', (109, 116))	('c.35G>A', 'Mutation', 'rs121913529', (67, 74))	('c.38G>A', 'Var', (169, 176))	('c.35G>A', 'Var', (67, 74))	('c.38G>A', 'Mutation', 'rs112445441', (169, 176))	('c.35G>T', 'Var', (134, 141))
188281	32948832	Putative binding sites for miR-34c-3p on the 3' UTR of CDK1 were predicted by Targetscan Version 7.2 software (http://www.targetscan.org).	('miR-34c-3p', 'Var', (27, 37))	('miR-34c-3p', 'Chemical', '-', (27, 37))	('binding', 'Interaction', (9, 16))	('CDK1', 'Gene', (55, 59))	('CDK1', 'Gene', '983', (55, 59))
188282	32948832	The identified region was cloned in pmiRglo plasmid (Promega) using the following primer: FW: 5'-CGCAAATTGTGGATTGCAACCCTTTAGTGATTTACGACCAGT-3'; RV: 5'-CTAGACTGGTCGTAAATCACTAAAGGGTTGCAATCCACAATTTGCGAGCT-3'.A549 and HCC827 cells (5000 cells per well) were seeded in a 96-well plate and co-transfected with 1 microg of 3'UTR CDK1 plasmid (and miR-34c-3p or miR-NC), using Lipofectamine 3000.	('CDK1', 'Gene', '983', (322, 326))	('CDK1', 'Gene', (322, 326))	('miR-34c-3p', 'Var', (340, 350))	('A549', 'CellLine', 'CVCL:0023', (205, 209))	('miR-34c-3p', 'Chemical', '-', (340, 350))	('HCC827', 'CellLine', 'CVCL:2063', (214, 220))
188290	32948832	Sequences of Gl21.T scrambled and Gl21.T-miR34c-3p have been reported before.	('miR34c', 'Gene', '407042', (41, 47))	('Gl21.T scrambled', 'Var', (13, 29))	('miR34c', 'Gene', (41, 47))
188297	32948832	We observed that in 15 paired LUADs with a KRAS mutation, the expression of miR-34c was downregulated vs. normal tissue (Fig.	('KRAS', 'Gene', '3845', (43, 47))	('miR-34c', 'Gene', (76, 83))	('expression', 'MPA', (62, 72))	('KRAS', 'Gene', (43, 47))	('mutation', 'Var', (48, 56))	('downregulated', 'NegReg', (88, 101))
188298	32948832	Moreover, we further interrogated the TGCA data base to assess miR-34c-3p and miR-34c-5p expression levels in LUAD/LUSC groups vs. matched, non-tumour counterparts in wild-type KRAS patients.	('miR-34c-5p', 'Chemical', '-', (78, 88))	('tumour', 'Phenotype', 'HP:0002664', (144, 150))	('tumour', 'Disease', 'MESH:D009369', (144, 150))	('miR-34c-5p', 'MPA', (78, 88))	('KRAS', 'Gene', (177, 181))	('tumour', 'Disease', (144, 150))	('miR-34c-3p', 'Var', (63, 73))	('miR-34c-3p', 'Chemical', '-', (63, 73))	('KRAS', 'Gene', '3845', (177, 181))	('patients', 'Species', '9606', (182, 190))
188299	32948832	Even if there were only 8 paired patients with data available for miR-34c-3p and miR-34c-5p, we observed a strong reduction of both miRNAs in tumour samples vs. matched, non-tumour samples (Supplementary Fig.	('tumour', 'Disease', (142, 148))	('tumour', 'Phenotype', 'HP:0002664', (174, 180))	('tumour', 'Disease', 'MESH:D009369', (174, 180))	('miR-34c-5p', 'Var', (81, 91))	('reduction', 'NegReg', (114, 123))	('patients', 'Species', '9606', (33, 41))	('miR-34c-3p', 'Var', (66, 76))	('tumour', 'Disease', (174, 180))	('tumour', 'Phenotype', 'HP:0002664', (142, 148))	('miR-34c-3p', 'Chemical', '-', (66, 76))	('miR-34c-5p', 'Chemical', '-', (81, 91))	('tumour', 'Disease', 'MESH:D009369', (142, 148))
188301	32948832	More interestingly, when stratifying KRAS-mutated patients into two groups on the basis of miR-34c expression (33 patients with miR-34chigh and 33 patients with miR-34clow), survival analysis indicated that high expression was associated with longer survival at 5 years (Fig.	('high', 'Var', (207, 211))	('longer', 'PosReg', (243, 249))	('patients', 'Species', '9606', (50, 58))	('KRAS', 'Gene', (37, 41))	('patients', 'Species', '9606', (147, 155))	('miR-34chigh', 'Var', (128, 139))	('patients', 'Species', '9606', (114, 122))	('KRAS', 'Gene', '3845', (37, 41))
188303	32948832	We then investigated by different means the mechanisms underlying the higher survival rate of miR-34c-3phigh KRAS-mutated patients.	('KRAS', 'Gene', (109, 113))	('miR-34c-3phigh', 'Var', (94, 108))	('patients', 'Species', '9606', (122, 130))	('KRAS', 'Gene', '3845', (109, 113))	('higher', 'PosReg', (70, 76))	('miR-34c-3p', 'Chemical', '-', (94, 104))
188307	32948832	Our previous data on the KRAS-mutated cell lines A549 and CALU-1 suggested that miR-34c-3p reduces cell proliferation.	('cell proliferation', 'CPA', (99, 117))	('miR-34c-3p', 'Chemical', '-', (80, 90))	('A549', 'CellLine', 'CVCL:0023', (49, 53))	('reduces', 'NegReg', (91, 98))	('miR-34c-3p', 'Var', (80, 90))	('KRAS', 'Gene', (25, 29))	('KRAS', 'Gene', '3845', (25, 29))
188309	32948832	To further assess the role of miR-34c-3p and KRAS signalling, primary cell lines (PT#13, PT#2) and HCC827 cells were co-transfected with KRASmut and miR-34c-3p, and cell viability assessed.	('KRAS', 'Gene', '3845', (45, 49))	('miR-34c-3p', 'Chemical', '-', (30, 40))	('miR-34c-3p', 'Var', (149, 159))	('KRAS', 'Gene', (137, 141))	('miR-34c-3p', 'Chemical', '-', (149, 159))	('KRAS', 'Gene', '3845', (137, 141))	('KRAS', 'Gene', (45, 49))	('HCC827', 'CellLine', 'CVCL:2063', (99, 105))
188310	32948832	2b, c, miR-34c-3p decreased viability also of KRASmutcells.	('decreased', 'NegReg', (18, 27))	('KRAS', 'Gene', (46, 50))	('viability', 'CPA', (28, 37))	('miR-34c-3p', 'Var', (7, 17))	('KRAS', 'Gene', '3845', (46, 50))	('miR-34c-3p', 'Chemical', '-', (7, 17))
188312	32948832	These results confirmed that miR-34c-3p behaves as a tumour suppressor in NSCLC cells and can overcome KRAS-mutant-induced oncogenesis.	('KRAS', 'Gene', (103, 107))	('KRAS', 'Gene', '3845', (103, 107))	('oncogenesis', 'CPA', (123, 134))	('tumour', 'Disease', (53, 59))	('NSCLC', 'Disease', (74, 79))	('overcome', 'PosReg', (94, 102))	('tumour', 'Phenotype', 'HP:0002664', (53, 59))	('miR-34c-3p', 'Var', (29, 39))	('NSCLC', 'Disease', 'MESH:D002289', (74, 79))	('tumour', 'Disease', 'MESH:D009369', (53, 59))	('miR-34c-3p', 'Chemical', '-', (29, 39))
188314	32948832	We analysed apoptosis activation in HCC827 cell lines upon overexpression of miR-34c-3p and KRASmut.	('miR-34c-3p', 'Var', (77, 87))	('miR-34c-3p', 'Chemical', '-', (77, 87))	('KRAS', 'Gene', (92, 96))	('overexpression', 'PosReg', (59, 73))	('KRAS', 'Gene', '3845', (92, 96))	('HCC827', 'CellLine', 'CVCL:2063', (36, 42))	('apoptosis', 'CPA', (12, 21))
188316	32948832	3a) revealed that the apoptotic rate was significantly increased in cells transfected with miR-34c-3p vs. controls.	('miR-34c-3p', 'Var', (91, 101))	('increased', 'PosReg', (55, 64))	('apoptotic rate', 'CPA', (22, 36))	('miR-34c-3p', 'Chemical', '-', (91, 101))
188317	32948832	Moreover, statistically significant increases in Annexin V+ and PI + apoptotic cells were observed in HCC827 cells expressing miR-34c-3p and KRASmut(Fig.	('miR-34c-3p', 'Var', (126, 136))	('KRAS', 'Gene', (141, 145))	('HCC827', 'CellLine', 'CVCL:2063', (102, 108))	('KRAS', 'Gene', '3845', (141, 145))	('miR-34c-3p', 'Chemical', '-', (126, 136))	('Annexin V', 'Gene', '308', (49, 58))	('Annexin V', 'Gene', (49, 58))	('increases', 'PosReg', (36, 45))	('PI + apoptotic cells', 'CPA', (64, 84))
188318	32948832	The same effect was observed for PT#18 primary cell lines co-transfected with KRASmut and miR-34c-3p (Fig.	('miR-34c-3p', 'Chemical', '-', (90, 100))	('KRAS', 'Gene', '3845', (78, 82))	('miR-34c-3p', 'Var', (90, 100))	('KRAS', 'Gene', (78, 82))
188320	32948832	In HCC827 and A549 continuous cell lines, and in two patient-derived cell lines (PT#2 and PT#13), caspase-3 activity was higher in the KRASmut- and miR-34c-3p-transfected cells (Fig.	('miR-34c-3p-transfected', 'Var', (148, 170))	('activity', 'MPA', (108, 116))	('A549', 'CellLine', 'CVCL:0023', (14, 18))	('HCC827', 'CellLine', 'CVCL:2063', (3, 9))	('caspase-3', 'Gene', (98, 107))	('KRAS', 'Gene', (135, 139))	('KRAS', 'Gene', '3845', (135, 139))	('higher', 'PosReg', (121, 127))	('caspase-3', 'Gene', '836', (98, 107))	('miR-34c-3p', 'Chemical', '-', (148, 158))	('patient', 'Species', '9606', (53, 60))
188322	32948832	Conversely, anti-miR-34c transfection reduced caspase 3/7 activity, as assessed by the caspase-Glo3/7 assay (Fig.	('caspase 3/7', 'Gene', '836;840', (46, 57))	('activity', 'MPA', (58, 66))	('reduced', 'NegReg', (38, 45))	('caspase 3/7', 'Gene', (46, 57))	('transfection', 'Var', (25, 37))	('anti-miR-34c transfection', 'Var', (12, 37))
188325	32948832	We identified a putative miR-34c-3p binding site on the 3' UTR of CDK1 (Fig.	('miR-34c-3p', 'Var', (25, 35))	('miR-34c-3p', 'Chemical', '-', (25, 35))	('CDK1', 'Gene', (66, 70))	('CDK1', 'Gene', '983', (66, 70))
188326	32948832	5a), recently reported to be involved in a synthetic lethality pathway of KRAS mutations.	('KRAS', 'Gene', (74, 78))	('KRAS', 'Gene', '3845', (74, 78))	('mutations', 'Var', (79, 88))
188327	32948832	To validate whether miR-34c-3p directly binds to the 3' UTR of CDK1 mRNA, a dual luciferase reporter assay was performed.	('miR-34c-3p', 'Chemical', '-', (20, 30))	('miR-34c-3p', 'Var', (20, 30))	('CDK1', 'Gene', '983', (63, 67))	('CDK1', 'Gene', (63, 67))
188329	32948832	We then assessed the effect of miR-34c-3p transfection on CDK1 protein levels in Calu-1, HCC827, and A549 cells.	('HCC827', 'CellLine', 'CVCL:2063', (89, 95))	('A549', 'CellLine', 'CVCL:0023', (101, 105))	('miR-34c-3p', 'Var', (31, 41))	('CDK1', 'Gene', (58, 62))	('miR-34c-3p', 'Chemical', '-', (31, 41))	('CDK1', 'Gene', '983', (58, 62))
188330	32948832	Exogenous expression of miR-34c-3p induced in these cells a significant reduction of CDK1 (Fig.	('reduction', 'NegReg', (72, 81))	('miR-34c-3p', 'Chemical', '-', (24, 34))	('CDK1', 'Gene', (85, 89))	('miR-34c-3p', 'Var', (24, 34))	('CDK1', 'Gene', '983', (85, 89))
188332	32948832	We then investigated whether targeted delivery of miR-34c-3p into AXL receptor-expressing NSCLC cells induced similar effects on CDK1 expression.	('miR-34c-3p', 'Chemical', '-', (50, 60))	('miR-34c-3p', 'Var', (50, 60))	('CDK1', 'Gene', (129, 133))	('expression', 'MPA', (134, 144))	('CDK1', 'Gene', '983', (129, 133))	('NSCLC', 'Disease', (90, 95))	('NSCLC', 'Disease', 'MESH:D002289', (90, 95))	('AXL', 'Gene', '558', (66, 69))	('AXL', 'Gene', (66, 69))
188334	32948832	Interestingly, the GL21.T-miR-34c-3p chimaera decreased CDK1 levels (Fig.	('miR-34c-3p', 'Chemical', '-', (26, 36))	('decreased', 'NegReg', (46, 55))	('GL21.T-miR-34c-3p', 'Var', (19, 36))	('CDK1', 'Gene', '983', (56, 60))	('CDK1', 'Gene', (56, 60))
188335	32948832	5d), supporting the possibility of using aptamer-based methods for targeted delivery of miR-34c-3p to NSCLC cells.	('NSCLC', 'Disease', 'MESH:D002289', (102, 107))	('miR-34c-3p', 'Var', (88, 98))	('NSCLC', 'Disease', (102, 107))	('miR-34c-3p', 'Chemical', '-', (88, 98))
188336	32948832	Moreover, correlation analysis carried out on 149 KRAS-mutated patients from the GDC Data Portal revealed a significant inverse correlation between CDK1 mRNA and miR-34c-3p (Fig.	('miR-34c-3p', 'Chemical', '-', (162, 172))	('inverse', 'NegReg', (120, 127))	('KRAS', 'Gene', (50, 54))	('miR-34c-3p', 'Var', (162, 172))	('KRAS', 'Gene', '3845', (50, 54))	('patients', 'Species', '9606', (63, 71))	('CDK1', 'Gene', '983', (148, 152))	('CDK1', 'Gene', (148, 152))
188341	32948832	Therefore, we studied proliferation and apoptosis on cells overexpressing miR-34c-3p and exposed to the CDK1 inhibitor RO3306.	('miR-34c-3p', 'Var', (74, 84))	('RO3306', 'Chemical', 'MESH:C512984', (119, 125))	('miR-34c-3p', 'Chemical', '-', (74, 84))	('CDK1', 'Gene', (104, 108))	('CDK1', 'Gene', '983', (104, 108))
188342	32948832	To this end, the KRAS-mutated A549 cell line was transfected with miR-34c-3p (or a miRNA control) and the effects of RO3306 on cell proliferation analysed by MTT assay.	('A549', 'CellLine', 'CVCL:0023', (30, 34))	('MTT', 'Chemical', 'MESH:C070243', (158, 161))	('miR-34c-3p', 'Var', (66, 76))	('RO3306', 'Chemical', 'MESH:C512984', (117, 123))	('miR-34c-3p', 'Chemical', '-', (66, 76))	('KRAS', 'Gene', (17, 21))	('KRAS', 'Gene', '3845', (17, 21))
188343	32948832	Experiments on A549 cells transfected with miR-34c-3p indicated that the number of viable cells was clearly reduced vs. the negative control; moreover, this effect was potentiated in the presence of RO3306 (Fig.	('miR-34c-3p', 'Var', (43, 53))	('RO3306', 'Chemical', 'MESH:C512984', (199, 205))	('RO3306', 'Var', (199, 205))	('reduced', 'NegReg', (108, 115))	('number of viable cells', 'CPA', (73, 95))	('potentiated', 'PosReg', (168, 179))	('A549', 'CellLine', 'CVCL:0023', (15, 19))	('miR-34c-3p', 'Chemical', '-', (43, 53))
188345	32948832	Similar results on cell viability were observed in a primary NSCLC cell line (PT#18) co-transfected with KRASmut and miR-34c-3p (Fig.	('KRAS', 'Gene', (105, 109))	('miR-34c-3p', 'Chemical', '-', (117, 127))	('miR-34c-3p', 'Var', (117, 127))	('NSCLC', 'Disease', (61, 66))	('KRAS', 'Gene', '3845', (105, 109))	('NSCLC', 'Disease', 'MESH:D002289', (61, 66))
188349	32948832	Recently, miR-34b and miR-34c have been reported to have more powerful anti-tumoural roles in lung adenocarcinoma than does miR-34a.	('miR-34c', 'Var', (22, 29))	('miR-34a', 'Gene', (124, 131))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('lung adenocarcinoma', 'Disease', (94, 113))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (94, 113))	('tumour', 'Phenotype', 'HP:0002664', (76, 82))	('miR-34b', 'Gene', (10, 17))	('tumour', 'Disease', 'MESH:D009369', (76, 82))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (94, 113))	('miR-34a', 'Gene', '407040', (124, 131))	('tumour', 'Disease', (76, 82))	('miR-34b', 'Gene', '407041', (10, 17))
188350	32948832	We have also previously reported that miR-34c-3p is downregulated in NSCLC and suppresses tumour growth.	('miR-34c-3p', 'Var', (38, 48))	('NSCLC', 'Disease', (69, 74))	('miR-34c-3p', 'Chemical', '-', (38, 48))	('NSCLC', 'Disease', 'MESH:D002289', (69, 74))	('tumour', 'Phenotype', 'HP:0002664', (90, 96))	('downregulated', 'NegReg', (52, 65))	('suppresses', 'NegReg', (79, 89))	('tumour', 'Disease', 'MESH:D009369', (90, 96))	('tumour', 'Disease', (90, 96))
188353	32948832	In lung cancer, KRAS is one of the most frequent genetic alterations, and its expression is associated with pathological features, prognosis, and response to therapy.In this manuscript, we show that high expression of miR-34c is correlated with survival in lung-adenocarcinoma patients carrying KRAS mutations.	('correlated with', 'Reg', (229, 244))	('survival', 'Disease', (245, 253))	('lung cancer', 'Disease', (3, 14))	('mutations', 'Var', (300, 309))	('lung cancer', 'Phenotype', 'HP:0100526', (3, 14))	('miR-34c', 'Gene', (218, 225))	('patients', 'Species', '9606', (277, 285))	('lung cancer', 'Disease', 'MESH:D008175', (3, 14))	('lung-adenocarcinoma', 'Phenotype', 'HP:0030078', (257, 276))	('KRAS', 'Gene', (16, 20))	('KRAS', 'Gene', (295, 299))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('lung-adenocarcinoma', 'Disease', 'MESH:D000077192', (257, 276))	('KRAS', 'Gene', '3845', (16, 20))	('carcinoma', 'Phenotype', 'HP:0030731', (267, 276))	('lung-adenocarcinoma', 'Disease', (257, 276))	('KRAS', 'Gene', '3845', (295, 299))
188354	32948832	In fact, TGCA data analysis highlighted that high miR-34c levels correlate with a better survival rate (at 5 years) in patients with an underlying KRAS mutation.	('better', 'PosReg', (82, 88))	('survival', 'CPA', (89, 97))	('patients', 'Species', '9606', (119, 127))	('miR-34c levels', 'Var', (50, 64))	('KRAS', 'Gene', (147, 151))	('mutation', 'Var', (152, 160))	('KRAS', 'Gene', '3845', (147, 151))
188357	32948832	KRAS alterations have been found to be strictly associated with lung adenocarcinoma development and smoking.	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (64, 83))	('associated', 'Reg', (48, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('smoking', 'Disease', (100, 107))	('alterations', 'Var', (5, 16))	('lung adenocarcinoma', 'Disease', (64, 83))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (64, 83))	('KRAS', 'Gene', (0, 4))	('KRAS', 'Gene', '3845', (0, 4))
188358	32948832	Oncogenic KRAS can activate up to 10 different pathways, the best characterized of which are the MAPK cascade and the PIK3-AKT-mTOR pathway.	('PIK3', 'Gene', '5294', (118, 122))	('MAPK cascade', 'Pathway', (97, 109))	('KRAS', 'Gene', '3845', (10, 14))	('AKT', 'Gene', '207', (123, 126))	('PIK3', 'Gene', (118, 122))	('mTOR', 'Gene', (127, 131))	('mTOR', 'Gene', '2475', (127, 131))	('AKT', 'Gene', (123, 126))	('Oncogenic', 'Var', (0, 9))	('KRAS', 'Gene', (10, 14))
188364	32948832	We addressed the possibility that synthetic lethality may be a mechanism of mutual interaction between KRAS and miR-34c-3p.	('KRAS', 'Gene', (103, 107))	('miR-34c-3p', 'Chemical', '-', (112, 122))	('KRAS', 'Gene', '3845', (103, 107))	('synthetic lethality', 'MPA', (34, 53))	('miR-34c-3p', 'Var', (112, 122))
188366	32948832	Here, for the first time, we describe that miR-34c-3p targets CDK1, a recently reported synthetic lethal target of mutated KRAS.	('miR-34c-3p', 'Var', (43, 53))	('targets', 'Reg', (54, 61))	('CDK1', 'Gene', '983', (62, 66))	('KRAS', 'Gene', (123, 127))	('CDK1', 'Gene', (62, 66))	('KRAS', 'Gene', '3845', (123, 127))	('miR-34c-3p', 'Chemical', '-', (43, 53))
188367	32948832	Our findings indicate that miR-34c-3p, but not miR-34a (data not shown), is able to reduce the expression of CDK1 protein.	('reduce', 'NegReg', (84, 90))	('CDK1', 'Gene', (109, 113))	('CDK1', 'Gene', '983', (109, 113))	('miR-34c-3p', 'Var', (27, 37))	('miR-34a', 'Gene', '407040', (47, 54))	('miR-34c-3p', 'Chemical', '-', (27, 37))	('miR-34a', 'Gene', (47, 54))	('expression', 'MPA', (95, 105))
188368	32948832	CDK1 is a cyclin-dependent kinase necessary for controlling cell cycle regulation, and its aberrant expression is responsible for uncontrolled proliferation in cancer cells as well as for genomic and chromosomal instability.	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('cancer', 'Disease', (160, 166))	('CDK1', 'Gene', (0, 4))	('CDK1', 'Gene', '983', (0, 4))	('chromosomal instability', 'Phenotype', 'HP:0040012', (200, 223))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('aberrant', 'Var', (91, 99))	('responsible', 'Reg', (114, 125))
188370	32948832	Interestingly, it has been recently proposed that CDK1 is responsible for apoptosis resistance in BRAFV600E colorectal cancer; indeed, the combination of a CDK1 inhibitor with a MEK/ERK inhibitor enhanced apoptosis.	('CDK1', 'Gene', '983', (156, 160))	('MEK', 'Gene', (178, 181))	('enhanced', 'PosReg', (196, 204))	('combination', 'Interaction', (139, 150))	('CDK1', 'Gene', (50, 54))	('apoptosis', 'CPA', (205, 214))	('colorectal cancer', 'Disease', 'MESH:D015179', (108, 125))	('inhibitor', 'Var', (161, 170))	('MEK', 'Gene', '5609', (178, 181))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('colorectal cancer', 'Phenotype', 'HP:0003003', (108, 125))	('BRAFV600E', 'Mutation', 'rs113488022', (98, 107))	('ERK', 'Gene', (182, 185))	('ERK', 'Gene', '2048', (182, 185))	('colorectal cancer', 'Disease', (108, 125))	('CDK1', 'Gene', (156, 160))	('CDK1', 'Gene', '983', (50, 54))
188371	32948832	Here, we propose that by targeting CDK1, miR-34c-3p is involved in synthetic lethality in KRAS mutant patients.	('CDK1', 'Gene', (35, 39))	('KRAS', 'Gene', (90, 94))	('patients', 'Species', '9606', (102, 110))	('miR-34c-3p', 'Var', (41, 51))	('KRAS', 'Gene', '3845', (90, 94))	('miR-34c-3p', 'Chemical', '-', (41, 51))	('CDK1', 'Gene', '983', (35, 39))
188372	32948832	Indeed, we observed that miR-34c-3p targets CDK1 and has an oncosuppressor effect in mutated KRAS NSCLC cells.	('KRAS', 'Gene', (93, 97))	('CDK1', 'Gene', '983', (44, 48))	('CDK1', 'Gene', (44, 48))	('oncosuppressor effect', 'MPA', (60, 81))	('KRAS', 'Gene', '3845', (93, 97))	('miR-34c-3p', 'Var', (25, 35))	('miR-34c-3p', 'Chemical', '-', (25, 35))	('mutated', 'Var', (85, 92))	('NSCLC', 'Disease', (98, 103))	('NSCLC', 'Disease', 'MESH:D002289', (98, 103))
188373	32948832	However, in NSCLC cells overexpressing mutated KRAS, we observed an additive effect on cell proliferation and apoptosis upon the combination of miR-34c-3p overexpression and exposure to RO03306, a small molecule inhibitor of CDK1.	('CDK1', 'Gene', (225, 229))	('miR-34c-3p', 'Var', (144, 154))	('combination', 'Interaction', (129, 140))	('cell proliferation', 'CPA', (87, 105))	('miR-34c-3p', 'Chemical', '-', (144, 154))	('mutated', 'Var', (39, 46))	('NSCLC', 'Disease', (12, 17))	('RO03306', 'Chemical', '-', (186, 193))	('KRAS', 'Gene', (47, 51))	('KRAS', 'Gene', '3845', (47, 51))	('overexpression', 'PosReg', (155, 169))	('NSCLC', 'Disease', 'MESH:D002289', (12, 17))	('apoptosis', 'CPA', (110, 119))	('CDK1', 'Gene', '983', (225, 229))
188374	32948832	Moreover, when stratifying KRAS-mutant patients into two groups based on miR-34c expression, survival analysis indicated that high miR-34c expression was associated with longer survival at 5 years.	('KRAS', 'Gene', '3845', (27, 31))	('patients', 'Species', '9606', (39, 47))	('high miR-34c', 'Var', (126, 138))	('KRAS', 'Gene', (27, 31))	('miR-34c', 'Var', (131, 138))	('longer', 'PosReg', (170, 176))
188377	32948832	Upon internalization, the chimaera increased the levels of miR-34c-3p in AXL-positive cells and reduced survival of NSCLC cells in vitro.	('NSCLC', 'Disease', 'MESH:D002289', (116, 121))	('miR-34c-3p', 'Chemical', '-', (59, 69))	('levels', 'MPA', (49, 55))	('increased', 'PosReg', (35, 44))	('AXL', 'Gene', (73, 76))	('miR-34c-3p', 'Var', (59, 69))	('survival', 'CPA', (104, 112))	('AXL', 'Gene', '558', (73, 76))	('NSCLC', 'Disease', (116, 121))	('reduced', 'NegReg', (96, 103))
188379	32948832	Altogether, our findings highlight that, in addition to its already known role as an oncosuppressor miRNA in NSCLC, miR-34c-3p acts in KRAS-mutated NSCLC as a regulator of the CDK1 gene, which is involved in a synthetic lethality pathway (Fig.	('miR-34c-3p', 'Var', (116, 126))	('NSCLC', 'Disease', 'MESH:D002289', (109, 114))	('miR-34c-3p', 'Chemical', '-', (116, 126))	('NSCLC', 'Disease', (148, 153))	('KRAS', 'Gene', (135, 139))	('KRAS', 'Gene', '3845', (135, 139))	('NSCLC', 'Disease', 'MESH:D002289', (148, 153))	('CDK1', 'Gene', '983', (176, 180))	('NSCLC', 'Disease', (109, 114))	('CDK1', 'Gene', (176, 180))
188387	32795325	Firstly, three genes expression profiles GSE44077, GSE18842 and GSE33532 were picked from Gene Expression Omnibus (GEO) to analyze the genes with different expression level (GDEs) between NSCLC and normal lung samples, and the cellular location, molecular function and the biology pathways the GDEs enriched in were analyzed.	('GSE33532', 'Var', (64, 72))	('NSCLC', 'Disease', 'MESH:D002289', (188, 193))	('GDEs', 'Chemical', '-', (174, 178))	('GDEs', 'Chemical', '-', (294, 298))	('NSCLC', 'Phenotype', 'HP:0030358', (188, 193))	('GSE18842', 'Var', (51, 59))	('GSE44077', 'Var', (41, 49))	('NSCLC', 'Disease', (188, 193))
188399	32795325	For instance, the discovery of the frequent mutation of EGFR in NSCLC especially lung adenocarcinoma in non-smoking female Asia patients leading to the development of generations EGFR-TKI (tyrosine kinase inhibitors) treatment, which has been showing effective results.	('NSCLC especially lung adenocarcinoma', 'Disease', (64, 100))	('EGFR', 'Gene', (179, 183))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (81, 100))	('mutation', 'Var', (44, 52))	('EGFR', 'Gene', '1956', (56, 60))	('NSCLC', 'Phenotype', 'HP:0030358', (64, 69))	('EGFR', 'Gene', (56, 60))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('NSCLC especially lung adenocarcinoma', 'Disease', 'MESH:D000077192', (64, 100))	('patients', 'Species', '9606', (128, 136))	('EGFR', 'Gene', '1956', (179, 183))
188400	32795325	Additionally, the rearrangements of ALK, ROS1 and RET genes bring in the development of therapeutic TKI treatments, for instance crizotinib and lorlatinib.	('RET', 'Gene', (50, 53))	('ALK', 'Gene', '238', (36, 39))	('ROS1', 'Gene', (41, 45))	('rearrangements', 'Var', (18, 32))	('crizotinib', 'Chemical', 'MESH:D000077547', (129, 139))	('ROS1', 'Gene', '6098', (41, 45))	('RET', 'Gene', '5979', (50, 53))	('lorlatinib', 'Chemical', 'MESH:C000590786', (144, 154))	('ALK', 'Gene', (36, 39))
188405	32795325	In the study, three cDNA expression profiles GSE44077, GSE18842 and GSE33532 were firstly picked from Gene Expression Omnibus (GEO) based on their sample number to detect the genes with different expression level (GDEs) in NSCLC versus normal lung samples.	('GSE33532', 'Var', (68, 76))	('NSCLC', 'Disease', (223, 228))	('GDEs', 'Chemical', '-', (214, 218))	('NSCLC', 'Disease', 'MESH:D002289', (223, 228))	('NSCLC', 'Phenotype', 'HP:0030358', (223, 228))	('GSE18842', 'Var', (55, 63))	('GSE44077', 'Var', (45, 53))
188424	32795325	Three GEO cDNA profiles GSE44077, GSE18842 and GSE33532 were picked to analyze the GDEs in cancer vs. normal lung samples.	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('GDEs', 'Chemical', '-', (83, 87))	('GSE44077', 'Var', (24, 32))
188425	32795325	And a whole of 1133, 4459 and 3775 GDEs including 691, 2505, 2351 down-regulated and 442, 1954, 1424 up-regulated genes were identified in GSE44077 (Fig.	('down-regulated', 'NegReg', (66, 80))	('up-regulated', 'PosReg', (101, 113))	('GSE44077', 'Var', (139, 147))	('GDEs', 'Chemical', '-', (35, 39))
188460	32795325	From the online open-access GEO databases, three cDNA expression profiles GSE44077, GSE18842 and GSE33532 containing a total of of 181 NSCLC cancer and 131 normal lung samples were picked, and the GDEs between cancer versus normal tissues were then analyzed, and we discoved that 664 genes were differently expressed in three cDNA profiles, including 232 up-regulated and 432 down-regulated genes.	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('NSCLC cancer', 'Disease', (135, 147))	('GSE18842', 'Var', (84, 92))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('up-regulated', 'PosReg', (355, 367))	('GDEs', 'Chemical', '-', (197, 201))	('NSCLC cancer', 'Disease', 'MESH:D009369', (135, 147))	('GSE44077', 'Var', (74, 82))	('down-regulated', 'NegReg', (376, 390))	('cancer', 'Disease', 'MESH:D009369', (210, 216))	('GSE33532', 'Var', (97, 105))	('cancer', 'Disease', (210, 216))	('cancer', 'Disease', (141, 147))	('NSCLC', 'Phenotype', 'HP:0030358', (135, 140))
188474	32795325	Aberrant expression of NDC80 has been reported in several other tumors, for instance osteosarcoma, hepatocellulcar carcinoma, colorectal cancer and breast cancer, indicating its potential as a newly bio target.	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('breast cancer', 'Phenotype', 'HP:0003002', (148, 161))	('NDC80', 'Gene', (23, 28))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('tumors', 'Disease', (64, 70))	('osteosarcoma', 'Disease', (85, 97))	('osteosarcoma', 'Disease', 'MESH:D012516', (85, 97))	('breast cancer', 'Disease', 'MESH:D001943', (148, 161))	('breast cancer', 'Disease', (148, 161))	('hepatocellulcar carcinoma', 'Disease', (99, 124))	('colorectal cancer', 'Disease', 'MESH:D015179', (126, 143))	('Aberrant expression', 'Var', (0, 19))	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('colorectal cancer', 'Disease', (126, 143))	('hepatocellulcar carcinoma', 'Disease', 'MESH:D009369', (99, 124))	('NDC80', 'Gene', '10403', (23, 28))	('osteosarcoma', 'Phenotype', 'HP:0002669', (85, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('reported', 'Reg', (38, 46))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('colorectal cancer', 'Phenotype', 'HP:0003003', (126, 143))
188477	32795325	BUB1, which is encoded by BUB1B, has been known as a checkpoint for proper chromosome segregation, the abnormal expression of BUB1 has been reported to associate with poor survival and metastasis in various tumors including colorectal cancer, gastric cancer, bladder cancer, hepatocellular carcinoma and so on.	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (275, 299))	('BUB1', 'Gene', (126, 130))	('tumors', 'Phenotype', 'HP:0002664', (207, 213))	('colorectal cancer', 'Disease', (224, 241))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('abnormal expression', 'Var', (103, 122))	('tumors', 'Disease', (207, 213))	('gastric cancer', 'Phenotype', 'HP:0012126', (243, 257))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (275, 299))	('tumors', 'Disease', 'MESH:D009369', (207, 213))	('bladder cancer', 'Disease', 'MESH:D001749', (259, 273))	('bladder cancer', 'Disease', (259, 273))	('colorectal cancer', 'Phenotype', 'HP:0003003', (224, 241))	('hepatocellular carcinoma', 'Disease', (275, 299))	('poor', 'NegReg', (167, 171))	('BUB1', 'Gene', '699', (26, 30))	('gastric cancer', 'Disease', (243, 257))	('cancer', 'Phenotype', 'HP:0002664', (267, 273))	('bladder cancer', 'Phenotype', 'HP:0009725', (259, 273))	('BUB1', 'Gene', '699', (0, 4))	('metastasis', 'CPA', (185, 195))	('BUB1', 'Gene', (26, 30))	('BUB1', 'Gene', (0, 4))	('associate', 'Reg', (152, 161))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('gastric cancer', 'Disease', 'MESH:D013274', (243, 257))	('BUB1', 'Gene', '699', (126, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (290, 299))	('BUB1B', 'Gene', '701', (26, 31))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))	('colorectal cancer', 'Disease', 'MESH:D015179', (224, 241))	('BUB1B', 'Gene', (26, 31))
188481	32795325	Aurora A dysregulation has been associated with high occurrence of various cancers, for example breast, prostate, bladder, colorectal, gastric, ovarian, esophagus and pancreatic cancers.	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('pancreatic cancers', 'Disease', 'MESH:D010190', (167, 185))	('esophagus', 'Disease', (153, 162))	('associated', 'Reg', (32, 42))	('ovarian', 'Disease', 'MESH:D010049', (144, 151))	('Aurora A', 'Gene', '6790', (0, 8))	('cancers', 'Disease', 'MESH:D009369', (75, 82))	('cancers', 'Disease', 'MESH:D009369', (178, 185))	('dysregulation', 'Var', (9, 22))	('bladder', 'Disease', (114, 121))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (167, 185))	('gastric', 'Disease', (135, 142))	('ovarian', 'Disease', (144, 151))	('breast', 'Disease', (96, 102))	('cancers', 'Phenotype', 'HP:0002664', (75, 82))	('cancers', 'Disease', (75, 82))	('pancreatic cancers', 'Disease', (167, 185))	('cancers', 'Phenotype', 'HP:0002664', (178, 185))	('Aurora A', 'Gene', (0, 8))	('colorectal', 'Disease', (123, 133))	('cancers', 'Disease', (178, 185))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('prostate', 'Disease', (104, 112))
188483	32795325	Osimertinib and rociletinib, two anti-cancer drugs for lung cancer, work by shutting off mutant EGFR, which initially kills cancerous tumors, but the tumors rewire and activate Aurora kinase A, becoming cancerous growths again.	('tumors', 'Phenotype', 'HP:0002664', (150, 156))	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('lung cancer', 'Disease', (55, 66))	('cancer', 'Disease', 'MESH:D009369', (203, 209))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('cancerous tumors', 'Disease', 'MESH:D009369', (124, 140))	('rociletinib', 'Chemical', 'MESH:C000589977', (16, 27))	('mutant', 'Var', (89, 95))	('cancerous', 'Disease', (203, 212))	('cancer', 'Disease', 'MESH:D009369', (124, 130))	('tumors', 'Disease', (150, 156))	('tumors', 'Disease', (134, 140))	('cancerous', 'Disease', (124, 133))	('EGFR', 'Gene', (96, 100))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('shutting off', 'NegReg', (76, 88))	('Aurora kinase A', 'Gene', '6790', (177, 192))	('cancer', 'Disease', (38, 44))	('tumors', 'Disease', 'MESH:D009369', (150, 156))	('tumors', 'Disease', 'MESH:D009369', (134, 140))	('lung cancer', 'Disease', 'MESH:D008175', (55, 66))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('cancer', 'Disease', (203, 209))	('lung cancer', 'Phenotype', 'HP:0100526', (55, 66))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('EGFR', 'Gene', '1956', (96, 100))	('cancer', 'Disease', (124, 130))	('cancerous', 'Disease', 'MESH:D009369', (203, 212))	('Aurora kinase A', 'Gene', (177, 192))	('cancerous tumors', 'Disease', (124, 140))	('activate', 'PosReg', (168, 176))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('cancer', 'Disease', (60, 66))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('cancerous', 'Disease', 'MESH:D009369', (124, 133))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
188500	32640421	In mouse xenograft model, we proved that targeting GGT5 with a small-molecule inhibitor GGsTop could inhibit tumor growth and increase the chemosensitivity of cancer cells.	('cancer', 'Disease', (159, 165))	('GGT5', 'Gene', (51, 55))	('GGsTop', 'Gene', (88, 94))	('inhibit', 'NegReg', (101, 108))	('mouse', 'Species', '10090', (3, 8))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('targeting', 'Var', (41, 50))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('increase', 'PosReg', (126, 134))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('GGsTop', 'Chemical', 'MESH:C569224', (88, 94))	('tumor', 'Disease', (109, 114))
188508	32640421	However, the overall survival of patients with LUAD is poorer than LUSC patients, which may be the result of the different pathogenesis, tumor microenvironment or aberrant oncogenes.	('tumor', 'Disease', (137, 142))	('patients', 'Species', '9606', (33, 41))	('LUAD', 'Phenotype', 'HP:0030078', (47, 51))	('poorer', 'NegReg', (55, 61))	('LUSC', 'Phenotype', 'HP:0030359', (67, 71))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('aberrant', 'Var', (163, 171))	('LUAD', 'Disease', (47, 51))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('patients', 'Species', '9606', (72, 80))
188515	32640421	For instance, overall survival for gallbladder cancer patients with elevated GGT was significantly worse than patients with the normal level of GGT.	('GGT', 'Gene', (77, 80))	('GGT', 'Gene', '2678', (144, 147))	('gallbladder cancer', 'Disease', (35, 53))	('patients', 'Species', '9606', (54, 62))	('gallbladder cancer', 'Disease', 'MESH:D005706', (35, 53))	('GGT', 'Gene', (144, 147))	('GGT', 'Gene', '2678', (77, 80))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('elevated', 'Var', (68, 76))	('patients', 'Species', '9606', (110, 118))	('worse', 'NegReg', (99, 104))
188517	32640421	Moreover, high pre-therapeutic GGT serum levels was associated with the advanced tumor stage and could serve as an independent prognostic marker for the worse survival in patients with epithelial ovarian cancer, pancreatic cancer and endometrial cancer.	('pancreatic cancer', 'Disease', 'MESH:D010190', (212, 229))	('GGT', 'Gene', '2678', (31, 34))	('GGT', 'Gene', (31, 34))	('epithelial ovarian cancer', 'Disease', 'MESH:D000077216', (185, 210))	('pancreatic cancer', 'Disease', (212, 229))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('ovarian cancer', 'Phenotype', 'HP:0100615', (196, 210))	('endometrial cancer', 'Phenotype', 'HP:0012114', (234, 252))	('patients', 'Species', '9606', (171, 179))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))	('endometrial cancer', 'Disease', (234, 252))	('tumor', 'Disease', (81, 86))	('endometrial cancer', 'Disease', 'MESH:D016889', (234, 252))	('associated', 'Reg', (52, 62))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (212, 229))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('epithelial ovarian cancer', 'Phenotype', 'HP:0025318', (185, 210))	('high', 'Var', (10, 14))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('epithelial ovarian cancer', 'Disease', (185, 210))
188526	32640421	In the present study, we first reported that high expression of protein GGT5 in cancer-associated fibroblasts (CAFs) predicted the poorer survival of LUAD patients.	('LUAD', 'Disease', (150, 154))	('LUAD', 'Phenotype', 'HP:0030078', (150, 154))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('poorer', 'NegReg', (131, 137))	('high', 'Var', (45, 49))	('protein GGT5', 'Protein', (64, 76))	('patients', 'Species', '9606', (155, 163))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('cancer', 'Disease', (80, 86))
188533	32640421	Survival analysis with Kaplan-Meier Plotter (http://kmplot.com/analysis/) suggested that both overall survival (P = 0.00054) and progression-free survival (P = 0.0099) of LUAD patients with high GGT5 expression (>= cutoff value 19) were significantly shorter than those with low levels of GGT5 expression (< cutoff value 19) (Figure 1E, 1F).	('patients', 'Species', '9606', (176, 184))	('GGT5', 'Gene', (195, 199))	('shorter', 'NegReg', (251, 258))	('overall survival', 'CPA', (94, 110))	('progression-free survival', 'CPA', (129, 154))	('LUAD', 'Phenotype', 'HP:0030078', (171, 175))	('high', 'Var', (190, 194))
188541	32640421	Moreover, foci formation in monolayer culture (Figure 3C) and spheres formation in soft agar (Figure 3D) analyses also suggested that interfering GGT5 expression in CAFs could inhibit tumor cell proliferation in vitro.	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('interfering', 'Var', (134, 145))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('GGT5', 'Gene', (146, 150))	('tumor', 'Disease', (184, 189))	('agar', 'Chemical', 'MESH:D000362', (88, 92))	('inhibit', 'NegReg', (176, 183))
188551	32640421	Results showed that GGT activity was increased in NFs after GGT5 overexpression and decreased in CAFs when GGT5 was silenced (Supplementary Figure 3B, 3C).	('GGT', 'Gene', (60, 63))	('activity', 'MPA', (24, 32))	('GGT', 'Gene', '2678', (107, 110))	('overexpression', 'Var', (65, 79))	('GGT', 'Gene', (20, 23))	('GGT', 'Gene', (107, 110))	('increased', 'PosReg', (37, 46))	('GGT', 'Gene', '2678', (60, 63))	('decreased', 'NegReg', (84, 93))	('GGT', 'Gene', '2678', (20, 23))
188575	32640421	Moreover, high GGT5 in LUAD tissues predicts the adverse overall survival and progression-free survival for LUAD patients.	('patients', 'Species', '9606', (113, 121))	('LUAD', 'Phenotype', 'HP:0030078', (108, 112))	('GGT5', 'Protein', (15, 19))	('overall survival', 'CPA', (57, 73))	('high', 'Var', (10, 14))	('progression-free survival', 'CPA', (78, 103))	('LUAD', 'Phenotype', 'HP:0030078', (23, 27))	('adverse', 'NegReg', (49, 56))
188585	32640421	Knockdown of GGT5 decreases the levels of cysteine and glutamate in CAFs-derived conditioned media.	('GGT5', 'Gene', (13, 17))	('cysteine', 'Chemical', 'MESH:D003545', (42, 50))	('decreases', 'NegReg', (18, 27))	('Knockdown', 'Var', (0, 9))	('glutamate', 'Chemical', 'MESH:D018698', (55, 64))
188594	32640421	In this study, we confirmed that blocking GGT5 with a small-molecule inhibitor GGsTop could inhibit tumor growth and increase the drug-sensitivity of LUAD cells in mouse xenograft tumor model.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('increase', 'PosReg', (117, 125))	('mouse', 'Species', '10090', (164, 169))	('LUAD', 'Phenotype', 'HP:0030078', (150, 154))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('GGT5', 'Gene', (42, 46))	('tumor', 'Disease', (100, 105))	('tumor', 'Disease', (180, 185))	('drug-sensitivity of', 'CPA', (130, 149))	('inhibit', 'NegReg', (92, 99))	('GGsTop', 'Chemical', 'MESH:C569224', (79, 85))	('drug-sensitivity', 'Phenotype', 'HP:0020174', (130, 146))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('GGsTop', 'Gene', (79, 85))	('blocking', 'Var', (33, 41))
188604	32640421	The slides were incubated with monoclonal antibodies against GGT5 (Santa Cruz Biotechnology, #sc-20640, 1:500 dilution), Ki67 (Abcam, #ab15580, 1:400 dilution), Fibronectin (Cell Signaling Technology, #26836, 1:200 dilution) or alpha-SMA (Cell Signaling Technology, #56856, 1:200 dilution) at 4 C overnight in a humidified chamber.	('GGT5', 'Gene', (61, 65))	('alpha-SMA', 'Gene', '58', (228, 237))	('Fibronectin', 'Gene', '2335', (161, 172))	('alpha-SMA', 'Gene', (228, 237))	('Fibronectin', 'Gene', (161, 172))	('#sc-20640', 'Var', (93, 102))
188643	33090728	Genetic alterations of AFTPH in cancers were explored using the cBioPortal website, revealing that gene copy number gains and amplification are common in BRCA, DLBC, LUSC, and PAAD.	('BRCA', 'Gene', '672', (154, 158))	('PAAD', 'Disease', (176, 180))	('cancers', 'Disease', 'MESH:D009369', (32, 39))	('cancers', 'Phenotype', 'HP:0002664', (32, 39))	('gene copy number gains', 'Var', (99, 121))	('BRCA', 'Gene', (154, 158))	('cancers', 'Disease', (32, 39))	('LUSC', 'Phenotype', 'HP:0030359', (166, 170))	('LUSC', 'Disease', (166, 170))	('amplification', 'Var', (126, 139))	('DLBC', 'Disease', (160, 164))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('BRCA', 'Phenotype', 'HP:0003002', (154, 158))	('common', 'Reg', (144, 150))
188655	33090728	Deletion of AFTPH and gamma-synergin has a negative effect on the secretory organelles in epithelial cells [6].	('gamma-synergin', 'Gene', (22, 36))	('negative', 'NegReg', (43, 51))	('secretory organelles in epithelial cells', 'MPA', (66, 106))	('gamma-synergin', 'Gene', '11276', (22, 36))	('AFTPH', 'Gene', (12, 17))	('Deletion', 'Var', (0, 8))
188679	33090728	The sequences of NC siRNA were as follows: sense 5' UUCUCCGAACGUGUCACGUTT 3' and antisense 5' ACGUGACACGUUCGGAGAATT 3'.	("antisense 5'", 'Var', (81, 93))	('NC siRNA', 'Disease', (17, 25))	('NC siRNA', 'Disease', 'OMIM:617025', (17, 25))
188699	33090728	Figure 6A shows the specific genetic alteration types of AFTPH in BRCA, DLBC, LUSC, and PAAD, which included missense mutation, amplification or gain, deep deletion, and shallow deletion.	('shallow deletion', 'Var', (170, 186))	('BRCA', 'Phenotype', 'HP:0003002', (66, 70))	('amplification', 'Var', (128, 141))	('BRCA', 'Gene', (66, 70))	('BRCA', 'Gene', '672', (66, 70))	('LUSC', 'Phenotype', 'HP:0030359', (78, 82))	('gain', 'PosReg', (145, 149))	('missense mutation', 'Var', (109, 126))	('deep deletion', 'Var', (151, 164))
188700	33090728	In particular, Kaplan-Meier survival curves revealed the relationship of alterations and patient OS in BRCA, DLBC, LUSC, and PAAD (Fig.	('BRCA', 'Phenotype', 'HP:0003002', (103, 107))	('patient', 'Species', '9606', (89, 96))	('BRCA', 'Gene', '672', (103, 107))	('alterations', 'Var', (73, 84))	('BRCA', 'Gene', (103, 107))	('LUSC', 'Disease', (115, 119))	('LUSC', 'Phenotype', 'HP:0030359', (115, 119))	('DLBC', 'Disease', (109, 113))
188713	33090728	Law's studies indicated that activation of NT/NTR1 in colonic epithelial cells and colitis models could induce the expression of miR-133alpha and reduce transcription of its downstream target AFTPH, which is involved in inflammatory signals in colonocytes and colitis models [7, 8].	('NT/NTR1', 'Gene', (43, 50))	('colitis', 'Disease', 'MESH:D003092', (83, 90))	('activation', 'PosReg', (29, 39))	('AFTPH', 'Gene', (192, 197))	('colitis', 'Phenotype', 'HP:0002583', (260, 267))	('miR-133alpha', 'Var', (129, 141))	('colitis', 'Disease', (83, 90))	('colitis', 'Phenotype', 'HP:0002583', (83, 90))	('induce', 'PosReg', (104, 110))	('expression', 'MPA', (115, 125))	('colitis', 'Disease', 'MESH:D003092', (260, 267))	('transcription', 'MPA', (153, 166))	('colitis', 'Disease', (260, 267))	('reduce', 'NegReg', (146, 152))
188714	33090728	In addition, it was reported that dysregulation of miR-133alpha and its target genes could activate ERK [28, 29] and AKT [30, 31] signaling and further promote colorectal cancer development [30, 32, 33, 34].	('AKT', 'Gene', '207', (117, 120))	('dysregulation', 'Var', (34, 47))	('colorectal cancer', 'Disease', 'MESH:D015179', (160, 177))	('AKT', 'Gene', (117, 120))	('colorectal cancer', 'Phenotype', 'HP:0003003', (160, 177))	('miR-133alpha', 'Var', (51, 63))	('activate', 'PosReg', (91, 99))	('ERK', 'Gene', '5594', (100, 103))	('promote', 'PosReg', (152, 159))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('colorectal cancer', 'Disease', (160, 177))	('ERK', 'Gene', (100, 103))
188727	33090728	Genetic alterations might be the most important factor affecting cancer development [35, 36].	('Genetic alterations', 'Var', (0, 19))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))
188729	33090728	It should be noted that genetic alterations of AFTPH in BRCA, DLBC, LUSC, and PAAD were not significantly associated with prognostic results.	('genetic alterations', 'Var', (24, 43))	('BRCA', 'Phenotype', 'HP:0003002', (56, 60))	('BRCA', 'Gene', '672', (56, 60))	('BRCA', 'Gene', (56, 60))	('LUSC', 'Phenotype', 'HP:0030359', (68, 72))	('AFTPH', 'Gene', (47, 52))
188737	33196759	The ceRNA analysis revealed that genes, such as EPHA2, EPHA7, NTRK2, CDK6, hsa_circ_027570, hsa_circ_006089, and hsa-circ_035997, had distinct expression patterns between LUSC and LUAD.	('EPHA2', 'Gene', '1969', (48, 53))	('NTRK2', 'Gene', '4915', (62, 67))	('EPHA7', 'Gene', '2045', (55, 60))	('expression', 'MPA', (143, 153))	('EPHA2', 'Gene', (48, 53))	('CDK6', 'Gene', (69, 73))	('hsa_circ_006089', 'Var', (92, 107))	('EPHA7', 'Gene', (55, 60))	('CDK6', 'Gene', '1021', (69, 73))	('NTRK2', 'Gene', (62, 67))	('hsa_circ_027570', 'Var', (75, 90))
188758	33196759	Among these, the top five miRNAs that had more co-expressive relationship with DEmRNAs included hsa-miR-200a-3p, hsa-miR-141-3p, hsa-miR-135b-5p, hsa-miR-135a-5p, and hsa-miR-182-5p.	('hsa-miR-135b-5p', 'Var', (129, 144))	('hsa-miR-182', 'Gene', (167, 178))	('miR-141-3p', 'Chemical', '-', (117, 127))	('hsa-miR-182', 'Gene', '406958', (167, 178))
188772	33196759	Subsequently, confirmed that knockdown of EPHA7 could suppress the growth of NSCLC cells, suggesting that silencing EPHA7 might provide a novel approach for the treatment of NSCLC.	('NSCLC', 'Disease', 'MESH:D002289', (77, 82))	('EPHA7', 'Gene', (116, 121))	('NSCLC', 'Disease', 'MESH:D002289', (174, 179))	('knockdown', 'Var', (29, 38))	('EPHA7', 'Gene', (42, 47))	('suppress', 'NegReg', (54, 62))	('EPHA7', 'Gene', '2045', (116, 121))	('silencing', 'Var', (106, 115))	('EPHA7', 'Gene', '2045', (42, 47))	('NSCLC', 'Disease', (77, 82))	('NSCLC', 'Disease', (174, 179))
188787	33196759	confirmed that miR-103a-3p played an anti-oncogenic role in cancer, suggesting that it might serve a novel potential therapeutic target for NSCLC.	('miR-103a-3p', 'Chemical', '-', (15, 26))	('NSCLC', 'Disease', 'MESH:D002289', (140, 145))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('miR-103a-3p', 'Var', (15, 26))	('NSCLC', 'Disease', (140, 145))	('cancer', 'Disease', (60, 66))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('anti-oncogenic', 'MPA', (37, 51))
188789	33196759	The expression level of miR-141-3p was significantly down-regulated in NSCLC tissues, suggesting that miR-141-3p might be a prognostic tumor suppressor involved in the NSCLC progression.	('expression level', 'MPA', (4, 20))	('miR-141-3p', 'Chemical', '-', (102, 112))	('miR-141-3p', 'Chemical', '-', (24, 34))	('miR-141-3p', 'Gene', (24, 34))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('NSCLC', 'Disease', 'MESH:D002289', (168, 173))	('tumor', 'Disease', (135, 140))	('tumor', 'Disease', 'MESH:D009369', (135, 140))	('miR-141-3p', 'Var', (102, 112))	('NSCLC', 'Disease', (71, 76))	('down-regulated', 'NegReg', (53, 67))	('NSCLC', 'Disease', (168, 173))	('NSCLC', 'Disease', 'MESH:D002289', (71, 76))
188800	33196759	PMEPA1 was found highly expressed in the lung cancer cell lines, whereas knockdown of PMEPA1 could significantly inhibit the proliferation of cancer cells.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('PMEPA1', 'Gene', (86, 92))	('cancer', 'Disease', (142, 148))	('cancer', 'Disease', (46, 52))	('lung cancer', 'Disease', (41, 52))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('PMEPA1', 'Gene', '56937', (86, 92))	('inhibit', 'NegReg', (113, 120))	('PMEPA1', 'Gene', '56937', (0, 6))	('PMEPA1', 'Gene', (0, 6))	('lung cancer', 'Phenotype', 'HP:0100526', (41, 52))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('lung cancer', 'Disease', 'MESH:D008175', (41, 52))	('knockdown', 'Var', (73, 82))
188801	33196759	Overexpression of PMEPA1 was associated with poor prognosis of lung cancer, which was in line with our findings.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('lung cancer', 'Disease', 'MESH:D008175', (63, 74))	('PMEPA1', 'Gene', (18, 24))	('lung cancer', 'Disease', (63, 74))	('PMEPA1', 'Gene', '56937', (18, 24))	('lung cancer', 'Phenotype', 'HP:0100526', (63, 74))	('Overexpression', 'Var', (0, 14))
188804	33196759	EPHA2 mutation was present in LUSC, and it could increase tumor invasion and survival by activating the focal adhesions and actin cytoskeletal regulatory proteins, indicating EPHA2 as a potential therapeutic target of LUSC, which was consistent with our findings.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('increase', 'PosReg', (49, 57))	('activating', 'PosReg', (89, 99))	('survival', 'CPA', (77, 85))	('focal adhesions', 'MPA', (104, 119))	('EPHA2', 'Gene', (175, 180))	('EPHA2', 'Gene', (0, 5))	('mutation', 'Var', (6, 14))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('EPHA2', 'Gene', '1969', (0, 5))	('actin cytoskeletal regulatory proteins', 'MPA', (124, 162))	('EPHA2', 'Gene', '1969', (175, 180))
188811	33196759	We identified several genes, such as EPHA2, EPHA7, NTRK2, CDK6, hsa_circ_027570, and hsa_circ_035997, might be used to distinguish LUAD and LUSC.	('EPHA2', 'Gene', (37, 42))	('EPHA7', 'Gene', (44, 49))	('hsa_circ_027570', 'Var', (64, 79))	('NTRK2', 'Gene', '4915', (51, 56))	('LUAD', 'Disease', (131, 135))	('EPHA7', 'Gene', '2045', (44, 49))	('CDK6', 'Gene', (58, 62))	('EPHA2', 'Gene', '1969', (37, 42))	('CDK6', 'Gene', '1021', (58, 62))	('NTRK2', 'Gene', (51, 56))
188835	31885720	Caspase-8 promoter methylation results in the loss of gene expression, which is associated with tumor severity in a variety of different tumor types.	('methylation', 'Var', (19, 30))	('tumor', 'Disease', (137, 142))	('gene expression', 'MPA', (54, 69))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('loss', 'NegReg', (46, 50))	('tumor', 'Disease', (96, 101))	('Caspase-8', 'Gene', '841', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('Caspase-8', 'Gene', (0, 9))
188836	31885720	The methylation-mediated silencing of key apoptosis-associated genes serves an important role in the pathogenesis and development of therapeutic resistance in human cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('methylation-mediated', 'Var', (4, 24))	('human', 'Species', '9606', (159, 164))	('apoptosis-associated genes', 'Gene', (42, 68))	('cancer', 'Disease', (165, 171))	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('silencing', 'NegReg', (25, 34))
188875	31885720	The univariate analysis revealed a significant association between the expression of EPHB4 and family history, metastasis, and tumor size, position and stage.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('metastasis', 'CPA', (111, 121))	('tumor', 'Disease', (127, 132))	('EPHB4', 'Gene', '2050', (85, 90))	('expression', 'Var', (71, 81))	('EPHB4', 'Gene', (85, 90))	('tumor', 'Disease', 'MESH:D009369', (127, 132))
188938	31810000	An increasing body of evidence suggests that epigenetic changes play critical roles in the development of cancer stemness.	('cancer stemness', 'Disease', (106, 121))	('epigenetic changes', 'Var', (45, 63))	('cancer stemness', 'Disease', 'MESH:D009369', (106, 121))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
188939	31810000	LncRNAs can have either tumor-suppressing or tumor-promoting activities, and genome-wide association studies of different tumor samples found that mutations and/or altered expressions of lncRNA could be responsible for both tumorigenesis and metastasis.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('mutations', 'Var', (147, 156))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('tumor', 'Disease', (24, 29))	('expressions', 'MPA', (172, 183))	('metastasis', 'CPA', (242, 252))	('tumor', 'Disease', (45, 50))	('tumor', 'Disease', (224, 229))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('lncRNA', 'Gene', (187, 193))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('responsible', 'Reg', (203, 214))	('altered', 'Reg', (164, 171))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('tumor', 'Disease', (122, 127))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('tumor', 'Disease', 'MESH:D009369', (224, 229))
188945	31810000	Although both MTA1 and MTA2 are generally considered as oncogenes mainly because they are capable of enhancing metastasis, MTA3 can serve as either a cancer repressor or an oncogene depending on cancer types.	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('metastasis', 'CPA', (111, 121))	('MTA2', 'Gene', (23, 27))	('MTA3', 'Var', (123, 127))	('cancer', 'Disease', (195, 201))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('cancer', 'Disease', (150, 156))	('enhancing', 'PosReg', (101, 110))	('MTA1', 'Gene', (14, 18))	('MTA2', 'Gene', '9219', (23, 27))	('MTA1', 'Gene', '9112', (14, 18))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
188949	31810000	Of note, it has been suggested that MTA3-mediated epigenetic remodeling of chromatins may be involved in the regulation of cancer stemness.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('cancer stemness', 'Disease', 'MESH:D009369', (123, 138))	('MTA3-mediated', 'Gene', (36, 49))	('involved', 'Reg', (93, 101))	('epigenetic', 'Var', (50, 60))	('cancer stemness', 'Disease', (123, 138))
188963	31810000	We chose four cell lines to examine the effect of MTA3 on the metastasis makers and found that knockdown MTA3 in ESCC cells leads to significant reduction and induction of the epithelial marker (E-cadherin) and mesenchymal markers (N-cadherin and vimentin), respectively (Figure S2B).	('N-cadherin', 'Gene', '1000', (232, 242))	('reduction', 'NegReg', (145, 154))	('epithelial marker', 'CPA', (176, 193))	('E-cadherin', 'Gene', (195, 205))	('MTA3', 'Gene', (105, 109))	('knockdown', 'Var', (95, 104))	('mesenchymal markers', 'CPA', (211, 230))	('E-cadherin', 'Gene', '999', (195, 205))	('vimentin', 'Gene', '7431', (247, 255))	('induction', 'PosReg', (159, 168))	('N-cadherin', 'Gene', (232, 242))	('vimentin', 'Gene', (247, 255))
188966	31810000	Figures S3C and S3D showed that tumors derived from EC9706 and EC109 cells were not only larger but also heavier when MTA3 is knocked down by shRNA (p < 0.01 for all).	('MTA3', 'Gene', (118, 122))	('EC9706', 'CellLine', 'CVCL:E307', (52, 58))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('tumors', 'Disease', 'MESH:D009369', (32, 38))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('larger', 'PosReg', (89, 95))	('tumors', 'Disease', (32, 38))	('heavier', 'PosReg', (105, 112))	('EC109', 'CellLine', 'CVCL:6898', (63, 68))	('EC9706', 'Var', (52, 58))
188967	31810000	On the other hand, the tumors derived from EC9706 and HKESC-1 cells were smaller and lighter when MTA3 is overexpressed (p < 0.01 for both; Figures S3E and S3F).	('tumors', 'Disease', 'MESH:D009369', (23, 29))	('tumors', 'Disease', (23, 29))	('lighter', 'NegReg', (85, 92))	('EC9706', 'Var', (43, 49))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('HKESC-1', 'CellLine', 'CVCL:D568', (54, 61))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))	('EC9706', 'CellLine', 'CVCL:E307', (43, 49))
188972	31810000	Finally, when these cells were injected into the tail vein of nude mice, more ESCC cells in the MTA3 knockdown group were found in the lungs (Figure 2D and 2E), which is substantiated with results of H&E staining (Figure 2G).	('MTA3', 'Gene', (96, 100))	('ESCC', 'Gene', (78, 82))	('H&E', 'Chemical', '-', (200, 203))	('nude mice', 'Species', '10090', (62, 71))	('knockdown', 'Var', (101, 110))
188976	31810000	Consistent with the qRT-PCR results, knockdown MTA3 has no effect on luciferase activity under the control of the Snai1 promoter (Figures S4E-S4G).	('Snai1', 'Gene', '6615', (114, 119))	('knockdown', 'Var', (37, 46))	('activity', 'MPA', (80, 88))	('MTA3', 'Gene', (47, 51))	('Snai1', 'Gene', (114, 119))	('luciferase', 'Enzyme', (69, 79))
188979	31810000	We then estimated MTA3's effect on mammosphere formation and found that knockdown and overexpression of MTA3 significantly (p < 0.01) increased and decreased the number of mammospheres, respectively (Figures 2I and S5A), suggesting that MTA3 possesses property against ESCC cancer stemness.	('cancer stemness', 'Disease', 'MESH:D009369', (274, 289))	('decreased', 'NegReg', (148, 157))	('overexpression', 'PosReg', (86, 100))	('cancer stemness', 'Disease', (274, 289))	('increased', 'PosReg', (134, 143))	('cancer', 'Phenotype', 'HP:0002664', (274, 280))	('knockdown', 'Var', (72, 81))	('MTA3', 'Gene', (104, 108))
188981	31810000	Finally, CD44 increased dramatically in ESCC cells when MTA3 is knocked down (Figures 2M and S5D).	('increased', 'PosReg', (14, 23))	('CD44', 'Gene', (9, 13))	('knocked down', 'Var', (64, 76))	('MTA3', 'Gene', (56, 60))	('CD44', 'Gene', '960', (9, 13))
188983	31810000	To understand the mechanism in MTA3-regulated ESCC cancer stemness, we conducted a stemness PCR array and found that MTA3 knockdown leads to certain stemness-related genes to be up- or down-regulated, and 11 of them were elevated more than 1.5-fold (Figure S6A).	('stemness-related genes', 'Gene', (149, 171))	('ESCC', 'Disease', (46, 50))	('MTA3', 'Gene', (117, 121))	('elevated', 'PosReg', (221, 229))	('cancer stemness', 'Disease', (51, 66))	('down-regulated', 'NegReg', (185, 199))	('up-', 'PosReg', (178, 181))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('knockdown', 'Var', (122, 131))	('cancer stemness', 'Disease', 'MESH:D009369', (51, 66))
188986	31810000	However, luciferase reporter assays showed that MTA3 has no regulatory effect on SOX2 promoter (Figures S6F and S6G), suggesting that MTA3 could regulate SOX2 indirectly.	('S6G', 'Mutation', 'p.S6G', (112, 115))	('S6G', 'Var', (112, 115))	('SOX2', 'Gene', (81, 85))
188990	31810000	Results from both semi-quantitative PCR (Figure 3H) and qPCR (Figures 3I and S7A) demonstrated that MTA3 is recruited to the promoter region of the SOX2OT gene by GATA3 because knockdown of GATA3 abolished MTA3's repressive effect on SOX2OT and inhibited the MTA3's occupation on the promoter region of SOX2OT (Figures 3J-3L, S7B, and S7C).	('S7C', 'Mutation', 'rs749206235', (335, 338))	('GATA3', 'Gene', (190, 195))	('GATA3', 'Gene', (163, 168))	('abolished', 'NegReg', (196, 205))	('knockdown', 'Var', (177, 186))	('GATA3', 'Gene', '2625', (190, 195))	('GATA3', 'Gene', '2625', (163, 168))	('occupation', 'MPA', (266, 276))	('repressive effect', 'MPA', (213, 230))	('inhibited', 'NegReg', (245, 254))
188991	31810000	To determine which GATA3-binding site(s) is responsible for MTA3 recruitment, we conducted luciferase reporter assays with one, two, or three potential GATA3 being deleted (Figure 3M) from the SOX2OT promoter.	('GATA3', 'Gene', (152, 157))	('deleted', 'Var', (164, 171))	('GATA3', 'Gene', (19, 24))	('GATA3', 'Gene', '2625', (152, 157))	('GATA3', 'Gene', '2625', (19, 24))
188993	31810000	In addition, potential GATA3-binding site #1 is likely to be not involved in MTA3 recruitment because deletion of this site has no effect on MTA3-mediated repression.	('deletion', 'Var', (102, 110))	('GATA3', 'Gene', (23, 28))	('GATA3', 'Gene', '2625', (23, 28))
188994	31810000	However, sites #2 and #3 are likely to be responsible for the recruitment of GATA3/MTA3 complex because deleting either of them reduced MTA3-mediated repression significantly (p < 0.001, Figure 3O).	('reduced', 'NegReg', (128, 135))	('GATA3', 'Gene', (77, 82))	('deleting', 'Var', (104, 112))	('MTA3-mediated repression', 'MPA', (136, 160))	('GATA3', 'Gene', '2625', (77, 82))
189003	31810000	Kaplan-Meier analyses found that patients with ESCC in the high-SOX2 group had a poorer prognosis than those in the low-SOX2 group (p < 0.001; Figure 5E).	('ESCC', 'Disease', (47, 51))	('patients', 'Species', '9606', (33, 41))	('high-SOX2', 'Var', (59, 68))
189004	31810000	Correlation analyses also found that tumors with low levels of MTA3 were more likely to have high levels of SOX2 (p < 0.01; Figure 5F).	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('high levels of SOX2', 'MPA', (93, 112))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumors', 'Disease', (37, 43))	('low', 'Var', (49, 52))	('MTA3', 'Protein', (63, 67))	('tumors', 'Disease', 'MESH:D009369', (37, 43))
189006	31810000	Kaplan-Meier analyses found that overall survival of patients in the low-MTA3/high-SOX2 group is significantly worse than those in the high-MTA3/low-SOX2 (p < 0.001; Figure 5G), high-MTA3/low-SOX2, high-MTA3/high-SOX2, and low-MTA3/low-SOX2 (p < 0.001; Figure 5H) groups.	('patients', 'Species', '9606', (53, 61))	('worse', 'NegReg', (111, 116))	('low-MTA3/high-SOX2', 'Var', (69, 87))
189007	31810000	Finally, multivariate Cox regression analyses found that low-MTA3/high-SOX2 (HR, 3.273; 95% CI, 1.815 to 5.901, p = 0.000) can be used as independent prognostic indicators in ESCC patient prognosis (Table 1).	('ESCC', 'Disease', (175, 179))	('low-MTA3/high-SOX2', 'Var', (57, 75))	('patient', 'Species', '9606', (180, 187))
189010	31810000	To do so, we first used EC9706 cells to establish overexpression of MTA3 or SOX2 individually or in combinations (Figure 6A) as well as knockdown of MTA3 or SOX2 by specific shRNA individually or in combination (Figure 6B).	('EC9706', 'CellLine', 'CVCL:E307', (24, 30))	('knockdown', 'Var', (136, 145))	('overexpression', 'PosReg', (50, 64))
189013	31810000	Figures 6C and 6D show that the tumors derived from the cells with MTA3 overexpression were significantly smaller/lighter and the tumors derived from the cells overexpressing either SOX2OT or SOX2 were significantly bigger/heavier.	('tumors', 'Disease', (130, 136))	('tumors', 'Disease', 'MESH:D009369', (130, 136))	('overexpression', 'Var', (72, 86))	('smaller/lighter', 'NegReg', (106, 121))	('MTA3', 'Gene', (67, 71))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumors', 'Disease', (32, 38))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('tumors', 'Disease', 'MESH:D009369', (32, 38))
189014	31810000	In addition, the size/weight of tumors derived from the cells overexpressing MTA3 with either SOX2OT or SOX2 was bigger/heavier than that with MTA3 overexpression alone but smaller/lighter than that with either SOX2OT or SOX2 overexpression.	('smaller/lighter', 'NegReg', (173, 188))	('MTA3', 'Var', (77, 81))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumors', 'Disease', (32, 38))	('tumors', 'Disease', 'MESH:D009369', (32, 38))
189015	31810000	On the other hand, the tumors derived from the cells with MTA3 and SOX2 knockdown were bigger/heavier and smaller/lighter, respectively.	('MTA3', 'Gene', (58, 62))	('tumors', 'Disease', 'MESH:D009369', (23, 29))	('tumors', 'Disease', (23, 29))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('SOX2', 'Gene', (67, 71))	('knockdown', 'Var', (72, 81))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))
189016	31810000	The size/weight of the tumors derived from the cells with knockdown of both MTA3 and SOX2 was similar to that of the control (Figure 6E).	('tumors', 'Disease', 'MESH:D009369', (23, 29))	('tumors', 'Disease', (23, 29))	('MTA3', 'Gene', (76, 80))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('SOX2', 'Gene', (85, 89))	('knockdown', 'Var', (58, 67))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))
189027	31810000	This finding is in line with the fact that MTA3 is capable of inhibiting the initiation of primitive hematopoiesis in vertebrate embryos, repressing EMT in breast cancer cells, and suppressing Wnt4 pathway in mammary epithelial cells, implicating a role for MTA3 in regulation of stem cell properties.	('repressing', 'PosReg', (138, 148))	('EMT', 'CPA', (149, 152))	('initiation', 'CPA', (77, 87))	('hematopoiesis', 'Disease', (101, 114))	('MTA3', 'Var', (43, 47))	('suppressing', 'NegReg', (181, 192))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('Wnt4', 'Gene', (193, 197))	('inhibiting', 'NegReg', (62, 72))	('Wnt4', 'Gene', '54361', (193, 197))	('breast cancer', 'Disease', 'MESH:D001943', (156, 169))	('breast cancer', 'Disease', (156, 169))	('breast cancer', 'Phenotype', 'HP:0003002', (156, 169))	('hematopoiesis', 'Disease', 'MESH:C536227', (101, 114))
189038	31810000	It has been reported that GATA3 plays an important role in the regulation of CSC activities and loss of GATA3 contributes to breast cancer metastasis.	('GATA3', 'Gene', (104, 109))	('loss', 'Var', (96, 100))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('GATA3', 'Gene', '2625', (104, 109))	('breast cancer', 'Disease', 'MESH:D001943', (125, 138))	('GATA3', 'Gene', (26, 31))	('breast cancer', 'Disease', (125, 138))	('breast cancer', 'Phenotype', 'HP:0003002', (125, 138))	('GATA3', 'Gene', '2625', (26, 31))
189039	31810000	In addition, GATA3 is mutated in >10% of breast tumors.	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('breast tumors', 'Phenotype', 'HP:0100013', (41, 54))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('mutated', 'Var', (22, 29))	('breast tumors', 'Disease', 'MESH:D001943', (41, 54))	('breast tumors', 'Disease', (41, 54))	('GATA3', 'Gene', (13, 18))	('GATA3', 'Gene', '2625', (13, 18))
189040	31810000	Mutations in the second zinc finger domain of GATA3 diminishes or abolishes its DNA-binding ability and reduces its stability in human breast cancers.	('DNA-binding', 'Interaction', (80, 91))	('GATA3', 'Gene', (46, 51))	('diminishes', 'NegReg', (52, 62))	('reduces', 'NegReg', (104, 111))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('breast cancers', 'Phenotype', 'HP:0003002', (135, 149))	('GATA3', 'Gene', '2625', (46, 51))	('cancers', 'Phenotype', 'HP:0002664', (142, 149))	('Mutations', 'Var', (0, 9))	('breast cancers', 'Disease', 'MESH:D001943', (135, 149))	('breast cancers', 'Disease', (135, 149))	('human', 'Species', '9606', (129, 134))	('abolishes', 'NegReg', (66, 75))	('stability', 'MPA', (116, 125))	('breast cancer', 'Phenotype', 'HP:0003002', (135, 148))
189041	31810000	These findings altogether suggest that GATA3 mutations are "drivers" of breast cancer development.	('mutations', 'Var', (45, 54))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('GATA3', 'Gene', (39, 44))	('breast cancer', 'Disease', 'MESH:D001943', (72, 85))	('GATA3', 'Gene', '2625', (39, 44))	('breast cancer', 'Disease', (72, 85))	('breast cancer', 'Phenotype', 'HP:0003002', (72, 85))
189044	31810000	Of note, genetic changes (mutation, amplification, and deletion) of GATA3 are extremely rare in esophageal cancer (0.62%, Table S3).	('GATA3', 'Gene', '2625', (68, 73))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('amplification', 'Var', (36, 49))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('deletion', 'Var', (55, 63))	('GATA3', 'Gene', (68, 73))	('cancer', 'Disease', (107, 113))
189052	31810000	Based on the results mainly derived from overexpression and/or knockdown of different genes in cultured cells and xenograft mouse models, we were able to demonstrate that, by targeting/repressing the SOX2OT/SOX2 axis, MTA3 can suppress cancer stemness and EMT in ESCC.	('suppress', 'NegReg', (227, 235))	('ESCC', 'Disease', (263, 267))	('cancer stemness', 'Disease', (236, 251))	('targeting/repressing', 'Var', (175, 195))	('mouse', 'Species', '10090', (124, 129))	('MTA3', 'Gene', (218, 222))	('EMT', 'CPA', (256, 259))	('targeting/repressing', 'PosReg', (175, 195))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('cancer stemness', 'Disease', 'MESH:D009369', (236, 251))
189053	31810000	However, the conclusions would be strengthened if the relevant experiments were conducted in tissue-specific MTA3 transgenic and/or MTA3 knockout mice.	('MTA3', 'Gene', (109, 113))	('transgenic', 'Var', (114, 124))	('mice', 'Species', '10090', (146, 150))
189075	29482649	Inhibition of mitosis does not cause the death of cells, but apoptosis does.	('mitosis', 'Disease', (14, 21))	('mitosis', 'Disease', 'None', (14, 21))	('Inhibition', 'Var', (0, 10))
189104	29482649	The patients in Arm A received induction chemotherapy with 5-FU 700 mg/m2, d1-5, DDP 15 mg/m2, d1-5, and PTX 200 mg/m2, civ 24 h, q4w * 2 and then CCR with 5-FU 300 mg/m2, civ 96 h, and PTX 50 mg/m2, d1, qw * 5.	('5-FU', 'Chemical', 'MESH:D005472', (59, 63))	('q4w *', 'Var', (130, 135))	('PTX', 'Chemical', 'MESH:D017239', (105, 108))	('PTX', 'Chemical', 'MESH:D017239', (186, 189))	('CR', 'Chemical', 'MESH:D002857', (148, 150))	('DDP', 'Gene', '1678', (81, 84))	('d1-5', 'Gene', '25802;1734;1735;397', (75, 79))	('d1-5', 'Gene', '25802;1734;1735;397', (95, 99))	('d1-5', 'Gene', (75, 79))	('d1-5', 'Gene', (95, 99))	('patients', 'Species', '9606', (4, 12))	('5-FU 700 mg/m2', 'Var', (59, 73))	('5-FU', 'Chemical', 'MESH:D005472', (156, 160))	('DDP', 'Gene', (81, 84))
189105	29482649	The patients in Arm B received induction chemotherapy with PTX 175 mg/m2, d1, and DDP 75 mg/m2, d1, q3w * 2 and then CCR with DDP 30 mg/m2, and PTX 60 mg/m2, civ 96 h, qw * 5.	('DDP', 'Gene', (82, 85))	('DDP', 'Gene', (126, 129))	('CR', 'Chemical', 'MESH:D002857', (118, 120))	('q3w *', 'Var', (100, 105))	('PTX', 'Chemical', 'MESH:D017239', (144, 147))	('DDP', 'Gene', '1678', (82, 85))	('patients', 'Species', '9606', (4, 12))	('DDP', 'Gene', '1678', (126, 129))	('PTX', 'Chemical', 'MESH:D017239', (59, 62))
189127	29482649	WBC >= 3*109/L, Hemoglobin >=9 g/dL, Neutrophils >=1.5 x 109/L, Platelet count (Plt) >=100*109/L, ALAT and ASAT < 2.5 * ULN, TBIL< 1.5 * ULN, Creatinine < 1.5 *ULN.	('>=100*109/L', 'Var', (85, 96))	('Creatinine', 'MPA', (142, 152))	('Creatinine', 'Chemical', 'MESH:D003404', (142, 152))	('TBIL', 'MPA', (125, 129))	('ALAT', 'Disease', (98, 102))	('ALAT', 'Disease', 'None', (98, 102))	('TBIL', 'Chemical', '-', (125, 129))
189145	29482649	Chemotherapy should be administered with 25% dose reduction if ANC < 0.5 x 109/L, Plt < 25 x 109/L or >=Grade 3 non-hematological toxicities.	('Plt', 'MPA', (82, 85))	('toxicities', 'Disease', 'MESH:D064420', (130, 140))	('toxicities', 'Disease', (130, 140))	('< 0.5 x 109/L', 'Var', (67, 80))
189177	28927749	Both in vitro and in vivo siRNA-induced knockdown of Orm1 suppressed proliferation of mouse regenerating HPCs and human hepatic cells.	('proliferation', 'CPA', (69, 82))	('rat', 'Species', '10116', (76, 79))	('mouse', 'Species', '10090', (86, 91))	('knockdown', 'Var', (40, 49))	('suppressed', 'NegReg', (58, 68))	('rat', 'Species', '10116', (98, 101))	('human', 'Species', '9606', (114, 119))	('Orm1', 'Gene', (53, 57))
189178	28927749	Microarray analysis in regenerating mouse livers revealed that the signaling pathways controlling chromatin replication, especially the minichromosome maintenance protein complex genes were uniformly down-regulated following Orm1 knockdown.	('rat', 'Species', '10116', (29, 32))	('Orm1', 'Gene', (225, 229))	('knockdown', 'Var', (230, 239))	('down-regulated', 'NegReg', (200, 214))	('minichromosome maintenance protein complex genes', 'Gene', (136, 184))	('signaling pathways', 'Pathway', (67, 85))	('mouse', 'Species', '10090', (36, 41))
189231	28927749	Serum Orm1 concentrations were measured using ELISA kits (SEA816HU and SEA816MU for human and mouse serum samples, respectively; Cloud-Clone Corp., Houston, TX, USA).	('rat', 'Species', '10116', (18, 21))	('SEA816MU', 'Var', (71, 79))	('SEA816HU', 'Var', (58, 66))	('mouse', 'Species', '10090', (94, 99))	('human', 'Species', '9606', (84, 89))
189272	28927749	In a human HCC functional liver cell-4 cell line (FLC4), which has a similar gene expression profile as human liver, silencing Orm1 expression by siRNA inhibited cell proliferation, accompanying the lowered expression of cell cycle-associated gene cyclin D1 (Fig.	('Orm1', 'Gene', (127, 131))	('silencing', 'Var', (117, 126))	('cell proliferation', 'CPA', (162, 180))	('cyclin D1', 'Gene', '595', (248, 257))	('human', 'Species', '9606', (104, 109))	('lowered', 'NegReg', (199, 206))	('rat', 'Species', '10116', (174, 177))	('HCC', 'Phenotype', 'HP:0001402', (11, 14))	('expression', 'MPA', (207, 217))	('human', 'Species', '9606', (5, 10))	('inhibited', 'NegReg', (152, 161))	('cyclin D1', 'Gene', (248, 257))
189273	28927749	In contrast, treatment with recombinant human Orm1 protein significantly promoted cell growth in both control and Orm1 siRNAs-transfected cells (Fig.	('Orm1', 'Var', (114, 118))	('Orm1', 'Gene', (46, 50))	('cell growth', 'CPA', (82, 93))	('promoted', 'PosReg', (73, 81))	('human', 'Species', '9606', (40, 45))
189276	28927749	Diseases or Functions Annotation in IPA also suggested that "organismal death" and "necrosis" were activated, while "proliferation of cells" and "migration of cells" were inhibited in the regenerating livers treated with siOrm1 compared with the control livers (Fig.	('rat', 'Species', '10116', (149, 152))	('rat', 'Species', '10116', (124, 127))	('proliferation', 'CPA', (117, 130))	('rat', 'Species', '10116', (194, 197))	('inhibited', 'NegReg', (171, 180))	('activated', 'PosReg', (99, 108))	('necrosis', 'Disease', (84, 92))	('necrosis', 'Disease', 'MESH:D009336', (84, 92))	('siOrm1', 'Var', (221, 227))
189279	28927749	RT-PCR analysis verified that siRNA-mediated knockdown of Orm1 alone did not inhibit the expression of MCM genes in mouse livers but significantly suppressed their induction at 48 h after PH (Fig.	('Orm1', 'Gene', (58, 62))	('suppressed', 'NegReg', (147, 157))	('induction', 'MPA', (164, 173))	('mouse', 'Species', '10090', (116, 121))	('knockdown', 'Var', (45, 54))
189296	28927749	This was in accordance with our results that Orm1 knockdown suppressed the expression of genes controlling the cell cycle and chromosomal replication in proliferating HPCs.	('expression of', 'MPA', (75, 88))	('Orm1', 'Gene', (45, 49))	('suppressed', 'NegReg', (60, 70))	('rat', 'Species', '10116', (160, 163))	('knockdown', 'Var', (50, 59))	('cell', 'CPA', (111, 115))
189304	28927749	During the repeated liver damage and compensatory regeneration, aberrant stabilization and activation of pro-regenerative regulators such as c-Myc has contributed to the development of liver cancers.	('contributed', 'Reg', (151, 162))	('Myc', 'Gene', '4609', (143, 146))	('rat', 'Species', '10116', (56, 59))	('rat', 'Species', '10116', (115, 118))	('cancers', 'Phenotype', 'HP:0002664', (191, 198))	('liver cancers', 'Phenotype', 'HP:0002896', (185, 198))	('liver cancer', 'Phenotype', 'HP:0002896', (185, 197))	('liver cancers', 'Disease', (185, 198))	('liver cancers', 'Disease', 'MESH:D006528', (185, 198))	('activation', 'PosReg', (91, 101))	('Myc', 'Gene', (143, 146))	('liver damage', 'Disease', (20, 32))	('liver damage', 'Disease', 'MESH:D056486', (20, 32))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('aberrant', 'Var', (64, 72))
189308	28927749	In this study, suppressed cell proliferation of HCC cells following Orm1 knockdown suggest that Orm1, as an important regulator for normal HPC proliferation during liver regeneration, may serve as a potential therapeutic target in HCC.	('HCC', 'Phenotype', 'HP:0001402', (48, 51))	('Orm1', 'Gene', (96, 100))	('rat', 'Species', '10116', (176, 179))	('HCC', 'Disease', (231, 234))	('HCC', 'Phenotype', 'HP:0001402', (231, 234))	('rat', 'Species', '10116', (150, 153))	('Orm1', 'Gene', (68, 72))	('rat', 'Species', '10116', (38, 41))	('cell proliferation', 'CPA', (26, 44))	('knockdown', 'Var', (73, 82))
189356	32612094	Tumors located in the main bronchus, advanced cancer stage, T4 stage, M1 stage, without surgery, and without chemotherapy were associated with worse survival outcomes both in OS and CSS.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('cancer', 'Disease', (46, 52))	('M1 stage', 'Var', (70, 78))	('T4 stage', 'Var', (60, 68))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))
189383	32612094	Nowadays, besides surgery, chemotherapy, and radiotherapy, EGFR tyrosine kinase inhibitors may be an alternative treatment for EGFR mutation positive LASC patients.	('LASC', 'Disease', (150, 154))	('EGFR', 'Gene', (59, 63))	('LASC', 'Chemical', '-', (150, 154))	('patients', 'Species', '9606', (155, 163))	('EGFR', 'Gene', '1956', (127, 131))	('mutation', 'Var', (132, 140))	('EGFR', 'Gene', (127, 131))	('EGFR', 'Gene', '1956', (59, 63))
189384	32612094	Through the search of the literature in PubMed, there are few articles on EGFR gene mutation in adenosquamous carcinoma of the lung.	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('carcinoma of the lung', 'Phenotype', 'HP:0100526', (110, 131))	('adenosquamous carcinoma of the lung', 'Disease', (96, 131))	('adenosquamous carcinoma of the lung', 'Disease', 'MESH:D018196', (96, 131))	('EGFR', 'Gene', '1956', (74, 78))	('EGFR', 'Gene', (74, 78))	('mutation', 'Var', (84, 92))
189385	32612094	Despite this, research from a single center showed that LASC patients harboring EGFR mutations who were treated with EGFR-TKIs had a better prognosis than those receiving chemotherapy or chemoradiotherapy alone.	('EGFR', 'Gene', '1956', (117, 121))	('EGFR', 'Gene', (117, 121))	('patients', 'Species', '9606', (61, 69))	('EGFR', 'Gene', '1956', (80, 84))	('EGFR', 'Gene', (80, 84))	('mutations', 'Var', (85, 94))	('LASC', 'Chemical', '-', (56, 60))
189386	32612094	Delete in exon 19 and point mutation at codon 858 (L858R) in exon 21 are the 2 most common gene mutations in LASC.	('LASC', 'Chemical', '-', (109, 113))	('point mutation', 'Var', (22, 36))	('L858R', 'Var', (51, 56))	('Delete', 'Var', (0, 6))	('L858R', 'Mutation', 'rs121434568', (51, 56))	('LASC', 'Gene', (109, 113))
189432	32357912	Gene amplification, gene mutation, and abnormalities in upstream and downstream regulators of cyclin D, CDK4, and CDK6 can all lead to abnormal activation of the cyclin D-CDK4/6-Rb pathway.	('CDK6', 'Gene', (114, 118))	('CDK6', 'Gene', '1021', (114, 118))	('CDK4/6', 'Gene', '1019;1021', (171, 177))	('cyclin', 'Gene', (94, 100))	('cyclin', 'Gene', (162, 168))	('Rb', 'Phenotype', 'HP:0009919', (178, 180))	('lead to', 'Reg', (127, 134))	('abnormalities', 'Var', (39, 52))	('CDK4/6', 'Gene', (171, 177))	('CDK4', 'Gene', (171, 175))	('activation', 'PosReg', (144, 154))	('gene mutation', 'Var', (20, 33))	('cyclin', 'Gene', '5111', (162, 168))	('CDK4', 'Gene', (104, 108))	('CDK4', 'Gene', '1019', (171, 175))	('cyclin', 'Gene', '5111', (94, 100))	('CDK4', 'Gene', '1019', (104, 108))
189442	32357912	Moreover, the cdk4, cdk6, and e2f1 genes show extensive gene amplification and gene mutation in various tumors; deep deletion and gene mutation of the rb1 gene were observed in various tumors, while gene fusion and multiple alterations in these four genes are rare (Fig.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('cdk4', 'Gene', (14, 18))	('gene mutation', 'Var', (130, 143))	('tumors', 'Disease', (185, 191))	('tumors', 'Disease', (104, 110))	('rb1', 'Gene', '5925', (151, 154))	('cdk4', 'Gene', '1019', (14, 18))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('tumors', 'Disease', 'MESH:D009369', (185, 191))	('observed', 'Reg', (165, 173))	('cdk6', 'Gene', '1021', (20, 24))	('e2f1', 'Gene', (30, 34))	('deep deletion', 'Var', (112, 125))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('tumors', 'Phenotype', 'HP:0002664', (185, 191))	('cdk6', 'Gene', (20, 24))	('rb1', 'Gene', (151, 154))	('e2f1', 'Gene', '1869', (30, 34))
189443	32357912	These gene changes may explain the difference in the clinical efficacy of and drug resistance to CDK4/6 inhibitors in different tumors.	('CDK4/6', 'Gene', (97, 103))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumors', 'Disease', (128, 134))	('changes', 'Var', (11, 18))	('tumors', 'Disease', 'MESH:D009369', (128, 134))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('CDK4/6', 'Gene', '1019;1021', (97, 103))	('drug resistance', 'Phenotype', 'HP:0020174', (78, 93))
189444	32357912	Based on the analysis from the UALCAN cancer database, moderate expression of the cdk4 gene in KIRC, LGG, KIRP, MESO, KICH, and SKCM was significantly negatively related to overall survival (p < 0.05); high expression of the cdk4 gene in LIHC was closely related to worse overall survival than low expression and may be a sensitive marker for predicting the prognosis of LIHC.	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('negatively', 'NegReg', (151, 161))	('cdk4', 'Gene', '1019', (225, 229))	('high', 'Var', (202, 206))	('LIHC', 'Disease', (371, 375))	('cdk4', 'Gene', (225, 229))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('cancer', 'Disease', (38, 44))	('cdk4', 'Gene', '1019', (82, 86))	('cdk4', 'Gene', (82, 86))
189450	32357912	CDK4/6 inhibitors hinder the transition from G1 phase to S phase by inhibiting Rb phosphorylation and E2F release and induce tumor cycle arrest at G1 phase, which can inhibit tumor cell growth and cause tumor regression.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('tumor', 'Disease', (203, 208))	('inhibit', 'NegReg', (167, 174))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('arrest', 'Disease', 'MESH:D006323', (137, 143))	('CDK4/6', 'Gene', (0, 6))	('inhibiting', 'NegReg', (68, 78))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('inhibitors', 'Var', (7, 17))	('cause', 'Reg', (197, 202))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('tumor', 'Disease', (175, 180))	('CDK4/6', 'Gene', '1019;1021', (0, 6))	('induce', 'Reg', (118, 124))	('hinder', 'NegReg', (18, 24))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('arrest', 'Disease', (137, 143))	('tumor', 'Disease', (125, 130))	('Rb', 'Phenotype', 'HP:0009919', (79, 81))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('E2F release', 'MPA', (102, 113))
189456	32357912	The mutation rate of cell cycle-related genes in breast cancer is as high as 38%.	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('mutation', 'Var', (4, 12))	('breast cancer', 'Disease', 'MESH:D001943', (49, 62))	('breast cancer', 'Disease', (49, 62))	('breast cancer', 'Phenotype', 'HP:0003002', (49, 62))	('cell cycle-related genes', 'Gene', (21, 45))
189457	32357912	Increased expression of cyclin D causes continuous phosphorylation of Rb and leads to continuous proliferation of breast cancer cells; blocking CDK4/6 exerts a lethal effect on breast cancer cells.	('breast cancer', 'Disease', (177, 190))	('CDK4/6', 'Gene', '1019;1021', (144, 150))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('breast cancer', 'Disease', 'MESH:D001943', (177, 190))	('cyclin', 'Gene', '5111', (24, 30))	('breast cancer', 'Phenotype', 'HP:0003002', (177, 190))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('phosphorylation', 'MPA', (51, 66))	('CDK4/6', 'Gene', (144, 150))	('Rb', 'Phenotype', 'HP:0009919', (70, 72))	('cyclin', 'Gene', (24, 30))	('breast cancer', 'Disease', 'MESH:D001943', (114, 127))	('breast cancer', 'Phenotype', 'HP:0003002', (114, 127))	('blocking', 'Var', (135, 143))	('breast cancer', 'Disease', (114, 127))	('leads to', 'Reg', (77, 85))
189476	32357912	The major adverse effects of CDK4/6 inhibitors are leukopenia and neutropenia, mainly caused by palbociclib and ribociclib.	('CDK4/6', 'Gene', (29, 35))	('ribociclib', 'Chemical', 'MESH:C000589651', (112, 122))	('leukopenia', 'Disease', (51, 61))	('leukopenia', 'Disease', 'MESH:D007970', (51, 61))	('palbociclib', 'Chemical', 'MESH:C500026', (96, 107))	('neutropenia', 'Disease', 'MESH:D009503', (66, 77))	('neutropenia', 'Phenotype', 'HP:0001875', (66, 77))	('palbociclib', 'Var', (96, 107))	('CDK4/6', 'Gene', '1019;1021', (29, 35))	('leukopenia', 'Phenotype', 'HP:0001882', (51, 61))	('neutropenia', 'Disease', (66, 77))
189477	32357912	CDK4/6 inhibitors can also cause gastrointestinal side effects such as diarrhea, nausea, and vomiting.	('nausea', 'Disease', (81, 87))	('nausea', 'Disease', 'MESH:D009325', (81, 87))	('diarrhea', 'Disease', (71, 79))	('diarrhea', 'Disease', 'MESH:D003967', (71, 79))	('CDK4/6', 'Gene', '1019;1021', (0, 6))	('diarrhea', 'Phenotype', 'HP:0002014', (71, 79))	('inhibitors', 'Var', (7, 17))	('cause', 'Reg', (27, 32))	('vomiting', 'Phenotype', 'HP:0002013', (93, 101))	('CDK4/6', 'Gene', (0, 6))	('vomiting', 'Disease', (93, 101))	('vomiting', 'Disease', 'MESH:D014839', (93, 101))	('gastrointestinal side effects', 'MPA', (33, 62))	('nausea', 'Phenotype', 'HP:0002018', (81, 87))
189485	32357912	CDK4/6 inhibitors may have the potential to be widely applied in multiple cancers, similar to traditional chemotherapy drugs such as cisplatin or paclitaxel.	('multiple cancers', 'Disease', (65, 81))	('cancers', 'Phenotype', 'HP:0002664', (74, 81))	('paclitaxel', 'Chemical', 'MESH:D017239', (146, 156))	('CDK4/6', 'Gene', '1019;1021', (0, 6))	('multiple cancers', 'Disease', 'MESH:D009369', (65, 81))	('inhibitors', 'Var', (7, 17))	('cisplatin', 'Chemical', 'MESH:D002945', (133, 142))	('CDK4/6', 'Gene', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
189487	32357912	Yang's study showed that CDK4/6 inhibitors increased the sensitivity of acute myeloid leukemia cells to cytotoxic drugs.	('acute myeloid leukemia', 'Disease', (72, 94))	('inhibitors', 'Var', (32, 42))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (72, 94))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (78, 94))	('CDK4/6', 'Gene', '1019;1021', (25, 31))	('leukemia', 'Phenotype', 'HP:0001909', (86, 94))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (72, 94))	('increased', 'PosReg', (43, 52))	('sensitivity', 'MPA', (57, 68))	('CDK4/6', 'Gene', (25, 31))
189488	32357912	Patnaik and Taylor's study showed that CDK4/6 inhibitors achieved disease control rates of 49% and 44%, respectively, in non-small-cell lung cancer patients (n = 68) and melanoma patients (n = 18).	('patients', 'Species', '9606', (148, 156))	('lung cancer', 'Phenotype', 'HP:0100526', (136, 147))	('inhibitors', 'Var', (46, 56))	('melanoma', 'Phenotype', 'HP:0002861', (170, 178))	('melanoma', 'Disease', (170, 178))	('CDK4/6', 'Gene', (39, 45))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('melanoma', 'Disease', 'MESH:D008545', (170, 178))	('disease control', 'CPA', (66, 81))	('lung cancer', 'Disease', 'MESH:D008175', (136, 147))	('patients', 'Species', '9606', (179, 187))	('CDK4/6', 'Gene', '1019;1021', (39, 45))	('lung cancer', 'Disease', (136, 147))
189489	32357912	Adkins' study indicated an objective response rate of 39% for CDK4/6 inhibitors in patients with head and neck squamous cell carcinoma (n = 62).	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('neck squamous cell carcinoma', 'Disease', (106, 134))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (111, 134))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (106, 134))	('CDK4/6', 'Gene', '1019;1021', (62, 68))	('patients', 'Species', '9606', (83, 91))	('CDK4/6', 'Gene', (62, 68))	('inhibitors', 'Var', (69, 79))
189500	32357912	First, CDK4/6 inhibitors downregulate E2F transcription factor-related gene expression and upregulate major histocompatibility complex class I molecule expression in breast cancer cell lines; CDK4/6 inhibitors activate endogenous retroviral components in tumor cells, stimulating the production of type III interferons to promote tumor antigen presentation.	('tumor', 'Phenotype', 'HP:0002664', (255, 260))	('E2F transcription factor-related gene', 'Gene', (38, 75))	('tumor', 'Disease', (330, 335))	('breast cancer', 'Disease', 'MESH:D001943', (166, 179))	('inhibitors', 'Var', (199, 209))	('breast cancer', 'Disease', (166, 179))	('CDK4/6', 'Gene', (7, 13))	('tumor', 'Disease', 'MESH:D009369', (330, 335))	('activate', 'PosReg', (210, 218))	('CDK4/6', 'Gene', '1019;1021', (192, 198))	('stimulating', 'PosReg', (268, 279))	('expression', 'MPA', (152, 162))	('production', 'MPA', (284, 294))	('upregulate', 'PosReg', (91, 101))	('tumor', 'Disease', (255, 260))	('tumor', 'Phenotype', 'HP:0002664', (330, 335))	('CDK4/6', 'Gene', '1019;1021', (7, 13))	('downregulate', 'NegReg', (25, 37))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('tumor', 'Disease', 'MESH:D009369', (255, 260))	('promote', 'PosReg', (322, 329))	('CDK4/6', 'Gene', (192, 198))	('expression', 'MPA', (76, 86))	('breast cancer', 'Phenotype', 'HP:0003002', (166, 179))
189501	32357912	Second, CDK4/6 inhibitors inhibit the proliferation of regulatory T (Treg) cells and DNA methyltransferase 1 expression in Treg cells, resulting in promoter hypomethylation and suppression of E2F release; other studies demonstrated that the expression of CDK6 in Treg cells was higher than that of other T cell subtypes.	('E2F release', 'MPA', (192, 203))	('proliferation', 'CPA', (38, 51))	('expression', 'MPA', (109, 119))	('CDK4/6', 'Gene', (8, 14))	('promoter hypomethylation', 'MPA', (148, 172))	('CDK6', 'Gene', (255, 259))	('inhibit', 'NegReg', (26, 33))	('expression', 'MPA', (241, 251))	('CDK6', 'Gene', '1021', (255, 259))	('DNA methyltransferase 1', 'Gene', '1786', (85, 108))	('suppression', 'NegReg', (177, 188))	('CDK4/6', 'Gene', '1019;1021', (8, 14))	('DNA methyltransferase 1', 'Gene', (85, 108))	('higher', 'PosReg', (278, 284))	('inhibitors', 'Var', (15, 25))
189503	32357912	Furthermore, CDK4/6 inhibitors promote tumor cell clearance by enhancing cytotoxic T cells (CTLs).	('cytotoxic T cells', 'CPA', (73, 90))	('CDK4/6', 'Gene', '1019;1021', (13, 19))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('enhancing', 'PosReg', (63, 72))	('inhibitors', 'Var', (20, 30))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('CDK4/6', 'Gene', (13, 19))	('promote', 'PosReg', (31, 38))	('tumor', 'Disease', (39, 44))
189504	32357912	CDK6 is an upstream regulatory element of nuclear factor of activated T cells (NFAT), and CDK4/6 inhibitors suppress NFAT phosphorylation, the activation of CTLs, and its ability to kill tumor cells.	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('phosphorylation', 'CPA', (122, 137))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('NFAT', 'Protein', (117, 121))	('CDK6', 'Gene', (0, 4))	('CDK6', 'Gene', '1021', (0, 4))	('tumor', 'Disease', (187, 192))	('CTLs', 'Protein', (157, 161))	('CDK4/6', 'Gene', '1019;1021', (90, 96))	('activation', 'PosReg', (143, 153))	('CDK4/6', 'Gene', (90, 96))	('suppress', 'NegReg', (108, 116))	('inhibitors', 'Var', (97, 107))
189505	32357912	Finally, the Cyclin D1-CDK4 complex directly phosphorylates speckle-type POZ protein (SPOP), and CDK4/6 inhibitors can enhance the immune escape of tumors by decreasing the ubiquitination of SPOP and reducing the degradation of PD-L1.	('enhance', 'PosReg', (119, 126))	('CDK4/6', 'Gene', (97, 103))	('speckle-type POZ protein', 'Gene', '8405', (60, 84))	('SPOP', 'Gene', (86, 90))	('CDK4', 'Gene', '1019', (23, 27))	('reducing', 'NegReg', (200, 208))	('inhibitors', 'Var', (104, 114))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('SPOP', 'Gene', '8405', (191, 195))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('CDK4/6', 'Gene', '1019;1021', (97, 103))	('CDK4', 'Gene', (97, 101))	('PD-L1', 'Gene', (228, 233))	('speckle-type POZ protein', 'Gene', (60, 84))	('SPOP', 'Gene', (191, 195))	('ubiquitination', 'MPA', (173, 187))	('PD-L1', 'Gene', '29126', (228, 233))	('tumors', 'Disease', (148, 154))	('Cyclin D1', 'Gene', '595', (13, 22))	('Cyclin D1', 'Gene', (13, 22))	('SPOP', 'Gene', '8405', (86, 90))	('CDK4', 'Gene', '1019', (97, 101))	('CDK4', 'Gene', (23, 27))	('decreasing', 'NegReg', (158, 168))	('degradation', 'MPA', (213, 224))	('tumors', 'Disease', 'MESH:D009369', (148, 154))
189510	32357912	Teo's study showed that CDK4/6 inhibitors combined with PI3K inhibitors increased the apoptosis of triple-negative breast cancer cell lines and induced persistent tumor regression in vivo.	('PI3', 'Gene', (56, 59))	('increased', 'PosReg', (72, 81))	('CDK4/6', 'Gene', '1019;1021', (24, 30))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('breast cancer', 'Phenotype', 'HP:0003002', (115, 128))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('CDK4/6', 'Gene', (24, 30))	('induced', 'Reg', (144, 151))	('tumor', 'Disease', (163, 168))	('breast cancer', 'Disease', 'MESH:D001943', (115, 128))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('PI3', 'Gene', '5266', (56, 59))	('breast cancer', 'Disease', (115, 128))	('inhibitors', 'Var', (31, 41))	('apoptosis', 'CPA', (86, 95))
189512	32357912	EGFR/HER2 inhibitors combined with CDK4/6 inhibitors may increase the sensitivity to EGFR inhibitor-resistant lung cancer cells.	('EGFR', 'Gene', (85, 89))	('lung cancer', 'Disease', 'MESH:D008175', (110, 121))	('EGFR', 'Gene', (0, 4))	('HER2', 'Gene', (5, 9))	('HER2', 'Gene', '2064', (5, 9))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('sensitivity', 'MPA', (70, 81))	('lung cancer', 'Disease', (110, 121))	('CDK4/6', 'Gene', '1019;1021', (35, 41))	('lung cancer', 'Phenotype', 'HP:0100526', (110, 121))	('increase', 'PosReg', (57, 65))	('inhibitors', 'Var', (10, 20))	('EGFR', 'Gene', '1956', (85, 89))	('EGFR', 'Gene', '1956', (0, 4))	('CDK4/6', 'Gene', (35, 41))
189513	32357912	Goel's study demonstrated that CDK4/6 inhibitors augmented the efficacy of EGFR inhibitors in esophageal squamous cell carcinoma and reversed drug resistance.	('reversed', 'Reg', (133, 141))	('augmented', 'PosReg', (49, 58))	('CDK4/6', 'Gene', (31, 37))	('inhibitors', 'Var', (38, 48))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (94, 128))	('CDK4/6', 'Gene', '1019;1021', (31, 37))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (105, 128))	('EGFR', 'Gene', '1956', (75, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('efficacy', 'MPA', (63, 71))	('drug resistance', 'Phenotype', 'HP:0020174', (142, 157))	('drug resistance', 'MPA', (142, 157))	('esophageal squamous cell carcinoma', 'Disease', (94, 128))	('EGFR', 'Gene', (75, 79))	('inhibitors', 'Var', (80, 90))
189517	32357912	Chen's study showed that RAF inhibitors combined with CDK4/6 inhibitors improve the therapeutic effects of RAS or BRAF mutant tumors.	('RAS', 'Disease', (107, 110))	('RAF', 'Gene', '22882', (25, 28))	('BRAF', 'Gene', (114, 118))	('tumors', 'Disease', (126, 132))	('BRAF', 'Gene', '673', (114, 118))	('tumors', 'Disease', 'MESH:D009369', (126, 132))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('RAF', 'Gene', (25, 28))	('improve', 'PosReg', (72, 79))	('CDK4/6', 'Gene', (54, 60))	('RAF', 'Gene', '22882', (115, 118))	('RAF', 'Gene', (115, 118))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('mutant', 'Var', (119, 125))	('CDK4/6', 'Gene', '1019;1021', (54, 60))	('therapeutic effects', 'CPA', (84, 103))
189520	32357912	Ribociclib combined with the ALK inhibitor ceritinib showed excellent therapeutic effects in ALK mutant neuroblastoma.	('ALK', 'Gene', (29, 32))	('neuroblastoma', 'Disease', (104, 117))	('ALK', 'Gene', '238', (93, 96))	('neuroblastoma', 'Phenotype', 'HP:0003006', (104, 117))	('mutant', 'Var', (97, 103))	('ceritinib', 'Chemical', 'MESH:C586847', (43, 52))	('ALK', 'Gene', '238', (29, 32))	('ALK', 'Gene', (93, 96))	('neuroblastoma', 'Disease', 'MESH:D009447', (104, 117))
189523	32357912	Vijayaraghavan's research showed that CDK4/6 inhibitors combined with autophagy inhibitors can maintain the integrity of the G1/S checkpoint and may be a new therapeutic pattern for multiple solid tumors.	('maintain', 'PosReg', (95, 103))	('tumors', 'Disease', 'MESH:D009369', (197, 203))	('integrity', 'CPA', (108, 117))	('CDK4/6', 'Gene', '1019;1021', (38, 44))	('tumors', 'Phenotype', 'HP:0002664', (197, 203))	('inhibitors', 'Var', (45, 55))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('CDK4/6', 'Gene', (38, 44))	('tumors', 'Disease', (197, 203))
189524	32357912	Francis's study confirmed that CDK4/6 inhibitors resensitize Rb-positive sarcoma cells to the Weel kinase inhibitor AZD1775.	('Rb', 'Phenotype', 'HP:0009919', (61, 63))	('AZD1775', 'Chemical', 'MESH:C549567', (116, 123))	('sarcoma', 'Disease', (73, 80))	('sarcoma', 'Phenotype', 'HP:0100242', (73, 80))	('CDK4/6', 'Gene', '1019;1021', (31, 37))	('inhibitors', 'Var', (38, 48))	('CDK4/6', 'Gene', (31, 37))	('sarcoma', 'Disease', 'MESH:D012509', (73, 80))
189527	32357912	Some researchers believe that CCNE1 amplification causes acquired resistance to CDK4/6 inhibitors, and that sensitivity can be restored by targeting CDK2.	('CDK2', 'Gene', '1017', (149, 153))	('CCNE1', 'Gene', '898', (30, 35))	('CCNE1', 'Gene', (30, 35))	('CDK4/6', 'Gene', (80, 86))	('amplification', 'Var', (36, 49))	('CDK2', 'Gene', (149, 153))	('CDK4/6', 'Gene', '1019;1021', (80, 86))	('causes', 'Reg', (50, 56))
189528	32357912	In addition, activating cyclin D gene mutations may enhance sensitivity to CDK4/6 inhibitors, while cyclin D deficiency is associated with CDK4/6 inhibitor resistance.	('CDK4/6', 'Gene', (139, 145))	('CDK4/6', 'Gene', '1019;1021', (75, 81))	('activating', 'PosReg', (13, 23))	('CDK4/6', 'Gene', (75, 81))	('cyclin', 'Gene', '5111', (24, 30))	('enhance', 'PosReg', (52, 59))	('CDK4/6', 'Gene', '1019;1021', (139, 145))	('cyclin', 'Gene', '5111', (100, 106))	('cyclin', 'Gene', (24, 30))	('mutations', 'Var', (38, 47))	('cyclin', 'Gene', (100, 106))
189532	32357912	A recent study revealed that amplification of fibroblast growth factor receptor 1 (FGFR1) might cause resistance to CDK4/6 inhibitors.	('fibroblast growth factor receptor 1', 'Gene', (46, 81))	('amplification', 'Var', (29, 42))	('CDK4/6', 'Gene', (116, 122))	('cause', 'Reg', (96, 101))	('FGFR1', 'Gene', (83, 88))	('fibroblast growth factor receptor 1', 'Gene', '2260', (46, 81))	('FGFR1', 'Gene', '2260', (83, 88))	('CDK4/6', 'Gene', '1019;1021', (116, 122))
189534	32357912	Studies have shown that deletion of p16 decreases the endogenous inhibition of CDK4/6 and that low levels of p16 may suggest that cells are sensitive to CDK4/6 inhibitors.	('p16', 'Gene', (109, 112))	('CDK4/6', 'Gene', (153, 159))	('endogenous inhibition', 'MPA', (54, 75))	('p16', 'Gene', '1029', (36, 39))	('CDK4/6', 'Gene', '1019;1021', (79, 85))	('p16', 'Gene', '1029', (109, 112))	('CDK4/6', 'Gene', '1019;1021', (153, 159))	('deletion', 'Var', (24, 32))	('decreases', 'NegReg', (40, 49))	('CDK4/6', 'Gene', (79, 85))	('p16', 'Gene', (36, 39))
189536	32357912	However, Wang's study showed that approximately 85% of breast cancer cells have normal Rb status, but due to the rare Rb deletion in ER+ breast cancer, it is less sensitive as a predictive marker.	('breast cancer', 'Disease', 'MESH:D001943', (137, 150))	('Rb', 'Phenotype', 'HP:0009919', (118, 120))	('breast cancer', 'Phenotype', 'HP:0003002', (137, 150))	('breast cancer', 'Disease', (137, 150))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('Rb status', 'MPA', (87, 96))	('breast cancer', 'Disease', 'MESH:D001943', (55, 68))	('breast cancer', 'Disease', (55, 68))	('Rb', 'Phenotype', 'HP:0009919', (87, 89))	('breast cancer', 'Phenotype', 'HP:0003002', (55, 68))	('deletion', 'Var', (121, 129))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
189541	32357912	CDK4/6 inhibitors achieve striking antitumor effects by regulating the cell cycle.	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('CDK4/6', 'Gene', '1019;1021', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('inhibitors', 'Var', (7, 17))	('regulating', 'Reg', (56, 66))	('tumor', 'Disease', (39, 44))	('CDK4/6', 'Gene', (0, 6))	('cell cycle', 'CPA', (71, 81))
189544	32357912	CDK4/6 inhibitors have great potential to become broad-spectrum antitumor drugs.	('tumor', 'Disease', (68, 73))	('CDK4/6', 'Gene', '1019;1021', (0, 6))	('inhibitors', 'Var', (7, 17))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('CDK4/6', 'Gene', (0, 6))
189555	31324732	It was demonstrated that PYGM and TNNC2 were significantly down-regulated in HNSCC and the aberrant expression of PYGM and TNNC2 were correlated with HNSCC prognosis, implying the potential of exploiting them as therapeutic targets for HNSCC treatment or potential biomarkers for diagnosis and prognosis.	('PYGM', 'Gene', (25, 29))	('HNSCC', 'Phenotype', 'HP:0012288', (150, 155))	('TNNC2', 'Gene', (34, 39))	('TNNC2', 'Gene', (123, 128))	('PYGM', 'Gene', '5837', (114, 118))	('TNNC2', 'Gene', '7125', (123, 128))	('expression', 'MPA', (100, 110))	('down-regulated', 'NegReg', (59, 73))	('correlated', 'Reg', (134, 144))	('HNSCC', 'Phenotype', 'HP:0012288', (77, 82))	('HNSCC', 'Disease', (77, 82))	('HNSCC', 'Disease', (150, 155))	('PYGM', 'Gene', (114, 118))	('PYGM', 'Gene', '5837', (25, 29))	('aberrant', 'Var', (91, 99))	('HNSCC', 'Phenotype', 'HP:0012288', (236, 241))	('TNNC2', 'Gene', '7125', (34, 39))
189566	31324732	The emerging molecular signatures pioneer a promising field where ectopic gene expression may serve as effective biomarker for HNSCC initiation and treatment methods focused on gene regulation may improve the existing therapeutic strategies.	('HNSCC initiation', 'Disease', 'MESH:D000077195', (127, 143))	('HNSCC initiation', 'Disease', (127, 143))	('ectopic gene', 'Var', (66, 78))	('HNSCC', 'Phenotype', 'HP:0012288', (127, 132))
189623	31324732	From the OncoPrint schematic, gene alteration of PYGM and TNNC2 was 4 and 0.8% in HNSCC samples, respectively (Figure 7A).	('TNNC2', 'Gene', (58, 63))	('PYGM', 'Gene', (49, 53))	('HNSCC', 'Phenotype', 'HP:0012288', (82, 87))	('TNNC2', 'Gene', '7125', (58, 63))	('PYGM', 'Gene', '5837', (49, 53))	('gene alteration', 'Var', (30, 45))
189660	29270239	Targeted bisulfite sequencing identified a panel of DNA methylation-based biomarkers for esophageal squamous cell carcinoma (ESCC) DNA methylation has been implicated as a promising biomarker for precise cancer diagnosis.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (100, 123))	('cancer', 'Disease', (204, 210))	('methylation', 'Var', (135, 146))	('or', 'Gene', '31118', (86, 88))	('cancer', 'Disease', 'MESH:D009369', (204, 210))	('esophageal squamous cell carcinoma', 'Disease', (89, 123))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('or', 'Gene', '31118', (193, 195))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('bisulfite', 'Chemical', 'MESH:C042345', (9, 18))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (89, 123))
189666	29270239	In the discovery stage, five hyper-methylated CpG sites were selected as candidate biomarkers for further analysis as shown below: cg15830431, P = 2.20 x 10-4; cg19396867, P = 3.60 x 10-4; cg20655070, P = 3.60 x 10-4; cg26671652, P = 5.77 x 10-4; and cg27062795, P = 3.60 x 10-4.	('cg27062795', 'Chemical', '-', (251, 261))	('cg26671652', 'Var', (218, 228))	('cg20655070', 'Var', (189, 199))	('cg19396867', 'Chemical', '-', (160, 170))	('cg26671652', 'Chemical', '-', (218, 228))	('or', 'Gene', '31118', (95, 97))	('cg15830431', 'Var', (131, 141))	('cg19396867', 'Var', (160, 170))	('cg15830431', 'Chemical', '-', (131, 141))	('cg27062795', 'Var', (251, 261))	('cg20655070', 'Chemical', '-', (189, 199))
189669	29270239	Methylation profiles of the five genomic regions covering cg15830431 (STK3), cg19396867, cg20655070, cg26671652 (ZNF418), and cg27062795 (ZNF542) can be used for effective methylation-based testing for ESCC diagnosis.	('cg26671652', 'Var', (101, 111))	('or', 'Gene', '31118', (159, 161))	('cg15830431', 'Var', (58, 68))	('ZNF418', 'Gene', '147686', (113, 119))	('ZNF542', 'Gene', (138, 144))	('cg19396867', 'Chemical', '-', (77, 87))	('ESCC', 'Disease', (202, 206))	('or', 'Gene', '31118', (199, 201))	('cg26671652', 'Chemical', '-', (101, 111))	('ZNF542', 'Gene', '147947', (138, 144))	('cg20655070', 'Chemical', '-', (89, 99))	('cg27062795', 'Chemical', '-', (126, 136))	('cg15830431', 'Chemical', '-', (58, 68))	('cg19396867', 'Var', (77, 87))	('cg27062795', 'Var', (126, 136))	('cg20655070', 'Var', (89, 99))	('ZNF418', 'Gene', (113, 119))
189676	29270239	Numerous studies have suggested that the altered DNA methylation patterns in tumor tissues may silence the tumor suppressor genes and activate the oncogenes through hyper/hypo methylation.	('or', 'Gene', '31118', (121, 123))	('or', 'Gene', '31118', (80, 82))	('altered', 'Var', (41, 48))	('hyper/hypo methylation', 'Var', (165, 187))	('activate', 'PosReg', (134, 142))	('tumor', 'Disease', (107, 112))	('or', 'Gene', '31118', (110, 112))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('oncogenes', 'Gene', (147, 156))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('tumor', 'Disease', (77, 82))	('silence', 'NegReg', (95, 102))
189677	29270239	In addition, DNA methylation alterations have been found to occur early in the carcinogenesis and therefore could be applied as a promising biomarker for cancer early detection.	('or', 'Gene', '31118', (104, 106))	('cancer', 'Disease', (154, 160))	('alterations', 'Var', (29, 40))	('carcinogenesis', 'Disease', 'MESH:D063646', (79, 93))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('methylation alterations', 'Var', (17, 40))	('carcinogenesis', 'Disease', (79, 93))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('DNA', 'Gene', (13, 16))	('or', 'Gene', '31118', (151, 153))
189689	29270239	1), cg15830431 (P = 2.20 x 10-4), cg19396867 (P = 3.60 x 10-4), cg20655070 (P = 1.71 x 10-3), cg26671652 (P = 5.77 x 10-4), and cg27062795 (P = 3.60 x 10-4) were selected for further validation.	('cg27062795', 'Chemical', '-', (128, 138))	('cg26671652', 'Chemical', '-', (94, 104))	('cg27062795', 'Var', (128, 138))	('cg15830431', 'Var', (4, 14))	('cg19396867', 'Chemical', '-', (34, 44))	('cg20655070', 'Chemical', '-', (64, 74))	('cg15830431', 'Chemical', '-', (4, 14))	('cg26671652', 'Var', (94, 104))	('cg19396867', 'Var', (34, 44))	('cg20655070', 'Var', (64, 74))	('or', 'Gene', '31118', (172, 174))
189690	29270239	Among them, cg19396867 and cg20655070 were not in the regulatory regions of specific genes, while cg15830431 (STK3, CpG Island), cg26671652 (ZNF418, CpG Shore), and cg27062795 (ZNF542, CpG Island) were either in CpG islands or the CpG shores of a gene.	('or', 'Gene', '31118', (224, 226))	('cg27062795', 'Chemical', '-', (165, 175))	('or', 'Gene', '31118', (155, 157))	('ZNF418', 'Gene', (141, 147))	('cg20655070', 'Var', (27, 37))	('cg19396867', 'Chemical', '-', (12, 22))	('cg26671652', 'Var', (129, 139))	('cg15830431', 'Chemical', '-', (98, 108))	('cg20655070', 'Chemical', '-', (27, 37))	('cg19396867', 'Var', (12, 22))	('ZNF418', 'Gene', '147686', (141, 147))	('ZNF542', 'Gene', (177, 183))	('or', 'Gene', '31118', (237, 239))	('or', 'Gene', '31118', (61, 63))	('cg26671652', 'Chemical', '-', (129, 139))	('ZNF542', 'Gene', '147947', (177, 183))	('cg15830431', 'Var', (98, 108))	('cg27062795', 'Var', (165, 175))
189702	29270239	A logistic regression model was then applied and showed significant hyper-methylation of the five selected CpG sites in the ESCCs (Table 2, cg15830431, P = 1.25 x 10-6; cg19396867, P = 2.71 x 10-11; cg20655070, P = 8.04 x 10-10; cg26671652, P = 4.82 x 10-11; cg27062795, P = 1.23 x 10-12).	('cg15830431', 'Var', (140, 150))	('cg26671652', 'Var', (229, 239))	('cg19396867', 'Chemical', '-', (169, 179))	('cg27062795', 'Var', (259, 269))	('cg19396867', 'Var', (169, 179))	('cg27062795', 'Chemical', '-', (259, 269))	('cg15830431', 'Chemical', '-', (140, 150))	('cg26671652', 'Chemical', '-', (229, 239))	('cg20655070', 'Chemical', '-', (199, 209))	('hyper-methylation', 'PosReg', (68, 85))	('cg20655070', 'Var', (199, 209))
189725	29270239	DNA methylation plays a key role in the gene expression regulation and therefore has great potential as a non-invasive biomarker for cancer diagnosis and prognosis.	('gene expression regulation', 'MPA', (40, 66))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('or', 'Gene', '31118', (77, 79))	('methylation', 'Var', (4, 15))	('cancer', 'Disease', (133, 139))	('or', 'Gene', '31118', (130, 132))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
189727	29270239	Previous studies have found several candidate methylation biomarkers for ESCC detection and prognosis as well as treatment response.	('ESCC', 'Disease', (73, 77))	('methylation', 'Var', (46, 57))	('or', 'Gene', '31118', (70, 72))
189732	29270239	In addition, the subgroup analyses identified that the diagnostic performance of the methylation testing is much better in the non-alcohol-consuming patients than in the ESCC patients who consume alcohol, suggesting the importance of taking the epidemiological data into considerations when performing ESCC diagnosis.	('alcohol', 'Chemical', 'MESH:D000438', (131, 138))	('methylation', 'Var', (85, 96))	('patients', 'Species', '9606', (149, 157))	('or', 'Gene', '31118', (70, 72))	('better', 'PosReg', (113, 119))	('alcohol', 'Chemical', 'MESH:D000438', (196, 203))	('patients', 'Species', '9606', (175, 183))	('or', 'Gene', '31118', (295, 297))	('or', 'Gene', '31118', (223, 225))
189734	29270239	Of the five genomic regions, two genomic regions covering cg19396867 and cg20655070 were not in the regulatory regions of specific genes.	('or', 'Gene', '31118', (107, 109))	('cg20655070', 'Chemical', '-', (73, 83))	('cg20655070', 'Var', (73, 83))	('cg19396867', 'Chemical', '-', (58, 68))	('cg19396867', 'Var', (58, 68))
189735	29270239	However, the H3k4me3, H3k4me1, and H3k27ac status of these two regions from the ENCODE project showed that these regions might be associated with the enhancers, indicating that the regions might also have important regulatory functions (data not shown).	('H3k4me1', 'Var', (22, 29))	('or', 'Gene', '31118', (208, 210))	('H3k27ac', 'Var', (35, 42))	('or', 'Gene', '31118', (222, 224))	('H3k4me3', 'Var', (13, 20))
189736	29270239	In contrast, cg15830431 (STK3, CpG Island), cg26671652 (ZNF418, CpG Shore), and cg27062795 (ZNF542, CpG Island) were either in the CpG islands or the CpG shores of a gene.	('cg15830431', 'Var', (13, 23))	('cg26671652', 'Var', (44, 54))	('cg27062795', 'Chemical', '-', (80, 90))	('or', 'Gene', '31118', (70, 72))	('cg27062795', 'Var', (80, 90))	('ZNF418', 'Gene', (56, 62))	('cg15830431', 'Chemical', '-', (13, 23))	('or', 'Gene', '31118', (156, 158))	('ZNF418', 'Gene', '147686', (56, 62))	('ZNF542', 'Gene', (92, 98))	('cg26671652', 'Chemical', '-', (44, 54))	('or', 'Gene', '31118', (143, 145))	('ZNF542', 'Gene', '147947', (92, 98))
189738	29270239	A previous study has found that the deletion of STK3 in mouse liver results in tissue overgrowth and tumor development, demonstrating its importance in suppressing carcinogenesis.	('suppressing', 'NegReg', (152, 163))	('or', 'Gene', '31118', (141, 143))	('deletion', 'Var', (36, 44))	('or', 'Gene', '31118', (104, 106))	('tissue overgrowth', 'CPA', (79, 96))	('STK3', 'Gene', (48, 52))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('mouse', 'Species', '10090', (56, 61))	('carcinogenesis', 'Disease', 'MESH:D063646', (164, 178))	('overgrowth', 'Phenotype', 'HP:0001548', (86, 96))	('carcinogenesis', 'Disease', (164, 178))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
189739	29270239	Also, hyper-methylation of STK3 has been found in soft tissue sarcoma as well as head and neck squamous cell carcinoma, which is in accordance with the present study.	('found', 'Reg', (41, 46))	('sarcoma', 'Phenotype', 'HP:0100242', (62, 69))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (50, 69))	('STK3', 'Gene', (27, 31))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (50, 69))	('or', 'Gene', '31118', (135, 137))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (95, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('hyper-methylation', 'Var', (6, 23))	('soft tissue sarcoma', 'Disease', (50, 69))	('squamous cell carcinoma', 'Disease', (95, 118))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (95, 118))
189744	29270239	Studies have found hyper-methylation of ZNF542 in oropharyngeal squamous cell carcinoma and sporadic colorectal cancer.	('or', 'Gene', '31118', (94, 96))	('colorectal cancer', 'Disease', 'MESH:D015179', (101, 118))	('ZNF542', 'Gene', '147947', (40, 46))	('or', 'Gene', '31118', (104, 106))	('hyper-methylation', 'Var', (19, 36))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('or', 'Gene', '31118', (50, 52))	('colorectal cancer', 'Phenotype', 'HP:0003003', (101, 118))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (64, 87))	('ZNF542', 'Gene', (40, 46))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('colorectal cancer', 'Disease', (101, 118))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (64, 87))	('oropharyngeal squamous cell carcinoma', 'Phenotype', 'HP:0012182', (50, 87))	('squamous cell carcinoma', 'Disease', (64, 87))
189755	29270239	Compared with the other kinds of biomarkers, DNA methylation alterations may occur in advance of the alterations of mRNA and protein levels in the carcinogenesis thus might have a better early diagnosis potential.	('carcinogenesis', 'Disease', 'MESH:D063646', (147, 161))	('alterations', 'Reg', (61, 72))	('carcinogenesis', 'Disease', (147, 161))	('DNA', 'MPA', (45, 48))	('methylation', 'Var', (49, 60))
189770	29270239	Methylation profiles of the five genomic regions covering cg15830431 (STK3), cg19396867, cg20655070, cg26671652 (ZNF418), and cg27062795 (ZNF542) may be effective DNA methylation-based testing for ESCC diagnosis.	('cg26671652', 'Var', (101, 111))	('cg15830431', 'Var', (58, 68))	('ZNF418', 'Gene', '147686', (113, 119))	('ZNF542', 'Gene', (138, 144))	('ESCC', 'Disease', (197, 201))	('cg19396867', 'Chemical', '-', (77, 87))	('cg26671652', 'Chemical', '-', (101, 111))	('cg15830431', 'Chemical', '-', (58, 68))	('ZNF542', 'Gene', '147947', (138, 144))	('cg20655070', 'Chemical', '-', (89, 99))	('cg27062795', 'Chemical', '-', (126, 136))	('or', 'Gene', '31118', (194, 196))	('cg19396867', 'Var', (77, 87))	('cg27062795', 'Var', (126, 136))	('cg20655070', 'Var', (89, 99))	('ZNF418', 'Gene', (113, 119))
189786	29270239	Moreover, we further removed the CpG sites with SNPs in their primers and the CpG sites whose corresponding genes have been studied in ESCC carcinogenesis.	('ESCC', 'Disease', (135, 139))	('carcinogenesis', 'Disease', 'MESH:D063646', (140, 154))	('carcinogenesis', 'Disease', (140, 154))	('or', 'Gene', '31118', (95, 97))	('or', 'Gene', '31118', (1, 3))	('SNPs', 'Var', (48, 52))
189789	29270239	Finally, five of our candidate biomarkers were selected for further validation: cg15830431, cg19396867, cg20655070, cg26671652, and cg27062795.	('cg20655070', 'Chemical', '-', (104, 114))	('cg27062795', 'Chemical', '-', (132, 142))	('cg20655070', 'Var', (104, 114))	('cg26671652', 'Var', (116, 126))	('cg19396867', 'Chemical', '-', (92, 102))	('cg27062795', 'Var', (132, 142))	('or', 'Gene', '31118', (57, 59))	('cg15830431', 'Var', (80, 90))	('cg19396867', 'Var', (92, 102))	('cg26671652', 'Chemical', '-', (116, 126))	('cg15830431', 'Chemical', '-', (80, 90))
189824	33614647	Based on these results, we assume that cancer cells successfully manage mitochondrial Ca2+ uptake to stimulate Ca2+-dependent mitochondrial metabolism while avoiding Ca2+-triggered cell death by fine-tuning ER-mitochondrial tethering and the expression of UCP2 in an inversed manner.	('ER', 'Gene', '2069', (207, 209))	('Ca2+-dependent mitochondrial metabolism', 'MPA', (111, 150))	('cancer', 'Disease', (39, 45))	('UCP2', 'Gene', '7351', (256, 260))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('Ca2+', 'Chemical', 'MESH:D000069285', (111, 115))	('Ca2+', 'Chemical', 'MESH:D000069285', (86, 90))	('Ca2+', 'Chemical', 'MESH:D000069285', (166, 170))	('UCP2', 'Gene', (256, 260))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('stimulate', 'PosReg', (101, 110))	('fine-tuning', 'Var', (195, 206))
189825	33614647	Disruption of this equilibrium yields cancer cell death and may serve as a treatment strategy to specifically kill cancer cells.	('cancer', 'Disease', (115, 121))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('yields', 'Reg', (31, 37))	('cancer', 'Disease', (38, 44))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('Disruption', 'Var', (0, 10))
189827	33614647	In mitochondria, Ca2+ elevations boost the activity of the mitochondrial electron transport chain (ETC) by stimulating Ca2+-dependent dehydrogenases of the Krebs cycle (Denton et al.,), modulates mitochondrial membrane potential, and induces apoptotic cell death upon mitochondrial Ca2+ overload (Madreiter-Sokolowski et al.,).	('mitochondrial membrane potential', 'MPA', (196, 228))	('Krebs cycle', 'Enzyme', (156, 167))	('stimulating', 'Reg', (107, 118))	('Ca2+', 'Chemical', 'MESH:D000069285', (17, 21))	('Ca2+', 'Chemical', 'MESH:D000069285', (282, 286))	('mitochondrial electron transport chain', 'Enzyme', (59, 97))	('Ca2+', 'Chemical', 'MESH:D000069285', (119, 123))	('induces', 'Reg', (234, 241))	('boost', 'PosReg', (33, 38))	('mitochondrial Ca2+', 'MPA', (268, 286))	('modulates', 'Reg', (186, 195))	('Ca2+-dependent dehydrogenases', 'Enzyme', (119, 148))	('activity', 'MPA', (43, 51))	('Ca2+', 'Var', (17, 21))	('apoptotic cell death', 'CPA', (242, 262))	('Krebs', 'Chemical', '-', (156, 161))
189855	33614647	While silencing of MCU did not affect proliferation or cell viability of MDA-MB-231 cells (Curry et al.,; Hall et al.,), the ionophore ionomycin was found to induce caspase-independent cell death in MDA-MB-231 depleted of MCU (Curry et al.,).	('MCU', 'Gene', '90550', (19, 22))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (199, 209))	('ionomycin', 'Chemical', 'MESH:D015759', (135, 144))	('MCU', 'Gene', '90550', (222, 225))	('caspase-independent cell death', 'CPA', (165, 195))	('depleted', 'NegReg', (210, 218))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (73, 83))	('MCU', 'Gene', (19, 22))	('silencing', 'Var', (6, 15))	('MCU', 'Gene', (222, 225))
189857	33614647	The crucial role of MCU regulators in cancer progression gets also obvious by the impact of MICU1 impairment, which results in the opening of MCU, enhanced mitochondrial Ca2+ uptake and ROS production in HeLa, and potentially boosts tumor growth (Marchi et al.,).	('MCU', 'Gene', (142, 145))	('Ca2+', 'Chemical', 'MESH:D000069285', (170, 174))	('MCU', 'Gene', '90550', (142, 145))	('tumor', 'Disease', (233, 238))	('MICU1', 'Gene', (92, 97))	('ROS production', 'MPA', (186, 200))	('cancer', 'Disease', (38, 44))	('MICU1', 'Gene', '10367', (92, 97))	('tumor', 'Disease', 'MESH:D009369', (233, 238))	('impairment', 'Var', (98, 108))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('MCU', 'Gene', (20, 23))	('MCU', 'Gene', '90550', (20, 23))	('mitochondrial Ca2+ uptake', 'MPA', (156, 181))	('ROS', 'Chemical', '-', (186, 189))	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('enhanced', 'PosReg', (147, 155))	('HeLa', 'CellLine', 'CVCL:0030', (204, 208))	('boosts', 'PosReg', (226, 232))	('cancer', 'Disease', 'MESH:D009369', (38, 44))
189865	33614647	To simulate conditions of low mitochondrial-ER interaction, we overexpressed the AKAP-RFP-CAAX construct tagging mitochondria to the plasma membrane (Csordas et al.,; Naghdi et al.,).	('RFP', 'Gene', '5987', (86, 89))	('tagging', 'Var', (105, 112))	('RFP', 'Gene', (86, 89))	('ER', 'Gene', '2069', (44, 46))	('AKAP', 'Gene', (81, 85))	('AKAP', 'Gene', '8165', (81, 85))
189869	33614647	In experiments measuring mitochondrial matrix Ca2+ levels, knockdown of UCP2 decreased and overexpression of UCP2 increased mitochondrial Ca2+ uptake in response to histamine-induced ER Ca2+ depletion in control HeLa cells (Figures 1D,E).	('ER', 'Gene', '2069', (183, 185))	('UCP2', 'Gene', '7351', (109, 113))	('UCP2', 'Gene', (72, 76))	('overexpression', 'PosReg', (91, 105))	('mitochondrial Ca2+ uptake', 'MPA', (124, 149))	('histamine', 'Chemical', 'MESH:D006632', (165, 174))	('Ca2+', 'Chemical', 'MESH:D000069285', (138, 142))	('increased', 'PosReg', (114, 123))	('UCP2', 'Gene', (109, 113))	('Ca2+', 'Chemical', 'MESH:D000069285', (46, 50))	('Ca2+', 'Chemical', 'MESH:D000069285', (186, 190))	('HeLa', 'CellLine', 'CVCL:0030', (212, 216))	('increased mitochondria', 'Phenotype', 'HP:0041045', (114, 136))	('knockdown', 'Var', (59, 68))	('UCP2', 'Gene', '7351', (72, 76))	('decreased', 'NegReg', (77, 86))	('response to', 'MPA', (153, 164))
189882	33614647	In contrast, knockdown of UCP2 rescued cell viability and normalized caspase 3/7 activity in cells with increased mitochondria-ER tethering (Figures 2A,B).	('UCP2', 'Gene', '7351', (26, 30))	('increased', 'PosReg', (104, 113))	('caspase 3/7', 'Gene', '836;840', (69, 80))	('rescued', 'PosReg', (31, 38))	('ER', 'Gene', '2069', (127, 129))	('increased mitochondria', 'Phenotype', 'HP:0041045', (104, 126))	('UCP2', 'Gene', (26, 30))	('activity', 'MPA', (81, 89))	('cell viability', 'CPA', (39, 53))	('normalized', 'NegReg', (58, 68))	('knockdown', 'Var', (13, 22))	('caspase 3/7', 'Gene', (69, 80))
189884	33614647	In contrast, siRNA-induced knockdown of UCP2 caused enhanced ER-mitochondrial colocalization in HeLa cells (Figures 2D,F), mitochondrial volume got increased, while the other parameters of mitochondrial morphology remained largely unchanged (Figure 2E).	('knockdown', 'Var', (27, 36))	('increased', 'PosReg', (148, 157))	('UCP2', 'Gene', (40, 44))	('ER', 'Gene', '2069', (61, 63))	('enhanced', 'PosReg', (52, 60))	('UCP2', 'Gene', '7351', (40, 44))	('HeLa', 'CellLine', 'CVCL:0030', (96, 100))	('mitochondrial volume', 'MPA', (123, 143))
189932	33614647	This assumption is further supported by data showing that the impact of UCP2 knockdown on mitochondrial Ca2+ sequestration is increased in cells with enforced mitochondria-ER tethering.	('mitochondrial Ca2+ sequestration', 'MPA', (90, 122))	('UCP2', 'Gene', (72, 76))	('Ca2+', 'Chemical', 'MESH:D000069285', (104, 108))	('knockdown', 'Var', (77, 86))	('ER', 'Gene', '2069', (172, 174))	('UCP2', 'Gene', '7351', (72, 76))	('increased', 'PosReg', (126, 135))
189942	33614647	The process of fine-tuning mitochondrial Ca2+ uptake by PRMT1-driven methylation of MICU1 is assumed to take several minutes (Qian et al.,).	('MICU1', 'Gene', (84, 89))	('Ca2+', 'Chemical', 'MESH:D000069285', (41, 45))	('mitochondrial Ca2+ uptake', 'MPA', (27, 52))	('PRMT1', 'Gene', '3276', (56, 61))	('PRMT1', 'Gene', (56, 61))	('MICU1', 'Gene', '10367', (84, 89))	('methylation', 'Var', (69, 80))
189944	33614647	Therefore, we assume that enhanced expression of UCP2, which is found in most human cancer types (Madreiter-Sokolowski et al.,), long lastingly facilitates mitochondrial ATP production by Ca2+-mediated stimulation of Krebs cycle dehydrogenases.	('enhanced', 'PosReg', (26, 34))	('facilitates', 'PosReg', (144, 155))	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('cancer', 'Disease', (84, 90))	('Ca2+', 'Chemical', 'MESH:D000069285', (188, 192))	('Krebs', 'Chemical', '-', (217, 222))	('UCP2', 'Gene', '7351', (49, 53))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('mitochondrial ATP production', 'MPA', (156, 184))	('human', 'Species', '9606', (78, 83))	('UCP2', 'Gene', (49, 53))	('expression', 'Var', (35, 45))	('ATP', 'Chemical', 'MESH:D000255', (170, 173))
189954	33614647	On the other hand, UCP2 knockdown results in more stable and elongated mitochondria, probably associated with a lower rate of mitochondrial fission and enhanced tethering with the ER (Hass and Barnstable,).	('UCP2', 'Gene', '7351', (19, 23))	('UCP2', 'Gene', (19, 23))	('more', 'PosReg', (45, 49))	('mitochondrial fission', 'MPA', (126, 147))	('enhanced', 'PosReg', (152, 160))	('tethering', 'MPA', (161, 170))	('knockdown', 'Var', (24, 33))	('lower', 'NegReg', (112, 117))	('ER', 'Gene', '2069', (180, 182))
189957	33614647	We found ER stress markers upregulated in breast invasive cancer tissues with high expression of UCP2 and prostate adenocarcinoma with low expression of UCP2.	('prostate adenocarcinoma', 'Disease', 'MESH:D011471', (106, 129))	('high', 'Var', (78, 82))	('UCP2', 'Gene', (97, 101))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('UCP2', 'Gene', '7351', (97, 101))	('ER', 'Gene', '2069', (9, 11))	('UCP2', 'Gene', (153, 157))	('breast invasive cancer', 'Disease', (42, 64))	('breast invasive cancer', 'Disease', 'MESH:D001943', (42, 64))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('upregulated', 'PosReg', (27, 38))	('UCP2', 'Gene', '7351', (153, 157))	('prostate adenocarcinoma', 'Disease', (106, 129))
189960	33614647	Moreover, modulation of Ca2+ signaling was found to increase the responsiveness of cancer cells toward chemotherapeutics (Kerkhofs et al.,).	('responsiveness', 'MPA', (65, 79))	('Ca2+', 'Chemical', 'MESH:D000069285', (24, 28))	('modulation', 'Var', (10, 20))	('increase', 'PosReg', (52, 60))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('Ca2+ signaling', 'MPA', (24, 38))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('cancer', 'Disease', (83, 89))
189964	30832751	Secreted Phosphoprotein 1 (SPP1) Contributes to Second-Generation EGFR Tyrosine Kinase Inhibitor Resistance in Non-Small Cell Lung Cancer Second-generation irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), afatinib, has been approved for treating EGFR mutant lung cancer patients, but the mechanism of acquired resistance to afatinib has not been well studied.	('lung cancer', 'Disease', (295, 306))	('EGFR', 'Gene', (203, 207))	('mutant', 'Var', (288, 294))	('patients', 'Species', '9606', (307, 315))	('Secreted Phosphoprotein 1', 'Gene', (0, 25))	('EGFR', 'Gene', (66, 70))	('SPP1', 'Gene', (27, 31))	('Non-Small Cell Lung Cancer', 'Disease', (111, 137))	('Secreted Phosphoprotein 1', 'Gene', '6696', (0, 25))	('afatinib', 'Chemical', 'MESH:D000077716', (242, 250))	('EGFR', 'Gene', '1956', (283, 287))	('Lung Cancer', 'Phenotype', 'HP:0100526', (126, 137))	('lung cancer', 'Disease', 'MESH:D008175', (295, 306))	('EGFR', 'Gene', '1956', (203, 207))	('Small Cell Lung Cancer', 'Phenotype', 'HP:0030357', (115, 137))	('Non-Small Cell Lung Cancer', 'Phenotype', 'HP:0030358', (111, 137))	('lung cancer', 'Phenotype', 'HP:0100526', (295, 306))	('SPP1', 'Gene', '6696', (27, 31))	('cancer', 'Phenotype', 'HP:0002664', (300, 306))	('epidermal growth factor receptor', 'Gene', (169, 201))	('afatinib', 'Chemical', 'MESH:D000077716', (361, 369))	('epidermal growth factor receptor', 'Gene', '1956', (169, 201))	('EGFR', 'Gene', '1956', (66, 70))	('Cancer', 'Phenotype', 'HP:0002664', (131, 137))	('EGFR', 'Gene', (283, 287))	('Non-Small Cell Lung Cancer', 'Disease', 'MESH:D002289', (111, 137))
189968	30832751	To study the effect of SPP1 on afatinib resistance, siSPP1 was used to knock down SSP1 in afatinib-resistant lung cancer cells.	('lung cancer', 'Disease', (109, 120))	('SPP1', 'Gene', '6696', (23, 27))	('afatinib', 'Chemical', 'MESH:D000077716', (31, 39))	('lung cancer', 'Phenotype', 'HP:0100526', (109, 120))	('SPP1', 'Gene', (23, 27))	('SPP1', 'Gene', (54, 58))	('SPP1', 'Gene', '6696', (54, 58))	('afatinib', 'Chemical', 'MESH:D000077716', (90, 98))	('knock down', 'Var', (71, 81))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('lung cancer', 'Disease', 'MESH:D008175', (109, 120))	('SSP1', 'Gene', '26054', (82, 86))	('SSP1', 'Gene', (82, 86))
189970	30832751	We found that knockdown of SPP1 increased sensitivity of lung cancer cells to afatinib and decrease the ability of invasion.	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('SPP1', 'Gene', '6696', (27, 31))	('lung cancer', 'Disease', (57, 68))	('SPP1', 'Gene', (27, 31))	('sensitivity', 'MPA', (42, 53))	('lung cancer', 'Disease', 'MESH:D008175', (57, 68))	('increased', 'PosReg', (32, 41))	('knockdown', 'Var', (14, 23))	('afatinib', 'Chemical', 'MESH:D000077716', (78, 86))	('ability of invasion', 'CPA', (104, 123))	('decrease', 'NegReg', (91, 99))	('lung cancer', 'Phenotype', 'HP:0100526', (57, 68))
189971	30832751	Of clinical significance, we found that SSP1 was upregulated in lung cancer tissues compared with adjacent normal tissues, and low level of SSP1 was strongly associated with better overall survival.	('SSP1', 'Gene', (140, 144))	('lung cancer', 'Disease', (64, 75))	('SSP1', 'Gene', '26054', (140, 144))	('lung cancer', 'Phenotype', 'HP:0100526', (64, 75))	('low level', 'Var', (127, 136))	('better', 'PosReg', (174, 180))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('SSP1', 'Gene', (40, 44))	('SSP1', 'Gene', '26054', (40, 44))	('lung cancer', 'Disease', 'MESH:D008175', (64, 75))	('upregulated', 'PosReg', (49, 60))	('overall survival', 'CPA', (181, 197))
189972	30832751	Our results suggest that SPP1 enhanced the second-generation EGFR TKI resistance in lung cancer, and inhibiting SPP1 might be a therapeutic target to overcome afatinib resistance.	('lung cancer', 'Disease', (84, 95))	('lung cancer', 'Phenotype', 'HP:0100526', (84, 95))	('enhanced', 'PosReg', (30, 38))	('SPP1', 'Gene', '6696', (112, 116))	('afatinib', 'Chemical', 'MESH:D000077716', (159, 167))	('SPP1', 'Gene', (112, 116))	('SPP1', 'Gene', '6696', (25, 29))	('SPP1', 'Gene', (25, 29))	('lung cancer', 'Disease', 'MESH:D008175', (84, 95))	('inhibiting', 'Var', (101, 111))	('EGFR', 'Gene', '1956', (61, 65))	('EGFR', 'Gene', (61, 65))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
189976	30832751	The most common resistance mechanism to first-generation TKIs is caused by the T790M gatekeeper mutation, which is detectable in about half of the patients exposed to first-generation reversible TKIs.	('caused', 'Reg', (65, 71))	('gatekeeper', 'Species', '111938', (85, 95))	('T790M', 'Mutation', 'rs121434569', (79, 84))	('patients', 'Species', '9606', (147, 155))	('T790M', 'Var', (79, 84))
189977	30832751	Afatinib is the second-generation irreversible HER family inhibitor, and preclinical experience has demonstrated a potential role in overcoming acquired resistance, including T790M mutation.	('overcoming', 'PosReg', (133, 143))	('T790M mutation', 'Var', (175, 189))	('T790M', 'Mutation', 'rs121434569', (175, 180))	('acquired resistance', 'MPA', (144, 163))	('Afatinib', 'Chemical', 'MESH:D000077716', (0, 8))
189984	30832751	Overexpression of SPP1 is involved in aggressive phenotypes of lung cancer.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('lung cancer', 'Disease', 'MESH:D008175', (63, 74))	('involved', 'Reg', (26, 34))	('SPP1', 'Gene', '6696', (18, 22))	('lung cancer', 'Disease', (63, 74))	('SPP1', 'Gene', (18, 22))	('lung cancer', 'Phenotype', 'HP:0100526', (63, 74))	('Overexpression', 'Var', (0, 14))
189990	30832751	SPP1 rendered afatinib resistance through increasing the invasive ability of lung cancer cells, while knockdown of SPP1 could regain the sensitivity to afatinib.	('lung cancer', 'Phenotype', 'HP:0100526', (77, 88))	('sensitivity', 'MPA', (137, 148))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('rendered', 'Reg', (5, 13))	('afatinib', 'Chemical', 'MESH:D000077716', (14, 22))	('SPP1', 'Gene', '6696', (0, 4))	('afatinib', 'MPA', (14, 22))	('knockdown', 'Var', (102, 111))	('regain', 'PosReg', (126, 132))	('SPP1', 'Gene', (0, 4))	('invasive ability', 'CPA', (57, 73))	('increasing', 'PosReg', (42, 52))	('afatinib', 'Chemical', 'MESH:D000077716', (152, 160))	('lung cancer', 'Disease', 'MESH:D008175', (77, 88))	('SPP1', 'Gene', '6696', (115, 119))	('lung cancer', 'Disease', (77, 88))	('SPP1', 'Gene', (115, 119))
189991	30832751	We also found that SSP1 was upregulated in lung cancer tissues compared with adjacent normal tissues, and low level of SSP1 was strongly associated with better overall survival.	('low level', 'Var', (106, 115))	('lung cancer', 'Disease', (43, 54))	('lung cancer', 'Phenotype', 'HP:0100526', (43, 54))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('SSP1', 'Gene', '26054', (119, 123))	('overall survival', 'CPA', (160, 176))	('SSP1', 'Gene', (19, 23))	('SSP1', 'Gene', '26054', (19, 23))	('lung cancer', 'Disease', 'MESH:D008175', (43, 54))	('better', 'PosReg', (153, 159))	('SSP1', 'Gene', (119, 123))	('upregulated', 'PosReg', (28, 39))
189997	30832751	Human lung cancer PC9 cells were obtained from MeiXuan Biological Science and Technology Co., Ltd. (Shanghai, P.R.	('lung cancer', 'Disease', 'MESH:D008175', (6, 17))	('Human', 'Species', '9606', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('lung cancer', 'Disease', (6, 17))	('lung cancer', 'Phenotype', 'HP:0100526', (6, 17))	('PC9', 'CellLine', 'CVCL:B260', (18, 21))	('Shanghai', 'Var', (100, 108))
190022	30832751	Also, we found that HCC827AR and PC9AR cells had increased invasive ability compared to parental cells (Fig.	('PC9', 'CellLine', 'CVCL:B260', (33, 36))	('increased', 'PosReg', (49, 58))	('invasive ability', 'CPA', (59, 75))	('HCC827AR', 'Var', (20, 28))
190032	30832751	We verified that high expression of SPP1 was associated with shorter overall survival time (Fig.	('shorter', 'NegReg', (61, 68))	('high', 'Var', (17, 21))	('overall survival time', 'MPA', (69, 90))	('SPP1', 'Gene', '6696', (36, 40))	('SPP1', 'Gene', (36, 40))
190036	30832751	The survival rate in a large cohort (246 patients) also indicated lower surviving percentage with high levels of SPP1 in TCGA database (Fig.	('SPP1', 'Gene', (113, 117))	('surviving percentage', 'CPA', (72, 92))	('lower', 'NegReg', (66, 71))	('patients', 'Species', '9606', (41, 49))	('SPP1', 'Gene', '6696', (113, 117))	('high levels', 'Var', (98, 109))
190043	30832751	These results showed that siSPP1-transfected afatinib-resistant cells were sensitive to afatinib, indicating that knock down of SPP1 overcomes afatinib resistance and invasive ability.	('overcomes', 'NegReg', (133, 142))	('afatinib', 'Chemical', 'MESH:D000077716', (143, 151))	('knock down', 'Var', (114, 124))	('afatinib', 'Chemical', 'MESH:D000077716', (45, 53))	('afatinib resistance', 'MPA', (143, 162))	('SPP1', 'Gene', '6696', (128, 132))	('invasive ability', 'CPA', (167, 183))	('SPP1', 'Gene', '6696', (28, 32))	('SPP1', 'Gene', (128, 132))	('SPP1', 'Gene', (28, 32))	('afatinib', 'Chemical', 'MESH:D000077716', (88, 96))
190048	30832751	Specific knockdown of SPP1 overcame afatinib resistance, reducing viability and invasive ability of afatinib-resistant cells.	('knockdown', 'Var', (9, 18))	('invasive ability', 'CPA', (80, 96))	('overcame', 'PosReg', (27, 35))	('afatinib', 'Chemical', 'MESH:D000077716', (100, 108))	('SPP1', 'Gene', (22, 26))	('SPP1', 'Gene', '6696', (22, 26))	('viability', 'CPA', (66, 75))	('afatinib', 'Chemical', 'MESH:D000077716', (36, 44))	('reducing', 'NegReg', (57, 65))
190050	30832751	Several studies recognized the T790M EGFR gatekeeper mutation as most prominent, explaining approximately half of gefitinib/erlotinib resistance.	('T790M', 'Var', (31, 36))	('erlotinib', 'Chemical', 'MESH:D000069347', (124, 133))	('gefitinib/erlotinib', 'MPA', (114, 133))	('explaining', 'Reg', (81, 91))	('EGFR', 'Gene', '1956', (37, 41))	('gefitinib', 'Chemical', 'MESH:D000077156', (114, 123))	('gatekeeper', 'Species', '111938', (42, 52))	('EGFR', 'Gene', (37, 41))	('T790M', 'Mutation', 'rs121434569', (31, 36))
190051	30832751	Afatinib, a second-generation EGFR TKI, has emerged as the good candidate to test in the clinical setting of acquired resistance focusing on T790M-mediated resistance.	('T790M-mediated', 'Var', (141, 155))	('EGFR', 'Gene', (30, 34))	('T790M', 'Mutation', 'rs121434569', (141, 146))	('Afatinib', 'Chemical', 'MESH:D000077716', (0, 8))	('EGFR', 'Gene', '1956', (30, 34))
190071	30832751	In conclusion, our results demonstrated that inhibiting SPP1 may provide a novel strategy for increasing therapeutic sensitivity to afatinib.	('inhibiting', 'Var', (45, 55))	('afatinib', 'Chemical', 'MESH:D000077716', (132, 140))	('SPP1', 'Gene', '6696', (56, 60))	('therapeutic sensitivity', 'MPA', (105, 128))	('SPP1', 'Gene', (56, 60))	('increasing', 'PosReg', (94, 104))
190127	32695099	Our previous research in mice has proven that Vgamma4 gammadelta T cells play a protective role in tumor immunity, whereas Vgamma1 gammadelta T cells suppress this function via interleukin 4 (IL-4) production.	('Vgamma1 gammadelta', 'Var', (123, 141))	('tumor', 'Disease', (99, 104))	('mice', 'Species', '10090', (25, 29))	('IL-4', 'Gene', (192, 196))	('interleukin 4', 'Gene', (177, 190))	('IL-4', 'Gene', '16189', (192, 196))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('suppress', 'NegReg', (150, 158))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('interleukin 4', 'Gene', '16189', (177, 190))
190130	32695099	Through survival analysis of lung cancer and breast cancer patients with mRNA expression in gene chip data of BTNs, as we expected, several BTN members were proven as playing important roles in the prognosis of LUAD, LUSC, and breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('LUSC', 'Disease', (217, 221))	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('mRNA expression', 'Var', (73, 88))	('breast cancer', 'Disease', 'MESH:D001943', (45, 58))	('lung cancer', 'Disease', 'MESH:D008175', (29, 40))	('breast cancer', 'Disease', 'MESH:D001943', (227, 240))	('LUAD', 'Phenotype', 'HP:0030078', (211, 215))	('breast cancer', 'Disease', (45, 58))	('breast cancer', 'Phenotype', 'HP:0003002', (227, 240))	('patients', 'Species', '9606', (59, 67))	('breast cancer', 'Disease', (227, 240))	('LUAD', 'Disease', (211, 215))	('breast cancer', 'Phenotype', 'HP:0003002', (45, 58))	('lung cancer', 'Disease', (29, 40))	('LUSC', 'Phenotype', 'HP:0030359', (217, 221))	('lung cancer', 'Phenotype', 'HP:0100526', (29, 40))
190153	30909672	The malignant phenotype of lung cancer may be partially attributable to abnormalities in growth factors and their receptors acting via both autocrine and paracrine pathways.	('growth factors', 'Protein', (89, 103))	('abnormalities in growth', 'Phenotype', 'HP:0001507', (72, 95))	('abnormalities', 'Var', (72, 85))	('lung cancer', 'Disease', (27, 38))	('lung cancer', 'Phenotype', 'HP:0100526', (27, 38))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('lung cancer', 'Disease', 'MESH:D008175', (27, 38))
190189	30909672	IL-8 levels is higher for responder patients compared to non-responder (p:0.031).	('responder', 'Var', (26, 35))	('patients', 'Species', '9606', (36, 44))	('higher', 'PosReg', (15, 21))	('IL-8', 'Gene', '3576', (0, 4))	('IL-8', 'Gene', (0, 4))
190219	31324166	Absence of an embryonic stem cell DNA methylation signature in human cancer Differentiated cells that arise from stem cells in early development contain DNA methylation features that provide a memory trace of their fetal cell origin (FCO).	('human', 'Species', '9606', (63, 68))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('methylation', 'Var', (157, 168))	('FCO', 'Chemical', '-', (234, 237))	('cancer', 'Disease', (69, 75))
190240	31324166	Programming the cancer stem cell phenotypes are genetic alterations and epigenetic changes in chromatin structure and DNA methylation.	('epigenetic changes', 'Var', (72, 90))	('chromatin structure', 'Protein', (94, 113))	('cancer', 'Disease', 'MESH:D009369', (16, 22))	('cancer', 'Disease', (16, 22))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('DNA methylation', 'MPA', (118, 133))	('genetic alterations', 'Var', (48, 67))
190241	31324166	The consequence of cancer stem cell epigenetic alterations is to unleash cellular plasticity that favors oncogenic cellular reprogramming.	('cancer', 'Disease', 'MESH:D009369', (19, 25))	('cancer', 'Disease', (19, 25))	('cellular plasticity', 'CPA', (73, 92))	('epigenetic alterations', 'Var', (36, 58))	('oncogenic cellular reprogramming', 'CPA', (105, 137))	('favors', 'PosReg', (98, 104))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))
190253	31324166	We were able to add nontumor normal samples of cervix, brain, adrenal gland and stomach from GEO data sets GSE46306, GSE80970, GSE77871 and GSE103186 to cervical squamous cell carcinoma and endocervical adenocarcinoma, glioblastoma multiforme, pheochromocytoma and stomach adenocarcinoma projects on TCGA.	('carcinoma', 'Phenotype', 'HP:0030731', (208, 217))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (162, 185))	('endocervical adenocarcinoma', 'Disease', (190, 217))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('stomach adenocarcinoma', 'Disease', 'MESH:D013274', (265, 287))	('GSE46306', 'Var', (107, 115))	('pheochromocytoma', 'Disease', (244, 260))	('carcinoma', 'Phenotype', 'HP:0030731', (278, 287))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (244, 260))	('squamous cell carcinoma', 'Disease', (162, 185))	('glioblastoma multiforme', 'Disease', (219, 242))	('glioblastoma', 'Phenotype', 'HP:0012174', (219, 231))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (219, 242))	('GSE77871', 'Var', (127, 135))	('carcinoma', 'Phenotype', 'HP:0030731', (176, 185))	('GSE80970', 'Var', (117, 125))	('endocervical adenocarcinoma', 'Disease', 'MESH:D000230', (190, 217))	('tumor', 'Disease', (23, 28))	('stomach adenocarcinoma', 'Disease', (265, 287))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (162, 185))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('GSE103186', 'Var', (140, 149))	('pheochromocytoma', 'Disease', 'MESH:D010673', (244, 260))
190304	31324166	We applied the FCO algorithm to GEO data sets GSE80241, representing 6 pancreatic ductal adenocarcinoma stem cell samples, and GSE92462, including 22 glioma stem cell samples.	('pancreatic ductal adenocarcinoma', 'Disease', (71, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (71, 103))	('FCO', 'Chemical', '-', (15, 18))	('GSE80241', 'Var', (46, 54))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (71, 103))	('glioma', 'Disease', (150, 156))	('glioma', 'Disease', 'MESH:D005910', (150, 156))	('glioma', 'Phenotype', 'HP:0009733', (150, 156))
190306	31324166	Further, among 27 FCO CpGs, 3 (cg10338787, cg17310258 and cg16154155) are associated with EZH2.	('cg17310258', 'Chemical', '-', (43, 53))	('cg17310258', 'Var', (43, 53))	('cg16154155', 'Var', (58, 68))	('EZH2', 'Gene', '2146', (90, 94))	('cg10338787', 'Chemical', '-', (31, 41))	('EZH2', 'Gene', (90, 94))	('cg16154155', 'Chemical', '-', (58, 68))	('FCO', 'Chemical', '-', (18, 21))	('associated', 'Reg', (74, 84))	('cg10338787', 'Var', (31, 41))
190307	31324166	We plotted the methylation beta values of these three loci in pancreatic carcinoma samples, normal pancreatic tissue samples and pancreatic cancer stem cell samples from GEO data sets GSE53051 and GSE80241.	('pancreatic carcinoma', 'Disease', (62, 82))	('GSE53051', 'Var', (184, 192))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (129, 146))	('GSE80241', 'Var', (197, 205))	('pancreatic carcinoma', 'Disease', 'MESH:C562463', (62, 82))	('pancreatic cancer', 'Disease', 'MESH:D010190', (129, 146))	('pancreatic cancer', 'Disease', (129, 146))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
190328	31324166	The former model is supported by recent research indicating that heterogeneous tumor cells develop over time as cancer stem cells differentiate via genetic and epigenetic alterations.	('tumor', 'Disease', (79, 84))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('epigenetic alterations', 'Var', (160, 182))	('genetic', 'Var', (148, 155))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
190332	31324166	Further, our observation of a diminished FCO in tumors is seemingly at odds with reports that DNA hypermethylation in cancer preferentially targets the subset of polycomb repressor loci in cancer stem cells that are developmental regulators.	('cancer', 'Disease', (118, 124))	('FCO', 'MPA', (41, 44))	('preferentially', 'PosReg', (125, 139))	('diminished', 'NegReg', (30, 40))	('tumors', 'Disease', (48, 54))	('tumors', 'Disease', 'MESH:D009369', (48, 54))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('FCO', 'Chemical', '-', (41, 44))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('hypermethylation', 'Var', (98, 114))	('cancer', 'Disease', (189, 195))
190372	31324166	The datasets analyzed during the current study are available on The Cancer Genome Atlas (TCGA) https://portal.gdc.cancer.gov and the Gene Expression Omnibus data repository https://www.ncbi.nlm.nih.gov/geo/ (Accession numbers: GSE49656, GSE53051, GSE52068, GSE52826, GSE52955, GSE54503, GSE56044, GSE75546, GSE77871, GSE85845, GSE76938, GSE112047, GSE101961, GSE72245, GSE106600, GSE80241, GSE92462).	('GSE85845', 'Var', (317, 325))	('Cancer', 'Phenotype', 'HP:0002664', (68, 74))	('GSE112047', 'Var', (337, 346))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('GSE76938', 'Var', (327, 335))	('GSE56044', 'Var', (287, 295))	('GSE52955', 'Var', (267, 275))	('GSE72245', 'Var', (359, 367))	('GSE80241', 'Var', (380, 388))	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (68, 87))	('GSE101961', 'Var', (348, 357))	('GSE53051', 'Var', (237, 245))	('GSE75546', 'Var', (297, 305))	('GSE106600', 'Var', (369, 378))	('Cancer Genome Atlas', 'Disease', (68, 87))	('GSE92462', 'Var', (390, 398))	('GSE77871', 'Var', (307, 315))	('cancer', 'Disease', (114, 120))
190405	31110410	The acquisition of invasive phenotype by a cell is better understood by studying tumor cell interaction with the basement membrane, as the breach in basement membrane is defined as the critical event of tumor invasion, that signals the initiation of the metastatic cascade.	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('tumor', 'Disease', (203, 208))	('men', 'Species', '9606', (117, 120))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('men', 'Species', '9606', (153, 156))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('breach', 'Var', (139, 145))	('tumor', 'Disease', (81, 86))
190433	31110410	Recent studies, have now indicated that Ln-5 expression at the invasive front of OSCC is primarily, a means to retard tumor invasion in OSCC.	('retard tumor', 'Disease', 'MESH:D009369', (111, 123))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('retard tumor', 'Disease', (111, 123))	('Ln-5', 'Gene', (40, 44))	('expression', 'Var', (45, 55))
190438	31110410	Dysfunctional E cadherin is associated with loss of differentiation and acquisition of invasive phenotype.	('Dysfunctional', 'Var', (0, 13))	('E cadherin', 'Gene', '999', (14, 24))	('E cadherin', 'Gene', (14, 24))
190445	31110410	has suggested two plausible reasons of E-cadherin loss from proliferative layers: (1) the proteolytic cleavage of its ectodomain by MMP-7 which may cause enhanced cytoplasmic accumulation and (2) loss or reduction of E-cadherin expression from the proliferative layer can be caused by somatic mutations, chromosomal deletions, proteolytic cleavage and silencing of the CDH1 promoter which can occur either by DNA hypermethylation or through the action of transcription factors such as Slug, Snail and Twist.	('reduction', 'NegReg', (204, 213))	('enhanced', 'PosReg', (154, 162))	('hypermethylation', 'Var', (413, 429))	('cleavage', 'Var', (339, 347))	('MMP-7', 'Gene', '4316', (132, 137))	('Slug', 'Gene', '6591', (485, 489))	('E-cadherin', 'Gene', (217, 227))	('Snail', 'Gene', '6615', (491, 496))	('E-cadherin', 'Gene', '999', (217, 227))	('CDH1', 'Gene', '999', (369, 373))	('silencing', 'NegReg', (352, 361))	('chromosomal deletions', 'Var', (304, 325))	('mutations', 'Var', (293, 302))	('CDH1', 'Gene', (369, 373))	('expression', 'MPA', (228, 238))	('E-cadherin', 'Gene', (39, 49))	('E-cadherin', 'Gene', '999', (39, 49))	('cytoplasmic accumulation', 'MPA', (163, 187))	('Slug', 'Gene', (485, 489))	('loss', 'NegReg', (196, 200))	('Snail', 'Gene', (491, 496))	('MMP-7', 'Gene', (132, 137))
190447	31110410	Numerous variant isoforms of CD44 are derived as a result of alternate splicing leading to combinations of exons which are inserted into the extracellular domain of proliferating epithelial cells and activated lymphocytes.	('CD44', 'Gene', '960', (29, 33))	('CD44', 'Gene', (29, 33))	('alternate splicing', 'Var', (61, 79))
190451	31110410	Studies on CD44 have correlated pattern of CD44 variants produced by neoplastic cells and clinicopathological parameters of tumors, such as grade, stage, presence of metastases and survival in carcinomas of the digestive tract, non-Hodgkin's lymphomas and thyroid carcinomas.	('carcinomas', 'Disease', 'MESH:D002277', (264, 274))	('CD44', 'Gene', '960', (43, 47))	('thyroid carcinomas', 'Phenotype', 'HP:0002890', (256, 274))	('CD44', 'Gene', (43, 47))	('carcinoma', 'Phenotype', 'HP:0030731', (193, 202))	('CD44', 'Gene', '960', (11, 15))	('carcinomas', 'Phenotype', 'HP:0030731', (193, 203))	('carcinomas', 'Disease', 'MESH:D002277', (193, 203))	('CD44', 'Gene', (11, 15))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('lymphomas', 'Phenotype', 'HP:0002665', (242, 251))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('carcinomas', 'Disease', (264, 274))	("non-Hodgkin's lymphomas", 'Disease', 'MESH:D008228', (228, 251))	('variants', 'Var', (48, 56))	('metastases', 'Disease', 'MESH:D009362', (166, 176))	('tumors', 'Disease', (124, 130))	('carcinomas', 'Disease', (193, 203))	('thyroid carcinomas', 'Disease', 'MESH:D013964', (256, 274))	('metastases', 'Disease', (166, 176))	("Hodgkin's lymphomas", 'Phenotype', 'HP:0012189', (232, 251))	('thyroid carcinomas', 'Disease', (256, 274))	("non-Hodgkin's lymphomas", 'Disease', (228, 251))	('tumors', 'Disease', 'MESH:D009369', (124, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (264, 273))	('carcinomas', 'Phenotype', 'HP:0030731', (264, 274))
190454	31110410	Mutations in collagen Type VII is known to cause epidermal squamous cell carcinoma in association with dystrophic epidermolysis bullosa.	('dystrophic epidermolysis bullosa', 'Disease', (103, 135))	('cause', 'Reg', (43, 48))	('Mutations', 'Var', (0, 9))	('Type VII', 'Disease', (22, 30))	('epidermal squamous cell carcinoma', 'Disease', 'MESH:D002294', (49, 82))	('dystrophic epidermolysis bullosa', 'Disease', 'MESH:D016108', (103, 135))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (59, 82))	('Type VII', 'Disease', 'MESH:C565200', (22, 30))	('dystrophic epidermolysis bullosa', 'Phenotype', 'HP:0007475', (103, 135))	('epidermal squamous cell carcinoma', 'Disease', (49, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
190475	28881680	Identification of dysregulated long non-coding RNAs/microRNAs/mRNAs in TNM I stage lung adenocarcinoma Lung adenocarcinoma (LUAD) is the primary subtype in lung cancer, which is the leading cause of cancer-related death worldwide.	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('cancer', 'Disease', (199, 205))	('cancer', 'Disease', (161, 167))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('Lung adenocarcinoma', 'Phenotype', 'HP:0030078', (103, 122))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('Lung adenocarcinoma', 'Disease', 'MESH:D000077192', (103, 122))	('lung adenocarcinoma', 'Disease', (83, 102))	('lung adenocarcinom', 'Phenotype', 'HP:0030078', (83, 101))	('lung cancer', 'Disease', (156, 167))	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('dysregulated', 'Var', (18, 30))	('LUAD', 'Phenotype', 'HP:0030078', (124, 128))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (83, 102))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('TNM', 'Gene', '10178', (71, 74))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (83, 102))	('Lung adenocarcinoma', 'Disease', (103, 122))	('TNM', 'Gene', (71, 74))	('lung cancer', 'Disease', 'MESH:D008175', (156, 167))	('lung cancer', 'Phenotype', 'HP:0100526', (156, 167))
190490	28881680	Ectopic expression of AFAP-AS1 promotes cell proliferation and inhibits cell apoptosis in esophageal squamous cell carcinoma (ESCC), which is significantly correlated with advanced TNM stage and larger tumor size.	('FAP', 'Disease', (23, 26))	('TNM', 'Gene', '10178', (181, 184))	('AS1', 'Gene', '5729', (27, 30))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (90, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('tumor', 'Disease', (202, 207))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (101, 124))	('inhibits', 'NegReg', (63, 71))	('promotes', 'PosReg', (31, 39))	('Ectopic expression', 'Var', (0, 18))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('TNM', 'Gene', (181, 184))	('cell apoptosis', 'CPA', (72, 86))	('AS1', 'Gene', (27, 30))	('esophageal squamous cell carcinoma', 'Disease', (90, 124))	('cell proliferation', 'CPA', (40, 58))	('FAP', 'Disease', 'MESH:C567782', (23, 26))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))
190492	28881680	In gallbladder, high expression level of MALAT1 is correlated with larger tumor size, lymphatic metastasis and shorter overall survival; silencing of MALAT1 inhibits cell proliferation, cell invasion and increases cell apoptosis.	('MALAT1', 'Gene', '378938', (41, 47))	('inhibits', 'NegReg', (157, 165))	('cell apoptosis', 'CPA', (214, 228))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('MALAT1', 'Gene', (41, 47))	('increases', 'PosReg', (204, 213))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('cell proliferation', 'CPA', (166, 184))	('cell invasion', 'CPA', (186, 199))	('tumor', 'Disease', (74, 79))	('silencing', 'Var', (137, 146))	('MALAT1', 'Gene', '378938', (150, 156))	('MALAT1', 'Gene', (150, 156))
190498	28881680	LOC80078 and LOC101930114 were the most significantly up- and down-regulated DELs; EEF1A2 and ANKRD1 were the most significantly up- and down-regulated DEMs in TNM I stage LUAD tissues compared to paired non-tumor tissues (Tables 1 and 2).	('EEF1A2', 'Gene', (83, 89))	('up-', 'PosReg', (129, 132))	('ANKRD1', 'Gene', (94, 100))	('LUAD', 'Phenotype', 'HP:0030078', (172, 176))	('TNM', 'Gene', (160, 163))	('LOC101930114', 'Gene', (13, 25))	('non-tumor', 'Disease', (204, 213))	('down-regulated', 'NegReg', (62, 76))	('down-regulated', 'NegReg', (137, 151))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('EEF1A2', 'Gene', '1917', (83, 89))	('LOC101930114', 'Gene', '101930114', (13, 25))	('LOC80078', 'Var', (0, 8))	('TNM', 'Gene', '10178', (160, 163))	('ANKRD1', 'Gene', '27063', (94, 100))	('non-tumor', 'Disease', 'MESH:D009369', (204, 213))	('up-', 'PosReg', (54, 57))
190512	28881680	1321 DEMs were significantly enriched in pathways in cancer (Kegg:05200), cell adhesion molecules(Kegg:04514), focal adhesion (Kegg:04510), cytokine-cytokine receptor interaction (Kegg:04060), ECM-receptor interaction (Kegg:04512) and tight junction (Kegg:04530) (Table 3).	('focal', 'MPA', (111, 116))	('cytokine-cytokine', 'MPA', (140, 157))	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('Kegg:04512', 'Var', (219, 229))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('cell', 'Protein', (74, 78))	('Kegg:04514', 'Var', (98, 108))	('Kegg:04510', 'Var', (127, 137))	('Kegg:04060', 'Var', (180, 190))
190514	28881680	qRT-PCR was subjected to validate the expression levels of dysregulated DEL/DEMI/DEM in 6 stage I LUAD tissues and 6 adjacent non-tumor tissues.	('dysregulated', 'Var', (59, 71))	('DEL/DEMI/DEM', 'Gene', (72, 84))	('non-tumor', 'Disease', 'MESH:D009369', (126, 135))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('LUAD', 'Phenotype', 'HP:0030078', (98, 102))	('non-tumor', 'Disease', (126, 135))
190528	28881680	In order to assess the discriminatory ability of the 12 candidate DELs among LUAD tissues and adjacent non-tumor tissues generated from TCGA database, ROC curve analyses were conducted and area under the curve (AUC) were calculated.	('non-tumor', 'Disease', (103, 112))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('non-tumor', 'Disease', 'MESH:D009369', (103, 112))	('DELs', 'Var', (66, 70))	('LUAD', 'Phenotype', 'HP:0030078', (77, 81))
190529	28881680	The AUC of CDKN2B-AS1 and HNF1A-AS1 was respective 0.563 and 0.529, less than 0.7 (Figure 7L, 7K).	('CDKN2B-AS1', 'Gene', (11, 21))	('CDKN2B-AS1', 'Gene', '100048912', (11, 21))	('0.529', 'Var', (61, 66))	('HNF1A-AS1', 'Gene', (26, 35))	('HNF1A-AS1', 'Gene', '283460', (26, 35))
190542	28881680	Copy number loss of CDKN2B predicts poor survival in patients with lung squamous cell carcinoma.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (72, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('patients', 'Species', '9606', (53, 61))	('poor', 'NegReg', (36, 40))	('CDKN2B', 'Gene', (20, 26))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (67, 95))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (67, 95))	('lung squamous cell carcinoma', 'Disease', (67, 95))	('Copy number loss', 'Var', (0, 16))
190543	28881680	CDKN2B deficiency accelerates mutant KRAS lung tumorigenesis in mice mode, which leads to cell metastasis and cell proliferation.	('cell metastasis', 'CPA', (90, 105))	('CDKN2B deficiency', 'Phenotype', 'HP:0032423', (0, 17))	('mutant', 'Var', (30, 36))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('KRAS', 'Gene', (37, 41))	('deficiency', 'Var', (7, 17))	('mice', 'Species', '10090', (64, 68))	('KRAS', 'Gene', '16653', (37, 41))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('cell proliferation', 'CPA', (110, 128))	('accelerates', 'PosReg', (18, 29))	('CDKN2B', 'Gene', (0, 6))	('tumor', 'Disease', (47, 52))	('leads', 'Reg', (81, 86))
190550	28881680	Ectopic expression of MMP13 (matrix metallopeptidase 13) predicts poorer-5-year survival in patients with NSCLC.	('NSCLC', 'Disease', 'MESH:D002289', (106, 111))	('MMP13', 'Gene', (22, 27))	('matrix metallopeptidase 13', 'Gene', '4322', (29, 55))	('patients', 'Species', '9606', (92, 100))	('MMP13', 'Gene', '4322', (22, 27))	('NSCLC', 'Phenotype', 'HP:0030358', (106, 111))	('matrix metallopeptidase 13', 'Gene', (29, 55))	('Ectopic', 'Var', (0, 7))	('poorer-5-year', 'NegReg', (66, 79))	('NSCLC', 'Disease', (106, 111))
190560	28881680	Genetic variants in ADRB2 confer the risk of chronic obstructive pulmonary disease and lung adenocarcinoma.	('chronic obstructive pulmonary disease', 'Phenotype', 'HP:0006510', (45, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('lung adenocarcinoma', 'Disease', (87, 106))	('obstructive pulmonary disease', 'Phenotype', 'HP:0006536', (53, 82))	('risk', 'Reg', (37, 41))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (87, 106))	('chronic obstructive pulmonary disease', 'Disease', 'MESH:D029424', (45, 82))	('chronic obstructive pulmonary disease', 'Disease', (45, 82))	('ADRB2', 'Gene', (20, 25))	('ADRB2', 'Gene', '154', (20, 25))	('lung adenocarcinom', 'Phenotype', 'HP:0030078', (87, 105))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (87, 106))	('Genetic variants', 'Var', (0, 16))
190635	33306799	Concordantly, 1271 edges between epigenetic regulators and oncogenes were lost in tumor networks, such as co-expression between BRAF and PRDM2 (Supplementary Figure 3).	('lost', 'NegReg', (74, 78))	('co-expression', 'Var', (106, 119))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('PRDM2', 'Gene', (137, 142))	('PRDM2', 'Gene', '7799', (137, 142))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('BRAF', 'Gene', '673', (128, 132))	('tumor', 'Disease', (82, 87))	('BRAF', 'Gene', (128, 132))
190685	30910843	NEF overexpression inhibited the migration and invasion of HPV-negative but not HPV-positive CSCC cells.	('inhibited', 'NegReg', (19, 28))	('HPV', 'Species', '10566', (59, 62))	('overexpression', 'Var', (4, 18))	('HPV', 'Species', '10566', (80, 83))	('expression', 'Species', '29278', (8, 18))	('NEF', 'Gene', (0, 3))	('NEF', 'Gene', '6285', (0, 3))
190747	30910843	TGF-beta1 plays pivotal roles in the metastasis of various types of malignancies, and inhibition of TGF-beta1 is considered to be a promising target for the treatment of cervical cancer.	('cervical cancer', 'Disease', (170, 185))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('malignancies', 'Disease', (68, 80))	('TGF-beta1', 'Gene', (100, 109))	('metastasis', 'CPA', (37, 47))	('inhibition', 'Var', (86, 96))	('malignancies', 'Disease', 'MESH:D009369', (68, 80))	('cervical cancer', 'Disease', 'MESH:D002583', (170, 185))	('TGF-beta1', 'Gene', (0, 9))
190752	30910843	Similarly, NEF overexpression also significantly promoted the invasion (Figure 6B) of cells of HPV-negative C33A cell line (P<0.05), but not cells of HPV-positive SiHa cells (P>0.05).	('HPV', 'Species', '10566', (95, 98))	('invasion', 'CPA', (62, 70))	('overexpression', 'Var', (15, 29))	('NEF', 'Gene', (11, 14))	('promoted', 'PosReg', (49, 57))	('SiHa', 'CellLine', 'CVCL:0032', (163, 167))	('HPV', 'Species', '10566', (150, 153))	('NEF', 'Gene', '6285', (11, 14))	('expression', 'Species', '29278', (19, 29))
190785	26464434	Genome-wide CpG island methylation and intergenic demethylation propensities vary among different tumor sites The epigenetic landscape of cancer includes both focal hypermethylation and broader hypomethylation in a genome-wide manner.	('focal hypermethylation', 'Var', (159, 181))	('cancer', 'Disease', (138, 144))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumor', 'Disease', (98, 103))	('cancer', 'Disease', 'MESH:D009369', (138, 144))
190786	26464434	By means of a comprehensive genomic analysis on 6637 tissues of 21 tumor types, we here show that the degrees of overall methylation in CpG island (CGI) and demethylation in intergenic regions, defined as 'backbone', largely vary among different tumors.	('tumors', 'Phenotype', 'HP:0002664', (246, 252))	('tumors', 'Disease', 'MESH:D009369', (246, 252))	('methylation', 'MPA', (121, 132))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('demethylation', 'Var', (157, 170))	('tumor', 'Disease', 'MESH:D009369', (246, 251))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('tumor', 'Disease', (67, 72))	('vary', 'Reg', (225, 229))	('tumor', 'Disease', (246, 251))	('tumors', 'Disease', (246, 252))
190787	26464434	Depending on tumor type, both CGI methylation and backbone demethylation are often associated with clinical, epidemiological and biological features such as age, sex, smoking history, anatomic location, histological type and grade, stage, molecular subtype and biological pathways.	('tumor', 'Disease', (13, 18))	('molecular', 'CPA', (239, 248))	('methylation', 'Var', (34, 45))	('CGI', 'Protein', (30, 33))	('backbone', 'MPA', (50, 58))	('associated', 'Reg', (83, 93))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
190788	26464434	We found connections between CGI methylation and hypermutability, microsatellite instability, IDH1 mutation, 19p gain and polycomb features, and backbone demethylation with chromosomal instability, NSD1 and TP53 mutations, 5q and 19p loss and long repressive domains.	('IDH1', 'Gene', (94, 98))	('microsatellite instability', 'MPA', (66, 92))	('IDH1', 'Gene', '3417', (94, 98))	('TP53', 'Gene', '7157', (207, 211))	('backbone', 'MPA', (145, 153))	('NSD1', 'Gene', '64324', (198, 202))	('mutation', 'Var', (99, 107))	('TP53', 'Gene', (207, 211))	('gain', 'PosReg', (113, 117))	('mutations', 'Var', (212, 221))	('NSD1', 'Gene', (198, 202))	('chromosomal instability', 'Phenotype', 'HP:0040012', (173, 196))	('loss', 'NegReg', (234, 238))
190789	26464434	These broad epigenetic patterns add a new dimension to our understanding of tumor biology and its clinical implications.	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('epigenetic patterns', 'Var', (12, 31))	('tumor', 'Disease', (76, 81))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
190790	26464434	Epigenetic alterations have pivotal roles in development and cancer biology.	('Epigenetic alterations', 'Var', (0, 22))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('cancer', 'Disease', (61, 67))	('cancer', 'Disease', 'MESH:D009369', (61, 67))
190791	26464434	A canonical observation in many cancers is the de novo methylation of CpG islands (CGIs) in the promoters of tumor-related genes, which is significantly associated with clinical behavior in many tumors.	('tumors', 'Disease', (195, 201))	('tumors', 'Disease', 'MESH:D009369', (195, 201))	('tumor', 'Disease', (195, 200))	('cancers', 'Disease', 'MESH:D009369', (32, 39))	('cancers', 'Phenotype', 'HP:0002664', (32, 39))	('tumors', 'Phenotype', 'HP:0002664', (195, 201))	('cancers', 'Disease', (32, 39))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('associated', 'Reg', (153, 163))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('methylation', 'Var', (55, 66))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('tumor', 'Disease', (109, 114))
190798	26464434	TF-binding sites behaved differently according to TF contents; the binding sites of embryonic stem cell (ESC)-related TFs including polycomb proteins and CTBP2 were frequently de novo methylated while the binding sites of other differentiation-associated TFs were rather demethylated or unchanged.	('CTBP2', 'Gene', '1488', (154, 159))	('polycomb proteins', 'Protein', (132, 149))	('methylated', 'Var', (184, 194))	('binding', 'Interaction', (67, 74))	('CTBP2', 'Gene', (154, 159))
190818	26464434	Likewise, we selected 49 277 CpGs in backbone, as defined above, and averaged their methylation levels for each tumor.	('CpGs', 'Var', (29, 33))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumor', 'Disease', (112, 117))	('methylation levels', 'MPA', (84, 102))
190823	26464434	Nonetheless, most tumors showed both CGI methylation and backbone demethylation with variable degrees (HC-LB; Figure 1F; Supplementary Figure S2).	('backbone demethylation', 'MPA', (57, 79))	('methylation', 'Var', (41, 52))	('HC-LB; Figure 1F; Supplementary Figure S2', 'Disease', 'MESH:D017034', (103, 144))	('tumors', 'Disease', (18, 24))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('HC-LB; Figure 1F; Supplementary Figure S2', 'Disease', (103, 144))	('CGI', 'MPA', (37, 40))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
190825	26464434	And in most tumors, DNA methylation correlated with mRNA expression, miRNA expression, copy number and pathway clusters suggesting an underlying biological background.	('copy number', 'Var', (87, 98))	('DNA', 'Gene', (20, 23))	('pathway clusters', 'Pathway', (103, 119))	('methylation', 'Var', (24, 35))	('correlated', 'Reg', (36, 46))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('miRNA expression', 'MPA', (69, 85))	('tumors', 'Disease', (12, 18))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('mRNA expression', 'MPA', (52, 67))	('tumors', 'Disease', 'MESH:D009369', (12, 18))
190829	26464434	In THCA, histories of lymphocytic thyroiditis significantly correlated with high CGI methylation (P = 6.3 x 10-4).	('CGI', 'Protein', (81, 84))	('thyroiditis', 'Phenotype', 'HP:0100646', (34, 45))	('THCA', 'Phenotype', 'HP:0002890', (3, 7))	('lymphocytic thyroiditis', 'Disease', (22, 45))	('lymphocytic thyroiditis', 'Phenotype', 'HP:0000872', (22, 45))	('lymphocytic thyroiditis', 'Disease', 'MESH:D013967', (22, 45))	('high', 'Var', (76, 80))
190831	26464434	In COADREAD, CGI methylation was highest in cecum tumors and became modest when moving towards the rectum (P = 1.3 x 10-16; Supplementary Figure S25A).	('highest', 'Reg', (33, 40))	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('S25A', 'SUBSTITUTION', 'None', (145, 149))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('S25A', 'Var', (145, 149))	('tumors', 'Disease', (50, 56))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))
190832	26464434	In HNSC, CGI methylation was highest in the oral cavity and lower in the caudal direction in the oropharangeal tract (P = 8.9 x 10-5; Supplementary Figure S25B).	('methylation', 'MPA', (13, 24))	('S25B', 'SUBSTITUTION', 'None', (155, 159))	('highest', 'Reg', (29, 36))	('S25B', 'Var', (155, 159))	('CGI', 'MPA', (9, 12))	('HNSC', 'Phenotype', 'HP:0012288', (3, 7))	('lower', 'NegReg', (60, 65))
190836	26464434	Type 2 KIRP, an eosinophilic tumor with worse prognosis, was associated with both CGI methylation and backbone demethylation (P = 4.4 x 10-5 and 1.9 x 10-3, respectively).	('backbone demethylation', 'MPA', (102, 124))	('Type 2 KIRP', 'Disease', (0, 11))	('eosinophilic tumor', 'Disease', (16, 34))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('methylation', 'Var', (86, 97))	('eosinophilic tumor', 'Disease', 'MESH:D004802', (16, 34))	('CGI', 'MPA', (82, 85))
190838	26464434	In PRAD, Gleason scores tended to be high both in CGI-methylated and backbone-demethylated tumors (P = 6.1 x 10-3 and 3.9 x 10-4, respectively).	('tumors', 'Disease', (91, 97))	('tumors', 'Disease', 'MESH:D009369', (91, 97))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('CGI-methylated', 'Var', (50, 64))	('high', 'PosReg', (37, 41))	('PRAD', 'Disease', (3, 7))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('Gleason', 'MPA', (9, 16))	('backbone-demethylated', 'Var', (69, 90))
190839	26464434	An association of CGI methylation with high mitosis was observed in ACC (P = 4.5 x 10-4).	('association', 'Interaction', (3, 14))	('high mitosis', 'Disease', (39, 51))	('ACC', 'Phenotype', 'HP:0006744', (68, 71))	('high mitosis', 'Disease', 'MESH:D008228', (39, 51))	('ACC', 'Disease', (68, 71))	('CGI', 'Protein', (18, 21))	('methylation', 'Var', (22, 33))
190842	26464434	MSI-H tumors were very significantly associated with CGI methylation in COADREAD, STAD and UCEC (P = 3.2 x 10-12, 2.4 x 10-7 and 2.0 x 10-22, respectively) (Figure 2B).	('methylation', 'Var', (57, 68))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('CGI', 'Protein', (53, 56))	('associated', 'Reg', (37, 47))	('MSI-H tumors', 'Disease', 'MESH:D009369', (0, 12))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('MSI-H tumors', 'Disease', (0, 12))
190843	26464434	In COADREAD, CGI methylation was associated with negative expression of MSH6 and PMS2 proteins (P = 9.3 x 10-3).	('MSH6', 'Gene', (72, 76))	('expression', 'MPA', (58, 68))	('proteins', 'Protein', (86, 94))	('PMS2', 'Gene', '5395', (81, 85))	('methylation', 'Var', (17, 28))	('negative', 'NegReg', (49, 57))	('MSH6', 'Gene', '2956', (72, 76))	('PMS2', 'Gene', (81, 85))
190844	26464434	In BRCA, CGI methylation was significantly associated with positive expression of estrogen and HER2/neu receptors (P = 1.5 x 10-5 and 8.3 x 10-8, respectively) and thus with luminal B subtype (P = 1.3 x 10-9).	('BRCA', 'Gene', (3, 7))	('CGI methylation', 'Var', (9, 24))	('expression', 'MPA', (68, 78))	('methylation', 'Var', (13, 24))	('BRCA', 'Gene', '672', (3, 7))	('positive', 'PosReg', (59, 67))	('estrogen', 'Protein', (82, 90))	('HER2/neu receptors', 'Protein', (95, 113))	('BRCA', 'Phenotype', 'HP:0003002', (3, 7))
190845	26464434	The number of gene mutations correlated positively with CGI methylation in THCA, KIRC, LAML, LGG, GBM, PRAD, STAD, BRCA, ACC and UCEC (Figure 2A and B).	('ACC', 'Phenotype', 'HP:0006744', (121, 124))	('CGI methylation', 'MPA', (56, 71))	('THCA', 'Phenotype', 'HP:0002890', (75, 79))	('BRCA', 'Phenotype', 'HP:0003002', (115, 119))	('BRCA', 'Gene', '672', (115, 119))	('mutations', 'Var', (19, 28))	('BRCA', 'Gene', (115, 119))
190846	26464434	In line with the previous knowledge, IDH1 mutation was associated with high CGI methylation in LGG (P = 2.1 x 10-20), GBM, PRAD and CESC, and IDH2 was so in LAML.	('IDH2', 'Gene', '3418', (142, 146))	('IDH1', 'Gene', (37, 41))	('mutation', 'Var', (42, 50))	('IDH1', 'Gene', '3417', (37, 41))	('CGI methylation', 'MPA', (76, 91))	('IDH2', 'Gene', (142, 146))
190847	26464434	Mutations in CIC, NOTCH1 and FUBP1 were very significantly associated with high CGI methylation in LGG (P = 5.7 x 10-11, 5.2 x 10-7 and 9.9 x 10-5, respectively), mutation in PIK3CA was so in STAD (P = 7.4 x 10-9), and mutations in PTEN and PIK3R1 were so in UCEC (P = 5.9 x 10-7 and 1.6 x 10-4, respectively).	('PIK3CA', 'Gene', (175, 181))	('NOTCH1', 'Gene', (18, 24))	('UCEC', 'Disease', (259, 263))	('PIK3R1', 'Gene', '5295', (241, 247))	('PIK3R1', 'Gene', (241, 247))	('PIK3CA', 'Gene', '5290', (175, 181))	('associated', 'Reg', (59, 69))	('high CGI methylation', 'MPA', (75, 95))	('Mutations', 'Var', (0, 9))	('FUBP1', 'Gene', '8880', (29, 34))	('PTEN', 'Gene', '5728', (232, 236))	('PTEN', 'Gene', (232, 236))	('mutations', 'Var', (219, 228))	('CIC', 'Gene', (13, 16))	('mutation', 'Var', (163, 171))	('FUBP1', 'Gene', (29, 34))	('NOTCH1', 'Gene', '4851', (18, 24))
190848	26464434	NRAS mutation was frequent in THCA with higher CGI methylation and BRAF was so in THCA with lower backbone methylation (P = 5.9 x 10-3 and 9.9 x 10-7, respectively) but this may be confounded by the difference in methylation according to histological type, as described above, and high frequency of NRAS mutation in follicular and BRAF mutation in papillary types.	('THCA', 'Phenotype', 'HP:0002890', (82, 86))	('BRAF', 'Gene', (331, 335))	('BRAF', 'Gene', '673', (67, 71))	('NRAS', 'Gene', '4893', (299, 303))	('higher', 'PosReg', (40, 46))	('BRAF', 'Gene', '673', (331, 335))	('backbone methylation', 'MPA', (98, 118))	('THCA', 'Phenotype', 'HP:0002890', (30, 34))	('BRAF', 'Gene', (67, 71))	('CGI methylation', 'MPA', (47, 62))	('NRAS', 'Gene', (0, 4))	('NRAS', 'Gene', '4893', (0, 4))	('mutation', 'Var', (5, 13))	('NRAS', 'Gene', (299, 303))
190849	26464434	TP53 mutation was associated with backbone demethylation in STAD and PRAD (P = 5.1 x 10-5 and 4.9 x 10-3, respectively) (Figure 2C), and NSD1 mutation was so in HNSC (P = 3.2 x 10-9) (Supplementary Figure S17B).	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('backbone demethylation', 'MPA', (34, 56))	('S17B', 'Var', (205, 209))	('S17B', 'SUBSTITUTION', 'None', (205, 209))	('mutation', 'Var', (5, 13))	('NSD1', 'Gene', '64324', (137, 141))	('HNSC', 'Phenotype', 'HP:0012288', (161, 165))	('NSD1', 'Gene', (137, 141))
190854	26464434	The most remarkable P value peak was in chromosome 5q showing recurrent correlations between deletion and backbone demethylation in many tumors (Figure 3A and B).	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('backbone demethylation', 'MPA', (106, 128))	('correlations', 'Reg', (72, 84))	('tumors', 'Disease', (137, 143))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('deletion', 'Var', (93, 101))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
190855	26464434	Candidate genes in this region include CHD1, LMNB1, KDM3B, HDAC3 and NSD1, and among them, NSD1 was of particular interest in that mutation in this gene also showed the most significant association with backbone demethylation in HNSC and other tumors (Figure 3C).	('NSD1', 'Gene', (69, 73))	('backbone demethylation', 'MPA', (203, 225))	('mutation', 'Var', (131, 139))	('tumor', 'Phenotype', 'HP:0002664', (244, 249))	('HDAC3', 'Gene', (59, 64))	('CHD1', 'Gene', '1105', (39, 43))	('LMNB1', 'Gene', '4001', (45, 50))	('tumors', 'Phenotype', 'HP:0002664', (244, 250))	('NSD1', 'Gene', '64324', (69, 73))	('NSD1', 'Gene', (91, 95))	('CHD1', 'Gene', (39, 43))	('HNSC', 'Disease', (229, 233))	('tumors', 'Disease', (244, 250))	('KDM3B', 'Gene', '51780', (52, 57))	('LMNB1', 'Gene', (45, 50))	('HDAC3', 'Gene', '8841', (59, 64))	('HNSC', 'Phenotype', 'HP:0012288', (229, 233))	('association', 'Reg', (186, 197))	('tumors', 'Disease', 'MESH:D009369', (244, 250))	('NSD1', 'Gene', '64324', (91, 95))	('KDM3B', 'Gene', (52, 57))
190856	26464434	Bi-allelic aberration of NSD1 either by mutation or copy loss showed more demethylation (Figure 3D).	('mutation', 'Var', (40, 48))	('NSD1', 'Gene', (25, 29))	('demethylation', 'MPA', (74, 87))	('copy loss', 'Var', (52, 61))	('NSD1', 'Gene', '64324', (25, 29))
190859	26464434	Among the pathways recurrently associated in several tumors, the bone morphogenic protein (BMP) receptor pathway was significantly suppressed among backbone-demethylated tumors in LGG, PRAD and LIHC and CGI-methylated tumors in LUAD.	('backbone-demethylated', 'Var', (148, 169))	('BMP', 'Gene', '649', (91, 94))	('LIHC', 'Disease', (194, 198))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('CGI-methylated', 'Var', (203, 217))	('tumors', 'Disease', 'MESH:D009369', (170, 176))	('LIHC', 'Disease', 'None', (194, 198))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('PRAD', 'Disease', (185, 189))	('BMP', 'Gene', (91, 94))	('tumors', 'Phenotype', 'HP:0002664', (218, 224))	('tumors', 'Disease', (53, 59))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('LGG', 'Disease', (180, 183))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('tumors', 'Phenotype', 'HP:0002664', (170, 176))	('suppressed', 'NegReg', (131, 141))	('LUAD', 'Phenotype', 'HP:0030078', (228, 232))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('tumors', 'Disease', (218, 224))	('tumors', 'Disease', (170, 176))	('tumors', 'Disease', 'MESH:D009369', (218, 224))
190866	26464434	In all tumor types, differentially methylated CpGs were highly enriched in binding sites of polycomb-related SUZ12, EZH2 and CTBP2, and the enrichment rate strongly correlated with the degree of CGI methylation (Supplementary Figure S30).	('EZH2', 'Gene', (116, 120))	('EZH2', 'Gene', '2146', (116, 120))	('tumor', 'Disease', (7, 12))	('SUZ12', 'Gene', (109, 114))	('differentially', 'Var', (20, 34))	('CTBP2', 'Gene', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))	('CGI methylation', 'MPA', (195, 210))	('CTBP2', 'Gene', '1488', (125, 130))	('tumor', 'Disease', 'MESH:D009369', (7, 12))	('binding sites', 'Interaction', (75, 88))	('SUZ12', 'Gene', '23512', (109, 114))	('correlated', 'Reg', (165, 175))
190867	26464434	Demethylated CpGs were often enriched in IKZF1, BATF and ZNF217 binding sites but the enrichment rate usually did not correlate with the degree of backbone demethylation, suggesting a minor role of transcription factors in the genome-wide demethylation (Supplementary Figure S31).	('BATF', 'Gene', (48, 52))	('BATF', 'Gene', '10538', (48, 52))	('IKZF1', 'Gene', '10320', (41, 46))	('ZNF217', 'Gene', (57, 63))	('ZNF217', 'Gene', '7764', (57, 63))	('IKZF1', 'Gene', (41, 46))	('Demethylated', 'Var', (0, 12))
190871	26464434	Intriguingly, CGI-methylated tumors showed better primary responses in STAD and LUAD (P = 7.5 x 10-3 and 1.8 x 10-2, respectively).	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('primary responses', 'CPA', (50, 67))	('LUAD', 'Disease', (80, 84))	('LUAD', 'Phenotype', 'HP:0030078', (80, 84))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('tumors', 'Disease', 'MESH:D009369', (29, 35))	('tumors', 'Disease', (29, 35))	('better', 'PosReg', (43, 49))	('STAD', 'Disease', (71, 75))	('CGI-methylated', 'Var', (14, 28))
190878	26464434	As supporting evidence, we could observe correlation of HC-tumors with many CIMP-associated features such as MSI-H and IDH1 mutation.	('HC-tumors', 'Disease', (56, 65))	('CIMP', 'Chemical', '-', (76, 80))	('MSI-H', 'Disease', (109, 114))	('correlation', 'Interaction', (41, 52))	('IDH1', 'Gene', (119, 123))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('MSI-H', 'Disease', 'MESH:D000848', (109, 114))	('mutation', 'Var', (124, 132))	('HC-tumors', 'Disease', 'MESH:D009369', (56, 65))	('IDH1', 'Gene', '3417', (119, 123))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
190883	26464434	Polycomb site methylation has now been accepted as a hallmark of cancers, and so the enrichment of polycomb proteins, SUZ12 and EZH2, should be an innate quality.	('hallmark of cancers', 'Disease', (53, 72))	('hallmark of cancers', 'Disease', 'MESH:D009369', (53, 72))	('Polycomb', 'Var', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('EZH2', 'Gene', (128, 132))	('SUZ12', 'Gene', '23512', (118, 123))	('EZH2', 'Gene', '2146', (128, 132))	('cancers', 'Phenotype', 'HP:0002664', (65, 72))	('SUZ12', 'Gene', (118, 123))
190885	26464434	Global demethylation in repetitive elements has been suggested in many cancers and yet a systematical analysis is lacking.	('cancers', 'Phenotype', 'HP:0002664', (71, 78))	('cancers', 'Disease', 'MESH:D009369', (71, 78))	('cancers', 'Disease', (71, 78))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('Global demethylation', 'Var', (0, 20))
190886	26464434	Associations of demethylation with histological grade and stage have been suggested in several tumors, and we could find such an association in an expanded set of tumors.	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('Associations', 'Interaction', (0, 12))	('demethylation', 'Var', (16, 29))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('tumors', 'Disease', (163, 169))	('tumors', 'Disease', 'MESH:D009369', (163, 169))	('tumors', 'Phenotype', 'HP:0002664', (163, 169))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumors', 'Disease', (95, 101))
190888	26464434	Although it has been experimentally shown that demethylation is linked to mitotic dysfunction and genomic rearrangement and anticipated to cause chromosome instability, it remained uninvestigated in clinical series.	('mitotic dysfunction', 'Disease', (74, 93))	('demethylation', 'Var', (47, 60))	('chromosome instability', 'MPA', (145, 167))	('mitotic dysfunction', 'Disease', 'MESH:C536987', (74, 93))	('linked', 'Reg', (64, 70))	('chromosome instability', 'Phenotype', 'HP:0040012', (145, 167))	('genomic rearrangement', 'CPA', (98, 119))	('cause', 'Reg', (139, 144))
190892	26464434	NSD1 is a SET domain histone methyltransferase that primarily dimethylates histone H3K36, implicated in Sotos and Weaver overgrowth syndromes.	('NSD1', 'Gene', (0, 4))	('dimethylates', 'Var', (62, 74))	('overgrowth', 'Phenotype', 'HP:0001548', (121, 131))	('Weaver overgrowth syndromes', 'Disease', 'MESH:C536687', (114, 141))	('histone H3K36', 'Protein', (75, 88))	('Weaver overgrowth syndromes', 'Disease', (114, 141))	('NSD1', 'Gene', '64324', (0, 4))
190897	26464434	TP53 was also among the most significant genes, and this can be understood on the basis that TP53 mutations can directly cause DNA demethylation.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('TP53', 'Gene', '7157', (93, 97))	('TP53', 'Gene', (93, 97))	('mutations', 'Var', (98, 107))	('cause', 'Reg', (121, 126))	('DNA demethylation', 'MPA', (127, 144))
190898	26464434	Moreover, TP53 plays critical roles DNA repair and maintaining genomic stability and its mutation may exhibit communal pathways with DNA demethylation leading to chromosome instability.	('chromosome instability', 'MPA', (162, 184))	('TP53', 'Gene', (10, 14))	('mutation', 'Var', (89, 97))	('TP53', 'Gene', '7157', (10, 14))	('genomic', 'MPA', (63, 70))	('chromosome instability', 'Phenotype', 'HP:0040012', (162, 184))	('leading to', 'Reg', (151, 161))	('exhibit', 'Reg', (102, 109))
190899	26464434	It is often hypothesized that demethylation in cancer cells can activate proto-oncogenes and thus contribute to tumorigenesis.	('tumor', 'Disease', (112, 117))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('cancer', 'Disease', (47, 53))	('contribute to', 'Reg', (98, 111))	('demethylation', 'Var', (30, 43))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('proto-oncogenes', 'Gene', (73, 88))	('activate', 'PosReg', (64, 72))
190900	26464434	As more supporting evidence, we found that many pathways such as BMP receptor, LPA receptor, Ephrin B, PLK1, Aurora A and B, FoxM1, neurotrophic factor and p75NTR pathways tended to be suppressed rather than activated in demethylated tumors.	('Ephrin B', 'Gene', (93, 101))	('tumors', 'Disease', 'MESH:D009369', (234, 240))	('LPA', 'Protein', (79, 82))	('neurotrophic factor', 'Gene', '4908', (132, 151))	('demethylated', 'Var', (221, 233))	('BMP', 'Gene', '649', (65, 68))	('Aurora A and B', 'Gene', '6790;9212', (109, 123))	('PLK1', 'Gene', (103, 107))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('activated', 'PosReg', (208, 217))	('tumors', 'Phenotype', 'HP:0002664', (234, 240))	('neurotrophic factor', 'Gene', (132, 151))	('p75NTR', 'Gene', (156, 162))	('FoxM1', 'Gene', '2305', (125, 130))	('LPA', 'Chemical', 'MESH:C032881', (79, 82))	('BMP', 'Gene', (65, 68))	('PLK1', 'Gene', '5347', (103, 107))	('suppressed', 'NegReg', (185, 195))	('tumors', 'Disease', (234, 240))	('p75NTR', 'Gene', '4804', (156, 162))	('FoxM1', 'Gene', (125, 130))
190902	26464434	We observed that low BMP, especially BMP-7, activity is associated with backbone demethylation and such demethylated tumors show aggressive features like high Gleason score and prostate specific antigen level (Supplementary Figure S10B).	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('S10B', 'Var', (231, 235))	('BMP', 'Gene', '649', (37, 40))	('associated', 'Reg', (56, 66))	('prostate specific antigen', 'Gene', (177, 202))	('demethylated', 'Var', (104, 116))	('prostate specific antigen', 'Gene', '354', (177, 202))	('BMP', 'Gene', (21, 24))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('BMP-7', 'Gene', '655', (37, 42))	('tumors', 'Disease', (117, 123))	('low', 'Var', (17, 20))	('BMP', 'Gene', (37, 40))	('BMP-7', 'Gene', (37, 42))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('activity', 'MPA', (44, 52))	('backbone demethylation', 'MPA', (72, 94))	('S10B', 'SUBSTITUTION', 'None', (231, 235))	('BMP', 'Gene', '649', (21, 24))
190904	26464434	We also noticed that the demethylated tumors also tended to have worse outcome although the significance varied according to the cutoffs for average backbone methylation (data not shown).	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumors', 'Disease', (38, 44))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('demethylated', 'Var', (25, 37))	('tumors', 'Disease', 'MESH:D009369', (38, 44))
190906	26464434	We observed low BMP activity in demethylated LGGs which showed higher histological grade and worse treatment response and survival (Supplementary Figure S9B).	('histological', 'CPA', (70, 82))	('BMP', 'Gene', '649', (16, 19))	('survival', 'CPA', (122, 130))	('treatment response', 'CPA', (99, 117))	('BMP', 'Gene', (16, 19))	('demethylated', 'Var', (32, 44))	('higher', 'PosReg', (63, 69))	('low', 'NegReg', (12, 15))
190913	26464434	We observed that Ephrin pathways are epigenetically suppressed in a set of tumors preferentially by backbone demethylation.	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('suppressed', 'NegReg', (52, 62))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('Ephrin pathways', 'Pathway', (17, 32))	('tumors', 'Disease', (75, 81))	('backbone demethylation', 'Var', (100, 122))
190915	26464434	We found that PLK1 and Aurora pathways are often suppressed and sometimes activated in backbone-demethylated or CGI-methylated tumors.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('CGI-methylated', 'Var', (112, 126))	('tumors', 'Disease', (127, 133))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('activated', 'PosReg', (74, 83))	('tumors', 'Disease', 'MESH:D009369', (127, 133))	('suppressed', 'NegReg', (49, 59))	('backbone-demethylated', 'Var', (87, 108))	('PLK1', 'Gene', (14, 18))	('Aurora pathways', 'Pathway', (23, 38))	('PLK1', 'Gene', '5347', (14, 18))
190917	26464434	Either loss or gain of FoxM function can alter cell fate and promote tumorigenesis, and we observed epigenetic suppression of FoxM1 pathway in a set of tumors.	('cell fate', 'CPA', (47, 56))	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('loss', 'NegReg', (7, 11))	('FoxM', 'Gene', (23, 27))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('tumors', 'Disease', 'MESH:D009369', (152, 158))	('tumor', 'Disease', (69, 74))	('FoxM1', 'Gene', '2305', (126, 131))	('promote', 'PosReg', (61, 68))	('FoxM1', 'Gene', (126, 131))	('tumor', 'Disease', (152, 157))	('alter', 'Reg', (41, 46))	('gain', 'PosReg', (15, 19))	('epigenetic suppression', 'Var', (100, 122))	('tumors', 'Disease', (152, 158))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('tumors', 'Phenotype', 'HP:0002664', (152, 158))
190927	26464434	The slightly-high tumors showed poor survival compared to slightly-low tumors.	('tumors', 'Disease', (18, 24))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('slightly-high', 'Var', (4, 17))	('tumors', 'Disease', (71, 77))	('tumors', 'Disease', 'MESH:D009369', (71, 77))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
190932	26464434	Collectively, we present a pan-cancer model connecting CGI methylation with hypermutability, MSI-H, IDH1 mutation, 19p gain and polycomb proteins and backbone demethylation with chromosomal instability, NSD1 and TP53 mutations, 5q and 19p loss and long repressive domains (Figure 5).	('MSI-H', 'Disease', 'MESH:D000848', (93, 98))	('mutation', 'Var', (105, 113))	('IDH1', 'Gene', '3417', (100, 104))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('chromosomal instability', 'Phenotype', 'HP:0040012', (178, 201))	('NSD1', 'Gene', (203, 207))	('MSI-H', 'Disease', (93, 98))	('loss', 'NegReg', (239, 243))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('TP53', 'Gene', '7157', (212, 216))	('IDH1', 'Gene', (100, 104))	('cancer', 'Disease', (31, 37))	('mutations', 'Var', (217, 226))	('NSD1', 'Gene', '64324', (203, 207))	('gain', 'PosReg', (119, 123))	('TP53', 'Gene', (212, 216))
190934	26464434	Since many pathways are suppressed in methylated and demethylated tumors, thoughtful usage of new targeted drugs inhibiting such pathways is warranted.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('methylated', 'Var', (38, 48))	('tumors', 'Disease', (66, 72))	('suppressed', 'NegReg', (24, 34))	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('pathways', 'Pathway', (11, 19))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('demethylated', 'Var', (53, 65))
190974	26459408	An X-chromosome clonality assay showed monoclonality of both components in a case of mixed LCNEC and mucinous carcinoma.	('mucinous carcinoma', 'Disease', 'MESH:D002288', (101, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('mucinous carcinoma', 'Disease', (101, 119))	('LCNEC', 'Phenotype', 'HP:0030360', (91, 96))	('NEC', 'Phenotype', 'HP:0100634', (93, 96))	('monoclonality', 'Var', (39, 52))	('mixed LCNEC', 'Disease', (85, 96))	('LCNEC', 'Chemical', '-', (91, 96))	('mucinous carcinoma', 'Phenotype', 'HP:0031495', (101, 119))
191086	26459408	A case of LCNEC associated with serous carcinoma revealed a different pattern of microsatellite instability in both components.	('serous carcinoma', 'Disease', (32, 48))	('LCNEC', 'Chemical', '-', (10, 15))	('LCNEC', 'Disease', (10, 15))	('serous carcinoma', 'Disease', 'MESH:D018284', (32, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (39, 48))	('microsatellite', 'Var', (81, 95))	('LCNEC', 'Phenotype', 'HP:0030360', (10, 15))	('NEC', 'Phenotype', 'HP:0100634', (12, 15))
191100	26459408	Recently, somatic and germline SMARCA4 mutations accompanied by the loss of BRG1 protein expression in immunohistochemistry have been described in SCCOHTs.	('BRG1', 'Gene', (76, 80))	('expression', 'MPA', (89, 99))	('BRG1', 'Gene', '6597', (76, 80))	('SMARCA4', 'Gene', (31, 38))	('SMARCA4', 'Gene', '6597', (31, 38))	('mutations', 'Var', (39, 48))	('SCCOHTs', 'Disease', (147, 154))	('loss', 'NegReg', (68, 72))	('protein', 'Protein', (81, 88))
191115	26459408	Currently, SCCOHT is considered to be an ovarian malignant rhabdoid tumor, as inactivation of SMARCA4 accompanied by the loss of BRG1 protein and the retention of INI- 1 in immunohistochemistry has been described in this aggressive tumor.	('ovarian malignant rhabdoid tumor', 'Disease', (41, 73))	('inactivation', 'Var', (78, 90))	('ovarian malignant rhabdoid tumor', 'Disease', 'MESH:D018335', (41, 73))	('BRG1', 'Gene', (129, 133))	('loss', 'NegReg', (121, 125))	('SCCOHT', 'Disease', (11, 17))	('INI- 1', 'Gene', (163, 169))	('SMARCA4', 'Gene', (94, 101))	('SMARCA4', 'Gene', '6597', (94, 101))	('aggressive tumor', 'Disease', 'MESH:D001523', (221, 237))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('BRG1', 'Gene', '6597', (129, 133))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('INI- 1', 'Gene', '6598', (163, 169))	('aggressive tumor', 'Disease', (221, 237))
191130	24439808	For example, bleomycin injures the alveolar epithelium, and naphthalene specifically injures the bronchiolar epithelium.	('bleomycin', 'Var', (13, 22))	('bleomycin', 'Chemical', 'MESH:D001761', (13, 22))	('naphthalene', 'Chemical', 'MESH:C031721', (60, 71))	('injures', 'NegReg', (85, 92))	('injures', 'Reg', (23, 30))
191154	24439808	BASCs increase in number after naphthalene bronchiolar injury and bleomycin alveolar injury, which suggests their role in repair.	('alveolar injury', 'Disease', 'MESH:D002282', (76, 91))	('naphthalene', 'Chemical', 'MESH:C031721', (31, 42))	('bleomycin', 'Var', (66, 75))	('bleomycin', 'Chemical', 'MESH:D001761', (66, 75))	('alveolar injury', 'Disease', (76, 91))	('bronchiolar injury', 'Disease', 'MESH:D002282', (43, 61))	('naphthalene', 'Var', (31, 42))	('bronchiolar injury', 'Disease', (43, 61))	('increase', 'PosReg', (6, 14))
191165	24439808	Specifically, after bleomycin lung injury and repair, the percentage of lineage-labeled AT2 and AT1 cells increased, indicating that a CCSP-expressing cell, such as a BASC or Clara cell contributed to alveolar epithelial repair.	('bleomycin', 'Chemical', 'MESH:D001761', (20, 29))	('bleomycin', 'Var', (20, 29))	('lung injury', 'Disease', 'MESH:D055370', (30, 41))	('lung injury', 'Disease', (30, 41))	('increased', 'PosReg', (106, 115))	('alveolar epithelial repair', 'CPA', (201, 227))
191176	24439808	Critical for regional specification of embryonic lung epithelium, MSCs at the distal tip of the branching epithelium are known to secrete FGF10, a critical component of the signaling network involving Bmp, Wnt, and sonic hedgehog pathways that is necessary for coordinating differentiation in the developing lung.	('embryonic lung epithelium', 'Disease', (39, 64))	('FGF10', 'Gene', (138, 143))	('FGF10', 'Gene', '14165', (138, 143))	('secrete', 'Var', (130, 137))	('embryonic lung epithelium', 'Disease', 'MESH:C536309', (39, 64))
191208	24439808	BPD leads to distal airway epithelial cell simplification and vascular injury, and most current treatments are palliative.	('distal airway epithelial cell simplification', 'CPA', (13, 57))	('BPD', 'Var', (0, 3))	('vascular injury', 'Disease', (62, 77))	('vascular injury', 'Disease', 'MESH:D057772', (62, 77))
191232	24439808	Adenocarcinomas have histology and biomarker expression consistent with distal lung, including expression of CK14, surfactant proteins, and amplification of the transcription factor Nkx2.1.	('Nkx2.1', 'Gene', '21869', (182, 188))	('Adenocarcinomas', 'Disease', (0, 15))	('Adenocarcinomas', 'Disease', 'MESH:D000230', (0, 15))	('carcinoma', 'Phenotype', 'HP:0030731', (5, 14))	('CK14', 'Gene', (109, 113))	('Nkx2.1', 'Gene', (182, 188))	('CK14', 'Gene', '16664', (109, 113))	('amplification', 'Var', (140, 153))	('carcinomas', 'Phenotype', 'HP:0030731', (5, 15))	('distal lung', 'Disease', (72, 83))
191245	24439808	However, an equally plausible explanation for how tumor cells with the capacity to self-renew arise is that a more differentiated cell acquires the capacity for self-renewal through genetic and/or epigenetic mechanisms.	('self-renewal', 'CPA', (161, 173))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('epigenetic', 'Var', (197, 207))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Disease', (50, 55))
191250	24439808	The lines appear to recapitulate many features of the primary tumors from which they were derived, including amplification of genes such as Nkx2.1 and Sox2.	('Sox2', 'Gene', (151, 155))	('primary tumors', 'Disease', 'MESH:D009369', (54, 68))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('Nkx2.1', 'Gene', (140, 146))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('Sox2', 'Gene', '20674', (151, 155))	('amplification', 'Var', (109, 122))	('Nkx2.1', 'Gene', '21869', (140, 146))	('primary tumors', 'Disease', (54, 68))
191260	24439808	This model allows for activation of oncogenic Kras by Cre recombinase-mediated excision of the Lox-Stop-Lox cassette preceding the Kras oncogene.	('Kras', 'Gene', (46, 50))	('Kras', 'Gene', '16653', (46, 50))	('Lox', 'Gene', '16948', (104, 107))	('Lox', 'Gene', (95, 98))	('Kras', 'Gene', '16653', (131, 135))	('activation', 'PosReg', (22, 32))	('excision', 'Var', (79, 87))	('Lox', 'Gene', '16948', (95, 98))	('Lox', 'Gene', (104, 107))	('Kras', 'Gene', (131, 135))
191264	24439808	This system has been particularly useful for expression of specific point mutants of epidermal growth factor receptor (EGFR) that were identified in patient samples.	('epidermal growth factor receptor', 'Gene', '1956', (85, 117))	('point mutants', 'Var', (68, 81))	('patient', 'Species', '9606', (149, 156))	('epidermal growth factor receptor', 'Gene', (85, 117))	('EGFR', 'Gene', (119, 123))
191266	24439808	They have been used successfully for preclinical or coclinical trials of targeted therapies for lung cancer such as inhibition of EGFR.	('lung cancer', 'Disease', 'MESH:D008175', (96, 107))	('inhibition', 'Var', (116, 126))	('lung cancer', 'Disease', (96, 107))	('lung cancer', 'Phenotype', 'HP:0100526', (96, 107))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('EGFR', 'Gene', (130, 134))
191271	24439808	However, no lung-specific tumor suppressor loss or oncogene expression has been able to produce solely squamous cell carcinoma in the mouse.	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (103, 126))	('expression', 'Var', (60, 70))	('squamous cell carcinoma', 'Disease', (103, 126))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (103, 126))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('mouse', 'Species', '10090', (134, 139))
191273	24439808	The mouse model consisting of lung-specific inactivation of both p53 and Rb (p53-null/Rb-null) leads to highly penetrant SCLC.	('SCLC', 'Disease', (121, 125))	('mouse', 'Species', '10090', (4, 9))	('p53', 'Gene', (65, 68))	('p53', 'Gene', '22059', (65, 68))	('SCLC', 'Disease', 'MESH:D018288', (121, 125))	('p53', 'Gene', (77, 80))	('p53', 'Gene', '22059', (77, 80))	('inactivation', 'Var', (44, 56))	('leads to', 'Reg', (95, 103))
191277	24439808	Furthermore, deletion of Rb and p53 by a Cre driven by the endogenous neuroendocrine gene CGRP was sufficient for SCLC development.	('CGRP', 'Gene', '12310', (90, 94))	('CGRP', 'Gene', (90, 94))	('SCLC', 'Disease', 'MESH:D018288', (114, 118))	('SCLC', 'Disease', (114, 118))	('p53', 'Gene', (32, 35))	('deletion', 'Var', (13, 21))	('p53', 'Gene', '22059', (32, 35))
191305	33098199	This study reports for the first time the prognostic value of ctDNA sequencing, with the presence of ctDNA alterations, specific ctDNA alterations in DNA repair genes and TP53, and unique ctDNA alterations within partially concordant genes predicting poor survival.	('TP53', 'Gene', (171, 175))	('ctDNA', 'Gene', (101, 106))	('alterations', 'Var', (135, 146))	('DNA repair genes', 'Gene', (150, 166))	('TP53', 'Gene', '7157', (171, 175))
191314	33098199	A recent analysis of ctDNA sequencing in gastrointestinal, brain, breast, lung, and head and neck tumors found that patients with head and neck cancer had the highest number of patients with ctDNA alterations detected (88%) and patients with three or more ctDNA alterations (48%) [5].	('neck tumors', 'Disease', 'MESH:D006258', (93, 104))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('head and neck tumors', 'Phenotype', 'HP:0012288', (84, 104))	('ctDNA', 'Gene', (191, 196))	('alterations', 'Var', (197, 208))	('patients', 'Species', '9606', (116, 124))	('patients', 'Species', '9606', (228, 236))	('patients', 'Species', '9606', (177, 185))	('neck tumors', 'Disease', (93, 104))	('head and neck cancer', 'Disease', 'MESH:D006258', (130, 150))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('head and neck cancer', 'Phenotype', 'HP:0012288', (130, 150))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
191323	33098199	Sequencing of ctDNA was performed using the Guardant360 platform (Guardant Health, Redwood City, CA), which assesses for single nucleotide variants in 73 genes, indels and fusion alterations, and CNAs in select genes.	('indels', 'Var', (161, 167))	('fusion alterations', 'Var', (172, 190))	('single nucleotide variants', 'Var', (121, 147))	('Redwood', 'Species', '28980', (83, 90))
191338	33098199	TP53 was the most altered gene, with 127 total alterations spread among 73.3% of patients, yielding an average of 1.67 +- 1.48 TP53 alterations per patient.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('patient', 'Species', '9606', (81, 88))	('patients', 'Species', '9606', (81, 89))	('patient', 'Species', '9606', (148, 155))	('alterations', 'Var', (47, 58))	('TP53', 'Gene', (127, 131))	('TP53', 'Gene', '7157', (127, 131))
191342	33098199	Other genes with alterations found only in tDNA include RB1, JAK2, JAK3, RET, IDH1, VHL, HER2, and PDGFRA.	('JAK2', 'Gene', '3717', (61, 65))	('VHL', 'Gene', (84, 87))	('RB1', 'Gene', (56, 59))	('RET', 'Gene', '5979', (73, 76))	('IDH1', 'Gene', (78, 82))	('VHL', 'Gene', '7428', (84, 87))	('JAK3', 'Gene', (67, 71))	('IDH1', 'Gene', '3417', (78, 82))	('JAK2', 'Gene', (61, 65))	('HER2', 'Gene', (89, 93))	('RB1', 'Gene', '5925', (56, 59))	('JAK3', 'Gene', '3718', (67, 71))	('RET', 'Gene', (73, 76))	('HER2', 'Gene', '2064', (89, 93))	('alterations', 'Var', (17, 28))	('PDGFRA', 'Gene', (99, 105))	('PDGFRA', 'Gene', '5156', (99, 105))
191343	33098199	Alterations in DNA repair genes (APC, ATM, BRCA1, and/or BRCA2) were present in 38.8% of patients, with a total of 32 tDNA alterations and 23 ctDNA alterations.	('BRCA1', 'Gene', (43, 48))	('ATM', 'Gene', '472', (38, 41))	('APC', 'Disease', 'MESH:D011125', (33, 36))	('APC', 'Disease', (33, 36))	('Alterations', 'Var', (0, 11))	('BRCA2', 'Gene', (57, 62))	('patients', 'Species', '9606', (89, 97))	('alterations', 'Reg', (123, 134))	('ATM', 'Gene', (38, 41))	('BRCA2', 'Gene', '675', (57, 62))	('BRCA1', 'Gene', '672', (43, 48))
191344	33098199	DNA repair gene alterations were present in 25.3% and 25.3% of patients in tDNA and ctDNA, respectively, in a nonexclusive manner.	('DNA repair gene', 'Gene', (0, 15))	('alterations', 'Var', (16, 27))	('tDNA', 'Disease', (75, 79))	('patients', 'Species', '9606', (63, 71))
191346	33098199	Advanced tumor progression status at time of ctDNA collection was associated with presence of ctDNA alterations (p = .0013), an increased number of ctDNA alterations (p = .0036), and presence of TP53 alterations in ctDNA (p = .015) (supplemental online Fig.	('TP53', 'Gene', (195, 199))	('alterations', 'Var', (200, 211))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('ctDNA alterations', 'Gene', (94, 111))	('tumor', 'Disease', (9, 14))	('TP53', 'Gene', '7157', (195, 199))
191349	33098199	Finally, at the time of ctDNA collection, only 9.1% of patients with no evidence of disease had ctDNA alterations in TP53 compared with 64.7% of patients with recurrent disease and 63.6% with metastatic disease (p = .015).	('patients', 'Species', '9606', (145, 153))	('alterations', 'Var', (102, 113))	('met', 'Gene', (192, 195))	('TP53', 'Gene', '7157', (117, 121))	('TP53', 'Gene', (117, 121))	('met', 'Gene', '79811', (192, 195))	('patients', 'Species', '9606', (55, 63))
191354	33098199	On the alteration level in a nonexclusive manner, 45.3% of ctDNA alterations had FDA-approved off-label therapies (such as PARP inhibitors for BRCA1 or BRCA2 alterations, copanlisib or duvelisib for PIK3CA alterations, etc.	('PARP', 'Gene', '1302', (123, 127))	('alterations', 'Var', (65, 76))	('PARP', 'Gene', (123, 127))	('BRCA1', 'Gene', '672', (143, 148))	('PIK3CA', 'Gene', (199, 205))	('duvelisib', 'Chemical', 'MESH:C586691', (185, 194))	('BRCA2', 'Gene', '675', (152, 157))	('BRCA1', 'Gene', (143, 148))	('PIK3CA', 'Gene', '5290', (199, 205))	('ctDNA', 'Gene', (59, 64))	('BRCA2', 'Gene', (152, 157))
191356	33098199	On a nonexclusive per-patient basis, 13.3% of patients had ctDNA alterations detected with FDA-approved off-label therapies, 62.7% had ctDNA alterations with clinical trial treatment options, and 33.3% of patients did not have altered ctDNA targets for treatment or clinical trial options, including 10.7% of patients who had only VUS alterations.	('patient', 'Species', '9606', (46, 53))	('alterations', 'Var', (65, 76))	('VUS alterations', 'Disease', (331, 346))	('patients', 'Species', '9606', (46, 54))	('patient', 'Species', '9606', (205, 212))	('patients', 'Species', '9606', (205, 213))	('patient', 'Species', '9606', (309, 316))	('VUS alterations', 'Disease', 'MESH:D004408', (331, 346))	('patients', 'Species', '9606', (309, 317))	('ctDNA', 'Gene', (59, 64))	('patient', 'Species', '9606', (22, 29))
191361	33098199	Increased tDNA tumor mutational burden was associated with decreased OS at 2 years after ctDNA sampling (p = .0015).	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('decreased', 'NegReg', (59, 68))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumor', 'Disease', (15, 20))	('mutational burden', 'Var', (21, 38))	('tDNA', 'Gene', (10, 14))
191362	33098199	NOTCH1 alterations were not associated with prognosis.	('alterations', 'Var', (7, 18))	('NOTCH1', 'Gene', '4851', (0, 6))	('NOTCH1', 'Gene', (0, 6))
191369	33098199	Presence of unique ctDNA alterations within partially concordant genes (n = 8) was markedly associated with decreased OS in univariate analysis (p = .041; HR, 2.6) and stepwise multivariate analysis when controlled for age, gender, smoking history, alcohol history, and stage at diagnosis (p = .0019; HR, 6.4; Table 2; Fig.	('alterations', 'Var', (25, 36))	('decreased', 'NegReg', (108, 117))	('alcohol', 'Chemical', 'MESH:D000438', (249, 256))	('ctDNA', 'Gene', (19, 24))
191370	33098199	Presence of DNA repair gene alterations (APC, ATM, BRCA1, and/or BRCA2) in ctDNA was markedly associated with decreased OS in univariate analysis (p = .0044; HR, 3.0), when stratified by tumor staging at diagnosis (p = .0040; HR, 3.0) or by HPV and/or p16 status (p = .0246), and in multivariate analysis when controlled for age, gender, smoking history, alcohol history, and stage at diagnosis (p = .0054; HR, 4.1) (Table 2; Fig.	('DNA repair gene', 'Gene', (12, 27))	('ATM', 'Gene', (46, 49))	('HPV', 'Species', '10566', (241, 244))	('BRCA2', 'Gene', '675', (65, 70))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('alterations', 'Var', (28, 39))	('APC', 'Disease', 'MESH:D011125', (41, 44))	('BRCA1', 'Gene', '672', (51, 56))	('p16', 'Gene', '1029', (252, 255))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('ATM', 'Gene', '472', (46, 49))	('decreased', 'NegReg', (110, 119))	('tumor', 'Disease', (187, 192))	('BRCA1', 'Gene', (51, 56))	('APC', 'Disease', (41, 44))	('BRCA2', 'Gene', (65, 70))	('p16', 'Gene', (252, 255))	('alcohol', 'Chemical', 'MESH:D000438', (355, 362))
191371	33098199	Presence of DNA repair genes alterations in ctDNA and/or tDNA was associated with decreased OS (p = .0055; HR, 3.0), maintained association when stratified for tumor stage at diagnosis (p = .0048; HR, 3.0) or HPV and/or p16 status (p = .028; HR, 3.4), and was associated with presence of DLV (p = .025).	('p16', 'Gene', '1029', (220, 223))	('p16', 'Gene', (220, 223))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('alterations', 'Var', (29, 40))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('DNA repair genes', 'Gene', (12, 28))	('tumor', 'Disease', (160, 165))	('decreased', 'NegReg', (82, 91))	('HPV', 'Species', '10566', (209, 212))
191373	33098199	TP53 alterations were detected in tDNA in 74.6% and ctDNA in 50.7% of patients included in the outcome analysis.	('patients', 'Species', '9606', (70, 78))	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('alterations', 'Var', (5, 16))	('detected', 'Reg', (22, 30))	('ctDNA', 'Disease', (52, 57))	('tDNA', 'Disease', (34, 38))
191374	33098199	All patients with TP53 alterations had TP53 alterations in tDNA.	('TP53', 'Gene', '7157', (18, 22))	('TP53', 'Gene', (18, 22))	('alterations', 'Var', (23, 34))	('patients', 'Species', '9606', (4, 12))	('TP53', 'Gene', '7157', (39, 43))	('TP53', 'Gene', (39, 43))
191375	33098199	Presence of TP53 alterations in ctDNA trended toward association with decreased OS (p = .051; HR, 2.2) and was significantly associated with OS at 1 year (p = .042) and presence (p = .0029) and extent (p = .014) of DLV (Table 2; Fig.	('DLV', 'Disease', (215, 218))	('decreased', 'NegReg', (70, 79))	('associated', 'Reg', (125, 135))	('TP53', 'Gene', '7157', (12, 16))	('TP53', 'Gene', (12, 16))	('alterations', 'Var', (17, 28))	('Presence', 'Var', (0, 8))
191376	33098199	Presence of TP53 alterations in tDNA was associated with decreased OS (p = .031; HR, 3.7) and decreased OS at 1 year (p = .0018).	('OS at 1 year', 'MPA', (104, 116))	('TP53', 'Gene', '7157', (12, 16))	('decreased', 'NegReg', (94, 103))	('TP53', 'Gene', (12, 16))	('decreased', 'NegReg', (57, 66))	('Presence', 'Var', (0, 8))
191377	33098199	Number of total TP53 alterations was also associated with decreased OS (p = .020; HR, 1.4), decreased OS at 1 year (p = .0053), and presence of DLV (p = .049).	('decreased', 'NegReg', (58, 67))	('TP53', 'Gene', '7157', (16, 20))	('decreased', 'NegReg', (92, 101))	('TP53', 'Gene', (16, 20))	('alterations', 'Var', (21, 32))	('OS at 1 year', 'MPA', (102, 114))
191379	33098199	When stratified by tumor staging at diagnosis, presence of tDNA alterations in TP53 and presence of either tDNA or ctDNA alterations in TP53 maintained significant association with OS (supplemental online Fig.	('alterations', 'Var', (121, 132))	('TP53', 'Gene', '7157', (79, 83))	('TP53', 'Gene', (79, 83))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('alterations', 'Var', (64, 75))	('tumor', 'Disease', (19, 24))	('TP53', 'Gene', '7157', (136, 140))	('TP53', 'Gene', (136, 140))
191382	33098199	The presence and number of TP53 alterations were associated with decreased OS, positive HPV or p16 results were associated with increased OS, and decreased TP53 and DNA repair gene alterations and the top five most altered genes in our analysis were TP53, CDKN2A, TERT, BRCA2, and NOTCH1 [1, 13, 14, 15, 16].	('decreased', 'NegReg', (65, 74))	('TP53', 'Gene', (156, 160))	('TP53', 'Gene', (27, 31))	('CDKN2A', 'Gene', (256, 262))	('BRCA2', 'Gene', (270, 275))	('DNA repair gene', 'Gene', (165, 180))	('TP53', 'Gene', (250, 254))	('p16', 'Gene', (95, 98))	('NOTCH1', 'Gene', (281, 287))	('p16', 'Gene', '1029', (95, 98))	('TP53', 'Gene', '7157', (156, 160))	('alterations', 'MPA', (181, 192))	('alterations', 'Var', (32, 43))	('CDKN2A', 'Gene', '1029', (256, 262))	('TERT', 'Gene', (264, 268))	('HPV', 'Species', '10566', (88, 91))	('TERT', 'Gene', '7015', (264, 268))	('BRCA2', 'Gene', '675', (270, 275))	('TP53', 'Gene', '7157', (27, 31))	('NOTCH1', 'Gene', '4851', (281, 287))	('decreased', 'NegReg', (146, 155))	('TP53', 'Gene', '7157', (250, 254))	('HPV', 'Gene', (88, 91))
191384	33098199	Furthermore, advanced tumor status at the time of ctDNA collection (recurrent tumor or presence of metastasis) was associated with presence of ctDNA alterations, increased number of ctDNA alterations, and presence of TP53 alterations in ctDNA.	('TP53', 'Gene', '7157', (217, 221))	('met', 'Gene', (99, 102))	('alterations', 'Var', (149, 160))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('TP53', 'Gene', (217, 221))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('met', 'Gene', '79811', (99, 102))	('tumor', 'Disease', (22, 27))	('tumor', 'Disease', (78, 83))	('ctDNA', 'Gene', (143, 148))
191390	33098199	These assertions are supported by our results that ctDNA was 33.8% sensitive among the top 15 genes and that the average number of alterations per patient among the 70 overlapping genes was greater in tDNA (4.35) than ctDNA (2.78) (Fig.	('patient', 'Species', '9606', (147, 154))	('tDNA', 'Disease', (201, 205))	('alterations', 'Var', (131, 142))
191393	33098199	NOTCH1 is the third most altered gene in HNSCC, with tDNA alterations seen in 15%-19% of patients and a hypothesized role as a tumor suppressor [2].	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('HNSCC', 'Phenotype', 'HP:0012288', (41, 46))	('tumor', 'Disease', (127, 132))	('patients', 'Species', '9606', (89, 97))	('NOTCH1', 'Gene', '4851', (0, 6))	('NOTCH1', 'Gene', (0, 6))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('alterations', 'Var', (58, 69))
191395	33098199	Previous studies demonstrated a NOTCH1 alteration rate of 5.8% and 23.0% in the ctDNA of various solid cancers, but a lack of NOTCH1 ctDNA alterations in HNSCC has not yet been reported [19, 20].	('alteration', 'Var', (39, 49))	('cancers', 'Disease', 'MESH:D009369', (103, 110))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('NOTCH1', 'Gene', '4851', (32, 38))	('NOTCH1', 'Gene', (32, 38))	('NOTCH1', 'Gene', '4851', (126, 132))	('NOTCH1', 'Gene', (126, 132))	('HNSCC', 'Gene', (154, 159))	('cancers', 'Phenotype', 'HP:0002664', (103, 110))	('HNSCC', 'Phenotype', 'HP:0012288', (154, 159))	('cancers', 'Disease', (103, 110))
191396	33098199	Further analysis of these patients found no difference in survival, staging, disease state, smoking, or HPV status, which indicates a lack of prognostic benefit to the detection of NOTCH1 alterations in HNSCC.	('HNSCC', 'Phenotype', 'HP:0012288', (203, 208))	('HPV', 'Species', '10566', (104, 107))	('patients', 'Species', '9606', (26, 34))	('NOTCH1', 'Gene', '4851', (181, 187))	('alterations', 'Var', (188, 199))	('NOTCH1', 'Gene', (181, 187))
191402	33098199	The presence of DNA repair alterations in ctDNA had the second strongest association with decreased OS in our analysis after controlling for age, gender, smoking history, alcohol history, and stage at diagnosis and was also associated with the extent of DLV.	('decreased', 'NegReg', (90, 99))	('alcohol', 'Chemical', 'MESH:D000438', (171, 178))	('associated', 'Reg', (224, 234))	('DNA', 'Gene', (16, 19))	('ctDNA', 'Gene', (42, 47))	('alterations', 'Var', (27, 38))
191405	33098199	Presence of TP53 alterations in ctDNA was associated with OS and had the strongest association of all variables with the presence and extent of DLV.	('associated with', 'Reg', (42, 57))	('TP53', 'Gene', '7157', (12, 16))	('association', 'Interaction', (83, 94))	('TP53', 'Gene', (12, 16))	('Presence', 'Var', (0, 8))
191407	33098199	A partially concordant gene is defined as having at least one identical alteration in ctDNA and tDNA (e.g., TP53 H178 frameshift) and additional unique alterations in ctDNA and/or tDNA (e.g., TP53 H214R and Y236C in ctDNA).	('Y236C', 'Var', (207, 212))	('TP53', 'Gene', '7157', (108, 112))	('TP53', 'Gene', (108, 112))	('alterations', 'Reg', (152, 163))	('H214R', 'Mutation', 'rs1057519992', (197, 202))	('Y236C', 'Mutation', 'rs730882026', (207, 212))	('TP53', 'Gene', '7157', (192, 196))	('TP53', 'Gene', (192, 196))
191408	33098199	The presence of partially concordant genes (n = 10) was insignificant, but patients with unique ctDNA alterations within partially concordant genes (n = 8, seven of which were partially concordant for TP53) showed decreased OS in multivariate analysis after controlling for age, gender, smoking history, alcohol history, and stage at diagnosis.	('alcohol', 'Chemical', 'MESH:D000438', (304, 311))	('TP53', 'Gene', '7157', (201, 205))	('patients', 'Species', '9606', (75, 83))	('TP53', 'Gene', (201, 205))	('alterations', 'Var', (102, 113))	('decreased', 'NegReg', (214, 223))	('ctDNA', 'Gene', (96, 101))
191414	33098199	Fifty-three percent of patients had genes with ctDNA alterations that were wild type in tDNA, indicating an additive therapeutic utility of ctDNA sequencing to the current standard of tDNA sequencing.	('patients', 'Species', '9606', (23, 31))	('ctDNA', 'Gene', (47, 52))	('alterations', 'Var', (53, 64))
191417	33098199	Nevertheless, the finding of genomic alterations being predictive of survival in the context of such a heterogenous population of patients with HNSCC raises the possibility that DNA alterations detected in blood and tumor could potentially circumvent canonical predictors of response such as tumor staging.	('tumor', 'Disease', (216, 221))	('tumor', 'Phenotype', 'HP:0002664', (292, 297))	('tumor', 'Disease', (292, 297))	('circumvent', 'NegReg', (240, 250))	('patients', 'Species', '9606', (130, 138))	('tumor', 'Disease', 'MESH:D009369', (216, 221))	('alterations', 'Var', (37, 48))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('tumor', 'Disease', 'MESH:D009369', (292, 297))	('HNSCC', 'Phenotype', 'HP:0012288', (144, 149))
191419	33098199	For the first time, presence of ctDNA alterations, ctDNA alterations in TP53 and DNA repair genes, and unique ctDNA alterations within partially concordant genes were shown to be significantly associated with poor prognosis in HNSCC.	('HNSCC', 'Disease', (227, 232))	('HNSCC', 'Phenotype', 'HP:0012288', (227, 232))	('TP53', 'Gene', '7157', (72, 76))	('DNA repair genes', 'Gene', (81, 97))	('TP53', 'Gene', (72, 76))	('alterations', 'Var', (38, 49))	('associated', 'Reg', (193, 203))
191509	30081853	TRH site-specific methylation in oral and oropharyngeal squamous cell carcinoma The incidence of oral squamous cell carcinoma (OSCC) continues to increase each year.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (56, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('squamous cell carcinoma', 'Disease', (56, 79))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (56, 79))	('SCC', 'Gene', (128, 131))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (97, 125))	('TRH', 'Gene', (0, 3))	('SCC', 'Phenotype', 'HP:0002860', (128, 131))	('SCC', 'Gene', '6317', (128, 131))	('methylation', 'Var', (18, 29))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('oropharyngeal squamous cell carcinoma', 'Phenotype', 'HP:0012182', (42, 79))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (102, 125))	('TRH', 'Gene', '7200', (0, 3))	('oral squamous cell carcinoma', 'Disease', (97, 125))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (102, 125))
191517	30081853	Among the 27,578 differentially methylated CpG sites, cg01009664 of the thyrotropin-releasing hormone (TRH) gene showed the greatest difference in methylation level between healthy and cancerous cells.	('thyrotropin-releasing hormone', 'Gene', '7200', (72, 101))	('cancerous', 'Disease', 'MESH:D009369', (185, 194))	('TRH', 'Gene', '7200', (103, 106))	('cg01009664', 'Chemical', '-', (54, 64))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('cg01009664', 'Var', (54, 64))	('thyrotropin-releasing hormone', 'Gene', (72, 101))	('TRH', 'Gene', (103, 106))	('cancerous', 'Disease', (185, 194))	('methylation level', 'MPA', (147, 164))
191521	30081853	We demonstrated cg01009664 of TRH as a potential biomarker for OSCC and oropharyngeal SCC screening using oral rinse and swab techniques.	('cg01009664', 'Var', (16, 26))	('SCC', 'Gene', (86, 89))	('TRH', 'Gene', (30, 33))	('cg01009664', 'Chemical', '-', (16, 26))	('SCC', 'Gene', '6317', (64, 67))	('SCC', 'Phenotype', 'HP:0002860', (86, 89))	('SCC', 'Gene', '6317', (86, 89))	('TRH', 'Gene', '7200', (30, 33))	('SCC', 'Gene', (64, 67))	('SCC', 'Phenotype', 'HP:0002860', (64, 67))
191526	30081853	To reduce the adverse effects of biopsy and to promote optimal treatment plan for OSCC, DNA methylation patterns of genes used as biomarkers for the early diagnosis of OSCC and, consequently, a better prognosis of patients' health.	('patients', 'Species', '9606', (214, 222))	('SCC', 'Gene', (83, 86))	('SCC', 'Gene', (169, 172))	('SCC', 'Phenotype', 'HP:0002860', (169, 172))	('SCC', 'Phenotype', 'HP:0002860', (83, 86))	('SCC', 'Gene', '6317', (83, 86))	('methylation patterns', 'Var', (92, 112))	('SCC', 'Gene', '6317', (169, 172))
191558	30081853	Ct values of all samples were used to calculate DNA concentrations on the basis of the standard curve prepared using 10-fold serial dilutions of universal methylated DNA standard (Zymo Research Corporation, Irvine, CA, USA) (10, 1, 0.1, 0.01, and 0.001 ng/muL).	('muL', 'Gene', (256, 259))	('muL', 'Gene', '4591', (256, 259))	('0.01', 'Var', (237, 241))
191561	30081853	This graph represented the CpG site, cg01009664 in the thyrotropin-releasing hormone (TRH) gene sequence (Fig.	('cg01009664', 'Chemical', '-', (37, 47))	('cg01009664', 'Var', (37, 47))	('thyrotropin-releasing hormone', 'Gene', (55, 84))	('TRH', 'Gene', (86, 89))	('thyrotropin-releasing hormone', 'Gene', '7200', (55, 84))	('TRH', 'Gene', '7200', (86, 89))
191562	30081853	DNA isolated from microdissected oral epithelial cells of nine healthy and nine OSCC FFPE samples were subjected to pyrosequencing for the validation of the CpG site, cg01009664.	('SCC', 'Gene', '6317', (81, 84))	('cg01009664', 'Var', (167, 177))	('cg01009664', 'Chemical', '-', (167, 177))	('SCC', 'Gene', (81, 84))	('SCC', 'Phenotype', 'HP:0002860', (81, 84))
191563	30081853	Pyrosequencing revealed five differentially methylated CpG sites surrounding cg01009664 in the TRH gene (Fig.	('cg01009664', 'Var', (77, 87))	('cg01009664', 'Chemical', '-', (77, 87))	('TRH', 'Gene', '7200', (95, 98))	('TRH', 'Gene', (95, 98))
191564	30081853	The average methylation percentage of the nine samples at the second CpG site of TRH (cg01009664) in healthy cells (7% +- 1.14%) was significantly lower than that in cancerous cells (58.44% +- 5.68%) (p < 0.001; Fig.	('TRH', 'Gene', (81, 84))	('lower', 'NegReg', (147, 152))	('cancerous', 'Disease', (166, 175))	('TRH', 'Gene', '7200', (81, 84))	('methylation', 'MPA', (12, 23))	('cancerous', 'Disease', 'MESH:D009369', (166, 175))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('cg01009664', 'Var', (86, 96))	('cg01009664', 'Chemical', '-', (86, 96))
191567	30081853	Oral rinse samples from healthy controls showed an amplification signal only for unmethylated TRH, whereas the amplification of methylated TRH was barely detectable (Fig.	('TRH', 'Gene', (139, 142))	('TRH', 'Gene', '7200', (94, 97))	('TRH', 'Gene', '7200', (139, 142))	('amplification', 'MPA', (51, 64))	('TRH', 'Gene', (94, 97))	('unmethylated', 'Var', (81, 93))
191568	30081853	By contrast, oral rinse samples from OSCC subjects showed amplification of both methylated and unmethylated TRH (Fig.	('TRH', 'Gene', '7200', (108, 111))	('SCC', 'Gene', (38, 41))	('SCC', 'Phenotype', 'HP:0002860', (38, 41))	('amplification', 'MPA', (58, 71))	('SCC', 'Gene', '6317', (38, 41))	('methylated', 'Var', (80, 90))	('TRH', 'Gene', (108, 111))
191581	30081853	Our bioinformatics approach revealed site-specific methylation at cg01009664 of the TRH gene, a novel marker for OSCC screening.	('TRH', 'Gene', (84, 87))	('SCC', 'Gene', (114, 117))	('TRH', 'Gene', '7200', (84, 87))	('SCC', 'Phenotype', 'HP:0002860', (114, 117))	('SCC', 'Gene', '6317', (114, 117))	('methylation', 'Var', (51, 62))	('cg01009664', 'Var', (66, 76))	('cg01009664', 'Chemical', '-', (66, 76))
191582	30081853	TRH methylation has been reported in pancreatic cancer, lung cancer and clear cell renal cell carcinoma.	('clear cell renal cell carcinoma', 'Disease', (72, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('reported', 'Reg', (25, 33))	('lung cancer', 'Phenotype', 'HP:0100526', (56, 67))	('lung cancer', 'Disease', 'MESH:D008175', (56, 67))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (37, 54))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (72, 103))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (83, 103))	('methylation', 'Var', (4, 15))	('pancreatic cancer', 'Disease', (37, 54))	('TRH', 'Gene', (0, 3))	('pancreatic cancer', 'Disease', 'MESH:D010190', (37, 54))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('TRH', 'Gene', '7200', (0, 3))	('lung cancer', 'Disease', (56, 67))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (72, 103))
191583	30081853	To the best of our knowledge, this is the first study to demonstrate TRH methylation in OSCC.	('SCC', 'Gene', '6317', (89, 92))	('methylation', 'Var', (73, 84))	('TRH', 'Gene', (69, 72))	('SCC', 'Gene', (89, 92))	('TRH', 'Gene', '7200', (69, 72))	('SCC', 'Phenotype', 'HP:0002860', (89, 92))
191588	30081853	Although the function of TRH in cancer is currently unknown, methylation of the TRH gene in cancerous cells revealed in this study and previous studies suggest that TRH functions involving carcinogenesis as a tumor suppressor gene.	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('cancerous', 'Disease', (92, 101))	('carcinogenesis', 'Disease', 'MESH:D063646', (189, 203))	('TRH', 'Gene', '7200', (25, 28))	('TRH', 'Gene', (80, 83))	('tumor', 'Disease', (209, 214))	('methylation', 'Var', (61, 72))	('cancer', 'Disease', (32, 38))	('TRH', 'Gene', (165, 168))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('tumor', 'Disease', 'MESH:D009369', (209, 214))	('cancer', 'Disease', (92, 98))	('TRH', 'Gene', '7200', (80, 83))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('TRH', 'Gene', '7200', (165, 168))	('cancerous', 'Disease', 'MESH:D009369', (92, 101))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('TRH', 'Gene', (25, 28))	('carcinogenesis', 'Disease', (189, 203))
191590	30081853	TRH methylation showed high sensitivity and specificity for screening OSCC and oropharyngeal SCC.	('SCC', 'Gene', (93, 96))	('methylation', 'Var', (4, 15))	('SCC', 'Phenotype', 'HP:0002860', (93, 96))	('TRH', 'Gene', (0, 3))	('SCC', 'Gene', (71, 74))	('SCC', 'Gene', '6317', (93, 96))	('TRH', 'Gene', '7200', (0, 3))	('SCC', 'Phenotype', 'HP:0002860', (71, 74))	('SCC', 'Gene', '6317', (71, 74))
191594	30081853	Biopsy is an invasive technique; methylation status of TRH CpG sites demonstrates the potential to serve as an OSCC and oropharyngeal SCC noninvasive biomarker.	('SCC', 'Phenotype', 'HP:0002860', (112, 115))	('methylation', 'Var', (33, 44))	('SCC', 'Phenotype', 'HP:0002860', (134, 137))	('SCC', 'Gene', '6317', (134, 137))	('SCC', 'Gene', '6317', (112, 115))	('SCC', 'Gene', (134, 137))	('TRH', 'Gene', (55, 58))	('TRH', 'Gene', '7200', (55, 58))	('SCC', 'Gene', (112, 115))
191603	30081853	Using a bioinformatics approach, we identified and validated TRH site-specific methylation as a candidate biomarker for OSCC detection.	('TRH', 'Gene', (61, 64))	('SCC', 'Gene', (121, 124))	('SCC', 'Phenotype', 'HP:0002860', (121, 124))	('methylation', 'Var', (79, 90))	('SCC', 'Gene', '6317', (121, 124))	('TRH', 'Gene', '7200', (61, 64))	('site-specific', 'Var', (65, 78))
191610	28415565	We demonstrated that loss of Rad52 not only increases the death of cells undergoing carcinogen-induced transformation in vivo, but that Rad52 loss also augments in vivo antitumor activity through an enhanced capacity for direct killing of LLC tumor cells by stimulated Rad52-/- NK and CD8+ T cells.	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('LLC tumor', 'Disease', (239, 248))	('Rad52', 'Gene', (136, 141))	('CD8', 'Gene', '925', (285, 288))	('Rad52', 'Gene', '19365', (29, 34))	('Rad52', 'Gene', '19365', (269, 274))	('increases', 'PosReg', (44, 53))	('tumor', 'Disease', (243, 248))	('loss', 'Var', (21, 25))	('enhanced', 'PosReg', (199, 207))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumor', 'Disease', 'MESH:D009369', (243, 248))	('LLC tumor', 'Disease', 'MESH:D009369', (239, 248))	('Rad52', 'Gene', (29, 34))	('Rad52', 'Gene', (269, 274))	('death', 'CPA', (58, 63))	('CD8', 'Gene', (285, 288))	('direct killing', 'CPA', (221, 235))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))	('augments', 'PosReg', (152, 160))	('Rad52', 'Gene', '19365', (136, 141))	('loss', 'NegReg', (142, 146))	('tumor', 'Disease', (173, 178))
191612	28415565	Loss of Rad52, however, appears to increase genomic instability beyond a manageable threshold, acceding the damaged cells to death before they are able to become tumor cells.	('increase', 'PosReg', (35, 43))	('genomic instability', 'MPA', (44, 63))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('tumor', 'Disease', (162, 167))	('Rad52', 'Gene', '19365', (8, 13))	('Loss', 'Var', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('Rad52', 'Gene', (8, 13))
191615	28415565	While therapeutic advances are occurring, such as molecular targeted therapies against activating mutations of epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) translocations, these have only helped sub-populations of patients at best, and often only for brief periods during their disease course.	('patients', 'Species', '9606', (246, 254))	('EGFR', 'Gene', '1956', (145, 149))	('anaplastic lymphoma kinase', 'Gene', '238', (155, 181))	('ALK', 'Gene', '238', (183, 186))	('mutations', 'Var', (98, 107))	('epidermal growth factor receptor', 'Gene', (111, 143))	('activating', 'PosReg', (87, 97))	('EGFR', 'Gene', (145, 149))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (155, 174))	('anaplastic lymphoma kinase', 'Gene', (155, 181))	('lymphoma', 'Phenotype', 'HP:0002665', (166, 174))	('ALK', 'Gene', (183, 186))	('epidermal growth factor receptor', 'Gene', '1956', (111, 143))
191617	28415565	Like most cancers, lung cancer is believed to arise from the accumulation of mutations in DNA that eventually disrupt the ability of a cell to both manage interactions with its environment and control its rate of proliferation.	('lung cancer', 'Phenotype', 'HP:0100526', (19, 30))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('control', 'Reg', (193, 200))	('interactions', 'Interaction', (155, 167))	('disrupt', 'NegReg', (110, 117))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('ability', 'MPA', (122, 129))	('DNA', 'Gene', (90, 93))	('lung cancer', 'Disease', 'MESH:D008175', (19, 30))	('rate', 'MPA', (205, 209))	('mutations', 'Var', (77, 86))	('cancers', 'Phenotype', 'HP:0002664', (10, 17))	('cancers', 'Disease', 'MESH:D009369', (10, 17))	('arise from', 'Reg', (46, 56))	('cancers', 'Disease', (10, 17))	('lung cancer', 'Disease', (19, 30))
191618	28415565	However, while lung cancer likely arises due to acquisiton of somatic mutations, contemporary evidence has begun to show that genetic variants also play a role in cancer progression and prognosis in patients.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('play', 'Reg', (148, 152))	('role', 'Reg', (155, 159))	('genetic variants', 'Var', (126, 142))	('lung cancer', 'Disease', 'MESH:D008175', (15, 26))	('cancer', 'Disease', 'MESH:D009369', (20, 26))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('cancer', 'Disease', (20, 26))	('patients', 'Species', '9606', (199, 207))	('lung cancer', 'Disease', (15, 26))	('cancer', 'Disease', 'MESH:D009369', (163, 169))	('lung cancer', 'Phenotype', 'HP:0100526', (15, 26))	('cancer', 'Disease', (163, 169))
191620	28415565	Previously, RAD51 and OGG1 have been shown to repair DNA damage and increase cellular resistance to oxidative stress, and RAD52 mediates RAD51 function in homologous recombinational repair (HRR) in both the yeast, Saccharomyces cerevisiae, and in mammalian cells of mice and humans.	('yeast', 'Species', '4932', (207, 212))	('mediates', 'Reg', (128, 136))	('cellular resistance to oxidative stress', 'MPA', (77, 116))	('RAD51', 'Gene', '856831', (12, 17))	('OGG1', 'Gene', (22, 26))	('DNA damage', 'MPA', (53, 63))	('oxidative stress', 'Phenotype', 'HP:0025464', (100, 116))	('RAD51', 'Gene', (12, 17))	('increase', 'PosReg', (68, 76))	('RAD51', 'Gene', '856831', (137, 142))	('OGG1', 'Gene', '854942', (22, 26))	('humans', 'Species', '9606', (275, 281))	('Saccharomyces cerevisiae', 'Species', '4932', (214, 238))	('RAD52', 'Var', (122, 127))	('mice', 'Species', '10090', (266, 270))	('mammalian', 'Species', '9606', (247, 256))	('RAD51', 'Gene', (137, 142))
191624	28415565	Our results demonstrate that Rad52 depletion increased cell death, decreased myeloid cell frequency, and augmented the incidence and activity of CD8+ T cells and NK effectors that ultimately led to reduced tumor growth.	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('increased', 'PosReg', (45, 54))	('tumor', 'Disease', (206, 211))	('tumor', 'Disease', 'MESH:D009369', (206, 211))	('incidence', 'CPA', (119, 128))	('CD8', 'Gene', (145, 148))	('reduced', 'NegReg', (198, 205))	('CD8', 'Gene', '925', (145, 148))	('activity', 'CPA', (133, 141))	('myeloid cell frequency', 'CPA', (77, 99))	('cell death', 'CPA', (55, 65))	('Rad52', 'Gene', '19365', (29, 34))	('decreased', 'NegReg', (67, 76))	('Rad52', 'Gene', (29, 34))	('augmented', 'PosReg', (105, 114))	('depletion', 'Var', (35, 44))
191627	28415565	Because C57BL6/J mice are more resistant to carcinogen-induced lung tumors than most other mouse strains, we extended the period of topical NTCU treatment from 24 weeks to 38 (Figure 1A).	('mice', 'Species', '10090', (17, 21))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('resistant', 'CPA', (31, 40))	('lung tumors', 'Disease', 'MESH:D008175', (63, 74))	('lung tumor', 'Phenotype', 'HP:0100526', (63, 73))	('C57BL6/J', 'Var', (8, 16))	('NTCU', 'Chemical', 'MESH:C572573', (140, 144))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('lung tumors', 'Phenotype', 'HP:0100526', (63, 74))	('lung tumors', 'Disease', (63, 74))	('mouse', 'Species', '10090', (91, 96))
191628	28415565	Rad52 knockout mice did not exhibit enhanced signs of ill health, nor have significant loss of body weight following treatment with NCTU compared to wild type.	('loss of body weight', 'Disease', (87, 106))	('Rad52', 'Gene', '19365', (0, 5))	('Rad52', 'Gene', (0, 5))	('knockout', 'Var', (6, 14))	('mice', 'Species', '10090', (15, 19))	('loss of body weight', 'Disease', 'MESH:D015431', (87, 106))
191639	28415565	This suggests that upon exposure to cytotoxic treatment, loss of Rad52 induces a level of instability within the erythrocyte progenitor, leading to immature RBCs in the peripheral circulation.	('immature RBCs', 'MPA', (148, 161))	('Rad52', 'Gene', '19365', (65, 70))	('Rad52', 'Gene', (65, 70))	('leading to', 'Reg', (137, 147))	('loss', 'Var', (57, 61))	('induces', 'Reg', (71, 78))	('instability', 'MPA', (90, 101))
191640	28415565	Based on our previous results demonstrating enhanced cell death upon Rad52 depletion in vitro and decreased incidence of LUSC in Rad52-/- mice in vivo, we wondered whether loss of Rad52 may also sensitize bronchial cells in the murine model to cell death due to excessive genomic insult by NTCU treatment.	('Rad52', 'Gene', (129, 134))	('murine', 'Species', '10090', (228, 234))	('loss', 'Var', (172, 176))	('depletion', 'Var', (75, 84))	('NTCU', 'Chemical', 'MESH:C572573', (290, 294))	('mice', 'Species', '10090', (138, 142))	('Rad52', 'Gene', '19365', (69, 74))	('Rad52', 'Gene', (69, 74))	('Rad52', 'Gene', '19365', (180, 185))	('sensitize', 'Reg', (195, 204))	('Rad52', 'Gene', (180, 185))	('decreased', 'NegReg', (98, 107))	('Rad52', 'Gene', '19365', (129, 134))	('enhanced', 'PosReg', (44, 52))	('cell death', 'CPA', (53, 63))
191646	28415565	When comparing populations of naive T cells from total lung digests, we observed a consistent trend toward increased T cell populations in the knockout mice (Figure 4A).	('increased T cell populations', 'Phenotype', 'HP:0100828', (107, 135))	('increased', 'PosReg', (107, 116))	('knockout', 'Var', (143, 151))	('mice', 'Species', '10090', (152, 156))	('T cell populations', 'CPA', (117, 135))
191664	28415565	We hypothesize that incurred genetic instability upon loss of Rad52 may lead to the observed cell death.	('genetic instability', 'Var', (29, 48))	('loss', 'NegReg', (54, 58))	('Rad52', 'Gene', '19365', (62, 67))	('Rad52', 'Gene', (62, 67))	('cell death', 'CPA', (93, 103))	('lead', 'Reg', (72, 76))
191668	28415565	Cells face continuous exposure to endogenous and exogenous DNA damage, such as single-strand and double-strand breaks (DSBs), which require unremitting activation of DNA repair pathways.	('double-strand', 'Var', (97, 110))	('DSBs', 'Chemical', '-', (119, 123))	('single-strand', 'Var', (79, 92))
191670	28415565	Interestingly, upon treating mice with single dose NTCU treatment we observed an increase in the number of cells in the stages of late apoptosis or necrosis in Rad52 knockout mice compared to wild type.	('Rad52', 'Gene', (160, 165))	('mice', 'Species', '10090', (175, 179))	('knockout', 'Var', (166, 174))	('necrosis', 'Disease', (148, 156))	('NTCU', 'Chemical', 'MESH:C572573', (51, 55))	('increase', 'PosReg', (81, 89))	('mice', 'Species', '10090', (29, 33))	('necrosis', 'Disease', 'MESH:D009336', (148, 156))	('Rad52', 'Gene', '19365', (160, 165))
191673	28415565	Our observations show that upon carcinogen challenge, loss of Rad52 leads to decreased mature erythrocytes and increased genetic instability in murine blood, as well as enhanced cell death in the lungs, suggesting that Rad52-depleted cells may succumb to cell death when faced with such a challenge instead of restoring their genome and progressing toward malignancy.	('malignancy', 'Disease', (356, 366))	('genetic instability', 'CPA', (121, 140))	('increased', 'PosReg', (111, 120))	('cell death', 'CPA', (178, 188))	('Rad52', 'Gene', '19365', (219, 224))	('Rad52', 'Gene', (219, 224))	('Rad52', 'Gene', '19365', (62, 67))	('loss', 'Var', (54, 58))	('murine', 'Species', '10090', (144, 150))	('Rad52', 'Gene', (62, 67))	('malignancy', 'Disease', 'MESH:D009369', (356, 366))	('enhanced', 'PosReg', (169, 177))	('decreased', 'NegReg', (77, 86))	('mature erythrocytes', 'CPA', (87, 106))
191675	28415565	As phenotypes in the blood are often systemically representative of other processes, this may be indicative of the enhanced levels of cell death we observed upon depletion of Rad52.	('depletion', 'Var', (162, 171))	('Rad52', 'Gene', (175, 180))	('Rad52', 'Gene', '19365', (175, 180))
191676	28415565	One of the most representative links between innate immunity and DDR is the activation of natural killer group 2 (NKG2D) in DNA-damaged cells by ataxia telangiectasia mutation (ATM), which alerts and recruits NK cells at the injured site.	('recruits', 'PosReg', (200, 208))	('ATM', 'Gene', (177, 180))	('ATM', 'Gene', '11920', (177, 180))	('ataxia telangiectasia', 'Disease', 'MESH:D001260', (145, 166))	('telangiectasia', 'Phenotype', 'HP:0001009', (152, 166))	('mutation', 'Var', (167, 175))	('ataxia', 'Phenotype', 'HP:0001251', (145, 151))	('NKG2D', 'Gene', (114, 119))	('NKG2D', 'Gene', '27007', (114, 119))	('ataxia telangiectasia', 'Disease', (145, 166))	('activation', 'PosReg', (76, 86))
191683	28415565	Interestingly, this group showed that crossing Atm knockout mice with Rad52 knockout mice partially rescued this phenotype, with Atm, Rad52 double knockout mice demonstrating improved mature CD4+ and CD8+ counts relative to Atm knockouts.	('Rad52', 'Gene', '19365', (134, 139))	('CD8', 'Gene', '925', (200, 203))	('Rad52', 'Gene', '19365', (70, 75))	('Atm', 'Gene', '11920', (47, 50))	('mice', 'Species', '10090', (156, 160))	('Atm', 'Gene', (129, 132))	('CD4', 'Gene', '12504', (191, 194))	('mice', 'Species', '10090', (60, 64))	('improved', 'PosReg', (175, 183))	('mice', 'Species', '10090', (85, 89))	('Rad52', 'Gene', (134, 139))	('Atm', 'Gene', (224, 227))	('double knockout', 'Var', (140, 155))	('Rad52', 'Gene', (70, 75))	('CD8', 'Gene', (200, 203))	('Atm', 'Gene', '11920', (129, 132))	('Atm', 'Gene', '11920', (224, 227))	('Atm', 'Gene', (47, 50))	('CD4', 'Gene', (191, 194))
191684	28415565	We found a similar phenomenon at work in our present studies, with a trend toward increased T cell lymphocyte count as a result of Rad52 knockout.	('increased T cell lymphocyte count', 'Phenotype', 'HP:0100828', (82, 115))	('knockout', 'Var', (137, 145))	('increased', 'PosReg', (82, 91))	('Rad52', 'Gene', '19365', (131, 136))	('Rad52', 'Gene', (131, 136))	('T cell lymphocyte count', 'CPA', (92, 115))
191687	28415565	We determined that loss of Rad52 in murine CD8+ T cells and NK cells increases tumor cell cytotoxicity as measured by cell-associated luciferase activity.	('increases', 'PosReg', (69, 78))	('CD8', 'Gene', (43, 46))	('tumor', 'Disease', (79, 84))	('murine', 'Species', '10090', (36, 42))	('cytotoxicity', 'Disease', 'MESH:D064420', (90, 102))	('CD8', 'Gene', '925', (43, 46))	('Rad52', 'Gene', '19365', (27, 32))	('Rad52', 'Gene', (27, 32))	('loss', 'Var', (19, 23))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('cytotoxicity', 'Disease', (90, 102))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
191688	28415565	Ex vivo analysis of these cell populations revealed that Rad52 knockout CTLs, as well as NK cells, have enhanced anti-tumor activity compared to wild type.	('Rad52', 'Gene', (57, 62))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('enhanced', 'PosReg', (104, 112))	('tumor', 'Disease', (118, 123))	('knockout', 'Var', (63, 71))	('Rad52', 'Gene', '19365', (57, 62))
191692	28415565	Our data suggests that loss of Rad52 not only augments in vivo antitumor activity as demonstrated by an enhanced capacity for direct killing of LLC tumor cells by stimulated Rad52-/- NK and CD8+ T cells, but that knockout lung cells more readily undergo cell death rather than transformation when exposed to carcinogen.	('augments', 'PosReg', (46, 54))	('CD8', 'Gene', '925', (190, 193))	('direct killing', 'CPA', (126, 140))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('LLC tumor', 'Disease', 'MESH:D009369', (144, 153))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Disease', (148, 153))	('Rad52', 'Gene', '19365', (174, 179))	('enhanced', 'PosReg', (104, 112))	('Rad52', 'Gene', (174, 179))	('Rad52', 'Gene', '19365', (31, 36))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('LLC tumor', 'Disease', (144, 153))	('Rad52', 'Gene', (31, 36))	('tumor', 'Disease', (67, 72))	('loss', 'Var', (23, 27))	('CD8', 'Gene', (190, 193))
191695	28415565	One important avenue would be to determine whether the defect observed in immune cells upon knockout of Rad52 is a cell intrinsic or extrinsic effect.	('knockout', 'Var', (92, 100))	('Rad52', 'Gene', (104, 109))	('Rad52', 'Gene', '19365', (104, 109))
191696	28415565	It is possible that loss of Rad52 within the immune cells is not the direct issue and the heightened immune response is actually due to an environmental shift within the host or the tumor microenvironment that alerts the immune system and enhances the immune response.	('immune response', 'CPA', (252, 267))	('loss', 'Var', (20, 24))	('tumor', 'Disease', (182, 187))	('enhances', 'PosReg', (239, 247))	('Rad52', 'Gene', '19365', (28, 33))	('Rad52', 'Gene', (28, 33))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('alerts', 'PosReg', (210, 216))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
191698	28415565	For instance, we showed that loss of Rad52 leads to enhanced cell death.	('Rad52', 'Gene', (37, 42))	('cell death', 'CPA', (61, 71))	('enhanced', 'PosReg', (52, 60))	('loss', 'Var', (29, 33))	('Rad52', 'Gene', '19365', (37, 42))
191709	28415565	Loss of Rad52 appears to increase genomic instability beyond a manageable threshold, consenting the damaged cells to death before they are able to become tumor cells.	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('genomic instability', 'MPA', (34, 53))	('Rad52', 'Gene', '19365', (8, 13))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('increase', 'PosReg', (25, 33))	('Loss', 'Var', (0, 4))	('Rad52', 'Gene', (8, 13))	('tumor', 'Disease', (154, 159))
191712	28415565	NTCU was diluted in acetone weekly for treatment and stored for up to one week at 4 C. We acquired the Rad52 transgenic model from The European Mutant Mouse Archive (EMMA, Munchen, Germany) as sperm which were later cryo-recovered by Jackson Laboratories (Bar Harbor, Maine) in the C57B6/J mouse inbred strain.	('Rad52', 'Gene', '19365', (103, 108))	('Mutant', 'Var', (144, 150))	('Rad52', 'Gene', (103, 108))	('acetone', 'Chemical', 'MESH:D000096', (20, 27))	('NTCU', 'Chemical', 'MESH:C572573', (0, 4))	('Mouse', 'Species', '10090', (151, 156))	('mouse', 'Species', '10090', (290, 295))
191772	27811365	In this study, our liquid chromatography with tandem mass spectrometry analysis revealed a number of significantly differentially expressed membrane/membrane-associated proteins between high invasive UM1 and low invasive UM2 cells.	('UM2', 'CellLine', 'CVCL:W393', (221, 224))	('differentially', 'Reg', (115, 129))	('UM1', 'CellLine', 'CVCL:W392', (200, 203))	('high invasive', 'Var', (186, 199))
191776	27811365	Finally, knockdown of syntenin-1 inhibited the proliferation, migration and invasion of HNSC cells, and opposite findings were observed when syntenin-1 was over-expressed.	('syntenin-1', 'Gene', '6386', (22, 32))	('invasion of HNSC cells', 'CPA', (76, 98))	('knockdown', 'Var', (9, 18))	('HNSC', 'Phenotype', 'HP:0012288', (88, 92))	('syntenin-1', 'Gene', (141, 151))	('syntenin-1', 'Gene', '6386', (141, 151))	('syntenin-1', 'Gene', (22, 32))	('inhibited', 'NegReg', (33, 42))
191796	27811365	In addition, the HNSC patients in the high SDCBP expression group had remarkably shorter long-term overall survival (P = 0.0028, Figure 2B).	('patients', 'Species', '9606', (22, 30))	('HNSC', 'Phenotype', 'HP:0012288', (17, 21))	('high', 'Var', (38, 42))	('SDCBP', 'Gene', (43, 48))	('SDCBP', 'Gene', '6386', (43, 48))	('shorter', 'NegReg', (81, 88))
191799	27811365	In addition, syntenin-1 was significantly upregulated in high invasive UM1 cells versus low invasive UM2 cells (P < 0.01) (Figure 4B).	('UM2', 'CellLine', 'CVCL:W393', (101, 104))	('high', 'Var', (57, 61))	('syntenin-1', 'Gene', '6386', (13, 23))	('upregulated', 'PosReg', (42, 53))	('UM1', 'CellLine', 'CVCL:W392', (71, 74))	('syntenin-1', 'Gene', (13, 23))
191806	27811365	Meanwhile, UM1 cells with sisyntenin-1 transfection had suppressed growth capacity as indicated by the colony formation assay, with significantly fewer colonies formed than the cells transfected with siCTRL (Figure 6C).	('fewer', 'NegReg', (146, 151))	('transfection', 'Var', (39, 51))	('growth capacity', 'CPA', (67, 82))	('syntenin-1', 'Gene', (28, 38))	('UM1', 'CellLine', 'CVCL:W392', (11, 14))	('colonies formed', 'CPA', (152, 167))	('syntenin-1', 'Gene', '6386', (28, 38))	('suppressed', 'NegReg', (56, 66))	('colony formation assay', 'CPA', (103, 125))	('suppressed growth capacity', 'Phenotype', 'HP:0001510', (56, 82))
191811	27811365	Matrigel invasion assay was used to measure the number of invaded UM1 cells after sisyntenin-1 or siCTRL transfection.	('UM1', 'CellLine', 'CVCL:W392', (66, 69))	('transfection', 'Var', (105, 117))	('syntenin-1', 'Gene', '6386', (84, 94))	('syntenin-1', 'Gene', (84, 94))
191817	27811365	As shown in Figure 7E, our results indicated that UM1 cells with syntenin-1 overexpression were more proficient than empty vector-transduced cells at closing the artificial wound (P < 0.01).	('syntenin-1', 'Gene', (65, 75))	('UM1', 'CellLine', 'CVCL:W392', (50, 53))	('overexpression', 'Var', (76, 90))	('syntenin-1', 'Gene', '6386', (65, 75))
191828	27811365	For instance, the expression level of Reticulon-4 protein was about 6 times higher in UM1 cells than UM2 cells.	('UM2', 'CellLine', 'CVCL:W393', (101, 104))	('expression level', 'MPA', (18, 34))	('Reticulon-4', 'Gene', (38, 49))	('Reticulon-4', 'Gene', '57142', (38, 49))	('UM1', 'CellLine', 'CVCL:W392', (86, 89))	('UM1', 'Var', (86, 89))	('higher', 'PosReg', (76, 82))
191837	27811365	Syntenin-1 deregulation has been reported in multiple primary cancers and its activity appears to be a driver of cancer progression.	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('deregulation', 'Var', (11, 23))	('Syntenin-1', 'Gene', '6386', (0, 10))	('Syntenin-1', 'Gene', (0, 10))	('cancer', 'Disease', (113, 119))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('reported', 'Reg', (33, 41))	('cancers', 'Disease', 'MESH:D009369', (62, 69))	('cancers', 'Phenotype', 'HP:0002664', (62, 69))	('activity', 'MPA', (78, 86))	('cancers', 'Disease', (62, 69))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
191841	27811365	Moreover, ectopic expression of syntenin-1 promoted the oncogenic activities of melanoma cells both in vitro and in vivo, and vice versa.	('promoted', 'PosReg', (43, 51))	('melanoma', 'Disease', 'MESH:D008545', (80, 88))	('melanoma', 'Phenotype', 'HP:0002861', (80, 88))	('melanoma', 'Disease', (80, 88))	('ectopic expression', 'Var', (10, 28))	('syntenin-1', 'Gene', (32, 42))	('syntenin-1', 'Gene', '6386', (32, 42))
191889	26490682	Hyperphosphorylation of ribosomal protein S6 predicts unfavorable clinical survival in non-small cell lung cancer Ribosomal protein S6 (rpS6), a component of the 40S ribosomal subunit, is involved in multiple cellular bioactivities.	('Ribosomal protein S6', 'Gene', '6194', (114, 134))	('ribosomal protein S6', 'Gene', '6194', (24, 44))	('Hyperphosphorylation', 'Var', (0, 20))	('Ribosomal protein S6', 'Gene', (114, 134))	('lung cancer', 'Phenotype', 'HP:0100526', (102, 113))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (87, 113))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('rpS6', 'Gene', (136, 140))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (91, 113))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('ribosomal protein S6', 'Gene', (24, 44))	('cancer', 'Disease', (107, 113))	('predicts', 'Reg', (45, 53))
191891	26490682	Expressions of total rpS6 (t-rpS6) and phosphorylated rpS6 (Ser235/236, p-rpS6) were detected immunohistochemically in 316 NSCLC tissues and 82 adjacent controls, followed by statistical evaluation of the relationship between proteins expressions and patients' survivals to identify their prognostic values.	('NSCLC', 'Disease', (123, 128))	('Ser235', 'Chemical', '-', (60, 66))	('NSCLC', 'Disease', 'MESH:D002289', (123, 128))	('NSCLC', 'Phenotype', 'HP:0030358', (123, 128))	('patients', 'Species', '9606', (251, 259))	('Ser235/236', 'Var', (60, 70))
191892	26490682	Cytological experiments with overexpressing or silencing rpS6 by lentivirus in human bronchial epithelial (HBE) and NSCLC cell lines were performed to explore potential mechanisms by which rpS6 affects the clinical development of NSCLC.	('NSCLC', 'Disease', 'MESH:D002289', (116, 121))	('clinical development of', 'CPA', (206, 229))	('human', 'Species', '9606', (79, 84))	('NSCLC', 'Disease', 'MESH:D002289', (230, 235))	('affects', 'Reg', (194, 201))	('NSCLC', 'Phenotype', 'HP:0030358', (230, 235))	('NSCLC', 'Phenotype', 'HP:0030358', (116, 121))	('rpS6', 'Gene', (57, 61))	('silencing', 'Var', (47, 56))	('HBE', 'Gene', '3046', (107, 110))	('NSCLC', 'Disease', (230, 235))	('NSCLC', 'Disease', (116, 121))	('HBE', 'Gene', (107, 110))
191894	26490682	Positive rates of t-rpS6 and p-rpS6 were both significantly increased in NSCLC tissues, compared with controls (82.91 vs 62.20 % for t-rpS6; 52.22 vs 21.95 % for p-rpS6; both P < 0.001).	('rat', 'Species', '10116', (9, 12))	('NSCLC', 'Disease', (73, 78))	('NSCLC', 'Phenotype', 'HP:0030358', (73, 78))	('NSCLC', 'Disease', 'MESH:D002289', (73, 78))	('p-rpS6', 'Var', (29, 35))	('increased', 'PosReg', (60, 69))	('t-rpS6', 'Var', (18, 24))
191895	26490682	However, only hyperphosphorylation of rpS6, expressed as either elevated p-rpS6 alone or the ratio of p-rpS6 to t-rpS6 (p-rpS6/t-rpS6) no less than 0.67, was greatly associated with the unfavorable survival of NSCLC patients, especially for cases at stage I (all P < 0.001).	('p-rpS6', 'MPA', (73, 79))	('elevated', 'PosReg', (64, 72))	('NSCLC', 'Phenotype', 'HP:0030358', (210, 215))	('NSCLC', 'Disease', (210, 215))	('patients', 'Species', '9606', (216, 224))	('hyperphosphorylation', 'Var', (14, 34))	('NSCLC', 'Disease', 'MESH:D002289', (210, 215))	('associated with', 'Reg', (166, 181))	('rat', 'Species', '10116', (93, 96))
191896	26490682	The independent adverse prognostic value of hyperphosphorylated rpS6 was confirmed by multivariate Cox regression analysis (hazard ratios for elevated p-rpS6 alone and p-rpS6/t-rpS6 no less than 0.67 were 2.403, 4.311 respectively, both P < 0.001).	('p-rpS6/t-rpS6', 'Var', (168, 181))	('elevated', 'PosReg', (142, 150))	('rat', 'Species', '10116', (131, 134))	('p-rpS6', 'MPA', (151, 157))
191897	26490682	Overexpression or knockdown of rpS6, along with parallel alterations of p-rpS6, led to increased or decreased cells proliferations respectively, which were dependent on redistributions of cell cycles (all P < 0.05).	('cells proliferations', 'CPA', (110, 130))	('knockdown', 'Var', (18, 27))	('rpS6', 'Gene', (31, 35))	('rat', 'Species', '10116', (61, 64))	('rat', 'Species', '10116', (123, 126))	('decreased', 'NegReg', (100, 109))
191899	26490682	Furthermore, upstream overexpression or knockdown of Akt2 or Akt2 phosphorylation inhibition, rather than Akt1 or Akt3, resulted in striking hyperphosphorylation or dephosphorylation of mTOR, p70S6K and rpS6 (all P < 0.05), without any change in total proteins expressions.	('hyperphosphorylation', 'PosReg', (141, 161))	('dephosphorylation', 'MPA', (165, 182))	('Akt1', 'Gene', (106, 110))	('rat', 'Species', '10116', (94, 97))	('overexpression', 'PosReg', (22, 36))	('Akt2', 'Gene', (53, 57))	('mTOR', 'Gene', (186, 190))	('Akt1', 'Gene', '207', (106, 110))	('mTOR', 'Gene', '2475', (186, 190))	('knockdown', 'Var', (40, 49))	('Akt3', 'Gene', (114, 118))	('Akt2', 'Gene', (61, 65))	('Akt2', 'Gene', '208', (53, 57))	('p70S6K', 'Gene', (192, 198))	('p70S6K', 'Gene', '6198', (192, 198))	('Akt2', 'Gene', '208', (61, 65))	('rpS6', 'Protein', (203, 207))	('Akt3', 'Gene', '10000', (114, 118))
191909	26490682	In most cases, phosphorylation at the evolutionary conserved c-terminal serine residues between Ser235 and Ser247 is believed to be the activation of rpS6 and exerts important successive effects.	('Ser247', 'Chemical', '-', (107, 113))	('activation', 'PosReg', (136, 146))	('rpS6', 'Protein', (150, 154))	('Ser235', 'Var', (96, 102))	('Ser235', 'Chemical', '-', (96, 102))	('serine', 'Chemical', 'MESH:D012694', (72, 78))	('Ser247', 'Var', (107, 113))	('phosphorylation', 'MPA', (15, 30))
191916	26490682	In this study, we immunohistochemically detected the expressions of total rpS6 (t-rpS6) and p-rpS6 in NSCLC clinical tissues and analyzed their relevance to the clinical characteristics respectively, establishing p-rpS6 as the activated form of rpS6 in NSCLC.	('NSCLC', 'Disease', 'MESH:D002289', (102, 107))	('p-rpS6', 'Var', (213, 219))	('NSCLC', 'Phenotype', 'HP:0030358', (253, 258))	('NSCLC', 'Phenotype', 'HP:0030358', (102, 107))	('NSCLC', 'Disease', (253, 258))	('NSCLC', 'Disease', (102, 107))	('NSCLC', 'Disease', 'MESH:D002289', (253, 258))
191918	26490682	To confirm the clinical findings and investigate the potential mechanisms in which the hyperphosphorylation of rpS6 promotes the development of NSCLC, subsequent cytological experiments with overexpressing or silencing t-rpS6 and p-rpS6 were carried out to observe the changes of cells bioactivities in vitro.	('NSCLC', 'Disease', (144, 149))	('development', 'CPA', (129, 140))	('rpS6', 'Gene', (111, 115))	('promotes', 'PosReg', (116, 124))	('NSCLC', 'Disease', 'MESH:D002289', (144, 149))	('NSCLC', 'Phenotype', 'HP:0030358', (144, 149))	('hyperphosphorylation', 'Var', (87, 107))	('silencing', 'Var', (209, 218))
191923	26490682	It is worth mentioning that in accordance with the frequently positive phosphorylation residues of rpS6 in tumors, we detected the phosphorylation of Ser235/236 of rpS6 in the present study.	('Ser235/236', 'Var', (150, 160))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('Ser235', 'Chemical', '-', (150, 156))	('tumors', 'Disease', (107, 113))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('tumors', 'Disease', 'MESH:D009369', (107, 113))	('phosphorylation', 'MPA', (131, 146))	('rpS6', 'Gene', (164, 168))
191949	26490682	In the rpS6 activation mechanism experiment, Akt inhibitor XII Isozyme-Selective Akti-2 (Merck, #124029-2MG) was supplied in the cell culture of H1650 and SK-MES-1 with 0.8 mumol/L, 3.2 mumol/L and 12.8 mumol/L separately, and treated for 24, 48, 72 and 96 h to determine the optimum working condition.	('SK-MES-1', 'CellLine', 'CVCL:0630', (155, 163))	('Akt', 'Gene', (45, 48))	('Akt', 'Gene', '207', (81, 84))	('rat', 'Species', '10116', (215, 218))	('Akt', 'Gene', (81, 84))	('H1650', 'Var', (145, 150))	('Akt', 'Gene', '207', (45, 48))
191953	26490682	Specific protein antibodies included anti-total rpS6 (CST, #2217), anti-p-rpS6 (Ser235/236, CST, #4858), anti-p21Cip1 (CST, #2947), anti-p27Kip1 (CST, #3688), anti-CDK2 (CST, #2546), anti-CDK4 (CST, #12790), anti-Cyclin E (SAB, #29030), anti-cyclin D1 (CST, #2978), anti-p-Rb (Ser780, CST, #3590), anti-Paxillin (CST, #12065), anti-p-Paxillin (Tyr118; CST, #2541), anti-vimentin (CST, #5741), anti-N-cadherin (CST, #4061), anti-E-cadherin (CST, #3195), anti-MMP-9 (CST, #13667), anti-MMP-2 (CST, # 5741), anti-t-Akt1 (CST, #2967), anti-p-Akt1 (Ser473, CST, # 9018), anti-t-Akt2 (CST, #2964), anti-p-Akt2 (Ser474, CST, #8599), anti-t-Akt3 (Biorbyt, #orb6787), anti-p-Akt3 (Ser472, Biorbyt, #orb6790), anti-t-mTOR (CST, #2983), anti-p-mTOR (Ser2448, CST, #5536), anti-t-p70S6K (SAB, #21276) and anti-p-p70S6K (Ser424, SAB, #21276) and anti-beta-actin (CST, #4970) as an internal control.	('p27Kip1', 'Gene', '1027', (137, 144))	('Ser473', 'Chemical', '-', (544, 550))	('cyclin D1', 'Gene', '595', (242, 251))	('p-Rb', 'Gene', '5925', (271, 275))	('CDK2', 'Gene', (164, 168))	('MMP-2', 'Gene', (484, 489))	('Akt3', 'Gene', '10000', (666, 670))	('MMP-9', 'Gene', '4318', (458, 463))	('p70S6K', 'Gene', '6198', (768, 774))	('p70S6K', 'Gene', '6198', (800, 806))	('Ser2448', 'Var', (739, 746))	('mTOR', 'Gene', (733, 737))	('CDK4', 'Gene', '1019', (188, 192))	('Akt1', 'Gene', '207', (512, 516))	('MMP-9', 'Gene', (458, 463))	('Akt3', 'Gene', (633, 637))	('beta-actin', 'Gene', (838, 848))	('Ser235', 'Chemical', '-', (80, 86))	('p21Cip1', 'Gene', '1026', (110, 117))	('p21Cip1', 'Gene', (110, 117))	('mTOR', 'Gene', '2475', (733, 737))	('Akt1', 'Gene', (538, 542))	('vimentin', 'Gene', '7431', (370, 378))	('Akt2', 'Gene', (599, 603))	('Akt3', 'Gene', '10000', (633, 637))	('mTOR', 'Gene', (707, 711))	('p70S6K', 'Gene', (768, 774))	('Akt2', 'Gene', '208', (599, 603))	('N-cadherin', 'Gene', (398, 408))	('Paxillin', 'Gene', '5829', (303, 311))	('Paxillin', 'Gene', '5829', (334, 342))	('p70S6K', 'Gene', (800, 806))	('beta-actin', 'Gene', '728378', (838, 848))	('N-cadherin', 'Gene', '1000', (398, 408))	('MMP-2', 'Gene', '4313', (484, 489))	('p-Rb', 'Gene', (271, 275))	('Akt3', 'Gene', (666, 670))	('Akt1', 'Gene', '207', (538, 542))	('mTOR', 'Gene', '2475', (707, 711))	('E-cadherin', 'Gene', (428, 438))	('E-cadherin', 'Gene', '999', (428, 438))	('p27Kip1', 'Gene', (137, 144))	('cyclin D1', 'Gene', (242, 251))	('CDK4', 'Gene', (188, 192))	('Akt1', 'Gene', (512, 516))	('CDK2', 'Gene', '1017', (164, 168))	('Akt2', 'Gene', (573, 577))	('Paxillin', 'Gene', (303, 311))	('Paxillin', 'Gene', (334, 342))	('Akt2', 'Gene', '208', (573, 577))	('vimentin', 'Gene', (370, 378))
191968	26490682	The expressions of t-rpS6 and p-rpS6 (Ser235/236) were immunohistochemically detected in 316 NSCLC tumor tissues and 82 adjacent normal controls.	('p-rpS6', 'Var', (30, 36))	('NSCLC tumor', 'Disease', 'MESH:D009369', (93, 104))	('t-rpS6', 'Protein', (19, 25))	('Ser235', 'Chemical', '-', (38, 44))	('NSCLC tumor', 'Disease', (93, 104))	('NSCLC', 'Phenotype', 'HP:0030358', (93, 98))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))
191971	26490682	1, both of t-rpS6 and p-rpS6 were abundantly accumulated in the cytoplasm of NSCLC cells, but less frequently found in non-tumor controls.	('non-tumor', 'Disease', (119, 128))	('NSCLC', 'Disease', 'MESH:D002289', (77, 82))	('p-rpS6', 'Var', (22, 28))	('non-tumor', 'Disease', 'MESH:D009369', (119, 128))	('NSCLC', 'Phenotype', 'HP:0030358', (77, 82))	('NSCLC', 'Disease', (77, 82))	('t-rpS6', 'Var', (11, 17))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('accumulated', 'PosReg', (45, 56))
191972	26490682	Of the 316 tumor specimens, 262 cases (82.91 %) were positively stained with t-rpS6 and 165 patients (52.22 %) revealed the p-rpS6 positive expression.	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('tumor', 'Disease', (11, 16))	('patients', 'Species', '9606', (92, 100))	('t-rpS6', 'Protein', (77, 83))	('p-rpS6', 'Var', (124, 130))	('tumor', 'Disease', 'MESH:D009369', (11, 16))
191973	26490682	In contrast, positive rates for t-rpS6 and p-rpS6 in normal tissues were 62.20 % (51/82) and 21.95 % (18/82) respectively.	('p-rpS6', 'Var', (43, 49))	('t-rpS6', 'Var', (32, 38))	('rat', 'Species', '10116', (22, 25))
191974	26490682	The results suggested that both of t-rpS6 and p-rpS6 were significantly elevated in NSCLC (both P < 0.001).	('elevated', 'PosReg', (72, 80))	('p-rpS6', 'Var', (46, 52))	('NSCLC', 'Phenotype', 'HP:0030358', (84, 89))	('t-rpS6', 'MPA', (35, 41))	('NSCLC', 'Disease', (84, 89))	('NSCLC', 'Disease', 'MESH:D002289', (84, 89))
191976	26490682	However, the hyperphosphorylation of rpS6 was significantly more prevalent in larger tumor size (P < 0.001), lymph node invasion (P < 0.001), distant metastasis (P = 0.015) and advanced stage (P < 0.001) patients, whereas the association with sex, age, tumor histological types or histological differentiation was weak (all P > 0.05).	('tumor', 'Disease', (85, 90))	('patients', 'Species', '9606', (204, 212))	('lymph node invasion', 'CPA', (109, 128))	('distant metastasis', 'CPA', (142, 160))	('tumor', 'Disease', 'MESH:D009369', (253, 258))	('hyperphosphorylation', 'Var', (13, 33))	('rpS6', 'Protein', (37, 41))	('tumor', 'Phenotype', 'HP:0002664', (253, 258))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('tumor', 'Disease', (253, 258))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('prevalent', 'Reg', (65, 74))
191981	26490682	However, the 5-year survival rate and median survival time of patients with p-rpS6 overexpression were significantly lower than those with negative p-rpS6 (Fig.	('overexpression', 'Var', (83, 97))	('rat', 'Species', '10116', (29, 32))	('lower', 'NegReg', (117, 122))	('p-rpS6', 'Gene', (76, 82))	('patients', 'Species', '9606', (62, 70))
191989	26490682	It was also easy to find out that rpS6 hyperphosphorylation, reported either the positive expression of p-rpS6 or elevated ratio of p-rpS6/t-rpS6, was a much more significant survival factor for the early staged patients (I stage) than of the late ones (II + III + IV stages) (Fig.	('rat', 'Species', '10116', (123, 126))	('p-rpS6', 'Var', (104, 110))	('patients', 'Species', '9606', (212, 220))	('rpS6', 'Var', (34, 38))
191991	26490682	In the further comparison, an elevated ratio of p-rpS6/t-rpS6 seemed to be a bit more powerful than p-rpS6 alone in predicting the bad outcomes of NSCLC patients (Fig.	('NSCLC', 'Disease', (147, 152))	('patients', 'Species', '9606', (153, 161))	('NSCLC', 'Disease', 'MESH:D002289', (147, 152))	('rat', 'Species', '10116', (39, 42))	('NSCLC', 'Phenotype', 'HP:0030358', (147, 152))	('p-rpS6/t-rpS6', 'Var', (48, 61))
191992	26490682	The above results indicated that the hyperphosphorylation of rpS6 was significantly associated with the unfavorable prognosis of NSCLC patients, especially in the early staged cases.	('patients', 'Species', '9606', (135, 143))	('NSCLC', 'Phenotype', 'HP:0030358', (129, 134))	('hyperphosphorylation', 'Var', (37, 57))	('rpS6', 'Protein', (61, 65))	('NSCLC', 'Disease', (129, 134))	('associated', 'Reg', (84, 94))	('NSCLC', 'Disease', 'MESH:D002289', (129, 134))
191993	26490682	As shown in Table 2 with univariate assays, risks for bad outcomes in the whole cohort substantially increased with a poor histological differentiation, enlarged tumor size, lymph node invasion, distant metastasis and advanced stage (hazard ratio, HR = 1.369, 2.154, 2.121, 1.835 and 4.143 respectively, all P < 0.05), which were completely consistent with the previous Kaplan-Meier survival curves.	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('increased', 'PosReg', (101, 110))	('lymph node invasion', 'CPA', (174, 193))	('enlarged tumor', 'Disease', 'MESH:D006332', (153, 167))	('distant metastasis', 'CPA', (195, 213))	('enlarged tumor', 'Disease', (153, 167))	('rat', 'Species', '10116', (241, 244))	('poor', 'Var', (118, 122))
191994	26490682	Moreover, patients with a high expression of p-rpS6 or rising p-rpS6/t-rpS6 were also at an increased risk for short survival, especially for the elevated p-rpS6/t-rpS6 (HR = 2.666 and 5.963 respectively with both P < 0.001).	('p-rpS6/t-rpS6', 'Var', (155, 168))	('p-rpS6', 'Var', (45, 51))	('patients', 'Species', '9606', (10, 18))	('p-rpS6/t-rpS6', 'Var', (62, 75))	('short survival', 'CPA', (111, 125))
191995	26490682	Only the hyperphosphorylation of rpS6 significantly conferred unfavorable survivals, both in early and advanced staged patients (HR = 5.916 and 12.304 for I stage; HR = 1.560 and 3.654 in late stage; all P < 0.001).	('hyperphosphorylation', 'Var', (9, 29))	('conferred', 'Reg', (52, 61))	('rpS6', 'Protein', (33, 37))	('patients', 'Species', '9606', (119, 127))	('survivals', 'MPA', (74, 83))
191997	26490682	Because of the similar meaning of p-rpS6 and p-rpS6/t-rpS6, the multivariate assays with one or two of them were performed separately.	('rat', 'Species', '10116', (127, 130))	('p-rpS6', 'Var', (34, 40))	('p-rpS6/t-rpS6', 'Var', (45, 58))
191998	26490682	No matter including either p-rpS6 alone or p-rpS6/t-rpS6 alone, the advanced clinical stage and increased hyperphosphorylation of rpS6 were always independent adverse prognostic factors for NSCLC development (all P < 0.05).	('increased', 'PosReg', (96, 105))	('hyperphosphorylation', 'MPA', (106, 126))	('NSCLC', 'Phenotype', 'HP:0030358', (190, 195))	('p-rpS6/t-rpS6', 'Var', (43, 56))	('rpS6', 'Protein', (130, 134))	('p-rpS6', 'Var', (27, 33))	('NSCLC', 'Disease', (190, 195))	('NSCLC', 'Disease', 'MESH:D002289', (190, 195))
192000	26490682	Based on the weak expressions of t-rpS6 and p-rpS6 in HBE but strong in the adenocarcinoma cell line of H1650 and squamous cell carcinoma of SK-MES-1 (Fig.	('adenocarcinoma', 'Disease', 'MESH:D000230', (76, 90))	('p-rpS6', 'Var', (44, 50))	('HBE', 'Gene', (54, 57))	('t-rpS6', 'Protein', (33, 39))	('SK-MES-1', 'CellLine', 'CVCL:0630', (141, 149))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (114, 137))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (114, 137))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('squamous cell carcinoma', 'Disease', (114, 137))	('adenocarcinoma', 'Disease', (76, 90))	('HBE', 'Gene', '3046', (54, 57))
192010	26490682	Conversely, rpS6 silence and dephosphorylation in H1650 and SK-MES-1 cell lines resulted in the cells predominant aggregation in G0-G1 phase, along with the reduced expressions of p-Rb, cyclin D1, cyclin E, CDK2 and CDK4 but increase in p21 and p27 (Fig.	('cyclin D1', 'Gene', '595', (186, 195))	('dephosphorylation', 'Var', (29, 46))	('p27', 'Gene', '3429', (245, 248))	('p27', 'Gene', (245, 248))	('CDK2', 'Gene', '1017', (207, 211))	('p21', 'Gene', (237, 240))	('rpS6 silence', 'Var', (12, 24))	('p-Rb', 'Gene', (180, 184))	('cells predominant aggregation', 'CPA', (96, 125))	('expressions', 'MPA', (165, 176))	('CDK2', 'Gene', (207, 211))	('CDK4', 'Gene', (216, 220))	('H1650', 'Var', (50, 55))	('increase', 'PosReg', (225, 233))	('p-Rb', 'Gene', '5925', (180, 184))	('cyclin E', 'Protein', (197, 205))	('CDK4', 'Gene', '1019', (216, 220))	('p21', 'Gene', '1026', (237, 240))	('reduced', 'NegReg', (157, 164))	('cyclin D1', 'Gene', (186, 195))	('SK-MES-1', 'CellLine', 'CVCL:0630', (60, 68))
192011	26490682	It was clear that overactivation of rpS6 induced the G0-G1 escape to promote the cells proliferation; while loss of rpS6 attenuated the cells viability by G0-G1 arrest.	('rat', 'Species', '10116', (94, 97))	('cells proliferation', 'CPA', (81, 100))	('arrest', 'Disease', (161, 167))	('attenuated', 'NegReg', (121, 131))	('loss', 'Var', (108, 112))	('rpS6', 'Gene', (36, 40))	('cells viability', 'CPA', (136, 151))	('rpS6', 'Gene', (116, 120))	('overactivation', 'PosReg', (18, 32))	('promote', 'PosReg', (69, 76))	('arrest', 'Disease', 'MESH:D006323', (161, 167))
192014	26490682	4a, overexpression of rpS6 and p-rpS6 prominently enhanced HBE migration.	('HBE', 'Gene', '3046', (59, 62))	('rpS6', 'Protein', (22, 26))	('p-rpS6', 'Var', (31, 37))	('HBE', 'Gene', (59, 62))	('overexpression', 'PosReg', (4, 18))	('enhanced', 'PosReg', (50, 58))	('rat', 'Species', '10116', (66, 69))
192015	26490682	To be specific, the area of the wound in rpS6 activated HBE cells was significantly recovered after 12 h from the gash; and it was almost completely closed after 24 h, which were evidently faster than the two controls (all P < 0.05).	('HBE', 'Gene', (56, 59))	('rpS6 activated', 'Var', (41, 55))	('HBE', 'Gene', '3046', (56, 59))
192022	26490682	On the contrary, Akt2 depletion, rather than Akt1 or Akt3, in the two NSCLC cell lines resulted in pronounced dephosphorylation of mTOR, p70S6K and rpS6 (Fig.	('Akt1', 'Gene', (45, 49))	('Akt3', 'Gene', '10000', (53, 57))	('NSCLC', 'Disease', (70, 75))	('mTOR', 'Gene', (131, 135))	('depletion', 'Var', (22, 31))	('p70S6K', 'Gene', (137, 143))	('Akt2', 'Gene', (17, 21))	('rat', 'Species', '10116', (33, 36))	('dephosphorylation', 'MPA', (110, 127))	('NSCLC', 'Disease', 'MESH:D002289', (70, 75))	('p70S6K', 'Gene', '6198', (137, 143))	('Akt3', 'Gene', (53, 57))	('mTOR', 'Gene', '2475', (131, 135))	('Akt2', 'Gene', '208', (17, 21))	('Akt1', 'Gene', '207', (45, 49))	('rpS6', 'Protein', (148, 152))	('NSCLC', 'Phenotype', 'HP:0030358', (70, 75))
192031	26490682	However, Akt2 silence by lentivirus or dephosphorylation by Akti-2 markedly deteriorated the phosphorylation of rpS6 and suppressed the proliferation of H1650 and SK-MES-1 cell lines (Fig.	('Akt2', 'Gene', (9, 13))	('rat', 'Species', '10116', (83, 86))	('SK-MES-1', 'CellLine', 'CVCL:0630', (163, 171))	('Akt', 'Gene', '207', (60, 63))	('Akt', 'Gene', (9, 12))	('deteriorated', 'PosReg', (76, 88))	('Akt2', 'Gene', '208', (9, 13))	('rpS6', 'Protein', (112, 116))	('dephosphorylation', 'Var', (39, 56))	('suppressed', 'NegReg', (121, 131))	('silence', 'NegReg', (14, 21))	('Akt', 'Gene', (60, 63))	('rat', 'Species', '10116', (143, 146))	('Akt', 'Gene', '207', (9, 12))	('phosphorylation', 'MPA', (93, 108))	('proliferation', 'CPA', (136, 149))
192032	26490682	Separate variation of p-rpS6, without any change of t-rpS6, significantly affected the proliferation in all tested cell lines, providing adequate evidence of the crucial employment of rpS6 phosphorylation in NSCLC, rather than its simple overexpression.	('affected', 'Reg', (74, 82))	('rpS6', 'Protein', (184, 188))	('rat', 'Species', '10116', (94, 97))	('NSCLC', 'Phenotype', 'HP:0030358', (208, 213))	('proliferation', 'CPA', (87, 100))	('rat', 'Species', '10116', (215, 218))	('NSCLC', 'Disease', (208, 213))	('rat', 'Species', '10116', (4, 7))	('variation', 'Var', (9, 18))	('NSCLC', 'Disease', 'MESH:D002289', (208, 213))	('p-rpS6', 'Gene', (22, 28))
192033	26490682	Analysis of the cell cycle profiles of asynchronous growing cells also revealed the detectable cell cycles redistributions by Akt2 overexpression or inhibition, with the correlate p-rpS6 increasing or reducing (Fig.	('increasing', 'PosReg', (187, 197))	('inhibition', 'NegReg', (149, 159))	('cell cycles redistributions', 'CPA', (95, 122))	('reducing', 'NegReg', (201, 209))	('Akt2', 'Gene', (126, 130))	('p-rpS6', 'Var', (180, 186))	('Akt2', 'Gene', '208', (126, 130))	('overexpression', 'PosReg', (131, 145))
192034	26490682	Enhanced migration capability with the high level of p-rpS6 was also observed in HBE by wound healing assays (Fig.	('HBE', 'Gene', '3046', (81, 84))	('rat', 'Species', '10116', (12, 15))	('HBE', 'Gene', (81, 84))	('migration capability', 'CPA', (9, 29))	('p-rpS6', 'Var', (53, 59))	('Enhanced', 'PosReg', (0, 8))
192039	26490682	However, only the hyperphosphorylation of rpS6 strongly correlated with the unfavorable clinicopathological characteristics of NSCLC patients and the adverse prognosis.	('NSCLC', 'Disease', (127, 132))	('NSCLC', 'Disease', 'MESH:D002289', (127, 132))	('patients', 'Species', '9606', (133, 141))	('NSCLC', 'Phenotype', 'HP:0030358', (127, 132))	('hyperphosphorylation', 'Var', (18, 38))	('rpS6', 'Protein', (42, 46))	('correlated', 'Reg', (56, 66))
192044	26490682	As expected, both of the high expression of p-rpS6 alone and the increased ratio of p-rpS6/t-rpS6 were identified as the independent prognostic factors for NSCLC patients.	('patients', 'Species', '9606', (162, 170))	('increased', 'PosReg', (65, 74))	('p-rpS6', 'Var', (44, 50))	('expression', 'MPA', (30, 40))	('rat', 'Species', '10116', (75, 78))	('NSCLC', 'Phenotype', 'HP:0030358', (156, 161))	('NSCLC', 'Disease', (156, 161))	('NSCLC', 'Disease', 'MESH:D002289', (156, 161))
192046	26490682	In addition, we also found that rpS6 hyperphosphorylation conferred the ominous survival in patients at stage I, which was rather more sensitive than it for the whole or advanced cases; with much more decided survival curves and far bigger HR values.	('rat', 'Species', '10116', (123, 126))	('conferred', 'Reg', (58, 67))	('patients', 'Species', '9606', (92, 100))	('rpS6 hyperphosphorylation', 'Var', (32, 57))
192048	26490682	Similar prognostic significance of p-rpS6 was also found in I and II stage esophagus squamous cell carcinoma subjects, substantiating the important early predictive values of p-rpS6.	('II stage esophagus squamous cell carcinoma', 'Disease', (66, 108))	('II stage esophagus squamous cell carcinoma', 'Disease', 'MESH:D002294', (66, 108))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (85, 108))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('p-rpS6', 'Var', (35, 41))
192050	26490682	We found that loss of t-rpS6, together with p-rpS6 downregulation, greatly suppressed the NSCLC cells viability by inducing G0-G1 cell cycles arrest, along with the reduction of CDKs, cyclins and p-Rb.	('p-Rb', 'Gene', '5925', (196, 200))	('p-rpS6', 'Gene', (44, 50))	('loss', 'Var', (14, 18))	('suppressed', 'NegReg', (75, 85))	('arrest', 'Disease', 'MESH:D006323', (142, 148))	('NSCLC', 'Disease', (90, 95))	('t-rpS6', 'Protein', (22, 28))	('NSCLC', 'Disease', 'MESH:D002289', (90, 95))	('CDKs', 'Gene', (178, 182))	('inducing', 'Reg', (115, 123))	('arrest', 'Disease', (142, 148))	('reduction', 'NegReg', (165, 174))	('downregulation', 'NegReg', (51, 65))	('CDKs', 'Gene', '1017;1019', (178, 182))	('p-Rb', 'Gene', (196, 200))	('cyclins', 'Protein', (184, 191))	('NSCLC', 'Phenotype', 'HP:0030358', (90, 95))
192052	26490682	Similar to our data, the proliferation of several other kinds of cells, including breast carcinoma, cervical carcinoma and even the normal embryonic kidney cell lines, is also dramatically promoted by rpS6 phosphorylation.	('rpS6', 'Protein', (201, 205))	('breast carcinoma', 'Disease', (82, 98))	('proliferation', 'CPA', (25, 38))	('rat', 'Species', '10116', (32, 35))	('breast carcinoma', 'Disease', 'MESH:D001943', (82, 98))	('promoted', 'PosReg', (189, 197))	('breast carcinoma', 'Phenotype', 'HP:0003002', (82, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('cervical carcinoma', 'Disease', 'MESH:D002575', (100, 118))	('cervical carcinoma', 'Disease', (100, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('phosphorylation', 'Var', (206, 221))
192053	26490682	Liver cells in the late gestation rat revealed p-rpS6 dependent growth as well.	('late gestation', 'Phenotype', 'HP:0001622', (19, 33))	('growth', 'MPA', (64, 70))	('p-rpS6', 'Var', (47, 53))	('rat', 'Species', '10116', (34, 37))
192054	26490682	Moreover, hepatic cells in the adult mice with conditional deletion of the gene encoding rpS6 failed to proliferate after partial hepatectomy.	('conditional deletion', 'Var', (47, 67))	('rat', 'Species', '10116', (111, 114))	('rpS6', 'Gene', (89, 93))	('mice', 'Species', '10090', (37, 41))
192055	26490682	These results support our findings and suggest that rpS6 phosphorylation plays a crucial role in variant cells proliferation.	('rpS6', 'Protein', (52, 56))	('rat', 'Species', '10116', (118, 121))	('variant', 'Var', (97, 104))
192057	26490682	Following studies provided more evidence that the depletion of rpS6 was able to cause p53 induced cell cycles checkpoint impeding or arrest, suggesting the possible molecular mechanisms of rpS6 in cell cycles regulation.	('cell cycles checkpoint impeding', 'CPA', (98, 129))	('rpS6', 'Gene', (63, 67))	('p53', 'Gene', '7157', (86, 89))	('arrest', 'Disease', 'MESH:D006323', (133, 139))	('cause', 'Reg', (80, 85))	('depletion', 'Var', (50, 59))	('arrest', 'Disease', (133, 139))	('p53', 'Gene', (86, 89))
192058	26490682	Recent researches even ascribed the cell cycles regulation effects to the phosphorylation at the site of Ser240/244.	('phosphorylation', 'MPA', (74, 89))	('Ser240', 'Chemical', '-', (105, 111))	('cell cycles', 'CPA', (36, 47))	('Ser240/244', 'Var', (105, 115))
192059	26490682	Continued investigations are required to determine whether the site of Ser235/236 is exclusive phosphorylating target of rpS6 in NSCLC.	('Ser235', 'Chemical', '-', (71, 77))	('NSCLC', 'Phenotype', 'HP:0030358', (129, 134))	('NSCLC', 'Disease', (129, 134))	('NSCLC', 'Disease', 'MESH:D002289', (129, 134))	('Ser235/236', 'Var', (71, 81))
192062	26490682	Conversely, H1650 and SK-MES-1 cells migration were dramatically inhibited after rpS6 knockdown.	('knockdown', 'Var', (86, 95))	('rat', 'Species', '10116', (40, 43))	('SK-MES-1', 'CellLine', 'CVCL:0630', (22, 30))	('inhibited', 'NegReg', (65, 74))	('rpS6', 'Gene', (81, 85))
192073	26490682	Phosphorylation inhibition of rpS6 may be an effective therapeutic strategy for the treatment of NSCLC.	('NSCLC', 'Disease', (97, 102))	('Phosphorylation inhibition', 'Var', (0, 26))	('rpS6', 'Protein', (30, 34))	('NSCLC', 'Disease', 'MESH:D002289', (97, 102))	('NSCLC', 'Phenotype', 'HP:0030358', (97, 102))	('rat', 'Species', '10116', (69, 72))
192077	25426553	We analyzed the outcomes of patients with metastatic or recurrent cervical carcinomas who had a test for PIK3CA mutation and/or PTEN loss/mutation, and received >=1 phase I therapeutic regimen between January 2006 and June 2013.	('PIK3CA', 'Gene', (105, 111))	('cervical carcinomas', 'Disease', (66, 85))	('mutation', 'Var', (112, 120))	('PTEN', 'Gene', (128, 132))	('cervical carcinomas', 'Disease', 'MESH:D002575', (66, 85))	('PTEN', 'Gene', '5728', (128, 132))	('loss/mutation', 'NegReg', (133, 146))	('PIK3CA', 'Gene', '5290', (105, 111))	('recurrent cervical carcinomas', 'Phenotype', 'HP:0030159', (56, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('metastatic', 'Disease', (42, 52))	('carcinomas', 'Phenotype', 'HP:0030731', (75, 85))	('patients', 'Species', '9606', (28, 36))
192078	25426553	Patients with adenocarcinoma had fewer PIK3CA mutations (14%), and survived longer (median, 14.2 months) than those with squamous cell carcinoma (48% and 7.2 months; p = 0.016, and 0.001, respectively).	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (121, 144))	('mutations', 'Var', (46, 55))	('PIK3CA', 'Gene', '5290', (39, 45))	('survived', 'CPA', (67, 75))	('squamous cell carcinoma', 'Disease', (121, 144))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('fewer', 'NegReg', (33, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (19, 28))	('Patients', 'Species', '9606', (0, 8))	('longer', 'PosReg', (76, 82))	('adenocarcinoma', 'Disease', (14, 28))	('PIK3CA', 'Gene', (39, 45))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (121, 144))	('adenocarcinoma', 'Disease', 'MESH:D000230', (14, 28))
192080	25426553	In patients with squamous cell carcinoma of the cervix, the presence of PIK3CA mutations was associated with a significantly longer overall survival (median, 9.4 months) than the absence of PIK3CA mutations (median, 4.2 months; p = 0.019).	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (17, 40))	('PIK3CA', 'Gene', '5290', (190, 196))	('carcinoma', 'Phenotype', 'HP:0030731', (31, 40))	('overall survival', 'MPA', (132, 148))	('presence', 'Var', (60, 68))	('PIK3CA', 'Gene', (72, 78))	('longer', 'PosReg', (125, 131))	('patients', 'Species', '9606', (3, 11))	('carcinoma of the cervix', 'Phenotype', 'HP:0030079', (31, 54))	('PIK3CA', 'Gene', (190, 196))	('PIK3CA', 'Gene', '5290', (72, 78))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (17, 40))	('mutations', 'Var', (79, 88))	('squamous cell carcinoma', 'Disease', (17, 40))
192092	25426553	Class I PI3Ks are heterodimeric lipid kinases composed of the p110 catalytic subunit and the p85 regulatory subunit.	('p110', 'Gene', (62, 66))	('p110', 'Gene', '100616443', (62, 66))	('PI3Ks', 'Var', (8, 13))
192095	25426553	Upon activation through either PIK3CA mutation or PTEN loss/mutation, PI3K phosphorylates PIP2 to PIP3, which facilitates recruitment and activation of AKT to initiate a cascade of downstream signaling events including the mTOR complex, a major downstream pathway.	('mTOR', 'Gene', '2475', (223, 227))	('AKT', 'Gene', '207', (152, 155))	('PIP3', 'Chemical', '-', (98, 102))	('PIP2', 'Chemical', 'MESH:D019269', (90, 94))	('activation', 'PosReg', (5, 15))	('PTEN', 'Gene', (50, 54))	('facilitates', 'PosReg', (110, 121))	('PIK3CA', 'Gene', (31, 37))	('AKT', 'Gene', (152, 155))	('activation', 'MPA', (138, 148))	('PTEN', 'Gene', '5728', (50, 54))	('PIK3CA', 'Gene', '5290', (31, 37))	('mutation', 'Var', (38, 46))	('mTOR', 'Gene', (223, 227))	('recruitment', 'MPA', (122, 133))	('loss/mutation', 'NegReg', (55, 68))
192096	25426553	Therefore, a regimen including a PI3K inhibitor and/or an mTOR inhibitor can be utilized to target PIK3CA mutation and/or PTEN loss/mutation-mediated activated PI3K/AKT/mTOR pathway.	('AKT', 'Gene', (165, 168))	('mTOR', 'Gene', (58, 62))	('PIK3CA', 'Gene', '5290', (99, 105))	('mTOR', 'Gene', '2475', (169, 173))	('mutation', 'Var', (106, 114))	('mTOR', 'Gene', (169, 173))	('PTEN', 'Gene', '5728', (122, 126))	('AKT', 'Gene', '207', (165, 168))	('PTEN', 'Gene', (122, 126))	('loss/mutation-mediated', 'Var', (127, 149))	('mTOR', 'Gene', '2475', (58, 62))	('PIK3CA', 'Gene', (99, 105))
192097	25426553	This strategy is defined as matched therapy: a therapeutic regimen including an agent (either as a single agent or as a part of a combination regimen) that is known to directly inhibit a specific mutation, and/or to inhibit its key downstream pathways, such as treatment with a PI3K inhibitor, an mTOR inhibitor, or these agent-based regimens for a cancer patient carrying a PIK3CA mutation and/or PTEN loss/mutation.	('PTEN', 'Gene', (398, 402))	('cancer', 'Phenotype', 'HP:0002664', (349, 355))	('specific', 'Protein', (187, 195))	('PTEN', 'Gene', '5728', (398, 402))	('loss/mutation', 'NegReg', (403, 416))	('inhibit', 'NegReg', (177, 184))	('patient', 'Species', '9606', (356, 363))	('key downstream pathways', 'Pathway', (228, 251))	('cancer', 'Disease', (349, 355))	('cancer', 'Disease', 'MESH:D009369', (349, 355))	('mTOR', 'Gene', '2475', (297, 301))	('PIK3CA', 'Gene', (375, 381))	('inhibit', 'NegReg', (216, 223))	('mTOR', 'Gene', (297, 301))	('mutation', 'Var', (382, 390))	('PIK3CA', 'Gene', '5290', (375, 381))
192099	25426553	We hypothesized that cervix cancer patients with aberrations in this pathway would achieve clinical benefit (defined as objective response and prolonged stable disease) when treated with PI3K/AKT/mTOR pathway targeted agents.	('AKT', 'Gene', (192, 195))	('aberrations', 'Var', (49, 60))	('benefit', 'PosReg', (100, 107))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('mTOR', 'Gene', (196, 200))	('AKT', 'Gene', '207', (192, 195))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('mTOR', 'Gene', '2475', (196, 200))	('cervix cancer', 'Phenotype', 'HP:0030079', (21, 34))	('patients', 'Species', '9606', (35, 43))	('cancer', 'Disease', (28, 34))
192102	25426553	Consecutive patients with metastatic or recurrent cervical carcinoma (either squamous cell carcinoma or adenocarcinoma) who were referred to the Department of Investigational Cancer Therapeutics (A Phase I Clinical Trials Program) at MD Anderson between January 1, 2006, and June 30, 2013, had a test for PIK3CA mutation and/or PTEN loss/mutation in a Clinical Laboratory Improvement Amendments-certified molecular diagnostic laboratory, and received treatment in at least one phase I clinical trial, were evaluated.	('metastatic', 'Disease', (26, 36))	('PIK3CA', 'Gene', (305, 311))	('patients', 'Species', '9606', (12, 20))	('mutation', 'Var', (312, 320))	('Cancer', 'Phenotype', 'HP:0002664', (175, 181))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (77, 100))	('squamous cell carcinoma or adenocarcinoma', 'Disease', (77, 118))	('PTEN', 'Gene', (328, 332))	('cervical carcinoma', 'Disease', (50, 68))	('Cancer', 'Disease', (175, 181))	('loss/mutation', 'NegReg', (333, 346))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('PTEN', 'Gene', '5728', (328, 332))	('carcinoma', 'Phenotype', 'HP:0030731', (59, 68))	('cervical carcinoma', 'Disease', 'MESH:D002575', (50, 68))	('Cancer', 'Disease', 'MESH:D009369', (175, 181))	('PIK3CA', 'Gene', '5290', (305, 311))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('squamous cell carcinoma or adenocarcinoma', 'Disease', 'MESH:D002294', (77, 118))
192105	25426553	Clinical information that was collected included race, prior treatment history (e.g., surgery, radiation therapy, and chemotherapy), date of birth, Eastern Cooperative Oncology Group performance status at the initial phase I clinic visit, mutation profiling of the tumor specimen including PIK3CA mutation and/or PTEN loss/mutation status, phase I clinical trial therapies, and clinical outcomes: severe adverse event (SAEs), progression-free survival (PFS), overall survival (OS), and objective responses including complete remission (CR), partial response (PR), and stable disease for 6 months or longer (SD >= 6months).	('severe adverse event', 'Disease', (397, 417))	('mutation', 'Var', (297, 305))	('PTEN', 'Gene', (313, 317))	('PIK3CA', 'Gene', (290, 296))	('complete', 'Disease', (516, 524))	('PTEN', 'Gene', '5728', (313, 317))	('loss/mutation', 'NegReg', (318, 331))	('SAEs', 'Chemical', '-', (419, 423))	('PIK3CA', 'Gene', '5290', (290, 296))	('tumor', 'Phenotype', 'HP:0002664', (265, 270))	('tumor', 'Disease', (265, 270))	('overall survival', 'CPA', (459, 475))	('Oncology', 'Phenotype', 'HP:0002664', (168, 176))	('stable', 'Disease', (568, 574))	('partial', 'CPA', (541, 548))	('tumor', 'Disease', 'MESH:D009369', (265, 270))	('progression-free survival', 'CPA', (426, 451))
192113	25426553	Fifty-five consecutive patients with metastatic or recurrent adenocarcinoma (n = 24) or squamous cell carcinoma (n = 31) who had a test for PIK3CA mutation and/or PTEN loss/mutation and underwent treatment in at least one phase I clinical trial in the Phase I Clinical Trials Program were included in this study.	('carcinoma', 'Phenotype', 'HP:0030731', (66, 75))	('PIK3CA', 'Gene', (140, 146))	('patients', 'Species', '9606', (23, 31))	('PTEN', 'Gene', (163, 167))	('mutation', 'Var', (147, 155))	('adenocarcinoma', 'Disease', 'MESH:D000230', (61, 75))	('PTEN', 'Gene', '5728', (163, 167))	('PIK3CA', 'Gene', '5290', (140, 146))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (88, 111))	('metastatic or', 'Disease', (37, 50))	('loss/mutation', 'NegReg', (168, 181))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (88, 111))	('squamous cell carcinoma', 'Disease', (88, 111))	('adenocarcinoma', 'Disease', (61, 75))
192116	25426553	Twenty-two patients were found to harbor PIK3CA mutations and/or PTEN loss: 17 (33%) of 51 tested patients with PIK3CA aberrations (E545K = 8, E542K = 4, H1047L = 1, H1047R = 1, E545K and D549H = 1, E542K and M1043I = 1, amplification = 1); 7 (18%) of 40 tested patients with PTEN loss (n = 6) and/or mutation (R173C = 1); and 2 patients have both of PIK3CA mutation (E545K) and PTEN loss.	('E542K', 'Mutation', 'rs121913273', (143, 148))	('PTEN', 'Gene', (379, 383))	('PIK3CA', 'Gene', '5290', (112, 118))	('M1043I', 'Mutation', 'rs121913283', (209, 215))	('PTEN', 'Gene', '5728', (276, 280))	('PIK3CA', 'Gene', '5290', (41, 47))	('H1047R', 'Mutation', 'rs121913279', (166, 172))	('H1047L', 'Mutation', 'rs121913279', (154, 160))	('mutations', 'Var', (48, 57))	('E545K = 8', 'Var', (132, 141))	('R173C', 'Mutation', 'rs121913293', (311, 316))	('PTEN', 'Gene', '5728', (379, 383))	('E545K', 'Mutation', 'rs104886003', (368, 373))	('PIK3CA', 'Gene', (351, 357))	('loss', 'NegReg', (281, 285))	('E545K', 'Mutation', 'rs104886003', (132, 137))	('PIK3CA', 'Gene', (112, 118))	('E542K = 4', 'Var', (143, 152))	('PTEN', 'Gene', (65, 69))	('patients', 'Species', '9606', (262, 270))	('E545K', 'Mutation', 'rs104886003', (178, 183))	('PIK3CA', 'Gene', (41, 47))	('M1043I = 1', 'Var', (209, 219))	('E545K', 'Var', (368, 373))	('patients', 'Species', '9606', (98, 106))	('H1047L = 1', 'Var', (154, 164))	('patients', 'Species', '9606', (329, 337))	('patients', 'Species', '9606', (11, 19))	('H1047R = 1', 'Var', (166, 176))	('mutation', 'Var', (301, 309))	('E542K', 'Mutation', 'rs121913273', (199, 204))	('PTEN', 'Gene', (276, 280))	('D549H = 1', 'Var', (188, 197))	('D549H', 'Mutation', 'p.D549H', (188, 193))	('PTEN', 'Gene', '5728', (65, 69))	('PIK3CA', 'Gene', '5290', (351, 357))
192117	25426553	Further analyses revealed that patients with squamous cell carcinomas were significantly younger and more likely to carry PIK3CA mutations than those with adenocarcinomas (p = 0.034 per independent samples t-test for age and p = 0.016 per Fisher's exact test for PIK3CA mutations, respectively).	('PIK3CA', 'Gene', (122, 128))	('PIK3CA', 'Gene', '5290', (263, 269))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (45, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (160, 169))	('carcinoma', 'Phenotype', 'HP:0030731', (59, 68))	('mutations', 'Var', (129, 138))	('carcinomas', 'Phenotype', 'HP:0030731', (59, 69))	('PIK3CA', 'Gene', '5290', (122, 128))	('adenocarcinomas', 'Disease', 'MESH:D000230', (155, 170))	('squamous cell carcinomas', 'Disease', (45, 69))	('adenocarcinomas', 'Disease', (155, 170))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (45, 69))	('patients', 'Species', '9606', (31, 39))	('carcinomas', 'Phenotype', 'HP:0030731', (160, 170))	('PIK3CA', 'Gene', (263, 269))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (45, 68))
192123	25426553	In patients who received PI3K/AKT/mTOR pathway targeted therapeutic regimens, no apparent difference was observed between patients with PI3KCA mutation and/or PTEN loss/mutation and those without.	('PI3KCA', 'Gene', (136, 142))	('PTEN', 'Gene', (159, 163))	('PTEN', 'Gene', '5728', (159, 163))	('AKT', 'Gene', '207', (30, 33))	('mutation', 'Var', (143, 151))	('patients', 'Species', '9606', (122, 130))	('patients', 'Species', '9606', (3, 11))	('loss/mutation', 'NegReg', (164, 177))	('AKT', 'Gene', (30, 33))	('mTOR', 'Gene', '2475', (34, 38))	('mTOR', 'Gene', (34, 38))
192126	25426553	Of 15 patients with PIK3CA mutations and/or PTEN loss/mutations who received matched therapy, 53% achieved SD >= 6 months/CR/PR (CR = 1, PR = 5 and SD >= 6 months = 2), and the median PFS in this group was 6.0 months (95% CI, 3.2-8.8).	('mutations', 'Var', (27, 36))	('PIK3CA', 'Gene', (20, 26))	('PIK3CA', 'Gene', '5290', (20, 26))	('loss/mutations', 'NegReg', (49, 63))	('PTEN', 'Gene', (44, 48))	('patients', 'Species', '9606', (6, 14))	('loss/mutations', 'Var', (49, 63))	('PTEN', 'Gene', '5728', (44, 48))
192132	25426553	Patients with PIK3CA mutation and/or PTEN loss/mutation who received matched therapy, achieved a median OS of 10.1 months (95% CI, 5.9-14.3), compared with those who did not (7.7 months; 95% CI, 1.6-13.8; p = 0.43; Figure 3B).	('PIK3CA', 'Gene', '5290', (14, 20))	('mutation', 'Var', (21, 29))	('PTEN', 'Gene', (37, 41))	('Patients', 'Species', '9606', (0, 8))	('PTEN', 'Gene', '5728', (37, 41))	('PIK3CA', 'Gene', (14, 20))	('loss/mutation', 'NegReg', (42, 55))
192133	25426553	Furthermore, patients with metastatic or recurrent squamous cell carcinomas who carried PIK3CA mutations (n = 14) achieved a median OS of 9.4 months (95% CI, 8.1-10.7), significantly longer than the median OS of those who did not carry PIK3CA mutations (n = 15; 4.2 months, 95% CI, 2.2-6.2; p = 0.019), as shown in Figure 4A.	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('PIK3CA', 'Gene', (236, 242))	('PIK3CA', 'Gene', '5290', (88, 94))	('PIK3CA', 'Gene', '5290', (236, 242))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (51, 74))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (51, 75))	('carcinomas', 'Phenotype', 'HP:0030731', (65, 75))	('patients', 'Species', '9606', (13, 21))	('squamous cell carcinomas', 'Disease', (51, 75))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (51, 75))	('metastatic', 'Disease', (27, 37))	('mutations', 'Var', (95, 104))	('PIK3CA', 'Gene', (88, 94))	('longer', 'PosReg', (183, 189))
192134	25426553	Patients with metastatic or recurrent adenocarcinomas who carried PIK3CA mutations (n = 3) achieved a median OS of 19.4 months (95% CI, 0 - 43.6), similar to those who did not carry PIK3CA mutations (n = 19; 14.2 months, 95% CI, 4.0-24.4; p = 0.75), as shown in Figure 4B.	('adenocarcinomas', 'Disease', 'MESH:D000230', (38, 53))	('adenocarcinomas', 'Disease', (38, 53))	('PIK3CA', 'Gene', (182, 188))	('PIK3CA', 'Gene', (66, 72))	('carcinoma', 'Phenotype', 'HP:0030731', (43, 52))	('PIK3CA', 'Gene', '5290', (182, 188))	('carcinomas', 'Phenotype', 'HP:0030731', (43, 53))	('Patients', 'Species', '9606', (0, 8))	('PIK3CA', 'Gene', '5290', (66, 72))	('mutations', 'Var', (73, 82))	('metastatic', 'Disease', (14, 24))
192136	25426553	In this study, we identified that patients with previously treated, locally advanced or metastatic cervical cancer harboring mutations in the PI3K/AKT/mTOR pathway achieved meaningful clinical benefit from a number of novel therapeutics administered in a phase I cancer center.	('mutations', 'Var', (125, 134))	('cancer', 'Disease', 'MESH:D009369', (263, 269))	('cervical cancer', 'Disease', 'MESH:D002583', (99, 114))	('cancer', 'Disease', (263, 269))	('cervical cancer', 'Disease', (99, 114))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('AKT', 'Gene', '207', (147, 150))	('patients', 'Species', '9606', (34, 42))	('cancer', 'Disease', 'MESH:D009369', (108, 114))	('benefit', 'PosReg', (193, 200))	('cancer', 'Phenotype', 'HP:0002664', (263, 269))	('mTOR', 'Gene', (151, 155))	('mTOR', 'Gene', '2475', (151, 155))	('cancer', 'Disease', (108, 114))	('AKT', 'Gene', (147, 150))
192141	25426553	In general, patients with metastatic or recurrent squamous cell carcinoma of the cervix were significantly younger, and had a higher prevalence of PIK3CA mutations.	('patients', 'Species', '9606', (12, 20))	('carcinoma of the cervix', 'Phenotype', 'HP:0030079', (64, 87))	('higher', 'PosReg', (126, 132))	('metastatic', 'Disease', (26, 36))	('PIK3CA', 'Gene', (147, 153))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (50, 73))	('PIK3CA', 'Gene', '5290', (147, 153))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (50, 73))	('mutations', 'Var', (154, 163))	('squamous cell carcinoma', 'Disease', (50, 73))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))
192144	25426553	However, in patients with metastatic or recurrent adenocarcinoma of the cervix, there was no significant difference in OS associated with matched therapy in spite of a higher rate of SD >= 6 months/CR/PR and significantly longer PFS, which might be owing to at least three potential factors: lower prevalence of the activated PI3K/AKT/mTOR pathway, intrinsic sensitivity to novel phase I trial therapy available at MD Anderson phase I service, and the presence of PIK3CA mutation and/or PTEN loss/mutation that cannot stratify for aggressiveness of disease.	('mTOR', 'Gene', (335, 339))	('patients', 'Species', '9606', (12, 20))	('AKT', 'Gene', '207', (331, 334))	('carcinoma', 'Phenotype', 'HP:0030731', (55, 64))	('adenocarcinoma', 'Disease', 'MESH:D000230', (50, 64))	('PIK3CA', 'Gene', (464, 470))	('aggressiveness', 'Phenotype', 'HP:0000718', (531, 545))	('aggressiveness of disease', 'Disease', (531, 556))	('aggressiveness of disease', 'Disease', 'MESH:D001523', (531, 556))	('mutation', 'Var', (471, 479))	('PTEN', 'Gene', (487, 491))	('AKT', 'Gene', (331, 334))	('PTEN', 'Gene', '5728', (487, 491))	('loss/mutation', 'NegReg', (492, 505))	('carcinoma of the cervix', 'Phenotype', 'HP:0030079', (55, 78))	('PIK3CA', 'Gene', '5290', (464, 470))	('mTOR', 'Gene', '2475', (335, 339))	('adenocarcinoma', 'Disease', (50, 64))
192145	25426553	Third, PIK3CA mutation, but not PTEN loss/mutation, was associated with significantly longer OS, indicating the differential effects of these genetic aberrations on sensitivity to matched therapy, as well as matched patients and the preferential choices of the treating physicians in the Phase I Clinical Trials Program, MD Anderson for assigning patients to matched therapy.	('PTEN', 'Gene', (32, 36))	('PIK3CA', 'Gene', (7, 13))	('PTEN', 'Gene', '5728', (32, 36))	('longer', 'PosReg', (86, 92))	('patients', 'Species', '9606', (216, 224))	('mutation', 'Var', (14, 22))	('PIK3CA', 'Gene', '5290', (7, 13))	('patients', 'Species', '9606', (347, 355))
192148	25426553	Almost half of the patients with metastatic or recurrent cervical carcinoma, especially those with squamous cell carcinoma, presented with PIK3CA mutation and/or PTEN loss/mutation, and this proportion was significantly higher in patients with advanced solid tumors (48% versus 22%, p = 0.002), suggesting that the activated PI3K/AKT/mTOR pathway is a driving mechanism for the survival of cervical carcinoma cells.	('cervical carcinoma', 'Disease', 'MESH:D002575', (390, 408))	('carcinoma', 'Phenotype', 'HP:0030731', (66, 75))	('metastatic', 'Disease', (33, 43))	('carcinoma', 'Phenotype', 'HP:0030731', (399, 408))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('PIK3CA', 'Gene', (139, 145))	('tumors', 'Phenotype', 'HP:0002664', (259, 265))	('mutation', 'Var', (146, 154))	('squamous cell carcinoma', 'Disease', (99, 122))	('mTOR', 'Gene', (334, 338))	('PTEN', 'Gene', (162, 166))	('AKT', 'Gene', (330, 333))	('loss/mutation', 'NegReg', (167, 180))	('solid tumors', 'Disease', 'MESH:D009369', (253, 265))	('tumor', 'Phenotype', 'HP:0002664', (259, 264))	('mTOR', 'Gene', '2475', (334, 338))	('cervical carcinoma', 'Disease', (57, 75))	('PTEN', 'Gene', '5728', (162, 166))	('patients', 'Species', '9606', (19, 27))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (99, 122))	('AKT', 'Gene', '207', (330, 333))	('cervical carcinoma', 'Disease', 'MESH:D002575', (57, 75))	('PIK3CA', 'Gene', '5290', (139, 145))	('cervical carcinoma', 'Disease', (390, 408))	('patients', 'Species', '9606', (230, 238))	('presented', 'Reg', (124, 133))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (99, 122))	('solid tumors', 'Disease', (253, 265))
192149	25426553	PIK3CA mutation was more prevalent in patients with KRAS mutation than in patients with wild-type KRAS, whereas in this report, a low frequency of KRAS mutation was found in metastatic or recurrent cervical carcinomas, and in squamous cell carcinomas specifically, no KRAS mutation was identified in any of the 26 tested patients (Table 1).	('KRAS', 'Gene', (268, 272))	('KRAS', 'Gene', '3845', (52, 56))	('cervical carcinomas', 'Disease', (198, 217))	('patients', 'Species', '9606', (38, 46))	('KRAS', 'Gene', '3845', (98, 102))	('KRAS', 'Gene', (147, 151))	('recurrent cervical carcinomas', 'Phenotype', 'HP:0030159', (188, 217))	('prevalent', 'Reg', (25, 34))	('KRAS', 'Gene', (52, 56))	('carcinomas', 'Phenotype', 'HP:0030731', (240, 250))	('patients', 'Species', '9606', (321, 329))	('carcinoma', 'Phenotype', 'HP:0030731', (207, 216))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (226, 250))	('PIK3CA', 'Gene', '5290', (0, 6))	('carcinomas', 'Phenotype', 'HP:0030731', (207, 217))	('KRAS', 'Gene', (98, 102))	('mutation', 'Var', (57, 65))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (226, 250))	('patients', 'Species', '9606', (74, 82))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (226, 249))	('cervical carcinomas', 'Disease', 'MESH:D002575', (198, 217))	('KRAS', 'Gene', '3845', (268, 272))	('squamous cell carcinomas', 'Disease', (226, 250))	('PIK3CA', 'Gene', (0, 6))	('mutation', 'Var', (7, 15))	('carcinoma', 'Phenotype', 'HP:0030731', (240, 249))	('KRAS', 'Gene', '3845', (147, 151))
192150	25426553	Since PIK3CA mutation and/or PTEN loss/mutation with simultaneous KRAS mutation were associated with significantly lower antitumor activity and shorter PFS than PIK3CA mutation and/or PTEN loss/mutation without simultaneous KRAS mutation, two or more coexisting mutations constitute different classes of mutation profiles that predict responses to various biologically targeting agents and/or their combinations and render matched therapy more complicated than expected.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('PTEN', 'Gene', (29, 33))	('PIK3CA', 'Gene', (6, 12))	('lower', 'NegReg', (115, 120))	('PIK3CA', 'Gene', '5290', (161, 167))	('loss/mutation', 'NegReg', (34, 47))	('KRAS', 'Gene', '3845', (224, 228))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('KRAS', 'Gene', '3845', (66, 70))	('PTEN', 'Gene', '5728', (29, 33))	('KRAS', 'Gene', (224, 228))	('KRAS', 'Gene', (66, 70))	('PTEN', 'Gene', (184, 188))	('predict', 'Reg', (327, 334))	('PIK3CA', 'Gene', (161, 167))	('PIK3CA', 'Gene', '5290', (6, 12))	('PFS', 'MPA', (152, 155))	('shorter', 'NegReg', (144, 151))	('mutation', 'Var', (71, 79))	('PTEN', 'Gene', '5728', (184, 188))	('tumor', 'Disease', (125, 130))
192151	25426553	When developing efficacious regimens to target the activated PI3K/AKT/mTOR pathway, metastatic or recurrent squamous cell carcinomas of the cervix might be an appropriate clinical model to be tested in early-phase clinical trials because of their high prevalence of PIK3CA mutation and/or PTEN loss/mutation as previously reported and their lack of simultaneous KRAS mutation, in agreement with the hypothesis that coexisting KRAS mutation become resistant to regimens targeting the activated PI3K/AKT/mTOR pathway.	('KRAS', 'Gene', (362, 366))	('mTOR', 'Gene', '2475', (70, 74))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (108, 132))	('carcinomas of the cervix', 'Phenotype', 'HP:0030079', (122, 146))	('PIK3CA', 'Gene', (266, 272))	('PTEN', 'Gene', (289, 293))	('mutation', 'Var', (273, 281))	('mTOR', 'Gene', (502, 506))	('loss/mutation', 'NegReg', (294, 307))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (108, 132))	('AKT', 'Gene', (498, 501))	('PTEN', 'Gene', '5728', (289, 293))	('AKT', 'Gene', (66, 69))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (108, 131))	('mTOR', 'Gene', '2475', (502, 506))	('squamous cell carcinomas', 'Disease', (108, 132))	('KRAS', 'Gene', '3845', (426, 430))	('AKT', 'Gene', '207', (498, 501))	('PIK3CA', 'Gene', '5290', (266, 272))	('mTOR', 'Gene', (70, 74))	('KRAS', 'Gene', '3845', (362, 366))	('KRAS', 'Gene', (426, 430))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('carcinomas', 'Phenotype', 'HP:0030731', (122, 132))	('AKT', 'Gene', '207', (66, 69))
192156	25426553	In conclusion, our results showed that almost half of the patients with metastatic or recurrent squamous cell carcinoma of the cervix had PIK3CA mutation and/or PTEN loss/mutation without coexisting KRAS mutation, providing an appropriate patient population to the test efficacy of a regimen including a single agent targeting the PI3K/AKT/mTOR pathway or a combination regimen with either another biologically targeted agent and/or conventional chemotherapeutic agent.	('AKT', 'Gene', '207', (336, 339))	('patient', 'Species', '9606', (239, 246))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (96, 119))	('PIK3CA', 'Gene', (138, 144))	('carcinoma of the cervix', 'Phenotype', 'HP:0030079', (110, 133))	('PTEN', 'Gene', (161, 165))	('loss/mutation', 'NegReg', (166, 179))	('mutation', 'Var', (145, 153))	('squamous cell carcinoma', 'Disease', (96, 119))	('KRAS', 'Gene', '3845', (199, 203))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (96, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('patients', 'Species', '9606', (58, 66))	('PTEN', 'Gene', '5728', (161, 165))	('AKT', 'Gene', (336, 339))	('KRAS', 'Gene', (199, 203))	('mTOR', 'Gene', (340, 344))	('patient', 'Species', '9606', (58, 65))	('mTOR', 'Gene', '2475', (340, 344))	('PIK3CA', 'Gene', '5290', (138, 144))
192171	32922662	A recent study demonstrated that patients with low degree of keratinization have an increased recurrence of disease, a high propensity for early metastasis to regional lymph nodes and a reduced incidence of 5-yr disease-free survival rates.	('patients', 'Species', '9606', (33, 41))	('disease-free survival rates', 'CPA', (212, 239))	('low', 'Var', (47, 50))	('reduced', 'NegReg', (186, 193))	('keratinization', 'Var', (61, 75))	('recurrence of disease', 'CPA', (94, 115))
192172	32922662	Notably, patients with both a high degree of keratinization and human papillomavirus (HPV)-positive oral cancers have an improved response to treatment and an improved prognosis compared with patients with a low degree of keratinization and HPV-negative OSCCs.	('HPV', 'Species', '10566', (241, 244))	('patients', 'Species', '9606', (9, 17))	('HPV', 'Species', '10566', (86, 89))	('human papillomavirus', 'Species', '10566', (64, 84))	('cancers', 'Phenotype', 'HP:0002664', (105, 112))	('HPV', 'Gene', (86, 89))	('improved', 'PosReg', (121, 129))	('cancers', 'Disease', (105, 112))	('keratinization', 'Var', (45, 59))	('cancers', 'Disease', 'MESH:D009369', (105, 112))	('patients', 'Species', '9606', (192, 200))	('high', 'Var', (30, 34))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))
192208	32922662	By aggregate analysis of pooled oral cancer samples, we identified a significant copy number gain of Ch7p11.2 (EGFR-100% CNV overlap and 81.81% frequency) and copy number loss of Ch3p21.1 (PBRM1-25.46% CNV overlap and 54.54% frequency), Ch3p14.2 (FHIT-0.32% CNV overlap and 54.54% frequency), Ch19p13.3 (STK11-100% CNV overlap and 45.45% frequency) and Ch16 p13.3 (TSC2-79.73% CNV overlap and 45.45% frequency).	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('copy number', 'Var', (81, 92))	('EGFR', 'Gene', '1956', (111, 115))	('TSC2', 'Gene', (365, 369))	('copy number', 'Var', (159, 170))	('p13', 'Gene', '440926', (297, 300))	('loss', 'NegReg', (171, 175))	('STK11', 'Gene', (304, 309))	('Ch3p21.1', 'Gene', (179, 187))	('Ch7p11.2', 'Gene', (101, 109))	('p13', 'Gene', (358, 361))	('PBRM1', 'Gene', '55193', (189, 194))	('cancer', 'Disease', (37, 43))	('STK11', 'Gene', '6794', (304, 309))	('FHIT', 'Gene', (247, 251))	('PBRM1', 'Gene', (189, 194))	('EGFR', 'Gene', (111, 115))	('p13', 'Gene', '440926', (358, 361))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('TSC2', 'Gene', '7249', (365, 369))	('gain', 'PosReg', (93, 97))	('p13', 'Gene', (297, 300))	('FHIT', 'Gene', '2272', (247, 251))
192209	32922662	After further validation, we detected EGFR amplification in 12 histopathologically characterized formalin-fixed, paraffin-embedded (FFPE) keratinized OSCCs, while EGFR amplification was detected in only 5 OC samples (Figure 6).	('EGFR', 'Gene', '1956', (38, 42))	('EGFR', 'Gene', (38, 42))	('EGFR', 'Gene', '1956', (163, 167))	('amplification', 'Var', (43, 56))	('EGFR', 'Gene', (163, 167))	('paraffin', 'Chemical', 'MESH:D010232', (113, 121))	('formalin', 'Chemical', 'MESH:D005557', (97, 105))
192219	32922662	This ISGylation may induce natural killer cell proliferation, which acts as a chemotactic factor for neutrophils and acts as an IFN-gamma-inducing cytokine.	('induce', 'PosReg', (20, 26))	('ISGylation', 'Var', (5, 15))	('IFN-gamma', 'Gene', '3458', (128, 137))	('IFN-gamma', 'Gene', (128, 137))	('natural killer cell proliferation', 'CPA', (27, 60))
192226	32922662	Oncogenic stress is balanced by mitochondrial biogenesis (PSMB6, PSMD8, DNAJB1, PRDX5, PSMC5, UBB, SOD2) and deregulated CDK5.	('PSMD8', 'Gene', (65, 70))	('UBB', 'Gene', '7314', (94, 97))	('DNAJB1', 'Gene', (72, 78))	('deregulated', 'Var', (109, 120))	('PSMC5', 'Gene', '5705', (87, 92))	('PSMB6', 'Gene', (58, 63))	('CDK5', 'Gene', '1020', (121, 125))	('PSMC5', 'Gene', (87, 92))	('PRDX5', 'Gene', '25824', (80, 85))	('PSMB6', 'Gene', '5694', (58, 63))	('PSMD8', 'Gene', '5714', (65, 70))	('UBB', 'Gene', (94, 97))	('SOD2', 'Gene', '6648', (99, 103))	('mitochondrial biogenesis', 'MPA', (32, 56))	('PRDX5', 'Gene', (80, 85))	('DNAJB1', 'Gene', '3337', (72, 78))	('CDK5', 'Gene', (121, 125))	('SOD2', 'Gene', (99, 103))
192242	32922662	The identified novel intrachromosomal Ch12 fusion between KRT6B-KRT6A and interchromosomal fusions between CKB-Ch14 and CKM-Ch19, ACTB-Ch7-ACTA2-Ch10, ACTB-Ch7-ACTC1-Ch15, ACTB-Ch7-ACTG2-Ch2, and IGKV1-27-IGKV3-15 identified through long-read sequencing after validation demonstrated IGKV/IGKJ rearrangements in keratinized OSCC.	('IGKV', 'Gene', (205, 209))	('KRT6A', 'Gene', '3853', (64, 69))	('ACTB', 'Gene', (130, 134))	('IGKV', 'Gene', (284, 288))	('IGKV1-27', 'Gene', '28935', (196, 204))	('ACTB', 'Gene', '60', (130, 134))	('IGKV3-15', 'Gene', '28913', (205, 213))	('IGKV', 'Gene', (196, 200))	('KRT6A', 'Gene', (64, 69))	('IGKV', 'Gene', '3519', (205, 209))	('rearrangements', 'Var', (294, 308))	('IGKV', 'Gene', '3519', (284, 288))	('IGKV3-15', 'Gene', (205, 213))	('IGKV', 'Gene', '3519', (196, 200))	('KRT6B', 'Gene', '3854', (58, 63))	('ACTG2', 'Gene', '72', (181, 186))	('CKB', 'Gene', '1152', (107, 110))	('ACTB', 'Gene', '60', (151, 155))	('keratinized OSCC', 'Disease', (312, 328))	('ACTB', 'Gene', (151, 155))	('ACTG2', 'Gene', (181, 186))	('CKM', 'Gene', '1158', (120, 123))	('IGKJ', 'Gene', (289, 293))	('CKB', 'Gene', (107, 110))	('KRT6B', 'Gene', (58, 63))	('IGKJ', 'Gene', '7842', (289, 293))	('IGKV1-27', 'Gene', (196, 204))	('ACTC1', 'Gene', '70', (160, 165))	('ACTA2', 'Gene', (139, 144))	('ACTC1', 'Gene', (160, 165))	('CKM', 'Gene', (120, 123))	('ACTA2', 'Gene', '59', (139, 144))	('ACTB', 'Gene', (172, 176))	('ACTB', 'Gene', '60', (172, 176))
192246	32922662	CKM-CKB and KRT6B-KRT6A fusions were observed in metabolic reprogramming and hemidesmosome assembly pathways (Supplementary Table 5B).	('CKB', 'Gene', '1152', (4, 7))	('CKM', 'Gene', (0, 3))	('observed', 'Reg', (37, 45))	('CKM', 'Gene', '1158', (0, 3))	('hemidesmosome assembly pathways', 'CPA', (77, 108))	('KRT6B', 'Gene', (12, 17))	('KRT6A', 'Gene', '3853', (18, 23))	('CKB', 'Gene', (4, 7))	('metabolic reprogramming', 'CPA', (49, 72))	('KRT6A', 'Gene', (18, 23))	('KRT6B', 'Gene', '3854', (12, 17))	('fusions', 'Var', (24, 31))
192252	32922662	The insertion of one exonic fragment between the 6th and 7th exons of constitutive UCHL3 may lower its stability than the reference transcript, subsequently altering its deubiquitination activity.	('altering', 'Reg', (157, 165))	('stability', 'MPA', (103, 112))	('UCHL3', 'Gene', '7347', (83, 88))	('insertion', 'Var', (4, 13))	('deubiquitination activity', 'MPA', (170, 195))	('lower', 'NegReg', (93, 98))	('UCHL3', 'Gene', (83, 88))
192279	32922662	Multiple alignments through Clustalw2 were performed to validate the insertion, deletion or fusion of exonic nucleotide sequences in the coding region of 33 FL transcripts of pooled-OC and pooled-OT samples and nmIDs of the human genome (hg38).	('deletion', 'Var', (80, 88))	('human', 'Species', '9606', (224, 229))	('hg38', 'Gene', (238, 242))	('hg38', 'Gene', '8549', (238, 242))	('FL', 'Gene', '2323', (157, 159))	('fusion', 'Var', (92, 98))
192297	31543899	For example, aberrant promoter hypermethylation that is associated with inappropriate gene silencing affects virtually every step in tumor progression.	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('promoter', 'MPA', (22, 30))	('tumor', 'Disease', (133, 138))	('aberrant', 'Var', (13, 21))	('affects', 'Reg', (101, 108))
192298	31543899	So, the investigation of differential methylation, which displays the inherent difference between normal and tumor samples, could help us deepen our perception of oncogenesis and may assist in the early diagnosis of cancers.	('assist', 'Reg', (183, 189))	('methylation', 'Var', (38, 49))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('cancers', 'Phenotype', 'HP:0002664', (216, 223))	('cancers', 'Disease', (216, 223))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('cancers', 'Disease', 'MESH:D009369', (216, 223))	('differential methylation', 'Var', (25, 49))	('tumor', 'Disease', (109, 114))
192302	31543899	Additionally, taking advantage of the large-scale Infinium 450K methylation data produced by The Cancer Genome Atlas (TCGA) project, we performed intensive analysis to look further into interrelationships between differential methylation and cancers and found that different cancers have common patterns, and robust DML sharing in pan-cancers is of the great potential to be biomarkers.	('Cancer Genome Atlas', 'Disease', (97, 116))	('cancers', 'Disease', 'MESH:D009369', (242, 249))	('cancers', 'Phenotype', 'HP:0002664', (242, 249))	('cancer', 'Phenotype', 'HP:0002664', (335, 341))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (97, 116))	('cancers', 'Disease', (242, 249))	('cancers', 'Phenotype', 'HP:0002664', (335, 342))	('cancer', 'Phenotype', 'HP:0002664', (275, 281))	('cancers', 'Disease', (335, 342))	('cancers', 'Disease', 'MESH:D009369', (335, 342))	('cancers', 'Phenotype', 'HP:0002664', (275, 282))	('pan-cancers', 'Disease', 'MESH:C537931', (331, 342))	('Cancer', 'Phenotype', 'HP:0002664', (97, 103))	('pan-cancers', 'Disease', (331, 342))	('cancer', 'Phenotype', 'HP:0002664', (242, 248))	('cancers', 'Disease', 'MESH:D009369', (275, 282))	('DML sharing', 'Var', (316, 327))	('cancers', 'Disease', (275, 282))
192307	31543899	The three data sets are also obtained by HM 450 technique, including samples of breast (GSE52635), liver (GSE54503), and lung (GSE66836) cancer, as well as corresponding normal tissue data records (Table S1).	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('GSE52635', 'Var', (88, 96))	('HM 450', 'Chemical', '-', (41, 47))	('lung (GSE66836) cancer', 'Disease', 'MESH:D008175', (121, 143))	('GSE54503', 'Var', (106, 114))	('liver', 'Disease', (99, 104))	('breast', 'Disease', (80, 86))
192319	31543899	However, considering that the promoter region occupied only a small part of the genome, the number of DML accounted for more than 20%, indicating that the abnormal methylation of this short functional region had an important impact on the tumorigenesis.	('impact', 'Reg', (225, 231))	('abnormal', 'Var', (155, 163))	('tumor', 'Disease', 'MESH:D009369', (239, 244))	('tumor', 'Phenotype', 'HP:0002664', (239, 244))	('tumor', 'Disease', (239, 244))	('methylation', 'MPA', (164, 175))
192338	31543899	In these pDML, we also found that, one probe, cg02829688, was significantly hypermethylated (the methylation level of loci in tumor samples was higher than that in normal samples) in all 13 cancers ( Figure 5 ).	('cancers', 'Phenotype', 'HP:0002664', (190, 197))	('cancers', 'Disease', (190, 197))	('cancers', 'Disease', 'MESH:D009369', (190, 197))	('hypermethylated', 'PosReg', (76, 91))	('methylation level', 'MPA', (97, 114))	('higher', 'PosReg', (144, 150))	('cg02829688', 'Var', (46, 56))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumor', 'Disease', (126, 131))
192349	31543899	Identifying DML is a promising approach to reveal the inherent intricacy between aberrant DNA methylation and tumorigenesis, and recent studies have paid more attention to this essential epigenetic mechanism.	('aberrant', 'Var', (81, 89))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
192355	31543899	We also found a locus (cg02829688), which was hypermethylated in 13 cancers, located in a functional region on the genome, and could be of great potential to be an oncogenesis biomarker.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('cancers', 'Phenotype', 'HP:0002664', (68, 75))	('cancers', 'Disease', (68, 75))	('cancers', 'Disease', 'MESH:D009369', (68, 75))	('cg02829688', 'Var', (23, 33))
192356	31543899	Enriched motifs analysis from the background sequences of pDML revealed the potential influence on transcription function by CpG methylation, and the most significantly enriched motif, IRF3, has been reported playing a vital role in tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('CpG', 'Protein', (125, 128))	('IRF3', 'Gene', (185, 189))	('IRF3', 'Gene', '3661', (185, 189))	('methylation', 'Var', (129, 140))	('tumor', 'Disease', (233, 238))	('transcription function', 'MPA', (99, 121))	('tumor', 'Disease', 'MESH:D009369', (233, 238))	('influence', 'Reg', (86, 95))
192382	31174496	This trial concluded that pembrolizumab was more effective in tumor cells with more than 50% PD-L1 expression.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', (62, 67))	('expression', 'Var', (99, 109))	('pembrolizumab', 'Chemical', 'MESH:C582435', (26, 39))	('PD-L1', 'Gene', (93, 98))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
192453	31174496	M. H. and M. T. contributed to pathological procedures and TPS evaluation.	('TPS', 'Disease', (59, 62))	('M. T.', 'Var', (10, 15))	('TPS', 'Chemical', '-', (59, 62))	('pathological procedures', 'CPA', (31, 54))
192478	28587135	In cancers, increased or altered expression of integrins on tumour cells and associated vasculature leads to tumour progression through a wide range of mechanisms, including supporting cell proliferation and tumour angiogenesis as previously mentioned, supporting the epithelial mesenchymal transition, promoting migration and invasion, interaction with the extracellular microenvironment during the metastatic process, and TGF-beta activation facilitating tumour immunosuppression.	('tumour', 'Disease', 'MESH:D009369', (109, 115))	('tumour', 'Phenotype', 'HP:0002664', (457, 463))	('supporting', 'PosReg', (253, 263))	('tumour immunosuppression', 'Disease', 'MESH:D009369', (457, 481))	('tumour', 'Disease', (109, 115))	('tumour', 'Disease', 'MESH:D009369', (457, 463))	('tumour', 'Disease', (457, 463))	('tumour', 'Phenotype', 'HP:0002664', (60, 66))	('tumour', 'Disease', 'MESH:D009369', (60, 66))	('epithelial mesenchymal transition', 'CPA', (268, 301))	('tumour', 'Disease', (60, 66))	('TGF-beta', 'Gene', (424, 432))	('cancers', 'Disease', 'MESH:D009369', (3, 10))	('tumour immunosuppression', 'Disease', (457, 481))	('tumour', 'Phenotype', 'HP:0002664', (208, 214))	('invasion', 'CPA', (327, 335))	('tumour', 'Disease', 'MESH:D009369', (208, 214))	('supporting cell proliferation', 'CPA', (174, 203))	('migration', 'CPA', (313, 322))	('tumour', 'Phenotype', 'HP:0002664', (109, 115))	('promoting', 'PosReg', (303, 312))	('expression', 'Var', (33, 43))	('tumour', 'Disease', (208, 214))	('altered expression', 'Var', (25, 43))	('interaction', 'Interaction', (337, 348))	('cancers', 'Phenotype', 'HP:0002664', (3, 10))	('TGF-beta', 'Gene', '7040;7043', (424, 432))	('cancers', 'Disease', (3, 10))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
192490	28587135	In vitro, alphav expression in the human nasopharyngeal cell line CNE-2 is upregulated in multi-cellular spheroids compared to standard culture conditions, and blocking alphav integrin signaling in the SAPK/JNK pathway increased the radiosensitivity of multi-cellular spheroids in vitro and in vivo.	('upregulated', 'PosReg', (75, 86))	('blocking', 'Var', (160, 168))	('JNK', 'Gene', (207, 210))	('CNE-2', 'CellLine', 'CVCL:6889', (66, 71))	('human', 'Species', '9606', (35, 40))	('alphav integrin signaling', 'MPA', (169, 194))	('JNK', 'Gene', '5599', (207, 210))	('alphav', 'Protein', (10, 16))	('radiosensitivity', 'CPA', (233, 249))	('increased', 'PosReg', (219, 228))
192491	28587135	Downregulation of the alphav integrin subunit by an antisense oligonucleotide has also been shown to inhibit the proliferation of laryngeal carcinoma cells and enhance their apoptosis.	('laryngeal carcinoma', 'Disease', (130, 149))	('oligonucleotide', 'Chemical', 'MESH:D009841', (62, 77))	('inhibit', 'NegReg', (101, 108))	('antisense oligonucleotide', 'Var', (52, 77))	('Downregulation', 'NegReg', (0, 14))	('laryngeal carcinoma', 'Disease', 'MESH:D007827', (130, 149))	('laryngeal carcinoma', 'Phenotype', 'HP:0012118', (130, 149))	('apoptosis', 'CPA', (174, 183))	('enhance', 'PosReg', (160, 167))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))	('proliferation', 'CPA', (113, 126))	('alphav integrin subunit', 'Protein', (22, 45))
192501	28587135	Transduction of an alphav-negative human SCC line (H357) with retroviral vectors encoding alphav integrins showed that alphavbeta5-expressing cells showed enhanced apoptosis (anoikis) and suppression of AKT activity, whereas alphav-negative cells and cells expressing alphavbeta6 did not.	('SCC', 'Gene', (41, 44))	('SCC', 'Phenotype', 'HP:0002860', (41, 44))	('AKT', 'Gene', (203, 206))	('H357', 'CellLine', 'CVCL:2462', (51, 55))	('human', 'Species', '9606', (35, 40))	('SCC', 'Gene', '6317', (41, 44))	('alphavbeta5-expressing', 'Var', (119, 141))	('enhanced', 'PosReg', (155, 163))	('apoptosis', 'CPA', (164, 173))	('suppression', 'NegReg', (188, 199))	('AKT', 'Gene', '207', (203, 206))
192525	28587135	However, inhibitors targeting both the alphav subunit, and alphavbeta3 have been shown to increase the effectiveness of radiotherapy which may be a valuable strategy in HNSCC given the importance of radiotherapy in its treatment.	('SCC', 'Gene', (171, 174))	('SCC', 'Phenotype', 'HP:0002860', (171, 174))	('alphav subunit', 'Protein', (39, 53))	('increase', 'PosReg', (90, 98))	('beta3', 'Gene', (65, 70))	('SCC', 'Gene', '6317', (171, 174))	('radiotherapy', 'CPA', (120, 132))	('effectiveness', 'MPA', (103, 116))	('beta3', 'Gene', '1934', (65, 70))	('inhibitors', 'Var', (9, 19))
192535	28587135	Cells expressing beta6 acquired a fibroblast-like morphology, increased expression of the mesenchymal marker vimentin, and reduced expression of the epithelial markers keratin and E-cadherin, whereas cells expressing a truncated form of beta6 lacking the C-terminus kept their epithelial morphology and did not change vimentin or E-cadherin expression.	('E-cadherin', 'Gene', '999', (180, 190))	('increased', 'PosReg', (62, 71))	('E-cadherin', 'Gene', '999', (330, 340))	('fibroblast-like morphology', 'CPA', (34, 60))	('vimentin', 'Gene', '7431', (318, 326))	('beta6', 'Var', (17, 22))	('expression', 'MPA', (72, 82))	('expression', 'MPA', (131, 141))	('keratin', 'Protein', (168, 175))	('vimentin', 'Gene', '7431', (109, 117))	('vimentin', 'Gene', (109, 117))	('vimentin', 'Gene', (318, 326))	('epithelial', 'MPA', (277, 287))	('E-cadherin', 'Gene', (330, 340))	('reduced', 'NegReg', (123, 130))	('E-cadherin', 'Gene', (180, 190))
192555	28587135	Expression of beta1 enhanced oral SCC cell motility by activating the ERK pathway, and its knockdown reduced the migration activity of OEC-M1 cells and ERK phosphorylation.	('ERK', 'Gene', '2048', (70, 73))	('ERK', 'Gene', '2048', (152, 155))	('SCC', 'Gene', (34, 37))	('enhanced', 'PosReg', (20, 28))	('ERK', 'Gene', (70, 73))	('beta1', 'Gene', '3779', (14, 19))	('SCC', 'Phenotype', 'HP:0002860', (34, 37))	('ERK', 'Gene', (152, 155))	('OEC-M1', 'CellLine', 'CVCL:6782', (135, 141))	('knockdown', 'Var', (91, 100))	('activating', 'PosReg', (55, 65))	('SCC', 'Gene', '6317', (34, 37))	('reduced', 'NegReg', (101, 108))	('beta1', 'Gene', (14, 19))	('migration activity', 'CPA', (113, 131))	('phosphorylation', 'MPA', (156, 171))
192557	28587135	Moreover, targeting beta1 integrin with an inhibitory antibody increased sensitivity to ionizing radiation and delayed the growth of HNSCC cell lines in 3D cultures and in xenografted mice, and has been shown to act by impairing repair of radiation-induced DNA double-strand breaks.	('impairing', 'NegReg', (219, 228))	('beta1 integrin', 'Gene', (20, 34))	('increased', 'PosReg', (63, 72))	('increased sensitivity to ionizing radiation', 'Phenotype', 'HP:0011133', (63, 106))	('sensitivity to ionizing radiation', 'MPA', (73, 106))	('repair', 'MPA', (229, 235))	('delayed', 'NegReg', (111, 118))	('SCC', 'Gene', (135, 138))	('targeting', 'Var', (10, 19))	('SCC', 'Phenotype', 'HP:0002860', (135, 138))	('mice', 'Species', '10090', (184, 188))	('beta1 integrin', 'Gene', '3688', (20, 34))	('SCC', 'Gene', '6317', (135, 138))
192565	28587135	Inhibition of alpha3 had the most significant effect in decreasing clonogenic cell survival, promoting apoptosis and enhancing radiosensitivity, while blocking the beta1 and alpha3 subunits resulted in increased cytotoxicity and radiosensitization compared to alpha3 integrin blocking alone.	('blocking', 'NegReg', (151, 159))	('increased', 'PosReg', (202, 211))	('radiosensitization', 'CPA', (229, 247))	('alpha3', 'Protein', (14, 20))	('clonogenic cell survival', 'CPA', (67, 91))	('promoting', 'PosReg', (93, 102))	('cytotoxicity', 'Disease', (212, 224))	('beta1 and alpha', 'Gene', '3779', (164, 179))	('enhancing', 'PosReg', (117, 126))	('decreasing', 'NegReg', (56, 66))	('Inhibition', 'Var', (0, 10))	('apoptosis', 'CPA', (103, 112))	('cytotoxicity', 'Disease', 'MESH:D064420', (212, 224))	('radiosensitivity', 'MPA', (127, 143))
192603	28587135	The observations that inhibiting alphav, alphavbeta3, or beta1 increases sensitivity to irradiation is particularly significant for HNSCC as it suggests integrin-targeted therapy could be used as part of a chemoradiotherapy strategy for high risk disease.	('beta1', 'Gene', '3779', (57, 62))	('increases', 'PosReg', (63, 72))	('SCC', 'Phenotype', 'HP:0002860', (134, 137))	('SCC', 'Gene', '6317', (134, 137))	('beta1', 'Gene', (57, 62))	('beta3', 'Gene', '1934', (47, 52))	('increases sensitivity to irradiation', 'Phenotype', 'HP:0011133', (63, 99))	('inhibiting', 'Var', (22, 32))	('sensitivity to irradiation', 'MPA', (73, 99))	('beta3', 'Gene', (47, 52))	('alphav', 'Protein', (33, 39))	('SCC', 'Gene', (134, 137))
192627	33614513	Due to the critical role of DPP4 in immunometabolism, our results indicate that pharmacological inhibition of DPP4 might provide beneficial therapeutic effects for SARS-CoV-2 treatment together with other strategies in specific tumor patients.	('DPP4', 'Gene', '1803', (110, 114))	('DPP4', 'Gene', '1803', (28, 32))	('tumor', 'Disease', 'MESH:D009369', (228, 233))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('patients', 'Species', '9606', (234, 242))	('DPP4', 'Gene', (28, 32))	('tumor', 'Disease', (228, 233))	('DPP4', 'Gene', (110, 114))	('beneficial', 'PosReg', (129, 139))	('pharmacological', 'Var', (80, 95))	('SARS-CoV-2', 'Species', '2697049', (164, 174))
192631	33614513	Cancer patients with defective immunity are especially susceptible to SARS-CoV-2 infection.	('defective immunity', 'Var', (21, 39))	('SARS-CoV-2 infection', 'Disease', 'MESH:C000657245', (70, 90))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('SARS-CoV-2 infection', 'Disease', (70, 90))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('susceptible', 'Reg', (55, 66))	('patients', 'Species', '9606', (7, 15))
192642	33614513	Additional DPP4 residues (Q286, I287, N338, V341, and R336) were also predicted to interact with the S1 domain of the spike protein of SARS-CoV-2.	('SARS-CoV-2', 'Species', '2697049', (135, 145))	('Q286', 'Var', (26, 30))	('interact', 'Interaction', (83, 91))	('I287', 'Var', (32, 36))	('DPP4', 'Gene', '1803', (11, 15))	('spike', 'Gene', (118, 123))	('V341', 'Var', (44, 48))	('N338', 'Var', (38, 42))	('spike', 'Gene', '43740568', (118, 123))	('DPP4', 'Gene', (11, 15))	('R336', 'Var', (54, 58))
192714	33614513	The results showed that DPP4 expression significantly correlated with infiltration of CD8+ T cells ( Figure 5A ), CD4+ T cells ( Figure 5B ), Treg ( Figure 5C ), B cells ( Figure 5D ), NK cells ( Figure 5E ), dendritic cells ( Figure 5F ), neutrophils ( Figure 5G ), macrophages ( Figure 5H ), monocytes ( Figure 5I ), and cancer-associated fibroblasts ( Figure 5J ) in pan-cancer patients.	('cancer', 'Disease', 'MESH:D009369', (323, 329))	('correlated with', 'Reg', (54, 69))	('infiltration', 'CPA', (70, 82))	('expression', 'Var', (29, 39))	('DPP4', 'Gene', '1803', (24, 28))	('cancer', 'Phenotype', 'HP:0002664', (374, 380))	('cancer', 'Disease', (323, 329))	('CD4', 'Gene', (114, 117))	('CD8', 'Gene', (86, 89))	('cancer', 'Disease', (374, 380))	('cancer', 'Disease', 'MESH:D009369', (374, 380))	('DPP4', 'Gene', (24, 28))	('patients', 'Species', '9606', (381, 389))	('CD4', 'Gene', '920', (114, 117))	('CD8', 'Gene', '925', (86, 89))	('cancer', 'Phenotype', 'HP:0002664', (323, 329))
192733	33614513	Taken together, these data suggested that expression of DPP4 may be closely associated with immune infiltration in specific cancers patients, which might also contribute to the cytokine storm in SARS-CoV-2 infected patients.	('immune infiltration', 'Disease', (92, 111))	('patients', 'Species', '9606', (215, 223))	('SARS-CoV-2 infected', 'Disease', 'MESH:C000657245', (195, 214))	('cytokine storm', 'MPA', (177, 191))	('DPP4', 'Gene', '1803', (56, 60))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('associated', 'Reg', (76, 86))	('expression', 'Var', (42, 52))	('cancers', 'Phenotype', 'HP:0002664', (124, 131))	('contribute', 'Reg', (159, 169))	('DPP4', 'Gene', (56, 60))	('cancers', 'Disease', (124, 131))	('patients', 'Species', '9606', (132, 140))	('cancers', 'Disease', 'MESH:D009369', (124, 131))	('SARS-CoV-2 infected', 'Disease', (195, 214))
192751	33614513	High DPP4 expression indicated a poor prognosis in some specific cancer types, including LUSC, bladder cancer, prostate adenocarcinoma, and brain lower grade glioma, and we found that the unique cancer LUSC was associated with DPP4 expression and prognosis ( Figure 3 ,  Supplementary Table 1 ).	('glioma', 'Phenotype', 'HP:0009733', (158, 164))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('DPP4', 'Gene', '1803', (5, 9))	('cancer', 'Disease', (103, 109))	('expression', 'MPA', (232, 242))	('cancer', 'Disease', (65, 71))	('LUSC', 'Phenotype', 'HP:0030359', (89, 93))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('High', 'Var', (0, 4))	('DPP4', 'Gene', '1803', (227, 231))	('expression', 'MPA', (10, 20))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('bladder cancer', 'Disease', 'MESH:D001749', (95, 109))	('bladder cancer', 'Disease', (95, 109))	('DPP4', 'Gene', (5, 9))	('bladder cancer', 'Phenotype', 'HP:0009725', (95, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('cancer', 'Disease', (195, 201))	('prostate adenocarcinoma', 'Disease', (111, 134))	('glioma', 'Disease', (158, 164))	('DPP4', 'Gene', (227, 231))	('associated', 'Reg', (211, 221))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('LUSC', 'Phenotype', 'HP:0030359', (202, 206))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('glioma', 'Disease', 'MESH:D005910', (158, 164))	('prostate adenocarcinoma', 'Disease', 'MESH:D011471', (111, 134))	('LUSC', 'Disease', (89, 93))
192774	33614513	DPP4 inhibitors such as sitagliptin, saxagliptin, and vildagliptin are now in clinical use as antidiabetic drugs and act by prolonging the insulinotropic effect of incretins through glucagonlike peptide-1 and the glucose-dependent insulinotropic polypeptide signaling pathway.	('DPP4', 'Gene', '1803', (0, 4))	('saxagliptin', 'Chemical', 'MESH:C502994', (37, 48))	('prolonging', 'PosReg', (124, 134))	('sitagliptin', 'Chemical', 'MESH:D000068900', (24, 35))	('insulinotropic effect', 'MPA', (139, 160))	('DPP4', 'Gene', (0, 4))	('inhibitors', 'Var', (5, 15))	('vildagliptin', 'Chemical', 'MESH:D000077597', (54, 66))	('glucagonlike peptide-1', 'Gene', '2641', (182, 204))	('glucagonlike peptide-1', 'Gene', (182, 204))	('glucose-dependent insulinotropic polypeptide', 'Gene', '2695', (213, 257))	('glucose-dependent insulinotropic polypeptide', 'Gene', (213, 257))
192775	33614513	Recent preclinical studies have further expanded the repertoire for the use of DPP4 inhibitors in the treatment of other metabolic diseases and their consequent complications, which may block the signaling pathway of DPP4 with NFkappaB and matrix metallopeptidase 9 in these patients.	('inhibitors', 'Var', (84, 94))	('DPP4', 'Gene', '1803', (79, 83))	('metabolic diseases', 'Disease', (121, 139))	('block', 'NegReg', (186, 191))	('matrix metallopeptidase 9', 'Gene', (240, 265))	('DPP4', 'Gene', (217, 221))	('metabolic diseases', 'Disease', 'MESH:D008659', (121, 139))	('NFkappaB', 'Gene', (227, 235))	('DPP4', 'Gene', (79, 83))	('patients', 'Species', '9606', (275, 283))	('signaling pathway', 'Pathway', (196, 213))	('NFkappaB', 'Gene', '4790', (227, 235))	('matrix metallopeptidase 9', 'Gene', '4318', (240, 265))	('DPP4', 'Gene', '1803', (217, 221))
192777	33614513	Furthermore, inhibition of DPP4 reveals IL-33-dependent eosinophil-mediated control of tumor growth.	('IL-33', 'Gene', (40, 45))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('inhibition', 'Var', (13, 23))	('tumor', 'Disease', (87, 92))	('IL-33', 'Gene', '90865', (40, 45))	('DPP4', 'Gene', (27, 31))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('DPP4', 'Gene', '1803', (27, 31))
192785	33614513	As a potential receptor for SARS-CoV-2, DPP4 inhibitors might exhibit beneficial therapeutic effects on SARS-CoV-2 treatment together with other effective strategies ( Figure 8 ).	('DPP4', 'Gene', (40, 44))	('beneficial', 'PosReg', (70, 80))	('SARS-CoV-2', 'Disease', (104, 114))	('SARS-CoV-2', 'Species', '2697049', (104, 114))	('DPP4', 'Gene', '1803', (40, 44))	('inhibitors', 'Var', (45, 55))	('SARS-CoV-2', 'Species', '2697049', (28, 38))
192786	33614513	Animal experiments and clinical trials should be conducted in the future to evaluate whether DPP4 inhibitors have therapeutic potential in preventing or alleviating SARS-CoV-2 infection in obese or specific cancer patients.	('alleviating', 'NegReg', (153, 164))	('cancer', 'Disease', 'MESH:D009369', (207, 213))	('patients', 'Species', '9606', (214, 222))	('SARS-CoV-2 infection', 'Disease', (165, 185))	('cancer', 'Disease', (207, 213))	('inhibitors', 'Var', (98, 108))	('DPP4', 'Gene', '1803', (93, 97))	('obese', 'Disease', 'MESH:D009765', (189, 194))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('obese', 'Disease', (189, 194))	('DPP4', 'Gene', (93, 97))	('SARS-CoV-2 infection', 'Disease', 'MESH:C000657245', (165, 185))
192798	33544704	New approaches in treating cancer have evolved since the discovery of specific small molecules that selectively inhibit cell survival, proliferation, and migration in intricate pathways of mutated cancer cells.	('cell survival', 'CPA', (120, 133))	('mutated', 'Var', (189, 196))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('cancer', 'Disease', 'MESH:D009369', (197, 203))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('cancer', 'Disease', (197, 203))	('inhibit', 'NegReg', (112, 119))	('proliferation', 'CPA', (135, 148))	('cancer', 'Disease', (27, 33))	('cancer', 'Disease', 'MESH:D009369', (27, 33))	('migration', 'CPA', (154, 163))
192802	33544704	STAT3 signaling is derived from the Janus Kinase/STAT pathway and it is activated by the assembly of growth factors and cytokines in cell's surface receptors through tyrosine phosphorylation.	('tyrosine', 'Chemical', 'MESH:D014443', (166, 174))	('STAT3 signaling', 'MPA', (0, 15))	('tyrosine phosphorylation', 'Var', (166, 190))	('activated', 'PosReg', (72, 81))	('Janus', 'Pathway', (36, 41))
192819	33544704	Mutations on p53 tumor suppressor gene, loss of phosphatase and tensin homolog (PTEN), retinoblastoma (RB1) gene, and STAT3 signaling alterations have been found in dogs and humans diagnosed with osteosarcoma.	('STAT3 signaling alterations', 'MPA', (118, 145))	('osteosarcoma', 'Phenotype', 'HP:0002669', (196, 208))	('osteosarcoma', 'Disease', (196, 208))	('tumor', 'Disease', (17, 22))	('PTEN', 'Gene', (80, 84))	('osteosarcoma', 'Disease', 'MESH:D012516', (196, 208))	('dogs', 'Species', '9615', (165, 169))	('retinoblastoma', 'Phenotype', 'HP:0009919', (87, 101))	('loss', 'NegReg', (40, 44))	('retinoblastoma (RB1', 'Gene', '476915', (87, 106))	('humans', 'Species', '9606', (174, 180))	('phosphatase and tensin homolog', 'Gene', '403832', (48, 78))	('Mutations', 'Var', (0, 9))	('sarcoma', 'Phenotype', 'HP:0100242', (201, 208))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('p53', 'Gene', (13, 16))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
192820	33544704	Similar to osteosarcoma, malignant canine mammary tumors and human breast cancer share similar epidemiology and disease behavior showing breaking point cluster region 1 (BRCA1) mutations and susceptibility to steroid hormones.	('osteosarcoma', 'Phenotype', 'HP:0002669', (11, 23))	('mutations', 'Var', (177, 186))	('BRCA1', 'Gene', '672', (170, 175))	('sarcoma', 'Phenotype', 'HP:0100242', (16, 23))	('BRCA1', 'Gene', (170, 175))	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('canine', 'Species', '9615', (35, 41))	('breast cancer', 'Phenotype', 'HP:0003002', (67, 80))	('osteosarcoma', 'Disease', (11, 23))	('osteosarcoma', 'Disease', 'MESH:D012516', (11, 23))	('breast cancer', 'Disease', 'MESH:D001943', (67, 80))	('human', 'Species', '9606', (61, 66))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('breast cancer', 'Disease', (67, 80))	('steroid', 'Chemical', 'MESH:D013256', (209, 216))	('breaking point', 'Phenotype', 'HP:0001061', (137, 151))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumors', 'Disease', (50, 56))
192823	33544704	Women6 and intact female dogs have a higher risk to develop mammary and skin cancer which are within the fifth most common types of cancer in both species.	('cancer', 'Disease', (132, 138))	('dogs', 'Species', '9615', (25, 29))	('skin cancer', 'Disease', 'MESH:D012878', (72, 83))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('skin cancer', 'Phenotype', 'HP:0008069', (72, 83))	('develop', 'PosReg', (52, 59))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('skin cancer', 'Disease', (72, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('mammary', 'Disease', (60, 67))	('Women6', 'Var', (0, 6))	('cancer', 'Disease', 'MESH:D009369', (132, 138))
192826	33544704	Mutations of PTEN and c-kit are found in both human and dog melanoma.	('dog', 'Species', '9615', (56, 59))	('melanoma', 'Disease', 'MESH:D008545', (60, 68))	('melanoma', 'Phenotype', 'HP:0002861', (60, 68))	('c-kit', 'Gene', (22, 27))	('melanoma', 'Disease', (60, 68))	('Mutations', 'Var', (0, 9))	('human', 'Species', '9606', (46, 51))	('PTEN', 'Gene', (13, 17))	('c-kit', 'Gene', '3815', (22, 27))
192828	33544704	This in vitro experiment was designed to establish the timely response of CT drug efficacy alone and combined with single drugs (MLN9708, SH4-54, HO-3867, lapatinib ditosylate, PX-478, paclitaxel, gefitinib, gemcitabine, capecitabine, metformin and cisplatin) in various human and canine cancer cell lines.	('metformin', 'Chemical', 'MESH:D008687', (235, 244))	('gefitinib', 'Chemical', 'MESH:D000077156', (197, 206))	('gemcitabine', 'Chemical', 'MESH:C056507', (208, 219))	('cancer', 'Disease', 'MESH:D009369', (288, 294))	('human', 'Species', '9606', (271, 276))	('PX-478', 'Chemical', 'MESH:C492908', (177, 183))	('lapatinib ditosylate', 'Chemical', 'MESH:D000077341', (155, 175))	('cancer', 'Disease', (288, 294))	('HO-3867', 'Chemical', 'MESH:C541427', (146, 153))	('capecitabine', 'Chemical', 'MESH:D000069287', (221, 233))	('cisplatin', 'Chemical', 'MESH:D002945', (249, 258))	('CT', 'Chemical', 'MESH:C037886', (74, 76))	('canine', 'Species', '9615', (281, 287))	('MLN9708', 'Var', (129, 136))	('paclitaxel', 'Chemical', 'MESH:D017239', (185, 195))	('cancer', 'Phenotype', 'HP:0002664', (288, 294))
192832	33544704	Twelve drugs with different concentrations were used in drug-screening analyses including, Cryptotanshinone 20 muM (STAT3 inhibitor), HO-3867 10 muM (selective STAT3 inhibitors), SH-4-54 5 muM (STAT3/STAT5 inhibitor), Paclitaxel 0.1 muM (microtubule polymer stabilizer), Gefitinib 10 muM (EGFR inhibitor), PX-478 25 muM (hypoxia-inducible factor-1alpha inhibitor), Lapatinib Ditosylate 5 muM (EGFR and ErbB2 inhibitor), MLN9708 10 muM (chymotrypsin-like proteolytic beta5 inhibitor), Metformin 10 mM (mTOR inhibitor), Capecitabine 50 muM (fluoropyrimidine carbamate), Cisplatin 40 muM, and Gemcitabine 2 muM (DNA synthesis inhibitors).	('STAT5', 'Gene', '6776', (200, 205))	('hypoxia', 'Disease', 'MESH:D000860', (321, 328))	('EGFR', 'Gene', (289, 293))	('ErbB2', 'Gene', (402, 407))	('EGFR', 'Gene', (393, 397))	('STAT5', 'Gene', (200, 205))	('HO-3867', 'Chemical', 'MESH:C541427', (134, 141))	('Metformin', 'Chemical', 'MESH:D008687', (484, 493))	('Lapatinib Ditosylate', 'Chemical', 'MESH:D000077341', (365, 385))	('Gefitinib', 'Chemical', 'MESH:D000077156', (271, 280))	('PX-478', 'Chemical', 'MESH:C492908', (306, 312))	('EGFR', 'Gene', '1956', (289, 293))	('Cisplatin', 'Chemical', 'MESH:D002945', (568, 577))	('Cryptotanshinone', 'Chemical', 'MESH:C037886', (91, 107))	('MLN9708 10 muM', 'Var', (420, 434))	('EGFR', 'Gene', '1956', (393, 397))	('PX-478', 'Var', (306, 312))	('ErbB2', 'Gene', '2064', (402, 407))	('hypoxia', 'Disease', (321, 328))	('SH-4-54', 'Var', (179, 186))
192835	33544704	A plate composed by human pancreatic cancer cell lines included five pancreatic carcinomas (PANC1, MIA Paca-2, HS 766T, PANC1 TD2, P4057), two pancreatic adenocarcinomas (HPAF-II, AsPC1), and one pancreatic ductal adenocarcinoma (PL45).	('MIA Paca', 'CellLine', 'CVCL:0428', (99, 107))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (196, 228))	('PANC1', 'CellLine', 'CVCL:0480', (92, 97))	('pancreatic adenocarcinomas', 'Disease', 'MESH:D000230', (143, 169))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('carcinoma', 'Phenotype', 'HP:0030731', (159, 168))	('carcinomas', 'Phenotype', 'HP:0030731', (159, 169))	('pancreatic adenocarcinomas', 'Phenotype', 'HP:0006725', (143, 169))	('carcinomas', 'Phenotype', 'HP:0030731', (80, 90))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (26, 43))	('pancreatic adenocarcinomas', 'Disease', (143, 169))	('pancreatic carcinomas', 'Disease', (69, 90))	('pancreatic carcinomas', 'Disease', 'MESH:D010190', (69, 90))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (196, 228))	('carcinoma', 'Phenotype', 'HP:0030731', (219, 228))	('pancreatic cancer', 'Disease', 'MESH:D010190', (26, 43))	('human', 'Species', '9606', (20, 25))	('PANC1', 'CellLine', 'CVCL:0480', (120, 125))	('P4057', 'Var', (131, 136))	('pancreatic ductal adenocarcinoma', 'Disease', (196, 228))	('pancreatic cancer', 'Disease', (26, 43))	('AsPC1', 'CellLine', 'CVCL:0152', (180, 185))
192845	33544704	The imaging media (IM) contained: 70% M-199 (11825015), 30% RPMI-1640 (11875085) supplemented with 10% FBS (16000044), 20 mM Hepes (15630080), 14 mM Glutamax (35050061), 7 mM of sodium pyruvate (11360070), 1% Penicillin-Streptomycin (15240062), 0.7 g of glucose (A2494001), 0.5 muM Vybrant  Dye-Cycle  Violet Stain (V35003) and, CellTox   Green Cytotoxicity Assay (G8742) at 1:5,000 dilution.	('11360070', 'Var', (195, 203))	('Cytotoxicity', 'Disease', 'MESH:D064420', (345, 357))	('15630080', 'Var', (132, 140))	('35050061', 'Var', (159, 167))	('15240062', 'Var', (234, 242))	('glucose', 'Chemical', 'MESH:D005947', (254, 261))	('Cytotoxicity', 'Disease', (345, 357))	('11875085', 'Var', (71, 79))	('A2494001', 'Var', (263, 271))
192848	33544704	Preceding the experiment, subconfluently grown cancer cells were dissociated using TrypLETM Select enzyme (12563029) and resuspended in IM media to establish the number of cells per milliliter in an automated cell counter (C10227).	('IM media', 'Chemical', '-', (136, 144))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('cancer', 'Disease', (47, 53))	('12563029', 'Var', (107, 115))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))
192857	33544704	The single drugs and their concentrations used in this experiment included: Cryptotanshinone 20 muM (STAT3 inhibitor), HO-3867 10 muM (selective STAT3 inhibitors), Paclitaxel 0.1 muM (microtubule polymer stabilizer), Gefitinib 10 muM (EGFR inhibitor), PX-478 25 muM (hypoxia-inducible factor-1alpha inhibitor), Lapatinib Ditosylate 5 muM (EGFR and ErbB2 inhibitor), MLN9708 10 muM (chymotrypsin-like proteolytic beta5 inhibitor), Metformin 10 mM (mTOR inhibitor), Capecitabine 50 muM (fluoropyrimidine carbamate), Cisplatin 40 muM, and Gemcitabine 2 muM (DNA synthesis inhibitors).	('EGFR', 'Gene', (339, 343))	('Cisplatin', 'Chemical', 'MESH:D002945', (514, 523))	('hypoxia', 'Disease', 'MESH:D000860', (267, 274))	('Gefitinib', 'Chemical', 'MESH:D000077156', (217, 226))	('Lapatinib Ditosylate', 'Chemical', 'MESH:D000077341', (311, 331))	('HO-3867', 'Chemical', 'MESH:C541427', (119, 126))	('Metformin', 'Chemical', 'MESH:D008687', (430, 439))	('PX-478', 'Chemical', 'MESH:C492908', (252, 258))	('MLN9708 10 muM', 'Var', (366, 380))	('EGFR', 'Gene', '1956', (235, 239))	('EGFR', 'Gene', '1956', (339, 343))	('ErbB2', 'Gene', '2064', (348, 353))	('Cryptotanshinone', 'Chemical', 'MESH:C037886', (76, 92))	('Paclitaxel', 'Var', (164, 174))	('hypoxia', 'Disease', (267, 274))	('HO-3867', 'Var', (119, 126))	('EGFR', 'Gene', (235, 239))	('PX-478 25 muM', 'Var', (252, 265))	('ErbB2', 'Gene', (348, 353))
192858	33544704	In addition, Cryptotanshinone at 20 muM concentration was paired with the following single drugs and their respective concentrations: HO-3867 10 muM, PX-478 25 muM were added to all types of cancer; Gefitinib 10 muM and Gemcitabine 2 muM (human pancreatic cancer), Paclitaxel 0.1 muM (breast and canine mammary cancer), Cisplatin 40 muM (human and canine osteosarcoma and human fibrosarcoma), Lapatinib Ditosylate 5 muM (human and canine melanoma, human glioblastoma), MLN9708 10 muM (human glioblastoma and human squamous cell carcinoma), Metformin 10 mM (human lung cancer), and Capecitabine 50 muM (human colorectal and human hepatocellular cancer).	('melanoma', 'Phenotype', 'HP:0002861', (438, 446))	('melanoma', 'Disease', (438, 446))	('lung cancer', 'Disease', (563, 574))	('sarcoma', 'Phenotype', 'HP:0100242', (360, 367))	('cancer', 'Disease', (311, 317))	('colorectal', 'Disease', 'MESH:D015179', (608, 618))	('cancer', 'Disease', (256, 262))	('fibrosarcoma', 'Disease', (378, 390))	('human', 'Species', '9606', (557, 562))	('osteosarcoma', 'Disease', (355, 367))	('PX-478', 'Chemical', 'MESH:C492908', (150, 156))	('pancreatic cancer', 'Disease', (245, 262))	('cancer', 'Phenotype', 'HP:0002664', (256, 262))	('osteosarcoma', 'Disease', 'MESH:D012516', (355, 367))	('MLN9708', 'Var', (469, 476))	('HO-3867', 'Chemical', 'MESH:C541427', (134, 141))	('human', 'Species', '9606', (239, 244))	('canine', 'Species', '9615', (296, 302))	('cancer', 'Phenotype', 'HP:0002664', (311, 317))	('cancer', 'Disease', 'MESH:D009369', (568, 574))	('cancer', 'Disease', (191, 197))	('Cryptotanshinone', 'Chemical', 'MESH:C037886', (13, 29))	('human', 'Species', '9606', (508, 513))	('human', 'Species', '9606', (372, 377))	('canine', 'Species', '9615', (431, 437))	('Metformin', 'Chemical', 'MESH:D008687', (540, 549))	('cancer', 'Disease', (644, 650))	('human', 'Species', '9606', (485, 490))	('human', 'Species', '9606', (602, 607))	('Gefitinib', 'Chemical', 'MESH:D000077156', (199, 208))	('glioblastoma', 'Disease', 'MESH:D005909', (454, 466))	('lung cancer', 'Disease', 'MESH:D008175', (563, 574))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (514, 537))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('cancer', 'Phenotype', 'HP:0002664', (644, 650))	('Lapatinib Ditosylate', 'Chemical', 'MESH:D000077341', (393, 413))	('human', 'Species', '9606', (421, 426))	('lung cancer', 'Phenotype', 'HP:0100526', (563, 574))	('glioblastoma', 'Phenotype', 'HP:0012174', (491, 503))	('cancer', 'Disease', 'MESH:D009369', (256, 262))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (245, 262))	('cancer', 'Disease', 'MESH:D009369', (311, 317))	('melanoma', 'Disease', 'MESH:D008545', (438, 446))	('osteosarcoma', 'Phenotype', 'HP:0002669', (355, 367))	('glioblastoma', 'Disease', (454, 466))	('glioblastoma', 'Disease', 'MESH:D005909', (491, 503))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (514, 537))	('colorectal', 'Disease', (608, 618))	('glioblastoma', 'Phenotype', 'HP:0012174', (454, 466))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (378, 390))	('cancer', 'Disease', (568, 574))	('Cisplatin', 'Chemical', 'MESH:D002945', (320, 329))	('human', 'Species', '9606', (448, 453))	('cancer', 'Disease', 'MESH:D009369', (191, 197))	('canine', 'Species', '9615', (348, 354))	('cancer', 'Disease', 'MESH:D009369', (644, 650))	('cancer', 'Phenotype', 'HP:0002664', (568, 574))	('human', 'Species', '9606', (338, 343))	('sarcoma', 'Phenotype', 'HP:0100242', (383, 390))	('glioblastoma', 'Disease', (491, 503))	('pancreatic cancer', 'Disease', 'MESH:D010190', (245, 262))	('human', 'Species', '9606', (623, 628))	('fibrosarcoma', 'Disease', 'MESH:D005354', (378, 390))	('carcinoma', 'Phenotype', 'HP:0030731', (528, 537))	('squamous cell carcinoma', 'Disease', (514, 537))	('hepatocellular cancer', 'Phenotype', 'HP:0001402', (629, 650))
192859	33544704	Other drug combinations included: MLN9708 10 muM plus SH-4-54 5 muM (STAT3/STAT5 inhibitor), Gemcitabine 2 muM plus HO-3867 10 muM, HO-3867 10 muM plus Placlitaxel 0.1 muM, HO-3867 10 muM plus Cisplatin 40 muM, HO-3867 plus Lapatinib Ditosylate 5 muM, HO-3867 10 muM plus Metformin 10 mM, and HO-3867 10 muM plus Capecitabine 50 muM.	('Metformin', 'Chemical', 'MESH:D008687', (272, 281))	('HO-3867', 'Var', (252, 259))	('Cisplatin', 'Chemical', 'MESH:D002945', (193, 202))	('HO-3867', 'Chemical', 'MESH:C541427', (173, 180))	('HO-3867', 'Chemical', 'MESH:C541427', (293, 300))	('HO-3867', 'Chemical', 'MESH:C541427', (132, 139))	('STAT5', 'Gene', '6776', (75, 80))	('HO-3867', 'Chemical', 'MESH:C541427', (211, 218))	('HO-3867', 'Chemical', 'MESH:C541427', (252, 259))	('Lapatinib Ditosylate', 'Chemical', 'MESH:D000077341', (224, 244))	('STAT5', 'Gene', (75, 80))	('MLN9708 10 muM', 'Var', (34, 48))	('HO-3867', 'Chemical', 'MESH:C541427', (116, 123))
192861	33544704	The composition of drugs delivered in triplicates included: Cryptotanshinone at 20 muM concentration in all combinations plus possible groupings of two other drugs including, HO-3867 10 muM, MLN9708 10 muM, Lapatinib Ditosylate 5 muM, SH-4-54 5 muM, Cisplatin 40 muM and PX-478 25 muM.	('Lapatinib Ditosylate', 'Chemical', 'MESH:D000077341', (207, 227))	('Cryptotanshinone', 'Chemical', 'MESH:C037886', (60, 76))	('MLN9708 10 muM', 'Var', (191, 205))	('Cisplatin', 'Var', (250, 259))	('Cisplatin', 'Chemical', 'MESH:D002945', (250, 259))	('PX-478', 'Chemical', 'MESH:C492908', (271, 277))	('SH-4-54 5 muM', 'Var', (235, 248))	('HO-3867', 'Chemical', 'MESH:C541427', (175, 182))
192875	33544704	Results acquired in our laboratory from several live cancer-cell imaging data found that CT at 20 muM was effective to induce complete cell death in several cancer cell types (Fig 1).	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('CT at 20 muM', 'Var', (89, 101))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('cancer', 'Disease', (157, 163))	('CT', 'Chemical', 'MESH:C037886', (89, 91))
192891	33544704	Human melanoma cells treated with CT and selected drug combinations showed 98% to 100% apoptosis, and canine melanoma cell lines had 92% to 100% percentage of apoptosis.	('Human', 'Species', '9606', (0, 5))	('melanoma', 'Disease', 'MESH:D008545', (109, 117))	('melanoma', 'Phenotype', 'HP:0002861', (109, 117))	('combinations', 'Var', (55, 67))	('melanoma', 'Disease', (109, 117))	('CT', 'Chemical', 'MESH:C037886', (34, 36))	('canine', 'Species', '9615', (102, 108))	('melanoma', 'Phenotype', 'HP:0002861', (6, 14))	('melanoma', 'Disease', (6, 14))	('melanoma', 'Disease', 'MESH:D008545', (6, 14))
192909	33544704	Moreover, CT in combination with other single drugs including, HO-3867, MLN9708 or paired drugs such as, MLN9708 plus SH-4-54, HO-3867 plus SH-4-54, HO-3867 plus Lapatinib, and HO-3867 plus Gefitinib or PX-478 produced synergistic effects observed by further decreasing cell death time in different types of cancer.	('CT', 'Chemical', 'MESH:C037886', (10, 12))	('decreasing', 'NegReg', (259, 269))	('MLN9708', 'Var', (72, 79))	('HO-3867', 'Chemical', 'MESH:C541427', (63, 70))	('HO-3867', 'Chemical', 'MESH:C541427', (149, 156))	('cancer', 'Disease', 'MESH:D009369', (308, 314))	('Lapatinib', 'Chemical', 'MESH:D000077341', (162, 171))	('cancer', 'Phenotype', 'HP:0002664', (308, 314))	('cancer', 'Disease', (308, 314))	('HO-3867 plus Gefitinib', 'Disease', (177, 199))	('HO-3867', 'Chemical', 'MESH:C541427', (177, 184))	('cell death time', 'CPA', (270, 285))	('PX-478', 'Chemical', 'MESH:C492908', (203, 209))	('HO-3867 plus Gefitinib', 'Disease', 'MESH:D007625', (177, 199))	('MLN9708', 'Var', (105, 112))	('HO-3867', 'Chemical', 'MESH:C541427', (127, 134))
192953	33544704	Although RAS mutations in canine melanoma have not been frequently found in spontaneous disease, human and canine melanoma cells in the present study showed a similar response to CT and drug combinations.	('melanoma', 'Disease', 'MESH:D008545', (114, 122))	('melanoma', 'Phenotype', 'HP:0002861', (33, 41))	('melanoma', 'Disease', (33, 41))	('human', 'Species', '9606', (97, 102))	('canine', 'Species', '9615', (26, 32))	('melanoma', 'Disease', 'MESH:D008545', (33, 41))	('mutations', 'Var', (13, 22))	('canine', 'Species', '9615', (107, 113))	('melanoma', 'Phenotype', 'HP:0002861', (114, 122))	('CT', 'Chemical', 'MESH:C037886', (179, 181))	('melanoma', 'Disease', (114, 122))
193028	32457351	The individuality of the TE series ESCC cell lines was confirmed by a short tandem repeat analysis at RIKEN and at the Cell Resource Center for Biomedical Research, Institute of Development, Aging and Cancer, Tohoku University (Sendai, Japan).	('TE', 'Chemical', 'MESH:D013691', (25, 27))	('Cancer', 'Disease', 'MESH:D009369', (201, 207))	('short tandem repeat analysis', 'Var', (70, 98))	('Cancer', 'Phenotype', 'HP:0002664', (201, 207))	('Cancer', 'Disease', (201, 207))
193035	32457351	We named the TAM-like macrophages polarized by TE-8CM, TE-9CM, and TE-15CM as, respectively, TAM8, TAM9, and TAM15 cells.	('TE-15CM', 'Var', (67, 74))	('TAM', 'Chemical', '-', (109, 112))	('TAM', 'Chemical', '-', (13, 16))	('TAM', 'Chemical', '-', (99, 102))	('TE-8CM', 'Var', (47, 53))	('TE', 'Chemical', 'MESH:D013691', (55, 57))	('TAM8', 'Chemical', '-', (93, 97))	('TAM', 'Chemical', '-', (93, 96))	('TE', 'Chemical', 'MESH:D013691', (67, 69))	('TE', 'Chemical', 'MESH:D013691', (47, 49))	('TE-9CM', 'Var', (55, 61))
193037	32457351	The inhibitors against PI3K (LY294002, #9901) and MEK (PD98059, #9900) were purchased from Cell Signaling Technology (Danvers, MA).	('MEK', 'Enzyme', (50, 53))	('LY294002', 'Chemical', 'MESH:C085911', (29, 37))	('PI3K', 'Pathway', (23, 27))	('PD98059', 'Var', (55, 62))	('LY294002', 'Var', (29, 37))	('PD98059', 'Chemical', 'MESH:C093973', (55, 62))
193039	32457351	For the CCR5 knockdown by siRNA, 5 x 105 TE-8, TE-9, and TE-15 cells on 60 mm dishes were transfected by 20 nM siRNA against CCR5 (siCCR5, #sc-35062; Santa Cruz Biotechnology) using Lipofectamine  RNAiMAX (Invitrogen) for 2 days.	('TE', 'Chemical', 'MESH:D013691', (41, 43))	('TE', 'Chemical', 'MESH:D013691', (57, 59))	('CCR5', 'Gene', (8, 12))	('knockdown', 'Var', (13, 22))	('TE', 'Chemical', 'MESH:D013691', (47, 49))
193044	32457351	A quantitative RT-PCR was performed using the following probes: CCL3 (Hs00234142_m1), MMP2 (Hs01548727_m1), MMP9 (Hs00234579_m1), VEGFA (Hs00900054_m1), and GAPDH (Hs02786624_g1) (Applied Biosystems, Foster City, CA) on an ABI StepOne Real-time PCR system (Applied Biosystems) using TaqMan Gene Expression Master Mix (Applied Biosystems).	('Hs01548727_m1', 'Var', (92, 105))	('Hs00234579_m1', 'Var', (114, 127))	('Hs00900054_m1', 'Var', (137, 150))	('Hs02786624_g1', 'Var', (164, 177))	('GAPDH', 'Gene', '2597', (157, 162))	('Hs00234142_m1', 'Var', (70, 83))	('GAPDH', 'Gene', (157, 162))
193051	32457351	Rabbit polyclonal antibody against CCR1 (1:250, #ab1681; Abcam, Cambridge, UK), mouse monoclonal antibody against CCR5 (1:100, #sc-32304; Santa Cruz Biotechnology), rabbit polyclonal antibody against CCL3 (1:100, #LS-C384561; LifeSpan BioSciences, Seattle, WA), and the following rabbit monoclonal antibodies (all from Cell Signaling Technology): phosphorylated Akt (Ser473; 1:250, #4060), phosphorylated Akt (Thr308; 1:250, #2965), total Akt (1:500, #9272), phosphorylated ERK1/2 (Thr202/Tyr204; 1:250, #9101), total ERK1/2 (1:500, #9102), and beta-actin (1:1000, #4970).	('ERK1/2', 'Gene', '26417;26413', (474, 480))	('ERK1/2', 'Gene', (474, 480))	('beta-actin', 'Protein', (545, 555))	('1:500', 'Var', (526, 531))	('Thr202/Tyr204; 1:250', 'Var', (482, 502))	('ERK1/2', 'Gene', '26417;26413', (518, 524))	('mouse', 'Species', '10090', (80, 85))	('Ser473', 'Chemical', '-', (367, 373))	('ERK1/2', 'Gene', (518, 524))	('Thr308', 'Chemical', '-', (410, 416))
193052	32457351	The secondary antibodies were horseradish peroxidase (HRP)-linked donkey anti-rabbit IgG (1:1000, #NA934V) and HRP-linked sheep anti-mouse IgG (1:1000, #NA931V), both were purchased from GE Healthcare Life Sciences (Little Chalfont, UK).	('1:1000', 'Var', (90, 96))	('mouse', 'Species', '10090', (133, 138))	('1:1000', 'Var', (144, 150))	('horseradish', 'Species', '3704', (30, 41))
193053	32457351	For the IF examination, 1 x 105 cultured cells on coverslips were fixed with methanol for 10 min at -20  C and incubated with primary antibodies against CCR5 (1:25, #sc-32304; Santa Cruz Biotechnology), CCL3 (1:100, #LS-C384561; LifeSpan BioSciences), and CD204 (1:100, #SRA-E5; TransGenic, Kobe, Japan) at 4  C overnight.	('SRA', 'Gene', '4481', (271, 274))	('1:100', 'Var', (263, 268))	('CD204', 'Gene', '4481', (256, 261))	('CD204', 'Gene', (256, 261))	('methanol', 'Chemical', 'MESH:D000432', (77, 85))	('SRA', 'Gene', (271, 274))	('1:25', 'Var', (159, 163))	('CCR5', 'Gene', (153, 157))
193058	32457351	Next, 20 microM LY294002, 20 microM PD98059, or 20 microg/ml Maraviroc was added to the upper chambers, and the neutralizing antibody against CCL3 (400 ng/ml) was added to the lower chambers.	('LY294002', 'Chemical', 'MESH:C085911', (16, 24))	('PD98059', 'Chemical', 'MESH:C093973', (36, 43))	('LY294002', 'Var', (16, 24))	('Maraviroc', 'Chemical', 'MESH:D000077592', (61, 70))	('PD98059', 'Var', (36, 43))
193069	32457351	The primary antibodies were CCL3 (1:200, #LS-C384561; LifeSpan BioSciences), CCR5 (1:25, #sc-32304; Santa Cruz Biotechnology), CD68 (1:100, #Kp-1; Dako), CD163 (1:100, #10D6; Novocastra, Newcastle upon Tyne, UK), CD204 (1:50, #SRA-E5; TransGenic), and CD34 (1:50, #NU-4A1, Nichirei, Tokyo, Japan).	('CD163', 'Gene', '9332', (154, 159))	('1:25', 'Var', (83, 87))	('CD163', 'Gene', (154, 159))	('SRA', 'Gene', '4481', (227, 230))	('CD34', 'Gene', (252, 256))	('CD34', 'Gene', '947', (252, 256))	('CD204', 'Gene', (213, 218))	('CD204', 'Gene', '4481', (213, 218))	('CD68', 'Gene', (127, 131))	('CD68', 'Gene', '968', (127, 131))	('SRA', 'Gene', (227, 230))
193075	32457351	Compared with the CCL3 mRNA expression level in the PBMo-derived TAM-like macrophages (1.0 +- 0.0-folds), the expression levels were significantly higher in the PBMo-derived TAM-like macrophages polarized by TE-8CM (TAM8 cells, 1.7 +- 0.1-fold, p = 0.002), TE-9CM (TAM9 cells, 1.6 +- 0.1-fold, p = 0.018), and TE-15CM (TAM15 cells, 2.5 +- 0.2-fold, p = 0.002) (Fig.	('TE-15CM', 'Var', (310, 317))	('TAM8', 'Chemical', '-', (216, 220))	('TE-8CM', 'Var', (208, 214))	('TE', 'Chemical', 'MESH:D013691', (257, 259))	('TAM', 'Chemical', '-', (319, 322))	('expression levels', 'MPA', (110, 127))	('TE', 'Chemical', 'MESH:D013691', (310, 312))	('TE', 'Chemical', 'MESH:D013691', (208, 210))	('TAM', 'Chemical', '-', (65, 68))	('TAM', 'Chemical', '-', (216, 219))	('TAM', 'Chemical', '-', (174, 177))	('higher', 'PosReg', (147, 153))	('TAM', 'Chemical', '-', (265, 268))	('TE-9CM', 'Var', (257, 263))
193081	32457351	The expression levels of CCR1 in TE-8 (1.3 +- 0.1-fold, p = 0.017), TE-9 (1.4 +- 0.1-fold, p = 0.010), and TE-15 cells (1.3 +- 0.0-fold, p = 0.008) were also significantly higher than that in the Het-1A cells (1.0 +- 0.0-fold), but relatively much lower than the CCR5 expression levels in the three ESCC cell lines (Fig.	('expression levels', 'MPA', (4, 21))	('TE', 'Chemical', 'MESH:D013691', (68, 70))	('TE', 'Chemical', 'MESH:D013691', (107, 109))	('lower', 'NegReg', (248, 253))	('CCR1', 'Gene', (25, 29))	('higher', 'PosReg', (172, 178))	('TE-9', 'Var', (68, 72))	('TE', 'Chemical', 'MESH:D013691', (33, 35))
193089	32457351	The western blotting revealed that the phosphorylations of Akt and ERK at 10 min after rhCCL3 treatment were suppressed by the CCR5 knockdown in TE-8, TE-9, and TE-15 (Figs.	('suppressed', 'NegReg', (109, 119))	('TE', 'Chemical', 'MESH:D013691', (161, 163))	('Akt', 'Pathway', (59, 62))	('knockdown', 'Var', (132, 141))	('TE', 'Chemical', 'MESH:D013691', (151, 153))	('TE', 'Chemical', 'MESH:D013691', (145, 147))	('rhCCL3', 'Chemical', '-', (87, 93))	('phosphorylations', 'MPA', (39, 55))	('ERK', 'Pathway', (67, 70))	('CCR5', 'Gene', (127, 131))
193090	32457351	Our findings first revealed that rhCCL3 significantly promoted the migration and invasion of TE-8 cells, and the migration and invasion were significantly suppressed by the inhibition of PI3K/Akt and MEK/ERK pathways using LY294002 and PD98059, respectively (Fig.	('promoted', 'PosReg', (54, 62))	('rhCCL3', 'Chemical', '-', (33, 39))	('inhibition', 'NegReg', (173, 183))	('LY294002', 'Var', (223, 231))	('PD98059', 'Chemical', 'MESH:C093973', (236, 243))	('invasion', 'CPA', (81, 89))	('invasion', 'CPA', (127, 135))	('suppressed', 'NegReg', (155, 165))	('migration', 'CPA', (67, 76))	('TE', 'Chemical', 'MESH:D013691', (93, 95))	('LY294002', 'Chemical', 'MESH:C085911', (223, 231))	('rhCCL3', 'Gene', (33, 39))	('PD98059', 'Var', (236, 243))	('MEK/ERK pathways', 'Pathway', (200, 216))
193091	32457351	Maraviroc and CCR5 knockdown were also effective for suppressing the rhCCL3-mediated migration and invasion (Fig.	('Maraviroc', 'Chemical', 'MESH:D000077592', (0, 9))	('CCR5', 'Gene', (14, 18))	('knockdown', 'Var', (19, 28))	('rhCCL3-mediated', 'Protein', (69, 84))	('invasion', 'CPA', (99, 107))	('rhCCL3', 'Chemical', '-', (69, 75))	('suppressing', 'NegReg', (53, 64))
193093	32457351	4d, e, i, j), and observed that TAM8 also significantly promoted the migration and invasion of TE-8 cells, and that the migration and invasion were significantly suppressed by Maraviroc and neutralizing antibody against CCL3.	('neutralizing', 'Var', (190, 202))	('Maraviroc', 'Chemical', 'MESH:D000077592', (176, 185))	('invasion', 'CPA', (134, 142))	('migration', 'CPA', (120, 129))	('TAM8', 'Chemical', '-', (32, 36))	('invasion of TE-8 cells', 'CPA', (83, 105))	('suppressed', 'NegReg', (162, 172))	('promoted', 'PosReg', (56, 64))	('TE', 'Chemical', 'MESH:D013691', (95, 97))	('migration', 'CPA', (69, 78))
193107	32457351	After observing that a CCL3-CCR5 axis promoted the migration and invasion of the three ESCC cell lines via PI3K/Akt and MEK/ERK pathways as described above, we investigated whether CCL3 upregulated the expressions of matrix metalloprotease-2 (MMP-2) and matrix metalloprotease-9 (MMP-9), which are well known to contribute to cell invasion by extracellular matrix remodeling in the tumor microenvironment.	('upregulated', 'PosReg', (186, 197))	('tumor', 'Phenotype', 'HP:0002664', (382, 387))	('matrix metalloprotease-2', 'Gene', (217, 241))	('MMP-2', 'Gene', (243, 248))	('migration', 'CPA', (51, 60))	('matrix metalloprotease-2', 'Gene', '4313', (217, 241))	('tumor', 'Disease', (382, 387))	('tumor', 'Disease', 'MESH:D009369', (382, 387))	('matrix metalloprotease-9', 'Gene', (254, 278))	('promoted', 'PosReg', (38, 46))	('MMP-9', 'Gene', '4318', (280, 285))	('MMP-2', 'Gene', '4313', (243, 248))	('invasion', 'CPA', (65, 73))	('matrix metalloprotease-9', 'Gene', '4318', (254, 278))	('MMP-9', 'Gene', (280, 285))	('CCL3', 'Var', (181, 185))
193112	32457351	Next, we investigated the MMP2, MMP9, and VEGFA mRNA expression levels after LY294002 or PD98059 treatment.	('LY294002', 'Chemical', 'MESH:C085911', (77, 85))	('PD98059', 'Var', (89, 96))	('LY294002', 'Var', (77, 85))	('PD98059', 'Chemical', 'MESH:C093973', (89, 96))
193113	32457351	TE-8 and TE-15 cells were treated with 100 ng/ml of rhCCL3 and 20 microM of LY294002 or PD98059 for the first 24 h, then they were treated with only rhCCL3 for the next 24 h. TE-9 cells were treated with 100 ng/ml of rhCCL3 and 20 microM of LY294002 or PD98059 for 48 h. The upregulated mRNA expression of MMP2 and VEGFA was suppressed by both LY294002 and PD98059 treatment (Fig.	('LY294002', 'Var', (344, 352))	('upregulated', 'PosReg', (275, 286))	('TE', 'Chemical', 'MESH:D013691', (9, 11))	('mRNA expression', 'MPA', (287, 302))	('TE', 'Chemical', 'MESH:D013691', (0, 2))	('TE', 'Chemical', 'MESH:D013691', (175, 177))	('suppressed', 'NegReg', (325, 335))	('VEGFA', 'Protein', (315, 320))	('LY294002', 'Chemical', 'MESH:C085911', (344, 352))	('rhCCL3', 'Chemical', '-', (149, 155))	('LY294002', 'Chemical', 'MESH:C085911', (76, 84))	('PD98059', 'Chemical', 'MESH:C093973', (88, 95))	('PD98059', 'Chemical', 'MESH:C093973', (357, 364))	('rhCCL3', 'Chemical', '-', (52, 58))	('MMP2', 'Protein', (306, 310))	('LY294002', 'Chemical', 'MESH:C085911', (241, 249))	('PD98059', 'Var', (357, 364))	('PD98059', 'Chemical', 'MESH:C093973', (253, 260))	('rhCCL3', 'Chemical', '-', (217, 223))
193114	32457351	In contrast, the MMP9 mRNA expression in TE-15 was upregulated by LY294002 or PD98059 with rhCCL3 treatment (Fig.	('PD98059', 'Chemical', 'MESH:C093973', (78, 85))	('rhCCL3', 'Chemical', '-', (91, 97))	('TE', 'Chemical', 'MESH:D013691', (41, 43))	('LY294002', 'Var', (66, 74))	('upregulated', 'PosReg', (51, 62))	('LY294002', 'Chemical', 'MESH:C085911', (66, 74))	('MMP9', 'Gene', (17, 21))	('PD98059', 'Var', (78, 85))
193120	32457351	A high expression of CCL3 did not significantly correlate with any of the clinicopathological factors, whereas a high expression of CCR5 was significantly correlated with deeper invasion (p = 0.016), presence of vascular invasion (p = 0.029), higher pathological stage (p = 0.041), higher numbers of infiltrating CD204+ TAMs (p = 0.006), and higher microvascular density (p = 0.006).	('higher pathological stage', 'CPA', (243, 268))	('correlated', 'Reg', (155, 165))	('high', 'Var', (113, 117))	('deeper invasion', 'CPA', (171, 186))	('higher', 'PosReg', (342, 348))	('microvascular density', 'CPA', (349, 370))	('TAMs', 'Chemical', '-', (320, 324))	('CCR5', 'Gene', (132, 136))	('CD204', 'Gene', '4481', (313, 318))	('CD204', 'Gene', (313, 318))	('vascular invasion', 'CPA', (212, 229))
193122	32457351	A high expression of CCL3 was significantly correlated with the patients' cause-specific survival (p = 0.041) (Fig.	('high', 'Var', (2, 6))	('CCL3', 'Gene', (21, 25))	('patients', 'Species', '9606', (64, 72))	('correlated', 'Reg', (44, 54))
193137	32457351	PDK1 phosphorylates Akt on Thr308, whereas mTORC2 phosphorylates Akt on Ser473.	('Ser473', 'Chemical', '-', (72, 78))	('mTORC2', 'Gene', (43, 49))	('mTORC2', 'Gene', '74343', (43, 49))	('Thr308', 'Chemical', '-', (27, 33))	('PDK1', 'Gene', '5163', (0, 4))	('PDK1', 'Gene', (0, 4))	('Thr308', 'Var', (27, 33))	('Akt', 'Pathway', (20, 23))
193151	32457351	All upregulated expressions of MMP2 and VEGFA after rhCCL3 treatment were suppressed by LY294002 and PD98059.	('LY294002', 'Chemical', 'MESH:C085911', (88, 96))	('suppressed', 'NegReg', (74, 84))	('PD98059', 'Chemical', 'MESH:C093973', (101, 108))	('MMP2', 'Protein', (31, 35))	('VEGFA', 'Protein', (40, 45))	('upregulated', 'PosReg', (4, 15))	('rhCCL3', 'Chemical', '-', (52, 58))	('LY294002', 'Var', (88, 96))	('PD98059', 'Var', (101, 108))	('expressions', 'MPA', (16, 27))
193153	32457351	In contrast, rhCCL3 treatment upregulated the MMP9 mRNA expression only in TE-15 cells, and paradoxically, the upregulated expression of MMP9 by rhCCL3 was further upregulated by LY294002 and PD98059.	('LY294002', 'Var', (179, 187))	('PD98059', 'Var', (192, 199))	('expression', 'MPA', (123, 133))	('upregulated', 'PosReg', (30, 41))	('upregulated', 'PosReg', (164, 175))	('rhCCL3', 'Gene', (145, 151))	('PD98059', 'Chemical', 'MESH:C093973', (192, 199))	('rhCCL3', 'Chemical', '-', (13, 19))	('LY294002', 'Chemical', 'MESH:C085911', (179, 187))	('MMP9', 'Gene', (46, 50))	('MMP9', 'Gene', (137, 141))	('TE', 'Chemical', 'MESH:D013691', (75, 77))	('mRNA expression', 'MPA', (51, 66))	('upregulated', 'PosReg', (111, 122))	('rhCCL3', 'Chemical', '-', (145, 151))
193154	32457351	CCL3-dependent MMP9 upregulation in ESCC cells may be not universal, and may occur via other signaling pathways, such as p38 MAPK, AMPK, or NF-kappaB, which were also reported to be activated downstream of CCL3-CCR5 axis.	('AMPK', 'Gene', (131, 135))	('AMPK', 'Gene', '5564', (131, 135))	('NF-kappaB', 'Gene', '4790', (140, 149))	('NF-kappaB', 'Gene', (140, 149))	('MMP9', 'Gene', (15, 19))	('upregulation', 'PosReg', (20, 32))	('p38', 'Var', (121, 124))
193155	32457351	The paradoxical MMP9 upregulation by LY294002 and PD98059 with rhCCL3 may be caused by the compensatory upregulation of other pathways due to Akt and ERK inhibition.	('upregulation', 'PosReg', (104, 116))	('PD98059', 'Chemical', 'MESH:C093973', (50, 57))	('ERK', 'Pathway', (150, 153))	('rhCCL3', 'Gene', (63, 69))	('LY294002', 'Chemical', 'MESH:C085911', (37, 45))	('Akt', 'Pathway', (142, 145))	('upregulation', 'PosReg', (21, 33))	('LY294002', 'Var', (37, 45))	('rhCCL3', 'Chemical', '-', (63, 69))	('MMP9', 'Gene', (16, 20))	('PD98059', 'Var', (50, 57))
193166	32457351	The clinicopathological association between high CCR5 expression and deeper invasion supports the findings of promoted cell invasion and upregulated MMP2 mRNA expression in the three ESCC cell lines by rhCCL3 treatment.	('expression', 'MPA', (54, 64))	('high', 'Var', (44, 48))	('cell invasion', 'CPA', (119, 132))	('upregulated', 'PosReg', (137, 148))	('CCR5', 'Gene', (49, 53))	('deeper invasion', 'CPA', (69, 84))	('rhCCL3', 'Chemical', '-', (202, 208))	('promoted', 'PosReg', (110, 118))	('MMP2 mRNA', 'Gene', (149, 158))
193167	32457351	In addition, the clinicopathological association between high CCR5 expression and presence of vascular invasion or higher microvascular density supports our observation of upregulated VEGFA mRNA expression in the ESCC cell lines following the rhCCL3 treatment.	('VEGFA', 'Protein', (184, 189))	('expression', 'MPA', (195, 205))	('high', 'Var', (57, 61))	('vascular invasion', 'CPA', (94, 111))	('rhCCL3', 'Chemical', '-', (243, 249))	('upregulated', 'PosReg', (172, 183))	('CCR5', 'Gene', (62, 66))	('expression', 'MPA', (67, 77))
193169	32457351	In oral squamous cell carcinoma, the mean survival rate for patients with high numbers of CCL3-positive cells in the tumor parenchyma was shorter than that of the patients with low numbers of CCL3-positive cells, although not significantly.	('survival', 'MPA', (42, 50))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('patients', 'Species', '9606', (163, 171))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (3, 31))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (8, 31))	('tumor', 'Disease', (117, 122))	('patients', 'Species', '9606', (60, 68))	('shorter', 'NegReg', (138, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('oral squamous cell carcinoma', 'Disease', (3, 31))	('CCL3-positive', 'Gene', (90, 103))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('high numbers', 'Var', (74, 86))
193173	32457351	Moreover, high expression of both CCL3 and CCR5 in the human ESCC tissue was significantly associated with poor overall, disease-free and cause-specific survivals.	('ESCC', 'Disease', (61, 65))	('human', 'Species', '9606', (55, 60))	('disease-free', 'CPA', (121, 133))	('expression', 'MPA', (15, 25))	('high', 'Var', (10, 14))	('CCL3', 'Gene', (34, 38))	('poor', 'NegReg', (107, 111))	('CCR5', 'Gene', (43, 47))	('associated', 'Reg', (91, 101))
193177	32457351	Many other types of CCR5 antagonists and inhibitors such as Vicriviroc, TAK-779, Met-CCL5 (Met-RANTES), OTR4120, OTR4131, anibamine, and DT-13 were also reported to inhibit the cell migration, invasion and/or metastasis of various malignancies including breast cancer, gastric cancer, pancreatic cancer and hepatocellular carcinoma in preclinical studies.	('OTR4120', 'Chemical', 'MESH:C533322', (104, 111))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (307, 331))	('breast cancer', 'Disease', 'MESH:D001943', (254, 267))	('cancer', 'Phenotype', 'HP:0002664', (296, 302))	('breast cancer', 'Disease', (254, 267))	('pancreatic cancer', 'Disease', 'MESH:D010190', (285, 302))	('inhibitors', 'Var', (41, 51))	('malignancies', 'Disease', 'MESH:D009369', (231, 243))	('Met-CCL5', 'Var', (81, 89))	('invasion', 'CPA', (193, 201))	('malignancies', 'Disease', (231, 243))	('gastric cancer', 'Disease', (269, 283))	('anibamine', 'Chemical', 'MESH:C488244', (122, 131))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (307, 331))	('pancreatic cancer', 'Disease', (285, 302))	('cell migration', 'CPA', (177, 191))	('DT-13', 'Chemical', '-', (137, 142))	('inhibit', 'NegReg', (165, 172))	('cancer', 'Phenotype', 'HP:0002664', (277, 283))	('RANTES', 'Gene', (95, 101))	('gastric cancer', 'Disease', 'MESH:D013274', (269, 283))	('RANTES', 'Gene', '6352', (95, 101))	('hepatocellular carcinoma', 'Disease', (307, 331))	('cancer', 'Phenotype', 'HP:0002664', (261, 267))	('carcinoma', 'Phenotype', 'HP:0030731', (322, 331))	('OTR4120', 'Var', (104, 111))	('metastasis', 'CPA', (209, 219))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (285, 302))	('OTR4131', 'Var', (113, 120))	('gastric cancer', 'Phenotype', 'HP:0012126', (269, 283))	('breast cancer', 'Phenotype', 'HP:0003002', (254, 267))	('TAK-779', 'Gene', (72, 79))	('OTR4131', 'Chemical', 'MESH:C542264', (113, 120))	('Vicriviroc', 'Chemical', 'MESH:C486781', (60, 70))	('TAK-779', 'Chemical', 'MESH:C119369', (72, 79))
193232	32441221	Similarly, the decreased expression of SEMA3F in 4 ESCC cell lines (Eca109, EC9706, KYSE70, and TE1) was demonstrated when compared to the normal cell line HET1A (all P < .01, Figure 1B).	('KYSE70', 'Var', (84, 90))	('EC9706', 'Var', (76, 82))	('expression', 'MPA', (25, 35))	('HET1A', 'CellLine', 'CVCL:3702', (156, 161))	('EC9706', 'CellLine', 'CVCL:E307', (76, 82))	('SEMA3F', 'Gene', (39, 45))	('decreased', 'NegReg', (15, 24))	('SEMA3F', 'Gene', '6405', (39, 45))
193246	32441221	The curves shown in Figure 4 revealed that patients having ESCC with low SEMA3F expression had shorter survival time compared with those with high SEMA3F expression (log-rank P = .007).	('SEMA3F', 'Gene', (147, 153))	('patients', 'Species', '9606', (43, 51))	('SEMA3F', 'Gene', '6405', (147, 153))	('SEMA3F', 'Gene', (73, 79))	('ESCC', 'Disease', (59, 63))	('SEMA3F', 'Gene', '6405', (73, 79))	('survival time', 'CPA', (103, 116))	('low', 'Var', (69, 72))	('shorter', 'NegReg', (95, 102))
193254	32441221	The functional experiment results indicated that knockdown of VEGF-C expression inhibited cell proliferation, migration, and invasion of Eca109 and TE1 cells (All P < .05, Figure 6C-H).	('knockdown', 'Var', (49, 58))	('VEGF-C', 'Gene', (62, 68))	('migration', 'CPA', (110, 119))	('cell proliferation', 'CPA', (90, 108))	('VEGF-C', 'Gene', '7424', (62, 68))	('inhibited', 'NegReg', (80, 89))
193266	32441221	Overexpression of NRP2 has been detected in various human cancers, and its promoting effect on cancer pathogenesis has also been reported.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('human', 'Species', '9606', (52, 57))	('cancer', 'Disease', (95, 101))	('NRP2', 'Gene', (18, 22))	('detected', 'Reg', (32, 40))	('cancers', 'Disease', (58, 65))	('cancers', 'Phenotype', 'HP:0002664', (58, 65))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('cancers', 'Disease', 'MESH:D009369', (58, 65))	('NRP2', 'Gene', '8828', (18, 22))	('Overexpression', 'Var', (0, 14))	('cancer', 'Disease', (58, 64))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('promoting effect', 'PosReg', (75, 91))
193319	31168300	Aberrant glycosylation is observed in many types of cancers, and glycan-based biomarker discovery has advanced significantly recently.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('cancers', 'Disease', (52, 59))	('Aberrant', 'Var', (0, 8))	('Aberrant glycosylation', 'Phenotype', 'HP:0012345', (0, 22))	('glycan', 'Chemical', 'MESH:D011134', (65, 71))	('observed', 'Reg', (26, 34))	('cancers', 'Phenotype', 'HP:0002664', (52, 59))	('glycosylation', 'MPA', (9, 22))	('cancers', 'Disease', 'MESH:D009369', (52, 59))
193323	31168300	Aberrant glycosylation changes in the serum glycome could provide promising biomarkers for NSCLC.	('NSCLC', 'Disease', 'MESH:D002289', (91, 96))	('Aberrant', 'Var', (0, 8))	('NSCLC', 'Phenotype', 'HP:0030358', (91, 96))	('Aberrant glycosylation', 'Phenotype', 'HP:0012345', (0, 22))	('glycosylation changes', 'MPA', (9, 30))	('Aberrant glycosylation changes', 'Phenotype', 'HP:0012345', (0, 30))	('NSCLC', 'Disease', (91, 96))
193332	31168300	Their cancer-free status was confirmed by testing for plasma levels of tumor biomarkers, including CEA, NSE, CYFRA21-1, SCCA, ProGRP, AFP, ferritin, PSA, CA-125, CA 15-3, CA 19-9 and CA 72-4, as well as computed tomography examination.	('PSA', 'Gene', (149, 152))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('CEA', 'Gene', (99, 102))	('cancer', 'Disease', 'MESH:D009369', (6, 12))	('SCC', 'Phenotype', 'HP:0002860', (120, 123))	('ProGRP', 'Gene', (126, 132))	('CYFRA21-1', 'Var', (109, 118))	('PSA', 'Gene', '354', (149, 152))	('SCC', 'Gene', '6317', (120, 123))	('CEA', 'Gene', '1048', (99, 102))	('ProGRP', 'Gene', '2922', (126, 132))	('CA-125, CA 15-3, CA 19-9 and CA 72-4', 'Gene', '94025;4582', (154, 190))	('tumor', 'Disease', (71, 76))	('cancer', 'Disease', (6, 12))	('SCC', 'Gene', (120, 123))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('ferritin', 'Protein', (139, 147))	('NSE', 'Gene', '2026', (104, 107))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('AFP', 'Gene', (134, 137))	('AFP', 'Gene', '174', (134, 137))	('NSE', 'Gene', (104, 107))
193358	31168300	the Fucalpha1-6GlcNAc (core fucose) binder AAL, the GlcNAc and alphaGal binder GSL-I, and the terminal GalNAc binder SBA, showed significantly increased NFIs in Stage I/II, Stage III and Stage IV adenocarcinoma groups.	('Stage III', 'Disease', (173, 182))	('increased', 'PosReg', (143, 152))	('GlcNAc', 'Chemical', 'MESH:D000117', (52, 58))	('fucose', 'Chemical', 'MESH:D005643', (28, 34))	('IV adenocarcinoma', 'Disease', 'MESH:D000230', (193, 210))	('Fucalpha1-6GlcNAc', 'Chemical', '-', (4, 21))	('NFIs', 'MPA', (153, 157))	('SBA', 'Chemical', '-', (117, 120))	('N', 'Chemical', 'MESH:D009584', (106, 107))	('Stage I/II', 'Disease', (161, 171))	('GalNAc', 'Chemical', 'MESH:C086195', (103, 109))	('N', 'Chemical', 'MESH:D009584', (18, 19))	('N', 'Chemical', 'MESH:D009584', (153, 154))	('Fucalpha1-6GlcNAc', 'Var', (4, 21))	('IV adenocarcinoma', 'Disease', (193, 210))	('carcinoma', 'Phenotype', 'HP:0030731', (201, 210))	('GSL-I', 'Chemical', '-', (79, 84))	('GlcNAc', 'Chemical', 'MESH:D000117', (15, 21))	('N', 'Chemical', 'MESH:D009584', (55, 56))
193373	31168300	Protein modifications, which occur as translational, post-translational, regulatory, and/or degradation products, play important roles in biological processes and increase the amount of useful cancer-related information obtained from the proteins.	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('increase', 'PosReg', (163, 171))	('cancer', 'Disease', (193, 199))	('modifications', 'Var', (8, 21))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))
193376	31168300	Aberrant glycosylation of serum proteins has been found in patients with various types of cancer, including breast, colon, ovarian, and pancreatic cancer.	('breast, colon, ovarian', 'Disease', 'MESH:D061325', (108, 130))	('glycosylation', 'MPA', (9, 22))	('pancreatic cancer', 'Disease', 'MESH:D010190', (136, 153))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('Aberrant', 'Var', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('serum proteins', 'Protein', (26, 40))	('Aberrant glycosylation', 'Phenotype', 'HP:0012345', (0, 22))	('found', 'Reg', (50, 55))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (136, 153))	('patients', 'Species', '9606', (59, 67))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('cancer', 'Disease', (147, 153))	('cancer', 'Disease', (90, 96))	('pancreatic cancer', 'Disease', (136, 153))
193440	26291056	We recently demonstrated that suppressing the expression of BIRC3 through the genetic silencing or the pharmacological inhibition of TAK1 markedly reverted the intrinsic chemoresistance of pancreatic cancer.	('pancreatic cancer', 'Disease', (189, 206))	('pancreatic cancer', 'Disease', 'MESH:D010190', (189, 206))	('suppressing', 'NegReg', (30, 41))	('reverted', 'NegReg', (147, 155))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('genetic silencing', 'Var', (78, 95))	('BIRC3', 'Gene', (60, 65))	('intrinsic chemoresistance', 'CPA', (160, 185))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (189, 206))	('TAK1', 'Gene', '6885', (133, 137))	('expression', 'MPA', (46, 56))	('BIRC3', 'Gene', '330', (60, 65))	('TAK1', 'Gene', (133, 137))
193445	26291056	AsPC-1shTAK1 cells stably expressing small hairpin RNA sequences to knockdown the expression of TAK1 has been previously described in.	('AsPC-1shTAK1', 'Gene', (0, 12))	('expression', 'MPA', (82, 92))	('TAK1', 'Gene', (96, 100))	('TAK1', 'Gene', '6885', (8, 12))	('knockdown', 'Var', (68, 77))	('AsPC-1shTAK1', 'Gene', '6885', (0, 12))	('TAK1', 'Gene', (8, 12))	('TAK1', 'Gene', '6885', (96, 100))
193463	26291056	To verify that the inhibition of TAK1 could modulate the expression of BIRC3 in oesophageal adenocarcinoma, we used the selective TAK1 inhibitor (5Z)-7-oxozeaenol, and we demonstrated that the inhibition of TAK1 markedly suppressed the expression of BIRC3 within 24 h of treatment in both FLO-1 and KYAE-1 distal oesophageal adenocarcinoma cell lines (Figure 1B and C).	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('FLO-1', 'Chemical', '-', (289, 294))	('oesophageal adenocarcinoma', 'Disease', 'MESH:D005764', (80, 106))	('modulate', 'Reg', (44, 52))	('(5Z)-7-oxozeaenol', 'Chemical', 'MESH:C403563', (145, 162))	('BIRC3', 'Gene', (250, 255))	('BIRC3', 'Gene', '330', (71, 76))	('inhibition', 'Var', (193, 203))	('oesophageal adenocarcinoma', 'Disease', (313, 339))	('suppressed', 'NegReg', (221, 231))	('oesophageal adenocarcinoma', 'Disease', 'MESH:D005764', (313, 339))	('men', 'Species', '9606', (276, 279))	('BIRC3', 'Gene', (71, 76))	('BIRC3', 'Gene', '330', (250, 255))	('TAK1', 'Gene', '6885', (130, 134))	('expression', 'MPA', (236, 246))	('TAK1', 'Gene', (130, 134))	('carcinoma', 'Phenotype', 'HP:0030731', (330, 339))	('TAK1', 'Gene', '6885', (207, 211))	('TAK1', 'Gene', '6885', (33, 37))	('TAK1', 'Gene', (207, 211))	('TAK1', 'Gene', (33, 37))	('oesophageal adenocarcinoma', 'Disease', (80, 106))	('KYAE-1', 'CellLine', 'CVCL:1825', (299, 305))
193485	26291056	The main obstacle to the clinical efficacy of chemo- and radiotherapy is the pre-existence of or the development of cellular drug resistance, a feature that appears to be closely connected to alterations in key pathways involved in cell cycle checkpoint control and, most importantly, apoptosis.	('men', 'Species', '9606', (108, 111))	('drug resistance', 'Phenotype', 'HP:0020174', (125, 140))	('connected', 'Reg', (179, 188))	('cellular drug resistance', 'MPA', (116, 140))	('alterations', 'Var', (192, 203))
193511	32508265	The expression of damage-specific DNA binding protein, cyclin-dependent kinase 1, and cell cycle checkpoint kinase 2 was detected in cells transfected with Si-USP53.	('cyclin-dependent kinase 1', 'Gene', (55, 80))	('cyclin-dependent kinase 1', 'Gene', '983', (55, 80))	('DNA binding protein', 'Gene', (34, 53))	('detected', 'Reg', (121, 129))	('DNA binding protein', 'Gene', '7335', (34, 53))	('expression', 'MPA', (4, 14))	('Si-USP53', 'Var', (156, 164))
193522	32508265	Kazmierczak et al showed that mutation of the gene encoding USP53 results in progressive hearing loss in the mouse.	('hearing loss', 'Disease', 'MESH:D034381', (89, 101))	('progressive hearing loss', 'Phenotype', 'HP:0001730', (77, 101))	('hearing loss', 'Phenotype', 'HP:0000365', (89, 101))	('mutation', 'Var', (30, 38))	('hearing loss', 'Disease', (89, 101))	('USP53', 'Gene', (60, 65))	('mouse', 'Species', '10090', (109, 114))
193523	32508265	Wenbin et al indicated that deregulation of USP53 in colorectal cancer is suggestive of poor prognosis.	('deregulation', 'Var', (28, 40))	('colorectal cancer', 'Disease', 'MESH:D015179', (53, 70))	('colorectal cancer', 'Phenotype', 'HP:0003003', (53, 70))	('USP53', 'Gene', (44, 49))	('colorectal cancer', 'Disease', (53, 70))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
193525	32508265	Zou et al showed that knockdown of DDB2 expression in human lung cancer cells decreases the G2 phase and the repair efficiency of homologous recombination to increase the sensitivity of lung cancer cells to radiotherapy.	('human', 'Species', '9606', (54, 59))	('sensitivity', 'MPA', (171, 182))	('lung cancer', 'Disease', (60, 71))	('lung cancer', 'Phenotype', 'HP:0100526', (60, 71))	('lung cancer', 'Disease', 'MESH:D008175', (186, 197))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('lung cancer', 'Disease', 'MESH:D008175', (60, 71))	('repair', 'MPA', (109, 115))	('knockdown', 'Var', (22, 31))	('DDB2', 'Gene', '1643', (35, 39))	('G2 phase', 'CPA', (92, 100))	('decreases', 'NegReg', (78, 87))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('lung cancer', 'Disease', (186, 197))	('lung cancer', 'Phenotype', 'HP:0100526', (186, 197))	('increase', 'PosReg', (158, 166))	('DDB2', 'Gene', (35, 39))
193549	32508265	We showed that knockdown of USP53 downregulated the mRNA and protein expression of DDB2 (Figure 4A, Figure 4B).	('knockdown', 'Var', (15, 24))	('downregulated', 'NegReg', (34, 47))	('DDB2', 'Gene', '1643', (83, 87))	('DDB2', 'Gene', (83, 87))	('USP53', 'Gene', (28, 33))
193551	32508265	Therefore, reversing ubiquitination does not stabilize DDB2 but reduces the expression of DDB2.	('reversing', 'Var', (11, 20))	('ubiquitination', 'MPA', (21, 35))	('DDB2', 'Gene', '1643', (55, 59))	('DDB2', 'Gene', '1643', (90, 94))	('expression', 'MPA', (76, 86))	('DDB2', 'Gene', (55, 59))	('DDB2', 'Gene', (90, 94))	('reduces', 'NegReg', (64, 71))
193553	32508265	In the Si-USP53 group, the expression of DDB2 was inhibited after radiation (Figure 4A), thus reducing the ability to repair DNA and increasing the sensitivity to radiation.	('Si-USP53', 'Var', (7, 15))	('DDB2', 'Gene', '1643', (41, 45))	('sensitivity to radiation', 'Phenotype', 'HP:0011133', (148, 172))	('increasing', 'PosReg', (133, 143))	('sensitivity to radiation', 'MPA', (148, 172))	('expression', 'MPA', (27, 37))	('DDB2', 'Gene', (41, 45))	('reducing', 'NegReg', (94, 102))	('ability', 'MPA', (107, 114))
193554	32508265	The levels of CDK1 (Figure 5B) and CHK2 (Figure 5A) in the CON +8 Gy group and the Si-USP53+ 8 Gy group increased after radiation treatment, indicating that knockdown of USP53/DDB2 may cause cell cycle arrest at the G2/M phase by regulating G2/M phase -associated proteins, thereby affecting the sensitivity of cells to radiation Radiotherapy is beneficial in the treatment of cervical cancer and is one of the main treatment methods for patients with cervical cancer; however, radiotherapy resistance is associated with poor prognosis in cervical cancer.	('regulating', 'Reg', (230, 240))	('cancer', 'Disease', (461, 467))	('CHK2', 'Gene', (35, 39))	('cancer', 'Disease', 'MESH:D009369', (386, 392))	('cancer', 'Phenotype', 'HP:0002664', (461, 467))	('cancer', 'Disease', (548, 554))	('affecting', 'Reg', (282, 291))	('cell cycle', 'CPA', (191, 201))	('cancer', 'Phenotype', 'HP:0002664', (548, 554))	('CHK2', 'Gene', '11200', (35, 39))	('arrest', 'Disease', (202, 208))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (191, 208))	('cancer', 'Disease', 'MESH:D009369', (461, 467))	('Rad', 'Gene', '6236', (330, 333))	('Rad', 'Gene', (330, 333))	('patients', 'Species', '9606', (438, 446))	('cancer', 'Disease', (386, 392))	('cause', 'Reg', (185, 190))	('G2/M', 'Protein', (241, 245))	('DDB2', 'Gene', '1643', (176, 180))	('cancer', 'Disease', 'MESH:D009369', (548, 554))	('knockdown', 'Var', (157, 166))	('CDK1', 'Gene', '983', (14, 18))	('cancer', 'Phenotype', 'HP:0002664', (386, 392))	('CDK1', 'Gene', (14, 18))	('DDB2', 'Gene', (176, 180))	('arrest', 'Disease', 'MESH:D006323', (202, 208))
193555	32508265	The reasons for radiotherapy resistance include DNA repair enhancement, cell cycle arrest, and gene variation.	('cell cycle arrest', 'Phenotype', 'HP:0011018', (72, 89))	('gene variation', 'Var', (95, 109))	('arrest', 'Disease', 'MESH:D006323', (83, 89))	('arrest', 'Disease', (83, 89))	('DNA', 'MPA', (48, 51))	('enhancement', 'PosReg', (59, 70))
193559	32508265	Therefore, we performed cell experiments to verify that the expression of USP53 was positively correlated with the expression of DDB2, and the results suggested that USP53 regulates the expression of DDB2 and the sensitivity to radiotherapy.	('DDB2', 'Gene', (129, 133))	('regulates', 'Reg', (172, 181))	('DDB2', 'Gene', '1643', (200, 204))	('expression', 'MPA', (186, 196))	('DDB2', 'Gene', '1643', (129, 133))	('USP53', 'Var', (166, 171))	('DDB2', 'Gene', (200, 204))
193561	32508265	Studies have suggested that when tumor cells undergo cell cycle arrest after irradiation, the checkpoint repair phase of the cell cycle is initiated, and the repair of damaged DNA increases radiation resistance.	('arrest', 'Disease', (64, 70))	('radiation resistance', 'CPA', (190, 210))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (53, 70))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('increases', 'PosReg', (180, 189))	('DNA', 'Gene', (176, 179))	('tumor', 'Disease', (33, 38))	('arrest', 'Disease', 'MESH:D006323', (64, 70))	('cell cycle', 'CPA', (53, 63))	('damaged', 'Var', (168, 175))	('checkpoint repair', 'CPA', (94, 111))
193563	32508265	We further investigated the mechanism underlying radiotherapy sensitization induced by USP53 knockdown and found that DDB2 was downregulated by USP53 knockdown, whereas the expression of DDB2 in the CON group increased after radiation treatment, suggesting an increase in intracellular DNA repair.	('DDB2', 'Gene', (118, 122))	('USP53', 'Gene', (87, 92))	('knockdown', 'Var', (150, 159))	('downregulated', 'NegReg', (127, 140))	('increase', 'PosReg', (260, 268))	('DDB2', 'Gene', '1643', (187, 191))	('expression', 'MPA', (173, 183))	('DDB2', 'Gene', '1643', (118, 122))	('DDB2', 'Gene', (187, 191))	('USP53', 'Gene', (144, 149))
193564	32508265	Damage-specific DNA binding protein was not upregulated in the Si-USP53 + 8 Gy group, indicating that knockdown of USP53 not only downregulated DDB2 expression but also reversed the increase in DDB2 caused by radiation and reduced DNA nucleic acid repair.	('increase', 'PosReg', (182, 190))	('downregulated', 'NegReg', (130, 143))	('DDB2', 'Gene', (194, 198))	('USP53', 'Gene', (115, 120))	('DDB2', 'Gene', '1643', (144, 148))	('reduced', 'NegReg', (223, 230))	('knockdown', 'Var', (102, 111))	('DDB2', 'Gene', (144, 148))	('DNA nucleic acid repair', 'MPA', (231, 254))	('DNA binding protein', 'Gene', (16, 35))	('expression', 'MPA', (149, 159))	('DNA binding protein', 'Gene', '7335', (16, 35))	('DDB2', 'Gene', '1643', (194, 198))	('reversed', 'NegReg', (169, 177))
193626	26095281	Rahadiani et al reported that high podoplanin expression was significantly correlated with tumor status, depth of invasion, and lymphatic and vascular invasion, and was associated with a poorer prognosis in ESCC.	('ESCC', 'Disease', (207, 211))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('high', 'Var', (30, 34))	('correlated', 'Reg', (75, 85))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('expression', 'MPA', (46, 56))	('tumor', 'Disease', (91, 96))	('podoplanin', 'Protein', (35, 45))
193666	30909662	Moreover, the aberrant expression of this lncRNA was correlated with clinicopathological features in a number of malignancies, indicating it as a potential marker for early cancer detection (Shi et al., 2015; Yan et al., 2015; Qin et al., 2016; Cui et al., 2017).	('Qin', 'Gene', (227, 230))	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('cancer', 'Disease', (173, 179))	('ncRNA', 'Gene', (43, 48))	('malignancies', 'Disease', (113, 125))	('correlated', 'Reg', (53, 63))	('aberrant', 'Var', (14, 22))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('ncRNA', 'Gene', '54719', (43, 48))	('Qin', 'Gene', '2290', (227, 230))	('malignancies', 'Disease', 'MESH:D009369', (113, 125))
193667	30909662	Dysregulation of lnc-PCAT-1 also designated as an independent prognostic factor for the overall survival (OS) rate of cancer patients (Shi et al., 2015; Yan et al., 2015; Qin et al., 2016; Cui et al., 2017).	('cancer', 'Disease', (118, 124))	('PCAT-1', 'Gene', (21, 27))	('Dysregulation', 'Var', (0, 13))	('Qin', 'Gene', '2290', (171, 174))	('PCAT-1', 'Gene', '100750225', (21, 27))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('overall', 'MPA', (88, 95))	('Qin', 'Gene', (171, 174))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('patients', 'Species', '9606', (125, 133))
193681	30909662	The overall and pooled results revealed that the high expression level of PCAT1 was significantly related to shorter overall survival in cancer patients (HR =1.9, 95% CI: 1.13-3.18, P<0.001).	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('PCAT1', 'Gene', '100750225', (74, 79))	('overall survival', 'MPA', (117, 133))	('PCAT1', 'Gene', (74, 79))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('patients', 'Species', '9606', (144, 152))	('cancer', 'Disease', (137, 143))	('high', 'Var', (49, 53))	('shorter', 'NegReg', (109, 116))
193687	30909662	Aberrant expression of some lncRNAs has been demonstrated to be associated with tumor progression, as well as with the clinical outcome in various cancers (Xue et al., 2016; Qian et al., 2017; Su et al., 2017; Zhuo and Kang., 2017).	('associated', 'Reg', (64, 74))	('Aberrant expression', 'Var', (0, 19))	('ncRNA', 'Gene', (29, 34))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('ncRNA', 'Gene', '54719', (29, 34))	('tumor', 'Disease', (80, 85))	('cancers', 'Disease', 'MESH:D009369', (147, 154))	('cancers', 'Phenotype', 'HP:0002664', (147, 154))	('cancers', 'Disease', (147, 154))	('Su', 'Chemical', 'MESH:C035067', (193, 195))
193694	30909662	Their result revealed the function of ncRNA transcriptome and confirmed dysregulation of three important target genes, BRCA2, CENPE and CENPF in prostate cancer.	('CENPF', 'Gene', (136, 141))	('ncRNA', 'Gene', '54719', (38, 43))	('prostate cancer', 'Disease', 'MESH:D011471', (145, 160))	('dysregulation', 'Var', (72, 85))	('CENPF', 'Gene', '1063', (136, 141))	('prostate cancer', 'Phenotype', 'HP:0012125', (145, 160))	('ncRNA', 'Gene', (38, 43))	('CENPE', 'Gene', '1062', (126, 131))	('BRCA2', 'Gene', (119, 124))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('prostate cancer', 'Disease', (145, 160))	('CENPE', 'Gene', (126, 131))	('BRCA2', 'Gene', '675', (119, 124))
193698	30909662	In the systematic review and meta-analysis, it was attempted to collect all published papers assessing the prognostic significance of long non-coding RNA PCAT-1 dysregulation in several cancers.	('long non-coding RNA', 'Var', (134, 153))	('PCAT-1', 'Gene', '100750225', (154, 160))	('cancers', 'Disease', 'MESH:D009369', (186, 193))	('cancers', 'Phenotype', 'HP:0002664', (186, 193))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('cancers', 'Disease', (186, 193))	('PCAT-1', 'Gene', (154, 160))
193700	30909662	The analyses showed that the patients with high lncRNA PCAT-1 expression had evidently poorer overall survival rates than those with low PCAT-1 expression.	('patients', 'Species', '9606', (29, 37))	('overall survival', 'MPA', (94, 110))	('ncRNA', 'Gene', '54719', (49, 54))	('PCAT-1', 'Gene', (55, 61))	('PCAT-1', 'Gene', '100750225', (137, 143))	('poorer', 'NegReg', (87, 93))	('PCAT-1', 'Gene', '100750225', (55, 61))	('ncRNA', 'Gene', (49, 54))	('PCAT-1', 'Gene', (137, 143))	('expression', 'Var', (62, 72))
193722	30300334	Kaplan-Meier curve showed that high EphA8 expression was significantly associated with poor prognosis, similar to age, smoking habit, drinking habit, tumor size, and TNM stage.	('TNM', 'Gene', (166, 169))	('EphA8', 'Gene', '2046', (36, 41))	('poor', 'Disease', (87, 91))	('expression', 'MPA', (42, 52))	('TNM', 'Gene', '10178', (166, 169))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('high', 'Var', (31, 35))	('EphA8', 'Gene', (36, 41))	('tumor', 'Disease', (150, 155))
193739	30300334	Of note, EphA8 has been found highly expressed in epithelial ovarian cancer tissues compared to normal ovarian tissues; and high EphA8 protein level has been shown to be an independent prognostic factor in epithelial ovarian cancer.	('EphA8', 'Gene', '2046', (129, 134))	('epithelial ovarian cancer', 'Disease', 'MESH:D000077216', (50, 75))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('ovarian cancer', 'Phenotype', 'HP:0100615', (217, 231))	('epithelial ovarian cancer', 'Disease', (50, 75))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('epithelial ovarian cancer', 'Phenotype', 'HP:0025318', (50, 75))	('epithelial ovarian cancer', 'Phenotype', 'HP:0025318', (206, 231))	('epithelial ovarian cancer', 'Disease', 'MESH:D000077216', (206, 231))	('EphA8', 'Gene', (9, 14))	('EphA8', 'Gene', (129, 134))	('EphA8', 'Gene', '2046', (9, 14))	('high', 'Var', (124, 128))	('epithelial ovarian cancer', 'Disease', (206, 231))	('ovarian cancer', 'Phenotype', 'HP:0100615', (61, 75))
193743	30300334	Univariate and multivariate analysis indicated that high EphA8 expression was significantly associated with poor prognosis and could serve as an independent prognostic factor in OTSCC.	('EphA8', 'Gene', '2046', (57, 62))	('expression', 'MPA', (63, 73))	('OTSCC', 'Disease', (178, 183))	('high', 'Var', (52, 56))	('EphA8', 'Gene', (57, 62))
193800	30300334	Due to the correlation of high EphA8 expression with a lower survival rate of OTSCC patients, we next explored whether high EphA8 expression could serve as an independent prognostic factor for OTSCC patients.	('high', 'Var', (26, 30))	('patients', 'Species', '9606', (84, 92))	('EphA8', 'Gene', (31, 36))	('EphA8', 'Gene', (124, 129))	('survival', 'MPA', (61, 69))	('lower', 'NegReg', (55, 60))	('patients', 'Species', '9606', (199, 207))	('expression', 'MPA', (37, 47))	('EphA8', 'Gene', '2046', (31, 36))	('EphA8', 'Gene', '2046', (124, 129))
193801	30300334	Multivariate analysis indicated that high expression of EphA8 (high vs. low; P<0.05) could serve as an independent prognostic factor, similar to tumor size (>5.0 cm vs. <=5.0 cm; P<0.05).	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('high', 'Var', (37, 41))	('EphA8', 'Gene', (56, 61))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumor', 'Disease', (145, 150))	('EphA8', 'Gene', '2046', (56, 61))
193802	30300334	These results highly suggested that high EphA8 expression might be a potent predictor of OTSCC patients' survival.	('patients', 'Species', '9606', (95, 103))	('OTSCC', 'Disease', (89, 94))	('EphA8', 'Gene', (41, 46))	('expression', 'MPA', (47, 57))	('EphA8', 'Gene', '2046', (41, 46))	('high', 'Var', (36, 40))
193805	30300334	As shown in Figure 3A and 3B, EphA8 was successfully overexpressed or knocked down in SCC-25 and H357 cells.	('EphA8', 'Gene', (30, 35))	('EphA8', 'Gene', '2046', (30, 35))	('H357', 'CellLine', 'CVCL:2462', (97, 101))	('knocked', 'Var', (70, 77))
193807	30300334	Furthermore, we conducted the Matrigel Transwell invasion assay and found that overexpression of EphA8 could significantly enhance the invasion capacity of SCC-25 and H357 cells; and on the contrary, knockdown of EphA8 significantly reduced the invasion capacity of SCC-25 and H357 cells (Figure 3E, 3F).	('Matrigel Transwell invasion assay', 'CPA', (30, 63))	('reduced', 'NegReg', (233, 240))	('knockdown', 'Var', (200, 209))	('enhance', 'PosReg', (123, 130))	('EphA8', 'Gene', (97, 102))	('EphA8', 'Gene', '2046', (213, 218))	('H357', 'CellLine', 'CVCL:2462', (167, 171))	('H357', 'CellLine', 'CVCL:2462', (277, 281))	('invasion capacity', 'CPA', (135, 152))	('overexpression', 'PosReg', (79, 93))	('EphA8', 'Gene', '2046', (97, 102))	('EphA8', 'Gene', (213, 218))
193808	30300334	These results indicated that high EphA8 expression might promote the progression of OTSCC via enhancing the invasion but not the proliferation capacity of tumor cells, resulting in poor prognosis of OTSCC patients.	('high', 'Var', (29, 33))	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('EphA8', 'Gene', (34, 39))	('patients', 'Species', '9606', (205, 213))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('promote', 'PosReg', (57, 64))	('OTSCC', 'Disease', (199, 204))	('tumor', 'Disease', (155, 160))	('EphA8', 'Gene', '2046', (34, 39))	('enhancing', 'PosReg', (94, 103))	('invasion', 'CPA', (108, 116))	('OTSCC', 'Disease', (84, 89))
193824	30300334	Similar to tumor size, high EphA8 expression was also shown to be an independent prognostic factor for OTSCC by multivariate Cox proportional hazards regression model.	('EphA8', 'Gene', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('expression', 'MPA', (34, 44))	('high', 'Var', (23, 27))	('tumor', 'Disease', (11, 16))	('EphA8', 'Gene', '2046', (28, 33))	('OTSCC', 'Disease', (103, 108))	('tumor', 'Disease', 'MESH:D009369', (11, 16))
193831	30300334	Consistent with other studies, we found high EphA8 expression could enhance the invasion capacity of tumor cells, which further supports that EphA8 participated in the progression of OTSCC.	('OTSCC', 'Disease', (183, 188))	('EphA8', 'Gene', (142, 147))	('EphA8', 'Gene', (45, 50))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('EphA8', 'Gene', '2046', (45, 50))	('EphA8', 'Gene', '2046', (142, 147))	('expression', 'Var', (51, 61))	('enhance', 'PosReg', (68, 75))
193833	30300334	Univariate and multivariate analysis revealed that high EphA8 expression correlated with a poor survival rate of OTSCC patients and served as an independent prognostic factor for OTSCC.	('EphA8', 'Gene', (56, 61))	('survival rate', 'CPA', (96, 109))	('patients', 'Species', '9606', (119, 127))	('OTSCC', 'Disease', (113, 118))	('poor', 'NegReg', (91, 95))	('high', 'Var', (51, 55))	('EphA8', 'Gene', '2046', (56, 61))
193835	26656844	Identification of focally amplified lineage-specific super-enhancers in human epithelial cancers Whole genome analysis approaches are revealing recurrent cancer-associated somatic alterations in non-coding DNA regions.	('epithelial cancers', 'Disease', 'MESH:D000077216', (78, 96))	('cancers', 'Phenotype', 'HP:0002664', (89, 96))	('alterations', 'Var', (180, 191))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('epithelial cancers', 'Disease', (78, 96))	('cancer', 'Disease', (154, 160))	('human', 'Species', '9606', (72, 77))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('cancer', 'Disease', (89, 95))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
193837	26656844	Copy-number gains of non-coding regions harboring super-enhancers near KLF5, USP12, PARD6B and MYC are associated with over-expression of these cancer-related genes.	('USP12', 'Gene', (77, 82))	('MYC', 'Gene', '4609', (95, 98))	('over-expression', 'MPA', (119, 134))	('PARD6B', 'Gene', '84612', (84, 90))	('USP12', 'Gene', '219333', (77, 82))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('cancer', 'Disease', (144, 150))	('MYC', 'Gene', (95, 98))	('KLF5', 'Gene', (71, 75))	('KLF5', 'Gene', '688', (71, 75))	('super-enhancers', 'PosReg', (50, 65))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('Copy-number gains', 'Var', (0, 17))	('PARD6B', 'Gene', (84, 90))
193839	26656844	CRISPR/Cas9-mediated repression or deletion of a constituent enhancer within the MYC-LASE region led to significant reductions in the expression of MYC and its target genes, and to the impairment of anchorage-independent and clonogenic growth, consistent with an oncogenic function.	('expression', 'MPA', (134, 144))	('MYC', 'Gene', '4609', (81, 84))	('reductions', 'NegReg', (116, 126))	('MYC', 'Gene', (148, 151))	('MYC', 'Gene', (81, 84))	('deletion', 'Var', (35, 43))	('MYC', 'Gene', '4609', (148, 151))	('impairment', 'NegReg', (185, 195))
193840	26656844	Our results demonstrate that genomic amplification of super-enhancers represents a common mechanism to activate cancer driver genes in multiple cancer types.	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('multiple cancer', 'Disease', 'MESH:D009369', (135, 150))	('cancer', 'Disease', (144, 150))	('genomic amplification', 'Var', (29, 50))	('activate', 'PosReg', (103, 111))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('multiple cancer', 'Disease', (135, 150))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
193841	26656844	Somatic copy number alterations (SCNAs), including chromosome arm-level copy changes as well as focal amplifications and deletions, are central events in cancer pathogenesis.	('copy changes', 'Var', (72, 84))	('cancer', 'Disease', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('deletions', 'Var', (121, 130))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))
193843	26656844	Enhancers are characterized by the histone modifications H3K4me1 and H3K27ac, binding of coactivators such as p300, and increased chromatin accessibility as defined by DNaseI hypersensitivity.	('binding', 'Interaction', (78, 85))	('hypersensitivity', 'Disease', (175, 191))	('hypersensitivity', 'Disease', 'MESH:D004342', (175, 191))	('p300', 'Gene', (110, 114))	('H3K27ac', 'Var', (69, 76))	('H3K4me1', 'Var', (57, 64))	('p300', 'Gene', '2033', (110, 114))	('increased', 'PosReg', (120, 129))	('chromatin accessibility', 'MPA', (130, 153))
193846	26656844	In this study, we systematically investigate SCNAs of non-coding regions at a pan-cancer scale and provide evidence suggesting that focal amplifications of super-enhancers are a common mechanism for upregulating the expression of cancer driver genes.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (230, 236))	('upregulating', 'PosReg', (199, 211))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('expression', 'MPA', (216, 226))	('cancer', 'Disease', (82, 88))	('super-enhancers', 'Gene', (156, 171))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('cancer', 'Disease', (230, 236))	('focal amplifications', 'Var', (132, 152))
193849	26656844	For 12 out of the 19 tumor types, H3K27ac ChIP-seq data from corresponding tissue or cell lines were available from either public datasets such as ENCODE and the Roadmap Epigenomics project or from our own collection (Supplementary Table 2).	('H3K27ac', 'Var', (34, 41))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))	('tumor', 'Disease', (21, 26))
193854	26656844	Similarly, the ESCA amplicon also harbors a super-enhancer based on the H3K27ac ChIP-seq profile of esophageal cells and ESCA tumors with this amplicon exhibited a trend towards increased KLF5 expression (Supplementary Fig.	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('H3K27ac', 'Var', (72, 79))	('ESCA tumors', 'Disease', (121, 132))	('ESCA tumors', 'Disease', 'MESH:D009369', (121, 132))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('KLF5', 'Gene', (188, 192))	('KLF5', 'Gene', '688', (188, 192))	('increased', 'PosReg', (178, 187))
193855	26656844	In lung adenocarcinomas and lung squamous cell carcinomas, KLF5 is also significantly mutated with recurrent missense alterations (Campbell et.	('KLF5', 'Gene', (59, 63))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (33, 56))	('KLF5', 'Gene', '688', (59, 63))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (33, 57))	('lung adenocarcinomas and lung squamous cell carcinomas', 'Disease', 'MESH:D000077192', (3, 57))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (3, 22))	('carcinoma', 'Phenotype', 'HP:0030731', (47, 56))	('missense alterations', 'Var', (109, 129))	('carcinomas', 'Phenotype', 'HP:0030731', (47, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (13, 22))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (3, 23))	('carcinomas', 'Phenotype', 'HP:0030731', (13, 23))
193859	26656844	CRC tumors containing the chr13q amplicon exhibited significantly higher expression of the nearest gene, ubiquitin specific peptidase 12, USP12, a deubiquitinating enzyme implicated in prostate cancer (Fig.	('CRC tumors', 'Disease', 'MESH:D015179', (0, 10))	('prostate cancer', 'Disease', 'MESH:D011471', (185, 200))	('chr13q', 'Var', (26, 32))	('USP12', 'Gene', (138, 143))	('prostate cancer', 'Phenotype', 'HP:0012125', (185, 200))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('expression', 'MPA', (73, 83))	('ubiquitin specific peptidase 12', 'Gene', (105, 136))	('prostate cancer', 'Disease', (185, 200))	('higher', 'PosReg', (66, 72))	('USP12', 'Gene', '219333', (138, 143))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('ubiquitin specific peptidase 12', 'Gene', '219333', (105, 136))	('CRC tumors', 'Disease', (0, 10))
193860	26656844	In LIHC tumors with the chr20q amplicon, the expression of the second nearest gene PARD6B, rather than the closest gene PTPN1, is upregulated, suggesting that PARD6B is the target gene (Fig.	('upregulated', 'PosReg', (130, 141))	('LIHC tumors', 'Disease', (3, 14))	('PARD6B', 'Gene', '84612', (83, 89))	('PARD6B', 'Gene', '84612', (159, 165))	('PTPN1', 'Gene', '5770', (120, 125))	('PTPN1', 'Gene', (120, 125))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('chr20q amplicon', 'Var', (24, 39))	('expression', 'MPA', (45, 55))	('tumors', 'Phenotype', 'HP:0002664', (8, 14))	('LIHC tumors', 'Disease', 'MESH:D009369', (3, 14))	('PARD6B', 'Gene', (83, 89))	('PARD6B', 'Gene', (159, 165))
193872	26656844	The H3K27ac and p300 ChIP-seq profiles of MYC-LASE and MYC-ECSE indicate that each super-enhancer is active only in cell lines from each respective tumor type (Fig.	('p300', 'Gene', (16, 20))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('MYC', 'Gene', (55, 58))	('MYC', 'Gene', (42, 45))	('p300', 'Gene', '2033', (16, 20))	('H3K27ac', 'Var', (4, 11))	('tumor', 'Disease', (148, 153))	('MYC', 'Gene', '4609', (42, 45))	('MYC', 'Gene', '4609', (55, 58))	('tumor', 'Disease', 'MESH:D009369', (148, 153))
193876	26656844	To determine if copy number gain of super-enhancers drives oncogene expression and tumorigenesis, we focused on MYC-LASE.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('copy number', 'Var', (16, 27))	('tumor', 'Disease', (83, 88))	('oncogene expression', 'MPA', (59, 78))	('drives', 'PosReg', (52, 58))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
193883	26656844	Deletion of specific transcription factor binding motif sequences within mini-e3 demonstrated that the NFE2L2 and CEBPB motifs were necessary to maintain maximal e3 enhancer activity (Fig.	('enhancer', 'PosReg', (165, 173))	('CEBPB', 'Gene', (114, 119))	('NFE2L2', 'Gene', '4780', (103, 109))	('CEBPB', 'Gene', '1051', (114, 119))	('NFE2L2', 'Gene', (103, 109))	('Deletion', 'Var', (0, 8))
193884	26656844	Short interfering RNA (siRNA)-mediated knockdown of NFE2L2 and CEBPB in A549 cells led to a significant reduction in e3-driven luciferase reporter activity as compared to control siRNAs (Fig.	('reduction', 'NegReg', (104, 113))	('knockdown', 'Var', (39, 48))	('NFE2L2', 'Gene', '4780', (52, 58))	('A549', 'CellLine', 'CVCL:0023', (72, 76))	('e3-driven luciferase', 'Enzyme', (117, 137))	('NFE2L2', 'Gene', (52, 58))	('CEBPB', 'Gene', (63, 68))	('CEBPB', 'Gene', '1051', (63, 68))
193891	26656844	Deletion of the e3 enhancer region resulted in a ~30% reduction in MYC expression (Fig.	('reduction', 'NegReg', (54, 63))	('MYC', 'Gene', '4609', (67, 70))	('MYC', 'Gene', (67, 70))	('Deletion', 'Var', (0, 8))
193892	26656844	These results suggest that copy number gain of the e3 enhancer region drives MYC over-expression, which contributes to the tumorigenic phenotype.	('over-expression', 'MPA', (81, 96))	('tumor', 'Disease', (123, 128))	('MYC', 'Gene', '4609', (77, 80))	('MYC', 'Gene', (77, 80))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('copy number gain', 'Var', (27, 43))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
193893	26656844	MYC overexpression has been observed as a consequence of rearrangements with the IgH locus in Burkitts lymphoma (Fig.	('MYC', 'Gene', (0, 3))	('Burkitts lymphoma', 'Disease', (94, 111))	('Burkitts lymphoma', 'Phenotype', 'HP:0030080', (94, 111))	('Burkitts lymphoma', 'Disease', 'MESH:D002051', (94, 111))	('MYC', 'Gene', '4609', (0, 3))	('overexpression', 'PosReg', (4, 18))	('lymphoma', 'Phenotype', 'HP:0002665', (103, 111))	('rearrangements', 'Var', (57, 71))	('IgH', 'Gene', '3492', (81, 84))	('IgH', 'Gene', (81, 84))
193894	26656844	6g, lower left diagram) as well as through amplifications of the MYC gene itself in several tumor types (Fig.	('amplifications', 'Var', (43, 57))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('MYC', 'Gene', (65, 68))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Disease', (92, 97))	('MYC', 'Gene', '4609', (65, 68))
193896	26656844	Collectively, these data suggest that copy number gain of super-enhancers is highly lineage-specific but may be a common mechanism for upregulating MYC expression in diverse types of cancer (Fig.	('cancer', 'Disease', (183, 189))	('MYC', 'Gene', (148, 151))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('upregulating', 'PosReg', (135, 147))	('copy number gain', 'Var', (38, 54))	('expression', 'MPA', (152, 162))	('MYC', 'Gene', '4609', (148, 151))	('cancer', 'Disease', 'MESH:D009369', (183, 189))
193900	26656844	These super-enhancer amplifications are associated with over-expression of the MYC oncogene as well as the KLF5, USP12 and PARD6B genes.	('MYC', 'Gene', (79, 82))	('USP12', 'Gene', (113, 118))	('USP12', 'Gene', '219333', (113, 118))	('KLF5', 'Gene', (107, 111))	('PARD6B', 'Gene', (123, 129))	('amplifications', 'Var', (21, 35))	('KLF5', 'Gene', '688', (107, 111))	('PARD6B', 'Gene', '84612', (123, 129))	('over-expression', 'MPA', (56, 71))	('MYC', 'Gene', '4609', (79, 82))	('associated', 'Reg', (40, 50))
193901	26656844	Thus, focal amplification of super-enhancers represents a new class of structural alterations with functional implications in cancer.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('focal amplification', 'Var', (6, 25))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))
193921	26656844	The following premade 5' nuclease assays were ordered from Integrated DNA Technologies: MYC (Hs.PT.58.26770695), NCL (Hs.PT.58.1260587), CDK4 (Hs.PT.58.584267), ODC1 (Hs.PT.58.27029915), NPM1 (Hs.PT.58.40019160) and internal reference HPRT1 (Hs.PT.58v.45621572).	('HPRT1', 'Gene', (235, 240))	('NCL', 'Gene', (113, 116))	('NCL', 'Gene', '4691', (113, 116))	('ODC1', 'Gene', (161, 165))	('NPM1', 'Gene', '4869', (187, 191))	('MYC', 'Gene', '4609', (88, 91))	('CDK4', 'Gene', '1019', (137, 141))	('CDK4', 'Gene', (137, 141))	('Hs.PT.58.40019160', 'Var', (193, 210))	('ODC1', 'Gene', '4953', (161, 165))	('MYC', 'Gene', (88, 91))	('NPM1', 'Gene', (187, 191))	('HPRT1', 'Gene', '3251', (235, 240))
193923	26656844	Pre-verified Silencer Select siRNAs (Life Technologies, s9491 and s9492 for NFE2L2, and s2891 and s2892 for CEBPB) were used.	('CEBPB', 'Gene', (108, 113))	('s2892', 'Var', (98, 103))	('CEBPB', 'Gene', '1051', (108, 113))	('NFE2L2', 'Gene', '4780', (76, 82))	('s9491', 'Var', (56, 61))	('NFE2L2', 'Gene', (76, 82))	('s2891', 'Var', (88, 93))	('s9492', 'Var', (66, 71))
193936	25409906	Both proliferating cells and transformed cells have been shown to favor expression of shortened 3' UTRs through APA, leading to activation of several proto-oncogenes, such as Cyclin D1.	('activation', 'PosReg', (128, 138))	('APA', 'Gene', (112, 115))	('favor', 'PosReg', (66, 71))	('shortened', 'Var', (86, 95))	('expression', 'MPA', (72, 82))	('Cyclin D1', 'Gene', '595', (175, 184))	('Cyclin D1', 'Gene', (175, 184))
193971	25409906	For example, PolyA-seq is designed to amplify polyA tags; therefore, some dynamic APA events reported by PolyA-seq may have a small magnitude of changes that are not readily detectable by RNA-seq (Supplementary Fig.	('PolyA-seq', 'Chemical', '-', (105, 114))	('polyA', 'Chemical', 'MESH:D011061', (46, 51))	('PolyA-seq', 'Chemical', '-', (13, 22))	('PolyA-seq', 'Var', (105, 114))	('APA', 'MPA', (82, 85))
193987	25409906	In addition, AATAAA and ATTAAA are the most prevalent motifs among variants of polyA signals (Supplementary Fig.	('polyA', 'Chemical', 'MESH:D011061', (79, 84))	('polyA signals', 'Gene', (79, 92))	('AATAAA', 'Disease', (13, 19))	('prevalent', 'Reg', (44, 53))	('variants', 'Var', (67, 75))
194034	25409906	The implication of the 3' UTR switch to GAC is that the expression of GLS is no longer regulated by miR-23 or MYC.	('GAC', 'Gene', '2744', (40, 43))	('GLS', 'Gene', (70, 73))	('GAC', 'Gene', (40, 43))	('MYC', 'Gene', (110, 113))	('miR-23', 'Chemical', '-', (100, 106))	('miR-23', 'Var', (100, 106))	('MYC', 'Gene', '4609', (110, 113))	('GLS', 'Gene', '2744', (70, 73))
194062	25409906	They reported 171 genes with lengthening in 3' UTRs upon knock down of CstF64, among which 46 genes from our analysis have shortened 3' UTRs in tumors where CstF64 is up-regulated (Fig.	('tumors', 'Disease', (144, 150))	('CstF64', 'Gene', '1478', (71, 77))	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('CstF64', 'Gene', (157, 163))	('shortened', 'NegReg', (123, 132))	('tumors', 'Disease', 'MESH:D009369', (144, 150))	('CstF64', 'Gene', '1478', (157, 163))	('knock down', 'Var', (57, 67))	('CstF64', 'Gene', (71, 77))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('up-regulated', 'PosReg', (167, 179))
194087	25409906	Fourth, our study reveals a novel link between altered 3' UTR usage and cancer metabolism.	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('altered', 'Var', (47, 54))	('cancer', 'Disease', (72, 78))
194096	25409906	These RNA aberrations represent an illustrative case of genomic "dark matter" beyond coding regions, and thus may also provide new directions for tumor gene discovery.	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('aberrations', 'Var', (10, 21))	('tumor', 'Disease', (146, 151))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
194140	24885564	Identification of novel driver mutations of the discoidin domain receptor 2 (DDR2) gene in squamous cell lung cancer of Chinese patients Although many of the recently approved genomically targeted therapies have improved outcomes for patients in non-small-cell lung cancer (NSCLC) with lung adenocarcinoma, little is known about the genomic alterations that drive lung squamous cell cancer (SCC) and development of effective targeted therapies in lung SCC is a promising area to be further investigated.	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (246, 272))	('lung cancer', 'Disease', (261, 272))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (286, 305))	('cancer', 'Phenotype', 'HP:0002664', (383, 389))	('lung cancer', 'Disease', 'MESH:D008175', (105, 116))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (286, 305))	('discoidin domain receptor 2', 'Gene', (48, 75))	('lung cancer', 'Phenotype', 'HP:0100526', (105, 116))	('discoidin domain receptor 2', 'Gene', '4921', (48, 75))	('lung squamous cell cancer', 'Phenotype', 'HP:0030359', (364, 389))	('squamous cell lung cancer', 'Disease', 'MESH:D002294', (91, 116))	('SCC', 'Gene', '6317', (391, 394))	('patients', 'Species', '9606', (234, 242))	('lung cancer', 'Disease', 'MESH:D008175', (261, 272))	('NSCLC', 'Disease', 'MESH:D002289', (274, 279))	('SCC', 'Gene', (391, 394))	('mutations', 'Var', (31, 40))	('DDR2', 'Gene', '4921', (77, 81))	('lung cancer', 'Phenotype', 'HP:0100526', (261, 272))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('NSCLC', 'Disease', (274, 279))	('patients', 'Species', '9606', (128, 136))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (250, 272))	('SCC', 'Gene', '6317', (452, 455))	('lung squamous cell cancer', 'Disease', 'MESH:D002294', (364, 389))	('lung adenocarcinoma', 'Disease', (286, 305))	('squamous cell lung cancer', 'Phenotype', 'HP:0030359', (91, 116))	('DDR2', 'Gene', (77, 81))	('lung squamous cell cancer', 'Disease', (364, 389))	('cancer', 'Phenotype', 'HP:0002664', (266, 272))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (369, 389))	('SCC', 'Gene', (452, 455))	('squamous cell lung cancer', 'Disease', (91, 116))	('carcinoma', 'Phenotype', 'HP:0030731', (296, 305))
194148	24885564	Moreover, there were 3 novel DDR2 mutations (G531V, S131C, T681I) in 4 patients and provide the mutation rate of 4.6% in the 86 patients with lung SCC.	('SCC', 'Gene', (147, 150))	('G531V', 'Mutation', 'p.G531V', (45, 50))	('DDR2', 'Gene', (29, 33))	('T681I', 'Var', (59, 64))	('patients', 'Species', '9606', (71, 79))	('S131C', 'Mutation', 'p.S131C', (52, 57))	('SCC', 'Gene', '6317', (147, 150))	('S131C', 'Var', (52, 57))	('T681I', 'Mutation', 'rs201701502', (59, 64))	('patients', 'Species', '9606', (128, 136))	('G531V', 'Var', (45, 50))
194149	24885564	The mutation of S131C in DDR2 could promote lung SCC cells proliferation, migration and invasion via inducing MMP-2, but reducing E-cadherin expression.	('promote', 'PosReg', (36, 43))	('invasion', 'CPA', (88, 96))	('MMP-2', 'Gene', '4313', (110, 115))	('SCC', 'Gene', (49, 52))	('E-cadherin', 'Gene', (130, 140))	('E-cadherin', 'Gene', '999', (130, 140))	('reducing', 'NegReg', (121, 129))	('migration', 'CPA', (74, 83))	('inducing', 'Reg', (101, 109))	('SCC', 'Gene', '6317', (49, 52))	('MMP-2', 'Gene', (110, 115))	('S131C', 'Mutation', 'p.S131C', (16, 21))	('DDR2', 'Gene', (25, 29))	('S131C', 'Var', (16, 21))
194150	24885564	These data indicated that the novel DDR2 mutation may contribute to the development and progression of lung SCC and this effect may be associated with increased proliferation and invasiveness, at least in part, via regulating E-cadherin expression.	('increased', 'PosReg', (151, 160))	('regulating', 'Reg', (215, 225))	('progression', 'CPA', (88, 99))	('DDR2', 'Gene', (36, 40))	('contribute', 'Reg', (54, 64))	('SCC', 'Gene', (108, 111))	('expression', 'MPA', (237, 247))	('mutation', 'Var', (41, 49))	('SCC', 'Gene', '6317', (108, 111))	('E-cadherin', 'Gene', (226, 236))	('E-cadherin', 'Gene', '999', (226, 236))	('invasiveness', 'CPA', (179, 191))	('proliferation', 'CPA', (161, 174))
194156	24885564	A striking example of this is the development of small-molecule inhibitors of the epidermal growth factor receptor (EGFR) tyrosine kinase therapies, which resulted in a great deal of progress in the targeted treatment of patients with NSCLC.	('epidermal growth factor receptor', 'Gene', (82, 114))	('patients', 'Species', '9606', (221, 229))	('epidermal growth factor receptor', 'Gene', '1956', (82, 114))	('NSCLC', 'Disease', (235, 240))	('small-molecule', 'Var', (49, 63))	('progress', 'PosReg', (183, 191))	('NSCLC', 'Disease', 'MESH:D002289', (235, 240))	('EGFR', 'Gene', '1956', (116, 120))	('EGFR', 'Gene', (116, 120))
194163	24885564	Moreover, DDR2 mutations have been noted in several cancer specimens including in NSCLC (R105S, H136H and N456S).	('R105S', 'Mutation', 'p.R105S', (89, 94))	('noted', 'Reg', (35, 40))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('N456S', 'Var', (106, 111))	('mutations', 'Var', (15, 24))	('H136H', 'Mutation', 'rs2271305', (96, 101))	('N456S', 'Mutation', 'rs1374888421', (106, 111))	('R105S', 'Var', (89, 94))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('NSCLC', 'Disease', (82, 87))	('H136H', 'Var', (96, 101))	('DDR2', 'Gene', (10, 14))	('NSCLC', 'Disease', 'MESH:D002289', (82, 87))
194165	24885564	We found three novel somatic mutations in the DDR2 at a frequency of 4.6% ( n = 4) in a sample set of 86 lung SCC samples.	('SCC', 'Gene', '6317', (110, 113))	('DDR2', 'Gene', (46, 50))	('mutations', 'Var', (29, 38))	('SCC', 'Gene', (110, 113))
194166	24885564	We also show that DDR2 mutations are oncogenic via promoting cells proliferation, migration and invasion by exogenous overexpression in lung SCC cells.	('cells proliferation', 'CPA', (61, 80))	('promoting', 'PosReg', (51, 60))	('SCC', 'Gene', (141, 144))	('migration', 'CPA', (82, 91))	('mutations', 'Var', (23, 32))	('invasion', 'CPA', (96, 104))	('SCC', 'Gene', '6317', (141, 144))	('DDR2', 'Gene', (18, 22))
194167	24885564	Furthermore, DDR2 mutation could induce Epithelial-to-Mesenchymal Transition in lung SCC cells by downregulating E-cadherin expression.	('SCC', 'Gene', '6317', (85, 88))	('Epithelial-to-Mesenchymal Transition', 'CPA', (40, 76))	('E-cadherin', 'Gene', (113, 123))	('DDR2', 'Gene', (13, 17))	('E-cadherin', 'Gene', '999', (113, 123))	('mutation', 'Var', (18, 26))	('downregulating', 'NegReg', (98, 112))	('SCC', 'Gene', (85, 88))	('induce', 'PosReg', (33, 39))
194180	24885564	In the discovery set, 86 patient samples were used for sequencing DDR2 gene mutation.	('patient', 'Species', '9606', (25, 32))	('mutation', 'Var', (76, 84))	('DDR2', 'Gene', (66, 70))
194181	24885564	Mutations were identified using an automated mutation caller and then verified manually with comparison made to the matched normal sequence in the case of all primary tumor samples.	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('Mutations', 'Var', (0, 9))	('tumor', 'Disease', (167, 172))	('tumor', 'Disease', 'MESH:D009369', (167, 172))
194182	24885564	To generate a DDR2 and its mutated transcript expression vector, the entire sequence of human DDR2 and mutatedDDR2 was synthesized and subcloned into pEGFP-N1 vector with incorporate external NheI and BamHI sites, respectively (Invitrogen, Shanghai, China).	('mutatedDDR2', 'Gene', (103, 114))	('EGF', 'Gene', (151, 154))	('mutatedDDR2', 'Var', (103, 114))	('human', 'Species', '9606', (88, 93))	('EGF', 'Gene', '1950', (151, 154))
194205	24885564	According to the median ratio of relative DDR2 expression (1.76) in tumor tissues, the 56 NSCLC patients were classified into two groups: High-DDR2 group (n = 27, DDR2 expression ratio >= median ratio) and Low-DDR2 group (n = 27, DDR2 expression ratio <= median ratio).	('tumor', 'Disease', (68, 73))	('NSCLC', 'Disease', (90, 95))	('NSCLC', 'Disease', 'MESH:D002289', (90, 95))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('DDR2', 'MPA', (163, 167))	('patients', 'Species', '9606', (96, 104))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('High-DDR2', 'Var', (138, 147))
194206	24885564	The Kaplan-Meier survival curve showed that there was no significantly difference in survival times between patients with high DDR2 expression and those with low DDR2 expression levels (Figure 1D).	('patients', 'Species', '9606', (108, 116))	('high', 'Var', (122, 126))	('expression', 'MPA', (132, 142))	('DDR2', 'Gene', (127, 131))
194207	24885564	We performed Sanger sequencing of DDR2 gene in an set of 86 primary lung SCC samples and identified four synonymous mutations in 7 samples and three novel recurrent somatic mutations (G531V, S131C, T681I) in 4 samples in the tyrosine kinase genes: DDR2, resulting in an overall frequency of 4.6% in 86 total primary lung SCC samples.	('DDR2', 'Gene', (248, 252))	('SCC', 'Gene', '6317', (321, 324))	('G531V', 'Var', (184, 189))	('T681I', 'Mutation', 'rs201701502', (198, 203))	('SCC', 'Gene', (73, 76))	('G531V', 'Mutation', 'p.G531V', (184, 189))	('SCC', 'Gene', (321, 324))	('SCC', 'Gene', '6317', (73, 76))	('S131C', 'Mutation', 'p.S131C', (191, 196))	('DDR2', 'Gene', (34, 38))	('S131C', 'Var', (191, 196))	('T681I', 'Var', (198, 203))
194208	24885564	The S131C mutation was identified in the exon5, G531V and T681I mutations were found in exon13 and exon15, respectively (Figure 2B, C and D).	('G531V', 'Mutation', 'p.G531V', (48, 53))	('S131C', 'Var', (4, 9))	('S131C', 'Mutation', 'p.S131C', (4, 9))	('T681I', 'Var', (58, 63))	('G531V', 'Var', (48, 53))	('T681I', 'Mutation', 'rs201701502', (58, 63))
194211	24885564	DDR2 mutations have been found to be associated with lung SCC cells growth and dasatinib sensitivity.	('SCC', 'Gene', (58, 61))	('dasatinib sensitivity', 'MPA', (79, 100))	('SCC', 'Gene', '6317', (58, 61))	('mutations', 'Var', (5, 14))	('dasatinib', 'Chemical', 'MESH:D000069439', (79, 88))	('associated', 'Reg', (37, 47))	('DDR2', 'Gene', (0, 4))
194212	24885564	Therefore, to investigate the potential biological function of these novel DDR2 mutations in lung SCC cells, we constructed the DDR2 wild type, S131C and T681I mutated DDR2 expression plasmid vector (pEGFP-DDR2, pEGFP-DDR2- S131C, pEGFP-DDR2- T681I).	('DDR2', 'Gene', (128, 132))	('EGF', 'Gene', (232, 235))	('T681I', 'Mutation', 'rs201701502', (243, 248))	('T681I mutated', 'Var', (154, 167))	('mutations', 'Var', (80, 89))	('EGF', 'Gene', (213, 216))	('EGF', 'Gene', '1950', (201, 204))	('S131C', 'Var', (144, 149))	('SCC', 'Gene', '6317', (98, 101))	('EGF', 'Gene', '1950', (232, 235))	('S131C', 'Mutation', 'p.S131C', (144, 149))	('S131C', 'Mutation', 'p.S131C', (224, 229))	('T681I', 'Mutation', 'rs201701502', (154, 159))	('EGF', 'Gene', '1950', (213, 216))	('EGF', 'Gene', (201, 204))	('DDR2', 'Gene', (168, 172))	('SCC', 'Gene', (98, 101))
194216	24885564	To investigate whether DDR2 mutation could have a direct functional effect in facilitating lung SCC cell migration and invasion, we evaluated cancer cell invasion through matrigel and migration through wound healing and transwell assays.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('invasion', 'CPA', (119, 127))	('SCC', 'Gene', (96, 99))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('DDR2', 'Gene', (23, 27))	('SCC', 'Gene', '6317', (96, 99))	('mutation', 'Var', (28, 36))	('cancer', 'Disease', (142, 148))
194217	24885564	As shown in Figure 4A, overexpression of DDR2 S131C could enhance the ability of migration and invasion in HBE cells when compared with cells treated with pEGFP-DDR2 wildtype vector.	('enhance', 'PosReg', (58, 65))	('overexpression', 'PosReg', (23, 37))	('EGF', 'Gene', '1950', (156, 159))	('S131C', 'Mutation', 'p.S131C', (46, 51))	('S131C', 'Var', (46, 51))	('DDR2', 'Gene', (41, 45))	('EGF', 'Gene', (156, 159))
194219	24885564	These data indicated that DDR2 S131C mutation can promote the migratory and invasive phenotype of lung SCC cells.	('promote', 'PosReg', (50, 57))	('SCC', 'Gene', (103, 106))	('DDR2', 'Gene', (26, 30))	('S131C', 'Mutation', 'p.S131C', (31, 36))	('S131C mutation', 'Var', (31, 45))	('SCC', 'Gene', '6317', (103, 106))
194220	24885564	To further provide in vivo evidence for the oncogenic role of DDR2 S131C mutation in lung SCC, we used a xenograft mouse model.	('DDR2', 'Gene', (62, 66))	('mouse', 'Species', '10090', (115, 120))	('SCC', 'Gene', (90, 93))	('SCC', 'Gene', '6317', (90, 93))	('S131C', 'Mutation', 'p.S131C', (67, 72))	('S131C mutation', 'Var', (67, 81))
194223	24885564	Compared to the control treatment, DDR2-S131C overexpression treatment dramatically increased tumor growth, which was demonstrated by significantly increased tumor size and weight (Figure 5A and B).	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumor', 'Disease', (158, 163))	('DDR2-S131C', 'Var', (35, 45))	('increased', 'PosReg', (148, 157))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Disease', (94, 99))	('increased', 'PosReg', (84, 93))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('S131C', 'Mutation', 'p.S131C', (40, 45))
194226	24885564	Firstly, we investigated the total DDR2 protein levels of H1703 cells after transfection of wildtype or mutated DDR2 and the results that there was no difference in wildtype or mutated DDR2 transfected H1703 cells.	('H1703', 'CellLine', 'CVCL:1490', (58, 63))	('H1703', 'CellLine', 'CVCL:1490', (202, 207))	('DDR2', 'Gene', (112, 116))	('mutated', 'Var', (104, 111))
194227	24885564	Furthermore, to investigate whether these mutations affect collagen binding, we detected the collagen Iprotein level in wildtype or mutated DDR2 transfected H1703 cells;however, there was no significantly difference.	('H1703', 'CellLine', 'CVCL:1490', (157, 162))	('mutated', 'Var', (132, 139))	('collagen Iprotein level', 'MPA', (93, 116))	('detected', 'Reg', (80, 88))	('DDR2', 'Gene', (140, 144))	('mutations', 'Var', (42, 51))	('affect', 'Reg', (52, 58))
194231	24885564	Therefore, we investigated whether the mechanism whereby DDR2 mutation could promote EMT process in lung SCC cells.	('promote', 'PosReg', (77, 84))	('EMT process', 'CPA', (85, 96))	('DDR2', 'Gene', (57, 61))	('mutation', 'Var', (62, 70))	('SCC', 'Gene', (105, 108))	('SCC', 'Gene', '6317', (105, 108))
194232	24885564	The results of qRT-PCR showed that DDR2 ovexpression could induce the MMP-2 mRNA expression and decrease E-cadherin mRNA expression, while transfection of pEGFP-DDR2-S131C could induce more significantly changes in E-cadherin and MMP-2 mRNA expression (Figure 6A).	('DDR2 ovexpression', 'Var', (35, 52))	('MMP-2', 'Gene', (230, 235))	('EGF', 'Gene', '1950', (156, 159))	('E-cadherin', 'Gene', (215, 225))	('E-cadherin', 'Gene', '999', (215, 225))	('S131C', 'Mutation', 'p.S131C', (166, 171))	('E-cadherin', 'Gene', (105, 115))	('E-cadherin', 'Gene', '999', (105, 115))	('decrease', 'NegReg', (96, 104))	('induce', 'PosReg', (59, 65))	('MMP-2', 'Gene', (70, 75))	('MMP-2', 'Gene', '4313', (230, 235))	('ovexpression', 'Var', (40, 52))	('MMP-2', 'Gene', '4313', (70, 75))	('EGF', 'Gene', (156, 159))
194233	24885564	These data indicated that DDR2 mutation may infuence lung SCC cells proliferation, migration and invasion via partly promoting the epithelial-mesenchymal transition.	('SCC', 'Gene', (58, 61))	('promoting', 'PosReg', (117, 126))	('mutation', 'Var', (31, 39))	('SCC', 'Gene', '6317', (58, 61))	('DDR2', 'Gene', (26, 30))	('epithelial-mesenchymal transition', 'CPA', (131, 164))	('infuence', 'NegReg', (44, 52))	('invasion', 'CPA', (97, 105))	('migration', 'CPA', (83, 92))
194235	24885564	In addition to TP53 mutations, lung SCC have been shown to harbor amplifications of SOX2 and EGFR variant III mutations as well as DDR2 mutations.	('EGFR', 'Gene', '1956', (93, 97))	('DDR2', 'Gene', (131, 135))	('SOX2', 'Gene', '6657', (84, 88))	('EGFR', 'Gene', (93, 97))	('SCC', 'Gene', (36, 39))	('SOX2', 'Gene', (84, 88))	('variant III', 'Var', (98, 109))	('TP53', 'Gene', (15, 19))	('mutations', 'Var', (136, 145))	('TP53', 'Gene', '7157', (15, 19))	('SCC', 'Gene', '6317', (36, 39))
194237	24885564	Moreover, 3 novel mutations in exon5, 13 and 15 of DDR2 gene in a screen of 86 lung SCC samples were identified, yielding an overall mutation rate of 4.6% in all samples, which indicated that there is no significant difference of DDR2 mutation rate in Chinese, Europe and American patients.	('SCC', 'Gene', '6317', (84, 87))	('patients', 'Species', '9606', (281, 289))	('DDR2', 'Gene', (230, 234))	('SCC', 'Gene', (84, 87))	('DDR2', 'Gene', (51, 55))	('mutations in', 'Var', (18, 30))
194239	24885564	Although the sample size was not large, the novel DDR2 mutations in lung SCC suggest that DDR2 mutations could contribute to the pathogenesis of lung SCC.	('SCC', 'Gene', '6317', (150, 153))	('DDR2', 'Gene', (50, 54))	('mutations', 'Var', (55, 64))	('SCC', 'Gene', (73, 76))	('SCC', 'Gene', (150, 153))	('SCC', 'Gene', '6317', (73, 76))	('contribute', 'Reg', (111, 121))
194240	24885564	The mechanism by which DDR2 and its mutations may contribute to oncogenesis in lung SCC is not well known; however, given its role in transmitting signals from the ECM, it is likely that DDR2 could act as regulators of cell proliferation, migration and subsequent tumor cells metastasis.	('DDR2', 'Gene', (187, 191))	('SCC', 'Gene', '6317', (84, 87))	('tumor', 'Phenotype', 'HP:0002664', (264, 269))	('contribute', 'Reg', (50, 60))	('ECM', 'Gene', (164, 167))	('tumor', 'Disease', (264, 269))	('cell proliferation', 'CPA', (219, 237))	('mutations', 'Var', (36, 45))	('DDR2', 'Gene', (23, 27))	('migration', 'CPA', (239, 248))	('SCC', 'Gene', (84, 87))	('act', 'Reg', (198, 201))	('tumor', 'Disease', 'MESH:D009369', (264, 269))	('ECM', 'Gene', '22915', (164, 167))	('regulators', 'Reg', (205, 215))
194241	24885564	Activated DDR2 can induce the expression of MMP-1, MMP-2 and MMP-13, and stimulation of DDR2 could promote fibroblast migration and proliferation.	('fibroblast migration', 'CPA', (107, 127))	('induce', 'PosReg', (19, 25))	('expression', 'MPA', (30, 40))	('MMP-1', 'Gene', (61, 66))	('stimulation', 'Var', (73, 84))	('MMP-1', 'Gene', (44, 49))	('promote', 'PosReg', (99, 106))	('DDR2', 'Gene', (88, 92))	('proliferation', 'CPA', (132, 145))	('MMP-2', 'Gene', (51, 56))	('MMP-13', 'Gene', '4322', (61, 67))	('MMP-13', 'Gene', (61, 67))	('MMP-1', 'Gene', '4312', (44, 49))	('MMP-2', 'Gene', '4313', (51, 56))	('DDR2', 'Gene', (10, 14))	('MMP-1', 'Gene', '4312', (61, 66))
194242	24885564	In addition, it is conceivable that altered expression of DDRs triggers abnormal activity, ultimately leading to enhanced proliferation and oncogenesis as well as EGFR.	('oncogenesis', 'CPA', (140, 151))	('EGFR', 'Gene', '1956', (163, 167))	('DDRs', 'Gene', (58, 62))	('EGFR', 'Gene', (163, 167))	('altered', 'Var', (36, 43))	('activity', 'MPA', (81, 89))	('enhanced', 'PosReg', (113, 121))
194243	24885564	In this study, DDR2 wildtype overexpression vector and two DDR2 mutations vector (pEGFP-DDR2-S131C, pEGFP-DDR2-T681) were constructed and transfected into HBE and lung SCC cells to explore the potential biological function and underlying molecular mechanism of DDR2 and its mutations in lung SCC development.	('SCC', 'Gene', (168, 171))	('EGF', 'Gene', (101, 104))	('SCC', 'Gene', (292, 295))	('EGF', 'Gene', '1950', (83, 86))	('EGF', 'Gene', '1950', (101, 104))	('SCC', 'Gene', '6317', (168, 171))	('S131C', 'Mutation', 'p.S131C', (93, 98))	('SCC', 'Gene', '6317', (292, 295))	('EGF', 'Gene', (83, 86))	('mutations', 'Var', (274, 283))	('DDR2', 'Gene', (261, 265))
194244	24885564	Further investigation indicated that enhanced DDR2 and its S131C mutation could promote HBE and lung SCC cells proliferation, migration and invasion partly via promoting EMT through regulating MMP-2 and E-cadherin expression.	('S131C', 'Mutation', 'p.S131C', (59, 64))	('expression', 'MPA', (214, 224))	('DDR2', 'Gene', (46, 50))	('MMP-2', 'Gene', '4313', (193, 198))	('EMT', 'CPA', (170, 173))	('SCC', 'Gene', '6317', (101, 104))	('promoting', 'PosReg', (160, 169))	('regulating', 'Reg', (182, 192))	('invasion', 'CPA', (140, 148))	('S131C mutation', 'Var', (59, 73))	('SCC', 'Gene', (101, 104))	('E-cadherin', 'Gene', (203, 213))	('E-cadherin', 'Gene', '999', (203, 213))	('MMP-2', 'Gene', (193, 198))	('migration', 'CPA', (126, 135))	('promote', 'PosReg', (80, 87))
194250	24885564	In this study, we showed that DDR2 and its mutation is an effective regulatory factor promoting EMT in lung SCC cells.	('EMT in', 'CPA', (96, 102))	('mutation', 'Var', (43, 51))	('SCC', 'Gene', (108, 111))	('promoting', 'PosReg', (86, 95))	('SCC', 'Gene', '6317', (108, 111))	('DDR2', 'Gene', (30, 34))
194252	24885564	However, we did not evaluate the effects of expression of mutated DDR2 in an large enough sample size to detect a statistically significant difference in the rates of DDR2 mutation, nor did we complete an assessment of function of all identified DDR2 mutants in lung SCC cells.	('SCC', 'Gene', '6317', (267, 270))	('DDR2', 'Gene', (246, 250))	('DDR2', 'Gene', (167, 171))	('SCC', 'Gene', (267, 270))	('mutants', 'Var', (251, 258))
194253	24885564	Finally, this study provides evidence that novel DDR2 mutations in lung SCC, and at least one of which is functionally significant adding to the knowledge of the genetic landscape of SCCs.	('mutations', 'Var', (54, 63))	('SCC', 'Gene', (183, 186))	('SCC', 'Gene', (72, 75))	('SCC', 'Gene', '6317', (183, 186))	('SCC', 'Gene', '6317', (72, 75))	('DDR2', 'Gene', (49, 53))
194254	24885564	We hope our data may stimulate the initiation of larger clinical trials of testing of lung SCC patients for DDR2 mutations leading to a more effective treatment for this deadly disease.	('patients', 'Species', '9606', (95, 103))	('SCC', 'Gene', '6317', (91, 94))	('lung', 'Disease', (86, 90))	('mutations', 'Var', (113, 122))	('SCC', 'Gene', (91, 94))	('DDR2', 'Gene', (108, 112))
194259	33146672	Down-regulating NEAT1 inhibited the viability and vasculogenic mimicry formation of sinonasal squamous cell carcinoma cells via miR-195-5p/VEGFA axis The role of long non-coding RNA nuclear-enriched abundant transcript 1 (lncRNA NEAT1) in sinonasal squamous cell carcinoma (SNSCC) remained obscure.	('inhibited', 'NegReg', (22, 31))	('carcinoma', 'Phenotype', 'HP:0030731', (263, 272))	('sinonasal squamous cell carcinoma', 'Phenotype', 'HP:0012182', (239, 272))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (249, 272))	('VEGFA', 'Gene', '7422', (139, 144))	('nuclear-enriched abundant transcript 1', 'Gene', '283131', (182, 220))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (94, 117))	('miR-195', 'Gene', '406971', (128, 135))	('SNSCC', 'Phenotype', 'HP:0012182', (274, 279))	('squamous cell carcinoma', 'Disease', (249, 272))	('NEAT1', 'Gene', (229, 234))	('nuclear-enriched abundant transcript 1', 'Gene', (182, 220))	('NEAT1', 'Gene', (16, 21))	('sinonasal squamous cell carcinoma', 'Phenotype', 'HP:0012182', (84, 117))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (94, 117))	('miR-195', 'Gene', (128, 135))	('viability', 'CPA', (36, 45))	('Down-regulating', 'Var', (0, 15))	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('squamous cell carcinoma', 'Disease', (94, 117))	('VEGFA', 'Gene', (139, 144))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (249, 272))	('NEAT1', 'Gene', '283131', (16, 21))	('NEAT1', 'Gene', '283131', (229, 234))
194266	33146672	Overexpressed VEGFA promoted the viability and capillary-like tube formation of SNSCC cells yet suppressed their apoptosis, while silencing VEGFA led to the opposite results.	('VEGFA', 'Gene', (140, 145))	('VEGFA', 'Gene', (14, 19))	('apoptosis', 'CPA', (113, 122))	('capillary-like tube formation', 'CPA', (47, 76))	('VEGFA', 'Gene', '7422', (140, 145))	('SNSCC', 'Phenotype', 'HP:0012182', (80, 85))	('suppressed', 'NegReg', (96, 106))	('promoted', 'PosReg', (20, 28))	('VEGFA', 'Gene', '7422', (14, 19))	('viability', 'CPA', (33, 42))	('silencing', 'Var', (130, 139))
194267	33146672	MiR-195-5p could bind to NEAT1, and down-regulating miR-195-5p reversed the effects of silencing NEAT1 on the expressions of NEAT1 and miR-195-5p, cell viability, apoptosis and capillary-like tube formation as well as PI3K/AKT pathway activation.	('PI3', 'Gene', '5266', (218, 221))	('silencing', 'Var', (87, 96))	('cell viability', 'CPA', (147, 161))	('-195-5p', 'Chemical', '-', (55, 62))	('AKT', 'Gene', (223, 226))	('down-regulating', 'NegReg', (36, 51))	('activation', 'PosReg', (235, 245))	('miR-195', 'Gene', '406971', (52, 59))	('NEAT1', 'Gene', '283131', (125, 130))	('expressions', 'MPA', (110, 121))	('NEAT1', 'Gene', (97, 102))	('miR-195', 'Gene', (52, 59))	('PI3', 'Gene', (218, 221))	('NEAT1', 'Gene', (25, 30))	('-195-5p', 'Chemical', '-', (3, 10))	('AKT', 'Gene', '207', (223, 226))	('apoptosis', 'CPA', (163, 172))	('-195-5p', 'Chemical', '-', (138, 145))	('MiR-195', 'Gene', (0, 7))	('NEAT1', 'Gene', '283131', (97, 102))	('NEAT1', 'Gene', (125, 130))	('miR-195', 'Gene', '406971', (135, 142))	('MiR-195', 'Gene', '406971', (0, 7))	('capillary-like tube formation', 'CPA', (177, 206))	('NEAT1', 'Gene', '283131', (25, 30))	('miR-195', 'Gene', (135, 142))
194269	33146672	Down-regulating NEAT1 inhibited the viability and vasculogenic mimicry formation of SNSCC cells yet promoted their apoptosis via the miR-195-5p/VEGFA axis, providing a possible therapeutic target for SNSCC treatment.	('inhibited', 'NegReg', (22, 31))	('miR-195', 'Gene', '406971', (133, 140))	('SNSCC', 'Phenotype', 'HP:0012182', (200, 205))	('SNSCC', 'Phenotype', 'HP:0012182', (84, 89))	('promoted', 'PosReg', (100, 108))	('NEAT1', 'Gene', (16, 21))	('-195-5p', 'Chemical', '-', (136, 143))	('VEGFA', 'Gene', '7422', (144, 149))	('NEAT1', 'Gene', '283131', (16, 21))	('apoptosis', 'CPA', (115, 124))	('VEGFA', 'Gene', (144, 149))	('miR-195', 'Gene', (133, 140))	('viability', 'CPA', (36, 45))	('Down-regulating', 'Var', (0, 15))	('vasculogenic mimicry formation', 'CPA', (50, 80))
194277	33146672	Besides, lncRNA AC091729.7 has been discovered as a novel lncRNA that promotes the proliferation and invasion of SNSCC cells through binding to serine/arginine-rich splicing factor 2 (SRSF2).	('proliferation', 'CPA', (83, 96))	('SRSF2', 'Gene', '6427', (184, 189))	('invasion', 'CPA', (101, 109))	('serine/arginine-rich splicing factor 2', 'Gene', (144, 182))	('promotes', 'PosReg', (70, 78))	('AC091729.7', 'Var', (16, 26))	('serine/arginine-rich splicing factor 2', 'Gene', '6427', (144, 182))	('SNSCC', 'Phenotype', 'HP:0012182', (113, 118))	('SRSF2', 'Gene', (184, 189))	('binding', 'Interaction', (133, 140))
194296	33146672	Overexpression plasmids of VEGFA were successfully constructed with pcDNA3.1 plasmid (V79020; Thermo Fisher Scientific, Waltham, MA, U.S.A.).	('VEGFA', 'Gene', (27, 32))	('V79020;', 'Var', (86, 93))	('VEGFA', 'Gene', '7422', (27, 32))
194300	33146672	A site-directed mutagenesis kit (F541; Thermo Fisher Scientific, U.S.A.) was used to perform 3'UTR mutagenesis at the miR-195-5p target site so as to form mutated NEAT1 and VEGFA (NEAT1-mut; VEGFA-mut) reporter plasmids.	('VEGFA', 'Gene', '7422', (173, 178))	('VEGFA', 'Gene', '7422', (191, 196))	('-195-5p', 'Chemical', '-', (121, 128))	('VEGFA', 'Gene', (173, 178))	('NEAT1', 'Gene', '283131', (180, 185))	('VEGFA', 'Gene', (191, 196))	('miR-195', 'Gene', (118, 125))	('miR-195', 'Gene', '406971', (118, 125))	('mutagenesis', 'Var', (99, 110))	('NEAT1', 'Gene', (180, 185))	('NEAT1', 'Gene', '283131', (163, 168))	('NEAT1', 'Gene', (163, 168))
194318	33146672	Then, for dual-luciferase reporter assay, wild-type or mutated NEAT1 and VEGFA (NEAT1-WT; NEAT1-MUT; VEGFA-WT; VEGFA-MUT) as well as miR-195-5p mimic or mimic control were co-transfected into RPMI-2650 cells.	('miR-195', 'Gene', '406971', (133, 140))	('RPMI-2650', 'CellLine', 'CVCL:1664', (192, 201))	('VEGFA', 'Gene', '7422', (111, 116))	('mutated', 'Var', (55, 62))	('VEGFA', 'Gene', (111, 116))	('NEAT1', 'Gene', (63, 68))	('VEGFA', 'Gene', (73, 78))	('VEGFA', 'Gene', (101, 106))	('NEAT1', 'Gene', '283131', (63, 68))	('-195-5p', 'Chemical', '-', (136, 143))	('NEAT1', 'Gene', '283131', (80, 85))	('NEAT1', 'Gene', (90, 95))	('NEAT1', 'Gene', '283131', (90, 95))	('VEGFA', 'Gene', '7422', (101, 106))	('NEAT1', 'Gene', (80, 85))	('VEGFA', 'Gene', '7422', (73, 78))	('miR-195', 'Gene', (133, 140))
194326	33146672	To discover the role of VEGFA in SNSCC cells, we transfected VEGFA overexpression plasmid as well as small interfering RNA for VEGFA (siVEGFA) into SNSCC RPMI-2650 cells.	('VEGFA', 'Gene', (24, 29))	('VEGFA', 'Gene', (127, 132))	('RPMI-2650', 'CellLine', 'CVCL:1664', (154, 163))	('SNSCC', 'Phenotype', 'HP:0012182', (148, 153))	('VEGFA', 'Gene', '7422', (61, 66))	('VEGFA', 'Gene', '7422', (136, 141))	('SNSCC', 'Phenotype', 'HP:0012182', (33, 38))	('VEGFA', 'Gene', '7422', (127, 132))	('VEGFA', 'Gene', '7422', (24, 29))	('VEGFA', 'Gene', (61, 66))	('small interfering', 'Var', (101, 118))	('VEGFA', 'Gene', (136, 141))
194327	33146672	As shown in Figure 3A, VEGFA expression was down-regulated after transfection with siVEGFA, whereas transfection with the VEGFA overexpression plasmid led to an opposite effect (P<0.01), suggesting that overexpressed VEGFA up-regulated VEGFA expression in SNSCC cells, whereas silencing VEGFA caused an opposite effect.	('down-regulated', 'NegReg', (44, 58))	('up-regulated', 'PosReg', (223, 235))	('VEGFA', 'Gene', (217, 222))	('VEGFA', 'Gene', '7422', (236, 241))	('VEGFA', 'Gene', '7422', (23, 28))	('VEGFA', 'Gene', '7422', (287, 292))	('VEGFA', 'Gene', '7422', (85, 90))	('VEGFA', 'Gene', '7422', (122, 127))	('VEGFA', 'Gene', (23, 28))	('VEGFA', 'Gene', '7422', (217, 222))	('SNSCC', 'Phenotype', 'HP:0012182', (256, 261))	('VEGFA', 'Gene', (236, 241))	('VEGFA', 'Gene', (85, 90))	('VEGFA', 'Gene', (287, 292))	('expression', 'MPA', (29, 39))	('VEGFA', 'Gene', (122, 127))	('expression', 'MPA', (242, 252))	('overexpressed', 'Var', (203, 216))
194329	33146672	As shown in Figure 3B, there was a decrease in the viability of SNSCC cells after silencing VEGFA, whereas overexpressed VEGFA resulted in an opposite effect (P<0.05), indicating that silencing VEGFA suppressed SNSCC cell viability while overexpressed VEGFA exerted an opposite effect.	('VEGFA', 'Gene', (121, 126))	('SNSCC cell viability', 'CPA', (211, 231))	('silencing', 'Var', (184, 193))	('VEGFA', 'Gene', '7422', (92, 97))	('VEGFA', 'Gene', '7422', (252, 257))	('SNSCC', 'Phenotype', 'HP:0012182', (64, 69))	('VEGFA', 'Gene', (194, 199))	('SNSCC', 'Phenotype', 'HP:0012182', (211, 216))	('silencing', 'Var', (82, 91))	('decrease', 'NegReg', (35, 43))	('VEGFA', 'Gene', (92, 97))	('VEGFA', 'Gene', '7422', (121, 126))	('VEGFA', 'Gene', (252, 257))	('suppressed', 'NegReg', (200, 210))	('VEGFA', 'Gene', '7422', (194, 199))
194330	33146672	It was discovered from the results of flow cytometry that after silencing VEGFA, the apoptosis rate of SNSCC cells was significantly up-regulated while overexpressed VEGFA caused a decrease in the apoptosis rate of SNSCC cells (Figure 3C, P<0.001), suggesting that silencing VEGFA resulted in the promotion of SNSCC cell apoptosis, whereas overexpressed VEGFA posed an opposite effect.	('silencing', 'Var', (265, 274))	('silencing', 'Var', (64, 73))	('SNSCC', 'Phenotype', 'HP:0012182', (103, 108))	('VEGFA', 'Gene', (166, 171))	('VEGFA', 'Gene', (275, 280))	('VEGFA', 'Gene', (354, 359))	('apoptosis rate', 'CPA', (85, 99))	('VEGFA', 'Gene', (74, 79))	('SNSCC', 'Phenotype', 'HP:0012182', (310, 315))	('SNSCC', 'Phenotype', 'HP:0012182', (215, 220))	('up-regulated', 'PosReg', (133, 145))	('promotion', 'PosReg', (297, 306))	('VEGFA', 'Gene', '7422', (166, 171))	('VEGFA', 'Gene', '7422', (275, 280))	('SNSCC cell apoptosis', 'CPA', (310, 330))	('VEGFA', 'Gene', '7422', (74, 79))	('VEGFA', 'Gene', '7422', (354, 359))
194333	33146672	Therefore, it could be summarized that silencing VEGFA suppressed capillary-like tube formation in SNSCC cell-mediated HUVECs whereas overexpressed VEGFA led to a contrary result.	('SNSCC', 'Phenotype', 'HP:0012182', (99, 104))	('VEGFA', 'Gene', (49, 54))	('VEGFA', 'Gene', (148, 153))	('capillary-like tube formation', 'CPA', (66, 95))	('silencing', 'Var', (39, 48))	('suppressed', 'NegReg', (55, 65))	('VEGFA', 'Gene', '7422', (49, 54))	('VEGFA', 'Gene', '7422', (148, 153))
194336	33146672	Furthermore, we also found that the effects of silencing NEAT1 on NEAT1 and miR-195-5p expressions in SNSCC cells were reversed by down-regulating miR-195-5p (Figure 4A,B, P<0.001).	('-195-5p', 'Chemical', '-', (79, 86))	('miR-195', 'Gene', (147, 154))	('NEAT1', 'Gene', (57, 62))	('down-regulating', 'NegReg', (131, 146))	('miR-195', 'Gene', '406971', (147, 154))	('NEAT1', 'Gene', '283131', (66, 71))	('-195-5p', 'Chemical', '-', (150, 157))	('NEAT1', 'Gene', (66, 71))	('silencing', 'Var', (47, 56))	('miR-195', 'Gene', (76, 83))	('miR-195', 'Gene', '406971', (76, 83))	('SNSCC', 'Phenotype', 'HP:0012182', (102, 107))	('NEAT1', 'Gene', '283131', (57, 62))
194338	33146672	As shown in Figure 4C, the results from MTT assay showed that silencing NEAT1 caused a decrease in SNSCC cell viability, whereas down-regulating miR-195-5p resulted in an opposite effect (P<0.05).	('silencing', 'Var', (62, 71))	('MTT', 'Chemical', 'MESH:C070243', (40, 43))	('-195-5p', 'Chemical', '-', (148, 155))	('miR-195', 'Gene', (145, 152))	('miR-195', 'Gene', '406971', (145, 152))	('SNSCC cell viability', 'CPA', (99, 119))	('down-regulating', 'NegReg', (129, 144))	('decrease', 'NegReg', (87, 95))	('NEAT1', 'Gene', (72, 77))	('NEAT1', 'Gene', '283131', (72, 77))	('SNSCC', 'Phenotype', 'HP:0012182', (99, 104))
194339	33146672	In addition, we discovered that down-regulating miR-195-5p could reverse the effects of silencing NEAT1 on SNSCC cell viability (Figure 4C, P<0.01).	('SNSCC', 'Phenotype', 'HP:0012182', (107, 112))	('-195-5p', 'Chemical', '-', (51, 58))	('NEAT1', 'Gene', (98, 103))	('miR-195', 'Gene', (48, 55))	('miR-195', 'Gene', '406971', (48, 55))	('down-regulating', 'NegReg', (32, 47))	('silencing', 'Var', (88, 97))	('NEAT1', 'Gene', '283131', (98, 103))
194340	33146672	Flow cytometry results revealed that after silencing NEAT1, the apoptosis rate of SNSCC cells was significantly up-regulated, while down-regulating miR-195-5p led to an opposite effect (Figure 4D, P<0.05).	('NEAT1', 'Gene', (53, 58))	('down-regulating', 'NegReg', (132, 147))	('apoptosis rate', 'CPA', (64, 78))	('silencing', 'Var', (43, 52))	('miR-195', 'Gene', (148, 155))	('miR-195', 'Gene', '406971', (148, 155))	('-195-5p', 'Chemical', '-', (151, 158))	('SNSCC', 'Phenotype', 'HP:0012182', (82, 87))	('up-regulated', 'PosReg', (112, 124))	('NEAT1', 'Gene', '283131', (53, 58))
194341	33146672	Besides, down-regulating miR-195-5p was found to reverse the effects of silencing NEAT1 on SNSCC cell apoptosis (Figure 4D, P<0.001).	('SNSCC', 'Disease', (91, 96))	('miR-195', 'Gene', (25, 32))	('NEAT1', 'Gene', (82, 87))	('silencing', 'Var', (72, 81))	('down-regulating', 'NegReg', (9, 24))	('miR-195', 'Gene', '406971', (25, 32))	('SNSCC', 'Phenotype', 'HP:0012182', (91, 96))	('NEAT1', 'Gene', '283131', (82, 87))	('-195-5p', 'Chemical', '-', (28, 35))
194342	33146672	Results from capillary-like tube formation exhibited a decrease in the angiogenesis rate of SNSCC cells-mediated HUVECs after silencing NEAT1, whereas down-regulating miR-195-5p caused an opposite effect (Figure 4E, P<0.01).	('angiogenesis rate', 'CPA', (71, 88))	('miR-195', 'Gene', '406971', (167, 174))	('NEAT1', 'Gene', (136, 141))	('-195-5p', 'Chemical', '-', (170, 177))	('decrease', 'NegReg', (55, 63))	('SNSCC', 'Phenotype', 'HP:0012182', (92, 97))	('silencing', 'Var', (126, 135))	('miR-195', 'Gene', (167, 174))	('NEAT1', 'Gene', '283131', (136, 141))
194343	33146672	In addition, we discovered that down-regulating miR-195-5p could reverse the effects of silencing NEAT1 on capillary-like tube formation of SNSCC cells-mediated HUVECs (Figure 4E, P<0.05).	('-195-5p', 'Chemical', '-', (51, 58))	('NEAT1', 'Gene', (98, 103))	('miR-195', 'Gene', (48, 55))	('miR-195', 'Gene', '406971', (48, 55))	('down-regulating', 'NegReg', (32, 47))	('silencing', 'Var', (88, 97))	('capillary-like tube formation', 'CPA', (107, 136))	('SNSCC', 'Phenotype', 'HP:0012182', (140, 145))	('NEAT1', 'Gene', '283131', (98, 103))
194345	33146672	As shown in Figure 5A, VEGFA, p-PI3K and p-AKT expressions were decreased after silencing NEAT1, whereas down-regulating miR-195-5p resulted in a contrary result (P<0.001).	('VEGFA', 'Gene', '7422', (23, 28))	('-195-5p', 'Chemical', '-', (124, 131))	('silencing', 'Var', (80, 89))	('AKT', 'Gene', '207', (43, 46))	('PI3', 'Gene', (32, 35))	('miR-195', 'Gene', (121, 128))	('VEGFA', 'Gene', (23, 28))	('miR-195', 'Gene', '406971', (121, 128))	('AKT', 'Gene', (43, 46))	('NEAT1', 'Gene', (90, 95))	('NEAT1', 'Gene', '283131', (90, 95))	('PI3', 'Gene', '5266', (32, 35))	('decreased', 'NegReg', (64, 73))
194346	33146672	We also found that the effects of silencing NEAT1 on VEGFA, p-PI3K and p-AKT expressions in SNSCC cells were reversed by down-regulating miR-195-5p (Figure 5A, P<0.01).	('miR-195', 'Gene', '406971', (137, 144))	('VEGFA', 'Gene', '7422', (53, 58))	('NEAT1', 'Gene', (44, 49))	('PI3', 'Gene', '5266', (62, 65))	('AKT', 'Gene', (73, 76))	('VEGFA', 'Gene', (53, 58))	('SNSCC', 'Phenotype', 'HP:0012182', (92, 97))	('-195-5p', 'Chemical', '-', (140, 147))	('PI3', 'Gene', (62, 65))	('NEAT1', 'Gene', '283131', (44, 49))	('down-regulating', 'NegReg', (121, 136))	('silencing', 'Var', (34, 43))	('AKT', 'Gene', '207', (73, 76))	('miR-195', 'Gene', (137, 144))
194347	33146672	Furthermore, we verified PI3K and AKT phosphorylation in SNSCCs after silencing NEAT1 and down-regulating miR-195-5p.	('down-regulating', 'NegReg', (90, 105))	('AKT', 'Gene', (34, 37))	('miR-195', 'Gene', (106, 113))	('miR-195', 'Gene', '406971', (106, 113))	('silencing', 'Var', (70, 79))	('PI3', 'Gene', '5266', (25, 28))	('NEAT1', 'Gene', '283131', (80, 85))	('-195-5p', 'Chemical', '-', (109, 116))	('SNSCC', 'Phenotype', 'HP:0012182', (57, 62))	('AKT', 'Gene', '207', (34, 37))	('NEAT1', 'Gene', (80, 85))	('PI3', 'Gene', (25, 28))	('verified', 'Reg', (16, 24))
194348	33146672	In this section, we found that silencing NEAT1 evidently down-regulated the phosphorylation levels of PI3K and AKT in SNSCCs (Figure 5B,C, P<0.01).	('down-regulated', 'NegReg', (57, 71))	('silencing', 'Var', (31, 40))	('AKT', 'Gene', '207', (111, 114))	('PI3', 'Gene', '5266', (102, 105))	('SNSCC', 'Phenotype', 'HP:0012182', (118, 123))	('NEAT1', 'Gene', (41, 46))	('PI3', 'Gene', (102, 105))	('AKT', 'Gene', (111, 114))	('NEAT1', 'Gene', '283131', (41, 46))	('phosphorylation levels', 'MPA', (76, 98))
194350	33146672	In conclusion, down-regulating miR-195-5p reversed the effects of silencing NEAT1 on the phosphorylation levels of PI3K and AKT in SNSCC cells.	('-195-5p', 'Chemical', '-', (34, 41))	('miR-195', 'Gene', (31, 38))	('silencing', 'Var', (66, 75))	('AKT', 'Gene', (124, 127))	('PI3', 'Gene', (115, 118))	('SNSCC', 'Phenotype', 'HP:0012182', (131, 136))	('down-regulating', 'NegReg', (15, 30))	('miR-195', 'Gene', '406971', (31, 38))	('phosphorylation levels', 'MPA', (89, 111))	('NEAT1', 'Gene', '283131', (76, 81))	('PI3', 'Gene', '5266', (115, 118))	('NEAT1', 'Gene', (76, 81))	('AKT', 'Gene', '207', (124, 127))
194352	33146672	As shown in Figure 6A-C, overexpressed VEGFA increased the protein and mRNA expressions of VEGFA (P<0.01) yet had no significant effect on miR-195-5p expression, while transfection with miR-195-5p mimic led to an opposite effect (P<0.05).	('VEGFA', 'Gene', '7422', (39, 44))	('VEGFA', 'Gene', '7422', (91, 96))	('-195-5p', 'Chemical', '-', (142, 149))	('overexpressed', 'Var', (25, 38))	('increased', 'PosReg', (45, 54))	('miR-195', 'Gene', '406971', (186, 193))	('VEGFA', 'Gene', (39, 44))	('VEGFA', 'Gene', (91, 96))	('miR-195', 'Gene', (186, 193))	('miR-195', 'Gene', (139, 146))	('miR-195', 'Gene', '406971', (139, 146))	('protein', 'MPA', (59, 66))	('mRNA expressions', 'MPA', (71, 87))	('-195-5p', 'Chemical', '-', (189, 196))
194357	33146672	Flow cytometry results indicated that overexpressed VEGFA exerted a significant down-regulatory effect on the apoptosis of SNSCC cells, while up-regulating miR-195-5p led to a contrary result (Figure 7A, P<0.05).	('overexpressed', 'Var', (38, 51))	('-195-5p', 'Chemical', '-', (159, 166))	('VEGFA', 'Gene', (52, 57))	('VEGFA', 'Gene', '7422', (52, 57))	('down-regulatory', 'NegReg', (80, 95))	('miR-195', 'Gene', (156, 163))	('miR-195', 'Gene', '406971', (156, 163))	('apoptosis', 'CPA', (110, 119))	('up-regulating', 'PosReg', (142, 155))	('SNSCC', 'Phenotype', 'HP:0012182', (123, 128))
194375	33146672	Also, the effects of silencing NEAT1 on the viability, apoptosis and capillary-like tube formation of SNSCC cells were reversed by miR-195-5p down-regulation.	('NEAT1', 'Gene', '283131', (31, 36))	('miR-195', 'Gene', (131, 138))	('miR-195', 'Gene', '406971', (131, 138))	('-195-5p', 'Chemical', '-', (134, 141))	('capillary-like tube formation', 'CPA', (69, 98))	('NEAT1', 'Gene', (31, 36))	('SNSCC', 'Phenotype', 'HP:0012182', (102, 107))	('apoptosis', 'CPA', (55, 64))	('silencing', 'Var', (21, 30))	('down-regulation', 'NegReg', (142, 157))
194382	33146672	However, the effects of silencing NEAT1 on the PI3K/AKT pathway were reversed by miR-195-5p down-regulation in SNSCC cells.	('miR-195', 'Gene', '406971', (81, 88))	('PI3', 'Gene', '5266', (47, 50))	('NEAT1', 'Gene', '283131', (34, 39))	('SNSCC', 'Phenotype', 'HP:0012182', (111, 116))	('AKT', 'Gene', (52, 55))	('-195-5p', 'Chemical', '-', (84, 91))	('NEAT1', 'Gene', (34, 39))	('down-regulation', 'NegReg', (92, 107))	('PI3', 'Gene', (47, 50))	('miR-195', 'Gene', (81, 88))	('silencing', 'Var', (24, 33))	('AKT', 'Gene', '207', (52, 55))
194383	33146672	VM is defined as a process in which invasive tumor cells can simulate endothelial cells and form a pipeline structure, and its presence has been found associated with high tumor grade, short survival, invasion and metastasis.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('associated with', 'Reg', (151, 166))	('tumor', 'Disease', (172, 177))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('metastasis', 'CPA', (214, 224))	('tumor', 'Disease', (45, 50))	('invasive tumor', 'Disease', 'MESH:D009361', (36, 50))	('short survival', 'CPA', (185, 199))	('invasive tumor', 'Disease', (36, 50))	('presence', 'Var', (127, 135))	('invasion', 'CPA', (201, 209))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
194389	33146672	In colorectal cancer progression, miR-150-5p was discovered to act as a suppressor via targeting VEGFA.	('VEGFA', 'Gene', (97, 102))	('colorectal cancer', 'Phenotype', 'HP:0003003', (3, 20))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('miR-150-5p', 'Var', (34, 44))	('colorectal cancer', 'Disease', (3, 20))	('miR-150-5p', 'Chemical', '-', (34, 44))	('VEGFA', 'Gene', '7422', (97, 102))	('colorectal cancer', 'Disease', 'MESH:D015179', (3, 20))
194390	33146672	In addition, miR-15a-5p could suppress peritoneal dialysis-induced inflammation and fibrosis of peritoneal mesothelial cells by targeting VEGFA.	('VEGFA', 'Gene', (138, 143))	('inflammation', 'Disease', 'MESH:D007249', (67, 79))	('miR-15a-5p', 'Var', (13, 23))	('VEGFA', 'Gene', '7422', (138, 143))	('targeting', 'Reg', (128, 137))	('inflammation', 'Disease', (67, 79))	('miR-15a-5p', 'Chemical', '-', (13, 23))	('peritoneal dialysis-induced', 'Disease', (39, 66))	('suppress', 'NegReg', (30, 38))	('fibrosis', 'Disease', 'MESH:D005355', (84, 92))	('fibrosis', 'Disease', (84, 92))
194399	33146672	Besides, the inhibitory effects of silencing NEAT1 on VEGFA levels were reversed by miR-195-5p down-regulation in SNSCC cells.	('-195-5p', 'Chemical', '-', (87, 94))	('silencing', 'Var', (35, 44))	('VEGFA', 'Gene', '7422', (54, 59))	('miR-195', 'Gene', '406971', (84, 91))	('SNSCC', 'Phenotype', 'HP:0012182', (114, 119))	('down-regulation', 'NegReg', (95, 110))	('NEAT1', 'Gene', '283131', (45, 50))	('NEAT1', 'Gene', (45, 50))	('miR-195', 'Gene', (84, 91))	('VEGFA', 'Gene', (54, 59))
194402	33146672	In addition, as transcription factor NF-kappaB plays an important role in regulating VEGF expression, it will be interesting to observe the effect of silencing/overexpressing NEAT1 on NF-kappaB signaling in future study.	('NEAT1', 'Gene', '283131', (175, 180))	('NF-kappaB', 'Gene', (37, 46))	('VEGF', 'Gene', '7422', (85, 89))	('silencing/overexpressing', 'Var', (150, 174))	('NEAT1', 'Gene', (175, 180))	('expression', 'MPA', (90, 100))	('NF-kappaB', 'Gene', '4790', (184, 193))	('VEGF', 'Gene', (85, 89))	('NF-kappaB', 'Gene', '4790', (37, 46))	('NF-kappaB', 'Gene', (184, 193))
194414	32093621	Taking the effect of clinicopathological variables on PRS into consideration, smoking history (P = 0.043), non-adenocarcinoma (P = 0.013), high architectural grade of LUAD (P = 0.019), EGFR wild status (P = 0.002), bone metastasis (P =0.040) and brain metastasis (P = 0.042) were substantially related with poorer PRS.	('bone metastasis', 'CPA', (215, 230))	('EGFR', 'Gene', (185, 189))	('non-adenocarcinoma', 'Disease', 'MESH:D000230', (107, 125))	('non-adenocarcinoma', 'Disease', (107, 125))	('brain metastasis', 'CPA', (246, 262))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('LUAD', 'Phenotype', 'HP:0030078', (167, 171))	('LUAD', 'Disease', (167, 171))	('high', 'Var', (139, 143))	('LUAD', 'Disease', 'MESH:C538231', (167, 171))	('EGFR', 'Gene', '1956', (185, 189))
194439	32093621	Postoperative assessment contained health checkup, serum tumor markers (CEA, CA125, CA199, NSE, CYFRA21-1), chest/upper-abdominal CT scans, and bone scintigraphy.	('NSE', 'Gene', (91, 94))	('CA199', 'Var', (84, 89))	('CYFRA21-1', 'Var', (96, 105))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('CA125', 'Gene', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('NSE', 'Gene', '2026', (91, 94))	('tumor', 'Disease', (57, 62))	('CA125', 'Gene', '94025', (77, 82))
194461	32093621	For univariate analysis, p-stage IB (versus IA) (HR: 2.048, 95%CI: 1.547-2.710; P<0.001), LVI (HR: 3.364, 95%CI: 2.247-5.038; P<0.001), visceral pleural invasion (VPI) (HR: 1.779, 95%CI: 1.408-2.248; P<0.001) were significantly correlated with the higher incidence of lung cancer recurrence.	('LVI', 'Disease', (90, 93))	('IA', 'Disease', 'MESH:D000230', (44, 46))	('VPI', 'Disease', 'MESH:D010997', (163, 166))	('visceral pleural invasion', 'Disease', (136, 161))	('lung cancer', 'Disease', 'MESH:D008175', (268, 279))	('p-stage IB', 'Var', (25, 35))	('cancer', 'Phenotype', 'HP:0002664', (273, 279))	('lung cancer', 'Disease', (268, 279))	('lung cancer', 'Phenotype', 'HP:0100526', (268, 279))	('visceral pleural invasion', 'Disease', 'MESH:D010997', (136, 161))	('VPI', 'Disease', (163, 166))
194476	32093621	In addition, the current study also demonstrated that high architectural grade including solid-predominant LUAD was significantly associated with poor PRS, which highlights the need for medical care for the postoperative clinical contact.	('poor PRS', 'Disease', (146, 154))	('LUAD', 'Phenotype', 'HP:0030078', (107, 111))	('LUAD', 'Disease', (107, 111))	('LUAD', 'Disease', 'MESH:C538231', (107, 111))	('high architectural', 'Var', (54, 72))
194486	32093621	With the rapid development of management of lung cancer, molecular target therapy of tyrosine kinase inhibitors (TKI) has exerted survival benefit for the NSCLC patients with EGFR mutations.	('lung cancer', 'Phenotype', 'HP:0100526', (44, 55))	('EGFR', 'Gene', (175, 179))	('mutations', 'Var', (180, 189))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('NSCLC', 'Disease', (155, 160))	('lung cancer', 'Disease', 'MESH:D008175', (44, 55))	('patients', 'Species', '9606', (161, 169))	('NSCLC', 'Disease', 'MESH:D002289', (155, 160))	('NSCLC', 'Phenotype', 'HP:0030358', (155, 160))	('EGFR', 'Gene', '1956', (175, 179))	('lung cancer', 'Disease', (44, 55))
194488	32093621	The current study also suggested that NSCLC patients with EGFR mutations, having received the EGFR-TKIs, obtained a favorable PRS.	('mutations', 'Var', (63, 72))	('EGFR', 'Gene', '1956', (58, 62))	('NSCLC', 'Disease', (38, 43))	('patients', 'Species', '9606', (44, 52))	('NSCLC', 'Disease', 'MESH:D002289', (38, 43))	('EGFR', 'Gene', '1956', (94, 98))	('EGFR', 'Gene', (58, 62))	('EGFR', 'Gene', (94, 98))	('NSCLC', 'Phenotype', 'HP:0030358', (38, 43))
194489	32093621	However, since no EGFR mutations accounts for the majority of the lung cancer, the most appropriate treatment modality for resected lung cancer with no mutations is needed to be investigated.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('EGFR', 'Gene', '1956', (18, 22))	('lung cancer', 'Disease', 'MESH:D008175', (132, 143))	('lung cancer', 'Disease', (66, 77))	('lung cancer', 'Phenotype', 'HP:0100526', (66, 77))	('EGFR', 'Gene', (18, 22))	('mutations', 'Var', (23, 32))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('lung cancer', 'Disease', (132, 143))	('lung cancer', 'Phenotype', 'HP:0100526', (132, 143))	('lung cancer', 'Disease', 'MESH:D008175', (66, 77))
194530	31257225	To examine the potential consequences of 3' UTR length changes in cancer and senescence, we first quantified the steady-state mRNA levels, as APA-mediated 3' UTR length changes could affect mRNA decay.	('changes', 'Var', (169, 176))	('cancer', 'Disease', (66, 72))	('affect', 'Reg', (183, 189))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('mRNA decay', 'MPA', (190, 200))
194533	31257225	Importantly, individuals with high HN1 expression tend to have lower survival rates in various cancer types, such as KIRP (Kidney renal papillary cell carcinoma), LIHC (Liver hepatocellular carcinoma), ACC (Adrenocortical carcinoma), HNSC (Head and Neck squamous cell carcinoma), KIRC, PAAD (Pancreatic adenocarcinoma), SKCM (Skin Cutaneous Melanoma), LUAD, and LUSC (Supplementary Figure 5), indicating that HN1 may function in tumor progression.	('Head and Neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (240, 277))	('LIHC', 'Disease', (163, 167))	('function', 'Reg', (417, 425))	('Kidney renal papillary cell carcinoma', 'Disease', (123, 160))	('tha', 'Chemical', 'MESH:D013619', (404, 407))	('Kidney renal papillary cell carcinoma', 'Disease', 'MESH:D007681', (123, 160))	('Adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (207, 231))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (254, 277))	('carcinoma', 'Phenotype', 'HP:0030731', (190, 199))	('LIHC', 'Disease', 'None', (163, 167))	('cancer', 'Disease', (95, 101))	('Skin Cutaneous Melanoma', 'Disease', (326, 349))	('carcinoma', 'Phenotype', 'HP:0030731', (222, 231))	('rat', 'Species', '10116', (78, 81))	('carcinoma', 'Phenotype', 'HP:0030731', (308, 317))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('Pancreatic adenocarcinoma', 'Disease', 'MESH:D010190', (292, 317))	('carcinoma', 'Phenotype', 'HP:0030731', (268, 277))	('carcinoma', 'Phenotype', 'HP:0030731', (151, 160))	('Adrenocortical carcinoma', 'Disease', (207, 231))	('tumor', 'Disease', (429, 434))	('Cutaneous Melanoma', 'Phenotype', 'HP:0012056', (331, 349))	('lower', 'NegReg', (63, 68))	('survival rates', 'CPA', (69, 83))	('Neck squamous cell carcinoma', 'Disease', (249, 277))	('Melanoma', 'Phenotype', 'HP:0002861', (341, 349))	('Neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (249, 277))	('high', 'Var', (30, 34))	('tumor', 'Disease', 'MESH:D009369', (429, 434))	('Liver hepatocellular carcinoma', 'Disease', (169, 199))	('HN1', 'Gene', (35, 38))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (175, 199))	('renal papillary cell carcinoma', 'Phenotype', 'HP:0006766', (130, 160))	('Liver hepatocellular carcinoma', 'Disease', 'MESH:D006528', (169, 199))	('expression', 'Var', (39, 49))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('Pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (292, 317))	('Pancreatic adenocarcinoma', 'Disease', (292, 317))	('Skin Cutaneous Melanoma', 'Disease', 'MESH:C562393', (326, 349))	('Adrenocortical carcinoma', 'Disease', 'MESH:D018268', (207, 231))	('tumor', 'Phenotype', 'HP:0002664', (429, 434))
194543	31257225	Next, HN1-KD induced G2/M cell cycle arrest in HUVEC cells and G1 arrest in A549 cells (Supplementary Figure 6A-6B; 6F-6G), in addition to a significantly decreased proportion of S-phase cells in both HN1-KD cell lines (Supplementary Figure 6A-6B; 6F-6G).	('G2/M cell cycle arrest', 'CPA', (21, 43))	('HN1-KD', 'Var', (6, 12))	('A549', 'CellLine', 'CVCL:0023', (76, 80))	('decreased', 'NegReg', (155, 164))	('G1 arrest', 'CPA', (63, 72))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (26, 43))	('HUVEC', 'CellLine', 'CVCL:2959', (47, 52))	('S-phase cells', 'CPA', (179, 192))
194545	31257225	What's more, the level of intracellular reactive oxygen species (ROS), a known senescence-associated phenotype and also a contributor to senescence, slightly increased in HN1-KD cells (Supplementary Figure 6D, 6I).	('reactive oxygen species', 'Chemical', 'MESH:D017382', (40, 63))	('ROS', 'Chemical', 'MESH:D017382', (65, 68))	('HN1-KD', 'Var', (171, 177))	('level of intracellular reactive oxygen species', 'MPA', (17, 63))	('increased', 'PosReg', (158, 167))
194547	31257225	The result showed that HN1-KD induced down-regulation of CDK1, CCNB1 and up-regulation of IL6 in both HUVECs and A549 cells (Supplementary Figure 6E, 6J).	('CCNB1', 'Gene', (63, 68))	('up-regulation', 'PosReg', (73, 86))	('CDK1', 'Gene', (57, 61))	('CDK1', 'Gene', '983', (57, 61))	('tha', 'Chemical', 'MESH:D013619', (18, 21))	('IL6', 'Gene', (90, 93))	('IL6', 'Gene', '3569', (90, 93))	('A549', 'CellLine', 'CVCL:0023', (113, 117))	('down-regulation', 'NegReg', (38, 53))	('HN1-KD', 'Var', (23, 29))	('CCNB1', 'Gene', '891', (63, 68))	('HUVEC', 'CellLine', 'CVCL:2959', (102, 107))
194548	31257225	These above combined to support the notion that HN1-KD could induce senescence-associated phenotypes in both normal and cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('induce', 'PosReg', (61, 67))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('senescence-associated', 'Disease', (68, 89))	('tha', 'Chemical', 'MESH:D013619', (43, 46))	('HN1-KD', 'Var', (48, 54))
194555	31257225	The ability of HNRNPA1 to regulate APA in HN1 was further validated separately in HNRNPA1-KD HEK293T cells (Supplementary Figure 8C-8D), A549 cells (Figure 4B-4D) and HUVEC cells (Supplementary Figure 8A, 8B).	('rat', 'Species', '10116', (72, 75))	('A549', 'CellLine', 'CVCL:0023', (137, 141))	('APA', 'MPA', (35, 38))	('HNRNPA1-KD', 'Var', (82, 92))	('HUVEC', 'CellLine', 'CVCL:2959', (167, 172))	('HEK293T', 'CellLine', 'CVCL:0063', (93, 100))
194557	31257225	These above results gave the strong evidences that splicing factor HNRNPA1 could promote the relative selection of proximal pA site in HN1, thereby adjusting the corresponding 3' UTR length.	('HN1', 'Gene', (135, 138))	('promote', 'PosReg', (81, 88))	('splicing factor HNRNPA1', 'Var', (51, 74))	("3' UTR length", 'MPA', (176, 189))	('adjusting', 'Reg', (148, 157))	('tha', 'Chemical', 'MESH:D013619', (46, 49))
194558	31257225	To further test whether HNRNPA1 could bind to mRNA of HN1, RNA immunoprecipitation coupled with reverse transcription PCR (RIP-PCR) was performed in cells expressing HA-tagged HNRNPA1.	('HN1', 'Gene', (54, 57))	('RIP', 'Gene', (123, 126))	('RIP', 'Gene', '8737', (123, 126))	('HNRNPA1', 'Gene', (176, 183))	('HA-tagged', 'Var', (166, 175))
194560	31257225	Since HNRNPA1-KD resulted in the higher proportion of HN1-L, which produced less protein and gave rise to senescence-related phenotypes, one would expect that down-regulation of HNRNPA1 could also induce cellular senescence.	('less', 'NegReg', (76, 80))	('HN1-L', 'Gene', '90861', (54, 59))	('HNRNPA1', 'Gene', (178, 185))	('down-regulation', 'Var', (159, 174))	('protein', 'MPA', (81, 88))	('senescence-related phenotypes', 'MPA', (106, 135))	('tha', 'Chemical', 'MESH:D013619', (154, 157))	('HN1-L', 'Gene', (54, 59))	('HNRNPA1-KD', 'Var', (6, 16))	('cellular senescence', 'CPA', (204, 223))	('induce', 'Reg', (197, 203))	('gave rise', 'Reg', (93, 102))
194561	31257225	To test this hypothesis, we knocked down HNRNPA1 in HUVEC and A549 cells (Figure 5A, 5B, 5F and 5G), and examined some senescence-associated phenotypes.	('HUVEC', 'CellLine', 'CVCL:2959', (52, 57))	('HNRNPA1', 'Protein', (41, 48))	('knocked', 'Var', (28, 35))	('A549', 'CellLine', 'CVCL:0023', (62, 66))
194562	31257225	Interestingly, HNRNPA1-KD led to a higher percentage of positive SA-beta-Gal stained cells and slower cell growth rate in both cell types (Figure 5C-5E, 5H-5J).	('SA-beta', 'Gene', (65, 72))	('rat', 'Species', '10116', (114, 117))	('slower', 'NegReg', (95, 101))	('SA-beta', 'Gene', '9467', (65, 72))	('cell growth rate', 'CPA', (102, 118))	('beta-Gal', 'Chemical', '-', (68, 76))	('HNRNPA1-KD', 'Var', (15, 25))	('higher', 'PosReg', (35, 41))
194565	31257225	These above results strongly suggest that APA-mediated reduction of HN1 protein contributes, at least in part, to HNRNPA1-KD induced cellular senescence.	('reduction', 'NegReg', (55, 64))	('cellular senescence', 'CPA', (133, 152))	('HN1 protein', 'Protein', (68, 79))	('HNRNPA1-KD', 'Var', (114, 124))	('tha', 'Chemical', 'MESH:D013619', (37, 40))
194567	31257225	These results prompted us to hypothesize that HNRNPA1-mediated changes in HN1 expression not only can regulate cellular senescence but also have the potential to regulate cancer-associated phenotypes.	('expression', 'MPA', (78, 88))	('tha', 'Chemical', 'MESH:D013619', (41, 44))	('regulate', 'Reg', (102, 110))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('HN1', 'Gene', (74, 77))	('cancer', 'Disease', (171, 177))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('changes', 'Var', (63, 70))	('cellular senescence', 'CPA', (111, 130))	('regulate', 'Reg', (162, 170))
194568	31257225	To test this, we performed colony formation and cell migration assays in the lung cancer cell line A549 before and after knocking down HN1 or HNRNPA1.	('lung cancer', 'Phenotype', 'HP:0100526', (77, 88))	('A549', 'CellLine', 'CVCL:0023', (99, 103))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('rat', 'Species', '10116', (56, 59))	('HN1', 'Gene', (135, 138))	('knocking down', 'Var', (121, 134))	('cell migration assays', 'CPA', (48, 69))	('lung cancer', 'Disease', 'MESH:D008175', (77, 88))	('colony formation', 'CPA', (27, 43))	('HNRNPA1', 'Gene', (142, 149))	('lung cancer', 'Disease', (77, 88))
194570	31257225	Coincidentally, knockdown of HNRNPA1 in A549 cells also resulted in similar phenotypes as that in HN1-KD cells (Figure 6C and 6D, Supplementary Figure 11B).	('resulted', 'Reg', (56, 64))	('HNRNPA1', 'Gene', (29, 36))	('tha', 'Chemical', 'MESH:D013619', (90, 93))	('knockdown', 'Var', (16, 25))	('A549', 'CellLine', 'CVCL:0023', (40, 44))
194571	31257225	Moreover, HN1-KD and HNRNPA1-KD also showed decreased cell migration rate in HUVEC cells (Figure 6E and 6F, Supplementary Figure 11C-11D).	('HN1-KD', 'Var', (10, 16))	('HNRNPA1-KD', 'Var', (21, 31))	('HUVEC', 'CellLine', 'CVCL:2959', (77, 82))	('rat', 'Species', '10116', (62, 65))	('rat', 'Species', '10116', (69, 72))	('cell migration rate in HUVEC cells', 'CPA', (54, 88))	('decreased', 'NegReg', (44, 53))
194578	31257225	The discovery that HNRNPA1-mediated 3' UTR length changes in HN1 contributed to cancer- and senescence-associated phenotypes largely expands our knowledge in post-transcriptional regulation in cancer and senescence (Figure 7).	('changes', 'Var', (50, 57))	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('contributed', 'Reg', (65, 76))	('cancer', 'Disease', (193, 199))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('tha', 'Chemical', 'MESH:D013619', (14, 17))	('HN1', 'Gene', (61, 64))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('HNRNPA1-mediated', 'Protein', (19, 35))	('cancer', 'Disease', (80, 86))
194599	31257225	Notably, decreased total protein levels and HN1 expression were observed in CX-5461-treated HUVECs and A549 cells (Supplementary Figure 17B-17E).	('A549', 'CellLine', 'CVCL:0023', (103, 107))	('expression', 'MPA', (48, 58))	('HN1', 'Protein', (44, 47))	('total protein levels', 'MPA', (19, 39))	('decreased', 'NegReg', (9, 18))	('CX-5461', 'Chemical', 'MESH:C557717', (76, 83))	('HUVEC', 'CellLine', 'CVCL:2959', (92, 97))	('CX-5461-treated', 'Var', (76, 91))
194600	31257225	Moreover, the rRNA synthesis inhibitor CX-5461 could also induce the increased senescence-associated SA-beta-Gal activity in both HUVEC and A549 cells (Supplementary Figure 17F-17I).	('A549', 'CellLine', 'CVCL:0023', (140, 144))	('CX-5461', 'Chemical', 'MESH:C557717', (39, 46))	('beta-Gal', 'Chemical', '-', (104, 112))	('increased', 'PosReg', (69, 78))	('CX-5461', 'Var', (39, 46))	('SA-beta', 'Gene', (101, 108))	('SA-beta', 'Gene', '9467', (101, 108))	('HUVEC', 'CellLine', 'CVCL:2959', (130, 135))
194606	31257225	Comprehensive misregulation of HNRNP proteins and alternative splicing disorders have been shown in many types of cancers.	('cancers', 'Disease', 'MESH:D009369', (114, 121))	('cancers', 'Phenotype', 'HP:0002664', (114, 121))	('HNRNP proteins', 'Protein', (31, 45))	('cancers', 'Disease', (114, 121))	('misregulation', 'Var', (14, 27))	('alternative splicing disorders', 'Var', (50, 80))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))
194610	31257225	Defects of HNRNPA1 could also cause aging-related diseases, such as amyotrophic lateral sclerosis (ALS) and Alzheimer's disease.	('cause', 'Reg', (30, 35))	("Alzheimer's disease", 'Disease', 'MESH:D000544', (108, 127))	('amyotrophic lateral sclerosis', 'Phenotype', 'HP:0007354', (68, 97))	('Defects', 'Var', (0, 7))	('HNRNPA1', 'Gene', (11, 18))	("Alzheimer's disease", 'Phenotype', 'HP:0002511', (108, 127))	("Alzheimer's disease", 'Disease', (108, 127))	('amyotrophic lateral sclerosis', 'Disease', 'MESH:D000690', (68, 97))	('amyotrophic lateral sclerosis', 'Disease', (68, 97))
194665	31242643	Over the past few decades, genome-wide cancer transcriptomic and mutational studies have produced a massive amount of data, allowing researchers to better understand lung cancer development at the molecular level, and has enabled the discovery of biomarkers that facilitate cancer treatments for individual patients ("precision medicine").	('mutational', 'Var', (65, 75))	('cancer', 'Phenotype', 'HP:0002664', (274, 280))	('cancer', 'Disease', (39, 45))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('cancer', 'Disease', 'MESH:D009369', (274, 280))	('lung cancer', 'Disease', 'MESH:D008175', (166, 177))	('cancer', 'Disease', (171, 177))	('cancer', 'Disease', (274, 280))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('facilitate', 'PosReg', (263, 273))	('lung cancer', 'Disease', (166, 177))	('lung cancer', 'Phenotype', 'HP:0100526', (166, 177))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('patients', 'Species', '9606', (307, 315))
194677	31242643	Through the meta-analyses of gene-expression difference in tumor vs. normal, in ADC vs. SQCC, and in mutants vs. WT for EGFR or KRAS as well as the meta-analyses of survival association and gene-gene correlation, we present multiple lines of evidence generated from our lung cancer database to strengthen the existing findings.	('lung cancer', 'Disease', (270, 281))	('KRAS', 'Gene', (128, 132))	('lung cancer', 'Phenotype', 'HP:0100526', (270, 281))	('tumor', 'Disease', (59, 64))	('cancer', 'Phenotype', 'HP:0002664', (275, 281))	('KRAS', 'Gene', '3845', (128, 132))	('mutants', 'Var', (101, 108))	('lung cancer', 'Disease', 'MESH:D008175', (270, 281))	('ADC', 'Disease', (80, 83))	('EGFR', 'Gene', '1956', (120, 124))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('SQCC', 'Phenotype', 'HP:0002860', (88, 92))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('EGFR', 'Gene', (120, 124))
194702	31242643	Genes on cytogenetic band chr3p22, on the other hand, are predominantly downregulated in cancer samples, in line with the previous report that allele loss on chromosome arm 3p is one of the most frequent and earliest known genetic events in lung cancer pathogenesis.	('cancer', 'Disease', 'MESH:D009369', (246, 252))	('cancer', 'Disease', (246, 252))	('lung cancer', 'Disease', (241, 252))	('lung cancer', 'Phenotype', 'HP:0100526', (241, 252))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('cancer', 'Disease', (89, 95))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))	('downregulated', 'NegReg', (72, 85))	('lung cancer', 'Disease', 'MESH:D008175', (241, 252))	('allele loss', 'Var', (143, 154))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
194711	31242643	For ADC-specific changes, we found that cell cycle gene expression was associated with worse survival, consistent with the idea that fast proliferation of the tumor cells is linked to worse prognosis.	('survival', 'MPA', (93, 101))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('worse', 'NegReg', (87, 92))	('changes', 'Var', (17, 24))	('tumor', 'Disease', (159, 164))	('cell cycle gene', 'Gene', (40, 55))	('tumor', 'Disease', 'MESH:D009369', (159, 164))
194717	31242643	It has been reported that the expression of MHC II in TILs is associated with the prognosis in lung cancer.	('lung cancer', 'Disease', (95, 106))	('lung cancer', 'Phenotype', 'HP:0100526', (95, 106))	('associated with', 'Reg', (62, 77))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('expression', 'Var', (30, 40))	('lung cancer', 'Disease', 'MESH:D008175', (95, 106))	('MHC II', 'Gene', (44, 50))
194734	31242643	were in disease-free survival, we additionally performed meta-analysis for studies with recurrence-free survival (RFS) data and showed that although both FAM83A and FAM83B expression were associated with worse prognosis in RFS, results were non-significant for both genes in SQCC (Figure S10A-D).	('SQCC', 'Phenotype', 'HP:0002860', (275, 279))	('S10A', 'SUBSTITUTION', 'None', (288, 292))	('FAM83B', 'Gene', '222584', (165, 171))	('FAM83B', 'Gene', (165, 171))	('FAM83A', 'Gene', (154, 160))	('FAM83A', 'Gene', '84985', (154, 160))	('S10A', 'Var', (288, 292))
194735	31242643	With these findings (Figure 5D and Figure S10A), we are now more confident that mRNA expression for FAM83B would not be a good prognostic marker for SQCC, while it remains to be seen whether the prognostic effects of FAM83B protein levels seen by Okabe et al.. could be validated in additional cohorts.	('S10A', 'Var', (42, 46))	('FAM83B', 'Gene', (217, 223))	('FAM83B', 'Gene', '222584', (217, 223))	('SQCC', 'Disease', (149, 153))	('FAM83B', 'Gene', '222584', (100, 106))	('FAM83B', 'Gene', (100, 106))	('SQCC', 'Phenotype', 'HP:0002860', (149, 153))	('S10A', 'SUBSTITUTION', 'None', (42, 46))
194737	31242643	As FAM83A and FAM8B have been shown to interact with different components within the EGFR pathway and mediate resistance to EGFR inhibitors, Richtmann et al.	('EGFR', 'Gene', (85, 89))	('resistance', 'MPA', (110, 120))	('EGFR', 'Gene', '1956', (124, 128))	('interact', 'Reg', (39, 47))	('FAM8B', 'Var', (14, 19))	('mediate', 'Reg', (102, 109))	('EGFR', 'Gene', (124, 128))	('FAM83A', 'Gene', '84985', (3, 9))	('FAM83A', 'Gene', (3, 9))	('EGFR', 'Gene', '1956', (85, 89))
194738	31242643	also investigated the expression levels of FAM83A and FAM83B in tumors with EGFR mutations compared to those without.	('FAM83B', 'Gene', (54, 60))	('tumors', 'Disease', (64, 70))	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('FAM83B', 'Gene', '222584', (54, 60))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('FAM83A', 'Gene', '84985', (43, 49))	('FAM83A', 'Gene', (43, 49))	('EGFR', 'Gene', '1956', (76, 80))	('EGFR', 'Gene', (76, 80))	('mutations', 'Var', (81, 90))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
194739	31242643	They found that FAM83A but not FAM83B was upregulated in tumors with EGFR mutation.	('EGFR', 'Gene', '1956', (69, 73))	('mutation', 'Var', (74, 82))	('FAM83A', 'Gene', (16, 22))	('EGFR', 'Gene', (69, 73))	('FAM83A', 'Gene', '84985', (16, 22))	('FAM83B', 'Gene', '222584', (31, 37))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('FAM83B', 'Gene', (31, 37))	('upregulated', 'PosReg', (42, 53))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('tumors', 'Disease', (57, 63))	('tumors', 'Disease', 'MESH:D009369', (57, 63))
194740	31242643	From our meta-analyses, we observed that both FAM83A and FAM83B were higher in tumors with EGFR mutations (Figure 6A,B).	('higher', 'Reg', (69, 75))	('FAM83B', 'Gene', (57, 63))	('EGFR', 'Gene', (91, 95))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('FAM83A', 'Gene', '84985', (46, 52))	('FAM83A', 'Gene', (46, 52))	('tumors', 'Disease', (79, 85))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('EGFR', 'Gene', '1956', (91, 95))	('FAM83B', 'Gene', '222584', (57, 63))	('mutations', 'Var', (96, 105))
194742	31242643	Interestingly, we found that FAM83A but not FAM83B was downregulated in tumors bearing KRAS mutations (Figure 6C,D) as the EGFR mutation, KRAS mutation, and ALK rearrangement are largely mutually exclusive events in lung cancer.	('EGFR', 'Gene', (123, 127))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('FAM83A', 'Gene', (29, 35))	('KRAS', 'Gene', '3845', (138, 142))	('tumors', 'Disease', (72, 78))	('ALK', 'Gene', (157, 160))	('lung cancer', 'Disease', 'MESH:D008175', (216, 227))	('FAM83A', 'Gene', '84985', (29, 35))	('FAM83B', 'Gene', '222584', (44, 50))	('KRAS', 'Gene', (138, 142))	('lung cancer', 'Phenotype', 'HP:0100526', (216, 227))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('EGFR', 'Gene', '1956', (123, 127))	('KRAS', 'Gene', '3845', (87, 91))	('mutations', 'Var', (92, 101))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('downregulated', 'NegReg', (55, 68))	('KRAS', 'Gene', (87, 91))	('FAM83B', 'Gene', (44, 50))	('lung cancer', 'Disease', (216, 227))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('ALK', 'Gene', '238', (157, 160))
194753	31242643	By examining the results from the two types of analyses in conjunction, we observed a positive correlation between the expression changes in tumors when compared to normal samples and worse survival association, and the direction of the changes could be attributed to the oncogenic or tumor suppressive roles of the genes (Figure 4).	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('expression', 'MPA', (119, 129))	('tumor', 'Phenotype', 'HP:0002664', (285, 290))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('changes', 'Var', (130, 137))	('tumor', 'Disease', (285, 290))	('tumors', 'Disease', (141, 147))	('tumor', 'Disease', (141, 146))	('tumors', 'Disease', 'MESH:D009369', (141, 147))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('tumor', 'Disease', 'MESH:D009369', (285, 290))
194764	31242643	This work was partially supported by the National Institute of Health [5R01CA152301, P50CA70907, 5P30CA142543, 1R01GM115473, and 1R01CA172211], and the Cancer Prevention and Research Institute of Texas [RP180805 and RP190107].	('Cancer', 'Disease', 'MESH:D009369', (152, 158))	('Cancer', 'Disease', (152, 158))	('Cancer', 'Phenotype', 'HP:0002664', (152, 158))	('5P30CA142543', 'Var', (97, 109))	('1R01GM115473', 'Var', (111, 123))	('P50CA70907', 'Var', (85, 95))	('1R01CA172211]', 'Var', (129, 142))
194770	26138067	Under Mendelian randomization assumptions, the association estimate [odds ratio (OR) = 2.78] is interpreted as the OR for lung adenocarcinoma corresponding to a 1000 bp increase in TL.	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (122, 141))	('increase', 'PosReg', (169, 177))	('bp increase', 'Phenotype', 'HP:0032263', (166, 177))	('1000 bp', 'Var', (161, 168))	('lung adenocarcinoma', 'Disease', (122, 141))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (122, 141))
194774	26138067	However, caution regarding this causal interpretation is warranted in light of the potential issue of pleiotropy, and a more general interpretation is that SNPs influencing telomere biology are also implicated in lung adenocarcinoma risk.	('SNPs', 'Var', (156, 160))	('S', 'Chemical', 'MESH:D013455', (156, 157))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (213, 232))	('implicated', 'Reg', (199, 209))	('lung adenocarcinoma', 'Disease', (213, 232))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (213, 232))	('carcinoma', 'Phenotype', 'HP:0030731', (223, 232))
194776	26138067	The critical role of telomeres and telomerase in carcinogenesis has led to the hypothesis that short telomere length (TL) is a risk factor for cancer.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('carcinogenesis', 'Disease', 'MESH:D063646', (49, 63))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('short', 'Var', (95, 100))	('short telomere length', 'Phenotype', 'HP:0031413', (95, 116))	('carcinogenesis', 'Disease', (49, 63))
194779	26138067	Furthermore, due to the retrospective nature of case-control studies from which many of these association estimates are obtained, telomere shortening that occurs after diagnosis, potentially due to treatment or disease progression, can result in biased estimates of the association between TL and cancer risk.	('cancer', 'Disease', (297, 303))	('cancer', 'Disease', 'MESH:D009369', (297, 303))	('men', 'Species', '9606', (203, 206))	('cancer', 'Phenotype', 'HP:0002664', (297, 303))	('telomere shortening', 'Var', (130, 149))	('association', 'Interaction', (270, 281))
194780	26138067	Genome-wide association (GWA) studies have identified several genomic regions containing variants associated with TL in peripheral blood cells, including the TERT (telomerase reverse transcriptase) region (5p15.33).	('telomerase reverse transcriptase', 'Gene', '7015', (164, 196))	('variants', 'Var', (89, 97))	('TERT', 'Gene', (158, 162))	('TERT', 'Gene', '7015', (158, 162))	('telomerase reverse transcriptase', 'Gene', (164, 196))
194781	26138067	Furthermore, GWA studies of cancer risk have observed that variants in the TERT region influence risk for multiple cancer types, including breast, colorectal, lung, prostate and ovarian cancer, although these associations do not appear to all be driven by the same causal variant.	('cancer', 'Disease', (115, 121))	('multiple cancer', 'Disease', 'MESH:D009369', (106, 121))	('ovarian cancer', 'Phenotype', 'HP:0100615', (178, 192))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('TERT', 'Gene', (75, 79))	('TERT', 'Gene', '7015', (75, 79))	('variants', 'Var', (59, 67))	('multiple cancer', 'Disease', (106, 121))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('breast', 'Disease', (139, 145))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('influence', 'Reg', (87, 96))	('colorectal, lung, prostate and ovarian cancer', 'Disease', 'MESH:D015179', (147, 192))	('cancer', 'Disease', (28, 34))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('cancer', 'Disease', (186, 192))	('cancer', 'Disease', 'MESH:D009369', (186, 192))
194783	26138067	In this work, we describe the associations between nine TL-associated genetic variants and risk for five cancer types (breast, lung, colorectal, ovarian and prostate), using data from the Genetic Associations and Mechanisms in Oncology (GAME-ON) network of consortia for post-GWA research.	('breast', 'Disease', (119, 125))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('colorectal, ovarian and prostate', 'Disease', 'MESH:D015179', (133, 165))	('associations', 'Interaction', (30, 42))	('TL-associated', 'Gene', (56, 69))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('Oncology', 'Phenotype', 'HP:0002664', (227, 235))	('lung', 'Disease', (127, 131))	('variants', 'Var', (78, 86))
194784	26138067	In addition, we estimate the association between a multi-variant TL score and cancer risk, which corresponds to the effect of TL on cancer risk under Mendelian randomization assumptions.	('cancer', 'Disease', (132, 138))	('cancer', 'Disease', (78, 84))	('TL score', 'Gene', (65, 73))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('multi-variant', 'Var', (51, 64))	('cancer', 'Disease', 'MESH:D009369', (132, 138))
194795	26138067	Prostate cancer risk also showed nominally significant positive associations with the long TL alleles for three of the nine SNPs (P < 0.05) (Supplementary Material, Fig.	('long TL', 'Var', (86, 93))	('Prostate cancer', 'Phenotype', 'HP:0012125', (0, 15))	('S', 'Chemical', 'MESH:D013455', (124, 125))	('S', 'Chemical', 'MESH:D013455', (141, 142))	('Prostate cancer', 'Disease', (0, 15))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('positive', 'PosReg', (55, 63))	('Prostate cancer', 'Disease', 'MESH:D011471', (0, 15))	('men', 'Species', '9606', (147, 150))
194798	26138067	Of note, we identified a highly statistically significant association between long TL and increased risk of lung adenocarcinoma with an odds ratio (OR) of 2.78 per 1 kb increase TL [95% confidence interval (CI) 2.16, 3.58; P = 6.3 x 10-15].	('lung adenocarcinoma', 'Disease', (108, 127))	('significant association', 'Reg', (46, 69))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (108, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('increase', 'PosReg', (169, 177))	('long TL', 'Var', (78, 85))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (108, 127))
194804	26138067	However, prostate cancer risk showed suggestive evidence of positive association with long TL with a Mendelian randomization OR of 1.21 per 1 kb increase in TL (95% CI 0.99, 1.46; P = 0.06).	('long TL', 'Var', (86, 93))	('prostate cancer', 'Disease', (9, 24))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('prostate cancer', 'Disease', 'MESH:D011471', (9, 24))	('prostate cancer', 'Phenotype', 'HP:0012125', (9, 24))
194812	26138067	To assess a potential violation of the first assumption, an additional analysis was performed after excluding the SNP near the PXK region (rs6772228), which may be a false-positive association evidenced by its lack of plausible biological explanation, and the lack of consistency in its association with TL across several study sites.	('S', 'Chemical', 'MESH:D013455', (114, 115))	('rs6772228', 'Var', (139, 148))	('PXK', 'Gene', (127, 130))	('PXK', 'Gene', '54899', (127, 130))	('rs6772228', 'Mutation', 'rs6772228', (139, 148))
194816	26138067	An inflation of the ratio for any single SNP may be an indication that the SNP exerts a pleiotropic effect on cancer that is unrelated to its effect on TL.	('S', 'Chemical', 'MESH:D013455', (41, 42))	('cancer', 'Disease', (110, 116))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('SNP', 'Var', (75, 78))	('S', 'Chemical', 'MESH:D013455', (75, 76))	('cancer', 'Disease', 'MESH:D009369', (110, 116))
194822	26138067	This difference in estimates between methods is eliminated after excluding the TERT SNP (rs2736100) that drives the heterogeneity in association estimates for lung adenocarcinoma.	('rs2736100', 'Var', (89, 98))	('lung adenocarcinoma', 'Disease', (159, 178))	('rs2736100', 'Mutation', 'rs2736100', (89, 98))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (159, 178))	('carcinoma', 'Phenotype', 'HP:0030731', (169, 178))	('S', 'Chemical', 'MESH:D013455', (84, 85))	('TERT', 'Gene', (79, 83))	('TERT', 'Gene', '7015', (79, 83))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (159, 178))
194824	26138067	We did not observe an association between the multi-SNP score and risk of breast, colorectal or ovarian cancer (including subtypes).	('S', 'Chemical', 'MESH:D013455', (52, 53))	('colorectal or ovarian cancer', 'Disease', (82, 110))	('multi-SNP', 'Var', (46, 55))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('ovarian cancer', 'Phenotype', 'HP:0100615', (96, 110))	('colorectal or ovarian cancer', 'Disease', 'MESH:D015179', (82, 110))	('breast', 'Disease', (74, 80))
194830	26138067	Three retrospective case-control studies reported an association between long TL and decreased lung cancer risk in US and Korean subjects.	('long TL', 'Var', (73, 80))	('lung cancer', 'Phenotype', 'HP:0100526', (95, 106))	('decreased lung', 'Phenotype', 'HP:0002089', (85, 99))	('decreased lung cancer', 'Disease', (85, 106))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('S', 'Chemical', 'MESH:D013455', (116, 117))	('decreased lung cancer', 'Disease', 'MESH:D008175', (85, 106))
194832	26138067	In two studies with prospective TL measurement, long TL was found to be associated with increased overall lung cancer risk among Caucasian male smokers and East Asian female never-smokers, while a large Danish general population study found no association.	('long TL', 'Var', (48, 55))	('men', 'Species', '9606', (42, 45))	('lung cancer', 'Disease', (106, 117))	('lung cancer', 'Phenotype', 'HP:0100526', (106, 117))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('increased', 'PosReg', (88, 97))	('lung cancer', 'Disease', 'MESH:D008175', (106, 117))
194833	26138067	In a pooled analysis of three prospective cohort studies including the two aforementioned studies and a third study conducted in the USA, long telomeres were associated with increased lung cancer risk, and the association was present in adenocarcinoma while absent in squamous cell carcinoma.	('lung cancer', 'Disease', (184, 195))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (268, 291))	('carcinoma', 'Phenotype', 'HP:0030731', (242, 251))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('lung cancer', 'Disease', 'MESH:D008175', (184, 195))	('squamous cell carcinoma', 'Disease', (268, 291))	('adenocarcinoma', 'Disease', (237, 251))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (268, 291))	('men', 'Species', '9606', (80, 83))	('adenocarcinoma', 'Disease', 'MESH:D000230', (237, 251))	('S', 'Chemical', 'MESH:D013455', (134, 135))	('long telomeres', 'Var', (138, 152))	('increased', 'PosReg', (174, 183))	('lung cancer', 'Phenotype', 'HP:0100526', (184, 195))	('carcinoma', 'Phenotype', 'HP:0030731', (282, 291))
194840	26138067	Consistent with our findings, the risk score for long TL was associated with an increase in lung cancer.	('lung cancer', 'Phenotype', 'HP:0100526', (92, 103))	('increase in lung cancer', 'Disease', (80, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('increase in lung cancer', 'Disease', 'MESH:D008175', (80, 103))	('long TL', 'Var', (49, 56))
194842	26138067	A protective effect of short TL on lung cancer risk has a biologically plausible explanation, as short telomeres could protect against cancer by triggering cell senescence or programmed cell death in the presence of functional cell cycle checkpoints and intact apoptotic pathways.	('cancer', 'Disease', (135, 141))	('lung cancer', 'Disease', 'MESH:D008175', (35, 46))	('short telomeres', 'Phenotype', 'HP:0031413', (97, 112))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('apoptotic pathways', 'Pathway', (261, 279))	('cell senescence', 'CPA', (156, 171))	('cancer', 'Disease', (40, 46))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('lung cancer', 'Disease', (35, 46))	('triggering', 'Reg', (145, 155))	('lung cancer', 'Phenotype', 'HP:0100526', (35, 46))	('programmed cell death', 'CPA', (175, 196))	('short telomeres', 'Var', (97, 112))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('cancer', 'Disease', 'MESH:D009369', (135, 141))
194843	26138067	Conversely, long telomeres may enable additional rounds of cell division, allowing more opportunities for the accumulation of somatic mutations that promote carcinogenesis, resulting in greater susceptibility to malignant transformation.	('carcinogenesis', 'Disease', 'MESH:D063646', (157, 171))	('mutations', 'Var', (134, 143))	('carcinogenesis', 'Disease', (157, 171))	('malignant transformation', 'CPA', (212, 236))	('promote', 'PosReg', (149, 156))
194844	26138067	The association between long TL SNPs and increased risk has also been previously observed for melanoma, with a proposed mechanism being that long telomeres increase the proliferative duration of cells, thus delaying senescence and allowing further mutations to occur.	('melanoma', 'Disease', 'MESH:D008545', (94, 102))	('melanoma', 'Phenotype', 'HP:0002861', (94, 102))	('long', 'Var', (24, 28))	('increase', 'PosReg', (156, 164))	('melanoma', 'Disease', (94, 102))	('delaying', 'NegReg', (207, 215))	('long telomeres', 'Var', (141, 155))	('S', 'Chemical', 'MESH:D013455', (32, 33))	('proliferative duration of cells', 'CPA', (169, 200))	('senescence', 'CPA', (216, 226))
194848	26138067	In contrast, we observe a suggestive association between long TL and increased risk for prostate cancer, an association that increases in significance in the context of the 'goodness-of-fit'-based sensitivity analyses.	('prostate cancer', 'Disease', (88, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('prostate cancer', 'Disease', 'MESH:D011471', (88, 103))	('long TL', 'Var', (57, 64))	('prostate cancer', 'Phenotype', 'HP:0012125', (88, 103))
194854	26138067	Although one prospective study showed evidence for association between long TL and increased breast cancer risk, two different meta-analyses of TL and breast cancer risk based on multiple retrospective and prospective studies concluded there was no overall evidence of association.	('long TL', 'Var', (71, 78))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('breast cancer', 'Disease', 'MESH:D001943', (151, 164))	('association', 'Interaction', (51, 62))	('breast cancer', 'Disease', 'MESH:D001943', (93, 106))	('breast cancer', 'Phenotype', 'HP:0003002', (151, 164))	('breast cancer', 'Disease', (151, 164))	('breast cancer', 'Disease', (93, 106))	('breast cancer', 'Phenotype', 'HP:0003002', (93, 106))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
194857	26138067	For ovarian cancer, two prior case-control studies observed an association between longer telomeres and decreased risk, one case-control study reported no association, while a prospective study also reported no association.	('risk', 'MPA', (114, 118))	('longer telomeres', 'Var', (83, 99))	('decreased', 'NegReg', (104, 113))	('ovarian cancer', 'Phenotype', 'HP:0100615', (4, 18))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('ovarian cancer', 'Disease', 'MESH:D010051', (4, 18))	('ovarian cancer', 'Disease', (4, 18))
194859	26138067	This lack of association is observed despite the inclusion of SNP rs2736100 located in the TERT region, which showed a nominally significant association with the serous subtype of ovarian cancer (P = 0.023) and is in high LD (r2 = 0.8) with a SNP previously observed to be associated with ovarian cancer .	('ovarian cancer', 'Disease', (289, 303))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('TERT', 'Gene', (91, 95))	('association', 'Interaction', (141, 152))	('serous subtype of ovarian cancer', 'Disease', (162, 194))	('rs2736100', 'Var', (66, 75))	('ovarian cancer', 'Disease', 'MESH:D010051', (289, 303))	('TERT', 'Gene', '7015', (91, 95))	('ovarian cancer', 'Phenotype', 'HP:0100615', (289, 303))	('rs2736100', 'Mutation', 'rs2736100', (66, 75))	('ovarian cancer', 'Phenotype', 'HP:0100615', (180, 194))	('cancer', 'Phenotype', 'HP:0002664', (297, 303))	('ovarian cancer', 'Disease', 'MESH:D010051', (180, 194))	('S', 'Chemical', 'MESH:D013455', (243, 244))	('serous subtype of ovarian cancer', 'Disease', 'MESH:D010051', (162, 194))	('S', 'Chemical', 'MESH:D013455', (62, 63))
194860	26138067	Estrogen has been demonstrated in experimental studies to have positive effects on telomerase activity, and in epidemiologic studies estrogen has been shown to have a positive association with TL.	('telomerase activity', 'MPA', (83, 102))	('men', 'Species', '9606', (40, 43))	('estrogen', 'Var', (133, 141))
194864	26138067	To address a potential violation of the first assumption:that the SNPs are associated with TL in our study population:we conducted analyses excluding PXK SNP rs6772228, whose association with TL has been questioned due to the lack of consistency in its association across several study sites.	('PXK', 'Gene', (150, 153))	('S', 'Chemical', 'MESH:D013455', (66, 67))	('PXK', 'Gene', '54899', (150, 153))	('rs6772228', 'Mutation', 'rs6772228', (158, 167))	('S', 'Chemical', 'MESH:D013455', (154, 155))	('rs6772228', 'Var', (158, 167))
194865	26138067	For overall prostate cancer, however, the association became statistically significant, lending support to the hypothesis that long TL is associated with an increased risk of prostate cancer.	('prostate cancer', 'Disease', (12, 27))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('prostate cancer', 'Phenotype', 'HP:0012125', (175, 190))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('prostate cancer', 'Disease', (175, 190))	('prostate cancer', 'Disease', 'MESH:D011471', (12, 27))	('prostate cancer', 'Phenotype', 'HP:0012125', (12, 27))	('long TL', 'Var', (127, 134))	('prostate cancer', 'Disease', 'MESH:D011471', (175, 190))
194868	26138067	For prostate cancer, the association with the multi-SNP score became statistically significant after excluding TERT SNP rs2736100 and CTC1 SNP rs3027234.	('prostate cancer', 'Disease', 'MESH:D011471', (4, 19))	('CTC1', 'Gene', '80169', (134, 138))	('S', 'Chemical', 'MESH:D013455', (52, 53))	('prostate cancer', 'Phenotype', 'HP:0012125', (4, 19))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('rs3027234', 'Mutation', 'rs3027234', (143, 152))	('rs2736100', 'Mutation', 'rs2736100', (120, 129))	('rs3027234', 'Var', (143, 152))	('S', 'Chemical', 'MESH:D013455', (139, 140))	('CTC1', 'Gene', (134, 138))	('prostate cancer', 'Disease', (4, 19))	('TERT', 'Gene', (111, 115))	('S', 'Chemical', 'MESH:D013455', (116, 117))	('TERT', 'Gene', '7015', (111, 115))
194869	26138067	The heterogeneity in association of SNPs in TERT and CTC1 identified by the goodness-of-fit test suggests potential pleiotropic effects of these genetic variants through mechanisms other than TL.	('TERT', 'Gene', (44, 48))	('SNPs', 'Var', (36, 40))	('TERT', 'Gene', '7015', (44, 48))	('CTC1', 'Gene', (53, 57))	('S', 'Chemical', 'MESH:D013455', (36, 37))	('variants', 'Var', (153, 161))	('CTC1', 'Gene', '80169', (53, 57))
194902	26138067	For the TL SNPs not available on the 500 K array, we were able to identify tag SNPs (r2 > 0.8) for all SNPs except PXK SNP rs6772228 (Supplementary Material, Table S5).	('rs6772228', 'Var', (123, 132))	('S', 'Chemical', 'MESH:D013455', (79, 80))	('men', 'Species', '9606', (140, 143))	('S', 'Chemical', 'MESH:D013455', (11, 12))	('S', 'Chemical', 'MESH:D013455', (103, 104))	('rs6772228', 'Mutation', 'rs6772228', (123, 132))	('S', 'Chemical', 'MESH:D013455', (134, 135))	('S', 'Chemical', 'MESH:D013455', (119, 120))	('S', 'Chemical', 'MESH:D013455', (164, 165))	('PXK', 'Gene', (115, 118))	('PXK', 'Gene', '54899', (115, 118))
194915	26138067	To assess a potential violation of the first assumption (i.e., a true association between each of the variant and TL), an additional analysis was performed after excluding the SNP near the PXK region (rs6772228), which may be a false-positive association evidenced by its lack of plausible biological explanation, and the lack of consistency in its association with TL across several study sites.	('S', 'Chemical', 'MESH:D013455', (176, 177))	('rs6772228', 'Var', (201, 210))	('PXK', 'Gene', (189, 192))	('variant', 'Var', (102, 109))	('rs6772228', 'Mutation', 'rs6772228', (201, 210))	('PXK', 'Gene', '54899', (189, 192))
194921	26138067	For each analysis in which the goodness-of-fit test null hypothesis was rejected (P < 0.05), we removed the SNP that resulted in the greatest reduction of the Qrs test statistic, and repeated the goodness-of-fit test.	('reduction', 'NegReg', (142, 151))	('SNP', 'Var', (108, 111))	('Qrs test statistic', 'MPA', (159, 177))	('S', 'Chemical', 'MESH:D013455', (108, 109))
194935	32705258	Silencing of BRF2 inhibits the growth and metastasis of lung cancer cells Transcription factor II B (TFIIB)-related factor 2 (BRF2) is involved in the development of cancer, but its role in lung cancer is underreported.	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('metastasis of lung cancer', 'Disease', (42, 67))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('Silencing', 'Var', (0, 9))	('lung cancer', 'Disease', (190, 201))	('cancer', 'Disease', (166, 172))	('lung cancer', 'Disease', 'MESH:D008175', (56, 67))	('cancer', 'Disease', (61, 67))	('cancer', 'Disease', (195, 201))	('lung cancer', 'Disease', 'MESH:D008175', (190, 201))	('metastasis of lung cancer', 'Disease', 'MESH:D008175', (42, 67))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('lung cancer', 'Phenotype', 'HP:0100526', (56, 67))	('lung cancer', 'Phenotype', 'HP:0100526', (190, 201))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('BRF2', 'Gene', '55290', (13, 17))	('Transcription factor II B (TFIIB)-related factor 2', 'Gene', '29105', (74, 124))	('BRF2', 'Gene', '55290', (126, 130))	('inhibits', 'NegReg', (18, 26))	('BRF2', 'Gene', (13, 17))	('BRF2', 'Gene', (126, 130))
194938	32705258	Following cell transfection with small interfering RNA for silencing BRF2, the cell proliferation was examined by Cell Counting Kit-8 and MTT assays.	('BRF2', 'Gene', '55290', (69, 73))	('MTT', 'Chemical', 'MESH:C070243', (138, 141))	('si', 'Chemical', 'MESH:D012825', (59, 61))	('silencing', 'Var', (59, 68))	('BRF2', 'Gene', (69, 73))
194941	32705258	The results demonstrated that BRF2 expression was increased in human lung cancer cells and tissues, and that silencing of BRF2 promoted cell apoptosis but inhibited cell proliferation and migration.	('lung cancer', 'Disease', 'MESH:D008175', (69, 80))	('BRF2', 'Gene', '55290', (122, 126))	('BRF2', 'Gene', '55290', (30, 34))	('human', 'Species', '9606', (63, 68))	('cell apoptosis', 'CPA', (136, 150))	('increased', 'PosReg', (50, 59))	('si', 'Chemical', 'MESH:D012825', (109, 111))	('expression', 'MPA', (35, 45))	('promoted', 'PosReg', (127, 135))	('BRF2', 'Gene', (122, 126))	('BRF2', 'Gene', (30, 34))	('lung cancer', 'Disease', (69, 80))	('silencing', 'Var', (109, 118))	('inhibited', 'NegReg', (155, 164))	('lung cancer', 'Phenotype', 'HP:0100526', (69, 80))	('si', 'Chemical', 'MESH:D012825', (41, 43))	('si', 'Chemical', 'MESH:D012825', (147, 149))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
194942	32705258	The protein expression levels of Akt, E-cadherin, p-Akt, Bcl-2, N-cadherin, Snail and EGFR in A549 cells were inhibited by silencing of BRF2, while expression levels of Bax and E-cadherin were increased by silencing BRF2.	('Akt', 'Gene', '207', (33, 36))	('Bax', 'Gene', '581', (169, 172))	('Snail', 'Gene', (76, 81))	('BRF2', 'Gene', '55290', (216, 220))	('si', 'Chemical', 'MESH:D012825', (18, 20))	('silencing', 'Var', (206, 215))	('EGFR', 'Gene', '1956', (86, 90))	('BRF2', 'Gene', (216, 220))	('si', 'Chemical', 'MESH:D012825', (206, 208))	('BRF2', 'Gene', '55290', (136, 140))	('E-cadherin', 'Gene', (177, 187))	('Akt', 'Gene', (52, 55))	('E-cadherin', 'Gene', '999', (177, 187))	('BRF2', 'Gene', (136, 140))	('Bcl-2', 'Gene', '596', (57, 62))	('protein expression levels', 'MPA', (4, 29))	('A549', 'CellLine', 'CVCL:0023', (94, 98))	('Bcl-2', 'Gene', (57, 62))	('silencing', 'Var', (123, 132))	('Akt', 'Gene', '207', (52, 55))	('Snail', 'Gene', '6615', (76, 81))	('N-cadherin', 'Gene', (64, 74))	('N-cadherin', 'Gene', '1000', (64, 74))	('EGFR', 'Gene', (86, 90))	('E-cadherin', 'Gene', (38, 48))	('Akt', 'Gene', (33, 36))	('si', 'Chemical', 'MESH:D012825', (154, 156))	('si', 'Chemical', 'MESH:D012825', (123, 125))	('expression', 'MPA', (148, 158))	('E-cadherin', 'Gene', '999', (38, 48))	('inhibited', 'NegReg', (110, 119))	('Bax', 'Gene', (169, 172))
194943	32705258	In conclusion, BRF2 demonstrates high expression in lung cancer and silencing of BRF2 inhibits the growth and metastasis of lung cancer cells.	('lung cancer', 'Disease', 'MESH:D008175', (52, 63))	('lung cancer', 'Phenotype', 'HP:0100526', (52, 63))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('metastasis of lung cancer', 'Disease', 'MESH:D008175', (110, 135))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('inhibits', 'NegReg', (86, 94))	('si', 'Chemical', 'MESH:D012825', (9, 11))	('si', 'Chemical', 'MESH:D012825', (117, 119))	('BRF2', 'Gene', '55290', (81, 85))	('metastasis of lung cancer', 'Disease', (110, 135))	('BRF2', 'Gene', (81, 85))	('lung cancer', 'Disease', (52, 63))	('silencing', 'Var', (68, 77))	('BRF2', 'Gene', '55290', (15, 19))	('lung cancer', 'Disease', 'MESH:D008175', (124, 135))	('BRF2', 'Gene', (15, 19))	('si', 'Chemical', 'MESH:D012825', (68, 70))	('si', 'Chemical', 'MESH:D012825', (44, 46))	('lung cancer', 'Phenotype', 'HP:0100526', (124, 135))
194951	32705258	Deregulation of TFIIIB-mediated transcription is an important factor in tumor development.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('Deregulation', 'Var', (0, 12))	('tumor', 'Disease', (72, 77))	('TFIIIB', 'Gene', '55814', (16, 22))	('TFIIIB', 'Gene', (16, 22))	('tumor', 'Disease', 'MESH:D009369', (72, 77))
194955	32705258	Lockwood et al demonstrated that genetic activation of BRF2 is a special mechanism of squamous cell carcinoma tumorigenesis, and this finding is the first clinical evidence to suggest that BRF2 is a novel oncogene in lung cancer.	('genetic', 'Var', (33, 40))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (86, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('lung cancer', 'Disease', 'MESH:D008175', (217, 228))	('lung cancer', 'Disease', (217, 228))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (86, 109))	('lung cancer', 'Phenotype', 'HP:0100526', (217, 228))	('squamous cell carcinoma', 'Disease', (86, 109))	('BRF2', 'Gene', '55290', (189, 193))	('tumor', 'Disease', (110, 115))	('si', 'Chemical', 'MESH:D012825', (120, 122))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('BRF2', 'Gene', '55290', (55, 59))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('BRF2', 'Gene', (189, 193))	('activation', 'PosReg', (41, 51))	('BRF2', 'Gene', (55, 59))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
195033	32705258	To explore the role of BRF2 in lung cancer cells, A549 cells were transfected with siRNA for silencing BRF2.	('lung cancer', 'Disease', 'MESH:D008175', (31, 42))	('BRF2', 'Gene', '55290', (23, 27))	('si', 'Chemical', 'MESH:D012825', (93, 95))	('silencing', 'Var', (93, 102))	('BRF2', 'Gene', '55290', (103, 107))	('BRF2', 'Gene', (23, 27))	('lung cancer', 'Disease', (31, 42))	('lung cancer', 'Phenotype', 'HP:0100526', (31, 42))	('A549', 'CellLine', 'CVCL:0023', (50, 54))	('BRF2', 'Gene', (103, 107))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('si', 'Chemical', 'MESH:D012825', (83, 85))
195038	32705258	3A, flow cytometry demonstrated that the rate of apoptosis of the siRNA group was significantly higher compared with that noted in the siNC group (Fig.	('si', 'Chemical', 'MESH:D012825', (135, 137))	('si', 'Chemical', 'MESH:D012825', (82, 84))	('siNC', 'Disease', (135, 139))	('si', 'Chemical', 'MESH:D012825', (66, 68))	('siRNA', 'Var', (66, 71))	('higher', 'PosReg', (96, 102))	('apoptosis', 'CPA', (49, 58))	('si', 'Chemical', 'MESH:D012825', (55, 57))	('siNC', 'Disease', 'None', (135, 139))
195043	32705258	4A and B) revealed that following transfection of BRF2 siRNA, relative protein expression levels of Akt (P<0.01 vs. siNC), p-Akt (P<0.001 vs. siNC) and Bcl-2 (P<0.01 vs. siNC) were suppressed, while relative protein expression level of Bax was significantly promoted.	('siNC', 'Disease', 'None', (170, 174))	('si', 'Chemical', 'MESH:D012825', (170, 172))	('siNC', 'Disease', (142, 146))	('relative protein expression level', 'MPA', (199, 232))	('BRF2', 'Gene', '55290', (50, 54))	('Akt', 'Gene', (100, 103))	('BRF2', 'Gene', (50, 54))	('Akt', 'Gene', (125, 128))	('suppressed', 'NegReg', (181, 191))	('si', 'Chemical', 'MESH:D012825', (222, 224))	('Akt', 'Gene', '207', (100, 103))	('siNC', 'Disease', 'None', (142, 146))	('Akt', 'Gene', '207', (125, 128))	('si', 'Chemical', 'MESH:D012825', (55, 57))	('siNC', 'Disease', (116, 120))	('Bax', 'Gene', (236, 239))	('si', 'Chemical', 'MESH:D012825', (142, 144))	('Bcl-2', 'Gene', (152, 157))	('si', 'Chemical', 'MESH:D012825', (116, 118))	('siNC', 'Disease', (170, 174))	('si', 'Chemical', 'MESH:D012825', (85, 87))	('promoted', 'PosReg', (258, 266))	('relative protein expression levels', 'MPA', (62, 96))	('Bax', 'Gene', '581', (236, 239))	('si', 'Chemical', 'MESH:D012825', (244, 246))	('Bcl-2', 'Gene', '596', (152, 157))	('siNC', 'Disease', 'None', (116, 120))	('transfection', 'Var', (34, 46))
195045	32705258	Notably, protein expression of E-cadherin (P<0.01 vs. siNC) was significantly promoted following transfection of BRF2 siRNA.	('transfection', 'Var', (97, 109))	('si', 'Chemical', 'MESH:D012825', (118, 120))	('siNC', 'Disease', 'None', (54, 58))	('BRF2', 'Gene', (113, 117))	('si', 'Chemical', 'MESH:D012825', (54, 56))	('BRF2', 'Gene', '55290', (113, 117))	('promoted', 'PosReg', (78, 86))	('si', 'Chemical', 'MESH:D012825', (23, 25))	('si', 'Chemical', 'MESH:D012825', (64, 66))	('protein expression', 'MPA', (9, 27))	('siNC', 'Disease', (54, 58))	('E-cadherin', 'Gene', (31, 41))	('E-cadherin', 'Gene', '999', (31, 41))
195052	32705258	It has been shown that ~40% of lung squamous cell carcinoma is closely related to the local amplification of chromosome 8p12 through comparative genomic hybridization.	('related', 'Reg', (71, 78))	('local amplification', 'Var', (86, 105))	('carcinoma', 'Phenotype', 'HP:0030731', (50, 59))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (36, 59))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (31, 59))	('lung squamous cell carcinoma', 'Disease', (31, 59))
195060	32705258	In the present study, following cell transfection with BRF2 siRNA, the protein expression levels of Akt, p-Akt, Bcl-2 and EGFR in A549 cells were inhibited, while Bax protein expression was increased, suggesting that silencing of BRF2 inhibited the activation of cell survival pathway PI3K/Akt, and promoted the activation of cell apoptosis.	('inhibited', 'NegReg', (235, 244))	('inhibited', 'NegReg', (146, 155))	('EGFR', 'Gene', (122, 126))	('Akt', 'Gene', (100, 103))	('expression', 'MPA', (175, 185))	('cell apoptosis', 'CPA', (326, 340))	('protein expression levels', 'MPA', (71, 96))	('Akt', 'Gene', (290, 293))	('Akt', 'Gene', '207', (100, 103))	('promoted', 'PosReg', (299, 307))	('Akt', 'Gene', (107, 110))	('Akt', 'Gene', '207', (290, 293))	('BRF2', 'Gene', '55290', (230, 234))	('si', 'Chemical', 'MESH:D012825', (85, 87))	('BRF2', 'Gene', '55290', (55, 59))	('Bcl-2', 'Gene', (112, 117))	('BRF2', 'Gene', (230, 234))	('si', 'Chemical', 'MESH:D012825', (181, 183))	('Akt', 'Gene', '207', (107, 110))	('EGFR', 'Gene', '1956', (122, 126))	('Bax', 'Gene', (163, 166))	('BRF2', 'Gene', (55, 59))	('silencing', 'Var', (217, 226))	('si', 'Chemical', 'MESH:D012825', (337, 339))	('increased', 'PosReg', (190, 199))	('Bax', 'Gene', '581', (163, 166))	('si', 'Chemical', 'MESH:D012825', (60, 62))	('si', 'Chemical', 'MESH:D012825', (217, 219))	('Bcl-2', 'Gene', '596', (112, 117))	('A549', 'CellLine', 'CVCL:0023', (130, 134))
195065	32705258	According to the results of western blot analysis in the present study, transfection of BRF2 siRNA into A549 cells increased E-cadherin expression but reduced N-cadherin expression.	('si', 'Chemical', 'MESH:D012825', (93, 95))	('E-cadherin', 'Gene', '999', (125, 135))	('reduced', 'NegReg', (151, 158))	('si', 'Chemical', 'MESH:D012825', (142, 144))	('A549', 'CellLine', 'CVCL:0023', (104, 108))	('BRF2', 'Gene', (88, 92))	('increased', 'PosReg', (115, 124))	('si', 'Chemical', 'MESH:D012825', (46, 48))	('N-cadherin', 'Gene', (159, 169))	('transfection', 'Var', (72, 84))	('N-cadherin', 'Gene', '1000', (159, 169))	('E-cadherin', 'Gene', (125, 135))	('BRF2', 'Gene', '55290', (88, 92))	('si', 'Chemical', 'MESH:D012825', (176, 178))
195066	32705258	Consistent with a previous study, in the present study silencing of BRF2 protein expression reduced the migration and invasion of NSCLC, suggesting that BRF2 expression plays an important role in invasiveness of NSCLC cells, possibly through EMT, which involves increased Snail expression and abnormal expression of E-cadherin and N-cadherin.	('BRF2', 'Gene', '55290', (68, 72))	('NSCLC', 'Disease', 'MESH:D002289', (212, 217))	('BRF2', 'Gene', (68, 72))	('N-cadherin', 'Gene', (331, 341))	('NSCLC', 'Disease', (212, 217))	('N-cadherin', 'Gene', '1000', (331, 341))	('Snail', 'Gene', (272, 277))	('silencing', 'Var', (55, 64))	('expression', 'MPA', (302, 312))	('BRF2', 'Gene', '55290', (153, 157))	('si', 'Chemical', 'MESH:D012825', (55, 57))	('NSCLC', 'Disease', 'MESH:D002289', (130, 135))	('si', 'Chemical', 'MESH:D012825', (87, 89))	('BRF2', 'Gene', (153, 157))	('si', 'Chemical', 'MESH:D012825', (228, 230))	('si', 'Chemical', 'MESH:D012825', (284, 286))	('si', 'Chemical', 'MESH:D012825', (308, 310))	('si', 'Chemical', 'MESH:D012825', (164, 166))	('NSCLC', 'Disease', (130, 135))	('increased', 'PosReg', (262, 271))	('si', 'Chemical', 'MESH:D012825', (122, 124))	('Snail', 'Gene', '6615', (272, 277))	('si', 'Chemical', 'MESH:D012825', (3, 5))	('reduced', 'NegReg', (92, 99))	('E-cadherin', 'Gene', (316, 326))	('si', 'Chemical', 'MESH:D012825', (200, 202))	('E-cadherin', 'Gene', '999', (316, 326))
195069	32705258	These above findings are in line with the results of the current study, in which the knockdown of BRF2 inhibited A549 cell migration and invasion, suppressed A549 cell proliferation, and enhanced apoptosis of A549 cells.	('BRF2', 'Gene', '55290', (98, 102))	('A549', 'CellLine', 'CVCL:0023', (158, 162))	('A549 cell proliferation', 'CPA', (158, 181))	('BRF2', 'Gene', (98, 102))	('suppressed', 'NegReg', (147, 157))	('inhibited', 'NegReg', (103, 112))	('apoptosis', 'CPA', (196, 205))	('enhanced', 'PosReg', (187, 195))	('knockdown', 'Var', (85, 94))	('A549', 'CellLine', 'CVCL:0023', (113, 117))	('si', 'Chemical', 'MESH:D012825', (202, 204))	('si', 'Chemical', 'MESH:D012825', (141, 143))	('A549', 'CellLine', 'CVCL:0023', (209, 213))
195080	32384443	High PDPN expression predicted poor overall survival (OS) and post-progression survival (PPS) particularly in gastric cancer (OS P = .0089; PPS P = .00085), especially among patients with Her-2 (+) and lymph node metastasis.	('gastric cancer', 'Disease', (110, 124))	('post-progression', 'MPA', (62, 78))	('Her-2', 'Gene', '2064', (188, 193))	('gastric cancer', 'Disease', 'MESH:D013274', (110, 124))	('High', 'Var', (0, 4))	('overall survival', 'MPA', (36, 52))	('PPS', 'Chemical', '-', (89, 92))	('PPS', 'Chemical', '-', (140, 143))	('gastric cancer', 'Phenotype', 'HP:0012126', (110, 124))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('patients', 'Species', '9606', (174, 182))	('PDPN', 'Gene', '10630', (5, 9))	('PDPN', 'Gene', (5, 9))	('poor', 'NegReg', (31, 35))	('Her-2', 'Gene', (188, 193))
195138	32384443	Moreover, in Supplementary Table 1, we could see that the medium OS (mOS) among GC patients with high PDPN expression was 3.5-month shorter than those with low PDPN expression patients.	('patients', 'Species', '9606', (176, 184))	('PDPN', 'Gene', (160, 164))	('GC', 'Phenotype', 'HP:0012126', (80, 82))	('shorter', 'NegReg', (132, 139))	('medium OS', 'CPA', (58, 67))	('PDPN', 'Gene', '10630', (160, 164))	('patients', 'Species', '9606', (83, 91))	('PDPN', 'Gene', '10630', (102, 106))	('PDPN', 'Gene', (102, 106))	('high', 'Var', (97, 101))
195140	32384443	Similarly, mPPS (medium PPS) is 2.5 months shorter among GC patients with high PDPN expression, while mPPS is 4 month shorter among Her-2 (+) GC patients with high PDPN expression.	('patients', 'Species', '9606', (145, 153))	('PPS', 'Chemical', '-', (12, 15))	('mPPS', 'Chemical', '-', (102, 106))	('PDPN', 'Gene', '10630', (164, 168))	('PDPN', 'Gene', (164, 168))	('PDPN', 'Gene', '10630', (79, 83))	('PDPN', 'Gene', (79, 83))	('high', 'Var', (74, 78))	('mPPS', 'MPA', (11, 15))	('patients', 'Species', '9606', (60, 68))	('Her-2', 'Gene', '2064', (132, 137))	('GC', 'Phenotype', 'HP:0012126', (142, 144))	('mPPS', 'Chemical', '-', (11, 15))	('Her-2', 'Gene', (132, 137))	('PPS', 'Chemical', '-', (24, 27))	('PPS', 'Chemical', '-', (103, 106))	('GC', 'Phenotype', 'HP:0012126', (57, 59))	('shorter', 'NegReg', (43, 50))
195142	32384443	In OncoLnc database, the results were consistent that high PDPN expression has significant poor prognosis in STAD (OS P = .00709).	('high', 'Var', (54, 58))	('STAD', 'Disease', (109, 113))	('PDPN', 'Gene', '10630', (59, 63))	('PDPN', 'Gene', (59, 63))
195146	32384443	From the results of our study, high PDPN mRNA expression predicts poor OS and PPS among different clinical features.	('poor', 'Disease', (66, 70))	('PPS', 'Chemical', '-', (78, 81))	('PDPN', 'Gene', (36, 40))	('PPS', 'Disease', (78, 81))	('PDPN', 'Gene', '10630', (36, 40))	('high', 'Var', (31, 35))
195150	32384443	Of note, high PDPN expression was significantly correlated with OS and PFS among Her-2 (+) GC patients (OS HR = 1.69, P = 6.10E-05; PFS HR = 2.16, P = 1.50E-06).	('expression', 'MPA', (19, 29))	('PDPN', 'Gene', '10630', (14, 18))	('PDPN', 'Gene', (14, 18))	('patients', 'Species', '9606', (94, 102))	('PFS', 'Disease', (71, 74))	('Her-2', 'Gene', '2064', (81, 86))	('Her-2', 'Gene', (81, 86))	('correlated', 'Reg', (48, 58))	('GC', 'Phenotype', 'HP:0012126', (91, 93))	('high', 'Var', (9, 13))
195151	32384443	Together, all those results showed that GC with high PDPN expression may significantly correlated with higher risk of lymph node metastasis and distance metastasis.	('correlated', 'Reg', (87, 97))	('expression', 'MPA', (58, 68))	('GC', 'Phenotype', 'HP:0012126', (40, 42))	('PDPN', 'Gene', '10630', (53, 57))	('PDPN', 'Gene', (53, 57))	('high', 'Var', (48, 52))
195161	32384443	We could imply that high PDPN expression in GC can predict poor prognosis, even though with high infiltrating level of various immune cells.	('high', 'Var', (20, 24))	('GC', 'Phenotype', 'HP:0012126', (44, 46))	('PDPN', 'Gene', '10630', (25, 29))	('PDPN', 'Gene', (25, 29))
195168	32384443	Those results indicated that high PDPN plays an important role in inducing M2 type TAM and T cell exhaustion.	('high', 'Var', (29, 33))	('PDPN', 'Gene', '10630', (34, 38))	('PDPN', 'Gene', (34, 38))	('T cell exhaustion', 'Phenotype', 'HP:0005435', (91, 108))	('inducing', 'PosReg', (66, 74))	('T cell exhaustion', 'CPA', (91, 108))	('TAM', 'Chemical', '-', (83, 86))
195193	32384443	Conversely, siRNA knock down or genetic deletion of PDPN also resulted in impaired DC migration in vivo in inflammatory disease.	('impaired', 'NegReg', (74, 82))	('PDPN', 'Gene', (52, 56))	('PDPN', 'Gene', '10630', (52, 56))	('genetic deletion', 'Var', (32, 48))	('inflammatory disease', 'Disease', (107, 127))	('DC migration', 'CPA', (83, 95))
195200	32384443	Thereby, inhibition of PDPN may reduce the infiltration of TAM, especially the M2 TAM infiltration, thus, improve T cell response, which may become a new thought for immunotherapy.	('reduce', 'NegReg', (32, 38))	('improve', 'PosReg', (106, 113))	('TAM', 'Chemical', '-', (82, 85))	('infiltration of TAM', 'MPA', (43, 62))	('TAM', 'Chemical', '-', (59, 62))	('PDPN', 'Gene', '10630', (23, 27))	('PDPN', 'Gene', (23, 27))	('inhibition', 'Var', (9, 19))	('T cell response', 'CPA', (114, 129))
195201	32384443	In non-cancer diseases, Rayes J has found deletion of PDPN reduces PDPN-dependent inflammatory macrophage migration to the infected peritoneum.	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('infected peritoneum', 'Phenotype', 'HP:0002586', (123, 142))	('infected', 'Disease', (123, 131))	('reduces', 'NegReg', (59, 66))	('cancer diseases', 'Disease', (7, 22))	('PDPN', 'Gene', (54, 58))	('cancer diseases', 'Disease', 'MESH:D009369', (7, 22))	('PDPN', 'Gene', '10630', (67, 71))	('PDPN', 'Gene', (67, 71))	('deletion', 'Var', (42, 50))	('PDPN', 'Gene', '10630', (54, 58))	('infected', 'Disease', 'MESH:D007239', (123, 131))
195202	32384443	Moreover, pharmacological inhibition of the CLEC-2-PDPN interaction could reduce macrophage infiltrating to the infection site and regulates their inflammatory phenotype in sepsis.	('sepsis', 'Disease', 'MESH:D018805', (173, 179))	('inflammatory phenotype', 'MPA', (147, 169))	('infection', 'Disease', 'MESH:D007239', (112, 121))	('PDPN', 'Gene', '10630', (51, 55))	('PDPN', 'Gene', (51, 55))	('macrophage', 'CPA', (81, 91))	('reduce', 'NegReg', (74, 80))	('interaction', 'Interaction', (56, 67))	('pharmacological', 'Var', (10, 25))	('CLEC-2', 'Gene', (44, 50))	('sepsis', 'Disease', (173, 179))	('CLEC-2', 'Gene', '51266', (44, 50))	('regulates', 'Reg', (131, 140))	('sepsis', 'Phenotype', 'HP:0100806', (173, 179))	('infection', 'Disease', (112, 121))
195233	32282333	In the LUSC group, a total of 46020 AS events in 10557 genes were detected, including 18029 ESs in 6810 genes, 9301 APs in 3737 genes, 8578 ATs in 3748 genes, 3752 AAs in 2636 genes, 3263 ADs in 2278 genes, 2862 RIs in 1908 genes, and 235 MEs in 227 genes (Figure 2B).	('LUSC', 'Phenotype', 'HP:0030359', (7, 11))	('ES', 'Chemical', '-', (92, 94))	('8578', 'Var', (135, 139))	('AD', 'Disease', 'MESH:D000544', (188, 190))	('AD', 'Disease', (188, 190))
195264	32282333	Recent evidence suggests that specific AS dysregulation has an important impact on the development and prognosis of NSCLC, and more than 12 splice variants have been suggested to be associated with lung cancer progression and/or response to therapies.	('NSCLC', 'Disease', 'MESH:D002289', (116, 121))	('lung cancer', 'Disease', (198, 209))	('impact', 'Reg', (73, 79))	('lung cancer', 'Phenotype', 'HP:0100526', (198, 209))	('associated with', 'Reg', (182, 197))	('NSCLC', 'Phenotype', 'HP:0030358', (116, 121))	('lung cancer', 'Disease', 'MESH:D008175', (198, 209))	('NSCLC', 'Disease', (116, 121))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('splice variants', 'Var', (140, 155))
195266	32282333	Boudria (2019) found that a high VEGF165b/VEGF165 ratio was related to lymph node metastasis.	('related', 'Reg', (60, 67))	('VEGF', 'Gene', (33, 37))	('lymph node metastasis', 'CPA', (71, 92))	('VEGF', 'Gene', '7422', (42, 46))	('high', 'Var', (28, 32))	('VEGF', 'Gene', '7422', (33, 37))	('VEGF', 'Gene', (42, 46))
195269	32282333	In addition, MET is a high-affinity receptor tyrosine kinase (RTK) that can initiate several pathways promoting cell proliferation, survival, and metastasis.	('cell proliferation', 'CPA', (112, 130))	('metastasis', 'CPA', (146, 156))	('RTK', 'Gene', '5979', (62, 65))	('receptor tyrosine kinase', 'Gene', '5979', (36, 60))	('receptor tyrosine kinase', 'Gene', (36, 60))	('promoting', 'PosReg', (102, 111))	('survival', 'CPA', (132, 140))	('RTK', 'Gene', (62, 65))	('MET', 'Var', (13, 16))
195270	32282333	Joanna (2018) demonstrated that MET Exon 14 splice site mutations defined unique molecular subgroups of NSCLC with poor prognosis, and MET inhibition might benefit this specific subgroup of patients.	('patients', 'Species', '9606', (190, 198))	('NSCLC', 'Disease', (104, 109))	('NSCLC', 'Disease', 'MESH:D002289', (104, 109))	('MET Exon', 'Var', (32, 40))	('NSCLC', 'Phenotype', 'HP:0030358', (104, 109))
195272	32282333	Therefore, we performed a systematic analysis to clarify the role that splice variants may play in the carcinogenesis of NSCLC.	('carcinogenesis', 'Disease', 'MESH:D063646', (103, 117))	('NSCLC', 'Disease', (121, 126))	('NSCLC', 'Disease', 'MESH:D002289', (121, 126))	('carcinogenesis', 'Disease', (103, 117))	('splice variants', 'Var', (71, 86))	('NSCLC', 'Phenotype', 'HP:0030358', (121, 126))
195277	32282333	Currently, many nomograms have been proven to be effective in lung cancer, such as the EGFR mutation model and noncytotoxic chemosensitizer model.	('EGFR', 'Gene', '1956', (87, 91))	('mutation', 'Var', (92, 100))	('lung cancer', 'Phenotype', 'HP:0100526', (62, 73))	('EGFR', 'Gene', (87, 91))	('lung cancer', 'Disease', (62, 73))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('lung cancer', 'Disease', 'MESH:D008175', (62, 73))
195287	32282333	HPCAL1, a neuronal calcium sensor protein, was found to be upregulated by Ca2+ in glioblastoma (GBM) tissues and cells.	('HPCAL1', 'Gene', '3241', (0, 6))	('glioblastoma', 'Disease', (82, 94))	('glioblastoma', 'Disease', 'MESH:D005909', (82, 94))	('calcium', 'Chemical', 'MESH:D002118', (19, 26))	('GBM', 'Phenotype', 'HP:0012174', (96, 99))	('upregulated', 'PosReg', (59, 70))	('glioblastoma', 'Phenotype', 'HP:0012174', (82, 94))	('Ca2+', 'Var', (74, 78))	('Ca2+', 'Chemical', 'MESH:D000069285', (74, 78))	('HPCAL1', 'Gene', (0, 6))
195338	31052553	According to recent publications, the direct methylation modification sites of C/D snoRNAs are located precisely 5 bp upstream of the D box of snoRNPs, reflecting the accurate positioning and effective regulatory contribution of snoRNAs.	('methylation modification', 'MPA', (45, 69))	('snoRNA', 'Gene', (229, 235))	('snoRNA', 'Gene', '85388', (229, 235))	('snoRNA', 'Gene', (83, 89))	('C/D', 'Var', (79, 82))	('snoRNA', 'Gene', '85388', (83, 89))	('D snoRNAs', 'Phenotype', 'HP:0025267', (81, 90))
195368	31052553	Ribosomal RNAs, transfer RNAs, and small nuclear RNAs are the three subgroups of snoRNAs.	('snoRNA', 'Gene', (81, 87))	('snoRNA', 'Gene', '85388', (81, 87))	('Ribosomal', 'Protein', (0, 9))	('small nuclear', 'Var', (35, 48))	('transfer', 'CPA', (16, 24))
195408	31052553	According to this rule, the high expression of U3 and low expression of SNORD123 and U94B may indicate that the potential tumor is LGG.	('SNORD123', 'Gene', '100113384', (72, 80))	('U94B', 'Var', (85, 89))	('low', 'NegReg', (54, 57))	('expression', 'MPA', (58, 68))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('SNORD123', 'Gene', (72, 80))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('expression', 'MPA', (33, 43))	('tumor', 'Disease', (122, 127))
195413	31052553	According to a recent clinical study on LUSC progression, the expression of hTR snoRNA promotes tumorigenesis, corresponding with this rule.	('hTR', 'Gene', (76, 79))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumor', 'Disease', (96, 101))	('hTR', 'Gene', '7012', (76, 79))	('promotes', 'PosReg', (87, 95))	('snoRNA', 'Gene', (80, 86))	('snoRNA', 'Gene', '85388', (80, 86))	('expression', 'Var', (62, 72))	('tumor', 'Disease', 'MESH:D009369', (96, 101))
195482	31143202	In this proof of concept study, we demonstrate the potential for alternative splicing interpretation as one of the Omics signals which should be considered for predicting cancer survival.	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('alternative splicing', 'Var', (65, 85))	('cancer', 'Disease', (171, 177))
195558	31143202	The reverse pattern lies in the staphylococcus-related pathway - more abundant alternative splicing in the pathway results in poor survival.	('results', 'Reg', (115, 122))	('alternative splicing', 'Var', (79, 99))	('poor', 'NegReg', (126, 130))	('staphylococcus', 'Species', '1280', (32, 46))
195678	32038987	PCI has been demonstrated to reduce the BM incidence by 50% as well as improve overall survival (OS) for limited-stage small cell lung cancer with complete remission after multi-modality treatment.	('overall survival', 'MPA', (79, 95))	('lung cancer', 'Phenotype', 'HP:0100526', (130, 141))	('small cell lung cancer', 'Disease', (119, 141))	('PCI', 'Var', (0, 3))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('small cell lung cancer', 'Disease', 'MESH:D055752', (119, 141))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (119, 141))	('reduce', 'NegReg', (29, 35))	('improve', 'PosReg', (71, 78))
195680	32038987	Recently, a randomized phase III trial RTOG 0214 published its long term updated results suggesting that PCI reduced the 10-years BM (HR = 0.43; 95% CI, 0.24-0.77; P = 0.003) while failed to prolong OS significantly (HR = 0.82; 95% CI, 0.63-1.06; P = 0.12) for stage III NSCLC.	('NSCLC', 'Disease', (271, 276))	('reduced', 'NegReg', (109, 116))	('NSCLC', 'Disease', 'MESH:D002289', (271, 276))	('PCI', 'Var', (105, 108))	('NSCLC', 'Phenotype', 'HP:0030358', (271, 276))
195720	31452762	Additionally, analysis of the DNA methylation data of the TCGA-LUAD Cohort revealed that CPSF3 DNA CpG sites (cg12057242 and cg25739938) were generally hypomethylated in LUAD compared with normal lung tissue.	('cg25739938', 'Var', (125, 135))	('LUAD', 'Phenotype', 'HP:0030078', (63, 67))	('cg12057242', 'Var', (110, 120))	('LUAD', 'Phenotype', 'HP:0030078', (170, 174))	('LUAD', 'Disease', (170, 174))	('CPSF3', 'Gene', '51692', (89, 94))	('CPSF3', 'Gene', (89, 94))	('hypomethylated', 'MPA', (152, 166))	('cg25739938', 'Chemical', '-', (125, 135))
195721	31452762	Correlation analysis identified the CPSF3 DNA CpG site cg25739938 to be negatively correlated with CPSF3 expression, while no correlation was identified with cg12057242.	('negatively', 'NegReg', (72, 82))	('CPSF3', 'Gene', '51692', (99, 104))	('cg25739938', 'Var', (55, 65))	('CPSF3', 'Gene', '51692', (36, 41))	('CPSF3', 'Gene', (36, 41))	('expression', 'MPA', (105, 115))	('CPSF3', 'Gene', (99, 104))	('cg25739938', 'Chemical', '-', (55, 65))
195729	31452762	Numerous types of RTKs, including epidermal growth factor receptor (EGFR), hepatocyte growth factor receptor (c-Met), ALK receptor tyrosine kinase (ALK) and BRAF, which have been reported to be frequently mutated in patients with NSCLC, have been used as targets in clinical therapy.	('NSCLC', 'Phenotype', 'HP:0030358', (230, 235))	('ALK', 'Gene', '238', (148, 151))	('mutated', 'Var', (205, 212))	('c-Met', 'Gene', (110, 115))	('ALK', 'Gene', (148, 151))	('hepatocyte growth factor receptor', 'Gene', '4233', (75, 108))	('BRAF', 'Gene', '673', (157, 161))	('EGFR', 'Gene', '1956', (68, 72))	('BRAF', 'Gene', (157, 161))	('epidermal growth factor receptor', 'Gene', (34, 66))	('hepatocyte growth factor receptor', 'Gene', (75, 108))	('epidermal growth factor receptor', 'Gene', '1956', (34, 66))	('patients', 'Species', '9606', (216, 224))	('c-Met', 'Gene', '4233', (110, 115))	('NSCLC', 'Disease', 'MESH:D002289', (230, 235))	('ALK', 'Gene', '238', (118, 121))	('ALK', 'Gene', (118, 121))	('NSCLC', 'Disease', (230, 235))	('EGFR', 'Gene', (68, 72))
195758	31452762	There was no difference in CPSF3 between the wild type and mutant samples categorized by any of the aforementioned genes of interest (Fig.	('mutant', 'Var', (59, 65))	('CPSF3', 'Gene', (27, 32))	('CPSF3', 'Gene', '51692', (27, 32))
195763	31452762	By analyzing CPSF3 DNA methylation and RNA-seq data in the TCGA-LUAD Cohort, two CPSF3 DNA methylation CpG sites (cg12057242 and cg25739938) were identified to be differentially methylated in TCGA-LUAD tissues compared with normal lung tissues (Table II).	('cg25739938', 'Var', (129, 139))	('cg12057242', 'Var', (114, 124))	('LUAD', 'Phenotype', 'HP:0030078', (64, 68))	('TCGA-LUAD', 'Disease', (192, 201))	('cg25739938', 'Chemical', '-', (129, 139))	('LUAD', 'Phenotype', 'HP:0030078', (197, 201))	('CPSF3', 'Gene', '51692', (81, 86))	('CPSF3', 'Gene', (81, 86))	('CPSF3', 'Gene', '51692', (13, 18))	('CPSF3', 'Gene', (13, 18))
195764	31452762	The correlation between the two differentially expressed DNA CpG sites and RNA expression was assessed, demonstrating that cg25739938 exhibited a negative correlation with CPSF3 expression (Fig.	('CPSF3', 'Gene', '51692', (172, 177))	('CPSF3', 'Gene', (172, 177))	('expression', 'MPA', (178, 188))	('cg25739938', 'Chemical', '-', (123, 133))	('negative', 'NegReg', (146, 154))	('cg25739938', 'Var', (123, 133))
195768	31452762	For example, DNA methylation of SOX30 is correlated with myelodysplastic syndrome progression, and has been reported to act as a potential predictive and prognostic biomarker in acute myeloid leukemia.	('myelodysplastic syndrome', 'Disease', 'MESH:D009190', (57, 81))	('leukemia', 'Phenotype', 'HP:0001909', (192, 200))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (178, 200))	('SOX30', 'Gene', '11063', (32, 37))	('SOX30', 'Gene', (32, 37))	('myelodysplastic syndrome', 'Phenotype', 'HP:0002863', (57, 81))	('acute myeloid leukemia', 'Disease', (178, 200))	('DNA methylation', 'Var', (13, 28))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (184, 200))	('correlated', 'Reg', (41, 51))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (178, 200))	('myelodysplastic syndrome', 'Disease', (57, 81))
195776	31452762	A previous study in prostate cancer demonstrated that knockdown of CPSF3 by a specific siRNA induces apoptosis, which verified that CPSF3 is associated with the proliferation of malignant carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (188, 197))	('malignant carcinoma', 'Disease', 'MESH:D009369', (178, 197))	('prostate cancer', 'Disease', 'MESH:D011471', (20, 35))	('knockdown', 'Var', (54, 63))	('prostate cancer', 'Phenotype', 'HP:0012125', (20, 35))	('CPSF3', 'Gene', '51692', (132, 137))	('CPSF3', 'Gene', (132, 137))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('CPSF3', 'Gene', '51692', (67, 72))	('associated', 'Reg', (141, 151))	('CPSF3', 'Gene', (67, 72))	('induces', 'Reg', (93, 100))	('prostate cancer', 'Disease', (20, 35))	('apoptosis', 'CPA', (101, 110))	('malignant carcinoma', 'Disease', (178, 197))
195780	31452762	Among all the mechanisms, genetic and epigenetic alterations, including DNA amplification, DNA methylation and somatic mutations, commonly lead to abnormal gene expression accompanied by anomalous cancer cell behavior.	('lead to', 'Reg', (139, 146))	('alterations', 'Var', (49, 60))	('anomalous cancer', 'Disease', 'MESH:D009369', (187, 203))	('DNA amplification', 'Var', (72, 89))	('anomalous cancer', 'Disease', (187, 203))	('DNA methylation', 'Var', (91, 106))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('epigenetic alterations', 'Var', (38, 60))	('mutations', 'Var', (119, 128))	('abnormal gene expression', 'MPA', (147, 171))
195781	31452762	For instance, heteroclite sulfatase 2 methylation acts as a prognostic marker for lung cancer survival.	('lung cancer', 'Phenotype', 'HP:0100526', (82, 93))	('sulfatase 2', 'Gene', '55959', (26, 37))	('methylation', 'Var', (38, 49))	('lung cancer', 'Disease', (82, 93))	('sulfatase 2', 'Gene', (26, 37))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('lung cancer', 'Disease', 'MESH:D008175', (82, 93))
195782	31452762	ERBB2 amplification results in erlotinib resistance in EGFR-L858R mutated tyrosine kinase inhibitor-naive LUAD.	('erlotinib resistance', 'MPA', (31, 51))	('EGFR', 'Gene', '1956', (55, 59))	('mutated', 'Var', (66, 73))	('LUAD', 'Phenotype', 'HP:0030078', (106, 110))	('L858R', 'Mutation', 'rs121434568', (60, 65))	('ERBB2', 'Gene', '2064', (0, 5))	('EGFR', 'Gene', (55, 59))	('ERBB2', 'Gene', (0, 5))	('results in', 'Reg', (20, 30))	('amplification', 'Var', (6, 19))	('erlotinib', 'Chemical', 'MESH:D000069347', (31, 40))
195784	31452762	Promoter methylation of cadherin 13 is strongly associated with LUAD and may function as a promising diagnostic biomarker for LUAD.	('LUAD', 'Phenotype', 'HP:0030078', (126, 130))	('associated', 'Reg', (48, 58))	('cadherin 13', 'Gene', (24, 35))	('cadherin 13', 'Gene', '1012', (24, 35))	('Promoter methylation', 'Var', (0, 20))	('LUAD', 'Disease', (64, 68))	('LUAD', 'Phenotype', 'HP:0030078', (64, 68))
195786	31452762	Further correlation analysis confirmed that cg25739938 was negatively correlated with CPSF3 expression, while cg12057242 in TCGA-LUAD Cohort patients and in LUAD cell lines has no correlation with CPSF3 expression.	('LUAD', 'Phenotype', 'HP:0030078', (157, 161))	('CPSF3', 'Gene', '51692', (86, 91))	('CPSF3', 'Gene', (86, 91))	('negatively', 'NegReg', (59, 69))	('cg12057242', 'Var', (110, 120))	('cg25739938', 'Chemical', '-', (44, 54))	('CPSF3', 'Gene', '51692', (197, 202))	('LUAD', 'Phenotype', 'HP:0030078', (129, 133))	('cg25739938', 'Var', (44, 54))	('CPSF3', 'Gene', (197, 202))	('patients', 'Species', '9606', (141, 149))	('expression', 'MPA', (92, 102))
195787	31452762	The aforementioned results suggested that the hypermethylation of cg25739938 may be the potential mechanism affecting CPSF3 mRNA expression in LUAD.	('cg25739938', 'Var', (66, 76))	('CPSF3', 'Gene', '51692', (118, 123))	('CPSF3', 'Gene', (118, 123))	('hypermethylation', 'Var', (46, 62))	('affecting', 'Reg', (108, 117))	('cg25739938', 'Chemical', '-', (66, 76))	('mRNA expression', 'MPA', (124, 139))	('LUAD', 'Phenotype', 'HP:0030078', (143, 147))	('LUAD', 'Disease', (143, 147))
195789	31452762	The results demonstrated that DNA CNAs were closely associated with increased CPSF3 expression, in TCGA LUAD Cohort patients and 53 LUAD cell lines.	('LUAD', 'Phenotype', 'HP:0030078', (104, 108))	('LUAD', 'Phenotype', 'HP:0030078', (132, 136))	('patients', 'Species', '9606', (116, 124))	('CPSF3', 'Gene', '51692', (78, 83))	('CPSF3', 'Gene', (78, 83))	('DNA', 'Var', (30, 33))	('expression', 'MPA', (84, 94))	('increased', 'PosReg', (68, 77))
195790	31452762	Overall, the dysregulation of CPSF3 may be caused by DNA methylation and DNA CNAs.	('methylation', 'Var', (57, 68))	('caused by', 'Reg', (43, 52))	('DNA methylation', 'Var', (53, 68))	('dysregulation', 'MPA', (13, 26))	('CPSF3', 'Gene', '51692', (30, 35))	('CPSF3', 'Gene', (30, 35))
195793	31452762	In conclusion, aberrant CPSF3 expression may be regulated by DNA CNAs, and it may function as a promising prognostic and diagnostic biomarker for LUAD.	('CPSF3', 'Gene', '51692', (24, 29))	('expression', 'MPA', (30, 40))	('CPSF3', 'Gene', (24, 29))	('LUAD', 'Phenotype', 'HP:0030078', (146, 150))	('LUAD', 'Disease', (146, 150))	('aberrant', 'Var', (15, 23))
195840	25400964	For the IDH1 and IDH2 assays, synthetic plasmids containing target regions or with introduced R132H (IDH1) and R172K (IDH2) mutations were used for validation.	('IDH1', 'Gene', (101, 105))	('IDH2', 'Gene', (118, 122))	('R172K', 'Var', (111, 116))	('IDH1', 'Gene', '3417', (101, 105))	('IDH1', 'Gene', (8, 12))	('IDH2', 'Gene', '3418', (118, 122))	('IDH2', 'Gene', (17, 21))	('R132H', 'Var', (94, 99))	('R132H', 'Mutation', 'rs121913500', (94, 99))	('IDH1', 'Gene', '3417', (8, 12))	('R172K', 'Mutation', 'rs121913503', (111, 116))	('IDH2', 'Gene', '3418', (17, 21))
195841	25400964	The cut-off values were determined to 10% tumor cells/5% mutant allele for all assays.	('mutant', 'Var', (57, 63))	('tumor', 'Disease', (42, 47))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
195850	25400964	Molecular examinations showed no KRAS mutations or mutations in isocitrate dehydrogenase 1 and 2 (IDH 1/2) genes.	('mutations', 'Var', (51, 60))	('IDH 1/2', 'Gene', (98, 105))	('KRAS', 'Gene', (33, 37))	('KRAS', 'Gene', '3845', (33, 37))	('IDH 1/2', 'Gene', '3417;3418', (98, 105))
195876	25400964	According to WHO classification of tumors in the liver, mutations in the KRAS gene are the most common genetic abnormality in CCs.	('mutations', 'Var', (56, 65))	('common', 'Reg', (96, 102))	('KRAS', 'Gene', (73, 77))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('KRAS', 'Gene', '3845', (73, 77))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('tumors', 'Disease', (35, 41))	('tumors', 'Disease', 'MESH:D009369', (35, 41))	('CCs', 'Disease', (126, 129))	('genetic abnormality', 'Disease', 'MESH:D030342', (103, 122))	('genetic abnormality', 'Disease', (103, 122))	('CC', 'Phenotype', 'HP:0030731', (126, 128))
195877	25400964	Concerning cases of ICC, mostly adenocarcinomas, 31% have a mutation in the KRAS gene and 21% have IDH 1 and 2 gene mutation.	('mutation', 'Var', (60, 68))	('mostly adenocarcinomas', 'Disease', (25, 47))	('CC', 'Phenotype', 'HP:0030731', (21, 23))	('KRAS', 'Gene', (76, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (37, 46))	('KRAS', 'Gene', '3845', (76, 80))	('carcinomas', 'Phenotype', 'HP:0030731', (37, 47))	('IDH 1 and 2', 'Gene', '3417;3418', (99, 110))	('mostly adenocarcinomas', 'Disease', 'MESH:D000230', (25, 47))	('ICC', 'Disease', (20, 23))
195903	33842328	APOBEC3B, a member of APOBEC (apolipoprotein B mRNA editing enzyme, catalytic-polypeptide-like) enzymes with cytidine deaminase activity, can induce prevalent mutagen of genomic DNA in multiple cancers.	('cytidine deaminase', 'Gene', (109, 127))	('cancers', 'Phenotype', 'HP:0002664', (194, 201))	('cancers', 'Disease', 'MESH:D009369', (194, 201))	('APOBEC3B', 'Gene', (0, 8))	('mutagen', 'Var', (159, 166))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('cancers', 'Disease', (194, 201))	('induce', 'Reg', (142, 148))	('cytidine deaminase', 'Gene', '978', (109, 127))
195905	33842328	High expression of APOBEC3B is associated with immune evasion of cancer.	('APOBEC3B', 'Gene', (19, 27))	('High', 'Var', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('associated', 'Reg', (31, 41))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))
195906	33842328	Notably, high expression of APOBEC3B also enhances the sensitivity to immune checkpoint blockade in melanoma.	('APOBEC3B', 'Gene', (28, 36))	('sensitivity to immune checkpoint blockade', 'MPA', (55, 96))	('melanoma', 'Phenotype', 'HP:0002861', (100, 108))	('enhances', 'PosReg', (42, 50))	('melanoma', 'Disease', (100, 108))	('melanoma', 'Disease', 'MESH:D008545', (100, 108))	('high', 'Var', (9, 13))
195927	33842328	To figure out the relationship between APOBEC3B and molecular subtypes, we further investigated the expression level of APOBEC3B among subtypes: increased expression level of APBOEC3B was found in CL and ME compared to PN and NE (P <.05, respectively;  Figure 1C ).	('APBOEC3B', 'Var', (175, 183))	('ME', 'Chemical', '-', (204, 206))	('CL', 'Disease', 'None', (197, 199))	('increased', 'PosReg', (145, 154))	('expression', 'MPA', (155, 165))
195930	33842328	Glioma patients with codeletion of 1p and 19q derived more benefits in several clinical trials.	('codeletion', 'Var', (21, 31))	('Glioma', 'Phenotype', 'HP:0009733', (0, 6))	('Glioma', 'Disease', 'MESH:D005910', (0, 6))	('Glioma', 'Disease', (0, 6))	('benefits', 'PosReg', (59, 67))	('patients', 'Species', '9606', (7, 15))
195931	33842328	We observed that the expression of APOBEC3B was decreased in the 1p19q codeletion cluster in pan-glioma analysis (P <.05, respectively;  Figure 1D ).	('glioma', 'Disease', (97, 103))	('1p19q', 'Var', (65, 70))	('decreased', 'NegReg', (48, 57))	('expression', 'MPA', (21, 31))	('APOBEC3B', 'Gene', (35, 43))	('glioma', 'Disease', 'MESH:D005910', (97, 103))	('glioma', 'Phenotype', 'HP:0009733', (97, 103))
195946	33842328	We revealed that APOBEC3Bhigh patients showed shorter overall survival (OS) than APOBEC3Blow patients in pan-glioma, LGG, and GBM (P <.05, respectively;  Figures 3A, B ).	('glioma', 'Phenotype', 'HP:0009733', (109, 115))	('APOBEC3Bhigh', 'Var', (17, 29))	('overall survival', 'MPA', (54, 70))	('glioma', 'Disease', (109, 115))	('patients', 'Species', '9606', (30, 38))	('shorter', 'NegReg', (46, 53))	('patients', 'Species', '9606', (93, 101))	('glioma', 'Disease', 'MESH:D005910', (109, 115))
195949	33842328	High APOBEC3B expression was significantly correlated to worse prognosis in nine cancer types, including ACC, CHOL, ESCA, LIHC, LUAD, PAAD, UCEC, UCS, and KICH (P <.0001, respectively;  Figure 3C ).	('CHOL', 'Disease', 'None', (110, 114))	('LUAD', 'Phenotype', 'HP:0030078', (128, 132))	('cancer', 'Disease', (81, 87))	('ACC', 'Phenotype', 'HP:0006744', (105, 108))	('ACC', 'Disease', (105, 108))	('LIHC', 'Disease', (122, 126))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('ESCA', 'Phenotype', 'HP:0011459', (116, 120))	('KICH', 'Disease', 'None', (155, 159))	('High', 'Var', (0, 4))	('LUAD', 'Disease', (128, 132))	('CHOL', 'Disease', (110, 114))	('UCEC', 'Disease', (140, 144))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('UCS', 'Phenotype', 'HP:0002891', (146, 149))	('CHOL', 'Phenotype', 'HP:0030153', (110, 114))	('PAAD', 'Phenotype', 'HP:0006725', (134, 138))	('KICH', 'Disease', (155, 159))	('APOBEC3B', 'Gene', (5, 13))	('ESCA', 'Disease', (116, 120))	('PAAD', 'Disease', (134, 138))	('expression', 'MPA', (14, 24))	('UCS', 'Disease', (146, 149))
195952	33842328	Besides the variation of chr1 and chr19, amplification of chr7 and deletion of chr10 most frequently occurred in glioma patients ( Figure 4A ).	('glioma', 'Disease', 'MESH:D005910', (113, 119))	('glioma', 'Phenotype', 'HP:0009733', (113, 119))	('occurred', 'Reg', (101, 109))	('deletion', 'Var', (67, 75))	('chr7', 'Gene', (58, 62))	('glioma', 'Disease', (113, 119))	('patients', 'Species', '9606', (120, 128))	('amplification', 'Var', (41, 54))	('chr10', 'Gene', (79, 84))
195953	33842328	As a genomic symbol of oligodendroglioma, deletion of 1p and 19q tended to appear in APOBEC3Blow cluster ( Figure 4B ).	('glioma', 'Phenotype', 'HP:0009733', (34, 40))	('APOBEC3Blow', 'Gene', (85, 96))	('oligodendroglioma', 'Disease', (23, 40))	('oligodendroglioma', 'Disease', 'MESH:D009837', (23, 40))	('deletion', 'Var', (42, 50))
195959	33842328	Common carcinogenic pathways were found to be more active in APOBEC3Bhigh group ( Figures 5E, G ).	('carcinogenic', 'Disease', (7, 19))	('carcinogenic', 'Disease', 'MESH:D063646', (7, 19))	('APOBEC3Bhigh', 'Var', (61, 73))	('more active', 'PosReg', (46, 57))
195960	33842328	The strongest co-occurrent pairs of gene alteration in the APOBEC3Bhigh group were ATRX-TP53, and in the APOBEC3Blow groups were ATRX-TP53 as well as ATRX-IDH1, which was in line with previous studies> Meanwhile, the most mutually exclusive pairs in APOBEC3Bhigh and APOBEC3Blow groups were CIC-TP53 and EGFR-IDH1, respectively ( Figures 5F, H ).	('TP53', 'Gene', (134, 138))	('ATRX', 'Gene', (150, 154))	('IDH1', 'Gene', '3417', (155, 159))	('TP53', 'Gene', '7157', (88, 92))	('ATRX', 'Gene', '546', (150, 154))	('IDH1', 'Gene', (309, 313))	('EGFR', 'Gene', (304, 308))	('TP53', 'Gene', '7157', (295, 299))	('ATRX', 'Gene', (83, 87))	('ATRX', 'Gene', '546', (83, 87))	('TP53', 'Gene', '7157', (134, 138))	('ATRX', 'Gene', (129, 133))	('rat', 'Species', '10116', (45, 48))	('IDH1', 'Gene', '3417', (309, 313))	('ATRX', 'Gene', '546', (129, 133))	('EGFR', 'Gene', '1956', (304, 308))	('alteration', 'Var', (41, 51))	('TP53', 'Gene', (88, 92))	('TP53', 'Gene', (295, 299))	('IDH1', 'Gene', (155, 159))
195985	33842328	Generally, somatic mutation has been considered as a therapy evasion promoter of cancer.	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('cancer', 'Disease', (81, 87))	('somatic mutation', 'Var', (11, 27))	('cancer', 'Disease', 'MESH:D009369', (81, 87))
195986	33842328	Correspondingly, mutation can also promote antitumor T-cell response.	('mutation', 'Var', (17, 25))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('promote', 'PosReg', (35, 42))	('tumor', 'Disease', (47, 52))
195989	33842328	For example, highly expressed APOBEC3B is regarded as an unfavorable prognostic factors in myeloma, ovarian cancer, and clear cell renal cell carcinoma.	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (131, 151))	('APOBEC3B', 'Gene', (30, 38))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (120, 151))	('clear cell renal cell carcinoma', 'Disease', (120, 151))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('ovarian cancer', 'Phenotype', 'HP:0100615', (100, 114))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (120, 151))	('myeloma, ovarian cancer', 'Disease', 'MESH:D009101', (91, 114))	('highly expressed', 'Var', (13, 29))	('carcinoma', 'Phenotype', 'HP:0030731', (142, 151))
195992	33842328	Most recently, the duality of APOBEC3B in immunotherapy has been demonstrated, in which APOBEC3B not only acts as the general driving force of therapy escape but also significantly activates the immune system in melanoma.	('rat', 'Species', '10116', (72, 75))	('APOBEC3B', 'Var', (88, 96))	('immune system', 'CPA', (195, 208))	('melanoma', 'Phenotype', 'HP:0002861', (212, 220))	('melanoma', 'Disease', (212, 220))	('activates', 'PosReg', (181, 190))	('melanoma', 'Disease', 'MESH:D008545', (212, 220))
195996	33842328	But the activation of tumor-infiltrating immune cells also mediates APOBEC3B deletion in breast cancer in Asian patients.	('breast cancer', 'Disease', 'MESH:D001943', (89, 102))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('APOBEC3B', 'Gene', (68, 76))	('breast cancer', 'Disease', (89, 102))	('patients', 'Species', '9606', (112, 120))	('breast cancer', 'Phenotype', 'HP:0003002', (89, 102))	('deletion', 'Var', (77, 85))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('tumor', 'Disease', (22, 27))	('rat', 'Species', '10116', (34, 37))
196004	33842328	Several immune infiltrating cell types possess the features of immunosuppression: It is well documented that MDSC is able to inhibit innate and adaptive immunity, and macrophages have been indicated to promote cancer cell proliferation, immunosuppression, and angiogenesis in cancers.	('cancers', 'Phenotype', 'HP:0002664', (276, 283))	('inhibit', 'NegReg', (125, 132))	('cancer', 'Disease', (276, 282))	('cancer', 'Disease', 'MESH:D009369', (276, 282))	('cancers', 'Disease', 'MESH:D009369', (276, 283))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('rat', 'Species', '10116', (229, 232))	('cancers', 'Disease', (276, 283))	('promote', 'PosReg', (202, 209))	('immunosuppression', 'CPA', (237, 254))	('angiogenesis', 'CPA', (260, 272))	('rat', 'Species', '10116', (21, 24))	('cancer', 'Phenotype', 'HP:0002664', (276, 282))	('MDSC', 'Var', (109, 113))	('cancer', 'Disease', 'MESH:D009369', (210, 216))	('cancer', 'Disease', (210, 216))
196007	33842328	Cell type enrichment analysis further revealed that APOBEC3B was significantly correlated with MDSC, macrophage, regulatory T cells, and Th2 cells in glioma, KICH, PAAD, and UCS, providing evidence to the statement that APOBEC3B was an immunotherapy escape driver in LGG.	('KICH', 'Disease', (158, 162))	('PAAD', 'Phenotype', 'HP:0006725', (164, 168))	('APOBEC3B', 'Var', (220, 228))	('Th2', 'Chemical', '-', (137, 140))	('glioma', 'Disease', (150, 156))	('KICH', 'Disease', 'None', (158, 162))	('UCS', 'Phenotype', 'HP:0002891', (174, 177))	('APOBEC3B', 'Gene', (52, 60))	('correlated', 'Reg', (79, 89))	('glioma', 'Disease', 'MESH:D005910', (150, 156))	('glioma', 'Phenotype', 'HP:0009733', (150, 156))
196015	33842328	CD276 has become a novel Cart-T target for GBM while inhibition of PD-1/PD-L1 pathway can be a latent treatment strategy for glioma.	('PD-1', 'Gene', (67, 71))	('glioma', 'Disease', (125, 131))	('inhibition', 'Var', (53, 63))	('rat', 'Species', '10116', (114, 117))	('PD-1', 'Gene', '5133', (67, 71))	('PD-L1', 'Gene', '29126', (72, 77))	('glioma', 'Disease', 'MESH:D005910', (125, 131))	('CD276', 'Gene', (0, 5))	('glioma', 'Phenotype', 'HP:0009733', (125, 131))	('CD276', 'Gene', '80381', (0, 5))	('PD-L1', 'Gene', (72, 77))
196060	33023080	Previous studies have revealed that TP53, CDKN2A, NOTCH1, FBXW7, HRAS, and PIK3CA genes were frequently mutated in patients with head and neck squamous cell carcinoma (HNSCC).	('CDKN2A', 'Gene', (42, 48))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (143, 166))	('TP53', 'Gene', (36, 40))	('PIK3CA', 'Gene', (75, 81))	('FBXW7', 'Gene', '55294', (58, 63))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (129, 166))	('carcinoma', 'Phenotype', 'HP:0030731', (157, 166))	('CDKN2A', 'Gene', '1029', (42, 48))	('HNSCC', 'Phenotype', 'HP:0012288', (168, 173))	('patients', 'Species', '9606', (115, 123))	('HRAS', 'Gene', '3265', (65, 69))	('HRAS', 'Gene', (65, 69))	('TP53', 'Gene', '7157', (36, 40))	('mutated', 'Var', (104, 111))	('PIK3CA', 'Gene', '5290', (75, 81))	('NOTCH1', 'Gene', (50, 56))	('neck squamous cell carcinoma', 'Disease', (138, 166))	('FBXW7', 'Gene', (58, 63))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (138, 166))
196061	33023080	As reported by many oncological studies, mutations in the TP53 gene are present in more than half of human cancers.	('mutations', 'Var', (41, 50))	('cancers', 'Disease', (107, 114))	('cancers', 'Disease', 'MESH:D009369', (107, 114))	('present', 'Reg', (72, 79))	('TP53', 'Gene', '7157', (58, 62))	('TP53', 'Gene', (58, 62))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('human', 'Species', '9606', (101, 106))	('cancers', 'Phenotype', 'HP:0002664', (107, 114))
196063	33023080	The high mutation rate is significant because TP53 mutation is believed to initiate the proliferation of mutated cells.	('TP53', 'Gene', '7157', (46, 50))	('TP53', 'Gene', (46, 50))	('mutation', 'Var', (51, 59))
196064	33023080	Among the various mutations observed in TP53, missense mutations are the most common.	('missense mutations', 'Var', (46, 64))	('TP53', 'Gene', '7157', (40, 44))	('TP53', 'Gene', (40, 44))	('common', 'Reg', (78, 84))
196065	33023080	Furthermore, most TP53 mutations are located near the DNA binding domain of the protein, which is highly associated with poor prognosis.	('TP53', 'Gene', '7157', (18, 22))	('binding', 'Interaction', (58, 65))	('TP53', 'Gene', (18, 22))	('mutations', 'Var', (23, 32))	('associated', 'Reg', (105, 115))
196066	33023080	Some studies investigated the relationship between gene mutations and HPV.	('investigated', 'Reg', (13, 25))	('HPV', 'Disease', (70, 73))	('mutations', 'Var', (56, 65))	('HPV', 'Species', '10566', (70, 73))
196067	33023080	Although there is no distinct relationship between p53 and HPV status, TP53 mutations occurred more frequently in HPV negative OSCCs than they did in HPV positive OSCCs.	('p53', 'Gene', (51, 54))	('p53', 'Gene', '7157', (51, 54))	('mutations', 'Var', (76, 85))	('HPV', 'Species', '10566', (59, 62))	('occurred', 'Reg', (86, 94))	('HPV', 'Species', '10566', (114, 117))	('HPV', 'Gene', (114, 117))	('negative', 'NegReg', (118, 126))	('HPV', 'Species', '10566', (150, 153))	('TP53', 'Gene', '7157', (71, 75))	('TP53', 'Gene', (71, 75))
196072	33023080	Unlike TP53, the PIK3CA gene mutations are commonly observed in HPV positive oral cancers.	('observed', 'Reg', (52, 60))	('oral cancer', 'Disease', (77, 88))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('TP53', 'Gene', '7157', (7, 11))	('TP53', 'Gene', (7, 11))	('PIK3CA', 'Gene', (17, 23))	('cancers', 'Phenotype', 'HP:0002664', (82, 89))	('mutations', 'Var', (29, 38))	('PIK3CA', 'Gene', '5290', (17, 23))	('cancers', 'Disease', (82, 89))	('cancers', 'Disease', 'MESH:D009369', (82, 89))	('oral cancer', 'Disease', 'MESH:D009369', (77, 88))	('HPV', 'Species', '10566', (64, 67))
196074	33023080	According to some studies, PIK3CA mutations may be associated with the later stages of OSCC, as PIK3CA is frequently mutated in stage IV OSCC.	('PIK3CA', 'Gene', (27, 33))	('associated', 'Reg', (51, 61))	('PIK3CA', 'Gene', (96, 102))	('PIK3CA', 'Gene', '5290', (96, 102))	('PIK3CA', 'Gene', '5290', (27, 33))	('OSCC', 'Disease', (87, 91))	('mutations', 'Var', (34, 43))
196075	33023080	Similarly, the deregulation of PI3KCA (due to mutation) leads to activation of the PI3K/Akt signaling pathway.	('Akt', 'Gene', '207', (88, 91))	('PI3KCA', 'Gene', (31, 37))	('deregulation', 'MPA', (15, 27))	('Akt', 'Gene', (88, 91))	('mutation', 'Var', (46, 54))	('activation', 'PosReg', (65, 75))
196077	33023080	Altogether, the heterogeneous findings regarding PIK3CA mutations provide an opportunity for the development of various therapies and treatments.	('mutations', 'Var', (56, 65))	('men', 'Species', '9606', (104, 107))	('men', 'Species', '9606', (139, 142))	('PIK3CA', 'Gene', (49, 55))	('PIK3CA', 'Gene', '5290', (49, 55))
196080	33023080	NOTCH1 mutations occur more frequently in Asian patients (specifically Chinese) than they do in Caucasian patients.	('Chinese', 'Species', '10029', (71, 78))	('patients', 'Species', '9606', (48, 56))	('patients', 'Species', '9606', (106, 114))	('NOTCH1', 'Gene', (0, 6))	('Asian', 'Disease', (42, 47))	('mutations', 'Var', (7, 16))
196084	33023080	Despite the efforts to identify mutations responsible for OSCC, the challenges of treating this malignancy remain due to tumor heterogeneity.	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('malignancy', 'Disease', 'MESH:D009369', (96, 106))	('malignancy', 'Disease', (96, 106))	('tumor', 'Disease', (121, 126))	('mutations', 'Var', (32, 41))	('OSCC', 'Disease', (58, 62))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
196096	33023080	STIMA-1 and MIRA-1 are also cysteine-binding compounds that prevent unfolding of p53 (both wild-type and mutant forms).	('cysteine', 'Chemical', 'MESH:D003545', (28, 36))	('unfolding', 'MPA', (68, 77))	('p53', 'Gene', '7157', (81, 84))	('p53', 'Gene', (81, 84))	('mutant', 'Var', (105, 111))
196128	33023080	In a study assessing the effect of temsirolimus on OSCC associated with bone destruction, temsirolimus successfully decreased the migrative and proliferative nature of HSC-2 OSCC cells.	('temsirolimus', 'Chemical', 'MESH:C401859', (35, 47))	('HSC-2 OSCC', 'CellLine', 'CVCL:L894', (168, 178))	('bone destruction', 'Phenotype', 'HP:0002797', (72, 88))	('temsirolimus', 'Chemical', 'MESH:C401859', (90, 102))	('temsirolimus', 'Var', (90, 102))	('decreased', 'NegReg', (116, 125))
196131	33023080	These characteristics highly suggest that administration of COX-2 inhibitors and celecoxib can effectively inhibit adhesion, migration, invasion, and metastasis of cells of the human tongue squamous cell carcinoma.	('inhibit', 'NegReg', (107, 114))	('tongue squamous cell carcinoma', 'Phenotype', 'HP:0030413', (183, 213))	('celecoxib', 'Chemical', 'MESH:D000068579', (81, 90))	('migration', 'CPA', (125, 134))	('carcinoma', 'Phenotype', 'HP:0030731', (204, 213))	('adhesion', 'CPA', (115, 123))	('COX-2', 'Gene', '4513', (60, 65))	('invasion', 'CPA', (136, 144))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (190, 213))	('metastasis', 'CPA', (150, 160))	('squamous cell carcinoma', 'Disease', (190, 213))	('COX-2', 'Gene', (60, 65))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (190, 213))	('inhibitors', 'Var', (66, 76))	('human', 'Species', '9606', (177, 182))
196165	33023080	This study showed that the differential expressions of miR-92b-3p, miR-375, and miR-486-5p were associated with the risk of OSCC recurrence 9-12 months postoperatively.	('miR-486-5p', 'Var', (80, 90))	('associated', 'Reg', (96, 106))	('OSCC recurrence', 'Disease', (124, 139))	('miR-486-5p', 'Chemical', '-', (80, 90))	('miR-375', 'Gene', (67, 74))	('miR-92b-3p', 'Var', (55, 65))	('miR-375', 'Gene', '494324', (67, 74))
196175	33023080	MiR-486-5p is the most promising diagnostic biomarker for OSCC among the three primary miRNAs.	('MiR-486-5p', 'Chemical', '-', (0, 10))	('MiR-486-5p', 'Var', (0, 10))	('OSCC', 'Disease', (58, 62))
196176	33023080	The expression of miR-486-5p was significantly lower in pre-operative samples than in healthy samples.	('lower', 'NegReg', (47, 52))	('miR-486-5p', 'Chemical', '-', (18, 28))	('expression', 'MPA', (4, 14))	('miR-486-5p', 'Var', (18, 28))
196178	33023080	miR-486-5p is likely associated with OSCC recurrence 9-12 months after surgery, because the expression level of miR-486-5p is not highly elevated in post-operative samples compared to those of pre-operative samples in OSCC patients with recurrence.	('miR-486-5p', 'Chemical', '-', (0, 10))	('associated', 'Reg', (21, 31))	('OSCC', 'Disease', (37, 41))	('miR-486-5p', 'Var', (0, 10))	('miR-486-5p', 'Chemical', '-', (112, 122))	('patients', 'Species', '9606', (223, 231))
196179	33023080	Altogether, these results suggest that miR-486-5p is a useful biomarker for monitoring OSCC recurrence after surgery.	('miR-486-5p', 'Var', (39, 49))	('OSCC', 'Disease', (87, 91))	('miR-486-5p', 'Chemical', '-', (39, 49))
196181	33023080	These results suggest that circulating miR-486-5p can be identified as a tumor-suppressive miRNA and a strong indicator of OSCC recurrence.	('miR-486-5p', 'Var', (39, 49))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('OSCC', 'Disease', (123, 127))	('tumor', 'Disease', (73, 78))	('miR-486-5p', 'Chemical', '-', (39, 49))
196182	33023080	The other miRNAs, including miR-486-5p and miR-375, are considered moderate risk indicators of OSCC recurrence 9-12 months after surgery.	('miR-486-5p', 'Chemical', '-', (28, 38))	('miR-375', 'Gene', '494324', (43, 50))	('OSCC', 'Disease', (95, 99))	('miR-486-5p', 'Var', (28, 38))	('miR-375', 'Gene', (43, 50))
196188	33023080	Mutation or deletion of PTEN leads to continuous activation of AKT, which increases anti-apoptotic gene expression (Figure 2).	('activation', 'PosReg', (49, 59))	('deletion', 'Var', (12, 20))	('PTEN', 'Gene', '5728', (24, 28))	('anti-apoptotic gene expression', 'MPA', (84, 114))	('AKT', 'Gene', (63, 66))	('Mutation', 'Var', (0, 8))	('increases', 'PosReg', (74, 83))	('AKT', 'Gene', '207', (63, 66))	('PTEN', 'Gene', (24, 28))
196193	33023080	As the PI3K/AKT pathway is involved in apoptosis and tumorigenesis, mutation or hindrance in PTEN is likely to lead to cancer.	('PTEN', 'Gene', (93, 97))	('AKT', 'Gene', '207', (12, 15))	('hindrance', 'NegReg', (80, 89))	('PTEN', 'Gene', '5728', (93, 97))	('mutation', 'Var', (68, 76))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('involved', 'Reg', (27, 35))	('AKT', 'Gene', (12, 15))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('cancer', 'Disease', (119, 125))	('tumor', 'Disease', (53, 58))	('lead to', 'Reg', (111, 118))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
196195	33023080	PTEN is widely known as a tumor-suppressive gene, and the frequency of PTEN mutation in various types of human cancers is comparable to that of p53.	('cancers', 'Disease', 'MESH:D009369', (111, 118))	('cancers', 'Phenotype', 'HP:0002664', (111, 118))	('cancers', 'Disease', (111, 118))	('p53', 'Gene', '7157', (144, 147))	('mutation', 'Var', (76, 84))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('PTEN', 'Gene', (71, 75))	('PTEN', 'Gene', '5728', (71, 75))	('human', 'Species', '9606', (105, 110))	('tumor', 'Disease', (26, 31))	('PTEN', 'Gene', (0, 4))	('PTEN', 'Gene', '5728', (0, 4))	('p53', 'Gene', (144, 147))
196201	33023080	They found that inhibiting miR-21-3p suppressed cell colonization, but had a negligible effect on cell proliferation.	('miR-21-3p', 'Gene', (27, 36))	('cell colonization', 'CPA', (48, 65))	('inhibiting', 'Var', (16, 26))	('miR-21-3p', 'Gene', '406995', (27, 36))	('suppressed', 'NegReg', (37, 47))
196206	33023080	Oral brushing specimens from OSCC patients revealed that a set of miRNAs were detected, and three of them were overexpressed (miR-21, miR-191, and miR-146).	('miR-191', 'Gene', (134, 141))	('miR-21', 'Gene', (126, 132))	('overexpressed', 'PosReg', (111, 124))	('miR-21', 'Gene', '406991', (126, 132))	('patients', 'Species', '9606', (34, 42))	('miR-146', 'Var', (147, 154))	('men', 'Species', '9606', (19, 22))	('miR-191', 'Gene', '406966', (134, 141))
196209	33023080	Among the miRNAs identified, three miRNAs (miR-150-5p, miR-222-3p, and miR-423-5p) were differentially expressed across the three groups.	('miR-423-5p', 'Var', (71, 81))	('miR-150-5p', 'Chemical', '-', (43, 53))	('miR-150-5p', 'Var', (43, 53))	('miR-423-5p', 'Chemical', '-', (71, 81))	('miR-222-3p', 'Chemical', '-', (55, 65))	('miR-222-3p', 'Var', (55, 65))
196211	33023080	However, miR-150-5p and miR-423-5p were significantly up-regulated in OSCC patients relative to normal and OL patient groups.	('OSCC', 'Disease', (70, 74))	('miR-423-5p', 'Chemical', '-', (24, 34))	('miR-150-5p', 'Var', (9, 19))	('OL', 'Phenotype', 'HP:0002745', (107, 109))	('patients', 'Species', '9606', (75, 83))	('miR-150-5p', 'Chemical', '-', (9, 19))	('miR-423-5p', 'Var', (24, 34))	('up-regulated', 'PosReg', (54, 66))	('patient', 'Species', '9606', (110, 117))	('patient', 'Species', '9606', (75, 82))
196212	33023080	Furthermore, miR-222-3p and miR-423-5p were down-regulated when tumors metastasized to the lymph node.	('miR-423-5p', 'Chemical', '-', (28, 38))	('down-regulated', 'NegReg', (44, 58))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('tumors metastasized', 'Disease', 'MESH:D009362', (64, 83))	('miR-222-3p', 'Chemical', '-', (13, 23))	('miR-423-5p', 'Var', (28, 38))	('miR-222-3p', 'Var', (13, 23))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('tumors metastasized', 'Disease', (64, 83))
196214	33023080	Interestingly, miR-150-5p expression levels did not correlate with lymph node metastasis and tumor progression but were lower at the later stage of tumorigenesis.	('lower', 'NegReg', (120, 125))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('miR-150-5p', 'Var', (15, 25))	('tumor', 'Disease', (148, 153))	('tumor', 'Disease', (93, 98))	('miR-150-5p', 'Chemical', '-', (15, 25))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
196215	33023080	As a result, this group suggested that miR-222 and miR-423-5p are useful indicators of tumor progression.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('miR-423-5p', 'Chemical', '-', (51, 61))	('miR-222', 'Gene', (39, 46))	('tumor', 'Disease', (87, 92))	('miR-423-5p', 'Var', (51, 61))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('miR-222', 'Gene', '407007', (39, 46))
196218	33023080	Among the 512 miRNAs, three significantly expressed miRNAs (miR-21-5p, miR-143-3p, and miR-148a-3p) accounted for 89% of all reads.	('miR-21-5p', 'Gene', (60, 69))	('miR-148a-3p', 'Var', (87, 98))	('miR-143-3p', 'Var', (71, 81))	('miR-21-5p', 'Gene', '406997', (60, 69))
196219	33023080	In addition, 567 mature miRNAs were detected in the OSCC samples and the three most expressed miRNAs were miR-143-3p, miR-22-3p, and miR-21-5p.	('miR-143-3p', 'Var', (106, 116))	('miR-22-3p', 'Gene', (118, 127))	('miR-22-3p', 'Gene', '407008', (118, 127))	('miR-21-5p', 'Gene', (133, 142))	('miR-21-5p', 'Gene', '406997', (133, 142))
196222	33023080	Inhibiting miR-21 function with antisense miR-21 oligonucleotide has effectively suppressed tumorigenesis and induced apoptosis in TSCC.	('apoptosis', 'CPA', (118, 127))	('suppressed', 'NegReg', (81, 91))	('miR-21', 'Gene', (42, 48))	('Inhibiting', 'NegReg', (0, 10))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('miR-21', 'Gene', (11, 17))	('antisense', 'Var', (32, 41))	('function', 'MPA', (18, 26))	('TSCC', 'Disease', (131, 135))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('miR-21', 'Gene', '406991', (42, 48))	('tumor', 'Disease', (92, 97))	('induced', 'Reg', (110, 117))	('miR-21', 'Gene', '406991', (11, 17))
196225	33023080	Although many studies have confirmed various gene mutations and miRNAs related to OSCC, more research is necessary for a deeper understanding of the molecular processes involved in tumorigenesis.	('tumor', 'Disease', (181, 186))	('mutations', 'Var', (50, 59))	('OSCC', 'Disease', (82, 86))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))
196245	30821103	Only 25-30% of tumors use the PD-1/PD-L1 pathway to suppress the immune response, whereas other tumors use other molecular pathways or mechanisms to escape the immune response, which we currently know little about.1, 4  Since 2015, the FDA has approved the use of four different ICIs for the treatment of NSCLC, including anti-PD-1 nivolumab and pembrolizumab and anti-PD-L1 atezolizumab and durvalumab.	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('PD-1', 'Gene', (30, 34))	('PD-1', 'Gene', '5133', (30, 34))	('tumors', 'Disease', (96, 102))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('atezolizumab', 'Chemical', 'MESH:C000594389', (375, 387))	('durvalumab', 'Chemical', 'MESH:C000613593', (392, 402))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('nivolumab', 'Chemical', 'MESH:D000077594', (332, 341))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('PD-1', 'Gene', (327, 331))	('PD-1', 'Gene', '5133', (327, 331))	('tumors', 'Disease', (15, 21))	('NSCLC', 'Disease', 'MESH:D002289', (305, 310))	('pembrolizumab', 'Chemical', 'MESH:C582435', (346, 359))	('NSCLC', 'Disease', (305, 310))	('anti-PD-L1', 'Var', (364, 374))	('tumors', 'Disease', 'MESH:D009369', (15, 21))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('NSCLC', 'Phenotype', 'HP:0030358', (305, 310))
196262	28938010	Sonoporation and EGFR-MB had a strong cytotoxic effect on Ca9-22 cells with low-dose bleomycin.	('EGFR-MB', 'Gene', (17, 24))	('cytotoxic effect', 'CPA', (38, 54))	('Sonoporation', 'Var', (0, 12))	('Ca9-22', 'CellLine', 'CVCL:1102', (58, 64))	('bleomycin', 'Chemical', 'MESH:D001761', (85, 94))
196266	28938010	Together, our results show that EGFR-MBs and ultrasound treatment increases the efficacy and specificity of intracellular drug uptake, suggesting this could be a novel drug-targeting modality for oral squamous cell carcinoma chemotherapy treatment.	('efficacy', 'MPA', (80, 88))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (196, 224))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (201, 224))	('EGFR-MBs', 'Var', (32, 40))	('increases', 'PosReg', (66, 75))	('oral squamous cell carcinoma', 'Disease', (196, 224))	('carcinoma', 'Phenotype', 'HP:0030731', (215, 224))	('specificity', 'MPA', (93, 104))
196316	28938010	Ca9-22 cells treated by sonoporation with BLM (5 mug/mL) and EGFR-MBs showed increased numbers of cells in subG1 phase (40.3%) compared with cells treated with BLM or BLM and MBs (17.1% and 19.8%, respectively) (Fig 3A).	('sonoporation', 'Var', (24, 36))	('BLM', 'Chemical', 'MESH:D001761', (167, 170))	('subG1 phase', 'CPA', (107, 118))	('BLM', 'Chemical', 'MESH:D001761', (42, 45))	('EGFR-MBs', 'Var', (61, 69))	('BLM', 'Chemical', 'MESH:D001761', (160, 163))	('increased', 'PosReg', (77, 86))	('Ca9-22', 'CellLine', 'CVCL:1102', (0, 6))
196343	28938010	Furthermore, apoptosis after sonoporation using low-concentration BLM (5 mug/mL) and EGFR-MBs was significantly higher compared with the other treatment groups (Fig 3).	('low-concentration', 'Var', (48, 65))	('BLM', 'Chemical', 'MESH:D001761', (66, 69))	('higher', 'PosReg', (112, 118))	('apoptosis', 'CPA', (13, 22))
196344	28938010	demonstrated that the combination of EGFR-targeting MBs and US exposure effectively eliminates tumor cells in vivo.	('EGFR-targeting', 'Gene', (37, 51))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('MBs', 'Var', (52, 55))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('eliminates', 'NegReg', (84, 94))	('tumor', 'Disease', (95, 100))
196351	28938010	Our results showed that sonoporation with EGFR-MBs showed a greater antitumor effect compared with sonoporation with MBs (Figs 4 and 5).	('EGFR-MBs', 'Var', (42, 50))	('tumor', 'Disease', (72, 77))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Disease', 'MESH:D009369', (72, 77))
196355	28938010	However, PEGylation reduces complement activation, which induce adaptive immune response with repeated usage.	('complement activation', 'MPA', (28, 49))	('PEGylation', 'Var', (9, 19))	('reduces', 'NegReg', (20, 27))	('PEG', 'Chemical', 'MESH:D011092', (9, 12))	('adaptive immune response', 'CPA', (64, 88))
196365	33191398	Its aberrant expression is frequently found in human cancers, where it was reported to act either as tumor-suppressor or oncogene depending on the specific tumor context and target genes.	('tumor-suppressor', 'Gene', '7248', (101, 117))	('cancers', 'Phenotype', 'HP:0002664', (53, 60))	('cancers', 'Disease', (53, 60))	('tumor-suppressor', 'Gene', (101, 117))	('cancers', 'Disease', 'MESH:D009369', (53, 60))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('aberrant expression', 'Var', (4, 23))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('tumor', 'Disease', (156, 161))	('human', 'Species', '9606', (47, 52))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
196372	33191398	Which mechanisms or factors modify the reciprocal production of miR-205 and MIR205HG long noncoding RNA?	('MIR205HG', 'Gene', '642587', (76, 84))	('MIR205HG', 'Gene', (76, 84))	('miR-205', 'Var', (64, 71))
196373	33191398	Indeed, several studies showed that dysregulated miRNA expression is functionally related to the onset of different human diseases, including cancer.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('related', 'Reg', (82, 89))	('dysregulated', 'Var', (36, 48))	('human', 'Species', '9606', (116, 121))	('miRNA', 'Protein', (49, 54))	('cancer', 'Disease', (142, 148))
196398	33191398	In prostate cancer, miR-205 was demonstrated to act as a tumor-suppressor by repressing the expression of factors (N-chimerin, E2F1, E2F5, ZEB2, and protein kinase Cepsilon) involved in EMT, cell motility and invasion.	('prostate cancer', 'Phenotype', 'HP:0012125', (3, 18))	('tumor-suppressor', 'Gene', '7248', (57, 73))	('miR-205', 'Var', (20, 27))	('N-chimerin', 'Gene', (115, 125))	('prostate cancer', 'Disease', (3, 18))	('N-chimerin', 'Gene', '1123', (115, 125))	('E2F1', 'Gene', (127, 131))	('E2F5', 'Gene', '1875', (133, 137))	('protein kinase Cepsilon', 'Gene', (149, 172))	('E2F1', 'Gene', '1869', (127, 131))	('tumor-suppressor', 'Gene', (57, 73))	('protein kinase Cepsilon', 'Gene', '5581', (149, 172))	('ZEB2', 'Gene', (139, 143))	('ZEB2', 'Gene', '9839', (139, 143))	('expression', 'MPA', (92, 102))	('E2F5', 'Gene', (133, 137))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('repressing', 'NegReg', (77, 87))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('prostate cancer', 'Disease', 'MESH:D011471', (3, 18))
196416	33191398	Similarly, aberrant DNA hypermethylation, H3K9 deacetylation and H3K27me3 in the pre-miR-205 locus are related to miR-205 silencing in muscle-invasive bladder cancer and in transformed lung epithelial cells.	('muscle-invasive bladder cancer', 'Disease', 'MESH:D001749', (135, 165))	('muscle-invasive bladder cancer', 'Disease', (135, 165))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('H3K9', 'Var', (42, 46))	('aberrant', 'Var', (11, 19))	('bladder cancer', 'Phenotype', 'HP:0009725', (151, 165))	('DNA', 'MPA', (20, 23))	('silencing', 'NegReg', (122, 131))	('H3K27me3', 'Var', (65, 73))	('invasive bladder', 'Phenotype', 'HP:0100645', (142, 158))	('miR-205', 'Gene', (114, 121))	('related', 'Reg', (103, 110))
196425	33191398	In this regard, it was reported that inactivating mutations of p53 that result in its defective binding to p53REs are responsible for decreased level of miR-205 in TNBC.	('decreased', 'NegReg', (134, 143))	('p53', 'Gene', (63, 66))	('p53', 'Gene', '7157', (63, 66))	('binding', 'Interaction', (96, 103))	('p53', 'Gene', (107, 110))	('level of miR-205', 'MPA', (144, 160))	('p53', 'Gene', '7157', (107, 110))	('inactivating mutations', 'Var', (37, 59))	('TNBC', 'Disease', 'None', (164, 168))	('defective', 'NegReg', (86, 95))	('TNBC', 'Disease', (164, 168))
196426	33191398	Conversely, p53 gain of function mutants (GOF-mutp53) induce the up-regulation of miR-205, which promotes proliferation in head and neck squamous cell carcinoma.	('p53', 'Gene', (49, 52))	('p53', 'Gene', '7157', (49, 52))	('miR-205', 'Gene', (82, 89))	('p53', 'Gene', (12, 15))	('p53', 'Gene', '7157', (12, 15))	('carcinoma', 'Phenotype', 'HP:0030731', (151, 160))	('neck squamous cell carcinoma', 'Disease', (132, 160))	('mutants', 'Var', (33, 40))	('promotes', 'PosReg', (97, 105))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (132, 160))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (137, 160))	('gain of function', 'PosReg', (16, 32))	('proliferation', 'CPA', (106, 119))	('up-regulation', 'PosReg', (65, 78))
196428	33191398	p53 mutants may impinge on miR-205 expression also through different mechanisms.	('p53', 'Gene', (0, 3))	('p53', 'Gene', '7157', (0, 3))	('mutants', 'Var', (4, 11))	('impinge', 'Reg', (16, 23))	('expression', 'MPA', (35, 45))	('miR-205', 'Gene', (27, 34))
196429	33191398	For example, in the prostate cancer context, p53 mutants reduce p63 stability and activity, with a consequent reduction of miR-205 transcriptional rate.	('p63', 'Gene', (64, 67))	('p53', 'Gene', (45, 48))	('reduce', 'NegReg', (57, 63))	('reduction', 'NegReg', (110, 119))	('p53', 'Gene', '7157', (45, 48))	('prostate cancer', 'Disease', 'MESH:D011471', (20, 35))	('mutants', 'Var', (49, 56))	('p63', 'Gene', '8626', (64, 67))	('prostate cancer', 'Phenotype', 'HP:0012125', (20, 35))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('prostate cancer', 'Disease', (20, 35))	('activity', 'MPA', (82, 90))	('miR-205 transcriptional rate', 'MPA', (123, 151))
196449	33191398	However, the same region tested by a different reporter construct showed only enhancer activity upon p53 transfection in HEK-293 cells.	('transfection', 'Var', (105, 117))	('HEK-293', 'CellLine', 'CVCL:0045', (121, 128))	('p53', 'Gene', '7157', (101, 104))	('p53', 'Gene', (101, 104))	('enhancer', 'PosReg', (78, 86))
196452	33191398	A recent work showed that the binding of the mutant p53 to region 2 increases the expression of both MIR205HG and miR-205, indicating that this region may act as the promoter for both RNAs.	('increases', 'PosReg', (68, 77))	('MIR205HG', 'Gene', '642587', (101, 109))	('mutant', 'Var', (45, 51))	('expression', 'MPA', (82, 92))	('MIR205HG', 'Gene', (101, 109))	('p53', 'Gene', (52, 55))	('p53', 'Gene', '7157', (52, 55))	('binding', 'Interaction', (30, 37))	('miR-205', 'Gene', (114, 121))
196458	33191398	Interestingly, Chang and co-workers, by sequencing pri-miRNA structures using a dominant-negative Drosha mutant, were able to map lowly expressed alternatively spliced MIR205HG transcripts that, by utilizing a distinct 3' terminal exon (exon 5.2, Fig.	('MIR205HG', 'Gene', '642587', (168, 176))	('Drosha', 'Gene', (98, 104))	('mutant', 'Var', (105, 111))	('Drosha', 'Gene', '29102', (98, 104))	('MIR205HG', 'Gene', (168, 176))
196459	33191398	Accordingly, reannotation of all possible MIR205HG transcripts made starting from recently acquired long read sequencing data suggested the existence of two locus configurations, one that acts as source of miR-205 (miR-205 compatible transcripts) and the other that gives rise to MIR205HG transcripts only (miR-205 incompatible transcripts).	('miR-205', 'Var', (206, 213))	('MIR205HG', 'Gene', (280, 288))	('MIR205HG', 'Gene', '642587', (42, 50))	('MIR205HG', 'Gene', '642587', (280, 288))	('MIR205HG', 'Gene', (42, 50))
196464	33191398	It is worth mentioning that, though processed from a common primary transcript, mature MIR205HG and miR-205 have been shown to act independently.	('MIR205HG', 'Gene', '642587', (87, 95))	('MIR205HG', 'Gene', (87, 95))	('miR-205', 'Var', (100, 107))
196470	33191398	MIR205HG and miR-205 were reported to play non redundant independent functions also in prostate basal cells, where MIR205HG maintains basal identity by regulating differentiation and miR-205 regulates the production of basement membrane.	('basal identity', 'CPA', (134, 148))	('MIR205HG', 'Gene', (115, 123))	('differentiation', 'CPA', (163, 178))	('regulating', 'Reg', (152, 162))	('MIR205HG', 'Gene', '642587', (0, 8))	('production of basement membrane', 'MPA', (205, 236))	('miR-205', 'Var', (183, 190))	('MIR205HG', 'Gene', '642587', (115, 123))	('MIR205HG', 'Gene', (0, 8))	('regulates', 'Reg', (191, 200))
196474	33191398	The long Intergenic Non-Protein Coding 00673 (LINC00673), enriched in hepatocellular carcinoma, by adsorbing miR-205 reduces its availability and consequently prevents miR-205 tumor-suppressor functions.	('LINC00673', 'Gene', '100499467', (46, 55))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('tumor-suppressor', 'Gene', (176, 192))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (70, 94))	('miR-205', 'Gene', (109, 116))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (70, 94))	('adsorbing', 'Var', (99, 108))	('hepatocellular carcinoma', 'Disease', (70, 94))	('reduces', 'NegReg', (117, 124))	('LINC00673', 'Gene', (46, 55))	('miR-205', 'Gene', (168, 175))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('tumor-suppressor', 'Gene', '7248', (176, 192))	('prevents', 'NegReg', (159, 167))	('availability', 'MPA', (129, 141))
196478	33191398	RP11-395G23.3 and LA16c-313D11.11 are two lncRNAs associated to the pathogenesis of endometrial cancer.	('RP11', 'Gene', '26121', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('LA16c-313D11.11', 'Var', (18, 33))	('endometrial cancer', 'Disease', (84, 102))	('endometrial cancer', 'Phenotype', 'HP:0012114', (84, 102))	('endometrial cancer', 'Disease', 'MESH:D016889', (84, 102))	('RP11', 'Gene', (0, 4))
196482	33191398	Similarly, SNHG16 was found to act as miR-205 sponge in the cardiovascular context, where reduced levels of miR-205 are related to increased proliferation and migration of aortic smooth muscle cells, suggesting a link with atherosclerosis.	('reduced', 'NegReg', (90, 97))	('increased', 'PosReg', (131, 140))	('SNHG16', 'Gene', (11, 17))	('migration', 'CPA', (159, 168))	('miR-205', 'Var', (108, 115))	('SNHG16', 'Gene', '100507246', (11, 17))	('atherosclerosis', 'Disease', 'MESH:D050197', (223, 238))	('proliferation', 'CPA', (141, 154))	('atherosclerosis', 'Phenotype', 'HP:0002621', (223, 238))	('atherosclerosis', 'Disease', (223, 238))	('levels', 'MPA', (98, 104))
196487	33191398	As reported by Sun and co-workers, the lncRNA HOX transcript antisense RNA (HOTAIR) participates to miR-205 silencing in bladder cancer by breaking the balance between the positive (H3K4me3) and negative (H3K27me3) chromatin marks on miR-205 promoter.	('silencing', 'NegReg', (108, 117))	('HOTAIR', 'Gene', (76, 82))	('bladder cancer', 'Disease', (121, 135))	('HOTAIR', 'Gene', '100124700', (76, 82))	('H3K27me3', 'Var', (205, 213))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('bladder cancer', 'Phenotype', 'HP:0009725', (121, 135))	('miR-205', 'Gene', (100, 107))	('breaking', 'NegReg', (139, 147))	('bladder cancer', 'Disease', 'MESH:D001749', (121, 135))
196490	33191398	In cancer, epigenetic modifications, mutated or alternatively spliced p53 family proteins and components of tumor microenvironment (hypoxia, inflammatory cytokines) mostly contribute to miR-205 dysregulation at the transcriptional level.	('miR-205', 'Gene', (186, 193))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('hypoxia', 'Disease', 'MESH:D000860', (132, 139))	('p53', 'Gene', (70, 73))	('dysregulation', 'MPA', (194, 207))	('p53', 'Gene', '7157', (70, 73))	('epigenetic modifications', 'Var', (11, 35))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('tumor', 'Disease', (108, 113))	('cancer', 'Disease', (3, 9))	('contribute', 'Reg', (172, 182))	('mutated', 'Var', (37, 44))	('hypoxia', 'Disease', (132, 139))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
196502	33194734	Ktrans-e0, Kep -e0, DeltaKtrans, and DeltaVe were positively correlated with the tumor regression rate.	('Ktrans-e0', 'Chemical', '-', (0, 9))	('Kep -e0', 'Var', (11, 18))	('DeltaKtrans', 'Var', (20, 31))	('correlated', 'Reg', (61, 71))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('Kep', 'Chemical', '-', (11, 14))	('DeltaKtrans', 'Chemical', '-', (20, 31))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('DeltaVe', 'Var', (37, 44))	('Ktrans-e0', 'Var', (0, 9))	('tumor', 'Disease', (81, 86))
196503	33194734	Mean values of Ktrans-e0, Ktrans-e3, DeltaKtrans, and DeltaVe were higher in the non-residual tumor group than residual tumor group and were independent prognostic factors for predicting residual tumor occurrence.	('DeltaKtrans', 'MPA', (37, 48))	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('Ktrans-e3', 'Var', (26, 35))	('higher', 'PosReg', (67, 73))	('tumor', 'Disease', (196, 201))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('Ktrans-e0', 'Var', (15, 24))	('DeltaVe', 'MPA', (54, 61))	('tumor', 'Disease', (94, 99))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('DeltaKtrans', 'Chemical', '-', (37, 48))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('Ktrans-e0', 'Chemical', '-', (15, 24))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('Ktrans-e3', 'Chemical', '-', (26, 35))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('tumor', 'Disease', (120, 125))
196558	33194734	Tumor regression rate was positively correlated with Ktrans-e0 (r=0.576, P<0.001), Kep-e0 (r = 0.528, P < 0.001), Ktrans-e3 (r = 0.617, P = 0.025), DeltaKtrans (r = 0.507, P < 0.001) and DeltaVe (r = 0.542, P < 0.001).	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('DeltaKtrans', 'Chemical', '-', (148, 159))	('DeltaKtrans', 'Var', (148, 159))	('Kep-e0', 'Var', (83, 89))	('Ktrans-e3', 'Chemical', '-', (114, 123))	('DeltaVe', 'Var', (187, 194))	('Ktrans-e0', 'Var', (53, 62))	('Tumor regression rate', 'CPA', (0, 21))	('Ktrans-e3', 'Var', (114, 123))	('Ktrans-e0', 'Chemical', '-', (53, 62))	('Kep', 'Chemical', '-', (83, 86))
196562	33194734	Univariate and multivariate logistic regression analysis revealed that Ktrans-e0, Ktrans-e3, and DeltaVe were independent prognostic factors for residual tumor occurrence.	('Ktrans-e0', 'Var', (71, 80))	('DeltaVe', 'Var', (97, 104))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('Ktrans-e3', 'Chemical', '-', (82, 91))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('Ktrans-e3', 'Var', (82, 91))	('Ktrans-e0', 'Chemical', '-', (71, 80))	('tumor', 'Disease', (154, 159))
196563	33194734	The lower Ktrans-e0, Ktrans-e3, DeltaKtrans, and DeltaVe had higher risk ratios for residual tumor occurrence.	('Ktrans-e3', 'Chemical', '-', (21, 30))	('DeltaKtrans', 'Chemical', '-', (32, 43))	('Ktrans-e0', 'Chemical', '-', (10, 19))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('Ktrans-e3', 'Var', (21, 30))	('tumor', 'Disease', (93, 98))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
196571	33194734	Here, we found that quantitative DCE-MRI parameters Ktrans-e0, Kep-e0, Ktrans-e3, DeltaKtrans, and DeltaVe positively correlated with tumor regression rate in LACSC.	('Ktrans-e0', 'Var', (52, 61))	('LACSC', 'Chemical', '-', (159, 164))	('Kep-e0', 'Var', (63, 69))	('Ktrans-e0', 'Chemical', '-', (52, 61))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('DeltaKtrans', 'Chemical', '-', (82, 93))	('correlated with', 'Reg', (118, 133))	('LACSC', 'Disease', (159, 164))	('Kep', 'Chemical', '-', (63, 66))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('DCE', 'Chemical', '-', (33, 36))	('Ktrans-e3', 'Chemical', '-', (71, 80))	('Ktrans-e3', 'Var', (71, 80))	('tumor', 'Disease', (134, 139))
196573	33194734	Several studies concluded that pretreatment parameters Ktrans and Kep were positively correlated with tumor regression rate, which is inconsistent with our results.	('correlated', 'Reg', (86, 96))	('Ktrans', 'Var', (55, 61))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('Ktrans', 'Chemical', '-', (55, 61))	('Kep', 'Chemical', '-', (66, 69))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('Kep', 'Var', (66, 69))
196587	33194734	Their results suggested that higher pretreatment Ktrans and lower pretreatment Ve tended to result in a larger tumor volume at 4 weeks of CCRT.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('Ktrans', 'Var', (49, 55))	('tumor', 'Disease', (111, 116))	('Ktrans', 'Chemical', '-', (49, 55))	('larger', 'PosReg', (104, 110))
196596	33194734	reported that pretreatment Ktrans and Ve were positively correlated with progression-free survival for cervical cancer patients.	('Ktrans', 'Var', (27, 33))	('progression-free survival', 'CPA', (73, 98))	('Ktrans', 'Chemical', '-', (27, 33))	('patients', 'Species', '9606', (119, 127))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('correlated with', 'Reg', (57, 72))	('cervical cancer', 'Disease', (103, 118))	('cervical cancer', 'Disease', 'MESH:D002583', (103, 118))
196599	33194734	We found that Ktrans-e0, Ktrans-e3, DeltaKtrans, and DeltaVe are significantly higher in the non-residual tumor group than the residual tumor group in LACSC.	('higher', 'PosReg', (79, 85))	('LACSC', 'Chemical', '-', (151, 156))	('DeltaVe', 'MPA', (53, 60))	('Ktrans-e0', 'Chemical', '-', (14, 23))	('DeltaKtrans', 'Chemical', '-', (36, 47))	('Ktrans-e3', 'Chemical', '-', (25, 34))	('Ktrans-e3', 'Var', (25, 34))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('DeltaKtrans', 'MPA', (36, 47))	('Ktrans-e0', 'Var', (14, 23))	('tumor', 'Disease', (136, 141))	('tumor', 'Disease', (106, 111))
196600	33194734	The parameters Ktrans-e0, Ktrans-e3, and DeltaKtrans were significantly higher in non-residual tumor group patients, which supported the hypothesis that better permeability represented better material exchange, thus better oxygenation and higher radiation sensitivity.	('higher', 'PosReg', (239, 245))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('material exchange', 'MPA', (192, 209))	('Ktrans-e0', 'Chemical', '-', (15, 24))	('patients', 'Species', '9606', (107, 115))	('non-residual', 'Disease', (82, 94))	('oxygenation', 'MPA', (223, 234))	('better', 'PosReg', (216, 222))	('better', 'PosReg', (185, 191))	('DeltaKtrans', 'Chemical', '-', (41, 52))	('tumor', 'Disease', (95, 100))	('permeability', 'MPA', (160, 172))	('Ktrans-e3', 'Var', (26, 35))	('Ktrans-e0', 'Var', (15, 24))	('radiation sensitivity', 'CPA', (246, 267))	('oxygen', 'Chemical', 'MESH:D010100', (223, 229))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('higher', 'PosReg', (72, 78))	('Ktrans-e3', 'Chemical', '-', (26, 35))
196609	33194734	We noticed that AUC of mid-treatment Ktrans-e3 was higher than pretreatment Ktrans-e0, probably indicated that the closer relation between mid-treatment parameter and treatment outcome.	('AUC', 'MPA', (16, 19))	('Ktrans-e0', 'Chemical', '-', (76, 85))	('Ktrans-e3', 'Chemical', '-', (37, 46))	('higher', 'PosReg', (51, 57))	('Ktrans-e3', 'Var', (37, 46))
196775	29331386	Photodynamic therapy (PDT) is a 2-part treatment consisting of topical application of a photosensitizer, either 5-aminolevulinic acid (ALA) or methylaminolevulinate (MAL), followed by 1 to several hours of incubation by light irradiation, typically with a blue, red, or broadband light source.	('ALA', 'Chemical', 'MESH:C000614854', (135, 138))	('Photodynamic therapy', 'Disease', (0, 20))	('5-aminolevulinic acid', 'Chemical', 'MESH:C000614854', (112, 133))	('methylaminolevulinate', 'Chemical', '-', (143, 164))	('MAL', 'Chemical', '-', (166, 169))	('men', 'Species', '9606', (44, 47))	('methylaminolevulinate', 'Var', (143, 164))
196839	29331386	Limited evidence is available to support the utility of other agents, including cyclic PDT, oral nicotinamide, and celecoxib, in reducing the risk for cSCC in patients with a history of keratinocyte carcinoma.	('cyclic PDT', 'Var', (80, 90))	('carcinoma', 'Disease', (199, 208))	('cSCC', 'Phenotype', 'HP:0006739', (151, 155))	('nicotinamide', 'Chemical', 'MESH:D009536', (97, 109))	('celecoxib', 'Chemical', 'MESH:D000068579', (115, 124))	('cSCC', 'Chemical', '-', (151, 155))	('carcinoma', 'Disease', 'MESH:D002277', (199, 208))	('patients', 'Species', '9606', (159, 167))	('cSCC', 'Disease', (151, 155))	('carcinoma', 'Phenotype', 'HP:0030731', (199, 208))
196875	30383737	Surgeon General reports also have concluded that the use of smokeless tobacco (i.e., snuff and chewing tobacco) causes cancers of the OCP and esophagus; cigar use causes cancers of the oral cavity, esophagus, larynx, and lung; and secondhand smoke exposure causes lung cancer.	('causes', 'Reg', (112, 118))	('cancers', 'Phenotype', 'HP:0002664', (170, 177))	('cancers', 'Disease', (170, 177))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('lung cancer', 'Disease', 'MESH:D008175', (264, 275))	('oral cavity', 'Disease', (185, 196))	('esophagus', 'Disease', (142, 151))	('cancers of the oral cavity', 'Phenotype', 'HP:0100649', (170, 196))	('cancers', 'Phenotype', 'HP:0002664', (119, 126))	('cancers', 'Disease', (119, 126))	('esophagus', 'Disease', (198, 207))	('lung cancer', 'Phenotype', 'HP:0100526', (264, 275))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('cancers', 'Disease', 'MESH:D009369', (170, 177))	('cancer', 'Phenotype', 'HP:0002664', (269, 275))	('causes', 'Reg', (163, 169))	('cancers', 'Disease', 'MESH:D009369', (119, 126))	('lung cancer', 'Disease', (264, 275))	('tobacco', 'Species', '4097', (70, 77))	('tobacco', 'Species', '4097', (103, 110))	('cigar', 'Var', (153, 158))	('larynx', 'Disease', (209, 215))
196904	30383737	Anatomic sites were restricted to cancers with histology codes 8000-9049, 9056-9139, and 9141-9589 (excluding mesothelioma, Kaposi sarcoma, and hematopoietic cancers).	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('hematopoietic cancers', 'Disease', 'MESH:D019337', (144, 165))	('cancers', 'Disease', 'MESH:D009369', (34, 41))	('9141-9589', 'Var', (89, 98))	('cancers', 'Phenotype', 'HP:0002664', (158, 165))	('mesothelioma', 'Disease', (110, 122))	('Kaposi sarcoma', 'Phenotype', 'HP:0100726', (124, 138))	('hematopoietic cancers', 'Disease', (144, 165))	('cancers', 'Disease', (158, 165))	('mesothelioma', 'Disease', 'MESH:D008654', (110, 122))	('cancers', 'Disease', 'MESH:D009369', (158, 165))	('sarcoma', 'Phenotype', 'HP:0100242', (131, 138))	('cancers', 'Phenotype', 'HP:0002664', (34, 41))	('cancers', 'Disease', (34, 41))	('Kaposi sarcoma', 'Disease', 'MESH:D012514', (124, 138))	('Kaposi sarcoma', 'Disease', (124, 138))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('9056-9139', 'Var', (74, 83))
197098	30383737	Human and animal studies have found that functional nicotinic receptors are present on pancreatic islet and beta cells, and nicotine can reduce the release of insulin through neuronal nicotinic acetylcholine receptors on islet cells.	('Human', 'Species', '9606', (0, 5))	('pancreatic', 'Disease', 'MESH:D010195', (87, 97))	('pancreatic', 'Disease', (87, 97))	('nicotine', 'Var', (124, 132))	('reduce', 'NegReg', (137, 143))	('release of insulin', 'MPA', (148, 166))	('nicotine', 'Chemical', 'MESH:D009538', (124, 132))
197198	30383737	Correspondingly, lung cancer incidence has decreased nearly four times faster in California than in the rest of the United States.	('decreased', 'NegReg', (43, 52))	('lung cancer', 'Disease', (17, 28))	('lung cancer', 'Phenotype', 'HP:0100526', (17, 28))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('lung cancer', 'Disease', 'MESH:D008175', (17, 28))	('California', 'Var', (81, 91))
197201	30383737	The Advisory Committee for Immunization Practices recommends hepatitis B virus and HPV vaccinations to prevent infection with these viruses that are also known to cause tobacco-associated cancers (liver, cervical, and OCP).	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('men', 'Species', '9606', (55, 58))	('HPV', 'Species', '10566', (83, 86))	('cancers', 'Phenotype', 'HP:0002664', (188, 195))	('cancers', 'Disease', (188, 195))	('infection', 'Disease', (111, 120))	('cancers', 'Disease', 'MESH:D009369', (188, 195))	('hepatitis B virus', 'Species', '10407', (61, 78))	('viruses', 'Var', (132, 139))	('infection', 'Disease', 'MESH:D007239', (111, 120))	('tobacco', 'Species', '4097', (169, 176))	('hepatitis', 'Phenotype', 'HP:0012115', (61, 70))	('cervical', 'Disease', (204, 212))	('cause', 'Reg', (163, 168))
197241	26292924	Currently several studies have analyzed genome-wide mutational patterns in different cancer types and identified genes harboring functional mutations implicated in cancerogenesis.	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('cancer', 'Disease', (85, 91))	('cancer', 'Disease', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('mutations', 'Var', (140, 149))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
197242	26292924	Cancer is thought to be driven by gene expression pattern changes due to the accumulation of mutations or epigenetic modifications; thus, a comprehensive characterization of alterations in gene expression will not only advance our understanding of cancer biology, it will also provide a large number of new potential diagnostic and therapeutic targets for cancer.	('cancer', 'Disease', (248, 254))	('cancer', 'Disease', 'MESH:D009369', (356, 362))	('advance', 'PosReg', (219, 226))	('cancer', 'Phenotype', 'HP:0002664', (248, 254))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('cancer', 'Disease', (356, 362))	('alterations', 'Var', (174, 185))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('cancer', 'Disease', 'MESH:D009369', (248, 254))	('cancer', 'Phenotype', 'HP:0002664', (356, 362))
197262	26292924	Driver mutations are causally implicated in carcinogenesis while passenger mutations don't contribute to the development of cancer.	('Driver mutations', 'Var', (0, 16))	('cancer', 'Disease', (124, 130))	('carcinogenesis', 'Disease', 'MESH:D063646', (44, 58))	('carcinogenesis', 'Disease', (44, 58))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('implicated', 'Reg', (30, 40))	('cancer', 'Disease', 'MESH:D009369', (124, 130))
197264	26292924	In cancers, as a result of mutations, this regulatory process malfunctions, resulting in uncontrolled cell proliferation that leads to carcinogenesis.	('mutations', 'Var', (27, 36))	('uncontrolled', 'MPA', (89, 101))	('leads to', 'Reg', (126, 134))	('carcinogenesis', 'Disease', (135, 149))	('resulting', 'Reg', (76, 85))	('cancers', 'Phenotype', 'HP:0002664', (3, 10))	('cancers', 'Disease', (3, 10))	('cancers', 'Disease', 'MESH:D009369', (3, 10))	('carcinogenesis', 'Disease', 'MESH:D063646', (135, 149))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
197266	26292924	1: (1) one or more driver mutations are within a cell cycle-associated pathway, altering its expression pattern and consequently leading to cancer; (2) one or more driver mutations lie in an organ/tissue-specific pathway or other pathways not related to cell cycle, which interacts with a cell cycle-associated pathway, alters its expression pattern, and ultimately results in cancer.	('cancer', 'Phenotype', 'HP:0002664', (377, 383))	('cancer', 'Disease', (140, 146))	('leading to', 'Reg', (129, 139))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('mutations', 'Var', (26, 35))	('results in', 'Reg', (366, 376))	('expression pattern', 'MPA', (93, 111))	('alters', 'Reg', (320, 326))	('cancer', 'Disease', (377, 383))	('altering', 'Reg', (80, 88))	('cancer', 'Disease', 'MESH:D009369', (377, 383))	('mutations', 'Var', (171, 180))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('expression pattern', 'MPA', (331, 349))
197275	26292924	Gene set CLUSTER2556 is significant in BLCA, COAD, and LUSC.	('LUSC', 'Disease', (55, 59))	('CLUSTER2556', 'Var', (9, 20))	('COAD', 'Disease', (45, 49))	('BLCA', 'Disease', (39, 43))	('COAD', 'Disease', 'MESH:D029424', (45, 49))
197279	26292924	We identified seven cross-cancer gene signatures: CLUSTER241, CLUSTER514, CLUSTER1011, CLUSTER932, CLUSTER574, CLUSTER3137, and CLUSTER184, that were altered in at least four types of human cancers.	('CLUSTER574', 'Var', (99, 109))	('cancers', 'Phenotype', 'HP:0002664', (190, 197))	('CLUSTER3137', 'Var', (111, 122))	('cancers', 'Disease', (190, 197))	('cross-cancer', 'Disease', (20, 32))	('CLUSTER1011', 'Var', (74, 85))	('cross-cancer', 'Disease', 'MESH:C537866', (20, 32))	('cancers', 'Disease', 'MESH:D009369', (190, 197))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('human', 'Species', '9606', (184, 189))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('CLUSTER184', 'Var', (128, 138))	('CLUSTER514', 'Var', (62, 72))	('CLUSTER932', 'Var', (87, 97))	('CLUSTER241', 'Var', (50, 60))
197292	26292924	Baculoviral IAP repeat containing 5 (BIRC5) is over-expressed in most human cancers; the microRNA targeting BIRC5 suppresses cell proliferation in triple-negative breast cancer (TNBC) cells.	('cancers', 'Phenotype', 'HP:0002664', (76, 83))	('BIRC5', 'Gene', '332', (37, 42))	('cancers', 'Disease', (76, 83))	('BIRC5', 'Gene', (37, 42))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('suppresses', 'NegReg', (114, 124))	('BIRC5', 'Gene', '332', (108, 113))	('Baculoviral IAP repeat containing 5', 'Gene', '332', (0, 35))	('BIRC5', 'Gene', (108, 113))	('breast cancer', 'Phenotype', 'HP:0003002', (163, 176))	('TNBC', 'Disease', 'None', (178, 182))	('cancers', 'Disease', 'MESH:D009369', (76, 83))	('microRNA targeting', 'Var', (89, 107))	('human', 'Species', '9606', (70, 75))	('cell proliferation', 'CPA', (125, 143))	('breast cancer', 'Disease', 'MESH:D001943', (163, 176))	('breast cancer', 'Disease', (163, 176))	('TNBC', 'Disease', (178, 182))	('Baculoviral IAP repeat containing 5', 'Gene', (0, 35))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))
197301	26292924	Mutations in BRCA1 interacting protein C-terminal helicase 1 (BRIP1) have been associated with ovarian cancer and breast cancer.	('BRIP1', 'Gene', (62, 67))	('associated', 'Reg', (79, 89))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('BRIP1', 'Gene', '83990', (62, 67))	('BRCA1', 'Gene', (13, 18))	('ovarian cancer', 'Disease', 'MESH:D010051', (95, 109))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('ovarian cancer', 'Phenotype', 'HP:0100615', (95, 109))	('ovarian cancer', 'Disease', (95, 109))	('Mutations', 'Var', (0, 9))	('helicase 1', 'Gene', '56916', (50, 60))	('breast cancer', 'Disease', 'MESH:D001943', (114, 127))	('breast cancer', 'Phenotype', 'HP:0003002', (114, 127))	('BRCA1', 'Gene', '672', (13, 18))	('breast cancer', 'Disease', (114, 127))	('helicase 1', 'Gene', (50, 60))
197308	26292924	The aberrant expression of cell division cycle 6 (CDC6) has been documented in multiple human cancers.	('cancers', 'Disease', 'MESH:D009369', (94, 101))	('CDC6', 'Gene', '990', (50, 54))	('aberrant', 'Var', (4, 12))	('CDC6', 'Gene', (50, 54))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('human', 'Species', '9606', (88, 93))	('cancers', 'Phenotype', 'HP:0002664', (94, 101))	('cancers', 'Disease', (94, 101))
197311	26292924	CLUSTER574 is significantly altered in six cancer types: BRCA, COAD, HNSC, LIHC, LUAD, and LUSC.	('LUSC', 'Disease', (91, 95))	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('HNSC', 'Disease', (69, 73))	('COAD', 'Disease', (63, 67))	('altered', 'Reg', (28, 35))	('CLUSTER574', 'Var', (0, 10))	('cancer', 'Disease', (43, 49))	('LIHC', 'Disease', (75, 79))	('BRCA', 'Gene', '672', (57, 61))	('LIHC', 'Disease', 'None', (75, 79))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('COAD', 'Disease', 'MESH:D029424', (63, 67))	('BRCA', 'Gene', (57, 61))	('LUAD', 'Disease', (81, 85))
197319	26292924	CLUSTER3137 is significantly altered in five cancer types: BLCA, COAD, LIHC, LUAD, and LUSC.	('LUAD', 'Disease', (77, 81))	('CLUSTER3137', 'Var', (0, 11))	('LUSC', 'Disease', (87, 91))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('LIHC', 'Disease', (71, 75))	('COAD', 'Disease', (65, 69))	('BLCA', 'Disease', (59, 63))	('LIHC', 'Disease', 'None', (71, 75))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('altered', 'Reg', (29, 36))	('cancer', 'Disease', (45, 51))	('COAD', 'Disease', 'MESH:D029424', (65, 69))
197324	26292924	The polymorphisms of DNMT1 have been reported to increase breast cancer risk.	('DNMT1', 'Gene', '1786', (21, 26))	('increase', 'PosReg', (49, 57))	('breast cancer', 'Disease', 'MESH:D001943', (58, 71))	('polymorphisms', 'Var', (4, 17))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('breast cancer', 'Disease', (58, 71))	('breast cancer', 'Phenotype', 'HP:0003002', (58, 71))	('DNMT1', 'Gene', (21, 26))
197332	26292924	Therefore, the perturbation of CLUSTER3137 might be an epigenetic trigger of tumorigenesis.	('CLUSTER3137', 'Gene', (31, 42))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('perturbation', 'Var', (15, 27))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Disease', (77, 82))
197333	26292924	The deregulation of CLUSTER1011 may reveal the roles of components of the Fanconi anemia/BRCA pathway in human cancers.	('cancers', 'Disease', 'MESH:D009369', (111, 118))	('deregulation', 'Var', (4, 16))	('CLUSTER1011', 'Gene', (20, 31))	('anemia', 'Phenotype', 'HP:0001903', (82, 88))	('cancers', 'Phenotype', 'HP:0002664', (111, 118))	('cancers', 'Disease', (111, 118))	('BRCA', 'Gene', (89, 93))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('Fanconi anemia', 'Disease', (74, 88))	('Fanconi anemia', 'Phenotype', 'HP:0001994', (74, 88))	('reveal', 'Reg', (36, 42))	('human', 'Species', '9606', (105, 110))	('Fanconi anemia', 'Disease', 'MESH:D005199', (74, 88))	('BRCA', 'Gene', '672', (89, 93))
197340	26292924	21 clusters were significantly altered only in one or both of lung cancers, three of which, CLUSTER1520, CLUSTER901 and CLUSTER1057, have been implicated in lung diseases.	('lung diseases', 'Disease', 'MESH:D008171', (157, 170))	('altered', 'Reg', (31, 38))	('cancers', 'Phenotype', 'HP:0002664', (67, 74))	('CLUSTER1520', 'Var', (92, 103))	('lung diseases', 'Disease', (157, 170))	('lung diseases', 'Phenotype', 'HP:0002088', (157, 170))	('lung cancers', 'Disease', (62, 74))	('lung cancer', 'Phenotype', 'HP:0100526', (62, 73))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('CLUSTER901', 'Var', (105, 115))	('implicated', 'Reg', (143, 153))	('lung cancers', 'Disease', 'MESH:D008175', (62, 74))	('lung cancers', 'Phenotype', 'HP:0100526', (62, 74))	('CLUSTER1057', 'Var', (120, 131))
197346	26292924	The top associated disease for CLUSTER901 is Lung Neoplasms (adjP = 0.0006).	('Neoplasms', 'Disease', 'MESH:D009369', (50, 59))	('CLUSTER901', 'Var', (31, 41))	('Neoplasms', 'Disease', (50, 59))	('Neoplasms', 'Phenotype', 'HP:0002664', (50, 59))	('Lung Neoplasms', 'Phenotype', 'HP:0100526', (45, 59))
197348	26292924	G protein-coupled receptor, class C, group 5, member A (Gprc5a) protein is detected in the lungs more than in any other tissue; Gprc5a knockout promotes lung inflammation and tumorigenesis in mice.	('tumor', 'Disease', (175, 180))	('mice', 'Species', '10090', (192, 196))	('knockout', 'Var', (135, 143))	('member A', 'Gene', (46, 54))	('Gprc5a', 'Gene', (56, 62))	('G protein-coupled receptor, class C, group 5', 'Gene', '23890', (0, 44))	('Gprc5a', 'Gene', '232431', (56, 62))	('promotes', 'PosReg', (144, 152))	('Gprc5a', 'Gene', (128, 134))	('Gprc5a', 'Gene', '232431', (128, 134))	('member A', 'Gene', '9052', (46, 54))	('lung inflammation', 'Disease', 'MESH:D011014', (153, 170))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('lung inflammation', 'Disease', (153, 170))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))
197351	26292924	Claudin 18 (CLDN18) deficiency is related to alveolar barrier dysfunction.	('alveolar barrier dysfunction', 'Disease', (45, 73))	('Claudin 18', 'Gene', (0, 10))	('deficiency', 'Var', (20, 30))	('alveolar barrier dysfunction', 'Disease', 'MESH:C536830', (45, 73))	('Claudin 18', 'Gene', '51208', (0, 10))	('CLDN18', 'Gene', (12, 18))	('related', 'Reg', (34, 41))	('CLDN18', 'Gene', '51208', (12, 18))
197353	26292924	The top associated diseases for CLUSTER1057 are Lung Diseases (adjP = 0.0037), Respiratory Tract Diseases (adjP = 0.0037), and Airway Obstruction (adjP = 0.0037).	('Lung Diseases', 'Disease', (48, 61))	('Airway Obstruction', 'Disease', (127, 145))	('CLUSTER1057', 'Var', (32, 43))	('Respiratory Tract Diseases', 'Disease', (79, 105))	('Airway Obstruction', 'Phenotype', 'HP:0002781', (127, 145))	('Respiratory Tract Diseases', 'Disease', 'MESH:D012140', (79, 105))	('Lung Diseases', 'Phenotype', 'HP:0002088', (48, 61))
197354	26292924	CLUSTER1057 contains many immunity-associated genes and might contribute to the immune reactions to lung cancers.	('lung cancers', 'Disease', (100, 112))	('CLUSTER1057', 'Var', (0, 11))	('cancers', 'Phenotype', 'HP:0002664', (105, 112))	('lung cancer', 'Phenotype', 'HP:0100526', (100, 111))	('lung cancers', 'Disease', 'MESH:D008175', (100, 112))	('lung cancers', 'Phenotype', 'HP:0100526', (100, 112))	('contribute', 'Reg', (62, 72))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))
197356	26292924	Thirteen clusters were significantly altered only in BLCA, two of which, CLUSTER2174 and CLUSTER1860, have been implicated in bladder abnormalities.	('CLUSTER2174', 'Var', (73, 84))	('bladder abnormalities', 'Disease', 'MESH:D001745', (126, 147))	('CLUSTER1860', 'Var', (89, 100))	('implicated', 'Reg', (112, 122))	('bladder abnormalities', 'Phenotype', 'HP:0000014', (126, 147))	('bladder abnormalities', 'Disease', (126, 147))	('altered', 'Reg', (37, 44))
197357	26292924	The top associated disease for CLUSTER2174 is Urogenital Abnormalities (adjP = 0.0008).	('CLUSTER2174', 'Var', (31, 42))	('Urogenital Abnormalities', 'Disease', 'MESH:D014564', (46, 70))	('Urogenital Abnormalities', 'Disease', (46, 70))	('Urogenital Abnormalities', 'Phenotype', 'HP:0000119', (46, 70))
197359	26292924	The top associated disease for CLUSTER1860 is Cystitis (adjP = 3.08e-05).	('Cystitis', 'Disease', 'MESH:D003556', (46, 54))	('CLUSTER1860', 'Var', (31, 42))	('Cystitis', 'Disease', (46, 54))
197362	26292924	CLUSTER891 is significantly altered only in BRCA.	('BRCA', 'Gene', (44, 48))	('CLUSTER891', 'Var', (0, 10))	('BRCA', 'Gene', '672', (44, 48))	('altered', 'Reg', (28, 35))
197365	26292924	p53 represses hepatoma-derived growth factor (HDGF), and loss of p53 function contributes to tumorigenesis by elevating HDGF expression.	('p53', 'Gene', (0, 3))	('p53', 'Gene', '7157', (0, 3))	('p53', 'Gene', (65, 68))	('p53', 'Gene', '7157', (65, 68))	('HDGF', 'Gene', (46, 50))	('HDGF', 'Gene', '3068', (120, 124))	('hepatoma-derived growth factor', 'Gene', (14, 44))	('elevating', 'PosReg', (110, 119))	('hepatoma-derived growth factor', 'Gene', '3068', (14, 44))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Disease', (93, 98))	('HDGF', 'Gene', (120, 124))	('expression', 'MPA', (125, 135))	('HDGF', 'Gene', '3068', (46, 50))	('loss', 'Var', (57, 61))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
197368	26292924	CLUSTER2240 is significantly altered only in KICH.	('CLUSTER2240', 'Var', (0, 11))	('KICH', 'Disease', 'None', (45, 49))	('altered', 'Reg', (29, 36))	('KICH', 'Disease', (45, 49))
197369	26292924	The top associated disease for CLUSTER2240 is Ciliary Motility Disorders (adjP = 1.85e-05), and Ciliary dysfunction is a risk factor for both syndromic and isolated kidney cystic disease.	('CLUSTER2240', 'Var', (31, 42))	('Ciliary dysfunction', 'Disease', 'MESH:D002925', (96, 115))	('syndromic and isolated kidney cystic disease', 'Disease', 'MESH:D052177', (142, 186))	('kidney cystic disease', 'Phenotype', 'HP:0000107', (165, 186))	('Ciliary Motility Disorders', 'Phenotype', 'HP:0012262', (46, 72))	('Ciliary Motility Disorders', 'Disease', (46, 72))	('Ciliary Motility Disorders', 'Disease', 'MESH:D002925', (46, 72))	('Ciliary dysfunction', 'Disease', (96, 115))
197370	26292924	Nephronophthisis 1 (NPHP1/NPH1) gene deletion is correlated with nephronophthisis.	('NPHP1', 'Gene', '4867', (20, 25))	('correlated', 'Reg', (49, 59))	('NPH1', 'Gene', (26, 30))	('NPH1', 'Gene', '4867', (26, 30))	('Nephronophthisis', 'Disease', 'MESH:C537699', (0, 16))	('deletion', 'Var', (37, 45))	('nephronophthisis', 'Disease', 'MESH:C537699', (65, 81))	('Nephronophthisis', 'Disease', (0, 16))	('NPHP1', 'Gene', (20, 25))	('nephronophthisis', 'Disease', (65, 81))	('Nephronophthisis', 'Phenotype', 'HP:0000090', (0, 16))	('nephronophthisis', 'Phenotype', 'HP:0000090', (65, 81))
197377	26292924	These partly verified our hypothesis that alterations in cell cycle-associated pathways directly contribute to the initiation and development of cancers, while some organ/tissue-specific pathways can lead to cancers possibly by altering the expression of cell-cycle associated pathways.	('cancers', 'Disease', (145, 152))	('lead to', 'Reg', (200, 207))	('cancers', 'Phenotype', 'HP:0002664', (145, 152))	('contribute', 'Reg', (97, 107))	('cancers', 'Phenotype', 'HP:0002664', (208, 215))	('alterations', 'Var', (42, 53))	('cancers', 'Disease', (208, 215))	('cancers', 'Disease', 'MESH:D009369', (208, 215))	('cancers', 'Disease', 'MESH:D009369', (145, 152))	('expression', 'MPA', (241, 251))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('cell cycle-associated pathways', 'Pathway', (57, 87))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('altering', 'Reg', (228, 236))	('cell-cycle associated pathways', 'Pathway', (255, 285))
197378	26292924	Seven gene sets, CLUSTER241, CLUSTER514, CLUSTER1011, CLUSTER932, CLUSTER574, CLUSTER3137, and CLUSTER184, were differentially expressed in at least four of the seven cancer types: BLCA, BRCA, COAD, HNSC, LUAD, and LUSC.	('CLUSTER184', 'Var', (95, 105))	('CLUSTER932', 'Var', (54, 64))	('COAD', 'Disease', 'MESH:D029424', (193, 197))	('HNSC', 'Disease', (199, 203))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('CLUSTER514', 'Var', (29, 39))	('cancer', 'Disease', (167, 173))	('LUAD', 'Disease', (205, 209))	('CLUSTER241', 'Var', (17, 27))	('BLCA', 'Disease', (181, 185))	('CLUSTER574', 'Var', (66, 76))	('CLUSTER1011', 'Var', (41, 52))	('COAD', 'Disease', (193, 197))	('LUSC', 'Disease', (215, 219))	('BRCA', 'Gene', (187, 191))	('CLUSTER3137', 'Var', (78, 89))	('BRCA', 'Gene', '672', (187, 191))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))
197384	26292924	To test if the same holds true for other non-TCGA data sources, we downloaded two RNA-Seq data sets, GSE40419 and GSE50760, and one microarray data set, GSE5364, from the Gene Expression Omnibus (GEO: http://www.ncbi.nlm.nih.gov/geo).	('GSE5364', 'Chemical', '-', (153, 160))	('GSE50760', 'Var', (114, 122))	('GSE40419', 'Var', (101, 109))
197385	26292924	GSE40419 includes the RNA-Seq expression values for 87 lung adenocarcinomas and 77 adjacent normal tissues, while GSE50760 contains the RNA-Seq expression values of 54 samples (18 primary colorectal cancer, 18 liver metastasis, and 18 normal colon) generated from 18 colorectal cancer patients.	('lung adenocarcinomas', 'Disease', (55, 75))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (55, 75))	('colorectal cancer', 'Disease', (188, 205))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('cancer', 'Phenotype', 'HP:0002664', (278, 284))	('GSE50760', 'Var', (114, 122))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (55, 75))	('carcinomas', 'Phenotype', 'HP:0030731', (65, 75))	('colorectal cancer', 'Disease', 'MESH:D015179', (267, 284))	('GSE40419', 'Var', (0, 8))	('colorectal cancer', 'Disease', 'MESH:D015179', (188, 205))	('colorectal cancer', 'Phenotype', 'HP:0003003', (267, 284))	('patients', 'Species', '9606', (285, 293))	('colorectal cancer', 'Phenotype', 'HP:0003003', (188, 205))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (55, 74))	('colorectal cancer', 'Disease', (267, 284))
197387	26292924	We found that the tumor and normal samples were accurately classified, the predictive accuracy for GSE40419 and GSE50760 were 97.14% and 93.33%, respectively.	('tumor', 'Disease', (18, 23))	('GSE40419', 'Var', (99, 107))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('GSE50760', 'Var', (112, 120))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
197392	26292924	We found that CLUSTER1520 is a lung cancer-specific gene signature.	('lung cancer', 'Disease', 'MESH:D008175', (31, 42))	('lung cancer', 'Disease', (31, 42))	('CLUSTER1520', 'Var', (14, 25))	('lung cancer', 'Phenotype', 'HP:0100526', (31, 42))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))
197394	26292924	Moreover, CLUSTER1520 showed a substantially reduced level of expression in the lung tumor samples as compared to lung normal samples.	('lung tumor', 'Disease', (80, 90))	('reduced', 'NegReg', (45, 52))	('lung tumor', 'Phenotype', 'HP:0100526', (80, 90))	('expression', 'MPA', (62, 72))	('CLUSTER1520', 'Var', (10, 21))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('lung tumor', 'Disease', 'MESH:D008175', (80, 90))
197397	26292924	We also validate that CLUSTER1520 is a lung cancer-specific gene signature on a non-TCGA microarray data set (GSE5364).	('lung cancer', 'Phenotype', 'HP:0100526', (39, 50))	('lung cancer', 'Disease', (39, 50))	('lung cancer', 'Disease', 'MESH:D008175', (39, 50))	('GSE5364', 'Chemical', '-', (110, 117))	('CLUSTER1520', 'Var', (22, 33))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
197398	26292924	GSE5364 includes 6 tumor types, and we divided those tumor samples into two classes: lung tumor samples and non-lung tumor samples (breast, colon, liver, oesophagus, thyroid).	('colon', 'Disease', (140, 145))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('lung tumor', 'Disease', 'MESH:D008175', (85, 95))	('lung tumor', 'Phenotype', 'HP:0100526', (112, 122))	('tumor', 'Disease', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('tumor', 'Disease', (90, 95))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('breast', 'Disease', (132, 138))	('GSE5364', 'Var', (0, 7))	('oesophagus', 'Disease', (154, 164))	('non-lung tumor', 'Disease', (108, 122))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('lung tumor', 'Disease', 'MESH:D008175', (112, 122))	('GSE5364', 'Chemical', '-', (0, 7))	('lung tumor', 'Disease', (85, 95))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('liver', 'Disease', (147, 152))	('lung tumor', 'Phenotype', 'HP:0100526', (85, 95))	('tumor', 'Disease', (117, 122))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('non-lung tumor', 'Disease', 'MESH:D002289', (108, 122))	('tumor', 'Disease', (53, 58))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
197399	26292924	The predictive accuracy of LOOCV for these two classes of tumor samples was 100%, this demonstrated that lung tumor samples and non-lung tumor samples were accurately classified based on CLUSTER1520.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('lung tumor', 'Disease', 'MESH:D008175', (132, 142))	('tumor', 'Disease', (137, 142))	('non-lung tumor', 'Disease', (128, 142))	('lung tumor', 'Disease', (105, 115))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('lung tumor', 'Phenotype', 'HP:0100526', (105, 115))	('lung tumor', 'Disease', 'MESH:D008175', (105, 115))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('lung tumor', 'Phenotype', 'HP:0100526', (132, 142))	('non-lung tumor', 'Disease', 'MESH:D002289', (128, 142))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('CLUSTER1520', 'Var', (187, 198))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
197400	26292924	These results show that CLUSTER1520 is a lung cancer-specific gene signature, and genes in this signature are potential targets for developing novel lung cancer therapies.	('lung cancer', 'Disease', 'MESH:D008175', (149, 160))	('lung cancer', 'Disease', (41, 52))	('CLUSTER1520', 'Var', (24, 35))	('lung cancer', 'Phenotype', 'HP:0100526', (41, 52))	('lung cancer', 'Phenotype', 'HP:0100526', (149, 160))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('lung cancer', 'Disease', (149, 160))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('lung cancer', 'Disease', 'MESH:D008175', (41, 52))
197401	26292924	In order to test if the significant gene sets we identified from TCGA data can be validated on non-TCGA data sources, we performed gene set association analysis on two non-TCGA cohorts: a lung adenocarcinoma data set (GSE40419) and a colorectal cancer data set (GSE50760), the results are shown in Supplementary Table S5.	('colorectal cancer', 'Phenotype', 'HP:0003003', (234, 251))	('GSE40419', 'Var', (218, 226))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (188, 207))	('colorectal cancer', 'Disease', (234, 251))	('colorectal cancer', 'Disease', 'MESH:D015179', (234, 251))	('cancer', 'Phenotype', 'HP:0002664', (245, 251))	('lung adenocarcinoma', 'Disease', (188, 207))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (188, 207))
197402	26292924	For GSE40419, we identified 1 significant gene set (FDR < 0.25), CLUSTER514, which is one of the seven cross-cancer gene signatures.	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('GSE40419', 'Var', (4, 12))	('cross-cancer', 'Disease', (103, 115))	('cross-cancer', 'Disease', 'MESH:C537866', (103, 115))
197403	26292924	For GSE50760, we identified five significant gene sets (FDR < 0.25), two of them, CLUSTER2556 and CLUSTER514, were also identified as significant using TCGA COAD data.	('COAD', 'Disease', 'MESH:D029424', (157, 161))	('GSE50760', 'Var', (4, 12))	('COAD', 'Disease', (157, 161))
197409	26292924	These results reveal the aberrations in cancer transcriptomes and lead to a deeper understanding of the formation and development of human cancers.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('aberrations', 'Var', (25, 36))	('cancers', 'Disease', 'MESH:D009369', (139, 146))	('cancers', 'Phenotype', 'HP:0002664', (139, 146))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('cancers', 'Disease', (139, 146))	('cancer', 'Disease', (40, 46))	('human', 'Species', '9606', (133, 138))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('cancer', 'Disease', (139, 145))
197411	26292924	Our results reveal that four gene sets, CLUSTER241, CLUSTER514, CLUSTER1011, and CLUSTER932, are significantly altered across seven cancer types: BLCA, BRCA, COAD, HNSC, LIHC, LUAD, and LUSC (Table 2).	('HNSC', 'Disease', (164, 168))	('CLUSTER241', 'Var', (40, 50))	('LIHC', 'Disease', (170, 174))	('cancer', 'Disease', (132, 138))	('CLUSTER932', 'Var', (81, 91))	('COAD', 'Disease', (158, 162))	('LIHC', 'Disease', 'None', (170, 174))	('altered', 'Reg', (111, 118))	('CLUSTER1011', 'Var', (64, 75))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('LUSC', 'Disease', (186, 190))	('LUAD', 'Disease', (176, 180))	('COAD', 'Disease', 'MESH:D029424', (158, 162))	('BRCA', 'Gene', '672', (152, 156))	('BRCA', 'Gene', (152, 156))	('BLCA', 'Disease', (146, 150))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('CLUSTER514', 'Var', (52, 62))
197416	26292924	We hypothesize that some of these mutations or epimutations may disrupt a pathway responsible for cell cycle regulation that directly drives cells into uncontrolled proliferation, while others may lie within an organ-specific pathway that turn a healthy cell into a cancer cell by altering the expression of cell cycle-associated pathways.	('altering', 'Reg', (281, 289))	('cancer', 'Disease', 'MESH:D009369', (266, 272))	('expression', 'MPA', (294, 304))	('cancer', 'Disease', (266, 272))	('cell cycle-associated pathways', 'Pathway', (308, 338))	('cell cycle regulation', 'MPA', (98, 119))	('cancer', 'Phenotype', 'HP:0002664', (266, 272))	('turn', 'Reg', (239, 243))	('disrupt', 'NegReg', (64, 71))	('epimutations', 'Var', (47, 59))	('mutations', 'Var', (34, 43))
197419	26292924	Some of these gene sets may be cancer-specific gene signatures, say CLUSTER1520 and CLUSTER2318, that shed light on the mechanisms underlying cancer-driving abnormalities in a specific organ, while many of them may still represent a cellular process broadly perturbed across cancer types, and the differentiation is just stronger in one cancer type than other cancer types.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('cancer', 'Phenotype', 'HP:0002664', (360, 366))	('cancer', 'Phenotype', 'HP:0002664', (337, 343))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('CLUSTER1520', 'Var', (68, 79))	('CLUSTER2318', 'Var', (84, 95))	('cancer', 'Phenotype', 'HP:0002664', (275, 281))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('cancer', 'Disease', (360, 366))	('cancer', 'Disease', 'MESH:D009369', (360, 366))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('cancer', 'Disease', 'MESH:D009369', (337, 343))	('cancer', 'Disease', 'MESH:D009369', (275, 281))	('cancer', 'Disease', (337, 343))	('cancer', 'Disease', (31, 37))	('cancer', 'Disease', (275, 281))	('cancer', 'Disease', (142, 148))
197423	26292924	Some genes, for example tumor protein p53 (TP53/p53), phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA), and retinoblastoma 1 (RB1), are frequently mutated in a number of cancers and are key genes contributing to tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('tumor', 'Phenotype', 'HP:0002664', (244, 249))	('retinoblastoma', 'Phenotype', 'HP:0009919', (140, 154))	('p53', 'Gene', '7157', (48, 51))	('PIK3CA', 'Gene', '5290', (127, 133))	('retinoblastoma 1 (RB1', 'Gene', '5925', (140, 161))	('cancers', 'Disease', 'MESH:D009369', (202, 209))	('TP53', 'Gene', (43, 47))	('mutated', 'Var', (179, 186))	('p53', 'Gene', (48, 51))	('p53', 'Gene', '7157', (38, 41))	('tumor', 'Disease', (24, 29))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('p53', 'Gene', (38, 41))	('tumor', 'Disease', (244, 249))	('PIK3CA', 'Gene', (127, 133))	('cancers', 'Phenotype', 'HP:0002664', (202, 209))	('cancers', 'Disease', (202, 209))	('TP53', 'Gene', '7157', (43, 47))	('tumor', 'Disease', 'MESH:D009369', (244, 249))
197424	26292924	However, among 20530 genes in the BLCA, BRCA, COAD, HNSC, LIHC, LUAD, LUSC, KICH, KIRC, KIRP, PRAD, and THCA datasets, we found that TP53 was ranked at 11834, 14601, 7752, 18515, 17359, 8769, 11116, 14995, 4200, 986, 4776, and 2094, PIK3CA at 16090, 7012, 14799, 4118, 13535, 13228, 6632, 12475, 14634, 17065, 19153, and 18438, RB1 at 15691, 15157, 6836, 16116, 16543, 9168, 19208, 8333, 9565, 4233, 16756, and 11160, respectively (Supplementary Table S1).	('6836', 'Var', (349, 353))	('COAD', 'Disease', 'MESH:D029424', (46, 50))	('15691', 'Var', (335, 340))	('LIHC', 'Disease', (58, 62))	('KICH', 'Disease', 'None', (76, 80))	('9565', 'Var', (388, 392))	('9168', 'Var', (369, 373))	('PIK3CA', 'Gene', (233, 239))	('11160', 'Var', (411, 416))	('COAD', 'Disease', (46, 50))	('8333', 'Var', (382, 386))	('16543', 'Var', (362, 367))	('TP53', 'Gene', '7157', (133, 137))	('LIHC', 'Disease', 'None', (58, 62))	('KICH', 'Disease', (76, 80))	('BRCA', 'Gene', '672', (40, 44))	('16116', 'Var', (355, 360))	('RB1', 'Gene', (328, 331))	('15157', 'Var', (342, 347))	('PIK3CA', 'Gene', '5290', (233, 239))	('BRCA', 'Gene', (40, 44))	('TP53', 'Gene', (133, 137))	('RB1', 'Gene', '5925', (328, 331))
197425	26292924	One reason could be that mutations in TP53/PIK3CA/RB1 substantially change the expression of its downstream target genes rather than genes harboring them.	('mutations', 'Var', (25, 34))	('PIK3CA', 'Gene', '5290', (43, 49))	('change', 'Reg', (68, 74))	('expression', 'MPA', (79, 89))	('TP53', 'Gene', (38, 42))	('TP53', 'Gene', '7157', (38, 42))	('RB1', 'Gene', (50, 53))	('RB1', 'Gene', '5925', (50, 53))	('PIK3CA', 'Gene', (43, 49))
197442	33801580	Furthermore, gene knockdown and knockout of Crk and CrkL in tumor cell lines suppress tumor cell functions, including cell proliferation, transformation, migration, invasion, epithelial-mesenchymal transition, resistance to chemotherapy drugs, and in vivo tumor growth and metastasis.	('tumor', 'Disease', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('rat', 'Species', '10116', (157, 160))	('CrkL', 'Gene', (52, 56))	('tumor', 'Disease', (256, 261))	('epithelial-mesenchymal transition', 'CPA', (175, 208))	('knockout', 'Var', (32, 40))	('tumor', 'Disease', 'MESH:D009369', (256, 261))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('cell proliferation', 'CPA', (118, 136))	('migration', 'CPA', (154, 163))	('resistance to chemotherapy', 'CPA', (210, 236))	('tumor', 'Disease', (86, 91))	('transformation', 'CPA', (138, 152))	('invasion', 'CPA', (165, 173))	('Crk', 'Gene', (44, 47))	('rat', 'Species', '10116', (130, 133))	('tumor', 'Phenotype', 'HP:0002664', (256, 261))	('suppress', 'NegReg', (77, 85))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
197460	33801580	Moreover, the heterozygous inactive mutation in CrkL in humans has been reported to cause congenital kidney anomalies of DiGeorge syndrome.	('congenital kidney anomalies of DiGeorge syndrome', 'Disease', (90, 138))	('congenital kidney anomalies of DiGeorge syndrome', 'Disease', 'MESH:D004062', (90, 138))	('kidney anomalies', 'Phenotype', 'HP:0000077', (101, 117))	('CrkL', 'Gene', (48, 52))	('heterozygous inactive mutation', 'Var', (14, 44))	('humans', 'Species', '9606', (56, 62))	('cause', 'Reg', (84, 89))
197475	33801580	Overexpression of T47D breast cancer epithelial cells with CrkII also caused dispersal of colonies.	('breast cancer', 'Disease', (23, 36))	('dispersal of colonies', 'CPA', (77, 98))	('breast cancer', 'Phenotype', 'HP:0003002', (23, 36))	('caused', 'Reg', (70, 76))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('T47D', 'Var', (18, 22))	('breast cancer', 'Disease', 'MESH:D001943', (23, 36))	('T47', 'CellLine', 'CVCL:3945', (18, 21))
197476	33801580	CrkII overexpression in NIH3T3 cells made cells larger with enhanced lamellipodium formation.	('NIH3T3', 'CellLine', 'CVCL:0594', (24, 30))	('overexpression', 'Var', (6, 20))	('lamellipodium formation', 'CPA', (69, 92))	('cells larger', 'CPA', (42, 54))	('enhanced', 'PosReg', (60, 68))
197479	33801580	Crk knockdown in NIH3T3 cells resulted in a slower rate of cell spreading, more filopodia formation, and reduced focal adhesion formation in the early stages of cell spreading onto fibronectin-coated surfaces.	('cell spreading', 'CPA', (59, 73))	('focal adhesion formation', 'CPA', (113, 137))	('slower', 'NegReg', (44, 50))	('NIH3T3', 'CellLine', 'CVCL:0594', (17, 23))	('filopodia formation', 'CPA', (80, 99))	('more', 'PosReg', (75, 79))	('rat', 'Species', '10116', (51, 54))	('reduced', 'NegReg', (105, 112))	('knockdown', 'Var', (4, 13))	('Crk', 'Gene', (0, 3))
197480	33801580	Furthermore, Crk/CrkL double knockdown, but not Crk or CrkL single knockdown, in NIH3T3 cells led to nearly complete inhibition of focal adhesion formation in the absence of PDGF.	('inhibition', 'NegReg', (117, 127))	('double knockdown', 'Var', (22, 38))	('focal adhesion formation', 'CPA', (131, 155))	('NIH3T3', 'CellLine', 'CVCL:0594', (81, 87))
197482	33801580	In addition, ablation of both Crk and CrkL from mouse embryonic fibroblasts resulted in a decrease in focal adhesion sites, reduced actin stress fibers, and a collapse of microtubule structures.	('reduced', 'NegReg', (124, 131))	('mouse', 'Species', '10090', (48, 53))	('collapse', 'NegReg', (159, 167))	('Crk', 'Protein', (30, 33))	('CrkL', 'Gene', (38, 42))	('focal', 'CPA', (102, 107))	('ablation', 'Var', (13, 21))	('actin stress', 'MPA', (132, 144))	('microtubule structures', 'MPA', (171, 193))	('decrease', 'NegReg', (90, 98))
197485	33801580	Crk knockdown resulted in decreased spreading of a breast cancer cell line onto a fibronectin substrate with decreases in focal adhesions and actin stress fibers.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('spreading', 'CPA', (36, 45))	('actin stress fibers', 'CPA', (142, 161))	('focal adhesions', 'CPA', (122, 137))	('rat', 'Species', '10116', (99, 102))	('breast cancer', 'Disease', 'MESH:D001943', (51, 64))	('breast cancer', 'Phenotype', 'HP:0003002', (51, 64))	('knockdown', 'Var', (4, 13))	('decreased', 'NegReg', (26, 35))	('decreases', 'NegReg', (109, 118))	('breast cancer', 'Disease', (51, 64))	('Crk', 'Gene', (0, 3))
197486	33801580	In addition, knockdown of both Crk and CrkL in the breast cancer cell line resulted in defective lamellipodia formation and delayed cell spreading on fibronectin.	('Crk', 'Gene', (31, 34))	('CrkL', 'Gene', (39, 43))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('lamellipodia formation', 'CPA', (97, 119))	('cell spreading on fibronectin', 'CPA', (132, 161))	('delayed', 'NegReg', (124, 131))	('defective', 'NegReg', (87, 96))	('breast cancer', 'Disease', 'MESH:D001943', (51, 64))	('breast cancer', 'Phenotype', 'HP:0003002', (51, 64))	('breast cancer', 'Disease', (51, 64))	('knockdown', 'Var', (13, 22))
197487	33801580	In a glioblastoma cell line, both CrkL knockdown and Crk/CrkL double knockdown caused cells to shrink and become rounded.	('glioblastoma', 'Disease', (5, 17))	('glioblastoma', 'Disease', 'MESH:D005909', (5, 17))	('knockdown', 'Var', (39, 48))	('glioblastoma', 'Phenotype', 'HP:0012174', (5, 17))	('shrink', 'NegReg', (95, 101))	('knockdown', 'Var', (69, 78))
197493	33801580	Ablation of endogenous Crk and CrkL from immortalized fibroblasts using Cre-loxP recombination-mediated gene knockout caused a blockage of cell proliferation and arrest of the cell cycle at the G1-S transition.	('Ablation', 'Var', (0, 8))	('arrest', 'Disease', 'MESH:D006323', (162, 168))	('Crk', 'Protein', (23, 26))	('cell proliferation', 'CPA', (139, 157))	('arrest', 'Disease', (162, 168))	('blockage', 'NegReg', (127, 135))	('rat', 'Species', '10116', (151, 154))
197494	33801580	While loss of either Crk or CrkL alone conferred a much more modest reduction in cell proliferation, reintroduction of CrkI, CrkII, or CrkL individually rescued cell proliferation in the absence of the endogenous Crk and CrkL, suggesting overlapping functions of Crk and CrkL in fibroblast proliferation.	('cell proliferation', 'CPA', (81, 99))	('CrkI', 'Gene', (125, 129))	('loss', 'Var', (6, 10))	('rat', 'Species', '10116', (173, 176))	('rat', 'Species', '10116', (297, 300))	('cell proliferation', 'CPA', (161, 179))	('CrkI', 'Gene', (119, 123))	('CrkI', 'Gene', '12928', (125, 129))	('rescued', 'PosReg', (153, 160))	('reduction', 'NegReg', (68, 77))	('Crk', 'Gene', (21, 24))	('CrkI', 'Gene', '12928', (119, 123))	('rat', 'Species', '10116', (93, 96))
197496	33801580	Reduction in CrkII and CrkI protein levels by Crk knockdown led to inhibition of cell proliferation in MCAS and SKOV3 ovarian cancer and synovial sarcoma cell lines (Table 1).	('cell proliferation', 'CPA', (81, 99))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('CrkI', 'Gene', '12928', (13, 17))	('inhibition', 'NegReg', (67, 77))	('synovial sarcoma', 'Disease', (137, 153))	('knockdown', 'Var', (50, 59))	('CrkI', 'Gene', (23, 27))	('CrkI', 'Gene', (13, 17))	('Crk', 'Gene', (46, 49))	('sarcoma', 'Phenotype', 'HP:0100242', (146, 153))	('ovarian cancer', 'Phenotype', 'HP:0100615', (118, 132))	('Reduction', 'NegReg', (0, 9))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (137, 153))	('synovial sarcoma', 'Disease', 'MESH:D013584', (137, 153))	('CrkI', 'Gene', '12928', (23, 27))	('MCAS and SKOV3 ovarian cancer', 'Disease', 'MESH:D010051', (103, 132))	('rat', 'Species', '10116', (93, 96))
197497	33801580	CrkL knockdown also inhibited cell proliferation in rhabdomyosarcoma, MDA-MB-453 breast cancer, MKN-45 gastric cancer, hepatocellular carcinoma, and HeLa cell lines.	('breast cancer', 'Disease', (81, 94))	('knockdown', 'Var', (5, 14))	('inhibited', 'NegReg', (20, 29))	('MDA-MB-453', 'CellLine', 'CVCL:0418', (70, 80))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('hepatocellular carcinoma', 'Disease', (119, 143))	('gastric cancer', 'Disease', 'MESH:D013274', (103, 117))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (52, 68))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (52, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('gastric cancer', 'Phenotype', 'HP:0012126', (103, 117))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (119, 143))	('sarcoma', 'Phenotype', 'HP:0100242', (61, 68))	('cell proliferation', 'CPA', (30, 48))	('CrkL', 'Gene', (0, 4))	('HeLa', 'CellLine', 'CVCL:0030', (149, 153))	('breast cancer', 'Phenotype', 'HP:0003002', (81, 94))	('gastric cancer', 'Disease', (103, 117))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (119, 143))	('rhabdomyosarcoma', 'Disease', (52, 68))	('rat', 'Species', '10116', (42, 45))	('breast cancer', 'Disease', 'MESH:D001943', (81, 94))
197499	33801580	In addition, individual and combined knockdown of Crk and CrkL in U-118MG glioblastoma cells demonstrated that CrkL knockdown and Crk/CrkL double knockdown, but not Crk knockdown, inhibited cell proliferation.	('glioblastoma', 'Disease', (74, 86))	('glioblastoma', 'Disease', 'MESH:D005909', (74, 86))	('knockdown', 'Var', (116, 125))	('U-118MG', 'CellLine', 'CVCL:0633', (66, 73))	('glioblastoma', 'Phenotype', 'HP:0012174', (74, 86))	('cell proliferation', 'CPA', (190, 208))	('rat', 'Species', '10116', (202, 205))	('inhibited', 'NegReg', (180, 189))	('CrkL', 'Protein', (111, 115))	('rat', 'Species', '10116', (100, 103))
197502	33801580	Crk knockdown and CrkL knockdown induced arrest of the cell cycle at G1 in synovial sarcoma and gastric cancer cells, respectively.	('gastric cancer', 'Phenotype', 'HP:0012126', (96, 110))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('synovial sarcoma', 'Disease', (75, 91))	('arrest', 'Disease', (41, 47))	('knockdown', 'Var', (23, 32))	('CrkL', 'Gene', (18, 22))	('sarcoma', 'Phenotype', 'HP:0100242', (84, 91))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (75, 91))	('gastric cancer', 'Disease', (96, 110))	('knockdown', 'Var', (4, 13))	('arrest', 'Disease', 'MESH:D006323', (41, 47))	('gastric cancer', 'Disease', 'MESH:D013274', (96, 110))	('synovial sarcoma', 'Disease', 'MESH:D013584', (75, 91))	('Crk', 'Gene', (0, 3))
197507	33801580	Systematic comparison among individual and combined knockdown in various cancer cell lines would provide in-depth insights into this question.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('knockdown', 'Var', (52, 61))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))
197518	33801580	Crk knockdown in human ovarian cancer cells and glioblastoma cells inhibited colony formation on soft agar.	('glioblastoma', 'Phenotype', 'HP:0012174', (48, 60))	('colony formation on soft agar', 'CPA', (77, 106))	('inhibited', 'NegReg', (67, 76))	('agar', 'Chemical', 'MESH:D000362', (102, 106))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('human', 'Species', '9606', (17, 22))	('ovarian cancer', 'Disease', (23, 37))	('glioblastoma', 'Disease', 'MESH:D005909', (48, 60))	('ovarian cancer', 'Phenotype', 'HP:0100615', (23, 37))	('glioblastoma', 'Disease', (48, 60))	('knockdown', 'Var', (4, 13))	('ovarian cancer', 'Disease', 'MESH:D010051', (23, 37))	('Crk', 'Gene', (0, 3))
197519	33801580	CrkL knockdown also inhibited colony formation of glioma and cervical cancer cell lines on soft agar.	('cervical cancer', 'Disease', 'MESH:D002583', (61, 76))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('CrkL', 'Gene', (0, 4))	('knockdown', 'Var', (5, 14))	('cervical cancer', 'Disease', (61, 76))	('agar', 'Chemical', 'MESH:D000362', (96, 100))	('glioma', 'Disease', (50, 56))	('inhibited', 'NegReg', (20, 29))	('glioma', 'Disease', 'MESH:D005910', (50, 56))	('glioma', 'Phenotype', 'HP:0009733', (50, 56))
197520	33801580	Ablation of CrkII, CrkI, and CrkL altogether suppressed anchorage-independent growth of MDA-231 breast cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('CrkI', 'Gene', (19, 23))	('CrkI', 'Gene', (12, 16))	('Ablation', 'Var', (0, 8))	('breast cancer', 'Disease', 'MESH:D001943', (96, 109))	('CrkI', 'Gene', '12928', (19, 23))	('suppressed', 'NegReg', (45, 55))	('MDA-231', 'CellLine', 'CVCL:0062', (88, 95))	('breast cancer', 'Disease', (96, 109))	('breast cancer', 'Phenotype', 'HP:0003002', (96, 109))	('anchorage-independent growth', 'CPA', (56, 84))	('CrkI', 'Gene', '12928', (12, 16))
197525	33801580	Crk knockdown in ovarian cancer, glioblastoma, breast cancer, and bladder cancer cells resulted in decreased tumor growth in nude mice.	('breast cancer', 'Phenotype', 'HP:0003002', (47, 60))	('bladder cancer', 'Phenotype', 'HP:0009725', (66, 80))	('knockdown', 'Var', (4, 13))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('breast cancer', 'Disease', 'MESH:D001943', (47, 60))	('decreased tumor', 'Disease', 'MESH:D002303', (99, 114))	('breast cancer', 'Disease', (47, 60))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('ovarian cancer', 'Disease', 'MESH:D010051', (17, 31))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('decreased tumor', 'Disease', (99, 114))	('Crk', 'Gene', (0, 3))	('nude mice', 'Species', '10090', (125, 134))	('glioblastoma', 'Disease', 'MESH:D005909', (33, 45))	('ovarian cancer', 'Disease', (17, 31))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('glioblastoma', 'Disease', (33, 45))	('ovarian cancer', 'Phenotype', 'HP:0100615', (17, 31))	('glioblastoma', 'Phenotype', 'HP:0012174', (33, 45))	('bladder cancer', 'Disease', 'MESH:D001749', (66, 80))	('bladder cancer', 'Disease', (66, 80))
197526	33801580	CrkL knockdown also inhibited in vivo tumor growth in head and neck squamous cell carcinoma, rhabdomyosarcoma, hepatocellular carcinoma, and colorectal cancer cells.	('knockdown', 'Var', (5, 14))	('colorectal cancer', 'Phenotype', 'HP:0003003', (141, 158))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (111, 135))	('inhibited', 'NegReg', (20, 29))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (93, 109))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('hepatocellular carcinoma', 'Disease', (111, 135))	('neck squamous cell carcinoma', 'Disease', (63, 91))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (63, 91))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('sarcoma', 'Phenotype', 'HP:0100242', (102, 109))	('colorectal cancer', 'Disease', 'MESH:D015179', (141, 158))	('colorectal cancer', 'Disease', (141, 158))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (68, 91))	('tumor', 'Disease', (38, 43))	('rhabdomyosarcoma', 'Disease', (93, 109))	('CrkL', 'Gene', (0, 4))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (111, 135))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (93, 109))
197527	33801580	In addition to suppressing tumor growth at the primary injection sites in nude mice, Crk or CrkL knockdown reduced metastatic tumor burden.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('CrkL', 'Gene', (92, 96))	('knockdown', 'Var', (97, 106))	('suppressing', 'NegReg', (15, 26))	('tumor', 'Disease', (27, 32))	('reduced', 'NegReg', (107, 114))	('nude mice', 'Species', '10090', (74, 83))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('Crk', 'Gene', (85, 88))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('tumor', 'Disease', (126, 131))
197528	33801580	Bone metastasis in vivo following intra-cardiac injection of basal breast cancer cells was reduced by Crk knockdown.	('breast cancer', 'Phenotype', 'HP:0003002', (67, 80))	('Bone metastasis', 'CPA', (0, 15))	('knockdown', 'Var', (106, 115))	('reduced', 'NegReg', (91, 98))	('Crk', 'Gene', (102, 105))	('breast cancer', 'Disease', 'MESH:D001943', (67, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('breast cancer', 'Disease', (67, 80))
197529	33801580	Crk knockdown reduced metastatic tumor burden in blood, liver, and lung together with reductions in tumor volume at the primary site and the number of circulating tumor cells following orthotopic injection of bladder cancer cells under the bladder muscle layer.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('reduced', 'NegReg', (14, 21))	('bladder cancer', 'Phenotype', 'HP:0009725', (209, 223))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('tumor', 'Disease', (100, 105))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('bladder cancer', 'Disease', 'MESH:D001749', (209, 223))	('bladder cancer', 'Disease', (209, 223))	('tumor', 'Disease', (163, 168))	('tumor', 'Disease', (33, 38))	('knockdown', 'Var', (4, 13))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('reductions', 'NegReg', (86, 96))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))	('Crk', 'Gene', (0, 3))
197535	33801580	Antoku and Mayer reported that PDGF-induced motility of NIH3T3 cells was decreased with Crk knockdown or CrkL knockdown and completely blocked with Crk/CrkL double knockdown.	('knockdown', 'Var', (110, 119))	('CrkL', 'Protein', (105, 109))	('decreased', 'NegReg', (73, 82))	('blocked', 'NegReg', (135, 142))	('knockdown', 'Var', (92, 101))	('NIH3T3', 'CellLine', 'CVCL:0594', (56, 62))	('Crk', 'Protein', (88, 91))
197536	33801580	Ablation of both Crk and CrkL in mouse embryonic fibroblasts resulted in a decrease in cell motility.	('decrease', 'NegReg', (75, 83))	('Ablation', 'Var', (0, 8))	('CrkL', 'Protein', (25, 29))	('cell motility', 'CPA', (87, 100))	('mouse', 'Species', '10090', (33, 38))	('Crk', 'Protein', (17, 20))
197539	33801580	In contrast, Crk knockdown enhanced endothelial cell migration under intermittent hypoxia.	('rat', 'Species', '10116', (56, 59))	('hypoxia', 'Disease', (82, 89))	('enhanced', 'PosReg', (27, 35))	('hypoxia', 'Disease', 'MESH:D000860', (82, 89))	('Crk', 'Gene', (13, 16))	('knockdown', 'Var', (17, 26))	('endothelial cell migration', 'CPA', (36, 62))
197541	33801580	Expression of CrkII with a mutated SH2 domain inhibited insulin-induced migration and invasion of COS-7 cells.	('invasion of COS-7 cells', 'CPA', (86, 109))	('mutated', 'Var', (27, 34))	('rat', 'Species', '10116', (75, 78))	('SH2 domain', 'Gene', (35, 45))	('inhibited', 'NegReg', (46, 55))	('COS-7', 'CellLine', 'CVCL:0224', (98, 103))
197544	33801580	reported that Crk knockdown led to inhibition of cell migration and invasion in breast cancer, cervical carcinoma, and non-small cell lung carcinoma.	('non-small cell lung carcinoma', 'Disease', (119, 148))	('knockdown', 'Var', (18, 27))	('cervical carcinoma', 'Disease', (95, 113))	('small cell lung carcinoma', 'Phenotype', 'HP:0030357', (123, 148))	('Crk', 'Gene', (14, 17))	('cell migration', 'CPA', (49, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (139, 148))	('invasion', 'CPA', (68, 76))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('breast cancer', 'Disease', 'MESH:D001943', (80, 93))	('cervical carcinoma', 'Disease', 'MESH:D002583', (95, 113))	('rat', 'Species', '10116', (57, 60))	('non-small cell lung carcinoma', 'Disease', 'MESH:D002289', (119, 148))	('non-small cell lung carcinoma', 'Phenotype', 'HP:0030358', (119, 148))	('breast cancer', 'Disease', (80, 93))	('breast cancer', 'Phenotype', 'HP:0003002', (80, 93))	('inhibition', 'NegReg', (35, 45))
197545	33801580	Furthermore, Crk knockdown inhibited hepatocyte growth factor (HGF)-induced migration of breast cancer cells.	('breast cancer', 'Disease', 'MESH:D001943', (89, 102))	('hepatocyte growth factor', 'Gene', '3082', (37, 61))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('breast cancer', 'Disease', (89, 102))	('HGF', 'Gene', (63, 66))	('rat', 'Species', '10116', (79, 82))	('breast cancer', 'Phenotype', 'HP:0003002', (89, 102))	('HGF', 'Gene', '3082', (63, 66))	('Crk', 'Gene', (13, 16))	('knockdown', 'Var', (17, 26))	('inhibited', 'NegReg', (27, 36))	('hepatocyte growth factor', 'Gene', (37, 61))
197546	33801580	Since then, Crk knockdown has been demonstrated to result in decreases in cancer cell migration and invasion in ovarian cancer, synovial cell carcinoma, glioblastoma, oral squamous cell carcinoma, prostate cancer, breast cancer, gastric cancer, bladder cancer, and pancreatic ductal adenocarcinoma cells.	('breast cancer', 'Phenotype', 'HP:0003002', (214, 227))	('cancer', 'Disease', 'MESH:D009369', (221, 227))	('cancer', 'Disease', 'MESH:D009369', (253, 259))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', (74, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (288, 297))	('breast cancer', 'Disease', 'MESH:D001943', (214, 227))	('pancreatic ductal adenocarcinoma', 'Disease', (265, 297))	('decreases', 'NegReg', (61, 70))	('breast cancer', 'Disease', (214, 227))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (167, 195))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('carcinoma', 'Phenotype', 'HP:0030731', (142, 151))	('bladder cancer', 'Disease', 'MESH:D001749', (245, 259))	('gastric cancer', 'Disease', (229, 243))	('oral squamous cell carcinoma', 'Disease', (167, 195))	('bladder cancer', 'Disease', (245, 259))	('bladder cancer', 'Phenotype', 'HP:0009725', (245, 259))	('cancer', 'Disease', (206, 212))	('cancer', 'Disease', (237, 243))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (172, 195))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (265, 297))	('synovial cell carcinoma', 'Disease', 'MESH:C538614', (128, 151))	('glioblastoma', 'Disease', 'MESH:D005909', (153, 165))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('cancer', 'Disease', (221, 227))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('gastric cancer', 'Disease', 'MESH:D013274', (229, 243))	('cancer', 'Disease', (253, 259))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('prostate cancer', 'Disease', 'MESH:D011471', (197, 212))	('ovarian cancer', 'Phenotype', 'HP:0100615', (112, 126))	('synovial cell carcinoma', 'Disease', (128, 151))	('prostate cancer', 'Phenotype', 'HP:0012125', (197, 212))	('glioblastoma', 'Disease', (153, 165))	('prostate cancer', 'Disease', (197, 212))	('glioblastoma', 'Phenotype', 'HP:0012174', (153, 165))	('carcinoma', 'Phenotype', 'HP:0030731', (186, 195))	('Crk', 'Gene', (12, 15))	('invasion in ovarian cancer', 'Disease', (100, 126))	('knockdown', 'Var', (16, 25))	('rat', 'Species', '10116', (89, 92))	('cancer', 'Disease', 'MESH:D009369', (237, 243))	('invasion in ovarian cancer', 'Disease', 'MESH:D009362', (100, 126))	('gastric cancer', 'Phenotype', 'HP:0012126', (229, 243))	('cancer', 'Disease', 'MESH:D009369', (206, 212))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (265, 297))	('synovial cell carcinoma', 'Phenotype', 'HP:0012570', (128, 151))	('rat', 'Species', '10116', (42, 45))
197547	33801580	CrkL knockdown also inhibited cell motility in head and neck squamous cell carcinoma and migration and invasion of cervical cancer cells.	('cervical cancer', 'Disease', 'MESH:D002583', (115, 130))	('cervical cancer', 'Disease', (115, 130))	('knockdown', 'Var', (5, 14))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (61, 84))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('rat', 'Species', '10116', (92, 95))	('CrkL', 'Protein', (0, 4))	('neck squamous cell carcinoma', 'Disease', (56, 84))	('inhibited', 'NegReg', (20, 29))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (56, 84))	('cell motility in', 'CPA', (30, 46))
197548	33801580	Furthermore, CrkL knockdown led to inhibition of TGF-beta1-induced cell motility in glioma and ovarian cancer cells.	('knockdown', 'Var', (18, 27))	('glioma and ovarian cancer', 'Disease', 'MESH:D005910', (84, 109))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('TGF-beta1', 'Gene', '7040', (49, 58))	('ovarian cancer', 'Phenotype', 'HP:0100615', (95, 109))	('CrkL', 'Protein', (13, 17))	('TGF-beta1', 'Gene', (49, 58))	('glioma', 'Phenotype', 'HP:0009733', (84, 90))	('inhibition', 'NegReg', (35, 45))	('cell motility', 'CPA', (67, 80))
197549	33801580	CrkL knockdown also resulted in a decrease in CCL20-induced migration and invasion of gastric cancer cells.	('gastric cancer', 'Disease', 'MESH:D013274', (86, 100))	('CCL20', 'Gene', '6364', (46, 51))	('invasion', 'CPA', (74, 82))	('knockdown', 'Var', (5, 14))	('gastric cancer', 'Phenotype', 'HP:0012126', (86, 100))	('decrease', 'NegReg', (34, 42))	('CrkL', 'Protein', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('migration', 'CPA', (60, 69))	('rat', 'Species', '10116', (63, 66))	('gastric cancer', 'Disease', (86, 100))	('CCL20', 'Gene', (46, 51))
197550	33801580	However, it was not clear whether the other protein between Crk and CrkL play similar roles because all the studies investigated effects by either Crk knockdown or CrkL knockdown in the given cancer cell type.	('knockdown', 'Var', (169, 178))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('CrkL', 'Gene', (164, 168))	('cancer', 'Disease', (192, 198))	('cancer', 'Disease', 'MESH:D009369', (192, 198))	('investigated effects', 'Reg', (116, 136))	('Crk', 'Gene', (147, 150))	('knockdown', 'Var', (151, 160))
197551	33801580	demonstrated that loss of Crk or CrkL alone using CRISPR/Cas9 substantially inhibited migration and invasion of colorectal cancer cells, while loss of both Crk and CrkL completely blocked cell migration and invasion.	('cell migration', 'CPA', (188, 202))	('blocked', 'NegReg', (180, 187))	('colorectal cancer', 'Disease', (112, 129))	('CrkL', 'Protein', (33, 37))	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('loss', 'Var', (18, 22))	('Crk', 'Protein', (156, 159))	('Crk', 'Protein', (26, 29))	('colorectal cancer', 'Disease', 'MESH:D015179', (112, 129))	('rat', 'Species', '10116', (89, 92))	('rat', 'Species', '10116', (7, 10))	('colorectal cancer', 'Phenotype', 'HP:0003003', (112, 129))	('rat', 'Species', '10116', (196, 199))	('inhibited', 'NegReg', (76, 85))	('invasion', 'CPA', (207, 215))
197552	33801580	Crk/CrkL double knockout also inhibited pancreatic cancer cell migration and invasion.	('Crk/CrkL', 'Protein', (0, 8))	('double knockout', 'Var', (9, 24))	('inhibited', 'NegReg', (30, 39))	('invasion', 'CPA', (77, 85))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (40, 57))	('pancreatic cancer', 'Disease', (40, 57))	('rat', 'Species', '10116', (66, 69))	('pancreatic cancer', 'Disease', 'MESH:D010190', (40, 57))
197553	33801580	To investigate distinct and overlapping functions of Crk and CrkL, individual and combined knockdown of Crk and CrkL were induced in U-118MG glioblastoma cells, and cell migration and invasion were analyzed in real-time.	('CrkL', 'Gene', (112, 116))	('rat', 'Species', '10116', (173, 176))	('glioblastoma', 'Phenotype', 'HP:0012174', (141, 153))	('Crk', 'Gene', (104, 107))	('U-118MG', 'CellLine', 'CVCL:0633', (133, 140))	('knockdown', 'Var', (91, 100))	('glioblastoma', 'Disease', (141, 153))	('glioblastoma', 'Disease', 'MESH:D005909', (141, 153))
197554	33801580	While CrkL knockdown reduced glioblastoma cell migration, Crk knockdown delayed the cell migration.	('reduced', 'NegReg', (21, 28))	('glioblastoma', 'Disease', 'MESH:D005909', (29, 41))	('glioblastoma', 'Phenotype', 'HP:0012174', (29, 41))	('rat', 'Species', '10116', (50, 53))	('delayed', 'NegReg', (72, 79))	('rat', 'Species', '10116', (92, 95))	('cell migration', 'CPA', (84, 98))	('CrkL', 'Protein', (6, 10))	('knockdown', 'Var', (11, 20))	('glioblastoma', 'Disease', (29, 41))
197555	33801580	When knockdown of both Crk and CrkL was induced, cell migration was completely blocked, suggesting the unique and overlapping functions of Crk and CrkL in glioblastoma cells.	('cell migration', 'CPA', (49, 63))	('knockdown', 'Var', (5, 14))	('glioblastoma', 'Disease', (155, 167))	('rat', 'Species', '10116', (57, 60))	('glioblastoma', 'Disease', 'MESH:D005909', (155, 167))	('blocked', 'NegReg', (79, 86))	('glioblastoma', 'Phenotype', 'HP:0012174', (155, 167))
197556	33801580	On the other hand, CrkL knockdown, but not Crk knockdown, inhibited glioblastoma cell invasion, and Crk/CrkL double knockdown completely blocked cell invasion.	('glioblastoma', 'Disease', (68, 80))	('glioblastoma', 'Disease', 'MESH:D005909', (68, 80))	('glioblastoma', 'Phenotype', 'HP:0012174', (68, 80))	('cell invasion', 'CPA', (145, 158))	('blocked', 'NegReg', (137, 144))	('inhibited', 'NegReg', (58, 67))	('knockdown', 'Var', (24, 33))
197557	33801580	These findings indicate that individual and combined ablation of Crk and CrkL are required to address their unique and overlapping functions in tumor cells.	('tumor', 'Disease', (144, 149))	('ablation', 'Var', (53, 61))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('CrkL', 'Protein', (73, 77))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('Crk', 'Protein', (65, 68))
197568	33801580	Abl-induced phosphorylation of CrkII on Tyr221 and subsequent intramolecular binding of the SH2 domain to the phosphorylated Tyr221 are known to disrupt the association of CrkII to its SH2 target proteins.	('Tyr221', 'Chemical', '-', (40, 46))	('disrupt', 'NegReg', (145, 152))	('phosphorylation', 'Var', (12, 27))	('association', 'Interaction', (157, 168))	('Tyr221', 'Chemical', '-', (125, 131))	('binding', 'Interaction', (77, 84))
197571	33801580	Whereas overexpression with CrkII-Y239F, like wild-type CrkII, increased migration of Crk-null fibroblasts and Hs683 glioblastoma cells, CrkII-Y239F, unlike wild-type CrkII, failed to increase migration of 4T1 breast cancer cells.	('CrkII-Y239F', 'Var', (137, 148))	('migration', 'CPA', (73, 82))	('increased', 'PosReg', (63, 72))	('rat', 'Species', '10116', (76, 79))	('breast cancer', 'Disease', 'MESH:D001943', (210, 223))	('4T1', 'CellLine', 'CVCL:0125', (206, 209))	('Y239F', 'Mutation', 'p.Y239F', (34, 39))	('Y239F', 'Mutation', 'p.Y239F', (143, 148))	('breast cancer', 'Disease', (210, 223))	('glioblastoma', 'Disease', (117, 129))	('breast cancer', 'Phenotype', 'HP:0003002', (210, 223))	('glioblastoma', 'Disease', 'MESH:D005909', (117, 129))	('rat', 'Species', '10116', (196, 199))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))	('glioblastoma', 'Phenotype', 'HP:0012174', (117, 129))
197572	33801580	Phosphorylation of CrkII on Tyr251 that is located on the C-terminal SH3 domain promoted motility of Crk-null mouse fibroblasts towards epidermal growth factor (EGF).	('motility', 'CPA', (89, 97))	('epidermal growth factor', 'Gene', '13645', (136, 159))	('promoted', 'PosReg', (80, 88))	('Tyr251', 'Var', (28, 34))	('EGF', 'Gene', (161, 164))	('Tyr251', 'Chemical', '-', (28, 34))	('mouse', 'Species', '10090', (110, 115))	('epidermal growth factor', 'Gene', (136, 159))	('EGF', 'Gene', '13645', (161, 164))
197573	33801580	On the other hand, CrkII-Ser41Gly expression decreased motility of NSCLC cells while wild-type CrkII expression increased the cell motility, suggesting that phosphorylation of CrkII on serine 41 by PAK1 promotes cell motility and invasion.	('PAK1', 'Gene', '5058', (198, 202))	('PAK1', 'Gene', (198, 202))	('cell motility', 'CPA', (212, 225))	('cell motility', 'CPA', (126, 139))	('Ser41Gly', 'SUBSTITUTION', 'None', (25, 33))	('decreased', 'NegReg', (45, 54))	('promotes', 'PosReg', (203, 211))	('serine', 'Chemical', 'MESH:D012694', (185, 191))	('Ser41Gly', 'Var', (25, 33))	('invasion', 'CPA', (230, 238))	('increased', 'PosReg', (112, 121))	('phosphorylation', 'Var', (157, 172))	('NSCLC', 'Disease', (67, 72))	('NSCLC', 'Disease', 'MESH:D002289', (67, 72))
197576	33801580	In most of these studies, loss of either Crk or CrkL resulted in decreases in tumor cell migration and invasion, suggesting that tumor cell migration and invasion are highly demanding cellular processes that require both Crk and CrkL to reorganize the cellular cytoskeletal network.	('decreases', 'NegReg', (65, 74))	('tumor', 'Disease', (129, 134))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('Crk', 'Protein', (41, 44))	('rat', 'Species', '10116', (92, 95))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('rat', 'Species', '10116', (143, 146))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Disease', (78, 83))	('loss', 'Var', (26, 30))	('CrkL', 'Protein', (48, 52))	('invasion', 'CPA', (103, 111))
197578	33801580	Furthermore, recent studies indicate that cell migration and invasion depend on Crk and CrkL in a dose-dependent manner since the loss of both Crk and CrkL led to more severe defects than the loss of one protein.	('cell migration', 'CPA', (42, 56))	('rat', 'Species', '10116', (50, 53))	('invasion', 'CPA', (61, 69))	('CrkL', 'Protein', (151, 155))	('Crk', 'Protein', (143, 146))	('loss', 'Var', (130, 134))
197587	33801580	CrkL knockdown also suppressed CCL19/CCR7-induced EMT marker expression and extracellular signal-regulated kinase (ERK) phosphorylation in epithelial ovarian carcinoma cells by decreasing expression of N-cadherin, Snail, and MMP9 and increasing E-cadherin expression.	('knockdown', 'Var', (5, 14))	('EMT marker', 'Gene', (50, 60))	('ERK', 'Gene', (115, 118))	('E-cadherin expression', 'MPA', (245, 266))	('extracellular signal-regulated kinase', 'Gene', (76, 113))	('CCL19', 'Gene', '6363', (31, 36))	('carcinoma', 'Phenotype', 'HP:0030731', (158, 167))	('CCR7', 'Gene', (37, 41))	('decreasing', 'NegReg', (177, 187))	('extracellular signal-regulated kinase', 'Gene', '5594', (76, 113))	('suppressed', 'NegReg', (20, 30))	('Snail', 'Protein', (214, 219))	('epithelial ovarian carcinoma', 'Disease', (139, 167))	('increasing', 'PosReg', (234, 244))	('MMP9', 'Gene', '4318', (225, 229))	('MMP9', 'Gene', (225, 229))	('CCL19', 'Gene', (31, 36))	('CCR7', 'Gene', '1236', (37, 41))	('expression', 'MPA', (188, 198))	('CrkL', 'Gene', (0, 4))	('N-cadherin', 'Protein', (202, 212))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (150, 167))	('epithelial ovarian carcinoma', 'Disease', 'MESH:D010051', (139, 167))	('ERK', 'Gene', '5594', (115, 118))
197588	33801580	CrkL knockdown inhibited CCL20/CCR6-induced EMT marker expression and ERK phosphorylation in gastric cancer cells by decreasing expression of N-cadherin, vimentin, and MMP2.	('CCL20', 'Gene', '6364', (25, 30))	('ERK', 'Gene', (70, 73))	('knockdown', 'Var', (5, 14))	('gastric cancer', 'Phenotype', 'HP:0012126', (93, 107))	('vimentin', 'Gene', '7431', (154, 162))	('CCL20', 'Gene', (25, 30))	('vimentin', 'Gene', (154, 162))	('CCR6', 'Gene', (31, 35))	('expression', 'MPA', (128, 138))	('gastric cancer', 'Disease', (93, 107))	('N-cadherin', 'Protein', (142, 152))	('MMP2', 'Gene', (168, 172))	('EMT', 'MPA', (44, 47))	('CCR6', 'Gene', '1235', (31, 35))	('ERK', 'Gene', '5594', (70, 73))	('inhibited', 'NegReg', (15, 24))	('gastric cancer', 'Disease', 'MESH:D013274', (93, 107))	('CrkL', 'Gene', (0, 4))	('decreasing', 'NegReg', (117, 127))	('MMP2', 'Gene', '4313', (168, 172))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))
197589	33801580	While CrkL knockout blocked SASH1 deficiency-induced EMT in HCT116 colon cancer cells, Crk/CrkL double knockout inhibited Src activation-induced EMT.	('inhibited', 'NegReg', (112, 121))	('SASH1', 'Gene', '23328', (28, 33))	('colon cancer', 'Disease', 'MESH:D015179', (67, 79))	('HCT116', 'CellLine', 'CVCL:0291', (60, 66))	('colon cancer', 'Phenotype', 'HP:0003003', (67, 79))	('Src', 'Gene', (122, 125))	('Src', 'Gene', '6714', (122, 125))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('colon cancer', 'Disease', (67, 79))	('deficiency-induced', 'Var', (34, 52))	('EMT', 'CPA', (53, 56))	('SASH1', 'Gene', (28, 33))
197590	33801580	Increased E-cadherin expression and decreased ZEB1 expression were observed by knockout of Crk, CrkL, or both in colon cancer cells and by Crk/CrkL double in pancreatic cancer cells.	('E-cadherin', 'Protein', (10, 20))	('pancreatic cancer', 'Disease', (158, 175))	('colon cancer', 'Phenotype', 'HP:0003003', (113, 125))	('ZEB1', 'Gene', (46, 50))	('pancreatic cancer', 'Disease', 'MESH:D010190', (158, 175))	('ZEB1', 'Gene', '6935', (46, 50))	('colon cancer', 'Disease', 'MESH:D015179', (113, 125))	('expression', 'MPA', (21, 31))	('colon cancer', 'Disease', (113, 125))	('Crk', 'Gene', (91, 94))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('Increased', 'PosReg', (0, 9))	('expression', 'MPA', (51, 61))	('CrkL', 'Protein', (96, 100))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (158, 175))	('knockout', 'Var', (79, 87))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('decreased', 'NegReg', (36, 45))
197593	33801580	demonstrated that suppression of EMT in pancreatic ductal adenocarcinoma mouse models by genetic ablation of EMT-inducing transcription factors such as Snail or Twist enhanced expression of nucleoside transporters in tumors, leading to enhanced sensitivity to gemcitabine treatment and increased overall survival of mice.	('tumors', 'Disease', 'MESH:D009369', (217, 223))	('suppression', 'NegReg', (18, 29))	('mice', 'Species', '10090', (316, 320))	('mouse', 'Species', '10090', (73, 78))	('rat', 'Species', '10116', (7, 10))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))	('expression of nucleoside transporters', 'MPA', (176, 213))	('enhanced', 'PosReg', (167, 175))	('Twist', 'Gene', (161, 166))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (40, 72))	('ablation', 'Var', (97, 105))	('Twist', 'Gene', '22160', (161, 166))	('pancreatic ductal adenocarcinoma', 'Disease', (40, 72))	('tumors', 'Phenotype', 'HP:0002664', (217, 223))	('enhanced', 'PosReg', (236, 244))	('gemcitabine', 'Chemical', 'MESH:C056507', (260, 271))	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('tumors', 'Disease', (217, 223))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (40, 72))	('increased', 'PosReg', (286, 295))	('sensitivity to gemcitabine treatment', 'MPA', (245, 281))
197594	33801580	demonstrated that breast cancer cells with EMT contribute to recurrent lung metastasis after chemotherapy, and that inhibition of EMT by overexpressing miR-200 abrogated the chemoresistance to cyclophosphamide treatment, leading to reduced lung metastasis.	('chemoresistance to cyclophosphamide treatment', 'MPA', (174, 219))	('inhibition', 'Var', (116, 126))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('breast cancer', 'Disease', 'MESH:D001943', (18, 31))	('lung metastasis', 'CPA', (71, 86))	('abrogated', 'NegReg', (160, 169))	('cyclophosphamide', 'Chemical', 'MESH:D003520', (193, 209))	('breast cancer', 'Disease', (18, 31))	('overexpressing', 'PosReg', (137, 151))	('miR-200', 'Gene', (152, 159))	('reduced', 'NegReg', (232, 239))	('rat', 'Species', '10116', (7, 10))	('miR-200', 'Chemical', '-', (152, 159))	('breast cancer', 'Phenotype', 'HP:0003002', (18, 31))	('lung metastasis', 'CPA', (240, 255))
197604	33801580	Analysis of the curated set of non-redundant studies in The Cancer Genome Atlas (TCGA) using the cBioPortal platform indicates that only 0.5% and 1% of cancer patients showed copy number increases for CRK and CRKL, respectively.	('rat', 'Species', '10116', (18, 21))	('CRKL', 'Protein', (209, 213))	('cancer', 'Disease', (152, 158))	('CRK', 'Protein', (201, 204))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('Cancer', 'Phenotype', 'HP:0002664', (60, 66))	('Cancer', 'Disease', (60, 66))	('Cancer', 'Disease', 'MESH:D009369', (60, 66))	('copy number', 'Var', (175, 186))	('increases', 'PosReg', (187, 196))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('patients', 'Species', '9606', (159, 167))
197608	33801580	Nevertheless, lower survival was observed for the patients with amplification of CRK or CRKL transcripts (46.78 and 53.92 months for the median months overall, respectively, compared to 118.30 months with the unaltered group) (Figure 3 and Table 2).	('CRK', 'Gene', (81, 84))	('patients', 'Species', '9606', (50, 58))	('lower', 'NegReg', (14, 19))	('amplification', 'Var', (64, 77))	('survival', 'MPA', (20, 28))	('CRKL', 'Gene', (88, 92))
197614	33801580	A similar analysis using cBioPortal of a smaller subset for lung, breast, and gastric cancer patients combined did not exhibit any apparent difference in overall survival among the patients with amplification of CRK and CRKL transcripts (data not shown).	('breast', 'Disease', (66, 72))	('CRKL', 'Protein', (220, 224))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('gastric cancer', 'Disease', (78, 92))	('patients', 'Species', '9606', (181, 189))	('gastric cancer', 'Disease', 'MESH:D013274', (78, 92))	('gastric cancer', 'Phenotype', 'HP:0012126', (78, 92))	('amplification', 'Var', (195, 208))	('patients', 'Species', '9606', (93, 101))	('CRK', 'Protein', (212, 215))
197615	33801580	Therefore, accumulation of more datasets, together with correlation studies between copy number alterations and protein level changes in cancer tissue, would provide a more concrete explanation of whether copy number alterations of CRK and CRKL contribute to overall patient survival in individual cancer types.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('patient', 'Species', '9606', (267, 274))	('rat', 'Species', '10116', (221, 224))	('CRKL', 'Protein', (240, 244))	('CRK', 'Protein', (232, 235))	('cancer', 'Disease', 'MESH:D009369', (298, 304))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('cancer', 'Disease', (298, 304))	('cancer', 'Disease', (137, 143))	('copy number alterations', 'Var', (205, 228))	('cancer', 'Phenotype', 'HP:0002664', (298, 304))	('rat', 'Species', '10116', (100, 103))	('contribute', 'Reg', (245, 255))
197623	33801580	FGFR2 was highly expressed in many pancreatic ductal adenocarcinoma (PDAC) tissues, and knockdown of FGFR2 IIIb and IIIc in PDAC cells inhibited cell proliferation, migration, invasion, and in vivo tumor formation.	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (35, 67))	('FGFR2', 'Gene', (101, 106))	('FGFR2', 'Gene', '2263', (101, 106))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('knockdown', 'Var', (88, 97))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('rat', 'Species', '10116', (168, 171))	('cell proliferation', 'CPA', (145, 163))	('rat', 'Species', '10116', (157, 160))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))	('invasion', 'CPA', (176, 184))	('tumor', 'Disease', (198, 203))	('FGFR2', 'Gene', (0, 5))	('inhibited', 'NegReg', (135, 144))	('FGFR2', 'Gene', '2263', (0, 5))	('pancreatic ductal adenocarcinoma', 'Disease', (35, 67))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (35, 67))
197624	33801580	FGF8 was elevated in colorectal cancer tissues, and high FGF8 expression in colorectal cancer cells led to EMT marker expression, enhanced proliferation and invasion, and in vivo tumor growth and metastasis in a YAP1-dependent manner.	('enhanced', 'PosReg', (130, 138))	('EMT marker', 'CPA', (107, 117))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('YAP1', 'Gene', '10413', (212, 216))	('colorectal cancer', 'Phenotype', 'HP:0003003', (21, 38))	('colorectal cancer', 'Phenotype', 'HP:0003003', (76, 93))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('YAP1', 'Gene', (212, 216))	('expression', 'MPA', (62, 72))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('proliferation', 'CPA', (139, 152))	('high', 'Var', (52, 56))	('FGF8', 'Gene', '2253', (57, 61))	('FGF8', 'Gene', (57, 61))	('colorectal cancer', 'Disease', 'MESH:D015179', (21, 38))	('FGF8', 'Gene', (0, 4))	('colorectal cancer', 'Disease', 'MESH:D015179', (76, 93))	('FGF8', 'Gene', '2253', (0, 4))	('rat', 'Species', '10116', (146, 149))	('invasion', 'CPA', (157, 165))	('colorectal cancer', 'Disease', (21, 38))	('colorectal cancer', 'Disease', (76, 93))	('tumor', 'Disease', (179, 184))
197626	33801580	FGFR4 expression was elevated in nasopharyngeal carcinoma tissues, and FGFR4 knockdown reduced proliferation and migration of nasopharyngeal carcinoma cells.	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (126, 150))	('knockdown', 'Var', (77, 86))	('FGFR4', 'Gene', '2264', (0, 5))	('proliferation', 'CPA', (95, 108))	('carcinoma', 'Phenotype', 'HP:0030731', (48, 57))	('carcinoma', 'Disease', (48, 57))	('FGFR4', 'Gene', '2264', (71, 76))	('rat', 'Species', '10116', (102, 105))	('FGFR4', 'Gene', (0, 5))	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('reduced', 'NegReg', (87, 94))	('carcinoma', 'Disease', (141, 150))	('rat', 'Species', '10116', (116, 119))	('carcinoma', 'Disease', 'MESH:D009369', (48, 57))	('FGFR4', 'Gene', (71, 76))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (33, 57))	('expression', 'MPA', (6, 16))	('elevated', 'PosReg', (21, 29))	('carcinoma', 'Disease', 'MESH:D009369', (141, 150))
197636	33801580	Overall, knockdown or knockout of Crk or CrkL suppressed tumor cell growth in vitro and in vivo, whereas overexpression of Crk or CrkL promoted tumor cell growth.	('Crk', 'Gene', (34, 37))	('tumor', 'Disease', (144, 149))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('CrkL', 'Gene', (41, 45))	('knockout', 'Var', (22, 30))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('tumor', 'Disease', (57, 62))	('suppressed', 'NegReg', (46, 56))
197637	33801580	Cancer cell migration and invasion were also inhibited by Crk or CrkL knockdown and promoted by Crk or CrkL overexpression.	('promoted', 'PosReg', (84, 92))	('knockdown', 'Var', (70, 79))	('rat', 'Species', '10116', (15, 18))	('invasion', 'CPA', (26, 34))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('Crk', 'Protein', (58, 61))	('inhibited', 'NegReg', (45, 54))	('CrkL', 'Protein', (65, 69))
197648	33801580	No inhibitory effect on cell migration and less pronounced inhibitory effects on cell invasion by transient, individual knockdown of Crk and CrkL indirectly suggest potentially overlapping functions of Crk and CrkL.	('cell migration', 'CPA', (24, 38))	('rat', 'Species', '10116', (32, 35))	('knockdown', 'Var', (120, 129))	('CrkL', 'Gene', (141, 145))	('Crk', 'Gene', (133, 136))	('cell invasion', 'CPA', (81, 94))
197649	33801580	induced individual and combined knockout of Crk and CrkL in colorectal cancer cells.	('CrkL', 'Protein', (52, 56))	('knockout', 'Var', (32, 40))	('colorectal cancer', 'Disease', 'MESH:D015179', (60, 77))	('Crk', 'Gene', (44, 47))	('colorectal cancer', 'Phenotype', 'HP:0003003', (60, 77))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('combined', 'Interaction', (23, 31))	('colorectal cancer', 'Disease', (60, 77))
197652	33801580	induced individual and combined knockdown of Crk and CrkL in a glioblastoma cell line and demonstrated a predominant role of CrkL and overlapping roles of Crk and CrkL in glioblastoma cell migration.	('rat', 'Species', '10116', (97, 100))	('glioblastoma', 'Disease', (171, 183))	('glioblastoma', 'Disease', (63, 75))	('knockdown', 'Var', (32, 41))	('rat', 'Species', '10116', (192, 195))	('glioblastoma', 'Disease', 'MESH:D005909', (171, 183))	('glioblastoma', 'Phenotype', 'HP:0012174', (171, 183))	('glioblastoma', 'Disease', 'MESH:D005909', (63, 75))	('glioblastoma', 'Phenotype', 'HP:0012174', (63, 75))	('Crk', 'Protein', (45, 48))	('CrkL', 'Protein', (125, 129))
197658	33801580	The peptides inhibited the binding of Crk to DOCK180, to SoS, and to C3G in vitro.	('SoS', 'Gene', '64132', (57, 60))	('SoS', 'Gene', (57, 60))	('binding', 'Interaction', (27, 34))	('inhibited', 'NegReg', (13, 22))	('peptides', 'Var', (4, 12))	('DOCK180', 'Gene', (45, 52))	('DOCK180', 'Gene', '1793', (45, 52))	('Crk', 'Protein', (38, 41))
197675	31844068	Recurrent PTPRT/JAK2 mutations in lung adenocarcinoma among African Americans Reducing or eliminating persistent disparities in lung cancer incidence and survival has been challenging because our current understanding of lung cancer biology is derived primarily from populations of European descent.	('lung adenocarcinoma', 'Disease', (34, 53))	('Reducing', 'NegReg', (78, 86))	('lung cancer', 'Disease', (221, 232))	('eliminating', 'NegReg', (90, 101))	('JAK2', 'Gene', '3717', (16, 20))	('lung cancer', 'Disease', 'MESH:D008175', (128, 139))	('PTPRT', 'Gene', (10, 15))	('lung cancer', 'Phenotype', 'HP:0100526', (128, 139))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (34, 53))	('lung cancer', 'Disease', 'MESH:D008175', (221, 232))	('JAK2', 'Gene', (16, 20))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (34, 53))	('lung cancer', 'Phenotype', 'HP:0100526', (221, 232))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('mutations', 'Var', (21, 30))	('PTPRT', 'Gene', '11122', (10, 15))	('lung cancer', 'Disease', (128, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (44, 53))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
197676	31844068	Here we show results from a targeted sequencing panel using NCI-MD Case Control Study patient samples and reveal a significantly higher prevalence of PTPRT and JAK2 mutations in lung adenocarcinomas among African Americans compared with European Americans.	('carcinoma', 'Phenotype', 'HP:0030731', (188, 197))	('JAK2', 'Gene', (160, 164))	('PTPRT', 'Gene', '11122', (150, 155))	('PTPRT', 'Gene', (150, 155))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (178, 197))	('patient', 'Species', '9606', (86, 93))	('lung adenocarcinomas', 'Disease', (178, 198))	('mutations', 'Var', (165, 174))	('JAK2', 'Gene', '3717', (160, 164))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (178, 198))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (178, 198))
197677	31844068	We find that patients carrying these mutations have a concomitant increase in IL-6/STAT3 signaling and miR-21 expression.	('increase', 'PosReg', (66, 74))	('STAT3', 'Gene', (83, 88))	('patients', 'Species', '9606', (13, 21))	('miR-21', 'Gene', (103, 109))	('IL-6', 'Gene', (78, 82))	('IL-6', 'Gene', '3569', (78, 82))	('mutations', 'Var', (37, 46))	('expression', 'MPA', (110, 120))	('miR-21', 'Gene', '406991', (103, 109))	('STAT3', 'Gene', '6774', (83, 88))
197680	31844068	Here, targeted sequencing in African American lung adenocarcinomas finds significantly higher prevalence of PTPRTand JAK2 mutations, validated independently by whole exome sequencing, highlighting potentially clinically actionable mutations in this population.	('JAK2', 'Gene', (117, 121))	('lung adenocarcinomas', 'Disease', (46, 66))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (46, 66))	('JAK2', 'Gene', '3717', (117, 121))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (46, 66))	('mutations', 'Var', (122, 131))	('PTPRT', 'Gene', '11122', (108, 113))	('PTPRT', 'Gene', (108, 113))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (46, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (56, 65))
197693	31844068	By identifying driver mutations, these studies have greatly contributed to the development of targeted pharmacological drugs for the treatment of cancer, and, through the ability to detect circulating tumor DNA, are also being leveraged for early diagnostics.	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('men', 'Species', '9606', (86, 89))	('men', 'Species', '9606', (138, 141))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('mutations', 'Var', (22, 31))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('tumor', 'Disease', (201, 206))
197701	31844068	As expected, tumors from smokers had more mutations than never smokers (average = 38, 37, and 5 for current, former and never smokers, respectively).	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('tumors', 'Disease', (13, 19))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('mutations', 'Var', (42, 51))
197702	31844068	The median number of mutations that passed the second filter, i.e., likely to alter protein function, was 14 (range = 0-132; Supplementary Data 5).	('men', 'Species', '9606', (131, 134))	('alter', 'Reg', (78, 83))	('protein', 'Protein', (84, 91))	('mutations', 'Var', (21, 30))
197703	31844068	Roughly a quarter (24%) of tumors did not harbor a mutation in the Oncovar gene panel, which is consistent with the previous observations.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('tumors', 'Disease', (27, 33))	('tumors', 'Disease', 'MESH:D009369', (27, 33))	('mutation', 'Var', (51, 59))	('Oncovar gene panel', 'Gene', (67, 85))
197705	31844068	The patient with the highest mutation burden was a current smoker with 64 pack-years of tobacco smoke consumption, who presented with adenocarcinoma.	('adenocarcinoma', 'Disease', (134, 148))	('mutation', 'Var', (29, 37))	('tobacco', 'Species', '4097', (88, 95))	('presented', 'Reg', (119, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (139, 148))	('adenocarcinoma', 'Disease', 'MESH:D000230', (134, 148))	('patient', 'Species', '9606', (4, 11))
197707	31844068	MSH2, MSH6, MLH1, and PMS2 were included in the gene panel and only one of the patients with a hypermutated tumor had a mutation, which was a missense R638S mutation in MSH2.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('MSH2', 'Gene', '4436', (169, 173))	('MLH1', 'Gene', '4292', (12, 16))	('missense R638S', 'Var', (142, 156))	('MLH1', 'Gene', (12, 16))	('PMS2', 'Gene', '5395', (22, 26))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('MSH2', 'Gene', (0, 4))	('MSH6', 'Gene', '2956', (6, 10))	('tumor', 'Disease', (108, 113))	('MSH2', 'Gene', '4436', (0, 4))	('patients', 'Species', '9606', (79, 87))	('R638S', 'Mutation', 'p.R638S', (151, 156))	('MSH2', 'Gene', (169, 173))	('PMS2', 'Gene', (22, 26))	('MSH6', 'Gene', (6, 10))
197722	31844068	However, STK11 and RB1 mutations occurred in 19% and 11% of LUAD tumors among AAs, respectively, which is higher than the frequency reported for EA patients in TCGA (Supplementary Fig.	('patients', 'Species', '9606', (148, 156))	('STK11', 'Gene', '6794', (9, 14))	('occurred', 'Reg', (33, 41))	('LUAD tumors', 'Disease', 'MESH:D009369', (60, 71))	('mutations', 'Var', (23, 32))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('RB1', 'Gene', (19, 22))	('LUAD tumors', 'Disease', (60, 71))	('LUAD', 'Phenotype', 'HP:0030078', (60, 64))	('STK11', 'Gene', (9, 14))	('men', 'Species', '9606', (172, 175))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('RB1', 'Gene', '5925', (19, 22))
197723	31844068	TP53 mutations were slightly higher among AAs compared with EAs, consistent with previous observations.	('TP53', 'Gene', '7157', (0, 4))	('higher', 'Reg', (29, 35))	('TP53', 'Gene', (0, 4))	('AAs', 'Disease', (42, 45))	('mutations', 'Var', (5, 14))
197724	31844068	We further found that the frequency of mutations in PTPRT and JAK2 are higher in AAs compared with EAs (Fig.	('higher', 'Reg', (71, 77))	('mutations', 'Var', (39, 48))	('JAK2', 'Gene', '3717', (62, 66))	('PTPRT', 'Gene', '11122', (52, 57))	('PTPRT', 'Gene', (52, 57))	('AAs', 'Disease', (81, 84))	('JAK2', 'Gene', (62, 66))
197725	31844068	Our data indicate that 13/54 (24%) of LUAD patients have mutations in PTPRT and that 4/54 (7.4%) have mutations in JAK2, compared with 8% and 2% in EAs, respectively (Fig.	('LUAD', 'Disease', (38, 42))	('JAK2', 'Gene', (115, 119))	('LUAD', 'Phenotype', 'HP:0030078', (38, 42))	('patients', 'Species', '9606', (43, 51))	('mutations', 'Var', (57, 66))	('mutations', 'Var', (102, 111))	('PTPRT', 'Gene', '11122', (70, 75))	('PTPRT', 'Gene', (70, 75))	('JAK2', 'Gene', '3717', (115, 119))
197727	31844068	Specifically, of the 15 patient samples (all histology combined) that carried a mutation in PTPRT and the 11 that carried a mutation in JAK2, only 1 sample had a mutation in both genes (two-sided Fisher's exact test P < 0.001).	('JAK2', 'Gene', '3717', (136, 140))	('PTPRT', 'Gene', '11122', (92, 97))	('PTPRT', 'Gene', (92, 97))	('patient', 'Species', '9606', (24, 31))	('JAK2', 'Gene', (136, 140))	('mutation', 'Var', (80, 88))
197729	31844068	Combined, PTPRT and JAK2 are mutated in >30% of tumors from AAs and ~10% of tumors from EAs (Fig.	('tumors', 'Disease', (48, 54))	('tumors', 'Disease', 'MESH:D009369', (48, 54))	('JAK2', 'Gene', '3717', (20, 24))	('PTPRT', 'Gene', '11122', (10, 15))	('PTPRT', 'Gene', (10, 15))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumors', 'Disease', (76, 82))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('mutated', 'Var', (29, 36))	('JAK2', 'Gene', (20, 24))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('AAs', 'Disease', (60, 63))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
197730	31844068	To validate these observations, we first used data from TCGA (Supplementary Data 1) and replicated the statistically higher frequency of PTPRT (AA 20%, EA 8%, two sample test of proportions P = 0.0004) and JAK2 (AA 6%, EA 2%, P = 0.025) mutations in LUAD from AAs (Fig.	('LUAD', 'Gene', (250, 254))	('PTPRT', 'Gene', '11122', (137, 142))	('JAK2', 'Gene', '3717', (206, 210))	('PTPRT', 'Gene', (137, 142))	('JAK2', 'Gene', (206, 210))	('LUAD', 'Phenotype', 'HP:0030078', (250, 254))	('men', 'Species', '9606', (68, 71))	('mutations', 'Var', (237, 246))
197733	31844068	Again, we observed a higher frequency of PTPRT (AAs 21%, EAs 9.6%, two sample test of proportions P = 0.014) and JAK2 (AAs 10%, EAs 0%, two sample test of proportions P = 0.08) mutations in tumors from AAs (Fig.	('tumors', 'Disease', 'MESH:D009369', (190, 196))	('AAs', 'Disease', (202, 205))	('JAK2', 'Gene', (113, 117))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('mutations', 'Var', (177, 186))	('PTPRT', 'Gene', '11122', (41, 46))	('PTPRT', 'Gene', (41, 46))	('tumors', 'Disease', (190, 196))	('JAK2', 'Gene', '3717', (113, 117))	('tumors', 'Phenotype', 'HP:0002664', (190, 196))
197737	31844068	Integrating total RNAseq data for 23 samples for which we had both targeted exome sequencing and RNAseq data (n = 6 mutant and 17 wild type), we observed an enrichment of IL6/JAK2/STAT3 and interferon signaling among lung tumors carrying either PTPRT or JAK2 mutations (Fig.	('IL6', 'Gene', '3569', (171, 174))	('STAT3', 'Gene', (180, 185))	('interferon signaling', 'MPA', (190, 210))	('mutations', 'Var', (259, 268))	('IL6', 'Gene', (171, 174))	('men', 'Species', '9606', (163, 166))	('JAK2', 'Gene', '3717', (175, 179))	('JAK2', 'Gene', '3717', (254, 258))	('lung tumors', 'Disease', (217, 228))	('lung tumors', 'Disease', 'MESH:D008175', (217, 228))	('JAK2', 'Gene', (175, 179))	('JAK2', 'Gene', (254, 258))	('lung tumors', 'Phenotype', 'HP:0100526', (217, 228))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('tumors', 'Phenotype', 'HP:0002664', (222, 228))	('STAT3', 'Gene', '6774', (180, 185))	('PTPRT', 'Gene', '11122', (245, 250))	('PTPRT', 'Gene', (245, 250))
197741	31844068	2) in tumor samples carrying mutations in PTPRT or JAK2, while non STAT3 targets, such as miR-126, were similar (Supplementary Fig.	('mutations', 'Var', (29, 38))	('JAK2', 'Gene', '3717', (51, 55))	('STAT3', 'Gene', '6774', (67, 72))	('miR-126', 'Gene', '406913', (90, 97))	('tumor', 'Disease', 'MESH:D009369', (6, 11))	('PTPRT', 'Gene', (42, 47))	('PTPRT', 'Gene', '11122', (42, 47))	('STAT3', 'Gene', (67, 72))	('JAK2', 'Gene', (51, 55))	('men', 'Species', '9606', (119, 122))	('miR-126', 'Gene', (90, 97))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('tumor', 'Disease', (6, 11))
197742	31844068	These data suggest that an increased frequency of loss of function PTPRT and JAK2 mutations may drive STAT3 activity in subsets of non-small cell lung cancer (NSCLC) that are enriched among AAs.	('non-small cell lung cancer', 'Disease', (131, 157))	('JAK2', 'Gene', '3717', (77, 81))	('PTPRT', 'Gene', '11122', (67, 72))	('PTPRT', 'Gene', (67, 72))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (135, 157))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('NSCLC', 'Disease', (159, 164))	('JAK2', 'Gene', (77, 81))	('lung cancer', 'Phenotype', 'HP:0100526', (146, 157))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (131, 157))	('NSCLC', 'Disease', 'MESH:D002289', (159, 164))	('STAT3', 'Gene', '6774', (102, 107))	('drive', 'Reg', (96, 101))	('mutations', 'Var', (82, 91))	('STAT3', 'Gene', (102, 107))	('loss of function', 'NegReg', (50, 66))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (131, 157))	('NSCLC', 'Phenotype', 'HP:0030358', (159, 164))
197744	31844068	Roughly, a quarter (24%) of the tumors in our analysis did not harbor a mutation in the Oncovar gene panel, which is consistent with the previous observations.	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('mutation', 'Var', (72, 80))	('tumors', 'Disease', (32, 38))	('Oncovar gene panel', 'Gene', (88, 106))	('tumors', 'Disease', 'MESH:D009369', (32, 38))
197745	31844068	However, we identified an increased prevalence of PTPRT and JAK2 mutations in LUAD from AAs.	('JAK2', 'Gene', '3717', (60, 64))	('PTPRT', 'Gene', '11122', (50, 55))	('PTPRT', 'Gene', (50, 55))	('JAK2', 'Gene', (60, 64))	('LUAD', 'Phenotype', 'HP:0030078', (78, 82))	('mutations', 'Var', (65, 74))
197746	31844068	Combined, ~30% of tumors from AAs carried mutations in PTPRT and/or JAK2 genes compared with 10% of EAs.	('JAK2', 'Gene', '3717', (68, 72))	('JAK2', 'Gene', (68, 72))	('tumors', 'Disease', (18, 24))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('PTPRT', 'Gene', '11122', (55, 60))	('PTPRT', 'Gene', (55, 60))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('mutations', 'Var', (42, 51))	('AAs', 'Disease', (30, 33))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
197750	31844068	We detected putative PTPRT fusion genes in nine samples, though none had a similar partner gene or the same partner as previous reported fusions in TCGA.	('PTPRT', 'Gene', '11122', (21, 26))	('PTPRT', 'Gene', (21, 26))	('fusion', 'Var', (27, 33))
197753	31844068	We hypothesize that patients with PTPRT and JAK2 mutations could be candidates for targeted therapy and as such, our findings have implications for the recruitment of patients into clinical trials.	('men', 'Species', '9606', (159, 162))	('mutations', 'Var', (49, 58))	('PTPRT', 'Gene', '11122', (34, 39))	('JAK2', 'Gene', (44, 48))	('patients', 'Species', '9606', (167, 175))	('PTPRT', 'Gene', (34, 39))	('patients', 'Species', '9606', (20, 28))	('JAK2', 'Gene', '3717', (44, 48))
197754	31844068	For example, the initial conception to use JAKs as therapeutic targets was based on the identification of an activating mutation in JAK2 linked to myeloproliferative neoplasms.	('neoplasms', 'Phenotype', 'HP:0002664', (166, 175))	('JAKs', 'Gene', (43, 47))	('myeloproliferative neoplasms', 'Phenotype', 'HP:0005547', (147, 175))	('JAKs', 'Gene', '3716;3717', (43, 47))	('mutation', 'Var', (120, 128))	('myeloproliferative neoplasms', 'Disease', 'MESH:D009196', (147, 175))	('JAK2', 'Gene', '3717', (132, 136))	('myeloproliferative neoplasms', 'Disease', (147, 175))	('JAK2', 'Gene', (132, 136))	('activating', 'PosReg', (109, 119))	('linked', 'Reg', (137, 143))
197756	31844068	Recent work by Pitroda and colleagues found that a selective JAK2 inhibitor is cytotoxic to NSCLC cells in the context of constitutive IFN-stimulated JAK/STAT gene expression and that tumor cell-intrinsic expression of IFN-inducible PD-L1 was abrogated by the selective inhibitor.	('JAK2', 'Gene', '3717', (61, 65))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('NSCLC', 'Phenotype', 'HP:0030358', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('inhibitor', 'Var', (66, 75))	('tumor', 'Disease', (184, 189))	('abrogated', 'NegReg', (243, 252))	('STAT', 'Gene', (154, 158))	('JAK2', 'Gene', (61, 65))	('PD-L1', 'Gene', (233, 238))	('NSCLC', 'Disease', (92, 97))	('STAT', 'Gene', '6774', (154, 158))	('NSCLC', 'Disease', 'MESH:D002289', (92, 97))	('PD-L1', 'Gene', '29126', (233, 238))
197757	31844068	In fact, somatic JAK1/2 mutations were shown to mediate primary resistance to PD-1 blockade because of an inability to signal through the interferon gamma receptor pathway, making it possible that patients harboring such mutations would be unlikely to respond to PD-1 blockade therapy.	('PD-1', 'Gene', (78, 82))	('JAK1/2', 'Gene', '3716;3717', (17, 23))	('patients', 'Species', '9606', (197, 205))	('PD-1', 'Gene', '9825', (263, 267))	('signal', 'MPA', (119, 125))	('JAK1/2', 'Gene', (17, 23))	('PD-1', 'Gene', '9825', (78, 82))	('interferon gamma receptor pathway', 'Pathway', (138, 171))	('inability', 'Disease', (106, 115))	('inability', 'Disease', 'MESH:D007319', (106, 115))	('mutations', 'Var', (24, 33))	('PD-1', 'Gene', (263, 267))
197761	31844068	Interestingly, we conducted an agnostic analysis of differential drug sensitivity among cell lines mutant for JAK2 or PTPRT using the depmap database [https://depmap.org] and identified a STAT inhibitor with selective growth inhibition in PTPRT mutant cells (Supplementary Data 11).	('PTPRT', 'Gene', (118, 123))	('PTPRT', 'Gene', '11122', (239, 244))	('PTPRT', 'Gene', (239, 244))	('men', 'Species', '9606', (265, 268))	('STAT', 'Gene', '6774', (188, 192))	('JAK2', 'Gene', '3717', (110, 114))	('STAT', 'Gene', (188, 192))	('drug sensitivity', 'Phenotype', 'HP:0020174', (65, 81))	('mutant', 'Var', (245, 251))	('mutant', 'Var', (99, 105))	('JAK2', 'Gene', (110, 114))	('PTPRT', 'Gene', '11122', (118, 123))
197762	31844068	Our findings therefore raise the hypothesis that patients carrying these mutations may be more likely to respond to drugs that target this pathway than patients without these mutations.	('respond to drugs', 'MPA', (105, 121))	('patients', 'Species', '9606', (152, 160))	('mutations', 'Var', (73, 82))	('patients', 'Species', '9606', (49, 57))
197763	31844068	However, detailed mechanistic experiments will be needed to determine whether these are indeed actionable mutations, especially given a recent report that up to half of JAK2 mutations in nonsmall cell lung cancer can be inactivating.	('nonsmall cell lung cancer', 'Disease', (187, 212))	('JAK2', 'Gene', (169, 173))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('nonsmall cell lung cancer', 'Disease', 'MESH:D002289', (187, 212))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (190, 212))	('men', 'Species', '9606', (36, 39))	('lung cancer', 'Phenotype', 'HP:0100526', (201, 212))	('mutations', 'Var', (174, 183))	('JAK2', 'Gene', '3717', (169, 173))
197766	31844068	Whether or not population differences in PTPRT/JAK2 mutations extend to populations of Asian descent, or indeed other minority and under-represented populations, remains to be determined.	('mutations', 'Var', (52, 61))	('JAK2', 'Gene', '3717', (47, 51))	('JAK2', 'Gene', (47, 51))	('PTPRT', 'Gene', '11122', (41, 46))	('PTPRT', 'Gene', (41, 46))
197767	31844068	TCGA has eight LUAD patients classified as Asian, one (12.5%) of which carries a PTPRT mutation, suggesting that the frequency in Asian populations is more closely aligned with EAs.	('PTPRT', 'Gene', '11122', (81, 86))	('PTPRT', 'Gene', (81, 86))	('patients', 'Species', '9606', (20, 28))	('LUAD', 'Phenotype', 'HP:0030078', (15, 19))	('mutation', 'Var', (87, 95))
197769	31844068	However, we present evidence that somatic mutations in PTPRT and JAK2 are enriched in AAs and hypothesize that these mutations may be actionable.	('JAK2', 'Gene', (65, 69))	('AAs', 'Disease', (86, 89))	('JAK2', 'Gene', '3717', (65, 69))	('PTPRT', 'Gene', '11122', (55, 60))	('PTPRT', 'Gene', (55, 60))	('mutations', 'Var', (42, 51))
197770	31844068	As this is a putatively targetable pathway, preclinical studies are needed to determine whether tumors carrying these mutations affect outcome or response to therapy directed against IL-6/JAK2/STAT3 signaling.	('JAK2', 'Gene', '3717', (188, 192))	('IL-6', 'Gene', '3569', (183, 187))	('affect', 'Reg', (128, 134))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('JAK2', 'Gene', (188, 192))	('mutations', 'Var', (118, 127))	('tumors', 'Disease', (96, 102))	('STAT3', 'Gene', '6774', (193, 198))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('STAT3', 'Gene', (193, 198))	('IL-6', 'Gene', (183, 187))
197818	30686962	The patient's laboratory data were follows: AST 629 IU/L; ALT 306 IU/L; ALP 4,030 U/mL; GGT 3,157 U/mL; and total bilirubin 5.15 mg/dL.	('GGT 3', 'Gene', (88, 93))	('ALP', 'MPA', (72, 75))	('GGT 3', 'Gene', '2679', (88, 93))	('patient', 'Species', '9606', (4, 11))	('bilirubin', 'Chemical', 'MESH:D001663', (114, 123))	('ALT 306 IU/L', 'Var', (58, 70))	('total bilirubin', 'MPA', (108, 123))
197819	30686962	The patient's tumor marker levels were elevated (CEA 22.4 ng/mL; and CA19-9 1,192.6 U/L).	('tumor', 'Disease', (14, 19))	('patient', 'Species', '9606', (4, 11))	('elevated', 'PosReg', (39, 47))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('CA19-9', 'Var', (69, 75))
197851	32746878	Besides, knock-down of circ-CPA4 inhibited cell growth, mobility and epithelial-mesenchymal transition (EMT), and promoted cell death in NSCLC cells by downregulating PD-L1 through serving as a RNA sponge for let-7 miRNA.	('NSCLC', 'Disease', (137, 142))	('cell death', 'CPA', (123, 133))	('circ-CPA4', 'Gene', (23, 32))	('PD-L1', 'Gene', (167, 172))	('NSCLC', 'Disease', 'MESH:D002289', (137, 142))	('mobility', 'CPA', (56, 64))	('cell growth', 'CPA', (43, 54))	('epithelial-mesenchymal transition', 'CPA', (69, 102))	('downregulating', 'NegReg', (152, 166))	('NSCLC', 'Phenotype', 'HP:0030358', (137, 142))	('knock-down', 'Var', (9, 19))	('promoted', 'PosReg', (114, 122))	('inhibited', 'NegReg', (33, 42))
197854	32746878	Further results suggested that circ-CPA4 also positively regulated exosomal PD-L1, and the NSCLC cells with circ-CPA4 ablation re-activated CD8+ T cells in the co-culturing system.	('ablation', 'Var', (118, 126))	('NSCLC', 'Disease', 'MESH:D002289', (91, 96))	('NSCLC', 'Phenotype', 'HP:0030358', (91, 96))	('CD8', 'Gene', (140, 143))	('CD8', 'Gene', '925', (140, 143))	('exosomal PD-L1', 'MPA', (67, 81))	('NSCLC', 'Disease', (91, 96))
197931	32746878	The immunocheckpoint protein PD-L1 could be sponged and inhibited by let-7 miRNA in multiple cancers, which further enhanced the efficacy of cancer immunotherapy.	('cancer', 'Disease', (93, 99))	('enhanced', 'PosReg', (116, 124))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('cancers', 'Phenotype', 'HP:0002664', (93, 100))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('multiple cancers', 'Disease', (84, 100))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('miRNA', 'Var', (75, 80))	('let-7', 'Gene', (69, 74))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('multiple cancers', 'Disease', 'MESH:D009369', (84, 100))	('cancer', 'Disease', (141, 147))	('efficacy', 'CPA', (129, 137))
197938	32746878	Consistently, let-7 miRNA overexpression also decreased the protein levels of PD-L1 in A549 and H1299 cells, which were increased by knocking down let-7 miRNA (Fig.	('H1299', 'CellLine', 'CVCL:0060', (96, 101))	('A549', 'CellLine', 'CVCL:0023', (87, 91))	('PD-L1', 'Gene', (78, 83))	('let-7', 'Gene', (147, 152))	('knocking down', 'Var', (133, 146))	('decreased', 'NegReg', (46, 55))	('increased', 'PosReg', (120, 129))	('protein levels', 'MPA', (60, 74))
197941	32746878	The Real-Time qPCR results showed that PD-L1 mRNA levels were increased by overexpressing circ-CPA4 and decreased by knocking down circ-CPA4 in NSCLC cells (A549, H1299, SK-MES-1 and Calu-3) (Fig.	('mRNA levels', 'MPA', (45, 56))	('NSCLC', 'Disease', (144, 149))	('circ-CPA4', 'Gene', (131, 140))	('PD-L1', 'Gene', (39, 44))	('knocking down', 'Var', (117, 130))	('increased', 'PosReg', (62, 71))	('A549', 'CellLine', 'CVCL:0023', (157, 161))	('SK-MES-1', 'CellLine', 'CVCL:0630', (170, 178))	('NSCLC', 'Disease', 'MESH:D002289', (144, 149))	('H1299', 'CellLine', 'CVCL:0060', (163, 168))	('overexpressing', 'PosReg', (75, 89))	('decreased', 'NegReg', (104, 113))	('NSCLC', 'Phenotype', 'HP:0030358', (144, 149))
197956	32746878	6c, d) in A549 and H1299 cells, which were reversed by both knocking down let-7 miRNA or upregulating PD-L1 (Fig.	('A549', 'CellLine', 'CVCL:0023', (10, 14))	('upregulating', 'PosReg', (89, 101))	('let-7', 'Gene', (74, 79))	('H1299', 'CellLine', 'CVCL:0060', (19, 24))	('PD-L1', 'Gene', (102, 107))	('knocking down', 'Var', (60, 73))
197958	32746878	The above cellular results were also validated in vivo, and the results showed that knock-down of circ-CPA4 inhibited Cyclin D1 and Bcl-2 expressions, while increased the expression levels of Bax in mice tumor tissues, which were reversed by downregulating let-7 miRNA or upregulating PD-L1 (Fig.	('Bcl-2 expressions', 'MPA', (132, 149))	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('mice', 'Species', '10090', (199, 203))	('circ-CPA4', 'Gene', (98, 107))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('Cyclin D1', 'MPA', (118, 127))	('let-7 miRNA', 'Protein', (257, 268))	('upregulating', 'PosReg', (272, 284))	('tumor', 'Disease', (204, 209))	('downregulating', 'NegReg', (242, 256))	('increased', 'PosReg', (157, 166))	('expression levels', 'MPA', (171, 188))	('knock-down', 'Var', (84, 94))	('inhibited', 'NegReg', (108, 117))
197959	32746878	In addition, silencing of circ-CPA4 hampered tumorigenesis of NSCLC cells in xenograft tumor-bearing mice models by regulating let-7 miRNA/PD-L1 axis in a similar manner (Fig.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('NSCLC', 'Disease', (62, 67))	('regulating', 'Reg', (116, 126))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('NSCLC', 'Disease', 'MESH:D002289', (62, 67))	('tumor', 'Disease', (45, 50))	('tumor', 'Disease', (87, 92))	('circ-CPA4', 'Gene', (26, 35))	('mice', 'Species', '10090', (101, 105))	('hampered', 'NegReg', (36, 44))	('NSCLC', 'Phenotype', 'HP:0030358', (62, 67))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('let-7 miRNA/PD-L1 axis', 'MPA', (127, 149))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('silencing', 'Var', (13, 22))
197960	32746878	The above results suggested that deficiency of circ-CPA4 inhibited NSCLC cell growth and promoted cell death in vitro and in vivo by targeting let-7 miRNA/PD-L1 axis.	('cell death', 'CPA', (98, 108))	('targeting', 'Reg', (133, 142))	('inhibited', 'NegReg', (57, 66))	('NSCLC', 'Phenotype', 'HP:0030358', (67, 72))	('circ-CPA4', 'Gene', (47, 56))	('promoted', 'PosReg', (89, 97))	('NSCLC', 'Disease', (67, 72))	('deficiency', 'Var', (33, 43))	('let-7', 'Protein', (143, 148))	('NSCLC', 'Disease', 'MESH:D002289', (67, 72))
197962	32746878	As expected, the transwell assay results showed that knock-down of circ-CPA4 inhibited the invasion ability of NSCLC cells (A549 and H1299), which were reversed by knocking down let-7 miRNA and upregulating PD-L1 (Fig.	('knocking down', 'Var', (164, 177))	('PD-L1', 'Gene', (207, 212))	('circ-CPA4', 'Gene', (67, 76))	('NSCLC', 'Disease', (111, 116))	('inhibited', 'NegReg', (77, 86))	('miRNA', 'Protein', (184, 189))	('A549', 'CellLine', 'CVCL:0023', (124, 128))	('NSCLC', 'Disease', 'MESH:D002289', (111, 116))	('H1299', 'CellLine', 'CVCL:0060', (133, 138))	('let-7', 'Gene', (178, 183))	('knock-down', 'Var', (53, 63))	('NSCLC', 'Phenotype', 'HP:0030358', (111, 116))	('upregulating', 'PosReg', (194, 206))
197964	32746878	7c-f), and the results showed that knock-down of circ-CPA4 inhibited the expressions of N-cadherin and Vimentin, which were also increased by knocking down let-7 miRNA and upregulating PD-L1 in A549 and H1299 cells (Fig.	('H1299', 'CellLine', 'CVCL:0060', (203, 208))	('miRNA', 'Protein', (162, 167))	('N-cadherin', 'Gene', '1000', (88, 98))	('Vimentin', 'Gene', (103, 111))	('let-7', 'Gene', (156, 161))	('inhibited', 'NegReg', (59, 68))	('knocking', 'Var', (142, 150))	('increased', 'PosReg', (129, 138))	('Vimentin', 'Gene', '7431', (103, 111))	('upregulating', 'PosReg', (172, 184))	('expressions', 'MPA', (73, 84))	('PD-L1', 'Gene', (185, 190))	('N-cadherin', 'Gene', (88, 98))	('A549', 'CellLine', 'CVCL:0023', (194, 198))	('circ-CPA4', 'Gene', (49, 58))
197968	32746878	Interestingly, CD8+ T cell viability was decreased in the co-culturing system, and silencing of PD-L1 in NSCLC cells or PD-L1/PD-1 blockade by their corresponding antibodies significantly promoted cell proliferation (Fig.	('NSCLC', 'Disease', 'MESH:D002289', (105, 110))	('CD8', 'Gene', '925', (15, 18))	('NSCLC', 'Phenotype', 'HP:0030358', (105, 110))	('promoted', 'PosReg', (188, 196))	('PD-1', 'Gene', (126, 130))	('PD-1', 'Gene', '5133', (126, 130))	('cell proliferation', 'CPA', (197, 215))	('PD-L1', 'Gene', (96, 101))	('NSCLC', 'Disease', (105, 110))	('CD8', 'Gene', (15, 18))	('silencing', 'Var', (83, 92))
197970	32746878	Furthermore, PD-L1 ablation also increased the expression levels of IFN-gamma and IL-4, while inhibited IL-10 expressions in CD8+ T cells (Fig.	('inhibited', 'NegReg', (94, 103))	('ablation', 'Var', (19, 27))	('IL-4', 'Gene', (82, 86))	('expression levels', 'MPA', (47, 64))	('IL-10', 'Gene', '3586', (104, 109))	('IL-4', 'Gene', '3565', (82, 86))	('increased', 'PosReg', (33, 42))	('PD-L1', 'Gene', (13, 18))	('expressions', 'MPA', (110, 121))	('IFN-gamma', 'Gene', '3458', (68, 77))	('CD8', 'Gene', (125, 128))	('IL-10', 'Gene', (104, 109))	('CD8', 'Gene', '925', (125, 128))	('IFN-gamma', 'Gene', (68, 77))
197976	32746878	In addition, silencing of circ-CPA4 in NSCLC cells activated CD8+ T cells in the co-culturing system (Fig.	('NSCLC', 'Phenotype', 'HP:0030358', (39, 44))	('CD8', 'Gene', (61, 64))	('CD8', 'Gene', '925', (61, 64))	('circ-CPA4', 'Gene', (26, 35))	('NSCLC', 'Disease', (39, 44))	('activated', 'PosReg', (51, 60))	('NSCLC', 'Disease', 'MESH:D002289', (39, 44))	('silencing', 'Var', (13, 22))
197979	32746878	The above results suggested that knock-down of circ-CPA4 in NSCLC cells promoted CD8+ T cell expansion and activation in the co-culturing system.	('CD8', 'Gene', (81, 84))	('CD8', 'Gene', '925', (81, 84))	('circ-CPA4', 'Gene', (47, 56))	('NSCLC', 'Disease', (60, 65))	('NSCLC', 'Phenotype', 'HP:0030358', (60, 65))	('NSCLC', 'Disease', 'MESH:D002289', (60, 65))	('knock-down', 'Var', (33, 43))	('promoted', 'PosReg', (72, 80))	('activation', 'CPA', (107, 117))
197987	32746878	Next, based on the previous studies, we also uncovered the regulating mechanisms of circ-CPA4, let-7 miRNA and PD-L1 in NSCLC cells, and found that circ-CPA4 overexpression promoted PD-L1 expressions by acting as RNA sponges for let-7 miRNA.	('expressions', 'MPA', (188, 199))	('NSCLC', 'Disease', 'MESH:D002289', (120, 125))	('promoted', 'PosReg', (173, 181))	('NSCLC', 'Phenotype', 'HP:0030358', (120, 125))	('circ-CPA4', 'Var', (148, 157))	('PD-L1', 'Gene', (182, 187))	('NSCLC', 'Disease', (120, 125))
197988	32746878	Furthermore, the gain-and-loss of function experiments validated that knock-down of circ-CPA4 inhibited NSCLC cell growth, mobility, EMT and tumorigenesis, and promoted cell death by regulating let-7 miRNA/PD-L1 axis in vitro and in vivo.	('let-7 miRNA/PD-L1 axis', 'Pathway', (194, 216))	('promoted', 'PosReg', (160, 168))	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('inhibited', 'NegReg', (94, 103))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('circ-CPA4', 'Gene', (84, 93))	('NSCLC', 'Disease', (104, 109))	('regulating', 'Reg', (183, 193))	('tumor', 'Disease', (141, 146))	('knock-down', 'Var', (70, 80))	('NSCLC', 'Disease', 'MESH:D002289', (104, 109))	('cell death', 'CPA', (169, 179))	('NSCLC', 'Phenotype', 'HP:0030358', (104, 109))	('mobility', 'CPA', (123, 131))
197989	32746878	The above results were in accordance with the previous data, and indicated that knock-down of circ-CPA4 inhibited NSCLC progression by inhibiting PD-L1 through releasing let-7 miRNA.	('NSCLC', 'Phenotype', 'HP:0030358', (114, 119))	('NSCLC', 'Disease', (114, 119))	('knock-down', 'Var', (80, 90))	('releasing', 'PosReg', (160, 169))	('inhibiting', 'NegReg', (135, 145))	('PD-L1', 'MPA', (146, 151))	('NSCLC', 'Disease', 'MESH:D002289', (114, 119))	('let-7 miRNA', 'MPA', (170, 181))	('inhibited', 'NegReg', (104, 113))	('circ-CPA4', 'Gene', (94, 103))
197994	32746878	Interestingly, the above results were also validated in NSCLC cells, and we found that NSCLC cells derived exosomes increased resistance of NSCLC cells to cisplatin treatment and upregulated stemness associated signatures (OCT4, SOX2, Nanog and ALDH1), which were all abrogated by treating cells with anti-PD-L1 antibody, indicating that NSCLC cells derived PD-L1 exosomes self-regulated cell stemness to increase resistance of NSCLC cells to cisplatin, and blockade of PD-L1 sensitized chemoresistant NSCLC cells to cisplatin, which were in accordance with the previous data.	('OCT4', 'Gene', '5460', (223, 227))	('NSCLC', 'Disease', (87, 92))	('blockade', 'Var', (458, 466))	('NSCLC', 'Disease', (56, 61))	('increase', 'PosReg', (405, 413))	('NSCLC', 'Disease', (428, 433))	('ALDH1', 'Gene', '216', (245, 250))	('cisplatin', 'Chemical', 'MESH:D002945', (517, 526))	('NSCLC', 'Phenotype', 'HP:0030358', (87, 92))	('NSCLC', 'Phenotype', 'HP:0030358', (56, 61))	('OCT4', 'Gene', (223, 227))	('NSCLC', 'Disease', 'MESH:D002289', (140, 145))	('NSCLC', 'Phenotype', 'HP:0030358', (428, 433))	('Nanog', 'Gene', '79923', (235, 240))	('Nanog', 'Gene', (235, 240))	('upregulated', 'PosReg', (179, 190))	('NSCLC', 'Disease', 'MESH:D002289', (338, 343))	('sensitized', 'Reg', (476, 486))	('NSCLC', 'Disease', (140, 145))	('resistance', 'MPA', (414, 424))	('cisplatin', 'Chemical', 'MESH:D002945', (443, 452))	('ALDH1', 'Gene', (245, 250))	('NSCLC', 'Disease', (338, 343))	('SOX2', 'Gene', '6657', (229, 233))	('chemoresistant', 'CPA', (487, 501))	('NSCLC', 'Disease', 'MESH:D002289', (502, 507))	('SOX2', 'Gene', (229, 233))	('NSCLC', 'Phenotype', 'HP:0030358', (140, 145))	('NSCLC', 'Phenotype', 'HP:0030358', (338, 343))	('cisplatin', 'Chemical', 'MESH:D002945', (155, 164))	('NSCLC', 'Disease', (502, 507))	('NSCLC', 'Disease', 'MESH:D002289', (87, 92))	('NSCLC', 'Disease', 'MESH:D002289', (56, 61))	('PD-L1', 'Gene', (470, 475))	('NSCLC', 'Disease', 'MESH:D002289', (428, 433))
198000	32746878	As expected, the NSCLC cells with circ-CPA4 ablation increased CD8+ T cell proliferation and activity, but circ-CPA4 overexpression had opposite effects.	('NSCLC', 'Disease', (17, 22))	('activity', 'CPA', (93, 101))	('ablation', 'Var', (44, 52))	('NSCLC', 'Disease', 'MESH:D002289', (17, 22))	('increased', 'PosReg', (53, 62))	('CD8', 'Gene', (63, 66))	('CD8', 'Gene', '925', (63, 66))	('NSCLC', 'Phenotype', 'HP:0030358', (17, 22))
198001	32746878	The above in vitro results indicated that knock-down of circ-CPA4 in NSCLC cells activated CD8+ T cells in tumor microenvironment by downregulating secreted PD-L1.	('downregulating', 'NegReg', (133, 147))	('CD8', 'Gene', (91, 94))	('CD8', 'Gene', '925', (91, 94))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('knock-down', 'Var', (42, 52))	('NSCLC', 'Disease', (69, 74))	('activated', 'PosReg', (81, 90))	('NSCLC', 'Disease', 'MESH:D002289', (69, 74))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('circ-CPA4', 'Gene', (56, 65))	('NSCLC', 'Phenotype', 'HP:0030358', (69, 74))
198014	32013250	In conclusion, this study indicates that (+)-usnic acid induces apoptosis of LUSC cells through ROS accumulation, probably via disrupting the mitochondrial respiratory chain (MRC) and the PI3K/Akt/Nrf2 pathway.	('Akt', 'Gene', '207', (193, 196))	('(+)-usnic acid', 'Chemical', 'MESH:C073339', (41, 55))	('Nrf2', 'Gene', (197, 201))	('ROS', 'Chemical', 'MESH:D017382', (96, 99))	('Akt', 'Gene', (193, 196))	('accumulation', 'PosReg', (100, 112))	('ROS', 'Protein', (96, 99))	('+)-usnic', 'Var', (42, 50))	('apoptosis', 'CPA', (64, 73))	('disrupting', 'NegReg', (127, 137))	('LUSC', 'Phenotype', 'HP:0030359', (77, 81))	('Nrf2', 'Gene', '4780', (197, 201))	('mitochondrial respiratory', 'MPA', (142, 167))
198037	32013250	Exposure of H520 and Calu-1 cells to (+)-usnic acid led to a significant increase in apoptosis in a dose-dependent manner after 24-hour treatment (Figure 2A).	('Calu-1', 'CellLine', 'CVCL:0608', (21, 27))	('increase', 'PosReg', (73, 81))	('(+)-usnic acid', 'Chemical', 'MESH:C073339', (37, 51))	('apoptosis', 'CPA', (85, 94))	('+)-usnic', 'Var', (38, 46))
198060	32013250	Therefore, these data strongly support that (+)-usnic acid induces apoptosis in LUSC cells, partially by inhibiting Nrf2 expression and accumulating ROS.	('inhibiting', 'NegReg', (105, 115))	('ROS', 'MPA', (149, 152))	('Nrf2', 'Gene', (116, 120))	('LUSC', 'Phenotype', 'HP:0030359', (80, 84))	('expression', 'MPA', (121, 131))	('ROS', 'Chemical', 'MESH:D017382', (149, 152))	('(+)-usnic acid', 'Chemical', 'MESH:C073339', (44, 58))	('+)-usnic', 'Var', (45, 53))	('Nrf2', 'Gene', '4780', (116, 120))	('accumulating', 'PosReg', (136, 148))
198065	32013250	After 8-hour administration, the selective PI3K/Akt pathway inhibitor LY294002 (30 microM) produced a similar inhibition of Nrf2 expression compared with (+)-usnic acid (Figure 6B).	('inhibition', 'NegReg', (110, 120))	('Akt', 'Gene', (48, 51))	('expression', 'MPA', (129, 139))	('Nrf2', 'Gene', '4780', (124, 128))	('LY294002', 'Var', (70, 78))	('(+)-usnic acid', 'Chemical', 'MESH:C073339', (154, 168))	('Akt', 'Gene', '207', (48, 51))	('Nrf2', 'Gene', (124, 128))	('LY294002', 'Chemical', 'MESH:C085911', (70, 78))
198066	32013250	When the PI3K/Akt signaling was inhibited by LY294002, (+)-usnic acid treatment did not exert additional inhibition of PI3K/Akt activity compared with LY294002 alone (Figure 6B).	('LY294002', 'Var', (45, 53))	('Akt', 'Gene', (14, 17))	('Akt', 'Gene', (124, 127))	('inhibited', 'NegReg', (32, 41))	('(+)-usnic acid', 'Chemical', 'MESH:C073339', (55, 69))	('LY294002', 'Chemical', 'MESH:C085911', (151, 159))	('LY294002', 'Chemical', 'MESH:C085911', (45, 53))	('Akt', 'Gene', '207', (14, 17))	('Akt', 'Gene', '207', (124, 127))
198077	32013250	The combination of (+)-usnic acid and paclitaxel produced greater inhibition of tumor growth compared with either agent administration.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('inhibition', 'NegReg', (66, 76))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('(+)-usnic acid', 'Chemical', 'MESH:C073339', (19, 33))	('tumor', 'Disease', (80, 85))	('paclitaxel', 'Chemical', 'MESH:D017239', (38, 48))	('+)-usnic acid', 'Var', (20, 33))
198082	32013250	The findings indicate that (+)-usnic acid induces apoptosis of LUSC cells through ROS accumulation.	('(+)-usnic acid', 'Chemical', 'MESH:C073339', (27, 41))	('LUSC', 'Phenotype', 'HP:0030359', (63, 67))	('ROS', 'Chemical', 'MESH:D017382', (82, 85))	('ROS accumulation', 'Protein', (82, 98))	('+)-usnic', 'Var', (28, 36))	('apoptosis', 'CPA', (50, 59))
198083	32013250	Besides, our study also supports that a combination treatment of (+)-usnic acid and paclitaxel produces a synergistic anticancer effect in LUSC.	('LUSC', 'Phenotype', 'HP:0030359', (139, 143))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('paclitaxel', 'Chemical', 'MESH:D017239', (84, 94))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('+)-usnic', 'Var', (66, 74))	('(+)-usnic acid', 'Chemical', 'MESH:C073339', (65, 79))
198086	32013250	In the present study, we found that (+)-usnic acid inhibited the viability of LUSC cells and induced apoptosis.	('(+)-usnic acid', 'Chemical', 'MESH:C073339', (36, 50))	('+)-usnic acid', 'Var', (37, 50))	('LUSC', 'Phenotype', 'HP:0030359', (78, 82))	('apoptosis', 'CPA', (101, 110))	('inhibited', 'NegReg', (51, 60))	('viability of LUSC cells', 'CPA', (65, 88))	('induced', 'Reg', (93, 100))
198088	32013250	These results demonstrate that (+)-usnic acid can induce apoptosis in LUSC cells via ROS accumulation.	('ROS', 'Protein', (85, 88))	('(+)-usnic acid', 'Chemical', 'MESH:C073339', (31, 45))	('LUSC', 'Phenotype', 'HP:0030359', (70, 74))	('apoptosis', 'CPA', (57, 66))	('+)-usnic acid', 'Var', (32, 45))	('ROS', 'Chemical', 'MESH:D017382', (85, 88))
198098	32013250	These results indicate that inhibition of Nrf2 is also critically involved in the (+)-usnic acid-induced ROS burst and resultant LUSC cell apoptosis.	('Nrf2', 'Gene', '4780', (42, 46))	('LUSC cell apoptosis', 'CPA', (129, 148))	('inhibition', 'Var', (28, 38))	('involved', 'Reg', (66, 74))	('ROS burst', 'MPA', (105, 114))	('LUSC', 'Phenotype', 'HP:0030359', (129, 133))	('ROS', 'Chemical', 'MESH:D017382', (105, 108))	('Nrf2', 'Gene', (42, 46))	('(+)-usnic acid', 'Chemical', 'MESH:C073339', (82, 96))
198099	32013250	This study found that (+)-usnic acid reduced Nrf2 expression at the protein level but not the mRNA level, suggesting that (+)-usnic acid may interfere with Nrf2 stability in LUSC cells.	('stability', 'MPA', (161, 170))	('Nrf2', 'Gene', '4780', (45, 49))	('+)-usnic', 'Var', (123, 131))	('(+)-usnic acid', 'Chemical', 'MESH:C073339', (22, 36))	('Nrf2', 'Gene', (45, 49))	('Nrf2', 'Gene', '4780', (156, 160))	('(+)-usnic acid', 'Chemical', 'MESH:C073339', (122, 136))	('interfere', 'NegReg', (141, 150))	('reduced', 'NegReg', (37, 44))	('LUSC', 'Phenotype', 'HP:0030359', (174, 178))	('expression', 'MPA', (50, 60))	('Nrf2', 'Gene', (156, 160))
198105	32013250	Accumulation of ROS by paclitaxel contributes largely to its cytotoxicity in cancer cells, and inhibition of Nrf2 enhances its efficacy in cancer cells.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('cytotoxicity', 'Disease', (61, 73))	('Nrf2', 'Gene', (109, 113))	('inhibition', 'Var', (95, 105))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('Nrf2', 'Gene', '4780', (109, 113))	('efficacy', 'MPA', (127, 135))	('cytotoxicity', 'Disease', 'MESH:D064420', (61, 73))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('ROS', 'Chemical', 'MESH:D017382', (16, 19))	('paclitaxel', 'Chemical', 'MESH:D017239', (23, 33))	('ROS', 'Protein', (16, 19))	('enhances', 'PosReg', (114, 122))	('cancer', 'Disease', (139, 145))
198106	32013250	In this study, we found that combining (+)-usnic acid and paclitaxel resulted in synergistic effects on viability inhibition in LUSC cells.	('LUSC', 'Phenotype', 'HP:0030359', (128, 132))	('viability inhibition', 'CPA', (104, 124))	('(+)-usnic acid', 'Chemical', 'MESH:C073339', (39, 53))	('+)-usnic acid', 'Var', (40, 53))	('paclitaxel', 'Chemical', 'MESH:D017239', (58, 68))
198196	30271214	In the multivariable Cox analysis, the patients' age at diagnosis, sex, tumor location, tumor grade, yp-T stage, and yp- mLNRS can independently predict patients' DSS (Table 2).	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('predict', 'Reg', (145, 152))	('patients', 'Species', '9606', (39, 47))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('patients', 'Species', '9606', (153, 161))	('tumor', 'Disease', (72, 77))	('yp- mLNRS', 'Var', (117, 126))	('DSS', 'Chemical', '-', (163, 166))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('DSS', 'MPA', (163, 166))	('tumor', 'Disease', (88, 93))
198246	26893682	A defective Fer-1 gene results in infertility, due to abnormal membrane fusion processes during the development of sperm.	('infertility', 'Disease', (34, 45))	('membrane fusion processes', 'CPA', (63, 88))	('Fer-1', 'Gene', (12, 17))	('results in', 'Reg', (23, 33))	('infertility', 'Disease', 'MESH:D007247', (34, 45))	('defective', 'Var', (2, 11))	('infertility', 'Phenotype', 'HP:0000789', (34, 45))
198255	26893682	In vitro, depletion of myoferlin induces a mesenchymal to epithelial transition and reduces cancer cell invasiveness.	('induces', 'Reg', (33, 40))	('myoferlin', 'Gene', '26509', (23, 32))	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('depletion', 'Var', (10, 19))	('myoferlin', 'Gene', (23, 32))	('reduces', 'NegReg', (84, 91))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('mesenchymal to epithelial transition', 'CPA', (43, 79))
198358	26893682	In a previous study, Sun et al reported clinically relevant mutations associated with pulmonary adenocarcinoma in 10 genes, EGFR, tumor protein p53, KRAS, ribosomal protein S6 kinase beta-2, Ataxin-2, DHX9, tyrosine-protein phosphatase non-receptor type 13, specificity protein 1*, spectrin alpha non-erythrocytic 1 and myoferlin (MYOF) using sequencing analysis.	('pulmonary adenocarcinoma', 'Disease', (86, 110))	('KRAS', 'Gene', (149, 153))	('pulmonary adenocarcinoma', 'Disease', 'MESH:D008175', (86, 110))	('Ataxin-2', 'Gene', '6311', (191, 199))	('tyrosine-protein phosphatase non-receptor type 13, specificity protein 1', 'Gene', '5783;6667', (207, 279))	('tumor', 'Disease', (130, 135))	('MYOF', 'Gene', (331, 335))	('spectrin alpha non-erythrocytic 1', 'Gene', '6709', (282, 315))	('DHX9', 'Gene', '1660', (201, 205))	('p53', 'Gene', '7157', (144, 147))	('EGFR', 'Gene', '1956', (124, 128))	('MYOF', 'Gene', '26509', (331, 335))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('associated', 'Reg', (70, 80))	('ribosomal protein S6 kinase beta-2', 'Gene', '6199', (155, 189))	('DHX9', 'Gene', (201, 205))	('p53', 'Gene', (144, 147))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('ribosomal protein S6 kinase beta-2', 'Gene', (155, 189))	('myoferlin', 'Gene', '26509', (320, 329))	('myoferlin', 'Gene', (320, 329))	('Ataxin-2', 'Gene', (191, 199))	('EGFR', 'Gene', (124, 128))	('KRAS', 'Gene', '3845', (149, 153))	('pulmonary adenocarcinoma', 'Phenotype', 'HP:0030078', (86, 110))	('spectrin alpha non-erythrocytic 1', 'Gene', (282, 315))	('mutations', 'Var', (60, 69))
198364	26893682	Yu et al and Bernatchez et al have previously reported that the physiological function of myoferlin is to regulate VEGFR-2 stability and activity; loss of myoferlin reduces the expression and autophosphorylation of VEGFR-2 in endothelial cells.	('myoferlin', 'Gene', (90, 99))	('reduces', 'NegReg', (165, 172))	('myoferlin', 'Gene', (155, 164))	('VEGFR-2', 'Gene', '3791', (115, 122))	('autophosphorylation', 'MPA', (192, 211))	('loss', 'Var', (147, 151))	('VEGFR-2', 'Gene', '3791', (215, 222))	('VEGFR-2', 'Gene', (115, 122))	('myoferlin', 'Gene', '26509', (155, 164))	('expression', 'MPA', (177, 187))	('VEGFR-2', 'Gene', (215, 222))	('myoferlin', 'Gene', '26509', (90, 99))
198436	33524217	Compared with other CUPs (median OS, 15.6; 95% CI, 13.4-17.9 months), patients with BCUP appeared to have poorer survival (HR, 1.18; 95% CI, 0.7-1.9; p = .43), and patients with LNCUP had a significantly better survival (HR, 0.51; 95% CI, 0.4-0.9; p < .001).	('patients', 'Species', '9606', (70, 78))	('poorer', 'NegReg', (106, 112))	('survival', 'MPA', (211, 219))	('BCUP', 'Var', (84, 88))	('OS', 'Gene', '17451', (33, 35))	('survival', 'MPA', (113, 121))	('better', 'PosReg', (204, 210))	('patients', 'Species', '9606', (164, 172))
198471	33524217	Although not readily available retrospectively, having an understanding of these tumors' mutational burden or mismatch repair deficiencies may elucidate a greater understanding of immunotherapy treatment options for these difficult-to-treat tumors.	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('tumors', 'Disease', (81, 87))	('deficiencies', 'Var', (126, 138))	('mismatch repair', 'Gene', (110, 125))	('tumors', 'Disease', (241, 247))	('tumors', 'Disease', 'MESH:D009369', (241, 247))	('tumors', 'Phenotype', 'HP:0002664', (241, 247))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))
198497	33650665	Zhai and coworkers also confirmed that when PLCE1 is knocked out, the transcriptional activity of SNAIL is particularly repressed.	('knocked out', 'Var', (53, 64))	('SNAIL', 'Gene', '6615', (98, 103))	('PLCE1', 'Gene', (44, 49))	('SNAIL', 'Gene', (98, 103))	('transcriptional activity', 'MPA', (70, 94))	('PLCE1', 'Gene', '51196', (44, 49))	('repressed', 'NegReg', (120, 129))
198537	33650665	Furthermore, the pathway analysis revealed that upregulated genes were involved in the metabolism of lipids, asparagine N-linked glycosylation, and constitutive signaling by AKT1 E17K in cancer (Fig.	('cancer', 'Disease', 'MESH:D009369', (187, 193))	('E17K', 'Var', (179, 183))	('cancer', 'Disease', (187, 193))	('AKT1', 'Gene', (174, 178))	('E17K', 'SUBSTITUTION', 'None', (179, 183))	('N', 'Chemical', 'MESH:D009584', (120, 121))	('asparagine N-linked glycosylation', 'MPA', (109, 142))	('metabolism of lipids', 'MPA', (87, 107))	('asparagine', 'Chemical', 'MESH:D001216', (109, 119))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('constitutive signaling', 'MPA', (148, 170))	('upregulated', 'PosReg', (48, 59))	('lipids', 'Chemical', 'MESH:D008055', (101, 107))	('AKT1', 'Gene', '207', (174, 178))
198539	33650665	5A-C, TUNEL and JC-1 staining experiments showed that the apoptosis rate of ESCC cells was markedly increased, whereas proliferation was significantly suppressed according to the EdU assays when PLCE1 was knocked down in the Eca109 ESCC cells.	('increased', 'PosReg', (100, 109))	('suppressed', 'NegReg', (151, 161))	('apoptosis rate', 'CPA', (58, 72))	('PLCE1', 'Gene', (195, 200))	('PLCE1', 'Gene', '51196', (195, 200))	('knocked down', 'Var', (205, 217))	('EdU', 'Chemical', '-', (179, 182))	('proliferation', 'CPA', (119, 132))	('N', 'Chemical', 'MESH:D009584', (8, 9))
198571	33650665	For instance, Li et al revealed that regulation of ZFAS1 by overexpression of miRNA-124 may mediate ESCC proliferation, invasion, migration, and apoptosis.	('regulation', 'Var', (37, 47))	('ZFAS1', 'Gene', (51, 56))	('miRNA-124', 'Gene', (78, 87))	('mediate', 'Reg', (92, 99))	('N', 'Chemical', 'MESH:D009584', (81, 82))	('overexpression', 'PosReg', (60, 74))	('invasion', 'CPA', (120, 128))	('ESCC', 'Disease', (100, 104))	('ZFAS1', 'Gene', '441951', (51, 56))	('migration', 'CPA', (130, 139))	('apoptosis', 'CPA', (145, 154))
198574	33650665	Additionally, a previous report indicated that HOTAIRM1 functions as a ceRNA to regulate the expression of miR-129-5p and miR-495-3p in glioma progression and is positively correlated with OS in glioma patients.	('glioma', 'Phenotype', 'HP:0009733', (195, 201))	('miR-129-5p', 'Gene', (107, 117))	('N', 'Chemical', 'MESH:D009584', (74, 75))	('glioma', 'Disease', 'MESH:D005910', (136, 142))	('HOTAIRM1', 'Gene', '100506311', (47, 55))	('correlated', 'Reg', (173, 183))	('HOTAIRM1', 'Gene', (47, 55))	('glioma', 'Disease', 'MESH:D005910', (195, 201))	('patients', 'Species', '9606', (202, 210))	('expression', 'MPA', (93, 103))	('glioma', 'Disease', (136, 142))	('glioma', 'Disease', (195, 201))	('miR-129-5p', 'Gene', '100302178', (107, 117))	('miR-495-3p', 'Var', (122, 132))	('glioma', 'Phenotype', 'HP:0009733', (136, 142))
198577	33650665	In our previous research, 14 DEmiRNAs in the ceRNA network were identified, among which hsa-miR-17-5p, hsa-miR-22-3p, and hsa-miR-1297 have been reported to be involved in tumorigenesis; hsa-miR-301b-3p and hsa-miR-455-5p have also been verified to be highly expressed in ESCA from the TCGA database (Fig.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('hsa-miR-17', 'Gene', '406952', (88, 98))	('hsa-miR-1297', 'Gene', (122, 134))	('hsa-miR-301b-3p', 'Var', (187, 202))	('tumor', 'Disease', (172, 177))	('hsa-miR-455', 'Gene', (207, 218))	('hsa-miR-22', 'Gene', (103, 113))	('ESCA', 'Disease', (272, 276))	('N', 'Chemical', 'MESH:D009584', (34, 35))	('hsa-miR-17', 'Gene', (88, 98))	('N', 'Chemical', 'MESH:D009584', (48, 49))	('hsa-miR-455', 'Gene', '619556', (207, 218))	('hsa-miR-22', 'Gene', '407004', (103, 113))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('hsa-miR-1297', 'Gene', '100302187', (122, 134))	('involved', 'Reg', (160, 168))
198610	32705281	Of note, the severity of COVID-19 shows a positive association with certain comorbidities which affect these tissues/systems, including asthma, obesity, diabetes and cancer.	('cancer', 'Disease', (166, 172))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('diabetes', 'Disease', 'MESH:D003920', (153, 161))	('asthma', 'Phenotype', 'HP:0002099', (136, 142))	('severity', 'Var', (13, 21))	('obesity', 'Phenotype', 'HP:0001513', (144, 151))	('COVID-19', 'Disease', 'MESH:C000657245', (25, 33))	('positive', 'PosReg', (42, 50))	('obesity', 'Disease', 'MESH:D009765', (144, 151))	('diabetes', 'Disease', (153, 161))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('obesity', 'Disease', (144, 151))	('COVID-19', 'Disease', (25, 33))	('asthma', 'Disease', 'MESH:D001249', (136, 142))	('asthma', 'Disease', (136, 142))
198611	32705281	Fusion of the SARS-CoV-2 spike proteins with the host transmembrane receptor angiotensin-converting enzyme 2 (ACE2) is shown to instigate spike protein cleavage through interaction with cellular proteases, such as transmembrane protease serine 2 (TMPRSS2), consequently allowing viral entry into the host cell.	('transmembrane receptor', 'Gene', (54, 76))	('angiotensin-converting enzyme 2', 'Gene', (77, 108))	('Fusion', 'Var', (0, 6))	('transmembrane protease serine 2', 'Gene', (214, 245))	('allowing', 'Reg', (270, 278))	('TMPRSS2', 'Gene', (247, 254))	('interaction', 'Interaction', (169, 180))	('SARS-CoV-2', 'Species', '2697049', (14, 24))	('instigate', 'Reg', (128, 137))	('angiotensin-converting enzyme 2', 'Gene', '59272', (77, 108))	('ACE2', 'Gene', (110, 114))	('viral entry', 'MPA', (279, 290))	('transmembrane receptor', 'Gene', '8829', (54, 76))	('TMPRSS2', 'Gene', '7113', (247, 254))	('cleavage', 'MPA', (152, 160))	('transmembrane protease serine 2', 'Gene', '7113', (214, 245))	('spike', 'MPA', (138, 143))	('ACE2', 'Gene', '59272', (110, 114))
198623	32705281	3 presents the GTEx gene expression data regarding the co-expression of ORs with ACE2, TMPRSS2 and CTSL in multiple normal tissues, including the lungs, oesophagus, salivary gland, colon, testis, thyroid and kidney, as well as tissues with established involvement in cardio-metabolic syndrome (e.g., the heart, pancreas and adipose tissue).	('ORs', 'Var', (72, 75))	('cardio-metabolic syndrome', 'Disease', (267, 292))	('TMPRSS2', 'Gene', '7113', (87, 94))	('ACE2', 'Gene', (81, 85))	('involvement', 'Reg', (252, 263))	('CTSL', 'Gene', '1514', (99, 103))	('cardio-metabolic syndrome', 'Disease', 'MESH:D059347', (267, 292))	('TMPRSS2', 'Gene', (87, 94))	('ACE2', 'Gene', '59272', (81, 85))	('CTSL', 'Gene', (99, 103))
198630	32705281	Finally, the data from cBioPortal revealed that the highest level of alterations in the data set for these ORs relates to gene amplification or mutation across the cancer panel (Fig.	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('mutation', 'Var', (144, 152))	('cancer', 'Disease', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('gene amplification', 'Var', (122, 140))
198636	32705281	As such, damage and potential interference with signalling pathways associated with OR functions, as noted for nasal epithelial ORs, may contribute to underlying mechanisms predisposing to adverse COVID-19 related clinical outcomes in patients with certain comorbidities (e.g., asthma or cancer).	('asthma', 'Disease', 'MESH:D001249', (278, 284))	('asthma', 'Disease', (278, 284))	('cancer', 'Disease', 'MESH:D009369', (288, 294))	('COVID-19', 'Disease', (197, 205))	('patients', 'Species', '9606', (235, 243))	('asthma', 'Phenotype', 'HP:0002099', (278, 284))	('damage', 'Var', (9, 15))	('interference', 'NegReg', (30, 42))	('cancer', 'Disease', (288, 294))	('signalling pathways', 'Pathway', (48, 67))	('contribute', 'Reg', (137, 147))	('cancer', 'Phenotype', 'HP:0002664', (288, 294))	('COVID-19', 'Disease', 'MESH:C000657245', (197, 205))
198637	32705281	In addition, our findings suggest potential links which should be explored in the context of male preponderance for severe COVID-19, given that a number of ORs were overexpressed in testes.	('links', 'Interaction', (44, 49))	('COVID-19', 'Disease', (123, 131))	('severe', 'Var', (116, 122))	('COVID-19', 'Disease', 'MESH:C000657245', (123, 131))
198653	32705281	Similarly, OR51E2 interactions were also noted with anoctamin 7 (ANO7), a prostate specific gene associated with aggressive disease; NKX3.1, a pros-tatic tumour suppressor gene; as well as prostate cancer susceptibility candidate 1 (PRAC1).	('tumour', 'Phenotype', 'HP:0002664', (154, 160))	('OR51E2', 'Gene', '81285', (11, 17))	('tumour', 'Disease', 'MESH:D009369', (154, 160))	('aggressive disease', 'Disease', (113, 131))	('interactions', 'Var', (18, 30))	('tumour', 'Disease', (154, 160))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('PRAC1', 'Gene', (233, 238))	('ANO7', 'Gene', (65, 69))	('anoctamin 7', 'Gene', '50636', (52, 63))	('aggressive disease', 'Disease', 'MESH:D001523', (113, 131))	('PRAC1', 'Gene', '84366', (233, 238))	('ANO7', 'Gene', '50636', (65, 69))	('prostate cancer', 'Disease', 'MESH:D011471', (189, 204))	('prostate cancer', 'Phenotype', 'HP:0012125', (189, 204))	('NKX3.1', 'Gene', '4824', (133, 139))	('OR51E2', 'Gene', (11, 17))	('prostate cancer', 'Disease', (189, 204))	('NKX3.1', 'Gene', (133, 139))	('anoctamin 7', 'Gene', (52, 63))
198661	30988278	Ferritinophagy is required for the induction of ferroptosis by the bromodomain protein BRD4 inhibitor (+)-JQ1 in cancer cells (+)-JQ1 is an inhibitor of the tumor-driver bromodomain protein BRD4 and produces satisfactory effects because it efficiently increases apoptosis.	('tumor', 'Disease', (157, 162))	('BRD4', 'Gene', (190, 194))	('Ferritinophagy', 'Disease', 'None', (0, 14))	('Ferritinophagy', 'Disease', (0, 14))	('BRD4', 'Gene', '23476', (87, 91))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('BRD4', 'Gene', '23476', (190, 194))	('cancer', 'Disease', (113, 119))	('+)-JQ1', 'Var', (127, 133))	('BRD4', 'Gene', (87, 91))	('apoptosis', 'CPA', (262, 271))	('increases', 'PosReg', (252, 261))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
198665	30988278	A nude mouse model was used to evaluate the function of (+)-JQ1 in ferroptosis in vivo.	('ferroptosis', 'Disease', (67, 78))	('+)-JQ1', 'Var', (57, 63))	('mouse', 'Species', '10090', (7, 12))
198667	30988278	Furthermore, ferroptosis was induced under (+)-JQ1 treatment and BRD4 knockdown, indicating that (+)-JQ1 induces ferroptosis via BRD4 inhibition.	('BRD4', 'Gene', (129, 133))	('BRD4', 'Gene', '23476', (65, 69))	('+)-JQ1', 'Var', (98, 104))	('inhibition', 'NegReg', (134, 144))	('BRD4', 'Gene', (65, 69))	('ferroptosis', 'CPA', (113, 124))	('BRD4', 'Gene', '23476', (129, 133))
198668	30988278	Moreover, the anticancer effect of (+)-JQ1 was enhanced by ferroptosis inducers.	('enhanced', 'PosReg', (47, 55))	('+)-JQ1', 'Var', (36, 42))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('cancer', 'Disease', (18, 24))	('cancer', 'Disease', 'MESH:D009369', (18, 24))
198669	30988278	Further studies confirmed that (+)-JQ1 induced ferroptosis via ferritinophagy, which featured autophagy enhancement by (+)-JQ1 and increased iron levels.	('enhancement', 'PosReg', (104, 115))	('iron levels', 'MPA', (141, 152))	('increased', 'PosReg', (131, 140))	('+)-JQ1', 'Var', (120, 126))	('iron', 'Chemical', 'MESH:D007501', (141, 145))	('autophagy', 'CPA', (94, 103))	('ferroptosis via ferritinophagy', 'Disease', (47, 77))	('ferroptosis via ferritinophagy', 'Disease', 'None', (47, 77))	('increased iron levels', 'Phenotype', 'HP:0012465', (131, 152))
198671	30988278	In addition, expression of the ferroptosis-associated genes GPX4, SLC7A11, and SLC3A2 was downregulated under (+)-JQ1 treatment and BRD4 knockdown, indicating that (+)-JQ1 may regulate ferroptosis by controlling the expression of ferroptosis-associated genes regulated by BRD4.	('GPX4', 'Gene', '2879', (60, 64))	('ferroptosis-associated', 'Gene', (31, 53))	('BRD4', 'Gene', '23476', (272, 276))	('expression', 'MPA', (13, 23))	('SLC3A2', 'Gene', '6520', (79, 85))	('BRD4', 'Gene', '23476', (132, 136))	('GPX4', 'Gene', (60, 64))	('expression', 'MPA', (216, 226))	('SLC7A11', 'Gene', (66, 73))	('knockdown', 'Var', (137, 146))	('downregulated', 'NegReg', (90, 103))	('SLC7A11', 'Gene', '23657', (66, 73))	('ferroptosis', 'Disease', (185, 196))	('BRD4', 'Gene', (272, 276))	('SLC3A2', 'Gene', (79, 85))	('BRD4', 'Gene', (132, 136))	('regulate', 'Reg', (176, 184))
198672	30988278	Finally, (+)-JQ1 regulated ferritinophagy and the expression of ferroptosis-associated genes via epigenetic inhibition of BRD4 by suppressing the expression of the histone methyltransferase G9a or enhancing the expression of the histone deacetylase SIRT1.	('suppressing', 'NegReg', (130, 141))	('SIRT1', 'Gene', '23411', (249, 254))	('SIRT1', 'Gene', (249, 254))	('epigenetic inhibition', 'Var', (97, 118))	('G9a', 'Gene', (190, 193))	('G9a', 'Gene', '10919', (190, 193))	('BRD4', 'Gene', (122, 126))	('ferroptosis-associated genes', 'Gene', (64, 92))	('histone deacetylase', 'Enzyme', (229, 248))	('BRD4', 'Gene', '23476', (122, 126))	('expression', 'MPA', (146, 156))	('expression', 'MPA', (211, 221))	('expression', 'MPA', (50, 60))	('enhancing', 'PosReg', (197, 206))
198673	30988278	In summary, the BRD4 inhibitor (+)-JQ1 induces ferroptosis via ferritinophagy or the regulation of ferroptosis-associated genes through epigenetic repression of BRD4.	('BRD4', 'Gene', '23476', (161, 165))	('BRD4', 'Gene', (16, 20))	('BRD4', 'Gene', (161, 165))	('epigenetic repression', 'Var', (136, 157))	('ferroptosis via ferritinophagy', 'Disease', (47, 77))	('ferroptosis-associated genes', 'Gene', (99, 127))	('ferroptosis via ferritinophagy', 'Disease', 'None', (47, 77))	('regulation', 'MPA', (85, 95))	('BRD4', 'Gene', '23476', (16, 20))	('induces', 'PosReg', (39, 46))
198679	30988278	Ferroptosis is mainly caused by deficits in the production of reduced glutathione or by the dysfunction of glutathione peroxidase 4 (GPX4), which are ROS eliminators.	('ROS', 'Chemical', 'MESH:D017382', (150, 153))	('GPX4', 'Gene', '2879', (133, 137))	('glutathione peroxidase 4', 'Gene', (107, 131))	('deficits', 'NegReg', (32, 40))	('production of reduced glutathione', 'MPA', (48, 81))	('glutathione', 'Chemical', 'MESH:D005978', (70, 81))	('caused', 'Reg', (22, 28))	('glutathione', 'Chemical', 'MESH:D005978', (107, 118))	('glutathione peroxidase 4', 'Gene', '2879', (107, 131))	('Ferroptosis', 'Disease', (0, 11))	('dysfunction', 'Var', (92, 103))	('GPX4', 'Gene', (133, 137))
198687	30988278	Moreover, JQ1 enhanced ferroptosis via the increase in ferritinophagy or the regulation of ferroptosis-associated genes through BRD4 inhibition.	('BRD4', 'Gene', '23476', (128, 132))	('enhanced', 'PosReg', (14, 22))	('ferroptosis-associated genes', 'Gene', (91, 119))	('inhibition', 'NegReg', (133, 143))	('regulation', 'MPA', (77, 87))	('increase', 'PosReg', (43, 51))	('ferritinophagy', 'MPA', (55, 69))	('JQ1', 'Var', (10, 13))	('BRD4', 'Gene', (128, 132))	('ferroptosis', 'CPA', (23, 34))
198688	30988278	Finally, we found that JQ1 regulated ferritinophagy and ferroptosis-associated genes via epigenetic inhibition of BRD4 by suppressing the expression of the histone methyltransferase G9a or enhancing the expression of the histone deacetylase SIRT1.	('BRD4', 'Gene', (114, 118))	('ferroptosis-associated genes', 'Gene', (56, 84))	('expression', 'MPA', (203, 213))	('enhancing', 'PosReg', (189, 198))	('suppressing', 'NegReg', (122, 133))	('G9a', 'Gene', (182, 185))	('expression', 'MPA', (138, 148))	('BRD4', 'Gene', '23476', (114, 118))	('SIRT1', 'Gene', '23411', (241, 246))	('G9a', 'Gene', '10919', (182, 185))	('SIRT1', 'Gene', (241, 246))	('epigenetic inhibition', 'Var', (89, 110))
198709	30988278	In summary, BRD4 expression is negatively related to the survival of cancer patients, and targeting BRD4 may confer a clinical benefit in cancer patients.	('patients', 'Species', '9606', (145, 153))	('BRD4', 'Gene', (12, 16))	('cancer', 'Disease', (138, 144))	('patients', 'Species', '9606', (76, 84))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('negatively', 'NegReg', (31, 41))	('BRD4', 'Gene', '23476', (100, 104))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('expression', 'MPA', (17, 27))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('BRD4', 'Gene', (100, 104))	('BRD4', 'Gene', '23476', (12, 16))	('targeting', 'Var', (90, 99))	('cancer', 'Disease', (69, 75))	('cancer', 'Disease', 'MESH:D009369', (138, 144))	('benefit', 'PosReg', (127, 134))
198715	30988278	Since JQ1 has been reported to induce apoptosis, we applied Z-VAD-FMK, a pan-caspase inhibitor that can suppress apoptosis to explore the type of death induced by JQ1.	('Z-VAD-FMK', 'Chemical', 'MESH:C096713', (60, 69))	('JQ1', 'Var', (6, 9))	('apoptosis', 'CPA', (38, 47))
198720	30988278	Surprisingly, in cells treated with the combination of Z-VAD-FMK and the inhibitor of ferroptosis, ferrostatin-1 (fer-1), JQ1-induced cell death was inhibited more noticeably than in cells treated with JQ1 plus Z-VAD-FMK (Fig.	('JQ1-induced', 'Gene', (122, 133))	('cell death', 'CPA', (134, 144))	('Z-VAD-FMK', 'Chemical', 'MESH:C096713', (55, 64))	('Z-VAD-FMK', 'Var', (55, 64))	('inhibited', 'NegReg', (149, 158))	('Z-VAD-FMK', 'Chemical', 'MESH:C096713', (211, 220))
198721	30988278	Furthermore, we performed ultrastructural analysis via transmission electron microscopy and observed more swollen mitochondria in the JQ1-treated groups, indicating an increase in intracellular ROS levels with JQ1 treatment (Fig.	('increase', 'PosReg', (168, 176))	('JQ1-treated', 'Gene', (134, 145))	('intracellular ROS levels', 'MPA', (180, 204))	('ROS', 'Chemical', 'MESH:D017382', (194, 197))	('JQ1', 'Var', (210, 213))	('more', 'PosReg', (101, 105))
198723	30988278	Our studies confirmed that the level of malondialdehyde (MDA), which is the final product of lipid peroxidation induced by ROS, was appreciably increased in cancer cell lines treated with JQ1 and was inhibited by treatment with fer-1 (Fig.	('ROS', 'Chemical', 'MESH:D017382', (123, 126))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('ROS', 'Gene', (123, 126))	('lipid', 'Chemical', 'MESH:D008055', (93, 98))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('JQ1', 'Var', (188, 191))	('cancer', 'Disease', (157, 163))	('malondialdehyde', 'MPA', (40, 55))	('malondialdehyde', 'Chemical', 'MESH:D008315', (40, 55))	('increased', 'PosReg', (144, 153))
198724	30988278	In addition, the level of iron was increased in cells treated with JQ1 (Fig.	('JQ1', 'Var', (67, 70))	('increased', 'PosReg', (35, 44))	('iron', 'Chemical', 'MESH:D007501', (26, 30))	('level of iron', 'MPA', (17, 30))
198727	30988278	Furthermore, cell viability was also decreased by knockdown of BRD4, and this decrease was reversed by fer-1 treatment (Fig.	('cell viability', 'CPA', (13, 27))	('BRD4', 'Gene', '23476', (63, 67))	('knockdown', 'Var', (50, 59))	('BRD4', 'Gene', (63, 67))	('decreased', 'NegReg', (37, 46))
198730	30988278	S1e) were increased by BRD4 knockdown (Fig.	('BRD4', 'Gene', (23, 27))	('increased', 'PosReg', (10, 19))	('BRD4', 'Gene', '23476', (23, 27))	('knockdown', 'Var', (28, 37))
198731	30988278	In sum, we can infer that JQ1 induces ferroptosis in vitro through the suppression of BRD4 expression.	('expression', 'MPA', (91, 101))	('ferroptosis', 'Disease', (38, 49))	('JQ1', 'Var', (26, 29))	('BRD4', 'Gene', '23476', (86, 90))	('suppression', 'NegReg', (71, 82))	('BRD4', 'Gene', (86, 90))	('induces', 'Reg', (30, 37))
198735	30988278	Moreover, the weight of the tumors from the JQ1 group was lower than that of the tumors from the control and JQ1 plus fer-1 groups (Fig.	('weight', 'MPA', (14, 20))	('tumors', 'Disease', (81, 87))	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('lower', 'NegReg', (58, 63))	('tumors', 'Disease', (28, 34))	('tumors', 'Disease', 'MESH:D009369', (28, 34))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('JQ1', 'Var', (44, 47))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))
198736	30988278	Immunohistochemistry showed that BRD4 expression in the JQ1 and JQ1 plus fer-1 groups was lower than that in the dimethyl sulfoxide (DMSO) group (Fig.	('JQ1', 'Var', (56, 59))	('BRD4', 'Gene', (33, 37))	('expression', 'MPA', (38, 48))	('DMSO', 'Chemical', 'MESH:D004121', (133, 137))	('lower', 'NegReg', (90, 95))	('BRD4', 'Gene', '23476', (33, 37))	('dimethyl sulfoxide', 'Chemical', 'MESH:D004121', (113, 131))
198738	30988278	As expected, the JQ1 group showed higher levels of iron (Fig.	('levels of iron', 'MPA', (41, 55))	('higher', 'PosReg', (34, 40))	('iron', 'Chemical', 'MESH:D007501', (51, 55))	('JQ1', 'Var', (17, 20))
198741	30988278	Overall, we can infer that JQ1 decreases tumor growth via ferroptosis mediated by BRD4 suppression in vivo.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('suppression', 'NegReg', (87, 98))	('BRD4', 'Gene', (82, 86))	('decreases tumor growth via ferroptosis', 'Disease', (31, 69))	('JQ1', 'Var', (27, 30))	('decreases tumor growth via ferroptosis', 'Disease', 'MESH:D006130', (31, 69))	('BRD4', 'Gene', '23476', (82, 86))
198744	30988278	We discovered that the combination of JQ1 with RSL3 induced cell death to a higher degree than the application of either RSL3 or JQ1 alone (Fig.	('JQ1', 'Var', (38, 41))	('RSL3', 'Chemical', '-', (121, 125))	('cell death', 'CPA', (60, 70))	('combination', 'Interaction', (23, 34))	('RSL3', 'Chemical', '-', (47, 51))
198748	30988278	Moreover, under treatment with the combination of JQ1 and RSL3, erastin, or sorafenib, the levels of iron (Fig.	('sorafenib', 'Chemical', 'MESH:D000077157', (76, 85))	('JQ1', 'Var', (50, 53))	('iron', 'Chemical', 'MESH:D007501', (101, 105))	('erastin', 'Chemical', 'MESH:C477224', (64, 71))	('sorafenib', 'Gene', (76, 85))	('levels of iron', 'MPA', (91, 105))	('RSL3', 'Chemical', '-', (58, 62))
198751	30988278	S3f, h) abilities of BRCA and LUAD cells were reduced more appreciably under treatment with JQ1 plus RSL3 than with either agent alone.	('BRCA', 'Gene', (21, 25))	('RSL3', 'Chemical', '-', (101, 105))	('JQ1', 'Var', (92, 95))	('reduced', 'NegReg', (46, 53))	('BRCA', 'Gene', '672', (21, 25))
198756	30988278	6j), and this effect was enhanced under the combination of JQ1 and RSL3, indicating that ferroptosis also occurs in normal cells.	('RSL3', 'Var', (67, 71))	('enhanced', 'PosReg', (25, 33))	('RSL3', 'Chemical', '-', (67, 71))	('JQ1', 'Var', (59, 62))
198759	30988278	Furthermore, the ratio of LC3B-II/LC3B-I was upregulated and the level of the autophagic cargo SQSTM1/p62 was downregulated under JQ1 treatment (Fig.	('p62', 'Gene', (102, 105))	('LC3B', 'Gene', (34, 38))	('ratio', 'MPA', (17, 22))	('SQSTM1', 'Gene', (95, 101))	('downregulated', 'NegReg', (110, 123))	('LC3B', 'Gene', '81631', (26, 30))	('upregulated', 'PosReg', (45, 56))	('JQ1', 'Var', (130, 133))	('SQSTM1', 'Gene', '8878', (95, 101))	('LC3B', 'Gene', '81631', (34, 38))	('LC3B', 'Gene', (26, 30))	('p62', 'Gene', '8878', (102, 105))
198760	30988278	Moreover, JQ1 treatment and BRD4 knockdown led to decreased FTH1 expression, indicating that JQ1 induces the degradation of FTH1 via BRD4 inhibition (Fig.	('inhibition', 'NegReg', (138, 148))	('FTH1', 'Gene', (60, 64))	('FTH1', 'Gene', '2495', (124, 128))	('BRD4', 'Gene', '23476', (28, 32))	('knockdown', 'Var', (33, 42))	('BRD4', 'Gene', (133, 137))	('decreased', 'NegReg', (50, 59))	('expression', 'MPA', (65, 75))	('degradation', 'MPA', (109, 120))	('BRD4', 'Gene', (28, 32))	('FTH1', 'Gene', (124, 128))	('FTH1', 'Gene', '2495', (60, 64))	('BRD4', 'Gene', '23476', (133, 137))
198761	30988278	In addition, when autophagy was inhibited via knockdown of autophagy-related 5 (ATG5) (Fig.	('autophagy', 'CPA', (18, 27))	('ATG5', 'Gene', '9474', (80, 84))	('knockdown', 'Var', (46, 55))	('inhibited', 'NegReg', (32, 41))	('ATG5', 'Gene', (80, 84))	('autophagy-related 5', 'Gene', (59, 78))	('autophagy-related 5', 'Gene', '9474', (59, 78))
198765	30988278	Furthermore, in cells treated with JQ1, we observed an increase in the iron and ROS levels that was abolished by treatment with JQ1 plus knockdown of either ATG5 (Fig.	('JQ1', 'Var', (35, 38))	('increase', 'PosReg', (55, 63))	('ATG5', 'Gene', (157, 161))	('knockdown', 'Var', (137, 146))	('ATG5', 'Gene', '9474', (157, 161))	('iron', 'Chemical', 'MESH:D007501', (71, 75))	('ROS', 'Chemical', 'MESH:D017382', (80, 83))
198768	30988278	Moreover, we found that the increase in ROS levels induced by JQ1 was alleviated by treatment with the combination of JQ1 plus iron chelator desferrioxamine (DFO) (Fig.	('DFO', 'Chemical', 'MESH:D003676', (158, 161))	('alleviated', 'NegReg', (70, 80))	('JQ1', 'Var', (118, 121))	('JQ1', 'Gene', (62, 65))	('desferrioxamine', 'Chemical', 'MESH:D003676', (141, 156))	('iron', 'Chemical', 'MESH:D007501', (127, 131))	('ROS levels', 'MPA', (40, 50))	('ROS', 'Chemical', 'MESH:D017382', (40, 43))	('increase', 'PosReg', (28, 36))
198769	30988278	7i, yellow and purple columns), indicating that, under JQ1 treatment, the levels of ROS increased via the augmentation of iron levels.	('augmentation', 'PosReg', (106, 118))	('ROS', 'MPA', (84, 87))	('increased', 'PosReg', (88, 97))	('levels', 'MPA', (74, 80))	('JQ1 treatment', 'Var', (55, 68))	('ROS', 'Chemical', 'MESH:D017382', (84, 87))	('iron levels', 'MPA', (122, 133))	('iron', 'Chemical', 'MESH:D007501', (122, 126))
198770	30988278	The viability of cancer cells treated with the combination of JQ1 and knockdown of ATG5 (Fig.	('knockdown', 'Var', (70, 79))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('ATG5', 'Gene', (83, 87))	('cancer', 'Disease', (17, 23))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))	('ATG5', 'Gene', '9474', (83, 87))
198774	30988278	7m) was increased compared to that of cells treated with JQ1 alone; however, treatment with knockdown of ATG5 or ATG7 or treatment with either 3-MA or DFO alone did not enhance cell viability.	('DFO', 'Chemical', 'MESH:D003676', (151, 154))	('knockdown', 'Var', (92, 101))	('ATG5', 'Gene', '9474', (105, 109))	('ATG7', 'Gene', (113, 117))	('3-MA', 'Chemical', 'MESH:C025946', (143, 147))	('ATG5', 'Gene', (105, 109))	('ATG7', 'Gene', '10533', (113, 117))
198779	30988278	The results showed that, when BRD4 expression was knocked down, the expression of GPX4, SLC7A11, and SLC3A2 was downregulated (Fig.	('downregulated', 'NegReg', (112, 125))	('BRD4', 'Gene', '23476', (30, 34))	('GPX4', 'Gene', (82, 86))	('expression', 'MPA', (68, 78))	('SLC7A11', 'Gene', (88, 95))	('SLC3A2', 'Gene', (101, 107))	('GPX4', 'Gene', '2879', (82, 86))	('BRD4', 'Gene', (30, 34))	('SLC7A11', 'Gene', '23657', (88, 95))	('SLC3A2', 'Gene', '6520', (101, 107))	('knocked down', 'Var', (50, 62))
198781	30988278	As expected, the expression levels of GPX4, SLC7A11, and SLC3A2 were decreased under JQ1 treatment (Fig.	('SLC7A11', 'Gene', (44, 51))	('expression levels', 'MPA', (17, 34))	('SLC7A11', 'Gene', '23657', (44, 51))	('SLC3A2', 'Gene', (57, 63))	('GPX4', 'Gene', (38, 42))	('decreased', 'NegReg', (69, 78))	('GPX4', 'Gene', '2879', (38, 42))	('SLC3A2', 'Gene', '6520', (57, 63))	('JQ1', 'Var', (85, 88))
198783	30988278	We found that the protein levels of ATG5 and LAMP1 were increased under treatment with JQ1; however, we did not observe this phenomenon in ribosomal protein S6 kinase (S6K), a downstream effector of mammalian target of rapamycin (Fig.	('S6K', 'Gene', (168, 171))	('protein levels', 'MPA', (18, 32))	('JQ1', 'Var', (87, 90))	('LAMP1', 'Gene', '3916', (45, 50))	('increased', 'PosReg', (56, 65))	('S6K', 'Gene', '6198', (168, 171))	('S6 kinase', 'Gene', '6198', (157, 166))	('ATG5', 'Gene', '9474', (36, 40))	('mammalian target of rapamycin', 'Gene', '2475', (199, 228))	('mammalian target of rapamycin', 'Gene', (199, 228))	('S6 kinase', 'Gene', (157, 166))	('ATG5', 'Gene', (36, 40))	('LAMP1', 'Gene', (45, 50))
198785	30988278	S4g), indicating that JQ1 increases the expression of ATG5 and LAMP1 via the suppression of BRD4 expression, subsequently inducing ferritinophagy.	('expression', 'MPA', (40, 50))	('LAMP1', 'Gene', '3916', (63, 68))	('BRD4', 'Gene', (92, 96))	('JQ1', 'Var', (22, 25))	('ATG5', 'Gene', '9474', (54, 58))	('ferritinophagy', 'CPA', (131, 145))	('LAMP1', 'Gene', (63, 68))	('BRD4', 'Gene', '23476', (92, 96))	('suppression', 'NegReg', (77, 88))	('increases', 'PosReg', (26, 35))	('ATG5', 'Gene', (54, 58))	('expression', 'MPA', (97, 107))	('inducing', 'PosReg', (122, 130))
198786	30988278	In summary, JQ1 induces ferroptosis by controlling ferroptosis-associated genes regulated by BRD4 and may activate ferritinophagy by increasing the ATG5 and LAMP1 expression.	('ATG5', 'Gene', '9474', (148, 152))	('JQ1', 'Var', (12, 15))	('activate', 'PosReg', (106, 114))	('increasing', 'PosReg', (133, 143))	('BRD4', 'Gene', '23476', (93, 97))	('ferroptosis', 'Disease', (24, 35))	('ATG5', 'Gene', (148, 152))	('LAMP1', 'Gene', (157, 162))	('ferritinophagy', 'CPA', (115, 129))	('expression', 'MPA', (163, 173))	('LAMP1', 'Gene', '3916', (157, 162))	('BRD4', 'Gene', (93, 97))	('ferroptosis-associated genes', 'Gene', (51, 79))
198790	30988278	Therefore, upregulation of BRD4 expression in cancer may result from histone methylation or acetylation.	('methylation', 'Var', (77, 88))	('result', 'Reg', (57, 63))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('acetylation', 'MPA', (92, 103))	('cancer', 'Disease', (46, 52))	('BRD4', 'Gene', (27, 31))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('histone', 'Protein', (69, 76))	('expression', 'MPA', (32, 42))	('upregulation', 'PosReg', (11, 23))	('BRD4', 'Gene', '23476', (27, 31))
198792	30988278	As expected, the expression of G9a was downregulated and the expression of SIRT1 was upregulated with JQ1 treatment (Fig.	('SIRT1', 'Gene', '23411', (75, 80))	('upregulated', 'PosReg', (85, 96))	('SIRT1', 'Gene', (75, 80))	('expression', 'MPA', (17, 27))	('JQ1', 'Var', (102, 105))	('G9a', 'Gene', (31, 34))	('expression', 'MPA', (61, 71))	('G9a', 'Gene', '10919', (31, 34))	('downregulated', 'NegReg', (39, 52))
198795	30988278	In addition, we found that, under treatment with BIX-01294 or CAY10602, autophagy markers LC3B-II/LC3B-I was increased but the levels of p62 and FTH1 were decreased (Fig.	('FTH1', 'Gene', (145, 149))	('p62', 'Gene', '8878', (137, 140))	('LC3B', 'Gene', (98, 102))	('LC3B', 'Gene', '81631', (90, 94))	('autophagy', 'CPA', (72, 81))	('p62', 'Gene', (137, 140))	('CAY10602', 'Chemical', '-', (62, 70))	('FTH1', 'Gene', '2495', (145, 149))	('LC3B', 'Gene', '81631', (98, 102))	('LC3B', 'Gene', (90, 94))	('decreased', 'NegReg', (155, 164))	('CAY10602', 'Var', (62, 70))	('BIX-01294', 'Chemical', 'MESH:C518299', (49, 58))	('increased', 'PosReg', (109, 118))	('levels', 'MPA', (127, 133))	('BIX-01294', 'Var', (49, 58))
198798	30988278	9g) were increased under treatment with BIX-01294 or CAY10602, indicating that the initiation of ferritinophagy or alteration of ferroptosis-associated genes by JQ1 may be mediated via suppression of BRD4 through the inhibition of G9a-induced histone methylation or enhancement of SIRT1-induced histone deacetylation.	('BIX-01294', 'Chemical', 'MESH:C518299', (40, 49))	('methylation', 'MPA', (251, 262))	('suppression', 'NegReg', (185, 196))	('SIRT1', 'Gene', '23411', (281, 286))	('BRD4', 'Gene', (200, 204))	('histone deacetylation', 'MPA', (295, 316))	('G9a', 'Gene', '10919', (231, 234))	('SIRT1', 'Gene', (281, 286))	('CAY10602', 'Chemical', '-', (53, 61))	('initiation of ferritinophagy', 'Disease', 'MESH:D007319', (83, 111))	('BRD4', 'Gene', '23476', (200, 204))	('enhancement', 'PosReg', (266, 277))	('histone', 'Protein', (243, 250))	('inhibition', 'NegReg', (217, 227))	('alteration', 'MPA', (115, 125))	('JQ1', 'Gene', (161, 164))	('initiation of ferritinophagy', 'Disease', (83, 111))	('G9a', 'Gene', (231, 234))	('ferroptosis-associated genes', 'Gene', (129, 157))	('CAY10602', 'Var', (53, 61))
198803	30988278	Moreover, in pan-cancer patients, the levels of DNA methylation at both the cg17726535 (Fig.	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('cancer', 'Disease', (17, 23))	('patients', 'Species', '9606', (24, 32))	('DNA methylation', 'MPA', (48, 63))	('cg17726535', 'Var', (76, 86))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
198805	30988278	Thus JQ1 may also induce ferroptosis by inhibiting the BRD4 expression through the enhancement of DNA methylation.	('expression', 'MPA', (60, 70))	('enhancement', 'PosReg', (83, 94))	('BRD4', 'Gene', '23476', (55, 59))	('DNA methylation', 'MPA', (98, 113))	('JQ1', 'Var', (5, 8))	('induce', 'PosReg', (18, 24))	('ferroptosis', 'Disease', (25, 36))	('BRD4', 'Gene', (55, 59))	('inhibiting', 'NegReg', (40, 50))
198814	30988278	However, whether JQ1 induces ferroptosis in cancer cells is unknown.	('ferroptosis', 'Disease', (29, 40))	('induces', 'Reg', (21, 28))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('JQ1', 'Var', (17, 20))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
198815	30988278	Treatment with JQ1 and RSL3, erastin, or sorafenib produced a satisfactory anticancer effect, suggesting that the combination of JQ1 with ferroptosis inducers could become a new therapeutic modality.	('sorafenib', 'Chemical', 'MESH:D000077157', (41, 50))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('RSL3', 'Chemical', '-', (23, 27))	('JQ1', 'Var', (129, 132))	('erastin', 'Chemical', 'MESH:C477224', (29, 36))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))
198821	30988278	Moreover, consistent with the fact that BRD4 could recruit other transcription factors to the acetylated histone to enhance gene expression, we found that the expression levels of the ferroptosis-associated genes GPX4, SLC7A11, and SLC3A2 were decreased under treatment with JQ1.	('BRD4', 'Gene', (40, 44))	('decreased', 'NegReg', (244, 253))	('enhance', 'PosReg', (116, 123))	('SLC3A2', 'Gene', (232, 238))	('expression levels', 'MPA', (159, 176))	('GPX4', 'Gene', (213, 217))	('GPX4', 'Gene', '2879', (213, 217))	('SLC7A11', 'Gene', (219, 226))	('SLC3A2', 'Gene', '6520', (232, 238))	('BRD4', 'Gene', '23476', (40, 44))	('SLC7A11', 'Gene', '23657', (219, 226))	('gene expression', 'MPA', (124, 139))	('JQ1', 'Var', (275, 278))
198875	30988278	The following reagents were purchased from MedChem Express (MonmouthJunction, NJ, USA): 3-MA (CA: HY-19312), BIX-01294 (CA: HY-10587), CAY10602 (CA: HY-104073), DFO (CA: HY-B0988), erastin (CA: HY-15763), fer-1 (CA: HY-100579), JQ1 (CA: HY-13030), nec-1 (CA: HY-15760), RSL3 (CA: HY-100218A), sorafenib (CA: HY-10201), and Z-VAD-FMK (CA: 16658).	('BIX-01294', 'Chemical', 'MESH:C518299', (109, 118))	('DFO', 'Chemical', 'MESH:D003676', (161, 164))	('CA: HY-100218A', 'Var', (276, 290))	('CA: HY-15763', 'Var', (190, 202))	('sorafenib', 'Chemical', 'MESH:D000077157', (293, 302))	('RSL3', 'Chemical', '-', (270, 274))	('CA', 'Var', (94, 96))	('CAY10602', 'Chemical', '-', (135, 143))	('Z-VAD-FMK', 'Chemical', 'MESH:C096713', (323, 332))	('CA: HY-104073', 'Var', (145, 158))	('CA: HY-15760', 'Var', (255, 267))	('3-MA', 'Chemical', 'MESH:C025946', (88, 92))	('CA: HY-10201', 'Var', (304, 316))	('CA: HY-100579', 'Var', (212, 225))	('CA: HY-13030', 'Var', (233, 245))	('erastin', 'Chemical', 'MESH:C477224', (181, 188))	('CA', 'Var', (120, 122))
198904	29212247	Indeed, CA19-9 and CA125 (also known as mucin 16) had the highest sensitivity and specificity, respectively, and a combination of CA19-9 and CEA was shown to be the best for predicting patient prognosis.	('CEA', 'Gene', (141, 144))	('mucin 16', 'Gene', (40, 48))	('CEA', 'Gene', '1084', (141, 144))	('mucin 16', 'Gene', '94025', (40, 48))	('CA19-9', 'Var', (130, 136))	('CA19-9', 'Chemical', 'MESH:C086528', (8, 14))	('CA125', 'Gene', (19, 24))	('patient', 'Species', '9606', (185, 192))	('CA19-9', 'Chemical', 'MESH:C086528', (130, 136))	('CA125', 'Gene', '94025', (19, 24))	('CA19-9', 'Var', (8, 14))
198959	29212247	used a Cox proportional hazards regression analysis to demonstrate that patients with liver cancer having the high expression of SRY-box 1 (SOX-1) had a better prognosis, and the SOX-1 status could be used as a prognostic factor in patients with liver cancer.	('SOX-1', 'Gene', '6656', (179, 184))	('Cox', 'Gene', (7, 10))	('liver cancer', 'Phenotype', 'HP:0002896', (86, 98))	('liver cancer', 'Disease', (86, 98))	('SRY-box 1', 'Gene', '6656', (129, 138))	('SRY-box 1', 'Gene', (129, 138))	('liver cancer', 'Disease', 'MESH:D006528', (246, 258))	('liver cancer', 'Phenotype', 'HP:0002896', (246, 258))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('high expression', 'Var', (110, 125))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('liver cancer', 'Disease', (246, 258))	('Cox', 'Gene', '1351', (7, 10))	('patients', 'Species', '9606', (232, 240))	('liver cancer', 'Disease', 'MESH:D006528', (86, 98))	('SOX-1', 'Gene', (140, 145))	('SOX-1', 'Gene', (179, 184))	('SOX-1', 'Gene', '6656', (140, 145))	('patients', 'Species', '9606', (72, 80))
198982	29212247	TMC8 plays an important role in the transmembrane channel-like domain, and its mutation is associated with high-risk HPV infection and HNSCC survival risk.	('HNSCC', 'Disease', (135, 140))	('HPV infection', 'Disease', 'MESH:D030361', (117, 130))	('TMC8', 'Gene', (0, 4))	('HNSCC', 'Phenotype', 'HP:0012288', (135, 140))	('mutation', 'Var', (79, 87))	('TMC8', 'Gene', '147138', (0, 4))	('HPV infection', 'Disease', (117, 130))	('associated', 'Reg', (91, 101))
199001	33466316	We showed that high iNOS expression is a marker of favorable prognosis for squamous cell lung carcinoma (SCC), and NSCLC in general.	('high', 'Var', (15, 19))	('iNOS', 'Gene', '4843', (20, 24))	('squamous cell lung carcinoma', 'Disease', (75, 103))	('iNOS', 'Gene', (20, 24))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('SCC', 'Phenotype', 'HP:0030359', (105, 108))	('expression', 'MPA', (25, 35))	('NSCLC', 'Disease', (115, 120))	('NSCLC', 'Disease', 'MESH:D002289', (115, 120))	('SCC', 'Phenotype', 'HP:0002860', (105, 108))	('squamous cell lung carcinoma', 'Phenotype', 'HP:0030359', (75, 103))	('squamous cell lung carcinoma', 'Disease', 'MESH:D002294', (75, 103))	('NSCLC', 'Phenotype', 'HP:0030358', (115, 120))
199002	33466316	Similarly, high CHID1 expression is a marker of good prognosis in adenocarcinoma and in NSCLC in general.	('NSCLC', 'Phenotype', 'HP:0030358', (88, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('adenocarcinoma', 'Disease', (66, 80))	('CHID1', 'Gene', (16, 21))	('NSCLC', 'Disease', (88, 93))	('adenocarcinoma', 'Disease', 'MESH:D000230', (66, 80))	('high', 'Var', (11, 15))	('NSCLC', 'Disease', 'MESH:D002289', (88, 93))	('expression', 'MPA', (22, 32))
199005	33466316	At the same time, high expression of iNOS in tumor cells is a marker of good prognosis in SCC.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumor', 'Disease', (45, 50))	('SCC', 'Phenotype', 'HP:0002860', (90, 93))	('SCC', 'Disease', (90, 93))	('high', 'Var', (18, 22))	('iNOS', 'Gene', '4843', (37, 41))	('iNOS', 'Gene', (37, 41))	('SCC', 'Phenotype', 'HP:0030359', (90, 93))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('expression', 'MPA', (23, 33))
199013	33466316	The use of anti-PD-1/PD-L1 and anti-CTLA-4 immune checkpoint inhibitors have entered clinical practice and have revolutionized the therapeutic treatment of this pathology in recent years.	('CTLA-4', 'Gene', (36, 42))	('CTLA-4', 'Gene', '1493', (36, 42))	('anti-PD-1/PD-L1', 'Var', (11, 26))
199046	33466316	Higher numbers of CD3+ and CD8+ cells were found to be associated with early stages of the disease.	('CD8', 'Gene', '925', (27, 30))	('CD3+', 'Var', (18, 22))	('associated', 'Reg', (55, 65))	('CD8', 'Gene', (27, 30))
199075	33466316	We established that high expression of iNOS was a marker of favorable prognosis for squamous cell lung carcinoma (HR = 0.3939, p = 0.0456), and also NSCLC in general (HR = 0.4418, p = 0.0453) (Figure 7).	('squamous cell lung carcinoma', 'Disease', (84, 112))	('NSCLC', 'Disease', (149, 154))	('high expression', 'Var', (20, 35))	('iNOS', 'Gene', '4843', (39, 43))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('squamous cell lung carcinoma', 'Disease', 'MESH:D002294', (84, 112))	('NSCLC', 'Disease', 'MESH:D002289', (149, 154))	('squamous cell lung carcinoma', 'Phenotype', 'HP:0030359', (84, 112))	('iNOS', 'Gene', (39, 43))	('NSCLC', 'Phenotype', 'HP:0030358', (149, 154))
199078	33466316	Analysis of prognostic value of high CHID1 expression showed that it was a marker of good prognosis in adenocarcinoma (HR = 0.3196, p = 0.0127) and in NSCLC in general (HR = 0.4019, p = 0.0115) (Figure 7).	('high', 'Var', (32, 36))	('NSCLC', 'Phenotype', 'HP:0030358', (151, 156))	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('NSCLC', 'Disease', (151, 156))	('NSCLC', 'Disease', 'MESH:D002289', (151, 156))	('adenocarcinoma', 'Disease', (103, 117))	('CHID1', 'Gene', (37, 42))	('adenocarcinoma', 'Disease', 'MESH:D000230', (103, 117))
199082	33466316	It is also important to mention that overall survival of patients from the low CHID1/iNOS expression group was 20 months, while overall survival in the low CHID1 group was 28 months and in the low iNOS group was 50 months.	('iNOS', 'Gene', (85, 89))	('low', 'Var', (75, 78))	('patients', 'Species', '9606', (57, 65))	('iNOS', 'Gene', '4843', (197, 201))	('iNOS', 'Gene', (197, 201))	('iNOS', 'Gene', '4843', (85, 89))
199112	33466316	Our studies have shown a poor prognostic significance of high IDO1 expression in squamous cell carcinoma of the lung.	('high', 'Var', (57, 61))	('IDO1', 'Gene', (62, 66))	('squamous cell carcinoma of the lung', 'Phenotype', 'HP:0030359', (81, 116))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (81, 104))	('expression', 'MPA', (67, 77))	('squamous cell carcinoma', 'Disease', (81, 104))	('carcinoma of the lung', 'Phenotype', 'HP:0100526', (95, 116))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (81, 104))	('IDO1', 'Gene', '3620', (62, 66))
199124	33466316	We showed that the high expression of this enzyme in tumor tissue is a marker of a good prognosis for NSCLC and for squamous lung cancer in particular (HR = 0.4418, p = 0.0453; HR = 0.3939, p = 0.0456, respectively).	('NSCLC', 'Disease', 'MESH:D002289', (102, 107))	('high', 'Var', (19, 23))	('squamous lung cancer', 'Disease', 'MESH:D008175', (116, 136))	('squamous lung cancer', 'Phenotype', 'HP:0030359', (116, 136))	('expression', 'MPA', (24, 34))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('NSCLC', 'Phenotype', 'HP:0030358', (102, 107))	('squamous lung cancer', 'Disease', (116, 136))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('tumor', 'Disease', (53, 58))	('NSCLC', 'Disease', (102, 107))	('lung cancer', 'Phenotype', 'HP:0100526', (125, 136))
199140	33466316	At the same time, high expression of iNOS in tumor cells is a marker of good prognosis in squamous cell carcinoma.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (90, 113))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('squamous cell carcinoma', 'Disease', (90, 113))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (90, 113))	('tumor', 'Disease', (45, 50))	('high', 'Var', (18, 22))	('iNOS', 'Gene', '4843', (37, 41))	('iNOS', 'Gene', (37, 41))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('expression', 'MPA', (23, 33))
199174	30041611	Ninety-four non-synonymous (missense [70.2%], nonsense [11.7%], splice site [10.6%], and insertion/deletion [7.5%]) mutations were detected in 40 OSCC patients with an allele frequency threshold of 10%.	('nonsense', 'Var', (46, 54))	('OSCC', 'Disease', (146, 150))	('OS', 'Chemical', '-', (146, 148))	('patients', 'Species', '9606', (151, 159))	('insertion/deletion', 'Var', (89, 107))	('mutations', 'Var', (116, 125))
199181	30041611	Previously, genomic analyses using NGS have detected mutations in several genes critical for tumor growth and survival as well as identified targeted hotspots of other genes.	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Disease', (93, 98))	('mutations', 'Var', (53, 62))	('detected', 'Reg', (44, 52))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
199183	30041611	For NGS studies of cancer samples, the allele frequency represents the percentage of sequence reads carrying a mutant allele of an individual patient's cancer, which can be influenced by many factors.	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (19, 25))	('mutant', 'Var', (111, 117))	('cancer', 'Disease', (19, 25))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('patient', 'Species', '9606', (142, 149))
199197	30041611	SIFT, Polyphen, Phylop, and Grantham scores were used to estimate evolutionary conservation and the effects of amino acid substitutions on the structure and function of the protein.	('SIFT', 'Disease', 'None', (0, 4))	('SIFT', 'Disease', (0, 4))	('substitutions', 'Var', (122, 135))
199200	30041611	Compared to matched non-cancerous tissues and reference sequences, a total of 94 non-synonymous (missense, nonsense, splicing site, insertion, and deletion) mutations were detected in the cancerous tissue samples from 40 OSCC patients with an allele frequency threshold of >=10%.	('insertion', 'Var', (132, 141))	('nonsense', 'Var', (107, 115))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('detected', 'Reg', (172, 180))	('cancerous', 'Disease', 'MESH:D009369', (188, 197))	('cancerous', 'Disease', 'MESH:D009369', (24, 33))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('mutations', 'Var', (157, 166))	('OS', 'Chemical', '-', (221, 223))	('cancerous', 'Disease', (188, 197))	('patients', 'Species', '9606', (226, 234))	('splicing', 'MPA', (117, 125))	('cancerous', 'Disease', (24, 33))
199201	30041611	With an allele frequency threshold of >=5%, 132 non-synonymous mutations were detected in the cancerous tissue samples from 41 patients.	('cancerous', 'Disease', (94, 103))	('non-synonymous mutations', 'Var', (48, 72))	('patients', 'Species', '9606', (127, 135))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('cancerous', 'Disease', 'MESH:D009369', (94, 103))
199202	30041611	With an allele frequency threshold of >=3%, 239 non-synonymous mutations were detected in the cancerous tissue samples from 42 patients.	('cancerous', 'Disease', (94, 103))	('non-synonymous mutations', 'Var', (48, 72))	('patients', 'Species', '9606', (127, 135))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('cancerous', 'Disease', 'MESH:D009369', (94, 103))
199203	30041611	TP53 mutation was selected as a representative example because it was the most frequently mutated gene with 46 genetic variates in our panel.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('mutation', 'Var', (5, 13))
199204	30041611	The TP53 Sanger sequencing was performed to confirm the TP53 variants.	('TP53', 'Gene', (4, 8))	('TP53', 'Gene', '7157', (56, 60))	('TP53', 'Gene', (56, 60))	('variants', 'Var', (61, 69))	('TP53', 'Gene', '7157', (4, 8))
199211	30041611	The mutation frequencies of NOTCH1 and CDH1 were much higher in our cohort than those reported in the TCGA database (30.4% vs. 18.3%, P = 0.056 and 6.5% vs. 1.4%, P = 0.062 for NOTCH1 and CDH1, respectively).	('NOTCH1', 'Gene', '4851', (177, 183))	('NOTCH1', 'Gene', (177, 183))	('CDH1', 'Gene', (39, 43))	('mutation', 'Var', (4, 12))	('NOTCH1', 'Gene', '4851', (28, 34))	('higher', 'Reg', (54, 60))	('CDH1', 'Gene', (188, 192))	('NOTCH1', 'Gene', (28, 34))	('CDH1', 'Gene', '999', (39, 43))	('CDH1', 'Gene', '999', (188, 192))
199212	30041611	TP53 was the most frequently mutated gene, with a total of 46 genetic variants (33 missense mutations, 4 nonsense mutations, 5 insertions/deletions, and 4 splice-site mutations) in 36 patients (78.3%).	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('insertions/deletions', 'Var', (127, 147))	('patients', 'Species', '9606', (184, 192))	('missense mutations', 'Var', (83, 101))
199213	30041611	Thirty-three out of 46 (71.7%) p53 mutations were found to be located in the DNA-binding domain, while 4 (8.7%) mutations were in the tetramerization motif, and 2 mutations (4.4%) were in the transactivation motif (Table 2).	('p53', 'Gene', '7157', (31, 34))	('p53', 'Gene', (31, 34))	('mutations', 'Var', (35, 44))
199214	30041611	When compared to the TCGA database, p.Val216Met, p.Pro151Thr, p.Arg175His, p.Arg337Cys, p.Arg282Trp, p.Ala159Val, p.Arg273His, p.Arg248Gln, p.Arg282Trp, p.His193Leu, p.His178fs, p.Gly245Ser, p.Pro152Leu, p.Tyr220Cys, p.Gln331Ter, p.Pro151His, p.Arg342Ter, p.Glu286Lys, and p.Arg213Ter appeared in the TCGA HNSCC database; p.Cys135Phe, p.Phe113Cys, p.Cys176Phe, p.Trp53Ter, p.His179Leu, p.Val272Leu, p.Cys135Tyr, p.Arg213Gln, p.Pro191del, p.Val274Phe, p.Thr253Ile, p.Asp184His, p.Cys135Phe, p.Val218Glu, p.Ile255Phe, p.Asp148Asn, p.Asp57Asn, p.Pro128Ser, p.Leu93fs, and p.Pro85Ser appeared in the TCGA database of breast, bladder, renal, lung, stomach cancers and melanomas.	('p.Arg337Cys', 'Mutation', 'rs587782529', (75, 86))	('p.Asp148Asn', 'Mutation', 'rs1131691007', (516, 527))	('p.His179Leu', 'Mutation', 'rs1057519991', (373, 384))	('p.Arg213Ter', 'Mutation', 'rs397516436', (273, 284))	('p.Arg282Trp', 'Mutation', 'rs28934574', (140, 151))	('p.Cys135Phe', 'Mutation', 'rs587781991', (477, 488))	('melanomas', 'Disease', (663, 672))	('p.Cys176Phe', 'Mutation', 'rs786202962', (348, 359))	('HNSCC', 'Phenotype', 'HP:0012288', (306, 311))	('lung', 'Disease', (637, 641))	('p.Arg175His', 'Mutation', 'rs28934578', (62, 73))	('p.Pro151His', 'Mutation', 'rs1057520000', (230, 241))	('p.Arg213Gln', 'Mutation', 'rs587778720', (412, 423))	('p.Glu286Lys', 'Mutation', 'rs786201059', (256, 267))	('stomach cancers', 'Disease', 'MESH:D013274', (643, 658))	('p.Pro85Ser', 'Var', (569, 579))	('cancers', 'Phenotype', 'HP:0002664', (651, 658))	('p.Ala159Val', 'Mutation', 'p.A159V', (101, 112))	('p.Cys135Phe', 'Var', (477, 488))	('p.Thr253Ile', 'Mutation', 'p.T253I', (451, 462))	('p.Val272Leu', 'Mutation', 'rs121912657', (386, 397))	('p.Cys135Tyr', 'Mutation', 'rs587781991', (399, 410))	('p.His193Leu', 'Mutation', 'rs786201838', (153, 164))	('p.Val218Glu', 'Var', (490, 501))	('cancer', 'Phenotype', 'HP:0002664', (651, 657))	('melanomas', 'Phenotype', 'HP:0002861', (663, 672))	('p.Pro151Thr', 'Mutation', 'rs28934874', (49, 60))	('p.Thr253Ile', 'Var', (451, 462))	('p.Asp57Asn', 'Var', (529, 539))	('stomach cancers', 'Disease', (643, 658))	('p.Ile255Phe', 'Mutation', 'rs1057519995', (503, 514))	('p.Asp184His', 'Mutation', 'p.D184H', (464, 475))	('p.Pro128Ser', 'Var', (541, 552))	('p.His178fs', 'Mutation', 'rs786202525', (166, 176))	('p.Val274Phe', 'Mutation', 'rs1057520005', (438, 449))	('p.Pro152Leu', 'Mutation', 'rs587782705', (191, 202))	('p.Val216Met', 'Mutation', 'rs730882025', (36, 47))	('stomach cancers', 'Phenotype', 'HP:0012126', (643, 658))	('p.Pro85Ser', 'Mutation', 'p.P85S', (569, 579))	('breast', 'Disease', (613, 619))	('p.Pro191del', 'Mutation', 'p.191del', (425, 436))	('bladder', 'Disease', (621, 628))	('p.Val218Glu', 'Mutation', 'p.V218E', (490, 501))	('p.Cys135Phe', 'Mutation', 'rs587781991', (322, 333))	('p.Asp148Asn', 'Var', (516, 527))	('p.Pro128Ser', 'Mutation', 'p.P128S', (541, 552))	('p.Arg282Trp', 'Mutation', 'rs28934574', (88, 99))	('p.Asp184His', 'Var', (464, 475))	('p.Gln331Ter', 'Mutation', 'p.Q331X', (217, 228))	('p.Arg273His', 'Mutation', 'rs28934576', (114, 125))	('p.Gly245Ser', 'Mutation', 'rs28934575', (178, 189))	('p.Leu93fs', 'Mutation', 'p.L93fsX', (554, 563))	('p.Leu93fs', 'Var', (554, 563))	('p.Trp53Ter', 'Mutation', 'rs876658483', (361, 371))	('p.Tyr220Cys', 'Mutation', 'rs121912666', (204, 215))	('p.Ile255Phe', 'Var', (503, 514))	('renal', 'Disease', (630, 635))	('p.Phe113Cys', 'Mutation', 'p.F113C', (335, 346))	('p.Arg342Ter', 'Mutation', 'rs730882029', (243, 254))	('p.Asp57Asn', 'Mutation', 'p.D57N', (529, 539))	('p.Arg248Gln', 'Mutation', 'rs11540652', (127, 138))	('melanomas', 'Disease', 'MESH:D008545', (663, 672))
199215	30041611	NOTCH1 was also frequently mutated, with a total of 25 genetic variants (22 missense mutations, 2 insertions and deletions, and 1 splice site mutation) in 14 patients (30.4%).	('insertions', 'Var', (98, 108))	('missense mutations', 'Var', (76, 94))	('NOTCH1', 'Gene', '4851', (0, 6))	('NOTCH1', 'Gene', (0, 6))	('patients', 'Species', '9606', (158, 166))
199216	30041611	When compared to the TCGA database, p.Ala465Thr and p.Asp338Asn appeared in the TCGA HNSCC database; p.Asn718Ser, p.Glu488Lys, p.Pro2332Leu, p.Arg2272Cys, p.Arg365Cys, p.Val1229Ile, p.Gly1195Arg, p.Pro1097Ser, p.Ala1338Thr, p.Ser2336Asn, p.Ser836Asn, p.Pro668Ser, p.Phe436Leu, p.Thr767Ile, p.Met2362Ile, p.Ser1541Asn, p.Pro148Leu, p.Arg1758Cys, p.Arg1211Gln, and p.Thr588Ile appeared in the TCGA breast, esophageal, colon, bladder, prostate, lung cancers and melanomas.	('cancer', 'Phenotype', 'HP:0002664', (447, 453))	('p.Pro1097Ser', 'Mutation', 'p.P1097S', (196, 208))	('melanomas', 'Phenotype', 'HP:0002861', (459, 468))	('lung cancers', 'Phenotype', 'HP:0100526', (442, 454))	('p.Met2362Ile', 'Var', (290, 302))	('esophageal', 'Disease', (404, 414))	('p.Pro668Ser', 'Mutation', 'rs780810308', (251, 262))	('p.Pro2332Leu', 'Mutation', 'p.P2332L', (127, 139))	('p.Thr588Ile', 'Mutation', 'p.T588I', (363, 374))	('p.Arg365Cys', 'Mutation', 'rs1064795070', (155, 166))	('p.Arg1758Cys', 'Var', (331, 343))	('colon', 'Disease', (416, 421))	('p.Val1229Ile', 'Mutation', 'rs766198119', (168, 180))	('p.Pro148Leu', 'Var', (318, 329))	('p.Arg1758Cys', 'Mutation', 'rs777859108', (331, 343))	('p.Met2362Ile', 'Mutation', 'rs970639283', (290, 302))	('p.Pro148Leu', 'Mutation', 'p.P148L', (318, 329))	('melanomas', 'Disease', 'MESH:D008545', (459, 468))	('p.Asn718Ser', 'Mutation', 'p.N718S', (101, 112))	('p.Ser1541Asn', 'Mutation', 'p.S1541N', (304, 316))	('p.Gly1195Arg', 'Mutation', 'rs777194812', (182, 194))	('prostate', 'Disease', (432, 440))	('p.Ser836Asn', 'Mutation', 'rs747068023', (238, 249))	('melanomas', 'Disease', (459, 468))	('bladder', 'Disease', (423, 430))	('p.Arg1211Gln', 'Var', (345, 357))	('p.Thr588Ile', 'Var', (363, 374))	('lung cancers', 'Disease', 'MESH:D008175', (442, 454))	('p.Glu488Lys', 'Mutation', 'rs753661188', (114, 125))	('p.Arg2272Cys', 'Mutation', 'rs752505638', (141, 153))	('p.Asp338Asn', 'Mutation', 'rs1376568738', (52, 63))	('p.Ala1338Thr', 'Mutation', 'p.A1338T', (210, 222))	('p.Ser1541Asn', 'Var', (304, 316))	('p.Thr767Ile', 'Var', (277, 288))	('p.Ser2336Asn', 'Mutation', 'rs1363351087', (224, 236))	('p.Arg1211Gln', 'Mutation', 'rs756362905', (345, 357))	('p.Thr767Ile', 'Mutation', 'rs1439517621', (277, 288))	('cancers', 'Phenotype', 'HP:0002664', (447, 454))	('p.Ala465Thr', 'Mutation', 'rs1057523819', (36, 47))	('HNSCC', 'Phenotype', 'HP:0012288', (85, 90))	('lung cancers', 'Disease', (442, 454))	('p.Phe436Leu', 'Mutation', 'rs587778247', (264, 275))
199217	30041611	Eight CASP8 mutations were identified in six patients (13.0%).	('mutations', 'Var', (12, 21))	('patients', 'Species', '9606', (45, 53))	('CASP8', 'Gene', (6, 11))	('CASP8', 'Gene', '841', (6, 11))
199218	30041611	Seven (87.5%) mutations were located in the caspase homology domain, and the other was in the death effector domain (Table 2).	('caspase', 'Gene', (44, 51))	('caspase', 'Gene', '841', (44, 51))	('death', 'Disease', 'MESH:D003643', (94, 99))	('death', 'Disease', (94, 99))	('mutations', 'Var', (14, 23))
199219	30041611	When compared to the TCGA database, p.Arg494Ter and p.Arg472Ter appeared in the TCGA HNSCC database; p.Lys532fs and p.Gln417Ter appeared in the TCGA colorectal and bladder cancer database, respectively.	('colorectal', 'Disease', (149, 159))	('p.Arg494Ter', 'Mutation', 'rs1368296717', (36, 47))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('bladder cancer', 'Disease', (164, 178))	('bladder cancer', 'Phenotype', 'HP:0009725', (164, 178))	('p.Gln417Ter', 'Mutation', 'p.Q417X', (116, 127))	('p.Lys532fs', 'Mutation', 'p.K532fsX', (101, 111))	('HNSCC', 'Phenotype', 'HP:0012288', (85, 90))	('p.Arg472Ter', 'Var', (52, 63))	('p.Gln417Ter', 'Var', (116, 127))	('bladder cancer', 'Disease', 'MESH:D001749', (164, 178))	('p.Arg494Ter', 'Var', (36, 47))	('p.Lys532fs', 'Var', (101, 111))	('colorectal', 'Disease', 'MESH:D015179', (149, 159))	('p.Arg472Ter', 'Mutation', 'rs1272714323', (52, 63))
199221	30041611	Four CDKN2A mutations were located in ankyrin repeats, and the other was a splice site mutation.	('CDKN2A', 'Gene', '1029', (5, 11))	('CDKN2A', 'Gene', (5, 11))	('mutations', 'Var', (12, 21))
199222	30041611	When compared to the TCGA database, p.Glu120Ter appeared in the TCGA HNSCC database.	('TCGA', 'Gene', (64, 68))	('p.Glu120Ter', 'Var', (36, 47))	('p.Glu120Ter', 'Mutation', 'p.E120X', (36, 47))	('HNSCC', 'Phenotype', 'HP:0012288', (69, 74))
199224	30041611	Two CDH1 mutations were located in the cadherin repeat domain, and the other was in the cadherin cytoplasmic region.	('CDH1', 'Gene', (4, 8))	('mutations', 'Var', (9, 18))	('CDH1', 'Gene', '999', (4, 8))
199225	30041611	p.Trp532Ter and p.Arg90Trp appeared in the TCGA cervical and mixed cancer database, respectively.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('p.Trp532Ter', 'Mutation', 'p.W532X', (0, 11))	('cancer', 'Disease', (67, 73))	('TCGA', 'Disease', (43, 47))	('p.Arg90Trp', 'Var', (16, 26))	('appeared', 'Reg', (27, 35))	('p.Arg90Trp', 'Mutation', 'rs730881661', (16, 26))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('p.Trp532Ter', 'Var', (0, 11))
199226	30041611	Three EGFR mutations were identified in one patient (2.2%), including 2 missense mutations and 1 splice site mutation.	('patient', 'Species', '9606', (44, 51))	('EGFR', 'Gene', '1956', (6, 10))	('EGFR', 'Gene', (6, 10))	('missense mutations', 'Var', (72, 90))
199227	30041611	The 2 missense mutations were located in the furin-like repeats of EGFR.	('EGFR', 'Gene', (67, 71))	('missense mutations', 'Var', (6, 24))	('EGFR', 'Gene', '1956', (67, 71))
199228	30041611	Two missense IGFBP3 mutations were identified in one patient (2.2%), and these mutations were located in the thyroglobulin type-1 repeat domain and the IGFBP homology domain, respectively.	('patient', 'Species', '9606', (53, 60))	('mutations', 'Var', (20, 29))	('IGFBP3', 'Gene', (13, 19))	('IGFBP3', 'Gene', '3486', (13, 19))
199231	30041611	The p53 DNA-binding domain was the major conserved domain that contained a mutation in 28 patients (60.9%), and the NOTCH1 EGF-like repeats domain was the second major conserved domain, with a mutation in 13 patients (28.3%), followed by the caspase homology domain of caspase 8 that was mutated in five patients (10.9%), the tetramerization motif of p53 with a mutation in four patients (8.7%), and the ankyrin repeat domains of p16, which contained mutations in four patients (8.7%) (Table 2).	('p53', 'Gene', '7157', (351, 354))	('caspase', 'Gene', '841', (269, 276))	('caspase 8', 'Gene', (269, 278))	('p53', 'Gene', (4, 7))	('patients', 'Species', '9606', (379, 387))	('p53', 'Gene', (351, 354))	('NOTCH1', 'Gene', (116, 122))	('caspase', 'Gene', '841', (242, 249))	('mutation', 'Var', (75, 83))	('p16', 'Gene', (430, 433))	('p16', 'Gene', '1029', (430, 433))	('caspase 8', 'Gene', '841', (269, 278))	('NOTCH1', 'Gene', '4851', (116, 122))	('patients', 'Species', '9606', (304, 312))	('caspase', 'Gene', (269, 276))	('patients', 'Species', '9606', (90, 98))	('p53', 'Gene', '7157', (4, 7))	('patients', 'Species', '9606', (208, 216))	('patients', 'Species', '9606', (469, 477))	('mutation', 'Var', (362, 370))	('caspase', 'Gene', (242, 249))
199233	30041611	Correlation analysis between non-synonymous mutant status (including all targeted genes of CAGE) and baseline characteristics was performed; no significant correlations were found (Table 3).	('non-synonymous mutant', 'Var', (29, 50))	('CAGE', 'Gene', (91, 95))	('CAGE', 'Gene', '168400', (91, 95))
199234	30041611	Survival analysis found no significant differences in outcomes with regard to OS, DFS, LRFS, and DMFS between patients with non-synonymous mutations and wild type carriers (Fig.	('LRFS', 'Disease', (87, 91))	('non-synonymous mutations', 'Var', (124, 148))	('DMFS', 'Chemical', '-', (97, 101))	('OS', 'Chemical', '-', (78, 80))	('patients', 'Species', '9606', (110, 118))
199243	30041611	Several studies have found pathogenic mutations in OSCC using NGS; however, some have only targeted a few genes or hotspots, while others lacked matched normal control tissues, making it impossible to rule out germline mutations in the tumor specimens.	('OS', 'Chemical', '-', (51, 53))	('tumor', 'Disease', 'MESH:D009369', (236, 241))	('pathogenic', 'Reg', (27, 37))	('tumor', 'Phenotype', 'HP:0002664', (236, 241))	('mutations', 'Var', (38, 47))	('tumor', 'Disease', (236, 241))	('OSCC', 'Gene', (51, 55))
199249	30041611	According to previous studies, TP53 was the most frequently mutated gene in OSCC, and 71.7% of mutations were located in the DNA-binding domain, 8.7% in the tetramerization motif, and 4.4% in the transactivation motif.	('OSCC', 'Disease', (76, 80))	('OS', 'Chemical', '-', (76, 78))	('TP53', 'Gene', '7157', (31, 35))	('TP53', 'Gene', (31, 35))	('mutations', 'Var', (95, 104))
199251	30041611	When TP53 mutations occur in the DNA-binding domain, the p53 protein cannot bind to these specific DNA sequences, and the rate of gene transcription changes to some extent.	('rate', 'MPA', (122, 126))	('TP53', 'Gene', '7157', (5, 9))	('p53', 'Gene', (57, 60))	('TP53', 'Gene', (5, 9))	('mutations', 'Var', (10, 19))	('changes', 'Reg', (149, 156))	('gene transcription', 'MPA', (130, 148))	('p53', 'Gene', '7157', (57, 60))
199252	30041611	Meanwhile, mutations in the tetramerization motif might deregulate the oligomerization process of p53.	('mutations', 'Var', (11, 20))	('deregulate', 'Reg', (56, 66))	('p53', 'Gene', (98, 101))	('tetramerization', 'Protein', (28, 43))	('oligomerization process', 'MPA', (71, 94))	('p53', 'Gene', '7157', (98, 101))
199253	30041611	For NOTCH1, in this study, more than two-thirds of the mutations were located within EGF-like repeats, which could significantly impact NOTCH1 protein activity.	('mutations', 'Var', (55, 64))	('NOTCH1', 'Gene', '4851', (136, 142))	('impact', 'Reg', (129, 135))	('NOTCH1', 'Gene', (136, 142))	('NOTCH1', 'Gene', '4851', (4, 10))	('NOTCH1', 'Gene', (4, 10))	('activity', 'MPA', (151, 159))	('protein', 'Protein', (143, 150))
199255	30041611	Mutations in this region can disturb signal transduction pathways since NOTCH1 signaling depends on these direct interactions.	('disturb', 'Reg', (29, 36))	('signal transduction pathways', 'Pathway', (37, 65))	('Mutations', 'Var', (0, 9))	('NOTCH1', 'Gene', '4851', (72, 78))	('interactions', 'Interaction', (113, 125))	('NOTCH1', 'Gene', (72, 78))
199256	30041611	At the same time, mutations in EGF-like repeat regions can intensify NOTCH1 signaling because the integrity of EGF-like repeats is necessary to suppress this activity.	('EGF-like', 'Gene', (31, 39))	('intensify', 'PosReg', (59, 68))	('suppress', 'NegReg', (144, 152))	('NOTCH1', 'Gene', '4851', (69, 75))	('NOTCH1', 'Gene', (69, 75))	('mutations', 'Var', (18, 27))
199257	30041611	Furthermore, the mutant NOTCH1 protein may not only lose its function, but could potentially gain new abilities like mutant p53.	('abilities', 'MPA', (102, 111))	('function', 'MPA', (61, 69))	('p53', 'Gene', (124, 127))	('protein', 'Protein', (31, 38))	('p53', 'Gene', '7157', (124, 127))	('NOTCH1', 'Gene', '4851', (24, 30))	('NOTCH1', 'Gene', (24, 30))	('gain', 'PosReg', (93, 97))	('mutant', 'Var', (17, 23))	('lose', 'NegReg', (52, 56))
199258	30041611	Further investigation is necessary with larger sample sizes to identify potential novel mechanisms of NOTCH1 mutations in OSCC.	('NOTCH1', 'Gene', '4851', (102, 108))	('OSCC', 'Disease', (122, 126))	('OS', 'Chemical', '-', (122, 124))	('NOTCH1', 'Gene', (102, 108))	('mutations', 'Var', (109, 118))
199259	30041611	The majority of CASP8 mutations were found in the caspase homology domain in the present study.	('caspase', 'Gene', (50, 57))	('caspase', 'Gene', '841', (50, 57))	('mutations', 'Var', (22, 31))	('CASP8', 'Gene', (16, 21))	('CASP8', 'Gene', '841', (16, 21))
199261	30041611	This domain has been reported to be the key part of caspase-8, and most CASP8 mutations are inactivating mutations.	('caspase-8', 'Gene', (52, 61))	('caspase-8', 'Gene', '841', (52, 61))	('mutations', 'Var', (78, 87))	('CASP8', 'Gene', (72, 77))	('CASP8', 'Gene', '841', (72, 77))
199262	30041611	Thus, suppression of apoptosis caused by CASP8 mutations may contribute to OSCC pathogenesis.	('suppression', 'NegReg', (6, 17))	('contribute', 'Reg', (61, 71))	('mutations', 'Var', (47, 56))	('CASP8', 'Gene', (41, 46))	('OS', 'Chemical', '-', (75, 77))	('CASP8', 'Gene', '841', (41, 46))	('OSCC', 'Disease', (75, 79))	('apoptosis', 'CPA', (21, 30))
199264	30041611	These have been investigated in HNSCC, and most CDKN2A mutations are inactivating mutations.	('mutations', 'Var', (55, 64))	('HNSCC', 'Disease', (32, 37))	('HNSCC', 'Phenotype', 'HP:0012288', (32, 37))	('CDKN2A', 'Gene', (48, 54))	('CDKN2A', 'Gene', '1029', (48, 54))
199265	30041611	Based on the transcription of CDKN2A, we deduced that most of the CDKN2A mutations were in the ankyrin repeats of p16.	('p16', 'Gene', '1029', (114, 117))	('CDKN2A', 'Gene', (30, 36))	('CDKN2A', 'Gene', '1029', (66, 72))	('CDKN2A', 'Gene', '1029', (30, 36))	('p16', 'Gene', (114, 117))	('CDKN2A', 'Gene', (66, 72))	('mutations', 'Var', (73, 82))
199266	30041611	The dysregulation of the cell cycle caused by CDKN2A mutations may also lead to OSCC development.	('cell cycle', 'CPA', (25, 35))	('OSCC', 'Disease', (80, 84))	('CDKN2A', 'Gene', (46, 52))	('OS', 'Chemical', '-', (80, 82))	('CDKN2A', 'Gene', '1029', (46, 52))	('mutations', 'Var', (53, 62))	('lead to', 'Reg', (72, 79))
199275	27340923	In addition, epigenetics and long non-coding RNAs (lncRNAs) are emerging as new fields for investigation, which might also account for tumor heterogeneity.	('epigenetics', 'Var', (13, 24))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('long non-coding RNAs', 'Var', (29, 49))	('tumor', 'Disease', (135, 140))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
199276	27340923	There is growing evidence that modifications of lncRNA expression profiles are involved in cancer progression through epigenetic regulation, activation of pro-oncogenic pathways and crosstalks with other RNA subtypes.	('modifications', 'Var', (31, 44))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('lncRNA', 'Protein', (48, 54))	('involved', 'Reg', (79, 87))	('pro-oncogenic pathways', 'Pathway', (155, 177))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('crosstalks', 'Reg', (182, 192))	('epigenetic regulation', 'MPA', (118, 139))	('activation', 'PosReg', (141, 151))
199281	27340923	Among them, the IMDC (international metastatic renal cell carcinoma database) prognostic classification for renal cell carcinoma, based on clinical and laboratory markers, defines the prognosis and therapeutic options for patients in the first-line setting; the pathological subtyping of breast cancer identifies the patients that will mostly benefit from endocrine or anti-HER2 therapy; the identification of deficient mismatch repair in colon cancer categorizes a subset of patients that will less likely benefit from adjuvant chemotherapy.	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (108, 128))	('patients', 'Species', '9606', (222, 230))	('patients', 'Species', '9606', (476, 484))	('colon cancer', 'Phenotype', 'HP:0003003', (439, 451))	('cancer', 'Phenotype', 'HP:0002664', (295, 301))	('HER2', 'Gene', '2064', (374, 378))	('colon cancer', 'Disease', 'MESH:D015179', (439, 451))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('cancer', 'Phenotype', 'HP:0002664', (445, 451))	('breast cancer', 'Phenotype', 'HP:0003002', (288, 301))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (47, 67))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (108, 128))	('HER2', 'Gene', (374, 378))	('breast cancer', 'Disease', 'MESH:D001943', (288, 301))	('colon cancer', 'Disease', (439, 451))	('breast cancer', 'Disease', (288, 301))	('renal cell carcinoma', 'Disease', (47, 67))	('deficient mismatch repair', 'Var', (410, 435))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (47, 67))	('patients', 'Species', '9606', (317, 325))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))	('renal cell carcinoma', 'Disease', (108, 128))
199282	27340923	In the last decade, predictive markers of tumor recurrence have benefited from the increasing accessibility of molecular biology and the arrival of next-generation sequencing technologies, that allow for more accurate depiction of genomic and epigenetic alterations in cancer.	('tumor', 'Disease', (42, 47))	('genomic', 'Var', (231, 238))	('cancer', 'Phenotype', 'HP:0002664', (269, 275))	('epigenetic alterations', 'Var', (243, 265))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('cancer', 'Disease', (269, 275))	('cancer', 'Disease', 'MESH:D009369', (269, 275))
199284	27340923	Another example is the CpG island methylator phenotype (CIMP), initially discovered in colon cancer that has since been reported to be associated with IDH1 and IDH2 mutations in glioblastoma and associated with improved prognosis.	('colon cancer', 'Disease', (87, 99))	('CIMP', 'Chemical', '-', (56, 60))	('glioblastoma', 'Disease', (178, 190))	('glioblastoma', 'Disease', 'MESH:D005909', (178, 190))	('IDH2', 'Gene', '3418', (160, 164))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('associated', 'Reg', (135, 145))	('glioblastoma', 'Phenotype', 'HP:0012174', (178, 190))	('IDH1', 'Gene', (151, 155))	('colon cancer', 'Phenotype', 'HP:0003003', (87, 99))	('mutations', 'Var', (165, 174))	('IDH1', 'Gene', '3417', (151, 155))	('colon cancer', 'Disease', 'MESH:D015179', (87, 99))	('IDH2', 'Gene', (160, 164))
199285	27340923	The latter association is explained by epigenetic reprogramming mediated by IDH1 and IDH2 alterations which are putative targets of experimental treatments.	('IDH1', 'Gene', (76, 80))	('alterations', 'Var', (90, 101))	('epigenetic', 'Var', (39, 49))	('IDH1', 'Gene', '3417', (76, 80))	('IDH2', 'Gene', (85, 89))	('IDH2', 'Gene', '3418', (85, 89))
199288	27340923	In addition, similar genetic alterations in different cancers are not always associated with identical outcomes.	('cancers', 'Phenotype', 'HP:0002664', (54, 61))	('cancers', 'Disease', (54, 61))	('cancers', 'Disease', 'MESH:D009369', (54, 61))	('genetic alterations', 'Var', (21, 40))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
199290	27340923	Among them, long non-coding RNAs (lncRNAs) are key regulators of cellular processes, and are currently emerging as drivers for tumor aggressiveness and patients' outcome.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumor aggressiveness', 'Disease', (127, 147))	('long non-coding RNAs', 'Var', (12, 32))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (127, 147))	('aggressiveness', 'Phenotype', 'HP:0000718', (133, 147))	('patients', 'Species', '9606', (152, 160))
199293	27340923	Recent studies have highlighted the implication of lncRNAs in cancer progression, mainly through epigenetic regulation, activation of oncogenic pathways and crosstalks with other RNA subtypes.	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('oncogenic pathways', 'Pathway', (134, 152))	('epigenetic', 'Var', (97, 107))	('activation', 'PosReg', (120, 130))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('crosstalks', 'Reg', (157, 167))
199300	27340923	MYC gene alterations consist mostly in amplifications, as a result of copy gains of 8p24.	('MYC', 'Gene', (0, 3))	('alterations', 'Var', (9, 20))	('amplifications', 'MPA', (39, 53))	('copy gains', 'Var', (70, 80))	('8p24', 'Protein', (84, 88))	('MYC', 'Gene', '4609', (0, 3))
199309	27340923	Among key oncogenic drivers, PI3K/MTOR/AKT and MAP kinases pathways are frequently promoted by lncRNAs alterations.	('MTOR', 'Gene', '2475', (34, 38))	('AKT', 'Gene', (39, 42))	('AKT', 'Gene', '207', (39, 42))	('promoted', 'PosReg', (83, 91))	('MTOR', 'Gene', (34, 38))	('lncRNAs alterations', 'Var', (95, 114))	('MAP kinases pathways', 'Pathway', (47, 67))
199338	27340923	As a result of the activation of oncogenic processes, lncRNA deregulations are associated with a more aggressive phenotype and drug resistance in cancer.	('cancer', 'Disease', (146, 152))	('associated', 'Reg', (79, 89))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('drug resistance', 'Phenotype', 'HP:0020174', (127, 142))	('activation', 'PosReg', (19, 29))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('deregulations', 'Var', (61, 74))	('oncogenic processes', 'CPA', (33, 52))	('lncRNA', 'Gene', (54, 60))	('aggressive phenotype', 'CPA', (102, 122))
199340	27340923	High expression of HOTAIR was associated with increased vascular invasion, advanced tumor stage, metastasis and poor prognosis.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('High', 'Var', (0, 4))	('vascular invasion', 'CPA', (56, 73))	('increased', 'PosReg', (46, 55))	('HOTAIR', 'Gene', (19, 25))	('metastasis', 'CPA', (97, 107))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumor', 'Disease', (84, 89))	('HOTAIR', 'Gene', '100124700', (19, 25))
199356	27340923	LncR1 subtype was associated with astroglial gene signature, epidermal growth factor (EGFR) amplification and patients displayed poor overall survival.	('astroglial', 'MPA', (34, 44))	('EGFR', 'Gene', '1950', (86, 90))	('patients', 'Species', '9606', (110, 118))	('associated', 'Reg', (18, 28))	('epidermal growth factor', 'Gene', (61, 84))	('EGFR', 'Gene', (86, 90))	('amplification', 'Var', (92, 105))	('LncR1', 'Gene', '450093', (0, 5))	('LncR1', 'Gene', (0, 5))	('epidermal growth factor', 'Gene', '1950', (61, 84))
199357	27340923	On the contrary, lncR3 subtype correlated with oligodendritic gene signature, IDH1 mutation, 1p/19q chromosomal deletions and patients had good prognosis.	('1p/19q chromosomal deletions', 'Var', (93, 121))	('oligodendritic', 'Disease', (47, 61))	('oligodendritic', 'Disease', 'None', (47, 61))	('IDH1', 'Gene', (78, 82))	('mutation', 'Var', (83, 91))	('IDH1', 'Gene', '3417', (78, 82))	('patients', 'Species', '9606', (126, 134))	('lncR3', 'Gene', '100271687', (17, 22))	('lncR3', 'Gene', (17, 22))	('correlated', 'Reg', (31, 41))
199359	27340923	Interestingly, this lncRNA classification correlates with various molecular prognostic factors, but it is still unknown whether lncRNA alterations are bound to specific genetic mutations such as IDH1, or chromatin remodeling genes alterations.	('IDH1', 'Gene', (195, 199))	('mutations', 'Var', (177, 186))	('IDH1', 'Gene', '3417', (195, 199))
199375	27340923	Cluster 2 was enriched for tumors harboring mutations in the chromatin-remodeling gene BAP1, and was strongly associated with high tumor grade and poor prognosis.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('BAP1', 'Gene', '8314', (87, 91))	('high tumor', 'Disease', 'MESH:D009369', (126, 136))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumors', 'Disease', (27, 33))	('BAP1', 'Gene', (87, 91))	('tumors', 'Disease', 'MESH:D009369', (27, 33))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('associated', 'Reg', (110, 120))	('mutations', 'Var', (44, 53))	('high tumor', 'Disease', (126, 136))
199376	27340923	In contrast, two clusters with better prognosis displayed PBRM1 mutations, a component of SWI/SNF transcriptional activator.	('PBRM1', 'Gene', (58, 63))	('PBRM1', 'Gene', '55193', (58, 63))	('mutations', 'Var', (64, 73))
199383	27340923	The luminal subgroup was associated with expression of progesterone (PGR) and estrogen receptor (ESR1) genes, while the CTNNB1 subgroup involved mutations in the beta-catenin gene and PTEN loss.	('ESR1', 'Gene', '2099', (97, 101))	('associated', 'Reg', (25, 35))	('expression', 'MPA', (41, 51))	('mutations', 'Var', (145, 154))	('beta-catenin', 'Gene', (162, 174))	('PTEN', 'Gene', (184, 188))	('CTNNB1', 'Gene', (120, 126))	('PGR', 'Gene', '5241', (69, 72))	('PTEN', 'Gene', '5728', (184, 188))	('ESR1', 'Gene', (97, 101))	('beta-catenin', 'Gene', '1499', (162, 174))	('CTNNB1', 'Gene', '1499', (120, 126))	('estrogen receptor', 'Gene', (78, 95))	('estrogen receptor', 'Gene', '2099', (78, 95))	('loss', 'NegReg', (189, 193))	('PGR', 'Gene', (69, 72))
199384	27340923	There was a trend towards poorer survival in the basal-like subgroup, which included more aggressive tumors that were enriched for p53 mutations and mutations of the MLL genes family.	('aggressive tumors', 'Disease', 'MESH:D001523', (90, 107))	('mutations', 'Var', (149, 158))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('aggressive tumors', 'Disease', (90, 107))	('mutations', 'Var', (135, 144))	('p53', 'Gene', (131, 134))	('p53', 'Gene', '7157', (131, 134))	('MLL', 'Gene', '4297', (166, 169))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('poorer', 'NegReg', (26, 32))	('MLL', 'Gene', (166, 169))
199417	26713674	Blockage of lymphatic flow in the left lower cervical area may allow retrograde spread and the involvement of more superior or contralateral neck nodes.	('Blockage', 'Var', (0, 8))	('Blockage of lymphatic flow', 'Phenotype', 'HP:0001004', (0, 26))	('allow', 'Reg', (63, 68))	('lower cervical area', 'Phenotype', 'HP:0000470', (39, 58))	('retrograde spread', 'CPA', (69, 86))	('men', 'Species', '9606', (102, 105))
199546	26713674	Depending on the location of metastases and whether it is single or multiple, surgery may play a role in the management of these patients and local resection may improve quality of life and can provide an excellent local disease control in the neck.	('quality of life', 'CPA', (170, 185))	('man', 'Species', '9606', (109, 112))	('patients', 'Species', '9606', (129, 137))	('metastases', 'Disease', (29, 39))	('men', 'Species', '9606', (115, 118))	('local disease control', 'CPA', (215, 236))	('metastases', 'Disease', 'MESH:D009362', (29, 39))	('local', 'Var', (142, 147))	('improve', 'PosReg', (162, 169))
199547	26713674	Excision of solitary metastatic lesions of a RCC after nephrectomy has been reported to achieve 41% survival at 2 years and 13% survival at 5 years, regardless of the time interval between nephrectomy and the diagnosis of the metastatic lesion.	('Excision', 'Var', (0, 8))	('RCC', 'Disease', 'MESH:C538614', (45, 48))	('RCC', 'Disease', (45, 48))	('RCC', 'Phenotype', 'HP:0005584', (45, 48))
199669	26713674	Demonstration of oligodendroglioma-specific 1p19q codeletion on tissue section by fluorescence in situ hybridization is a reliable technique for detection of this tumor.	('oligodendroglioma', 'Disease', (17, 34))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('1p19q codeletion', 'Var', (44, 60))	('oligodendroglioma', 'Disease', 'MESH:D009837', (17, 34))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('tumor', 'Disease', (163, 168))
199699	26110843	Furthermore, we quantified global proteomic changes by mass spectrometry after EZH2 inhibition.	('inhibition', 'Var', (84, 94))	('EZH2', 'Gene', (79, 83))	('EZH2', 'Gene', '2146', (79, 83))
199714	26110843	Most of the current driver identification approaches aim to uncover somatic alterations, point mutations in particular, that occur at a statistically significant rate in cancer.	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('point mutations', 'Var', (89, 104))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('cancer', 'Disease', (170, 176))
199724	26110843	The extents of copy number deletions and amplifications for each gene in each cancer study were determined as the proportions of tumors with 'deep loss' and 'high-level gain' changes, respectively.	('tumors', 'Disease', (129, 135))	("'deep loss'", 'NegReg', (141, 152))	('tumors', 'Disease', 'MESH:D009369', (129, 135))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('copy number deletions', 'Var', (15, 36))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('changes', 'Reg', (175, 182))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))
199746	26110843	Cells were cultivated in SILAC RMPI 1640 medium containing 13C615N2-lysine (Lys8) and 13C615N4-arginine (Arg10), as described.	('Lys8', 'Chemical', '-', (76, 80))	('13C615N2-lysine', 'Chemical', '-', (59, 74))	('13C615N4-arginine', 'Var', (86, 103))	('SILAC RMPI 1640 medium', 'Chemical', '-', (25, 47))	('13C615N2-lysine', 'Var', (59, 74))	('Arg10', 'Chemical', '-', (105, 110))	('13C615N4-arginine', 'Chemical', '-', (86, 103))
199758	26110843	We used Cytoscape and BinGO to derive biological functions that were significantly overrepresented in co-expressed gene networks or proteins with intensity changes after EZH2 inhibition.	('changes', 'Reg', (156, 163))	('inhibition', 'Var', (175, 185))	('overrepresented', 'PosReg', (83, 98))	('proteins', 'Protein', (132, 140))	('intensity', 'MPA', (146, 155))	('EZH2', 'Gene', '2146', (170, 174))	('EZH2', 'Gene', (170, 174))
199769	26110843	These include the proportions of tumors with significant copy number alterations, non-synonymous sequence mutations within the gene coding region, and the degree of differential expression between tumors and adjacent normal tissues.	('tumors', 'Disease', 'MESH:D009369', (197, 203))	('tumors', 'Disease', (33, 39))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumors', 'Phenotype', 'HP:0002664', (197, 203))	('tumors', 'Disease', 'MESH:D009369', (33, 39))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('non-synonymous sequence mutations', 'Var', (82, 115))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('tumors', 'Disease', (197, 203))	('copy number alterations', 'Var', (57, 80))
199770	26110843	The frequencies of copy number deletions or amplifications for each gene were determined as the proportions of tumors with 'deep loss' or 'high-level gain' changes based on GISTIC calculations, respectively.	('amplifications', 'Var', (44, 58))	('copy number deletions', 'Var', (19, 40))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	("'deep", 'NegReg', (123, 128))	('tumors', 'Disease', (111, 117))	('tumors', 'Disease', 'MESH:D009369', (111, 117))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))
199774	26110843	For OG prediction, the most reliable parameters were the occurrence of mutation hot spots, represented by the mutation selection score (p = 5.8 x 10-13, one-tailed Mann-Whitney U test, beta coefficient = 5.3), the ratio of HiFI to LoFI missense mutations (p = 2.2 x 10-3, beta = 0.06), and the amplification frequency (p = 1.8 x 10-5, beta = 2.48) (Figure 2A).	('missense mutations', 'Var', (236, 254))	('beta = 2', 'Gene', '10242', (335, 343))	('beta = 2', 'Gene', (335, 343))	('amplification', 'MPA', (294, 307))
199775	26110843	Examples for such somatic mutation hot spots include V600E in BRAF (265 tumors), H1047R in PIK3CA (113 tumors), or G12D in KRAS (63 tumors) (Figure 2B, Additional file 7).	('G12D', 'Var', (115, 119))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('V600E', 'Mutation', 'rs113488022', (53, 58))	('G12D', 'Mutation', 'rs121913529', (115, 119))	('tumors', 'Disease', (72, 78))	('tumors', 'Disease', (103, 109))	('KRAS', 'Gene', (123, 127))	('PIK3CA', 'Gene', (91, 97))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('tumors', 'Disease', 'MESH:D009369', (103, 109))	('V600E', 'Var', (53, 58))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('BRAF', 'Gene', '673', (62, 66))	('BRAF', 'Gene', (62, 66))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('H1047R', 'Var', (81, 87))	('tumors', 'Disease', (132, 138))	('H1047R', 'Mutation', 'rs121913279', (81, 87))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('PIK3CA', 'Gene', '5290', (91, 97))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('tumors', 'Disease', 'MESH:D009369', (132, 138))	('KRAS', 'Gene', '3845', (123, 127))
199776	26110843	Overall, BRAF (Sm = 2.71), PIK3CA (Sm = 1.25), KRAS (Sm = 1.11), and IDH1 (Sm = 0.82) showed the highest selection scores for missense mutations (Sm) among OGs.	('Sm = 1', 'Gene', '7911', (53, 59))	('IDH1', 'Gene', '3417', (69, 73))	('PIK3CA', 'Gene', '5290', (27, 33))	('missense mutations', 'Var', (126, 144))	('BRAF', 'Gene', (9, 13))	('Sm = 1', 'Gene', (35, 41))	('PIK3CA', 'Gene', (27, 33))	('Sm = 2', 'Gene', (15, 21))	('Sm = 2', 'Gene', '53366', (15, 21))	('Sm = 1', 'Gene', (53, 59))	('KRAS', 'Gene', (47, 51))	('KRAS', 'Gene', '3845', (47, 51))	('Sm = 1', 'Gene', '7911', (35, 41))	('IDH1', 'Gene', (69, 73))	('BRAF', 'Gene', '673', (9, 13))
199779	26110843	The most reliable feature set for TSG prediction included the ratio of LOF to benign mutations (p = 2.1 x 10-26, beta = 2.13), splicing to benign mutations (p = 3.1 x 10-22, beta = 1.85) and the frequency of homozygous copy number losses (p = 1.1 x 10-8, beta = 1.08) (Figures 2A and 2D).	('beta = 1', 'Gene', '10678', (174, 182))	('TSG', 'Gene', '57045', (34, 37))	('LOF', 'NegReg', (71, 74))	('beta = 1', 'Gene', '10678', (255, 263))	('copy number loss', 'Disease', 'MESH:D016388', (219, 235))	('beta = 2', 'Gene', '10242', (113, 121))	('splicing', 'Var', (127, 135))	('copy number loss', 'Disease', (219, 235))	('beta = 1', 'Gene', (174, 182))	('beta = 1', 'Gene', (255, 263))	('TSG', 'Gene', (34, 37))	('beta = 2', 'Gene', (113, 121))
199781	26110843	This indicates that canonical TSGs are characterized by copy number loss or mutations that have deleterious effects on protein function.	('mutations', 'Var', (76, 85))	('TSG', 'Gene', (30, 33))	('copy number loss', 'Disease', (56, 72))	('protein', 'Protein', (119, 126))	('copy number loss', 'Disease', 'MESH:D016388', (56, 72))	('TSG', 'Gene', '57045', (30, 33))
199782	26110843	Interestingly, multiple TSGs showed significantly recurrent LOF or splice site mutations including APC (R1450*; 22 tumors) and VHL (V155splice; 13 tumors) as well as missense mutations including TP53 (R175H; 51 tumors) and PTEN (R130G; 26 tumors) (Figure 2B, Additional file 7).	('tumors', 'Disease', 'MESH:D009369', (211, 217))	('tumors', 'Phenotype', 'HP:0002664', (239, 245))	('PTEN', 'Gene', '5728', (223, 227))	('VHL', 'Disease', 'MESH:D006623', (127, 130))	('LOF', 'NegReg', (60, 63))	('tumors', 'Disease', 'MESH:D009369', (147, 153))	('missense mutations', 'Var', (166, 184))	('R130G;', 'Var', (229, 235))	('tumors', 'Disease', (239, 245))	('TP53', 'Gene', (195, 199))	('R175H;', 'Var', (201, 207))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('R1450*', 'SUBSTITUTION', 'None', (104, 110))	('R1450*', 'Var', (104, 110))	('tumors', 'Phenotype', 'HP:0002664', (211, 217))	('tumors', 'Disease', 'MESH:D009369', (239, 245))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumors', 'Phenotype', 'HP:0002664', (147, 153))	('TSG', 'Gene', '57045', (24, 27))	('VHL', 'Disease', (127, 130))	('R175H', 'Mutation', 'rs28934578', (201, 206))	('tumors', 'Disease', (115, 121))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('tumors', 'Disease', (211, 217))	('TP53', 'Gene', '7157', (195, 199))	('TSG', 'Gene', (24, 27))	('R130G', 'Mutation', 'rs121909224', (229, 234))	('APC', 'Gene', (99, 102))	('PTEN', 'Gene', (223, 227))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumors', 'Disease', (147, 153))	('tumor', 'Phenotype', 'HP:0002664', (239, 244))	('tumors', 'Disease', 'MESH:D009369', (115, 121))
199783	26110843	Consequently, the selection scores for non-synonymous mutations (p = 4.1 x 10-18, beta = 1.89) were high in the training set (Figures 2A and 2C) and thus selected for TSG prediction by Lasso.	('TSG', 'Gene', '57045', (167, 170))	('beta = 1', 'Gene', '10678', (82, 90))	('beta = 1', 'Gene', (82, 90))	('TSG', 'Gene', (167, 170))	('non-synonymous mutations', 'Var', (39, 63))
199790	26110843	ARID1A had the highest ratio of LOF to benign mutations among ERGs, and was mutated in 25.4% of urothelial bladder tumors, 31.1% of gastric tumors, and 33.5% of endometrial tumors.	('tumors', 'Phenotype', 'HP:0002664', (173, 179))	('gastric tumors', 'Disease', (132, 146))	('urothelial bladder tumors', 'Disease', 'MESH:D001749', (96, 121))	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('mutations', 'Var', (46, 55))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('endometrial tumors', 'Disease', 'MESH:D016889', (161, 179))	('LOF', 'NegReg', (32, 35))	('mutated', 'Var', (76, 83))	('ARID1A', 'Gene', (0, 6))	('gastric tumors', 'Disease', 'MESH:D013274', (132, 146))	('endometrial tumors', 'Disease', (161, 179))	('bladder tumors', 'Phenotype', 'HP:0009725', (107, 121))	('gastric tumors', 'Phenotype', 'HP:0006753', (132, 146))	('ERG', 'Gene', (62, 65))	('ARID1A', 'Gene', '8289', (0, 6))	('urothelial bladder tumors', 'Disease', (96, 121))	('ERG', 'Gene', '2078', (62, 65))
199791	26110843	Overall 72.2% of all non-synonymous mutations in ARID1A were LOF.	('ARID1A', 'Gene', '8289', (49, 55))	('LOF', 'NegReg', (61, 64))	('ARID1A', 'Gene', (49, 55))	('non-synonymous mutations', 'Var', (21, 45))
199792	26110843	PBRM1 was mutated in 36.5% of clear cell renal carcinomas, of which 75.0% were LOF.	('renal carcinomas', 'Phenotype', 'HP:0005584', (41, 57))	('mutated', 'Var', (10, 17))	('clear cell renal carcinomas', 'Disease', 'MESH:C538614', (30, 57))	('PBRM1', 'Gene', (0, 5))	('clear cell renal carcinoma', 'Phenotype', 'HP:0006770', (30, 56))	('PBRM1', 'Gene', '55193', (0, 5))	('carcinoma', 'Phenotype', 'HP:0030731', (47, 56))	('carcinomas', 'Phenotype', 'HP:0030731', (47, 57))	('clear cell renal carcinomas', 'Phenotype', 'HP:0006770', (30, 57))	('renal carcinoma', 'Phenotype', 'HP:0005584', (41, 56))	('clear cell renal carcinomas', 'Disease', (30, 57))
199793	26110843	SETD2 was also classified as TSG with 39.9% of all non-synonymous mutations classified as LOF.	('SETD2', 'Gene', '29072', (0, 5))	('non-synonymous mutations', 'Var', (51, 75))	('TSG', 'Gene', (29, 32))	('SETD2', 'Gene', (0, 5))	('TSG', 'Gene', '57045', (29, 32))
199794	26110843	Consistent with the mutation profiles of TSGs in the training set, multiple LOF mutations had a non-random distribution within predicted TSGs in more than one tumor (Figures 3B and 3C).	('LOF', 'NegReg', (76, 79))	('TSG', 'Gene', '57045', (41, 44))	('mutations', 'Var', (80, 89))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('tumor', 'Disease', (159, 164))	('TSG', 'Gene', (137, 140))	('TSG', 'Gene', (41, 44))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('TSG', 'Gene', '57045', (137, 140))
199795	26110843	ARID1A, for example, showed a frameshift mutation at position 1848 in 20 tumors (Figure 3C).	('ARID1A', 'Gene', '8289', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('frameshift mutation at position 1848', 'Var', (30, 66))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('ARID1A', 'Gene', (0, 6))	('tumors', 'Disease', (73, 79))	('tumors', 'Disease', 'MESH:D009369', (73, 79))
199796	26110843	Overall, with the exception of alterations in DNMT3A, the most recurrent mutations within ERG families were associated with loss of function (Figure 3B).	('loss', 'NegReg', (124, 128))	('DNMT3A', 'Gene', (46, 52))	('ERG', 'Gene', '2078', (90, 93))	('DNMT3A', 'Gene', '1788', (46, 52))	('ERG', 'Gene', (90, 93))	('mutations', 'Var', (73, 82))
199797	26110843	Using the missense mutation selection score and the ratio of HiFI to LoFI mutations, only DNMT3A was predicted as OG.	('DNMT3A', 'Gene', '1788', (90, 96))	('missense mutation', 'Var', (10, 27))	('mutations', 'Var', (74, 83))	('DNMT3A', 'Gene', (90, 96))
199798	26110843	This result reflects the lack of recurrent and potentially activating hotspot missense mutations within ERG families in our tumor panel.	('missense mutations', 'Var', (78, 96))	('ERG', 'Gene', '2078', (104, 107))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('activating hotspot', 'PosReg', (59, 77))	('tumor', 'Disease', (124, 129))	('ERG', 'Gene', (104, 107))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
199799	26110843	With the exception of DNMT3A, we detected nonsense mutations and indels, but no missense point mutations among ERGs that occurred in more than four tumors.	('nonsense mutations', 'Var', (42, 60))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('DNMT3A', 'Gene', (22, 28))	('DNMT3A', 'Gene', '1788', (22, 28))	('ERG', 'Gene', '2078', (111, 114))	('ERG', 'Gene', (111, 114))	('tumors', 'Disease', (148, 154))	('tumors', 'Disease', 'MESH:D009369', (148, 154))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('indels', 'Var', (65, 71))
199801	26110843	In total 28 (14.4%) of the 195 tumors showed a missense mutation on position 882 resulting in an overall mutation selection score of 0.55.	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumors', 'Disease', (31, 37))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('tumors', 'Disease', 'MESH:D009369', (31, 37))	('missense mutation on', 'Var', (47, 67))
199803	26110843	Activating mutations within the SET domain of EZH2 are frequent in non-Hodgkin's lymphoma, but were not found as recurrent in the analyzed cancer types.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	("non-Hodgkin's lymphoma", 'Disease', 'MESH:D008228', (67, 89))	('Activating mutations', 'Var', (0, 20))	("Hodgkin's lymphoma", 'Phenotype', 'HP:0012189', (71, 89))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('lymphoma', 'Phenotype', 'HP:0002665', (81, 89))	("non-Hodgkin's lymphoma", 'Phenotype', 'HP:0012539', (67, 89))	('EZH2', 'Gene', '2146', (46, 50))	('EZH2', 'Gene', (46, 50))	('frequent', 'Reg', (55, 63))	("non-Hodgkin's lymphoma", 'Disease', (67, 89))	('cancer', 'Disease', (139, 145))
199805	26110843	The Lasso-based feature selection for OG/TSG prediction showed that canonical cancer drivers are usually characterized by significant mutation patterns or copy number alterations (Figure 2A), but not by consistent gene expression patterns.	('TSG', 'Gene', '57045', (41, 44))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('copy number alterations', 'Var', (155, 178))	('TSG', 'Gene', (41, 44))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))
199806	26110843	Consequently, while our machine learning approach enabled us to uncover cancer driver-like mutation and copy number alterations among ERGs, significant gene expression patterns could not be detected by prediction.	('ERG', 'Gene', (134, 137))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('copy number alterations', 'Var', (104, 127))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('ERG', 'Gene', '2078', (134, 137))	('cancer', 'Disease', (72, 78))
199847	26110843	Inhibition of EZH2 has been suggested to induce cell cycle arrest in G1 phase and antiproliferative response in the mutant-bearing lymphoma cell line WSU-DLCL2 (EZH2Y641F).	('cell cycle arrest in G1 phase', 'CPA', (48, 77))	('EZH2', 'Gene', '2146', (161, 165))	('EZH2', 'Gene', (161, 165))	('EZH2', 'Gene', (14, 18))	('EZH2', 'Gene', '2146', (14, 18))	('induce', 'PosReg', (41, 47))	('lymphoma', 'Disease', (131, 139))	('Inhibition', 'Var', (0, 10))	('lymphoma', 'Disease', 'MESH:D008223', (131, 139))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (48, 65))	('antiproliferative response', 'CPA', (82, 108))	('lymphoma', 'Phenotype', 'HP:0002665', (131, 139))
199851	26110843	Consistent with previous findings, we observed decreased viability of WSU-DLCL2 cells after EZH2 inhibition.	('inhibition', 'Var', (97, 107))	('viability', 'CPA', (57, 66))	('EZH2', 'Gene', (92, 96))	('EZH2', 'Gene', '2146', (92, 96))	('decreased', 'NegReg', (47, 56))
199852	26110843	Concordant with EZH2 as member of the PRC2 complex, which trimethylates histone 3 on lysine 27, the level of the H3K27me3 histone mark decreased by a factor of 2 and 3.3 after 2 and 5 days respectively (Additional file 14).	('EZH2', 'Gene', (16, 20))	('H3K27me3', 'Var', (113, 121))	('level', 'MPA', (100, 105))	('lysine', 'Chemical', 'MESH:D008239', (85, 91))	('decreased', 'NegReg', (135, 144))	('EZH2', 'Gene', '2146', (16, 20))
199853	26110843	We identified 2530 proteins on average and quantified their intensity changes between EPZ-6438 treated cells (heavy labeled) and their respective non-treated control cells (light labeled) (Additional file 15).	('EPZ-6438', 'Var', (86, 94))	('EPZ-6438', 'Chemical', 'MESH:C000593333', (86, 94))	('intensity', 'MPA', (60, 69))	('proteins', 'Protein', (19, 27))
199855	26110843	Overall, 24 cell cycle associated proteins were up-regulated after EZH2 inhibition including tumor suppressors ATM, BRCA2 and cell cycle inhibitor CDN2C.	('ATM', 'Gene', (111, 114))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('up-regulated', 'PosReg', (48, 60))	('ATM', 'Gene', '472', (111, 114))	('tumor', 'Disease', (93, 98))	('BRCA2', 'Gene', '675', (116, 121))	('BRCA2', 'Gene', (116, 121))	('inhibition', 'Var', (72, 82))	('cell', 'Protein', (12, 16))	('BRCA', 'Phenotype', 'HP:0003002', (116, 120))	('EZH2', 'Gene', (67, 71))	('EZH2', 'Gene', '2146', (67, 71))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
199858	26110843	By training cancer gene predictors based on TCGA data, we found that classical cancer drivers are characterized by significant mutation or copy number patterns, but not by altered expression.	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('copy number patterns', 'Var', (139, 159))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('cancer', 'Disease', (12, 18))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))
199859	26110843	Among ERGs we identified multiple TSGs with significant proportions of loss of function mutations.	('loss of function', 'NegReg', (71, 87))	('ERG', 'Gene', '2078', (6, 9))	('TSG', 'Gene', '57045', (34, 37))	('ERG', 'Gene', (6, 9))	('mutations', 'Var', (88, 97))	('TSG', 'Gene', (34, 37))
199865	26110843	Activating mutations within the catalytic SET domain of EZH2, for example, are known in non-Hodgkin's lymphoma, but were absent in our tumor cohort.	("non-Hodgkin's lymphoma", 'Disease', 'MESH:D008228', (88, 110))	('Activating', 'PosReg', (0, 10))	("non-Hodgkin's lymphoma", 'Disease', (88, 110))	('mutations', 'Var', (11, 20))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('lymphoma', 'Phenotype', 'HP:0002665', (102, 110))	('tumor', 'Disease', (135, 140))	("Hodgkin's lymphoma", 'Phenotype', 'HP:0012189', (92, 110))	("non-Hodgkin's lymphoma", 'Phenotype', 'HP:0012539', (88, 110))	('EZH2', 'Gene', '2146', (56, 60))	('EZH2', 'Gene', (56, 60))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
199866	26110843	Many ERGs, which were not predicted as drivers, had dysregulated expression in cancer.	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('dysregulated', 'Var', (52, 64))	('expression', 'MPA', (65, 75))	('ERG', 'Gene', '2078', (5, 8))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('ERG', 'Gene', (5, 8))
199871	26110843	Despite the limitations of mass spectrometry to identify a subset of the whole human proteome only, we confirmed the down-regulation of cell cycle proteins and showed a decrease of the PRC2-associated H3K27 methylation mark after EZH2 inhibition.	('PRC2-associated H3K27', 'Protein', (185, 206))	('human', 'Species', '9606', (79, 84))	('decrease', 'NegReg', (169, 177))	('methylation mark', 'MPA', (207, 223))	('EZH2', 'Gene', (230, 234))	('EZH2', 'Gene', '2146', (230, 234))	('inhibition', 'Var', (235, 245))	('cell', 'Protein', (136, 140))	('down-regulation', 'NegReg', (117, 132))
199879	26110843	Taken together, our prediction method identified several ERGs with mutation alteration profiles characteristic of classical TSGs.	('TSG', 'Gene', (124, 127))	('ERG', 'Gene', (57, 60))	('TSG', 'Gene', '57045', (124, 127))	('ERG', 'Gene', '2078', (57, 60))	('mutation alteration', 'Var', (67, 86))
199894	30755833	For example, knockdown of AFAP1-AS1 could suppress cell proliferation, migration and invasion in TSCC.	('suppress', 'NegReg', (42, 50))	('AS1', 'Gene', '5729', (32, 35))	('AFAP1', 'Gene', (26, 31))	('AS1', 'Gene', (32, 35))	('AFAP1', 'Gene', '60312', (26, 31))	('TSCC', 'Disease', (97, 101))	('migration', 'CPA', (71, 80))	('TSCC', 'Phenotype', 'HP:0030413', (97, 101))	('invasion', 'CPA', (85, 93))	('cell proliferation', 'CPA', (51, 69))	('knockdown', 'Var', (13, 22))
199909	30755833	For example, LINC00472 interacted with GREM2 mediated by mir-503 and SFTAIP regulated IL11 levels by sponging mir-211 (Fig.	('mir', 'Gene', (110, 113))	('mir-503', 'Gene', '574506', (57, 64))	('mir', 'Gene', '220972', (57, 60))	('mir-503', 'Gene', (57, 64))	('sponging', 'Var', (101, 109))	('mir', 'Gene', '220972', (110, 113))	('LINC00472', 'Gene', (13, 22))	('mir', 'Gene', (57, 60))	('GREM2', 'Gene', '64388', (39, 44))	('IL11', 'Gene', (86, 90))	('GREM2', 'Gene', (39, 44))	('LINC00472', 'Gene', '79940', (13, 22))	('IL11', 'Gene', '3589', (86, 90))
199912	30755833	Stage I + II) and TNM stage (T3 + T4 vs. T1 + T2, N2 + N3 vs. N0 + N1).	('N2 + N3 vs.', 'Var', (50, 61))	('TNM', 'Gene', (18, 21))	('TNM', 'Gene', '10178', (18, 21))	('T3 + T4', 'Var', (29, 36))
199913	30755833	We found six lncRNAs with a high expression level (LINC00355, PSORS1C3, LINC00520, AC112721.1, AL139147.1, SFTA1P) and four lncRNAs with a low expression level (HCG22, LINC00492, AL035696.1, ERVH48-1) were significantly associated with the progression of TSCC (Table 4).	('ERVH48-1', 'Gene', (191, 199))	('LINC00520', 'Gene', '645687', (72, 81))	('expression', 'MPA', (33, 43))	('HCG22', 'Gene', '285834', (161, 166))	('LINC00492', 'Gene', (168, 177))	('TSCC', 'Phenotype', 'HP:0030413', (255, 259))	('PSORS1C3', 'Gene', (62, 70))	('SFTA1P', 'Gene', '207107', (107, 113))	('LINC00355', 'Gene', '144766', (51, 60))	('LINC00492', 'Gene', '100861468', (168, 177))	('HCG22', 'Gene', (161, 166))	('PSORS1C3', 'Gene', '100130889', (62, 70))	('AC112721.1', 'Var', (83, 93))	('SFTA1P', 'Gene', (107, 113))	('LINC00520', 'Gene', (72, 81))	('AL139147.1', 'Var', (95, 105))	('LINC00355', 'Gene', (51, 60))	('AL035696.1', 'Var', (179, 189))	('associated with', 'Reg', (220, 235))	('ERVH48-1', 'Gene', '90625', (191, 199))	('TSCC', 'Disease', (255, 259))
199918	30755833	However, there is no research to clearly explain the function of AL163952.1, C2orf48, FAM87A, STEAR-AS1, TSPEAR-AS1 and ERVH48-1.	('FAM87A', 'Gene', (86, 92))	('C2orf48', 'Gene', (77, 84))	('AS1', 'Gene', (112, 115))	('AL163952.1', 'Var', (65, 75))	('C2orf48', 'Gene', '348738', (77, 84))	('AS1', 'Gene', '5729', (112, 115))	('ERVH48-1', 'Gene', (120, 128))	('AS1', 'Gene', '5729', (100, 103))	('AS1', 'Gene', (100, 103))	('FAM87A', 'Gene', '157693', (86, 92))	('ERVH48-1', 'Gene', '90625', (120, 128))
199922	30755833	In our ceRNA network, low PART1 expression reduced levels of NR3C2 mediated by mir-301b, and reduced expression of NR3C2 promotes tumor cell proliferation, metastasis and epithelial-to-mesenchymal transition.	('mir-301b', 'Gene', (79, 87))	('PART1', 'Protein', (26, 31))	('low', 'Var', (22, 25))	('reduced', 'NegReg', (93, 100))	('metastasis', 'CPA', (156, 166))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('levels of', 'MPA', (51, 60))	('promotes', 'PosReg', (121, 129))	('NR3C2', 'Gene', (115, 120))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('expression', 'MPA', (101, 111))	('epithelial-to-mesenchymal transition', 'CPA', (171, 207))	('reduced', 'NegReg', (43, 50))	('tumor', 'Disease', (130, 135))
199923	30755833	In addition, patients with low levels of NR3C2 have a poor prognosis in pancreatic cancer and renal cell carcinoma.	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (94, 114))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (72, 89))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (94, 114))	('pancreatic cancer', 'Disease', (72, 89))	('patients', 'Species', '9606', (13, 21))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('pancreatic cancer', 'Disease', 'MESH:D010190', (72, 89))	('low levels', 'Var', (27, 37))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('NR3C2', 'Gene', (41, 46))	('renal cell carcinoma', 'Disease', (94, 114))
199931	30755833	Low expression of ENPP2 increases reactive oxygen species (ROS) level, and high ROS level could promote tumor cell apoptosis.	('increases', 'PosReg', (24, 33))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('ROS', 'Chemical', 'MESH:D017382', (59, 62))	('ENPP2', 'Gene', '5168', (18, 23))	('tumor', 'Disease', (104, 109))	('promote', 'PosReg', (96, 103))	('ENPP2', 'Gene', (18, 23))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (34, 57))	('ROS', 'Chemical', 'MESH:D017382', (80, 83))	('Low expression', 'Var', (0, 14))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
200014	28819406	However, for patients with metastasis of N2 + N3 (3 or more locoregional lymph nodes), patients of Group S had significantly worse OS and DFS than those in the other two groups (p=0.04; p=0.004, respectively; Fig 2C&D).	('N2 + N3', 'Var', (41, 48))	('OS', 'Chemical', '-', (131, 133))	('patients', 'Species', '9606', (13, 21))	('worse', 'NegReg', (125, 130))	('DFS', 'MPA', (138, 141))	('patients', 'Species', '9606', (87, 95))
200060	33596971	In this study we have investigated FAMC3 copy number gain in different cancers and its potential connection to MET amplifications.	('cancers', 'Disease', 'MESH:D009369', (71, 78))	('cancers', 'Phenotype', 'HP:0002664', (71, 78))	('cancers', 'Disease', (71, 78))	('MET', 'Gene', '79811', (111, 114))	('FAMC3', 'Gene', (35, 40))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('copy number', 'Var', (41, 52))	('MET', 'Gene', (111, 114))
200062	33596971	Copy numbers of the two genes were correlated with mRNA levels, with relapse-free survival in lung cancer patient samples as well as with clinicopathological parameters in primary samples from 49 advanced stage colorectal cancer patients.	('correlated', 'Reg', (35, 45))	('mRNA levels', 'MPA', (51, 62))	('patients', 'Species', '9606', (229, 237))	('lung cancer', 'Disease', 'MESH:D008175', (94, 105))	('colorectal cancer', 'Disease', 'MESH:D015179', (211, 228))	('patient', 'Species', '9606', (106, 113))	('relapse-free', 'Disease', (69, 81))	('colorectal cancer', 'Phenotype', 'HP:0003003', (211, 228))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('lung cancer', 'Disease', (94, 105))	('Copy numbers', 'Var', (0, 12))	('lung cancer', 'Phenotype', 'HP:0100526', (94, 105))	('colorectal cancer', 'Disease', (211, 228))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('patient', 'Species', '9606', (229, 236))
200067	33596971	c-MET inhibition reduced ILEI secretion, and shRNA mediated ILEI knock-down prevented c-MET-signaling induced elevated expression and secretion of matrix metalloproteinase (MMP)-2 and MMP-9.	('expression', 'MPA', (119, 129))	('secretion', 'MPA', (134, 143))	('MMP-9', 'Gene', '4318', (184, 189))	('knock-down', 'Var', (65, 75))	('matrix metalloproteinase (MMP)-2', 'Gene', '4313', (147, 179))	('MMP-9', 'Gene', (184, 189))	('c-MET-signaling', 'MPA', (86, 101))	('prevented', 'NegReg', (76, 85))	('ILEI secretion', 'MPA', (25, 39))	('inhibition reduced', 'NegReg', (6, 24))	('c-MET', 'Protein', (0, 5))	('elevated', 'PosReg', (110, 118))
200073	33596971	An example is when proto-oncogenes with physiological functions within healthy cells become hyperactive or dysregulated leading to uncontrolled cell growth.	('proto-oncogenes', 'Gene', (19, 34))	('hyperactive', 'Disease', 'MESH:D006948', (92, 103))	('hyperactive', 'Disease', (92, 103))	('dysregulated', 'Var', (107, 119))	('uncontrolled', 'MPA', (131, 143))	('leading to', 'Reg', (120, 130))
200078	33596971	An increased gene copy number (CN) can result from gene amplification or aneuploidy.	('increased', 'PosReg', (3, 12))	('result', 'Reg', (39, 45))	('aneuploidy', 'Disease', (73, 83))	('gene amplification', 'Var', (51, 69))	('gene copy number', 'MPA', (13, 29))	('aneuploidy', 'Disease', 'MESH:D000782', (73, 83))
200091	33596971	Further in vitro mechanistic investigations and xenograft experiments with combined counteraction of ILEI and c-MET activities suggest that c-MET and ILEI cooperate to increase the invasiveness of cancer cells.	('increase', 'PosReg', (168, 176))	('cancer', 'Disease', 'MESH:D009369', (197, 203))	('cancer', 'Disease', (197, 203))	('c-MET', 'Var', (140, 145))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))
200111	33596971	Cells were plated in 100 mul complete medium in 96-well flat bottom plates in the presence or absence of crizotinib (500 nM) or vehicle (DMSO) or increasing concentrations of PHA665752 (Sigma) and Savolitinib (Selleckchem).	('crizotinib', 'Chemical', 'MESH:D000077547', (105, 115))	('PHA665752', 'Var', (175, 184))	('DMSO', 'Chemical', 'MESH:D004121', (137, 141))	('Savolitinib', 'Chemical', 'MESH:C000593259', (197, 208))	('PHA665752', 'Chemical', 'MESH:C480541', (175, 184))	('500 nM', 'Var', (117, 123))
200140	33596971	Patients with MET and/or FAM3C amplification also had a significantly worse survival compared to the pooled cohort of patients with deletions, normal, or slight gain in the CN of the two gene loci, albeit low case number and early loss on patient follow-up prevented a proper analysis on the survival of LUSC FAM3C amplified patients (Fig.	('patient', 'Species', '9606', (325, 332))	('patient', 'Species', '9606', (239, 246))	('patients', 'Species', '9606', (325, 333))	('FAM3C', 'Gene', '10447', (309, 314))	('MET', 'Gene', '79811', (14, 17))	('survival', 'MPA', (76, 84))	('worse', 'NegReg', (70, 75))	('FAM3C', 'Gene', '10447', (25, 30))	('FAM3C', 'Gene', (309, 314))	('Patients', 'Species', '9606', (0, 8))	('MET', 'Gene', (14, 17))	('FAM3C', 'Gene', (25, 30))	('patient', 'Species', '9606', (118, 125))	('patients', 'Species', '9606', (118, 126))	('amplification', 'Var', (31, 44))
200144	33596971	In addition, cluster and correlation analysis of FAM3C amplification with available clinicopathological parameters elucidated a significant enrichment of FAM3C amplification in patients with extramural venous invasion (EMVI) (Supplemental Fig.S1B, C).	('amplification', 'Var', (160, 173))	('FAM3C', 'Gene', '10447', (154, 159))	('FAM3C', 'Gene', '10447', (49, 54))	('patients', 'Species', '9606', (177, 185))	('FAM3C', 'Gene', (154, 159))	('extramural venous invasion', 'Disease', (191, 217))	('FAM3C', 'Gene', (49, 54))
200146	33596971	Although ILEI has not been linked so far to EMVI, our finding is in accordance with the described function of ILEI in inducing EMT and invasion and reflects that FAM3C amplification might affect gene function resulting in a clinically worse outcome.	('inducing', 'PosReg', (118, 126))	('gene function', 'MPA', (195, 208))	('FAM3C', 'Gene', '10447', (162, 167))	('amplification', 'Var', (168, 181))	('affect', 'Reg', (188, 194))	('FAM3C', 'Gene', (162, 167))
200147	33596971	So, these results support the database analysis showing frequent co-amplification of MET and FAM3C and the likelihood of poor survival rates in patients with increased CNs of these genes.	('MET', 'Gene', (85, 88))	('FAM3C', 'Gene', '10447', (93, 98))	('patients', 'Species', '9606', (144, 152))	('survival rates', 'CPA', (126, 140))	('MET', 'Gene', '79811', (85, 88))	('FAM3C', 'Gene', (93, 98))	('co-amplification', 'Var', (65, 81))	('poor', 'NegReg', (121, 125))	('increased', 'PosReg', (158, 167))
200165	33596971	To address any concerns of the polypharmacological action of crizotinib, which inhibits other targets such as ALK5, we also investigated the action of two additional c-MET inhibitors: PHA665752 and savolitinib.	('PHA665752', 'Chemical', 'MESH:C480541', (184, 193))	('crizotinib', 'Chemical', 'MESH:D000077547', (61, 71))	('investigated', 'Reg', (124, 136))	('savolitinib', 'Chemical', 'MESH:C000593259', (198, 209))	('ALK5', 'Gene', '7046', (110, 114))	('ALK5', 'Gene', (110, 114))	('PHA665752', 'Var', (184, 193))
200175	33596971	Activation of Erk, an important downstream effector of c-MET, was also significantly reduced upon drug treatment in these cells, whereas it remained unaltered in SKBR3 cells, which do not express c-MET (Fig.	('Erk', 'Gene', (14, 17))	('drug', 'Var', (98, 102))	('Erk', 'Gene', '5594', (14, 17))	('Activation', 'MPA', (0, 10))	('reduced', 'NegReg', (85, 92))
200177	33596971	Importantly, however, crizotinib decreased the secretion of ILEI in all c-Met expressing cell lines, but not in SKBR3 cells (Fig.	('crizotinib', 'Chemical', 'MESH:D000077547', (22, 32))	('c-Met', 'Gene', (72, 77))	('secretion of ILEI', 'MPA', (47, 64))	('c-Met', 'Gene', '4233', (72, 77))	('crizotinib', 'Var', (22, 32))	('decreased', 'NegReg', (33, 42))
200187	33596971	The secretion of MMP-9 from NCI-H441 cells decreased slightly with crizotinib treatment or ILEI KD, and the combination of the two lead to a significant reduction (Figs.	('NCI-H441', 'Chemical', '-', (28, 36))	('crizotinib', 'Chemical', 'MESH:D000077547', (67, 77))	('MMP-9', 'Gene', (17, 22))	('reduction', 'NegReg', (153, 162))	('crizotinib', 'Var', (67, 77))	('decreased', 'NegReg', (43, 52))	('MMP-9', 'Gene', '4318', (17, 22))
200200	33596971	However, in accordance with some earlier findings, we observed that inhibition of c-MET with crizotinib reduced the growth and tumor mass of both of the xenografts (Fig.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('reduced', 'NegReg', (104, 111))	('tumor', 'Disease', (127, 132))	('inhibition', 'Var', (68, 78))	('crizotinib', 'Gene', (93, 103))	('c-MET', 'Protein', (82, 87))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('crizotinib', 'Chemical', 'MESH:D000077547', (93, 103))
200203	33596971	The tumor mass was significantly decreased in cells with ILEI KD compared to those with ILEI expression and was lowest in cells with ILEI KD and crizotinib combined (Fig.	('lowest', 'NegReg', (112, 118))	('tumor', 'Disease', (4, 9))	('ILEI KD', 'Var', (57, 64))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('decreased', 'NegReg', (33, 42))	('crizotinib', 'Chemical', 'MESH:D000077547', (145, 155))
200213	33596971	So, the smaller tumors are likely to be due to the decreased proliferation upon crizotinib treatment rather than an increase in apoptotic cell death.	('crizotinib', 'Chemical', 'MESH:D000077547', (80, 90))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('crizotinib', 'Var', (80, 90))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('decreased', 'NegReg', (51, 60))	('tumors', 'Disease', 'MESH:D009369', (16, 22))	('smaller', 'NegReg', (8, 15))	('proliferation', 'CPA', (61, 74))	('tumors', 'Disease', (16, 22))
200226	33596971	In both, NCI-H441 and NCI-H1993 xenografts immunohistochemistry of tumor sections showed a slight increase of E-cadherin at the membranes of tumors treated with crizotinib and those derived from ILEI KD cells, and this became significant when they were in combination (Fig.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('crizotinib', 'Var', (161, 171))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('E-cadherin', 'Protein', (110, 120))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumors', 'Disease', (141, 147))	('tumors', 'Disease', 'MESH:D009369', (141, 147))	('tumor', 'Disease', (141, 146))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('NCI-H441', 'Chemical', '-', (9, 17))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('increase', 'PosReg', (98, 106))	('crizotinib', 'Chemical', 'MESH:D000077547', (161, 171))	('NCI-H1993', 'CellLine', 'CVCL:1512', (22, 31))	('tumor', 'Disease', (67, 72))
200235	33596971	Amplified MET CN has been shown to negatively influence patient survival in a lot of cancer types including esophageal squamous cell carcinoma, NSCLC, clear-cell renal cell carcinoma, and ovarian carcinoma.	('NSCLC', 'Disease', (144, 149))	('MET', 'Gene', (10, 13))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('clear-cell renal cell carcinoma', 'Disease', (151, 182))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (119, 142))	('influence', 'Reg', (46, 55))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (162, 182))	('negatively', 'NegReg', (35, 45))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (108, 142))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('patient', 'Species', '9606', (56, 63))	('clear-cell renal cell carcinoma', 'Disease', 'MESH:C538614', (151, 182))	('MET', 'Gene', '79811', (10, 13))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (188, 205))	('carcinoma', 'Phenotype', 'HP:0030731', (173, 182))	('patient survival', 'CPA', (56, 72))	('cancer', 'Disease', (85, 91))	('ovarian carcinoma', 'Disease', (188, 205))	('carcinoma', 'Phenotype', 'HP:0030731', (196, 205))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('Amplified', 'Var', (0, 9))	('NSCLC', 'Disease', 'MESH:D002289', (144, 149))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (188, 205))	('esophageal squamous cell carcinoma', 'Disease', (108, 142))
200241	33596971	The high efficiency of the combined inhibition of c-MET and ILEI function on the inhibition of invasion and tumor growth of cancer cells bearing MET and FAM3C amplifications found in this study justifies the relevance of this co-amplification on clinical outcomes.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('MET', 'Gene', (52, 55))	('FAM3C', 'Gene', (153, 158))	('cancer', 'Disease', (124, 130))	('invasion', 'CPA', (95, 103))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('MET', 'Gene', '79811', (145, 148))	('inhibition', 'NegReg', (36, 46))	('inhibition', 'NegReg', (81, 91))	('MET', 'Gene', '79811', (52, 55))	('tumor', 'Disease', (108, 113))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('MET', 'Gene', (145, 148))	('FAM3C', 'Gene', '10447', (153, 158))	('amplifications', 'Var', (159, 173))	('cancer', 'Disease', 'MESH:D009369', (124, 130))
200258	33596971	While interactions between c-MET and human epidermal growth factor receptor (HER) family members allow tumor progression and treatment resistance, and cooperative signaling between c-MET and HER2 might be a mechanism by which c-MET promotes cancer progression.	('treatment resistance', 'CPA', (125, 145))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('promotes', 'PosReg', (232, 240))	('interactions', 'Interaction', (6, 18))	('HER2', 'Gene', (191, 195))	('epidermal growth factor receptor', 'Gene', '1956', (43, 75))	('tumor', 'Disease', (103, 108))	('HER2', 'Gene', '2064', (191, 195))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('cancer', 'Disease', 'MESH:D009369', (241, 247))	('epidermal growth factor receptor', 'Gene', (43, 75))	('allow', 'Reg', (97, 102))	('cancer', 'Disease', (241, 247))	('human', 'Species', '9606', (37, 42))	('c-MET', 'Var', (226, 231))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
200262	33596971	Because of the importance of c-MET in many cancer types, inhibitors of c-MET are in clinical trials as cancer treatment, but a significant percentage of tumors acquire resistance to these treatments.	('inhibitors', 'Var', (57, 67))	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('cancer', 'Disease', (43, 49))	('c-MET', 'Gene', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumors', 'Disease', (153, 159))	('tumors', 'Phenotype', 'HP:0002664', (153, 159))	('resistance', 'MPA', (168, 178))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('tumors', 'Disease', 'MESH:D009369', (153, 159))
200264	33596971	Combination treatments may help address this problem and the results of this study suggest that ILEI might be a potential target for these treatments as highlighted by the xenograft experiments that showed tumor growth was mostly inhibited by combined crizotinib and ILEI KD.	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('crizotinib', 'Chemical', 'MESH:D000077547', (252, 262))	('inhibited', 'NegReg', (230, 239))	('tumor', 'Disease', (206, 211))	('crizotinib', 'Var', (252, 262))	('tumor', 'Disease', 'MESH:D009369', (206, 211))
200282	33596971	However, crizotinib reduced the growth and tumor mass of xenografts induced by both sensitive (NCI-H1993) and resistant (NCI-H441) cell types.	('NCI-H441', 'Chemical', '-', (121, 129))	('reduced', 'NegReg', (20, 27))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('crizotinib', 'Var', (9, 19))	('NCI-H1993', 'CellLine', 'CVCL:1512', (95, 104))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Disease', (43, 48))	('crizotinib', 'Chemical', 'MESH:D000077547', (9, 19))
200283	33596971	This was is in accordance with some earlier findings and suggested that crizotinib was able to counteract the resistence of NCI-H441 cells to inhibit c-MET, most probably via non-cell intrinsic mechanisms that will require further investigation.	('crizotinib', 'Var', (72, 82))	('NCI-H441', 'Chemical', '-', (124, 132))	('inhibit', 'NegReg', (142, 149))	('c-MET', 'MPA', (150, 155))	('crizotinib', 'Chemical', 'MESH:D000077547', (72, 82))
200285	33596971	Combination of ILEI KD and crizotinib also resulted in lower expression of MMPs in a similar way to the cell-based studies.	('crizotinib', 'Var', (27, 37))	('MMPs', 'Protein', (75, 79))	('crizotinib', 'Chemical', 'MESH:D000077547', (27, 37))	('lower', 'NegReg', (55, 60))	('expression', 'MPA', (61, 71))
200290	33596971	The results of this study show that amplification of FAM3C CN can contribute to increase the level of ILEI expression in a wide range of cancer types.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('FAM3C', 'Gene', (53, 58))	('increase', 'PosReg', (80, 88))	('level', 'MPA', (93, 98))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('ILEI expression', 'MPA', (102, 117))	('amplification', 'Var', (36, 49))	('FAM3C', 'Gene', '10447', (53, 58))	('cancer', 'Disease', (137, 143))
200299	33011746	We demonstrate that the substitution of the putative phosphorylation site of caspase-2, Serine-384 to Alanine, blocks caspase-2 processing and decreases its enzymatic activity.	('Serine-384 to Alanine', 'Mutation', 'rs775379645', (88, 109))	('enzymatic activity', 'MPA', (157, 175))	('decreases', 'NegReg', (143, 152))	('Serine-384', 'Var', (88, 98))	('blocks', 'NegReg', (111, 117))	('substitution', 'Var', (24, 36))	('caspase-2', 'Gene', (77, 86))	('processing', 'MPA', (128, 138))	('caspase-2', 'Protein', (118, 127))
200301	33011746	It stabilizes Arginine-378, which forms a crucial hydrogen bond with the aspartate residue of a substrate.	('hydrogen', 'Chemical', 'MESH:D006859', (50, 58))	('Arginine-378', 'Var', (14, 26))	('hydrogen bond', 'MPA', (50, 63))	('Arginine', 'Chemical', 'MESH:D001120', (14, 22))	('aspartate', 'Chemical', 'MESH:D001224', (73, 82))
200304	33011746	Importantly, a multiple alignment has demonstrated that both Serine-384 and Arg-378 residues are highly conservative across all members of caspase family, which allows us to suggest that this diade is indispensable for caspase processing and activity.	('caspase', 'Gene', '835;12366;838;839;841;12370;842;12371;843', (219, 226))	('caspase', 'Gene', (139, 146))	('Serine-384', 'Var', (61, 71))	('Arg', 'Chemical', 'MESH:D001120', (76, 79))	('Serine', 'Chemical', 'MESH:D012694', (61, 67))	('caspase', 'Gene', (219, 226))	('Arg-378 residues', 'Var', (76, 92))	('caspase', 'Gene', '835;12366;838;839;841;12370;842;12371;843', (139, 146))
200305	33011746	Spontaneous mutations in this diade might influence oncosuppressive function of caspases, in particular of caspase-2.	('caspases', 'Gene', '835;12366;838;839;841;12370;842;12371;843', (80, 88))	('mutations', 'Var', (12, 21))	('caspase-2', 'Enzyme', (107, 116))	('influence', 'Reg', (42, 51))	('oncosuppressive function', 'MPA', (52, 76))	('caspases', 'Gene', (80, 88))
200306	33011746	Likewise, the mutation of Ser-384 is associated with the development of lung squamous cell carcinoma and adenocarcinoma.	('Ser-384', 'Gene', (26, 33))	('associated with', 'Reg', (37, 52))	('adenocarcinoma', 'Disease', (105, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('adenocarcinoma', 'Disease', 'MESH:D000230', (105, 119))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (72, 100))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (77, 100))	('mutation', 'Var', (14, 22))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (72, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('Ser', 'Chemical', 'MESH:D012694', (26, 29))	('lung squamous cell carcinoma', 'Disease', (72, 100))
200307	33011746	A number of factors, such as gamma-irradiation, DNA damaging agents, hypoxic conditions, deprivation of growth factors or death receptor activation, induce apoptotic cell death.	('apo', 'Gene', '84909', (156, 159))	('hypoxic conditions', 'Disease', 'MESH:D000071069', (69, 87))	('apo', 'Gene', (156, 159))	('induce', 'Reg', (149, 155))	('hypoxic conditions', 'Disease', (69, 87))	('deprivation', 'Var', (89, 100))
200322	33011746	In metabolic pathways, induction of the pentose phosphate pathway leads to calcium/calmodulin-dependent kinase II (CaMKII) activation and the inhibition of caspase-2 by phosphorylation at Ser-135 (Ser-164 in humans).	('pentose phosphate pathway', 'Pathway', (40, 65))	('CaMKII', 'Gene', '818', (115, 121))	('CaMKII', 'Gene', (115, 121))	('phosphorylation', 'Var', (169, 184))	('inhibition', 'NegReg', (142, 152))	('humans', 'Species', '9606', (208, 214))	('calcium/calmodulin-dependent kinase II', 'Gene', (75, 113))	('Ser', 'Chemical', 'MESH:D012694', (197, 200))	('activation', 'PosReg', (123, 133))	('calcium/calmodulin-dependent kinase II', 'Gene', '818', (75, 113))	('metabolic pathways', 'Pathway', (3, 21))	('pentose phosphate', 'Chemical', 'MESH:D010428', (40, 57))	('caspase-2', 'Protein', (156, 165))	('Ser', 'Chemical', 'MESH:D012694', (188, 191))
200324	33011746	Furthermore, using mutagenesis and several biochemical assays, we have shown an importance of Ser-384 for caspase-2 processing and activation.	('caspase-2', 'Protein', (106, 115))	('Ser', 'Chemical', 'MESH:D012694', (94, 97))	('processing', 'MPA', (116, 126))	('mutagenesis', 'Var', (19, 30))	('activation', 'MPA', (131, 141))
200325	33011746	Furthermore, molecular dynamics has demonstrated that Ser-384 plays a crucial role in the stabilization of a key residue of the active center:Arg-378:and is, therefore, essential for substrate binding.	('stabilization', 'MPA', (90, 103))	('Arg', 'Chemical', 'MESH:D001120', (142, 145))	('Arg-378', 'Var', (142, 149))	('Ser', 'Chemical', 'MESH:D012694', (54, 57))
200328	33011746	Based on the highest score results, we selected several residues (Ser-220, Ser-307, Thr-380, Ser-384) for further investigation (Fig.	('Ser-307', 'Var', (75, 82))	('Thr', 'Chemical', 'MESH:D013912', (84, 87))	('Ser', 'Chemical', 'MESH:D012694', (66, 69))	('Ser-220', 'Var', (66, 73))	('Ser', 'Chemical', 'MESH:D012694', (93, 96))	('Ser-384', 'Var', (93, 100))	('Thr-380', 'Var', (84, 91))	('Ser', 'Chemical', 'MESH:D012694', (75, 78))
200329	33011746	To verify the results of predictions in silico, mutants of caspase-2 (Ser-220Ala, Ser-307Ala, Thr-380Ala, Ser-384Ala) were generated by the substitution of Serine/Threonine residues to Alanine.	('Threonine', 'Chemical', 'MESH:D013912', (163, 172))	('Serine', 'Chemical', 'MESH:D012694', (156, 162))	('Ser-307Ala', 'Var', (82, 92))	('Alanine', 'Chemical', 'MESH:D000409', (185, 192))	('Thr-380Ala', 'Var', (94, 104))	('Thr-380Ala', 'Mutation', 'p.T380A', (94, 104))	('Ser-384Ala', 'Mutation', 'rs775379645', (106, 116))	('Ser-307Ala', 'Mutation', 'p.S307A', (82, 92))	('Ser-220Ala', 'Var', (70, 80))	('Ser-220Ala', 'Mutation', 'p.S220A', (70, 80))	('Ser-384Ala', 'Var', (106, 116))	('caspase-2', 'Gene', (59, 68))	('Serine/Threonine', 'Protein', (156, 172))
200330	33011746	The caspase-2 mutants and non-mutated caspase-2 (Caspase-2WT) were transiently overexpressed in the human embryonic kidney cell line HEK293T.	('caspase-2', 'Gene', (4, 13))	('mutants', 'Var', (14, 21))	('Caspase-2', 'Gene', (49, 58))	('embryonic kidney', 'Disease', 'MESH:D007674', (106, 122))	('HEK293T', 'CellLine', 'CVCL:0063', (133, 140))	('human', 'Species', '9606', (100, 105))	('Caspase-2', 'Gene', '835', (49, 58))	('embryonic kidney', 'Disease', (106, 122))
200332	33011746	Accordingly, the overexpression of caspase-2WT as well as of caspase-2Ser-220Ala, caspase-2Ser-307Ala, and caspase-2Thr-380Ala was sufficient to induce their autocatalytic processing to cleavage products p37 and p19 and generation of caspase-2 catalytic activity (Fig.	('Thr-380Ala', 'Mutation', 'p.T380A', (116, 126))	('caspase-2Ser-307Ala', 'Var', (82, 101))	('caspase-2 catalytic activity', 'MPA', (234, 262))	('p19', 'Gene', '1032', (212, 215))	('2Ser', 'Chemical', '-', (69, 73))	('Ser-307Ala', 'Mutation', 'p.S307A', (91, 101))	('2Ser', 'Chemical', '-', (90, 94))	('p37', 'Gene', '926', (204, 207))	('induce', 'PosReg', (145, 151))	('caspase-2Ser-220Ala', 'Var', (61, 80))	('overexpression', 'PosReg', (17, 31))	('cleavage products', 'MPA', (186, 203))	('caspase-2Thr-380Ala', 'Var', (107, 126))	('Ser-220Ala', 'Mutation', 'p.S220A', (70, 80))	('p37', 'Gene', (204, 207))	('autocatalytic processing', 'MPA', (158, 182))	('p19', 'Gene', (212, 215))
200334	33011746	This led to increased processing of caspase-2WT as well as of caspase-2Ser-220Ala, caspase-2Ser307Ala, and caspase-2Thr-380Ala and more pronounced decrease of procaspase-2 levels.	('Thr-380Ala', 'Mutation', 'p.T380A', (116, 126))	('Ser-220Ala', 'Mutation', 'p.S220A', (71, 81))	('processing', 'MPA', (22, 32))	('2Ser', 'Chemical', '-', (70, 74))	('decrease', 'NegReg', (147, 155))	('increased', 'PosReg', (12, 21))	('procaspase-2 levels', 'MPA', (159, 178))	('Ala', 'Chemical', 'MESH:D000409', (78, 81))	('caspase-2Thr-380Ala', 'Var', (107, 126))	('Ala', 'Chemical', 'MESH:D000409', (123, 126))	('Ala', 'Chemical', 'MESH:D000409', (98, 101))	('2Ser', 'Chemical', '-', (91, 95))
200335	33011746	Importantly, the mutation Ser-384Ala almost completely blocked the processing of caspase-2.	('processing', 'MPA', (67, 77))	('Ser-384Ala', 'Mutation', 'rs775379645', (26, 36))	('caspase-2', 'Protein', (81, 90))	('Ser-384Ala', 'Var', (26, 36))	('blocked', 'NegReg', (55, 62))
200337	33011746	Taken together, only mutation of Ser-384 but not Ser-220, Ser-307 or Thr-380 resulted in the inhibition of caspase-2 proteolysis.	('Ser', 'Chemical', 'MESH:D012694', (58, 61))	('inhibition', 'NegReg', (93, 103))	('Ser-384', 'Var', (33, 40))	('Ser', 'Chemical', 'MESH:D012694', (49, 52))	('mutation', 'Var', (21, 29))	('Thr', 'Chemical', 'MESH:D013912', (69, 72))	('caspase-2', 'Enzyme', (107, 116))	('Ser', 'Chemical', 'MESH:D012694', (33, 36))
200338	33011746	Next, we studied the effect of the Ser-384Ala substitution of caspase-2 on apoptotic cell death.	('Ser-384Ala', 'Var', (35, 45))	('Ser-384Ala', 'Mutation', 'rs775379645', (35, 45))	('apo', 'Gene', '84909', (75, 78))	('apo', 'Gene', (75, 78))
200344	33011746	On the contrary, the overexpression of caspase-2Ser-384Ala demonstrated minor caspase-2 processing in HEK293T cells compared to the overexpression of caspase-2WT.	('processing', 'MPA', (88, 98))	('2Ser-384Ala', 'Chemical', '-', (47, 58))	('caspase-2Ser-384Ala', 'Var', (39, 58))	('HEK293T', 'CellLine', 'CVCL:0063', (102, 109))	('caspase-2', 'Enzyme', (78, 87))
200346	33011746	Apparently, the presence of endogenous caspase-2 in HEK293T might lead to the marginal caspase-2 processing observed in the above-mentioned experiments.	('HEK293T', 'Var', (52, 59))	('caspase-2', 'Protein', (39, 48))	('caspase-2 processing', 'MPA', (87, 107))	('HEK293T', 'CellLine', 'CVCL:0063', (52, 59))
200348	33011746	In line with the inhibition of caspase-2Ser-384Ala processing, the cleavage of caspase-8, caspase-3 and PARP was largely reduced upon overexpression of caspase-2Ser-384Ala.	('cleavage', 'MPA', (67, 75))	('caspase-8', 'Gene', (79, 88))	('caspase-2Ser-384Ala', 'Var', (152, 171))	('overexpression', 'PosReg', (134, 148))	('caspase-3', 'Gene', (90, 99))	('PARP', 'Gene', '1302', (104, 108))	('caspase-8', 'Gene', '841', (79, 88))	('reduced', 'NegReg', (121, 128))	('caspase-3', 'Gene', '836', (90, 99))	('PARP', 'Gene', (104, 108))	('2Ser-384Ala', 'Chemical', '-', (160, 171))	('2Ser-384Ala', 'Chemical', '-', (39, 50))
200355	33011746	The western blot results clearly demonstrated the absence of p19-fragment of caspase-2 in samples with the mutant form of caspase-2 and the level of full-length Bid comparable to the untransfected cells (Fig.	('p19', 'Gene', '1032', (61, 64))	('absence', 'NegReg', (50, 57))	('mutant', 'Var', (107, 113))	('Bid', 'Gene', (161, 164))	('Bid', 'Gene', '637', (161, 164))	('caspase-2', 'Gene', (77, 86))	('caspase-2', 'Gene', (122, 131))	('p19', 'Gene', (61, 64))
200358	33011746	Furthermore, we studied the effect of Ser-384Ala substitution on apoptotic cell death by Annexin V/Propidium iodide staining (AnV/PI) in combination with flow cytometry.	('Annexin V', 'Gene', '308', (89, 98))	('Annexin V', 'Gene', (89, 98))	('Propidium iodide', 'Chemical', 'MESH:D011419', (99, 115))	('Ser-384Ala', 'Mutation', 'rs775379645', (38, 48))	('apo', 'Gene', '84909', (65, 68))	('Ser-384Ala', 'Var', (38, 48))	('apo', 'Gene', (65, 68))
200361	33011746	Interestingly, the overexpression of caspase-2Ser-384Ala inhibited cisplatin-induced apoptosis compared to the overexpression of caspase-2WT.	('overexpression', 'PosReg', (19, 33))	('caspase-2Ser-384Ala', 'Protein', (37, 56))	('inhibited', 'NegReg', (57, 66))	('2Ser-384Ala', 'Chemical', '-', (45, 56))	('apo', 'Gene', '84909', (85, 88))	('cisplatin-induced', 'MPA', (67, 84))	('apo', 'Gene', (85, 88))	('caspase-2Ser-384Ala', 'Var', (37, 56))	('cisplatin', 'Chemical', 'MESH:D002945', (67, 76))
200363	33011746	Taken together, the caspase-2Ser-384Ala did not possess the ability to undergo processing and activation.	('2Ser-384Ala', 'Chemical', '-', (28, 39))	('caspase-2Ser-384Ala', 'Protein', (20, 39))	('caspase-2Ser-384Ala', 'Var', (20, 39))
200364	33011746	Moreover, the overexpression of this mutant inhibited cisplatin-induced cell death in comparison to caspase-2WT.	('inhibited', 'NegReg', (44, 53))	('cisplatin', 'Chemical', 'MESH:D002945', (54, 63))	('mutant', 'Var', (37, 43))	('cisplatin-induced cell death', 'CPA', (54, 82))	('overexpression', 'PosReg', (14, 28))
200376	33011746	To validate the mass-spectrometry results, a phospho-mimetic mutant was constructed by the substitution of Ser-384 with Aspartate (Asp).	('substitution', 'Var', (91, 103))	('Asp', 'Chemical', 'MESH:D001224', (120, 123))	('Asp', 'Chemical', 'MESH:D001224', (131, 134))	('Ser-384', 'Gene', (107, 114))	('Ser-384 with Aspartate', 'Mutation', 'p.S384D', (107, 129))
200377	33011746	4a, the overexpression of both caspase-2Ser-384Asp and caspase-2Ser-384Ala in HEK293T cells demonstrated a decrease in the processing of caspase-2 in comparison to caspase-2WT (Fig.	('overexpression', 'PosReg', (8, 22))	('caspase-2Ser-384Ala', 'Var', (55, 74))	('caspase-2', 'Protein', (137, 146))	('2Ser', 'Chemical', '-', (63, 67))	('2Ser-384Ala', 'Chemical', '-', (63, 74))	('HEK293T', 'CellLine', 'CVCL:0063', (78, 85))	('processing', 'MPA', (123, 133))	('decrease', 'NegReg', (107, 115))	('2Ser', 'Chemical', '-', (39, 43))	('Ser-384Asp', 'Mutation', 'p.S384D', (40, 50))
200378	33011746	Importantly, regardless of genotoxic stress, the substitution at the Ser-384 site with a negatively charged amino acid did not restore caspase-2 activation, similar to that seen for the Ser-384Ala substitution.	('Ser-384Ala', 'Mutation', 'rs775379645', (186, 196))	('Ser', 'Chemical', 'MESH:D012694', (69, 72))	('genotoxic stress', 'Disease', 'MESH:D000079225', (27, 43))	('genotoxic stress', 'Disease', (27, 43))	('Ser', 'Chemical', 'MESH:D012694', (186, 189))	('activation', 'MPA', (145, 155))	('substitution', 'Var', (49, 61))	('Ser-384', 'Gene', (69, 76))	('caspase-2', 'Protein', (135, 144))
200380	33011746	Interestingly, the overexpression of caspase-2WT and caspase-2Ser-384Ala induces the appearance of several bands on western blot that correspond to non-phosphorylated and phosphorylated forms of caspase-2.	('overexpression', 'PosReg', (19, 33))	('caspase-2Ser-384Ala', 'Var', (53, 72))	('caspase-2Ser-384Ala', 'Gene', (53, 72))	('2Ser-384Ala', 'Chemical', '-', (61, 72))
200382	33011746	Thus, we can conclude that caspase-2 could be phosphorylated at Ser-340, as shown by mass-spectrometry analysis, but was not phosphorylated at Ser-384.	('Ser', 'Chemical', 'MESH:D012694', (143, 146))	('Ser', 'Chemical', 'MESH:D012694', (64, 67))	('caspase-2', 'Protein', (27, 36))	('Ser-340', 'Var', (64, 71))
200390	33011746	The S1-pocket residues Arg-219 and Arg-378 form hydrogen bonds with the aspartate D1 while Ser-384 does not mediate direct interactions with the substrate (Fig.	('hydrogen', 'Interaction', (48, 56))	('Arg', 'Chemical', 'MESH:D001120', (35, 38))	('Arg-219', 'Var', (23, 30))	('Arg-378', 'Var', (35, 42))	('Ser', 'Chemical', 'MESH:D012694', (91, 94))	('hydrogen', 'Chemical', 'MESH:D006859', (48, 56))	('Arg', 'Chemical', 'MESH:D001120', (23, 26))	('aspartate', 'Chemical', 'MESH:D001224', (72, 81))	('form', 'Reg', (43, 47))
200391	33011746	Instead, Ser-384 forms hydrogen bonds with the Asp-225 side chain (Fig.	('Ser-384', 'Var', (9, 16))	('hydrogen', 'Chemical', 'MESH:D006859', (23, 31))	('Asp', 'Chemical', 'MESH:D001224', (47, 50))	('hydrogen bonds', 'MPA', (23, 37))	('Ser', 'Chemical', 'MESH:D012694', (9, 12))
200392	33011746	Thus, the Ser-384Ala substitution does not seem to produce new direct interactions with the substrate but could influence the structure of the caspase-2 active site.	('Ser-384Ala', 'Var', (10, 20))	('structure', 'MPA', (126, 135))	('influence', 'Reg', (112, 121))	('caspase-2', 'Enzyme', (143, 152))	('interactions', 'Interaction', (70, 82))	('Ser-384Ala', 'Mutation', 'rs775379645', (10, 20))
200394	33011746	Upon mutation of Ser-384 to Ala, this amino acid loses one of the hydrogen bonds with Asp-225 and forms a hydrophobic contact with the Ile-387 side chain (Fig.	('Asp', 'Chemical', 'MESH:D001224', (86, 89))	('Ser-384', 'Gene', (17, 24))	('loses', 'NegReg', (49, 54))	('forms', 'Reg', (98, 103))	('hydrophobic contact', 'MPA', (106, 125))	('mutation', 'Var', (5, 13))	('Ser-384 to Ala', 'Mutation', 'rs775379645', (17, 31))	('hydrogen', 'Chemical', 'MESH:D006859', (66, 74))	('Ile', 'Chemical', 'MESH:D007532', (135, 138))	('hydrogen bonds', 'MPA', (66, 80))
200396	33011746	Among the key residues involved in substrate binding, Arg-378 undergoes a major conformational change: the guanidinium group turns so that the Nepsilon atom loses the ability to form an important hydrogen bond with the substrate's aspartate residue (Fig.	('aspartate', 'Chemical', 'MESH:D001224', (231, 240))	('Arg-378', 'Var', (54, 61))	('hydrogen', 'Chemical', 'MESH:D006859', (196, 204))	('ability', 'MPA', (167, 174))	('Nepsilon', 'Chemical', '-', (143, 151))	('Arg', 'Chemical', 'MESH:D001120', (54, 57))	('guanidinium', 'Chemical', 'MESH:D019791', (107, 118))	('loses', 'NegReg', (157, 162))
200398	33011746	In both the native and mutant forms of caspase-2, the SH-group of catalytic Cys-320 is oriented directly towards the Ndelta1 atom of His-227 (Fig.	('mutant', 'Var', (23, 29))	('Cys', 'Chemical', 'MESH:D003545', (76, 79))	('caspase-2', 'Enzyme', (39, 48))	('His', 'Chemical', 'MESH:D006639', (133, 136))
200400	33011746	The Ser-384Ala substitution in caspase-2 does not affect the catalytic dyad His-227 to Cys-320, but apparently disrupts the binding of the substrate to Arg-378.	('Arg', 'Chemical', 'MESH:D001120', (152, 155))	('His-227 to Cys', 'Mutation', 'p.H227C', (76, 90))	('binding', 'Interaction', (124, 131))	('Ser-384Ala', 'Mutation', 'rs775379645', (4, 14))	('Arg-378', 'Protein', (152, 159))	('disrupts', 'NegReg', (111, 119))	('Ser-384Ala', 'Var', (4, 14))
200401	33011746	The mutation prevents the electrostatic interaction between the Ogamma atom of Ser-384 (partial negative charge) and Arg-378 guanidinium group (positive charge) and induces the conformational change of Arg-378 with the formation of compensatory hydrogen bonds between the guanidinium group and the bulk solvent.	('hydrogen', 'Chemical', 'MESH:D006859', (245, 253))	('Arg', 'Chemical', 'MESH:D001120', (117, 120))	('prevents', 'NegReg', (13, 21))	('Ser', 'Chemical', 'MESH:D012694', (79, 82))	('induces', 'Reg', (165, 172))	('mutation', 'Var', (4, 12))	('guanidinium', 'Chemical', 'MESH:D019791', (272, 283))	('electrostatic interaction', 'MPA', (26, 51))	('Arg-378', 'Var', (202, 209))	('Arg-378', 'Gene', (117, 124))	('guanidinium', 'Chemical', 'MESH:D019791', (125, 136))	('conformational change', 'MPA', (177, 198))	('Arg', 'Chemical', 'MESH:D001120', (202, 205))
200402	33011746	Additionally, a multiple alignment of the primary structure of initiator, executor and inflammatory caspases and comparison of their tertiary structure demonstrated a high conservation of both Ser-384 and Arg-378 residues across the caspase family (Fig.	('Ser-384', 'Var', (193, 200))	('caspase', 'Gene', '835;12366;838;839;841;12370;842;12371;843', (233, 240))	('caspase', 'Gene', '835;12366;838;839;841;12370;842;12371;843', (100, 107))	('Arg', 'Chemical', 'MESH:D001120', (205, 208))	('caspase', 'Gene', (233, 240))	('Ser', 'Chemical', 'MESH:D012694', (193, 196))	('caspases', 'Gene', (100, 108))	('caspase', 'Gene', (100, 107))	('Arg-378 residues', 'Var', (205, 221))	('caspases', 'Gene', '835;12366;838;839;841;12370;842;12371;843', (100, 108))
200404	33011746	Taken together, these results clearly showed that the Ser-384 residue plays a crucial role in substrate binding and is necessary for caspase-2 processing and enzymatic activity to induce apoptotic cell death.	('caspase-2', 'Protein', (133, 142))	('apo', 'Gene', (187, 190))	('substrate binding', 'Interaction', (94, 111))	('induce', 'PosReg', (180, 186))	('Ser', 'Chemical', 'MESH:D012694', (54, 57))	('Ser-384 residue', 'Var', (54, 69))	('apo', 'Gene', '84909', (187, 190))
200408	33011746	Notably, the ScanSite and NetPhos programs that were used for the prediction of modification sites have already been successfully applied for the prediction of caspase phosphorylation.	('caspase', 'Gene', (160, 167))	('modification', 'Var', (80, 92))	('caspase', 'Gene', '835;12366;838;839;841;12370;842;12371;843', (160, 167))	('Phos', 'Chemical', '-', (29, 33))
200409	33011746	Using site-directed mutagenesis (Ser/Thr to Ala) of the selected phosphorylation sites and biochemical techniques, we demonstrated that only the mutation of Ser-384Ala prevented caspase-2 processing and blocked enzymatic activity.	('Thr', 'Chemical', 'MESH:D013912', (37, 40))	('Ser', 'Chemical', 'MESH:D012694', (157, 160))	('prevented', 'NegReg', (168, 177))	('caspase-2', 'Protein', (178, 187))	('Ser', 'Chemical', 'MESH:D012694', (33, 36))	('Ser-384Ala', 'Mutation', 'rs775379645', (157, 167))	('processing', 'MPA', (188, 198))	('Ala', 'Chemical', 'MESH:D000409', (44, 47))	('Ser-384Ala', 'Var', (157, 167))	('enzymatic activity', 'MPA', (211, 229))	('Ala', 'Chemical', 'MESH:D000409', (164, 167))	('blocked', 'NegReg', (203, 210))	('mutation', 'Var', (145, 153))
200410	33011746	Moreover, we found that the mutation of Ser-384 independent of the endogenous levels of caspase-2 impaired caspase-2 activation and the induction of apoptotic cell death.	('Ser-384', 'Gene', (40, 47))	('apo', 'Gene', (149, 152))	('activation', 'MPA', (117, 127))	('apo', 'Gene', '84909', (149, 152))	('mutation', 'Var', (28, 36))	('impaired', 'NegReg', (98, 106))	('Ser', 'Chemical', 'MESH:D012694', (40, 43))	('caspase-2', 'Protein', (107, 116))
200412	33011746	Our observations were confirmed by the fact that the cleavage of Bid, one of the important caspase-2 substrates, was significantly decreased in the cells overexpressed caspase-2 Ser-384Ala mutant.	('cleavage', 'MPA', (53, 61))	('Ser-384Ala mutant', 'Var', (178, 195))	('caspase-2', 'Gene', (168, 177))	('decreased', 'NegReg', (131, 140))	('Ser-384Ala', 'Mutation', 'rs775379645', (178, 188))	('Bid', 'Gene', '637', (65, 68))	('Bid', 'Gene', (65, 68))
200413	33011746	As was mentioned above, the Ser-384 residue is located in close proximity to the active center of caspase-2 at the same spatial region of the alpha-helix in the large catalytic subunit as Thr-263 of caspase-8 and Ser-183 of caspase-9.	('caspase-8', 'Gene', (199, 208))	('Ser', 'Chemical', 'MESH:D012694', (28, 31))	('caspase-9', 'Gene', '842', (224, 233))	('Thr', 'Chemical', 'MESH:D013912', (188, 191))	('caspase-8', 'Gene', '841', (199, 208))	('caspase-9', 'Gene', (224, 233))	('Ser-384', 'Var', (28, 35))	('Thr-263', 'Var', (188, 195))	('Ser', 'Chemical', 'MESH:D012694', (213, 216))
200419	33011746	Using this approach, we demonstrated that the disturbance of caspase-2 activity and processing caused by Ser-384 substitution might result from the loss of the ability to bind the substrate molecule.	('Ser-384', 'Gene', (105, 112))	('caspase-2', 'Enzyme', (61, 70))	('processing', 'MPA', (84, 94))	('loss', 'NegReg', (148, 152))	('substitution', 'Var', (113, 125))	('bind the substrate molecule', 'Interaction', (171, 198))	('Ser', 'Chemical', 'MESH:D012694', (105, 108))	('activity', 'MPA', (71, 79))	('ability', 'MPA', (160, 167))
200420	33011746	Interestingly, Ser-384 does not affect the catalytic dyad His-227/Cys-320 or directly interact with the substrate but is involved in electrostatic interactions with Arg-378, which in turn forms a hydrogen bond with the substrate aspartate residue.	('hydrogen bond', 'MPA', (196, 209))	('Ser-384', 'Var', (15, 22))	('Arg', 'Chemical', 'MESH:D001120', (165, 168))	('interactions', 'Interaction', (147, 159))	('hydrogen', 'Chemical', 'MESH:D006859', (196, 204))	('His-227/Cys', 'SUBSTITUTION', 'None', (58, 69))	('Arg-378', 'Var', (165, 172))	('forms', 'Reg', (188, 193))	('Ser', 'Chemical', 'MESH:D012694', (15, 18))	('electrostatic', 'MPA', (133, 146))	('involved in', 'Reg', (121, 132))	('aspartate', 'Chemical', 'MESH:D001224', (229, 238))	('His-227/Cys', 'Var', (58, 69))
200421	33011746	clearly demonstrated the importance of the Arg-378 residue location and its role in caspase-2 activation by crystallization methods.	('Arg', 'Chemical', 'MESH:D001120', (43, 46))	('Arg-378 residue', 'Var', (43, 58))	('caspase-2', 'Enzyme', (84, 93))
200422	33011746	As described above, the discovered mechanism of substrate molecular recognition and stabilization by Arg-378 and Ser-384 is strongly conservative across all members of the caspase family and seemingly plays a crucial role in caspase activity Recently, the data describing the role of Ser-384 in caspase-2 activation were reported.	('Ser-384', 'Var', (113, 120))	('caspase', 'Gene', (225, 232))	('caspase', 'Gene', '835;12366;838;839;841;12370;842;12371;843', (172, 179))	('caspase', 'Gene', '835;12366;838;839;841;12370;842;12371;843', (295, 302))	('caspase', 'Gene', (172, 179))	('caspase', 'Gene', (295, 302))	('Arg', 'Chemical', 'MESH:D001120', (101, 104))	('Ser', 'Chemical', 'MESH:D012694', (284, 287))	('caspase', 'Gene', '835;12366;838;839;841;12370;842;12371;843', (225, 232))	('Ser', 'Chemical', 'MESH:D012694', (113, 116))	('Arg-378', 'Var', (101, 108))
200424	33011746	Using phospho-mimetic substitutions, it was demonstrated that only Ser-384Glu substitution blocks caspase-2 processing and suppresses substrate cleavage.	('blocks', 'NegReg', (91, 97))	('caspase-2', 'Protein', (98, 107))	('substrate cleavage', 'MPA', (134, 152))	('Ser-384Glu', 'Mutation', 'p.S384E', (67, 77))	('Ser-384Glu substitution', 'Var', (67, 90))	('suppresses', 'NegReg', (123, 133))	('processing', 'MPA', (108, 118))
200426	33011746	In addition, the authors have suggested that Ser-384Glu mimics caspase-2 phosphorylation that negatively regulates activation of the protein.	('Ser-384Glu', 'Var', (45, 55))	('caspase-2', 'Protein', (63, 72))	('activation', 'MPA', (115, 125))	('mimics', 'Reg', (56, 62))	('phosphorylation', 'MPA', (73, 88))	('Ser-384Glu', 'Mutation', 'p.S384E', (45, 55))
200427	33011746	In contrast to these data, we demonstrated that Ser-384Ala substitution has the same effect and blocks caspase-2 activity.	('Ser-384Ala', 'Mutation', 'rs775379645', (48, 58))	('caspase-2', 'Enzyme', (103, 112))	('blocks', 'NegReg', (96, 102))	('activity', 'MPA', (113, 121))	('Ser-384Ala', 'Var', (48, 58))
200428	33011746	In case of phosphorylation, the mutation Ser-384Ala should withdraw the negative regulation of this modification and promote caspase-2 processing and activation.	('processing', 'MPA', (135, 145))	('negative regulation', 'MPA', (72, 91))	('Ser-384Ala', 'Mutation', 'rs775379645', (41, 51))	('caspase-2', 'Protein', (125, 134))	('withdraw', 'NegReg', (59, 67))	('promote', 'PosReg', (117, 124))	('Ser-384Ala', 'Var', (41, 51))	('activation', 'MPA', (150, 160))
200430	33011746	Consequently, the substitution of Ser-384 with Ala has the same negative effect on caspase-2 activation as the replacement of phosphomimetic amino acid residue (Glu or Asp) because any substations disrupt the interaction between Ser-384 and Arg-378.	('interaction', 'Interaction', (209, 220))	('Glu', 'Chemical', 'MESH:D018698', (161, 164))	('Ser', 'Chemical', 'MESH:D012694', (34, 37))	('Asp', 'Chemical', 'MESH:D001224', (168, 171))	('Arg-378', 'Protein', (241, 248))	('Ser-384 with Ala', 'Mutation', 'rs775379645', (34, 50))	('caspase-2', 'Enzyme', (83, 92))	('disrupt', 'NegReg', (197, 204))	('activation', 'MPA', (93, 103))	('Ser', 'Chemical', 'MESH:D012694', (229, 232))	('Ser-384', 'Protein', (229, 236))	('substitution', 'Var', (18, 30))	('Arg', 'Chemical', 'MESH:D001120', (241, 244))
200434	33011746	Another fascinating feature that we derived from the TCGA database analysis is the presence of missense and stop-gain mutations in caspase-2/-3/-6 at a conserved arginine position, which corresponds to the Arg-378 residue in caspase-2 (Data generated by the TCGA Research Network: https://www.cancer.gov/tcga).	('cancer', 'Disease', (293, 299))	('stop-gain', 'PosReg', (108, 117))	('Arg', 'Chemical', 'MESH:D001120', (206, 209))	('cancer', 'Disease', 'MESH:D009369', (293, 299))	('mutations', 'Var', (118, 127))	('caspase-2/-3/-6', 'Gene', '835;836;839', (131, 146))	('cancer', 'Phenotype', 'HP:0002664', (293, 299))	('missense', 'Var', (95, 103))	('arginine', 'Chemical', 'MESH:D001120', (162, 170))	('caspase-2/-3/-6', 'Gene', (131, 146))
200435	33011746	The Arg-378Trp mutation in caspase-2, or Arg-207Stop in caspase-3, or Arg-220Trp in caspase-6 were found in uterine corpus endometrial carcinoma and is probably involved in apoptotic cell death disturbances and tumorogenesis.	('involved', 'Reg', (161, 169))	('caspase-3', 'Gene', '836', (56, 65))	('Arg-220Trp', 'Mutation', 'rs752173591', (70, 80))	('found', 'Reg', (99, 104))	('caspase-3', 'Gene', (56, 65))	('death disturbances and tumorogenesis', 'Disease', 'MESH:D003643', (188, 224))	('endometrial carcinoma', 'Disease', (123, 144))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('Arg-378Trp', 'Mutation', 'rs1292777212', (4, 14))	('Arg-220Trp', 'Var', (70, 80))	('apo', 'Gene', '84909', (173, 176))	('Arg-378Trp', 'Var', (4, 14))	('Arg-207Stop', 'Mutation', 'rs757302190', (41, 52))	('caspase-2', 'Gene', (27, 36))	('apo', 'Gene', (173, 176))	('caspase-6', 'Gene', (84, 93))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (123, 144))	('Arg-207Stop', 'Var', (41, 52))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (123, 144))	('caspase-6', 'Gene', '839', (84, 93))
200436	33011746	Interestingly, the Serine conserved position that corresponds to the Ser-384 residue in caspase-2 is also subjected to missense mutagenesis in caspase-5 and -6 in lung squamous cell carcinoma and adenocarcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (201, 210))	('Ser', 'Chemical', 'MESH:D012694', (69, 72))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (163, 191))	('Serine', 'Chemical', 'MESH:D012694', (19, 25))	('caspase-5 and -6', 'Gene', '838;839', (143, 159))	('adenocarcinoma', 'Disease', (196, 210))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (163, 191))	('caspase-2', 'Gene', (88, 97))	('adenocarcinoma', 'Disease', 'MESH:D000230', (196, 210))	('missense mutagenesis', 'Var', (119, 139))	('lung squamous cell carcinoma', 'Disease', (163, 191))	('carcinoma', 'Phenotype', 'HP:0030731', (182, 191))	('Ser', 'Chemical', 'MESH:D012694', (19, 22))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (168, 191))
200437	33011746	Thus, the obtained results demonstrate the crucial role of the Ser-384 and Arg-378 residues in substrate binding, caspase-2 processing, and enzymatic activity.	('processing', 'MPA', (124, 134))	('Arg-378 residues', 'Var', (75, 91))	('Ser', 'Chemical', 'MESH:D012694', (63, 66))	('Arg', 'Chemical', 'MESH:D001120', (75, 78))	('Ser-384', 'Var', (63, 70))	('caspase-2', 'Protein', (114, 123))	('binding', 'Interaction', (105, 112))
200439	33011746	The mutations of these residues were found in endometrial carcinoma and lung cancer.	('found', 'Reg', (37, 42))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (46, 67))	('lung cancer', 'Disease', (72, 83))	('endometrial carcinoma', 'Disease', (46, 67))	('lung cancer', 'Phenotype', 'HP:0100526', (72, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('mutations', 'Var', (4, 13))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (46, 67))	('lung cancer', 'Disease', 'MESH:D008175', (72, 83))
200448	33011746	Then, cells (0.2x106) were resuspended in 200 microl Annexin-binding buffer (#556454, BD Biosciences, USA) and 2 microl of Annexin-V-FITC (A13199, Invitrogen, USA) were added to the sample and incubated in the dark at 4  C for 15 min.	('Annexin-binding buffer', 'Chemical', '-', (53, 75))	('Annexin-V', 'Gene', '308', (123, 132))	('#556454', 'Var', (77, 84))	('Annexin-V', 'Gene', (123, 132))	('A13199', 'Chemical', '-', (139, 145))
200476	33011746	The Ser-384Ala mutant was generated by removing the Ogamma atom in Ser-384.	('Ser', 'Chemical', 'MESH:D012694', (4, 7))	('Ogamma atom', 'MPA', (52, 63))	('removing', 'NegReg', (39, 47))	('Ser', 'Chemical', 'MESH:D012694', (67, 70))	('Ser-384Ala', 'Mutation', 'rs775379645', (4, 14))	('Ser-384Ala', 'Var', (4, 14))
200481	32726920	Integrated analysis revealed a distinct genomic landscape of low TP53 mutation rate (11%), low incidence of known drivers in the RTK/RAS/RAF (11%) and PI3K/AKT/mTOR pathways (7%), but enriched for loss-of-function mutations in multiple negative regulators of the NF-kappaB pathway.	('RAF', 'Gene', (137, 140))	('NF-kappaB', 'Gene', (263, 272))	('AKT', 'Gene', '207', (156, 159))	('RAF', 'Gene', '22882', (137, 140))	('TP53', 'Gene', '7157', (65, 69))	('TP53', 'Gene', (65, 69))	('low', 'NegReg', (61, 64))	('mTOR', 'Gene', '2475', (160, 164))	('AKT', 'Gene', (156, 159))	('mutations', 'Var', (214, 223))	('mTOR', 'Gene', (160, 164))	('loss-of-function', 'NegReg', (197, 213))	('mutation', 'Var', (70, 78))	('NF-kappaB', 'Gene', '4790', (263, 272))
200483	32726920	Subsets of the patients with actionable fibroblast growth factor receptor 3 (FGFR3) aberrations (4%) and mismatch repair deficiency (4%) were potentially eligible for precision medicine.	('FGFR3', 'Gene', (77, 82))	('patients', 'Species', '9606', (15, 23))	('fibroblast growth factor receptor 3', 'Gene', '2261', (40, 75))	('aberrations', 'Var', (84, 95))	('FGFR3', 'Gene', '2261', (77, 82))	('fibroblast growth factor receptor 3', 'Gene', (40, 75))	('mismatch', 'MPA', (105, 113))
200507	32726920	Signature C, mainly composed of SBS5 and SBS40 (Mutational Signatures V3, COSMIC), was the predominant pattern that was reported to be correlated with patient age (Figure 2B).	('SBS5', 'Var', (32, 36))	('patient', 'Species', '9606', (151, 158))	('SBS40', 'Var', (41, 46))
200510	32726920	Signature B contained SBS2 and SBS13, both of which were attributed to the apolipoprotein B mRNA-editing catalytic polypeptide-like (APOBEC) family of enzymes.	('apolipoprotein B', 'Gene', (75, 91))	('apolipoprotein B', 'Gene', '338', (75, 91))	('SBS13', 'Var', (31, 36))	('SBS2', 'Var', (22, 26))
200511	32726920	Whole genome sequencing identified a mean of 59 (range 37-95) structural variations per tumor, including 116 deletions, 81 inversions, 52 duplications and 103 chromosomal translocations (Table S5).	('deletions', 'Var', (109, 118))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('structural variations', 'Var', (62, 83))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('duplications', 'Var', (138, 150))	('tumor', 'Disease', (88, 93))
200522	32726920	We employed 93 genes with non-silent single nucleotide variations (SNV) and/or insertion/deletion (indel) identified in at least two pulmonary LELC patients by targeted sequencing.	('patients', 'Species', '9606', (148, 156))	('insertion/deletion', 'Var', (79, 97))	('single nucleotide variations', 'Var', (37, 65))	('pulmonary LELC', 'Disease', (133, 147))
200526	32726920	These included HRAS (4%, G13V and Q61R), KRAS (2%, G12V), PIK3CA (2%, E545K) and AKT1 (2%, E17K).	('KRAS', 'Gene', '3845', (41, 45))	('Q61R', 'Mutation', 'rs121913240', (34, 38))	('AKT1', 'Gene', (81, 85))	('HRAS', 'Gene', '3265', (15, 19))	('E545K', 'Mutation', 'rs104886003', (70, 75))	('Q61R', 'Var', (34, 38))	('PIK3CA', 'Gene', (58, 64))	('G12V', 'Mutation', 'rs121913529', (51, 55))	('PIK3CA', 'Gene', '5290', (58, 64))	('E17K', 'Mutation', 'rs121434592', (91, 95))	('E545K', 'Var', (70, 75))	('G12V', 'Var', (51, 55))	('G13V', 'Mutation', 'rs104894226', (25, 29))	('HRAS', 'Gene', (15, 19))	('KRAS', 'Gene', (41, 45))	('AKT1', 'Gene', '207', (81, 85))	('G13V', 'Var', (25, 29))
200527	32726920	Notably, we detected an activating mutation of ALK (2%, R1275Q) and actionable alterations in FGFR3 (4%, FGFR3 R248C and FGFR3-TACC3 fusion).	('FGFR3', 'Gene', (105, 110))	('TACC3', 'Gene', '10460', (127, 132))	('activating', 'PosReg', (24, 34))	('R248C', 'Var', (111, 116))	('FGFR3', 'Gene', '2261', (121, 126))	('TACC3', 'Gene', (127, 132))	('ALK', 'Gene', (47, 50))	('FGFR3', 'Gene', '2261', (94, 99))	('R248C', 'Mutation', 'rs121913482', (111, 116))	('FGFR3', 'Gene', (121, 126))	('R1275Q', 'Mutation', 'rs113994087', (56, 62))	('FGFR3', 'Gene', '2261', (105, 110))	('ALK', 'Gene', '238', (47, 50))	('FGFR3', 'Gene', (94, 99))	('R1275Q', 'Var', (56, 62))
200528	32726920	The mutations in HRAS, KRAS, PIK3CA, AKT1, ALK and FGFR3 were confirmed by Sanger sequencing.	('AKT1', 'Gene', (37, 41))	('FGFR3', 'Gene', '2261', (51, 56))	('ALK', 'Gene', (43, 46))	('KRAS', 'Gene', (23, 27))	('PIK3CA', 'Gene', (29, 35))	('ALK', 'Gene', '238', (43, 46))	('HRAS', 'Gene', '3265', (17, 21))	('AKT1', 'Gene', '207', (37, 41))	('mutations', 'Var', (4, 13))	('FGFR3', 'Gene', (51, 56))	('KRAS', 'Gene', '3845', (23, 27))	('PIK3CA', 'Gene', '5290', (29, 35))	('HRAS', 'Gene', (17, 21))
200531	32726920	Loss-of-function mutations were found in a tumor suppressor gene, PTEN (4%).	('Loss-of-function', 'NegReg', (0, 16))	('PTEN', 'Gene', (66, 70))	('PTEN', 'Gene', '5728', (66, 70))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Disease', (43, 48))	('mutations', 'Var', (17, 26))
200533	32726920	The overall mutation rate was 11% in the RTK/RAS/RAF and 7% in the PI3K/AKT/mTOR pathway.	('AKT', 'Gene', '207', (72, 75))	('RAF', 'Gene', '22882', (49, 52))	('mTOR', 'Gene', (76, 80))	('mTOR', 'Gene', '2475', (76, 80))	('RAF', 'Gene', (49, 52))	('AKT', 'Gene', (72, 75))	('mutation', 'Var', (12, 20))
200536	32726920	In addition, deletion of RB1 and amplification of cyclins, such as CDK4 and CDK6, occurred in pulmonary LELC.	('amplification', 'MPA', (33, 46))	('RB1', 'Gene', '5925', (25, 28))	('CDK4', 'Gene', (67, 71))	('pulmonary LELC', 'Disease', (94, 108))	('CDK4', 'Gene', '1019', (67, 71))	('deletion', 'Var', (13, 21))	('occurred', 'Reg', (82, 90))	('RB1', 'Gene', (25, 28))	('CDK6', 'Gene', (76, 80))	('CDK6', 'Gene', '1021', (76, 80))
200538	32726920	Multiple loss-of-function mutations were identified in negative regulators of the NF-kappaB pathway, namely TRAF3, CYLD, NFKBIA and TNFAIP3.	('TRAF3', 'Gene', (108, 113))	('NFKBIA', 'Gene', (121, 127))	('NF-kappaB', 'Gene', (82, 91))	('CYLD', 'Gene', '1540', (115, 119))	('TNFAIP3', 'Gene', (132, 139))	('NFKBIA', 'Gene', '4792', (121, 127))	('TRAF3', 'Gene', '7187', (108, 113))	('mutations', 'Var', (26, 35))	('CYLD', 'Gene', (115, 119))	('loss-of-function', 'NegReg', (9, 25))	('NF-kappaB', 'Gene', '4790', (82, 91))	('TNFAIP3', 'Gene', '7128', (132, 139))
200539	32726920	TRAF3 was mutated at 18% of pulmonary LELC.	('TRAF3', 'Gene', (0, 5))	('TRAF3', 'Gene', '7187', (0, 5))	('mutated', 'Var', (10, 17))	('pulmonary LELC', 'Disease', (28, 42))
200540	32726920	The TRAF3 mutations were predominantly truncating mutations, including nonsense and frameshift mutations (8/10, 80%).	('nonsense', 'Var', (71, 79))	('TRAF3', 'Gene', (4, 9))	('frameshift mutations', 'Var', (84, 104))	('mutations', 'Var', (10, 19))	('TRAF3', 'Gene', '7187', (4, 9))
200541	32726920	The mutation rates of CYLD, NFKBIA and TNFAIP3 were 5% (3/57), 9% (5/57) and 2% (1/57), respectively, and all the mutations were truncating mutations (Figure S4).	('CYLD', 'Gene', (22, 26))	('CYLD', 'Gene', '1540', (22, 26))	('mutations', 'Var', (114, 123))	('truncating', 'Var', (129, 139))	('NFKBIA', 'Gene', '4792', (28, 34))	('TNFAIP3', 'Gene', '7128', (39, 46))	('mutation', 'Var', (4, 12))	('TNFAIP3', 'Gene', (39, 46))	('NFKBIA', 'Gene', (28, 34))
200550	32726920	Mutations of KMT2D and EP400 were frequently detected and each was found to be mutated in 9% of pulmonary LELC.	('KMT2D', 'Gene', (13, 18))	('KMT2D', 'Gene', '8085', (13, 18))	('Mutations', 'Var', (0, 9))	('EP400', 'Gene', '57634', (23, 28))	('EP400', 'Gene', (23, 28))	('pulmonary LELC', 'Disease', (96, 110))
200551	32726920	Multiple cases harbored mutations in a group of histone methyltransferases, including KMT2A, KMT2B and KMT2C.	('KMT2A', 'Gene', '4297', (86, 91))	('KMT2B', 'Gene', '9757', (93, 98))	('KMT2C', 'Gene', (103, 108))	('mutations', 'Var', (24, 33))	('harbored', 'Reg', (15, 23))	('KMT2B', 'Gene', (93, 98))	('KMT2C', 'Gene', '58508', (103, 108))	('KMT2A', 'Gene', (86, 91))	('histone methyltransferases', 'Enzyme', (48, 74))
200552	32726920	Loss-of-function mutations were present in key players such as NOTCH1, NOTCH4 and FBXW7 in 7% of the cases.	('Loss-of-function', 'NegReg', (0, 16))	('FBXW7', 'Gene', (82, 87))	('NOTCH4', 'Gene', (71, 77))	('NOTCH4', 'Gene', '4855', (71, 77))	('FBXW7', 'Gene', '55294', (82, 87))	('NOTCH1', 'Gene', '4851', (63, 69))	('NOTCH1', 'Gene', (63, 69))	('mutations', 'Var', (17, 26))
200553	32726920	Deletion of JAG2, one of five Notch ligands, was detected in 11% of the patients.	('detected', 'Reg', (49, 57))	('JAG2', 'Gene', (12, 16))	('JAG2', 'Gene', '3714', (12, 16))	('Deletion', 'Var', (0, 8))	('patients', 'Species', '9606', (72, 80))
200555	32726920	TP53 mutations occurred in 11% of pulmonary LELC.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('occurred', 'Reg', (15, 23))	('mutations', 'Var', (5, 14))	('pulmonary LELC', 'Disease', (34, 48))
200556	32726920	Missense mutations and non-frameshift substitutions mainly occurred at the DNA binding domain of TP53 (Figure 3 and Table S7).	('TP53', 'Gene', '7157', (97, 101))	('TP53', 'Gene', (97, 101))	('non-frameshift substitutions', 'Var', (23, 51))	('occurred', 'Reg', (59, 67))	('Missense mutations', 'Var', (0, 18))
200557	32726920	Amplification of MDM2, a negative regulator of p53, and deletion of ATM, one of the master regulators of DNA damage response, occurred in 11% of pulmonary LELC patients (Figure 4).	('deletion', 'Var', (56, 64))	('Amplification', 'Var', (0, 13))	('patients', 'Species', '9606', (160, 168))	('p53', 'Gene', '7157', (47, 50))	('MDM2', 'Gene', '4193', (17, 21))	('ATM', 'Gene', (68, 71))	('MDM2', 'Gene', (17, 21))	('occurred', 'Reg', (126, 134))	('p53', 'Gene', (47, 50))	('ATM', 'Gene', '472', (68, 71))	('pulmonary LELC', 'Disease', (145, 159))
200567	32726920	Enrichment of somatic alterations implicated aberrant signaling in the cell cycle, NF-kappaB, Notch and TP53 pathways.	('TP53', 'Gene', '7157', (104, 108))	('TP53', 'Gene', (104, 108))	('aberrant', 'Var', (45, 53))	('NF-kappaB', 'Gene', '4790', (83, 92))	('cell cycle', 'Pathway', (71, 81))	('alterations', 'Var', (22, 33))	('implicated', 'Reg', (34, 44))	('NF-kappaB', 'Gene', (83, 92))
200571	32726920	Genetic alterations and altered pathways in pulmonary LELC were different from those of other major NSCLC subtypes.	('Genetic alterations', 'Var', (0, 19))	('NSCLC', 'Disease', (100, 105))	('NSCLC', 'Disease', 'MESH:D002289', (100, 105))	('pulmonary LELC', 'Disease', (44, 58))	('NSCLC', 'Phenotype', 'HP:0030358', (100, 105))
200573	32726920	However, their genomic profiling lacked diverse genetic alterations characterized in squamous cell carcinoma, such as SOX2 amplification in the squamous differentiation pathway; PIK3CA amplification in the PI3K signaling; and FGFR1 amplification in the RTK signaling pathway.	('FGFR1', 'Gene', (226, 231))	('PIK3CA', 'Gene', (178, 184))	('PI3K signaling', 'Pathway', (206, 220))	('amplification', 'Var', (232, 245))	('squamous differentiation pathway', 'Pathway', (144, 176))	('SOX2', 'Gene', '6657', (118, 122))	('FGFR1', 'Gene', '2260', (226, 231))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (85, 108))	('SOX2', 'Gene', (118, 122))	('PIK3CA', 'Gene', '5290', (178, 184))	('RTK signaling pathway', 'Pathway', (253, 274))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (85, 108))	('amplification', 'Var', (123, 136))	('amplification', 'Var', (185, 198))	('squamous cell carcinoma', 'Disease', (85, 108))
200574	32726920	Concordant with previous molecular studies, major driver events in adenocarcinoma, namely EGFR activating mutations, ALK gene rearrangement and ROS1 gene rearrangement, were rarely present in pulmonary LELC, indicating that they were less important events in the pathogenesis of pulmonary LELC.	('adenocarcinoma', 'Disease', (67, 81))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('adenocarcinoma', 'Disease', 'MESH:D000230', (67, 81))	('rearrangement', 'Var', (126, 139))	('ALK', 'Gene', '238', (117, 120))	('EGFR', 'Gene', '1956', (90, 94))	('ROS1', 'Gene', (144, 148))	('ROS1', 'Gene', '6098', (144, 148))	('EGFR', 'Gene', (90, 94))	('mutations', 'Var', (106, 115))	('pulmonary LELC', 'Disease', (192, 206))	('ALK', 'Gene', (117, 120))
200577	32726920	Interestingly, it was the first study to identify actionable alterations of FGFR3 in 4% of pulmonary LELC.	('pulmonary LELC', 'Disease', (91, 105))	('FGFR3', 'Gene', (76, 81))	('alterations', 'Var', (61, 72))	('FGFR3', 'Gene', '2261', (76, 81))
200579	32726920	Recurrent FGFR3-TACC3 fusions were reported in 2.5% of NPC.	('NPC', 'Phenotype', 'HP:0100630', (55, 58))	('FGFR3', 'Gene', '2261', (10, 15))	('NPC', 'Disease', (55, 58))	('fusions', 'Var', (22, 29))	('FGFR3', 'Gene', (10, 15))	('TACC3', 'Gene', '10460', (16, 21))	('TACC3', 'Gene', (16, 21))
200581	32726920	FGFR3 hotspot mutations, R248C and S249C, and FGFR3 fusions were found in 0.1% and 0.14% of NSCLC, respectively.	('R248C', 'Var', (25, 30))	('NSCLC', 'Phenotype', 'HP:0030358', (92, 97))	('FGFR3', 'Gene', (0, 5))	('S249C', 'Var', (35, 40))	('FGFR3', 'Gene', '2261', (46, 51))	('R248C', 'Mutation', 'rs121913482', (25, 30))	('S249C', 'Mutation', 'rs121913483', (35, 40))	('NSCLC', 'Disease', (92, 97))	('FGFR3', 'Gene', (46, 51))	('NSCLC', 'Disease', 'MESH:D002289', (92, 97))	('FGFR3', 'Gene', '2261', (0, 5))
200582	32726920	FGFR fusions were detected in 0.1% and 0.6% of adenocarcinoma and squamous cell carcinoma, respectively.	('detected', 'Reg', (18, 26))	('squamous cell carcinoma', 'Disease', (66, 89))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('carcinoma', 'Phenotype', 'HP:0030731', (52, 61))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (66, 89))	('FGFR', 'Gene', (0, 4))	('FGFR', 'Gene', 'None', (0, 4))	('adenocarcinoma', 'Disease', 'MESH:D000230', (47, 61))	('fusions', 'Var', (5, 12))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (66, 89))	('adenocarcinoma', 'Disease', (47, 61))
200583	32726920	Tumors with FGFR3 fusions were sensitive to FGFR inhibition.	('FGFR3', 'Gene', (12, 17))	('FGFR', 'Gene', (44, 48))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('fusions', 'Var', (18, 25))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('FGFR3', 'Gene', '2261', (12, 17))	('FGFR', 'Gene', 'None', (44, 48))	('FGFR', 'Gene', (12, 16))	('FGFR', 'Gene', 'None', (12, 16))
200584	32726920	With the prevalence of FGFR3 at 4%, FGFR3 aberrations might represent an opportunity for targeted therapy in pulmonary LELC.	('FGFR3', 'Gene', (23, 28))	('FGFR3', 'Gene', (36, 41))	('aberrations', 'Var', (42, 53))	('pulmonary LELC', 'Disease', (109, 123))	('FGFR3', 'Gene', '2261', (23, 28))	('FGFR3', 'Gene', '2261', (36, 41))
200585	32726920	Clinical trials using FGFR inhibitors may be warranted for LELC patients harboring the FGFR3 aberrations.	('FGFR', 'Gene', (22, 26))	('FGFR', 'Gene', 'None', (22, 26))	('patients', 'Species', '9606', (64, 72))	('FGFR3', 'Gene', '2261', (87, 92))	('LELC', 'Disease', (59, 63))	('aberrations', 'Var', (93, 104))	('FGFR', 'Gene', (87, 91))	('FGFR', 'Gene', 'None', (87, 91))	('FGFR3', 'Gene', (87, 92))
200592	32726920	reported that NFKBIA mutations were frequently detected in pulmonary LELC.	('NFKBIA', 'Gene', (14, 20))	('NFKBIA', 'Gene', '4792', (14, 20))	('pulmonary LELC', 'Disease', (59, 73))	('detected', 'Reg', (47, 55))	('mutations', 'Var', (21, 30))
200593	32726920	Intriguing, we revealed multiple loss-of-function mutations in TRAF3, CYLD, NFKBIA and TNFAIP3.	('NFKBIA', 'Gene', (76, 82))	('TRAF3', 'Gene', '7187', (63, 68))	('mutations', 'Var', (50, 59))	('TNFAIP3', 'Gene', (87, 94))	('NFKBIA', 'Gene', '4792', (76, 82))	('TRAF3', 'Gene', (63, 68))	('CYLD', 'Gene', (70, 74))	('CYLD', 'Gene', '1540', (70, 74))	('TNFAIP3', 'Gene', '7128', (87, 94))	('loss-of-function', 'NegReg', (33, 49))
200594	32726920	Such a feature of multiple loss-of-function mutations of NF-kappaB pathway regulators, leading to activation of NF-kappaB pathway, has been recently reported in NPC.	('NF-kappaB', 'Gene', '4790', (112, 121))	('NPC', 'Disease', (161, 164))	('NF-kappaB', 'Gene', (57, 66))	('activation', 'PosReg', (98, 108))	('loss-of-function', 'NegReg', (27, 43))	('NF-kappaB', 'Gene', (112, 121))	('mutations', 'Var', (44, 53))	('NPC', 'Phenotype', 'HP:0100630', (161, 164))	('NF-kappaB', 'Gene', '4790', (57, 66))
200595	32726920	The dysregulation of NF-kappaB signaling, relating to viral oncoprotein LMP1 and genetic alterations of NF-kappaB regulators, was a crucial event in NPC tumorigenesis.	('LMP1', 'Gene', '9260', (72, 76))	('genetic', 'Var', (81, 88))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('NPC', 'Phenotype', 'HP:0100630', (149, 152))	('LMP1', 'Gene', (72, 76))	('NF-kappaB', 'Gene', '4790', (21, 30))	('NPC', 'Disease', (149, 152))	('tumor', 'Disease', (153, 158))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('dysregulation', 'MPA', (4, 17))	('NF-kappaB', 'Gene', (21, 30))	('NF-kappaB', 'Gene', '4790', (104, 113))	('NF-kappaB', 'Gene', (104, 113))
200596	32726920	Our findings unveiled the genetic lesions regarding NF-kappaB and implicated the involvement of the NF-kappaB pathway underlying the pathogenesis of the disease.	('involvement', 'Reg', (81, 92))	('lesions', 'Var', (34, 41))	('NF-kappaB', 'Gene', '4790', (52, 61))	('NF-kappaB', 'Gene', '4790', (100, 109))	('NF-kappaB', 'Gene', (52, 61))	('NF-kappaB', 'Gene', (100, 109))
200597	32726920	The uniqueness of loss-of-function mutations of NF-kappaB negative regulators and an association of EBV infection suggested a resemblance between pulmonary LELC and NPC in pathogenesis of the disease.	('pulmonary LELC', 'Disease', (146, 160))	('NPC', 'Disease', (165, 168))	('EBV', 'Gene', (100, 103))	('NF-kappaB', 'Gene', '4790', (48, 57))	('loss-of-function', 'NegReg', (18, 34))	('infection', 'Disease', (104, 113))	('infection', 'Disease', 'MESH:D007239', (104, 113))	('NF-kappaB', 'Gene', (48, 57))	('EBV', 'Species', '10376', (100, 103))	('NPC', 'Phenotype', 'HP:0100630', (165, 168))	('mutations', 'Var', (35, 44))
200600	32726920	In general, they found a low somatic mutation rate and revealed the genetic lesions of NF-kappaB largely owing to copy number variations.	('copy number variations', 'Var', (114, 136))	('NF-kappaB', 'Gene', (87, 96))	('owing', 'Reg', (105, 110))	('NF-kappaB', 'Gene', '4790', (87, 96))
200605	32726920	The actionable FGFR3 alterations including a hotspot mutation and FGFR3-TACC3 gene fusion were detected by our "deep" targeted capture sequencing.	('FGFR3', 'Gene', (15, 20))	('TACC3', 'Gene', '10460', (72, 77))	('FGFR3', 'Gene', '2261', (66, 71))	('TACC3', 'Gene', (72, 77))	('FGFR3', 'Gene', '2261', (15, 20))	('FGFR3', 'Gene', (66, 71))	('alterations', 'Var', (21, 32))
200607	32726920	The unique gene panel design and high coverage deep targeted sequencing allows us to detect the important druggable targets, such as FGFR3-TACC3 and other rare mutations in pulmonary LELC.	('FGFR3', 'Gene', (133, 138))	('pulmonary LELC', 'Disease', (173, 187))	('mutations', 'Var', (160, 169))	('TACC3', 'Gene', '10460', (139, 144))	('FGFR3', 'Gene', '2261', (133, 138))	('TACC3', 'Gene', (139, 144))
200609	32726920	The use of specific targeted therapy includes the selective tyrosine kinase inhibitors for the treatment of NSCLC with EGFR mutation, ALK rearrangement or ROS1 rearrangement.	('NSCLC', 'Phenotype', 'HP:0030358', (108, 113))	('ALK', 'Gene', (134, 137))	('NSCLC', 'Disease', (108, 113))	('ROS1', 'Gene', (155, 159))	('EGFR', 'Gene', '1956', (119, 123))	('mutation', 'Var', (124, 132))	('ROS1', 'Gene', '6098', (155, 159))	('NSCLC', 'Disease', 'MESH:D002289', (108, 113))	('ALK', 'Gene', '238', (134, 137))	('EGFR', 'Gene', (119, 123))
200612	32726920	As shown in our study, the detection of somatic alterations of various double strand DNA repair genes including ATM, BRCA1 and BRCA2 (7/57, 12.3%, Figure 3B) suggested a subgroup of patients might be sensitive to PARP1 inhibitor treatment.	('BRCA2', 'Gene', '675', (127, 132))	('BRCA1', 'Gene', '672', (117, 122))	('alterations', 'Var', (48, 59))	('ATM', 'Gene', (112, 115))	('BRCA1', 'Gene', (117, 122))	('ATM', 'Gene', '472', (112, 115))	('patients', 'Species', '9606', (182, 190))	('BRCA2', 'Gene', (127, 132))	('PARP1', 'Gene', '142', (213, 218))	('PARP1', 'Gene', (213, 218))
200623	32726920	The predictive biomarkers are MSI-high/mismatch repair deficiency and programmed death-1 (PD-1)/PDL-1 protein expression.	('PDL-1', 'Gene', '29126', (96, 101))	('MSI-high/mismatch repair', 'Protein', (30, 54))	('deficiency', 'Var', (55, 65))	('expression', 'MPA', (110, 120))	('PD-1', 'Gene', (90, 94))	('PD-1', 'Gene', '5133', (90, 94))	('PDL-1', 'Gene', (96, 101))	('protein', 'Protein', (102, 109))
200624	32726920	Although a previous study showed that none of seven pulmonary LELC patients was MSI-high, we discovered that mismatch repair deficiency was prevalent at 4% (2/57) of pulmonary LELC.	('mismatch', 'Var', (109, 117))	('pulmonary LELC', 'Disease', (166, 180))	('prevalent', 'Reg', (140, 149))	('patients', 'Species', '9606', (67, 75))
200655	32726920	MSI-positive tumors were defined as those with the proportion of microsatellite loci showing instability greater than one standard deviation above the mean (Figure S6).	('microsatellite', 'Var', (65, 79))	('instability', 'MPA', (93, 104))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Disease', (13, 19))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
200660	32726920	Amplification of CCND1, FGFR1, PIK3CA and SOX2, and deletion of CDKN2A were assessed by dual-color FISH probes listed in Table S10.	('SOX2', 'Gene', '6657', (42, 46))	('SOX2', 'Gene', (42, 46))	('CCND1', 'Gene', '595', (17, 22))	('CDKN2A', 'Gene', (64, 70))	('PIK3CA', 'Gene', (31, 37))	('FGFR1', 'Gene', (24, 29))	('FGFR1', 'Gene', '2260', (24, 29))	('CDKN2A', 'Gene', '1029', (64, 70))	('PIK3CA', 'Gene', '5290', (31, 37))	('CCND1', 'Gene', (17, 22))	('deletion', 'Var', (52, 60))
200667	32726920	SNV, single nucleotide variation; Mb, megabase; Figure S2: FGFR3-TACC3 fusion identified in pulmonary lymphoepithelioma-like carcinoma.	('identified', 'Reg', (78, 88))	('FGFR3', 'Gene', '2261', (59, 64))	('TACC3', 'Gene', '10460', (65, 70))	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('TACC3', 'Gene', (65, 70))	('FGFR3', 'Gene', (59, 64))	('pulmonary lymphoepithelioma-like carcinoma', 'Disease', (92, 134))	('single nucleotide variation', 'Var', (5, 32))	('fusion', 'Var', (71, 77))	('pulmonary lymphoepithelioma-like carcinoma', 'Disease', 'MESH:D008175', (92, 134))
200670	32726920	(C) FGFR3-TACC3 fusion transcript detected by RNA-seq.	('TACC3', 'Gene', '10460', (10, 15))	('TACC3', 'Gene', (10, 15))	('FGFR3', 'Gene', (4, 9))	('FGFR3', 'Gene', '2261', (4, 9))	('fusion', 'Var', (16, 22))
200671	32726920	; Figure S3: Homozygous deletion of CDKN2A in LLELC38 validated by dual color fluorescence in situ hybridization assay of chromosome 9 probe, centromere 9 (red)/ 9p21.3-CDKN2A (green).	('CDKN2A', 'Gene', (169, 175))	('CDKN2A', 'Gene', (36, 42))	('CDKN2A', 'Gene', '1029', (169, 175))	('CDKN2A', 'Gene', '1029', (36, 42))	('deletion', 'Var', (24, 32))
200676	32726920	This project is supported by the Vice-Chancellor's One-off Discretionary Fund, Focused Innovations Scheme and Faculty Strategic Research (4620513) of the Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong and the Research Grants Council (RGC) of Hong Kong (T12-401/13-R; C4001-18GF; C7027-16G; C5012-15E; 14113620; 14117316; 14138016; 14104415).	('C7027-16G', 'Var', (300, 309))	('C5012-15E; 14113620; 14117316; 14138016; 14104415', 'Var', (311, 360))	('C7027-16G', 'SUBSTITUTION', 'None', (300, 309))
200679	29700001	Our approach highlights canonical oncogenes in chr11q13 that displayed the strongest associations between expression and copy number, including CCND1 and CTTN, genes not identified by copy number analysis in the primary reports.	('CCND1', 'Gene', '595', (144, 149))	('expression', 'MPA', (106, 116))	('chr11q13', 'Gene', (47, 55))	('copy number', 'Var', (121, 132))	('CTTN', 'Gene', (154, 158))	('CCND1', 'Gene', (144, 149))	('CTTN', 'Gene', '2017', (154, 158))
200690	29700001	Level 3 mRNA expression, miRNA expression, and DNA methylation data for CESC (n = 191), HNSC (n = 279), and LUSC (n = 178) were downloaded from the Legacy Archive of the Genomic Data Commons (https://portal.gdc.cancer.gov/legacy-archive/search/f), for the following platforms: Illumina HiSeq (mRNA and miRNA) and Illumina 450K (DNA methylation).	('LUSC', 'Phenotype', 'HP:0030359', (108, 112))	('cancer', 'Disease', 'MESH:D009369', (211, 217))	('cancer', 'Disease', (211, 217))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('Illumina', 'Var', (313, 321))
200701	29700001	This suggests that at the gene level there are exceptions to the broad association between regions of somatic copy number alteration and corresponding changes in gene expression as depicted in Figures 1A/B.	('1A/B', 'SUBSTITUTION', 'None', (201, 205))	('changes', 'Reg', (151, 158))	('1A/B', 'Var', (201, 205))	('gene expression', 'MPA', (162, 177))
200707	29700001	Indeed, it may be the case that the complexity of the transcriptional regulation of CCND1 contribute to the observation that copy number changes have less of an effect on expression than other regional genes such as FADD and CTTN.	('expression', 'MPA', (171, 181))	('FADD', 'Gene', (216, 220))	('CTTN', 'Gene', (225, 229))	('CCND1', 'Gene', (84, 89))	('FADD', 'Gene', '8772', (216, 220))	('CTTN', 'Gene', '2017', (225, 229))	('CCND1', 'Gene', '595', (84, 89))	('copy number changes', 'Var', (125, 144))
200710	29700001	There are a number of striking differences, including 7p11 (EGFR), 11q13 (FADD), 14q32 (TRAF3), and 20q11 (E2F1).	('FADD', 'Gene', (74, 78))	('E2F1', 'Gene', '1869', (107, 111))	('E2F1', 'Gene', (107, 111))	('TRAF3', 'Gene', (88, 93))	('20q11', 'Var', (100, 105))	('p11', 'Gene', (55, 58))	('EGFR', 'Gene', '1956', (60, 64))	('TRAF3', 'Gene', '7187', (88, 93))	('FADD', 'Gene', '8772', (74, 78))	('EGFR', 'Gene', (60, 64))	('14q32', 'Var', (81, 86))	('p11', 'Gene', '6281', (55, 58))
200711	29700001	Figure 3B shows that broad copy number gains in chr7p and focal amplification of EGFR are seen almost exclusively in HPV- subjects.	('HPV-', 'Disease', (117, 121))	('gains', 'PosReg', (39, 44))	('HPV', 'Species', '10566', (117, 120))	('copy number', 'Var', (27, 38))	('chr7p', 'Protein', (48, 53))	('focal', 'MPA', (58, 63))	('EGFR', 'Gene', '1956', (81, 85))	('EGFR', 'Gene', (81, 85))
200713	29700001	On the other hand, HPV+ samples have large CN/GE rho values in chr14 that appear to be driven by copy number losses and decreased expression of regional genes, including TRAF3 (Figure 3D/E).	('decreased', 'NegReg', (120, 129))	('expression', 'MPA', (130, 140))	('TRAF3', 'Gene', (170, 175))	('copy number losses', 'Var', (97, 115))	('3D/E', 'Var', (184, 188))	('3D/E', 'SUBSTITUTION', 'None', (184, 188))	('TRAF3', 'Gene', '7187', (170, 175))	('HPV', 'Species', '10566', (19, 22))	('chr14', 'Gene', (63, 68))
200715	29700001	On chr20, copy number gains and increased expression of E2F1 are seen in HPV+ subjects (Figure 3F/G).	('3F/G', 'Var', (95, 99))	('E2F1', 'Gene', '1869', (56, 60))	('HPV+', 'Disease', (73, 77))	('E2F1', 'Gene', (56, 60))	('expression', 'MPA', (42, 52))	('HPV', 'Species', '10566', (73, 76))	('gains', 'PosReg', (22, 27))	('copy number', 'Var', (10, 21))	('increased', 'PosReg', (32, 41))	('3F/G', 'SUBSTITUTION', 'None', (95, 99))
200716	29700001	Figure 3G also shows that among E2F1 copy neutral samples, expression levels are markedly higher in HPV+ samples than in HPV- samples, perhaps because of E2F1 transcription autoregulation in the absence of negative control by pRb.	('HPV', 'Species', '10566', (100, 103))	('expression levels', 'MPA', (59, 76))	('E2F1', 'Gene', '1869', (32, 36))	('E2F1', 'Gene', (32, 36))	('autoregulation', 'PosReg', (173, 187))	('HPV', 'Species', '10566', (121, 124))	('copy neutral', 'Var', (37, 49))	('E2F1', 'Gene', '1869', (154, 158))	('higher', 'PosReg', (90, 96))	('E2F1', 'Gene', (154, 158))	('HPV+', 'Disease', (100, 104))
200720	29700001	On the other hand, CN changes have a less pronounced effect on CCND1 expression, particularly in HPV+ subjects (Supplementary Figure 2A-C).	('CCND1', 'Gene', '595', (63, 68))	('changes', 'Var', (22, 29))	('HPV', 'Species', '10566', (97, 100))	('HPV+', 'Disease', (97, 101))	('expression', 'MPA', (69, 79))	('CCND1', 'Gene', (63, 68))
200721	29700001	Although the reason for this behavior is not clear, the hypothesis that it may be connected to inactivation of RB1 in HPV+ samples is intriguing.	('HPV', 'Species', '10566', (118, 121))	('inactivation', 'Var', (95, 107))	('RB1', 'Gene', (111, 114))
200723	29700001	For example, a subset of HPV- samples is essentially copy neutral throughout chr3, and two HPV+ samples have gains on both arms.	('HPV', 'Species', '10566', (25, 28))	('copy neutral', 'Var', (53, 65))	('gains', 'PosReg', (109, 114))	('HPV', 'Species', '10566', (91, 94))	('HPV-', 'Disease', (25, 29))
200726	29700001	MLH1 is a mismatch repair gene, and a previous study found an association between promoter methylation and decreased expression.	('expression', 'MPA', (117, 127))	('MLH1', 'Gene', '4292', (0, 4))	('decreased', 'NegReg', (107, 116))	('MLH1', 'Gene', (0, 4))	('promoter methylation', 'Var', (82, 102))
200727	29700001	Although we did not observe altered methylation in the TCGA cohort, the effect of copy number losses suggests an alternate method for regulating MLH1 expression in HNSC.	('copy number losses', 'Var', (82, 100))	('expression', 'MPA', (150, 160))	('MLH1', 'Gene', (145, 149))	('MLH1', 'Gene', '4292', (145, 149))
200738	29700001	In the previous paragraph, we discussed the potential relevance of DVL3 in HNSC, and the fact that DCUN1D1 and SENP2 also have large values of rho in CESC and HNSC (Supplementary Figure 4C/D) suggests that they may be important in these tumor types as well.	('SENP2', 'Gene', '59343', (111, 116))	('DVL3', 'Gene', (67, 71))	('tumor', 'Disease', (237, 242))	('rho', 'MPA', (143, 146))	('DCUN1D1', 'Gene', (99, 106))	('4C/D', 'SUBSTITUTION', 'None', (186, 190))	('DCUN1D1', 'Gene', '54165', (99, 106))	('HNSC', 'Disease', (75, 79))	('DVL3', 'Gene', '1857', (67, 71))	('tumor', 'Disease', 'MESH:D009369', (237, 242))	('4C/D', 'Var', (186, 190))	('SENP2', 'Gene', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))
200740	29700001	In particular, the CN/GE rho values for CESC and HNSC display a surprising level of similarity at the YAP1, BIRC2, and DCUN1D5 loci (Supplementary Figure 4E/F).	('YAP1', 'Gene', '10413', (102, 106))	('DCUN1D5', 'Gene', '84259', (119, 126))	('4E/F', 'SUBSTITUTION', 'None', (154, 158))	('DCUN1D5', 'Gene', (119, 126))	('BIRC2', 'Gene', '329', (108, 113))	('4E/F', 'Var', (154, 158))	('YAP1', 'Gene', (102, 106))	('BIRC2', 'Gene', (108, 113))
200755	29700001	noted that different mechanisms of epigenetic regulation of mir-200 family members contributed to a mesenchymal phenotype (histone modification for miR-429/200a/b and methylation for miR-141/200c).	('miR-141/200c', 'Gene', '406933;406985', (183, 195))	('contributed', 'Reg', (83, 94))	('miR-429', 'Gene', (148, 155))	('mesenchymal phenotype', 'CPA', (100, 121))	('miR-429', 'Gene', '554210', (148, 155))	('mir-200', 'Gene', (60, 67))	('methylation', 'MPA', (167, 178))	('miR-141/200c', 'Gene', (183, 195))	('epigenetic regulation', 'Var', (35, 56))
200756	29700001	miR-205 and the members of the miR-200 family do not appear to be the targets of copy number loss.	('copy number loss', 'Var', (81, 97))	('miR-205', 'Gene', '406988', (0, 7))	('miR-205', 'Gene', (0, 7))
200766	29465512	MicroRNA Changes in Firefighters Firefighters have elevated cancer incidence and mortality rates.	('elevated cancer', 'Disease', 'MESH:D009369', (51, 66))	('MicroRNA', 'Var', (0, 8))	('mortality rates', 'CPA', (81, 96))	('elevated cancer', 'Disease', (51, 66))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
200779	29465512	Epigenetic changes, including histone modifications, DNA methylation, and microRNA (miRNA) mediated pathways, play prominent roles in carcinogenesis and cancer prevention, and have been associated with activation of oncogenes or inhibition of tumor suppressor genes.	('carcinogenesis', 'Disease', 'MESH:D063646', (134, 148))	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('miR', 'Gene', '220972', (84, 87))	('miR', 'Gene', (84, 87))	('DNA', 'MPA', (53, 56))	('cancer', 'Disease', (153, 159))	('inhibition', 'NegReg', (229, 239))	('carcinogenesis', 'Disease', (134, 148))	('oncogenes', 'Gene', (216, 225))	('tumor', 'Disease', 'MESH:D009369', (243, 248))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('histone', 'MPA', (30, 37))	('activation', 'PosReg', (202, 212))	('roles', 'Reg', (125, 130))	('Epigenetic changes', 'Var', (0, 18))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))	('tumor', 'Disease', (243, 248))
200782	29465512	These epigenetic changes serve as molecular biomarkers of environmental exposures and carcinogenesis.	('carcinogenesis', 'Disease', (86, 100))	('carcinogenesis', 'Disease', 'MESH:D063646', (86, 100))	('epigenetic changes', 'Var', (6, 24))
200826	29465512	Upregulation of miR-486-3p is associated with K-ras mutation in colorectal cancer.	('Upregulation', 'PosReg', (0, 12))	('colorectal cancer', 'Disease', (64, 81))	('K-ras', 'Gene', (46, 51))	('K-ras', 'Gene', '3845', (46, 51))	('colorectal cancer', 'Disease', 'MESH:D015179', (64, 81))	('mutation', 'Var', (52, 60))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('miR', 'Gene', '220972', (16, 19))	('miR', 'Gene', (16, 19))	('colorectal cancer', 'Phenotype', 'HP:0003003', (64, 81))
200829	29465512	Aging and obesity are major risk factors for cancer, and they are also associated with epigenetic changes.	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('obesity', 'Phenotype', 'HP:0001513', (10, 17))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('epigenetic changes', 'Var', (87, 105))	('obesity', 'Disease', 'MESH:D009765', (10, 17))	('cancer', 'Disease', (45, 51))	('obesity', 'Disease', (10, 17))	('associated', 'Reg', (71, 81))
200836	29465512	MiR-313-3p expression, decreased in incumbent firefighters in our study, was reduced following short-term PM10 exposure in a population of overweight/obese subjects, but was increased in lung adenocarcinoma patients exposed to asbestos compared with nonexposed patients with adenocarcinoma.	('lung adenocarcinoma', 'Disease', (187, 206))	('adenocarcinoma', 'Disease', 'MESH:D000230', (192, 206))	('asbestos', 'Chemical', 'MESH:D001194', (227, 235))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (187, 206))	('obese', 'Disease', (150, 155))	('adenocarcinoma', 'Disease', (275, 289))	('MiR-313-3p', 'Gene', (0, 10))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (187, 206))	('obese', 'Disease', 'MESH:D009765', (150, 155))	('carcinoma', 'Phenotype', 'HP:0030731', (197, 206))	('reduced', 'NegReg', (77, 84))	('adenocarcinoma', 'Disease', 'MESH:D000230', (275, 289))	('overweight', 'Phenotype', 'HP:0025502', (139, 149))	('patients', 'Species', '9606', (207, 215))	('carcinoma', 'Phenotype', 'HP:0030731', (280, 289))	('adenocarcinoma', 'Disease', (192, 206))	('PM10', 'Var', (106, 110))	('MiR-313-3p', 'Gene', '100422942', (0, 10))	('patients', 'Species', '9606', (261, 269))	('increased', 'PosReg', (174, 183))
200915	29258258	Moreover, it was demonstrated that patients with tongue carcinoma expressing low level of gal-3 had a favorable five-year disease-free survival (73.9%) compared to patients expressing high levels (40.8%).	('gal-3', 'Gene', (90, 95))	('tongue carcinoma', 'Phenotype', 'HP:0030415', (49, 65))	('disease-free survival', 'CPA', (122, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (56, 65))	('tongue carcinoma', 'Disease', 'MESH:D014062', (49, 65))	('tongue carcinoma', 'Disease', (49, 65))	('gal-3', 'Gene', '3958', (90, 95))	('patients', 'Species', '9606', (35, 43))	('patients', 'Species', '9606', (164, 172))	('low level', 'Var', (77, 86))
200935	29258258	Additionally, the mutation of gal-3 (serine6 to alanine or glutamic acid) prevents phosphorylation, resulting in a decrease of its anti-apoptotic activity.	('gal-3', 'Gene', '3958', (30, 35))	('prevents', 'NegReg', (74, 82))	('gal-3', 'Gene', (30, 35))	('phosphorylation', 'MPA', (83, 98))	('serine6 to alanine', 'Mutation', 'p.S6A', (37, 55))	('mutation', 'Var', (18, 26))	('serine6 to alanine or glutamic acid', 'Var', (37, 72))	('decrease', 'NegReg', (115, 123))	('anti-apoptotic activity', 'CPA', (131, 154))	('serine6 to alanine or glutamic acid', 'SUBSTITUTION', 'None', (37, 72))
200936	29258258	Furthermore, gal-3 has a role in cell proliferation, as the inhibition of this protein by knockdown lead to the decrease of esophageal and renal cancer cell proliferation in vitro.	('esophageal and renal cancer', 'Disease', 'MESH:D007680', (124, 151))	('knockdown', 'Var', (90, 99))	('decrease', 'NegReg', (112, 120))	('gal-3', 'Gene', '3958', (13, 18))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('inhibition', 'NegReg', (60, 70))	('gal-3', 'Gene', (13, 18))	('renal cancer', 'Phenotype', 'HP:0009726', (139, 151))
200938	29258258	Inversely, the knockdown of gal-3 in Tca8113 cells exhibited a decrease of cell proliferation.	('knockdown', 'Var', (15, 24))	('gal-3', 'Gene', '3958', (28, 33))	('decrease', 'NegReg', (63, 71))	('gal-3', 'Gene', (28, 33))	('cell proliferation', 'CPA', (75, 93))
200944	29258258	Concerning gal-1, it was demonstrated that its knockdown caused a decrease in cell proliferation in anaplastic, but not in papillary thyroid cancer cells.	('papillary thyroid cancer', 'Disease', (123, 147))	('gal-1', 'Gene', (11, 16))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('papillary thyroid cancer', 'Disease', 'MESH:D000077273', (123, 147))	('knockdown', 'Var', (47, 56))	('papillary thyroid cancer', 'Phenotype', 'HP:0002895', (123, 147))	('anaplastic', 'CPA', (100, 110))	('decrease', 'NegReg', (66, 74))	('thyroid cancer', 'Phenotype', 'HP:0002890', (133, 147))	('cell proliferation', 'CPA', (78, 96))
200954	29258258	Similar results have been published for HNSCC, where silencing of Wnt reduced the ability of gal-3 to stimulate cell migration and invasion of oral tongue squamous cell carcinoma.	('oral tongue squamous cell carcinoma', 'Disease', 'MESH:D002294', (143, 178))	('invasion', 'CPA', (131, 139))	('reduced', 'NegReg', (70, 77))	('carcinoma', 'Phenotype', 'HP:0030731', (169, 178))	('stimulate', 'PosReg', (102, 111))	('ability', 'MPA', (82, 89))	('gal-3', 'Gene', '3958', (93, 98))	('oral tongue squamous cell carcinoma', 'Disease', (143, 178))	('HNSCC', 'Disease', (40, 45))	('silencing', 'Var', (53, 62))	('HNSCC', 'Phenotype', 'HP:0012288', (40, 45))	('cell migration', 'CPA', (112, 126))	('tongue squamous cell carcinoma', 'Phenotype', 'HP:0030413', (148, 178))	('gal-3', 'Gene', (93, 98))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (155, 178))
200957	29258258	Interestingly, the knockdown of RhoA in tongue squamous cell carcinoma (TSCC) cells negatively affects cell migration and invasion.	('tongue squamous cell carcinoma', 'Phenotype', 'HP:0030413', (40, 70))	('knockdown', 'Var', (19, 28))	('affects', 'Reg', (95, 102))	('negatively', 'NegReg', (84, 94))	('RhoA', 'Gene', (32, 36))	('RhoA', 'Gene', '387', (32, 36))	('TSCC', 'Phenotype', 'HP:0030413', (72, 76))	('tongue squamous cell carcinoma', 'Disease', 'MESH:D002294', (40, 70))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (47, 70))	('tongue squamous cell carcinoma', 'Disease', (40, 70))
200959	29258258	Silencing of RhoA in such tumors downregulates the expression of gal-3, beta-catenin and MMP-9 (Figure 3).	('downregulates', 'NegReg', (33, 46))	('RhoA', 'Gene', '387', (13, 17))	('beta-catenin', 'Gene', (72, 84))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('beta-catenin', 'Gene', '1499', (72, 84))	('gal-3', 'Gene', '3958', (65, 70))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('expression', 'MPA', (51, 61))	('RhoA', 'Gene', (13, 17))	('gal-3', 'Gene', (65, 70))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('MMP-9', 'Gene', '4318', (89, 94))	('Silencing', 'Var', (0, 9))	('tumors', 'Disease', (26, 32))	('MMP-9', 'Gene', (89, 94))
200960	29258258	Concerning gal-1, it was demonstrated that in cancer-associated fibroblasts (CAF), which play an important role in cell migration and invasion, under-expression of gal-1 significantly decreased breast cancer cell migration.	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('under-expression', 'Var', (144, 160))	('CAF', 'Gene', (77, 80))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('gal-1', 'Gene', (164, 169))	('cancer', 'Disease', (201, 207))	('cancer', 'Disease', (46, 52))	('CAF', 'Gene', '8850', (77, 80))	('decreased', 'NegReg', (184, 193))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('breast cancer', 'Disease', 'MESH:D001943', (194, 207))	('breast cancer', 'Disease', (194, 207))	('breast cancer', 'Phenotype', 'HP:0003002', (194, 207))
200961	29258258	Additionally, MMP-9 expression levels were attenuated in CAF silenced for gal-1, thus limiting the degradation of the extracellular matrix.	('silenced', 'Var', (61, 69))	('MMP-9', 'Gene', (14, 19))	('CAF', 'Gene', (57, 60))	('limiting', 'NegReg', (86, 94))	('CAF', 'Gene', '8850', (57, 60))	('attenuated', 'NegReg', (43, 53))	('gal-1', 'Gene', (74, 79))	('degradation of the extracellular matrix', 'MPA', (99, 138))	('expression levels', 'MPA', (20, 37))	('MMP-9', 'Gene', '4318', (14, 19))
200962	29258258	Similarly, in oral squamous cell carcinoma (OSCC), the silencing of gal-1 in CAF negatively affected cell migration and invasion by reducing the amount of monocyte chemotactic protein-1 (MCP-1/CCL2).	('CAF', 'Gene', (77, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (33, 42))	('cell migration', 'CPA', (101, 115))	('MCP-1', 'Gene', '20296', (187, 192))	('silencing', 'Var', (55, 64))	('CCL2', 'Gene', (193, 197))	('negatively', 'NegReg', (81, 91))	('MCP-1', 'Gene', (187, 192))	('monocyte chemotactic protein-1', 'Gene', (155, 185))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (14, 42))	('invasion', 'CPA', (120, 128))	('reducing', 'NegReg', (132, 140))	('oral squamous cell carcinoma', 'Disease', (14, 42))	('gal-1', 'Gene', (68, 73))	('monocyte chemotactic protein-1', 'Gene', '20296', (155, 185))	('CAF', 'Gene', '8850', (77, 80))	('CCL2', 'Gene', '20296', (193, 197))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (19, 42))	('OSCC', 'CellLine', 'CVCL:L894', (44, 48))
200967	29258258	In thyroid cancer, our group recently demonstrated that the knockdown of gal-1 in papillary and anaplastic thyroid cancer cell lines induced decreased cell motility and invasion.	('thyroid cancer', 'Disease', (107, 121))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('thyroid cancer', 'Phenotype', 'HP:0002890', (107, 121))	('invasion', 'CPA', (169, 177))	('thyroid cancer', 'Disease', 'MESH:D013964', (3, 17))	('anaplastic thyroid cancer', 'Phenotype', 'HP:0011779', (96, 121))	('thyroid cancer', 'Disease', 'MESH:D013964', (107, 121))	('gal-1', 'Gene', (73, 78))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('knockdown', 'Var', (60, 69))	('thyroid cancer', 'Disease', (3, 17))	('decreased cell motility', 'Disease', 'MESH:D015835', (141, 164))	('thyroid cancer', 'Phenotype', 'HP:0002890', (3, 17))	('decreased cell motility', 'Disease', (141, 164))
200972	29258258	Moreover, human umbilical vein endothelial cell (HUVECs) adhesion to laminin was significantly increased by stimulating the expression of extracellular gal-1, and dramatically decreased by its silencing.	('human', 'Species', '9606', (10, 15))	('adhesion', 'CPA', (57, 65))	('decreased', 'NegReg', (176, 185))	('silencing', 'Var', (193, 202))	('laminin', 'Protein', (69, 76))	('expression', 'MPA', (124, 134))	('stimulating', 'PosReg', (108, 119))	('increased', 'PosReg', (95, 104))	('extracellular', 'Protein', (138, 151))
200975	29258258	VEGFR-2 silencing leads to a reduction in gal-1-induced HUVECs migration.	('VEGFR-2', 'Gene', (0, 7))	('reduction', 'NegReg', (29, 38))	('gal-1-induced HUVECs migration', 'CPA', (42, 72))	('silencing', 'Var', (8, 17))	('VEGFR-2', 'Gene', '3791', (0, 7))
200981	29258258	Additionally, endogenous gal-3 silencing significantly reduced VEGF- and bFGF-mediated endothelial cell migration, as well as capillary tubule formation in vitro, with a reversible effect when exogenous gal-3 was added to the cells.	('silencing', 'Var', (31, 40))	('capillary tubule formation', 'CPA', (126, 152))	('reduced', 'NegReg', (55, 62))	('gal-3', 'Gene', '3958', (203, 208))	('bFGF', 'Gene', '2247', (73, 77))	('VEGF-', 'Gene', (63, 68))	('gal-3', 'Gene', '3958', (25, 30))	('bFGF', 'Gene', (73, 77))	('gal-3', 'Gene', (203, 208))	('gal-3', 'Gene', (25, 30))	('VEGF-', 'Gene', '7422', (63, 68))
201003	29258258	In vivo data revealed that injection of GM-CT-01 to colon tumor-bearing mice potentiated the anti-tumor activity of 5-fluorouracil (5-FU).	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('colon tumor', 'Phenotype', 'HP:0100273', (52, 63))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (116, 130))	('colon tumor', 'Disease', (52, 63))	('potentiated', 'PosReg', (77, 88))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('GM-CT-01', 'Var', (40, 48))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('5-FU', 'Chemical', 'MESH:D005472', (132, 136))	('mice', 'Species', '10090', (72, 76))	('tumor', 'Disease', (98, 103))	('CT-01', 'CellLine', 'CVCL:Z282', (43, 48))	('colon tumor', 'Disease', 'MESH:D015179', (52, 63))
201006	29258258	This property is used in a phase I/II study in which GM-CT-01 is associated with a peptide vaccination to induce a more efficient and long-lasting anti-tumor immune response in metastatic melanoma patients (NCT01723813).	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('patients', 'Species', '9606', (197, 205))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('tumor', 'Disease', (152, 157))	('GM-CT-01', 'Var', (53, 61))	('CT-01', 'CellLine', 'CVCL:Z282', (56, 61))	('melanoma', 'Disease', 'MESH:D008545', (188, 196))	('melanoma', 'Phenotype', 'HP:0002861', (188, 196))	('melanoma', 'Disease', (188, 196))
201009	29258258	The researchers observed in these models that GR-MD-02 potentiated the effect of immune modulators such as anti-PD1, anti-CTLA4, and anti-OX40 antibodies by reducing tumor size and improving mice survival.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('anti-CTLA4', 'Var', (117, 127))	('GR-MD-02', 'Chemical', '-', (46, 54))	('reducing', 'NegReg', (157, 165))	('PD1', 'Gene', '18566', (112, 115))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('tumor', 'Disease', (166, 171))	('OX40', 'Gene', (138, 142))	('GR-MD-02', 'Var', (46, 54))	('mice survival', 'CPA', (191, 204))	('improving', 'PosReg', (181, 190))	('mice', 'Species', '10090', (191, 195))	('OX40', 'Gene', '22163', (138, 142))	('PD1', 'Gene', (112, 115))	('potentiated', 'PosReg', (55, 66))
201027	28135248	In this group, telomere length positively correlated with TP53 and RB1 mutations.	('TP53', 'Gene', '7157', (58, 62))	('TP53', 'Gene', (58, 62))	('RB1', 'Gene', (67, 70))	('mutations', 'Var', (71, 80))	('correlated', 'Reg', (42, 52))	('telomere length', 'MPA', (15, 30))
201032	28135248	The telomerase enzymatic subunit is encoded by TERT, and while it is transcriptionally silent in most non-neoplastic cells, reactivation may endow a small population of cells with the ability to survive crisis, at which point they become immortalized.	('TERT', 'Gene', (47, 51))	('reactivation', 'Var', (124, 136))	('TERT', 'Gene', '7015', (47, 51))	('ran', 'Gene', (70, 73))	('ran', 'Gene', '5901', (70, 73))
201036	28135248	Deactivating mutations in ATRX and its binding partner DAXX were found tightly correlated with long telomeres in pancreatic neuroendocrine tumors and glioma.	('ATRX', 'Gene', (26, 30))	('DAXX', 'Gene', '1616', (55, 59))	('long telomeres', 'MPA', (95, 109))	('DAXX', 'Gene', (55, 59))	('Deactivating mutations', 'Var', (0, 22))	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (124, 145))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('ATRX', 'Gene', '546', (26, 30))	('glioma', 'Disease', (150, 156))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('glioma', 'Phenotype', 'HP:0009733', (150, 156))	('correlated', 'Reg', (79, 89))	('pancreatic neuroendocrine tumors', 'Disease', (113, 145))	('glioma', 'Disease', 'MESH:D005910', (150, 156))	('pancreatic neuroendocrine tumors', 'Disease', 'MESH:D018358', (113, 145))
201037	28135248	Recent evidence suggested that loss of ATRX may contribute to ALT by promoting sustained sister telomere cohesion and chromatid exchange.	('ATRX', 'Gene', (39, 43))	('promoting', 'PosReg', (69, 78))	('ATRX', 'Gene', '546', (39, 43))	('loss', 'Var', (31, 35))	('contribute', 'Reg', (48, 58))	('ALT', 'Disease', (62, 65))	('chromatid exchange', 'CPA', (118, 136))
201049	28135248	We curated a core sample set that consisted of 473 T/N pairs with the most comprehensive molecular profiling and an extended set that consisted of 6,835 T/N pairs with varying numbers of cases profiled by each individual platform (Figure 1a, Online Methods).	('835 T/N', 'Var', (149, 156))	('835 T/N', 'SUBSTITUTION', 'None', (149, 156))	('473 T/N', 'Var', (47, 54))	('473 T/N', 'SUBSTITUTION', 'None', (47, 54))
201050	28135248	TERT promoter (TERTp) mutations, predominantly C250T and C228T, were detected in 27% of the extended set for the cases where TERTp status could be determined (n=1,581).	('C250T', 'Var', (47, 52))	('TERT', 'Gene', '7015', (15, 19))	('C250T', 'Mutation', 'c.250C>T', (47, 52))	('C228T', 'Mutation', 'c.228C>T', (57, 62))	('TERTp', 'Gene', (125, 130))	('TERT', 'Gene', (0, 4))	('TERT', 'Gene', '7015', (0, 4))	('TERTp', 'Gene', '7015', (125, 130))	('TERTp', 'Gene', (15, 20))	('TERT', 'Gene', (125, 129))	('C228T', 'Var', (57, 62))	('TERTp', 'Gene', '7015', (15, 20))	('TERT', 'Gene', '7015', (125, 129))	('TERT', 'Gene', (15, 19))
201051	28135248	In agreement with previous reports; high incidence of TERTp mutations was found in bladder cancer (42/60, 70%), liver cancer (73/162, 45%), melanoma (93/129, 72%), lower grade glioma (127/285, 45%) and glioblastoma (25/28, 89%, Supplementary Figure 4a).	('glioblastoma', 'Disease', 'MESH:D005909', (202, 214))	('melanoma', 'Disease', 'MESH:D008545', (140, 148))	('TERTp', 'Gene', (54, 59))	('TERTp', 'Gene', '7015', (54, 59))	('glioma', 'Disease', (176, 182))	('glioma', 'Disease', 'MESH:D005910', (176, 182))	('glioblastoma', 'Disease', (202, 214))	('glioblastoma', 'Phenotype', 'HP:0012174', (202, 214))	('liver cancer', 'Disease', 'MESH:D006528', (112, 124))	('glioma', 'Phenotype', 'HP:0009733', (176, 182))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('melanoma', 'Phenotype', 'HP:0002861', (140, 148))	('melanoma', 'Disease', (140, 148))	('bladder cancer', 'Disease', 'MESH:D001749', (83, 97))	('liver cancer', 'Phenotype', 'HP:0002896', (112, 124))	('bladder cancer', 'Disease', (83, 97))	('liver cancer', 'Disease', (112, 124))	('bladder cancer', 'Phenotype', 'HP:0009725', (83, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('mutations', 'Var', (60, 69))
201057	28135248	In the majority of TERTp structural variants (65%), at least one predicted super enhancer was found to directly overlap with the juxtaposed position (Supplementary Table 3).	('TERTp', 'Gene', (19, 24))	('TERTp', 'Gene', '7015', (19, 24))	('variants', 'Var', (36, 44))
201066	28135248	Taken together, we found somatic TERT alterations including TERTp mutations, TERT amplifications and TERT structural variants involving gene promoter or gene body in 32% of core set samples.	('TERT', 'Gene', '7015', (101, 105))	('TERT', 'Gene', (33, 37))	('TERT', 'Gene', '7015', (33, 37))	('TERT', 'Gene', (77, 81))	('TERT', 'Gene', '7015', (77, 81))	('TERT', 'Gene', '7015', (60, 64))	('variants', 'Var', (117, 125))	('TERT', 'Gene', (101, 105))	('TERTp', 'Gene', (60, 65))	('TERTp', 'Gene', '7015', (60, 65))	('TERT', 'Gene', (60, 64))
201072	28135248	As previously described in pediatric brain tumors, TERT promoter probe cg11625005 demonstrated a strong correlation with TERT expression (Rho=0.52, FDR<0.0001).	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('brain tumors', 'Phenotype', 'HP:0030692', (37, 49))	('pediatric brain tumors', 'Disease', (27, 49))	('TERT', 'Gene', (51, 55))	('correlation', 'Interaction', (104, 115))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('cg11625005', 'Var', (71, 81))	('TERT', 'Gene', '7015', (51, 55))	('TERT', 'Gene', (121, 125))	('TERT', 'Gene', '7015', (121, 125))	('pediatric brain tumors', 'Disease', 'MESH:D001932', (27, 49))
201077	28135248	TERTp methylation (two-sided t-test P<0.05) and TERTp mutations (two-sided t-test P<0.0001) were associated with relative TL shortening compared to other types of TERT alterations (Supplementary Figure 5c).	('TERTp', 'Gene', '7015', (0, 5))	('TERT', 'Gene', '7015', (163, 167))	('TERTp', 'Gene', (48, 53))	('TERTp', 'Gene', '7015', (48, 53))	('mutations', 'Var', (54, 63))	('TERT', 'Gene', (0, 4))	('TERT', 'Gene', (48, 52))	('shortening', 'NegReg', (125, 135))	('TERT', 'Gene', '7015', (0, 4))	('methylation', 'Var', (6, 17))	('TERT', 'Gene', (163, 167))	('TERT', 'Gene', '7015', (48, 52))	('TERTp', 'Gene', (0, 5))
201081	28135248	Focal TERC amplifications were associated with increased TERC expression (two-sided t-test P<0.0001) (Supplementary Figure 5d), and were enriched in TERT expressing samples (Odds Ratio (OR) 2.59, Fisher's Exact P<0.0001).	('TERT', 'Gene', '7015', (149, 153))	('TERC', 'Gene', (57, 61))	('TERC', 'Gene', (6, 10))	('amplifications', 'Var', (11, 25))	('TERC', 'Gene', '7012', (57, 61))	('increased', 'PosReg', (47, 56))	('TERT', 'Gene', (149, 153))	('TERC', 'Gene', '7012', (6, 10))
201091	28135248	TERC amplification was additionally associated with higher telomerase signature scores compared to non-amplified samples (two-sided t-test, P<0.0001), which may in part be explained by the co-expression patterns of TERT and TERC.	('TERT', 'Gene', '7015', (215, 219))	('amplification', 'Var', (5, 18))	('TERC', 'Gene', (0, 4))	('TERC', 'Gene', (224, 228))	('higher', 'PosReg', (52, 58))	('telomerase signature scores', 'MPA', (59, 86))	('TERC', 'Gene', '7012', (0, 4))	('TERT', 'Gene', (215, 219))	('TERC', 'Gene', '7012', (224, 228))
201094	28135248	We found alterations of ATRX and IDH1 as the most significantly associated with relative TL elongation (both FDR<0.0001; Figure 3a).	('associated', 'Reg', (64, 74))	('IDH1', 'Gene', (33, 37))	('ATRX', 'Gene', (24, 28))	('alterations', 'Var', (9, 20))	('IDH1', 'Gene', '3417', (33, 37))	('ATRX', 'Gene', '546', (24, 28))
201095	28135248	Since IDH1 mutations frequently co-occur with ATRX in glioma, we tested a model with both tumor type and IDH1 as covariates, and found IDH1 no longer associated with TL ratio (two-sided t-test P=0.15).	('associated', 'Reg', (150, 160))	('IDH1', 'Gene', '3417', (6, 10))	('mutations', 'Var', (11, 20))	('glioma', 'Disease', 'MESH:D005910', (54, 60))	('ATRX', 'Gene', '546', (46, 50))	('IDH1', 'Gene', (135, 139))	('IDH1', 'Gene', (105, 109))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('glioma', 'Phenotype', 'HP:0009733', (54, 60))	('IDH1', 'Gene', '3417', (135, 139))	('IDH1', 'Gene', '3417', (105, 109))	('glioma', 'Disease', (54, 60))	('ATRX', 'Gene', (46, 50))	('IDH1', 'Gene', (6, 10))	('TL ratio', 'MPA', (166, 174))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
201097	28135248	Alterations of the VHL were found to be associated with relative TL shortening (TL ratio 0.7, 95%CI 0.61-0.8, FDR<0.0001).	('relative TL shortening', 'MPA', (56, 78))	('Alterations', 'Var', (0, 11))	('VHL', 'Disease', 'MESH:D006623', (19, 22))	('VHL', 'Disease', (19, 22))
201100	28135248	A linear regression model showed that in addition to older age, positive TERRA expression, TP53 deletion, TP53 mutations, ATRX deletion, ATRX structural variants and absent/undetectable TERT expression were all independently associated with relative TL elongation (Figure 3b-c).	('mutations', 'Var', (111, 120))	('TP53', 'Gene', (91, 95))	('ATRX', 'Gene', (137, 141))	('positive', 'PosReg', (64, 72))	('ATRX', 'Gene', (122, 126))	('ATRX', 'Gene', '546', (122, 126))	('TP53', 'Gene', '7157', (91, 95))	('ATRX', 'Gene', '546', (137, 141))	('deletion', 'Var', (127, 135))	('deletion', 'Var', (96, 104))	('variants', 'Var', (153, 161))	('TERT', 'Gene', '7015', (186, 190))	('associated', 'Reg', (225, 235))	('TERT', 'Gene', (186, 190))	('relative TL elongation', 'CPA', (241, 263))	('TP53', 'Gene', '7157', (106, 110))	('TP53', 'Gene', (106, 110))
201101	28135248	Although DAXX has been linked to telomere length and ALT, DAXX mutations (n=51/6,835) and deletions (n=5/6,835) did not associate with TL.	('mutations', 'Var', (63, 72))	('DAXX', 'Gene', (58, 62))	('DAXX', 'Gene', '1616', (9, 13))	('deletions', 'Var', (90, 99))	('DAXX', 'Gene', (9, 13))	('DAXX', 'Gene', '1616', (58, 62))
201103	28135248	In addition to non-synonymous mutations and deletions, we detected ATRX structural variants from WGS data in 5% of the core set samples (n=26/473).	('variants', 'Var', (83, 91))	('ATRX', 'Gene', (67, 71))	('ATRX', 'Gene', '546', (67, 71))
201109	28135248	We observed a significant decrease in ATRX expression in samples showing mutations, deletions, fusions and structural variants compared to cases with wild type ATRX (Figure 4a).	('ATRX', 'Gene', '546', (160, 164))	('decrease', 'NegReg', (26, 34))	('structural variants', 'Var', (107, 126))	('ATRX', 'Gene', (38, 42))	('fusions', 'Var', (95, 102))	('ATRX', 'Gene', (160, 164))	('ATRX', 'Gene', '546', (38, 42))	('expression', 'MPA', (43, 53))	('mutations', 'Var', (73, 82))	('deletions', 'Var', (84, 93))
201110	28135248	We found that all of types of ATRX alteration associated with significantly longer TL compared to wild type ATRX, consistent with the previously established association between ATRX deactivation and ALT (Figure 4b).	('ATRX', 'Gene', (30, 34))	('ATRX', 'Gene', '546', (177, 181))	('ATRX', 'Gene', (108, 112))	('longer', 'PosReg', (76, 82))	('ATRX', 'Gene', '546', (30, 34))	('alteration', 'Var', (35, 45))	('ATRX', 'Gene', '546', (108, 112))	('ATRX', 'Gene', (177, 181))
201111	28135248	Recent studies found that ATRX knockdown resulted in elevated levels of telomeric repeat containing RNA (TERRA).	('ATRX', 'Gene', '546', (26, 30))	('ATRX', 'Gene', (26, 30))	('knockdown', 'Var', (31, 40))	('elevated', 'PosReg', (53, 61))
201112	28135248	Our results demonstrate a significantly higher fraction of TERRA expressing samples in all groups of ATRX altered samples (Figure 4c, Fisher's Exact test P<0.05) compared to the group of ATRX wild type samples.	('ATRX', 'Gene', '546', (187, 191))	('higher', 'PosReg', (40, 46))	('TERRA expressing', 'MPA', (59, 75))	('ATRX', 'Gene', (187, 191))	('ATRX', 'Gene', (101, 105))	('ATRX', 'Gene', '546', (101, 105))	('altered', 'Var', (106, 113))
201116	28135248	ATRX/DAXX mutations were found in 210 TERT expressing samples, representing 3% of the cohort.	('ATRX', 'Gene', (0, 4))	('DAXX', 'Gene', '1616', (5, 9))	('TERT', 'Gene', (38, 42))	('DAXX', 'Gene', (5, 9))	('ATRX', 'Gene', '546', (0, 4))	('TERT', 'Gene', '7015', (38, 42))	('mutations', 'Var', (10, 19))
201117	28135248	These events were in majority non-truncating, while ATRX/DAXX mutations in TERT-negative cases were mostly truncating (Supplementary Methods, Supplementary Figure 9a).	('non-truncating', 'MPA', (30, 44))	('mutations', 'Var', (62, 71))	('TERT', 'Gene', (75, 79))	('TERT', 'Gene', '7015', (75, 79))	('DAXX', 'Gene', '1616', (57, 61))	('ATRX', 'Gene', (52, 56))	('ATRX', 'Gene', '546', (52, 56))	('DAXX', 'Gene', (57, 61))	('truncating', 'MPA', (107, 117))
201118	28135248	TERT-expressing ATRX/DAXX mutants showed higher telomerase signature scores compared to ATRX/DAXX altered samples lacking TERT expression (Supplementary Figure 9b).	('TERT', 'Gene', (122, 126))	('DAXX', 'Gene', '1616', (93, 97))	('TERT', 'Gene', '7015', (122, 126))	('DAXX', 'Gene', (21, 25))	('ATRX', 'Gene', '546', (88, 92))	('ATRX', 'Gene', '546', (16, 20))	('TERT', 'Gene', (0, 4))	('DAXX', 'Gene', (93, 97))	('TERT', 'Gene', '7015', (0, 4))	('telomerase signature scores', 'MPA', (48, 75))	('mutants', 'Var', (26, 33))	('higher', 'PosReg', (41, 47))	('DAXX', 'Gene', '1616', (21, 25))	('ATRX', 'Gene', (88, 92))	('ATRX', 'Gene', (16, 20))
201132	28135248	In addition to IDH1 and TP53, RB1 (TL ratio 1.5, 95%CI 1.2-1.87, FDR=0.001) and MDM2 (TL ratio 1.51, 95%CI 1.14-2, FDR=0.01) were revealed to associate with relatively long TLs.	('MDM2', 'Gene', (80, 84))	('IDH1', 'Gene', (15, 19))	('TP53', 'Gene', (24, 28))	('IDH1', 'Gene', '3417', (15, 19))	('RB1', 'Var', (30, 33))	('MDM2', 'Gene', '4193', (80, 84))	('TP53', 'Gene', '7157', (24, 28))
201133	28135248	The finding of RB1 is consistent with experimental data demonstrating markedly elongated telomeres in Rb1 deficient mice independent of telomerase.	('mice', 'Species', '10090', (116, 120))	('telomeres', 'CPA', (89, 98))	('deficient', 'Var', (106, 115))	('elongated', 'PosReg', (79, 88))	('Rb1', 'Gene', (102, 105))	('Rb1', 'Gene', '19645', (102, 105))
201134	28135248	In the opposite direction, somatic alterations in PBRM1 (TL ratio 0.67, 95%CI 0.55-0.83, FDR=0.001), NRAS (TL ratio 0.68, 95%CI 0.52-0.9, FDR=0.02) and VHL (TL ratio 0.7, 95%CI 0.57-0.85, FDR=0.002) were associated with relative TL shortening (Figure 5d).	('NRAS', 'Gene', (101, 105))	('alterations', 'Var', (35, 46))	('PBRM1', 'Gene', (50, 55))	('PBRM1', 'Gene', '55193', (50, 55))	('NRAS', 'Gene', '4893', (101, 105))	('VHL', 'Disease', (152, 155))	('VHL', 'Disease', 'MESH:D006623', (152, 155))
201144	28135248	This paradoxical association between TERT promoter methylation and increased TERT expression may result from loss of CTCF binding, a transcriptional repressor reported to bind to the unmethylated TERT promoter.	('TERT', 'Gene', (37, 41))	('binding', 'Interaction', (122, 129))	('ran', 'Gene', (134, 137))	('TERT', 'Gene', (77, 81))	('TERT', 'Gene', '7015', (37, 41))	('TERT', 'Gene', '7015', (77, 81))	('ran', 'Gene', '5901', (134, 137))	('TERT', 'Gene', (196, 200))	('CTCF', 'Gene', (117, 121))	('loss', 'NegReg', (109, 113))	('TERT', 'Gene', '7015', (196, 200))	('increased', 'PosReg', (67, 76))	('methylation', 'Var', (51, 62))	('CTCF', 'Gene', '10664', (117, 121))
201145	28135248	Structural TERT variants have been documented and we detected these across several novel cancer types, including sarcoma, prostate and liver carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('liver carcinoma', 'Phenotype', 'HP:0001402', (135, 150))	('liver carcinoma', 'Disease', (135, 150))	('sarcoma', 'Disease', 'MESH:D012509', (113, 120))	('prostate', 'Disease', (122, 130))	('liver carcinoma', 'Disease', 'MESH:D006528', (135, 150))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('detected', 'Reg', (53, 61))	('sarcoma', 'Disease', (113, 120))	('cancer', 'Disease', (89, 95))	('TERT', 'Gene', (11, 15))	('sarcoma', 'Phenotype', 'HP:0100242', (113, 120))	('TERT', 'Gene', '7015', (11, 15))	('variants', 'Var', (16, 24))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
201146	28135248	Hepatitis B virus and adeno-associated virus type 2 integration in TERT was found in about 5% of hepatocellular carcinomas.	('TERT', 'Gene', (67, 71))	('integration', 'Var', (52, 63))	('found', 'Reg', (76, 81))	('TERT', 'Gene', '7015', (67, 71))	('Hepatitis', 'Phenotype', 'HP:0012115', (0, 9))	('hepatocellular carcinomas', 'Phenotype', 'HP:0001402', (97, 122))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (97, 121))	('Hepatitis B virus', 'Species', '10407', (0, 17))	('hepatocellular carcinomas', 'Disease', 'MESH:D006528', (97, 122))	('adeno-associated virus type 2', 'Species', '10804', (22, 51))	('hepatocellular carcinomas', 'Disease', (97, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('carcinomas', 'Phenotype', 'HP:0030731', (112, 122))	('Hepatitis B virus', 'Disease', (0, 17))
201151	28135248	An estimated 5-10% of TERC and TERRA carry the poly-A tails required for oligo-dT primer based RNA sequencing quantification.	('poly-A', 'Chemical', 'MESH:D011061', (47, 53))	('TERC', 'Gene', '7012', (22, 26))	('TERC', 'Gene', (22, 26))	('poly-A tails', 'Var', (47, 59))
201157	28135248	A detailed review of ATRX somatic changes revealed a large spectrum of potentially protein truncating changes, including inactivating mutations, deletions and structural variants.	('inactivating mutations', 'Var', (121, 143))	('protein truncating changes', 'MPA', (83, 109))	('structural variants', 'Var', (159, 178))	('ATRX', 'Gene', (21, 25))	('ATRX', 'Gene', '546', (21, 25))	('deletions', 'Var', (145, 154))
201159	28135248	Our analysis reinforced the association of inactivate ATRX/DAXX and ALT, demonstrating relative TL elongation in samples affected by somatic alterations in one of these two genes and a higher frequency of TERRA expression in tumors with these alterations.	('alterations', 'Var', (141, 152))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('DAXX', 'Gene', (59, 63))	('tumors', 'Phenotype', 'HP:0002664', (225, 231))	('ATRX', 'Gene', '546', (54, 58))	('TL elongation', 'CPA', (96, 109))	('tumors', 'Disease', 'MESH:D009369', (225, 231))	('affected', 'Reg', (121, 129))	('DAXX', 'Gene', '1616', (59, 63))	('tumors', 'Disease', (225, 231))	('ATRX', 'Gene', (54, 58))	('inactivate', 'Var', (43, 53))
201162	28135248	Such mechanisms may involve some RB1 and TP53 alterations, as somatic changes in these genes were associated with telomere elongation within this group.	('TP53', 'Gene', '7157', (41, 45))	('TP53', 'Gene', (41, 45))	('telomere elongation', 'CPA', (114, 133))	('RB1', 'Gene', (33, 36))	('changes', 'Var', (70, 77))	('associated', 'Reg', (98, 108))
201181	28135248	There was sufficient coverage for TERTp mutation calling in 903 samples, and we detected TERTp mutations in n=183, including C228T (n=128), C250T (n=49), C242/243T (n=5) and C169T (n=1).	('TERTp', 'Gene', '7015', (89, 94))	('C250T', 'Var', (140, 145))	('C250T', 'Mutation', 'c.250C>T', (140, 145))	('TERTp', 'Gene', '7015', (34, 39))	('C228T', 'Var', (125, 130))	('C169T', 'Var', (174, 179))	('detected', 'Reg', (80, 88))	('C169T', 'Mutation', 'c.169C>T', (174, 179))	('C242/243T', 'Var', (154, 163))	('C228T', 'Mutation', 'c.228C>T', (125, 130))	('TERTp', 'Gene', (89, 94))	('TERTp', 'Gene', (34, 39))
201184	28135248	Because we were only interested in variants involving TERT (chr5:1253287-1315162, including 20kb upstream of the TSS) and ATRX (chrX:76760356-77041719), variants not overlapping one of these regions were excluded.	('ATRX', 'Gene', (122, 126))	('chr5:1253287-1315162', 'STRUCTURAL_ABNORMALITY', 'None', (60, 80))	('variants', 'Var', (35, 43))	('TERT', 'Gene', '7015', (54, 58))	('chrX:76760356-77041719', 'STRUCTURAL_ABNORMALITY', 'None', (128, 150))	('ATRX', 'Gene', '546', (122, 126))	('TERT', 'Gene', (54, 58))
201195	28135248	This analysis found overlapping super-enhancers in 11/17 TERTp structural variants, and this was significantly more than expected by chance (Chi-Square test P=0.001).	('super-enhancers', 'PosReg', (32, 47))	('variants', 'Var', (74, 82))	('TERTp', 'Gene', (57, 62))	('TERTp', 'Gene', '7015', (57, 62))
201196	28135248	For each structural variant proximal (adjacent to the TERT promoter) and distal breakpoint (juxtaposed to the TERT promoter) we calculated the number of reads mapping to each of three histone marks (H3K27ac, H3K27me3 and H3Kme1) individually within each tissue and cell/type.	('H3Kme1', 'Var', (221, 227))	('H3K27ac', 'Var', (199, 206))	('H3K27me3', 'Var', (208, 216))	('TERT', 'Gene', '7015', (54, 58))	('TERT', 'Gene', (110, 114))	('TERT', 'Gene', '7015', (110, 114))	('TERT', 'Gene', (54, 58))
201208	28135248	Spearman correlation was used to associate TERT expression and methylation, and to correlate gene expression and TL.	('TERT', 'Gene', (43, 47))	('methylation', 'Var', (63, 74))	('TERT', 'Gene', '7015', (43, 47))
201217	27793210	EZH2 targeting resulted in greater inhibition of growth and survival in HPV-positive compared to HPV-negative cells lines.	('targeting', 'Var', (5, 14))	('EZH2', 'Gene', '2146', (0, 4))	('HPV', 'Species', '10566', (97, 100))	('EZH2', 'Gene', (0, 4))	('growth', 'CPA', (49, 55))	('HPV', 'Species', '10566', (72, 75))	('inhibition', 'NegReg', (35, 45))
201219	27793210	Inhibition of EZH2 has anti-tumorigenic effects on OPSCC cells in culture that is more pronounced in HPV-positive cell lines.	('tumor', 'Disease', (28, 33))	('OPSCC', 'Phenotype', 'HP:0012182', (51, 56))	('EZH2', 'Gene', (14, 18))	('EZH2', 'Gene', '2146', (14, 18))	('HPV', 'Species', '10566', (101, 104))	('Inhibition', 'Var', (0, 10))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
201221	27793210	Epigenetic deregulation of cellular programs is a key hallmark of human cancers.	('Epigenetic deregulation', 'Var', (0, 23))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('human', 'Species', '9606', (66, 71))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('cancers', 'Disease', (72, 79))	('cancers', 'Disease', 'MESH:D009369', (72, 79))	('cellular', 'CPA', (27, 35))
201223	27793210	Deregulation of histone methylation results in altered tumorigenic gene expression profiles that can be reproducibly identified for diagnostic purposes and specifically reversed for novel cancer therapeutics.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('Deregulation', 'Var', (0, 12))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Disease', (55, 60))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('cancer', 'Disease', (188, 194))	('altered', 'Reg', (47, 54))	('histone', 'Protein', (16, 23))
201235	27793210	Overexpression of EZH2 is correlated with advanced disease and a poor prognosis in HNSCC.	('HNSCC', 'Disease', (83, 88))	('EZH2', 'Gene', '2146', (18, 22))	('advanced disease', 'Disease', (42, 58))	('advanced disease', 'Disease', 'MESH:D020178', (42, 58))	('EZH2', 'Gene', (18, 22))	('Overexpression', 'Var', (0, 14))
201260	27793210	However, no appreciable reductions in H3K27me3 could be seen with EPZ5687, comparable to DMSO or untreated cells.	('EPZ5687', 'Chemical', '-', (66, 73))	('DMSO', 'Chemical', 'MESH:D004121', (89, 93))	('H3K27me3', 'Protein', (38, 46))	('reductions', 'NegReg', (24, 34))	('EPZ5687', 'Var', (66, 73))
201262	27793210	In SCC9 cells, GSK343 treatment also caused a similar reduction in H3K27me3 levels, with a slight reduction from DZNeP.	('H3K27me3', 'Protein', (67, 75))	('GSK343', 'Chemical', 'MESH:C586265', (15, 21))	('reduction', 'NegReg', (54, 63))	('reduction', 'NegReg', (98, 107))	('DZNeP', 'Chemical', '-', (113, 118))	('SCC9', 'CellLine', 'CVCL:1685', (3, 7))	('DZNeP', 'MPA', (113, 118))	('GSK343', 'Var', (15, 21))
201263	27793210	We examined the expression of EZH2 and H3K27me3 in SCC9 and SCC104 cells in response to epigenetic inhibitors by immunofluorescence microscopy and quantitative imaging analysis.	('EZH2', 'Gene', '2146', (30, 34))	('H3K27me3', 'Var', (39, 47))	('EZH2', 'Gene', (30, 34))	('SCC9', 'CellLine', 'CVCL:1685', (51, 55))	('SCC104', 'CellLine', 'CVCL:C050', (60, 66))
201264	27793210	In SCC9 cells, GSK343 resulted in a >58.3 % reduction in EZH2 positive nuclei (compared to control intensity) with a slight reduction in H3K27me3 levels (3.4 %) (Fig.	('EZH2', 'Gene', (57, 61))	('GSK343', 'Chemical', 'MESH:C586265', (15, 21))	('reduction', 'NegReg', (124, 133))	('SCC9', 'CellLine', 'CVCL:1685', (3, 7))	('H3K27me3 levels', 'MPA', (137, 152))	('reduction', 'NegReg', (44, 53))	('EZH2', 'Gene', '2146', (57, 61))	('GSK343', 'Var', (15, 21))
201265	27793210	EPZ 5687 did not appear to have a notable impact on EZH2 or H3K27me3 levels.	('EPZ 5687', 'Var', (0, 8))	('H3K27me3', 'Protein', (60, 68))	('EZH2', 'Gene', (52, 56))	('EZH2', 'Gene', '2146', (52, 56))
201267	27793210	In SCC104 cells, GSK343 reduced the amount of EZH2 positive nuclei by ~ 20 % while cause a near complete reduction in H3K27me3 levels (Fig.	('H3K27me3 levels', 'MPA', (118, 133))	('reduced', 'NegReg', (24, 31))	('GSK343', 'Chemical', 'MESH:C586265', (17, 23))	('reduction', 'NegReg', (105, 114))	('EZH2', 'Gene', '2146', (46, 50))	('SCC104', 'CellLine', 'CVCL:C050', (3, 9))	('EZH2', 'Gene', (46, 50))	('GSK343', 'Var', (17, 23))
201268	27793210	Although EPZ5687 and DZNeP showed a greater reduction in EZH2 positive nuclei, this resulted in a minimal reduction in H3K27me3.	('EZH2', 'Gene', (57, 61))	('H3K27me3', 'Protein', (119, 127))	('EPZ5687', 'Var', (9, 16))	('reduction', 'NegReg', (44, 53))	('EPZ5687', 'Chemical', '-', (9, 16))	('DZNeP', 'Chemical', '-', (21, 26))	('DZNeP', 'Var', (21, 26))	('EZH2', 'Gene', '2146', (57, 61))
201269	27793210	In SCC9 cells, GSK 343 and DZNeP treated cells had ~ 10 % reduction in cell counts, whereas EPZ5687 treated cells had ~ 25 % reduction (Fig.	('EPZ5687', 'Chemical', '-', (92, 99))	('GSK', 'Chemical', '-', (15, 18))	('SCC9', 'CellLine', 'CVCL:1685', (3, 7))	('DZNeP', 'Chemical', '-', (27, 32))	('cell counts', 'CPA', (71, 82))	('reduction', 'NegReg', (58, 67))	('DZNeP', 'Var', (27, 32))
201278	27793210	Epigenetic aberrancies involving histone methylation are a hallmark of human cancers.	('histone', 'Protein', (33, 40))	('cancers', 'Disease', 'MESH:D009369', (77, 84))	('cancers', 'Phenotype', 'HP:0002664', (77, 84))	('cancers', 'Disease', (77, 84))	('Epigenetic aberrancies', 'Var', (0, 22))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('human', 'Species', '9606', (71, 76))
201281	27793210	Overexpression of EZH2 has been shown to have an important role in various malignancies, including breast, prostate, gastric, hepatic, and bladder carcinoma.	('malignancies', 'Disease', 'MESH:D009369', (75, 87))	('prostate', 'Disease', (107, 115))	('malignancies', 'Disease', (75, 87))	('gastric', 'Disease', (117, 124))	('EZH2', 'Gene', '2146', (18, 22))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (139, 156))	('hepatic', 'Disease', (126, 133))	('EZH2', 'Gene', (18, 22))	('Overexpression', 'Var', (0, 14))	('bladder carcinoma', 'Disease', (139, 156))	('bladder carcinoma', 'Disease', 'MESH:D001749', (139, 156))	('breast', 'Disease', (99, 105))	('carcinoma', 'Phenotype', 'HP:0030731', (147, 156))
201284	27793210	EZH2 has also been shown serve as an independent prognostic marker for overall survival in patients with OCSCC, with high EZH2 expression being significantly associated with poorer survival outcomes.	('high', 'Var', (117, 121))	('EZH2', 'Gene', (122, 126))	('EZH2', 'Gene', '2146', (122, 126))	('EZH2', 'Gene', '2146', (0, 4))	('patients', 'Species', '9606', (91, 99))	('associated', 'Reg', (158, 168))	('expression', 'MPA', (127, 137))	('EZH2', 'Gene', (0, 4))	('OCSCC', 'Disease', (105, 110))
201287	27793210	In HPV+ OPSCC cell lines, inhibition of EZH2 caused a dramatic reduction in H3K27me3 and significant depletion in cell counts.	('inhibition', 'Var', (26, 36))	('OPSCC', 'Phenotype', 'HP:0012182', (8, 13))	('H3K27me3', 'Protein', (76, 84))	('depletion', 'NegReg', (101, 110))	('reduction', 'NegReg', (63, 72))	('EZH2', 'Gene', (40, 44))	('EZH2', 'Gene', '2146', (40, 44))	('HPV', 'Species', '10566', (3, 6))	('cell', 'CPA', (114, 118))
201309	27793210	DZNep is believed to deplete EZH2 by proteasome-mediated protein degradation, while GSK343 and EPZ00568 directly inhibit the EZH2 enzyme activity through competing with the co-factor SAM.	('GSK343', 'Chemical', 'MESH:C586265', (84, 90))	('EPZ00568', 'Var', (95, 103))	('proteasome-mediated protein degradation', 'MPA', (37, 76))	('DZNep', 'Chemical', 'MESH:C048460', (0, 5))	('inhibit', 'NegReg', (113, 120))	('EZH2', 'Gene', '2146', (125, 129))	('deplete', 'NegReg', (21, 28))	('activity', 'MPA', (137, 145))	('SAM', 'Chemical', 'MESH:D012436', (183, 186))	('EZH2', 'Gene', (125, 129))	('EZH2', 'Gene', (29, 33))	('EZH2', 'Gene', '2146', (29, 33))
201324	27599460	The areas under the curve predicting 3-year OS were 0.603 for CONUT, 0.561 for PLR, 0.564 for NLR, and 0.563 for GPS.	('CONUT', 'Disease', (62, 67))	('0.564', 'Var', (84, 89))	('OS', 'Chemical', '-', (44, 46))	('0.563', 'Var', (103, 108))
201325	27599460	The high-CONUT group was significantly associated with lower BMI, high-PLR, high-NLR, and GPS1/2 groups.	('GPS1/2', 'Gene', '2873;2874', (90, 96))	('GPS1/2', 'Gene', (90, 96))	('lower BMI', 'Phenotype', 'HP:0045082', (55, 64))	('high-CONUT', 'Var', (4, 14))	('lower', 'NegReg', (55, 60))	('high-PLR', 'Disease', (66, 74))	('BMI', 'MPA', (61, 64))
201326	27599460	On univariate analysis, high-CONUT, high-PLR, high-NLR, and GPS 1/2 groups were significantly associated with poorer OS and RFS.	('RFS', 'CPA', (124, 127))	('high-PLR', 'Var', (36, 44))	('poorer OS', 'CPA', (110, 119))	('OS', 'Chemical', '-', (117, 119))	('GPS 1/2', 'Gene', (60, 67))	('high-CONUT', 'Var', (24, 34))	('high-NLR', 'Var', (46, 54))	('GPS 1/2', 'Gene', '2873;2874', (60, 67))
201366	27599460	The OS and RFS rates were significantly lower in the high-CONUT (p < 0.001, p = 0.002), high-PLR (p = 0.023, p = 0.031), high-NLR (p = 0.016, p = 0.028), and GPS 1/2 (p < 0.001, p = 0.004) groups.	('high-CONUT', 'Var', (53, 63))	('OS', 'Chemical', '-', (4, 6))	('high-PLR', 'Var', (88, 96))	('GPS 1/2', 'Gene', (158, 165))	('GPS 1/2', 'Gene', '2873;2874', (158, 165))	('RFS rates', 'CPA', (11, 20))	('lower', 'NegReg', (40, 45))
201373	27599460	The proportion of patients who died of primary disease was significantly higher in the high-CONUT group than in the low-CONUT group (47.1 % vs. 20.8 %, p = 0.015), whereas there were no significant differences in the rates of patients who died of other disease, other cancer, and postoperative complications.	('cancer', 'Disease', (268, 274))	('primary disease', 'Disease', (39, 54))	('cancer', 'Phenotype', 'HP:0002664', (268, 274))	('patients', 'Species', '9606', (226, 234))	('patients', 'Species', '9606', (18, 26))	('cancer', 'Disease', 'MESH:D009369', (268, 274))	('high-CONUT', 'Var', (87, 97))	('higher', 'PosReg', (73, 79))
201381	27599460	Indeed, the high-CONUT group was significantly associated with lower BMI, high-PLR, high-NLR, and GPS1/2.	('GPS1/2', 'Gene', '2873;2874', (98, 104))	('lower BMI', 'Phenotype', 'HP:0045082', (63, 72))	('lower', 'NegReg', (63, 68))	('high-NLR', 'MPA', (84, 92))	('BMI', 'MPA', (69, 72))	('GPS1/2', 'Gene', (98, 104))	('high-CONUT', 'Var', (12, 22))	('high-PLR', 'MPA', (74, 82))
201404	27599460	In the present study, the high-CONUT group was significantly associated with primary cancer death and poorer RFS.	('high-CONUT', 'Var', (26, 36))	('primary cancer death', 'Disease', 'MESH:D003643', (77, 97))	('primary cancer death', 'Disease', (77, 97))	('associated', 'Reg', (61, 71))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
201469	27346236	Among patients diagnosed with stage IA to IIIB cancers, the average adjusted age of patients with T1b, T2a, T2b, T3 and T4 tumors was significantly older than that of patients with T1a tumors (by 0.08, 0.15, 0.63, 0.62 and 0.92 years, respectively, p < 0.001 for all).	('tumors', 'Disease', 'MESH:D009369', (123, 129))	('T1a tumors', 'Disease', 'MESH:D009369', (181, 191))	('tumors', 'Disease', (185, 191))	('older', 'PosReg', (148, 153))	('patients', 'Species', '9606', (6, 14))	('T2a', 'Var', (103, 106))	('patients', 'Species', '9606', (84, 92))	('tumors', 'Disease', 'MESH:D009369', (185, 191))	('IIIB cancers', 'Disease', (42, 54))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('IIIB cancers', 'Disease', 'MESH:C566890', (42, 54))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('cancers', 'Phenotype', 'HP:0002664', (47, 54))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('tumors', 'Disease', (123, 129))	('T2b', 'Var', (108, 111))	('T1b', 'Var', (98, 101))	('tumors', 'Phenotype', 'HP:0002664', (185, 191))	('patients', 'Species', '9606', (167, 175))	('T1a tumors', 'Disease', (181, 191))
201495	27346236	Many biomarkers, including K-ras and epidermal growth factor receptor (EGFR) somatic mutations have clearly demonstrated different characteristics between NSCLC patients in Asian and Caucasian populations.	('K-ras', 'Gene', '3845', (27, 32))	('epidermal growth factor receptor', 'Gene', '1956', (37, 69))	('NSCLC', 'Disease', (155, 160))	('mutations', 'Var', (85, 94))	('patients', 'Species', '9606', (161, 169))	('epidermal growth factor receptor', 'Gene', (37, 69))	('EGFR', 'Gene', '1956', (71, 75))	('NSCLC', 'Disease', 'MESH:D002289', (155, 160))	('EGFR', 'Gene', (71, 75))	('K-ras', 'Gene', (27, 32))
201496	27346236	K-ras mutation is predominantly observed in Caucasian patients.	('patients', 'Species', '9606', (54, 62))	('K-ras', 'Gene', '3845', (0, 5))	('mutation', 'Var', (6, 14))	('K-ras', 'Gene', (0, 5))
201497	27346236	The EGFR mutation rate is approximately 5~13% among Caucasians but 30~40% among East Asians.	('EGFR', 'Gene', (4, 8))	('mutation', 'Var', (9, 17))	('EGFR', 'Gene', '1956', (4, 8))
201536	32855723	Changes in expression levels usually indicate pathological states, as proteins encoded by DEGs may be involved in tumorigenesis and tumor progression.	('DEGs', 'Var', (90, 94))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('involved', 'Reg', (102, 110))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('expression levels', 'MPA', (11, 28))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('proteins', 'Protein', (70, 78))	('tumor', 'Disease', (114, 119))	('tumor', 'Disease', (132, 137))	('Changes', 'Reg', (0, 7))
201573	32855723	Cancer is a genetic disease wherein cumulative mutations drive the multi-step progression towards oncogenesis, eventually culminating in unrestrained cancer growth.	('oncogenesis', 'CPA', (98, 109))	('culminating in', 'Reg', (122, 136))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('mutations', 'Var', (47, 56))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('cancer', 'Disease', (150, 156))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('genetic disease', 'Disease', (12, 27))	('genetic disease', 'Disease', 'MESH:D030342', (12, 27))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
201580	32855723	To summarize, the identified DEGs may regulate the proliferation, invasion, migration and drug-resistance of cancer cells through these pathways, thus affecting the occurrence and development of NSCLC.	('NSCLC', 'Disease', 'MESH:D002289', (195, 200))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('DEGs', 'Var', (29, 33))	('migration', 'CPA', (76, 85))	('drug-resistance', 'CPA', (90, 105))	('cancer', 'Disease', (109, 115))	('proliferation', 'CPA', (51, 64))	('NSCLC', 'Phenotype', 'HP:0030358', (195, 200))	('affecting', 'Reg', (151, 160))	('regulate', 'Reg', (38, 46))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('invasion', 'CPA', (66, 74))	('NSCLC', 'Disease', (195, 200))
201591	32855723	CDC20 is an important regulator of the cell cycle and altered expression or functional impairment may induce mitotic arrest to prevent activation of adenomatous polyposis coli and hence, increase premature anaphase manifesting as aneuploidy in daughter cells.	('mitotic arrest', 'Disease', (109, 123))	('aneuploidy', 'Disease', (230, 240))	('induce', 'Reg', (102, 108))	('increase', 'PosReg', (187, 195))	('mitotic arrest', 'Disease', 'MESH:D006323', (109, 123))	('prevent', 'NegReg', (127, 134))	('adenomatous polyposis', 'Phenotype', 'HP:0005227', (149, 170))	('expression', 'MPA', (62, 72))	('aneuploidy', 'Disease', 'MESH:D000782', (230, 240))	('adenomatous polyposis coli', 'Disease', 'MESH:D011125', (149, 175))	('activation', 'MPA', (135, 145))	('altered', 'Var', (54, 61))	('adenomatous polyposis coli', 'Disease', (149, 175))	('CDC20', 'Gene', (0, 5))	('CDC20', 'Gene', '991', (0, 5))	('premature anaphase', 'CPA', (196, 214))
201593	32855723	Of note, knockdown of CDC20 caused inhibition of growth, migration ability and formation of colonies in lung cancer cells, as well as cell cycle arrest in G2/M phase and induction of apoptosis, making this oncogene a potential target molecule to address NSCLC therapy.	('migration ability', 'CPA', (57, 74))	('lung cancer', 'Disease', 'MESH:D008175', (104, 115))	('NSCLC', 'Disease', (254, 259))	('knockdown', 'Var', (9, 18))	('arrest', 'Disease', 'MESH:D006323', (145, 151))	('NSCLC', 'Disease', 'MESH:D002289', (254, 259))	('growth', 'CPA', (49, 55))	('arrest', 'Disease', (145, 151))	('lung cancer', 'Disease', (104, 115))	('induction', 'Reg', (170, 179))	('CDC20', 'Gene', (22, 27))	('CDC20', 'Gene', '991', (22, 27))	('lung cancer', 'Phenotype', 'HP:0100526', (104, 115))	('NSCLC', 'Phenotype', 'HP:0030358', (254, 259))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('formation of colonies', 'CPA', (79, 100))	('apoptosis', 'CPA', (183, 192))	('inhibition', 'NegReg', (35, 45))
201598	32855723	Several anti-cancer agents have been developed to target this gene, and the development of drug resistance has been associated with mutation of TOP2A.	('TOP2A', 'Gene', (144, 149))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('TOP2A', 'Gene', '7153', (144, 149))	('drug resistance', 'MPA', (91, 106))	('cancer', 'Disease', (13, 19))	('cancer', 'Disease', 'MESH:D009369', (13, 19))	('drug resistance', 'Phenotype', 'HP:0020174', (91, 106))	('mutation', 'Var', (132, 140))
201602	32855723	CCNB2 is a cyclin gene that activates cyclin-dependent kinase 1 to drive the G2/M cell cycle transition, and inhibition of CCNB2 leads to cell cycle arrest.	('cyclin-dependent kinase 1', 'Gene', (38, 63))	('CCNB2', 'Gene', (0, 5))	('drive', 'PosReg', (67, 72))	('G2/M cell cycle transition', 'CPA', (77, 103))	('inhibition', 'Var', (109, 119))	('arrest', 'Disease', 'MESH:D006323', (149, 155))	('CCNB2', 'Gene', (123, 128))	('cyclin', 'Gene', '5111', (38, 44))	('cyclin', 'Gene', '5111', (11, 17))	('arrest', 'Disease', (149, 155))	('CCNB2', 'Gene', '9133', (0, 5))	('cyclin', 'Gene', (38, 44))	('cyclin', 'Gene', (11, 17))	('cyclin-dependent kinase 1', 'Gene', '983', (38, 63))	('activates', 'PosReg', (28, 37))	('CCNB2', 'Gene', '9133', (123, 128))
201612	32855723	In the present study, a total of 46 DEMs were identified, and miRWalk-mediated predictive analyses were performed to identify those DEMs that were predicted to interact with DEGs, yielding 6 hub miRNAs and associated mRNAs, including miR-127-5p, miR134-5p, miR-130b-3p, miR-1181, miR-145-3p, miR-153-3p, CDO1, SLIT3 and PGM5.	('miR-130b', 'Gene', (257, 265))	('miR-153-3p', 'Var', (292, 302))	('hub', 'Gene', (191, 194))	('miR-127', 'Gene', (234, 241))	('miR-1181', 'Gene', (270, 278))	('CDO1', 'Gene', (304, 308))	('hub', 'Gene', '1993', (191, 194))	('miR134', 'Gene', (246, 252))	('PGM5', 'Gene', (320, 324))	('PGM5', 'Gene', '5239', (320, 324))	('miR134', 'Gene', '406924', (246, 252))	('miR-127', 'Gene', '406914', (234, 241))	('CDO1', 'Gene', '1036', (304, 308))	('miR-145', 'Gene', '406937', (280, 287))	('SLIT3', 'Gene', '6586', (310, 315))	('SLIT3', 'Gene', (310, 315))	('miR-1181', 'Gene', '100302213', (270, 278))	('miR-145', 'Gene', (280, 287))	('miR-130b', 'Gene', '406920', (257, 265))
201613	32855723	Survival analyses revealed that dysregulation of miR-127-5p, miR-130b-3p, miR-1181, CDO1, SLIT3, PGM5, EMCN and DPYSL2 were significantly associated with the prognosis of patients with LUAD.	('DPYSL2', 'Gene', (112, 118))	('CDO1', 'Gene', '1036', (84, 88))	('PGM5', 'Gene', (97, 101))	('LUAD', 'Disease', (185, 189))	('PGM5', 'Gene', '5239', (97, 101))	('SLIT3', 'Gene', '6586', (90, 95))	('patients', 'Species', '9606', (171, 179))	('miR-127', 'Gene', (49, 56))	('SLIT3', 'Gene', (90, 95))	('EMCN', 'Gene', '51705', (103, 107))	('DPYSL2', 'Gene', '1808', (112, 118))	('miR-1181', 'Gene', '100302213', (74, 82))	('EMCN', 'Gene', (103, 107))	('miR-127', 'Gene', '406914', (49, 56))	('dysregulation', 'Var', (32, 45))	('associated', 'Reg', (138, 148))	('miR-130b', 'Gene', '406920', (61, 69))	('miR-1181', 'Gene', (74, 82))	('miR-130b', 'Gene', (61, 69))	('CDO1', 'Gene', (84, 88))
201704	28675081	However, as is the case with other types of chemotherapy, BAI chemotherapy also resulted in worsening symptoms in some patients (2.8%), although symptom worsening associated with BAI occurred less often than symptom worsening associated with conventional intravenous chemotherapy.	('patients', 'Species', '9606', (119, 127))	('BAI', 'Var', (58, 61))	('symptoms', 'MPA', (102, 110))
201789	27188458	Downregulation of PFN2 inhibited, rather than proliferated, cell invasion and migration, as well as induced an EMT phenotype, including increased expression of epithelial marker E-cadherin, decreased mesenchymal marker Vimentin, Snail, Slug and ZEB1, and morphological changes in ESCC cells in vitro.	('ZEB1', 'Gene', (245, 249))	('EMT', 'CPA', (111, 114))	('expression', 'MPA', (146, 156))	('Snail', 'Gene', '6615', (229, 234))	('Downregulation', 'Var', (0, 14))	('morphological changes', 'CPA', (255, 276))	('decreased', 'NegReg', (190, 199))	('E-cadherin', 'Gene', (178, 188))	('E-cadherin', 'Gene', '999', (178, 188))	('Slug', 'Gene', (236, 240))	('Vimentin', 'Gene', '7431', (219, 227))	('ZEB1', 'Gene', '6935', (245, 249))	('induced', 'Reg', (100, 107))	('increased', 'PosReg', (136, 145))	('Snail', 'Gene', (229, 234))	('Vimentin', 'Gene', (219, 227))	('inhibited', 'NegReg', (23, 32))	('PFN2', 'Gene', (18, 22))	('mesenchymal marker', 'CPA', (200, 218))	('Slug', 'Gene', '6591', (236, 240))	('cell invasion', 'CPA', (60, 73))
201800	27188458	In addition, the disruption of profilin by gene deletion of PFN1 in null mice or by anti-profilin transfection in bovine oocytes, results in early embryonic death.	('embryonic death', 'Disease', 'MESH:D003643', (147, 162))	('PFN1', 'Gene', (60, 64))	('results in', 'Reg', (130, 140))	('profilin', 'Protein', (31, 39))	('mice', 'Species', '10090', (73, 77))	('disruption', 'Var', (17, 27))	('bovine', 'Species', '9913', (114, 120))	('gene deletion', 'Var', (43, 56))	('embryonic death', 'Disease', (147, 162))
201806	27188458	Other reports suggested that post-translational modifications, such as phosphorylation of PFN1 at Ser 137 or Tyr 129, could change the properties of cancer cells.	('phosphorylation', 'MPA', (71, 86))	('cancer', 'Disease', (149, 155))	('PFN1', 'Gene', (90, 94))	('Ser 137', 'Var', (98, 105))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('Tyr 129', 'Var', (109, 116))	('Tyr', 'Chemical', 'MESH:D014443', (109, 112))	('change', 'Reg', (124, 130))	('Ser', 'Chemical', 'MESH:D012694', (98, 101))	('cancer', 'Disease', 'MESH:D009369', (149, 155))
201858	27188458	The median survival time for patients with high PFN2 expression was 12 months (range, 1-96 months) and 42 months (range, 1-96 months) for patients with low PFN2 expression, which indicated that ESCC patients with high PFN2 expression had significantly shorter OS rates and greater risk of death than those with low PFN2 expression (log-rank test, chi2 = 5.203, P = 0.023) (Fig.	('patients', 'Species', '9606', (29, 37))	('PFN2', 'Gene', (218, 222))	('high', 'Var', (213, 217))	('OS', 'Chemical', '-', (260, 262))	('patients', 'Species', '9606', (199, 207))	('death', 'Disease', 'MESH:D003643', (289, 294))	('shorter', 'NegReg', (252, 259))	('death', 'Disease', (289, 294))	('patients', 'Species', '9606', (138, 146))	('OS rates', 'CPA', (260, 268))
201867	27188458	Subsequently, Transwell assays showed that depletion of PFN2 significantly suppressed the migration and invasion of Eca109 and EC9706 cell lines.	('suppressed', 'NegReg', (75, 85))	('PFN2', 'Gene', (56, 60))	('EC9706', 'CellLine', 'CVCL:E307', (127, 133))	('depletion', 'Var', (43, 52))
201884	27188458	Another important finding in this study was found that PFN2 expression was positively associated with invasion depth amongst Han patients with ESCC, as well as lymph node metastasis amongst Kazakh ESCC patients.	('PFN2', 'Gene', (55, 59))	('patients', 'Species', '9606', (129, 137))	('expression', 'Var', (60, 70))	('lymph node metastasis', 'CPA', (160, 181))	('associated', 'Reg', (86, 96))	('ESCC', 'Disease', (143, 147))	('patients', 'Species', '9606', (202, 210))	('invasion depth', 'CPA', (102, 116))
201895	27188458	In our study, E-cadherin was clearly up-regulated by the knockdown of PFN2.	('E-cadherin', 'Gene', '999', (14, 24))	('PFN2', 'Gene', (70, 74))	('knockdown', 'Var', (57, 66))	('up-regulated', 'PosReg', (37, 49))	('E-cadherin', 'Gene', (14, 24))
201899	27188458	In our study, silencing PFN2 significantly suppressed the expressions of Snail, Slug and ZEB1.	('silencing', 'Var', (14, 23))	('PFN2', 'Gene', (24, 28))	('expressions', 'MPA', (58, 69))	('Slug', 'Gene', '6591', (80, 84))	('Snail', 'Gene', '6615', (73, 78))	('ZEB1', 'Gene', (89, 93))	('Slug', 'Gene', (80, 84))	('ZEB1', 'Gene', '6935', (89, 93))	('Snail', 'Gene', (73, 78))	('suppressed', 'NegReg', (43, 53))
201902	27188458	Similarly, another mesenchymal marker, Vimentin, was obviously downregulated by the knockdown of PFN2.	('PFN2', 'Gene', (97, 101))	('knockdown', 'Var', (84, 93))	('downregulated', 'NegReg', (63, 76))	('Vimentin', 'Gene', (39, 47))	('Vimentin', 'Gene', '7431', (39, 47))
201909	26491361	The association of GSTT1 deletion polymorphism with lung cancer risk among Chinese population: evidence based on a cumulative meta-analysis Previous studies investigating the relationship between glutathione S-transferase T1 (GSTT1) gene deletion polymorphism and lung cancer risk among Chinese population produced inconsistent results.	('GSTT1', 'Gene', (19, 24))	('lung cancer', 'Disease', 'MESH:D008175', (52, 63))	('GSTT1', 'Gene', '2952', (19, 24))	('lung cancer', 'Disease', 'MESH:D008175', (264, 275))	('deletion polymorphism', 'Var', (238, 259))	('cancer', 'Phenotype', 'HP:0002664', (269, 275))	('glutathione S-transferase T1', 'Gene', (196, 224))	('glutathione S-transferase T1', 'Gene', '2952', (196, 224))	('GSTT1', 'Gene', '2952', (226, 231))	('GSTT1', 'Gene', (226, 231))	('lung cancer', 'Disease', (52, 63))	('lung cancer', 'Disease', (264, 275))	('lung cancer', 'Phenotype', 'HP:0100526', (52, 63))	('lung cancer', 'Phenotype', 'HP:0100526', (264, 275))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('deletion polymorphism', 'Var', (25, 46))
201910	26491361	To obtain a precise conclusion, we performed this meta-analysis to evaluate the association between GSTT1 deletion polymorphism and lung cancer risk among Chinese population.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('lung cancer', 'Disease', 'MESH:D008175', (132, 143))	('deletion polymorphism', 'Var', (106, 127))	('lung cancer', 'Disease', (132, 143))	('GSTT1', 'Gene', '2952', (100, 105))	('lung cancer', 'Phenotype', 'HP:0100526', (132, 143))	('GSTT1', 'Gene', (100, 105))
201911	26491361	Overall, we found an increased lung cancer risk among subjects carrying GSTT1 null genotype compared with those carrying present genotype (OR =1.31, 95% CI: 1.12-1.52) on the basis of 20 studies with 3,351 cases and 4,683 controls.	('lung cancer', 'Disease', 'MESH:D008175', (31, 42))	('lung cancer', 'Disease', (31, 42))	('lung cancer', 'Phenotype', 'HP:0100526', (31, 42))	('GSTT1', 'Gene', '2952', (72, 77))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('GSTT1', 'Gene', (72, 77))	('null', 'Var', (78, 82))
201912	26491361	We also observed an increased risk of lung cancer among subjects carrying GSTT1 null genotype compared with those carrying present genotype in stratified analyses (OR =1.31, 95% CI: 1.11-1.55 for healthy subjects-based control; OR =2.29, 95% CI: 1.84-2.85 for squamous cell carcinoma and OR =1.47, 95% CI: 1.22-1.77 for adenocarcinoma, respectively).	('GSTT1', 'Gene', '2952', (74, 79))	('lung cancer', 'Disease', (38, 49))	('GSTT1', 'Gene', (74, 79))	('lung cancer', 'Phenotype', 'HP:0100526', (38, 49))	('null', 'Var', (80, 84))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (260, 283))	('adenocarcinoma', 'Disease', (320, 334))	('carcinoma', 'Phenotype', 'HP:0030731', (274, 283))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('lung cancer', 'Disease', 'MESH:D008175', (38, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (325, 334))	('squamous cell carcinoma', 'Disease', (260, 283))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (260, 283))	('adenocarcinoma', 'Disease', 'MESH:D000230', (320, 334))
201913	26491361	This meta-analysis suggested that GSTT1 deletion polymorphism might contribute to lung cancer risk among Chinese population.	('lung cancer', 'Phenotype', 'HP:0100526', (82, 93))	('lung cancer', 'Disease', (82, 93))	('deletion polymorphism', 'Var', (40, 61))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('GSTT1', 'Gene', (34, 39))	('contribute', 'Reg', (68, 78))	('GSTT1', 'Gene', '2952', (34, 39))	('lung cancer', 'Disease', 'MESH:D008175', (82, 93))
201920	26491361	Recently, more and more results have supported the hypothesis that common genetic variations of drug-metabolizing enzyme genes may be of importance in determining an individual's sensitivity to develop lung cancer.	('lung cancer', 'Disease', (202, 213))	('lung cancer', 'Phenotype', 'HP:0100526', (202, 213))	('common genetic variations', 'Var', (67, 92))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('importance', 'Reg', (137, 147))	('lung cancer', 'Disease', 'MESH:D008175', (202, 213))
201922	26491361	GSTT1 deletion polymorphism is known to abolish enzyme activities and modulate lung cancer risk.	('lung cancer', 'Disease', 'MESH:D008175', (79, 90))	('modulate', 'Reg', (70, 78))	('GSTT1', 'Gene', '2952', (0, 5))	('activities', 'MPA', (55, 65))	('GSTT1', 'Gene', (0, 5))	('lung cancer', 'Disease', (79, 90))	('deletion polymorphism', 'Var', (6, 27))	('enzyme', 'Enzyme', (48, 54))	('abolish', 'NegReg', (40, 47))	('lung cancer', 'Phenotype', 'HP:0100526', (79, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))
201923	26491361	Lan et al, for the first time, explored the association of GSTT1 deletion polymorphism with lung cancer risk in the Chinese population in 1999.	('lung cancer', 'Disease', (92, 103))	('lung cancer', 'Phenotype', 'HP:0100526', (92, 103))	('GSTT1', 'Gene', (59, 64))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('deletion polymorphism', 'Var', (65, 86))	('GSTT1', 'Gene', '2952', (59, 64))	('lung cancer', 'Disease', 'MESH:D008175', (92, 103))	('association', 'Interaction', (44, 55))
201924	26491361	This urged us to perform this meta-analysis using the updated data, which aims at deriving a precise estimate of GSTT1 deletion polymorphism associated with lung cancer risk among Chinese population.	('deletion polymorphism', 'Var', (119, 140))	('lung cancer', 'Disease', (157, 168))	('GSTT1', 'Gene', (113, 118))	('lung cancer', 'Phenotype', 'HP:0100526', (157, 168))	('GSTT1', 'Gene', '2952', (113, 118))	('associated', 'Reg', (141, 151))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('lung cancer', 'Disease', 'MESH:D008175', (157, 168))
201926	26491361	Criteria for inclusion: 1) the subjects of study must be Chinese; 2) papers should include GSTT1 deletion polymorphism and lung cancer risk; 3) case-control study and cohort study; and 4) complete data on genotype of GSTT1 deletion polymorphism for calculating odds ratio (OR) with 95% confidence intervals (95% CI).	('GSTT1', 'Gene', (91, 96))	('lung cancer', 'Disease', (123, 134))	('GSTT1', 'Gene', '2952', (91, 96))	('lung cancer', 'Phenotype', 'HP:0100526', (123, 134))	('GSTT1', 'Gene', '2952', (217, 222))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('lung cancer', 'Disease', 'MESH:D008175', (123, 134))	('GSTT1', 'Gene', (217, 222))	('deletion polymorphism', 'Var', (223, 244))	('deletion polymorphism', 'Var', (97, 118))
201927	26491361	In total, 38 published studies were identified which studied the association between GSTT1 deletion polymorphism and lung cancer risk among Chinese population.	('deletion polymorphism', 'Var', (91, 112))	('GSTT1', 'Gene', (85, 90))	('lung cancer', 'Disease', (117, 128))	('GSTT1', 'Gene', '2952', (85, 90))	('lung cancer', 'Phenotype', 'HP:0100526', (117, 128))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('lung cancer', 'Disease', 'MESH:D008175', (117, 128))
201928	26491361	A meta-analysis was conducted to evaluate the relationship between GSTT1 deletion polymorphism and lung cancer risk among Chinese population.	('lung cancer', 'Disease', (99, 110))	('GSTT1', 'Gene', '2952', (67, 72))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('GSTT1', 'Gene', (67, 72))	('lung cancer', 'Disease', 'MESH:D008175', (99, 110))	('deletion polymorphism', 'Var', (73, 94))	('lung cancer', 'Phenotype', 'HP:0100526', (99, 110))
201929	26491361	There were a total of 20 studies, with 3,351 cases and 4,683 controls concerning the association of GSTT1 deletion polymorphism with lung cancer risk among Chinese population.	('lung cancer', 'Disease', (133, 144))	('lung cancer', 'Phenotype', 'HP:0100526', (133, 144))	('GSTT1', 'Gene', '2952', (100, 105))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('deletion polymorphism', 'Var', (106, 127))	('lung cancer', 'Disease', 'MESH:D008175', (133, 144))	('GSTT1', 'Gene', (100, 105))	('association', 'Interaction', (85, 96))
201931	26491361	Table 2 shows the association between GSTT1 deletion polymorphism and lung cancer risk among Chinese population.	('lung cancer', 'Disease', 'MESH:D008175', (70, 81))	('lung cancer', 'Disease', (70, 81))	('association', 'Interaction', (18, 29))	('deletion polymorphism', 'Var', (44, 65))	('GSTT1', 'Gene', '2952', (38, 43))	('GSTT1', 'Gene', (38, 43))	('lung cancer', 'Phenotype', 'HP:0100526', (70, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))
201933	26491361	Table 2 listed the summary ORs of the association between GSTT1 deletion polymorphism and lung cancer risk among Chinese population on the basis of 3,351 cases and 4,683 controls.	('lung cancer', 'Disease', 'MESH:D008175', (90, 101))	('deletion polymorphism', 'Var', (64, 85))	('lung cancer', 'Disease', (90, 101))	('GSTT1', 'Gene', '2952', (58, 63))	('lung cancer', 'Phenotype', 'HP:0100526', (90, 101))	('GSTT1', 'Gene', (58, 63))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))
201934	26491361	Overall, there was a statistically significant correlation of GSTT1 null genotype with an increased lung cancer risk among Chinese population, and the summary OR was 1.31 (95% CI: 1.12-1.52; Figure 1).	('lung cancer', 'Phenotype', 'HP:0100526', (100, 111))	('null genotype', 'Var', (68, 81))	('lung cancer', 'Disease', (100, 111))	('GSTT1', 'Gene', (62, 67))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('GSTT1', 'Gene', '2952', (62, 67))	('lung cancer', 'Disease', 'MESH:D008175', (100, 111))
201935	26491361	Our results showed that there was still a significant association between GSTT1 deletion polymorphism and lung cancer risk among Chinese population; the cumulative OR was 1.31 with 95% CI: 1.12-1.52 (Figure 2).	('deletion polymorphism', 'Var', (80, 101))	('GSTT1', 'Gene', '2952', (74, 79))	('GSTT1', 'Gene', (74, 79))	('lung cancer', 'Disease', (106, 117))	('lung cancer', 'Phenotype', 'HP:0100526', (106, 117))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('lung cancer', 'Disease', 'MESH:D008175', (106, 117))
201936	26491361	In subgroup analysis for source of control, we observed an increased risk of lung cancer among subjects carrying GSTT1 null genotype compared with those carrying present genotype in healthy subjects-based controls (OR =1.31, 95% CI: 1.11-1.55), but not in hospitalized patient-based controls (OR =1.28, 95% CI: 0.89-1.83).	('lung cancer', 'Phenotype', 'HP:0100526', (77, 88))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('GSTT1', 'Gene', (113, 118))	('GSTT1', 'Gene', '2952', (113, 118))	('lung cancer', 'Disease', 'MESH:D008175', (77, 88))	('null genotype', 'Var', (119, 132))	('patient', 'Species', '9606', (269, 276))	('lung cancer', 'Disease', (77, 88))
201937	26491361	We observed an increased risk of lung squamous cell carcinoma and lung adenocarcinoma among subjects carrying GSTT1 null genotype compared with those carrying present genotype in stratified analysis by histological subtype (OR =2.29, 95% CI: 1.84-2.85 and OR =1.47, 95% CI: 1.22-1.77, respectively).	('carcinoma', 'Phenotype', 'HP:0030731', (52, 61))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('lung squamous cell carcinoma and lung adenocarcinoma', 'Disease', 'MESH:D000077192', (33, 85))	('null genotype', 'Var', (116, 129))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (66, 85))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (33, 61))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (38, 61))	('GSTT1', 'Gene', '2952', (110, 115))	('GSTT1', 'Gene', (110, 115))
201945	26491361	Ruano-Ravina et al reported that lung cancer patients with deleted GSTT1 genotype had a significantly shorter survival than those with present GSTT1 genotype.	('shorter', 'NegReg', (102, 109))	('lung cancer', 'Phenotype', 'HP:0100526', (33, 44))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('survival', 'MPA', (110, 118))	('deleted', 'Var', (59, 66))	('GSTT1', 'Gene', '2952', (67, 72))	('GSTT1', 'Gene', (67, 72))	('GSTT1', 'Gene', (143, 148))	('lung cancer', 'Disease', 'MESH:D008175', (33, 44))	('GSTT1', 'Gene', '2952', (143, 148))	('patients', 'Species', '9606', (45, 53))	('lung cancer', 'Disease', (33, 44))
201948	26491361	Several meta-analyses explored the association of GSTT1 null genotype with the development of several kinds of cancers among Chinese population.	('cancers', 'Disease', 'MESH:D009369', (111, 118))	('cancers', 'Phenotype', 'HP:0002664', (111, 118))	('cancers', 'Disease', (111, 118))	('GSTT1', 'Gene', (50, 55))	('GSTT1', 'Gene', '2952', (50, 55))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('association', 'Interaction', (35, 46))	('null genotype', 'Var', (56, 69))
201949	26491361	In this paper, we performed a systematic literature review to comprehensively evaluate the association of GSTT1 deletion polymorphism with lung cancer risk among Chinese population.	('lung cancer', 'Disease', (139, 150))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('deletion polymorphism', 'Var', (112, 133))	('lung cancer', 'Disease', 'MESH:D008175', (139, 150))	('GSTT1', 'Gene', '2952', (106, 111))	('GSTT1', 'Gene', (106, 111))	('lung cancer', 'Phenotype', 'HP:0100526', (139, 150))	('association', 'Interaction', (91, 102))
201950	26491361	In summary, we observed an increased lung cancer risk among Chinese population with GSTT1 null genotype compared with those carrying present genotype.	('GSTT1', 'Gene', (84, 89))	('lung cancer', 'Disease', (37, 48))	('lung cancer', 'Phenotype', 'HP:0100526', (37, 48))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('lung cancer', 'Disease', 'MESH:D008175', (37, 48))	('null genotype', 'Var', (90, 103))	('GSTT1', 'Gene', '2952', (84, 89))
201951	26491361	To our knowledge, four published papers have addressed the association between GSTT1 deletion polymorphism and lung cancer risk among Chinese population.	('lung cancer', 'Disease', 'MESH:D008175', (111, 122))	('deletion polymorphism', 'Var', (85, 106))	('GSTT1', 'Gene', (79, 84))	('GSTT1', 'Gene', '2952', (79, 84))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('lung cancer', 'Disease', (111, 122))	('lung cancer', 'Phenotype', 'HP:0100526', (111, 122))
201952	26491361	However, the conclusions are mixed, for example, three previous meta-analyses observed a positive association between GSTT1 null genotype and an increased lung cancer risk among Chinese population, but one not.	('GSTT1', 'Gene', '2952', (118, 123))	('GSTT1', 'Gene', (118, 123))	('lung cancer', 'Disease', (155, 166))	('lung cancer', 'Phenotype', 'HP:0100526', (155, 166))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('null genotype', 'Var', (124, 137))	('lung cancer', 'Disease', 'MESH:D008175', (155, 166))
201953	26491361	We believed that this current meta-analysis presented a precise estimate of the association between GSTT1 deletion polymorphism and lung cancer risk among Chinese population.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('lung cancer', 'Disease', 'MESH:D008175', (132, 143))	('deletion polymorphism', 'Var', (106, 127))	('association', 'Interaction', (80, 91))	('lung cancer', 'Disease', (132, 143))	('GSTT1', 'Gene', '2952', (100, 105))	('lung cancer', 'Phenotype', 'HP:0100526', (132, 143))	('GSTT1', 'Gene', (100, 105))
201955	26491361	To address the effect of cigarette smoke on the correlation of GSTT1 deletion polymorphism with lung cancer risk, subgroup analysis was conducted in the light of smoking status.	('lung cancer', 'Disease', 'MESH:D008175', (96, 107))	('GSTT1', 'Gene', '2952', (63, 68))	('lung cancer', 'Disease', (96, 107))	('GSTT1', 'Gene', (63, 68))	('lung cancer', 'Phenotype', 'HP:0100526', (96, 107))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('deletion polymorphism', 'Var', (69, 90))
201959	26491361	We observed a statistically significant association of GSTT1 deletion polymorphism with an increased risk of squamous cell carcinoma and adenocarcinoma.	('deletion polymorphism', 'Var', (61, 82))	('association', 'Reg', (40, 51))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (109, 132))	('carcinoma', 'Phenotype', 'HP:0030731', (142, 151))	('squamous cell carcinoma and adenocarcinoma', 'Disease', 'MESH:D002294', (109, 151))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('GSTT1', 'Gene', (55, 60))	('GSTT1', 'Gene', '2952', (55, 60))
201961	26491361	In summary, this meta-analysis found that GSTT1 null genotype was associated with an increased risk of lung cancer among Chinese population.	('lung cancer', 'Disease', 'MESH:D008175', (103, 114))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('GSTT1', 'Gene', '2952', (42, 47))	('lung cancer', 'Disease', (103, 114))	('null genotype', 'Var', (48, 61))	('GSTT1', 'Gene', (42, 47))	('lung cancer', 'Phenotype', 'HP:0100526', (103, 114))
201962	26491361	Studies with larger sample size are required to evaluate gene-gene and gene-environment interactions on GSTT1 deletion polymorphism and lung cancer risk among Chinese population further.	('deletion polymorphism', 'Var', (110, 131))	('lung cancer', 'Phenotype', 'HP:0100526', (136, 147))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('lung cancer', 'Disease', 'MESH:D008175', (136, 147))	('GSTT1', 'Gene', '2952', (104, 109))	('GSTT1', 'Gene', (104, 109))	('lung cancer', 'Disease', (136, 147))
202005	24959038	Studies done regarding the presence of MFs in oral epithelial dysplasia and squamous cell carcinoma revealed a higher number of MFs in oral squamous cell carcinoma [Figure 2g and h] compared to normal and dysplastic epithelium, which were devoid of MFs.	('oral squamous cell carcinoma', 'Disease', (135, 163))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (76, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('squamous cell carcinoma', 'Disease', (76, 99))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (76, 99))	('oral epithelial dysplasia', 'Disease', 'MESH:D017573', (46, 71))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (135, 163))	('dysplastic', 'Disease', 'MESH:D004416', (205, 215))	('MFs', 'Var', (128, 131))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (140, 163))	('dysplastic', 'Disease', (205, 215))	('carcinoma', 'Phenotype', 'HP:0030731', (154, 163))	('oral epithelial dysplasia', 'Disease', (46, 71))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (140, 163))
202012	24959038	The presence of MFs was also thought to be associated with tumor prognosis.	('tumor', 'Disease', (59, 64))	('associated', 'Reg', (43, 53))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('presence', 'Var', (4, 12))	('MFs', 'Gene', (16, 19))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
202014	24959038	Patients whose specimens were weakly positive for alpha-SMA had 5 year mean survival rate of 82%; whereas, patients with samples that were strongly positive with alpha-SMA had a mean survival rate of 38% indicating that the presence of more number of MFs in the stroma is associated with poor prognosis.	('presence', 'Var', (224, 232))	('MFs', 'Gene', (251, 254))	('alpha-SMA', 'Chemical', '-', (162, 171))	('Patients', 'Species', '9606', (0, 8))	('alpha-SMA', 'Chemical', '-', (50, 59))	('patients', 'Species', '9606', (107, 115))
202022	24531128	Pharmacological Lox inhibition promotes the transdifferentiation, whereas ectopic Lox expression significantly inhibits this process.	('inhibition', 'Var', (20, 30))	('promotes', 'PosReg', (31, 39))	('inhibits', 'NegReg', (111, 119))	('expression', 'Species', '29278', (86, 96))	('transdifferentiation', 'CPA', (44, 64))
202032	24531128	The mixed ADC and SCC pathology with identical genetic mutations has been frequently observed in a single lesion of human lung tumours, so called adenosquamous cell carcinoma (Ad-SCC), suggesting a monoclonality and the potential lineage transition between these subtypes.	('lung tumours', 'Disease', (122, 134))	('SCC', 'Phenotype', 'HP:0002860', (18, 21))	('SCC', 'Gene', '6317', (179, 182))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (151, 174))	('adenosquamous cell carcinoma', 'Phenotype', 'HP:0002860', (146, 174))	('SCC', 'Gene', (179, 182))	('SCC', 'Gene', '6317', (18, 21))	('lung tumour', 'Phenotype', 'HP:0100526', (122, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (165, 174))	('lung tumours', 'Disease', 'MESH:D008175', (122, 134))	('tumours', 'Phenotype', 'HP:0002664', (127, 134))	('SCC', 'Gene', (18, 21))	('mutations', 'Var', (55, 64))	('adenosquamous cell carcinoma', 'Disease', 'MESH:D018196', (146, 174))	('human', 'Species', '9606', (116, 121))	('SCC', 'Phenotype', 'HP:0002860', (179, 182))	('adenosquamous cell carcinoma', 'Disease', (146, 174))	('tumour', 'Phenotype', 'HP:0002664', (127, 133))	('Ad-SCC', 'Phenotype', 'HP:0002860', (176, 182))
202036	24531128	Loss-of-function mutations of LKB1 have been observed in human lung ADC, SCC and Ad-SCC specimens.	('LKB1', 'Gene', (30, 34))	('Loss-of-function', 'NegReg', (0, 16))	('SCC', 'Gene', '6317', (84, 87))	('Ad-SCC', 'Phenotype', 'HP:0002860', (81, 87))	('lung ADC', 'Disease', (63, 71))	('SCC', 'Gene', (73, 76))	('SCC', 'Phenotype', 'HP:0002860', (73, 76))	('SCC', 'Gene', '6317', (73, 76))	('SCC', 'Gene', (84, 87))	('SCC', 'Phenotype', 'HP:0002860', (84, 87))	('mutations', 'Var', (17, 26))	('human', 'Species', '9606', (57, 62))
202051	24531128	At an even longer time (12 weeks) post Ad-Cre treatment, the number of SCC increased concomitantly with a decrease of ADC number, while the total tumour number showed no significant change (Fig.	('ADC number', 'MPA', (118, 128))	('tumour', 'Disease', (146, 152))	('Ad-Cre', 'Var', (39, 45))	('decrease', 'NegReg', (106, 114))	('SCC', 'Gene', (71, 74))	('tumour', 'Phenotype', 'HP:0002664', (146, 152))	('SCC', 'Phenotype', 'HP:0002860', (71, 74))	('SCC', 'Gene', '6317', (71, 74))	('tumour', 'Disease', 'MESH:D009369', (146, 152))
202062	24531128	However, the percentage of mAd-SCC gradually decreased to ~30% at 10-12 weeks post Ad-Cre treatment, and to only 10% post an even longer time treatment (12-14 weeks).	('SCC', 'Gene', (31, 34))	('decreased', 'NegReg', (45, 54))	('SCC', 'Phenotype', 'HP:0002860', (31, 34))	('SCC', 'Gene', '6317', (31, 34))	('Ad-SCC', 'Phenotype', 'HP:0002860', (28, 34))	('Ad-Cre', 'Var', (83, 89))
202064	24531128	Consistently, statistical analysis revealed that the average percentage of p63-positive cells progressively increased from 66 to 92% concomitantly with a decrease of average percentage of cells positive for SP-C from 34 to 8% in mAd-SCC from 8 to 12 weeks post Ad-Cre treatment (Supplementary Fig.	('SCC', 'Gene', (233, 236))	('SCC', 'Phenotype', 'HP:0002860', (233, 236))	('increased', 'PosReg', (108, 117))	('SCC', 'Gene', '6317', (233, 236))	('decrease', 'NegReg', (154, 162))	('p63-positive', 'Var', (75, 87))	('SP-C', 'Gene', (207, 211))	('Ad-SCC', 'Phenotype', 'HP:0002860', (230, 236))	('SP-C', 'Gene', '6440', (207, 211))
202089	24531128	Even though the Kras activation and Lkb1 inactivation were initially engineered in our mouse models, it is unlikely to exclude the occurrence of new mutations in the mature tumours, which may confound our observation of transdifferentiation process.	('Lkb1', 'Gene', (36, 40))	('tumours', 'Disease', 'MESH:D009369', (173, 180))	('tumours', 'Disease', (173, 180))	('mouse', 'Species', '10090', (87, 92))	('Kras', 'Gene', (16, 20))	('Kras', 'Gene', '16653', (16, 20))	('inactivation', 'Var', (41, 53))	('Lkb1', 'Gene', '20869', (36, 40))	('tumour', 'Phenotype', 'HP:0002664', (173, 179))	('tumours', 'Phenotype', 'HP:0002664', (173, 180))
202099	24531128	Studies using regular sequencing or deep sequencing of genomic DNA show that LKB1 inactivating mutations are frequently observed in ~20% of human ADC but only ~2% SCC.	('LKB1', 'Gene', (77, 81))	('inactivating mutations', 'Var', (82, 104))	('human', 'Species', '9606', (140, 145))	('SCC', 'Gene', (163, 166))	('SCC', 'Phenotype', 'HP:0002860', (163, 166))	('ADC', 'Disease', (146, 149))	('SCC', 'Gene', '6317', (163, 166))
202100	24531128	Since LKB1 genetic alteration involves point mutation as well as exonic deletion, we have previously identified ~19% (8/42) of human lung SCC with LKB1 genetic alterations by the combination of direct sequencing and molecular analysis with multiplex ligation-dependent probe amplification (MLPA) analysis of genomic DNA.	('LKB1', 'Gene', (147, 151))	('human', 'Species', '9606', (127, 132))	('genetic alterations', 'Var', (152, 171))	('SCC', 'Gene', (138, 141))	('LKB1', 'Gene', (6, 10))	('SCC', 'Phenotype', 'HP:0002860', (138, 141))	('SCC', 'Gene', '6317', (138, 141))	('exonic deletion', 'Var', (65, 80))	('point mutation', 'Var', (39, 53))
202101	24531128	Using the same method, we analysed another ethnically different cohort with 101 Chinese lung SCC samples and identified ~13% (13 of 101) of Chinese squamous cell carcinoma with LKB1 exonic deletions plus 5% (5 of 101) patients harbouring LKB1 F354L mutation, which has been indicated as an inactivating mutation (Supplementary Table 4).	('patients', 'Species', '9606', (218, 226))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (148, 171))	('squamous cell carcinoma', 'Disease', (148, 171))	('SCC', 'Gene', (93, 96))	('SCC', 'Phenotype', 'HP:0002860', (93, 96))	('exonic deletions', 'Var', (182, 198))	('F354L', 'Mutation', 'rs59912467', (243, 248))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (148, 171))	('SCC', 'Gene', '6317', (93, 96))	('LKB1', 'Gene', (238, 242))	('LKB1', 'Gene', (177, 181))	('F354L', 'Var', (243, 248))	('carcinoma', 'Phenotype', 'HP:0030731', (162, 171))
202103	24531128	We recently found that upregulated Lox expression through activation of mTOR-Hif1alpha signalling axis correlates with Lkb1 inactivation status and triggers excessive collagen deposition in Lkb1-deficient lung ADC to enhance tumour cell proliferation and invasion.	('triggers', 'Reg', (148, 156))	('upregulated', 'PosReg', (23, 34))	('inactivation status', 'Var', (124, 143))	('deficient lung', 'Phenotype', 'HP:0002089', (195, 209))	('Lkb1-deficient lung', 'Disease', 'MESH:D008171', (190, 209))	('collagen deposition', 'MPA', (167, 186))	('activation', 'PosReg', (58, 68))	('Lkb1', 'Gene', (119, 123))	('invasion', 'CPA', (255, 263))	('Lox expression', 'MPA', (35, 49))	('tumour', 'Phenotype', 'HP:0002664', (225, 231))	('enhance', 'PosReg', (217, 224))	('tumour', 'Disease', 'MESH:D009369', (225, 231))	('Lkb1', 'Gene', (190, 194))	('tumour', 'Disease', (225, 231))	('Lkb1-deficient lung', 'Disease', (190, 209))	('Lkb1', 'Gene', '20869', (119, 123))	('mTOR-Hif1alpha', 'Pathway', (72, 86))	('Lkb1', 'Gene', '20869', (190, 194))	('expression', 'Species', '29278', (39, 49))
202111	24531128	With a relatively slower progression pattern than Ad-Cre treatment, Lenti-Cre administration led to similar pathological phenotype, including ADC, mAd-SCC and typical SCC formation (Supplementary Fig.	('SCC', 'Phenotype', 'HP:0002860', (167, 170))	('SCC', 'Gene', '6317', (167, 170))	('SCC', 'Phenotype', 'HP:0002860', (151, 154))	('SCC', 'Gene', '6317', (151, 154))	('ADC', 'Disease', (142, 145))	('Lenti-Cre', 'Var', (68, 77))	('Ad-SCC', 'Phenotype', 'HP:0002860', (148, 154))	('SCC', 'Gene', (167, 170))	('SCC', 'Gene', (151, 154))
202115	24531128	Together, these data suggest a role of Lox downregulation in the ADC to SCC transdifferentiation potentially through decreasing collagen deposition.	('collagen deposition', 'MPA', (128, 147))	('downregulation', 'NegReg', (43, 57))	('ADC', 'Disease', (65, 68))	('Lox', 'Var', (39, 42))	('SCC', 'Gene', (72, 75))	('SCC', 'Phenotype', 'HP:0002860', (72, 75))	('decreasing', 'NegReg', (117, 127))	('SCC', 'Gene', '6317', (72, 75))
202118	24531128	Consistent with Ad-Cre treatment, Lenti-Cre administration led to similar pathological phenotype, including ADC, Ad-SCC and typical SCC formation.	('SCC', 'Gene', (116, 119))	('SCC', 'Phenotype', 'HP:0002860', (116, 119))	('Ad-SCC', 'Phenotype', 'HP:0002860', (113, 119))	('SCC', 'Gene', '6317', (116, 119))	('SCC', 'Gene', (132, 135))	('ADC', 'Disease', (108, 111))	('SCC', 'Phenotype', 'HP:0002860', (132, 135))	('SCC', 'Gene', '6317', (132, 135))	('Lenti-Cre', 'Var', (34, 43))
202120	24531128	Strikingly, only 27% (3/11) of mice in Lenti-Cre-Lox group developed SCC, in contrast to 91% (10/11) of mice in Lenti-Cre group with SCC post 13 weeks of viral treatment, indicating that the incidence of SCC formation was significantly inhibited by ectopic Lox expression.	('SCC', 'Gene', '6317', (204, 207))	('SCC', 'Gene', '6317', (133, 136))	('SCC', 'Gene', (69, 72))	('inhibited', 'NegReg', (236, 245))	('ectopic Lox expression', 'Var', (249, 271))	('mice', 'Species', '10090', (104, 108))	('expression', 'Species', '29278', (261, 271))	('SCC', 'Phenotype', 'HP:0002860', (69, 72))	('mice', 'Species', '10090', (31, 35))	('SCC', 'Gene', (204, 207))	('SCC', 'Gene', '6317', (69, 72))	('SCC', 'Phenotype', 'HP:0002860', (204, 207))	('SCC', 'Gene', (133, 136))	('SCC', 'Phenotype', 'HP:0002860', (133, 136))
202124	24531128	These data demonstrated that ectopic Lox expression inhibits ADC to SCC transdifferentiation potentially through ECM remodelling.	('expression', 'Species', '29278', (41, 51))	('SCC', 'Phenotype', 'HP:0002860', (68, 71))	('SCC', 'Gene', '6317', (68, 71))	('ectopic Lox', 'Var', (29, 40))	('inhibits', 'NegReg', (52, 60))	('SCC', 'Gene', (68, 71))
202129	24531128	Strikingly, we found that a high percentage of BAPN-treated mice (86%, 12/14) developed SCC, in contrast to only 17% (3/18) of control mice with SCC (Table 1).	('BAPN', 'Chemical', 'MESH:D000629', (47, 51))	('BAPN-treated', 'Var', (47, 59))	('SCC', 'Gene', (145, 148))	('SCC', 'Phenotype', 'HP:0002860', (145, 148))	('mice', 'Species', '10090', (135, 139))	('SCC', 'Gene', (88, 91))	('SCC', 'Gene', '6317', (145, 148))	('mice', 'Species', '10090', (60, 64))	('SCC', 'Phenotype', 'HP:0002860', (88, 91))	('SCC', 'Gene', '6317', (88, 91))
202148	24531128	In addition, increased expression of p63 was also detected in BAPN-treated subcutaneous tumours from human NSCLC cell line A549 in nude mice (Fig.	('expression', 'Species', '29278', (23, 33))	('nude mice', 'Species', '10090', (131, 140))	('NSCLC', 'Disease', (107, 112))	('tumours', 'Phenotype', 'HP:0002664', (88, 95))	('NSCLC', 'Disease', 'MESH:D002289', (107, 112))	('BAPN', 'Chemical', 'MESH:D000629', (62, 66))	('p63', 'Var', (37, 40))	('human', 'Species', '9606', (101, 106))	('subcutaneous tumours', 'Disease', (75, 95))	('tumour', 'Phenotype', 'HP:0002664', (88, 94))	('NSCLC', 'Phenotype', 'HP:0030358', (107, 112))	('A549', 'CellLine', 'CVCL:0023', (123, 127))	('subcutaneous tumours', 'Disease', 'MESH:D012871', (75, 95))	('increased', 'PosReg', (13, 22))	('expression', 'MPA', (23, 33))
202156	24531128	Our data showed that transient DNp63a expression in Kras/p53 cells activated Krt5 and Krt14 expression (Supplementary Figs 8b,c and 9b), and cells with stable DNp63a expression showed distinct morphologies from parental cells (Supplementary Fig.	('DNp63a', 'Gene', (31, 37))	('expression', 'Species', '29278', (38, 48))	('Krt5', 'Gene', (77, 81))	('p53', 'Gene', '22060', (57, 60))	('activated', 'PosReg', (67, 76))	('Krt5', 'Gene', '110308', (77, 81))	('expression', 'MPA', (92, 102))	('expression', 'Var', (38, 48))	('expression', 'Species', '29278', (166, 176))	('Kras', 'Gene', (52, 56))	('p53', 'Gene', (57, 60))	('expression', 'Species', '29278', (92, 102))	('Kras', 'Gene', '16653', (52, 56))	('Krt14', 'Gene', '16664', (86, 91))	('Krt14', 'Gene', (86, 91))
202157	24531128	Notably, apart from certain known p63 target genes (Krt5 and Krt14), DNp63a-expressing Kras/p53 cells also expressed a series of genes previously identified as SCC signature genes (Fig.	('p53', 'Gene', '22060', (92, 95))	('DNp63a-expressing', 'Var', (69, 86))	('Krt5', 'Gene', (52, 56))	('Krt14', 'Gene', (61, 66))	('p53', 'Gene', (92, 95))	('SCC', 'Gene', (160, 163))	('Kras', 'Gene', (87, 91))	('Kras', 'Gene', '16653', (87, 91))	('Krt14', 'Gene', '16664', (61, 66))	('Krt5', 'Gene', '110308', (52, 56))	('SCC', 'Phenotype', 'HP:0002860', (160, 163))	('SCC', 'Gene', '6317', (160, 163))
202160	24531128	These data demonstrate that ectopic expression of lineage survival oncogene DNp63a is able to partially drive de novo ADC to SCC transdifferentiation.	('DNp63a', 'Gene', (76, 82))	('SCC', 'Gene', (125, 128))	('SCC', 'Phenotype', 'HP:0002860', (125, 128))	('ADC', 'Disease', (118, 121))	('drive', 'Reg', (104, 109))	('expression', 'Species', '29278', (36, 46))	('SCC', 'Gene', '6317', (125, 128))	('ectopic expression', 'Var', (28, 46))
202166	24531128	Notably, the transition from neuroendocrine to mesenchymal phenotype could also be achieved by ectopic expression of oncogenic RasV12 in SCLC.	('RasV12', 'Gene', (127, 133))	('expression', 'Species', '29278', (103, 113))	('SCLC', 'Disease', (137, 141))	('SCLC', 'Disease', 'MESH:D018288', (137, 141))	('oncogenic', 'Var', (117, 126))
202179	24531128	Beyond this, we have established an important regulatory pathway for ECM in shaping phenotypic plasticity of lung ADC with LKB1 deficiency: At the early stage, loss of the tumour suppressor LKB1 promotes ADC progression partly through Lox; as the tumours grow up, Lox reduction following reduced hypoxia level would lead to ECM remodelling, which then results in the dramatic change so that the ADC cells might robustly and systematically transit to SCC.	('Lox', 'Var', (264, 267))	('SCC', 'Gene', (450, 453))	('tumour', 'Phenotype', 'HP:0002664', (172, 178))	('tumour', 'Disease', 'MESH:D009369', (172, 178))	('hypoxia', 'Disease', 'MESH:D000860', (296, 303))	('tumour', 'Disease', (172, 178))	('tumours', 'Disease', (247, 254))	('tumours', 'Phenotype', 'HP:0002664', (247, 254))	('tumours', 'Disease', 'MESH:D009369', (247, 254))	('tumour', 'Phenotype', 'HP:0002664', (247, 253))	('SCC', 'Phenotype', 'HP:0002860', (450, 453))	('tumour', 'Disease', 'MESH:D009369', (247, 253))	('tumour', 'Disease', (247, 253))	('ADC', 'Disease', (204, 207))	('LKB1 deficiency', 'Disease', 'MESH:D007153', (123, 138))	('LKB1 deficiency', 'Disease', (123, 138))	('SCC', 'Gene', '6317', (450, 453))	('loss', 'Var', (160, 164))	('lead to', 'Reg', (316, 323))	('hypoxia', 'Disease', (296, 303))	('LKB1', 'Gene', (190, 194))	('reduction', 'NegReg', (268, 277))
202184	24531128	Consistently, ADC metastasis was only observed after 10 weeks post Ad-Cre treatment, while ADC to SCC transdifferentiation was observed at 8 weeks post Ad-Cre treatment.	('SCC', 'Phenotype', 'HP:0002860', (98, 101))	('Ad-Cre', 'Var', (67, 73))	('SCC', 'Gene', '6317', (98, 101))	('ADC metastasis', 'CPA', (14, 28))	('SCC', 'Gene', (98, 101))
202186	24531128	Together with our previous findings, we unveil the dual function of Lox in LKB1-deficient lung ADC, one hand to promote ADC progression and metastasis, the other hand to inhibit ADC to SCC transdifferentiation via ECM remodelling (the present study).	('deficient lung', 'Phenotype', 'HP:0002089', (80, 94))	('inhibit', 'NegReg', (170, 177))	('promote', 'PosReg', (112, 119))	('SCC', 'Gene', (185, 188))	('SCC', 'Phenotype', 'HP:0002860', (185, 188))	('LKB1-deficient lung ADC', 'Disease', 'MESH:D008171', (75, 98))	('SCC', 'Gene', '6317', (185, 188))	('Lox', 'Var', (68, 71))	('metastasis', 'CPA', (140, 150))	('ADC progression', 'CPA', (120, 135))	('LKB1-deficient lung ADC', 'Disease', (75, 98))
202188	24531128	Although this possibility remains to be tested clinically, our study might provide helpful insights into therapeutic strategy development for lung ADC in which somatic LKB1 mutations are highly prevalent.	('mutations', 'Var', (173, 182))	('LKB1', 'Gene', (168, 172))	('clinical', 'Species', '191496', (47, 55))	('lung ADC', 'Disease', (142, 150))
202247	33846793	In the present study, it was revealed that cAMP response element-binding protein (CREB) was highly expressed in LUAD, and knockdown of CREB inhibited cell viability and growth by promoting apoptosis- and ferroptosis-like cell death, concurrently.	('CREB', 'Gene', '1385', (135, 139))	('cAMP response element-binding protein', 'Gene', '1385', (43, 80))	('CREB', 'Gene', (82, 86))	('apoptosis-', 'CPA', (189, 199))	('cAMP response element-binding protein', 'Gene', (43, 80))	('CREB', 'Gene', '1385', (82, 86))	('inhibited', 'NegReg', (140, 149))	('knockdown', 'Var', (122, 131))	('LUAD', 'Phenotype', 'HP:0030078', (112, 116))	('growth', 'CPA', (169, 175))	('ferroptosis-like cell death', 'CPA', (204, 231))	('CREB', 'Gene', (135, 139))	('promoting', 'PosReg', (179, 188))	('cell viability', 'CPA', (150, 164))
202250	33846793	Finally, it was revealed that CREB, GPX4, EP300 and 4-HNE were closely related to tumor size and stage, and tumors with a higher degree of malignancy were more likely to have a low degree of lipid peroxidation.	('tumor', 'Disease', (108, 113))	('tumor', 'Disease', (82, 87))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('4-HNE', 'Chemical', '-', (52, 57))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('malignancy', 'Disease', 'MESH:D009369', (139, 149))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('CREB', 'Gene', (30, 34))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumors', 'Disease', (108, 114))	('malignancy', 'Disease', (139, 149))	('GPX4', 'Gene', (36, 40))	('GPX4', 'Gene', '2879', (36, 40))	('lipid', 'Chemical', 'MESH:D008055', (191, 196))	('EP300', 'Var', (42, 47))	('lipid peroxidation', 'MPA', (191, 209))	('related', 'Reg', (71, 78))	('CREB', 'Gene', '1385', (30, 34))	('tumors', 'Disease', 'MESH:D009369', (108, 114))
202260	33846793	Studies have revealed that cancer cells grow slowly when cAMP response element-binding protein (CREB), a transcription factor, is knocked down.	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('cAMP response element-binding protein', 'Gene', '1385', (57, 94))	('knocked', 'Var', (130, 137))	('cAMP response element-binding protein', 'Gene', (57, 94))	('CREB', 'Gene', (96, 100))	('CREB', 'Gene', '1385', (96, 100))	('cancer', 'Disease', (27, 33))	('slowly', 'NegReg', (45, 51))	('cancer', 'Disease', 'MESH:D009369', (27, 33))	('grow', 'CPA', (40, 44))
202271	33846793	Empty vector, GFP-sh and EP300-sh1/sh2 cells were purchased from Shanghai Biolink Co., Ltd. CREB-Del-KID, CREB-Del-bZIP, EP300-Del-KIX, EP300-Del-Bromo and EP300-Del-CBP/p300-HAT were constructed using overlapping PCR and cloned into the pcDNA3.1(+) vector.	('CREB', 'Gene', (106, 110))	('EP300-Del-Bromo', 'Var', (136, 151))	('EP300-Del-KIX', 'Var', (121, 134))	('CREB', 'Gene', '1385', (92, 96))	('EP300-Del-CBP/p300-HAT', 'Var', (156, 178))	('KID', 'Disease', (101, 104))	('CREB', 'Gene', '1385', (106, 110))	('KID', 'Disease', 'MESH:C536168', (101, 104))	('CREB', 'Gene', (92, 96))
202280	33846793	2367 and 3724) all from CST; and anti-EP300 (product codes ab54984 and ab275378) and anti-SET domain bifurcated histone lysine methyltransferase 2 (SETDB2) (product code ab5517) all from Abcam.	('anti-SET', 'Var', (85, 93))	('SETDB2', 'Gene', (148, 154))	('CST', 'Gene', (24, 27))	('SETDB2', 'Gene', '83852', (148, 154))	('CST', 'Gene', '106478911', (24, 27))
202296	33846793	Wild-type (WT)- and mutant (Mut)-GPX4-promoter luciferase reporters were constructed using the pGL4.21 vector at our laboratory (Shanghai Institute of Thoracic Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China), and co-transfected into lung cancer cells with Renilla plasmids using Lipofectamine  2000 transfection reagent (Invitrogen; Thermo Fisher Scientific, Inc.).	('mutant', 'Var', (20, 26))	('lung cancer', 'Disease', 'MESH:D008175', (268, 279))	('cancer', 'Phenotype', 'HP:0002664', (273, 279))	('lung cancer', 'Disease', (268, 279))	('lung cancer', 'Phenotype', 'HP:0100526', (268, 279))	('GPX4', 'Gene', (33, 37))	('GPX4', 'Gene', '2879', (33, 37))	('Lipofectamine  2000', 'Chemical', 'MESH:C086724', (314, 333))	('Oncology', 'Phenotype', 'HP:0002664', (160, 168))
202305	33846793	9104; 1:100; CST), anti-EP300 (product code ab54984; 1:100; Abcam) and anti-SETDB2 (product code ab13712; 1:50; Abcam).	('CST', 'Gene', (13, 16))	('SETDB2', 'Gene', (76, 82))	('SETDB2', 'Gene', '83852', (76, 82))	('anti-EP300', 'Var', (19, 29))	('CST', 'Gene', '106478911', (13, 16))
202306	33846793	Lipid ROS generation was measured by adding C11-BODIPY (Invitrogen; Thermo Fisher Scientific, Inc.) to a final concentration of 1.5 microM for 20 min before cell harvest.	('Lipid ROS', 'Chemical', '-', (0, 9))	('Lipid ROS generation', 'MPA', (0, 20))	('C11-BODIPY', 'Var', (44, 54))
202324	33846793	It was observed that knockdown of CREB inhibited cell viability, and 3D cell growth, whereas these effects could be reversed by the apoptotic inhibitor ZVAD-FMK and the ferroptotic inhibitor Fer-1.	('inhibited', 'NegReg', (39, 48))	('ZVAD-FMK', 'Chemical', 'MESH:C096713', (152, 160))	('cell viability', 'CPA', (49, 63))	('CREB', 'Gene', (34, 38))	('3D cell growth', 'CPA', (69, 83))	('CREB', 'Gene', '1385', (34, 38))	('knockdown', 'Var', (21, 30))
202325	33846793	However, the CREB knockdown-induced effects could not be regulated by the necrotic inhibitor necrostatin-1 (Nec-1) (Fig.	('CREB', 'Gene', (13, 17))	('knockdown-induced', 'Var', (18, 35))	('necrotic', 'Disease', 'MESH:D009336', (74, 82))	('CREB', 'Gene', '1385', (13, 17))	('necrotic', 'Disease', (74, 82))	('necrostatin-1', 'Chemical', 'MESH:C507699', (93, 106))	('Nec-1', 'Chemical', 'MESH:C507699', (108, 113))
202326	33846793	Compared to ZVAD-FMK, Fer-1 reversed the decrease of cell viability and 3D cell growth induced by CREB knockdown to a greater extent (Fig.	('CREB', 'Gene', (98, 102))	('3D cell growth', 'CPA', (72, 86))	('decrease', 'NegReg', (41, 49))	('ZVAD-FMK', 'Chemical', 'MESH:C096713', (12, 20))	('CREB', 'Gene', '1385', (98, 102))	('cell viability', 'CPA', (53, 67))	('knockdown', 'Var', (103, 112))
202327	33846793	It was also confirmed that CREB knockdown upregulated the level of the lipid peroxidation product MDA and the ferroptotic biomarkers lipid ROS and Fe2+, and these effects could not be reversed by ZVAD-FMK and Nec-1 (Fig.	('Fe2+', 'Chemical', '-', (147, 151))	('CREB', 'Gene', (27, 31))	('lipid ROS', 'Chemical', '-', (133, 142))	('level of the lipid peroxidation product MDA', 'MPA', (58, 101))	('knockdown', 'Var', (32, 41))	('CREB', 'Gene', '1385', (27, 31))	('Nec-1', 'Chemical', 'MESH:C507699', (209, 214))	('upregulated', 'PosReg', (42, 53))	('ZVAD-FMK', 'Chemical', 'MESH:C096713', (196, 204))	('MDA', 'Chemical', 'MESH:D008315', (98, 101))	('lipid', 'Chemical', 'MESH:D008055', (71, 76))	('lipid', 'Chemical', 'MESH:D008055', (133, 138))
202328	33846793	Moreover, it was revealed that ectopically expressed CREB could reverse the apoptotic stimulus Apoptozole- and ferroptosis stimulus erastin-induced decrease of cell viability and 3D cell growth (Fig.	('CREB', 'Gene', '1385', (53, 57))	('erastin', 'Chemical', 'MESH:C477224', (132, 139))	('ectopically expressed', 'Var', (31, 52))	('Apoptozole', 'Chemical', 'MESH:C000608805', (95, 105))	('decrease', 'NegReg', (148, 156))	('cell viability', 'CPA', (160, 174))	('CREB', 'Gene', (53, 57))	('3D cell growth', 'CPA', (179, 193))
202330	33846793	These data indicated that knockdown of CREB concurrently induced apoptosis- and ferroptosis-like cell death.	('CREB', 'Gene', (39, 43))	('CREB', 'Gene', '1385', (39, 43))	('apoptosis-', 'CPA', (65, 75))	('induced', 'Reg', (57, 64))	('knockdown', 'Var', (26, 35))	('ferroptosis-like cell death', 'CPA', (80, 107))
202343	33846793	After a STRING analysis detecting potential CREB-binding methyltransferase/acetyltransferase, it was revealed that EP300 had the highest possibility of binding with CREB (Fig.	('CREB', 'Gene', (165, 169))	('CREB', 'Gene', '1385', (44, 48))	('EP300', 'Var', (115, 120))	('CREB', 'Gene', '1385', (165, 169))	('binding', 'Interaction', (152, 159))	('CREB', 'Gene', (44, 48))
202344	33846793	The co-IP experiments confirmed that CREB could interact with EP300, whereas an obvious interaction was not detected between CREB and SETDB2 (Fig.	('SETDB2', 'Gene', '83852', (134, 140))	('EP300', 'Var', (62, 67))	('interact', 'Interaction', (48, 56))	('CREB', 'Gene', '1385', (37, 41))	('SETDB2', 'Gene', (134, 140))	('CREB', 'Gene', (125, 129))	('CREB', 'Gene', '1385', (125, 129))	('CREB', 'Gene', (37, 41))
202346	33846793	Reciprocal co-IP experiments revealed that deletion of the bZIP or CBP/300-HAT domain completely abolished the interaction between CREB and EP300, suggesting that these two domains are essential for the CREB-EP300 interaction (Fig.	('deletion', 'Var', (43, 51))	('bZIP', 'Gene', (59, 63))	('CREB', 'Gene', (203, 207))	('abolished', 'NegReg', (97, 106))	('CREB', 'Gene', '1385', (203, 207))	('interaction', 'Interaction', (111, 122))	('CREB', 'Gene', (131, 135))	('CBP/', 'Gene', '1387', (67, 71))	('CBP/', 'Gene', (67, 71))	('CREB', 'Gene', '1385', (131, 135))
202350	33846793	Furthermore, it was observed that ectopically expressed CREB or EP300 increased the H3K27Ac levels, and stimulated the enrichment of CREB and EP300 around the CREB motif in the GPX4 promoter, whereas these effects could be blocked by deletion of the bZIP domain and CBP/p300-HAT domain, respectively (Fig.	('CREB', 'Gene', '1385', (56, 60))	('CREB', 'Gene', (133, 137))	('stimulated', 'PosReg', (104, 114))	('GPX4', 'Gene', '2879', (177, 181))	('EP300', 'Var', (142, 147))	('increased', 'PosReg', (70, 79))	('enrichment', 'MPA', (119, 129))	('CREB', 'Gene', '1385', (133, 137))	('CREB', 'Gene', (159, 163))	('CREB', 'Gene', (56, 60))	('H3K27Ac', 'Protein', (84, 91))	('EP300', 'Var', (64, 69))	('GPX4', 'Gene', (177, 181))	('CREB', 'Gene', '1385', (159, 163))
202352	33846793	It was determined that CREB could reverse the erastin-induced decrease in cell viability and the MDA increase; however, these effects were abolished by further knocking down EP300 (Fig.	('CREB', 'Gene', '1385', (23, 27))	('EP300', 'Gene', (174, 179))	('MDA', 'Chemical', 'MESH:D008315', (97, 100))	('increase', 'PosReg', (101, 109))	('MDA', 'CPA', (97, 100))	('knocking down', 'Var', (160, 173))	('erastin', 'Chemical', 'MESH:C477224', (46, 53))	('decrease', 'NegReg', (62, 70))	('cell viability', 'CPA', (74, 88))	('CREB', 'Gene', (23, 27))
202353	33846793	Collectively, these data demonstrated that EP300 was essential and had a promoting role in CREB-induced GPX4 transcription.	('CREB', 'Gene', (91, 95))	('promoting', 'PosReg', (73, 82))	('CREB', 'Gene', '1385', (91, 95))	('GPX4', 'Gene', (104, 108))	('GPX4', 'Gene', '2879', (104, 108))	('EP300', 'Var', (43, 48))	('transcription', 'MPA', (109, 122))
202354	33846793	Other paired LUAD tissues were selected to investigate the correlation among CREB, GPX4, EP300 and 4-HNE, a reactive breakdown product of the lipid peroxides that execute ferroptosis.	('CREB', 'Gene', (77, 81))	('lipid peroxides', 'Chemical', 'MESH:D008054', (142, 157))	('CREB', 'Gene', '1385', (77, 81))	('GPX4', 'Gene', (83, 87))	('GPX4', 'Gene', '2879', (83, 87))	('LUAD', 'Phenotype', 'HP:0030078', (13, 17))	('EP300', 'Var', (89, 94))	('4-HNE', 'Chemical', '-', (99, 104))
202355	33846793	It was observed that the mRNA levels of CREB, GPX4, and EP300 were significantly higher in the tumor tissues than in the normal tissues, while the level of 4-HNE was significantly higher in the normal tissues than in the tumor tissues (Fig.	('CREB', 'Gene', '1385', (40, 44))	('EP300', 'Var', (56, 61))	('higher', 'PosReg', (81, 87))	('tumor', 'Disease', (221, 226))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Disease', 'MESH:D009369', (221, 226))	('4-HNE', 'Chemical', '-', (156, 161))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('GPX4', 'Gene', (46, 50))	('CREB', 'Gene', (40, 44))	('GPX4', 'Gene', '2879', (46, 50))	('higher', 'PosReg', (180, 186))	('tumor', 'Disease', (95, 100))	('mRNA levels', 'MPA', (25, 36))
202356	33846793	In addition, the level of 4-HNE was negatively associated with the CREB, EP300 and GPX4 levels, whereas significant positive correlations were observed between GPX4 and CREB, EP300 and CREB, and EP300 and GPX4 (Fig.	('EP300', 'Var', (195, 200))	('CREB', 'Gene', '1385', (169, 173))	('CREB', 'Gene', '1385', (67, 71))	('CREB', 'Gene', (185, 189))	('GPX4', 'Gene', (83, 87))	('GPX4', 'Gene', '2879', (83, 87))	('GPX4', 'Gene', '2879', (160, 164))	('4-HNE', 'Chemical', '-', (26, 31))	('GPX4', 'Gene', (205, 209))	('GPX4', 'Gene', (160, 164))	('negatively', 'NegReg', (36, 46))	('CREB', 'Gene', '1385', (185, 189))	('CREB', 'Gene', (169, 173))	('GPX4', 'Gene', '2879', (205, 209))	('CREB', 'Gene', (67, 71))	('EP300', 'MPA', (73, 78))
202358	33846793	Furthermore, high expression of CREB was significantly associated with poor prognosis in 52 LUAD patients (P=0.008) (Fig.	('CREB', 'Gene', '1385', (32, 36))	('LUAD', 'Phenotype', 'HP:0030078', (92, 96))	('high', 'Var', (13, 17))	('CREB', 'Gene', (32, 36))	('patients', 'Species', '9606', (97, 105))
202360	33846793	6M and N), whereas high CREB, GPX4 and EP300 levels were associated with more advanced tumor stages and larger tumor diameters (Tables I and II).	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('high', 'Var', (19, 23))	('EP300', 'MPA', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('GPX4', 'Gene', (30, 34))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('GPX4', 'Gene', '2879', (30, 34))	('tumor', 'Disease', (87, 92))	('CREB', 'Gene', (24, 28))	('tumor', 'Disease', (111, 116))	('CREB', 'Gene', '1385', (24, 28))	('tumor', 'Disease', 'MESH:D009369', (87, 92))
202361	33846793	It was also revealed that high levels of CREB, GPX4 and EP300 were associated with advanced N factors (Table II).	('GPX4', 'Gene', (47, 51))	('GPX4', 'Gene', '2879', (47, 51))	('CREB', 'Gene', (41, 45))	('EP300', 'Var', (56, 61))	('advanced N factors', 'Disease', (83, 101))	('CREB', 'Gene', '1385', (41, 45))	('associated', 'Reg', (67, 77))
202363	33846793	Collectively, CREB, GPX4, EP300 and 4-HNE, which are related to lipid peroxidation, were closely related to tumor size and stage, and the tumors with a high degree of malignancy were more likely to have a low degree of lipid peroxidation.	('tumor', 'Disease', (138, 143))	('lipid', 'Chemical', 'MESH:D008055', (219, 224))	('tumor', 'Disease', (108, 113))	('tumors', 'Disease', 'MESH:D009369', (138, 144))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('CREB', 'Gene', (14, 18))	('4-HNE', 'Chemical', '-', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('low', 'MPA', (205, 208))	('CREB', 'Gene', '1385', (14, 18))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('malignancy', 'Disease', 'MESH:D009369', (167, 177))	('related', 'Reg', (97, 104))	('lipid', 'Chemical', 'MESH:D008055', (64, 69))	('GPX4', 'Gene', (20, 24))	('GPX4', 'Gene', '2879', (20, 24))	('tumors', 'Disease', (138, 144))	('EP300', 'Var', (26, 31))	('malignancy', 'Disease', (167, 177))
202366	33846793	For instance, in NSCLC, loss of serine/threonine kinase 11 (LKB1) induced CREB-regulated transcription coactivator (CRTC)-CREB complex activation; the increased enrichment of the CRTC-CREB complex was revealed in the promoter region of LINC00473, and this LINC00473 was essential for the NSCLC cell growth and survival.	('loss', 'Var', (24, 28))	('NSCLC', 'Disease', (17, 22))	('LINC00473', 'Gene', '90632', (236, 245))	('CREB', 'Gene', '1385', (74, 78))	('CREB', 'Gene', '1385', (122, 126))	('NSCLC', 'Phenotype', 'HP:0030358', (288, 293))	('LINC00473', 'Gene', (236, 245))	('NSCLC', 'Phenotype', 'HP:0030358', (17, 22))	('LKB1', 'Gene', (60, 64))	('CREB', 'Gene', '1385', (184, 188))	('serine/threonine kinase 11', 'Gene', (32, 58))	('activation', 'PosReg', (135, 145))	('LINC00473', 'Gene', '90632', (256, 265))	('LINC00473', 'Gene', (256, 265))	('LKB1', 'Gene', '6794', (60, 64))	('CREB', 'Gene', (74, 78))	('CREB', 'Gene', (122, 126))	('NSCLC', 'Disease', 'MESH:D002289', (288, 293))	('NSCLC', 'Disease', 'MESH:D002289', (17, 22))	('serine/threonine kinase 11', 'Gene', '6794', (32, 58))	('CREB', 'Gene', (184, 188))	('NSCLC', 'Disease', (288, 293))
202373	33846793	The CBP/p300-HAT domain was revealed to be critical for the interaction of EP300 with histones or the transcription factor AP-2 alpha (TFAP2A).	('histones', 'Protein', (86, 94))	('AP-2 alpha', 'Gene', (123, 133))	('TFAP2A', 'Gene', (135, 141))	('EP300', 'Var', (75, 80))	('interaction', 'Interaction', (60, 71))	('TFAP2A', 'Gene', '7020', (135, 141))	('AP-2 alpha', 'Gene', '7020', (123, 133))
202385	33846793	In the present study, it was observed that knockdown of CREB caused ferroptotic-like effects in LUAD cells by inhibiting GPX4 transcription.	('CREB', 'Gene', '1385', (56, 60))	('ferroptotic-like effects', 'CPA', (68, 92))	('LUAD', 'Phenotype', 'HP:0030078', (96, 100))	('knockdown', 'Var', (43, 52))	('GPX4', 'Gene', (121, 125))	('inhibiting', 'NegReg', (110, 120))	('GPX4', 'Gene', '2879', (121, 125))	('CREB', 'Gene', (56, 60))
202386	33846793	Therefore, in the future, a combination of drug treatment and gene knockout to inhibit both system XC- and GPX4 may produce improved therapeutic effects for cancer treatment.	('inhibit', 'NegReg', (79, 86))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('gene knockout', 'Var', (62, 75))	('improved', 'PosReg', (124, 132))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('GPX4', 'Gene', (107, 111))	('GPX4', 'Gene', '2879', (107, 111))	('cancer', 'Disease', (157, 163))
202396	32266176	Thus, a high expression level of CIP2A was associated with shorter survival.	('high', 'Var', (8, 12))	('shorter', 'NegReg', (59, 66))	('CIP2A', 'Gene', (33, 38))	('expression level', 'MPA', (13, 29))	('CIP2A', 'Gene', '57650', (33, 38))
202412	32266176	These include mutation analysis, examination of HNSCC cancer locoregional diversity, and investigation of radio/chemosensitivity mechanisms.	('HNSCC cancer', 'Disease', (48, 60))	('mutation analysis', 'Var', (14, 31))	('SCC', 'Phenotype', 'HP:0002860', (50, 53))	('HNSCC cancer', 'Disease', 'MESH:D000077195', (48, 60))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
202439	32266176	There is, however, considerable evidence that the disturbance of this harmony, including the activation of protein kinases and phosphatase inhibition, contributes to the source and development of several diseases, including cancer.	('activation', 'PosReg', (93, 103))	('diseases', 'Disease', (204, 212))	('inhibition', 'NegReg', (139, 149))	('contributes', 'Reg', (151, 162))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('protein', 'Enzyme', (107, 114))	('cancer', 'Disease', 'MESH:D009369', (224, 230))	('phosphatase', 'MPA', (127, 138))	('cancer', 'Disease', (224, 230))	('disturbance', 'Var', (50, 61))
202457	32266176	Based on our current study and previous ones by others, the therapeutic targeting of CIP2A could promote a new therapeutic strategy in the management of OSCC and other malignancies.	('OSCC', 'Disease', (153, 157))	('CIP2A', 'Gene', '57650', (85, 90))	('malignancies', 'Disease', 'MESH:D009369', (168, 180))	('SCC', 'Phenotype', 'HP:0002860', (154, 157))	('malignancies', 'Disease', (168, 180))	('therapeutic targeting', 'Var', (60, 81))	('CIP2A', 'Gene', (85, 90))
202590	30761248	The cellular ratio F340/380 was increased by exposing the cells to sequential heat stimulation (44  C and 53  C, which is the putative activation temperature threshold for TRPV-1 and 2, respectively) 3, 6.	('cellular', 'MPA', (4, 12))	('rat', 'Species', '10116', (13, 16))	('increased', 'PosReg', (32, 41))	('TRPV-1 and 2', 'Gene', '7442;51393', (172, 184))	('rat', 'Species', '10116', (151, 154))	('F340/380', 'Var', (19, 27))
202595	30761248	3B, ratio F340/380 was enhanced by the application of capsaicin in a dose-dependent manner (capsaicin doses over 50 mum obtained similar effects to that of 50 mum, data not shown).	('enhanced', 'PosReg', (23, 31))	('F340/380', 'Var', (10, 18))	('capsaicin', 'Chemical', 'MESH:D002211', (54, 63))	('capsaicin', 'Chemical', 'MESH:D002211', (92, 101))	('rat', 'Species', '10116', (4, 7))
202605	30761248	S1B, [Ca2 +]i was elevated markedly in response to 20 mum capsaicin (P < 0.001 to [Ca2 +]i control) and the elevation was inhibited significantly by AMG9810 (10 nm) (P < 0.001 to [Ca2 +]i capsaicin), indicating that the oscillation of [Ca2 +]i was modulated by TRPV1.	('Ca2 +', 'Chemical', 'MESH:D000069285', (83, 88))	('capsaicin', 'Chemical', 'MESH:D002211', (188, 197))	('capsaicin', 'Chemical', 'MESH:D002211', (58, 67))	('Ca2 +', 'Chemical', 'MESH:D000069285', (180, 185))	('inhibited', 'NegReg', (122, 131))	('[Ca2 +]i', 'MPA', (5, 13))	('AMG9810', 'Chemical', 'MESH:C500530', (149, 156))	('Ca2 +', 'Chemical', 'MESH:D000069285', (236, 241))	('Ca2 +', 'Chemical', 'MESH:D000069285', (6, 11))	('elevated', 'PosReg', (18, 26))	('AMG9810', 'Var', (149, 156))
202606	30761248	A substantial rise in [Ca2 +]i (P < 0.01 to [Ca2 +]i control) was observed in the presence of O1821 (30 mum), a newly developed TRPV2 activator 43, while the rise in [Ca2 +]i was suppressed significantly by 100 mum tranilast (P < 0.01 to [Ca2 +]i O1821), suggesting that the mobilization of [Ca2 +]i was mediated by TRPV2.	('Ca2 +', 'Chemical', 'MESH:D000069285', (292, 297))	('rise', 'PosReg', (14, 18))	('Ca2 +', 'Chemical', 'MESH:D000069285', (45, 50))	('TRPV2', 'Gene', '51393', (316, 321))	('TRPV2', 'Gene', (128, 133))	('O1821', 'Var', (94, 99))	('Ca2 +', 'Chemical', 'MESH:D000069285', (23, 28))	('Ca2 +', 'Chemical', 'MESH:D000069285', (239, 244))	('TRPV2', 'Gene', '51393', (128, 133))	('[Ca2 +]i', 'MPA', (22, 30))	('Ca2 +', 'Chemical', 'MESH:D000069285', (167, 172))	('TRPV2', 'Gene', (316, 321))
202657	30761248	Notably, the TRPV2 agonist O1821 (Cayman Chemicals, Ann Arbor, Michigan, USA) is a new synthetic cannabinoid that effectively stimulates TRPV2, but does not stimulate TRPV1 or the cannabinoid receptors 43, 49.	('O1821', 'Var', (27, 32))	('stimulates', 'PosReg', (126, 136))	('TRPV2', 'Gene', (13, 18))	('cannabinoid', 'Chemical', 'MESH:D002186', (97, 108))	('TRPV2', 'Gene', (137, 142))	('cannabinoid', 'Chemical', 'MESH:D002186', (180, 191))	('TRPV2', 'Gene', '51393', (13, 18))	('TRPV2', 'Gene', '51393', (137, 142))
202668	30761248	Our previous study suggested that TRPV2 acts as an important enhancer for H2O2-induced cytotoxicity in HepG2 cells 56.	('cytotoxicity', 'Disease', 'MESH:D064420', (87, 99))	('H2O2-induced', 'Var', (74, 86))	('H2O2', 'Chemical', 'MESH:D006861', (74, 78))	('TRPV2', 'Gene', (34, 39))	('cytotoxicity', 'Disease', (87, 99))	('enhancer', 'PosReg', (61, 69))	('HepG2', 'CellLine', 'CVCL:0027', (103, 108))	('TRPV2', 'Gene', '51393', (34, 39))
202680	30761248	Moreover, proliferation of Eca109 cells was promoted markedly by repeatedly brief heat stimulation (44  C) and this effect was inhibited significantly by AMG9810, which further confirmed that the activation of TRPV1 could promote the proliferation of ESCC cells (Fig.	('proliferation', 'CPA', (234, 247))	('promoted', 'PosReg', (44, 52))	('proliferation', 'CPA', (10, 23))	('AMG9810', 'Chemical', 'MESH:C500530', (154, 161))	('activation', 'Var', (196, 206))	('promote', 'PosReg', (222, 229))	('ESCC', 'Disease', (251, 255))	('rat', 'Species', '10116', (17, 20))	('rat', 'Species', '10116', (241, 244))	('TRPV1', 'Gene', (210, 215))
202691	30761248	Previous in vivo work reported that sensory neurons did not exhibit osmosensitive inward currents and the activation of peripheral osmoreceptors was abolished by knockout of TRPV4 62, revealing that TRPV4 is the key channel responding to osmotic stimuli, thus further supporting the notion that overactivation of TRPV4 plays a pro-migration role in ESCC cells.	('overactivation', 'PosReg', (295, 309))	('ESCC', 'Disease', (349, 353))	('TRPV4 62', 'Gene', (174, 182))	('rat', 'Species', '10116', (334, 337))	('knockout', 'Var', (162, 170))
202796	28963353	Somatic super-enhancer duplications and hotspot mutations lead to oncogenic activation of the KLF5 transcription factor The Kruppel-like family of transcription factors (KLF) plays critical roles in human development and is associated with cancer pathogenesis.	('duplications', 'Var', (23, 35))	('human', 'Species', '9606', (199, 204))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('KLF5', 'Gene', (94, 98))	('KLF5', 'Gene', '688', (94, 98))	('associated', 'Reg', (224, 234))	('cancer', 'Disease', 'MESH:D009369', (240, 246))	('cancer', 'Disease', (240, 246))	('activation', 'PosReg', (76, 86))	('mutations', 'Var', (48, 57))
202799	28963353	Here we show that these alterations activate KLF5 by three distinct mechanisms.	('alterations', 'Var', (24, 35))	('KLF5', 'Gene', (45, 49))	('KLF5', 'Gene', '688', (45, 49))	('activate', 'PosReg', (36, 44))
202801	28963353	2) Missense mutations disrupt KLF5-FBXW7 interactions to increase KLF5 protein stability in colorectal cancer.	('KLF5', 'Gene', '688', (30, 34))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('KLF5', 'Gene', (66, 70))	('KLF5', 'Gene', '688', (66, 70))	('interactions', 'Interaction', (41, 53))	('FBXW7', 'Gene', '55294', (35, 40))	('colorectal cancer', 'Disease', 'MESH:D015179', (92, 109))	('disrupt', 'NegReg', (22, 29))	('increase', 'PosReg', (57, 65))	('colorectal cancer', 'Phenotype', 'HP:0003003', (92, 109))	('FBXW7', 'Gene', (35, 40))	('KLF5', 'Gene', (30, 34))	('Missense mutations', 'Var', (3, 21))	('colorectal cancer', 'Disease', (92, 109))
202802	28963353	3) Cancer type-specific hotspot mutations within a zinc-finger DNA binding domain of KLF5 change its DNA binding specificity and reshape cellular transcription.	('DNA', 'MPA', (101, 104))	('KLF5', 'Gene', (85, 89))	('KLF5', 'Gene', '688', (85, 89))	('Cancer', 'Disease', (3, 9))	('change', 'Reg', (90, 96))	('Cancer', 'Disease', 'MESH:D009369', (3, 9))	('cellular transcription', 'MPA', (137, 159))	('mutations', 'Var', (32, 41))	('Cancer', 'Phenotype', 'HP:0002664', (3, 9))	('reshape', 'Reg', (129, 136))
202805	28963353	For example, somatic structural variations such as copy number amplifications increase gene dosage of MYC, MYCN, AR, MITF and SOX2 and upregulate their expression; chromosomal translocations can place regulatory elements such as enhancers or super-enhancers adjacent to oncogenes and activate their expression, as observed with MYC, MYB and ERG; while amplification of noncoding super-enhancers are known to activate MYC.	('MYC', 'Gene', (107, 110))	('gene dosage', 'MPA', (87, 98))	('ERG', 'Gene', '2078', (341, 344))	('MYC', 'Gene', '4609', (102, 105))	('increase', 'PosReg', (78, 86))	('MYC', 'Gene', (328, 331))	('MYC', 'Gene', '4609', (417, 420))	('MYB', 'Gene', '4602', (333, 336))	('MYCN', 'Gene', (107, 111))	('amplifications', 'Var', (63, 77))	('MYB', 'Gene', (333, 336))	('variations', 'Var', (32, 42))	('MITF', 'Gene', '4286', (117, 121))	('expression', 'MPA', (152, 162))	('MYC', 'Gene', '4609', (107, 110))	('MYC', 'Gene', '4609', (328, 331))	('chromosomal translocations', 'Var', (164, 190))	('MITF', 'Gene', (117, 121))	('SOX2', 'Gene', '6657', (126, 130))	('SOX2', 'Gene', (126, 130))	('MYC', 'Gene', (102, 105))	('copy number amplifications', 'Var', (51, 77))	('MYC', 'Gene', (417, 420))	('MYCN', 'Gene', '4613', (107, 111))	('expression', 'MPA', (299, 309))	('ERG', 'Gene', (341, 344))	('activate', 'PosReg', (284, 292))	('upregulate', 'PosReg', (135, 145))
202806	28963353	In addition, somatic single nucleotide variants (SNV) can activate oncogenic transcription factors: for example, missense mutations in the degron domains of NFE2L2 stabilize the protein by preventing its binding to the E3 ubiquitin ligase, KEAP1.	('protein', 'Protein', (178, 185))	('KEAP1', 'Gene', '9817', (240, 245))	('missense mutations', 'Var', (113, 131))	('activate', 'PosReg', (58, 66))	('NFE2L2', 'Gene', '4780', (157, 163))	('KEAP1', 'Gene', (240, 245))	('NFE2L2', 'Gene', (157, 163))	('binding', 'Interaction', (204, 211))	('stabilize', 'PosReg', (164, 173))	('preventing', 'NegReg', (189, 199))	('single nucleotide variants', 'Var', (21, 47))
202807	28963353	In noncoding regions, somatic mutations are known to increase the activity of distal enhancers or super-enhancers to activate ESR1 and TAL1 expression.	('TAL1', 'Gene', '6886', (135, 139))	('ESR1', 'Gene', (126, 130))	('expression', 'MPA', (140, 150))	('activity', 'MPA', (66, 74))	('increase', 'PosReg', (53, 61))	('activate', 'PosReg', (117, 125))	('mutations', 'Var', (30, 39))	('TAL1', 'Gene', (135, 139))	('ESR1', 'Gene', '2099', (126, 130))
202810	28963353	In addition, we have identified recurrent missense mutations in a zinc-finger DNA binding domain of KLF5 in lung adenocarcinomas and lung squamous cell carcinomas, and in a phospho-degron domain of KLF5 in colorectal carcinomas.	('carcinoma', 'Phenotype', 'HP:0030731', (152, 161))	('KLF5', 'Gene', (100, 104))	('lung adenocarcinomas and lung squamous cell carcinomas', 'Disease', 'MESH:D000077192', (108, 162))	('colorectal carcinomas', 'Disease', 'MESH:D015179', (206, 227))	('colorectal carcinomas', 'Disease', (206, 227))	('carcinomas', 'Phenotype', 'HP:0030731', (152, 162))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (138, 162))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (133, 161))	('binding', 'Interaction', (82, 89))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (108, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('carcinomas', 'Phenotype', 'HP:0030731', (118, 128))	('KLF5', 'Gene', '688', (198, 202))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (138, 161))	('KLF5', 'Gene', '688', (100, 104))	('missense mutations', 'Var', (42, 60))	('KLF5', 'Gene', (198, 202))	('carcinoma', 'Phenotype', 'HP:0030731', (217, 226))	('carcinomas', 'Phenotype', 'HP:0030731', (217, 227))
202815	28963353	In addition to its role of as a positive regulator of cancer cell proliferation, overexpression of KLF5 has been reported to promote tumorigenesis of multiple cancer types including intestinal, bladder and gastric cancers.	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('cancer', 'Disease', (159, 165))	('KLF5', 'Gene', '688', (99, 103))	('cancer', 'Disease', (214, 220))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('intestinal', 'Disease', (182, 192))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('overexpression', 'Var', (81, 95))	('KLF5', 'Gene', (99, 103))	('cancers', 'Phenotype', 'HP:0002664', (214, 221))	('bladder', 'Disease', (194, 201))	('cancer', 'Disease', (54, 60))	('gastric cancers', 'Disease', 'MESH:D013274', (206, 221))	('gastric cancers', 'Disease', (206, 221))	('tumor', 'Disease', (133, 138))	('gastric cancers', 'Phenotype', 'HP:0012126', (206, 221))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('promote', 'PosReg', (125, 132))	('cancer', 'Disease', 'MESH:D009369', (214, 220))	('tumor', 'Disease', 'MESH:D009369', (133, 138))
202819	28963353	We performed functional analysis of each of these genomic alterations to understand how they contribute to oncogenic activation of KLF5 and their effects on KLF5 gene expression, protein stability and protein function.	('protein stability', 'MPA', (179, 196))	('KLF5', 'Gene', '688', (157, 161))	('effects', 'Reg', (146, 153))	('KLF5', 'Gene', (157, 161))	('KLF5', 'Gene', (131, 135))	('KLF5', 'Gene', '688', (131, 135))	('protein function', 'MPA', (201, 217))	('activation', 'PosReg', (117, 127))	('expression', 'MPA', (167, 177))	('alterations', 'Var', (58, 69))
202820	28963353	Our results highlight a variety of somatic genome alterations that converge to enhance the levels and activity of KLF5, and thereby to reshape cellular transcriptional programs and promote cancer cell proliferation.	('KLF5', 'Gene', '688', (114, 118))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('alterations', 'Var', (50, 61))	('KLF5', 'Gene', (114, 118))	('levels', 'MPA', (91, 97))	('enhance', 'PosReg', (79, 86))	('promote', 'PosReg', (181, 188))	('cellular transcriptional programs', 'CPA', (143, 176))	('activity', 'MPA', (102, 110))	('reshape', 'Reg', (135, 142))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('cancer', 'Disease', (189, 195))
202822	28963353	We discovered recurrent amplifications of this noncoding region in six other cancer types beyond head and neck squamous cell carcinoma (15/522), including esophageal carcinomas (ESCA, 7/184), cervical squamous cell carcinomas (CESC, 14/295), lung squamous cell carcinomas (LUSC, 14/501), bladder carcinomas (BLCA, 12/408), stomach adenocarcinomas (STAD, 7/441), and colorectal adenocarcinomas (CRC, 5/615) (Figure 1A).	('carcinomas', 'Phenotype', 'HP:0030731', (296, 306))	('cervical squamous cell carcinomas', 'Disease', 'MESH:D002294', (192, 225))	('neck squamous cell carcinoma', 'Disease', (106, 134))	('amplifications', 'Var', (24, 38))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (106, 134))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('esophageal carcinomas', 'Disease', (155, 176))	('cervical squamous cell carcinomas', 'Disease', (192, 225))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (247, 270))	('carcinomas', 'Phenotype', 'HP:0030731', (336, 346))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (111, 134))	('carcinoma', 'Phenotype', 'HP:0030731', (166, 175))	('carcinoma', 'Phenotype', 'HP:0030731', (215, 224))	('bladder carcinomas', 'Phenotype', 'HP:0002862', (288, 306))	('carcinomas', 'Phenotype', 'HP:0030731', (215, 225))	('bladder carcinomas', 'Disease', 'MESH:D001749', (288, 306))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (201, 225))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (97, 134))	('lung squamous cell carcinomas', 'Disease', 'MESH:D002294', (242, 271))	('carcinoma', 'Phenotype', 'HP:0030731', (261, 270))	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('carcinomas', 'Phenotype', 'HP:0030731', (261, 271))	('colorectal adenocarcinomas', 'Disease', 'MESH:D015179', (366, 392))	('stomach adenocarcinomas', 'Disease', (323, 346))	('cancer', 'Disease', (77, 83))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (247, 271))	('carcinomas', 'Phenotype', 'HP:0030731', (166, 176))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (242, 270))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('bladder carcinomas', 'Disease', (288, 306))	('stomach adenocarcinomas', 'Disease', 'MESH:D013274', (323, 346))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (201, 224))	('lung squamous cell carcinomas', 'Disease', (242, 271))	('esophageal carcinomas', 'Phenotype', 'HP:0011459', (155, 176))	('colorectal adenocarcinomas', 'Disease', (366, 392))	('esophageal carcinomas', 'Disease', 'MESH:D004938', (155, 176))	('carcinoma', 'Phenotype', 'HP:0030731', (296, 305))
202826	28963353	Correspondingly, DNA rearrangement analysis of WGS data from three cancer cell lines with this amplification, from disparate cancer types, revealed tandem duplication of the noncoding region (Figure S1B).	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('tandem duplication', 'Var', (148, 166))	('cancer', 'Disease', (67, 73))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))
202829	28963353	Taken together, these data suggest that focal amplification of noncoding super-enhancers near the KLF5 gene is a recurrent event in multiple cancer types, particularly squamous cell carcinomas.	('focal amplification', 'Var', (40, 59))	('KLF5', 'Gene', '688', (98, 102))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (168, 192))	('squamous cell carcinomas', 'Disease', (168, 192))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (168, 191))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (168, 192))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('carcinoma', 'Phenotype', 'HP:0030731', (182, 191))	('carcinomas', 'Phenotype', 'HP:0030731', (182, 192))	('cancer', 'Disease', (141, 147))	('KLF5', 'Gene', (98, 102))
202833	28963353	We performed chromosome conformation capture (3C) assays and validated the physical interaction between the super-enhancer region and the KLF5 promoter in cells with (BICR31) or without (BICR6) the super-enhancer duplication (Figure 2C, upper panel).	('KLF5', 'Gene', (138, 142))	('KLF5', 'Gene', '688', (138, 142))	('BICR6', 'CellLine', 'CVCL:2314', (187, 192))	('BICR31', 'CellLine', 'CVCL:2312', (167, 173))	('BICR31', 'Var', (167, 173))
202836	28963353	In addition, we observed a mean of 39.7% statistically significant elevation in expression (t test: P<0.0001) of KLF5 in cancers harboring the super-enhancer amplifications, compared to tumors without the amplifications, but no significant increase of KLF12 expression (Figure S2B).	('cancers', 'Disease', (121, 128))	('elevation', 'PosReg', (67, 76))	('cancers', 'Disease', 'MESH:D009369', (121, 128))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('amplifications', 'Var', (158, 172))	('KLF12', 'Gene', (252, 257))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('tumors', 'Phenotype', 'HP:0002664', (186, 192))	('KLF5', 'Gene', (113, 117))	('tumors', 'Disease', (186, 192))	('tumors', 'Disease', 'MESH:D009369', (186, 192))	('expression', 'MPA', (80, 90))	('KLF12', 'Gene', '11278', (252, 257))	('KLF5', 'Gene', '688', (113, 117))	('cancers', 'Phenotype', 'HP:0002664', (121, 128))
202847	28963353	Further analysis revealed that the KLF5 binding sites are enriched for p300 binding and H3K27ac modifications, indicating that KLF5 binding is associated with active regulatory elements (Figure 3B).	('modifications', 'Var', (96, 109))	('KLF5', 'Gene', (35, 39))	('H3K27ac', 'Protein', (88, 95))	('KLF5', 'Gene', '688', (35, 39))	('p300', 'Gene', '2033', (71, 75))	('KLF5', 'Gene', (127, 131))	('KLF5', 'Gene', '688', (127, 131))	('p300', 'Gene', (71, 75))
202849	28963353	Annotating KLF5 binding sites in more detail, we observed that KLF5 binding sites are more prevalent in super-enhancers than in typical enhancers.	('KLF5', 'Gene', (63, 67))	('KLF5', 'Gene', '688', (63, 67))	('KLF5', 'Gene', (11, 15))	('KLF5', 'Gene', '688', (11, 15))	('prevalent', 'Reg', (91, 100))	('super-enhancers', 'Var', (104, 119))
202851	28963353	To investigate the transcriptional impact of KLF5 expression, we conducted RNA-sequencing (RNA-seq) assays in BICR31 cells with and without siRNA-mediated silencing of KLF5 (Figure S5A).	('KLF5', 'Gene', (45, 49))	('KLF5', 'Gene', (168, 172))	('KLF5', 'Gene', '688', (45, 49))	('silencing', 'Var', (155, 164))	('KLF5', 'Gene', '688', (168, 172))	('BICR31', 'CellLine', 'CVCL:2312', (110, 116))
202858	28963353	In addition to focal amplifications of noncoding super-enhancers, mutations within the KLF5 gene are also frequently found in cancer.	('mutations', 'Var', (66, 75))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('KLF5', 'Gene', (87, 91))	('KLF5', 'Gene', '688', (87, 91))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('found', 'Reg', (117, 122))
202862	28963353	Our analysis revealed that the second CPD (amino acids 301-307: PPSPPSS) is a target of missense mutations, seen mainly in colorectal adenocarcinomas (7/619; P = 5.65 x 10-30; data from) (Figures 4A and S7A).	('carcinoma', 'Phenotype', 'HP:0030731', (139, 148))	('carcinomas', 'Phenotype', 'HP:0030731', (139, 149))	('colorectal adenocarcinomas', 'Disease', 'MESH:D015179', (123, 149))	('missense mutations', 'Var', (88, 106))	('colorectal adenocarcinomas', 'Disease', (123, 149))
202863	28963353	A previous study has shown that the P301S mutation inhibits the interaction between FBXW7 and KLF5 and increases the protein stability of KLF5.	('FBXW7', 'Gene', (84, 89))	('P301S', 'Var', (36, 41))	('increases', 'PosReg', (103, 112))	('KLF5', 'Gene', (138, 142))	('inhibits', 'NegReg', (51, 59))	('protein stability', 'MPA', (117, 134))	('KLF5', 'Gene', (94, 98))	('KLF5', 'Gene', '688', (138, 142))	('KLF5', 'Gene', '688', (94, 98))	('P301S', 'Mutation', 'p.P301S', (36, 41))	('FBXW7', 'Gene', '55294', (84, 89))	('interaction', 'Interaction', (64, 75))
202864	28963353	To assess if this is a common mechanism for the hotspot mutations, we included two other mutations, S303P and P304A, and performed a cycloheximide (CHX) chase assay in the colorectal cancer cell line HCT116 to measure their effects on KLF5 protein stability.	('colorectal cancer', 'Disease', 'MESH:D015179', (172, 189))	('CHX', 'Chemical', 'MESH:D003513', (148, 151))	('S303P', 'Mutation', 'p.S303P', (100, 105))	('colorectal cancer', 'Phenotype', 'HP:0003003', (172, 189))	('S303P', 'Var', (100, 105))	('P304A', 'Var', (110, 115))	('colorectal cancer', 'Disease', (172, 189))	('KLF5', 'Gene', (235, 239))	('cycloheximide', 'Chemical', 'MESH:D003513', (133, 146))	('HCT116', 'CellLine', 'CVCL:0291', (200, 206))	('P304A', 'Mutation', 'p.P304A', (110, 115))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('KLF5', 'Gene', '688', (235, 239))
202865	28963353	We found that the three tested mutations significantly reduced degradation of KLF5 to a similar extent, compared to wild-type (WT) KLF5 (Figure 4B).	('mutations', 'Var', (31, 40))	('reduced', 'NegReg', (55, 62))	('KLF5', 'Gene', (131, 135))	('KLF5', 'Gene', '688', (131, 135))	('KLF5', 'Gene', (78, 82))	('KLF5', 'Gene', '688', (78, 82))
202866	28963353	Co-immunoprecipitation assays confirmed that the mutations impaired the interaction of KLF5 with FBXW7 (Figure 4C).	('KLF5', 'Gene', (87, 91))	('mutations', 'Var', (49, 58))	('interaction', 'Interaction', (72, 83))	('KLF5', 'Gene', '688', (87, 91))	('FBXW7', 'Gene', '55294', (97, 102))	('impaired', 'NegReg', (59, 67))	('FBXW7', 'Gene', (97, 102))
202867	28963353	Notably, the FBXW7 gene is also significantly mutated in colorectal cancers (~13%), with recurrent mutations enriched in the WD40 repeat domains required for interaction with its substrates (Figure S8A).	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('colorectal cancers', 'Disease', (57, 75))	('FBXW7', 'Gene', '55294', (13, 18))	('cancers', 'Phenotype', 'HP:0002664', (68, 75))	('FBXW7', 'Gene', (13, 18))	('mutations', 'Var', (99, 108))	('colorectal cancer', 'Phenotype', 'HP:0003003', (57, 74))	('colorectal cancers', 'Disease', 'MESH:D015179', (57, 75))
202868	28963353	None of the colorectal cancer samples harboring KLF5 hotspot mutations had mutations in FBXW7 (Figure S8B).	('colorectal cancer', 'Disease', (12, 29))	('KLF5', 'Gene', (48, 52))	('FBXW7', 'Gene', (88, 93))	('KLF5', 'Gene', '688', (48, 52))	('mutations', 'Var', (61, 70))	('colorectal cancer', 'Disease', 'MESH:D015179', (12, 29))	('mutations', 'Var', (75, 84))	('colorectal cancer', 'Phenotype', 'HP:0003003', (12, 29))	('FBXW7', 'Gene', '55294', (88, 93))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))
202869	28963353	We tested three of the most recurrent FBXW7 missense mutations, R465C, R465H and R505C, and found that they indeed impaired the interaction of FBXW7 with KLF5 (Figure 4D).	('R465C', 'Var', (64, 69))	('R505C', 'Var', (81, 86))	('FBXW7', 'Gene', '55294', (143, 148))	('FBXW7', 'Gene', '55294', (38, 43))	('impaired', 'NegReg', (115, 123))	('KLF5', 'Gene', '688', (154, 158))	('R465H', 'Var', (71, 76))	('interaction', 'Interaction', (128, 139))	('FBXW7', 'Gene', (143, 148))	('FBXW7', 'Gene', (38, 43))	('R465C', 'Mutation', 'rs867384286', (64, 69))	('R505C', 'Mutation', 'rs149680468', (81, 86))	('R465H', 'Mutation', 'rs1057519895', (71, 76))	('KLF5', 'Gene', (154, 158))
202870	28963353	While overexpression of wild-type FBXW7 in HCT116 cells decreased the protein level of KLF5, the FBXW7 mutants showed an opposite effect (Figure 4E), consistent with previous findings that FBXW7 mutations have dominant-negative effects.	('FBXW7', 'Gene', '55294', (34, 39))	('KLF5', 'Gene', (87, 91))	('FBXW7', 'Gene', '55294', (189, 194))	('mutants', 'Var', (103, 110))	('decreased', 'NegReg', (56, 65))	('FBXW7', 'Gene', (189, 194))	('FBXW7', 'Gene', (34, 39))	('FBXW7', 'Gene', '55294', (97, 102))	('KLF5', 'Gene', '688', (87, 91))	('mutations', 'Var', (195, 204))	('FBXW7', 'Gene', (97, 102))	('HCT116', 'CellLine', 'CVCL:0291', (43, 49))
202871	28963353	Taken together, we found here that hotspot mutations within either the KLF5 CPD domain or the FBXW7 WD40 repeat domains act to stabilize KLF5 levels by preventing its binding to FBXW7.	('KLF5', 'Gene', '688', (137, 141))	('FBXW7', 'Gene', '55294', (178, 183))	('preventing', 'NegReg', (152, 162))	('FBXW7', 'Gene', (94, 99))	('FBXW7', 'Gene', (178, 183))	('mutations', 'Var', (43, 52))	('FBXW7', 'Gene', '55294', (94, 99))	('KLF5', 'Gene', (137, 141))	('KLF5', 'Gene', (71, 75))	('KLF5', 'Gene', '688', (71, 75))	('binding', 'Interaction', (167, 174))
202872	28963353	An additional hotspot mutation is found in KLF5 (P = 4.26x10-63; TCGA pan-cancer dataset) within the second of three DNA-binding zinc-finger (ZNF) domains that are highly conserved within KLF family members, with significant recurrent mutations at the codons for D418 and E419 in lung adenocarcinomas (2/502) and lung squamous cell carcinomas (7/464) (Figure 5A and S7B).	('lung adenocarcinomas', 'Disease', (280, 300))	('cancer', 'Disease', (74, 80))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (318, 341))	('KLF5', 'Gene', '688', (43, 47))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('lung squamous cell carcinomas', 'Disease', 'MESH:D002294', (313, 342))	('carcinoma', 'Phenotype', 'HP:0030731', (332, 341))	('E419', 'Var', (272, 276))	('KLF5', 'Gene', (43, 47))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (280, 300))	('carcinomas', 'Phenotype', 'HP:0030731', (332, 342))	('lung squamous cell carcinomas', 'Disease', (313, 342))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (313, 341))	('D418', 'Var', (263, 267))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (318, 342))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (280, 300))	('carcinoma', 'Phenotype', 'HP:0030731', (290, 299))	('carcinomas', 'Phenotype', 'HP:0030731', (290, 300))
202873	28963353	Pan-cancer analysis identified additional hotspot mutations at these positions in cervical squamous cell carcinomas (6/272), bladder carcinomas (5/398), and stomach adenocarcinomas (1/383) (Figure 5A).	('cervical squamous cell carcinomas', 'Disease', 'MESH:D002294', (82, 115))	('bladder carcinomas', 'Disease', (125, 143))	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('Pan-cancer', 'Disease', 'MESH:C537931', (0, 10))	('cervical squamous cell carcinomas', 'Disease', (82, 115))	('carcinomas', 'Phenotype', 'HP:0030731', (170, 180))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('carcinomas', 'Phenotype', 'HP:0030731', (105, 115))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (91, 115))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('stomach adenocarcinomas', 'Disease', (157, 180))	('stomach adenocarcinomas', 'Disease', 'MESH:D013274', (157, 180))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (91, 114))	('carcinomas', 'Phenotype', 'HP:0030731', (133, 143))	('bladder carcinomas', 'Phenotype', 'HP:0002862', (125, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (170, 179))	('mutations', 'Var', (50, 59))	('Pan-cancer', 'Disease', (0, 10))	('bladder carcinomas', 'Disease', 'MESH:D001749', (125, 143))
202874	28963353	Interestingly, these mutations are cancer-type specific.	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('cancer', 'Disease', (35, 41))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('mutations', 'Var', (21, 30))
202875	28963353	For example, the E419K mutation occurs predominantly in cervical squamous cell carcinomas while the E419Q mutation is observed only in lung cancers (Figure 5A).	('carcinomas', 'Phenotype', 'HP:0030731', (79, 89))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (65, 88))	('cervical squamous cell carcinomas', 'Disease', (56, 89))	('lung cancers', 'Phenotype', 'HP:0100526', (135, 147))	('E419Q', 'Mutation', 'p.E419Q', (100, 105))	('cancers', 'Phenotype', 'HP:0002664', (140, 147))	('E419K', 'Var', (17, 22))	('lung cancers', 'Disease', (135, 147))	('cervical squamous cell carcinomas', 'Disease', 'MESH:D002294', (56, 89))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (65, 89))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('E419K', 'Mutation', 'p.E419K', (17, 22))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('lung cancers', 'Disease', 'MESH:D008175', (135, 147))	('lung cancer', 'Phenotype', 'HP:0100526', (135, 146))
202876	28963353	To assess the function of these mutations, we generated N-terminal V5-tagged versions of wild-type KLF5 and three of the most recurrent mutants, D418N, E419K and E419Q, and infected them into HEK293T cells (Figure S9A).	('KLF5', 'Gene', (99, 103))	('KLF5', 'Gene', '688', (99, 103))	('E419Q', 'Var', (162, 167))	('HEK293T', 'CellLine', 'CVCL:0063', (192, 199))	('E419Q', 'Mutation', 'p.E419Q', (162, 167))	('D418N', 'Var', (145, 150))	('D418N', 'SUBSTITUTION', 'None', (145, 150))	('E419K', 'Var', (152, 157))	('E419K', 'Mutation', 'p.E419K', (152, 157))
202877	28963353	ChIP-seq analysis of these cells revealed that the mutations in the DNA binding domain alter the DNA binding specificity of KLF5 in a mutation-specific manner (Figure 5B).	('mutations', 'Var', (51, 60))	('KLF5', 'Gene', (124, 128))	('KLF5', 'Gene', '688', (124, 128))	('alter', 'Reg', (87, 92))	('DNA', 'MPA', (97, 100))
202879	28963353	The D418N mutant, seen in lung squamous cell carcinomas and bladder carcinomas, preferentially binds to thymidine (T) at the 6th nucleotide in the DNA motif, compared to guanine (G) for wild-type KLF5 (Figure 5B).	('preferentially', 'PosReg', (80, 94))	('guanine', 'Chemical', 'MESH:D006147', (170, 177))	('bladder carcinomas', 'Phenotype', 'HP:0002862', (60, 78))	('lung squamous cell carcinomas', 'Disease', (26, 55))	('bladder carcinomas', 'Disease', 'MESH:D001749', (60, 78))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (31, 54))	('thymidine', 'Chemical', 'MESH:D013936', (104, 113))	('bladder carcinomas', 'Disease', (60, 78))	('binds', 'Interaction', (95, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (45, 54))	('KLF5', 'Gene', '688', (196, 200))	('lung squamous cell carcinomas', 'Disease', 'MESH:D002294', (26, 55))	('D418N', 'Var', (4, 9))	('D418N', 'SUBSTITUTION', 'None', (4, 9))	('carcinomas', 'Phenotype', 'HP:0030731', (45, 55))	('carcinoma', 'Phenotype', 'HP:0030731', (68, 77))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (26, 54))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (31, 55))	('carcinomas', 'Phenotype', 'HP:0030731', (68, 78))	('KLF5', 'Gene', (196, 200))
202880	28963353	In addition, the E419K mutant, seen mainly in cervical squamous cell carcinomas, binds preferentially to guanine (G) at the 5th nucleotide of the DNA motif, while the E419Q mutant, specific to lung cancers, binds preferentially to adenine (A) at the same nucleotide position, compared to cytosine (C) or thymidine (T) for wild-type KLF5 (Figure 5B).	('lung cancers', 'Disease', 'MESH:D008175', (193, 205))	('preferentially', 'PosReg', (87, 101))	('cytosine', 'Chemical', 'MESH:D003596', (288, 296))	('lung cancers', 'Disease', (193, 205))	('guanine', 'Chemical', 'MESH:D006147', (105, 112))	('preferentially', 'PosReg', (213, 227))	('lung cancer', 'Phenotype', 'HP:0100526', (193, 204))	('lung cancers', 'Phenotype', 'HP:0100526', (193, 205))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (55, 78))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('binds', 'Interaction', (81, 86))	('cervical squamous cell carcinomas', 'Disease', 'MESH:D002294', (46, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))	('cancers', 'Phenotype', 'HP:0002664', (198, 205))	('cervical squamous cell carcinomas', 'Disease', (46, 79))	('binds', 'Interaction', (207, 212))	('E419Q', 'Mutation', 'p.E419Q', (167, 172))	('E419Q', 'Var', (167, 172))	('KLF5', 'Gene', '688', (332, 336))	('carcinomas', 'Phenotype', 'HP:0030731', (69, 79))	('E419K', 'Var', (17, 22))	('adenine', 'Chemical', 'MESH:D000225', (231, 238))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (55, 79))	('thymidine', 'Chemical', 'MESH:D013936', (304, 313))	('E419K', 'Mutation', 'p.E419K', (17, 22))	('KLF5', 'Gene', (332, 336))
202881	28963353	Accordingly, KLF5 WT and mutant proteins bind to different regions of the genome (Figure 5B).	('mutant', 'Var', (25, 31))	('proteins', 'Protein', (32, 40))	('KLF5', 'Gene', (13, 17))	('KLF5', 'Gene', '688', (13, 17))	('bind', 'Interaction', (41, 45))
202882	28963353	When KLF5 binding sites are ranked by variability among HEK293T cells overexpressing different wild-type or mutant constructs, ~44%, 26% and 15% of the top 10% variable sites are preferentially bound by KLF5 D418N, E419K and E419Q, respectively (Figure 5B right panel for overview; Figure S9B for examples).	('KLF5', 'Gene', (203, 207))	('E419K', 'Var', (215, 220))	('KLF5', 'Gene', '688', (5, 9))	('KLF5', 'Gene', '688', (203, 207))	('E419K', 'Mutation', 'p.E419K', (215, 220))	('E419Q', 'Var', (225, 230))	('E419Q', 'Mutation', 'p.E419Q', (225, 230))	('KLF5', 'Gene', (5, 9))	('preferentially', 'PosReg', (179, 193))	('bound', 'Interaction', (194, 199))	('HEK293T', 'CellLine', 'CVCL:0063', (56, 63))	('D418N', 'Var', (208, 213))	('D418N', 'SUBSTITUTION', 'None', (208, 213))
202883	28963353	To study the function of mutations in the KLF5 DNA binding domain in a more physiologically relevant context, we analyzed the lung cancer-specific E419Q mutation in the lung squamous cancer cell line HCC95, which is wild-type for the KLF5 gene based on RNA sequencing results from the Cancer Cell Line Encyclopedia project.	('KLF5', 'Gene', '688', (234, 238))	('lung squamous cancer', 'Phenotype', 'HP:0030359', (169, 189))	('squamous cancer', 'Phenotype', 'HP:0002860', (174, 189))	('KLF5', 'Gene', (234, 238))	('Cancer Cell Line Encyclopedia', 'Disease', 'MESH:C538614', (285, 314))	('KLF5', 'Gene', '688', (42, 46))	('lung squamous cancer', 'Disease', (169, 189))	('lung cancer', 'Disease', (126, 137))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('KLF5', 'Gene', (42, 46))	('E419Q', 'Mutation', 'p.E419Q', (147, 152))	('E419Q', 'Var', (147, 152))	('Cancer', 'Phenotype', 'HP:0002664', (285, 291))	('Cancer Cell Line Encyclopedia', 'Disease', (285, 314))	('lung cancer', 'Disease', 'MESH:D008175', (126, 137))	('lung squamous cancer', 'Disease', 'MESH:D008175', (169, 189))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('lung cancer', 'Phenotype', 'HP:0100526', (126, 137))	('HCC95', 'CellLine', 'CVCL:5137', (200, 205))
202884	28963353	Ectopic expression and ChIP-seq analysis of V5-tagged KLF5 WT and KLF5 E419Q in HCC95 (Figure S10A-B) revealed that both wild-type and mutant KLF5 share 5,511 binding sites.	('S10A', 'SUBSTITUTION', 'None', (94, 98))	('KLF5', 'Gene', '688', (54, 58))	('KLF5', 'Gene', (66, 70))	('KLF5', 'Gene', (142, 146))	('KLF5', 'Gene', '688', (66, 70))	('KLF5', 'Gene', '688', (142, 146))	('mutant', 'Var', (135, 141))	('binding sites', 'Interaction', (159, 172))	('S10A', 'Var', (94, 98))	('KLF5', 'Gene', (54, 58))	('E419Q', 'Mutation', 'p.E419Q', (71, 76))	('E419Q', 'Var', (71, 76))	('HCC95', 'CellLine', 'CVCL:5137', (80, 85))
202885	28963353	Relative to KLF5 WT, however, KLF5 E419Q lost 483 binding sites and gained 5,611 new binding sites (Figure 5C).	('gained', 'PosReg', (68, 74))	('KLF5', 'Gene', '688', (30, 34))	('lost', 'NegReg', (41, 45))	('E419Q', 'Mutation', 'p.E419Q', (35, 40))	('binding sites', 'Interaction', (50, 63))	('E419Q', 'Var', (35, 40))	('KLF5', 'Gene', (12, 16))	('KLF5', 'Gene', '688', (12, 16))	('KLF5', 'Gene', (30, 34))	('binding', 'Interaction', (85, 92))
202886	28963353	Electrophoretic mobility shift assays (EMSAs) using fluorescently-labeled DNA probes containing the KLF5 DNA motifs with the C, T and A variants at the 5th nucleotide revealed that KLF5 E419Q had a stronger binding affinity for the A variant, compared to wild-type KLF5 (Figure S10C), consistent with our results in HCC95 cells, above (Figure 5C).	('KLF5', 'Gene', (100, 104))	('stronger', 'PosReg', (198, 206))	('binding affinity', 'Interaction', (207, 223))	('KLF5', 'Gene', '688', (181, 185))	('HCC95', 'CellLine', 'CVCL:5137', (316, 321))	('KLF5', 'Gene', (265, 269))	('KLF5', 'Gene', '688', (100, 104))	('E419Q', 'Var', (186, 191))	('KLF5', 'Gene', '688', (265, 269))	('E419Q', 'Mutation', 'p.E419Q', (186, 191))	('KLF5', 'Gene', (181, 185))	('S10C', 'Mutation', 'p.S10C', (278, 282))
202887	28963353	However, like wild-type KLF5, KLF5 E419Q also binds to DNA motifs with the C and T variants (Figure S10C), which explains the observation that KLF5 E419Q gains more binding sites across the genome, compared to KLF5 WT.	('KLF5', 'Gene', (24, 28))	('KLF5', 'Gene', '688', (143, 147))	('KLF5', 'Gene', '688', (30, 34))	('KLF5', 'Gene', (210, 214))	('binding', 'Interaction', (165, 172))	('KLF5', 'Gene', '688', (210, 214))	('KLF5', 'Gene', '688', (24, 28))	('binds', 'Interaction', (46, 51))	('E419Q', 'Var', (148, 153))	('E419Q', 'Mutation', 'p.E419Q', (35, 40))	('E419Q', 'Mutation', 'p.E419Q', (148, 153))	('gains', 'PosReg', (154, 159))	('S10C', 'Mutation', 'p.S10C', (100, 104))	('KLF5', 'Gene', (143, 147))	('KLF5', 'Gene', (30, 34))
202889	28963353	We then investigated the effect of KLF5 E419Q binding on enhancer activity.	('E419Q', 'Var', (40, 45))	('KLF5', 'Gene', (35, 39))	('E419Q', 'Mutation', 'p.E419Q', (40, 45))	('KLF5', 'Gene', '688', (35, 39))
202890	28963353	In HCC95 cells overexpressing KLF5 E419Q, the gained binding sites show enrichment of H3K27ac, compared to cells overexpressing KLF5 WT (Figure 5D).	('KLF5', 'Gene', '688', (30, 34))	('KLF5', 'Gene', (128, 132))	('KLF5', 'Gene', '688', (128, 132))	('E419Q', 'Mutation', 'p.E419Q', (35, 40))	('E419Q', 'Var', (35, 40))	('HCC95', 'CellLine', 'CVCL:5137', (3, 8))	('H3K27ac', 'Protein', (86, 93))	('binding', 'Interaction', (53, 60))	('KLF5', 'Gene', (30, 34))
202891	28963353	We next performed gene expression analysis of HCC95 cells overexpressing untagged KLF5 WT or E419Q.	('KLF5', 'Gene', '688', (82, 86))	('E419Q', 'Mutation', 'p.E419Q', (93, 98))	('E419Q', 'Var', (93, 98))	('KLF5', 'Gene', (82, 86))	('HCC95', 'CellLine', 'CVCL:5137', (46, 51))
202892	28963353	Ectopic expression of either KLF5 WT or E419Q had little effect on the expression level of the endogenous KLF5 gene, as measured by the PCR primers targeting the 3'UTR of KLF5 (Figure S10B).	('E419Q', 'Var', (40, 45))	('KLF5', 'Gene', '688', (171, 175))	('S10B', 'Var', (184, 188))	('S10B', 'SUBSTITUTION', 'None', (184, 188))	('KLF5', 'Gene', (29, 33))	('expression level', 'MPA', (71, 87))	('KLF5', 'Gene', '688', (29, 33))	('KLF5', 'Gene', '688', (106, 110))	('KLF5', 'Gene', (106, 110))	('E419Q', 'Mutation', 'p.E419Q', (40, 45))	('KLF5', 'Gene', (171, 175))
202893	28963353	By integrating the results of RNA sequencing and ChIP-seq using the BETA pipeline, we found that the binding sites gained by KLF5 E419Q are significantly associated with activation of the target genes (Figure 5E), suggesting a gene activation role for this mutant.	('E419Q', 'Mutation', 'p.E419Q', (130, 135))	('activation', 'PosReg', (170, 180))	('KLF5', 'Gene', (125, 129))	('gained', 'PosReg', (115, 121))	('KLF5', 'Gene', '688', (125, 129))	('binding', 'Interaction', (101, 108))	('E419Q', 'Var', (130, 135))
202896	28963353	The FOXE1 gene, encoding the Forkhead box protein E1, has been linked to thyroid cancer susceptibility and inherited loss-of-function mutations of FOXE1 cause cleft palate and hypothyroidism.	('cleft palate', 'Disease', (159, 171))	('hypothyroidism', 'Disease', 'MESH:D007037', (176, 190))	('hypothyroidism', 'Phenotype', 'HP:0000821', (176, 190))	('hypothyroidism', 'Disease', (176, 190))	('thyroid cancer', 'Disease', (73, 87))	('thyroid cancer', 'Phenotype', 'HP:0002890', (73, 87))	('cleft palate', 'Disease', 'MESH:D002972', (159, 171))	('linked', 'Reg', (63, 69))	('FOXE1', 'Gene', (4, 9))	('FOXE1', 'Gene', '2304', (4, 9))	('FOXE1', 'Gene', '2304', (147, 152))	('thyroid cancer', 'Disease', 'MESH:D013964', (73, 87))	('FOXE1', 'Gene', (147, 152))	('loss-of-function', 'NegReg', (117, 133))	('cleft palate', 'Phenotype', 'HP:0000175', (159, 171))	('mutations', 'Var', (134, 143))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))
202898	28963353	Similarly, the binding of KLF5 E419Q ~95 kb upstream of NAMPT created a novel super-enhancer and activated NAMPT expression (Figure 5F).	('NAMPT', 'Gene', (56, 61))	('KLF5', 'Gene', '688', (26, 30))	('NAMPT', 'Gene', (107, 112))	('NAMPT', 'Gene', '10135', (56, 61))	('super-enhancer', 'MPA', (78, 92))	('E419Q', 'Var', (31, 36))	('E419Q', 'Mutation', 'p.E419Q', (31, 36))	('KLF5', 'Gene', (26, 30))	('NAMPT', 'Gene', '10135', (107, 112))	('binding', 'Interaction', (15, 22))	('activated', 'PosReg', (97, 106))
202900	28963353	NAMPT is overexpressed in many cancer types including colorectal, breast, gastric and prostate cancers and inhibition of NAMPT has been shown to impair tumor growth, suggesting its oncogenic function.	('gastric and prostate cancers', 'Disease', 'MESH:D013274', (74, 102))	('cancers', 'Phenotype', 'HP:0002664', (95, 102))	('cancer', 'Disease', (95, 101))	('tumor', 'Disease', (152, 157))	('overexpressed', 'PosReg', (9, 22))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('cancer', 'Disease', (31, 37))	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('NAMPT', 'Gene', '10135', (121, 126))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('breast', 'Disease', (66, 72))	('colorectal', 'Disease', (54, 64))	('prostate cancers', 'Phenotype', 'HP:0012125', (86, 102))	('impair', 'NegReg', (145, 151))	('NAMPT', 'Gene', '10135', (0, 5))	('NAMPT', 'Gene', (121, 126))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('inhibition', 'Var', (107, 117))	('NAMPT', 'Gene', (0, 5))
202901	28963353	In summary, our results indicate that the KLF5 E419Q mutant gains novel binding sites, creates new super-enhancers, and activates genes implicated in tumorigenesis.	('KLF5', 'Gene', (42, 46))	('genes', 'Gene', (130, 135))	('binding', 'Interaction', (72, 79))	('KLF5', 'Gene', '688', (42, 46))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('super-enhancers', 'MPA', (99, 114))	('gains', 'PosReg', (60, 65))	('activates', 'PosReg', (120, 129))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('E419Q', 'Mutation', 'p.E419Q', (47, 52))	('tumor', 'Disease', (150, 155))	('E419Q', 'Var', (47, 52))
202903	28963353	Silencing of KLF5 using small interfering RNAs (siRNA) in the head and neck squamous cell carcinomas cell line BICR31, in which KLF5 overexpression is driven by the 13q22.1 super-enhancer amplification (Figure 2), resulted in a marked reduction of cell proliferation (Figure 6A).	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (76, 100))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (76, 99))	('head and neck squamous cell carcinomas', 'Phenotype', 'HP:0012288', (62, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('BICR31', 'CellLine', 'CVCL:2312', (111, 117))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (62, 99))	('KLF5', 'Gene', (128, 132))	('reduction', 'NegReg', (235, 244))	('KLF5', 'Gene', (13, 17))	('neck squamous cell carcinomas', 'Disease', 'MESH:D000077195', (71, 100))	('KLF5', 'Gene', '688', (128, 132))	('carcinomas', 'Phenotype', 'HP:0030731', (90, 100))	('cell proliferation', 'CPA', (248, 266))	('neck squamous cell carcinomas', 'Disease', (71, 100))	('Silencing', 'Var', (0, 9))	('KLF5', 'Gene', '688', (13, 17))
202905	28963353	The proliferation-inhibitory effect of silencing KLF5 can be partially rescued by ectopic expression of ID1 (Figure 6B), a target gene of KLF5 in head and neck squamous carcinoma cells (Figure 3E-F).	('KLF5', 'Gene', (138, 142))	('KLF5', 'Gene', (49, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (169, 178))	('KLF5', 'Gene', '688', (49, 53))	('ID1', 'Gene', (104, 107))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (160, 178))	('proliferation-inhibitory effect', 'CPA', (4, 35))	('head and neck squamous carcinoma', 'Phenotype', 'HP:0012288', (146, 178))	('KLF5', 'Gene', '688', (138, 142))	('neck squamous carcinoma', 'Disease', (155, 178))	('silencing', 'Var', (39, 48))	('neck squamous carcinoma', 'Disease', 'MESH:D000077195', (155, 178))	('ID1', 'Gene', '3397', (104, 107))
202906	28963353	We then investigated the phenotypic outcomes of mutations in KLF5.	('KLF5', 'Gene', (61, 65))	('mutations', 'Var', (48, 57))	('KLF5', 'Gene', '688', (61, 65))	('investigated', 'Reg', (8, 20))
202907	28963353	Overexpression of the KLF5 E419Q mutant identified in lung squamous carcinomas significantly increased proliferation of the lung squamous cell carcinoma cell line, HCC95, compared to KLF5 WT, in low serum media (Figure 6C), suggesting an oncogenic role for the KLF5 E419Q mutant.	('proliferation', 'CPA', (103, 116))	('KLF5', 'Gene', (261, 265))	('increased', 'PosReg', (93, 102))	('KLF5', 'Gene', (22, 26))	('KLF5', 'Gene', '688', (183, 187))	('carcinoma', 'Phenotype', 'HP:0030731', (143, 152))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (59, 77))	('E419Q', 'Var', (266, 271))	('E419Q', 'Mutation', 'p.E419Q', (266, 271))	('E419Q', 'Mutation', 'p.E419Q', (27, 32))	('KLF5', 'Gene', (183, 187))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (124, 152))	('E419Q', 'Var', (27, 32))	('lung squamous carcinomas', 'Disease', (54, 78))	('HCC95', 'CellLine', 'CVCL:5137', (164, 169))	('lung squamous carcinomas', 'Disease', 'MESH:D002294', (54, 78))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (129, 152))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (124, 152))	('lung squamous cell carcinoma', 'Disease', (124, 152))	('KLF5', 'Gene', '688', (261, 265))	('carcinoma', 'Phenotype', 'HP:0030731', (68, 77))	('carcinomas', 'Phenotype', 'HP:0030731', (68, 78))	('KLF5', 'Gene', '688', (22, 26))
202913	28963353	Here we describe the functional analysis of the altered KLF5 gene, with findings that support the concept of an oncogenic role for KLF5.	('KLF5', 'Gene', (56, 60))	('altered', 'Var', (48, 55))	('KLF5', 'Gene', (131, 135))	('KLF5', 'Gene', '688', (131, 135))	('KLF5', 'Gene', '688', (56, 60))
202914	28963353	These discoveries are based on the identification of somatic cancer genome alterations in or near the KLF5 gene.	('KLF5', 'Gene', '688', (102, 106))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('cancer', 'Disease', (61, 67))	('alterations', 'Var', (75, 86))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('KLF5', 'Gene', (102, 106))
202915	28963353	Our pan-cancer analysis showed that KLF5 is activated by multiple somatic genomic alterations including noncoding super-enhancer amplifications and coding mutations in a phospho-degron domain or a DNA binding domain (Figure 6E).	('amplifications', 'Var', (129, 143))	('cancer', 'Disease', (8, 14))	('KLF5', 'Gene', (36, 40))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('activated', 'PosReg', (44, 53))	('alterations', 'Var', (82, 93))	('coding mutations', 'Var', (148, 164))	('KLF5', 'Gene', '688', (36, 40))	('cancer', 'Disease', 'MESH:D009369', (8, 14))	('noncoding', 'Protein', (104, 113))
202917	28963353	However, the combination of the three types of alterations markedly enhances the significance of KLF5 as a candidate oncogene.	('alterations', 'Var', (47, 58))	('KLF5', 'Gene', '688', (97, 101))	('enhances', 'PosReg', (68, 76))	('KLF5', 'Gene', (97, 101))
202923	28963353	In addition to transcriptional regulation, we show that KLF5 is activated at the protein level by missense mutations.	('KLF5', 'Gene', (56, 60))	('activated', 'PosReg', (64, 73))	('missense mutations', 'Var', (98, 116))	('KLF5', 'Gene', '688', (56, 60))
202925	28963353	Studies have shown that several oncogenic proteins including CCNE1, MYC and NOTCH1 are substrates of FBXW7 and are stabilized by mutations in the FBXW7 WD40 repeat domains required for substrate recognition.	('CCNE1', 'Gene', '898', (61, 66))	('CCNE1', 'Gene', (61, 66))	('mutations', 'Var', (129, 138))	('FBXW7', 'Gene', '55294', (146, 151))	('MYC', 'Gene', '4609', (68, 71))	('FBXW7', 'Gene', '55294', (101, 106))	('FBXW7', 'Gene', (146, 151))	('NOTCH1', 'Gene', '4851', (76, 82))	('NOTCH1', 'Gene', (76, 82))	('FBXW7', 'Gene', (101, 106))	('MYC', 'Gene', (68, 71))
202926	28963353	Our studies show that KLF5 is a substrate of FBXW7 in colorectal cancers, and that mutations either in a phospho-degron domain of KLF5 or in the WD40-repeat domains of FBXW7 stabilize KLF5 protein levels by preventing the interaction of KLF5 and FBXW7.	('KLF5', 'Gene', (237, 241))	('FBXW7', 'Gene', (168, 173))	('FBXW7', 'Gene', '55294', (45, 50))	('cancers', 'Phenotype', 'HP:0002664', (65, 72))	('KLF5', 'Gene', '688', (130, 134))	('KLF5', 'Gene', (22, 26))	('interaction', 'Interaction', (222, 233))	('FBXW7', 'Gene', (246, 251))	('colorectal cancers', 'Disease', (54, 72))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('KLF5', 'Gene', '688', (184, 188))	('KLF5', 'Gene', (130, 134))	('FBXW7', 'Gene', '55294', (168, 173))	('KLF5', 'Gene', (184, 188))	('FBXW7', 'Gene', (45, 50))	('FBXW7', 'Gene', '55294', (246, 251))	('stabilize', 'PosReg', (174, 183))	('colorectal cancers', 'Disease', 'MESH:D015179', (54, 72))	('mutations', 'Var', (83, 92))	('KLF5', 'Gene', '688', (237, 241))	('preventing', 'NegReg', (207, 217))	('colorectal cancer', 'Phenotype', 'HP:0003003', (54, 71))	('KLF5', 'Gene', '688', (22, 26))
202927	28963353	The observation that no colorectal cancer samples have both KLF5 CPD mutations and coding FBXW7 mutations further supports their functional convergence.	('colorectal cancer', 'Phenotype', 'HP:0003003', (24, 41))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('colorectal cancer', 'Disease', (24, 41))	('FBXW7', 'Gene', '55294', (90, 95))	('KLF5', 'Gene', (60, 64))	('colorectal cancer', 'Disease', 'MESH:D015179', (24, 41))	('KLF5', 'Gene', '688', (60, 64))	('FBXW7', 'Gene', (90, 95))	('mutations', 'Var', (96, 105))
202931	28963353	We find that these mutations promote a change-of-function role, by altering KLF5 DNA binding specificity.	('KLF5', 'Gene', (76, 80))	('altering', 'Reg', (67, 75))	('KLF5', 'Gene', '688', (76, 80))	('mutations', 'Var', (19, 28))
202932	28963353	Our observations are consistent with recent findings reporting recurrent mutations in KLF4, another KLF family member gene, in meningiomas.	('meningiomas', 'Phenotype', 'HP:0002858', (127, 138))	('KLF4', 'Gene', '9314', (86, 90))	('meningiomas', 'Disease', 'MESH:D008577', (127, 138))	('meningiomas', 'Disease', (127, 138))	('KLF4', 'Gene', (86, 90))	('mutations', 'Var', (73, 82))
202934	28963353	Accordingly, the DNA motifs recognized by KLF5 and KLF4 mutants are different from the canonical KLF motif at the 5-6th and 9th nucleotide position, respectively.	('KLF5', 'Gene', (42, 46))	('mutants', 'Var', (56, 63))	('KLF4', 'Gene', '9314', (51, 55))	('KLF5', 'Gene', '688', (42, 46))	('KLF4', 'Gene', (51, 55))
202936	28963353	Interestingly, although KLF5 change-of-function mutations occur within a single zinc-finger domain, each mutation is highly cancer-type specific.	('KLF5', 'Gene', (24, 28))	('cancer', 'Disease', (124, 130))	('change-of-function', 'PosReg', (29, 47))	('KLF5', 'Gene', '688', (24, 28))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('mutations', 'Var', (48, 57))	('cancer', 'Disease', 'MESH:D009369', (124, 130))
202937	28963353	Moreover, different mutations guide KLF5 to recognize different DNA sequences, suggesting that individual KLF5 mutants direct unique gene expression programs to drive tumorigenesis via distinct mechanisms in the relevant tumor types.	('KLF5', 'Gene', (106, 110))	('drive', 'PosReg', (161, 166))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('tumor', 'Disease', (221, 226))	('direct', 'Reg', (119, 125))	('mutants', 'Var', (111, 118))	('gene expression programs', 'MPA', (133, 157))	('KLF5', 'Gene', (36, 40))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('KLF5', 'Gene', '688', (36, 40))	('tumor', 'Disease', (167, 172))	('tumor', 'Disease', 'MESH:D009369', (221, 226))	('KLF5', 'Gene', '688', (106, 110))
202938	28963353	We showed that the lung cancer-specific KLF5 E419Q mutant gains novel binding sites in the genome relative to wild-type KLF5 while also maintaining the binding sites of the wild-type protein.	('lung cancer', 'Phenotype', 'HP:0100526', (19, 30))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('binding sites', 'MPA', (152, 165))	('binding', 'Interaction', (70, 77))	('E419Q', 'Mutation', 'p.E419Q', (45, 50))	('E419Q', 'Var', (45, 50))	('lung cancer', 'Disease', 'MESH:D008175', (19, 30))	('KLF5', 'Gene', (40, 44))	('KLF5', 'Gene', '688', (40, 44))	('KLF5', 'Gene', '688', (120, 124))	('gains', 'PosReg', (58, 63))	('KLF5', 'Gene', (120, 124))	('lung cancer', 'Disease', (19, 30))
202939	28963353	This result contrasts with the finding of change-of-function mutations in TP53 that lead to a switch in the DNA binding specificity of TP53 toward novel binding sites while eliminating binding sites recognized by wild-type TP53.	('TP53', 'Gene', '7157', (223, 227))	('DNA binding specificity', 'MPA', (108, 131))	('TP53', 'Gene', (223, 227))	('TP53', 'Gene', '7157', (135, 139))	('mutations', 'Var', (61, 70))	('TP53', 'Gene', '7157', (74, 78))	('TP53', 'Gene', (135, 139))	('switch', 'Reg', (94, 100))	('binding sites', 'MPA', (185, 198))	('TP53', 'Gene', (74, 78))
202941	28963353	The gained binding sites of KLF5 E419Q are associated with gene activation, as evident by the increased enhancer activity at these binding sites.	('binding', 'Interaction', (11, 18))	('gained', 'PosReg', (4, 10))	('KLF5', 'Gene', (28, 32))	('KLF5', 'Gene', '688', (28, 32))	('activation', 'PosReg', (64, 74))	('E419Q', 'Mutation', 'p.E419Q', (33, 38))	('E419Q', 'Var', (33, 38))	('gene', 'MPA', (59, 63))	('increased enhancer', 'PosReg', (94, 112))
202942	28963353	Importantly, the newly acquired KLF5 E419Q binding sites also create novel super-enhancers that drive expression of cancer-associated genes such as FOXE1 and NAMPT, revealing new therapeutic targets.	('expression', 'MPA', (102, 112))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('FOXE1', 'Gene', (148, 153))	('KLF5', 'Gene', (32, 36))	('drive', 'PosReg', (96, 101))	('KLF5', 'Gene', '688', (32, 36))	('E419Q', 'Mutation', 'p.E419Q', (37, 42))	('FOXE1', 'Gene', '2304', (148, 153))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('E419Q', 'Var', (37, 42))	('NAMPT', 'Gene', '10135', (158, 163))	('NAMPT', 'Gene', (158, 163))
202943	28963353	In addition to KLF5, somatic hotspot mutations have been identified in the DNA binding domains of other transcription factors such as FOXA1 and MAX.	('FOXA1', 'Gene', '3169', (134, 139))	('mutations', 'Var', (37, 46))	('KLF5', 'Gene', (15, 19))	('KLF5', 'Gene', '688', (15, 19))	('FOXA1', 'Gene', (134, 139))
202945	28963353	This is reminiscent of the noncoding region near the MYC oncogene, where genetic variants have been associated with predisposition to multiple cancers.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('multiple cancers', 'Disease', 'MESH:D009369', (134, 150))	('multiple cancers', 'Disease', (134, 150))	('MYC', 'Gene', '4609', (53, 56))	('associated', 'Reg', (100, 110))	('cancers', 'Phenotype', 'HP:0002664', (143, 150))	('MYC', 'Gene', (53, 56))	('variants', 'Var', (81, 89))
202946	28963353	It is known that cancer risk-associated variants often target regulatory elements, modulate transcription factor binding and regulate expression of cancer-related genes.	('cancer', 'Disease', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('modulate', 'Reg', (83, 91))	('expression', 'MPA', (134, 144))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('transcription', 'Protein', (92, 105))	('cancer', 'Disease', (17, 23))	('target', 'Reg', (55, 61))	('variants', 'Var', (40, 48))	('regulatory elements', 'Protein', (62, 81))	('regulate', 'Reg', (125, 133))	('binding', 'Interaction', (113, 120))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
202947	28963353	Interestingly, some of the cancer-risk variants near KLF5, such as rs9573163 and rs9543325 that are associated with pancreatic cancer risk, are within the super-enhancer regions that we found to be amplified in squamous carcinomas.	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('rs9543325', 'Mutation', 'rs9543325', (81, 90))	('squamous carcinomas', 'Disease', (211, 230))	('KLF5', 'Gene', (53, 57))	('pancreatic cancer', 'Disease', 'MESH:D010190', (116, 133))	('rs9573163', 'Var', (67, 76))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (211, 229))	('carcinoma', 'Phenotype', 'HP:0030731', (220, 229))	('cancer', 'Disease', (127, 133))	('cancer', 'Disease', 'MESH:D009369', (27, 33))	('pancreatic cancer', 'Disease', (116, 133))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('associated', 'Reg', (100, 110))	('squamous carcinomas', 'Disease', 'MESH:D002294', (211, 230))	('carcinomas', 'Phenotype', 'HP:0030731', (220, 230))	('rs9543325', 'Var', (81, 90))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (116, 133))	('rs9573163', 'Mutation', 'rs9573163', (67, 76))	('cancer', 'Disease', (27, 33))	('KLF5', 'Gene', '688', (53, 57))
202949	28963353	In summary, we demonstrate that a single oncogenic transcription factor, KLF5, can be activated by multiple somatic genomic alterations including by the creation of noncoding structural genome variations and by hotspot missense mutations within the KLF5 coding region.	('KLF5', 'Gene', (73, 77))	('KLF5', 'Gene', '688', (73, 77))	('missense mutations', 'Var', (219, 237))	('KLF5', 'Gene', (249, 253))	('KLF5', 'Gene', '688', (249, 253))	('variations', 'Var', (193, 203))	('activated', 'PosReg', (86, 95))
202962	28963353	For clustering binding sites of KLF5 WT and mutants in HEK293T cells, we first concatenated and merged all of their binding sites identified by MACS2 and then mapped the sequencing reads to each of the merged binding sites by Bedtools.	('Bedtools', 'Chemical', '-', (226, 234))	('KLF5', 'Gene', (32, 36))	('KLF5', 'Gene', '688', (32, 36))	('mutants', 'Var', (44, 51))	('HEK293T', 'CellLine', 'CVCL:0063', (55, 62))
202963	28963353	For identifying binding sites that are specific to KLF5 WT or E419Q in the lung squamous cell carcinoma cell line HCC95, we used MACS2 and compared the ChIP-seq signal of V5-tagged KLF5 WT and E419Q by using each other as 'treatment' and 'control' for MACS2 input.	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (75, 103))	('lung squamous cell carcinoma', 'Disease', (75, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('KLF5', 'Gene', (51, 55))	('KLF5', 'Gene', '688', (181, 185))	('KLF5', 'Gene', '688', (51, 55))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (80, 103))	('E419Q', 'Mutation', 'p.E419Q', (62, 67))	('E419Q', 'Var', (62, 67))	('E419Q', 'Mutation', 'p.E419Q', (193, 198))	('E419Q', 'Var', (193, 198))	('KLF5', 'Gene', (181, 185))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (75, 103))	('HCC95', 'CellLine', 'CVCL:5137', (114, 119))
202964	28963353	For comparing the H3K27ac ChIP-seq signal between KLF5 E419Q and WT binding sites, because the difference of total sequencing reads between the ChIP-seq experiments are over 10%, we randomly subsampled the larger sample by Samtools to normalize the signal.	('H3K27ac', 'Var', (18, 25))	('E419Q', 'Mutation', 'p.E419Q', (55, 60))	('KLF5', 'Gene', (50, 54))	('E419Q', 'Var', (55, 60))	('KLF5', 'Gene', '688', (50, 54))
202965	28963353	For each cancer type, H3K27ac ChIP-seq data from multiple cell lines was merged into one dataset.	('cancer', 'Disease', (9, 15))	('H3K27ac', 'Var', (22, 29))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))
202967	28963353	To identify super-enhancers that are gained by KLF5 E419Q bindings, we used Bedtools to compare the super-enhancers called from H3K27ac ChIP-seq signal in HCC95 cells overexpressing KLF5 WT and E419Q.	('KLF5', 'Gene', (182, 186))	('KLF5', 'Gene', '688', (182, 186))	('E419Q', 'Mutation', 'p.E419Q', (52, 57))	('Bedtools', 'Chemical', '-', (76, 84))	('E419Q', 'Mutation', 'p.E419Q', (194, 199))	('KLF5', 'Gene', (47, 51))	('E419Q', 'Var', (194, 199))	('H3K27ac', 'Gene', (128, 135))	('HCC95', 'CellLine', 'CVCL:5137', (155, 160))	('KLF5', 'Gene', '688', (47, 51))
202968	28963353	We identified the super-enhancers that have > 75% region unique to cells overexpressing KLF5 E419Q and also overlap with KLF5 E419Q-specific binding sites.	('E419Q', 'Mutation', 'p.E419Q', (93, 98))	('KLF5', 'Gene', (121, 125))	('KLF5', 'Gene', '688', (121, 125))	('E419Q', 'Var', (93, 98))	('KLF5', 'Gene', (88, 92))	('KLF5', 'Gene', '688', (88, 92))	('E419Q', 'Mutation', 'p.E419Q', (126, 131))
202969	28963353	Genomic coordinates of the KLF5 E419Q-gained super-enhancers and the nearest genes are listed in Table S1.	('KLF5', 'Gene', (27, 31))	('KLF5', 'Gene', '688', (27, 31))	('E419Q-gained', 'Var', (32, 44))	('super-enhancers', 'PosReg', (45, 60))	('E419Q', 'Mutation', 'p.E419Q', (32, 37))
202976	28963353	BICR31 cells were transfected with negative control, non-targeting siRNA (siNC) or siKLF5 using Lipofectamine RNAiMAX (Thermo Scientific).	('KLF5', 'Gene', (85, 89))	('KLF5', 'Gene', '688', (85, 89))	('Lipofectamine', 'Chemical', 'MESH:C086724', (96, 109))	('BICR31', 'CellLine', 'CVCL:2312', (0, 6))	('non-targeting', 'Var', (53, 66))
202977	28963353	Preverified Silencer Select siRNAs (Thermo Scientific, Negative Control No.1 and No.2 for siNC; s2115 and s2116 for siKLF5) were used.	('KLF5', 'Gene', (118, 122))	('KLF5', 'Gene', '688', (118, 122))	('s2116', 'Var', (106, 111))
202981	28963353	We implemented a binomial null distribution with n as the total number of KLF5 mutations and p as the fraction of the primary structure of KLF5 represented by our window.	('KLF5', 'Gene', (139, 143))	('KLF5', 'Gene', (74, 78))	('KLF5', 'Gene', '688', (139, 143))	('KLF5', 'Gene', '688', (74, 78))	('mutations', 'Var', (79, 88))
202984	28963353	Quik-change mutatageneis was then performed to generate cDNA of KLF5 mutants (P301S, S303P, P304A, D418N, E419K, and E419Q) and FBXW7 mutants (R465C, R465H, and R505C).	('D418N', 'Var', (99, 104))	('D418N', 'SUBSTITUTION', 'None', (99, 104))	('E419Q', 'Mutation', 'p.E419Q', (117, 122))	('R465C', 'Var', (143, 148))	('E419Q', 'Var', (117, 122))	('R505C', 'Mutation', 'rs149680468', (161, 166))	('P304A', 'Mutation', 'p.P304A', (92, 97))	('FBXW7', 'Gene', (128, 133))	('R465H', 'Mutation', 'rs1057519895', (150, 155))	('KLF5', 'Gene', '688', (64, 68))	('P304A', 'Var', (92, 97))	('R465C', 'Mutation', 'rs867384286', (143, 148))	('R505C', 'Var', (161, 166))	('E419K', 'Var', (106, 111))	('R465H', 'Var', (150, 155))	('E419K', 'Mutation', 'p.E419K', (106, 111))	('FBXW7', 'Gene', '55294', (128, 133))	('KLF5', 'Gene', (64, 68))	('P301S', 'Var', (78, 83))	('S303P', 'Var', (85, 90))	('P301S', 'Mutation', 'p.P301S', (78, 83))	('S303P', 'Mutation', 'p.S303P', (85, 90))
202985	28963353	The KLF5 and FBXW7 (WT and mutants) cDNA were then subcloned into the overexpression vector pLenti-EF1a-PGK-puro and pLenti-EF1a-PGK-blasti, respectively, with or without the V5 tag fused to the N-terminus.	('mutants', 'Var', (27, 34))	('EF1a', 'Gene', (124, 128))	('FBXW7', 'Gene', '55294', (13, 18))	('KLF5', 'Gene', '688', (4, 8))	('FBXW7', 'Gene', (13, 18))	('EF1a', 'Gene', '1917', (124, 128))	('EF1a', 'Gene', '1917', (99, 103))	('EF1a', 'Gene', (99, 103))	('KLF5', 'Gene', (4, 8))
202989	28963353	For KLF5 WT vesus E419Q overexpression experiments, HCC95 cells infected with KLF5 WT and E419Q overexpression constructs (with or without V5-tagged) were maintained in low serum condition (RPMI-1640 media supplemented with 1% FBS) for 7 days before cell counting.	('E419Q', 'Mutation', 'p.E419Q', (18, 23))	('FBS', 'Disease', (227, 230))	('KLF5', 'Gene', '688', (4, 8))	('E419Q', 'Mutation', 'p.E419Q', (90, 95))	('E419Q', 'Var', (90, 95))	('KLF5', 'Gene', (78, 82))	('FBS', 'Disease', 'MESH:D005198', (227, 230))	('KLF5', 'Gene', '688', (78, 82))	('RPMI-1640 media', 'Chemical', '-', (190, 205))	('HCC95', 'CellLine', 'CVCL:5137', (52, 57))	('KLF5', 'Gene', (4, 8))
202991	28963353	For KLF5 WT vs. E419Q overexpression experiments, HCC95 cells infected with KLF5 WT and E419Q overexpression constructs (no-tagged, two biological replicates) were maintained in low serum condition (RPMI-1640 media supplemented with 1% FBS), which is consistent with the condition of cell proliferation assays of KLF5 E419Q overexpression, for 2 days before RNA extraction.	('KLF5', 'Gene', (313, 317))	('KLF5', 'Gene', '688', (313, 317))	('RPMI-1640 media', 'Chemical', '-', (199, 214))	('KLF5', 'Gene', '688', (4, 8))	('KLF5', 'Gene', (76, 80))	('HCC95', 'CellLine', 'CVCL:5137', (50, 55))	('FBS', 'Disease', (236, 239))	('KLF5', 'Gene', '688', (76, 80))	('E419Q', 'Mutation', 'p.E419Q', (318, 323))	('E419Q', 'Mutation', 'p.E419Q', (88, 93))	('E419Q', 'Mutation', 'p.E419Q', (16, 21))	('E419Q', 'Var', (88, 93))	('FBS', 'Disease', 'MESH:D005198', (236, 239))	('KLF5', 'Gene', (4, 8))
202997	28963353	Similarly, we perfromed BETA analysis for analyzing KLF5 E419Q-unique binding sites and genes that are regulated by KLF5 E419Q overexpression (compared to KLF5 WT) in HCC95 cells.	('genes', 'Gene', (88, 93))	('KLF5', 'Gene', (52, 56))	('binding sites', 'Interaction', (70, 83))	('E419Q', 'Mutation', 'p.E419Q', (121, 126))	('HCC95', 'CellLine', 'CVCL:5137', (167, 172))	('KLF5', 'Gene', (155, 159))	('E419Q', 'Var', (121, 126))	('KLF5', 'Gene', '688', (155, 159))	('KLF5', 'Gene', '688', (52, 56))	('overexpression', 'PosReg', (127, 141))	('E419Q', 'Mutation', 'p.E419Q', (57, 62))	('KLF5', 'Gene', (116, 120))	('KLF5', 'Gene', '688', (116, 120))
203000	28963353	HEK293T cells infected with KLF5 WT, P301S, S303P, P304A were treated with 100 ug/ml cycloheximide (CHX) for 0, 1, 2, and 3 hours before protein extraction and immunoblot analysis.	('S303P', 'Var', (44, 49))	('KLF5', 'Gene', (28, 32))	('KLF5', 'Gene', '688', (28, 32))	('P304A', 'Var', (51, 56))	('P301S', 'Mutation', 'p.P301S', (37, 42))	('S303P', 'Mutation', 'p.S303P', (44, 49))	('P304A', 'Mutation', 'p.P304A', (51, 56))	('HEK293T', 'CellLine', 'CVCL:0063', (0, 7))	('cycloheximide', 'Chemical', 'MESH:D003513', (85, 98))	('CHX', 'Chemical', 'MESH:D003513', (100, 103))	('P301S', 'Var', (37, 42))
203004	28963353	KLF5 WT and E419Q proteins were translated by using the TNT Quick Coupled Transcription/Translation System (Promega L1170).	('E419Q', 'Var', (12, 17))	('KLF5', 'Gene', (0, 4))	('KLF5', 'Gene', '688', (0, 4))	('E419Q', 'Mutation', 'p.E419Q', (12, 17))
203015	33061852	LinkedOmics and Metascape were used to predict functions of E2Fs, and in vitro experiments were performed to assess the tumorigenic role of E2F2 and E2F7.	('E2F2', 'Var', (140, 144))	('E2F7', 'Var', (149, 153))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('tumor', 'Disease', (120, 125))
203016	33061852	In silico analysis showed that E2F1/2/7/8 were significantly overexpressed in cervical cancer, findings which were confirmed at the protein level using immunohistochemistry.	('cervical cancer', 'Disease', 'MESH:D002583', (78, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cervical cancer', 'Disease', (78, 93))	('E2F1/2/7/8', 'Var', (31, 41))	('overexpressed', 'PosReg', (61, 74))
203017	33061852	Increased expression of E2F1/2/7/8 was also related to shorter overall survival (OS) and disease-free survival (DFS) in patients with cervical cancer.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('disease-free survival', 'CPA', (89, 110))	('overall', 'MPA', (63, 70))	('cervical cancer', 'Disease', (134, 149))	('cervical cancer', 'Disease', 'MESH:D002583', (134, 149))	('expression', 'MPA', (10, 20))	('shorter', 'NegReg', (55, 62))	('expression', 'Species', '29278', (10, 20))	('Increased', 'PosReg', (0, 9))	('E2F1/2/7/8', 'Var', (24, 34))	('patients', 'Species', '9606', (120, 128))
203018	33061852	Using multivariate analysis, we confirmed E2F1/2/7/8 as independent prognostic factors for shorter OS of patients with cervical cancer.	('patients', 'Species', '9606', (105, 113))	('cervical cancer', 'Disease', 'MESH:D002583', (119, 134))	('cervical cancer', 'Disease', (119, 134))	('E2F1/2/7/8', 'Var', (42, 52))	('shorter OS', 'Disease', (91, 101))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))
203019	33061852	Finally, in vitro experiments showed that E2F2 and E2F7 are involved in cell proliferation and migration and cell cycle regulation in both HPV-positive and HPV-negative cervical cancer cells.	('cell cycle regulation', 'CPA', (109, 130))	('cervical cancer', 'Disease', (169, 184))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('E2F2', 'Var', (42, 46))	('HPV', 'Species', '10566', (156, 159))	('cell proliferation', 'CPA', (72, 90))	('HPV', 'Species', '10566', (139, 142))	('migration', 'CPA', (95, 104))	('cervical cancer', 'Disease', 'MESH:D002583', (169, 184))	('E2F7', 'Var', (51, 55))	('involved', 'Reg', (60, 68))
203020	33061852	E2F1/2/7/8 may be prognostic biomarkers for survival of patients with cervical cancer.	('patients', 'Species', '9606', (56, 64))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('E2F1/2/7/8', 'Var', (0, 10))	('cervical cancer', 'Disease', (70, 85))	('cervical cancer', 'Disease', 'MESH:D002583', (70, 85))
203021	33061852	E2F2 and E2F7 are involved in cell proliferation, migration, and cell cycle in both HPV-positive and HPV-negative cervical cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('cell proliferation', 'CPA', (30, 48))	('E2F2', 'Var', (0, 4))	('E2F7', 'Var', (9, 13))	('migration', 'CPA', (50, 59))	('cell cycle', 'CPA', (65, 75))	('involved', 'Reg', (18, 26))	('HPV', 'Species', '10566', (101, 104))	('HPV', 'Species', '10566', (84, 87))	('cervical cancer', 'Disease', (114, 129))	('cervical cancer', 'Disease', 'MESH:D002583', (114, 129))
203033	33061852	Further, aberrant expression of E2F family members and their association with clinicopathological features and prognosis in patients with cancer have been demonstrated.	('cancer', 'Disease', (138, 144))	('patients', 'Species', '9606', (124, 132))	('expression', 'Species', '29278', (18, 28))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('expression', 'MPA', (18, 28))	('aberrant', 'Var', (9, 17))	('cancer', 'Disease', 'MESH:D009369', (138, 144))	('E2F family', 'Protein', (32, 42))	('association', 'Interaction', (61, 72))
203034	33061852	In this study, we used bioinformatics to broadly investigate and obtain a deeper understanding of the relationship between E2Fs and cervical cancer.	('cervical cancer', 'Disease', (132, 147))	('E2Fs', 'Var', (123, 127))	('cervical cancer', 'Disease', 'MESH:D002583', (132, 147))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))
203063	33061852	In the present study, we explored the frequency of mutations in the eight genes of the E2F family, putative copy number variation from the Genomic Identification of Significant Targets in Cancer, and mRNA expression z-scores (RNASeq V2 RSEM) with a z-score threshold of +- 1.8.	('mutations', 'Var', (51, 60))	('E2F', 'Gene', (87, 90))	('Cancer', 'Phenotype', 'HP:0002664', (188, 194))	('Cancer', 'Disease', (188, 194))	('Cancer', 'Disease', 'MESH:D009369', (188, 194))	('expression', 'Species', '29278', (205, 215))
203064	33061852	We also graphically displayed the relationships between gene mutations in E2Fs and overall survival (OS) and disease-free survival (DFS) of patients with cervical cancer using Kaplan-Meier plots.	('cervical cancer', 'Disease', (154, 169))	('cervical cancer', 'Disease', 'MESH:D002583', (154, 169))	('mutations', 'Var', (61, 70))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('E2Fs', 'Gene', (74, 78))	('patients', 'Species', '9606', (140, 148))
203081	33061852	The respective anti-E2F2 or anti-E2F7 secondary antibody (200 muL of 1:400 dilution) was then added and incubated at room temperature for 2 h protected from light, followed by three washes with PBS.	('muL', 'Gene', '4591', (62, 65))	('PBS', 'Chemical', '-', (194, 197))	('anti-E2F2', 'Var', (15, 24))	('anti-E2F7', 'Var', (28, 37))	('muL', 'Gene', (62, 65))
203114	33061852	We found that mRNA expression of E2F1/2/7/8 was significantly upregulated in cervical cancer tissues compared with that found in normal tissues (all p < 0.05), whereas no differences in mRNA levels were found for E2F3/4/5/6.	('E2F1/2/7/8', 'Var', (33, 43))	('E2F3', 'Gene', '1871', (213, 217))	('cervical cancer', 'Disease', (77, 92))	('cervical cancer', 'Disease', 'MESH:D002583', (77, 92))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('upregulated', 'PosReg', (62, 73))	('mRNA expression', 'MPA', (14, 29))	('expression', 'Species', '29278', (19, 29))	('E2F3', 'Gene', (213, 217))
203116	33061852	3, E2F1/2/7/8 were highly expressed in cervical squamous cell carcinoma tissues, with no detectable expression found in normal tissues.	('cervical squamous cell carcinoma', 'Disease', (39, 71))	('expression', 'Species', '29278', (100, 110))	('E2F1/2/7/8', 'Var', (3, 13))	('cervical squamous cell carcinoma', 'Disease', 'MESH:D002294', (39, 71))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (48, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (62, 71))
203117	33061852	Furthermore, E2F1/2/7/8 were mainly localized in the nuclei of tumor cells.	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('tumor', 'Disease', (63, 68))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('E2F1/2/7/8', 'Var', (13, 23))
203123	33061852	We found by log-rank test that increased expression of E2F1 (p = 0.001), E2F2 (p < 0.001), E2F7 (p < 0.001), and E2F8 protein (p = 0.001) was associated with significantly shorter OS compared to those in the low-expression group (Fig.	('expression', 'Species', '29278', (41, 51))	('E2F8', 'Var', (113, 117))	('expression', 'Species', '29278', (212, 222))	('increased', 'PosReg', (31, 40))	('expression', 'MPA', (41, 51))	('shorter', 'NegReg', (172, 179))	('E2F2', 'Var', (73, 77))	('protein', 'Protein', (118, 125))	('E2F1', 'Var', (55, 59))	('E2F7', 'Var', (91, 95))
203124	33061852	In terms of DFS, patients with increased E2F1 (p < 0.001), E2F2 (p < 0.001), E2F7 (p < 0.001), and E2F8 (p = 0.001) tumor expression have a poorer prognosis (Fig.	('increased', 'PosReg', (31, 40))	('E2F2', 'Var', (59, 63))	('increased E2F1', 'Phenotype', 'HP:0030269', (31, 45))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('E2F1', 'Var', (41, 45))	('E2F8', 'Var', (99, 103))	('E2F7', 'Var', (77, 81))	('patients', 'Species', '9606', (17, 25))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumor', 'Disease', (116, 121))	('expression', 'Species', '29278', (122, 132))
203126	33061852	In univariate analysis, we found that high histological grade (hazard ratio (HR) = 6.38, 95% confidence interval (CI): 2.855-14.026, p < 0.001), positivity for lymph vessel invasion, and high protein expression of E2F1 (HR = 5.141, 95% CI: 1.738-15.211, p = 0.003), E2F2 (HR = 10.668, 95% CI: 2.503-45.644, p = 0.001), E2F7 (HR = 27.611, 95% CI: 3.669-207.762, p = 0.001), and E2F8 (HR = 5.141, 95% CI: 1.738-15.211, p = 0.003) were related to shorter OS of patients with cervical squamous cell carcinoma (Additional file 2: Tables S2-S5, left table).	('E2F7', 'Var', (319, 323))	('carcinoma', 'Phenotype', 'HP:0030731', (495, 504))	('E2F1', 'Var', (214, 218))	('patients', 'Species', '9606', (458, 466))	('cervical squamous cell carcinoma', 'Disease', 'MESH:D002294', (472, 504))	('expression', 'Species', '29278', (200, 210))	('E2F8', 'Var', (377, 381))	('E2F2', 'Var', (266, 270))	('cervical squamous cell carcinoma', 'Disease', (472, 504))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (481, 504))
203127	33061852	Further, multivariate analysis showed that high protein expression levels of E2F1 (HR = 3.51, 95% CI: 1.177-10.469, p = 0.024), E2F2 (HR = 5.038, 95% CI: 1.145-22.168, p = 0.032), E2F7 (HR = 8.443, 95% CI: 1.089-65.443, p = 0.041), and E2F8 (HR = 4.393, 95% CI: 1.017-18.975, p = 0.047) were independently associated with significantly shorter OS of patients with cervical cancer (Additional file 2: Tables S2-S5, right table).	('cancer', 'Phenotype', 'HP:0002664', (373, 379))	('shorter', 'NegReg', (336, 343))	('E2F1', 'Var', (77, 81))	('expression', 'Species', '29278', (56, 66))	('E2F7', 'Var', (180, 184))	('E2F8', 'Var', (236, 240))	('patients', 'Species', '9606', (350, 358))	('E2F2', 'Var', (128, 132))	('cervical cancer', 'Disease', 'MESH:D002583', (364, 379))	('cervical cancer', 'Disease', (364, 379))
203129	33061852	We found that members of the E2F family have a high mutation rate in patients with cervical cancer (Fig.	('cervical cancer', 'Disease', 'MESH:D002583', (83, 98))	('mutation', 'Var', (52, 60))	('patients', 'Species', '9606', (69, 77))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('cervical cancer', 'Disease', (83, 98))
203130	33061852	Among 294 sequenced cervical cancer samples, genetic alterations occurred in 186 patients, indicating a mutation rate of 63%.	('patients', 'Species', '9606', (81, 89))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('cervical cancer', 'Disease', 'MESH:D002583', (20, 35))	('cervical cancer', 'Disease', (20, 35))	('occurred', 'Reg', (65, 73))	('genetic alterations', 'Var', (45, 64))
203131	33061852	E2F1, E2F3, E2F4, and E2F6 showed high mutation rates of 21, 18, 16, and 13%, respectively.	('E2F3', 'Gene', '1871', (6, 10))	('E2F4', 'Gene', (12, 16))	('E2F1', 'Var', (0, 4))	('E2F4', 'Gene', '1874', (12, 16))	('E2F6', 'Gene', '1876', (22, 26))	('E2F6', 'Gene', (22, 26))	('E2F3', 'Gene', (6, 10))
203136	33061852	Genes relevant to E2Fs in cervical cancer were particularly associated with mitotic nuclear division, DNA repair, DNA replication, microtubule organizing center organization, mRNA processing, regulation of DNA metabolic process, regulation of chromosome segregation, regulation of mitotic centrosome separation, microtubule cytoskeleton organization involved in mitosis, signal transduction by p53 class mediator protein acylation, cell cycle checkpoint, DNA conformation change, chromosomal region, spindle, nuclear membrane, nuclear body, chromatin binding, histone binding, and mismatch repair complex binding.	('histone binding', 'Protein', (560, 575))	('cervical cancer', 'Disease', 'MESH:D002583', (26, 41))	('E2Fs', 'Var', (18, 22))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('cervical cancer', 'Disease', (26, 41))	('binding', 'Interaction', (605, 612))	('p53', 'Gene', (394, 397))	('p53', 'Gene', '7157', (394, 397))	('associated', 'Reg', (60, 70))
203137	33061852	6c, d, and Table 3, nine KEGG pathways were significantly associated with genes relevant to E2Fs in cervical cancer.	('associated', 'Reg', (58, 68))	('cervical cancer', 'Disease', (100, 115))	('cervical cancer', 'Disease', 'MESH:D002583', (100, 115))	('E2Fs', 'Var', (92, 96))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))
203138	33061852	To obtain a better understanding of the correlations between these genes relevant to E2Fs in cervical cancer, we analyzed protein-protein interactions through Metascape.	('cervical cancer', 'Disease', (93, 108))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('E2Fs', 'Var', (85, 89))	('cervical cancer', 'Disease', 'MESH:D002583', (93, 108))
203140	33061852	Expression levels of E2F2 and E2F7 in cervical cancer tissues were determined by RT-qPCR.	('cervical cancer', 'Disease', 'MESH:D002583', (38, 53))	('Expression', 'Species', '29278', (0, 10))	('cervical cancer', 'Disease', (38, 53))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('E2F7', 'Var', (30, 34))
203142	33061852	Further, based on immunofluorescence assay, we found that E2F2 and E2F7 were located in the nuclei of C-33 A cells, whereas E2F2 and E2F7 located both in the nucleus and in cytoplasm of HeLa cells (Fig.	('C-33 A', 'Mutation', 'rs988383869', (102, 108))	('E2F2', 'Var', (58, 62))	('HeLa', 'CellLine', 'CVCL:0030', (186, 190))	('E2F7', 'Var', (67, 71))
203144	33061852	HeLa and C-33 A cells were transfected with sh-E2F2 and sh-E2F7.	('sh-E2F7', 'Var', (56, 63))	('sh-E2F2', 'Var', (44, 51))	('C-33 A', 'Mutation', 'rs988383869', (9, 15))	('HeLa', 'CellLine', 'CVCL:0030', (0, 4))
203145	33061852	Our findings show that expression levels of E2F2 and E2F7 in cells transfected with sh-E2F2 and sh-E2F7, were significantly decreased compared with NC HeLa and C-33 A cells (Fig.	('expression', 'Species', '29278', (23, 33))	('C-33 A', 'Mutation', 'rs988383869', (160, 166))	('decreased', 'NegReg', (124, 133))	('HeLa', 'CellLine', 'CVCL:0030', (151, 155))	('expression levels', 'MPA', (23, 40))	('sh-E2F2', 'Var', (84, 91))	('sh-E2F7', 'Var', (96, 103))
203146	33061852	Because expression of E2Fs was associated with lymph node metastasis, lymph vessel invasion, and depth of invasion of cervical stroma, we further evaluated the effect of E2Fs on tumorigenic activity of cervical cancer cells.	('tumor', 'Disease', (178, 183))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('associated', 'Reg', (31, 41))	('expression', 'Species', '29278', (8, 18))	('depth of invasion', 'CPA', (97, 114))	('cervical cancer', 'Disease', (202, 217))	('lymph node metastasis', 'CPA', (47, 68))	('cervical cancer', 'Disease', 'MESH:D002583', (202, 217))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('E2Fs', 'Var', (22, 26))	('lymph vessel invasion', 'CPA', (70, 91))
203147	33061852	First, we observed cell cycle changes through knockdown of E2F2 and E2F7 in HeLa and C-33 A cells, and determined the percentage of cells in G0/G1, S, and G2/M phase by flow cytometry.	('HeLa', 'CellLine', 'CVCL:0030', (76, 80))	('G2/M phase', 'CPA', (155, 165))	('cell cycle changes', 'CPA', (19, 37))	('E2F2', 'Var', (59, 63))	('E2F7', 'Var', (68, 72))	('C-33 A', 'Mutation', 'rs988383869', (85, 91))	('G0/G1', 'CPA', (141, 146))
203148	33061852	Compared to control groups, we found that cells in the G0/G1 phase were significantly increased in sh-E2F2- and sh-E2F7-transfected HeLa and C-33 A cells (p < 0.05).	('sh-E2F2-', 'Var', (99, 107))	('C-33 A', 'Mutation', 'rs988383869', (141, 147))	('HeLa', 'CellLine', 'CVCL:0030', (132, 136))	('increased', 'PosReg', (86, 95))	('sh-E2F7-transfected', 'Var', (112, 131))	('cells in the G0/G1 phase', 'CPA', (42, 66))
203149	33061852	Thus, E2F2 and E2F7 promote cervical cancer cell proliferation through regulating the cell cycle (Fig.	('regulating', 'Reg', (71, 81))	('cell cycle', 'CPA', (86, 96))	('E2F2', 'Var', (6, 10))	('E2F7', 'Var', (15, 19))	('promote', 'PosReg', (20, 27))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('cervical cancer', 'Disease', 'MESH:D002583', (28, 43))	('cervical cancer', 'Disease', (28, 43))
203150	33061852	Next, the inhibitory effect of E2F2 and E2F7 knockdown on cervical cancer cell growth was validated by CCK-8 analysis.	('cervical cancer', 'Disease', 'MESH:D002583', (58, 73))	('E2F7 knockdown', 'Var', (40, 54))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('E2F2', 'Var', (31, 35))	('cervical cancer', 'Disease', (58, 73))	('knockdown', 'Var', (45, 54))
203151	33061852	After E2F2 and E2F7 knockdown, we found that the number of cells in sh-E2F2- and sh-E2F7-transfected groups was significantly lower compared to that found in sh-NC-transfected HeLa and C-33 A cells (Fig.	('HeLa', 'CellLine', 'CVCL:0030', (176, 180))	('sh-E2F2-', 'Var', (68, 76))	('lower', 'NegReg', (126, 131))	('sh-E2F7-transfected', 'Var', (81, 100))	('C-33 A', 'Mutation', 'rs988383869', (185, 191))
203152	33061852	These results confirm that E2F2 and E2F7 markedly suppress proliferation of HeLa and C-33 A cells.	('HeLa', 'CellLine', 'CVCL:0030', (76, 80))	('suppress', 'NegReg', (50, 58))	('E2F2', 'Var', (27, 31))	('E2F7', 'Var', (36, 40))	('C-33 A', 'Mutation', 'rs988383869', (85, 91))	('proliferation of HeLa', 'CPA', (59, 80))
203154	33061852	We conclude that downregulation of E2F2 and E2F7 results in a decrease in visible metastases.	('E2F2', 'Var', (35, 39))	('downregulation', 'NegReg', (17, 31))	('decrease', 'NegReg', (62, 70))	('E2F7', 'Var', (44, 48))	('metastases', 'Disease', (82, 92))	('metastases', 'Disease', 'MESH:D009362', (82, 92))
203155	33061852	HeLa and C-33 A cells were cultured in serum-free medium for 5 days for spheroid formation, and we found that the diameter of tumor microspheres in sh-E2F2- and sh-E2F7-transfected HeLa and C-33 A cells was shorter than that found in the control group (Fig.	('C-33 A', 'Mutation', 'rs988383869', (9, 15))	('C-33 A', 'Mutation', 'rs988383869', (190, 196))	('diameter', 'CPA', (114, 122))	('sh-E2F2-', 'Var', (148, 156))	('HeLa', 'CellLine', 'CVCL:0030', (181, 185))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('shorter', 'NegReg', (207, 214))	('HeLa', 'CellLine', 'CVCL:0030', (0, 4))	('tumor', 'Disease', (126, 131))
203158	33061852	We also found that upregulation of E2F1/2/7/8 is an independent prognostic factor for patient OS and that genetic alterations of E2Fs were associated with poor DFS in cervical cancer, indicating that dysregulation of E2F1/2/7/8 may be associated with progression of cervical cancer.	('associated', 'Reg', (235, 245))	('cervical cancer', 'Disease', 'MESH:D002583', (266, 281))	('cervical cancer', 'Disease', (266, 281))	('cancer', 'Phenotype', 'HP:0002664', (275, 281))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('upregulation', 'PosReg', (19, 31))	('cervical cancer', 'Disease', (167, 182))	('E2Fs', 'Gene', (129, 133))	('cervical cancer', 'Disease', 'MESH:D002583', (167, 182))	('patient', 'Species', '9606', (86, 93))	('patient OS', 'Disease', (86, 96))	('genetic alterations', 'Var', (106, 125))	('dysregulation', 'Var', (200, 213))	('poor', 'NegReg', (155, 159))
203160	33061852	We discovered that E2F2 and E2F7 knockdown suppressed proliferation and migration abilities, promoted cell cycle arrest, and inhibited stemness of both HeLa and C-33 A cells in vitro, suggesting that E2F2 and E2F7 may function as oncogenes, leading to tumor progression or metastasis of HPV-positive and HPV-negative cervical cancer.	('E2F2', 'Gene', (19, 23))	('tumor', 'Disease', 'MESH:D009369', (252, 257))	('arrest', 'Disease', 'MESH:D006323', (113, 119))	('proliferation', 'CPA', (54, 67))	('cervical cancer', 'Disease', (317, 332))	('cervical cancer', 'Disease', 'MESH:D002583', (317, 332))	('HeLa', 'CellLine', 'CVCL:0030', (152, 156))	('leading to', 'Reg', (241, 251))	('E2F7', 'Gene', (28, 32))	('tumor', 'Phenotype', 'HP:0002664', (252, 257))	('HPV', 'Species', '10566', (304, 307))	('E2F2', 'Var', (200, 204))	('promoted', 'PosReg', (93, 101))	('cancer', 'Phenotype', 'HP:0002664', (326, 332))	('knockdown', 'Var', (33, 42))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (102, 119))	('metastasis', 'CPA', (273, 283))	('C-33 A', 'Mutation', 'rs988383869', (161, 167))	('E2F7', 'Var', (209, 213))	('HPV', 'Species', '10566', (287, 290))	('stemness of', 'CPA', (135, 146))	('suppressed', 'NegReg', (43, 53))	('arrest', 'Disease', (113, 119))	('inhibited', 'NegReg', (125, 134))	('tumor', 'Disease', (252, 257))
203162	33061852	Other studies have similarly reported an association between increased expression of E2Fs and high-risk clinicopathological factors in lung carcinoma, breast cancer, clear cell renal cell carcinoma, and non-muscle invasive bladder cancer.	('E2Fs', 'Var', (85, 89))	('non-muscle invasive bladder cancer', 'Disease', 'MESH:D001749', (203, 237))	('breast cancer', 'Phenotype', 'HP:0003002', (151, 164))	('increased', 'PosReg', (61, 70))	('lung carcinoma', 'Disease', 'MESH:D008175', (135, 149))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (166, 197))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (177, 197))	('bladder cancer', 'Phenotype', 'HP:0009725', (223, 237))	('breast cancer', 'Disease', 'MESH:D001943', (151, 164))	('breast cancer', 'Disease', (151, 164))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('expression', 'MPA', (71, 81))	('clear cell renal cell carcinoma', 'Disease', (166, 197))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))	('carcinoma', 'Phenotype', 'HP:0030731', (188, 197))	('invasive bladder', 'Phenotype', 'HP:0100645', (214, 230))	('lung carcinoma', 'Disease', (135, 149))	('non-muscle invasive bladder cancer', 'Disease', (203, 237))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (166, 197))	('expression', 'Species', '29278', (71, 81))
203164	33061852	demonstrated that E2F1/2/3/5/7/8 are potential biomarkers for the diagnosis of colon cancer and E2F3/4/7/8 are potential targets of precision therapy.	('colon cancer', 'Disease', (79, 91))	('E2F3', 'Gene', '1871', (96, 100))	('colon cancer', 'Phenotype', 'HP:0003003', (79, 91))	('colon cancer', 'Disease', 'MESH:D015179', (79, 91))	('E2F1/2/3/5/7/8', 'Var', (18, 32))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('E2F3', 'Gene', (96, 100))
203165	33061852	In the current study, we found that genetic mutations in E2Fs are associated with poor DFS in cervical cancer, a finding that may be accounted for by Shan et al..	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('genetic mutations', 'Var', (36, 53))	('E2Fs', 'Gene', (57, 61))	('DFS', 'MPA', (87, 90))	('cervical cancer', 'Disease', (94, 109))	('cervical cancer', 'Disease', 'MESH:D002583', (94, 109))
203166	33061852	They demonstrated that point mutations in E2F1 resulted in a failure of protein binding to retinoblastoma protein (Rb), which functions as a negative regulator of cell proliferation.	('E2F1', 'Gene', (42, 46))	('retinoblastoma', 'Phenotype', 'HP:0009919', (91, 105))	('Rb', 'Protein', (115, 117))	('point mutations', 'Var', (23, 38))	('protein', 'Protein', (72, 79))	('failure', 'NegReg', (61, 68))	('retinoblastoma', 'Disease', 'MESH:D012175', (91, 105))	('retinoblastoma', 'Disease', (91, 105))
203167	33061852	also demonstrated that alterations such as point mutations, deletions, amplifications or promoter methylation in components of the RB pathway including E2Fs often occur in human tumors.	('amplifications', 'Var', (71, 85))	('promoter', 'MPA', (89, 97))	('point mutations', 'Var', (43, 58))	('deletions', 'Var', (60, 69))	('tumors', 'Disease', (178, 184))	('RB', 'Disease', 'MESH:D012175', (131, 133))	('tumors', 'Disease', 'MESH:D009369', (178, 184))	('tumors', 'Phenotype', 'HP:0002664', (178, 184))	('human', 'Species', '9606', (172, 177))	('E2Fs', 'Gene', (152, 156))	('occur', 'Reg', (163, 168))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))
203171	33061852	Our findings showed that E2F2 and E2F7 knockdown induced cell cycle arrest in the G0/G1 phase in cervical cancer cells.	('cervical cancer', 'Disease', (97, 112))	('arrest', 'Disease', (68, 74))	('E2F2', 'Var', (25, 29))	('knockdown', 'Var', (39, 48))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (57, 74))	('induced', 'Reg', (49, 56))	('E2F7 knockdown', 'Var', (34, 48))	('arrest', 'Disease', 'MESH:D006323', (68, 74))	('cervical cancer', 'Disease', 'MESH:D002583', (97, 112))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
203172	33061852	demonstrated a tumorigenic role of E2F2 in vitro and in vivo, suggesting E2F2 is closely involved in gliomagenesis and may be a potential therapeutic target in malignant gliomas.	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('involved', 'Reg', (89, 97))	('gliomas', 'Phenotype', 'HP:0009733', (170, 177))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('E2F2', 'Var', (73, 77))	('gliomagenesis', 'Disease', 'None', (101, 114))	('tumor', 'Disease', (15, 20))	('malignant gliomas', 'Disease', (160, 177))	('malignant gliomas', 'Disease', 'MESH:D005910', (160, 177))	('gliomagenesis', 'Disease', (101, 114))
203176	33061852	It was also found that downregulation of E2F7 by miRNA-302a/d decreased proliferation of hepatocellular carcinoma cells and significantly inhibited stemness of lung cancer stem cells by targeting the E2F7/AKT/beta-catenin/CCND1 signaling pathway.	('downregulation', 'NegReg', (23, 37))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (89, 113))	('beta-catenin', 'Gene', '1499', (209, 221))	('proliferation', 'CPA', (72, 85))	('AKT', 'Gene', (205, 208))	('inhibited', 'NegReg', (138, 147))	('targeting', 'Reg', (186, 195))	('hepatocellular carcinoma', 'Disease', (89, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('CCND1', 'Gene', '595', (222, 227))	('stemness of lung cancer', 'Disease', (148, 171))	('lung cancer', 'Phenotype', 'HP:0100526', (160, 171))	('stemness of lung cancer', 'Disease', 'MESH:D008175', (148, 171))	('AKT', 'Gene', '207', (205, 208))	('E2F7', 'Gene', (41, 45))	('decreased', 'NegReg', (62, 71))	('CCND1', 'Gene', (222, 227))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (89, 113))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('miRNA-302a/d', 'Var', (49, 61))	('beta-catenin', 'Gene', (209, 221))
203177	33061852	In this study, we comprehensively explored the transcriptional expression of E2Fs in cervical cancer, finding that E2F1/2/7/8 are significantly overexpressed in this disease.	('overexpressed', 'PosReg', (144, 157))	('cervical cancer', 'Disease', 'MESH:D002583', (85, 100))	('expression', 'Species', '29278', (63, 73))	('cervical cancer', 'Disease', (85, 100))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('E2F1/2/7/8', 'Var', (115, 125))
203178	33061852	We then confirmed these findings using IHC and RT-qPCR at the protein and mRNA level, and using in vitro experiments, showed that E2F2 and E2F7 are involved in cell proliferation, migration, and cell cycle regulation in both HPV-positive and HPV-negative cervical cancer cells.	('E2F2', 'Var', (130, 134))	('migration', 'CPA', (180, 189))	('cancer', 'Phenotype', 'HP:0002664', (264, 270))	('cell cycle regulation', 'CPA', (195, 216))	('E2F7', 'Var', (139, 143))	('HPV', 'Species', '10566', (225, 228))	('HPV', 'Species', '10566', (242, 245))	('cervical cancer', 'Disease', (255, 270))	('cervical cancer', 'Disease', 'MESH:D002583', (255, 270))	('involved', 'Reg', (148, 156))	('cell proliferation', 'CPA', (160, 178))
203180	33061852	Furthermore, we showed that high expression of E2F1/2/7/8 proteins was significantly associated with shorter OS and DFS in patients with cervical cancer.	('proteins', 'Protein', (58, 66))	('E2F1/2/7/8', 'Var', (47, 57))	('DFS', 'Disease', (116, 119))	('shorter OS', 'Disease', (101, 111))	('patients', 'Species', '9606', (123, 131))	('cervical cancer', 'Disease', 'MESH:D002583', (137, 152))	('expression', 'Species', '29278', (33, 43))	('cervical cancer', 'Disease', (137, 152))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('expression', 'MPA', (33, 43))
203181	33061852	Using multivariate analysis, we also confirmed E2F1/2/7/8 as independent prognostic factors for shorter OS of patients with cervical cancer.	('shorter OS', 'Disease', (96, 106))	('E2F1/2/7/8', 'Var', (47, 57))	('cervical cancer', 'Disease', (124, 139))	('cervical cancer', 'Disease', 'MESH:D002583', (124, 139))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('patients', 'Species', '9606', (110, 118))
203182	33061852	These results indicate that E2F1, E2F2, E2F7, and E2F8 may serve as prognostic biomarkers and potential therapeutic targets for cervical cancer.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('E2F8', 'Var', (50, 54))	('E2F2', 'Var', (34, 38))	('E2F7', 'Var', (40, 44))	('E2F1', 'Var', (28, 32))	('cervical cancer', 'Disease', (128, 143))	('cervical cancer', 'Disease', 'MESH:D002583', (128, 143))
203186	32629386	Fucosyltransferase 4 shapes oncogenic glycoproteome to drive metastasis of lung adenocarcinoma Aberrant fucosylation plays a critical role in lung cancer progression.	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (75, 94))	('Fucosyltransferase 4', 'Gene', '2526', (0, 20))	('Fucosyltransferase 4', 'Gene', (0, 20))	('lung cancer', 'Disease', 'MESH:D008175', (142, 153))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('fucosylation', 'Protein', (104, 116))	('lung adenocarcinoma', 'Disease', (75, 94))	('lung cancer', 'Disease', (142, 153))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (75, 94))	('lung cancer', 'Phenotype', 'HP:0100526', (142, 153))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('Aberrant', 'Var', (95, 103))
203190	32629386	We show that FUT4 is associated with poor overall survival in lung adenocarcinoma patients.	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (62, 81))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('overall', 'MPA', (42, 49))	('poor', 'NegReg', (37, 41))	('FUT4', 'Var', (13, 17))	('patients', 'Species', '9606', (82, 90))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (62, 81))	('lung adenocarcinoma', 'Disease', (62, 81))
203193	32629386	Notably, genetic depletion of FUT4 or targeting FUT4-driven pathways diminishes lung colonization and distant metastases of lung cancer cells in mouse xenograft models.	('lung colonization', 'CPA', (80, 97))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('FUT4-driven', 'Gene', (48, 59))	('diminishes', 'NegReg', (69, 79))	('lung cancer', 'Phenotype', 'HP:0100526', (124, 135))	('mouse', 'Species', '10090', (145, 150))	('diminishes lung', 'Phenotype', 'HP:0002089', (69, 84))	('metastases of lung cancer', 'Disease', 'MESH:D008175', (110, 135))	('genetic depletion', 'Var', (9, 26))	('FUT4', 'Gene', (30, 34))	('metastases of lung cancer', 'Disease', (110, 135))
203198	32629386	While some groups found that terminal fucosyltransferases such as FUT4 or FUT7 may promote lung cancer progression via epithelial-mesenchymal transition (EMT) and epidermal growth factor receptor (EGFR) activation, others demonstrated that FUT4- or FUT6-mediated fucosylation could suppress EGFR activation thereby hindering cancer invasiveness.	('lung cancer', 'Phenotype', 'HP:0100526', (91, 102))	('suppress', 'NegReg', (282, 290))	('FUT7', 'Gene', (74, 78))	('FUT7', 'Gene', '2529', (74, 78))	('FUT4', 'Var', (66, 70))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('epidermal growth factor receptor', 'Gene', (163, 195))	('cancer invasiveness', 'Disease', (325, 344))	('cancer', 'Phenotype', 'HP:0002664', (325, 331))	('epidermal growth factor receptor', 'Gene', '1956', (163, 195))	('epithelial-mesenchymal transition', 'CPA', (119, 152))	('lung cancer', 'Disease', (91, 102))	('FUT6', 'Gene', (249, 253))	('activation', 'MPA', (296, 306))	('FUT6', 'Gene', '2528', (249, 253))	('EGFR', 'Protein', (291, 295))	('hindering', 'NegReg', (315, 324))	('cancer invasiveness', 'Disease', 'MESH:D009362', (325, 344))	('lung cancer', 'Disease', 'MESH:D008175', (91, 102))	('promote', 'PosReg', (83, 90))
203202	32629386	Our data open a new possibility in targeting FUT4 or FUT4-mediated networks such as vesicular transport or oncogenic signaling to curtail cancer metastasis and highlight the potential for integration of glycomics into precision medicine-based therapeutics.	('cancer', 'Disease', (138, 144))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('FUT4', 'Var', (45, 49))	('cancer', 'Disease', 'MESH:D009369', (138, 144))	('curtail', 'NegReg', (130, 137))
203206	32629386	Abundant evidence indicates that aberrant glycosylation plays critical roles in fundamental steps of tumor development and progression, including cell-cell/cell-matrix interactions, metastasis, cancer metabolism as well as immune surveillance.	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('cancer metabolism', 'Disease', 'MESH:D009369', (194, 211))	('glycosylation', 'MPA', (42, 55))	('aberrant glycosylation', 'Phenotype', 'HP:0012345', (33, 55))	('aberrant', 'Var', (33, 41))	('metastasis', 'CPA', (182, 192))	('cancer metabolism', 'Disease', (194, 211))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
203214	32629386	Furthermore, while some groups found that terminal fucosyltransferases such as FUT4 or FUT7 may promote lung cancer progression, another group demonstrated that FUT4- or FUT6-mediated fucosylation of epidermal growth factor receptor (EGFR) could suppress EGFR dimerization and activation.	('lung cancer', 'Disease', 'MESH:D008175', (104, 115))	('FUT6', 'Gene', (170, 174))	('EGFR', 'Gene', (234, 238))	('epidermal growth factor receptor', 'Gene', (200, 232))	('epidermal growth factor receptor', 'Gene', '1956', (200, 232))	('promote', 'PosReg', (96, 103))	('lung cancer', 'Disease', (104, 115))	('suppress', 'NegReg', (246, 254))	('activation', 'MPA', (277, 287))	('lung cancer', 'Phenotype', 'HP:0100526', (104, 115))	('dimerization', 'MPA', (260, 272))	('FUT6', 'Gene', '2528', (170, 174))	('FUT7', 'Gene', (87, 91))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('FUT7', 'Gene', '2529', (87, 91))	('EGFR', 'Protein', (255, 259))	('FUT4-', 'Var', (161, 166))
203220	32629386	Normalized RNA-seq expression datasets and EGFR mutation status of The Cancer Genome Atlas (TCGA) lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) cohorts were acquired from Firehose data repository using the R/Bioconductor package "RTCGAToolbox" (version 2.10.0, run data 2016-01-28).	('Cancer', 'Disease', (71, 77))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (129, 157))	('lung squamous cell carcinoma', 'Disease', (129, 157))	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('Cancer', 'Disease', 'MESH:D009369', (71, 77))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (98, 117))	('LUSC', 'Phenotype', 'HP:0030359', (159, 163))	('mutation', 'Var', (48, 56))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (134, 157))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (98, 117))	('LUAD', 'Phenotype', 'HP:0030078', (119, 123))	('lung adenocarcinoma', 'Disease', (98, 117))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (129, 157))	('EGFR', 'Gene', (43, 47))	('carcinoma', 'Phenotype', 'HP:0030731', (148, 157))	('Cancer', 'Phenotype', 'HP:0002664', (71, 77))
203232	32629386	Cells were incubated for 16 h and selected by fresh RPMI medium with 2 mug/mL puromycin for 24 h. The effects of shRNA knockdown will be evaluated using proliferation assays, migration assays, and invasion assays.	('puromycin', 'Chemical', 'MESH:D011691', (78, 87))	('shRNA', 'Gene', (113, 118))	('knockdown', 'Var', (119, 128))	('RPMI medium', 'Chemical', '-', (52, 63))
203246	32629386	Experiments were performed at five mice in each group (A549_Vector, A549_FUT4med, and A549_FUT4high).	('A549_FUT4med', 'Var', (68, 80))	('A549_FUT4high', 'Var', (86, 99))	('A549', 'CellLine', 'CVCL:0023', (55, 59))	('A549', 'CellLine', 'CVCL:0023', (86, 90))	('mice', 'Species', '10090', (35, 39))	('A549_Vector', 'Var', (55, 66))	('A549', 'CellLine', 'CVCL:0023', (68, 72))
203303	32629386	We found that A549_FUT4highand A549_FUT4med showed markedly increased invasion abilities through the Matrigel -coated Boyden chamber (Fig.	('A549', 'CellLine', 'CVCL:0023', (14, 18))	('A549_FUT4highand', 'Var', (14, 30))	('A549', 'CellLine', 'CVCL:0023', (31, 35))	('A549_FUT4med', 'Var', (31, 43))	('increased', 'PosReg', (60, 69))	('invasion abilities through the', 'CPA', (70, 100))
203304	32629386	Moreover, single-cell migration assays in a live-cell imaging and tracking system revealed increased migration abilities of A549_FUT4high and A549_FUT4med cells.	('migration abilities', 'CPA', (101, 120))	('A549', 'CellLine', 'CVCL:0023', (124, 128))	('A549_FUT4med cells', 'Var', (142, 160))	('A549', 'CellLine', 'CVCL:0023', (142, 146))	('increased', 'PosReg', (91, 100))	('A549_FUT4high', 'Var', (124, 137))
203307	32629386	Furthermore, to confirm whether FUT4-mediated aberrant fucosylation may lead to a stronger cell adhesion:an early step in the metastatic cascade, we performed in vitro adhesion assays with several common adhesion molecules within human tissues and blood vessels.	('stronger', 'PosReg', (82, 90))	('fucosylation', 'Protein', (55, 67))	('aberrant', 'Var', (46, 54))	('cell adhesion', 'CPA', (91, 104))	('human', 'Species', '9606', (230, 235))
203311	32629386	Marked retention of A549_FUT4high and CL1-0_FUT4 cells in the lungs was observed under a microscope as opposed to their respective vector controls (Fig.	('A549', 'CellLine', 'CVCL:0023', (20, 24))	('A549_FUT4high', 'Var', (20, 33))	('CL1', 'Gene', '9201', (38, 41))	('CL1', 'Gene', (38, 41))
203313	32629386	To substantiate the role of FUT4 on lung cancer metastasis, we investigated whether aberrant FUT4 expression led to spontaneous distant metastasis using two mouse xenograft models.	('FUT4', 'Gene', (93, 97))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('led to', 'Reg', (109, 115))	('lung cancer metastasis', 'Disease', (36, 58))	('lung cancer metastasis', 'Disease', 'MESH:D008175', (36, 58))	('mouse', 'Species', '10090', (157, 162))	('lung cancer', 'Phenotype', 'HP:0100526', (36, 47))	('aberrant', 'Var', (84, 92))
203314	32629386	In the tail vein assay for cancer metastasis in nude mice, we observed a rapid lung homing phenomenon enhanced by FUT4.	('lung homing', 'CPA', (79, 90))	('enhanced', 'PosReg', (102, 110))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('cancer', 'Disease', (27, 33))	('cancer', 'Disease', 'MESH:D009369', (27, 33))	('nude mice', 'Species', '10090', (48, 57))	('FUT4', 'Var', (114, 118))
203315	32629386	As short as one day post tail vein injection, more A549_FUT4med and A549_FUT4high tumor cells were trapped in the lung areas shown by the IVIS  Spectrum imaging system compared to A549_vector cells (Fig.	('A549', 'CellLine', 'CVCL:0023', (51, 55))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('A549', 'CellLine', 'CVCL:0023', (180, 184))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('A549_FUT4med', 'Var', (51, 63))	('tumor', 'Disease', (82, 87))	('A549', 'CellLine', 'CVCL:0023', (68, 72))	('A549_FUT4high', 'Var', (68, 81))
203316	32629386	When we sacrificed mice 28 days post-injections, we found that mice in the FUT4high group had a much greater number of metastatic lung nodules compared to those in the FUT4med and vector groups (p < 0.001) (Fig.	('FUT4high', 'Var', (75, 83))	('metastatic lung nodules', 'CPA', (119, 142))	('mice', 'Species', '10090', (63, 67))	('greater', 'PosReg', (101, 108))	('mice', 'Species', '10090', (19, 23))
203317	32629386	In the second xenograft model, we subcutaneously injected A549_FUT4med, A549_FUT4high cells, and A549_vector into NOD/SCID immunocompromised mice and evaluated spontaneous metastasis of cancer cells.	('SCID', 'Disease', (118, 122))	('A549_vector', 'Var', (97, 108))	('A549_FUT4high', 'Var', (72, 85))	('A549', 'CellLine', 'CVCL:0023', (58, 62))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('A549', 'CellLine', 'CVCL:0023', (97, 101))	('SCID', 'Disease', 'MESH:D053632', (118, 122))	('A549', 'CellLine', 'CVCL:0023', (72, 76))	('mice', 'Species', '10090', (141, 145))	('A549_FUT4med', 'Var', (58, 70))	('cancer', 'Disease', (186, 192))	('cancer', 'Disease', 'MESH:D009369', (186, 192))
203318	32629386	When mice were sacrificed 56 days post-injection, we observed that mice carrying subcutaneous tumors of A549_FUT4high cells and A549_FUT4med cells had higher frequencies of metastatic lung nodules (Fig.	('mice', 'Species', '10090', (5, 9))	('subcutaneous tumors', 'Phenotype', 'HP:0001482', (81, 100))	('A549', 'CellLine', 'CVCL:0023', (104, 108))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('A549_FUT4med cells', 'Var', (128, 146))	('A549', 'CellLine', 'CVCL:0023', (128, 132))	('A549_FUT4high cells', 'Var', (104, 123))	('subcutaneous tumor', 'Phenotype', 'HP:0001482', (81, 99))	('higher', 'PosReg', (151, 157))	('tumors', 'Disease', (94, 100))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('metastatic lung nodules', 'CPA', (173, 196))	('mice', 'Species', '10090', (67, 71))
203320	32629386	Thus, we performed a transcriptomic analysis on A549_FUT4high and CL1-0_FUT4 cells using genome-wide RNA-seq technologies (GEO: GSE120622).	('CL1', 'Gene', (66, 69))	('A549_FUT4high', 'Var', (48, 61))	('A549', 'CellLine', 'CVCL:0023', (48, 52))	('CL1', 'Gene', '9201', (66, 69))
203326	32629386	In addition, FUT4 appears to modulate pathways related to cell cycle (e.g., CDC6, CDC23, etc.	('CDC23', 'Gene', '8697', (82, 87))	('CDC6', 'Gene', '990', (76, 80))	('CDC6', 'Gene', (76, 80))	('FUT4', 'Var', (13, 17))	('modulate', 'Reg', (29, 37))	('pathways', 'Pathway', (38, 46))	('CDC23', 'Gene', (82, 87))
203328	32629386	As a functional validation to activating TGFbeta and EGF signaling in FUT4-overexpressing cells, we demonstrated that FUT4 leads to morphological changes characteristic of EMT, a phenomenon mediated by the two signaling pathways, with a prominent reorganization of the cytoskeleton toward a more mesenchymal phenotype in A549_FUT4med, A549_FUT4high and CL1-0_FUT4 cells (Fig.	('A549', 'CellLine', 'CVCL:0023', (321, 325))	('FUT4', 'Var', (118, 122))	('CL1', 'Gene', (353, 356))	('reorganization', 'PosReg', (247, 261))	('EGF', 'Gene', (53, 56))	('A549_FUT4med', 'Var', (321, 333))	('A549', 'CellLine', 'CVCL:0023', (335, 339))	('TGFbeta', 'Gene', '7039', (41, 48))	('TGFbeta', 'Gene', (41, 48))	('EGF', 'Gene', '1950', (53, 56))	('CL1', 'Gene', '9201', (353, 356))	('A549_FUT4high', 'Var', (335, 348))	('EMT', 'CPA', (172, 175))
203330	32629386	Interestingly, minimal increases of mesenchymal proteins:VIM (vimentin) and CDH2 (N-cadherin) are noted, suggesting FUT4 induces an intermediate EMT phenotype in A549 lung cancer cells (Fig.	('CDH2', 'Gene', '1000', (76, 80))	('VIM', 'Gene', '7431', (57, 60))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('lung cancer', 'Disease', (167, 178))	('vimentin', 'Gene', (62, 70))	('N-cadherin', 'Gene', (82, 92))	('FUT4', 'Var', (116, 120))	('lung cancer', 'Phenotype', 'HP:0100526', (167, 178))	('A549', 'CellLine', 'CVCL:0023', (162, 166))	('N-cadherin', 'Gene', '1000', (82, 92))	('induces', 'Reg', (121, 128))	('VIM', 'Gene', (57, 60))	('lung cancer', 'Disease', 'MESH:D008175', (167, 178))	('vimentin', 'Gene', '7431', (62, 70))	('CDH2', 'Gene', (76, 80))
203332	32629386	Consistent with cell line data, we found that high FUT4-expressing tumors displayed significantly enhanced activities in oncogenic signaling networks, including TGFbeta, EGF, MAPK, and WNT as opposed to low FUT4-expressing tumors (Fig.	('enhanced', 'PosReg', (98, 106))	('TGFbeta', 'Gene', '7039', (161, 168))	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('tumors', 'Disease', 'MESH:D009369', (67, 73))	('tumors', 'Disease', (223, 229))	('activities', 'MPA', (107, 117))	('tumors', 'Disease', 'MESH:D009369', (223, 229))	('high FUT4-expressing', 'Var', (46, 66))	('EGF', 'Gene', '1950', (170, 173))	('WNT', 'CPA', (185, 188))	('tumors', 'Phenotype', 'HP:0002664', (223, 229))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('TGFbeta', 'Gene', (161, 168))	('oncogenic signaling networks', 'Pathway', (121, 149))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('MAPK', 'Pathway', (175, 179))	('tumors', 'Disease', (67, 73))	('EGF', 'Gene', (170, 173))
203341	32629386	5a) that there is a significant increase in fucosyl LacNAc in both A549 and CL1-0 overexpressing FUT4, concomitant with an overall decrease in terminal sialylation (m/z 376) and sialyl LacNAc.	('sialyl LacNAc', 'MPA', (178, 191))	('LacNAc', 'Chemical', '-', (52, 58))	('fucosyl LacNAc', 'MPA', (44, 58))	('increase', 'PosReg', (32, 40))	('CL1', 'Gene', '9201', (76, 79))	('LacNAc', 'Chemical', '-', (185, 191))	('A549', 'CellLine', 'CVCL:0023', (67, 71))	('CL1', 'Gene', (76, 79))	('FUT4', 'Var', (97, 101))	('decrease', 'NegReg', (131, 139))
203344	32629386	The finding was also validated using flow cytometric analysis, which showed that Lex-expressing cell populations were markedly increased in A549_FUT4med, A549_FUT4high , and CL1-0_FUT4 cells.	('CL1', 'Gene', (174, 177))	('A549', 'CellLine', 'CVCL:0023', (154, 158))	('CL1', 'Gene', '9201', (174, 177))	('A549', 'CellLine', 'CVCL:0023', (140, 144))	('Lex', 'Gene', (81, 84))	('A549_FUT4med', 'Var', (140, 152))	('A549_FUT4high', 'Var', (154, 167))	('increased', 'PosReg', (127, 136))	('Lex', 'Gene', '2526', (81, 84))
203350	32629386	We identified 3348 and 1936 proteins bearing Lex antigen in A549_FUT4high and CL1-0_FUT4 cells, and 1187 and 1012 proteins in their respective vector controls (Fig.	('proteins', 'Protein', (28, 36))	('Lex', 'Gene', '2526', (45, 48))	('A549_FUT4high', 'Var', (60, 73))	('CL1', 'Gene', '9201', (78, 81))	('Lex', 'Gene', (45, 48))	('A549', 'CellLine', 'CVCL:0023', (60, 64))	('CL1', 'Gene', (78, 81))
203351	32629386	Among the Lex-bearing proteins upregulated in A549_FUT4high and CL1-0_FUT4 cells, many of them participate in the activated cellular processes and signaling pathways revealed by RNA-seq, including membrane trafficking, cell cycle, TGFbeta signaling, etc.	('membrane trafficking', 'CPA', (197, 217))	('cell cycle', 'CPA', (219, 229))	('TGFbeta', 'Gene', (231, 238))	('A549_FUT4high', 'Var', (46, 59))	('participate', 'Reg', (95, 106))	('upregulated', 'PosReg', (31, 42))	('Lex', 'Gene', '2526', (10, 13))	('TGFbeta', 'Gene', '7039', (231, 238))	('A549', 'CellLine', 'CVCL:0023', (46, 50))	('CL1', 'Gene', '9201', (64, 67))	('Lex', 'Gene', (10, 13))	('CL1', 'Gene', (64, 67))
203352	32629386	In particular, components of a coatomer complex:ARCN1, COPA1, COPB1, as well as SEC family proteins that form the coat protein complex II (COPII):SEC23, 24, 31A, 61A1, appear to be enriched in the lysates of FUT4-overexpressing cells after pull down by anti-Lex antibody (Fig.	('COPB1', 'Gene', (62, 67))	('61A1', 'Var', (162, 166))	('SEC23', 'Var', (146, 151))	('31A', 'Var', (157, 160))	('Lex', 'Gene', '2526', (258, 261))	('COPA', 'Gene', (55, 59))	('ARCN1', 'Gene', '372', (48, 53))	('COPA', 'Gene', '1314', (55, 59))	('Lex', 'Gene', (258, 261))	('COPB1', 'Gene', '1315', (62, 67))	('ARCN1', 'Gene', (48, 53))
203353	32629386	Moreover, aberrant fucosylation of RAB13, a small GTPase regulating vesicular trafficking between trans-Golgi network and recycling endosomes, is also noted (Fig.	('RAB13', 'Gene', (35, 40))	('fucosylation', 'MPA', (19, 31))	('aberrant', 'Var', (10, 18))	('RAB13', 'Gene', '5872', (35, 40))
203354	32629386	In addition to facilitating intracellular transport, FUT4-fucosylated proteins are simultaneously involved in several major signaling pathways known for metastasis, angiogenesis, and EMT, including EGF, TGFbeta, WNT and HIPPO pathways (Fig.	('involved', 'Reg', (98, 106))	('EGF', 'Gene', (198, 201))	('WNT', 'Pathway', (212, 215))	('TGFbeta', 'Gene', '7039', (203, 210))	('FUT4-fucosylated', 'Var', (53, 69))	('HIPPO pathways', 'Pathway', (220, 234))	('EGF', 'Gene', '1950', (198, 201))	('TGFbeta', 'Gene', (203, 210))
203359	32629386	6e and f) pathway activation in A549_FUT4high compared to the vector control.	('A549_FUT4high', 'Var', (32, 45))	('activation', 'PosReg', (18, 28))	('A549', 'CellLine', 'CVCL:0023', (32, 36))
203362	32629386	Migration and invasion abilities of cancer cells appeared to be reduced in CL1-5_shFUT4#751 cells, which contain the lowest expression level of FUT4 among all shRNA clones (#751, #753 and #792) compared to the vector control (Fig 7b and c).	('expression level', 'MPA', (124, 140))	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('#751', 'Var', (173, 177))	('cancer', 'Disease', (36, 42))	('CL1-5', 'Gene', (75, 80))	('lowest', 'NegReg', (117, 123))	('CL1-5', 'Gene', '9201;100862695;23284;100862696', (75, 80))	('reduced', 'NegReg', (64, 71))	('FUT4', 'Gene', (144, 148))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))
203363	32629386	Moreover, knock-down of FUT4 significantly decreased the extravasation and retention ability of CL1-5 cells in the pulmonary vasculature when we injected the cells into the right ventricle of C57BL6 mice to evaluate their organotropic extravasation ability (Fig 7d).	('CL1-5', 'Gene', (96, 101))	('CL1-5', 'Gene', '9201;100862695;23284;100862696', (96, 101))	('mice', 'Species', '10090', (199, 203))	('knock-down', 'Var', (10, 20))	('retention ability', 'CPA', (75, 92))	('extravasation', 'MPA', (57, 70))	('decreased', 'NegReg', (43, 52))	('FUT4', 'Gene', (24, 28))
203364	32629386	Furthermore, when we silenced FUT4 using shRNA in CL1-5 lung cancer cells, which have spontaneous in vivo metastatic ability, we found that FUT4 silencing markedly abolished metastasis of lung cancer cells (Fig.	('lung cancer', 'Disease', (188, 199))	('abolished', 'NegReg', (164, 173))	('lung cancer', 'Phenotype', 'HP:0100526', (188, 199))	('lung cancer', 'Disease', 'MESH:D008175', (56, 67))	('silencing', 'Var', (145, 154))	('FUT4', 'Gene', (140, 144))	('CL1-5', 'Gene', (50, 55))	('CL1-5', 'Gene', '9201;100862695;23284;100862696', (50, 55))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('lung cancer', 'Disease', 'MESH:D008175', (188, 199))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('lung cancer', 'Disease', (56, 67))	('metastasis', 'CPA', (174, 184))	('lung cancer', 'Phenotype', 'HP:0100526', (56, 67))
203365	32629386	In addition, to test whether FUT4-mediated malignant phenotype could be pharmacologically diminished by targeting signaling networks provoked by FUT4, we performed in vivo lung cancer metastasis assay via tail vein injection of A549_vector or A549_FUT4high cells into nude mice, which subsequently received intraperitoneal treatment of either 0.25 mg/kg afatinib (an EGFR inhibitor) or 15 mg/kg LY2157299 (a TGF-beta inhibitor) three times a week (Fig.	('LY2157299', 'Var', (395, 404))	('lung cancer metastasis', 'Disease', (172, 194))	('lung cancer metastasis', 'Disease', 'MESH:D008175', (172, 194))	('afatinib', 'Chemical', 'MESH:D000077716', (354, 362))	('lung cancer', 'Phenotype', 'HP:0100526', (172, 183))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('A549', 'CellLine', 'CVCL:0023', (228, 232))	('A549', 'CellLine', 'CVCL:0023', (243, 247))	('nude mice', 'Species', '10090', (268, 277))	('LY2157299', 'Chemical', 'MESH:C557799', (395, 404))
203367	32629386	Interestingly, afatinib demonstrated differential inhibitory effects between A549_FUT4high and A549_vector cells (Fig.	('inhibitory effects', 'MPA', (50, 68))	('afatinib', 'Gene', (15, 23))	('A549_FUT4high', 'Var', (77, 90))	('afatinib', 'Chemical', 'MESH:D000077716', (15, 23))	('A549', 'CellLine', 'CVCL:0023', (77, 81))	('A549', 'CellLine', 'CVCL:0023', (95, 99))
203368	32629386	7g), which implies A459_FUT4high cells have a higher dependency on EGF signaling for distant metastasis.	('EGF', 'Gene', '1950', (67, 70))	('higher', 'PosReg', (46, 52))	('dependency', 'MPA', (53, 63))	('distant metastasis', 'CPA', (85, 103))	('A459_FUT4high', 'Var', (19, 32))	('EGF', 'Gene', (67, 70))
203372	32629386	Asian lung cancer is known to be a molecularly and etiologically distinct identity composed of a much higher percentage of never smokers and EGFR mutations as compared to the western counterpart.	('lung cancer', 'Disease', 'MESH:D008175', (6, 17))	('mutations', 'Var', (146, 155))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('lung cancer', 'Disease', (6, 17))	('EGFR', 'Gene', (141, 145))	('lung cancer', 'Phenotype', 'HP:0100526', (6, 17))
203381	32629386	In addition to major oncogenic pathways such as EGF/MAPK, NF-kappaB/p65, and TGF-beta pathways, our data reveal that FUT4 induces an active intracellular trafficking state as the top enriched cellular process.	('EGF', 'Gene', '1950', (48, 51))	('induces', 'Reg', (122, 129))	('p65', 'Gene', (68, 71))	('EGF', 'Gene', (48, 51))	('active intracellular trafficking state', 'MPA', (133, 171))	('p65', 'Gene', '5970', (68, 71))	('FUT4', 'Var', (117, 121))
203382	32629386	Notably, the alterations of intracellular vesicle trafficking have recently been shown to drive oncogenesis and regulate cancer behavior.	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('intracellular vesicle trafficking', 'MPA', (28, 61))	('regulate', 'Reg', (112, 120))	('oncogenesis', 'CPA', (96, 107))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('alterations', 'Var', (13, 24))	('drive', 'PosReg', (90, 95))	('cancer', 'Disease', (121, 127))
203385	32629386	This provides a molecular basis for targeting these pathways as novel therapeutic strategies in treating high FUT4-expressing tumors.	('high', 'Var', (105, 109))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('tumors', 'Disease', 'MESH:D009369', (126, 132))	('tumors', 'Disease', (126, 132))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))
203386	32629386	In addition, based on the glycomic profiles in the FUT4 overexpressing cells, we observed a preference for the formation of fucosyl LacNAc (m/z 638) over Sialyl LacNAc (m/z 999), with Lex being a main glycan synthesized by FUT4.	('Lex', 'Gene', (184, 187))	('LacNAc', 'Chemical', '-', (161, 167))	('LacNAc', 'Chemical', '-', (132, 138))	('glycan', 'Chemical', 'MESH:D011134', (201, 207))	('m/z 638', 'Var', (140, 147))	('Lex', 'Gene', '2526', (184, 187))
203391	32629386	Indeed, knockdown of FUT4 in our study significantly diminished lung metastases in mouse xenograft models without apparent toxicities.	('metastases', 'Disease', (69, 79))	('diminished', 'NegReg', (53, 63))	('toxicities', 'Disease', 'MESH:D064420', (123, 133))	('diminished lung', 'Phenotype', 'HP:0002089', (53, 68))	('knockdown', 'Var', (8, 17))	('mouse', 'Species', '10090', (83, 88))	('metastases', 'Disease', 'MESH:D009362', (69, 79))	('toxicities', 'Disease', (123, 133))	('FUT4', 'Gene', (21, 25))
203411	32321585	It is well known that the development, therapeutic response and prognosis of tumors are associated with the intratumoral heterogeneity, such as gene mutation-expression, cellular histology, angiogenesis and tumor microenvironment.	('tumors', 'Disease', (77, 83))	('tumor', 'Disease', (113, 118))	('tumors', 'Disease', 'MESH:D009369', (77, 83))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('tumoral', 'Disease', (113, 120))	('tumoral', 'Disease', 'MESH:D009369', (113, 120))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('gene mutation-expression', 'Var', (144, 168))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('tumor', 'Disease', (207, 212))	('tumor', 'Disease', (77, 82))
203469	32321585	In our study, survival results of patients undergoing partial laryngectomy was better than patients undergoing total laryngectomy.	('patients', 'Species', '9606', (91, 99))	('partial laryngectomy', 'Phenotype', 'HP:0005950', (54, 74))	('survival', 'CPA', (14, 22))	('patients', 'Species', '9606', (34, 42))	('partial laryngectomy', 'Var', (54, 74))
203474	29367650	HOXC8 promotes proliferation and migration through transcriptional up-regulation of TGFbeta1 in non-small cell lung cancer Homeobox (HOX) genes encode a family of transcription factors, which play crucial roles in numerous processes, and their dysregulation is involved in the carcinogenesis of many human cancers.	('cancers', 'Phenotype', 'HP:0002664', (306, 313))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (100, 122))	('promotes', 'PosReg', (6, 14))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('proliferation', 'CPA', (15, 28))	('cancer', 'Disease', 'MESH:D009369', (306, 312))	('TGFbeta1', 'Gene', (84, 92))	('involved', 'Reg', (261, 269))	('HOXC8', 'Gene', '3224', (0, 5))	('cancer', 'Disease', (116, 122))	('carcinogenesis of many human cancers', 'Disease', 'MESH:D063646', (277, 313))	('carcinogenesis of many human cancers', 'Disease', (277, 313))	('HOXC8', 'Gene', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('lung cancer', 'Phenotype', 'HP:0100526', (111, 122))	('cancer', 'Disease', (306, 312))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (96, 122))	('migration', 'CPA', (33, 42))	('cancer', 'Phenotype', 'HP:0002664', (306, 312))	('up-regulation', 'PosReg', (67, 80))	('dysregulation', 'Var', (244, 257))	('TGFbeta1', 'Gene', '7040', (84, 92))
203485	29367650	Numerous evidences show that HOX genes are deregulated in multiple cancers such as prostate cancer, pancreatic cancer, breast cancer and lung cancer, in which deregulation of HOX genes can promote or repress cancer processes.	('prostate cancer', 'Disease', 'MESH:D011471', (83, 98))	('multiple cancers', 'Disease', 'MESH:D009369', (58, 74))	('breast cancer', 'Phenotype', 'HP:0003002', (119, 132))	('prostate cancer', 'Phenotype', 'HP:0012125', (83, 98))	('repress cancer', 'Disease', (200, 214))	('lung cancer', 'Disease', 'MESH:D008175', (137, 148))	('prostate cancer', 'Disease', (83, 98))	('breast cancer', 'Disease', 'MESH:D001943', (119, 132))	('breast cancer', 'Disease', (119, 132))	('lung cancer', 'Phenotype', 'HP:0100526', (137, 148))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('pancreatic cancer', 'Disease', 'MESH:D010190', (100, 117))	('multiple cancers', 'Disease', (58, 74))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('pancreatic cancer', 'Disease', (100, 117))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('promote', 'PosReg', (189, 196))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('repress cancer', 'Disease', 'MESH:D009369', (200, 214))	('cancers', 'Phenotype', 'HP:0002664', (67, 74))	('deregulation', 'Var', (159, 171))	('lung cancer', 'Disease', (137, 148))	('HOX genes', 'Gene', (175, 184))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (100, 117))
203487	29367650	HOXB7 expression is significantly upregulated in colorectal cancer, and expression of HOXB7 promotes the aggressiveness of cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('aggressiveness of cancer', 'Disease', (105, 129))	('promotes', 'PosReg', (92, 100))	('expression', 'Species', '29278', (6, 16))	('colorectal cancer', 'Phenotype', 'HP:0003003', (49, 66))	('upregulated', 'PosReg', (34, 45))	('expression', 'MPA', (6, 16))	('HOXB7', 'Gene', (86, 91))	('HOXB7', 'Gene', '15415', (0, 5))	('expression', 'Species', '29278', (72, 82))	('aggressiveness', 'Phenotype', 'HP:0000718', (105, 119))	('colorectal cancer', 'Disease', (49, 66))	('aggressiveness of cancer', 'Disease', 'MESH:D009369', (105, 129))	('HOXB7', 'Gene', '15415', (86, 91))	('colorectal cancer', 'Disease', 'MESH:D015179', (49, 66))	('expression', 'Var', (72, 82))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('HOXB7', 'Gene', (0, 5))
203494	29367650	We found that HOXC8 contributed to NSCLC cell proliferation, anchorage-independent and migration via regulating TGF-beta1 expression, and high expression of HOXC8 was associated with aggressive phenotypes and poor relapse free survival for lung cancer patients.	('expression', 'Species', '29278', (143, 153))	('migration', 'CPA', (87, 96))	('expression', 'MPA', (122, 132))	('high expression', 'Var', (138, 153))	('TGF-beta1', 'Gene', (112, 121))	('lung cancer', 'Disease', 'MESH:D008175', (240, 251))	('patients', 'Species', '9606', (252, 260))	('lung cancer', 'Phenotype', 'HP:0100526', (240, 251))	('poor', 'NegReg', (209, 213))	('expression', 'Species', '29278', (122, 132))	('HOXC8', 'Gene', '3224', (157, 162))	('NSCLC', 'Disease', 'MESH:D002289', (35, 40))	('HOXC8', 'Gene', '3224', (14, 19))	('cancer', 'Phenotype', 'HP:0002664', (245, 251))	('NSCLC', 'Disease', (35, 40))	('relapse free survival', 'CPA', (214, 235))	('HOXC8', 'Gene', (157, 162))	('lung cancer', 'Disease', (240, 251))	('HOXC8', 'Gene', (14, 19))	('NSCLC', 'Phenotype', 'HP:0030358', (35, 40))	('associated', 'Reg', (167, 177))
203509	29367650	To determine the role of HOXC8 in lung cancer cells, we carried out experiments to knockdown HOXC8 expression or ectopically express HOXC8 in NSCLC cell line A549 or NCI-H460.	('NSCLC', 'Disease', (142, 147))	('lung cancer', 'Phenotype', 'HP:0100526', (34, 45))	('NSCLC', 'Phenotype', 'HP:0030358', (142, 147))	('knockdown', 'Var', (83, 92))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('expression', 'Species', '29278', (99, 109))	('HOXC8', 'Gene', '3224', (25, 30))	('A549', 'CellLine', 'CVCL:0023', (158, 162))	('HOXC8', 'Gene', '3224', (133, 138))	('lung cancer', 'Disease', (34, 45))	('HOXC8', 'Gene', (25, 30))	('HOXC8', 'Gene', '3224', (93, 98))	('NCI-H460', 'CellLine', 'CVCL:0459', (166, 174))	('ecto', 'Gene', (113, 117))	('HOXC8', 'Gene', (133, 138))	('NSCLC', 'Disease', 'MESH:D002289', (142, 147))	('lung cancer', 'Disease', 'MESH:D008175', (34, 45))	('HOXC8', 'Gene', (93, 98))	('ecto', 'Gene', '51592', (113, 117))
203510	29367650	HOXC8 shRNAs knockdown led to a clear reduction in HOXC8 expression at both protein levels and mRNA levels, and HOXC8 ecto-expression greatly increased both HOXC8 protein levels and mRNA levels in A549 or NCI-H460 cells (Supplementary Fig.	('knockdown', 'Var', (13, 22))	('HOXC8', 'Gene', '3224', (51, 56))	('HOXC8', 'Gene', '3224', (112, 117))	('HOXC8', 'Gene', '3224', (0, 5))	('mRNA levels', 'MPA', (95, 106))	('HOXC8', 'Gene', (51, 56))	('mRNA levels', 'MPA', (182, 193))	('ecto', 'Gene', (118, 122))	('expression', 'Species', '29278', (123, 133))	('HOXC8', 'Gene', (112, 117))	('HOXC8', 'Gene', '3224', (157, 162))	('HOXC8', 'Gene', (0, 5))	('expression at', 'MPA', (57, 70))	('A549', 'CellLine', 'CVCL:0023', (197, 201))	('expression', 'Species', '29278', (57, 67))	('ecto', 'Gene', '51592', (118, 122))	('NCI-H460', 'CellLine', 'CVCL:0459', (205, 213))	('increased', 'PosReg', (142, 151))	('HOXC8', 'Gene', (157, 162))	('reduction', 'NegReg', (38, 47))
203511	29367650	In MTT assays, silencing HOXC8 significantly reduced lung cancer cell proliferation as shown by the growth curves (Fig.	('reduced', 'NegReg', (45, 52))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('lung cancer', 'Disease', 'MESH:D008175', (53, 64))	('MTT', 'Chemical', 'MESH:C070243', (3, 6))	('silencing', 'Var', (15, 24))	('HOXC8', 'Gene', (25, 30))	('lung cancer', 'Disease', (53, 64))	('lung cancer', 'Phenotype', 'HP:0100526', (53, 64))	('HOXC8', 'Gene', '3224', (25, 30))
203517	29367650	We found that HOXC8 shRNA knockdown resulted in significant reduction of migratory cells (Fig.	('migratory cells', 'CPA', (73, 88))	('reduction', 'NegReg', (60, 69))	('knockdown', 'Var', (26, 35))	('HOXC8', 'Gene', '3224', (14, 19))	('HOXC8', 'Gene', (14, 19))
203526	29367650	Moreover, silencing HOXC8 decreased the protein and mRNA levels of vimentin (Fig.	('mRNA levels', 'MPA', (52, 63))	('protein', 'MPA', (40, 47))	('vimentin', 'Protein', (67, 75))	('HOXC8', 'Gene', '3224', (20, 25))	('HOXC8', 'Gene', (20, 25))	('decreased', 'NegReg', (26, 35))	('silencing', 'Var', (10, 19))
203536	29367650	These data indicated that HOXC8 bound to the nucleotides -1941 to -1936 in TGFbeta1 promoter in NSCLC cells.	('NSCLC', 'Disease', (96, 101))	('TGFbeta1', 'Gene', '7040', (75, 83))	('HOXC8', 'Gene', '3224', (26, 31))	('TGFbeta1', 'Gene', (75, 83))	('HOXC8', 'Gene', (26, 31))	('NSCLC', 'Disease', 'MESH:D002289', (96, 101))	('nucleotides -1941 to -1936', 'Var', (45, 71))	('NSCLC', 'Phenotype', 'HP:0030358', (96, 101))
203538	29367650	Luciferase analyses showed that silencing HOXC8 resulted in significant decreases in the luciferase activities (Fig.	('activities', 'MPA', (100, 110))	('decreases', 'NegReg', (72, 81))	('silencing', 'Var', (32, 41))	('luciferase', 'Enzyme', (89, 99))	('HOXC8', 'Gene', '3224', (42, 47))	('HOXC8', 'Gene', (42, 47))
203540	29367650	Next, we performed deletion mutagenesis to delete the HOXC8 binding site in TGFbeta1 promoter, and found that the mutation completely abolished HOXC8 effects on the activities of TGFbeta1 promoter (Supplementary Fig.	('activities', 'MPA', (165, 175))	('delete', 'NegReg', (43, 49))	('HOXC8', 'Gene', (54, 59))	('HOXC8', 'Gene', '3224', (54, 59))	('TGFbeta1', 'Gene', '7040', (179, 187))	('HOXC8', 'Gene', '3224', (144, 149))	('HOXC8', 'Gene', (144, 149))	('TGFbeta1', 'Gene', (179, 187))	('mutation', 'Var', (114, 122))	('TGFbeta1', 'Gene', '7040', (76, 84))	('TGFbeta1', 'Gene', (76, 84))	('abolished', 'NegReg', (134, 143))
203544	29367650	MTT assays showed that knockdown of TGFbeta1 significantly decreased the proliferation of A549 or NCI-H460 cells, and ectopic expression of TGFbeta1 markedly increased the cell proliferation (Fig.	('expression', 'Species', '29278', (126, 136))	('decreased', 'NegReg', (59, 68))	('NCI-H460', 'CellLine', 'CVCL:0459', (98, 106))	('cell proliferation', 'CPA', (172, 190))	('knockdown', 'Var', (23, 32))	('MTT', 'Chemical', 'MESH:C070243', (0, 3))	('TGFbeta1', 'Gene', (140, 148))	('TGFbeta1', 'Gene', '7040', (140, 148))	('A549', 'CellLine', 'CVCL:0023', (90, 94))	('ecto', 'Gene', '51592', (118, 122))	('ecto', 'Gene', (118, 122))	('TGFbeta1', 'Gene', '7040', (36, 44))	('increased', 'PosReg', (158, 167))	('TGFbeta1', 'Gene', (36, 44))
203545	29367650	In soft-agar colony formation assay, depletion of TGFbeta1 significantly impaired anchorage-independent cell growth of both A549 and NCI-H460 cells (Fig.	('impaired', 'NegReg', (73, 81))	('TGFbeta1', 'Gene', '7040', (50, 58))	('TGFbeta1', 'Gene', (50, 58))	('depletion', 'Var', (37, 46))	('A549', 'CellLine', 'CVCL:0023', (124, 128))	('NCI-H460', 'CellLine', 'CVCL:0459', (133, 141))	('agar', 'Chemical', 'MESH:D000362', (8, 12))	('anchorage-independent cell growth', 'CPA', (82, 115))
203547	29367650	Transwell assays further showed that knockdown of TGFbeta1 significantly inhibited the migration of A549 or NCI-H460 cells (Fig.	('A549', 'CellLine', 'CVCL:0023', (100, 104))	('TGFbeta1', 'Gene', '7040', (50, 58))	('TGFbeta1', 'Gene', (50, 58))	('migration of A549', 'CPA', (87, 104))	('knockdown', 'Var', (37, 46))	('inhibited', 'NegReg', (73, 82))	('NCI-H460', 'CellLine', 'CVCL:0459', (108, 116))
203551	29367650	In both A549 and NCI-H460, HOXC8 silencing by shRNA knockdown decreased the expression of vimentin, which was completely recovered by ectopic expression of TGFbeta1 in HOXC8 knockdown cells (Fig.	('TGFbeta1', 'Gene', (156, 164))	('vimentin', 'Protein', (90, 98))	('ecto', 'Gene', (134, 138))	('silencing', 'NegReg', (33, 42))	('decreased', 'NegReg', (62, 71))	('NCI-H460', 'CellLine', 'CVCL:0459', (17, 25))	('ecto', 'Gene', '51592', (134, 138))	('shRNA', 'Gene', (46, 51))	('expression', 'Species', '29278', (76, 86))	('expression', 'Species', '29278', (142, 152))	('HOXC8', 'Gene', (168, 173))	('expression', 'MPA', (76, 86))	('HOXC8', 'Gene', (27, 32))	('HOXC8', 'Gene', '3224', (168, 173))	('A549', 'CellLine', 'CVCL:0023', (8, 12))	('HOXC8', 'Gene', '3224', (27, 32))	('knockdown', 'Var', (52, 61))	('TGFbeta1', 'Gene', '7040', (156, 164))
203559	29367650	We found that HOXC8 knockdown significantly enhanced cisplatin-induced repression on NSCLC viability (Fig.	('NSCLC', 'Disease', (85, 90))	('NSCLC', 'Disease', 'MESH:D002289', (85, 90))	('NSCLC', 'Phenotype', 'HP:0030358', (85, 90))	('cisplatin', 'Chemical', 'MESH:D002945', (53, 62))	('HOXC8', 'Gene', '3224', (14, 19))	('HOXC8', 'Gene', (14, 19))	('knockdown', 'Var', (20, 29))	('enhanced', 'PosReg', (44, 52))
203562	29367650	Compared to negative control, cisplatin treatment induced apoptosis, which was evidenced by cleavage of caspase-3 and cleaved PARP in both A549 and NCI-H460 cells.	('PARP', 'Gene', '1302', (126, 130))	('cleavage', 'MPA', (92, 100))	('PARP', 'Gene', (126, 130))	('cisplatin', 'Var', (30, 39))	('caspase-3', 'Gene', '836', (104, 113))	('A549', 'CellLine', 'CVCL:0023', (139, 143))	('apoptosis', 'CPA', (58, 67))	('cisplatin', 'Chemical', 'MESH:D002945', (30, 39))	('NCI-H460', 'CellLine', 'CVCL:0459', (148, 156))	('cleaved', 'MPA', (118, 125))	('caspase-3', 'Gene', (104, 113))
203564	29367650	7c), which indicated that knockdown of HOXC8 combined with cisplatin treatment enhanced cell apoptosis in NSCLS.	('cell apoptosis', 'CPA', (88, 102))	('HOXC8', 'Gene', (39, 44))	('HOXC8', 'Gene', '3224', (39, 44))	('NSCLS', 'Disease', (106, 111))	('enhanced', 'PosReg', (79, 87))	('knockdown', 'Var', (26, 35))	('cisplatin', 'Chemical', 'MESH:D002945', (59, 68))
203566	29367650	Taken together, these data indicated that HOXC8 expression could amplify the chemoresistance NSCLC to cisplatin-based chemotherapy and down-regulation of HOXC8 effectively improved the sensitivity of NSCLS to cisplatin treatment.	('improved', 'PosReg', (172, 180))	('NSCLC', 'Disease', (93, 98))	('expression', 'Species', '29278', (48, 58))	('amplify', 'PosReg', (65, 72))	('HOXC8', 'Gene', (154, 159))	('NSCLC', 'Disease', 'MESH:D002289', (93, 98))	('down-regulation', 'Var', (135, 150))	('cisplatin', 'Chemical', 'MESH:D002945', (102, 111))	('HOXC8', 'Gene', '3224', (154, 159))	('sensitivity of NSCLS to cisplatin treatment', 'MPA', (185, 228))	('expression', 'Var', (48, 58))	('HOXC8', 'Gene', '3224', (42, 47))	('HOXC8', 'Gene', (42, 47))	('NSCLC', 'Phenotype', 'HP:0030358', (93, 98))	('cisplatin', 'Chemical', 'MESH:D002945', (209, 218))
203568	29367650	The HOX gene expressions that are critical for embryonic development are aberrant in abnormal development and malignancy, indicating that altered expression of HOX genes is important for oncogenesis.	('expression', 'Species', '29278', (13, 23))	('abnormal development', 'CPA', (85, 105))	('embryonic', 'Disease', 'MESH:D009373', (47, 56))	('HOX gene', 'Gene', (4, 12))	('malignancy', 'Disease', 'MESH:D009369', (110, 120))	('aberrant', 'Var', (73, 81))	('malignancy', 'Disease', (110, 120))	('embryonic', 'Disease', (47, 56))	('expression', 'Species', '29278', (146, 156))
203569	29367650	Numerous examples of aberrant HOX gene expression have been found in various types of cancer, including breast, prostate, cervical and lung cancer, etc.	('aberrant', 'Var', (21, 29))	('HOX gene', 'Gene', (30, 38))	('cervical', 'Disease', (122, 130))	('breast', 'Disease', (104, 110))	('prostate', 'Disease', (112, 120))	('lung cancer', 'Phenotype', 'HP:0100526', (135, 146))	('cancer', 'Disease', (140, 146))	('lung cancer', 'Disease', 'MESH:D008175', (135, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('found', 'Reg', (60, 65))	('expression', 'MPA', (39, 49))	('expression', 'Species', '29278', (39, 49))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('lung cancer', 'Disease', (135, 146))	('cancer', 'Disease', (86, 92))
203573	29367650	Importantly, high expression of HOXC8 was linked to poor relapse-free survival for lung cancer patients (Fig.	('lung cancer', 'Disease', 'MESH:D008175', (83, 94))	('HOXC8', 'Gene', '3224', (32, 37))	('HOXC8', 'Gene', (32, 37))	('patients', 'Species', '9606', (95, 103))	('high', 'Var', (13, 17))	('relapse-free survival', 'CPA', (57, 78))	('expression', 'Species', '29278', (18, 28))	('lung cancer', 'Disease', (83, 94))	('expression', 'MPA', (18, 28))	('lung cancer', 'Phenotype', 'HP:0100526', (83, 94))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('poor', 'NegReg', (52, 56))
203575	29367650	Furthermore, gain- and loss-of-function experiments indicated that HOXC8 expression promoted the proliferation, anchorage-independent cell growth and migration of lung cancer cells (Fig.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('expression', 'Var', (73, 83))	('promoted', 'PosReg', (84, 92))	('migration of lung cancer', 'Disease', 'MESH:D008175', (150, 174))	('HOXC8', 'Gene', '3224', (67, 72))	('HOXC8', 'Gene', (67, 72))	('proliferation', 'CPA', (97, 110))	('expression', 'Species', '29278', (73, 83))	('migration of lung cancer', 'Disease', (150, 174))	('lung cancer', 'Phenotype', 'HP:0100526', (163, 174))	('anchorage-independent cell growth', 'CPA', (112, 145))
203583	29367650	In the present study, we found that HOXC8 silencing led to a decrease in TGFbeta1 mRNA and protein levels and HOXC8 ectopic expression increased the mRNA and protein levels of TGFbeta1.	('HOXC8', 'Gene', (110, 115))	('silencing', 'Var', (42, 51))	('ecto', 'Gene', (116, 120))	('decrease', 'NegReg', (61, 69))	('ecto', 'Gene', '51592', (116, 120))	('HOXC8', 'Gene', '3224', (36, 41))	('HOXC8', 'Gene', (36, 41))	('expression', 'Species', '29278', (124, 134))	('increased', 'PosReg', (135, 144))	('TGFbeta1', 'Gene', '7040', (176, 184))	('TGFbeta1', 'Gene', '7040', (73, 81))	('TGFbeta1', 'Gene', (176, 184))	('TGFbeta1', 'Gene', (73, 81))	('HOXC8', 'Gene', '3224', (110, 115))
203589	29367650	Consistently, we further showed that knockdown of HOXC8 significantly inhibited proliferation, anchorage-independent cell growth and migration of lung cancer cells, which can be rescued by ecto-expression of TGFbeta1 (Fig.	('TGFbeta1', 'Gene', '7040', (208, 216))	('TGFbeta1', 'Gene', (208, 216))	('migration of lung cancer', 'Disease', 'MESH:D008175', (133, 157))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('HOXC8', 'Gene', '3224', (50, 55))	('HOXC8', 'Gene', (50, 55))	('proliferation', 'CPA', (80, 93))	('ecto', 'Gene', (189, 193))	('knockdown', 'Var', (37, 46))	('ecto', 'Gene', '51592', (189, 193))	('expression', 'Species', '29278', (194, 204))	('migration of lung cancer', 'Disease', (133, 157))	('lung cancer', 'Phenotype', 'HP:0100526', (146, 157))	('inhibited', 'NegReg', (70, 79))
203596	29367650	Moreover, the enhanced apoptosis induced by cisplatin in combination with HOXC8 knockdown suggested that the combination of cisplatin with other therapies that modulated HOXC8 could be exploited as a plausible strategy to enhance therapeutic efficacy for NSCLC.	('HOXC8', 'Gene', (74, 79))	('enhance', 'PosReg', (222, 229))	('knockdown', 'Var', (80, 89))	('HOXC8', 'Gene', '3224', (170, 175))	('apoptosis', 'CPA', (23, 32))	('NSCLC', 'Disease', (255, 260))	('HOXC8', 'Gene', '3224', (74, 79))	('cisplatin', 'Chemical', 'MESH:D002945', (124, 133))	('enhanced', 'PosReg', (14, 22))	('NSCLC', 'Disease', 'MESH:D002289', (255, 260))	('cisplatin', 'Chemical', 'MESH:D002945', (44, 53))	('NSCLC', 'Phenotype', 'HP:0030358', (255, 260))	('HOXC8', 'Gene', (170, 175))
203601	29367650	Anti-HOXC8 antibody (15448-1-AP), anti-E-cadherin antibody (20874-1-AP) and Anti-TGFbeta1 antibody (20328-1-AP) were from ProteinTech Group (Wuhan, China).	('HOXC8', 'Gene', (5, 10))	('15448-1-AP', 'Var', (21, 31))	('E-cadherin', 'Gene', (39, 49))	('E-cadherin', 'Gene', '999', (39, 49))	('HOXC8', 'Gene', '3224', (5, 10))	('TGFbeta1', 'Gene', '7040', (81, 89))	('TGFbeta1', 'Gene', (81, 89))	('20874-1-AP', 'Var', (60, 70))	('20328-1-AP', 'Var', (100, 110))
203603	29367650	Anti-cleaved caspase-3 (#9661), anti-cleaved PARP (#9541) and anti-vimentin (#5741) antibodies were from Cell Signaling Technology (Shanghai, China).	('#9661', 'Var', (24, 29))	('caspase-3', 'Gene', '836', (13, 22))	('PARP', 'Gene', '1302', (45, 49))	('PARP', 'Gene', (45, 49))	('anti-cleaved', 'Var', (32, 44))	('#5741', 'Var', (77, 82))	('caspase-3', 'Gene', (13, 22))	('#9541', 'Var', (51, 56))
203635	27912828	Through the recognition of novel biomarkers, such as epidermal growth factor receptor mutations and anaplastic lymphoma kinase translocations, it has been possible to identify subsets of patients who benefit from targeted molecular therapies.	('epidermal growth factor receptor', 'Gene', '1956', (53, 85))	('mutations', 'Var', (86, 95))	('patients', 'Species', '9606', (187, 195))	('anaplastic lymphoma kinase', 'Gene', '238', (100, 126))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (100, 119))	('epidermal growth factor receptor', 'Gene', (53, 85))	('anaplastic lymphoma kinase', 'Gene', (100, 126))	('translocations', 'Var', (127, 141))	('lymphoma', 'Phenotype', 'HP:0002665', (111, 119))
203664	27912828	Approximately 10% of patients with adenocarcinoma of the lung in the United States and 30% to 50% in East Asia have lung tumors associated with EGFR mutations.	('lung tumors', 'Disease', 'MESH:D008175', (116, 127))	('EGFR', 'Gene', (144, 148))	('mutations', 'Var', (149, 158))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('lung tumors', 'Disease', (116, 127))	('patients', 'Species', '9606', (21, 29))	('lung tumors', 'Phenotype', 'HP:0100526', (116, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (40, 49))	('associated', 'Reg', (128, 138))	('carcinoma of the lung', 'Phenotype', 'HP:0100526', (40, 61))	('adenocarcinoma of the lung', 'Disease', 'MESH:D000077192', (35, 61))	('adenocarcinoma of the lung', 'Disease', (35, 61))
203665	27912828	EGFR mutations are found more often in adenocarcinomas with lepidic features from female never smokers.	('EGFR', 'Gene', (0, 4))	('adenocarcinomas', 'Disease', (39, 54))	('mutations', 'Var', (5, 14))	('carcinoma', 'Phenotype', 'HP:0030731', (44, 53))	('carcinomas', 'Phenotype', 'HP:0030731', (44, 54))	('adenocarcinomas', 'Disease', 'MESH:D000230', (39, 54))
203666	27912828	The high response rates (55%-78%) to treatment with tyrosine kinase inhibitors (TKIs), such as gefitinib, erlotinib and afatinib, in patients with EGFR-mutant tumors, and the significantly greater progression-free survival (PFS) of these patients, have made EGFR TKIs the standard treatment for patients with these mutations.	('rat', 'Species', '10116', (18, 21))	('afatinib', 'Chemical', 'MESH:D000077716', (120, 128))	('EGFR-mutant', 'Gene', (147, 158))	('patients', 'Species', '9606', (238, 246))	('greater', 'PosReg', (189, 196))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('patients', 'Species', '9606', (133, 141))	('patients', 'Species', '9606', (295, 303))	('tumors', 'Disease', (159, 165))	('tumors', 'Phenotype', 'HP:0002664', (159, 165))	('erlotinib', 'Chemical', 'MESH:D000069347', (106, 115))	('tumors', 'Disease', 'MESH:D009369', (159, 165))	('gefitinib', 'Chemical', 'MESH:D000077156', (95, 104))	('EGFR-mutant', 'Var', (147, 158))	('progression-free survival', 'CPA', (197, 222))
203667	27912828	However, most of these patients develop resistance and relapse in a short time, owing to the occurrence of a new mutation (T790M) in exon 20 of the EGFR kinase domain (50%), amplification of the MET oncogene (21%), or mutations of PI3KCA.	('patients', 'Species', '9606', (23, 31))	('mutations', 'Var', (218, 227))	('resistance', 'Disease', (40, 50))	('T790M', 'Mutation', 'rs121434569', (123, 128))	('develop', 'PosReg', (32, 39))	('MET oncogene', 'Gene', (195, 207))	('T790M', 'Var', (123, 128))	('PI3KCA', 'Gene', (231, 237))
203670	27912828	ALK gene rearrangement was originally identified in anaplastic large cell lymphoma and was subsequently described in a subset of NSCLC tumors harboring a fusion of ALK and echinoderm microtubule-associated protein-like 4 (EML4) genes.	('EML4', 'Gene', (222, 226))	('cell lymphoma', 'Phenotype', 'HP:0012191', (69, 82))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('lymphoma', 'Phenotype', 'HP:0002665', (74, 82))	('EML4', 'Gene', '27436', (222, 226))	('ALK', 'Gene', (164, 167))	('echinoderm microtubule-associated protein-like 4', 'Gene', (172, 220))	('fusion', 'Interaction', (154, 160))	('anaplastic large cell lymphoma', 'Phenotype', 'HP:0012193', (52, 82))	('NSCLC tumors', 'Disease', (129, 141))	('rearrangement', 'Var', (9, 22))	('lymphoma', 'Disease', (74, 82))	('lymphoma', 'Disease', 'MESH:D008223', (74, 82))	('NSCLC tumors', 'Disease', 'MESH:D009369', (129, 141))	('NSCLC', 'Phenotype', 'HP:0030358', (129, 134))	('echinoderm microtubule-associated protein-like 4', 'Gene', '27436', (172, 220))	('described', 'Reg', (104, 113))	('ALK', 'Gene', (0, 3))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))
203673	27912828	There are several EML4-ALK rearrangement variants and also ALK fusion with other less frequent partners, such as kinesin family member 5B (KIF5B), TRK-fused gene (TFG), kinesin light chain 1 (KLC1), and huntingtin-interacting protein 1 (HIP1) genes, resulting in oncogenic transformation.	('KIF5B', 'Gene', '3799', (139, 144))	('kinesin family member 5B', 'Gene', '3799', (113, 137))	('TFG', 'Gene', '10342', (163, 166))	('TRK', 'Gene', (147, 150))	('kinesin light chain 1', 'Gene', '3831', (169, 190))	('kinesin family member 5B', 'Gene', (113, 137))	('rearrangement variants', 'Var', (27, 49))	('KLC1', 'Gene', (192, 196))	('variants', 'Var', (41, 49))	('kinesin light chain 1', 'Gene', (169, 190))	('TRK', 'Gene', '4914', (147, 150))	('TFG', 'Gene', (163, 166))	('KIF5B', 'Gene', (139, 144))	('ALK', 'Var', (59, 62))	('HIP1', 'Gene', '3092', (237, 241))	('huntingtin-interacting protein 1', 'Gene', (203, 235))	('EML4', 'Gene', (18, 22))	('resulting in', 'Reg', (250, 262))	('fusion', 'Interaction', (63, 69))	('HIP1', 'Gene', (237, 241))	('oncogenic transformation', 'CPA', (263, 287))	('EML4', 'Gene', '27436', (18, 22))	('huntingtin-interacting protein 1', 'Gene', '3092', (203, 235))	('KLC1', 'Gene', '3831', (192, 196))
203676	27912828	Patients treated with crizotinib demonstrated significantly better median PFS and response rate compared to patients who received chemotherapy.	('PFS', 'MPA', (74, 77))	('better', 'PosReg', (60, 66))	('rat', 'Species', '10116', (91, 94))	('crizotinib', 'Chemical', 'MESH:D000077547', (22, 32))	('rat', 'Species', '10116', (40, 43))	('response', 'CPA', (82, 90))	('crizotinib', 'Var', (22, 32))	('Patients', 'Species', '9606', (0, 8))	('patients', 'Species', '9606', (108, 116))
203677	27912828	As a result, testing for ALK rearrangements in patients with advanced lung adenocarcinoma is recommended in current clinical practice guidelines.	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (70, 89))	('patients', 'Species', '9606', (47, 55))	('ALK', 'Gene', (25, 28))	('rearrangements', 'Var', (29, 43))	('testing', 'Reg', (13, 20))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (70, 89))	('lung adenocarcinoma', 'Disease', (70, 89))
203678	27912828	However, despite initial responses, a fraction of the patients develop acquired resistance to crizotinib, owing to secondary mutations within the kinase domain of EML4-ALK; these include L1196M, C1156Y, and F1174L, among others.	('crizotinib', 'Chemical', 'MESH:D000077547', (94, 104))	('EML4', 'Gene', '27436', (163, 167))	('F1174L', 'Var', (207, 213))	('patients', 'Species', '9606', (54, 62))	('C1156Y', 'Mutation', 'rs1057519859', (195, 201))	('C1156Y', 'Var', (195, 201))	('L1196M', 'Mutation', 'rs1057519784', (187, 193))	('EML4', 'Gene', (163, 167))	('F1174L', 'Mutation', 'rs863225281', (207, 213))	('L1196M', 'Var', (187, 193))
203683	27912828	KRAS mutations occur in 25% to 35% of patients with NSCLC, principally adenocarcinomas with a solid pattern, and are found more often in white patients compared to Asians, in former or current smokers, but without sex predilection.	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('NSCLC', 'Disease', (52, 57))	('carcinomas', 'Phenotype', 'HP:0030731', (76, 86))	('NSCLC', 'Disease', 'MESH:D002289', (52, 57))	('mutations', 'Var', (5, 14))	('patients', 'Species', '9606', (143, 151))	('patients', 'Species', '9606', (38, 46))	('adenocarcinomas', 'Disease', 'MESH:D000230', (71, 86))	('NSCLC', 'Phenotype', 'HP:0030358', (52, 57))	('KRAS', 'Gene', (0, 4))	('adenocarcinomas', 'Disease', (71, 86))
203684	27912828	In never smokers, the most common KRAS mutations are G12D and G12V, whereas G12C is the most common mutation associated with smoking.	('G12C', 'Var', (76, 80))	('G12C', 'Mutation', 'rs121913530', (76, 80))	('G12D', 'Var', (53, 57))	('KRAS', 'Disease', (34, 38))	('G12V', 'Mutation', 'rs121913529', (62, 66))	('G12D', 'Mutation', 'rs121913529', (53, 57))	('G12V', 'Var', (62, 66))
203687	27912828	Although there are no targeted therapies approved for patients with lung cancer and KRAS mutation, several clinical trials aimed at downstream signaling targets are under way.	('lung cancer', 'Disease', (68, 79))	('lung cancer', 'Phenotype', 'HP:0100526', (68, 79))	('patients', 'Species', '9606', (54, 62))	('mutation', 'Var', (89, 97))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('KRAS', 'Gene', (84, 88))	('lung cancer', 'Disease', 'MESH:D008175', (68, 79))
203692	27912828	ROS1 rearrangements were originally described in glioblastoma and have also been reported in cholangiocarcinoma and ovarian cancer.	('cholangiocarcinoma and ovarian cancer', 'Disease', 'MESH:D018281', (93, 130))	('ROS1', 'Gene', (0, 4))	('ROS1', 'Gene', '6098', (0, 4))	('glioblastoma', 'Disease', (49, 61))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('rearrangements', 'Var', (5, 19))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('described', 'Reg', (36, 45))	('glioblastoma', 'Disease', 'MESH:D005909', (49, 61))	('glioblastoma', 'Phenotype', 'HP:0012174', (49, 61))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (93, 111))	('ovarian cancer', 'Phenotype', 'HP:0100615', (116, 130))	('reported', 'Reg', (81, 89))
203693	27912828	Approximately 1% to 2% of NSCLCs harbor ROS1 rearrangements, and several fusion partners, including CD74, solute carrier family 34, member 2 (SLC34A2), leucine-rich repeats and immunoglobulin-like domains 3 (LRIG3), ezrin (EZR), syndecan 4 (SDC4), tropomyosin 3 (TPM3), and FIG, have been reported in these tumors.	('ezrin', 'Gene', (216, 221))	('NSCLC', 'Phenotype', 'HP:0030358', (26, 31))	('syndecan 4', 'Gene', (229, 239))	('leucine-rich repeats and immunoglobulin-like domains 3', 'Gene', '121227', (152, 206))	('TPM3', 'Gene', '7170', (263, 267))	('syndecan 4', 'Gene', '6385', (229, 239))	('SLC34A2', 'Gene', '10568', (142, 149))	('EZR', 'Gene', (223, 226))	('SDC4', 'Gene', '6385', (241, 245))	('ezrin', 'Gene', '7430', (216, 221))	('tropomyosin 3', 'Gene', (248, 261))	('SDC4', 'Gene', (241, 245))	('SLC34A2', 'Gene', (142, 149))	('CD74', 'Gene', '972', (100, 104))	('tumors', 'Phenotype', 'HP:0002664', (307, 313))	('solute carrier family 34, member 2', 'Gene', '10568', (106, 140))	('ROS1', 'Gene', '6098', (40, 44))	('tropomyosin 3', 'Gene', '7170', (248, 261))	('tumor', 'Phenotype', 'HP:0002664', (307, 312))	('LRIG3', 'Gene', (208, 213))	('TPM3', 'Gene', (263, 267))	('rearrangements', 'Var', (45, 59))	('EZR', 'Gene', '7430', (223, 226))	('tumors', 'Disease', (307, 313))	('LRIG3', 'Gene', '121227', (208, 213))	('NSCLC', 'Disease', 'MESH:D002289', (26, 31))	('CD74', 'Gene', (100, 104))	('tumors', 'Disease', 'MESH:D009369', (307, 313))	('NSCLC', 'Disease', (26, 31))	('ROS1', 'Gene', (40, 44))
203695	27912828	Clinical trials have reported that patients with advanced NSCLC harboring ROS1 rearrangement have benefited from crizotinib treatment, showing response rates up to 80%.	('NSCLC', 'Disease', (58, 63))	('ROS1', 'Gene', '6098', (74, 78))	('benefited', 'PosReg', (98, 107))	('rat', 'Species', '10116', (152, 155))	('NSCLC', 'Disease', 'MESH:D002289', (58, 63))	('crizotinib', 'Chemical', 'MESH:D000077547', (113, 123))	('rearrangement', 'Var', (79, 92))	('NSCLC', 'Phenotype', 'HP:0030358', (58, 63))	('patients', 'Species', '9606', (35, 43))	('ROS1', 'Gene', (74, 78))
203701	27912828	In fact, studies have found that ROS1 IHC (D4D6 clone) has a high sensitivity (100%) and specificity (92%-97%) for ROS1 rearrangements compared to FISH.	('rearrangements', 'Var', (120, 134))	('ROS1', 'Gene', (115, 119))	('ROS1', 'Gene', (33, 37))	('ROS1', 'Gene', '6098', (115, 119))	('ROS1', 'Gene', '6098', (33, 37))
203707	27912828	HER2 expression and/or amplification is found in many cancers including breast and gastric cancer.	('breast and gastric cancer', 'Disease', 'MESH:D013274', (72, 97))	('expression', 'MPA', (5, 15))	('gastric cancer', 'Phenotype', 'HP:0012126', (83, 97))	('cancers', 'Phenotype', 'HP:0002664', (54, 61))	('cancers', 'Disease', (54, 61))	('cancers', 'Disease', 'MESH:D009369', (54, 61))	('amplification', 'Var', (23, 36))	('found', 'Reg', (40, 45))	('HER2', 'Gene', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('HER2', 'Gene', '2064', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
203708	27912828	Overexpression of HER2 has been reported in 7% to 34.9% of NSCLCs and has been associated with poor prognosis in patients with these tumors.	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('NSCLC', 'Disease', 'MESH:D002289', (59, 64))	('HER2', 'Gene', '2064', (18, 22))	('tumors', 'Disease', (133, 139))	('tumors', 'Disease', 'MESH:D009369', (133, 139))	('patients', 'Species', '9606', (113, 121))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('NSCLC', 'Phenotype', 'HP:0030358', (59, 64))	('Overexpression', 'Var', (0, 14))	('NSCLC', 'Disease', (59, 64))	('HER2', 'Gene', (18, 22))
203709	27912828	Activating mutations of HER2 have been found in 1.6% to 4% of lung cancers.	('cancers', 'Phenotype', 'HP:0002664', (67, 74))	('Activating mutations', 'Var', (0, 20))	('found', 'Reg', (39, 44))	('lung cancers', 'Disease', (62, 74))	('lung cancer', 'Phenotype', 'HP:0100526', (62, 73))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('HER2', 'Gene', (24, 28))	('lung cancers', 'Disease', 'MESH:D008175', (62, 74))	('lung cancers', 'Phenotype', 'HP:0100526', (62, 74))	('HER2', 'Gene', '2064', (24, 28))
203710	27912828	These mutations occur in the 4 exons of the tyrosine kinase domain (exons 18-21) and are found more often in adenocarcinomas in female, Asian, never or light smokers.	('adenocarcinomas', 'Disease', (109, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('carcinomas', 'Phenotype', 'HP:0030731', (114, 124))	('adenocarcinomas', 'Disease', 'MESH:D000230', (109, 124))	('mutations', 'Var', (6, 15))
203711	27912828	HER2 mutations are almost always mutually exclusive with other driver oncogene alterations in lung cancer described above.	('rat', 'Species', '10116', (83, 86))	('lung cancer', 'Disease', 'MESH:D008175', (94, 105))	('mutations', 'Var', (5, 14))	('lung cancer', 'Disease', (94, 105))	('HER2', 'Gene', (0, 4))	('lung cancer', 'Phenotype', 'HP:0100526', (94, 105))	('HER2', 'Gene', '2064', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
203712	27912828	Different studies reinforce the importance of screening lung adenocarcinomas for HER2 mutation as a method to select patients who could benefit from HER2-targeted therapies (afatinib and trastuzumab), which have shown response rates of approximately 50%.	('rat', 'Species', '10116', (227, 230))	('lung adenocarcinomas', 'Disease', (56, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (66, 75))	('HER2', 'Gene', (149, 153))	('carcinomas', 'Phenotype', 'HP:0030731', (66, 76))	('HER2', 'Gene', '2064', (149, 153))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (56, 76))	('HER2', 'Gene', (81, 85))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (56, 76))	('trastuzumab', 'Chemical', 'MESH:D000068878', (187, 198))	('HER2', 'Gene', '2064', (81, 85))	('mutation', 'Var', (86, 94))	('patients', 'Species', '9606', (117, 125))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (56, 75))	('afatinib', 'Chemical', 'MESH:D000077716', (174, 182))
203713	27912828	Several clinical trials of targeted agents, such as trastuzumab, neratinib and pyrotinib, among others, are being conducted in patients with HER2 mutation.	('HER2', 'Gene', '2064', (141, 145))	('trastuzumab', 'Chemical', 'MESH:D000068878', (52, 63))	('patients', 'Species', '9606', (127, 135))	('pyrotinib', 'Chemical', 'MESH:C000622954', (79, 88))	('neratinib', 'Chemical', 'MESH:C487932', (65, 74))	('mutation', 'Var', (146, 154))	('HER2', 'Gene', (141, 145))
203714	27912828	HER2 mutations are usually assessed via sequencing approaches.	('HER2', 'Gene', '2064', (0, 4))	('HER2', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))
203726	27912828	MET alterations were first reported in patients with renal papillary carcinoma and mutations in the MET kinase domain leading to constitutive activation of the receptor.	('mutations in', 'Var', (83, 95))	('constitutive activation', 'MPA', (129, 152))	('rat', 'Species', '10116', (8, 11))	('patients', 'Species', '9606', (39, 47))	('renal papillary carcinoma', 'Disease', (53, 78))	('renal papillary carcinoma', 'Disease', 'MESH:D007681', (53, 78))	('renal papillary carcinoma', 'Phenotype', 'HP:0006766', (53, 78))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))
203727	27912828	In lung cancer, MET mutations are found in the extracellular semaphorin and juxtamembrane domains, occurring in 3% of squamous cell lung cancers and 8% of lung adenocarcinomas.	('lung cancer', 'Phenotype', 'HP:0100526', (3, 14))	('occurring', 'Reg', (99, 108))	('cancers', 'Phenotype', 'HP:0002664', (137, 144))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('squamous cell lung cancers', 'Disease', 'MESH:D002294', (118, 144))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (155, 175))	('squamous cell lung cancers', 'Disease', (118, 144))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (155, 174))	('carcinoma', 'Phenotype', 'HP:0030731', (165, 174))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (155, 175))	('lung cancer', 'Disease', (3, 14))	('mutations', 'Var', (20, 29))	('lung adenocarcinomas', 'Disease', (155, 175))	('carcinomas', 'Phenotype', 'HP:0030731', (165, 175))	('lung cancer', 'Disease', 'MESH:D008175', (132, 143))	('lung cancer', 'Phenotype', 'HP:0100526', (132, 143))	('lung cancer', 'Disease', 'MESH:D008175', (3, 14))	('lung cancers', 'Phenotype', 'HP:0100526', (132, 144))
203728	27912828	MET amplifications are found in 4% of lung adenocarcinomas and 1% of squamous cell lung cancers and are associated with sensitivity to MET inhibitors.	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (38, 58))	('MET amplifications', 'Var', (0, 18))	('carcinomas', 'Phenotype', 'HP:0030731', (48, 58))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (38, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (48, 57))	('squamous cell lung cancers', 'Disease', (69, 95))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (38, 57))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('lung adenocarcinomas', 'Disease', (38, 58))	('lung cancer', 'Phenotype', 'HP:0100526', (83, 94))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('lung cancers', 'Phenotype', 'HP:0100526', (83, 95))	('squamous cell lung cancers', 'Disease', 'MESH:D002294', (69, 95))
203730	27912828	Activating point mutations affecting splice sites of exon 14 of the MET gene (METex14), which occur in 4% of lung adenocarcinomas, represent a possible oncogenic driver and identify a subset of patients who may benefit from MET inhibitors such as capmatinib and crizotinib.	('patients', 'Species', '9606', (194, 202))	('capmatinib', 'Chemical', 'MESH:C000613976', (247, 257))	('lung adenocarcinomas', 'Disease', (109, 129))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (109, 128))	('carcinomas', 'Phenotype', 'HP:0030731', (119, 129))	('point mutations', 'Var', (11, 26))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (109, 129))	('benefit', 'PosReg', (211, 218))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('crizotinib', 'Chemical', 'MESH:D000077547', (262, 272))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (109, 129))
203734	27912828	When activated by oncogenic mutations, BRAF phosphorylates MEK and promotes cell growth, proliferation, and survival.	('proliferation', 'CPA', (89, 102))	('promotes', 'PosReg', (67, 75))	('BRAF', 'Gene', '673', (39, 43))	('MEK', 'Gene', (59, 62))	('BRAF', 'Gene', (39, 43))	('MEK', 'Gene', '5609', (59, 62))	('survival', 'CPA', (108, 116))	('rat', 'Species', '10116', (96, 99))	('cell growth', 'CPA', (76, 87))	('mutations', 'Var', (28, 37))
203735	27912828	The highest incidence of BRAF mutation is in malignant melanoma (27%-70%), followed by papillary thyroid cancer, colorectal cancer, and serous ovarian cancer.	('colorectal cancer', 'Disease', (113, 130))	('ovarian cancer', 'Phenotype', 'HP:0100615', (143, 157))	('thyroid cancer', 'Phenotype', 'HP:0002890', (97, 111))	('mutation', 'Var', (30, 38))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('serous ovarian cancer', 'Disease', (136, 157))	('melanoma', 'Phenotype', 'HP:0002861', (55, 63))	('malignant melanoma', 'Disease', (45, 63))	('papillary thyroid cancer', 'Disease', (87, 111))	('colorectal cancer', 'Phenotype', 'HP:0003003', (113, 130))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('papillary thyroid cancer', 'Phenotype', 'HP:0002895', (87, 111))	('serous ovarian cancer', 'Disease', 'MESH:D010051', (136, 157))	('malignant melanoma', 'Phenotype', 'HP:0002861', (45, 63))	('colorectal cancer', 'Disease', 'MESH:D015179', (113, 130))	('malignant melanoma', 'Disease', 'MESH:D008545', (45, 63))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('BRAF', 'Gene', '673', (25, 29))	('papillary thyroid cancer', 'Disease', 'MESH:D000077273', (87, 111))	('BRAF', 'Gene', (25, 29))
203736	27912828	BRAF mutations have also been reported in 1% to 3% of NSCLCs.	('reported', 'Reg', (30, 38))	('NSCLC', 'Phenotype', 'HP:0030358', (54, 59))	('mutations', 'Var', (5, 14))	('BRAF', 'Gene', '673', (0, 4))	('NSCLC', 'Disease', (54, 59))	('BRAF', 'Gene', (0, 4))	('NSCLC', 'Disease', 'MESH:D002289', (54, 59))
203737	27912828	In contrast to melanoma, only half of BRAF mutations in NSCLC are V600E mutations.	('melanoma', 'Phenotype', 'HP:0002861', (15, 23))	('melanoma', 'Disease', (15, 23))	('V600E', 'Var', (66, 71))	('NSCLC', 'Disease', (56, 61))	('melanoma', 'Disease', 'MESH:D008545', (15, 23))	('BRAF', 'Gene', '673', (38, 42))	('NSCLC', 'Disease', 'MESH:D002289', (56, 61))	('mutations', 'Var', (43, 52))	('BRAF', 'Gene', (38, 42))	('NSCLC', 'Phenotype', 'HP:0030358', (56, 61))	('V600E', 'Mutation', 'rs113488022', (66, 71))
203738	27912828	Other non-V600E mutations reported in NSCLC include G469A (~35%) and D594G (~10%).	('NSCLC', 'Disease', (38, 43))	('G469A', 'Mutation', 'rs121913355', (52, 57))	('non-V600E', 'Var', (6, 15))	('NSCLC', 'Disease', 'MESH:D002289', (38, 43))	('D594G', 'Var', (69, 74))	('NSCLC', 'Phenotype', 'HP:0030358', (38, 43))	('V600E', 'Mutation', 'rs113488022', (10, 15))	('G469A', 'Var', (52, 57))	('D594G', 'Mutation', 'rs121913338', (69, 74))
203739	27912828	All BRAF mutations are mutually exclusive with other driver alterations such as those of EGFR, KRAS, and ALK.	('rat', 'Species', '10116', (64, 67))	('mutations', 'Var', (9, 18))	('BRAF', 'Gene', '673', (4, 8))	('BRAF', 'Gene', (4, 8))
203741	27912828	Nevertheless, patients with NSCLC and BRAF V600E mutations have a worse prognosis and lower response to platinum-based chemotherapy than patients with wild-type BRAF.	('platinum', 'Chemical', 'MESH:D010984', (104, 112))	('NSCLC', 'Disease', (28, 33))	('response to platinum-based chemotherapy', 'MPA', (92, 131))	('NSCLC', 'Disease', 'MESH:D002289', (28, 33))	('V600E', 'Mutation', 'rs113488022', (43, 48))	('lower', 'NegReg', (86, 91))	('BRAF', 'Gene', '673', (38, 42))	('BRAF', 'Gene', (161, 165))	('BRAF', 'Gene', '673', (161, 165))	('patients', 'Species', '9606', (137, 145))	('BRAF', 'Gene', (38, 42))	('NSCLC', 'Phenotype', 'HP:0030358', (28, 33))	('patients', 'Species', '9606', (14, 22))	('V600E', 'Var', (43, 48))
203743	27912828	BRAF inhibitors, such as vemurafenib and dabrafenib, have high and selective activity against the V600E-mutant BRAF kinase, with overall responses rates from 33% to 42%.	('vemurafenib', 'Chemical', 'MESH:D000077484', (25, 36))	('V600E', 'Mutation', 'rs113488022', (98, 103))	('BRAF', 'Gene', '673', (0, 4))	('rat', 'Species', '10116', (147, 150))	('BRAF', 'Gene', '673', (111, 115))	('BRAF', 'Gene', (0, 4))	('dabrafenib', 'Chemical', 'MESH:C561627', (41, 51))	('BRAF', 'Gene', (111, 115))	('V600E-mutant', 'Var', (98, 110))
203744	27912828	BRAF and MEK inhibitors targeting BRAF mutation-positive NSCLC, such as trametinib, selumetinib, and dasatinib, among others, are currently under evaluation in clinical trials.	('NSCLC', 'Disease', (57, 62))	('mutation-positive', 'Var', (39, 56))	('MEK', 'Gene', '5609', (9, 12))	('NSCLC', 'Phenotype', 'HP:0030358', (57, 62))	('selumetinib', 'Chemical', 'MESH:C517975', (84, 95))	('BRAF', 'Gene', '673', (0, 4))	('BRAF', 'Gene', '673', (34, 38))	('dasatinib', 'Chemical', 'MESH:D000069439', (101, 110))	('MEK', 'Gene', (9, 12))	('trametinib', 'Chemical', 'MESH:C560077', (72, 82))	('BRAF', 'Gene', (0, 4))	('BRAF', 'Gene', (34, 38))	('NSCLC', 'Disease', 'MESH:D002289', (57, 62))
203746	27912828	PKI3CA amplifications, deletions, and somatic missense mutations have been reported in many tumors including lung cancers.	('deletions', 'Var', (23, 32))	('missense mutations', 'Var', (46, 64))	('PKI3CA', 'Gene', (0, 6))	('tumors', 'Disease', 'MESH:D009369', (92, 98))	('lung cancer', 'Phenotype', 'HP:0100526', (109, 120))	('cancers', 'Phenotype', 'HP:0002664', (114, 121))	('lung cancers', 'Disease', 'MESH:D008175', (109, 121))	('lung cancers', 'Phenotype', 'HP:0100526', (109, 121))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('lung cancers', 'Disease', (109, 121))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('tumors', 'Disease', (92, 98))	('reported', 'Reg', (75, 83))
203748	27912828	Mutations are found in 1% to 4% of patients with NSCLC, usually affecting exons 9 and 20 (80%).	('NSCLC', 'Disease', (49, 54))	('affecting', 'Reg', (64, 73))	('NSCLC', 'Disease', 'MESH:D002289', (49, 54))	('Mutations', 'Var', (0, 9))	('patients', 'Species', '9606', (35, 43))	('NSCLC', 'Phenotype', 'HP:0030358', (49, 54))
203749	27912828	These mutations are not mutually exclusive with other driver alterations and have been reported more frequently in lung squamous cell carcinoma compared to adenocarcinoma (6.5% vs 1.5%).	('adenocarcinoma', 'Disease', (156, 170))	('adenocarcinoma', 'Disease', 'MESH:D000230', (156, 170))	('rat', 'Species', '10116', (65, 68))	('reported', 'Reg', (87, 95))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (115, 143))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (120, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (115, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (161, 170))	('lung squamous cell carcinoma', 'Disease', (115, 143))	('mutations', 'Var', (6, 15))
203750	27912828	However, PIK3CA mutations have not shown association with any clinicopathologic features.	('PIK3CA', 'Gene', '5290', (9, 15))	('mutations', 'Var', (16, 25))	('PIK3CA', 'Gene', (9, 15))
203752	27912828	Studies have shown that PIK3CA mutations in EGFR-mutated lung cancer confer resistance to EGFRTKIs and are a negative prognostic predictor in patients with NSCLC treated with EGFR-TKIs.	('resistance to EGFRTKIs', 'MPA', (76, 98))	('mutations', 'Var', (31, 40))	('PIK3CA', 'Gene', (24, 30))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('NSCLC', 'Phenotype', 'HP:0030358', (156, 161))	('lung cancer', 'Disease', 'MESH:D008175', (57, 68))	('PIK3CA', 'Gene', '5290', (24, 30))	('EGFR-mutated', 'Gene', (44, 56))	('NSCLC', 'Disease', (156, 161))	('negative', 'NegReg', (109, 117))	('patients', 'Species', '9606', (142, 150))	('NSCLC', 'Disease', 'MESH:D002289', (156, 161))	('lung cancer', 'Disease', (57, 68))	('lung cancer', 'Phenotype', 'HP:0100526', (57, 68))
203753	27912828	PI3KCA alterations and their downstream effectors, such as phosphatase and tensin homolog (PTEN), mTOR, and AKT, are potential therapeutic targets for NSCLC therapy and are being evaluated in clinical trials for lung cancer.	('AKT', 'Gene', '207', (108, 111))	('NSCLC', 'Disease', (151, 156))	('lung cancer', 'Disease', (212, 223))	('lung cancer', 'Phenotype', 'HP:0100526', (212, 223))	('PI3KCA', 'Gene', (0, 6))	('NSCLC', 'Disease', 'MESH:D002289', (151, 156))	('AKT', 'Gene', (108, 111))	('mTOR', 'Gene', '2475', (98, 102))	('lung cancer', 'Disease', 'MESH:D008175', (212, 223))	('rat', 'Species', '10116', (11, 14))	('NSCLC', 'Phenotype', 'HP:0030358', (151, 156))	('PTEN', 'Gene', (91, 95))	('mTOR', 'Gene', (98, 102))	('PTEN', 'Gene', '5728', (91, 95))	('alterations', 'Var', (7, 18))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))
203757	27912828	NTRK1 rearrangements have been found in colon cancer, thyroid cancer, and glioblastoma multiforme.	('NTRK1', 'Gene', (0, 5))	('colon cancer', 'Phenotype', 'HP:0003003', (40, 52))	('colon cancer', 'Disease', 'MESH:D015179', (40, 52))	('rearrangements', 'Var', (6, 20))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('glioblastoma multiforme', 'Disease', (74, 97))	('thyroid cancer', 'Disease', (54, 68))	('NTRK1', 'Gene', '4914', (0, 5))	('colon cancer', 'Disease', (40, 52))	('glioblastoma', 'Phenotype', 'HP:0012174', (74, 86))	('thyroid cancer', 'Phenotype', 'HP:0002890', (54, 68))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (74, 97))	('found', 'Reg', (31, 36))	('thyroid cancer', 'Disease', 'MESH:D013964', (54, 68))
203758	27912828	In lung cancer, approximately 3% of adenocarcinomas harbor NTRK1 fusions, and some fusion partners, including myosin phosphatase RHO-interacting protein (MPRIP)-NTRK1 and CD74-NTRK1, have been reported.	('NTRK1', 'Gene', (59, 64))	('myosin phosphatase RHO-interacting protein', 'Gene', (110, 152))	('lung cancer', 'Phenotype', 'HP:0100526', (3, 14))	('NTRK1', 'Gene', '4914', (161, 166))	('adenocarcinomas', 'Disease', 'MESH:D000230', (36, 51))	('NTRK1', 'Gene', (161, 166))	('NTRK1', 'Gene', '4914', (176, 181))	('adenocarcinomas', 'Disease', (36, 51))	('carcinoma', 'Phenotype', 'HP:0030731', (41, 50))	('carcinomas', 'Phenotype', 'HP:0030731', (41, 51))	('NTRK1', 'Gene', (176, 181))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('MPRIP', 'Gene', '23164', (154, 159))	('lung cancer', 'Disease', (3, 14))	('CD74', 'Gene', '972', (171, 175))	('fusions', 'Var', (65, 72))	('MPRIP', 'Gene', (154, 159))	('myosin phosphatase RHO-interacting protein', 'Gene', '23164', (110, 152))	('NTRK1', 'Gene', '4914', (59, 64))	('lung cancer', 'Disease', 'MESH:D008175', (3, 14))	('CD74', 'Gene', (171, 175))
203759	27912828	All of these fusions result in constitutive TRKA kinase activity, which has been reported to be oncogenic.	('TRK', 'Gene', (44, 47))	('result in', 'Reg', (21, 30))	('TRK', 'Gene', '4914', (44, 47))	('fusions', 'Var', (13, 20))
203760	27912828	In early phase 1 studies, NTRK inhibitors, such as entrectinib and LOXO-101, have shown promising results in patients with solid tumors harboring NTRK fusions.	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('patients', 'Species', '9606', (109, 117))	('solid tumors', 'Disease', (123, 135))	('NTRK', 'Gene', '4914', (146, 150))	('solid tumors', 'Disease', 'MESH:D009369', (123, 135))	('NTRK', 'Gene', (26, 30))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('entrectinib', 'Chemical', 'MESH:C000607349', (51, 62))	('NTRK', 'Gene', '4914', (26, 30))	('LOXO-101', 'Chemical', 'MESH:C000609083', (67, 75))	('fusions', 'Var', (151, 158))	('NTRK', 'Gene', (146, 150))
203762	27912828	In cancer, FGFR gene amplifications, somatic missense mutations, and chromosomal translocations are the most frequent mechanisms of activation.	('activation', 'PosReg', (132, 142))	('chromosomal translocations', 'Var', (69, 95))	('amplifications', 'Var', (21, 35))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('cancer', 'Disease', (3, 9))	('FGFR gene', 'Gene', (11, 20))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
203764	27912828	In lung cancer, the incidence of FGFR1 amplification is significantly higher in squamous cell carcinoma (20%) compared to adenocarcinoma (3%) and is more frequent in current smokers compared to former and never smokers.	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('higher', 'Reg', (70, 76))	('adenocarcinoma', 'Disease', (122, 136))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (80, 103))	('lung cancer', 'Disease', (3, 14))	('FGFR1', 'Gene', '2260', (33, 38))	('lung cancer', 'Phenotype', 'HP:0100526', (3, 14))	('squamous cell carcinoma', 'Disease', (80, 103))	('amplification', 'Var', (39, 52))	('adenocarcinoma', 'Disease', 'MESH:D000230', (122, 136))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (80, 103))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('lung cancer', 'Disease', 'MESH:D008175', (3, 14))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('FGFR1', 'Gene', (33, 38))
203765	27912828	Other specific clinic-demographic features also correlate with FGFR1 amplification.	('FGFR1', 'Gene', (63, 68))	('FGFR1', 'Gene', '2260', (63, 68))	('amplification', 'Var', (69, 82))
203766	27912828	Some studies have recognized FGFR amplification as an independent negative prognostic factor in patients with NSCLC, whereas other studies have shown the opposite.	('NSCLC', 'Disease', (110, 115))	('NSCLC', 'Disease', 'MESH:D002289', (110, 115))	('negative', 'NegReg', (66, 74))	('patients', 'Species', '9606', (96, 104))	('amplification', 'Var', (34, 47))	('FGFR', 'Gene', (29, 33))	('NSCLC', 'Phenotype', 'HP:0030358', (110, 115))
203767	27912828	In addition, FGFR amplifications may be found in concurrence with other tumor genetic alterations including TP53 and PIK3CA mutation and platelet-derived growth factor receptor A (PDGFRA) amplification.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('FGFR', 'Gene', (13, 17))	('TP53', 'Gene', '7157', (108, 112))	('PDGFRA', 'Gene', (180, 186))	('TP53', 'Gene', (108, 112))	('platelet-derived growth factor receptor A', 'Gene', (137, 178))	('tumor', 'Disease', (72, 77))	('amplification', 'Var', (188, 201))	('PDGFRA', 'Gene', '5156', (180, 186))	('PIK3CA', 'Gene', (117, 123))	('platelet-derived growth factor receptor A', 'Gene', '5156', (137, 178))	('amplifications', 'Var', (18, 32))	('PIK3CA', 'Gene', '5290', (117, 123))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('rat', 'Species', '10116', (90, 93))
203768	27912828	Somatic FGFR mutations in lung tumors usually occur in FGFR2 and FGFR3 and have been detected in 6% of lung squamous cell carcinomas.	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('lung tumors', 'Phenotype', 'HP:0100526', (26, 37))	('FGFR2', 'Gene', '2263', (55, 60))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (108, 132))	('FGFR', 'Gene', (8, 12))	('lung squamous cell carcinomas', 'Disease', (103, 132))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('lung tumors', 'Disease', (26, 37))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (103, 131))	('occur', 'Reg', (46, 51))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (108, 131))	('FGFR3', 'Gene', (65, 70))	('mutations', 'Var', (13, 22))	('FGFR3', 'Gene', '2261', (65, 70))	('FGFR2', 'Gene', (55, 60))	('lung squamous cell carcinomas', 'Disease', 'MESH:D002294', (103, 132))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('carcinomas', 'Phenotype', 'HP:0030731', (122, 132))	('lung tumors', 'Disease', 'MESH:D008175', (26, 37))
203770	27912828	Phase 1 and 2 clinical trials of FGFR inhibitors (dovitinib, nintedanib, ponatinib, and AZD4547, among others) are ongoing in patients with NSCLC.	('dovitinib', 'Chemical', 'MESH:C500007', (50, 59))	('NSCLC', 'Disease', 'MESH:D002289', (140, 145))	('nintedanib', 'Chemical', 'MESH:C530716', (61, 71))	('NSCLC', 'Phenotype', 'HP:0030358', (140, 145))	('patients', 'Species', '9606', (126, 134))	('AZD4547', 'Var', (88, 95))	('FGFR', 'Gene', (33, 37))	('ponatinib', 'Chemical', 'MESH:C545373', (73, 82))	('AZD4547', 'Chemical', 'MESH:C572463', (88, 95))	('NSCLC', 'Disease', (140, 145))
203773	27912828	In cancer, DDR2 mutations have been reported in melanoma as well as uterine, gastric, bladder, and colorectal cancers.	('colorectal cancers', 'Disease', 'MESH:D015179', (99, 117))	('melanoma', 'Phenotype', 'HP:0002861', (48, 56))	('DDR2', 'Gene', (11, 15))	('melanoma', 'Disease', (48, 56))	('mutations', 'Var', (16, 25))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('uterine', 'Disease', (68, 75))	('cancers', 'Phenotype', 'HP:0002664', (110, 117))	('colorectal cancer', 'Phenotype', 'HP:0003003', (99, 116))	('cancer', 'Disease', (110, 116))	('colorectal cancers', 'Disease', (99, 117))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('gastric', 'Disease', (77, 84))	('melanoma', 'Disease', 'MESH:D008545', (48, 56))	('reported', 'Reg', (36, 44))	('cancer', 'Disease', (3, 9))	('DDR2', 'Gene', '4921', (11, 15))	('bladder', 'Disease', (86, 93))	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
203774	27912828	In lung cancer, DDR2 mutations occur in 3% to 4% of lung squamous cell carcinomas compared to 0.5% of adenocarcinomas and are only present in smokers.	('adenocarcinomas', 'Disease', 'MESH:D000230', (102, 117))	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('carcinomas', 'Phenotype', 'HP:0030731', (107, 117))	('lung squamous cell carcinomas', 'Disease', (52, 81))	('DDR2', 'Gene', '4921', (16, 20))	('lung cancer', 'Disease', (3, 14))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (52, 80))	('lung cancer', 'Phenotype', 'HP:0100526', (3, 14))	('adenocarcinomas', 'Disease', (102, 117))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (57, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (57, 81))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('DDR2', 'Gene', (16, 20))	('lung squamous cell carcinomas', 'Disease', 'MESH:D002294', (52, 81))	('carcinomas', 'Phenotype', 'HP:0030731', (71, 81))	('lung cancer', 'Disease', 'MESH:D008175', (3, 14))	('mutations', 'Var', (21, 30))
203775	27912828	At least 11 different DDR2 mutations have been identified distributed throughout the gene and include the extracellular-binding discoidin domain and the cytoplasmic kinase domain.	('mutations', 'Var', (27, 36))	('DDR2', 'Gene', (22, 26))	('DDR2', 'Gene', '4921', (22, 26))
203776	27912828	DDR2 mutations have been associated with response to dasatinib (a multitargeted kinase inhibitor) in preclinical models and early phase clinical trials.	('dasatinib', 'Chemical', 'MESH:D000069439', (53, 62))	('associated', 'Reg', (25, 35))	('DDR2', 'Gene', '4921', (0, 4))	('mutations', 'Var', (5, 14))	('response', 'MPA', (41, 49))	('DDR2', 'Gene', (0, 4))
203790	27912828	A recent study has reported that greater nonsynonymous mutation burden is associated with improved objective response, durable clinical benefit, and PFS in patients with NSCLC treated with pembrolizumab.	('pembrolizumab', 'Chemical', 'MESH:C582435', (189, 202))	('patients', 'Species', '9606', (156, 164))	('NSCLC', 'Phenotype', 'HP:0030358', (170, 175))	('nonsynonymous mutation burden', 'Var', (41, 70))	('PFS', 'Disease', (149, 152))	('improved', 'PosReg', (90, 98))	('NSCLC', 'Disease', (170, 175))	('NSCLC', 'Disease', 'MESH:D002289', (170, 175))	('objective', 'MPA', (99, 108))
203791	27912828	Furthermore, IHC PD-L1 positivity in NSCLC has been identified as a potential predictor of response to anti- PD-1 and anti-PD-L1 monoclonal antibody therapy and also as a prognostic biomarker.	('NSCLC', 'Disease', 'MESH:D002289', (37, 42))	('PD-L1', 'Gene', '29126', (17, 22))	('NSCLC', 'Phenotype', 'HP:0030358', (37, 42))	('NSCLC', 'Disease', (37, 42))	('PD-L1', 'Gene', (123, 128))	('PD-1', 'Gene', '5133', (109, 113))	('PD-L1', 'Gene', (17, 22))	('PD-1', 'Gene', (109, 113))	('PD-L1', 'Gene', '29126', (123, 128))	('positivity', 'Var', (23, 33))
203987	33628089	Conclusions: HNF4a plays different roles in different malignancies, and the abnormal expression of HNF4a has a great correlation with the biological characteristics of BLCA.	('expression', 'MPA', (85, 95))	('malignancies', 'Disease', (54, 66))	('abnormal', 'Var', (76, 84))	('correlation', 'Reg', (117, 128))	('malignancies', 'Disease', 'MESH:D009369', (54, 66))	('BLCA', 'Disease', (168, 172))	('HNF4a', 'Gene', (99, 104))
203992	33628089	It has been shown that HNF4a can not only reduce or inhibit cell proliferation but can also accelerate the differentiation speed of poorly differentiated liver cancer by re-expressing HNF4a in liver cancer and maintaining a highly differentiated phenotype, which reduces its invasiveness.	('re-expressing', 'Var', (170, 183))	('invasiveness', 'CPA', (275, 287))	('inhibit', 'NegReg', (52, 59))	('cell proliferation', 'CPA', (60, 78))	('liver cancer', 'Disease', 'MESH:D006528', (154, 166))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('liver cancer', 'Phenotype', 'HP:0002896', (154, 166))	('HNF4a', 'Gene', (184, 189))	('liver cancer', 'Disease', (154, 166))	('liver cancer', 'Phenotype', 'HP:0002896', (193, 205))	('reduce', 'NegReg', (42, 48))	('liver cancer', 'Disease', 'MESH:D006528', (193, 205))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('reduces', 'NegReg', (263, 270))	('maintaining', 'Reg', (210, 221))	('accelerate', 'PosReg', (92, 102))	('liver cancer', 'Disease', (193, 205))	('differentiation speed', 'CPA', (107, 128))
204005	33628089	It was shown in our study that patients with high HNF4a expression showed a significantly longer overall survival (OS, p < 0.05) than patients with low HNF4a expression in BLCA, KIRC, and READ, while patients with high expression of HNF4a exhibited a significantly shorter OS (p < 0.05) than patients with low expression of HNF4a in LUSC (Figure 1).	('high HNF4a', 'Var', (45, 55))	('patients', 'Species', '9606', (200, 208))	('overall survival', 'MPA', (97, 113))	('patients', 'Species', '9606', (292, 300))	('patients', 'Species', '9606', (134, 142))	('longer', 'PosReg', (90, 96))	('patients', 'Species', '9606', (31, 39))	('HNF4a', 'Var', (50, 55))
204033	33628089	The overall survival time of patients with high expression of the HNF4a protein is long, whereas, the overall survival time of patients with low HNF4a protein expression is short.	('patients', 'Species', '9606', (29, 37))	('HNF4a', 'Gene', (66, 71))	('high', 'Var', (43, 47))	('expression', 'MPA', (48, 58))	('patients', 'Species', '9606', (127, 135))
204199	31024612	Together, modularized perturbation of splicing represents an functionally important and common mechanism across cancer types.	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('perturbation', 'Var', (22, 34))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('cancer', 'Disease', (112, 118))
204200	31024612	Deregulation of AS also contributes to human diseases and various aspects of cancer development (David and Manley,; Scotti and Swanson,).	('Scotti', 'Disease', (116, 122))	('Deregulation', 'Var', (0, 12))	('cancer', 'Disease', (77, 83))	('Manley', 'Disease', (107, 113))	('human diseases', 'Disease', (39, 53))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('contributes', 'Reg', (24, 35))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('human', 'Species', '9606', (39, 44))	('Swanson', 'Disease', (127, 134))
204218	31024612	The splicing classes included are exon skipping (ES), retention of introns (RI), alternative donor (AD), alternative acceptor (AA), mutually exclusive exons (ME), alternative terminator (AT).	('AT', 'Disease', 'None', (187, 189))	('AD', 'Disease', 'MESH:D000544', (100, 102))	('AD', 'Disease', (100, 102))	('exon skipping', 'Var', (34, 47))	('donor', 'Species', '9606', (93, 98))
204219	31024612	The numbers of quantified events were found in at least 99% of the samples in each cancer type range from 21129 to 43937 across the cancer types.	('21129', 'Var', (106, 111))	('43937', 'Var', (115, 120))	('cancer', 'Disease', (132, 138))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('cancer', 'Disease', (83, 89))
204260	30463017	Interrogation of a set of soluble receptors revealed that TMPRSS11B promotes solubilization of Basigin, an obligate chaperone of the lactate monocarboxylate transporter MCT4.	('MCT4', 'Gene', (169, 173))	('promotes', 'PosReg', (68, 76))	('TMPRSS11B', 'Var', (58, 67))	('solubilization', 'MPA', (77, 91))	('MCT4', 'Gene', '9123', (169, 173))	('lactate', 'Chemical', 'MESH:D019344', (133, 140))	('Basigin', 'Gene', '682', (95, 102))	('Basigin', 'Gene', (95, 102))
204286	30463017	To identify genes that promote transformation of human bronchial epithelial cells (HBECs), we performed Sleeping Beauty (SB)-mediated transposon mutagenesis of immortalized HBECs stably expressing CDK4, human telomerase reverse transcriptase (hTERT), and short hairpin RNA (shRNA) targeting TP53 (HBEC-shp53).	('hTERT', 'Gene', '7015', (243, 248))	('TP53', 'Gene', (291, 295))	('telomerase reverse transcriptase', 'Gene', '7015', (209, 241))	('N', 'Chemical', 'MESH:D009584', (270, 271))	('hTERT', 'Gene', (243, 248))	('mutagenesis', 'Var', (145, 156))	('human', 'Species', '9606', (203, 208))	('N', 'Chemical', 'MESH:D009584', (277, 278))	('human', 'Species', '9606', (49, 54))	('CDK4', 'Gene', '1019', (197, 201))	('CDK4', 'Gene', (197, 201))	('TP53', 'Gene', '7157', (291, 295))	('telomerase reverse transcriptase', 'Gene', (209, 241))
204287	30463017	These cells progress to full malignancy upon overexpression of oncogenes such as KRASG12V and MYC.	('MYC', 'Disease', (94, 97))	('malignancy', 'Disease', 'MESH:D009369', (29, 39))	('malignancy', 'Disease', (29, 39))	('progress', 'PosReg', (12, 20))	('overexpression', 'PosReg', (45, 59))	('KRASG12V', 'Var', (81, 89))
204292	30463017	Moreover, high expression of TMPRSS11B mRNA correlated with poor overall survival in NSCLC patients, warranting further investigation of the role of this enzyme in tumorigenesis (Figure S1B).	('NSCLC', 'Disease', (85, 90))	('TMPRSS11B', 'Gene', (29, 38))	('tumor', 'Disease', (164, 169))	('patients', 'Species', '9606', (91, 99))	('NSCLC', 'Disease', 'MESH:D002289', (85, 90))	('poor', 'NegReg', (60, 64))	('N', 'Chemical', 'MESH:D009584', (85, 86))	('NSCLC', 'Phenotype', 'HP:0030358', (85, 90))	('expression', 'MPA', (15, 25))	('high', 'Var', (10, 14))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('N', 'Chemical', 'MESH:D009584', (41, 42))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('overall survival', 'MPA', (65, 81))
204294	30463017	To test whether catalytic function is necessary for transforming activity, we mutated residues in the catalytic triad of this family of proteases (D270N and S366A) (Figure 1A).	('S366A', 'Mutation', 'rs17881470', (157, 162))	('D270N', 'Var', (147, 152))	('D270N', 'Mutation', 'p.D270N', (147, 152))	('S366A', 'Var', (157, 162))
204295	30463017	The S366A mutation resulted in faster migration of the protein, consistent with disruption of a nearby N-linked glycosylation site (Figures S2A and S2B).	('S366A', 'Mutation', 'rs17881470', (4, 9))	('faster', 'PosReg', (31, 37))	('S366A', 'Var', (4, 9))	('protein', 'Protein', (55, 62))	('N', 'Chemical', 'MESH:D009584', (103, 104))	('migration', 'MPA', (38, 47))
204297	30463017	To determine whether inhibition of TMPRSS11B limits tumor growth, we performed loss-of-function studies using shRNAmediated knockdown and CRISPR-mediated genome editing.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('limits', 'NegReg', (45, 51))	('tumor', 'Disease', (52, 57))	('N', 'Chemical', 'MESH:D009584', (113, 114))	('inhibition', 'Var', (21, 31))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('TMPRSS11B', 'Gene', (35, 44))
204299	30463017	Xenograft assays in immunocompromised non-obese diabetic/severe combined immunodeficiency (NOD/SCID) Il2rggamma_/_ (NSG) mice demonstrated a strong impairment of tumorigenesis following depletion of TMPRSS11B in each of these cell lines (Figures 1E-1G; Figure S2D).	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('N', 'Chemical', 'MESH:D009584', (116, 117))	('immunodeficiency', 'Phenotype', 'HP:0002721', (73, 89))	('combined immunodeficiency', 'Phenotype', 'HP:0005387', (64, 89))	('immunodeficiency', 'Disease', (73, 89))	('immunodeficiency', 'Disease', 'MESH:D007153', (73, 89))	('tumor', 'Disease', (162, 167))	('N', 'Chemical', 'MESH:D009584', (91, 92))	('impairment', 'NegReg', (148, 158))	('SCID', 'Gene', '19090', (95, 99))	('mice', 'Species', '10090', (121, 125))	('TMPRSS11B', 'Gene', (199, 208))	('obese diabetic', 'Disease', (42, 56))	('SCID', 'Gene', (95, 99))	('obese diabetic', 'Disease', 'MESH:D009765', (42, 56))	('depletion', 'Var', (186, 195))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('/severe combined immunodeficiency', 'Phenotype', 'HP:0004430', (56, 89))
204300	30463017	To confirm these findings, we mutated the endogenous TMPRSS11B locus using CRISPR-mediated genome editing in HCC2814 cells.	('HCC2814', 'CellLine', 'CVCL:V586', (109, 116))	('TMPRSS11B', 'Gene', (53, 62))	('mutated', 'Var', (30, 37))
204302	30463017	Altogether, these data demonstrate that inhibition of TMPRSS11B impairs tumorigenesis, raising the possibility that targeting TMPRSS11B may provide a therapeutic strategy in LSCC.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('TMPRSS11B', 'Gene', (54, 63))	('inhibition', 'Var', (40, 50))	('impairs', 'NegReg', (64, 71))	('tumor', 'Disease', (72, 77))	('LSCC', 'Disease', (174, 178))	('LSCC', 'Phenotype', 'HP:0030359', (174, 178))	('tumor', 'Disease', 'MESH:D009369', (72, 77))
204304	30463017	This revealed an ~10-fold enrichment in the levels of soluble Basigin/CD147 in conditioned media from cells expressing TMPRSS11B (Figures 2A and 2B).	('TMPRSS11B', 'Var', (119, 128))	('Basigin', 'Gene', (62, 69))	('CD147', 'Gene', '682', (70, 75))	('Basigin', 'Gene', '682', (62, 69))	('CD147', 'Gene', (70, 75))
204310	30463017	Furthermore, similar levels of Basigin mRNA and protein were observed in LSCC cells with control and TMPRSS11B shRNA and in AEBSF-treated HBEC-shp53 cells (Figures S3E-S3H).	('N', 'Chemical', 'MESH:D009584', (114, 115))	('Basigin', 'Gene', '682', (31, 38))	('Basigin', 'Gene', (31, 38))	('AEBSF', 'Chemical', 'MESH:C002010', (124, 129))	('TMPRSS11B', 'Var', (101, 110))	('LSCC', 'Phenotype', 'HP:0030359', (73, 77))	('N', 'Chemical', 'MESH:D009584', (41, 42))
204313	30463017	Conditioned media from HBEC-shp53 cells expressing GFP, TMPRSS11B-D270N, TMPRSS11B-S366A, or WT TMPRSS11B were transferred to untransfected HBEC-shp53 cells.	('D270N', 'Mutation', 'p.D270N', (66, 71))	('TMPRSS11B-S366A', 'Var', (73, 88))	('S366A', 'Mutation', 'rs17881470', (83, 88))	('TMPRSS11B-D270N', 'Var', (56, 71))	('GFP', 'Var', (51, 54))
204321	30463017	TMPRSS11B knockdown in HCC2814 cells resulted in less distinct membrane staining of Basigin relative to control cells (Figure S4B).	('TMPRSS11B', 'Gene', (0, 9))	('Basigin', 'Gene', '682', (84, 91))	('Basigin', 'Gene', (84, 91))	('HCC2814', 'CellLine', 'CVCL:V586', (23, 30))	('knockdown', 'Var', (10, 19))	('less', 'NegReg', (49, 53))
204322	30463017	Total levels of cellular Basigin remain unchanged in these cells (Figure S3F), suggesting that TMPRSS11B may influence trafficking of Basigin to the plasma membrane.	('TMPRSS11B', 'Var', (95, 104))	('Basigin', 'Gene', '682', (25, 32))	('Basigin', 'Gene', (25, 32))	('influence', 'Reg', (109, 118))	('Basigin', 'Gene', '682', (134, 141))	('Basigin', 'Gene', (134, 141))
204325	30463017	Moreover, Basigin and MCT4 are expressed similarly in control HBEC-shp53-GFP and HBEC-shp53-TMPRSS11B cells (Figure S3B), suggesting that membrane release of Basigin mediated by TMPRSS11B does not alter MCT4 expression.	('MCT4', 'Gene', '9123', (203, 207))	('TMPRSS11B', 'Var', (178, 187))	('Basigin', 'Gene', '682', (10, 17))	('Basigin', 'Gene', (10, 17))	('MCT4', 'Gene', (22, 26))	('MCT4', 'Gene', '9123', (22, 26))	('membrane release', 'MPA', (138, 154))	('MCT4', 'Gene', (203, 207))	('Basigin', 'Gene', '682', (158, 165))	('Basigin', 'Gene', (158, 165))
204328	30463017	However, stable expression of TMPRSS11B failed to significantly stimulate proliferation in Basigin knockout cells (Figure 4A), and TMPRSS11B-mediated anchorage-independent growth was reduced (Figure 4B).	('TMPRSS11B-mediated', 'Var', (131, 149))	('anchorage-independent growth', 'CPA', (150, 178))	('TMPRSS11B', 'Gene', (30, 39))	('reduced', 'NegReg', (183, 190))	('Basigin', 'Gene', '682', (91, 98))	('Basigin', 'Gene', (91, 98))
204331	30463017	Consistent with this hypothesis, intracellular lactate quantification revealed an ~25% reduction in steady-state lactate content of HBEC-shp53-TMPRSS11B compared with control HBEC-shp53-GFP cells (Figure 4C).	('lactate', 'Chemical', 'MESH:D019344', (113, 120))	('lactate', 'Chemical', 'MESH:D019344', (47, 54))	('reduction', 'NegReg', (87, 96))	('HBEC-shp53-TMPRSS11B', 'Var', (132, 152))	('lactate content', 'MPA', (113, 128))
204334	30463017	Extracellular flux analysis demonstrated that TMPRSS11B enhanced extracellular acidification rates (ECARs), a readout of glycolytic flux and a commonly used proxy for lactate secretion (Figure 4D).	('readout', 'MPA', (110, 117))	('lactate', 'Chemical', 'MESH:D019344', (167, 174))	('extracellular acidification rates', 'MPA', (65, 98))	('enhanced', 'PosReg', (56, 64))	('TMPRSS11B', 'Var', (46, 55))
204338	30463017	To distinguish between the roles of MCT1 and MCT4 in this system, we compared HBEC-shp53-TMPRSS11B cells with either MCT4 deletion or treatment with the chemical MCT1 inhibitor SR13800 and observed that ECAR was reduced dramatically in MCT4 KO cells but minimally upon MCT1 inhibition (Figure 4F; Figure S5D).	('MCT1', 'Gene', '6566', (36, 40))	('MCT4', 'Gene', (236, 240))	('MCT4', 'Gene', '9123', (117, 121))	('MCT4', 'Gene', '9123', (45, 49))	('MCT1', 'Gene', (162, 166))	('SR13800', 'Chemical', '-', (177, 184))	('deletion', 'Var', (122, 130))	('MCT4', 'Gene', (45, 49))	('MCT1', 'Gene', '6566', (162, 166))	('MCT4', 'Gene', '9123', (236, 240))	('MCT1', 'Gene', (269, 273))	('MCT1', 'Gene', (36, 40))	('ECAR', 'MPA', (203, 207))	('MCT1', 'Gene', '6566', (269, 273))	('reduced', 'NegReg', (212, 219))	('MCT4', 'Gene', (117, 121))
204339	30463017	Altogether, these findings provide evidence that TMPRSS11B enhances the lactate transport efficiency of Basigin/MCT4 complexes in HBEC-shp53 cells.	('Basigin', 'Gene', '682', (104, 111))	('Basigin', 'Gene', (104, 111))	('MCT4', 'Gene', (112, 116))	('TMPRSS11B', 'Var', (49, 58))	('lactate', 'Chemical', 'MESH:D019344', (72, 79))	('MCT4', 'Gene', '9123', (112, 116))	('enhances', 'PosReg', (59, 67))
204341	30463017	CRISPR-medi-ated genome editing was used to mutate the endogenous TMPRSS11B locus in polyclonal populations of the lung adenocarcinoma cell line H2073 and in clonal lines of HCC2814 cells (Figure S5E; Table S2).	('mutate', 'Var', (44, 50))	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('lung adenocarcinoma', 'Disease', (115, 134))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (115, 134))	('H2073', 'CellLine', 'CVCL:1521', (145, 150))	('TMPRSS11B', 'Gene', (66, 75))	('HCC2814', 'CellLine', 'CVCL:V586', (174, 181))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (115, 134))
204343	30463017	Increased intracellular lactate in TMPRSS11B KO clones was specifically due to TMPRSS11B loss of function, because restoring TMPRSS11B expression with cDNA harboring silent mutations in the single guide RNA (sgRNA) targeting site led to a significant reduction in intracellular lactate levels (Figure 5G).	('silent mutations', 'Var', (166, 182))	('N', 'Chemical', 'MESH:D009584', (153, 154))	('N', 'Chemical', 'MESH:D009584', (204, 205))	('loss of function', 'NegReg', (89, 105))	('N', 'Chemical', 'MESH:D009584', (211, 212))	('intracellular lactate', 'MPA', (10, 31))	('intracellular lactate levels', 'MPA', (264, 292))	('lactate', 'Chemical', 'MESH:D019344', (278, 285))	('TMPRSS11B', 'Gene', (79, 88))	('TMPRSS11B', 'Gene', (125, 134))	('lactate', 'Chemical', 'MESH:D019344', (24, 31))	('reduction', 'NegReg', (251, 260))	('Increased intracellular lactate', 'Phenotype', 'HP:0002151', (0, 31))
204345	30463017	To monitor the metabolic consequences of TMPRSS11B inhibition, we performed [1,6-13C]glucose tracing in HCC2814 cells with shRNA-mediated TMPRSS11B knockdown and observed a reduction in lactatem+1 export (Figure S7A) in the same cells in which we documented significant accumulation of steady-state intracellular lactate (Figure 5A).	('HCC2814', 'CellLine', 'CVCL:V586', (104, 111))	('reduction', 'NegReg', (173, 182))	('lactate', 'Chemical', 'MESH:D019344', (186, 193))	('lactate', 'Chemical', 'MESH:D019344', (313, 320))	('N', 'Chemical', 'MESH:D009584', (126, 127))	('lactatem', 'Chemical', '-', (186, 194))	('1,6-13C]glucose', 'Chemical', '-', (77, 92))	('TMPRSS11B', 'Gene', (138, 147))	('accumulation', 'PosReg', (270, 282))	('lactatem+1 export', 'MPA', (186, 203))	('knockdown', 'Var', (148, 157))
204346	30463017	Overall, our findings suggest that TMPRSS11B in LSCC enhances tumorigenesis by facilitating lactate export.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('lactate', 'Chemical', 'MESH:D019344', (92, 99))	('enhances', 'PosReg', (53, 61))	('tumor', 'Disease', (62, 67))	('TMPRSS11B', 'Var', (35, 44))	('lactate export', 'MPA', (92, 106))	('facilitating', 'PosReg', (79, 91))	('LSCC', 'Phenotype', 'HP:0030359', (48, 52))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
204351	30463017	This is in agreement with earlier studies demonstrating that depletion of MCT4, Basigin, or both induces lactate accumulation and slows glycolytic flux.	('depletion', 'Var', (61, 70))	('slows', 'NegReg', (130, 135))	('MCT4', 'Gene', (74, 78))	('lactate', 'Chemical', 'MESH:D019344', (105, 112))	('glycolytic flux', 'MPA', (136, 151))	('Basigin', 'Gene', '682', (80, 87))	('MCT4', 'Gene', '9123', (74, 78))	('Basigin', 'Gene', (80, 87))	('lactate accumulation', 'MPA', (105, 125))	('induces', 'Reg', (97, 104))
204359	30463017	TMPRSS11B overexpression induces cellular transformation in vitro, while depletion of TMPRSS11B reduces the tumor growth of LSCC and prostate cancer cells in mice, supporting an oncogenic function for this protein in tumorigenesis.	('mice', 'Species', '10090', (158, 162))	('tumor', 'Disease', (108, 113))	('depletion', 'MPA', (73, 82))	('TMPRSS11B', 'Gene', (86, 95))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('tumor', 'Disease', (217, 222))	('reduces', 'NegReg', (96, 103))	('tumor', 'Disease', 'MESH:D009369', (217, 222))	('LSCC', 'Phenotype', 'HP:0030359', (124, 128))	('cellular transformation', 'CPA', (33, 56))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('overexpression', 'Var', (10, 24))	('prostate cancer', 'Disease', 'MESH:D011471', (133, 148))	('prostate cancer', 'Phenotype', 'HP:0012125', (133, 148))	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('prostate cancer', 'Disease', (133, 148))	('induces', 'Reg', (25, 32))	('TMPRSS11B', 'Gene', (0, 9))	('LSCC', 'Disease', (124, 128))
204360	30463017	Our mechanistic studies support a model whereby TMPRSS11B interacts with and promotes Basigin solubilization, resulting in enhanced MCT4-mediated lactate export.	('enhanced', 'PosReg', (123, 131))	('Basigin', 'Gene', '682', (86, 93))	('Basigin', 'Gene', (86, 93))	('promotes', 'PosReg', (77, 85))	('MCT4', 'Gene', '9123', (132, 136))	('TMPRSS11B', 'Var', (48, 57))	('interacts', 'Interaction', (58, 67))	('MCT4', 'Gene', (132, 136))	('lactate', 'Chemical', 'MESH:D019344', (146, 153))
204377	30463017	In a mouse model of LSCC with homozygous deletion of Pten and Stk11 (Lkb1), the mouse ortholog of TMPRSS11B, Tmprss11bnl, is among the top 20 upregulated genes in tumors, hinting at a conserved mechanism of tumor metabolic regulation.	('Pten', 'Gene', (53, 57))	('LSCC', 'Disease', (20, 24))	('Lkb1', 'Gene', '20869', (69, 73))	('Pten', 'Gene', '19211', (53, 57))	('mouse', 'Species', '10090', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('tumor', 'Disease', (163, 168))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('Tmprss11bnl', 'Gene', (109, 120))	('tumors', 'Phenotype', 'HP:0002664', (163, 169))	('mouse', 'Species', '10090', (5, 10))	('Stk11', 'Gene', (62, 67))	('Tmprss11bnl', 'Gene', '319875', (109, 120))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('LSCC', 'Phenotype', 'HP:0030359', (20, 24))	('tumors', 'Disease', (163, 169))	('tumor', 'Disease', (207, 212))	('Lkb1', 'Gene', (69, 73))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('deletion', 'Var', (41, 49))	('tumors', 'Disease', 'MESH:D009369', (163, 169))	('Stk11', 'Gene', '20869', (62, 67))	('upregulated', 'PosReg', (142, 153))
204389	30463017	Lung squamous cell carcinomas (HCC95 (M), HCC1313 (M), HCC1588 (F), HCC2814 (M), and H157(M)), lung adenocarcinoma (H2073 (F)), and prostate carcinoma (DU145 (M)) cells were cultured in ATCC-formulated RPMI-1640 with 5% FBS and antibiotic-antimycotic (ThermoFisher Cat.	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (95, 114))	('HCC2814', 'CellLine', 'CVCL:V586', (68, 75))	('prostate carcinoma', 'Disease', 'MESH:D011472', (132, 150))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('RPMI-1640', 'Chemical', '-', (202, 211))	('carcinomas', 'Phenotype', 'HP:0030731', (19, 29))	('prostate carcinoma', 'Phenotype', 'HP:0012125', (132, 150))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (5, 29))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (5, 29))	('HCC95', 'CellLine', 'CVCL:5137', (31, 36))	('DU145', 'CellLine', 'CVCL:0105', (152, 157))	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('HCC1588', 'Var', (55, 62))	('HCC1313', 'CellLine', 'CVCL:L087', (42, 49))	('H2073', 'CellLine', 'CVCL:1521', (116, 121))	('prostate carcinoma', 'Disease', (132, 150))	('lung adenocarcinoma', 'Disease', (95, 114))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (5, 28))	('HCC1588', 'CellLine', 'CVCL:A351', (55, 62))	('squamous cell carcinomas', 'Disease', (5, 29))	('carcinoma', 'Phenotype', 'HP:0030731', (19, 28))	('H157', 'Var', (85, 89))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (95, 114))
204395	30463017	TMPRSS11BD270N and TMPRSS11BS366A mutant constructs were generated with Phusion site-directed mutagenesis (ThermoFisher) of IOH35719 (pENTR221, Invitrogen Ultimate ORF collection).	('S366A', 'Mutation', 'rs17881470', (28, 33))	('D270N', 'Mutation', 'p.D270N', (9, 14))	('N', 'Chemical', 'MESH:D009584', (136, 137))	('N', 'Chemical', 'MESH:D009584', (13, 14))	('TMPRSS11BD270N', 'Var', (0, 14))	('TMPRSS11BS366A', 'Var', (19, 33))
204397	30463017	For Basigin rescue experiments, Basigin (IOH3378, Invitrogen Ultimate ORF collection) was modified by site-directed mutagenesis to introduce synonymous mutations to sgRNA binding residues at 2, 6, and 9nt from the PAM and cloned into pLX307 (pLX303 modified to express mCherry instead of a BlastR cassette) using Gateway LR clonase II.	('Basigin', 'Gene', '682', (4, 11))	('mutations', 'Var', (152, 161))	('Basigin', 'Gene', (4, 11))	('Basigin', 'Gene', '682', (32, 39))	('N', 'Chemical', 'MESH:D009584', (168, 169))	('Basigin', 'Gene', (32, 39))
204417	30463017	TaqMan probes (Invitrogen) corresponding to TMPRSS11B (Hs01113515 m1 and Hs00699337 m1), BSG (Hs00936295_m1), and GAPDH (Hs03929097) were used to detect transcripts in 384-well format, and expression calculating using the 2ddCt method.	('Hs01113515 m1', 'Var', (55, 68))	('Hs00699337 m1', 'Var', (73, 86))	('Hs03929097', 'Var', (121, 131))	('GAPDH', 'Gene', '2597', (114, 119))	('expression', 'MPA', (189, 199))	('GAPDH', 'Gene', (114, 119))	('Hs00936295_m1', 'Var', (94, 107))
204438	30463017	Cells were washed 3x10 minutes in PBS and incubated in Alexa Flour-conjugated secondary antibodies (CST, 1:500 dilution; Anti-Mouse Alexa Flour 488, Anti-Mouse Alexa Flour 594, Anti-Rabbit Alexa Flour 488, Anti-Rabbit Alexa Flour 594 and Anti-Rat Alexa Flour 647) in 2%BSA in PBS for 2 hours at room temperature.	('Alexa Flour', 'Chemical', '-', (55, 66))	('Alexa Flour 488', 'Chemical', '-', (132, 147))	('Alexa Flour 647', 'Chemical', '-', (247, 262))	('Mouse', 'Species', '10090', (126, 131))	('Anti-Mouse', 'Var', (149, 159))	('Alexa Flour', 'Chemical', '-', (189, 200))	('Alexa Flour', 'Chemical', '-', (132, 143))	('PBS', 'Chemical', 'MESH:D007854', (34, 37))	('Alexa Flour 594', 'Chemical', '-', (218, 233))	('Rabbit', 'Species', '9986', (182, 188))	('Rat', 'Species', '10116', (243, 246))	('CST, 1', 'Gene', '1469', (100, 106))	('Mouse', 'Species', '10090', (154, 159))	('Alexa Flour 594', 'Chemical', '-', (160, 175))	('Anti-Mouse', 'Var', (121, 131))	('Alexa Flour', 'Chemical', '-', (218, 229))	('Alexa Flour', 'Chemical', '-', (247, 258))	('PBS', 'Chemical', 'MESH:D007854', (276, 279))	('Rabbit', 'Species', '9986', (211, 217))	('Alexa Flour', 'Chemical', '-', (160, 171))	('Alexa Flour 488', 'Chemical', '-', (189, 204))
204454	30577741	Thus, abnormal miRNA regulatory events can cause a significant impact on various cellular functions, ultimately resulting in complex events leading to cancer.	('resulting in', 'Reg', (112, 124))	('cause', 'Reg', (43, 48))	('abnormal', 'Var', (6, 14))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('cancer', 'Disease', (151, 157))	('miRNA regulatory events', 'MPA', (15, 38))	('cellular functions', 'MPA', (81, 99))	('impact', 'Reg', (63, 69))	('cancer', 'Disease', 'MESH:D009369', (151, 157))
204491	30577741	We have developed an efficient method to identify dysregulations among millions of potential regulatory relationships between 1,881 miRNAs and more than 20,000 mRNAs across multiple lung cancer subtypes.	('multiple lung cancer', 'Disease', 'MESH:D008175', (173, 193))	('lung cancer', 'Phenotype', 'HP:0100526', (182, 193))	('dysregulations', 'Var', (50, 64))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('multiple lung cancer', 'Disease', (173, 193))
204499	30577741	Since miRNA-target dysregulations are implicated in many cancers, where multi-modal differential analyses between multiple cancer subtypes have mainly left undiscovered, we believe this tool can have broad applications in the development of new diagnosis and treatment strategies.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('dysregulations', 'Var', (19, 33))	('cancer', 'Disease', (57, 63))	('cancers', 'Phenotype', 'HP:0002664', (57, 64))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('cancers', 'Disease', (57, 64))	('cancers', 'Disease', 'MESH:D009369', (57, 64))	('cancer', 'Disease', (123, 129))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('miRNA-target', 'Var', (6, 18))	('implicated', 'Reg', (38, 48))
204502	27496222	Disrupted cooperation between TFs, leading to dysregulation of target genes, contributes to the pathogenesis of many diseases, including cancer.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('dysregulation of target genes', 'MPA', (46, 75))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('cancer', 'Disease', (137, 143))	('Disrupted cooperation', 'Var', (0, 21))	('TFs', 'Gene', (30, 33))	('contributes', 'Reg', (77, 88))
204503	27496222	Although the aberrant activation of individual TFs and the functional effects have been widely studied, the perturbation of TF cooperativity in cancer has rarely been explored.	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('activation', 'PosReg', (22, 32))	('cancer', 'Disease', (144, 150))	('TFs', 'Protein', (47, 50))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('aberrant', 'Var', (13, 21))
204511	27496222	Disrupted cooperation of TFs provides potential clinical utility as prognostic markers for predicting the patient survival.	('TFs', 'Gene', (25, 28))	('patient', 'Species', '9606', (106, 113))	('Disrupted cooperation', 'Var', (0, 21))
204514	27496222	The deregulation of these TFs, reshaping the expression of their target genes, leads to tumor formation, progression, and metastasis.	('deregulation', 'Var', (4, 16))	('progression', 'CPA', (105, 116))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('leads to', 'Reg', (79, 87))	('expression', 'MPA', (45, 55))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('metastasis', 'CPA', (122, 132))	('tumor', 'Disease', (88, 93))
204515	27496222	Numerous studies have revealed the functional impact of aberrant activation of individual TFs on tumor progression.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('TFs', 'Gene', (90, 93))	('aberrant', 'Var', (56, 64))	('tumor', 'Disease', (97, 102))	('activation', 'PosReg', (65, 75))
204516	27496222	For example, mutations of BRCA1 and BRCA2 cause the genetic instability of the cell and thus confer a substantial risk of breast and ovarian cancer.	('ovarian cancer', 'Phenotype', 'HP:0100615', (133, 147))	('BRCA1', 'Gene', (26, 31))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('BRCA2', 'Gene', (36, 41))	('cause', 'Reg', (42, 47))	('BRCA', 'Phenotype', 'HP:0003002', (36, 40))	('BRCA2', 'Gene', '675', (36, 41))	('genetic instability of the cell', 'CPA', (52, 83))	('BRCA', 'Phenotype', 'HP:0003002', (26, 30))	('BRCA1', 'Gene', '672', (26, 31))	('breast and ovarian cancer', 'Disease', 'MESH:D010051', (122, 147))	('mutations', 'Var', (13, 22))
204520	27496222	Three transcription factors TTF1/NKX2-1, NKX2-8, and PAX9 show pronounced synergy in promoting the proliferation of immortalized human lung epithelial cells, and the alteration of their cooperativity contributes to lung cancer development.	('lung cancer', 'Disease', (215, 226))	('NKX2-1', 'Gene', '7080', (33, 39))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('TTF1', 'Gene', (28, 32))	('lung cancer', 'Disease', 'MESH:D008175', (215, 226))	('NKX2-8', 'Gene', '26257;4824', (41, 47))	('contributes', 'Reg', (200, 211))	('NKX2-1', 'Gene', (33, 39))	('TTF1', 'Gene', '7270', (28, 32))	('PAX9', 'Gene', '5083', (53, 57))	('human', 'Species', '9606', (129, 134))	('lung cancer', 'Phenotype', 'HP:0100526', (215, 226))	('cooperativity', 'Interaction', (186, 199))	('NKX2-8', 'Gene', (41, 47))	('promoting', 'PosReg', (85, 94))	('proliferation', 'CPA', (99, 112))	('alteration', 'Var', (166, 176))	('PAX9', 'Gene', (53, 57))
204584	27496222	The observation that the dysregulation of the target genes is mainly caused by the disrupted TF cooperation rather than differentially expressed TF itself suggests that the analysis of TF cooperativity in tumor is more important than previously recognized.	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumor', 'Disease', (205, 210))	('disrupted', 'Var', (83, 92))	('caused by', 'Reg', (69, 78))	('dysregulation', 'MPA', (25, 38))
204590	27496222	Repeated studies on the two independent datasets reproduced the findings from the discovery cohort, which demonstrate that the disruption of TF cooperativity is highly reproducible and biological meaningful in cancer.	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('TF cooperativity', 'MPA', (141, 157))	('disruption', 'Var', (127, 137))	('cancer', 'Disease', 'MESH:D009369', (210, 216))	('cancer', 'Disease', (210, 216))
204603	27496222	Our findings underscore the far more important role of TF cooperativity in tumorigenesis than previously recognized.	('cooperativity', 'Var', (58, 71))	('tumor', 'Disease', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', 'MESH:D009369', (75, 80))
204605	27496222	The microarray data for NSCLC (GSE19804), PRAD (GSE6919), COADREAD (GSE8671), and BRCA (GSE14999) were downloaded from the Gene Expression Omnibus (GEO, http://www.ncbi.nlm.nih.gov/geo/).	('NSCLC', 'Disease', (24, 29))	('BRCA', 'Gene', (82, 86))	('GSE19804', 'Var', (31, 39))	('NSCLC', 'Disease', 'MESH:D002289', (24, 29))	('GSE14999', 'Var', (88, 96))	('GSE6919', 'Chemical', '-', (48, 55))	('BRCA', 'Phenotype', 'HP:0003002', (82, 86))	('GSE8671', 'Var', (68, 75))	('GSE6919', 'Var', (48, 55))	('GSE8671', 'Chemical', '-', (68, 75))	('BRCA', 'Gene', '672', (82, 86))
204606	27496222	For affymetrix microarray data, we applied data-dependent cutoffs to remove lowly expressed genes based on their average signal (log2 signal intensity <7 for GSE32665, log2 signal intensity <2 for GSE6919 and GSE8671).	('GSE6919', 'Var', (197, 204))	('GSE6919', 'Chemical', '-', (197, 204))	('GSE8671', 'Var', (209, 216))	('GSE32665', 'Var', (158, 166))	('GSE8671', 'Chemical', '-', (209, 216))
204632	31684119	In comparison to the preoperative measurements, patients whose COP increased by day 1 post-op showed a better OS (hazard ratio (HR) per 50 G/L increase: 0.73, 95% confidence interval (CI): 0.58-0.93, p = 0.013) and DFS (HR per 50 G/L increase: 0.74, 95% CI: 0.58-0.94, p = 0.018) in multivariable analysis.	('DFS', 'MPA', (215, 218))	('COP', 'Gene', '114769', (63, 66))	('50 G/L', 'Var', (136, 142))	('COP', 'Gene', (63, 66))	('50 G/L', 'SUBSTITUTION', 'None', (136, 142))	('50 G/L', 'Var', (227, 233))	('patients', 'Species', '9606', (48, 56))	('50 G/L', 'SUBSTITUTION', 'None', (227, 233))
204669	31684119	Hazard ratio (HR) and 95% confidence intervals (95% CI) were calculated per 50 G/L increase for COP, per 1 FL increase in platelet volume for MPV and per 1 fraction for the MPV/COP ratio.	('COP', 'Gene', '114769', (96, 99))	('increase', 'PosReg', (110, 118))	('50 G/L', 'SUBSTITUTION', 'None', (76, 82))	('increase', 'PosReg', (83, 91))	('platelet volume for', 'MPA', (122, 141))	('COP', 'Gene', (96, 99))	('COP', 'Gene', '114769', (177, 180))	('COP', 'Gene', (177, 180))	('increase in platelet volume', 'Phenotype', 'HP:0011877', (110, 137))	('50 G/L', 'Var', (76, 82))
204679	31684119	The median preoperative COP and MPV values were 237 G/L (191-302) and 10.3 FL (9.8-11.1), respectively, and the median MPV/COP ratio was 4.3 (3.3-5.4) (Figure 1).	('237 G/L', 'SUBSTITUTION', 'None', (48, 55))	('237 G/L', 'Var', (48, 55))	('COP', 'Gene', '114769', (24, 27))	('COP', 'Gene', (24, 27))	('COP', 'Gene', '114769', (123, 126))	('COP', 'Gene', (123, 126))
204684	31684119	The median COP and MPV on day 1 post-op were 176 G/L (142-225.5) and 10.5 (9.65-11.3) and at one week post-op were 286 G/L (218-346) and 10.2 fl (9.65-11), respectively.	('176 G/L', 'SUBSTITUTION', 'None', (45, 52))	('COP', 'Gene', '114769', (11, 14))	('176 G/L', 'Var', (45, 52))	('COP', 'Gene', (11, 14))	('286 G/L', 'Var', (115, 122))	('286 G/L', 'SUBSTITUTION', 'None', (115, 122))
204690	31684119	Furthermore, we observed a numerically worse OS for patients with a high MPV/COP ratio, with a significant difference at one week post-op (5-year OS for MPV/COP > Q2 ratio 48% (95% CI 34-61) vs. MPV/COP <= Q2 75% (95% CI 61-84)).	('COP', 'Gene', '114769', (157, 160))	('COP', 'Gene', '114769', (199, 202))	('high', 'Var', (68, 72))	('COP', 'Gene', (157, 160))	('COP', 'Gene', (199, 202))	('COP', 'Gene', '114769', (77, 80))	('COP', 'Gene', (77, 80))	('patients', 'Species', '9606', (52, 60))
204691	31684119	In univariable Cox regression, we observed an association for COP at day 1 post-op and OS (HR per 50 G/L increase: 0.78, 95% CI: 0.62-0.99, p = 0.046).	('50 G/L', 'Var', (98, 104))	('50 G/L', 'SUBSTITUTION', 'None', (98, 104))	('COP', 'Gene', (62, 65))	('COP', 'Gene', '114769', (62, 65))
204697	31684119	In univariable analysis for DFS, we observed differences for postoperative COP on day 1 (HR per 50 G/L increase: 0.70, 95% CI 0.52-0.94, p = 0.021) and one week (HR per 50 G/L increase: 0.80, 95% CI 0.66-0.99, p = 0.040) and MPV/COP ratio on day 1 (HR per 1 fraction increase: 1.13, 95% CI 1.01-1.27, p = 0.022) and one week (HR per 1 fraction increase: 1.26, 95% CI 1.05-1.51, p = 0.013).	('50 G/L', 'SUBSTITUTION', 'None', (96, 102))	('50 G/L', 'Var', (169, 175))	('50 G/L', 'SUBSTITUTION', 'None', (169, 175))	('COP', 'Gene', '114769', (229, 232))	('differences', 'Reg', (45, 56))	('COP', 'Gene', '114769', (75, 78))	('50 G/L', 'Var', (96, 102))	('COP', 'Gene', (229, 232))	('COP', 'Gene', (75, 78))
204703	31684119	While the MPV trajectory was not associated with OS or DFS, an increase in COP on day 1 post-op was associated with better OS in univariable analysis (HR per 50 G/L increase: 0.73, 95% CI: 0.59-0.90, p = 0.004).	('increase', 'PosReg', (63, 71))	('50 G/L', 'Var', (158, 164))	('COP', 'Gene', '114769', (75, 78))	('50 G/L', 'SUBSTITUTION', 'None', (158, 164))	('COP', 'Gene', (75, 78))
204705	31684119	An increase in COP on day 1 was also associated with a better DFS in univariable (HR per 50 G/L increase: 0.72, 95% CI: 0.56-0.91, p = 0.006) and multivariable analysis (HR per 50 G/L increase: 0.74, 95% CI: 0.58-0.94, p = 0.018) (Figure 3B, Table 3).	('50 G/L', 'Var', (177, 183))	('50 G/L', 'SUBSTITUTION', 'None', (177, 183))	('DFS', 'MPA', (62, 65))	('50 G/L', 'Var', (89, 95))	('50 G/L', 'SUBSTITUTION', 'None', (89, 95))	('COP', 'Gene', '114769', (15, 18))	('COP', 'Gene', (15, 18))
204724	31684119	analyzed the postoperative change in the platelet to lymphocyte ratio (PLR):a marker for systemic inflammation:in T3-T4 laryngeal squamous cell carcinoma.	('T3-T4', 'Var', (114, 119))	('inflammation', 'Disease', 'MESH:D007249', (98, 110))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (130, 153))	('inflammation', 'Disease', (98, 110))	('squamous cell carcinoma', 'Disease', (130, 153))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (130, 153))
204726	31684119	For postoperative COP, however, we observed a worse OS and DFS for patients with low COP (<= median), with a risk reduction of 24% for OS and 31% for DFS per 50 G/L increase in COP at day 1 post-op.	('increase', 'PosReg', (165, 173))	('COP', 'Gene', (85, 88))	('low', 'NegReg', (81, 84))	('patients', 'Species', '9606', (67, 75))	('reduction', 'NegReg', (114, 123))	('COP', 'Gene', '114769', (18, 21))	('50 G/L', 'Var', (158, 164))	('COP', 'Gene', (18, 21))	('COP', 'Gene', '114769', (177, 180))	('COP', 'Gene', (177, 180))	('50 G/L', 'SUBSTITUTION', 'None', (158, 164))	('COP', 'Gene', '114769', (85, 88))
204757	31408934	Furthermore, impairment in the regulation of the TGF-beta signaling pathway may cause a broad range of illnesses, such as cardiovascular disease, tissue fibrosis, cancer, and congenital diseases.	('regulation', 'MPA', (31, 41))	('impairment', 'Var', (13, 23))	('cardiovascular disease', 'Phenotype', 'HP:0001626', (122, 144))	('cardiovascular disease', 'Disease', 'MESH:D002318', (122, 144))	('TGF-beta signaling pathway', 'Pathway', (49, 75))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('congenital diseases', 'Disease', 'MESH:D030342', (175, 194))	('cardiovascular disease', 'Disease', (122, 144))	('congenital diseases', 'Disease', (175, 194))	('fibrosis', 'Disease', 'MESH:D005355', (153, 161))	('fibrosis', 'Disease', (153, 161))	('cancer', 'Disease', 'MESH:D009369', (163, 169))	('cause', 'Reg', (80, 85))	('cancer', 'Disease', (163, 169))
204764	31408934	Phosphorylation allows Smad 2/3 proteins to form heteromeric complexes and allows Smad 4 proteins to be translocated into the nucleus.	('translocated', 'MPA', (104, 116))	('Smad 2/3', 'Gene', '4087;4088', (23, 31))	('Phosphorylation', 'Var', (0, 15))	('Smad 4', 'Gene', '4089', (82, 88))	('proteins', 'Protein', (32, 40))	('Smad 4', 'Gene', (82, 88))	('heteromeric complexes', 'MPA', (49, 70))	('Smad 2/3', 'Gene', (23, 31))	('form', 'Reg', (44, 48))
204771	31408934	Once the tumor cell has undergone certain genetic and/or epigenetic changes that attenuate the growth suppressive pathway of TGF-beta, targeted overexpression of TGF-beta1 can provide tumorigenic advantages, such as driving malignant progression and metastasis.	('epigenetic changes', 'Var', (57, 75))	('attenuate', 'NegReg', (81, 90))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('TGF-beta1', 'Gene', '7040', (162, 171))	('TGF-beta', 'Gene', (125, 133))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('TGF-beta1', 'Gene', (162, 171))	('growth suppressive pathway', 'Pathway', (95, 121))	('tumor', 'Disease', (184, 189))	('metastasis', 'CPA', (250, 260))	('tumor', 'Disease', (9, 14))	('driving malignant progression', 'CPA', (216, 245))	('overexpression', 'PosReg', (144, 158))
204777	31408934	Transfection of dominant-negative TbetaRII into highly metastatic mesenchymal mouse colon carcinoma cells attenuated TGF-beta-induced EMT.	('attenuated', 'NegReg', (106, 116))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('TGF-beta-induced', 'Gene', (117, 133))	('mouse', 'Species', '10090', (78, 83))	('dominant-negative', 'Var', (16, 33))	('colon carcinoma', 'Disease', 'MESH:D015179', (84, 99))	('colon carcinoma', 'Disease', (84, 99))
204789	31408934	A known ubiquitin E3 ligase, c-Cbl (Casitas B-lineage Lymphoma), augments TGF-beta signaling by covenant integrating NEDD8 to TbetaRII at Lys556 and Lys567.	('c-Cbl', 'Gene', '867', (29, 34))	('Lys556', 'Var', (138, 144))	('B-lineage Lymphoma', 'Phenotype', 'HP:0012191', (44, 62))	('Lymphoma', 'Disease', 'MESH:D008223', (54, 62))	('NEDD8', 'Gene', (117, 122))	('Lymphoma', 'Phenotype', 'HP:0002665', (54, 62))	('augments', 'NegReg', (65, 73))	('TGF-beta signaling', 'MPA', (74, 92))	('Lys567', 'Var', (149, 155))	('NEDD8', 'Gene', '4738', (117, 122))	('Lymphoma', 'Disease', (54, 62))	('Lys556', 'Chemical', '-', (138, 144))	('B', 'Gene', '2035', (44, 45))	('c-Cbl', 'Gene', (29, 34))	('Lys567', 'Chemical', '-', (149, 155))
204804	31408934	Improper intracellular trafficking of the TGF-beta receptor has been described based on clinical observation and has been reported in connection with several human diseases.	('intracellular trafficking', 'MPA', (9, 34))	('reported', 'Reg', (122, 130))	('human', 'Species', '9606', (158, 163))	('TGF-beta receptor', 'Gene', (42, 59))	('Improper', 'Var', (0, 8))
204805	31408934	Mislocalization has been suggested to contribute to diminishing cell surface TbetaRII in mitogen-activated CD4+ T cells in patients with Sezary syndrome.	('diminishing', 'NegReg', (52, 63))	('Mislocalization', 'Var', (0, 15))	('patients', 'Species', '9606', (123, 131))	('cell surface', 'MPA', (64, 76))	('Sezary syndrome', 'Disease', (137, 152))	('Sezary syndrome', 'Disease', 'MESH:D012751', (137, 152))
204808	31408934	As mentioned earlier in the text, neddylation of TbetaRII by c-Cbl promotes clathrin-mediated receptor endocytosis.	('c-Cbl', 'Gene', '867', (61, 66))	('c-Cbl', 'Gene', (61, 66))	('promotes', 'PosReg', (67, 75))	('clathrin-mediated receptor endocytosis', 'MPA', (76, 114))	('neddylation', 'Var', (34, 45))
204809	31408934	c-Cbl with a neddylation-defective mutant was found in leukemia patients, which indicates a causal link between aberrant TbetaRII neddylation and trafficking and leukemia development.	('c-Cbl', 'Gene', (0, 5))	('aberrant', 'Var', (112, 120))	('patients', 'Species', '9606', (64, 72))	('c-Cbl', 'Gene', '867', (0, 5))	('leukemia', 'Phenotype', 'HP:0001909', (55, 63))	('mutant', 'Var', (35, 41))	('leukemia', 'Disease', 'MESH:D007938', (55, 63))	('leukemia', 'Disease', (55, 63))	('leukemia', 'Disease', (162, 170))	('leukemia', 'Phenotype', 'HP:0001909', (162, 170))	('leukemia', 'Disease', 'MESH:D007938', (162, 170))	('found', 'Reg', (46, 51))	('TbetaRII', 'Protein', (121, 129))
204810	31408934	TbetaRII with the E221V/N238I mutant found in human oral squamous cell carcinoma showed impaired endocytosis and enhanced TGF-beta signaling.	('impaired endocytosis', 'Disease', 'MESH:D009422', (88, 108))	('impaired endocytosis', 'Disease', (88, 108))	('N238I', 'Var', (24, 29))	('E221V', 'Var', (18, 23))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (57, 80))	('E221V', 'SUBSTITUTION', 'None', (18, 23))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (52, 80))	('human', 'Species', '9606', (46, 51))	('TGF-beta signaling', 'MPA', (122, 140))	('N238I', 'SUBSTITUTION', 'None', (24, 29))	('enhanced', 'PosReg', (113, 121))	('oral squamous cell carcinoma', 'Disease', (52, 80))
204811	31408934	Recently, we reported that among the inhibitors of nonconventional myosins, namely pentachloropseudilin (PClP) and pentabromopseudilin (PBrP), PClP is a reversible and allosteric inhibitor of Myo1c, which inhibits the delivery of TbetaRII to the plasma membrane through the lipid-raft recycling machinery, resulting in the accumulation of receptors in late endosomes and recycling compartments, and it eventually is rerouted for subsequent degradation in lysosomes.	('PClP', 'Chemical', 'MESH:C493099', (143, 147))	('lipid', 'Chemical', 'MESH:D008055', (274, 279))	('myosin', 'Gene', '79784', (67, 73))	('pentabromopseudilin', 'Chemical', 'MESH:C094409', (115, 134))	('pentachloropseudilin', 'Chemical', 'MESH:C493099', (83, 103))	('delivery', 'MPA', (218, 226))	('receptors', 'MPA', (339, 348))	('PClP', 'Var', (143, 147))	('inhibits', 'NegReg', (205, 213))	('PBrP', 'Chemical', 'MESH:C094409', (136, 140))	('accumulation', 'PosReg', (323, 335))	('PClP', 'Chemical', 'MESH:C493099', (105, 109))	('myosin', 'Gene', (67, 73))
204830	31408934	Short-tailed class I myosins include Myo1a, Myo1b, Myo1c, Myo1d, Myo1g, and Myo1h; Myo1e and Myo1f are long-tailed myosins that regulate a number of cellular processes, including the regulation of the cytoskeleton, intracellular transport, cell surface local motion, and regulation of membrane-related events, which includes exocytosis, endocytosis, and phagocytosis.	('Myo1b', 'Gene', '4430', (44, 49))	('Myo1h', 'Gene', (76, 81))	('myosin', 'Gene', (21, 27))	('myosin', 'Gene', (115, 121))	('Myo1h', 'Gene', '283446', (76, 81))	('exocytosis', 'MPA', (325, 335))	('Myo1f', 'Gene', '4542', (93, 98))	('Myo1g', 'Gene', (65, 70))	('Myo1g', 'Gene', '64005', (65, 70))	('Myo1a', 'Gene', (37, 42))	('myosin', 'Gene', '79784', (21, 27))	('regulate', 'Reg', (128, 136))	('Myo1b', 'Gene', (44, 49))	('Myo1a', 'Gene', '4640', (37, 42))	('myosin', 'Gene', '79784', (115, 121))	('endocytosis', 'MPA', (337, 348))	('Myo1e', 'Var', (83, 88))	('Myo1d', 'Gene', '4642', (58, 63))	('Myo1d', 'Gene', (58, 63))	('Myo1f', 'Gene', (93, 98))
204831	31408934	In floxed mice harboring podocytes-specific Myo1c deletion, injury-induced fibrosis was attenuated in the kidney, and podocyte function and morphology were preserved.	('fibrosis', 'Disease', 'MESH:D005355', (75, 83))	('fibrosis', 'Disease', (75, 83))	('deletion', 'Var', (50, 58))	('mice', 'Species', '10090', (10, 14))	('attenuated', 'NegReg', (88, 98))	('podocyte function', 'CPA', (118, 135))	('Myo1c', 'Gene', (44, 49))
204837	31408934	This function is supported by the finding that Myo1c facilitates the exocytosis and delivery of several raft-associated proteins, such as VEGFR2, aquaporin 2, GLUT4, and NEPH1, to the cell surface.	('GLUT4', 'Gene', (159, 164))	('aquaporin 2', 'Gene', (146, 157))	('GLUT4', 'Gene', '6517', (159, 164))	('NEPH1', 'Gene', '55243', (170, 175))	('exocytosis', 'MPA', (69, 79))	('VEGFR2', 'Gene', '3791', (138, 144))	('delivery', 'MPA', (84, 92))	('aquaporin 2', 'Gene', '359', (146, 157))	('Myo1c', 'Var', (47, 52))	('VEGFR2', 'Gene', (138, 144))	('facilitates', 'PosReg', (53, 64))	('NEPH1', 'Gene', (170, 175))
204839	31408934	Myo1e is the only "long-tailed" type I myosin that is ubiquitously expressed in mammalian cells.	('Myo1e', 'Var', (0, 5))	('mammalian', 'Species', '9606', (80, 89))	('myosin', 'Gene', (39, 45))	('myosin', 'Gene', '79784', (39, 45))
204842	31408934	Inhibition of actin assembly and depletion of Myo1e caused reduced transferrin endocytosis and a profound delay in its trafficking to early endosomal compartments.	('delay', 'NegReg', (106, 111))	('depletion', 'Var', (33, 42))	('reduced', 'NegReg', (59, 66))	('Myo1e', 'Gene', (46, 51))	('transferrin', 'Gene', '7018', (67, 78))	('actin assembly', 'Protein', (14, 28))	('transferrin', 'Gene', (67, 78))	('Inhibition', 'Var', (0, 10))	('trafficking to early endosomal compartments', 'MPA', (119, 162))
204843	31408934	In terms of pathological relevance, high Myo1e expression has been identified as part of the gene signature that predicts poor outcome in patients with basal-like breast cancer; additional meta-analysis shows an inverse correlation between Myo1e expression in grade 1 breast cancer and patient survival, suggesting that Myo1e promotes tumorigenesis.	('promotes', 'PosReg', (326, 334))	('breast cancer', 'Phenotype', 'HP:0003002', (163, 176))	('Myo1e', 'Gene', (240, 245))	('cancer', 'Phenotype', 'HP:0002664', (275, 281))	('inverse', 'NegReg', (212, 219))	('breast cancer', 'Disease', 'MESH:D001943', (268, 281))	('tumor', 'Phenotype', 'HP:0002664', (335, 340))	('tumor', 'Disease', 'MESH:D009369', (335, 340))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('breast cancer', 'Disease', (268, 281))	('Myo1e', 'Var', (320, 325))	('patient', 'Species', '9606', (138, 145))	('patient', 'Species', '9606', (286, 293))	('breast cancer', 'Disease', 'MESH:D001943', (163, 176))	('breast cancer', 'Phenotype', 'HP:0003002', (268, 281))	('breast cancer', 'Disease', (163, 176))	('patients', 'Species', '9606', (138, 146))	('tumor', 'Disease', (335, 340))
204855	31408934	A study from the Phillips research group that used renal proximal tubular cells showed that co-localization of CD44 and TGF-beta receptors facilitates modulation of both Smad and non-Smad-dependent TGF-beta-mediated events by HA.	('Smad', 'Gene', '33529;4089;4089;4092', (170, 174))	('CD44', 'Gene', (111, 115))	('TGF-beta receptors', 'Gene', (120, 138))	('Smad', 'Gene', (183, 187))	('HA', 'Chemical', 'MESH:D006820', (226, 228))	('co-localization', 'Var', (92, 107))	('modulation', 'MPA', (151, 161))	('Smad', 'Gene', (170, 174))	('facilitates', 'PosReg', (139, 150))	('Smad', 'Gene', '33529;4089;4089;4092', (183, 187))	('CD44', 'Gene', '960', (111, 115))
204856	31408934	This suggests that the alteration of Myo1g activity may represent an endogenous mechanism to regulate TGF-beta cellular function.	('alteration', 'Var', (23, 33))	('Myo1g', 'Gene', '64005', (37, 42))	('activity', 'MPA', (43, 51))	('regulate', 'Reg', (93, 101))	('Myo1g', 'Gene', (37, 42))	('TGF-beta', 'Protein', (102, 110))
204877	31408934	In HeLa cells, mutation of the PtdIns(4,5)P2 binding site abrogates the targeting of Myo6 and its tail to CCP structures.	('mutation', 'Var', (15, 23))	('Myo6', 'Gene', (85, 89))	('Myo6', 'Gene', '4646', (85, 89))	('targeting', 'MPA', (72, 81))	('HeLa', 'CellLine', 'CVCL:0030', (3, 7))	('abrogates', 'NegReg', (58, 67))	('PtdIns(4,5)P2', 'Chemical', 'MESH:D019269', (31, 44))
204880	31408934	PtdIns(4,5)P2 is concentrated at active sites of CME, where it may recruit Myo6, Dab2, and accessory/cytoskeletal proteins to the membrane at the initiation of the CCP assembly.	('Myo6', 'Gene', '4646', (75, 79))	('Dab2', 'Gene', (81, 85))	('Dab2', 'Gene', '1601', (81, 85))	('Myo6', 'Gene', (75, 79))	('PtdIns', 'Var', (0, 6))	('recruit', 'PosReg', (67, 74))	('PtdIns(4,5)P2', 'Chemical', 'MESH:D019269', (0, 13))
204881	31408934	Because Dab2 has been shown to be associated with the type I and type II TGF-beta receptors and modulate Smad activation, knocking down Dab2 has a substantial impact on TGF-beta receptor recycling and subcellular localization.	('Dab2', 'Gene', (136, 140))	('activation', 'PosReg', (110, 120))	('Dab2', 'Gene', '1601', (136, 140))	('Smad', 'Gene', '33529;4089;4089;4092', (105, 109))	('associated', 'Interaction', (34, 44))	('TGF-beta', 'Protein', (73, 81))	('Smad', 'Gene', (105, 109))	('TGF-beta receptor recycling', 'MPA', (169, 196))	('subcellular localization', 'MPA', (201, 225))	('modulate', 'Reg', (96, 104))	('B', 'Gene', '2035', (0, 1))	('impact', 'Reg', (159, 165))	('Dab2', 'Gene', (8, 12))	('knocking down', 'Var', (122, 135))	('Dab2', 'Gene', '1601', (8, 12))
204896	31408934	Several classes of unconventional myosins (classes VII, X, XII, and XV) have been reported to share a conserved structural feature in their tail domains:the presence of a MyTH4 domain followed by FERM.	('MyTH4 domain', 'Var', (171, 183))	('myosin', 'Gene', (34, 40))	('myosin', 'Gene', '79784', (34, 40))
204902	31408934	Depletion of Myo10 using siRNA abrogated TGF-beta-induced collagen gel infiltration of SK-MES1 cells.	('abrogated', 'NegReg', (31, 40))	('Myo10', 'Gene', (13, 18))	('Depletion', 'Var', (0, 9))	('collagen gel infiltration', 'CPA', (58, 83))	('Myo10', 'Gene', '4651', (13, 18))	('SK-MES1', 'CellLine', 'CVCL:0630', (87, 94))
204903	31408934	These observations also support previous findings demonstrating that shRNA knockdown of Myo10 in the MDA-MB-231 cells inhibited Matrigel invasion experiments and in vivo pervasion in lung colonization and mammary fat pads assays.	('inhibited', 'NegReg', (118, 127))	('Matrigel invasion experiments', 'CPA', (128, 157))	('Myo10', 'Gene', '4651', (88, 93))	('knockdown', 'Var', (75, 84))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (101, 111))	('Myo10', 'Gene', (88, 93))
204906	31408934	The multiple functions of the unconventional myosin motors are subjected to regulation in several ways; for example, through PtdIns(4,5)P2 binding, the presence or absence of light chains in both the neck domains, calcium binding, formation of processive dimer, phosphorylation, binding companion proteins, and other signals and modifications, which may together modulate their functions in the cell and further affect the intracellular compartmentalization of TGF-beta receptors and TGF-beta signaling.	('PtdIns(4,5)P2', 'Chemical', 'MESH:D019269', (125, 138))	('intracellular compartmentalization of', 'MPA', (423, 460))	('calcium', 'Chemical', 'MESH:D002118', (214, 221))	('absence', 'Var', (164, 171))	('myosin', 'Gene', (45, 51))	('phosphorylation', 'MPA', (262, 277))	('modulate', 'Reg', (363, 371))	('myosin', 'Gene', '79784', (45, 51))	('TGF-beta receptors', 'Protein', (461, 479))	('TGF-beta signaling', 'MPA', (484, 502))	('modifications', 'Var', (329, 342))	('functions', 'MPA', (378, 387))	('affect', 'Reg', (412, 418))
204920	33173312	Patients with high PD-L1 expression and CD4+ T cell infiltration may have favourable OS in hypopharyngeal cancer.	('PD-L1', 'Gene', (19, 24))	('hypopharyngeal cancer', 'Disease', 'MESH:D007012', (91, 112))	('expression', 'MPA', (25, 35))	('high', 'Var', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('hypopharyngeal cancer', 'Disease', (91, 112))	('CD4+ T cell infiltration', 'Phenotype', 'HP:0005407', (40, 64))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
204922	33173312	The expression of PD-L1 was correlated with Glut-1, and inhibition of GLUT-1 expression may decrease the expression of PD-L1.	('GLUT-1', 'Gene', (70, 76))	('expression', 'MPA', (77, 87))	('Glut-1', 'Gene', (44, 50))	('Glut-1', 'Gene', '6513', (44, 50))	('decrease', 'NegReg', (92, 100))	('PD-L1', 'Gene', (119, 124))	('inhibition', 'Var', (56, 66))	('PD-L1', 'Gene', (18, 23))	('expression', 'MPA', (105, 115))
204942	33173312	Jiang et al demonstrated that positive PD-L1 expression was associated with a longer survival in patients with esophageal squamous cell carcinoma (ESCC) who underwent RT.	('PD-L1', 'Gene', (39, 44))	('positive', 'Var', (30, 38))	('longer', 'PosReg', (78, 84))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (111, 145))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (122, 145))	('esophageal squamous cell carcinoma', 'Disease', (111, 145))	('survival', 'MPA', (85, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('patients', 'Species', '9606', (97, 105))
204943	33173312	They found that patients with high PD-L1 expression had increased infiltration of tumor-infiltrating lymphocytes (TILs) and highly immunogenic tumors prior to RT.	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('tumor', 'Disease', (143, 148))	('increased', 'PosReg', (56, 65))	('immunogenic tumors', 'Disease', (131, 149))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('patients', 'Species', '9606', (16, 24))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('high', 'Var', (30, 34))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('immunogenic tumors', 'Disease', 'MESH:D009369', (131, 149))	('expression', 'Var', (41, 51))	('PD-L1', 'Gene', (35, 40))	('tumor', 'Disease', (82, 87))	('infiltration', 'CPA', (66, 78))
204944	33173312	Hence, high PD-L1 expression was an independent predictor of favourable prognosis for patients with ESCC.	('PD-L1', 'Protein', (12, 17))	('ESCC', 'Disease', (100, 104))	('expression', 'MPA', (18, 28))	('high', 'Var', (7, 11))	('patients', 'Species', '9606', (86, 94))
204965	33173312	We selected the median number of CD4+ and CD8+ T cells as the cut-off point for their cell density.	('CD8', 'Gene', '925', (42, 45))	('CD4+', 'Var', (33, 37))	('CD8', 'Gene', (42, 45))
204995	33173312	The OS was significantly different between patients with high and low PD-L1 expression, as presented by the Kaplan-Meier analysis (p=0.0025, Figure 2A).	('high', 'Var', (57, 61))	('patients', 'Species', '9606', (43, 51))	('expression', 'MPA', (76, 86))	('low', 'NegReg', (66, 69))	('PD-L1', 'Gene', (70, 75))
205015	33173312	However, only GLUT1 expression showed a tendency of increase in post-RT specimens compared with pre-RT specimens (p=0.097).	('expression', 'MPA', (20, 30))	('increase', 'PosReg', (52, 60))	('GLUT1', 'Gene', (14, 19))	('GLUT1', 'Gene', '6513', (14, 19))	('post-RT', 'Var', (64, 71))
205031	33173312	Multivariate analysis revealed that high PD-L1 expression, high CD4+ T cell infiltration, and early clinical stage were independent prognostic factors of favorable OS in patients with hypopharyngeal cancer.	('patients', 'Species', '9606', (170, 178))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('hypopharyngeal cancer', 'Disease', (184, 205))	('favorable OS', 'Disease', (154, 166))	('expression', 'MPA', (47, 57))	('high CD4+ T cell infiltration', 'Phenotype', 'HP:0005407', (59, 88))	('CD4+ T cell infiltration', 'Phenotype', 'HP:0005407', (64, 88))	('hypopharyngeal cancer', 'Disease', 'MESH:D007012', (184, 205))	('PD-L1', 'Gene', (41, 46))	('high', 'Var', (36, 40))
205032	33173312	According to our findings, Fukushima et al demonstrated that in oropharyngeal squamous cell carcinoma, patients with high PD-L1 expression in tumor cells had a favourable outcome than those with low PD-L1 expression in terms of progression-free survival (PFS) and OS.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('oropharyngeal squamous cell carcinoma', 'Phenotype', 'HP:0012182', (64, 101))	('tumor', 'Disease', (142, 147))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('PD-L1', 'Gene', (122, 127))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (78, 101))	('high', 'Var', (117, 121))	('squamous cell carcinoma', 'Disease', (78, 101))	('patients', 'Species', '9606', (103, 111))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (78, 101))	('tumor', 'Disease', 'MESH:D009369', (142, 147))
205036	33173312	Adversely, Lin et al found that high PD-L1 expression was associated with poor outcome and metastasis in oral squamous cell carcinoma.	('high', 'Var', (32, 36))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (110, 133))	('PD-L1', 'Gene', (37, 42))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('oral squamous cell carcinoma', 'Disease', (105, 133))	('metastasis', 'CPA', (91, 101))	('expression', 'MPA', (43, 53))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (105, 133))
205037	33173312	Furthermore, several clinical reports suggested that a high density of TILs was associated with favorable prognosis in patients with locally advanced non-small cell lung cancer and breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('breast cancer', 'Disease', 'MESH:D001943', (181, 194))	('breast cancer', 'Phenotype', 'HP:0003002', (181, 194))	('lung cancer', 'Disease', (165, 176))	('lung cancer', 'Phenotype', 'HP:0100526', (165, 176))	('patients', 'Species', '9606', (119, 127))	('breast cancer', 'Disease', (181, 194))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (154, 176))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('high', 'Var', (55, 59))	('lung cancer', 'Disease', 'MESH:D008175', (165, 176))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (150, 176))
205038	33173312	As mentioned above, high PD-L1 expression was correlated with favorable and unfavorable prognosis in different tumors and different studies.	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumors', 'Disease', 'MESH:D009369', (111, 117))	('tumors', 'Disease', (111, 117))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('expression', 'MPA', (31, 41))	('high', 'Var', (20, 24))	('PD-L1', 'Gene', (25, 30))
205039	33173312	This may be attributed to the use of different cutoffs to determine PD-L1 positivity, as well as the heterogeneity of the clinical and pathological features in diverse tumors.	('positivity', 'Var', (74, 84))	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('tumors', 'Disease', (168, 174))	('tumors', 'Disease', 'MESH:D009369', (168, 174))	('PD-L1', 'Gene', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
205049	33173312	Similar to our study, other preclinical studies have demonstrated that RT could upregulate PD-L1 expression in tumor cells, and RT and PD-L1 blockade had a synergistic antitumor effect on MC38 colon adenocarcinoma and TUBO mammary carcinoma.	('upregulate', 'PosReg', (80, 90))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumor', 'Disease', (172, 177))	('carcinoma', 'Phenotype', 'HP:0030731', (231, 240))	('MC38', 'Var', (188, 192))	('carcinoma', 'Disease', (231, 240))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('mammary carcinoma', 'Phenotype', 'HP:0003002', (223, 240))	('colon adenocarcinoma', 'Disease', 'MESH:D003110', (193, 213))	('expression', 'MPA', (97, 107))	('carcinoma', 'Disease', 'MESH:D009369', (231, 240))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('carcinoma', 'Phenotype', 'HP:0030731', (204, 213))	('tumor', 'Disease', (111, 116))	('carcinoma', 'Disease', (204, 213))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('PD-L1', 'Gene', (91, 96))	('colon adenocarcinoma', 'Disease', (193, 213))	('carcinoma', 'Disease', 'MESH:D009369', (204, 213))
205076	33173312	It increases the effects of anti-PD-1/PD-L1 immunotherapy by enhancing the expression of PD-L1 in tumor cells.	('increases', 'PosReg', (3, 12))	('anti-PD-1/PD-L1', 'Var', (28, 43))	('effects', 'MPA', (17, 24))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('PD-L1', 'Gene', (89, 94))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumor', 'Disease', (98, 103))	('expression', 'MPA', (75, 85))	('enhancing', 'PosReg', (61, 70))
205084	33173312	Furthermore, the present study also demonstrated for the first time that high PD-L1 expression and high CD4+ T cell infiltration were associated with a favorable OS in patients with hypopharyngeal cancer.	('CD4+ T cell infiltration', 'Phenotype', 'HP:0005407', (104, 128))	('PD-L1', 'Gene', (78, 83))	('high CD4+ T cell infiltration', 'Phenotype', 'HP:0005407', (99, 128))	('hypopharyngeal cancer', 'Disease', 'MESH:D007012', (182, 203))	('patients', 'Species', '9606', (168, 176))	('CD4+', 'MPA', (104, 108))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('expression', 'MPA', (84, 94))	('high', 'Var', (73, 77))	('hypopharyngeal cancer', 'Disease', (182, 203))
205089	32471518	Collapsing pathogenic and likely pathogenic variants to cancer predisposition genes (CPG), we analyzed the association between CPGs and cancer types within ancestral groups.	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('cancer', 'Disease', (136, 142))	('pathogenic', 'Reg', (11, 21))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('variants', 'Var', (44, 52))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
205090	32471518	We also identified the predisposition-associated two-hit events and gene expression effects in tumors.	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('tumors', 'Disease', (95, 101))	('effects', 'Reg', (84, 91))	('gene expression', 'Var', (68, 83))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))
205095	32471518	Most predisposing variants were found exclusively in one ancestry in the TCGA and gnomAD datasets.	('AD', 'Disease', 'MESH:D000544', (86, 88))	('AD', 'Disease', (86, 88))	('variants', 'Var', (18, 26))
205096	32471518	Further, tumors from the SDHB or BRCA2 carriers showed simultaneous allelic-specific expression and low gene expression of their respective affected genes, and FH splice-site variant carriers showed mis-splicing of FH.	('BRCA2', 'Gene', (33, 38))	('mis-splicing', 'Var', (199, 211))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumors', 'Disease', (9, 15))	('carriers', 'Var', (39, 47))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('BRCA2', 'Gene', '675', (33, 38))	('SDHB', 'Gene', '6390', (25, 29))	('low', 'NegReg', (100, 103))	('SDHB', 'Gene', (25, 29))	('gene expression', 'MPA', (104, 119))	('tumors', 'Disease', 'MESH:D009369', (9, 15))
205097	32471518	While several CPGs are shared across patients, many pathogenic variants are found to be ancestry-specific and trigger somatic effects.	('patients', 'Species', '9606', (37, 45))	('trigger', 'Reg', (110, 117))	('variants', 'Var', (63, 71))
205100	32471518	Previous studies revealed different carrier rates of pathogenic variants across ancestries, albeit often in a limited panel of genes or selected cancer types.	('cancer', 'Disease', (145, 151))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('pathogenic', 'Reg', (53, 63))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('variants', 'Var', (64, 72))
205101	32471518	While multiple large-scale genome-wide association studies have investigated the common risk variants contributing to cancer, fewer studies have interrogated rare pathogenic variants in non-European ancestries.	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('cancer', 'Disease', (118, 124))	('variants', 'Var', (93, 101))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))
205103	32471518	Consequently, germline genetic testing in non-White patients often results in higher rates of variants of unknown significance (VUSs).	('VUSs', 'Disease', (128, 132))	('VUSs', 'Disease', 'None', (128, 132))	('higher rates', 'PosReg', (78, 90))	('variants of', 'Var', (94, 105))	('patients', 'Species', '9606', (52, 60))
205106	32471518	Herein, we analyzed germline variant data of 9899 cancer cases across 33 cancer types from the Cancer Genome Atlas Project (TCGA) to identify ancestry-specific cancer-gene associations where the genes show an excess of pathogenic/likely pathogenic germline variants the TCGA samples.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('Cancer', 'Disease', (95, 101))	('variants', 'Var', (257, 265))	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('pathogenic/likely', 'CPA', (219, 236))	('cancer', 'Disease', (160, 166))	('Cancer', 'Disease', 'MESH:D009369', (95, 101))	('Cancer', 'Phenotype', 'HP:0002664', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('excess', 'PosReg', (209, 215))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))
205110	32471518	Evidence of a somatic second hit event (i.e., loss of heterozygosity [LOH] or a biallelic mutation) was found in two thirds of the tumors with germline predisposing variants.	('variants', 'Var', (165, 173))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('loss of', 'NegReg', (46, 53))	('tumors', 'Disease', 'MESH:D009369', (131, 137))	('tumors', 'Disease', (131, 137))	('biallelic mutation', 'Var', (80, 98))
205111	32471518	Many carriers of ancestry-specific predisposition variants showed altered expression of the affected genes, including allelic-specific expression (ASE), mis-splicing, and reduced tumor suppressor gene expression, further supporting these genetic variants' contribution to cancer predisposition.	('expression', 'MPA', (74, 84))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('cancer', 'Phenotype', 'HP:0002664', (272, 278))	('altered', 'Reg', (66, 73))	('mis-splicing', 'MPA', (153, 165))	('cancer', 'Disease', 'MESH:D009369', (272, 278))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('variants', 'Var', (50, 58))	('cancer', 'Disease', (272, 278))	('expression', 'MPA', (201, 211))	('allelic-specific', 'MPA', (118, 134))	('tumor', 'Disease', (179, 184))	('reduced', 'NegReg', (171, 178))
205116	32471518	We further required the variants to have an allelic depth (AD) >= 5 for the alternative allele.	('AD', 'Disease', 'MESH:D000544', (59, 61))	('AD', 'Disease', (59, 61))	('variants', 'Var', (24, 32))
205119	32471518	We subsequently retained only cancer-relevant pathogenic variants, based on whether they were found in the curated cancer variant databases or a 152 curated cancer predisposing gene list.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('cancer', 'Disease', (115, 121))	('cancer', 'Disease', (30, 36))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('cancer', 'Disease', (157, 163))	('variants', 'Var', (57, 65))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
205123	32471518	To acquire enough CharGer points to be classified as likely pathogenic, the variants typically need to be predicted to result in truncation in cancer predisposition genes where the loss of function (LOF) is a known disease mechanism and harbor variants with a dominant (evidence level PVS1, + 8 points) or a recessive (evidence level PSC1, + 4 points) mode of inheritance.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('truncation', 'MPA', (129, 139))	('PSC1', 'Gene', '54439', (334, 338))	('loss of function', 'NegReg', (181, 197))	('variants', 'Var', (76, 84))	('PSC1', 'Gene', (334, 338))	('cancer', 'Disease', (143, 149))	('result in', 'Reg', (119, 128))	('cancer', 'Disease', 'MESH:D009369', (143, 149))
205124	32471518	Additionally, evidence level PS1, + 7 points are scored if the variant results in the same peptide sequence change as an established pathogenic variant.	('variant', 'Var', (63, 70))	('PS1', 'Gene', '338399', (29, 32))	('PS1', 'Gene', (29, 32))	('peptide sequence change', 'MPA', (91, 114))
205134	32471518	For each cancer type with at least 20 cases of the tested ancestry with at least one predisposing variant carrier, we tested the burden of predisposing variants for each gene against all other cancer cohorts as controls.	('cancer', 'Disease', (9, 15))	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('cancer', 'Disease', (193, 199))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('variants', 'Var', (152, 160))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('tested', 'Reg', (118, 124))
205137	32471518	We further retained pathogenic and likely pathogenic variants per ACMG/AMP criteria as ascertained by InterVar and annotated using ANNOVAR.	('OV', 'Phenotype', 'HP:0012887', (134, 136))	('OV', 'Phenotype', 'HP:0100615', (134, 136))	('AMP', 'Chemical', 'MESH:D000249', (71, 74))	('AC', 'Chemical', '-', (66, 68))	('pathogenic', 'Reg', (20, 30))	('pathogenic', 'Reg', (42, 52))	('variants', 'Var', (53, 61))
205140	32471518	The tumor expression percentile of individual genes in each cancer cohort was calculated using the empirical cumulative distribution function (ecdf), as implemented in R. We annotated germline carriers of predisposition variants with extreme mRNA tumor expression (> 80th or < 20th percentile) of the affected gene.	('tumor', 'Disease', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (247, 252))	('variants', 'Var', (220, 228))	('tumor', 'Disease', (247, 252))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('cancer', 'Disease', (60, 66))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('tumor', 'Disease', 'MESH:D009369', (247, 252))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
205141	32471518	For samples within the same ancestry and same cancer cohort, we then used the two-sample Kolmogorov-Smirnov test to compare the expression percentile distribution between variants of oncogenes and tumor suppressors.	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('cancer', 'Disease', (46, 52))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('tumor', 'Disease', (197, 202))	('variants', 'Var', (171, 179))
205147	32471518	We considered cancer predisposing genes as those statistically enriched for pooled pathogenic and likely pathogenic variants (referred to here as predisposing variants) as previously classified).	('cancer', 'Disease', (14, 20))	('variants', 'Var', (116, 124))	('cancer', 'Disease', 'MESH:D009369', (14, 20))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))
205154	32471518	For example, in LUSC, BRCA2 predisposing variants were found in 2 of the 29 African ancestry samples (6.9%), whereas we only found 1 BRCA2 carrier out of the 455 European-ancestry samples (0.44%).	('variants', 'Var', (41, 49))	('BRCA2', 'Gene', (133, 138))	('BRCA2', 'Gene', (22, 27))	('LUSC', 'Phenotype', 'HP:0030359', (16, 20))	('BRCA2', 'Gene', '675', (133, 138))	('BRCA2', 'Gene', '675', (22, 27))
205155	32471518	Specifically, we examined the gene-level rates of individuals carrying pathogenic and likely pathogenic variants in the gnomAD non-cancer cohort (118,479 WES and 15,708 WGS samples, the "Methods" section, Additional file 2: Table S3).	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('variants', 'Var', (104, 112))	('gnomAD non-cancer', 'Disease', (120, 137))	('gnomAD non-cancer', 'Disease', 'MESH:D009369', (120, 137))
205162	32471518	The cancer-gene pairs included 15 predisposing variants within the African ancestry and another 6 within the East Asian ancestry.	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('variants', 'Var', (47, 55))	('cancer', 'Disease', (4, 10))	('cancer', 'Disease', 'MESH:D009369', (4, 10))
205163	32471518	None of the above variants discovered in the African ancestry were observed in any other ancestry within that cancer type (Fig.	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('cancer', 'Disease', (110, 116))	('variants', 'Var', (18, 26))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))
205164	32471518	Across the pan-cancer TCGA cohort, all of the BRCA2 frameshift variants found in LUSC and OV were unique to the African ancestry.	('BRCA2', 'Gene', (46, 51))	('cancer', 'Disease', (15, 21))	('cancer', 'Disease', 'MESH:D009369', (15, 21))	('OV', 'Phenotype', 'HP:0012887', (90, 92))	('frameshift variants', 'Var', (52, 71))	('BRCA2', 'Gene', '675', (46, 51))	('OV', 'Phenotype', 'HP:0100615', (90, 92))	('LUSC', 'Phenotype', 'HP:0030359', (81, 85))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))
205165	32471518	For other associated genes in the African ancestry, including ATM (PRAD), FH (KIRP), and VHL (KIRC), the predisposing variants differ between the African and European ancestries (Fig.	('ATM', 'Gene', '472', (62, 65))	('AD', 'Disease', (69, 71))	('VHL', 'Gene', (89, 92))	('variants', 'Var', (118, 126))	('VHL', 'Gene', '7428', (89, 92))	('ATM', 'Gene', (62, 65))	('AD', 'Disease', 'MESH:D000544', (69, 71))	('differ', 'Reg', (127, 133))
205166	32471518	The African ancestry-specific predisposing variants include splice site variants ATM c.2921+1G>A and FH c.556-2A>T, protein-truncating variants ATM p.T2333fs and FH p.S187*, and missense variants ATM p.R3008C.	('c.556-2A>T', 'Var', (104, 114))	('p.R3008C', 'Mutation', 'rs587782292', (200, 208))	('ATM', 'Gene', '472', (196, 199))	('ATM', 'Gene', '472', (144, 147))	('ATM', 'Gene', (81, 84))	('c.2921+1G>A', 'Mutation', 'rs587781558', (85, 96))	('p.T2333fs', 'Mutation', 'rs587781299', (148, 157))	('p.S187*', 'Mutation', 'p.S187*', (165, 172))	('c.556-2A>T', 'Mutation', 'c.556-2A>T', (104, 114))	('ATM', 'Gene', '472', (81, 84))	('ATM', 'Gene', (196, 199))	('ATM', 'Gene', (144, 147))	('p.T2333fs', 'Var', (148, 157))	('c.2921+1G>A', 'Var', (85, 96))	('p.S187*', 'Var', (165, 172))
205167	32471518	VHL p.C162F is the only recurrent variant found in two KIRC cases.	('p.C162F', 'Var', (4, 11))	('VHL', 'Gene', '7428', (0, 3))	('VHL', 'Gene', (0, 3))	('p.C162F', 'Mutation', 'rs397516444', (4, 11))
205168	32471518	In the East Asian ancestry, we assessed predisposing variants in BRIP1 (STAD), POLE (LIHC), and RECQL (STAD) (Fig.	('RECQL', 'Gene', (96, 101))	('BRIP1', 'Gene', '83990', (65, 70))	('AD', 'Disease', 'MESH:D000544', (74, 76))	('AD', 'Disease', 'MESH:D000544', (105, 107))	('AD', 'Disease', (74, 76))	('AD', 'Disease', (105, 107))	('RECQL', 'Gene', '5965', (96, 101))	('BRIP1', 'Gene', (65, 70))	('variants', 'Var', (53, 61))
205169	32471518	These include two BRIP1 variants p.I525fs and p.E1222fs and two protein-truncating variants in POLE and RECQL, respectively.	('p.E1222fs', 'Mutation', 'rs752586524', (46, 55))	('p.E1222fs', 'Var', (46, 55))	('BRIP1', 'Gene', '83990', (18, 23))	('RECQL', 'Gene', (104, 109))	('p.I525fs', 'Mutation', 'p.I525fsX', (33, 41))	('protein-truncating', 'NegReg', (64, 82))	('RECQL', 'Gene', '5965', (104, 109))	('p.I525fs', 'Var', (33, 41))	('BRIP1', 'Gene', (18, 23))
205171	32471518	Among the African ancestry-specific predisposing variants, splice-site variant ATM c.2921+1G>A (African ancestry allelic count [AC]/total allele number [AN] = 1/14,878; allelic frequency [AF] = 0.0067%) and BRCA2 p.R3128* (African ancestry AC/AN = 4/23,610; AF = 0.016%) were the only variants present in the African and non-Finnish European ancestries in gnomAD-non-cancer dataset.	('ATM', 'Gene', '472', (79, 82))	('gnomAD-non-cancer', 'Disease', (356, 373))	('AF', 'Disease', 'MESH:D001281', (188, 190))	('cancer', 'Phenotype', 'HP:0002664', (367, 373))	('AF', 'Disease', 'MESH:D001281', (258, 260))	('BRCA2', 'Gene', (207, 212))	('c.2921+1G>A', 'Var', (83, 94))	('gnomAD-non-cancer', 'Disease', 'MESH:D009369', (356, 373))	('p.R3128*', 'Mutation', 'p.R3128*', (213, 221))	('c.2921+1G>A', 'Mutation', 'rs587781558', (83, 94))	('AC', 'Chemical', '-', (240, 242))	('BRCA2', 'Gene', '675', (207, 212))	('AC', 'Chemical', '-', (128, 130))	('ATM', 'Gene', (79, 82))	('p.R3128*', 'Var', (213, 221))
205172	32471518	All other variants were absent within African ancestry and most other ancestries in gnomAD except SDHB p.R46* (Finnish European ancestry AC/AN = 2/25,066; AF = 0.007%) and ATM p.R3008C (East Asian ancestry AC/AN = 1/17,688; AF = 0.005%).	('p.R3008C', 'Mutation', 'rs587782292', (176, 184))	('AF', 'Disease', 'MESH:D001281', (155, 157))	('p.R46*', 'Mutation', 'p.R46*', (103, 109))	('AD', 'Disease', 'MESH:D000544', (88, 90))	('AD', 'Disease', (88, 90))	('SDHB', 'Gene', '6390', (98, 102))	('AF', 'Disease', 'MESH:D001281', (224, 226))	('AC', 'Chemical', '-', (137, 139))	('SDHB', 'Gene', (98, 102))	('AC', 'Chemical', '-', (206, 208))	('ATM', 'Gene', (172, 175))	('p.R46*', 'Var', (103, 109))	('ATM', 'Gene', '472', (172, 175))	('p.R3008C', 'Var', (176, 184))
205173	32471518	Similarly, only two of the six East Asian ancestry-specific predisposing variants, BRIP1 p.E1222Gfs (East Asian ancestry AC/AN = 11/19,232; AF = 0.05%) and POLE p.Tyr1078fs (East Asian ancestry AC/AN = 1/17,692; AF = 0.005%), were present exclusively in the East Asian ancestry of gnomAD-non-cancer dataset.	('p.E1222G', 'Var', (89, 97))	('AF', 'Disease', 'MESH:D001281', (140, 142))	('AC', 'Chemical', '-', (194, 196))	('cancer', 'Phenotype', 'HP:0002664', (292, 298))	('AF', 'Disease', 'MESH:D001281', (212, 214))	('BRIP1', 'Gene', '83990', (83, 88))	('gnomAD-non-cancer', 'Disease', 'MESH:D009369', (281, 298))	('p.E1222G', 'SUBSTITUTION', 'None', (89, 97))	('AC', 'Chemical', '-', (121, 123))	('p.Tyr1078fs', 'Var', (161, 172))	('p.Tyr1078fs', 'Mutation', 'p.Y1078fsX', (161, 172))	('gnomAD-non-cancer', 'Disease', (281, 298))	('BRIP1', 'Gene', (83, 88))
205174	32471518	Of note, 7 of the 15 predisposing variants, including BRCA2 variants in OV (p.Y1710fs, p.K1202fs) and in LUSC (p.V3082fs), were not found in ClinVar.	('p.Y1710fs', 'Var', (76, 85))	('OV', 'Phenotype', 'HP:0012887', (72, 74))	('p.K1202fs', 'Mutation', 'p.K1202fsX', (87, 96))	('OV', 'Phenotype', 'HP:0100615', (72, 74))	('LUSC', 'Phenotype', 'HP:0030359', (105, 109))	('BRCA2', 'Gene', (54, 59))	('p.V3082fs', 'Mutation', 'p.V3082fsX', (111, 120))	('p.V3082fs', 'Var', (111, 120))	('p.K1202fs', 'Var', (87, 96))	('BRCA2', 'Gene', '675', (54, 59))	('p.Y1710fs', 'Mutation', 'p.Y1710fsX', (76, 85))
205175	32471518	While VHL p.C162F lacks a ClinVar record, the co-localizing p.C162W showed three reports of pathogenicity and one report of uncertain significance.	('p.C162F', 'Mutation', 'rs397516444', (10, 17))	('VHL', 'Gene', (6, 9))	('p.C162W', 'Var', (60, 67))	('p.C162W', 'SUBSTITUTION', 'None', (60, 67))	('VHL', 'Gene', '7428', (6, 9))
205177	32471518	Only the POLE p.Y1078fs (AC/AN = 1/17,692, AF = 0.0056%) and BRIP1 p.E1222fs (AC/AN = 11/19,232, AF = 0.057%) were present exclusively in the East Asian ancestry of gnomAD-non-cancer dataset.	('gnomAD-non-cancer', 'Disease', (165, 182))	('AC', 'Chemical', '-', (78, 80))	('p.E1222fs', 'Var', (67, 76))	('gnomAD-non-cancer', 'Disease', 'MESH:D009369', (165, 182))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('p.E1222fs', 'Mutation', 'rs752586524', (67, 76))	('BRIP1', 'Gene', (61, 66))	('AC', 'Chemical', '-', (25, 27))	('p.Y1078fs', 'Var', (14, 23))	('BRIP1', 'Gene', '83990', (61, 66))	('AF', 'Disease', 'MESH:D001281', (97, 99))	('AF', 'Disease', 'MESH:D001281', (43, 45))	('p.Y1078fs', 'Mutation', 'p.Y1078fsX', (14, 23))
205178	32471518	First, we investigated the extent of loss of heterozygosity (LOH) of the predisposing variants using our previously developed statistical test (the "Methods" section) that compares the variant allele fractions in tumor vs. normal samples.	('tumor', 'Disease', (213, 218))	('tumor', 'Disease', 'MESH:D009369', (213, 218))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('variants', 'Var', (86, 94))
205179	32471518	Among the variants observed in the African ancestry, we observed significant LOH (FDR < 0.05) for both truncating variants in SDHB p.R116fs and p.R46* in PCPG (Fig.	('p.R46*', 'Mutation', 'p.R46*', (144, 150))	('p.R116fs', 'Mutation', 'p.R116fsX', (131, 139))	('p.R46*', 'Var', (144, 150))	('SDHB', 'Gene', '6390', (126, 130))	('SDHB', 'Gene', (126, 130))	('p.R116fs', 'Var', (131, 139))
205180	32471518	Three additional variants exhibited significant LOH, including BRCA2 p.R3128* (LUSC), BRCA2 p.K1202fs (OV), and FH p.S187* (KIRP).	('LUSC', 'Phenotype', 'HP:0030359', (79, 83))	('BRCA2', 'Gene', (86, 91))	('FH p.S187*', 'Var', (112, 122))	('BRCA2', 'Gene', '675', (63, 68))	('p.K1202fs', 'Var', (92, 101))	('OV', 'Phenotype', 'HP:0012887', (103, 105))	('p.S187*', 'Var', (115, 122))	('BRCA2', 'Gene', '675', (86, 91))	('OV', 'Phenotype', 'HP:0100615', (103, 105))	('p.R3128*', 'Mutation', 'p.R3128*', (69, 77))	('p.S187*', 'Mutation', 'p.S187*', (115, 122))	('p.K1202fs', 'Mutation', 'p.K1202fsX', (92, 101))	('BRCA2', 'Gene', (63, 68))	('p.R3128*', 'Var', (69, 77))
205181	32471518	We also observed suggestive LOH (FDR < 0.15 or tumor VAF > 0.6) for ATM c.2921+1G>A (PRAD) and BRCA2 p.Y1710fs (OV) (Fig.	('BRCA2', 'Gene', '675', (95, 100))	('AF', 'Disease', 'MESH:D001281', (54, 56))	('p.Y1710fs', 'Var', (101, 110))	('c.2921+1G>A', 'Var', (72, 83))	('OV', 'Phenotype', 'HP:0100615', (112, 114))	('OV', 'Phenotype', 'HP:0012887', (112, 114))	('ATM', 'Gene', (68, 71))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('c.2921+1G>A', 'Mutation', 'rs587781558', (72, 83))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('BRCA2', 'Gene', (95, 100))	('ATM', 'Gene', '472', (68, 71))	('AD', 'Disease', 'MESH:D000544', (87, 89))	('tumor', 'Disease', (47, 52))	('AD', 'Disease', (87, 89))	('p.Y1710fs', 'Mutation', 'p.Y1710fsX', (101, 110))
205182	32471518	Among the six predisposing variants in the East Asian ancestry, only POLE p.E2137* (LIHC) showed significant LOH (Fig.	('p.E2137*', 'Mutation', 'p.E2137*', (74, 82))	('LOH', 'NegReg', (109, 112))	('p.E2137*', 'Var', (74, 82))
205183	32471518	In a PRAD carrier of ATM, the germline p.L2332fs variant was coupled with a somatic p.E2164K mutation; in the KIRC carrier of VHL, the germline p.C162F variant was coupled with somatic p.E186* mutation.	('p.E2164K', 'Mutation', 'rs1317619286', (84, 92))	('p.C162F', 'Mutation', 'rs397516444', (144, 151))	('p.E186* mutation', 'Var', (185, 201))	('p.L2332fs', 'Mutation', 'p.L2332fsX', (39, 48))	('p.L2332fs', 'Var', (39, 48))	('AD', 'Disease', 'MESH:D000544', (7, 9))	('p.E2164K', 'Var', (84, 92))	('VHL', 'Gene', (126, 129))	('ATM', 'Gene', (21, 24))	('AD', 'Disease', (7, 9))	('p.E186*', 'Mutation', 'p.E186*', (185, 192))	('VHL', 'Gene', '7428', (126, 129))	('ATM', 'Gene', '472', (21, 24))
205184	32471518	4a), germline p.S187* variant was coupled with a somatic splice-site mutation c.1390+6T>A.	('p.S187*', 'Var', (14, 21))	('c.1390+6T>A', 'Mutation', 'c.1390+6T>A', (78, 89))	('p.S187*', 'Mutation', 'p.S187*', (14, 21))	('c.1390+6T>A', 'Var', (78, 89))
205185	32471518	Analysis of RNA from the KIRP tumor revealed that the somatic FH: c.1390+6T>A causes mis-splicing of 27.6% of the transcripts in tumor RNA, as indicated by the number of reads spanning consensus splice site (n = 68) and the new cryptic splice site (n = 26) (case 2 in Fig.	('mis-splicing', 'MPA', (85, 97))	('c.1390+6T>A', 'Var', (66, 77))	('causes', 'Reg', (78, 84))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('tumor', 'Disease', (129, 134))	('tumor', 'Disease', (30, 35))	('c.1390+6T>A', 'Mutation', 'c.1390+6T>A', (66, 77))
205187	32471518	We observed 154 overall and 27 non-European ancestry-specific predisposing variants co-occurring with an extreme expression (> 80% or < 20% in the same cancer cohort) of the respective gene, although the current sample sizes preclude us from discovering significantly associated genes compared to non-carriers within each ancestry-cancer cohort (Additional file 2: Table S5a).	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('cancer', 'Disease', (331, 337))	('cancer', 'Disease', 'MESH:D009369', (331, 337))	('S5a', 'Gene', '5710', (371, 374))	('S5a', 'Gene', (371, 374))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('cancer', 'Phenotype', 'HP:0002664', (331, 337))	('variants', 'Var', (75, 83))
205188	32471518	The degree of their variant allele fraction in the tumor RNAseq data (RNA VAF) thus indicates the degree of allelic-specific expression (ASE).	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor', 'Disease', (51, 56))	('AF', 'Disease', 'MESH:D001281', (75, 77))	('variant', 'Var', (20, 27))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
205189	32471518	The African carriers of SDHB truncating variants p.R116fs (the corresponding gene's expression ranks at the bottom 0.5 percentile among all PCPG cases [0.5%], RNA VAF = 0.25 and p.R46* (9% in PCGP, RNA VAF = 0.80) showed low SDHB expression.	('p.R46*', 'Mutation', 'p.R46*', (178, 184))	('p.R116fs', 'Mutation', 'p.R116fsX', (49, 57))	('AF', 'Disease', 'MESH:D001281', (164, 166))	('SDHB', 'Gene', '6390', (225, 229))	('AF', 'Disease', 'MESH:D001281', (203, 205))	('SDHB', 'Gene', (225, 229))	('expression', 'MPA', (230, 240))	('p.R116fs', 'Var', (49, 57))	('p.R46*', 'Var', (178, 184))	('SDHB', 'Gene', '6390', (24, 28))	('SDHB', 'Gene', (24, 28))	('PCGP', 'Chemical', '-', (192, 196))	('low', 'NegReg', (221, 224))
205190	32471518	The African carriers of BRCA2 p.Y1710fs (6% in OV, RNA VAF = 0) and p.3082fs (15% in LUSC, RNA VAF = 0) also exhibited low BRCA2 (Fig.	('BRCA2', 'Gene', '675', (123, 128))	('BRCA2', 'Gene', '675', (24, 29))	('OV', 'Phenotype', 'HP:0012887', (47, 49))	('low', 'NegReg', (119, 122))	('AF', 'Disease', 'MESH:D001281', (96, 98))	('OV', 'Phenotype', 'HP:0100615', (47, 49))	('p.3082fs', 'Mutation', 'p.3082fs', (68, 76))	('AF', 'Disease', 'MESH:D001281', (56, 58))	('p.Y1710fs', 'Mutation', 'p.Y1710fsX', (30, 39))	('p.Y1710fs', 'Var', (30, 39))	('BRCA2', 'Gene', (123, 128))	('BRCA2', 'Gene', (24, 29))	('LUSC', 'Phenotype', 'HP:0030359', (85, 89))
205191	32471518	In the OV case, the germline BRCA2 p.Y1710fs is coupled with a somatic LOH event, resulting in nearly complete loss of BRCA2 expression.	('loss', 'NegReg', (111, 115))	('OV', 'Phenotype', 'HP:0012887', (7, 9))	('BRCA2', 'Gene', (29, 34))	('OV', 'Phenotype', 'HP:0100615', (7, 9))	('expression', 'MPA', (125, 135))	('BRCA2', 'Gene', (119, 124))	('BRCA2', 'Gene', '675', (29, 34))	('p.Y1710fs', 'Mutation', 'p.Y1710fsX', (35, 44))	('BRCA2', 'Gene', '675', (119, 124))	('p.Y1710fs', 'Var', (35, 44))
205192	32471518	Both of the African ancestry carriers of FH predisposing variants, FH p.S187* (2% in KIRP, RNA VAF = 0.13) and FH:c.556-2A>T (2% in KIRP, RNA VAF = 0.50), showed low FH expression.	('FH:c.556-2A>T', 'Var', (111, 124))	('p.S187*', 'Var', (70, 77))	('AF', 'Disease', 'MESH:D001281', (143, 145))	('p.S187*', 'Mutation', 'p.S187*', (70, 77))	('AF', 'Disease', 'MESH:D001281', (96, 98))	('FH:c.556-2A>T', 'SUBSTITUTION', 'None', (111, 124))	('FH expression', 'MPA', (166, 179))	('low', 'NegReg', (162, 165))
205193	32471518	In addition to the biallelic somatic FH:c.1390+6T>A mutation in the carrier of germline FH p.S187* described earlier, we also observed a mis-splicing event in a different case carrying germline FH:c.556-2A>T at the RNA level (case 1 in Fig.	('FH:c.556-2A>T', 'Var', (194, 207))	('FH:c.1390+6T>A', 'SUBSTITUTION', 'None', (37, 51))	('FH:c.556-2A>T', 'SUBSTITUTION', 'None', (194, 207))	('p.S187*', 'Mutation', 'p.S187*', (91, 98))	('FH:c.1390+6T>A', 'Var', (37, 51))
205194	32471518	For other ancestries, the tumor from one predisposing variant carrier of the Native/Latin American ancestry, NF1 p.Y489C, showed low NF1 mRNA expression (2% in BRCA, RNA VAF = 0).	('AF', 'Disease', 'MESH:D001281', (171, 173))	('low', 'NegReg', (129, 132))	('NF1', 'Gene', (109, 112))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('NF1', 'Gene', (133, 136))	('NF1', 'Gene', '4763', (109, 112))	('BRCA', 'Gene', '672', (160, 164))	('NF1', 'Gene', '4763', (133, 136))	('p.Y489C', 'Mutation', 'rs137854557', (113, 120))	('BRCA', 'Gene', (160, 164))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('p.Y489C', 'Var', (113, 120))
205195	32471518	Overall, RNA VAF of the majority of protein-truncating variants not accompanied by LOH varied between 0 and 0.25 (Additional file 2: Table S5a), suggesting degradation of the mutant allele.	('S5a', 'Gene', '5710', (139, 142))	('S5a', 'Gene', (139, 142))	('variants', 'Var', (55, 63))	('protein-truncating', 'Protein', (36, 54))	('AF', 'Disease', 'MESH:D001281', (14, 16))
205196	32471518	Many predisposing truncating variants of tumor suppressors are assumed to lead to loss of gene expression through mechanisms such as nonsense-mediated decay (NMD).	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('nonsense-mediated decay', 'Disease', (133, 156))	('tumor', 'Disease', (41, 46))	('truncating variants', 'Var', (18, 37))	('gene expression', 'MPA', (90, 105))	('loss', 'NegReg', (82, 86))	('tumor', 'Disease', 'MESH:D009369', (41, 46))
205197	32471518	These results support that a fraction of predisposing variants likely result in reduced gene products of tumor suppressors in ancestral groups.	('gene products', 'MPA', (88, 101))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('reduced', 'NegReg', (80, 87))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('variants', 'Var', (54, 62))	('tumor', 'Disease', (105, 110))
205198	32471518	Conversely, for the rare tumors with germline variants in oncogenes, the two predisposing RET variants are coupled with elevated RET expression in their African ancestry carriers, including p.C631Y (84% in KIRC) and p.D634Y (91% in PCGP).	('expression', 'MPA', (133, 143))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('RET', 'Gene', (129, 132))	('tumors', 'Disease', (25, 31))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('RET', 'Gene', '5979', (90, 93))	('p.D634Y', 'Var', (216, 223))	('p.C631Y', 'Var', (190, 197))	('tumors', 'Disease', 'MESH:D009369', (25, 31))	('p.C631Y', 'Mutation', 'p.C631Y', (190, 197))	('elevated', 'PosReg', (120, 128))	('RET', 'Gene', '5979', (129, 132))	('p.D634Y', 'Mutation', 'p.D634Y', (216, 223))	('RET', 'Gene', (90, 93))	('PCGP', 'Chemical', '-', (232, 236))	('elevated RET', 'Phenotype', 'HP:0008151', (120, 132))
205215	32471518	In the East Asian ancestry, we found predisposing variants affecting BRIP1 in STAD that warrants further investigation.	('AD', 'Disease', (80, 82))	('BRIP1', 'Gene', '83990', (69, 74))	('variants', 'Var', (50, 58))	('AD', 'Disease', 'MESH:D000544', (80, 82))	('BRIP1', 'Gene', (69, 74))
205225	32471518	Many of the predisposing variants found in the African or East Asian ancestry were not identified in the much larger European-ancestry population of TCGA (n = 8184) or even the gnomAD non-cancer cohort (n = 134,187) or submitted to ClinVar by clinical laboratories assessing patients for cancer predisposition.	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('variants', 'Var', (25, 33))	('gnomAD non-cancer', 'Disease', (177, 194))	('cancer', 'Disease', 'MESH:D009369', (288, 294))	('cancer', 'Disease', (288, 294))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('cancer', 'Disease', (188, 194))	('patients', 'Species', '9606', (275, 283))	('cancer', 'Phenotype', 'HP:0002664', (288, 294))	('gnomAD non-cancer', 'Disease', 'MESH:D009369', (177, 194))
205226	32471518	The identification of ancestry-specific predisposing variants further highlights this challenge in minority groups, where current germline sequencing often results in higher rates of variants of unknown significance (VUSs).	('VUSs', 'Disease', (217, 221))	('variants', 'Var', (183, 191))	('VUSs', 'Disease', 'None', (217, 221))	('higher rates', 'PosReg', (167, 179))	('variants', 'Var', (53, 61))
205231	32471518	To aid interpretation of low-frequency ancestry-specific variants, evidence of a somatic second hit event (i.e., loss of heterozygosity [LOH] or a biallelic mutation) in tumor samples can support functionality.	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('heterozygosity', 'MPA', (121, 135))	('loss', 'NegReg', (113, 117))	('tumor', 'Disease', (170, 175))	('biallelic', 'Var', (147, 156))	('variants', 'Var', (57, 65))
205233	32471518	While the majority of cancer genomic studies focus exclusively on the germline or somatic genome, pathogenic germline variants are associated with different somatic mutational signatures, allele-specific imbalance, or somatic drivers.	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('imbalance', 'Phenotype', 'HP:0002172', (204, 213))	('cancer', 'Disease', (22, 28))	('variants', 'Var', (118, 126))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))
205235	32471518	Collectively, these findings are providing the roadmaps of how germline variants may trigger and collaborate with specific somatic mutations, eventually leading to cancer development.	('germline variants', 'Var', (63, 80))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('leading to', 'Reg', (153, 163))	('trigger', 'Reg', (85, 92))	('cancer', 'Disease', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (164, 170))
205236	32471518	In summary, we identify ancestry-specific predisposing genes and variants contributing to multiple cancer types.	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('variants', 'Var', (65, 73))	('cancer', 'Disease', (99, 105))	('contributing', 'Reg', (74, 86))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
205237	32471518	While the identified cancer predisposition genes are known, most predisposing variants are found to be exclusive within ancestries, supporting the "clan-genomics" hypothesis.	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('variants', 'Var', (78, 86))	('cancer', 'Disease', (21, 27))	('cancer', 'Disease', 'MESH:D009369', (21, 27))
205251	27130805	Despite this difference, peroxidase activities of both 1-Cys and 2-Cys groups commonly contribute to cellular protection against oxidative stress.	('1-Cys', 'Var', (55, 60))	('contribute', 'Reg', (87, 97))	('oxidative stress', 'Phenotype', 'HP:0025464', (129, 145))	('2-Cys', 'Var', (65, 70))	('activities', 'MPA', (36, 46))	('peroxidase', 'Enzyme', (25, 35))	('2-Cys', 'Chemical', '-', (65, 70))	('cellular protection', 'CPA', (101, 120))	('1-Cys', 'Chemical', '-', (55, 60))
205285	27130805	PRDX1 gene is mapped on chromosome 1p34.1 and is a member of the peroxiredoxin family that contains a consensus site (Thr(90)-Pro-Lys-Lys) for phosphorylation by cyclin dependent kinases.	('PRDX1', 'Gene', (0, 5))	('Thr(90)-Pro', 'Var', (118, 129))	('phosphorylation', 'MPA', (143, 158))	('Lys', 'Chemical', 'MESH:D008239', (134, 137))	('Thr(90)-Pro', 'SUBSTITUTION', 'None', (118, 129))	('Lys', 'Chemical', 'MESH:D008239', (130, 133))
205299	27130805	PRDX2 also enhances the activation of platelet-derived growth factor (PDGF) receptor and phospholipase Cgamma1 in PDGF signaling via the modulation of H2O2.	('platelet-derived', 'Protein', (38, 54))	('H2O2', 'Gene', (151, 155))	('H2O2', 'Chemical', 'MESH:D006861', (151, 155))	('activation', 'MPA', (24, 34))	('phospholipase Cgamma1', 'Gene', '5335', (89, 110))	('phospholipase Cgamma1', 'Gene', (89, 110))	('PD', 'Disease', 'MESH:D010300', (70, 72))	('PD', 'Disease', 'MESH:D010300', (114, 116))	('enhances', 'PosReg', (11, 19))	('modulation', 'Var', (137, 147))	('PRDX2', 'Gene', (0, 5))
205336	27130805	Recent findings suggest that Fkbp52 deficiency diminishes the threshold against OS by reducing PRDX6 levels.	('threshold against OS', 'MPA', (62, 82))	('PRDX6 levels', 'MPA', (95, 107))	('Fkbp52', 'Gene', '2288', (29, 35))	('reducing', 'NegReg', (86, 94))	('Fkbp52', 'Gene', (29, 35))	('diminishes', 'NegReg', (47, 57))	('deficiency', 'Var', (36, 46))
205337	27130805	A recent study also suggested that 67 (phox) binds to phospho-PRDX6 and inhibits its PLA2 activity, an interaction that could function to terminate the PLA2-mediated NOX2 activation signal.	('PLA2', 'Gene', '8398', (152, 156))	('PLA2', 'Gene', (152, 156))	('binds', 'Interaction', (45, 50))	('PLA2', 'Gene', '8398', (85, 89))	('inhibits', 'NegReg', (72, 80))	('PLA2', 'Gene', (85, 89))	('phospho-PRDX6', 'Var', (54, 67))	('NOX2', 'Gene', '1536', (166, 170))	('NOX2', 'Gene', (166, 170))
205363	27130805	PRDX1 enhances p65-mediated cyclooxygenase (COX)-2 gene expression in estrogen receptor (ER) deficient human breast cancer cells (MDA-MB-231), and knockdown of PRDX1 can attenuate COX-2 expression by reducing the occupancy of NF-kappaB transactivation potential of NF-kappaB in ER-deficient-breast cancer cells.	('deficient human breast cancer', 'Disease', (93, 122))	('ER', 'Gene', '2099', (278, 280))	('estrogen receptor', 'Gene', (70, 87))	('NF-kappaB', 'Gene', '4790', (265, 274))	('reducing', 'NegReg', (200, 208))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (130, 140))	('COX-2', 'Gene', (180, 185))	('breast cancer', 'Phenotype', 'HP:0003002', (291, 304))	('breast cancer', 'Phenotype', 'HP:0003002', (109, 122))	('ER-deficient-breast cancer', 'Disease', (278, 304))	('attenuate', 'NegReg', (170, 179))	('expression', 'MPA', (56, 66))	('COX-2', 'Gene', '4513', (180, 185))	('knockdown', 'Var', (147, 156))	('cyclooxygenase (COX)-2', 'Gene', '4513', (28, 50))	('NF-kappaB', 'Gene', (226, 235))	('enhances', 'PosReg', (6, 14))	('estrogen receptor', 'Gene', '2099', (70, 87))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('PRDX1', 'Gene', (0, 5))	('NF-kappaB', 'Gene', '4790', (226, 235))	('ER-deficient-breast cancer', 'Disease', 'MESH:D001943', (278, 304))	('deficient human breast cancer', 'Disease', 'MESH:D001943', (93, 122))	('occupancy', 'MPA', (213, 222))	('expression', 'MPA', (186, 196))	('NF-kappaB', 'Gene', (265, 274))	('ER', 'Gene', '2099', (89, 91))	('PRDX1', 'Gene', (160, 165))	('cyclooxygenase (COX)-2', 'Gene', (28, 50))	('cancer', 'Phenotype', 'HP:0002664', (298, 304))
205385	27130805	Other researchers also demonstrated that PRDX2 knockdown using a lentiviral vector-mediated specific shRNA inhibited cell growth, stimulated apoptosis, and augmented the production of endogenous ROS that led to an altered expression of proteins associated with the Wnt signaling pathway.	('expression of', 'MPA', (222, 235))	('ROS', 'Chemical', 'MESH:D017382', (195, 198))	('production of endogenous ROS', 'MPA', (170, 198))	('PRDX2', 'Gene', (41, 46))	('stimulated', 'PosReg', (130, 140))	('rat', 'Species', '10116', (30, 33))	('knockdown', 'Var', (47, 56))	('augmented', 'PosReg', (156, 165))	('proteins', 'Protein', (236, 244))	('altered', 'Reg', (214, 221))	('cell growth', 'CPA', (117, 128))	('apoptosis', 'CPA', (141, 150))	('inhibited', 'NegReg', (107, 116))
205399	27130805	In a gene silencing study in breast cancer cells, silencing the PRDX3 gene inhibits cell proliferation and induces cell cycle arrest in breast cancers.	('arrest', 'Disease', (126, 132))	('breast cancer', 'Disease', 'MESH:D001943', (136, 149))	('breast cancer', 'Phenotype', 'HP:0003002', (29, 42))	('cancers', 'Phenotype', 'HP:0002664', (143, 150))	('arrest', 'Disease', 'MESH:D006323', (126, 132))	('breast cancer', 'Disease', 'MESH:D001943', (29, 42))	('breast cancer', 'Disease', (29, 42))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('breast cancers', 'Disease', 'MESH:D001943', (136, 150))	('breast cancers', 'Disease', (136, 150))	('silencing', 'Var', (50, 59))	('induces', 'Reg', (107, 114))	('breast cancers', 'Phenotype', 'HP:0003002', (136, 150))	('cell proliferation', 'CPA', (84, 102))	('inhibits', 'NegReg', (75, 83))	('breast cancer', 'Phenotype', 'HP:0003002', (136, 149))	('PRDX3', 'Gene', (64, 69))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('rat', 'Species', '10116', (96, 99))
205403	27130805	Antiandrogen-resistant prostate cancer cells also possess an upregulation of the tricarboxylic acid (TCA) pathway and resistance to H2O2-induced apoptosis through a failure to activate pro-apoptotic pathways, but knockdown of PRDX3 restored H2O2 sensitivity.	('H2O2', 'Chemical', 'MESH:D006861', (132, 136))	('H2O2', 'Chemical', 'MESH:D006861', (241, 245))	('tricarboxylic acid', 'Chemical', 'MESH:D014233', (81, 99))	('prostate cancer', 'Phenotype', 'HP:0012125', (23, 38))	('Antiandrogen-resistant', 'Disease', (0, 22))	('prostate cancer', 'Disease', (23, 38))	('upregulation', 'PosReg', (61, 73))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('TCA', 'Chemical', 'MESH:D014233', (101, 104))	('prostate cancer', 'Disease', 'MESH:D011471', (23, 38))	('knockdown', 'Var', (213, 222))	('resistance', 'CPA', (118, 128))
205413	27130805	Downregulation of PRDX3 upregulated pro-apoptotic proteins Bax, Caspase-3 and Caspase-9, and the silencing of PRDX3 triggered cisplatin-mediated apoptosis in the ovarian cancer cells through suppression of the NF-kappaB signaling pathway.	('PRDX3', 'Gene', (110, 115))	('Caspase-3', 'Gene', '836', (64, 73))	('Bax', 'Gene', '581', (59, 62))	('Downregulation', 'NegReg', (0, 14))	('NF-kappaB', 'Gene', '4790', (210, 219))	('suppression', 'NegReg', (191, 202))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('pro-apoptotic', 'MPA', (36, 49))	('Caspase-9', 'Gene', '842', (78, 87))	('ovarian cancer', 'Disease', (162, 176))	('Caspase-9', 'Gene', (78, 87))	('ovarian cancer', 'Phenotype', 'HP:0100615', (162, 176))	('PRDX3', 'Gene', (18, 23))	('cisplatin', 'Chemical', 'MESH:D002945', (126, 135))	('Caspase-3', 'Gene', (64, 73))	('cisplatin-mediated apoptosis', 'CPA', (126, 154))	('triggered', 'PosReg', (116, 125))	('silencing', 'Var', (97, 106))	('upregulated', 'PosReg', (24, 35))	('ovarian cancer', 'Disease', 'MESH:D010051', (162, 176))	('Bax', 'Gene', (59, 62))	('NF-kappaB', 'Gene', (210, 219))
205421	27130805	Alteration in expression of PRDX4 results in an alteration to the rate of tumor progression and metastasis which is indicated by anchorage independent colony formation, cell migration and invasion of human lung cancer cells.	('metastasis', 'CPA', (96, 106))	('Alteration', 'Var', (0, 10))	('lung cancer', 'Disease', (206, 217))	('human', 'Species', '9606', (200, 205))	('tumor', 'Disease', (74, 79))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('anchorage independent colony formation', 'CPA', (129, 167))	('cell migration', 'CPA', (169, 183))	('lung cancer', 'Disease', 'MESH:D008175', (206, 217))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('lung cancer', 'Phenotype', 'HP:0100526', (206, 217))	('PRDX4', 'Gene', (28, 33))	('rat', 'Species', '10116', (4, 7))	('rat', 'Species', '10116', (66, 69))	('alteration', 'Reg', (48, 58))	('rat', 'Species', '10116', (52, 55))	('rat', 'Species', '10116', (177, 180))	('invasion', 'CPA', (188, 196))	('expression', 'MPA', (14, 24))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))
205423	27130805	Alteration of PRDX4 expression is proposed to play a role in the development of different types of leukemia.	('leukemia', 'Phenotype', 'HP:0001909', (99, 107))	('play', 'Reg', (46, 50))	('leukemia', 'Disease', 'MESH:D007938', (99, 107))	('Alteration', 'Var', (0, 10))	('leukemia', 'Disease', (99, 107))	('role', 'Reg', (53, 57))	('PRDX4', 'Gene', (14, 19))	('rat', 'Species', '10116', (4, 7))
205428	27130805	This fusion of AML1 gene with the PRDX4 gene is supposed to play a role in the altered expression of PRDX4 in acute myeloid leukemia.	('PRDX4', 'Gene', (101, 106))	('AML1', 'Gene', (15, 19))	('fusion', 'Var', (5, 11))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (110, 132))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (116, 132))	('leukemia', 'Phenotype', 'HP:0001909', (124, 132))	('AML', 'Phenotype', 'HP:0004808', (15, 18))	('AML1', 'Gene', '861', (15, 19))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (110, 132))	('acute myeloid leukemia', 'Disease', (110, 132))
205430	27130805	They found that the knockdown of PRDX4 results in reduced Glioblastoma multiform cell growth and radiation resistance along with increased ROS level, DNA damage and apoptosis in in-vitro model, suggesting the importance of PRDX4 in radiation resistance and tumor maintenance of GBM.	('PRDX4', 'Gene', (33, 38))	('tumor', 'Disease', (257, 262))	('Glioblastoma', 'Phenotype', 'HP:0012174', (58, 70))	('Glioblastoma', 'Disease', (58, 70))	('apoptosis', 'CPA', (165, 174))	('increased', 'PosReg', (129, 138))	('DNA damage', 'MPA', (150, 160))	('Glioblastoma', 'Disease', 'MESH:D005909', (58, 70))	('ROS', 'Chemical', 'MESH:D017382', (139, 142))	('reduced', 'NegReg', (50, 57))	('tumor', 'Disease', 'MESH:D009369', (257, 262))	('knockdown', 'Var', (20, 29))	('radiation resistance', 'CPA', (97, 117))	('ROS level', 'MPA', (139, 148))	('tumor', 'Phenotype', 'HP:0002664', (257, 262))
205470	27130805	IHC revealed significant overexpression of PRDX3 in prostate cancer, associated with age, increased prostate specific antigen (PSA), tumor stage, or Gleason score, and high PRDX3 staining was associated with early age and elevated Gleason score at time of radical prostatectomy in African-American patients but not in Caucasian patients with prostate cancer.	('cancer', 'Phenotype', 'HP:0002664', (351, 357))	('PRDX3', 'Gene', (173, 178))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('prostate cancer', 'Disease', 'MESH:D011471', (52, 67))	('high', 'Var', (168, 172))	('prostate cancer', 'Phenotype', 'HP:0012125', (52, 67))	('prostate cancer', 'Disease', (52, 67))	('PRDX3', 'Gene', (43, 48))	('patients', 'Species', '9606', (298, 306))	('prostate cancer', 'Disease', 'MESH:D011471', (342, 357))	('prostate specific antigen', 'Gene', (100, 125))	('prostate cancer', 'Phenotype', 'HP:0012125', (342, 357))	('Gleason score', 'MPA', (231, 244))	('PSA', 'Gene', '354', (127, 130))	('increased', 'PosReg', (90, 99))	('patients', 'Species', '9606', (328, 336))	('associated', 'Reg', (69, 79))	('prostate specific antigen', 'Gene', '354', (100, 125))	('prostate cancer', 'Disease', (342, 357))	('tumor', 'Disease', (133, 138))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('overexpression', 'PosReg', (25, 39))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('PSA', 'Gene', (127, 130))
205472	27130805	The platinum-resistant ovarian cancer patient group had significantly higher PRDX3 protein compared to the platinum-sensitive ovarian cancer patient group, suggesting PRDX3 may be associated with drug resistance in ovarian cancer.	('ovarian cancer', 'Phenotype', 'HP:0100615', (126, 140))	('platinum', 'Chemical', 'MESH:D010984', (107, 115))	('ovarian cancer', 'Phenotype', 'HP:0100615', (215, 229))	('drug resistance', 'Phenotype', 'HP:0020174', (196, 211))	('platinum-resistant ovarian cancer', 'Disease', 'MESH:D010051', (4, 37))	('PRDX3 protein', 'Protein', (77, 90))	('higher', 'PosReg', (70, 76))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('associated', 'Reg', (180, 190))	('patient', 'Species', '9606', (141, 148))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('ovarian cancer', 'Disease', 'MESH:D010051', (23, 37))	('ovarian cancer', 'Disease', 'MESH:D010051', (215, 229))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('platinum-resistant ovarian cancer', 'Disease', (4, 37))	('ovarian cancer', 'Disease', 'MESH:D010051', (126, 140))	('patient', 'Species', '9606', (38, 45))	('PRDX3', 'Var', (167, 172))	('protein', 'Protein', (83, 90))	('ovarian cancer', 'Disease', (215, 229))	('ovarian cancer', 'Disease', (126, 140))	('ovarian cancer', 'Phenotype', 'HP:0100615', (23, 37))	('platinum', 'Chemical', 'MESH:D010984', (4, 12))
205479	27130805	Overexpression of PRDX6 leads to a more invasive phenotype and metastatic potential in human breast cancer.	('human', 'Species', '9606', (87, 92))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('breast cancer', 'Disease', 'MESH:D001943', (93, 106))	('PRDX6', 'Gene', (18, 23))	('invasive phenotype', 'CPA', (40, 58))	('breast cancer', 'Disease', (93, 106))	('Overexpression', 'Var', (0, 14))	('breast cancer', 'Phenotype', 'HP:0003002', (93, 106))	('more', 'PosReg', (35, 39))	('metastatic potential', 'CPA', (63, 83))
205483	27130805	In principle, PRDXs could have a different function in the nucleus because NF-kappaB interactions with DNA are governed by a redox-sensitive cysteine (Cys62) on the p50 subunit of the NF-kappaB dimer.	('cysteine', 'Chemical', 'MESH:D003545', (141, 149))	('interactions', 'Interaction', (85, 97))	('NF-kappaB', 'Gene', (75, 84))	('governed by', 'Reg', (111, 122))	('NF-kappaB', 'Gene', '4790', (75, 84))	('Cys62', 'Chemical', '-', (151, 156))	('NF-kappaB', 'Gene', '4790', (184, 193))	('Cys62', 'Var', (151, 156))	('NF-kappaB', 'Gene', (184, 193))
205484	27130805	Oxidation of Cys62 inhibits NF-kappaB binding and decreases the effectiveness of NF-kappaB signaling.	('NF-kappaB', 'Gene', '4790', (81, 90))	('Cys62', 'Chemical', '-', (13, 18))	('binding', 'Interaction', (38, 45))	('NF-kappaB', 'Gene', (81, 90))	('NF-kappaB', 'Gene', '4790', (28, 37))	('decreases', 'NegReg', (50, 59))	('NF-kappaB', 'Gene', (28, 37))	('Cys62', 'Var', (13, 18))	('inhibits', 'NegReg', (19, 27))
205491	27130805	Under conditions of TNF-alpha stimulation in which PRDX2 activity was either partially blocked using a dominant negative mutant version or was completely abolished by gene knockout, JNK and p38 MAP kinase activation were enhanced whereas the activation of extracellular signal related kinase (ERK) was suppressed.	('abolished', 'NegReg', (154, 163))	('negative', 'NegReg', (112, 120))	('mutant', 'Var', (121, 127))	('ERK', 'Gene', (293, 296))	('activation', 'PosReg', (205, 215))	('extracellular signal related kinase', 'Gene', (256, 291))	('PRDX2', 'Gene', (51, 56))	('p38 MAP kinase', 'Gene', '1432', (190, 204))	('ERK', 'Gene', '5594', (293, 296))	('extracellular signal related kinase', 'Gene', '5594', (256, 291))	('enhanced', 'PosReg', (221, 229))	('activity', 'MPA', (57, 65))	('JNK', 'Gene', (182, 185))	('p38 MAP kinase', 'Gene', (190, 204))	('JNK', 'Gene', '5599', (182, 185))	('blocked', 'NegReg', (87, 94))
205499	27130805	Furthermore, the silencing of PRDX3 triggered cisplatin-mediated apoptosis in the ovarian cancer cells, which may act through suppression of the NF-kappaB signaling pathway.	('cisplatin-mediated apoptosis', 'CPA', (46, 74))	('ovarian cancer', 'Phenotype', 'HP:0100615', (82, 96))	('suppression', 'NegReg', (126, 137))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('ovarian cancer', 'Disease', 'MESH:D010051', (82, 96))	('PRDX3', 'Gene', (30, 35))	('cisplatin', 'Chemical', 'MESH:D002945', (46, 55))	('ovarian cancer', 'Disease', (82, 96))	('NF-kappaB', 'Gene', '4790', (145, 154))	('triggered', 'Reg', (36, 45))	('silencing', 'Var', (17, 26))	('NF-kappaB', 'Gene', (145, 154))
205501	27130805	Also, knockdown of PRDX3 restored H2O2 sensitivity, and PRDX3 has been identified as a gene induced by oncogenic c-Myc.	('PRDX3', 'Gene', (19, 24))	('restored', 'PosReg', (25, 33))	('H2O2', 'Chemical', 'MESH:D006861', (34, 38))	('c-Myc', 'Gene', '4609', (113, 118))	('knockdown', 'Var', (6, 15))	('PRDX3', 'Gene', (56, 61))	('H2O2 sensitivity', 'MPA', (34, 50))	('c-Myc', 'Gene', (113, 118))
205509	27130805	Wei et al demonstrated that an alteration in the expression of PRDX4 results in an alteration in the rate of tumor progression and metastasis which is indicated by anchorage independent colony formation, cell migration and invasion of human lung cancer cells.	('rat', 'Species', '10116', (101, 104))	('alteration', 'Reg', (83, 93))	('lung cancer', 'Disease', (241, 252))	('rat', 'Species', '10116', (17, 20))	('lung cancer', 'Phenotype', 'HP:0100526', (241, 252))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('rat', 'Species', '10116', (212, 215))	('cell migration', 'CPA', (204, 218))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))	('alteration', 'Var', (31, 41))	('PRDX4', 'Gene', (63, 68))	('human', 'Species', '9606', (235, 240))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('rat', 'Species', '10116', (35, 38))	('rat', 'Species', '10116', (87, 90))	('lung cancer', 'Disease', 'MESH:D008175', (241, 252))	('tumor', 'Disease', (109, 114))
205512	27130805	They showed that knockdown of GATA1 led to an increased expression of PRDX5 and inhibition of apoptosis, suggesting that PRDX5 may protect cells from oxidative stress-mediated apoptosis in a GATA1-regulated manner.	('PRDX5', 'Gene', '25824', (70, 75))	('oxidative stress', 'Phenotype', 'HP:0025464', (150, 166))	('PRDX5', 'Gene', '25824', (121, 126))	('GATA1', 'Gene', '2623', (30, 35))	('increased', 'PosReg', (46, 55))	('GATA1', 'Gene', (191, 196))	('expression', 'MPA', (56, 66))	('PRDX5', 'Gene', (70, 75))	('oxidative stress-mediated', 'MPA', (150, 175))	('PRDX5', 'Gene', (121, 126))	('knockdown', 'Var', (17, 26))	('GATA1', 'Gene', (30, 35))	('apoptosis', 'CPA', (94, 103))	('GATA1', 'Gene', '2623', (191, 196))
205524	27130805	In addition, mutant PRDX6 (C47S) attenuated PRDX6-mediated p38, ERK1/2, and AP-1 activities as well as its enzyme activities in the A549 and NCI-H460 lines.	('mutant', 'Var', (13, 19))	('PRDX6-mediated', 'Gene', (44, 58))	('AP-1', 'Enzyme', (76, 80))	('PRDX6', 'Gene', (20, 25))	('ERK1/2', 'Gene', '26417;26413', (64, 70))	('A549', 'CellLine', 'CVCL:0023', (132, 136))	('C47S', 'Var', (27, 31))	('attenuated', 'NegReg', (33, 43))	('C47S', 'Mutation', 'p.C47S', (27, 31))	('enzyme activities', 'MPA', (107, 124))	('p38', 'Enzyme', (59, 62))	('NCI-H460', 'CellLine', 'CVCL:0459', (141, 149))	('ERK1/2', 'Gene', (64, 70))	('activities', 'MPA', (81, 91))
205525	27130805	Furthermore, tumor growth and p38, ERK1/2, and AP-1 activities were also inhibited in nude mice bearing mutant PRDX6 (C47S) compared to PRDX6.	('C47S', 'Mutation', 'p.C47S', (118, 122))	('tumor', 'Disease', (13, 18))	('nude mice', 'Species', '10090', (86, 95))	('activities', 'MPA', (52, 62))	('p38', 'Enzyme', (30, 33))	('ERK1/2', 'Gene', (35, 41))	('mutant', 'Var', (104, 110))	('AP-1', 'Enzyme', (47, 51))	('inhibited', 'NegReg', (73, 82))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('PRDX6', 'Gene', (111, 116))	('ERK1/2', 'Gene', '26417;26413', (35, 41))
205528	27130805	PRDX6 was colocalized with JAK2 in tumor tissues and lung cancer cells and also showed physical interaction with JAK2, and increased levels of PRDX6 increase the activation of the JAK2/STAT3 pathway.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('increased', 'PosReg', (123, 132))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('increase', 'PosReg', (149, 157))	('lung cancer', 'Disease', 'MESH:D008175', (53, 64))	('tumor', 'Disease', (35, 40))	('PRDX6', 'Gene', (143, 148))	('JAK2/STAT3 pathway', 'Pathway', (180, 198))	('lung cancer', 'Disease', (53, 64))	('lung cancer', 'Phenotype', 'HP:0100526', (53, 64))	('levels', 'Var', (133, 139))
205546	27130805	In a histochemical study of brains from AD patients, nitrated PRDX2 was identified.	('rat', 'Species', '10116', (56, 59))	('PRDX2', 'Gene', (62, 67))	('patients', 'Species', '9606', (43, 51))	('AD', 'Disease', 'MESH:D000544', (40, 42))	('AD', 'Disease', (40, 42))	('nitrated', 'Var', (53, 61))
205548	27130805	Fang et al observed increased S-nitrosylation of PRDX2 in human Parkinson's disease (PD) brains, and S-nitrosylation of PRDX2 inhibited both its enzymatic activity and protective function from oxidative stress.	('PRDX2', 'Gene', (120, 125))	('increased', 'PosReg', (20, 29))	('PD', 'Disease', 'MESH:D010300', (85, 87))	('S-nitrosylation', 'MPA', (30, 45))	('human', 'Species', '9606', (58, 63))	('PRDX2', 'Gene', (49, 54))	("Parkinson's disease", 'Disease', (64, 83))	('S-nitrosylation', 'Var', (101, 116))	('enzymatic activity', 'MPA', (145, 163))	('inhibited', 'NegReg', (126, 135))	('protective function from', 'CPA', (168, 192))	('oxidative stress', 'Phenotype', 'HP:0025464', (193, 209))	("Parkinson's disease", 'Disease', 'MESH:D010300', (64, 83))
205555	27130805	A recent study also suggested that the autosomal dominant mutation of LRRK2 that is important for PD, increased the phosphorylation of PRDX3 and resulted in the oxidative stress induced neuronal death.	('neuronal death', 'Disease', 'MESH:D009410', (186, 200))	('PRDX3', 'Protein', (135, 140))	('phosphorylation', 'MPA', (116, 131))	('LRRK2', 'Gene', (70, 75))	('PD', 'Disease', 'MESH:D010300', (98, 100))	('oxidative stress', 'Phenotype', 'HP:0025464', (161, 177))	('mutation', 'Var', (58, 66))	('neuronal death', 'Disease', (186, 200))	('oxidative stress induced', 'MPA', (161, 185))	('LRRK2', 'Gene', '120892', (70, 75))	('increased', 'PosReg', (102, 111))	('resulted in', 'Reg', (145, 156))
205556	27130805	These data indicate that PRDX3 is involved in the neuroprotection against oxidative insults in the mitochondria, and involved in neurodegeneration through increased phosphorylation by LRRK2 mutation.	('mutation', 'Var', (190, 198))	('neurodegeneration', 'Phenotype', 'HP:0002180', (129, 146))	('increased', 'PosReg', (155, 164))	('LRRK2', 'Gene', (184, 189))	('phosphorylation', 'MPA', (165, 180))	('neurodegeneration', 'Disease', (129, 146))	('involved', 'Reg', (117, 125))	('neurodegeneration', 'Disease', 'MESH:D019636', (129, 146))	('LRRK2', 'Gene', '120892', (184, 189))
205562	27130805	PRDX6 transgenic mice displayed a significant decrease in clinical severity and attenuated demyelination in EAE compared to wild type mice, suggesting that PRDX6 expression may represent a therapeutic way to restrict inflammation in the central nervous system and potentiate oligodendrocyte survival, and suggest a new molecule for neuroprotective therapies in MS.	('inflammation', 'Disease', (217, 229))	('PRDX6', 'Gene', (156, 161))	('mice', 'Species', '10090', (134, 138))	('mice', 'Species', '10090', (17, 21))	('PRDX6', 'Gene', (0, 5))	('potentiate', 'PosReg', (264, 274))	('inflammation', 'Disease', 'MESH:D007249', (217, 229))	('clinical severity', 'CPA', (58, 75))	('attenuated demyelination', 'Disease', (80, 104))	('restrict', 'NegReg', (208, 216))	('oligodendrocyte survival', 'CPA', (275, 299))	('attenuated demyelination', 'Disease', 'MESH:C538265', (80, 104))	('transgenic mice', 'Species', '10090', (6, 21))	('demyelination', 'Phenotype', 'HP:0011096', (91, 104))	('decrease', 'NegReg', (46, 54))	('transgenic', 'Var', (6, 16))
205565	27130805	In a mouse model after amyloid beta infusion, memory impairment in PRDX6 transgenic mice was worse than C57BL/6 mice.	('PRDX6', 'Gene', (67, 72))	('transgenic', 'Var', (73, 83))	('transgenic mice', 'Species', '10090', (73, 88))	('mice', 'Species', '10090', (84, 88))	('memory impairment', 'Disease', (46, 63))	('mouse', 'Species', '10090', (5, 10))	('memory impairment', 'Phenotype', 'HP:0002354', (46, 63))	('mice', 'Species', '10090', (112, 116))	('memory impairment', 'Disease', 'MESH:D008569', (46, 63))
205566	27130805	In addition, the astrocytes and microglia cells of amyloid-infused PRDX6 transgenic mice were more activated, lipid peroxidation and protein carbonyl levels were increased and glutathione levels were lower, suggesting that PRDX6 is promoting rather than preventing oxidative stress.	('glutathione levels', 'MPA', (176, 194))	('PRDX6', 'Gene', (67, 72))	('rat', 'Species', '10116', (242, 245))	('lipid peroxidation', 'MPA', (110, 128))	('transgenic', 'Var', (73, 83))	('increased', 'PosReg', (162, 171))	('transgenic mice', 'Species', '10090', (73, 88))	('activated', 'PosReg', (99, 108))	('oxidative stress', 'Phenotype', 'HP:0025464', (265, 281))	('lower', 'NegReg', (200, 205))	('protein carbonyl levels', 'MPA', (133, 156))	('glutathione', 'Chemical', 'MESH:D005978', (176, 187))	('lipid', 'Chemical', 'MESH:D008055', (110, 115))
205584	27130805	In cells expressing the LRRK2 mutant gene that is responsible for up to 30-40% of PD cases in some ethnic populations, the phosphorylation of PRDX3 is increased but decreased peroxidase activity and increased death in neuronal cells.	('decreased', 'NegReg', (165, 174))	('PRDX3', 'Protein', (142, 147))	('increased', 'PosReg', (151, 160))	('phosphorylation', 'MPA', (123, 138))	('LRRK2', 'Gene', (24, 29))	('PD', 'Disease', 'MESH:D010300', (82, 84))	('death', 'CPA', (209, 214))	('LRRK2', 'Gene', '120892', (24, 29))	('peroxidase activity', 'MPA', (175, 194))	('mutant', 'Var', (30, 36))	('increased', 'PosReg', (199, 208))
205587	27130805	Our recent study also demonstrated that Abeta1-42-induced memory impairment in PRDX6 transgenic mice was worse than C57BL/6 mice, and the expression of amyloid precursor protein cleavage, C99, beta-site APP-cleaving enzyme 1, inducible nitric oxide synthase, and cyclooxygenase-2 was greatly increased.	('increased', 'PosReg', (292, 301))	('cyclooxygenase-2', 'Gene', '19225', (263, 279))	('mice', 'Species', '10090', (124, 128))	('memory impairment', 'Phenotype', 'HP:0002354', (58, 75))	('cyclooxygenase-2', 'Gene', (263, 279))	('expression', 'MPA', (138, 148))	('memory impairment', 'Disease', (58, 75))	('transgenic mice', 'Species', '10090', (85, 100))	('amyloid precursor protein', 'Gene', (152, 177))	('mice', 'Species', '10090', (96, 100))	('rat', 'Species', '10116', (29, 32))	('C99, beta-site APP-cleaving enzyme 1', 'Gene', '23821', (188, 224))	('transgenic', 'Var', (85, 95))	('amyloid precursor protein', 'Gene', '11820', (152, 177))	('worse', 'NegReg', (105, 110))	('inducible nitric oxide synthase', 'Gene', (226, 257))	('PRDX6', 'Gene', (79, 84))	('memory impairment', 'Disease', 'MESH:D008569', (58, 75))	('inducible nitric oxide synthase', 'Gene', '18126', (226, 257))
205588	27130805	In addition, the astrocytes and microglia cells of Abeta-infused PRDX6 transgenic mice were more activated, and Abeta also significantly increased lipid peroxidation and protein carbonyl levels, but decreased glutathione levels.	('glutathione', 'Chemical', 'MESH:D005978', (209, 220))	('protein carbonyl levels', 'MPA', (170, 193))	('decreased', 'NegReg', (199, 208))	('lipid', 'Chemical', 'MESH:D008055', (147, 152))	('decreased glutathione', 'Phenotype', 'HP:0003343', (199, 220))	('transgenic', 'Var', (71, 81))	('transgenic mice', 'Species', '10090', (71, 86))	('PRDX6', 'Gene', (65, 70))	('increased lipid', 'Phenotype', 'HP:0003077', (137, 152))	('glutathione levels', 'MPA', (209, 227))	('increased', 'PosReg', (137, 146))	('lipid peroxidation', 'MPA', (147, 165))	('activated', 'PosReg', (97, 106))
205589	27130805	Furthermore, we found that translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) to the nucleus was increased in Abeta-infused PRDX6 transgenic mice.	('increased', 'PosReg', (114, 123))	('Nrf2', 'Gene', (89, 93))	('translocation', 'MPA', (27, 40))	('nuclear factor erythroid 2-related factor 2', 'Gene', '18024', (44, 87))	('transgenic mice', 'Species', '10090', (147, 162))	('nuclear factor erythroid 2-related factor 2', 'Gene', (44, 87))	('transgenic', 'Var', (147, 157))
205594	27130805	MPTP-induced GPx activity was not different between PRDX6 Tg mice and non-Tg mice, which is accompanied by hyperoxidation of PRDX6.	('mice', 'Species', '10090', (77, 81))	('GPx', 'Gene', '384001', (13, 16))	('mice', 'Species', '10090', (61, 65))	('GPx', 'Gene', (13, 16))	('PRDX6 Tg', 'Var', (52, 60))	('MPTP', 'Chemical', 'MESH:D015632', (0, 4))
205618	27130805	A recent report showed that PRDX2 is more susceptible than PRDX1 to hyperoxidation in cells subjected to sustained global oxidative stress, which suggests that PRDX2 deficiency may lead to accelerated atherosclerosis due to failure to eliminate ROS.	('accelerated atherosclerosis', 'Phenotype', 'HP:0004943', (189, 216))	('atherosclerosis', 'Disease', (201, 216))	('oxidative stress', 'Phenotype', 'HP:0025464', (122, 138))	('lead to', 'Reg', (181, 188))	('atherosclerosis', 'Phenotype', 'HP:0002621', (201, 216))	('atherosclerosis', 'Disease', 'MESH:D050197', (201, 216))	('rat', 'Species', '10116', (195, 198))	('accelerated', 'PosReg', (189, 200))	('ROS', 'Chemical', 'MESH:D017382', (245, 248))	('PRDX2', 'Gene', (160, 165))	('deficiency', 'Var', (166, 176))
205628	27130805	They suggested that endogenous PRDX3 may play an essential role in maintaining normal characteristics of adipocytes and that a defect in PRDX3 alters mitochondrial redox state and function, and adipokine expression in adipocytes leading to metabolic alteration.	('leading to', 'Reg', (229, 239))	('alters', 'Reg', (143, 149))	('mitochondrial redox state', 'MPA', (150, 175))	('function', 'MPA', (180, 188))	('metabolic alteration', 'MPA', (240, 260))	('PRDX3', 'Gene', (137, 142))	('adipokine expression', 'MPA', (194, 214))	('rat', 'Species', '10116', (254, 257))	('defect', 'Var', (127, 133))
205631	27130805	It was reported that HFD-induced hepatic steatosis and insulin resistance were prevented in PRDX4 transgenic mice by amelioration of oxidative stress.	('insulin resistance', 'Phenotype', 'HP:0000855', (55, 73))	('hepatic steatosis', 'Phenotype', 'HP:0001397', (33, 50))	('amelioration', 'PosReg', (117, 129))	('oxidative stress', 'Phenotype', 'HP:0025464', (133, 149))	('PRDX4', 'Gene', (92, 97))	('transgenic', 'Var', (98, 108))	('hepatic steatosis', 'Disease', (33, 50))	('prevented', 'NegReg', (79, 88))	('oxidative stress', 'MPA', (133, 149))	('rat', 'Species', '10116', (123, 126))	('transgenic mice', 'Species', '10090', (98, 113))	('hepatic steatosis', 'Disease', 'MESH:D005234', (33, 50))	('insulin', 'Gene', (55, 62))	('insulin', 'Gene', '3630', (55, 62))
205643	27130805	Our data and other data suggest that PRDX6 inhibits inflammatory diseases by suppression of free radical-induced damage and mitochondrial generation of H2O2, and induces inflammatory diseases through activation of NF-kappaB/AP-1 coupled with the JNK pathway.	('free radical-induced damage', 'MPA', (92, 119))	('NF-kappaB', 'Gene', '4790', (214, 223))	('NF-kappaB', 'Gene', (214, 223))	('inflammatory diseases', 'Disease', (170, 191))	('JNK', 'Gene', (246, 249))	('rat', 'Species', '10116', (142, 145))	('H2O2', 'Chemical', 'MESH:D006861', (152, 156))	('inflammatory diseases', 'Disease', 'MESH:D007249', (170, 191))	('induces', 'PosReg', (162, 169))	('inflammatory diseases', 'Disease', 'MESH:D007249', (52, 73))	('JNK', 'Gene', '5599', (246, 249))	('PRDX6', 'Var', (37, 42))	('suppression', 'NegReg', (77, 88))	('mitochondrial generation of H2O2', 'MPA', (124, 156))	('inflammatory diseases', 'Disease', (52, 73))	('inhibits', 'NegReg', (43, 51))	('free radical', 'Chemical', 'MESH:D005609', (92, 104))	('activation', 'PosReg', (200, 210))
205660	27130805	PRDX1 deficiency enhanced the regulated secretion pathway in endothelial cells by promotion of excessive release of several proinflammatory components of Weibel-Palade bodies, such as P-selectin and von Willebrand factor.	('PRDX1', 'Gene', (0, 5))	('enhanced', 'PosReg', (17, 25))	('von Willebrand factor', 'Gene', '7450', (199, 220))	('P-selectin', 'Gene', '6403', (184, 194))	('deficiency', 'Var', (6, 16))	('Palade bodies', 'Phenotype', 'HP:0100789', (161, 174))	('von Willebrand factor', 'Gene', (199, 220))	('regulated secretion', 'MPA', (30, 49))	('promotion', 'PosReg', (82, 91))	('release of several proinflammatory components', 'MPA', (105, 150))	('P-selectin', 'Gene', (184, 194))
205661	27130805	However, PRDX1 deficiency did not affect transcriptional regulation of receptors such as intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule-1 (VCAM-1).	('intercellular adhesion molecule (ICAM)-1', 'Gene', '3383', (89, 129))	('VCAM-1', 'Gene', (169, 175))	('vascular cell adhesion molecule-1', 'Gene', (134, 167))	('vascular cell adhesion molecule-1', 'Gene', '7412', (134, 167))	('PRDX1', 'Gene', (9, 14))	('deficiency', 'Var', (15, 25))	('VCAM-1', 'Gene', '7412', (169, 175))	('transcriptional', 'MPA', (41, 56))
205663	27130805	Deficiency of PRDX2 in apoE-/- mice accelerated plaque formation with enhanced activation of p65, c-Jun, JNKs, and p38 mitogen-activated protein kinase; and these proatherogenic effects of PRDX2 deficiency were rescued by the administration of the antioxidant ebselen.	('p65', 'Pathway', (93, 96))	('ebselen', 'Chemical', 'MESH:C042986', (260, 267))	('apoE', 'Gene', (23, 27))	('accelerated', 'PosReg', (36, 47))	('plaque formation', 'CPA', (48, 64))	('deficiency', 'Var', (195, 205))	('PRDX2', 'Gene', (189, 194))	('PRDX2', 'Gene', (14, 19))	('apoE', 'Gene', '11816', (23, 27))	('JNK', 'Gene', (105, 108))	('c-Jun', 'MPA', (98, 103))	('enhanced activation', 'PosReg', (70, 89))	('mice', 'Species', '10090', (31, 35))	('JNK', 'Gene', '5599', (105, 108))	('rat', 'Species', '10116', (234, 237))	('rat', 'Species', '10116', (42, 45))	('p38 mitogen-activated protein kinase', 'Pathway', (115, 151))	('Deficiency', 'Var', (0, 10))
205664	27130805	Also, they showed that PRDX2 deficiency resulted in increased expression of vascular adhesion molecule-1, intercellular adhesion molecule-1, and monocyte chemotactic protein-1, which led to increased immune cell adhesion and infiltration into the aortic intima.	('intercellular adhesion molecule-1', 'Gene', (106, 139))	('increased', 'PosReg', (52, 61))	('immune cell adhesion', 'CPA', (200, 220))	('monocyte chemotactic protein-1', 'Gene', (145, 175))	('rat', 'Species', '10116', (231, 234))	('expression', 'MPA', (62, 72))	('increased', 'PosReg', (190, 199))	('intercellular adhesion molecule-1', 'Gene', '3383', (106, 139))	('PRDX2', 'Gene', (23, 28))	('monocyte chemotactic protein-1', 'Gene', '6347', (145, 175))	('vascular', 'MPA', (76, 84))	('deficiency', 'Var', (29, 39))	('infiltration into the aortic intima', 'CPA', (225, 260))
205665	27130805	Moreover, compared with deficiency of glutathione peroxidase 1 or catalase, PRDX2 deficiency showed a severe predisposition to develop atherosclerosis.	('catalase', 'Gene', (66, 74))	('deficiency', 'Var', (82, 92))	('PRDX2', 'Gene', (76, 81))	('atherosclerosis', 'Disease', (135, 150))	('catalase', 'Gene', '847', (66, 74))	('glutathione peroxidase 1', 'Gene', '2876', (38, 62))	('glutathione peroxidase 1', 'Gene', (38, 62))	('atherosclerosis', 'Disease', 'MESH:D050197', (135, 150))	('atherosclerosis', 'Phenotype', 'HP:0002621', (135, 150))
205670	27130805	These observations indicate that Tg mice could become a useful animal model to study the relevance of oxidative stress to inflammation, and that a specific accelerator of PRDX4 might prove to be a potential therapeutic agent for ameliorating various chronic inflammatory diseases.	('rat', 'Species', '10116', (162, 165))	('oxidative stress', 'Phenotype', 'HP:0025464', (102, 118))	('rat', 'Species', '10116', (235, 238))	('PRDX4', 'Gene', (171, 176))	('inflammatory diseases', 'Disease', 'MESH:D007249', (258, 279))	('inflammation', 'Disease', 'MESH:D007249', (122, 134))	('inflammatory diseases', 'Disease', (258, 279))	('accelerator', 'Var', (156, 167))	('mice', 'Species', '10090', (36, 40))	('inflammation', 'Disease', (122, 134))
205671	27130805	It was also reported that HFD-induced hepatic steatosis and insulin resistance were prevented in PRDX4 transgenic mice by amelioration of oxidative stress.	('insulin', 'Gene', (60, 67))	('oxidative stress', 'MPA', (138, 154))	('PRDX4', 'Gene', (97, 102))	('transgenic mice', 'Species', '10090', (103, 118))	('hepatic steatosis', 'Disease', 'MESH:D005234', (38, 55))	('insulin', 'Gene', '3630', (60, 67))	('insulin resistance', 'Phenotype', 'HP:0000855', (60, 78))	('oxidative stress', 'Phenotype', 'HP:0025464', (138, 154))	('hepatic steatosis', 'Phenotype', 'HP:0001397', (38, 55))	('amelioration', 'PosReg', (122, 134))	('prevented', 'NegReg', (84, 93))	('rat', 'Species', '10116', (128, 131))	('transgenic', 'Var', (103, 113))	('hepatic steatosis', 'Disease', (38, 55))
205686	27130805	He et al showed that PRDX1 knockdown enhances sensitization to beta-lap that is an anticancer agent through modulating ROS accumulation and MAPK activation.	('sensitization to', 'MPA', (46, 62))	('ROS', 'Protein', (119, 122))	('knockdown', 'Var', (27, 36))	('cancer', 'Disease', (87, 93))	('PRDX1', 'Gene', (21, 26))	('beta-lap', 'Protein', (63, 71))	('enhances', 'PosReg', (37, 45))	('MAPK', 'Protein', (140, 144))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('modulating', 'Reg', (108, 118))	('activation', 'MPA', (145, 155))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('ROS', 'Chemical', 'MESH:D017382', (119, 122))
205693	27130805	The silencing of PRDX3 triggered cisplatin-mediated apoptosis in ovarian cancer cells through suppression of the NF-kappaB signaling pathway, suggesting that PRDX3 is involved in drug resistance.	('NF-kappaB', 'Gene', '4790', (113, 122))	('suppression', 'NegReg', (94, 105))	('drug resistance', 'Phenotype', 'HP:0020174', (179, 194))	('ovarian cancer', 'Disease', (65, 79))	('ovarian cancer', 'Phenotype', 'HP:0100615', (65, 79))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('NF-kappaB', 'Gene', (113, 122))	('cisplatin', 'Chemical', 'MESH:D002945', (33, 42))	('cisplatin-mediated', 'MPA', (33, 51))	('ovarian cancer', 'Disease', 'MESH:D010051', (65, 79))	('PRDX3', 'Gene', (17, 22))	('silencing', 'Var', (4, 13))
205710	27130805	Cdk5 inhibition rescues mitochondrial damage upon neurotoxic insults, thereby revealing Cdk5 as an upstream regulator of mitochondrial dysfunction.	('Cdk5', 'Gene', (88, 92))	('inhibition', 'Var', (5, 15))	('mitochondrial dysfunction', 'Disease', 'MESH:D028361', (121, 146))	('mitochondrial damage', 'MPA', (24, 44))	('Cdk5', 'Gene', '1020', (88, 92))	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (121, 146))	('neurotoxic', 'Disease', (50, 60))	('Cdk5', 'Gene', (0, 4))	('mitochondrial dysfunction', 'Disease', (121, 146))	('Cdk5', 'Gene', '1020', (0, 4))	('rescues', 'PosReg', (16, 23))	('neurotoxic', 'Disease', 'MESH:D020258', (50, 60))
205715	27130805	On the other hand, PRDX3 is involved in neurodegeneration through increased phosphorylation by LRRK2 mutation, providing therapeutic target in PD patients carrying LRRK2 mutations.	('LRRK2', 'Gene', (95, 100))	('increased', 'PosReg', (66, 75))	('LRRK2', 'Gene', '120892', (95, 100))	('PD', 'Disease', 'MESH:D010300', (143, 145))	('LRRK2', 'Gene', '120892', (164, 169))	('neurodegeneration', 'Phenotype', 'HP:0002180', (40, 57))	('phosphorylation', 'MPA', (76, 91))	('neurodegeneration', 'Disease', (40, 57))	('mutation', 'Var', (101, 109))	('patients', 'Species', '9606', (146, 154))	('neurodegeneration', 'Disease', 'MESH:D019636', (40, 57))	('LRRK2', 'Gene', (164, 169))
205724	27130805	On the other hand, PRDX2 enhances the risk of RA because PRDX2 is involved in the persistence of pro-inflammatory cells in chronic inflammation, providing PRDX2 can be used as therapeutic target of RA.	('RA', 'Phenotype', 'HP:0001370', (198, 200))	('inflammation', 'Disease', 'MESH:D007249', (131, 143))	('inflammation', 'Disease', (131, 143))	('PRDX2', 'Var', (19, 24))	('RA', 'Disease', 'MESH:D001172', (46, 48))	('enhances', 'PosReg', (25, 33))	('RA', 'Disease', 'MESH:D001172', (198, 200))	('involved', 'Reg', (66, 74))	('PRDX2', 'Gene', (57, 62))	('RA', 'Phenotype', 'HP:0001370', (46, 48))
205733	30999681	One of the main factors responsible for skin cancer, natural and artificial UV radiation, causes the mutations that transform healthy cells into cancer cells.	('cancer', 'Disease', (145, 151))	('skin cancer', 'Disease', (40, 51))	('mutations', 'Var', (101, 110))	('skin cancer', 'Disease', 'MESH:D012878', (40, 51))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('cancer', 'Disease', (45, 51))	('skin cancer', 'Phenotype', 'HP:0008069', (40, 51))
205739	30999681	In our opinion, antisense oligonucleotides, which can be used in the form of targeted ointments, provide real hope as a treatment that will eliminate cancer cells near the tumor focus both before and after surgery.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('oligonucleotides', 'Chemical', 'MESH:D009841', (26, 42))	('men', 'Species', '9606', (90, 93))	('tumor', 'Disease', (172, 177))	('men', 'Species', '9606', (125, 128))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('antisense', 'Var', (16, 25))	('cancer', 'Disease', (150, 156))	('eliminate', 'NegReg', (140, 149))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
205785	30999681	Generally, UVR is an important risk factor for all skin cancers and is considered as a 'complete carcinogen' because it causes both general (nonspecific) skin damage and mutations and functions both as an initiator and as a promoter of tumors.	('causes', 'Reg', (120, 126))	('mutations', 'Var', (170, 179))	('skin cancers', 'Phenotype', 'HP:0008069', (51, 63))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('tumors', 'Disease', 'MESH:D009369', (236, 242))	('skin cancer', 'Phenotype', 'HP:0008069', (51, 62))	('skin damage', 'Disease', (154, 165))	('skin cancers', 'Disease', (51, 63))	('tumors', 'Phenotype', 'HP:0002664', (236, 242))	('tumor', 'Phenotype', 'HP:0002664', (236, 241))	('tumors', 'Disease', (236, 242))	('cancers', 'Phenotype', 'HP:0002664', (56, 63))	('skin cancers', 'Disease', 'MESH:D012878', (51, 63))	('skin damage', 'Disease', 'MESH:D012871', (154, 165))
205786	30999681	UVR is responsible for damage to the DNA (where it causes cyclobutane pyrimidine dimers to form) and gene mutations, including mutations to the p53 tumor suppressor genes involved in DNA repair and/or in the apoptosis of cells disabled by extensive DNA damage.	('cyclobutane pyrimidine', 'Chemical', '-', (58, 80))	('cyclobutane pyrimidine dimers', 'MPA', (58, 87))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('p53', 'Gene', '7157', (144, 147))	('tumor', 'Disease', (148, 153))	('mutations', 'Var', (127, 136))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('p53', 'Gene', (144, 147))
205803	30999681	An increased risk of these malignancies has consistently been linked with variants of the melanocortin 1 receptor (MC1R) gene.	('malignancies', 'Disease', 'MESH:D009369', (27, 39))	('variants', 'Var', (74, 82))	('melanocortin 1 receptor', 'Gene', '4157', (90, 113))	('melanocortin 1 receptor', 'Gene', (90, 113))	('MC1R', 'Gene', '4157', (115, 119))	('malignancies', 'Disease', (27, 39))	('MC1R', 'Gene', (115, 119))	('linked', 'Reg', (62, 68))
205814	30999681	Moreover, Merkel cell carcinomas that are not associated with Merkel cell polyomavirus develop directly from UV-associated mutations.	('Merkel cell carcinomas', 'Disease', 'MESH:D015266', (10, 32))	('UV-associated', 'Gene', (109, 122))	('Merkel cell carcinomas', 'Disease', (10, 32))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('carcinomas', 'Phenotype', 'HP:0030731', (22, 32))	('develop', 'Reg', (87, 94))	('mutations', 'Var', (123, 132))	('Merkel cell polyomavirus', 'Species', '493803', (62, 86))
205886	30999681	For patients with the B-RAFV600E mutation, therapies specifically targeting the MAPK (mitogen-activated protein kinase) pathway, such as vemurafenib (PLX-4032), dabrafenib, and trametinib, have significantly improved their overall survival.	('trametinib', 'Chemical', 'MESH:C560077', (177, 187))	('overall', 'MPA', (223, 230))	('PLX-4032', 'Chemical', 'MESH:D000077484', (150, 158))	('B-RAFV600E', 'Var', (22, 32))	('improved', 'PosReg', (208, 216))	('dabrafenib', 'Chemical', 'MESH:C561627', (161, 171))	('patients', 'Species', '9606', (4, 12))	('vemurafenib', 'Chemical', 'MESH:D000077484', (137, 148))
205887	30999681	Approximately 50% of melanomas have been found to harbor activating B-RAF mutations.	('mutations', 'Var', (74, 83))	('melanomas', 'Disease', (21, 30))	('melanoma', 'Phenotype', 'HP:0002861', (21, 29))	('melanomas', 'Disease', 'MESH:D008545', (21, 30))	('B-RAF', 'Protein', (68, 73))	('activating', 'PosReg', (57, 67))	('melanomas', 'Phenotype', 'HP:0002861', (21, 30))
205888	30999681	Over 95% of B-RAF mutations include the V600E mutation, which cause the substitution of glutamic acid for valine at residue 600 of the protein.	('B-RAF', 'Gene', (12, 17))	('glutamic acid', 'MPA', (88, 101))	('glutamic acid for valine at residue 600', 'Mutation', 'rs113488022', (88, 127))	('V600E', 'Mutation', 'rs113488022', (40, 45))	('valine', 'MPA', (106, 112))	('V600E', 'Var', (40, 45))	('mutations', 'Var', (18, 27))
205889	30999681	As is the case with so many skin cancers, exposure to UV radiation plays a role in the genesis of B-RAF mutations in cutaneous melanoma.	('mutations', 'Var', (104, 113))	('cutaneous melanoma', 'Disease', (117, 135))	('cancers', 'Phenotype', 'HP:0002664', (33, 40))	('B-RAF', 'Gene', (98, 103))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (117, 135))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (117, 135))	('skin cancer', 'Phenotype', 'HP:0008069', (28, 39))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('skin cancers', 'Disease', (28, 40))	('skin cancers', 'Phenotype', 'HP:0008069', (28, 40))	('melanoma', 'Phenotype', 'HP:0002861', (127, 135))	('skin cancers', 'Disease', 'MESH:D012878', (28, 40))
205890	30999681	For example, B-RAF V600E mutation has been implicated in different mechanisms underlying the initiation and development of melanoma, owing mostly to deregulated activation of the downstream MEK/ERK effectors.	('V600E', 'Mutation', 'rs113488022', (19, 24))	('implicated', 'Reg', (43, 53))	('men', 'Species', '9606', (115, 118))	('V600E', 'Var', (19, 24))	('melanoma', 'Disease', 'MESH:D008545', (123, 131))	('melanoma', 'Phenotype', 'HP:0002861', (123, 131))	('melanoma', 'Disease', (123, 131))	('MEK', 'Gene', (190, 193))	('activation', 'PosReg', (161, 171))	('B-RAF', 'Protein', (13, 18))	('MEK', 'Gene', '5609', (190, 193))
205894	30999681	It is no surprise, therefore, that these treatments have no effect in patients lacking the B-RAF V600E mutation.	('patients', 'Species', '9606', (70, 78))	('V600E', 'Var', (97, 102))	('B-RAF', 'Gene', (91, 96))	('men', 'Species', '9606', (46, 49))	('V600E', 'Mutation', 'rs113488022', (97, 102))
205895	30999681	It is noteworthy that the prognosis for metastatic melanoma patients with B-RAF mutations improves dramatically when immunocheckpoint inhibitors are used.	('B-RAF', 'Gene', (74, 79))	('mutations', 'Var', (80, 89))	('patients', 'Species', '9606', (60, 68))	('melanoma', 'Phenotype', 'HP:0002861', (51, 59))	('melanoma', 'Disease', (51, 59))	('improves', 'PosReg', (90, 98))	('melanoma', 'Disease', 'MESH:D008545', (51, 59))
205902	30999681	Another cohort of mutations driving the development of melanoma is found in the neuroblastoma RAS viral (v-ras) oncogene homolog (NRAS), which codes for a small guanine triphosphate (GTP)-binding protein.	('neuroblastoma RAS viral (v-ras) oncogene homolog', 'Gene', '4893', (80, 128))	('melanoma', 'Disease', 'MESH:D008545', (55, 63))	('mutations', 'Var', (18, 27))	('guanine triphosphate', 'Chemical', '-', (161, 181))	('neuroblastoma', 'Phenotype', 'HP:0003006', (80, 93))	('NRAS', 'Gene', (130, 134))	('men', 'Species', '9606', (47, 50))	('NRAS', 'Gene', '4893', (130, 134))	('melanoma', 'Phenotype', 'HP:0002861', (55, 63))	('melanoma', 'Disease', (55, 63))	('GTP', 'Chemical', '-', (183, 186))
205903	30999681	RAS oncogenes with activating mutations have been observed in a third of all human cancers; 15-20% of melanomas carry NRAS mutations, most frequently at hotspots in exon 2 (codon 61) (NRAS Q61L/R).	('cancers', 'Disease', 'MESH:D009369', (83, 90))	('cancers', 'Phenotype', 'HP:0002664', (83, 90))	('NRAS', 'Gene', (184, 188))	('melanomas', 'Disease', (102, 111))	('NRAS', 'Gene', '4893', (184, 188))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('NRAS', 'Gene', (118, 122))	('melanoma', 'Phenotype', 'HP:0002861', (102, 110))	('melanomas', 'Phenotype', 'HP:0002861', (102, 111))	('NRAS', 'Gene', '4893', (118, 122))	('melanomas', 'Disease', 'MESH:D008545', (102, 111))	('Q61L', 'Mutation', 'rs11554290', (189, 193))	('mutations', 'Var', (123, 132))	('cancers', 'Disease', (83, 90))	('human', 'Species', '9606', (77, 82))
205904	30999681	Compared to melanomas without any NRAS mutations, the subset of melanomas with NRAS mutations is more aggressive and inevitably associated with poorer outcomes.	('NRAS', 'Gene', '4893', (79, 83))	('melanomas', 'Disease', (64, 73))	('melanoma', 'Phenotype', 'HP:0002861', (12, 20))	('melanomas', 'Phenotype', 'HP:0002861', (12, 21))	('melanoma', 'Phenotype', 'HP:0002861', (64, 72))	('melanomas', 'Disease', 'MESH:D008545', (12, 21))	('mutations', 'Var', (84, 93))	('melanomas', 'Phenotype', 'HP:0002861', (64, 73))	('associated with', 'Reg', (128, 143))	('NRAS', 'Gene', (34, 38))	('melanomas', 'Disease', 'MESH:D008545', (64, 73))	('melanomas', 'Disease', (12, 21))	('NRAS', 'Gene', '4893', (34, 38))	('NRAS', 'Gene', (79, 83))
205905	30999681	NRAS mutation status has been shown to be a useful independent predictor of shorter survival rates following diagnosis with Stage IV melanoma.	('IV melanoma', 'Disease', 'MESH:D008545', (130, 141))	('melanoma', 'Phenotype', 'HP:0002861', (133, 141))	('NRAS', 'Gene', (0, 4))	('shorter', 'NegReg', (76, 83))	('IV melanoma', 'Disease', (130, 141))	('NRAS', 'Gene', '4893', (0, 4))	('mutation', 'Var', (5, 13))
205906	30999681	Although increased use of immune checkpoint inhibitors and targeted therapies for B-RAF-mutant melanomas has transformed the treatment of certain metastatic melanomas, the ideal treatment for NRAS-mutant melanomas remains unknown.	('men', 'Species', '9606', (130, 133))	('melanomas', 'Disease', (157, 166))	('melanomas', 'Disease', 'MESH:D008545', (204, 213))	('melanoma', 'Phenotype', 'HP:0002861', (204, 212))	('melanomas', 'Disease', (95, 104))	('melanomas', 'Phenotype', 'HP:0002861', (204, 213))	('men', 'Species', '9606', (183, 186))	('melanoma', 'Phenotype', 'HP:0002861', (95, 103))	('melanomas', 'Phenotype', 'HP:0002861', (157, 166))	('melanomas', 'Disease', 'MESH:D008545', (95, 104))	('melanomas', 'Phenotype', 'HP:0002861', (95, 104))	('melanomas', 'Disease', 'MESH:D008545', (157, 166))	('melanoma', 'Phenotype', 'HP:0002861', (157, 165))	('NRAS', 'Gene', (192, 196))	('B-RAF-mutant', 'Gene', (82, 94))	('B-RAF-mutant', 'Var', (82, 94))	('melanomas', 'Disease', (204, 213))	('NRAS', 'Gene', '4893', (192, 196))
205907	30999681	Since patients with mutant NRAS tumors tend to be older, with a history of chronic ultraviolet (UV) exposure, their cancers are more challenging to treat successfully.	('NRAS', 'Gene', '4893', (27, 31))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('cancers', 'Disease', 'MESH:D009369', (116, 123))	('cancers', 'Phenotype', 'HP:0002664', (116, 123))	('patients', 'Species', '9606', (6, 14))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cancers', 'Disease', (116, 123))	('tumors', 'Disease', (32, 38))	('NRAS', 'Gene', (27, 31))	('mutant', 'Var', (20, 26))	('tumors', 'Disease', 'MESH:D009369', (32, 38))
205909	30999681	While immune-based therapies are not genotype-specific, compared with their efficacy in other melanomas, they seem to be at least as effective, possibly more so, in the subset with NRAS mutations.	('melanomas', 'Phenotype', 'HP:0002861', (94, 103))	('mutations', 'Var', (186, 195))	('melanomas', 'Disease', 'MESH:D008545', (94, 103))	('melanoma', 'Phenotype', 'HP:0002861', (94, 102))	('NRAS', 'Gene', (181, 185))	('melanomas', 'Disease', (94, 103))	('NRAS', 'Gene', '4893', (181, 185))
205912	30999681	While some mutations, including TP53, retinoblastoma, and PIK3CA, have been documented in certain subsets of patients, it is likely that other mechanisms are also involved, including some patients infected with the Merkel cell polyomavirus, dysregulated immune surveillance, epigenetic alterations, aberrant protein expression, post-translational modifications, and microRNAs.	('epigenetic alterations', 'Var', (275, 297))	('patients', 'Species', '9606', (109, 117))	('retinoblastoma', 'Phenotype', 'HP:0009919', (38, 52))	('post-translational modifications', 'Var', (328, 360))	('aberrant', 'Var', (299, 307))	('protein', 'Protein', (308, 315))	('TP53', 'Gene', '7157', (32, 36))	('PIK3CA', 'Gene', (58, 64))	('patients', 'Species', '9606', (188, 196))	('men', 'Species', '9606', (80, 83))	('PIK3CA', 'Gene', '5290', (58, 64))	('Merkel cell polyomavirus', 'Species', '493803', (215, 239))	('TP53', 'Gene', (32, 36))	('dysregulated immune surveillance', 'Phenotype', 'HP:0002958', (241, 273))	('retinoblastoma', 'Disease', 'MESH:D012175', (38, 52))	('retinoblastoma', 'Disease', (38, 52))
205918	30999681	The mechanisms responsible for MCPyV-negative Merkel cell carcinoma oncogenesis, which are also poorly understood, may involve somatic mutations in tumor suppressors, such as RB1 and TP53, or epigenetic alterations that cause aberrant expression and activity in oncogenes.	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('RB1', 'Gene', '5925', (175, 178))	('Merkel cell carcinoma', 'Disease', (46, 67))	('TP53', 'Gene', '7157', (183, 187))	('tumor', 'Disease', (148, 153))	('mutations', 'Var', (135, 144))	('TP53', 'Gene', (183, 187))	('epigenetic alterations', 'Var', (192, 214))	('carcinoma oncogenesis', 'Disease', (58, 79))	('activity', 'MPA', (250, 258))	('MCPyV', 'Species', '493803', (31, 36))	('RB1', 'Gene', (175, 178))	('carcinoma oncogenesis', 'Disease', 'MESH:D063646', (58, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('Merkel cell carcinoma', 'Disease', 'MESH:D015266', (46, 67))
205928	30999681	These include unique differences in chromosomal abnormalities, genetic mutations, expression profiles, and epigenetic controls of individual tumors.	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('expression', 'MPA', (82, 92))	('tumors', 'Disease', (141, 147))	('tumors', 'Disease', 'MESH:D009369', (141, 147))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('differences', 'Reg', (21, 32))	('genetic mutations', 'Var', (63, 80))	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (36, 61))	('chromosomal abnormalities', 'Disease', (36, 61))
205930	30999681	An important factor in the analysis of mutations in Merkel cell carcinoma is MCPyV status.	('MCPyV', 'Species', '493803', (77, 82))	('mutations', 'Var', (39, 48))	('Merkel cell carcinoma', 'Disease', 'MESH:D015266', (52, 73))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))	('Merkel cell carcinoma', 'Disease', (52, 73))
205945	30999681	Changes in the genetic code of certain genes in the human dermis and epidermis are the source that 'gives birth' to skin cancer.	('skin cancer', 'Phenotype', 'HP:0008069', (116, 127))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('skin cancer', 'Disease', (116, 127))	('human', 'Species', '9606', (52, 57))	('skin cancer', 'Disease', 'MESH:D012878', (116, 127))	('Changes', 'Var', (0, 7))
205965	30999681	The data suggest that BCL-2 and BCL-XL are promising targets for the development of antisense therapies for melanoma, including additional clinical benefits from the simultaneous downregulation of their expression.	('melanoma', 'Disease', 'MESH:D008545', (108, 116))	('expression', 'MPA', (203, 213))	('antisense', 'Var', (84, 93))	('BCL-XL', 'Gene', '598', (32, 38))	('downregulation', 'NegReg', (179, 193))	('men', 'Species', '9606', (76, 79))	('BCL-XL', 'Gene', (32, 38))	('melanoma', 'Phenotype', 'HP:0002861', (108, 116))	('melanoma', 'Disease', (108, 116))
205970	30999681	Another antiapoptotic protein, survivin, may prove useful in developing therapies using antisense oligonucleotides in melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (118, 126))	('melanoma', 'Disease', (118, 126))	('antisense', 'Var', (88, 97))	('melanoma', 'Disease', 'MESH:D008545', (118, 126))	('oligonucleotides', 'Chemical', 'MESH:D009841', (98, 114))
205973	30999681	During mitosis, overexpressed survivin associates with microtubules of the mitotic spindles and demonstrates oncogenic properties by overriding the G2-M phase checkpoint.	('overriding', 'PosReg', (133, 143))	('associates', 'Interaction', (39, 49))	('overexpressed', 'Var', (16, 29))	('microtubules', 'Protein', (55, 67))	('G2-M phase checkpoint', 'CPA', (148, 169))	('mitosis', 'Disease', (7, 14))	('mitosis', 'Disease', 'None', (7, 14))	('survivin', 'Protein', (30, 38))
205974	30999681	LY2181308 (Eli Lilly and Co.) is an antisense oligonucleotide molecule designed to inhibit survivin.	('LY2181308', 'Var', (0, 9))	('LY2181308', 'Chemical', 'MESH:C529350', (0, 9))	('survivin', 'Protein', (91, 99))	('oligonucleotide', 'Chemical', 'MESH:D009841', (46, 61))	('inhibit', 'NegReg', (83, 90))
205976	30999681	When LY2181308 binds to the translation initiation codon on survivin mRNA, it blocks translation, which leads to degradation of the transcript.	('transcript', 'MPA', (132, 142))	('blocks', 'NegReg', (78, 84))	('LY2181308', 'Chemical', 'MESH:C529350', (5, 14))	('translation', 'MPA', (85, 96))	('LY2181308', 'Var', (5, 14))	('degradation', 'MPA', (113, 124))
205977	30999681	In a dose-escalation study of protein expression and apoptosis, patients received intravenous LY218308 before and after their breast tumors were biopsied.	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('LY218308', 'Var', (94, 102))	('breast tumors', 'Phenotype', 'HP:0100013', (126, 139))	('patients', 'Species', '9606', (64, 72))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('breast tumors', 'Disease', 'MESH:D001943', (126, 139))	('breast tumors', 'Disease', (126, 139))	('LY218308', 'Chemical', '-', (94, 102))
205979	30999681	In addition, in patients receiving long-term treatment with antisense oligonucleotides, kidney function should be monitored frequently.	('oligonucleotides', 'Chemical', 'MESH:D009841', (70, 86))	('patients', 'Species', '9606', (16, 24))	('men', 'Species', '9606', (50, 53))	('antisense oligonucleotides', 'Var', (60, 86))	('kidney function', 'MPA', (88, 103))
205985	30999681	Western blot analysis of the tissue from oligodeoxynucleotide-treated tumors showed a 30% reduction of BCL-2 levels of in the antisense group, a reduction not found in any other treatment group.	('BCL-2 levels', 'MPA', (103, 115))	('reduction', 'NegReg', (90, 99))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('oligodeoxynucleotide-treated tumors', 'Disease', 'MESH:D019553', (41, 76))	('men', 'Species', '9606', (183, 186))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('antisense', 'Var', (126, 135))	('oligodeoxynucleotide-treated tumors', 'Disease', (41, 76))
205986	30999681	While this reduction of BCL-2 levels seems rather small, it became obvious that the growth of tumors in the antisense group was also reduced after the second week of treatment.	('antisense', 'Var', (108, 117))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumors', 'Disease', (94, 100))	('BCL-2 levels', 'MPA', (24, 36))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('men', 'Species', '9606', (171, 174))	('reduced', 'NegReg', (133, 140))
205987	30999681	However, when tested in a Phase II trial in humans, these same antisense oligonucleotides demonstrated very little, if any, efficacy in patients with Merkel cell carcinoma.	('antisense oligonucleotides', 'Var', (63, 89))	('Merkel cell carcinoma', 'Disease', 'MESH:D015266', (150, 171))	('humans', 'Species', '9606', (44, 50))	('Merkel cell carcinoma', 'Disease', (150, 171))	('patients', 'Species', '9606', (136, 144))	('oligonucleotides', 'Chemical', 'MESH:D009841', (73, 89))	('carcinoma', 'Phenotype', 'HP:0030731', (162, 171))
205990	30999681	With difficult cancers such as melanoma and Merkel cell carcinoma, gene silencing remains an effective prospective strategy to limit disease progression.	('gene silencing', 'Var', (67, 81))	('Merkel cell carcinoma', 'Disease', 'MESH:D015266', (44, 65))	('cancers', 'Disease', 'MESH:D009369', (15, 22))	('cancers', 'Phenotype', 'HP:0002664', (15, 22))	('Merkel cell carcinoma', 'Disease', (44, 65))	('cancers', 'Disease', (15, 22))	('melanoma', 'Disease', 'MESH:D008545', (31, 39))	('melanoma', 'Phenotype', 'HP:0002861', (31, 39))	('melanoma', 'Disease', (31, 39))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('carcinoma', 'Phenotype', 'HP:0030731', (56, 65))
205991	30999681	Cutaneous delivery of antisense oligonucleotides provides a simpler, less stressful alternative to intravenous injection with an excellent potential in the treatment of skin diseases.	('skin diseases', 'Disease', (169, 182))	('oligonucleotides', 'Chemical', 'MESH:D009841', (32, 48))	('skin diseases', 'Disease', 'MESH:D012871', (169, 182))	('antisense oligonucleotides', 'Var', (22, 48))	('men', 'Species', '9606', (161, 164))
205992	30999681	The skin, which is easily accessible, is the perfect target for gene-silencing strategies developed to treat localized skin diseases including skin cancer, psoriasis, and atopic dermatitis.	('dermatitis', 'Phenotype', 'HP:0011123', (178, 188))	('skin cancer', 'Phenotype', 'HP:0008069', (143, 154))	('psoriasis', 'Disease', (156, 165))	('psoriasis', 'Phenotype', 'HP:0003765', (156, 165))	('atopic dermatitis', 'Disease', 'MESH:D003876', (171, 188))	('localized skin diseases', 'Phenotype', 'HP:0011355', (109, 132))	('skin cancer', 'Disease', (143, 154))	('atopic dermatitis', 'Phenotype', 'HP:0001047', (171, 188))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('skin diseases', 'Disease', (119, 132))	('atopic dermatitis', 'Disease', (171, 188))	('skin cancer', 'Disease', 'MESH:D012878', (143, 154))	('skin diseases', 'Disease', 'MESH:D012871', (119, 132))	('gene-silencing', 'Var', (64, 78))	('psoriasis', 'Disease', 'MESH:D011565', (156, 165))
206001	30999681	Chemical modification of the phosphate backbone improves the stability of antisense oligonucleotides, but membrane permeability, which is vital, remains a challenge.	('oligonucleotides', 'Chemical', 'MESH:D009841', (84, 100))	('phosphate', 'Chemical', 'MESH:D010710', (29, 38))	('Chemical modification', 'Var', (0, 21))	('antisense', 'Var', (74, 83))	('improves', 'PosReg', (48, 56))	('stability', 'MPA', (61, 70))
206014	30999681	Another prospective method of delivery of antisense oligonucleotides, which has not yet been tested on melanoma or Merkel cell carcinoma, is use of a specific cream or ointment formula as the vehicle.	('men', 'Species', '9606', (172, 175))	('melanoma', 'Disease', 'MESH:D008545', (103, 111))	('melanoma', 'Phenotype', 'HP:0002861', (103, 111))	('oligonucleotides', 'Chemical', 'MESH:D009841', (52, 68))	('Merkel cell carcinoma', 'Disease', 'MESH:D015266', (115, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('antisense', 'Var', (42, 51))	('Merkel cell carcinoma', 'Disease', (115, 136))	('melanoma', 'Disease', (103, 111))
206022	30999681	In one study carried out on human skin transplanted onto severely compromised immunodeficient mice, researchers applied a cream formulation containing a 20-nucleotide phosphorothioate intercellular adhesion molecule-1 antisense oligodeoxynucleotide.	('20-nucleotide phosphorothioate', 'Chemical', '-', (153, 183))	('immunodeficient', 'Disease', 'MESH:D007153', (78, 93))	('human', 'Species', '9606', (28, 33))	('immunodeficient', 'Disease', (78, 93))	('antisense oligodeoxynucleotide', 'Var', (218, 248))	('oligodeoxynucleotide', 'Chemical', 'MESH:D009838', (228, 248))	('mice', 'Species', '10090', (94, 98))
206024	30999681	This antisense oligodeoxynucleotide effectively inhibited TNF-alpha-induced expression of intercellular adhesion molecule-1.	('TNF-alpha', 'Gene', '7124', (58, 67))	('oligodeoxynucleotide', 'Chemical', 'MESH:D009838', (15, 35))	('TNF-alpha', 'Gene', (58, 67))	('antisense', 'Var', (5, 14))	('expression', 'MPA', (76, 86))	('inhibited', 'NegReg', (48, 57))
206029	30999681	In a study investigating ASOs carried in a lipophilic vehicle, it was observed that these topically applied oligonucleotides accumulated in the hair follicles, from which area they were trafficked into the dermis along with their vehicle.	('oligonucleotides', 'Chemical', 'MESH:D009841', (108, 124))	('ASOs', 'Chemical', 'MESH:D016376', (25, 29))	('accumulated', 'PosReg', (125, 136))	('oligonucleotides', 'Var', (108, 124))
206033	30999681	Our research group has concentrated on the creation of an antimelanoma ointment with antisense BCL-2 and antisense survivin phosphorothioate oligonucleotides as the basic active substances (Figure 7).	('melanoma', 'Disease', (62, 70))	('antisense', 'Var', (105, 114))	('men', 'Species', '9606', (75, 78))	('phosphorothioate oligonucleotides', 'Chemical', 'MESH:D054735', (124, 157))	('melanoma', 'Disease', 'MESH:D008545', (62, 70))	('melanoma', 'Phenotype', 'HP:0002861', (62, 70))
206034	30999681	In our opinion, the cumulative effect of the proposed antisense oligonucleotides combined with the special ointment formula will achieve a more pronounced apoptotic effect both in melanoma cell lines and on the skin of experimental animals.	('melanoma', 'Phenotype', 'HP:0002861', (180, 188))	('melanoma', 'Disease', (180, 188))	('antisense', 'Var', (54, 63))	('oligonucleotides', 'Chemical', 'MESH:D009841', (64, 80))	('melanoma', 'Disease', 'MESH:D008545', (180, 188))	('men', 'Species', '9606', (111, 114))	('apoptotic effect', 'CPA', (155, 171))	('men', 'Species', '9606', (225, 228))
206037	30999681	This in turn allows the antisense oligonucleotides to reach the proposed zones of the melanoma precursor cells, which include dedifferentiated melanocytes, melanocyte progenitors in the bulge region of hair follicles, and neural crest-derived Schwann cell precursors.	('antisense oligonucleotides', 'Var', (24, 50))	('melanoma', 'Disease', 'MESH:D008545', (86, 94))	('melanoma', 'Phenotype', 'HP:0002861', (86, 94))	('melanoma', 'Disease', (86, 94))	('oligonucleotides', 'Chemical', 'MESH:D009841', (34, 50))
206046	30999681	This fusion would then activate the master regulatory genes that activate multiple pathways, particularly those related to epithelial-mesenchymal transition, such as SNAIL, SLUG, SPARC, and TWIST.	('activate', 'PosReg', (23, 31))	('TWIST', 'Gene', '7291', (190, 195))	('SNAIL', 'Gene', '6615', (166, 171))	('SNAIL', 'Gene', (166, 171))	('SLUG', 'Gene', (173, 177))	('fusion', 'Var', (5, 11))	('SLUG', 'Gene', '6591', (173, 177))	('SPARC', 'Gene', '6678', (179, 184))	('TWIST', 'Gene', (190, 195))	('SPARC', 'Gene', (179, 184))	('activate', 'PosReg', (65, 73))	('master regulatory genes', 'Gene', (36, 59))
206060	30104567	However, the pathogenic pathways, through which susceptibility SNPs within chromosome 15q25.1 affects lung cancer risk, have not been explored.	('lung cancer', 'Phenotype', 'HP:0100526', (102, 113))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('lung cancer', 'Disease', (102, 113))	('SNPs', 'Var', (63, 67))	('lung cancer', 'Disease', 'MESH:D008175', (102, 113))	('affects', 'Reg', (94, 101))
206068	30104567	Epigenetic analyses provided evidence that epigenetic silencing of nAChR-encoding genes clustered at the 15q25.1 locus may contribute to lung cancer risk.	('nAChR', 'Gene', '1137', (67, 72))	('nAChR', 'Gene', (67, 72))	('lung cancer', 'Disease', (137, 148))	('lung cancer', 'Phenotype', 'HP:0100526', (137, 148))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('contribute', 'Reg', (123, 133))	('lung cancer', 'Disease', 'MESH:D008175', (137, 148))	('epigenetic silencing', 'Var', (43, 63))
206069	30104567	In addition, expression quantitative trait loci (eQTL) studies showed an influence of alleles in this region on the expression of several genes at chromosome 15q25.1, providing a mechanism by which these variations might affect lung cancer risk.	('expression', 'MPA', (116, 126))	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('lung cancer', 'Disease', 'MESH:D008175', (228, 239))	('affect', 'Reg', (221, 227))	('variations', 'Var', (204, 214))	('influence', 'Reg', (73, 82))	('lung cancer', 'Disease', (228, 239))	('lung cancer', 'Phenotype', 'HP:0100526', (228, 239))
206070	30104567	Our previous GWA studies found that variants in chromosome 15q25.1, including single-nucleotide polymorphisms (SNPs) and haplotypes, are involved in the etiology of overall lung cancer susceptibility and by histology and smoking status.	('involved', 'Reg', (137, 145))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('lung cancer', 'Disease', 'MESH:D008175', (173, 184))	('lung cancer', 'Phenotype', 'HP:0100526', (173, 184))	('variants', 'Var', (36, 44))	('lung cancer', 'Disease', (173, 184))	('etiology', 'Reg', (153, 161))
206073	30104567	The pathogenic pathways, through which lung cancer susceptibility SNPs within chromosome 15q25.1 affect disease etiology and development of lung cancer, have not been studied comprehensively, limiting mechanistic understanding.	('lung cancer', 'Disease', (140, 151))	('lung cancer', 'Phenotype', 'HP:0100526', (39, 50))	('lung cancer', 'Phenotype', 'HP:0100526', (140, 151))	('lung cancer', 'Disease', (39, 50))	('affect', 'Reg', (97, 103))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('lung cancer', 'Disease', 'MESH:D008175', (39, 50))	('lung cancer', 'Disease', 'MESH:D008175', (140, 151))	('SNPs', 'Var', (66, 70))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
206074	30104567	The objective of this study was to explore the underlying pathways that are involved in the molecular mechanisms by which variants at the chromosome 15q25.1 locus modify lung cancer risk and increase lung cancer occurrence and development.	('modify', 'Reg', (163, 169))	('variants', 'Var', (122, 130))	('lung cancer', 'Disease', 'MESH:D008175', (200, 211))	('increase lung cancer', 'Disease', 'MESH:D008175', (191, 211))	('lung cancer', 'Disease', 'MESH:D008175', (170, 181))	('increase lung cancer', 'Disease', (191, 211))	('development', 'CPA', (227, 238))	('lung cancer', 'Phenotype', 'HP:0100526', (200, 211))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('lung cancer', 'Disease', (170, 181))	('lung cancer', 'Phenotype', 'HP:0100526', (170, 181))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
206075	30104567	We first performed a GWAS analysis with a cohort of 1923 lung cancer cases and 1977 healthy controls of Italian origin combined with a cohort of 2995 lung cases and 3578 controls of European ancestry, and then conducted a meta-analysis to identify the index SNPs within the chromosome 15q25.1 locus that were significantly associated with lung cancer risk.	('lung cancer', 'Disease', (339, 350))	('lung cancer', 'Phenotype', 'HP:0100526', (339, 350))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('lung cancer', 'Disease', 'MESH:D008175', (57, 68))	('cancer', 'Phenotype', 'HP:0002664', (344, 350))	('associated with', 'Reg', (323, 338))	('lung cancer', 'Disease', 'MESH:D008175', (339, 350))	('SNPs', 'Var', (258, 262))	('lung cancer', 'Disease', (57, 68))	('lung cancer', 'Phenotype', 'HP:0100526', (57, 68))
206086	30104567	We defined the eight significant SNPs, which were rs1051730 in CHRNA3; rs1996371, rs6495314, rs11638372, rs4887077, and rs6495309 in CHRNB4; and rs8034191 and rs2036534 in HYKK, as the index SNPs for lung cancer risk, and used these eight SNPs to further select the candidate SNPs, which interacted with the eight index SNPs.	('lung cancer', 'Disease', 'MESH:D008175', (200, 211))	('CHRNB4', 'Gene', '1143', (133, 139))	('rs1996371', 'Mutation', 'rs1996371', (71, 80))	('rs6495309', 'Mutation', 'rs6495309', (120, 129))	('rs11638372', 'Mutation', 'rs11638372', (93, 103))	('rs6495309', 'Var', (120, 129))	('rs6495314', 'Mutation', 'rs6495314', (82, 91))	('lung cancer', 'Phenotype', 'HP:0100526', (200, 211))	('rs4887077', 'Mutation', 'rs4887077', (105, 114))	('rs6495314', 'Var', (82, 91))	('rs8034191', 'Mutation', 'rs8034191', (145, 154))	('rs2036534', 'Var', (159, 168))	('rs4887077', 'Var', (105, 114))	('HYKK', 'Gene', (172, 176))	('rs11638372', 'Var', (93, 103))	('CHRNB4', 'Gene', (133, 139))	('CHRNA3', 'Gene', '1136', (63, 69))	('lung cancer', 'Disease', (200, 211))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('rs2036534', 'Mutation', 'rs2036534', (159, 168))	('rs1051730', 'Var', (50, 59))	('rs1996371', 'Var', (71, 80))	('rs8034191', 'Var', (145, 154))	('rs1051730', 'Mutation', 'rs1051730', (50, 59))	('CHRNA3', 'Gene', (63, 69))	('HYKK', 'Gene', '123688', (172, 176))
206100	30104567	Because rs16969968 was a functional SNP that changes signal transduction through CHRNA5, and since rs16969968 had an estimated R-square LD value of 0.98 with rs1051730, which was the most significant SNP associated with lung cancer risk in discovery and replication cohorts, we used rs16969968 as a surrogate for CHRNA3-CHRNA5 and to investigate the influence of rs16969968 on whole-genome gene expression level.	('rs16969968', 'Var', (8, 18))	('CHRNA3', 'Gene', '1136', (313, 319))	('rs16969968', 'Mutation', 'rs16969968', (8, 18))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('lung cancer', 'Disease', (220, 231))	('CHRNA5', 'Gene', '1138', (320, 326))	('changes', 'Reg', (45, 52))	('rs1051730', 'Var', (158, 167))	('rs16969968', 'Mutation', 'rs16969968', (283, 293))	('associated', 'Reg', (204, 214))	('rs16969968', 'Mutation', 'rs16969968', (363, 373))	('CHRNA3', 'Gene', (313, 319))	('CHRNA5', 'Gene', '1138', (81, 87))	('CHRNA5', 'Gene', (320, 326))	('rs1051730', 'Mutation', 'rs1051730', (158, 167))	('rs16969968', 'Var', (99, 109))	('CHRNA5', 'Gene', (81, 87))	('rs16969968', 'Mutation', 'rs16969968', (99, 109))	('lung cancer', 'Disease', 'MESH:D008175', (220, 231))	('lung cancer', 'Phenotype', 'HP:0100526', (220, 231))
206101	30104567	In addition, because rs6495309 in CHRNB4 and rs8034191 in HYKK had been reported to exhibit the strongest association with lung cancer risk in CHRNB4 and HYKK, separately, we also explored the effect of rs6495309 and rs8034191 on whole-genome gene expression level (Supplementary Data 4).	('lung cancer', 'Phenotype', 'HP:0100526', (123, 134))	('rs8034191', 'Mutation', 'rs8034191', (217, 226))	('HYKK', 'Gene', '123688', (154, 158))	('HYKK', 'Gene', '123688', (58, 62))	('CHRNB4', 'Gene', '1143', (34, 40))	('CHRNB4', 'Gene', (143, 149))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('lung cancer', 'Disease', (123, 134))	('HYKK', 'Gene', (154, 158))	('rs8034191', 'Var', (45, 54))	('HYKK', 'Gene', (58, 62))	('rs6495309', 'Mutation', 'rs6495309', (203, 212))	('rs6495309', 'Var', (203, 212))	('rs6495309', 'Mutation', 'rs6495309', (21, 30))	('rs6495309', 'Var', (21, 30))	('CHRNB4', 'Gene', (34, 40))	('rs8034191', 'Var', (217, 226))	('association', 'Interaction', (106, 117))	('CHRNB4', 'Gene', '1143', (143, 149))	('lung cancer', 'Disease', 'MESH:D008175', (123, 134))	('rs8034191', 'Mutation', 'rs8034191', (45, 54))
206106	30104567	We also evaluated whether the functional eQTL analysis identified the same lung cancer-related pathways after removing the HYKK and CHRNB4, which were eQTL related pathways of genes underlying rs16969968, rs6495309, and rs8034191.	('lung cancer', 'Disease', (75, 86))	('lung cancer', 'Phenotype', 'HP:0100526', (75, 86))	('rs6495309', 'Mutation', 'rs6495309', (205, 214))	('rs8034191', 'Var', (220, 229))	('rs6495309', 'Var', (205, 214))	('HYKK', 'Gene', (123, 127))	('rs16969968', 'Var', (193, 203))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('lung cancer', 'Disease', 'MESH:D008175', (75, 86))	('rs16969968', 'Mutation', 'rs16969968', (193, 203))	('HYKK', 'Gene', '123688', (123, 127))	('rs8034191', 'Mutation', 'rs8034191', (220, 229))	('CHRNB4', 'Gene', '1143', (132, 138))	('CHRNB4', 'Gene', (132, 138))
206115	30104567	In total, for the neuroactive ligand receptor interaction pathway, CHRNA3 rs1051730 and CHRNB4 rs6495309 reached the criterion and were included for further analysis of the independent association and combined effects of SNPs on lung cancer risk.	('CHRNA3', 'Gene', (67, 73))	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('rs1051730', 'Var', (74, 83))	('lung cancer', 'Disease', 'MESH:D008175', (229, 240))	('rs6495309', 'Mutation', 'rs6495309', (95, 104))	('rs6495309', 'Var', (95, 104))	('CHRNB4', 'Gene', (88, 94))	('neuroactive ligand receptor interaction pathway', 'Pathway', (18, 65))	('CHRNA3', 'Gene', '1136', (67, 73))	('CHRNB4', 'Gene', '1143', (88, 94))	('lung cancer', 'Disease', (229, 240))	('lung cancer', 'Phenotype', 'HP:0100526', (229, 240))	('rs1051730', 'Mutation', 'rs1051730', (74, 83))
206116	30104567	With respect to the gated channel activity term, CHRNA3 rs1051730, CHRNB4 rs6495309, KCNJ4 rs138396, and SCN2B rs7944321 reached the criterion and were included for further analysis.	('KCNJ4', 'Gene', (85, 90))	('rs138396', 'Mutation', 'rs138396', (91, 99))	('rs6495309', 'Mutation', 'rs6495309', (74, 83))	('rs6495309', 'Var', (74, 83))	('rs7944321', 'Mutation', 'rs7944321', (111, 120))	('CHRNA3', 'Gene', '1136', (49, 55))	('rs1051730', 'Var', (56, 65))	('SCN2B', 'Gene', '6327', (105, 110))	('CHRNB4', 'Gene', '1143', (67, 73))	('SCN2B', 'Gene', (105, 110))	('rs1051730', 'Mutation', 'rs1051730', (56, 65))	('rs138396', 'Var', (91, 99))	('KCNJ4', 'Gene', '3761', (85, 90))	('rs7944321', 'Var', (111, 120))	('CHRNA3', 'Gene', (49, 55))	('CHRNB4', 'Gene', (67, 73))
206117	30104567	Because the frequency of CHRNA3 rs1051730 T, CHRNB4 rs6495309 C, KCNJ4 rs138396 A, and SCN2B rs7944321 A alleles among the cases were slightly higher than among controls in the discovery cohorts and in the replication cohort, we assumed these alleles may be putative risk alleles in further combined analyses.	('rs7944321 A', 'Var', (93, 104))	('SCN2B', 'Gene', '6327', (87, 92))	('rs1051730', 'Mutation', 'rs1051730', (32, 41))	('SCN2B', 'Gene', (87, 92))	('KCNJ4', 'Gene', (65, 70))	('rs138396', 'Mutation', 'rs138396', (71, 79))	('CHRNA3', 'Gene', '1136', (25, 31))	('rs7944321', 'Mutation', 'rs7944321', (93, 102))	('rs6495309 C', 'Var', (52, 63))	('CHRNB4', 'Gene', '1143', (45, 51))	('CHRNB4', 'Gene', (45, 51))	('higher', 'PosReg', (143, 149))	('rs6495309', 'Mutation', 'rs6495309', (52, 61))	('KCNJ4', 'Gene', '3761', (65, 70))	('CHRNA3', 'Gene', (25, 31))	('rs1051730 T', 'Var', (32, 43))	('rs138396 A', 'Var', (71, 81))
206120	30104567	With respect to CHRNA3 rs1051730, compared with the CC homozygote, the CT heterozygote was associated with an elevated risk of lung cancer with ORs being 1.32 (adjusted 95% CI, 1.21-1.44) in meta-analysis of the discovery cohorts and 1.27 (adjusted 95% CI, 1.21-1.33) in replication, while the TT homozygote was associated with increased lung cancer risk with ORs being 1.89 (adjusted 95% CI, 1.67-2.14) in meta-analysis of the discovery cohorts and 1.63 (adjusted 95% CI, 1.52-1.75) in replication.	('cancer', 'Phenotype', 'HP:0002664', (343, 349))	('CHRNA3', 'Gene', (16, 22))	('lung cancer', 'Disease', (127, 138))	('rs1051730', 'Mutation', 'rs1051730', (23, 32))	('lung cancer', 'Phenotype', 'HP:0100526', (127, 138))	('lung cancer', 'Disease', 'MESH:D008175', (338, 349))	('rs1051730', 'Var', (23, 32))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('CHRNA3', 'Gene', '1136', (16, 22))	('lung cancer', 'Disease', (338, 349))	('lung cancer', 'Disease', 'MESH:D008175', (127, 138))	('lung cancer', 'Phenotype', 'HP:0100526', (338, 349))
206121	30104567	We also found and validated a significant dose-response relationship between the number of CHRNA3 rs1051730 T alleles and lung cancer risk (adjusted trend test P = 2.68 x 10-24 for discovery (Table 5) and adjusted trend test P = 1.82 x 10-44 for replication (Table 6)).	('rs1051730', 'Mutation', 'rs1051730', (98, 107))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('rs1051730 T', 'Var', (98, 109))	('lung cancer', 'Disease', (122, 133))	('lung cancer', 'Phenotype', 'HP:0100526', (122, 133))	('CHRNA3', 'Gene', (91, 97))	('lung cancer', 'Disease', 'MESH:D008175', (122, 133))	('CHRNA3', 'Gene', '1136', (91, 97))
206122	30104567	The risk allele of CHRNB4 rs6495309 also significantly increased lung cancer risk in discovery and replication.	('lung cancer', 'Disease', 'MESH:D008175', (65, 76))	('CHRNB4', 'Gene', (19, 25))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('rs6495309', 'Mutation', 'rs6495309', (26, 35))	('increased', 'PosReg', (55, 64))	('rs6495309', 'Var', (26, 35))	('lung cancer', 'Disease', (65, 76))	('lung cancer', 'Phenotype', 'HP:0100526', (65, 76))	('CHRNB4', 'Gene', '1143', (19, 25))
206123	30104567	A significant dose-response relationship was demonstrated between the number of risk alleles of CHRNB4 rs6495309 and the risk of lung cancer.	('lung cancer', 'Disease', (129, 140))	('lung cancer', 'Phenotype', 'HP:0100526', (129, 140))	('CHRNB4', 'Gene', '1143', (96, 102))	('lung cancer', 'Disease', 'MESH:D008175', (129, 140))	('CHRNB4', 'Gene', (96, 102))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('rs6495309', 'Mutation', 'rs6495309', (103, 112))	('rs6495309', 'Var', (103, 112))
206124	30104567	Each of the other SNPs, including KCNJ4 rs138396 and SCN2B rs7944321, appeared to have a slightly elevated risk of lung cancer in discovery and replication.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('KCNJ4', 'Gene', (34, 39))	('SCN2B', 'Gene', '6327', (53, 58))	('rs7944321', 'Var', (59, 68))	('SCN2B', 'Gene', (53, 58))	('lung cancer', 'Disease', 'MESH:D008175', (115, 126))	('KCNJ4', 'Gene', '3761', (34, 39))	('elevated', 'Reg', (98, 106))	('rs138396', 'Var', (40, 48))	('lung cancer', 'Phenotype', 'HP:0100526', (115, 126))	('lung cancer', 'Disease', (115, 126))	('rs7944321', 'Mutation', 'rs7944321', (59, 68))	('rs138396', 'Mutation', 'rs138396', (40, 48))
206125	30104567	For the neuroactive ligand receptor interaction pathway, based on the number of risk alleles of the combined CHRNA3 rs1051730 and CHRNB4 rs6495309 genotypes, we grouped the individuals into four genotype groups, as follows: zero or one risk alleles of either gene; only two risk alleles; three risk alleles; and four risk alleles (Tables 5 and 6).	('CHRNB4', 'Gene', (130, 136))	('rs1051730', 'Mutation', 'rs1051730', (116, 125))	('rs6495309', 'Mutation', 'rs6495309', (137, 146))	('rs6495309', 'Var', (137, 146))	('CHRNA3', 'Gene', (109, 115))	('rs1051730', 'Var', (116, 125))	('CHRNA3', 'Gene', '1136', (109, 115))	('neuroactive ligand receptor interaction pathway', 'Pathway', (8, 55))	('CHRNB4', 'Gene', '1143', (130, 136))
206127	30104567	The difference in CHRNA3 rs1051730 and CHRNB4 rs6495309 combination was associated with lung cancer risk in a dose-dependent fashion in discovery (adjusted trend test P = 1.55 x 10-24) and replication (adjusted trend test P = 4.80 x 10-50).	('lung cancer', 'Disease', (88, 99))	('rs6495309', 'Mutation', 'rs6495309', (46, 55))	('rs6495309', 'Var', (46, 55))	('CHRNA3', 'Gene', '1136', (18, 24))	('associated with', 'Reg', (72, 87))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('lung cancer', 'Disease', 'MESH:D008175', (88, 99))	('rs1051730', 'Var', (25, 34))	('rs1051730', 'Mutation', 'rs1051730', (25, 34))	('CHRNB4', 'Gene', '1143', (39, 45))	('CHRNA3', 'Gene', (18, 24))	('CHRNB4', 'Gene', (39, 45))	('lung cancer', 'Phenotype', 'HP:0100526', (88, 99))
206134	30104567	We did not explore chromosome 15q25.1-related for lung cancer in never smokers because the association between SNPs within chromosomes 15q25.1 and lung cancer did not reach genome-wide significance in the discovery cohorts.	('lung cancer', 'Disease', (50, 61))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('lung cancer', 'Disease', 'MESH:D008175', (50, 61))	('lung cancer', 'Disease', (147, 158))	('lung cancer', 'Phenotype', 'HP:0100526', (147, 158))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('lung cancer', 'Phenotype', 'HP:0100526', (50, 61))	('SNPs', 'Var', (111, 115))	('lung cancer', 'Disease', 'MESH:D008175', (147, 158))
206136	30104567	However, to our knowledge, no study to date has investigated how this locus affects lung cancer etiology, nor documented the susceptibility pathways by which chromosome 15q25.1 modifies lung cancer risk and is involved in lung cancer pathogenesis.	('lung cancer', 'Disease', (84, 95))	('lung cancer', 'Phenotype', 'HP:0100526', (84, 95))	('lung cancer', 'Disease', (222, 233))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('lung cancer', 'Phenotype', 'HP:0100526', (222, 233))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('modifies', 'Reg', (177, 185))	('involved', 'Reg', (210, 218))	('lung cancer', 'Disease', 'MESH:D008175', (186, 197))	('lung cancer', 'Disease', 'MESH:D008175', (84, 95))	('chromosome', 'Var', (158, 168))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('lung cancer', 'Disease', 'MESH:D008175', (222, 233))	('lung cancer', 'Disease', (186, 197))	('lung cancer', 'Phenotype', 'HP:0100526', (186, 197))	('affects', 'Reg', (76, 83))
206140	30104567	In addition, risk alleles in SNPs in the genes in our susceptibility pathways can be combines to confer the lung cancer risk.	('lung cancer', 'Disease', 'MESH:D008175', (108, 119))	('SNPs', 'Var', (29, 33))	('lung cancer', 'Disease', (108, 119))	('lung cancer', 'Phenotype', 'HP:0100526', (108, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
206147	30104567	These two reports revealed the dysregulation of the neuroactive ligand receptor interaction pathway in lung cancer and supported our findings that this pathway plays a role in lung cancer etiology.	('lung cancer', 'Disease', 'MESH:D008175', (103, 114))	('lung cancer', 'Disease', 'MESH:D008175', (176, 187))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('lung cancer', 'Disease', (103, 114))	('dysregulation', 'Var', (31, 44))	('neuroactive ligand receptor interaction pathway', 'Pathway', (52, 99))	('lung cancer', 'Phenotype', 'HP:0100526', (103, 114))	('lung cancer', 'Disease', (176, 187))	('lung cancer', 'Phenotype', 'HP:0100526', (176, 187))
206155	30104567	Another important finding in our study is that a few transporter activity GO terms, such as gated channel activity, were implicated in the mechanisms of chromosome 15q25.1-modified lung cancer risk.	('chromosome', 'Var', (153, 163))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('implicated', 'Reg', (121, 131))	('lung cancer', 'Disease', (181, 192))	('lung cancer', 'Phenotype', 'HP:0100526', (181, 192))	('gated channel activity', 'MPA', (92, 114))	('lung cancer', 'Disease', 'MESH:D008175', (181, 192))
206160	30104567	In addition, our finding that genes from our susceptibility transporter activity GO terms jointly affected the chromosome 15q25.1-related lung cancer risk also supported the hypothesis that these pathways were implicated in the mechanisms of lung cancer.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('lung cancer', 'Disease', 'MESH:D008175', (138, 149))	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('affected', 'Reg', (98, 106))	('lung cancer', 'Phenotype', 'HP:0100526', (138, 149))	('lung cancer', 'Disease', 'MESH:D008175', (242, 253))	('lung cancer', 'Disease', (138, 149))	('lung cancer', 'Disease', (242, 253))	('lung cancer', 'Phenotype', 'HP:0100526', (242, 253))	('chromosome', 'Var', (111, 121))
206167	30104567	Many genetic variants certainly contribute to the large unexplained portion of lung cancer pathogenesis, and it is expected that more mechanisms contributing to increased lung cancer risk will be identified in the future.	('variants', 'Var', (13, 21))	('contribute', 'Reg', (32, 42))	('lung cancer', 'Disease', 'MESH:D008175', (79, 90))	('lung cancer', 'Disease', (171, 182))	('lung cancer', 'Phenotype', 'HP:0100526', (171, 182))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('lung cancer', 'Disease', (79, 90))	('lung cancer', 'Phenotype', 'HP:0100526', (79, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('lung cancer', 'Disease', 'MESH:D008175', (171, 182))
206201	30104567	Association tests between the expression traits, which were adjusted for age, sex, and smoking status, and the most significant SNPs in each genes within chromosome 15q25.1 associated with lung cancer risk in previous reports, including rs16969968, rs6495309, and rs8034191, were estimated with the application of quantitative association tests implemented in PLINK.	('rs6495309', 'Mutation', 'rs6495309', (249, 258))	('rs16969968', 'Mutation', 'rs16969968', (237, 247))	('rs6495309', 'Var', (249, 258))	('rs8034191', 'Var', (264, 273))	('lung cancer', 'Phenotype', 'HP:0100526', (189, 200))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('lung cancer', 'Disease', (189, 200))	('associated', 'Reg', (173, 183))	('rs8034191', 'Mutation', 'rs8034191', (264, 273))	('rs16969968', 'Var', (237, 247))	('lung cancer', 'Disease', 'MESH:D008175', (189, 200))
206207	30104567	The access numbers are "phs000336.v1.p1.c1" for EAGLE study, "phs000753.v1.p1" for MDACC study, and "phs001273" for Oncoarray study in dbGAP.	('phs001273', 'Var', (101, 110))	('p1"', 'Gene', '1423', (75, 78))	('c1"', 'Gene', (40, 43))	('c1"', 'Gene', '6966', (40, 43))	('p1"', 'Gene', (75, 78))
206209	24166361	Tobacco Smoking, NBS1 Polymorphisms, and Survival in Lung and Upper Aerodigestive Tract Cancers with Semi-Bayes Adjustment for Hazard-ratio Variation Although single nucleotide polymorphisms (SNPs) of NBS1 have been associated with susceptibility to lung and upper aerodigestive tract (UADT) cancers, their relations to cancer survival and measures of effect are largely unknown.	('Cancers', 'Phenotype', 'HP:0002664', (88, 95))	('associated with susceptibility', 'Reg', (216, 246))	('Tract Cancers', 'Disease', (82, 95))	('cancer', 'Phenotype', 'HP:0002664', (320, 326))	('Tobacco', 'Species', '4097', (0, 7))	('Cancer', 'Phenotype', 'HP:0002664', (88, 94))	('cancers', 'Phenotype', 'HP:0002664', (292, 299))	('cancers', 'Disease', (292, 299))	('cancer', 'Disease', (292, 298))	('cancer', 'Disease', 'MESH:D009369', (320, 326))	('cancer', 'Phenotype', 'HP:0002664', (292, 298))	('NBS1', 'Gene', '4683', (201, 205))	('single nucleotide polymorphisms', 'Var', (159, 190))	('NBS1', 'Gene', '4683', (17, 21))	('NBS1', 'Gene', (201, 205))	('Tract Cancers', 'Disease', 'MESH:D014571', (82, 95))	('NBS1', 'Gene', (17, 21))	('cancer', 'Disease', 'MESH:D009369', (292, 298))	('cancers', 'Disease', 'MESH:D009369', (292, 299))	('UADT', 'Chemical', '-', (286, 290))	('cancer', 'Disease', (320, 326))
206214	24166361	The adjusted HR relating smoking to mortality in non-small cell lung cancer (NSCLC) was greater for cases with the GG genotype of NBS1 rs1061302 than for cases with AA/AG genotypes (semi-Bayes adjusted RHR = 1.97; 95% limits = 1.14, 3.41).	('NSCLC', 'Disease', 'MESH:D002289', (77, 82))	('lung cancer', 'Phenotype', 'HP:0100526', (64, 75))	('rs1061302', 'Var', (135, 144))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (53, 75))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (49, 75))	('NBS1', 'Gene', (130, 134))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('NSCLC', 'Phenotype', 'HP:0030358', (77, 82))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (49, 75))	('greater', 'PosReg', (88, 95))	('NSCLC', 'Disease', (77, 82))	('rs1061302', 'Mutation', 'rs1061302', (135, 144))	('NBS1', 'Gene', '4683', (130, 134))	('non-small cell lung cancer', 'Disease', (49, 75))
206216	24166361	The HR relating smoking to mortality appeared to vary with the NBS1 rs1061302 genotype among NSCLC cases.	('rs1061302', 'Var', (68, 77))	('NSCLC', 'Disease', (93, 98))	('NBS1', 'Gene', '4683', (63, 67))	('vary', 'Reg', (49, 53))	('NSCLC', 'Disease', 'MESH:D002289', (93, 98))	('rs1061302', 'Mutation', 'rs1061302', (68, 77))	('NBS1', 'Gene', (63, 67))	('NSCLC', 'Phenotype', 'HP:0030358', (93, 98))
206222	24166361	The associations between genetic variations such as single nucleotide polymorphisms (SNPs) on NBS1 and cancer susceptibility have been reported in several studies of lung and UADT cancers.	('single nucleotide polymorphisms', 'Var', (52, 83))	('cancers', 'Phenotype', 'HP:0002664', (180, 187))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('NBS1', 'Gene', '4683', (94, 98))	('lung and UADT cancers', 'Disease', 'MESH:D008175', (166, 187))	('reported', 'Reg', (135, 143))	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('NBS1', 'Gene', (94, 98))	('cancer', 'Disease', (180, 186))	('associations', 'Interaction', (4, 16))
206224	24166361	The association between NBS1 SNPs and cancer susceptibility is postulated through the functional change of the MRN nuclease complex, resulting in diminished DNA repair ability.	('NBS1', 'Gene', '4683', (24, 28))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('SNPs', 'Var', (29, 33))	('NBS1', 'Gene', (24, 28))	('DNA repair', 'MPA', (157, 167))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('cancer', 'Disease', (38, 44))	('diminished', 'NegReg', (146, 156))
206225	24166361	While studies suggest that NBS1 polymorphisms may be involved in carcinogenesis at several cancer sites, there is limited information on their relationship to lung or UADT cancer survival.	('polymorphisms', 'Var', (32, 45))	('involved', 'Reg', (53, 61))	('NBS1', 'Gene', '4683', (27, 31))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', (172, 178))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('NBS1', 'Gene', (27, 31))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('lung or UADT cancer', 'Disease', 'MESH:D008175', (159, 178))	('carcinogenesis', 'Disease', 'MESH:D063646', (65, 79))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('lung or UADT cancer', 'Disease', (159, 178))	('carcinogenesis', 'Disease', (65, 79))
206227	24166361	Our study aims to explore potential prognostic roles of NBS1 SNPs for lung and UADT cancers, given their high association with cancer susceptibility.	('NBS1', 'Gene', (56, 60))	('association', 'Reg', (110, 121))	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('cancer', 'Disease', (84, 90))	('cancers', 'Phenotype', 'HP:0002664', (84, 91))	('NBS1', 'Gene', '4683', (56, 60))	('lung and UADT cancers', 'Disease', 'MESH:D008175', (70, 91))	('SNPs', 'Var', (61, 65))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('cancer', 'Disease', (127, 133))
206228	24166361	We hypothesized that five NBS1 polymorphisms might be positively associated with overall mortality among patients with lung or UADT cancer.	('patients', 'Species', '9606', (105, 113))	('lung or UADT cancer', 'Disease', 'MESH:D008175', (119, 138))	('lung or UADT cancer', 'Disease', (119, 138))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('NBS1', 'Gene', (26, 30))	('associated', 'Reg', (65, 75))	('polymorphisms', 'Var', (31, 44))	('NBS1', 'Gene', '4683', (26, 30))
206229	24166361	These polymorphisms might also modify the associations between tobacco smoking or alcohol drinking and mortality, leading to variation of the hazard ratios between exposure strata.	('associations', 'Interaction', (42, 54))	('alcohol', 'Chemical', 'MESH:D000438', (82, 89))	('alcohol drinking', 'Phenotype', 'HP:0030955', (82, 98))	('polymorphisms', 'Var', (6, 19))	('tobacco', 'Species', '4097', (63, 70))	('modify', 'Reg', (31, 37))	('alcohol drink', 'Phenotype', 'HP:0030955', (82, 95))
206243	24166361	SNPs on NBS1 were selected based on the following criteria: (i) genomic context suggesting a possibility of functional change, such as SNPs located in an exon or 3' untranslated region (3'-UTR); (ii) SNPs previously reported with minor allele frequency of at least 5% in the SNP database of the National Center for Biotechnology Information; (iii) SNPs associated with disease outcomes including smoking-related cancers.	('SNPs', 'Var', (348, 352))	('NBS1', 'Gene', (8, 12))	('associated', 'Reg', (353, 363))	('cancer', 'Phenotype', 'HP:0002664', (412, 418))	('cancers', 'Disease', 'MESH:D009369', (412, 419))	('cancers', 'Phenotype', 'HP:0002664', (412, 419))	('NBS1', 'Gene', '4683', (8, 12))	('cancers', 'Disease', (412, 419))
206244	24166361	Five SNPs (rs709816, rs1061302, rs1063053, rs1063054 and rs2735383) were selected and genotyped by TaqMan and SNPlex platforms (Applied Biosystems, Foster City, CA).	('rs2735383', 'Mutation', 'rs2735383', (57, 66))	('rs709816', 'Mutation', 'rs709816', (11, 19))	('rs1063054', 'Mutation', 'rs1063054', (43, 52))	('rs1061302', 'Var', (21, 30))	('rs1063054', 'Var', (43, 52))	('rs709816', 'Var', (11, 19))	('rs1063053', 'Var', (32, 41))	('rs2735383', 'Var', (57, 66))	('rs1061302', 'Mutation', 'rs1061302', (21, 30))	('rs1063053', 'Mutation', 'rs1063053', (32, 41))
206245	24166361	All five SNPs were genotyped by the SNPlex platform and four SNPs (rs1061302, rs1063053, rs1063054 and rs2735383) were validated by TaqMan.	('rs1063054', 'Mutation', 'rs1063054', (89, 98))	('rs2735383', 'Var', (103, 112))	('rs1061302', 'Mutation', 'rs1061302', (67, 76))	('rs1063053', 'Var', (78, 87))	('rs1063054', 'Var', (89, 98))	('rs2735383', 'Mutation', 'rs2735383', (103, 112))	('rs1063053', 'Mutation', 'rs1063053', (78, 87))	('rs1061302', 'Var', (67, 76))
206246	24166361	Preliminary analysis indicated that three SNPs (rs1063054, rs1063053 and rs2735383) were in high linkage disequilibrium (LD) (r2 > 0.99).	('rs1063053', 'Mutation', 'rs1063053', (59, 68))	('rs2735383', 'Var', (73, 82))	('rs1063054', 'Mutation', 'rs1063054', (48, 57))	('rs1063054', 'Var', (48, 57))	('rs2735383', 'Mutation', 'rs2735383', (73, 82))	('rs1063053', 'Var', (59, 68))
206248	24166361	The NBS1 rs1063054 also had the highest call rate.	('NBS1', 'Gene', '4683', (4, 8))	('rs1063054', 'Var', (9, 18))	('rs1063054', 'Mutation', 'rs1063054', (9, 18))	('NBS1', 'Gene', (4, 8))	('call rate', 'CPA', (40, 49))
206249	24166361	Finally, three NBS1 SNPs--rs709816 (exon 10, D399D), rs1061302 (exon 13, P672P), and rs1063054 (3'UTR)--were analyzed on survival of lung and UADT cancer patients.	('rs709816', 'Mutation', 'rs709816', (26, 34))	('NBS1', 'Gene', (15, 19))	('rs1061302', 'Var', (53, 62))	('rs1063054', 'Mutation', 'rs1063054', (85, 94))	('rs1061302', 'Mutation', 'rs1061302', (53, 62))	('rs709816', 'Var', (26, 34))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('P672P', 'Mutation', 'rs1061302', (73, 78))	('patients', 'Species', '9606', (154, 162))	('rs1063054', 'Var', (85, 94))	('NBS1', 'Gene', '4683', (15, 19))	('UADT cancer', 'Disease', 'MESH:D006258', (142, 153))	('D399D', 'Mutation', 'rs709816', (45, 50))	('UADT cancer', 'Disease', (142, 153))	('lung', 'Disease', (133, 137))
206289	24166361	Large cell lung carcinoma patients who carry variant C allele of NBS1 rs709816 showed shorter survival (adjusted HR = 1.63 [1.04-2.55]).	('lung carcinoma', 'Disease', (11, 25))	('NBS1', 'Gene', '4683', (65, 69))	('shorter', 'NegReg', (86, 93))	('rs709816', 'Mutation', 'rs709816', (70, 78))	('survival', 'MPA', (94, 102))	('Large cell lung carcinoma', 'Phenotype', 'HP:0030360', (0, 25))	('patients', 'Species', '9606', (26, 34))	('carcinoma', 'Phenotype', 'HP:0030731', (16, 25))	('rs709816', 'Var', (70, 78))	('NBS1', 'Gene', (65, 69))	('lung carcinoma', 'Disease', 'MESH:D008175', (11, 25))
206290	24166361	Small cell lung carcinoma patients with variant G allele of NBS1 rs1061302 showed higher death hazards (adjusted HR = 1.96 [1.22-3.15]).	('NBS1', 'Gene', (60, 64))	('Small cell lung carcinoma', 'Disease', 'MESH:D055752', (0, 25))	('higher', 'PosReg', (82, 88))	('patients', 'Species', '9606', (26, 34))	('carcinoma', 'Phenotype', 'HP:0030731', (16, 25))	('rs1061302', 'Var', (65, 74))	('Small cell lung carcinoma', 'Phenotype', 'HP:0030357', (0, 25))	('rs1061302', 'Mutation', 'rs1061302', (65, 74))	('NBS1', 'Gene', '4683', (60, 64))	('Small cell lung carcinoma', 'Disease', (0, 25))	('variant G', 'Var', (40, 49))
206293	24166361	Among lung cancer patients who ever smoked, carrying a GG genotype of NBS1 rs1061302 was associated with lower survival in non-small cell lung cancer (NSCLC, adjusted HR = 1.41 [0.97-2.04]), squamous cell carcinoma (adjusted HR = 2.51 [1.00-6.26]), and small cell carcinoma (adjusted HR = 2.54 [1.00-6.44]).	('lung cancer', 'Disease', 'MESH:D008175', (138, 149))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('NSCLC', 'Disease', 'MESH:D002289', (151, 156))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (191, 214))	('non-small cell lung cancer', 'Disease', (123, 149))	('lung cancer', 'Phenotype', 'HP:0100526', (138, 149))	('NSCLC', 'Disease', (151, 156))	('NBS1', 'Gene', '4683', (70, 74))	('lung cancer', 'Disease', (6, 17))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (191, 214))	('NSCLC', 'Phenotype', 'HP:0030358', (151, 156))	('lower', 'NegReg', (105, 110))	('NBS1', 'Gene', (70, 74))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (123, 149))	('carcinoma', 'Phenotype', 'HP:0030731', (205, 214))	('squamous cell carcinoma', 'Disease', (191, 214))	('small cell carcinoma', 'Disease', (253, 273))	('patients', 'Species', '9606', (18, 26))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (127, 149))	('small cell carcinoma', 'Disease', 'MESH:D018288', (253, 273))	('lung cancer', 'Disease', 'MESH:D008175', (6, 17))	('rs1061302', 'Var', (75, 84))	('rs1061302', 'Mutation', 'rs1061302', (75, 84))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (123, 149))	('lung cancer', 'Phenotype', 'HP:0100526', (6, 17))	('carcinoma', 'Phenotype', 'HP:0030731', (264, 273))
206294	24166361	Among non-drinking patients with UADT squamous cell carcinoma, we observed inverse associations between NBS1 rs1063054 genotype and overall death (AC/CC vs. AA, adjusted HR = 0.32 [0.13-0.79]).	('rs1063054', 'Mutation', 'rs1063054', (109, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (52, 61))	('UADT squamous cell carcinoma', 'Disease', 'MESH:D002294', (33, 61))	('patients', 'Species', '9606', (19, 27))	('NBS1', 'Gene', '4683', (104, 108))	('rs1063054', 'Var', (109, 118))	('NBS1', 'Gene', (104, 108))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (38, 61))	('UADT squamous cell carcinoma', 'Disease', (33, 61))	('overall', 'Disease', (132, 139))	('inverse', 'NegReg', (75, 82))
206296	24166361	We explored variations of the hazard ratios relating tobacco smoking to survival among NSCLC patients by NBS1 rs1061302, and relating alcohol drinking to survival among patients with UADT squamous cell carcinoma by NBS1 rs1063054.	('NBS1', 'Gene', (215, 219))	('NSCLC', 'Disease', (87, 92))	('alcohol', 'Chemical', 'MESH:D000438', (134, 141))	('NSCLC', 'Phenotype', 'HP:0030358', (87, 92))	('rs1063054', 'Var', (220, 229))	('patients', 'Species', '9606', (93, 101))	('alcohol drinking', 'Phenotype', 'HP:0030955', (134, 150))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (188, 211))	('rs1061302', 'Var', (110, 119))	('rs1061302', 'Mutation', 'rs1061302', (110, 119))	('NBS1', 'Gene', '4683', (105, 109))	('UADT squamous cell carcinoma', 'Disease', 'MESH:D002294', (183, 211))	('NBS1', 'Gene', (105, 109))	('patients', 'Species', '9606', (169, 177))	('rs1063054', 'Mutation', 'rs1063054', (220, 229))	('NSCLC', 'Disease', 'MESH:D002289', (87, 92))	('NBS1', 'Gene', '4683', (215, 219))	('UADT squamous cell carcinoma', 'Disease', (183, 211))	('carcinoma', 'Phenotype', 'HP:0030731', (202, 211))	('tobacco', 'Species', '4097', (53, 60))	('alcohol drink', 'Phenotype', 'HP:0030955', (134, 147))
206297	24166361	Compared to NSCLC patients who never smoked and carry AA or AG genotype of NBS1 rs1061302, never smokers who carry GG genotype appeared to have had improved overall survival (adjusted HR = 0.47 [0.21-1.08]) while ever-smokers who carry AA or AG genotype had similar survival (adjusted HR = 1.07 [0.74-1.57]).	('NSCLC', 'Phenotype', 'HP:0030358', (12, 17))	('NBS1', 'Gene', (75, 79))	('improved', 'PosReg', (148, 156))	('NSCLC', 'Disease', (12, 17))	('overall survival', 'MPA', (157, 173))	('rs1061302', 'Var', (80, 89))	('patients', 'Species', '9606', (18, 26))	('NSCLC', 'Disease', 'MESH:D002289', (12, 17))	('rs1061302', 'Mutation', 'rs1061302', (80, 89))	('NBS1', 'Gene', '4683', (75, 79))
206298	24166361	The adjusted ratio of hazard ratios (RHR) relating smoking and mortality among NSCLC patients across NBS1 rs1061302 genotypes was 3.00 (1.22-7.38).	('rs1061302', 'Var', (106, 115))	('NSCLC', 'Disease', 'MESH:D002289', (79, 84))	('rs1061302', 'Mutation', 'rs1061302', (106, 115))	('NBS1', 'Gene', '4683', (101, 105))	('patients', 'Species', '9606', (85, 93))	('NSCLC', 'Phenotype', 'HP:0030358', (79, 84))	('NBS1', 'Gene', (101, 105))	('NSCLC', 'Disease', (79, 84))
206299	24166361	In patients with squamous cell carcinoma at the UADT sites, hazard ratios relating alcohol drinking and survival differed across strata of NBS1 rs1063054 (adjusted RHR = 2.90 [1.14-7.33]).	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (17, 40))	('rs1063054', 'Mutation', 'rs1063054', (144, 153))	('NBS1', 'Gene', (139, 143))	('alcohol drink', 'Phenotype', 'HP:0030955', (83, 96))	('NBS1', 'Gene', '4683', (139, 143))	('alcohol drinking', 'Phenotype', 'HP:0030955', (83, 99))	('patients', 'Species', '9606', (3, 11))	('rs1063054', 'Var', (144, 153))	('alcohol', 'Chemical', 'MESH:D000438', (83, 90))	('UADT', 'Chemical', '-', (48, 52))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (17, 40))	('carcinoma', 'Phenotype', 'HP:0030731', (31, 40))	('squamous cell carcinoma', 'Disease', (17, 40))
206302	24166361	Among NSCLC patients who ever smoked, the NBS1 rs1061302 GG carriers had lower survival than AA/AG carriers (P = 0.048).	('patients', 'Species', '9606', (12, 20))	('NSCLC', 'Disease', 'MESH:D002289', (6, 11))	('rs1061302', 'Mutation', 'rs1061302', (47, 56))	('NBS1', 'Gene', '4683', (42, 46))	('NSCLC', 'Phenotype', 'HP:0030358', (6, 11))	('rs1061302 GG', 'Var', (47, 59))	('lower', 'NegReg', (73, 78))	('NBS1', 'Gene', (42, 46))	('survival', 'MPA', (79, 87))	('NSCLC', 'Disease', (6, 11))
206303	24166361	For non-smokers, two NSCLC survival curves across NBS1 rs1061302 genotypes were not separate (P = 0.18, data not shown).	('NSCLC', 'Disease', (21, 26))	('NBS1', 'Gene', (50, 54))	('NSCLC', 'Disease', 'MESH:D002289', (21, 26))	('NBS1', 'Gene', '4683', (50, 54))	('NSCLC', 'Phenotype', 'HP:0030358', (21, 26))	('rs1061302', 'Var', (55, 64))	('rs1061302', 'Mutation', 'rs1061302', (55, 64))
206304	24166361	Among NSCLC patients with GG genotype of NBS1 rs1061302, smokers had lower survival than non-smokers (P = 0.011).	('patients', 'Species', '9606', (12, 20))	('NSCLC', 'Disease', 'MESH:D002289', (6, 11))	('NBS1', 'Gene', '4683', (41, 45))	('lower', 'NegReg', (69, 74))	('NSCLC', 'Phenotype', 'HP:0030358', (6, 11))	('NBS1', 'Gene', (41, 45))	('survival', 'MPA', (75, 83))	('rs1061302', 'Var', (46, 55))	('rs1061302', 'Mutation', 'rs1061302', (46, 55))	('NSCLC', 'Disease', (6, 11))
206305	24166361	For UADT squamous cell carcinoma patients who never drank, we observed differences in survival curves across NBS1 1063054 genotypes (P = 0.001) and between drinkers and non-drinkers with AC or CC genotype of NBS1 rs1063054 (P = 0.031).	('differences', 'Reg', (71, 82))	('NBS1', 'Gene', (208, 212))	('patients', 'Species', '9606', (33, 41))	('NBS1', 'Gene', (109, 113))	('rs1063054', 'Mutation', 'rs1063054', (213, 222))	('UADT squamous cell carcinoma', 'Disease', (4, 32))	('carcinoma', 'Phenotype', 'HP:0030731', (23, 32))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (9, 32))	('rs1063054', 'Var', (213, 222))	('NBS1', 'Gene', '4683', (208, 212))	('UADT squamous cell carcinoma', 'Disease', 'MESH:D002294', (4, 32))	('NBS1', 'Gene', '4683', (109, 113))
206306	24166361	Among NSCLC patients, the exponentiated estimate of the continuous rs1061302*smoking coefficient was 1.90 (95% posterior limits: 1.11, 3.26).	('patients', 'Species', '9606', (12, 20))	('NSCLC', 'Disease', 'MESH:D002289', (6, 11))	('rs1061302', 'Mutation', 'rs1061302', (67, 76))	('NSCLC', 'Phenotype', 'HP:0030358', (6, 11))	('rs1061302*', 'Var', (67, 77))	('NSCLC', 'Disease', (6, 11))
206312	24166361	Although our study did not observe clear associations between NBS1 polymorphisms and survival in lung or UADT cancer patients, stratified analyses by cancer subtypes and cancer risk factors suggested (1) Borderline yet consistent associations between NBS1 rs1061302 GG genotype and lower survival among smokers with NSCLC, squamous cell lung carcinoma, or small cell lung carcinoma; (2) Improved survival among non-drinking UADT squamous cell carcinoma patients who carry the AC or CC genotype of NBS1 rs1063054.	('rs1061302', 'Var', (256, 265))	('rs1061302', 'Mutation', 'rs1061302', (256, 265))	('cancer', 'Disease', (170, 176))	('small cell lung carcinoma', 'Disease', 'MESH:D055752', (356, 381))	('NSCLC', 'Disease', 'MESH:D002289', (316, 321))	('carcinoma', 'Phenotype', 'HP:0030731', (342, 351))	('lower', 'NegReg', (282, 287))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('squamous cell lung carcinoma', 'Phenotype', 'HP:0030359', (323, 351))	('patients', 'Species', '9606', (117, 125))	('lung or UADT cancer', 'Disease', (97, 116))	('NBS1', 'Gene', '4683', (251, 255))	('carcinoma', 'Phenotype', 'HP:0030731', (372, 381))	('NSCLC', 'Disease', (316, 321))	('NBS1', 'Gene', '4683', (62, 66))	('rs1063054', 'Mutation', 'rs1063054', (502, 511))	('cancer', 'Disease', (150, 156))	('NBS1', 'Gene', (251, 255))	('small cell lung carcinoma', 'Disease', (356, 381))	('carcinoma', 'Phenotype', 'HP:0030731', (443, 452))	('NSCLC', 'Phenotype', 'HP:0030358', (316, 321))	('NBS1', 'Gene', (62, 66))	('Improved', 'PosReg', (387, 395))	('squamous cell lung carcinoma', 'Disease', (323, 351))	('NBS1', 'Gene', '4683', (497, 501))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('cancer', 'Disease', (110, 116))	('UADT squamous cell carcinoma', 'Disease', 'MESH:D002294', (424, 452))	('survival', 'MPA', (396, 404))	('NBS1', 'Gene', (497, 501))	('small cell lung carcinoma', 'Phenotype', 'HP:0030357', (356, 381))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('squamous cell lung carcinoma', 'Disease', 'MESH:D002294', (323, 351))	('lung or UADT cancer', 'Disease', 'MESH:D008175', (97, 116))	('UADT squamous cell carcinoma', 'Disease', (424, 452))	('rs1063054', 'Var', (502, 511))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('patients', 'Species', '9606', (453, 461))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (429, 452))	('cancer', 'Disease', 'MESH:D009369', (110, 116))
206313	24166361	After semi-Bayes shrinkage, it still appeared that NBS1 rs1061302 may modify hazard-ratio relating tobacco smoking to survival among NSCLC patients.	('tobacco', 'Species', '4097', (99, 106))	('hazard-ratio', 'MPA', (77, 89))	('patients', 'Species', '9606', (139, 147))	('NBS1', 'Gene', '4683', (51, 55))	('NSCLC', 'Phenotype', 'HP:0030358', (133, 138))	('rs1061302', 'Mutation', 'rs1061302', (56, 65))	('tobacco smoking', 'MPA', (99, 114))	('rs1061302', 'Var', (56, 65))	('NSCLC', 'Disease', (133, 138))	('NBS1', 'Gene', (51, 55))	('modify', 'Reg', (70, 76))	('NSCLC', 'Disease', 'MESH:D002289', (133, 138))
206323	24166361	Associations between NBS1 polymorphisms with cancer susceptibility have been widely studied, in particular NBS1 rs1805794 (E184Q) -- a 3'-UTR polymorphism in a complete LD (r2 = 1) with rs1061302 (exon 13, P672P) in our study.	('P672P', 'Mutation', 'rs1061302', (206, 211))	('NBS1', 'Gene', '4683', (21, 25))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('rs1805794 (E184Q) --', 'Var', (112, 132))	('NBS1', 'Gene', '4683', (107, 111))	('NBS1', 'Gene', (21, 25))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('E184Q', 'Mutation', 'rs1805794', (123, 128))	('rs1805794', 'Mutation', 'rs1805794', (112, 121))	('cancer', 'Disease', (45, 51))	('rs1061302', 'Var', (186, 195))	('NBS1', 'Gene', (107, 111))	('rs1061302', 'Mutation', 'rs1061302', (186, 195))
206324	24166361	The susceptibility of lung, head and neck, prostate, breast, bladder, leukemia, and liver cancers has been shown to be associated with NBS1 rs1805794 or rs1061302.	('NBS1', 'Gene', (135, 139))	('rs1805794', 'Var', (140, 149))	('prostate', 'Disease', (43, 51))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('bladder', 'Disease', (61, 68))	('rs1061302', 'Var', (153, 162))	('liver cancers', 'Disease', 'MESH:D006528', (84, 97))	('leukemia', 'Disease', (70, 78))	('NBS1', 'Gene', '4683', (135, 139))	('breast', 'Disease', (53, 59))	('leukemia', 'Disease', 'MESH:D007938', (70, 78))	('rs1805794', 'Mutation', 'rs1805794', (140, 149))	('leukemia', 'Phenotype', 'HP:0001909', (70, 78))	('liver cancers', 'Disease', (84, 97))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('lung', 'Disease', (22, 26))	('liver cancers', 'Phenotype', 'HP:0002896', (84, 97))	('rs1061302', 'Mutation', 'rs1061302', (153, 162))
206326	24166361	One recent pilot study reported an improved progression-free survival with minor C allele of NBS1 rs1805794 (SNP in a complete LD with NBS1 rs1061302 in our study) among 147 Chinese patients with inoperable NSCLC who received platinum-based chemotherapy.	('platinum', 'Chemical', 'MESH:D010984', (226, 234))	('NBS1', 'Gene', (135, 139))	('improved', 'PosReg', (35, 43))	('NSCLC', 'Phenotype', 'HP:0030358', (207, 212))	('rs1061302', 'Mutation', 'rs1061302', (140, 149))	('rs1805794', 'Mutation', 'rs1805794', (98, 107))	('NBS1', 'Gene', '4683', (93, 97))	('NBS1', 'Gene', '4683', (135, 139))	('patients', 'Species', '9606', (182, 190))	('NSCLC', 'Disease', (207, 212))	('progression-free survival', 'CPA', (44, 69))	('NBS1', 'Gene', (93, 97))	('rs1805794', 'Var', (98, 107))	('NSCLC', 'Disease', 'MESH:D002289', (207, 212))
206327	24166361	Our study suggests an increased hazard of overall death among NSCLC patients carrying the minor G allele of rs1061302.	('NSCLC', 'Disease', (62, 67))	('NSCLC', 'Disease', 'MESH:D002289', (62, 67))	('patients', 'Species', '9606', (68, 76))	('rs1061302', 'Var', (108, 117))	('NSCLC', 'Phenotype', 'HP:0030358', (62, 67))	('rs1061302', 'Mutation', 'rs1061302', (108, 117))
206330	24166361	Our findings, along with these emerging clinical observations, further raise awareness of a potential prognostic role for NBS1 polymorphisms in cancer progression and outcome.	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('NBS1', 'Gene', (122, 126))	('polymorphisms', 'Var', (127, 140))	('cancer', 'Disease', (144, 150))	('NBS1', 'Gene', '4683', (122, 126))
206331	24166361	Since the NBS1 rs1061302 is located at the binding domain of MRN complex, it might hinder MRN binding ability and DSB repair function and thus be related to carcinogenesis and cancer progression.	('related', 'Reg', (146, 153))	('rs1061302', 'Mutation', 'rs1061302', (15, 24))	('NBS1', 'Gene', '4683', (10, 14))	('MRN', 'Protein', (61, 64))	('DSB repair function', 'CPA', (114, 133))	('carcinogenesis', 'Disease', 'MESH:D063646', (157, 171))	('binding', 'Interaction', (94, 101))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('hinder', 'NegReg', (83, 89))	('MRN', 'Protein', (90, 93))	('carcinogenesis', 'Disease', (157, 171))	('NBS1', 'Gene', (10, 14))	('rs1061302', 'Var', (15, 24))	('cancer', 'Disease', (176, 182))	('cancer', 'Disease', 'MESH:D009369', (176, 182))
206333	24166361	We observed variation in hazard-ratio relating tobacco smoking to mortality among NSCLC patients across NBS1 rs1061302 genotypes, shown in Table 3 and Fig.	('rs1061302', 'Var', (109, 118))	('NSCLC', 'Phenotype', 'HP:0030358', (82, 87))	('NBS1', 'Gene', '4683', (104, 108))	('tobacco', 'Species', '4097', (47, 54))	('patients', 'Species', '9606', (88, 96))	('rs1061302', 'Mutation', 'rs1061302', (109, 118))	('NBS1', 'Gene', (104, 108))	('NSCLC', 'Disease', (82, 87))	('NSCLC', 'Disease', 'MESH:D002289', (82, 87))
206334	24166361	3(a) indicates the variation - survival curves by smoking status highly overlapped in NSCLC patients with AA/AG genotype (curve (1) and (2)) and were separate among patients with GG genotype (curve (3) vs. (4), P = 0.011).	('AA/AG', 'Var', (106, 111))	('NSCLC', 'Disease', (86, 91))	('patients', 'Species', '9606', (92, 100))	('NSCLC', 'Disease', 'MESH:D002289', (86, 91))	('patients', 'Species', '9606', (165, 173))	('NSCLC', 'Phenotype', 'HP:0030358', (86, 91))
206335	24166361	Similarly, the proportional-hazards model also suggested hazard-ratio variation: the adjusted HR relating NBS1 rs1061302 GG genotype to all-cause mortality in NSCLC patients was 1.41 (0.97-2.04) among smokers and 0.55 (0.22-1.39) among non-smokers.	('rs1061302 GG', 'Var', (111, 123))	('NSCLC', 'Disease', (159, 164))	('NBS1', 'Gene', (106, 110))	('NSCLC', 'Disease', 'MESH:D002289', (159, 164))	('patients', 'Species', '9606', (165, 173))	('rs1061302', 'Mutation', 'rs1061302', (111, 120))	('NSCLC', 'Phenotype', 'HP:0030358', (159, 164))	('NBS1', 'Gene', '4683', (106, 110))
206336	24166361	After shrinkage and adjustment for two potential confounders of SNP*drinking and smoking*drinking, we were more confident that there exists variation in the adjusted HR relating smoking to mortality among NSCLC patients by the NBS1 rs1061302.	('patients', 'Species', '9606', (211, 219))	('NSCLC', 'Phenotype', 'HP:0030358', (205, 210))	('rs1061302', 'Mutation', 'rs1061302', (232, 241))	('NBS1', 'Gene', '4683', (227, 231))	('NSCLC', 'Disease', 'MESH:D002289', (205, 210))	('NSCLC', 'Disease', (205, 210))	('smoking', 'MPA', (178, 185))	('NBS1', 'Gene', (227, 231))	('rs1061302', 'Var', (232, 241))
206338	24166361	Additionally, it appeared that smoking NSCLC patients with NBS1 rs1061302 GG genotype showed the highest hazard of mortality, compared to non-smoking patients with AA/AG genotype.	('NSCLC', 'Phenotype', 'HP:0030358', (39, 44))	('rs1061302', 'Mutation', 'rs1061302', (64, 73))	('rs1061302 GG', 'Var', (64, 76))	('patients', 'Species', '9606', (150, 158))	('patients', 'Species', '9606', (45, 53))	('NBS1', 'Gene', (59, 63))	('NSCLC', 'Disease', (39, 44))	('NSCLC', 'Disease', 'MESH:D002289', (39, 44))	('NBS1', 'Gene', '4683', (59, 63))
206339	24166361	These findings underscore the importance of reducing smoking for improved cancer prognosis, especially for high risk groups with genetic variants such as NBS1 rs1061302 GG genotype carriers.	('NBS1', 'Gene', '4683', (154, 158))	('improved', 'PosReg', (65, 73))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('NBS1', 'Gene', (154, 158))	('cancer', 'Disease', (74, 80))	('rs1061302 GG', 'Var', (159, 171))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('rs1061302', 'Mutation', 'rs1061302', (159, 168))
206346	24166361	For example, adjusted HR relating NBS1 rs1063054 to survival among UADT cancer patients changed from 0.75 (0.56-1.00) to 0.76 (0.56-1.02).	('UADT cancer', 'Disease', (67, 78))	('NBS1', 'Gene', '4683', (34, 38))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('rs1063054', 'Var', (39, 48))	('NBS1', 'Gene', (34, 38))	('patients', 'Species', '9606', (79, 87))	('rs1063054', 'Mutation', 'rs1063054', (39, 48))	('UADT cancer', 'Disease', 'MESH:D006258', (67, 78))
206355	24166361	Our study further suggested several associations between NBS1 polymorphisms and all-cause mortality in smoking lung cancer patients and non-drinking patients with squamous cell carcinoma at the UADT sites.	('UADT', 'Chemical', '-', (194, 198))	('smoking lung cancer', 'Disease', (103, 122))	('patients', 'Species', '9606', (149, 157))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (163, 186))	('all-cause mortality', 'MPA', (80, 99))	('NBS1', 'Gene', (57, 61))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (163, 186))	('patients', 'Species', '9606', (123, 131))	('squamous cell carcinoma', 'Disease', (163, 186))	('carcinoma', 'Phenotype', 'HP:0030731', (177, 186))	('lung cancer', 'Phenotype', 'HP:0100526', (111, 122))	('polymorphisms', 'Var', (62, 75))	('associations', 'Interaction', (36, 48))	('smoking lung cancer', 'Disease', 'MESH:D008175', (103, 122))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('NBS1', 'Gene', '4683', (57, 61))
206356	24166361	Our results indicated that NBS1 rs1061302 may modify the hazard-ratio relating tobacco smoking (both ever/never status and pack-years) to mortality of NSCLC patients.	('hazard-ratio', 'MPA', (57, 69))	('NBS1', 'Gene', '4683', (27, 31))	('NSCLC', 'Disease', (151, 156))	('modify', 'Reg', (46, 52))	('rs1061302', 'Mutation', 'rs1061302', (32, 41))	('NSCLC', 'Disease', 'MESH:D002289', (151, 156))	('patients', 'Species', '9606', (157, 165))	('NBS1', 'Gene', (27, 31))	('tobacco', 'Species', '4097', (79, 86))	('NSCLC', 'Phenotype', 'HP:0030358', (151, 156))	('rs1061302', 'Var', (32, 41))
206358	24166361	Further studies are needed to explore NBS1 polymorphisms associations with NBS1 protein expression, as well as with cancer outcomes, among better-defined subgroups.	('polymorphisms', 'Var', (43, 56))	('NBS1', 'Gene', '4683', (38, 42))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('NBS1', 'Gene', (75, 79))	('protein', 'Protein', (80, 87))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('NBS1', 'Gene', (38, 42))	('associations', 'Reg', (57, 69))	('NBS1', 'Gene', '4683', (75, 79))
206376	33000392	Therefore, the clinical stage of the gallbladder cancer was diagnosed as T4N1M1 Stage IV-B (in case of peritoneal dissemination or lymph node metastasis) or T4N1M0 Stage IV-A (in case of inflammatory lymph node swelling) according to the TNM classification of malignant tumors (eighth edition) edited by the Union for International Cancer Control.	('TNM', 'Gene', (238, 241))	('lymph node swelling', 'Disease', (200, 219))	('T4N1M0', 'Var', (157, 163))	('lymph node swelling', 'Phenotype', 'HP:0002716', (200, 219))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('Cancer', 'Phenotype', 'HP:0002664', (332, 338))	('Cancer', 'Disease', (332, 338))	('malignant tumors', 'Disease', (260, 276))	('TNM', 'Gene', '10178', (238, 241))	('inflammatory lymph node swelling', 'Phenotype', 'HP:0002840', (187, 219))	('Cancer', 'Disease', 'MESH:D009369', (332, 338))	('gallbladder cancer', 'Disease', (37, 55))	('gallbladder cancer', 'Disease', 'MESH:D005706', (37, 55))	('malignant tumors', 'Disease', 'MESH:D009369', (260, 276))	('lymph node swelling', 'Disease', 'MESH:D000072717', (200, 219))	('tumor', 'Phenotype', 'HP:0002664', (270, 275))	('T4N1M1', 'Var', (73, 79))	('tumors', 'Phenotype', 'HP:0002664', (270, 276))
206461	31780460	A D5PS score of 3 on follow-up imaging also likely signifies a CMR but may be interpreted as an inadequate response to avoid undertreating patients being considered for de-escalation of therapy.	('CMR', 'Disease', (63, 66))	('patients', 'Species', '9606', (139, 147))	('D5PS score of 3', 'Var', (2, 17))
206493	31780460	When using 2-year disease-free survival as the reference standard, the negative predictive value for patients with NI-RADS 2 scores on the first posttreatment PET/CT was 85%, compared with 91% for patients with NI-RADS 1 scores.	('scores', 'Var', (125, 131))	('patients', 'Species', '9606', (101, 109))	('patients', 'Species', '9606', (197, 205))	('NI-RADS 2', 'Gene', (115, 124))
206516	30548184	There is growing evidence that deregulated ncRNA have an important function in the onset and progression of lung cancer (Berindan-Neagoe et al., 2014; Catana et al., 2015), contributing to disease prognosis as well, and regulating the response to therapy (Braicu et al., 2014; Pan et al., 2017; Volinia et al., 2006).	('lung cancer', 'Disease', 'MESH:D008175', (108, 119))	('response to therapy', 'MPA', (235, 254))	('ncRNA', 'Gene', (43, 48))	('lung cancer', 'Disease', (108, 119))	('deregulated', 'Var', (31, 42))	('regulating', 'Reg', (220, 230))	('contributing', 'Reg', (173, 185))	('ncRNA', 'Gene', '220202', (43, 48))	('lung cancer', 'Phenotype', 'HP:0100526', (108, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
206524	30548184	Variations of miRNAs levels in liquid biopsies are important minimally invasive diagnostic/prognostic tools and also therapeutic targets (e.g.	('Variations', 'Var', (0, 10))	('miR', 'Gene', '220972', (14, 17))	('miR', 'Gene', (14, 17))
206566	30548184	miR-181b is downregulated in A549/cis (cisplatin resitant) compared with A549 cells, suppression that mediates drug-resistant mechanisms and migratory features.	('downregulated', 'NegReg', (12, 25))	('A549', 'CellLine', 'CVCL:0023', (73, 77))	('A549/cis', 'Var', (29, 37))	('miR', 'Gene', '220972', (0, 3))	('miR', 'Gene', (0, 3))	('cisplatin', 'Chemical', 'MESH:D002945', (39, 48))	('A549', 'CellLine', 'CVCL:0023', (29, 33))
206609	30548184	Silencing of the lncRNA resulted in increased expression of the miRNA together with suppression of MAPK1 and MAP2K1 mediated by the high levels of miR-181a achieved.	('miR-181a', 'Gene', '387176', (147, 155))	('MAPK1', 'Gene', (99, 104))	('miR', 'Gene', '220972', (64, 67))	('miR', 'Gene', (64, 67))	('Silencing', 'Var', (0, 9))	('MAP2K1', 'Gene', '5604', (109, 115))	('miR', 'Gene', '220972', (147, 150))	('MAPK1', 'Gene', '5594', (99, 104))	('miR', 'Gene', (147, 150))	('increased', 'PosReg', (36, 45))	('suppression', 'NegReg', (84, 95))	('MAP2K1', 'Gene', (109, 115))	('ncRNA', 'Gene', (18, 23))	('expression', 'MPA', (46, 56))	('ncRNA', 'Gene', '220202', (18, 23))	('miR-181a', 'Gene', (147, 155))
206615	30548184	Modulation of miR-181a may become a promising strategy to prevent resistance to the main chemotherapeutics, in spite of the fact that some studies show minimal effects of miR-181a/b on cisplatin-resistant cells (Li et al., 2015; Pouliot et al., 2013).	('Modulation', 'Var', (0, 10))	('miR-181a', 'Gene', (14, 22))	('miR-181a', 'Gene', '387176', (14, 22))	('cisplatin-resistant', 'MPA', (185, 204))	('miR-181a', 'Gene', (171, 179))	('cisplatin', 'Chemical', 'MESH:D002945', (185, 194))	('miR-181a', 'Gene', '387176', (171, 179))
206617	30548184	The importance of the TME in chemotherapy efficiency is limited to in vitro studies or to immunocompromised mice models, decreasing the true translational value of miR-181a modulation.	('miR-181a', 'Gene', (164, 172))	('miR-181a', 'Gene', '387176', (164, 172))	('mice', 'Species', '10090', (108, 112))	('modulation', 'Var', (173, 183))	('decreasing', 'NegReg', (121, 131))
206640	30272335	Furthermore, the number of Gr-1+CD11b+ myeloid derived suppressor cells (MDSCs) and CD4+ Foxp3+ regulatory T cells (Tregs) during oral carcinogenesis and the association with autophagy status was also examined.	('oral carcinogenesis', 'Disease', 'MESH:D063646', (130, 149))	('oral carcinogenesis', 'Disease', (130, 149))	('CD4+ Foxp3+', 'Var', (84, 95))
206641	30272335	The results revealed that the expression of autophagy biomarkers, including dihydrosphingosine 1-phosphate phosphatase LCB3 (LC3B), p62/SQSTM1 (p62) and Beclin 1 increased during 4NQO-induced carcinogenesis and in human oral cancer.	('expression', 'MPA', (30, 40))	('increased', 'PosReg', (162, 171))	('oral cancer', 'Disease', 'MESH:D009062', (220, 231))	('4NQO', 'Chemical', 'MESH:D015112', (179, 183))	('p62/SQSTM1', 'Var', (132, 142))	('LC3B', 'Gene', (125, 129))	('Beclin 1', 'Gene', (153, 161))	('carcinogenesis', 'Disease', 'MESH:D063646', (192, 206))	('oral cancer', 'Disease', (220, 231))	('carcinogenesis', 'Disease', (192, 206))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('autophagy', 'CPA', (44, 53))	('human', 'Species', '9606', (214, 219))
206667	30272335	After a week of acclimation, mice were randomly assigned into three separate experimental groups: Control group (n=10), low-4NQO group (n=18), high-4NQO group (n=20).	('4NQO', 'Chemical', 'MESH:D015112', (124, 128))	('low-4NQO', 'Var', (120, 128))	('4NQO', 'Chemical', 'MESH:D015112', (148, 152))	('mice', 'Species', '10090', (29, 33))	('high-4NQO', 'Var', (143, 152))
206734	30272335	Furthermore, SCC exhibited increased cytoplasmic expression of p62 compared with dysplastic epithelium (Fig.	('increased', 'PosReg', (27, 36))	('p62', 'Var', (63, 66))	('dysplastic epithelium', 'Disease', 'MESH:C536309', (81, 102))	('cytoplasmic expression', 'MPA', (37, 59))	('dysplastic epithelium', 'Disease', (81, 102))
206769	30272335	Although a previous study reported that no differences in p62 expression were observed among normal oral mucosa, verrucous hyperplasia, and OSCC, p62 has been found to be upregulated in several human cancers, including colorectal carcinoma, epithelial ovarian cancer and gliomas.	('epithelial ovarian cancer', 'Disease', (241, 266))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('carcinoma', 'Phenotype', 'HP:0030731', (230, 239))	('verrucous hyperplasia', 'Disease', (113, 134))	('epithelial ovarian cancer', 'Disease', 'MESH:D000077216', (241, 266))	('ovarian cancer', 'Phenotype', 'HP:0100615', (252, 266))	('cancers', 'Phenotype', 'HP:0002664', (200, 207))	('cancers', 'Disease', (200, 207))	('upregulated', 'PosReg', (171, 182))	('gliomas', 'Disease', (271, 278))	('colorectal carcinoma', 'Disease', (219, 239))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (219, 239))	('p62', 'Var', (146, 149))	('verrucous hyperplasia', 'Disease', 'MESH:D018289', (113, 134))	('cancer', 'Phenotype', 'HP:0002664', (260, 266))	('gliomas', 'Disease', 'MESH:D005910', (271, 278))	('epithelial ovarian cancer', 'Phenotype', 'HP:0025318', (241, 266))	('cancers', 'Disease', 'MESH:D009369', (200, 207))	('human', 'Species', '9606', (194, 199))	('gliomas', 'Phenotype', 'HP:0009733', (271, 278))
206770	30272335	Valencia et al demonstrated that in the tumor microenvironment, p62 can promote the inflammatory response via NF-kappaB activation and upregulation of c-Myc genes by activating mechanistic target of rapamycin kinase complex 1.	('NF-kappaB', 'Protein', (110, 119))	('p62', 'Var', (64, 67))	('upregulation', 'PosReg', (135, 147))	('inflammatory response', 'CPA', (84, 105))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('activation', 'PosReg', (120, 130))	('promote', 'PosReg', (72, 79))	('c-Myc genes', 'Gene', (151, 162))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('activating', 'PosReg', (166, 176))
206771	30272335	Taken together, p62 may act as a pro-oncogenic regulator in oral carcinogenesis but the underlying mechanism is not clear.	('oral carcinogenesis', 'Disease', 'MESH:D063646', (60, 79))	('oral carcinogenesis', 'Disease', (60, 79))	('p62', 'Var', (16, 19))
206830	26869799	And, we observed that knocking down HIF-1alpha or HIF-2alpha individually inhibited the xenograft tumor angiogenesis and growth, and knocking them down simultaneously revealed a better inhibitory effect than knocking down either unit alone.	('inhibited', 'NegReg', (74, 83))	('HIF-1alpha or HIF-2alpha', 'Disease', 'None', (36, 60))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('HIF-1alpha or HIF-2alpha', 'Disease', (36, 60))	('knocking down', 'Var', (22, 35))	('tumor', 'Disease', (98, 103))	('knocking', 'Var', (133, 141))
206837	26869799	In this model with OSC-19 cell lines, metastasis to the cervical lymph node was markedly inhibited by cisplatin or peplomycin and the combination of neoadjuvant chemotherapy and tumor resection.	('tumor', 'Disease', (178, 183))	('OSC-19', 'CellLine', 'CVCL:3086', (19, 25))	('cisplatin', 'Var', (102, 111))	('inhibited', 'NegReg', (89, 98))	('metastasis to the cervical lymph node', 'CPA', (38, 75))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('cisplatin', 'Chemical', 'MESH:D002945', (102, 111))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('peplomycin', 'Var', (115, 125))	('peplomycin', 'Chemical', 'MESH:D017663', (115, 125))
206853	26869799	With a NOD/SCID mouse model, Prince et al tested the tumorigenic potential of different populations of cancer cells derived from primary, unmanipulated human HNSCC samples and found that the CD44+ population possessed the unique properties of self-renewal and differentiation.	('SCID', 'Gene', (11, 15))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('human', 'Species', '9606', (152, 157))	('mouse', 'Species', '10090', (16, 21))	('cancer', 'Disease', (103, 109))	('differentiation', 'CPA', (260, 275))	('self-renewal', 'CPA', (243, 255))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('NOD', 'Gene', '1822', (7, 10))	('CD44+', 'Var', (191, 196))	('SCC', 'Gene', '6317', (160, 163))	('NOD', 'Gene', (7, 10))	('SCC', 'Gene', (160, 163))	('tested', 'Reg', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('SCID', 'Gene', '19090', (11, 15))	('HNSCC', 'Phenotype', 'HP:0012288', (158, 163))	('SCID', 'Phenotype', 'HP:0004430', (11, 15))	('tumor', 'Disease', (53, 58))
206857	26869799	The NOG mouse model combines the features of SCID and IL-2 receptor gamma chain deficiency.	('SCID', 'Phenotype', 'HP:0004430', (45, 49))	('SCID', 'Gene', '19090', (45, 49))	('deficiency', 'Var', (80, 90))	('IL-2', 'Gene', '16183', (54, 58))	('mouse', 'Species', '10090', (8, 13))	('SCID', 'Gene', (45, 49))	('IL-2', 'Gene', (54, 58))
206900	26869799	DNA hypomethylation was shown to suppress oral squamous cell carcinogenesis in 4-NQO mice model.	('mice', 'Species', '10090', (85, 89))	('4-NQO', 'Chemical', 'MESH:D015112', (79, 84))	('hypomethylation', 'Var', (4, 19))	('oral squamous cell carcinogenesis', 'Disease', (42, 75))	('oral squamous cell carcinogenesis', 'Disease', 'MESH:D063646', (42, 75))	('suppress', 'NegReg', (33, 41))
206902	26869799	Inactivation of VEGFR or EGFR could significantly suppress oral cancer development and progression in 4-NQO mouse model.	('EGFR', 'Gene', '13649', (17, 21))	('EGFR', 'Gene', (25, 29))	('EGFR', 'Gene', '13649', (25, 29))	('oral cancer', 'Disease', 'MESH:D009062', (59, 70))	('suppress', 'NegReg', (50, 58))	('mouse', 'Species', '10090', (108, 113))	('oral cancer', 'Disease', (59, 70))	('progression in 4-NQO mouse model', 'CPA', (87, 119))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('4-NQO', 'Chemical', 'MESH:D015112', (102, 107))	('Inactivation', 'Var', (0, 12))	('EGFR', 'Gene', (17, 21))
206917	26869799	They found that various cancer-derived cytokines, such as IL-6, PTHrP, TNF-alpha, RANK, RANKL, osteoproteger, played important roles in the OSCC invading bone, and by inhibiting these cytokines, YM529 (a third-generation bisphosphonate) could suppress osteoclast-mediated bone invasion.	('TNF-alpha', 'Gene', '21926', (71, 80))	('cancer', 'Disease', (24, 30))	('PTHrP', 'Gene', '19227', (64, 69))	('bisphosphonate', 'Chemical', 'MESH:D004164', (221, 235))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('PTHrP', 'Gene', (64, 69))	('RANKL', 'Gene', (88, 93))	('rat', 'Species', '10116', (214, 217))	('osteoclast-mediated bone invasion', 'CPA', (252, 285))	('YM529', 'Var', (195, 200))	('RANKL', 'Gene', '21943', (88, 93))	('TNF-alpha', 'Gene', (71, 80))	('inhibiting', 'NegReg', (167, 177))	('cancer', 'Disease', 'MESH:D009369', (24, 30))	('SCC', 'Gene', '6317', (141, 144))	('IL-6', 'Gene', (58, 62))	('SCC', 'Gene', (141, 144))	('suppress', 'NegReg', (243, 251))	('IL-6', 'Gene', '16193', (58, 62))
206927	26869799	Ras as an oncogene, frequently activated by point mutations or overexpression, plays a crucial role in human tumors.	('point mutations', 'Var', (44, 59))	('tumors', 'Disease', 'MESH:D009369', (109, 115))	('human', 'Species', '9606', (103, 108))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumors', 'Disease', (109, 115))
206932	26869799	Using K5-rTA, tet-ras, and tetO-LacZ transgenic mice, Raimondi et al proved that inducing expression of K-ras gene under the control of K5 promoter could trigger a full carcinogenesis.	('K-ras', 'Gene', '16653', (104, 109))	('inducing', 'Var', (81, 89))	('carcinogenesis', 'Disease', (169, 183))	('K-ras', 'Gene', (104, 109))	('trigger', 'Reg', (154, 161))	('expression', 'MPA', (90, 100))	('transgenic mice', 'Species', '10090', (37, 52))	('carcinogenesis', 'Disease', 'MESH:D063646', (169, 183))
206936	26869799	In a H-ras mutation model, male CB6F1-Tg-rasH2 @Jcl mice, Miyamoto et al demonstrated that 4-NQO more easily induced tongue and esophageal carcinogenesis.	('H-ras', 'Gene', (5, 10))	('rat', 'Species', '10116', (80, 83))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (128, 153))	('induced', 'Reg', (109, 116))	('mice', 'Species', '10090', (52, 56))	('esophageal carcinogenesis', 'Disease', (128, 153))	('4-NQO', 'Var', (91, 96))	('H-ras', 'Gene', '15461', (5, 10))	('4-NQO', 'Chemical', 'MESH:D015112', (91, 96))
206939	26869799	A type of dominant-negative p53 transgenic mouse was shown to be highly susceptible to 4-NQO with higher prevalence and more rapid development of OSCC.	('p53', 'Gene', (28, 31))	('SCC', 'Gene', (147, 150))	('4-NQO', 'Chemical', 'MESH:D015112', (87, 92))	('p53', 'Gene', '22059', (28, 31))	('transgenic', 'Species', '10090', (32, 42))	('dominant-negative', 'Var', (10, 27))	('SCC', 'Gene', '6317', (147, 150))	('susceptible', 'Reg', (72, 83))	('mouse', 'Species', '10090', (43, 48))
206941	26869799	In xeroderma pigmentosum group A gene-deficient (XPA-/-) mouse strain carrying mutant alleles for p53, treated with 4-NQO, Ide et al found the accelerated tongue tumor growth might be a consequence of haplonin sufficiency rather than the mutation of p53 in the context of nucleotide excision repair deficiency.	('rat', 'Species', '10116', (149, 152))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('xeroderma pigmentosum', 'Disease', (3, 24))	('p53', 'Gene', '22059', (98, 101))	('tumor', 'Disease', (162, 167))	('tongue tumor', 'Phenotype', 'HP:0100648', (155, 167))	('accelerated', 'PosReg', (143, 154))	('rat', 'Species', '10116', (222, 225))	('XPA-/-', 'Gene', (49, 55))	('mouse', 'Species', '10090', (57, 62))	('p53', 'Gene', (250, 253))	('XPA-/-)', 'Gene', '22590', (49, 56))	('p53', 'Gene', (98, 101))	('p53', 'Gene', '22059', (250, 253))	('4-NQO', 'Chemical', 'MESH:D015112', (116, 121))	('mutant alleles', 'Var', (79, 93))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('xeroderma pigmentosum', 'Disease', 'MESH:D014983', (3, 24))
206945	26869799	Hyperproliferation, reduced apoptosis, and increased genomic instability are related to defective TGF-beta signal in epithelial cells.	('TGF-beta', 'Gene', '21803;21808', (98, 106))	('reduced', 'NegReg', (20, 27))	('rat', 'Species', '10116', (12, 15))	('genomic instability', 'CPA', (53, 72))	('apoptosis', 'CPA', (28, 37))	('increased', 'PosReg', (43, 52))	('TGF-beta', 'Gene', (98, 106))	('Hyperproliferation', 'Disease', (0, 18))	('defective', 'Var', (88, 97))
206947	26869799	Activation of either K-ras or H-ras in combination with TGF-betaRII deletion from mouse head-and-neck epithelia caused HNSCC with complete penetrance, some of which progressed to metastases.	('H-ras', 'Gene', (30, 35))	('TGF-beta', 'Gene', (56, 64))	('SCC', 'Gene', (121, 124))	('deletion', 'Var', (68, 76))	('K-ras', 'Gene', '16653', (21, 26))	('progressed', 'PosReg', (165, 175))	('TGF-beta', 'Gene', '21803;21808', (56, 64))	('caused', 'Reg', (112, 118))	('metastases', 'Disease', (179, 189))	('HNSCC', 'Phenotype', 'HP:0012288', (119, 124))	('SCC', 'Gene', '6317', (121, 124))	('K-ras', 'Gene', (21, 26))	('mouse', 'Species', '10090', (82, 87))	('metastases', 'Disease', 'MESH:D009362', (179, 189))	('H-ras', 'Gene', '15461', (30, 35))
206948	26869799	With the same model system, their further findings demonstrated that the abrogation of TGF-beta signaling would continuously stimulate NF-kappaB, and then result in malignant progression.	('abrogation', 'Var', (73, 83))	('result in', 'Reg', (155, 164))	('TGF-beta', 'Gene', (87, 95))	('NF-kappaB', 'Protein', (135, 144))	('malignant progression', 'CPA', (165, 186))	('TGF-beta', 'Gene', '21803;21808', (87, 95))	('rat', 'Species', '10116', (58, 61))	('stimulate', 'PosReg', (125, 134))
206949	26869799	Bian et al developed an inducible mouse model by knocking out Tgf-betaR1 and Pten.	('knocking out', 'Var', (49, 61))	('mouse', 'Species', '10090', (34, 39))	('Tgf-betaR1', 'Gene', (62, 72))	('Pten', 'Gene', (77, 81))	('Pten', 'Gene', '19211', (77, 81))
206952	26869799	PI3K-mTOR inhibition can enhance TP53/p73 expression and significantly inhibit tumor growth alone.	('tumor', 'Disease', (79, 84))	('inhibit', 'NegReg', (71, 78))	('enhance', 'PosReg', (25, 32))	('p73', 'Gene', (38, 41))	('TP53', 'Gene', '22059', (33, 37))	('p73', 'Gene', '22062', (38, 41))	('TP53', 'Gene', (33, 37))	('inhibition', 'Var', (10, 20))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('PI3K-mTOR', 'Var', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
206958	26869799	To study the biological activities of the HPV 16 E6 and E7 genes in epithelial cells in vivo, transgenic mice with HPV 16 E6 and E7 were established and tumorigenicity by HPV 16 E6 and E7 was obtained.	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('transgenic mice', 'Species', '10090', (94, 109))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('HPV 16', 'Species', '333760', (171, 177))	('HPV 16', 'Species', '333760', (42, 48))	('HPV', 'Var', (115, 118))	('HPV 16', 'Species', '333760', (115, 121))
206959	26869799	Further, Song et al have used transgenic mice that express HPV 16 E6 or E7 in the epidermis to find the mechanism by which HPV 16 E6 or E7 abrogates radiation-induced DNA damage responses in vivo through p53-dependent and p53-independent pathways.	('HPV 16 E6', 'Var', (123, 132))	('abrogates', 'NegReg', (139, 148))	('p53', 'Gene', '22059', (222, 225))	('p53', 'Gene', (204, 207))	('p53', 'Gene', '22059', (204, 207))	('HPV 16', 'Species', '333760', (123, 129))	('transgenic mice', 'Species', '10090', (30, 45))	('radiation-induced DNA damage responses', 'MPA', (149, 187))	('p53', 'Gene', (222, 225))	('HPV 16', 'Species', '333760', (59, 65))
206961	26869799	These mice exhibit a radiation response similar to that of the K14E6 (wild-type [WT]) mice, demonstrating that HPV16 E6 retains an ability to inactivate p53.	('inactivate', 'NegReg', (142, 152))	('HPV16 E6', 'Var', (111, 119))	('K14', 'Gene', '3861', (63, 66))	('mice', 'Species', '10090', (6, 10))	('rat', 'Species', '10116', (99, 102))	('mice', 'Species', '10090', (86, 90))	('p53', 'Gene', (153, 156))	('p53', 'Gene', '22059', (153, 156))	('HPV16', 'Species', '333760', (111, 116))	('K14', 'Gene', (63, 66))
206964	26869799	Zinc-deficient mice with genetic COX-2 deletion developed significantly greater upper aerodigestive tract tumor than WT controls, and presented strong LTA(4)H immunostaining in induced tumors.	('tumor', 'Disease', (185, 190))	('COX-2', 'Gene', '17709', (33, 38))	('greater', 'PosReg', (72, 79))	('COX-2', 'Gene', (33, 38))	('tumors', 'Disease', (185, 191))	('deletion', 'Var', (39, 47))	('tumors', 'Phenotype', 'HP:0002664', (185, 191))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('LTA(4)H', 'Gene', (151, 158))	('tumors', 'Disease', 'MESH:D009369', (185, 191))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('upper aerodigestive', 'CPA', (80, 99))	('LTA(4)H', 'Gene', '16993', (151, 158))	('mice', 'Species', '10090', (15, 19))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('tumor', 'Disease', (106, 111))
206974	26869799	Andl et al developed two mouse models targeting ablation of Cdh1 and Tgfbr2 genes constitutively or inducibly in the oral-esophageal epithelium, which had long latency and could phenocopy the human disease quite accurately.	('Tgfbr2', 'Gene', (69, 75))	('human', 'Species', '9606', (192, 197))	('mouse', 'Species', '10090', (25, 30))	('Tgfbr2', 'Gene', '21813', (69, 75))	('Cdh1', 'Gene', '12550', (60, 64))	('ablation', 'Var', (48, 56))	('rat', 'Species', '10116', (216, 219))	('Cdh1', 'Gene', (60, 64))
206984	32228656	circFOXM1 promotes proliferation of non-small cell lung carcinoma cells by acting as a ceRNA to upregulate FAM83D Biological role and clinical significance of circular RNAs (circRNAs) remain largely unknown.	('lung carcinoma', 'Disease', (51, 65))	('promotes', 'PosReg', (10, 18))	('non-small cell lung carcinoma', 'Phenotype', 'HP:0030358', (36, 65))	('proliferation', 'CPA', (19, 32))	('upregulate', 'PosReg', (96, 106))	('lung carcinoma', 'Disease', 'MESH:D008175', (51, 65))	('circFOXM1', 'Var', (0, 9))	('carcinoma', 'Phenotype', 'HP:0030731', (56, 65))	('small cell lung carcinoma', 'Phenotype', 'HP:0030357', (40, 65))
206991	32228656	Gain or loss-of-function assay showed that circFOXM1 promoted cell proliferation and cell cycle progression.	('promoted', 'PosReg', (53, 61))	('cell proliferation', 'CPA', (62, 80))	('loss-of-function', 'NegReg', (8, 24))	('circFOXM1', 'Var', (43, 52))	('circFOXM1', 'Chemical', '-', (43, 52))	('cell cycle progression', 'CPA', (85, 107))
206992	32228656	In vivo assays showed that silencing circFOXM1 inhibited xenograft tumor growth.	('inhibited', 'NegReg', (47, 56))	('silencing', 'Var', (27, 36))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('circFOXM1', 'Gene', (37, 46))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Disease', (67, 72))	('circFOXM1', 'Chemical', '-', (37, 46))
206993	32228656	Mechanically, transcriptome sequencing data indicated that silencing circFOXM1 led to the downregulation of cell cycle-related mRNAs.	('circFOXM1', 'Chemical', '-', (69, 78))	('cell', 'CPA', (108, 112))	('circFOXM1', 'Gene', (69, 78))	('downregulation', 'NegReg', (90, 104))	('silencing', 'Var', (59, 68))
207005	32228656	For example, circTP63 is positively correlated with tumor size and TNM stage, exerting oncogenic potential by sponging to miR-873 in lung squamous cell carcinoma.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (152, 161))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (138, 161))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (133, 161))	('lung squamous cell carcinoma', 'Disease', (133, 161))	('miR-873', 'Gene', (122, 129))	('tumor', 'Disease', (52, 57))	('correlated', 'Reg', (36, 46))	('TNM', 'Gene', '10178', (67, 70))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('miR-873', 'Gene', '100126316', (122, 129))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (133, 161))	('TNM', 'Gene', (67, 70))	('circTP63', 'Var', (13, 21))
207010	32228656	have shown that both of the mRNA and protein levels of FAM83D are upregulated in gastric cancer, and high expression of FAM83D predicts worse overall survival and disease-free survival.	('worse', 'NegReg', (136, 141))	('FAM83D', 'Gene', '81610', (55, 61))	('FAM83D', 'Gene', (120, 126))	('overall survival', 'CPA', (142, 158))	('upregulated', 'PosReg', (66, 77))	('gastric cancer', 'Disease', 'MESH:D013274', (81, 95))	('gastric cancer', 'Disease', (81, 95))	('FAM83D', 'Gene', '81610', (120, 126))	('mRNA and', 'MPA', (28, 36))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('disease-free survival', 'CPA', (163, 184))	('FAM83D', 'Gene', (55, 61))	('high expression', 'Var', (101, 116))	('gastric cancer', 'Phenotype', 'HP:0012126', (81, 95))
207016	32228656	circFOXM1 was correlated with advanced clinical stage and worse overall survival in NSCLC patients.	('NSCLC', 'Phenotype', 'HP:0030358', (84, 89))	('worse', 'NegReg', (58, 63))	('NSCLC', 'Disease', (84, 89))	('overall survival', 'MPA', (64, 80))	('NSCLC', 'Disease', 'MESH:D002289', (84, 89))	('patients', 'Species', '9606', (90, 98))	('circFOXM1', 'Var', (0, 9))	('circFOXM1', 'Chemical', '-', (0, 9))
207017	32228656	In vitro and in vivo assays showed that circFOXM1 promoted cell proliferation and cell cycle progression.	('promoted', 'PosReg', (50, 58))	('cell proliferation', 'CPA', (59, 77))	('circFOXM1', 'Var', (40, 49))	('circFOXM1', 'Chemical', '-', (40, 49))	('cell cycle progression', 'CPA', (82, 104))
207018	32228656	RNA-sequencing results suggested that cell-cycle related genes were modulated by circFOXM1.	('cell-cycle related genes', 'Gene', (38, 62))	('circFOXM1', 'Chemical', '-', (81, 90))	('circFOXM1', 'Var', (81, 90))	('modulated', 'Reg', (68, 77))
207047	32228656	For dual-luciferase assay, wild-type and mutant fragments of circFOXM1 as well as FAM83D 3' UTR were cloned into pmirGLO vector (Promega) to form luciferase reporter vector.	('mutant', 'Var', (41, 47))	('circFOXM1', 'Gene', (61, 70))	('FAM83D', 'Gene', (82, 88))	('FAM83D', 'Gene', '81610', (82, 88))	('circFOXM1', 'Chemical', '-', (61, 70))
207048	32228656	For pZW-circFOXM1, sh-circFOXM1 or sh-FAM83D transfection, 2 x 105 cells were seed in 60 mm dishes for 24 h before transfection.	('sh-circFOXM1', 'Var', (19, 31))	('FAM83D', 'Gene', (38, 44))	('pZW-circFOXM1', 'Var', (4, 17))	('circFOXM1', 'Chemical', '-', (8, 17))	('FAM83D', 'Gene', '81610', (38, 44))	('circFOXM1', 'Chemical', '-', (22, 31))
207051	32228656	For dual-luciferase assay, plasmids with wild-type or mutant fragments were co-transfected with miR-614, respectively.	('mutant', 'Var', (54, 60))	('miR-614', 'Gene', '693199', (96, 103))	('miR-614', 'Gene', (96, 103))
207053	32228656	Gene set enrichment analysis (GSEA) software (version 3.0, www.broadinstitute.org/gsea/) was employed to identify gene sets that were significantly overrepresented among genes up- or down-regulated in circFOXM1 silencing cells.	('silencing', 'Var', (211, 220))	('circFOXM1', 'Chemical', '-', (201, 210))	('down-regulated', 'NegReg', (183, 197))	('overrepresented', 'PosReg', (148, 163))	('up-', 'PosReg', (176, 179))	('GSEA', 'Chemical', '-', (30, 34))
207079	32228656	H2170 cells transfected with vector control, pZW-circFOXM1, sh-circFOXM1 or negative control (sh-NC) were subcutaneously injected into the back of the nude mice (1 x 106, 100 mul).	('sh-circFOXM1', 'Var', (60, 72))	('circFOXM1', 'Chemical', '-', (63, 72))	('circFOXM1', 'Chemical', '-', (49, 58))	('H2170', 'CellLine', 'CVCL:1535', (0, 5))	('pZW-circFOXM1', 'Var', (45, 58))	('nude mice', 'Species', '10090', (151, 160))
207082	32228656	After being immersed in antigen retrieval solution (AR0023, Boster, China) and heated for 15 min, sections were then incubated with anti-human Ki-67 antibody (M7240, Dako, Denmark) for 1 h and counterstained with hematoxylin (BA-4226, BASO, China) for 2 min.	('human', 'Species', '9606', (137, 142))	('Ki-67', 'Gene', (143, 148))	('hematoxylin', 'Chemical', 'MESH:D006416', (213, 224))	('M7240', 'Var', (159, 164))	('Ki-67', 'Gene', '17345', (143, 148))
207083	32228656	Based on the analysis for our previous microarray data (GSE126533), we found that has_circ_0025039 (chr12:2975558-2,977,920) was evaluated as an upregulated circRNA in NSCLC (Fig.	('chr12:2975558-2', 'STRUCTURAL_ABNORMALITY', 'None', (100, 115))	('NSCLC', 'Disease', 'MESH:D002289', (168, 173))	('NSCLC', 'Phenotype', 'HP:0030358', (168, 173))	('upregulated', 'PosReg', (145, 156))	('has_circ_0025039', 'Var', (82, 98))	('NSCLC', 'Disease', (168, 173))
207084	32228656	By browsing the human reference genome (GRCh37/hg19), we knew that has_circ_0025039 was derived from the exon 4 and 5 of FOXM1 loci, and thus named it circFOXM1 in this study.	('FOXM1', 'Gene', (121, 126))	('FOXM1', 'Gene', (155, 160))	('FOXM1', 'Gene', '2305', (121, 126))	('FOXM1', 'Gene', '2305', (155, 160))	('circFOXM1', 'Chemical', '-', (151, 160))	('has_circ_0025039', 'Var', (67, 83))	('human', 'Species', '9606', (16, 21))
207088	32228656	In addition, high expression of circFOXM1may predict an unfavorable overall survival of NSCLC patients (Fig.	('circFOXM1may', 'Gene', (32, 44))	('patients', 'Species', '9606', (94, 102))	('NSCLC', 'Phenotype', 'HP:0030358', (88, 93))	('high', 'Var', (13, 17))	('overall survival', 'MPA', (68, 84))	('NSCLC', 'Disease', (88, 93))	('NSCLC', 'Disease', 'MESH:D002289', (88, 93))	('circFOXM1', 'Chemical', '-', (32, 41))
207093	32228656	Taken together, these results indicate that circular RNA circFOXM1 is upregulated in NSCLC, and high expression of circFOXM1 is associated with advanced stage and poor survival of NSCLC patients.	('NSCLC', 'Disease', (85, 90))	('NSCLC', 'Disease', (180, 185))	('NSCLC', 'Disease', 'MESH:D002289', (85, 90))	('NSCLC', 'Phenotype', 'HP:0030358', (85, 90))	('circFOXM1', 'Chemical', '-', (115, 124))	('NSCLC', 'Disease', 'MESH:D002289', (180, 185))	('associated', 'Reg', (128, 138))	('high', 'Var', (96, 100))	('upregulated', 'PosReg', (70, 81))	('NSCLC', 'Phenotype', 'HP:0030358', (180, 185))	('circFOXM1', 'Chemical', '-', (57, 66))	('patients', 'Species', '9606', (186, 194))
207102	32228656	CCK-8 results revealed that the viability of both H1299 and H2170 cells was increased in circFOXM1 overexpressing group while decreased in circFOXM1 silencing group (Fig.	('decreased', 'NegReg', (126, 135))	('circFOXM1', 'Chemical', '-', (89, 98))	('increased', 'PosReg', (76, 85))	('CCK', 'Gene', '885', (0, 3))	('H2170', 'CellLine', 'CVCL:1535', (60, 65))	('H1299', 'CellLine', 'CVCL:0060', (50, 55))	('CCK', 'Gene', (0, 3))	('circFOXM1', 'Chemical', '-', (139, 148))	('circFOXM1', 'Var', (89, 98))
207104	32228656	Furthermore, cell cycle analyses showed that the number of cells was increased in G2/M phase when overexpressing circFOXM1.	('circFOXM1', 'Var', (113, 122))	('circFOXM1', 'Chemical', '-', (113, 122))	('G2/M phase', 'CPA', (82, 92))	('increased', 'PosReg', (69, 78))
207105	32228656	In contrast, silencing circFOXM1 made cells arrested in G0/G1 phase (Fig.	('circFOXM1', 'Gene', (23, 32))	('G0/G1 phase', 'CPA', (56, 67))	('circFOXM1', 'Chemical', '-', (23, 32))	('silencing', 'Var', (13, 22))
207106	32228656	These data indicate that circFOXM1 promotes NSCLC cell proliferation and cell cycle progression in vitro.	('NSCLC', 'Disease', 'MESH:D002289', (44, 49))	('circFOXM1', 'Var', (25, 34))	('circFOXM1', 'Chemical', '-', (25, 34))	('cell cycle progression', 'CPA', (73, 95))	('promotes', 'PosReg', (35, 43))	('NSCLC', 'Phenotype', 'HP:0030358', (44, 49))	('NSCLC', 'Disease', (44, 49))
207108	32228656	Results showed that tumor cells with circFOXM1overexpressing grew rapidly compared to control.	('circFOXM1overexpressing', 'Var', (37, 60))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('grew', 'CPA', (61, 65))	('circFOXM1', 'Chemical', '-', (37, 46))	('tumor', 'Disease', (20, 25))
207109	32228656	In addition, Ki-67 staining showed that circFOXM1 made more Ki-67 positive cells.	('Ki-67', 'Gene', '17345', (60, 65))	('Ki-67', 'Gene', (60, 65))	('Ki-67', 'Gene', '17345', (13, 18))	('circFOXM1', 'Var', (40, 49))	('circFOXM1', 'Chemical', '-', (40, 49))	('Ki-67', 'Gene', (13, 18))
207110	32228656	In contrast, silencing circFOXM1 obviously blocked upon tumor growth and decreased Ki-67 staining cells (Fig.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('Ki-67', 'Gene', (83, 88))	('decreased', 'NegReg', (73, 82))	('circFOXM1', 'Gene', (23, 32))	('tumor', 'Disease', (56, 61))	('blocked', 'NegReg', (43, 50))	('circFOXM1', 'Chemical', '-', (23, 32))	('Ki-67', 'Gene', '17345', (83, 88))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('silencing', 'Var', (13, 22))
207112	32228656	Using RNA-sequencing technology, we identified 685 dysregulated genes ( Fold change  > 2, FDR < 0.1) (328 genes upregulated and 357 genes downregulated) after silencing circFOXM1in H1299 cells (Fig.	('silencing', 'Var', (159, 168))	('upregulated', 'PosReg', (112, 123))	('downregulated', 'NegReg', (138, 151))	('circFOXM1', 'Chemical', '-', (169, 178))	('H1299', 'CellLine', 'CVCL:0060', (181, 186))	('circFOXM1in', 'Gene', (169, 180))
207114	32228656	To further illustrate the mechanism of circFOXM1, we analyzed GSEA results and found that the signatures of cell cycle, cell cycle mitotic, mitotic G2/G2-M phase, and G1 phase were significantly enriched in downregulated genes, indicating that these biologic processes may be suppressed by circFOXM1 silencing (Fig.	('GSEA', 'Chemical', '-', (62, 66))	('silencing', 'Var', (300, 309))	('cell cycle mitotic', 'CPA', (120, 138))	('circFOXM1', 'Gene', (290, 299))	('cell cycle', 'CPA', (108, 118))	('downregulated', 'NegReg', (207, 220))	('circFOXM1', 'Chemical', '-', (39, 48))	('genes', 'Gene', (221, 226))	('suppressed', 'NegReg', (276, 286))	('mitotic G2/G2-M phase', 'CPA', (140, 161))	('circFOXM1', 'Chemical', '-', (290, 299))
207116	32228656	These results were consistent with above phenotypes that silencing circFOXM1 made cell cycle arrested in G0/G1 phase.	('silencing', 'Var', (57, 66))	('cell cycle arrested', 'CPA', (82, 101))	('circFOXM1', 'Chemical', '-', (67, 76))	('circFOXM1', 'Gene', (67, 76))
207117	32228656	Thus, circFOXM1 may promote cell proliferation by modulating cell cycle-related genes.	('circFOXM1', 'Var', (6, 15))	('circFOXM1', 'Chemical', '-', (6, 15))	('cell proliferation', 'CPA', (28, 46))	('promote', 'PosReg', (20, 27))	('cell cycle-related genes', 'Gene', (61, 85))	('modulating', 'Reg', (50, 60))
207128	32228656	Importantly, cells transfected with plasmids of mutant circFOXM1 could not significantly promote cell proliferation and cell cycle progression (Fig.	('mutant', 'Var', (48, 54))	('promote', 'PosReg', (89, 96))	('circFOXM1', 'Chemical', '-', (55, 64))	('cell proliferation', 'CPA', (97, 115))	('cell cycle progression', 'CPA', (120, 142))	('circFOXM1', 'Gene', (55, 64))
207134	32228656	Taken together, these results indicate that circFOXM1 promotes cell proliferation mediated by miR-614.	('circFOXM1', 'Chemical', '-', (44, 53))	('miR-614', 'Gene', (94, 101))	('cell proliferation', 'CPA', (63, 81))	('circFOXM1', 'Var', (44, 53))	('miR-614', 'Gene', '693199', (94, 101))	('promotes', 'PosReg', (54, 62))
207138	32228656	Then, we analyzed the downregulated RNAs in our RNA-sequencing data after silencing circFOXM1(Additional file 2: Table S2).	('circFOXM1', 'Gene', (84, 93))	('RNAs', 'Gene', (36, 40))	('silencing', 'Var', (74, 83))	('circFOXM1', 'Chemical', '-', (84, 93))	('downregulated', 'NegReg', (22, 35))
207140	32228656	5a).Results of western blot and qRT-PCR showed that the protein and mRNA levels of FAM83D were downregulated by miR-614 transfection(Fig.	('FAM83D', 'Gene', '81610', (83, 89))	('downregulated', 'NegReg', (95, 108))	('transfection', 'Var', (120, 132))	('miR-614', 'Gene', '693199', (112, 119))	('miR-614', 'Gene', (112, 119))	('mRNA levels', 'MPA', (68, 79))	('FAM83D', 'Gene', (83, 89))	('protein', 'MPA', (56, 63))
207145	32228656	CCK-8 assays, colony formation assays, and cell cycle assays showed that silencing FAM83D inhibited cell proliferation, colony formation, and cell cycle progression (Fig.	('silencing', 'Var', (73, 82))	('FAM83D', 'Gene', '81610', (83, 89))	('cell cycle progression', 'CPA', (142, 164))	('cell proliferation', 'CPA', (100, 118))	('colony formation', 'CPA', (120, 136))	('CCK', 'Gene', (0, 3))	('FAM83D', 'Gene', (83, 89))	('CCK', 'Gene', '885', (0, 3))	('inhibited', 'NegReg', (90, 99))
207152	32228656	However, silencing circFOXM1 caused a significant increase in the recruitment of FAM83D in miR-614 pull-down assay (Fig.	('FAM83D', 'Gene', (81, 87))	('circFOXM1', 'Gene', (19, 28))	('silencing', 'Var', (9, 18))	('miR-614', 'Gene', '693199', (91, 98))	('increase', 'PosReg', (50, 58))	('FAM83D', 'Gene', '81610', (81, 87))	('circFOXM1', 'Chemical', '-', (19, 28))	('recruitment', 'MPA', (66, 77))	('miR-614', 'Gene', (91, 98))
207157	32228656	6f, overexpression ofcircFOXM1 increased protein levels of CCND1 and CCNE1while silencing FAM83D suppressed the effects of circFOXM1 on upregulation of CCND1 and CCNE1, and their expression levels were decreased.	('silencing', 'Var', (80, 89))	('increased', 'PosReg', (31, 40))	('circFOXM1', 'Chemical', '-', (21, 30))	('decreased', 'NegReg', (202, 211))	('CCND1', 'Gene', '595', (152, 157))	('CCNE1', 'Gene', (69, 74))	('upregulation', 'PosReg', (136, 148))	('FAM83D', 'Gene', (90, 96))	('suppressed', 'NegReg', (97, 107))	('CCND1', 'Gene', (152, 157))	('FAM83D', 'Gene', '81610', (90, 96))	('circFOXM1', 'Chemical', '-', (123, 132))	('CCNE1', 'Gene', '898', (69, 74))	('CCNE1', 'Gene', (162, 167))	('expression levels', 'MPA', (179, 196))	('CCNE1', 'Gene', '898', (162, 167))	('CCND1', 'Gene', '595', (59, 64))	('CCND1', 'Gene', (59, 64))	('protein levels', 'MPA', (41, 55))
207158	32228656	CCK-8 assays also showed that silencing FAM83D decreased the promotion effects of circFOXM1 on cell proliferation (Fig.	('cell proliferation', 'CPA', (95, 113))	('FAM83D', 'Gene', (40, 46))	('FAM83D', 'Gene', '81610', (40, 46))	('CCK', 'Gene', (0, 3))	('promotion effects', 'MPA', (61, 78))	('CCK', 'Gene', '885', (0, 3))	('silencing', 'Var', (30, 39))	('circFOXM1', 'Chemical', '-', (82, 91))	('decreased', 'NegReg', (47, 56))
207159	32228656	These results indicate that circFOXM1 promotes cell proliferation of NSCLC cells via the miR-614/FAM83D regulatory axis.	('circFOXM1', 'Var', (28, 37))	('circFOXM1', 'Chemical', '-', (28, 37))	('FAM83D', 'Gene', '81610', (97, 103))	('NSCLC', 'Disease', (69, 74))	('miR-614', 'Gene', '693199', (89, 96))	('promotes', 'PosReg', (38, 46))	('NSCLC', 'Disease', 'MESH:D002289', (69, 74))	('NSCLC', 'Phenotype', 'HP:0030358', (69, 74))	('FAM83D', 'Gene', (97, 103))	('miR-614', 'Gene', (89, 96))	('cell proliferation', 'CPA', (47, 65))
207160	32228656	Then, many genes are reported to produce individual circRNAs, such as ETS-1, SRY, and P450 in different cells.	('ETS-1', 'Gene', '2113', (70, 75))	('P450', 'Gene', '1555', (86, 90))	('produce', 'Reg', (33, 40))	('genes', 'Var', (11, 16))	('SRY', 'Gene', '6736', (77, 80))	('SRY', 'Gene', (77, 80))	('P450', 'Gene', (86, 90))	('ETS-1', 'Gene', (70, 75))
207163	32228656	Serval studies have been reported that the abnormally expressed circRNAs are correlated with clinical features and have the potential to be biomarkers in NSCLC.	('Serval', 'Species', '61405', (0, 6))	('NSCLC', 'Disease', 'MESH:D002289', (154, 159))	('abnormally expressed', 'Var', (43, 63))	('NSCLC', 'Phenotype', 'HP:0030358', (154, 159))	('correlated', 'Reg', (77, 87))	('circRNAs', 'Gene', (64, 72))	('NSCLC', 'Disease', (154, 159))
207164	32228656	In this study, we found a circular RNA, has_circ_0025039 derived from the exons 4 and 5 of FOXM1 (named circFOXM1), was obviously upregulated in NSCLC tissues.	('upregulated', 'PosReg', (130, 141))	('FOXM1', 'Gene', (108, 113))	('FOXM1', 'Gene', '2305', (108, 113))	('NSCLC', 'Disease', (145, 150))	('circFOXM1', 'Chemical', '-', (104, 113))	('FOXM1', 'Gene', (91, 96))	('has_circ_0025039', 'Var', (40, 56))	('NSCLC', 'Disease', 'MESH:D002289', (145, 150))	('FOXM1', 'Gene', '2305', (91, 96))	('NSCLC', 'Phenotype', 'HP:0030358', (145, 150))
207167	32228656	report that hsa_circ_0025033, another circular RNA derived from the exons 2-10 of FOXM1, also promotes the NSCLC progression.	('NSCLC', 'Disease', (107, 112))	('NSCLC', 'Disease', 'MESH:D002289', (107, 112))	('FOXM1', 'Gene', (82, 87))	('hsa_circ_0025033', 'Var', (12, 28))	('FOXM1', 'Gene', '2305', (82, 87))	('NSCLC', 'Phenotype', 'HP:0030358', (107, 112))	('promotes', 'PosReg', (94, 102))
207175	32228656	However, some miRNAs, such as miR-198, miR-516, and miR-6812, could also be enriched in H1299 cells, but not be enriched in H2170 cells.	('miR-198', 'Gene', (30, 37))	('H2170', 'CellLine', 'CVCL:1535', (124, 129))	('miR-198', 'Gene', '406975', (30, 37))	('miR-516', 'Var', (39, 46))	('H1299', 'CellLine', 'CVCL:0060', (88, 93))	('miR-6812', 'Gene', '102465487', (52, 60))	('miR-6812', 'Gene', (52, 60))
207199	32005108	Additional bioinformatic analyses would reveal that these methylation markers are independent of patient race and age, and positively associated with signaling pathways associated with BrCa progression (such as those related to retinoid nuclear receptor, PTEN, p53, pRB, and p27).	('retinoid', 'Protein', (228, 236))	('associated', 'Reg', (134, 144))	('BrCa', 'Gene', (185, 189))	('signaling pathways', 'Pathway', (150, 168))	('p53', 'Gene', (261, 264))	('p53', 'Gene', '7157', (261, 264))	('p27', 'Gene', '3429', (275, 278))	('p27', 'Gene', (275, 278))	('BrCa', 'Gene', '672', (185, 189))	('pRB', 'Gene', '5925', (266, 269))	('methylation', 'Var', (58, 69))	('patient', 'Species', '9606', (97, 104))	('PTEN', 'Gene', (255, 259))	('PTEN', 'Gene', '5728', (255, 259))	('pRB', 'Gene', (266, 269))	('methyl', 'Chemical', 'MESH:C031105', (58, 64))
207203	32005108	BRCA1/2 mutations) is an important contributing factor (5-10%), most BrCa cases are those without clear genetic link (it may still be due to unknown genetic risk, thus considered familial).	('BRCA1', 'Gene', (0, 5))	('BrCa', 'Gene', (69, 73))	('BrCa', 'Gene', '672', (69, 73))	('mutations', 'Var', (8, 17))	('BRCA1', 'Gene', '672', (0, 5))
207212	32005108	mutation, copy number variation, CpG methylation) found in cancer tissues are largely concordant with those identified in ctDNAs.	('mutation', 'Var', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('methyl', 'Chemical', 'MESH:C031105', (37, 43))	('copy number variation', 'Var', (10, 31))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))
207213	32005108	Already marketed are early cancer diagnostic tests based on interrogating site-specific CpG hypermethylation in ctDNAs isolated from patient plasma.	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('CpG', 'Var', (88, 91))	('patient', 'Species', '9606', (133, 140))	('methyl', 'Chemical', 'MESH:C031105', (97, 103))	('hypermethylation', 'Var', (92, 108))	('cancer', 'Disease', (27, 33))	('cancer', 'Disease', 'MESH:D009369', (27, 33))
207214	32005108	These include: a) Epi proColon, ColoVantage, Realtime mS9, all of which detect methylation in the SEPT9 gene for colon cancer detection; b) Epi proLung which detects methylation of SHOX2 for lung cancer detection, and c) Colvera, which detects methylation at BCAT1 and IKZF1 for colon cancer recurrence.	('methyl', 'Chemical', 'MESH:C031105', (79, 85))	('colon cancer', 'Phenotype', 'HP:0003003', (113, 125))	('methyl', 'Chemical', 'MESH:C031105', (166, 172))	('mS9', 'Gene', '69077', (54, 57))	('BCAT1', 'Gene', '586', (259, 264))	('colon cancer', 'Phenotype', 'HP:0003003', (279, 291))	('methylation', 'Var', (166, 177))	('BCAT1', 'Gene', (259, 264))	('methyl', 'Chemical', 'MESH:C031105', (244, 250))	('lung cancer', 'Disease', 'MESH:D008175', (191, 202))	('colon cancer', 'Disease', 'MESH:D015179', (113, 125))	('IKZF1', 'Gene', '10320', (269, 274))	('mS9', 'Gene', (54, 57))	('methylation', 'Var', (244, 255))	('colon cancer', 'Disease', 'MESH:D015179', (279, 291))	('lung cancer', 'Phenotype', 'HP:0100526', (191, 202))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('SEPT9', 'Gene', (98, 103))	('SHOX2', 'Gene', (181, 186))	('SHOX2', 'Gene', '6474', (181, 186))	('cancer', 'Phenotype', 'HP:0002664', (285, 291))	('colon cancer', 'Disease', (113, 125))	('colon cancer', 'Disease', (279, 291))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('lung cancer', 'Disease', (191, 202))	('SEPT9', 'Gene', '10801', (98, 103))	('IKZF1', 'Gene', (269, 274))
207223	32005108	Also crucial to our biomarker identification is the integration of various GEO datasets such as: GSE65820 (ovarian cancer PTs and matching normals), GSE46306 (normal tissues of the cervix), GSE99553 (gastric mucosa), GSE74104 (testis), GSE77871 (adrenal tissues), GSE51954 (dermis and epidermis), GSE64509 (various brain tissues), GSE42861 (peripheral blood), and GSE59250 (various immune cells from healthy individuals).	('GSE59250', 'Var', (364, 372))	('GSE99553', 'Var', (190, 198))	('GSE42861', 'Var', (331, 339))	('GSE64509', 'Var', (297, 305))	('GSE51954', 'Var', (264, 272))	('ovarian cancer', 'Disease', 'MESH:D010051', (107, 121))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('ovarian cancer', 'Phenotype', 'HP:0100615', (107, 121))	('GSE74104', 'Var', (217, 225))	('gastric mucosa', 'Disease', (200, 214))	('GSE65820', 'Var', (97, 105))	('GSE46306', 'Var', (149, 157))	('gastric mucosa', 'Disease', 'MESH:D013274', (200, 214))	('GSE77871', 'Var', (236, 244))	('ovarian cancer', 'Disease', (107, 121))
207229	32005108	First, the combined transcriptional and methylation data enabled us to predict if the CpG sites can potentially influence the transcription of their respective genes.	('CpG sites', 'Var', (86, 95))	('transcription', 'MPA', (126, 139))	('influence', 'Reg', (112, 121))	('methyl', 'Chemical', 'MESH:C031105', (40, 46))	('sites', 'Var', (90, 95))
207258	32005108	Among the major cancer types, the marker m_PRKCB exhibits the highest degree of methylation ( PT equals 0.561).	('methyl', 'Chemical', 'MESH:C031105', (80, 86))	('methylation', 'MPA', (80, 91))	('cancer type', 'Disease', 'MESH:D009369', (16, 27))	('cancer type', 'Disease', (16, 27))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('m_PRKCB', 'Var', (41, 48))
207265	32005108	The methylation level of either m_NR5A2 or m_PRKCB, apparently does not correlate with its transcript level (the respective R values are - 0.198 and - 0.123) (Additional file 1: Supplement 10).	('m_NR5A2', 'Var', (32, 39))	('methyl', 'Chemical', 'MESH:C031105', (4, 10))	('m_PRKCB', 'Gene', (43, 50))	('methylation', 'MPA', (4, 15))
207272	32005108	ERBB3 expression, which is positively correlated with methylation at m_PRKCB and m_NR5A2 (Fig.	('ERBB3', 'Gene', (0, 5))	('ERBB3', 'Gene', '2065', (0, 5))	('methylation', 'Var', (54, 65))	('expression', 'MPA', (6, 16))	('m_PRKCB', 'Gene', (69, 76))	('m_NR5A2', 'Gene', (81, 88))	('methyl', 'Chemical', 'MESH:C031105', (54, 60))	('correlated', 'Reg', (38, 48))
207286	32005108	The positive association between the methylation markers and CARM1 pathway is consistent with previous studies indicating that CARM1 (which codes for arginine methyltransferase) is involved in epigenetic transactivation of many nuclear receptors (NRs) including ERalpha.	('CARM1', 'Gene', '10498', (127, 132))	('methyl', 'Chemical', 'MESH:C031105', (159, 165))	('arginine', 'Chemical', 'MESH:D001127', (150, 158))	('epigenetic', 'Var', (193, 203))	('ERalpha', 'Gene', (262, 269))	('involved', 'Reg', (181, 189))	('methyl', 'Chemical', 'MESH:C031105', (37, 43))	('CARM1', 'Gene', (61, 66))	('ERalpha', 'Gene', '2099', (262, 269))	('CARM1', 'Gene', '10498', (61, 66))	('CARM1', 'Gene', (127, 132))
207298	32005108	According to the datasets GSE57342, GSE68379, GSE78875, and GSE94943, the average beta values for the CpG markers m_NR5A2, m_PRKCB, and m_ncr1 in the BrCa cell line MCF7 are 0.96, 0.97, and 0.98 respectively (Fig.	('BrCa', 'Gene', (150, 154))	('GSE57342', 'Var', (26, 34))	('BrCa', 'Gene', '672', (150, 154))	('GSE68379', 'Var', (36, 44))	('GSE94943', 'Var', (60, 68))	('GSE78875', 'Var', (46, 54))	('MCF7', 'CellLine', 'CVCL:0031', (165, 169))	('m_NR5A2', 'Var', (114, 121))
207307	32005108	For this experiment, we performed the 2-step PCR and LDR reactions as described above, using the primers for the detection of methylation at the CpG site located in the promoter region of the gene GRK7 (m_GRK7 or cg18768784; Chr3:_141516271-141,516,272), although highly methylated in the BrCa cohort, has low BRCA-specificity.	('GRK7', 'Gene', (197, 201))	('methyl', 'Chemical', 'MESH:C031105', (271, 277))	('BrCa', 'Gene', (289, 293))	('GRK7', 'Gene', '131890', (205, 209))	('BRCA', 'Gene', '672', (310, 314))	('BrCa', 'Gene', '672', (289, 293))	('GRK7', 'Gene', '131890', (197, 201))	('cg18768784', 'Var', (213, 223))	('BRCA', 'Gene', (310, 314))	('methyl', 'Chemical', 'MESH:C031105', (126, 132))	('GRK7', 'Gene', (205, 209))
207309	32005108	In the digital PCR detection system, the corresponding readings are 8164, 4986, and 805 for the MCF7, MDA-MB-134VI, and control (peripheral blood only) respectively.	('MDA-MB-134', 'CellLine', 'CVCL:0617', (102, 112))	('MDA-MB-134VI', 'Var', (102, 114))	('MCF7', 'Var', (96, 100))	('MCF7', 'CellLine', 'CVCL:0031', (96, 100))
207313	32005108	As expected, ctDNA fragments possess the same molecular signatures (somatic mutations, methylation, copy number variation/aberration, SNPs) present in gDNAs isolated from the tumor tissue samples.	('tumor', 'Disease', (175, 180))	('methyl', 'Chemical', 'MESH:C031105', (87, 93))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('methylation', 'Var', (87, 98))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('copy number variation/aberration', 'Var', (100, 132))
207343	32005108	However, bisulfite conversion can cause the degradation of around 84-96% of the input cfDNA, and is thus a significant contributing factor to MSP's limitations in liquid biopsy.	('degradation', 'MPA', (44, 55))	('bisulfite', 'Chemical', 'MESH:C042345', (9, 18))	('bisulfite conversion', 'Var', (9, 29))
207361	31765370	GPCRs show widespread differential mRNA expression and frequent mutation and copy number variation in solid tumors G protein-coupled receptors (GPCRs) are the most widely targeted gene family for Food and Drug Administration (FDA)-approved drugs.	('copy number variation', 'Var', (77, 98))	('solid tumors', 'Disease', (102, 114))	('GPCR', 'Gene', '148', (144, 148))	('GPCR', 'Gene', '148', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('GPCR', 'Gene', (144, 148))	('GPCR', 'Gene', (0, 4))	('solid tumors', 'Disease', 'MESH:D009369', (102, 114))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))
207369	31765370	Certain GPCRs are frequently mutated and appear to be hotspots, serving as bellwethers of accumulated genomic damage.	('GPCR', 'Gene', '148', (8, 12))	('mutated', 'Var', (29, 36))	('GPCR', 'Gene', (8, 12))
207374	31765370	Expression of certain GPCRs appears to have prognostic relevance, and many GPCRs undergo widespread mutation and copy number variation.	('GPCR', 'Gene', '148', (75, 79))	('copy number variation', 'Var', (113, 134))	('undergo', 'Reg', (81, 88))	('GPCR', 'Gene', (22, 26))	('GPCR', 'Gene', (75, 79))	('GPCR', 'Gene', '148', (22, 26))
207378	31765370	One reason for their limited use is the notion that GPCRs are rarely mutated in cancer :although mutations occur in heterotrimeric GTP binding (G) proteins that GPCRs activate :and that GPCRs regulate pathways, such as Wnt, mitogen-activated protein kinase (MAPK), and Phosphoinositide 3-Kinase (PI3K) signaling, with mutations in cancer.	('mutations', 'Var', (97, 106))	('Wnt', 'Pathway', (219, 222))	('mutations', 'Var', (318, 327))	('GTP', 'Chemical', 'MESH:D006160', (131, 134))	('cancer', 'Disease', (80, 86))	('cancer', 'Disease', 'MESH:D009369', (331, 337))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('GPCR', 'Gene', '148', (52, 56))	('GPCR', 'Gene', '148', (186, 190))	('Phosphoinositide 3-Kinase', 'Gene', '5293', (269, 294))	('GPCR', 'Gene', (52, 56))	('GPCR', 'Gene', '148', (161, 165))	('GPCR', 'Gene', (186, 190))	('regulate', 'Reg', (192, 200))	('GPCR', 'Gene', (161, 165))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('Phosphoinositide 3-Kinase', 'Gene', (269, 294))	('cancer', 'Disease', (331, 337))	('cancer', 'Phenotype', 'HP:0002664', (331, 337))
207380	31765370	To define the landscape of GPCRs in cancer, we undertook an integrated analysis of Differential Expression (DE), mutations, and copy number variation (CNV) of GPCRs, which are annotated by the Guide to Pharmacology database (GtoPdb), in 20 types of solid tumors (Table 1 and S1 and S2 Tables).	('GPCR', 'Gene', '148', (27, 31))	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('tumor', 'Phenotype', 'HP:0002664', (255, 260))	('cancer', 'Disease', (36, 42))	('solid tumors', 'Disease', 'MESH:D009369', (249, 261))	('tumors', 'Phenotype', 'HP:0002664', (255, 261))	('GPCR', 'Gene', (27, 31))	('mutations', 'Var', (113, 122))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('GPCR', 'Gene', '148', (159, 163))	('copy number variation', 'Var', (128, 149))	('solid tumors', 'Disease', (249, 261))	('GPCR', 'Gene', (159, 163))
207421	31765370	We compiled a list of GPCRs overexpressed in solid tumors with fold-changes and FDR along with expression in TPM (for median expression and within-group comparisons of different genes) and Counts Per Million (CPM; for intergroup comparisons of the same gene).	('TPM', 'Gene', (109, 112))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('GPCR', 'Gene', (22, 26))	('solid tumors', 'Disease', (45, 57))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('solid tumors', 'Disease', 'MESH:D009369', (45, 57))	('TPM', 'Chemical', '-', (109, 112))	('GPCR', 'Gene', '148', (22, 26))	('fold-changes', 'Var', (63, 75))
207472	31765370	EDNRB, which is highly overexpressed in SKCM, promotes migration and transformation of melanocytes and melanoma cells, and inhibition of EDNRB is pro-apoptotic.	('melanoma', 'Disease', 'MESH:D008545', (103, 111))	('EDNRB', 'Gene', (0, 5))	('inhibition', 'Var', (123, 133))	('migration', 'CPA', (55, 64))	('EDNRB', 'Gene', (137, 142))	('transformation', 'CPA', (69, 83))	('transformation of melanocytes', 'Phenotype', 'HP:0002861', (69, 98))	('EDNRB', 'Gene', '1910', (0, 5))	('promotes', 'PosReg', (46, 54))	('EDNRB', 'Gene', '1910', (137, 142))	('melanoma', 'Phenotype', 'HP:0002861', (103, 111))	('melanoma', 'Disease', (103, 111))
207486	31765370	GPCR expression appears largely independent of driver mutations, such as in BRCA HR+ IDC tumors with either PI3KA or TP53 mutations (Fig 7A-7C); both groups have similar GPCR expression and DE of the same GPCRs compared to normal breast tissue.	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('GPCR', 'Gene', '148', (0, 4))	('PI3KA', 'Gene', (108, 113))	('TP53', 'Gene', '7157', (117, 121))	('TP53', 'Gene', (117, 121))	('BRCA HR+ IDC tumors', 'Disease', 'MESH:D001919', (76, 95))	('BRCA', 'Phenotype', 'HP:0003002', (76, 80))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('GPCR', 'Gene', '148', (205, 209))	('GPCR', 'Gene', (0, 4))	('BRCA HR+ IDC tumors', 'Disease', (76, 95))	('mutations', 'Var', (122, 131))	('GPCR', 'Gene', '148', (170, 174))	('GPCR', 'Gene', (205, 209))	('GPCR', 'Gene', (170, 174))
207487	31765370	Similar results occur for lung adenocarcinoma (LUAD) and stomach adenocarcinoma (STAD) that have or lack TP53 mutations.	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (26, 45))	('mutations', 'Var', (110, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('stomach adenocarcinoma', 'Disease', (57, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (36, 45))	('TP53', 'Gene', '7157', (105, 109))	('lung adenocarcinoma', 'Disease', (26, 45))	('TP53', 'Gene', (105, 109))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (26, 45))	('LUAD', 'Phenotype', 'HP:0030078', (47, 51))	('stomach adenocarcinoma', 'Disease', 'MESH:D000230', (57, 79))
207511	31765370	In SKCM, which has the highest mutation burden among TCGA tumor types, the most highly overexpressed GPCRs (GPR143, EDNRB, and GPR56) are mutated in <2% of SKCM tumors, whereas frequently mutated GPCRs (e.g., GPR98, mutated in nearly 40% of tumors) typically have low expression.	('GPCR', 'Gene', '148', (196, 200))	('tumors', 'Disease', (161, 167))	('tumors', 'Disease', 'MESH:D009369', (241, 247))	('GPCR', 'Gene', (196, 200))	('GPCR', 'Gene', '148', (101, 105))	('GPR98', 'Gene', (209, 214))	('tumor', 'Disease', (161, 166))	('GPR56', 'Gene', (127, 132))	('GPCR', 'Gene', (101, 105))	('tumor', 'Disease', (58, 63))	('GPR143', 'Gene', (108, 114))	('tumor', 'Disease', (241, 246))	('SKCM tumors', 'Disease', (156, 167))	('SKCM tumors', 'Disease', 'MESH:D009369', (156, 167))	('tumors', 'Disease', 'MESH:D009369', (161, 167))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('EDNRB', 'Gene', '1910', (116, 121))	('tumor', 'Disease', 'MESH:D009369', (241, 246))	('EDNRB', 'Gene', (116, 121))	('GPR98', 'Gene', '84059', (209, 214))	('mutated', 'Var', (138, 145))	('tumors', 'Phenotype', 'HP:0002664', (241, 247))	('overexpressed', 'PosReg', (87, 100))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('GPR56', 'Gene', '9289', (127, 132))	('tumors', 'Phenotype', 'HP:0002664', (161, 167))	('tumors', 'Disease', (241, 247))	('GPR143', 'Gene', '4935', (108, 114))
207515	31765370	Furthermore, as discussed in the following sections on GPCR mutation, mutations to these GPCRs are predicted to have no functional impact and are not enriched significantly for mutations at specific sites; thus, overexpressed GPCRs in tumors are not expected to be altered in their function by mutations.	('GPCR', 'Gene', '148', (226, 230))	('mutations', 'Var', (70, 79))	('GPCR', 'Gene', '148', (89, 93))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('GPCR', 'Gene', (226, 230))	('GPCR', 'Gene', '148', (55, 59))	('tumors', 'Phenotype', 'HP:0002664', (235, 241))	('GPCR', 'Gene', (89, 93))	('GPCR', 'Gene', (55, 59))	('tumors', 'Disease', 'MESH:D009369', (235, 241))	('tumors', 'Disease', (235, 241))	('overexpressed', 'PosReg', (212, 225))
207517	31765370	Tissues and tumors typically express >150 GPCRs (at detection thresholds >0.1 TPM) that couple to the major types of G proteins (Gs, Gi/o, Gq/11, G12/13), most frequently Gi/Go and Gq/G11 (S7A and S7B Fig).	('Gi/Go', 'Var', (171, 176))	('S7', 'Gene', '6264', (189, 191))	('TPM', 'Chemical', '-', (78, 81))	('GPCR', 'Gene', '148', (42, 46))	('S7', 'Gene', '6264', (197, 199))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('tumors', 'Disease', (12, 18))	('GPCR', 'Gene', (42, 46))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('tumors', 'Disease', 'MESH:D009369', (12, 18))	('couple', 'Reg', (88, 94))
207559	31765370	Analysis of 5,103 TCGA samples in 20 tumor types (S3 Table; 21 tumor types if one divides ESCA into esophageal adenocarcinoma and squamous cell carcinomas) revealed many GPCRs with frequent nonsilent mutations (Figs 11A and S8A), including a more frequently mutated subset (Fig 11A, inset).	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('squamous cell carcinomas', 'Disease', (130, 154))	('mutations', 'Var', (200, 209))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('carcinomas', 'Phenotype', 'HP:0030731', (144, 154))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (100, 125))	('adenocarcinoma', 'Disease', 'MESH:D000230', (111, 125))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('GPCR', 'Gene', '148', (170, 174))	('GPCR', 'Gene', (170, 174))	('tumor', 'Disease', (63, 68))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (130, 154))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (130, 153))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (130, 154))	('tumor', 'Disease', (37, 42))	('adenocarcinoma', 'Disease', (111, 125))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
207562	31765370	SKCM has the highest frequency: approximately 40% of SKCM tumors have GPR98 mutations (Fig 11C and 11H).	('GPR98', 'Gene', (70, 75))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('mutations', 'Var', (76, 85))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('SKCM tumors', 'Disease', (53, 64))	('SKCM tumors', 'Disease', 'MESH:D009369', (53, 64))	('GPR98', 'Gene', '84059', (70, 75))
207564	31765370	Certain GPCRs are mutated in >10% of specific tumor types (Fig 11C).	('GPCR', 'Gene', (8, 12))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('mutated', 'Var', (18, 25))	('tumor', 'Disease', (46, 51))	('GPCR', 'Gene', '148', (8, 12))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
207566	31765370	Frequently mutated GPCRs (e.g., GPR98, GPR112, and BAI3) are more likely to be mutated as Nmut increases (Fig 11E, SKCM as an example).	('BAI3', 'Gene', (51, 55))	('GPCR', 'Gene', (19, 23))	('mutated', 'Var', (79, 86))	('GPR112', 'Gene', '139378', (39, 45))	('GPR98', 'Gene', (32, 37))	('GPR112', 'Gene', (39, 45))	('GPCR', 'Gene', '148', (19, 23))	('GPR98', 'Gene', '84059', (32, 37))	('BAI3', 'Gene', '577', (51, 55))
207567	31765370	The relationship between Nmut and likelihood of GPR98 mutation is similar in SKCM and other cancers (Fig 11F); this is also observed for other frequently mutated GPCRs.	('mutation', 'Var', (54, 62))	('cancers', 'Phenotype', 'HP:0002664', (92, 99))	('GPR98', 'Gene', '84059', (48, 53))	('cancers', 'Disease', 'MESH:D009369', (92, 99))	('GPCR', 'Gene', '148', (162, 166))	('SKCM', 'Disease', (77, 81))	('cancers', 'Disease', (92, 99))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('GPCR', 'Gene', (162, 166))	('GPR98', 'Gene', (48, 53))
207568	31765370	Hence, the likelihood of a GPCR being mutated appears to depend on the accumulation of genome damage and to be independent of the mechanisms for the mutations.	('GPCR', 'Gene', (27, 31))	('mutated', 'Var', (38, 45))	('GPCR', 'Gene', '148', (27, 31))
207570	31765370	Mutations of certain GPCRs, such as GPR98, may thus serve as a bellwether for genome-wide DNA damage.	('GPCR', 'Gene', '148', (21, 25))	('GPCR', 'Gene', (21, 25))	('Mutations', 'Var', (0, 9))	('GPR98', 'Gene', (36, 41))	('GPR98', 'Gene', '84059', (36, 41))
207571	31765370	Missense mutations and in-frame deletions are the most frequent nonsilent mutations in GPCR genes (S8C and S8D Fig and S5 Table).	('in-frame deletions', 'Var', (23, 41))	('GPCR', 'Gene', (87, 91))	('GPCR', 'Gene', '148', (87, 91))	('Missense mutations', 'Var', (0, 18))
207572	31765370	Mutations in frequently mutated GPCRs occur at many sites (S9A Fig), which contrasts with the smaller number of such sites in common oncogenes, e.g., KRAS.	('mutated', 'Var', (24, 31))	('GPCR', 'Gene', (32, 36))	('occur', 'Reg', (38, 43))	('Mutations', 'Var', (0, 9))	('GPCR', 'Gene', '148', (32, 36))	('KRAS', 'Gene', (150, 154))	('KRAS', 'Gene', '3845', (150, 154))
207573	31765370	Certain GPCR genes (e.g., GPR98) may be in genomic regions vulnerable to dysregulation of DNA damage and repair and belong to a subset of mutated genes; GPR98 mutations frequently occur alongside other frequently mutated genes such as TTN and MUC16 (S10A-S10G Fig).	('TTN', 'Gene', (235, 238))	('GPR98', 'Gene', '84059', (26, 31))	('GPCR', 'Gene', (8, 12))	('TTN', 'Gene', '7273', (235, 238))	('MUC16', 'Gene', '94025', (243, 248))	('mutations', 'Var', (159, 168))	('occur', 'Reg', (180, 185))	('GPR98', 'Gene', (153, 158))	('S10A', 'SUBSTITUTION', 'None', (250, 254))	('GPR98', 'Gene', (26, 31))	('GPR98', 'Gene', '84059', (153, 158))	('GPCR', 'Gene', '148', (8, 12))	('MUC16', 'Gene', (243, 248))	('S10G', 'Mutation', 'p.S10G', (255, 259))	('S10A', 'Var', (250, 254))
207579	31765370	Survival analysis of metastatic SKCM samples was performed in order to evaluate the impact on tumors of somatic nonsilent mutations to GPR98, GPR112, or other frequently mutated GPCRs.	('GPCR', 'Gene', '148', (178, 182))	('GPR112', 'Gene', '139378', (142, 148))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('GPR98', 'Gene', (135, 140))	('GPR112', 'Gene', (142, 148))	('mutations', 'Var', (122, 131))	('tumors', 'Disease', (94, 100))	('GPR98', 'Gene', '84059', (135, 140))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('GPCR', 'Gene', (178, 182))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))
207582	31765370	We find the same result in other tumor types as well and thus conclude that somatic nonsilent mutations to GPCRs have no impact on patient survival.	('mutations', 'Var', (94, 103))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('GPCR', 'Gene', '148', (107, 111))	('tumor', 'Disease', (33, 38))	('patient', 'Species', '9606', (131, 138))	('GPCR', 'Gene', (107, 111))
207585	31765370	As cell-surface receptors, frequently mutated, well-expressed GPCRs may represent neo-antigens.	('GPCR', 'Gene', '148', (62, 66))	('mutated', 'Var', (38, 45))	('cell-surface', 'Protein', (3, 15))	('GPCR', 'Gene', (62, 66))
207586	31765370	For SKCM, which has the most GPCR mutations among tumors types surveyed, DE analysis of primary melanomas and distant metastases that have or lack GPCR mutations (e.g., GPR98 and LPHN2) revealed little evidence that these mutations alter the tumor transcriptome, implying that such GPCR mutations are likely passenger, rather than driver, mutations (Figs 11H and S8C and S8D).	('LPHN2', 'Gene', '23266', (179, 184))	('melanomas', 'Phenotype', 'HP:0002861', (96, 105))	('mutations', 'Var', (287, 296))	('tumor', 'Disease', (242, 247))	('GPCR', 'Gene', '148', (29, 33))	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('GPCR', 'Gene', '148', (147, 151))	('GPCR', 'Gene', (29, 33))	('alter', 'Reg', (232, 237))	('tumor', 'Disease', 'MESH:D009369', (242, 247))	('GPCR', 'Gene', '148', (282, 286))	('GPR98', 'Gene', (169, 174))	('GPCR', 'Gene', (147, 151))	('mutations', 'Var', (222, 231))	('GPCR', 'Gene', (282, 286))	('tumor', 'Disease', (50, 55))	('LPHN2', 'Gene', (179, 184))	('melanomas', 'Disease', 'MESH:D008545', (96, 105))	('tumor', 'Phenotype', 'HP:0002664', (242, 247))	('melanomas', 'Disease', (96, 105))	('metastases', 'Disease', 'MESH:D009362', (118, 128))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('GPR98', 'Gene', '84059', (169, 174))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('metastases', 'Disease', (118, 128))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('melanoma', 'Phenotype', 'HP:0002861', (96, 104))	('tumors', 'Disease', (50, 56))
207587	31765370	Conversely, previous work has suggested that for known oncogenes (e.g., for TP53), there are often widespread transcriptomic changes associated with specific mutations.	('transcriptomic changes', 'MPA', (110, 132))	('mutations', 'Var', (158, 167))	('TP53', 'Gene', (76, 80))	('TP53', 'Gene', '7157', (76, 80))
207588	31765370	We found similar behavior for other tumors (e.g., BLCA) that have frequent GPCR mutations.	('GPCR', 'Gene', '148', (75, 79))	('tumors', 'Disease', 'MESH:D009369', (36, 42))	('mutations', 'Var', (80, 89))	('GPCR', 'Gene', (75, 79))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumors', 'Disease', (36, 42))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))	('BLCA', 'Phenotype', 'HP:0009725', (50, 54))
207589	31765370	As a further approach, we evaluated GPCR mutations, predicting the likelihood of functional consequences and site-specific enrichment of the mutations via MutSig 2CV version 3.1 (gdac.broadinstitute.org).	('GPCR', 'Gene', '148', (36, 40))	('GPCR', 'Gene', (36, 40))	('mutations', 'Var', (141, 150))
207590	31765370	The majority of GPCRs frequently mutated (Fig 11I, SKCM as example) show nonsilent mutations that are nonsignificant in terms of enrichment (compared to the background mutation rate of silent mutations over the same regions) for individual mutation sites.	('GPCR', 'Gene', '148', (16, 20))	('GPCR', 'Gene', (16, 20))	('mutated', 'Var', (33, 40))
207591	31765370	These mutations are not predicted to be functional (calculated from estimations of functional impact of mutations based on whether mutated regions are highly evolutionarily conserved) by MutSig 2CV, consistent with the idea that the frequent GPCR mutations are likely passenger and not driver mutations.	('mutations', 'Var', (247, 256))	('GPCR', 'Gene', '148', (242, 246))	('GPCR', 'Gene', (242, 246))
207597	31765370	Single-copy/heterozygous deletions of GPCRs are widespread, whereas homozygous deletions are rare (Fig 13A and 13D).	('GPCR', 'Gene', '148', (38, 42))	('Single-copy/heterozygous', 'Var', (0, 24))	('GPCR', 'Gene', (38, 42))
207598	31765370	GPCR genes with single-copy deletions are generally not significantly expressed in tumors or normal tissues, implying that such deletions lack functional effects, but exceptions exist.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('GPCR', 'Gene', '148', (0, 4))	('tumors', 'Disease', (83, 89))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('GPCR', 'Gene', (0, 4))	('tumors', 'Disease', 'MESH:D009369', (83, 89))	('single-copy deletions', 'Var', (16, 37))
207607	31765370	However, tumors with amplification of GPR160 show a higher likelihood (approximately 33%, p = 0.003, Fig 13H) of expressing GPR160 at levels above the median for OV.	('GPR160', 'Gene', '26996', (124, 130))	('GPR160', 'Gene', (124, 130))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('GPR160', 'Gene', (38, 44))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('OV', 'Phenotype', 'HP:0100615', (162, 164))	('tumors', 'Disease', (9, 15))	('amplification', 'Var', (21, 34))	('tumors', 'Disease', 'MESH:D009369', (9, 15))	('GPR160', 'Gene', '26996', (38, 44))
207612	31765370	In this study, we identified mutations, CNVs, and alterations in mRNA expression of GPCRs in a range of solid tumors.	('GPCR', 'Gene', (84, 88))	('mutations', 'Var', (29, 38))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('alterations', 'Reg', (50, 61))	('solid tumors', 'Disease', (104, 116))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('mRNA expression', 'MPA', (65, 80))	('GPCR', 'Gene', '148', (84, 88))	('solid tumors', 'Disease', 'MESH:D009369', (104, 116))
207614	31765370	Mutations of certain GPCRs have been implicated in cancer, but a comprehensive analysis of GPCR amplification, expression, and DE has been lacking.	('GPCR', 'Gene', '148', (21, 25))	('implicated', 'Reg', (37, 47))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('GPCR', 'Gene', (21, 25))	('GPCR', 'Gene', (91, 95))	('Mutations', 'Var', (0, 9))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('GPCR', 'Gene', '148', (91, 95))
207619	31765370	GPCR mutations appear to reflect accumulation of DNA damage and mutations across the genome and may be tumor markers for this process.	('DNA damage', 'MPA', (49, 59))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('GPCR', 'Gene', '148', (0, 4))	('tumor', 'Disease', (103, 108))	('mutations', 'Var', (5, 14))	('GPCR', 'Gene', (0, 4))	('mutations', 'Var', (64, 73))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
207625	31765370	Known driver mutations do not appear to influence GPCR expression in tumors, but we excluded rare mutations.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('GPCR', 'Gene', (50, 54))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('GPCR', 'Gene', '148', (50, 54))	('tumors', 'Disease', 'MESH:D009369', (69, 75))	('tumors', 'Disease', (69, 75))	('mutations', 'Var', (13, 22))
207657	31765370	GPCR mutations, CNV, and DE thus occur at a high frequency in solid tumors.	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('GPCR', 'Gene', '148', (0, 4))	('mutations', 'Var', (5, 14))	('GPCR', 'Gene', (0, 4))	('solid tumors', 'Disease', (62, 74))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('occur', 'Reg', (33, 38))	('solid tumors', 'Disease', 'MESH:D009369', (62, 74))
207674	31765370	The two methods yielded nearly identical results (S11C and S11D Fig).	('S11D', 'SUBSTITUTION', 'None', (59, 63))	('S11D', 'Var', (59, 63))	('S11C', 'SUBSTITUTION', 'None', (50, 54))	('S11C', 'Var', (50, 54))
207676	31765370	EBseq and edgeR yielded very similar results (S11A and S11B Fig), in particular for GPCRs, implying that assumptions implicit in the DE analysis via edgeR/TMM normalization do not skew or bias the results.	('GPCR', 'Gene', (84, 88))	('S11B', 'SUBSTITUTION', 'None', (55, 59))	('S11B', 'Var', (55, 59))	('S11A', 'Var', (46, 50))	('GPCR', 'Gene', '148', (84, 88))	('S11A', 'SUBSTITUTION', 'None', (46, 50))
207710	31765370	In general, DE of GPCRs is similar whether TCGA normal tissue or GTEx tissue is compared to TCGA tumor samples (e.g., S11E and S11F Fig), suggesting that such differences are unlikely to impact upon the general conclusions of this study.	('S11F', 'Mutation', 'p.S11F', (127, 131))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('S11F', 'Var', (127, 131))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('GPCR', 'Gene', '148', (18, 22))	('tumor', 'Disease', (97, 102))	('S11E', 'Mutation', 'p.S11E', (118, 122))	('GPCR', 'Gene', (18, 22))	('GTEx', 'Chemical', '-', (65, 69))
207721	31765370	This method was also used to evaluate the significance of associations between expression of GPCRs and presence of specific driver mutations (e.g., presence or absence of mutations to TP53 or KRAS) and association between GPCR mRNA expression and the thresholded GISTIC 2.0 CNV call.	('KRAS', 'Gene', '3845', (192, 196))	('absence', 'NegReg', (160, 167))	('association', 'Interaction', (202, 213))	('GPCR', 'Gene', (222, 226))	('TP53', 'Gene', '7157', (184, 188))	('GPCR', 'Gene', '148', (93, 97))	('TP53', 'Gene', (184, 188))	('KRAS', 'Gene', (192, 196))	('mutations', 'Var', (171, 180))	('GPCR', 'Gene', (93, 97))	('GPCR', 'Gene', '148', (222, 226))
207738	31567982	Genome hypomethylation and local hypermethylation are common in cancer tissues.	('local', 'MPA', (27, 32))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('Genome hypomethylation', 'Var', (0, 22))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
207739	31567982	Hypermethylation of the promoter of tumor-suppressor gene has its specific alteration pattern at all stages of the occurrence and development of many tumors, including cervical cancer.	('tumors', 'Disease', (150, 156))	('tumors', 'Disease', 'MESH:D009369', (150, 156))	('tumor-suppressor', 'Gene', '7248', (36, 52))	('tumors', 'Phenotype', 'HP:0002664', (150, 156))	('Hypermethylation', 'Var', (0, 16))	('tumor-suppressor', 'Gene', (36, 52))	('cervical cancer', 'Disease', 'MESH:D002583', (168, 183))	('alteration', 'Reg', (75, 85))	('cervical cancer', 'Disease', (168, 183))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))
207740	31567982	In the course of progression, hypermethylation of promoters causes inactivation of different tumor-suppressor genes.	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor-suppressor', 'Gene', (93, 109))	('inactivation', 'MPA', (67, 79))	('tumor-suppressor', 'Gene', '7248', (93, 109))	('hypermethylation', 'Var', (30, 46))
207741	31567982	The cumulative effect of epigenetic changes plays an important role in the development of cervical cancer from normal tissues and precancerous lesions.	('precancerous lesions', 'Disease', 'MESH:D011230', (130, 150))	('epigenetic changes', 'Var', (25, 43))	('precancerous lesions', 'Disease', (130, 150))	('cervical cancer', 'Disease', (90, 105))	('cervical cancer', 'Disease', 'MESH:D002583', (90, 105))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
207743	31567982	The epigenetic changes represented by DNA methylation can lead to cervical cancer.	('epigenetic changes', 'Var', (4, 22))	('lead to', 'Reg', (58, 65))	('cervical cancer', 'Disease', (66, 81))	('cervical cancer', 'Disease', 'MESH:D002583', (66, 81))	('DNA methylation', 'Var', (38, 53))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))
207746	31567982	In the present study, we used Infinium MethylationEPIC BeadChip (850K) technology from Illumina to screen abnormal methylation gene in cervical adenocarcinoma, and bisulfite sequencing PCR (BSP) and quantitative real-time polymerase chain reaction (qRT-PCR) to verify these results.	('methylation', 'Var', (115, 126))	('carcinoma', 'Phenotype', 'HP:0030731', (149, 158))	('bisulfite', 'Chemical', 'MESH:C042345', (164, 173))	('cervical adenocarcinoma', 'Disease', (135, 158))	('cervical adenocarcinoma', 'Disease', 'MESH:D000230', (135, 158))
207761	31567982	2B), and the methylation percentages for cervical adenocarcinoma, cervical squamous cell carcinoma, and normal cervical tissues were 97.50%, 87.08%, and 41.26%, respectively.	('cervical squamous cell carcinoma', 'Disease', 'MESH:D002294', (66, 98))	('methylation', 'Var', (13, 24))	('carcinoma', 'Phenotype', 'HP:0030731', (55, 64))	('cervical squamous cell carcinoma', 'Disease', (66, 98))	('cervical adenocarcinoma', 'Disease', 'MESH:D000230', (41, 64))	('cervical adenocarcinoma', 'Disease', (41, 64))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (75, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))
207770	31567982	The DeltaCt values of SOX1 gene in cervical adenocarcinoma tissues, cervical squamous cell carcinoma tissues, and normal cervical tissues were 15.0080 +- 1.8648 (F = 0.7200 +- 0.6630), 12.5183 +- 0.3462 (F = 2.3200 +- 0.4990), and 12.5717 +- 1.9868 (F = 4.2000 +- 4.1070), respectively (Fig.	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('cervical adenocarcinoma tissues', 'Disease', (35, 66))	('cervical squamous cell carcinoma', 'Disease', (68, 100))	('15.0080 +- 1.8648', 'Var', (143, 160))	('cervical squamous cell carcinoma', 'Disease', 'MESH:D002294', (68, 100))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (77, 100))	('SOX1', 'Gene', '6656', (22, 26))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('12.5717 +- 1.9868', 'Var', (231, 248))	('SOX1', 'Gene', (22, 26))	('12.5183 +- 0.3462', 'Var', (185, 202))	('cervical adenocarcinoma tissues', 'Disease', 'MESH:D002583', (35, 66))
207771	31567982	In addition, the DeltaCt values of CCND1 gene in cervical adenocarcinoma tissues, cervical squamous cell carcinoma tissues, and normal cervical tissues were 6.1200 +- 1.6130 (F = 0.6200 +- 0.5290), 5.2200 +- 0.2020 (F = 0.7500 +- 0.1080), and 2.3600 +- 1.6960 (F = 8.7900 +- 7.6660), respectively (Fig.	('cervical adenocarcinoma tissues', 'Disease', (49, 80))	('cervical squamous cell carcinoma', 'Disease', (82, 114))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))	('CCND1', 'Gene', '595', (35, 40))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (91, 114))	('cervical adenocarcinoma tissues', 'Disease', 'MESH:D002583', (49, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('6.1200 +- 1.6130', 'Var', (157, 173))	('cervical squamous cell carcinoma', 'Disease', 'MESH:D002294', (82, 114))	('CCND1', 'Gene', (35, 40))
207773	31567982	The expression of methylated SOX1 or CCND1 in cervical adenocarcinoma tissues was significantly different from that in normal cervical tissues (P < .05) (Table 4).	('different', 'Reg', (96, 105))	('cervical adenocarcinoma tissues', 'Disease', (46, 77))	('CCND1', 'Gene', (37, 42))	('SOX1', 'Gene', '6656', (29, 33))	('expression', 'MPA', (4, 14))	('methylated', 'Var', (18, 28))	('CCND1', 'Gene', '595', (37, 42))	('carcinoma', 'Phenotype', 'HP:0030731', (60, 69))	('SOX1', 'Gene', (29, 33))	('cervical adenocarcinoma tissues', 'Disease', 'MESH:D002583', (46, 77))
207774	31567982	Moreover, the expression of methylated CCND1 in cervical squamous cell carcinoma tissues was significantly different from that in normal cervical tissues (P < .05), but the expression of methylated SOX1 in cervical squamous cell carcinoma tissues was not significantly different from that in normal cervical tissues (P > .05) (Table 5).	('cervical squamous cell carcinoma', 'Disease', 'MESH:D002294', (48, 80))	('CCND1', 'Gene', (39, 44))	('methylated', 'Var', (28, 38))	('cervical squamous cell carcinoma', 'Disease', (206, 238))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (57, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (229, 238))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('different', 'Reg', (107, 116))	('SOX1', 'Gene', '6656', (198, 202))	('cervical squamous cell carcinoma', 'Disease', (48, 80))	('expression', 'MPA', (14, 24))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (215, 238))	('SOX1', 'Gene', (198, 202))	('CCND1', 'Gene', '595', (39, 44))	('cervical squamous cell carcinoma', 'Disease', 'MESH:D002294', (206, 238))
207779	31567982	DNA methylation is the most common epigenetic alteration of key genes in cervical cancer, and it often occurs at the early stage of cervical cancer and causes abnormal gene expression in promoter region, which leads to tumorigenesis.	('cervical cancer', 'Disease', (132, 147))	('cervical cancer', 'Disease', 'MESH:D002583', (132, 147))	('cervical cancer', 'Disease', 'MESH:D002583', (73, 88))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('tumor', 'Disease', (219, 224))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('promoter', 'MPA', (187, 195))	('abnormal', 'Var', (159, 167))	('leads to', 'Reg', (210, 218))	('gene expression', 'MPA', (168, 183))	('occurs', 'Reg', (103, 109))	('tumor', 'Disease', 'MESH:D009369', (219, 224))	('causes', 'Reg', (152, 158))	('cervical cancer', 'Disease', (73, 88))
207780	31567982	DNA methylation occurs in about 70% to 100% of cervical cancer cases, and can also be detected in 30% to 80% of precancerous cervical lesions.	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('methylation', 'Var', (4, 15))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('cervical cancer', 'Disease', (47, 62))	('cervical cancer', 'Disease', 'MESH:D002583', (47, 62))	('precancerous cervical lesions', 'Disease', (112, 141))	('precancerous cervical lesions', 'Disease', 'MESH:D011230', (112, 141))
207787	31567982	Hypermethylation of gene promoter region that leads to inactivation of tumor-suppressor genes is an early event in tumorigenesis.	('inactivation', 'MPA', (55, 67))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumor-suppressor', 'Gene', '7248', (71, 87))	('Hypermethylation', 'Var', (0, 16))	('tumor', 'Disease', (115, 120))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor-suppressor', 'Gene', (71, 87))	('tumor', 'Disease', (71, 76))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
207789	31567982	It is proposed that the methylation status of paired box1 and SOX1 may be a new molecular marker for colorectal cancer screening.	('paired box1', 'Gene', '5075', (46, 57))	('SOX1', 'Gene', '6656', (62, 66))	('colorectal cancer', 'Disease', 'MESH:D015179', (101, 118))	('SOX1', 'Gene', (62, 66))	('paired box1', 'Gene', (46, 57))	('colorectal cancer', 'Phenotype', 'HP:0003003', (101, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('colorectal cancer', 'Disease', (101, 118))	('methylation status', 'Var', (24, 42))
207790	31567982	There was a significant correlation between the down-regulation of SOX1 expression and the methylation of SOX1 promoter in primary hepatocellular carcinoma, and the methylation rate is 57.30%, being significantly higher than that in chronic hepatitis and cirrhosis.	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('down-regulation', 'NegReg', (48, 63))	('chronic hepatitis and cirrhosis', 'Disease', 'MESH:D006521', (233, 264))	('hepatitis', 'Phenotype', 'HP:0012115', (241, 250))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (131, 155))	('methylation', 'Var', (165, 176))	('higher', 'PosReg', (213, 219))	('hepatocellular carcinoma', 'Disease', (131, 155))	('expression', 'MPA', (72, 82))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (131, 155))	('SOX1', 'Gene', '6656', (67, 71))	('cirrhosis', 'Phenotype', 'HP:0001394', (255, 264))	('SOX1', 'Gene', '6656', (106, 110))	('methylation', 'MPA', (91, 102))	('SOX1', 'Gene', (67, 71))	('chronic hepatitis', 'Phenotype', 'HP:0200123', (233, 250))	('SOX1', 'Gene', (106, 110))
207797	31567982	It is reported that polymorphism CCND1 increases the risk of lung cancer among smokers in northern India and may be associated with overall survival in patients with small cell lung cancer.	('lung cancer', 'Disease', (61, 72))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('lung cancer', 'Phenotype', 'HP:0100526', (61, 72))	('polymorphism', 'Var', (20, 32))	('associated with', 'Reg', (116, 131))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (166, 188))	('CCND1', 'Gene', (33, 38))	('lung cancer', 'Disease', 'MESH:D008175', (177, 188))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('small cell lung cancer', 'Disease', (166, 188))	('lung cancer', 'Disease', 'MESH:D008175', (61, 72))	('CCND1', 'Gene', '595', (33, 38))	('increases', 'PosReg', (39, 48))	('lung cancer', 'Phenotype', 'HP:0100526', (177, 188))	('patients', 'Species', '9606', (152, 160))	('small cell lung cancer', 'Disease', 'MESH:D055752', (166, 188))
207799	31567982	In addition, the epigenetic negative regulation of CCND1 by microRNA-490 is the key to glioma, and it provides a new perspective for the diagnosis, treatment, prognosis, and further transformation of glioma.	('glioma', 'Disease', (200, 206))	('CCND1', 'Gene', (51, 56))	('glioma', 'Disease', (87, 93))	('CCND1', 'Gene', '595', (51, 56))	('glioma', 'Disease', 'MESH:D005910', (200, 206))	('glioma', 'Phenotype', 'HP:0009733', (200, 206))	('glioma', 'Disease', 'MESH:D005910', (87, 93))	('glioma', 'Phenotype', 'HP:0009733', (87, 93))	('epigenetic', 'Var', (17, 27))	('microRNA-490', 'Gene', (60, 72))
207803	31567982	Hypermethylation of SOX1 promoter region is an important event in the occurrence and development of cervical adenocarcinoma and is expected to become a specific molecular marker for the diagnosis of cervical adenocarcinoma.	('SOX1', 'Gene', (20, 24))	('cervical adenocarcinoma', 'Disease', 'MESH:D000230', (199, 222))	('Hypermethylation', 'Var', (0, 16))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('cervical adenocarcinoma', 'Disease', (199, 222))	('cervical adenocarcinoma', 'Disease', 'MESH:D000230', (100, 123))	('cervical adenocarcinoma', 'Disease', (100, 123))	('carcinoma', 'Phenotype', 'HP:0030731', (213, 222))	('SOX1', 'Gene', '6656', (20, 24))
207812	31259255	The overall survival rate of patients with high expression of CENPE was poor, and the prognosis of patients with low expression of CENPE was better (P<0.05).	('patients', 'Species', '9606', (29, 37))	('high', 'Var', (43, 47))	('CENPE', 'Gene', (62, 67))	('CENPE', 'Gene', (131, 136))	('patients', 'Species', '9606', (99, 107))	('CENPE', 'Gene', '1062', (62, 67))	('CENPE', 'Gene', '1062', (131, 136))	('poor', 'NegReg', (72, 76))
207820	31259255	The kinesin superfamily is a kind of microtubule-based molecular motor protein, which mediates a variety of functions, and its abnormal expression plays an important role in the occurrence and development of tumors.	('abnormal', 'Var', (127, 135))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('tumors', 'Disease', (208, 214))	('tumors', 'Phenotype', 'HP:0002664', (208, 214))	('tumors', 'Disease', 'MESH:D009369', (208, 214))	('plays', 'Reg', (147, 152))
207839	31259255	The overall survival time of patients with CENPE high expression group was significantly lower than that of the low expression group.	('lower', 'NegReg', (89, 94))	('patients', 'Species', '9606', (29, 37))	('CENPE', 'Gene', '1062', (43, 48))	('high expression', 'Var', (49, 64))	('CENPE', 'Gene', (43, 48))
207853	31259255	In vivo and in vitro experiments have demonstrated that genetic deletion or pharmacological inhibition of CENPE significantly inhibits the proliferation of prostate cancer cells.	('inhibits', 'NegReg', (126, 134))	('prostate cancer', 'Disease', (156, 171))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('CENPE', 'Gene', '1062', (106, 111))	('prostate cancer', 'Disease', 'MESH:D011471', (156, 171))	('proliferation', 'CPA', (139, 152))	('genetic deletion', 'Var', (56, 72))	('prostate cancer', 'Phenotype', 'HP:0012125', (156, 171))	('CENPE', 'Gene', (106, 111))
207866	29259311	The OS and CSS rates were significantly worse in the elevated CRP group than in the normal CRP group, according to Kaplan-Meier survival curves analysed by a Log-rank test (p = 0.005 and p < 0.001, respectively).	('OS', 'Chemical', '-', (4, 6))	('CRP', 'Gene', '1401', (62, 65))	('CRP', 'Gene', (91, 94))	('elevated CRP', 'Phenotype', 'HP:0011227', (53, 65))	('CRP', 'Gene', '1401', (91, 94))	('elevated', 'Var', (53, 61))	('CRP', 'Gene', (62, 65))	('CSS rates', 'CPA', (11, 20))	('CSS', 'Chemical', '-', (11, 14))	('worse', 'NegReg', (40, 45))
207877	29259311	Although various factors have been suggested as prognostic indicators in cancer patient, measurements of CRP seem to be a fast, simple and cost-effective predictor in clinical practice.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('CRP', 'Gene', (105, 108))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('measurements', 'Var', (89, 101))	('CRP', 'Gene', '1401', (105, 108))	('patient', 'Species', '9606', (80, 87))
207882	29259311	The results of the Radiation Therapy Oncology Group 91-11 study revealed that cisplatin-radiotherapy is superior in loco regional control and larynx preservation compared with induction chemotherapy.	('Oncology', 'Phenotype', 'HP:0002664', (37, 45))	('cisplatin-radiotherapy', 'Var', (78, 100))	('larynx preservation', 'CPA', (142, 161))	('cisplatin', 'Chemical', 'MESH:D002945', (78, 87))	('loco regional control', 'CPA', (116, 137))
207916	29259311	The OS and CSS rates were significantly worse in the elevated CRP group than in the normal CRP group, according to a comparison of Kaplan-Meier curves analysed by a Log-rank test (p = 0.005 and p < 0.001) (Fig.	('OS', 'Chemical', '-', (4, 6))	('CRP', 'Gene', (91, 94))	('elevated CRP', 'Phenotype', 'HP:0011227', (53, 65))	('CRP', 'Gene', '1401', (91, 94))	('elevated', 'Var', (53, 61))	('CRP', 'Gene', (62, 65))	('CRP', 'Gene', '1401', (62, 65))	('CSS', 'Chemical', '-', (11, 14))	('worse', 'NegReg', (40, 45))
207983	33270369	At present, these drugs are used in clinical practice or ongoing clinical trials on EGFR mutations, ALK rearrangements, ROS1 rearrangements, BRAF V600E mutation, MET exon 14 splice site, and KRAS G12c mutation-positive NSCLC treatment.	('NSCLC', 'Disease', (219, 224))	('ROS1', 'Gene', (120, 124))	('BRAF', 'Gene', (141, 145))	('KRAS', 'Gene', (191, 195))	('ROS1', 'Gene', '6098', (120, 124))	('NSCLC', 'Disease', 'MESH:D002289', (219, 224))	('MET', 'Gene', '79811', (162, 165))	('EGFR', 'Gene', '1956', (84, 88))	('ALK', 'Gene', (100, 103))	('KRAS', 'Gene', '3845', (191, 195))	('NSCLC', 'Phenotype', 'HP:0030358', (219, 224))	('mutations', 'Var', (89, 98))	('EGFR', 'Gene', (84, 88))	('MET', 'Gene', (162, 165))	('BRAF', 'Gene', '673', (141, 145))	('V600E', 'Mutation', 'rs113488022', (146, 151))	('ALK', 'Gene', '238', (100, 103))
207984	33270369	1 ,  2 ,  3 ,  4 ,  5 ,  6 ,  7 ,  8 ,  9 ,  10  In NSCLC harboring driver gene mutations, the effects of molecular targeted drugs are generally better than those of cytotoxic agents.	('NSCLC', 'Disease', (52, 57))	('mutations', 'Var', (80, 89))	('NSCLC', 'Disease', 'MESH:D002289', (52, 57))	('better', 'PosReg', (145, 151))	('NSCLC', 'Phenotype', 'HP:0030358', (52, 57))
208027	33270369	A total of 45 patients underwent NGS analysis using bronchoscopy samples to detect driver gene mutations, while NGS analysis was not performed in the remaining 20 patients based on the judgment of the attending physicians.	('patients', 'Species', '9606', (14, 22))	('driver gene', 'Gene', (83, 94))	('patients', 'Species', '9606', (163, 171))	('mutations', 'Var', (95, 104))
208047	33270369	The following driver gene mutations were detected via NGS analysis: EGFR 5, KRAS 3, ERBB 2, MET 1, and PIK3CA 1 in the TBLC group and EGFR 1, KRAS 1, MET 1, ROS1 1, and PIK3CA 1 in the TBNA group.	('MET 1', 'Gene', (92, 97))	('KRAS', 'Gene', '3845', (76, 80))	('mutations', 'Var', (26, 35))	('KRAS 1', 'Gene', (142, 148))	('PIK3CA', 'Gene', '5290', (103, 109))	('EGFR', 'Gene', '1956', (134, 138))	('KRAS 1', 'Gene', '3845', (142, 148))	('KRAS', 'Gene', (76, 80))	('ROS1', 'Gene', (157, 161))	('EGFR', 'Gene', '1956', (68, 72))	('ERBB 2', 'Gene', '2064', (84, 90))	('PIK3CA', 'Gene', (169, 175))	('ERBB 2', 'Gene', (84, 90))	('MET 1', 'Gene', '3004', (150, 155))	('KRAS', 'Gene', '3845', (142, 146))	('PIK3CA', 'Gene', (103, 109))	('EGFR 5', 'Gene', (68, 74))	('KRAS', 'Gene', (142, 146))	('MET 1', 'Gene', '3004', (92, 97))	('MET 1', 'Gene', (150, 155))	('EGFR', 'Gene', (134, 138))	('ROS1', 'Gene', '6098', (157, 161))	('EGFR 5', 'Gene', '161198', (68, 74))	('TBLC', 'Chemical', '-', (119, 123))	('TBNA', 'Chemical', '-', (185, 189))	('EGFR', 'Gene', (68, 72))	('PIK3CA', 'Gene', '5290', (169, 175))
208134	30692511	Total RNA was isolated from the A549 cells with linc00665 knockdown and control A549 cells.	('linc00665', 'Gene', '100506930', (48, 57))	('A549', 'CellLine', 'CVCL:0023', (80, 84))	('A549', 'CellLine', 'CVCL:0023', (32, 36))	('linc00665', 'Gene', (48, 57))	('knockdown', 'Var', (58, 67))
208156	30692511	Consistently, analysis of TCGA-LUAD datasets by using "Kaplan-Meier Plotter" (http://www.kmplot.com/analysis/index.php?p=service&cancer=lung) also showed that patients with high linc00665 expression in LUAD tissues suffered worse overall survival (p = 0.0085, supplementary Figure 3a).	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('linc00665', 'Gene', '100506930', (178, 187))	('with', 'Var', (168, 172))	('LUAD', 'Phenotype', 'HP:0030078', (31, 35))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('linc00665', 'Gene', (178, 187))	('high', 'Gene', (173, 177))	('suffered', 'NegReg', (215, 223))	('worse', 'MPA', (224, 229))	('patients', 'Species', '9606', (159, 167))	('LUAD', 'Phenotype', 'HP:0030078', (202, 206))
208164	30692511	In both A549 and H1299 cell lines, siRNA-mediated knockdown and plasmid-mediated overexpression were conducted for manipulating linc00665 expression, which was validated by qRT-PCR (Fig.	('linc00665', 'Gene', (128, 137))	('expression', 'MPA', (138, 148))	('A549', 'CellLine', 'CVCL:0023', (8, 12))	('linc00665', 'Gene', '100506930', (128, 137))	('H1299', 'CellLine', 'CVCL:0060', (17, 22))	('manipulating', 'Var', (115, 127))
208167	30692511	Functionally, CCK-8 assays showed that linc00665 knockdown significantly inhibited vitality of A549 and H1299 cells, whereas linc00665 overexpression promoted cell proliferation in comparison with that of their counterparts (Fig.	('knockdown', 'Var', (49, 58))	('H1299', 'CellLine', 'CVCL:0060', (104, 109))	('linc00665', 'Gene', (39, 48))	('promoted', 'PosReg', (150, 158))	('linc00665', 'Gene', '100506930', (125, 134))	('A549', 'CellLine', 'CVCL:0023', (95, 99))	('cell proliferation', 'CPA', (159, 177))	('inhibited', 'NegReg', (73, 82))	('linc00665', 'Gene', (125, 134))	('linc00665', 'Gene', '100506930', (39, 48))
208168	30692511	Similarly, colony formation assays revealed that linc00665 knockdown caused a remarkable decrease in clonogenic survival of A549 and H1299 cells, and that linc00665 overexpression exhibited a significant increase in the clonogenic survival (Fig.	('linc00665', 'Gene', (49, 58))	('clonogenic survival', 'CPA', (220, 239))	('A549', 'CellLine', 'CVCL:0023', (124, 128))	('increase', 'PosReg', (204, 212))	('decrease', 'NegReg', (89, 97))	('linc00665', 'Gene', '100506930', (49, 58))	('linc00665', 'Gene', '100506930', (155, 164))	('H1299', 'CellLine', 'CVCL:0060', (133, 138))	('overexpression', 'PosReg', (165, 179))	('knockdown', 'Var', (59, 68))	('linc00665', 'Gene', (155, 164))
208169	30692511	Notably, the proliferation promoted by linc00665 overexpression in CCK-8 and colony formation assays could be reversed by subsequent linc00665 knockdown in A549 and H1299 cells (supplementary Figure 4).	('proliferation', 'CPA', (13, 26))	('linc00665', 'Gene', (133, 142))	('linc00665', 'Gene', (39, 48))	('A549', 'CellLine', 'CVCL:0023', (156, 160))	('colony formation assays', 'CPA', (77, 100))	('overexpression', 'PosReg', (49, 63))	('knockdown', 'Var', (143, 152))	('H1299', 'CellLine', 'CVCL:0060', (165, 170))	('linc00665', 'Gene', '100506930', (133, 142))	('linc00665', 'Gene', '100506930', (39, 48))
208171	30692511	Furthermore, wound-healing assays and transwell migration assays indicated that linc00665 knockdown markedly suppressed the migration ability of A549 and H1299 cells, whereas linc00665 overexpression facilitated cell migration (Fig.	('suppressed', 'NegReg', (109, 119))	('linc00665', 'Gene', (80, 89))	('cell migration', 'CPA', (212, 226))	('knockdown', 'Var', (90, 99))	('linc00665', 'Gene', '100506930', (175, 184))	('migration ability', 'CPA', (124, 141))	('linc00665', 'Gene', '100506930', (80, 89))	('linc00665', 'Gene', (175, 184))	('A549', 'CellLine', 'CVCL:0023', (145, 149))	('H1299', 'CellLine', 'CVCL:0060', (154, 159))	('facilitated', 'PosReg', (200, 211))
208178	30692511	Western blot data showed that linc00665 knockdown significantly elevated the expression of epithelial marker E-cadherin and decreased the levels of mesenchymal marker Vimentin and N-cadherin in A549 and H1299 cells (Fig.	('H1299', 'CellLine', 'CVCL:0060', (203, 208))	('Vimentin', 'Gene', '7431', (167, 175))	('linc00665', 'Gene', '100506930', (30, 39))	('elevated', 'PosReg', (64, 72))	('knockdown', 'Var', (40, 49))	('E-cadherin', 'Gene', (109, 119))	('N-cadherin', 'Gene', (180, 190))	('decreased', 'NegReg', (124, 133))	('linc00665', 'Gene', (30, 39))	('E-cadherin', 'Gene', '999', (109, 119))	('A549', 'CellLine', 'CVCL:0023', (194, 198))	('N-cadherin', 'Gene', '1000', (180, 190))	('Vimentin', 'Gene', (167, 175))
208181	30692511	Linc00665 knockdown in A549 and H1299 cells induced cell cycle arrest at G0/G1 phase and a decrease of cells at S phase compared with negative control (Fig.	('cell cycle arrest', 'Phenotype', 'HP:0011018', (52, 69))	('arrest', 'Disease', 'MESH:D006323', (63, 69))	('Linc00665', 'Gene', '100506930', (0, 9))	('cells at S phase', 'CPA', (103, 119))	('H1299', 'CellLine', 'CVCL:0060', (32, 37))	('arrest', 'Disease', (63, 69))	('Linc00665', 'Gene', (0, 9))	('A549', 'CellLine', 'CVCL:0023', (23, 27))	('knockdown', 'Var', (10, 19))	('decrease', 'NegReg', (91, 99))
208182	30692511	Meanwhile, the proportion of apoptotic cells was significantly increased following linc00665 knockdown in A549 and H1299 cells (Fig.	('knockdown', 'Var', (93, 102))	('H1299', 'CellLine', 'CVCL:0060', (115, 120))	('increased', 'PosReg', (63, 72))	('linc00665', 'Gene', '100506930', (83, 92))	('linc00665', 'Gene', (83, 92))	('apoptotic cells', 'CPA', (29, 44))	('A549', 'CellLine', 'CVCL:0023', (106, 110))
208183	30692511	Consistently, expression levels of apoptosis-related proteins, including Bax, Cleaved Caspase-3, and Cleaved poly ADP-ribose polymerase (PARP), were markedly increased in linc00665 knockdown A549 and H1299 cells, whereas Bcl-2 expression was significantly diminished compared with negative controls (Fig.	('Bax', 'Gene', (73, 76))	('linc00665', 'Gene', '100506930', (171, 180))	('PARP', 'Gene', (137, 141))	('expression levels', 'MPA', (14, 31))	('H1299', 'CellLine', 'CVCL:0060', (200, 205))	('Bcl-2', 'Gene', (221, 226))	('Bcl-2', 'Gene', '596', (221, 226))	('poly ADP-ribose polymerase', 'Gene', (109, 135))	('Caspase-3', 'Gene', (86, 95))	('linc00665', 'Gene', (171, 180))	('PARP', 'Gene', '142', (137, 141))	('Bax', 'Gene', '581', (73, 76))	('Caspase-3', 'Gene', '836', (86, 95))	('poly ADP-ribose polymerase', 'Gene', '142', (109, 135))	('A549', 'CellLine', 'CVCL:0023', (191, 195))	('knockdown', 'Var', (181, 190))	('increased', 'PosReg', (158, 167))
208184	30692511	Collectively, these results showed that linc00665 knockdown led to promotion of the proportion of G0/G1 phase and cell apoptosis.	('linc00665', 'Gene', '100506930', (40, 49))	('proportion of G0/G1 phase', 'CPA', (84, 109))	('knockdown', 'Var', (50, 59))	('linc00665', 'Gene', (40, 49))	('promotion', 'PosReg', (67, 76))	('cell apoptosis', 'CPA', (114, 128))
208190	30692511	Notably, metastatic lung nodes were observed in 4 of the 10 xenograft mice treated with A549/shRNA-NC, whereas none metastatic lung node was found in linc00665-silenced groups (Fig.	('observed', 'Reg', (36, 44))	('metastatic lung nodes', 'CPA', (9, 30))	('A549/shRNA-NC', 'Var', (88, 101))	('linc00665', 'Gene', (150, 159))	('mice', 'Species', '10090', (70, 74))	('A549', 'CellLine', 'CVCL:0023', (88, 92))	('linc00665', 'Gene', '100506930', (150, 159))
208191	30692511	Taken together, these data implied that knockdown of linc00665 inhibited tumor growth and metastasis in vivo.	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('linc00665', 'Gene', (53, 62))	('knockdown', 'Var', (40, 49))	('tumor', 'Disease', (73, 78))	('inhibited', 'NegReg', (63, 72))	('linc00665', 'Gene', '100506930', (53, 62))
208192	30692511	To assess linc00665-associated gene expression profiles in LUAD, RNA transcriptome sequencing was carried out with linc00665 knockdown A549 cells and control cells.	('LUAD', 'Phenotype', 'HP:0030078', (59, 63))	('linc00665', 'Gene', (115, 124))	('knockdown', 'Var', (125, 134))	('linc00665', 'Gene', '100506930', (10, 19))	('linc00665', 'Gene', '100506930', (115, 124))	('A549', 'CellLine', 'CVCL:0023', (135, 139))	('linc00665', 'Gene', (10, 19))
208194	30692511	Accordingly, expression of selective oncogenes or tumor suppressor genes was examined by qRT-PCR in linc00665 knockdown A549 cells and control cells.	('knockdown', 'Var', (110, 119))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('linc00665', 'Gene', '100506930', (100, 109))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Disease', (50, 55))	('linc00665', 'Gene', (100, 109))	('A549', 'CellLine', 'CVCL:0023', (120, 124))
208202	30692511	Analysis of TCGA survival data revealed that high AKR1B10 expression in LUAD was correlated with poor overall survival (supplementary Figure 3b) and that the cohorts with synchronously high expressions of linc00665 and AKR1B10 in LUAD tissues had the worst 5-year overall survival (p = 0.005, supplementary Figure 3c).	('overall survival', 'MPA', (264, 280))	('worst', 'NegReg', (251, 256))	('AKR1B10', 'Gene', (219, 226))	('AKR1B10', 'Gene', '57016', (219, 226))	('LUAD', 'Phenotype', 'HP:0030078', (230, 234))	('expression', 'MPA', (58, 68))	('linc00665', 'Gene', (205, 214))	('LUAD', 'Phenotype', 'HP:0030078', (72, 76))	('high', 'Var', (45, 49))	('overall survival', 'MPA', (102, 118))	('AKR1B10', 'Gene', '57016', (50, 57))	('AKR1B10', 'Gene', (50, 57))	('linc00665', 'Gene', '100506930', (205, 214))	('poor', 'NegReg', (97, 101))
208206	30692511	The results indicated that p-ERK1/2, MMP2 and vimentin were upregulated in linc00665 overexpressed cells, whereas their expression levels were decreased in AKR1B10 knockdown cells.	('p-ERK', 'Gene', '9451', (27, 32))	('p-ERK', 'Gene', (27, 32))	('upregulated', 'PosReg', (60, 71))	('vimentin', 'Protein', (46, 54))	('ERK1/2', 'Gene', '5595', (29, 35))	('ERK1/2', 'Gene', (29, 35))	('linc00665', 'Gene', (75, 84))	('AKR1B10', 'Gene', '57016', (156, 163))	('overexpressed', 'Var', (85, 98))	('MMP2', 'Gene', (37, 41))	('linc00665', 'Gene', '100506930', (75, 84))	('AKR1B10', 'Gene', (156, 163))	('expression levels', 'MPA', (120, 137))
208208	30692511	ERK signaling pathway has been well documented in the regulation of cell growth and differentiation, and improperly activation contributes to malignant transformation.	('contributes', 'Reg', (127, 138))	('malignant transformation', 'CPA', (142, 166))	('improperly', 'Var', (105, 115))	('ERK', 'Gene', '5594', (0, 3))	('ERK', 'Gene', (0, 3))
208214	30692511	In A549 and H1299 cells, linc00665 knockdown enhanced miR-98 expression, whereas linc00665 overexpression significantly reduced miR-98 levels (Fig.	('miR-98', 'Gene', (128, 134))	('knockdown', 'Var', (35, 44))	('A549', 'CellLine', 'CVCL:0023', (3, 7))	('reduced', 'NegReg', (120, 127))	('linc00665', 'Gene', '100506930', (25, 34))	('miR-98', 'Gene', '407054', (54, 60))	('enhanced', 'PosReg', (45, 53))	('H1299', 'CellLine', 'CVCL:0060', (12, 17))	('miR-98', 'Gene', (54, 60))	('linc00665', 'Gene', '100506930', (81, 90))	('linc00665', 'Gene', (81, 90))	('miR-98', 'Gene', '407054', (128, 134))	('expression', 'MPA', (61, 71))	('linc00665', 'Gene', (25, 34))
208225	30692511	Moreover, linc00665 overexpression partly reversed the inhibiting effect of miR-98 mimics on AKR1B10 in A549 cells (p < 0.05), whereas no significant differences in AKR1B10 protein levels were observed in H1299 cells (p > 0.05).	('A549', 'CellLine', 'CVCL:0023', (104, 108))	('AKR1B10', 'Gene', (165, 172))	('linc00665', 'Gene', '100506930', (10, 19))	('AKR1B10', 'Gene', '57016', (165, 172))	('AKR1B10', 'Gene', (93, 100))	('AKR1B10', 'Gene', '57016', (93, 100))	('H1299', 'CellLine', 'CVCL:0060', (205, 210))	('mimics', 'Var', (83, 89))	('inhibiting', 'NegReg', (55, 65))	('linc00665', 'Gene', (10, 19))	('miR-98', 'Gene', '407054', (76, 82))	('miR-98', 'Gene', (76, 82))
208231	30692511	In A549 cells, the expression of linc00665 was noticeably attenuated upon SP1 knockdown (p < 0.01), and substantially increased upon SP1 overexpression (p < 0.01) (Fig.	('expression', 'MPA', (19, 29))	('linc00665', 'Gene', (33, 42))	('attenuated', 'NegReg', (58, 68))	('A549', 'CellLine', 'CVCL:0023', (3, 7))	('knockdown', 'Var', (78, 87))	('SP1', 'Gene', (74, 77))	('increased', 'PosReg', (118, 127))	('linc00665', 'Gene', '100506930', (33, 42))
208247	30692511	Our results showed that inhibition of linc00665 increased the expression of epithelial markers and decreased mesenchymal markers, indicating that effects of linc00665 on cell migration and invasion were partly associated with EMT process.	('increased', 'PosReg', (48, 57))	('linc00665', 'Gene', '100506930', (157, 166))	('decreased', 'NegReg', (99, 108))	('EMT process', 'CPA', (226, 237))	('linc00665', 'Gene', '100506930', (38, 47))	('expression', 'MPA', (62, 72))	('linc00665', 'Gene', (157, 166))	('cell migration', 'CPA', (170, 184))	('inhibition', 'Var', (24, 34))	('epithelial markers', 'Protein', (76, 94))	('invasion', 'CPA', (189, 197))	('linc00665', 'Gene', (38, 47))	('mesenchymal markers', 'CPA', (109, 128))
208254	30692511	Additionally, miR-98 was previously reported to act as a tumor suppressor in NSCLC, and low serum miR-98 might be an unfavorable prognostic biomarker for NSCLC patients.	('NSCLC', 'Disease', 'MESH:D002289', (77, 82))	('miR-98', 'Gene', (14, 20))	('patients', 'Species', '9606', (160, 168))	('NSCLC', 'Disease', 'MESH:D002289', (154, 159))	('NSCLC', 'Phenotype', 'HP:0030358', (154, 159))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('NSCLC', 'Phenotype', 'HP:0030358', (77, 82))	('NSCLC', 'Disease', (77, 82))	('miR-98', 'Gene', '407054', (98, 104))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('miR-98', 'Gene', (98, 104))	('low serum', 'Var', (88, 97))	('tumor', 'Disease', (57, 62))	('miR-98', 'Gene', '407054', (14, 20))	('NSCLC', 'Disease', (154, 159))
208393	33256552	The mutation burden analysis showed that mutation level was associated with the risk score in patients with LUAD.	('patients', 'Species', '9606', (94, 102))	('LUAD', 'Disease', (108, 112))	('LUAD', 'Phenotype', 'HP:0030078', (108, 112))	('mutation', 'Var', (41, 49))	('associated', 'Reg', (60, 70))
208416	33256552	Somatic mutations and neoantigen production are associated with cancer immunity and immunotherapy.	('neoantigen', 'MPA', (22, 32))	('associated', 'Reg', (48, 58))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('Somatic mutations', 'Var', (0, 17))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
208480	32811533	Greater number of stromal TILS (> 300/mm2, 20%), CD4+ TILs (> 250/mm2), and CD8+ TILs (> 70/mm2) in MBC were found associated with longer disease-free survival.	('TIL', 'Gene', (26, 29))	('MBC', 'Disease', (100, 103))	('> 300/mm2', 'Var', (32, 41))	('CD4', 'Gene', (49, 52))	('TIL', 'Gene', (54, 57))	('TIL', 'Gene', (81, 84))	('CD4', 'Gene', '920', (49, 52))	('TIL', 'Gene', '7096', (54, 57))	('disease-free survival', 'CPA', (138, 159))	('MBC', 'Disease', 'MESH:D001943', (100, 103))	('CD8', 'Gene', (76, 79))	('longer', 'PosReg', (131, 137))	('TIL', 'Gene', '7096', (81, 84))	('CD8', 'Gene', '925', (76, 79))	('TIL', 'Gene', '7096', (26, 29))
208558	32811533	The presence of TLS in tumor predicted better prognoses as well (HR, 0.2; 95%CI, 0.05-0.75; p = 0.014) (Fig.	('prognoses', 'CPA', (46, 55))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('tumor', 'Disease', (23, 28))	('TLS', 'Gene', (16, 19))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('presence', 'Var', (4, 12))	('better', 'PosReg', (39, 45))
208582	32811533	TLSs are induced in a chronic inflammatory environment and their presence is associated with the exacerbation of local immune responses.	('exacerbation', 'PosReg', (97, 109))	('TLSs', 'Disease', 'None', (0, 4))	('local immune responses', 'CPA', (113, 135))	('TLSs', 'Disease', (0, 4))	('presence', 'Var', (65, 73))
208583	32811533	Here, we found that the presence of TLS was associated with longer survival in MBC (HR, 0.2; 95%CI, 0.05-0.75; p = 0.014), as well as which were found in TNBC.	('presence', 'Var', (24, 32))	('MBC', 'Disease', (79, 82))	('TLS', 'Gene', (36, 39))	('longer', 'PosReg', (60, 66))	('MBC', 'Disease', 'MESH:D001943', (79, 82))
208586	32811533	Our data suggested that PDL1 expression correlated with better survival (HR, 0.19; 95%CI, 0.04-0.85; p = 0.03) in MBC, which was consistent with some previous studies but contradicted with that of a meta-analysis involving 9 studies.	('expression', 'Var', (29, 39))	('MBC', 'Disease', (114, 117))	('PDL1', 'Gene', (24, 28))	('better', 'PosReg', (56, 62))	('MBC', 'Disease', 'MESH:D001943', (114, 117))	('survival', 'MPA', (63, 71))
208618	32811533	TILs, CD4+ TILs, CD8+ TILs, and the presence of TLS were found to be correlated with better prognosis in MBC.	('CD4', 'Gene', (6, 9))	('MBC', 'Disease', 'MESH:D001943', (105, 108))	('TLS', 'Gene', (48, 51))	('TIL', 'Gene', '7096', (11, 14))	('TIL', 'Gene', '7096', (0, 3))	('presence', 'Var', (36, 44))	('CD8', 'Gene', (17, 20))	('CD4', 'Gene', '920', (6, 9))	('CD8', 'Gene', '925', (17, 20))	('TIL', 'Gene', '7096', (22, 25))	('TIL', 'Gene', (11, 14))	('TIL', 'Gene', (0, 3))	('MBC', 'Disease', (105, 108))	('TIL', 'Gene', (22, 25))
208626	32587768	Mutations in the FHL1 gene are associated with various myopathies.	('associated', 'Reg', (31, 41))	('myopathies', 'Phenotype', 'HP:0003198', (55, 65))	('Mutations', 'Var', (0, 9))	('myopathies', 'Disease', 'MESH:D009135', (55, 65))	('myopathies', 'Disease', (55, 65))	('FHL1', 'Gene', (17, 21))
208643	32587768	Anomalies in the FHL1 gene have been identified as the causative factor in various myopathies, such as X-linked myopathy, muscular dystrophy, myofibrillar myopathy, inflammatory myopathy, reducing body myopathy, and others.	('muscular dystrophy', 'Disease', (122, 140))	('muscular dystrophy', 'Disease', 'MESH:D009136', (122, 140))	('myopathy', 'Disease', 'MESH:D009135', (178, 186))	('myopathies', 'Phenotype', 'HP:0003198', (83, 93))	('myopathy', 'Disease', 'MESH:D009135', (202, 210))	('myopathies', 'Disease', (83, 93))	('muscular dystrophy', 'Phenotype', 'HP:0003560', (122, 140))	('causative factor', 'Reg', (55, 71))	('myofibrillar myopathy', 'Disease', (142, 163))	('myopathy', 'Phenotype', 'HP:0003198', (155, 163))	('myopathy', 'Disease', (155, 163))	('inflammatory myopathy', 'Phenotype', 'HP:0009071', (165, 186))	('FHL1', 'Gene', (17, 21))	('myopathy', 'Phenotype', 'HP:0003198', (178, 186))	('myopathy', 'Disease', (178, 186))	('myopathy', 'Disease', 'MESH:D009135', (155, 163))	('myopathy', 'Disease', (202, 210))	('myopathy', 'Phenotype', 'HP:0003198', (202, 210))	('identified', 'Reg', (37, 47))	('myopathies', 'Disease', 'MESH:D009135', (83, 93))	('myopathy', 'Disease', 'MESH:D009135', (112, 120))	('Anomalies', 'Var', (0, 9))	('myofibrillar myopathy', 'Disease', 'MESH:C580316', (142, 163))	('X-linked myopathy', 'Disease', 'MESH:D009135', (103, 120))	('X-linked myopathy', 'Disease', (103, 120))	('myofibrillar myopathy', 'Phenotype', 'HP:0003715', (142, 163))	('myopathy', 'Phenotype', 'HP:0003198', (112, 120))	('myopathy', 'Disease', (112, 120))
208665	32587768	FHL1C is the shorter variant of FHL1 encoding a 22.0 kDa protein that is identical to FHL1 over the first two and a half N-terminal LIM domains but contains different protein sequences at the C-terminus, with a 27 residue putative RBP-Jkappa binding region similar to that in FHL1B.	('FHL1C', 'Var', (0, 5))	('FHL1B', 'Gene', (276, 281))	('LIM', 'Gene', (132, 135))	('LIM', 'Gene', '10611', (132, 135))	('RBP-Jkappa', 'Gene', '3516', (231, 241))	('FHL1', 'Gene', (32, 36))	('RBP-Jkappa', 'Gene', (231, 241))	('FHL1B', 'Gene', '2273', (276, 281))
208677	32587768	FHL1 silencing inhibited myoblast differentiation and expression of ATG5 and ATG7.	('expression', 'MPA', (54, 64))	('inhibited', 'NegReg', (15, 24))	('ATG7', 'Gene', '10533', (77, 81))	('FHL1', 'Gene', (0, 4))	('silencing', 'Var', (5, 14))	('ATG7', 'Gene', (77, 81))	('ATG5', 'Gene', '9474', (68, 72))	('myoblast differentiation', 'CPA', (25, 49))	('ATG5', 'Gene', (68, 72))
208679	32587768	Another report showed that FHL1 overexpression enhances migration and proliferation of primary human pulmonary artery smooth muscle cells (PASMCs).	('migration', 'CPA', (56, 65))	('human', 'Species', '9606', (95, 100))	('rat', 'Species', '10116', (77, 80))	('FHL1', 'Gene', (27, 31))	('proliferation', 'CPA', (70, 83))	('enhances', 'PosReg', (47, 55))	('overexpression', 'Var', (32, 46))	('rat', 'Species', '10116', (59, 62))
208681	32587768	The group generated a knock-in mouse model with the same FHL1 mutation as human X-linked scapuloperoneal myopathy, one of the known FHL1-related diseases.	('myopathy', 'Disease', 'MESH:D009135', (105, 113))	('mouse', 'Species', '10090', (31, 36))	('scapuloperoneal myopathy', 'Phenotype', 'HP:0009054', (89, 113))	('mutation', 'Var', (62, 70))	('human', 'Species', '9606', (74, 79))	('myopathy', 'Phenotype', 'HP:0003198', (105, 113))	('FHL1', 'Gene', (57, 61))	('myopathy', 'Disease', (105, 113))	('rat', 'Species', '10116', (14, 17))
208682	32587768	In their study, 20 month-old mutant female mice showed signs of cardiomyopathy on echocardiograms, with increased systolic diameter and lower fractional shortening.	('mice', 'Species', '10090', (43, 47))	('lower', 'NegReg', (136, 141))	('cardiomyopathy', 'Disease', (64, 78))	('increased', 'PosReg', (104, 113))	('systolic diameter', 'MPA', (114, 131))	('mutant', 'Var', (29, 35))	('fractional shortening', 'MPA', (142, 163))	('myopathy', 'Phenotype', 'HP:0003198', (70, 78))	('cardiomyopathy', 'Phenotype', 'HP:0001638', (64, 78))	('cardiomyopathy', 'Disease', 'MESH:D009202', (64, 78))
208683	32587768	Proteomic analyses indicated that abnormalities of the integrin signaling pathway (ISP) were associated with cardiac dysfunction, implicating ISP dysregulation in the pathogenesis of FHL1 myopathy.	('myopathy', 'Phenotype', 'HP:0003198', (188, 196))	('myopathy', 'Disease', (188, 196))	('integrin signaling pathway', 'Pathway', (55, 81))	('associated', 'Reg', (93, 103))	('cardiac dysfunction', 'Disease', 'MESH:D006331', (109, 128))	('cardiac dysfunction', 'Disease', (109, 128))	('myopathy', 'Disease', 'MESH:D009135', (188, 196))	('abnormalities', 'Var', (34, 47))
208687	32587768	Consistent with this finding, knockdown of FHL1 markedly inhibited CHIKV21 infection and release of infectious particles.	('CHIKV21 infection', 'Disease', (67, 84))	('FHL1', 'Gene', (43, 47))	('release of infectious particles', 'MPA', (89, 120))	('inhibited', 'NegReg', (57, 66))	('CHIKV21 infection', 'Disease', 'MESH:D007239', (67, 84))	('knockdown', 'Var', (30, 39))
208696	32587768	identified FHL1 as a tumor suppressor gene on chromosome X inactivated by promoter methylation in gastrointestinal cancer.	('gastrointestinal cancer', 'Disease', 'MESH:D004067', (98, 121))	('tumor', 'Disease', (21, 26))	('inactivated', 'NegReg', (59, 70))	('gastrointestinal cancer', 'Disease', (98, 121))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('FHL1', 'Gene', (11, 15))	('promoter methylation', 'Var', (74, 94))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (98, 121))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
208697	32587768	Consistently, methylation-silencing of FHL1 has been detected in multiple gastric and colon cancer cell lines and surgical gastrointestinal cancer specimens.	('colon cancer', 'Disease', (86, 98))	('gastrointestinal cancer', 'Disease', 'MESH:D004067', (123, 146))	('methylation-silencing', 'Var', (14, 35))	('gastrointestinal cancer', 'Disease', (123, 146))	('detected', 'Reg', (53, 61))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (123, 146))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('colon cancer', 'Phenotype', 'HP:0003003', (86, 98))	('colon cancer', 'Disease', 'MESH:D015179', (86, 98))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('FHL1', 'Gene', (39, 43))
208699	32587768	Analogous to these findings, FHL1 gene silencing through CpG hypermethylation is reported to promote proliferation, migration, and invasion activities of human bladder cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('rat', 'Species', '10116', (108, 111))	('human', 'Species', '9606', (154, 159))	('invasion activities', 'CPA', (131, 150))	('bladder cancer', 'Disease', 'MESH:D001749', (160, 174))	('bladder cancer', 'Phenotype', 'HP:0009725', (160, 174))	('promote', 'PosReg', (93, 100))	('bladder cancer', 'Disease', (160, 174))	('proliferation', 'CPA', (101, 114))	('silencing', 'NegReg', (39, 48))	('rat', 'Species', '10116', (119, 122))	('hypermethylation', 'Var', (61, 77))	('migration', 'CPA', (116, 125))	('FHL1', 'Gene', (29, 33))
208709	32587768	FHL1 methylation is additionally involved in the associated mechanisms in human liver cancer.	('involved', 'Reg', (33, 41))	('methylation', 'Var', (5, 16))	('FHL1', 'Gene', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('liver cancer', 'Phenotype', 'HP:0002896', (80, 92))	('liver cancer', 'Disease', 'MESH:D006528', (80, 92))	('human', 'Species', '9606', (74, 79))	('liver cancer', 'Disease', (80, 92))
208711	32587768	A recent epigenetic analysis identified FHL1 as a tumor suppressor gene in human liver cancer and indicated that EZH2-imediated H3K27me3 is involved in epigenetic repression of FHL1 in HCC.	('liver cancer', 'Disease', 'MESH:D006528', (81, 93))	('human', 'Species', '9606', (75, 80))	('HCC', 'Phenotype', 'HP:0001402', (185, 188))	('epigenetic', 'Var', (152, 162))	('liver cancer', 'Disease', (81, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('liver cancer', 'Phenotype', 'HP:0002896', (81, 93))	('EZH2', 'Gene', '2146', (113, 117))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('HCC', 'Disease', (185, 188))	('H3K27me3', 'Var', (128, 136))	('FHL1', 'Gene', (40, 44))	('FHL1', 'Gene', (177, 181))	('tumor', 'Disease', (50, 55))	('EZH2', 'Gene', (113, 117))
208724	32587768	Their results showed that tumors expressing low levels of FHL1 displayed deeper invasive ability into the serosal layer.	('low levels', 'Var', (44, 54))	('FHL1', 'Gene', (58, 62))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('invasive ability into the serosal layer', 'CPA', (80, 119))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('deeper', 'PosReg', (73, 79))	('tumors', 'Disease', (26, 32))
208736	32587768	MiR-105 was further identified as a direct target of LINC00261 and FHL1 as a novel downstream target of miR-105.	('FHL1', 'Gene', (67, 71))	('miR-105', 'Chemical', '-', (104, 111))	('MiR-105', 'Gene', (0, 7))	('LINC00261', 'Gene', '140828', (53, 62))	('MiR-105', 'Chemical', '-', (0, 7))	('miR-105', 'Var', (104, 111))	('LINC00261', 'Gene', (53, 62))
208739	32587768	Significant downregulation of FHL1 was demonstrated in all oral squamous cell carcinoma (OSCC)-derived cell lines and tissues from human patients, mediated by CpG hypermethylation of the FHL1 promoter region.	('downregulation', 'NegReg', (12, 26))	('CpG hypermethylation', 'Var', (159, 179))	('FHL1', 'Gene', (30, 34))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (59, 87))	('hypermethylation', 'Var', (163, 179))	('rat', 'Species', '10116', (46, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('patients', 'Species', '9606', (137, 145))	('human', 'Species', '9606', (131, 136))	('oral squamous cell carcinoma', 'Disease', (59, 87))	('FHL1', 'Gene', (187, 191))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (64, 87))
208749	32587768	Knockdown of FHL1 in HCC cells rendered the cells more sensitive to paclitaxel than oxaliplatin.	('FHL1', 'Gene', (13, 17))	('more', 'PosReg', (50, 54))	('Knockdown', 'Var', (0, 9))	('HCC', 'Phenotype', 'HP:0001402', (21, 24))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (84, 95))	('paclitaxel', 'Chemical', 'MESH:D017239', (68, 78))	('sensitive to paclitaxel', 'MPA', (55, 78))
208750	32587768	Inhibition of FHL1 function could be explored as a potential therapeutic strategy to increase the anticancer activity of the drug.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('rat', 'Species', '10116', (75, 78))	('FHL1', 'Gene', (14, 18))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('Inhibition', 'Var', (0, 10))	('increase', 'PosReg', (85, 93))
208753	32587768	Interestingly, no significant differences in DFS and OS of non-treated breast cancer patients were observed between groups with high and low FHL1 expression.	('breast cancer', 'Disease', (71, 84))	('breast cancer', 'Phenotype', 'HP:0003002', (71, 84))	('low', 'NegReg', (137, 140))	('FHL1', 'Gene', (141, 145))	('patients', 'Species', '9606', (85, 93))	('high', 'Var', (128, 132))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('breast cancer', 'Disease', 'MESH:D001943', (71, 84))
208754	32587768	Consistently, knockdown of FHL1 in vitro increased the sensitivity of cancer cells to ionizing radiation (IR).	('increased', 'PosReg', (41, 50))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('FHL1', 'Gene', (27, 31))	('sensitivity', 'MPA', (55, 66))	('knockdown', 'Var', (14, 23))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))
208760	32587768	The collective results indicate that inhibition of LIM protein or use of eLIM may present novel strategies for improving tumor response to radiotherapy.	('inhibition', 'Var', (37, 47))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('LIM', 'Gene', '10611', (51, 54))	('LIM', 'Gene', (74, 77))	('tumor', 'Disease', (121, 126))	('improving', 'PosReg', (111, 120))	('rat', 'Species', '10116', (98, 101))	('LIM', 'Gene', '10611', (74, 77))	('LIM', 'Gene', (51, 54))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
208762	32587768	Specifically, Src phosphorylates the protein at two tyrosine residues, Y149 and Y272.	('Y149', 'Var', (71, 75))	('tyrosine', 'Chemical', 'MESH:D014443', (52, 60))	('Src', 'Gene', '6714', (14, 17))	('Src', 'Gene', (14, 17))	('Y272', 'Var', (80, 84))
208763	32587768	Following phosphorylation, FHL1 translocates into the nucleus where it binds the transcription factor BCLAF1.	('FHL1', 'Gene', (27, 31))	('BCLAF1', 'Gene', '9774', (102, 108))	('BCLAF1', 'Gene', (102, 108))	('binds', 'Interaction', (71, 76))	('phosphorylation', 'Var', (10, 25))
208765	32587768	Consistent with previous reports, wild-type FHL1 repressed cell growth and migration in vitro and a nonphosphorylatable mutant of FHL1 exerted an even stronger inhibitory effect on cell growth and migration.	('inhibitory', 'NegReg', (160, 170))	('FHL1', 'Gene', (130, 134))	('rat', 'Species', '10116', (200, 203))	('rat', 'Species', '10116', (78, 81))	('migration', 'CPA', (75, 84))	('cell growth', 'CPA', (181, 192))	('cell growth', 'CPA', (59, 70))	('mutant', 'Var', (120, 126))
208766	32587768	Conversely, a phosphomimetic mutant of FHL1 promoted proliferation and migration.	('promoted', 'PosReg', (44, 52))	('rat', 'Species', '10116', (60, 63))	('rat', 'Species', '10116', (74, 77))	('migration', 'CPA', (71, 80))	('proliferation', 'CPA', (53, 66))	('phosphomimetic', 'Var', (14, 28))	('FHL1', 'Gene', (39, 43))
208767	32587768	When cells expressing different FHL1 mutants were injected into mice, similar effects were observed in vivo.	('mutants', 'Var', (37, 44))	('FHL1', 'Gene', (32, 36))	('mice', 'Species', '10090', (64, 68))
208768	32587768	Cells expressing phosphomimetic FHL1 grew faster and displayed larger tumors than those expressing wild-type or nonphosphorylatable FHL1.	('larger', 'PosReg', (63, 69))	('faster', 'PosReg', (42, 48))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('grew', 'CPA', (37, 41))	('FHL1', 'Var', (32, 36))	('tumors', 'Disease', (70, 76))	('phosphomimetic FHL1', 'Var', (17, 36))	('tumors', 'Disease', 'MESH:D009369', (70, 76))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))
208776	32587768	Upon phosphorylation, FHL1 translocates to the nucleus where it acts as a tumor promoter (Figure 3).	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('phosphorylation', 'Var', (5, 20))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor', 'Disease', (74, 79))	('FHL1', 'Gene', (22, 26))
208780	32587768	FHL1 was further identified as an independent predictor of poor outcomes in AML when combined with prognosis-related clinical factors and genetic abnormalities, such as MLL-PTD, TP53, and RUNX1 mutations.	('RUNX1', 'Gene', '861', (188, 193))	('TP53', 'Gene', '7157', (178, 182))	('FHL1', 'Gene', (0, 4))	('AML', 'Disease', (76, 79))	('TP53', 'Gene', (178, 182))	('AML', 'Phenotype', 'HP:0004808', (76, 79))	('mutations', 'Var', (194, 203))	('MLL-PTD', 'Disease', (169, 176))	('MLL-PTD', 'Disease', 'MESH:C537633', (169, 176))	('genetic abnormalities', 'Disease', 'MESH:D030342', (138, 159))	('RUNX1', 'Gene', (188, 193))	('genetic abnormalities', 'Disease', (138, 159))	('AML', 'Disease', 'MESH:D015470', (76, 79))
208782	32587768	Furthermore, FHL1 was highly expressed in LSCs and its knockdown enhanced the sensitivity of AML cells to cytarabine in vitro, supporting the involvement of FHL1 in chemotherapy resistance and relapse of AML.	('sensitivity', 'MPA', (78, 89))	('knockdown', 'Var', (55, 64))	('FHL1', 'Gene', (13, 17))	('AML', 'Disease', 'MESH:D015470', (204, 207))	('AML', 'Phenotype', 'HP:0004808', (93, 96))	('AML', 'Disease', (93, 96))	('AML', 'Disease', (204, 207))	('cytarabine', 'Chemical', 'MESH:D003561', (106, 116))	('enhanced', 'PosReg', (65, 73))	('AML', 'Phenotype', 'HP:0004808', (204, 207))	('AML', 'Disease', 'MESH:D015470', (93, 96))	('involvement', 'Reg', (142, 153))
208788	32587768	Mutations in the FHL1 gene have been identified as the cause of several skeletal muscle diseases.	('skeletal muscle diseases', 'Disease', (72, 96))	('skeletal muscle diseases', 'Disease', 'MESH:D005207', (72, 96))	('Mutations', 'Var', (0, 9))	('identified', 'Reg', (37, 47))	('cause', 'Reg', (55, 60))	('FHL1', 'Gene', (17, 21))
208790	32587768	FHL1 is widely downregulated in various cancers, mainly through gene silencing owing to CpG hypermethylation.	('cancers', 'Phenotype', 'HP:0002664', (40, 47))	('FHL1', 'Gene', (0, 4))	('cancers', 'Disease', 'MESH:D009369', (40, 47))	('gene', 'MPA', (64, 68))	('cancers', 'Disease', (40, 47))	('CpG hypermethylation', 'Var', (88, 108))	('hypermethylation', 'Var', (92, 108))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('downregulated', 'NegReg', (15, 28))
208798	32587768	In view of our finding that phosphorylation of FHL1 dramatically alters the role of FHL1 from tumor suppressor to promoter, it is worth investigating whether other types of PTM, such as acetylation and ubquitination, regulate subcellular location and cellular function of FHL1.	('phosphorylation', 'Var', (28, 43))	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Disease', (94, 99))	('regulate', 'Reg', (217, 225))	('alters', 'Reg', (65, 71))
208799	32587768	Perhaps the most promising area of future study is elucidation of the precise roles and regulatory mechanisms of FHL1 in both nuclear and cytoplasmic compartments, which should offer novel insights into how aberrant FHL1 expression and modification patterns influence tumor progression and provide new avenues for therapeutic intervention.	('FHL1', 'Gene', (216, 220))	('tumor', 'Phenotype', 'HP:0002664', (268, 273))	('tumor', 'Disease', (268, 273))	('aberrant', 'Var', (207, 215))	('influence', 'Reg', (258, 267))	('FHL1', 'Gene', (113, 117))	('tumor', 'Disease', 'MESH:D009369', (268, 273))
208801	30355483	Pharmacological blockade of Jumonji demethy-lases with JIB-04 leads to specific accumulation of H3K4me3 at sites marked by gammaH2AX and impaired recruitment of DNA repair factors, preventing resolution of damage and resulting in robust sensitization to radiation therapy.	('H3K4me3', 'Protein', (96, 103))	('DNA', 'Protein', (161, 164))	('sensitization', 'MPA', (237, 250))	('JIB-04', 'Chemical', 'MESH:C585278', (55, 61))	('recruitment', 'MPA', (146, 157))	('sensitization to radiation therapy', 'Phenotype', 'HP:0011133', (237, 271))	('JIB-04', 'Gene', (55, 61))	('impaired', 'NegReg', (137, 145))	('damage', 'MPA', (206, 212))	('resolution', 'MPA', (192, 202))	('gammaH2AX', 'Chemical', '-', (123, 132))	('accumulation', 'PosReg', (80, 92))	('gammaH2AX', 'Var', (123, 132))	('preventing', 'NegReg', (181, 191))	('Jumonji', 'Chemical', '-', (28, 35))
208802	30355483	In DNA-repair-proficient cancer cells, knockdown of the H3K4me3 demethylase KDM5B, but not other Jumonji enzymes, mimics pharmacological inhibition, and KDM5B overexpression rescues this phenotype and increases radioresistance.	('radioresistance', 'CPA', (211, 226))	('KDM5B', 'Gene', (76, 81))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('Jumonji', 'Chemical', '-', (97, 104))	('KDM5B', 'Gene', '10765', (76, 81))	('KDM5B', 'Gene', (153, 158))	('knockdown', 'Var', (39, 48))	('increases', 'PosReg', (201, 210))	('overexpression rescues', 'PosReg', (159, 181))	('cancer', 'Disease', 'MESH:D009369', (25, 31))	('cancer', 'Disease', (25, 31))	('KDM5B', 'Gene', '10765', (153, 158))
208809	30355483	Genetic or pharmacological inhibition of JARID1B robustly radiosensitizes cancers in vitro and in vivo through defects in DNA repair, providing a therapeutic option for radioresistant tumors.	('defects', 'NegReg', (111, 118))	('DNA repair', 'MPA', (122, 132))	('radiosensitizes', 'NegReg', (58, 73))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('cancers', 'Disease', 'MESH:D009369', (74, 81))	('JARID1B', 'Gene', '10765', (41, 48))	('cancers', 'Phenotype', 'HP:0002664', (74, 81))	('tumors', 'Disease', (184, 190))	('JARID1B', 'Gene', (41, 48))	('cancers', 'Disease', (74, 81))	('inhibition', 'Var', (27, 37))	('tumors', 'Disease', 'MESH:D009369', (184, 190))	('tumors', 'Phenotype', 'HP:0002664', (184, 190))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
208819	30355483	In the present study, we demonstrate that JIB-04 and inhibitors of H3K4me3 demethylases, but not of H3K27me3 demethylases, sensitize radioresistant NSCLC to radiation, impairing both NHEJ and HR.	('inhibitors', 'Var', (53, 63))	('NSCLC', 'Disease', (148, 153))	('NSCLC', 'Disease', 'MESH:D002289', (148, 153))	('H3K4me3', 'Protein', (67, 74))	('JIB-04', 'Chemical', 'MESH:C585278', (42, 48))	('sensitize', 'Reg', (123, 132))	('NSCLC', 'Phenotype', 'HP:0030358', (148, 153))	('impairing', 'NegReg', (168, 177))
208823	30355483	In vivo, Jumonji inhibition robustly enhances the effects of radiation treatment and prolongs survival.	('Jumonji', 'Chemical', '-', (9, 16))	('prolongs', 'NegReg', (85, 93))	('enhances', 'PosReg', (37, 45))	('inhibition', 'Var', (17, 27))	('Jumonji', 'Protein', (9, 16))	('survival', 'CPA', (94, 102))
208826	30355483	Thus, we provide proof-of-principle studies in support of the use of Jumonji or KDM5 inhibitors to overcome radiation resistance.	('Jumonji', 'Chemical', '-', (69, 76))	('inhibitors', 'Var', (85, 95))	('KDM5', 'Gene', (80, 84))	('radiation resistance', 'CPA', (108, 128))	('KDM5', 'Chemical', '-', (80, 84))
208827	30355483	We first evaluated whether inhibition of Jumonji histone demethylases, which should increase histone methylation, would alter the response to radiation due to the underlying known connections between histone methylation and DNA repair.	('alter', 'Reg', (120, 125))	('response to radiation', 'MPA', (130, 151))	('increase', 'PosReg', (84, 92))	('inhibition', 'Var', (27, 37))	('Jumonji', 'Chemical', '-', (41, 48))	('histone methylation', 'MPA', (93, 112))
208834	30355483	Interestingly, the dose enhancement ratio at 25% cell kill, DER25 (the radiation dose required to reduce the survival fraction to 25% in the absence or presence of JIB-04) was higher for cells that were more radioresistant and consequently had high SF2 values than for cells with intrinsically lower SF2 values (Table S1).	('SF2', 'Gene', (249, 252))	('radioresistant', 'CPA', (208, 222))	('SF2', 'Gene', '6426', (300, 303))	('SF2', 'Gene', '6426', (249, 252))	('high', 'Var', (244, 248))	('JIB-04', 'Chemical', 'MESH:C585278', (164, 170))	('SF2', 'Gene', (300, 303))	('higher', 'PosReg', (176, 182))
208850	30355483	We have previously confirmed that in NSCLC cells, including H1299, GSK-J4 only affects H3K27me3 demethylation and not H3K4me3 or H3K9me3 de-methylation and that this specificity is maintained in vivo (; see Figure 6F in).	('NSCLC', 'Disease', 'MESH:D002289', (37, 42))	('NSCLC', 'Phenotype', 'HP:0030358', (37, 42))	('H1299', 'Var', (60, 65))	('H1299', 'CellLine', 'CVCL:0060', (60, 65))	('NSCLC', 'Disease', (37, 42))	('H3K27me3', 'Protein', (87, 95))	('GSK-J4', 'Gene', (67, 73))	('affects', 'Reg', (79, 86))
208864	30355483	As demonstrated in Figures 4B and S5A, both NHEJ and HR were significantly inhibited in the presence of JIB-04 to 50% or less of normal levels.	('JIB-04', 'Gene', (104, 110))	('inhibited', 'NegReg', (75, 84))	('presence', 'Var', (92, 100))	('NHEJ', 'CPA', (44, 48))	('JIB-04', 'Chemical', 'MESH:C585278', (104, 110))
208871	30355483	In contrast, cells treated with JIB-04 plus IR exhibited a clear deficiency in forming active DNA-PKcs foci with delayed foci formation post-IR.	('DNA-PKcs', 'Gene', '5591', (94, 102))	('clear deficiency', 'Disease', (59, 75))	('JIB-04', 'Chemical', 'MESH:C585278', (32, 38))	('DNA-PKcs', 'Gene', (94, 102))	('clear deficiency', 'Disease', 'MESH:D018227', (59, 75))	('JIB-04', 'Var', (32, 38))	('forming active', 'MPA', (79, 93))
208874	30355483	To determine whether JIB-04 was also impairing proper recruitment of HR factors to sites of damage, we measured RAD51 foci formation and resolution over a time course.	('JIB-04', 'Chemical', 'MESH:C585278', (21, 27))	('JIB-04', 'Var', (21, 27))	('impairing', 'NegReg', (37, 46))	('recruitment', 'MPA', (54, 65))	('RAD51', 'Gene', (112, 117))	('RAD51', 'Gene', '5888', (112, 117))
208879	30355483	Since inhibition of Jumonji histone demethylase enzymes with JIB-04 can result in increased histone methylation levels, we hypothesized that H3K4me3 or H3K9me3 marks may be accumulating around DSBs in drug-treated cells, contributing to defective repair factor recruitment and defective resolution of damage.	('recruitment', 'MPA', (261, 272))	('defective', 'NegReg', (277, 286))	('repair', 'Protein', (247, 253))	('JIB-04', 'Chemical', 'MESH:C585278', (61, 67))	('JIB-04', 'Gene', (61, 67))	('resolution', 'MPA', (287, 297))	('defective', 'NegReg', (237, 246))	('histone methylation levels', 'MPA', (92, 118))	('H3K4me3', 'Var', (141, 148))	('increased', 'PosReg', (82, 91))	('inhibition', 'NegReg', (6, 16))	('H3K9me3', 'Var', (152, 159))	('Jumonji', 'Chemical', '-', (20, 27))
208883	30355483	Consistent with this result, we found that the total enzy-matic activity of H3K4me3 Jumonji demethylasess (Figure 5C),but not that of H3K9me3 demethylases (Figure 5D), could be increased upon IR exposure and that just 4 hr of pretreatment with JIB-04 blocked this IR-induced increase in enzyme activity (Figures 5C and 5D).	('enzy-matic activity', 'MPA', (53, 72))	('Jumonji', 'Chemical', '-', (84, 91))	('increased', 'PosReg', (177, 186))	('H3K4me3', 'Var', (76, 83))	('JIB-04', 'Chemical', 'MESH:C585278', (244, 250))
208888	30355483	Together, these results indicate that an H3K4me3 Jumonji demethylase enzyme(s) may be inhibited by JIB-04 during the response to IR, leading to the specific accumulation of its trimethylated histone substrate at transcriptionally active regions harboring DNA damage.	('accumulation', 'PosReg', (157, 169))	('trimethylated histone substrate', 'MPA', (177, 208))	('JIB-04', 'Chemical', 'MESH:C585278', (99, 105))	('JIB-04', 'Gene', (99, 105))	('H3K4me3', 'Var', (41, 48))	('inhibited', 'NegReg', (86, 95))	('Jumonji', 'Chemical', '-', (49, 56))
208893	30355483	The accumulation of unresolved DSBs seen in KDM4B knockdown NSCLC cells (Figures 6A and 6B) is likely due to further DNA damage, as has been reported to occur in other cancer cell types upon KDM4B depletion.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('KDM4B', 'Gene', (191, 196))	('accumulation', 'PosReg', (4, 16))	('KDM4B', 'Gene', '23030', (191, 196))	('knockdown', 'Var', (50, 59))	('KDM4B', 'Gene', (44, 49))	('KDM4B', 'Gene', '23030', (44, 49))	('NSCLC', 'Phenotype', 'HP:0030358', (60, 65))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('cancer', 'Disease', (168, 174))	('DNA', 'MPA', (117, 120))	('NSCLC', 'Disease', (60, 65))	('NSCLC', 'Disease', 'MESH:D002289', (60, 65))
208894	30355483	Thus, among H3K4me3 and H3K9me3 demethylases, KDM5B plays an important role in the DNA damage response, and its genetic or pharmacological inhibition triggers a defect in DSB repair that can be exploited therapeutically to enhance radiation sensitivity.	('inhibition', 'Var', (139, 149))	('defect', 'NegReg', (161, 167))	('DSB', 'Gene', (171, 174))	('KDM5B', 'Gene', '10765', (46, 51))	('DNA damage response', 'MPA', (83, 102))	('KDM5B', 'Gene', (46, 51))
208903	30355483	Tumors were established to a volume of 200 mm3 before initiating treatment with JIB-04, IR, or JIB-04 plus IR as described in detail in STAR Methods.	('JIB-04', 'Chemical', 'MESH:C585278', (80, 86))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('JIB-04', 'Chemical', 'MESH:C585278', (95, 101))	('JIB-04', 'Var', (80, 86))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('JIB-04', 'Var', (95, 101))
208908	30355483	Whereas it took 5-8 days on average for tumors treated with vehicle, JIB-04 alone, or IR to reach this volume, tumors in animals receiving JIB-04 with IR took 22 days to reach this size.	('JIB-04', 'Chemical', 'MESH:C585278', (69, 75))	('JIB-04', 'Chemical', 'MESH:C585278', (139, 145))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('tumors', 'Disease', 'MESH:D009369', (40, 46))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('JIB-04', 'Var', (139, 145))	('tumors', 'Disease', 'MESH:D009369', (111, 117))	('tumors', 'Disease', (111, 117))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumors', 'Disease', (40, 46))
208910	30355483	As can be seen in Figure 7A (right panel), mice treated with JIB-04 and IR survived significantly longer than mice treated with either agent alone or vehicle.	('mice', 'Species', '10090', (43, 47))	('longer', 'PosReg', (98, 104))	('mice', 'Species', '10090', (110, 114))	('JIB-04', 'Chemical', 'MESH:C585278', (61, 67))	('JIB-04', 'Var', (61, 67))
208912	30355483	Thus, there was strong synergy between JIB04 and IR in vivo as shown by both robust reduction in tumor growth rate and increased median survival, even after cessation of treatment.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('reduction', 'NegReg', (84, 93))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('JIB04', 'Chemical', 'MESH:C585278', (39, 44))	('tumor', 'Disease', (97, 102))	('JIB04', 'Var', (39, 44))	('median survival', 'CPA', (129, 144))	('increased', 'PosReg', (119, 128))
208924	30355483	Mechanistically, inhibition of KDM5B activity results in defective recruitment of repair factors, lower efficacy of repair by both HR and NHEJ, and consequently radiosensitization of lung cancer cells and tumors.	('radiosensitization of lung', 'Phenotype', 'HP:0010997', (161, 187))	('tumors', 'Phenotype', 'HP:0002664', (205, 211))	('lower', 'NegReg', (98, 103))	('recruitment', 'MPA', (67, 78))	('defective', 'NegReg', (57, 66))	('lung cancer', 'Disease', 'MESH:D008175', (183, 194))	('inhibition', 'Var', (17, 27))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('KDM5B', 'Gene', '10765', (31, 36))	('radiosensitization', 'CPA', (161, 179))	('tumors', 'Disease', (205, 211))	('lung cancer', 'Phenotype', 'HP:0100526', (183, 194))	('efficacy', 'MPA', (104, 112))	('activity', 'MPA', (37, 45))	('tumors', 'Disease', 'MESH:D009369', (205, 211))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('repair factors', 'Protein', (82, 96))	('lung cancer', 'Disease', (183, 194))	('KDM5B', 'Gene', (31, 36))
208925	30355483	Knockdown of KDM5B, in turn, phenocopies the effects of pharmacological inhibition of this enzyme on DNA repair, consistent with the radiosensitizing effects of silencing KDM5B in oral carcinomas.	('DNA repair', 'MPA', (101, 111))	('KDM5B', 'Gene', '10765', (171, 176))	('oral carcinomas', 'Disease', 'MESH:D020820', (180, 195))	('KDM5B', 'Gene', '10765', (13, 18))	('carcinoma', 'Phenotype', 'HP:0030731', (185, 194))	('KDM5B', 'Gene', (171, 176))	('KDM5B', 'Gene', (13, 18))	('silencing', 'Var', (161, 170))	('oral carcinomas', 'Disease', (180, 195))	('carcinomas', 'Phenotype', 'HP:0030731', (185, 195))
208928	30355483	Our overall findings are in agreement with the reported importance of KDM5B in maintaining genome stability and support the idea that H3K4me3 demethylation and partial chromatin condensation may be required for efficient recruitment of repair factors at active chromatin.	('KDM5B', 'Gene', '10765', (70, 75))	('H3K4me3', 'Var', (134, 141))	('genome', 'MPA', (91, 97))	('KDM5B', 'Gene', (70, 75))
208929	30355483	The enhanced response to radiation triggered by inhibition of KDM5B activity appears to be the result of inefficient DNA repair.	('enhanced', 'PosReg', (4, 12))	('inhibition', 'Var', (48, 58))	('response to radiation', 'MPA', (13, 34))	('enhanced response to radiation', 'Phenotype', 'HP:0011133', (4, 34))	('KDM5B', 'Gene', '10765', (62, 67))	('activity', 'MPA', (68, 76))	('KDM5B', 'Gene', (62, 67))
208949	30355483	NSCLC cells were injected subcutaneously (5 3 106 cells in 100 mL PBS H1299, 2 3 106 in 100 mL PBS A549 cells) into the right posterior leg of mice.	('PBS', 'Chemical', 'MESH:D007854', (95, 98))	('H1299', 'CellLine', 'CVCL:0060', (70, 75))	('NSCLC', 'Disease', 'MESH:D002289', (0, 5))	('A549', 'CellLine', 'CVCL:0023', (99, 103))	('NSCLC', 'Phenotype', 'HP:0030358', (0, 5))	('PBS', 'Chemical', 'MESH:D007854', (66, 69))	('5 3', 'Var', (42, 45))	('NSCLC', 'Disease', (0, 5))	('mice', 'Species', '10090', (143, 147))
209000	30355483	Protein was transferred to nitrocellulose membranes and blotted for phospho-Histone gammaH2AX (Ser139), Ku-70, H3K4me3 and H3K9me3.	('Histone gammaH2AX', 'Chemical', '-', (76, 93))	('Ku-70', 'Gene', (104, 109))	('Ser139', 'Chemical', '-', (95, 101))	('H3K9me3', 'Var', (123, 130))	('Ku-70', 'Gene', '2547', (104, 109))	('H3K4me3', 'Var', (111, 118))
209017	30355483	Inhibition of JARID demethylases sensitizes cancers to radiation in vitro and in vivo Radiotherapy increases JARID enzyme activity, and blocking it prevents DNA repair H3K4me3 accumulates at and near DSBs and impedes recruitment of DNA repair factors Human tumors with high levels of JARID1B expression are resistant to radiotherapy	('accumulates', 'PosReg', (176, 187))	('cancers', 'Phenotype', 'HP:0002664', (44, 51))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('Human', 'Species', '9606', (251, 256))	('impedes', 'NegReg', (209, 216))	('JARID enzyme', 'Enzyme', (109, 121))	('blocking', 'Var', (136, 144))	('cancers', 'Disease', (44, 51))	('tumors', 'Disease', (257, 263))	('tumors', 'Disease', 'MESH:D009369', (257, 263))	('cancers', 'Disease', 'MESH:D009369', (44, 51))	('tumors', 'Phenotype', 'HP:0002664', (257, 263))	('JARID1B', 'Gene', (284, 291))	('JARID1B', 'Gene', '10765', (284, 291))	('increases', 'PosReg', (99, 108))	('tumor', 'Phenotype', 'HP:0002664', (257, 262))	('activity', 'MPA', (122, 130))
209085	26975833	Such mutation patterns could vastly augment comparisons of REGs with their anatomically-corresponding cancers.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('REG', 'Gene', (59, 62))	('cancers', 'Disease', 'MESH:D009369', (102, 109))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))	('cancers', 'Disease', (102, 109))	('mutation', 'Var', (5, 13))	('REG', 'Gene', '5967', (59, 62))	('augment', 'NegReg', (36, 43))
209087	26975833	4, the top 100 ranked REGs (comprised of 81 top ranked genes and the 19 genes used as the ToppGene training set) have an overwhelming number of mutations in cancers (Table S7); these 100 genes are mutated in over 90% of patients across 30 different cancer types.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('cancer', 'Disease', 'MESH:D009369', (249, 255))	('cancer', 'Disease', (249, 255))	('mutated', 'Var', (197, 204))	('REG', 'Gene', '5967', (22, 25))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('patients', 'Species', '9606', (220, 228))	('cancers', 'Disease', 'MESH:D009369', (157, 164))	('cancers', 'Disease', (157, 164))	('cancer', 'Disease', (157, 163))	('cancers', 'Phenotype', 'HP:0002664', (157, 164))	('mutations', 'Var', (144, 153))	('cancer', 'Phenotype', 'HP:0002664', (249, 255))	('REG', 'Gene', (22, 25))
209088	26975833	A most striking case exemplifying this can be observed analyzing the lung squamous cell carcinoma cohort comprised of 178 patients, who all presented with mutations in the top 100 REGs.	('mutations', 'Var', (155, 164))	('REG', 'Gene', '5967', (180, 183))	('presented', 'Reg', (140, 149))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (74, 97))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (69, 97))	('REG', 'Gene', (180, 183))	('lung squamous cell carcinoma', 'Disease', (69, 97))	('patients', 'Species', '9606', (122, 130))
209089	26975833	In like fashion, the top 100 REGs are mutated in (99.60%) of a 239-strong cohort of Uterine Corpus Endometrioid Carcinoma patients; over half of which were single nucleotide mutations.	('mutated', 'Var', (38, 45))	('single nucleotide mutations', 'Var', (156, 183))	('Corpus Endometrioid Carcinoma', 'Disease', (92, 121))	('Carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('Endometrioid Carcinoma', 'Phenotype', 'HP:0012114', (99, 121))	('Corpus Endometrioid Carcinoma', 'Disease', 'MESH:D016889', (92, 121))	('patients', 'Species', '9606', (122, 130))	('REG', 'Gene', '5967', (29, 32))	('REG', 'Gene', (29, 32))
209091	26975833	As summarized in Table S7, the top 100 REGs have mutations in over 50% of patients across 67 major cancer types.	('mutations', 'Var', (49, 58))	('patients', 'Species', '9606', (74, 82))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('cancer', 'Disease', (99, 105))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('REG', 'Gene', '5967', (39, 42))	('REG', 'Gene', (39, 42))
209095	26975833	In total, the 19 REGs possess 8221 mutation events in multiple cancer types, mainly concentrated in regions encoding protein functional domains.	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('REG', 'Gene', (17, 20))	('mutation', 'Var', (35, 43))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('cancer', 'Disease', (63, 69))	('REG', 'Gene', '5967', (17, 20))
209140	30519324	P53 Codon 72 Polymorphism and Risk for Squamous Cell Carcinoma of the Penis: A Caucasian Case-Control Study Squamous cell carcinoma of the penis is a rare but often aggressive disease.	('Polymorphism', 'Var', (13, 25))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (39, 62))	('carcinoma of the penis', 'Phenotype', 'HP:0100850', (122, 144))	('Squamous Cell Carcinoma of the Penis', 'Disease', 'MESH:D002294', (39, 75))	('P53', 'Gene', (0, 3))	('Squamous cell carcinoma of the penis', 'Disease', (108, 144))	('aggressive disease', 'Disease', 'MESH:D001523', (165, 183))	('Squamous cell carcinoma', 'Phenotype', 'HP:0002860', (108, 131))	('P53', 'Gene', '7157', (0, 3))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('Squamous Cell Carcinoma of the Penis', 'Disease', (39, 75))	('Carcinoma of the Penis', 'Phenotype', 'HP:0100850', (53, 75))	('aggressive disease', 'Disease', (165, 183))	('Squamous cell carcinoma of the penis', 'Disease', 'MESH:D002294', (108, 144))	('Carcinoma', 'Phenotype', 'HP:0030731', (53, 62))
209142	30519324	From other HPV-related malignancies a link between a functional SNP in the p53 gene (rs1042522, p.Arg72Pro) and a higher disease risk in the presence of HPV is documented.	('p.Arg72Pro', 'Var', (96, 106))	('HPV', 'Species', '10566', (11, 14))	('malignancies', 'Disease', (23, 35))	('p.Arg72Pro', 'Mutation', 'rs1042522', (96, 106))	('rs1042522', 'Mutation', 'rs1042522', (85, 94))	('malignancies', 'Disease', 'MESH:D009369', (23, 35))	('p53', 'Gene', (75, 78))	('p53', 'Gene', '7157', (75, 78))	('HPV', 'Species', '10566', (153, 156))	('rs1042522', 'Var', (85, 94))	('men', 'Species', '9606', (164, 167))
209143	30519324	The p53 p.Arg72 variant was described as a risk factor for developing a malignancy in combination with the presence of HPV as the p.72Arg variant is more prone to HPV E6 protein-mediated degradation than the p.72Pro variant.	('Arg72', 'Chemical', '-', (10, 15))	('HPV E6 protein-mediated degradation', 'MPA', (163, 198))	('malignancy', 'Disease', 'MESH:D009369', (72, 82))	('p53', 'Gene', '7157', (4, 7))	('p.Arg72', 'Var', (8, 15))	('developing', 'Disease', (59, 69))	('HPV', 'Species', '10566', (163, 166))	('malignancy', 'Disease', (72, 82))	('HPV', 'Species', '10566', (119, 122))	('p.72Arg', 'Var', (130, 137))	('prone', 'Reg', (154, 159))	('Arg', 'Chemical', 'MESH:D001120', (134, 137))	('p53', 'Gene', (4, 7))	('Arg', 'Chemical', 'MESH:D001120', (10, 13))
209153	30519324	Epidemiological studies revealed several risk factors for penile carcinoma like low standards of hygiene, phimosis, high number of sexual partners (early age at first sexual intercourse), presence of Human Papilloma Virus (HPV) infection, circumcision practice, recurrent balanitis, strong tobacco consumption, genital ultraviolet radiation and penile trauma.	('balanitis', 'Disease', (272, 281))	('penile carcinoma', 'Disease', 'MESH:D004414', (58, 74))	('sexual intercourse', 'Phenotype', 'HP:0030214', (167, 185))	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('tobacco', 'Species', '4097', (290, 297))	('phimosis', 'Phenotype', 'HP:0001741', (106, 114))	('penile carcinoma', 'Disease', (58, 74))	('phimosis', 'Disease', 'MESH:D010688', (106, 114))	('phimosis', 'Disease', (106, 114))	('presence', 'Var', (188, 196))	('Papilloma', 'Phenotype', 'HP:0012740', (206, 215))	('penile trauma', 'Disease', 'MESH:D004414', (345, 358))	('penile trauma', 'Disease', (345, 358))	('Human Papilloma Virus (HPV) infection', 'Disease', 'MESH:D030361', (200, 237))	('balanitis', 'Disease', 'MESH:D001446', (272, 281))
209163	30519324	This E6 protein guided degradation is also influenced by a functional single nucleotide polymorphism (SNP) in exon 4 of the p53 gene.	('single nucleotide polymorphism', 'Var', (70, 100))	('p53', 'Gene', '7157', (124, 127))	('p53', 'Gene', (124, 127))	('influenced by', 'Reg', (43, 56))
209164	30519324	At position 215 of the p53 cDNA either a guanine (5'-CGC-3', encoding for the amino acid arginine) or a cytosine (5'-CCC-3', encoding for the amino acid proline) base is located resulting in a polymorphic amino acid site at codon 72 of P53 (p.Arg72Pro).	('guanine', 'Chemical', 'MESH:D006147', (41, 48))	('amino acid proline', 'Chemical', '-', (142, 160))	('P53', 'Gene', '7157', (236, 239))	('p.Arg72Pro', 'Mutation', 'rs1042522', (241, 251))	('amino acid arginine', 'Chemical', '-', (78, 97))	('p53', 'Gene', (23, 26))	('p53', 'Gene', '7157', (23, 26))	('cytosine', 'Chemical', 'MESH:D003596', (104, 112))	('p.Arg72Pro', 'Var', (241, 251))	('P53', 'Gene', (236, 239))
209165	30519324	The p.Arg72 variant was shown to be more prone to the E6 protein guided degradation than the p.72Pro variant.	('p.Arg72', 'Var', (4, 11))	('prone', 'PosReg', (41, 46))	('E6 protein guided degradation', 'MPA', (54, 83))	('Arg72', 'Chemical', '-', (6, 11))
209168	30519324	oral cancer, cervical cancer, vulvar and vaginal carcinoma) disease risk was shown to be influenced by the p53 p.Arg72Pro SNP suggesting the p.72Arg variant as a risk factor for cancer development in high risk HPV positive individuals.	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('vaginal carcinoma', 'Disease', 'MESH:D014627', (41, 58))	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('Arg', 'Chemical', 'MESH:D001120', (145, 148))	('p53', 'Gene', (107, 110))	('p.72Arg', 'Var', (141, 148))	('influenced', 'Reg', (89, 99))	('vulvar', 'Disease', (30, 36))	('men', 'Species', '9606', (192, 195))	('Arg', 'Chemical', 'MESH:D001120', (113, 116))	('risk', 'Reg', (162, 166))	('HPV', 'Species', '10566', (210, 213))	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('cancer', 'Disease', 'MESH:D009369', (5, 11))	('p.Arg72Pro SNP', 'Var', (111, 125))	('cervical cancer', 'Disease', (13, 28))	('cervical cancer', 'Disease', 'MESH:D002583', (13, 28))	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))	('vaginal carcinoma', 'Disease', (41, 58))	('cancer', 'Disease', (22, 28))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('p53', 'Gene', '7157', (107, 110))	('oral cancer', 'Disease', 'MESH:D009062', (0, 11))	('cancer', 'Disease', (5, 11))	('vaginal carcinoma', 'Phenotype', 'HP:0100650', (41, 58))	('oral cancer', 'Disease', (0, 11))	('cancer', 'Disease', (178, 184))	('p.Arg72Pro', 'Mutation', 'rs1042522', (111, 121))
209178	30519324	SNP analysis was performed using restriction fragment length polymorphism analysis (RFLP) of the polymorphic region in exon 4 of the p53 gene which contains a Bst UI recognition site (5' -CG   CG-3') in the presence of the G-allele (p.72Arg) as described previously.	('men', 'Species', '9606', (49, 52))	('p.72Arg', 'Var', (233, 240))	('p53', 'Gene', '7157', (133, 136))	('p53', 'Gene', (133, 136))	('Arg', 'Chemical', 'MESH:D001120', (237, 240))
209179	30519324	Presence of the p.72Arg allele resulted in digestion of the PCR product (196bp = 113 + 83bp), whereas PCR products containing the C-allele (p.72Pro) remained unaffected.	('p.72Arg', 'Var', (16, 23))	('Arg', 'Chemical', 'MESH:D001120', (20, 23))	('digestion', 'MPA', (43, 52))
209210	30519324	Although the most prominent p53 variant plays no important role in penile carcinogenesis p53 alterations are a major feature of penile carcinomas.	('p53', 'Gene', (28, 31))	('penile carcinomas', 'Disease', (128, 145))	('p53', 'Gene', '7157', (28, 31))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('alterations', 'Var', (93, 104))	('carcinomas', 'Phenotype', 'HP:0030731', (135, 145))	('p53', 'Gene', (89, 92))	('penile carcinomas', 'Disease', 'MESH:D004414', (128, 145))	('penile carcinogenesis', 'Disease', 'MESH:D004414', (67, 88))	('p53', 'Gene', '7157', (89, 92))	('penile carcinogenesis', 'Disease', (67, 88))
209212	30519324	However, inconsistent data can be found on the frequency of p53 mutations.	('p53', 'Gene', (60, 63))	('mutations', 'Var', (64, 73))	('p53', 'Gene', '7157', (60, 63))
209213	30519324	Previous studies reported only a lower frequency (17% - 25%) of p53 mutations, whereas recent genomic profiling studies reported p53 alterations in up to 76% of the cases analyzed.	('alterations', 'Var', (133, 144))	('p53', 'Gene', (129, 132))	('p53', 'Gene', '7157', (129, 132))	('mutations', 'Var', (68, 77))	('p53', 'Gene', (64, 67))	('p53', 'Gene', '7157', (64, 67))
209214	30519324	different sensitivity levels for detection of mutations for SSCP, Sanger and next-generation sequencing), ethnical differences (Asian and Caucasian cohorts), HPV status and number of analyzed samples or histopathological characteristics of the tumors.	('tumor', 'Phenotype', 'HP:0002664', (244, 249))	('mutations', 'Var', (46, 55))	('tumors', 'Disease', (244, 250))	('tumors', 'Disease', 'MESH:D009369', (244, 250))	('tumors', 'Phenotype', 'HP:0002664', (244, 250))	('HPV', 'Species', '10566', (158, 161))	('SSCP', 'Gene', (60, 64))	('HPV', 'Gene', (158, 161))
209216	30519324	But despite inconsistent findings p53 dysregulation obviously plays a crucial role in the development of penile carcinoma whose elucidation would be important for a better understanding of this disease.	('p53', 'Gene', (34, 37))	('p53', 'Gene', '7157', (34, 37))	('men', 'Species', '9606', (97, 100))	('penile carcinoma', 'Disease', 'MESH:D004414', (105, 121))	('dysregulation', 'Var', (38, 51))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('penile carcinoma', 'Disease', (105, 121))
209219	30519324	Especially, in heterozygous individuals LOH could cause an enrichment of one allele in the tumors that biased the frequencies of allelic distribution between cases and controls.	('cause', 'Reg', (50, 55))	('tumors', 'Disease', 'MESH:D009369', (91, 97))	('tumors', 'Disease', (91, 97))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('men', 'Species', '9606', (65, 68))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('LOH', 'Var', (40, 43))
209227	30519324	inflammation after laser-assisted evaporation of pre-neoplastic lesions, inactivation of p53 degeneration pathways) might be taken in consideration as it was already discussed for penile carcinoma and in other cancer entities.	('penile carcinoma', 'Disease', 'MESH:D004414', (180, 196))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('carcinoma', 'Phenotype', 'HP:0030731', (187, 196))	('inactivation', 'Var', (73, 85))	('p53', 'Gene', (89, 92))	('penile carcinoma', 'Disease', (180, 196))	('neoplastic lesions', 'Phenotype', 'HP:0002664', (53, 71))	('cancer', 'Disease', 'MESH:D009369', (210, 216))	('p53', 'Gene', '7157', (89, 92))	('cancer', 'Disease', (210, 216))
209239	30214895	The first N-terminal WW domain of WWOX binds protein ligands harboring motifs with core proline-rich sequences, not only PPXY (amino acid single-letter code; X is any amino acid) (PY) but also LPXY and LPXF motifs (where F is phenylalanine and L is leucine).	('proline', 'Chemical', 'MESH:D011392', (88, 95))	('LPXY', 'Var', (193, 197))	('PPXY', 'Var', (121, 125))	('LPXY', 'Chemical', '-', (193, 197))	('phenylalanine', 'Chemical', 'MESH:D010649', (226, 239))	('leucine', 'Chemical', 'MESH:D007930', (249, 256))
209245	30214895	WWOX is located on the common fragile site FRA16D, which has been linked to cancer-causing deletions and translocations.	('FRA16D', 'Gene', '2463', (43, 49))	('deletions', 'Var', (91, 100))	('linked', 'Reg', (66, 72))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('FRA16D', 'Gene', (43, 49))
209249	30214895	The authors agree with the opinion that "despite many lines of evidence that suggest a role for loss of WWOX in the progression of cancer, our understanding of WWOX tumor-suppressive function is incomplete, as found in a recent remarkable report from Schrock et al..	('cancer', 'Disease', (131, 137))	('loss', 'Var', (96, 100))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('WWOX', 'Gene', (104, 108))	('tumor', 'Disease', (165, 170))
209258	30214895	First, WWOX spans in the second most common human chromosomal fragile site, FRA16D at 16q23.	('human', 'Species', '9606', (44, 49))	('FRA16D', 'Gene', '2463', (76, 82))	('WWOX', 'Var', (7, 11))	('chromosomal fragile site', 'Phenotype', 'HP:0040012', (50, 74))	('FRA16D', 'Gene', (76, 82))
209293	30214895	Further study exploring whether loss of WWOX participates in cutaneous adnexal tumorigenesis is needed.	('cutaneous adnexal tumor', 'Phenotype', 'HP:0012842', (61, 84))	('cutaneous adnexal tumor', 'Disease', 'MESH:D000292', (61, 84))	('cutaneous adnexal tumor', 'Disease', (61, 84))	('WWOX', 'Gene', (40, 44))	('cutaneous adnexal tumorigenesis', 'Phenotype', 'HP:0012842', (61, 92))	('loss', 'Var', (32, 36))	('participates', 'Reg', (45, 57))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
209296	30214895	Mutational studies in mice have shown that Mitf is essential for melanocyte and eye development However, renal cystogenesis has not been reported in mice with MITF mutations.	('Mitf', 'Gene', '17342', (43, 47))	('MITF', 'Gene', (159, 163))	('Mitf', 'Gene', (43, 47))	('MITF', 'Gene', '17342', (159, 163))	('mice', 'Species', '10090', (149, 153))	('mutations', 'Var', (164, 173))	('mice', 'Species', '10090', (22, 26))
209315	30214895	Overexpression of TMEM207 is significantly associated with nodal metastasis and poor prognosis of OSCC patients.	('nodal metastasis', 'Disease', (59, 75))	('OSCC', 'Disease', (98, 102))	('nodal metastasis', 'Disease', 'MESH:D009362', (59, 75))	('Overexpression', 'Var', (0, 14))	('associated', 'Reg', (43, 53))	('patients', 'Species', '9606', (103, 111))	('TMEM207', 'Gene', (18, 25))
209326	30214895	Overexpression of TMEM207 may participate in cancer metabolism to promote cancer growth.	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('participate', 'Reg', (30, 41))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('promote', 'PosReg', (66, 73))	('cancer', 'Disease', (74, 80))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('Overexpression', 'Var', (0, 14))	('cancer', 'Disease', (45, 51))	('TMEM207', 'Gene', (18, 25))
209328	30214895	Moreover, Kaplan Meier plotter analysis, http://kmplot.com/analysis/, indicated that high expression of TMEM207 correlates with worse prognosis in gastric cancer.	('gastric cancer', 'Phenotype', 'HP:0012126', (147, 161))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('high', 'Var', (85, 89))	('gastric cancer', 'Disease', (147, 161))	('gastric cancer', 'Disease', 'MESH:D013274', (147, 161))	('TMEM207', 'Gene', (104, 111))
209360	29575529	Interestingly, PDPN downregulation caused an increase in E-Cadherin expression, suggesting that PDPN induces NHEK migration coupled with a loss of E-cadherin.	('NHEK migration', 'CPA', (109, 123))	('E-Cadherin', 'Gene', (57, 67))	('expression', 'MPA', (68, 78))	('loss', 'NegReg', (139, 143))	('downregulation', 'NegReg', (20, 34))	('E-cadherin', 'Gene', '999', (147, 157))	('E-Cadherin', 'Gene', '999', (57, 67))	('E-cadherin', 'Gene', (147, 157))	('PDPN', 'Gene', (15, 19))	('induces', 'Reg', (101, 108))	('PDPN', 'Var', (96, 100))	('increase', 'PosReg', (45, 53))
209373	29575529	For example, a derivative of 4-O-benzoyl-3-methoxy-beta-nitrostyrene (BMNS), compound "2CP," effectively suppresses PDPN-mediated platelet aggregation and tumor cell-induced platelet activation.33 2CP specifically binds to CLEC-2 and interacts with critical positions (Asn105, Arg107, Phe116, Arg118 and Arg157) to inhibit its binding to PDPN, as shown in Figure 1.33, 43 As the first defined CLEC-2 antagonist, 2CP not only possesses anti-cancer metastatic activity but also enlarges the therapeutic efficacy of cisplatin while decreasing the risk of bleeding in experimental metastasis models.	('platelet aggregation', 'Phenotype', 'HP:0003540', (130, 150))	('cancer', 'Phenotype', 'HP:0002664', (440, 446))	('tumor', 'Disease', (155, 160))	('bleeding', 'Disease', (552, 560))	('decreasing', 'NegReg', (529, 539))	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('inhibit', 'NegReg', (315, 322))	('Phe116', 'Var', (285, 291))	('cancer', 'Disease', 'MESH:D009369', (440, 446))	('platelet aggregation', 'Disease', 'MESH:D001791', (130, 150))	('Arg118', 'Var', (293, 299))	('cancer', 'Disease', (440, 446))	('Arg157', 'Var', (304, 310))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('binding', 'Interaction', (327, 334))	('2CP', 'Var', (412, 415))	('enlarges', 'PosReg', (476, 484))	('bleeding', 'Disease', 'MESH:D006470', (552, 560))	('therapeutic', 'MPA', (489, 500))	('platelet aggregation', 'Disease', (130, 150))	('Arg107', 'Var', (277, 283))
209376	29575529	Platelet deletion of CLEC-2 or PDPN-deficient hematopoietic cells increased the clinical severity of sepsis associated with enhanced systemic inflammation and accelerated organ injury.	('sepsis', 'Disease', (101, 107))	('CLEC-2', 'Gene', (21, 27))	('increased', 'PosReg', (66, 75))	('inflammation', 'Disease', 'MESH:D007249', (142, 154))	('deletion', 'Var', (9, 17))	('inflammation', 'Disease', (142, 154))	('sepsis', 'Disease', 'MESH:D018805', (101, 107))	('organ injury', 'Disease', 'MESH:D019965', (171, 183))	('enhanced', 'PosReg', (124, 132))	('organ injury', 'Disease', (171, 183))	('PDPN-deficient', 'Gene', (31, 45))	('clinical', 'Species', '191496', (80, 88))	('sepsis', 'Phenotype', 'HP:0100806', (101, 107))	('clinical severity', 'MPA', (80, 97))	('accelerated', 'PosReg', (159, 170))
209383	29575529	Furthermore, both serines need to be phosphorylated to inhibit cell migration.4, 58 Phosphorylation can modify the structural conformation of amino acids in the PDPN intracellular domain, as shown in Figure 3.	('migration.4', 'Var', (68, 79))	('structural conformation of amino acids', 'MPA', (115, 153))	('Phosphorylation', 'Var', (84, 99))	('modify', 'Reg', (104, 110))	('serines', 'Chemical', 'MESH:D012694', (18, 25))
209400	29575529	Moreover, high levels of PDPN expression is associated with reduced survival and cancer aggression.	('aggression', 'Phenotype', 'HP:0000718', (88, 98))	('expression', 'MPA', (30, 40))	('PDPN', 'Gene', (25, 29))	('survival', 'CPA', (68, 76))	('high levels', 'Var', (10, 21))	('cancer aggression', 'Disease', 'MESH:D009369', (81, 98))	('reduced', 'NegReg', (60, 67))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('cancer aggression', 'Disease', (81, 98))
209526	26716504	Notably, we confirmed that Rab23 was co-localized with integrin beta1 in cell membrane of Rab23 WT and Rab23 Q68L stable expression cells and Rab23 efficiently coprecipitated with integrin beta1 and Tiam1 in a GTP-dependent manner.	('Tiam1', 'Gene', (199, 204))	('integrin beta1', 'Gene', '3688', (180, 194))	('integrin beta1', 'Gene', '3688', (55, 69))	('Tiam1', 'Gene', '7074', (199, 204))	('GTP', 'Chemical', 'MESH:D006160', (210, 213))	('Rab23', 'Gene', (103, 108))	('Q68L', 'Var', (109, 113))	('Rab23', 'Gene', (90, 95))	('Q68L', 'Mutation', 'p.Q68L', (109, 113))	('integrin beta1', 'Gene', (180, 194))	('integrin beta1', 'Gene', (55, 69))
209545	26716504	Knocking down Rab23 suppressed Hep3B cell growth.	('Knocking down', 'Var', (0, 13))	('suppressed', 'NegReg', (20, 30))	('Hep3B', 'CellLine', 'CVCL:0326', (31, 36))	('Rab23', 'Gene', (14, 19))	('Hep3B cell growth', 'CPA', (31, 48))
209561	26716504	Silencing of Rab23 with siRNA fragment suppressed cell invasion in HSQ-89 cell line, while overexpression of Rab23 increased Rab23 mRNA and protein expression and promoted cell invasion in Sa3 cell lines (Figure 2D, 2E).	('promoted', 'PosReg', (163, 171))	('Rab23', 'Gene', (109, 114))	('increased', 'PosReg', (115, 124))	('Rab23', 'Gene', (13, 18))	('cell invasion', 'CPA', (172, 185))	('Sa3', 'CellLine', 'CVCL:8063', (189, 192))	('cell invasion', 'CPA', (50, 63))	('Rab23', 'Gene', (125, 130))	('Silencing', 'Var', (0, 9))	('suppressed', 'NegReg', (39, 49))
209562	26716504	Furthermore, to determine whether Rab23 promotes cell invasion resulted from GTP-bound form of Rab23, we overexpressed Rab23 Q68L or Rab23 S23N that are constitutively GTP or GDP bound forms and act in a dominant active or dominant negative manner respectively.	('Rab23', 'Gene', (119, 124))	('GDP', 'Chemical', 'MESH:D006153', (175, 178))	('GTP', 'Chemical', 'MESH:D006160', (168, 171))	('S23N', 'Mutation', 'p.S23N', (139, 143))	('Q68L', 'Var', (125, 129))	('Q68L', 'Mutation', 'p.Q68L', (125, 129))	('cell invasion', 'CPA', (49, 62))	('GTP', 'Chemical', 'MESH:D006160', (77, 80))	('Rab23', 'Gene', (133, 138))
209565	26716504	As shown in Figure 3D and 3E, Rab23 Q68L promoted tumor formation while Rab23 S23N restrained tumor formation, compared to control (EGFP).	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('Rab23 S23N', 'Var', (72, 82))	('restrained', 'NegReg', (83, 93))	('Rab23 Q68L', 'Var', (30, 40))	('promoted', 'PosReg', (41, 49))	('tumor', 'Disease', (94, 99))	('Q68L', 'Var', (36, 40))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('Q68L', 'Mutation', 'p.Q68L', (36, 40))	('S23N', 'Mutation', 'p.S23N', (78, 82))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Disease', (50, 55))
209572	26716504	As shown in Figure 5G, the active conformation of GTP-bound Rac1 was upregulated in Rab23 WT and Rab23 Q68L stably expressing cells, while GTP-bound Rac1 was downregulated in Rab23 S23N stably expressing cells.	('GTP', 'Chemical', 'MESH:D006160', (50, 53))	('Q68L', 'Var', (103, 107))	('Q68L', 'Mutation', 'p.Q68L', (103, 107))	('Rab23 Q68L', 'Var', (97, 107))	('active conformation', 'MPA', (27, 46))	('Rac1', 'Gene', (60, 64))	('upregulated', 'PosReg', (69, 80))	('S23N', 'Mutation', 'p.S23N', (181, 185))	('Rab23', 'Gene', (84, 89))	('GTP', 'Chemical', 'MESH:D006160', (139, 142))
209577	26716504	Further, we observed that Rab23 was colocalized with integrin beta1 in cell membrane of Rab23 WT and Rab23 Q68L stable expression Sa3 cells (Figure 6A).	('integrin beta1', 'Gene', (53, 67))	('Q68L', 'Mutation', 'p.Q68L', (107, 111))	('integrin beta1', 'Gene', '3688', (53, 67))	('Sa3', 'CellLine', 'CVCL:8063', (130, 133))	('Q68L', 'Var', (107, 111))	('Rab23', 'Gene', (101, 106))	('Rab23', 'Gene', (88, 93))
209599	26716504	We found that Rab23 WT and Rab23 Q68L overexpression promoted cell migration and invasion and Rac1 was activated in Rab23 WT and Rab23 Q68L overexpression Sa3 cells (Figure 5G).	('Rab23', 'Gene', (116, 121))	('promoted', 'PosReg', (53, 61))	('cell migration', 'CPA', (62, 76))	('invasion', 'CPA', (81, 89))	('Q68L', 'Mutation', 'p.Q68L', (135, 139))	('Rab23 Q68L', 'Var', (129, 139))	('Q68L', 'Mutation', 'p.Q68L', (33, 37))	('Sa3', 'CellLine', 'CVCL:8063', (155, 158))	('activated', 'PosReg', (103, 112))	('Rac1', 'Gene', (94, 98))
209605	26716504	Besides, we found Rab23 could not coprecipitated with Tiam1 after integrinbeta1 knock down (Figure 6C) and cell invasion promoted by Rab23 were reduced after integrinbeta1 knock down (Figure 6D, 6E).	('reduced', 'NegReg', (144, 151))	('integrinbeta1', 'Gene', (66, 79))	('knock down', 'Var', (80, 90))	('integrinbeta1', 'Gene', '3688', (66, 79))	('cell invasion', 'CPA', (107, 120))	('integrinbeta1', 'Gene', (158, 171))	('integrinbeta1', 'Gene', '3688', (158, 171))	('Tiam1', 'Gene', (54, 59))	('Tiam1', 'Gene', '7074', (54, 59))	('Rab23', 'Gene', (133, 138))	('knock down', 'Var', (172, 182))
209608	26716504	Further, we revealed a direct interaction among integrin beta1, Rab23 and Tiam1, the direct interaction between Rab23 and Tiam1 was disappeared after integrin beta1 knock down.	('Rab23', 'Gene', (64, 69))	('integrin beta1', 'Gene', (150, 164))	('interaction', 'Interaction', (30, 41))	('knock', 'Var', (165, 170))	('integrin beta1', 'Gene', '3688', (150, 164))	('Tiam1', 'Gene', '7074', (74, 79))	('Tiam1', 'Gene', (74, 79))	('integrin beta1', 'Gene', (48, 62))	('Tiam1', 'Gene', '7074', (122, 127))	('Tiam1', 'Gene', (122, 127))	('integrin beta1', 'Gene', '3688', (48, 62))
209619	26716504	siRNAs targeting Rac1 and Integrin beta1 were transfected at 100nM concentration to EGFP, Rab23 WT, Rab23 Q68L or Rab23 S23N stable expression cells using Lipofectamine 2000 (Invitrogen) according to the manufacturer's instructions.	('Rab23', 'Var', (100, 105))	('Integrin beta1', 'Gene', (26, 40))	('Rab23 S23N', 'Var', (114, 124))	('S23N', 'Mutation', 'p.S23N', (120, 124))	('Q68L', 'Mutation', 'p.Q68L', (106, 110))	('Lipofectamine 2000', 'Chemical', 'MESH:C086724', (155, 173))	('Integrin beta1', 'Gene', '3688', (26, 40))	('Q68L', 'Var', (106, 110))
209623	26716504	Sa3 cells expressing EGFP, Rab23 Q68L and Rab23 S23N were grown in Dulbecco's Modified Eagle's Minimal Essential Medium (DMEM) (Gibco-Invitrogen) supplemented with 10% fetal bovine serum (Gibco- Invitrogen) in a humidified atmosphere containing 5% CO2 at 37 C. Then nude female mice at 6 weeks of age were injected with 1.0 x 106 cells form tail vein.	('Rab23 S23N', 'Var', (42, 52))	('bovine', 'Species', '9913', (174, 180))	('DMEM', 'Chemical', '-', (121, 125))	('Sa3', 'CellLine', 'CVCL:8063', (0, 3))	('mice', 'Species', '10090', (278, 282))	('EGFP', 'Gene', (21, 25))	('Q68L', 'Mutation', 'p.Q68L', (33, 37))	('Rab23 Q68L', 'Var', (27, 37))	('CO2', 'Chemical', '-', (248, 251))	('S23N', 'Mutation', 'p.S23N', (48, 52))	("Dulbecco's Modified Eagle's Minimal Essential Medium", 'Chemical', '-', (67, 119))
209627	26716504	After 24 h, successful co-transfection of plasmid including the Scramble RNA, Rab23 RNAi, EGFP, Rab23 WT, Rab23 Q68L or Rab23 S23N with pHelper 1.0 and pHelper 2.0 plasmid by the Lipofectamine 2000 method according to the manufacturer's instructions.	('Lipofectamine 2000', 'Chemical', 'MESH:C086724', (179, 197))	('Rab23 Q68L', 'Var', (106, 116))	('S23N', 'Mutation', 'p.S23N', (126, 130))	('Q68L', 'Mutation', 'p.Q68L', (112, 116))	('Rab23 S23N', 'Var', (120, 130))
209631	26716504	Then, Sa3 cells were infected with lentiviral particles containing Scramble RNA, Rab23 RNAi, EGFP, Rab23 WT, Rab23 Q68L or Rab23 S23N for 8h.	('S23N', 'Mutation', 'p.S23N', (129, 133))	('Q68L', 'Mutation', 'p.Q68L', (115, 119))	('Rab23 Q68L', 'Var', (109, 119))	('Sa3', 'CellLine', 'CVCL:8063', (6, 9))	('Rab23 S23N', 'Var', (123, 133))
209640	33549049	A prognosis-related molecular subtype for early-stage non-small lung cell carcinoma by multi-omics integration analysis Early-stage non-small cell lung carcinoma (NSCLC) accounts for more than 80% of lung cancer, which is a kind of cancer with high heterogeneity, so the genetic heterogeneity and molecular subtype should be explored.	('carcinoma', 'Phenotype', 'HP:0030731', (152, 161))	('cancer', 'Disease', 'MESH:D009369', (205, 211))	('lung cancer', 'Disease', 'MESH:D008175', (200, 211))	('cancer', 'Disease', (232, 238))	('non-small cell lung carcinoma', 'Phenotype', 'HP:0030358', (132, 161))	('non-small lung cell carcinoma', 'Phenotype', 'HP:0030358', (54, 83))	('lung cancer', 'Phenotype', 'HP:0100526', (200, 211))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('small cell lung carcinoma', 'Phenotype', 'HP:0030357', (136, 161))	('lung cell carcinoma', 'Disease', (64, 83))	('NSCLC', 'Disease', 'MESH:D002289', (163, 168))	('lung carcinoma', 'Disease', (147, 161))	('small lung', 'Phenotype', 'HP:0002089', (58, 68))	('cancer', 'Disease', 'MESH:D009369', (232, 238))	('cancer', 'Disease', (205, 211))	('NSCLC', 'Disease', (163, 168))	('Early-stage', 'Var', (120, 131))	('small lung cell carcinoma', 'Phenotype', 'HP:0030357', (58, 83))	('lung cancer', 'Disease', (200, 211))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('lung cell carcinoma', 'Disease', 'MESH:D055752', (64, 83))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('lung carcinoma', 'Disease', 'MESH:D008175', (147, 161))
209674	33549049	For LUAD patients, the methylated genes were significantly enriched in 11 biological process terms, 9 cellular component terms, 7 molecular function terms, and 2 KEGG pathways (Supplementary Table 2).	('patients', 'Species', '9606', (9, 17))	('KEGG pathways', 'Pathway', (162, 175))	('methylated genes', 'Var', (23, 39))
209682	33549049	Five methylation sites (cg00894870, cg03041700, cg08356572, cg11416447 and cg22627950) were selected as biomarkers for both LUSC-C1 and LUSC-C3, in which the function of 4 methylated genes were associated with cancer.	('cg00894870', 'Var', (24, 34))	('cg22627950', 'Var', (75, 85))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('cg11416447', 'Var', (60, 70))	('cg03041700', 'Var', (36, 46))	('associated', 'Reg', (194, 204))	('cg08356572', 'Var', (48, 58))	('cancer', 'Disease', 'MESH:D009369', (210, 216))	('cancer', 'Disease', (210, 216))
209685	33549049	KIAA0090, which was positively related with hypo-methylated cg00894870, was associated with cancer metastasis and prognosis.	('prognosis', 'CPA', (114, 123))	('cancer', 'Disease', (92, 98))	('KIAA0090', 'Gene', (0, 8))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('hypo-methylated', 'Var', (44, 59))	('associated', 'Reg', (76, 86))	('KIAA0090', 'Gene', '23065', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('cg00894870', 'Gene', (60, 70))
209692	33549049	The aberrant methylations of these genes were also found in breast cancer.	('breast cancer', 'Disease', (60, 73))	('methylations', 'Var', (13, 25))	('aberrant methylations', 'Var', (4, 25))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('breast cancer', 'Disease', 'MESH:D001943', (60, 73))	('found', 'Reg', (51, 56))	('breast cancer', 'Phenotype', 'HP:0003002', (60, 73))
209716	27851819	NACT can decrease tumor size, eliminate subclinical lesions and decrease the risk of lymph node metastasis thereby minimizing the need for postsurgical radiotherapy.	('NACT', 'Chemical', '-', (0, 4))	('decrease the risk of lymph node metastasis', 'Phenotype', 'HP:0002732', (64, 106))	('decrease', 'NegReg', (64, 72))	('tumor', 'Disease', (18, 23))	('eliminate', 'NegReg', (30, 39))	('lymph node metastasis', 'CPA', (85, 106))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('decrease', 'NegReg', (9, 17))	('subclinical lesions', 'MPA', (40, 59))	('NACT', 'Var', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
209772	27851819	Our study showed that FBG >= 100 mg/dl was a significant risk factor for recurrence and cancer-specific death.	('recurrence', 'CPA', (73, 83))	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('>= 100 mg/dl', 'Var', (26, 38))	('FBG', 'Gene', (22, 25))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))
209780	27851819	They reported that patients with glucose levels >=102 mg/dl had decreased CSS time and progression-free intervals after adjusting for other clinical factors.	('>=102 mg/dl', 'Var', (48, 59))	('patients', 'Species', '9606', (19, 27))	('progression-free intervals', 'CPA', (87, 113))	('glucose', 'Chemical', 'MESH:D005947', (33, 40))	('CSS', 'Chemical', '-', (74, 77))	('CSS time', 'CPA', (74, 82))	('decreased', 'NegReg', (64, 73))
209830	27669306	To date, several vaccination strategies have been applied, including the transfection of TAA expression plasmids into patient tissues (DNA vaccines), the administration of TAA peptides (peptide vaccines), and the use of cultured human or microbial cells to generate an antitumor immune response.	('TAA', 'Gene', (89, 92))	('tumor', 'Disease', 'MESH:D009369', (273, 278))	('peptides', 'Chemical', 'MESH:D010455', (176, 184))	('human', 'Species', '9606', (229, 234))	('tumor', 'Disease', (273, 278))	('transfection', 'Var', (73, 85))	('tumor', 'Phenotype', 'HP:0002664', (273, 278))	('patient', 'Species', '9606', (118, 125))
209866	27669306	Furthermore, in a trial of 43 patients, HPV16-positive high-grade vulvar and vaginal intraepithelial neoplasia treated with ISA101 plus imiquimod or ISA101 alone, clinical response was observed at 3 months in 18 of 34 patients completing the vaccine series and in 15 of 29 patients evaluated at 12 months.	('ISA101', 'Var', (124, 130))	('HPV16', 'Species', '333760', (40, 45))	('patients', 'Species', '9606', (273, 281))	('patients', 'Species', '9606', (218, 226))	('neoplasia', 'Phenotype', 'HP:0002664', (101, 110))	('patients', 'Species', '9606', (30, 38))	('intraepithelial neoplasia', 'Phenotype', 'HP:0032187', (85, 110))	('vaginal intraepithelial neoplasia', 'Disease', (77, 110))	('HPV16-positive', 'Gene', (40, 54))	('vaginal intraepithelial neoplasia', 'Disease', 'MESH:D019048', (77, 110))
209873	27669306	Similarly, preliminary results from the GOG-0265 trial demonstrated a 1-year survival rate of 38.5% for 26 women with persistent or recurrent metastatic cervical cancer treated with three doses of ADXS11-001 at 1 x 109 CFU, compared to a 20% 1-year survival rate for historical controls.	('cervical cancer', 'Disease', (153, 168))	('ADXS11-001', 'Var', (197, 207))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('women', 'Species', '9606', (107, 112))	('cervical cancer', 'Disease', 'MESH:D002583', (153, 168))
209886	27669306	Although these antibodies target a range of molecules, many antibodies mediate their antitumor effects through similar mechanisms including the targeting of tumor cells for antibody-dependent cell-mediated cytotoxicity (ADCC), the direct inhibition of tumor growth signals, and inhibiting signaling pathways involved in maintaining immune self-tolerance.	('tumor', 'Disease', (157, 162))	('antibodies', 'Var', (60, 70))	('target', 'Reg', (26, 32))	('inhibition', 'NegReg', (238, 248))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('cytotoxicity', 'Disease', (206, 218))	('tumor', 'Disease', 'MESH:D009369', (252, 257))	('self-tolerance', 'Phenotype', 'HP:0100716', (339, 353))	('inhibiting', 'NegReg', (278, 288))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('signaling pathways', 'Pathway', (289, 307))	('tumor', 'Phenotype', 'HP:0002664', (252, 257))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('cytotoxicity', 'Disease', 'MESH:D064420', (206, 218))	('tumor', 'Disease', (252, 257))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
209890	27669306	Importantly, for colorectal cancer cetuximab is only effective for tumors expressing wild-type KRAS, as mutant KRAS provides growth signals that bypass EGFR inhibition.	('KRAS', 'Gene', '3845', (95, 99))	('colorectal cancer', 'Phenotype', 'HP:0003003', (17, 34))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('KRAS', 'Gene', (111, 115))	('tumors', 'Disease', 'MESH:D009369', (67, 73))	('cetuximab', 'Chemical', 'MESH:D000068818', (35, 44))	('mutant', 'Var', (104, 110))	('colorectal cancer', 'Disease', (17, 34))	('KRAS', 'Gene', '3845', (111, 115))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('KRAS', 'Gene', (95, 99))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('colorectal cancer', 'Disease', 'MESH:D015179', (17, 34))	('tumors', 'Disease', (67, 73))	('growth signals', 'MPA', (125, 139))
209907	27669306	A similar phase IIb study of 76 Indian patients comparing nimotuzumab plus chemoradiation therapy, nimotuzumab plus radiation therapy, chemoradiation therapy, and radiation therapy alone demonstrated improved survival in patients receiving nimotuzumab, with maximal OS in the nimotuzumab plus chemoradiation therapy group.	('patients', 'Species', '9606', (221, 229))	('patients', 'Species', '9606', (39, 47))	('nimotuzumab', 'Var', (240, 251))	('nimotuzumab', 'Chemical', 'MESH:C501466', (276, 287))	('survival', 'CPA', (209, 217))	('nimotuzumab', 'Chemical', 'MESH:C501466', (99, 110))	('nimotuzumab', 'Chemical', 'MESH:C501466', (58, 69))	('improved', 'PosReg', (200, 208))	('nimotuzumab', 'Chemical', 'MESH:C501466', (240, 251))
209915	27669306	Unfortunately, a phase II trial of ficlatuzumab plus the EGFR inhibitor gefitinib versus gefitinib alone showed no difference in PFS, although biomarker analysis demonstrated a paradoxically increased response to ficlatuzumab therapy for patients with activating EGFR mutations and lower cMET expression.	('response', 'MPA', (201, 209))	('gefitinib', 'Chemical', 'MESH:D000077156', (89, 98))	('mutations', 'Var', (268, 277))	('gefitinib', 'Chemical', 'MESH:D000077156', (72, 81))	('cMET', 'Gene', '4233', (288, 292))	('increased', 'PosReg', (191, 200))	('lower', 'NegReg', (282, 287))	('cMET', 'Gene', (288, 292))	('ficlatuzumab', 'Chemical', 'MESH:C583360', (213, 225))	('expression', 'MPA', (293, 303))	('activating', 'PosReg', (252, 262))	('EGFR', 'Gene', (263, 267))	('patients', 'Species', '9606', (238, 246))	('ficlatuzumab', 'Chemical', 'MESH:C583360', (35, 47))
209944	27669306	A large Phase II study of patients with NSCLC or small cell lung cancer (SCLC) found that while ipilimumab increased overall PFS and immune-related PFS, which accounts for the unique response characteristics of ipilimumab, there was no increase in OS for either SCLC or NSCLC patients.	('patients', 'Species', '9606', (276, 284))	('NSCLC', 'Disease', 'MESH:D002289', (270, 275))	('lung cancer', 'Phenotype', 'HP:0100526', (60, 71))	('small cell lung cancer', 'Disease', (49, 71))	('SCLC', 'Disease', 'MESH:D018288', (73, 77))	('PFS', 'MPA', (125, 128))	('NSCLC', 'Disease', (40, 45))	('NSCLC', 'Disease', (270, 275))	('SCLC', 'Disease', 'MESH:D018288', (262, 266))	('ipilimumab', 'Chemical', 'MESH:D000074324', (96, 106))	('NSCLC', 'Phenotype', 'HP:0030358', (270, 275))	('increased', 'PosReg', (107, 116))	('NSCLC', 'Phenotype', 'HP:0030358', (40, 45))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('SCLC', 'Disease', (271, 275))	('SCLC', 'Disease', (41, 45))	('SCLC', 'Phenotype', 'HP:0030357', (271, 275))	('SCLC', 'Disease', (73, 77))	('SCLC', 'Phenotype', 'HP:0030357', (41, 45))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (49, 71))	('SCLC', 'Phenotype', 'HP:0030357', (73, 77))	('SCLC', 'Disease', (262, 266))	('SCLC', 'Phenotype', 'HP:0030357', (262, 266))	('immune-related PFS', 'MPA', (133, 151))	('patients', 'Species', '9606', (26, 34))	('SCLC', 'Disease', 'MESH:D018288', (271, 275))	('ipilimumab', 'Chemical', 'MESH:D000074324', (211, 221))	('SCLC', 'Disease', 'MESH:D018288', (41, 45))	('ipilimumab', 'Var', (96, 106))	('NSCLC', 'Disease', 'MESH:D002289', (40, 45))	('small cell lung cancer', 'Disease', 'MESH:D055752', (49, 71))
209958	27669306	The vTK deletion renders the virus replication-deficient in normal human cells that express constitutive levels of cellular thymidine kinase (cTK), but permits virus replication in tumor cells that overexpress cTK.	('cellular thymidine kinase', 'Gene', '4145', (115, 140))	('permits', 'Reg', (152, 159))	('tumor', 'Disease', (181, 186))	('cTK', 'Gene', '4145', (210, 213))	('cTK', 'Gene', '4145', (142, 145))	('vTK', 'Gene', (4, 7))	('virus replication', 'MPA', (160, 177))	('cellular thymidine kinase', 'Gene', (115, 140))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('human', 'Species', '9606', (67, 72))	('cTK', 'Gene', (210, 213))	('replication-deficient', 'MPA', (35, 56))	('cTK', 'Gene', (142, 145))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('deletion', 'Var', (8, 16))
209978	27669306	Phase I trials have demonstrated that motolimod has an acceptable safety profile and increases NK cell activation in HNSCC patients, which may augment NK-mediated tumor lysis in response to other therapies, such as cetuximab.	('HNSCC', 'Phenotype', 'HP:0012288', (117, 122))	('augment', 'PosReg', (143, 150))	('HNSCC', 'Disease', (117, 122))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('motolimod', 'Chemical', 'MESH:C573973', (38, 47))	('NK cell activation', 'CPA', (95, 113))	('patients', 'Species', '9606', (123, 131))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('motolimod', 'Var', (38, 47))	('tumor', 'Disease', (163, 168))	('cetuximab', 'Chemical', 'MESH:D000068818', (215, 224))	('increases', 'PosReg', (85, 94))
209982	27669306	However, a phase I study of IMO-2055 provided only limited evidence that IMO-2055 produces clinically-relevant antitumor effects in vivo.	('IMO-2055', 'Var', (73, 81))	('IMO-2055', 'Chemical', 'MESH:C587694', (28, 36))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('IMO-2055', 'Chemical', 'MESH:C587694', (73, 81))	('tumor', 'Disease', (115, 120))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
209996	27669306	In animal model systems, intratumoral electroporation of an IL-12 expression plasmid (pIL-12) resulted in significant intratumoral IL-12 expression, leading to disease stabilization and eventually complete regression without systemic toxicity.	('tumor', 'Disease', (123, 128))	('expression', 'MPA', (137, 147))	('toxicity', 'Disease', 'MESH:D064420', (234, 242))	('toxicity', 'Disease', (234, 242))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('pIL-12', 'Gene', (86, 92))	('electroporation', 'Var', (38, 53))	('tumor', 'Disease', (30, 35))	('disease stabilization', 'CPA', (160, 181))
209997	27669306	Phase I trials of intratumoral plasmid IL-12 electroporation in patients with metastatic melanoma resulted in a dose-dependent increase in tumor cell necrosis and lymphocyte infiltration, in addition to stabilization or regression of non-electroporated metastases in over 50% of treated patients.	('tumor', 'Disease', (139, 144))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('melanoma', 'Phenotype', 'HP:0002861', (89, 97))	('melanoma', 'Disease', (89, 97))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('electroporation', 'Var', (45, 60))	('tumor cell necrosis', 'Disease', 'MESH:D009336', (139, 158))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('lymphocyte infiltration', 'CPA', (163, 186))	('IL-12', 'Gene', (39, 44))	('metastases', 'Disease', 'MESH:D009362', (253, 263))	('tumor', 'Disease', (23, 28))	('melanoma', 'Disease', 'MESH:D008545', (89, 97))	('patients', 'Species', '9606', (64, 72))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('patients', 'Species', '9606', (287, 295))	('metastases', 'Disease', (253, 263))	('increase', 'PosReg', (127, 135))	('tumor cell necrosis', 'Disease', (139, 158))
210010	27669306	Indeed, for many immunotherapeutics only a subset of patients respond to any given therapy, likely due to variations in HLA subtype or other immunomodulatory proteins.	('variations', 'Var', (106, 116))	('patients', 'Species', '9606', (53, 61))	('HLA', 'Protein', (120, 123))
210017	26840267	Pan-cancer analysis of intratumor heterogeneity as a prognostic determinant of survival As tumors accumulate genetic alterations, an evolutionary process occurs in which genetically distinct subclonal populations of cells co-exist, resulting in intratumor genetic heterogeneity (ITH).	('alterations', 'Var', (117, 128))	('tumors', 'Disease', (91, 97))	('tumors', 'Disease', 'MESH:D009369', (91, 97))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('tumor', 'Disease', (28, 33))	('Pan-cancer', 'Disease', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('tumor', 'Disease', 'MESH:D009369', (250, 255))	('Pan-cancer', 'Disease', 'MESH:C537931', (0, 10))	('genetic alterations', 'Var', (109, 128))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (250, 255))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('tumor', 'Disease', (91, 96))	('tumor', 'Disease', (250, 255))
210020	26840267	While some gene mutations are subclonal, the majority of driver gene mutations are clonal events, present in nearly all cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('mutations', 'Var', (69, 78))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))
210022	26840267	High ITH tends to be associated with lower levels of tumor-infiltrating immune cells, but this association is not able to explain the observed survival differences.	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Disease', (53, 58))	('lower', 'NegReg', (37, 42))	('High ITH', 'Var', (0, 8))
210025	26840267	Many of the somatic mutations found in cancer are clonal events, which occur in the founding cell at the time of tumor initiation, and are then propagated during clonal expansion.	('cancer', 'Disease', (39, 45))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('tumor initiation', 'Disease', 'MESH:D009369', (113, 129))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('tumor initiation', 'Disease', (113, 129))	('mutations', 'Var', (20, 29))
210026	26840267	The model of branching evolution in cancer proposes that these "trunk mutations" are found in every cancer cell comprising a solid tumor.	('mutations', 'Var', (70, 79))	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('cancer', 'Disease', (36, 42))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('solid tumor', 'Disease', (125, 136))	('solid tumor', 'Disease', 'MESH:D009369', (125, 136))
210027	26840267	Subsequent "branch mutations" are subclonal events that only exist in a subpopulation of tumor cells.	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))	('mutations', 'Var', (19, 28))	('tumor', 'Disease', 'MESH:D009369', (89, 94))
210039	26840267	The strongest evidence for this comes from a study of head and neck cancers, in which the degree of variation in mutational allelic frequencies was associated with poorer outcome.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('neck cancers', 'Disease', (63, 75))	('cancers', 'Phenotype', 'HP:0002664', (68, 75))	('neck cancers', 'Disease', 'MESH:D006258', (63, 75))	('mutational', 'Var', (113, 123))	('head and neck cancer', 'Phenotype', 'HP:0012288', (54, 74))	('head and neck cancers', 'Phenotype', 'HP:0012288', (54, 75))
210044	26840267	To measure intratumor genetic heterogeneity (ITH) in cancers, we analyzed data from studies performed by The Cancer Genome Atlas Network (TCGA), for which 3 types of complete data were available for >100 tumors: 1) SNP 6.0 array copy number, 2) single nucleotide variant read counts, and 3) clinical patient and tumor data (Figure 1).	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('cancers', 'Disease', 'MESH:D009369', (53, 60))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('tumor', 'Disease', (312, 317))	('tumors', 'Phenotype', 'HP:0002664', (204, 210))	('tumor', 'Disease', 'MESH:D009369', (312, 317))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('patient', 'Species', '9606', (300, 307))	('tumors', 'Disease', (204, 210))	('cancers', 'Phenotype', 'HP:0002664', (53, 60))	('cancers', 'Disease', (53, 60))	('tumor', 'Phenotype', 'HP:0002664', (312, 317))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('tumor', 'Disease', (16, 21))	('tumors', 'Disease', 'MESH:D009369', (204, 210))	('single nucleotide variant', 'Var', (245, 270))	('Cancer', 'Phenotype', 'HP:0002664', (109, 115))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('tumor', 'Disease', (204, 209))
210052	26840267	PyClone estimates the cancer cell prevalence for each somatic mutation in a sequenced tumor sample, and subsequently uses Bayesian methodology to cluster cancer cell prevalence estimates into clonal populations.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('tumor', 'Disease', (86, 91))	('cancer', 'Disease', (22, 28))	('cancer', 'Disease', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('mutation', 'Var', (62, 70))	('cluster cancer', 'Disease', 'MESH:D009369', (146, 160))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('cluster cancer', 'Disease', (146, 160))
210070	26840267	For each cancer type, the majority of MutSig significantly (q<.10) mutated genes had SNVs with mean cancer cell prevalence (CCP) >90%.	('cancer', 'Disease', (9, 15))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('mutated', 'Var', (67, 74))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (9, 15))
210071	26840267	This indicates that most recurrent cancer gene mutations are present in every cancer cell.	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('mutations', 'Var', (47, 56))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('cancer', 'Disease', (35, 41))
210073	26840267	For example, frequent mutations in driver genes such as TP53, RB1, CTNNB1, KEAP1, MLL2, PTEN and CDKN2A were almost universally clonal events (>90% mean CCP).	('KEAP1', 'Gene', (75, 80))	('CDKN2A', 'Gene', (97, 103))	('RB1', 'Gene', '5925', (62, 65))	('MLL2', 'Gene', '9757', (82, 86))	('CDKN2A', 'Gene', '1029', (97, 103))	('TP53', 'Gene', '7157', (56, 60))	('CTNNB1', 'Gene', '1499', (67, 73))	('MLL2', 'Gene', (82, 86))	('PTEN', 'Gene', (88, 92))	('TP53', 'Gene', (56, 60))	('PTEN', 'Gene', '5728', (88, 92))	('mutations', 'Var', (22, 31))	('KEAP1', 'Gene', '9817', (75, 80))	('CTNNB1', 'Gene', (67, 73))	('RB1', 'Gene', (62, 65))
210076	26840267	In fact, nearly all mutated genes in clear cell renal carcinoma, which had the highest overall degree of ITH, were commonly subclonal (Figure 2C and Supplementary Figure 1).	('carcinoma', 'Phenotype', 'HP:0030731', (54, 63))	('clear cell renal carcinoma', 'Phenotype', 'HP:0006770', (37, 63))	('mutated', 'Var', (20, 27))	('clear cell renal carcinoma', 'Disease', 'MESH:C538614', (37, 63))	('clear cell renal carcinoma', 'Disease', (37, 63))	('renal carcinoma', 'Phenotype', 'HP:0005584', (48, 63))
210079	26840267	Analyzing clinical, pathologic and genetic data from 280 tumors in the TCGA HNSC dataset, we confirmed that a number of known prognostic factors were associated with overall survival (OS), including clinical stage (tumor/node/metastasis), human papillomavirus (HPV) status, TP53 mutation, degree of copy number alteration and mutational load, and predominance of copy number alteration (C class) or mutations (M class) (Supplementary Figure 2).	('mutations', 'Var', (399, 408))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('TP53', 'Gene', (274, 278))	('tumors', 'Disease', 'MESH:D009369', (57, 63))	('associated', 'Reg', (150, 160))	('mutational', 'Var', (326, 336))	('mutation', 'Var', (279, 287))	('tumor', 'Disease', (57, 62))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('TP53', 'Gene', '7157', (274, 278))	('tumor', 'Disease', (215, 220))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('overall', 'Disease', (166, 173))	('HPV', 'Species', '10566', (261, 264))	('human papillomavirus', 'Species', '10566', (239, 259))	('tumor', 'Disease', 'MESH:D009369', (215, 220))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumors', 'Disease', (57, 63))	('copy number alteration', 'Var', (363, 385))
210080	26840267	Perhaps because MATH is based on variability in mutation allelic frequencies, MATH scores were most strongly associated with each tumor's degree of copy number alteration (p < 0.001), moreso than with measures of (sub)clonal populations (p = 0.35) (Supplementary Figure 4, Supplementary Table 3).	('associated', 'Interaction', (109, 119))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('copy number alteration', 'Var', (148, 170))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumor', 'Disease', (130, 135))
210083	26840267	This demonstrated that high ITH was independently associated with OS (HR = 2.51; p = .007), when adjusting for HPV status, TP53 mutation, and stage (Figure 3B, Supplementary Table 5A).	('associated with', 'Reg', (50, 65))	('high ITH', 'Var', (23, 31))	('HPV', 'Species', '10566', (111, 114))	('TP53', 'Gene', '7157', (123, 127))	('TP53', 'Gene', (123, 127))
210084	26840267	The association between high ITH and OS was independent of adjuvant radiotherapy administration (Supplementary Table 5D, Supplementary Figure 5), indicating that ITH reflects prognostic aspects of tumor biology, rather than simply response to therapy.	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('tumor', 'Disease', (197, 202))	('high', 'Var', (24, 28))	('tumor', 'Disease', 'MESH:D009369', (197, 202))
210085	26840267	Having established that high ITH had prognostic value in HNSC, we then asked if this factor was informative in the 8 other cancer types.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('cancer', 'Disease', (123, 129))	('high ITH', 'Var', (24, 32))	('HNSC', 'Disease', (57, 61))
210089	26840267	We found that high ITH was associated with significantly poorer survival in LGG (HR = 8.30, p = .011), PRAD (HR = 5.76, p = .016), KIRC (HR = 6.06, p = .003), HNSC (HR = 3.75, p = .007), and BRCA (HR = 2.50, p = .015).	('survival', 'CPA', (64, 72))	('BRCA', 'Gene', (191, 195))	('BRCA', 'Gene', '672', (191, 195))	('high ITH', 'Var', (14, 22))	('poorer', 'NegReg', (57, 63))
210092	26840267	We performed additional analyses to determine if tumors with high ITH had poorer prognosis due to an association with more aggressive molecular subtypes, and found that this was not the case.	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('high ITH', 'Var', (61, 69))	('tumors', 'Disease', 'MESH:D009369', (49, 55))	('tumors', 'Disease', (49, 55))	('association', 'Interaction', (101, 112))
210096	26840267	Within this category of tumors, high ITH remained associated with poorer survival (p = .01) (Supplementary Figure 6B).	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('survival', 'MPA', (73, 81))	('high ITH', 'Var', (32, 40))	('tumors', 'Disease', 'MESH:D009369', (24, 30))	('tumors', 'Disease', (24, 30))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('poorer', 'NegReg', (66, 72))
210097	26840267	In the BRCA cohort, we found that high ITH was associated with poorer survival, independent of clinical stage and receptor status.	('BRCA', 'Gene', '672', (7, 11))	('survival', 'MPA', (70, 78))	('BRCA', 'Gene', (7, 11))	('poorer', 'NegReg', (63, 69))	('high ITH', 'Var', (34, 42))
210098	26840267	High ITH was not more common in poorer-prognosis tumors such as triple negative receptor status or basal-like molecular subtype.	('basal-like molecular subtype', 'Disease', (99, 127))	('triple negative', 'Var', (64, 79))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('tumors', 'Disease', (49, 55))	('tumors', 'Disease', 'MESH:D009369', (49, 55))
210100	26840267	The prognostic impact of high ITH appeared to affect all molecular subtypes but was most significant in the Her2-enriched tumors (p = .04) (Supplementary Figure 7B).	('tumors', 'Disease', (122, 128))	('tumors', 'Disease', 'MESH:D009369', (122, 128))	('Her2', 'Gene', '2064', (108, 112))	('affect', 'Reg', (46, 52))	('high ITH', 'Var', (25, 33))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumors', 'Phenotype', 'HP:0002664', (122, 128))	('Her2', 'Gene', (108, 112))
210101	26840267	As would be expected, the degree of ITH was strongly correlated with mutation number in most cancer types - all except LUAD and LUSC (Supplementary Table 6A).	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('correlated', 'Reg', (53, 63))	('LUSC', 'Disease', (128, 132))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('mutation', 'Var', (69, 77))	('LUAD', 'Disease', (119, 123))
210103	26840267	In fact, any prognostic aspect of mutational load in tumors could be mediated by ITH.	('mutational load', 'Var', (34, 49))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('tumors', 'Disease', (53, 59))
210104	26840267	High ITH was associated with older age in 1 of 9 cancer types - LGG (p = .001) (Supplementary Table 7A).	('High ITH', 'Var', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('cancer', 'Disease', (49, 55))	('cancer', 'Disease', 'MESH:D009369', (49, 55))
210107	26840267	Recent data in melanoma and non-small cell lung cancer have shown that tumors with a higher mutational burden have an increased number of predicted neoantigens, and are more likely to respond to immunotherapy.	('lung cancer', 'Phenotype', 'HP:0100526', (43, 54))	('neoantigens', 'MPA', (148, 159))	('melanoma', 'Phenotype', 'HP:0002861', (15, 23))	('melanoma', 'Disease', (15, 23))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (28, 54))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (32, 54))	('melanoma', 'Disease', 'MESH:D008545', (15, 23))	('mutational', 'Var', (92, 102))	('increased', 'PosReg', (118, 127))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (28, 54))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('tumors', 'Disease', (71, 77))	('respond', 'Reg', (184, 191))	('non-small cell lung cancer', 'Disease', (28, 54))	('tumors', 'Disease', 'MESH:D009369', (71, 77))
210108	26840267	It is believed that the neoantigens resulting from tumor mutations promote anti-tumor immunity and thereby facilitate therapeutic responses.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('facilitate', 'PosReg', (107, 117))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumor', 'Disease', (51, 56))	('tumor', 'Disease', (80, 85))	('mutations', 'Var', (57, 66))	('therapeutic responses', 'CPA', (118, 139))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('promote', 'PosReg', (67, 74))
210113	26840267	Tumors with high ITH tended to have lower levels of immune cell infiltration, or T cell infiltration, controlling for cancer type with logistic regression (immune infiltration p = .020, T cell infiltration p = .055) (Supplementary Table 8; Supplementary Figure 8C-E).	('lower levels of immune cell', 'Phenotype', 'HP:0002721', (36, 63))	('cancer', 'Disease', (118, 124))	('lower', 'NegReg', (36, 41))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('high', 'Var', (12, 16))	('T cell infiltration', 'MPA', (81, 100))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('immune cell infiltration', 'MPA', (52, 76))
210127	26840267	The association between high ITH and poorer survival was most evident in lower grade glioma, prostate, clear cell kidney, head and neck, and breast cancers, and had borderline significance in melanoma.	('prostate', 'Disease', (93, 101))	('clear cell kidney', 'Disease', (103, 120))	('glioma', 'Disease', 'MESH:D005910', (85, 91))	('cancers', 'Phenotype', 'HP:0002664', (148, 155))	('breast cancers', 'Phenotype', 'HP:0003002', (141, 155))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('breast cancers', 'Disease', (141, 155))	('melanoma', 'Phenotype', 'HP:0002861', (192, 200))	('glioma', 'Disease', (85, 91))	('melanoma', 'Disease', (192, 200))	('breast cancers', 'Disease', 'MESH:D001943', (141, 155))	('melanoma', 'Disease', 'MESH:D008545', (192, 200))	('high ITH', 'Var', (24, 32))	('breast cancer', 'Phenotype', 'HP:0003002', (141, 154))	('glioma', 'Phenotype', 'HP:0009733', (85, 91))
210132	26840267	For example, in a study of patients with relapsed chronic lymphocytic leukemia, subclonal mutations were associated with more aggressive disease.	('lymphocytic leukemia', 'Disease', 'MESH:D007945', (58, 78))	('lymphocytic leukemia', 'Disease', (58, 78))	('aggressive disease', 'Disease', 'MESH:D001523', (126, 144))	('patients', 'Species', '9606', (27, 35))	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (50, 78))	('leukemia', 'Phenotype', 'HP:0001909', (70, 78))	('aggressive disease', 'Disease', (126, 144))	('subclonal mutations', 'Var', (80, 99))	('associated with', 'Reg', (105, 120))
210133	26840267	Similar findings were observed in 11 patients with lung adenocarcinoma: recurrent tumors had more subclonal mutations.	('tumors', 'Disease', (82, 88))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('patients', 'Species', '9606', (37, 45))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (51, 70))	('subclonal mutations', 'Var', (98, 117))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (51, 70))	('lung adenocarcinoma', 'Disease', (51, 70))
210137	26840267	In a pan-cancer study examining the landscape of ITH, Andor et al did not observe a clear association between ITH and survival within individual cancers, but did observe that prognosis appeared poorest among tumors with intermediate levels of copy number variation.	('cancers', 'Disease', (145, 152))	('cancer', 'Disease', (9, 15))	('cancer', 'Disease', (145, 151))	('cancers', 'Phenotype', 'HP:0002664', (145, 152))	('copy number variation', 'Var', (243, 264))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('cancers', 'Disease', 'MESH:D009369', (145, 152))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('tumors', 'Disease', 'MESH:D009369', (208, 214))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('tumors', 'Disease', (208, 214))	('tumors', 'Phenotype', 'HP:0002664', (208, 214))	('poorest', 'NegReg', (194, 201))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('cancer', 'Disease', 'MESH:D009369', (9, 15))
210143	26840267	We also noted a tendency for high ITH tumors to have lower levels of immune infiltration.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('high ITH', 'Var', (29, 37))	('tumors', 'Disease', (38, 44))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('tumors', 'Disease', 'MESH:D009369', (38, 44))	('lower levels of immune infiltration', 'Phenotype', 'HP:0002721', (53, 88))	('lower', 'NegReg', (53, 58))
210152	26840267	However, if immunoediting can in fact constrain ITH, one could speculate that the cancers most likely to benefit from immunotherapy would be those with high mutational loads (and thus, many neoantigens), but low ITH (thereby, having undergone more immunoediting by a functional immune surveillance system).	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('cancers', 'Phenotype', 'HP:0002664', (82, 89))	('cancers', 'Disease', (82, 89))	('cancers', 'Disease', 'MESH:D009369', (82, 89))	('high mutational loads', 'Var', (152, 173))
210153	26840267	The vast majority of highly prevalent driver mutations tended to be clonal events, present in every cancer cell, suggestive that these are generally early or "trunk" mutational events.	('mutations', 'Var', (45, 54))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('driver', 'Disease', (38, 44))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))
210155	26840267	These findings provide empirical evidence for recent theoretical models of tumor evolution, showing that driver mutations with even a small fitness advantage are able to expand and become dominant within a short period of time, whereas passenger mutations without a major fitness advantage are more likely to remain subclonal.	('fitness advantage', 'Disease', (140, 157))	('fitness advantage', 'Disease', (272, 289))	('fitness advantage', 'Disease', 'MESH:D012640', (140, 157))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('mutations', 'Var', (112, 121))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('fitness advantage', 'Disease', 'MESH:D012640', (272, 289))	('tumor', 'Disease', (75, 80))
210157	26840267	Furthermore, in other cancer types, some prevalent driver gene mutations appeared to be frequently subclonal.	('mutations', 'Var', (63, 72))	('driver gene', 'Gene', (51, 62))	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('cancer', 'Disease', (22, 28))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))
210158	26840267	This phenomenon has also been observed in a prior study, which reported that 15-20% of mutations in driver genes such as IDH1, PIK3CA and EGFR were subclonal, and linked many of these to a mutational signature of APOBEC-mediated mutagenesis.	('IDH1', 'Gene', (121, 125))	('EGFR', 'Gene', '1956', (138, 142))	('IDH1', 'Gene', '3417', (121, 125))	('PIK3CA', 'Gene', (127, 133))	('EGFR', 'Gene', (138, 142))	('PIK3CA', 'Gene', '5290', (127, 133))	('mutations', 'Var', (87, 96))
210164	26840267	Higher levels of heterogeneity increase the likelihood of a tumor harboring a subclonal population with a driver mutation that will be resistant to treatment.	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Disease', (60, 65))	('mutation', 'Var', (113, 121))	('tumor', 'Disease', 'MESH:D009369', (60, 65))
210208	33604380	In particular, evaluation of the mutations in immune cells is capable of predicting the outcome of patients with cancerous tumors.	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('cancerous tumors', 'Disease', 'MESH:D009369', (113, 129))	('mutations', 'Var', (33, 42))	('patients', 'Species', '9606', (99, 107))	('cancerous tumors', 'Disease', (113, 129))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
210218	33604380	We discovered that the related immune cell infiltration signatures were differently expressed between low and high CDCA3 expression groups.	('CDCA3', 'Gene', (115, 120))	('high', 'Var', (110, 114))	('CDCA3', 'Gene', '83461', (115, 120))
210219	33604380	We also found that the higher proportion of CD8+ T cells, CD4+ T cells, and B cells appeared in the high CDCA3 expression group.	('CD8', 'Gene', (44, 47))	('CD8', 'Gene', '925', (44, 47))	('CD4', 'Gene', '920', (58, 61))	('CDCA3', 'Gene', '83461', (105, 110))	('high', 'Var', (100, 104))	('CDCA3', 'Gene', (105, 110))	('CD4', 'Gene', (58, 61))
210220	33604380	Our data suggested that the high CDCA3 expression promoted the infiltration of T cells and exhausted these cells, and the patients with high CDCA3 expression might have poorer outcomes by analyzing the information of HCC patients obtained from The Cancer Genome Atlas (TCGA) database.	('CDCA3', 'Gene', '83461', (141, 146))	('patients', 'Species', '9606', (221, 229))	('promoted', 'PosReg', (50, 58))	('CDCA3', 'Gene', (141, 146))	('expression', 'Var', (39, 49))	('CDCA3', 'Gene', '83461', (33, 38))	('CDCA3', 'Gene', (33, 38))	('patients', 'Species', '9606', (122, 130))	('Cancer', 'Phenotype', 'HP:0002664', (248, 254))	('Cancer', 'Disease', (248, 254))	('high', 'Var', (28, 32))	('Cancer', 'Disease', 'MESH:D009369', (248, 254))	('HCC', 'Phenotype', 'HP:0001402', (217, 220))	('infiltration of T cells', 'CPA', (63, 86))
210230	33604380	Significance of HR referred to the ratio of risk rate produced by high CDCA3 expression to the risk rate produced by low CDCA3 expression, on the premise that p < 0.05.	('expression', 'MPA', (77, 87))	('CDCA3', 'Gene', (121, 126))	('CDCA3', 'Gene', '83461', (71, 76))	('CDCA3', 'Gene', (71, 76))	('high', 'Var', (66, 70))	('CDCA3', 'Gene', '83461', (121, 126))
210231	33604380	The higher the HR value, the bigger the ratio of risk rate produced by high CDCA3 expression on survival.	('HR value', 'MPA', (15, 23))	('CDCA3', 'Gene', (76, 81))	('CDCA3', 'Gene', '83461', (76, 81))	('high', 'Var', (71, 75))
210242	33604380	Here, we established a standard to describe the association between CDCA3 expression and gene markers of infiltrating immune cells, where 0.00-0.29 was considered weak, 0.30-0.59 was considered moderate, 0.60-0.79 was considered strong, and 0.80-1.00 was considered very strong expression.	('association', 'Interaction', (48, 59))	('0.60-0.79', 'Var', (204, 213))	('0.30-0.59', 'Var', (169, 178))	('CDCA3', 'Gene', '83461', (68, 73))	('CDCA3', 'Gene', (68, 73))
210248	33604380	Here, logrank p < 0.05 was statistically significant, and significance of HR referred to the ratio of risk rate produced by the application of high expression of CDCA3 to the risk rate produced by low expression of CDCA3.	('CDCA3', 'Gene', '83461', (162, 167))	('high expression', 'Var', (143, 158))	('CDCA3', 'Gene', (162, 167))	('CDCA3', 'Gene', (215, 220))	('CDCA3', 'Gene', '83461', (215, 220))
210270	33604380	As revealed by PPS (HR = 0.67, 95%CI = 0.54-0.84, p = 0.00038) (Figure 2(j)), the high CDCA3 expression was associated with the better prognosis in gastric cancer because the HR < 1 and p < 0.05.	('PPS', 'Chemical', '-', (15, 18))	('CDCA3', 'Gene', (87, 92))	('gastric cancer', 'Disease', (148, 162))	('high', 'Var', (82, 86))	('gastric cancer', 'Disease', 'MESH:D013274', (148, 162))	('gastric cancer', 'Phenotype', 'HP:0012126', (148, 162))	('expression', 'MPA', (93, 103))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('CDCA3', 'Gene', '83461', (87, 92))
210273	33604380	These results indicated that a high expression of CDCA3 had a strong association with poor outcomes for patients with various cancers, especially in HCC, and the correlation depended on the type of tumor.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('HCC', 'Phenotype', 'HP:0001402', (149, 152))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('CDCA3', 'Gene', '83461', (50, 55))	('cancers', 'Phenotype', 'HP:0002664', (126, 133))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('cancers', 'Disease', (126, 133))	('CDCA3', 'Gene', (50, 55))	('cancers', 'Disease', 'MESH:D009369', (126, 133))	('high', 'Var', (31, 35))	('tumor', 'Disease', (198, 203))	('patients', 'Species', '9606', (104, 112))	('expression', 'MPA', (36, 46))	('HCC', 'Disease', (149, 152))
210280	33604380	p < 0.05 was statistically significant, and the hazard ratio > 1 represented the higher risk factors produced by high CDCA3 expression affected in the prognosis of patients with different clinicopathologic features.	('high', 'Var', (113, 117))	('CDCA3', 'Gene', '83461', (118, 123))	('CDCA3', 'Gene', (118, 123))	('expression', 'MPA', (124, 134))	('patients', 'Species', '9606', (164, 172))	('affected', 'Reg', (135, 143))
210284	33604380	It was remarkable that the hazard ratio (HR) of CDCA3 expression in univariate analysis equaled to 2.075, the value of HR and the p < 0.001 both indicated that CDCA3 can predict the prognosis in HCC, and the hazard ratio revealed that the patients with high CDCA3 expression had 2.075 times of higher risk in poor OS than the patients with low CDCA3 expression in univariate analysis.	('CDCA3', 'Gene', (258, 263))	('high', 'Var', (253, 257))	('CDCA3', 'Gene', (48, 53))	('CDCA3', 'Gene', '83461', (344, 349))	('poor OS', 'Disease', (309, 316))	('CDCA3', 'Gene', (344, 349))	('CDCA3', 'Gene', '83461', (160, 165))	('patients', 'Species', '9606', (239, 247))	('patients', 'Species', '9606', (326, 334))	('CDCA3', 'Gene', (160, 165))	('HCC', 'Disease', (195, 198))	('HCC', 'Phenotype', 'HP:0001402', (195, 198))	('expression', 'Var', (264, 274))	('CDCA3', 'Gene', '83461', (258, 263))	('CDCA3', 'Gene', '83461', (48, 53))
210286	33604380	The results showed that high expression of CDCA3 was associated with poor outcomes in HCC patients, and it could act as a potential independent predictor of survival (HR = 2.037; 95%CI = 1.484-2.796; p < 0.001; Figure 3(d)) by excluding confounding factors.	('CDCA3', 'Gene', '83461', (43, 48))	('CDCA3', 'Gene', (43, 48))	('high', 'Var', (24, 28))	('HCC', 'Disease', (86, 89))	('patients', 'Species', '9606', (90, 98))	('HCC', 'Phenotype', 'HP:0001402', (86, 89))
210287	33604380	Besides, the value of the hazard ratio revealed that the patients with high CDCA3 expression had 2.037 times of higher risk in poor OS than the patients with low CDCA3 expression.	('poor OS', 'Disease', (127, 134))	('CDCA3', 'Gene', '83461', (162, 167))	('CDCA3', 'Gene', '83461', (76, 81))	('high', 'Var', (71, 75))	('patients', 'Species', '9606', (57, 65))	('CDCA3', 'Gene', (162, 167))	('CDCA3', 'Gene', (76, 81))	('expression', 'Var', (82, 92))	('patients', 'Species', '9606', (144, 152))
210294	33604380	The results showed that high expression of CDCA3 was associated with poor prognosis of patients, high levels of infiltrating immune cells, and tumor purity in HCC and ACC.	('tumor', 'Disease', (143, 148))	('patients', 'Species', '9606', (87, 95))	('CDCA3', 'Gene', '83461', (43, 48))	('CDCA3', 'Gene', (43, 48))	('ACC', 'Phenotype', 'HP:0006744', (167, 170))	('high', 'Var', (24, 28))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('expression', 'MPA', (29, 39))	('HCC', 'Disease', (159, 162))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('HCC', 'Phenotype', 'HP:0001402', (159, 162))
210297	33604380	The high CDCA3 expression was also correlated with a poorer survival (OS: HR = 2.5, p = 6.4E - 07; DFS: HR = 1.8, p = 0.00026) (Figure S1 ac-ad) but was positively related to the infiltrating levels of B cells (partial cor = 0.252, p = 2.42E - 08), CD4+ T cells (partial cor = 0.222, p = 1.01E - 06), macrophages (partial cor = 0.207, p = 5.93E - 06), neutrophils (partial cor = 0.174, p = 1.35E - 04), and dendritic cells (partial cor = 0.229, p = 4.54E - 07) in LGG (Figure S2 s).	('CDCA3', 'Gene', '83461', (9, 14))	('CDCA3', 'Gene', (9, 14))	('related', 'Reg', (164, 171))	('expression', 'MPA', (15, 25))	('high', 'Var', (4, 8))	('CD4', 'Gene', (249, 252))	('CD4', 'Gene', '920', (249, 252))
210325	33604380	According to the univariate and multivariate analyses, we identified that T stage, M stage, and CDCA3 expression had significant prognostic values for predicting the survival of patients with HCC; in fact, the high expression determined poor OS of patients with HCC and suggested that increased CDCA3 expression deteriorated the state of patients with HCC.	('HCC', 'Phenotype', 'HP:0001402', (262, 265))	('HCC', 'Disease', (352, 355))	('CDCA3', 'Gene', (96, 101))	('increased', 'PosReg', (285, 294))	('HCC', 'Phenotype', 'HP:0001402', (352, 355))	('patients', 'Species', '9606', (178, 186))	('determined', 'Reg', (226, 236))	('HCC', 'Phenotype', 'HP:0001402', (192, 195))	('high', 'Var', (210, 214))	('CDCA3', 'Gene', '83461', (295, 300))	('patients', 'Species', '9606', (338, 346))	('patients', 'Species', '9606', (248, 256))	('HCC', 'Disease', (262, 265))	('CDCA3', 'Gene', (295, 300))	('CDCA3', 'Gene', '83461', (96, 101))
210329	33604380	Thus, CDCA3 expression can potentially influence the immunosuppressive effect in HCC.	('influence', 'Reg', (39, 48))	('HCC', 'Disease', (81, 84))	('expression', 'Var', (12, 22))	('HCC', 'Phenotype', 'HP:0001402', (81, 84))	('immunosuppressive', 'MPA', (53, 70))	('CDCA3', 'Gene', '83461', (6, 11))	('CDCA3', 'Gene', (6, 11))
210340	33604380	According to the results of the univariate and multivariate analyses, T stage, M stage, and CDCA3 expression were important prognostic factors for the survival of patients with HCC; importantly, high CDCA3 expression had the potential to be an independent predictor for poor outcome for patients with HCC according to the results of multivariate analyses.	('patients', 'Species', '9606', (163, 171))	('HCC', 'Disease', (301, 304))	('CDCA3', 'Gene', '83461', (200, 205))	('expression', 'MPA', (206, 216))	('HCC', 'Phenotype', 'HP:0001402', (177, 180))	('HCC', 'Phenotype', 'HP:0001402', (301, 304))	('patients', 'Species', '9606', (287, 295))	('CDCA3', 'Gene', (200, 205))	('CDCA3', 'Gene', '83461', (92, 97))	('high', 'Var', (195, 199))	('CDCA3', 'Gene', (92, 97))
210567	32385885	Another line of investigation by this group showed that F. nucleatum potentiates intestinal tumorigenesis by modulating the antitumor immune system.108 Fusobacterium nucleatum were shown to expand myeloid-derived immune cell types such as Fox-alpha3 and T-reg cells that promote tumor progression by suppressing cytotoxic and effector T cells, thus diminishing local antitumor immunity.	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('tumor', 'Phenotype', 'HP:0002664', (279, 284))	('tumor', 'Disease', (371, 376))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Disease', (279, 284))	('tumor', 'Disease', (92, 97))	('Fusobacterium nucleatum', 'Species', '851', (152, 175))	('diminishing', 'NegReg', (349, 360))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('Fusobacterium', 'Var', (152, 165))	('tumor', 'Disease', 'MESH:D009369', (371, 376))	('tumor', 'Phenotype', 'HP:0002664', (371, 376))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('promote', 'PosReg', (271, 278))	('suppressing', 'NegReg', (300, 311))	('tumor', 'Disease', (128, 133))	('F. nucleatum', 'Species', '851', (56, 68))	('tumor', 'Disease', 'MESH:D009369', (279, 284))
210573	32385885	They also found that the abundance of P. gingivalis trended with a higher risk of esophageal squamous cell carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('esophageal squamous cell carcinoma', 'Disease', (82, 116))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (93, 116))	('P. gingivalis', 'Species', '837', (38, 51))	('P. gingivalis', 'Var', (38, 51))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (82, 116))
210574	32385885	These results are consistent with the findings of Gao et al,114 who reported that P. gingivalis was found in 61% of their samples of esophageal tissues from patients with esophageal squamous cell carcinoma, but was not detected in normal esophageal mucosa.	('P. gingivalis', 'Species', '837', (82, 95))	('esophageal squamous cell carcinoma', 'Disease', (171, 205))	('patients', 'Species', '9606', (157, 165))	('carcinoma', 'Phenotype', 'HP:0030731', (196, 205))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (171, 205))	('found', 'Reg', (100, 105))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (182, 205))	('P. gingivalis', 'Var', (82, 95))
210579	32385885	In a similar fashion, using data based on the National Health and Nutrition Examination Survey I study, Scannapieco et al146 found that poor oral hygiene was linked to chronic respiratory disease (n = 23 808; cases of chronic respiratory disease, n = 386).	('respiratory disease', 'Disease', (176, 195))	('respiratory disease', 'Disease', (226, 245))	('respiratory disease', 'Phenotype', 'HP:0011947', (226, 245))	('respiratory disease', 'Phenotype', 'HP:0011947', (176, 195))	('poor', 'Var', (136, 140))	('poor oral', 'Phenotype', 'HP:0000160', (136, 145))	('al1', 'Species', '999426', (119, 122))	('respiratory disease', 'Disease', 'MESH:D012140', (176, 195))	('linked', 'Reg', (158, 164))	('respiratory disease', 'Disease', 'MESH:D012140', (226, 245))
210624	31816603	The GEO dataset GSE103512 was selected for identification of DEGs in 60 human NSCLC specimens against 9 matched normal tissue samples using the GEO2R tool.	('GSE103512', 'Var', (16, 25))	('SCLC', 'Phenotype', 'HP:0030357', (79, 83))	('NSCLC', 'Phenotype', 'HP:0030358', (78, 83))	('human', 'Species', '9606', (72, 77))	('DEGs', 'Var', (61, 65))	('NSCLC', 'Disease', (78, 83))	('NSCLC', 'Disease', 'MESH:D002289', (78, 83))
210626	31816603	For molecular function (MF), the top ten terms were GO: 0005539~glycosaminoglycan binding, GO: 0008201~heparin binding, GO: 1901681~sulfur compound binding, GO: 0050840~extracellular matrix binding, GO: 0005509~calcium ion binding, GO: 0005201~extracellular matrix structural constituent, GO: 0030234~enzyme regulator activity, GO: 0016209~antioxidant activity, GO: 0097367~carbohydrate derivative binding, and GO: 0008047~enzyme activator activity (Figure 2B).	('sulfur', 'Chemical', 'MESH:D013455', (132, 138))	('GO: 0008201~heparin', 'Var', (91, 110))	('GO: 0030234~enzyme', 'Var', (289, 307))	('GO: 0005201~extracellular', 'Var', (232, 257))	('calcium', 'Chemical', 'MESH:D002118', (211, 218))	('0097367~carbohydrate derivative', 'MPA', (366, 397))	('GO: 0005539~glycosaminoglycan', 'Var', (52, 81))	('GO: 0050840~extracellular', 'Var', (157, 182))	('GO: 0005509~calcium', 'Var', (199, 218))	('0030234~enzyme regulator activity', 'MPA', (293, 326))	('0097367~carbohydrate', 'Chemical', 'MESH:D002241', (366, 386))	('GO: 0097367~carbohydrate', 'Var', (362, 386))	('0016209~antioxidant activity', 'MPA', (332, 360))	('GO: 1901681~sulfur', 'Var', (120, 138))	('GO: 0008047~enzyme', 'Var', (411, 429))	('GO: 0016209~antioxidant', 'Var', (328, 351))
210627	31816603	For biological process (BP), the top ten terms were GO: 1901700~response to oxygen-containing compound, GO: 0042060~wound healing, GO: 0009611~response to wounding, GO: 0072593~reactive oxygen species metabolic process, GO: 0070887~cellular response to chemical stimulus, GO: 0022610~biological adhesion, GO: 0006979~response to oxidative stress, GO: 0010033~response to organic substance, GO: 0009605~response to external stimulus, and GO: 0007155~cell adhesion (Figure 2C).	('GO: 0022610~biological', 'Var', (272, 294))	('GO: 0007155~cell', 'Var', (437, 453))	('0010033~response to organic substance', 'MPA', (351, 388))	('0022610~biological adhesion', 'CPA', (276, 303))	('oxidative stress', 'Phenotype', 'HP:0025464', (329, 345))	('GO: 0006979~response', 'Var', (305, 325))	('GO: 0010033~response', 'Var', (347, 367))	('GO: 0070887~cellular', 'Var', (220, 240))	('oxygen', 'Chemical', 'MESH:D010100', (76, 82))	('oxygen', 'Chemical', 'MESH:D010100', (186, 192))	('GO: 0009605~response', 'Var', (390, 410))	('0007155~cell adhesion', 'CPA', (441, 462))
210643	31816603	Using sample-associated clinical data, Kaplan-Meier analysis confirmed that patients with high TOP2A expression had significantly worse OS (P = 0.0259) (Figure 6F).	('clinical', 'Species', '191496', (24, 32))	('patients', 'Species', '9606', (76, 84))	('high', 'Var', (90, 94))	('TOP2A', 'Gene', '7153', (95, 100))	('expression', 'MPA', (101, 111))	('TOP2A', 'Gene', (95, 100))
210646	31816603	High TOP2A expression was significantly associated with poor OS in both female (P = 1.3e-05) and male (P = 5.8e-06) patients.	('High', 'Var', (0, 4))	('expression', 'MPA', (11, 21))	('patients', 'Species', '9606', (116, 124))	('TOP2A', 'Gene', '7153', (5, 10))	('poor OS', 'Disease', (56, 63))	('TOP2A', 'Gene', (5, 10))
210647	31816603	In addition, high TOP2A expression was associated with poor OS in Stage 1 (P = 9.6e-08), Stage T1 (P = 7.6e-05), Stage N0 (P = 3.6e-04), and Stage M0 (P = 3.2e-05) patients.	('TOP2A', 'Gene', '7153', (18, 23))	('TOP2A', 'Gene', (18, 23))	('high', 'Var', (13, 17))	('expression', 'MPA', (24, 34))	('poor OS', 'Disease', (55, 62))	('patients', 'Species', '9606', (164, 172))
210665	31816603	Overall, our qPCR assays on 17 independent NSCLC samples confirmed that all the upregulated DEGs in the GEO dataset were also expressed at higher levels in our NSCLC samples, compared to matched non-tumor controls.	('SCLC', 'Phenotype', 'HP:0030357', (161, 165))	('NSCLC', 'Disease', (160, 165))	('non-tumor', 'Disease', 'MESH:C580335', (195, 204))	('DEGs', 'Var', (92, 96))	('NSCLC', 'Disease', 'MESH:D002289', (160, 165))	('NSCLC', 'Phenotype', 'HP:0030358', (43, 48))	('NSCLC', 'Phenotype', 'HP:0030358', (160, 165))	('upregulated', 'PosReg', (80, 91))	('SCLC', 'Phenotype', 'HP:0030357', (44, 48))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('NSCLC', 'Disease', (43, 48))	('non-tumor', 'Disease', (195, 204))	('NSCLC', 'Disease', 'MESH:D002289', (43, 48))
210679	31816603	In breast cancer, TPX2 silencing repressed PI3K/AKT and activated p53 signaling, which inhibited proliferation and promoted apoptosis.	('promoted', 'PosReg', (115, 123))	('apoptosis', 'CPA', (124, 133))	('p53', 'Gene', '7157', (66, 69))	('TPX2', 'Gene', '22974', (18, 22))	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('AKT', 'Gene', (48, 51))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('breast cancer', 'Disease', (3, 16))	('proliferation', 'CPA', (97, 110))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('silencing', 'Var', (23, 32))	('TPX2', 'Gene', (18, 22))	('inhibited', 'NegReg', (87, 96))	('activated', 'PosReg', (56, 65))	('AKT', 'Gene', '207', (48, 51))	('p53', 'Gene', (66, 69))
210683	31816603	In prostate cancer, high ASPM expression correlated with tumor progression and predicted poor outcome.	('prostate cancer', 'Phenotype', 'HP:0012125', (3, 18))	('ASPM', 'Gene', '259266', (25, 29))	('correlated with', 'Reg', (41, 56))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('high', 'Var', (20, 24))	('prostate cancer', 'Disease', (3, 18))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('ASPM', 'Gene', (25, 29))	('tumor', 'Disease', (57, 62))	('prostate cancer', 'Disease', 'MESH:D011471', (3, 18))
210687	31816603	Moreover, for TOP2A, high expression was associated with poor OS in Stage 1, Stage T1, Stage N0, and Stage M0 NSCLC patients.	('poor OS', 'Disease', (57, 64))	('TOP2A', 'Gene', (14, 19))	('patients', 'Species', '9606', (116, 124))	('NSCLC', 'Disease', (110, 115))	('high', 'Var', (21, 25))	('SCLC', 'Phenotype', 'HP:0030357', (111, 115))	('NSCLC', 'Disease', 'MESH:D002289', (110, 115))	('TOP2A', 'Gene', '7153', (14, 19))	('NSCLC', 'Phenotype', 'HP:0030358', (110, 115))
210714	31816603	Then, sections were incubated with anti-TOP2A (66541-1-Ig, Proteintech, USA) diluted 1:100, at 4 C overnight.	('TOP2A', 'Gene', '7153', (40, 45))	('66541-1-Ig', 'Var', (47, 57))	('TOP2A', 'Gene', (40, 45))
210754	31671550	In oral cancer, the high density of TAM is associated with poor prognosis.	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('high density', 'Var', (20, 32))	('cancer', 'Disease', (8, 14))	('cancer', 'Disease', 'MESH:D009369', (8, 14))
210761	31671550	Indeed, in the pivotal CheckMate 141 phase III study, nivolumab (3 mg/kg every two weeks until disease progression, unacceptable toxicity, or withdrawal of consent) demonstrated a survival benefit in patients with R/M HNSCC, with tumor progression/recurrence within 6 months of platinum therapy vs. standard of care (SoC; docetaxel, methotrexate, or cetuximab, according to investigator's choice): mOS was 7.5 vs. 5.1 months, respectively, p = 0.01; regardless of PD-L1 expression (>1% or <1%) and regardless of tumor HPV status.	('toxicity', 'Disease', (129, 137))	('docetaxel', 'Chemical', 'MESH:C067311', (322, 331))	('tumor', 'Disease', (512, 517))	('HNSCC', 'Phenotype', 'HP:0012288', (218, 223))	('tumor', 'Disease', 'MESH:D009369', (512, 517))	('mOS', 'Gene', '17451', (398, 401))	('HPV', 'Species', '10566', (518, 521))	('platinum', 'Chemical', 'MESH:D010984', (278, 286))	('tumor', 'Disease', (230, 235))	('tumor', 'Phenotype', 'HP:0002664', (512, 517))	('tumor', 'Disease', 'MESH:D009369', (230, 235))	('PD-L1', 'Gene', (464, 469))	('toxicity', 'Disease', 'MESH:D064420', (129, 137))	('PD-L1', 'Gene', '29126', (464, 469))	('patients', 'Species', '9606', (200, 208))	('methotrexate', 'Chemical', 'MESH:D008727', (333, 345))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))	('mOS', 'Gene', (398, 401))	('R/M', 'Var', (214, 217))
210786	31671550	In these interim analyses, the combination of pembrolizumab plus chemotherapy was found to be noninferior and superior to SoC for OS (mOS 13.0 vs. 10.7 months, HR 0.77, 95% CI 0.63-0.93, p = 0.0034), and similarly for the ORR (36% in both arms).	('mOS', 'Gene', '17451', (134, 137))	('pembrolizumab', 'Var', (46, 59))	('OS', 'Gene', '17451', (135, 137))	('OS', 'Gene', '17451', (130, 132))	('mOS', 'Gene', (134, 137))
210823	31671550	Furthermore, the combination of nivolumab and ipilimumab is currently being evaluated in the phase I/II IMCISION trial as a neoadjuvant therapy in patients with previously untreated resectable LA HNSCC (NCT03003637).	('HNSCC', 'Phenotype', 'HP:0012288', (196, 201))	('NCT03003637', 'Var', (203, 214))	('patients', 'Species', '9606', (147, 155))	('LA HNSCC', 'Disease', (193, 201))	('NCT03003637', 'Chemical', 'MESH:C079985', (203, 214))
210825	31671550	An anti-LAG-3 mAb, relatlimab (BMS-986016), is evaluated in a phase I/IIA dose escalation and expansion study, alone and in combination with nivolumab in advanced solid tumors, including an HNSCC cohort (CA224-020 study, NCT01968109).	('solid tumors', 'Disease', 'MESH:D009369', (163, 175))	('LAG-3', 'Gene', '3902', (8, 13))	('LAG-3', 'Gene', (8, 13))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('HNSCC', 'Phenotype', 'HP:0012288', (190, 195))	('solid tumors', 'Disease', (163, 175))	('tumors', 'Phenotype', 'HP:0002664', (169, 175))	('BMS-986016', 'Var', (31, 41))	('BMS-986016', 'Chemical', 'MESH:C095300', (31, 41))
210830	31671550	The combination of durvalumab and either danvatirsen (AZD9150, a STAT3 inhibitor) or AZD5069 (a CXC chemokine receptor 2 (CXCR2) inhibitor) was evaluated in a phase IB/II trial (SCORES study, NCT02499328).	('CXCR2', 'Gene', (122, 127))	('CXC chemokine receptor 2', 'Gene', (96, 120))	('AZD5069', 'Chemical', 'MESH:C000597960', (85, 92))	('STAT3', 'Gene', '6774', (65, 70))	('AZD9150', 'Chemical', 'MESH:C049195', (54, 61))	('CXC chemokine receptor 2', 'Gene', '3579', (96, 120))	('AZD5069', 'Var', (85, 92))	('STAT3', 'Gene', (65, 70))	('CXCR2', 'Gene', '3579', (122, 127))
210832	31671550	Part B included a dose-expansion cohort for HNSCC, and tested the combination of durvalumab with either danvatirsen (STAT3 inhibitor) or AZD5069 (CXCR2 inhibitor) in PD-L1 pretreated/naive patients, and as monotherapy with primary-endpoint ORR and disease-control rate (DCR).	('PD-L1', 'Gene', '29126', (166, 171))	('HNSCC', 'Phenotype', 'HP:0012288', (44, 49))	('CXCR2', 'Gene', '3579', (146, 151))	('AZD5069', 'Chemical', 'MESH:C000597960', (137, 144))	('combination', 'Interaction', (66, 77))	('CXCR2', 'Gene', (146, 151))	('STAT3', 'Gene', '6774', (117, 122))	('patients', 'Species', '9606', (189, 197))	('tested', 'Reg', (55, 61))	('PD-L1', 'Gene', (166, 171))	('AZD5069', 'Var', (137, 144))	('STAT3', 'Gene', (117, 122))
210841	31671550	Unfortunately, unlike results of the STAT3 inhibitor, the addition of AZD5069 did not seem to improve outcome as the ORR was 10% and causally related AEs occurred in 76% of patients.	('AZD5069', 'Var', (70, 77))	('STAT3', 'Gene', '6774', (37, 42))	('patients', 'Species', '9606', (173, 181))	('STAT3', 'Gene', (37, 42))	('AZD5069', 'Chemical', 'MESH:C000597960', (70, 77))
210866	31671550	In preclinical studies, oncolytic viruses have been found to reduce tumor burden and to prime antitumor immunity as well as overcome resistance to checkpoint inhibitors by broadening neo-antigenome-directed T-cell responses.	('tumor', 'Disease', (68, 73))	('oncolytic viruses', 'Var', (24, 41))	('reduce', 'NegReg', (61, 67))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('broadening', 'PosReg', (172, 182))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('neo-antigenome-directed', 'MPA', (183, 206))	('tumor', 'Disease', (98, 103))	('prime', 'PosReg', (88, 93))
210898	31671550	Interestingly, patients with HPV-negative cancers who responded to ICI had a greater OS of up to 20 months in the presence of high TMB compared to 6 months in patients with low TMB.	('cancers', 'Disease', (42, 49))	('ICI', 'Chemical', 'MESH:C481040', (67, 70))	('patients', 'Species', '9606', (15, 23))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('high', 'Var', (126, 130))	('HPV', 'Species', '10566', (29, 32))	('cancers', 'Phenotype', 'HP:0002664', (42, 49))	('OS', 'Gene', '17451', (85, 87))	('cancers', 'Disease', 'MESH:D009369', (42, 49))	('patients', 'Species', '9606', (159, 167))
210925	31720124	The impact of genomic aberrations on protein is known as a risk factor that associated with complex diseases including cancer.	('genomic aberrations', 'Var', (14, 33))	('complex diseases', 'Disease', (92, 108))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('associated', 'Reg', (76, 86))	('cancer', 'Disease', (119, 125))	('complex diseases', 'Disease', 'MESH:D007105', (92, 108))	('protein', 'Protein', (37, 44))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
210962	31720124	We first identified dysregulated lncRNAs in LUAD and LUSC with the cutoff criteria as  log2FC  > 2 and adjusted P value < 0.01 (Figs.	('LUSC', 'Disease', 'MESH:D002294', (53, 57))	('LUAD', 'Phenotype', 'HP:0030078', (44, 48))	('LUAD', 'Disease', (44, 48))	('LUAD', 'Disease', 'MESH:C538231', (44, 48))	('LUSC', 'Disease', (53, 57))	('log2FC', 'Var', (87, 93))
210985	31720124	Up to now, an increasing amount of dysregulated lncRNAs have been identified to play vital roles in human cancers including NSCLC.	('dysregulated', 'Var', (35, 47))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('roles', 'Reg', (91, 96))	('NSCLC', 'Disease', (124, 129))	('human', 'Species', '9606', (100, 105))	('cancers', 'Phenotype', 'HP:0002664', (106, 113))	('NSCLC', 'Disease', 'MESH:D002289', (124, 129))	('cancers', 'Disease', (106, 113))	('cancers', 'Disease', 'MESH:D009369', (106, 113))	('lncRNAs', 'Protein', (48, 55))	('NSCLC', 'Phenotype', 'HP:0030358', (124, 129))
210994	31720124	Interestingly, cancer susceptibility candidate eight (CASC8) is a lncRNA that has been reported to be involved in various of cancers by its gene polymorphism, including lung cancer.	('lung cancer', 'Disease', 'MESH:D008175', (169, 180))	('cancer', 'Disease', 'MESH:D009369', (15, 21))	('lung cancer', 'Phenotype', 'HP:0100526', (169, 180))	('cancers', 'Disease', 'MESH:D009369', (125, 132))	('cancer', 'Disease', (174, 180))	('cancer', 'Disease', (125, 131))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('involved', 'Reg', (102, 110))	('cancer', 'Disease', (15, 21))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('polymorphism', 'Var', (145, 157))	('CASC8', 'Gene', (54, 59))	('lung cancer', 'Disease', (169, 180))	('CASC8', 'Gene', '727677', (54, 59))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('cancers', 'Phenotype', 'HP:0002664', (125, 132))	('cancers', 'Disease', (125, 132))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('cancer', 'Disease', 'MESH:D009369', (125, 131))
211008	31720124	Specifically, many overlapped mRNAs among these three ceRNAs were reported to be oncogenes in various cancers, which are consist with our study.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('cancers', 'Disease', 'MESH:D009369', (102, 109))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))	('cancers', 'Disease', (102, 109))	('mRNAs', 'Var', (30, 35))
211052	31697737	Membranes were blocked for 1 h in 5% nonfat milk in PBS, followed by overnight incubation with antibodies against Alix and TSG101 as well as Calnexin as negative control (Acris antibodies, Herford, Germany).	('antibodies', 'Var', (95, 105))	('Alix', 'Gene', (114, 118))	('Calnexin', 'Gene', (141, 149))	('Calnexin', 'Gene', '821', (141, 149))	('Alix', 'Gene', '10015', (114, 118))	('TSG101', 'Gene', (123, 129))	('TSG101', 'Gene', '7251', (123, 129))
211072	31697737	Fig 2 shows THP1 uptake of BICR18-derived exosomes (below) and BICR18 uptake of THP1-derived exosomes (above).	('THP1', 'Gene', '2736', (80, 84))	('BICR18', 'Var', (63, 69))	('THP1', 'Gene', '2736', (12, 16))	('THP1', 'Gene', (80, 84))	('THP1', 'Gene', (12, 16))
211083	31697737	Inhibition of exosome secretion with GW4869 treatment abolishes the changes observed in co-culture.	('GW4869', 'Var', (37, 43))	('exosome secretion', 'MPA', (14, 31))	('abolishes', 'NegReg', (54, 63))	('GW4869', 'Chemical', 'MESH:C468773', (37, 43))
211087	31697737	We found that exosomes triggered the expression of STAT-3 and the blockage of STAT3 activation also resulted in the inhibition of SOCS3.	('blockage', 'Var', (66, 74))	('STAT3', 'Gene', '6774', (78, 83))	('SOCS3', 'Gene', (130, 135))	('inhibition', 'NegReg', (116, 126))	('STAT3', 'Gene', (78, 83))	('expression', 'MPA', (37, 47))	('STAT-3', 'Gene', '6774', (51, 57))	('STAT-3', 'Gene', (51, 57))	('SOCS3', 'Gene', '9021', (130, 135))
211094	31697737	These results were confirmed by the inhibition of exosome release treating the cells with GW4869.	('inhibition', 'NegReg', (36, 46))	('GW4869', 'Var', (90, 96))	('exosome release', 'MPA', (50, 65))	('GW4869', 'Chemical', 'MESH:C468773', (90, 96))
211095	31697737	The increase in migration induced by co-culture was reduced in a dose-dependent manner under GW4869 treatment.	('migration', 'CPA', (16, 25))	('GW4869', 'Var', (93, 99))	('GW4869', 'Chemical', 'MESH:C468773', (93, 99))	('reduced', 'NegReg', (52, 59))
211129	31612029	Data has demonstrated that more than 1 in 3 patients with lung adenocarcinoma (LUAD) benefit from molecular-targeted therapies.	('LUAD', 'Disease', (79, 83))	('molecular-targeted', 'Var', (98, 116))	('LUAD', 'Disease', 'MESH:C538231', (79, 83))	('rat', 'Species', '10116', (16, 19))	('patients', 'Species', '9606', (44, 52))	('LUAD', 'Phenotype', 'HP:0030078', (79, 83))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (58, 77))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (58, 77))	('carcinoma', 'Phenotype', 'HP:0030731', (68, 77))	('lung adenocarcinoma', 'Disease', (58, 77))
211149	31612029	Three gene expression datasets [GSE31552, GSE6044 and GSE12428 ] were downloaded from the GEO (Affymetrix GPL6244 platform, Affymetrix Human Gene 1.0 ST Array; Affymetrix GPL201 platform, Affymetrix Human HG-Focus Target Array; Affymetrix GPL1708 platform, Agilent-012391 Whole Human Genome Oligo Microarray G4112A).	('Human', 'Species', '9606', (199, 204))	('GSE6044', 'Var', (42, 49))	('GSE12428 ]', 'Var', (54, 64))	('Human', 'Species', '9606', (278, 283))	('Human', 'Species', '9606', (135, 140))	('[GSE31552', 'Var', (31, 40))	('G4112A', 'Mutation', 'g.4112G>A', (308, 314))
211181	31612029	Mutations or amplifications of phosphatidylinositol-3 kinases (PI3K), phosphatase and Tensin homolog (PTEN), erythropoietin-producing hepatocellular A2 (EphA2) and liver kinase B1 (LKB1) were reported to be associated with the incidence, progression and prognosis of LUSC.	('LKB1', 'Gene', (181, 185))	('amplifications', 'Var', (13, 27))	('LKB1', 'Gene', '6794', (181, 185))	('EphA2', 'Gene', (153, 158))	('erythropoietin-producing hepatocellular A2', 'Gene', '1969', (109, 151))	('liver kinase B1', 'Gene', '6794', (164, 179))	('erythropoietin-producing hepatocellular A2', 'Gene', (109, 151))	('LUSC', 'Phenotype', 'HP:0030359', (267, 271))	('Mutations', 'Var', (0, 9))	('EphA2', 'Gene', '1969', (153, 158))	('phosphatidylinositol-3 kinases', 'Gene', (31, 61))	('associated', 'Reg', (207, 217))	('LUSC', 'Disease', (267, 271))	('PTEN', 'Gene', (102, 106))	('liver kinase B1', 'Gene', (164, 179))	('LUSC', 'Disease', 'MESH:D002294', (267, 271))	('PTEN', 'Gene', '5728', (102, 106))	('phosphatidylinositol-3 kinases', 'Gene', '5290', (31, 61))
211182	31612029	A study conducted using the Cancer Genome Atlas Research Network demonstrated the dysfunction of NFE2L2, KEAP1, CDKN2A and RB1, and the abnormal structures of their products are associated with the occurrence and development of LUSC.	('RB1', 'Gene', '5925', (123, 126))	('NFE2L2', 'Gene', (97, 103))	('rat', 'Species', '10116', (72, 75))	('CDKN2A', 'Gene', (112, 118))	('associated with', 'Reg', (178, 193))	('abnormal', 'Reg', (136, 144))	('CDKN2A', 'Gene', '1029', (112, 118))	('LUSC', 'Disease', 'MESH:D002294', (228, 232))	('LUSC', 'Disease', (228, 232))	('LUSC', 'Phenotype', 'HP:0030359', (228, 232))	('Cancer', 'Phenotype', 'HP:0002664', (28, 34))	('KEAP1', 'Gene', '9817', (105, 110))	('RB1', 'Gene', (123, 126))	('NFE2L2', 'Gene', '4780', (97, 103))	('KEAP1', 'Gene', (105, 110))	('dysfunction', 'Var', (82, 93))
211188	31612029	Previous studies have illustrated that dysregulations of cell cycle and cell proliferation serve roles in the carcinogenesis and malignant change of LUSC.	('dysregulations', 'Var', (39, 53))	('malignant change', 'Phenotype', 'HP:0002664', (129, 145))	('rat', 'Species', '10116', (84, 87))	('rat', 'Species', '10116', (28, 31))	('LUSC', 'Disease', 'MESH:D002294', (149, 153))	('LUSC', 'Disease', (149, 153))	('LUSC', 'Phenotype', 'HP:0030359', (149, 153))	('cell proliferation', 'CPA', (72, 90))	('carcinogenesis', 'Disease', 'MESH:D063646', (110, 124))	('cell cycle', 'CPA', (57, 67))	('carcinogenesis', 'Disease', (110, 124))	('malignant change', 'CPA', (129, 145))
211190	31612029	Furthermore, gene polymorphism of tetrahydrofolate induces a decreased activity of tetrahydrofolate reductase, which affects the normal metabolism of folate in cells, where tetrahydrofolate metabolic disorder is closely associated with tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (236, 241))	('folate', 'Chemical', 'MESH:D005492', (93, 99))	('tetrahydrofolate', 'Chemical', 'MESH:D013763', (34, 50))	('tetrahydrofolate', 'Gene', (34, 50))	('metabolic disorder', 'Disease', 'MESH:D008659', (190, 208))	('affects', 'Reg', (117, 124))	('folate', 'Chemical', 'MESH:D005492', (44, 50))	('metabolic disorder', 'Disease', (190, 208))	('metabolic disorder', 'Phenotype', 'HP:0001939', (190, 208))	('tumor', 'Phenotype', 'HP:0002664', (236, 241))	('activity', 'MPA', (71, 79))	('tetrahydrofolate', 'Chemical', 'MESH:D013763', (173, 189))	('associated', 'Reg', (220, 230))	('folate', 'Chemical', 'MESH:D005492', (183, 189))	('decreased', 'NegReg', (61, 70))	('gene polymorphism', 'Var', (13, 30))	('folate', 'Chemical', 'MESH:D005492', (150, 156))	('tetrahydrofolate reductase', 'Enzyme', (83, 109))	('tetrahydrofolate', 'Chemical', 'MESH:D013763', (83, 99))	('tumor', 'Disease', (236, 241))
211198	31612029	Gene polymorphisms of TYMS have been reported to have potential in improving the diagnosis, prevention and treatment of breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('breast cancer', 'Disease', (120, 133))	('breast cancer', 'Disease', 'MESH:D001943', (120, 133))	('breast cancer', 'Phenotype', 'HP:0003002', (120, 133))	('Gene polymorphisms', 'Var', (0, 18))	('improving', 'PosReg', (67, 76))	('TYMS', 'Gene', '7298', (22, 26))	('TYMS', 'Gene', (22, 26))
211199	31612029	Hence, several studies are now focusing on the association between gene polymorphic variations of TYMS with various types of cancer.	('TYMS', 'Gene', (98, 102))	('gene polymorphic variations', 'Var', (67, 94))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('TYMS', 'Gene', '7298', (98, 102))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('association', 'Interaction', (47, 58))
211222	31612029	The presence of EZH2 was associated with the aggressiveness of cancer development.	('EZH2', 'Gene', (16, 20))	('aggressiveness of cancer', 'Disease', 'MESH:D009369', (45, 69))	('associated', 'Reg', (25, 35))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('presence', 'Var', (4, 12))	('aggressiveness', 'Phenotype', 'HP:0000718', (45, 59))	('EZH2', 'Gene', '2146', (16, 20))	('aggressiveness of cancer', 'Disease', (45, 69))
211238	31612029	Recent studies demonstrated that various non-coding RNAs lead to cancer cell growth and metastasis via PTTG1.	('metastasis', 'CPA', (88, 98))	('rat', 'Species', '10116', (22, 25))	('lead to', 'Reg', (57, 64))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('PTTG1', 'Gene', '9232', (103, 108))	('PTTG1', 'Gene', (103, 108))	('non-coding RNAs', 'Var', (41, 56))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))
211252	31612029	In conclusion, the present study was conducted in order to identify potential DEGs that may be associated with carcinogenesis or adverse progression of LUSC.	('carcinogenesis', 'Disease', (111, 125))	('LUSC', 'Phenotype', 'HP:0030359', (152, 156))	('DEGs', 'Var', (78, 82))	('LUSC', 'Disease', 'MESH:D002294', (152, 156))	('LUSC', 'Disease', (152, 156))	('carcinogenesis', 'Disease', 'MESH:D063646', (111, 125))	('associated', 'Reg', (95, 105))
211265	31210172	Patients with an MPV <9.5 fL had a significantly longer OS compared with patients with an MPV >=9.5 fL (P=0.026).	('OS', 'Chemical', '-', (56, 58))	('MPV <9.5 fL', 'Var', (17, 28))	('Patients', 'Species', '9606', (0, 8))	('longer', 'PosReg', (49, 55))	('patients', 'Species', '9606', (73, 81))
211302	31210172	The OS of patients with LSCC and an MPV <9.5 fL was significantly longer compared with patients with MPV >=0.5 fL (P=0.026).	('MPV <9.5 fL', 'Var', (36, 47))	('OS', 'Chemical', '-', (4, 6))	('LSCC', 'Disease', (24, 28))	('patients', 'Species', '9606', (10, 18))	('patients', 'Species', '9606', (87, 95))
211322	31210172	Further analysis suggested that the patients with an increased NLR >=2.22 had a significantly shorter DFS and OS when compared with patients with a low NLR <2.22.	('DFS', 'CPA', (102, 105))	('OS', 'Chemical', '-', (110, 112))	('patients', 'Species', '9606', (36, 44))	('shorter', 'NegReg', (94, 101))	('NLR >=2.22', 'Var', (63, 73))	('patients', 'Species', '9606', (132, 140))
211323	31210172	In this study, evaluation of the prognostic role of the preoperative mean platelet volume (MPV) for patients with LSCC showed that the OS of patients with LSCC with MPV <9.5 fL was significantly increased when compared with patients with MPV >=9.5 fL.	('OS', 'Chemical', '-', (135, 137))	('MPV <9.5 fL', 'Var', (165, 176))	('LSCC', 'Disease', (155, 159))	('patients', 'Species', '9606', (100, 108))	('patients', 'Species', '9606', (224, 232))	('increased', 'PosReg', (195, 204))	('patients', 'Species', '9606', (141, 149))
211326	31210172	This was the first study to investigate the prognostic value of MPV in patients with LSCC and the findings supported that increased MPV was associated with poor prognosis.	('MPV', 'Var', (132, 135))	('patients', 'Species', '9606', (71, 79))	('LSCC', 'Disease', (85, 89))	('increased MPV', 'Phenotype', 'HP:0005518', (122, 135))
211368	27900322	Patterns of Transposable Element Expression and Insertion in Cancer Human transposable element (TE) activity in somatic tissues causes mutations that can contribute to tumorigenesis.	('Cancer', 'Phenotype', 'HP:0002664', (61, 67))	('Cancer', 'Disease', (61, 67))	('Human', 'Species', '9606', (68, 73))	('tumor', 'Disease', (168, 173))	('Cancer', 'Disease', 'MESH:D009369', (61, 67))	('mutations', 'Var', (135, 144))	('contribute', 'Reg', (154, 164))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('causes', 'Reg', (128, 134))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
211376	27900322	Tumor-specific TE insertions are enriched for private mutations, consistent with a potentially causal role in tumorigenesis.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('private mutations', 'Var', (46, 63))	('TE insertions', 'Var', (15, 28))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
211378	27900322	An Alu insertion in an upstream enhancer of the CBL tumor suppressor gene is associated with down-regulation of the gene in a single breast cancer patient, and an L1 insertion in the first exon of the BAALC gene also disrupts its expression in head and neck squamous cell carcinoma.	('breast cancer', 'Phenotype', 'HP:0003002', (133, 146))	('tumor', 'Disease', (52, 57))	('head and neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (244, 281))	('single breast', 'Phenotype', 'HP:0012813', (126, 139))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('insertion', 'Var', (166, 175))	('breast cancer', 'Disease', 'MESH:D001943', (133, 146))	('breast cancer', 'Disease', (133, 146))	('BAALC', 'Gene', '79870', (201, 206))	('CBL', 'Gene', (48, 51))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('down-regulation', 'NegReg', (93, 108))	('expression', 'MPA', (230, 240))	('CBL', 'Gene', '867', (48, 51))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('BAALC', 'Gene', (201, 206))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (258, 281))	('patient', 'Species', '9606', (147, 154))	('disrupts', 'NegReg', (217, 225))	('carcinoma', 'Phenotype', 'HP:0030731', (272, 281))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (244, 281))
211379	27900322	Our results are consistent with widespread somatic activity of human TEs leading to numerous insertion mutations that can contribute to tumorigenesis in a variety of tissues.	('human', 'Species', '9606', (63, 68))	('contribute', 'Reg', (122, 132))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('insertion mutations', 'Var', (93, 112))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('tumor', 'Disease', (136, 141))
211386	27900322	Active TE families are of great interest since they have the ability to generate de novo mutations, many of which have been linked to human disease (Hancks and Kazazian,; Solyom and and Kazazian,).	('human', 'Species', '9606', (134, 139))	('Kazazian', 'Disease', (160, 168))	('mutations', 'Var', (89, 98))	('linked', 'Reg', (124, 130))
211387	27900322	For instance, TE insertions have been shown to contribute to the etiology of a variety of different cancer types (Belancio et al.,; Carreira et al.,).	('contribute', 'Reg', (47, 57))	('TE insertions', 'Var', (14, 27))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))
211389	27900322	L1 insertions in particular have been implicated as potential cancer causing mutations in those and other studies (Morse et al.,; Miki et al.,; Iskow et al.,; Lee et al.,; Scott et al.,).	('insertions', 'Var', (3, 13))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))
211390	27900322	L1 activity is thought to promote tumor development by causing genomic instability, via impaired chromosomal pairing during mitosis, and/or by disrupting coding or regulatory sequences (Kemp and Longworth,).	('promote', 'PosReg', (26, 33))	('tumor', 'Disease', (34, 39))	('mitosis', 'Disease', 'None', (124, 131))	('coding or regulatory sequences', 'MPA', (154, 184))	('impaired', 'NegReg', (88, 96))	('causing', 'Reg', (55, 62))	('chromosomal', 'Protein', (97, 108))	('disrupting', 'NegReg', (143, 153))	('activity', 'Var', (3, 11))	('genomic instability', 'MPA', (63, 82))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('mitosis', 'Disease', (124, 131))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
211395	27900322	With respect to TE insertional activity, studies on matched normal and tumor tissues have found that novel L1 insertions occur at high frequencies in lung cancer genomes (Iskow et al.,).	('lung cancer', 'Phenotype', 'HP:0100526', (150, 161))	('lung cancer', 'Disease', (150, 161))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('lung cancer', 'Disease', 'MESH:D008175', (150, 161))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('insertions', 'Var', (110, 120))	('tumor', 'Disease', (71, 76))
211396	27900322	Such insertions frequently occur in oncogenes and tumor suppressors, underscoring their putative role in tumorigenesis (Lee et al.,).	('insertions', 'Var', (5, 15))	('occur', 'Reg', (27, 32))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Disease', (105, 110))	('tumor', 'Disease', (50, 55))
211401	27900322	One such study analyzed 19 hepatocellular carcinoma genomes utilizing the RC-Seq methodology (Baillie et al.,) and discovered two separate L1 insertions that initiate tumorigenesis via distinct oncogenic pathways (Shukla et al.,).	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (27, 51))	('hepatocellular carcinoma', 'Disease', (27, 51))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('initiate', 'PosReg', (158, 166))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('insertions', 'Var', (142, 152))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (27, 51))	('tumor', 'Disease', (167, 172))	('carcinoma', 'Phenotype', 'HP:0030731', (42, 51))	('oncogenic pathways', 'Pathway', (194, 212))
211402	27900322	This study found L1 insertions in two different tumor suppressor genes: Mutated in Colorectal Cancers (MCC) and Suppression of Tumorigenicity (ST18).	('Mutated', 'Var', (72, 79))	('Colorectal Cancers', 'Disease', 'MESH:D015179', (83, 101))	('Colorectal Cancers', 'Disease', (83, 101))	('tumor', 'Disease', (48, 53))	('insertions', 'Var', (20, 30))	('Tumor', 'Phenotype', 'HP:0002664', (127, 132))	('Suppression', 'NegReg', (112, 123))	('Cancers', 'Phenotype', 'HP:0002664', (94, 101))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('Cancer', 'Phenotype', 'HP:0002664', (94, 100))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('Tumorigenicity', 'CPA', (127, 141))
211403	27900322	Most recently, a role for L1 insertional activity was conclusively demonstrated for colorectal cancer caused by an insertion in the APC tumor suppressor gene (Scott et al.,).	('colorectal cancer', 'Disease', (84, 101))	('colorectal cancer', 'Disease', 'MESH:D015179', (84, 101))	('APC tumor', 'Disease', 'MESH:D011125', (132, 141))	('caused by', 'Reg', (102, 111))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('colorectal cancer', 'Phenotype', 'HP:0003003', (84, 101))	('APC tumor', 'Disease', (132, 141))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('insertion', 'Var', (115, 124))
211404	27900322	This paper describes a somatic L1 insertion into one copy of the APC gene that, when coupled with a point mutation in the other copy of the gene, initiates tumorigenesis through the two hit colorectal cancer pathway.	('initiates', 'Reg', (146, 155))	('APC', 'Gene', (65, 68))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('colorectal cancer', 'Disease', 'MESH:D015179', (190, 207))	('insertion', 'Var', (34, 43))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('colorectal cancer', 'Phenotype', 'HP:0003003', (190, 207))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('APC', 'Gene', '324', (65, 68))	('tumor', 'Disease', (156, 161))	('colorectal cancer', 'Disease', (190, 207))	('L1 insertion', 'Var', (31, 43))
211436	27900322	When all three families of active human TEs are considered together, we observed a total of 3672 TE insertions across the nine individuals analyzed for normal and cancer tissue pairs, 693 of which are unique insertions found in only one individual and one tissue type.	('human', 'Species', '9606', (34, 39))	('TE insertions', 'Var', (97, 110))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('insertions', 'Var', (100, 110))	('cancer', 'Disease', (163, 169))	('cancer', 'Disease', 'MESH:D009369', (163, 169))
211442	27900322	Given the relatively high level of L1 insertional activity in the tumor tissue samples analyzed here, we tested whether tumor-specific L1 insertions are found at lower frequencies among the (presumably) healthy donors from the 1KGP compared to L1 insertions found in matched normal tissue.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Disease', (66, 71))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('insertions', 'Var', (138, 148))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('tumor', 'Disease', (120, 125))
211443	27900322	The idea was to evaluate whether the tumor-specific L1 insertions represent mutations that are private, and thereby more likely to be deleterious or disease-causing.	('insertions', 'Var', (55, 65))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('tumor', 'Disease', 'MESH:D009369', (37, 42))
211445	27900322	The same pattern of an increased frequency of private L1 insertions in tumor tissue is observed (P < 2.0e-7) when all three cancer types are analyzed for sets of patients (Figures 3D-F) and when samples for individual patients are analyzed separately (Supplementary Figure 4).	('patients', 'Species', '9606', (162, 170))	('cancer', 'Disease', (124, 130))	('patients', 'Species', '9606', (218, 226))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Disease', (71, 76))	('insertions', 'Var', (57, 67))	('cancer', 'Disease', 'MESH:D009369', (124, 130))
211447	27900322	The pattern of a significant excess of private L1 insertions in tumor compared to normal tissue, observed for all three cancer types studied here, provides further evidence in support of a possible role for L1 activity in tumorigenesis.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('tumor', 'Disease', (64, 69))	('tumor', 'Disease', 'MESH:D009369', (222, 227))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('tumor', 'Disease', (222, 227))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('insertions', 'Var', (50, 60))
211451	27900322	To do so, we performed an integrated analysis of TE insertion, gene expression and chromatin data (see Materials and Methods) in an effort to identify the cancer-specific TE insertions that are most likely to play a causal role in tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (231, 236))	('insertions', 'Var', (174, 184))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('tumor', 'Disease', (231, 236))	('cancer', 'Disease', (155, 161))	('cancer', 'Disease', 'MESH:D009369', (155, 161))
211453	27900322	We observed a total of 141 intragenic (35.9%) insertions and 246 intronic insertions (62.6%) out of the 393 total cancer-specific insertions in our dataset.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('insertions', 'Var', (46, 56))	('cancer', 'Disease', (114, 120))
211454	27900322	None of these intergenic or intronic cancer-specific TE insertions were found to disrupt any known functional (regulatory) sequence element.	('cancer', 'Disease', (37, 43))	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('insertions', 'Var', (56, 66))
211455	27900322	Thus, consistent with previous studies, the vast majority of TE insertions that we observed are not likely to affect gene function or expression in cancer.	('cancer', 'Disease', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('affect', 'Reg', (110, 116))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('TE insertions', 'Var', (61, 74))
211460	27900322	It has been found to be mutated or translocated in a number of cancers including acute myeloid leukemia (Abbas et al.,; Naramura et al.,; Aranaz et al.,); mutations in CBL are also the cause of Noonan syndrome-like disorder (Martinelli et al.,).	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (81, 103))	('CBL', 'Gene', (168, 171))	('mutations', 'Var', (155, 164))	('CBL', 'Gene', '867', (168, 171))	('acute myeloid leukemia', 'Disease', (81, 103))	('Noonan syndrome-like disorder', 'Disease', (194, 223))	('cause', 'Reg', (185, 190))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (81, 103))	('Noonan syndrome-like disorder', 'Disease', 'MESH:C537846', (194, 223))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (87, 103))	('cancers', 'Phenotype', 'HP:0002664', (63, 70))	('leukemia', 'Phenotype', 'HP:0001909', (95, 103))	('cancers', 'Disease', (63, 70))	('cancers', 'Disease', 'MESH:D009369', (63, 70))
211462	27900322	The tumor-specific Alu enhancer insertion that we characterized is associated with down-regulation of CBL expression, consistent with a potential role in tumorigenesis via the activation of signal transduction pathways associated with cell proliferation (Sever and Brugge,).	('CBL', 'Gene', (102, 105))	('insertion', 'Var', (32, 41))	('tumor', 'Disease', (4, 9))	('signal transduction pathways', 'Pathway', (190, 218))	('CBL', 'Gene', '867', (102, 105))	('expression', 'MPA', (106, 116))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('activation', 'PosReg', (176, 186))	('down-regulation', 'NegReg', (83, 98))	('tumor', 'Disease', (154, 159))
211463	27900322	We also found a private L1 insertion that was unique to a head and neck squamous cell carcinoma tissue sample, located within the first exon of the Brain and Acute Leukemia, Cytoplasmic (BAALC) gene (Figure 4B).	('BAALC', 'Gene', (187, 192))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (72, 95))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (58, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('BAALC', 'Gene', '79870', (187, 192))	('Leukemia', 'Disease', 'MESH:D007938', (164, 172))	('Leukemia', 'Disease', (164, 172))	('head and neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (58, 95))	('insertion', 'Var', (27, 36))	('Acute Leukemia', 'Phenotype', 'HP:0002488', (158, 172))	('Leukemia', 'Phenotype', 'HP:0001909', (164, 172))
211466	27900322	This is consistent with previous results showing that the presence of fixed L1 insertions genome-wide is strongly associated with the down-regulation of human gene expression (Han et al.,).	('human', 'Species', '9606', (153, 158))	('human gene expression', 'MPA', (153, 174))	('down-regulation', 'NegReg', (134, 149))	('insertions', 'Var', (79, 89))
211469	27900322	A recent study discovered a role for the change in methylation status of a cancer-specific L1 insertion in tumorigenesis (Scott et al.,); this could be an additional mechanism by which the BAALC L1 insertion observed here exerts a regulatory effect.	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('BAALC', 'Gene', (189, 194))	('methylation', 'MPA', (51, 62))	('cancer', 'Disease', (75, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('BAALC', 'Gene', '79870', (189, 194))	('insertion', 'Var', (94, 103))	('tumor', 'Disease', 'MESH:D009369', (107, 112))
211476	27900322	Our results are consistent with previous studies showing expression of L1 transcripts in lung cancer (Belancio et al.,) and expression of L1 ORF1p in breast cancer (Harris et al.,), and tumor-specific L1 insertions have also previously been found in breast (Morse et al.,), head and neck (Helman et al.,), and lung tumors (Helman et al.,).	('breast cancer', 'Phenotype', 'HP:0003002', (150, 163))	('lung tumors', 'Disease', 'MESH:D008175', (310, 321))	('tumor', 'Disease', (186, 191))	('tumor', 'Disease', 'MESH:D009369', (315, 320))	('found', 'Reg', (241, 246))	('lung cancer', 'Disease', 'MESH:D008175', (89, 100))	('tumors', 'Phenotype', 'HP:0002664', (315, 321))	('lung tumors', 'Phenotype', 'HP:0100526', (310, 321))	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('breast cancer', 'Disease', 'MESH:D001943', (150, 163))	('lung cancer', 'Phenotype', 'HP:0100526', (89, 100))	('breast cancer', 'Disease', (150, 163))	('breast', 'Disease', (250, 256))	('tumor', 'Phenotype', 'HP:0002664', (315, 320))	('lung tumors', 'Disease', (310, 321))	('L1 ORF1p', 'Gene', (138, 146))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('lung cancer', 'Disease', (89, 100))	('insertions', 'Var', (204, 214))	('tumor', 'Disease', (315, 320))
211477	27900322	We confirmed the presence of numerous tumor-specific L1 insertions in these three cancer types and identify two potentially tumorigenic TE insertions, an Alu insertion in the enhancer region of the tumor suppressor gene CBL and an L1 insertion in the first exon of the BAALC gene.	('tumor', 'Disease', (124, 129))	('cancer', 'Disease', (82, 88))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('BAALC', 'Gene', (269, 274))	('tumor', 'Disease', 'MESH:D009369', (124, 129))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('Alu insertion in', 'Var', (154, 170))	('numerous tumor', 'Disease', (29, 43))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('CBL', 'Gene', (220, 223))	('insertions', 'Var', (56, 66))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('tumor', 'Disease', (198, 203))	('tumor', 'Disease', (38, 43))	('BAALC', 'Gene', '79870', (269, 274))	('numerous tumor', 'Disease', 'MESH:D009369', (29, 43))	('CBL', 'Gene', '867', (220, 223))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('L1 insertion in', 'Var', (231, 246))	('tumor', 'Disease', 'MESH:D009369', (38, 43))
211510	24550648	To define the presence of LN recurrence in this study, the criteria on CT scans were: 1) cervical, mediastinal and upper abdominal LNs >=10 mm in short-axis diameter except the LNs in the subdiaphragmatic nodes >=8 mm, retropharyngeal nodes >=5 mm and supraclavicular regions >=5 mm; 2) a nodal mass with the central low-density necrosis strengthening the ring on enhanced CT; and 3) multiple nodes or an ill-defined mass in any level fusion in a LN area.	('necrosis', 'Disease', (329, 337))	('necrosis', 'Disease', 'MESH:D009336', (329, 337))	('>=10', 'Var', (135, 139))
211561	32927736	The two protein isoforms are distinguished by their C-terminal sequences, which include a serine-rich region (polyS-domain) in JMJD6-2 that is not present in JMJD6-Ex5.	('serine-rich region', 'MPA', (90, 108))	('JMJD6-2', 'Var', (127, 134))	('polyS', 'Chemical', '-', (110, 115))	('serine', 'Chemical', 'MESH:D012694', (90, 96))
211565	32927736	The polyS domain of JMJD6-2 might block the interaction with polyS-domains of other proteins.	('block', 'NegReg', (34, 39))	('polyS domain', 'Var', (4, 16))	('JMJD6-2', 'Gene', (20, 27))	('polyS', 'Chemical', '-', (61, 66))	('polyS', 'Chemical', '-', (4, 9))	('interaction', 'Interaction', (44, 55))
211569	32927736	The distinct molecular properties of JMJD6-2 and JMJD6-Ex5 open a lead into the functional implications of the variations of their relative abundance in tumors.	('JMJD6-2', 'Gene', (37, 44))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('JMJD6-Ex5', 'Var', (49, 58))	('tumors', 'Disease', (153, 159))	('tumors', 'Phenotype', 'HP:0002664', (153, 159))	('tumors', 'Disease', 'MESH:D009369', (153, 159))
211571	32927736	Genetic knock-out experiments in mice showed severe developmental defects affecting the brain, heart, lung, kidney and colon of embryos on embryonic day E13.5 and E17.5 with perinatal death or death shortly after birth.	('affecting', 'Reg', (74, 83))	('death', 'Disease', 'MESH:D003643', (193, 198))	('death', 'Disease', (193, 198))	('E17.5', 'Var', (163, 168))	('brain', 'CPA', (88, 93))	('developmental defects', 'Disease', (52, 73))	('developmental defects', 'Disease', 'MESH:D000014', (52, 73))	('mice', 'Species', '10090', (33, 37))	('heart', 'CPA', (95, 100))	('death', 'Disease', 'MESH:D003643', (184, 189))	('death', 'Disease', (184, 189))
211576	32927736	Accordingly, the knock-down of JMJD6 in HEK-293T cells resulted in a significant change of the outcome for 14% of all alternative splicing events (n = 3710), and 74% of those were co-regulated with U2AF65.	('change', 'Reg', (81, 87))	('HEK-293T', 'CellLine', 'CVCL:0063', (40, 48))	('U2AF65', 'Gene', '11338', (198, 204))	('knock-down', 'Var', (17, 27))	('alternative splicing events', 'MPA', (118, 145))	('JMJD6', 'Gene', (31, 36))	('U2AF65', 'Gene', (198, 204))
211582	32927736	This has been attributed to JMJD6 targeting a number of proteins involved in the regulation of gene expression (BRD4, N-Myc) and the cell cycle (p53).	('N-Myc', 'Gene', (118, 123))	('p53', 'Gene', (145, 148))	('BRD4', 'Gene', (112, 116))	('p53', 'Gene', '7157', (145, 148))	('N-Myc', 'Gene', '4613', (118, 123))	('proteins', 'Protein', (56, 64))	('JMJD6', 'Var', (28, 33))	('BRD4', 'Gene', '23476', (112, 116))
211585	32927736	Four isoforms are listed in the NCBI database (NP_001074930.1, NP_055982.2, ABU68577.1, ABU68576.1).	('ABU68576.1', 'Var', (88, 98))	('I', 'Chemical', '-', (35, 36))	('NP_001074930.1', 'Var', (47, 61))
211609	32927736	In order to confirm the specific protein-protein interaction of JMJD6-Ex5 with FCP1 we performed co-IP assays in human embryonic kidney cells (HEK 293T).	('FCP1', 'Gene', (79, 83))	('JMJD6-Ex5', 'Var', (64, 73))	('FCP1', 'Gene', '2221', (79, 83))	('embryonic kidney', 'Disease', 'MESH:D007674', (119, 135))	('HEK 293T', 'CellLine', 'CVCL:0063', (143, 151))	('I', 'Chemical', '-', (0, 1))	('embryonic kidney', 'Disease', (119, 135))	('human', 'Species', '9606', (113, 118))	('I', 'Chemical', '-', (100, 101))
211611	32927736	This revealed that Flag-FCP1 was co-precipitated with GFP-JMJD6-Ex5 but not with GFP-JMJD6-2 (Figure 4a, lane 4-9).	('GFP-JMJD6-Ex5', 'Var', (54, 67))	('FCP1', 'Gene', (24, 28))	('FCP1', 'Gene', '2221', (24, 28))
211612	32927736	However, when we deleted the polyS-domain from GFP-JMJD6-2, the interaction of the resulting JMJD6 mutant (JMJD6-2-DeltapolyS, find the sequence in Figure 4a, bottom part) with FCP1 did occur (Figure 4a, 10-12) suggesting that the polyS-domain of JMJD6-2 blocks binding of JMJD6-2 to FCP1.	('polyS', 'Chemical', '-', (231, 236))	('polyS', 'Chemical', '-', (29, 34))	('binding', 'Interaction', (262, 269))	('FCP1', 'Gene', (177, 181))	('blocks', 'NegReg', (255, 261))	('polyS-domain', 'Var', (231, 243))	('FCP1', 'Gene', (284, 288))	('FCP1', 'Gene', '2221', (284, 288))	('FCP1', 'Gene', '2221', (177, 181))	('JMJD6', 'Gene', (93, 98))	('polyS', 'Chemical', '-', (120, 125))	('mutant', 'Var', (99, 105))	('interaction', 'Interaction', (64, 75))
211613	32927736	An inhibitory effect of the polyS-domain of JMJD6-2 on a protein-protein interaction was next shown for the RNA polymerase I transcription factor upstream binding factor (UBF).	('UBF', 'Gene', '7343', (171, 174))	('polyS-domain', 'Var', (28, 40))	('UBF', 'Gene', (171, 174))	('upstream binding factor', 'Gene', '7343', (146, 169))	('inhibitory effect', 'NegReg', (3, 20))	('protein-protein interaction', 'MPA', (57, 84))	('I', 'Chemical', '-', (123, 124))	('upstream binding factor', 'Gene', (146, 169))	('polyS', 'Chemical', '-', (28, 33))	('JMJD6-2', 'Gene', (44, 51))
211615	32927736	We therefore co-expressed GFP-tagged UBF with HA-tagged JMJD6-Ex5, JMJD6-2 or JMJD6-2-DeltapolyS in HEK 293T-cells and performed anti-GFP-IP (Figure 4b).	('UBF', 'Gene', (37, 40))	('JMJD6-2', 'Var', (67, 74))	('HEK 293T-cells', 'CellLine', 'CVCL:0063', (100, 114))	('JMJD6-2-DeltapolyS', 'Var', (78, 96))	('polyS', 'Chemical', '-', (91, 96))	('UBF', 'Gene', '7343', (37, 40))	('I', 'Chemical', '-', (138, 139))
211616	32927736	GFP-UBF co-precipitated JMJD6-Ex5 and JMJD6-2-DeltapolyS (Figure 4b, lane 7-12), but not JMJD6-2 (Figure 4b, lane 4-6), suggesting that the polyS-domain of JMJD6-2 blocked the interaction with UBF.	('UBF', 'Gene', '7343', (4, 7))	('JMJD6-Ex5', 'Var', (24, 33))	('polyS', 'Chemical', '-', (51, 56))	('UBF', 'Gene', (4, 7))	('interaction', 'Interaction', (176, 187))	('UBF', 'Gene', '7343', (193, 196))	('polyS', 'Chemical', '-', (140, 145))	('UBF', 'Gene', (193, 196))	('polyS-domain', 'Var', (140, 152))
211617	32927736	In conclusion, the presence or absence of the polyS-domain in JMJD6 isoforms has a profound effect on their engagement in specific protein-protein interactions.	('polyS', 'Chemical', '-', (46, 51))	('polyS-domain', 'Var', (46, 58))	('engagement', 'MPA', (108, 118))	('specific protein-protein interactions', 'MPA', (122, 159))	('I', 'Chemical', '-', (0, 1))	('JMJD6', 'Gene', (62, 67))
211621	32927736	Co-IP (Figure 4c, lane 10-18) and quantification of the Western Blot signals revealed that significantly more JMJD6-2 than JMJD6-Ex5 or JMJD6-2-DeltapolyS were co-precipitated by GFP-U2AF6520-70 (Figure 4d).	('JMJD6-2', 'Var', (110, 117))	('polyS', 'Chemical', '-', (149, 154))	('U2AF6520-70', 'Gene', '11338', (183, 194))	('I', 'Chemical', '-', (3, 4))	('U2AF6520-70', 'Gene', (183, 194))
211628	32927736	Tethering U2AF65-MS2 to exon 3 substantially increased its inclusion four-fold (Figure 5c).	('U2AF65', 'Gene', '11338', (10, 16))	('increased', 'PosReg', (45, 54))	('Tethering', 'Var', (0, 9))	('U2AF65', 'Gene', (10, 16))	('inclusion', 'MPA', (59, 68))	('MS2', 'Species', '2710868', (17, 20))
211630	32927736	Likewise, in the absence of U2AF65-MS2 tethering a significant decrease in exon 3 inclusion was also seen, when only co-expressing JMJD6-2 but not JMJD6-Ex5 (Figure 5d).	('MS2', 'Species', '2710868', (35, 38))	('JMJD6-2', 'Var', (131, 138))	('exon 3', 'Protein', (75, 81))	('U2AF65', 'Gene', (28, 34))	('inclusion', 'MPA', (82, 91))	('decrease', 'NegReg', (63, 71))	('U2AF65', 'Gene', '11338', (28, 34))
211632	32927736	However, co-expression of JMJD6-AxA with the splicing reporter also led to a significant decrease in exon 3 inclusion, comparable to the JMJD6-2 wildtype levels independent of U2AF65-MS2 tethering (Figure 5e).	('U2AF65', 'Gene', '11338', (176, 182))	('MS2', 'Species', '2710868', (183, 186))	('decrease', 'NegReg', (89, 97))	('JMJD6-AxA', 'Var', (26, 35))	('exon 3 inclusion', 'MPA', (101, 117))	('U2AF65', 'Gene', (176, 182))
211633	32927736	In summary, these results indicate that JMJD6-2 inhibits exon 3 inclusion in this splicing assay independent of its catalytic activity and of U2AF65-MS2.	('U2AF65', 'Gene', '11338', (142, 148))	('inhibits', 'NegReg', (48, 56))	('MS2', 'Species', '2710868', (149, 152))	('JMJD6-2', 'Var', (40, 47))	('exon', 'Protein', (57, 61))	('I', 'Chemical', '-', (0, 1))	('U2AF65', 'Gene', (142, 148))
211637	32927736	Silencing jmjd6 by 60% (Figure 6a) promoted exon 5 inclusion (Figure 6b), resulting in an increase of jmjd6-Ex5 transcripts.	('jmjd6', 'Gene', (10, 15))	('increase', 'PosReg', (90, 98))	('exon 5 inclusion', 'Protein', (44, 60))	('jmjd6', 'Gene', '23210', (102, 107))	('promoted', 'PosReg', (35, 43))	('jmjd6', 'Gene', '23210', (10, 15))	('Silencing', 'Var', (0, 9))	('jmjd6', 'Gene', (102, 107))
211639	32927736	Therefore, we silenced U2af65.	('U2af65', 'Gene', (23, 29))	('silenced', 'Var', (14, 22))	('U2af65', 'Gene', '11338', (23, 29))
211640	32927736	However, silencing U2af65 (Figure 6c) did not change the splicing outcome (Figure 6d).	('silencing', 'Var', (9, 18))	('U2af65', 'Gene', (19, 25))	('splicing', 'MPA', (57, 65))	('U2af65', 'Gene', '11338', (19, 25))
211641	32927736	This suggests that JMJD6 autoregulates exon 5 recognition, which seems to be independent of U2AF65.	('U2AF65', 'Gene', (92, 98))	('JMJD6', 'Var', (19, 24))	('exon', 'Protein', (39, 43))	('U2AF65', 'Gene', '11338', (92, 98))	('autoregulates', 'Reg', (25, 38))
211643	32927736	There are four isoforms of JMJD6 resulting from alternative splicing of the jmjd6 pre-mRNA.	('jmjd6', 'Gene', '23210', (76, 81))	('jmjd6', 'Gene', (76, 81))	('JMJD6', 'Gene', (27, 32))	('resulting from', 'Reg', (33, 47))	('alternative splicing', 'Var', (48, 68))
211650	32927736	Moreover, in direct Co-IPs, we found that JMJD6-Ex5 interacted only weakly with RS-domains in comparison with JMJD6-2.	('Co-IPs', 'Chemical', '-', (20, 26))	('interacted', 'Interaction', (52, 62))	('JMJD6-Ex5', 'Var', (42, 51))
211651	32927736	The major protein pulled down with JMJD6-Ex5 was FCP1 (TFIIF-associating CTD phosphatase).	('JMJD6-Ex5', 'Var', (35, 44))	('FCP1', 'Gene', (49, 53))	('FCP1', 'Gene', '2221', (49, 53))
211655	32927736	We could attribute this failure to an inhibitory function of the polyS-domain of JMJD6-2.	('JMJD6-2', 'Gene', (81, 88))	('inhibitory function', 'MPA', (38, 57))	('polyS-domain', 'Var', (65, 77))	('polyS', 'Chemical', '-', (65, 70))
211656	32927736	When we deleted this domain, JMJD6-2-DeltapolyS strongly interacted with FCP1.	('JMJD6-2-DeltapolyS', 'Var', (29, 47))	('FCP1', 'Gene', '2221', (73, 77))	('interacted', 'Interaction', (57, 67))	('polyS', 'Chemical', '-', (42, 47))	('FCP1', 'Gene', (73, 77))
211658	32927736	UBF has a C-terminal polyS-domain; it interacts only with JMJD6-2-DeltapolyS and JMJD6-Ex5 but not with JMJD6-2.	('polyS', 'Chemical', '-', (21, 26))	('JMJD6-Ex5', 'Var', (81, 90))	('UBF', 'Gene', '7343', (0, 3))	('UBF', 'Gene', (0, 3))	('polyS', 'Chemical', '-', (71, 76))	('interacts', 'Interaction', (38, 47))
211659	32927736	From these data, we conclude that the polyS-domain of JMJD6-2 blocks the interaction with polyS-domains of other proteins.	('polyS-domain', 'Var', (38, 50))	('polyS', 'Chemical', '-', (38, 43))	('interaction', 'Interaction', (73, 84))	('polyS', 'Chemical', '-', (90, 95))	('blocks', 'NegReg', (62, 68))	('JMJD6-2', 'Gene', (54, 61))
211661	32927736	Cryo-EM micrographs have shown that JMJD6-2 forms large distinct oligomers and the deletion of its polyS domain changed the oligomeric structure from rings to fibrils.	('polyS', 'Gene', (99, 104))	('oligomeric structure', 'MPA', (124, 144))	('deletion', 'Var', (83, 91))	('changed', 'Reg', (112, 119))	('polyS', 'Chemical', '-', (99, 104))	('rings', 'MPA', (150, 155))	('JMJD6-2', 'Gene', (36, 43))
211665	32927736	We monitored the splicing of a HIV-1-based splicing reporter and found that JMJD6-2 significantly changed the splicing outcome by inhibiting exon inclusion.	('inhibiting', 'NegReg', (130, 140))	('exon inclusion', 'MPA', (141, 155))	('splicing outcome', 'MPA', (110, 126))	('HIV-1', 'Species', '11676', (31, 36))	('JMJD6-2', 'Var', (76, 83))	('changed', 'Reg', (98, 105))
211667	32927736	In the presence or absence of U2AF65-MS2, JMJD6-2 decreased exon inclusion by half.	('U2AF65', 'Gene', (30, 36))	('decreased', 'NegReg', (50, 59))	('I', 'Chemical', '-', (0, 1))	('MS2', 'Species', '2710868', (37, 40))	('U2AF65', 'Gene', '11338', (30, 36))	('exon inclusion', 'MPA', (60, 74))	('JMJD6-2', 'Var', (42, 49))
211672	32927736	Knocking down jmjd6 led to a significant increase of exon 5 inclusion, resulting in increased jmjd6-Ex5-trancripts.	('Knocking down', 'Var', (0, 13))	('jmjd6', 'Gene', '23210', (94, 99))	('jmjd6', 'Gene', (14, 19))	('jmjd6', 'Gene', '23210', (14, 19))	('jmjd6', 'Gene', (94, 99))	('increased', 'PosReg', (84, 93))	('inclusion', 'MPA', (60, 69))	('exon 5', 'Protein', (53, 59))	('increase', 'PosReg', (41, 49))
211677	32927736	While JMJD6-2, as previously reported by several authors, interacts with SR-like proteins and is involved in splice regulation (amongst other functions), JMJD6-Ex5 interacts with FCP1 and UBF, and is not involved in splice regulation of the HIV-1-based reporter gene.	('JMJD6-Ex5', 'Var', (154, 163))	('HIV-1', 'Species', '11676', (241, 246))	('UBF', 'Gene', (188, 191))	('SR-like', 'Protein', (73, 80))	('interacts', 'Interaction', (164, 173))	('involved', 'Reg', (97, 105))	('interacts', 'Interaction', (58, 67))	('FCP1', 'Gene', (179, 183))	('splice', 'MPA', (109, 115))	('UBF', 'Gene', '7343', (188, 191))	('FCP1', 'Gene', '2221', (179, 183))
211680	32927736	HEK293T cells were transfected at a confluency of 60% with C-terminal HA-tagged JMJD6-2, JMJD6-Ex5 or JMJD6-2-DeltapolyS and GFP-tagged U2AF65, U2AF6520-70 or UBF (26672, Addgene, Watertown, MA, USA) using Lipofectamine 2000 (11668030, Thermo Fisher, Waltham, MA, USA).	('11668030', 'Var', (226, 234))	('polyS', 'Chemical', '-', (115, 120))	('U2AF65', 'Gene', (136, 142))	('U2AF6520-70', 'Gene', (144, 155))	('U2AF65', 'Gene', (144, 150))	('UBF', 'Gene', '7343', (159, 162))	('JMJD6-2-DeltapolyS', 'Var', (102, 120))	('UBF', 'Gene', (159, 162))	('HEK293T', 'CellLine', 'CVCL:0063', (0, 7))	('U2AF65', 'Gene', '11338', (144, 150))	('U2AF65', 'Gene', '11338', (136, 142))	('Lipofectamine 2000', 'Chemical', 'MESH:C086724', (206, 224))	('U2AF6520-70', 'Gene', '11338', (144, 155))
211681	32927736	The same experiment was conducted with HEK293T cells transfected with GFP-tagged JMJD6-2, JMJD6-Ex5 or JMJD6-2-DeltapolyS and Flag-tagged FCP1.	('FCP1', 'Gene', (138, 142))	('FCP1', 'Gene', '2221', (138, 142))	('HEK293T', 'CellLine', 'CVCL:0063', (39, 46))	('JMJD6-Ex5', 'Var', (90, 99))	('polyS', 'Chemical', '-', (116, 121))	('JMJD6-2-DeltapolyS', 'Var', (103, 121))
211720	32503451	AC-predominant ASC were more commonly presented with air bronchogram, and were with a better prognosis than SCC-predominant ASC.	('SCC', 'Gene', (108, 111))	('presented', 'Reg', (38, 47))	('SCC', 'Phenotype', 'HP:0002860', (108, 111))	('SCC', 'Gene', '6317', (108, 111))	('AC-predominant', 'Var', (0, 14))	('air bronchogram', 'Disease', (53, 68))
211766	32503451	The 3- and 5-year survival rates (53.5% at 3 years and 25.6% at 5 years) of all patients with stage I,II,IIIA were lower than those with AC or SCC.	('SCC', 'Gene', (143, 146))	('SCC', 'Phenotype', 'HP:0002860', (143, 146))	('patients', 'Species', '9606', (80, 88))	('SCC', 'Gene', '6317', (143, 146))	('lower', 'NegReg', (115, 120))	('IIIA', 'Var', (105, 109))
211790	31097034	The rate of progression-free survival was higher in patients with increased immune scores compared with the remaining patients (83.1% vs. 57.1%, p = 0.25).	('increased', 'PosReg', (66, 75))	('patients', 'Species', '9606', (118, 126))	('higher', 'PosReg', (42, 48))	('progression-free survival', 'CPA', (12, 37))	('immune scores', 'Var', (76, 89))	('patients', 'Species', '9606', (52, 60))
211804	31097034	Patients with esophageal cancer at clinical stages T1b-T4a and N0 or N+ were evaluated for surgery by a multidisciplinary team that included a medical oncologist, a radiation oncologist, a radiologist, and a thoracic surgeon.	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('T1b-T4a', 'Var', (51, 58))	('esophageal cancer', 'Disease', (14, 31))	('esophageal cancer', 'Disease', 'MESH:D004938', (14, 31))	('Patients', 'Species', '9606', (0, 8))
211814	31097034	TMB was measured by the number of somatic single nucleotide variants and indel mutations per megabase in the coding region.	('TMB', 'Chemical', '-', (0, 3))	('single nucleotide variants', 'Var', (42, 68))	('indel mutations', 'Var', (73, 88))
211815	31097034	In addition, known somatic alterations in COSMIC and truncations in tumor suppressor genes were excluded from the count.	('tumor', 'Disease', (68, 73))	('truncations', 'Var', (53, 64))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('OS', 'Chemical', '-', (43, 45))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))
211820	31097034	The first primary antibodies for CD4 (ab133616, Abcam, dilution 1:100) were incubated for 30 min, followed by detection using the Polymer HRP Ms. + Rb (ARH1001EA, Perkin-Elmer) for 10 min.	('CD4', 'Gene', (33, 36))	('CD4', 'Gene', '920', (33, 36))	('ab133616', 'Var', (38, 46))
211833	31097034	Twenty-four pre-CCRT samples had missense, nonsense, or splicing mutations in the tumor suppressor gene, TP53, and these alterations were maintained in 11 samples after CCRT.	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('nonsense', 'Var', (43, 51))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('TP53', 'Gene', '7157', (105, 109))	('TP53', 'Gene', (105, 109))	('tumor', 'Disease', (82, 87))	('missense', 'Var', (33, 41))
211834	31097034	Although nine pre-CCRT samples had a missense mutation in the nuclear factor erythroid 2 like 2 gene, NFE2L2, only two post-CCRT samples retained that mutation.	('NFE2L2', 'Gene', '4780', (102, 108))	('nuclear factor erythroid 2 like 2', 'Gene', (62, 95))	('NFE2L2', 'Gene', (102, 108))	('missense mutation', 'Var', (37, 54))	('nuclear factor erythroid 2 like 2', 'Gene', '4780', (62, 95))
211838	31097034	We found that the TMB and neoantigen load were significantly lower in post-CCRT samples (p < 0.001) compared with pre-CCRT samples (Fig.	('TMB', 'MPA', (18, 21))	('lower', 'NegReg', (61, 66))	('post-CCRT', 'Var', (70, 79))	('neoantigen load', 'MPA', (26, 41))	('TMB', 'Chemical', '-', (18, 21))
211855	31097034	CCF estimation analysis showed that NFE2L2 p.D15E was the only unique variant in pCR samples.	('p.D15E', 'Mutation', 'p.D15E', (43, 49))	('NFE2L2', 'Gene', (36, 42))	('pCR', 'Disease', (81, 84))	('NFE2L2', 'Gene', '4780', (36, 42))	('p.D15E', 'Var', (43, 49))
211868	31097034	A gain-of-function NRF2 mutation confers resistance to therapy in ESCC cells.	('gain-of-function', 'PosReg', (2, 18))	('resistance', 'CPA', (41, 51))	('NRF2', 'Gene', '4780', (19, 23))	('SCC', 'Gene', (67, 70))	('SCC', 'Phenotype', 'HP:0002860', (67, 70))	('NRF2', 'Gene', (19, 23))	('mutation', 'Var', (24, 32))	('SCC', 'Gene', '6317', (67, 70))
211869	31097034	However, our results showed no significant correlation between NFE2L2 missense mutations and the pCR of the study population (pCR rate of 14.3% in patients with NFE2L2 mutations vs. 20.0% in the remaining patients).	('patients', 'Species', '9606', (205, 213))	('pCR', 'Disease', (97, 100))	('NFE2L2', 'Gene', '4780', (161, 167))	('NFE2L2', 'Gene', '4780', (63, 69))	('missense mutations', 'Var', (70, 88))	('patients', 'Species', '9606', (147, 155))	('NFE2L2', 'Gene', (161, 167))	('NFE2L2', 'Gene', (63, 69))	('mutations', 'Var', (168, 177))
211870	31097034	It is possible that the missense mutations observed in our study population failed to affect NFE2L2 function and further analysis is needed to study the functional alteration of the mutated forms of NFE2L2 in the ESCC tissue samples.	('NFE2L2', 'Gene', '4780', (199, 205))	('affect', 'Reg', (86, 92))	('SCC', 'Gene', '6317', (214, 217))	('missense mutations', 'Var', (24, 42))	('function', 'MPA', (100, 108))	('NFE2L2', 'Gene', (199, 205))	('NFE2L2', 'Gene', '4780', (93, 99))	('SCC', 'Gene', (214, 217))	('SCC', 'Phenotype', 'HP:0002860', (214, 217))	('NFE2L2', 'Gene', (93, 99))
211880	31097034	Clinical trials have shown that high TMB increases the efficacy of immune checkpoint blockades in cancer immunotherapy.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('high', 'Var', (32, 36))	('increases', 'PosReg', (41, 50))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('immune', 'Protein', (67, 73))	('cancer', 'Disease', (98, 104))	('efficacy', 'MPA', (55, 63))	('TMB', 'Chemical', '-', (37, 40))
211959	32650830	Clinical features, treatment, and survival outcome of primary pulmonary NUT midline carcinoma NUT midline carcinoma (NMC), a rare type of squamous cell carcinoma, is genetically characterised by NUT midline carcinoma family member 1 (NUTM1) gene rearrangement.	('carcinoma', 'Phenotype', 'HP:0030731', (152, 161))	('NUTM1', 'Gene', '256646', (234, 239))	('NUTM1', 'Gene', (234, 239))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (138, 161))	('NUT midline carcinoma', 'Disease', 'MESH:D009436', (94, 115))	('NUT midline carcinoma', 'Disease', 'MESH:D009436', (195, 216))	('men', 'Species', '9606', (255, 258))	('carcinoma', 'Phenotype', 'HP:0030731', (207, 216))	('squamous cell carcinoma', 'Disease', (138, 161))	('NUT midline carcinoma family member 1', 'Gene', (195, 232))	('primary pulmonary NUT midline carcinoma', 'Disease', 'MESH:D008175', (54, 93))	('NMC', 'Chemical', '-', (117, 120))	('men', 'Species', '9606', (24, 27))	('NUT midline carcinoma family member 1', 'Gene', '256646', (195, 232))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('rearrangement', 'Var', (246, 259))	('NUT midline carcinoma', 'Disease', 'MESH:D009436', (72, 93))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (138, 161))	('primary pulmonary NUT midline carcinoma', 'Disease', (54, 93))	('NUT midline carcinoma', 'Disease', (94, 115))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))
212009	32650830	The NUTM1 gene on 15q14 was probed separately using RH54191 (211 KB, green) and SHGC-110339 (306 KB, red) (Ambiping [LBP], Guangzhou, China).	('LBP', 'Gene', '3929', (117, 120))	('NUTM1', 'Gene', '256646', (4, 9))	('NUTM1', 'Gene', (4, 9))	('RH54191', 'Var', (52, 59))	('LBP', 'Gene', (117, 120))
212042	32650830	1), and ataxin 3 (ATXN3) and zinc finger protein 429 [ZNF429] mutations were detected in all samples.	('zinc finger protein 429', 'Gene', '353088', (29, 52))	('ATXN3', 'Gene', (18, 23))	('ZNF429', 'Gene', '353088', (54, 60))	('ZNF429', 'Gene', (54, 60))	('ataxin 3', 'Gene', '4287', (8, 16))	('zinc finger protein 429', 'Gene', (29, 52))	('ataxin 3', 'Gene', (8, 16))	('mutations', 'Var', (62, 71))	('ATXN3', 'Gene', '4287', (18, 23))
212045	32650830	The TRS report of Case 5 showed high TMB and an exon 6 nonsense mutation in phosphatase and tensin homolog (PTEN) with an allele fraction of 70.64%.	('PTEN', 'Gene', (108, 112))	('exon 6 nonsense', 'Var', (48, 63))	('PTEN', 'Gene', '5728', (108, 112))	('phosphatase and tensin homolog', 'Gene', '5728', (76, 106))	('TMB', 'MPA', (37, 40))	('TMB', 'Chemical', '-', (37, 40))
212046	32650830	The small-panel TRS reports showed an EGFR exon 19 deletion in Case 2 and a phosphoinositide-3-kinase regulatory subunit 1 (PIK3R1) p.I29L mutation with an allele fraction of 70.64%.	('EGFR', 'Gene', '1956', (38, 42))	('phosphoinositide-3-kinase regulatory subunit 1', 'Gene', (76, 122))	('p.I29L', 'Var', (132, 138))	('EGFR', 'Gene', (38, 42))	('PIK3R1', 'Gene', (124, 130))	('p.I29L', 'Mutation', 'p.I29L', (132, 138))	('PIK3R1', 'Gene', '5295', (124, 130))	('phosphoinositide-3-kinase regulatory subunit 1', 'Gene', '5295', (76, 122))
212098	32650830	Rapid squamous differentiation caused by knockdown of NUT fusion oncogenes in NMC cell lines suggests that NMCs are derived from squamous cells.	('NUT', 'Gene', '256646', (54, 57))	('NMC', 'Chemical', '-', (107, 110))	('NUT', 'Gene', (54, 57))	('NMC', 'Chemical', '-', (78, 81))	('knockdown', 'Var', (41, 50))
212100	32650830	Immunotherapy is more effective in patients with high TMB and/or PD-L1 expression.	('PD-L1', 'Gene', (65, 70))	('high', 'Var', (49, 53))	('TMB', 'Chemical', '-', (54, 57))	('patients', 'Species', '9606', (35, 43))	('PD-L1', 'Gene', '29126', (65, 70))
212106	32650830	However, given the small number of cases and the long survival time of patients with primary tracheal tumours (case 6 and case 7), it is difficult to prove that high TMB predicts better immunotherapy outcome in these patients.	('primary tracheal tumours', 'Disease', 'MESH:D014134', (85, 109))	('tumour', 'Phenotype', 'HP:0002664', (102, 108))	('patients', 'Species', '9606', (71, 79))	('tumours', 'Phenotype', 'HP:0002664', (102, 109))	('high', 'Var', (161, 165))	('TMB', 'Chemical', '-', (166, 169))	('primary tracheal tumours', 'Disease', (85, 109))	('patients', 'Species', '9606', (217, 225))
212141	30535430	On the whole, the findings of this study provide evidence that inhibiting these targets affects the expression of glycodelin and its immunosuppressive effect in NSCLC tumours.	('glycodelin', 'Gene', '5047', (114, 124))	('affects', 'Reg', (88, 95))	('tumours', 'Phenotype', 'HP:0002664', (167, 174))	('inhibiting', 'Var', (63, 73))	('immunosuppressive effect', 'CPA', (133, 157))	('expression', 'MPA', (100, 110))	('glycodelin', 'Gene', (114, 124))	('tumour', 'Phenotype', 'HP:0002664', (167, 173))	('NSCLC tumours', 'Disease', 'MESH:D009369', (161, 174))	('NSCLC tumours', 'Disease', (161, 174))
212146	30535430	Mutations within the epidermal growth factor receptor (EGFR) occur frequently in NSCLC.	('EGFR', 'Gene', '1956', (55, 59))	('epidermal growth factor receptor', 'Gene', (21, 53))	('EGFR', 'Gene', (55, 59))	('epidermal growth factor receptor', 'Gene', '1956', (21, 53))	('Mutations', 'Var', (0, 9))	('NSCLC', 'Disease', (81, 86))	('occur', 'Reg', (61, 66))	('NSCLC', 'Disease', 'MESH:D002289', (81, 86))
212147	30535430	Often this mutation leads to a constitutive activation of the receptor and increases downstream signalling cascades, such as the mitogen-activated protein kinase kinase (MEK)/extracellular-signal regulated kinases (ERK), phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) and signal transducer and activator (STAT) pathway.	('receptor', 'Protein', (62, 70))	('AKT', 'Gene', (272, 275))	('ERK', 'Gene', '5594', (215, 218))	('activation', 'PosReg', (44, 54))	('ERK', 'Gene', (215, 218))	('phosphoinositide 3-kinase', 'Gene', '5290', (221, 246))	('MEK', 'Gene', '5609', (170, 173))	('phosphoinositide 3-kinase', 'Gene', (221, 246))	('mutation', 'Var', (11, 19))	('AKT', 'Gene', '207', (272, 275))	('MEK', 'Gene', (170, 173))	('increases', 'PosReg', (75, 84))
212178	30535430	The H1975 lung adenocarcinoma (ADC) cell line was purchased from American Type Culture Collection (CRL-5908; ATCC, Manassas, VA, USA) and authenticated by DNA profiling using 8 different and highly polymorphic short tandem repeat (STR) (Leibniz-Institut DSMZ, Braunschweig, Germany).	('CRL', 'Gene', (99, 102))	('carcinoma', 'Phenotype', 'HP:0030731', (20, 29))	('CRL', 'Gene', '133396', (99, 102))	('short tandem repeat', 'Var', (210, 229))	('H1975 lung adenocarcinoma', 'Disease', 'MESH:D000077192', (4, 29))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (10, 29))	('H1975 lung adenocarcinoma', 'Disease', (4, 29))
212184	30535430	The following signalling pathway inducers and modulators were used: LPA (Santa Cruz Biotechnology), PMA (Cayman Chemical, Ann Arbor, MI, USA), epidermal growth factor (EGF; Biomol, Hamburg, Germany), heparin-binding (HB)-EGF (Biomol), TGF-beta1, -2, -3 (WuXi Biosciences, San Diego, CA, USA), Bryostatin1 (Selleckchem, Houston, TX, USA), GF109203X (StressMarq Biosciences, Victoria, BC, Canada), MK-2206 (Selleckchem) as well as RO5126766 (Selleckchem).	('EGF', 'Gene', (221, 224))	('epidermal growth factor', 'Gene', (143, 166))	('RO5126766', 'Var', (429, 438))	('heparin-binding (HB)-EGF', 'Gene', (200, 224))	('GF109203X', 'Var', (338, 347))	('epidermal growth factor', 'Gene', '1950', (143, 166))	('heparin-binding (HB)-EGF', 'Gene', '1839', (200, 224))	('EGF', 'Gene', '1950', (221, 224))	('MK-2206', 'Var', (396, 403))	('EGF', 'Gene', (168, 171))	('RO5126766', 'Chemical', 'MESH:C577924', (429, 438))	('MK-2206', 'Chemical', 'MESH:C548887', (396, 403))	('TGF-beta1', 'Gene', '7040', (235, 244))	('LPA', 'Chemical', 'MESH:C032881', (68, 71))	('EGF', 'Gene', '1950', (168, 171))	('TGF-beta1', 'Gene', (235, 244))	('PMA', 'Chemical', 'MESH:D013755', (100, 103))	('GF109203X', 'Chemical', 'MESH:C070515', (338, 347))
212189	30535430	610843; BD Biosciences, Franklin Lakes, NJ, USA), AKT (pan; 1:2,000; C67E7; anti-rabbit; cat.	('C67E7', 'Var', (69, 74))	('AKT', 'Gene', (50, 53))	('rabbit', 'Species', '9986', (81, 87))	('AKT', 'Gene', '207', (50, 53))
212190	30535430	4691), JUNB (1:2,500; C37F9; anti-rabbit; cat.	('C37F9', 'Var', (22, 27))	('JUNB', 'Gene', (7, 11))	('rabbit', 'Species', '9986', (34, 40))	('JUNB', 'Gene', '3726', (7, 11))
212198	30535430	6967), phospho-Smad2 (Ser465/467; 1:1,000; 138D4; anti-rabbit; cat.	('Smad2', 'Gene', '4087', (15, 20))	('rabbit', 'Species', '9986', (55, 61))	('Smad2', 'Gene', (15, 20))	('Ser465/467', 'Var', (22, 32))
212213	30535430	Among these histological subtypes, H1975 [containing the EGFR mutations (T790M and L858R), as well as the PIK3CA mutation (G118D)] and 2106T were the only cell lines that secreted glycodelin.	('H1975', 'CellLine', 'CVCL:1511', (35, 40))	('T790M', 'Var', (73, 78))	('PIK3CA', 'Gene', (106, 112))	('L858R', 'Var', (83, 88))	('glycodelin', 'Gene', (180, 190))	('2106T', 'CellLine', 'CVCL:M069', (135, 140))	('PIK3CA', 'Gene', '5290', (106, 112))	('EGFR', 'Gene', '1956', (57, 61))	('L858R', 'Mutation', 'rs121434568', (83, 88))	('glycodelin', 'Gene', '5047', (180, 190))	('EGFR', 'Gene', (57, 61))	('T790M', 'Mutation', 'rs121434569', (73, 78))	('G118D', 'Mutation', 'rs587777790', (123, 128))
212214	30535430	In NSCLC, various mutations activate different pathways, such as the MEK/ERK, PI3K/AKT and/or STAT signalling cascades.	('AKT', 'Gene', '207', (83, 86))	('NSCLC', 'Disease', (3, 8))	('ERK', 'Gene', '5594', (73, 76))	('ERK', 'Gene', (73, 76))	('NSCLC', 'Disease', 'MESH:D002289', (3, 8))	('activate', 'PosReg', (28, 36))	('AKT', 'Gene', (83, 86))	('MEK', 'Gene', (69, 72))	('MEK', 'Gene', '5609', (69, 72))	('STAT signalling cascades', 'Pathway', (94, 118))	('mutations', 'Var', (18, 27))
212215	30535430	This is also the case in H1975 cells due to their EGFR and PIK3CA mutations.	('mutations', 'Var', (66, 75))	('H1975', 'CellLine', 'CVCL:1511', (25, 30))	('EGFR', 'Gene', '1956', (50, 54))	('PIK3CA', 'Gene', (59, 65))	('EGFR', 'Gene', (50, 54))	('PIK3CA', 'Gene', '5290', (59, 65))
212216	30535430	By using the H1975 and 2106T cells in the following experiments, we covered a rather representative range of mutation associated activated, as well as unaffected pathways in NSCLC.	('NSCLC', 'Disease', 'MESH:D002289', (174, 179))	('activated', 'PosReg', (129, 138))	('2106T', 'CellLine', 'CVCL:M069', (23, 28))	('NSCLC', 'Disease', (174, 179))	('H1975', 'CellLine', 'CVCL:1511', (13, 18))	('mutation', 'Var', (109, 117))
212222	30535430	Additional pregnancy-associated hormones (relaxin1 and 2, progesterone, and hCG), as well as other hormones [endothelin-1, prostaglandins (PGE1, PGE2, PGI2, PGF2)], which were upregulated after PAEP silencing in the NSCLC cell lines in our previous study, were analysed with regard to their influence on PAEP/glycodelin expression.	('PGI2', 'Chemical', 'MESH:D011464', (151, 155))	('hCG', 'Gene', (76, 79))	('PGF2', 'Chemical', 'MESH:D015237', (157, 161))	('progesterone', 'Chemical', 'MESH:D011374', (58, 70))	('prostaglandins', 'Chemical', 'MESH:D011453', (123, 137))	('glycodelin', 'Gene', '5047', (309, 319))	('PGE2', 'Chemical', 'MESH:D015232', (145, 149))	('PGE1', 'Chemical', 'MESH:D000527', (139, 143))	('glycodelin', 'Gene', (309, 319))	('NSCLC', 'Disease', 'MESH:D002289', (216, 221))	('endothelin-1', 'Gene', '1906', (109, 121))	('PAEP', 'Gene', '5047', (194, 198))	('PAEP', 'Gene', '5047', (304, 308))	('hCG', 'Gene', '93659', (76, 79))	('upregulated', 'PosReg', (176, 187))	('NSCLC', 'Disease', (216, 221))	('endothelin-1', 'Gene', (109, 121))	('relaxin1 and 2', 'Gene', '6013;6019', (42, 56))	('PAEP', 'Gene', (304, 308))	('silencing', 'Var', (199, 208))	('PAEP', 'Gene', (194, 198))
212236	30535430	The PKC inhibitor GF109203X had a slight inducing or no effect at low concentrations (1 and 5 microM), but markedly decreased the PAEP/glycodelin amounts at the highest concentration (10 microM) (Fig.	('PAEP', 'Gene', '5047', (130, 134))	('glycodelin', 'Gene', '5047', (135, 145))	('PKC', 'Gene', (4, 7))	('PAEP', 'Gene', (130, 134))	('PKC', 'Gene', '112476', (4, 7))	('glycodelin', 'Gene', (135, 145))	('GF109203X', 'Chemical', 'MESH:C070515', (18, 27))	('GF109203X', 'Var', (18, 27))	('decreased', 'NegReg', (116, 125))
212237	30535430	The inhibition of AKT with MK-2206 led to an increase in PAEP/glycodelin expression in the H1975, but not in the 2106T cells (Fig.	('MK-2206', 'Chemical', 'MESH:C548887', (27, 34))	('MK-2206', 'Var', (27, 34))	('glycodelin', 'Gene', (62, 72))	('AKT', 'Gene', (18, 21))	('AKT', 'Gene', '207', (18, 21))	('H1975', 'CellLine', 'CVCL:1511', (91, 96))	('H1975', 'Var', (91, 96))	('PAEP', 'Gene', '5047', (57, 61))	('glycodelin', 'Gene', '5047', (62, 72))	('inhibition', 'NegReg', (4, 14))	('PAEP', 'Gene', (57, 61))	('2106T', 'CellLine', 'CVCL:M069', (113, 118))	('increase', 'PosReg', (45, 53))
212238	30535430	The PAEP/glycodelin levels were negatively affected by the RAF/MEK inhibitor, RO5126766, in both cell lines (Fig.	('glycodelin', 'Gene', '5047', (9, 19))	('RAF', 'Gene', '22882', (59, 62))	('RO5126766', 'Chemical', 'MESH:C577924', (78, 87))	('RAF', 'Gene', (59, 62))	('PAEP', 'Gene', '5047', (4, 8))	('PAEP', 'Gene', (4, 8))	('MEK', 'Gene', (63, 66))	('glycodelin', 'Gene', (9, 19))	('MEK', 'Gene', '5609', (63, 66))	('negatively', 'NegReg', (32, 42))	('RO5126766', 'Var', (78, 87))
212243	30535430	The knockdown of the 3 genes led to a decreased PAEP expression in both cell lines (Fig.	('PAEP', 'Gene', '5047', (48, 52))	('knockdown', 'Var', (4, 13))	('decreased', 'NegReg', (38, 47))	('PAEP', 'Gene', (48, 52))
212283	30535430	Therefore, we hypothesised that stimulating these pathways with the different pathway inducers should increase PAEP/glycodelin levels.	('PAEP', 'Gene', '5047', (111, 115))	('glycodelin', 'Gene', '5047', (116, 126))	('PAEP', 'Gene', (111, 115))	('increase', 'PosReg', (102, 110))	('stimulating', 'Var', (32, 43))	('glycodelin', 'Gene', (116, 126))
212289	30535430	Currently, the reason for these distinct results is unclear; however, activating EGFR (T790M, L858R) and PIK3CA (G118D) mutations in H1975 cells may play a role.	('PIK3CA', 'Gene', (105, 111))	('activating', 'PosReg', (70, 80))	('PIK3CA', 'Gene', '5290', (105, 111))	('L858R', 'Var', (94, 99))	('H1975', 'CellLine', 'CVCL:1511', (133, 138))	('T790M', 'Mutation', 'rs121434569', (87, 92))	('L858R', 'Mutation', 'rs121434568', (94, 99))	('G118D', 'Var', (113, 118))	('G118D', 'Mutation', 'rs587777790', (113, 118))	('T790M', 'Var', (87, 92))	('EGFR', 'Gene', '1956', (81, 85))	('H1975', 'Gene', (133, 138))	('EGFR', 'Gene', (81, 85))
212290	30535430	Each of these three mutations has been previously shown to be associated with the activation of AKT.	('activation', 'PosReg', (82, 92))	('AKT', 'Gene', (96, 99))	('mutations', 'Var', (20, 29))	('AKT', 'Gene', '207', (96, 99))
212301	30535430	As already mentioned, we assume that only an activated PI3K/AKT pathway, as it was shown for the mutations T790M (EGFR), L858R (EGFR) and G118D (PIK3CA) of H1975 cells, influences PAEP/glycodelin expression.	('glycodelin', 'Gene', '5047', (185, 195))	('T790M', 'Mutation', 'rs121434569', (107, 112))	('glycodelin', 'Gene', (185, 195))	('EGFR', 'Gene', (128, 132))	('PAEP', 'Gene', '5047', (180, 184))	('H1975', 'CellLine', 'CVCL:1511', (156, 161))	('PIK3CA', 'Gene', (145, 151))	('AKT', 'Gene', (60, 63))	('EGFR', 'Gene', (114, 118))	('L858R', 'Mutation', 'rs121434568', (121, 126))	('T790M', 'Var', (107, 112))	('G118D', 'Mutation', 'rs587777790', (138, 143))	('PAEP', 'Gene', (180, 184))	('G118D', 'Var', (138, 143))	('EGFR', 'Gene', '1956', (128, 132))	('AKT', 'Gene', '207', (60, 63))	('L858R', 'Var', (121, 126))	('EGFR', 'Gene', '1956', (114, 118))	('influences', 'Reg', (169, 179))	('PIK3CA', 'Gene', '5290', (145, 151))
212310	30535430	According to our results, the treatment of patients with mutational activated AKT might increase the expression of glycodelin and therefore could promote immunosurveillance mediated by cancer cells.	('glycodelin', 'Gene', '5047', (115, 125))	('immunosurveillance mediated', 'CPA', (154, 181))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('patients', 'Species', '9606', (43, 51))	('increase', 'PosReg', (88, 96))	('glycodelin', 'Gene', (115, 125))	('mutational', 'Var', (57, 67))	('AKT', 'Gene', '207', (78, 81))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('expression', 'MPA', (101, 111))	('AKT', 'Gene', (78, 81))	('promote', 'PosReg', (146, 153))	('cancer', 'Disease', (185, 191))
212319	30535430	Our results provide evidence that inhibiting these targets affects the expression of glycodelin and therefore, exerts an immunosuppressive effect on NSCLC tumours.	('inhibiting', 'Var', (34, 44))	('expression', 'MPA', (71, 81))	('NSCLC tumours', 'Disease', 'MESH:D009369', (149, 162))	('immunosuppressive effect', 'MPA', (121, 145))	('NSCLC tumours', 'Disease', (149, 162))	('affects', 'Reg', (59, 66))	('glycodelin', 'Gene', '5047', (85, 95))	('tumours', 'Phenotype', 'HP:0002664', (155, 162))	('tumour', 'Phenotype', 'HP:0002664', (155, 161))	('glycodelin', 'Gene', (85, 95))
212350	28859661	In addition, the patient had negative test results for epidermal growth factor receptor (EGFR), K-ras, and anaplastic lymphoma kinase mutations, all consistent with adenocarcinoma (Fig.	('K-ras', 'Gene', (96, 101))	('K-ras', 'Gene', '3845', (96, 101))	('anaplastic lymphoma', 'Disease', (107, 126))	('carcinoma', 'Phenotype', 'HP:0030731', (170, 179))	('EGFR', 'Gene', (89, 93))	('lymphoma', 'Phenotype', 'HP:0002665', (118, 126))	('epidermal growth factor receptor', 'Gene', (55, 87))	('anaplastic lymphoma', 'Disease', 'MESH:D017728', (107, 126))	('adenocarcinoma', 'Disease', (165, 179))	('mutations', 'Var', (134, 143))	('epidermal growth factor receptor', 'Gene', '1956', (55, 87))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (107, 126))	('EGFR', 'Gene', '1956', (89, 93))
212362	28859661	Mutations in the p53 tumor suppressor gene (chromosome 17) occur frequently in lung carcinoma, with rates up to 70% in small cell lung cancer and 50% in non-small cell lung cancer.	('lung cancer', 'Phenotype', 'HP:0100526', (130, 141))	('small cell lung cancer', 'Disease', (119, 141))	('non-small cell lung cancer', 'Disease', (153, 179))	('lung cancer', 'Phenotype', 'HP:0100526', (168, 179))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (157, 179))	('Mutations', 'Var', (0, 9))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (153, 179))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('lung carcinoma', 'Disease', 'MESH:D008175', (79, 93))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (119, 141))	('p53', 'Gene', (17, 20))	('lung carcinoma', 'Disease', (79, 93))	('p53', 'Gene', '7157', (17, 20))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
212363	28859661	In addition, mutation of EGFR is a common early event in lung cancer pathogenesis, and therefore it is a useful marker, alone or with p53, for differentiating the clonal origin of lung tumors, especially when multiple tumors have similar histopathological features.	('multiple tumors', 'Disease', 'MESH:D009369', (209, 224))	('EGFR', 'Gene', (25, 29))	('lung tumors', 'Phenotype', 'HP:0100526', (180, 191))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('lung cancer', 'Phenotype', 'HP:0100526', (57, 68))	('mutation', 'Var', (13, 21))	('lung tumor', 'Phenotype', 'HP:0100526', (180, 190))	('tumors', 'Phenotype', 'HP:0002664', (185, 191))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('tumors', 'Phenotype', 'HP:0002664', (218, 224))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('lung cancer', 'Disease', (57, 68))	('multiple tumors', 'Disease', (209, 224))
212364	28859661	Tumors that derive from a single clone may contain cell populations that harbor similar genetic events, including loss of heterozygosity.	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('loss of heterozygosity', 'Var', (114, 136))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))
212372	24919055	The mean ADCmean values, ADCmin values and median NCR were (1.07+-0.12)x10-3 mm2/s, (0.86+-0.14)x10-3 mm2/s, and (14.9+-2.6) %, respectively, in adenocarcinoma; (0.88+-0.10)x10-3 mm2/s, (0.73+-0.12)x10-3 mm2/s, and (20.6+-4.4) %, respectively, in squamous cell carcinoma; and (0.89+-0.13)x10-3 mm2/s, (0.67+-0.13)x10-3 mm2/s, and (18.3+-3.5) %, respectively in small cell lung cancer.	('0.73+-0.12', 'Var', (187, 197))	('0.86+-0.14', 'Var', (85, 95))	('squamous cell carcinoma', 'Disease', (247, 270))	('cancer', 'Phenotype', 'HP:0002664', (377, 383))	('carcinoma', 'Phenotype', 'HP:0030731', (261, 270))	('small cell lung cancer', 'Disease', 'MESH:D055752', (361, 383))	('0.89+-0.13)x10-3 mm2/s', 'Var', (277, 299))	('adenocarcinoma', 'Disease', 'MESH:D000230', (145, 159))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (361, 383))	('carcinoma', 'Phenotype', 'HP:0030731', (150, 159))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (247, 270))	('adenocarcinoma', 'Disease', (145, 159))	('small cell lung cancer', 'Disease', (361, 383))	('0.88+-0.10', 'Var', (162, 172))	('lung cancer', 'Phenotype', 'HP:0100526', (372, 383))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (247, 270))	('0.67+-0.13', 'Var', (302, 312))
212409	24919055	The ADCmin value of the primary tumours was (0.80+-0.15) x 10-3 mm2/s in total, (0.67+-0.13) x 10-3 mm2/s in small cell lung cancer, (0.86+-0.13) x 10-3 mm2/s in adenocarcinoma, and (0.73+-0.13) x 10-3 mm2/s in squamous cell carcinoma.	('small cell lung cancer', 'Disease', (109, 131))	('lung cancer', 'Phenotype', 'HP:0100526', (120, 131))	('carcinoma', 'Phenotype', 'HP:0030731', (225, 234))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (211, 234))	('0.67+-0.13', 'Var', (81, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (167, 176))	('primary tumours', 'Disease', (24, 39))	('adenocarcinoma', 'Disease', (162, 176))	('primary tumours', 'Disease', 'MESH:D009369', (24, 39))	('small cell lung cancer', 'Disease', 'MESH:D055752', (109, 131))	('squamous cell carcinoma', 'Disease', (211, 234))	('tumours', 'Phenotype', 'HP:0002664', (32, 39))	('adenocarcinoma', 'Disease', 'MESH:D000230', (162, 176))	('0.86+-0.13', 'Var', (134, 144))	('tumour', 'Phenotype', 'HP:0002664', (32, 38))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (109, 131))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (211, 234))
212443	33166276	Lung cancer patients with elevated TMB treated with Nivolumab and Ipilumab, for example, were found to have a 3-fold higher likelihood of one-year progression free survival compared to an unstratified control group receiving chemotherapy.	('Ipilumab', 'Var', (66, 74))	('patients', 'Species', '9606', (12, 20))	('TMB', 'MPA', (35, 38))	('progression free survival', 'CPA', (147, 172))	('Ipilumab', 'Chemical', '-', (66, 74))	('Lung cancer', 'Phenotype', 'HP:0100526', (0, 11))	('TMB', 'Chemical', '-', (35, 38))	('Lung cancer', 'Disease', (0, 11))	('Nivolumab', 'Chemical', 'MESH:D000077594', (52, 61))	('higher', 'PosReg', (117, 123))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))	('Lung cancer', 'Disease', 'MESH:D008175', (0, 11))
212470	33166276	sampling noise, driver mutations, germline mutations, etc., see Methods), and eventually achieved a tissue-independent mapping from TMB measurements of a panel to WES (no offset; Fig 1J).	('mutations', 'Var', (23, 32))	('TMB', 'Chemical', '-', (132, 135))	('germline mutations', 'Var', (34, 52))
212528	33166276	Eq (5), contains two noise terms: a centered gaussian noise source that represents the noise characteristic of a panel and is defined as  Note that sigma is a function of panel size and mutational burden, and mutational burden is related to cancer type.	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('mutational', 'Var', (186, 196))	('cancer', 'Disease', (241, 247))	('cancer', 'Disease', 'MESH:D009369', (241, 247))
212530	33166276	Moreover, we introduced a second Poisson noise term to recapitulate the biases due to cancer driver mutations, germline mutations, etc.	('mutations', 'Var', (100, 109))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('germline mutations', 'Var', (111, 129))	('cancer', 'Disease', (86, 92))
212533	33166276	We assume C0 and lambda do not depend on the panel size and the tissue type since most commercial panels include cancer driver mutations regardless of the size of a panel.	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('include', 'Reg', (105, 112))	('cancer', 'Disease', (113, 119))	('C0', 'Chemical', '-', (10, 12))	('mutations', 'Var', (127, 136))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
212534	33166276	Such driver genes are biologically selected throughout the clonal evolution of cancer and thus, have a substantially higher probability of being observed on a targeted panel that is specifically designed to detect such variants rather than the passenger mutations that dominate TMB.	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('variants', 'Var', (219, 227))	('TMB', 'Chemical', '-', (278, 281))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))
212566	27863400	Cancer cells with abnormal mutation could provoke the body's immune responses therefore to be identified and eliminated.	('provoke', 'PosReg', (42, 49))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('abnormal mutation', 'Var', (18, 35))	('immune responses', 'CPA', (61, 77))
212580	27863400	Comparative GO analysis revealed that the enriched biological processes among DEIRGs with pattern 42 of LUAD were similar to those among DEIRGs with pattern 35 of LUSC (Supplementary Figure S4), and most of these processes were related to cell proliferation, cell cycle and DNA repair processes (Figure 3A).	('related', 'Reg', (228, 235))	('cell proliferation', 'CPA', (239, 257))	('cell cycle', 'CPA', (259, 269))	('pattern 42', 'Var', (90, 100))	('DNA repair processes', 'CPA', (274, 294))	('men', 'Species', '9606', (175, 178))
212581	27863400	Correspondingly, at stage IA, the expression levels of cell proliferation and cell cycle related genes with pattern 42 of LUAD were generally lower than those with pattern 35 of LUSC (Supplementary Table S4).	('cell cycle related genes', 'Gene', (78, 102))	('LUAD', 'Var', (122, 126))	('lower', 'NegReg', (142, 147))	('cell proliferation', 'CPA', (55, 73))	('men', 'Species', '9606', (190, 193))	('pattern 42', 'Var', (108, 118))	('expression levels', 'MPA', (34, 51))
212584	27863400	Malfunction of the proteasome complex could also contribute to the pathogenesis of cancer.	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('Malfunction', 'Var', (0, 11))	('contribute', 'Reg', (49, 59))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('cancer', 'Disease', (83, 89))
212599	27863400	Reports have shown that the Toll-like receptors play a fundamental role in pathogen recognition and activation of innate immunity, and defects of the CD3-TCR complex could also facilitate tumor progression through immune evasion.	('tumor', 'Disease', (188, 193))	('CD3-TCR', 'Gene', (150, 157))	('defects', 'Var', (135, 142))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('facilitate', 'PosReg', (177, 187))	('men', 'Species', '9606', (60, 63))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('immune evasion', 'MPA', (214, 228))
212622	24410919	The present study was designed to detect hTERC and SOX2 amplifications in OSSC exfoliative tumor cells and evaluate whether those two gene amplifications might serve as a supportive biomarker in early detection and diagnosis of oral and oropharyngeal SCC.	('SCC', 'Gene', '6317', (251, 254))	('hTERC', 'Gene', (41, 46))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('hTERC', 'Gene', '7012', (41, 46))	('amplifications', 'Var', (56, 70))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('SOX2', 'Gene', '6657', (51, 55))	('tumor', 'Disease', (91, 96))	('SCC', 'Gene', (251, 254))	('SOX2', 'Gene', (51, 55))
212625	24410919	The over representation of polyploidy and/or TERC/SOX2 amplification in tumour samples was statistically significant when compared to controls (p = 0.01).	('over', 'PosReg', (4, 8))	('amplification', 'Var', (55, 68))	('polyploidy', 'Disease', 'MESH:D011123', (27, 37))	('tumour', 'Phenotype', 'HP:0002664', (72, 78))	('SOX2', 'Gene', '6657', (50, 54))	('TERC', 'Gene', (45, 49))	('SOX2', 'Gene', (50, 54))	('tumour', 'Disease', 'MESH:D009369', (72, 78))	('tumour', 'Disease', (72, 78))	('TERC', 'Gene', '7012', (45, 49))	('polyploidy', 'Disease', (27, 37))
212626	24410919	SOX2 and TERC gene amplifications are common in all squamous cell carcinomas and their detection in early stages could be crucial for early detection and more accurate prognosis.	('SOX2', 'Gene', '6657', (0, 4))	('TERC', 'Gene', (9, 13))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (52, 75))	('carcinoma', 'Phenotype', 'HP:0030731', (66, 75))	('carcinomas', 'Phenotype', 'HP:0030731', (66, 76))	('TERC', 'Gene', '7012', (9, 13))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (52, 76))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (52, 76))	('squamous cell carcinomas', 'Disease', (52, 76))	('amplifications', 'Var', (19, 33))	('SOX2', 'Gene', (0, 4))	('common', 'Reg', (38, 44))
212633	24410919	Many such copy number aberrations harbor oncogenes or tumor suppressor genes and have therefore emerged as predictive and prognostic markers for tumors.	('copy number aberrations', 'Var', (10, 33))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('oncogenes', 'Protein', (41, 50))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumors', 'Disease', (145, 151))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('tumor', 'Disease', (145, 150))	('harbor', 'Reg', (34, 40))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumors', 'Disease', 'MESH:D009369', (145, 151))	('tumor', 'Disease', (54, 59))
212638	24410919	TERC gene amplifications are described in the development of various SCCs, such as those in the larynx, cervix, esophagus and lungs.	('SCC', 'Gene', (69, 72))	('TERC', 'Gene', (0, 4))	('SCC', 'Gene', '6317', (69, 72))	('amplifications', 'Var', (10, 24))	('TERC', 'Gene', '7012', (0, 4))	('esophagus', 'Disease', (112, 121))
212639	24410919	Our results, as well those of other authors, obtained from cervical smears have demonstrated that TERC gene amplifications correlate with high-grade squamous intraepithelial lesions that lead to invasive cervical cancer.	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('TERC', 'Gene', (98, 102))	('invasive cervical cancer', 'Disease', 'MESH:D002583', (195, 219))	('squamous intraepithelial lesions', 'Disease', (149, 181))	('squamous intraepithelial lesions', 'Disease', 'MESH:D000081483', (149, 181))	('amplifications', 'Var', (108, 122))	('invasive cervical cancer', 'Disease', (195, 219))	('TERC', 'Gene', '7012', (98, 102))	('lead to', 'Reg', (187, 194))
212640	24410919	SRY-related HMG-box 2 (SOX2) gene amplifications are also described in esophageal and lung squamous cell carcinomas.	('described', 'Reg', (58, 67))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (91, 115))	('amplifications', 'Var', (34, 48))	('esophageal and lung squamous cell carcinomas', 'Disease', 'MESH:D000077277', (71, 115))	('SOX2', 'Gene', (23, 27))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (91, 114))	('SOX2', 'Gene', '6657', (23, 27))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('carcinomas', 'Phenotype', 'HP:0030731', (105, 115))
212643	24410919	In a study by Bass et al., amplifications of SOX2 were detected in 23% of lung SCCs and 15% of esophageal SCCs.	('detected', 'Reg', (55, 63))	('SCC', 'Gene', (79, 82))	('SCC', 'Gene', '6317', (106, 109))	('amplifications', 'Var', (27, 41))	('SCC', 'Gene', '6317', (79, 82))	('esophageal SCCs', 'Disease', (95, 110))	('esophageal SCCs', 'Disease', 'MESH:D004941', (95, 110))	('SCC', 'Gene', (106, 109))	('SOX2', 'Gene', '6657', (45, 49))	('SOX2', 'Gene', (45, 49))
212645	24410919	detected SOX2 amplifications in lung SCCs at similar frequencies (20%).	('SCC', 'Gene', '6317', (37, 40))	('SOX2', 'Gene', (9, 13))	('SOX2', 'Gene', '6657', (9, 13))	('amplifications', 'Var', (14, 28))	('SCC', 'Gene', (37, 40))
212647	24410919	detected a SOX2 gene copy number gain in 52% of OSCC tumors in, which a high expression of SOX2 was suspected to be correlated with gene copy number gain.	('OSCC', 'Phenotype', 'HP:0012182', (48, 52))	('SOX2', 'Gene', (11, 15))	('OSCC tumors', 'Disease', (48, 59))	('SOX2', 'Gene', '6657', (91, 95))	('SOX2', 'Gene', '6657', (11, 15))	('OSCC tumors', 'Disease', 'MESH:D009369', (48, 59))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('gain', 'PosReg', (33, 37))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('gene copy number', 'Var', (16, 32))	('SOX2', 'Gene', (91, 95))
212650	24410919	The present study was designed to detect hTERC and SOX2 amplifications in OSSC exfoliative tumor cells and evaluate whether these two gene amplifications might serve as a supportive bio-marker for the non-invasive detection and diagnosis of oral and oropharyngeal SCC.	('SCC', 'Gene', (264, 267))	('hTERC', 'Gene', (41, 46))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('hTERC', 'Gene', '7012', (41, 46))	('amplifications', 'Var', (56, 70))	('SCC', 'Gene', '6317', (264, 267))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('SOX2', 'Gene', '6657', (51, 55))	('tumor', 'Disease', (91, 96))	('SOX2', 'Gene', (51, 55))
212664	24410919	When cancer samples were stratified according to the disease stage the presence of polypolidy and/or amplification did not differ significantly, regardless of how the stages were combined.	('cancer', 'Disease', (5, 11))	('polypolidy', 'Var', (83, 93))	('cancer', 'Disease', 'MESH:D009369', (5, 11))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))
212668	24410919	Recurrent gene copy number aberrations are a frequent finding in OSCC and are belived to be critically involved in tumor formation.	('SCC', 'Gene', (66, 69))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('SCC', 'Gene', '6317', (66, 69))	('gene copy number aberrations', 'Var', (10, 38))	('tumor', 'Disease', (115, 120))	('OSCC', 'Phenotype', 'HP:0012182', (65, 69))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
212670	24410919	Amplification of the genes located in this region, particularly SOX2 and TERC, could be useful markers for malignant cell detection and could be used as prognostic markers in oral brush smears performed in the oral and oropharyngeal cavity.	('Amplification', 'Var', (0, 13))	('TERC', 'Gene', '7012', (73, 77))	('SOX2', 'Gene', '6657', (64, 68))	('TERC', 'Gene', (73, 77))	('malignant cell detection', 'CPA', (107, 131))	('SOX2', 'Gene', (64, 68))
212677	24410919	High SOX2 expression is detected in various oral squamous cell carcinomas (e.g., oral cavity and tongue); such expression is thought to be activated through gene copy number gain and is associated with poor prognosis.	('carcinomas', 'Phenotype', 'HP:0030731', (63, 73))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (49, 72))	('activated', 'PosReg', (139, 148))	('oral squamous cell carcinomas', 'Disease', (44, 73))	('oral squamous cell carcinomas', 'Disease', 'MESH:D002294', (44, 73))	('gene copy number gain', 'Var', (157, 178))	('SOX2', 'Gene', (5, 9))	('expression', 'MPA', (10, 20))	('SOX2', 'Gene', '6657', (5, 9))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (49, 73))	('tongue)', 'Disease', (97, 104))	('oral cavity', 'Disease', (81, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))
212694	24410919	Tetraploidy often precedes the development of aneuploidy.	('Tetraploidy', 'Var', (0, 11))	('aneuploidy', 'Disease', 'MESH:D000782', (46, 56))	('aneuploidy', 'Disease', (46, 56))
212698	24410919	demonstrated that SOX2 gene amplification is a common event in SCC of different organ sites, such as lung and cervix, and that it appears to be an early event in tumorigenesis.	('SOX2', 'Gene', '6657', (18, 22))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('SOX2', 'Gene', (18, 22))	('SCC', 'Gene', (63, 66))	('cervix', 'Disease', (110, 116))	('tumor', 'Disease', (162, 167))	('lung', 'Disease', (101, 105))	('SCC', 'Gene', '6317', (63, 66))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('amplification', 'Var', (28, 41))
212699	24410919	analyzed the abundance of copy number alterations and various gene amplifications in the dysplastic transitional area of oral squamous cell carcinoma using array-CGH on fresh tissues.	('dysplastic', 'Disease', (89, 99))	('dysplastic', 'Disease', 'MESH:D004416', (89, 99))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (121, 149))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))	('copy number alterations', 'Var', (26, 49))	('oral squamous cell carcinoma', 'Disease', (121, 149))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (126, 149))
212700	24410919	Those results appear to support our hypothesis that SOX2 and TERC gene amplifications are prognostic markers for OSSC and that amplifications are an early event in tumorigenesis.	('amplifications', 'Var', (71, 85))	('tumor', 'Disease', (164, 169))	('SOX2', 'Gene', '6657', (52, 56))	('SOX2', 'Gene', (52, 56))	('TERC', 'Gene', (61, 65))	('OSSC', 'Disease', (113, 117))	('TERC', 'Gene', '7012', (61, 65))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))
212702	24410919	In conclusion, SOX2 and TERC gene amplifications are common in all squamous cell carcinomas, and their detection in early stages could be crucial for the detection and moreaccurate prognosis of OSCCs.	('SCC', 'Gene', (195, 198))	('amplifications', 'Var', (34, 48))	('OSCC', 'Phenotype', 'HP:0012182', (194, 198))	('common', 'Reg', (53, 59))	('SOX2', 'Gene', '6657', (15, 19))	('TERC', 'Gene', (24, 28))	('SCC', 'Gene', '6317', (195, 198))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (67, 90))	('SOX2', 'Gene', (15, 19))	('squamous cell carcinomas', 'Disease', (67, 91))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (67, 91))	('OSCCs', 'Phenotype', 'HP:0012182', (194, 199))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('carcinomas', 'Phenotype', 'HP:0030731', (81, 91))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (67, 91))	('TERC', 'Gene', '7012', (24, 28))
212708	24410919	Two probes were used for FISH: a combined TERC-specific DNA probe (RH17919 - 370Kb- RH10606) in red fluorescence emission and a centromere 3-specific control probe (D3Z1) in green fluorescence emission (ON hTERC 3q26/3q11 - Kreatech), or a SOX2 specific DNA probe (D3S3416 - 800Kb - D3S3957) in green combined with a centromere 3-specific probe in red (ZytoLight SPEC SOX2/CEN3 Dual Colour Probe - ZytoVision).	('SOX2', 'Gene', '6657', (240, 244))	('TERC', 'Gene', '7012', (42, 46))	('SOX2', 'Gene', (368, 372))	('SOX2', 'Gene', '6657', (368, 372))	('TERC', 'Gene', '7012', (207, 211))	('hTERC', 'Gene', (206, 211))	('hTERC', 'Gene', '7012', (206, 211))	('TERC', 'Gene', (42, 46))	('D3S3416 - 800Kb - D3S3957', 'Var', (265, 290))	('TERC', 'Gene', (207, 211))	('RH17919 - 370Kb- RH10606', 'Var', (67, 91))	('SOX2', 'Gene', (240, 244))
212736	31861976	We used two cohorts with acute myeloid leukemia (AML), one exclusively with individuals over the age of 60 (GSE6891) (461 patients) with samples collected from both blood and bone marrow and the second (GSE15434) of exclusively normal karyotype (NK) AML (251 patients) with samples collected from mononuclear cells.	('AML', 'Disease', (49, 52))	('patients', 'Species', '9606', (259, 267))	('AML', 'Disease', 'MESH:D015470', (250, 253))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (25, 47))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (31, 47))	('AML', 'Disease', (250, 253))	('patients', 'Species', '9606', (122, 130))	('GSE15434', 'Var', (203, 211))	('acute myeloid leukemia', 'Disease', (25, 47))	('AML', 'Phenotype', 'HP:0004808', (250, 253))	('AML', 'Disease', 'MESH:D015470', (49, 52))	('leukemia', 'Phenotype', 'HP:0001909', (39, 47))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (25, 47))	('AML', 'Phenotype', 'HP:0004808', (49, 52))
212781	31861976	We hypothesize that deviations between the methylation of loci between patient sub-groups creates tail regions.	('methylation', 'Var', (43, 54))	('patient', 'Species', '9606', (71, 78))	('deviations', 'Var', (20, 30))
212810	31807072	LNR less than 0.42 was associated with improved OS and CSS for patients with resected N2 stage lung squamous cell carcinoma.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (100, 123))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (95, 123))	('lung squamous cell carcinoma', 'Disease', (95, 123))	('improved', 'PosReg', (39, 47))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('patients', 'Species', '9606', (63, 71))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (95, 123))	('CSS', 'Gene', '55907', (55, 58))	('LNR less than 0.42', 'Var', (0, 18))	('CSS', 'Gene', (55, 58))
212828	31807072	We primarily obtained and analyzed the data of lung squamous cell carcinoma (8052/3, 8070/3, 8071/3, 8072/3, 8073/3, 8074/3, 8083/3, 8084/3).	('carcinoma', 'Phenotype', 'HP:0030731', (66, 75))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (47, 75))	('lung squamous cell carcinoma', 'Disease', (47, 75))	('8052/3', 'Var', (77, 83))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (47, 75))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (52, 75))
212854	31807072	As shown in Figure 2A-D, patients with LNR >0.42 had significantly worse OS and CSS than patients with LNR <=0.42 in both training and validation cohorts (log-rank P<0.05).	('CSS', 'Gene', '55907', (80, 83))	('CSS', 'Gene', (80, 83))	('LNR >0.42', 'Var', (39, 48))	('patients', 'Species', '9606', (89, 97))	('patients', 'Species', '9606', (25, 33))	('worse', 'NegReg', (67, 72))
212881	31807072	Therefore, we did subgroup analysis and found that patients with LNR >0.42 would benefit more from postoperative adjuvant therapy in comparison with those with lower LNR.	('patients', 'Species', '9606', (51, 59))	('benefit', 'PosReg', (81, 88))	('>0.42', 'Var', (69, 74))
212888	28746384	Detection of brain-directed autoantibodies in the serum of non-small cell lung cancer patients Antibodies against brain proteins were identified in the plasma of cancer patients and are defined to cause paraneoplastic neurological syndromes.	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('brain proteins', 'Protein', (114, 128))	('patients', 'Species', '9606', (169, 177))	('lung cancer', 'Phenotype', 'HP:0100526', (74, 85))	('cancer', 'Disease', (162, 168))	('patients', 'Species', '9606', (86, 94))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (59, 85))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('paraneoplastic neurological syndromes', 'Disease', 'MESH:D020361', (203, 240))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('neurological syndrome', 'Phenotype', 'HP:0000707', (218, 239))	('Antibodies', 'Var', (95, 105))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('paraneoplastic neurological syndromes', 'Disease', (203, 240))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (63, 85))	('cause', 'Reg', (197, 202))
212905	28746384	Since some autoimmune disease-associated antibodies have been proven to induce tissue damage, it is essential to identify autoantibody accumulation sites in the target organs.	('antibodies', 'Var', (41, 51))	('autoimmune disease', 'Disease', (11, 29))	('tissue damage', 'CPA', (79, 92))	('autoimmune disease', 'Disease', 'MESH:D001327', (11, 29))	('autoimmune disease', 'Phenotype', 'HP:0002960', (11, 29))
213006	28746384	For example, valine (V) is a neutral and nonpolar amino acid in the epitope of cerebellar degeneration-related protein 2 (CDR2), which corresponded in rodents to another neutral and nonpolar amino acid, leucine (L).	('CDR2', 'Gene', '101060399', (122, 126))	('leucine', 'Chemical', 'MESH:D007930', (203, 210))	('CDR2', 'Gene', (122, 126))	('valine', 'Chemical', 'MESH:D014633', (13, 19))	('cerebellar degeneration-related protein 2', 'Gene', (79, 120))	('cerebellar degeneration', 'Phenotype', 'HP:0001272', (79, 102))	('cerebellar degeneration-related protein 2', 'Gene', '101060399', (79, 120))	('valine', 'Var', (13, 19))
213015	28746384	Even though a large number of PNNS are strongly associated with SCLC (3-5%), based on case reports or small series it can also be diagnosed in NSCLC patients.	('SCLC', 'Gene', (144, 148))	('patients', 'Species', '9606', (149, 157))	('NSCLC', 'Disease', (143, 148))	('associated', 'Reg', (48, 58))	('NSCLC', 'Disease', 'MESH:D002289', (143, 148))	('PNNS', 'Var', (30, 34))	('SCLC', 'Gene', '7864', (64, 68))	('SCLC', 'Gene', (64, 68))	('SCLC', 'Gene', '7864', (144, 148))
213029	28746384	Our results support the presence of anti-NMDAR IgGs in NSCLC patients and their targeting of neuronal, glial and endothelial cells.	('anti-NMDAR', 'Var', (36, 46))	('patients', 'Species', '9606', (61, 69))	('NSCLC', 'Disease', 'MESH:D002289', (55, 60))	('NSCLC', 'Disease', (55, 60))
213048	28746384	In our study of NSCLC patients, antibodies against 100 kDa band have highest specificity and sensitivity to female adenocarcinoma patients.	('patients', 'Species', '9606', (22, 30))	('patients', 'Species', '9606', (130, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('NSCLC', 'Disease', (16, 21))	('male adenocarcinoma', 'Disease', (110, 129))	('antibodies against 100 kDa', 'Var', (32, 58))	('male adenocarcinoma', 'Disease', 'MESH:D000230', (110, 129))	('NSCLC', 'Disease', 'MESH:D002289', (16, 21))	('specificity', 'MPA', (77, 88))
213127	24799899	Chromosomal imbalances in ameloblastomas are reported to be rare, with losses in chromosomes 22 and 10 being most frequent.	('ameloblastomas', 'Disease', 'MESH:D000564', (26, 40))	('imbalances', 'Phenotype', 'HP:0002172', (12, 22))	('ameloblastomas', 'Disease', (26, 40))	('losses', 'Var', (71, 77))
213144	24799899	In genome analysis, the CpG methylation of p16 (cyclin-dependent kinase inhibitor 2A) is observed in all ameloblastic carcinoma samples, but only one ameloblastoma specimen exhibits the mutation.	('p16', 'Gene', (43, 46))	('CpG methylation', 'Var', (24, 39))	('ameloblastoma', 'Disease', 'MESH:D000564', (150, 163))	('ameloblastic carcinoma', 'Disease', 'MESH:D009810', (105, 127))	('ameloblastic carcinoma', 'Disease', (105, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('observed', 'Reg', (89, 97))	('p16', 'Gene', '1029', (43, 46))	('cyclin-dependent kinase inhibitor 2A', 'Gene', (48, 84))	('cyclin-dependent kinase inhibitor 2A', 'Gene', '1029', (48, 84))	('ameloblastoma', 'Disease', (150, 163))
213146	24799899	have suggested the role of aberrant beta-catenin expression and adenomatous polyposis coli gene mutation in AC.	('adenomatous polyposis coli', 'Disease', (64, 90))	('aberrant', 'Var', (27, 35))	('mutation', 'Var', (96, 104))	('beta-catenin', 'Gene', (36, 48))	('adenomatous polyposis coli', 'Phenotype', 'HP:0005227', (64, 90))	('beta-catenin', 'Gene', '1499', (36, 48))	('adenomatous polyposis coli', 'Disease', 'MESH:D011125', (64, 90))
213152	24799899	Aberrant beta-catenin expression and adenomatous polyposis coli gene mutation were proven by authors.	('adenomatous polyposis coli', 'Disease', (37, 63))	('Aberrant', 'Var', (0, 8))	('beta-catenin', 'Gene', (9, 21))	('adenomatous polyposis coli', 'Phenotype', 'HP:0005227', (37, 63))	('mutation', 'Var', (69, 77))	('beta-catenin', 'Gene', '1499', (9, 21))	('adenomatous polyposis coli', 'Disease', 'MESH:D011125', (37, 63))
213199	31169680	Tyrosine kinase inhibitors have made good progress for the treatment of NSCLC, particularly in patients with adenocarcinoma and epidermal growth factor receptor (EGFR) gene mutations.	('adenocarcinoma', 'Disease', (109, 123))	('NSCLC', 'Disease', (72, 77))	('patients', 'Species', '9606', (95, 103))	('EGFR', 'Gene', '1956', (162, 166))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('EGFR', 'Gene', (162, 166))	('adenocarcinoma', 'Disease', 'MESH:D000230', (109, 123))	('NSCLC', 'Disease', 'MESH:D002289', (72, 77))	('mutations', 'Var', (173, 182))	('epidermal growth factor receptor', 'Gene', (128, 160))	('men', 'Species', '9606', (64, 67))	('epidermal growth factor receptor', 'Gene', '1956', (128, 160))	('NSCLC', 'Phenotype', 'HP:0030358', (72, 77))
213232	31169680	Furthermore, a significant increase in T-cell proliferation was detected in T-cell assays after RFA in cancer.	('T-cell proliferation', 'CPA', (39, 59))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('T-cell assays', 'CPA', (76, 89))	('increase', 'PosReg', (27, 35))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('RFA', 'Var', (96, 99))
213233	31169680	Shaobin et al found that, in late-stage lung cancer patients, the helper T lymphocyte (Th) 1 cell level declined, and the level of Th1 cells and Th1/Th2 ratio were increased after RFA, manifested as an improvement in the anti-tumor immunity capability.	('Th1', 'Gene', '51497', (131, 134))	('late-stage lung cancer', 'Disease', (29, 51))	('lung cancer', 'Phenotype', 'HP:0100526', (40, 51))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('RFA', 'Var', (180, 183))	('tumor', 'Disease', (226, 231))	('late-stage lung cancer', 'Disease', 'MESH:D008175', (29, 51))	('Th1', 'Gene', (145, 148))	('man', 'Species', '9606', (185, 188))	('tumor', 'Disease', 'MESH:D009369', (226, 231))	('Th1', 'Gene', (131, 134))	('patients', 'Species', '9606', (52, 60))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('men', 'Species', '9606', (209, 212))	('improvement', 'PosReg', (202, 213))	('Th1', 'Gene', '51497', (145, 148))	('declined', 'NegReg', (104, 112))	('increased', 'PosReg', (164, 173))
213237	31169680	However, although typically safe, RFA still can result in pulmonary hemorrhage ranging from mild to life-threatening.	('RFA', 'Var', (34, 37))	('pulmonary hemorrhage', 'Phenotype', 'HP:0040223', (58, 78))	('pulmonary hemorrhage', 'Disease', (58, 78))	('pulmonary hemorrhage', 'Disease', 'MESH:D006470', (58, 78))	('result in', 'Reg', (48, 57))
213266	31239839	One of the other types of EGFR-blocking drug known as TKI, gefitinib is effective in the treatment of lung cancer with EGFR mutations; however, its benefits in HNSCCs are unknown.	('mutations', 'Var', (124, 133))	('lung cancer', 'Phenotype', 'HP:0100526', (102, 113))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('lung cancer', 'Disease', (102, 113))	('lung cancer', 'Disease', 'MESH:D008175', (102, 113))	('HNSCC', 'Phenotype', 'HP:0012288', (160, 165))	('HNSCCs', 'Phenotype', 'HP:0012288', (160, 166))	('EGFR', 'Gene', (119, 123))
213271	31239839	These tumors have a direct effect on basic physiologic functions like the ability to chew, swallow, and breathe and the senses such as taste, smell, hearing, even uniquely human characteristics like appearance and voice.	('hearing', 'Disease', (149, 156))	('ability', 'MPA', (74, 81))	('breathe', 'CPA', (104, 111))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('human', 'Species', '9606', (172, 177))	('tumors', 'Var', (6, 12))	('chew', 'CPA', (85, 89))	('swallow', 'CPA', (91, 98))	('effect', 'Reg', (27, 33))
213289	29068150	However, CellSearch, which detects viable CTCs based on epithelial cellular adhesion molecule (EpCAM) expression, cannot detect CTCs with downregulated or deleted EpCAM.	('epithelial cellular adhesion molecule', 'Gene', '4072', (56, 93))	('deleted', 'Var', (155, 162))	('EpCAM', 'Gene', (163, 168))	('downregulated', 'NegReg', (138, 151))	('EpCAM', 'Gene', (95, 100))	('EpCAM', 'Gene', '4072', (163, 168))	('epithelial cellular adhesion molecule', 'Gene', (56, 93))	('EpCAM', 'Gene', '4072', (95, 100))
213336	28623316	We also identified known and potential connections for anti-cancer drugs and gene mutations using DI in pharmacogenomic data.	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('cancer', 'Disease', (60, 66))	('mutations', 'Var', (82, 91))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('DI', 'Chemical', '-', (98, 100))
213346	28623316	Erlotinib and Lapatinib, which selectively target EGFR mutants, have been extensively developed and approved to treat non-small cell lung cancer, whose clinical outcome is poor under traditional treatments, with higher survival benefit.	('Lapatinib', 'Chemical', 'MESH:D000077341', (14, 23))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (118, 144))	('lung cancer', 'Phenotype', 'HP:0100526', (133, 144))	('mutants', 'Var', (55, 62))	('non-small cell lung cancer', 'Disease', (118, 144))	('EGFR', 'Gene', '1956', (50, 54))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (122, 144))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (118, 144))	('EGFR', 'Gene', (50, 54))	('Erlotinib', 'Chemical', 'MESH:D000069347', (0, 9))
213348	28623316	Although treating cancers with targeted therapies by inhibiting or neutralizing cancer specific genetic alterations has been remarkable, there are still cases showing inert responses to these drugs.	('genetic alterations', 'Var', (96, 115))	('cancers', 'Disease', (18, 25))	('cancer', 'Disease', 'MESH:D009369', (18, 24))	('cancers', 'Phenotype', 'HP:0002664', (18, 25))	('neutralizing', 'Var', (67, 79))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancers', 'Disease', 'MESH:D009369', (18, 25))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('cancer', 'Disease', (18, 24))	('inhibiting', 'NegReg', (53, 63))	('cancer', 'Disease', (80, 86))
213351	28623316	For example, a TP53 mutation impairs the efficacy of MEK inhibitors and MDM2 inhibitor, while a BRAF mutation increases patients' sensitivity to MEK inhibitors.	('impairs', 'NegReg', (29, 36))	('MDM2', 'Gene', (72, 76))	('mutation', 'Var', (20, 28))	('increases', 'PosReg', (110, 119))	('MEK', 'Gene', (145, 148))	('efficacy', 'MPA', (41, 49))	('MEK', 'Gene', '5609', (145, 148))	('TP53', 'Gene', (15, 19))	('BRAF', 'Gene', (96, 100))	('patients', 'Species', '9606', (120, 128))	('BRAF', 'Gene', '673', (96, 100))	('MDM2', 'Gene', '4193', (72, 76))	('TP53', 'Gene', '7157', (15, 19))	('mutation', 'Var', (101, 109))	('MEK', 'Gene', (53, 56))	('MEK', 'Gene', '5609', (53, 56))
213367	28623316	We built a pan-cancer protein coupling network and identified gene mutations strongly related with response of cancer cell lines to certain drugs.	('cancer', 'Disease', (15, 21))	('cancer', 'Disease', 'MESH:D009369', (15, 21))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('mutations', 'Var', (67, 76))	('related', 'Reg', (86, 93))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))
213383	28623316	Studies have shown that the heterodimer of EGFR and HER2 leads to a more activated EGFR state than EGFR homodimer, and thereby carries stronger tumorigenic effect.	('EGFR', 'Gene', '1956', (83, 87))	('tumor', 'Disease', (144, 149))	('EGFR', 'Gene', (99, 103))	('HER2', 'Gene', '2064', (52, 56))	('EGFR', 'Gene', (83, 87))	('stronger', 'PosReg', (135, 143))	('EGFR', 'Gene', '1956', (43, 47))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('more activated', 'PosReg', (68, 82))	('EGFR', 'Gene', '1956', (99, 103))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('EGFR', 'Gene', (43, 47))	('heterodimer', 'Var', (28, 39))	('HER2', 'Gene', (52, 56))
213385	28623316	Indeed, 97% of cancers with HER2 phosphorylated at Y1248 exhibit detectable EGFR and HER2 stabilizes EGFR by reducing Y1068 phosphorylation.	('HER2', 'Gene', '2064', (28, 32))	('Y1068', 'Var', (118, 123))	('HER2', 'Gene', (28, 32))	('cancers', 'Disease', 'MESH:D009369', (15, 22))	('EGFR', 'Gene', '1956', (101, 105))	('EGFR', 'Gene', '1956', (76, 80))	('EGFR', 'Gene', (101, 105))	('cancers', 'Phenotype', 'HP:0002664', (15, 22))	('cancers', 'Disease', (15, 22))	('HER2', 'Gene', (85, 89))	('EGFR', 'Gene', (76, 80))	('HER2', 'Gene', '2064', (85, 89))	('reducing', 'NegReg', (109, 117))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))
213408	28623316	Mutations could not only provide the means for uncontrolled cancer growth but also can confer drug resistance.	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('confer', 'Reg', (87, 93))	('cancer', 'Disease', (60, 66))	('drug resistance', 'Phenotype', 'HP:0020174', (94, 109))	('Mutations', 'Var', (0, 9))	('drug resistance', 'MPA', (94, 109))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
213414	28623316	These results suggest that DI is an effective metric at capturing the biological connections between mutated genes in cancer cell lines and their effects on drugs.	('cancer', 'Disease', (118, 124))	('DI', 'Chemical', '-', (27, 29))	('mutated', 'Var', (101, 108))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('cancer', 'Disease', 'MESH:D009369', (118, 124))
213416	28623316	DCA uncovers more meaningful relationships on MEK inhibitors, AZD6244 and PD0325901, with ratios of known interactions/total pairs at 6/6 and 10/12 respectively.	('PD0325901', 'Var', (74, 83))	('relationships', 'Interaction', (29, 42))	('PD0325901', 'Chemical', 'MESH:C506614', (74, 83))	('DCA', 'Chemical', '-', (0, 3))	('AZD6244', 'Var', (62, 69))	('MEK', 'Gene', (46, 49))	('MEK', 'Gene', '5609', (46, 49))	('AZD6244', 'Chemical', 'MESH:C517975', (62, 69))
213418	28623316	Both RAF inhibitors are found 3 times in the top 100 pairs, however, the ratio of PLX4720 is as high as 1, while only one RAF265-mutated gene pair is regarded as known interactions.	('RAF', 'Gene', '22882', (122, 125))	('RAF', 'Gene', (122, 125))	('PLX4720', 'Var', (82, 89))	('RAF', 'Gene', '22882', (5, 8))	('RAF', 'Gene', (5, 8))
213419	28623316	By calculating direct couplings we observe that for 4 drugs, AZD6244, Nutlin-3, PHA 665752, and 17AAG, we are able to infer correctly a 100% of their gene mutation-drug relationships while the ENR method does this for three drugs, PD 0325901, ZD6474, and PD 0332991.	('PD', 'Disease', 'MESH:D010300', (231, 233))	('PHA 665752', 'Var', (80, 90))	('ZD6474', 'Chemical', 'MESH:C452423', (243, 249))	('AZD6244', 'Var', (61, 68))	('gene mutation-drug', 'MPA', (150, 168))	('PD', 'Disease', 'MESH:D010300', (255, 257))	('ZD6474', 'Var', (243, 249))	('AZD6244', 'Chemical', 'MESH:C517975', (61, 68))
213425	28623316	There is evidence of a BRAF mutation being involved in the response to the MEK inhibitors since RAF triggers the MEK signaling pathway.	('RAF', 'Gene', (96, 99))	('MEK', 'Gene', '5609', (113, 116))	('RAF', 'Gene', '22882', (96, 99))	('RAF', 'Gene', '22882', (24, 27))	('BRAF', 'Gene', '673', (23, 27))	('RAF', 'Gene', (24, 27))	('BRAF', 'Gene', (23, 27))	('mutation', 'Var', (28, 36))	('MEK', 'Gene', (75, 78))	('MEK', 'Gene', '5609', (75, 78))	('MEK', 'Gene', (113, 116))
213426	28623316	Also, a BRAF mutation has been used to predict the sensitivity to MEK inhibitors.	('BRAF', 'Gene', '673', (8, 12))	('mutation', 'Var', (13, 21))	('BRAF', 'Gene', (8, 12))	('MEK', 'Gene', (66, 69))	('MEK', 'Gene', '5609', (66, 69))
213427	28623316	As the activators of RAF, KRAS and NRAS mutations are also highly connected with MEK inhibitors, AZD6244 and PD0325901.	('RAF', 'Gene', '22882', (21, 24))	('RAF', 'Gene', (21, 24))	('NRAS', 'Gene', (35, 39))	('AZD6244', 'Chemical', 'MESH:C517975', (97, 104))	('NRAS', 'Gene', '4893', (35, 39))	('PD0325901', 'Chemical', 'MESH:C506614', (109, 118))	('mutations', 'Var', (40, 49))	('KRAS', 'Gene', (26, 30))	('KRAS', 'Gene', '3845', (26, 30))	('MEK', 'Gene', (81, 84))	('MEK', 'Gene', '5609', (81, 84))
213428	28623316	Indeed, the ability of using KRAS and NRAS mutations to predict the response to MEK inhibitors has been reported by other groups.	('NRAS', 'Gene', '4893', (38, 42))	('KRAS', 'Gene', (29, 33))	('response', 'MPA', (68, 76))	('mutations', 'Var', (43, 52))	('KRAS', 'Gene', '3845', (29, 33))	('NRAS', 'Gene', (38, 42))	('MEK', 'Gene', (80, 83))	('MEK', 'Gene', '5609', (80, 83))
213431	28623316	Interestingly, a mutation of KRAS indeed affects the response to EGFR inhibitor, while the efficacy of TKI258 in colorectal cancer is not dependent on the mutation status of KRAS we do find a connection in the DCA results, indicating a possibly distinct effect of KRAS mutation status on TKI258 efficacy in other types of cancer.	('colorectal cancer', 'Disease', (113, 130))	('cancer', 'Disease', 'MESH:D009369', (322, 328))	('KRAS', 'Gene', (29, 33))	('cancer', 'Disease', 'MESH:D009369', (124, 130))	('EGFR', 'Gene', (65, 69))	('KRAS', 'Gene', '3845', (264, 268))	('mutation', 'Var', (17, 25))	('colorectal cancer', 'Phenotype', 'HP:0003003', (113, 130))	('KRAS', 'Gene', (264, 268))	('cancer', 'Disease', (322, 328))	('affects', 'Reg', (41, 48))	('cancer', 'Phenotype', 'HP:0002664', (322, 328))	('KRAS', 'Gene', '3845', (174, 178))	('cancer', 'Disease', (124, 130))	('EGFR', 'Gene', '1956', (65, 69))	('colorectal cancer', 'Disease', 'MESH:D015179', (113, 130))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('DCA', 'Chemical', '-', (210, 213))	('KRAS', 'Gene', '3845', (29, 33))	('KRAS', 'Gene', (174, 178))
213432	28623316	Additionally, a KRAS mutation status also affects the sensitivity of cancer cells to topoisomerase I inhibitor and its relation with Topotecan is captured by our framework and is classified as a strong interactions.	('Topotecan', 'Chemical', 'MESH:D019772', (133, 142))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('KRAS', 'Gene', (16, 20))	('KRAS', 'Gene', '3845', (16, 20))	('affects', 'Reg', (42, 49))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('mutation status', 'Var', (21, 36))	('sensitivity', 'MPA', (54, 65))	('cancer', 'Disease', (69, 75))
213435	28623316	TP53 mutation has frequently occurred in most types of tumors and contributes to the initiation and progression of cancer.	('cancer', 'Disease', (115, 121))	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('contributes', 'Reg', (66, 77))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('tumors', 'Disease', (55, 61))	('tumors', 'Disease', 'MESH:D009369', (55, 61))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('mutation', 'Var', (5, 13))
213436	28623316	The presence or absence of mutations relate with the resistance or sensitivity to many drugs, such as the MDM2 inhibitor, RAF/MEK inhibitors, and RTK inhibitors.	('mutations', 'Var', (27, 36))	('RAF', 'Gene', '22882', (122, 125))	('RAF', 'Gene', (122, 125))	('resistance', 'MPA', (53, 63))	('MEK', 'Gene', (126, 129))	('MDM2', 'Gene', '4193', (106, 110))	('MEK', 'Gene', '5609', (126, 129))	('MDM2', 'Gene', (106, 110))	('sensitivity', 'MPA', (67, 78))	('relate', 'Reg', (37, 43))
213437	28623316	We find that TP53 mutation is associated with 6 anti-cancer drugs in our analysis, including 2 MEK inhibitors, 2 RTK inhibitors, Nutlin3, and an RAF inhibitor, substantiating that TP53 plays a key role in the determinant of drug sensitivity.	('associated', 'Reg', (30, 40))	('TP53', 'Gene', (13, 17))	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('RAF', 'Gene', '22882', (145, 148))	('RAF', 'Gene', (145, 148))	('TP53', 'Gene', '7157', (180, 184))	('TP53', 'Gene', (180, 184))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('mutation', 'Var', (18, 26))	('TP53', 'Gene', '7157', (13, 17))	('drug sensitivity', 'Phenotype', 'HP:0020174', (224, 240))	('MEK', 'Gene', (95, 98))	('MEK', 'Gene', '5609', (95, 98))
213439	28623316	In the other 4 gene mutation-drug response pairs characterized with strong interactions, BIRC6 knockout affects the sensitivity to Sorafenib, the activity of NF kappa B pathway is altered by the administration of 17AAG, HDAC6 inhibition promotes the degradation of Bcr-Abl, the target of Nilotinib, and PGR forms a complex with the AEW541 target, IGF1R.	('sensitivity', 'MPA', (116, 127))	('PGR', 'Gene', (303, 306))	('HDAC6', 'Gene', '10013', (220, 225))	('promotes', 'PosReg', (237, 245))	('NF kappa B pathway', 'Pathway', (158, 176))	('BIRC6', 'Gene', '57448', (89, 94))	('Bcr-Abl', 'Gene', (265, 272))	('complex', 'Interaction', (315, 322))	('Sorafenib', 'Chemical', 'MESH:D000077157', (131, 140))	('degradation', 'MPA', (250, 261))	('IGF1R', 'Gene', '3480', (347, 352))	('BIRC6', 'Gene', (89, 94))	('knockout', 'Var', (95, 103))	('PGR', 'Gene', '5241', (303, 306))	('altered', 'Reg', (180, 187))	('HDAC6', 'Gene', (220, 225))	('affects', 'Reg', (104, 111))	('IGF1R', 'Gene', (347, 352))	('inhibition', 'NegReg', (226, 236))	('activity', 'MPA', (146, 154))	('Bcr-Abl', 'Gene', '25', (265, 272))	('Nilotinib', 'Chemical', 'MESH:C498826', (288, 297))
213441	28623316	Also, some gene products are involved with certain pathways where the drug targets are in by some intermediates, such as NIN and ZD6474 through GSK3beta.	('GSK3beta', 'Gene', '2932', (144, 152))	('NIN', 'Disease', (121, 124))	('ZD6474', 'Chemical', 'MESH:C452423', (129, 135))	('NIN', 'Disease', 'None', (121, 124))	('ZD6474', 'Var', (129, 135))	('GSK3beta', 'Gene', (144, 152))	('involved', 'Reg', (29, 37))
213443	28623316	AZD0530 is a tyrosine kinase inhibitor, while NEK9 protein binds to NEK7 and releases its auto-inhibitory tyrosine kinase motif.	('AZD0530', 'Var', (0, 7))	('releases', 'PosReg', (77, 85))	('binds', 'Interaction', (59, 64))	('auto-inhibitory tyrosine kinase motif', 'MPA', (90, 127))	('AZD0530', 'Chemical', 'MESH:C515233', (0, 7))	('NEK7', 'Gene', (68, 72))	('NEK7', 'Gene', '140609', (68, 72))	('NEK9', 'Gene', '91754', (46, 50))	('NEK9', 'Gene', (46, 50))
213452	28623316	Our methodology can also be applied to an ever increasing number of samples to generate more confident predictions and more diverse cancer associated data, such as copy number variation, epigenetic modification, miRNA expression, to name a few, in order to extract directly connected genetic features for anti-cancer drug efficacy.	('cancer', 'Disease', (310, 316))	('cancer', 'Disease', (132, 138))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('cancer', 'Phenotype', 'HP:0002664', (310, 316))	('miRNA expression', 'MPA', (212, 228))	('copy number variation', 'Var', (164, 185))	('cancer', 'Disease', 'MESH:D009369', (310, 316))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('epigenetic modification', 'Var', (187, 210))
213455	28623316	We have identified several well-known mutations that affect anti-cancer drug response, such as those in TP53, BRAF, NRAS, KRAS.	('TP53', 'Gene', '7157', (104, 108))	('TP53', 'Gene', (104, 108))	('cancer', 'Disease', (65, 71))	('affect', 'Reg', (53, 59))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('NRAS', 'Gene', (116, 120))	('NRAS', 'Gene', '4893', (116, 120))	('BRAF', 'Gene', '673', (110, 114))	('mutations', 'Var', (38, 47))	('KRAS', 'Gene', (122, 126))	('BRAF', 'Gene', (110, 114))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('KRAS', 'Gene', '3845', (122, 126))
213456	28623316	In this analysis, the cellular response to Nutlin3, is found to be related with MDM2 expression and TP53 mutation.	('MDM2', 'Gene', (80, 84))	('cellular', 'MPA', (22, 30))	('TP53', 'Gene', '7157', (100, 104))	('mutation', 'Var', (105, 113))	('related', 'Reg', (67, 74))	('TP53', 'Gene', (100, 104))	('MDM2', 'Gene', '4193', (80, 84))
213462	28623316	This dataset contains protein expression data for 190 proteins, among which 52 are modified by phosphorylation and 1 is modified by acetylation, across 4776 tumor samples.	('tumor', 'Disease', (157, 162))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('phosphorylation', 'Var', (95, 110))	('proteins', 'Protein', (54, 62))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('modified', 'Reg', (120, 128))	('modified', 'Reg', (83, 91))
213465	28623316	The pharmacogenomic data, including mRNA expression, hybrid capture sequencing mutation, and a pharmacological profiling drug data were obtained from the Cancer Cell Line Encyclopedia (CCLE) database.	('mRNA expression', 'MPA', (36, 51))	('Cancer', 'Phenotype', 'HP:0002664', (154, 160))	('Cancer Cell Line Encyclopedia', 'Disease', (154, 183))	('mutation', 'Var', (79, 87))	('Cancer Cell Line Encyclopedia', 'Disease', 'MESH:C538614', (154, 183))
213478	28623316	Similar as with MI, DI represents a metric between two columns, i and j, that is a result from direct correlation: i and j are the positions of the proteins, with 0 < i < 191 and i < j < 191, for protein expression data matrix.	('0 < i < 191', 'Var', (163, 174))	('DI', 'Chemical', '-', (20, 22))	('i < j < 191', 'Var', (179, 190))
213489	27931212	The MSC markers CD90+, CD105+, and gremlin-1+ were found to co-localize on cells within the tumor microenvironment in oral cavity SCC specimens distinct from alpha-smooth muscle actin staining CAFs.	('SCC', 'Gene', (130, 133))	('CD105+', 'Var', (23, 29))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('SCC', 'Gene', '6317', (130, 133))	('gremlin-1', 'Gene', '26585', (35, 44))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('MSC', 'Gene', '9242', (4, 7))	('tumor microenvironment in oral cavity', 'Phenotype', 'HP:0100649', (92, 129))	('tumor', 'Disease', (92, 97))	('gremlin-1', 'Gene', (35, 44))	('MSC', 'Gene', (4, 7))	('CD90+', 'Var', (16, 21))	('AF', 'Disease', 'MESH:D001281', (194, 196))
213490	27931212	The conditioned media from JHU-011, -012, and -019 caused a significant increase in MSC migration (>60%) and invasion (>50%; p < 0.0001) compared to oral keratinocyte (OKT) controls.	('MSC', 'Gene', '9242', (84, 87))	('increase', 'PosReg', (72, 80))	('invasion', 'CPA', (109, 117))	('and -019', 'Var', (42, 50))	('MSC', 'Gene', (84, 87))	('JHU-011', 'Var', (27, 34))
213563	27931212	Neutralization of PDGF resulted in a >50% reduction in 3/3 HNSCC cell lines with a near complete arrest of MSC chemotaxis in 2/3 HNSCC cell lines (Fig.	('MSC', 'Gene', (107, 110))	('SCC', 'Gene', '6317', (61, 64))	('PDGF', 'Gene', (18, 22))	('SCC', 'Gene', (131, 134))	('Neutralization', 'Var', (0, 14))	('SCC', 'Gene', '6317', (131, 134))	('reduction', 'NegReg', (42, 51))	('SCC', 'Gene', (61, 64))	('MSC', 'Gene', '9242', (107, 110))
213564	27931212	5b; *p < 0.0001) whereas neutralization of IL-6 resulted in a ~50% reduction in MSC chemotaxis in 1/3 cell lines (Fig.	('MSC', 'Gene', '9242', (80, 83))	('IL-6', 'Gene', (43, 47))	('MSC', 'Gene', (80, 83))	('reduction', 'NegReg', (67, 76))	('IL-6', 'Gene', '3569', (43, 47))	('neutralization', 'Var', (25, 39))
213569	27931212	Blockade of PDGFRalpha resulted in a significant reduction of MSC chemotaxis whereas blockade of PDGFRbeta did not (Fig.	('reduction', 'NegReg', (49, 58))	('PDGFRbeta', 'Gene', (97, 106))	('Blockade', 'Var', (0, 8))	('PDGFRalpha', 'Gene', '5156', (12, 22))	('MSC', 'Gene', '9242', (62, 65))	('PDGFRalpha', 'Gene', (12, 22))	('MSC', 'Gene', (62, 65))	('PDGFRbeta', 'Gene', '5159', (97, 106))
213572	27931212	After 48-h, PDGF-AA secretion remained elevated without evidence of reaching a plateau, suggesting, PDGF-AA is likely the key chemotactic agent underlying MSC chemotaxis in HNSCC and may cause tumor cell release of IL-6 as a later phenomenon.	('MSC', 'Gene', (155, 158))	('PDGF-AA', 'Var', (100, 107))	('SCC', 'Gene', (175, 178))	('MSC', 'Gene', '9242', (155, 158))	('IL-6', 'Gene', (215, 219))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('IL-6', 'Gene', '3569', (215, 219))	('SCC', 'Gene', '6317', (175, 178))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('tumor', 'Disease', (193, 198))	('cause', 'Reg', (187, 192))
213585	27931212	We have shown here that PDGF-AA causes a ~100% increase in the migration of HMSCs compared to OKT cells and neutralization of PDGF in the conditioned media from OPSCC cell lines resulted in arrest of MSC chemotaxis to levels comparable with controls (Fig.	('MSC', 'Gene', '9242', (200, 203))	('PDGF-AA', 'Var', (24, 31))	('arrest', 'CPA', (190, 196))	('neutralization', 'Var', (108, 122))	('MSC', 'Gene', '9242', (77, 80))	('PDGF', 'Gene', (126, 130))	('MSC', 'Gene', (200, 203))	('MSC', 'Gene', (77, 80))	('SCC', 'Gene', (163, 166))	('increase', 'PosReg', (47, 55))	('SCC', 'Gene', '6317', (163, 166))
213586	27931212	Neutralization of IL-6 resulted in reduced HNSCC-induced HMSC chemotaxis (Fig.	('IL-6', 'Gene', '3569', (18, 22))	('SCC', 'Gene', (45, 48))	('reduced', 'NegReg', (35, 42))	('MSC', 'Gene', '9242', (58, 61))	('SCC', 'Gene', '6317', (45, 48))	('Neutralization', 'Var', (0, 14))	('MSC', 'Gene', (58, 61))	('IL-6', 'Gene', (18, 22))
213587	27931212	Our hypothesis that PDGF-AA is the primary driver of MSC chemotaxis in OPSCC is further strengthened as inhibition of only the PDGFRalpha significantly reduced MSC migration (Fig.	('PDGFRalpha', 'Gene', (127, 137))	('MSC', 'Gene', '9242', (160, 163))	('MSC', 'Gene', '9242', (53, 56))	('SCC', 'Gene', (73, 76))	('MSC', 'Gene', (160, 163))	('reduced', 'NegReg', (152, 159))	('MSC', 'Gene', (53, 56))	('inhibition', 'Var', (104, 114))	('SCC', 'Gene', '6317', (73, 76))	('PDGFRalpha', 'Gene', '5156', (127, 137))
213596	27931212	Our data suggest that PDGF-AA is a more potent MSC chemoattractant in OC and OPSCC, than other PDGF isoforms and IL-6.	('SCC', 'Gene', (79, 82))	('IL-6', 'Gene', (113, 117))	('IL-6', 'Gene', '3569', (113, 117))	('MSC', 'Gene', '9242', (47, 50))	('PDGF-AA', 'Var', (22, 29))	('SCC', 'Gene', '6317', (79, 82))	('MSC', 'Gene', (47, 50))
213605	26295375	Refined diagnostic criteria for type A, AB, B1-B3 thymomas and thymic squamous cell carcinoma are given and will hopefully improve the reproducibility of the classification and its clinical relevance.	('B1-B3', 'Var', (44, 49))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (70, 93))	('squamous cell carcinoma', 'Disease', (70, 93))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (70, 93))	('thymoma', 'Phenotype', 'HP:0100522', (50, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('thymomas', 'Disease', 'MESH:D013945', (50, 58))	('thymomas', 'Disease', (50, 58))	('type A', 'Disease', (32, 38))
213631	26295375	The latter show mutations of epigenetic regulatory genes, methylation patterns and expression profiles of anti-apoptotic genes that clearly distinguish them from thymomas.	('methylation', 'MPA', (58, 69))	('thymoma', 'Phenotype', 'HP:0100522', (162, 169))	('thymomas', 'Disease', (162, 170))	('epigenetic regulatory genes', 'Gene', (29, 56))	('mutations', 'Var', (16, 25))	('thymomas', 'Disease', 'MESH:D013945', (162, 170))	('expression', 'MPA', (83, 93))	('anti-apoptotic genes', 'Gene', (106, 126))
213632	26295375	On the other hand, the identification of a highly recurrent point mutation in the GTF2I oncogene in all major thymoma subtypes and thymic carcinomas is a seminal finding that underlines the unique tumor biology of thymic epithelial tumors and lends strong support to the WHO-based subtyping of thymic tumors.	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('carcinomas', 'Phenotype', 'HP:0030731', (138, 148))	('thymic tumors', 'Disease', (294, 307))	('GTF2I', 'Gene', '2969', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (301, 306))	('thymic tumors', 'Disease', 'MESH:D013953', (294, 307))	('thymic epithelial tumors', 'Disease', 'MESH:C536905', (214, 238))	('GTF2I', 'Gene', (82, 87))	('thymic carcinomas', 'Disease', 'MESH:D013945', (131, 148))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('tumor', 'Disease', (232, 237))	('thymic carcinomas', 'Disease', (131, 148))	('thymoma subtypes', 'Disease', (110, 126))	('tumor', 'Disease', 'MESH:D009369', (232, 237))	('tumor', 'Disease', (301, 306))	('tumor', 'Disease', (197, 202))	('tumors', 'Phenotype', 'HP:0002664', (232, 238))	('thymoma', 'Phenotype', 'HP:0100522', (110, 117))	('thymoma subtypes', 'Disease', 'MESH:D013945', (110, 126))	('point mutation', 'Var', (60, 74))	('thymic epithelial tumors', 'Disease', (214, 238))	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('tumor', 'Disease', 'MESH:D009369', (301, 306))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('tumors', 'Phenotype', 'HP:0002664', (301, 307))
213666	26295375	Translocation of the MAML2 gene is characteristic of almost all low-grade MECs and many high-grade MECs of salivary glands, bronchi and lung.	('Translocation', 'Var', (0, 13))	('MAML2', 'Gene', '84441', (21, 26))	('MAML2', 'Gene', (21, 26))	('low-grade MECs', 'Disease', (64, 78))	('bronchi', 'Disease', (124, 131))
213672	26295375	These tumors are now known to occur at all ages, outside the thorax (and rarely outside the midline) in ~40%, and to show variant NUT (nuclear protein in testis) translocations in ~30% of cases.	('NUT', 'Gene', '256646', (130, 133))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('NUT', 'Gene', (130, 133))	('tumors', 'Disease', (6, 12))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('variant', 'Var', (122, 129))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('translocations', 'Var', (162, 176))
213683	26295375	In advanced stage refractory disease, KIT mutations have exclusively been reported to occur in thymic carcinomas, but their potential role as biomarkers needs further studies; meanwhile, targeting angiogenesis using multikinase inhibitors is of higher relevance in carcinomas irrespective of their KIT mutational status.	('carcinomas', 'Disease', 'MESH:D002277', (102, 112))	('carcinomas', 'Phenotype', 'HP:0030731', (265, 275))	('carcinomas', 'Disease', (265, 275))	('thymic carcinomas', 'Disease', (95, 112))	('carcinomas', 'Disease', 'MESH:D002277', (265, 275))	('occur', 'Reg', (86, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('thymic carcinomas', 'Disease', 'MESH:D013945', (95, 112))	('mutations', 'Var', (42, 51))	('carcinomas', 'Phenotype', 'HP:0030731', (102, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (265, 274))	('carcinomas', 'Disease', (102, 112))
213693	26295375	The progressive increase and overlap of genetic gains and losses from typical carcinoids through atypical carcinoids to LCNECs and small cell carcinomas lends support to the WHO classification.	('carcinoid', 'Phenotype', 'HP:0100570', (106, 115))	('LCNECs', 'Disease', (120, 126))	('carcinoids', 'Phenotype', 'HP:0100570', (78, 88))	('carcinoids', 'Phenotype', 'HP:0100570', (106, 116))	('carcinomas', 'Phenotype', 'HP:0030731', (142, 152))	('small cell carcinomas', 'Disease', 'MESH:D018288', (131, 152))	('carcinoma', 'Phenotype', 'HP:0030731', (142, 151))	('small cell carcinomas', 'Phenotype', 'HP:0030357', (131, 152))	('small cell carcinomas', 'Disease', (131, 152))	('carcinoid', 'Phenotype', 'HP:0100570', (78, 87))	('losses', 'NegReg', (58, 64))	('genetic', 'Var', (40, 47))	('small cell carcinoma', 'Phenotype', 'HP:0030357', (131, 151))	('gains', 'PosReg', (48, 53))
213707	26295375	Among the novel genetic alterations reported since 2004, the following are of special interest from a biological and potentially immunotherapeutic perspective: translocations of the HLA class II transactivator CIITA at 16p13.13 associated with down-regulation of HLA class II molecules; and the almost specific amplification and/or translocation of the 9p24.1 region including the loci coding for the immune checkpoint molecules PD-L1 and PD-L2, which are overexpressed and helpful immunohistochemical markers in PMBL.	('PD-L1', 'Gene', '29126', (429, 434))	('HLA class II molecules', 'Protein', (263, 285))	('translocations', 'Var', (160, 174))	('PD-L1', 'Gene', (429, 434))	('CIITA', 'Gene', (210, 215))	('CIITA', 'Gene', '4261', (210, 215))	('PD-L2', 'Gene', (439, 444))	('PD-L2', 'Gene', '80380', (439, 444))	('translocation', 'Var', (332, 345))	('down-regulation', 'NegReg', (244, 259))
213711	26295375	Among many novel genetic alterations detected, mutations of NOTCH1/FXBW are associated with a favourable outcome, while loss of heterozygocity (LOH) at 6q has a negative impact on prognosis.	('NOTCH1', 'Gene', '4851', (60, 66))	('NOTCH1', 'Gene', (60, 66))	('mutations', 'Var', (47, 56))
213716	26295375	Recognition that genetic and transcriptomic variation of the tumor cells, and tumor-associated T cells and macrophages have prognostic relevance is also new.	('variation', 'Var', (44, 53))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Disease', (78, 83))	('tumor', 'Disease', (61, 66))
213730	26295375	A new finding is the detection of BRAF mutations in about 50% of all cases of Langerhans cell histiocytosis, including mediastinal cases.	('histiocytosis', 'Phenotype', 'HP:0100727', (94, 107))	('mutations', 'Var', (39, 48))	('BRAF', 'Gene', '673', (34, 38))	('mediastinal cases', 'Disease', (119, 136))	('Langerhans cell histiocytosis', 'Disease', (78, 107))	('detection', 'Reg', (21, 30))	('BRAF', 'Gene', (34, 38))
213750	25088195	Comparison of gene expression patterns across twelve tumor types identifies a cancer supercluster characterized by TP53 mutations and cell cycle defects Transcriptional profile based subtypes of cancer are often viewed as identifying different diseases from the same tissue origin.	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('TP53', 'Gene', '7157', (115, 119))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', (195, 201))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('TP53', 'Gene', (115, 119))	('mutations', 'Var', (120, 129))	('tumor', 'Disease', (53, 58))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('cell cycle defects', 'Phenotype', 'HP:0011018', (134, 152))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
213752	25088195	One of the largest superclusters was determined by the upregulation of a proliferation signature, significant enrichment in TP53 mutations, genomic loss of CDKN2A (p16ARF), evidence of increased numbers of DNA double strand breaks and high expression of cyclin B1 protein.	('cyclin B1', 'Gene', (254, 263))	('CDKN2A', 'Gene', (156, 162))	('TP53', 'Gene', '7157', (124, 128))	('loss', 'NegReg', (148, 152))	('mutations', 'Var', (129, 138))	('CDKN2A', 'Gene', '1029', (156, 162))	('TP53', 'Gene', (124, 128))	('expression', 'MPA', (240, 250))	('upregulation', 'PosReg', (55, 67))	('increased', 'PosReg', (185, 194))	('cyclin B1', 'Gene', '891', (254, 263))
213753	25088195	These correlations suggested that abrogation of the P53 mediated apoptosis response to DNA damage results in activation of cell cycle pathways and represents a common theme in cancer.	('P53', 'Gene', '7157', (52, 55))	('cell', 'Pathway', (123, 127))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('activation', 'PosReg', (109, 119))	('abrogation', 'Var', (34, 44))	('apoptosis', 'CPA', (65, 74))	('P53', 'Gene', (52, 55))	('cancer', 'Disease', (176, 182))	('cancer', 'Disease', 'MESH:D009369', (176, 182))
213759	25088195	Furthermore, molecular subtypes are frequently found to associate with somatic alterations, such as EGFR abnormalities in the classical subtype of glioblastoma, or the enrichment of NF1 deletions and mutations in the primitive group of lung squamous carcinoma.	('associate', 'Reg', (56, 65))	('EGFR', 'Gene', '1956', (100, 104))	('lung squamous carcinoma', 'Phenotype', 'HP:0030359', (236, 259))	('mutations', 'Var', (200, 209))	('glioblastoma', 'Disease', (147, 159))	('glioblastoma', 'Disease', 'MESH:D005909', (147, 159))	('EGFR', 'Gene', (100, 104))	('abnormalities', 'Var', (105, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (250, 259))	('lung squamous carcinoma', 'Disease', (236, 259))	('glioblastoma', 'Phenotype', 'HP:0012174', (147, 159))	('NF1', 'Gene', (182, 185))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (241, 259))	('NF1', 'Gene', '4763', (182, 185))	('deletions', 'Var', (186, 195))	('lung squamous carcinoma', 'Disease', 'MESH:D002294', (236, 259))
213793	25088195	As expected, both stromal and immune scores were significantly higher in supercluster 1 compared to other superclusters (stromal score, posthoc maximum P = 0.00065; immune score, posthoc maximum P = 1.3E-15) (Figure 4).	('stroma', 'Disease', (121, 127))	('immune scores', 'CPA', (30, 43))	('stroma', 'Disease', (18, 24))	('supercluster 1', 'Var', (73, 87))	('stroma', 'Disease', 'None', (121, 127))	('higher', 'PosReg', (63, 69))	('stroma', 'Disease', 'None', (18, 24))
213797	25088195	We used reverse phase protein array (RPPA) profiles available for a subset of samples and found that the protein expression levels of mitotic cycle marker cyclin B1 (CCNB1) was significantly up-regulated in supercluster 5 relative to other superclusters (P = 1.56E-8) (Supplementary Figure 4).	('protein expression levels', 'MPA', (105, 130))	('CCNB1', 'Gene', '891', (166, 171))	('cyclin B1', 'Gene', (155, 164))	('cyclin B1', 'Gene', '891', (155, 164))	('up-regulated', 'PosReg', (191, 203))	('supercluster', 'Var', (207, 219))	('CCNB1', 'Gene', (166, 171))
213800	25088195	Interestingly, a higher number of mutations in the apoptosis and cell cycle regulator TP53 were observed in supercluster 5 (77% of samples; Figure 5a), which may explain why cells are not entering apoptosis despite a high level of DNA damage.	('TP53', 'Gene', (86, 90))	('apoptosis', 'Gene', (51, 60))	('mutations', 'Var', (34, 43))	('TP53', 'Gene', '7157', (86, 90))
213801	25088195	In addition, all subtypes except OV_Proliferative in supercluster 5 harbored deletions of cyclin-dependent kinase inhibitor 2A (CDKN2A) in more than 10% of samples (Supplementary Figure 6, Supplementary Table 6 and 7).	('harbored', 'Reg', (68, 76))	('deletions', 'Var', (77, 86))	('CDKN2A', 'Gene', (128, 134))	('CDKN2A', 'Gene', '1029', (128, 134))	('cyclin-dependent kinase inhibitor 2A', 'Gene', (90, 126))	('cyclin-dependent kinase inhibitor 2A', 'Gene', '1029', (90, 126))
213803	25088195	The association between TP53 mutation and CDKN2A deletion showed a trend towards mutually exclusivity (Fisher's exact test, P = 0.10).	('mutation', 'Var', (29, 37))	('TP53', 'Gene', (24, 28))	('association', 'Interaction', (4, 15))	('CDKN2A', 'Gene', (42, 48))	('deletion', 'Var', (49, 57))	('CDKN2A', 'Gene', '1029', (42, 48))	('TP53', 'Gene', '7157', (24, 28))
213817	25088195	The role of the tumor microenvironment is increasingly being appreciated, most prominently as immunotherapeutics such as anti-PD1 and anti-CTL4A that have shown efficacy in advanced melanoma and other tumor types.	('PD1', 'Gene', (126, 129))	('PD1', 'Gene', '9825', (126, 129))	('anti-CTL4A', 'Var', (134, 144))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('tumor', 'Disease', (16, 21))	('tumor', 'Disease', (201, 206))	('melanoma', 'Phenotype', 'HP:0002861', (182, 190))	('melanoma', 'Disease', (182, 190))	('melanoma', 'Disease', 'MESH:D008545', (182, 190))
213821	25088195	A second large supercluster, plus a third smaller supercluster, unified the cell cycle and apoptosis pathways, through combined presence of an increased level of DNA double strand breaks, mutations in TP53, loss of CDKN2A, and cell cycle protein levels.	('apoptosis pathways', 'Pathway', (91, 109))	('increased', 'PosReg', (143, 152))	('CDKN2A', 'Gene', (215, 221))	('cell cycle', 'Pathway', (76, 86))	('loss', 'NegReg', (207, 211))	('TP53', 'Gene', '7157', (201, 205))	('CDKN2A', 'Gene', '1029', (215, 221))	('cell cycle protein levels', 'MPA', (227, 252))	('DNA double strand breaks', 'MPA', (162, 186))	('TP53', 'Gene', (201, 205))	('mutations', 'Var', (188, 197))
213822	25088195	While TP53 mutations are frequent across cancer lineages and may generally serve an anti-apoptotic role, we speculate that in the context of the proliferation transcriptomic signature, these mutations were selected to negate the apoptotic signals resulting from high levels of DNA damage.	('mutations', 'Var', (11, 20))	('TP53', 'Gene', '7157', (6, 10))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('TP53', 'Gene', (6, 10))	('mutations', 'Var', (191, 200))	('negate', 'NegReg', (218, 224))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('apoptotic', 'CPA', (229, 238))
213834	25088195	To identify a squamous signature specifically related to the presence of squamous cell carcinoma, four microarray data sets were obtained from the Gene Expression Omnibus (GSE10245, lung cancer; GSE28571, lung cancer; GSE26886, esophageal cancer; and GSE27388, cervical cancer).	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (73, 96))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('lung cancer', 'Disease', (182, 193))	('esophageal cancer', 'Disease', (228, 245))	('cervical cancer', 'Disease', 'MESH:D002583', (261, 276))	('lung cancer', 'Disease', (205, 216))	('GSE26886', 'Var', (218, 226))	('cervical cancer', 'Disease', (261, 276))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (73, 96))	('cancer', 'Phenotype', 'HP:0002664', (270, 276))	('lung cancer', 'Disease', 'MESH:D008175', (182, 193))	('GSE28571', 'Var', (195, 203))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))	('lung cancer', 'Disease', 'MESH:D008175', (205, 216))	('lung cancer', 'Phenotype', 'HP:0100526', (182, 193))	('squamous cell carcinoma', 'Disease', (73, 96))	('lung cancer', 'Phenotype', 'HP:0100526', (205, 216))	('GSE10245', 'Var', (172, 180))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('GSE27388', 'Var', (251, 259))	('esophageal cancer', 'Disease', 'MESH:D004938', (228, 245))
213921	33505797	For convenience, genes 1 to d are assumed to be associated with disease 1 and genes d - o + 1 to 2d - o are associated with disease 2, where d >= o.	('d', 'Chemical', 'MESH:D003903', (98, 99))	('d', 'Chemical', 'MESH:D003903', (40, 41))	('d', 'Chemical', 'MESH:D003903', (57, 58))	('d', 'Chemical', 'MESH:D003903', (124, 125))	('associated', 'Reg', (48, 58))	('d', 'Chemical', 'MESH:D003903', (64, 65))	('d', 'Chemical', 'MESH:D003903', (28, 29))	('associated', 'Reg', (108, 118))	('d', 'Chemical', 'MESH:D003903', (117, 118))	('d', 'Chemical', 'MESH:D003903', (76, 77))	('d - o + 1 to 2d - o', 'Var', (84, 103))	('d', 'Chemical', 'MESH:D003903', (141, 142))	('d', 'Chemical', 'MESH:D003903', (84, 85))
213938	33505797	1A, 1E and 1I), the power of SimSIP has almost a 10% increase compared with that of WeiSumE* and OrderedList, is more than two times the powers of FES0.01, and almost more than 8 times the powers of FES0.001 and EucD.	('d', 'Chemical', 'MESH:D003903', (95, 96))	('d', 'Chemical', 'MESH:D003903', (99, 100))	('d', 'Chemical', 'MESH:D003903', (158, 159))	('increase', 'PosReg', (53, 61))	('d', 'Chemical', 'MESH:D003903', (103, 104))	('SimSIP', 'Var', (29, 35))	('d', 'Chemical', 'MESH:D003903', (210, 211))	('d', 'Chemical', 'MESH:D003903', (69, 70))	('d', 'Chemical', 'MESH:D003903', (9, 10))
213976	33505797	Among the 10 significant cancer pairs (shown in red in Table S2) found with SimSIP, not WeiSumE*, five cancer pairs can be explained in pan-cancer studies: For cancer pair COAD and UCEC, the diversity of high antigen-specific TCR repertoires correlates with the improved prognostic progression-free interval in COAD and UCEC; the expression of TMEM173 in tumor tissues is significantly upregulated and hypomethylated in cancer pair COAD and THCA but significantly downregulated and hypermethylated in cancer pair LUSC and PRAD.	('d', 'Chemical', 'MESH:D003903', (50, 51))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('TMEM173', 'Gene', (344, 351))	('d', 'Chemical', 'MESH:D003903', (396, 397))	('cancer', 'Disease', (501, 507))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', (25, 31))	('upregulated', 'PosReg', (386, 397))	('COAD', 'Disease', (311, 315))	('d', 'Chemical', 'MESH:D003903', (191, 192))	('d', 'Chemical', 'MESH:D003903', (476, 477))	('cancer', 'Disease', (420, 426))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('d', 'Chemical', 'MESH:D003903', (150, 151))	('cancer', 'Disease', (160, 166))	('tumor', 'Phenotype', 'HP:0002664', (355, 360))	('cancer', 'Phenotype', 'HP:0002664', (420, 426))	('COAD', 'Disease', 'MESH:D029424', (432, 436))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('COAD', 'Disease', 'MESH:D029424', (172, 176))	('d', 'Chemical', 'MESH:D003903', (269, 270))	('hypomethylated', 'Var', (402, 416))	('d', 'Chemical', 'MESH:D003903', (179, 180))	('d', 'Chemical', 'MESH:D003903', (464, 465))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (501, 507))	('cancer', 'Disease', 'MESH:D009369', (25, 31))	('d', 'Chemical', 'MESH:D003903', (400, 401))	('d', 'Chemical', 'MESH:D003903', (520, 521))	('d', 'Chemical', 'MESH:D003903', (69, 70))	('d', 'Chemical', 'MESH:D003903', (131, 132))	('TMEM173', 'Gene', '340061', (344, 351))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (420, 426))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('COAD', 'Disease', (432, 436))	('d', 'Chemical', 'MESH:D003903', (496, 497))	('d', 'Chemical', 'MESH:D003903', (480, 481))	('COAD', 'Disease', (172, 176))	('downregulated', 'NegReg', (464, 477))	('tumor', 'Disease', (355, 360))	('expression', 'MPA', (330, 340))	('d', 'Chemical', 'MESH:D003903', (439, 440))	('d', 'Chemical', 'MESH:D003903', (415, 416))	('COAD', 'Disease', 'MESH:D029424', (311, 315))	('hypermethylated', 'PosReg', (482, 497))	('d', 'Chemical', 'MESH:D003903', (318, 319))	('tumor', 'Disease', 'MESH:D009369', (355, 360))
213977	33505797	Furthermore, there are high mutations rates for TBK1 in cancer pair COAD and UCEC, and the expression of TMEM173 is positively associated with the infiltration of immune cells in cancer pair BRCA and THCA.	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('d', 'Chemical', 'MESH:D003903', (136, 137))	('infiltration of immune cells', 'CPA', (147, 175))	('cancer', 'Disease', (56, 62))	('d', 'Chemical', 'MESH:D003903', (198, 199))	('TBK1', 'Gene', '29110', (48, 52))	('TMEM173', 'Gene', (105, 112))	('COAD', 'Disease', 'MESH:D029424', (68, 72))	('expression', 'Var', (91, 101))	('TBK1', 'Gene', (48, 52))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('THCA', 'Disease', (200, 204))	('associated with', 'Reg', (127, 142))	('d', 'Chemical', 'MESH:D003903', (85, 86))	('COAD', 'Disease', (68, 72))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('mutations', 'Var', (28, 37))	('TMEM173', 'Gene', '340061', (105, 112))	('d', 'Chemical', 'MESH:D003903', (75, 76))	('cancer', 'Disease', (179, 185))
213988	33505797	Further, for the three types of kidney tumors, KICH, KIRP, and KIPC, the similarity between KIRP and KIPC is more significant than KICH and KIPC or KIRP and KIPC, which may be explained by the fact that KIRC and KIRP are cancers of the proximal tubule segments, whereas KICH is a cancer of the distal tubule segments.	('cancer', 'Disease', 'MESH:D009369', (221, 227))	('cancers', 'Disease', 'MESH:D009369', (221, 228))	('kidney tumors', 'Phenotype', 'HP:0009726', (32, 45))	('cancer', 'Disease', (280, 286))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('cancer', 'Phenotype', 'HP:0002664', (280, 286))	('KICH', 'Disease', (47, 51))	('KICH', 'Disease', 'None', (131, 135))	('d', 'Chemical', 'MESH:D003903', (294, 295))	('KIRP', 'Var', (212, 216))	('kidney tumors', 'Disease', (32, 45))	('KIRC', 'Var', (203, 207))	('cancer', 'Disease', 'MESH:D009369', (280, 286))	('KICH', 'Disease', 'None', (270, 274))	('cancers', 'Phenotype', 'HP:0002664', (221, 228))	('cancer', 'Disease', (221, 227))	('cancers', 'Disease', (221, 228))	('d', 'Chemical', 'MESH:D003903', (61, 62))	('KICH', 'Disease', (131, 135))	('d', 'Chemical', 'MESH:D003903', (138, 139))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('d', 'Chemical', 'MESH:D003903', (155, 156))	('kidney tumors', 'Disease', 'MESH:D007680', (32, 45))	('KICH', 'Disease', 'None', (47, 51))	('d', 'Chemical', 'MESH:D003903', (34, 35))	('d', 'Chemical', 'MESH:D003903', (99, 100))	('KICH', 'Disease', (270, 274))	('d', 'Chemical', 'MESH:D003903', (210, 211))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('d', 'Chemical', 'MESH:D003903', (184, 185))
214009	33505797	CDH3, the top 1 gene detected by MAG, is located in a region on the long arm of chromosome 16. advised that genetic or epigenetic changes in this gene or changes in its protein expression often lead to tissue disorders, cellular dedifferentiation, and enhanced invasiveness of tumor cells.	('tissue disorders', 'CPA', (202, 218))	('CDH3', 'Gene', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (277, 282))	('MAG', 'Gene', '4099', (33, 36))	('d', 'Chemical', 'MESH:D003903', (96, 97))	('top 1', 'Gene', '7150', (10, 15))	('d', 'Chemical', 'MESH:D003903', (229, 230))	('d', 'Chemical', 'MESH:D003903', (214, 215))	('d', 'Chemical', 'MESH:D003903', (47, 48))	('epigenetic changes', 'Var', (119, 137))	('changes', 'Var', (154, 161))	('genetic', 'Var', (108, 115))	('d', 'Chemical', 'MESH:D003903', (101, 102))	('d', 'Chemical', 'MESH:D003903', (259, 260))	('lead to', 'Reg', (194, 201))	('MAG', 'Gene', (33, 36))	('d', 'Chemical', 'MESH:D003903', (197, 198))	('d', 'Chemical', 'MESH:D003903', (28, 29))	('CDH3', 'Gene', '1001', (0, 4))	('d', 'Chemical', 'MESH:D003903', (21, 22))	('tumor', 'Disease', (277, 282))	('d', 'Chemical', 'MESH:D003903', (250, 251))	('enhanced', 'PosReg', (252, 260))	('tumor', 'Disease', 'MESH:D009369', (277, 282))	('d', 'Chemical', 'MESH:D003903', (209, 210))	('cellular dedifferentiation', 'CPA', (220, 246))	('d', 'Chemical', 'MESH:D003903', (231, 232))	('top 1', 'Gene', (10, 15))
214022	33505797	In detail, the circadian entrainment pathway closely interacts with the cell division cycle and pharmacological pathways in the treatment of metastatic colorectal cancer and accelerates or slows down cancer growth through modifications of host and tumor circadian clocks, which drives 24 h changes in drug metabolism, cellular proliferation and apoptosis, cell cycle events, DNA repair, and angiogenesis.	('slows down', 'NegReg', (189, 199))	('colorectal cancer', 'Disease', 'MESH:D015179', (152, 169))	('d', 'Chemical', 'MESH:D003903', (343, 344))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('interacts', 'Reg', (53, 62))	('d', 'Chemical', 'MESH:D003903', (278, 279))	('colorectal cancer', 'Disease', (152, 169))	('d', 'Chemical', 'MESH:D003903', (224, 225))	('d', 'Chemical', 'MESH:D003903', (389, 390))	('cancer', 'Disease', 'MESH:D009369', (163, 169))	('d', 'Chemical', 'MESH:D003903', (301, 302))	('tumor', 'Disease', (248, 253))	('d', 'Chemical', 'MESH:D003903', (246, 247))	('accelerates', 'PosReg', (174, 185))	('tumor', 'Disease', 'MESH:D009369', (248, 253))	('modifications', 'Var', (222, 235))	('cancer', 'Disease', 'MESH:D009369', (200, 206))	('d', 'Chemical', 'MESH:D003903', (94, 95))	('d', 'Chemical', 'MESH:D003903', (259, 260))	('d', 'Chemical', 'MESH:D003903', (77, 78))	('d', 'Chemical', 'MESH:D003903', (20, 21))	('colorectal cancer', 'Phenotype', 'HP:0003003', (152, 169))	('d', 'Chemical', 'MESH:D003903', (172, 173))	('d', 'Chemical', 'MESH:D003903', (195, 196))	('cancer', 'Disease', (163, 169))	('tumor', 'Phenotype', 'HP:0002664', (248, 253))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('d', 'Chemical', 'MESH:D003903', (3, 4))	('cancer', 'Disease', (200, 206))
214026	33505797	Up to 15% of colorectal cancers are distinguished by DNA microsatellite instability and manifested by the presence of DNA replication errors.	('d', 'Chemical', 'MESH:D003903', (36, 37))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('colorectal cancers', 'Disease', 'MESH:D015179', (13, 31))	('colorectal cancers', 'Disease', (13, 31))	('d', 'Chemical', 'MESH:D003903', (48, 49))	('DNA microsatellite instability', 'Var', (53, 83))	('d', 'Chemical', 'MESH:D003903', (97, 98))	('d', 'Chemical', 'MESH:D003903', (86, 87))	('cancers', 'Phenotype', 'HP:0002664', (24, 31))	('colorectal cancer', 'Phenotype', 'HP:0003003', (13, 30))
214047	33076565	The viability of SCC-15 cells was inhibited by cisplatin with a dose-dependent manner and CAP treatment time.	('CAP', 'Chemical', '-', (90, 93))	('cisplatin', 'Var', (47, 56))	('SCC-15', 'CellLine', 'CVCL:1681', (17, 23))	('viability', 'CPA', (4, 13))	('inhibited', 'NegReg', (34, 43))	('cisplatin', 'Chemical', 'MESH:D002945', (47, 56))
214048	33076565	HGF-1 cells also showed decreased viability by treatment with cisplatin and CAP.	('cisplatin', 'Chemical', 'MESH:D002945', (62, 71))	('decreased', 'NegReg', (24, 33))	('viability', 'CPA', (34, 43))	('CAP', 'Chemical', '-', (76, 79))	('HGF-1', 'Gene', (0, 5))	('HGF-1', 'CellLine', 'CVCL:3710', (0, 5))	('cisplatin', 'Var', (62, 71))
214071	33076565	For example, the electroporation significantly improves anticancer activity of cisplatin against metastatic pancreatic cancer.	('cisplatin', 'Chemical', 'MESH:D002945', (79, 88))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('improves', 'PosReg', (47, 55))	('pancreatic cancer', 'Disease', (108, 125))	('cancer', 'Disease', (60, 66))	('cancer', 'Disease', (119, 125))	('pancreatic cancer', 'Disease', 'MESH:D010190', (108, 125))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('electroporation', 'Var', (17, 32))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (108, 125))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
214087	33076565	This result indicated that the specific peaks of Ar+, OH and O- ions were observed in the UV range (200 nm-400 nm) and visible range (690 nm-950 nm).	('690 nm-950', 'Var', (134, 144))	('Ar+', 'Var', (49, 52))	('Ar+', 'Chemical', 'MESH:D001128', (49, 52))
214095	33076565	That is, the viability of SCC-15 cells was lower than 50% at 3 muM cisplatin, while HGF-1 cells showed higher than 90% in cell viability at the same concentration.	('cisplatin', 'Var', (67, 76))	('cisplatin', 'Chemical', 'MESH:D002945', (67, 76))	('SCC-15', 'CellLine', 'CVCL:1681', (26, 32))	('HGF-1', 'CellLine', 'CVCL:3710', (84, 89))	('lower', 'NegReg', (43, 48))
214114	33076565	Otherwise, SCC-15 cells showed greater changes in the morphology and the cell density by treatment of cisplatin and/or CAP.	('cisplatin', 'Var', (102, 111))	('changes', 'Reg', (39, 46))	('SCC-15', 'CellLine', 'CVCL:1681', (11, 17))	('cell density', 'CPA', (73, 85))	('morphology', 'CPA', (54, 64))	('CAP', 'Chemical', '-', (119, 122))	('cisplatin', 'Chemical', 'MESH:D002945', (102, 111))
214115	33076565	At 3 muM cisplatin plus 3 min of CAP treatment, the cell density and the morphology of SCC-15 cells were significantly decreased and changed, as shown in Figure 5B.	('cisplatin', 'Var', (9, 18))	('decreased', 'NegReg', (119, 128))	('cell density', 'CPA', (52, 64))	('cisplatin', 'Chemical', 'MESH:D002945', (9, 18))	('CAP', 'Chemical', '-', (33, 36))	('SCC-15', 'CellLine', 'CVCL:1681', (87, 93))	('morphology of SCC-15 cells', 'CPA', (73, 99))	('changed', 'Reg', (133, 140))
214126	33076565	Interestingly, ROS production of HGF-1 cells was not significantly changed between 1 muM and 3 muM cisplatin, while the ROS level was significantly changed in SCC-15 cells, as shown in Figure 7C,D.	('ROS level', 'MPA', (120, 129))	('HGF-1', 'CellLine', 'CVCL:3710', (33, 38))	('ROS', 'Chemical', 'MESH:D017382', (120, 123))	('cisplatin', 'Var', (99, 108))	('changed', 'Reg', (148, 155))	('SCC-15', 'CellLine', 'CVCL:1681', (159, 165))	('ROS', 'Chemical', 'MESH:D017382', (15, 18))	('cisplatin', 'Chemical', 'MESH:D002945', (99, 108))
214127	33076565	Notably, 1 muM cisplatin plus 1 min CAP or 3 muM cisplatin plus 1 min CAP resulted in higher than 300% or 500% increases in ROS levels in SCC-15 cells, respectively, while ROS generation in HGF-1 cells in same treatment option was controlled under 150% and 170%, respectively.	('cisplatin', 'Var', (15, 24))	('ROS', 'Chemical', 'MESH:D017382', (172, 175))	('CAP', 'Chemical', '-', (70, 73))	('increases', 'PosReg', (111, 120))	('cisplatin', 'Chemical', 'MESH:D002945', (49, 58))	('CAP', 'Chemical', '-', (36, 39))	('ROS levels', 'MPA', (124, 134))	('SCC-15', 'CellLine', 'CVCL:1681', (138, 144))	('cisplatin', 'Chemical', 'MESH:D002945', (15, 24))	('ROS', 'Chemical', 'MESH:D017382', (124, 127))	('HGF-1', 'CellLine', 'CVCL:3710', (190, 195))
214148	33076565	They observed that PAM selectively induces apoptotic death of cancer cells but not in normal cells.	('death', 'Disease', 'MESH:D003643', (53, 58))	('death', 'Disease', (53, 58))	('PAM', 'Chemical', '-', (19, 22))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('PAM', 'Var', (19, 22))	('induces', 'Reg', (35, 42))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))
214201	33076565	Viability of SCC-15 cells was inhibited by cisplatin with a dose-dependent manner and/or CAP treatment time.	('SCC-15', 'CellLine', 'CVCL:1681', (13, 19))	('Viability', 'CPA', (0, 9))	('cisplatin', 'Var', (43, 52))	('inhibited', 'NegReg', (30, 39))	('CAP', 'Chemical', '-', (89, 92))	('cisplatin', 'Chemical', 'MESH:D002945', (43, 52))
214204	30452490	Hyper-phosphorylation of Rb S249 together with CDK5R2/p39 overexpression are associated with impaired cell adhesion and epithelial-to-mesenchymal transition: Implications as a potential lung cancer grading and staging biomarker Prediction of lung cancer metastasis relies on post-resection assessment of tumor histology, which is a severe limitation since only a minority of lung cancer patients are diagnosed with resectable disease.	('lung cancer', 'Disease', 'MESH:D008175', (375, 386))	('lung cancer', 'Disease', 'MESH:D008175', (186, 197))	('Hyper-phosphorylation', 'Var', (0, 21))	('patients', 'Species', '9606', (387, 395))	('lung cancer', 'Phenotype', 'HP:0100526', (375, 386))	('tumor', 'Disease', (304, 309))	('cell adhesion', 'CPA', (102, 115))	('lung cancer', 'Phenotype', 'HP:0100526', (186, 197))	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('Rb S249', 'Gene', (25, 32))	('tumor', 'Disease', 'MESH:D009369', (304, 309))	('CDK5R2', 'Gene', '8941', (47, 53))	('overexpression', 'PosReg', (58, 72))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('lung cancer', 'Disease', (242, 253))	('CDK5R2', 'Gene', (47, 53))	('cancer', 'Phenotype', 'HP:0002664', (380, 386))	('tumor', 'Phenotype', 'HP:0002664', (304, 309))	('lung cancer', 'Disease', (375, 386))	('impaired cell adhesion', 'Phenotype', 'HP:0008352', (93, 115))	('lung cancer', 'Disease', (186, 197))	('epithelial-to-mesenchymal transition', 'CPA', (120, 156))	('lung cancer', 'Disease', 'MESH:D008175', (242, 253))	('p39', 'Gene', '8941', (54, 57))	('p39', 'Gene', (54, 57))	('lung cancer', 'Phenotype', 'HP:0100526', (242, 253))
214209	30452490	Linear regression analyses showed that the combined scoring for phospho-Rb S249, p39 and E-cadherin in SCC is even more accurate at predicting tumor staging, relative to each score individually.	('tumor', 'Disease', (143, 148))	('predicting', 'Reg', (132, 142))	('SCC', 'Gene', (103, 106))	('E-cadherin', 'Gene', (89, 99))	('E-cadherin', 'Gene', '999', (89, 99))	('p39', 'Gene', '8941', (81, 84))	('SCC', 'Gene', '6317', (103, 106))	('p39', 'Gene', (81, 84))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('phospho-Rb', 'Var', (64, 74))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
214212	30452490	The retinoblastoma protein (Rb) is one of the most important tumor suppressors, as illustrated by the fact that either Rb itself or some of its pathway components is the target of oncogenic driver mutations in most, if not all, human cancers.	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('retinoblastoma', 'Gene', (4, 18))	('retinoblastoma', 'Gene', '5925', (4, 18))	('mutations', 'Var', (197, 206))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('retinoblastoma', 'Phenotype', 'HP:0009919', (4, 18))	('cancers', 'Phenotype', 'HP:0002664', (234, 241))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('cancers', 'Disease', (234, 241))	('human', 'Species', '9606', (228, 233))	('cancers', 'Disease', 'MESH:D009369', (234, 241))	('tumor', 'Disease', (61, 66))
214213	30452490	We showed that Rb deletion abrogates cellular adhesion by preventing the formation of adherens junctions and by affecting the transcriptional profile of several cadherins and integrins.	('transcriptional profile of several', 'MPA', (126, 160))	('affecting', 'Reg', (112, 121))	('formation', 'MPA', (73, 82))	('cadherin', 'Gene', '999;1000', (161, 169))	('cadherin', 'Gene', (161, 169))	('cellular adhesion', 'CPA', (37, 54))	('deletion', 'Var', (18, 26))	('preventing', 'NegReg', (58, 68))	('abrogates', 'NegReg', (27, 36))
214216	30452490	We found that in H520 cells Rb is hyper-phosphorylated on residues serine 249 (S249) and threonine 821 (T821) relative to H1666 cells.	('hyper-phosphorylated', 'PosReg', (34, 54))	('H1666', 'CellLine', 'CVCL:1485', (122, 127))	('S249', 'Var', (79, 83))	('H520', 'CellLine', 'CVCL:1566', (17, 21))	('threonine', 'Chemical', 'MESH:D013912', (89, 98))	('serine', 'Chemical', 'MESH:D012694', (67, 73))
214217	30452490	In H520 cells Rb hyper-phosphorylation in S249 and T821 coexists with lack of adherens junctions, low E-cadherin levels, increased N-cadherin and vimentin levels, diminished integrin alpha5 expression, activation of Focal Adhesion Kinase (FAK), diminished cell-to-cell contacts, and p39 overexpression.	('vimentin', 'Gene', '7431', (146, 154))	('vimentin', 'Gene', (146, 154))	('low', 'NegReg', (98, 101))	('p39', 'Gene', '8941', (283, 286))	('E-cadherin', 'Gene', (102, 112))	('N-cadherin', 'Gene', (131, 141))	('E-cadherin', 'Gene', '999', (102, 112))	('integrin alpha5', 'Gene', '3678', (174, 189))	('activation', 'PosReg', (202, 212))	('N-cadherin', 'Gene', '1000', (131, 141))	('p39', 'Gene', (283, 286))	('S249', 'Var', (42, 46))	('H520', 'CellLine', 'CVCL:1566', (3, 7))	('hyper-phosphorylation', 'PosReg', (17, 38))	('diminished', 'NegReg', (163, 173))	('expression', 'MPA', (190, 200))	('diminished', 'NegReg', (245, 255))	('Focal Adhesion Kinase', 'Gene', '5747', (216, 237))	('cell-to-cell contacts', 'CPA', (256, 277))	('overexpression', 'PosReg', (287, 301))	('increased', 'PosReg', (121, 130))	('FAK', 'Gene', (239, 242))	('Focal Adhesion Kinase', 'Gene', (216, 237))	('integrin alpha5', 'Gene', (174, 189))	('FAK', 'Gene', '5747', (239, 242))	('lack', 'NegReg', (70, 74))	('T821', 'Var', (51, 55))	('adherens junctions', 'MPA', (78, 96))
214218	30452490	We thus hypothesized that Rb hyper-phosphorylation in S249 and T821 together with p39 over-expression could serve as a clinically informative biomarker for tumor stage, grade, and metastatic potential in pre-resection small NSCLC biopsy samples.	('p39', 'Gene', (82, 85))	('T821', 'Var', (63, 67))	('p39', 'Gene', '8941', (82, 85))	('over-expression', 'PosReg', (86, 101))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('metastatic potential', 'CPA', (180, 200))	('S249', 'Var', (54, 58))	('NSCLC', 'Disease', (224, 229))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('NSCLC', 'Disease', 'MESH:D002289', (224, 229))	('tumor', 'Disease', (156, 161))	('hyper-phosphorylation', 'PosReg', (29, 50))
214222	30452490	Linear regression analyses showed that the combined score for phospho-Rb S249 and p39 is even more clinically informative than either score alone, predicting tumor stage with good precision.	('p39', 'Gene', (82, 85))	('tumor', 'Disease', (158, 163))	('phospho-Rb S249', 'Var', (62, 77))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('p39', 'Gene', '8941', (82, 85))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('predicting', 'Reg', (147, 157))
214227	30452490	Cell lines tested negative for mycoplasma contamination and were authenticated by short tandem repeat (STR) analysis of loci TH01, TPOX, vWA, CSF1PO, D16S539, D7S820, D13S317 and D5S818.	('TH01', 'Gene', (125, 129))	('mycoplasma', 'Disease', (31, 41))	('mycoplasma', 'Disease', 'MESH:D009175', (31, 41))	('D16S539', 'Var', (150, 157))	('D13S317', 'Var', (167, 174))	('CSF1PO', 'Gene', (142, 148))	('D5S818', 'Var', (179, 185))	('D7S820', 'Var', (159, 165))	('TPOX', 'Gene', (131, 135))
214248	30452490	4705s, Cell Signaling, Danvers, MA); p35, C64B10 mouse monoclonal, 1:1000 (Cat No.	('mouse', 'Species', '10090', (49, 54))	('p35', 'Gene', (37, 40))	('p35', 'Gene', '8851', (37, 40))	('C64B10', 'Var', (42, 48))
214252	30452490	2148s, Cell Signaling, Danvers, MA); phospho-FAK (Y397), D20B1 Rabbit polyclonal, 1:1000 (Cat.	('FAK', 'Gene', (45, 48))	('D20B1', 'Var', (57, 62))	('FAK', 'Gene', '5747', (45, 48))	('Rabbit', 'Species', '9986', (63, 69))
214265	30452490	Briefly, 50 ng of cDNA were subjected to 50 amplification cycles, following the instructions provided by the different gene-specific Applied Biosystems (Foster City, CA) Taqman assays as follows: N-cadherin (Mm00483213_m1), E-cadherin (Hs00170423_m1); and Vimentin (Hs00958111_m1).	('Vimentin', 'Gene', '7431', (256, 264))	('Hs00958111_m1', 'Var', (266, 279))	('Mm00483213_m1', 'Var', (208, 221))	('N-cadherin', 'Gene', (196, 206))	('N-cadherin', 'Gene', '1000', (196, 206))	('Vimentin', 'Gene', (256, 264))	('Hs00170423_m1', 'Var', (236, 249))	('E-cadherin', 'Gene', (224, 234))	('E-cadherin', 'Gene', '999', (224, 234))
214278	30452490	Lung cancer tumor microarrays (TMAs) with formalin fixed, paraffin embedded tissues mounted on positively charged SuperFrost Plus glass slides were obtained from US Biomax, with catalog numbers LC241c, LC488, and T041 (US Biomax, Derwood, MD).	('LC488', 'Var', (202, 207))	('cancer tumor', 'Disease', 'MESH:D009369', (5, 17))	('paraffin', 'Chemical', 'MESH:D010232', (58, 66))	('LC241c', 'Var', (194, 200))	('Lung cancer', 'Phenotype', 'HP:0100526', (0, 11))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('TMAs', 'Chemical', '-', (31, 35))	('formalin', 'Chemical', 'MESH:D005557', (42, 50))	('cancer tumor', 'Disease', (5, 17))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))
214286	30452490	The positivity (number of positive pixels over total number of pixels) of each sample was obtained for statistical analysis for phospho-Rb S249 and phospho-Rb T821, E-cadherin, and for p39 expression.	('p39', 'Gene', (185, 188))	('phospho-Rb T821', 'Var', (148, 163))	('phospho-Rb S249', 'Var', (128, 143))	('expression', 'MPA', (189, 199))	('E-cadherin', 'Gene', (165, 175))	('p39', 'Gene', '8941', (185, 188))	('E-cadherin', 'Gene', '999', (165, 175))
214287	30452490	A linear regression model with Minitab Statistical Software version 17 was conducted to assess the possible association between lung squamous cell lung cancer staging and the positivity scores for phospho-Rb S249 and phospho-Rb T821, E-cadherin, and for p39 expression.	('p39', 'Gene', '8941', (254, 257))	('expression', 'MPA', (258, 268))	('lung squamous cell lung cancer', 'Disease', 'MESH:D008175', (128, 158))	('p39', 'Gene', (254, 257))	('lung squamous cell lung cancer', 'Disease', (128, 158))	('lung cancer', 'Phenotype', 'HP:0100526', (147, 158))	('phospho-Rb S249', 'Var', (197, 212))	('E-cadherin', 'Gene', (234, 244))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('E-cadherin', 'Gene', '999', (234, 244))	('phospho-Rb T821', 'Var', (217, 232))
214293	30452490	As can be seen in Fig 1A, H1666 and H1650 cells show a strong and membrane-associated E-cadherin staining, labeling being more intense in H1666 cells.	('H1650', 'CellLine', 'CVCL:1483', (36, 41))	('H1666', 'CellLine', 'CVCL:1485', (26, 31))	('H1666', 'CellLine', 'CVCL:1485', (138, 143))	('H1666', 'Var', (138, 143))	('E-cadherin', 'Gene', (86, 96))	('E-cadherin', 'Gene', '999', (86, 96))
214298	30452490	Conversely, N-cadherin levels are increased in H520 cells relative to H1666 cells (Fig 1B and 1C), indicative of the cadherin switch known to occur during EMT.	('N-cadherin', 'Gene', '1000', (12, 22))	('EMT', 'Gene', (155, 158))	('cadherin', 'Gene', '999;1000', (14, 22))	('EMT', 'Gene', '3702', (155, 158))	('N-cadherin', 'Gene', (12, 22))	('H520', 'Var', (47, 51))	('H520', 'CellLine', 'CVCL:1566', (47, 51))	('H1666', 'CellLine', 'CVCL:1485', (70, 75))	('increased', 'PosReg', (34, 43))	('cadherin', 'Gene', '999;1000', (117, 125))	('cadherin', 'Gene', (117, 125))	('cadherin', 'Gene', (14, 22))
214299	30452490	Increased vimentin expression, another EMT trait, is also observed in H520 cells relative to H1666 (Fig 1B and 1C).	('expression', 'MPA', (19, 29))	('vimentin', 'Gene', (10, 18))	('H520', 'CellLine', 'CVCL:1566', (70, 74))	('Increased', 'PosReg', (0, 9))	('H1666', 'CellLine', 'CVCL:1485', (93, 98))	('vimentin', 'Gene', '7431', (10, 18))	('EMT', 'Gene', (39, 42))	('EMT', 'Gene', '3702', (39, 42))	('H520', 'Var', (70, 74))
214300	30452490	Expression of integrin alpha5, a subunit of the fibronectin receptor, is diminished in H520 cells relative to H1666 cells, while the opposite is observed for phosphorylated focal adhesion kinase (FAK), a cytosolic protein tyrosine kinase that connects integrins with the actin cortical skeleton, and whose activation triggers cell motility and invasion (Fig 1B).	('focal adhesion kinase', 'Gene', (173, 194))	('activation', 'PosReg', (306, 316))	('H520', 'CellLine', 'CVCL:1566', (87, 91))	('diminished', 'NegReg', (73, 83))	('integrin alpha5', 'Gene', '3678', (14, 29))	('H520', 'Var', (87, 91))	('Expression', 'MPA', (0, 10))	('FAK', 'Gene', '5747', (196, 199))	('cell motility', 'CPA', (326, 339))	('focal adhesion kinase', 'Gene', '5747', (173, 194))	('FAK', 'Gene', (196, 199))	('invasion', 'CPA', (344, 352))	('H1666', 'CellLine', 'CVCL:1485', (110, 115))	('integrin alpha5', 'Gene', (14, 29))	('triggers', 'Reg', (317, 325))
214302	30452490	Taken together, our data show the manifestation of EMT markers in H520 cells relative to H1666 cells.	('H520', 'CellLine', 'CVCL:1566', (66, 70))	('EMT', 'Gene', (51, 54))	('H1666', 'CellLine', 'CVCL:1485', (89, 94))	('EMT', 'Gene', '3702', (51, 54))	('H520', 'Var', (66, 70))
214303	30452490	Given that H520 cells have decreased E-cadherin expression, lack adherens junction structures and express EMT markers, we wanted to investigate if these cells have diminished cell-to-cell adhesion.	('EMT', 'Gene', (106, 109))	('H520', 'Var', (11, 15))	('E-cadherin', 'Gene', (37, 47))	('EMT', 'Gene', '3702', (106, 109))	('H520', 'CellLine', 'CVCL:1566', (11, 15))	('decreased', 'NegReg', (27, 36))	('E-cadherin', 'Gene', '999', (37, 47))	('expression', 'MPA', (48, 58))	('cell-to-cell adhesion', 'CPA', (175, 196))	('lack', 'NegReg', (60, 64))	('adherens', 'CPA', (65, 73))
214305	30452490	Spheroids continue to grow in size in H1666 cells at 24 and 48 hours, while spheroid size in H520 cells remain comparatively small even at 48 hours.	('H520', 'CellLine', 'CVCL:1566', (93, 97))	('H1666', 'Var', (38, 43))	('H1666', 'CellLine', 'CVCL:1485', (38, 43))	('grow', 'PosReg', (22, 26))
214310	30452490	Statistically significant differences between H1666 and H520 cells become apparent at 4 hours in culture, when H1666 cells form more than thrice as many spheroids/10X field than H520 cells, an increase that is abrogated by trypsin-EDTA.	('spheroids/10X', 'CPA', (153, 166))	('H520', 'CellLine', 'CVCL:1566', (56, 60))	('EDTA', 'Chemical', 'MESH:D004492', (231, 235))	('H1666', 'CellLine', 'CVCL:1485', (46, 51))	('H1666', 'Var', (111, 116))	('H1666', 'CellLine', 'CVCL:1485', (111, 116))	('H520', 'CellLine', 'CVCL:1566', (178, 182))
214311	30452490	When evaluating the spheroid size in H1666 and H520 cells, no differences in size between H1666 and H520 cells were apparent at 2 hours, differences becoming noticeable at 4 hours, when H1666 cell spheroids were significantly larger than those formed by H520 cells, with spheroid size being reduced by trypsin-EDTA treatment (Fig 2D).	('H1666', 'Var', (186, 191))	('H520', 'CellLine', 'CVCL:1566', (254, 258))	('EDTA', 'Chemical', 'MESH:D004492', (310, 314))	('H520', 'CellLine', 'CVCL:1566', (47, 51))	('H520', 'CellLine', 'CVCL:1566', (100, 104))	('larger', 'PosReg', (226, 232))	('H1666', 'CellLine', 'CVCL:1485', (90, 95))	('H1666', 'CellLine', 'CVCL:1485', (186, 191))	('H1666', 'CellLine', 'CVCL:1485', (37, 42))
214320	30452490	Our triplicate analysis showed that the Rb residues S249, S612, S807, and T821 were hyper-phosphorylated in H520 cells relative to H1666 cells.	('H520', 'CellLine', 'CVCL:1566', (108, 112))	('T821', 'Var', (74, 78))	('S807', 'Var', (64, 68))	('S612', 'Var', (58, 62))	('hyper-phosphorylated', 'PosReg', (84, 104))	('H520', 'Var', (108, 112))	('H1666', 'CellLine', 'CVCL:1485', (131, 136))
214321	30452490	Fig 3A shows a representative immunoblot (from triplicates) conducted in a panel of lung cancer cell lines, performed using antibodies that recognize total Rb, anti-Rb-phospho-S249, anti-Rb-phospho-S612, anti-Rb-phospho-S807, and anti-Rb-phospho-T821, using alpha/beta tubulin as a loading control.	('lung cancer', 'Disease', (84, 95))	('lung cancer', 'Phenotype', 'HP:0100526', (84, 95))	('anti-Rb-phospho-S612', 'Var', (182, 202))	('anti-Rb-phospho-T821', 'Var', (230, 250))	('anti-Rb-phospho-S249', 'Var', (160, 180))	('anti-Rb-phospho-S807', 'Var', (204, 224))	('lung cancer', 'Disease', 'MESH:D008175', (84, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
214322	30452490	As can be seen, H520 cells (sixth lane) show slightly elevated levels of total Rb relative to H1666 cells (first lane), as well as increased phosphorylation in Rb residues S249, S612, S807 and T821.	('levels', 'MPA', (63, 69))	('S807', 'Var', (184, 188))	('increased', 'PosReg', (131, 140))	('T821', 'Var', (193, 197))	('elevated', 'PosReg', (54, 62))	('H520', 'CellLine', 'CVCL:1566', (16, 20))	('phosphorylation', 'MPA', (141, 156))	('S612', 'Var', (178, 182))	('S249', 'Var', (172, 176))	('H1666', 'CellLine', 'CVCL:1485', (94, 99))
214323	30452490	The graphs in Fig 3B show that only residues S249 and T821 are hyper-phosphorylated in H520 cells relative to H1666 cells in a statistically significant manner, with p-values of 0.004 and 0.002, respectively.	('H520', 'CellLine', 'CVCL:1566', (87, 91))	('H1666', 'CellLine', 'CVCL:1485', (110, 115))	('hyper-phosphorylated', 'PosReg', (63, 83))	('T821', 'Var', (54, 58))
214324	30452490	We also immunoblotted for the phosphorylation of other Rb residues not shown by our LC-MS/MS analysis to be differentially phosphorylated between H1666 and H520 cells, such as S608, S780, and S795.	('S795', 'Var', (192, 196))	('H520', 'CellLine', 'CVCL:1566', (156, 160))	('S608', 'Var', (176, 180))	('S780', 'Var', (182, 186))	('H1666', 'CellLine', 'CVCL:1485', (146, 151))
214327	30452490	In summary, H520 cells, which show decreased adhesive properties and EMT traits, appear to have increased phosphorylation on Rb residues S249 and T821, relative to H1666 cells.	('increased', 'PosReg', (96, 105))	('H520', 'Var', (12, 16))	('adhesive properties', 'CPA', (45, 64))	('T821', 'Var', (146, 150))	('phosphorylation', 'MPA', (106, 121))	('EMT', 'Gene', (69, 72))	('EMT', 'Gene', '3702', (69, 72))	('H520', 'CellLine', 'CVCL:1566', (12, 16))	('decreased', 'NegReg', (35, 44))	('H1666', 'CellLine', 'CVCL:1485', (164, 169))	('residues S249', 'Var', (128, 141))
214328	30452490	We next attempted to identify a kinase that could phosphorylate Rb on S249 and T821, focusing on cyclin-dependent kinase 5 (Cdk5) as a potential candidate.	('T821', 'Var', (79, 83))	('cyclin-dependent kinase 5', 'Gene', '1020', (97, 122))	('Cdk5', 'Gene', (124, 128))	('Cdk5', 'Gene', '1020', (124, 128))	('S249', 'Var', (70, 74))	('cyclin-dependent kinase 5', 'Gene', (97, 122))
214331	30452490	However, we did observe a dramatic increase in p39 in H520 cells relative to H1666 cells (Fig 4A and 4B).	('increase', 'PosReg', (35, 43))	('p39', 'Gene', (47, 50))	('H520', 'Var', (54, 58))	('H1666', 'CellLine', 'CVCL:1485', (77, 82))	('H520', 'CellLine', 'CVCL:1566', (54, 58))	('p39', 'Gene', '8941', (47, 50))
214338	30452490	We next assessed the clinical value of Rb S249 and T821 phosphorylation and of p39 expression by immunohistochemical (IHC) staining of lung cancer tumor microarrays (TMAs) followed by establishing correlations with the clinical data accompanying each tumor core.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('p39', 'Gene', '8941', (79, 82))	('tumor', 'Disease', (251, 256))	('tumor', 'Phenotype', 'HP:0002664', (251, 256))	('p39', 'Gene', (79, 82))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('TMAs', 'Chemical', '-', (166, 170))	('expression', 'MPA', (83, 93))	('phosphorylation', 'MPA', (56, 71))	('tumor', 'Disease', 'MESH:D009369', (251, 256))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('T821', 'Var', (51, 55))	('lung cancer tumor', 'Disease', 'MESH:D008175', (135, 152))	('lung cancer tumor', 'Disease', (135, 152))	('lung cancer', 'Phenotype', 'HP:0100526', (135, 146))
214339	30452490	We obtained three commercial lung cancer TMAs (TMA1 LC241C, TMA2 LC488, and TMA3 T041 from US Biomax, Inc.), and independently IHC-stained them with antibodies against phospho-Rb-S249, phospho-Rb-T821 and p39.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('commercial lung cancer TMAs', 'Disease', 'MESH:D008175', (18, 45))	('TMA', 'Chemical', '-', (60, 63))	('p39', 'Gene', '8941', (205, 208))	('TMA', 'Chemical', '-', (47, 50))	('TMA1', 'Chemical', '-', (47, 51))	('TMA', 'Chemical', '-', (41, 44))	('p39', 'Gene', (205, 208))	('phospho-Rb-S249', 'Var', (168, 183))	('TMA', 'Chemical', '-', (76, 79))	('commercial lung cancer TMAs', 'Disease', (18, 45))	('lung cancer', 'Phenotype', 'HP:0100526', (29, 40))
214341	30452490	Each core in the TMAs had accompanying clinical data, such as tumor stage, grade, size, and spread to lymph nodes or distant metastases, which we correlated with Rb S249 and T821 phosphorylation and with p39 expression.	('metastases', 'Disease', (125, 135))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('TMAs', 'Chemical', '-', (17, 21))	('phosphorylation', 'MPA', (179, 194))	('tumor', 'Disease', (62, 67))	('metastases', 'Disease', 'MESH:D009362', (125, 135))	('p39', 'Gene', '8941', (204, 207))	('expression', 'MPA', (208, 218))	('p39', 'Gene', (204, 207))	('T821', 'Var', (174, 178))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
214346	30452490	SCLC lack Rb (over 90%) due to the mutational inactivation of the RB1 locus, therefore they are suitable internal negative controls included in the TMAs.	('SCLC', 'Gene', '7864', (0, 4))	('mutational', 'Var', (35, 45))	('RB1', 'Gene', '5925', (66, 69))	('TMAs', 'Chemical', '-', (148, 152))	('SCLC', 'Gene', (0, 4))	('RB1', 'Gene', (66, 69))
214347	30452490	The raw scoring data for all cores stained for phospho-Rb S249, phospho-Rb T821 and p39 in each TMA is shown in S2, S3 and S4 Tables.	('phospho-Rb T821', 'Var', (64, 79))	('phospho-Rb S249', 'Var', (47, 62))	('p39', 'Gene', '8941', (84, 87))	('TMA', 'Chemical', '-', (96, 99))	('p39', 'Gene', (84, 87))
214349	30452490	As can be seen in Table 4, average staining scores for phospho-Rb-S249 and phospho-Rb-T821 did not significantly differ between cancer tissues relative to non-cancerous controls, even when breaking the scoring down into lung cancer sub-types.	('cancer', 'Disease', (159, 165))	('non-cancer', 'Disease', (155, 165))	('lung cancer', 'Disease', 'MESH:D008175', (220, 231))	('phospho-Rb-T821', 'Var', (75, 90))	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('cancer', 'Disease', 'MESH:D009369', (225, 231))	('cancer', 'Disease', (225, 231))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('lung cancer', 'Disease', (220, 231))	('lung cancer', 'Phenotype', 'HP:0100526', (220, 231))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('non-cancer', 'Disease', 'MESH:D009369', (155, 165))	('phospho-Rb-S249', 'Var', (55, 70))	('cancer', 'Disease', (128, 134))
214351	30452490	We next performed correlation analyses to determine if phospho-Rb-S249, phospho-Rb-T821, and p39 staining scores correlate with tumor grade, stage, size, lymph node invasion and metastases.	('metastases', 'Disease', 'MESH:D009362', (178, 188))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('p39', 'Gene', '8941', (93, 96))	('lymph node invasion', 'CPA', (154, 173))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('p39', 'Gene', (93, 96))	('metastases', 'Disease', (178, 188))	('phospho-Rb-T821', 'Var', (72, 87))	('tumor', 'Disease', (128, 133))	('phospho-Rb-S249', 'Var', (55, 70))
214357	30452490	Fig 6A shows strong nuclear staining for Rb S249 phosphorylation in high tumor grade cores LC241c-B2, LC241c-B5, LC241c-C1 and LC241c-C2, all of which are SCC with a tumor grading of 3 and a Rb phospho-S249 staining score of 3.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('high tumor', 'Disease', 'MESH:D009369', (68, 78))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('SCC', 'Gene', (155, 158))	('LC241c-B5', 'Var', (102, 111))	('LC241c-C1', 'Var', (113, 122))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Disease', (166, 171))	('LC241c-B2', 'Var', (91, 100))	('tumor', 'Disease', (73, 78))	('SCC', 'Gene', '6317', (155, 158))	('high tumor', 'Disease', (68, 78))	('LC241c-C2', 'Var', (127, 136))
214358	30452490	In contrast, Fig 6B shows grade 1 SCC cores LC488-D2 and LC488-E2 that have a Rb phospho-S249 staining score of 0.	('LC488-E2', 'Var', (57, 65))	('LC488-D2', 'Var', (44, 52))	('SCC', 'Gene', (34, 37))	('SCC', 'Gene', '6317', (34, 37))
214367	30452490	The top of Fig 10 shows the ROC curves for phospho-Rb S249 and p39 scores, and the table below shows the associated numerical values for the area under the curve, confidence interval, p-value, sensitivity, and specificity.	('phospho-Rb S249', 'Var', (43, 58))	('p39', 'Gene', '8941', (63, 66))	('p39', 'Gene', (63, 66))
214368	30452490	As can be seen in this table, phospho-Rb S249 score had an area under the curve of 0.7396, while p39 score had an area of 0.9375, both being close to 1.0 and thus indicating a strong predictive value for grading and staging and metastasis, respectively.	('phospho-Rb S249 score', 'Var', (30, 51))	('p39', 'Gene', '8941', (97, 100))	('p39', 'Gene', (97, 100))
214369	30452490	Phospho-Rb S249 and p39 scores had a sensitivity of 75% and 87.5%, respectively, meaning that 75% of the tumor samples with high phospho-Rb S249 score also had high grading, and 87.5% of the tumor samples with high p39 score had high staging and lymph node involvement and distant metastasis.	('phospho-Rb S249 score', 'Var', (129, 150))	('p39', 'Gene', (20, 23))	('p39', 'Gene', '8941', (20, 23))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('lymph node involvement', 'CPA', (246, 268))	('distant metastasis', 'CPA', (273, 291))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('p39', 'Gene', '8941', (215, 218))	('high grading', 'CPA', (160, 172))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('tumor', 'Disease', (191, 196))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('high staging', 'CPA', (229, 241))	('p39', 'Gene', (215, 218))	('tumor', 'Disease', (105, 110))
214371	30452490	Finally, we wanted to determine if the biomarkers of phospho-Rb S249 and phospho-Rb T821, E-cadherin, and p39 expression have a stronger predictive performance when considered together.	('p39', 'Gene', (106, 109))	('phospho-Rb T821', 'Var', (73, 88))	('phospho-Rb S249', 'Var', (53, 68))	('p39', 'Gene', '8941', (106, 109))	('E-cadherin', 'Gene', (90, 100))	('E-cadherin', 'Gene', '999', (90, 100))
214374	30452490	Consistent with our previous analyses, Rb phosphorylation in T821was not associated with SCC staging.	('SCC', 'Gene', '6317', (89, 92))	('T821was', 'Var', (61, 68))	('SCC', 'Gene', (89, 92))	('associated', 'Reg', (73, 83))
214375	30452490	Based on this, our regression model is represented by the following equation: Stage = 7.79-0.0669 X% score for Rb S249 positive cells:0.1432 X% score for p39 positive cells:0.1509 X% score for E-cadherin positive cells.	('E-cadherin', 'Gene', (193, 203))	('cells:0.1432', 'Var', (128, 140))	('E-cadherin', 'Gene', '999', (193, 203))	('Rb S249', 'Gene', (111, 118))	('p39', 'Gene', '8941', (154, 157))	('p39', 'Gene', (154, 157))
214383	30452490	However, as shown in Table 8, the combination of phospho-Rb S249 and p39 scores was able to accurately match the staging clinical data provided by the vendor in 4 out of 7 instances, and in the two patients in which the staging did not match, the difference between stages was only of 1-2.	('p39', 'Gene', '8941', (69, 72))	('patients', 'Species', '9606', (198, 206))	('phospho-Rb S249', 'Var', (49, 64))	('p39', 'Gene', (69, 72))
214385	30452490	In summary, our data show a correlation between phospho-Rb S249 scoring and tumor grading, and between p39 scoring and tumor staging and metastases to lymph nodes and to distant sites.	('tumor', 'Disease', (119, 124))	('metastases to lymph nodes', 'Disease', 'MESH:D009362', (137, 162))	('p39', 'Gene', '8941', (103, 106))	('phospho-Rb S249', 'Var', (48, 63))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('p39', 'Gene', (103, 106))	('metastases to lymph nodes', 'Disease', (137, 162))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('correlation', 'Reg', (28, 39))
214391	30452490	Oncogenic Rb hyper-phosphorylation is common in NSCLC, and being a strong driver of oncogenesis, this event may be a constant in a large fraction of tumor cells not subject to tumor heterogeneity.	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('NSCLC', 'Disease', (48, 53))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('NSCLC', 'Disease', 'MESH:D002289', (48, 53))	('tumor', 'Disease', (176, 181))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('tumor', 'Disease', (149, 154))	('hyper-phosphorylation', 'Var', (13, 34))	('tumor', 'Disease', 'MESH:D009369', (176, 181))
214397	30452490	Rb phosphorylation by Cdk5 has been documented and Rb S249 and T821 residues are Cdk5 targets.	('Cdk5', 'Gene', (22, 26))	('Cdk5', 'Gene', '1020', (22, 26))	('S249', 'Var', (54, 58))	('Cdk5', 'Gene', '1020', (81, 85))	('Cdk5', 'Gene', (81, 85))
214403	30452490	Therefore, there is the need to further sub-classify NSCLC into SCC, AC and LCC, and thus we postulate that Rb phosphorylation on S249, by being prominent in high-grade tumors exclusively of the SCC sub-type, could help to distinguish poorly differentiated SCC from other histological subtypes.	('SCC', 'Gene', (195, 198))	('help', 'Reg', (215, 219))	('SCC', 'Gene', '6317', (64, 67))	('SCC', 'Gene', '6317', (257, 260))	('S249', 'Var', (130, 134))	('tumors', 'Disease', 'MESH:D009369', (169, 175))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('SCC', 'Gene', '6317', (195, 198))	('tumors', 'Phenotype', 'HP:0002664', (169, 175))	('NSCLC', 'Disease', (53, 58))	('tumors', 'Disease', (169, 175))	('NSCLC', 'Disease', 'MESH:D002289', (53, 58))	('SCC', 'Gene', (64, 67))	('SCC', 'Gene', (257, 260))
214414	30452490	NSCLC-NOS diagnostic rates increase when evaluating poorly differentiated tumors, and poor tumor differentiation has been identified as a predominant factor driving the increase in NSCLC-NOS diagnoses.	('NSCLC-NOS', 'Disease', (181, 190))	('NSCLC-NOS', 'Disease', 'MESH:D002289', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Disease', (91, 96))	('NSCLC-NOS', 'Disease', 'MESH:D002289', (181, 190))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor', 'Disease', (74, 79))	('poorly differentiated', 'Var', (52, 73))	('tumors', 'Disease', 'MESH:D009369', (74, 80))	('NSCLC-NOS', 'Disease', (0, 9))	('increase', 'PosReg', (27, 35))	('tumors', 'Disease', (74, 80))
214433	30452490	It is worth noticing that H520 cells not only express EMT traits, but they are derived from a SCC tumor, in contrast to H1666 cells which are derived from AC.	('derived from', 'Reg', (79, 91))	('SCC tumor', 'Disease', 'MESH:D009369', (94, 103))	('H1666', 'CellLine', 'CVCL:1485', (120, 125))	('H520', 'Var', (26, 30))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('EMT', 'Gene', (54, 57))	('H520', 'CellLine', 'CVCL:1566', (26, 30))	('EMT', 'Gene', '3702', (54, 57))	('SCC tumor', 'Disease', (94, 103))
214435	30452490	The fact that we identified the strongest associations between Rb S249 phosphorylation and p39 overexpression with tumor stage and grade only in SCC is fully consistent with the fact that we originally identified this biomarker in an EMT-positive SCC cell line.	('SCC', 'Gene', (247, 250))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('EMT', 'Gene', (234, 237))	('phosphorylation', 'Var', (71, 86))	('EMT', 'Gene', '3702', (234, 237))	('SCC', 'Gene', (145, 148))	('tumor', 'Disease', (115, 120))	('S249 phosphorylation', 'Var', (66, 86))	('SCC', 'Gene', '6317', (247, 250))	('overexpression', 'PosReg', (95, 109))	('p39', 'Gene', '8941', (91, 94))	('SCC', 'Gene', '6317', (145, 148))	('p39', 'Gene', (91, 94))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
214442	32833672	High SNAI1 expression was closely related with poorer overall survival in gastrointestinal cancers in TCGA cohort.	('SNAI1', 'Gene', '6615', (5, 10))	('cancers', 'Phenotype', 'HP:0002664', (91, 98))	('High', 'Var', (0, 4))	('gastrointestinal cancers', 'Disease', (74, 98))	('gastrointestinal cancers', 'Disease', 'MESH:D004067', (74, 98))	('expression', 'MPA', (11, 21))	('SNAI1', 'Gene', (5, 10))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (74, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('overall', 'MPA', (54, 61))	('poorer', 'NegReg', (47, 53))
214443	32833672	High SNAI1 expression was closely related with poorer overall survival in gastrointestinal cancers, and was validated in GEO database.	('SNAI1', 'Gene', '6615', (5, 10))	('cancers', 'Phenotype', 'HP:0002664', (91, 98))	('High', 'Var', (0, 4))	('gastrointestinal cancers', 'Disease', (74, 98))	('gastrointestinal cancers', 'Disease', 'MESH:D004067', (74, 98))	('expression', 'MPA', (11, 21))	('SNAI1', 'Gene', (5, 10))	('overall survival', 'MPA', (54, 70))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (74, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('poorer', 'NegReg', (47, 53))
214447	32833672	Finally, high SNAI1 expression was closely related with poorer overall survival and correlates with clinical relevance of gastrointestinal cancers in an independent validation cohort.	('overall survival', 'MPA', (63, 79))	('expression', 'MPA', (20, 30))	('cancers', 'Phenotype', 'HP:0002664', (139, 146))	('poorer', 'NegReg', (56, 62))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (122, 145))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('gastrointestinal cancers', 'Disease', (122, 146))	('SNAI1', 'Gene', '6615', (14, 19))	('gastrointestinal cancers', 'Disease', 'MESH:D004067', (122, 146))	('SNAI1', 'Gene', (14, 19))	('high', 'Var', (9, 13))
214468	32833672	Notably, high SNAI1 expression levels was closely related with poorer prognosis of overall survival (OS) in STAD (p=0.002), COAD (p=0.013), ESCA (p=0.031), KIRP (p=0.045), LGG (p<0.001), LUAD (p=0.026), LUSC (p<0.001), MESO (p=0.007), OV (p=0.048), and THYM (p=0.001) (Figure 2A, 2B and Supplementary Figure 4).	('overall survival', 'CPA', (83, 99))	('SNAI1', 'Gene', '6615', (14, 19))	('SNAI1', 'Gene', (14, 19))	('expression levels', 'MPA', (20, 37))	('high', 'Var', (9, 13))
214469	32833672	Simultaneously, high SNAI1 expression levels was moderate closely related with poorer prognosis of OS in READ (p=0.093) (Figure 2C).	('expression levels', 'MPA', (27, 44))	('high', 'Var', (16, 20))	('OS in READ', 'Disease', (99, 109))	('SNAI1', 'Gene', '6615', (21, 26))	('SNAI1', 'Gene', (21, 26))
214474	32833672	Interestingly, a cohorts including GSE62254, GSE14210, GSE15459, GSE22377, GSE29272, and GSE51105 indicated that high SNAI1 expression was closely related with poorer prognosis in STAD (OS HR = 2.09, 95% CI =1.73 to 2.52, P<0.001; FP HR = 2.06, 95% CI =1.68 to 2.52, P<0.001; PFS HR = 2.46, 95% CI = 1.97 to 3.08, P<0.001) (Figure 2D-2F).	('SNAI1', 'Gene', '6615', (118, 123))	('high', 'Var', (113, 117))	('SNAI1', 'Gene', (118, 123))	('STAD', 'Disease', (180, 184))	('expression', 'MPA', (124, 134))	('GSE51105', 'Var', (89, 97))
214475	32833672	Moreover, two cohorts including GSE17536, GSE39582 indicated that high SNAI1 expression was closely related with poorer prognosis in CRC (OS HR = 1.50, 95% CI =1.03 to 2.18, P=0.035) (Figure 2G-2I).	('poorer', 'NegReg', (113, 119))	('expression', 'MPA', (77, 87))	('SNAI1', 'Gene', '6615', (71, 76))	('SNAI1', 'Gene', (71, 76))	('CRC', 'Disease', (133, 136))	('high', 'Var', (66, 70))
214477	32833672	As shown in Table 1, high SNAI1 expression was closely related with poorer prognosis in female (OS HR = 2.24, P<0.001; PFS HR =1.91, P = 0.002) and male (OS HR = 2.27, P <0.001; PFS HR =2.43, P<0.001).	('SNAI1', 'Gene', '6615', (26, 31))	('SNAI1', 'Gene', (26, 31))	('high', 'Var', (21, 25))	('poorer prognosis', 'CPA', (68, 84))	('expression', 'MPA', (32, 42))
214478	32833672	Moreover, high SNAI1 expression was closely related with poorer OS and PFS in stage 1 (OS HR = 3.63, P=0.011; PFS HR =2.88, P = 0.023), stage 2 (OS HR = 2.03, P=0.021; PFS HR =1.93, P = 0.030), stage 3 (OS HR = 1.98, P<0.001; PFS HR =2.06, P <0.001), and stage 4 (OS HR = 2.06, P<0.001; PFS HR =2.30, P <0.001) of STAD, and poorer OS and PFS in TNM stage.	('SNAI1', 'Gene', (15, 20))	('SNAI1', 'Gene', '6615', (15, 20))	('high', 'Var', (10, 14))	('expression', 'MPA', (21, 31))
214479	32833672	Furthermore, high SNAI1 expression was closely related with poorer prognosis in the lauren classification (OS HR = 1.89, P<0.001; PFS HR =2.33, P <0.001), moderate differentiation (OS HR = 1.94, P=0.046; PFS HR =2.27, P =0.011), negative (OS HR = 1.98, P<0.001; PFS HR =2.02, P <0.001) and positive (OS HR = 2.14, P<0.001; PFS HR =2.36, P <0.001) HER-2 status (Table 1).	('expression', 'MPA', (24, 34))	('high', 'Var', (13, 17))	('SNAI1', 'Gene', '6615', (18, 23))	('HER-2', 'Gene', '2064', (347, 352))	('moderate differentiation', 'CPA', (155, 179))	('lauren', 'Disease', (84, 90))	('SNAI1', 'Gene', (18, 23))	('HER-2', 'Gene', (347, 352))
214480	32833672	These results suggest that high SNAI1 expression can impact the prognosis in STAD with lymph node metastasis, and SNAI1 is an independent prognostic marker but can also predict the clinicopathological features of STAD.	('impact', 'Reg', (53, 59))	('STAD', 'Disease', (213, 217))	('SNAI1', 'Gene', (114, 119))	('predict', 'Reg', (169, 176))	('SNAI1', 'Gene', '6615', (32, 37))	('expression', 'MPA', (38, 48))	('SNAI1', 'Gene', (32, 37))	('high', 'Var', (27, 31))	('SNAI1', 'Gene', '6615', (114, 119))	('STAD', 'Disease', (77, 81))
214496	32833672	Additionally, Kaplan-Meier and Cox's proportional hazards regression model survival analysis revealed that patients with high expression levels of SNAI1 had shorter overall survival in CRC (HR = 1.71, 95% CI = 1.28 to 2.94, P = 0.023) and GC (HR = 1.68, 95% CI = 1.23 to 2.57, P = 0.022) (Figure 6B, 6D).	('shorter', 'NegReg', (157, 164))	('high expression levels', 'Var', (121, 143))	('SNAI1', 'Gene', '6615', (147, 152))	('SNAI1', 'Gene', (147, 152))	('overall survival', 'MPA', (165, 181))	('patients', 'Species', '9606', (107, 115))
214519	32833672	Its expression level in gastric cancer is significantly correlated with tumor size, degree of differentiation, clinical stage, lymph node and distant metastasis, and the overall survival rate of gastric cancer patients with high expression of SNAI1 is significantly lower than that of patients with low expression of SNAI1.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('SNAI1', 'Gene', '6615', (243, 248))	('SNAI1', 'Gene', (243, 248))	('gastric cancer', 'Disease', 'MESH:D013274', (24, 38))	('lower', 'NegReg', (266, 271))	('gastric cancer', 'Disease', (195, 209))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('SNAI1', 'Gene', '6615', (317, 322))	('patients', 'Species', '9606', (210, 218))	('high expression', 'Var', (224, 239))	('correlated', 'Reg', (56, 66))	('SNAI1', 'Gene', (317, 322))	('gastric cancer', 'Phenotype', 'HP:0012126', (24, 38))	('survival rate', 'CPA', (178, 191))	('tumor', 'Disease', (72, 77))	('gastric cancer', 'Disease', 'MESH:D013274', (195, 209))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('expression level', 'MPA', (4, 20))	('gastric cancer', 'Disease', (24, 38))	('patients', 'Species', '9606', (285, 293))	('gastric cancer', 'Phenotype', 'HP:0012126', (195, 209))
214542	32833672	In summary, we applied integrated bioinformatics approaches to suggest that high SNAI1 was closely related with prognosis and immune infiltrating levels in gastrointestinal cancer.	('gastrointestinal cancer', 'Disease', (156, 179))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (156, 179))	('related', 'Reg', (99, 106))	('SNAI1', 'Gene', '6615', (81, 86))	('SNAI1', 'Gene', (81, 86))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('gastrointestinal cancer', 'Disease', 'MESH:D004067', (156, 179))	('high', 'Var', (76, 80))
214569	29492204	In contrast, high frequencies of CD3 cells in the tumor core area were associated with reduced metastasis.	('reduced', 'NegReg', (87, 94))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('metastasis', 'CPA', (95, 105))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Disease', (50, 55))	('CD3 cells', 'Var', (33, 42))
214570	29492204	Overall survival was reduced in patients with high stromal CD45, high tumoral CD11b and high tumoral COX-2 expression.	('reduced', 'NegReg', (21, 28))	('tumor', 'Disease', 'MESH:D009369', (93, 98))	('patients', 'Species', '9606', (32, 40))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('COX-2', 'Gene', (101, 106))	('tumor', 'Disease', (70, 75))	('CD45', 'Gene', '5788', (59, 63))	('tumor', 'Disease', (93, 98))	('expression', 'MPA', (107, 117))	('CD11b', 'Gene', '3684', (78, 83))	('CD11b', 'Gene', (78, 83))	('high stromal', 'Var', (46, 58))	('Overall survival', 'CPA', (0, 16))	('CD45', 'Gene', (59, 63))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('COX-2', 'Gene', '4513', (101, 106))
214628	29492204	On the other side, high tumoral, but not stromal CD11b expression was associated with reduced 3-year overall survival rate (p = 0.043) For CD3 and MMP-9 neither stromal (p = 0.738 for CD3; p = 0.915 for MMP-9) nor tumoral (p = 0.675 for CD3; p = 0.097 for MMP-9) expression correlated with overall survival rates.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('reduced', 'NegReg', (86, 93))	('MMP-9', 'Gene', '4318', (256, 261))	('MMP-9', 'Gene', (147, 152))	('MMP-9', 'Gene', (203, 208))	('tumor', 'Disease', (24, 29))	('CD11b', 'Gene', '3684', (49, 54))	('tumor', 'Disease', 'MESH:D009369', (214, 219))	('CD11b', 'Gene', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('CD3', 'Var', (139, 142))	('tumor', 'Disease', (214, 219))	('overall survival rate', 'MPA', (101, 122))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('MMP-9', 'Gene', '4318', (147, 152))	('MMP-9', 'Gene', '4318', (203, 208))	('MMP-9', 'Gene', (256, 261))
214630	29492204	Combining high stromal CD45 and tumoral COX-2 also showed a significantly lower 3-years survival rate (p = 0.037, Figure 4B).	('tumor', 'Disease', (32, 37))	('high stromal', 'Var', (10, 22))	('COX-2', 'Gene', '4513', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('CD45', 'Gene', (23, 27))	('COX-2', 'Gene', (40, 45))	('lower', 'NegReg', (74, 79))	('3-years survival rate', 'CPA', (80, 101))	('CD45', 'Gene', '5788', (23, 27))
214660	29492204	However, our analyses did not support this notion and stromal leukocyte subsets explaining the correlation of high stromal CD45 with survival still need to be identified in future studies.	('CD45', 'Gene', (123, 127))	('high', 'Var', (110, 114))	('CD45', 'Gene', '5788', (123, 127))
214714	33623898	Inhibiting or down-regulating SPHK1 could decrease cell proliferation and arrest the cell cycle in glioblastoma cells and breast cancer cells, and a dominant-negative form of SPHK1 was able to suppress tumor formation in nude mice.	('SPHK1', 'Gene', (30, 35))	('Inhibiting', 'Var', (0, 10))	('suppress', 'NegReg', (193, 201))	('glioblastoma', 'Disease', 'MESH:D005909', (99, 111))	('cancer', 'Disease', (129, 135))	('cell proliferation', 'CPA', (51, 69))	('arrest', 'Disease', 'MESH:D006323', (74, 80))	('nude mice', 'Species', '10090', (221, 230))	('glioblastoma', 'Disease', (99, 111))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('tumor', 'Disease', (202, 207))	('glioblastoma', 'Phenotype', 'HP:0012174', (99, 111))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('breast cancer', 'Phenotype', 'HP:0003002', (122, 135))	('SPHK1', 'Gene', (175, 180))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('decrease', 'NegReg', (42, 50))	('dominant-negative', 'Var', (149, 166))	('arrest', 'Disease', (74, 80))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('cell cycle', 'CPA', (85, 95))	('down-regulating', 'NegReg', (14, 29))
214760	33623898	Increased expression of SPHK1 has been found to enhance the antiapoptotic ability of the MCF-7 breast cancer cells, increase cell proliferation, and promote estrogen-dependent tumorigenesis.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('breast cancer', 'Phenotype', 'HP:0003002', (95, 108))	('tumor', 'Disease', (176, 181))	('MCF-7 breast cancer', 'Disease', 'MESH:D001943', (89, 108))	('MCF-7 breast cancer', 'Disease', (89, 108))	('SPHK1', 'Gene', (24, 29))	('enhance', 'PosReg', (48, 55))	('cell proliferation', 'CPA', (125, 143))	('increase', 'PosReg', (116, 124))	('antiapoptotic ability', 'MPA', (60, 81))	('promote', 'PosReg', (149, 156))	('tumor', 'Disease', 'MESH:D009369', (176, 181))	('expression', 'Var', (10, 20))
214761	33623898	Ectopic expression of SPHK1 could promote G1S transition and stimulate cell growth, colony formation in soft agar, and tumor growth in immunodeficient mice.	('tumor', 'Disease', (119, 124))	('G1S transition', 'CPA', (42, 56))	('stimulate', 'PosReg', (61, 70))	('mice', 'Species', '10090', (151, 155))	('cell growth', 'CPA', (71, 82))	('colony formation in soft agar', 'CPA', (84, 113))	('Ectopic expression', 'Var', (0, 18))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('promote', 'PosReg', (34, 41))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('agar', 'Chemical', 'MESH:D000362', (109, 113))	('immunodeficient', 'Disease', 'MESH:D007153', (135, 150))	('SPHK1', 'Gene', (22, 27))	('immunodeficient', 'Disease', (135, 150))
214762	33623898	Overexpression of SPHK1 elevates the expression of cyclooxygenase-2 in colon cancer.	('elevates', 'PosReg', (24, 32))	('colon cancer', 'Phenotype', 'HP:0003003', (71, 83))	('colon cancer', 'Disease', 'MESH:D015179', (71, 83))	('SPHK1', 'Gene', (18, 23))	('Overexpression', 'Var', (0, 14))	('colon cancer', 'Disease', (71, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('expression', 'MPA', (37, 47))	('cyclooxygenase-2', 'Gene', (51, 67))	('cyclooxygenase-2', 'Gene', '5743', (51, 67))
214765	33623898	Furthermore, it has been suggested that S1P promotes EMT in cancer by remodeling the glycocalyx and inhibiting the Snail-matrix metalloproteinases signaling pathway.	('glycocalyx', 'MPA', (85, 95))	('promotes', 'PosReg', (44, 52))	('EMT in', 'CPA', (53, 59))	('remodeling', 'Reg', (70, 80))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('inhibiting', 'NegReg', (100, 110))	('cancer', 'Disease', (60, 66))	('S1P', 'Var', (40, 43))	('S1P', 'Chemical', 'MESH:C060506', (40, 43))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('Snail-matrix metalloproteinases signaling pathway', 'Pathway', (115, 164))
214768	33623898	Recently, it was reported that microRNA-506-3p inhibited the expression of SPHK1 and the treatment of SPHK1 inhibited the EMT.	('inhibited', 'NegReg', (108, 117))	('inhibited', 'NegReg', (47, 56))	('SPHK1', 'Gene', (75, 80))	('treatment', 'Var', (89, 98))	('men', 'Species', '9606', (94, 97))	('SPHK1', 'Var', (102, 107))	('microRNA-506-3p', 'Var', (31, 46))	('expression', 'MPA', (61, 71))
214770	33623898	Furthermore, it was reported that high SPHK1 expression is associated with shorter overall survival and increased risk of disease relapse in patients with NSCLC treated with adjuvant chemotherapy in recent study.	('overall survival', 'MPA', (83, 99))	('NSCLC', 'Disease', (155, 160))	('disease relapse', 'CPA', (122, 137))	('SCLC', 'Phenotype', 'HP:0030357', (156, 160))	('high', 'Var', (34, 38))	('expression', 'MPA', (45, 55))	('NSCLC', 'Disease', 'MESH:D002289', (155, 160))	('shorter', 'NegReg', (75, 82))	('patients', 'Species', '9606', (141, 149))	('SPHK1', 'Gene', (39, 44))
214771	33623898	Ectopic expression of SPHK1 in NSCLC cells dramatically enhances their resistance to apoptosis induced by doxorubicin or docetaxel, 2 commonly used chemotherapeutics, whereas suppressing SPHK1 expression with small-hairpin RNAs or inhibiting SPHK1 activity with a specific SPHK1 inhibitor (SK1-I) markedly abrogated the ability of NSCLC cells to resist cytotoxic reagent-induced cell death, suggesting that SPHK1 activity contributes to sustaining the unwanted survival of NSCLC cells under the treatment of chemotherapeutics.	('docetaxel', 'Chemical', 'MESH:D000077143', (121, 130))	('SCLC', 'Phenotype', 'HP:0030357', (474, 478))	('NSCLC', 'Disease', 'MESH:D002289', (31, 36))	('SK1-I', 'Chemical', '-', (290, 295))	('NSCLC', 'Disease', 'MESH:D002289', (331, 336))	('SPHK1', 'Gene', (187, 192))	('NSCLC', 'Disease', (31, 36))	('death', 'Disease', 'MESH:D003643', (384, 389))	('Ectopic expression', 'Var', (0, 18))	('NSCLC', 'Disease', (331, 336))	('men', 'Species', '9606', (500, 503))	('enhances', 'PosReg', (56, 64))	('abrogated', 'NegReg', (306, 315))	('NSCLC', 'Disease', 'MESH:D002289', (473, 478))	('SCLC', 'Phenotype', 'HP:0030357', (32, 36))	('NSCLC', 'Disease', (473, 478))	('inhibiting', 'NegReg', (231, 241))	('resistance', 'MPA', (71, 81))	('suppressing', 'NegReg', (175, 186))	('death', 'Disease', (384, 389))	('SCLC', 'Phenotype', 'HP:0030357', (332, 336))	('SPHK1', 'Gene', (22, 27))
214773	33623898	Furthermore, it was recently reported that high SPHK1 mRNA expression is significantly correlated to worse OS in NSCLC patients.	('mRNA expression', 'MPA', (54, 69))	('high', 'Var', (43, 47))	('patients', 'Species', '9606', (119, 127))	('SPHK1', 'Gene', (48, 53))	('worse OS', 'Disease', (101, 109))	('SCLC', 'Phenotype', 'HP:0030357', (114, 118))	('NSCLC', 'Disease', (113, 118))	('NSCLC', 'Disease', 'MESH:D002289', (113, 118))
214818	32752138	To observe the relationship between smoking e-cigarettes and ACE2 expression, we used the following datasets: GSE138326 and GSE112073.	('GSE112073', 'Var', (124, 133))	('cig', 'Gene', '2335', (46, 49))	('cig', 'Gene', (46, 49))
214846	32752138	For the e-cig studies, we noticed that there are significant differences between vapers who used nicotine-less and flavor-less e-cig and vapers who used nicotine/flavor-containing e-cig.	('nicotine', 'Chemical', 'MESH:D009538', (97, 105))	('cig', 'Gene', '2335', (182, 185))	('cig', 'Gene', '2335', (129, 132))	('nicotine-less', 'Var', (97, 110))	('cig', 'Gene', '2335', (10, 13))	('cig', 'Gene', (129, 132))	('nicotine', 'Chemical', 'MESH:D009538', (153, 161))	('cig', 'Gene', (182, 185))	('cig', 'Gene', (10, 13))
215026	32293345	Box plot of these scores clearly demonstrated the shared directionality in pathway dysregulation in SS and SLC, i.e., in both these conditions there was up-regulation of the pathway (Fig.	('SLC', 'Gene', '6366', (107, 110))	('SLC', 'Gene', (107, 110))	('up-regulation', 'PosReg', (153, 166))	('dysregulation', 'Var', (83, 96))	('SS', 'Phenotype', 'HP:0100806', (100, 102))
215065	32293345	It is worth mentioning that viral integration or bacterial infection in a setting of cancer has been reported to favour survival in SLC cancers of oropharynx, liver and kidney.	('bacterial infection', 'Phenotype', 'HP:0002718', (49, 68))	('SLC cancers', 'Disease', (132, 143))	('SLC cancers', 'Disease', 'MESH:D009369', (132, 143))	('cancers', 'Phenotype', 'HP:0002664', (136, 143))	('bacterial infection', 'Disease', 'MESH:D001424', (49, 68))	('survival', 'CPA', (120, 128))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('bacterial infection', 'Disease', (49, 68))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('cancer', 'Disease', (85, 91))	('favour', 'PosReg', (113, 119))	('cancer', 'Disease', (136, 142))	('kidney', 'Disease', (169, 175))	('viral integration', 'Var', (28, 45))	('liver', 'Disease', (159, 164))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
215066	32293345	Alteration of intestinal permeability is known in both sepsis and cancer.	('sepsis', 'Disease', 'MESH:D018805', (55, 61))	('Alteration', 'Var', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('sepsis', 'Phenotype', 'HP:0100806', (55, 61))	('sepsis', 'Disease', (55, 61))	('intestinal permeability', 'MPA', (14, 37))	('cancer', 'Disease', (66, 72))
215083	32039035	A Novel LncRNA, AC091729.7 Promotes Sinonasal Squamous Cell Carcinomas Proliferation and Invasion Through Binding SRSF2 Long non-coding RNAs (lncRNAs) play important roles in various biological progresses of carcinogenesis.	('Promotes', 'PosReg', (27, 35))	('carcinogenesis', 'Disease', (208, 222))	('Carcinoma', 'Phenotype', 'HP:0030731', (60, 69))	('Invasion', 'CPA', (89, 97))	('Squamous Cell Carcinomas', 'Phenotype', 'HP:0002860', (46, 70))	('Squamous Cell Carcinomas Proliferation', 'Disease', 'MESH:D002294', (46, 84))	('Carcinomas', 'Phenotype', 'HP:0030731', (60, 70))	('AC091729.7', 'Var', (16, 26))	('Binding', 'Interaction', (106, 113))	('SRSF2', 'Gene', (114, 119))	('Squamous Cell Carcinomas Proliferation', 'Disease', (46, 84))	('carcinogenesis', 'Disease', 'MESH:D063646', (208, 222))
215087	32039035	Xenograft mouse models were employed to evaluate the role of AC091729.7 in growth of SNSCC in vivo.	('AC091729.7', 'Var', (61, 71))	('SCC', 'Disease', 'MESH:D002294', (87, 90))	('mouse', 'Species', '10090', (10, 15))	('SCC', 'Phenotype', 'HP:0002860', (87, 90))	('SCC', 'Disease', (87, 90))	('SNSCC', 'Phenotype', 'HP:0012182', (85, 90))
215089	32039035	Results showed AC091729.7 was upregulated and closely connected with the survival of the SNSCC patients.	('connected', 'Reg', (54, 63))	('SCC', 'Disease', (91, 94))	('patients', 'Species', '9606', (95, 103))	('upregulated', 'PosReg', (30, 41))	('SCC', 'Disease', 'MESH:D002294', (91, 94))	('AC091729.7', 'Var', (15, 25))	('SNSCC', 'Phenotype', 'HP:0012182', (89, 94))	('SCC', 'Phenotype', 'HP:0002860', (91, 94))
215091	32039035	Furthermore, downregulation of AC091729.7 could inhibit the growth of SNSCC in vivo.	('SNSCC', 'Phenotype', 'HP:0012182', (70, 75))	('SCC', 'Disease', 'MESH:D002294', (72, 75))	('AC091729.7', 'Var', (31, 41))	('downregulation', 'NegReg', (13, 27))	('SCC', 'Phenotype', 'HP:0002860', (72, 75))	('SCC', 'Disease', (72, 75))	('inhibit', 'NegReg', (48, 55))
215092	32039035	Moreover, Human protein microarray and RIP suggested that AC091729.7 directly combine with the serine/arginine rich splicing factor 2 (SRSF2).	('serine/arginine rich splicing factor 2', 'Gene', (95, 133))	('SRSF2', 'Gene', '6427', (135, 140))	('Human', 'Species', '9606', (10, 15))	('AC091729.7', 'Var', (58, 68))	('serine/arginine rich splicing factor 2', 'Gene', '6427', (95, 133))	('SRSF2', 'Gene', (135, 140))
215093	32039035	Our results suggest that in the cell progression of SNSCC, lncRNA AC091729.7 plays a carcinogenic role and serves as a novel biomarker and latent curative target in SNSCC patients.	('SCC', 'Disease', (54, 57))	('SNSCC', 'Phenotype', 'HP:0012182', (52, 57))	('SCC', 'Phenotype', 'HP:0002860', (167, 170))	('SCC', 'Disease', (167, 170))	('carcinogenic role', 'Disease', (85, 102))	('patients', 'Species', '9606', (171, 179))	('SCC', 'Disease', 'MESH:D002294', (54, 57))	('lncRNA AC091729.7', 'Var', (59, 76))	('SNSCC', 'Phenotype', 'HP:0012182', (165, 170))	('SCC', 'Disease', 'MESH:D002294', (167, 170))	('SCC', 'Phenotype', 'HP:0002860', (54, 57))	('carcinogenic role', 'Disease', 'MESH:D063646', (85, 102))
215109	32039035	Our results showed that AC091729.7 is overexpressed in SNSCC tissues, and knockdown of AC091729.7 can inhibit the proliferation of SNSCC cells both in vitro and in vivo.	('SCC', 'Disease', (133, 136))	('SCC', 'Phenotype', 'HP:0002860', (57, 60))	('SCC', 'Disease', (57, 60))	('SNSCC', 'Phenotype', 'HP:0012182', (55, 60))	('SNSCC', 'Phenotype', 'HP:0012182', (131, 136))	('knockdown', 'Var', (74, 83))	('SCC', 'Disease', 'MESH:D002294', (133, 136))	('proliferation', 'CPA', (114, 127))	('inhibit', 'NegReg', (102, 109))	('AC091729.7', 'Var', (87, 97))	('SCC', 'Disease', 'MESH:D002294', (57, 60))	('SCC', 'Phenotype', 'HP:0002860', (133, 136))
215110	32039035	Herein, we firstly demonstrated that AC091729.7 binds to SRSF2.	('SRSF2', 'Gene', '6427', (57, 62))	('binds', 'Interaction', (48, 53))	('AC091729.7', 'Var', (37, 47))	('SRSF2', 'Gene', (57, 62))
215130	32039035	For overexpression assay, the cells were allowed to grow for 24 h prior to transfection with pcDNA3.1 or pcDNA3.1-SRSF2 (pcSRSF2).	('SRSF2', 'Gene', '6427', (114, 119))	('SRSF2', 'Gene', (123, 128))	('pcDNA3.1', 'Var', (93, 101))	('SRSF2', 'Gene', (114, 119))	('SRSF2', 'Gene', '6427', (123, 128))
215150	32039035	Consistently, ISH results showed that the level of AC091729.7 was also significantly increased in 60 SNSCC tissues as compared to that in the corresponding adjacent tissues (Figure 2B).	('SNSCC', 'Phenotype', 'HP:0012182', (101, 106))	('SCC', 'Disease', 'MESH:D002294', (103, 106))	('AC091729.7', 'Var', (51, 61))	('SCC', 'Phenotype', 'HP:0002860', (103, 106))	('increased', 'PosReg', (85, 94))	('SCC', 'Disease', (103, 106))
215152	32039035	As shown in Figure 2C, the overall survival time of 34 patients with high AC091729.7 expression was significantly shorter than the 26 patients with low AC091729.7 expression (p < 0.05).	('patients', 'Species', '9606', (55, 63))	('high AC091729.7 expression', 'Var', (69, 95))	('patients', 'Species', '9606', (134, 142))	('shorter', 'NegReg', (114, 121))
215154	32039035	Furthermore, we evaluated the correlation between AC091729.7 expression and the clinicopathological parameters in 60 SNSCC patients.	('AC091729.7', 'Var', (50, 60))	('SNSCC', 'Phenotype', 'HP:0012182', (117, 122))	('SCC', 'Disease', (119, 122))	('patients', 'Species', '9606', (123, 131))	('SCC', 'Disease', 'MESH:D002294', (119, 122))	('SCC', 'Phenotype', 'HP:0002860', (119, 122))
215156	32039035	To investigate the function of AC091729.7 on the proliferation of SNSCC cells, RPMI-2650 cells were satisfactorily transfected with sh-AC091729.7 using shRNA as a negative control for about 48 h (Figure 3A).	('SNSCC', 'Phenotype', 'HP:0012182', (66, 71))	('SCC', 'Phenotype', 'HP:0002860', (68, 71))	('SCC', 'Disease', (68, 71))	('RPMI-2650', 'CellLine', 'CVCL:1664', (79, 88))	('SCC', 'Disease', 'MESH:D002294', (68, 71))	('sh-AC091729.7', 'Var', (132, 145))
215157	32039035	As shown in Figure 3B, after sh-AC091729.7 transfection, the viability of RPMI-2650 cells decreased significantly at different time points (48, 72, and 96 h, respectively).	('sh-AC091729.7 transfection', 'Var', (29, 55))	('viability', 'CPA', (61, 70))	('decreased', 'NegReg', (90, 99))	('RPMI-2650', 'CellLine', 'CVCL:1664', (74, 83))
215159	32039035	These results indicated that the downregulation of AC091729.7 suppresses the capacity of SNSCC in vitro.	('SCC', 'Disease', (91, 94))	('SCC', 'Disease', 'MESH:D002294', (91, 94))	('SCC', 'Phenotype', 'HP:0002860', (91, 94))	('AC091729.7', 'Var', (51, 61))	('SNSCC', 'Phenotype', 'HP:0012182', (89, 94))	('suppresses', 'NegReg', (62, 72))	('downregulation', 'NegReg', (33, 47))
215162	32039035	Compared to the control, AC091729.7 shRNA significantly inhibited the tumor growth in mice, and the tumor mass weight also reduced significantly (Figure 3D).	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', (100, 105))	('AC091729.7 shRNA', 'Var', (25, 41))	('tumor', 'Disease', (70, 75))	('mice', 'Species', '10090', (86, 90))	('inhibited', 'NegReg', (56, 65))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('reduced', 'NegReg', (123, 130))
215164	32039035	As shown in Figures 3E,F, after AC091729.7 downregulation, both migratory and invasive capabilities of RPMI-2650 cells were remarkably inhibited, thereby indicating that AC091729.7 promotes the migration and invasion of SNSCC cells.	('invasion', 'CPA', (208, 216))	('SCC', 'Phenotype', 'HP:0002860', (222, 225))	('SNSCC', 'Phenotype', 'HP:0012182', (220, 225))	('RPMI-2650', 'CellLine', 'CVCL:1664', (103, 112))	('downregulation', 'NegReg', (43, 57))	('SCC', 'Disease', (222, 225))	('invasive capabilities', 'CPA', (78, 99))	('migratory', 'CPA', (64, 73))	('promotes', 'PosReg', (181, 189))	('migration', 'CPA', (194, 203))	('SCC', 'Disease', 'MESH:D002294', (222, 225))	('AC091729.7', 'Var', (170, 180))	('inhibited', 'NegReg', (135, 144))	('AC091729.7', 'Var', (32, 42))
215165	32039035	To further investigate the function of AC091729.7 on the proliferation of SNSCC cells, RPMI-2650 cells were satisfactorily transfected with pcAC091729.7 using vector as a negative control for about 48 h (Figure 4A).	('pcAC091729.7', 'Var', (140, 152))	('RPMI-2650', 'CellLine', 'CVCL:1664', (87, 96))	('SCC', 'Disease', 'MESH:D002294', (76, 79))	('SNSCC', 'Phenotype', 'HP:0012182', (74, 79))	('SCC', 'Phenotype', 'HP:0002860', (76, 79))	('SCC', 'Disease', (76, 79))
215166	32039035	As shown in Figure 4B, after pcAC091729.7 transfection, the viability of RPMI-2650 cells increased significantly at different time points (48, 72, and 96 h, respectively).	('viability', 'CPA', (60, 69))	('4B', 'Chemical', 'MESH:D001895', (19, 21))	('RPMI-2650', 'CellLine', 'CVCL:1664', (73, 82))	('pcAC091729.7 transfection', 'Var', (29, 54))	('increased', 'PosReg', (89, 98))
215167	32039035	Moreover, the colony assay further confirmed that the overexpression of AC091729.7 contributed to enhanced colony formation and invasive capabilities in SNSCC cells (Figures 4C,D).	('enhanced', 'PosReg', (98, 106))	('colony formation', 'CPA', (107, 123))	('SCC', 'Phenotype', 'HP:0002860', (155, 158))	('overexpression', 'PosReg', (54, 68))	('SNSCC', 'Phenotype', 'HP:0012182', (153, 158))	('AC091729.7', 'Var', (72, 82))	('SCC', 'Disease', (155, 158))	('SCC', 'Disease', 'MESH:D002294', (155, 158))	('invasive capabilities', 'CPA', (128, 149))
215171	32039035	The SRSF2 antibody worked well and the precipitates were significantly enriched for AC091729.7 (Figure 6A).	('SRSF2', 'Gene', '6427', (4, 9))	('SRSF2', 'Gene', (4, 9))	('AC091729.7', 'Var', (84, 94))
215178	32039035	These findings indicated that AC091729.7 binds to SRSF2.	('SRSF2', 'Gene', (50, 55))	('SRSF2', 'Gene', '6427', (50, 55))	('binds', 'Interaction', (41, 46))	('AC091729.7', 'Var', (30, 40))
215179	32039035	Therefore, follow-up experiments focused on whether the function of AC091729.7 was a result of regulating the SRSF2 expression.	('regulating', 'Reg', (95, 105))	('expression', 'MPA', (116, 126))	('AC091729.7', 'Var', (68, 78))	('SRSF2', 'Gene', '6427', (110, 115))	('SRSF2', 'Gene', (110, 115))
215180	32039035	In order to investigate whether AC091729.7 promoted the viability of SNSCC cells and wound-healing through SRSF2, we conducted rescue experiments.	('SCC', 'Disease', (71, 74))	('wound-healing', 'CPA', (85, 98))	('SNSCC', 'Phenotype', 'HP:0012182', (69, 74))	('SRSF2', 'Gene', '6427', (107, 112))	('promoted', 'PosReg', (43, 51))	('SCC', 'Disease', 'MESH:D002294', (71, 74))	('viability', 'CPA', (56, 65))	('SRSF2', 'Gene', (107, 112))	('SCC', 'Phenotype', 'HP:0002860', (71, 74))	('AC091729.7', 'Var', (32, 42))
215182	32039035	Consequently, the overexpression of SRSF2 significantly reduced the cell viability and migration ability induced by AC091729.7 knockdown.	('cell viability', 'CPA', (68, 82))	('SRSF2', 'Gene', (36, 41))	('overexpression', 'PosReg', (18, 32))	('reduced', 'NegReg', (56, 63))	('migration ability', 'CPA', (87, 104))	('SRSF2', 'Gene', '6427', (36, 41))	('AC091729.7', 'Var', (116, 126))
215183	32039035	Conversely, the silencing of SRSF2 reduced the cell viability and migration ability caused by the overexpression of AC091729.7 (Figures 7B,C).	('reduced', 'NegReg', (35, 42))	('overexpression', 'PosReg', (98, 112))	('SRSF2', 'Gene', '6427', (29, 34))	('silencing', 'Var', (16, 25))	('migration ability', 'CPA', (66, 83))	('cell viability', 'CPA', (47, 61))	('SRSF2', 'Gene', (29, 34))
215184	32039035	Taken together, the current findings indicated that AC091729.7 regulates SRSF2 to play a carcinogenic role.	('carcinogenic role', 'Disease', 'MESH:D063646', (89, 106))	('SRSF2', 'Gene', '6427', (73, 78))	('carcinogenic role', 'Disease', (89, 106))	('regulates', 'Reg', (63, 72))	('AC091729.7', 'Var', (52, 62))	('SRSF2', 'Gene', (73, 78))
215198	32039035	The current study first selected lncRNA AC091729.7 as the research object in SNSCC and found that AC091729.7 expression was upregulated in tumor tissues as assessed by microarray, RNAscope in situ hybridization, and qRT-PCR in independent cohorts.	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('expression', 'MPA', (109, 119))	('SCC', 'Phenotype', 'HP:0002860', (79, 82))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('SCC', 'Disease', (79, 82))	('SNSCC', 'Phenotype', 'HP:0012182', (77, 82))	('upregulated', 'PosReg', (124, 135))	('AC091729.7', 'Var', (98, 108))	('SCC', 'Disease', 'MESH:D002294', (79, 82))
215200	32039035	In the current study, the clinical data analysis of the SNSCC cancer patients showed that high level of AC091729.7 significantly correlated with the T grade, recurrence, and poor survival of SNSCC.	('SCC', 'Phenotype', 'HP:0002860', (58, 61))	('SNSCC', 'Phenotype', 'HP:0012182', (56, 61))	('correlated with', 'Reg', (129, 144))	('poor survival', 'CPA', (174, 187))	('SCC', 'Disease', (58, 61))	('SCC', 'Disease', 'MESH:D002294', (193, 196))	('SCC', 'Disease', 'MESH:D002294', (58, 61))	('T grade', 'CPA', (149, 156))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('SNSCC', 'Phenotype', 'HP:0012182', (191, 196))	('recurrence', 'CPA', (158, 168))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('AC091729.7', 'Var', (104, 114))	('SCC', 'Phenotype', 'HP:0002860', (193, 196))	('patients', 'Species', '9606', (69, 77))	('SCC', 'Disease', (193, 196))
215201	32039035	Furthermore, the knockdown of AC091729.7 could significantly suppress the proliferation and invasion of SNSCC cells both in vitro and in vivo.	('proliferation', 'CPA', (74, 87))	('SNSCC', 'Phenotype', 'HP:0012182', (104, 109))	('SCC', 'Phenotype', 'HP:0002860', (106, 109))	('SCC', 'Disease', (106, 109))	('suppress', 'NegReg', (61, 69))	('knockdown', 'Var', (17, 26))	('SCC', 'Disease', 'MESH:D002294', (106, 109))	('AC091729.7', 'Var', (30, 40))
215202	32039035	These results suggested that AC091729.7 promotes the malignant phenotypes and functions as an oncogene in SNSCC.	('SCC', 'Phenotype', 'HP:0002860', (108, 111))	('malignant phenotypes', 'CPA', (53, 73))	('SCC', 'Disease', (108, 111))	('AC091729.7', 'Var', (29, 39))	('SNSCC', 'Phenotype', 'HP:0012182', (106, 111))	('promotes', 'PosReg', (40, 48))	('SCC', 'Disease', 'MESH:D002294', (108, 111))
215209	32039035	Furthermore, the inhibitory effect of AC091729.7 knockdown on the proliferation of SNSCC cells could be rescued by the overexpression of SRSF2.	('knockdown', 'Var', (49, 58))	('SNSCC', 'Phenotype', 'HP:0012182', (83, 88))	('SCC', 'Disease', (85, 88))	('AC091729.7', 'Var', (38, 48))	('SRSF2', 'Gene', (137, 142))	('SCC', 'Disease', 'MESH:D002294', (85, 88))	('SCC', 'Phenotype', 'HP:0002860', (85, 88))	('SRSF2', 'Gene', '6427', (137, 142))
215211	32039035	In the present study, we found that a novel lncRNA, AC091729.7, was prominently overexpressed in SNSCC tissues and associated with the progression of SNSCC patients.	('patients', 'Species', '9606', (156, 164))	('SCC', 'Phenotype', 'HP:0002860', (99, 102))	('SCC', 'Disease', (99, 102))	('SNSCC', 'Phenotype', 'HP:0012182', (97, 102))	('SCC', 'Disease', 'MESH:D002294', (152, 155))	('overexpressed', 'PosReg', (80, 93))	('SCC', 'Disease', 'MESH:D002294', (99, 102))	('AC091729.7', 'Var', (52, 62))	('SNSCC', 'Phenotype', 'HP:0012182', (150, 155))	('SCC', 'Phenotype', 'HP:0002860', (152, 155))	('SCC', 'Disease', (152, 155))	('associated with', 'Reg', (115, 130))
215212	32039035	Furthermore, the downregulation of AC091729.7 significantly inhibited the ability of proliferation and invasion of SNSCC cells.	('SCC', 'Disease', 'MESH:D002294', (117, 120))	('SNSCC', 'Phenotype', 'HP:0012182', (115, 120))	('inhibited', 'NegReg', (60, 69))	('AC091729.7', 'Var', (35, 45))	('downregulation', 'NegReg', (17, 31))	('SCC', 'Phenotype', 'HP:0002860', (117, 120))	('SCC', 'Disease', (117, 120))
215213	32039035	The oncogenic effects of AC091729.7 are related to the regulation of SRSF2 protein.	('SRSF2', 'Gene', '6427', (69, 74))	('AC091729.7', 'Var', (25, 35))	('SRSF2', 'Gene', (69, 74))	('protein', 'Protein', (75, 82))	('oncogenic effects', 'CPA', (4, 21))	('regulation', 'MPA', (55, 65))
215214	32039035	In summary, AC091729.7 may be a prognostic marker for SNSCC and a potential target for therapeutic intervention.	('SCC', 'Disease', 'MESH:D002294', (56, 59))	('SCC', 'Phenotype', 'HP:0002860', (56, 59))	('SNSCC', 'Phenotype', 'HP:0012182', (54, 59))	('SCC', 'Disease', (56, 59))	('AC091729.7', 'Var', (12, 22))
215223	31231463	Taken together, our findings show that the effects of mutational signatures on the immune microenvironment and response to immunotherapy can be affected by context such as cancer type, anatomic site, and histology.	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('affected', 'Reg', (144, 152))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('mutational', 'Var', (54, 64))	('cancer', 'Disease', (172, 178))
215228	31231463	Tobacco smoke contains many carcinogenic chemicals that disrupt DNA such as polycyclic aromatic hydrocarbons and nitrosamines, which can cause G T transversions and distinct mutational signatures.	('transversions', 'Var', (147, 160))	('nitrosamines', 'Chemical', 'MESH:D009602', (113, 125))	('carcinogenic', 'Disease', 'MESH:D063646', (28, 40))	('cause', 'Reg', (137, 142))	('Tobacco', 'Species', '4097', (0, 7))	('carcinogenic', 'Disease', (28, 40))	('polycyclic aromatic hydrocarbons', 'Chemical', 'MESH:D011084', (76, 108))	('mutational', 'MPA', (174, 184))
215237	31231463	In both LUSC and HNSC, we found that a higher mutational smoking signature was associated with a higher TMB, as would be expected.	('TMB', 'Disease', (104, 107))	('TMB', 'Chemical', '-', (104, 107))	('HNSC', 'Phenotype', 'HP:0012288', (17, 21))	('mutational', 'Var', (46, 56))	('LUSC', 'Phenotype', 'HP:0030359', (8, 12))
215240	31231463	It was first observed by the Chan group that the genetic smoking signature was associated with a higher TMB and a higher response to anti-PD-1 immunotherapy.	('higher', 'PosReg', (97, 103))	('genetic smoking', 'Var', (49, 64))	('TMB', 'Chemical', '-', (104, 107))	('higher', 'PosReg', (114, 120))	('TMB', 'CPA', (104, 107))
215271	30734525	EGRF-tyrosine kinase inhibitors, anti-EGFR monoclonal antibodies, and tumor angiogenesis inhibitors have outstanding efficacy for patients with lung adenocarcinoma.3 However, EGFR-TKIs are only effective for lung squamous cell carcinoma (SCC) with EGFR mutations, and few SCC patients exhibit such mutations.	('patients', 'Species', '9606', (276, 284))	('SCC', 'Phenotype', 'HP:0002860', (272, 275))	('SCC', 'Phenotype', 'HP:0002860', (238, 241))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (208, 236))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (213, 236))	('EGFR', 'Gene', '1956', (38, 42))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('EGFR', 'Gene', (248, 252))	('mutations', 'Var', (253, 262))	('SCC', 'Gene', '6317', (272, 275))	('SCC', 'Gene', '6317', (238, 241))	('lung adenocarcinoma', 'Disease', (144, 163))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (208, 236))	('lung squamous cell carcinoma', 'Disease', (208, 236))	('EGFR', 'Gene', (175, 179))	('SCC', 'Gene', (272, 275))	('SCC', 'Gene', (238, 241))	('patients', 'Species', '9606', (130, 138))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (144, 163))	('carcinoma', 'Phenotype', 'HP:0030731', (227, 236))	('EGFR', 'Gene', '1956', (248, 252))	('EGFR', 'Gene', (38, 42))	('tumor', 'Disease', (70, 75))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (144, 163))	('carcinoma', 'Phenotype', 'HP:0030731', (154, 163))	('EGFR', 'Gene', '1956', (175, 179))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
215312	30734525	In summary, these results revealed that alteration of SQLE expression regulated ERK phosphorylation levels.	('regulated', 'Reg', (70, 79))	('ERK', 'Gene', '5594', (80, 83))	('SQLE', 'Gene', '6713', (54, 58))	('alteration', 'Var', (40, 50))	('ERK', 'Gene', (80, 83))	('SQLE', 'Gene', (54, 58))
215408	30739231	In a recent case report of a giant panda (Ailuropoda melanoleuca) with ovarian cancer, histopathological studies revealed multiple lesions in the lungs, kidneys, perianal tissue and spleen at necropsy, that stained positive by immunohistochemistry for B7-H4, CA125, and HE4, as well as the presence of significantly high serum levels of the tumour antigen AFP.	('B7-H4', 'Var', (252, 257))	('ovarian cancer', 'Disease', 'MESH:D010051', (71, 85))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('HE4', 'Gene', '10406', (270, 273))	('ovarian cancer', 'Phenotype', 'HP:0100615', (71, 85))	('ovarian cancer', 'Disease', (71, 85))	('HE4', 'Gene', (270, 273))	('CA125', 'Gene', (259, 264))	('tumour', 'Phenotype', 'HP:0002664', (341, 347))	('giant panda', 'Species', '9646', (29, 40))	('Ailuropoda melanoleuca', 'Species', '9646', (42, 64))	('tumour', 'Disease', 'MESH:D009369', (341, 347))	('CA125', 'Gene', '94025', (259, 264))	('tumour', 'Disease', (341, 347))	('high', 'PosReg', (316, 320))
215437	30739231	As with metastatic breast cancer in humans, reduction and aberrant expression of BRCA1 in canine mammary tumours has been found to be significantly associated with malignant characteristics.	('breast cancer', 'Phenotype', 'HP:0003002', (19, 32))	('tumours', 'Phenotype', 'HP:0002664', (105, 112))	('canine', 'Species', '9615', (90, 96))	('BRCA1', 'Gene', (81, 86))	('tumours', 'Disease', 'MESH:D009369', (105, 112))	('aberrant expression', 'Var', (58, 77))	('tumours', 'Disease', (105, 112))	('humans', 'Species', '9606', (36, 42))	('malignant characteristics', 'CPA', (164, 189))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('associated', 'Reg', (148, 158))	('breast cancer', 'Disease', 'MESH:D001943', (19, 32))	('BRCA1', 'Gene', '672', (81, 86))	('tumour', 'Phenotype', 'HP:0002664', (105, 111))	('breast cancer', 'Disease', (19, 32))
215438	30739231	Similarly, altered derlin-1 and stanniocalcin-1 expression levels are associated with the metastasis of human breast cancer cells and metastisizing canine mammary adenocarcinomas.	('carcinoma', 'Phenotype', 'HP:0030731', (168, 177))	('carcinomas', 'Phenotype', 'HP:0030731', (168, 178))	('stanniocalcin-1', 'Gene', (32, 47))	('derlin-1', 'Gene', (19, 27))	('expression levels', 'MPA', (48, 65))	('altered', 'Var', (11, 18))	('canine', 'Species', '9615', (148, 154))	('metastasis', 'CPA', (90, 100))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('stanniocalcin-1', 'Gene', '6781', (32, 47))	('associated', 'Reg', (70, 80))	('human', 'Species', '9606', (104, 109))	('adenocarcinomas', 'Disease', 'MESH:D000230', (163, 178))	('derlin-1', 'Gene', '79139', (19, 27))	('breast cancer', 'Disease', 'MESH:D001943', (110, 123))	('adenocarcinomas', 'Disease', (163, 178))	('breast cancer', 'Disease', (110, 123))	('breast cancer', 'Phenotype', 'HP:0003002', (110, 123))
215448	30739231	In both species, the GISTs arise due to oncogenic mutations in the KIT tyrosine kinase, which also drives canine cutaneous mast cell tumours.	('tumour', 'Phenotype', 'HP:0002664', (133, 139))	('cutaneous mast cell tumours', 'Disease', (113, 140))	('mutations', 'Var', (50, 59))	('KIT', 'Gene', (67, 70))	('mast cell tumour', 'Phenotype', 'HP:0100495', (123, 139))	('tumours', 'Phenotype', 'HP:0002664', (133, 140))	('canine', 'Species', '9615', (106, 112))	('cutaneous mast cell tumours', 'Disease', 'MESH:D034801', (113, 140))	('drives', 'PosReg', (99, 105))
215450	30739231	Although there are conflicting reports of the presence of BRAF, NRAS and c-KIT mutations in canine mucosal melanomas, possibly reflecting the complexity and heterogeneity of cancer seen in humans, a strong parallel between human and canine mucosal melanoma is frequent in activation of the RAS/MAPK and/or PI3K/AKT/mTOR signalling pathways with synergistic targeted inhibition of MEK and dual PI3K/mTOR inhibiting tumour growth of a canine melanoma cell line in nu/nu athymic mice.	('melanoma', 'Disease', (248, 256))	('mucosal melanoma', 'Disease', 'MESH:D008545', (240, 256))	('mTOR', 'Gene', '478232', (315, 319))	('canine', 'Species', '9615', (233, 239))	('activation', 'PosReg', (272, 282))	('melanoma', 'Disease', 'MESH:D008545', (440, 448))	('mutations', 'Var', (79, 88))	('melanoma', 'Disease', 'MESH:D008545', (107, 115))	('human', 'Species', '9606', (223, 228))	('mucosal melanoma', 'Disease', (240, 256))	('cancer', 'Disease', (174, 180))	('NRAS', 'Gene', (64, 68))	('tumour', 'Phenotype', 'HP:0002664', (414, 420))	('mucosal melanomas', 'Disease', 'MESH:D008545', (99, 116))	('tumour', 'Disease', 'MESH:D009369', (414, 420))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('c-KIT', 'Gene', '403811', (73, 78))	('melanoma', 'Disease', 'MESH:D008545', (248, 256))	('tumour', 'Disease', (414, 420))	('humans', 'Species', '9606', (189, 195))	('melanoma', 'Phenotype', 'HP:0002861', (248, 256))	('melanomas', 'Phenotype', 'HP:0002861', (107, 116))	('RAS/MAPK and/or', 'Pathway', (290, 305))	('mTOR', 'Gene', (398, 402))	('mucosal melanomas', 'Disease', (99, 116))	('human', 'Species', '9606', (189, 194))	('BRAF', 'Gene', '475526', (58, 62))	('melanoma', 'Phenotype', 'HP:0002861', (440, 448))	('melanoma', 'Disease', (440, 448))	('melanoma', 'Phenotype', 'HP:0002861', (107, 115))	('mTOR', 'Gene', '478232', (398, 402))	('melanoma', 'Disease', (107, 115))	('mucosal melanoma', 'Disease', 'MESH:D008545', (99, 115))	('NRAS', 'Gene', '403872', (64, 68))	('canine', 'Species', '9615', (92, 98))	('c-KIT', 'Gene', (73, 78))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('canine', 'Species', '9615', (433, 439))	('mTOR', 'Gene', (315, 319))	('inhibiting', 'NegReg', (403, 413))	('mice', 'Species', '10090', (476, 480))	('BRAF', 'Gene', (58, 62))	('MEK', 'Gene', (380, 383))
215469	30739231	A Phase II trial using L-MTP-PE in patients with osteosarcoma and synchronous or metachronous lung metastases concluded that there was evidence for a biological effect of L-MTP-PE on osteosarcoma lung metastases.	('L-MTP-PE', 'Chemical', 'MESH:C037144', (23, 31))	('osteosarcoma lung metastases', 'Disease', (183, 211))	('osteosarcoma and synchronous or metachronous lung metastases', 'Disease', 'MESH:D009362', (49, 109))	('osteosarcoma lung metastases', 'Disease', 'MESH:D009362', (183, 211))	('osteosarcoma', 'Phenotype', 'HP:0002669', (49, 61))	('L-MTP-PE', 'Var', (171, 179))	('osteosarcoma', 'Phenotype', 'HP:0002669', (183, 195))	('sarcoma', 'Phenotype', 'HP:0100242', (54, 61))	('patients', 'Species', '9606', (35, 43))	('sarcoma', 'Phenotype', 'HP:0100242', (188, 195))	('L-MTP-PE', 'Chemical', 'MESH:C037144', (171, 179))
215470	30739231	A phase I dose escalation clinical trial in dogs with osteosarcoma found that ADXS31-164 (Listeria expressing a chimeric human HER2/neu fusion protein) administered in the setting of minimal residual disease could induce HER2/neu-specific immunity and may reduce the incidence of metastatic disease and prolong overall survival.	('metastatic disease', 'CPA', (280, 298))	('HER2/neu-specific', 'Protein', (221, 238))	('prolong', 'PosReg', (303, 310))	('reduce', 'NegReg', (256, 262))	('sarcoma', 'Phenotype', 'HP:0100242', (59, 66))	('overall survival', 'CPA', (311, 327))	('human', 'Species', '9606', (121, 126))	('induce', 'PosReg', (214, 220))	('osteosarcoma', 'Disease', (54, 66))	('osteosarcoma', 'Phenotype', 'HP:0002669', (54, 66))	('osteosarcoma', 'Disease', 'MESH:D012516', (54, 66))	('ADXS31-164', 'Var', (78, 88))	('dogs', 'Species', '9615', (44, 48))
215503	29658571	For example, Zha et al found that HOXA1 was overexpressed in hepatocellular carcinoma (HCC), and high HOXA1 expression was positively associated with the T classification, N classification, distant metastasis and the clinical stage of HCC patients.	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (61, 85))	('overexpressed', 'PosReg', (44, 57))	('T classification', 'CPA', (154, 170))	('HCC', 'Gene', '619501', (87, 90))	('associated', 'Reg', (134, 144))	('distant metastasis', 'CPA', (190, 208))	('HCC', 'Gene', (87, 90))	('HOXA1', 'Gene', (102, 107))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (61, 85))	('HOXA1', 'Gene', '3198', (34, 39))	('N classification', 'CPA', (172, 188))	('HCC', 'Gene', '619501', (235, 238))	('hepatocellular carcinoma', 'Disease', (61, 85))	('HCC', 'Gene', (235, 238))	('HOXA1', 'Gene', (34, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('patients', 'Species', '9606', (239, 247))	('expression', 'MPA', (108, 118))	('HOXA1', 'Gene', '3198', (102, 107))	('high', 'Var', (97, 101))
215544	29658571	3F), indicating that high HOXA1 expression may be associated with increased survival time of NSCLC patients.	('increased', 'PosReg', (66, 75))	('NSCLC', 'Disease', (93, 98))	('associated', 'Reg', (50, 60))	('NSCLC', 'Disease', 'MESH:D002289', (93, 98))	('survival time', 'CPA', (76, 89))	('high', 'Var', (21, 25))	('patients', 'Species', '9606', (99, 107))	('HOXA1', 'Gene', (26, 31))	('expression', 'MPA', (32, 42))	('HOXA1', 'Gene', '3198', (26, 31))
215566	29658571	HOXA1 was confirmed as a tumorigenic gene, and high HOXA1 expression was associated with TNM stage and LNM.	('TNM stage', 'Disease', (89, 98))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('LNM', 'Disease', (103, 106))	('expression', 'MPA', (58, 68))	('tumor', 'Disease', (25, 30))	('high', 'Var', (47, 51))	('HOXA1', 'Gene', '3198', (52, 57))	('associated', 'Reg', (73, 83))	('HOXA1', 'Gene', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('HOXA1', 'Gene', '3198', (0, 5))	('HOXA1', 'Gene', (52, 57))
215578	29658571	Liu et al found that p53 was the most commonly mutated gene in NSCLC, being mutated in 45-70% of LUAD samples and 60-80% of LUSC samples.	('NSCLC', 'Disease', (63, 68))	('NSCLC', 'Disease', 'MESH:D002289', (63, 68))	('p53', 'Gene', '7157', (21, 24))	('mutated', 'Var', (76, 83))	('LUAD', 'Disease', (97, 101))	('p53', 'Gene', (21, 24))
215588	30891063	Data was generated for a set of exposure experiments on immortalized human lung epithelial (AALE) cells in a two-by-two study design, in which samples received both genetic and chemical perturbations of known oncogenes/tumor suppressors and lung carcinogens.	('perturbations', 'Var', (186, 199))	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('tumor', 'Disease', (219, 224))	('lung carcinogens', 'Disease', 'MESH:D008171', (241, 257))	('human', 'Species', '9606', (69, 74))	('tumor', 'Disease', 'MESH:D009369', (219, 224))	('rat', 'Species', '10116', (13, 16))	('lung carcinogens', 'Disease', (241, 257))
215602	30891063	Genotypic perturbations included CRISPR knockouts of FAT1, and CDKN2A, as well as overexpression of NRF2 (NFE2L2), FGFR1, NRG1, and PIK3CA.	('NRF2', 'Gene', (100, 104))	('CDKN2A', 'Gene', '1029', (63, 69))	('NFE2L2', 'Gene', '4780', (106, 112))	('NRG1', 'Gene', (122, 126))	('FAT1', 'Gene', '2195', (53, 57))	('PIK3CA', 'Gene', '5290', (132, 138))	('FAT1', 'Gene', (53, 57))	('NFE2L2', 'Gene', (106, 112))	('overexpression', 'PosReg', (82, 96))	('knockouts', 'Var', (40, 49))	('NRG1', 'Gene', '3084', (122, 126))	('PIK3CA', 'Gene', (132, 138))	('CDKN2A', 'Gene', (63, 69))	('FGFR1', 'Gene', (115, 120))	('FGFR1', 'Gene', '2260', (115, 120))	('NRF2', 'Gene', '4780', (100, 104))
215603	30891063	In addition, full coverage poly-A RNA-seq was performed on a separate set of samples for a subset of genotypic exposures, including CRISPR knockouts of FAT1, as well as overexpression of NRF2, NRG1, and PIK3CA.	('FAT1', 'Gene', '2195', (152, 156))	('NRF2', 'Gene', '4780', (187, 191))	('knockouts', 'Var', (139, 148))	('PIK3CA', 'Gene', (203, 209))	('NRG1', 'Gene', (193, 197))	('FAT1', 'Gene', (152, 156))	('rat', 'Species', '10116', (65, 68))	('NRG1', 'Gene', '3084', (193, 197))	('NRF2', 'Gene', (187, 191))	('PIK3CA', 'Gene', '5290', (203, 209))	('overexpression', 'PosReg', (169, 183))
215620	30891063	The two smoking gene sets consist of genes reported as either up- or down-regulated in response to smoking in at least one of the two publications, while TCGA gene sets were derived by probing differential expression of individual genes between patients with or without point mutations or copy number alterations (CNA) in genes of interest.	('point mutations', 'Var', (270, 285))	('patients', 'Species', '9606', (245, 253))	('rat', 'Species', '10116', (305, 308))	('up-', 'PosReg', (62, 65))	('copy number alterations', 'Var', (289, 312))	('down-regulated', 'NegReg', (69, 83))
215622	30891063	Specifically, point mutation signatures were derived from LUSC and LUAD, independently, by performing differential analysis of subjects with and without point mutations in genes of interest, matched for age, sex, and cancer stage.	('LUSC', 'Phenotype', 'HP:0030359', (58, 62))	('cancer', 'Disease', (217, 223))	('cancer', 'Disease', 'MESH:D009369', (217, 223))	('LUAD', 'Phenotype', 'HP:0030078', (67, 71))	('point mutations', 'Var', (153, 168))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))
215624	30891063	All models for mutations and CNA were adjusted for tumor purity, as reported.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('mutations', 'Var', (15, 24))	('tumor', 'Disease', (51, 56))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
215627	30891063	For example, the PIK3CA overexpression signatures were compared to the gene sets derived from PIK3CA mutation and CNA in the TCGA data.	('PIK3CA', 'Gene', (17, 23))	('PIK3CA', 'Gene', '5290', (17, 23))	('PIK3CA', 'Gene', (94, 100))	('mutation', 'Var', (101, 109))	('PIK3CA', 'Gene', '5290', (94, 100))
215632	30891063	The lower mapping rate of 3'DGE is most likely due to the lower read quality scores of 3'DGE compared to full coverage RNA-seq and SFL (Supplementary Figure S1B).	('rat', 'Species', '10116', (18, 21))	('lower', 'NegReg', (4, 9))	('read quality scores', 'MPA', (64, 83))	('lower', 'NegReg', (58, 63))	("3'DGE", 'Var', (87, 92))	('mapping', 'MPA', (10, 17))
215636	30891063	Although these differences are considerably more prominent when comparing full coverage RNA-seq to either SFL or 3'DGE, we do observe that when down-sampling from 10 to 100% of the counted library size, the PC error decreases at a consistently faster rate for SFL than for 3'DGE.	('down-sampling', 'NegReg', (144, 157))	('SFL', 'Var', (260, 263))	('PC error decreases', 'Disease', (207, 225))	('PC error decreases', 'Disease', 'MESH:D015324', (207, 225))	('rat', 'Species', '10116', (251, 254))
215648	30891063	Conversely, the set of down-regulated genes in "smokers vs. non-smokers" was only enriched in the microarray signature of "NRF2 over-expressed; CSC vs. DMSO" (Supplementary Figure S7).	('DMSO', 'Chemical', 'MESH:D004121', (152, 156))	('NRF2', 'Gene', '4780', (123, 127))	('over-expressed', 'PosReg', (128, 142))	('CSC vs.', 'Var', (144, 151))	('NRF2', 'Gene', (123, 127))
215649	30891063	The enrichment results of TCGA-derived gene sets with respect to differential signatures of genotypic perturbations were in agreement with the gene-level results, in that they consistently demonstrated smaller discovery rates by 3'DGE than by SFL or by microarrays (Figure 4A).	('TCGA-derived', 'Gene', (26, 38))	('rat', 'Species', '10116', (196, 199))	('smaller', 'NegReg', (202, 209))	("3'DGE", 'Var', (229, 234))	('rat', 'Species', '10116', (220, 223))	('discovery rates', 'MPA', (210, 225))
215677	30891063	For example, in the signatures of NRF2 overexpression, we consistently observe enrichment of the gene sets derived from NRF2 amplifications and KEAP1 deletions, each of which should increase NRF2 activity (Supplementary Figure S7).	('increase', 'PosReg', (182, 190))	('KEAP1', 'Gene', '9817', (144, 149))	('NRF2', 'Gene', '4780', (191, 195))	('deletions', 'Var', (150, 159))	('NRF2', 'Gene', (34, 38))	('KEAP1', 'Gene', (144, 149))	('NRF2', 'Gene', (191, 195))	('amplifications', 'Var', (125, 139))	('NRF2', 'Gene', '4780', (120, 124))	('NRF2', 'Gene', '4780', (34, 38))	('activity', 'MPA', (196, 204))	('NRF2', 'Gene', (120, 124))
215754	29914539	High HOXA11 expression may lead to carcinogenesis and the development of LUSC.	('High', 'Var', (0, 4))	('development of LUSC', 'CPA', (58, 77))	('HOXA11', 'Gene', '3207', (5, 11))	('carcinogenesis', 'Disease', 'MESH:D063646', (35, 49))	('HOXA11', 'Gene', (5, 11))	('lead to', 'Reg', (27, 34))	('expression', 'MPA', (12, 22))	('carcinogenesis', 'Disease', (35, 49))	('LUSC', 'Phenotype', 'HP:0030359', (73, 77))
215759	29914539	For example, EGFR targeted therapy had a modest effect in advanced LUSC patients.	('targeted therapy', 'Var', (18, 34))	('LUSC', 'Phenotype', 'HP:0030359', (67, 71))	('advanced LUSC', 'Disease', (58, 71))	('EGFR', 'Gene', '1956', (13, 17))	('EGFR', 'Gene', (13, 17))	('patients', 'Species', '9606', (72, 80))
215782	29914539	Genetic alterations of HOXA11, including amplification, deep deletion, and mRNA upregulation were additionally acquired from cBioPortal.	('deep deletion', 'Var', (56, 69))	('upregulation', 'PosReg', (80, 92))	('mRNA', 'MPA', (75, 79))	('HOXA11', 'Gene', '3207', (23, 29))	('amplification', 'Var', (41, 54))	('HOXA11', 'Gene', (23, 29))
215804	29914539	Alterations of HOXA11 were indicated via cBioPortal, which showed that HOXA11 expression was upregulated in 27 LUSC patients, deleted in 2 LUSC patients, and amplified in 8 LUSC patients (Fig.	('expression', 'MPA', (78, 88))	('deleted', 'Var', (126, 133))	('LUSC', 'Disease', (111, 115))	('patients', 'Species', '9606', (116, 124))	('patients', 'Species', '9606', (178, 186))	('LUSC', 'Phenotype', 'HP:0030359', (111, 115))	('HOXA11', 'Gene', '3207', (71, 77))	('LUSC', 'Phenotype', 'HP:0030359', (139, 143))	('HOXA11', 'Gene', (71, 77))	('patients', 'Species', '9606', (144, 152))	('LUSC', 'Phenotype', 'HP:0030359', (173, 177))	('HOXA11', 'Gene', '3207', (15, 21))	('HOXA11', 'Gene', (15, 21))	('upregulated', 'PosReg', (93, 104))
215808	29914539	The HPA database indicated that there were lower levels of the six hub genes in NSCLC tissues: ILK (Antibody CAB004041), PARVA (Antibody HPA005964), COL4A1 (Antibody CAB001695), ITGB1 (Antibody CAB003434), ITGA5 (Antibody CAB009008), and COL4A2 (Antibody CAB010751) (Fig.	('Antibody CAB001695', 'Var', (157, 175))	('COL4A1', 'Gene', '1282', (149, 155))	('ITGB1', 'Gene', (178, 183))	('NSCLC', 'Disease', (80, 85))	('Antibody CAB010751', 'Var', (246, 264))	('Antibody CAB009008', 'Var', (213, 231))	('COL4A2', 'Gene', '1284', (238, 244))	('ITGA5', 'Gene', (206, 211))	('NSCLC', 'Phenotype', 'HP:0030358', (80, 85))	('HPA', 'Disease', 'MESH:D010661', (4, 7))	('ITGA5', 'Gene', '3678', (206, 211))	('Antibody CAB003434', 'Var', (185, 203))	('HPA', 'Disease', (4, 7))	('COL4A1', 'Gene', (149, 155))	('PARVA', 'Gene', (121, 126))	('ITGB1', 'Gene', '3688', (178, 183))	('hub', 'Gene', (67, 70))	('ILK', 'Gene', (95, 98))	('HPA', 'Disease', 'MESH:D010661', (137, 140))	('HPA', 'Disease', (137, 140))	('ILK', 'Gene', '3611', (95, 98))	('hub', 'Gene', '1993', (67, 70))	('Antibody CAB004041', 'Var', (100, 118))	('COL4A2', 'Gene', (238, 244))	('PARVA', 'Gene', '55742', (121, 126))	('NSCLC', 'Disease', 'MESH:D002289', (80, 85))
215844	29914539	The findings of the present study indicate that HOXA11 high expression might lead to the occurrence and development of LUSC.	('HOXA11', 'Gene', '3207', (48, 54))	('lead to', 'Reg', (77, 84))	('HOXA11', 'Gene', (48, 54))	('high expression', 'Var', (55, 70))	('LUSC', 'Disease', (119, 123))	('LUSC', 'Phenotype', 'HP:0030359', (119, 123))	('development of', 'CPA', (104, 118))
215857	29515971	Using data from 10,355, primary tumor resection samples and 2,787 normal samples that we extracted from The Cancer Genome Atlas and Genotype-Tissue Expression project databases, we screened the variation of CYT across 32 different cancer types and 28 different normal tissue types.	('cancer', 'Disease', 'MESH:D009369', (231, 237))	('Cancer', 'Phenotype', 'HP:0002664', (108, 114))	('cancer', 'Disease', (231, 237))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('Cancer Genome Atlas', 'Disease', (108, 127))	('tumor', 'Disease', (32, 37))	('screened', 'Reg', (181, 189))	('variation', 'Var', (194, 203))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (108, 127))	('CYT', 'Gene', (207, 210))
215886	29515971	Using the Genomic Data Commons (GDC) Data Portal (The Cancer Genome Atlas, TCGA program3) and the GTEx web portal (Genotype-Tissue Expression project4), we extracted data from a total of 10,355 tumor resection samples and 2,935 normal samples and screened the variation of CYT across these 32 different cancer types and 28 different normal solid tissue types.	('CYT', 'Gene', (273, 276))	('Cancer Genome Atlas', 'Disease', (54, 73))	('cancer', 'Disease', (303, 309))	('Cancer', 'Phenotype', 'HP:0002664', (54, 60))	('variation', 'Var', (260, 269))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (54, 73))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('cancer', 'Phenotype', 'HP:0002664', (303, 309))	('screened', 'Reg', (247, 255))	('tumor', 'Disease', (194, 199))	('cancer', 'Disease', 'MESH:D009369', (303, 309))
215903	29515971	GZMA was stained with an anti-GZMA antibody produced in rabbit (HPA054134, 1:200 dilution, Sigma-Aldrich) and PRF1 using two different antibodies produced in rabbit (either HPA037940, 1:29 dilution, or CAB002436, 1:10 dilution, Sigma-Aldrich).	('rabbit', 'Species', '9986', (56, 62))	('CAB002436', 'Var', (202, 211))	('rabbit', 'Species', '9986', (158, 164))	('GZMA', 'Gene', (30, 34))	('GZMA', 'Gene', (0, 4))	('GZMA', 'Gene', '3001', (30, 34))	('GZMA', 'Gene', '3001', (0, 4))
215920	29515971	Importantly, we show for the first time that DLBCL and testicular cancer also rank among the top cytolytic active tumors, with DLBCL exhibiting even higher cytolytic levels compared to KIRC (>100 TPM).	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('testicular cancer', 'Phenotype', 'HP:0010788', (55, 72))	('testicular cancer', 'Disease', (55, 72))	('cytolytic levels', 'MPA', (156, 172))	('tumors', 'Disease', (114, 120))	('tumors', 'Disease', 'MESH:D009369', (114, 120))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('DLBCL', 'Disease', (45, 50))	('higher', 'PosReg', (149, 155))	('DLBCL', 'Var', (127, 132))	('testicular cancer', 'Disease', 'MESH:D013736', (55, 72))
215945	29515971	We next performed Kaplan-Meier survival analysis on 37 TCGA-datasets deriving from 25 different cancer types in order to estimate the risk of individual and/or simultaneous high (or low) PRF1 and GZMA expression on patient overall survival.	('high', 'Var', (173, 177))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('low', 'NegReg', (182, 185))	('GZMA', 'Gene', (196, 200))	('PRF1', 'Gene', (187, 191))	('GZMA', 'Gene', '3001', (196, 200))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Disease', (96, 102))	('patient', 'Species', '9606', (215, 222))
215946	29515971	In TCGA-ACC, non-metastatic cutaneous melanoma ("m0" TCGA-SKCM), and bladder urothelial carcinoma (TCGA-BLCA but not the GSE32894 dataset), both individual and simultaneous high levels of PRF1 and GZMA were significantly associated with better prognosis.	('ACC', 'Phenotype', 'HP:0006744', (8, 11))	('non-metastatic cutaneous melanoma', 'Phenotype', 'HP:0012057', (13, 46))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (28, 46))	('cutaneous melanoma', 'Disease', (28, 46))	('bladder urothelial carcinoma', 'Disease', (69, 97))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (28, 46))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('high levels', 'Var', (173, 184))	('GZMA', 'Gene', (197, 201))	('GZMA', 'Gene', '3001', (197, 201))	('melanoma', 'Phenotype', 'HP:0002861', (38, 46))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (69, 97))	('PRF1', 'Gene', (188, 192))
215950	29515971	In TCGA-LIHC, only the individual high levels of PRF1 and GZMA were significantly associated with a positive effect on patient survival.	('GZMA', 'Gene', '3001', (58, 62))	('patient', 'Species', '9606', (119, 126))	('LIHC', 'Disease', (8, 12))	('PRF1', 'Gene', (49, 53))	('LIHC', 'Disease', 'None', (8, 12))	('high levels', 'Var', (34, 45))	('GZMA', 'Gene', (58, 62))
215951	29515971	A similar non-significant association of (individual or simultaneous) high GZMA and PRF1 expression with better effect on patient survival could also be observed in TCGA-MESO, ovarian cancer (GSE13876 and GSE49997), TCGA-STAD, TCGA-THCA, and TCGA-UCEC (Figure S1 in Supplementary Material).	('GZMA', 'Gene', '3001', (75, 79))	('patient', 'Species', '9606', (122, 129))	('ovarian cancer', 'Phenotype', 'HP:0100615', (176, 190))	('GSE49997', 'Var', (205, 213))	('TCGA-MESO', 'Disease', (165, 174))	('TCGA-UCEC', 'Disease', (242, 251))	('GSE13876', 'Var', (192, 200))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('GZMA', 'Gene', (75, 79))	('ovarian cancer', 'Disease', 'MESH:D010051', (176, 190))	('high', 'Var', (70, 74))	('TCGA-THCA', 'Disease', (227, 236))	('TCGA-STAD', 'Disease', (216, 225))	('ovarian cancer', 'Disease', (176, 190))	('PRF1', 'Gene', (84, 88))
215952	29515971	These data suggest that high CYT is widely associated with an improved prognosis among the above-mentioned cancer types.	('improved', 'PosReg', (62, 70))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('high CYT', 'Var', (24, 32))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('cancer', 'Disease', (107, 113))
215953	29515971	On the contrary, across TCGA-LGG, BRCAs (GSE25066), and TCGA-THYM, both individual and simultaneous high levels of GZMA and PRF1 were significantly associated with a worse prognosis, whereas the simultaneous low levels of both genes led to a significant shift toward positive effect (Figure 6B).	('BRCA', 'Gene', '672', (34, 38))	('GSE25066', 'Var', (41, 49))	('BRCA', 'Gene', (34, 38))	('GZMA', 'Gene', (115, 119))	('GZMA', 'Gene', '3001', (115, 119))	('PRF1', 'Gene', (124, 128))	('associated with', 'Reg', (148, 163))
215956	29515971	Analogous non-significant associations of (individual or simultaneous) high cytolytic levels with worse effect on patient survival were also observed in lung cancer (GSE30219, TCGA-LUAD, and TCGA-LUSC), TCGA-PAAD, TCGA-PRAD and GSE16560, and TCGA-READ (Figure S2 in Supplementary Material).	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('lung cancer', 'Disease', 'MESH:D008175', (153, 164))	('lung cancer', 'Disease', (153, 164))	('high cytolytic levels', 'MPA', (71, 92))	('lung cancer', 'Phenotype', 'HP:0100526', (153, 164))	('patient', 'Species', '9606', (114, 121))	('GSE30219', 'Var', (166, 174))	('PAAD', 'Phenotype', 'HP:0006725', (208, 212))
215958	29515971	Depending on the probe used, it seemed that a combination of high PRF1 and low GZMA levels yields a better patient outcome (GSE39582, TCGA-COAD, TCGA-COADREAD).	('COAD', 'Disease', (150, 154))	('low', 'NegReg', (75, 78))	('GZMA', 'Gene', '3001', (79, 83))	('PRF1', 'MPA', (66, 70))	('COAD', 'Disease', 'MESH:D029424', (139, 143))	('high', 'Var', (61, 65))	('COAD', 'Disease', 'MESH:D029424', (150, 154))	('COAD', 'Disease', (139, 143))	('patient', 'Species', '9606', (107, 114))	('GZMA', 'Gene', (79, 83))
215964	29515971	In DLBCL (GSE10846, and GSE32918), using various combinations of distinct molecular probes for the two cytolytic genes (PRF1, 214617_AT, 1553681_A_AT, or ILMN_1740633; GZMA, 205488_AT, or ILMN_1779324), we could not provide any significant association with patient survival.	('GSE32918', 'Var', (24, 32))	('GZMA', 'Gene', '3001', (168, 172))	('ILMN_1740633', 'Var', (154, 166))	('patient', 'Species', '9606', (257, 264))	('AT', 'Disease', 'None', (133, 135))	('AT', 'Disease', 'None', (147, 149))	('GSE10846', 'Var', (10, 18))	('PRF1', 'Var', (120, 124))	('AT', 'Disease', 'None', (181, 183))	('GZMA', 'Gene', (168, 172))
215965	29515971	A similar absence of significant associations was also detected in glioblastoma (GSE4271, GSE13041, and TCGA-GBM) and non-metastatic HNSCs.	('glioblastoma', 'Disease', (67, 79))	('glioblastoma', 'Disease', 'MESH:D005909', (67, 79))	('GBM', 'Phenotype', 'HP:0012174', (109, 112))	('non-metastatic HNSCs', 'Disease', (118, 138))	('glioblastoma', 'Phenotype', 'HP:0012174', (67, 79))	('GSE13041', 'Var', (90, 98))	('GSE4271', 'Chemical', '-', (81, 88))	('GSE4271', 'Var', (81, 88))
216003	29515971	Among them, recurrent mutations in immune-related genes have been proposed, such as B2M, HLA-A, -B, and -C, and CASP8, as well as copy number aberrations in loci containing immunosuppressive factors, including the receptors PD-L1/2 and CTLA-4.	('B2M', 'Gene', (84, 87))	('CASP8', 'Gene', '841', (112, 117))	('B2M', 'Gene', '567', (84, 87))	('CTLA-4', 'Gene', '1493', (236, 242))	('copy number aberrations', 'Var', (130, 153))	('CTLA-4', 'Gene', (236, 242))	('HLA-A, -B, and -C', 'Gene', '3105;3106;3107', (89, 106))	('mutations', 'Var', (22, 31))	('PD-L1/2', 'Gene', '29126;80380', (224, 231))	('PD-L1/2', 'Gene', (224, 231))	('CASP8', 'Gene', (112, 117))
216008	29515971	Actually, recent clinical trials have demonstrated that blockage of this signaling can benefit patients with advanced melanoma, kidney, or non-small cell lung cancer.	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (139, 165))	('melanoma', 'Phenotype', 'HP:0002861', (118, 126))	('melanoma', 'Disease', (118, 126))	('lung cancer', 'Phenotype', 'HP:0100526', (154, 165))	('melanoma', 'Disease', 'MESH:D008545', (118, 126))	('non-small cell lung cancer', 'Disease', (139, 165))	('blockage', 'Var', (56, 64))	('patients', 'Species', '9606', (95, 103))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (139, 165))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (143, 165))	('kidney', 'Disease', (128, 134))
216016	29515971	Importantly, CTLA-4 blockade was reported to associate with bowel inflammation in melanoma patients, signifying that its signaling is crucial for the preservation of immune homeostasis in the gut.	('associate', 'Reg', (45, 54))	('patients', 'Species', '9606', (91, 99))	('bowel inflammation', 'Phenotype', 'HP:0002037', (60, 78))	('melanoma', 'Phenotype', 'HP:0002861', (82, 90))	('melanoma', 'Disease', (82, 90))	('CTLA-4', 'Gene', '1493', (13, 19))	('blockade', 'Var', (20, 28))	('melanoma', 'Disease', 'MESH:D008545', (82, 90))	('bowel inflammation', 'Disease', 'MESH:D007249', (60, 78))	('CTLA-4', 'Gene', (13, 19))	('bowel inflammation', 'Disease', (60, 78))
216022	29515971	Inhibition of both IDO and arginase can enhance intratumoral inflammation.	('IDO', 'Gene', '3620', (19, 22))	('IDO', 'Gene', (19, 22))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('arginase', 'Protein', (27, 35))	('enhance', 'PosReg', (40, 47))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('inflammation', 'Disease', 'MESH:D007249', (61, 73))	('inflammation', 'Disease', (61, 73))	('Inhibition', 'Var', (0, 10))	('tumor', 'Disease', (53, 58))
216036	29515971	A very interesting improvement in the field was further made by Riaz et al., who showed that the mutation burden in melanoma patients decreases with successful anti-PD-1 blockade therapy, suggesting that the selection against mutant neoepitopes is a critical mechanism of action of this immunotherapy.	('Riaz', 'Gene', (64, 68))	('mutant', 'Var', (226, 232))	('mutation burden', 'MPA', (97, 112))	('PD-1', 'Gene', (165, 169))	('PD-1', 'Gene', '5133', (165, 169))	('Riaz', 'Gene', '23598', (64, 68))	('melanoma', 'Phenotype', 'HP:0002861', (116, 124))	('melanoma', 'Disease', (116, 124))	('melanoma', 'Disease', 'MESH:D008545', (116, 124))	('decreases', 'NegReg', (134, 143))	('patients', 'Species', '9606', (125, 133))
216040	29515971	Overall, it seems that CYT is part of an inflammatory environment in a premalignant state of certain tumor types, whereas, in others, oncogenic mutations, copy number aberrations, or viral infection can induce a tumor-promoting inflammatory microenvironment, within which complex interactions between different cell types regulate cancer development and metastasis.	('copy number aberrations', 'Var', (155, 178))	('cancer', 'Disease', (331, 337))	('cancer', 'Disease', 'MESH:D009369', (331, 337))	('induce', 'PosReg', (203, 209))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('viral infection', 'Disease', 'MESH:D001102', (183, 198))	('tumor', 'Disease', 'MESH:D009369', (212, 217))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('cancer', 'Phenotype', 'HP:0002664', (331, 337))	('viral infection', 'Disease', (183, 198))	('tumor', 'Disease', (212, 217))	('mutations', 'Var', (144, 153))
216047	29515971	In some tumor types (ACC, SKCM, BLCA, LIHC, MESO, OV, STAD, THCA, and UCEC), high CYT was associated with an improved outcome; whereas in others (LGG, BRCA, THYM, LUAD/LUSC, PAAD, PRAD, and READ) it is correlated with a worse outcome.	('BRCA', 'Gene', '672', (151, 155))	('LIHC', 'Disease', 'None', (38, 42))	('BRCA', 'Gene', (151, 155))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('MESO', 'Disease', (44, 48))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('ACC', 'Phenotype', 'HP:0006744', (21, 24))	('PAAD', 'Phenotype', 'HP:0006725', (174, 178))	('PAAD', 'Disease', (174, 178))	('LUAD/LUSC', 'Disease', (163, 172))	('improved', 'PosReg', (109, 117))	('tumor', 'Disease', (8, 13))	('THYM', 'Disease', (157, 161))	('PRAD', 'Disease', (180, 184))	('LIHC', 'Disease', (38, 42))	('high CYT', 'Var', (77, 85))
216048	29515971	Among LGG, THYM, and BRCA, we showed that both individual and simultaneous high levels of GZMA and PRF1 were significantly associated with a worse prognosis, whereas the simultaneous low levels of both cytolytic genes led to a significant shift toward a positive effect.	('GZMA', 'Gene', (90, 94))	('associated', 'Reg', (123, 133))	('BRCA', 'Gene', (21, 25))	('PRF1', 'Gene', (99, 103))	('high', 'Var', (75, 79))	('GZMA', 'Gene', '3001', (90, 94))	('BRCA', 'Gene', '672', (21, 25))
216098	29459639	Following mutations' categorization into 5 representative lung SQCC pathways, it was assessed that 21 (36.8%) patients showed alternation of redox stress pathway, 46 (80.7%) in apoptosis pathway, 32 (56.1%) in proliferation pathway, 14 (24.6%) in differentiation pathway, and 28 (49.1%) in chromatic remodelers pathways.	('differentiation pathway', 'Pathway', (247, 270))	('redox stress pathway', 'Pathway', (141, 161))	('apoptosis pathway', 'Pathway', (177, 194))	('alternation', 'Reg', (126, 137))	('proliferation pathway', 'Pathway', (210, 231))	('mutations', 'Var', (10, 19))	('patients', 'Species', '9606', (110, 118))	('chromatic remodelers pathways', 'Pathway', (290, 319))
216100	29459639	Most patients (77%) with alteration pathways had aberration of one of the genes associated with the pathway.	('aberration', 'Var', (49, 59))	('alteration', 'Var', (25, 35))	('patients', 'Species', '9606', (5, 13))
216117	29459639	In contrast, imaging is more representative of the whole tumors and may facilitate identification of mutations and have a clinical influence on precision medicine.	('mutations', 'Var', (101, 110))	('facilitate', 'PosReg', (72, 82))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('tumors', 'Disease', (57, 63))	('tumors', 'Disease', 'MESH:D009369', (57, 63))
216120	29459639	In lung adenocarcinoma with well-known, targetable mutations, studies have found imaging biomarkers that reflect gene expression or treatment response.	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (3, 22))	('mutations', 'Var', (51, 60))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (3, 22))	('men', 'Species', '9606', (137, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (13, 22))	('lung adenocarcinoma', 'Disease', (3, 22))
216122	29459639	Our previous study described that lung SQCCs showed a high mutational burden in lungs SQCCs in a large cohort of East Asians, and statistical enrichment for mutations in 7 genes; TP53, RB1, PTEN, NFE2L2, KEAP1, MLL2, and PIK3CA.	('mutational', 'Var', (59, 69))	('PIK3CA', 'Gene', '5290', (221, 227))	('MLL2', 'Gene', '9757', (211, 215))	('PTEN', 'Gene', (190, 194))	('RB1', 'Gene', '5925', (185, 188))	('NFE2L2', 'Gene', '4780', (196, 202))	('MLL2', 'Gene', (211, 215))	('men', 'Species', '9606', (148, 151))	('KEAP1', 'Gene', '9817', (204, 209))	('PTEN', 'Gene', '5728', (190, 194))	('TP53', 'Gene', '7157', (179, 183))	('mutations', 'Var', (157, 166))	('NFE2L2', 'Gene', (196, 202))	('PIK3CA', 'Gene', (221, 227))	('KEAP1', 'Gene', (204, 209))	('RB1', 'Gene', (185, 188))	('TP53', 'Gene', (179, 183))
216131	29459639	In adenocarcinoma, local features were found to be associated with mutations in genes such as epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK).	('lymphoma', 'Phenotype', 'HP:0002665', (148, 156))	('anaplastic lymphoma kinase', 'Gene', '238', (137, 163))	('ALK', 'Gene', '238', (165, 168))	('EGFR', 'Gene', '1956', (128, 132))	('carcinoma', 'Phenotype', 'HP:0030731', (8, 17))	('EGFR', 'Gene', (128, 132))	('adenocarcinoma', 'Disease', (3, 17))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (137, 156))	('mutations', 'Var', (67, 76))	('anaplastic lymphoma kinase', 'Gene', (137, 163))	('epidermal growth factor receptor', 'Gene', (94, 126))	('associated', 'Reg', (51, 61))	('adenocarcinoma', 'Disease', 'MESH:D000230', (3, 17))	('ALK', 'Gene', (165, 168))	('epidermal growth factor receptor', 'Gene', '1956', (94, 126))
216137	29459639	Consequently, we hypothesized that alterations in lung SQCC cancer pathways may be associated with emphysema on CT.	('alterations', 'Var', (35, 46))	('lung SQCC cancer', 'Disease', (50, 66))	('emphysema', 'Disease', (99, 108))	('emphysema', 'Disease', 'MESH:D004646', (99, 108))	('associated', 'Reg', (83, 93))	('lung SQCC cancer', 'Disease', 'MESH:D008175', (50, 66))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('emphysema', 'Phenotype', 'HP:0002097', (99, 108))
216144	29459639	A study with lung adenocarcinoma reported that the irregular shape of tumor was associated with worse survival, similar to our results.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', (70, 75))	('worse', 'NegReg', (96, 101))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (13, 32))	('carcinoma', 'Phenotype', 'HP:0030731', (23, 32))	('survival', 'MPA', (102, 110))	('lung adenocarcinoma', 'Disease', (13, 32))	('irregular', 'Var', (51, 60))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (13, 32))
216177	29127303	Notably, the AJUBA mutations and mutational signature4 were significantly correlated with a poorer survival in patients with ESCC.	('mutational signature4', 'Var', (33, 54))	('AJUBA', 'Gene', '84962', (13, 18))	('poorer', 'NegReg', (92, 98))	('signature4', 'Chemical', '-', (44, 54))	('mutations', 'Var', (19, 28))	('correlated', 'Reg', (74, 84))	('survival', 'MPA', (99, 107))	('AJUBA', 'Gene', (13, 18))	('ESCC', 'Disease', (125, 129))	('patients', 'Species', '9606', (111, 119))
216178	29127303	Hierarchical clustering analysis of the copy number alteration (CNA) of cancer gene census (CGC) genes in ESCC patients revealed three subtypes, and subtype3 exhibited more CNAs and marked for worse prognosis compared with subtype2.	('CGC) genes', 'Gene', (92, 102))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('ESCC', 'Disease', (106, 110))	('patients', 'Species', '9606', (111, 119))	('more', 'PosReg', (168, 172))	('CNAs', 'MPA', (173, 177))	('copy number alteration', 'Var', (40, 62))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('cancer', 'Disease', (72, 78))
216184	29127303	Recently, large-scale investigations on ESCC have been performed in China, focusing on the discovery of new driver mutations that may be closely associated with the development of oesophageal cancer.	('mutations', 'Var', (115, 124))	('associated', 'Reg', (145, 155))	('oesophageal cancer', 'Disease', 'MESH:D009369', (180, 198))	('oesophageal cancer', 'Disease', (180, 198))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))
216185	29127303	identified the new oncogene mutant FAM135B, which promoted malignant phenotypes in 17 whole genome sequencing (WGS) and 71 whole exome sequencing (WES) cases.	('mutant', 'Var', (28, 34))	('promoted', 'PosReg', (50, 58))	('FAM135B', 'Gene', (35, 42))	('FAM135B', 'Gene', '51059', (35, 42))	('malignant', 'CPA', (59, 68))
216195	29127303	Signature1 was characterized primarily by C > T and C > G mutations at TpCpN trinucleotides, and has been confirmed to be associated with the APOBEC family of cytidine deaminases, which played an important role in the deaminase activity of single-stranded DNA (ssDNA).	('associated', 'Reg', (122, 132))	('C > G mutations', 'Var', (52, 67))	('TpCpN', 'Gene', (71, 76))	('C > T', 'Var', (42, 47))	('trinucleotides', 'Chemical', '-', (77, 91))
216196	29127303	Signature2 was characterized by C > T mutations at NpCpG trinucleotides.	('C > T mutations', 'Var', (32, 47))	('NpCpG', 'Gene', (51, 56))	('trinucleotides', 'Chemical', '-', (57, 71))
216200	29127303	Patients with signature4 exhibited poor survival (Fig.	('Patients', 'Species', '9606', (0, 8))	('signature4', 'Var', (14, 24))	('poor', 'NegReg', (35, 39))	('signature4', 'Chemical', '-', (14, 24))
216201	29127303	Signature5 has been found in oesophageal cancer, but the aetiology of this process remains unknown.	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('Signature5', 'Var', (0, 10))	('found', 'Reg', (20, 25))	('oesophageal cancer', 'Disease', 'MESH:D009369', (29, 47))	('oesophageal cancer', 'Disease', (29, 47))
216202	29127303	The comprehensive analysis of larger sample set enabled us to identify more comprehensive mutational signatures of ESCC and analyse the different mechanisms of carcinogenesis.	('carcinogenesis', 'Disease', 'MESH:D063646', (160, 174))	('mutational', 'Var', (90, 100))	('carcinogenesis', 'Disease', (160, 174))	('ESCC', 'Gene', (115, 119))
216209	29127303	In our study, the nonsilent mutation rate of AJUBA was 3.9%, including two stop-gain and three frame shift mutations in the LIM domain (Fig.	('AJUBA', 'Gene', (45, 50))	('LIM', 'Gene', '10611', (124, 127))	('AJUBA', 'Gene', '84962', (45, 50))	('frame shift mutations', 'Var', (95, 116))	('LIM', 'Gene', (124, 127))
216215	29127303	We identified six mutations in the phosphatase domain (p.A86T, p.R130*, p.R130Q(2), p.F145I, p.Q171*) and six mutations in the C2 domain (p.G209A, p.F215C, p.K263*, p.Q245*, p.F257S, p.VL317fs) of the tumour repressor PTEN (Supplementary Fig.	('p.G209A', 'Mutation', 'p.G209A', (138, 145))	('p.A86T', 'Mutation', 'p.A86T', (55, 61))	('p.F145I', 'Mutation', 'p.F145I', (84, 91))	('p.VL317fs', 'Var', (183, 192))	('p.A86T', 'Var', (55, 61))	('p.R130*', 'Var', (63, 70))	('p.K263*', 'Var', (156, 163))	('p.K263*', 'Mutation', 'p.K263*', (156, 163))	('PTEN', 'Gene', (218, 222))	('tumour', 'Phenotype', 'HP:0002664', (201, 207))	('p.F215C', 'Var', (147, 154))	('p.F145I', 'Var', (84, 91))	('p.VL317fs', 'Mutation', 'p.VL317fs', (183, 192))	('p.Q171*', 'Var', (93, 100))	('p.Q245*', 'Var', (165, 172))	('tumour', 'Disease', 'MESH:D009369', (201, 207))	('tumour', 'Disease', (201, 207))	('p.G209A', 'Var', (138, 145))	('PTEN', 'Gene', '5728', (218, 222))	('p.Q171*', 'Mutation', 'p.Q171*', (93, 100))	('p.F257S', 'Var', (174, 181))	('p.R130Q', 'Mutation', 'rs121909229', (72, 79))	('p.F257S', 'Mutation', 'p.F257S', (174, 181))	('p.Q245*', 'Mutation', 'p.Q245*', (165, 172))	('p.F215C', 'Mutation', 'p.F215C', (147, 154))	('p.R130*', 'Mutation', 'p.R130*', (63, 70))
216216	29127303	We identified 14 somatic mutations in CUL3 gene, 13 of which were located in the Cullin domain (Supplementary Fig.	('CUL3', 'Gene', (38, 42))	('mutations', 'Var', (25, 34))	('CUL3', 'Gene', '8452', (38, 42))
216217	29127303	We identified 4 mutations in the ecTbetaR2 domain of the gene TGFBR2, which was also known as transforming growth factor beta receptor 2 ectodomain and transmits signals from the cell surface into the cell.	('transforming growth factor beta receptor 2', 'Gene', (94, 136))	('TGFBR2', 'Gene', (62, 68))	('mutations in', 'Var', (16, 28))	('transforming growth factor beta receptor 2', 'Gene', '7048', (94, 136))	('TGFBR2', 'Gene', '7048', (62, 68))
216218	29127303	We also identified 7 mutations in another important domain, protein tyrosine kinase, which is a key regulator of normal cellular processes and has a critical role in the development of many cancers.	('cancers', 'Phenotype', 'HP:0002664', (190, 197))	('cancers', 'Disease', (190, 197))	('cancers', 'Disease', 'MESH:D009369', (190, 197))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('mutations', 'Var', (21, 30))
216219	29127303	We identified 15 nonsilent mutations in DCDC1 gene, of which 11 were missense mutations and 3 were nonsense mutations.	('DCDC1', 'Gene', (40, 45))	('missense mutations', 'Var', (69, 87))	('DCDC1', 'Gene', '341019', (40, 45))
216228	29127303	In our study, in addition to finding the nonsense mutations in PTEN that could cause loss of function, we also detected hotspot mutations in the p110a domain (p.N345K, p.C420R, p.E545K, p.E542K) and C-terminal portion (p.H1047R, p.H1047L) coded by PIK3CA.	('p.N345K', 'Mutation', 'rs121913284', (159, 166))	('p.H1047R', 'Var', (219, 227))	('PTEN', 'Gene', '5728', (63, 67))	('p.H1047L', 'Var', (229, 237))	('p.N345K', 'Var', (159, 166))	('PTEN', 'Gene', (63, 67))	('p.C420R', 'Mutation', 'rs121913272', (168, 175))	('p.E542K', 'Var', (186, 193))	('p.H1047R', 'Mutation', 'rs121913279', (219, 227))	('p.H1047L', 'Mutation', 'rs121913279', (229, 237))	('PIK3CA', 'Gene', (248, 254))	('p.E545K', 'Var', (177, 184))	('p.E545K', 'Mutation', 'rs104886003', (177, 184))	('PIK3CA', 'Gene', '5290', (248, 254))	('p.E542K', 'Mutation', 'rs121913273', (186, 193))	('p.C420R', 'Var', (168, 175))
216229	29127303	In recent years, frequent mutations in the NFE2L2/KEAP1/CUL3 pathway had been reported in many types of cancers, including ESCC.	('KEAP1', 'Gene', (50, 55))	('NFE2L2', 'Gene', '4780', (43, 49))	('NFE2L2', 'Gene', (43, 49))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('mutations', 'Var', (26, 35))	('KEAP1', 'Gene', '9817', (50, 55))	('cancers', 'Phenotype', 'HP:0002664', (104, 111))	('CUL3', 'Gene', '8452', (56, 60))	('cancers', 'Disease', (104, 111))	('CUL3', 'Gene', (56, 60))	('cancers', 'Disease', 'MESH:D009369', (104, 111))	('reported', 'Reg', (78, 86))
216230	29127303	In our study, we identified mutations in NFE2L2 in 9.6% of the ESCC samples and mutations in KEAP1 and CUL3 in 2.9% of the ESCC samples.	('KEAP1', 'Gene', '9817', (93, 98))	('mutations', 'Var', (80, 89))	('NFE2L2', 'Gene', '4780', (41, 47))	('KEAP1', 'Gene', (93, 98))	('CUL3', 'Gene', '8452', (103, 107))	('NFE2L2', 'Gene', (41, 47))	('CUL3', 'Gene', (103, 107))	('ESCC', 'Disease', (63, 67))	('mutations', 'Var', (28, 37))
216231	29127303	We found that the mutations in NFE2L2 were almost mutually exclusive with mutations in KEAP1 and CUL3 and that the mutations in KEAP1 and CUL3 were mutually exclusive (Supplementary Fig.	('CUL3', 'Gene', (97, 101))	('KEAP1', 'Gene', '9817', (87, 92))	('CUL3', 'Gene', '8452', (97, 101))	('NFE2L2', 'Gene', '4780', (31, 37))	('KEAP1', 'Gene', (87, 92))	('KEAP1', 'Gene', '9817', (128, 133))	('CUL3', 'Gene', '8452', (138, 142))	('NFE2L2', 'Gene', (31, 37))	('CUL3', 'Gene', (138, 142))	('KEAP1', 'Gene', (128, 133))	('mutations', 'Var', (18, 27))
216235	29127303	In our study, the nonsilent mutation frequency of KMT2D was 11%, and 30 mutations (46.9%) were truncating (nonsense mutation and frame shift).	('frame shift', 'Var', (129, 140))	('KMT2D', 'Gene', (50, 55))	('KMT2D', 'Gene', '8085', (50, 55))
216236	29127303	4), including 11q13.3 amplification and 9p21.3 deletion, which have been reported to be associated with human cancers.	('cancers', 'Disease', (110, 117))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('human', 'Species', '9606', (104, 109))	('deletion', 'Var', (47, 55))	('associated', 'Reg', (88, 98))	('cancers', 'Phenotype', 'HP:0002664', (110, 117))	('11q13.3', 'Gene', (14, 21))	('cancers', 'Disease', 'MESH:D009369', (110, 117))	('9p21.3', 'Gene', (40, 46))
216241	29127303	PIK3CA amplification was found in 15.7%(8 of 51) and 71.8%(89 of 124) cases in subtype2 and subtype3, respectively, which has been reported to be associated with sensitivity to several drugs in epithelial ovarian cancer, stomach carcinoma and head and neck squamous cell carcinoma.	('epithelial ovarian cancer', 'Disease', 'MESH:D000077216', (194, 219))	('ovarian cancer', 'Phenotype', 'HP:0100615', (205, 219))	('carcinoma', 'Phenotype', 'HP:0030731', (271, 280))	('stomach carcinoma', 'Disease', 'MESH:D013274', (221, 238))	('carcinoma', 'Phenotype', 'HP:0030731', (229, 238))	('PIK3CA', 'Gene', '5290', (0, 6))	('neck squamous cell carcinoma', 'Disease', (252, 280))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (252, 280))	('stomach carcinoma', 'Phenotype', 'HP:0012126', (221, 238))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('epithelial ovarian cancer', 'Phenotype', 'HP:0025318', (194, 219))	('subtype2', 'Var', (79, 87))	('subtype3', 'Var', (92, 100))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (257, 280))	('stomach carcinoma', 'Disease', (221, 238))	('epithelial ovarian cancer', 'Disease', (194, 219))	('PIK3CA', 'Gene', (0, 6))	('associated', 'Reg', (146, 156))	('amplification', 'Var', (7, 20))
216242	29127303	FBXW7 deletion was found in 0%(0 of 51) and 46.8%(58 of 124) cases in subtype2 and subtype3, respectively, and has been reported to be associated with increased sensitivity of drugs in breast cancer and renal cell carcinoma.	('increased', 'PosReg', (151, 160))	('FBXW7', 'Gene', '55294', (0, 5))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (203, 223))	('breast cancer', 'Disease', 'MESH:D001943', (185, 198))	('carcinoma', 'Phenotype', 'HP:0030731', (214, 223))	('breast cancer', 'Disease', (185, 198))	('FBXW7', 'Gene', (0, 5))	('associated', 'Reg', (135, 145))	('breast cancer', 'Phenotype', 'HP:0003002', (185, 198))	('deletion', 'Var', (6, 14))	('sensitivity of drugs', 'MPA', (161, 181))	('renal cell carcinoma', 'Disease', (203, 223))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (203, 223))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))
216245	29127303	Disrupted JAK-STAT functionality can result in immune deficiency syndromes and cancers.	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('immune deficiency', 'Phenotype', 'HP:0002721', (47, 64))	('result in', 'Reg', (37, 46))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('immune deficiency syndromes and cancers', 'Disease', 'MESH:D009369', (47, 86))	('Disrupted', 'Var', (0, 9))
216247	29127303	Notably, our survival analysis showed that signature4 was associated with poor survival in ESCC patients (Supplementary Fig.	('ESCC', 'Disease', (91, 95))	('poor', 'NegReg', (74, 78))	('signature4', 'Chemical', '-', (43, 53))	('patients', 'Species', '9606', (96, 104))	('signature4', 'Var', (43, 53))
216254	29127303	These results indicated that the mutations in CUL3 gene may affect the degradation of NFE2L2 protein in ESCC cells.	('NFE2L2', 'Gene', '4780', (86, 92))	('mutations', 'Var', (33, 42))	('NFE2L2', 'Gene', (86, 92))	('affect', 'Reg', (60, 66))	('CUL3', 'Gene', '8452', (46, 50))	('degradation of', 'MPA', (71, 85))	('CUL3', 'Gene', (46, 50))
216256	29127303	An important finding here was that the mutations of AJUBA were significantly associated with prognosis (p = 0.026, log-rank test, Fig.	('AJUBA', 'Gene', (52, 57))	('mutations', 'Var', (39, 48))	('AJUBA', 'Gene', '84962', (52, 57))	('associated with', 'Reg', (77, 92))	('prognosis', 'Disease', (93, 102))
216257	29127303	Most of the mutations identified in AJUBA were stop-gain and frame shift mutations that occurred in the LIM domain and were predicted to truncate the protein (Fig.	('AJUBA', 'Gene', '84962', (36, 41))	('LIM', 'Gene', '10611', (104, 107))	('frame shift', 'Var', (61, 72))	('mutations', 'Var', (12, 21))	('AJUBA', 'Gene', (36, 41))	('protein', 'Protein', (150, 157))	('truncate', 'NegReg', (137, 145))	('LIM', 'Gene', (104, 107))
216260	29127303	Overexpression of AJUBA was also shown to increase the proliferation of head and neck squamous cell carcinoma (HNSCC) cells, and mutations in AJUBA were associated with the sensitivity of HNSCC to treatment with cell-cycle inhibitors.	('AJUBA', 'Gene', (18, 23))	('increase', 'PosReg', (42, 50))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (81, 109))	('AJUBA', 'Gene', (142, 147))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (86, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('mutations', 'Var', (129, 138))	('proliferation', 'CPA', (55, 68))	('AJUBA', 'Gene', '84962', (18, 23))	('associated', 'Reg', (153, 163))	('sensitivity', 'MPA', (173, 184))	('AJUBA', 'Gene', '84962', (142, 147))	('neck squamous cell carcinoma', 'Disease', (81, 109))
216263	29127303	In this study, we found that loss of functional mutations in AJUBA is associated with a better outcome of ESCC patient.	('AJUBA', 'Gene', '84962', (61, 66))	('ESCC patient', 'Disease', (106, 118))	('loss of functional', 'NegReg', (29, 47))	('AJUBA', 'Gene', (61, 66))	('patient', 'Species', '9606', (111, 118))	('mutations', 'Var', (48, 57))
216268	29127303	Inactivation of this pathway was usually caused by mutations in key genes, such as gain-of-function mutations in PIK3CA and AKT, and loss of function mutations of PTEN.	('mutations', 'Var', (100, 109))	('loss of function', 'NegReg', (133, 149))	('mutations', 'Var', (51, 60))	('PIK3CA', 'Gene', (113, 119))	('AKT', 'Gene', (124, 127))	('PTEN', 'Gene', (163, 167))	('PIK3CA', 'Gene', '5290', (113, 119))	('PTEN', 'Gene', '5728', (163, 167))	('mutations', 'Var', (150, 159))	('Inactivation', 'NegReg', (0, 12))	('gain-of-function', 'PosReg', (83, 99))	('AKT', 'Gene', '207', (124, 127))
216269	29127303	The detection of loss of function mutations in PTEN and gain of function mutations in PIK3CA in our study indicated different mechanisms of dysregulation of the PIK3CA/AKT pathway contributing to ESCC development.	('loss of function', 'NegReg', (17, 33))	('PIK3CA', 'Gene', (161, 167))	('PIK3CA', 'Gene', (86, 92))	('AKT', 'Gene', '207', (168, 171))	('mutations', 'Var', (73, 82))	('dysregulation', 'MPA', (140, 153))	('PTEN', 'Gene', (47, 51))	('ESCC development', 'Disease', (196, 212))	('PIK3CA', 'Gene', '5290', (161, 167))	('PTEN', 'Gene', '5728', (47, 51))	('PIK3CA', 'Gene', '5290', (86, 92))	('gain of function', 'PosReg', (56, 72))	('AKT', 'Gene', (168, 171))	('mutations', 'Var', (34, 43))
216271	29127303	In tumour cells, mutations of NFE2L2 were reported to increase resistance to oxidative stress, and promote tumour growth.	('tumour', 'Phenotype', 'HP:0002664', (3, 9))	('oxidative stress', 'Phenotype', 'HP:0025464', (77, 93))	('NFE2L2', 'Gene', (30, 36))	('promote', 'PosReg', (99, 106))	('tumour', 'Disease', 'MESH:D009369', (3, 9))	('increase', 'PosReg', (54, 62))	('NFE2L2', 'Gene', '4780', (30, 36))	('tumour', 'Phenotype', 'HP:0002664', (107, 113))	('tumour growth', 'Disease', (107, 120))	('tumour', 'Disease', 'MESH:D009369', (107, 113))	('tumour', 'Disease', (3, 9))	('tumour growth', 'Disease', 'MESH:D006130', (107, 120))	('resistance to oxidative stress', 'MPA', (63, 93))	('mutations', 'Var', (17, 26))	('tumour', 'Disease', (107, 113))
216272	29127303	Notably, we also found that the mutations in NFE2L2, KEAP1, and CUL3 were almost mutually exclusive (Supplementary Fig.	('CUL3', 'Gene', '8452', (64, 68))	('CUL3', 'Gene', (64, 68))	('NFE2L2', 'Gene', '4780', (45, 51))	('KEAP1', 'Gene', '9817', (53, 58))	('mutations', 'Var', (32, 41))	('NFE2L2', 'Gene', (45, 51))	('KEAP1', 'Gene', (53, 58))
216273	29127303	3C), which was consistent with the finding in SqCC and HNSCC and indicated that the mutation and dysfunction of the NFE2L2/KEAP1/CUL3 pathway may contribute to the development of ESCC by increasing the resistance to oxidative stress.	('increasing', 'PosReg', (187, 197))	('CUL3', 'Gene', '8452', (129, 133))	('contribute', 'Reg', (146, 156))	('CUL3', 'Gene', (129, 133))	('NFE2L2', 'Gene', (116, 122))	('oxidative stress', 'Phenotype', 'HP:0025464', (216, 232))	('ESCC', 'Disease', (179, 183))	('KEAP1', 'Gene', '9817', (123, 128))	('KEAP1', 'Gene', (123, 128))	('dysfunction', 'Var', (97, 108))	('resistance to oxidative stress', 'MPA', (202, 232))	('NFE2L2', 'Gene', '4780', (116, 122))	('mutation', 'Var', (84, 92))
216278	29127303	Moreover, Kaplan-Meier analysis showed that the combination of group3 and group4 (subtype3) marked for worse patient prognosis compared with patients of group2 (subtype2).	('patient', 'Species', '9606', (109, 116))	('group3', 'Var', (63, 69))	('worse', 'NegReg', (103, 108))	('patient', 'Species', '9606', (141, 148))	('patients', 'Species', '9606', (141, 149))	('group4', 'Var', (74, 80))
216283	29127303	And according to the annotation result of CIViC, we found that PIK3CA amplification was associated with partial response to treatment with PI3K inhibitor pictilisib (GDC-0941) in epithelial ovarian cancer patients, and positively associated with the sensitive of PI3K inhibitor in stomach carcinoma and head and neck squamous cell carcinoma (HNSCC).	('patients', 'Species', '9606', (205, 213))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (312, 340))	('carcinoma', 'Phenotype', 'HP:0030731', (289, 298))	('stomach carcinoma', 'Phenotype', 'HP:0012126', (281, 298))	('pictilisib', 'Chemical', 'MESH:C532162', (154, 164))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (317, 340))	('partial', 'NegReg', (104, 111))	('associated', 'Reg', (230, 240))	('stomach carcinoma', 'Disease', (281, 298))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('PIK3CA', 'Gene', '5290', (63, 69))	('epithelial ovarian cancer', 'Phenotype', 'HP:0025318', (179, 204))	('carcinoma', 'Phenotype', 'HP:0030731', (331, 340))	('epithelial ovarian cancer', 'Disease', (179, 204))	('GDC-0941', 'Chemical', 'MESH:C532162', (166, 174))	('PIK3CA', 'Gene', (63, 69))	('epithelial ovarian cancer', 'Disease', 'MESH:D000077216', (179, 204))	('stomach carcinoma', 'Disease', 'MESH:D013274', (281, 298))	('ovarian cancer', 'Phenotype', 'HP:0100615', (190, 204))	('neck squamous cell carcinoma', 'Disease', (312, 340))	('amplification', 'Var', (70, 83))
216286	29127303	We identified deletion of FBXW7 gene in 58/124 (46.8%) of patients in subtype3, but found no deletion of this gene in subtype2.	('patients', 'Species', '9606', (58, 66))	('deletion', 'Var', (14, 22))	('FBXW7', 'Gene', (26, 31))	('FBXW7', 'Gene', '55294', (26, 31))
216287	29127303	And according to the annotation result of CIViC, we found that FBXW7 deletion enhanced the sensitivity to mTOR inhibitors in breast cancer and renal cell carcinoma.	('renal cell carcinoma', 'Disease', 'MESH:C538614', (143, 163))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (143, 163))	('FBXW7', 'Gene', '55294', (63, 68))	('breast cancer', 'Disease', (125, 138))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('breast cancer', 'Disease', 'MESH:D001943', (125, 138))	('FBXW7', 'Gene', (63, 68))	('renal cell carcinoma', 'Disease', (143, 163))	('deletion', 'Var', (69, 77))	('mTOR', 'Gene', (106, 110))	('carcinoma', 'Phenotype', 'HP:0030731', (154, 163))	('mTOR', 'Gene', '2475', (106, 110))	('breast cancer', 'Phenotype', 'HP:0003002', (125, 138))	('enhanced', 'PosReg', (78, 86))
216288	29127303	Although further clinical trials are still needed, the dramatically differences of FBXW7 deletion and PIK3CA amplification between the subtype2 and subtype3 in our ESCC cohort, suggested that mTOR inhibitors and PI3K inhibitors may also suit for certain groups of ESCC patient.	('PIK3CA', 'Gene', (102, 108))	('FBXW7', 'Gene', '55294', (83, 88))	('differences', 'Reg', (68, 79))	('PIK3CA', 'Gene', '5290', (102, 108))	('deletion', 'Var', (89, 97))	('FBXW7', 'Gene', (83, 88))	('patient', 'Species', '9606', (269, 276))	('mTOR', 'Gene', (192, 196))	('mTOR', 'Gene', '2475', (192, 196))
216302	33673374	In gastro-oesophageal junction and gastric cancer, the addition of nivolumab to chemotherapy in first-line treatment improves OS in pts with advanced disease with PD-L1 CPS >= 5 (CHECKMATE-649).	('nivolumab', 'Chemical', 'MESH:D000077594', (67, 76))	('PD-L1 CPS >= 5', 'Var', (163, 177))	('gastric cancer', 'Phenotype', 'HP:0012126', (35, 49))	('PD-L1 CPS', 'Chemical', '-', (163, 172))	('gastro-oesophageal junction', 'Disease', (3, 30))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('men', 'Species', '9606', (112, 115))	('gastric cancer', 'Disease', (35, 49))	('improves', 'PosReg', (117, 125))	('pts', 'Species', '9606', (132, 135))	('gastric cancer', 'Disease', 'MESH:D013274', (35, 49))
216320	33673374	Inhibition of immune checkpoints is changing the treatment paradigms of many solid tumors and has also been investigated in gastro-oesophageal cancer.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('changing', 'Reg', (36, 44))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumors', 'Disease', (83, 89))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('tumors', 'Disease', 'MESH:D009369', (83, 89))	('Inhibition', 'Var', (0, 10))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('cancer', 'Disease', (143, 149))	('men', 'Species', '9606', (54, 57))
216333	33673374	Anti-PD-L1 antibodies bind to PD-L1 proteins, inhibit the link between PD-1 and PD-L1, and may mediate antibody-dependent cellular cytotoxicity of natural killer cells (via Fc receptors for IgG) as well as activation of dendritic cells which in turn activate anti-tumour T-cell induced immune response.	('tumour', 'Disease', (264, 270))	('mediate', 'Reg', (95, 102))	('PD-L1', 'Gene', (80, 85))	('cytotoxicity', 'Disease', 'MESH:D064420', (131, 143))	('inhibit', 'NegReg', (46, 53))	('tumour', 'Phenotype', 'HP:0002664', (264, 270))	('antibodies', 'Var', (11, 21))	('tumour', 'Disease', 'MESH:D009369', (264, 270))	('link', 'Interaction', (58, 62))	('PD-1', 'Protein', (71, 75))	('cytotoxicity', 'Disease', (131, 143))	('activate', 'PosReg', (250, 258))
216356	33673374	There was a significant improvement of OS in EAC and ESCC patients with PD-L1 CPS >= 10 (median OS 9.3 vs. 6.7 months, HR 0.69, 95% CI 0.52-0.93, p = 0.0074, significant).	('improvement', 'PosReg', (24, 35))	('ESCC', 'Disease', (53, 57))	('men', 'Species', '9606', (31, 34))	('CPS >= 1', 'Gene', '1373', (78, 86))	('CPS >= 1', 'Gene', (78, 86))	('PD-L1 CPS', 'Chemical', '-', (72, 81))	('PD-L1', 'Var', (72, 77))	('patients', 'Species', '9606', (58, 66))	('EAC', 'Disease', (45, 48))
216379	33673374	Whereas pembrolizumab monotherapy was non inferior to chemotherapy in patients with CPS >= 1 (10.6 vs. 11.1 months, HR 0.74 (95% CI 0.74-1.10), p = 0.162) (primary endpoint), pembrolizumab monotherapy prolonged OS in patients with PD-L1 CPS >= 10 (median OS 17.4 vs. 10.8 months, HR 0.69, 95% CI 0.49-0.97).	('CPS >= 1', 'Gene', '1373', (84, 92))	('CPS >= 1', 'Gene', (84, 92))	('patients', 'Species', '9606', (70, 78))	('PD-L1', 'Var', (231, 236))	('pembrolizumab', 'Chemical', 'MESH:C582435', (175, 188))	('pembrolizumab', 'Chemical', 'MESH:C582435', (8, 21))	('prolonged', 'PosReg', (201, 210))	('CPS >= 1', 'Gene', '1373', (237, 245))	('CPS >= 1', 'Gene', (237, 245))	('PD-L1 CPS', 'Chemical', '-', (231, 240))	('patients', 'Species', '9606', (217, 225))
216396	33673374	In particular, patients with CPS >= 5 and MSI (microsatellite instability)-high tumours seem to benefit from the combination of nivolumab and chemotherapy as presented in detail in the biomarker paragraph below.	('patients', 'Species', '9606', (15, 23))	('benefit', 'PosReg', (96, 103))	('tumours', 'Disease', 'MESH:D009369', (80, 87))	('tumours', 'Disease', (80, 87))	('CPS >= 5', 'Var', (29, 37))	('tumour', 'Phenotype', 'HP:0002664', (80, 86))	('CPS', 'Chemical', '-', (29, 32))	('tumours', 'Phenotype', 'HP:0002664', (80, 87))	('MSI', 'Gene', (42, 45))	('nivolumab', 'Chemical', 'MESH:D000077594', (128, 137))
216427	33673374	HER2-positivity is defined as immunohistochemical expression of level 3+ or level 2+ combined with positive FISH verification of HER2 gene amplification.	('HER2', 'Gene', (129, 133))	('level 3+', 'Var', (64, 72))	('HER2', 'Gene', '2064', (129, 133))	('HER2', 'Gene', (0, 4))	('HER2', 'Gene', '2064', (0, 4))
216448	33673374	Response to immunotherapy seems to be dependent on the grade of PD-L1 CPS positivity with the strongest effect in OS in PD-L1 CPS >= 10 patients.	('PD-L1 CPS', 'Chemical', '-', (64, 73))	('PD-L1 CPS', 'Chemical', '-', (120, 129))	('CPS >= 1', 'Gene', '1373', (126, 134))	('PD-L1', 'Gene', (64, 69))	('CPS >= 1', 'Gene', (126, 134))	('PD-L1', 'Var', (120, 125))	('patients', 'Species', '9606', (136, 144))
216474	33673374	From 55 patients with an available positive PD-L1 CPS score (PD-L1 CPS >= 1%), the ORR was significantly higher in PD-L1 positive gastric cancer compared with PD-L1 negative cancers (50% vs. 0%, p < 0.001).	('PD-L1 CPS', 'Chemical', '-', (44, 53))	('CPS >= 1', 'Gene', '1373', (67, 75))	('CPS >= 1', 'Gene', (67, 75))	('higher', 'PosReg', (105, 111))	('cancers', 'Phenotype', 'HP:0002664', (174, 181))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('gastric cancer', 'Disease', (130, 144))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('ORR', 'MPA', (83, 86))	('gastric cancer', 'Disease', 'MESH:D013274', (130, 144))	('PD-L1 positive', 'Var', (115, 129))	('PD-L1 negative cancers', 'Disease', (159, 181))	('PD-L1 CPS', 'Chemical', '-', (61, 70))	('PD-L1 negative cancers', 'Disease', 'MESH:D010300', (159, 181))	('gastric cancer', 'Phenotype', 'HP:0012126', (130, 144))	('patients', 'Species', '9606', (8, 16))
216476	33673374	In particular, tumors with microsatellite instability (MSI), distinctive of deficient mismatch repair, exhibit a high mutational load by creating tumor neoantigens and thereby are targeted, in particular, by immune response mechanisms.	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('creating', 'Reg', (137, 145))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumor', 'Disease', (146, 151))	('tumors', 'Disease', 'MESH:D009369', (15, 21))	('tumor', 'Disease', (15, 20))	('mutational load', 'MPA', (118, 133))	('tumor', 'Disease', 'MESH:D009369', (146, 151))	('tumors', 'Disease', (15, 21))	('microsatellite instability', 'Var', (27, 53))
216480	33673374	Furthermore, the combination of nivolumab and chemotherapy in the first-line treatment of PD-L1 CPS >= 5 GEJ cancer/gastric cancer patients also showed a pronounced benefit in OS in the MSI-high subgroup (HR 0.33, 09% CI; CHECKMATE-649 trial).	('patients', 'Species', '9606', (131, 139))	('CPS >= 5', 'Var', (96, 104))	('benefit', 'PosReg', (165, 172))	('cancer', 'Disease', (124, 130))	('MSI-high', 'Disease', (186, 194))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('nivolumab', 'Chemical', 'MESH:D000077594', (32, 41))	('cancer', 'Disease', (109, 115))	('gastric cancer', 'Disease', (116, 130))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('PD-L1 CPS', 'Chemical', '-', (90, 99))	('gastric cancer', 'Disease', 'MESH:D013274', (116, 130))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('men', 'Species', '9606', (82, 85))	('gastric cancer', 'Phenotype', 'HP:0012126', (116, 130))	('cancer', 'Disease', 'MESH:D009369', (124, 130))
216485	33673374	The PD-L1 CPS score and the microsatellite status prove to be good predictive markers for predicting response to checkpoint inhibition.	('PD-L1', 'Gene', (4, 9))	('PD-L1 CPS', 'Chemical', '-', (4, 13))	('microsatellite', 'Var', (28, 42))
216506	33549031	The potential associations between high HRAS expression levels, age, smoking status and histological type of cancer were observed, which emphasizes the need for further study of the RAS family.	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('HRAS', 'Gene', '3265', (40, 44))	('cancer', 'Disease', (109, 115))	('HRAS', 'Gene', (40, 44))	('high', 'Var', (35, 39))
216518	33549031	Abnormally activated RAS proteins regulate the function of major signaling pathways involved in the initiation and development in one-third of human cancers.	('cancers', 'Disease', (149, 156))	('function', 'MPA', (47, 55))	('RAS proteins', 'Protein', (21, 33))	('Abnormally', 'Var', (0, 10))	('human', 'Species', '9606', (143, 148))	('cancers', 'Phenotype', 'HP:0002664', (149, 156))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('regulate', 'Reg', (34, 42))	('activated', 'PosReg', (11, 20))	('major signaling pathways', 'Pathway', (59, 83))	('men', 'Species', '9606', (122, 125))	('cancers', 'Disease', 'MESH:D009369', (149, 156))
216521	33549031	RAS mutations have quite different patterns and vary with cancer.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('RAS', 'Gene', (0, 3))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('cancer', 'Disease', (58, 64))	('mutations', 'Var', (4, 13))
216522	33549031	An oncogenic alteration in KRAS gene is the most frequent in pancreatic cancer, colorectal cancer and lung cancer, while mutated HRAS is the most common in dermatological, head and neck cancers.	('KRAS', 'Gene', '3845', (27, 31))	('cancers', 'Phenotype', 'HP:0002664', (186, 193))	('neck cancers', 'Disease', (181, 193))	('neck cancers', 'Disease', 'MESH:D006258', (181, 193))	('KRAS', 'Gene', (27, 31))	('pancreatic cancer', 'Disease', 'MESH:D010190', (61, 78))	('frequent', 'Reg', (49, 57))	('colorectal cancer', 'Disease', 'MESH:D015179', (80, 97))	('lung cancer', 'Disease', (102, 113))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('HRAS', 'Gene', '3265', (129, 133))	('colorectal cancer', 'Disease', (80, 97))	('HRAS', 'Gene', (129, 133))	('pancreatic cancer', 'Disease', (61, 78))	('common', 'Reg', (146, 152))	('lung cancer', 'Disease', 'MESH:D008175', (102, 113))	('lung cancer', 'Phenotype', 'HP:0100526', (102, 113))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (61, 78))	('mutated', 'Var', (121, 128))	('colorectal cancer', 'Phenotype', 'HP:0003003', (80, 97))	('head and neck cancers', 'Phenotype', 'HP:0012288', (172, 193))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('rat', 'Species', '10116', (17, 20))
216523	33549031	The NRAS mutations are often detected in hematological malignancies.	('mutations', 'Var', (9, 18))	('detected', 'Reg', (29, 37))	('hematological malignancies', 'Disease', (41, 67))	('hematological malignancies', 'Disease', 'MESH:D019337', (41, 67))	('NRAS', 'Gene', (4, 8))	('hematological malignancies', 'Phenotype', 'HP:0004377', (41, 67))	('NRAS', 'Gene', '4893', (4, 8))
216525	33549031	The molecular development of NSCLC is initiated by the activation of oncogenes or the inactivation of tumor suppressor genes.	('oncogenes', 'Protein', (69, 78))	('SCLC', 'Phenotype', 'HP:0030357', (30, 34))	('NSCLC', 'Phenotype', 'HP:0030358', (29, 34))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('NSCLC', 'Disease', (29, 34))	('inactivation', 'Var', (86, 98))	('NSCLC', 'Disease', 'MESH:D002289', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('men', 'Species', '9606', (21, 24))	('activation', 'PosReg', (55, 65))
216526	33549031	Mutation of KRAS gene in lung cancer is more frequent than NRAS and HRAS and is often associated with poor prognosis and worse therapeutic outcome.	('Mutation', 'Var', (0, 8))	('lung cancer', 'Disease', (25, 36))	('associated', 'Reg', (86, 96))	('lung cancer', 'Phenotype', 'HP:0100526', (25, 36))	('KRAS', 'Gene', (12, 16))	('HRAS', 'Gene', '3265', (68, 72))	('KRAS', 'Gene', '3845', (12, 16))	('NRAS', 'Gene', (59, 63))	('frequent', 'Reg', (45, 53))	('HRAS', 'Gene', (68, 72))	('NRAS', 'Gene', '4893', (59, 63))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('lung cancer', 'Disease', 'MESH:D008175', (25, 36))
216527	33549031	Lung adenocarcinoma, the most common histological subtype of non-small-cell lung cancer (NSCLC), often carries a KRAS mutation with 20-50% frequency, followed by squamous cell carcinoma, subtype of NSCLC.	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (162, 185))	('NSCLC', 'Phenotype', 'HP:0030358', (89, 94))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (65, 87))	('KRAS', 'Gene', '3845', (113, 117))	('NSCLC', 'Disease', (198, 203))	('Lung adenocarcinoma', 'Phenotype', 'HP:0030078', (0, 19))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('Lung adenocarcinoma', 'Disease', 'MESH:D000077192', (0, 19))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (61, 87))	('NSCLC', 'Phenotype', 'HP:0030358', (198, 203))	('squamous cell carcinoma', 'Disease', (162, 185))	('lung cancer', 'Disease', (76, 87))	('KRAS', 'Gene', (113, 117))	('SCLC', 'Phenotype', 'HP:0030357', (90, 94))	('mutation', 'Var', (118, 126))	('Lung adenocarcinoma', 'Disease', (0, 19))	('carries', 'Reg', (103, 110))	('lung cancer', 'Disease', 'MESH:D008175', (76, 87))	('NSCLC', 'Disease', 'MESH:D002289', (89, 94))	('SCLC', 'Phenotype', 'HP:0030357', (199, 203))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (162, 185))	('lung cancer', 'Phenotype', 'HP:0100526', (76, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (10, 19))	('NSCLC', 'Disease', (89, 94))	('NSCLC', 'Disease', 'MESH:D002289', (198, 203))	('carcinoma', 'Phenotype', 'HP:0030731', (176, 185))
216614	33549031	The KRAS mutation is common in smoking lung adenocarcinoma patients with frequency between 12 and 36%.	('mutation', 'Var', (9, 17))	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('KRAS', 'Gene', '3845', (4, 8))	('lung adenocarcinoma', 'Disease', (39, 58))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (39, 58))	('patients', 'Species', '9606', (59, 67))	('common', 'Reg', (21, 27))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (39, 58))	('KRAS', 'Gene', (4, 8))
216616	33549031	The HRAS mutations are detected very rarely in lung cancers (< 1%).	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('HRAS', 'Gene', (4, 8))	('lung cancer', 'Phenotype', 'HP:0100526', (47, 58))	('mutations', 'Var', (9, 18))	('lung cancers', 'Disease', 'MESH:D008175', (47, 59))	('lung cancers', 'Phenotype', 'HP:0100526', (47, 59))	('lung cancers', 'Disease', (47, 59))	('HRAS', 'Gene', '3265', (4, 8))	('cancers', 'Phenotype', 'HP:0002664', (52, 59))
216617	33549031	The prognostic value of KRAS and HRAS expression has been evaluated in various types of cancers so far, but only few studies indicated the association between the RAS family overexpression or mutation and the high degree lesions.	('KRAS', 'Gene', '3845', (24, 28))	('mutation', 'Var', (192, 200))	('cancers', 'Disease', 'MESH:D009369', (88, 95))	('HRAS', 'Gene', '3265', (33, 37))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('cancers', 'Disease', (88, 95))	('overexpression', 'PosReg', (174, 188))	('HRAS', 'Gene', (33, 37))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('RAS', 'Protein', (163, 166))	('association', 'Interaction', (139, 150))	('KRAS', 'Gene', (24, 28))
216636	33549031	Another explanation for the significant differences in the HRAS gene expression level but not KRAS in NSCLC patients, seems the fact that oncogenic alterations in KRAS are more frequent in patients with lung malignancies.	('NSCLC', 'Disease', 'MESH:D002289', (102, 107))	('HRAS', 'Gene', (59, 63))	('KRAS', 'Gene', (94, 98))	('alterations', 'Var', (148, 159))	('frequent', 'Reg', (177, 185))	('rat', 'Species', '10116', (152, 155))	('SCLC', 'Phenotype', 'HP:0030357', (103, 107))	('KRAS', 'Gene', (163, 167))	('NSCLC', 'Phenotype', 'HP:0030358', (102, 107))	('lung malignancies', 'Disease', 'MESH:D008175', (203, 220))	('KRAS', 'Gene', '3845', (163, 167))	('KRAS', 'Gene', '3845', (94, 98))	('lung malignancies', 'Disease', (203, 220))	('patients', 'Species', '9606', (108, 116))	('patients', 'Species', '9606', (189, 197))	('NSCLC', 'Disease', (102, 107))	('HRAS', 'Gene', '3265', (59, 63))	('lung malignancies', 'Phenotype', 'HP:0100526', (203, 220))
216646	33549031	revealed KRAS overexpression in patients with colorectal cancer and the high expression of KRAS predicted poor treatment outcomes in patients.	('expression', 'MPA', (77, 87))	('patients', 'Species', '9606', (32, 40))	('colorectal cancer', 'Disease', 'MESH:D015179', (46, 63))	('KRAS', 'Gene', '3845', (91, 95))	('KRAS', 'Gene', (9, 13))	('patients', 'Species', '9606', (133, 141))	('colorectal cancer', 'Phenotype', 'HP:0003003', (46, 63))	('KRAS', 'Gene', (91, 95))	('KRAS', 'Gene', '3845', (9, 13))	('colorectal cancer', 'Disease', (46, 63))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('treatment outcomes', 'CPA', (111, 129))	('overexpression', 'PosReg', (14, 28))	('men', 'Species', '9606', (116, 119))	('high', 'Var', (72, 76))
216653	33549031	Therefore, a cell with mutated KRAS will persist to allow succeeding genetic events to promote tumor progression, which could be an explanation as for why we did not notice statistically significant changes in the KRAS gene expression.	('KRAS', 'Gene', (31, 35))	('KRAS', 'Gene', (214, 218))	('KRAS', 'Gene', '3845', (31, 35))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('mutated', 'Var', (23, 30))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('KRAS', 'Gene', '3845', (214, 218))	('promote', 'PosReg', (87, 94))	('tumor', 'Disease', (95, 100))
216674	32769903	The results suggested that high expression of MIF was significantly related to poor overall survival and disease-free survival in cancer patients.	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('poor', 'NegReg', (79, 83))	('MIF', 'Gene', (46, 49))	('cancer', 'Disease', (130, 136))	('patients', 'Species', '9606', (137, 145))	('high', 'Var', (27, 31))	('overall survival', 'CPA', (84, 100))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('disease-free survival', 'CPA', (105, 126))	('MIF', 'Gene', '4282', (46, 49))
216689	32769903	The extracted data were as follows: first author, publication year, country, cancer type, sample size, sex, median age, tumor stage, study period, follow-up period, endpoints, MIF expression associated with poor prognosis, cut-off value of MIF expression, and adjusted HR with 95% CI for survival.	('MIF', 'Gene', (240, 243))	('MIF', 'Gene', (176, 179))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('poor prognosis', 'CPA', (207, 221))	('tumor', 'Disease', (120, 125))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('MIF', 'Gene', '4282', (240, 243))	('associated', 'Reg', (191, 201))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('MIF', 'Gene', '4282', (176, 179))	('expression', 'Var', (180, 190))
216695	32769903	The pooled HR for OS in cancer patients with high expression of MIF compared with low expression was 2.23 (95% CI 1.67-2.99, P < .001), indicating that high expression of MIF was significantly associated with poor OS in cancer patients (Fig.	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('MIF', 'Gene', '4282', (64, 67))	('MIF', 'Gene', '4282', (171, 174))	('cancer', 'Disease', (24, 30))	('cancer', 'Disease', 'MESH:D009369', (24, 30))	('MIF', 'Gene', (64, 67))	('patients', 'Species', '9606', (31, 39))	('associated with', 'Reg', (193, 208))	('cancer', 'Disease', 'MESH:D009369', (220, 226))	('cancer', 'Disease', (220, 226))	('MIF', 'Gene', (171, 174))	('patients', 'Species', '9606', (227, 235))	('poor OS', 'Disease', (209, 216))	('high expression', 'Var', (152, 167))
216699	32769903	The pooled HR for DFS in cancer patients with high expression of MIF compared with low expression was 2.24 (95% CI 1.69-2.96, P < .001), indicating that high expression of MIF was significantly related with worse DFS in cancer patients (Fig.	('MIF', 'Gene', (65, 68))	('patients', 'Species', '9606', (32, 40))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('cancer', 'Disease', (25, 31))	('DFS', 'Disease', (213, 216))	('MIF', 'Gene', '4282', (172, 175))	('patients', 'Species', '9606', (227, 235))	('MIF', 'Gene', '4282', (65, 68))	('cancer', 'Disease', 'MESH:D009369', (25, 31))	('cancer', 'Disease', 'MESH:D009369', (220, 226))	('cancer', 'Disease', (220, 226))	('high', 'Var', (153, 157))	('MIF', 'Gene', (172, 175))
216708	32769903	Han et al showed that high expression of MIF was related with poor OS and metastasis-free survival in patients with high-grade osteosarcoma.	('osteosarcoma', 'Phenotype', 'HP:0002669', (127, 139))	('osteosarcoma', 'Disease', 'MESH:D012516', (127, 139))	('high', 'Var', (22, 26))	('patients', 'Species', '9606', (102, 110))	('MIF', 'Gene', '4282', (41, 44))	('metastasis-free survival', 'CPA', (74, 98))	('poor', 'NegReg', (62, 66))	('MIF', 'Gene', (41, 44))	('osteosarcoma', 'Disease', (127, 139))
216709	32769903	Zhang et al and Koh et al demonstrated significantly poorer OS or disease-specific survival and DFS with high expression of MIF compared with low expression in patient with esophageal squamous cell carcinoma and lung squamous cell carcinoma, respectively.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (184, 207))	('MIF', 'Gene', (124, 127))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (212, 240))	('Koh', 'Chemical', 'MESH:C029943', (16, 19))	('carcinoma', 'Phenotype', 'HP:0030731', (231, 240))	('carcinoma', 'Phenotype', 'HP:0030731', (198, 207))	('lung squamous cell carcinoma', 'Disease', (212, 240))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (212, 240))	('disease-specific survival', 'CPA', (66, 91))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (173, 207))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (217, 240))	('poorer', 'NegReg', (53, 59))	('MIF', 'Gene', '4282', (124, 127))	('patient', 'Species', '9606', (160, 167))	('esophageal squamous cell carcinoma', 'Disease', (173, 207))	('high expression', 'Var', (105, 120))
216711	32769903	Liao et al and Pei et al showed that high expression of MIF was associated with poor OS in patients with nasopharyngeal carcinoma.	('carcinoma', 'Disease', (120, 129))	('associated', 'Reg', (64, 74))	('high expression', 'Var', (37, 52))	('patients', 'Species', '9606', (91, 99))	('carcinoma', 'Disease', 'MESH:D009369', (120, 129))	('MIF', 'Gene', (56, 59))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('poor OS', 'Disease', (80, 87))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (105, 129))	('MIF', 'Gene', '4282', (56, 59))
216712	32769903	He et al and Wang et al revealed that high expression of MIF was related with unfavorable OS in patients with gastric cancer and pancreatic ductal adenocarcinoma, respectively.	('gastric cancer', 'Disease', (110, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (152, 161))	('gastric cancer', 'Disease', 'MESH:D013274', (110, 124))	('MIF', 'Gene', '4282', (57, 60))	('high expression', 'Var', (38, 53))	('pancreatic ductal adenocarcinoma', 'Disease', (129, 161))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (129, 161))	('gastric cancer', 'Phenotype', 'HP:0012126', (110, 124))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (129, 161))	('unfavorable OS', 'Disease', (78, 92))	('MIF', 'Gene', (57, 60))	('patients', 'Species', '9606', (96, 104))	('related', 'Reg', (65, 72))
216713	32769903	We finally identified that cancer patients with high expression of MIF tended to have worse OS and DFS than those with low expression through meta-analysis.	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('MIF', 'Gene', (67, 70))	('patients', 'Species', '9606', (34, 42))	('high expression', 'Var', (48, 63))	('cancer', 'Disease', (27, 33))	('cancer', 'Disease', 'MESH:D009369', (27, 33))	('DFS', 'CPA', (99, 102))	('MIF', 'Gene', '4282', (67, 70))
216718	32769903	This meta-analysis revealed that high expression of MIF was associated with poor survival in cancer patients and could be a useful prognostic factor.	('cancer', 'Disease', (93, 99))	('poor', 'NegReg', (76, 80))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('high expression', 'Var', (33, 48))	('MIF', 'Gene', (52, 55))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('patients', 'Species', '9606', (100, 108))	('MIF', 'Gene', '4282', (52, 55))
216726	32160365	The PD-L1 positivity of tumor cells was possibly associated with better PFS (2.04 vs 1.41 months, cut-off 1%) and OS (11.33 vs 6.24 months, cut-off 1%).	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumor', 'Disease', (24, 29))	('PFS', 'Disease', (72, 75))	('positivity', 'Var', (10, 20))	('PD-L1', 'Gene', (4, 9))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('PD-L1', 'Gene', '29126', (4, 9))
216790	32160365	Time to response results for a small number of responding patients (n = 2-5) were numerically shorter in negative patients compared with positive patients at all PD-L1 cut-off values (Table 2).	('PD-L1', 'Gene', '29126', (162, 167))	('Time', 'MPA', (0, 4))	('shorter', 'NegReg', (94, 101))	('negative', 'Var', (105, 113))	('patients', 'Species', '9606', (58, 66))	('patients', 'Species', '9606', (114, 122))	('patients', 'Species', '9606', (146, 154))	('PD-L1', 'Gene', (162, 167))
216808	32160365	Studies investigating the relationship between response to treatment with other PD-1/PD-L1-targeted agents have generally shown that the presence of PD-L1 expression is related to response to treatment 21 ,  22 ,  23 ,  24 ; this relationship needs to be explored further with nivolumab.	('PD-L1', 'Gene', (149, 154))	('nivolumab', 'Chemical', 'MESH:D000077594', (277, 286))	('response to', 'MPA', (180, 191))	('PD-L1', 'Gene', '29126', (149, 154))	('PD-L1', 'Gene', (85, 90))	('presence', 'Var', (137, 145))	('PD-L1', 'Gene', '29126', (85, 90))	('PD-1', 'Gene', (80, 84))	('related', 'Reg', (169, 176))	('PD-1', 'Gene', '5133', (80, 84))
216810	32160365	25 ,  26 ,  27 ,  28 ,  29 ,  30 ,  31  Similar to the present study, patients with basal-like breast cancer showed that those with CD8+ TILs survived 3.5 years longer than those who did not 31  in other studies of patients with breast cancer, the presence of TILs was prognostic for both DFS and OS 28  and event-free survival.	('presence', 'Var', (248, 256))	('breast cancer', 'Phenotype', 'HP:0003002', (95, 108))	('TIL', 'Gene', (260, 263))	('breast cancer', 'Disease', 'MESH:D001943', (229, 242))	('breast cancer', 'Disease', (229, 242))	('breast cancer', 'Disease', 'MESH:D001943', (95, 108))	('TIL', 'Gene', '7096', (137, 140))	('patients', 'Species', '9606', (70, 78))	('breast cancer', 'Disease', (95, 108))	('CD8', 'Gene', '925', (132, 135))	('OS 28', 'Disease', (297, 302))	('TIL', 'Gene', (137, 140))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('DFS', 'Disease', (289, 292))	('TIL', 'Gene', '7096', (260, 263))	('patients', 'Species', '9606', (215, 223))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('CD8', 'Gene', (132, 135))	('breast cancer', 'Phenotype', 'HP:0003002', (229, 242))	('prognostic', 'Reg', (269, 279))
216834	31196171	Aberrant methylation-mediated downregulation of lncRNA SSTR5-AS1 promotes progression and metastasis of laryngeal squamous cell carcinoma Laryngeal squamous cell carcinoma (LSCC) is among the most common malignant tumors with poor prognosis.	('progression', 'CPA', (74, 85))	('malignant tumors', 'Disease', 'MESH:D018198', (204, 220))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('metastasis of laryngeal squamous cell carcinoma', 'Disease', 'MESH:D002294', (90, 137))	('Aberrant methylation-mediated', 'Var', (0, 29))	('Laryngeal squamous cell carcinoma', 'Disease', (138, 171))	('malignant tumors', 'Disease', (204, 220))	('metastasis of laryngeal squamous cell carcinoma', 'Disease', (90, 137))	('downregulation', 'NegReg', (30, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('carcinoma Laryngeal squamous cell carcinoma', 'Phenotype', 'HP:0012118', (128, 171))	('SSTR5-AS1', 'Gene', (55, 64))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (148, 171))	('promotes', 'PosReg', (65, 73))	('methylation-mediated', 'Var', (9, 29))	('carcinoma', 'Phenotype', 'HP:0030731', (162, 171))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (114, 137))	('tumors', 'Phenotype', 'HP:0002664', (214, 220))	('Laryngeal squamous cell carcinoma', 'Disease', 'MESH:D002294', (138, 171))	('SSTR5-AS1', 'Gene', '146336;6755;5729', (55, 64))
216863	31196171	There are two transcripts of SSTR5, and the main transcript (NM_001053) is located at chr16: 1078781-1081454 (GRCh38/hg38).	('SSTR5', 'Gene', '6755', (29, 34))	('SSTR5', 'Gene', (29, 34))	('hg38', 'Gene', (117, 121))	('hg38', 'Gene', '8549', (117, 121))	('NM_001053', 'Var', (61, 70))
216882	31196171	3b, c, the expression levels of SSTR5 and SSTR5-AS1 were significantly increased in the 5-Aza-dC-, TSA-, 5-Aza-dC/TSA-treated laryngeal carcinoma cells, and the effect was more apparent in the 5-Aza-dC/TSA-treated cells, indicating that the expression of SSTR5 and SSTR5-AS1 might be co-regulated by DNA methylation and histone modification.	('SSTR5', 'Gene', (255, 260))	('SSTR5', 'Gene', (32, 37))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('SSTR5', 'Gene', '6755', (255, 260))	('5-Aza-dC-', 'Var', (88, 97))	('TSA', 'Chemical', 'MESH:C012589', (99, 102))	('SSTR5', 'Gene', '6755', (32, 37))	('TSA', 'Chemical', 'MESH:C012589', (202, 205))	('laryngeal carcinoma', 'Disease', (126, 145))	('5-Aza-dC/TSA-treated', 'Var', (105, 125))	('TSA', 'Chemical', 'MESH:C012589', (114, 117))	('5-Aza-dC', 'Chemical', 'MESH:D000077209', (193, 201))	('TSA-', 'Var', (99, 103))	('5-Aza-dC', 'Chemical', 'MESH:D000077209', (105, 113))	('laryngeal carcinoma', 'Phenotype', 'HP:0012118', (126, 145))	('SSTR5', 'Gene', (42, 47))	('SSTR5', 'Gene', (265, 270))	('5-Aza-dC', 'Chemical', 'MESH:D000077209', (88, 96))	('expression levels', 'MPA', (11, 28))	('SSTR5', 'Gene', '6755', (42, 47))	('laryngeal carcinoma', 'Disease', 'MESH:D007827', (126, 145))	('increased', 'PosReg', (71, 80))	('SSTR5', 'Gene', '6755', (265, 270))
216884	31196171	3d, frequent CpG sites methylation was observed in the exon 1 region of SSTR5, while frequent methylated CpG sites were located in the promoter region of SSTR5-AS1 (Fig.	('methylation', 'Var', (23, 34))	('SSTR5', 'Gene', '6755', (154, 159))	('SSTR5', 'Gene', (154, 159))	('SSTR5', 'Gene', '6755', (72, 77))	('SSTR5', 'Gene', (72, 77))
216891	31196171	The methylation status of promoter region of SSTR5 in LSCC tissues was not associated with any clinicopathologic characteristics, while the methylation status of exon 1 in LSCC tissues was associated with TNM stage and lymph node metastasis (P < 0.05) (Table 1).	('methylation', 'Var', (140, 151))	('TNM stage', 'CPA', (205, 214))	('associated', 'Reg', (189, 199))	('SSTR5', 'Gene', '6755', (45, 50))	('lymph node metastasis', 'CPA', (219, 240))	('SSTR5', 'Gene', (45, 50))
216892	31196171	The mRNA expression level of SSTR5 in LSCC tissues with hypermethylation of exon 1 was significantly decreased than that with unmethylation of this region (P < 0.05); however, the expression level of SSTR5 was not associated with methylation status of promoter region (P > 0.05) (Fig.	('SSTR5', 'Gene', (200, 205))	('mRNA expression level', 'MPA', (4, 25))	('SSTR5', 'Gene', '6755', (29, 34))	('SSTR5', 'Gene', (29, 34))	('hypermethylation', 'Var', (56, 72))	('decreased', 'NegReg', (101, 110))	('SSTR5', 'Gene', '6755', (200, 205))
216894	31196171	To determine the potential role of histone modifications on SSTR5 downregulation, the presence of active (H3K4me3, H3K9ac) and inactive (H3K9me2) histone modifications at SSTR5 promoter was further examined by chromatin immunoprecipitation assay in AMC-HN-8 cells (Fig.	('SSTR5', 'Gene', '6755', (171, 176))	('SSTR5', 'Gene', '6755', (60, 65))	('H3K4me3', 'Var', (106, 113))	('SSTR5', 'Gene', (171, 176))	('SSTR5', 'Gene', (60, 65))	('H3K9ac', 'Var', (115, 121))	('AMC-HN-8', 'CellLine', 'CVCL:5966', (249, 257))
216896	31196171	Increased enrichment of H3K4me3 and decreased enrichment of H3K9me2 were detected in 5-Aza-dC-treated AMC-HN-8 cells, and significant increased enrichment of H3K9ac was detected in TSA-treated AMC-HN-8 cells, indicating that in addition to DNA methylation, histone modification is also involved in the regulation of SSTR5 expression.	('SSTR5', 'Gene', (316, 321))	('TSA', 'Chemical', 'MESH:C012589', (181, 184))	('SSTR5', 'Gene', '6755', (316, 321))	('5-Aza-dC-treated', 'Var', (85, 101))	('5-Aza-dC', 'Chemical', 'MESH:D000077209', (85, 93))	('H3K4me3', 'Var', (24, 31))	('involved', 'Reg', (286, 294))	('enrichment', 'MPA', (10, 20))	('AMC-HN-8', 'CellLine', 'CVCL:5966', (193, 201))	('enrichment', 'MPA', (46, 56))	('AMC-HN-8', 'CellLine', 'CVCL:5966', (102, 110))	('decreased', 'NegReg', (36, 45))
216924	31196171	Promoter CpG sites hypermethylation of E-cadherin is a recognized mechanism of its inactivation in numerous cancers.	('numerous cancers', 'Disease', 'MESH:D009369', (99, 115))	('E-cadherin', 'Gene', (39, 49))	('inactivation', 'NegReg', (83, 95))	('E-cadherin', 'Gene', '999', (39, 49))	('numerous cancers', 'Disease', (99, 115))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('hypermethylation', 'Var', (19, 35))	('cancers', 'Phenotype', 'HP:0002664', (108, 115))
216928	31196171	The hMeDIP-qPCR assay was used to track the 5hmC change in the CpG-rich regions of E-cadherin promoters, and co-expression of SSTR5-AS1 and TET1 in AMC-HN-8 cells significantly increased 5hmC levels at the promoter regions of E-cadherin (Fig.	('E-cadherin', 'Gene', (83, 93))	('E-cadherin', 'Gene', '999', (83, 93))	('TET1', 'Gene', '80312', (140, 144))	('SSTR5-AS1', 'Var', (126, 135))	('5hmC', 'Chemical', '-', (187, 191))	('increased', 'PosReg', (177, 186))	('5hmC levels', 'MPA', (187, 198))	('AMC-HN-8', 'CellLine', 'CVCL:5966', (148, 156))	('E-cadherin', 'Gene', (226, 236))	('E-cadherin', 'Gene', '999', (226, 236))	('5hmC', 'Chemical', '-', (44, 48))	('TET1', 'Gene', (140, 144))
216940	31196171	AChE-AS represses AChE expression via epigenetic modification of the AChE promoter region and demonstrates an anti-apoptotic effect in hepatocellular carcinoma cells.	('AChE', 'Gene', '43', (0, 4))	('AChE', 'Gene', (18, 22))	('AChE', 'Gene', '43', (18, 22))	('AChE', 'Gene', '43', (69, 73))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (135, 159))	('carcinoma', 'Phenotype', 'HP:0030731', (150, 159))	('hepatocellular carcinoma', 'Disease', (135, 159))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (135, 159))	('epigenetic', 'Var', (38, 48))	('AChE', 'Gene', (0, 4))	('anti-apoptotic', 'CPA', (110, 124))	('AChE', 'Gene', (69, 73))
216942	31196171	Moreover, by genomic sequence analysis, obvious CpG islands were found in the promoter and exon 1 regions of SSTR5 and SSTR5-AS1, indicating the possible epigenetic regulation mechanisms on their expression regulation.	('SSTR5', 'Gene', '6755', (109, 114))	('SSTR5', 'Gene', '6755', (119, 124))	('SSTR5', 'Gene', (109, 114))	('CpG islands', 'Var', (48, 59))	('SSTR5', 'Gene', (119, 124))
216946	31196171	In the present study, we verified the tumor suppressor role of SSTR5 and SSTR5-AS1 in LSCC progression; DNA hypermethylation and histone modification may co-regulate the expression of SSTR5 and SSTR5-AS1.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('SSTR5', 'Gene', '6755', (184, 189))	('SSTR5', 'Gene', '6755', (73, 78))	('SSTR5', 'Gene', (184, 189))	('SSTR5', 'Gene', (73, 78))	('SSTR5', 'Gene', '6755', (194, 199))	('SSTR5', 'Gene', (63, 68))	('SSTR5', 'Gene', (194, 199))	('SSTR5', 'Gene', '6755', (63, 68))	('co-regulate', 'Reg', (154, 165))	('DNA hypermethylation', 'Var', (104, 124))	('LSCC', 'Disease', (86, 90))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('histone modification', 'Var', (129, 149))	('expression', 'MPA', (170, 180))
216959	31196171	In the process of laryngeal squamous cell carcinogenesis, when CpG sites hypermethylation occurs in the promoter region of E-cadherin, SSTR5-AS1 may also act as a tumor suppressor gene to upregulate the expression of E-cadherin by recruiting TET1 to E-cadherin to hydrolyze 5'-mc to 5'-hmc, thus inhibiting the occurrence of EMT.	('hypermethylation', 'Var', (73, 89))	('laryngeal squamous cell carcinogenesis', 'Disease', 'MESH:D063646', (18, 56))	('TET1', 'Gene', (242, 246))	('tumor', 'Disease', (163, 168))	('laryngeal squamous cell carcinogenesis', 'Disease', (18, 56))	("hydrolyze 5'-mc to 5'-hmc", 'MPA', (264, 289))	('SSTR5-AS1', 'Gene', (135, 144))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('E-cadherin', 'Gene', (250, 260))	('E-cadherin', 'Gene', '999', (250, 260))	('E-cadherin', 'Gene', (123, 133))	('E-cadherin', 'Gene', '999', (123, 133))	('upregulate', 'PosReg', (188, 198))	('inhibiting', 'NegReg', (296, 306))	('E-cadherin', 'Gene', (217, 227))	('E-cadherin', 'Gene', '999', (217, 227))	("5'-mc", 'Chemical', 'MESH:D044503', (274, 279))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('TET1', 'Gene', '80312', (242, 246))	('recruiting', 'PosReg', (231, 241))	('expression', 'MPA', (203, 213))	("5'-hmc", 'Chemical', 'MESH:C011865', (283, 289))
216960	31196171	SSTR5 may act as a tumor suppressor gene in LSCC, and aberrant DNA hypermethylation of the CpG sites clustered in the exon 1 and histone modification on its promoter region may be epigenetic mechanisms for its inactivation.	('LSCC', 'Disease', (44, 48))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('CpG', 'Gene', (91, 94))	('SSTR5', 'Gene', '6755', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('tumor', 'Disease', (19, 24))	('SSTR5', 'Gene', (0, 5))	('histone modification', 'Var', (129, 149))	('aberrant', 'Var', (54, 62))
216961	31196171	SSTR5-AS1 may play anti-tumor role in LSCC and may be regulated by hypermethylation of the same CpG sites with SSTR5.	('SSTR5', 'Gene', '6755', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('SSTR5', 'Gene', (111, 116))	('tumor', 'Disease', (24, 29))	('LSCC', 'Disease', (38, 42))	('SSTR5', 'Gene', '6755', (0, 5))	('hypermethylation', 'Var', (67, 83))	('SSTR5', 'Gene', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (24, 29))
216998	31196171	Antibodies against H3K4me3, H3K9ac, H3K9me2, MLL3, and TET1 (Upstate, Millipore, MA, USA) were used for immunoprecipitation.	('H3K9me2', 'Var', (36, 43))	('TET1', 'Gene', (55, 59))	('H3K4me3', 'Var', (19, 26))	('H3K9ac', 'Var', (28, 34))	('MLL3', 'Gene', (45, 49))	('TET1', 'Gene', '80312', (55, 59))	('MLL3', 'Gene', '58508', (45, 49))
217014	31262096	Despite promising advancements in the conventional therapeutic approaches currently available for patients with oral cancer, many drawbacks are still to be addressed; surgical resection leads to permanent disfigurement, altered sense of self and debilitating physiological consequences, while chemo- and radio-therapies result in significant toxicities, all affecting patient wellbeing and quality of life.	('oral cancer', 'Disease', 'MESH:D009062', (112, 123))	('patient', 'Species', '9606', (98, 105))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('altered', 'Reg', (220, 227))	('surgical resection', 'Var', (167, 185))	('oral cancer', 'Disease', (112, 123))	('patients', 'Species', '9606', (98, 106))	('toxicities', 'Disease', (342, 352))	('toxicities', 'Disease', 'MESH:D064420', (342, 352))	('sense of self', 'MPA', (228, 241))	('men', 'Species', '9606', (214, 217))	('patient', 'Species', '9606', (368, 375))	('affecting', 'Reg', (358, 367))	('men', 'Species', '9606', (25, 28))
217036	31262096	The conventional approaches for oral cancer treatment involve surgery, which is the treatment of choice, ionizing radiation which is the prevalent non-surgical therapeutic approach, or a combination of radio-, chemotherapy, and surgery; surgical resection leads to permanent disfigurement, altered sense of self and debilitating physiological consequences, substantial functional impairment, and morbidity, while chemo- and radio-therapies result in significant toxicities, all affecting patient wellbeing and quality of life.	('leads to', 'Reg', (256, 264))	('oral cancer', 'Disease', (32, 43))	('sense of self', 'MPA', (298, 311))	('men', 'Species', '9606', (49, 52))	('morbidity', 'CPA', (396, 405))	('disfigurement', 'MPA', (275, 288))	('men', 'Species', '9606', (386, 389))	('toxicities', 'Disease', (462, 472))	('men', 'Species', '9606', (284, 287))	('patient', 'Species', '9606', (488, 495))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('functional', 'MPA', (369, 379))	('surgical resection', 'Var', (237, 255))	('affecting', 'Reg', (478, 487))	('men', 'Species', '9606', (89, 92))	('oral cancer', 'Disease', 'MESH:D009062', (32, 43))	('altered', 'Reg', (290, 297))	('toxicities', 'Disease', 'MESH:D064420', (462, 472))
217090	31262096	Cisplatin causes apoptosis (cell death) of cancer cells due to its ability to crosslink with purine bases on DNA, interfering with DNA repair mechanism, and causing DNA damage.	('DNA damage', 'MPA', (165, 175))	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('purine', 'Chemical', 'MESH:C030985', (93, 99))	('cancer', 'Disease', (43, 49))	('Cisplatin', 'Chemical', 'MESH:D002945', (0, 9))	('apoptosis', 'CPA', (17, 26))	('interfering', 'NegReg', (114, 125))	('Cisplatin', 'Var', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('DNA repair mechanism', 'MPA', (131, 151))	('crosslink', 'MPA', (78, 87))	('causing', 'Reg', (157, 164))
217159	31262096	In vivo studies investigating anti-EGFR-PEG-TiO2-UCNs showed no toxic side effects, whereas in vitro studies showed enhanced apoptosis and tumor growth inhibition.	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('enhanced', 'PosReg', (116, 124))	('PEG', 'Chemical', 'MESH:D011092', (40, 43))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('anti-EGFR-PEG-TiO2-UCNs', 'Var', (30, 53))	('TiO2-UCNs', 'Chemical', '-', (44, 53))	('apoptosis', 'CPA', (125, 134))
217229	31262096	They performed in vivo studies, where mice were treated with a combination of nanoparticles loaded with cisplatin and pyrolipid; a remarkable tumor reduction (83%) occurred in cisplatin-resistant SQ20B subcutaneous xenograft murine HNSCC model after the combined treatment of loaded nanoparticles and irradiation.	('reduction', 'NegReg', (148, 157))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('murine', 'Species', '10090', (225, 231))	('pyrolipid', 'Chemical', '-', (118, 127))	('cisplatin', 'Chemical', 'MESH:D002945', (176, 185))	('cisplatin', 'Chemical', 'MESH:D002945', (104, 113))	('mice', 'Species', '10090', (38, 42))	('tumor', 'Disease', (142, 147))	('men', 'Species', '9606', (268, 271))	('cisplatin-resistant', 'Var', (176, 195))	('tumor', 'Disease', 'MESH:D009369', (142, 147))
217243	31262096	A novel immunotherapy strategy involves using small molecules as monotherapy or combined with other anticancer therapies.	('small', 'Var', (46, 51))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))
217272	33937395	In the bladder cancer, high expression of NRP2 is associated with chemoresistance and epithelial-to-mesenchymal transition and poor patient prognosis.	('epithelial-to-mesenchymal transition', 'CPA', (86, 122))	('high expression', 'Var', (23, 38))	('bladder cancer', 'Phenotype', 'HP:0009725', (7, 21))	('NRP2', 'Gene', (42, 46))	('bladder cancer', 'Disease', 'MESH:D001749', (7, 21))	('chemoresistance', 'CPA', (66, 81))	('patient', 'Species', '9606', (132, 139))	('associated', 'Reg', (50, 60))	('bladder cancer', 'Disease', (7, 21))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))
217285	33937395	In addition, high NRP1 expression was associated with higher stroma, microenvironment, and immune scores, as well as more endothelial cell infiltration in most tumours.	('tumours', 'Disease', 'MESH:D009369', (160, 167))	('higher', 'PosReg', (54, 60))	('high', 'Var', (13, 17))	('tumours', 'Disease', (160, 167))	('tumours', 'Phenotype', 'HP:0002664', (160, 167))	('stroma', 'CPA', (61, 67))	('immune scores', 'CPA', (91, 104))	('NRP1', 'Gene', (18, 22))	('tumour', 'Phenotype', 'HP:0002664', (160, 166))	('expression', 'MPA', (23, 33))
217286	33937395	In KIRC, a high NRP1 expression was associated with a larger tumour size, higher risk of distant metastases, and worse stage staging and grade staging.	('metastases', 'Disease', (97, 107))	('high', 'Var', (11, 15))	('NRP1', 'Protein', (16, 20))	('expression', 'MPA', (21, 31))	('tumour size', 'CPA', (61, 72))	('metastases', 'Disease', 'MESH:D009362', (97, 107))	('grade staging', 'CPA', (137, 150))	('tumour', 'Phenotype', 'HP:0002664', (61, 67))
217289	33937395	Anti-NRP1 therapy can block tumour angiogenesis and upregulate the antitumour immune response.	('Anti-NRP1', 'Var', (0, 9))	('tumour', 'Phenotype', 'HP:0002664', (28, 34))	('tumour', 'Phenotype', 'HP:0002664', (71, 77))	('antitumour immune response', 'CPA', (67, 93))	('upregulate', 'PosReg', (52, 62))	('block tumour', 'Disease', (22, 34))	('block tumour', 'Disease', 'MESH:D006327', (22, 34))
217290	33937395	NRP2 has also been found to be closely associated with metastasis and BRAFV600E in thyroid cancer.	('NRP2', 'Gene', (0, 4))	('metastasis', 'CPA', (55, 65))	('thyroid cancer', 'Disease', 'MESH:D013964', (83, 97))	('BRAFV600E', 'Var', (70, 79))	('BRAFV600E', 'Mutation', 'rs113488022', (70, 79))	('associated', 'Reg', (39, 49))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('thyroid cancer', 'Phenotype', 'HP:0002890', (83, 97))	('thyroid cancer', 'Disease', (83, 97))
217297	32062069	Epigenomic analysis of 5-hydroxymethylcytosine (5hmC) reveals novel DNA methylation markers for lung cancers DNA methylation at the fifth position of cytosine (5mC) is a common epigenetic alteration affecting a range of cellular processes.	('cancers', 'Phenotype', 'HP:0002664', (101, 108))	('lung cancers', 'Disease', (96, 108))	('5mC', 'Chemical', '-', (160, 163))	('affecting', 'Reg', (199, 208))	('DNA methylation', 'Var', (109, 124))	('cytosine', 'Chemical', 'MESH:D003596', (150, 158))	('lung cancers', 'Disease', 'MESH:D008175', (96, 108))	('lung cancer', 'Phenotype', 'HP:0100526', (96, 107))	('cytosine', 'Chemical', 'MESH:D003596', (38, 46))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('lung cancers', 'Phenotype', 'HP:0100526', (96, 108))	('5hmC', 'Chemical', 'MESH:C011865', (48, 52))	('5-hydroxymethylcytosine', 'Chemical', 'MESH:C011865', (23, 46))
217301	32062069	We observed global hypomethylation of 5hmC comparing tumor to normal tissues, and hypermethylated 5hmC were enriched in CpG islands and gene upstream.	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('5hmC', 'Chemical', 'MESH:C011865', (98, 102))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('hypermethylated', 'Var', (82, 97))	('5hmC', 'Chemical', 'MESH:C011865', (38, 42))	('tumor', 'Disease', (53, 58))
217305	32062069	We observed global hypomethylation of 5hmC in lung cancers, and hypermethylated 5hmC enriched in CpG islands and gene upstream.	('lung cancers', 'Phenotype', 'HP:0100526', (46, 58))	('5hmC', 'Chemical', 'MESH:C011865', (80, 84))	('hypermethylated', 'Var', (64, 79))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('lung cancers', 'Disease', (46, 58))	('5hmC', 'Chemical', 'MESH:C011865', (38, 42))	('5hmC', 'Protein', (38, 42))	('cancers', 'Phenotype', 'HP:0002664', (51, 58))	('lung cancers', 'Disease', 'MESH:D008175', (46, 58))	('lung cancer', 'Phenotype', 'HP:0100526', (46, 57))
217314	32062069	DNA methylation abnormalities, such as global hypomethylation and hypermethylation at promoters of tumor suppressor genes, are found in most tumors including lung cancer.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('tumor', 'Disease', (99, 104))	('global', 'MPA', (39, 45))	('lung cancer', 'Disease', (158, 169))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('hypermethylation', 'Var', (66, 82))	('lung cancer', 'Phenotype', 'HP:0100526', (158, 169))	('tumors', 'Disease', (141, 147))	('tumors', 'Disease', 'MESH:D009369', (141, 147))	('tumor', 'Disease', (141, 146))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('lung cancer', 'Disease', 'MESH:D008175', (158, 169))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('found', 'Reg', (127, 132))
217319	32062069	Mutations in IDH, SDH, and FH genes can control 5hmC genomic levels and trigger carcinogenesis by regulating TET activity.	('IDH', 'Gene', '3417', (13, 16))	('TET', 'Chemical', '-', (109, 112))	('control', 'Reg', (40, 47))	('SDH', 'Gene', '6390', (18, 21))	('5hmC', 'Chemical', 'MESH:C011865', (48, 52))	('TET activity', 'MPA', (109, 121))	('Mutations', 'Var', (0, 9))	('SDH', 'Gene', (18, 21))	('trigger', 'Reg', (72, 79))	('5hmC genomic levels', 'MPA', (48, 67))	('IDH', 'Gene', (13, 16))	('carcinogenesis', 'CPA', (80, 94))
217361	32062069	Further examination of the distribution pattern of significant 5hmC loci by CGI status revealed that significant hypomethylated 5hmC loci were overrepresented in opensea (OR = 2.22, 95% CI = 2.15-2.28) whereas hypermethylated 5hmC loci were enriched in CGI (OR = 4.26, 95% CI = 4.01-4.52) (Fig.	('5hmC', 'Gene', (128, 132))	('overrepresented', 'PosReg', (143, 158))	('hypomethylated', 'Var', (113, 127))	('5hmC', 'Chemical', 'MESH:C011865', (226, 230))	('5hmC', 'Chemical', 'MESH:C011865', (63, 67))	('5hmC', 'Chemical', 'MESH:C011865', (128, 132))
217370	32062069	We aggregated probes into regions and identified 26 regions with differentially methylated 5hmC at FDR < 0.01, and 875 regions with differentially methylated 5modC at FDR < 0.05.	('FDR < 0.01', 'Var', (99, 109))	('5hmC', 'Protein', (91, 95))	('5hmC', 'Chemical', 'MESH:C011865', (91, 95))
217377	32062069	We found that the differentially methylated 5hmC genes were more likely to congregate at pathways involved in cellular process, biological regulation, and metabolic process, whereas the differentially methylated 5modC genes were more frequent among pathways related to localization, signaling, and multicellular organismal process.	('5hmC', 'Chemical', 'MESH:C011865', (44, 48))	('congregate', 'Reg', (75, 85))	('differentially methylated', 'Var', (18, 43))	('5hmC genes', 'Gene', (44, 54))
217385	32062069	Notably, we found hypermethylation of 5hmC among tumors that were enriched in gene upstream (e.g.	('hypermethylation', 'Var', (18, 34))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('tumors', 'Disease', 'MESH:D009369', (49, 55))	('tumors', 'Disease', (49, 55))	('5hmC', 'Chemical', 'MESH:C011865', (38, 42))	('5hmC', 'Gene', (38, 42))
217386	32062069	promoters), and previous in vitro studies reported that the presence of 5hmC at the promoter strongly suppressed transcription.	('transcription', 'MPA', (113, 126))	('presence', 'Var', (60, 68))	('suppressed', 'NegReg', (102, 112))	('5hmC', 'Chemical', 'MESH:C011865', (72, 76))	('5hmC', 'Protein', (72, 76))
217393	29950151	High TSTA3 Expression as a Candidate Biomarker for Poor Prognosis of Patients With ESCC Esophageal squamous cell carcinoma is the sixth most lethal cancer worldwide and the fourth most lethal cancer in China.	('cancer', 'Disease', (148, 154))	('TSTA3', 'Gene', '7264', (5, 10))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('High', 'Var', (0, 4))	('TSTA3', 'Gene', (5, 10))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (99, 122))	('cancer', 'Disease', (192, 198))	('cancer', 'Disease', 'MESH:D009369', (192, 198))	('Esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (88, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('Esophageal squamous cell carcinoma', 'Disease', (88, 122))	('Patients', 'Species', '9606', (69, 77))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))
217397	29950151	It is not clear whether tissue-specific transplantation antigen P35B has any effect on the development of esophageal squamous cell carcinoma.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (117, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('esophageal squamous cell carcinoma', 'Disease', (106, 140))	('P35B', 'Var', (64, 68))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (106, 140))	('P35B', 'SUBSTITUTION', 'None', (64, 68))
217398	29950151	We used an immunohistochemical method to assess the expression of tissue-specific transplantation antigen P35B in 104 esophageal squamous cell carcinoma samples.	('carcinoma', 'Phenotype', 'HP:0030731', (143, 152))	('P35B', 'SUBSTITUTION', 'None', (106, 110))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (118, 152))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (129, 152))	('P35B', 'Var', (106, 110))	('esophageal squamous cell carcinoma', 'Disease', (118, 152))
217399	29950151	The results showed tissue-specific transplantation antigen P35B expression was associated with some clinical features in patients, such as age (P = .017), clinical stage (P = .010), and lymph node metastasis (P = .043).	('associated', 'Reg', (79, 89))	('lymph node metastasis', 'CPA', (186, 207))	('P35B', 'SUBSTITUTION', 'None', (59, 63))	('patients', 'Species', '9606', (121, 129))	('P35B', 'Var', (59, 63))
217400	29950151	Kaplan-Meier analysis and log-rank test showed that patients with esophageal squamous cell carcinoma having high tissue-specific transplantation antigen P35B expression had a worse prognosis compared to the patients with low expression (P = .048).	('patients', 'Species', '9606', (207, 215))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (66, 100))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (77, 100))	('P35B', 'Var', (153, 157))	('esophageal squamous cell carcinoma', 'Disease', (66, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('P35B', 'SUBSTITUTION', 'None', (153, 157))	('patients', 'Species', '9606', (52, 60))
217401	29950151	Multivariate Cox proportional hazards regression model showed that high expression of tissue-specific transplantation antigen P35B could predict poor prognosis for patients with esophageal squamous cell carcinoma independently.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (189, 212))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (178, 212))	('high', 'Var', (67, 71))	('Cox', 'Gene', (13, 16))	('P35B', 'SUBSTITUTION', 'None', (126, 130))	('esophageal squamous cell carcinoma', 'Disease', (178, 212))	('patients', 'Species', '9606', (164, 172))	('carcinoma', 'Phenotype', 'HP:0030731', (203, 212))	('P35B', 'Var', (126, 130))	('Cox', 'Gene', '1351', (13, 16))
217402	29950151	In conclusion, abnormal fucosylation might participate in the progress of esophageal squamous cell carcinoma and tissue-specific transplantation antigen P35B may serve as a novel biomarker for prognosis of patients with esophageal squamous cell carcinoma.	('esophageal squamous cell carcinoma', 'Disease', (74, 108))	('esophageal squamous cell carcinoma', 'Disease', (220, 254))	('fucosylation', 'Protein', (24, 36))	('carcinoma', 'Phenotype', 'HP:0030731', (245, 254))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (231, 254))	('P35B', 'Var', (153, 157))	('participate', 'Reg', (43, 54))	('abnormal', 'Var', (15, 23))	('patients', 'Species', '9606', (206, 214))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (74, 108))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (85, 108))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('P35B', 'SUBSTITUTION', 'None', (153, 157))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (220, 254))
217409	29950151	Tissue-specific transplantation antigen P35B (TSTA3), also known as GDP-4-keto-6-deoxy-d-mannose-3,5-epimerase-4-reductase, and GDP-d-mannose-4,6-dehydratase (GMD) participate in the de novo way and convert cellular GDP-d-mannose into GDP-l-fucose.	('GMD', 'Gene', '2762', (159, 162))	('GDP-4-keto-6-deoxy-d-mannose-3,5-epimerase-4-reductase', 'Gene', '7264', (68, 122))	('TSTA3', 'Gene', (46, 51))	('P35B', 'SUBSTITUTION', 'None', (40, 44))	('P35B', 'Var', (40, 44))	('GDP-d-mannose', 'Chemical', 'MESH:D006155', (128, 141))	('GDP-d-mannose', 'Chemical', 'MESH:D006155', (216, 229))	('GDP-d-mannose-4,6-dehydratase', 'Gene', '2762', (128, 157))	('TSTA3', 'Gene', '7264', (46, 51))	('GDP-l-fucose', 'Chemical', 'MESH:D006154', (235, 247))	('GDP-l-fucose', 'MPA', (235, 247))	('GMD', 'Gene', (159, 162))	('convert', 'MPA', (199, 206))
217413	29950151	Previously, we showed missense mutation frequency of TSTA3 gene was 2% in ESCC.	('TSTA3', 'Gene', '7264', (53, 58))	('ESCC', 'Disease', (74, 78))	('TSTA3', 'Gene', (53, 58))	('missense mutation frequency', 'Var', (22, 49))
217419	29950151	Our results indicated that abnormal expression of TSTA3 may contribute toward ESCC progression, and TSTA3 may act as a potential novel biomarker for prognosis of patients with ESCC.	('ESCC', 'Disease', (176, 180))	('abnormal', 'Var', (27, 35))	('patients', 'Species', '9606', (162, 170))	('TSTA3', 'Gene', (100, 105))	('ESCC', 'Disease', (78, 82))	('TSTA3', 'Gene', '7264', (50, 55))	('contribute', 'Reg', (60, 70))	('TSTA3', 'Gene', (50, 55))	('TSTA3', 'Gene', '7264', (100, 105))	('expression', 'MPA', (36, 46))
217435	29950151	The H-Score of TSTA3 protein ranged from 66.3158 to 297.3680 in ESCC tumor tissues, and the median was 184.926.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('297.3680', 'Var', (52, 60))	('tumor', 'Disease', (69, 74))	('TSTA3', 'Gene', (15, 20))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('protein', 'Protein', (21, 28))	('TSTA3', 'Gene', '7264', (15, 20))
217436	29950151	According to the ROC curve analyses (area under curve = 0.709, P = .00037, 95% confidence interval (CI), 0.600-0.818; Figure 2A), all cancer samples were divided into 2 groups: TSTA3low (H-Score <195.2735) and TSTA3high (H-Score >=195.2735).	('H-Score >=195.2735', 'Var', (221, 239))	('TSTA3', 'Gene', (210, 215))	('cancer', 'Disease', (134, 140))	('TSTA3', 'Gene', (177, 182))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('TSTA3', 'Gene', '7264', (210, 215))	('H-Score <195.2735', 'Var', (187, 204))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('TSTA3', 'Gene', '7264', (177, 182))
217457	29950151	Aberrations of glycosylation are involved in a number of diseases, such as tumorigenesis and chronic inflammation.	('involved', 'Reg', (33, 41))	('inflammation', 'Disease', 'MESH:D007249', (101, 113))	('inflammation', 'Disease', (101, 113))	('glycosylation', 'Protein', (15, 28))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('Aberrations', 'Var', (0, 11))	('tumor', 'Disease', (75, 80))
217458	29950151	Fucosylation is one of the most common glycosylation modifications on glycoproteins and glycolipids, and abnormal fucosylation is closely related to the tumor.	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('Fucosylation', 'MPA', (0, 12))	('tumor', 'Disease', (153, 158))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('abnormal', 'Var', (105, 113))	('related', 'Reg', (138, 145))	('fucosylation', 'MPA', (114, 126))
217466	29950151	As our results showed in ESCC, TSTA3high patients tended to have a deeper invasion depth and a higher LN metastasis rate, which indicated that high TSTA3 may promote the invasion and metastasis of ESCC cells, more experiments are required for making clear whether such function is through aberrant fucosylation of glycoproteins.	('TSTA3', 'Gene', (31, 36))	('TSTA3', 'Gene', (148, 153))	('promote', 'PosReg', (158, 165))	('higher', 'PosReg', (95, 101))	('high', 'Var', (143, 147))	('patients', 'Species', '9606', (41, 49))	('ESCC', 'Disease', (25, 29))	('invasion depth', 'CPA', (74, 88))	('TSTA3', 'Gene', '7264', (31, 36))	('TSTA3', 'Gene', '7264', (148, 153))	('LN metastasis rate', 'CPA', (102, 120))
217471	29950151	Engineering anti-Lewis-Y hu3S193 and IGN311 antibodies have been tested as passive immunotherapy approaches of epithelial cancers and may be applied clinically.	('epithelial cancers', 'Disease', (111, 129))	('epithelial cancers', 'Disease', 'MESH:D000077216', (111, 129))	('hu3S193', 'Var', (25, 32))	('cancers', 'Phenotype', 'HP:0002664', (122, 129))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('IGN311', 'Gene', (37, 43))
217477	29950151	AFP alpha-fetoprotein CI confidence interval ESCC esophageal squamous cell carcinoma FUTs fucosyltransferases GMD GDP-d-mannose-4,6-dehydratase H-Score Histoscore IHC immunohistochemical LN lymph node OS overall survival PH proportional hazards ROC receiver operating characteristic TSTA3 tissue-specific transplantation antigen P35B	('GMD', 'Gene', '2762', (110, 113))	('TSTA3', 'Gene', '7264', (283, 288))	('P35B', 'SUBSTITUTION', 'None', (329, 333))	('alpha-fetoprotein', 'Gene', (4, 21))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (61, 84))	('TSTA3', 'Gene', (283, 288))	('AFP', 'Gene', (0, 3))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (50, 84))	('OS', 'Chemical', '-', (201, 203))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('GDP-d-mannose-4,6-dehydratase', 'Gene', '2762', (114, 143))	('P35B', 'Var', (329, 333))	('AFP', 'Gene', '174', (0, 3))	('alpha-fetoprotein', 'Gene', '174', (4, 21))	('esophageal squamous cell carcinoma', 'Disease', (50, 84))	('GMD', 'Gene', (110, 113))
217498	32629428	Exome sequencing identifies somatic mutations in novel driver genes in non-small cell lung cancer Lung cancer is the leading cause of cancer death worldwide and accounts for more than one-third of all newly diagnosed cancer cases in China.	('Lung cancer', 'Phenotype', 'HP:0100526', (98, 109))	('Lung cancer', 'Disease', (98, 109))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (75, 97))	('cancer', 'Disease', (103, 109))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (217, 223))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('cancer death', 'Disease', 'MESH:D009369', (134, 146))	('lung cancer', 'Phenotype', 'HP:0100526', (86, 97))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('cancer', 'Disease', (91, 97))	('mutations', 'Var', (36, 45))	('cancer death', 'Disease', (134, 146))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('cancer', 'Disease', (217, 223))	('Lung cancer', 'Disease', 'MESH:D008175', (98, 109))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (71, 97))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))
217499	32629428	Therefore, it is of great clinical significance to explore new driver gene mutations in non-small-cell lung cancer (NSCLC).	('NSCLC', 'Disease', 'MESH:D002289', (116, 121))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (88, 114))	('NSCLC', 'Phenotype', 'HP:0030358', (116, 121))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('mutations', 'Var', (75, 84))	('lung cancer', 'Phenotype', 'HP:0100526', (103, 114))	('non-small-cell lung cancer', 'Disease', (88, 114))	('NSCLC', 'Disease', (116, 121))	('non-small-cell lung cancer', 'Disease', 'MESH:D002289', (88, 114))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (92, 114))
217501	32629428	Recurrent mutations were detected in UNC5D (7.9%), PREX1 (5.0%), HECW1 (4.0%), DACH1 (2.0%), and GPC5 (2.0%).	('HECW1', 'Gene', '23072', (65, 70))	('GPC5', 'Gene', '2262', (97, 101))	('UNC5D', 'Gene', (37, 42))	('GPC5', 'Gene', (97, 101))	('DACH1', 'Gene', (79, 84))	('PREX1', 'Gene', (51, 56))	('DACH1', 'Gene', '1602', (79, 84))	('UNC5D', 'Gene', '137970', (37, 42))	('mutations', 'Var', (10, 19))	('PREX1', 'Gene', '57580', (51, 56))	('HECW1', 'Gene', (65, 70))
217503	32629428	Mutations in UNC5D promoted tumorigenesis by abolishing the tumor suppressor function of the encoded protein.	('promoted', 'PosReg', (19, 27))	('tumor', 'Disease', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('abolishing', 'NegReg', (45, 55))	('Mutations', 'Var', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('tumor', 'Disease', (60, 65))	('UNC5D', 'Gene', (13, 18))	('UNC5D', 'Gene', '137970', (13, 18))
217504	32629428	Additionally, in ten patients with lung squamous cell carcinoma, we identified mutations in KEAP1/NFE2L2 that influenced the expression of target genes in vivo and in vitro.	('influenced', 'Reg', (110, 120))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (35, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (54, 63))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (35, 63))	('expression', 'MPA', (125, 135))	('patients', 'Species', '9606', (21, 29))	('lung squamous cell carcinoma', 'Disease', (35, 63))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (40, 63))	('KEAP1/NFE2L2', 'Gene', (92, 104))	('mutations', 'Var', (79, 88))
217505	32629428	Overall, the results of our study expanded the known spectrum of driver mutations involved in the pathogenesis of NSCLC.	('mutations', 'Var', (72, 81))	('NSCLC', 'Phenotype', 'HP:0030358', (114, 119))	('NSCLC', 'Disease', 'MESH:D002289', (114, 119))	('NSCLC', 'Disease', (114, 119))
217509	32629428	Mutations in 10 driver genes have been identified in patients with lung ADC that contribute to its pathogenesis.	('lung ADC', 'Disease', (67, 75))	('Mutations', 'Var', (0, 9))	('patients', 'Species', '9606', (53, 61))
217510	32629428	Next-generation sequencing (NGS) enables large-scale analyses of DNA sequence alterations in human tissue and was used to identify additional genes related to the pathogenesis of lung cancer and potential therapeutic targets.	('lung cancer', 'Disease', (179, 190))	('lung cancer', 'Phenotype', 'HP:0100526', (179, 190))	('human', 'Species', '9606', (93, 98))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('alterations', 'Var', (78, 89))	('lung cancer', 'Disease', 'MESH:D008175', (179, 190))
217511	32629428	Recently, an exome-sequencing study identified recurrent mutations in CREBBP, EP300, and MLL that encode histone modifiers and showed evidence for the inactivation of TP53 and RB1 in small-cell lung cancer.	('lung cancer', 'Phenotype', 'HP:0100526', (194, 205))	('EP300', 'Gene', (78, 83))	('MLL', 'Gene', (89, 92))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('MLL', 'Gene', '4297', (89, 92))	('inactivation', 'NegReg', (151, 163))	('CREBBP', 'Gene', '1387', (70, 76))	('RB1', 'Gene', (176, 179))	('mutations', 'Var', (57, 66))	('small-cell lung cancer', 'Disease', 'MESH:D055752', (183, 205))	('TP53', 'Gene', '7157', (167, 171))	('RB1', 'Gene', '5925', (176, 179))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (183, 205))	('CREBBP', 'Gene', (70, 76))	('EP300', 'Gene', '2033', (78, 83))	('small-cell lung cancer', 'Disease', (183, 205))	('TP53', 'Gene', (167, 171))
217518	32629428	To control for tumor heterogeneity and passenger mutations, the tumors included in our study all harbored TP53 mutations, which are known to play an important role in the tumorigenesis of lung epithelial cells.	('mutations', 'Var', (111, 120))	('tumors', 'Disease', (64, 70))	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('tumor', 'Disease', (64, 69))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumor', 'Disease', (15, 20))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('harbored', 'Reg', (97, 105))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', (171, 176))	('TP53', 'Gene', '7157', (106, 110))	('TP53', 'Gene', (106, 110))
217519	32629428	Through a series of bioinformatic analyses (including somatic mutation selection, filtration of nonpathogenic single nucleotide polymorphisms from dbSNP 135, and single nucleotide variants from the ESP 6500 database), we observed that C>A/G>T alterations were more frequent than other forms (Figure 1A), which is similar to the somatic single nucleotide variant spectrum of NSCLC reported in other studies.	('NSCLC', 'Disease', 'MESH:D002289', (374, 379))	('ESP', 'Gene', (198, 201))	('NSCLC', 'Phenotype', 'HP:0030358', (374, 379))	('ESP', 'Gene', '148713', (198, 201))	('C>A/G>T', 'Var', (235, 242))	('NSCLC', 'Disease', (374, 379))
217520	32629428	Among these genes, mutations in TP53, CDKN2A, PTEN, KEAP1, NF1, RELN, KRAS, and CDH10 have been reported in NSCLC in previous studies.	('KRAS', 'Gene', (70, 74))	('TP53', 'Gene', '7157', (32, 36))	('PTEN', 'Gene', '5728', (46, 50))	('CDH10', 'Gene', (80, 85))	('reported', 'Reg', (96, 104))	('NSCLC', 'Disease', 'MESH:D002289', (108, 113))	('NF1', 'Gene', '4763', (59, 62))	('RELN', 'Gene', (64, 68))	('NSCLC', 'Disease', (108, 113))	('CDH10', 'Gene', '1008', (80, 85))	('TP53', 'Gene', (32, 36))	('CDKN2A', 'Gene', (38, 44))	('NF1', 'Gene', (59, 62))	('NSCLC', 'Phenotype', 'HP:0030358', (108, 113))	('PTEN', 'Gene', (46, 50))	('KRAS', 'Gene', '3845', (70, 74))	('mutations', 'Var', (19, 28))	('CDKN2A', 'Gene', '1029', (38, 44))	('RELN', 'Gene', '5649', (64, 68))
217530	32629428	The eight UNC5D variants were all missense mutations (Figures 1C and 2A).	('UNC5D', 'Gene', (10, 15))	('missense mutations', 'Var', (34, 52))	('UNC5D', 'Gene', '137970', (10, 15))
217532	32629428	The C862F mutation is located in the death domain of UNC5D, for which alterations have been shown to influence protein function and induce tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('death', 'Disease', (37, 42))	('protein', 'Protein', (111, 118))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('C862F', 'Mutation', 'p.C862F', (4, 9))	('UNC5D', 'Gene', (53, 58))	('UNC5D', 'Gene', '137970', (53, 58))	('influence', 'Reg', (101, 110))	('induce', 'PosReg', (132, 138))	('death', 'Disease', 'MESH:D003643', (37, 42))	('C862F', 'Var', (4, 9))
217536	32629428	According to our preliminary experiment, Q135L and R777H were used to investigate the function of mutants.	('Q135L', 'Mutation', 'rs1267601411', (41, 46))	('R777H', 'Mutation', 'rs1334662855', (51, 56))	('R777H', 'Var', (51, 56))	('Q135L', 'Var', (41, 46))
217537	32629428	We next performed cell proliferation and colony formation assays and found that cell growth was inhibited by UNC5D-WT but not the mutant variants (Figure 3B-3D).	('inhibited', 'NegReg', (96, 105))	('UNC5D-WT', 'Gene', '137970', (109, 117))	('mutant', 'Var', (130, 136))	('UNC5D-WT', 'Gene', (109, 117))	('cell growth', 'CPA', (80, 91))
217542	32629428	To investigate the impact of KEAP1 or NFE2L2 mutations in NSCLC, we compared the expression of known NFE2L2 target genes involved in oxidative stress in samples with (n = 9) or without (n = 18) either of these mutations.	('NSCLC', 'Disease', (58, 63))	('mutations', 'Var', (45, 54))	('NSCLC', 'Disease', 'MESH:D002289', (58, 63))	('oxidative stress', 'Phenotype', 'HP:0025464', (133, 149))	('NFE2L2', 'Gene', (38, 44))	('NSCLC', 'Phenotype', 'HP:0030358', (58, 63))	('compared', 'Reg', (68, 76))	('expression', 'MPA', (81, 91))
217543	32629428	We found that samples with KEAP1 or NFE2L2 mutations had significantly increased expression of UGT1A1, GSTA, NQO1, GCLC, and GPX (Figure 4A).	('NFE2L2', 'Gene', (36, 42))	('GCLC', 'Gene', '2729', (115, 119))	('UGT1A1', 'Gene', (95, 101))	('NQO1', 'Gene', (109, 113))	('NQO1', 'Gene', '1728', (109, 113))	('mutations', 'Var', (43, 52))	('increased', 'PosReg', (71, 80))	('UGT1A1', 'Gene', '54658', (95, 101))	('GSTA', 'Gene', (103, 107))	('expression', 'MPA', (81, 91))	('GCLC', 'Gene', (115, 119))
217544	32629428	This increase was validated in vitro, where the expression levels of HMOX1, GCLC, GCLM, TXN, TXNRD, NQO1, G6PD, and GSR were higher in lung cancer cell lines with KEAP1/NFE2L2 mutations (i.e., cell lines A549, NCI-H460, and NCI-H838) than in those without mutations (i.e., cell lines NCI-H292, 95D, SPC-A1, and NCI-H1299) (Figure 4B).	('mutations', 'Var', (176, 185))	('GCLM', 'Gene', (82, 86))	('NCI-H460', 'CellLine', 'CVCL:0459', (210, 218))	('higher', 'PosReg', (125, 131))	('NQO1', 'Gene', (100, 104))	('lung cancer', 'Disease', (135, 146))	('GCLC', 'Gene', (76, 80))	('TXN', 'Gene', (88, 91))	('TXN', 'Gene', '7295', (88, 91))	('KEAP1/NFE2L2', 'Gene', (163, 175))	('expression', 'MPA', (48, 58))	('GCLM', 'Gene', '2730', (82, 86))	('SPC-A1', 'Gene', (299, 305))	('SPC-A1', 'Gene', '27032', (299, 305))	('G6PD', 'Gene', '2539', (106, 110))	('HMOX1', 'Gene', '3162', (69, 74))	('NCI-H1299', 'CellLine', 'CVCL:0060', (311, 320))	('lung cancer', 'Disease', 'MESH:D008175', (135, 146))	('TXN', 'Gene', (93, 96))	('A549', 'CellLine', 'CVCL:0023', (204, 208))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('TXN', 'Gene', '7295', (93, 96))	('lung cancer', 'Phenotype', 'HP:0100526', (135, 146))	('GCLC', 'Gene', '2729', (76, 80))	('G6PD', 'Gene', (106, 110))	('HMOX1', 'Gene', (69, 74))	('NQO1', 'Gene', '1728', (100, 104))	('NCI-H292', 'CellLine', 'CVCL:0455', (284, 292))
217545	32629428	These findings suggest that there may be altered responses to oxidative stress in the tumors of patients with KEAP1/NFE2L2 mutations and may thus represent much-needed potential therapeutic targets for NSCLC.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('altered', 'Reg', (41, 48))	('NSCLC', 'Disease', (202, 207))	('responses to oxidative stress', 'MPA', (49, 78))	('KEAP1/NFE2L2', 'Gene', (110, 122))	('NSCLC', 'Disease', 'MESH:D002289', (202, 207))	('tumors', 'Disease', (86, 92))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('oxidative stress', 'Phenotype', 'HP:0025464', (62, 78))	('patients', 'Species', '9606', (96, 104))	('NSCLC', 'Phenotype', 'HP:0030358', (202, 207))	('mutations', 'Var', (123, 132))
217548	32629428	Recently, Dong D et al found UNC5D as a putative metastatic suppressor gene that is commonly downregulated by hypermethylation in PCa.	('metastatic suppressor gene', 'Gene', (49, 75))	('hypermethylation', 'Var', (110, 126))	('UNC5D', 'Gene', (29, 34))	('UNC5D', 'Gene', '137970', (29, 34))	('downregulated', 'NegReg', (93, 106))
217549	32629428	Notably, we discovered UNC5D somatic mutations in 13 NSCLC patients and confirmed these mutations in an extended validation group of 88 patients.	('NSCLC', 'Phenotype', 'HP:0030358', (53, 58))	('UNC5D', 'Gene', (23, 28))	('mutations', 'Var', (37, 46))	('patients', 'Species', '9606', (136, 144))	('patients', 'Species', '9606', (59, 67))	('NSCLC', 'Disease', (53, 58))	('UNC5D', 'Gene', '137970', (23, 28))	('NSCLC', 'Disease', 'MESH:D002289', (53, 58))
217551	32629428	Additionally, further research in UNC5D mutants predicted that the mutations of UNC5D we found in NSCLC might deprive the suppression function of UNC5D.	('UNC5D', 'Gene', (34, 39))	('UNC5D', 'Gene', '137970', (34, 39))	('UNC5D', 'Gene', (146, 151))	('UNC5D', 'Gene', (80, 85))	('UNC5D', 'Gene', '137970', (146, 151))	('NSCLC', 'Phenotype', 'HP:0030358', (98, 103))	('UNC5D', 'Gene', '137970', (80, 85))	('deprive', 'NegReg', (110, 117))	('mutations', 'Var', (67, 76))	('NSCLC', 'Disease', (98, 103))	('NSCLC', 'Disease', 'MESH:D002289', (98, 103))	('suppression function', 'MPA', (122, 142))
217552	32629428	These results suggest that mutated UNC5D might be a driver gene in NSCLC and promote the development and progression of lung cancer.	('UNC5D', 'Gene', (35, 40))	('promote', 'PosReg', (77, 84))	('mutated', 'Var', (27, 34))	('progression', 'CPA', (105, 116))	('lung cancer', 'Disease', (120, 131))	('lung cancer', 'Phenotype', 'HP:0100526', (120, 131))	('development', 'CPA', (89, 100))	('NSCLC', 'Phenotype', 'HP:0030358', (67, 72))	('UNC5D', 'Gene', '137970', (35, 40))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('NSCLC', 'Disease', (67, 72))	('lung cancer', 'Disease', 'MESH:D008175', (120, 131))	('NSCLC', 'Disease', 'MESH:D002289', (67, 72))
217554	32629428	However, our results revealed that UNC5D mutations and TP53 mutations coexisted (Figure 1C), which suggests that the inactivation of both UNC5D and TP53 could promote NSCLC.	('UNC5D', 'Gene', (35, 40))	('UNC5D', 'Gene', (138, 143))	('NSCLC', 'Disease', 'MESH:D002289', (167, 172))	('UNC5D', 'Gene', '137970', (138, 143))	('TP53', 'Gene', '7157', (55, 59))	('NSCLC', 'Phenotype', 'HP:0030358', (167, 172))	('TP53', 'Gene', (55, 59))	('TP53', 'Gene', '7157', (148, 152))	('TP53', 'Gene', (148, 152))	('UNC5D', 'Gene', '137970', (35, 40))	('inactivation', 'Var', (117, 129))	('promote', 'PosReg', (159, 166))	('NSCLC', 'Disease', (167, 172))
217556	32629428	Among other candidate drivers, we identified mutations in PREX1 and HECW1 that occurred at high frequencies in NSCLC.	('HECW1', 'Gene', '23072', (68, 73))	('mutations', 'Var', (45, 54))	('NSCLC', 'Disease', (111, 116))	('NSCLC', 'Disease', 'MESH:D002289', (111, 116))	('PREX1', 'Gene', (58, 63))	('HECW1', 'Gene', (68, 73))	('PREX1', 'Gene', '57580', (58, 63))	('NSCLC', 'Phenotype', 'HP:0030358', (111, 116))	('occurred', 'Reg', (79, 87))
217558	32629428	We found 5 cases with PREX1 gene mutations in our patients.	('PREX1', 'Gene', '57580', (22, 27))	('PREX1', 'Gene', (22, 27))	('patients', 'Species', '9606', (50, 58))	('mutations', 'Var', (33, 42))
217560	32629428	Therefore, PREX1 mutations may be activating mutations, thereby promoting cell migration and distant metastasis in NSCLC.	('cell migration', 'CPA', (74, 88))	('NSCLC', 'Disease', (115, 120))	('PREX1', 'Gene', (11, 16))	('NSCLC', 'Disease', 'MESH:D002289', (115, 120))	('distant metastasis', 'CPA', (93, 111))	('PREX1', 'Gene', '57580', (11, 16))	('mutations', 'Var', (17, 26))	('NSCLC', 'Phenotype', 'HP:0030358', (115, 120))	('promoting', 'PosReg', (64, 73))
217562	32629428	Recently, recurrent mutations in exon 11 of HECW1 were identified in muscle-invasive transitional cell carcinoma.	('identified', 'Reg', (55, 65))	('muscle-invasive transitional cell carcinoma', 'Disease', 'MESH:D002295', (69, 112))	('muscle-invasive transitional cell carcinoma', 'Disease', (69, 112))	('HECW1', 'Gene', (44, 49))	('mutations in', 'Var', (20, 32))	('HECW1', 'Gene', '23072', (44, 49))	('invasive transitional cell carcinoma', 'Phenotype', 'HP:0006740', (76, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))
217563	32629428	In this study, we found HECW1 mutations in exons 2, 7, 10 and 18 in NSCLC.	('HECW1', 'Gene', '23072', (24, 29))	('NSCLC', 'Disease', 'MESH:D002289', (68, 73))	('NSCLC', 'Phenotype', 'HP:0030358', (68, 73))	('mutations', 'Var', (30, 39))	('NSCLC', 'Disease', (68, 73))	('HECW1', 'Gene', (24, 29))
217565	32629428	Lignito's results showed that loss of Keap1 or Fbxo22 induces metastasis in a Bach1-dependent manner and causes a notable increase in the metastatic phenotype in mouse models of lung cancers.	('Fbxo22', 'Gene', (47, 53))	('metastasis', 'CPA', (62, 72))	('Keap1', 'Gene', '50868', (38, 43))	('metastatic phenotype', 'CPA', (138, 158))	('Keap1', 'Gene', (38, 43))	('Bach1', 'Gene', '12013', (78, 83))	('lung cancer', 'Phenotype', 'HP:0100526', (178, 189))	('lung cancers', 'Disease', 'MESH:D008175', (178, 190))	('mouse', 'Species', '10090', (162, 167))	('Fbxo22', 'Gene', '71999', (47, 53))	('lung cancers', 'Phenotype', 'HP:0100526', (178, 190))	('Bach1', 'Gene', (78, 83))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('lung cancers', 'Disease', (178, 190))	('induces', 'Reg', (54, 61))	('loss', 'Var', (30, 34))	('increase', 'PosReg', (122, 130))	('cancers', 'Phenotype', 'HP:0002664', (183, 190))
217566	32629428	Furthermore, KEAP1 and NFE2L2 mutations were mutually exclusive in NSCLC.	('NSCLC', 'Phenotype', 'HP:0030358', (67, 72))	('KEAP1', 'Gene', (13, 18))	('NFE2L2', 'Gene', (23, 29))	('mutations', 'Var', (30, 39))	('NSCLC', 'Disease', (67, 72))	('NSCLC', 'Disease', 'MESH:D002289', (67, 72))
217567	32629428	first reported KEAP1 mutations in 19% of NSCLC samples, all of which occurred within either the highly conserved Kelch domain or the intervening region domain of the protein.	('mutations', 'Var', (21, 30))	('NSCLC', 'Disease', (41, 46))	('NSCLC', 'Disease', 'MESH:D002289', (41, 46))	('NSCLC', 'Phenotype', 'HP:0030358', (41, 46))	('KEAP1', 'Gene', (15, 20))	('occurred', 'Reg', (69, 77))
217568	32629428	Interestingly, most of the KEAP1/NFE2L2 mutations were found in samples from patients with SCC (33.3% (10/30)).	('found', 'Reg', (55, 60))	('SCC', 'Disease', (91, 94))	('mutations', 'Var', (40, 49))	('patients', 'Species', '9606', (77, 85))	('KEAP1/NFE2L2', 'Gene', (27, 39))	('SCC', 'Phenotype', 'HP:0002860', (91, 94))
217569	32629428	Our study found that UGTA1A, NQO1 and GSTA gene expression levels in lung cancer tissues carrying KEAP1/NRF2 gene mutations significantly increased in comparison with those in lung cancer tissues without KEAP1/NRF2 gene mutations.	('mutations', 'Var', (114, 123))	('NQO1', 'Gene', '1728', (29, 33))	('NRF2', 'Gene', '4780', (104, 108))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('NQO1', 'Gene', (29, 33))	('increased', 'PosReg', (138, 147))	('NRF2', 'Gene', (210, 214))	('lung cancer', 'Disease', 'MESH:D008175', (176, 187))	('lung cancer', 'Disease', (69, 80))	('lung cancer', 'Phenotype', 'HP:0100526', (176, 187))	('lung cancer', 'Disease', (176, 187))	('NRF2', 'Gene', (104, 108))	('UGTA1A', 'MPA', (21, 27))	('GSTA', 'Gene', (38, 42))	('UGTA1A', 'Mutation', 'c.1UGTA>A', (21, 27))	('lung cancer', 'Disease', 'MESH:D008175', (69, 80))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('lung cancer', 'Phenotype', 'HP:0100526', (69, 80))	('NRF2', 'Gene', '4780', (210, 214))
217570	32629428	These results indicated that the KEAP1 mutations were inactivation mutations, while NRF2 mutations were activating mutations.	('NRF2', 'Gene', (84, 88))	('KEAP1', 'Gene', (33, 38))	('NRF2', 'Gene', '4780', (84, 88))	('mutations', 'Var', (39, 48))
217571	32629428	Mutated KEAP1/NRF2 genes activate downstream oxidation reaction components (AREs), detoxification, and cell metabolism-related gene transcription levels, thereby changing cell oxidative stress levels to promote the occurrence of lung cancer.	('cell oxidative stress levels', 'MPA', (171, 199))	('NRF2', 'Gene', (14, 18))	('changing', 'Reg', (162, 170))	('activate', 'PosReg', (25, 33))	('detoxification', 'MPA', (83, 97))	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('lung cancer', 'Disease', 'MESH:D008175', (229, 240))	('NRF2', 'Gene', '4780', (14, 18))	('downstream', 'MPA', (34, 44))	('lung cancer', 'Disease', (229, 240))	('oxidative stress', 'Phenotype', 'HP:0025464', (176, 192))	('promote', 'PosReg', (203, 210))	('Mutated', 'Var', (0, 7))	('lung cancer', 'Phenotype', 'HP:0100526', (229, 240))	('cell metabolism-related gene transcription levels', 'MPA', (103, 152))
217573	32629428	We further demonstrated that recurrent mutations of UNC5D in NSCLC lead to a loss of tumor suppressor function in vitro and in vivo.	('tumor', 'Disease', (85, 90))	('UNC5D', 'Gene', (52, 57))	('UNC5D', 'Gene', '137970', (52, 57))	('NSCLC', 'Phenotype', 'HP:0030358', (61, 66))	('mutations', 'Var', (39, 48))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('NSCLC', 'Disease', (61, 66))	('loss', 'NegReg', (77, 81))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('NSCLC', 'Disease', 'MESH:D002289', (61, 66))
217574	32629428	Finally, we showed that the expression of genes involved in oxidative stress is upregulated in tumors with KEAP1/NFE2L2 mutations.	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('oxidative stress', 'Phenotype', 'HP:0025464', (60, 76))	('KEAP1/NFE2L2', 'Gene', (107, 119))	('expression', 'MPA', (28, 38))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('upregulated', 'PosReg', (80, 91))	('mutations', 'Var', (120, 129))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumors', 'Disease', (95, 101))
217578	32629428	TP53 mutations were detected in all tumor samples by Sanger sequencing (Supplementary Table 5).	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumor', 'Disease', (36, 41))
217586	32629428	We further filtered by (i) nonpathogenic single nucleotide polymorphisms from dbSNP 135 and SNVs from the ESP 6500 database and (ii) SNVs identified in our in-house control samples (87 healthy Chinese individuals), as described previously.	('ESP', 'Gene', '148713', (106, 109))	('single nucleotide polymorphisms', 'Var', (41, 72))	('dbSNP 135', 'Gene', (78, 87))	('ESP', 'Gene', (106, 109))
217611	32629428	With methods of random grouping, forty-four athymic nude mice (5 weeks old, male) (Shanghai SLAC Laboratory Animal Co. Ltd, China) were divided into four groups: vector, wild type, Q135L, and R777H.	('Q135L', 'Var', (181, 186))	('Q135L', 'Mutation', 'rs1267601411', (181, 186))	('R777H', 'Mutation', 'rs1334662855', (192, 197))	('nude mice', 'Species', '10090', (52, 61))	('R777H', 'Var', (192, 197))
217629	31681566	Molecular profiling of NSCLC identified mutations in the tumor suppressor genes (TP53, RB1), oncogenes (EGFR, KRAS, AKT, MAPK) and translocations in oncogenes (ALK, RET, ROS1, NTRK1, NRG1), which alter the important signal-transduction pathways.	('RB1', 'Gene', (87, 90))	('NSCLC', 'Disease', (23, 28))	('ROS1', 'Gene', '6098', (170, 174))	('NRG1', 'Gene', (183, 187))	('TP53', 'Gene', '7157', (81, 85))	('NTRK1', 'Gene', '4914', (176, 181))	('NRG1', 'Gene', '3084', (183, 187))	('NSCLC', 'Phenotype', 'HP:0030358', (23, 28))	('NTRK1', 'Gene', (176, 181))	('EGFR', 'Gene', (104, 108))	('RB1', 'Gene', '5925', (87, 90))	('mutations', 'Var', (40, 49))	('tumor', 'Disease', (57, 62))	('AKT', 'Gene', (116, 119))	('RET', 'Gene', '5979', (165, 168))	('KRAS', 'Gene', '3845', (110, 114))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('ALK', 'Gene', '238', (160, 163))	('ROS1', 'Gene', (170, 174))	('KRAS', 'Gene', (110, 114))	('TP53', 'Gene', (81, 85))	('EGFR', 'Gene', '1956', (104, 108))	('ALK', 'Gene', (160, 163))	('translocations', 'Var', (131, 145))	('SCLC', 'Phenotype', 'HP:0030357', (24, 28))	('RET', 'Gene', (165, 168))	('alter', 'Reg', (196, 201))	('AKT', 'Gene', '207', (116, 119))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('NSCLC', 'Disease', 'MESH:D002289', (23, 28))
217630	31681566	EGFR mutants have been reported more frequently in NSCLC in nonsmokers Asians patients and showed highly sensitive to therapy with EGFR tyrosine kinase inhibitors such as gefitinib and erlotinib.	('NSCLC', 'Phenotype', 'HP:0030358', (51, 56))	('EGFR', 'Gene', (0, 4))	('SCLC', 'Phenotype', 'HP:0030357', (52, 56))	('NSCLC', 'Disease', (51, 56))	('tyrosine', 'Chemical', 'None', (136, 144))	('patients', 'Species', '9606', (78, 86))	('gefitinib', 'Chemical', 'MESH:C419708', (171, 180))	('EGFR', 'Gene', '1956', (131, 135))	('NSCLC', 'Disease', 'MESH:D002289', (51, 56))	('EGFR', 'Gene', (131, 135))	('mutants', 'Var', (5, 12))	('EGFR', 'Gene', '1956', (0, 4))	('erlotinib', 'Chemical', 'MESH:C400278', (185, 194))
217631	31681566	Similarly, ALK rearranged gene fusion was also highly reported in NSCLC and has been proven more effective treatment with ALK-targeted inhibitors (crizotinib and alectinib).	('rearranged gene fusion', 'Var', (15, 37))	('NSCLC', 'Phenotype', 'HP:0030358', (66, 71))	('NSCLC', 'Disease', (66, 71))	('crizotinib', 'Chemical', 'MESH:C551994', (147, 157))	('NSCLC', 'Disease', 'MESH:D002289', (66, 71))	('ALK', 'Gene', (122, 125))	('ALK', 'Gene', (11, 14))	('SCLC', 'Phenotype', 'HP:0030357', (67, 71))	('reported', 'Reg', (54, 62))	('ALK', 'Gene', '238', (122, 125))	('ALK', 'Gene', '238', (11, 14))
217632	31681566	The genomic mutations not only alter the protein structure but also affect the expression level of genes involved in the cell division resulting in uncontrolled cell proliferation, cell survival, and NSCLC.	('cell survival', 'CPA', (181, 194))	('NSCLC', 'Phenotype', 'HP:0030358', (200, 205))	('SCLC', 'Phenotype', 'HP:0030357', (201, 205))	('mutations', 'Var', (12, 21))	('NSCLC', 'Disease', (200, 205))	('uncontrolled', 'MPA', (148, 160))	('expression level of genes', 'MPA', (79, 104))	('NSCLC', 'Disease', 'MESH:D002289', (200, 205))	('protein structure', 'MPA', (41, 58))	('alter', 'Reg', (31, 36))	('affect', 'Reg', (68, 74))
217666	31681566	The cumulative contribution of PC1, PC2, and PC3 is 38.59, 33.64, and 36.47% for GSE27262, GSE18842, and GSE19804 datasets, respectively.	('PC1', 'Gene', (31, 34))	('GSE18842', 'Var', (91, 99))	('PC2', 'Gene', '3854', (36, 39))	('PC3', 'Gene', '3853', (45, 48))	('GSE27262', 'Var', (81, 89))	('PC2', 'Gene', (36, 39))	('PC1', 'Gene', '3868', (31, 34))	('GSE19804', 'Var', (105, 113))	('PC3', 'Gene', (45, 48))
217695	31681566	However, only FOXM1 and MYBL2 are up-regulated gene showing log2FC >1, while, TFDP1 and E2F4 show slight up-regulated while SIN3A show slight down-regulated in our list of DEGs of NSCLC.	('DEGs', 'Chemical', 'MESH:C062694', (172, 176))	('SCLC', 'Phenotype', 'HP:0030357', (181, 185))	('MYBL2', 'Gene', (24, 29))	('NSCLC', 'Disease', (180, 185))	('SIN3A', 'Gene', '25942', (124, 129))	('up-regulated', 'PosReg', (105, 117))	('E2F4', 'Var', (88, 92))	('SIN3A', 'Gene', (124, 129))	('NSCLC', 'Disease', 'MESH:D002289', (180, 185))	('TFDP1', 'Gene', '7027', (78, 83))	('down-regulated', 'NegReg', (142, 156))	('log2FC >1', 'Var', (60, 69))	('TFDP1', 'Gene', (78, 83))	('FOXM1', 'Gene', (14, 19))	('NSCLC', 'Phenotype', 'HP:0030358', (180, 185))
217714	31681566	Kaplan-Meier plots showed that high expression of all the up-regulated genes of Cluster 1 make worse the OS [HR >1], while high expression of down-regulated gene SIN3A makes better the OS [HR <1] in NSCLC (Figure 4B; Figure S10).	('up-regulated', 'PosReg', (58, 70))	('SIN3A', 'Gene', '25942', (162, 167))	('NSCLC', 'Disease', 'MESH:D002289', (199, 204))	('SCLC', 'Phenotype', 'HP:0030357', (200, 204))	('SIN3A', 'Gene', (162, 167))	('NSCLC', 'Phenotype', 'HP:0030358', (199, 204))	('high', 'Var', (31, 35))	('OS [HR >1]', 'MPA', (105, 115))	('NSCLC', 'Disease', (199, 204))
217715	31681566	Kaplan-Meier plots of the gene of other clusters showed very much similar patterns that high expression of up-regulated genes make worse the OS, while high expression of down-regulated genes make better the OS in NSCLC (Figures S11-S14).	('high', 'Var', (88, 92))	('up-regulated', 'PosReg', (107, 119))	('NSCLC', 'Disease', 'MESH:D002289', (213, 218))	('NSCLC', 'Phenotype', 'HP:0030358', (213, 218))	('SCLC', 'Phenotype', 'HP:0030357', (214, 218))	('NSCLC', 'Disease', (213, 218))
217729	31681566	An earlier study integrated the gene expression data, DNA copy number alteration (CAN) and PPI data, and identified "driver-networks" containing potential target genes in breast cancer.	('breast cancer', 'Disease', 'MESH:D001943', (171, 184))	('copy number alteration', 'Var', (58, 80))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('breast cancer', 'Disease', (171, 184))	('breast cancer', 'Phenotype', 'HP:0003002', (171, 184))	('CAN', 'Chemical', 'MESH:C000596933', (82, 85))
217739	31681566	Silencing the expression of SPP1 using siRNA decreased the NSCLC tumor volume and weight in mice demonstrated it as a promising therapeutic target.	('NSCLC tumor', 'Disease', (59, 70))	('mice', 'Species', '10090', (92, 96))	('decreased', 'NegReg', (45, 54))	('NSCLC', 'Phenotype', 'HP:0030358', (59, 64))	('expression', 'MPA', (14, 24))	('SPP1', 'Gene', (28, 32))	('SCLC', 'Phenotype', 'HP:0030357', (60, 64))	('Silencing', 'Var', (0, 9))	('NSCLC tumor', 'Disease', 'MESH:D009369', (59, 70))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
217748	31681566	The pan-cancer study reported mutation in SIX1, TAL1, and ID4 were present in the Wilms Tumors, T-lineage acute lymphoblastic leukemias, and B-lineage acute lymphoblastic leukemias, respectively.	('-lineage acute lymphoblastic leukemias', 'Phenotype', 'HP:0006727', (142, 180))	('TAL1', 'Gene', (48, 52))	('B-lineage acute lymphoblastic leukemias', 'Phenotype', 'HP:0004812', (141, 180))	('lymphoblastic leukemias', 'Disease', 'MESH:D054198', (112, 135))	('mutation', 'Var', (30, 38))	('lymphoblastic leukemias', 'Phenotype', 'HP:0005526', (157, 180))	('acute lymphoblastic leukemias', 'Phenotype', 'HP:0006721', (106, 135))	('Wilms Tumors', 'Disease', 'MESH:D009396', (82, 94))	('leukemias', 'Phenotype', 'HP:0001909', (126, 135))	('SIX1', 'Gene', '6495', (42, 46))	('cancer', 'Disease', (8, 14))	('lymphoblastic leukemias', 'Disease', (157, 180))	('acute lymphoblastic leukemias', 'Phenotype', 'HP:0006721', (151, 180))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('ID4', 'Gene', (58, 61))	('Wilms Tumors', 'Phenotype', 'HP:0002667', (82, 94))	('SIX1', 'Gene', (42, 46))	('leukemias', 'Phenotype', 'HP:0001909', (171, 180))	('ID4', 'Gene', '3400', (58, 61))	('T-lineage acute lymphoblastic leukemias', 'Phenotype', 'HP:0006727', (96, 135))	('lymphoblastic leukemias', 'Phenotype', 'HP:0005526', (112, 135))	('lymphoblastic leukemias', 'Disease', 'MESH:D054198', (157, 180))	('present', 'Reg', (67, 74))	('TAL1', 'Gene', '6886', (48, 52))	('Tumors', 'Phenotype', 'HP:0002664', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (8, 14))	('-lineage acute lymphoblastic leukemias', 'Phenotype', 'HP:0006727', (97, 135))	('lymphoblastic leukemias', 'Disease', (112, 135))	('Wilms Tumors', 'Disease', (82, 94))
217765	31681566	Overexpression of CCNB1 resulting in cell proliferation and was reported in various cancers including NSCLC.	('NSCLC', 'Disease', 'MESH:D002289', (102, 107))	('CCNB1', 'Gene', '891', (18, 23))	('cancers', 'Disease', 'MESH:D009369', (84, 91))	('SCLC', 'Phenotype', 'HP:0030357', (103, 107))	('cancers', 'Phenotype', 'HP:0002664', (84, 91))	('cancers', 'Disease', (84, 91))	('NSCLC', 'Phenotype', 'HP:0030358', (102, 107))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('Overexpression', 'Var', (0, 14))	('CCNB1', 'Gene', (18, 23))	('reported', 'Reg', (64, 72))	('NSCLC', 'Disease', (102, 107))	('cell proliferation', 'CPA', (37, 55))
217766	31681566	Inhibiting the expression of CCNB1 using siRNAs promotes apoptosis in colorectal cancer cells.	('colorectal cancer', 'Disease', 'MESH:D015179', (70, 87))	('Inhibiting', 'Var', (0, 10))	('apoptosis', 'CPA', (57, 66))	('CCNB1', 'Gene', (29, 34))	('colorectal cancer', 'Phenotype', 'HP:0003003', (70, 87))	('CCNB1', 'Gene', '891', (29, 34))	('promotes', 'PosReg', (48, 56))	('expression', 'MPA', (15, 25))	('colorectal cancer', 'Disease', (70, 87))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))
217786	31681566	Furthermore, NSCLC patients with their overexpression had significantly worse OS (Figure 4B; Figure S10).	('NSCLC', 'Disease', (13, 18))	('SCLC', 'Phenotype', 'HP:0030357', (14, 18))	('patients', 'Species', '9606', (19, 27))	('NSCLC', 'Disease', 'MESH:D002289', (13, 18))	('worse', 'NegReg', (72, 77))	('NSCLC', 'Phenotype', 'HP:0030358', (13, 18))	('overexpression', 'Var', (39, 53))
217787	31681566	The previous study found that MuvB core proteins interact with E2F4-DP1 and p130 or p107 to form a DREAM complex in G0/G1 phase of the cell cycle, which put the cell in quiescence state by globally repressing more than 800 cell cycle genes.	('cell cycle genes', 'Gene', (223, 239))	('DREAM', 'Gene', (99, 104))	('E2F4-DP1', 'Var', (63, 71))	('p107', 'Gene', '5933', (84, 88))	('repressing', 'NegReg', (198, 208))	('p130', 'Gene', (76, 80))	('DREAM', 'Gene', '30818', (99, 104))	('p130', 'Gene', '9221', (76, 80))	('p107', 'Gene', (84, 88))	('MuvB', 'Gene', (30, 34))
217800	31681566	Silencing of FOXM1 expression by siRNA in A549 lung adenocarcinoma cells resulted in significant reduction in cell cycle-promoting cyclin A2 and cyclin B1 genes, as well as DNA replication and mitosis.	('reduction', 'NegReg', (97, 106))	('cyclin A2', 'Gene', (131, 140))	('mitosis', 'Disease', (193, 200))	('cyclin A2', 'Gene', '890', (131, 140))	('cyclin B1', 'Gene', '891', (145, 154))	('cyclin B1', 'Gene', (145, 154))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (47, 66))	('A549', 'CellLine', 'CVCL:0023', (42, 46))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (47, 66))	('carcinoma', 'Phenotype', 'HP:0030731', (57, 66))	('cell', 'MPA', (110, 114))	('FOXM1', 'Gene', (13, 18))	('DNA replication', 'CPA', (173, 188))	('lung adenocarcinoma', 'Disease', (47, 66))	('mitosis', 'Disease', 'OMIM:604588', (193, 200))	('Silencing', 'Var', (0, 9))
217802	31681566	Furthermore, the study showed that depleting FOXM1 expression decrease the TOP2A mRNA and protein level in A549 human lung adenocarcinoma cells.	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (118, 137))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('depleting', 'Var', (35, 44))	('lung adenocarcinoma', 'Disease', (118, 137))	('A549', 'CellLine', 'CVCL:0023', (107, 111))	('decrease', 'NegReg', (62, 70))	('human', 'Species', '9606', (112, 117))	('TOP2A', 'Gene', '7153', (75, 80))	('TOP2A', 'Gene', (75, 80))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (118, 137))	('FOXM1', 'Gene', (45, 50))
217810	31681566	Overexpression of MYBL2 is associated with poor patient survival in various cancers patient including NSCLC.	('NSCLC', 'Disease', 'MESH:D002289', (102, 107))	('cancers', 'Disease', 'MESH:D009369', (76, 83))	('cancers', 'Phenotype', 'HP:0002664', (76, 83))	('cancers', 'Disease', (76, 83))	('MYBL2', 'Gene', (18, 23))	('poor', 'NegReg', (43, 47))	('SCLC', 'Phenotype', 'HP:0030357', (103, 107))	('NSCLC', 'Phenotype', 'HP:0030358', (102, 107))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('patient', 'Species', '9606', (48, 55))	('Overexpression', 'Var', (0, 14))	('NSCLC', 'Disease', (102, 107))	('patient', 'Species', '9606', (84, 91))
217812	31681566	Abnormal expression of E2F4 and its mutations are reported in several cancers including NSCLC.	('SCLC', 'Phenotype', 'HP:0030357', (89, 93))	('NSCLC', 'Phenotype', 'HP:0030358', (88, 93))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('E2F4', 'Gene', (23, 27))	('mutations', 'Var', (36, 45))	('expression', 'MPA', (9, 19))	('NSCLC', 'Disease', (88, 93))	('cancers', 'Disease', 'MESH:D009369', (70, 77))	('cancers', 'Phenotype', 'HP:0002664', (70, 77))	('reported', 'Reg', (50, 58))	('NSCLC', 'Disease', 'MESH:D002289', (88, 93))	('cancers', 'Disease', (70, 77))
217814	31681566	Furthermore, it was reported that silencing of their expression using siRNAs inhibit the cancer cell growth.	('inhibit', 'NegReg', (77, 84))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('cancer', 'Disease', (89, 95))	('expression', 'MPA', (53, 63))	('silencing', 'Var', (34, 43))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
217818	31681566	Interestingly, another study also supports that E2F4 and FOXM1 bind to the promoter of NEK2 gene.	('bind', 'Interaction', (63, 67))	('E2F4', 'Var', (48, 52))	('FOXM1', 'Gene', (57, 62))	('NEK2', 'Gene', (87, 91))	('NEK2', 'Gene', '4751', (87, 91))
217828	31681566	The decrease expression of other miRNAs in NSCLC and their role in cell proliferation and EMT has been demonstrated in several studies including hsa-miR-194-5p, hsa-miR-204-5p, hsa-miR-26b-5p, hsa-miR-320a, hsa-miR-370-3p and hsa-miR-630.	('hsa-miR-320a', 'Gene', (193, 205))	('hsa-miR-26b-5p', 'Var', (177, 191))	('cell proliferation', 'CPA', (67, 85))	('hsa-miR-630', 'Gene', (226, 237))	('expression', 'MPA', (13, 23))	('EMT', 'CPA', (90, 93))	('hsa-miR-320a', 'Gene', '407037', (193, 205))	('miR-204', 'Gene', '406987', (165, 172))	('NSCLC', 'Phenotype', 'HP:0030358', (43, 48))	('miR-204', 'Gene', (165, 172))	('decrease', 'NegReg', (4, 12))	('SCLC', 'Phenotype', 'HP:0030357', (44, 48))	('hsa-miR-630', 'Gene', '693215', (226, 237))	('NSCLC', 'Disease', (43, 48))	('hsa-miR-194-5p', 'Var', (145, 159))	('NSCLC', 'Disease', 'MESH:D002289', (43, 48))
217829	31681566	MYBL2 and TFDP1 are targeted by five common miRNAs (hsa-miR-30a-5p, hsa-miR-30b-5p, hsa-miR-30c-5p, hsa-miR-30d-5p, hsa-miR-30e-5p), though they belong from same miRNA family.	('TFDP1', 'Gene', (10, 15))	('TFDP1', 'Gene', '7027', (10, 15))	('hsa-miR-30a-5p', 'Var', (52, 66))	('hsa-miR-30d-5p', 'Var', (100, 114))	('hsa-miR-30c-5p', 'Var', (84, 98))	('MYBL2', 'Gene', (0, 5))
217837	31681566	However, our study has following limitations: (a) All the findings are based upon computational analysis using integrated data of gene expression, PPI, TFs, and miRNAs; (b) Our study did not integrate the data of gene mutations and gene copy number variations, which could abolish the cis- and trans-regulatory elements of a gene resulting aberrant gene expression and cancer; and (c) Finally, our study lacks the experimental validation and therefore need further experimental testing.	('cancer', 'Disease', (369, 375))	('abolish', 'NegReg', (273, 280))	('cancer', 'Phenotype', 'HP:0002664', (369, 375))	('cancer', 'Disease', 'MESH:D009369', (369, 375))	('variations', 'Var', (249, 259))
217881	27471396	After overnight incubation, the cells were treated with 30 microM, 10 microM, 3.3 microM, 1.1 microM, 0.37 microM, 0.12 microM, 0.04 microM, 0.013 microM, 0.0045 microM, 0.0015 microM, and 0.0005 microM lobaplatin for 24 hours, 48 hours, and 72 hours.	('0.04', 'Var', (128, 132))	('lobaplatin', 'Chemical', 'MESH:C066228', (203, 213))	('0.0015 microM', 'Var', (170, 183))	('0.0045 microM', 'Var', (155, 168))	('0.0005 microM', 'Var', (189, 202))	('0.013 microM', 'Var', (141, 153))
217901	27471396	When the average tumor volume reached ~100 mm3, the mice were assigned randomly to control and treatment groups and treated with saline (d1, d8, and saline only, n=6) or lobaplatin (d1, d8, 12 mg/kg, n=6) via tail vein, respectively.	('saline', 'Chemical', 'MESH:D012965', (129, 135))	('tumor', 'Disease', (17, 22))	('men', 'Species', '9606', (100, 103))	('mice', 'Species', '10090', (52, 56))	('lobaplatin', 'Chemical', 'MESH:C066228', (170, 180))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('saline', 'Chemical', 'MESH:D012965', (149, 155))	('d1', 'Var', (182, 184))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
217910	27471396	The cells were treated with lobaplatin at the concentration of 30 microM, 10 microM, 3.3 microM, 1.1 microM, 0.37 microM, 0.12 microM, 0.04 microM, 0.013 microM, 0.0045 microM, 0.0015 microM, and 0.0005 microM for 48 hours and 72 hours, respectively.	('lobaplatin', 'Chemical', 'MESH:C066228', (28, 38))	('0.0045 microM', 'Var', (162, 175))	('0.04 microM', 'Var', (135, 146))	('0.0015 microM', 'Var', (177, 190))	('0.013 microM', 'Var', (148, 160))
217939	27471396	Our data showed that the lobaplatin-treated mice showed a slight but not significant body weight loss as compared with that in the control group (Figure 6A) and lobaplatin could cause inhibi tory effects on the growth of SK-MES-1 tumors (Figure 6B-D).	('body weight', 'CPA', (85, 96))	('SK-MES-1 tumors', 'Disease', 'MESH:C536133', (221, 236))	('loss', 'NegReg', (97, 101))	('lobaplatin', 'Chemical', 'MESH:C066228', (161, 171))	('lobaplatin', 'Chemical', 'MESH:C066228', (25, 35))	('SK-MES-1 tumors', 'Disease', (221, 236))	('tumors', 'Phenotype', 'HP:0002664', (230, 236))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))	('growth', 'CPA', (211, 217))	('weight loss', 'Phenotype', 'HP:0001824', (90, 101))	('lobaplatin', 'Var', (161, 171))	('mice', 'Species', '10090', (44, 48))
217961	27471396	Cisplatin can induce apoptosis in A549 cells by elevating the expression level of Bcl-2, Bax, PARP, and cleavage-caspase-3, -8, and -9.	('elevating', 'PosReg', (48, 57))	('expression level', 'MPA', (62, 78))	('A549', 'CellLine', 'CVCL:0023', (34, 38))	('PARP', 'Gene', '142', (94, 98))	('Bax', 'Gene', (89, 92))	('Cisplatin', 'Chemical', 'MESH:D002945', (0, 9))	('Bcl-2', 'Gene', '596', (82, 87))	('Cisplatin', 'Var', (0, 9))	('Bcl-2', 'Gene', (82, 87))	('Bax', 'Gene', '581', (89, 92))	('PARP', 'Gene', (94, 98))	('caspase-3, -8, and -9', 'Gene', '836;841;842', (113, 134))
217982	33161227	A pan-cancer analysis of HER2 index revealed transcriptional pattern for precise selection of HER2-targeted therapy The prevalence of HER2 alterations in pan-cancer indicates a broader range of application of HER2-targeted therapies; however, biomarkers for such therapies are still insufficient and limited to breast cancer and gastric cancer.	('breast cancer', 'Disease', 'MESH:D001943', (311, 324))	('cancer', 'Disease', (318, 324))	('breast cancer', 'Disease', (311, 324))	('cancer', 'Phenotype', 'HP:0002664', (318, 324))	('cancer', 'Disease', 'MESH:D009369', (6, 12))	('cancer', 'Disease', 'MESH:D009369', (337, 343))	('gastric cancer', 'Phenotype', 'HP:0012126', (329, 343))	('alterations', 'Var', (139, 150))	('cancer', 'Disease', (158, 164))	('HER2', 'Gene', (25, 29))	('HER2', 'Gene', (209, 213))	('HER2', 'Gene', '2064', (134, 138))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('cancer', 'Disease', 'MESH:D009369', (318, 324))	('HER2', 'Gene', '2064', (94, 98))	('gastric cancer', 'Disease', (329, 343))	('cancer', 'Disease', (337, 343))	('cancer', 'Disease', (6, 12))	('breast cancer', 'Phenotype', 'HP:0003002', (311, 324))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('cancer', 'Phenotype', 'HP:0002664', (337, 343))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('gastric cancer', 'Disease', 'MESH:D013274', (329, 343))	('HER2', 'Gene', (134, 138))	('HER2', 'Gene', '2064', (25, 29))	('HER2', 'Gene', '2064', (209, 213))	('HER2', 'Gene', (94, 98))
217986	33161227	Increased HER2 somatic copy number alterations (SCNAs) could be divided into two patterns, focal- or arm-level.	('HER2', 'Gene', (10, 14))	('somatic', 'Var', (15, 22))	('HER2', 'Gene', '2064', (10, 14))
217992	33161227	Therapies targeting human epidermal growth factor receptor 2 (HER2) have been routinely applied to patients of breast cancer and gastric cancer harboring HER2 alterations; such applications could be broader given the prevalence of aberrant HER2 status in multi-omics level in pan-cancer.	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('cancer', 'Disease', (280, 286))	('gastric cancer', 'Disease', 'MESH:D013274', (129, 143))	('breast cancer', 'Disease', 'MESH:D001943', (111, 124))	('cancer', 'Disease', (137, 143))	('human epidermal growth factor receptor 2', 'Gene', (20, 60))	('cancer', 'Phenotype', 'HP:0002664', (280, 286))	('breast cancer', 'Disease', (111, 124))	('aberrant', 'Var', (231, 239))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('HER2', 'Gene', (240, 244))	('HER2', 'Gene', (154, 158))	('gastric cancer', 'Phenotype', 'HP:0012126', (129, 143))	('HER2', 'Gene', '2064', (62, 66))	('cancer', 'Disease', (118, 124))	('cancer', 'Disease', 'MESH:D009369', (280, 286))	('alterations', 'Var', (159, 170))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('patients', 'Species', '9606', (99, 107))	('human epidermal growth factor receptor 2', 'Gene', '2064', (20, 60))	('gastric cancer', 'Disease', (129, 143))	('breast cancer', 'Phenotype', 'HP:0003002', (111, 124))	('HER2', 'Gene', '2064', (240, 244))	('HER2', 'Gene', '2064', (154, 158))	('HER2', 'Gene', (62, 66))
218001	33161227	Since aberrant HER2 status of multiple levels have been identified in a wide range of other tumors, including uterine cancer, gastroesophageal junction cancer, biliary tract cancer, colorectal cancer, non-small-cell lung cancer and bladder cancer, its application may be far beyond than the current.	('cancer', 'Disease', 'MESH:D009369', (221, 227))	('colorectal cancer', 'Phenotype', 'HP:0003003', (182, 199))	('bladder cancer', 'Disease', 'MESH:D001749', (232, 246))	('cancer', 'Disease', (193, 199))	('bladder cancer', 'Disease', (232, 246))	('biliary tract cancer', 'Phenotype', 'HP:0100574', (160, 180))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('non-small-cell lung cancer', 'Disease', (201, 227))	('non-small-cell lung cancer', 'Disease', 'MESH:D002289', (201, 227))	('cancer', 'Disease', (240, 246))	('bladder cancer', 'Phenotype', 'HP:0009725', (232, 246))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('biliary tract cancer', 'Disease', 'MESH:D001661', (160, 180))	('cancer', 'Disease', (152, 158))	('identified', 'Reg', (56, 66))	('lung cancer', 'Phenotype', 'HP:0100526', (216, 227))	('cancer', 'Disease', (174, 180))	('HER2', 'Gene', '2064', (15, 19))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('gastroesophageal junction cancer', 'Disease', 'MESH:D009369', (126, 158))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (205, 227))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('tumors', 'Disease', (92, 98))	('colorectal cancer', 'Disease', 'MESH:D015179', (182, 199))	('cancer', 'Disease', (118, 124))	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('uterine cancer', 'Phenotype', 'HP:0010784', (110, 124))	('cancer', 'Disease', (221, 227))	('aberrant', 'Var', (6, 14))	('colorectal cancer', 'Disease', (182, 199))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('cancer', 'Disease', 'MESH:D009369', (240, 246))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (201, 227))	('tumors', 'Disease', 'MESH:D009369', (92, 98))	('biliary tract cancer', 'Disease', (160, 180))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('HER2', 'Gene', (15, 19))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('gastroesophageal junction cancer', 'Disease', (126, 158))	('cancer', 'Disease', 'MESH:D009369', (118, 124))
218013	33161227	Samples harbored mutations in ERBB2 were labeled as "mutation", while the rest were labeled as "wild".	('ERBB2', 'Gene', (30, 35))	('mutations', 'Var', (17, 26))	('ERBB2', 'Gene', '2064', (30, 35))
218016	33161227	Five cohorts "GSE81002", "GSE22358", "GSE20194", "GSE50948", and "GSE55348" were utilized to validate the performance of HER2 index in separating HER2-enriched subtype from other samples of BRCA.	('HER2', 'Gene', '2064', (121, 125))	('HER2', 'Gene', '2064', (146, 150))	('BRCA', 'Phenotype', 'HP:0003002', (190, 194))	('BRCA', 'Gene', '672', (190, 194))	('HER2', 'Gene', (146, 150))	('BRCA', 'Gene', (190, 194))	('GSE55348', 'Var', (66, 74))	('HER2', 'Gene', (121, 125))
218049	33161227	We investigated HER2 status of 11020 tumor samples from the TCGA database, encompassing 33 cancer types in aspect of copy number variation (CNV), single nucleotide variant (SNV), mRNA, reverse phase protein and phospho-protein array data (RPPA).	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('HER2', 'Gene', (16, 20))	('HER2', 'Gene', '2064', (16, 20))	('tumor', 'Disease', (37, 42))	('mRNA', 'MPA', (179, 183))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('single nucleotide variant', 'Var', (146, 171))
218065	33161227	HER2 is an oncogene targeted by somatic copy-number alterations (SCNAs) to drive cancer growth.	('drive', 'PosReg', (75, 80))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('cancer', 'Disease', (81, 87))	('HER2', 'Gene', (0, 4))	('HER2', 'Gene', '2064', (0, 4))	('copy-number alterations', 'Var', (40, 63))
218080	33161227	Focal-amplification at the HER2 gene is associated with overexpressed HER2 mRNA, whereas arm-level gain had little influence on HER2 mRNA expression (Figure S5).	('HER2', 'Gene', (128, 132))	('HER2', 'Gene', (70, 74))	('HER2', 'Gene', '2064', (128, 132))	('HER2', 'Gene', '2064', (70, 74))	('overexpressed', 'PosReg', (56, 69))	('Focal-amplification', 'Var', (0, 19))	('HER2', 'Gene', (27, 31))	('HER2', 'Gene', '2064', (27, 31))
218093	33161227	Luminal B was associated with elevated cell proliferation, in which cell cycle mitotic, G2-M transition, P53 pathway etc.	('P53', 'Gene', (105, 108))	('Luminal B', 'Var', (0, 9))	('P53', 'Gene', '7157', (105, 108))	('Luminal', 'Chemical', 'MESH:D010634', (0, 7))	('cell cycle mitotic', 'CPA', (68, 86))	('G2-M transition', 'CPA', (88, 103))	('elevated', 'PosReg', (30, 38))	('cell proliferation', 'CPA', (39, 57))
218140	33161227	As for transcription level, the majority of HER2-aberrant tumors with high HER2 index displayed a HER2 transcription level below the cutoff (log10(HER2 mRNA cutoff) = 1.74).	('HER2-aberrant tumors', 'Disease', (44, 64))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('below', 'NegReg', (123, 128))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('HER2-aberrant tumors', 'Disease', 'MESH:D002869', (44, 64))	('HER2', 'Gene', (75, 79))	('HER2', 'Gene', (44, 48))	('HER2', 'Gene', (98, 102))	('HER2', 'Gene', '2064', (147, 151))	('HER2', 'Gene', '2064', (75, 79))	('HER2', 'Gene', (147, 151))	('HER2', 'Gene', '2064', (44, 48))	('HER2', 'Gene', '2064', (98, 102))	('high', 'Var', (70, 74))
218141	33161227	HNSC with high HER2 index had a significantly elevated HER2 protein and phosphor-protein level despite few HER2 amplifications and mRNA overexpression, coinciding with the landscape of HER2 status displayed in the total of HNSC samples (Fig.	('HER2', 'Gene', '2064', (107, 111))	('elevated', 'PosReg', (46, 54))	('HER2', 'Gene', (15, 19))	('HER2', 'Gene', '2064', (15, 19))	('high', 'Var', (10, 14))	('HER2', 'Gene', (185, 189))	('HER2', 'Gene', (55, 59))	('HER2', 'Gene', '2064', (185, 189))	('HER2', 'Gene', (107, 111))	('HER2', 'Gene', '2064', (55, 59))
218164	33161227	HER2 mutation has been suggested as an alternative mechanism for activating HER2 signaling, and functional analysis have revealed several recurrent HER2 mutations that are likely to be driver alterations.	('HER2', 'Gene', (148, 152))	('HER2', 'Gene', (76, 80))	('HER2', 'Gene', '2064', (148, 152))	('mutations', 'Var', (153, 162))	('HER2', 'Gene', '2064', (76, 80))	('activating', 'PosReg', (65, 75))	('HER2', 'Gene', (0, 4))	('HER2', 'Gene', '2064', (0, 4))
218165	33161227	We found that HER2 mutations were also common in pan-cancer, but they are mainly independent from HER2-amplification.	('HER2', 'Gene', '2064', (14, 18))	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('common', 'Reg', (39, 45))	('mutations', 'Var', (19, 28))	('HER2', 'Gene', (98, 102))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('HER2', 'Gene', '2064', (98, 102))	('HER2', 'Gene', (14, 18))
218167	33161227	There is a small fraction of tumors having both HER2 amplification and mutation, however, whether they are same with purely HER2-amplified tumors remains uncertain.	('HER2', 'Gene', '2064', (48, 52))	('HER2', 'Gene', '2064', (124, 128))	('mutation', 'Var', (71, 79))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('tumors', 'Disease', 'MESH:D009369', (29, 35))	('tumors', 'Disease', (139, 145))	('tumors', 'Disease', 'MESH:D009369', (139, 145))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('tumors', 'Disease', (29, 35))	('HER2', 'Gene', (48, 52))	('HER2', 'Gene', (124, 128))
218168	33161227	Since oncogenic potentials have been identified in HER2 mutations, amplifications and changes in HER2 protein and variations in different cancers, thus identifying the significance of each alteration in the context of each cancer is needed in the future.	('HER2', 'Gene', (97, 101))	('mutations', 'Var', (56, 65))	('cancer', 'Disease', (138, 144))	('HER2', 'Gene', '2064', (97, 101))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('cancer', 'Disease', 'MESH:D009369', (223, 229))	('HER2', 'Gene', (51, 55))	('cancers', 'Phenotype', 'HP:0002664', (138, 145))	('cancer', 'Disease', (223, 229))	('HER2', 'Gene', '2064', (51, 55))	('cancers', 'Disease', (138, 145))	('cancer', 'Disease', 'MESH:D009369', (138, 144))	('cancers', 'Disease', 'MESH:D009369', (138, 145))	('protein', 'Protein', (102, 109))
218174	33161227	Besides, we found different frequencies of Chr17q22-23 amplification between gynecologic tumors and gastrointestinal tumors.	('tumors', 'Disease', (89, 95))	('amplification', 'Var', (55, 68))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('tumors', 'Disease', (117, 123))	('gastrointestinal tumors', 'Disease', (100, 123))	('gastrointestinal tumors', 'Disease', 'MESH:D004067', (100, 123))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('Chr17q22-23', 'Gene', (43, 54))	('gastrointestinal tumors', 'Phenotype', 'HP:0007378', (100, 123))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))
218205	33161227	In recent years, emerging trials exploring the potential efficacy of HER2 targeted therapy in colorectal tumors, non-small cell lung cancer and bladder cancer with HER2 alterations (amplification,overexpression and mutations) exhibited variable responses, some of which are impressive.	('colorectal tumors', 'Disease', (94, 111))	('HER2', 'Gene', (164, 168))	('bladder cancer', 'Disease', 'MESH:D001749', (144, 158))	('bladder cancer', 'Disease', (144, 158))	('bladder cancer', 'Phenotype', 'HP:0009725', (144, 158))	('alterations', 'Var', (169, 180))	('lung cancer', 'Disease', 'MESH:D008175', (128, 139))	('mutations', 'Var', (215, 224))	('lung cancer', 'Phenotype', 'HP:0100526', (128, 139))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('HER2', 'Gene', '2064', (69, 73))	('colorectal tumors', 'Disease', 'MESH:D015179', (94, 111))	('HER2', 'Gene', '2064', (164, 168))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (117, 139))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (113, 139))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('lung cancer', 'Disease', (128, 139))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('HER2', 'Gene', (69, 73))
218207	33161227	It is still unknown whether and what kind of HER2 alterations are relevant oncogenic drivers in pan-cancer tumor types, such as in NSCLC.	('cancer tumor', 'Disease', (100, 112))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('NSCLC', 'Disease', (131, 136))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('alterations', 'Var', (50, 61))	('NSCLC', 'Disease', 'MESH:D002289', (131, 136))	('cancer tumor', 'Disease', 'MESH:D009369', (100, 112))	('HER2', 'Gene', (45, 49))	('HER2', 'Gene', '2064', (45, 49))
218211	33161227	The findings above suggested that therapeutics for HER2 may have potential value in a certain population of gastrointestinal tumors, HNSC, NSCLC, BLCA, CESC and UCEC identified by transcriptional pattern and HER2 alterations.	('HER2', 'Gene', (208, 212))	('CESC', 'Disease', (152, 156))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('HER2', 'Gene', '2064', (208, 212))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('NSCLC', 'Disease', (139, 144))	('UCEC', 'Disease', (161, 165))	('gastrointestinal tumors', 'Phenotype', 'HP:0007378', (108, 131))	('NSCLC', 'Disease', 'MESH:D002289', (139, 144))	('gastrointestinal tumors', 'Disease', (108, 131))	('alterations', 'Var', (213, 224))	('BLCA', 'Disease', (146, 150))	('HER2', 'Gene', (51, 55))	('HNSC', 'Disease', (133, 137))	('HER2', 'Gene', '2064', (51, 55))	('gastrointestinal tumors', 'Disease', 'MESH:D004067', (108, 131))
218212	33161227	Additionally, the discordance between high index and absence of HER2 amplifications and overexpression in some samples may be explained by activating HER2 mutations as in NSCLC or alternative pathway activated in HER2-enriched expression pattern, such as KRAS mutation or AR signaling.	('HER2', 'Gene', '2064', (150, 154))	('KRAS', 'Gene', '3845', (255, 259))	('mutations', 'Var', (155, 164))	('HER2', 'Gene', (64, 68))	('alternative pathway', 'Pathway', (180, 199))	('HER2', 'Gene', (150, 154))	('HER2', 'Gene', (213, 217))	('HER2', 'Gene', '2064', (64, 68))	('NSCLC', 'Disease', (171, 176))	('activating', 'PosReg', (139, 149))	('KRAS', 'Gene', (255, 259))	('HER2', 'Gene', '2064', (213, 217))	('NSCLC', 'Disease', 'MESH:D002289', (171, 176))
218221	33161227	Assessed by the combination of HER2 index and HER2 alterations, a certain population of gastrointestinal tumors, HNSC, NSCLC, BLCA, CESC and UCEC were identified which may benefit from therapeutics for HER2 target, of which BLCA.3 and HNSC.Basal are promising subtypes.	('HER2', 'Gene', '2064', (31, 35))	('gastrointestinal tumors', 'Disease', (88, 111))	('alterations', 'Var', (51, 62))	('gastrointestinal tumors', 'Disease', 'MESH:D004067', (88, 111))	('HER2', 'Gene', (46, 50))	('NSCLC', 'Disease', 'MESH:D002289', (119, 124))	('gastrointestinal tumors', 'Phenotype', 'HP:0007378', (88, 111))	('HER2', 'Gene', '2064', (46, 50))	('HER2', 'Gene', (202, 206))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('HER2', 'Gene', '2064', (202, 206))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('NSCLC', 'Disease', (119, 124))	('HER2', 'Gene', (31, 35))
218229	32151067	Inhibition of SIRT1, either pharmacologically, with EX527 or through siRNA, stimulated p53 acetylation and apoptosis in LS513 cells when treated with ActD.	('EX527', 'Chemical', 'MESH:C550547', (52, 57))	('acetylation', 'MPA', (91, 102))	('p53', 'Gene', (87, 90))	('p53', 'Gene', '7157', (87, 90))	('SIRT1', 'Gene', (14, 19))	('EX527', 'Var', (52, 57))	('ActD', 'Chemical', 'MESH:D003609', (150, 154))	('SIRT1', 'Gene', '23411', (14, 19))	('LS513', 'CellLine', 'CVCL:1386', (120, 125))	('siRNA', 'Gene', (69, 74))	('apoptosis', 'CPA', (107, 116))	('stimulated', 'PosReg', (76, 86))
218231	32151067	Inhibition of AKT abrogated ActD-induced upregulation of SIRT1, suggesting that the AKT-SIRT1 pathway is important in ActD resistance.	('SIRT1', 'Gene', '23411', (88, 93))	('ActD', 'Chemical', 'MESH:D003609', (118, 122))	('SIRT1', 'Gene', (88, 93))	('AKT', 'Gene', (14, 17))	('SIRT1', 'Gene', '23411', (57, 62))	('AKT', 'Gene', '207', (84, 87))	('SIRT1', 'Gene', (57, 62))	('AKT', 'Gene', (84, 87))	('Inhibition', 'Var', (0, 10))	('ActD', 'Chemical', 'MESH:D003609', (28, 32))	('AKT', 'Gene', '207', (14, 17))	('upregulation', 'PosReg', (41, 53))	('abrogated', 'NegReg', (18, 27))
218232	32151067	Rp1 inhibited both ActD-induced AKT activation and SIRT1 upregulation and re-sensitized the cells to ActD.	('ActD', 'Chemical', 'MESH:D003609', (19, 23))	('AKT', 'Gene', '207', (32, 35))	('activation', 'PosReg', (36, 46))	('inhibited', 'NegReg', (4, 13))	('AKT', 'Gene', (32, 35))	('upregulation', 'PosReg', (57, 69))	('SIRT1', 'Gene', '23411', (51, 56))	('Rp1', 'Var', (0, 3))	('ActD', 'Chemical', 'MESH:D003609', (101, 105))	('SIRT1', 'Gene', (51, 56))
218241	32151067	Inhibition of SIRT1 decreases growth and viability of cancer cells while its overexpression impairs apoptosis, suggesting that SIRT1 is a critical regulator of cell proliferation and survival.	('decreases', 'NegReg', (20, 29))	('overexpression', 'PosReg', (77, 91))	('impairs', 'NegReg', (92, 99))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('SIRT1', 'Gene', '23411', (127, 132))	('cancer', 'Disease', (54, 60))	('SIRT1', 'Gene', '23411', (14, 19))	('decreases growth', 'Phenotype', 'HP:0001510', (20, 36))	('SIRT1', 'Gene', (127, 132))	('Inhibition', 'Var', (0, 10))	('SIRT1', 'Gene', (14, 19))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('apoptosis', 'CPA', (100, 109))
218242	32151067	In addition, siRNA-mediated depletion of SIRT1 re-sensitizes cisplatin-resistant cancer cells to cisplatin.	('re-sensitizes', 'PosReg', (47, 60))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('cisplatin', 'Chemical', 'MESH:D002945', (97, 106))	('cancer', 'Disease', (81, 87))	('depletion', 'Var', (28, 37))	('cisplatin', 'Chemical', 'MESH:D002945', (61, 70))	('SIRT1', 'Gene', '23411', (41, 46))	('cisplatin-resistant', 'MPA', (61, 80))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('SIRT1', 'Gene', (41, 46))
218243	32151067	Therefore, modulation of SIRT1 activity could be a viable strategy for overcoming MDR.	('activity', 'MPA', (31, 39))	('modulation', 'Var', (11, 21))	('MDR', 'Disease', (82, 85))	('SIRT1', 'Gene', '23411', (25, 30))	('SIRT1', 'Gene', (25, 30))
218261	32151067	To gain insights into the mechanisms mediating this effect, we quantified the levels of histone gamma-H2AX (indicator of DNA double-strand breaks) to assess whether Rp1 could potentiate ActD-induced DNA damage.	('ActD', 'Chemical', 'MESH:D003609', (186, 190))	('potentiate', 'PosReg', (175, 185))	('gamma-H2AX', 'Chemical', '-', (96, 106))	('ActD-induced DNA damage', 'MPA', (186, 209))	('Rp1', 'Var', (165, 168))
218262	32151067	ActD (30 nM) did not affect gamma-H2AX foci levels in LS513 cells, but Rp1 augmented ActD-induced gamma-H2AX (Figure 1F).	('gamma-H2AX', 'Chemical', '-', (28, 38))	('ActD', 'Chemical', 'MESH:D003609', (85, 89))	('Rp1', 'Var', (71, 74))	('ActD', 'Chemical', 'MESH:D003609', (0, 4))	('LS513', 'CellLine', 'CVCL:1386', (54, 59))	('gamma-H2AX', 'Chemical', '-', (98, 108))	('augmented', 'PosReg', (75, 84))
218263	32151067	These data suggest that Rp1 enhances ActD-induced DNA damage in multidrug-resistant LS513 cells and, consequently, increases their sensitivity to ActD.	('Rp1', 'Var', (24, 27))	('ActD', 'Chemical', 'MESH:D003609', (37, 41))	('increases', 'PosReg', (115, 124))	('LS513', 'CellLine', 'CVCL:1386', (84, 89))	('enhances', 'PosReg', (28, 36))	('ActD', 'Chemical', 'MESH:D003609', (146, 150))	('ActD-induced DNA damage', 'MPA', (37, 60))	('sensitivity to ActD', 'MPA', (131, 150))
218266	32151067	Notably, ActD also upregulated SIRT1 levels in doxorubicin-resistant lung cancer cell line A549-DXR.	('upregulated', 'PosReg', (19, 30))	('lung cancer', 'Disease', 'MESH:D008175', (69, 80))	('ActD', 'Chemical', 'MESH:D003609', (9, 13))	('doxorubicin', 'Chemical', 'MESH:D004317', (47, 58))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('lung cancer', 'Disease', (69, 80))	('lung cancer', 'Phenotype', 'HP:0100526', (69, 80))	('ActD', 'Var', (9, 13))	('SIRT1', 'Gene', '23411', (31, 36))	('A549', 'CellLine', 'CVCL:0023', (91, 95))	('SIRT1', 'Gene', (31, 36))
218269	32151067	Contrastingly, in ActD-sensitive SW620 cells, ActD decreased SIRT1 levels and increased PARP cleavage (Figure 2C).	('SIRT1', 'Gene', '23411', (61, 66))	('ActD', 'Chemical', 'MESH:D003609', (46, 50))	('decreased', 'NegReg', (51, 60))	('SIRT1', 'Gene', (61, 66))	('increased', 'PosReg', (78, 87))	('PARP', 'Gene', '1302', (88, 92))	('ActD', 'Chemical', 'MESH:D003609', (18, 22))	('ActD', 'Var', (46, 50))	('SW620', 'CellLine', 'CVCL:0547', (33, 38))	('PARP', 'Gene', (88, 92))
218272	32151067	SIRT1 overexpression attenuated PARP cleavage induced by Rp1 and ActD co-treatment (Figure 2D).	('attenuated', 'NegReg', (21, 31))	('ActD', 'Chemical', 'MESH:D003609', (65, 69))	('SIRT1', 'Gene', '23411', (0, 5))	('SIRT1', 'Gene', (0, 5))	('Rp1', 'Var', (57, 60))	('overexpression', 'PosReg', (6, 20))	('PARP', 'Gene', '1302', (32, 36))	('PARP', 'Gene', (32, 36))
218275	32151067	While EX527 (50 muM) alone was only mildly cytotoxic, in combination with ActD, it significantly impaired the growth of both LS513 and OVCAR-DXR cells (multidrug-resistant cells derived from the human ovarian cancer cell line OVCAR-8) (Figure 3A,D).	('human', 'Species', '9606', (195, 200))	('EX527', 'Var', (6, 11))	('impaired', 'NegReg', (97, 105))	('LS513', 'CellLine', 'CVCL:1386', (125, 130))	('ActD', 'Chemical', 'MESH:D003609', (74, 78))	('ovarian cancer', 'Disease', (201, 215))	('ovarian cancer', 'Disease', 'MESH:D010051', (201, 215))	('EX527', 'Chemical', 'MESH:C550547', (6, 11))	('muM', 'Gene', '56925', (16, 19))	('ovarian cancer', 'Phenotype', 'HP:0100615', (201, 215))	('growth', 'MPA', (110, 116))	('muM', 'Gene', (16, 19))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
218277	32151067	SIRT1 deacetylates p53 to decrease cell death.	('decrease', 'NegReg', (26, 34))	('SIRT1', 'Gene', '23411', (0, 5))	('SIRT1', 'Gene', (0, 5))	('p53', 'Gene', (19, 22))	('p53', 'Gene', '7157', (19, 22))	('cell death', 'CPA', (35, 45))	('deacetylates', 'Var', (6, 18))
218278	32151067	Accordingly, co-exposure to EX527 and ActD promoted p53 acetylation and synergistically induced cell death, as evidenced by increased PARP cleavage (Figure 3B,E).	('acetylation', 'MPA', (56, 67))	('induced', 'Reg', (88, 95))	('promoted', 'PosReg', (43, 51))	('EX527', 'Var', (28, 33))	('PARP', 'Gene', (134, 138))	('increased', 'PosReg', (124, 133))	('p53', 'Gene', (52, 55))	('p53', 'Gene', '7157', (52, 55))	('ActD', 'Chemical', 'MESH:D003609', (38, 42))	('cell death', 'CPA', (96, 106))	('EX527', 'Chemical', 'MESH:C550547', (28, 33))	('PARP', 'Gene', '1302', (134, 138))
218279	32151067	Next, we tested whether siRNA-mediated silencing of SIRT1 could re-sensitize drug-resistant cells to ActD.	('SIRT1', 'Gene', (52, 57))	('silencing', 'Var', (39, 48))	('SIRT1', 'Gene', '23411', (52, 57))	('ActD', 'Chemical', 'MESH:D003609', (101, 105))
218280	32151067	SIRT1 knockdown abrogated ActD-induced SIRT1 upregulation to increase p53 acetylation and PARP cleavage in LS513 and OVCAR-DXR cells (Figure 3C,F).	('LS513', 'CellLine', 'CVCL:1386', (107, 112))	('p53', 'Gene', (70, 73))	('p53', 'Gene', '7157', (70, 73))	('SIRT1', 'Gene', (39, 44))	('acetylation', 'MPA', (74, 85))	('ActD', 'Chemical', 'MESH:D003609', (26, 30))	('SIRT1', 'Gene', '23411', (39, 44))	('SIRT1', 'Gene', '23411', (0, 5))	('PARP', 'Gene', '1302', (90, 94))	('SIRT1', 'Gene', (0, 5))	('upregulation', 'PosReg', (45, 57))	('abrogated', 'NegReg', (16, 25))	('PARP', 'Gene', (90, 94))	('knockdown', 'Var', (6, 15))	('increase', 'PosReg', (61, 69))
218282	32151067	SIRT1 inhibition in combination with ActD treatment synergistically enhanced cell death and DNA damage, as determined by increased gamma-H2AX levels (Figure 3E,F).	('enhanced', 'PosReg', (68, 76))	('cell death', 'CPA', (77, 87))	('ActD', 'Chemical', 'MESH:D003609', (37, 41))	('increased', 'PosReg', (121, 130))	('SIRT1', 'Gene', '23411', (0, 5))	('SIRT1', 'Gene', (0, 5))	('gamma-H2AX', 'Chemical', '-', (131, 141))	('inhibition', 'Var', (6, 16))	('gamma-H2AX levels', 'MPA', (131, 148))	('DNA damage', 'CPA', (92, 102))
218285	32151067	Inhibition of SIRT1 enhanced p53 acetylation and ActD-induced cell death (Figure 3).	('enhanced', 'PosReg', (20, 28))	('acetylation', 'MPA', (33, 44))	('p53', 'Gene', (29, 32))	('SIRT1', 'Gene', '23411', (14, 19))	('Inhibition', 'Var', (0, 10))	('p53', 'Gene', '7157', (29, 32))	('SIRT1', 'Gene', (14, 19))	('ActD-induced cell death', 'Disease', 'MESH:D003643', (49, 72))	('ActD-induced cell death', 'Disease', (49, 72))
218287	32151067	Although si-SIRT1 treatment enhanced ActD-induced PARP cleavage in LS513 cells, this synergistic effect was reduced when p53 was knocked down despite comparable gamma-H2AX levels (Figure 4A).	('knocked down', 'Var', (129, 141))	('ActD', 'Chemical', 'MESH:D003609', (37, 41))	('SIRT1', 'Gene', (12, 17))	('p53', 'Gene', (121, 124))	('p53', 'Gene', '7157', (121, 124))	('gamma-H2AX', 'Chemical', '-', (161, 171))	('enhanced', 'PosReg', (28, 36))	('PARP', 'Gene', '1302', (50, 54))	('LS513', 'CellLine', 'CVCL:1386', (67, 72))	('PARP', 'Gene', (50, 54))	('SIRT1', 'Gene', '23411', (12, 17))
218289	32151067	SIRT1 knockdown enhanced ActD-induced apoptosis of HCT116-p53 WT cells, but not of HCT116-p53-null cells, as determined by the MTS assay (Figure 4B) and PARP cleavage (Figure 4C).	('p53', 'Gene', (90, 93))	('p53', 'Gene', '7157', (90, 93))	('SIRT1', 'Gene', '23411', (0, 5))	('ActD-induced', 'MPA', (25, 37))	('ActD', 'Chemical', 'MESH:D003609', (25, 29))	('SIRT1', 'Gene', (0, 5))	('HCT116', 'CellLine', 'CVCL:0291', (51, 57))	('PARP', 'Gene', '1302', (153, 157))	('HCT116', 'CellLine', 'CVCL:0291', (83, 89))	('knockdown', 'Var', (6, 15))	('PARP', 'Gene', (153, 157))	('p53', 'Gene', (58, 61))	('enhanced', 'PosReg', (16, 24))	('p53', 'Gene', '7157', (58, 61))
218295	32151067	When AKT was knocked down, cell death was significantly increased upon ActD treatment, as determined by the MTS assay (Figure 5B) and PARP cleavage (Figure 5C).	('ActD', 'Chemical', 'MESH:D003609', (71, 75))	('increased', 'PosReg', (56, 65))	('PARP', 'Gene', (134, 138))	('knocked down', 'Var', (13, 25))	('AKT', 'Gene', '207', (5, 8))	('cell death', 'CPA', (27, 37))	('AKT', 'Gene', (5, 8))	('PARP', 'Gene', '1302', (134, 138))
218296	32151067	AKT knockdown by itself had minimal effect on SIRT1 in control cells, but it significantly downregulated SIRT1 expression in ActD-treated cells (Figure 5C), suggesting that SIRT1 could be regulated by AKT.	('AKT', 'Gene', (0, 3))	('SIRT1', 'Gene', (46, 51))	('AKT', 'Gene', '207', (201, 204))	('downregulated', 'NegReg', (91, 104))	('SIRT1', 'Gene', (173, 178))	('SIRT1', 'Gene', '23411', (105, 110))	('SIRT1', 'Gene', '23411', (46, 51))	('SIRT1', 'Gene', (105, 110))	('AKT', 'Gene', (201, 204))	('expression', 'MPA', (111, 121))	('AKT', 'Gene', '207', (0, 3))	('knockdown', 'Var', (4, 13))	('ActD', 'Chemical', 'MESH:D003609', (125, 129))	('SIRT1', 'Gene', '23411', (173, 178))
218297	32151067	To explore this possibility, cells were treated with LY294002, a PI3K/AKT inhibitor.	('LY294002', 'Chemical', 'MESH:C085911', (53, 61))	('AKT', 'Gene', '207', (70, 73))	('LY294002', 'Var', (53, 61))	('AKT', 'Gene', (70, 73))
218298	32151067	As expected, LY294002 significantly reduced cell viability and abolished ActD-induced increase in SIRT1 expression in ActD-treated cells (Figure 5D,E).	('increase', 'PosReg', (86, 94))	('ActD', 'Chemical', 'MESH:D003609', (118, 122))	('SIRT1', 'Gene', '23411', (98, 103))	('ActD', 'Chemical', 'MESH:D003609', (73, 77))	('abolished', 'NegReg', (63, 72))	('SIRT1', 'Gene', (98, 103))	('LY294002', 'Chemical', 'MESH:C085911', (13, 21))	('expression', 'MPA', (104, 114))	('reduced', 'NegReg', (36, 43))	('LY294002', 'Var', (13, 21))	('cell viability', 'CPA', (44, 58))
218306	32151067	Collectively, these results suggest that Rp1 and ActD act synergistically through downregulation of the AKT/SIRT1 pathway, which can be modulated by cholesterol levels and/or lipid raft integrity.	('SIRT1', 'Gene', (108, 113))	('lipid', 'Chemical', 'MESH:D008055', (175, 180))	('AKT', 'Gene', (104, 107))	('downregulation', 'NegReg', (82, 96))	('ActD', 'Chemical', 'MESH:D003609', (49, 53))	('cholesterol', 'Chemical', 'MESH:D002784', (149, 160))	('Rp1', 'Var', (41, 44))	('SIRT1', 'Gene', '23411', (108, 113))	('AKT', 'Gene', '207', (104, 107))
218310	32151067	As shown in Figure 7A,B, SIRT1 expression was significantly correlated with poor overall survival (OS) in stomach adenocarcinoma patients and poor recurrence-free survival (RFS) in kidney renal papillary cell carcinoma patients (p < 0.05).	('poor', 'NegReg', (142, 146))	('patients', 'Species', '9606', (219, 227))	('poor', 'NegReg', (76, 80))	('renal papillary cell carcinoma', 'Phenotype', 'HP:0006766', (188, 218))	('SIRT1', 'Gene', '23411', (25, 30))	('patients', 'Species', '9606', (129, 137))	('stomach adenocarcinoma', 'Disease', 'MESH:D000230', (106, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (209, 218))	('recurrence-free survival', 'CPA', (147, 171))	('stomach adenocarcinoma', 'Disease', (106, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('overall survival', 'MPA', (81, 97))	('kidney renal papillary cell carcinoma', 'Disease', (181, 218))	('expression', 'Var', (31, 41))	('kidney renal papillary cell carcinoma', 'Disease', 'MESH:C538614', (181, 218))	('SIRT1', 'Gene', (25, 30))
218312	32151067	Taken together, these results suggest that SIRT1 overexpression is associated with ActD resistance, and that inhibiting SIRT1 with Rp1 could be of therapeutic benefit to overcome drug resistance in tumor cells.	('ActD', 'MPA', (83, 87))	('SIRT1', 'Gene', '23411', (43, 48))	('drug resistance', 'Phenotype', 'HP:0020174', (179, 194))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('SIRT1', 'Gene', '23411', (120, 125))	('SIRT1', 'Gene', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('SIRT1', 'Gene', (120, 125))	('associated', 'Reg', (67, 77))	('ActD', 'Chemical', 'MESH:D003609', (83, 87))	('overexpression', 'PosReg', (49, 63))	('inhibiting', 'Var', (109, 119))	('tumor', 'Disease', (198, 203))
218321	32151067	We previously reported that Rp1 inhibits MDR through downregulation of MDR1 and modulation of lipid rafts.	('Rp1', 'Var', (28, 31))	('MDR1', 'Gene', (71, 75))	('downregulation', 'NegReg', (53, 67))	('lipid rafts', 'MPA', (94, 105))	('lipid', 'Chemical', 'MESH:D008055', (94, 99))	('inhibits', 'NegReg', (32, 40))	('MDR', 'MPA', (41, 44))	('modulation', 'Reg', (80, 90))
218334	32151067	SIRT1-mediated drug resistance appeared not to be related to MDR1 expression because SIRT1 knockdown had a limited effect on MDR1 expression in LS513 cells.	('expression', 'MPA', (130, 140))	('SIRT1', 'Gene', '23411', (85, 90))	('SIRT1', 'Gene', '23411', (0, 5))	('knockdown', 'Var', (91, 100))	('SIRT1', 'Gene', (0, 5))	('SIRT1', 'Gene', (85, 90))	('MDR1', 'Gene', (125, 129))	('LS513', 'CellLine', 'CVCL:1386', (144, 149))	('drug resistance', 'Phenotype', 'HP:0020174', (15, 30))
218340	32151067	When SIRT1 was inhibited, either by EX527 or siRNA-mediated silencing, p53 acetylation and PARP cleavage increased upon ActD treatment (Figure 3B,C).	('inhibited', 'NegReg', (15, 24))	('EX527', 'Var', (36, 41))	('SIRT1', 'Gene', '23411', (5, 10))	('PARP', 'Gene', (91, 95))	('acetylation', 'MPA', (75, 86))	('EX527', 'Chemical', 'MESH:C550547', (36, 41))	('SIRT1', 'Gene', (5, 10))	('ActD', 'Chemical', 'MESH:D003609', (120, 124))	('p53', 'Gene', (71, 74))	('p53', 'Gene', '7157', (71, 74))	('silencing', 'NegReg', (60, 69))	('increased', 'PosReg', (105, 114))	('PARP', 'Gene', '1302', (91, 95))
218342	32151067	reported that pharmacological inhibition of SIRT1 or SIRT1 knockdown increase apoptosis in leukemia stem cells, and that the inhibitory effects of SIRT1 depend on p53 expression and acetylation.	('increase', 'PosReg', (69, 77))	('apoptosis', 'CPA', (78, 87))	('SIRT1', 'Gene', '23411', (44, 49))	('p53', 'Gene', (163, 166))	('SIRT1', 'Gene', (53, 58))	('p53', 'Gene', '7157', (163, 166))	('SIRT1', 'Gene', (44, 49))	('acetylation', 'MPA', (182, 193))	('SIRT1', 'Gene', '23411', (147, 152))	('SIRT1', 'Gene', (147, 152))	('leukemia', 'Phenotype', 'HP:0001909', (91, 99))	('knockdown', 'Var', (59, 68))	('leukemia', 'Disease', 'MESH:D007938', (91, 99))	('SIRT1', 'Gene', '23411', (53, 58))	('leukemia', 'Disease', (91, 99))
218346	32151067	However, ActD could not increase PARP cleavage when both SIRT1 and p53 were knocked down even though ActD-induced DNA damage (assessed by gamma-H2AX levels) was similar to that in SIRT1-depleted cells (Figure 4A).	('SIRT1', 'Gene', (180, 185))	('ActD', 'Chemical', 'MESH:D003609', (9, 13))	('SIRT1', 'Gene', '23411', (57, 62))	('SIRT1', 'Gene', (57, 62))	('p53', 'Gene', (67, 70))	('PARP', 'Gene', (33, 37))	('p53', 'Gene', '7157', (67, 70))	('SIRT1', 'Gene', '23411', (180, 185))	('gamma-H2AX', 'Chemical', '-', (138, 148))	('PARP', 'Gene', '1302', (33, 37))	('knocked down', 'Var', (76, 88))	('ActD', 'Chemical', 'MESH:D003609', (101, 105))
218347	32151067	In line with these results, SIRT1 knockdown re-sensitized p53-expressing HCT-116 cells, but not p53-deficient HCT-116 cells, to ActD (Figure 4B,C), implying that p53 activation through SIRT1 inhibition is critical for ActD-induced cell death.	('p53', 'Gene', (96, 99))	('HCT-116', 'CellLine', 'CVCL:0291', (73, 80))	('HCT-116', 'CellLine', 'CVCL:0291', (110, 117))	('ActD-induced cell death', 'Disease', 'MESH:D003643', (218, 241))	('p53', 'Gene', (162, 165))	('p53', 'Gene', '7157', (96, 99))	('ActD', 'Chemical', 'MESH:D003609', (218, 222))	('ActD-induced cell death', 'Disease', (218, 241))	('SIRT1', 'Gene', '23411', (185, 190))	('knockdown', 'Var', (34, 43))	('p53', 'Gene', '7157', (162, 165))	('deficient HCT', 'Phenotype', 'HP:0031851', (100, 113))	('SIRT1', 'Gene', '23411', (28, 33))	('SIRT1', 'Gene', (185, 190))	('SIRT1', 'Gene', (28, 33))	('p53', 'Gene', (58, 61))	('ActD', 'Chemical', 'MESH:D003609', (128, 132))	('p53', 'Gene', '7157', (58, 61))
218352	32151067	Deacetylation of AKT is necessary for its binding to PIP3 and, in turn, its membrane localization and activation.	('AKT', 'Gene', (17, 20))	('activation', 'MPA', (102, 112))	('PIP3', 'Chemical', '-', (53, 57))	('binding', 'Interaction', (42, 49))	('membrane localization', 'MPA', (76, 97))	('Deacetylation', 'Var', (0, 13))	('AKT', 'Gene', '207', (17, 20))	('PIP3', 'Protein', (53, 57))
218353	32151067	However, SIRT1 knockdown decreased AKT phosphorylation only to a small extent.	('AKT', 'Gene', (35, 38))	('SIRT1', 'Gene', (9, 14))	('knockdown', 'Var', (15, 24))	('SIRT1', 'Gene', '23411', (9, 14))	('decreased', 'NegReg', (25, 34))	('AKT', 'Gene', '207', (35, 38))
218354	32151067	AKT inactivation, either through siRNA or using LY294002, a PI3K/AKT inhibitor, deceased SIRT1 levels and re-sensitized LS513 cells to ActD (Figure 5B-E), implying that SRIT1 could be a downstream target of AKT.	('AKT', 'Gene', (0, 3))	('AKT', 'Gene', '207', (207, 210))	('LY294002', 'Var', (48, 56))	('AKT', 'Gene', (65, 68))	('deceased', 'NegReg', (80, 88))	('SIRT1', 'Gene', '23411', (89, 94))	('AKT', 'Gene', (207, 210))	('ActD', 'MPA', (135, 139))	('SIRT1', 'Gene', (89, 94))	('LS513', 'CellLine', 'CVCL:1386', (120, 125))	('AKT', 'Gene', '207', (0, 3))	('LY294002', 'Chemical', 'MESH:C085911', (48, 56))	('AKT', 'Gene', '207', (65, 68))	('ActD', 'Chemical', 'MESH:D003609', (135, 139))	('inactivation', 'NegReg', (4, 16))
218358	32151067	It is possible that co-treatment with Rp1 and ActD amplifies modification of lipid rafts, leading to AKT inactivation and drug sensitivity.	('Rp1', 'Var', (38, 41))	('AKT', 'Gene', '207', (101, 104))	('drug sensitivity', 'CPA', (122, 138))	('ActD', 'Chemical', 'MESH:D003609', (46, 50))	('AKT', 'Gene', (101, 104))	('drug sensitivity', 'Phenotype', 'HP:0020174', (122, 138))	('inactivation', 'NegReg', (105, 117))	('lipid', 'Chemical', 'MESH:D008055', (77, 82))	('modification', 'MPA', (61, 73))
218398	32151067	This work was supported by a research grant from the National Cancer Center, Republic of Korea (NCC-1810291 and NCC-1810931) and a National Research Foundation (NRF) grant funded by Korea government (NRF- 2015R1A2A2A01005585).	('Cancer', 'Disease', 'MESH:D009369', (62, 68))	('Cancer', 'Disease', (62, 68))	('Cancer', 'Phenotype', 'HP:0002664', (62, 68))	('NCC-1810931', 'Var', (112, 123))
218403	31052530	MiRNA dysregulation is known to be involved in the development of cutaneous squamous cell carcinoma (CSCC).	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (76, 99))	('SCC', 'Gene', '6317', (102, 105))	('cutaneous squamous cell carcinoma', 'Disease', (66, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('involved', 'Reg', (35, 43))	('MiRNA', 'Protein', (0, 5))	('dysregulation', 'Var', (6, 19))	('cutaneous squamous cell carcinoma', 'Phenotype', 'HP:0006739', (66, 99))	('cutaneous squamous cell carcinoma', 'Disease', 'MESH:D002294', (66, 99))	('CSCC', 'Phenotype', 'HP:0006739', (101, 105))	('SCC', 'Gene', (102, 105))
218410	31052530	P53 mutations, induced by ultraviolet radiation, are early events in CSCC development and are responsible for severe genomic instability.	('SCC', 'Gene', (70, 73))	('CSCC', 'Phenotype', 'HP:0006739', (69, 73))	('P53', 'Gene', (0, 3))	('SCC', 'Gene', '6317', (70, 73))	('P53', 'Gene', '7157', (0, 3))	('mutations', 'Var', (4, 13))
218413	31052530	The accumulation of genetic changes ultimately affects important signaling pathways, involving EGFR overexpression, NF-kB activation and NOTCH inactivation.	('genetic changes', 'Var', (20, 35))	('affects', 'Reg', (47, 54))	('expression', 'Species', '29278', (104, 114))	('NOTCH', 'MPA', (137, 142))	('NF-kB', 'Protein', (116, 121))	('activation', 'PosReg', (122, 132))	('signaling pathways', 'Pathway', (65, 83))	('EGFR', 'Gene', '1956', (95, 99))	('overexpression', 'PosReg', (100, 114))	('inactivation', 'NegReg', (143, 155))	('EGFR', 'Gene', (95, 99))
218414	31052530	In addition to genetic changes, some critical epigenetic modifications contribute to the process of CSCC carcinogenesis.	('contribute', 'Reg', (71, 81))	('CSCC carcinogenesis', 'Disease', (100, 119))	('CSCC', 'Phenotype', 'HP:0006739', (100, 104))	('epigenetic modifications', 'Var', (46, 70))	('CSCC carcinogenesis', 'Disease', 'MESH:D063646', (100, 119))
218419	31052530	MicroRNAs have been implicated in a wide variety of biological processes, including differentiation, proliferation, survival, and apoptosis, as well as immune modulation, inflammation, metabolic control and development.	('MicroRNAs', 'Var', (0, 9))	('survival', 'CPA', (116, 124))	('apoptosis', 'CPA', (130, 139))	('inflammation', 'Disease', 'MESH:D007249', (171, 183))	('proliferation', 'CPA', (101, 114))	('implicated', 'Reg', (20, 30))	('differentiation', 'CPA', (84, 99))	('inflammation', 'Disease', (171, 183))
218433	31052530	The inhibition of miR-21 suppresses tumor growth and invasion, and such inhibition exerts proapoptotic functions in CSCC cells.	('miR-21', 'Gene', '406991', (18, 24))	('CSCC', 'Phenotype', 'HP:0006739', (116, 120))	('SCC', 'Gene', (117, 120))	('miR-21', 'Gene', (18, 24))	('inhibition', 'Var', (4, 14))	('proapoptotic functions', 'MPA', (90, 112))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('SCC', 'Gene', '6317', (117, 120))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('suppresses', 'NegReg', (25, 35))	('tumor', 'Disease', (36, 41))
218443	31052530	MiR-205 maintains epithelial proliferation during skin development, helping to maintain skin stemness, and the lack of expression of this miRNA inhibits the proliferation of cells in the basal layer.	('proliferation of cells in the basal layer', 'CPA', (157, 198))	('skin stemness', 'Disease', (88, 101))	('inhibits', 'NegReg', (144, 152))	('MiR-205', 'Gene', '406988', (0, 7))	('MiR-205', 'Gene', (0, 7))	('lack of', 'Var', (111, 118))	('skin stemness', 'Disease', 'MESH:D012871', (88, 101))	('expression', 'Species', '29278', (119, 129))
218453	31052530	In a study of the miRNA expression profile in the NIH 3T3 cell line, after irradiation with UVB, miR-365 was found to be an miRNA with extremely high sensitivity to ultraviolet irradiation, which is the most important cause of skin cancer.	('miR-365', 'Var', (97, 104))	('expression', 'Species', '29278', (24, 34))	('NIH 3T3', 'CellLine', 'CVCL:0594', (50, 57))	('skin cancer', 'Phenotype', 'HP:0008069', (227, 238))	('skin cancer', 'Disease', (227, 238))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('skin cancer', 'Disease', 'MESH:D012878', (227, 238))
218457	31052530	Loss of HOXA9 upregulates HIF-1alpha, which helps regulate hypoxia response, glucose metabolism and tumor progression.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('regulate', 'Reg', (50, 58))	('HIF-1alpha', 'Gene', '3091', (26, 36))	('glucose metabolism and tumor', 'Disease', 'MESH:D044882', (77, 105))	('HOXA9', 'Gene', '3205', (8, 13))	('HIF-1alpha', 'Gene', (26, 36))	('hypoxia', 'Disease', (59, 66))	('hypoxia', 'Disease', 'MESH:D000860', (59, 66))	('upregulates', 'PosReg', (14, 25))	('Loss', 'Var', (0, 4))	('HOXA9', 'Gene', (8, 13))
218464	31052530	Experiments with the CSCC cell line UT-SCC-7 showed that inhibition of endogenous miR-31 suppresses cell motility and colony-forming ability.	('SCC', 'Gene', '6317', (39, 42))	('miR-31', 'Gene', (82, 88))	('inhibition', 'Var', (57, 67))	('CSCC', 'Phenotype', 'HP:0006739', (21, 25))	('SCC', 'Gene', (22, 25))	('cell motility', 'CPA', (100, 113))	('suppresses', 'NegReg', (89, 99))	('miR-31', 'Gene', '407035', (82, 88))	('UT-SCC-7', 'CellLine', 'CVCL:7868', (36, 44))	('SCC', 'Gene', '6317', (22, 25))	('SCC', 'Gene', (39, 42))	('colony-forming ability', 'CPA', (118, 140))
218478	31052530	In CSCC, microRNA-142-5p acts as an oncogene.	('SCC', 'Gene', (4, 7))	('SCC', 'Gene', '6317', (4, 7))	('CSCC', 'Phenotype', 'HP:0006739', (3, 7))	('microRNA-142-5p', 'Var', (9, 24))
218502	31052530	For example, microRNA-125a inhibits proliferation and invasion, and facilitates lung cancer cell apoptosis.	('facilitates', 'PosReg', (68, 79))	('microRNA-125a', 'Var', (13, 26))	('inhibits', 'NegReg', (27, 35))	('lung cancer', 'Disease', 'MESH:D008175', (80, 91))	('lung cancer', 'Disease', (80, 91))	('lung cancer', 'Phenotype', 'HP:0100526', (80, 91))	('proliferation', 'CPA', (36, 49))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
218504	31052530	MicroRNA-125b is one of the most misregulated microRNAs in cancer.	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('MicroRNA-125b', 'Var', (0, 13))
218510	31052530	These findings support the tumor-suppressive role of miR-125b in CSCC.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('SCC', 'Gene', (66, 69))	('miR-125b', 'Var', (53, 61))	('tumor', 'Disease', (27, 32))	('SCC', 'Gene', '6317', (66, 69))	('miR-125b', 'Chemical', '-', (53, 61))	('CSCC', 'Phenotype', 'HP:0006739', (65, 69))	('tumor', 'Disease', 'MESH:D009369', (27, 32))
218516	31052530	They also reveal that miR-181a mediates its tumor-suppressive role through KRAS signaling via the MAPK pathway.	('MAPK', 'Gene', '5595;5594;5595', (98, 102))	('MAPK', 'Gene', (98, 102))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('miR-181a', 'Var', (22, 30))	('KRAS', 'Gene', (75, 79))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumor', 'Disease', (44, 49))	('KRAS', 'Gene', '3845', (75, 79))
218533	31052530	The phosphorylation of LIMK1 results in the inactivation of cofilin and the subsequent stabilization of actin filaments, formation of stress fibers and cell invasion.	('cofilin', 'Gene', (60, 67))	('actin filaments', 'MPA', (104, 119))	('cell invasion', 'CPA', (152, 165))	('LIMK1', 'Gene', '3984', (23, 28))	('cofilin', 'Gene', '1072', (60, 67))	('inactivation', 'NegReg', (44, 56))	('stabilization', 'MPA', (87, 100))	('LIMK1', 'Gene', (23, 28))	('phosphorylation', 'Var', (4, 19))	('stress', 'MPA', (134, 140))
218562	31052530	Moreover, miR-199a regulates the interaction between CD44 and Ezrin, a complex implicated in metastasis.	('regulates', 'Reg', (19, 28))	('Ezrin', 'Gene', '7430', (62, 67))	('CD44', 'Gene', '960', (53, 57))	('CD44', 'Gene', (53, 57))	('Ezrin', 'Gene', (62, 67))	('miR-199a', 'Var', (10, 18))	('interaction', 'Interaction', (33, 44))
218566	31052530	MicroRNA-124 is the most abundant miRNA in the brain, and it has a central role in nervous system disorders.	('nervous system disorders', 'Disease', (83, 107))	('nervous system disorders', 'Phenotype', 'HP:0000707', (83, 107))	('nervous system disorders', 'Disease', 'MESH:D009421', (83, 107))	('MicroRNA-124', 'Var', (0, 12))
218573	31052530	MicroRNA-214 is an important microRNA in neurogenesis, but also acts in tumors as a tumor suppressor or oncogene.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('tumor', 'Disease', (72, 77))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumors', 'Disease', (72, 78))	('MicroRNA-214', 'Var', (0, 12))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('tumor', 'Disease', (84, 89))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('tumor', 'Disease', 'MESH:D009369', (72, 77))
218576	31052530	In CSCC, microRNA-214 acts as a tumor suppressor miRNA, and it is downregulated in vivo and in vitro.	('SCC', 'Gene', (4, 7))	('SCC', 'Gene', '6317', (4, 7))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('downregulated', 'NegReg', (66, 79))	('microRNA-214', 'Var', (9, 21))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('CSCC', 'Phenotype', 'HP:0006739', (3, 7))	('tumor', 'Disease', (32, 37))
218578	31052530	Taken together, levels of miR-124/214 and its targets ERK1 and ERK2 could be a tool for early diagnosis and treatment.	('miR-124/214', 'Var', (26, 37))	('ERK2', 'Gene', '5594', (63, 67))	('ERK1', 'Gene', (54, 58))	('ERK2', 'Gene', (63, 67))	('ERK1', 'Gene', '5595', (54, 58))
218587	31052530	Several miRNAs are dysregulated in CSCC, exhibiting oncogenic functions (such as mir-21, mir-205, mir-365, mir-31, mir-135b, mir-142, and mir-186) or suppressor functions (such as mir-20a, mir-203, mir-181a, mir-125b, mir-34a, mir-148a, mir-214, mir-124, mir-204, and mir-199a).	('mir-214', 'Gene', (237, 244))	('mir-199a', 'Var', (268, 276))	('mir-205', 'Gene', '406988', (89, 96))	('mir-142', 'Gene', '406934', (125, 132))	('mir-135b', 'Gene', (115, 123))	('SCC', 'Gene', (36, 39))	('mir-31', 'Gene', (107, 113))	('mir-21', 'Gene', '406991', (237, 243))	('mir-20a', 'Gene', (180, 187))	('mir-186', 'Gene', (138, 145))	('mir-135b', 'Gene', '442891', (115, 123))	('mir-124', 'Var', (246, 253))	('mir-148a', 'Gene', '406940', (227, 235))	('mir-203', 'Gene', '406986', (189, 196))	('mir-125b', 'Var', (208, 216))	('mir-186', 'Gene', '406962', (138, 145))	('CSCC', 'Phenotype', 'HP:0006739', (35, 39))	('mir-204', 'Gene', '406987', (255, 262))	('mir-203', 'Gene', (189, 196))	('mir-142', 'Gene', (125, 132))	('mir-21', 'Gene', (81, 87))	('mir-34a', 'Gene', (218, 225))	('mir-181a', 'Var', (198, 206))	('mir-31', 'Gene', '407035', (107, 113))	('mir-214', 'Gene', '406996', (237, 244))	('mir-205', 'Gene', (89, 96))	('mir-34a', 'Gene', '407040', (218, 225))	('mir-204', 'Gene', (255, 262))	('mir-20a', 'Gene', '406982', (180, 187))	('mir-148a', 'Gene', (227, 235))	('mir-365', 'Var', (98, 105))	('mir-21', 'Gene', '406991', (81, 87))	('mir-21', 'Gene', (237, 243))	('SCC', 'Gene', '6317', (36, 39))	('oncogenic functions', 'CPA', (52, 71))
218595	23996575	There were no differences between patients treated with ND+RT and definitive RT in overall survival (OS), progression-free survival (PFS), or locoregional-relapse-free survival, freedom-from-locoregional failure, or freedom-from-distant failure.	('overall survival', 'CPA', (83, 99))	('progression-free', 'CPA', (106, 122))	('al', 'Chemical', 'MESH:D000535', (87, 89))	('al', 'Chemical', 'MESH:D000535', (152, 154))	('ND+RT', 'Var', (56, 61))	('al', 'Chemical', 'MESH:D000535', (97, 99))	('patients', 'Species', '9606', (34, 42))	('freedom-from-locoregional failure', 'CPA', (178, 211))	('locoregional-relapse-free survival', 'CPA', (142, 176))	('al', 'Chemical', 'MESH:D000535', (201, 203))	('al', 'Chemical', 'MESH:D000535', (129, 131))	('al', 'Chemical', 'MESH:D000535', (174, 176))
218597	23996575	The prognostic implications of HPV(+) nodes in HNCUP are similar to those in oropharyngeal primary cancers.	('HNCUP', 'Disease', (47, 52))	('HPV', 'Species', '10566', (31, 34))	('HPV(+) nodes', 'Var', (31, 43))	('cancers', 'Phenotype', 'HP:0002664', (99, 106))	('primary cancers', 'Disease', (91, 106))	('primary cancers', 'Disease', 'MESH:D009369', (91, 106))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('al', 'Chemical', 'MESH:D000535', (88, 90))
218604	23996575	We examined our institutional experience to assess whether ND has an additional benefit to RT in these patients, and assessed human papillomavirus (HPV) in available nodal tissue to assess whether the presence of HPV infection in HNCUP is associated with favorable outcomes analogous to those observed in HPV-associated oropharyngeal cancer .	('al', 'Chemical', 'MESH:D000535', (27, 29))	('presence', 'Var', (201, 209))	('HPV-associated oropharyngeal cancer', 'Disease', (305, 340))	('human papillomavirus', 'Species', '10566', (126, 146))	('HPV', 'Species', '10566', (148, 151))	('cancer', 'Phenotype', 'HP:0002664', (334, 340))	('HPV infection', 'Disease', (213, 226))	('HPV-associated oropharyngeal cancer', 'Disease', 'MESH:D009959', (305, 340))	('al', 'Chemical', 'MESH:D000535', (169, 171))	('al', 'Chemical', 'MESH:D000535', (331, 333))	('al', 'Chemical', 'MESH:D000535', (276, 278))	('HPV', 'Species', '10566', (305, 308))	('al', 'Chemical', 'MESH:D000535', (77, 79))	('patients', 'Species', '9606', (103, 111))	('HPV', 'Species', '10566', (213, 216))	('HPV infection', 'Disease', 'MESH:D030361', (213, 226))
218654	23996575	Although there was a higher prevalence of N3 disease in the ND+RT group (27%) than the definitive RT group (16%), this difference was not statistically significant (p=0.62).	('N3 disease', 'Disease', (42, 52))	('al', 'Chemical', 'MESH:D000535', (147, 149))	('al', 'Chemical', 'MESH:D000535', (32, 34))	('ND+RT', 'Var', (60, 65))
218691	23996575	al further demonstrated no survival or regional control benefit with the use of neck dissection rather than excisional biopsy prior to RT, despite the presence of N2 or N3 disease in 91% of their HNCUP patient cohort .	('al', 'Chemical', 'MESH:D000535', (0, 2))	('al', 'Chemical', 'MESH:D000535', (45, 47))	('patient', 'Species', '9606', (202, 209))	('survival', 'CPA', (27, 35))	('N3 disease', 'Var', (169, 179))	('regional control', 'CPA', (39, 55))	('al', 'Chemical', 'MESH:D000535', (33, 35))	('al', 'Chemical', 'MESH:D000535', (116, 118))
218702	23996575	Patients with EBV-expression in metastatic lymph nodes, on the other hand, are highly likely to have occult nasopharyngeal primary tumors, and in these patients the hypopharynx, larynx, and oropharynx can be excluded .	('primary tumors', 'Disease', (123, 137))	('hypopharynx', 'Disease', 'None', (165, 176))	('hypopharynx', 'Disease', (165, 176))	('EBV-expression', 'Var', (14, 28))	('primary tumors', 'Disease', 'MESH:D009369', (123, 137))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('Patients', 'Species', '9606', (0, 8))	('al', 'Chemical', 'MESH:D000535', (120, 122))	('patients', 'Species', '9606', (152, 160))	('nasopharyngeal primary tumors', 'Phenotype', 'HP:0100630', (108, 137))
218713	23996575	It is similarly possible that selection of poorer prognosis patients for more aggressive therapy may account for the higher observed frequency of distant metastases in the ND+RT arm (28.1% vs. 11.2%), although this difference was not statistically significant (p=0.26) and no such trends were observed for the endpoints of LRFS (p=0.99), PFS (p=0.82), and OS (p=0.64).	('al', 'Chemical', 'MESH:D000535', (243, 245))	('PFS', 'Disease', (338, 341))	('patients', 'Species', '9606', (60, 68))	('LRFS', 'Disease', (323, 327))	('metastases', 'Disease', (154, 164))	('ND+RT', 'Var', (172, 177))	('al', 'Chemical', 'MESH:D000535', (201, 203))	('metastases', 'Disease', 'MESH:D009362', (154, 164))
218723	25246945	We uncover the existence of an underlying gene network that at least partially controls cancer 'survivalness', with mutations that are significantly correlated with patient survival, yet independent of tumour origin and type.	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('correlated', 'Reg', (149, 159))	('tumour', 'Phenotype', 'HP:0002664', (202, 208))	('controls', 'Reg', (79, 87))	('tumour', 'Disease', 'MESH:D009369', (202, 208))	('patient', 'Species', '9606', (165, 172))	('mutations', 'Var', (116, 125))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('tumour', 'Disease', (202, 208))
218727	25246945	Cancer is also a genomic disease in which genetic/epigenetic mutations contribute to tumour progression and heterogeneity.	('tumour', 'Disease', 'MESH:D009369', (85, 91))	('contribute', 'Reg', (71, 81))	('genetic/epigenetic mutations', 'Var', (42, 70))	('tumour', 'Disease', (85, 91))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('tumour', 'Phenotype', 'HP:0002664', (85, 91))
218744	25246945	TCGA mutation and survival data were obtained from the supplemental tables published in, retaining for analysis only cancer patients with survival information available.	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('patients', 'Species', '9606', (124, 132))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('TCGA', 'Gene', (0, 4))	('cancer', 'Disease', (117, 123))	('mutation', 'Var', (5, 13))
218745	25246945	This results in somatic mutational profiles for 3,096 patients with mutations in 19,171 genes (mapped to the Entrez Genes).	('mutations', 'Var', (68, 77))	('patients', 'Species', '9606', (54, 62))	('results', 'Reg', (5, 12))
218748	25246945	Survival analysis was applied to TCGA mutation and survival data based on the Cox proportional hazards model.	('TCGA', 'Gene', (33, 37))	('Cox', 'Gene', '1351', (78, 81))	('Cox', 'Gene', (78, 81))	('mutation', 'Var', (38, 46))
218752	25246945	The calculated Cox HR and P value are indicative of prognostic value: the extent to which mutation status for a gene correlates with patient survival advantage (after adjusting for age, gender and tumour type).	('tumour type', 'Disease', 'MESH:D009369', (197, 208))	('tumour type', 'Disease', (197, 208))	('patient survival advantage', 'CPA', (133, 159))	('patient', 'Species', '9606', (133, 140))	('Cox', 'Gene', '1351', (15, 18))	('tumour', 'Phenotype', 'HP:0002664', (197, 203))	('mutation status', 'Var', (90, 105))	('Cox', 'Gene', (15, 18))
218780	25246945	In addition, dGSEA is also applied to look at the tendency of these survival genes to be at the top of the gene list pre-ranked according to: cross-tumour mutation ubiquity, mutation frequency within a single tumour type, and mutation numbers in each individual patient.	('tumour', 'Phenotype', 'HP:0002664', (209, 215))	('mutation', 'Var', (174, 182))	('tumour type', 'Disease', (209, 220))	('cross-tumour', 'Disease', (142, 154))	('tumour type', 'Disease', 'MESH:D009369', (209, 220))	('cross-tumour', 'Disease', 'MESH:C537866', (142, 154))	('tumour', 'Phenotype', 'HP:0002664', (148, 154))	('patient', 'Species', '9606', (262, 269))	('GSEA', 'Chemical', '-', (14, 18))
218791	25246945	By analysing the 'TCGA' mutation and clinical data of patients covering multiple tumour types, we uncovered a core gene network indicative of cross-tumour patient survival (Figure 3; also see Additional file 1).	('patient', 'Species', '9606', (54, 61))	('tumour type', 'Disease', (81, 92))	('multiple tumour', 'Disease', 'MESH:D009369', (72, 87))	('patients', 'Species', '9606', (54, 62))	("'TCGA'", 'Gene', (17, 23))	('tumour type', 'Disease', 'MESH:D009369', (81, 92))	('cross-tumour', 'Disease', (142, 154))	('patient', 'Species', '9606', (155, 162))	('multiple tumour', 'Disease', (72, 87))	('cross-tumour', 'Disease', 'MESH:C537866', (142, 154))	('tumour', 'Phenotype', 'HP:0002664', (148, 154))	('mutation', 'Var', (24, 32))	('tumour', 'Phenotype', 'HP:0002664', (81, 87))
218800	25246945	For example, two tumour types of lung tissue of origins (LUAD and LUSC) locate at the bottom, with the highest proportion of survival genes frequently mutated.	('tumour', 'Phenotype', 'HP:0002664', (17, 23))	('survival genes', 'Gene', (125, 139))	('tumour type', 'Disease', (17, 28))	('tumour type', 'Disease', 'MESH:D009369', (17, 28))	('mutated', 'Var', (151, 158))
218822	25246945	Prognostic power is seen when compared to the naive use (chosen at random); an average of 10-fold increases in Cox HR will be expected using genes in the survival network.	('Cox', 'Gene', '1351', (111, 114))	('increases', 'PosReg', (98, 107))	('Cox', 'Gene', (111, 114))	('genes', 'Var', (141, 146))
218832	25246945	Viewing genes in the survival network as a signature, we conducted gene set enrichment analysis (GSEA) to look at the extent to which these genes are enriched in terms of cross-tumour mutation ubiquity, mutation frequency within a single tumour type, and mutation numbers for each individual patient (Figure 7).	('tumour type', 'Disease', (238, 249))	('cross-tumour', 'Disease', (171, 183))	('cross-tumour', 'Disease', 'MESH:C537866', (171, 183))	('GSEA', 'Chemical', '-', (97, 101))	('patient', 'Species', '9606', (292, 299))	('mutation', 'Var', (203, 211))	('tumour', 'Phenotype', 'HP:0002664', (238, 244))	('tumour', 'Phenotype', 'HP:0002664', (177, 183))	('tumour type', 'Disease', 'MESH:D009369', (238, 249))
218842	25246945	When simultaneously displaying the mutation frequency matrix and their first-created ancestors for survival genes (Figure 8), we notice a tendency for Deuterostomia-originated genes to mutate ubiquitously across tumour types.	('tumour', 'Phenotype', 'HP:0002664', (212, 218))	('Deuterostomia', 'Disease', 'None', (151, 164))	('tumour type', 'Disease', (212, 223))	('tumour type', 'Disease', 'MESH:D009369', (212, 223))	('mutate', 'Var', (185, 191))	('Deuterostomia', 'Disease', (151, 164))
218856	25246945	Applying dnet in analysing all of the 'TCGA' mutation and clinical data of >3,000 patients covering multiple tumour types (Figure 1), we uncovered a network of genes (Figure 3) for which most of their mutations are significantly correlated with patient survival.	('mutations', 'Var', (201, 210))	('tumour type', 'Disease', (109, 120))	('patient', 'Species', '9606', (82, 89))	('multiple tumour', 'Disease', (100, 115))	('multiple tumour', 'Disease', 'MESH:D009369', (100, 115))	('tumour type', 'Disease', 'MESH:D009369', (109, 120))	('patients', 'Species', '9606', (82, 90))	("'TCGA'", 'Gene', (38, 44))	('correlated', 'Reg', (229, 239))	('mutation', 'Var', (45, 53))	('patient survival', 'CPA', (245, 261))	('patient', 'Species', '9606', (245, 252))	('tumour', 'Phenotype', 'HP:0002664', (109, 115))
218900	30717802	Except in lungs, the expression of miR-34a is higher than miR-34b/c in most human tissues.	('miR-34a', 'Var', (35, 42))	('human', 'Species', '9606', (76, 81))	('expression', 'MPA', (21, 31))	('higher', 'PosReg', (46, 52))
218901	30717802	Whereas, in various cancers, miR-34a and miR-34b/c expression level is much lower because of the CpG methylation.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('miR-34b/c', 'Var', (41, 50))	('lower', 'NegReg', (76, 81))	('miR-34a', 'Var', (29, 36))	('cancers', 'Phenotype', 'HP:0002664', (20, 27))	('CpG', 'Var', (97, 100))	('cancers', 'Disease', (20, 27))	('cancers', 'Disease', 'MESH:D009369', (20, 27))
218905	30717802	found that compared with normal tissues, miR-34a and miR-34c were down-regulated in human colon cancer tissue, and the reason for down-regulating was promoter hypermethylation.	('miR-34a', 'Gene', (41, 48))	('miR-34c', 'Gene', '407042', (53, 60))	('colon cancer', 'Disease', 'MESH:D015179', (90, 102))	('colon cancer', 'Disease', (90, 102))	('miR-34c', 'Gene', (53, 60))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('down-regulated', 'NegReg', (66, 80))	('down-regulating', 'NegReg', (130, 145))	('human', 'Species', '9606', (84, 89))	('promoter hypermethylation', 'Var', (150, 175))	('colon cancer', 'Phenotype', 'HP:0003003', (90, 102))
218906	30717802	Notwithstanding the cause of decrease expression of miR-34 is hypermethylation, but not only that, SUMOylation has also been verified to regulate miR-34b/c level in colon cancer.	('hypermethylation', 'Var', (62, 78))	('miR-34', 'Gene', '407040', (52, 58))	('miR-34', 'Gene', (146, 152))	('expression', 'MPA', (38, 48))	('regulate', 'Reg', (137, 145))	('colon cancer', 'Phenotype', 'HP:0003003', (165, 177))	('miR-34', 'Gene', '407040', (146, 152))	('colon cancer', 'Disease', 'MESH:D015179', (165, 177))	('miR-34', 'Gene', (52, 58))	('colon cancer', 'Disease', (165, 177))	('decrease', 'NegReg', (29, 37))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))
218908	30717802	In the ApcMin/+ mice model which deleted miR-34a or miR-34b/c, the number of tumors and risk of death were shown to be significantly increased.	('tumors', 'Disease', (77, 83))	('tumors', 'Disease', 'MESH:D009369', (77, 83))	('miR-34a', 'Var', (41, 48))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('miR-34b/c', 'Var', (52, 61))	('death', 'Disease', 'MESH:D003643', (96, 101))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('increased', 'PosReg', (133, 142))	('mice', 'Species', '10090', (16, 20))	('death', 'Disease', (96, 101))	('deleted miR-34a', 'Var', (33, 48))
218909	30717802	Moreover, miR-34a or miR-34b could inhibit cell migration and invasion in colorectal cancer (CRC) cells.	('miR-34b', 'Var', (21, 28))	('miR-34a', 'Var', (10, 17))	('colorectal cancer', 'Disease', 'MESH:D015179', (74, 91))	('CRC', 'Phenotype', 'HP:0003003', (93, 96))	('colorectal cancer', 'Phenotype', 'HP:0003003', (74, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('invasion', 'CPA', (62, 70))	('cell migration', 'CPA', (43, 57))	('inhibit', 'NegReg', (35, 42))	('colorectal cancer', 'Disease', (74, 91))
218917	30717802	showed the decrease of miR-34a in 20 human primary prostate cancer specimens, meanwhile they found that miR-34a can regulate Wnt signal pathway negatively to inhibit EMT-associated migration and invasion.	('miR-34a', 'Var', (104, 111))	('prostate cancer', 'Disease', 'MESH:D011471', (51, 66))	('men', 'Species', '9606', (72, 75))	('prostate cancer', 'Phenotype', 'HP:0012125', (51, 66))	('inhibit', 'NegReg', (158, 165))	('decrease', 'NegReg', (11, 19))	('human', 'Species', '9606', (37, 42))	('miR-34a', 'Gene', (23, 30))	('Wnt signal pathway', 'Pathway', (125, 143))	('prostate cancer', 'Disease', (51, 66))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('negatively', 'NegReg', (144, 154))
218919	30717802	Moreover, the overexpression of miR-34b or miR-34c in PCa cells revealed pronounced inhibition in cell migration, invasion and proliferation, whereas showed no influence on apoptosis.	('P', 'Chemical', 'MESH:D010758', (54, 55))	('inhibition', 'NegReg', (84, 94))	('PCa', 'Phenotype', 'HP:0012125', (54, 57))	('miR-34c', 'Gene', '407042', (43, 50))	('miR-34c', 'Gene', (43, 50))	('miR-34b', 'Var', (32, 39))	('cell migration', 'CPA', (98, 112))	('overexpression', 'PosReg', (14, 28))	('invasion', 'CPA', (114, 122))
218923	30717802	Moreover, miR-34a and miR-34c were associated with the metastasis of BC.	('metastasis', 'CPA', (55, 65))	('miR-34c', 'Gene', '407042', (22, 29))	('miR-34a', 'Var', (10, 17))	('miR-34c', 'Gene', (22, 29))	('associated with', 'Reg', (35, 50))	('BC', 'Phenotype', 'HP:0003002', (69, 71))
218925	30717802	And in vitro experiments showed that the overexpression of miR-34a or miR-34c repressed the migration and invasion of BC cells.	('BC', 'Phenotype', 'HP:0003002', (118, 120))	('miR-34a', 'Var', (59, 66))	('invasion of BC cells', 'CPA', (106, 126))	('migration', 'CPA', (92, 101))	('miR-34c', 'Gene', '407042', (70, 77))	('men', 'Species', '9606', (19, 22))	('overexpression', 'PosReg', (41, 55))	('miR-34c', 'Gene', (70, 77))
218928	30717802	Not only that, BC-bearing nude mice which treated with miR-34a showed significant inhibition of tumor formation.	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('BC', 'Phenotype', 'HP:0003002', (15, 17))	('miR-34a', 'Var', (55, 62))	('nude mice', 'Species', '10090', (26, 35))	('tumor', 'Disease', (96, 101))	('inhibition', 'NegReg', (82, 92))	('tumor', 'Disease', 'MESH:D009369', (96, 101))
218930	30717802	For example, miR-34b showed a minor effect on cell growth, apoptosis and migration than miR-34c in breast cancer cell line MDA-MB-231.	('migration', 'CPA', (73, 82))	('breast cancer', 'Disease', 'MESH:D001943', (99, 112))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (123, 133))	('miR-34b', 'Var', (13, 20))	('breast cancer', 'Disease', (99, 112))	('cell growth', 'CPA', (46, 57))	('miR-34c', 'Gene', '407042', (88, 95))	('breast cancer', 'Phenotype', 'HP:0003002', (99, 112))	('miR-34c', 'Gene', (88, 95))	('apoptosis', 'CPA', (59, 68))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
218935	30717802	It showed the possibility of regarding miR-34a and miR-34c as potential prognostic markers in NSCLC.	('NSCLC', 'Phenotype', 'HP:0030358', (94, 99))	('SCLC', 'Phenotype', 'HP:0030357', (95, 99))	('NSCLC', 'Disease', (94, 99))	('NSCLC', 'Disease', 'MESH:D002289', (94, 99))	('miR-34c', 'Gene', '407042', (51, 58))	('miR-34a', 'Var', (39, 46))	('miR-34c', 'Gene', (51, 58))
218946	30717802	Additionally, miR-34b also shows the anti-tumor effect in OSA.	('tumor', 'Disease', (42, 47))	('OSA', 'Disease', (58, 61))	('miR-34b', 'Var', (14, 21))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('OSA', 'Phenotype', 'HP:0002669', (58, 61))
218947	30717802	Mice which suffered with OSA exhibited smaller tumor volume and more apoptotic cells after treating with miR-34b, suggesting that miR-34b could inhibit growth and induce apoptosis of OSA.	('OSA', 'Disease', (25, 28))	('OSA', 'Phenotype', 'HP:0002669', (183, 186))	('miR-34b', 'Var', (130, 137))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('growth', 'CPA', (152, 158))	('induce', 'PosReg', (163, 169))	('inhibit', 'NegReg', (144, 151))	('Mice', 'Species', '10090', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor', 'Disease', (47, 52))	('apoptosis', 'CPA', (170, 179))	('OSA', 'Phenotype', 'HP:0002669', (25, 28))
218950	30717802	Except various solid tumors, miR-34 family members have also been detected dysregulation in some haematological neoplasms.	('miR-34', 'Gene', (29, 35))	('dysregulation', 'Var', (75, 88))	('haematological neoplasms', 'Disease', (97, 121))	('solid tumors', 'Disease', 'MESH:D009369', (15, 27))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('neoplasms', 'Phenotype', 'HP:0002664', (112, 121))	('miR-34', 'Gene', '407040', (29, 35))	('haematological neoplasms', 'Disease', 'MESH:D019337', (97, 121))	('haematological neoplasms', 'Phenotype', 'HP:0004377', (97, 121))	('solid tumors', 'Disease', (15, 27))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
218954	30717802	In addition, about 18% chronic lymphocytic leukemia (CLL) patients are deficiency of the long arm of chromosome 11 where miR-34b and miR-34c located, thus the expression of miR-34b/c is much lower in CLL.	('lymphocytic leukemia', 'Disease', 'MESH:D007945', (31, 51))	('lymphocytic leukemia', 'Disease', (31, 51))	('deficiency of the long', 'Disease', 'MESH:D008133', (71, 93))	('miR-34c', 'Gene', '407042', (133, 140))	('expression', 'MPA', (159, 169))	('miR-34c', 'Gene', (133, 140))	('CLL', 'Phenotype', 'HP:0005550', (53, 56))	('CLL', 'Phenotype', 'HP:0005550', (200, 203))	('miR-34b', 'Var', (121, 128))	('patients', 'Species', '9606', (58, 66))	('lower', 'NegReg', (191, 196))	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (23, 51))	('leukemia', 'Phenotype', 'HP:0001909', (43, 51))	('deficiency of the long', 'Disease', (71, 93))
218955	30717802	Not only that, p53 has been found to be lost or mutated in a large proportion of fludarabine refractory CLL cases, and as the direct downstream target of p53, miR-34a indeed shows a low expression in CLL.	('mutated', 'Var', (48, 55))	('CLL', 'Phenotype', 'HP:0005550', (104, 107))	('miR-34a', 'Var', (159, 166))	('low', 'NegReg', (182, 185))	('fludarabine', 'Chemical', 'MESH:C024352', (81, 92))	('p53', 'Gene', (15, 18))	('p53', 'Gene', '7157', (15, 18))	('CLL', 'Phenotype', 'HP:0005550', (200, 203))	('p53', 'Gene', (154, 157))	('CLL', 'Disease', (200, 203))	('expression', 'MPA', (186, 196))	('p53', 'Gene', '7157', (154, 157))
218958	30717802	Besides in leukemia, the dysregulation of miR-34 also has been found in multiple myeloma (MM).	('miR-34', 'Gene', '407040', (42, 48))	('multiple myeloma', 'Disease', 'MESH:D009101', (72, 88))	('leukemia', 'Phenotype', 'HP:0001909', (11, 19))	('leukemia', 'Disease', 'MESH:D007938', (11, 19))	('multiple myeloma', 'Phenotype', 'HP:0006775', (72, 88))	('leukemia', 'Disease', (11, 19))	('multiple myeloma', 'Disease', (72, 88))	('dysregulation', 'Var', (25, 38))	('miR-34', 'Gene', (42, 48))	('found', 'Reg', (63, 68))
218959	30717802	Moreover, miR-34a not just plays the antitumor effect directly, also has been demonstrated to enhance the anticancer effect of three anticancer agents, gamma-secretase inhibitor, sirtinol and zoledronic acid, in multiple myeloma.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('multiple myeloma', 'Disease', (212, 228))	('zoledronic acid', 'Chemical', 'MESH:D000077211', (192, 207))	('cancer', 'Disease', (110, 116))	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('sirtinol', 'Chemical', 'MESH:C439060', (179, 187))	('tumor', 'Disease', (41, 46))	('miR-34a', 'Var', (10, 17))	('enhance', 'PosReg', (94, 101))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('cancer', 'Disease', (137, 143))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('multiple myeloma', 'Phenotype', 'HP:0006775', (212, 228))	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('multiple myeloma', 'Disease', 'MESH:D009101', (212, 228))
218983	30717802	In addition, when treated cells with Nutlin-3a, a kind of chemical activator of p53, the expression of miR-34a was dramatically increased.	('expression', 'MPA', (89, 99))	('miR-34a', 'Var', (103, 110))	('p53', 'Gene', (80, 83))	('increased', 'PosReg', (128, 137))	('p53', 'Gene', '7157', (80, 83))
218985	30717802	However, miR-34b/c showed little effect on p53 activity.	('activity', 'MPA', (47, 55))	('p53', 'Gene', '7157', (43, 46))	('miR-34b/c', 'Var', (9, 18))	('p53', 'Gene', (43, 46))
218990	30717802	It is reported that LEF-1 expression was decreased by miR-34a via directly binding with the 3'-UTR of LEF-1, resulted in the inhibition of migration and invasion of PCa cells and the attenuation of EMT.	('expression', 'MPA', (26, 36))	('LEF-1', 'Gene', (20, 25))	('P', 'Chemical', 'MESH:D010758', (165, 166))	('decreased', 'NegReg', (41, 50))	('migration', 'CPA', (139, 148))	('LEF-1', 'Gene', '51176', (102, 107))	('PCa', 'Phenotype', 'HP:0012125', (165, 168))	('miR-34a', 'Var', (54, 61))	('EMT', 'CPA', (198, 201))	('attenuation', 'NegReg', (183, 194))	('LEF-1', 'Gene', '51176', (20, 25))	('binding', 'Interaction', (75, 82))	('LEF-1', 'Gene', (102, 107))	('inhibition', 'NegReg', (125, 135))
218991	30717802	Notably, miR-34a also indirectly suppressed LEF-1 expression through regulating beta-catenin, thereby inhibiting the invasion of colon cancer cells.	('colon cancer', 'Phenotype', 'HP:0003003', (129, 141))	('inhibiting', 'NegReg', (102, 112))	('colon cancer', 'Disease', 'MESH:D015179', (129, 141))	('LEF-1', 'Gene', '51176', (44, 49))	('beta-catenin', 'Gene', (80, 92))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('miR-34a', 'Var', (9, 16))	('beta-catenin', 'Gene', '1499', (80, 92))	('colon cancer', 'Disease', (129, 141))	('regulating', 'Reg', (69, 79))	('suppressed', 'NegReg', (33, 43))	('expression', 'MPA', (50, 60))	('LEF-1', 'Gene', (44, 49))
218993	30717802	It is reported that miR-34a could inhibit the migration and invasion of cholangiocarcinoma cells by suppressing the activity of TGF-beta/Smad4 pathway.	('TGF-beta', 'Gene', '7040', (128, 136))	('Smad4', 'Gene', (137, 142))	('Smad4', 'Gene', '4089', (137, 142))	('miR-34a', 'Var', (20, 27))	('TGF-beta', 'Gene', (128, 136))	('cholangiocarcinoma', 'Disease', (72, 90))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('suppressing', 'NegReg', (100, 111))	('activity', 'MPA', (116, 124))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (72, 90))	('inhibit', 'NegReg', (34, 41))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (72, 90))
219003	30717802	As the well-studied tumor suppressor, miR-34a absolutely is an appropriate candidate for cancer therapy.	('miR-34a', 'Var', (38, 45))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('cancer', 'Disease', (89, 95))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('tumor', 'Disease', (20, 25))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
219008	30717802	In addition, the MM xenografts formation and average size were dramatically reduced by lentiviral miR-34a in the severe combined immunodeficien (SCID) mice.	('average size', 'CPA', (45, 57))	('MM xenografts formation', 'CPA', (17, 40))	('SCID', 'Gene', '19090', (145, 149))	('mice', 'Species', '10090', (151, 155))	('SCID', 'Gene', (145, 149))	('severe combined immunodeficien', 'Disease', (113, 143))	('reduced', 'NegReg', (76, 83))	('miR-34a', 'Var', (98, 105))	('lentiviral miR-34a', 'Var', (87, 105))
219009	30717802	Lentiviral vector was also used to systemically deliver miR-34a to PCa, and results showed that the miR-34a lentiviral delivery system inhibited tumor cell metastasis and prolonged animal survival.	('prolonged', 'PosReg', (171, 180))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('animal survival', 'CPA', (181, 196))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('miR-34a', 'Var', (100, 107))	('tumor', 'Disease', (145, 150))	('P', 'Chemical', 'MESH:D010758', (67, 68))	('inhibited', 'NegReg', (135, 144))	('PCa', 'Phenotype', 'HP:0012125', (67, 70))
219011	30717802	AdCN205 is an oncolytic adenovirus which modified by CR2 region deletion and replacement with human telomerase reverse transcriptase (hTERT) promoter to E1A promoter.	('CR2', 'Gene', (53, 56))	('deletion', 'Var', (64, 72))	('men', 'Species', '9606', (84, 87))	('human', 'Species', '9606', (94, 99))	('CR2', 'Species', '2498238', (53, 56))	('hTERT', 'Gene', '7015', (134, 139))	('hTERT', 'Gene', (134, 139))
219012	30717802	miR-34a and tumor suppressor gene IL-24 were co-delivered via AdCN205 to HCC cells, and the infected HCC cells showed proliferation inhibition.	('HCC', 'Gene', '619501', (73, 76))	('HCC', 'Phenotype', 'HP:0001402', (73, 76))	('miR-34a', 'Var', (0, 7))	('HCC', 'Gene', '619501', (101, 104))	('inhibition', 'NegReg', (132, 142))	('HCC', 'Phenotype', 'HP:0001402', (101, 104))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('proliferation', 'CPA', (118, 131))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('HCC', 'Gene', (101, 104))	('HCC', 'Gene', (73, 76))	('tumor', 'Disease', (12, 17))
219013	30717802	Impressively, AdCN205-IL-24-miR-34a prominently inhibited tumor growth and induced tumor regression without tumor recurrence at HCC mice.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('tumor', 'Disease', (58, 63))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('HCC', 'Phenotype', 'HP:0001402', (128, 131))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('tumor', 'Disease', (83, 88))	('tumor', 'Disease', (108, 113))	('AdCN205-IL-24-miR-34a', 'Var', (14, 35))	('HCC', 'Gene', (128, 131))	('induced', 'PosReg', (75, 82))	('inhibited', 'NegReg', (48, 57))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('mice', 'Species', '10090', (132, 136))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('HCC', 'Gene', '619501', (128, 131))
219021	30717802	In order to achieve better antitumor activity, SNALPs-miR-34a system was upgraded by means of conjugating SNALPs with transferrin (Tf) and modifying miR-34a by 2'-O-methylated (OMet).	('SNALPs', 'Chemical', '-', (106, 112))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumor', 'Disease', (31, 36))	('transferrin', 'Gene', '7018', (118, 129))	('miR-34a', 'Gene', (149, 156))	('Tf', 'Gene', '7018', (131, 133))	('transferrin', 'Gene', (118, 129))	('SNALPs', 'Chemical', '-', (47, 53))	('modifying', 'Var', (139, 148))	('SNALPs', 'Gene', (106, 112))
219022	30717802	Indeed, the Tf-SNALPs encapsulating OMet miR-34a prolong MM mice survival compared with previous unmodified SNALPs miR-34a delivery system.	('OMet miR-34a', 'Var', (36, 48))	('Tf', 'Gene', '7018', (12, 14))	('SNALPs', 'Chemical', '-', (108, 114))	('SNALPs', 'Chemical', '-', (15, 21))	('mice', 'Species', '10090', (60, 64))	('prolong', 'PosReg', (49, 56))
219024	30717802	constructed a TV-miR-34a plasmid consisted of hTERT promoter-driven VP16-GAL4-WPRE integrated systemic amplifier (VISA) and miR-34a, and delivered TV-miR-34a to breast cancer stem cells (BCSC) by synthesized DODAP and CHOL liposomes.	('CHOL', 'Chemical', 'MESH:D002784', (218, 222))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('breast cancer', 'Disease', 'MESH:D001943', (161, 174))	('breast cancer', 'Phenotype', 'HP:0003002', (161, 174))	('hTERT', 'Gene', '7015', (46, 51))	('DODAP', 'Chemical', '-', (208, 213))	('P', 'Chemical', 'MESH:D010758', (79, 80))	('breast cancer', 'Disease', (161, 174))	('delivered', 'Reg', (137, 146))	('P', 'Chemical', 'MESH:D010758', (212, 213))	('hTERT', 'Gene', (46, 51))	('VP16', 'Gene', (68, 72))	('P', 'Chemical', 'MESH:D010758', (69, 70))	('VP16', 'Gene', '3054', (68, 72))	('TV-miR-34a', 'Var', (147, 157))	('BC', 'Phenotype', 'HP:0003002', (187, 189))
219026	30717802	Moreover, the BCSC-bearing tumors mice which treated with TV-miR-34a showed pronounced inhibition of tumor growth.	('inhibition', 'NegReg', (87, 97))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('mice', 'Species', '10090', (34, 38))	('tumor', 'Disease', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('tumors', 'Disease', (27, 33))	('tumors', 'Disease', 'MESH:D009369', (27, 33))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('TV-miR-34a', 'Var', (58, 68))	('BC', 'Phenotype', 'HP:0003002', (14, 16))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
219027	30717802	The oncotherapy of miR-34a which depended on lipid-based vectors has also been verified in other cancers, such as neuroblastoma and pancreatic cancer.	('cancers', 'Disease', 'MESH:D009369', (97, 104))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('cancers', 'Phenotype', 'HP:0002664', (97, 104))	('neuroblastoma', 'Disease', 'MESH:D009447', (114, 127))	('cancers', 'Disease', (97, 104))	('neuroblastoma', 'Disease', (114, 127))	('pancreatic cancer', 'Disease', (132, 149))	('lipid', 'Chemical', 'MESH:D008055', (45, 50))	('pancreatic cancer', 'Disease', 'MESH:D010190', (132, 149))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('neuroblastoma', 'Phenotype', 'HP:0003006', (114, 127))	('miR-34a', 'Var', (19, 26))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (132, 149))
219042	30717802	And the anticancer effect became more prominent in condition of treatment with miR-34a and siRNA-Kras together.	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('men', 'Species', '9606', (69, 72))	('miR-34a', 'Var', (79, 86))	('cancer', 'Disease', (12, 18))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))
219043	30717802	An effective delivery vector provides possibility for miR-34a to overcome numerous extracellular and intracellular obstacles, it is the guarantee for miR-34a to exert anti-tumor effect.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('tumor', 'Disease', (172, 177))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('miR-34a', 'Var', (150, 157))
219052	30717802	Moreover, NOV340, the encapsulated vehicle in the clinical trial, was also used to co-deliver miR-34a and let-7b to NSCLC mice which resistance to conventional anticancer therapy.	('NSCLC', 'Disease', 'MESH:D002289', (116, 121))	('mice', 'Species', '10090', (122, 126))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('let-7b', 'Gene', '387245', (106, 112))	('SCLC', 'Phenotype', 'HP:0030357', (117, 121))	('miR-34a', 'Var', (94, 101))	('NSCLC', 'Phenotype', 'HP:0030358', (116, 121))	('let-7b', 'Gene', (106, 112))	('cancer', 'Disease', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('NSCLC', 'Disease', (116, 121))
219055	30717802	The authors found that these patients who were treated with MRX34 showed several adverse events including fever, fatigue etcetera.	('patients', 'Species', '9606', (29, 37))	('fever', 'Disease', 'MESH:D005334', (106, 111))	('fever', 'Disease', (106, 111))	('fatigue', 'Disease', 'MESH:D005221', (113, 120))	('MRX34', 'Var', (60, 65))	('etcetera', 'Disease', (121, 129))	('fever', 'Phenotype', 'HP:0001945', (106, 111))	('fatigue', 'Disease', (113, 120))	('fatigue', 'Phenotype', 'HP:0012378', (113, 120))
219061	30717802	As an excellent tumor suppressor, miR-34a is considered for cancer therapy.	('miR-34a', 'Var', (34, 41))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('cancer', 'Disease', (60, 66))	('tumor', 'Disease', (16, 21))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
219062	30717802	A large number of studies about miR-34a therapeutics have been carried out, and verified its tumor-supressive role in cancer.	('cancer', 'Disease', (118, 124))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Disease', (93, 98))	('miR-34a', 'Var', (32, 39))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
219066	30717802	Even so, miR-34a is also a promising cancer therapeutic candidate.	('cancer', 'Disease', (37, 43))	('miR-34a', 'Var', (9, 16))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('cancer', 'Disease', 'MESH:D009369', (37, 43))
219102	29541592	Therefore, blockade of the PD-1 receptor alone in a human could, but only rarely, induce non-bacterial cystitis as irAEs, as seen in these cases.	('induce', 'Reg', (82, 88))	('human', 'Species', '9606', (52, 57))	('cystitis', 'Disease', (103, 111))	('cystitis', 'Disease', 'MESH:D003556', (103, 111))	('blockade', 'Var', (11, 19))
219143	33924832	The whole cohort of 33 patients had an indication for postoperative adjuvant therapy due to advanced tumor stage, the presence of neck node metastases, incomplete tumor resection status, histopathological risk factors (L+, V+, pN+), or a combination of several factors.	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('patients', 'Species', '9606', (23, 31))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('pN', 'Gene', '79650', (227, 229))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('L+', 'Var', (219, 221))	('metastases', 'Disease', (140, 150))	('tumor', 'Disease', (163, 168))	('metastases', 'Disease', 'MESH:D009362', (140, 150))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
219170	33924832	Although this rate generally might be critically discussed, it has to be considered under the aspect of the dominance of advanced tumors in this cohort (97% T3/T4 tumors), including 36.4% recurrent tumors and a history of prior multi-modality-treatment in 33.3% of the patients.	('tumors', 'Disease', (130, 136))	('tumors', 'Disease', 'MESH:D009369', (130, 136))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('tumors', 'Disease', (163, 169))	('tumors', 'Disease', 'MESH:D009369', (163, 169))	('T3/T4', 'Var', (157, 162))	('tumors', 'Phenotype', 'HP:0002664', (163, 169))	('tumors', 'Disease', (198, 204))	('tumors', 'Disease', 'MESH:D009369', (198, 204))	('tumors', 'Phenotype', 'HP:0002664', (198, 204))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('patients', 'Species', '9606', (269, 277))
219206	33621951	MET inhibitor, capmatinib overcomes osimertinib resistance via suppression of MET/Akt/snail signaling in non-small cell lung cancer and decreased generation of cancer-associated fibroblasts Background: Patients with non-small cell lung cancer (NSCLC) initially responding to tyrosine kinase inhibitors (TKIs) eventually develop resistance due to accumulating mutations in the EGFR and additional lesser investigated mechanisms such as the participation of the tumor microenvironment (TME).	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (105, 131))	('cancer', 'Disease', 'MESH:D009369', (236, 242))	('NSCLC', 'Disease', 'MESH:D002289', (244, 249))	('mutations', 'Var', (359, 368))	('capmatinib', 'Chemical', 'MESH:C000613976', (15, 25))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (216, 242))	('EGFR', 'Gene', (376, 380))	('osimertinib', 'Chemical', 'MESH:C000596361', (36, 47))	('NSCLC', 'Disease', (244, 249))	('snail', 'Gene', (86, 91))	('cancer', 'Disease', (160, 166))	('non-small cell lung cancer', 'Disease', (105, 131))	('MET', 'Gene', (0, 3))	('resistance', 'MPA', (328, 338))	('NSCLC', 'Phenotype', 'HP:0030358', (244, 249))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('cancer', 'Disease', (125, 131))	('tumor', 'Disease', (460, 465))	('non-small cell lung cancer', 'Disease', (216, 242))	('lung cancer', 'Phenotype', 'HP:0100526', (231, 242))	('MET', 'Gene', (78, 81))	('EGFR', 'Gene', '1956', (376, 380))	('lung cancer', 'Phenotype', 'HP:0100526', (120, 131))	('cancer', 'Disease', (236, 242))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('tumor', 'Disease', 'MESH:D009369', (460, 465))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('Akt', 'Gene', (82, 85))	('accumulating', 'PosReg', (346, 358))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (105, 131))	('MET', 'Gene', '79811', (0, 3))	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('Akt', 'Gene', '207', (82, 85))	('develop', 'PosReg', (320, 327))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (216, 242))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (220, 242))	('snail', 'Gene', '6615', (86, 91))	('Patients', 'Species', '9606', (202, 210))	('tumor', 'Phenotype', 'HP:0002664', (460, 465))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (109, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('MET', 'Gene', '79811', (78, 81))
219210	33621951	We subsequently found that both CAF-cultured HCC827 and H1975 showed a significantly higher expression of MET, Akt, Snail and IL-1beta, which were associated with survival and inflammatory responses.	('MET', 'Gene', '79811', (106, 109))	('Snail', 'Gene', (116, 121))	('associated', 'Reg', (147, 157))	('higher', 'PosReg', (85, 91))	('Akt', 'Gene', (111, 114))	('H1975', 'Var', (56, 61))	('MET', 'Gene', (106, 109))	('IL-1beta', 'Gene', '3552', (126, 134))	('Snail', 'Gene', '6615', (116, 121))	('expression', 'MPA', (92, 102))	('IL-1beta', 'Gene', (126, 134))	('CAF', 'Gene', '8850', (32, 35))	('H1975', 'CellLine', 'CVCL:1511', (56, 61))	('HCC827', 'CellLine', 'CVCL:2063', (45, 51))	('CAF', 'Gene', (32, 35))	('Akt', 'Gene', '207', (111, 114))	('HCC827', 'Var', (45, 51))
219218	33621951	Activating EGFR mutation represents one of the key driver oncogenes in patients with non-small cell lung cancer.	('mutation', 'Var', (16, 24))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (85, 111))	('EGFR', 'Gene', '1956', (11, 15))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (85, 111))	('EGFR', 'Gene', (11, 15))	('patients', 'Species', '9606', (71, 79))	('lung cancer', 'Phenotype', 'HP:0100526', (100, 111))	('non-small cell lung cancer', 'Disease', (85, 111))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (89, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('Activating', 'Reg', (0, 10))
219219	33621951	The discovery of gefitinib, the first generation of EGFR-tyrosine kinase inhibitors (TKIs) paved the way for targeted therapy for NSCLC patients with activating EGFR mutations (L858R and exon-19 deletion).	('NSCLC', 'Disease', 'MESH:D002289', (130, 135))	('gefitinib', 'Chemical', 'MESH:D000077156', (17, 26))	('L858R', 'Mutation', 'rs121434568', (177, 182))	('activating', 'PosReg', (150, 160))	('exon-19 deletion', 'Var', (187, 203))	('EGFR', 'Gene', (161, 165))	('EGFR', 'Gene', '1956', (52, 56))	('EGFR', 'Gene', (52, 56))	('NSCLC', 'Phenotype', 'HP:0030358', (130, 135))	('patients', 'Species', '9606', (136, 144))	('NSCLC', 'Disease', (130, 135))	('EGFR', 'Gene', '1956', (161, 165))	('L858R', 'Var', (177, 182))
219220	33621951	The acquisition of EGFR T790M mutation was identified to be the cause for resistance against the gefitinib found in approximately 50% of all initial responders.	('cause', 'Reg', (64, 69))	('gefitinib', 'Chemical', 'MESH:D000077156', (97, 106))	('EGFR', 'Gene', '1956', (19, 23))	('T790M', 'Mutation', 'rs121434569', (24, 29))	('T790M', 'Var', (24, 29))	('EGFR', 'Gene', (19, 23))	('resistance against the gefitinib', 'MPA', (74, 106))
219221	33621951	Subsequently, the third generation TKIs, AZD9291 (osimertinib) which irreversibly binds to and inactivate EGFR T790M was developed and provided impressive responses in EGFR T790M-positive patients.	('T790M', 'Mutation', 'rs121434569', (173, 178))	('EGFR', 'Gene', '1956', (168, 172))	('inactivate', 'NegReg', (95, 105))	('EGFR', 'Gene', (168, 172))	('T790M', 'Var', (111, 116))	('responses', 'MPA', (155, 164))	('T790M-positive', 'Var', (173, 187))	('AZD9291', 'Chemical', 'MESH:C000596361', (41, 48))	('osimertinib', 'Chemical', 'MESH:C000596361', (50, 61))	('patients', 'Species', '9606', (188, 196))	('EGFR', 'Gene', '1956', (106, 110))	('binds', 'Interaction', (82, 87))	('T790M', 'Mutation', 'rs121434569', (111, 116))	('EGFR', 'Gene', (106, 110))
219222	33621951	Unfortunately, patients who received osimertinib eventually develop resistance via acquired additional EGFR C797S mutation.	('EGFR', 'Gene', '1956', (103, 107))	('C797S', 'Var', (108, 113))	('patients', 'Species', '9606', (15, 23))	('EGFR', 'Gene', (103, 107))	('resistance', 'MPA', (68, 78))	('osimertinib', 'Chemical', 'MESH:C000596361', (37, 48))	('C797S', 'Mutation', 'rs1057519861', (108, 113))	('develop', 'PosReg', (60, 67))
219223	33621951	More importantly, additional activation of other survival signaling pathways such as MET and associated signaling, were also observed to be activated in patients who picked up the C797S mutation.	('MET', 'Gene', (85, 88))	('activation', 'PosReg', (29, 39))	('patients', 'Species', '9606', (153, 161))	('survival signaling pathways', 'Pathway', (49, 76))	('activated', 'PosReg', (140, 149))	('C797S', 'Mutation', 'rs1057519861', (180, 185))	('MET', 'Gene', '79811', (85, 88))	('C797S', 'Var', (180, 185))
219240	33621951	We found that the presence of CAFs increased osimertinib resistance in both cell lines.	('presence', 'Var', (18, 26))	('CAFs increased osimertinib', 'Disease', (30, 56))	('CAFs increased osimertinib', 'Disease', 'MESH:D006973', (30, 56))
219269	33621951	Unfortunately, like their predecessors, patients received osimertinib gradually develop resistance via acquiring additional mutant, C797S.	('C797S', 'Mutation', 'rs1057519861', (132, 137))	('resistance', 'MPA', (88, 98))	('C797S', 'Var', (132, 137))	('patients', 'Species', '9606', (40, 48))	('develop', 'PosReg', (80, 87))	('osimertinib', 'Chemical', 'MESH:C000596361', (58, 69))
219290	33621951	In agreement, a recent study just demonstrated that dual inhibition of MET and PI3K (upstream of Akt) by a small molecule, could suppress NSCLC tumorigenesis.	('tumor', 'Disease', (144, 149))	('NSCLC', 'Disease', (138, 143))	('Akt', 'Gene', (97, 100))	('PI3K', 'Var', (79, 83))	('NSCLC', 'Disease', 'MESH:D002289', (138, 143))	('suppress', 'NegReg', (129, 137))	('inhibition', 'NegReg', (57, 67))	('MET', 'Gene', '79811', (71, 74))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('NSCLC', 'Phenotype', 'HP:0030358', (138, 143))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('MET', 'Gene', (71, 74))	('Akt', 'Gene', '207', (97, 100))
219298	33621951	Recently, capmatinib was approved by the FDA for the treatment of patients with metastatic NSCLC harboring a MET exon-14 skipping mutation with disease progression on or after platinum-based chemotherapy.	('MET', 'Gene', (109, 112))	('NSCLC', 'Disease', 'MESH:D002289', (91, 96))	('platinum', 'Chemical', 'MESH:D010984', (176, 184))	('NSCLC', 'Phenotype', 'HP:0030358', (91, 96))	('capmatinib', 'Chemical', 'MESH:C000613976', (10, 20))	('skipping mutation', 'Var', (121, 138))	('NSCLC', 'Disease', (91, 96))	('MET', 'Gene', '79811', (109, 112))	('patients', 'Species', '9606', (66, 74))
219299	33621951	Human lung cancer cell lines, H1975 (with activating EGFR L858R+T790M mutations) and HCC827 (E746 - A750 deletion), normal human lung fibroblasts (HLF, PCS-201-013) were obtained from the ATCC (American Type Culture Collection, USA) and maintained according to the conditions suggested by ATCC.	('lung cancer', 'Disease', 'MESH:D008175', (6, 17))	('Human', 'Species', '9606', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('L858R+T790M mutations', 'Var', (58, 79))	('human', 'Species', '9606', (123, 128))	('activating', 'PosReg', (42, 52))	('HLF', 'Gene', '3131', (147, 150))	('lung cancer', 'Disease', (6, 17))	('T790M', 'Mutation', 'rs121434569', (64, 69))	('L858R', 'Mutation', 'rs121434568', (58, 63))	('HCC827', 'CellLine', 'CVCL:2063', (85, 91))	('lung cancer', 'Phenotype', 'HP:0100526', (6, 17))	('EGFR', 'Gene', '1956', (53, 57))	('E746', 'Var', (93, 97))	('EGFR', 'Gene', (53, 57))	('H1975', 'CellLine', 'CVCL:1511', (30, 35))	('HLF', 'Gene', (147, 150))
219314	33621951	p-MET (1:500, CST), p-EGFR (1:500, CST) Vimentin (1:600, CST), Snail (1:1000, abcam), beta-catenin (1:1000, CST), MMP9 (1:1000, CST), E-cadherin (1:1000, CTS) and beta-actin (1:10000, 60008-1-Ig) in Supplementary Table 1.	('CST', 'Gene', '106478911', (128, 131))	('CST', 'Gene', (35, 38))	('Vimentin', 'Gene', (40, 48))	('Snail', 'Gene', '6615', (63, 68))	('CST', 'Gene', '106478911', (57, 60))	('1:10000', 'Var', (175, 182))	('MET', 'Gene', '79811', (2, 5))	('CST', 'Gene', (128, 131))	('EGFR', 'Gene', '1956', (22, 26))	('CST', 'Gene', '106478911', (14, 17))	('CST', 'Gene', '106478911', (108, 111))	('CST', 'Gene', (57, 60))	('beta-catenin', 'Gene', (86, 98))	('Snail', 'Gene', (63, 68))	('beta-catenin', 'Gene', '1499', (86, 98))	('CST', 'Gene', '106478911', (35, 38))	('E-cadherin', 'Gene', (134, 144))	('CST', 'Gene', (14, 17))	('E-cadherin', 'Gene', '999', (134, 144))	('MMP9', 'Gene', '4318', (114, 118))	('CST', 'Gene', (108, 111))	('MMP9', 'Gene', (114, 118))	('MET', 'Gene', (2, 5))	('Vimentin', 'Gene', '7431', (40, 48))	('EGFR', 'Gene', (22, 26))
219339	33414372	Three tumor-associated genes, zinc finger and BTB domain-containing 16 (ZBTB16), peroxisome proliferator activated receptor gamma (PPARG), and transforming growth factor beta receptor 2 (TGFBR2), were downregulated with copy number variation (CNV) loss.	('PPARG', 'Gene', '5468', (131, 136))	('peroxisome proliferator activated receptor gamma', 'Gene', '5468', (81, 129))	('ZBTB16', 'Gene', '7704', (72, 78))	('TGFBR2', 'Gene', '7048', (187, 193))	('PPARG', 'Gene', (131, 136))	('TGFBR2', 'Gene', (187, 193))	('peroxisome proliferator activated receptor gamma', 'Gene', (81, 129))	('ZBTB16', 'Gene', (72, 78))	('transforming growth factor beta receptor 2', 'Gene', (143, 185))	('copy number variation', 'Var', (220, 241))	('downregulated', 'NegReg', (201, 214))	('tumor', 'Disease', 'MESH:D009369', (6, 11))	('zinc finger and BTB domain-containing 16', 'Gene', '7704', (30, 70))	('transforming growth factor beta receptor 2', 'Gene', '7048', (143, 185))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('tumor', 'Disease', (6, 11))	('loss', 'NegReg', (248, 252))
219348	33414372	With the rise of immunotherapies, monoclonal antibodies against programmed cell death ligand 1 (PD-L1) have attracted researchers' attention in pLELC treatment.	('PD-L1', 'Gene', (96, 101))	('PD-L1', 'Gene', '29126', (96, 101))	('monoclonal antibodies', 'Var', (34, 55))
219356	33414372	To evaluate factors influencing survival in pLELC, PD-L1 expression was detected by immunohistochemical (IHC) analysis of surgically resected paraffin-embedded samples, as well as TP53 mutation, which has been implicated in the regulation of PD-L1 in oncogenesis.	('PD-L1', 'Gene', (242, 247))	('paraffin', 'Chemical', 'MESH:D010232', (142, 150))	('PD-L1', 'Gene', '29126', (51, 56))	('TP53', 'Gene', '7157', (180, 184))	('PD-L1', 'Gene', '29126', (242, 247))	('mutation', 'Var', (185, 193))	('TP53', 'Gene', (180, 184))	('PD-L1', 'Gene', (51, 56))
219359	33414372	Three tumor-associated genes were identified, which were clearly downregulated with simultaneous copy number variation (CNV) loss.	('loss', 'NegReg', (125, 129))	('downregulated', 'NegReg', (65, 78))	('tumor', 'Disease', 'MESH:D009369', (6, 11))	('copy number variation', 'Var', (97, 118))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('tumor', 'Disease', (6, 11))
219370	33414372	Among the 128 pLELC patients, 47 patients who underwent radical surgery were enrolled for expression detection and prognostic significance analyses of nuclear p53 and membranous/cytoplasmic PD-L1.	('PD-L1', 'Gene', (190, 195))	('patients', 'Species', '9606', (33, 41))	('p53', 'Gene', '7157', (159, 162))	('p53', 'Gene', (159, 162))	('PD-L1', 'Gene', '29126', (190, 195))	('nuclear', 'Var', (151, 158))	('patients', 'Species', '9606', (20, 28))
219376	33414372	Moreover, mutation-type p53 expression was observed in more than half of the cohort (26/47), and this group showed shorter DFS than the group with normal p53 expression (median DFS 20.0 months vs. 45.1 months; Fig.	('p53', 'Gene', (24, 27))	('p53', 'Gene', '7157', (24, 27))	('DFS', 'MPA', (123, 126))	('expression', 'MPA', (28, 38))	('shorter', 'NegReg', (115, 122))	('mutation-type', 'Var', (10, 23))	('p53', 'Gene', (154, 157))	('p53', 'Gene', '7157', (154, 157))
219377	33414372	As abnormal expression of p53 is a strong predictor of an underlying TP53 mutation, the results indicated that TP53 mutation status is correlated with the prognosis of pLELC.	('mutation', 'Var', (74, 82))	('correlated', 'Reg', (135, 145))	('TP53', 'Gene', '7157', (111, 115))	('TP53', 'Gene', (69, 73))	('mutation', 'Var', (116, 124))	('TP53', 'Gene', '7157', (69, 73))	('pLELC', 'Disease', (168, 173))	('p53', 'Gene', (26, 29))	('TP53', 'Gene', (111, 115))	('p53', 'Gene', '7157', (26, 29))
219378	33414372	Taken together, the prognosis data above suggest that pLELC might be a particular type of NSCLC, which is usually at an advanced stage at the time of diagnosis but has a favorable prognosis, especially with high expression of PD-L1 and wild-type p53.	('pLELC', 'Disease', (54, 59))	('NSCLC', 'Disease', (90, 95))	('p53', 'Gene', (246, 249))	('p53', 'Gene', '7157', (246, 249))	('PD-L1', 'Gene', (226, 231))	('NSCLC', 'Disease', 'MESH:D002289', (90, 95))	('PD-L1', 'Gene', '29126', (226, 231))	('high expression', 'Var', (207, 222))	('NSCLC', 'Phenotype', 'HP:0030358', (90, 95))
219417	33414372	High expression of PD-L1 has been suggested to be a biomarker for survival prediction and optional immunotherapy, while TP53 mutation and membranous PD-L1 expression levels were highly correlated in NSCLC.	('PD-L1', 'Gene', (149, 154))	('PD-L1', 'Gene', (19, 24))	('expression', 'MPA', (5, 15))	('NSCLC', 'Disease', 'MESH:D002289', (199, 204))	('PD-L1', 'Gene', '29126', (149, 154))	('PD-L1', 'Gene', '29126', (19, 24))	('expression', 'MPA', (155, 165))	('NSCLC', 'Phenotype', 'HP:0030358', (199, 204))	('TP53', 'Gene', (120, 124))	('correlated', 'Reg', (185, 195))	('TP53', 'Gene', '7157', (120, 124))	('mutation', 'Var', (125, 133))	('NSCLC', 'Disease', (199, 204))
219418	33414372	Here we explored the prognostic significance of PD-L1 expression and TP53 mutation status in pLELC and found that pLELC patients with high PD-L1 expression tend to have longer DFS, which is consistent with previous studies.	('PD-L1', 'Gene', (139, 144))	('PD-L1', 'Gene', '29126', (48, 53))	('TP53', 'Gene', '7157', (69, 73))	('TP53', 'Gene', (69, 73))	('high', 'Var', (134, 138))	('PD-L1', 'Gene', '29126', (139, 144))	('expression', 'MPA', (145, 155))	('patients', 'Species', '9606', (120, 128))	('PD-L1', 'Gene', (48, 53))	('DFS', 'MPA', (176, 179))	('longer', 'PosReg', (169, 175))
219425	33414372	demonstrated that mutations of chromosomal-modifying genes and the ERBB-PIK3CA signaling pathway were important in NPC, directly affecting epigenetic modification and promoting invasion.	('invasion', 'CPA', (177, 185))	('ERBB', 'Gene', (67, 71))	('NPC', 'Phenotype', 'HP:0100630', (115, 118))	('epigenetic modification', 'MPA', (139, 162))	('PIK3CA', 'Gene', (72, 78))	('affecting', 'Reg', (129, 138))	('ERBB', 'Gene', '1956', (67, 71))	('NPC', 'Disease', (115, 118))	('promoting', 'PosReg', (167, 176))	('PIK3CA', 'Gene', '5290', (72, 78))	('mutations', 'Var', (18, 27))
219430	33414372	Downregulation of ZBTB16 was observed in pancreatic cancer and prostate cancer, and the high expression of ZBTB16 was associated with long-term survival in cancer patients.	('ZBTB16', 'Gene', '7704', (107, 113))	('high', 'Var', (88, 92))	('Downregulation', 'NegReg', (0, 14))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (41, 58))	('ZBTB16', 'Gene', (18, 24))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('cancer', 'Disease', (72, 78))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('pancreatic cancer', 'Disease', 'MESH:D010190', (41, 58))	('patients', 'Species', '9606', (163, 171))	('ZBTB16', 'Gene', '7704', (18, 24))	('prostate cancer', 'Disease', 'MESH:D011471', (63, 78))	('prostate cancer', 'Phenotype', 'HP:0012125', (63, 78))	('ZBTB16', 'Gene', (107, 113))	('prostate cancer', 'Disease', (63, 78))	('associated with', 'Reg', (118, 133))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('pancreatic cancer', 'Disease', (41, 58))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('cancer', 'Disease', (156, 162))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))
219438	33414372	High expression of PPARG impairs CD8+ T cell infiltration in bladder cancer and confers resistance to immunotherapies, while knockdown/inhibition of PPARG increases cytokine expression and revives immunosurveillance.	('cytokine expression', 'MPA', (165, 184))	('revives', 'PosReg', (189, 196))	('CD8', 'Gene', (33, 36))	('PPARG', 'Gene', '5468', (149, 154))	('CD8', 'Gene', '925', (33, 36))	('knockdown/inhibition', 'Var', (125, 145))	('PPARG', 'Gene', '5468', (19, 24))	('increases', 'PosReg', (155, 164))	('resistance to immunotherapies', 'CPA', (88, 117))	('bladder cancer', 'Disease', 'MESH:D001749', (61, 75))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('PPARG', 'Gene', (149, 154))	('PPARG', 'Gene', (19, 24))	('bladder cancer', 'Disease', (61, 75))	('impairs', 'NegReg', (25, 32))	('bladder cancer', 'Phenotype', 'HP:0009725', (61, 75))	('immunosurveillance', 'CPA', (197, 215))
219439	33414372	Therefore, we speculated that the loss of PPARG in pLELC might improve immunosurveillance, leading to a good prognosis in pLELC cases.	('loss', 'Var', (34, 38))	('immunosurveillance', 'CPA', (71, 89))	('pLELC', 'Disease', (122, 127))	('improve', 'PosReg', (63, 70))	('PPARG', 'Gene', '5468', (42, 47))	('PPARG', 'Gene', (42, 47))
219445	33414372	Taken together, the loss of ZBTB16 can be hypothesized to improve pLELC tumorigenesis, while reductions in PPARG and TGFBR2 may promote antitumor immunity, leading to a favorable prognosis.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('pLELC tumor', 'Disease', (66, 77))	('loss', 'Var', (20, 24))	('pLELC tumor', 'Disease', 'MESH:D009369', (66, 77))	('reductions', 'NegReg', (93, 103))	('TGFBR2', 'Gene', (117, 123))	('tumor', 'Disease', (72, 77))	('improve', 'PosReg', (58, 65))	('ZBTB16', 'Gene', (28, 34))	('ZBTB16', 'Gene', '7704', (28, 34))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('TGFBR2', 'Gene', '7048', (117, 123))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('promote', 'PosReg', (128, 135))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('PPARG', 'Gene', '5468', (107, 112))	('PPARG', 'Gene', (107, 112))	('tumor', 'Disease', (140, 145))
219470	33414372	Combined with report indicating that PD-L1 was correlated with p53 in NSCLC and oral squamous cell carcinoma, EBV insertion can be assumed to promote the expression of BART5-3P, consequently inhibiting p53 and PD-L1.	('PD-L1', 'Gene', (210, 215))	('PD-L1', 'Gene', '29126', (210, 215))	('EBV', 'Species', '10376', (110, 113))	('NSCLC', 'Disease', 'MESH:D002289', (70, 75))	('BART', 'Gene', '23568', (168, 172))	('p53', 'Gene', '7157', (63, 66))	('BART', 'Gene', (168, 172))	('NSCLC', 'Disease', (70, 75))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (85, 108))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (80, 108))	('promote', 'PosReg', (142, 149))	('NSCLC', 'Phenotype', 'HP:0030358', (70, 75))	('oral squamous cell carcinoma', 'Disease', (80, 108))	('PD-L1', 'Gene', (37, 42))	('p53', 'Gene', (63, 66))	('PD-L1', 'Gene', '29126', (37, 42))	('EBV', 'Gene', (110, 113))	('p53', 'Gene', '7157', (202, 205))	('inhibiting', 'NegReg', (191, 201))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('p53', 'Gene', (202, 205))	('insertion', 'Var', (114, 123))	('expression', 'MPA', (154, 164))
219512	29371589	What is the role of driving mutations in targeting therapy for lung adenocarcinoma?	('lung adenocarcinoma', 'Disease', (63, 82))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (63, 82))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (63, 82))	('mutations', 'Var', (28, 37))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
219513	29371589	What should be done to improve the outcome of patients with tumors harboring specific alterations?	('patients', 'Species', '9606', (46, 54))	('alterations', 'Var', (86, 97))	('tumors', 'Disease', 'MESH:D009369', (60, 66))	('tumors', 'Disease', (60, 66))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('rat', 'Species', '10116', (90, 93))
219528	29371589	The discovery of mutated oncogenes, which encode activated signaling molecules that drive cellular proliferation and promote tumor growth, has now led to the development of more effective and less toxic targeted drugs for LC patients.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('patients', 'Species', '9606', (225, 233))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('oncogenes', 'Gene', (25, 34))	('tumor', 'Disease', (125, 130))	('LC', 'Phenotype', 'HP:0100526', (222, 224))	('rat', 'Species', '10116', (106, 109))	('promote', 'PosReg', (117, 124))	('cellular proliferation', 'CPA', (90, 112))	('mutated', 'Var', (17, 24))	('drive', 'PosReg', (84, 89))
219529	29371589	Gene mutations and focal amplification are genetic changes that modulate the sensitivity of tumors to the induction of cell death, and, therefore, differences in treatment sensitivity may depend on the susceptibility of LC cells, in general, and lung ADC cells, in particular, to undergo cell death.	('tumors', 'Disease', 'MESH:D009369', (92, 98))	('depend', 'Reg', (188, 194))	('cell death', 'CPA', (288, 298))	('LC', 'Phenotype', 'HP:0100526', (220, 222))	('mutations', 'Var', (5, 14))	('modulate', 'Reg', (64, 72))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('tumors', 'Disease', (92, 98))
219531	29371589	These mutations represent molecular alterations essential for tumor initiation and growth.	('tumor initiation', 'Disease', 'MESH:D009369', (62, 78))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('rat', 'Species', '10116', (40, 43))	('tumor initiation', 'Disease', (62, 78))	('mutations', 'Var', (6, 15))
219533	29371589	Thus, tumors might rely on the expression of these single-mutant oncogenes to promote tumor growth and survival, also known as the concept of oncogene addiction.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('promote', 'PosReg', (78, 85))	('tumor', 'Disease', (86, 91))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('tumors', 'Disease', (6, 12))	('tumor', 'Disease', 'MESH:D009369', (6, 11))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('survival', 'CPA', (103, 111))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('single-mutant', 'Var', (51, 64))	('tumor', 'Disease', (6, 11))
219534	29371589	As tumor cells depend on the aberrant activity of a specific mutated gene or pathway for survival and proliferation, their inactivation is generally sufficient to induce growth arrest and/or cell death.	('inactivation', 'Var', (123, 135))	('cell death', 'CPA', (191, 201))	('tumor', 'Disease', (3, 8))	('growth arrest', 'Phenotype', 'HP:0001510', (170, 183))	('pathway', 'Pathway', (77, 84))	('growth arrest', 'CPA', (170, 183))	('induce', 'Reg', (163, 169))	('rat', 'Species', '10116', (109, 112))	('mutated', 'Var', (61, 68))	('aberrant', 'Var', (29, 37))	('tumor', 'Disease', 'MESH:D009369', (3, 8))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))
219536	29371589	According to this hypothesis, the apoptotic response observed in tumors in the case of acute disruption of an oncogene product results from differential decay of several pro-survival and pro-apoptotic signals emanating from the oncoproteins.	('oncogene', 'Gene', (110, 118))	('apoptotic response', 'CPA', (34, 52))	('tumors', 'Disease', (65, 71))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('disruption', 'Var', (93, 103))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('decay', 'NegReg', (153, 158))
219537	29371589	The disturbance in the balance between pro-apoptotic and pro-survival signals could trigger oncogenic shock, which eventually might drive tumor cell death.	('oncogenic shock', 'Disease', (92, 107))	('trigger', 'Reg', (84, 91))	('tumor', 'Disease', (138, 143))	('balance', 'MPA', (23, 30))	('disturbance', 'Var', (4, 15))	('shock', 'Phenotype', 'HP:0031273', (102, 107))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
219538	29371589	The first actionable mutation detected in lung ADC was mutation in epidermal growth factor receptor (EGFR), a transmembrane receptor tyrosine kinase (RTK) that represents either somatic mutation deletion in exon 19 or L858R point mutation (Fig.	('epidermal growth factor receptor', 'Gene', '1956', (67, 99))	('RTK', 'Gene', '5979', (150, 153))	('L858R', 'Mutation', 'rs121434568', (218, 223))	('EGFR', 'Gene', '1956', (101, 105))	('tyrosine kinase', 'Gene', (133, 148))	('EGFR', 'Gene', (101, 105))	('deletion', 'Var', (195, 203))	('epidermal growth factor receptor', 'Gene', (67, 99))	('RTK', 'Gene', (150, 153))	('mutation', 'Var', (55, 63))	('tyrosine kinase', 'Gene', '7294', (133, 148))	('L858R', 'Var', (218, 223))
219539	29371589	EGFR mutations near the ATP cleft of the tyrosine kinase (TK) domain result in increased receptor activation and act as oncogenic drivers.	('increased', 'PosReg', (79, 88))	('EGFR', 'Gene', (0, 4))	('tyrosine kinase', 'Gene', '7294', (41, 56))	('activation', 'PosReg', (98, 108))	('receptor', 'MPA', (89, 97))	('mutations', 'Var', (5, 14))	('ATP', 'Chemical', 'MESH:D000255', (24, 27))	('TK', 'Gene', '7294', (58, 60))	('tyrosine kinase', 'Gene', (41, 56))	('EGFR', 'Gene', '1956', (0, 4))
219544	29371589	Several types of activating mutations are known to occur in EGFR in NSCLC: Class I exon 19 in-frame deletions (44% of all EGFR mutations), Class II single amino acid changes (L858R 41%, G719 4%, other missense mutations 6%), and Class III exon 20 in-frame duplication/insertions (5%).	('L858R', 'Var', (175, 180))	('NSCLC', 'Disease', 'MESH:D002289', (68, 73))	('SCLC', 'Phenotype', 'HP:0030357', (69, 73))	('in-frame', 'Reg', (247, 255))	('activating', 'PosReg', (17, 27))	('L858R', 'Mutation', 'rs121434568', (175, 180))	('LC', 'Phenotype', 'HP:0100526', (71, 73))	('NSCLC', 'Phenotype', 'HP:0030358', (68, 73))	('EGFR', 'Gene', '1956', (60, 64))	('mutations', 'Var', (127, 136))	('EGFR', 'Gene', '1956', (122, 126))	('EGFR', 'Gene', (60, 64))	('EGFR', 'Gene', (122, 126))	('G719', 'Var', (186, 190))	('NSCLC', 'Disease', (68, 73))
219545	29371589	All these mutations occur in the TK domain of EGFR.	('occur', 'Reg', (20, 25))	('EGFR', 'Gene', '1956', (46, 50))	('EGFR', 'Gene', (46, 50))	('mutations', 'Var', (10, 19))	('TK', 'Gene', '7294', (33, 35))
219546	29371589	In 85% of all EGFR-activating mutations are exon 19 in-frame deletions or L858R, and they tend to be sensitive to currently approved EGFR inhibitors.	('L858R', 'Mutation', 'rs121434568', (74, 79))	('EGFR', 'Gene', '1956', (14, 18))	('EGFR', 'Gene', (14, 18))	('EGFR', 'Gene', '1956', (133, 137))	('L858R', 'Var', (74, 79))	('mutations', 'Var', (30, 39))	('EGFR', 'Gene', (133, 137))
219547	29371589	Class III mutations are generally insensitive to EGFR inhibitors with the exception of A763_Y764insFQEA.	('EGFR', 'Gene', '1956', (49, 53))	('EGFR', 'Gene', (49, 53))	('A763_Y764insFQEA', 'Var', (87, 103))	('Y764insFQEA', 'Mutation', 'c.764insY,FQEA', (92, 103))
219550	29371589	EML4-ALK fusions are found in around 3-13% of lung ADC patients, and are largely mutually exclusive with alterations in other RTKs or KRAS based on analysis of almost 1700 tumors.	('KRAS', 'Gene', '3845', (134, 138))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('ALK', 'Gene', (5, 8))	('tumors', 'Disease', (172, 178))	('fusions', 'Var', (9, 16))	('EML4', 'Gene', (0, 4))	('RTK', 'Gene', '5979', (126, 129))	('tumors', 'Disease', 'MESH:D009369', (172, 178))	('tumors', 'Phenotype', 'HP:0002664', (172, 178))	('ALK', 'Gene', '238', (5, 8))	('rat', 'Species', '10116', (109, 112))	('EML4', 'Gene', '27436', (0, 4))	('KRAS', 'Gene', (134, 138))	('lung ADC', 'Disease', (46, 54))	('patients', 'Species', '9606', (55, 63))	('RTK', 'Gene', (126, 129))
219552	29371589	Almost 97% of KRAS mutations in lung ADCs result in amino-acid substitution at codon 12 and 13.	('KRAS', 'Gene', '3845', (14, 18))	('amino-acid', 'MPA', (52, 62))	('mutations', 'Var', (19, 28))	('KRAS', 'Gene', (14, 18))	('result in', 'Reg', (42, 51))
219553	29371589	The mutated KRAS proteins exhibit impaired GTPase activity, resulting in constitutive activation of RAS signaling.	('mutated', 'Var', (4, 11))	('activation', 'PosReg', (86, 96))	('GTPase', 'Protein', (43, 49))	('constitutive', 'MPA', (73, 85))	('KRAS', 'Gene', (12, 16))	('activity', 'MPA', (50, 58))	('KRAS', 'Gene', '3845', (12, 16))	('RAS', 'Pathway', (100, 103))	('impaired', 'NegReg', (34, 42))	('proteins', 'Protein', (17, 25))
219555	29371589	The role of KRAS mutational status as a marker of response to standard chemotherapy alone in NSCLC is poorly understood, but it has been clearly demonstrated that the occurrence of KRAS mutations is associated with the shortest survival of NSCLC patients treated with platinum-based and anti-EGFR therapies.	('rat', 'Species', '10116', (152, 155))	('patients', 'Species', '9606', (246, 254))	('NSCLC', 'Disease', 'MESH:D002289', (93, 98))	('SCLC', 'Phenotype', 'HP:0030357', (94, 98))	('KRAS', 'Gene', '3845', (12, 16))	('EGFR', 'Gene', '1956', (292, 296))	('NSCLC', 'Disease', (93, 98))	('KRAS', 'Gene', (12, 16))	('NSCLC', 'Phenotype', 'HP:0030358', (93, 98))	('LC', 'Phenotype', 'HP:0100526', (243, 245))	('NSCLC', 'Disease', 'MESH:D002289', (240, 245))	('SCLC', 'Phenotype', 'HP:0030357', (241, 245))	('shortest survival', 'NegReg', (219, 236))	('KRAS', 'Gene', '3845', (181, 185))	('platinum', 'Chemical', 'MESH:D010984', (268, 276))	('NSCLC', 'Disease', (240, 245))	('LC', 'Phenotype', 'HP:0100526', (96, 98))	('mutations', 'Var', (186, 195))	('EGFR', 'Gene', (292, 296))	('NSCLC', 'Phenotype', 'HP:0030358', (240, 245))	('KRAS', 'Gene', (181, 185))
219558	29371589	Although c-MET is important for the control of tissue homeostasis under normal physiological conditions, it has also been found to be aberrantly activated in human cancers via gene mutation, amplification or protein overexpression.	('activated', 'PosReg', (145, 154))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('human', 'Species', '9606', (158, 163))	('amplification', 'Var', (191, 204))	('c-MET', 'Gene', (9, 14))	('cancers', 'Phenotype', 'HP:0002664', (164, 171))	('cancers', 'Disease', (164, 171))	('cancers', 'Disease', 'MESH:D009369', (164, 171))	('c-MET', 'Gene', '4233', (9, 14))	('overexpression', 'PosReg', (216, 230))	('protein', 'Protein', (208, 215))	('gene mutation', 'Var', (176, 189))
219559	29371589	In addition, several other NSCLC driver mutations/gene translocations are currently under investigation, including ROS1/RET rearrangements, and BRAF/PIK3CA and HER2/MEK mutations, all of which might undergo specific targeted therapy.	('mutations', 'Var', (169, 178))	('HER2', 'Gene', '2064', (160, 164))	('MEK', 'Gene', '5609', (165, 168))	('BRAF', 'Gene', '673', (144, 148))	('BRAF', 'Gene', (144, 148))	('LC', 'Phenotype', 'HP:0100526', (30, 32))	('RET', 'Gene', '5979', (120, 123))	('ROS1', 'Gene', '6098', (115, 119))	('SCLC', 'Phenotype', 'HP:0030357', (28, 32))	('MEK', 'Gene', (165, 168))	('PIK3CA', 'Gene', '5290', (149, 155))	('HER2', 'Gene', (160, 164))	('NSCLC', 'Disease', 'MESH:D002289', (27, 32))	('rearrangements', 'Var', (124, 138))	('RET', 'Gene', (120, 123))	('ROS1', 'Gene', (115, 119))	('NSCLC', 'Disease', (27, 32))	('PIK3CA', 'Gene', (149, 155))	('NSCLC', 'Phenotype', 'HP:0030358', (27, 32))
219560	29371589	The identification of driver mutations in lung ADCs has led to the development of effective personalized treatment strategies (Table 1).	('lung ADCs', 'Gene', (42, 51))	('rat', 'Species', '10116', (117, 120))	('mutations', 'Var', (29, 38))
219563	29371589	The outcome of EGFR targeting is characterized by the disruption of a number of cellular processes that mirror the physiological consequences of EGFR signal transduction at the level of cell division, angiogenesis and apoptosis.	('EGFR', 'Gene', '1956', (145, 149))	('targeting', 'Var', (20, 29))	('EGFR', 'Gene', (145, 149))	('disruption', 'Reg', (54, 64))	('EGFR', 'Gene', (15, 19))	('EGFR', 'Gene', '1956', (15, 19))	('cellular processes', 'MPA', (80, 98))
219564	29371589	Different randomized controlled phase III trials have demonstrated that first or second generations EGFR TKIs represent the best first-line treatment option in patients with advanced lung ADC and whose tumors harbor EGFR mutations, considerably superior to conventional chemotherapy, because they significantly improved the response rate and progression-free survival (Fig.	('EGFR', 'Gene', (216, 220))	('patients', 'Species', '9606', (160, 168))	('mutations', 'Var', (221, 230))	('EGFR', 'Gene', '1956', (100, 104))	('tumors', 'Phenotype', 'HP:0002664', (202, 208))	('improved', 'PosReg', (311, 319))	('response rate', 'CPA', (324, 337))	('TK', 'Gene', '7294', (105, 107))	('EGFR', 'Gene', (100, 104))	('tumors', 'Disease', (202, 208))	('rat', 'Species', '10116', (333, 336))	('tumors', 'Disease', 'MESH:D009369', (202, 208))	('rat', 'Species', '10116', (61, 64))	('rat', 'Species', '10116', (92, 95))	('EGFR', 'Gene', '1956', (216, 220))	('progression-free survival', 'CPA', (342, 367))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))
219565	29371589	As mentioned above, like EGFR mutations, ALK rearrangements define a unique molecular subset of NSCLCs.	('NSCLC', 'Disease', (96, 101))	('EGFR', 'Gene', (25, 29))	('NSCLC', 'Disease', 'MESH:D002289', (96, 101))	('rearrangements', 'Var', (45, 59))	('SCLC', 'Phenotype', 'HP:0030357', (97, 101))	('ALK', 'Gene', (41, 44))	('NSCLC', 'Phenotype', 'HP:0030358', (96, 101))	('EGFR', 'Gene', '1956', (25, 29))	('ALK', 'Gene', '238', (41, 44))	('LC', 'Phenotype', 'HP:0100526', (99, 101))
219571	29371589	The outcome of TK targeting is characterized by the disruption of a number of cellular processes that mirror all levels of the physiological consequences of EGFR signal transduction.	('EGFR', 'Gene', (157, 161))	('disruption', 'Reg', (52, 62))	('cellular processes', 'MPA', (78, 96))	('TK', 'Gene', '7294', (15, 17))	('targeting', 'Var', (18, 27))	('EGFR', 'Gene', '1956', (157, 161))
219579	29371589	Inhibition of EML4-ALK with TAE684, a small-molecule ALK inhibitor, or via knockdown using RNA interference results in the abrogation of downstream signaling and induction of apoptosis through the activation of the pro-apoptotic protein Bim.	('TAE684', 'Var', (28, 34))	('ALK', 'Gene', (19, 22))	('ALK', 'Gene', (53, 56))	('Bim', 'Gene', (237, 240))	('apoptosis', 'CPA', (175, 184))	('induction', 'Reg', (162, 171))	('activation', 'PosReg', (197, 207))	('RNA', 'MPA', (91, 94))	('TAE684', 'Chemical', 'MESH:C516714', (28, 34))	('EML4', 'Gene', (14, 18))	('ALK', 'Gene', '238', (19, 22))	('ALK', 'Gene', '238', (53, 56))	('EML4', 'Gene', '27436', (14, 18))	('Bim', 'Gene', '10018', (237, 240))	('abrogation', 'NegReg', (123, 133))	('downstream signaling', 'MPA', (137, 157))
219581	29371589	The resistant mechanisms identified can be categorized as secondary mutations in EGFR, bypass or alternative activations, or histological transformations.	('mutations', 'Var', (68, 77))	('EGFR', 'Gene', '1956', (81, 85))	('EGFR', 'Gene', (81, 85))
219582	29371589	The gatekeeper Thr790Met mutation is the most frequent secondary EGFR mutation, occurring in 50-65% of resistant re-biopsies.	('EGFR', 'Gene', '1956', (65, 69))	('EGFR', 'Gene', (65, 69))	('Thr790Met', 'Var', (15, 24))	('gatekeeper', 'Species', '111938', (4, 14))	('Thr790Met', 'SUBSTITUTION', 'None', (15, 24))
219583	29371589	In addition, HER2 amplifications and mutations have been observed in lung ADC biopsies in 10 and 2% of tumors with acquired resistance to erlotinib and gefitinib, respectively, but in only 1% of untreated tumors.	('tumors', 'Disease', 'MESH:D009369', (205, 211))	('erlotinib', 'Chemical', 'MESH:D000069347', (138, 147))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('acquired resistance', 'MPA', (115, 134))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('lung ADC', 'Disease', (69, 77))	('observed', 'Reg', (57, 65))	('gefitinib', 'Chemical', 'MESH:D000077156', (152, 161))	('tumors', 'Disease', (103, 109))	('tumors', 'Disease', 'MESH:D009369', (103, 109))	('mutations', 'Var', (37, 46))	('HER2', 'Gene', (13, 17))	('amplifications', 'Var', (18, 32))	('tumors', 'Phenotype', 'HP:0002664', (205, 211))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('HER2', 'Gene', '2064', (13, 17))	('tumors', 'Disease', (205, 211))
219585	29371589	The development of third-generation irreversible inhibitor (AZD9291, osimertinib), which targets both Thr790Met and EGFR TKI-sensitizing mutations, has shown an objective response rate of 61% and a median progression-free survival of almost 10 months in patients with Thr790 Met-positive NSCLCs who progressed after previous TKI therapy (Fig.	('Thr790 Met-positive', 'Var', (268, 287))	('NSCLC', 'Disease', 'MESH:D002289', (288, 293))	('Thr790Met', 'SUBSTITUTION', 'None', (102, 111))	('rat', 'Species', '10116', (180, 183))	('Thr790 Met', 'Mutation', 'rs121434569', (268, 278))	('SCLC', 'Phenotype', 'HP:0030357', (289, 293))	('TK', 'Gene', '7294', (325, 327))	('NSCLC', 'Phenotype', 'HP:0030358', (288, 293))	('rat', 'Species', '10116', (29, 32))	('Thr790Met', 'Var', (102, 111))	('osimertinib', 'Chemical', 'MESH:C000603933', (69, 80))	('TK', 'Gene', '7294', (121, 123))	('LC', 'Phenotype', 'HP:0100526', (291, 293))	('EGFR', 'Gene', '1956', (116, 120))	('patients', 'Species', '9606', (254, 262))	('EGFR', 'Gene', (116, 120))	('AZD9291', 'Chemical', 'MESH:C000596361', (60, 67))	('NSCLC', 'Disease', (288, 293))
219588	29371589	Moreover, the occurrence of de novo secondary ALK mutations results in variants that are intrinsically less sensitive to the drug.	('mutations', 'Var', (50, 59))	('results in', 'Reg', (60, 70))	('ALK', 'Gene', '238', (46, 49))	('variants', 'MPA', (71, 79))	('ALK', 'Gene', (46, 49))
219589	29371589	Analysis of pleural fluid from these patients revealed two non-overlapping mutations, L1196M and C1156Y, within the ALK kinase domain.	('pleural fluid', 'Phenotype', 'HP:0002202', (12, 25))	('C1156Y', 'Var', (97, 103))	('patients', 'Species', '9606', (37, 45))	('L1196M', 'Mutation', 'rs1057519784', (86, 92))	('ALK', 'Gene', (116, 119))	('pleural', 'Disease', 'MESH:D010995', (12, 19))	('C1156Y', 'Mutation', 'rs1057519859', (97, 103))	('L1196M', 'Var', (86, 92))	('pleural', 'Disease', (12, 19))	('ALK', 'Gene', '238', (116, 119))
219591	29371589	The L1196M substitution is notable because it involves the ALK gatekeeper residue, analogous to T790M in EGFR.	('ALK', 'Gene', '238', (59, 62))	('involves', 'Reg', (46, 54))	('EGFR', 'Gene', '1956', (105, 109))	('L1196M', 'Mutation', 'rs1057519784', (4, 10))	('ALK', 'Gene', (59, 62))	('L1196M', 'Var', (4, 10))	('EGFR', 'Gene', (105, 109))	('T790M', 'Mutation', 'rs121434569', (96, 101))	('gatekeeper', 'Species', '111938', (63, 73))
219592	29371589	The L1196M mutation, which replaces a leucine moiety with a bulkier methionine residue, likely causes resistance by steric interference with crizotinib binding.	('causes', 'Reg', (95, 101))	('crizotinib', 'Protein', (141, 151))	('L1196M', 'Mutation', 'rs1057519784', (4, 10))	('leucine', 'Chemical', 'MESH:D007930', (38, 45))	('binding', 'Interaction', (152, 159))	('methionine', 'Chemical', 'MESH:D008715', (68, 78))	('resistance', 'MPA', (102, 112))	('L1196M', 'Var', (4, 10))	('crizotinib', 'Chemical', 'MESH:D000077547', (141, 151))
219593	29371589	Since the initial case report of crizotinib resistance, additional second-site ALK mutations have been identified in patient-derived NSCLC specimens.	('mutations', 'Var', (83, 92))	('crizotinib', 'Chemical', 'MESH:D000077547', (33, 43))	('ALK', 'Gene', '238', (79, 82))	('NSCLC', 'Phenotype', 'HP:0030358', (133, 138))	('NSCLC', 'Disease', (133, 138))	('ALK', 'Gene', (79, 82))	('patient', 'Species', '9606', (117, 124))	('LC', 'Phenotype', 'HP:0100526', (136, 138))	('NSCLC', 'Disease', 'MESH:D002289', (133, 138))	('SCLC', 'Phenotype', 'HP:0030357', (134, 138))
219598	29371589	These include increased activity of additional kinases owing to MET, HER2 or ERK amplification, as well as an additional mutation of PIK3CA (which encodes the PI3K p110alpha subunit).	('increased', 'PosReg', (14, 23))	('activity', 'MPA', (24, 32))	('MET', 'Var', (64, 67))	('PIK3CA', 'Gene', (133, 139))	('ERK', 'Gene', '5594', (77, 80))	('PIK3CA', 'Gene', '5290', (133, 139))	('ERK', 'Gene', (77, 80))	('amplification', 'Var', (81, 94))	('mutation', 'Var', (121, 129))	('kinases', 'Enzyme', (47, 54))	('HER2', 'Gene', (69, 73))	('HER2', 'Gene', '2064', (69, 73))
219599	29371589	Enhanced NF-kappaB signaling activity has also been proposed as one possible resistance mechanism that is evident from an improved response and survival in patients with EGFR mutations who have an increased expression of the NF-kappaB inhibitor IkappaBalpha (also known as NFKBIA).	('patients', 'Species', '9606', (156, 164))	('NF-kappaB signaling activity', 'MPA', (9, 37))	('EGFR', 'Gene', '1956', (170, 174))	('improved', 'PosReg', (122, 130))	('NFKBIA', 'Gene', (273, 279))	('increased', 'PosReg', (197, 206))	('EGFR', 'Gene', (170, 174))	('mutations', 'Var', (175, 184))	('NFKBIA', 'Gene', '4792', (273, 279))	('expression', 'MPA', (207, 217))	('Enhanced', 'PosReg', (0, 8))
219603	29371589	Thus, the inhibition of EGFR in mtEGFR cells may initiate the apoptotic program via Bim/Mcl-1 alteration.	('EGFR', 'Gene', '1956', (24, 28))	('Bim', 'Gene', (84, 87))	('Bim', 'Gene', '10018', (84, 87))	('Mcl-1', 'Gene', (88, 93))	('EGFR', 'Gene', (34, 38))	('EGFR', 'Gene', (24, 28))	('apoptotic program', 'CPA', (62, 79))	('rat', 'Species', '10116', (98, 101))	('Mcl-1', 'Gene', '4170', (88, 93))	('inhibition', 'Var', (10, 20))	('EGFR', 'Gene', '1956', (34, 38))	('initiate', 'Reg', (49, 57))
219604	29371589	Moreover, the Bim polymorphism that results in changes in the splicing and deletion of the pro-apoptotic Bcl-2-homology domain (BH3) has been shown potentially to mediate intrinsic resistance to EGFR inhibitors, highlighting the complexity of possible resistance mechanisms (Fig.	('polymorphism', 'Var', (18, 30))	('EGFR', 'Gene', (195, 199))	('changes', 'Reg', (47, 54))	('Bcl-2', 'Gene', (105, 110))	('Bcl-2', 'Gene', '596', (105, 110))	('deletion', 'MPA', (75, 83))	('splicing', 'MPA', (62, 70))	('Bim', 'Gene', (14, 17))	('mediate', 'Reg', (163, 170))	('BH3', 'Gene', (128, 131))	('Bim', 'Gene', '10018', (14, 17))	('intrinsic resistance', 'MPA', (171, 191))	('EGFR', 'Gene', '1956', (195, 199))
219607	29371589	In addition, EMT regulated by loss of Mediator Complex Subunit 12 (MED12) has been shown to modulate the response to inhibitors of EGFR, ALK, and BRAF68 through negative regulation of TGF-betaR2 leading to apoptosis.	('BRAF', 'Gene', (146, 150))	('ALK', 'Gene', '238', (137, 140))	('MED12', 'Gene', (67, 72))	('Mediator Complex Subunit 12', 'Gene', (38, 65))	('negative regulation', 'NegReg', (161, 180))	('ALK', 'Gene', (137, 140))	('modulate', 'Reg', (92, 100))	('response to inhibitors', 'MPA', (105, 127))	('EGFR', 'Gene', '1956', (131, 135))	('MED12', 'Gene', '9968', (67, 72))	('EGFR', 'Gene', (131, 135))	('TGF-betaR2', 'Gene', (184, 194))	('Mediator Complex Subunit 12', 'Gene', '9968', (38, 65))	('apoptosis', 'CPA', (206, 215))	('BRAF', 'Gene', '673', (146, 150))	('loss', 'Var', (30, 34))
219608	29371589	As tumors with KRAS mutations do not respond to either gefitinib or erlotinib, it has been suggested that the presence of these mutations be used as a biomarker for predicting resistance of lung ADCs to TKI therapy.	('tumors', 'Phenotype', 'HP:0002664', (3, 9))	('tumors', 'Disease', (3, 9))	('KRAS', 'Gene', (15, 19))	('tumors', 'Disease', 'MESH:D009369', (3, 9))	('gefitinib', 'Chemical', 'MESH:D000077156', (55, 64))	('TK', 'Gene', '7294', (203, 205))	('erlotinib', 'Chemical', 'MESH:D000069347', (68, 77))	('KRAS', 'Gene', '3845', (15, 19))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))	('mutations', 'Var', (20, 29))
219609	29371589	However, as described earlier, mutations in EGFR and KRAS are usually mutually exclusive, which makes KRAS an independent therapeutic target.	('mutations', 'Var', (31, 40))	('KRAS', 'Gene', '3845', (53, 57))	('KRAS', 'Gene', (53, 57))	('EGFR', 'Gene', '1956', (44, 48))	('EGFR', 'Gene', (44, 48))	('KRAS', 'Gene', (102, 106))	('KRAS', 'Gene', '3845', (102, 106))
219610	29371589	Mutations of KRAS are not a chemically druggable target but can potentially be treated with synthetic lethal approaches such as a combination of MEK inhibitors plus PIK3CA or AKT1 inhibitors.	('AKT1', 'Gene', '207', (175, 179))	('AKT1', 'Gene', (175, 179))	('PIK3CA', 'Gene', (165, 171))	('MEK', 'Gene', (145, 148))	('MEK', 'Gene', '5609', (145, 148))	('Mutations', 'Var', (0, 9))	('PIK3CA', 'Gene', '5290', (165, 171))	('KRAS', 'Gene', (13, 17))	('KRAS', 'Gene', '3845', (13, 17))
219612	29371589	The suggestion to use MEK inhibitors in clinics was based on their ability to enhance apoptosis in KRAS and mutated NSCLC.	('NSCLC', 'Disease', 'MESH:D002289', (116, 121))	('LC', 'Phenotype', 'HP:0100526', (119, 121))	('enhance', 'PosReg', (78, 85))	('mutated', 'Var', (108, 115))	('SCLC', 'Phenotype', 'HP:0030357', (117, 121))	('NSCLC', 'Phenotype', 'HP:0030358', (116, 121))	('MEK', 'Gene', '5609', (22, 25))	('KRAS', 'Gene', (99, 103))	('NSCLC', 'Disease', (116, 121))	('MEK', 'Gene', (22, 25))	('KRAS', 'Gene', '3845', (99, 103))	('apoptosis', 'CPA', (86, 95))
219614	29371589	A possible explanation, which has formed the basis of combined approaches, is an activation of compensatory signaling pathway(s) triggered by the inhibition of MEK, thus providing escape routes for the cancer cells that ensure their survival.	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('activation', 'PosReg', (81, 91))	('compensatory signaling pathway', 'Pathway', (95, 125))	('cancer', 'Disease', 'MESH:D009369', (202, 208))	('cancer', 'Disease', (202, 208))	('MEK', 'Gene', (160, 163))	('MEK', 'Gene', '5609', (160, 163))	('inhibition', 'Var', (146, 156))
219615	29371589	Although targeted drugs dramatically improve the outcome of patients with tumors harboring specific alterations, clinical responses are generally short-lived.	('outcome', 'MPA', (49, 56))	('improve', 'PosReg', (37, 44))	('rat', 'Species', '10116', (104, 107))	('patients', 'Species', '9606', (60, 68))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumors', 'Disease', (74, 80))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('tumors', 'Disease', 'MESH:D009369', (74, 80))	('alterations', 'Var', (100, 111))
219620	29371589	Early concurrent combination studies were designed before the discovery of EGFR mutations and the results of these studies in unselected populations showed that combination treatment did not improved survival compared with chemotherapy alone.	('EGFR', 'Gene', '1956', (75, 79))	('EGFR', 'Gene', (75, 79))	('mutations', 'Var', (80, 89))
219625	29371589	There are multiple mechanisms of resistance via bypass pathways, such as MET or HER2 amplifications, and PIK3CA or BRAF mutations.	('PIK3CA', 'Gene', (105, 111))	('amplifications', 'Var', (85, 99))	('BRAF', 'Gene', '673', (115, 119))	('HER2', 'Gene', '2064', (80, 84))	('HER2', 'Gene', (80, 84))	('BRAF', 'Gene', (115, 119))	('MET', 'Var', (73, 76))	('PIK3CA', 'Gene', '5290', (105, 111))	('mutations', 'Var', (120, 129))
219626	29371589	Amplification of MET, the main bypass signaling resistance, has been found in 20% of EGFR-driven resistant tumors, conferring resistance through ERBB3-mediated activation of downstream PI3K/AKT signaling, and effectively bypassing the inhibited EGFR.	('EGFR', 'Gene', (85, 89))	('Amplification', 'Var', (0, 13))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('MET', 'Gene', (17, 20))	('activation', 'PosReg', (160, 170))	('tumors', 'Disease', (107, 113))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('EGFR', 'Gene', '1956', (245, 249))	('resistance', 'MPA', (126, 136))	('ERBB3', 'Gene', '2065', (145, 150))	('tumors', 'Disease', 'MESH:D009369', (107, 113))	('ERBB3', 'Gene', (145, 150))	('EGFR', 'Gene', (245, 249))	('EGFR', 'Gene', '1956', (85, 89))
219631	29371589	Dacomitinib (PF-00299804, Pfizer; New London, CT, USA) is an irreversible pan-HER inhibitor that has shown remarkable activity in tumors with gefitinib-resistant EGFR T790M or HER2 mutations.	('tumors', 'Disease', (130, 136))	('tumors', 'Disease', 'MESH:D009369', (130, 136))	('HER2', 'Gene', (176, 180))	('gefitinib', 'Chemical', 'MESH:D000077156', (142, 151))	('activity', 'MPA', (118, 126))	('HER2', 'Gene', '2064', (176, 180))	('EGFR', 'Gene', '1956', (162, 166))	('T790M', 'Mutation', 'rs121434569', (167, 172))	('T790M', 'Var', (167, 172))	('EGFR', 'Gene', (162, 166))	('PF-00299804', 'Chemical', 'MESH:C525726', (13, 24))	('Dacomitinib', 'Chemical', 'MESH:C525726', (0, 11))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('mutations', 'Var', (181, 190))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))
219632	29371589	Recently, genetic alterations in effectors downstream of EGFR have also been identified as potential mediators of resistance.	('genetic alterations', 'Var', (10, 29))	('resistance', 'Disease', (114, 124))	('rat', 'Species', '10116', (22, 25))	('EGFR', 'Gene', '1956', (57, 61))	('EGFR', 'Gene', (57, 61))
219633	29371589	The ligand-independent activation of RTKs in lung ADC may arise from chromosomal rearrangements related to RTK genes and/or from point mutations or amplification of RTK genes.	('RTK', 'Gene', (107, 110))	('point mutations', 'Var', (129, 144))	('RTK', 'Gene', '5979', (165, 168))	('lung ADC', 'Disease', (45, 53))	('RTK', 'Gene', (37, 40))	('activation', 'PosReg', (23, 33))	('RTK', 'Gene', '5979', (107, 110))	('RTK', 'Gene', (165, 168))	('RTK', 'Gene', '5979', (37, 40))	('amplification', 'Var', (148, 161))
219640	29371589	The disruption of autophagy with chloroquine could accelerate erlotinib-induced apoptosis and overcome resistance of lung ADC cells to treatment with gefitinib or erlotinib.	('erlotinib', 'Chemical', 'MESH:D000069347', (62, 71))	('autophagy', 'CPA', (18, 27))	('erlotinib', 'Chemical', 'MESH:D000069347', (163, 172))	('erlotinib-induced', 'Disease', (62, 79))	('accelerate', 'PosReg', (51, 61))	('rat', 'Species', '10116', (57, 60))	('overcome', 'NegReg', (94, 102))	('disruption', 'Var', (4, 14))	('gefitinib', 'Chemical', 'MESH:D000077156', (150, 159))	('resistance', 'MPA', (103, 113))	('apoptosis', 'CPA', (80, 89))	('chloroquine', 'Chemical', 'MESH:D002738', (33, 44))
219641	29371589	It has been reported that gefitinib causes a strong induction of autophagy in the NSCLC cell line PC-9.	('autophagy', 'CPA', (65, 74))	('NSCLC', 'Phenotype', 'HP:0030358', (82, 87))	('SCLC', 'Phenotype', 'HP:0030357', (83, 87))	('gefitinib', 'Var', (26, 35))	('PC-9', 'CellLine', 'CVCL:B260', (98, 102))	('LC', 'Phenotype', 'HP:0100526', (85, 87))	('NSCLC', 'Disease', (82, 87))	('gefitinib', 'Chemical', 'MESH:D000077156', (26, 35))	('NSCLC', 'Disease', 'MESH:D002289', (82, 87))
219643	29371589	ALK inhibition might also provoke autophagy-dependent resistance.	('autophagy-dependent resistance', 'CPA', (34, 64))	('inhibition', 'Var', (4, 14))	('ALK', 'Gene', (0, 3))	('provoke', 'PosReg', (26, 33))	('ALK', 'Gene', '238', (0, 3))
219649	29371589	Importantly, in this case cell death was inhibited by knockdown of the autophagy gene ATG7.	('ATG7', 'Gene', (86, 90))	('knockdown', 'Var', (54, 63))	('cell death', 'CPA', (26, 36))	('inhibited', 'NegReg', (41, 50))	('ATG7', 'Gene', '10533', (86, 90))
219650	29371589	Similarly, in EGFR TKI-resistant LC cells with T790M mutation, the combination of a protein kinase CK2 inhibitor and an EGFR TKI led to a high level of autophagy that degraded EGFR protein and promoted apoptosis.	('promoted', 'PosReg', (193, 201))	('degraded', 'NegReg', (167, 175))	('T790M mutation', 'Var', (47, 61))	('EGFR', 'Gene', '1956', (14, 18))	('TK', 'Gene', '7294', (19, 21))	('EGFR', 'Gene', (14, 18))	('T790M', 'Mutation', 'rs121434569', (47, 52))	('autophagy', 'CPA', (152, 161))	('EGFR', 'Gene', '1956', (176, 180))	('LC', 'Phenotype', 'HP:0100526', (33, 35))	('EGFR', 'Gene', (176, 180))	('apoptosis', 'CPA', (202, 211))	('EGFR', 'Gene', '1956', (120, 124))	('TK', 'Gene', '7294', (125, 127))	('EGFR', 'Gene', (120, 124))
219658	29371589	Moreover, VEGF-targeted therapies exert their effects through a number of potential mechanisms, including inhibition of new vessel growth, regression of newly formed tumor vasculature, alteration of vascular function and tumor blood flow ("normalization"), and direct effects on tumor cells.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('tumor', 'Phenotype', 'HP:0002664', (279, 284))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('VEGF', 'Gene', (10, 14))	('new vessel growth', 'CPA', (120, 137))	('tumor', 'Disease', (279, 284))	('tumor', 'Disease', (221, 226))	('vascular function', 'CPA', (199, 216))	('tumor', 'Disease', (166, 171))	('regression', 'CPA', (139, 149))	('therapies', 'Var', (24, 33))	('VEGF', 'Gene', '7422', (10, 14))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('inhibition', 'NegReg', (106, 116))	('alteration', 'Reg', (185, 195))	('rat', 'Species', '10116', (189, 192))	('tumor', 'Disease', 'MESH:D009369', (279, 284))	('tumor', 'Disease', 'MESH:D009369', (221, 226))
219680	29371589	Inhibition of VEGFR and PDGFR by sunitinib prevents further growth of new vessels.	('prevents', 'NegReg', (43, 51))	('VEGFR', 'Gene', '3791', (14, 19))	('sunitinib', 'Chemical', 'MESH:D000077210', (33, 42))	('Inhibition', 'Var', (0, 10))	('PDGFR', 'Gene', (24, 29))	('VEGFR', 'Gene', (14, 19))	('PDGFR', 'Gene', '5159', (24, 29))
219731	29371589	A retrospective study that included 125 patients with NSCLC with mutant and wild-type EGFR, KRAS and ALK, all with PD-L1 expression revealed a correlation between PD-L1 expression and EGFR mutation.	('PD-L1', 'Gene', (163, 168))	('ALK', 'Gene', (101, 104))	('SCLC', 'Phenotype', 'HP:0030357', (55, 59))	('EGFR', 'Gene', '1956', (86, 90))	('EGFR', 'Gene', '1956', (184, 188))	('patients', 'Species', '9606', (40, 48))	('mutant', 'Var', (65, 71))	('NSCLC', 'Phenotype', 'HP:0030358', (54, 59))	('KRAS', 'Gene', (92, 96))	('ALK', 'Gene', '238', (101, 104))	('EGFR', 'Gene', (86, 90))	('EGFR', 'Gene', (184, 188))	('mutation', 'Var', (189, 197))	('LC', 'Phenotype', 'HP:0100526', (57, 59))	('expression', 'MPA', (169, 179))	('NSCLC', 'Disease', (54, 59))	('KRAS', 'Gene', '3845', (92, 96))	('NSCLC', 'Disease', 'MESH:D002289', (54, 59))
219736	29371589	As such, VEGF inhibition in combination with a checkpoint inhibitor may have synergistic effects.	('VEGF', 'Gene', (9, 13))	('inhibition', 'Var', (14, 24))	('VEGF', 'Gene', '7422', (9, 13))
219754	29371589	In addition to well-known mechanisms, several novel mechanisms of resistance have recently been discovered, involving new resistance-conferring mutations within the target proteins (such as T790M in EGFR) or activating bypass signal-transduction pathways via unique mutations or changes in the expression level of the key proteins.	('T790M', 'Mutation', 'rs121434569', (190, 195))	('T790M', 'Var', (190, 195))	('EGFR', 'Gene', (199, 203))	('bypass signal-transduction pathways', 'Pathway', (219, 254))	('resistance-conferring', 'Disease', (122, 143))	('changes', 'Reg', (279, 286))	('mutations', 'Var', (266, 275))	('expression level', 'MPA', (294, 310))	('activating', 'PosReg', (208, 218))	('EGFR', 'Gene', '1956', (199, 203))
219781	29274153	Tobacco-specific N-nitrosamines, especially 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and N'-nitrosonornicotine (NNN), have been demonstrated to cause cancer in experimental animals.	('cause', 'Reg', (156, 161))	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('NNN', 'Chemical', 'MESH:C008655', (124, 127))	('cancer', 'Disease', (162, 168))	('NNK', 'Chemical', 'MESH:C016583', (92, 95))	("N'-nitrosonornicotine", 'Var', (101, 122))	('Tobacco', 'Species', '4097', (0, 7))	('N-nitrosamines', 'Chemical', '-', (17, 31))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	("N'-nitrosonornicotine", 'Chemical', 'MESH:C008655', (101, 122))	('4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone', 'Chemical', 'MESH:C016583', (44, 90))
219784	29274153	The resulting DNA adducts may induce deleterious mutations in oncogenes and tumor suppressor genes which could be considered as tumor initiation.	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('mutations', 'Var', (49, 58))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumor', 'Disease', (128, 133))	('oncogenes', 'Gene', (62, 71))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('induce', 'Reg', (30, 36))
219790	29274153	Any defect in these enzymes (ADH and ALDH) may influence the carcinogenesis by alcohol.	('ADH', 'Disease', 'MESH:D007177', (29, 32))	('influence', 'Reg', (47, 56))	('ALDH', 'Gene', (37, 41))	('carcinogenesis', 'Disease', (61, 75))	('ADH', 'Disease', (29, 32))	('alcohol', 'Chemical', 'MESH:D000438', (79, 86))	('defect', 'Var', (4, 10))	('carcinogenesis', 'Disease', 'MESH:D063646', (61, 75))
219859	28730646	The inclusion criteria were as follows: (i) histologically confirmed NSCC; (ii) N0-1 M0; (iii) measurable tumor; (iv) age 16-80 years; and (v) performance status 0-2.	('NSCC', 'Disease', (69, 73))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Disease', (106, 111))	('N0-1 M0', 'Var', (80, 87))
219905	28730646	Radiotherapy resulted in temporary, non-significant MCS impairment at 1 month, but MCS returned to baseline levels at 3 months after treatment.	('impairment', 'NegReg', (56, 66))	('MCS', 'Gene', (52, 55))	('MCS', 'Gene', (83, 86))	('Radiotherapy', 'Var', (0, 12))	('MCS', 'Gene', '4183', (52, 55))	('MCS', 'Gene', '4183', (83, 86))
219996	32268506	So, it was revealed that deregulated Notch signaling and abnormally activated Hedgehog signaling promote self-renewal of CSCs in malignancies with different origins and localization by ruling the expression of known modulators and markers of the stemness, such as Slug, Twist, SOX2, B lymphoma Mo-MLV insertion region 1 homolog (BMI1), and OCT4.	('N', 'Chemical', 'MESH:D009584', (37, 38))	('malignancies', 'Disease', (129, 141))	('Twist', 'Gene', '7291', (270, 275))	('OCT4', 'Gene', '5460', (340, 344))	('promote', 'PosReg', (97, 104))	('BMI1', 'Gene', '648', (329, 333))	('Slug', 'Gene', '6591', (264, 268))	('deregulated', 'Var', (25, 36))	('lymphoma', 'Phenotype', 'HP:0002665', (285, 293))	('abnormally', 'Var', (57, 67))	('OCT4', 'Gene', (340, 344))	('self-renewal', 'CPA', (105, 117))	('B lymphoma Mo-MLV insertion region 1 homolog', 'Gene', '648', (283, 327))	('SOX2', 'Gene', (277, 281))	('SOX2', 'Gene', '6657', (277, 281))	('Twist', 'Gene', (270, 275))	('B lymphoma Mo-MLV insertion region 1 homolog', 'Gene', (283, 327))	('B lymphoma', 'Phenotype', 'HP:0012191', (283, 293))	('expression', 'MPA', (196, 206))	('BMI1', 'Gene', (329, 333))	('Slug', 'Gene', (264, 268))	('malignancies', 'Disease', 'MESH:D009369', (129, 141))
220010	32268506	Such alternating EMT and MET promotes multiple and accelerated growth of solid carcinomas in various organs, which aggravates the pathogenesis.	('growth', 'CPA', (63, 69))	('solid carcinomas', 'Disease', (73, 89))	('solid carcinomas', 'Disease', 'MESH:D009369', (73, 89))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('accelerated', 'PosReg', (51, 62))	('carcinomas', 'Phenotype', 'HP:0030731', (79, 89))	('MET', 'Var', (25, 28))
220079	32268506	Importantly, inhibition of the ATP-ase activity of intracellular HSP90 (e.g., by cell-permeable inhibitors) may lead to CHIP-mediated ubiquitination and proteasomal degradation of bound client proteins instead of their maturation and stabilization (the upper path in Figure 2); such an approach is considered as a promising strategy for repressing tumors and sensitizing them to therapeutics.	('ubiquitination', 'MPA', (134, 148))	('lead to', 'Reg', (112, 119))	('proteasomal degradation', 'MPA', (153, 176))	('inhibition', 'Var', (13, 23))	('tumor', 'Phenotype', 'HP:0002664', (348, 353))	('stabilization', 'MPA', (234, 247))	('ATP', 'Chemical', 'MESH:D000255', (31, 34))	('tumors', 'Disease', (348, 354))	('tumors', 'Disease', 'MESH:D009369', (348, 354))	('tumors', 'Phenotype', 'HP:0002664', (348, 354))	('ase', 'Chemical', '-', (35, 38))
220096	32268506	The so-called "ER stress" provoked by hypoglycemia, hypoxia, acidosis, Ca2+ imbalance, inhibition of N-glycosylation, or other stressing exposure leads to the failure of proper protein folding within the ER compartment, thereby triggering the "unfolded protein response" (UPR) and GRP induction (Figure 4 and).	('failure', 'NegReg', (159, 166))	('hypoglycemia', 'Phenotype', 'HP:0001943', (38, 50))	('hypoxia', 'Disease', 'MESH:D000860', (52, 59))	('induction', 'MPA', (285, 294))	('triggering', 'Reg', (228, 238))	('hypoglycemia', 'Disease', 'MESH:D007003', (38, 50))	('acidosis', 'Disease', (61, 69))	('acidosis', 'Phenotype', 'HP:0001941', (61, 69))	('inhibition', 'Var', (87, 97))	('Ca2+', 'Chemical', 'MESH:D000069285', (71, 75))	('GRP', 'Gene', '2922', (281, 284))	('acidosis', 'Disease', 'MESH:D000138', (61, 69))	('unfolded protein response', 'MPA', (244, 269))	('GRP', 'Gene', (281, 284))	('imbalance', 'Phenotype', 'HP:0002172', (76, 85))	('protein', 'Protein', (177, 184))	('hypoxia', 'Disease', (52, 59))	('N', 'Chemical', 'MESH:D009584', (101, 102))	('hypoglycemia', 'Disease', (38, 50))
220114	32268506	Upon HSP90 dysfunction, these client proteins are inactivated, destabilized, and quickly degrade (the upper path in Figure 2), followed by the failing of the proliferative and defensive potential of tumor cells; consequently, it is expected that HSP90-targeting agents would sometime be used in cancer treatment (reviewed in).	('tumor', 'Disease', (199, 204))	('degrade', 'NegReg', (89, 96))	('cancer', 'Disease', 'MESH:D009369', (295, 301))	('dysfunction', 'Var', (11, 22))	('cancer', 'Disease', (295, 301))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('destabilized', 'NegReg', (63, 75))	('inactivated', 'NegReg', (50, 61))	('cancer', 'Phenotype', 'HP:0002664', (295, 301))	('HSP90', 'Protein', (5, 10))
220118	32268506	Later, it was revealed by clustered regularly interspaced short palindromic repeat (CRISPR)/Case9-mediated knocking out that HSP90alpha is required for the activities of tumor cells, such as migration, invasion, and metastasis spread, that are generally accepted attributes of CSCs.	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('HSP90alpha', 'Gene', '3320', (125, 135))	('ase', 'Chemical', '-', (93, 96))	('knocking', 'Var', (107, 115))	('metastasis spread', 'CPA', (216, 233))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('HSP90alpha', 'Gene', (125, 135))	('tumor', 'Disease', (170, 175))	('migration', 'CPA', (191, 200))	('invasion', 'CPA', (202, 210))
220123	32268506	Interestingly, inhibitory targeting of the HSP90 chaperone function may not only suppress EMT together with EMT-evoked CSC accumulation but also may reverse the cancer cell stemness by inducing MET in existing CSCs (both opportunities are designated in Figure 1).	('inducing', 'PosReg', (185, 193))	('cancer cell stemness', 'Disease', (161, 181))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('MET', 'MPA', (194, 197))	('EMT', 'CPA', (90, 93))	('reverse', 'NegReg', (149, 156))	('HSP90 chaperone', 'Protein', (43, 58))	('suppress', 'NegReg', (81, 89))	('cancer cell stemness', 'Disease', 'MESH:D009369', (161, 181))	('inhibitory targeting', 'Var', (15, 35))	('EMT-evoked CSC accumulation', 'MPA', (108, 135))
220124	32268506	Subramanian and coauthors reported that CSCs from head and neck squamous cell carcinoma decrease stemness markers as CD44, ALDH and vimentin but increase E-cadherin after treatments with two novel HSP90 activity inhibitors, Ku711 and Ku757.	('vimentin', 'Gene', '7431', (132, 140))	('ase', 'Chemical', '-', (93, 96))	('vimentin', 'Gene', (132, 140))	('neck squamous cell carcinoma decrease stemness', 'Disease', (59, 105))	('increase', 'PosReg', (145, 153))	('CD44', 'MPA', (117, 121))	('ase', 'Chemical', '-', (150, 153))	('neck squamous cell carcinoma decrease stemness', 'Disease', 'MESH:D000077195', (59, 105))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('E-cadherin', 'Gene', (154, 164))	('E-cadherin', 'Gene', '999', (154, 164))	('ALDH', 'MPA', (123, 127))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (64, 87))	('HSP90', 'Protein', (197, 202))	('Ku757', 'Var', (234, 239))
220150	32268506	The authors explained such effects of the CHIP depletion by a failure in CHIP-mediated ubiquitination and degradation of OCT4, a transcription factor promoting stemness that is a client protein of HSP90; in support of that, they demonstrated direct CHIP-OCT4 interactions and also the CHIP depletion-mimicking action of a ubiquitination-defective OKT4 mutant.	('OCT4', 'Gene', '5460', (121, 125))	('OCT4', 'Gene', (121, 125))	('OCT4', 'Gene', (254, 258))	('OKT4', 'Gene', (347, 351))	('mutant', 'Var', (352, 358))	('interactions', 'Interaction', (259, 271))	('OCT4', 'Gene', '5460', (254, 258))	('CHIP', 'MPA', (285, 289))
220158	32268506	The dysfunction of cytosolic HSP90 in inhibitor-treated tumor cells may result in the inactivation and degradation of several cancer-promoting proteins, thus impairing the viability and adaptiveness of target tumor cells (see Figure 2 and).	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('inactivation', 'MPA', (86, 98))	('tumor', 'Disease', (209, 214))	('cytosolic', 'Protein', (19, 28))	('degradation', 'MPA', (103, 114))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('viability', 'CPA', (172, 181))	('adaptiveness', 'CPA', (186, 198))	('tumor', 'Disease', (56, 61))	('dysfunction', 'Var', (4, 15))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('tumor', 'Disease', 'MESH:D009369', (209, 214))	('impairing', 'NegReg', (158, 167))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
220159	32268506	Therefore, inhibitors of HSP90 chaperone activity may be used to repress tumors and sensitize them to therapeutics.	('repress', 'NegReg', (65, 72))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('HSP90', 'Protein', (25, 30))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('inhibitors', 'Var', (11, 21))	('tumors', 'Disease', (73, 79))	('tumors', 'Disease', 'MESH:D009369', (73, 79))
220160	32268506	So, experimental ways to prevent or reverse EMT have been described for inhibitors of HSP90 activity, such as NVP-AUY922, ganetespib, KU711, and KU757.	('KU711', 'Chemical', '-', (134, 139))	('KU757', 'Var', (145, 150))	('HSP90', 'Protein', (86, 91))	('KU711', 'Var', (134, 139))	('activity', 'MPA', (92, 100))	('N', 'Chemical', 'MESH:D009584', (110, 111))
220161	32268506	In many research groups, the CSC-repressing and/or CSC-sensitizing effects of the inhibition of intracellular HSP90 activity were observed with geldanamycin, AR-42 (a histone deacetylase inhibitor), emodin, 17AAG, 17DMAG, NVP-AUY922, WGA-TA, KU711, Ku757, L80, and panaxynol.	('emodin', 'Chemical', 'MESH:D004642', (199, 205))	('ase', 'Chemical', '-', (183, 186))	('KU711', 'Chemical', '-', (242, 247))	('N', 'Chemical', 'MESH:D009584', (222, 223))	('AR', 'Chemical', 'MESH:D001128', (158, 160))	('geldanamycin', 'Chemical', 'MESH:C001277', (144, 156))	('panaxynol', 'Chemical', 'MESH:C018541', (265, 274))	('intracellular', 'MPA', (96, 109))	('AR-42', 'Var', (158, 163))	('inhibition', 'NegReg', (82, 92))	('activity', 'MPA', (116, 124))	('17AAG', 'Chemical', 'MESH:C112765', (207, 212))
220162	32268506	In a system with in vitro and in vivo models, NVP-AUY922 has recently been used to inhibit the HSP90A-dependent TCL1A/Akt pathway, which confers stemness-like properties in immune-refractory tumors.	('HSP90A', 'Gene', (95, 101))	('tumors', 'Phenotype', 'HP:0002664', (191, 197))	('N', 'Chemical', 'MESH:D009584', (46, 47))	('Akt', 'Gene', (118, 121))	('tumors', 'Disease', 'MESH:D009369', (191, 197))	('HSP90A', 'Gene', '3320', (95, 101))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('TCL1A', 'Gene', (112, 117))	('Akt', 'Gene', '207', (118, 121))	('TCL1A', 'Gene', '8115', (112, 117))	('tumors', 'Disease', (191, 197))	('NVP-AUY922', 'Var', (46, 56))	('inhibit', 'NegReg', (83, 90))
220164	32268506	There are opportunities to escape such a complication, as some inhibitors of HSP90 activity do not cause the HSF1 activation with subsequent expression of HSPs and MDR1.	('HSP', 'Gene', (155, 158))	('activity', 'MPA', (83, 91))	('MDR1', 'Gene', '5243', (164, 168))	('HSP', 'Gene', '7190', (155, 158))	('MDR1', 'Gene', (164, 168))	('HSP', 'Gene', (77, 80))	('inhibitors', 'Var', (63, 73))	('HSP', 'Gene', '7190', (77, 80))	('HSF1', 'Gene', (109, 113))
220165	32268506	For example, KU711 and panaxynol were shown to inhibit HSP90 activity in CSCs without induction of HSP70 and gp170, which was correlated with better targeting of CSCs.	('HSP90', 'Protein', (55, 60))	('gp170', 'Gene', '5243', (109, 114))	('inhibit', 'NegReg', (47, 54))	('KU711', 'Chemical', '-', (13, 18))	('gp170', 'Gene', (109, 114))	('KU711', 'Var', (13, 18))	('panaxynol', 'Chemical', 'MESH:C018541', (23, 32))	('activity', 'MPA', (61, 69))
220183	32268506	Interestingly, the in vitro formation of 3D (sphere-like) organoid structures by prostate tumor-derived cell lines was accompanied by the enhanced secretion of HSP90- and EpCAM-containing exosomes and also multiple stemness marker expression; on the other hand, extracellular HSP90 appears to stimulate spheroid growth, EMT, and CSC accumulation.	('EpCAM', 'Gene', '4072', (171, 176))	('stimulate', 'PosReg', (293, 302))	('prostate tumor', 'Disease', 'MESH:D011471', (81, 95))	('EMT', 'CPA', (320, 323))	('HSP90-', 'Protein', (160, 166))	('spheroid growth', 'CPA', (303, 318))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('prostate tumor', 'Phenotype', 'HP:0100787', (81, 95))	('secretion', 'MPA', (147, 156))	('prostate tumor', 'Disease', (81, 95))	('enhanced', 'PosReg', (138, 146))	('CSC accumulation', 'CPA', (329, 345))	('EpCAM', 'Gene', (171, 176))	('extracellular', 'Var', (262, 275))
220206	32268506	Besides, it seems likely that cell-impermeable inhibitors of HSP90 activity are able to downregulate cancer stemness-associated extracellular proteinases, such as MMP2 and MMP9, whose expression, secretion, and activity are dependent on extracellular HSP90.	('MMP2', 'Gene', '4313', (163, 167))	('ase', 'Chemical', '-', (149, 152))	('MMP9', 'Gene', '4318', (172, 176))	('inhibitors', 'Var', (47, 57))	('downregulate', 'NegReg', (88, 100))	('cancer stemness', 'Disease', (101, 116))	('MMP9', 'Gene', (172, 176))	('secretion', 'MPA', (196, 205))	('MMP2', 'Gene', (163, 167))	('activity', 'MPA', (67, 75))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('HSP90', 'Protein', (61, 66))	('cancer stemness', 'Disease', 'MESH:D009369', (101, 116))
220207	32268506	Here, one can notice the important advantages of cell-impermeable inhibitors of HSP90 activity: (i) They are much less toxic for normal cells than cell-penetrating HSP90 inhibitors and (ii) they do not activate HSF1, so the problem shown in Figure 5 will not arise in the case of the application of such inhibitors against tumors.	('tumor', 'Phenotype', 'HP:0002664', (323, 328))	('ase', 'Chemical', '-', (273, 276))	('HSP90', 'Protein', (80, 85))	('tumors', 'Disease', (323, 329))	('tumors', 'Disease', 'MESH:D009369', (323, 329))	('tumors', 'Phenotype', 'HP:0002664', (323, 329))	('inhibitors', 'Var', (66, 76))	('HSF1', 'Gene', (211, 215))
220225	32268506	In the same study, HSP70 knockout was shown to reduce a pool of tumorigenic cells with the CSC-like phenotype and impair the invasion and metastasis formation; at the molecular level, these effects of HSP70 gene inactivation were associated with reduced activation of the oncogenic c-Met protein.	('tumor', 'Disease', (64, 69))	('inactivation', 'NegReg', (212, 224))	('c-Met', 'Gene', (282, 287))	('c-Met', 'Gene', '4233', (282, 287))	('HSP70', 'Gene', (201, 206))	('reduced', 'NegReg', (246, 253))	('gene', 'Var', (207, 211))	('activation', 'PosReg', (254, 264))	('oncogenic', 'MPA', (272, 281))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('impair', 'NegReg', (114, 120))	('invasion and metastasis formation', 'CPA', (125, 158))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
220226	32268506	In another model with HSP70-2 (HSPA1B) gene silencing in human ovarian cancer cells, HSP70-2 knockdown upregulated the epithelial markers E-cadherin and cytokeratin, whereas it downregulated a set of EMT- and cancer stemness-associated proteins, including N-cadherin, vimentin, Snail, Slug, Twist, MMP2, MMP9, and others.	('knockdown', 'Var', (93, 102))	('cytokeratin', 'Protein', (153, 164))	('Twist', 'Gene', (291, 296))	('HSP70-2', 'Gene', (22, 29))	('HSP70-2', 'Gene', (85, 92))	('Slug', 'Gene', (285, 289))	('ovarian cancer', 'Phenotype', 'HP:0100615', (63, 77))	('Snail', 'Gene', '6615', (278, 283))	('upregulated', 'PosReg', (103, 114))	('downregulated', 'NegReg', (177, 190))	('human', 'Species', '9606', (57, 62))	('HSPA1B', 'Gene', '3304', (31, 37))	('cancer stemness', 'Disease', 'MESH:D009369', (209, 224))	('MMP2', 'Gene', '4313', (298, 302))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('Twist', 'Gene', '7291', (291, 296))	('E-cadherin', 'Gene', (138, 148))	('N-cadherin', 'Gene', (256, 266))	('E-cadherin', 'Gene', '999', (138, 148))	('HSP70-2', 'Gene', '3304', (22, 29))	('N-cadherin', 'Gene', '1000', (256, 266))	('HSP70-2', 'Gene', '3304', (85, 92))	('Slug', 'Gene', '6591', (285, 289))	('HSPA1B', 'Gene', (31, 37))	('Snail', 'Gene', (278, 283))	('cancer stemness', 'Disease', (209, 224))	('MMP9', 'Gene', '4318', (304, 308))	('MMP9', 'Gene', (304, 308))	('ovarian cancer', 'Disease', 'MESH:D010051', (63, 77))	('epithelial', 'MPA', (119, 129))	('vimentin', 'Gene', '7431', (268, 276))	('gene silencing', 'Var', (39, 53))	('vimentin', 'Gene', (268, 276))	('MMP2', 'Gene', (298, 302))	('ovarian cancer', 'Disease', (63, 77))
220227	32268506	These HSP70 knockdown-induced alterations in the protein profile's expression toward the non-stem cancer cell phenotype were accompanied by a shift towards the upregulation of known effectors of apoptosis, such as cytochrome-c, caspase 3, caspase 7, caspase 9, Apaf1, and others, and downregulation of pro-survival and anti-apoptotic proteins, including poly (ADP-ribose) polymerase 1 (PARP1), Bcl-2, Bcl-xL, survivin, XIAP, and others.	('caspase 9', 'Gene', (250, 259))	('XIAP', 'Gene', (419, 423))	('caspase 7', 'Gene', '840', (239, 248))	('upregulation', 'PosReg', (160, 172))	('poly (ADP-ribose) polymerase 1', 'Gene', (354, 384))	('PARP1', 'Gene', (386, 391))	('cancer', 'Disease', (98, 104))	('Bcl-2', 'Gene', (394, 399))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('downregulation', 'NegReg', (284, 298))	('caspase 9', 'Gene', '842', (250, 259))	('pro-survival', 'CPA', (302, 314))	('apoptosis', 'CPA', (195, 204))	('anti-apoptotic', 'CPA', (319, 333))	('poly (ADP-ribose) polymerase 1', 'Gene', '142', (354, 384))	('Bcl-2', 'Gene', '596', (394, 399))	('survivin', 'Protein', (409, 417))	('Apaf1', 'Gene', '317', (261, 266))	('XIAP', 'Gene', '331', (419, 423))	('caspase 3', 'Gene', (228, 237))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('PARP1', 'Gene', '142', (386, 391))	('caspase 3', 'Gene', '836', (228, 237))	('HSP70', 'Gene', (6, 11))	('caspase 7', 'Gene', (239, 248))	('Bcl-xL', 'Gene', (401, 407))	('alterations', 'Var', (30, 41))	('Apaf1', 'Gene', (261, 266))	('expression', 'MPA', (67, 77))	('cytochrome-c', 'MPA', (214, 226))	('Bcl-xL', 'Gene', '598', (401, 407))
220229	32268506	Overall, except one publication describing rather hypothetical mechanisms by which HSP70 might suppress CSC phenotype development, all other reports testified that intracellular HSP70 promotes cancer cell stemness.	('HSP70', 'Protein', (83, 88))	('CSC phenotype development', 'CPA', (104, 129))	('cancer cell stemness', 'Disease', 'MESH:D009369', (193, 213))	('suppress', 'NegReg', (95, 103))	('intracellular', 'Var', (164, 177))	('cancer cell stemness', 'Disease', (193, 213))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('HSP70', 'Protein', (178, 183))	('promotes', 'PosReg', (184, 192))
220246	32268506	Importantly, pifithrin-micro (2-phenylethynesulfonamide), a known HSP70-inhibiting agent, was found to induce cell death (necroptosis) in malignant mesothelioma cells while stimulating EMT in the surviving cells and thus increasing the risk of metastases.	('increasing', 'PosReg', (221, 231))	('metastases', 'Disease', 'MESH:D009362', (244, 254))	('pifithrin-micro', 'Var', (13, 28))	('pifithrin', 'Chemical', 'MESH:C121565', (13, 22))	('2-phenylethynesulfonamide', 'Chemical', 'MESH:C545747', (30, 55))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (138, 160))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (138, 160))	('EMT in', 'CPA', (185, 191))	('stimulating', 'PosReg', (173, 184))	('cell death', 'CPA', (110, 120))	('malignant mesothelioma', 'Disease', (138, 160))	('metastases', 'Disease', (244, 254))
220247	32268506	Consequently, treatments of CSCs with inhibitors of the HSP70 chaperone function may cause the activation of HSF1 and induction of cytoprotective HSPs and gp170 followed by adaptation of the surviving cells, i.e., a scenario shown in Figure 5.	('HSP', 'Gene', (56, 59))	('gp170', 'Gene', (155, 160))	('cytoprotective', 'MPA', (131, 145))	('HSP', 'Gene', (146, 149))	('activation', 'PosReg', (95, 105))	('inhibitors', 'Var', (38, 48))	('adaptation', 'CPA', (173, 183))	('HSP', 'Gene', '7190', (56, 59))	('HSP', 'Gene', '7190', (146, 149))	('gp170', 'Gene', '5243', (155, 160))	('induction', 'PosReg', (118, 127))	('HSF1', 'Gene', (109, 113))
220255	32268506	Specific monoclonal antibodies recognizing HSP70 on the surface of CSCs may be one of the tools for such attacks aimed at the elimination or inactivation of CSCs; hypothetically, antibody targeting of HSP70 on the surface of CSCs may (i) promote their immunogenic cell death or (ii) inhibit their cancer-aggravating activities, or (iii) be used for the delivery of cell-killing agents to them.	('cancer', 'Disease', (297, 303))	('cancer', 'Disease', 'MESH:D009369', (297, 303))	('inhibit', 'NegReg', (283, 290))	('HSP70', 'Protein', (201, 206))	('immunogenic cell death', 'CPA', (252, 274))	('cancer', 'Phenotype', 'HP:0002664', (297, 303))	('promote', 'PosReg', (238, 245))	('antibody targeting', 'Var', (179, 197))
220259	32268506	Later, DnaJB8 overexpression in colon cancer cells was shown to enhance both the expression of stemness markers and tumorigenicity, thus confirming the contribution of this chaperone to the CSC phenotype's formation.	('enhance', 'PosReg', (64, 71))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('colon cancer', 'Disease', (32, 44))	('overexpression', 'Var', (14, 28))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('stemness markers', 'CPA', (95, 111))	('DnaJB8', 'Gene', '165721', (7, 13))	('DnaJB8', 'Gene', (7, 13))	('tumor', 'Disease', (116, 121))	('colon cancer', 'Phenotype', 'HP:0003003', (32, 44))	('colon cancer', 'Disease', 'MESH:D015179', (32, 44))	('expression', 'MPA', (81, 91))
220262	32268506	In the same study, DnaJB8 knockout in renal cell carcinoma cells conferred them sensitivity to docetaxel, thus indicating a link between HSP40 and drug resistance intrinsic to CSCs.	('conferred', 'Reg', (65, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (38, 58))	('HSP40', 'Gene', (137, 142))	('drug resistance', 'Phenotype', 'HP:0020174', (147, 162))	('DnaJB8', 'Gene', '165721', (19, 25))	('DnaJB8', 'Gene', (19, 25))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (38, 58))	('HSP40', 'Gene', '171221', (137, 142))	('knockout', 'Var', (26, 34))	('docetaxel', 'Chemical', 'MESH:D000077143', (95, 104))	('link', 'Reg', (124, 128))	('sensitivity to docetaxel', 'MPA', (80, 104))	('renal cell carcinoma', 'Disease', (38, 58))
220263	32268506	Notably, an increase in the amounts of the SP cells and SOX2 expression was found in kidney cancer cells being subjected to heat stress; by means of DnaJB8 knockdown with siRNAs, it was shown that the observed effects were due to HSF1-induced DnaJB8 upregulation.	('DnaJB8', 'Gene', (149, 155))	('kidney cancer', 'Phenotype', 'HP:0009726', (85, 98))	('knockdown', 'Var', (156, 165))	('ase', 'Chemical', '-', (17, 20))	('SOX2', 'Gene', '6657', (56, 60))	('upregulation', 'PosReg', (250, 262))	('kidney cancer', 'Disease', (85, 98))	('SOX2', 'Gene', (56, 60))	('N', 'Chemical', 'MESH:D009584', (0, 1))	('DnaJB8', 'Gene', '165721', (243, 249))	('N', 'Chemical', 'MESH:D009584', (174, 175))	('DnaJB8', 'Gene', (243, 249))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('kidney cancer', 'Disease', 'MESH:D007680', (85, 98))	('DnaJB8', 'Gene', '165721', (149, 155))
220272	32268506	In this study, KNK437 reduced metastasis formation, which allowed the authors to suggest an important role of DnaJA1 in promoting the pro-metastatic (CSC-like) phenotype development.	('metastasis formation', 'CPA', (30, 50))	('DnaJA1', 'Gene', '3301', (110, 116))	('KNK437', 'Var', (15, 21))	('reduced', 'NegReg', (22, 29))	('DnaJA1', 'Gene', (110, 116))	('promoting', 'PosReg', (120, 129))	('KNK437', 'Chemical', 'MESH:C410027', (15, 21))
220279	32268506	There is crosstalk between the p38/MAPK/HSP27 pathway and Akt signaling: phosphorylated HSP27 can induce phosphorylation (activation) of Akt.	('HSP27', 'Protein', (88, 93))	('p38', 'Gene', (31, 34))	('phosphorylation', 'MPA', (105, 120))	('Akt', 'Gene', '207', (137, 140))	('Akt', 'Gene', '207', (58, 61))	('p38', 'Gene', '1432', (31, 34))	('Akt', 'Gene', (137, 140))	('phosphorylated', 'Var', (73, 87))	('Akt', 'Gene', (58, 61))
220287	32268506	In the case of IL-6-induced EMT in prostate cancer, silencing HSP27 reversed the phenotypic transition by impairing MMP activity, cell migration, and invasion.	('MMP', 'Gene', (116, 119))	('silencing', 'Var', (52, 61))	('ase', 'Chemical', '-', (8, 11))	('IL-6', 'Gene', (15, 19))	('prostate cancer', 'Disease', 'MESH:D011471', (35, 50))	('MMP', 'Gene', '4313;4318', (116, 119))	('IL-6', 'Gene', '3569', (15, 19))	('prostate cancer', 'Phenotype', 'HP:0012125', (35, 50))	('invasion', 'CPA', (150, 158))	('HSP27', 'Protein', (62, 67))	('impairing', 'NegReg', (106, 115))	('cell migration', 'CPA', (130, 144))	('prostate cancer', 'Disease', (35, 50))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
220288	32268506	At the molecular level, it was due to the HSP27 depletion-associated decrease in IL-6-dependent phosphorylation of STAT3 and, as a consequence, a decrease in STAT3 binding to the Twist promoter.	('STAT3', 'Gene', '6774', (115, 120))	('Twist', 'Gene', '7291', (179, 184))	('STAT3', 'Gene', (115, 120))	('depletion-associated', 'Var', (48, 68))	('HSP27', 'Protein', (42, 47))	('Twist', 'Gene', (179, 184))	('decrease', 'NegReg', (69, 77))	('ase', 'Chemical', '-', (74, 77))	('IL-6', 'Gene', (81, 85))	('ase', 'Chemical', '-', (151, 154))	('STAT3', 'Gene', '6774', (158, 163))	('IL-6', 'Gene', '3569', (81, 85))	('decrease', 'NegReg', (146, 154))	('STAT3', 'Gene', (158, 163))	('binding', 'Interaction', (164, 171))
220290	32268506	In this study, silencing Hsp27 decreased EGF-dependent phosphorylation of beta-catenin on tyrosine 142 and 654, which, in turn, led to the enhancement of beta-catenin ubiquitination and degradation, thereby inhibiting nuclear translocation of beta-catenin and its binding to the Slug promoter.	('ase', 'Chemical', '-', (36, 39))	('beta-catenin', 'Gene', '1499', (154, 166))	('silencing', 'Var', (15, 24))	('ubiquitination', 'MPA', (167, 181))	('Slug', 'Gene', '6591', (279, 283))	('nuclear translocation', 'MPA', (218, 239))	('phosphorylation', 'MPA', (55, 70))	('EGF', 'Gene', '1950', (41, 44))	('degradation', 'MPA', (186, 197))	('decreased', 'NegReg', (31, 40))	('binding', 'Interaction', (264, 271))	('Hsp27', 'Gene', '3315', (25, 30))	('beta-catenin', 'Gene', (243, 255))	('beta-catenin', 'Gene', '1499', (243, 255))	('inhibiting', 'NegReg', (207, 217))	('tyrosine', 'Chemical', 'MESH:D014443', (90, 98))	('enhancement', 'PosReg', (139, 150))	('Slug', 'Gene', (279, 283))	('EGF', 'Gene', (41, 44))	('beta-catenin', 'Gene', (74, 86))	('Hsp27', 'Gene', (25, 30))	('beta-catenin', 'Gene', (154, 166))	('beta-catenin', 'Gene', '1499', (74, 86))
220292	32268506	found that inactivation of p38 favors manifestations of CSC properties in non-small cell lung cancer cells because HSP27 phosphorylation mediates ubiquitination and proteasomal degradation of stemness-driving proteins, such as SOX2, OCT4, NANOG, KLF4, and c-Myc.	('OCT4', 'Gene', (233, 237))	('SOX2', 'Gene', '6657', (227, 231))	('SOX2', 'Gene', (227, 231))	('ubiquitination', 'MPA', (146, 160))	('lung cancer', 'Disease', 'MESH:D008175', (89, 100))	('c-Myc', 'Gene', (256, 261))	('p38', 'Gene', (27, 30))	('KLF4', 'Gene', (246, 250))	('lung cancer', 'Phenotype', 'HP:0100526', (89, 100))	('c-Myc', 'Gene', '4609', (256, 261))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (74, 100))	('NANOG', 'Gene', '79923', (239, 244))	('NANOG', 'Gene', (239, 244))	('CSC properties', 'CPA', (56, 70))	('proteasomal degradation', 'MPA', (165, 188))	('p38', 'Gene', '1432', (27, 30))	('inactivation', 'Var', (11, 23))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (78, 100))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('favors', 'PosReg', (31, 37))	('KLF4', 'Gene', '9314', (246, 250))	('OCT4', 'Gene', '5460', (233, 237))	('lung cancer', 'Disease', (89, 100))	('phosphorylation', 'MPA', (121, 136))	('HSP27', 'Protein', (115, 120))
220301	32268506	By means of silencing HSP27 and its overexpression in salivary adenoid cystic carcinoma cell lines, it was shown that HSP27 increases CSC-like (CD133+/CD44+) cells exhibiting radioresistance, reduced E-cadherin levels, and the enhanced capacity for cell migration and invasion; all these effects were due to the HSP27-mediated upregulation of Snail1 and Prrx1 expression.	('expression', 'MPA', (360, 370))	('upregulation', 'PosReg', (327, 339))	('increases', 'PosReg', (124, 133))	('cell migration', 'CPA', (249, 263))	('Prrx1', 'Gene', '5396', (354, 359))	('salivary adenoid cystic carcinoma', 'Disease', 'MESH:D003528', (54, 87))	('reduced', 'NegReg', (192, 199))	('CD133', 'Gene', (144, 149))	('CD133', 'Gene', '8842', (144, 149))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('ase', 'Chemical', '-', (129, 132))	('Prrx1', 'Gene', (354, 359))	('E-cadherin', 'Gene', (200, 210))	('E-cadherin', 'Gene', '999', (200, 210))	('salivary adenoid cystic carcinoma', 'Disease', (54, 87))	('Snail1', 'Gene', '6615', (343, 349))	('silencing', 'Var', (12, 21))	('Snail1', 'Gene', (343, 349))	('HSP27', 'Gene', (118, 123))	('enhanced', 'PosReg', (227, 235))	('invasion', 'CPA', (268, 276))
220309	32268506	Interestingly, antisense long noncoding RNAs (lncRNAs) may also affect HSP27 phosphorylation/dephosphorylation, as BX357664 was found to downregulate the EMT-driving TGFbeta1/p38/HSP27 pathway in renal cell carcinoma.	('HSP27', 'Protein', (71, 76))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (196, 216))	('antisense', 'Var', (15, 24))	('N', 'Chemical', 'MESH:D009584', (50, 51))	('downregulate', 'NegReg', (137, 149))	('p38', 'Gene', '1432', (175, 178))	('carcinoma', 'Phenotype', 'HP:0030731', (207, 216))	('renal cell carcinoma', 'Disease', (196, 216))	('affect', 'Reg', (64, 70))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (196, 216))	('phosphorylation/dephosphorylation', 'MPA', (77, 110))	('N', 'Chemical', 'MESH:D009584', (41, 42))	('p38', 'Gene', (175, 178))	('TGFbeta1', 'Gene', '7040', (166, 174))	('EMT-driving', 'CPA', (154, 165))	('TGFbeta1', 'Gene', (166, 174))	('BX357664', 'Var', (115, 123))
220328	32268506	Importantly, cell-permeable inhibitors of the HSP90 chaperone function are able to activate HSF1 and thus stimulate HSP induction in inhibitor-treated cells (see).	('HSP', 'Gene', '7190', (116, 119))	('stimulate', 'PosReg', (106, 115))	('HSP', 'Gene', (46, 49))	('activate', 'PosReg', (83, 91))	('inhibitors', 'Var', (28, 38))	('HSP', 'Gene', '7190', (46, 49))	('HSP', 'Gene', (116, 119))	('HSF1', 'Gene', (92, 96))
220347	32268506	Meanwhile, the same cause, namely the accumulation of misfolded proteins, can result in the activation of HSF1 and expression of additional chaperones (HSPs), which can impair the cytotoxic and sensitizing action of hyperthermia or proteasome inhibitors on CSCs (see Figure 6).	('misfolded', 'Var', (54, 63))	('HSF1', 'Gene', (106, 110))	('activation', 'PosReg', (92, 102))	('HSP', 'Gene', (152, 155))	('accumulation', 'PosReg', (38, 50))	('cytotoxic', 'CPA', (180, 189))	('expression', 'MPA', (115, 125))	('hyperthermia', 'Disease', 'MESH:D005334', (216, 228))	('impair', 'NegReg', (169, 175))	('proteins', 'Protein', (64, 72))	('HSP', 'Gene', '7190', (152, 155))	('hyperthermia', 'Phenotype', 'HP:0001945', (216, 228))	('hyperthermia', 'Disease', (216, 228))
220351	32268506	In this respect, HSF1 really appears to be a universal target to attack the cancer stemness because inhibiting HSF1 activation in tumors would yield an opportunity to downregulate the entire spectrum of inducible HSPs, which promote EMT and the generation/maintenance of CSCs.	('tumors', 'Disease', (130, 136))	('tumors', 'Disease', 'MESH:D009369', (130, 136))	('cancer stemness', 'Disease', (76, 91))	('HSP', 'Gene', '7190', (213, 216))	('downregulate', 'NegReg', (167, 179))	('inhibiting', 'Var', (100, 110))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('cancer stemness', 'Disease', 'MESH:D009369', (76, 91))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('HSP', 'Gene', (213, 216))	('HSF1', 'Gene', (111, 115))	('spectrum', 'MPA', (191, 199))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('promote', 'PosReg', (225, 232))	('EMT', 'CPA', (233, 236))
220367	32268506	It was shown that FKBP12 knockdown increased the mammosphere formation and tumorigenicity in breast cancer cell lines.	('increased', 'PosReg', (35, 44))	('FKBP12', 'Gene', '2285', (18, 24))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('breast cancer', 'Disease', 'MESH:D001943', (93, 106))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('mammosphere formation', 'CPA', (49, 70))	('ase', 'Chemical', '-', (40, 43))	('FKBP12', 'Gene', (18, 24))	('breast cancer', 'Disease', (93, 106))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('breast cancer', 'Phenotype', 'HP:0003002', (93, 106))	('knockdown', 'Var', (25, 34))	('tumor', 'Disease', (75, 80))
220375	32268506	In a more recent study, PIN1 expression in human gallbladder cancer was found to be correlated with the activating phosphorylation of STAT3 (serine 727) and NFkappaB-p65 (serine 276), which induced EMT in tumor cells; accordingly, PIN1 knockdown impaired the phosphorylation/activation of both STAT3 and NFkappaB, which was accompanied by decreased Snail and ZEB2 expression in PIN1-depleted tumor cells, which lost a mesenchymal phenotype.	('serine', 'Chemical', 'MESH:D012694', (171, 177))	('PIN1', 'Gene', (231, 235))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('NFkappaB', 'Gene', (157, 165))	('gallbladder cancer', 'Disease', 'MESH:D005706', (49, 67))	('tumor', 'Disease', (392, 397))	('knockdown', 'Var', (236, 245))	('NFkappaB-p65', 'Gene', '5970', (157, 169))	('PIN1', 'Gene', (24, 28))	('STAT3', 'Gene', (134, 139))	('STAT3', 'Gene', (294, 299))	('tumor', 'Disease', 'MESH:D009369', (392, 397))	('ase', 'Chemical', '-', (344, 347))	('NFkappaB', 'Gene', '4790', (304, 312))	('Snail', 'Gene', '6615', (349, 354))	('phosphorylation/activation', 'MPA', (259, 285))	('PIN1', 'Gene', '5300', (378, 382))	('STAT3', 'Gene', '6774', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('STAT3', 'Gene', '6774', (294, 299))	('NFkappaB', 'Gene', (304, 312))	('tumor', 'Phenotype', 'HP:0002664', (392, 397))	('gallbladder cancer', 'Disease', (49, 67))	('expression', 'MPA', (364, 374))	('PIN1', 'Gene', (378, 382))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('PIN1', 'Gene', '5300', (231, 235))	('ZEB2', 'Gene', (359, 363))	('decreased', 'NegReg', (339, 348))	('Snail', 'Gene', (349, 354))	('impaired', 'NegReg', (246, 254))	('PIN1', 'Gene', '5300', (24, 28))	('NFkappaB', 'Gene', '4790', (157, 165))	('serine', 'Chemical', 'MESH:D012694', (141, 147))	('tumor', 'Disease', (205, 210))	('NFkappaB-p65', 'Gene', (157, 169))	('phosphorylation/activation', 'PosReg', (259, 285))	('ZEB2', 'Gene', '9839', (359, 363))	('human', 'Species', '9606', (43, 48))
220392	32268506	It follows from the latter publication that cyclophilin A promotes the self-renewal and radioresistance of neurosphere-forming (CSC-like) glioma cells through stimulating the Wnt/beta-catenin pathway.	('beta-catenin', 'Gene', '1499', (179, 191))	('glioma', 'Disease', (138, 144))	('self-renewal', 'CPA', (71, 83))	('radioresistance of neurosphere-forming', 'CPA', (88, 126))	('promotes', 'PosReg', (58, 66))	('glioma', 'Phenotype', 'HP:0009733', (138, 144))	('stimulating', 'PosReg', (159, 170))	('cyclophilin A', 'Var', (44, 57))	('glioma', 'Disease', 'MESH:D005910', (138, 144))	('beta-catenin', 'Gene', (179, 191))
220394	32268506	For example, the binding of FKBP51 and FKBP52 to HSP90, which is so important for the HSP90-dependent mechanisms of cell regulation, may somehow be related to the formation of the CSC phenotype as well.	('CSC', 'Disease', (180, 183))	('binding', 'Interaction', (17, 24))	('HSP90', 'Protein', (49, 54))	('FKBP52', 'Gene', '2288', (39, 45))	('FKBP51', 'Var', (28, 34))	('related', 'Reg', (148, 155))	('FKBP52', 'Gene', (39, 45))
220402	32268506	FKBPL knockdown in breast cancer cells upregulated the stemness markers NANOG, OCT4, and SOX2 and increased the CSC fraction.	('SOX2', 'Gene', '6657', (89, 93))	('ase', 'Chemical', '-', (103, 106))	('breast cancer', 'Phenotype', 'HP:0003002', (19, 32))	('FKBPL', 'Gene', (0, 5))	('breast cancer', 'Disease', (19, 32))	('upregulated', 'PosReg', (39, 50))	('CSC fraction', 'CPA', (112, 124))	('stemness', 'CPA', (55, 63))	('NANOG', 'Gene', '79923', (72, 77))	('FKBPL', 'Gene', '63943', (0, 5))	('increased', 'PosReg', (98, 107))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('breast cancer', 'Disease', 'MESH:D001943', (19, 32))	('knockdown', 'Var', (6, 15))	('NANOG', 'Gene', (72, 77))	('OCT4', 'Gene', '5460', (79, 83))	('SOX2', 'Gene', (89, 93))	('OCT4', 'Gene', (79, 83))
220403	32268506	In the latter study, FKBPL overexpression in breast cancer cells was shown to reduce the number of CSCs via downregulation of DLL4 and Notch4.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('overexpression', 'Var', (27, 41))	('reduce', 'NegReg', (78, 84))	('DLL4', 'Gene', (126, 130))	('FKBPL', 'Gene', (21, 26))	('breast cancer', 'Disease', 'MESH:D001943', (45, 58))	('breast cancer', 'Disease', (45, 58))	('FKBPL', 'Gene', '63943', (21, 26))	('breast cancer', 'Phenotype', 'HP:0003002', (45, 58))	('downregulation', 'NegReg', (108, 122))	('DLL4', 'Gene', '54567', (126, 130))	('Notch4', 'Gene', (135, 141))	('Notch4', 'Gene', '4855', (135, 141))
220404	32268506	In turn, FKBP12 knockdown in breast cancer cell enhanced the mammosphere formation and other stemness features, whereas FKBP12 overexpression exerted the opposite effects.	('stemness features', 'CPA', (93, 110))	('FKBP12', 'Gene', (120, 126))	('mammosphere formation', 'CPA', (61, 82))	('enhanced', 'PosReg', (48, 56))	('FKBP12', 'Gene', '2285', (120, 126))	('knockdown', 'Var', (16, 25))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('breast cancer', 'Disease', 'MESH:D001943', (29, 42))	('FKBP12', 'Gene', (9, 15))	('breast cancer', 'Disease', (29, 42))	('FKBP12', 'Gene', '2285', (9, 15))	('breast cancer', 'Phenotype', 'HP:0003002', (29, 42))
220407	32268506	Later, it was found that another plant-derived compound, celastrol, strongly suppresses PIN1 expression in ovarian cancer cells and this is accompanied by downregulation of the expression of CD44, NANOG, KLF4, and OCT4 as well as a decrease in the CD44 high/CD24 low cell population (i.e., CSC-like cells).	('NANOG', 'Gene', (197, 202))	('CD44', 'MPA', (248, 252))	('PIN1', 'Gene', (88, 92))	('OCT4', 'Gene', '5460', (214, 218))	('expression', 'MPA', (177, 187))	('ovarian cancer', 'Disease', (107, 121))	('ovarian cancer', 'Phenotype', 'HP:0100615', (107, 121))	('OCT4', 'Gene', (214, 218))	('celastrol', 'Chemical', 'MESH:C050414', (57, 66))	('downregulation', 'NegReg', (155, 169))	('CD44', 'Var', (191, 195))	('KLF4', 'Gene', (204, 208))	('CD24', 'Gene', (258, 262))	('ase', 'Chemical', '-', (237, 240))	('decrease', 'NegReg', (232, 240))	('PIN1', 'Gene', '5300', (88, 92))	('suppresses', 'NegReg', (77, 87))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('expression', 'MPA', (93, 103))	('CD24', 'Gene', '100133941', (258, 262))	('ovarian cancer', 'Disease', 'MESH:D010051', (107, 121))	('NANOG', 'Gene', '79923', (197, 202))	('KLF4', 'Gene', '9314', (204, 208))
220411	32268506	As for pharmaceutical targeting, all-trans retinoic acid-mediated inhibition of PIN1 was shown to eliminate gastric CSCs and also impair their self-renewal and tumorigenic potential.	('retinoic acid', 'Chemical', 'MESH:D014212', (43, 56))	('gastric CSCs', 'Disease', 'MESH:D013274', (108, 120))	('self-renewal', 'CPA', (143, 155))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('inhibition', 'Var', (66, 76))	('eliminate', 'NegReg', (98, 107))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('PIN1', 'Gene', '5300', (80, 84))	('tumor', 'Disease', (160, 165))	('gastric CSCs', 'Disease', (108, 120))	('impair', 'NegReg', (130, 136))	('PIN1', 'Gene', (80, 84))
220441	32268506	demonstrated that knockdown of GRP78 in tumor-initiating (CSC-like) cells from head and neck cancer impairs their self-renewing capacity, tumorigenic potential, and expression of stemness-related genes, while reducing the SP cell's proportion and enhancing apoptosis.	('proportion', 'CPA', (232, 242))	('tumor', 'Disease', (138, 143))	('reducing', 'NegReg', (209, 217))	('GRP78', 'Gene', (31, 36))	('enhancing', 'PosReg', (247, 256))	('impairs', 'NegReg', (100, 107))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('SP cell', 'CPA', (222, 229))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('knockdown', 'Var', (18, 27))	('tumor', 'Disease', (40, 45))	('apoptosis', 'CPA', (257, 266))	('self-renewing capacity', 'CPA', (114, 136))	('head and neck cancer', 'Phenotype', 'HP:0012288', (79, 99))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('expression', 'MPA', (165, 175))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('stemness-related', 'CPA', (179, 195))	('neck cancer', 'Disease', 'MESH:D006258', (88, 99))	('neck cancer', 'Disease', (88, 99))
220451	32268506	However, in another similar study, overexpressed GRP78 was shown to stimulate EMT in colon cancer cells via an autocrine mechanism, enhancing the expression/secretion of TGF-beta1 and triggering TGF-beta/Smad2/3 signaling.	('TGF-beta', 'Gene', '7039', (170, 178))	('GRP78', 'Gene', (49, 54))	('expression/secretion', 'MPA', (146, 166))	('stimulate', 'PosReg', (68, 77))	('overexpressed', 'Var', (35, 48))	('TGF-beta1', 'Gene', '7040', (170, 179))	('TGF-beta1', 'Gene', (170, 179))	('TGF-beta', 'Gene', (170, 178))	('TGF-beta', 'Gene', '7039', (195, 203))	('colon cancer', 'Phenotype', 'HP:0003003', (85, 97))	('colon cancer', 'Disease', 'MESH:D015179', (85, 97))	('colon cancer', 'Disease', (85, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('triggering', 'Reg', (184, 194))	('EMT', 'CPA', (78, 81))	('enhancing', 'PosReg', (132, 141))	('TGF-beta', 'Gene', (195, 203))
220462	32268506	Silencing of GRP78 suppressed self-renewal and radioresistance of glioma CSCs, which was due to the increase in the microRNA-205 level.	('self-renewal', 'CPA', (30, 42))	('radioresistance', 'CPA', (47, 62))	('glioma CSCs', 'Disease', (66, 77))	('GRP78', 'Gene', (13, 18))	('suppressed', 'NegReg', (19, 29))	('N', 'Chemical', 'MESH:D009584', (122, 123))	('ase', 'Chemical', '-', (105, 108))	('glioma CSCs', 'Disease', 'MESH:D005910', (66, 77))	('glioma', 'Phenotype', 'HP:0009733', (66, 72))	('Silencing', 'Var', (0, 9))	('increase', 'PosReg', (100, 108))	('microRNA-205 level', 'MPA', (116, 134))
220468	32268506	Meanwhile, the EMT- and cancer stemness-promoting activities of intracellular GRP78 may be downregulated by certain endogenous protein factors, such as DAL-1, P4HB, and YAP1, and also by a set of three microRNAs: miR495, miR205 or miR-30d, miR181a, and miR-199a-5p.	('downregulated', 'NegReg', (91, 104))	('P4HB', 'Gene', (159, 163))	('DAL-1', 'Gene', '23136', (152, 157))	('YAP1', 'Gene', (169, 173))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('cancer stemness', 'Disease', (24, 39))	('miR205', 'Gene', (221, 227))	('DAL-1', 'Gene', (152, 157))	('miR-30d', 'Gene', (231, 238))	('miR-199a-5p', 'Var', (253, 264))	('N', 'Chemical', 'MESH:D009584', (208, 209))	('miR495', 'Gene', '574453', (213, 219))	('miR-30d', 'Gene', '407033', (231, 238))	('miR205', 'Gene', '406988', (221, 227))	('miR181a', 'Var', (240, 247))	('P4HB', 'Gene', '5034', (159, 163))	('miR495', 'Gene', (213, 219))	('cancer stemness', 'Disease', 'MESH:D009369', (24, 39))	('GRP78', 'Gene', (78, 83))	('YAP1', 'Gene', '10413', (169, 173))
220486	32268506	In particular, the known GRP78 inhibitor HA15 (N-[4-[3-[[[5-(Dimethylamino)-1-naphthalenyl]sulfonyl]amino]phenyl]-2-thiazolyl]-acetamide), if combined with PRDM14 knockdown, diminished the fraction of CSC-like SP cells in breast cancer HCC1937 cells.	('HCC1937', 'CellLine', 'CVCL:0290', (236, 243))	('breast cancer', 'Disease', (222, 235))	('HA15', 'Chemical', '-', (41, 45))	('PRDM14', 'Gene', '63978', (156, 162))	('breast cancer', 'Phenotype', 'HP:0003002', (222, 235))	('GRP78', 'Gene', (25, 30))	('diminished', 'NegReg', (174, 184))	('HA15', 'Var', (41, 45))	('N-[4-[3-[[[5-(Dimethylamino)-1-naphthalenyl]sulfonyl]amino]phenyl]-2-thiazolyl]-acetamide', 'Chemical', '-', (47, 136))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('breast cancer', 'Disease', 'MESH:D001943', (222, 235))	('PRDM14', 'Gene', (156, 162))
220497	32268506	Later, in a murine model of ovarian cancer, fractions of ascites cancer cells expressing GRP78 on the plasma membrane were also identified as self-renewing CSCs with an enhanced spheroid-forming capacity and higher tumorigenicity as compared with ascites cancer cells whose plasma membrane did not contain GRP78.	('ascites', 'Phenotype', 'HP:0001541', (57, 64))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('ovarian cancer', 'Disease', (28, 42))	('ascites cancer', 'Disease', 'MESH:D001201', (57, 71))	('ascites cancer', 'Disease', (247, 261))	('enhanced', 'PosReg', (169, 177))	('ascites cancer', 'Disease', 'MESH:D001201', (247, 261))	('cancer', 'Phenotype', 'HP:0002664', (255, 261))	('ovarian cancer', 'Phenotype', 'HP:0100615', (28, 42))	('fractions of ascites cancer', 'Disease', 'MESH:D001201', (44, 71))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('spheroid-forming capacity', 'CPA', (178, 203))	('murine', 'Species', '10090', (12, 18))	('tumor', 'Disease', (215, 220))	('higher', 'PosReg', (208, 214))	('tumor', 'Disease', 'MESH:D009369', (215, 220))	('ascites', 'Phenotype', 'HP:0001541', (247, 254))	('GRP78', 'Var', (89, 94))	('ovarian cancer', 'Disease', 'MESH:D010051', (28, 42))	('fractions of ascites cancer', 'Disease', (44, 71))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))
220498	32268506	showed that endogenous GRP78 expressed on the cell surface was shown to facilitate the adhesion and invasion of hepatocellular carcinoma cells along with enhancement of the secretion and activity of MMP2.	('endogenous', 'Var', (12, 22))	('MMP2', 'Gene', (199, 203))	('facilitate', 'PosReg', (72, 82))	('adhesion', 'CPA', (87, 95))	('activity', 'MPA', (187, 195))	('enhancement', 'PosReg', (154, 165))	('invasion', 'CPA', (100, 108))	('MMP2', 'Gene', '4313', (199, 203))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (112, 136))	('GRP78', 'Protein', (23, 28))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('hepatocellular carcinoma', 'Disease', (112, 136))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (112, 136))	('secretion', 'MPA', (173, 182))
220511	32268506	Anti-GRP78 antibodies were used for targeting cell surface-associated GRP78 in hepatocellular carcinoma cells (Mahlavu and SMMC7721 cell lines); such antibody-conferred neutralization of the endogenous cell surface chaperone led to the inhibition of cell adhesion and invasion.	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('hepatocellular carcinoma', 'Disease', (79, 103))	('neutralization', 'Var', (169, 183))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (79, 103))	('inhibition', 'NegReg', (236, 246))	('invasion', 'CPA', (268, 276))	('SMMC7721', 'CellLine', 'CVCL:0534', (123, 131))	('cell adhesion', 'CPA', (250, 263))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (79, 103))
220512	32268506	Moreover, targeting cell surface GRP78 with neutralizing antibodies suppressed the secretion and activity of MMP2 and elevated the E-cadherin level, while downregulating N-cadherin.	('E-cadherin', 'Gene', '999', (131, 141))	('downregulating', 'NegReg', (155, 169))	('N-cadherin', 'Gene', '1000', (170, 180))	('MMP2', 'Gene', '4313', (109, 113))	('activity', 'MPA', (97, 105))	('suppressed', 'NegReg', (68, 78))	('secretion', 'MPA', (83, 92))	('targeting', 'Var', (10, 19))	('MMP2', 'Gene', (109, 113))	('GRP78', 'Protein', (33, 38))	('E-cadherin', 'Gene', (131, 141))	('elevated', 'PosReg', (118, 126))	('N-cadherin', 'Gene', (170, 180))
220513	32268506	Such results indicate that cancer stemness-associated traits are sensitive to the neutralization of cell surface GRP78, which may be achieved with anti-GRP78 antibodies.	('GRP78', 'Protein', (113, 118))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('cancer stemness', 'Disease', 'MESH:D009369', (27, 42))	('neutralization', 'Var', (82, 96))	('cancer stemness', 'Disease', (27, 42))
220515	32268506	Both publications suggest the possibility of the application of an antibody-based therapy aimed at the neutralization (inactivation) of GRP78 expressed on the surface of CSCs and their precursors.	('neutralization', 'Var', (103, 117))	('GRP78', 'Protein', (136, 141))	('ase', 'Chemical', '-', (77, 80))
220528	32268506	Besides the upregulated stemness markers, GRP75-overexpressing malignant cells exhibited a greater predisposition to migration and spheroid formation and were less susceptible to a number of antitumor drugs, while GRP75 knockdown with small hairpin RNA (shRNA) sensitized those cells to chemotherapeutics.	('GRP75', 'Gene', (214, 219))	('GRP75', 'Gene', '3313', (214, 219))	('tumor', 'Disease', (195, 200))	('N', 'Chemical', 'MESH:D009584', (250, 251))	('less', 'NegReg', (159, 163))	('GRP75', 'Gene', (42, 47))	('GRP75', 'Gene', '3313', (42, 47))	('N', 'Chemical', 'MESH:D009584', (257, 258))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('knockdown', 'Var', (220, 229))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('upregulated', 'PosReg', (12, 23))
220546	32268506	TRAP1 seems to be a promising target for anti-CSC therapy because inhibiting this chaperone may prevent CSC phenotype formation through EMT, as well as eliminating existing CSCs or sensitizing them to the conventional treatment of cancer.	('cancer', 'Disease', 'MESH:D009369', (231, 237))	('eliminating', 'NegReg', (152, 163))	('inhibiting', 'Var', (66, 76))	('prevent', 'NegReg', (96, 103))	('cancer', 'Disease', (231, 237))	('TRAP1', 'Gene', '10131', (0, 5))	('CSCs', 'Disease', (173, 177))	('TRAP1', 'Gene', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('CSC phenotype', 'Disease', (104, 117))	('EMT', 'CPA', (136, 139))
220565	32268506	In the case of prostate cancer, secreted AGR2 was shown to stimulate angiogenesis by enhancing VEGF receptor 2 activity and facilitate metastasis spread.	('enhancing', 'PosReg', (85, 94))	('VEGF', 'Gene', '7422', (95, 99))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('ase', 'Chemical', '-', (8, 11))	('prostate cancer', 'Disease', (15, 30))	('secreted', 'Var', (32, 40))	('activity', 'MPA', (111, 119))	('facilitate', 'PosReg', (124, 134))	('AGR2', 'Gene', (41, 45))	('stimulate', 'PosReg', (59, 68))	('metastasis spread', 'CPA', (135, 152))	('prostate cancer', 'Disease', 'MESH:D011471', (15, 30))	('VEGF', 'Gene', (95, 99))	('prostate cancer', 'Phenotype', 'HP:0012125', (15, 30))	('angiogenesis', 'CPA', (69, 81))	('AGR2', 'Gene', '10551', (41, 45))
220569	32268506	The development of various small molecule inhibitors of protein disulfide isomerases is being continued and the newly created variants should be tested in cancer stemness-relevant models.	('cancer stemness', 'Disease', (155, 170))	('variants', 'Var', (126, 134))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('ase', 'Chemical', '-', (80, 83))	('cancer stemness', 'Disease', 'MESH:D009369', (155, 170))	('disulfide', 'Chemical', 'MESH:D004220', (64, 73))
220582	32268506	Notably, one of the mutations driving the myeloproliferative neoplasm (MPN) development is that of the calreticulin-encoding CALR gene; this mutation activates MPL/JAK/STAT signaling in MPN stem cells, thereby promoting better survival and expansion outside the bone marrow niche.	('CALR', 'Gene', '811', (125, 129))	('N', 'Chemical', 'MESH:D009584', (188, 189))	('activates', 'PosReg', (150, 159))	('MPL', 'Gene', '4352', (160, 163))	('MPN', 'Phenotype', 'HP:0005547', (71, 74))	('neoplasm', 'Phenotype', 'HP:0002664', (61, 69))	('STAT', 'Gene', '6774', (168, 172))	('STAT', 'Gene', (168, 172))	('promoting better', 'PosReg', (210, 226))	('expansion', 'CPA', (240, 249))	('MPL', 'Gene', (160, 163))	('N', 'Chemical', 'MESH:D009584', (0, 1))	('N', 'Chemical', 'MESH:D009584', (73, 74))	('neoplasm', 'Disease', 'MESH:D009369', (61, 69))	('myeloproliferative neoplasm', 'Phenotype', 'HP:0005547', (42, 69))	('neoplasm', 'Disease', (61, 69))	('CALR', 'Gene', (125, 129))	('mutation', 'Var', (141, 149))	('MPN', 'Phenotype', 'HP:0005547', (186, 189))
220583	32268506	Therefore, in the case of MPN, mutated calreticulin may be responsible for the development and maintenance of malignancy-associated stemness.	('MPN', 'Phenotype', 'HP:0005547', (26, 29))	('ase', 'Chemical', '-', (19, 22))	('malignancy', 'Disease', 'MESH:D009369', (110, 120))	('malignancy', 'Disease', (110, 120))	('N', 'Chemical', 'MESH:D009584', (28, 29))	('responsible', 'Reg', (59, 70))	('calreticulin', 'Gene', (39, 51))	('mutated', 'Var', (31, 38))
220584	32268506	The recently discovered function of calreticulin in cancer cells is preventing the p53-mediated caspase-independent cell-death response; the latter can be induced by calreticulin knockdown, leading to mitochondrial Ca2+ overload followed by cell killing through a mitochondrial permeability transition pore-dependent mechanism.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('p53', 'Gene', (83, 86))	('p53', 'Gene', '7157', (83, 86))	('mitochondrial Ca2+ overload', 'MPA', (201, 228))	('calreticulin', 'Gene', (166, 178))	('cell killing', 'CPA', (241, 253))	('knockdown', 'Var', (179, 188))	('caspase', 'Gene', (96, 103))	('preventing', 'NegReg', (68, 78))	('Ca2+', 'Chemical', 'MESH:D000069285', (215, 219))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('caspase', 'Gene', '842', (96, 103))	('induced', 'Reg', (155, 162))
220603	32268506	FKBL-derived peptides, AD-01 and ALM201, were shown to suppress cancer stemness in vitro and in vivo; ALM201 is currently undergoing clinical trials as an antitumor agent.	('cancer stemness', 'Disease', 'MESH:D009369', (64, 79))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('tumor', 'Disease', (159, 164))	('ALM201', 'Var', (102, 108))	('cancer stemness', 'Disease', (64, 79))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('suppress', 'NegReg', (55, 63))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
220604	32268506	The many dozens of publications cited in this review demonstrate in various models in vitro and in vivo that inhibitors of the activity or expression of chaperones can (i) prevent (or even reverse) EMT and similar phenotypic modulations toward cancer stemness; (ii) suppress the most critical manifestations of cancer stemness, such as self-renewal, migration, invasion, and metastatic behavior of CSCs; and (iii) sensitize CSCs to chemotherapy and radiotherapy.	('invasion', 'CPA', (361, 369))	('metastatic behavior', 'CPA', (375, 394))	('cancer stemness', 'Disease', (244, 259))	('sensitize', 'Reg', (414, 423))	('self-renewal', 'CPA', (336, 348))	('inhibitors', 'Var', (109, 119))	('suppress', 'NegReg', (266, 274))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('prevent', 'NegReg', (172, 179))	('cancer stemness', 'Disease', (311, 326))	('cancer stemness', 'Disease', 'MESH:D009369', (244, 259))	('EMT', 'CPA', (198, 201))	('migration', 'CPA', (350, 359))	('cancer', 'Phenotype', 'HP:0002664', (311, 317))	('cancer stemness', 'Disease', 'MESH:D009369', (311, 326))
220608	32268506	(3) Prevention of the induction of new cytoprotective chaperones in CSCs treated with inhibitors of the chaperone activity or hyperthermia, or proteasome inhibitors.	('CSCs', 'Disease', (68, 72))	('hyperthermia', 'Disease', 'MESH:D005334', (126, 138))	('inhibitors', 'Var', (86, 96))	('hyperthermia', 'Phenotype', 'HP:0001945', (126, 138))	('hyperthermia', 'Disease', (126, 138))
220611	32268506	(6) The use of liposomes, nanoparticles, or artificially prepared exosomes as vector-directed vehicles for targeted delivery of chaperone-suppressing agents into CSCs and their precursors: Thanks to such an approach, it will be possible to introduce into cells certain tools of 'gene therapy', e.g., siRNAs, or microRNAs, or antisense-based constructs for knockdown of either chaperone.	('antisense-based constructs', 'Var', (325, 351))	('knockdown', 'Var', (356, 365))	('ase', 'Chemical', '-', (336, 339))	('N', 'Chemical', 'MESH:D009584', (317, 318))	('N', 'Chemical', 'MESH:D009584', (303, 304))
220621	32185124	In this review, we summarize the role of lncRNA in cutaneous squamous cell carcinoma to make a better understanding of mutations in cSCC and lay the foundation for effective target therapy of cSCC.	('cSCC', 'Disease', 'MESH:D002294', (192, 196))	('cSCC', 'Disease', (132, 136))	('cutaneous squamous cell carcinoma', 'Disease', 'MESH:D002294', (51, 84))	('cSCC', 'Disease', 'MESH:D002294', (132, 136))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (61, 84))	('cSCC', 'Phenotype', 'HP:0006739', (192, 196))	('cutaneous squamous cell carcinoma', 'Phenotype', 'HP:0006739', (51, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('cSCC', 'Disease', (192, 196))	('cSCC', 'Phenotype', 'HP:0006739', (132, 136))	('mutations', 'Var', (119, 128))	('cutaneous squamous cell carcinoma', 'Disease', (51, 84))
220630	32185124	In addition, mutations of p53 and RAS have been found in patients with actinic keratosis induced by UV.	('actinic keratosis', 'Phenotype', 'HP:0025127', (71, 88))	('RAS', 'Gene', (34, 37))	('patients', 'Species', '9606', (57, 65))	('p53', 'Gene', (26, 29))	('keratosis', 'Disease', 'MESH:D007642', (79, 88))	('found', 'Reg', (48, 53))	('keratosis', 'Disease', (79, 88))	('p53', 'Gene', '7157', (26, 29))	('mutations', 'Var', (13, 22))
220631	32185124	It can be inferred that mutation of p53 and RAS may be early changes of UV damage, which laid the foundation for the development of cSCC.	('UV damage', 'Disease', 'MESH:C563466', (72, 81))	('cSCC', 'Disease', (132, 136))	('UV damage', 'Disease', (72, 81))	('p53', 'Gene', (36, 39))	('cSCC', 'Disease', 'MESH:D002294', (132, 136))	('p53', 'Gene', '7157', (36, 39))	('mutation', 'Var', (24, 32))	('RAS', 'Gene', (44, 47))	('cSCC', 'Phenotype', 'HP:0006739', (132, 136))
220634	32185124	And telomerase reverse transcriptase gene promoter (TERTp) mutation may be a molecular biomarker with prognostic significance for invasive cSCC, but further study is still needed.	('cSCC', 'Phenotype', 'HP:0006739', (139, 143))	('TERTp', 'Gene', (52, 57))	('TERTp', 'Gene', '7015', (52, 57))	('cSCC', 'Disease', (139, 143))	('mutation', 'Var', (59, 67))	('cSCC', 'Disease', 'MESH:D002294', (139, 143))
220642	32185124	Consequently, we reviewed the role of lncRNA in cutaneous squamous cell carcinoma to make a better understanding of mutations in cSCC and lay the foundation for effective target therapy of cSCC.	('cSCC', 'Disease', (189, 193))	('cutaneous squamous cell carcinoma', 'Disease', (48, 81))	('cSCC', 'Phenotype', 'HP:0006739', (129, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('cSCC', 'Disease', 'MESH:D002294', (189, 193))	('cutaneous squamous cell carcinoma', 'Disease', 'MESH:D002294', (48, 81))	('cSCC', 'Disease', (129, 133))	('mutations', 'Var', (116, 125))	('cSCC', 'Phenotype', 'HP:0006739', (189, 193))	('cutaneous squamous cell carcinoma', 'Phenotype', 'HP:0006739', (48, 81))	('cSCC', 'Disease', 'MESH:D002294', (129, 133))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (58, 81))
220656	32185124	Besides, knockout of PICSAR suppressed the proliferation and migration of cSCC cells and inhibited the growth of human cSCC xenografts in vivo.	('PICSAR', 'Gene', (21, 27))	('cSCC', 'Disease', 'MESH:D002294', (119, 123))	('knockout', 'Var', (9, 17))	('cSCC', 'Phenotype', 'HP:0006739', (74, 78))	('inhibited', 'NegReg', (89, 98))	('cSCC', 'Phenotype', 'HP:0006739', (119, 123))	('suppressed', 'NegReg', (28, 38))	('cSCC', 'Disease', (74, 78))	('cSCC', 'Disease', (119, 123))	('PICSAR', 'Gene', '378825', (21, 27))	('proliferation', 'CPA', (43, 56))	('cSCC', 'Disease', 'MESH:D002294', (74, 78))	('human', 'Species', '9606', (113, 118))
220657	32185124	Meanwhile, it has been mentioned that knockdown of PICSAR increased adhesion and decreased cell migration on collagen I and fibronectin by downregulating alpha2beta1 and alpha5beta1 integrin expression.	('decreased', 'NegReg', (81, 90))	('increased', 'PosReg', (58, 67))	('PICSAR', 'Gene', (51, 57))	('alpha2beta1', 'Protein', (154, 165))	('expression', 'MPA', (191, 201))	('downregulating', 'NegReg', (139, 153))	('adhesion', 'CPA', (68, 76))	('knockdown', 'Var', (38, 47))	('alpha5beta1 integrin', 'Protein', (170, 190))	('cell migration', 'CPA', (91, 105))	('PICSAR', 'Gene', '378825', (51, 57))
220678	32185124	AK144841 is a new long noncoding found by Gilles et al., the expression of which in cSCCs was 40 times higher than that in healthy skin.	('cSCC', 'Disease', 'MESH:D002294', (84, 88))	('AK144841', 'Chemical', '-', (0, 8))	('cSCC', 'Phenotype', 'HP:0006739', (84, 88))	('AK144841', 'Var', (0, 8))	('cSCC', 'Disease', (84, 88))	('higher', 'PosReg', (103, 109))	('expression', 'MPA', (61, 71))
220679	32185124	AK144841 was absent from normal keratinocytes, indicating that it may play a possible role in tumoral progression.	('AK144841', 'Chemical', '-', (0, 8))	('play', 'Reg', (70, 74))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('AK144841', 'Var', (0, 8))	('tumoral', 'Disease', (94, 101))	('tumoral', 'Disease', 'MESH:D009369', (94, 101))
220688	32185124	Meanwhile, knocking down MALAT1 significantly increased the protein expression of E-cadherin and beta-catenin and decreased the protein expression of vimentin.	('knocking down', 'Var', (11, 24))	('beta-catenin', 'Gene', (97, 109))	('increased', 'PosReg', (46, 55))	('MALAT1', 'Gene', (25, 31))	('E-cadherin', 'Gene', (82, 92))	('protein expression', 'MPA', (128, 146))	('decreased', 'NegReg', (114, 123))	('E-cadherin', 'Gene', '999', (82, 92))	('beta-catenin', 'Gene', '1499', (97, 109))	('vimentin', 'Gene', '7431', (150, 158))	('protein expression', 'MPA', (60, 78))	('MALAT1', 'Gene', '378938', (25, 31))	('vimentin', 'Gene', (150, 158))
220690	32185124	Knockout of LINC01048 inhibited cell proliferation and promoted cell apoptosis, suggesting the carcinogenic role of LINC01048 in cSCCs.	('carcinogenic', 'Disease', 'MESH:D063646', (95, 107))	('cSCC', 'Phenotype', 'HP:0006739', (129, 133))	('inhibited', 'NegReg', (22, 31))	('carcinogenic', 'Disease', (95, 107))	('cell apoptosis', 'CPA', (64, 78))	('LINC01048', 'Gene', (12, 21))	('LINC01048', 'Gene', '103695431', (12, 21))	('cSCC', 'Disease', (129, 133))	('Knockout', 'Var', (0, 8))	('LINC01048', 'Gene', (116, 125))	('promoted', 'PosReg', (55, 63))	('LINC01048', 'Gene', '103695431', (116, 125))	('cSCC', 'Disease', 'MESH:D002294', (129, 133))	('cell proliferation', 'CPA', (32, 50))
220701	32185124	Another study showed that HOTAIR (HOX transcript antisense RNA) knockdown inhibited the motility and invasiveness of A375 cells and reduced the degradation of the extracellular matrix.	('inhibited', 'NegReg', (74, 83))	('A375', 'CellLine', 'CVCL:0132', (117, 121))	('HOX transcript antisense RNA', 'Gene', (34, 62))	('reduced', 'NegReg', (132, 139))	('HOTAIR', 'Gene', (26, 32))	('HOTAIR', 'Gene', '100124700', (26, 32))	('HOX transcript antisense RNA', 'Gene', '100124700', (34, 62))	('knockdown', 'Var', (64, 73))	('degradation of the extracellular matrix', 'MPA', (144, 183))
220710	32185124	In this review, we summarized the role of lncRNA in cutaneous squamous cell carcinoma to make a better understanding of mutations in cSCC and lay the foundation for effective target therapy of cSCC.	('cutaneous squamous cell carcinoma', 'Disease', (52, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('cSCC', 'Disease', (193, 197))	('cSCC', 'Phenotype', 'HP:0006739', (133, 137))	('cutaneous squamous cell carcinoma', 'Phenotype', 'HP:0006739', (52, 85))	('cSCC', 'Disease', 'MESH:D002294', (193, 197))	('cutaneous squamous cell carcinoma', 'Disease', 'MESH:D002294', (52, 85))	('cSCC', 'Disease', (133, 137))	('cSCC', 'Phenotype', 'HP:0006739', (193, 197))	('mutations', 'Var', (120, 129))	('cSCC', 'Disease', 'MESH:D002294', (133, 137))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (62, 85))
220715	32185124	PICSAR, LINC00319, THOR, AK144841, LINC10148, TINCR, and LINC00520 were only found in cSCC, which have a potential to be specific markers of cSCC.	('LINC00520', 'Gene', '645687', (57, 66))	('THOR', 'Chemical', '-', (19, 23))	('AK144841', 'Chemical', '-', (25, 33))	('cSCC', 'Disease', (141, 145))	('TINCR', 'Gene', (46, 51))	('cSCC', 'Disease', (86, 90))	('AK144841', 'Var', (25, 33))	('LINC00520', 'Gene', (57, 66))	('cSCC', 'Disease', 'MESH:D002294', (141, 145))	('LINC00319', 'Gene', '284836', (8, 17))	('cSCC', 'Disease', 'MESH:D002294', (86, 90))	('LINC00319', 'Gene', (8, 17))	('PICSAR', 'Gene', '378825', (0, 6))	('TINCR', 'Gene', '257000', (46, 51))	('cSCC', 'Phenotype', 'HP:0006739', (86, 90))	('PICSAR', 'Gene', (0, 6))	('cSCC', 'Phenotype', 'HP:0006739', (141, 145))	('LINC10148', 'Var', (35, 44))
220740	31408937	Over time, great efforts have been made to improve the efficacy of TCRm antibodies through affinity maturation, Fc glycosylation and chimeric antigen receptor(CAR) modification, which exhibited higher potency while none of them were applied in clinical studies.	('Fc glycosylation and chimeric antigen receptor(CAR)', 'Gene', '653108', (112, 163))	('improve', 'PosReg', (43, 50))	('TCRm', 'Protein', (67, 71))	('modification', 'Var', (164, 176))	('efficacy', 'MPA', (55, 63))	('Fc glycosylation and chimeric antigen receptor(CAR', 'Gene', (112, 162))
220746	31408937	The Bi-TCRm-ADC exerted more potent tumor cytotoxicity compared with TCRm-ADCs, which is a promising strategy to enhance the antitumor effects of TCRm-ADCs.	('cytotoxicity', 'Disease', 'MESH:D064420', (42, 54))	('Bi-TCRm-ADC', 'Var', (4, 15))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('cytotoxicity', 'Disease', (42, 54))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumor', 'Disease', (129, 134))	('tumor', 'Disease', (36, 41))
220755	31408937	We used RMF-pulsed T2, K562-A2-WT1126-134, and A431 to verify the specificity of ESK and Q2L.	('ESK', 'Gene', (81, 84))	('K562-A2-WT1126-134', 'CellLine', 'CVCL:9120', (23, 41))	('ESK', 'Gene', '7272', (81, 84))	('K562-A2-WT1126-134', 'Var', (23, 41))	('A431', 'CellLine', 'CVCL:0037', (47, 51))
220760	31408937	As Figure 2D showed, TCRm-ADCs could bind to K562-A2-WT1126-134 in a dose-dependent manner, which means that the higher the concentration is, the more TCRm-ADCs bind to the cell surface.	('K562-A2-WT1126-134', 'Var', (45, 63))	('bind', 'Interaction', (37, 41))	('K562-A2-WT1126-134', 'CellLine', 'CVCL:9120', (45, 63))	('more', 'PosReg', (146, 150))	('bind', 'Interaction', (161, 165))
220762	31408937	As shown in Figure 3A, approximately 50%-65% of TCRm antibodies and conjugates were internalized by K562-A2-WT1126-134 after 2 h of incubation.	('internalized', 'MPA', (84, 96))	('K562-A2-WT1126-134', 'CellLine', 'CVCL:9120', (100, 118))	('K562-A2-WT1126-134', 'Var', (100, 118))	('TCRm antibodies', 'Protein', (48, 63))
220764	31408937	TCRm antibodies/TCRm-ADCs pre-incubated with K562-A2-WT1126-134 at 37  C were stained with Cy5-labeled anti-human Fc antibody and lysosomal-associated membrane protein-1 (LAMP-1, the lysosomal marker) was stained by Cy3.	('LAMP-1', 'Gene', (171, 177))	('Cy5', 'Chemical', 'MESH:C085321', (91, 94))	('K562-A2-WT1126-134', 'Var', (45, 63))	('LAMP-1', 'Gene', '3916', (171, 177))	('human', 'Species', '9606', (108, 113))	('K562-A2-WT1126-134', 'CellLine', 'CVCL:9120', (45, 63))	('Cy3', 'Chemical', '-', (216, 219))
220767	31408937	In order to evaluate the cytotoxicity of TCRm-ADCs, WT1 RMF/HLA-A*02:01 complex positive and negative cell lines were exposed to ESK-MMAE and Q2L-MMAE for 96 h. The results showed that ESK-MMAE and Q2L-MMAE displayed a specific killing effect on K562-A2-WT1126-134 compared to negative cells (A431) (Figure 4A).	('cytotoxicity', 'Disease', 'MESH:D064420', (25, 37))	('ESK', 'Gene', (129, 132))	('K562-A2-WT1126-134', 'CellLine', 'CVCL:9120', (246, 264))	('HLA-A', 'Gene', '3105', (60, 65))	('HLA-A', 'Gene', (60, 65))	('WT1', 'Gene', '7490', (254, 257))	('A431', 'CellLine', 'CVCL:0037', (293, 297))	('ESK', 'Gene', (185, 188))	('WT1', 'Gene', (254, 257))	('WT1', 'Gene', '7490', (52, 55))	('cytotoxicity', 'Disease', (25, 37))	('ESK', 'Gene', '7272', (129, 132))	('Q2L-MMAE', 'Var', (198, 206))	('WT1', 'Gene', (52, 55))	('ESK', 'Gene', '7272', (185, 188))	('killing', 'CPA', (228, 235))
220768	31408937	Although the affinity of ESK-MMAE was higher than that of Q2L-MMAE, two TCRm-ADCs showed similar antitumor activity on K562-A2-WT1126-134 and the IC50 of ESK-MMAE and Q2L-MMAE was 7 and 9 mug/mL, respectively, which was probably caused by the low peptide presentation on the K562-A2-WT1126-134 cell surface.	('ESK', 'Gene', (154, 157))	('K562-A2-WT1126-134', 'Var', (119, 137))	('K562-A2-WT1126-134', 'CellLine', 'CVCL:9120', (119, 137))	('tumor', 'Disease', (101, 106))	('ESK', 'Gene', (25, 28))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('K562-A2-WT1126-134', 'CellLine', 'CVCL:9120', (275, 293))	('affinity', 'Interaction', (13, 21))	('higher', 'PosReg', (38, 44))	('ESK', 'Gene', '7272', (154, 157))	('ESK', 'Gene', '7272', (25, 28))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
220769	31408937	The in vivo efficacy of TCRm-ADCs was modeled from K562-A2-WT1126-134 leukemia xenograft model in BALB/c nude mice.	('nude mice', 'Species', '10090', (105, 114))	('leukemia', 'Disease', (70, 78))	('K562-A2-WT1126-134', 'Var', (51, 69))	('leukemia', 'Disease', 'MESH:D007938', (70, 78))	('leukemia', 'Phenotype', 'HP:0001909', (70, 78))	('K562-A2-WT1126-134', 'CellLine', 'CVCL:9120', (51, 69))
220777	31408937	Although the relative body weights of each group were slightly reduced, the body weight changes of TCRm-ADC-treated mice were less than that of PBS-treated mice, suggesting that the body weight of the mice was largely affected by tumor burden.	('tumor', 'Disease', (230, 235))	('mice', 'Species', '10090', (116, 120))	('TCRm-ADC-treated', 'Var', (99, 115))	('affected', 'Reg', (218, 226))	('reduced', 'NegReg', (63, 70))	('PBS', 'Chemical', 'MESH:D007854', (144, 147))	('mice', 'Species', '10090', (201, 205))	('tumor', 'Disease', 'MESH:D009369', (230, 235))	('mice', 'Species', '10090', (156, 160))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))
220784	31408937	K562-A2-NY-ESO-1157-165 is an HLA-A*02:01+, WT1+ and NY-ESO-1+ cell line and 1G4113-4 was a Fc-fused TCR against NY-ESO-1 SLL/HLA-A*02:01 complex that we established before (Figure 5A).	('HLA-A', 'Gene', '3105', (30, 35))	('WT1', 'Gene', (44, 47))	('HLA-A', 'Gene', '3105', (126, 131))	('NY-ESO-1', 'Gene', '246100', (8, 16))	('NY-ESO-1', 'Gene', (8, 16))	('HLA-A', 'Gene', (30, 35))	('K562', 'CellLine', 'CVCL:0004', (0, 4))	('HLA-A', 'Gene', (126, 131))	('NY-ESO-1', 'Gene', '246100', (53, 61))	('NY-ESO-1', 'Gene', (53, 61))	('NY-ESO-1', 'Gene', '246100', (113, 121))	('NY-ESO-1', 'Gene', (113, 121))	('1G4113-4', 'Var', (77, 85))	('WT1', 'Gene', '7490', (44, 47))
220792	31408937	We next determined the in vitro antitumor activity of ESK-1G4-MMAE, ESK-MMAE, and 1G4113-4-MMAE against K562-A2-NY-ESO-1157-165.	('ESK', 'Gene', (68, 71))	('ESK', 'Gene', (54, 57))	('ESK', 'Gene', '7272', (68, 71))	('K562', 'CellLine', 'CVCL:0004', (104, 108))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('ESK', 'Gene', '7272', (54, 57))	('1G4113-4-MMAE', 'Var', (82, 95))	('NY-ESO-1', 'Gene', '246100', (112, 120))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('NY-ESO-1', 'Gene', (112, 120))	('tumor', 'Disease', (36, 41))
220814	31408937	HLA I-mediated presentation of intracellular tumor-associated proteins (including highly expressed proteins and mutant proteins) provides promising tumor targets for antibody-based immunotherapy (e.g., mAbs, ADCs, CAR-T, CAR-NK) and remarkably broadens antigen selection.	('CAR', 'Gene', (214, 217))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('tumor', 'Disease', (45, 50))	('tumor', 'Disease', (148, 153))	('CAR', 'Gene', '653108', (221, 224))	('CAR', 'Gene', '653108', (214, 217))	('CAR-T', 'Gene', '9607', (214, 219))	('mutant', 'Var', (112, 118))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('CAR-T', 'Gene', (214, 219))	('CAR', 'Gene', (221, 224))
220815	31408937	Tumor mutant peptides presented on the cell surface by HLA I molecules (e.g., KRAS G12V, EGFR L858R) as tumor-specific antigens (TSAs, also called neoantigens), are likely favorable targets for TCRm-ADCs since they are solely present on tumor cell surfaces, although it is still difficult so far for us to screen the specific TCRm antibodies which can discriminate between the wild types and mutant forms of the antigenic peptides, especially when some mutant residues are shielded by the HLA-I molecules.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('G12V', 'Mutation', 'p.G12V', (83, 87))	('tumor', 'Disease', (237, 242))	('L858R', 'Mutation', 'p.L858R', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumor', 'Disease', (104, 109))	('mutant', 'Var', (392, 398))	('tumor', 'Disease', 'MESH:D009369', (237, 242))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
220827	31408937	The C-terminus of the heavy chain of ESK and 1G4113-4 was genetically fused with GGGGSLPETGHHHHHH and GGGGSLPETGG, respectively.	('ESK', 'Gene', '7272', (37, 40))	('ESK', 'Gene', (37, 40))	('1G4113-4', 'Var', (45, 53))
220830	31408937	Another 384-well microplate contained WT1 RMF/HLA-A*02:01-Fc complex at 5 different concentrations (6.25-100 nM (ESK)/100-1600 nM (Q2L), in 2-fold serial dilutions).	('6.25-100 nM', 'Var', (100, 111))	('ESK', 'Gene', (113, 116))	('WT1', 'Gene', '7490', (38, 41))	('ESK', 'Gene', '7272', (113, 116))	('WT1', 'Gene', (38, 41))	('HLA-A', 'Gene', '3105', (46, 51))	('HLA-A', 'Gene', (46, 51))
220837	31408937	Antibodies with C-terminal LPETG sequence were conjugated to Gly3-val-cit-PAB-MMAE (vcMMAE, Concortis, San Diego, CA, USA) by incubating 2 muM antibodies with 200 muM vcMMAE in the presence of 50 muM sortase A in reaction buffer (50 mM Tris, 150 mM NaCl, 5 mM CaCl2, pH 7.5) for 24 h at 37  C. ADCs were purified by protein A chromatography and washed repeatedly with PBS by ultrafiltration.	('muM', 'Gene', '56925', (196, 199))	('CaCl2', 'Chemical', 'MESH:D002122', (260, 265))	('muM', 'Gene', '56925', (163, 166))	('muM', 'Gene', (196, 199))	('NaCl', 'Chemical', 'MESH:D012965', (249, 253))	('muM', 'Gene', '56925', (139, 142))	('PBS', 'Chemical', 'MESH:D007854', (368, 371))	('muM', 'Gene', (163, 166))	('Gly3-val', 'SUBSTITUTION', 'None', (61, 69))	('Tris', 'Chemical', '-', (236, 240))	('muM', 'Gene', (139, 142))	('Gly3-val', 'Var', (61, 69))
220887	29673314	For instance, the mutation rate at TC* sites is particularly high in skin cutaneous melanoma, with the largest proportion of mutations at TCC positions of all cancer types.	('cancer', 'Disease', (159, 165))	('melanoma', 'Phenotype', 'HP:0002861', (84, 92))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (69, 92))	('skin cutaneous melanoma', 'Disease', (69, 92))	('high', 'Reg', (61, 65))	('mutation', 'Var', (18, 26))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (74, 92))
220889	29673314	In colorectal cancer, we observe a high proportion of mutations at TCG and TCT sites.	('TCG', 'Chemical', '-', (67, 70))	('colorectal cancer', 'Phenotype', 'HP:0003003', (3, 20))	('mutations', 'Var', (54, 63))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('colorectal cancer', 'Disease', (3, 20))	('colorectal cancer', 'Disease', 'MESH:D015179', (3, 20))
220890	29673314	These can be attributed to mutations in the POLE gene that cause DNA polymerase epsilon deficiency: we find an increased overall mutation rate, a very high proportion of T[C >A]T and T[C >T]G mutations and a high contribution of COSMIC signature 10 in six out of 42 colon cancer samples.	('cancer', 'Phenotype', 'HP:0002664', (272, 278))	('colon cancer', 'Disease', 'MESH:D015179', (266, 278))	('increased', 'PosReg', (111, 120))	('epsilon deficiency', 'Disease', (80, 98))	('epsilon deficiency', 'Disease', 'MESH:D001321', (80, 98))	('colon cancer', 'Phenotype', 'HP:0003003', (266, 278))	('T[C >A]', 'Var', (170, 177))	('colon cancer', 'Disease', (266, 278))	('mutation', 'MPA', (129, 137))	('T[C >T]G mutations', 'Var', (183, 201))
220891	29673314	Five of those (and three of the other colon cancer samples) have a nonsynonymous mutation in POLE and one of them in addition in POLD1, which encodes the DNA polymerase delta (Additional file 1: Figure S1).	('nonsynonymous mutation', 'Var', (67, 89))	('POLE', 'Gene', (93, 97))	('DNA polymerase delta', 'Gene', '5424', (154, 174))	('POLD1', 'Gene', (129, 134))	('POLD1', 'Gene', '5424', (129, 134))	('DNA polymerase delta', 'Gene', (154, 174))	('colon cancer', 'Phenotype', 'HP:0003003', (38, 50))	('colon cancer', 'Disease', 'MESH:D015179', (38, 50))	('colon cancer', 'Disease', (38, 50))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
220893	29673314	Coding regions tend to have fewer mutations in all cancer types.	('fewer', 'NegReg', (28, 33))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('mutations', 'Var', (34, 43))
220913	29673314	Here, the observed mutations are more spread than in KRAS, but they mainly occur in highly conserved exonic regions, where the neutral model predicts a low mutation rate.	('KRAS', 'Gene', '3845', (53, 57))	('occur', 'Reg', (75, 80))	('KRAS', 'Gene', (53, 57))	('mutations', 'Var', (19, 28))
220918	29673314	In breast cancer, head and neck squamous cell carcinoma, kidney chromophobe and thyroid carcinoma, this difference is much more pronounced at A:T positions than at G:C positions, but there is no general pattern with respect to the mutation type.	('A:T positions', 'Var', (142, 155))	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (80, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (46, 55))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('breast cancer', 'Disease', (3, 16))	('thyroid carcinoma', 'Disease', (80, 97))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (32, 55))	('head and neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (18, 55))	('kidney chromophobe', 'Disease', (57, 75))	('kidney chromophobe', 'Disease', 'MESH:D000238', (57, 75))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (80, 97))
220919	29673314	2c; later replicating regions have more mutations), but the regression coefficient varies significantly between the different cancer types and the mutation types (Fig.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('varies', 'Reg', (83, 89))	('mutations', 'Var', (40, 49))
220923	29673314	The most extreme example is the probability of a C > T mutation in highly expressed regions in melanoma, which is only one fifth of the probability in lowly expressed ones (Fig.	('C > T mutation', 'Var', (49, 63))	('melanoma', 'Disease', 'MESH:D008545', (95, 103))	('melanoma', 'Phenotype', 'HP:0002861', (95, 103))	('melanoma', 'Disease', (95, 103))
220926	29673314	We find that the mutation rates differ between the different types of mutations, but also between the specific contexts that we consider: CpG, to capture the pattern of spontaneous deamination, and TpCp[AT], to capture the APOBEC signature.	('mutations', 'Var', (70, 79))	('TpCp', 'Gene', (198, 202))	('APOBEC', 'MPA', (223, 229))	('spontaneous deamination', 'MPA', (169, 192))	('TpCp', 'Gene', '8030', (198, 202))	('AT', 'Disease', 'None', (203, 205))
220927	29673314	We find that the C > T mutation rate is higher in CpG sites than in other sites in all cancer types.	('cancer', 'Disease', (87, 93))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('higher', 'Reg', (40, 46))	('C > T mutation', 'Var', (17, 31))	('CpG', 'Disease', (50, 53))
220928	29673314	In skin cutaneous melanoma, we also observe elevated mutation rate for CC context, which is related to the elevated CC > TT mutation rate due to UV light.	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (3, 26))	('mutation', 'Var', (53, 61))	('elevated', 'PosReg', (44, 52))	('skin cutaneous melanoma', 'Disease', (3, 26))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (8, 26))	('melanoma', 'Phenotype', 'HP:0002861', (18, 26))
220929	29673314	We observe elevated rates of mutations that fit the APOBEC pattern in breast cancer, bladder urothelial carcinoma, head and neck squamous cell carcinoma, lung squamous cell carcinoma and skin cutaneous melanoma.	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (192, 210))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (159, 182))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (154, 182))	('lung squamous cell carcinoma', 'Disease', (154, 182))	('breast cancer', 'Phenotype', 'HP:0003002', (70, 83))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('breast cancer', 'Disease', 'MESH:D001943', (70, 83))	('breast cancer', 'Disease', (70, 83))	('head and neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (115, 152))	('bladder urothelial carcinoma', 'Disease', (85, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (143, 152))	('mutations', 'Var', (29, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (173, 182))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (187, 210))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (85, 113))	('melanoma', 'Phenotype', 'HP:0002861', (202, 210))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('skin cutaneous melanoma', 'Disease', (187, 210))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (129, 152))
220940	29673314	Since TCR is a subpathway of nucleotide excision repair (NER), it is expected to act on helix-distorting mutations like for example the well-known UV light induced CC > TT mutations in melanoma.	('melanoma', 'Disease', 'MESH:D008545', (185, 193))	('mutations', 'Var', (172, 181))	('melanoma', 'Phenotype', 'HP:0002861', (185, 193))	('melanoma', 'Disease', (185, 193))
220941	29673314	Thus, the cancer specific differences that we see might be explained by varying effectiveness of TCR, but also by different proportions of mutations that create bulky distortions.	('mutations', 'Var', (139, 148))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('cancer', 'Disease', (10, 16))	('cancer', 'Disease', 'MESH:D009369', (10, 16))
220942	29673314	For example, the rate of C > T mutations is further decreased in highly expressed regions in melanoma than the other mutation types.	('melanoma', 'Phenotype', 'HP:0002861', (93, 101))	('melanoma', 'Disease', (93, 101))	('melanoma', 'Disease', 'MESH:D008545', (93, 101))	('decreased', 'NegReg', (52, 61))	('C > T mutations', 'Var', (25, 40))
220949	29673314	Known somatic or germline mutations that are associated with specific mutational processes or repair pathways can also be used as explanatory variables, e. g. a germline deletion of APOBEC3B that fuses APOBEC3A with the 3' UTR of APOBEC3B has been found to be associated with an increased number of APOBEC-type mutations.	('APOBEC3A', 'Gene', '200315', (202, 210))	('APOBEC3B', 'Gene', (182, 190))	('APOBEC3B', 'Gene', (230, 238))	('APOBEC-type mutations', 'Disease', (299, 320))	('APOBEC3B', 'Gene', '9582', (230, 238))	('APOBEC3B', 'Gene', '9582', (182, 190))	('APOBEC3A', 'Gene', (202, 210))	('associated', 'Reg', (260, 270))	('deletion', 'Var', (170, 178))
220976	25028671	Patients with epidermal growth factor receptor mutation (EGFR-M) reached the highest PFS (204 days), as did patients with good performance status (ECOG 0-1: 94 versus ECOG 2-3: 65 days, P = 0.035).	('PFS', 'MPA', (85, 88))	('mutation', 'Var', (47, 55))	('epidermal growth factor receptor', 'Gene', (14, 46))	('EGFR', 'Gene', '1956', (57, 61))	('epidermal growth factor receptor', 'Gene', '1956', (14, 46))	('EGFR', 'Gene', (57, 61))
220981	25028671	It is approved in the treatment of non-small-cell lung cancer (NSCLC) in the first-line when patients are EGFR mutation-positive and in second-line and more-line therapy regardless of mutation status.	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('non-small-cell lung cancer', 'Disease', (35, 61))	('non-small-cell lung cancer', 'Disease', 'MESH:D002289', (35, 61))	('NSCLC', 'Phenotype', 'HP:0030358', (63, 68))	('lung cancer', 'Phenotype', 'HP:0100526', (50, 61))	('mutation-positive', 'Var', (111, 128))	('EGFR', 'Gene', (106, 110))
221001	33572359	Upon such interplay, both cancer cells and fibroblasts are reprogrammed to sustain malignancy, with changes in the repertoire of noncoding RNAs, mainly microRNAs and long noncoding RNAs.	('cancer', 'Disease', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('malignancy', 'Disease', 'MESH:D009369', (83, 93))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('malignancy', 'Disease', (83, 93))	('changes', 'Reg', (100, 107))	('noncoding RNAs', 'Protein', (129, 143))	('long noncoding RNAs', 'Var', (166, 185))
221008	33572359	Upon presenting a comprehensive view of the existing literature, we provide our critical opinion regarding the possible clinical utility of tumor-stroma related noncoding RNAs as therapeutic target/tools or prognostic/predictive biomarkers.	('tumor-stroma', 'Disease', 'MESH:D009369', (140, 152))	('tumor-stroma', 'Disease', (140, 152))	('noncoding RNAs', 'Var', (161, 175))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))
221013	33572359	CAF-induced changes cover almost all of the hallmarks of cancer, such as the increased cell proliferation, epithelial-mesenchymal transition (EMT) with enhanced invasion capabilities, angiogenesis and metabolic reprogramming (Figure 1a).	('metabolic reprogramming', 'CPA', (201, 224))	('angiogenesis', 'CPA', (184, 196))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('cancer', 'Disease', (57, 63))	('invasion capabilities', 'CPA', (161, 182))	('cell proliferation', 'CPA', (87, 105))	('CAF', 'Gene', (0, 3))	('epithelial-mesenchymal transition', 'CPA', (107, 140))	('enhanced', 'PosReg', (152, 160))	('increased', 'PosReg', (77, 86))	('CAF', 'Gene', '8850', (0, 3))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('changes', 'Var', (12, 19))
221019	33572359	Plenty of evidence has been collected to show that the aberrant miRNA expression found in almost all types of human cancer is not only the consequence rather one of the causes of transformation and tumor progression.	('cancer', 'Disease', (116, 122))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('aberrant', 'Var', (55, 63))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('human', 'Species', '9606', (110, 115))	('miRNA', 'Protein', (64, 69))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('tumor', 'Disease', (198, 203))
221042	33572359	In this regard, Mitra showed that inhibiting miR-31/miR-214 and overexpressing miR-155 in normal ovarian fibroblasts (thus mimicking the miRNA expression pattern found in CAFs) induced their conversion to a CAF-like state.	('inhibiting', 'Var', (34, 44))	('induced', 'Reg', (177, 184))	('CAF', 'Gene', (207, 210))	('CAFs', 'Gene', (171, 175))	('miR-155', 'Gene', '406947', (79, 86))	('miR-214', 'Gene', (52, 59))	('miR-31', 'Gene', (45, 51))	('CAF', 'Gene', '8850', (207, 210))	('miR-214', 'Gene', '406996', (52, 59))	('conversion', 'MPA', (191, 201))	('CAF', 'Gene', (171, 174))	('CAFs', 'Gene', '6899', (171, 175))	('CAF', 'Gene', '8850', (171, 174))	('miR-31', 'Gene', '407035', (45, 51))	('miR-155', 'Gene', (79, 86))
221056	33572359	Inhibition of miR-21 in CAFs was shown to reduce glycolysis and inhibit their capability to reprogram the metabolism of adjacent tumor cells, thus ultimately reducing cancer aggressiveness.	('miR-21', 'Gene', '406991', (14, 20))	('cancer aggressiveness', 'Disease', (167, 188))	('CAFs', 'Gene', (24, 28))	('miR-21', 'Gene', (14, 20))	('reducing', 'NegReg', (158, 166))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('aggressiveness', 'Phenotype', 'HP:0000718', (174, 188))	('inhibit', 'NegReg', (64, 71))	('cancer aggressiveness', 'Disease', 'MESH:D009369', (167, 188))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('reduce', 'NegReg', (42, 48))	('Inhibition', 'Var', (0, 10))	('CAFs', 'Gene', '6899', (24, 28))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('tumor', 'Disease', (129, 134))	('glycolysis', 'MPA', (49, 59))
221063	33572359	The former was found to act as molecular sponge for miR-14, which thus resulted to be depleted in CAF-exosomes and ultimately led to increased invasion and metastasis of oral squamous cell carcinoma cells.	('miR-14', 'Var', (52, 58))	('CAF', 'Gene', (98, 101))	('invasion', 'CPA', (143, 151))	('metastasis', 'CPA', (156, 166))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (170, 198))	('miR-14', 'Chemical', '-', (52, 58))	('CAF', 'Gene', '8850', (98, 101))	('increased', 'PosReg', (133, 142))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (175, 198))	('carcinoma', 'Phenotype', 'HP:0030731', (189, 198))	('oral squamous cell carcinoma', 'Disease', (170, 198))
221065	33572359	A comprehensive list of intracellular ncRNAs found to be deregulated in CAFs and/or associated with fibroblast activation is reported in Table 1 (left).	('deregulated', 'Var', (57, 68))	('ncRNA', 'Gene', (38, 43))	('CAFs', 'Gene', (72, 76))	('associated', 'Reg', (84, 94))	('fibroblast activation', 'CPA', (100, 121))	('ncRNA', 'Gene', '220202', (38, 43))	('CAFs', 'Gene', '6899', (72, 76))
221082	33572359	Such lncRNA demonstrated to be essential for TGFbeta1-driven EMT, as ZEB2NAT depletion reversed CAF-induced acquisition of mesenchymal features and invasive phenotype, though the reduction of ZEB2 protein levels.	('ZEB2', 'Gene', '9839', (192, 196))	('ZEB2NAT', 'Gene', '100303491', (69, 76))	('depletion', 'Var', (77, 86))	('invasive phenotype', 'CPA', (148, 166))	('ZEB2', 'Gene', '9839', (69, 73))	('acquisition', 'CPA', (108, 119))	('ncRNA', 'Gene', (6, 11))	('ZEB2', 'Gene', (192, 196))	('CAF', 'Gene', (96, 99))	('TGFbeta1', 'Gene', '7040', (45, 53))	('TGFbeta1', 'Gene', (45, 53))	('reduction', 'NegReg', (179, 188))	('ncRNA', 'Gene', '220202', (6, 11))	('ZEB2', 'Gene', (69, 73))	('CAF', 'Gene', '8850', (96, 99))	('ZEB2NAT', 'Gene', (69, 76))
221083	33572359	Aside from cell proliferation and EMT, metabolic reprogramming in tumors cells is also mediated by the CAF-induced variation of lncRNAs.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('metabolic reprogramming', 'CPA', (39, 62))	('ncRNA', 'Gene', (129, 134))	('CAF', 'Gene', '8850', (103, 106))	('mediated by', 'Reg', (87, 98))	('tumors', 'Disease', (66, 72))	('ncRNA', 'Gene', '220202', (129, 134))	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('variation', 'Var', (115, 124))	('CAF', 'Gene', (103, 106))
221100	33572359	This class of exosomal miRNAs includes miR-34a-5p in oral squamous cell carcinoma, miR-4516 and miR-1-3p in breast cancer, miR-148b and miR-320a in endometrial cancer and miR-320a in hepatocellular carcinoma.	('miR-4516', 'Gene', '100616258', (83, 91))	('hepatocellular carcinoma', 'Disease', (183, 207))	('miR-34a', 'Gene', '407040', (39, 46))	('miR-320a', 'Gene', (171, 179))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('miR-1-3p', 'Var', (96, 104))	('carcinoma', 'Phenotype', 'HP:0030731', (198, 207))	('endometrial cancer', 'Phenotype', 'HP:0012114', (148, 166))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('breast cancer', 'Phenotype', 'HP:0003002', (108, 121))	('miR-320a', 'Gene', '407037', (171, 179))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (183, 207))	('endometrial cancer', 'Disease', (148, 166))	('miR-148b', 'Gene', '442892', (123, 131))	('miR-320a', 'Gene', (136, 144))	('breast cancer', 'Disease', 'MESH:D001943', (108, 121))	('endometrial cancer', 'Disease', 'MESH:D016889', (148, 166))	('miR-148b', 'Gene', (123, 131))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (58, 81))	('breast cancer', 'Disease', (108, 121))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (53, 81))	('miR-4516', 'Gene', (83, 91))	('oral squamous cell carcinoma', 'Disease', (53, 81))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (183, 207))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('miR-34a', 'Gene', (39, 46))	('miR-320a', 'Gene', '407037', (136, 144))
221101	33572359	Notably, for miR-148b, miR-1-3p and miR-320a, a role in tumor invasion and metastasis was also reported.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('miR-320a', 'Gene', (36, 44))	('tumor', 'Disease', (56, 61))	('miR-320a', 'Gene', '407037', (36, 44))	('metastasis', 'CPA', (75, 85))	('miR-1-3p', 'Var', (23, 31))	('miR-148b', 'Gene', '442892', (13, 21))	('miR-148b', 'Gene', (13, 21))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
221120	33572359	Melanosomes were also shown to carry the Gm26809 lncRNA, which was reported to mediate the reprogramming of NIH/3T3 fibroblasts into CAF-like cells, as evidenced by increased expression of activation markers (alpha-smooth actin and fibroblast activation protein) and cell migration.	('expression', 'MPA', (175, 185))	('ncRNA', 'Gene', (50, 55))	('alpha-smooth actin', 'Protein', (209, 227))	('Gm26809', 'Var', (41, 48))	('fibroblast activation protein', 'Gene', '14089', (232, 261))	('CAF', 'Gene', (133, 136))	('CAF', 'Gene', '8850', (133, 136))	('ncRNA', 'Gene', '220202', (50, 55))	('cell migration', 'CPA', (267, 281))	('NIH/3T3', 'CellLine', 'CVCL:0594', (108, 115))	('Gm26809', 'Chemical', '-', (41, 48))	('increased', 'PosReg', (165, 174))	('fibroblast activation protein', 'Gene', (232, 261))
221128	33572359	Aside from such direct anticancer effects, interruption of tumor-stroma interplay may also increase the response to conventional oncological therapies, in view of the increasingly reported role of CAFs in determining the sensitivity/resistance of tumor cells to a wide spectrum of chemo-, endocrine and radiotherapeutic regimens.	('tumor', 'Phenotype', 'HP:0002664', (247, 252))	('tumor-stroma', 'Disease', 'MESH:D009369', (59, 71))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Disease', (59, 64))	('tumor', 'Disease', (247, 252))	('interruption', 'Var', (43, 55))	('CAFs', 'Gene', '6899', (197, 201))	('increase', 'PosReg', (91, 99))	('tumor-stroma', 'Disease', (59, 71))	('cancer', 'Disease', (27, 33))	('cancer', 'Disease', 'MESH:D009369', (27, 33))	('tumor', 'Disease', 'MESH:D009369', (247, 252))	('response', 'MPA', (104, 112))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('CAFs', 'Gene', (197, 201))
221129	33572359	For example, CAF exosomes were shown to promote cisplatin resistance of ovarian cancer cells and head and neck cancer cells, through the delivery of miR-98-5p and miR-196a, respectively.	('promote', 'PosReg', (40, 47))	('cisplatin', 'Chemical', 'MESH:D002945', (48, 57))	('miR-98', 'Gene', (149, 155))	('CAF', 'Gene', (13, 16))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('ovarian cancer', 'Phenotype', 'HP:0100615', (72, 86))	('cisplatin resistance', 'MPA', (48, 68))	('head and neck cancer', 'Phenotype', 'HP:0012288', (97, 117))	('neck cancer', 'Disease', 'MESH:D006258', (106, 117))	('ovarian cancer', 'Disease', 'MESH:D010051', (72, 86))	('CAF', 'Gene', '8850', (13, 16))	('miR-98', 'Gene', '407054', (149, 155))	('ovarian cancer', 'Disease', (72, 86))	('neck cancer', 'Disease', (106, 117))	('miR-196a', 'Var', (163, 171))
221139	33572359	Such tools include chemically modified antisense oligonucleotides for the silencing of both miRNAs and lncRNAs or mimics for miRNA overexpression (Figure 1b).	('miRNAs', 'Protein', (92, 98))	('ncRNA', 'Gene', '220202', (104, 109))	('antisense', 'Var', (39, 48))	('silencing', 'NegReg', (74, 83))	('oligonucleotides', 'Chemical', 'MESH:D009841', (49, 65))	('ncRNA', 'Gene', (104, 109))
221145	33572359	In fact, lncRNAs can locally fold into a variety of secondary structures including helices, hairpins, loops, bulges, G-quadruplexes and pseudoknots, which can then interact to form higher order hierarchical structures.	('fold', 'Reg', (29, 33))	('ncRNA', 'Gene', (10, 15))	('G-quadruplexes', 'Var', (117, 131))	('ncRNA', 'Gene', '220202', (10, 15))	('pseudoknots', 'Disease', (136, 147))
221148	33572359	For example, through high-throughput molecular docking-based virtual screening of the PubChem library, the small compounds AC1Q3QWB and AC1NOD4Q were revealed to specifically interfere with HOTAIR function by inhibiting the interaction with EZH2.	('AC1Q3QWB', 'Var', (123, 131))	('HOTAIR', 'Gene', (190, 196))	('HOTAIR', 'Gene', '100124700', (190, 196))	('inhibiting', 'NegReg', (209, 219))	('interaction', 'Interaction', (224, 235))	('interfere', 'NegReg', (175, 184))	('EZH2', 'Gene', '2146', (241, 245))	('EZH2', 'Gene', (241, 245))	('AC1NOD4Q', 'Var', (136, 144))
221159	33572359	In this regard, high stromal TIRY expression in a prospective cohort of oral squamous cell carcinoma specimens was associated with tumor stage, metastasis status and poor prognosis, in terms of a shorter progression-free survival of patients.	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('shorter', 'NegReg', (196, 203))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('patients', 'Species', '9606', (233, 241))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (77, 100))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (72, 100))	('tumor', 'Disease', (131, 136))	('progression-free survival', 'CPA', (204, 229))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('metastasis', 'CPA', (144, 154))	('high stromal', 'Var', (16, 28))	('oral squamous cell carcinoma', 'Disease', (72, 100))
221173	33572359	In this context, high levels of plasma exosomal miR-196a were shown to be correlated with poor overall survival and chemoresistance in head and neck cancer patients.	('patients', 'Species', '9606', (156, 164))	('poor', 'NegReg', (90, 94))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('neck cancer', 'Disease', 'MESH:D006258', (144, 155))	('neck cancer', 'Disease', (144, 155))	('overall survival', 'CPA', (95, 111))	('chemoresistance', 'CPA', (116, 131))	('head and neck cancer', 'Phenotype', 'HP:0012288', (135, 155))	('miR-196a', 'Var', (48, 56))
221196	32772818	Further loss of function and enhancement experiments revealed that inhibition of microRNA9 could significantly inhibit lung squamous carcinoma cell proliferation and migration.	('inhibition', 'Var', (67, 77))	('inhibit', 'NegReg', (111, 118))	('lung squamous carcinoma', 'Disease', 'MESH:D002294', (119, 142))	('lung squamous carcinoma', 'Phenotype', 'HP:0030359', (119, 142))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('lung squamous carcinoma', 'Disease', (119, 142))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (124, 142))	('microRNA9', 'Gene', (81, 90))
221197	32772818	Luciferase reporter assay demonstrated that microRNA9 could bind to NRSF messenger RNA and inhibit its expression, neuron-restricted silencing factor overexpression also exerted inhibitory effects on cell proliferation and migration.	('migration', 'CPA', (223, 232))	('inhibit', 'NegReg', (91, 98))	('expression', 'MPA', (103, 113))	('neuron-restricted silencing factor', 'Gene', (115, 149))	('neuron-restricted silencing factor', 'Gene', '5978', (115, 149))	('NRSF', 'Gene', (68, 72))	('cell proliferation', 'CPA', (200, 218))	('bind', 'Interaction', (60, 64))	('microRNA9', 'Var', (44, 53))
221200	32772818	MicroRNA9 inhibits proliferation and migration of lung squamous cell carcinoma cells by inhibiting neuron-restricted silencing factor/epidermal growth factor receptor axis.	('epidermal growth factor receptor', 'Gene', (134, 166))	('lung squamous cell carcinoma', 'Disease', (50, 78))	('neuron-restricted silencing factor', 'Gene', '5978', (99, 133))	('inhibits', 'NegReg', (10, 18))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (55, 78))	('epidermal growth factor receptor', 'Gene', '1956', (134, 166))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (50, 78))	('proliferation', 'CPA', (19, 32))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (50, 78))	('MicroRNA9', 'Var', (0, 9))	('neuron-restricted silencing factor', 'Gene', (99, 133))	('inhibiting', 'NegReg', (88, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))
221209	32772818	Recent studies have shown that miRNA9 is unusually high in many cancers, but its role in tumors is controversial, for example, in promoting breast cancer but can inhibit the progression of melanoma.In addition, it has been reported that miRNA9 can influence the development of liver cancer.	('tumors', 'Disease', (89, 95))	('liver cancer', 'Disease', (277, 289))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('miRNA9', 'Var', (237, 243))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('breast cancer', 'Phenotype', 'HP:0003002', (140, 153))	('cancers', 'Phenotype', 'HP:0002664', (64, 71))	('cancers', 'Disease', (64, 71))	('development', 'CPA', (262, 273))	('melanoma', 'Disease', (189, 197))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('breast cancer', 'Disease', 'MESH:D001943', (140, 153))	('breast cancer', 'Disease', (140, 153))	('cancer', 'Phenotype', 'HP:0002664', (283, 289))	('liver cancer', 'Disease', 'MESH:D006528', (277, 289))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('cancers', 'Disease', 'MESH:D009369', (64, 71))	('influence', 'Reg', (248, 257))	('melanoma', 'Disease', 'MESH:D008545', (189, 197))	('liver cancer', 'Phenotype', 'HP:0002896', (277, 289))
221215	32772818	However, there are so many mutations in patients with SCC with EGFR that the current drugs are ineffective.	('mutations', 'Var', (27, 36))	('EGFR', 'Gene', '1956', (63, 67))	('SCC', 'Gene', '6317', (54, 57))	('EGFR', 'Gene', (63, 67))	('patients', 'Species', '9606', (40, 48))	('SCC', 'Gene', (54, 57))	('SCC', 'Phenotype', 'HP:0002860', (54, 57))
221238	32772818	NRSF-mut and EGFR-wt design binding site mutations based on NRSF-mu and EGFR-mu.	('mutations', 'Var', (41, 50))	('EGFR', 'Gene', '1956', (72, 76))	('binding', 'Interaction', (28, 35))	('EGFR', 'Gene', (72, 76))	('NRSF-mu', 'Gene', (60, 67))	('EGFR', 'Gene', '1956', (13, 17))	('EGFR', 'Gene', (13, 17))
221266	32772818	Overexpression of NRSF was able to downregulate EGFR expression, whereas knockdown of NRSF was able to upregulate EGFR (Figure 4E-G).	('NRSF', 'Gene', (86, 90))	('EGFR', 'Gene', '1956', (48, 52))	('EGFR', 'Gene', (48, 52))	('EGFR', 'Gene', '1956', (114, 118))	('downregulate', 'NegReg', (35, 47))	('upregulate', 'PosReg', (103, 113))	('expression', 'MPA', (53, 63))	('EGFR', 'Gene', (114, 118))	('knockdown', 'Var', (73, 82))
221267	32772818	Luciferase reporter gene experiments showed that overexpression of NRSF was able to significantly inhibit EGFR wild-type luciferase activity but had no significant effect on EGFR binding mutants (Figure 4H).	('EGFR', 'Gene', (174, 178))	('NRSF', 'Var', (67, 71))	('activity', 'MPA', (132, 140))	('EGFR', 'Gene', '1956', (174, 178))	('inhibit', 'NegReg', (98, 105))	('EGFR', 'Gene', '1956', (106, 110))	('EGFR', 'Gene', (106, 110))
221276	32772818	In this study, we found that miRNA9 is highly expressed in lung cancer and inhibition of miRNA9 can inhibit tumor proliferation and migration.	('lung cancer', 'Disease', 'MESH:D008175', (59, 70))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('inhibition', 'Var', (75, 85))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('miRNA9', 'Gene', (89, 95))	('lung cancer', 'Disease', (59, 70))	('tumor', 'Disease', (108, 113))	('lung cancer', 'Phenotype', 'HP:0100526', (59, 70))	('inhibit', 'NegReg', (100, 107))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
221280	32772818	In this study, we found that miRNA9 could inhibit the expression of NRSF, which was lower in cancer tissues in patients with pulmonary squamous cell carcinoma, and found that its low level of expression meant higher cancer malignancy and less patient survival.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (135, 158))	('cancer malignancy', 'Disease', (216, 233))	('pulmonary squamous cell carcinoma', 'Phenotype', 'HP:0030359', (125, 158))	('cancer', 'Disease', (216, 222))	('miRNA9', 'Var', (29, 35))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('patient', 'Species', '9606', (111, 118))	('pulmonary squamous cell carcinoma', 'Disease', (125, 158))	('pulmonary squamous cell carcinoma', 'Disease', 'MESH:D002294', (125, 158))	('cancer malignancy', 'Disease', 'MESH:D009369', (216, 233))	('carcinoma', 'Phenotype', 'HP:0030731', (149, 158))	('less', 'NegReg', (238, 242))	('higher', 'PosReg', (209, 215))	('cancer', 'Disease', 'MESH:D009369', (216, 222))	('expression', 'MPA', (54, 64))	('cancer', 'Disease', (93, 99))	('patient', 'Species', '9606', (243, 250))	('NRSF', 'Gene', (68, 72))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('lower', 'NegReg', (84, 89))	('inhibit', 'NegReg', (42, 49))	('patient survival', 'CPA', (243, 259))	('patients', 'Species', '9606', (111, 119))
221288	32772818	Because of the large number of mutations in EGFR in patients with lung cancer, the current drug treatment effect is not so useful.	('mutations', 'Var', (31, 40))	('lung cancer', 'Disease', (66, 77))	('lung cancer', 'Phenotype', 'HP:0100526', (66, 77))	('EGFR', 'Gene', '1956', (44, 48))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('EGFR', 'Gene', (44, 48))	('lung cancer', 'Disease', 'MESH:D008175', (66, 77))	('patients', 'Species', '9606', (52, 60))
221289	32772818	In this work, we found for the first time that miRNA9 can increase the expression level of EGFR by inhibiting NSFR and then the expression level of EGFR.	('expression level', 'MPA', (128, 144))	('increase', 'PosReg', (58, 66))	('EGFR', 'Gene', (91, 95))	('inhibiting', 'NegReg', (99, 109))	('miRNA9', 'Var', (47, 53))	('EGFR', 'Gene', '1956', (148, 152))	('EGFR', 'Gene', (148, 152))	('NSFR', 'MPA', (110, 114))	('expression level', 'MPA', (71, 87))	('EGFR', 'Gene', '1956', (91, 95))
221304	28072762	The KWIAIES motif, unique to TAM family members, is critical for kinase activity and shares close homology to similar sequences in related tyrosine kinases, including a similar motif in RET, which harbours the M918T-activating mutation frequently found in medullary thyroid cancer.	('RET', 'Gene', (186, 189))	('M918T', 'Mutation', 'rs74799832', (210, 215))	('TAM', 'Chemical', '-', (29, 32))	('thyroid cancer', 'Disease', (266, 280))	('tyrosine', 'Chemical', 'MESH:D014443', (139, 147))	('RET', 'Gene', '5979', (186, 189))	('thyroid cancer', 'Phenotype', 'HP:0002890', (266, 280))	('thyroid cancer', 'Disease', 'MESH:D013964', (266, 280))	('medullary thyroid cancer', 'Phenotype', 'HP:0002865', (256, 280))	('cancer', 'Phenotype', 'HP:0002664', (274, 280))	('M918T-activating', 'Var', (210, 226))
221323	28072762	Other studies have identified target sequences for microRNA (miRs) including miR-34 and miR-199a/b in the AXL 3' untranslated region (Figure 2C), with correlative findings confirming the effects of miRs on AXL expression.	('miR-199a/b', 'Var', (88, 98))	('AXL expression', 'MPA', (206, 220))	('miR-34', 'Gene', (77, 83))	('effects', 'Reg', (187, 194))	('miR-34', 'Gene', '407040', (77, 83))
221325	28072762	AXL mutations, fusions and/or amplifications are found in 3% or fewer of breast cancer, head and neck squamous cell carcinoma, lung adenocarcinoma, lung squamous cell carcinoma and acute myeloid leukaemia (Figure 2D) - each an example of a malignancy in which AXL over-expression is proposed to play a significant role in disease development, progression, metastasis or treatment resistance.	('fusions', 'Var', (15, 22))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (127, 146))	('acute myeloid leukaemia', 'Disease', (181, 204))	('carcinoma', 'Phenotype', 'HP:0030731', (167, 176))	('malignancy', 'Disease', (240, 250))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (102, 125))	('myeloid leukaemia', 'Phenotype', 'HP:0012324', (187, 204))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (88, 125))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (148, 176))	('acute myeloid leukaemia', 'Disease', 'MESH:D007938', (181, 204))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('breast cancer', 'Phenotype', 'HP:0003002', (73, 86))	('mutations', 'Var', (4, 13))	('lung adenocarcinoma', 'Disease', (127, 146))	('head and neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (88, 125))	('malignancy', 'Disease', 'MESH:D009369', (240, 250))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (153, 176))	('acute myeloid leukaemia', 'Phenotype', 'HP:0004808', (181, 204))	('breast cancer', 'Disease', 'MESH:D001943', (73, 86))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('breast cancer', 'Disease', (73, 86))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (148, 176))	('AXL', 'Gene', (0, 3))	('lung squamous cell carcinoma', 'Disease', (148, 176))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (127, 146))
221326	28072762	One study reported a fusion gene construct between AXL and MBIP in large-scale sequencing of primary lung adenocarcinoma samples, but this fusion event has not been reported elsewhere and is unlikely to offer further insights into the overexpression of AXL seen in these tumour types.	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (101, 120))	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('tumour', 'Phenotype', 'HP:0002664', (271, 277))	('primary lung adenocarcinoma', 'Disease', 'MESH:D000077192', (93, 120))	('MBIP', 'Gene', (59, 63))	('fusion', 'Var', (21, 27))	('MBIP', 'Gene', '51562', (59, 63))	('tumour', 'Disease', 'MESH:D009369', (271, 277))	('tumour', 'Disease', (271, 277))	('primary lung adenocarcinoma', 'Disease', (93, 120))
221328	28072762	Similar discordance is noted between genetic alterations and mRNA/protein expression in head and neck squamous cell carcinoma, and acute myeloid leukaemia.	('mRNA/protein expression', 'MPA', (61, 84))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (88, 125))	('acute myeloid leukaemia', 'Disease', (131, 154))	('acute myeloid leukaemia', 'Phenotype', 'HP:0004808', (131, 154))	('myeloid leukaemia', 'Phenotype', 'HP:0012324', (137, 154))	('acute myeloid leukaemia', 'Disease', 'MESH:D007938', (131, 154))	('genetic alterations', 'Var', (37, 56))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (102, 125))	('head and neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (88, 125))
221331	28072762	Small hairpin RNA-mediated knockdown of AXL expression in osteosarcoma cells has been associated with decreased proliferation, as marked by Ki-67 expression, and increased expression of apoptotic markers.	('knockdown', 'Var', (27, 36))	('osteosarcoma', 'Disease', (58, 70))	('increased', 'PosReg', (162, 171))	('osteosarcoma', 'Phenotype', 'HP:0002669', (58, 70))	('osteosarcoma', 'Disease', 'MESH:D012516', (58, 70))	('expression', 'MPA', (172, 182))	('AXL', 'Gene', (40, 43))	('proliferation', 'CPA', (112, 125))	('decreased', 'NegReg', (102, 111))
221332	28072762	Similarly, in prostate cancer cell lines, treatment with GAS6 stimulated proliferation, whereas AXL knockdown predictably led to decreased proliferation.	('knockdown', 'Var', (100, 109))	('AXL', 'Protein', (96, 99))	('proliferation', 'CPA', (73, 86))	('prostate cancer', 'Disease', 'MESH:D011471', (14, 29))	('GAS6', 'Var', (57, 61))	('prostate cancer', 'Phenotype', 'HP:0012125', (14, 29))	('proliferation', 'CPA', (139, 152))	('stimulated', 'PosReg', (62, 72))	('prostate cancer', 'Disease', (14, 29))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('decreased', 'NegReg', (129, 138))
221334	28072762	Small hairpin RNA knockdown of AXL resulted in decreased migration and invasion in colorectal and cervical cancer cell lines.	('knockdown', 'Var', (18, 27))	('AXL', 'Gene', (31, 34))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('invasion', 'CPA', (71, 79))	('migration', 'CPA', (57, 66))	('colorectal and cervical cancer', 'Disease', 'MESH:D015179', (83, 113))	('decreased', 'NegReg', (47, 56))
221342	28072762	Our data and other studies have shown that AXL knockdown leads to downregulation of transcription factors required for EMT, including Slug, Twist, and Zeb1, and to increased expression of E-cadherin (; unpublished data).	('EMT', 'Gene', '3702', (119, 122))	('Zeb1', 'Gene', '6935', (151, 155))	('Slug', 'Gene', '6591', (134, 138))	('Slug', 'Gene', (134, 138))	('Zeb1', 'Gene', (151, 155))	('expression', 'MPA', (174, 184))	('Twist', 'CPA', (140, 145))	('knockdown', 'Var', (47, 56))	('E-cadherin', 'Gene', (188, 198))	('E-cadherin', 'Gene', '999', (188, 198))	('downregulation', 'NegReg', (66, 80))	('AXL', 'Protein', (43, 46))	('EMT', 'Gene', (119, 122))	('increased', 'PosReg', (164, 173))
221344	28072762	For example, AXL expression is positively regulated by EZH2 in glioma cells, and silencing AXL in these cell lines mimicked the effect of EZH2 inhibition.	('positively', 'PosReg', (31, 41))	('EZH2', 'Gene', '2146', (55, 59))	('AXL expression', 'MPA', (13, 27))	('EZH2', 'Gene', '2146', (138, 142))	('EZH2', 'Gene', (55, 59))	('glioma', 'Disease', 'MESH:D005910', (63, 69))	('glioma', 'Phenotype', 'HP:0009733', (63, 69))	('silencing', 'Var', (81, 90))	('EZH2', 'Gene', (138, 142))	('regulated', 'Reg', (42, 51))	('glioma', 'Disease', (63, 69))
221351	28072762	In chick chorion allantoic membrane samples, GAS6 appears to inhibit VEGFA:VEGFR2-dependent angiogenesis in an AXL-dependent manner.	('VEGFA', 'Gene', (69, 74))	('GAS6', 'Var', (45, 49))	('inhibit', 'NegReg', (61, 68))	('VEGFA', 'Gene', '395909', (69, 74))	('chick', 'Species', '9031', (3, 8))
221366	28072762	Further findings showed that the overexpression of a wild-type AXL construct was sufficient to impair response to erlotinib in vitro, whereas a kinase-impaired AXL mutant induced no such resistance.	('overexpression', 'PosReg', (33, 47))	('mutant', 'Var', (164, 170))	('erlotinib', 'Chemical', 'MESH:D000069347', (114, 123))	('response to erlotinib', 'MPA', (102, 123))	('impair', 'NegReg', (95, 101))
221367	28072762	Upregulation of AXL protein was seen in 7 of 35 patient samples of EGFR-mutated NSCLC taken before treatment with EGFR inhibitor and after resistance occurred, including 2 of 8 samples with the EGFR p.Thr790Met resistance mutation.	('Upregulation', 'PosReg', (0, 12))	('EGFR', 'Gene', (67, 71))	('NSCLC', 'Disease', (80, 85))	('EGFR', 'Gene', '1956', (114, 118))	('p.Thr790Met', 'Var', (199, 210))	('patient', 'Species', '9606', (48, 55))	('EGFR', 'Gene', '1956', (194, 198))	('AXL protein', 'Protein', (16, 27))	('EGFR', 'Gene', (194, 198))	('EGFR', 'Gene', '1956', (67, 71))	('EGFR', 'Gene', (114, 118))	('p.Thr790Met', 'Mutation', 'rs121434569', (199, 210))	('NSCLC', 'Disease', 'MESH:D002289', (80, 85))
221370	28072762	Selective knockdown of AXL restored sensitivity in imatinib-resistant chronic myeloid leukaemia cell lines.	('imatinib', 'Chemical', 'MESH:D000068877', (51, 59))	('chronic myeloid leukaemia', 'Disease', (70, 95))	('myeloid leukaemia', 'Phenotype', 'HP:0012324', (78, 95))	('chronic myeloid leukaemia', 'Disease', 'MESH:D015464', (70, 95))	('AXL', 'Gene', (23, 26))	('chronic myeloid leukaemia', 'Phenotype', 'HP:0005506', (70, 95))	('sensitivity', 'MPA', (36, 47))	('knockdown', 'Var', (10, 19))
221373	28072762	For example, in PIK3CA mutant or amplified head and neck squamous cell carcinoma, resistance to PI3K inhibitors is linked to high AXL expression.	('head and neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (43, 80))	('PIK3CA', 'Gene', '5290', (16, 22))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (57, 80))	('linked', 'Reg', (115, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (43, 80))	('PIK3CA', 'Gene', (16, 22))	('high', 'PosReg', (125, 129))	('AXL expression', 'MPA', (130, 144))	('mutant', 'Var', (23, 29))
221375	28072762	Similarly, in BRAF V600E mutant melanoma, low MITF to AXL expression ratio is associated with resistance to BRAF inhibitors.	('MITF', 'Gene', '4286', (46, 50))	('V600E', 'Mutation', 'rs113488022', (19, 24))	('melanoma', 'Disease', 'MESH:D008545', (32, 40))	('melanoma', 'Phenotype', 'HP:0002861', (32, 40))	('melanoma', 'Disease', (32, 40))	('BRAF', 'Gene', '673', (14, 18))	('V600E mutant', 'Var', (19, 31))	('BRAF', 'Gene', '673', (108, 112))	('low', 'NegReg', (42, 45))	('BRAF', 'Gene', (14, 18))	('BRAF', 'Gene', (108, 112))	('MITF', 'Gene', (46, 50))
221399	28072762	Given AXL's putative role as a mediator of EMT and cancer stemness, inhibiting AXL may also reveal intriguing results regarding the role of these processes in metastatic potential and/or chemosensitivity and chemoresistance.	('metastatic potential', 'CPA', (159, 179))	('cancer stemness', 'Disease', (51, 66))	('inhibiting', 'Var', (68, 78))	('AXL', 'Protein', (79, 82))	('chemoresistance', 'CPA', (208, 223))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('cancer stemness', 'Disease', 'MESH:D009369', (51, 66))	('chemosensitivity', 'CPA', (187, 203))	('EMT', 'Gene', (43, 46))	('EMT', 'Gene', '3702', (43, 46))
221401	32488984	PRKAA1 rs13361707 C/T polymorphism confers decreased susceptibility to esophageal cancer: A case-control study Several studies probed into the connection between esophageal cancer (EC) risk and PRKAA1 rs13361707 C/T polymorphism, but obtained insignificant findings.	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('PRKAA1', 'Gene', (0, 6))	('PRKAA1', 'Gene', '5562', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('cancer', 'Disease', (173, 179))	('rs13361707 C/T', 'Var', (7, 21))	('rs13361707', 'Mutation', 'rs13361707', (7, 17))	('PRKAA1', 'Gene', (194, 200))	('PRKAA1', 'Gene', '5562', (194, 200))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('rs13361707 C/T', 'Var', (201, 215))	('probed', 'Reg', (127, 133))	('decreased', 'NegReg', (43, 52))	('rs13361707', 'Mutation', 'rs13361707', (201, 211))
221402	32488984	Data suggested rs13361707 C/T polymorphism in PRKAA1 gene was significantly related with a lower risk for EC.	('rs13361707', 'Mutation', 'rs13361707', (15, 25))	('PRKAA1', 'Gene', (46, 52))	('rs13361707 C/T', 'Var', (15, 29))	('PRKAA1', 'Gene', '5562', (46, 52))
221403	32488984	In summary, PRKAA1 rs13361707 C/T polymorphism is related to the risk and clinical properties of EC patients in East China.	('related', 'Reg', (50, 57))	('rs13361707', 'Mutation', 'rs13361707', (19, 29))	('PRKAA1', 'Gene', (12, 18))	('patients', 'Species', '9606', (100, 108))	('PRKAA1', 'Gene', '5562', (12, 18))	('rs13361707 C/T', 'Var', (19, 33))
221411	32488984	Rs13361707 C/T polymorphism is positioned in the first intron of PRKAA1 gene.	('Rs13361707', 'Mutation', 'Rs13361707', (0, 10))	('PRKAA1', 'Gene', '5562', (65, 71))	('PRKAA1', 'Gene', (65, 71))	('Rs13361707 C/T', 'Var', (0, 14))
221413	32488984	Besides, two Chinese studies investigating the relationship between EC risk and rs13361707 C/T polymorphism in PRKAA1 gene yielded no positive results.	('rs13361707 C/T', 'Var', (80, 94))	('PRKAA1', 'Gene', '5562', (111, 117))	('PRKAA1', 'Gene', (111, 117))	('rs13361707', 'Mutation', 'rs13361707', (80, 90))
221414	32488984	10 ,  11  Thus, the aims of this study were to explore the connection between this variant in PRKAA1 gene and EC susceptibility in Chinese individuals.	('variant', 'Var', (83, 90))	('PRKAA1', 'Gene', (94, 100))	('PRKAA1', 'Gene', '5562', (94, 100))
221415	32488984	In addition, we aimed to explore the relationship between PRKAA1 rs13361707 C/T polymorphism and clinical features of EC patients.	('PRKAA1', 'Gene', (58, 64))	('PRKAA1', 'Gene', '5562', (58, 64))	('rs13361707 C/T', 'Var', (65, 79))	('rs13361707', 'Mutation', 'rs13361707', (65, 75))	('patients', 'Species', '9606', (121, 129))
221420	32488984	13  Relationship between PRKAA1 rs13361707 C/T polymorphism and EC risk was assessed by logistic regression with multiple genetic models adjusted by age and gender.	('PRKAA1', 'Gene', '5562', (25, 31))	('PRKAA1', 'Gene', (25, 31))	('rs13361707', 'Mutation', 'rs13361707', (32, 42))	('rs13361707 C/T', 'Var', (32, 46))
221423	32488984	We found CC genotype or C allele carriers showed a decreased risk for EC patients (CC vs TT: OR, 0.64, 95% CI, 0.49-0.83; C vs T: 0.80, 0.70-0.91; both P = .001).	('patients', 'Species', '9606', (73, 81))	('C allele carriers', 'Var', (24, 41))	('decreased', 'NegReg', (51, 60))
221424	32488984	Data revealed that a protective role of rs13361707 C/T polymorphism in EC susceptibility was strengthened in the subgroups of males, smokers, drinkers, and individuals at age >= 60 years (Table 2).	('rs13361707', 'Mutation', 'rs13361707', (40, 50))	('rs13361707 C/T', 'Var', (40, 54))	('strengthened', 'PosReg', (93, 105))
221425	32488984	CC or TC + CC genotype was involved in avoidance of EC patients from differentiation deterioration, distant metastasis, and squamous cell carcinoma, indicating the rs13361707 C/T polymorphism participated in the pathological grading, distant metastasis, and histology of EC (Table 3).	('participated', 'Reg', (192, 204))	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('rs13361707 C/T', 'Var', (164, 178))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (124, 147))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (124, 147))	('rs13361707', 'Mutation', 'rs13361707', (164, 174))	('squamous cell carcinoma', 'Disease', (124, 147))	('TC', 'Chemical', 'MESH:D013667', (6, 8))	('patients', 'Species', '9606', (55, 63))
221427	32488984	In this study, rs13361707 C/T polymorphism of PRKAA1 gene was related with a lower risk of EC in this tested Chinese Han population.	('lower', 'NegReg', (77, 82))	('PRKAA1', 'Gene', (46, 52))	('PRKAA1', 'Gene', '5562', (46, 52))	('rs13361707', 'Mutation', 'rs13361707', (15, 25))	('rs13361707 C/T', 'Var', (15, 29))
221428	32488984	Furthermore, rs13361707 C/T polymorphism was linked with pathological grading, distant metastasis, and squamous cell carcinoma.	('rs13361707 C/T', 'Var', (13, 27))	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('linked', 'Reg', (45, 51))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (103, 126))	('rs13361707', 'Mutation', 'rs13361707', (13, 23))	('squamous cell carcinoma', 'Disease', (103, 126))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (103, 126))	('distant metastasis', 'CPA', (79, 97))
221429	32488984	A host of studies have evaluated the relationship between rs13361707 C/T polymorphism of PRKAA1 gene and the risk of several cancers.	('cancers', 'Disease', 'MESH:D009369', (125, 132))	('cancers', 'Phenotype', 'HP:0002664', (125, 132))	('rs13361707 C/T', 'Var', (58, 72))	('cancers', 'Disease', (125, 132))	('rs13361707', 'Mutation', 'rs13361707', (58, 68))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('PRKAA1', 'Gene', (89, 95))	('PRKAA1', 'Gene', '5562', (89, 95))
221435	32488984	22  Another study implied rs13361707 C/T polymorphism was unrelated to lung cancer risk.	('rs13361707', 'Mutation', 'rs13361707', (26, 36))	('lung cancer', 'Disease', 'MESH:D008175', (71, 82))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('rs13361707 C/T', 'Var', (26, 40))	('lung cancer', 'Disease', (71, 82))	('lung cancer', 'Phenotype', 'HP:0100526', (71, 82))
221436	32488984	10 ,  11  Our study revealed that rs13361707 C/T polymorphism in PRKAA1 gene was related to EC susceptibility, which was consistent with the findings of the above meta-analysis.	('PRKAA1', 'Gene', (65, 71))	('rs13361707', 'Mutation', 'rs13361707', (34, 44))	('rs13361707 C/T', 'Var', (34, 48))	('PRKAA1', 'Gene', '5562', (65, 71))	('related', 'Reg', (81, 88))
221438	32488984	Additionally, rs13361707 C/T polymorphism was also found to be connected with the pathological grading, distant metastasis, and squamous cell carcinoma of EC patients.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (128, 151))	('rs13361707 C/T', 'Var', (14, 28))	('connected', 'Reg', (63, 72))	('squamous cell carcinoma of EC', 'Disease', (128, 157))	('rs13361707', 'Mutation', 'rs13361707', (14, 24))	('patients', 'Species', '9606', (158, 166))	('squamous cell carcinoma of EC', 'Disease', 'MESH:D002294', (128, 157))	('distant metastasis', 'CPA', (104, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (142, 151))
221439	32488984	Third, the functions of PRKAA1 rs13361707 C/T polymorphism should be studied.	('PRKAA1', 'Gene', '5562', (24, 30))	('PRKAA1', 'Gene', (24, 30))	('rs13361707', 'Mutation', 'rs13361707', (31, 41))	('rs13361707 C/T', 'Var', (31, 45))
221443	32488984	The PRKAA1 rs13361707 C/T polymorphism is related to a lower risk of EC in the tested Chinese Han population.	('PRKAA1', 'Gene', (4, 10))	('PRKAA1', 'Gene', '5562', (4, 10))	('rs13361707', 'Mutation', 'rs13361707', (11, 21))	('rs13361707 C/T', 'Var', (11, 25))	('lower', 'NegReg', (55, 60))
221450	32297697	The interaction between miR-450b-5p/miR-515-5p and LINC00519/YAP1 was verified by RIP, RNA pull-down and luciferase reporter assays.	('miR-450b-5p', 'Chemical', '-', (24, 35))	('LINC00519', 'Gene', '161342', (51, 60))	('interaction', 'Interaction', (4, 15))	('miR-515-5p', 'Chemical', '-', (36, 46))	('YAP1', 'Gene', '10413', (61, 65))	('LINC00519', 'Gene', (51, 60))	('miR-450b-5p/miR-515-5p', 'Var', (24, 46))	('YAP1', 'Gene', (61, 65))
221453	32297697	Then, loss-of-function assays suggested the inhibitive role of silenced LINC00519 in cell proliferation, migration, invasion and tumour growth and promoting effect on cell apoptosis in LUSC.	('tumour', 'Phenotype', 'HP:0002664', (129, 135))	('LUSC', 'Disease', (185, 189))	('tumour growth', 'Disease', 'MESH:D006130', (129, 142))	('cell proliferation', 'CPA', (85, 103))	('promoting', 'PosReg', (147, 156))	('cell apoptosis', 'CPA', (167, 181))	('LUSC', 'Phenotype', 'HP:0030359', (185, 189))	('LINC00519', 'Gene', '161342', (72, 81))	('silenced', 'Var', (63, 71))	('inhibitive', 'NegReg', (44, 54))	('loss-of-function', 'NegReg', (6, 22))	('invasion', 'CPA', (116, 124))	('LUSC', 'Chemical', '-', (185, 189))	('migration', 'CPA', (105, 114))	('LINC00519', 'Gene', (72, 81))	('tumour growth', 'Disease', (129, 142))
221455	32297697	Moreover, LINC00519 sponged miR-450b-5p and miR-515-5p to up-regulate Yes1 associated transcriptional regulator (YAP1).	('miR-450b-5p', 'Chemical', '-', (28, 39))	('up-regulate', 'PosReg', (58, 69))	('LINC00519', 'Gene', '161342', (10, 19))	('miR-515-5p', 'Chemical', '-', (44, 54))	('Yes1', 'Gene', '7525', (70, 74))	('LINC00519', 'Gene', (10, 19))	('YAP1', 'Gene', (113, 117))	('Yes1', 'Gene', (70, 74))	('YAP1', 'Gene', '10413', (113, 117))	('miR-515-5p', 'Var', (44, 54))
221456	32297697	Additionally, miR-450b-5p and miR-515-5p elicited anti-carcinogenic effects in LUSC.	('LUSC', 'Phenotype', 'HP:0030359', (79, 83))	('carcinogenic', 'Disease', 'MESH:D063646', (55, 67))	('miR-515-5p', 'Chemical', '-', (30, 40))	('LUSC', 'Chemical', '-', (79, 83))	('carcinogenic', 'Disease', (55, 67))	('miR-450b-5p', 'Var', (14, 25))	('miR-450b-5p', 'Chemical', '-', (14, 25))	('miR-515-5p', 'Var', (30, 40))
221458	32297697	H3K27ac-activated LINC00519 acts as a competing endogenous RNA (ceRNA) to promote LUSC progression by targeting miR-450b-5p/miR-515-5p/YAP1 axis.	('LUSC', 'Chemical', '-', (82, 86))	('LINC00519', 'Gene', '161342', (18, 27))	('targeting', 'Reg', (102, 111))	('promote', 'PosReg', (74, 81))	('LUSC', 'Phenotype', 'HP:0030359', (82, 86))	('YAP1', 'Gene', (135, 139))	('YAP1', 'Gene', '10413', (135, 139))	('miR-450b-5p', 'Chemical', '-', (112, 123))	('LINC00519', 'Gene', (18, 27))	('LUSC', 'Disease', (82, 86))	('H3K27ac-activated', 'Var', (0, 17))	('miR-515-5p', 'Chemical', '-', (124, 134))
221464	32297697	Abnormally expressed lncRNAs have been identified in hepatocellular carcinoma,6 cervical cancer,7 gastric cancer8 and pancreatic cancer,9 suggesting that the dysregulation of certain lncRNAs contributes to tumorigenesis.	('ncRNA', 'Gene', (184, 189))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('ncRNA', 'Gene', (22, 27))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('gastric cancer', 'Disease', (98, 112))	('dysregulation', 'Var', (158, 171))	('ncRNA', 'Gene', '54719', (184, 189))	('gastric cancer', 'Disease', 'MESH:D013274', (98, 112))	('ncRNA', 'Gene', '54719', (22, 27))	('hepatocellular carcinoma,6 cervical cancer', 'Disease', 'MESH:D006528', (53, 95))	('pancreatic cancer', 'Disease', (118, 135))	('carcinoma', 'Phenotype', 'HP:0030731', (68, 77))	('contributes', 'Reg', (191, 202))	('pancreatic cancer', 'Disease', 'MESH:D010190', (118, 135))	('gastric cancer', 'Phenotype', 'HP:0012126', (98, 112))	('tumorigenesis', 'CPA', (206, 219))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
221482	32297697	The miR-450b-5p inhibitor, miR-515-5p inhibitor and control (NC inhibitor) were procured from RiboBio to knock down miR-450b-5p and miR-515-5p.	('miR-515-5p', 'Chemical', '-', (132, 142))	('miR-450b-5p', 'Gene', (116, 127))	('knock down', 'Var', (105, 115))	('miR-515-5p', 'Chemical', '-', (27, 37))	('miR-450b-5p', 'Chemical', '-', (116, 127))	('miR-515-5p', 'Var', (132, 142))	('miR-450b-5p', 'Chemical', '-', (4, 15))
221503	32297697	Lysates were sonicated and immunoprecipitated for 1 hour at room temperature with anti-H3K27ac, anti-CBP anti-P300 or control anti-IgG antibody (both from Abcam).	('IgG antibody', 'Phenotype', 'HP:0003237', (131, 143))	('P300', 'Gene', '2033', (110, 114))	('CBP', 'Gene', '1387', (101, 104))	('CBP', 'Gene', (101, 104))	('anti-H3K27ac', 'Var', (82, 94))	('P300', 'Gene', (110, 114))
221504	32297697	Transfected cells were lysed using RIPA, and thereafter, the collected lysates underwent immunoprecipitation using anti-CBP, anti-P300 or anti-IgG (Abcam) for 1 hour, followed by the addition of Protein A-agarose into lysates and the incubation for 12 hours.	('agarose', 'Chemical', 'MESH:D012685', (205, 212))	('P300', 'Gene', '2033', (130, 134))	('CBP', 'Gene', '1387', (120, 123))	('anti-IgG', 'Var', (138, 146))	('P300', 'Gene', (130, 134))	('CBP', 'Gene', (120, 123))
221514	32297697	The wild type (WT) and mutant (Mut) miR-450b-5p or miR-515-5p binding sites to LINC00519 sequence or YAP1 3'-UTR were separately cloned to pmirGLO (Promega) vectors to obtain LINC00519-WT/Mut and YAP1-WT/Mut vectors.	('YAP1', 'Gene', (196, 200))	('YAP1', 'Gene', '10413', (196, 200))	('LINC00519', 'Gene', '161342', (79, 88))	('YAP1', 'Gene', (101, 105))	('LINC00519', 'Gene', (175, 184))	('miR-450b-5p', 'Chemical', '-', (36, 47))	('YAP1', 'Gene', '10413', (101, 105))	('LINC00519', 'Gene', (79, 88))	('LINC00519', 'Gene', '161342', (175, 184))	('miR-515-5p', 'Gene', (51, 61))	('miR-515-5p', 'Chemical', '-', (51, 61))	('mutant', 'Var', (23, 29))
221523	32297697	As a result, LUSC patients with high LINC00519 expression showed a shorter survival time (Figure 1E).	('survival time', 'CPA', (75, 88))	('high', 'Var', (32, 36))	('LUSC', 'Chemical', '-', (13, 17))	('LINC00519', 'Gene', (37, 46))	('LINC00519', 'Gene', '161342', (37, 46))	('LUSC', 'Phenotype', 'HP:0030359', (13, 17))	('patients', 'Species', '9606', (18, 26))	('shorter', 'NegReg', (67, 74))
221526	32297697	Firstly, LINC00519-specific shRNAs (sh-LINC00519#1, sh-LINC00519#2) were transfected into H266 and SK-MES-1 cells for knocking down endogenous LINC00519 expression.	('LINC00519', 'Gene', (55, 64))	('LINC00519', 'Gene', (9, 18))	('knocking', 'Var', (118, 126))	('LINC00519', 'Gene', (39, 48))	('LINC00519', 'Gene', '161342', (55, 64))	('LINC00519', 'Gene', '161342', (9, 18))	('LINC00519', 'Gene', (143, 152))	('LINC00519', 'Gene', '161342', (39, 48))	('expression', 'MPA', (153, 163))	('SK-MES-1', 'CellLine', 'CVCL:0630', (99, 107))	('LINC00519', 'Gene', '161342', (143, 152))
221534	32297697	Besides, LUAC cells invading to the lower transwell chamber was less in sh-LINC00519#1/2 groups than in sh-NC group (Figure 2E), indicating that LINC00519 knock-down effectively weakened the invasive capacity of LUSC cells.	('LINC00519', 'Gene', (145, 154))	('invasive capacity of LUSC cells', 'CPA', (191, 222))	('LUSC', 'Chemical', '-', (212, 216))	('LUAC cells invading to the lower transwell chamber', 'CPA', (9, 59))	('less', 'NegReg', (64, 68))	('weakened', 'NegReg', (178, 186))	('LINC00519', 'Gene', (75, 84))	('knock-down', 'Var', (155, 165))	('LINC00519', 'Gene', '161342', (145, 154))	('LUSC', 'Phenotype', 'HP:0030359', (212, 216))	('LINC00519', 'Gene', '161342', (75, 84))
221537	32297697	Then, it was discovered that LINC00519 depletion efficiently reduced tumour volume and weight (Figure 2F,G and Figure S1D).	('tumour', 'Disease', (69, 75))	('depletion', 'Var', (39, 48))	('LINC00519', 'Gene', (29, 38))	('tumour', 'Phenotype', 'HP:0002664', (69, 75))	('LINC00519', 'Gene', '161342', (29, 38))	('tumour', 'Disease', 'MESH:D009369', (69, 75))	('reduced', 'NegReg', (61, 68))
221539	32297697	As displayed in lung metastasis model, LINC00519 knock-down remarkably decreased the number of metastatic nodules which formed in mouse lungs (Figure 2I).	('mouse', 'Species', '10090', (130, 135))	('LINC00519', 'Gene', (39, 48))	('knock-down', 'Var', (49, 59))	('LINC00519', 'Gene', '161342', (39, 48))	('decreased', 'NegReg', (71, 80))
221540	32297697	Taken together, silenced LINC00519 restrains LUSC progression.	('LINC00519', 'Gene', '161342', (25, 34))	('LUSC progression', 'CPA', (45, 61))	('restrains', 'NegReg', (35, 44))	('LUSC', 'Chemical', '-', (45, 49))	('LINC00519', 'Gene', (25, 34))	('silenced', 'Var', (16, 24))	('LUSC', 'Phenotype', 'HP:0030359', (45, 49))
221543	32297697	Data implied that the enrichment of H3K27ac in LINC00519 promoter region was higher in H266 and SK-MES-1 cells than in HBE cells (Figure 3B).	('higher', 'PosReg', (77, 83))	('LINC00519', 'Gene', (47, 56))	('HBE', 'CellLine', 'CVCL:0287', (119, 122))	('H3K27ac', 'Var', (36, 43))	('LINC00519', 'Gene', '161342', (47, 56))	('SK-MES-1', 'CellLine', 'CVCL:0630', (96, 104))	('enrichment', 'MPA', (22, 32))
221547	32297697	Consequently, LINC00519 expression declined in H266 and SK-MES-1 cells treated with C646 (Figure 3D).	('LINC00519', 'Gene', '161342', (14, 23))	('SK-MES-1', 'CellLine', 'CVCL:0630', (56, 64))	('expression', 'MPA', (24, 34))	('C646', 'Chemical', '-', (84, 88))	('LINC00519', 'Gene', (14, 23))	('declined', 'NegReg', (35, 43))	('C646', 'Var', (84, 88))
221548	32297697	Also, luciferase activity of LINC00519 promoter was repressed markedly by C646 in LUSC cells (Figure S2A), indicating that H3K27ac was related to LINC00519 expression and transcription in LUSC cells.	('LUSC', 'Chemical', '-', (188, 192))	('LUSC', 'Chemical', '-', (82, 86))	('LINC00519', 'Gene', '161342', (146, 155))	('activity', 'MPA', (17, 25))	('LINC00519', 'Gene', (29, 38))	('C646', 'Chemical', '-', (74, 78))	('LINC00519', 'Gene', '161342', (29, 38))	('LUSC', 'Phenotype', 'HP:0030359', (82, 86))	('LUSC', 'Phenotype', 'HP:0030359', (188, 192))	('LINC00519', 'Gene', (146, 155))	('luciferase', 'Enzyme', (6, 16))	('C646', 'Var', (74, 78))
221560	32297697	Besides, to preliminarily determine whether CBP/P300 was the crucial factor for H3K27ac in LINC00519 promoter, we tested other acetyltransferases reported to regulate H3K27ac, including HDAC720 and PCAF.21 We first validated the knock-down of HDAC7 and PCAF in LUSC cells after transfecting specific shRNAs (Figure S2F and Figure S5E).	('knock-down', 'Var', (229, 239))	('PCAF', 'Gene', (253, 257))	('LUSC', 'Phenotype', 'HP:0030359', (261, 265))	('HDAC7', 'Gene', (243, 248))	('CBP/P300', 'Gene', (44, 52))	('LINC00519', 'Gene', (91, 100))	('HDAC7', 'Gene', '51564', (186, 191))	('CBP/P300', 'Gene', '1387;2033', (44, 52))	('PCAF', 'Gene', '8850', (198, 202))	('HDAC7', 'Gene', (186, 191))	('PCAF', 'Gene', '8850', (253, 257))	('LUSC', 'Chemical', '-', (261, 265))	('LINC00519', 'Gene', '161342', (91, 100))	('HDAC7', 'Gene', '51564', (243, 248))	('PCAF', 'Gene', (198, 202))
221561	32297697	However, we discovered that knocking down either HDAC7 or PCAF failed to alter the luciferase activity of LINC00519 promoter activity and expression in LUSC cells (Figure S2G,H), indicating that CBP/P300 might be vital for promoter H3K27ac and upregulation of LINC00519 in LUSC cells.	('HDAC7', 'Gene', '51564', (49, 54))	('knocking', 'Var', (28, 36))	('LUSC', 'Phenotype', 'HP:0030359', (152, 156))	('LINC00519', 'Gene', '161342', (106, 115))	('LUSC', 'Chemical', '-', (152, 156))	('CBP/P300', 'Gene', '1387;2033', (195, 203))	('LINC00519', 'Gene', (260, 269))	('HDAC7', 'Gene', (49, 54))	('CBP/P300', 'Gene', (195, 203))	('upregulation', 'PosReg', (244, 256))	('LINC00519', 'Gene', (106, 115))	('activity', 'MPA', (125, 133))	('PCAF', 'Gene', (58, 62))	('activity', 'MPA', (94, 102))	('luciferase', 'Enzyme', (83, 93))	('PCAF', 'Gene', '8850', (58, 62))	('LUSC', 'Phenotype', 'HP:0030359', (273, 277))	('LINC00519', 'Gene', '161342', (260, 269))	('LUSC', 'Chemical', '-', (273, 277))
221563	32297697	We discovered that similar to LUSC cells, H3K27ac enrichment in LINC00519 promoter was higher in LUAD cell lines (A549 and H1299) versus normal HBE cells (Figure S3A).	('HBE', 'CellLine', 'CVCL:0287', (144, 147))	('H3K27ac', 'Var', (42, 49))	('LUSC', 'Chemical', '-', (30, 34))	('LUAD', 'Phenotype', 'HP:0030078', (97, 101))	('LINC00519', 'Gene', (64, 73))	('A549', 'CellLine', 'CVCL:0023', (114, 118))	('LINC00519', 'Gene', '161342', (64, 73))	('H1299', 'CellLine', 'CVCL:0060', (123, 128))	('LUSC', 'Phenotype', 'HP:0030359', (30, 34))	('higher', 'PosReg', (87, 93))
221565	32297697	As expected, knocking down either P300 or CBP reduced LINC00519 level in LUAD cells (Figure S3C).	('knocking down', 'Var', (13, 26))	('CBP', 'Gene', (42, 45))	('LINC00519', 'Gene', (54, 63))	('P300', 'Gene', '2033', (34, 38))	('LUAD', 'Phenotype', 'HP:0030078', (73, 77))	('CBP', 'Gene', '1387', (42, 45))	('LINC00519', 'Gene', '161342', (54, 63))	('reduced', 'NegReg', (46, 53))	('P300', 'Gene', (34, 38))
221566	32297697	Accordingly, less LINC00519 promoter was enriched in the ChIP products of H3K27ac (Figure S3D), indicating that CBP/P300 regulated H3K27ac in LINC00519 promoter in LUAD cells.	('LINC00519', 'Gene', '161342', (18, 27))	('LUAD', 'Phenotype', 'HP:0030078', (164, 168))	('LINC00519', 'Gene', '161342', (142, 151))	('CBP/P300', 'Gene', (112, 120))	('CBP/P300', 'Gene', '1387;2033', (112, 120))	('H3K27ac', 'Var', (131, 138))	('LINC00519', 'Gene', (18, 27))	('LINC00519', 'Gene', (142, 151))
221567	32297697	Moreover, either P300 or CBP knock-down repressed activity of LINC00519 promoter reporter IN LUAD cells (Figure S3E).	('CBP', 'Gene', '1387', (25, 28))	('LINC00519', 'Gene', '161342', (62, 71))	('P300', 'Gene', '2033', (17, 21))	('LUAD', 'Phenotype', 'HP:0030078', (93, 97))	('activity', 'MPA', (50, 58))	('P300', 'Gene', (17, 21))	('LINC00519', 'Gene', (62, 71))	('CBP', 'Gene', (25, 28))	('knock-down', 'Var', (29, 39))
221568	32297697	In brief, all results above suggested that CBP-mediated H3K27ac could activate the expression of LINC00519.	('LINC00519', 'Gene', '161342', (97, 106))	('H3K27ac', 'Var', (56, 63))	('activate', 'PosReg', (70, 78))	('expression', 'MPA', (83, 93))	('CBP', 'Gene', '1387', (43, 46))	('CBP', 'Gene', (43, 46))	('LINC00519', 'Gene', (97, 106))
221571	32297697	Consequently, LINC00519 knock-down decreased only YAP1 protein level but failed to alter the levels of MST1/2, p-MST1/2 and p-YAP1 (Figure 4B and Figure S5B), indicating that LINC00519 positively regulated YAP1.	('YAP1', 'Gene', (126, 130))	('LINC00519', 'Gene', '161342', (14, 23))	('MST1/2', 'Gene', '4485;6788', (113, 119))	('YAP1', 'Gene', (206, 210))	('YAP1', 'Gene', '10413', (206, 210))	('YAP1', 'Gene', '10413', (126, 130))	('knock-down', 'Var', (24, 34))	('MST1/2', 'Gene', (113, 119))	('MST1/2', 'Gene', '4485;6788', (103, 109))	('LINC00519', 'Gene', (175, 184))	('decreased', 'NegReg', (35, 44))	('YAP1', 'Gene', (50, 54))	('YAP1', 'Gene', '10413', (50, 54))	('MST1/2', 'Gene', (103, 109))	('LINC00519', 'Gene', (14, 23))	('LINC00519', 'Gene', '161342', (175, 184))
221574	32297697	qRT-PCR analysis delineated the diminished YAP1 expression with the transfection of sh-LINC00519 (Figure 4E).	('LINC00519', 'Gene', '161342', (87, 96))	('transfection', 'Var', (68, 80))	('expression', 'MPA', (48, 58))	('YAP1', 'Gene', '10413', (43, 47))	('LINC00519', 'Gene', (87, 96))	('YAP1', 'Gene', (43, 47))	('diminished', 'NegReg', (32, 42))
221576	32297697	As presented in Figure 4F, the treatment of XMU-MP-1 failed to alter the inhibitive effect of silenced LINC00519 on cell proliferation.	('LINC00519', 'Gene', '161342', (103, 112))	('cell proliferation', 'CPA', (116, 134))	('LINC00519', 'Gene', (103, 112))	('silenced', 'Var', (94, 102))
221577	32297697	Besides, the facilitated apoptosis caused by LINC00519 knock-down was not changed under XMU-MP-1 treatment (Figure 4G).	('knock-down', 'Var', (55, 65))	('LINC00519', 'Gene', '161342', (45, 54))	('LINC00519', 'Gene', (45, 54))
221587	32297697	According to RNA pull-down assay, we found that miR-450b-5p and miR-515-5p were pulled down by LINC00519 biotin probe and YAP1 biotin probe (Figure 5E).	('biotin', 'Chemical', 'MESH:D001710', (105, 111))	('miR-450b-5p', 'Chemical', '-', (48, 59))	('miR-515-5p', 'Var', (64, 74))	('biotin', 'Chemical', 'MESH:D001710', (127, 133))	('miR-515-5p', 'Chemical', '-', (64, 74))	('LINC00519', 'Gene', (95, 104))	('LINC00519', 'Gene', '161342', (95, 104))	('YAP1', 'Gene', '10413', (122, 126))	('miR-450b-5p', 'Var', (48, 59))	('YAP1', 'Gene', (122, 126))
221590	32297697	Next, we transfected miR-450b-5p mimics and miR-515-5p mimics, respectively, into LUSC cells and verified the overexpression of miR-450b-5p and miR-515-5p (Figure S4A).	('miR-450b-5p', 'Chemical', '-', (128, 139))	('LUSC', 'Chemical', '-', (82, 86))	('miR-515-5p', 'Var', (144, 154))	('miR-515-5p', 'Chemical', '-', (44, 54))	('miR-515-5p', 'Chemical', '-', (144, 154))	('LUSC', 'Phenotype', 'HP:0030359', (82, 86))	('miR-450b-5p', 'Chemical', '-', (21, 32))	('miR-450b-5p', 'Var', (128, 139))	('overexpression', 'PosReg', (110, 124))
221591	32297697	We discovered that miR-450b-5p mimics and miR-515-5p mimics decreased the luciferase activity of LINC00519-WT/YAP1-WT rather than LINC00519-Mut/YAP1-Mut (Figure 5G).	('decreased', 'NegReg', (60, 69))	('LINC00519', 'Gene', (97, 106))	('YAP1', 'Gene', (144, 148))	('YAP1', 'Gene', '10413', (144, 148))	('LINC00519', 'Gene', '161342', (97, 106))	('YAP1', 'Gene', (110, 114))	('YAP1', 'Gene', '10413', (110, 114))	('miR-450b-5p', 'Chemical', '-', (19, 30))	('LINC00519', 'Gene', (130, 139))	('luciferase', 'Enzyme', (74, 84))	('miR-515-5p', 'Chemical', '-', (42, 52))	('LINC00519', 'Gene', '161342', (130, 139))	('activity', 'MPA', (85, 93))	('miR-450b-5p mimics', 'Var', (19, 37))
221594	32297697	Data revealed that LINC00519 overexpression restored luciferase activity of YAP1-WT that was repressed by miR-450b-5p mimics/miR-515-5p mimics whereas YAP1-Mut was hardly changed (Figure 5H).	('YAP1', 'Gene', (151, 155))	('LINC00519', 'Gene', (19, 28))	('YAP1', 'Gene', '10413', (151, 155))	('luciferase', 'Enzyme', (53, 63))	('LINC00519', 'Gene', '161342', (19, 28))	('YAP1', 'Gene', (76, 80))	('YAP1', 'Gene', '10413', (76, 80))	('activity', 'MPA', (64, 72))	('miR-450b-5p', 'Chemical', '-', (106, 117))	('miR-515-5p', 'Chemical', '-', (125, 135))	('miR-450b-5p mimics/miR-515-5p', 'Var', (106, 135))
221596	32297697	Finally, mRNA and protein levels of YAP1 down-regulated by LINC00519 silence were partially reserved by miR-450b-5p inhibitor, and the co-transfection of miR-450b-5p and miR-515-5p inhibitors nearly fully restored the effect of LINC00519 silence (Figure 5I-J and Figure S5C).	('LINC00519', 'Gene', (228, 237))	('miR-515-5p', 'Chemical', '-', (170, 180))	('silence', 'Var', (69, 76))	('LINC00519', 'Gene', '161342', (228, 237))	('down-regulated', 'NegReg', (41, 55))	('miR-450b-5p', 'Chemical', '-', (154, 165))	('LINC00519', 'Gene', (59, 68))	('YAP1', 'Gene', (36, 40))	('YAP1', 'Gene', '10413', (36, 40))	('LINC00519', 'Gene', '161342', (59, 68))	('miR-450b-5p', 'Chemical', '-', (104, 115))
221599	32297697	We discovered that miR-450b-5p and miR-515-5p were under-expressed in LUSC tissues and cell lines (Figure 6A,B).	('LUSC', 'Phenotype', 'HP:0030359', (70, 74))	('miR-450b-5p', 'Var', (19, 30))	('miR-450b-5p', 'Chemical', '-', (19, 30))	('miR-515-5p', 'Var', (35, 45))	('miR-515-5p', 'Chemical', '-', (35, 45))	('LUSC', 'Chemical', '-', (70, 74))
221600	32297697	Then, colony formation, TUNEL, wound healing and transwell assays were conducted to identify the biological function of miR-450b-5p and miR-515-5p on LUSC cell growth and metastasis.	('LUSC', 'Chemical', '-', (150, 154))	('miR-515-5p', 'Chemical', '-', (136, 146))	('miR-450b-5p', 'Var', (120, 131))	('miR-450b-5p', 'Chemical', '-', (120, 131))	('LUSC', 'Phenotype', 'HP:0030359', (150, 154))	('miR-515-5p', 'Var', (136, 146))
221601	32297697	As shown in Figure 6C, miR-450b-5p mimics and miR-515-5p mimics restrained cell proliferation.	('miR-450b-5p mimics', 'Var', (23, 41))	('miR-515-5p', 'Chemical', '-', (46, 56))	('miR-515-5p mimics', 'Var', (46, 63))	('miR-450b-5p', 'Chemical', '-', (23, 34))	('restrained', 'NegReg', (64, 74))	('cell proliferation', 'CPA', (75, 93))
221602	32297697	The apoptosis of H266 and SK-MES-1 cells was facilitated by miR-450b-5p mimics and miR-515-5p mimics (Figure 6D).	('miR-515-5p', 'Chemical', '-', (83, 93))	('miR-515-5p mimics', 'Var', (83, 100))	('miR-450b-5p mimics', 'Var', (60, 78))	('apoptosis', 'CPA', (4, 13))	('SK-MES-1', 'CellLine', 'CVCL:0630', (26, 34))	('miR-450b-5p', 'Chemical', '-', (60, 71))	('facilitated', 'PosReg', (45, 56))
221603	32297697	Based on the result of wound healing assay, cell migration was suppressed by the overexpression of miR-450b-5p and miR-515-5p (Figure 6E).	('miR-450b-5p', 'Var', (99, 110))	('overexpression', 'PosReg', (81, 95))	('miR-515-5p', 'Var', (115, 125))	('miR-450b-5p', 'Chemical', '-', (99, 110))	('suppressed', 'NegReg', (63, 73))	('cell migration', 'CPA', (44, 58))	('miR-515-5p', 'Chemical', '-', (115, 125))
221604	32297697	At last, transwell assay revealed the repressive effect of miR-450b-5p and miR-515-5p overexpression on the invasive capability of H266 and SK-MES-1 cells (Figure 6F).	('miR-515-5p', 'Var', (75, 85))	('miR-515-5p', 'Chemical', '-', (75, 85))	('miR-450b-5p', 'Var', (59, 70))	('SK-MES-1', 'CellLine', 'CVCL:0630', (140, 148))	('overexpression', 'PosReg', (86, 100))	('miR-450b-5p', 'Chemical', '-', (59, 70))	('invasive capability', 'CPA', (108, 127))
221605	32297697	Namely, miR-450b-5p and miR-515-5p inhibit LUSC cell growth and metastasis in vitro.	('inhibit', 'NegReg', (35, 42))	('LUSC', 'Chemical', '-', (43, 47))	('miR-450b-5p', 'Chemical', '-', (8, 19))	('miR-515-5p', 'Var', (24, 34))	('miR-515-5p', 'Chemical', '-', (24, 34))	('LUSC', 'Phenotype', 'HP:0030359', (43, 47))	('miR-450b-5p', 'Var', (8, 19))
221608	32297697	The result of colony formation assay depicted that cell proliferation weakened by LINC00519 depletion was counteracted by overexpressed YAP1 (Figure 7A).	('depletion', 'Var', (92, 101))	('LINC00519', 'Gene', (82, 91))	('LINC00519', 'Gene', '161342', (82, 91))	('YAP1', 'Gene', '10413', (136, 140))	('cell proliferation', 'CPA', (51, 69))	('weakened', 'NegReg', (70, 78))	('YAP1', 'Gene', (136, 140))
221609	32297697	The elevated cell apoptosis resulted from silenced LINC00519 was reversed by YAP1 overexpression (Figure 7B).	('LINC00519', 'Gene', '161342', (51, 60))	('YAP1', 'Gene', '10413', (77, 81))	('silenced', 'Var', (42, 50))	('cell apoptosis', 'CPA', (13, 27))	('YAP1', 'Gene', (77, 81))	('LINC00519', 'Gene', (51, 60))
221611	32297697	Finally, up-regulated YAP1 recovered the repressive effect of silenced LINC00519 on cell invasion (Figure 7D).	('recovered', 'PosReg', (27, 36))	('LINC00519', 'Gene', (71, 80))	('silenced', 'Var', (62, 70))	('up-regulated', 'PosReg', (9, 21))	('LINC00519', 'Gene', '161342', (71, 80))	('repressive', 'MPA', (41, 51))	('YAP1', 'Gene', '10413', (22, 26))	('cell invasion', 'CPA', (84, 97))	('YAP1', 'Gene', (22, 26))
221617	32297697	In vitro functional experiments depicted that silenced LINC00519 prohibited proliferation, migration, invasion and stimulated apoptosis in LUSC cells.	('LINC00519', 'Gene', (55, 64))	('LUSC', 'Phenotype', 'HP:0030359', (139, 143))	('apoptosis', 'CPA', (126, 135))	('invasion', 'CPA', (102, 110))	('LINC00519', 'Gene', '161342', (55, 64))	('proliferation', 'CPA', (76, 89))	('silenced', 'Var', (46, 54))	('migration', 'CPA', (91, 100))	('prohibited', 'NegReg', (65, 75))	('stimulated', 'PosReg', (115, 125))	('LUSC', 'Chemical', '-', (139, 143))
221618	32297697	In vivo data demonstrated that LINC00519 knock-down inhibited tumour growth and lung metastasis.	('lung metastasis', 'CPA', (80, 95))	('tumour', 'Phenotype', 'HP:0002664', (62, 68))	('tumour growth', 'Disease', (62, 75))	('LINC00519', 'Gene', '161342', (31, 40))	('knock-down', 'Var', (41, 51))	('tumour growth', 'Disease', 'MESH:D006130', (62, 75))	('inhibited', 'NegReg', (52, 61))	('LINC00519', 'Gene', (31, 40))
221620	32297697	H3K27ac was firstly found in yeast.33 Long pliable N-terminal tails in histone proteins could be subject to numerous covalent modifications, containing acetylation.34 In addition, acetylation weakens DNA-histone interaction by neutralizing positive charge of Lys and thereby activated transcription.35 With the great improvement in DNA sequencing technology, it was possible to analyse the distribution patterns of histone acetylation through the whole genome.36 Former researches have confirmed the association between histone H3K27ac dysregulation and tumour progression.37 For example, lncRNA GHET1 is verified to be up-regulated and activated by H3K27ac at promoter region.38 Herein, genome bioinformatics analysis in UCSC showed that H3K27ac was abundant at LINC00519 promoter region, suggesting that LINC00519 might be transcriptionally activated by histone acetylation in LUSC.	('tumour', 'Disease', (554, 560))	('LINC00519', 'Gene', '161342', (763, 772))	('LUSC', 'Phenotype', 'HP:0030359', (879, 883))	('H3K27ac', 'Var', (739, 746))	('lncRNA GHET1', 'Gene', (589, 601))	('LINC00519', 'Gene', (806, 815))	('LUSC', 'Chemical', '-', (879, 883))	('tumour', 'Phenotype', 'HP:0002664', (554, 560))	('tumour', 'Disease', 'MESH:D009369', (554, 560))	('LINC00519', 'Gene', (763, 772))	('lncRNA GHET1', 'Gene', '102723099', (589, 601))	('yeast', 'Species', '4932', (29, 34))	('LINC00519', 'Gene', '161342', (806, 815))
221632	32297697	For instance, lncRNA UICLM acts as a ceRNA to regulate ZEB2 expression and trigger tumour growth and liver metastasis by sponging miRNA-215 in colorectal cancer.41 LncRNA CRNDE acts as a ceRNA to up-regulate IRS1 expression and facilitate cell proliferation and metastasis through sponging miR-384 in pancreatic cancer.42 LncRNA RP11-436H11.5 acts as a ceRNA to up-regulate BCL-W expression and promote the proliferation and invasion via sponging miR-335-5p in renal cell carcinoma.30 Herein, we first validated that miR-450b-5p and miR-515-5p combined with LINC00519 and YAP1 in LUSC.	('miR-384', 'Gene', (290, 297))	('RP11', 'Gene', '26121', (329, 333))	('ncRNA', 'Gene', '54719', (323, 328))	('ZEB2', 'Gene', '9839', (55, 59))	('tumour growth', 'Disease', 'MESH:D006130', (83, 96))	('pancreatic cancer', 'Disease', (301, 318))	('liver metastasis', 'Disease', (101, 117))	('miR-384', 'Gene', '494333', (290, 297))	('colorectal cancer', 'Disease', 'MESH:D015179', (143, 160))	('YAP1', 'Gene', (572, 576))	('LUSC', 'Phenotype', 'HP:0030359', (580, 584))	('miR-335', 'Gene', (447, 454))	('miR-515-5p', 'Chemical', '-', (533, 543))	('cancer', 'Phenotype', 'HP:0002664', (312, 318))	('LUSC', 'Chemical', '-', (580, 584))	('colorectal cancer', 'Disease', (143, 160))	('LINC00519', 'Gene', '161342', (558, 567))	('BCL-W', 'Gene', (374, 379))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (461, 481))	('tumour', 'Phenotype', 'HP:0002664', (83, 89))	('RP11', 'Gene', (329, 333))	('miRNA-215', 'Gene', '406997', (130, 139))	('tumour growth', 'Disease', (83, 96))	('miR-450b-5p', 'Chemical', '-', (517, 528))	('IRS1', 'Gene', '3667', (208, 212))	('miR-515-5p', 'Var', (533, 543))	('IRS1', 'Gene', (208, 212))	('liver metastasis', 'Disease', 'MESH:D009362', (101, 117))	('renal cell carcinoma', 'Disease', (461, 481))	('LINC00519', 'Gene', (558, 567))	('miR-450b-5p', 'Var', (517, 528))	('miRNA-215', 'Gene', (130, 139))	('YAP1', 'Gene', '10413', (572, 576))	('ncRNA', 'Gene', (15, 20))	('miR-335', 'Gene', '442904', (447, 454))	('CRNDE', 'Gene', (171, 176))	('pancreatic cancer', 'Disease', 'MESH:D010190', (301, 318))	('ncRNA', 'Gene', '54719', (15, 20))	('carcinoma', 'Phenotype', 'HP:0030731', (472, 481))	('ncRNA', 'Gene', (165, 170))	('BCL-W', 'Gene', '599', (374, 379))	('CRNDE', 'Gene', '643911', (171, 176))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('ncRNA', 'Gene', '54719', (165, 170))	('ncRNA', 'Gene', (323, 328))	('ZEB2', 'Gene', (55, 59))
221633	32297697	Besides, miR-450b-5p and miR-515-5p expressions were evidently down-regulated in LUSC tissues and cells, and played suppressive role in LUSC cells by repressing proliferation, migration, invasion and stimulating role in cell apoptosis.	('miR-450b-5p', 'Var', (9, 20))	('LUSC', 'Chemical', '-', (136, 140))	('LUSC', 'Chemical', '-', (81, 85))	('migration', 'CPA', (176, 185))	('miR-450b-5p', 'Chemical', '-', (9, 20))	('LUSC', 'Phenotype', 'HP:0030359', (81, 85))	('cell apoptosis', 'CPA', (220, 234))	('miR-515-5p', 'Var', (25, 35))	('repressing', 'PosReg', (150, 160))	('down-regulated', 'NegReg', (63, 77))	('miR-515-5p', 'Chemical', '-', (25, 35))	('LUSC', 'Phenotype', 'HP:0030359', (136, 140))	('stimulating', 'PosReg', (200, 211))	('invasion', 'CPA', (187, 195))	('proliferation', 'CPA', (161, 174))
221635	32297697	In conclusion, the oncogenic role of LINC00519 was first revealed in this study, and H3K27ac-activated LINC00519 promotes LUSC progression by targeting miR-450b-5p/miR-515-5p and regulating YAP1 (Figure 8).	('promotes', 'PosReg', (113, 121))	('LINC00519', 'Gene', '161342', (103, 112))	('LUSC', 'Chemical', '-', (122, 126))	('LINC00519', 'Gene', (37, 46))	('miR-450b-5p/miR-515-5p', 'Var', (152, 174))	('miR-450b-5p', 'Chemical', '-', (152, 163))	('regulating', 'Reg', (179, 189))	('LUSC progression', 'CPA', (122, 138))	('LINC00519', 'Gene', '161342', (37, 46))	('YAP1', 'Gene', (190, 194))	('YAP1', 'Gene', '10413', (190, 194))	('LINC00519', 'Gene', (103, 112))	('targeting', 'Reg', (142, 151))	('miR-515-5p', 'Chemical', '-', (164, 174))	('LUSC', 'Phenotype', 'HP:0030359', (122, 126))	('H3K27ac-activated', 'Var', (85, 102))
221742	32071596	Studies also found smoking can raise CEA levels.	('raise', 'PosReg', (31, 36))	('smoking', 'Var', (19, 26))	('CEA', 'Gene', '1048', (37, 40))	('raise CEA', 'Phenotype', 'HP:0031029', (31, 40))	('CEA', 'Gene', (37, 40))
221762	32030321	More importantly, the focal amplicon in Telomerase Reverse Transcriptase in nonsmokers, the broad deletion in ChrY in male nonsmokers and the greater amplification of MDM2 in female nonsmokers may explain why nonsmokers of both genders tend to suffer LUAD.	('LUAD', 'Phenotype', 'HP:0030078', (251, 255))	('ChrY', 'Gene', (110, 114))	('LUAD', 'Disease', (251, 255))	('LUAD', 'Disease', 'MESH:C538231', (251, 255))	('MDM2', 'Gene', (167, 171))	('deletion', 'Var', (98, 106))	('Telomerase Reverse Transcriptase', 'Gene', '107815112', (40, 72))	('Telomerase Reverse Transcriptase', 'Gene', (40, 72))
221819	32030321	MDM2 is known as a negative regulator of the p53 pathway, which is a very important suppressor pathway for NSCLC.	('p53', 'Gene', (45, 48))	('p53', 'Gene', '7157', (45, 48))	('NSCLC', 'Disease', (107, 112))	('MDM2', 'Var', (0, 4))	('NSCLC', 'Disease', 'MESH:D002289', (107, 112))	('NSCLC', 'Phenotype', 'HP:0030358', (107, 112))
221826	32030321	O(6)-methylguanine-DNA methyltransferase (MGMT) promoter ME has been demonstrated to be associated with increased occurrence of p53 mutation including the G:C A:T transition and other p53 mutation patterns in lung cancer, especially among nonsmokers.	('G:C A:T transition', 'Var', (155, 173))	('MGMT', 'Gene', (42, 46))	('MGMT', 'Gene', '4255', (42, 46))	('p53', 'Gene', (128, 131))	('lung cancer', 'Disease', (209, 220))	('p53', 'Gene', '7157', (128, 131))	('lung cancer', 'Phenotype', 'HP:0100526', (209, 220))	('p53', 'Gene', (184, 187))	('p53', 'Gene', '7157', (184, 187))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('O(6)-methylguanine', 'Chemical', 'MESH:C008449', (0, 18))	('lung cancer', 'Disease', 'MESH:D008175', (209, 220))
221827	32030321	Genetic alterations, including mutation of the epidermal growth factor receptor (or v-Ki-ras2 kirsten rat sarcoma viral oncogene homolog) and fusion of ALK, RET proto-oncogene (RET), or v-ros UR2 sarcoma virus oncogene homolog 1 (ROS1), occur in NSCLCs, and these oncogenic drivers are important biomarkers for targeted therapies.	('ROS1', 'Gene', '107813371', (230, 234))	('sarcoma', 'Phenotype', 'HP:0100242', (106, 113))	('epidermal growth factor receptor', 'Gene', '24329', (47, 79))	('ROS1', 'Gene', (230, 234))	('sarcoma', 'Disease', 'MESH:D012509', (196, 203))	('RET', 'Gene', (177, 180))	('RET', 'Gene', '24716', (177, 180))	('sarcoma', 'Disease', (196, 203))	('NSCLC', 'Phenotype', 'HP:0030358', (246, 251))	('epidermal growth factor receptor', 'Gene', (47, 79))	('NSCLCs', 'Disease', (246, 252))	('v-ros UR2 sarcoma virus oncogene homolog 1', 'Gene', (186, 228))	('sarcoma', 'Phenotype', 'HP:0100242', (196, 203))	('mutation', 'Var', (31, 39))	('sarcoma', 'Disease', 'MESH:D012509', (106, 113))	('NSCLCs', 'Disease', 'MESH:D002289', (246, 252))	('sarcoma', 'Disease', (106, 113))	('ALK', 'Gene', (152, 155))	('RET', 'Gene', '24716', (157, 160))	('RET', 'Gene', (157, 160))	('fusion', 'Var', (142, 148))	('v-ros UR2 sarcoma virus oncogene homolog 1', 'Gene', '25346', (186, 228))	('ALK', 'Gene', '266802', (152, 155))
221828	32030321	ALK (EML4-ALK is a well-known fusion oncogene) translocations are more frequent in nonsmokers' than in smokers' lung cancer.	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('lung cancer', 'Disease', (112, 123))	('lung cancer', 'Phenotype', 'HP:0100526', (112, 123))	('frequent', 'Reg', (71, 79))	('ALK', 'Gene', '266802', (0, 3))	('ALK', 'Gene', (10, 13))	('translocations', 'Var', (47, 61))	('ALK', 'Gene', (0, 3))	('lung cancer', 'Disease', 'MESH:D008175', (112, 123))	('ALK', 'Gene', '266802', (10, 13))
221834	32030321	Increased copy number and overexpression of this gene are associated with many types of cancers including breast and ovarian cancers, acute myeloid leukemia and Hodgkin lymphoma.	('acute myeloid leukemia', 'Disease', (134, 156))	('Hodgkin lymphoma', 'Disease', 'MESH:D006689', (161, 177))	('Hodgkin lymphoma', 'Phenotype', 'HP:0012189', (161, 177))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('cancers', 'Disease', 'MESH:D009369', (125, 132))	('lymphoma', 'Phenotype', 'HP:0002665', (169, 177))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('cancers', 'Disease', (88, 95))	('leukemia', 'Phenotype', 'HP:0001909', (148, 156))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (134, 156))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (134, 156))	('overexpression', 'PosReg', (26, 40))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (140, 156))	('ovarian cancers', 'Phenotype', 'HP:0100615', (117, 132))	('Increased copy number', 'Var', (0, 21))	('Hodgkin lymphoma', 'Disease', (161, 177))	('cancers', 'Phenotype', 'HP:0002664', (125, 132))	('cancers', 'Disease', (125, 132))	('associated', 'Reg', (58, 68))	('cancers', 'Disease', 'MESH:D009369', (88, 95))	('breast and ovarian cancers', 'Disease', 'MESH:D061325', (106, 132))
221835	32030321	TRAPPC9 encodes a protein that likely plays a role in NF-kappa Tumor Protein D52 is showed to be associated with Lung Squamous Cell Carcinoma.	('Squamous Cell Carcinoma', 'Disease', (118, 141))	('Tumor', 'Phenotype', 'HP:0002664', (63, 68))	('TRAPPC9', 'Gene', (0, 7))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (118, 141))	('associated', 'Reg', (97, 107))	('Carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('D52', 'Var', (77, 80))	('Squamous Cell Carcinoma', 'Disease', 'MESH:D002294', (118, 141))
221840	32030321	Additionally, the broad deletion on ChrY and the amplicon on TERT in nonsmokers, especially the amplicon of MDM2 in female nonsmokers may provide clues for the initiation and progression of LUAD in nonsmokers of different genders.	('broad deletion', 'Var', (18, 32))	('LUAD', 'Phenotype', 'HP:0030078', (190, 194))	('LUAD', 'Disease', (190, 194))	('LUAD', 'Disease', 'MESH:C538231', (190, 194))	('MDM2', 'Gene', (108, 112))
221845	31283542	Next-generation sequencing revealed that multiple genetic aberrations were present, including epidermal growth factor receptor copy number amplification, and mutations in ERBB4, ALK, RET, and BRCA2.	('RET', 'Gene', (183, 186))	('epidermal growth factor receptor', 'Gene', '1956', (94, 126))	('ERBB4', 'Gene', (171, 176))	('ALK', 'Gene', (178, 181))	('RET', 'Gene', '5979', (183, 186))	('epidermal growth factor receptor', 'Gene', (94, 126))	('BRCA2', 'Gene', (192, 197))	('ALK', 'Gene', '238', (178, 181))	('mutations', 'Var', (158, 167))	('ERBB4', 'Gene', '2066', (171, 176))	('BRCA2', 'Gene', '675', (192, 197))
221851	31283542	Although EGFR mutations are rare in SqCC, there is biological rationale for ERBB family inhibition in this setting because EGFR overexpression occurs in 60%-80% of tumours, and approximately 10% of tumours demonstrate EGFR copy number alterations.	('EGFR', 'Gene', (123, 127))	('SqCC', 'Disease', (36, 40))	('tumour', 'Phenotype', 'HP:0002664', (164, 170))	('EGFR', 'Gene', (218, 222))	('ERBB', 'Gene', (76, 80))	('copy number alterations', 'Var', (223, 246))	('ERBB', 'Gene', '1956', (76, 80))	('EGFR', 'Gene', (9, 13))	('EGFR', 'Gene', '1956', (123, 127))	('tumours', 'Disease', (198, 205))	('EGFR', 'Gene', '1956', (218, 222))	('tumour', 'Phenotype', 'HP:0002664', (198, 204))	('tumours', 'Disease', (164, 171))	('SqCC', 'Disease', 'MESH:D002294', (36, 40))	('SqCC', 'Phenotype', 'HP:0002860', (36, 40))	('overexpression', 'PosReg', (128, 142))	('tumours', 'Phenotype', 'HP:0002664', (198, 205))	('tumours', 'Disease', 'MESH:D009369', (198, 205))	('tumours', 'Phenotype', 'HP:0002664', (164, 171))	('EGFR', 'Gene', '1956', (9, 13))	('tumours', 'Disease', 'MESH:D009369', (164, 171))
221857	31283542	Thus, it was hypothesized that specific genetic aberrations within the ERBB family might predict the long-term response to afatinib observed in some patients.	('patients', 'Species', '9606', (149, 157))	('afatinib', 'Chemical', 'MESH:C522924', (123, 131))	('ERBB', 'Gene', (71, 75))	('genetic aberrations', 'Var', (40, 59))	('predict', 'Reg', (89, 96))	('ERBB', 'Gene', '1956', (71, 75))
221876	31283542	Foundation Medicine FoundationOne NGS analysis conducted on archived paraffin-embedded tissue samples revealed that the patient had multiple genetic aberrations: EGFR copy number amplification (copy number = 3.68); FGFR1 copy number amplification (copy number = 3.38); a missense S408F mutation in exon 5 of ALK; a missense V130A mutation in exon 4 of BRCA2; a missense R982H mutation in exon 18 of RET; and a missense R847H mutation in exon 21 of ERBB4.	('ALK', 'Gene', (308, 311))	('BRCA2', 'Gene', (352, 357))	('EGFR', 'Gene', (162, 166))	('missense S408F', 'Var', (271, 285))	('RET', 'Gene', (399, 402))	('FGFR1', 'Gene', (215, 220))	('patient', 'Species', '9606', (120, 127))	('BRCA2', 'Gene', '675', (352, 357))	('V130A', 'Mutation', 'p.V130A', (324, 329))	('R982H', 'Mutation', 'p.R982H', (370, 375))	('EGFR', 'Gene', '1956', (162, 166))	('S408F', 'Mutation', 'p.S408F', (280, 285))	('ERBB4', 'Gene', '2066', (448, 453))	('R847H', 'Mutation', 'p.R847H', (419, 424))	('ERBB4', 'Gene', (448, 453))	('RET', 'Gene', '5979', (399, 402))	('FGFR1', 'Gene', '2260', (215, 220))	('missense R982H', 'Var', (361, 375))	('missense R847H', 'Var', (410, 424))	('ALK', 'Gene', '238', (308, 311))	('missense V130A', 'Var', (315, 329))
221891	31283542	Notably, the patient harboured a missense ERBB4 mutation.	('patient', 'Species', '9606', (13, 20))	('ERBB4', 'Gene', '2066', (42, 47))	('harboured', 'Reg', (21, 30))	('mutation', 'Var', (48, 56))	('ERBB4', 'Gene', (42, 47))	('missense', 'Var', (33, 41))
221892	31283542	Although rare in the LUX-Lung 8 trial (present in 14 of the 245 patients treated with afatinib included in NGS analysis), ERBB4 mutations were associated with a trend towards improved OS [HR 0.22; 95% confidence interval (CI) 0.05-1.04] and PFS (HR 0.21; 95% CI 0.02-1.94).	('ERBB4', 'Gene', '2066', (122, 127))	('patients', 'Species', '9606', (64, 72))	('mutations', 'Var', (128, 137))	('ERBB4', 'Gene', (122, 127))	('PFS', 'CPA', (241, 244))	('afatinib', 'Chemical', 'MESH:C522924', (86, 94))	('improved', 'PosReg', (175, 183))
221893	31283542	Other putative biomarkers, such as EGFR expression and EGFR copy number, and positive Veristrat classification, which was associated with favourable survival outcomes in LUX-Lung 8, may also prove useful when evaluating patient suitability for targeted therapy.	('associated', 'Reg', (122, 132))	('EGFR', 'Gene', '1956', (55, 59))	('copy number', 'Var', (60, 71))	('EGFR', 'Gene', (55, 59))	('EGFR', 'Gene', '1956', (35, 39))	('EGFR', 'Gene', (35, 39))	('LUX-Lung 8', 'Disease', (170, 180))	('patient', 'Species', '9606', (220, 227))
221942	29158828	In general, studies have shown that bacteria alone are unable to induce cancer; the process is commonly accompanied by chronic inflammation and requires independent mutations in oncogenic signalling pathways.	('chronic inflammation', 'Disease', 'MESH:D007249', (119, 139))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('oncogenic signalling pathways', 'Pathway', (178, 207))	('chronic inflammation', 'Disease', (119, 139))	('mutations', 'Var', (165, 174))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('cancer', 'Disease', (72, 78))
221946	29158828	It is postulated that the increase in reactive oxygen species released from the recruited neutrophils to kill invading pathogens may also damage the host cell DNA, causing genetic mutations that ultimately trigger tumour initiation.	('reactive oxygen species', 'MPA', (38, 61))	('trigger', 'Reg', (206, 213))	('tumour initiation', 'Disease', 'MESH:D009369', (214, 231))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (38, 61))	('tumour', 'Phenotype', 'HP:0002664', (214, 220))	('increase', 'PosReg', (26, 34))	('tumour initiation', 'Disease', (214, 231))	('causing', 'Reg', (164, 171))	('genetic mutations', 'Var', (172, 189))
221955	29158828	Researchers have shown that H. pylori strains that are CagA-positive are associated with more severe gastritis and are at a higher risk of carcinogenesis.	('carcinogenesis', 'Disease', (139, 153))	('gastritis', 'Disease', (101, 110))	('H. pylori', 'Gene', (28, 37))	('H. pylori', 'Species', '210', (28, 37))	('associated', 'Reg', (73, 83))	('gastritis', 'Disease', 'MESH:D005756', (101, 110))	('strains', 'Var', (38, 45))	('CagA', 'Gene', (55, 59))	('gastritis', 'Phenotype', 'HP:0005263', (101, 110))	('CagA', 'Gene', '6279', (55, 59))	('carcinogenesis', 'Disease', 'MESH:D063646', (139, 153))
222062	29030590	On the other hand, CDDP and TQ induced apoptosis and necrosis in OEC cell line as well (Fig.	('CDDP', 'Var', (19, 23))	('necrosis', 'Disease', 'MESH:D009336', (53, 61))	('apoptosis', 'CPA', (39, 48))	('TQ', 'Chemical', 'MESH:C003466', (28, 30))	('CDDP', 'Chemical', 'MESH:D002945', (19, 23))	('necrosis', 'Disease', (53, 61))
222145	29030590	After staining at room temperature, cells were injected through ACEA Novocyte  flowcytometer (ACEA Biosciences Inc., San Diego, CA, USA) and analyzed for FITC and PI fluorescent signals using FL1 and FL2 signal detector, respectively (lambdaex/em 488/530 nm for FITC and lambdaex/em 535/617 nm for PI).	('lambdaex/em 488/530 nm', 'Var', (235, 257))	('FL1', 'Gene', (192, 195))	('FITC', 'Chemical', 'MESH:D016650', (154, 158))	('lambdaex/em 535/617 nm', 'Var', (271, 293))	('FITC', 'Chemical', 'MESH:D016650', (262, 266))	('FL1', 'Gene', '100306940', (192, 195))
222165	26852330	Besides these test statistics, one can quantify the difference between tumor and control methylation values, which allows the user to estimate if a complete gene or parts of a gene is hyper- or hypomethylated.	('hypomethylated', 'Var', (194, 208))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('tumor', 'Disease', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('hyper-', 'Var', (184, 190))
222170	26852330	As expected, the overall mutation rate for TP53 is much higher in BRCA (33.1 %) than in KIRC (1.8 %), vice versa for VHL and extremely low for TSHZ3 in both entities.	('higher', 'Reg', (56, 62))	('TSHZ3', 'Gene', '57616', (143, 148))	('BRCA', 'Gene', (66, 70))	('mutation', 'Var', (25, 33))	('BRCA', 'Gene', '672', (66, 70))	('VHL', 'Disease', (117, 120))	('VHL', 'Disease', 'MESH:D006623', (117, 120))	('TP53', 'Gene', '7157', (43, 47))	('TSHZ3', 'Gene', (143, 148))	('TP53', 'Gene', (43, 47))
222171	26852330	Here, the mutation frequencies of these three genes within each cancer entity are depicted, divided into the percentage of non-sense mutations, missense mutations, frame-shift deletions and insertions and splice sites alterations.	('missense mutations', 'Var', (144, 162))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('frame-shift deletions', 'Var', (164, 185))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
222172	26852330	Of great advantage, these graphs highlight that structure-changing variants of TP53 and VHL are highly associated with the BRCA and KIRC cancer types.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('BRCA', 'Gene', (123, 127))	('TP53', 'Gene', '7157', (79, 83))	('TP53', 'Gene', (79, 83))	('associated', 'Reg', (103, 113))	('variants', 'Var', (67, 75))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('cancer', 'Disease', (137, 143))	('BRCA', 'Gene', '672', (123, 127))	('VHL', 'Disease', (88, 91))	('VHL', 'Disease', 'MESH:D006623', (88, 91))
222308	33607825	While associations between HPV and cSCC are less clearly delineated, Nadhan et al found that up to 67% of SCC lesions in the anogenital area of non-White transplant patients carried high-risk HPV subtypes.	('HPV', 'Species', '10566', (27, 30))	('SCC', 'Disease', (106, 109))	('lesions', 'Var', (110, 117))	('patients', 'Species', '9606', (165, 173))	('HPV', 'Species', '10566', (192, 195))	('cSCC', 'Phenotype', 'HP:0006739', (35, 39))
222336	26697149	Many molecular studies have explored a number of genes that are altered, amplified, deregulated in the expression or deleted in the head and neck tumorigenesis and several hypotheses have been put forward to identify specific prognostic markers predicting the malignant potential of a more widely prevalent oral PMDs along with the early identification of second primary tumors that develop from clonal expansion explained by the hypothesis of field cancerization.	('tumor', 'Disease', (371, 376))	('deregulated', 'Var', (84, 95))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('cancer', 'Phenotype', 'HP:0002664', (450, 456))	('expression', 'MPA', (103, 113))	('tumors', 'Disease', (371, 377))	('tumors', 'Disease', 'MESH:D009369', (371, 377))	('tumor', 'Disease', (146, 151))	('tumors', 'Phenotype', 'HP:0002664', (371, 377))	('oral PMDs', 'Disease', (307, 316))	('cancer', 'Disease', 'MESH:D009369', (450, 456))	('cancer', 'Disease', (450, 456))	('tumor', 'Disease', 'MESH:D009369', (371, 376))	('tumor', 'Phenotype', 'HP:0002664', (371, 376))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
222342	26697149	Alterations in the function of EGFR have been linked with oncogenic transformation, autonomous cell growth, invasion, angiogenesis and development of metastases in several cancers and are key characteristics of tumors.	('tumors', 'Disease', 'MESH:D009369', (211, 217))	('EGFR', 'Gene', '1956', (31, 35))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('oncogenic transformation', 'CPA', (58, 82))	('autonomous cell growth', 'CPA', (84, 106))	('Alterations', 'Var', (0, 11))	('EGFR', 'Gene', (31, 35))	('tumors', 'Phenotype', 'HP:0002664', (211, 217))	('cancers', 'Disease', 'MESH:D009369', (172, 179))	('linked', 'Reg', (46, 52))	('metastases', 'Disease', (150, 160))	('cancers', 'Phenotype', 'HP:0002664', (172, 179))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('cancers', 'Disease', (172, 179))	('metastases', 'Disease', 'MESH:D009362', (150, 160))	('tumors', 'Disease', (211, 217))	('invasion', 'CPA', (108, 116))	('angiogenesis', 'CPA', (118, 130))
222410	26697149	Over-expression of EGFR in study cases suggested more aggressive behavior, which may be attributable to the activation of different signaling pathways that control diverse biological processes.	('aggressive behavior', 'CPA', (54, 73))	('aggressive behavior', 'Phenotype', 'HP:0000718', (54, 73))	('EGFR', 'Gene', '1956', (19, 23))	('Over-expression', 'Var', (0, 15))	('more', 'PosReg', (49, 53))	('EGFR', 'Gene', (19, 23))
222432	24525228	Because HH regulates key pluripotency and growth genes such as MYC, Cyclin D1, Nanog, and BMI1, it comes as no surprise that alteration of the HH pathway drives tumor growth.	('MYC', 'Gene', (63, 66))	('pluripotency', 'Disease', 'None', (25, 37))	('BMI1', 'Gene', '648', (90, 94))	('Cyclin D1', 'Gene', '595', (68, 77))	('MYC', 'Gene', '4609', (63, 66))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('drives', 'Reg', (154, 160))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('Cyclin D1', 'Gene', (68, 77))	('Nanog', 'Gene', '79923', (79, 84))	('alteration', 'Var', (125, 135))	('Nanog', 'Gene', (79, 84))	('tumor', 'Disease', (161, 166))	('BMI1', 'Gene', (90, 94))	('pluripotency', 'Disease', (25, 37))
222434	24525228	Tumorigenic HH signaling operates through cell-intrinsic mutations that cause inappropriate pathway activation or by autocrine/paracrine events where the tumor produces HH ligand to feed itself or adjacent growth factor-producing stroma (Figure 1).	('pathway', 'Pathway', (92, 99))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('mutations', 'Var', (57, 66))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('activation', 'PosReg', (100, 110))	('tumor', 'Disease', (154, 159))
222447	24525228	BCCs that have become addicted to PKCiota are vulnerable to pharmacological inhibition of kinase activity, which results in pathway suppression and the blockade of tumor growth.	('tumor', 'Disease', (164, 169))	('suppression', 'NegReg', (132, 143))	('blockade', 'NegReg', (152, 160))	('pathway', 'CPA', (124, 131))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('inhibition', 'Var', (76, 86))	('BCC', 'Phenotype', 'HP:0002671', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))
222453	24525228	Similarly, RNA knockdown of PKCiota, GLI1, or HHAT in orthotopic tumors originating from LSCC oncospheres significantly reduced tumor take rate and decreased tumor size.	('HHAT', 'Disease', (46, 50))	('GLI1', 'Gene', '2735', (37, 41))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('LSCC', 'Phenotype', 'HP:0030359', (89, 93))	('tumors', 'Disease', (65, 71))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('PKCiota', 'Gene', (28, 35))	('tumor', 'Disease', (65, 70))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('reduced', 'NegReg', (120, 127))	('decreased', 'NegReg', (148, 157))	('HHAT', 'Disease', 'None', (46, 50))	('GLI1', 'Gene', (37, 41))	('tumor', 'Disease', (128, 133))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('tumor', 'Disease', (158, 163))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('knockdown', 'Var', (15, 24))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('tumor', 'Disease', 'MESH:D009369', (158, 163))
222455	24525228	Chromatin immunoprecipitation of SOX2 showed occupancy of the HHAT promoter and loss of SOX2 significantly decreased HHAT mRNA and protein levels suggesting a novel link between a stem cell gene and HH pathway activation that drives LSCC tumor growth.	('HHAT', 'Disease', (117, 121))	('tumor', 'Disease', 'MESH:D009369', (238, 243))	('HHAT', 'Disease', 'None', (62, 66))	('SOX2', 'Gene', '6657', (33, 37))	('LSCC', 'Disease', (233, 237))	('HHAT', 'Disease', 'None', (117, 121))	('loss', 'Var', (80, 84))	('decreased', 'NegReg', (107, 116))	('SOX2', 'Gene', (33, 37))	('SOX2', 'Gene', '6657', (88, 92))	('tumor', 'Phenotype', 'HP:0002664', (238, 243))	('tumor', 'Disease', (238, 243))	('SOX2', 'Gene', (88, 92))	('LSCC', 'Phenotype', 'HP:0030359', (233, 237))	('HHAT', 'Disease', (62, 66))
222457	24525228	SOX2 phosphorylation enhanced binding to the HHAT promoter, increased expression of HH target genes, and augmented growth of oncospheres (Figure 1B).	('SOX2', 'Gene', '6657', (0, 4))	('HHAT', 'Disease', 'None', (45, 49))	('HHAT', 'Disease', (45, 49))	('SOX2', 'Gene', (0, 4))	('enhanced', 'PosReg', (21, 29))	('phosphorylation', 'Var', (5, 20))	('expression', 'MPA', (70, 80))	('growth of oncospheres', 'CPA', (115, 136))	('binding', 'Interaction', (30, 37))	('augmented', 'PosReg', (105, 114))	('increased', 'PosReg', (60, 69))	('HH target genes', 'Gene', (84, 99))
222467	32447486	Therefore, a type of chitosan-molecular beacon (CS-MB) probe was developed to recognize the miR-155-5p and image the lung cancer cells for the early diagnosis.	('lung cancer', 'Disease', (117, 128))	('CS-MB', 'Chemical', '-', (48, 53))	('lung cancer', 'Phenotype', 'HP:0100526', (117, 128))	('miR-155-5p', 'Var', (92, 102))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('lung cancer', 'Disease', 'MESH:D008175', (117, 128))
222471	32447486	The CS-MB probe was used to recognize the miR-155-5p and image the lung cancer cells by confocal microscopy in vitro and by living imaging system in vivo.	('miR-155-5p', 'Var', (42, 52))	('CS-MB', 'Chemical', '-', (4, 9))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('lung cancer', 'Disease', 'MESH:D008175', (67, 78))	('lung cancer', 'Disease', (67, 78))	('lung cancer', 'Phenotype', 'HP:0100526', (67, 78))
222472	32447486	The CS-MB probe could be used to recognize the miR-155-5p and image the lung cancer cells significantly in these cells and models.	('CS-MB', 'Chemical', '-', (4, 9))	('miR-155-5p', 'Var', (47, 57))	('lung cancer', 'Disease', (72, 83))	('lung cancer', 'Phenotype', 'HP:0100526', (72, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('lung cancer', 'Disease', 'MESH:D008175', (72, 83))
222475	32447486	In addition, the miR-155-5p in human lung cancer tissues could be detected by the miR-155-5p MB.	('lung cancer', 'Disease', (37, 48))	('lung cancer', 'Phenotype', 'HP:0100526', (37, 48))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('MB', 'Chemical', '-', (93, 95))	('human', 'Species', '9606', (31, 36))	('lung cancer', 'Disease', 'MESH:D008175', (37, 48))	('miR-155-5p', 'Var', (82, 92))
222476	32447486	Both in vivo and in vitro experiments demonstrated that the CS-MB probe could be utilized to recognize the miR-155-5p and image the lung cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('miR-155-5p', 'Var', (107, 117))	('CS-MB', 'Chemical', '-', (60, 65))	('lung cancer', 'Disease', 'MESH:D008175', (132, 143))	('lung cancer', 'Disease', (132, 143))	('lung cancer', 'Phenotype', 'HP:0100526', (132, 143))
222496	32447486	), we used CS nanoparticles combined with MB for the detection and imaging miR-155-5p in non-small cells lung cancer.	('lung cancer', 'Phenotype', 'HP:0100526', (105, 116))	('non-small cells lung cancer', 'Phenotype', 'HP:0030358', (89, 116))	('MB', 'Chemical', '-', (42, 44))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('lung cancer', 'Disease', 'MESH:D008175', (105, 116))	('miR-155-5p', 'Var', (75, 85))	('small cells lung cancer', 'Phenotype', 'HP:0030357', (93, 116))	('CS', 'Chemical', 'MESH:D048271', (11, 13))	('lung cancer', 'Disease', (105, 116))
222500	32447486	Therefore, in the present study, nanotechnology and MB technology were combined, and lung cancer cells, TICs, subcutaneous and lung xenografts in nude mice, and transgenic mice were used as the study subjects to investigate the feasibility of CS nanoparticles (as miR-155-5p MB carrier) in recognizing and imaging miR-155-5p in lung cancer cells (Fig.	('MB', 'Chemical', '-', (52, 54))	('MB', 'Chemical', '-', (275, 277))	('lung cancer', 'Disease', (85, 96))	('lung cancer', 'Disease', (328, 339))	('lung cancer', 'Phenotype', 'HP:0100526', (85, 96))	('lung cancer', 'Phenotype', 'HP:0100526', (328, 339))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('TIC', 'Phenotype', 'HP:0100033', (104, 107))	('miR-155-5p', 'Var', (314, 324))	('TICs', 'Disease', (104, 108))	('CS', 'Chemical', 'MESH:D048271', (243, 245))	('TICs', 'Phenotype', 'HP:0100033', (104, 108))	('lung cancer', 'Disease', 'MESH:D008175', (85, 96))	('TICs', 'Disease', 'MESH:D020323', (104, 108))	('transgenic mice', 'Species', '10090', (161, 176))	('lung cancer', 'Disease', 'MESH:D008175', (328, 339))	('cancer', 'Phenotype', 'HP:0002664', (333, 339))	('nude mice', 'Species', '10090', (146, 155))
222527	32447486	The hsa-miR-155-5p, mmu-miR-155-5p, and U6 Primer Set catalog numbers' are MQPS0000685, MQPS0002476, and MQPS0000002, respectively.	('MQPS0002476', 'Var', (88, 99))	('MQPS0000002', 'Var', (105, 116))	('mmu-miR-155', 'Gene', '387173', (20, 31))	('mmu-miR-155', 'Gene', (20, 31))	('MQPS0000685', 'Var', (75, 86))
222542	32447486	In vitro experiments showed strong red fluorescent signals in the cytoplasm in each group of cells in the presence of CS-miR-155 MB, while only a few signals were detected in the nuclei (Fig.	('red fluorescent signals', 'MPA', (35, 58))	('CS', 'Chemical', 'MESH:D048271', (118, 120))	('MB', 'Chemical', '-', (129, 131))	('CS-miR-155 MB', 'Var', (118, 131))
222543	32447486	The mean fluorescence intensity of TICs was the strongest, followed by H446, SPC-A1, and A549 cells, and the fluorescence intensity was significantly increased in the presence of the CS-miR-155-5p MB compare with the presence of the CS-RS MB (Fig.	('CS-miR-155-5p MB', 'Var', (183, 199))	('A549', 'CellLine', 'CVCL:0023', (89, 93))	('H446', 'Chemical', '-', (71, 75))	('TIC', 'Phenotype', 'HP:0100033', (35, 38))	('CS', 'Chemical', 'MESH:D048271', (233, 235))	('TICs', 'Disease', 'MESH:D020323', (35, 39))	('MB', 'Chemical', '-', (239, 241))	('MB', 'Chemical', '-', (197, 199))	('fluorescence intensity', 'MPA', (9, 31))	('increased', 'PosReg', (150, 159))	('TICs', 'Phenotype', 'HP:0100033', (35, 39))	('TICs', 'Disease', (35, 39))	('CS', 'Chemical', 'MESH:D048271', (183, 185))	('fluorescence', 'MPA', (109, 121))
222545	32447486	Therefore, CS-MB probe could be used for detecting miR-155-5p expression and imaging lung cancer cells.	('miR-155-5p expression', 'Var', (51, 72))	('lung cancer', 'Disease', (85, 96))	('lung cancer', 'Phenotype', 'HP:0100526', (85, 96))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('lung cancer', 'Disease', 'MESH:D008175', (85, 96))	('CS-MB', 'Chemical', '-', (11, 16))	('detecting', 'Reg', (41, 50))
222546	32447486	HE staining was used to prove that lung xenograft model and different disease stages of transgenic mice were established, while qRT-PCR technology was used to detect the expression of miR-155-5p in lung cancer cells and animal models.	('lung cancer', 'Disease', (198, 209))	('lung cancer', 'Phenotype', 'HP:0100526', (198, 209))	('miR-155-5p', 'Var', (184, 194))	('transgenic mice', 'Species', '10090', (88, 103))	('lung cancer', 'Disease', 'MESH:D008175', (198, 209))	('HE', 'Chemical', '-', (0, 2))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))
222553	32447486	3e), suggesting that miR-155-5p plays a major role in the occurrence and development of lung cancer, and can be used as a target for tracing, detection, and imaging.	('miR-155-5p', 'Var', (21, 31))	('lung cancer', 'Disease', (88, 99))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('lung cancer', 'Disease', 'MESH:D008175', (88, 99))	('lung cancer', 'Phenotype', 'HP:0100526', (88, 99))
222555	32447486	After the tumor or lung tissues were removed, the imaging showed that the fluorescent signals were stronger in the H446 group than in the A546 group.	('A546', 'Chemical', '-', (138, 142))	('H446', 'Chemical', '-', (115, 119))	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('tumor', 'Disease', (10, 15))	('stronger', 'PosReg', (99, 107))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('fluorescent signals', 'MPA', (74, 93))	('H446', 'Var', (115, 119))
222556	32447486	The fluorescence intensity was analyzed after injection using the Spectrum Living Image 4.0 software, and the results demonstrated that fluorescent signals in the H446 group with high miR-155-5p expression were stronger than those in the A549 group.	('H446', 'Chemical', '-', (163, 167))	('high miR-155-5p expression', 'Var', (179, 205))	('A549', 'CellLine', 'CVCL:0023', (238, 242))	('stronger', 'PosReg', (211, 219))	('fluorescent signals', 'MPA', (136, 155))
222567	32447486	The ability of miR-155-5p MB to detect miR-155-5p in human lung cancer tissues was investigated further.	('lung cancer', 'Disease', 'MESH:D008175', (59, 70))	('lung cancer', 'Disease', (59, 70))	('lung cancer', 'Phenotype', 'HP:0100526', (59, 70))	('MB', 'Chemical', '-', (26, 28))	('miR-155-5p', 'Var', (39, 49))	('human', 'Species', '9606', (53, 58))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
222568	32447486	After miR-155-5p MB was added to frozen lung cancer tissues, red fluorescent signals with different intensities could be detected in squamous and adenocarcinoma tissues.	('adenocarcinoma', 'Disease', 'MESH:D000230', (146, 160))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('detected', 'Reg', (121, 129))	('lung cancer', 'Disease', (40, 51))	('lung cancer', 'Disease', 'MESH:D008175', (40, 51))	('carcinoma', 'Phenotype', 'HP:0030731', (151, 160))	('miR-155-5p MB', 'Var', (6, 19))	('squamous', 'Disease', (133, 141))	('adenocarcinoma', 'Disease', (146, 160))	('MB', 'Chemical', '-', (17, 19))	('lung cancer', 'Phenotype', 'HP:0100526', (40, 51))	('red fluorescent signals', 'MPA', (61, 84))
222573	32447486	miR-155 is not only overexpressed in several cancers such as breast, colorectal, gastric, and liver cancers, but also increased abnormally in the tissues and serum of the lung cancer patients, thereby miR-155 is a potential molecular marker for the early diagnosis of lung cancer, Moreover, lung cancer patients with high expression of miR-155 have a short survival time and poor prognosis (Liu et al.	('cancer', 'Phenotype', 'HP:0002664', (296, 302))	('lung cancer', 'Phenotype', 'HP:0100526', (171, 182))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('cancers', 'Disease', 'MESH:D009369', (45, 52))	('high', 'Var', (317, 321))	('liver cancers', 'Disease', (94, 107))	('cancers', 'Disease', 'MESH:D009369', (100, 107))	('gastric', 'Disease', (81, 88))	('breast', 'Disease', (61, 67))	('lung cancer', 'Disease', (291, 302))	('lung cancer', 'Disease', (268, 279))	('lung cancer', 'Disease', (171, 182))	('lung cancer', 'Disease', 'MESH:D008175', (291, 302))	('cancers', 'Phenotype', 'HP:0002664', (45, 52))	('liver cancers', 'Disease', 'MESH:D006528', (94, 107))	('cancers', 'Disease', (45, 52))	('cancers', 'Phenotype', 'HP:0002664', (100, 107))	('patients', 'Species', '9606', (183, 191))	('patients', 'Species', '9606', (303, 311))	('cancers', 'Disease', (100, 107))	('lung cancer', 'Phenotype', 'HP:0100526', (291, 302))	('colorectal', 'Disease', (69, 79))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('lung cancer', 'Disease', 'MESH:D008175', (268, 279))	('miR-155', 'Gene', (336, 343))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('cancer', 'Phenotype', 'HP:0002664', (273, 279))	('liver cancers', 'Phenotype', 'HP:0002896', (94, 107))	('lung cancer', 'Phenotype', 'HP:0100526', (268, 279))	('lung cancer', 'Disease', 'MESH:D008175', (171, 182))	('overexpressed', 'PosReg', (20, 33))
222582	32447486	Therefore, in this study, lung adenocarcinoma cell lines A549 and SPC-A1, SCLC line H446, and TICs with high expression of miR-155-5p were used as models.	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (26, 45))	('H446', 'Chemical', '-', (84, 88))	('SCLC', 'Disease', 'MESH:D018288', (74, 78))	('TIC', 'Phenotype', 'HP:0100033', (94, 97))	('SCLC', 'Disease', (74, 78))	('carcinoma', 'Phenotype', 'HP:0030731', (36, 45))	('lung adenocarcinoma', 'Disease', (26, 45))	('TICs', 'Disease', (94, 98))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (26, 45))	('TICs', 'Phenotype', 'HP:0100033', (94, 98))	('miR-155-5p', 'Var', (123, 133))	('A549', 'CellLine', 'CVCL:0023', (57, 61))	('TICs', 'Disease', 'MESH:D020323', (94, 98))
222583	32447486	After miR-155-5p MB was transfected with CS nanoparticles, the results showed that miR-155-5p MB could detect miR-155-5p and image the lung cancer living cells.	('MB', 'Chemical', '-', (94, 96))	('miR-155-5p', 'Var', (110, 120))	('miR-155-5p', 'Var', (83, 93))	('lung cancer', 'Disease', (135, 146))	('lung cancer', 'Disease', 'MESH:D008175', (135, 146))	('CS', 'Chemical', 'MESH:D048271', (41, 43))	('detect', 'MPA', (103, 109))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('MB', 'Chemical', '-', (17, 19))	('lung cancer', 'Phenotype', 'HP:0100526', (135, 146))
222584	32447486	Moreover, the fluorescence intensity of TICs with the highest expression of miR-155-5p was the maximal and can be easily detected.	('TICs', 'Disease', 'MESH:D020323', (40, 44))	('miR-155-5p', 'Var', (76, 86))	('fluorescence intensity', 'MPA', (14, 36))	('maximal', 'MPA', (95, 102))	('expression', 'MPA', (62, 72))	('TICs', 'Disease', (40, 44))	('TICs', 'Phenotype', 'HP:0100033', (40, 44))	('TIC', 'Phenotype', 'HP:0100033', (40, 43))
222586	32447486	Further analysis of the fluorescence intensity demonstrated that the fluorescence intensity of the four cell lines after transfection with MB was consistent with the expression of miR-155-5p as assessed by qRT-PCR.	('MB', 'Chemical', '-', (139, 141))	('miR-155-5p', 'Var', (180, 190))	('fluorescence', 'MPA', (69, 81))
222588	32447486	These findings demonstrated that miR-155-5p in living cells and TICs of lung cancer could be recognized and imaged at the cell level.	('TIC', 'Phenotype', 'HP:0100033', (64, 67))	('TICs of lung cancer', 'Disease', 'MESH:D008175', (64, 83))	('miR-155-5p', 'Var', (33, 43))	('lung cancer', 'Phenotype', 'HP:0100526', (72, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('TICs of lung cancer', 'Disease', (64, 83))	('TICs', 'Phenotype', 'HP:0100033', (64, 68))
222595	32447486	The results showed that red fluorescent signals with different intensities could be detected after frozen lung cancer tissues were incubated with miR-155-5p MB, indicating that miR-155-5p MB can bind to miR-155-5p in the tissues to produce fluorescent signals, which laid the foundation for subsequent preclinical studies.	('produce', 'Reg', (232, 239))	('lung cancer', 'Disease', (106, 117))	('lung cancer', 'Phenotype', 'HP:0100526', (106, 117))	('fluorescent signals', 'MPA', (240, 259))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('miR-155-5p MB', 'Var', (177, 190))	('MB', 'Chemical', '-', (188, 190))	('lung cancer', 'Disease', 'MESH:D008175', (106, 117))	('bind', 'Interaction', (195, 199))	('MB', 'Chemical', '-', (157, 159))
222597	32447486	It can recognize the highly expressed miR-155-5p and image the cancer cells of TICs, lung cancer xenografts, and transgenic mice in the different stages of the disease.	('lung cancer', 'Disease', (85, 96))	('lung cancer', 'Phenotype', 'HP:0100526', (85, 96))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('TIC', 'Phenotype', 'HP:0100033', (79, 82))	('TICs', 'Disease', (79, 83))	('transgenic mice', 'Species', '10090', (113, 128))	('lung cancer', 'Disease', 'MESH:D008175', (85, 96))	('TICs', 'Phenotype', 'HP:0100033', (79, 83))	('TICs', 'Disease', 'MESH:D020323', (79, 83))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('miR-155-5p', 'Var', (38, 48))	('cancer', 'Disease', (63, 69))
222599	32447486	In addition, MB was used to primarily recognize and image miR-155-5p in human lung cancer tissues.	('lung cancer', 'Disease', (78, 89))	('MB', 'Chemical', '-', (13, 15))	('lung cancer', 'Phenotype', 'HP:0100526', (78, 89))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('human', 'Species', '9606', (72, 77))	('lung cancer', 'Disease', 'MESH:D008175', (78, 89))	('miR-155-5p', 'Var', (58, 68))
222652	31053962	Tumor diameter (> 4 cm), poor differentiation, and pN3-4 have been reported as prognostic factors in ESCC.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('SCC', 'Phenotype', 'HP:0002860', (102, 105))	('SCC', 'Gene', '6317', (102, 105))	('pN3-4', 'Var', (51, 56))	('SCC', 'Gene', (102, 105))
222809	28851360	Statistical analysis demonstrated that high expression of PLPP4 significantly and positively correlated with clinicopathological features, including pathological grade, T category and stage, and poor overall and progression-free survival in lung carcinoma patients.	('progression-free survival', 'CPA', (212, 237))	('overall', 'CPA', (200, 207))	('high', 'Var', (39, 43))	('lung carcinoma', 'Disease', 'MESH:D008175', (241, 255))	('correlated', 'Reg', (93, 103))	('PLPP4', 'Gene', (58, 63))	('patients', 'Species', '9606', (256, 264))	('carcinoma', 'Phenotype', 'HP:0030731', (246, 255))	('poor', 'NegReg', (195, 199))	('lung carcinoma', 'Disease', (241, 255))
222810	28851360	Silencing PLPP4 inhibits proliferation and cell cycle progression in vitro and tumorigenesis in vivo in lung carcinoma cells.	('proliferation', 'CPA', (25, 38))	('tumor', 'Disease', (79, 84))	('lung carcinoma cells', 'Disease', 'MESH:D055752', (104, 124))	('PLPP4', 'Gene', (10, 15))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('cell cycle progression', 'CPA', (43, 65))	('inhibits', 'NegReg', (16, 24))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('lung carcinoma cells', 'Disease', (104, 124))	('Silencing', 'Var', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
222811	28851360	Our results further reveal that PLPP4 silencing inhibits Ca2+-permeable cationic channel, suggesting that downregulation of PLPP4 inhibits proliferation and tumorigenesis in lung carcinoma cells via reducing the influx of intracellular Ca2+.	('tumor', 'Disease', (157, 162))	('PLPP4', 'Gene', (32, 37))	('Ca2', 'Gene', '760', (236, 239))	('downregulation', 'NegReg', (106, 120))	('inhibits', 'NegReg', (48, 56))	('reducing', 'NegReg', (199, 207))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('lung carcinoma cells', 'Disease', (174, 194))	('Ca2', 'Gene', '760', (57, 60))	('Ca2', 'Gene', (236, 239))	('proliferation', 'CPA', (139, 152))	('PLPP4', 'Gene', (124, 129))	('carcinoma', 'Phenotype', 'HP:0030731', (179, 188))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('lung carcinoma cells', 'Disease', 'MESH:D055752', (174, 194))	('Ca2', 'Gene', (57, 60))	('inhibits', 'NegReg', (130, 138))	('silencing', 'Var', (38, 47))
222820	28851360	This increase in diacylglycerol concentration has been referred to as the second phase of diacylglycerol signaling in which LPPs are believed to play an important role, which further results in the release and influx of intracellular Ca2+.Furthermore, accumulating evidence has shown that aberrant expression of LPPs has been implicated in the development and progression of cancer.	('diacylglycerol', 'Chemical', 'MESH:D004075', (90, 104))	('implicated', 'Reg', (326, 336))	('cancer', 'Phenotype', 'HP:0002664', (375, 381))	('LPPs', 'Gene', (312, 316))	('Ca2', 'Gene', '760', (234, 237))	('diacylglycerol', 'Chemical', 'MESH:D004075', (17, 31))	('aberrant expression', 'Var', (289, 308))	('cancer', 'Disease', (375, 381))	('cancer', 'Disease', 'MESH:D009369', (375, 381))	('Ca2', 'Gene', (234, 237))
222823	28851360	reported that overexpression of PLPP5 caused by amplification of the 8p11-12 chromosomal region, a common genetic event in many epithelial cancers, was found in several cancers, including breast cancer, pancreatic adenocarcinomas and lung carcinoma.	('cancers', 'Disease', (169, 176))	('breast cancer', 'Phenotype', 'HP:0003002', (188, 201))	('cancers', 'Phenotype', 'HP:0002664', (139, 146))	('carcinoma', 'Phenotype', 'HP:0030731', (239, 248))	('cancers', 'Disease', (139, 146))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('overexpression', 'PosReg', (14, 28))	('found', 'Reg', (152, 157))	('epithelial cancers', 'Disease', (128, 146))	('breast cancer', 'Disease', 'MESH:D001943', (188, 201))	('PLPP5', 'Gene', (32, 37))	('breast cancer', 'Disease', (188, 201))	('epithelial cancers', 'Disease', 'MESH:D000077216', (128, 146))	('cancers', 'Disease', 'MESH:D009369', (169, 176))	('cancers', 'Disease', 'MESH:D009369', (139, 146))	('pancreatic adenocarcinomas and lung carcinoma', 'Disease', 'MESH:D000077192', (203, 248))	('pancreatic adenocarcinomas', 'Phenotype', 'HP:0006725', (203, 229))	('carcinoma', 'Phenotype', 'HP:0030731', (219, 228))	('amplification', 'Var', (48, 61))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('PLPP5', 'Gene', '84513', (32, 37))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('cancers', 'Phenotype', 'HP:0002664', (169, 176))
222827	28851360	Silencing PLPP4 inhibits the proliferation and tumorigenicity of lung carcinoma cells both in vitro and in vivo.	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('lung carcinoma cells', 'Disease', 'MESH:D055752', (65, 85))	('PLPP4', 'Gene', (10, 15))	('proliferation', 'CPA', (29, 42))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('inhibits', 'NegReg', (16, 24))	('lung carcinoma cells', 'Disease', (65, 85))	('Silencing', 'Var', (0, 9))	('tumor', 'Disease', (47, 52))
222843	28851360	Stable cell lines expressing shPLPP4#1or shPLPP4#2 were generated by lentiviral infection using HEK293T cells, and selected with 0.5 mg/L puromycin for 10 days.	('shPLPP4#1or', 'Var', (29, 40))	('puromycin', 'Chemical', 'MESH:D011691', (138, 147))	('HEK293T', 'CellLine', 'CVCL:0063', (96, 103))	('shPLPP4#2', 'Var', (41, 50))
222855	28851360	Tumor cell proportion were scored as follows: 0 (no positive tumor cells); 1 (<10% positive tumor cells); 2 (10-35% positive tumor cells); 3 (35-70% positive tumor cells) and 4 (>70% positive tumor cells).	('10-35', 'Var', (109, 114))	('tumor', 'Disease', (158, 163))	('tumor', 'Disease', (192, 197))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Disease', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Disease', (92, 97))	('35-70', 'Var', (142, 147))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('tumor', 'Disease', (61, 66))
222880	28851360	Therefore, our findings indicated that high expression of PLPP4 is positively associated with advanced clinicopathological features in lung carcinoma patients.	('associated', 'Reg', (78, 88))	('lung carcinoma', 'Disease', (135, 149))	('high', 'Var', (39, 43))	('lung carcinoma', 'Disease', 'MESH:D008175', (135, 149))	('PLPP4', 'Gene', (58, 63))	('patients', 'Species', '9606', (150, 158))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))
222881	28851360	To investigate the clinical correlation of PLPP4 with survival in lung carcinoma patients, lung carcinoma datasets from TCGA, ArrayExpress and Kaplan-Meier Plotter were further analyzed and the results revealed that non-small-cell lung carcinoma (NSCLC) patients with high expression of PLPP4 exhibited shorter overall and progression-free survival rates compared with NSCLC patients with low expression of PLPP4 (Fig.	('NSCLC', 'Disease', (247, 252))	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('lung carcinoma', 'Disease', (91, 105))	('lung carcinoma', 'Disease', 'MESH:D008175', (231, 245))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('NSCLC', 'Disease', 'MESH:D002289', (369, 374))	('lung carcinoma', 'Disease', (66, 80))	('shorter', 'NegReg', (303, 310))	('carcinoma', 'Phenotype', 'HP:0030731', (236, 245))	('NSCLC', 'Disease', (369, 374))	('progression-free survival rates', 'CPA', (323, 354))	('PLPP4', 'Gene', (287, 292))	('patients', 'Species', '9606', (375, 383))	('NSCLC', 'Disease', 'MESH:D002289', (247, 252))	('lung carcinoma', 'Disease', 'MESH:D008175', (91, 105))	('patients', 'Species', '9606', (81, 89))	('lung carcinoma', 'Disease', (231, 245))	('lung carcinoma', 'Disease', 'MESH:D008175', (66, 80))	('patients', 'Species', '9606', (254, 262))	('high expression', 'Var', (268, 283))
222882	28851360	In-depth analysis of lung carcinoma TCGA and ArrayExpress datasets showed that ADC or SQC patients with high expression of PLPP4 displayed poor overall and progression-free survival rates (Fig.	('SQC', 'Phenotype', 'HP:0002860', (86, 89))	('poor', 'NegReg', (139, 143))	('ADC', 'Disease', (79, 82))	('PLPP4', 'Gene', (123, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (26, 35))	('lung carcinoma', 'Disease', (21, 35))	('high expression', 'Var', (104, 119))	('lung carcinoma', 'Disease', 'MESH:D008175', (21, 35))	('patients', 'Species', '9606', (90, 98))	('progression-free survival rates', 'CPA', (156, 187))
222886	28851360	As the highest expression of PLPP4 was in A549 and Calu-3 cells, we constructed PLPP4-stably suppressing A549 and Calu-3 lung carcinoma cells by endogenously knocking down PLPP4 via retroviral infection (Fig.	('lung carcinoma cells', 'Disease', (121, 141))	('retroviral infection', 'Disease', 'MESH:D000071297', (182, 202))	('suppressing', 'NegReg', (93, 104))	('A549', 'CellLine', 'CVCL:0023', (42, 46))	('Calu-3', 'CellLine', 'CVCL:0609', (51, 57))	('PLPP4', 'Gene', (172, 177))	('lung carcinoma cells', 'Disease', 'MESH:D055752', (121, 141))	('Calu-3', 'CellLine', 'CVCL:0609', (114, 120))	('A549', 'CellLine', 'CVCL:0023', (105, 109))	('retroviral infection', 'Disease', (182, 202))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('knocking down', 'Var', (158, 171))
222888	28851360	Colony formation assays revealed that silencing PLPP4 dramatically inhibited the colony-forming ability of A549 and Calu-3 cells (Fig.	('inhibited', 'NegReg', (67, 76))	('PLPP4', 'Gene', (48, 53))	('A549', 'CellLine', 'CVCL:0023', (107, 111))	('Calu-3', 'CellLine', 'CVCL:0609', (116, 122))	('silencing', 'Var', (38, 47))
222889	28851360	We further performed anchorage-independent growth assays to investigate the effects of PLPP4 on the tumorigenic activity of lung carcinoma cells and found that silencing PLPP4 not only reduced the number of colonies formed by A549 and Calu-3 cells, but also significantly decreased the colony size of lung carcinoma cells (Fig.	('lung carcinoma cells', 'Disease', (124, 144))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('carcinoma', 'Phenotype', 'HP:0030731', (306, 315))	('tumor', 'Disease', (100, 105))	('decreased', 'NegReg', (272, 281))	('lung carcinoma cells', 'Disease', (301, 321))	('silencing', 'Var', (160, 169))	('lung carcinoma cells', 'Disease', 'MESH:D055752', (124, 144))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('A549', 'CellLine', 'CVCL:0023', (226, 230))	('lung carcinoma cells', 'Disease', 'MESH:D055752', (301, 321))	('PLPP4', 'Gene', (170, 175))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('Calu-3', 'CellLine', 'CVCL:0609', (235, 241))	('reduced', 'NegReg', (185, 192))
222890	28851360	Taken together, these findings demonstrated that silencing PLPP4 inhibits the proliferation ability of lung carcinoma cells.	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('silencing', 'Var', (49, 58))	('inhibits', 'NegReg', (65, 73))	('PLPP4', 'Gene', (59, 64))	('lung carcinoma cells', 'Disease', 'MESH:D055752', (103, 123))	('proliferation ability of', 'CPA', (78, 102))	('lung carcinoma cells', 'Disease', (103, 123))
222892	28851360	Flow cytometry analysis showed that silencing PLPP4 dramatically decreased the percentage of cells in the S phase and increased that of cells in the G1/G0 phase, indicating that silencing PLPP4 induced G1/S arrest in lung carcinoma cells (Fig.	('lung carcinoma cells', 'Disease', 'MESH:D055752', (217, 237))	('PLPP4', 'Gene', (188, 193))	('induced', 'Reg', (194, 201))	('decreased', 'NegReg', (65, 74))	('increased', 'PosReg', (118, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (222, 231))	('silencing', 'Var', (36, 45))	('PLPP4', 'Gene', (46, 51))	('lung carcinoma cells', 'Disease', (217, 237))	('silencing', 'Var', (178, 187))	('S arrest', 'Disease', (205, 213))	('S arrest', 'Disease', 'MESH:D006323', (205, 213))
222893	28851360	Real-time PCR and Western blot analysis revealed that silencing PLPP4 repressed the mRNA and protein expression levels of critical cell cycle regulators of the G1/S checkpoint CCND1, CCNA2 and CCNB1 in lung carcinoma cells (Fig.	('CCND1', 'Gene', (176, 181))	('lung carcinoma cells', 'Disease', 'MESH:D055752', (202, 222))	('CCNB1', 'Gene', (193, 198))	('silencing', 'Var', (54, 63))	('PLPP4', 'Gene', (64, 69))	('CCND1', 'Gene', '595', (176, 181))	('carcinoma', 'Phenotype', 'HP:0030731', (207, 216))	('CCNA2', 'Gene', (183, 188))	('CCNB1', 'Gene', '891', (193, 198))	('lung carcinoma cells', 'Disease', (202, 222))	('CCNA2', 'Gene', '890', (183, 188))	('repressed', 'PosReg', (70, 79))
222898	28851360	We further examined the effects of PLPP4 silencing on the growth ability of A549 cells in the lung.	('PLPP4', 'Gene', (35, 40))	('A549', 'CellLine', 'CVCL:0023', (76, 80))	('silencing', 'Var', (41, 50))
222901	28851360	Collectively, these findings indicate that PLPP4 silencing inhibits the tumorigenesis and lung colonization capabilities of lung carcinoma cells.	('lung carcinoma cells', 'Disease', (124, 144))	('lung colonization capabilities of', 'CPA', (90, 123))	('PLPP4', 'Gene', (43, 48))	('silencing', 'Var', (49, 58))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('inhibits', 'NegReg', (59, 67))	('tumor', 'Disease', (72, 77))	('lung carcinoma cells', 'Disease', 'MESH:D055752', (124, 144))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('tumor', 'Disease', 'MESH:D009369', (72, 77))
222903	28851360	Fluorescence-activated cell sorting (FACS) analysis showed that silencing PLPP4 decreased intracellular Ca2+ in lung carcinoma cells, which was more obvious in cells treated with SKF 96365, a novel inhibitor of receptor-mediated Ca2+ entry (5 mum, 24 h) (Fig.	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('SKF 96365', 'Chemical', 'MESH:C063159', (179, 188))	('Ca2', 'Gene', '760', (229, 232))	('Ca2', 'Gene', (104, 107))	('Ca2', 'Gene', '760', (104, 107))	('decreased', 'NegReg', (80, 89))	('lung carcinoma cells', 'Disease', (112, 132))	('lung carcinoma cells', 'Disease', 'MESH:D055752', (112, 132))	('Ca2', 'Gene', (229, 232))	('silencing', 'Var', (64, 73))	('PLPP4', 'Gene', (74, 79))
222904	28851360	Western blot analysis showed that silencing PLPP4 or SKF 96365 reduced the cytoplasmic S54 phosphorylated NFAT1 and its nuclear translocation (Fig.	('cytoplasmic S54 phosphorylated', 'MPA', (75, 105))	('PLPP4', 'Gene', (44, 49))	('SKF 96365', 'Chemical', 'MESH:C063159', (53, 62))	('reduced', 'NegReg', (63, 70))	('NFAT1', 'Gene', (106, 111))	('nuclear translocation', 'CPA', (120, 141))	('SKF 96365', 'Gene', (53, 62))	('silencing', 'Var', (34, 43))	('NFAT1', 'Gene', '4773', (106, 111))
222906	28851360	Collectively, our results suggest that silencing PLPP4 inhibits Ca2+-permeable cationic channel in lung carcinoma cells (Fig.	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('inhibits', 'NegReg', (55, 63))	('lung carcinoma cells', 'Disease', (99, 119))	('Ca2', 'Gene', '760', (64, 67))	('silencing', 'Var', (39, 48))	('PLPP4', 'Gene', (49, 54))	('Ca2', 'Gene', (64, 67))	('lung carcinoma cells', 'Disease', 'MESH:D055752', (99, 119))
222908	28851360	Moreover, silencing PLPP4 inhibits the proliferation, cell cycle progression, tumorigenicity and lung metastasis abilities of lung carcinoma cells both in vitro and in vivo.	('inhibits', 'NegReg', (26, 34))	('lung carcinoma cells', 'Disease', 'MESH:D055752', (126, 146))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('PLPP4', 'Gene', (20, 25))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('lung metastasis abilities of lung carcinoma', 'Disease', (97, 140))	('lung metastasis abilities of lung carcinoma', 'Disease', 'MESH:D008175', (97, 140))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('lung carcinoma cells', 'Disease', (126, 146))	('proliferation', 'CPA', (39, 52))	('tumor', 'Disease', (78, 83))	('cell cycle progression', 'CPA', (54, 76))	('silencing', 'Var', (10, 19))
222911	28851360	Numerous studies have reported that altered expression of LPPs has been involved in the development and progression of several human cancers.	('expression', 'MPA', (44, 54))	('human', 'Species', '9606', (127, 132))	('cancers', 'Phenotype', 'HP:0002664', (133, 140))	('cancers', 'Disease', (133, 140))	('cancers', 'Disease', 'MESH:D009369', (133, 140))	('involved', 'Reg', (72, 80))	('altered', 'Var', (36, 43))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('LPPs', 'Gene', (58, 62))
222917	28851360	In vitro and in vivo assays demonstrated that silencing PLPP4 inhibited the proliferation and cell cycle progression, and the tumorigenesis of lung carcinoma cells in subcutaneous, as well as in the lung.	('lung carcinoma cells', 'Disease', 'MESH:D055752', (143, 163))	('silencing', 'Var', (46, 55))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('PLPP4', 'Gene', (56, 61))	('lung carcinoma cells', 'Disease', (143, 163))	('inhibited', 'NegReg', (62, 71))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('carcinoma', 'Phenotype', 'HP:0030731', (148, 157))	('tumor', 'Disease', (126, 131))
222918	28851360	Thus, our results indicate that high expression of PLPP4 is implicated in the progression of lung carcinoma via promoting the proliferation and cell cycle in lung carcinoma cells.	('proliferation', 'CPA', (126, 139))	('lung carcinoma', 'Disease', (93, 107))	('cell cycle', 'CPA', (144, 154))	('lung carcinoma', 'Disease', 'MESH:D008175', (93, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (163, 172))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('lung carcinoma cells', 'Disease', (158, 178))	('implicated', 'Reg', (60, 70))	('lung carcinoma', 'Disease', 'MESH:D008175', (158, 172))	('PLPP4', 'Gene', (51, 56))	('promoting', 'PosReg', (112, 121))	('high expression', 'Var', (32, 47))	('lung carcinoma cells', 'Disease', 'MESH:D055752', (158, 178))
222925	28851360	Moreover, silencing PLPP4 repressed the proliferation, tumorigenicity and lung metastasis abilities of lung carcinoma cells both in in vitro and in vivo, as well as inhibited Ca2+-permeable cationic channel in lung carcinoma cells.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('lung carcinoma cells', 'Disease', 'MESH:D055752', (210, 230))	('PLPP4', 'Gene', (20, 25))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('inhibited', 'NegReg', (165, 174))	('lung carcinoma cells', 'Disease', 'MESH:D055752', (103, 123))	('tumor', 'Disease', (55, 60))	('lung metastasis abilities of lung carcinoma', 'Disease', 'MESH:D008175', (74, 117))	('Ca2', 'Gene', '760', (175, 178))	('carcinoma', 'Phenotype', 'HP:0030731', (215, 224))	('lung metastasis abilities of lung carcinoma', 'Disease', (74, 117))	('silencing', 'Var', (10, 19))	('lung carcinoma cells', 'Disease', (210, 230))	('lung carcinoma cells', 'Disease', (103, 123))	('Ca2', 'Gene', (175, 178))
222928	28851360	The increment of diacylglycerol concentration could directly activate some transient receptor potential channel (TRPC) family members without depleting intracellular Ca2+ stores, leading to the release and influx of intracellular Ca2+.	('Ca2', 'Gene', '760', (166, 169))	('Ca2', 'Gene', (230, 233))	('activate', 'PosReg', (61, 69))	('release', 'MPA', (194, 201))	('TRPC) family', 'Gene', (113, 125))	('Ca2', 'Gene', (166, 169))	('increment', 'Var', (4, 13))	('Ca2', 'Gene', '760', (230, 233))	('diacylglycerol', 'Chemical', 'MESH:D004075', (17, 31))
222932	28851360	In the current study, our results found that silencing PLPP4 effectively reduced intracellular Ca2+ and S54 phosphorylated levels of NFAT1, which further inhibited the proliferation and tumorigenesis in lung carcinoma cells.	('silencing', 'Var', (45, 54))	('proliferation', 'CPA', (168, 181))	('NFAT1', 'Gene', (133, 138))	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('Ca2', 'Gene', '760', (95, 98))	('lung carcinoma cells', 'Disease', 'MESH:D055752', (203, 223))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('carcinoma', 'Phenotype', 'HP:0030731', (208, 217))	('reduced', 'NegReg', (73, 80))	('inhibited', 'NegReg', (154, 163))	('tumor', 'Disease', (186, 191))	('Ca2', 'Gene', (95, 98))	('NFAT1', 'Gene', '4773', (133, 138))	('lung carcinoma cells', 'Disease', (203, 223))	('PLPP4', 'Gene', (55, 60))	('S54 phosphorylated levels', 'MPA', (104, 129))
222933	28851360	Our findings indicate that inhibition of PLPP4 may be used as a novel therapeutic strategy in the treatment of lung carcinoma.	('PLPP4', 'Gene', (41, 46))	('inhibition', 'Var', (27, 37))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('lung carcinoma', 'Disease', (111, 125))	('lung carcinoma', 'Disease', 'MESH:D008175', (111, 125))
222940	28851360	Therefore, our data may lead us to further in vivo studies, namely, inhibition of PLPP4 may be used as a complementary strategy in the treatment of lung carcinoma.	('PLPP4', 'Gene', (82, 87))	('lung carcinoma', 'Disease', 'MESH:D008175', (148, 162))	('lung carcinoma', 'Disease', (148, 162))	('inhibition', 'Var', (68, 78))	('carcinoma', 'Phenotype', 'HP:0030731', (153, 162))
222956	27143814	A potential limitation in the use of saliva as a diagnostic fluid is oral dryness caused by the failure to produce saliva.	('oral dryness', 'Disease', 'MESH:D014987', (69, 81))	('oral dryness', 'Disease', (69, 81))	('oral dryness', 'Phenotype', 'HP:0000217', (69, 81))	('failure', 'Var', (96, 103))
223008	27143814	This central database is crucial in the identification of combinations of biomarker panels that may provide distinct diagnostic information and thus serves as a valuable resource for identifying deviations within proteins or peptides that align with oral and systemic disease and will aid in the development of saliva-based diagnostic tests.	('proteins', 'Protein', (213, 221))	('systemic disease', 'Disease', (259, 275))	('deviations', 'Var', (195, 205))	('systemic disease', 'Disease', 'MESH:D034721', (259, 275))
223016	27143814	(2005) which showed significant differences between the levels of 8-OHdG in saliva in patients with aggressive and advanced periodontitis and in individuals with clinically healthy periodontal tissues.	('8-OHdG', 'Var', (66, 72))	('8-OHdG', 'Chemical', 'MESH:C067134', (66, 72))	('periodontitis', 'Disease', 'MESH:D010518', (124, 137))	('periodontitis', 'Phenotype', 'HP:0000704', (124, 137))	('aggressive', 'Disease', (100, 110))	('periodontitis', 'Disease', (124, 137))	('patients', 'Species', '9606', (86, 94))
223077	28694483	Importantly, mutations in ZFHX4, SPHKAP, NRXN1, KIAA1109, DNAH5 and KCNH7 were associated with poor survival.	('KIAA1109', 'Gene', '84162', (48, 56))	('associated', 'Reg', (79, 89))	('SPHKAP', 'Gene', (33, 39))	('DNAH5', 'Gene', '1767', (58, 63))	('KCNH7', 'Gene', '90134', (68, 73))	('KIAA1109', 'Gene', (48, 56))	('poor', 'NegReg', (95, 99))	('NRXN1', 'Gene', '9378', (41, 46))	('SPHKAP', 'Gene', '80309', (33, 39))	('KCNH7', 'Gene', (68, 73))	('ZFHX4', 'Gene', (26, 31))	('NRXN1', 'Gene', (41, 46))	('mutations', 'Var', (13, 22))	('ZFHX4', 'Gene', '79776', (26, 31))	('DNAH5', 'Gene', (58, 63))
223078	28694483	In addition, ZFHX4 was overexpressed in tumor tissues compared to normal controls, and knockdown of ZFHX4 in vitro significantly inhibited cell migration and invasion.	('inhibited', 'NegReg', (129, 138))	('ZFHX4', 'Gene', '79776', (13, 18))	('ZFHX4', 'Gene', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('ZFHX4', 'Gene', '79776', (100, 105))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('ZFHX4', 'Gene', (13, 18))	('knockdown', 'Var', (87, 96))
223079	28694483	Mutations in ZFHX4 were strongly associated with poor prognosis and the down-regulation of ZFHX4 inhibits the progression of esophageal squamous cell carcinoma.	('ZFHX4', 'Gene', '79776', (13, 18))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (125, 159))	('inhibits', 'NegReg', (97, 105))	('carcinoma', 'Phenotype', 'HP:0030731', (150, 159))	('Mutations', 'Var', (0, 9))	('associated', 'Reg', (33, 43))	('ZFHX4', 'Gene', (91, 96))	('ZFHX4', 'Gene', '79776', (91, 96))	('esophageal squamous cell carcinoma', 'Disease', (125, 159))	('progression', 'CPA', (110, 121))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (136, 159))	('ZFHX4', 'Gene', (13, 18))	('down-regulation', 'NegReg', (72, 87))
223085	28694483	It can be utilized to characterize the alterations of an individual cancer genome, providing a comprehensive way to identify somatic mutations that might contribute to the initiation and progression of cancer.	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('contribute', 'Reg', (154, 164))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('cancer', 'Disease', 'MESH:D009369', (202, 208))	('mutations', 'Var', (133, 142))	('cancer', 'Disease', (68, 74))	('cancer', 'Disease', (202, 208))
223087	28694483	Seventeen significantly mutated genes (SMGs), including TP53, PIK3CA, NOTHC1, CDKN2A, NFE2L2 and MLL2 mutated in at least 10% of ESCCs.	('MLL2', 'Gene', (97, 101))	('TP53', 'Gene', '7157', (56, 60))	('NOTHC1', 'Gene', (70, 76))	('PIK3CA', 'Gene', (62, 68))	('CDKN2A', 'Gene', (78, 84))	('SMG', 'Gene', (39, 42))	('NFE2L2', 'Gene', '4780', (86, 92))	('SMG', 'Gene', '23034', (39, 42))	('CDKN2A', 'Gene', '1029', (78, 84))	('TP53', 'Gene', (56, 60))	('MLL2', 'Gene', '8085', (97, 101))	('NFE2L2', 'Gene', (86, 92))	('PIK3CA', 'Gene', '5290', (62, 68))	('mutated', 'Var', (102, 109))
223090	28694483	We found that mutations in ZFHX4, SPHKAP, NRXN1, KIAA1109, DNAH5 and KCNH7 were associated with poor overall survival.	('KCNH7', 'Gene', '90134', (69, 74))	('KCNH7', 'Gene', (69, 74))	('overall survival', 'MPA', (101, 117))	('DNAH5', 'Gene', '1767', (59, 64))	('NRXN1', 'Gene', '9378', (42, 47))	('KIAA1109', 'Gene', (49, 57))	('SPHKAP', 'Gene', (34, 40))	('ZFHX4', 'Gene', '79776', (27, 32))	('NRXN1', 'Gene', (42, 47))	('associated', 'Reg', (80, 90))	('KIAA1109', 'Gene', '84162', (49, 57))	('poor', 'NegReg', (96, 100))	('DNAH5', 'Gene', (59, 64))	('mutations', 'Var', (14, 23))	('SPHKAP', 'Gene', '80309', (34, 40))	('ZFHX4', 'Gene', (27, 32))
223091	28694483	We also examined somatic mutations and expression profiles of ZFHX4 in The Cancer Genome Alas (TCGA) datasets and found that the mutations of ZFHX4 were also associated with poor overall survival of liver hepatocellular carcinoma patients.	('liver hepatocellular carcinoma', 'Disease', (199, 229))	('Alas', 'Chemical', 'MESH:D000409', (89, 93))	('Cancer', 'Disease', (75, 81))	('ZFHX4', 'Gene', (62, 67))	('overall', 'MPA', (179, 186))	('associated with', 'Reg', (158, 173))	('liver hepatocellular carcinoma', 'Disease', 'MESH:D006528', (199, 229))	('ZFHX4', 'Gene', (142, 147))	('Cancer', 'Disease', 'MESH:D009369', (75, 81))	('mutations', 'Var', (129, 138))	('ZFHX4', 'Gene', '79776', (62, 67))	('Cancer', 'Phenotype', 'HP:0002664', (75, 81))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (205, 229))	('ZFHX4', 'Gene', '79776', (142, 147))	('patients', 'Species', '9606', (230, 238))	('poor', 'NegReg', (174, 178))	('carcinoma', 'Phenotype', 'HP:0030731', (220, 229))
223093	28694483	In vitro siRNA-mediated silencing of ZFHX4 effectively inhibited migration and invasion abilities in two ESCC cell lines.	('ZFHX4', 'Gene', (37, 42))	('ZFHX4', 'Gene', '79776', (37, 42))	('inhibited', 'NegReg', (55, 64))	('silencing', 'Var', (24, 33))
223107	28694483	SMGs were analyzed with MutSigCV that detects genes associated with cancer as mutated more frequently than by chance.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('mutated', 'Var', (78, 85))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('SMG', 'Gene', (0, 3))	('SMG', 'Gene', '23034', (0, 3))	('cancer', 'Disease', (68, 74))
223119	28694483	siRNA molecule (GenePharma, China) sequences ZFHX4-siRNA 5'GCAGGUCUCGAGGAUUCAATT and 5'UUGAAUCCUCGAGACCUGCTT were used to knock down ZFHX4 expression.	('ZFHX4', 'Gene', (45, 50))	('knock', 'Var', (122, 127))	('ZFHX4', 'Gene', '79776', (45, 50))	('ZFHX4', 'Gene', (133, 138))	('expression', 'MPA', (139, 149))	('ZFHX4', 'Gene', '79776', (133, 138))
223125	28694483	Sixty-six percent (66%) of the somatic mutations are missense and indels, and were detected in 239 (54%) patients.	('patients', 'Species', '9606', (105, 113))	('missense', 'Var', (53, 61))	('mutations', 'Var', (39, 48))
223126	28694483	The 32,493 somatic mutations were located in 12,074 human genes, including 407 genes recorded in the Catalogue of Somatic Mutations in Cancer database (COSMIC).	('Cancer', 'Disease', 'MESH:D009369', (135, 141))	('human', 'Species', '9606', (52, 57))	('mutations', 'Var', (19, 28))	('Cancer', 'Phenotype', 'HP:0002664', (135, 141))	('Cancer', 'Disease', (135, 141))
223127	28694483	Not surprisingly, TP53 mutations are the most common genetic events occurring in 79.4% patients, followed by nine genes mutated in more than 10% of the patients, including TNN (36.4%), MUC16 (16.3%), MLL2 (14.3%), CSMD3 (13.6%), NOTCH1 (12.6%), FAT1 (12.2%), PCLO (12.2%), SYNE1 (12.0%) and LRP1B (11.3%).	('MLL2', 'Gene', (200, 204))	('TP53', 'Gene', '7157', (18, 22))	('MUC16', 'Gene', '94025', (185, 190))	('CSMD3', 'Gene', (214, 219))	('LRP1B', 'Gene', (291, 296))	('FAT1', 'Gene', '2195', (245, 249))	('NOTCH1', 'Gene', (229, 235))	('mutations', 'Var', (23, 32))	('MUC16', 'Gene', (185, 190))	('NOTCH1', 'Gene', '4851', (229, 235))	('TP53', 'Gene', (18, 22))	('LRP1B', 'Gene', '53353', (291, 296))	('SYNE1', 'Gene', (273, 278))	('patients', 'Species', '9606', (152, 160))	('FAT1', 'Gene', (245, 249))	('CSMD3', 'Gene', '114788', (214, 219))	('SYNE1', 'Gene', '23345', (273, 278))	('MLL2', 'Gene', '8085', (200, 204))	('patients', 'Species', '9606', (87, 95))
223135	28694483	Kaplan-Meier analysis showed that mutations in ZFHX4, SPHKAP, NRXN1 and KIAA1109 were significantly (p < 0.05) correlated with poor overall survival (Fig.	('correlated', 'Reg', (111, 121))	('KIAA1109', 'Gene', '84162', (72, 80))	('overall survival', 'MPA', (132, 148))	('KIAA1109', 'Gene', (72, 80))	('SPHKAP', 'Gene', (54, 60))	('poor', 'NegReg', (127, 131))	('NRXN1', 'Gene', '9378', (62, 67))	('NRXN1', 'Gene', (62, 67))	('ZFHX4', 'Gene', (47, 52))	('SPHKAP', 'Gene', '80309', (54, 60))	('ZFHX4', 'Gene', '79776', (47, 52))	('mutations', 'Var', (34, 43))
223136	28694483	Notably, ZFHX4 mutations were detected in 8.6% (38/442) of the patients.	('ZFHX4', 'Gene', (9, 14))	('mutations', 'Var', (15, 24))	('ZFHX4', 'Gene', '79776', (9, 14))	('patients', 'Species', '9606', (63, 71))	('detected', 'Reg', (30, 38))
223137	28694483	Missense mutations and frame-shift indels were the most deleterious mutation types in cancer, because they change gene-coding sequences, potentially altering protein functions.	('Missense mutations', 'Var', (0, 18))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('change', 'Reg', (107, 113))	('altering', 'Reg', (149, 157))	('gene-coding sequences', 'MPA', (114, 135))	('frame-shift indels', 'Var', (23, 41))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('protein functions', 'MPA', (158, 175))	('cancer', 'Disease', (86, 92))
223138	28694483	Overall survival of patients with ZFHX4 and SPHKAP mutations (missense and frame shift) decreased dramatically (log-rank test p value = 3.2 x 10-5 and 0.023, respectively, Fig.	('mutations', 'Var', (51, 60))	('ZFHX4', 'Gene', '79776', (34, 39))	('SPHKAP', 'Gene', (44, 50))	('patients', 'Species', '9606', (20, 28))	('decreased', 'NegReg', (88, 97))	('Overall survival', 'MPA', (0, 16))	('SPHKAP', 'Gene', '80309', (44, 50))	('ZFHX4', 'Gene', (34, 39))
223139	28694483	In addition, we identified two additional genes DNAH5 and KCNH7, whose missense mutations and frame-shift indels are strongly associated with patient survival (a log-rank test p-value of 0.016 and 0.034, respectively).	('missense mutations', 'Var', (71, 89))	('DNAH5', 'Gene', (48, 53))	('associated with', 'Reg', (126, 141))	('DNAH5', 'Gene', '1767', (48, 53))	('frame-shift indels', 'Var', (94, 112))	('patient survival', 'CPA', (142, 158))	('patient', 'Species', '9606', (142, 149))	('KCNH7', 'Gene', '90134', (58, 63))	('KCNH7', 'Gene', (58, 63))
223140	28694483	However, the missense and frame shift variations of NRXN1 and KIAA1109 were not associated with clinical outcomes (Fig.	('missense', 'Var', (13, 21))	('KIAA1109', 'Gene', '84162', (62, 70))	('KIAA1109', 'Gene', (62, 70))	('NRXN1', 'Gene', '9378', (52, 57))	('associated', 'Reg', (80, 90))	('NRXN1', 'Gene', (52, 57))
223143	28694483	4, 83 patients who carried at least one mutation in at least one of the six genes exhibited significantly poorer survival with a log-rank test p-value of 3.9 x 10-6, suggesting that integrating mutations of multiple genes could better predict patient overall survival.	('mutation', 'Var', (40, 48))	('poorer', 'NegReg', (106, 112))	('patient', 'Species', '9606', (243, 250))	('patient', 'Species', '9606', (6, 13))	('mutations', 'Var', (194, 203))	('predict', 'Reg', (235, 242))	('survival', 'MPA', (113, 121))	('patients', 'Species', '9606', (6, 14))
223144	28694483	As ZFHX4 mutations significantly contributed to poor survival of Chinese ESCC patients, we further examined the prognostic role of ZFHX4 mutations in 12 cancer types investigated by TCGA including ESCC and esophageal adenocarcinoma (EAD) of Vietnam, Brazil, United States and other populations.	('cancer', 'Disease', (153, 159))	('ZFHX4', 'Gene', '79776', (3, 8))	('mutations', 'Var', (9, 18))	('ESCC', 'Disease', (197, 201))	('patients', 'Species', '9606', (78, 86))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('esophageal adenocarcinoma', 'Disease', (206, 231))	('EAD', 'Phenotype', 'HP:0011459', (233, 236))	('examined', 'Reg', (99, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (222, 231))	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('ZFHX4', 'Gene', (131, 136))	('EAD', 'Disease', (233, 236))	('ZFHX4', 'Gene', (3, 8))	('ZFHX4', 'Gene', '79776', (131, 136))	('mutations', 'Var', (137, 146))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (206, 231))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (206, 231))	('EAD', 'Disease', 'MESH:C566415', (233, 236))
223145	28694483	ZFHX4 mutations were widely detected in 12 cancer types as listed in Supplementary Table1.	('ZFHX4', 'Gene', '79776', (0, 5))	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('detected', 'Reg', (28, 36))	('cancer', 'Disease', (43, 49))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('ZFHX4', 'Gene', (0, 5))	('mutations', 'Var', (6, 15))
223146	28694483	The mutation rate of ZFHX4 in 12 cancer types ranged from 2.2% (prostate adenocarcinoma, PRAD) to 43.8% (lung adenocarcinoma, LUAD).	('prostate adenocarcinoma', 'Disease', 'MESH:D011471', (64, 87))	('cancer', 'Disease', (33, 39))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (105, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('ZFHX4', 'Gene', '79776', (21, 26))	('lung adenocarcinoma', 'Disease', (105, 124))	('PRAD', 'Disease', (89, 93))	('mutation', 'Var', (4, 12))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (105, 124))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('prostate adenocarcinoma', 'Disease', (64, 87))	('ZFHX4', 'Gene', (21, 26))
223147	28694483	2A showed the distribution of somatic mutations on the gene body of ZFHX4 and several recurrent mutations in cancer were observed, such as p.L408fs/G407fs and p.P1042P/S.	('p.P1042P', 'Var', (159, 167))	('p.L408fs', 'FRAMESHIFT', 'None', (139, 147))	('p.P1042P', 'SUBSTITUTION', 'None', (159, 167))	('ZFHX4', 'Gene', '79776', (68, 73))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('G407fs', 'Mutation', 'p.G407fsX', (148, 154))	('p.L408fs', 'Var', (139, 147))	('cancer', 'Disease', (109, 115))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('ZFHX4', 'Gene', (68, 73))
223148	28694483	2B, mutations of ZFHX4 were correlated with poor overall survival of liver hepatocellular carcinoma (LIHC) patients with a log-rank test p-value of 0.01.	('ZFHX4', 'Gene', (17, 22))	('liver hepatocellular carcinoma', 'Disease', (69, 99))	('LIHC', 'Disease', (101, 105))	('LIHC', 'Disease', 'None', (101, 105))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('ZFHX4', 'Gene', '79776', (17, 22))	('liver hepatocellular carcinoma', 'Disease', 'MESH:D006528', (69, 99))	('poor', 'NegReg', (44, 48))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (75, 99))	('mutations', 'Var', (4, 13))	('patients', 'Species', '9606', (107, 115))
223149	28694483	However, although ZFHX4 mutations were observed in eight ESCC patients in the TCGA datasets, there was no correlation between ZFHX4 mutations and survival of ESCC patients, EAD (Supplementary Fig.	('ZFHX4', 'Gene', '79776', (126, 131))	('patients', 'Species', '9606', (163, 171))	('mutations', 'Var', (132, 141))	('ZFHX4', 'Gene', '79776', (18, 23))	('EAD', 'Disease', 'MESH:C566415', (173, 176))	('ESCC', 'Disease', (158, 162))	('EAD', 'Phenotype', 'HP:0011459', (173, 176))	('ZFHX4', 'Gene', (126, 131))	('patients', 'Species', '9606', (62, 70))	('ZFHX4', 'Gene', (18, 23))	('EAD', 'Disease', (173, 176))
223155	28694483	Given the facts that mutations in ZFHX4 were frequently observed in ESCC patients and were associated with poorer survival and that ZFHX4 was overexpressed in ESCC, we knocked down ZFHX4 expression in KYSE150 and TE-1 cell lines using RNA interference sequences to determine whether ZFHX4 plays an important role in ESCC progression.	('ZFHX4', 'Gene', '79776', (181, 186))	('observed', 'Reg', (56, 64))	('knocked', 'Reg', (168, 175))	('ESCC', 'Disease', (68, 72))	('ZFHX4', 'Gene', '79776', (34, 39))	('ZFHX4', 'Gene', (181, 186))	('patients', 'Species', '9606', (73, 81))	('ZFHX4', 'Gene', (132, 137))	('ZFHX4', 'Gene', (283, 288))	('associated', 'Reg', (91, 101))	('ZFHX4', 'Gene', '79776', (132, 137))	('ZFHX4', 'Gene', '79776', (283, 288))	('ESCC', 'Disease', (316, 320))	('ZFHX4', 'Gene', (34, 39))	('mutations', 'Var', (21, 30))
223158	28694483	5A, real time reverse transcription PCR (RT-PCR) assays showed that the mRNA expression of ZFHX4 was reduced by 78.1% in KYSE150 and 88.0% in TE1 due to siRNA silencing.	('KYSE150', 'Var', (121, 128))	('ZFHX4', 'Gene', (91, 96))	('reduced', 'NegReg', (101, 108))	('mRNA expression', 'MPA', (72, 87))	('ZFHX4', 'Gene', '79776', (91, 96))
223159	28694483	Transwell motility assays were used to estimate the effect of ZFHX4 gene knockdown on invasion ability.	('ZFHX4', 'Gene', '79776', (62, 67))	('ZFHX4', 'Gene', (62, 67))	('knockdown', 'Var', (73, 82))
223160	28694483	The invasion ability of KYSE150 cells with ZFHX4 gene knockdown is impaired by 15.1% compared with their control cells.	('knockdown', 'Var', (54, 63))	('invasion ability', 'CPA', (4, 20))	('impaired', 'NegReg', (67, 75))	('ZFHX4', 'Gene', (43, 48))	('ZFHX4', 'Gene', '79776', (43, 48))
223161	28694483	For TE-1, consistent with what was observed in KYSE150 cells, knockdown of ZFHX4 expression inhibited cell invasion ability by 26.0%.	('inhibited', 'NegReg', (92, 101))	('cell invasion ability', 'CPA', (102, 123))	('ZFHX4', 'Gene', (75, 80))	('ZFHX4', 'Gene', '79776', (75, 80))	('knockdown', 'Var', (62, 71))
223164	28694483	We also performed cell proliferation and apoptosis assays, but knockdown of ZFHX4 showed no significant effects on cell proliferation and apoptosis (results not shown).	('ZFHX4', 'Gene', '79776', (76, 81))	('ZFHX4', 'Gene', (76, 81))	('knockdown', 'Var', (63, 72))	('cell proliferation', 'CPA', (115, 133))
223165	28694483	In summary, these experimental results indicated that loss of ZFHX4 resulted in impaired migration and invasion abilities of ESCC cells.	('ZFHX4', 'Gene', (62, 67))	('impaired migration', 'Disease', 'MESH:D054081', (80, 98))	('invasion abilities of', 'CPA', (103, 124))	('ZFHX4', 'Gene', '79776', (62, 67))	('loss', 'Var', (54, 58))	('impaired migration', 'Disease', (80, 98))
223167	28694483	Survival analysis of frequently mutated genes in patients suggested that mutations in ZFHX4, SPHKAP, NRXN1, KIAA1109, DNAH5 and KCNH7 were associated with poor prognosis.	('SPHKAP', 'Gene', (93, 99))	('KIAA1109', 'Gene', '84162', (108, 116))	('ZFHX4', 'Gene', (86, 91))	('KCNH7', 'Gene', '90134', (128, 133))	('KCNH7', 'Gene', (128, 133))	('KIAA1109', 'Gene', (108, 116))	('ZFHX4', 'Gene', '79776', (86, 91))	('DNAH5', 'Gene', (118, 123))	('NRXN1', 'Gene', '9378', (101, 106))	('SPHKAP', 'Gene', '80309', (93, 99))	('associated', 'Reg', (139, 149))	('DNAH5', 'Gene', '1767', (118, 123))	('patients', 'Species', '9606', (49, 57))	('NRXN1', 'Gene', (101, 106))	('mutations', 'Var', (73, 82))
223168	28694483	Secondly, SMG analysis found that 26 genes were significantly mutated in ESCC, and 12 genes had not been reported as SMGs in previous ESCC studies.	('SMG', 'Gene', (117, 120))	('SMG', 'Gene', '23034', (117, 120))	('ESCC', 'Disease', (73, 77))	('SMG', 'Gene', (10, 13))	('SMG', 'Gene', '23034', (10, 13))	('mutated', 'Var', (62, 69))
223179	28694483	ZFHX4 silencing resulted in decreased tumorigenesis and prolonged cancer-free survival of glioblastoma.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('ZFHX4', 'Gene', '79776', (0, 5))	('ZFHX4', 'Gene', (0, 5))	('glioblastoma', 'Disease', 'MESH:D005909', (90, 102))	('glioblastoma', 'Phenotype', 'HP:0012174', (90, 102))	('decreased', 'NegReg', (28, 37))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('prolonged', 'PosReg', (56, 65))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('glioblastoma', 'Disease', (90, 102))	('silencing', 'Var', (6, 15))	('cancer', 'Disease', (66, 72))
223180	28694483	Our data provided strong evidence that mutations in ZFHX4 contribute to the development and progression of ESCC.	('ZFHX4', 'Gene', (52, 57))	('ZFHX4', 'Gene', '79776', (52, 57))	('mutations', 'Var', (39, 48))	('contribute', 'Reg', (58, 68))	('ESCC', 'Disease', (107, 111))
223181	28694483	We further examined the prognostic role of ZFHX4 mutations in 12 cancer types in TCGA.	('mutations', 'Var', (49, 58))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('examined', 'Reg', (11, 19))	('ZFHX4', 'Gene', (43, 48))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('ZFHX4', 'Gene', '79776', (43, 48))
223182	28694483	Mutations of ZFHX4 significantly contributed to the poor survival of LIHC patients (p = 0.012) as shown in Supplementary Fig.	('LIHC', 'Disease', 'None', (69, 73))	('ZFHX4', 'Gene', '79776', (13, 18))	('patients', 'Species', '9606', (74, 82))	('contributed', 'Reg', (33, 44))	('Mutations', 'Var', (0, 9))	('LIHC', 'Disease', (69, 73))	('poor', 'NegReg', (52, 56))	('ZFHX4', 'Gene', (13, 18))
223183	28694483	However, mutations of ZFHX4 were not significantly associated with patient survival of both ESCC and EAD in TCGA (Supplementary Fig.	('ESCC', 'Disease', (92, 96))	('EAD', 'Disease', (101, 104))	('mutations', 'Var', (9, 18))	('EAD', 'Disease', 'MESH:C566415', (101, 104))	('associated', 'Reg', (51, 61))	('ZFHX4', 'Gene', (22, 27))	('EAD', 'Phenotype', 'HP:0011459', (101, 104))	('ZFHX4', 'Gene', '79776', (22, 27))	('patient', 'Species', '9606', (67, 74))
223186	28694483	Secondly, only 8 of the 91 patients in the TCGA dataset carried ZFHX4 mutations.	('ZFHX4', 'Gene', '79776', (64, 69))	('mutations', 'Var', (70, 79))	('carried', 'Reg', (56, 63))	('patients', 'Species', '9606', (27, 35))	('ZFHX4', 'Gene', (64, 69))
223311	33499364	In some cases, a person inherits the abnormal gene that leads to cancer from his/her parents.	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('leads to', 'Reg', (56, 64))	('abnormal gene', 'Var', (37, 50))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))
223470	25254213	CXCR4 is upregulated in metastatic breast cancer cell lines and lymph node metastasis, and cells expressing CXCR4 predominantly migrate to tissues that express the ligand CXCL12.	('upregulated', 'PosReg', (9, 20))	('CXCL12', 'Gene', '6387', (171, 177))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('CXCR4', 'MPA', (0, 5))	('breast cancer', 'Phenotype', 'HP:0003002', (35, 48))	('breast cancer', 'Disease', 'MESH:D001943', (35, 48))	('CXCR4', 'Var', (108, 113))	('breast cancer', 'Disease', (35, 48))	('CXCL12', 'Gene', (171, 177))
223472	25254213	Interestingly, in vivo inhibition of the CXCR4/CXCL12 axis reduced lymph node and lung metastasis.	('CXCL12', 'Gene', '6387', (47, 53))	('reduced', 'NegReg', (59, 66))	('inhibition', 'Var', (23, 33))	('reduced lymph node', 'Phenotype', 'HP:0002732', (59, 77))	('CXCL12', 'Gene', (47, 53))
223475	25254213	In prostate cancer, CXCR4 expression has been shown to increase tumor invasion and metastasis.	('prostate cancer', 'Phenotype', 'HP:0012125', (3, 18))	('increase', 'PosReg', (55, 63))	('tumor', 'Disease', (64, 69))	('metastasis', 'CPA', (83, 93))	('prostate cancer', 'Disease', 'MESH:D011471', (3, 18))	('prostate cancer', 'Disease', (3, 18))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('CXCR4 expression', 'Var', (20, 36))
223482	25254213	Senescence can be prematurely induced by stress factors and DNA damage, for example, upon oncogene expression or UV irradiation, and is mediated by activation of the Arf/p53/p21 and/or p16/pRb pathways.	('pRb', 'Gene', '5925', (189, 192))	('p21', 'Gene', (174, 177))	('p21', 'Gene', '644914', (174, 177))	('activation', 'PosReg', (148, 158))	('oncogene expression', 'Var', (90, 109))	('p53', 'Gene', (170, 173))	('p16', 'Gene', (185, 188))	('expression', 'Var', (99, 109))	('p16', 'Gene', '1029', (185, 188))	('p53', 'Gene', '7157', (170, 173))	('pRb', 'Gene', (189, 192))	('Senescence', 'CPA', (0, 10))
223484	25254213	Human nevi, for instance, are frequently positive for activating BRafV600E mutations; however, these cells bear a senescent phenotype.	('activating', 'PosReg', (54, 64))	('Human', 'Species', '9606', (0, 5))	('nevi', 'Phenotype', 'HP:0003764', (6, 10))	('BRafV600E', 'Var', (65, 74))	('BRafV600E', 'Mutation', 'rs113488022', (65, 74))
223485	25254213	Abrogation of such oncogene-induced senescence by PI3K activation allows for melanoma formation.	('melanoma', 'Phenotype', 'HP:0002861', (77, 85))	('Abrogation', 'NegReg', (0, 10))	('melanoma', 'Disease', (77, 85))	('melanoma', 'Disease', 'MESH:D008545', (77, 85))	('PI3K', 'Var', (50, 54))
223487	25254213	Recently, however, it became apparent that senescence in surrounding tissue cells might have both tumor-suppressive as well as promoting consequences.	('tumor', 'Disease', (98, 103))	('senescence', 'Var', (43, 53))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))
223492	25254213	Importantly, induction of senescence in NK cells has recently been reported to promote vascular remodeling and angiogenesis, opening the possibility that senescence and SASP may also contribute to tumor-associated lymphangiogenesis, although this remains to be demonstrated experimentally.	('angiogenesis', 'CPA', (111, 123))	('induction', 'Var', (13, 22))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('SASP', 'Gene', (169, 173))	('SASP', 'Gene', '7295', (169, 173))	('promote', 'PosReg', (79, 86))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('vascular remodeling', 'CPA', (87, 106))	('tumor', 'Disease', (197, 202))	('contribute', 'Reg', (183, 193))
223509	25254213	However, it was demonstrated recently that low molecular weight hyaluronan promoted lymphatic endothelial cell (LEC) proliferation, migration, and tube formation, mediated via binding to LYVE-1.	('hyaluronan', 'Chemical', 'MESH:D006820', (64, 74))	('tube formation', 'CPA', (147, 161))	('promoted', 'PosReg', (75, 83))	('migration', 'CPA', (132, 141))	('low molecular weight', 'Var', (43, 63))	('binding', 'Interaction', (176, 183))	('LYVE-1', 'Gene', '10894', (187, 193))	('LYVE-1', 'Gene', (187, 193))
223522	25254213	The modulation of the tumor microenvironment induces angiogenesis and lymphangiogenesis.	('lymphangiogenesis', 'CPA', (70, 87))	('modulation', 'Var', (4, 14))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('angiogenesis', 'CPA', (53, 65))	('induces', 'Reg', (45, 52))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('tumor', 'Disease', (22, 27))
223558	25254213	pDCs seem to have immunoregulatory properties in the tumor microenvironment and induce Tregs in the human ovarian carcinoma.	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('human', 'Species', '9606', (100, 105))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (106, 123))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('Tregs', 'CPA', (87, 92))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (106, 123))	('induce', 'PosReg', (80, 86))	('ovarian carcinoma', 'Disease', (106, 123))	('tumor', 'Disease', (53, 58))	('pDCs', 'Var', (0, 4))
223582	25254213	TAMs have also been shown to express LYVE-1 and F4/80+ LYVE-1 + macrophages integrated into peritumoral lymphatic vessels.	('LYVE-1', 'Gene', (37, 43))	('TAMs', 'Chemical', '-', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumor', 'Disease', (96, 101))	('LYVE-1', 'Gene', '10894', (55, 61))	('F4/80+', 'Var', (48, 54))	('LYVE-1', 'Gene', '10894', (37, 43))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('LYVE-1', 'Gene', (55, 61))
223607	25254213	Moreover, VEGF increased IL-10 secretion of these cells and might therefore direct chemotaxis and immune modulation of T-cells in tumor tissues.	('VEGF', 'Var', (10, 14))	('IL-10', 'Gene', '3586', (25, 30))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('increased', 'PosReg', (15, 24))	('IL-10', 'Gene', (25, 30))	('secretion', 'MPA', (31, 40))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumor', 'Disease', (130, 135))
223619	25254213	In a mice lung cancer model celecoxib, a selective COX2 inhibitor reduced lymphangiogenesis and lymph node metastasis indicating that VEGF expression and thereby lymphangiogenesis might be associated with prostaglandins.	('reduced', 'NegReg', (66, 73))	('mice', 'Species', '10090', (5, 9))	('celecoxib', 'Chemical', 'MESH:D000068579', (28, 37))	('inhibitor', 'Var', (56, 65))	('lung cancer', 'Disease', (10, 21))	('COX2', 'Gene', '5743', (51, 55))	('COX2', 'Gene', (51, 55))	('lung cancer', 'Phenotype', 'HP:0100526', (10, 21))	('lymph node metastasis', 'CPA', (96, 117))	('prostaglandins', 'Chemical', 'MESH:D011453', (205, 219))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('lung cancer', 'Disease', 'MESH:D008175', (10, 21))	('VEGF', 'Protein', (134, 138))
223622	25254213	Therefore, blocking this ligand on the tumor cells and on antigen presenting cells improves tumor defense and T-cells with anticancer properties restore their effector function.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('tumor', 'Disease', (92, 97))	('cancer', 'Disease', (127, 133))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('blocking', 'Var', (11, 19))	('improves', 'PosReg', (83, 91))	('tumor', 'Disease', (39, 44))	('effector function', 'MPA', (159, 176))
223632	25254213	Anti-CTLA4 antibodies such as ipilimumab are immune modulatory biologics and are regarded as a milestone in the treatment of metastatic melanoma.	('Anti-CTLA4', 'Var', (0, 10))	('melanoma', 'Disease', 'MESH:D008545', (136, 144))	('melanoma', 'Phenotype', 'HP:0002861', (136, 144))	('melanoma', 'Disease', (136, 144))	('ipilimumab', 'Chemical', 'MESH:D000074324', (30, 40))
223635	25254213	CTLA4 deficient mice die early as a result of an uncontrolled lymphocyte proliferation that leads to multiorgan destruction.	('multiorgan destruction', 'CPA', (101, 123))	('CTLA4', 'Gene', (0, 5))	('mice', 'Species', '10090', (16, 20))	('deficient', 'Var', (6, 15))	('leads to', 'Reg', (92, 100))
223639	25254213	Antagonists of CCL21 seem to prevent the development of chronic graft versus host disease or reduced allergic conjunctivitis by blocking CCR7 in mice.	('CCR7', 'Gene', (137, 141))	('blocking', 'NegReg', (128, 136))	('Antagonists', 'Var', (0, 11))	('conjunctivitis', 'Phenotype', 'HP:0000509', (110, 124))	('CCL21', 'Gene', '6366', (15, 20))	('chronic graft versus host disease', 'Disease', 'MESH:D006086', (56, 89))	('CCL21', 'Gene', (15, 20))	('reduced allergic conjunctivitis', 'Disease', (93, 124))	('mice', 'Species', '10090', (145, 149))	('reduced allergic conjunctivitis', 'Disease', 'MESH:D004342', (93, 124))	('allergic conjunctivitis', 'Phenotype', 'HP:0007879', (101, 124))	('chronic graft versus host disease', 'Disease', (56, 89))	('prevent', 'NegReg', (29, 36))
223660	24804374	Prior research on individual level factors has demonstrated that indicators of socioeconomic status, such as low income and educational attainment may be associated with a higher incidence of cervical cancer among Hispanic women; and language spoken is also a barrier to cervical cancer screening.	('cervical cancer', 'Disease', (192, 207))	('cervical cancer', 'Disease', 'MESH:D002583', (192, 207))	('cervical cancer', 'Disease', (271, 286))	('cervical cancer', 'Disease', 'MESH:D002583', (271, 286))	('low income', 'Var', (109, 119))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('women', 'Species', '9606', (223, 228))	('cancer', 'Phenotype', 'HP:0002664', (280, 286))
223684	24804374	Those Hispanic women residing in the counties with the worst characteristic profiles (i.e., high percent of language isolation, low levels of income and education) have a significantly higher incidence of cervical cancer compared to Hispanic women who live in counties with the best characteristic profiles (i.e., low percent of language isolation, high levels of income and education).	('low', 'Var', (128, 131))	('cervical cancer', 'Disease', 'MESH:D002583', (205, 220))	('women', 'Species', '9606', (15, 20))	('cervical cancer', 'Disease', (205, 220))	('women', 'Species', '9606', (242, 247))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('language isolation', 'Var', (108, 126))
223699	24804374	Once separated, we examined the incidence rates of squamous cell carcinoma of the cervix for different combinations of income and education (i.e., high income and high education; high income and low education; low income and high education; and low income and low education).	('low education', 'Phenotype', 'HP:0001249', (195, 208))	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('low education', 'Phenotype', 'HP:0001249', (260, 273))	('squamous cell carcinoma', 'Disease', (51, 74))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (51, 74))	('carcinoma of the cervix', 'Phenotype', 'HP:0030079', (65, 88))	('low income', 'Var', (210, 220))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (51, 74))
223740	32021443	To conclude, we attended to explore the biological function and regulatory mechanism of MAGI2-AS3 in LUSC and discovered that lncRNA MAGI2-AS3 suppressed several cellular processes of lung squamous cell carcinoma cells by regulating miR-374a/b-5p/CADM2 axis.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (189, 212))	('b-5p', 'Gene', '122876', (242, 246))	('LUSC', 'Phenotype', 'HP:0030359', (101, 105))	('CADM2', 'Gene', '253559', (247, 252))	('b-5p', 'Gene', (242, 246))	('suppressed', 'NegReg', (143, 153))	('CADM2', 'Gene', (247, 252))	('cellular processes', 'CPA', (162, 180))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (184, 212))	('miR-374a', 'Gene', (233, 241))	('MAGI2-AS3', 'Var', (133, 142))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (184, 212))	('lung squamous cell carcinoma', 'Disease', (184, 212))	('carcinoma', 'Phenotype', 'HP:0030731', (203, 212))	('miR-374a', 'Gene', '442919', (233, 241))	('regulating', 'Reg', (222, 232))
223760	32021443	Membranes blocked by 5% nonfat milk powder were incubated with primary antibodies against Cleaved caspase-3 (ab2302), total caspase-3 (ab13847), Bax (ab32503), Bcl-2 (ab32124), CADM2 (ab64873) and GAPDH (ab8245) which were bought from Abcam (Cambridge, MA, USA).	('CADM2', 'Gene', (177, 182))	('caspase-3', 'Gene', (124, 133))	('ab64873', 'Var', (184, 191))	('ab32503', 'Var', (150, 157))	('caspase-3', 'Gene', (98, 107))	('Bax', 'Gene', '581', (145, 148))	('ab13847', 'Var', (135, 142))	('caspase-3', 'Gene', '836', (124, 133))	('Bax', 'Gene', (145, 148))	('GAPDH', 'Gene', '2597', (197, 202))	('Bcl-2', 'Gene', (160, 165))	('GAPDH', 'Gene', (197, 202))	('Bcl-2', 'Gene', '596', (160, 165))	('ab32124', 'Var', (167, 174))	('CADM2', 'Gene', '253559', (177, 182))	('caspase-3', 'Gene', '836', (98, 107))
223777	32021443	Besides, the CADM2 3'-UTR plasmid containing wild-type or mutant miR-374a/b-5p or miR-23a-3p binding sites was inserted into the pmirGLO reporter vector (Promega).	('CADM2', 'Gene', '253559', (13, 18))	('mutant', 'Var', (58, 64))	('miR', 'Gene', '22877', (65, 68))	('miR', 'Gene', (82, 85))	('b-5p', 'Gene', (74, 78))	('CADM2', 'Gene', (13, 18))	('miR', 'Gene', (65, 68))	('miR', 'Gene', '22877', (82, 85))	('miR-374a', 'Gene', (65, 73))	('miR-374a', 'Gene', '442919', (65, 73))	('b-5p', 'Gene', '122876', (74, 78))
223781	32021443	To monitor tumor growth, A549 cells (1x107) were transfected with pcDNA3.1 or pcDNA3.1/MAGI2-AS3 and then were subcutaneously injected into the mice.	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('A549', 'CellLine', 'CVCL:0023', (25, 29))	('mice', 'Species', '10090', (144, 148))	('tumor', 'Disease', (11, 16))	('pcDNA3.1/MAGI2-AS3', 'Var', (78, 96))	('tumor', 'Disease', 'MESH:D009369', (11, 16))
223789	32021443	Subsequently, the MAGI2-AS3 level was prominently elevated by the transfection of pcDNA3.1/MAGI2-AS3 in SW900 and SK-MES-1 cells (Figure 1D).	('SK-MES-1', 'CellLine', 'CVCL:0630', (114, 122))	('MAGI2-AS3 level', 'MPA', (18, 33))	('elevated', 'PosReg', (50, 58))	('SW900', 'CellLine', 'CVCL:1731', (104, 109))	('transfection', 'Var', (66, 78))	('pcDNA3.1/MAGI2-AS3', 'Var', (82, 100))
223790	32021443	Under the overexpression of MAGI2-AS3, colonies generated from SW900 cells were decreased from around 190 to around 70, and colonies generated by SK-MES-1 cells were decreased from around 160 to around 60 (Figure 1E).	('SK-MES-1', 'CellLine', 'CVCL:0630', (146, 154))	('SW900', 'Var', (63, 68))	('decreased', 'NegReg', (80, 89))	('colonies generated', 'CPA', (39, 57))	('SW900', 'CellLine', 'CVCL:1731', (63, 68))
223801	32021443	High expression of miR-374a/b-5p was observed by RT-qPCR in LUSC cells, compared with normal cells (Figure 2F).	('expression', 'MPA', (5, 15))	('miR-374a', 'Gene', (19, 27))	('LUSC', 'Phenotype', 'HP:0030359', (60, 64))	('miR-374a', 'Gene', '442919', (19, 27))	('b-5p', 'Gene', (28, 32))	('b-5p', 'Gene', '122876', (28, 32))	('RT-qPCR', 'Var', (49, 56))
223818	32021443	CADM2 mRNA and protein expression were prominently upregulated by the transfection of pcDNA3.1/CADM2 (Figure 4A).	('CADM2', 'Gene', '253559', (0, 5))	('CADM2', 'Gene', (0, 5))	('CADM2', 'Gene', (95, 100))	('transfection', 'Var', (70, 82))	('upregulated', 'PosReg', (51, 62))	('CADM2', 'Gene', '253559', (95, 100))
223822	32021443	The migrated cells and invaded cells were decreased under CADM2 ectopic expression in LUSC cells (Figure S1F and G).	('decreased', 'NegReg', (42, 51))	('CADM2', 'Gene', '253559', (58, 63))	('LUSC', 'Phenotype', 'HP:0030359', (86, 90))	('CADM2', 'Gene', (58, 63))	('ectopic expression', 'Var', (64, 82))
223852	32021443	The migration and invasion of LUSC cells were decreased by MAGI2-AS3 overexpression and restored by miR-23a-3p mimic, and the restoration of migration and invasion was later counteracted by PTEN overexpression (Figure S3G and H).	('migration', 'CPA', (141, 150))	('PTEN', 'Gene', (190, 194))	('LUSC', 'Phenotype', 'HP:0030359', (30, 34))	('PTEN', 'Gene', '5728', (190, 194))	('overexpression', 'Var', (69, 83))	('miR', 'Gene', (100, 103))	('invasion', 'CPA', (155, 163))	('decreased', 'NegReg', (46, 55))	('invasion of LUSC cells', 'CPA', (18, 40))	('miR', 'Gene', '22877', (100, 103))
223856	32021443	The levels of MAGI2-AS3, CAMD2, and PTEN were increased in xenografts with MAGI2-AS3 overexpression (Figure 5C).	('CAMD2', 'MPA', (25, 30))	('levels', 'MPA', (4, 10))	('increased', 'PosReg', (46, 55))	('overexpression', 'PosReg', (85, 99))	('PTEN', 'Gene', (36, 40))	('PTEN', 'Gene', '5728', (36, 40))	('MAGI2-AS3', 'Var', (75, 84))
223860	32021443	Together, these results indicated that MAGI2-AS3 retarded tumorigenesis and metastasis in vivo.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('MAGI2-AS3', 'Var', (39, 48))	('retarded', 'NegReg', (49, 57))
223869	32021443	We demonstrated the MAGI2-AS3 inhibited proliferation, induced apoptosis, and increased migration and invasion in vitro, and proved that MAGI2-AS3 overexpression attenuated tumorigenesis and metastasis in vivo.	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('inhibited', 'NegReg', (30, 39))	('attenuated', 'NegReg', (162, 172))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumor', 'Disease', (173, 178))	('increased', 'PosReg', (78, 87))	('overexpression', 'PosReg', (147, 161))	('apoptosis', 'CPA', (63, 72))	('MAGI2-AS3', 'Gene', (137, 146))	('induced', 'Reg', (55, 62))	('proliferation', 'CPA', (40, 53))	('MAGI2-AS3', 'Var', (20, 29))
223889	31881010	Strikingly, a wide range of core clock genes are epigenetically altered in lung adenocarcinomas and lung squamous cell carcinomas but not esophageal carcinomas.	('lung adenocarcinomas', 'Disease', 'MESH:C538231', (75, 95))	('esophageal carcinomas', 'Disease', (138, 159))	('lung squamous cell carcinomas', 'Disease', 'MESH:D002294', (100, 129))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('carcinomas', 'Phenotype', 'HP:0030731', (119, 129))	('epigenetically altered', 'Var', (49, 71))	('lung squamous cell carcinomas', 'Disease', (100, 129))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (75, 94))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (105, 129))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (100, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (149, 158))	('carcinomas', 'Phenotype', 'HP:0030731', (149, 159))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (75, 95))	('carcinomas', 'Phenotype', 'HP:0030731', (85, 95))	('clock', 'Gene', '9575', (33, 38))	('lung adenocarcinomas', 'Disease', (75, 95))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (105, 128))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (138, 158))	('esophageal carcinomas', 'Phenotype', 'HP:0011459', (138, 159))	('clock', 'Gene', (33, 38))	('esophageal carcinomas', 'Disease', 'MESH:D004938', (138, 159))
223903	31881010	Another study highlighted the lethal effects of the pharmacological activation of NRD1/2.	('NRD1/2', 'Gene', '4898', (82, 88))	('pharmacological activation', 'Var', (52, 78))	('NRD1/2', 'Gene', (82, 88))
223906	31881010	reported that mice knocking out Cry1 and Cry2 unexpectedly displayed the autoimmune phenotype of higher serum IgG levels and antinuclear antibodies.	('antinuclear antibodies', 'MPA', (125, 147))	('higher serum IgG levels', 'Phenotype', 'HP:0003237', (97, 120))	('higher', 'PosReg', (97, 103))	('Cry2', 'Gene', (41, 45))	('IgG', 'Gene', '16059', (110, 113))	('mice', 'Species', '10090', (14, 18))	('Cry1', 'Gene', '12952', (32, 36))	('knocking out', 'Var', (19, 31))	('Cry2', 'Gene', '12953', (41, 45))	('antinuclear antibodies', 'Phenotype', 'HP:0003493', (125, 147))	('Cry1', 'Gene', (32, 36))	('IgG', 'Gene', (110, 113))
223907	31881010	Interestingly, another independent group found that loss of BMAL1, which is another key component of circadian clock, induced T cell-associated CNS autoimmune diseases.	('BMAL1', 'Gene', '406', (60, 65))	('autoimmune diseases', 'Phenotype', 'HP:0002960', (148, 167))	('loss', 'Var', (52, 56))	('BMAL1', 'Gene', (60, 65))	('autoimmune diseases', 'Disease', 'MESH:D001327', (148, 167))	('clock', 'Gene', (111, 116))	('clock', 'Gene', '9575', (111, 116))	('autoimmune diseases', 'Disease', (148, 167))	('induced', 'Reg', (118, 125))
223919	31881010	As for LUAD and LUSC, over a half of core circadian clock genes was differently methylated between tumors and controls (Figure 1).	('LUAD', 'Phenotype', 'HP:0030078', (7, 11))	('tumors', 'Disease', 'MESH:D009369', (99, 105))	('LUAD', 'Disease', (7, 11))	('LUAD', 'Disease', 'MESH:C538231', (7, 11))	('differently', 'Reg', (68, 79))	('clock', 'Gene', '9575', (52, 57))	('clock', 'Gene', (52, 57))	('methylated', 'Var', (80, 90))	('LUSC', 'Disease', 'MESH:D002294', (16, 20))	('LUSC', 'Disease', (16, 20))	('LUSC', 'Phenotype', 'HP:0030359', (16, 20))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))	('tumors', 'Disease', (99, 105))
223921	31881010	We also found that methylation downregulated almost all the circadian clock gene expressions in thoracic cancers (Figure 1).	('methylation', 'Var', (19, 30))	('cancers', 'Phenotype', 'HP:0002664', (105, 112))	('clock', 'Gene', (70, 75))	('downregulated', 'NegReg', (31, 44))	('circadian', 'MPA', (60, 69))	('thoracic cancers', 'Disease', (96, 112))	('clock', 'Gene', '9575', (70, 75))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('thoracic cancers', 'Disease', 'MESH:D009369', (96, 112))
223922	31881010	These data supports that core circadian clock genes are epigenetically altered in thoracic cancers.	('clock', 'Gene', '9575', (40, 45))	('clock', 'Gene', (40, 45))	('cancers', 'Phenotype', 'HP:0002664', (91, 98))	('thoracic cancers', 'Disease', 'MESH:D009369', (82, 98))	('thoracic cancers', 'Disease', (82, 98))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('epigenetically altered', 'Var', (56, 78))
223926	31881010	In other words, disruption of circadian clock may trigger the dysfunction of cell cycle, thus inducing the tumor growth, which was in accordance with another independent group's publication.	('trigger', 'Reg', (50, 57))	('clock', 'Gene', (40, 45))	('clock', 'Gene', '9575', (40, 45))	('disruption', 'Var', (16, 26))	('tumor', 'Disease', (107, 112))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('inducing', 'Reg', (94, 102))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('cell cycle', 'CPA', (77, 87))
223933	31881010	Previous evidence has shown that disruption of circadian clock could accelerate tumorigenesis and circadian genes were closely correlated with prognosis.	('disruption', 'Var', (33, 43))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('clock', 'Gene', '9575', (57, 62))	('clock', 'Gene', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumor', 'Disease', (80, 85))	('accelerate', 'PosReg', (69, 79))
223960	31881010	Our results showed that a high fraction of clock molecules are epigenetically and transcriptionally down-regulated in LUAD and LUSC samples.	('clock', 'Gene', '9575', (43, 48))	('clock', 'Gene', (43, 48))	('down-regulated', 'NegReg', (100, 114))	('LUAD', 'Disease', (118, 122))	('LUAD', 'Disease', 'MESH:C538231', (118, 122))	('LUSC', 'Disease', 'MESH:D002294', (127, 131))	('transcriptionally', 'MPA', (82, 99))	('LUAD', 'Phenotype', 'HP:0030078', (118, 122))	('epigenetically', 'Var', (63, 77))	('LUSC', 'Phenotype', 'HP:0030359', (127, 131))	('LUSC', 'Disease', (127, 131))
223974	31881010	We collected the Illumina human methylation, single nucleotide variation, and mRNA normalized RPKM values from LUAD, LUSC, and ESCA patients (n = 576, 533, and 196, respectively).	('ESCA', 'Disease', (127, 131))	('LUSC', 'Disease', 'MESH:D002294', (117, 121))	('LUSC', 'Phenotype', 'HP:0030359', (117, 121))	('single nucleotide variation', 'Var', (45, 72))	('LUSC', 'Disease', (117, 121))	('LUAD', 'Phenotype', 'HP:0030078', (111, 115))	('LUAD', 'Disease', (111, 115))	('ESCA', 'Disease', 'MESH:D004938', (127, 131))	('LUAD', 'Disease', 'MESH:C538231', (111, 115))	('ESCA', 'Phenotype', 'HP:0011459', (127, 131))	('patients', 'Species', '9606', (132, 140))	('human', 'Species', '9606', (26, 31))
224011	31101846	Six of them: HSPA2, DNAJC20, HSP90AA1, CCT1, CCT2 and CCT6A were statistically significant in both datasets (TCGA and KM plotter) and they were selected for further validation (Table 1).	('HSP90AA1', 'Gene', (29, 37))	('CCT1', 'Gene', (39, 43))	('HSP90AA1', 'Gene', '3320', (29, 37))	('CCT1', 'Gene', '6950', (39, 43))	('DNAJC20', 'Gene', '150274', (20, 27))	('CCT6A', 'Gene', (54, 59))	('CCT2', 'Gene', (45, 49))	('CCT2', 'Gene', '10576', (45, 49))	('HSPA2', 'Var', (13, 18))	('CCT6A', 'Gene', '908', (54, 59))	('DNAJC20', 'Gene', (20, 27))
224015	31101846	Interestingly, high expression of HSPA2 and DNAJC20 was significantly associated with better prognosis for breast cancer patients from TCGA cohort (p = 6,4e-03 and p = 4,3e-02, respectively), longer overall survival in KM plotter cohort (p = 4,5e-04 and p = 5,3e-03, respectively) and longer relapse-free survival in KM plotter cohort (p = 1,5e-07 and p = 5,3e-12, respectively) (Figs 1A, S3).	('overall survival', 'CPA', (199, 215))	('HSPA2', 'Gene', (34, 39))	('high expression', 'Var', (15, 30))	('longer', 'PosReg', (192, 198))	('breast cancer', 'Disease', 'MESH:D001943', (107, 120))	('better', 'PosReg', (86, 92))	('DNAJC20', 'Gene', (44, 51))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('breast cancer', 'Disease', (107, 120))	('breast cancer', 'Phenotype', 'HP:0003002', (107, 120))	('relapse-free survival', 'CPA', (292, 313))	('DNAJC20', 'Gene', '150274', (44, 51))	('patients', 'Species', '9606', (121, 129))
224022	31101846	We have observed that patients with high expression of HSPA2 (better prognosis) were associated with smaller tumors (p = 0,0162), ER-positive and PR-positive cancers (p < 0,0001 and p < 0,0001, respectively).	('high expression', 'Var', (36, 51))	('tumors', 'Disease', 'MESH:D009369', (109, 115))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('PR', 'Gene', '5241', (146, 148))	('HSPA2', 'Gene', (55, 60))	('patients', 'Species', '9606', (22, 30))	('cancers', 'Phenotype', 'HP:0002664', (158, 165))	('cancers', 'Disease', (158, 165))	('cancers', 'Disease', 'MESH:D009369', (158, 165))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('ER', 'Gene', '2099', (130, 132))	('smaller', 'NegReg', (101, 108))	('tumors', 'Disease', (109, 115))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
224027	31101846	Moreover, mutated TP53 lose the oncosuppressive role and acquire new oncogenic functions.	('mutated', 'Var', (10, 17))	('oncogenic functions', 'CPA', (69, 88))	('TP53', 'Gene', '7157', (18, 22))	('lose', 'NegReg', (23, 27))	('TP53', 'Gene', (18, 22))	('oncosuppressive role', 'CPA', (32, 52))
224039	31101846	Risk score was constructed with the formula: Risk score = (-0,4181 x HSPA2 0/1) + (-0,1813 x DNAJC20 0/1) + (0,6861 x HSP90AA1 0/1) + (0,0824 x CCT1 0/1) + (0,11 x CCT2 0/1) + (0,8427 x Stage 1/2/3/4).	('DNAJC20', 'Gene', (93, 100))	('HSP90AA1', 'Gene', (118, 126))	('HSP90AA1', 'Gene', '3320', (118, 126))	('CCT2', 'Gene', '10576', (164, 168))	('CCT2', 'Gene', (164, 168))	('CCT1', 'Gene', (144, 148))	('DNAJC20', 'Gene', '150274', (93, 100))	('-0,4181', 'Var', (59, 66))	('CCT1', 'Gene', '6950', (144, 148))
224076	31101846	High expression of HSPA2 have been associated with shorter overall survival in stage I-II of non-small cell lung carcinoma patients.	('non-small cell lung carcinoma', 'Phenotype', 'HP:0030358', (93, 122))	('High', 'Var', (0, 4))	('cell lung carcinoma', 'Disease', 'MESH:D055752', (103, 122))	('shorter', 'NegReg', (51, 58))	('patients', 'Species', '9606', (123, 131))	('HSPA2', 'Gene', (19, 24))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('small cell lung carcinoma', 'Phenotype', 'HP:0030357', (97, 122))	('cell lung carcinoma', 'Disease', (103, 122))	('overall survival', 'MPA', (59, 75))
224092	31101846	HSP90 is also involved in many cancer-associated processes like cellular transformation, DNA double-strand break repair, apoptosis, invasion, genetic variation.	('cancer', 'Disease', (31, 37))	('HSP90', 'Gene', (0, 5))	('HSP90', 'Gene', '3320', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('genetic variation', 'Var', (142, 159))	('cellular transformation', 'CPA', (64, 87))	('involved', 'Reg', (14, 22))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('apoptosis', 'CPA', (121, 130))	('invasion', 'CPA', (132, 140))
224096	31101846	Additionally, overexpression of HSP90AA1 was observed in tumors containing mutation in TP53, one of the most frequent genetic alteration in cancer that is often associated with accelerated tumor progression.	('associated', 'Reg', (161, 171))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('overexpression', 'PosReg', (14, 28))	('tumors', 'Disease', 'MESH:D009369', (57, 63))	('TP53', 'Gene', '7157', (87, 91))	('mutation', 'Var', (75, 83))	('tumor', 'Disease', (57, 62))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('cancer', 'Disease', (140, 146))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('HSP90AA1', 'Gene', (32, 40))	('tumor', 'Disease', (189, 194))	('TP53', 'Gene', (87, 91))	('HSP90AA1', 'Gene', '3320', (32, 40))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('tumors', 'Disease', (57, 63))
224105	31101846	Moreover, high expression of identified CCT subunits was associated with aggressive clinical features including the high stage and grade of cancer.	('high', 'Disease', (116, 120))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('high', 'Var', (10, 14))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('associated', 'Reg', (57, 67))
224136	30244662	The Study of MDM2 rs937283 Variant and Cancer Susceptibility in a Central Chinese Population The rs937283 variant, locating in murine double minute 2 promoter region, has been previously reported to potentially alter the promoter activity and to influence cancer susceptibility.	('rs937283', 'Mutation', 'rs937283', (18, 26))	('Cancer', 'Disease', 'MESH:D009369', (39, 45))	('promoter activity', 'MPA', (221, 238))	('influence', 'Reg', (246, 255))	('cancer', 'Disease', 'MESH:D009369', (256, 262))	('rs937283', 'Mutation', 'rs937283', (97, 105))	('alter', 'Reg', (211, 216))	('MDM2', 'Gene', '4193', (13, 17))	('Cancer', 'Phenotype', 'HP:0002664', (39, 45))	('MDM2', 'Gene', (13, 17))	('cancer', 'Disease', (256, 262))	('murine double minute 2', 'Gene', '17246', (127, 149))	('murine double minute 2', 'Gene', (127, 149))	('cancer', 'Phenotype', 'HP:0002664', (256, 262))	('rs937283', 'Var', (97, 105))	('Cancer', 'Disease', (39, 45))
224137	30244662	In this study, we investigated the association of murine double minute 2 rs937283 variant and cancer susceptibility in a central Chinese population, followed by a meta-analysis.	('rs937283', 'Mutation', 'rs937283', (73, 81))	('murine double minute 2', 'Gene', '17246', (50, 72))	('murine double minute 2', 'Gene', (50, 72))	('association', 'Interaction', (35, 46))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('rs937283', 'Var', (73, 81))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
224139	30244662	The murine double minute 2 rs937283 was genotyped by polymerase chain reaction restriction fragment length polymorphism and confirmed by sequencing.	('murine double minute 2', 'Gene', '17246', (4, 26))	('murine double minute 2', 'Gene', (4, 26))	('rs937283', 'Var', (27, 35))	('men', 'Species', '9606', (95, 98))	('rs937283', 'Mutation', 'rs937283', (27, 35))
224140	30244662	Our case-control analysis revealed that rs937283 was associated with the susceptibility to breast and liver cancer, but not cervical, colon, or rectal cancer.	('colon', 'Disease', (134, 139))	('rs937283', 'Var', (40, 48))	('breast and liver cancer', 'Disease', 'MESH:D006528', (91, 114))	('rectal cancer', 'Disease', 'MESH:D012004', (144, 157))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('rectal cancer', 'Disease', (144, 157))	('rectal cancer', 'Phenotype', 'HP:0100743', (144, 157))	('rs937283', 'Mutation', 'rs937283', (40, 48))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('associated', 'Reg', (53, 63))	('colon', 'Disease', 'MESH:D015179', (134, 139))	('liver cancer', 'Phenotype', 'HP:0002896', (102, 114))
224142	30244662	Moreover, results of meta-analysis demonstrated that rs937283 was significantly associated with cancer susceptibility, and this significant association remained in Asian (Chinese) population, but not in Caucasian population.	('rs937283', 'Var', (53, 61))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('rs937283', 'Mutation', 'rs937283', (53, 61))	('associated', 'Reg', (80, 90))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Disease', (96, 102))
224143	30244662	Collectively, the murine double minute 2 rs937283 variant may serve as a potential biomarker for cancer predisposition in Chinese population.	('cancer', 'Disease', (97, 103))	('murine double minute 2', 'Gene', '17246', (18, 40))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('rs937283', 'Var', (41, 49))	('rs937283', 'Mutation', 'rs937283', (41, 49))	('murine double minute 2', 'Gene', (18, 40))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
224150	30244662	The current knowledge suggests that occurrence of human tumor is the result of accumulation of genetic and epigenetic changes in genome.	('genetic', 'Var', (95, 102))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('accumulation', 'PosReg', (79, 91))	('tumor', 'Disease', (56, 61))	('epigenetic changes', 'Var', (107, 125))	('human', 'Species', '9606', (50, 55))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
224151	30244662	The association of genetic factors (especially genetic variants) and human cancers has attracted a lot of attention.	('cancers', 'Phenotype', 'HP:0002664', (75, 82))	('variants', 'Var', (55, 63))	('cancers', 'Disease', 'MESH:D009369', (75, 82))	('cancers', 'Disease', (75, 82))	('human', 'Species', '9606', (69, 74))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))
224152	30244662	Interestingly, the rs937283 is such a genetic variant that significantly enhances the transcription activity of the MDM2 gene and thereby increases the messenger RNA (mRNA) and protein expression levels of MDM2.	('MDM2 gene', 'Gene', (116, 125))	('protein expression levels', 'MPA', (177, 202))	('rs937283', 'Var', (19, 27))	('increases', 'PosReg', (138, 147))	('rs937283', 'Mutation', 'rs937283', (19, 27))	('transcription activity', 'MPA', (86, 108))	('enhances', 'PosReg', (73, 81))
224154	30244662	To determine the role of MDM2 rs937283 variant in these cancers, we in this study analyzed the distribution of rs937283 and assessed the association of MDM2 with susceptibility to breast cancer, cervical cancer, liver cancer, colon cancer, and rectal cancer in a central Chinese population.	('cancers', 'Disease', 'MESH:D009369', (56, 63))	('liver cancer', 'Phenotype', 'HP:0002896', (212, 224))	('rs937283', 'Mutation', 'rs937283', (111, 119))	('liver cancer', 'Disease', (212, 224))	('colon cancer', 'Disease', 'MESH:D015179', (226, 238))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('breast cancer', 'Phenotype', 'HP:0003002', (180, 193))	('rs937283', 'Var', (30, 38))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('breast cancer', 'Disease', 'MESH:D001943', (180, 193))	('rectal cancer', 'Disease', (244, 257))	('breast cancer', 'Disease', (180, 193))	('rectal cancer', 'Phenotype', 'HP:0100743', (244, 257))	('colon cancer', 'Disease', (226, 238))	('rs937283', 'Mutation', 'rs937283', (30, 38))	('cancers', 'Phenotype', 'HP:0002664', (56, 63))	('MDM2', 'Gene', (152, 156))	('cancers', 'Disease', (56, 63))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('cervical cancer', 'Disease', (195, 210))	('cervical cancer', 'Disease', 'MESH:D002583', (195, 210))	('association', 'Interaction', (137, 148))	('liver cancer', 'Disease', 'MESH:D006528', (212, 224))	('rectal cancer', 'Disease', 'MESH:D012004', (244, 257))	('colon cancer', 'Phenotype', 'HP:0003003', (226, 238))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('rs937283', 'Var', (111, 119))
224155	30244662	Several studies have investigated the association between rs937283 and susceptibility to multiple cancers.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('multiple cancers', 'Disease', 'MESH:D009369', (89, 105))	('cancers', 'Phenotype', 'HP:0002664', (98, 105))	('rs937283', 'Var', (58, 66))	('multiple cancers', 'Disease', (89, 105))	('rs937283', 'Mutation', 'rs937283', (58, 66))
224156	30244662	To solve the discrepancies and the problem of inadequate statistical strength among previous studies, we further performed a meta-analysis, integrating the data from previous literatures and our present study, to get a more precise and reliable assessment of the association between MDM2 rs937283 variant and cancer susceptibility.	('rs937283', 'Var', (288, 296))	('MDM2', 'Gene', (283, 287))	('cancer', 'Phenotype', 'HP:0002664', (309, 315))	('rs937283', 'Mutation', 'rs937283', (288, 296))	('cancer', 'Disease', 'MESH:D009369', (309, 315))	('cancer', 'Disease', (309, 315))	('men', 'Species', '9606', (251, 254))
224163	30244662	The A to G substitution at rs937283 creates an AvaII restriction site; thus, genotyping of MDM2 rs937283 variant was subsequently performed via polymerase chain reaction (PCR) restriction fragment length polymorphism technique.	('MDM2', 'Gene', (91, 95))	('rs937283', 'Var', (96, 104))	('rs937283', 'Var', (27, 35))	('men', 'Species', '9606', (192, 195))	('rs937283', 'Mutation', 'rs937283', (27, 35))	('rs937283', 'Mutation', 'rs937283', (96, 104))
224169	30244662	Genotypic frequency of rs937283 in healthy controls was tested for departure from Hardy-Weinberg equilibrium (HWE).	('rs937283', 'Var', (23, 31))	('Hardy-Weinberg equilibrium', 'Disease', (82, 108))	('rs937283', 'Mutation', 'rs937283', (23, 31))
224170	30244662	Logistic regression analysis was used to estimate the association between rs937283 and cancer susceptibility.	('cancer', 'Disease', (87, 93))	('rs937283', 'Var', (74, 82))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('rs937283', 'Mutation', 'rs937283', (74, 82))	('cancer', 'Disease', 'MESH:D009369', (87, 93))
224171	30244662	The search terms used were as follows: mouse double minute 2 homolog, proto-oncogene proteins c-mdm2, MDM2, MDM2 proto-oncogene, E3 ubiquitin protein ligase, human homolog of mouse double minute 2, murine double minute 2, polymorphism, variant, mutation, SNP, single nucleotide polymorphism, rs937283, cancer, tumor, carcinoma.	('murine double minute 2', 'Gene', (198, 220))	('tumor', 'Phenotype', 'HP:0002664', (310, 315))	('mouse', 'Species', '10090', (39, 44))	('rs937283', 'Var', (292, 300))	('cancer', 'Disease', (302, 308))	('carcinoma', 'Phenotype', 'HP:0030731', (317, 326))	('murine double minute 2', 'Gene', '17246', (198, 220))	('rs937283', 'Mutation', 'rs937283', (292, 300))	('cancer', 'Phenotype', 'HP:0002664', (302, 308))	('carcinoma', 'Disease', (317, 326))	('mdm2', 'Gene', '4193', (96, 100))	('human', 'Species', '9606', (158, 163))	('variant', 'Var', (236, 243))	('tumor', 'Disease', (310, 315))	('cancer', 'Disease', 'MESH:D009369', (302, 308))	('carcinoma', 'Disease', 'MESH:D002277', (317, 326))	('single nucleotide polymorphism', 'Var', (260, 290))	('tumor', 'Disease', 'MESH:D009369', (310, 315))	('mdm2', 'Gene', (96, 100))	('polymorphism', 'Var', (222, 234))	('mouse', 'Species', '10090', (175, 180))
224172	30244662	Next, studies were eligible for inclusion in the meta-analysis if they met the following criteria: (1) studies on humans, (2) investigation of the MDM2 rs937283 variant and cancer susceptibility, (3) case-control study design, (4) valid data were accessible to estimate the OR and its 95% CI, and (5) HWE equilibrium should be established in control groups.	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('rs937283', 'Mutation', 'rs937283', (152, 160))	('cancer', 'Disease', (173, 179))	('MDM2', 'Gene', (147, 151))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('humans', 'Species', '9606', (114, 120))	('rs937283', 'Var', (152, 160))
224177	30244662	Five types of patients with cancer (breast cancer, cervical cancer, liver cancer, colon cancer, and rectal cancer) were included in this study, and the MDM2 rs937283 variant was successfully genotyped in a total of 3189 participants.	('cancer', 'Disease', (88, 94))	('colon cancer', 'Phenotype', 'HP:0003003', (82, 94))	('cancer', 'Disease', (74, 80))	('rs937283', 'Var', (157, 165))	('rectal cancer', 'Disease', 'MESH:D012004', (100, 113))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('rs937283', 'Mutation', 'rs937283', (157, 165))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('patients', 'Species', '9606', (14, 22))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('liver cancer', 'Phenotype', 'HP:0002896', (68, 80))	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('liver cancer', 'Disease', (68, 80))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('colon cancer', 'Disease', 'MESH:D015179', (82, 94))	('MDM2', 'Gene', (152, 156))	('breast cancer', 'Phenotype', 'HP:0003002', (36, 49))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('colon cancer', 'Disease', (82, 94))	('rectal cancer', 'Disease', (100, 113))	('cervical cancer', 'Disease', (51, 66))	('cancer', 'Disease', (28, 34))	('cervical cancer', 'Disease', 'MESH:D002583', (51, 66))	('cancer', 'Disease', (107, 113))	('rectal cancer', 'Phenotype', 'HP:0100743', (100, 113))	('breast cancer', 'Disease', 'MESH:D001943', (36, 49))	('breast cancer', 'Disease', (36, 49))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('cancer', 'Disease', (43, 49))	('participants', 'Species', '9606', (220, 232))	('cancer', 'Disease', (60, 66))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('liver cancer', 'Disease', 'MESH:D006528', (68, 80))
224178	30244662	Table 3 showed us the allele/genotype distributions of rs937283 and their association with cancer susceptibility.	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('association', 'Reg', (74, 85))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('rs937283', 'Var', (55, 63))	('rs937283', 'Mutation', 'rs937283', (55, 63))
224180	30244662	No significant association was identified for rs937283 with the susceptibility to cervical cancer, colon cancer, rectal cancer, or combined colorectal cancer.	('rs937283', 'Mutation', 'rs937283', (46, 54))	('colon cancer', 'Disease', 'MESH:D015179', (99, 111))	('rectal cancer', 'Disease', (113, 126))	('rectal cancer', 'Phenotype', 'HP:0100743', (113, 126))	('rectal cancer', 'Phenotype', 'HP:0100743', (144, 157))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('colorectal cancer', 'Phenotype', 'HP:0003003', (140, 157))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('colon cancer', 'Disease', (99, 111))	('rectal cancer', 'Disease', 'MESH:D012004', (113, 126))	('rectal cancer', 'Disease', 'MESH:D012004', (144, 157))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('colorectal cancer', 'Disease', 'MESH:D015179', (140, 157))	('colon cancer', 'Phenotype', 'HP:0003003', (99, 111))	('colorectal cancer', 'Disease', (140, 157))	('cervical cancer', 'Disease', (82, 97))	('cervical cancer', 'Disease', 'MESH:D002583', (82, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('rs937283', 'Var', (46, 54))
224181	30244662	In contrast, rs937283 was shown to significantly associate with the susceptibility to breast and liver cancers.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('associate', 'Reg', (49, 58))	('rs937283', 'Var', (13, 21))	('liver cancer', 'Phenotype', 'HP:0002896', (97, 109))	('liver cancers', 'Phenotype', 'HP:0002896', (97, 110))	('rs937283', 'Mutation', 'rs937283', (13, 21))	('cancers', 'Phenotype', 'HP:0002664', (103, 110))	('breast and liver cancers', 'Disease', 'MESH:D006528', (86, 110))
224182	30244662	The allele/genotype distributions of rs937283 were significantly different between patients with breast cancer and healthy females (P = .003 and .008, respectively), as well as between patients with liver cancer and healthy controls (P = .001 and .004, respectively).	('liver cancer', 'Phenotype', 'HP:0002896', (199, 211))	('liver cancer', 'Disease', 'MESH:D006528', (199, 211))	('different', 'Reg', (65, 74))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('rs937283', 'Var', (37, 45))	('liver cancer', 'Disease', (199, 211))	('rs937283', 'Mutation', 'rs937283', (37, 45))	('breast cancer', 'Disease', 'MESH:D001943', (97, 110))	('breast cancer', 'Phenotype', 'HP:0003002', (97, 110))	('patients', 'Species', '9606', (185, 193))	('breast cancer', 'Disease', (97, 110))	('patients', 'Species', '9606', (83, 91))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))
224183	30244662	Furthermore, logistic regression analysis was applied to estimate the association of rs937283 with susceptibility to breast and liver cancer.	('association', 'Interaction', (70, 81))	('liver cancer', 'Phenotype', 'HP:0002896', (128, 140))	('rs937283', 'Var', (85, 93))	('breast and liver cancer', 'Disease', 'MESH:D006528', (117, 140))	('rs937283', 'Mutation', 'rs937283', (85, 93))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
224184	30244662	After Bonferroni correction for multiple testing (0.05/5 = 0.01), it was still found that the G allele and GG genotype of rs937283 were associated with an increased susceptibility to breast cancer than the A allele and AG/AA genotypes, respectively (G vs A, GG vs AA, and GG vs AG + AA).	('rs937283', 'Var', (122, 130))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('breast cancer', 'Disease', 'MESH:D001943', (183, 196))	('rs937283', 'Mutation', 'rs937283', (122, 130))	('breast cancer', 'Disease', (183, 196))	('breast cancer', 'Phenotype', 'HP:0003002', (183, 196))
224185	30244662	Similarly, the G allele and G variant genotypes of rs937283 significantly increased the susceptibility to liver cancer (G vs A, GG vs AA, GG vs AG + AA, and GG + AG vs AA).	('liver cancer', 'Phenotype', 'HP:0002896', (106, 118))	('liver cancer', 'Disease', 'MESH:D006528', (106, 118))	('liver cancer', 'Disease', (106, 118))	('increased', 'PosReg', (74, 83))	('rs937283', 'Var', (51, 59))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('increased the susceptibility to liver cancer', 'Phenotype', 'HP:0001402', (74, 118))	('rs937283', 'Mutation', 'rs937283', (51, 59))
224187	30244662	As shown in Table 5, the meta-analysis revealed a significant association between rs937283 and cancer susceptibility in 2 genetic models (G vs A, odds ratio [OR] = 1.17, 95% confidence interval [CI] = 1.06-1.30, P = .003; GG + AG vs AA, OR = 1.21, 95% CI = 1.06-1.38, P = .004).	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('rs937283', 'Var', (82, 90))	('cancer', 'Disease', (95, 101))	('rs937283', 'Mutation', 'rs937283', (82, 90))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))
224188	30244662	In the further ethnicity-stratified analysis, no association was found for rs937283 with cancer susceptibility in Caucasian population, whereas rs937283 was significantly associated with cancer susceptibility in Asian population in 3 genetic models (G vs A, OR = 1.30, 95% CI = 1.13-1.49, P < .001; AG vs AA, OR = 1.26, 95% CI = 1.13-1.41, P < .001; GG + AG vs AA, OR = 1.30, 95% CI = 1.17-1.44, P < 0.001).	('cancer', 'Disease', 'MESH:D009369', (187, 193))	('cancer', 'Disease', (187, 193))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('rs937283', 'Var', (75, 83))	('cancer', 'Disease', (89, 95))	('rs937283', 'Var', (144, 152))	('rs937283', 'Mutation', 'rs937283', (75, 83))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('rs937283', 'Mutation', 'rs937283', (144, 152))	('associated', 'Reg', (171, 181))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
224194	30244662	Therefore, identification of the inherited variants associated with cancer susceptibility would be useful in making early diagnosis and risk prediction.	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('variants', 'Var', (43, 51))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('cancer', 'Disease', (68, 74))
224196	30244662	The dysregulation of MDM2 would impair the MDM2-TP53 pathway and thereby might affect individual susceptibility to cancer.	('affect', 'Reg', (79, 85))	('cancer', 'Disease', (115, 121))	('TP53', 'Gene', '7157', (48, 52))	('dysregulation', 'Var', (4, 17))	('TP53', 'Gene', (48, 52))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('MDM2', 'Gene', (21, 25))	('impair', 'NegReg', (32, 38))	('cancer', 'Disease', 'MESH:D009369', (115, 121))
224197	30244662	The rs937283 variant was a novel functional variant identified in MDM2 gene promoter.	('MDM2', 'Gene', (66, 70))	('rs937283', 'Mutation', 'rs937283', (4, 12))	('rs937283', 'Var', (4, 12))
224198	30244662	Jiao et al proved that the transition of A to G at rs937283 significantly enhanced the transcription activity of the MDM2 gene in vitro.	('rs937283', 'Mutation', 'rs937283', (51, 59))	('MDM2 gene', 'Gene', (117, 126))	('transcription activity', 'MPA', (87, 109))	('rs937283', 'Var', (51, 59))	('enhanced', 'PosReg', (74, 82))
224199	30244662	Therefore, rs937283 variant was a potential risk factor for cancer susceptibility.	('rs937283', 'Mutation', 'rs937283', (11, 19))	('risk', 'Reg', (44, 48))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('cancer', 'Disease', (60, 66))	('rs937283', 'Var', (11, 19))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
224200	30244662	Indeed, we here identified that MDM2 rs937283 variant significantly increased the susceptibility to breast and liver cancer in a central Chinese population.	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('rs937283', 'Var', (37, 45))	('liver cancer', 'Phenotype', 'HP:0002896', (111, 123))	('rs937283', 'Mutation', 'rs937283', (37, 45))	('breast and liver cancer', 'Disease', 'MESH:D006528', (100, 123))	('MDM2', 'Gene', (32, 36))
224201	30244662	However, inconsistent results were observed when exploring the association between rs937283 and susceptibility to cervical and colorectal cancer.	('colorectal cancer', 'Phenotype', 'HP:0003003', (127, 144))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('colorectal cancer', 'Disease', (127, 144))	('cervical', 'Disease', (114, 122))	('colorectal cancer', 'Disease', 'MESH:D015179', (127, 144))	('rs937283', 'Var', (83, 91))	('rectal cancer', 'Phenotype', 'HP:0100743', (131, 144))	('rs937283', 'Mutation', 'rs937283', (83, 91))
224202	30244662	So far 9 studies have been investigated the association between rs937283 and cancer susceptibility, including lung cancer (LuC), oral squamous cell carcinoma (OSCC), salivary gland carcinoma (SGC), retinoblastoma (RB), squamous cell carcinoma of the head and neck (SCCHN), differentiated thyroid carcinoma (DTC), esophageal squamous cell carcinoma (ESCC), and laryngeal carcinoma (LaC).	('squamous cell carcinoma', 'Disease', (219, 242))	('oral squamous cell carcinoma', 'Disease', (129, 157))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('salivary gland carcinoma', 'Phenotype', 'HP:0100684', (166, 190))	('lung cancer', 'Disease', (110, 121))	('carcinoma of the head and neck', 'Phenotype', 'HP:0012288', (233, 263))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (134, 157))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('laryngeal carcinoma', 'Phenotype', 'HP:0012118', (360, 379))	('LaC', 'Phenotype', 'HP:0012118', (381, 384))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (288, 305))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (324, 347))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (313, 347))	('LuC', 'Phenotype', 'HP:0100526', (123, 126))	('salivary gland carcinoma', 'Disease', (166, 190))	('thyroid carcinoma', 'Disease', (288, 305))	('retinoblastoma', 'Gene', (198, 212))	('carcinoma', 'Phenotype', 'HP:0030731', (181, 190))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (219, 242))	('laryngeal carcinoma', 'Disease', 'MESH:D007827', (360, 379))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (134, 157))	('SGC', 'Phenotype', 'HP:0100684', (192, 195))	('RB', 'Phenotype', 'HP:0009919', (214, 216))	('carcinoma', 'Phenotype', 'HP:0030731', (148, 157))	('salivary gland carcinoma', 'Disease', 'MESH:D012468', (166, 190))	('lung cancer', 'Disease', 'MESH:D008175', (110, 121))	('cancer', 'Disease', (77, 83))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (288, 305))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (324, 347))	('lung cancer', 'Phenotype', 'HP:0100526', (110, 121))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (219, 242))	('cancer', 'Disease', (115, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (338, 347))	('rs937283', 'Var', (64, 72))	('rs937283', 'Mutation', 'rs937283', (64, 72))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('retinoblastoma', 'Phenotype', 'HP:0009919', (198, 212))	('carcinoma', 'Phenotype', 'HP:0030731', (296, 305))	('esophageal squamous cell carcinoma', 'Disease', (313, 347))	('retinoblastoma', 'Gene', '5925', (198, 212))	('laryngeal carcinoma', 'Disease', (360, 379))	('RB', 'Gene', '5925', (214, 216))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (129, 157))	('carcinoma', 'Phenotype', 'HP:0030731', (233, 242))	('DTC', 'Chemical', '-', (307, 310))
224203	30244662	Specifically, MDM2 rs937283 was shown to be associated with the susceptibility to OSCC, LaC, and RB (in Asian), but not to LuC, SGC, SCCHN, DTC, ESCC, or RB (in Caucasian).	('associated', 'Reg', (44, 54))	('susceptibility', 'Reg', (64, 78))	('rs937283', 'Var', (19, 27))	('RB', 'Phenotype', 'HP:0009919', (154, 156))	('SGC', 'Phenotype', 'HP:0100684', (128, 131))	('LuC', 'Phenotype', 'HP:0100526', (123, 126))	('LaC', 'Disease', (88, 91))	('rs937283', 'Mutation', 'rs937283', (19, 27))	('RB', 'Gene', '5925', (97, 99))	('OSCC', 'Disease', (82, 86))	('LaC', 'Phenotype', 'HP:0012118', (88, 91))	('DTC', 'Chemical', '-', (140, 143))	('MDM2', 'Gene', (14, 18))	('RB', 'Phenotype', 'HP:0009919', (97, 99))	('RB', 'Gene', '5925', (154, 156))
224205	30244662	The regulation of MDM2 expression is complex in normal cells, and the regulation of rs937283 variant on MDM2 expression may vary from cell types.	('MDM2', 'Gene', (18, 22))	('rs937283', 'Var', (84, 92))	('rs937283', 'Mutation', 'rs937283', (84, 92))
224206	30244662	Admittedly, different environments, lifestyles, and genetic backgrounds among different ethnic populations and small sample size may also contribute to the differences in the association of rs937283 and susceptibility to different types of cancers.	('rs937283', 'Var', (190, 198))	('association', 'Interaction', (175, 186))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('rs937283', 'Mutation', 'rs937283', (190, 198))	('men', 'Species', '9606', (29, 32))	('cancers', 'Phenotype', 'HP:0002664', (240, 247))	('cancers', 'Disease', (240, 247))	('cancers', 'Disease', 'MESH:D009369', (240, 247))	('differences', 'Reg', (156, 167))
224207	30244662	Therefore, a meta-analysis was further performed to estimate the real effect of rs937283 on cancer susceptibility.	('rs937283', 'Var', (80, 88))	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('rs937283', 'Mutation', 'rs937283', (80, 88))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
224208	30244662	Interestingly, we found a positive association between rs937283 variant and increased cancer susceptibility in the overall population and Asian population.	('increased', 'PosReg', (76, 85))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('rs937283', 'Var', (55, 63))	('cancer', 'Disease', (86, 92))	('rs937283', 'Mutation', 'rs937283', (55, 63))
224209	30244662	The explanation for this observation may be that the G allele of rs937283 variant in the MDM2 promoter region is closely linked to the high expression levels ofMDM2 mRNA and protein, which enhances the degradation of TP53 and thereby increases the cancer susceptibility.	('cancer', 'Disease', (248, 254))	('TP53', 'Gene', '7157', (217, 221))	('linked', 'Reg', (121, 127))	('TP53', 'Gene', (217, 221))	('cancer', 'Phenotype', 'HP:0002664', (248, 254))	('enhances', 'PosReg', (189, 197))	('rs937283', 'Var', (65, 73))	('cancer', 'Disease', 'MESH:D009369', (248, 254))	('rs937283', 'Mutation', 'rs937283', (65, 73))	('degradation', 'MPA', (202, 213))	('increases', 'PosReg', (234, 243))	('expression levels', 'MPA', (140, 157))
224210	30244662	However, no significant association between rs937283 and cancer susceptibility was present in the Caucasian-stratified analysis, suggesting differences in genetic background may be a possible reflection of rs937283 on cancer susceptibility.	('cancer', 'Disease', 'MESH:D009369', (218, 224))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('rs937283', 'Var', (44, 52))	('cancer', 'Disease', (218, 224))	('cancer', 'Disease', (57, 63))	('rs937283', 'Mutation', 'rs937283', (44, 52))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('rs937283', 'Var', (206, 214))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('rs937283', 'Mutation', 'rs937283', (206, 214))
224211	30244662	Genetic testing can identify individuals with an increased risk for human diseases such as cancer.	('human', 'Species', '9606', (68, 73))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('Genetic', 'Var', (0, 7))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))
224215	30244662	Second, it cannot rule out the possibility that the MDM2 rs937283 variant may not be the causal loci but rather be in linkage disequilibrium with the causal loci.	('rs937283', 'Mutation', 'rs937283', (57, 65))	('MDM2', 'Gene', (52, 56))	('rs937283', 'Var', (57, 65))
224216	30244662	Third, the effect of rs937283 variant on MDM2 expression was not assessed in liver/breast cancer tissues from individuals with different rs937283 genotypes, which should be analyzed in further confirmatory study.	('liver/breast cancer', 'Disease', (77, 96))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('rs937283', 'Var', (137, 145))	('breast cancer', 'Phenotype', 'HP:0003002', (83, 96))	('rs937283', 'Mutation', 'rs937283', (137, 145))	('rs937283', 'Mutation', 'rs937283', (21, 29))	('liver/breast cancer', 'Disease', 'MESH:D006528', (77, 96))
224217	30244662	Fourth, the underlying molecular mechanism for the regulation of rs937283 on MDM2 transcription activity remains unclear, which needs to be addressed in future functional studies.	('rs937283', 'Var', (65, 73))	('rs937283', 'Mutation', 'rs937283', (65, 73))	('MDM2', 'Gene', (77, 81))	('transcription activity', 'MPA', (82, 104))
224218	30244662	Our study provided statistical evidence that MDM2 rs937283 variant significantly increases the susceptibility to breast and liver cancer, but not cervical cancer, colon cancer, or rectal cancer in a central Chinese population.	('cervical cancer', 'Disease', (146, 161))	('cervical cancer', 'Disease', 'MESH:D002583', (146, 161))	('colon cancer', 'Disease', (163, 175))	('breast and liver cancer', 'Disease', 'MESH:D006528', (113, 136))	('rs937283', 'Var', (50, 58))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('liver cancer', 'Phenotype', 'HP:0002896', (124, 136))	('rs937283', 'Mutation', 'rs937283', (50, 58))	('MDM2', 'Gene', (45, 49))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('rectal cancer', 'Disease', 'MESH:D012004', (180, 193))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('colon cancer', 'Phenotype', 'HP:0003003', (163, 175))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('rectal cancer', 'Disease', (180, 193))	('rectal cancer', 'Phenotype', 'HP:0100743', (180, 193))	('colon cancer', 'Disease', 'MESH:D015179', (163, 175))	('increases', 'PosReg', (81, 90))
224219	30244662	We further demonstrated that MDM2 rs937283 variant is more likely to confer an increased genetic susceptibility to cancer susceptibility in Asian (Chinese) population, but not in Caucasian population.	('cancer', 'Disease', (115, 121))	('MDM2', 'Gene', (29, 33))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('rs937283', 'Var', (34, 42))	('rs937283', 'Mutation', 'rs937283', (34, 42))	('cancer', 'Disease', 'MESH:D009369', (115, 121))
224220	30244662	MDM2 rs937283 variant may serve as a valuable risk factor or diagnostic biomarker among Chinese patients with cancer and needs more supporting evidence.	('cancer', 'Disease', (110, 116))	('rs937283', 'Var', (5, 13))	('rs937283', 'Mutation', 'rs937283', (5, 13))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('MDM2', 'Gene', (0, 4))	('patients', 'Species', '9606', (96, 104))	('cancer', 'Disease', 'MESH:D009369', (110, 116))
224222	33578572	Integrated analysis of deregulation microRNA expression in head and neck squamous cell carcinoma MicroRNAs (miRNAs) play critical roles in carcinogenesis and development of cancers.	('carcinogenesis', 'Disease', (139, 153))	('neck squamous cell carcinoma', 'Disease', (68, 96))	('cancers', 'Disease', 'MESH:D009369', (173, 180))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (73, 96))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (68, 96))	('cancers', 'Disease', (173, 180))	('microRNA expression', 'MPA', (36, 55))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('carcinogenesis', 'Disease', 'MESH:D063646', (139, 153))	('deregulation', 'Var', (23, 35))	('cancers', 'Phenotype', 'HP:0002664', (173, 180))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (59, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))
224226	33578572	Compared with the expression in control tissues, the levels of hsa-miR-410-3p, hsa-miR-411-5p, hsa-miR-125b-2-3p, and hsa-miR-99a-3p were significantly lower in HNSCC.	('hsa-miR-125b-2-3p', 'Var', (95, 112))	('miR-410-3p', 'Chemical', '-', (67, 77))	('hsa-miR-99a-3p', 'Var', (118, 132))	('hsa-miR-411', 'Gene', '693121', (79, 90))	('levels', 'MPA', (53, 59))	('hsa-miR-125b-2-3p', 'Chemical', '-', (95, 112))	('hsa-miR-411', 'Gene', (79, 90))	('lower', 'NegReg', (152, 157))	('expression', 'MPA', (18, 28))	('HNSCC', 'Disease', (161, 166))	('HNSCC', 'Phenotype', 'HP:0012288', (161, 166))
224227	33578572	According to the Cancer Genome Atlas dataset analyzed, all 4 miRNAs were shown to inhibit tumor progression (T stage), positive lymph node metastasis (N stage), and distant metastasis (M stage) in HNSCC.	('positive lymph node metastasis', 'CPA', (119, 149))	('Cancer', 'Disease', (17, 23))	('miRNAs', 'Var', (61, 67))	('tumor', 'Disease', (90, 95))	('inhibit', 'NegReg', (82, 89))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('HNSCC', 'Disease', (197, 202))	('Cancer', 'Disease', 'MESH:D009369', (17, 23))	('Cancer', 'Phenotype', 'HP:0002664', (17, 23))	('HNSCC', 'Phenotype', 'HP:0012288', (197, 202))	('distant metastasis', 'CPA', (165, 183))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
224236	33578572	For instance, miR-26, miR-107, miR-125b, and miR-203 have been reported to be prognostic biomarkers of overall survival of HNSCC patients.	('HNSCC', 'Phenotype', 'HP:0012288', (123, 128))	('miR-107', 'Gene', '406901', (22, 29))	('patients', 'Species', '9606', (129, 137))	('miR-125b', 'Var', (31, 39))	('miR-26', 'Var', (14, 20))	('miR-107', 'Gene', (22, 29))	('miR-203', 'Gene', '406986', (45, 52))	('miR-203', 'Gene', (45, 52))	('HNSCC', 'Disease', (123, 128))
224241	33578572	The 4 most differentially expressed miRNAs (hsa-miR-410-3p, hsa-miR-411-5p, hsa-miR-125b-2-3p, and hsa-miR-99a-3p) with AUC > 0.80 were selected for further analysis of their potential roles and diagnostic value in carcinogenesis.	('hsa-miR-411', 'Gene', (60, 71))	('hsa-miR-125b-2-3p', 'Chemical', '-', (76, 93))	('carcinogenesis', 'Disease', 'MESH:D063646', (215, 229))	('carcinogenesis', 'Disease', (215, 229))	('hsa-miR-125b-2-3p', 'Var', (76, 93))	('miR-410-3p', 'Chemical', '-', (48, 58))	('hsa-miR-410-3p', 'Var', (44, 58))	('hsa-miR-411', 'Gene', '693121', (60, 71))
224248	33578572	Four miRNAs with the greatest differential expression (hsa-miR-410-3p, hsa-miR-411-5p, hsa-miR-125b-2-3p, and hsa-miR-99a-3p) were selected for further analysis of their potential roles in carcinogenesis and diagnostic value.	('miR-410-3p', 'Chemical', '-', (59, 69))	('hsa-miR-410-3p', 'Var', (55, 69))	('carcinogenesis', 'Disease', 'MESH:D063646', (189, 203))	('hsa-miR-125b-2-3p', 'Var', (87, 104))	('carcinogenesis', 'Disease', (189, 203))	('hsa-miR-411', 'Gene', '693121', (71, 82))	('hsa-miR-411', 'Gene', (71, 82))	('hsa-miR-125b-2-3p', 'Chemical', '-', (87, 104))
224249	33578572	Hsa-miR-410-3p, hsa-miR-411-5p, hsa-miR-125b-2-3p, and hsa-miR-99a-3p inhibit tumor progression (T stage), positive lymph node metastasis (N stage), and distant metastasis (M stage) in HNSCC (*P < .05, **P < .01, Fig.	('hsa-miR-99a-3p', 'Var', (55, 69))	('distant metastasis', 'CPA', (153, 171))	('HNSCC', 'Phenotype', 'HP:0012288', (185, 190))	('hsa-miR-125b-2-3p', 'Chemical', '-', (32, 49))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('positive lymph node metastasis', 'CPA', (107, 137))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Disease', (78, 83))	('inhibit', 'NegReg', (70, 77))	('hsa-miR-411', 'Gene', '693121', (16, 27))	('hsa-miR-411', 'Gene', (16, 27))	('miR-410-3p', 'Chemical', '-', (4, 14))	('hsa-miR-125b-2-3p', 'Var', (32, 49))
224256	33578572	Dysregulation of miRNA expression has been described in a variety of diseases, particularly in cancers, including HNSCC.	('miRNA expression', 'Protein', (17, 33))	('Dysregulation', 'Var', (0, 13))	('cancers', 'Phenotype', 'HP:0002664', (95, 102))	('HNSCC', 'Disease', (114, 119))	('cancers', 'Disease', (95, 102))	('HNSCC', 'Phenotype', 'HP:0012288', (114, 119))	('cancers', 'Disease', 'MESH:D009369', (95, 102))	('described', 'Reg', (43, 52))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))
224258	33578572	In addition, it was found that miR-30e-5p could represses angiogenesis and metastasis by directly targeting AEG-1 in squamous cell carcinoma of the head and neck.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (117, 140))	('represses', 'NegReg', (48, 57))	('squamous cell carcinoma', 'Disease', (117, 140))	('targeting', 'Reg', (98, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (117, 140))	('miR-30e-5p', 'Chemical', '-', (31, 41))	('AEG-1', 'Gene', '92140', (108, 113))	('AEG-1', 'Gene', (108, 113))	('miR-30e-5p', 'Var', (31, 41))	('angiogenesis', 'CPA', (58, 70))
224261	33578572	Li reported that hsa-miR-125b-2-3p may be a potential biomarker of ischemic stroke.	('ischemic stroke', 'Disease', (67, 82))	('ischemic stroke', 'Phenotype', 'HP:0002140', (67, 82))	('hsa-miR-125b-2-3p', 'Var', (17, 34))	('stroke', 'Phenotype', 'HP:0001297', (76, 82))	('ischemic stroke', 'Disease', 'MESH:D002544', (67, 82))	('hsa-miR-125b-2-3p', 'Chemical', '-', (17, 34))
224262	33578572	Recently, Okada confirmed low expression of miR-99a-5p and miR-99a-3p significantly predicts poor prognosis in HNSCC, and these miRNAs regulate cancer cell migration and invasion.	('regulate', 'Reg', (135, 143))	('expression', 'MPA', (30, 40))	('HNSCC', 'Phenotype', 'HP:0012288', (111, 116))	('miR-99a-5p', 'Var', (44, 54))	('HNSCC', 'Disease', (111, 116))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('cancer', 'Disease', (144, 150))	('miR-99a-3p', 'Var', (59, 69))	('invasion', 'CPA', (170, 178))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
224263	33578572	Arai confirmed that hsa-miR-99a-3p acts as an antitumor miRNA in castration-resistant prostate cancer.	('prostate cancer', 'Disease', 'MESH:D011471', (86, 101))	('prostate cancer', 'Phenotype', 'HP:0012125', (86, 101))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('prostate cancer', 'Disease', (86, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('hsa-miR-99a-3p', 'Var', (20, 34))	('tumor', 'Disease', (50, 55))
224264	33578572	Wang proved that miR-410-3p functions as a tumor suppressor in glioma by directly targeting RAP1A.	('targeting', 'Reg', (82, 91))	('RAP1A', 'Gene', (92, 97))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('miR-410-3p', 'Var', (17, 27))	('glioma', 'Disease', 'MESH:D005910', (63, 69))	('glioma', 'Phenotype', 'HP:0009733', (63, 69))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Disease', (43, 48))	('miR-410-3p', 'Chemical', '-', (17, 27))	('RAP1A', 'Gene', '5906', (92, 97))	('glioma', 'Disease', (63, 69))
224265	33578572	In the present study, the top 4 aberrantly expressed miRNAs (hsa-miR-410-3p, hsa-miR-411-5p, hsa-miR-125b-2-3p, and hsa-miR-99a-3p) showed high diagnostic value for HNSCC, with AUCs exceeding 0.80.	('hsa-miR-411', 'Gene', (77, 88))	('miR-410-3p', 'Chemical', '-', (65, 75))	('hsa-miR-125b-2-3p', 'Var', (93, 110))	('hsa-miR-411', 'Gene', '693121', (77, 88))	('hsa-miR-410-3p', 'Var', (61, 75))	('HNSCC', 'Disease', (165, 170))	('hsa-miR-125b-2-3p', 'Chemical', '-', (93, 110))	('HNSCC', 'Phenotype', 'HP:0012288', (165, 170))
224269	33578572	Deregulated TGF-beta expression has been reported to play important roles in tumor occurrence and progression in many types of cancer.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('Deregulated', 'Var', (0, 11))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('expression', 'MPA', (21, 31))	('play', 'Reg', (53, 57))	('roles', 'Reg', (68, 73))	('TGF-beta', 'Gene', (12, 20))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('cancer', 'Disease', (127, 133))	('tumor', 'Disease', (77, 82))	('TGF-beta', 'Gene', '7039', (12, 20))
224272	33578572	You has reported that miRNA-495 confers inhibitory effects on cancer stem cells in oral squamous cell carcinoma through the HOXC6-mediated TGF-beta signaling pathway.	('TGF-beta', 'Gene', '7039', (139, 147))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('miRNA-495', 'Chemical', '-', (22, 31))	('HOXC6', 'Gene', '3223', (124, 129))	('HOXC6', 'Gene', (124, 129))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (88, 111))	('TGF-beta', 'Gene', (139, 147))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (88, 111))	('miRNA-495', 'Var', (22, 31))	('squamous cell carcinoma', 'Disease', (88, 111))	('inhibitory effects', 'NegReg', (40, 58))
224273	33578572	Similar to the TGF-beta signaling pathway, Hippo signaling pathway dysregulation has been shown to contribute to the development of cancer.	('dysregulation', 'Var', (67, 80))	('cancer', 'Disease', (132, 138))	('contribute', 'Reg', (99, 109))	('TGF-beta', 'Gene', (15, 23))	('Hippo signaling pathway', 'Pathway', (43, 66))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('TGF-beta', 'Gene', '7039', (15, 23))
224275	33578572	Alzahrani revealed that Hippo signaling pathway dysregulation is involved in oropharyngeal squamous cell carcinoma tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('oropharyngeal squamous cell carcinoma', 'Phenotype', 'HP:0012182', (77, 114))	('squamous cell carcinoma tumorigenesis', 'Disease', 'MESH:D002294', (91, 128))	('dysregulation', 'Var', (48, 61))	('squamous cell carcinoma tumorigenesis', 'Disease', (91, 128))	('involved', 'Reg', (65, 73))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (91, 114))	('Alzahrani', 'Chemical', '-', (0, 9))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('Hippo signaling pathway', 'Pathway', (24, 47))
224280	33578572	Therefore, we speculate that hsa-miR-410-3p, hsa-miR-411-5p, hsa-miR-125b-2-3p, hsa-miR-99a-3p have anticancer effects in HNSCC and their target genes may be potential oncogenes; however, the exact mechanism requires further investigation.	('hsa-miR-125b-2-3p', 'Var', (61, 78))	('hsa-miR-99a-3p', 'Var', (80, 94))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('hsa-miR-411', 'Gene', '693121', (45, 56))	('hsa-miR-411', 'Gene', (45, 56))	('hsa-miR-125b-2-3p', 'Chemical', '-', (61, 78))	('miR-410-3p', 'Chemical', '-', (33, 43))	('hsa-miR-410-3p', 'Var', (29, 43))	('HNSCC', 'Disease', (122, 127))	('HNSCC', 'Phenotype', 'HP:0012288', (122, 127))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))
224303	33536022	A series of functional studies demonstrated that circ-ANXA7 accelerated proliferation and invasion of LUAD cells as well as tumor growth.	('invasion of LUAD cells', 'CPA', (90, 112))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('accelerated', 'PosReg', (60, 71))	('proliferation', 'CPA', (72, 85))	('tumor', 'Disease', (124, 129))	('circ-ANXA7', 'Var', (49, 59))	('LUAD', 'Phenotype', 'HP:0030078', (102, 106))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
224355	33536022	Patients with high circ-ANXA7 expression usually indicated a poorer overall survival than those with its low expression (Fig.	('Patients', 'Species', '9606', (0, 8))	('overall survival', 'MPA', (68, 84))	('poorer', 'NegReg', (61, 67))	('high circ-ANXA7', 'Var', (14, 29))
224359	33536022	Furthermore, EdU assay results showed that relative EdU staining positive cells in the sh-circ-ANXA7 group was prominently reduced (Fig.	('sh-circ-ANXA7', 'Var', (87, 100))	('EdU', 'Chemical', 'MESH:C031086', (13, 16))	('EdU', 'Chemical', 'MESH:C031086', (52, 55))	('reduced', 'NegReg', (123, 130))
224360	33536022	Transwell invasion experiments showed that A549 and PC9 cells exhibited lower invasive ability after transfection with sh-circ-ANXA7 than the NC group (Fig.	('PC9', 'CellLine', 'CVCL:B260', (52, 55))	('sh-circ-ANXA7', 'Var', (119, 132))	('invasive ability', 'CPA', (78, 94))	('lower', 'NegReg', (72, 77))	('A549', 'CellLine', 'CVCL:0023', (43, 47))
224364	33536022	Furthermore, sh-circ-ANXA7 distinctly decreased the tumor volume of LUAD mice model (Fig.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('decreased', 'NegReg', (38, 47))	('sh-circ-ANXA7', 'Var', (13, 26))	('tumor', 'Disease', (52, 57))	('mice', 'Species', '10090', (73, 77))	('LUAD', 'Phenotype', 'HP:0030078', (68, 72))	('tumor', 'Disease', 'MESH:D009369', (52, 57))
224365	33536022	H&E and immunohistochemistry results showed that silencing circ-ANXA7 remarkedly suppressed abnormal proliferation of LUAD cells (Fig.	('silencing', 'Gene', (49, 58))	('H&E', 'Chemical', '-', (0, 3))	('that', 'Var', (44, 48))	('LUAD', 'Phenotype', 'HP:0030078', (118, 122))	('remarkedly', 'NegReg', (70, 80))
224369	33536022	In A549 cells transfected with pcDNA3.1-circ-ANXA7, miR-331 expression was distinctly decreased compared to NC group (Fig.	('expression', 'MPA', (60, 70))	('miR-331', 'Gene', '442903', (52, 59))	('A549', 'CellLine', 'CVCL:0023', (3, 7))	('miR-331', 'Gene', (52, 59))	('pcDNA3.1-circ-ANXA7', 'Var', (31, 50))	('decreased', 'NegReg', (86, 95))
224374	33536022	5a, in comparison to controls, miR-331 mimics restrained cell viability of A549 and PC9.	('cell viability of A549', 'CPA', (57, 79))	('miR-331', 'Gene', '442903', (31, 38))	('miR-331', 'Gene', (31, 38))	('PC9', 'CellLine', 'CVCL:B260', (84, 87))	('restrained', 'NegReg', (46, 56))	('mimics', 'Var', (39, 45))	('A549', 'CellLine', 'CVCL:0023', (75, 79))
224375	33536022	Furthermore, cell viability of A549 and PC9 was induced by circ-ANXA7 overexpression, which was suppressed after co-transfection with miR-331 mimics.	('cell viability', 'CPA', (13, 27))	('PC9', 'CellLine', 'CVCL:B260', (40, 43))	('overexpression', 'Var', (70, 84))	('A549', 'CellLine', 'CVCL:0023', (31, 35))	('miR-331', 'Gene', '442903', (134, 141))	('induced', 'PosReg', (48, 55))	('miR-331', 'Gene', (134, 141))	('circ-ANXA7', 'Gene', (59, 69))
224377	33536022	When transfected with pcDNA3.1-circ-ANXA7, proliferative capacity of A549 and PC9 cells was promoted, which was suppressed following co-transfection with miR-331 mimics (Fig.	('proliferative capacity', 'CPA', (43, 65))	('pcDNA3.1-circ-ANXA7', 'Var', (22, 41))	('PC9', 'CellLine', 'CVCL:B260', (78, 81))	('A549', 'CellLine', 'CVCL:0023', (69, 73))	('promoted', 'PosReg', (92, 100))	('miR-331', 'Gene', '442903', (154, 161))	('miR-331', 'Gene', (154, 161))
224379	33536022	Also, invasive ability of PC9 cells was conspicuously enhanced by pcDNA3.1-circ-ANXA7, which was inhibited after co-transfection with miR-331 mimics.	('PC9', 'CellLine', 'CVCL:B260', (26, 29))	('miR-331', 'Gene', '442903', (134, 141))	('pcDNA3.1-circ-ANXA7', 'Var', (66, 85))	('miR-331', 'Gene', (134, 141))	('enhanced', 'PosReg', (54, 62))	('invasive ability of PC9 cells', 'CPA', (6, 35))
224386	33536022	7b, proliferative ability of PC9 cells was remarkably promoted by transfection of pcDNA3.1-LAD1.	('promoted', 'PosReg', (54, 62))	('pcDNA3.1-LAD1', 'Gene', (82, 95))	('PC9', 'CellLine', 'CVCL:B260', (29, 32))	('transfection', 'Var', (66, 78))	('proliferative ability', 'CPA', (4, 25))
224387	33536022	Furthermore, transwell assay results demonstrated that pcDNA3.1-LAD1 significantly elevated the invasive capacity of PC9 cells (Fig.	('elevated', 'PosReg', (83, 91))	('PC9', 'CellLine', 'CVCL:B260', (117, 120))	('invasive capacity of PC9 cells', 'CPA', (96, 126))	('pcDNA3.1-LAD1', 'Var', (55, 68))
224388	33536022	In comparison to sh-circ-ANXA7, invasion ability of PC9 cells was distinctly elevated after co-transfection with pcDNA3.1-LAD1.	('pcDNA3.1-LAD1', 'Var', (113, 126))	('elevated', 'PosReg', (77, 85))	('PC9', 'CellLine', 'CVCL:B260', (52, 55))	('invasion ability', 'CPA', (32, 48))
224401	33536022	More importantly, in vivo, silencing circ-ANXA7 distinctly inhibited tumor growth.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('silencing', 'Var', (27, 36))	('tumor', 'Disease', (69, 74))	('inhibited', 'NegReg', (59, 68))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('circ-ANXA7', 'Gene', (37, 47))
224407	33536022	Circulating miR-331-3p possesses underlying potential for early diagnosing and supervising of lung cancer.	('lung cancer', 'Disease', 'MESH:D008175', (94, 105))	('miR-331-3p', 'Chemical', '-', (12, 22))	('lung cancer', 'Disease', (94, 105))	('lung cancer', 'Phenotype', 'HP:0100526', (94, 105))	('miR-331-3p', 'Var', (12, 22))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
224408	33536022	miR-331-3p has been identified to be down-regulated in NSCLC, which could be an independent prognostic factor.	('miR-331-3p', 'Chemical', '-', (0, 10))	('NSCLC', 'Disease', (55, 60))	('miR-331-3p', 'Var', (0, 10))	('NSCLC', 'Disease', 'MESH:D002289', (55, 60))	('NSCLC', 'Phenotype', 'HP:0030358', (55, 60))	('down-regulated', 'NegReg', (37, 51))
224409	33536022	miR-331-3p could distinctly suppress invasion and metastasis of NSCLC cells.	('suppress', 'NegReg', (28, 36))	('miR-331-3p', 'Chemical', '-', (0, 10))	('NSCLC', 'Disease', 'MESH:D002289', (64, 69))	('miR-331-3p', 'Var', (0, 10))	('NSCLC', 'Phenotype', 'HP:0030358', (64, 69))	('NSCLC', 'Disease', (64, 69))
224410	33536022	Furthermore, miR-331-3p could be sponged by circ-0001649 in NSCLC.	('miR-331-3p', 'Var', (13, 23))	('NSCLC', 'Phenotype', 'HP:0030358', (60, 65))	('miR-331-3p', 'Chemical', '-', (13, 23))	('NSCLC', 'Disease', (60, 65))	('NSCLC', 'Disease', 'MESH:D002289', (60, 65))
224416	33536022	Further studies verified that circ-ANXA7 could induce proliferation and invasion of LUAD cells and promote tumor growth.	('induce', 'PosReg', (47, 53))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('circ-ANXA7', 'Var', (30, 40))	('promote', 'PosReg', (99, 106))	('LUAD', 'Phenotype', 'HP:0030078', (84, 88))	('proliferation', 'CPA', (54, 67))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('invasion of LUAD cells', 'CPA', (72, 94))
224419	33536022	Besides, circ-ANXA7 knockdown suppressed tumor growth.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('suppressed', 'NegReg', (30, 40))	('tumor', 'Disease', (41, 46))	('knockdown', 'Var', (20, 29))	('tumor', 'Disease', 'MESH:D009369', (41, 46))
224426	33210069	One study reported that nonsmokers had significantly fewer TP53 mutations, while 9 studies found no difference in the prevalence of TP53 mutations.	('TP53', 'Gene', (59, 63))	('TP53', 'Gene', '7157', (132, 136))	('fewer', 'NegReg', (53, 58))	('TP53', 'Gene', (132, 136))	('mutations', 'Var', (64, 73))	('TP53', 'Gene', '7157', (59, 63))
224427	33210069	TP53 mutations may occur at a similar rate in YLERs with OCSCC as compared with older patients or those with risk factors.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))	('OCSCC', 'Disease', (57, 62))	('patients', 'Species', '9606', (86, 94))
224447	33210069	Ten studies showed negative evidence for increased TP53 gene mutations in YLERs with OCSCC; 1 showed experimental evidence for other genetic alterations in YLERs with OCSCC; and 2 had genetic evidence in OCSCC-related disease.	('increased', 'PosReg', (41, 50))	('TP53', 'Gene', (51, 55))	('men', 'Species', '9606', (107, 110))	('mutations', 'Var', (61, 70))	('OCSCC', 'Disease', (85, 90))	('TP53', 'Gene', '7157', (51, 55))
224450	33210069	Two studies revealed that YLERs did not have mutations in exons 5 to 9 of TP53, whereas older smokers had mutations in this region.	('mutations', 'Var', (45, 54))	('TP53', 'Gene', '7157', (74, 78))	('TP53', 'Gene', (74, 78))
224451	33210069	However, 2 studies identified mutations within this region of TP53.	('TP53', 'Gene', '7157', (62, 66))	('mutations', 'Var', (30, 39))	('TP53', 'Gene', (62, 66))
224454	33210069	Krishnan et al reported that TP53 mutations were similar among YLERs and their counterparts, but they reported a 20% lower TP53 mutational frequency (somatic mutation frequency per megabase) in the nonsmoking group across all ages.	('mutational', 'Var', (128, 138))	('lower', 'NegReg', (117, 122))	('TP53', 'Gene', '7157', (29, 33))	('TP53', 'Gene', (29, 33))	('TP53', 'Gene', '7157', (123, 127))	('TP53', 'Gene', (123, 127))
224456	33210069	When comparing expression of p53 with mutations in TP53, 1 study noted that 81% of YLERs with OCSCC overexpressed p53 by immunohistochemistry and that the pattern of overexpression was highly correlated with the histologic grade of the tumor, despite not finding any TP53 mutations in the targeted region, exons 5 to 9, where 92% of TP53 mutations typically occur.	('TP53', 'Gene', '7157', (51, 55))	('p53', 'Gene', (114, 117))	('TP53', 'Gene', (51, 55))	('TP53', 'Gene', (333, 337))	('p53', 'Gene', '7157', (114, 117))	('tumor', 'Disease', 'MESH:D009369', (236, 241))	('p53', 'Gene', (29, 32))	('TP53', 'Gene', '7157', (267, 271))	('tumor', 'Phenotype', 'HP:0002664', (236, 241))	('correlated', 'Reg', (192, 202))	('p53', 'Gene', '7157', (29, 32))	('mutations', 'Var', (38, 47))	('tumor', 'Disease', (236, 241))	('TP53', 'Gene', (267, 271))	('TP53', 'Gene', '7157', (333, 337))
224458	33210069	One study revealed that nonsmokers had significantly fewer TP53 mutations when compared with smokers.	('TP53', 'Gene', '7157', (59, 63))	('fewer', 'NegReg', (53, 58))	('mutations', 'Var', (64, 73))	('TP53', 'Gene', (59, 63))
224459	33210069	We were able to obtain demographic data on the 6 never-smokers: 5 of the 6 were <=50 years old, 1 of whom had a TP53 mutation.	('mutation', 'Var', (117, 125))	('TP53', 'Gene', '7157', (112, 116))	('TP53', 'Gene', (112, 116))
224460	33210069	In contrast, all 5 sequenced smokers had TP53 mutations.	('TP53', 'Gene', '7157', (41, 45))	('TP53', 'Gene', (41, 45))	('mutations', 'Var', (46, 55))
224461	33210069	Never-smokers had significantly fewer TP53 mutations than smokers.	('TP53', 'Gene', (38, 42))	('TP53', 'Gene', '7157', (38, 42))	('mutations', 'Var', (43, 52))	('fewer', 'NegReg', (32, 37))
224464	33210069	The authors found no evidence of HPV-16 infection or FANC-C IVSF-4+ mutations in any of the nonsmoker samples.	('FANC-C', 'Gene', (53, 59))	('HPV-16 infection', 'Disease', 'MESH:D030361', (33, 49))	('IVSF-4+', 'Gene', (60, 67))	('mutations', 'Var', (68, 77))	('HPV-16 infection', 'Disease', (33, 49))
224465	33210069	Li et al reported distinct mutational spectrums between the cohorts, with a greater proportion of C:G>G:C transversions in cancers from nonsmokers (P < .0001) and A:T>G:C (P < .0001) or A:T>T:A substitutions (P < .0001) among smokers.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('transversions', 'Var', (106, 119))	('A:T>G:C', 'Var', (163, 170))	('A:T>T:A substitutions', 'Var', (186, 207))	('cancers', 'Disease', 'MESH:D009369', (123, 130))	('cancers', 'Phenotype', 'HP:0002664', (123, 130))	('cancers', 'Disease', (123, 130))	('C:G>G:C transversions', 'Var', (98, 119))
224469	33210069	The rate of TP53 mutations is overall similar between YLERs with OTSCC and older smoking patients with OTSCC.	('TP53', 'Gene', '7157', (12, 16))	('TP53', 'Gene', (12, 16))	('patients', 'Species', '9606', (89, 97))	('mutations', 'Var', (17, 26))
224470	33210069	Our findings do differ somewhat from prior studies indicating that TP53 mutations may be less predominant among nonsmokers with head and neck squamous cell carcinoma (HNSCC).	('mutations', 'Var', (72, 81))	('carcinoma', 'Phenotype', 'HP:0030731', (156, 165))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (142, 165))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (137, 165))	('TP53', 'Gene', '7157', (67, 71))	('TP53', 'Gene', (67, 71))	('neck squamous cell carcinoma', 'Disease', (137, 165))
224471	33210069	Of 10 studies evaluating TP53 mutations in this population, only 1 reported significantly fewer TP53 mutations among never-smokers.	('TP53', 'Gene', (25, 29))	('mutations', 'Var', (101, 110))	('TP53', 'Gene', (96, 100))	('fewer', 'NegReg', (90, 95))	('TP53', 'Gene', '7157', (25, 29))	('TP53', 'Gene', '7157', (96, 100))
224472	33210069	However, it is also possible that the TP53 mutations found in this cohort differ from those typically seen in other HNSCCs.	('HNSCCs', 'Disease', 'MESH:D000077195', (116, 122))	('TP53', 'Gene', (38, 42))	('mutations', 'Var', (43, 52))	('HNSCCs', 'Disease', (116, 122))	('TP53', 'Gene', '7157', (38, 42))
224473	33210069	For instance, several studies suggest that TP53 mutations in this population may be occurring in locations other than those traditionally seen in HNSCC.	('TP53', 'Gene', '7157', (43, 47))	('TP53', 'Gene', (43, 47))	('occurring', 'Reg', (84, 93))	('mutations', 'Var', (48, 57))
224474	33210069	Although it was previously shown that almost all TP53 mutations seen in HNSCC occur within exons 5 to 9, multiple studies included in our review found mutations either to be absent or outside this region.	('TP53', 'Gene', (49, 53))	('mutations', 'Var', (54, 63))	('TP53', 'Gene', '7157', (49, 53))
224475	33210069	In fact, Singh and colleagues found that exon 4 was the most commonly mutated exon, and they identified several novel TP53 mutations, many occurring outside predetermined "hot spots."	('TP53', 'Gene', '7157', (118, 122))	('TP53', 'Gene', (118, 122))	('mutations', 'Var', (123, 132))
224477	33210069	One study reported a higher rate of truncating-type TP53 mutations in younger patients.	('TP53', 'Gene', '7157', (52, 56))	('truncating-type', 'Var', (36, 51))	('patients', 'Species', '9606', (78, 86))	('TP53', 'Gene', (52, 56))	('mutations', 'Var', (57, 66))
224480	33210069	Overall, it appears that TP53 mutations are present at similar rates in YLERs with OTSCC, though clinical history and associated mutational spectra suggest an underlying mechanism unrelated to direct carcinogen exposure that has yet to be ascertained.	('mutations', 'Var', (30, 39))	('TP53', 'Gene', (25, 29))	('TP53', 'Gene', '7157', (25, 29))
224488	33210069	A study not included in our review found increased rates of LOH in distal regions of chromosome 17p, home to TP53, and other loci in YLERs, which have been linked to driving the transition from hyperplasia to dysplasia in HNSCC.	('hyperplasia to dysplasia', 'Disease', (194, 218))	('hyperplasia to dysplasia', 'Disease', 'MESH:D006965', (194, 218))	('TP53', 'Gene', '7157', (109, 113))	('TP53', 'Gene', (109, 113))	('LOH', 'Var', (60, 63))
224492	33210069	For instance, Asian patients with OTSCC were found to have mutations in genes such as DST, RNF213, STK-11, and BRAF, whereas the largely North American cohort represented in The Cancer Genome Atlas had more frequent mutations in TP53, CDKN2A, and NOTCH1.	('CDKN2A', 'Gene', (235, 241))	('STK-11', 'Gene', '6794', (99, 105))	('NOTCH1', 'Gene', '4851', (247, 253))	('Cancer', 'Phenotype', 'HP:0002664', (178, 184))	('RNF213', 'Gene', '57674', (91, 97))	('mutations', 'Var', (216, 225))	('BRAF', 'Gene', '673', (111, 115))	('BRAF', 'Gene', (111, 115))	('RNF213', 'Gene', (91, 97))	('STK-11', 'Gene', (99, 105))	('Cancer', 'Disease', (178, 184))	('CDKN2A', 'Gene', '1029', (235, 241))	('TP53', 'Gene', '7157', (229, 233))	('patients', 'Species', '9606', (20, 28))	('Cancer', 'Disease', 'MESH:D009369', (178, 184))	('DST', 'Gene', '667', (86, 89))	('OTSCC', 'Disease', (34, 39))	('DST', 'Gene', (86, 89))	('mutations', 'Var', (59, 68))	('NOTCH1', 'Gene', (247, 253))	('TP53', 'Gene', (229, 233))
224506	33210069	Our review suggests that TP53 mutations in YLERs with OTSCC likely occur at a rate similar to that in the "traditional" cohort of older smokers, and no additional genetic mutations were found to be specific to this cohort.	('mutations', 'Var', (30, 39))	('TP53', 'Gene', (25, 29))	('TP53', 'Gene', '7157', (25, 29))
224512	32547080	However, the mechanisms and biological function of miR-181c-5p in cervical squamous cell carcinoma (SCC) have not been well elucidated.	('SCC', 'Gene', (100, 103))	('cervical squamous cell carcinoma', 'Disease', 'MESH:D002294', (66, 98))	('SCC', 'Phenotype', 'HP:0002860', (100, 103))	('cervical squamous cell carcinoma', 'Disease', (66, 98))	('SCC', 'Gene', '6317', (100, 103))	('miR-181c-5p', 'Chemical', '-', (51, 62))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (75, 98))	('miR-181c-5p', 'Var', (51, 62))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('CC', 'Phenotype', 'HP:0002664', (101, 103))
224514	32547080	Targetscan was used to predict the binding site of miR-181c-5p and GSKIP.	('binding', 'Interaction', (35, 42))	('GSKIP', 'Gene', '51527', (67, 72))	('miR-181c-5p', 'Chemical', '-', (51, 62))	('miR-181c-5p', 'Var', (51, 62))	('GSKIP', 'Gene', (67, 72))
224517	32547080	GSKIP was predicted to be the target gene of miR-181c-5p in cervical SCC.	('GSKIP', 'Gene', (0, 5))	('SCC', 'Gene', (69, 72))	('miR-181c-5p', 'Chemical', '-', (45, 56))	('SCC', 'Phenotype', 'HP:0002860', (69, 72))	('SCC', 'Gene', '6317', (69, 72))	('miR-181c-5p', 'Var', (45, 56))	('GSKIP', 'Gene', '51527', (0, 5))	('CC', 'Phenotype', 'HP:0002664', (70, 72))
224518	32547080	MiR-181c-5p overexpression suppressed SiHa cells proliferation and promoted apoptosis; the protein expressions of Ki67 and PCNA were decreased, but the expressions of Caspase-3 and Bax/Bcl-2 were increased.	('Ki67', 'Gene', (114, 118))	('PCNA', 'Gene', '5111', (123, 127))	('Caspase-3', 'Gene', (167, 176))	('protein expressions', 'MPA', (91, 110))	('increased', 'PosReg', (196, 205))	('SiHa cells proliferation', 'CPA', (38, 62))	('apoptosis', 'CPA', (76, 85))	('Bcl-2', 'Gene', (185, 190))	('decreased', 'NegReg', (133, 142))	('MiR-181c-5p', 'Chemical', '-', (0, 11))	('Bax', 'Gene', (181, 184))	('Bcl-2', 'Gene', '596', (185, 190))	('Caspase-3', 'Gene', '836', (167, 176))	('PCNA', 'Gene', (123, 127))	('promoted', 'PosReg', (67, 75))	('MiR-181c-5p', 'Var', (0, 11))	('Bax', 'Gene', '581', (181, 184))	('SiHa', 'CellLine', 'CVCL:0032', (38, 42))	('suppressed', 'NegReg', (27, 37))	('expressions', 'MPA', (152, 163))
224519	32547080	The overexpression of miR-181c-5p inhibited the stem-like properties of SiHa cells; the expressions of SOX2, OCT4 and CD44 were decreased.	('expressions', 'MPA', (88, 99))	('CD44', 'Gene', '960', (118, 122))	('SOX2', 'Gene', (103, 107))	('CD44', 'Gene', (118, 122))	('SOX2', 'Gene', '6657', (103, 107))	('inhibited', 'NegReg', (34, 43))	('OCT4', 'Gene', '5460', (109, 113))	('OCT4', 'Gene', (109, 113))	('decreased', 'NegReg', (128, 137))	('SiHa', 'CellLine', 'CVCL:0032', (72, 76))	('overexpression', 'PosReg', (4, 18))	('stem-like properties of SiHa cells', 'CPA', (48, 82))	('miR-181c-5p', 'Chemical', '-', (22, 33))	('miR-181c-5p', 'Var', (22, 33))
224520	32547080	Furthermore, miR-181c-5p upregulation limited the invasion of SiHa cells; the expression of E-cadherin was higher, but the expressions of N-cadherin and Vimentin were lower.	('lower', 'NegReg', (167, 172))	('expression', 'MPA', (78, 88))	('expressions', 'MPA', (123, 134))	('miR-181c-5p', 'Chemical', '-', (13, 24))	('E-cadherin', 'Gene', (92, 102))	('E-cadherin', 'Gene', '999', (92, 102))	('miR-181c-5p', 'Var', (13, 24))	('limited', 'NegReg', (38, 45))	('SiHa', 'CellLine', 'CVCL:0032', (62, 66))	('invasion of SiHa cells', 'CPA', (50, 72))	('N-cadherin', 'Gene', (138, 148))	('higher', 'PosReg', (107, 113))	('N-cadherin', 'Gene', '1000', (138, 148))	('upregulation', 'PosReg', (25, 37))
224521	32547080	MiR-181c-5p overexpression inhibited tumorigenesis in cervical SCC tissues; the expressions of Ki67, Caspase-3, CD44 and Vimentin in vivo were consistent with those in vitro.	('overexpression', 'PosReg', (12, 26))	('MiR-181c-5p', 'Var', (0, 11))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('CD44', 'Gene', '960', (112, 116))	('SCC', 'Gene', (63, 66))	('CC', 'Phenotype', 'HP:0002664', (64, 66))	('SCC', 'Phenotype', 'HP:0002860', (63, 66))	('Caspase-3', 'Gene', '836', (101, 110))	('MiR-181c-5p', 'Chemical', '-', (0, 11))	('Caspase-3', 'Gene', (101, 110))	('CD44', 'Gene', (112, 116))	('tumor', 'Disease', (37, 42))	('Ki67', 'Gene', (95, 99))	('SCC', 'Gene', '6317', (63, 66))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('inhibited', 'NegReg', (27, 36))
224522	32547080	Taken together, miR-181c-5p was able to mitigate the cancer cell characteristic and invasive properties of cervical SCC through targeting GSKIP gene.	('SCC', 'Gene', (116, 119))	('invasive properties', 'CPA', (84, 103))	('SCC', 'Phenotype', 'HP:0002860', (116, 119))	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('GSKIP', 'Gene', (138, 143))	('SCC', 'Gene', '6317', (116, 119))	('CC', 'Phenotype', 'HP:0002664', (117, 119))	('mitigate', 'NegReg', (40, 48))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('miR-181c-5p', 'Chemical', '-', (16, 27))	('thr', 'Chemical', 'MESH:D013912', (120, 123))	('targeting', 'Reg', (128, 137))	('miR-181c-5p', 'Var', (16, 27))	('GSKIP', 'Gene', '51527', (138, 143))
224526	32547080	Epidemiological studies have reported that more than 99% of patients with cervical SCC are positive for high-risk HPV (HPV16, HPV18 and HPV31).	('HPV', 'Species', '333760', (136, 139))	('HPV31', 'Var', (136, 141))	('HPV', 'Species', '333760', (126, 129))	('SCC', 'Gene', (83, 86))	('patients', 'Species', '9606', (60, 68))	('HPV16', 'Species', '333760', (119, 124))	('HPV16', 'Var', (119, 124))	('CC', 'Phenotype', 'HP:0002664', (84, 86))	('HPV', 'Species', '333760', (114, 117))	('SCC', 'Phenotype', 'HP:0002860', (83, 86))	('SCC', 'Gene', '6317', (83, 86))	('HPV', 'Species', '333760', (119, 122))	('positive', 'Reg', (91, 99))
224530	32547080	Previous studies have reported that miRNAs affected multiple biological pathways of cervical cancer, by analyzing 246 dysregulated miRNAs and 40 confirmed CC target genes.	('affected', 'Reg', (43, 51))	('cervical cancer', 'Disease', 'MESH:D002583', (84, 99))	('cervical cancer', 'Disease', (84, 99))	('miRNAs', 'Var', (36, 42))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('CC', 'Phenotype', 'HP:0002664', (155, 157))	('biological pathways', 'Pathway', (61, 80))
224531	32547080	Evidences have indicated that miR-181 family contains four highly conserved mature miRNAs: miR-181a, miR -181b, miR -181c and miR -181d, which come from six precursors on three different chromosomes.	('miR-181a', 'Var', (91, 99))	('miR -181b', 'Var', (101, 110))	('miR -181d', 'Gene', '574457', (126, 135))	('miR -181c', 'Gene', (112, 121))	('miR -181c', 'Gene', '406957', (112, 121))	('ser', 'Chemical', 'MESH:D012694', (69, 72))	('miR -181d', 'Gene', (126, 135))	('thr', 'Chemical', 'MESH:D013912', (171, 174))
224532	32547080	MiR-181a-1 and miR-181b-1 are located on chromosome 1, miR-181a-2 and miR-181b-2 on chromosome 9, and miR-181c and miR-181d on chromosome 19.	('miR-181b-1', 'Gene', (15, 25))	('miR-181a-2', 'Gene', (55, 65))	('miR-181d', 'Gene', (115, 123))	('miR-181b-2', 'Gene', '406956', (70, 80))	('MiR-181a-1', 'Gene', '406995', (0, 10))	('miR-181a-2', 'Gene', '406954', (55, 65))	('miR-181d', 'Gene', '574457', (115, 123))	('MiR-181a-1', 'Gene', (0, 10))	('miR-181c', 'Var', (102, 110))	('miR-181b-1', 'Gene', '406955', (15, 25))	('miR-181b-2', 'Gene', (70, 80))
224533	32547080	Studies have found that the aberrant expression of miR-181s in tumor tissues suggest a crucial role in cancer development and progression.	('tumor', 'Disease', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('miR-181s', 'Gene', (51, 59))	('aberrant', 'Var', (28, 36))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))
224539	32547080	MiR-150-5p significantly inhibited Wnt/beta-catenin signaling by simultaneously targeting GSKIP and beta-catenin in NSCLC cells.	('NSCLC', 'Disease', 'MESH:D002289', (116, 121))	('beta-catenin', 'Gene', (100, 112))	('GSKIP', 'Gene', '51527', (90, 95))	('beta-catenin', 'Gene', '1499', (100, 112))	('MiR-150-5p', 'Var', (0, 10))	('MiR-150-5p', 'Chemical', '-', (0, 10))	('inhibited', 'NegReg', (25, 34))	('beta-catenin', 'Gene', (39, 51))	('GSKIP', 'Gene', (90, 95))	('NSCLC', 'Disease', (116, 121))	('beta-catenin', 'Gene', '1499', (39, 51))	('targeting', 'Reg', (80, 89))
224540	32547080	However, the role of miR-181c-5p in cervical SCC has been rarely reported.	('SCC', 'Gene', (45, 48))	('miR-181c-5p', 'Chemical', '-', (21, 32))	('SCC', 'Phenotype', 'HP:0002860', (45, 48))	('SCC', 'Gene', '6317', (45, 48))	('miR-181c-5p', 'Var', (21, 32))	('CC', 'Phenotype', 'HP:0002664', (46, 48))
224553	32547080	Targets between GSKIP and miR-181c-5p were speculated by Targetscan7.0 (http://www.targetscan.org).	('GSKIP', 'Gene', '51527', (16, 21))	('miR-181c-5p', 'Var', (26, 37))	('GSKIP', 'Gene', (16, 21))	('miR-181c-5p', 'Chemical', '-', (26, 37))
224560	32547080	After being blocked by 5% skim milk, proteins were incubated with the primary antibodies overnight at 4  C. The primary antibodies were as follows: Ki67 (sc-23900, 1:1000 Santa Cruz Biotechnology, USA), PCNA (#2586, 1:1000, CST, USA), cleaved caspase-3 (#9660, 1:1000, CST, USA), Bcl-2 (#13-8800, 1 microg/mL, invitrogen, USA), Bax (#2772,1:1000, CST, USA), SOX2 (#2748, 1:1000, CST, USA), OCT4 (#2750, 1:1000, CST, USA), CD44 (#3578, 1:1000, CST, USA), E-cadherin (#14472, 1:1000, CST, USA), N-cadherin (#14215, 1:1000, CST, USA), Vimentin (#39325, 1:1000, CST, USA) and GAPDH (#97166, 1:1000, CST, USA).	('#14472', 'Var', (466, 472))	('CST', 'Gene', (521, 524))	('CST', 'Gene', '106478911', (224, 227))	('CD44', 'Gene', '960', (422, 426))	('OCT4', 'Gene', (390, 394))	('CST', 'Gene', (558, 561))	('CD44', 'Gene', (422, 426))	('Bax', 'Gene', (328, 331))	('CST', 'Gene', '106478911', (443, 446))	('GAPDH', 'Gene', '2597', (572, 577))	('PCNA', 'Gene', '5111', (203, 207))	('CST', 'Gene', '106478911', (269, 272))	('Bax', 'Gene', '581', (328, 331))	('SOX2', 'Gene', '6657', (358, 362))	('CST', 'Gene', '106478911', (379, 382))	('SOX2', 'Gene', (358, 362))	('#14215', 'Var', (505, 511))	('CST', 'Gene', '106478911', (595, 598))	('CST', 'Gene', '106478911', (482, 485))	('#3578', 'Var', (428, 433))	('#97166', 'Var', (579, 585))	('CST', 'Gene', (224, 227))	('N-cadherin', 'Gene', (493, 503))	('GAPDH', 'Gene', (572, 577))	('CST', 'Gene', '106478911', (411, 414))	('caspase-3', 'Gene', '836', (243, 252))	('N-cadherin', 'Gene', '1000', (493, 503))	('CST', 'Gene', (443, 446))	('CST', 'Gene', '106478911', (347, 350))	('#39325', 'Var', (542, 548))	('caspase-3', 'Gene', (243, 252))	('CST', 'Gene', (269, 272))	('CST', 'Gene', '106478911', (521, 524))	('CST', 'Gene', (379, 382))	('Bcl-2', 'Gene', (280, 285))	('CST', 'Gene', (595, 598))	('E-cadherin', 'Gene', (454, 464))	('CST', 'Gene', (482, 485))	('Vimentin', 'Protein', (532, 540))	('E-cadherin', 'Gene', '999', (454, 464))	('CST', 'Gene', '106478911', (558, 561))	('OCT4', 'Gene', '5460', (390, 394))	('CST', 'Gene', (411, 414))	('PCNA', 'Gene', (203, 207))	('CST', 'Gene', (347, 350))	('Bcl-2', 'Gene', '596', (280, 285))
224561	32547080	Then, the samples were washed with PBS and incubated with anti-rabbit IgG (#7074, 1:2000, CST, USA) and anti-biotin HRP-linked Antibody (#7074, 1:1000, CST, USA) for 1h.	('CST', 'Gene', '106478911', (90, 93))	('CST', 'Gene', '106478911', (152, 155))	('#7074', 'Var', (75, 80))	('PBS', 'Chemical', 'MESH:D007854', (35, 38))	('CST', 'Gene', (90, 93))	('#7074', 'Var', (137, 142))	('CST', 'Gene', (152, 155))	('1h', 'Chemical', '-', (166, 168))
224565	32547080	SiHa cells (purchased from Procell BioTech Inc., China) transfected with miR-181c-5p mimic were subcutaneously injected into the right thigh to form xenograft tumors.	('miR-181c-5p mimic', 'Var', (73, 90))	('SiHa', 'CellLine', 'CVCL:0032', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('tumors', 'Disease', (159, 165))	('tumors', 'Phenotype', 'HP:0002664', (159, 165))	('miR-181c-5p', 'Chemical', '-', (73, 84))	('tumors', 'Disease', 'MESH:D009369', (159, 165))
224569	32547080	After dewaxing, rehydration and repair, the paraffin section was sealed with 5% normal goat serum for 1h and co-cultured with primary antibodies Ki67 (#9449S, 1:400, CST, USA), cleaved caspase-3 (#9661, 1:200, CST, USA), CD44 (#3570, 1:50, CST, USA), Vimentin (#5741, 1:200, CST, USA) overnight at 4  C. Sections were then washed with TBST and incubated with SignalStain  Boost IHC Detection Reagent (#8125, CST, USA) for 30 min at room temperature.	('CST', 'Gene', '106478911', (240, 243))	('#5741', 'Var', (261, 266))	('#8125', 'Var', (401, 406))	('CD44', 'Gene', (221, 225))	('CST', 'Gene', (408, 411))	('caspase-3', 'Gene', '836', (185, 194))	('CST', 'Gene', '106478911', (210, 213))	('1h', 'Chemical', '-', (102, 104))	('CST', 'Gene', '106478911', (166, 169))	('CST', 'Gene', (210, 213))	('CST', 'Gene', (275, 278))	('ser', 'Chemical', 'MESH:D012694', (92, 95))	('CST', 'Gene', (240, 243))	('caspase-3', 'Gene', (185, 194))	('CST', 'Gene', '106478911', (408, 411))	('CST', 'Gene', (166, 169))	('CD44', 'Gene', '960', (221, 225))	('CST', 'Gene', '106478911', (275, 278))
224571	32547080	As shown in Figure 1, we detected the expression level of miR-181c-5p in Ect/E6E7 (cervical immobilized cell line), Hela (cervical cancer cell line), SiHa (cervical squamous cell carcinoma cell line), HEC-1-A (endometrial adenocarcinoma cell line), and ME-180 (cervical epidermal cancer cell line).	('cancer', 'Disease', (280, 286))	('cervical squamous cell carcinoma', 'Disease', 'MESH:D002294', (156, 188))	('cancer', 'Phenotype', 'HP:0002664', (280, 286))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('endometrial adenocarcinoma', 'Phenotype', 'HP:0012114', (210, 236))	('miR-181c-5p', 'Chemical', '-', (58, 69))	('Hela', 'CellLine', 'CVCL:0030', (116, 120))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (165, 188))	('endometrial adenocarcinoma', 'Disease', (210, 236))	('cancer', 'Disease', 'MESH:D009369', (280, 286))	('Ect', 'Gene', '100379198', (73, 76))	('endometrial adenocarcinoma', 'Disease', 'MESH:D016889', (210, 236))	('carcinoma', 'Phenotype', 'HP:0030731', (179, 188))	('cancer', 'Disease', (131, 137))	('carcinoma', 'Phenotype', 'HP:0030731', (227, 236))	('SiHa', 'CellLine', 'CVCL:0032', (150, 154))	('Ect', 'Gene', (73, 76))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('HEC-1', 'CellLine', 'CVCL:1274', (201, 206))	('cervical cancer', 'Disease', 'MESH:D002583', (122, 137))	('miR-181c-5p', 'Var', (58, 69))	('cervical squamous cell carcinoma', 'Disease', (156, 188))	('cervical cancer', 'Disease', (122, 137))
224572	32547080	The results showed that miR-181c-5p was down-regulated in all tumor cell lines, especially in SiHa cell line, compared with that in the normal Ect/E6E7 cell line.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', (62, 67))	('miR-181c-5p', 'Chemical', '-', (24, 35))	('miR-181c-5p', 'Var', (24, 35))	('Ect', 'Gene', '100379198', (143, 146))	('SiHa', 'CellLine', 'CVCL:0032', (94, 98))	('Ect', 'Gene', (143, 146))	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('down-regulated', 'NegReg', (40, 54))
224574	32547080	Bioinformatics software predicted that the putative target gene of miR181c-5p might be GSKIP, and that the binding site of miR-181c-5p and GSKIP was on the position 664-671 of GSKIP 3'UTR (Figure 2A).	('GSKIP', 'Gene', '51527', (176, 181))	('miR-181c-5p', 'Chemical', '-', (123, 134))	('GSKIP', 'Gene', '51527', (87, 92))	('miR-181c-5p', 'Var', (123, 134))	('GSKIP', 'Gene', '51527', (139, 144))	('GSKIP', 'Gene', (176, 181))	('GSKIP', 'Gene', (87, 92))	('miR181c', 'Gene', '406957', (67, 74))	('GSKIP', 'Gene', (139, 144))	('miR181c', 'Gene', (67, 74))
224576	32547080	The relative expression levels of miR-181c-5p and GSKIP mRNA were detected by qRT-PCR.	('GSKIP', 'Gene', (50, 55))	('miR-181c-5p', 'Chemical', '-', (34, 45))	('GSKIP', 'Gene', '51527', (50, 55))	('miR-181c-5p', 'Var', (34, 45))
224577	32547080	The results suggested that the relative level of miR-181c-5p in the mimic group was significantly increased; but the relative level of GSKIP mRNA in the mimic group was obviously decreased compared with that in the control group (Figure 2B).	('decreased', 'NegReg', (179, 188))	('GSKIP', 'Gene', '51527', (135, 140))	('GSKIP', 'Gene', (135, 140))	('miR-181c-5p', 'Chemical', '-', (49, 60))	('miR-181c-5p', 'Var', (49, 60))
224581	32547080	Thus, miR-181c-5p significantly offset the overexpression of GSKIP.	('GSKIP', 'Gene', (61, 66))	('overexpression', 'MPA', (43, 57))	('miR-181c-5p', 'Chemical', '-', (6, 17))	('miR-181c-5p', 'Var', (6, 17))	('GSKIP', 'Gene', '51527', (61, 66))	('offset', 'NegReg', (32, 38))
224583	32547080	The result demonstrated that, in the GSKIP wild type, the luciferase activity was significantly reduced after the addition of miR-181c-5p mimic; but in the GSKIP mutation type, there was no obvious change in the luciferase activity even if miR-181c-5p mimic was added.	('activity', 'MPA', (69, 77))	('activity', 'MPA', (223, 231))	('GSKIP', 'Gene', '51527', (37, 42))	('miR-181c-5p', 'Chemical', '-', (126, 137))	('miR-181c-5p', 'Var', (126, 137))	('GSKIP', 'Gene', '51527', (156, 161))	('miR-181c-5p', 'Chemical', '-', (240, 251))	('luciferase', 'Enzyme', (58, 68))	('luciferase', 'Enzyme', (212, 222))	('GSKIP', 'Gene', (156, 161))	('GSKIP', 'Gene', (37, 42))	('reduced', 'NegReg', (96, 103))
224584	32547080	In summary, these data indicated that miR-181c-5p directly targeted the 3'UTR of the GSKIP gene in cervical squamous carcinoma cells (Figure 2D).	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('GSKIP', 'Gene', (85, 90))	('miR-181c-5p', 'Chemical', '-', (38, 49))	('targeted', 'Reg', (59, 67))	('miR-181c-5p', 'Var', (38, 49))	('squamous carcinoma', 'Disease', 'MESH:D002294', (108, 126))	('squamous carcinoma', 'Disease', (108, 126))	('GSKIP', 'Gene', '51527', (85, 90))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (108, 126))
224588	32547080	The results showed that the expressions of Ki67 and PCNAof the mimic group were decreased and those of Caspase-3 and Bax/bcl-2 were increased, both of which compared with those of the control group; The expressions of Ki67 and PCNA of the pc-GSKIP group were greatly increased and those of Caspase-3 and Bax/bcl-2 were greatly decreased, both of which compared with those of the control group.	('Ki67', 'Var', (218, 222))	('Caspase-3', 'Gene', (290, 299))	('Bax', 'Gene', (304, 307))	('decreased', 'NegReg', (327, 336))	('increased', 'PosReg', (267, 276))	('Bax', 'Gene', '581', (304, 307))	('bcl-2', 'Gene', '596', (121, 126))	('GSKIP', 'Gene', (242, 247))	('PCNA', 'Gene', '5111', (227, 231))	('PCNA', 'Gene', '5111', (52, 56))	('bcl-2', 'Gene', (308, 313))	('Caspase-3', 'Gene', (103, 112))	('GSKIP', 'Gene', '51527', (242, 247))	('Caspase-3', 'Gene', '836', (290, 299))	('bcl-2', 'Gene', '596', (308, 313))	('expressions', 'MPA', (203, 214))	('Bax', 'Gene', (117, 120))	('Bax', 'Gene', '581', (117, 120))	('Caspase-3', 'Gene', '836', (103, 112))	('bcl-2', 'Gene', (121, 126))	('PCNA', 'Gene', (227, 231))	('PCNA', 'Gene', (52, 56))
224589	32547080	In the mimic+ pc-GSKIP group, Ki67and PCNA were obviously decreased and Caspase-3 and Bax/Bcl-2 were significantly increased, both of which compared with those of the pc-GSKIP group (Figure 3C).	('Bax', 'Gene', '581', (86, 89))	('Bcl-2', 'Gene', (90, 95))	('GSKIP', 'Gene', (17, 22))	('increased', 'PosReg', (115, 124))	('decreased', 'NegReg', (58, 67))	('Bcl-2', 'Gene', '596', (90, 95))	('PCNA', 'Gene', (38, 42))	('Caspase-3', 'Gene', (72, 81))	('GSKIP', 'Gene', '51527', (170, 175))	('Caspase-3', 'Gene', '836', (72, 81))	('PCNA', 'Gene', '5111', (38, 42))	('GSKIP', 'Gene', (170, 175))	('Bax', 'Gene', (86, 89))	('GSKIP', 'Gene', '51527', (17, 22))	('Ki67and', 'Var', (30, 37))
224590	32547080	All the above experiments indicated that miR-181c-5p overexpression limited the proliferation of SiHa cells growth by targeting GSKIP.	('proliferation of SiHa cells growth', 'CPA', (80, 114))	('miR-181c-5p', 'Chemical', '-', (41, 52))	('GSKIP', 'Gene', '51527', (128, 133))	('miR-181c-5p', 'Var', (41, 52))	('SiHa', 'CellLine', 'CVCL:0032', (97, 101))	('GSKIP', 'Gene', (128, 133))	('limited', 'NegReg', (68, 75))
224594	32547080	The above two experiments showed that miR-181c-5p overexpression which targeted GSKIP could inhibit stem cell-like characteristics in SiHa cells.	('miR-181c-5p', 'Chemical', '-', (38, 49))	('SiHa', 'CellLine', 'CVCL:0032', (134, 138))	('GSKIP', 'Gene', '51527', (80, 85))	('miR-181c-5p', 'Var', (38, 49))	('inhibit', 'NegReg', (92, 99))	('GSKIP', 'Gene', (80, 85))	('stem cell-like characteristics in SiHa cells', 'CPA', (100, 144))
224599	32547080	These data indicated that miR-181c-5p overexpression restrained the invasion of SiHa cells by targeting GSKIP.	('miR-181c-5p', 'Var', (26, 37))	('GSKIP', 'Gene', '51527', (104, 109))	('restrained', 'NegReg', (53, 63))	('GSKIP', 'Gene', (104, 109))	('SiHa', 'CellLine', 'CVCL:0032', (80, 84))	('invasion of SiHa cells', 'CPA', (68, 90))	('miR-181c-5p', 'Chemical', '-', (26, 37))
224602	32547080	The expressions of miR-181c-5p and GSKIP mRNA in tumor tissues were detected by qRT-PCR.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('miR-181c-5p', 'Var', (19, 30))	('GSKIP', 'Gene', '51527', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor', 'Disease', (49, 54))	('GSKIP', 'Gene', (35, 40))	('miR-181c-5p', 'Chemical', '-', (19, 30))
224603	32547080	The result showed that the relative level of miR-181c-5p in mimic group was significantly increased and the relative level of GSKIP mRNA was significantly decreased, both of which compared with those in the control group (Figure 6C).	('GSKIP', 'Gene', (126, 131))	('increased', 'PosReg', (90, 99))	('miR-181c-5p', 'Chemical', '-', (45, 56))	('decreased', 'NegReg', (155, 164))	('miR-181c-5p', 'Var', (45, 56))	('GSKIP', 'Gene', '51527', (126, 131))
224605	32547080	In a word, in vivo experiments demonstrated that miR-181c-5p overexpression inhibited the growth of squamous cell carcinoma in vivo.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (100, 123))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (100, 123))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('squamous cell carcinoma', 'Disease', (100, 123))	('miR-181c-5p', 'Chemical', '-', (49, 60))	('miR-181c-5p', 'Var', (49, 60))	('growth', 'MPA', (90, 96))	('inhibited', 'NegReg', (76, 85))
224606	32547080	It has been indicated that the aberrant expression of the miR-181s in tumor tissues played a potentially important role in tumor development and progression.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', (123, 128))	('aberrant', 'Var', (31, 39))	('tumor', 'Disease', (70, 75))	('miR-181s', 'Gene', (58, 66))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('progression', 'CPA', (145, 156))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
224607	32547080	However, what roles miR-181c-5p plays in cervical SCC has been rarely reported.	('SCC', 'Gene', '6317', (50, 53))	('miR-181c-5p', 'Chemical', '-', (20, 31))	('CC', 'Phenotype', 'HP:0002664', (51, 53))	('miR-181c-5p', 'Var', (20, 31))	('SCC', 'Gene', (50, 53))	('SCC', 'Phenotype', 'HP:0002860', (50, 53))
224608	32547080	In this study, we first investigated the expression of miR-181c-5p in the normal cervical cell line (Ect/E6E7) and other four cervical cancer cell lines (SiHa, Hela, HEC-1-A and ME-180).	('HEC-1', 'CellLine', 'CVCL:1274', (166, 171))	('Ect', 'Gene', (101, 104))	('Ect', 'Gene', '100379198', (101, 104))	('SiHa', 'CellLine', 'CVCL:0032', (154, 158))	('Hela', 'CellLine', 'CVCL:0030', (160, 164))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('cervical cancer', 'Disease', (126, 141))	('cervical cancer', 'Disease', 'MESH:D002583', (126, 141))	('miR-181c-5p', 'Chemical', '-', (55, 66))	('miR-181c-5p', 'Var', (55, 66))
224609	32547080	The results showed that the expression of miR-181c-5p was down-regulated in all cervical tumor cell lines and lowest in SiHa cell lines from cervical squamous cell carcinoma.	('SiHa', 'CellLine', 'CVCL:0032', (120, 124))	('cervical squamous cell carcinoma', 'Disease', 'MESH:D002294', (141, 173))	('down-regulated', 'NegReg', (58, 72))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('expression', 'MPA', (28, 38))	('cervical squamous cell carcinoma', 'Disease', (141, 173))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('miR-181c-5p', 'Chemical', '-', (42, 53))	('cervical tumor', 'Phenotype', 'HP:0030159', (80, 94))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (150, 173))	('carcinoma', 'Phenotype', 'HP:0030731', (164, 173))	('miR-181c-5p', 'Var', (42, 53))	('lowest', 'NegReg', (110, 116))	('tumor', 'Disease', (89, 94))
224611	32547080	The prediction of target gene of miR-181c-5p indicated that GSKIP mRNA was potentially regulated by miR-181-5p.	('GSKIP', 'Gene', (60, 65))	('GSKIP', 'Gene', '51527', (60, 65))	('regulated', 'Reg', (87, 96))	('miR-181c-5p', 'Chemical', '-', (33, 44))	('miR-181-5p', 'Var', (100, 110))
224612	32547080	Then, it was found that mir-181c-5p was negatively correlated with the expression of GSKIP in SiHa cells through experiments, and further luciferase detection confirmed that GSKIP was the target gene of miR-181c-5p.	('GSKIP', 'Gene', '51527', (85, 90))	('GSKIP', 'Gene', (85, 90))	('mir-181c', 'Gene', '406957', (24, 32))	('GSKIP', 'Gene', (174, 179))	('miR-181c-5p', 'Chemical', '-', (203, 214))	('miR-181c-5p', 'Var', (203, 214))	('thr', 'Chemical', 'MESH:D013912', (105, 108))	('negatively', 'NegReg', (40, 50))	('mir-181c', 'Gene', (24, 32))	('SiHa', 'CellLine', 'CVCL:0032', (94, 98))	('GSKIP', 'Gene', '51527', (174, 179))
224614	32547080	Reports showed that transfection of the precursor miR-181c molecule blocked growth of two gastric cancer cell lines.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('gastric cancer', 'Disease', 'MESH:D013274', (90, 104))	('miR-181c', 'Var', (50, 58))	('blocked', 'NegReg', (68, 75))	('gastric cancer', 'Phenotype', 'HP:0012126', (90, 104))	('growth of two', 'CPA', (76, 89))	('gastric cancer', 'Disease', (90, 104))
224615	32547080	Studies showed that miR-181c exhibited tumor-suppression via the regulation of NCAPG levels in hepatocellular carcinoma tissue samples.	('NCAPG', 'Gene', '64151', (79, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('regulation', 'Reg', (65, 75))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (95, 119))	('NCAPG', 'Gene', (79, 84))	('tumor', 'Disease', (39, 44))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (95, 119))	('miR-181c', 'Var', (20, 28))	('hepatocellular carcinoma', 'Disease', (95, 119))
224616	32547080	It has been elucidated that miR-181c inhibited the biological progression of osteosarcoma via targeting SMAD7 and regulating TGF-beta signaling pathway.	('miR-181c', 'Var', (28, 36))	('inhibited', 'NegReg', (37, 46))	('osteosarcoma', 'Disease', 'MESH:D012516', (77, 89))	('TGF-beta', 'Gene', (125, 133))	('biological progression', 'CPA', (51, 73))	('SMAD7', 'Gene', (104, 109))	('osteosarcoma', 'Phenotype', 'HP:0002669', (77, 89))	('TGF-beta', 'Gene', '7039', (125, 133))	('regulating', 'Reg', (114, 124))	('targeting', 'Reg', (94, 103))	('SMAD7', 'Gene', '4092', (104, 109))	('osteosarcoma', 'Disease', (77, 89))
224617	32547080	Consistent with these reports, this study found that the colony forming rate of SiHa cells with increased expression of miR-181c-5p was obviously reduced.	('increased', 'PosReg', (96, 105))	('colony forming rate', 'CPA', (57, 76))	('expression', 'MPA', (106, 116))	('reduced', 'NegReg', (146, 153))	('miR-181c-5p', 'Var', (120, 131))	('miR-181c-5p', 'Chemical', '-', (120, 131))	('SiHa', 'CellLine', 'CVCL:0032', (80, 84))
224618	32547080	These results indicated that miR-181c-5p suppressed the viability of cervical SCC.	('miR-181c-5p', 'Var', (29, 40))	('SCC', 'Gene', '6317', (78, 81))	('SCC', 'Phenotype', 'HP:0002860', (78, 81))	('suppressed', 'NegReg', (41, 51))	('CC', 'Phenotype', 'HP:0002664', (79, 81))	('SCC', 'Gene', (78, 81))	('miR-181c-5p', 'Chemical', '-', (29, 40))
224626	32547080	Here, we identified GSKIP gene as the target of miR-181c-5p in cervical SCC.	('GSKIP', 'Gene', (20, 25))	('SCC', 'Gene', (72, 75))	('miR-181c-5p', 'Chemical', '-', (48, 59))	('SCC', 'Phenotype', 'HP:0002860', (72, 75))	('GSKIP', 'Gene', '51527', (20, 25))	('CC', 'Phenotype', 'HP:0002664', (73, 75))	('SCC', 'Gene', '6317', (72, 75))	('miR-181c-5p', 'Var', (48, 59))
224628	32547080	We found that miR-181c-5p attenuated the stemness of SiHa cells by inhibiting the expression of GSKIP.	('SiHa', 'CellLine', 'CVCL:0032', (53, 57))	('stemness of SiHa cells', 'CPA', (41, 63))	('GSKIP', 'Gene', '51527', (96, 101))	('expression', 'MPA', (82, 92))	('miR-181c-5p', 'Chemical', '-', (14, 25))	('GSKIP', 'Gene', (96, 101))	('miR-181c-5p', 'Var', (14, 25))	('attenuated', 'NegReg', (26, 36))	('inhibiting', 'NegReg', (67, 77))
224629	32547080	In addition, at the protein level, miR-181c-5p down-regulated the levels of SOX2, OCT4 and CD44 with stem cell characterization.	('levels', 'MPA', (66, 72))	('SOX2', 'Gene', '6657', (76, 80))	('CD44', 'Gene', '960', (91, 95))	('SOX2', 'Gene', (76, 80))	('OCT4', 'Gene', '5460', (82, 86))	('CD44', 'Gene', (91, 95))	('miR-181c-5p', 'Chemical', '-', (35, 46))	('miR-181c-5p', 'Var', (35, 46))	('OCT4', 'Gene', (82, 86))	('down-regulated', 'NegReg', (47, 61))
224630	32547080	This suggested that miR-181c-5p reduced the stemness in SiHa cells by targeting the GSKIP gene.	('stemness in SiHa cells', 'CPA', (44, 66))	('GSKIP', 'Gene', '51527', (84, 89))	('miR-181c-5p', 'Chemical', '-', (20, 31))	('reduced', 'NegReg', (32, 39))	('miR-181c-5p', 'Var', (20, 31))	('SiHa', 'CellLine', 'CVCL:0032', (56, 60))	('GSKIP', 'Gene', (84, 89))	('targeting', 'Reg', (70, 79))
224634	32547080	For example, He et al confirmed that upregulation of miR-181c inhibited EMT, with E-cadherin increased, and N-cadherin and Vimentin decreased in glioblastoma cells.	('glioblastoma', 'Phenotype', 'HP:0012174', (145, 157))	('increased', 'PosReg', (93, 102))	('upregulation', 'PosReg', (37, 49))	('EMT', 'CPA', (72, 75))	('N-cadherin', 'Gene', (108, 118))	('E-cadherin', 'Gene', (82, 92))	('E-cadherin', 'Gene', '999', (82, 92))	('inhibited', 'NegReg', (62, 71))	('miR-181c', 'Var', (53, 61))	('decreased', 'NegReg', (132, 141))	('glioblastoma', 'Disease', (145, 157))	('Vimentin', 'Protein', (123, 131))	('N-cadherin', 'Gene', '1000', (108, 118))	('glioblastoma', 'Disease', 'MESH:D005909', (145, 157))
224636	32547080	In this study, Transwell assay was used to investigate whether miR-181c-5p regulated migration and invasion of cervical SCC.	('SCC', 'Phenotype', 'HP:0002860', (120, 123))	('SCC', 'Gene', '6317', (120, 123))	('regulated', 'Reg', (75, 84))	('miR-181c-5p', 'Chemical', '-', (63, 74))	('CC', 'Phenotype', 'HP:0002664', (121, 123))	('invasion', 'CPA', (99, 107))	('migration', 'CPA', (85, 94))	('miR-181c-5p', 'Var', (63, 74))	('SCC', 'Gene', (120, 123))
224638	32547080	We found that the expression of E-cadherin was high while both of N-cadherin and Vimentin were low in SiHa cells transfected with miR-181c-5p mimics.	('miR-181c-5p mimics', 'Var', (130, 148))	('miR-181c-5p', 'Chemical', '-', (130, 141))	('low', 'NegReg', (95, 98))	('E-cadherin', 'Gene', (32, 42))	('SiHa', 'CellLine', 'CVCL:0032', (102, 106))	('high', 'PosReg', (47, 51))	('E-cadherin', 'Gene', '999', (32, 42))	('N-cadherin', 'Gene', (66, 76))	('expression', 'MPA', (18, 28))	('N-cadherin', 'Gene', '1000', (66, 76))
224640	32547080	Obviously, the data showed that EMT-like changes could be inhibited by miR-181c-5p overexpression.	('miR-181c-5p', 'Var', (71, 82))	('overexpression', 'PosReg', (83, 97))	('inhibited', 'NegReg', (58, 67))	('miR-181c-5p', 'Chemical', '-', (71, 82))	('EMT-like changes', 'CPA', (32, 48))
224641	32547080	In addition, in vivo experiments in mice further verified that miR-181c-5p overexpression can significantly inhibit cell proliferation and metastasis.	('inhibit', 'NegReg', (108, 115))	('miR-181c-5p', 'Chemical', '-', (63, 74))	('mice', 'Species', '10090', (36, 40))	('miR-181c-5p', 'Var', (63, 74))
224642	32547080	In ICH assay, it was also further confirmed that miR-181c-5p inhibited the expressions of Ki67, CD44 and Vimentin but improved the expression of Caspase-3 in cervical SCC tissues.	('inhibited', 'NegReg', (61, 70))	('ICH', 'Disease', (3, 6))	('SCC', 'Gene', (167, 170))	('SCC', 'Gene', '6317', (167, 170))	('SCC', 'Phenotype', 'HP:0002860', (167, 170))	('improved', 'PosReg', (118, 126))	('Ki67', 'Protein', (90, 94))	('CC', 'Phenotype', 'HP:0002664', (168, 170))	('Caspase-3', 'Gene', (145, 154))	('CD44', 'Gene', '960', (96, 100))	('expression', 'MPA', (131, 141))	('Caspase-3', 'Gene', '836', (145, 154))	('ICH', 'Disease', 'MESH:D002543', (3, 6))	('miR-181c-5p', 'Chemical', '-', (49, 60))	('miR-181c-5p', 'Var', (49, 60))	('CD44', 'Gene', (96, 100))	('Vimentin', 'Protein', (105, 113))	('expressions', 'MPA', (75, 86))
224643	32547080	In conclusion, the miR-181c5p overexpression was considered to be negatively correlated with the expression of GSKIP in cervical SCC tissues.	('SCC', 'Phenotype', 'HP:0002860', (129, 132))	('negatively', 'NegReg', (66, 76))	('SCC', 'Gene', '6317', (129, 132))	('GSKIP', 'Gene', '51527', (111, 116))	('overexpression', 'PosReg', (30, 44))	('miR-181c5p', 'Var', (19, 29))	('GSKIP', 'Gene', (111, 116))	('SCC', 'Gene', (129, 132))	('expression', 'MPA', (97, 107))	('CC', 'Phenotype', 'HP:0002664', (130, 132))
224644	32547080	MiR-181c-5p inhibited the migration and invasion of cervical SCCs as well as EMT via Wnt/beta-catenin signaling.	('inhibited', 'NegReg', (12, 21))	('MiR-181c-5p', 'Var', (0, 11))	('SCC', 'Phenotype', 'HP:0002860', (61, 64))	('SCC', 'Gene', '6317', (61, 64))	('beta-catenin', 'Gene', '1499', (89, 101))	('MiR-181c-5p', 'Chemical', '-', (0, 11))	('CC', 'Phenotype', 'HP:0002664', (62, 64))	('EMT', 'CPA', (77, 80))	('beta-catenin', 'Gene', (89, 101))	('SCC', 'Gene', (61, 64))
224645	32547080	These results offer basic data on the role of miR-181-5p in the progress of cervical SCC.	('SCC', 'Gene', '6317', (85, 88))	('miR-181-5p', 'Var', (46, 56))	('CC', 'Phenotype', 'HP:0002664', (86, 88))	('SCC', 'Gene', (85, 88))	('SCC', 'Phenotype', 'HP:0002860', (85, 88))
224664	31516563	A previous investigation also revealed that defects in MTERF1 binding may lead to mitochondrial diseases, including Kearns-Sayre syndrome.	('lead to', 'Reg', (74, 81))	('binding', 'Interaction', (62, 69))	('MTERF1', 'Gene', '7978', (55, 61))	('MTERF1', 'Gene', (55, 61))	('mitochondrial diseases', 'Disease', (82, 104))	('defects', 'Var', (44, 51))	('Kearns-Sayre syndrome', 'Disease', (116, 137))	('Kearns-Sayre syndrome', 'Disease', 'MESH:D007625', (116, 137))	('mitochondrial diseases', 'Disease', 'MESH:D028361', (82, 104))
224665	31516563	In post-transcriptional modification patterns of mitochondrial genes, a mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) mutation in the mtDNA binding-site for the transcription termination factor was revealed to cause defects in protein-synthesis in respiration; however, it does not alter the upstream and downstream mature transcription levels.	('mitochondrial genes', 'Gene', (49, 68))	('stroke', 'Phenotype', 'HP:0001297', (126, 132))	('encephalomyopathy', 'Disease', (86, 103))	('stroke', 'Disease', (126, 132))	('stroke-like episodes', 'Phenotype', 'HP:0002401', (126, 146))	('lactic acidosis', 'Disease', 'MESH:D000140', (105, 120))	('defects', 'NegReg', (253, 260))	('stroke', 'Disease', 'MESH:D020521', (126, 132))	('acidosis', 'Phenotype', 'HP:0001941', (112, 120))	('lactic acidosis', 'Phenotype', 'HP:0003128', (105, 120))	('encephalomyopathy', 'Disease', 'MESH:D017237', (86, 103))	('mutation', 'Var', (155, 163))	('myopathy', 'Phenotype', 'HP:0003198', (95, 103))	('mitochondrial encephalomyopathy', 'Phenotype', 'HP:0006789', (72, 103))	('protein-synthesis in respiration', 'MPA', (264, 296))	('lactic acidosis', 'Disease', (105, 120))	('mitochondrial', 'Disease', (72, 85))
224670	31516563	MTERF4 contributes to the regulation of mitochondrial translation by targeting NOP2/sun RNA methyltransferase family member 4 (NSUN4) to large mitochondrial ribosome, and MTERF4-knockout also leads to mouse embryo death.	('leads to', 'Reg', (192, 200))	('NSUN4', 'Gene', (127, 132))	('mouse', 'Species', '10090', (201, 206))	('mouse embryo death', 'CPA', (201, 219))	('MTERF4-knockout', 'Var', (171, 186))
224692	31516563	A total of two original datasets (GSE10072 and GSE19804) for patients with LC were downloaded from GEO.	('patients', 'Species', '9606', (61, 69))	('GSE19804', 'Var', (47, 55))	('LC', 'Phenotype', 'HP:0100526', (75, 77))	('GSE10072', 'Var', (34, 42))
224697	31516563	The following Affymetrix IDs were valid: 204871_at (MTERF1), 225346_at (MTERF2), 219363_s_at (MTERF3) and 1557965_at (MTERF4).	('MTERF1', 'Gene', '7978', (52, 58))	('MTERF1', 'Gene', (52, 58))	('225346_at', 'Var', (61, 70))	('1557965_at', 'Var', (106, 116))	('219363_s_at', 'Var', (81, 92))	('204871_at', 'Var', (41, 50))
224700	31516563	MTERF2 was revealed to exhibit a high deep deletion rate in patients with LUAD and a high mutation rate in patients with LUSC (Fig.	('mutation', 'MPA', (90, 98))	('MTERF2', 'Gene', (0, 6))	('LUSC', 'Phenotype', 'HP:0030359', (121, 125))	('patients', 'Species', '9606', (60, 68))	('LUAD', 'Phenotype', 'HP:0030078', (74, 78))	('LUAD', 'Disease', (74, 78))	('patients', 'Species', '9606', (107, 115))	('deep deletion', 'Var', (38, 51))
224704	31516563	To investigate the mRNA expression of MTERFs in NSCLC and normal tissues, the raw data was retrieved by searching terms 'GSE#19804' and 'GSE#10072' from the GEO dataset.	('NSCLC', 'Disease', (48, 53))	('NSCLC', 'Disease', 'MESH:D002289', (48, 53))	('LC', 'Phenotype', 'HP:0100526', (51, 53))	("'GSE", 'Var', (120, 124))	('NSCLC', 'Phenotype', 'HP:0030358', (48, 53))
224714	31516563	High MTERF1 mRNA expression was significantly associated with improved OS rate in patients with LUAD (n=720; HR, 0.52; 95% CI, 0.39-0.70; P=8x10-6; Fig.	('LUAD', 'Phenotype', 'HP:0030078', (96, 100))	('LUAD', 'Disease', (96, 100))	('High', 'Var', (0, 4))	('improved', 'PosReg', (62, 70))	('patients', 'Species', '9606', (82, 90))	('MTERF1', 'Gene', '7978', (5, 11))	('MTERF1', 'Gene', (5, 11))
224716	31516563	Notably, high mRNA expression of MTERF2 was significantly associated with improved OS rate in patients with LUAD (n=673; HR 0.48; 95% CI, 0.36-0.66; P=1.9x10-6; Fig.	('patients', 'Species', '9606', (94, 102))	('LUAD', 'Disease', (108, 112))	('improved', 'PosReg', (74, 82))	('LUAD', 'Phenotype', 'HP:0030078', (108, 112))	('MTERF2', 'Gene', (33, 39))	('mRNA expression', 'MPA', (14, 29))	('high', 'Var', (9, 13))
224717	31516563	Furthermore, high MTERF3 mRNA expression was significantly associated with improved OS rate for patients with LUAD (n=591; HR, 0.69; 95% CI, 0.54-0.88; P=0.0028; Fig.	('improved', 'PosReg', (75, 83))	('LUAD', 'Disease', (110, 114))	('high', 'Var', (13, 17))	('LUAD', 'Phenotype', 'HP:0030078', (110, 114))	('MTERF3', 'Gene', (18, 24))	('patients', 'Species', '9606', (96, 104))
224718	31516563	For MTERF4, a high mRNA expression level was significantly associated with an improved OS rate for patients with LUAD (n=673; HR, 0.51; 95% CI, 0.38-0.68; P=2.4x10-6; Fig.	('patients', 'Species', '9606', (99, 107))	('high', 'Var', (14, 18))	('LUAD', 'Disease', (113, 117))	('MTERF4', 'Gene', (4, 10))	('mRNA expression level', 'MPA', (19, 40))	('LUAD', 'Phenotype', 'HP:0030078', (113, 117))	('improved', 'PosReg', (78, 86))
224720	31516563	Higher mRNA expression of MTERF2 was also marginally associated with improved OS in patients with LUSC for MTERF2 (n=271; HR, 1.5; 95% CI, 1.05-2.13; P=0.024; Fig.	('improved', 'PosReg', (69, 77))	('patients', 'Species', '9606', (84, 92))	('MTERF2', 'Var', (107, 113))	('mRNA expression', 'MPA', (7, 22))	('Higher', 'PosReg', (0, 6))	('MTERF2', 'Gene', (26, 32))	('LUSC', 'Phenotype', 'HP:0030359', (98, 102))
224724	31516563	However, a high expression of MTERF3 was significantly associated with a higher OS in patients who never smoked (HR, 0.25; 95% CI, 0.09-0.69; P=0.0037) but not in patients who smoked.	('patients', 'Species', '9606', (163, 171))	('MTERF3', 'Gene', (30, 36))	('high expression', 'Var', (11, 26))	('higher OS', 'MPA', (73, 82))	('patients', 'Species', '9606', (86, 94))
224725	31516563	Additionally, a high expression of MTERF4 was identified to be significantly associated with OS of patients who smoked (HR, 0.33; 95% CI, 0.19-0.59; P=4.1x10-5) but not patients who never smoked.	('patients', 'Species', '9606', (169, 177))	('high', 'Var', (16, 20))	('patients', 'Species', '9606', (99, 107))	('MTERF4', 'Gene', (35, 41))	('associated', 'Reg', (77, 87))
224727	31516563	Particularly, for patients in stage I, lower expression levels of MTERF1 (P=0.0006), MTERF2 (P=1.3x10-5), MTERF3 (P=2.4x10-8) and MTERF4 (P=2.4x10-8) were significantly associated with a worse OS rates (Table III).	('expression levels', 'MPA', (45, 62))	('MTERF1', 'Gene', '7978', (66, 72))	('MTERF1', 'Gene', (66, 72))	('MTERF4', 'Gene', (130, 136))	('patients', 'Species', '9606', (18, 26))	('MTERF3', 'Var', (106, 112))	('lower', 'NegReg', (39, 44))	('MTERF2', 'Gene', (85, 91))
224736	31516563	The pathogenic MELAS mutation of MTERF1 has been demonstrated to attenuate the ability of transcription termination in vitro.	('attenuate', 'NegReg', (65, 74))	('mutation', 'Var', (21, 29))	('MTERF1', 'Gene', '7978', (33, 39))	('MTERF1', 'Gene', (33, 39))	('ability', 'MPA', (79, 86))	('pathogenic', 'Reg', (4, 14))	('MELAS', 'Disease', (15, 20))
224738	31516563	In addition, the loss of MTERF2 in mice results in decreased oxidative phosphorylation complexes and causes a respiratory defect.	('causes', 'Reg', (101, 107))	('MTERF2', 'Gene', (25, 31))	('decreased', 'NegReg', (51, 60))	('oxidative phosphorylation complexes', 'MPA', (61, 96))	('respiratory defect', 'Disease', 'MESH:D012131', (110, 128))	('mice', 'Species', '10090', (35, 39))	('respiratory defect', 'Disease', (110, 128))	('loss', 'Var', (17, 21))
224740	31516563	Knockout of MTERF3 in mice results in embryo mortality, which indicates that MTERF3 functions as an essential factor in mouse embryonic development.	('embryo mortality', 'CPA', (38, 54))	('Knockout', 'Var', (0, 8))	('MTERF3', 'Gene', (12, 18))	('mice', 'Species', '10090', (22, 26))	('mouse', 'Species', '10090', (120, 125))
224741	31516563	Furthermore, tissue specific inactivation of MTERF3 in the heart significantly decreased the life span of mice, and may affect heart and skeletal muscle functions by regulating mitochondrial functions.	('heart', 'MPA', (127, 132))	('mice', 'Species', '10090', (106, 110))	('MTERF3', 'Gene', (45, 51))	('decreased', 'NegReg', (79, 88))	('affect', 'Reg', (120, 126))	('mitochondrial functions', 'MPA', (177, 200))	('inactivation', 'Var', (29, 41))	('regulating', 'Reg', (166, 176))
224742	31516563	MTERF4 has a common fold similar to MTERF1 and MTERF3, which contains positively charged surfaces and may be beneficial for nucleic acid interaction.	('nucleic', 'MPA', (124, 131))	('beneficial', 'Reg', (109, 119))	('MTERF1', 'Gene', '7978', (36, 42))	('MTERF1', 'Gene', (36, 42))	('MTERF4', 'Var', (0, 6))
224744	31516563	In a human neuroblast cell line, knockdown of MTERF4 increased the MPP+-induced mitochondrial dysfunction, which may be due to increased mtDNA transcription and translation levels.	('transcription', 'MPA', (143, 156))	('MTERF4', 'Gene', (46, 52))	('translation levels', 'MPA', (161, 179))	('mitochondrial dysfunction', 'Disease', 'MESH:D028361', (80, 105))	('knockdown', 'Var', (33, 42))	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (80, 105))	('mitochondrial dysfunction', 'Disease', (80, 105))	('increased', 'PosReg', (53, 62))	('human', 'Species', '9606', (5, 10))	('mtDNA', 'Gene', (137, 142))	('increased', 'PosReg', (127, 136))
224745	31516563	Similar to MTERF3, MTERF4-knockdown in mice also induces embryo mortality.	('MTERF4-knockdown', 'Var', (19, 35))	('mice', 'Species', '10090', (39, 43))	('embryo mortality', 'CPA', (57, 73))	('induces', 'Reg', (49, 56))
224746	31516563	Furthermore, the loss of MTERF4 in the mouse heart also disrupts the transfer RNA pool; however, it increases steady-state levels of mtDNA transcripts.	('increases', 'PosReg', (100, 109))	('steady-state', 'MPA', (110, 122))	('transfer RNA pool', 'MPA', (69, 86))	('disrupts', 'NegReg', (56, 64))	('mouse', 'Species', '10090', (39, 44))	('MTERF4', 'Gene', (25, 31))	('loss', 'Var', (17, 21))
224748	31516563	Defects in mitochondrial gene expression are associated with numerous diseases, including LC.	('mitochondrial gene', 'Gene', (11, 29))	('expression', 'MPA', (30, 40))	('numerous diseases', 'Disease', 'MESH:D004194', (61, 78))	('LC', 'Phenotype', 'HP:0100526', (90, 92))	('Defects', 'Var', (0, 7))	('associated', 'Reg', (45, 55))	('numerous diseases', 'Disease', (61, 78))
224749	31516563	Mitochondrial gene mutations are common in cancer development and may regulate mitochondrial metabolism.	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('cancer', 'Disease', (43, 49))	('mutations', 'Var', (19, 28))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('regulate', 'Reg', (70, 78))	('Mitochondrial gene', 'Gene', (0, 18))	('mitochondrial metabolism', 'MPA', (79, 103))
224752	31516563	Notably, high expression levels of MTERF1, 2, 3 and 4 were significantly associated with an improved OS for patients with LUAD, and patients with early stage NSCLC.	('LC', 'Phenotype', 'HP:0100526', (161, 163))	('NSCLC', 'Disease', (158, 163))	('NSCLC', 'Disease', 'MESH:D002289', (158, 163))	('NSCLC', 'Phenotype', 'HP:0030358', (158, 163))	('patients', 'Species', '9606', (108, 116))	('improved', 'PosReg', (92, 100))	('LUAD', 'Disease', (122, 126))	('patients', 'Species', '9606', (132, 140))	('MTERF1, 2, 3 and 4', 'Gene', '7978;80298;51001;130916', (35, 53))	('LUAD', 'Phenotype', 'HP:0030078', (122, 126))	('high', 'Var', (9, 13))
224776	30097507	However, in addition to their shared morphology, HNSCC and SQCLC exhibit largely overlapping patterns of genetic mutations and copy number alterations (van Oijen et al, 2000; Tabor et al, 2002; Geurts et al, 2005, 2009; Talbot et al, 2005; Vachani et al, 2007; Cancer Genome Atlas Research, 2012; Cancer Genome Atlas, 2015; Ichinose et al, 2016a).	('Cancer', 'Phenotype', 'HP:0002664', (297, 303))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (297, 316))	('HNSCC', 'Phenotype', 'HP:0012288', (49, 54))	('SQCLC', 'Phenotype', 'HP:0030359', (59, 64))	('Cancer Genome Atlas', 'Disease', (261, 280))	('mutations', 'Var', (113, 122))	('Cancer', 'Phenotype', 'HP:0002664', (261, 267))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (261, 280))	('Cancer Genome Atlas', 'Disease', (297, 316))
224788	30097507	The mutations detected affected mostly the PI3-kinase (PI3K) and Ras pathways, receptor tyrosine kinases (RTK), TP53 and the NFE2L2/KEAP1 pathway (Fig 1B and Dataset EV1).	('PI3-kinase', 'Gene', (43, 53))	('affected', 'Reg', (23, 31))	('EV1', 'Gene', '11322', (166, 169))	('NFE2L2', 'Gene', '4780', (125, 131))	('EV1', 'Gene', (166, 169))	('PI3-kinase', 'Gene', '5290', (43, 53))	('KEAP1', 'Gene', '9817', (132, 137))	('Ras pathways', 'Pathway', (65, 77))	('NFE2L2', 'Gene', (125, 131))	('TP53', 'Gene', '7157', (112, 116))	('mutations', 'Var', (4, 13))	('KEAP1', 'Gene', (132, 137))	('TP53', 'Gene', (112, 116))
224820	30097507	Earlier studies that analysed loss of heterozygosity, p53 mutation status, gene expression, copy number alterations or protein expression by immunohistochemistry (Geurts et al, 2005, 2009; Talbot et al, 2005; Ichinose et al, 2016a; Campbell et al, 2018) likewise failed to distinguish reliably between metHNSCC and SQCLC.	('HNSCC', 'Phenotype', 'HP:0012288', (305, 310))	('SQCLC', 'Phenotype', 'HP:0030359', (315, 320))	('p53', 'Gene', (54, 57))	('mutation', 'Var', (58, 66))	('p53', 'Gene', '7157', (54, 57))	('SQCLC', 'Disease', (315, 320))	('metHNSCC', 'Disease', (302, 310))
224826	30097507	HMGCS-1 activity was shown to be important for oncogenic survival-promoting signalling by mutant B-Raf, highlighting the direct involvement of HMGCS-1 in oncogenic signalling pathways (Snijders et al, 2017; Zhao et al, 2017).	('HMGCS-1', 'Gene', '3157', (143, 150))	('HMGCS-1', 'Gene', '3157', (0, 7))	('mutant', 'Var', (90, 96))	('HMGCS-1', 'Gene', (143, 150))	('HMGCS-1', 'Gene', (0, 7))	('B-Raf', 'Gene', (97, 102))	('B-Raf', 'Gene', '673', (97, 102))	('involvement', 'Reg', (128, 139))
224848	30097507	The custom-made lung cancer panel consisted of 205 amplicons for the detection of mutations in 17 lung cancer-related genes including ARAF exon 7; BRAF exons 11, 15; CTNNB1 exon 3; DDR2 exons 3-18; EGFR exons 18-21; FGFR2 exons 8, 9, 10, 12, 17, 20; FGFR3 exons 7, 10, 15; HER2 exon 19, 20; KEAP1 exons 2-6; KRAS exons 2-4; MAP2K1 exon 2; MET exon 14, 16-19 and intron 14, 15; NFE2L2 exon 2; NRAS exons 2-4; PIK3CA exons 9, 20; PTEN exons 1-8, and TP53 exons 5-8.	('PTEN', 'Gene', '5728', (428, 432))	('lung cancer', 'Disease', 'MESH:D008175', (98, 109))	('FGFR2', 'Gene', (216, 221))	('MAP2K1', 'Gene', '5604', (324, 330))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('NFE2L2', 'Gene', '4780', (377, 383))	('lung cancer', 'Disease', 'MESH:D008175', (16, 27))	('MAP2K1', 'Gene', (324, 330))	('PIK3CA', 'Gene', (408, 414))	('DDR2', 'Gene', '4921', (181, 185))	('HER2', 'Gene', (273, 277))	('lung cancer', 'Phenotype', 'HP:0100526', (98, 109))	('lung cancer', 'Phenotype', 'HP:0100526', (16, 27))	('TP53', 'Gene', (448, 452))	('FGFR2', 'Gene', '2263', (216, 221))	('FGFR3', 'Gene', (250, 255))	('CTNNB1', 'Gene', '1499', (166, 172))	('BRAF', 'Gene', (147, 151))	('BRAF', 'Gene', '673', (147, 151))	('NFE2L2', 'Gene', (377, 383))	('KRAS', 'Gene', '3845', (308, 312))	('FGFR3', 'Gene', '2261', (250, 255))	('KEAP1', 'Gene', '9817', (291, 296))	('DDR2', 'Gene', (181, 185))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('KEAP1', 'Gene', (291, 296))	('CTNNB1', 'Gene', (166, 172))	('lung cancer', 'Disease', (98, 109))	('PTEN', 'Gene', (428, 432))	('ARAF', 'Gene', '369', (134, 138))	('PIK3CA', 'Gene', '5290', (408, 414))	('ARAF', 'Gene', (134, 138))	('KRAS', 'Gene', (308, 312))	('mutations', 'Var', (82, 91))	('TP53', 'Gene', '7157', (448, 452))	('HER2', 'Gene', '2064', (273, 277))	('lung cancer', 'Disease', (16, 27))
224874	30097507	For SILAC quantification, multiplicity was set to two for double SILAC (Lys + 0/Arg + 0, Lys + 8/Arg + 10) labelling.	('Arg', 'Chemical', 'MESH:D001120', (97, 100))	('Lys', 'Chemical', 'MESH:D008239', (72, 75))	('Arg', 'Chemical', 'MESH:D001120', (80, 83))	('Lys + 8/Arg + 10', 'Var', (89, 105))	('Lys', 'Chemical', 'MESH:D008239', (89, 92))	('Lys + 0/Arg + 0', 'Var', (72, 87))
224889	29749538	Methylation-sequencing information, mRNA expression profiling data and clinical data were downloaded from cBioPortal database to screen out candidate genes related to the methylation of TRIM58/cg26157385 in squamous cell lung carcinoma.	('TRIM58', 'Gene', (186, 192))	('TRIM58', 'Gene', '25893', (186, 192))	('methylation', 'Var', (171, 182))	('carcinoma', 'Phenotype', 'HP:0030731', (226, 235))	('squamous cell lung carcinoma', 'Disease', 'MESH:D002294', (207, 235))	('squamous cell lung carcinoma', 'Phenotype', 'HP:0030359', (207, 235))	('squamous cell lung carcinoma', 'Disease', (207, 235))
224893	29749538	Based on their expression level and the corresponding survival information for 347 out of 370 samples with squamous cell lung carcinoma, 183 genes significantly associated with prognosis were gained, and the top 8 ones, including alpha-2-macroglobulin-like 1 (A2ML1), cyclin-E1 (CCNE1), COBL, establishment of sister chromatid cohesion N-acetyltransferase 2 (ESCO2), G protein-coupled receptor 115 (GPR115), matrix metalloproteinases 10 (MMP10), OVO homologue-like 1 (OVOL1) and secretoglobin family 1A member 1 (SCGB1A1), were candidate signature genes significantly correlated with TRIM58 methylation.	('correlated', 'Reg', (568, 578))	('alpha-2-macroglobulin-like 1', 'Gene', (230, 258))	('associated', 'Reg', (161, 171))	('OVO homologue-like 1', 'Gene', '5017', (446, 466))	('CCNE1', 'Gene', '898', (279, 284))	('OVOL1', 'Gene', '5017', (468, 473))	('A2ML1', 'Gene', (260, 265))	('ESCO2', 'Gene', (359, 364))	('COBL', 'Gene', '23242', (287, 291))	('squamous cell lung carcinoma', 'Phenotype', 'HP:0030359', (107, 135))	('OVOL1', 'Gene', (468, 473))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('TRIM58', 'Gene', (584, 590))	('SCGB1A1', 'Gene', '7356', (513, 520))	('matrix metalloproteinases 10', 'Gene', '4319', (408, 436))	('G protein-coupled receptor 115', 'Gene', (367, 397))	('cyclin-E1', 'Gene', '898', (268, 277))	('GPR115', 'Gene', '221393', (399, 405))	('men', 'Species', '9606', (302, 305))	('N-acetyltransferase 2', 'Gene', (336, 357))	('squamous cell lung carcinoma', 'Disease', (107, 135))	('GPR115', 'Gene', (399, 405))	('TRIM58', 'Gene', '25893', (584, 590))	('COBL', 'Gene', (287, 291))	('methylation', 'Var', (591, 602))	('G protein-coupled receptor 115', 'Gene', '221393', (367, 397))	('MMP10', 'Gene', '4319', (438, 443))	('secretoglobin family 1A member 1', 'Gene', (479, 511))	('cyclin-E1', 'Gene', (268, 277))	('A2ML1', 'Gene', '144568', (260, 265))	('N-acetyltransferase 2', 'Gene', '10', (336, 357))	('secretoglobin family 1A member 1', 'Gene', '7356', (479, 511))	('CCNE1', 'Gene', (279, 284))	('ESCO2', 'Gene', '157570', (359, 364))	('matrix metalloproteinases 10', 'Gene', (408, 436))	('squamous cell lung carcinoma', 'Disease', 'MESH:D002294', (107, 135))	('OVO homologue-like 1', 'Gene', (446, 466))	('alpha-2-macroglobulin-like 1', 'Gene', '144568', (230, 258))	('SCGB1A1', 'Gene', (513, 520))	('MMP10', 'Gene', (438, 443))
224895	29749538	Eight genes, including A2ML1, CCNE1, COBL, ESCO2, GPR115, MMP10, OVOL1 and SCGB1A1, were significantly related to TRIM58 methylation and treatment of lung squamous cell carcinoma, and may be used as potential prognostic biomarkers.	('SCGB1A1', 'Gene', (75, 82))	('TRIM58', 'Gene', '25893', (114, 120))	('carcinoma', 'Phenotype', 'HP:0030731', (169, 178))	('ESCO2', 'Gene', (43, 48))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (150, 178))	('COBL', 'Gene', (37, 41))	('OVOL1', 'Gene', (65, 70))	('CCNE1', 'Gene', (30, 35))	('TRIM58', 'Gene', (114, 120))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (155, 178))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (150, 178))	('lung squamous cell carcinoma', 'Disease', (150, 178))	('men', 'Species', '9606', (142, 145))	('CCNE1', 'Gene', '898', (30, 35))	('A2ML1', 'Gene', '144568', (23, 28))	('SCGB1A1', 'Gene', '7356', (75, 82))	('GPR115', 'Gene', '221393', (50, 56))	('MMP10', 'Gene', '4319', (58, 63))	('methylation', 'Var', (121, 132))	('GPR115', 'Gene', (50, 56))	('ESCO2', 'Gene', '157570', (43, 48))	('COBL', 'Gene', '23242', (37, 41))	('MMP10', 'Gene', (58, 63))	('OVOL1', 'Gene', '5017', (65, 70))	('related', 'Reg', (103, 110))	('A2ML1', 'Gene', (23, 28))
224902	29749538	Among numerous tumor pathogenesis, methylation of the functional genes has attracted the interest of many researchers.	('numerous tumor', 'Disease', 'MESH:D009369', (6, 20))	('numerous tumor', 'Disease', (6, 20))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('methylation', 'Var', (35, 46))
224903	29749538	Aberrant promoter island methylation of tumor suppressor genes, including overall low level methylation and hyper-methylation in some local regions, has been established as a common epigenetic mechanism underlying the pathogenesis of human cancers.	('Aberrant', 'Var', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('human', 'Species', '9606', (234, 239))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('low', 'NegReg', (82, 85))	('promoter island', 'MPA', (9, 24))	('cancers', 'Disease', (240, 247))	('cancers', 'Phenotype', 'HP:0002664', (240, 247))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('hyper-methylation', 'MPA', (108, 125))	('cancers', 'Disease', 'MESH:D009369', (240, 247))
224907	29749538	Furthermore, aberrant inactivation of TRIM58 consequent to CpG island hyper-methylation may stimulate early carcinogenesis of lung adenocarcinoma.	('stimulate', 'PosReg', (92, 101))	('TRIM58', 'Gene', '25893', (38, 44))	('aberrant inactivation', 'Var', (13, 34))	('carcinogenesis of lung adenocarcinoma', 'Disease', 'MESH:D063646', (108, 145))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (126, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('carcinogenesis of lung adenocarcinoma', 'Disease', (108, 145))	('TRIM58', 'Gene', (38, 44))	('hyper-methylation', 'Var', (70, 87))
224909	29749538	In the present study to elucidate the influence of TRIM58/cg26157385 methylation on lung cancer prognosis, we used the large quantities of mRNA-Seq data in lung squamous cell carcinoma patients published in cBioPortal database , to screen out candidate genes related to the methylation of TRIM58/cg26157385, and construct a prognostic discrimination system based on these genes.	('lung cancer', 'Disease', (84, 95))	('TRIM58', 'Gene', (51, 57))	('lung cancer', 'Phenotype', 'HP:0100526', (84, 95))	('TRIM58', 'Gene', '25893', (51, 57))	('TRIM58', 'Gene', (289, 295))	('TRIM58', 'Gene', '25893', (289, 295))	('methylation', 'Var', (274, 285))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (156, 184))	('lung cancer', 'Disease', 'MESH:D008175', (84, 95))	('patients', 'Species', '9606', (185, 193))	('carcinoma', 'Phenotype', 'HP:0030731', (175, 184))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (161, 184))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (156, 184))	('lung squamous cell carcinoma', 'Disease', (156, 184))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
224937	29749538	Aberrant promoter island methylation of tumor suppressor genes has been established as a common epigenetic mechanism underlying the pathogenesis of human cancers, and may be used as diagnostic marker for tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('Aberrant', 'Var', (0, 8))	('cancers', 'Phenotype', 'HP:0002664', (154, 161))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('human', 'Species', '9606', (148, 153))	('cancers', 'Disease', 'MESH:D009369', (154, 161))	('promoter island', 'MPA', (9, 24))	('tumor', 'Disease', (204, 209))	('cancers', 'Disease', (154, 161))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))
224938	29749538	In the present study, we tried to use the large quantities of mRNA-Seq data in lung squamous cell carcinoma patients published in cBioPortal database  to screen out candidate genes related to the methylation of TRIM58/cg26157385.	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (79, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('methylation', 'Var', (196, 207))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (79, 107))	('TRIM58', 'Gene', (211, 217))	('TRIM58', 'Gene', '25893', (211, 217))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (84, 107))	('lung squamous cell carcinoma', 'Disease', (79, 107))	('patients', 'Species', '9606', (108, 116))
224944	29749538	As a candidate tumor suppressor and a novel methylated gene, aberrant inactivation of TRIM58 consequent to CpG island hyper-methylation may stimulate the early carcinogenesis of lung adenocarcinoma, and furthermore, TRIM58 methylation may be a possible early diagnostic and epigenetic therapeutic target in lung adenocarcinoma.	('lung adenocarcinoma', 'Disease', (307, 326))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('carcinoma', 'Phenotype', 'HP:0030731', (317, 326))	('TRIM58', 'Gene', '25893', (216, 222))	('aberrant inactivation', 'Var', (61, 82))	('carcinogenesis of lung adenocarcinoma', 'Disease', (160, 197))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (307, 326))	('carcinogenesis of lung adenocarcinoma', 'Disease', 'MESH:D063646', (160, 197))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (307, 326))	('TRIM58', 'Gene', (216, 222))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (178, 197))	('TRIM58', 'Gene', '25893', (86, 92))	('hyper-methylation', 'Var', (118, 135))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (178, 197))	('stimulate', 'PosReg', (140, 149))	('tumor', 'Disease', (15, 20))	('carcinoma', 'Phenotype', 'HP:0030731', (188, 197))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('TRIM58', 'Gene', (86, 92))
224945	29749538	Therefore, the association between the significantly differentially expressed genes related to TRIM58 methylation and lung cancer should be documented by combining with clinical information.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('men', 'Species', '9606', (144, 147))	('lung cancer', 'Disease', 'MESH:D008175', (118, 129))	('methylation', 'Var', (102, 113))	('TRIM58', 'Gene', (95, 101))	('TRIM58', 'Gene', '25893', (95, 101))	('lung cancer', 'Disease', (118, 129))	('lung cancer', 'Phenotype', 'HP:0100526', (118, 129))
224950	29749538	A2ML1 is a kind of protease inhibitor belonging to the alpha-macroglobulin superfamily and displays a unique trap mechanism of inhibition, by which the A2M inhibitor undergoes a major conformational change upon its cleavage by a protease, thereby trapping the protease and blocking it from subsequent substrate binding.	('A2ML1', 'Gene', (0, 5))	('A2ML1', 'Gene', '144568', (0, 5))	('trapping', 'PosReg', (247, 255))	('conformational change', 'MPA', (184, 205))	('A2M', 'Var', (152, 155))	('blocking', 'NegReg', (273, 281))	('cleavage', 'MPA', (215, 223))
224953	29749538	CCNE1 is the most frequent amplified gene in ovarian serous carcinomas and its gene amplification is related to poor survival and potential therapeutic target in ovarian cancer, and therefore, CCNE1-targeted therapy may benefit ovarian cancer patients with CCNE1 amplification.	('CCNE1', 'Gene', '898', (193, 198))	('CCNE1', 'Gene', '898', (0, 5))	('ovarian cancer', 'Disease', (228, 242))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('ovarian serous carcinomas', 'Disease', 'MESH:D010051', (45, 70))	('ovarian cancer', 'Phenotype', 'HP:0100615', (228, 242))	('ovarian cancer', 'Disease', (162, 176))	('patients', 'Species', '9606', (243, 251))	('ovarian cancer', 'Phenotype', 'HP:0100615', (162, 176))	('ovarian serous carcinomas', 'Disease', (45, 70))	('amplification', 'Var', (263, 276))	('CCNE1', 'Gene', (257, 262))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('ovarian cancer', 'Disease', 'MESH:D010051', (228, 242))	('CCNE1', 'Gene', (193, 198))	('benefit', 'PosReg', (220, 227))	('CCNE1', 'Gene', (0, 5))	('CCNE1', 'Gene', '898', (257, 262))	('carcinoma', 'Phenotype', 'HP:0030731', (60, 69))	('ovarian cancer', 'Disease', 'MESH:D010051', (162, 176))	('carcinomas', 'Phenotype', 'HP:0030731', (60, 70))
224958	29749538	There was one gene in the last group, SCGB1A1, an anti-inflammatory protein predominantly expressed by Clara cells in the lung, and a certain number of results indicated that low SCGB1A1 level may play a key role in the pathophysiology of asthma.	('asthma', 'Phenotype', 'HP:0002099', (239, 245))	('SCGB1A1', 'Gene', '7356', (38, 45))	('low', 'Var', (175, 178))	('SCGB1A1', 'Gene', (179, 186))	('SCGB1A1', 'Gene', '7356', (179, 186))	('SCGB1A1', 'Gene', (38, 45))	('asthma', 'Disease', 'MESH:D001249', (239, 245))	('asthma', 'Disease', (239, 245))
224960	29749538	Further validation of these 8 prognostic genes associated with TRIM58 methylation were performed using risk score, clinical and molecular characteristics of patients in the training dataset.	('methylation', 'Var', (70, 81))	('TRIM58', 'Gene', (63, 69))	('TRIM58', 'Gene', '25893', (63, 69))	('patients', 'Species', '9606', (157, 165))
224967	29749538	The results indicated that all of them were significantly related to the methylation of TRIM58/cg26157385 and treatment of lung squamous cell carcinoma.	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (123, 151))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (128, 151))	('lung squamous cell carcinoma', 'Disease', (123, 151))	('TRIM58', 'Gene', (88, 94))	('TRIM58', 'Gene', '25893', (88, 94))	('men', 'Species', '9606', (115, 118))	('related', 'Reg', (58, 65))	('methylation', 'Var', (73, 84))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (123, 151))	('carcinoma', 'Phenotype', 'HP:0030731', (142, 151))
224978	26045178	The ranks of the disease terms in the AML patient group were compared with those in the healthy control group using "Leukemia, Myeloid, Acute" (C04.557.337.539.550) as the corresponding MeSH disease term.	('AML', 'Disease', (38, 41))	('Leukemia', 'Phenotype', 'HP:0001909', (117, 125))	('Myeloid', 'Disease', (127, 134))	('Leukemia', 'Disease', 'MESH:D007938', (117, 125))	('patient', 'Species', '9606', (42, 49))	('AML', 'Disease', 'MESH:D015470', (38, 41))	('Leukemia', 'Disease', (117, 125))	('C04.557.337.539.550', 'Var', (144, 163))	('AML', 'Phenotype', 'HP:0004808', (38, 41))
224985	26045178	They estimated a patient's risk of several common diseases using several types of information, including single-nucleotide polymorphisms that have been associated with the risk of these diseases.	('patient', 'Species', '9606', (17, 24))	('single-nucleotide polymorphisms', 'Var', (105, 136))	('common', 'Disease', (43, 49))
224993	26045178	Quantify damaging missense mutations in personal genome sequences using the Sorting Intolerant From Tolerant (SIFT) tool.	('person', 'Species', '9606', (40, 46))	('missense mutations', 'Var', (18, 36))	('SIFT', 'Disease', 'None', (110, 114))	('SIFT', 'Disease', (110, 114))
224995	26045178	Pairwise computation of mutual information between the SIFT score vectors of variants in the personal genomes and the disease-gene association vectors.	('SIFT', 'Disease', 'None', (55, 59))	('SIFT', 'Disease', (55, 59))	('variants', 'Var', (77, 85))	('person', 'Species', '9606', (93, 99))
225000	26045178	In order to measure the relative closeness between personal genomes and diseases, we created SIFT score vectors of variants (VSiftVar) for the personal genome sequences, and binary vectors for disease-gene association (VDisGene) obtained from OMIM.	('person', 'Species', '9606', (51, 57))	('SIFT', 'Disease', (93, 97))	('variants', 'Var', (115, 123))	('SIFT', 'Disease', 'None', (93, 97))	('person', 'Species', '9606', (143, 149))
225001	26045178	To assess the effect of a substitution, SIFT assumes that important positions in a protein sequence have been conserved throughout evolution, and substitutions at these positions may affect protein function.	('substitutions', 'Var', (146, 159))	('affect', 'Reg', (183, 189))	('SIFT', 'Disease', (40, 44))	('SIFT', 'Disease', 'None', (40, 44))	('protein function', 'MPA', (190, 206))
225002	26045178	By using sequence homology, SIFT predicts the effects of all possible substitutions at each position in the protein sequence.	('SIFT', 'Disease', 'None', (28, 32))	('SIFT', 'Disease', (28, 32))	('substitutions', 'Var', (70, 83))
225008	26045178	Higher mutual information between VSiftVar of a personal genome and VDisGene of a disease from OMIM means that the personal genome is more likely to be associated with the disease.	('person', 'Species', '9606', (48, 54))	('person', 'Species', '9606', (115, 121))	('mutual information', 'MPA', (7, 25))	('Higher', 'PosReg', (0, 6))	('associated', 'Reg', (152, 162))	('VSiftVar', 'Var', (34, 42))
225010	26045178	This means that mutual information can be used as a metric between SIFT scores of variants in the personal genome sequencing data and the disease-gene association obtained from OMIM related to their degree of independence.	('variants', 'Var', (82, 90))	('person', 'Species', '9606', (98, 104))	('SIFT', 'Disease', 'None', (67, 71))	('SIFT', 'Disease', (67, 71))
225011	26045178	We hypothesized that a higher mutual information score between VSiftVar of a personal genome and VDisGene of a disease implies that the personal genome is more susceptible to the disease than other diseases.	('higher', 'PosReg', (23, 29))	('mutual information score', 'MPA', (30, 54))	('person', 'Species', '9606', (77, 83))	('person', 'Species', '9606', (136, 142))	('VSiftVar', 'Var', (63, 71))
225015	26045178	To identify the different extent of damaging effects of variants between patients and healthy controls, we obtained SIFT scores for 494 variants in 447 genes from 50 unrelated AML patients, and extracted SIFT scores for the variants of the same genes in the healthy controls from the 1000 Genomes Project data.	('variants', 'Var', (136, 144))	('SIFT', 'Disease', 'None', (116, 120))	('AML', 'Phenotype', 'HP:0004808', (176, 179))	('AML', 'Disease', (176, 179))	('variants', 'Var', (56, 64))	('SIFT', 'Disease', (204, 208))	('SIFT', 'Disease', (116, 120))	('AML', 'Disease', 'MESH:D015470', (176, 179))	('SIFT', 'Disease', 'None', (204, 208))	('patients', 'Species', '9606', (73, 81))	('patients', 'Species', '9606', (180, 188))
225017	26045178	SIFT assigns a "functional importance" score to variants with a default cutoff threshold of 0.05, with variants with a SIFT score higher than this threshold regarded as "benign."	('SIFT', 'Disease', 'None', (119, 123))	('SIFT', 'Disease', 'None', (0, 4))	('variants', 'Var', (48, 56))	('SIFT', 'Disease', (119, 123))	('SIFT', 'Disease', (0, 4))
225018	26045178	Among the AML patients, 41.30% of the variants exhibit SIFT scores of < 0.05 and were thus designated as variants that are functionally damaging.	('SIFT', 'Disease', (55, 59))	('AML', 'Disease', (10, 13))	('variants', 'Var', (38, 46))	('SIFT', 'Disease', 'None', (55, 59))	('AML', 'Disease', 'MESH:D015470', (10, 13))	('patients', 'Species', '9606', (14, 22))	('AML', 'Phenotype', 'HP:0004808', (10, 13))
225019	26045178	In order to show that AML patients had statistically more variants with a damaging impact, we performed Fisher's exact test using the number of variants with damaging (< 0.05) and non-damaging (>= 0.05) effect because a SIFT score is smaller than 0.05, it is predicted to be "damaging"; otherwise, it is predicted to be "tolerated."	('AML', 'Disease', 'MESH:D015470', (22, 25))	('variants', 'Var', (58, 66))	('SIFT', 'Disease', 'None', (220, 224))	('AML', 'Phenotype', 'HP:0004808', (22, 25))	('patients', 'Species', '9606', (26, 34))	('AML', 'Disease', (22, 25))	('SIFT', 'Disease', (220, 224))
225020	26045178	The Fisher's exact test showed that AML patients had statistically more variants with a damaging impact than healthy controls in the 1000 Genome Project data (P = 6.441e-08, African controls; P = 1.808e-08, European controls; P = 1.206e-06, Asian controls).	('AML', 'Disease', 'MESH:D015470', (36, 39))	('patients', 'Species', '9606', (40, 48))	('AML', 'Disease', (36, 39))	('AML', 'Phenotype', 'HP:0004808', (36, 39))	('variants', 'Var', (72, 80))
225025	26045178	In particular, arthritis (C05.550.114), ichthyosis vulgaris (C16.131.831.512.410, C16.320.850.405, C17.800.428.333.410, C17.800.804.512.410, and C17.800.827.405) and viremia (C02.937, C23.550.470.790.500.900) are only associated with Asian subpopulations, and AIDS-related complex (C02.782.815.616.400.080, C02.800.801.400.080, C02.839.080, and C20.673.480.080) and hematuria (C12.777.934.442, C13.351.968.934.442, and C23.550.414.849) are only associated with European subpopulations.	('hematuria', 'Disease', (366, 375))	('C16.320.850.405', 'Var', (82, 97))	('AIDS', 'Disease', 'MESH:D000163', (260, 264))	('C13.351.968.934.442', 'Var', (394, 413))	('C17', 'Gene', '54360', (99, 102))	('C02.800.801.400.080', 'Var', (307, 326))	('C02.937', 'Var', (175, 182))	('ichthyosis', 'Phenotype', 'HP:0008064', (40, 50))	('C17', 'Gene', '54360', (145, 148))	('C17', 'Gene', (99, 102))	('C23', 'Gene', (184, 187))	('hematuria', 'Disease', 'MESH:D006417', (366, 375))	('C02.839.080', 'Var', (328, 339))	('arthritis', 'Disease', 'MESH:D001168', (15, 24))	('C23', 'Gene', '4691', (184, 187))	('C16.131.831.512.410', 'CellLine', 'CVCL:8662', (61, 80))	('viremia', 'Phenotype', 'HP:0020071', (166, 173))	('C17', 'Gene', (145, 148))	('hematuria', 'Phenotype', 'HP:0000790', (366, 375))	('C20.673.480.080', 'Var', (345, 360))	('AIDS', 'Disease', (260, 264))	('C16.131.831.512.410', 'Var', (61, 80))	('arthritis', 'Disease', (15, 24))	('C12.777.934.442', 'CellLine', 'CVCL:0899', (377, 392))	('C23', 'Gene', (419, 422))	('viremia', 'Disease', 'MESH:D014766', (166, 173))	('C12.777.934.442', 'Var', (377, 392))	('ichthyosis vulgaris', 'Disease', (40, 59))	('C17', 'Gene', '54360', (120, 123))	('C02.782.815.616.400.080', 'Var', (282, 305))	('C23', 'Gene', '4691', (419, 422))	('C17', 'Gene', (120, 123))	('viremia', 'Disease', (166, 173))	('arthritis', 'Phenotype', 'HP:0001369', (15, 24))	('C05.550.114', 'Var', (26, 37))	('C13.351.968.934.442', 'CellLine', 'CVCL:1031', (394, 413))	('ichthyosis vulgaris', 'Disease', 'MESH:D016112', (40, 59))
225030	26045178	The red solid line in Figure 4 indicates the distribution of the rank of the disease term "leukemia, myeloid, acute" (C04.557.337.539.550) in the AML patient group, and the dashed lines indicate the distribution of the rank of the disease term in the healthy control group according to the various subpopulations.	('patient', 'Species', '9606', (150, 157))	('AML', 'Disease', (146, 149))	('AML', 'Phenotype', 'HP:0004808', (146, 149))	('C04.557.337.539.550', 'Var', (118, 137))	('myeloid', 'Disease', (101, 108))	('leukemia', 'Phenotype', 'HP:0001909', (91, 99))	('leukemia', 'Disease', 'MESH:D007938', (91, 99))	('AML', 'Disease', 'MESH:D015470', (146, 149))	('leukemia', 'Disease', (91, 99))
225041	26045178	The bar plot of rank percentage shows that AML patient group have higher rank on "leukemia, myeloid, acute" (C04.557.337.539.550) than healthy controls (Additional file 4).	('leukemia', 'Disease', (82, 90))	('patient', 'Species', '9606', (47, 54))	('AML', 'Disease', 'MESH:D015470', (43, 46))	('AML', 'Phenotype', 'HP:0004808', (43, 46))	('AML', 'Disease', (43, 46))	('higher', 'PosReg', (66, 72))	('C04.557.337.539.550', 'Var', (109, 128))	('myeloid', 'Disease', (92, 99))	('leukemia', 'Phenotype', 'HP:0001909', (82, 90))	('leukemia', 'Disease', 'MESH:D007938', (82, 90))
225078	26005340	In patients with CF, an autosomal recessive disease with radiological features of bronchiectasis, the CF gene mutation is inversely associated with malignancies such as melanoma, breast cancer, colon cancer, and prostate cancer.	('melanoma', 'Phenotype', 'HP:0002861', (169, 177))	('melanoma', 'Disease', (169, 177))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('bronchiectasis', 'Disease', (82, 96))	('colon cancer', 'Disease', 'MESH:D015179', (194, 206))	('autosomal recessive disease', 'Disease', (24, 51))	('breast cancer', 'Phenotype', 'HP:0003002', (179, 192))	('breast cancer', 'Disease', 'MESH:D001943', (179, 192))	('breast cancer', 'Disease', (179, 192))	('malignancies', 'Disease', 'MESH:D009369', (148, 160))	('melanoma', 'Disease', 'MESH:D008545', (169, 177))	('colon cancer', 'Disease', (194, 206))	('patients', 'Species', '9606', (3, 11))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('mutation', 'Var', (110, 118))	('associated', 'Reg', (132, 142))	('CF gene', 'Gene', (102, 109))	('malignancies', 'Disease', (148, 160))	('prostate cancer', 'Disease', 'MESH:D011471', (212, 227))	('bronchiectasis', 'Phenotype', 'HP:0002110', (82, 96))	('prostate cancer', 'Phenotype', 'HP:0012125', (212, 227))	('autosomal recessive disease', 'Disease', 'MESH:D030342', (24, 51))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('prostate cancer', 'Disease', (212, 227))	('colon cancer', 'Phenotype', 'HP:0003003', (194, 206))
225079	26005340	These reports suggest that the association between non-CF bronchiectasis and lung cancer might not be consistent with the positive association between chronic bronchitis/emphysema and lung cancer, and on the basis of these findings, we assumed that non-CF bronchiectasis could be associated with lower risk of lung cancer in COPD patients.	('COPD', 'Disease', 'MESH:D029424', (325, 329))	('COPD', 'Disease', (325, 329))	('patients', 'Species', '9606', (330, 338))	('chronic bronchitis', 'Phenotype', 'HP:0004469', (151, 169))	('lung cancer', 'Disease', (77, 88))	('lung cancer', 'Disease', 'MESH:D008175', (310, 321))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('lung cancer', 'Disease', 'MESH:D008175', (184, 195))	('lung cancer', 'Phenotype', 'HP:0100526', (310, 321))	('non-CF', 'Var', (249, 255))	('lung cancer', 'Phenotype', 'HP:0100526', (184, 195))	('bronchitis/emphysema', 'Disease', (159, 179))	('bronchiectasis', 'Phenotype', 'HP:0002110', (58, 72))	('bronchitis', 'Phenotype', 'HP:0012387', (159, 169))	('bronchitis/emphysema', 'Disease', 'MESH:D001991', (159, 179))	('emphysema', 'Phenotype', 'HP:0002097', (170, 179))	('lung cancer', 'Disease', 'MESH:D008175', (77, 88))	('cancer', 'Phenotype', 'HP:0002664', (315, 321))	('bronchiectasis', 'Phenotype', 'HP:0002110', (256, 270))	('lung cancer', 'Phenotype', 'HP:0100526', (77, 88))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('lung cancer', 'Disease', (310, 321))	('lung cancer', 'Disease', (184, 195))	('COPD', 'Phenotype', 'HP:0006510', (325, 329))
225081	26005340	We screened COPD patients older than 40 years who had moderate to very severe airflow limitation with a post-bronchodilator forced expiratory volume in one second (FEV1) <=70% and FEV1/forced vital capacity (FVC) <0.7 and who underwent chest computed tomography (CT) between January 1, 2010 and May 30, 2013.	('COPD', 'Disease', (12, 16))	('airflow limitation', 'Disease', (78, 96))	('<=70', 'Var', (170, 174))	('FEV1/forced', 'Var', (180, 191))	('COPD', 'Phenotype', 'HP:0006510', (12, 16))	('patients', 'Species', '9606', (17, 25))	('COPD', 'Disease', 'MESH:D029424', (12, 16))	('forced expiratory volume in one second', 'Phenotype', 'HP:0032342', (124, 162))
225109	26005340	CF is a life-limiting autosomal recessive disorder involving the CFTR mutation and shows the radiological features of bronchiectasis.	('autosomal recessive disorder', 'Disease', 'MESH:D030342', (22, 50))	('autosomal recessive disorder', 'Disease', (22, 50))	('CFTR', 'Gene', (65, 69))	('bronchiectasis', 'Phenotype', 'HP:0002110', (118, 132))	('bronchiectasis', 'Disease', (118, 132))	('mutation', 'Var', (70, 78))	('CFTR', 'Gene', '1080', (65, 69))
225110	26005340	In CF patients, the CF gene mutation is inversely associated with the incidence of melanoma, breast cancer, colon cancer, and prostate cancer.	('mutation', 'Var', (28, 36))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('patients', 'Species', '9606', (6, 14))	('breast cancer', 'Phenotype', 'HP:0003002', (93, 106))	('melanoma', 'Disease', 'MESH:D008545', (83, 91))	('colon cancer', 'Disease', (108, 120))	('breast cancer', 'Disease', 'MESH:D001943', (93, 106))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('breast cancer', 'Disease', (93, 106))	('colon cancer', 'Phenotype', 'HP:0003003', (108, 120))	('melanoma', 'Phenotype', 'HP:0002861', (83, 91))	('melanoma', 'Disease', (83, 91))	('prostate cancer', 'Disease', 'MESH:D011471', (126, 141))	('prostate cancer', 'Phenotype', 'HP:0012125', (126, 141))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('prostate cancer', 'Disease', (126, 141))	('colon cancer', 'Disease', 'MESH:D015179', (108, 120))	('associated', 'Reg', (50, 60))	('CF gene', 'Gene', (20, 27))
225111	26005340	Furthermore, a case-control study suggested that the  F508 deletion in the CFTR gene is an important protective variant for lung cancer risk.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('lung cancer', 'Disease', 'MESH:D008175', (124, 135))	('F508 deletion', 'Var', (54, 67))	('CFTR', 'Gene', (75, 79))	('CFTR', 'Gene', '1080', (75, 79))	('lung cancer', 'Disease', (124, 135))	('lung cancer', 'Phenotype', 'HP:0100526', (124, 135))
225186	30917608	Typical risk factors for these oral epithelial cancers can be subdivided into three groups: chronic irritants of the aerodigestive tract (e.g., tobacco and alcoholic beverages), genetic syndromes caused by genomic instability and DNA repair defects, and human papillomavirus infections leading to cell cycle alterations.	('genetic syndromes', 'Disease', (178, 195))	('genetic syndromes', 'Disease', 'MESH:D030342', (178, 195))	('oral epithelial cancers', 'Disease', (31, 54))	('leading to', 'Reg', (286, 296))	('oral epithelial cancers', 'Disease', 'MESH:D009062', (31, 54))	('human', 'Species', '9606', (254, 259))	('papillomavirus infections', 'Phenotype', 'HP:0012740', (260, 285))	('papilloma', 'Phenotype', 'HP:0012740', (260, 269))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('alcohol', 'Chemical', 'MESH:D000438', (156, 163))	('cancers', 'Phenotype', 'HP:0002664', (47, 54))	('papillomavirus infections', 'Disease', (260, 285))	('cell cycle alterations', 'CPA', (297, 319))	('caused', 'Reg', (196, 202))	('papillomavirus infections', 'Disease', 'MESH:D030361', (260, 285))	('cell cycle alterations', 'Phenotype', 'HP:0011018', (297, 319))	('tobacco', 'Species', '4097', (144, 151))	('rat', 'Species', '10116', (312, 315))	('defects', 'Var', (241, 248))
225187	30917608	Patients with a history of tobacco consumption have more gene mutations associated with tumor growth than non-tobacco users, especially when combined with the abuse of alcohol.	('abuse of alcohol', 'Phenotype', 'HP:0030955', (159, 175))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('tobacco', 'Species', '4097', (27, 34))	('alcohol', 'Chemical', 'MESH:D000438', (168, 175))	('Patients', 'Species', '9606', (0, 8))	('gene mutations', 'Var', (57, 71))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tobacco', 'Species', '4097', (110, 117))	('tumor', 'Disease', (88, 93))
225192	30917608	Normal epithelial cells might develop into cancerous cells as a consequence of specific genetic alterations, gene deletions/amplifications or epigenetic modifications.	('gene deletions/amplifications', 'Var', (109, 138))	('cancerous', 'Disease', (43, 52))	('epithelia', 'Disease', 'None', (7, 16))	('genetic alterations', 'Var', (88, 107))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('epigenetic modifications', 'Var', (142, 166))	('epithelia', 'Disease', (7, 16))	('rat', 'Species', '10116', (100, 103))	('cancerous', 'Disease', 'MESH:D009369', (43, 52))
225194	30917608	It is required for cell fate decisions at multiple stages of embryonic development as well as in the adult organism, while dysregulation of the pathway is associated with genetic and acquired diseases, including cancer.	('associated', 'Reg', (155, 165))	('dysregulation', 'Var', (123, 136))	('cancer', 'Disease', (212, 218))	('cancer', 'Disease', 'MESH:D009369', (212, 218))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))
225195	30917608	In mammals, four Notch receptors have been described (Notch1, Notch2, Notch3, and Notch4) and five ligands: two of the Jagged family (Jagged 1 and Jagged2) and three members of the Delta-like family (Dll1, Dll3, Dll4).	('Jagged 1', 'Gene', '182', (134, 142))	('Dll3', 'Gene', '10683', (206, 210))	('Notch4', 'Gene', '4855', (82, 88))	('Dll3', 'Gene', (206, 210))	('Notch3', 'Gene', '4854', (70, 76))	('Notch4', 'Gene', (82, 88))	('Notch2', 'Gene', (62, 68))	('Notch3', 'Gene', (70, 76))	('Dll4', 'Gene', (212, 216))	('Notch1', 'Var', (54, 60))	('Jagged 1', 'Gene', (134, 142))	('Dll4', 'Gene', '54567', (212, 216))	('Notch2', 'Gene', '4853', (62, 68))	('Dll1', 'Gene', (200, 204))	('Dll1', 'Gene', '28514', (200, 204))
225199	30917608	Upon S3 cleavage, the NICD binds to importin alpha3, alpha4, or alpha7 with its nuclear localizing sequence (NLS).	('binds', 'Interaction', (27, 32))	('S3 cleavage', 'Var', (5, 16))	('importin alpha3', 'Gene', (36, 51))	('importin alpha3', 'Gene', '3839', (36, 51))	('alpha4', 'Protein', (53, 59))	('alpha7', 'Protein', (64, 70))
225202	30917608	Recently, noncanonical activation of Notch has been associated with tumorigenic events in various cancers (breast cancer tumor progression, leukemia and hematopoietic proliferation, neuroblastoma models).	('cancers', 'Phenotype', 'HP:0002664', (98, 105))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('rat', 'Species', '10116', (174, 177))	('cancers', 'Disease', (98, 105))	('breast cancer tumor', 'Disease', 'MESH:D001943', (107, 126))	('breast cancer tumor', 'Phenotype', 'HP:0100013', (107, 126))	('tumor', 'Disease', (68, 73))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('tumor', 'Disease', (121, 126))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('breast cancer', 'Phenotype', 'HP:0003002', (107, 120))	('neuroblastoma', 'Disease', (182, 195))	('tumor', 'Disease', 'MESH:D009369', (121, 126))	('neuroblastoma', 'Phenotype', 'HP:0003006', (182, 195))	('leukemia', 'Phenotype', 'HP:0001909', (140, 148))	('associated', 'Reg', (52, 62))	('cancers', 'Disease', 'MESH:D009369', (98, 105))	('hematopoietic proliferation', 'Disease', (153, 180))	('neuroblastoma', 'Disease', 'MESH:D009447', (182, 195))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('noncanonical activation', 'Var', (10, 33))	('breast cancer tumor', 'Disease', (107, 126))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('leukemia', 'Disease', (140, 148))	('leukemia', 'Disease', 'MESH:D007938', (140, 148))	('Notch', 'Gene', (37, 42))
225218	30917608	Mutations in the Notch pathway lead to a variety of disorders and malformations.	('malformations', 'Disease', 'MESH:D000014', (66, 79))	('malformations', 'Disease', (66, 79))	('lead to', 'Reg', (31, 38))	('Mutations', 'Var', (0, 9))	('Notch pathway', 'Pathway', (17, 30))	('disorders', 'Disease', (52, 61))
225220	30917608	The interaction Notch-Jagged has been directly associated with misregulated fusion, and mutant mouse models for Jagged2 develop palate clefting.	('palate clefting', 'Phenotype', 'HP:0000175', (128, 143))	('Notch-Jagged', 'Gene', (16, 28))	('develop', 'Reg', (120, 127))	('palate clefting', 'Disease', (128, 143))	('mutant', 'Var', (88, 94))	('Jagged2', 'Gene', (112, 119))	('palate clefting', 'Disease', 'MESH:D002972', (128, 143))	('mouse', 'Species', '10090', (95, 100))
225222	30917608	Based on genetic screenings, most cases are thought to be caused by mutations in the Jagged1 and Notch2 genes.	('Notch2', 'Gene', '4853', (97, 103))	('Jagged1', 'Gene', (85, 92))	('mutations', 'Var', (68, 77))	('Notch2', 'Gene', (97, 103))	('caused by', 'Reg', (58, 67))	('Jagged1', 'Gene', '182', (85, 92))
225225	30917608	During vasculature establishment and maintenance, the altered expression of Notch3 and Notch4 receptors results in arteriovenous malformation.	('Notch4', 'Gene', (87, 93))	('arteriovenous malformation', 'Phenotype', 'HP:0100026', (115, 141))	('arteriovenous malformation', 'Disease', 'MESH:D001165', (115, 141))	('Notch3', 'Gene', '4854', (76, 82))	('arteriovenous malformation', 'Disease', (115, 141))	('Notch3', 'Gene', (76, 82))	('altered expression', 'Var', (54, 72))	('Notch4', 'Gene', '4855', (87, 93))	('expression', 'Var', (62, 72))	('results in', 'Reg', (104, 114))
225232	30917608	Loss of Notch1 promotes a tumor-inducing effect, impairing barrier integrity and generating a wound-like environment in the underlying stroma.	('impairing', 'NegReg', (49, 58))	('wound-like environment', 'MPA', (94, 116))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('Notch1', 'Gene', (8, 14))	('rat', 'Species', '10116', (85, 88))	('barrier', 'MPA', (59, 66))	('generating', 'Reg', (81, 91))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('Loss', 'Var', (0, 4))
225235	30917608	Inactivating mutations of Notch1 can be found in approximately 10% of all cases of squamous cell carcinoma including the oral cavity, indicating that Notch1 is one of the most mutated gene in squamous cell carcinoma.	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (192, 215))	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (206, 215))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (83, 106))	('squamous cell carcinoma', 'Disease', (83, 106))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (83, 106))	('Inactivating mutations', 'Var', (0, 22))	('found', 'Reg', (40, 45))	('Notch1', 'Gene', (26, 32))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (192, 215))	('carcinoma including the oral cavity', 'Phenotype', 'HP:0100649', (97, 132))	('squamous cell carcinoma', 'Disease', (192, 215))
225258	30917608	Macrophages found in the tumor microenvironment participate in the regulation of vasculature remodeling, and strongly express Notch1, Notch2, and Notch4, together with VEGFR1 (Figure 3).	('Notch4', 'Gene', (146, 152))	('participate', 'Reg', (48, 59))	('VEGFR1', 'Gene', (168, 174))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('Notch2', 'Gene', (134, 140))	('vasculature remodeling', 'MPA', (81, 103))	('tumor', 'Disease', (25, 30))	('Notch1', 'Var', (126, 132))	('Notch2', 'Gene', '4853', (134, 140))	('Notch4', 'Gene', '4855', (146, 152))	('VEGFR1', 'Gene', '2321', (168, 174))
225260	30917608	In lung cancer, VEGF directly affects expression of Dll4 in tumor vessels, as well as in neuroblastoma models, where blocking VEGFR2 increases the level of Jagged1 expression and consequent Notch1 hyperactivation.	('affects', 'Reg', (30, 37))	('Notch1', 'MPA', (190, 196))	('lung cancer', 'Phenotype', 'HP:0100526', (3, 14))	('neuroblastoma', 'Disease', (89, 102))	('tumor', 'Disease', (60, 65))	('neuroblastoma', 'Phenotype', 'HP:0003006', (89, 102))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('neuroblastoma', 'Disease', 'MESH:D009447', (89, 102))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('blocking', 'Var', (117, 125))	('Jagged1', 'Gene', '182', (156, 163))	('Dll4', 'Gene', '54567', (52, 56))	('VEGFR2', 'Gene', (126, 132))	('lung cancer', 'Disease', (3, 14))	('expression', 'MPA', (38, 48))	('Jagged1', 'Gene', (156, 163))	('Dll4', 'Gene', (52, 56))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('increases', 'PosReg', (133, 142))	('VEGFR2', 'Gene', '3791', (126, 132))	('VEGF', 'Gene', '7422', (16, 20))	('expression', 'MPA', (164, 174))	('VEGF', 'Gene', '7422', (126, 130))	('hyperactivation', 'PosReg', (197, 212))	('VEGF', 'Gene', (16, 20))	('VEGF', 'Gene', (126, 130))	('lung cancer', 'Disease', 'MESH:D008175', (3, 14))
225265	30917608	Finally, blocking Notch in tumor vasculature significantly reduces tumor growth, suggesting that endothelial Notch is a potential target for disrupting tumor microenvironment and pathological progression.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('tumor', 'Disease', (27, 32))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('reduces', 'NegReg', (59, 66))	('tumor', 'Disease', (152, 157))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('disrupting tumor', 'Disease', (141, 157))	('disrupting tumor', 'Disease', 'MESH:D019958', (141, 157))	('tumor', 'Disease', (67, 72))	('blocking', 'Var', (9, 17))
225270	30917608	Dysregulation of EMT can result in scar formation and fibrosis with consequent malfunctioning of the organ.	('EMT', 'Gene', (17, 20))	('Dysregulation', 'Var', (0, 13))	('scar formation', 'CPA', (35, 49))	('scar', 'Phenotype', 'HP:0100699', (35, 39))	('result in', 'Reg', (25, 34))	('fibrosis', 'Disease', 'MESH:D005355', (54, 62))	('fibrosis', 'Disease', (54, 62))
225281	30917608	In a subset of lung cancer cells, Gefitinib-resistant cells displayed an EMT phenotype as well as an increase in Notch1 expression, when compared to their parental cells.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('expression', 'MPA', (120, 130))	('EMT phenotype', 'CPA', (73, 86))	('increase', 'PosReg', (101, 109))	('Gefitinib', 'Chemical', 'MESH:D000077156', (34, 43))	('lung cancer', 'Disease', 'MESH:D008175', (15, 26))	('Gefitinib-resistant', 'Var', (34, 53))	('lung cancer', 'Disease', (15, 26))	('lung cancer', 'Phenotype', 'HP:0100526', (15, 26))	('Notch1', 'Gene', (113, 119))
225282	30917608	On the other hand, when Notch1 was ablated in parental lung carcinoma cells, EMT was inhibited.	('inhibited', 'NegReg', (85, 94))	('ablated', 'Var', (35, 42))	('EMT', 'CPA', (77, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (60, 69))	('parental lung carcinoma', 'Disease', (46, 69))	('parental lung carcinoma', 'Disease', 'MESH:D063129', (46, 69))	('Notch1', 'Gene', (24, 30))
225283	30917608	Gefitinib-sensitive parental cells were capable of acquiring an EMT phenotype upon Notch1 overexpression, which leads to the conclusion that Notch1 is a key player in the regulation of EMT.	('overexpression', 'Var', (90, 104))	('EMT phenotype', 'CPA', (64, 77))	('Notch1', 'Gene', (83, 89))	('Gefitinib', 'Chemical', 'MESH:D000077156', (0, 9))
225304	30917608	In this context, Notch1 plays a coordinating role, as inhibition of the Notch-Hes1 signaling inhibits CSC phenotype in OSCC (Figure 3).	('inhibition', 'Var', (54, 64))	('Hes1', 'Gene', (78, 82))	('Hes1', 'Gene', '3280', (78, 82))	('inhibits', 'NegReg', (93, 101))	('OSCC', 'Disease', (119, 123))	('CSC', 'Disease', (102, 105))
225307	30917608	In more than 50% of T-ALL cases, the patients have a chromosomal translocation (q34; q34.3) resulting in a truncated Notch receptor, which leads to a constantly active Notch1.	('Notch receptor', 'Protein', (117, 131))	('patients', 'Species', '9606', (37, 45))	('T-ALL', 'Phenotype', 'HP:0006727', (20, 25))	('truncated', 'Var', (107, 116))	('leads to', 'Reg', (139, 147))	('q34; q34.3', 'Var', (80, 90))	('Notch1', 'MPA', (168, 174))
225334	30917608	Elevated levels of the Notch1 receptor have been found during CAF activation, as shown in melanoma, where Notch1-expression negatively influences cancer growth and invasion.	('Notch1-expression', 'Var', (106, 123))	('melanoma', 'Disease', (90, 98))	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('melanoma', 'Disease', 'MESH:D008545', (90, 98))	('levels', 'MPA', (9, 15))	('negatively', 'NegReg', (124, 134))	('CAF', 'Gene', (62, 65))	('influences', 'Reg', (135, 145))	('invasion', 'CPA', (164, 172))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('CAF', 'Gene', '8850', (62, 65))	('melanoma', 'Phenotype', 'HP:0002861', (90, 98))
225342	30917608	In regard to tumor-suppressing roles, it could be shown that blockage of NF-kB, as well as Ras, leads to invasive epidermal neoplasia mediated by the activity of tumor necrosis factor/c-Jun N-terminal kinase (TNF/JNK).	('tumor', 'Disease', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('invasive epidermal neoplasia', 'Disease', (105, 133))	('tumor necrosis', 'Disease', 'MESH:D009336', (162, 176))	('TNF/JNK', 'Gene', '7124;5599', (209, 216))	('tumor', 'Disease', (162, 167))	('leads to', 'Reg', (96, 104))	('NF-kB', 'Gene', (73, 78))	('neoplasia', 'Phenotype', 'HP:0002664', (124, 133))	('TNF/JNK', 'Gene', (209, 216))	('invasive epidermal neoplasia', 'Disease', 'MESH:D009369', (105, 133))	('tumor necrosis', 'Disease', (162, 176))	('blockage', 'Var', (61, 69))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('activity', 'MPA', (150, 158))
225349	30917608	Similarly, in an in vivo model for HNSCC, activation of Notch1 resulted in reduced tumorigenicity.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('HNSCC', 'Phenotype', 'HP:0012288', (35, 40))	('HNSCC', 'Disease', (35, 40))	('tumor', 'Disease', (83, 88))	('Notch1', 'Gene', (56, 62))	('activation', 'Var', (42, 52))	('reduced', 'NegReg', (75, 82))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
225356	30917608	Notch1 activation leads to an increased level of the E3 ubiquitin ligase mouse double minute homolog 2 (MDM2), which targets p53 for subsequent degradation (Figure 4).	('level', 'MPA', (40, 45))	('E3 ubiquitin ligase', 'Protein', (53, 72))	('Notch1', 'Gene', (0, 6))	('activation', 'Var', (7, 17))	('increased', 'PosReg', (30, 39))	('mouse', 'Species', '10090', (73, 78))	('degradation', 'MPA', (144, 155))
225360	30917608	Aberration in the EGFR-PI3K-AKT pathways is a hallmark for oral cancer, where the cytoplasmatic phosphorylated form of AKT is expressed in more than 64% of cases (Figure 4).	('EGFR', 'Gene', '1956', (18, 22))	('AKT', 'Gene', (28, 31))	('oral cancer', 'Disease', 'MESH:D009062', (59, 70))	('AKT', 'Gene', '207', (119, 122))	('EGFR', 'Gene', (18, 22))	('oral cancer', 'Disease', (59, 70))	('AKT', 'Gene', (119, 122))	('rat', 'Species', '10116', (4, 7))	('AKT', 'Gene', '207', (28, 31))	('Aberration', 'Var', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
225362	30917608	Blockage of AKT and PI3K phosphorylation induces cell cycle arrest and apoptosis in OSCC cells.	('Blockage', 'Var', (0, 8))	('AKT', 'Gene', '207', (12, 15))	('apoptosis', 'CPA', (71, 80))	('PI3K', 'Protein', (20, 24))	('AKT', 'Gene', (12, 15))	('arrest', 'Disease', 'MESH:D006323', (60, 66))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (49, 66))	('arrest', 'Disease', (60, 66))
225365	30917608	In a screening for Notch1 inactivating mutation, the oncogenic phenotype was associated with activation of the EGF-PI3K/AKT pathway and resulted in increased cell proliferation, EMT, and invasion in OSCC cell lines.	('AKT', 'Gene', (120, 123))	('inactivating mutation', 'Var', (26, 47))	('activation', 'PosReg', (93, 103))	('cell proliferation', 'CPA', (158, 176))	('increased', 'PosReg', (148, 157))	('rat', 'Species', '10116', (170, 173))	('EGF', 'Gene', '1950', (111, 114))	('AKT', 'Gene', '207', (120, 123))	('EMT', 'CPA', (178, 181))	('Notch1', 'Gene', (19, 25))	('invasion', 'CPA', (187, 195))	('EGF', 'Gene', (111, 114))
225368	30917608	In OSCC, activation of the Wnt pathway can occur in absence of beta-catenin and colon-cancer specific mutations, suggesting that altered epigenetic changes might compensate for the canonical activation of the pathway (Figure 4).	('beta-catenin', 'Gene', (63, 75))	('activation', 'PosReg', (9, 19))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('beta-catenin', 'Gene', '1499', (63, 75))	('Wnt pathway', 'Pathway', (27, 38))	('colon-cancer', 'Disease', (80, 92))	('mutations', 'Var', (102, 111))	('colon-cancer', 'Disease', 'MESH:D015179', (80, 92))	('OSCC', 'Disease', (3, 7))
225370	30917608	Mutations in HH-pathways have been found in basal cell carcinoma, medulloblastoma, and rhabdomyosarcoma, and normally correlate with an hyperactivation of the pathway.	('sarcoma', 'Phenotype', 'HP:0100242', (96, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (55, 64))	('medulloblastoma', 'Disease', 'MESH:D008527', (66, 81))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (87, 103))	('HH-pathways', 'Gene', (13, 24))	('medulloblastoma', 'Phenotype', 'HP:0002885', (66, 81))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (44, 64))	('Mutations', 'Var', (0, 9))	('hyperactivation', 'PosReg', (136, 151))	('basal cell carcinoma', 'Disease', (44, 64))	('basal cell carcinoma', 'Disease', 'MESH:D002280', (44, 64))	('rhabdomyosarcoma', 'Disease', (87, 103))	('medulloblastoma', 'Disease', (66, 81))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (87, 103))	('found', 'Reg', (35, 40))
225382	30917608	As the p53 gene is mutated in 70% of HNSCC, this mouse was further crossed with p53+/- and p53-/- mice, resulting in mice that develop invasive oral-esophageal squamous cell carcinoma.	('develop', 'PosReg', (127, 134))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (160, 183))	('mutated', 'Var', (19, 26))	('mice', 'Species', '10090', (117, 121))	('mouse', 'Species', '10090', (49, 54))	('HNSCC', 'Phenotype', 'HP:0012288', (37, 42))	('carcinoma', 'Phenotype', 'HP:0030731', (174, 183))	('oral-esophageal squamous cell carcinoma', 'Disease', (144, 183))	('oral-esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (144, 183))	('p53', 'Gene', (7, 10))	('mice', 'Species', '10090', (98, 102))
225387	30917608	Upon induced-ablation of the two genes, mice develop hyperplasia in the oral epithelium.	('induced-ablation', 'Var', (5, 21))	('hyperplasia', 'Disease', (53, 64))	('hyperplasia', 'Disease', 'MESH:D006965', (53, 64))	('mice', 'Species', '10090', (40, 44))	('hyperplasia in the oral epithelium', 'Phenotype', 'HP:0410340', (53, 87))
225388	30917608	The loss of Tgfbr1 and Pten was shown to lead to cancer-related inflammation as well as cancer stem cell expansion in the basal epithelial layer of this model.	('epithelia', 'Disease', 'None', (128, 137))	('epithelia', 'Disease', (128, 137))	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('Pten', 'Gene', (23, 27))	('inflammation', 'Disease', 'MESH:D007249', (64, 76))	('Tgfbr1', 'Gene', (12, 18))	('inflammation', 'Disease', (64, 76))	('lead to', 'Reg', (41, 48))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('cancer', 'Disease', (49, 55))	('loss', 'Var', (4, 8))
225392	30917608	Overexpression of KrasG12D under the control of cK5 affects the basal epithelium, while under the regulation of cK14, alterations are mainly found in the basal layer of oral mucosa and the tongue.	('KrasG12D', 'Var', (18, 26))	('alterations', 'Reg', (118, 129))	('rat', 'Species', '10116', (122, 125))	('cK5', 'Gene', (48, 51))	('affects', 'Reg', (52, 59))
225401	30917608	Inhibiting Notch1 in an HNSCC xenograft mouse model resulted in reduced cancer stem cell renewal.	('Inhibiting', 'Var', (0, 10))	('Notch1', 'Gene', (11, 17))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('reduced', 'NegReg', (64, 71))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('mouse', 'Species', '10090', (40, 45))	('HNSCC', 'Phenotype', 'HP:0012288', (24, 29))	('cancer', 'Disease', (72, 78))
225430	29568882	The prognostic risk model consisting of RP5-821D11.7, APCDD1L-AS1 and RP11-277P12.9 was established, which had a good classification effect.	('RP11', 'Gene', (70, 74))	('APCDD1L-AS1', 'Gene', (54, 65))	('RP11', 'Gene', '26121', (70, 74))	('APCDD1L-AS1', 'Gene', '149773', (54, 65))	('RP5-821D11.7', 'Var', (40, 52))
225433	29568882	In conclusion, the expression levels of the lncRNAs RP5-821D11.7, APCDD1L-AS1 and RP11-277P12.9 may affect the prognosis of LUSC.	('APCDD1L-AS1', 'Gene', '149773', (66, 77))	('LUSC', 'Phenotype', 'HP:0030359', (124, 128))	('expression', 'MPA', (19, 29))	('affect', 'Reg', (100, 106))	('LUSC', 'Disease', (124, 128))	('RP11', 'Gene', (82, 86))	('RP5-821D11.7', 'Var', (52, 64))	('APCDD1L-AS1', 'Gene', (66, 77))	('prognosis', 'CPA', (111, 120))	('RP11', 'Gene', '26121', (82, 86))
225438	29568882	For example, Zhang et al reported that lncRNA 1133 (LINC01133) is overexpressed in patients with LUSC and may shorten their survival time, thus LINC01133 is a promising biomarker for LUSC.	('LUSC', 'Phenotype', 'HP:0030359', (183, 187))	('LINC01133', 'Gene', '100505633', (52, 61))	('LINC01133', 'Gene', (144, 153))	('overexpressed', 'PosReg', (66, 79))	('LUSC', 'Phenotype', 'HP:0030359', (97, 101))	('LINC01133', 'Gene', (52, 61))	('survival time', 'CPA', (124, 137))	('shorten', 'NegReg', (110, 117))	('patients', 'Species', '9606', (83, 91))	('lncRNA 1133', 'Var', (39, 50))	('LINC01133', 'Gene', '100505633', (144, 153))
225461	29568882	Subsequently, Cox multivariate regression analysis indicated that 3 prognosis-associated DELs (including RP5-821D11.7, APCDD1L-AS1 and RP11-277P12.9) had important prognostic value.	('APCDD1L-AS1', 'Gene', '149773', (119, 130))	('RP11', 'Gene', (135, 139))	('Cox', 'Gene', '1351', (14, 17))	('Cox', 'Gene', (14, 17))	('RP11', 'Gene', '26121', (135, 139))	('APCDD1L-AS1', 'Gene', (119, 130))	('RP5-821D11.7', 'Var', (105, 117))
225462	29568882	The prognostic risk score was calculated using the following formula: Prognostic risk score=expression value of RP5-821D11.7 x (-0.392) + expression value of APCDD1L-AS1 x (0.101) + expression value of RP11-277P12.9 x (-0.114).	('RP5-821D11.7', 'Var', (112, 124))	('APCDD1L-AS1', 'Gene', (158, 169))	('RP11', 'Gene', (202, 206))	('APCDD1L-AS1', 'Gene', '149773', (158, 169))	('RP11', 'Gene', '26121', (202, 206))
225463	29568882	Furthermore, the KM survival analysis demonstrated that the samples with high expression levels of the three prognosis-associated DELs had significantly lower OS compared with those with low expression levels (P<0.05; Fig.	('OS', 'Chemical', '-', (159, 161))	('high expression levels', 'Var', (73, 95))	('lower', 'NegReg', (153, 158))
225475	29568882	A prognostic risk model involving three prognosis-associated DELs (including RP5-821D11.7, APCDD1L-AS1 and RP11-277P12.9) was established.	('RP5-821D11.7', 'Var', (77, 89))	('RP11', 'Gene', (107, 111))	('RP11', 'Gene', '26121', (107, 111))	('APCDD1L-AS1', 'Gene', (91, 102))	('APCDD1L-AS1', 'Gene', '149773', (91, 102))
225478	29568882	In addition, certain co-expression genes of RP5-821D11.7 (including PCNA), APCDD1L-AS1 (including SEMA5A, SEMA6D, ADAMTSL1, ADAMTS6, SLIT3 and TNC) and RP11-277P12.9 (including WNT2B) were screened.	('TNC', 'Gene', (143, 146))	('WNT2B', 'Gene', (177, 182))	('PCNA', 'Gene', '5111', (68, 72))	('RP11', 'Gene', '26121', (152, 156))	('SEMA5A', 'Gene', '9037', (98, 104))	('TNC', 'Gene', '3371', (143, 146))	('ADAMTSL1', 'Gene', '92949', (114, 122))	('ADAMTS6', 'Gene', (124, 131))	('WNT2B', 'Gene', '7482', (177, 182))	('APCDD1L-AS1', 'Gene', (75, 86))	('APCDD1L-AS1', 'Gene', '149773', (75, 86))	('SEMA6D', 'Gene', '80031', (106, 112))	('RP11', 'Gene', (152, 156))	('ADAMTS6', 'Gene', '11174', (124, 131))	('SLIT3', 'Gene', '6586', (133, 138))	('RP5-821D11.7', 'Var', (44, 56))	('SLIT3', 'Gene', (133, 138))	('SEMA6D', 'Gene', (106, 112))	('PCNA', 'Gene', (68, 72))	('SEMA5A', 'Gene', (98, 104))	('ADAMTSL1', 'Gene', (114, 122))
225488	29568882	The ECM is important in mesenchymal cancer cells; in particular, its compositional and structural alterations may affect metastasis of mesenchymal lung cancer cells.	('mesenchymal cancer', 'Disease', 'MESH:C535700', (24, 42))	('mesenchymal lung cancer', 'Disease', 'MESH:D008175', (135, 158))	('affect', 'Reg', (114, 120))	('lung cancer', 'Phenotype', 'HP:0100526', (147, 158))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('mesenchymal cancer', 'Disease', (24, 42))	('alterations', 'Var', (98, 109))	('mesenchymal lung cancer', 'Disease', (135, 158))
225489	29568882	Dysregulation of certain ADAMTS proteinases may be directly implicated in tumor development and metastasis.	('metastasis', 'CPA', (96, 106))	('ADAMTS proteinases', 'Enzyme', (25, 43))	('men', 'Species', '9606', (87, 90))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('Dysregulation', 'Var', (0, 13))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('implicated', 'Reg', (60, 70))	('tumor', 'Disease', (74, 79))
225491	29568882	A previous study reported that PCNA is specifically targeted by miR-363-3p, and may inhibit tumor growth in LAD.	('PCNA', 'Gene', (31, 35))	('PCNA', 'Gene', '5111', (31, 35))	('LAD', 'Disease', (108, 111))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('inhibit', 'NegReg', (84, 91))	('miR-363-3p', 'Var', (64, 74))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('LAD', 'Disease', 'MESH:C535887', (108, 111))	('tumor', 'Disease', (92, 97))	('LAD', 'Phenotype', 'HP:0030078', (108, 111))
225492	29568882	PCNA may be inhibited by the small molecule AOH1160, which suppresses the growth of SCLC cells without inducing any unacceptable side-effects and may be used as a potential anticancer therapy.	('cancer', 'Disease', (177, 183))	('cancer', 'Disease', 'MESH:D009369', (177, 183))	('AOH1160', 'Var', (44, 51))	('PCNA', 'Gene', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('suppresses', 'NegReg', (59, 69))	('growth of SCLC cells', 'MPA', (74, 94))	('PCNA', 'Gene', '5111', (0, 4))
225493	29568882	Dysregulated Wnt signaling functions in the progression and metastasis of lung cancer, and inhibitors of WNT signaling are promising for the treatment of the disease.	('inhibitors', 'Var', (91, 101))	('lung cancer', 'Phenotype', 'HP:0100526', (74, 85))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('Wnt signaling', 'Pathway', (13, 26))	('metastasis of lung cancer', 'Disease', 'MESH:D009362', (60, 85))	('men', 'Species', '9606', (146, 149))	('Dysregulated', 'Var', (0, 12))	('metastasis of lung cancer', 'Disease', (60, 85))
225495	29568882	Thus, RP5-821D11.7 (co-expressed with PCNA) and RP11-277P12.9 (co-expressed with WNT2B) may be used for predicting the prognosis of LUSC.	('RP11', 'Gene', (48, 52))	('LUSC', 'Disease', (132, 136))	('LUSC', 'Phenotype', 'HP:0030359', (132, 136))	('RP11', 'Gene', '26121', (48, 52))	('RP5-821D11.7', 'Var', (6, 18))	('PCNA', 'Gene', (38, 42))	('WNT2B', 'Gene', (81, 86))	('WNT2B', 'Gene', '7482', (81, 86))	('PCNA', 'Gene', '5111', (38, 42))
225500	29568882	Similarly, the number of patients with N2-N3 stages was significantly lower compared with N0 and N1 stages.	('lower', 'NegReg', (70, 75))	('patients', 'Species', '9606', (25, 33))	('N2-N3 stages', 'Var', (39, 51))
225502	29568882	RP5-821D11.7 (co-expressed with PCNA), APCDD1L-AS1 (co-expressed with SEMA5A, SEMA6D, ADAMTSL1, ADAMTS6, SLIT3 and TNC) and RP11-277P12.9 (co-expressed with WNT2B) may be important lncRNAs associated with the prognosis of LUSC.	('RP11', 'Gene', (124, 128))	('ADAMTSL1', 'Gene', '92949', (86, 94))	('ADAMTS6', 'Gene', '11174', (96, 103))	('APCDD1L-AS1', 'Gene', (39, 50))	('LUSC', 'Disease', (222, 226))	('APCDD1L-AS1', 'Gene', '149773', (39, 50))	('SEMA6D', 'Gene', (78, 84))	('PCNA', 'Gene', (32, 36))	('SEMA5A', 'Gene', (70, 76))	('RP5-821D11.7', 'Var', (0, 12))	('WNT2B', 'Gene', (157, 162))	('SLIT3', 'Gene', '6586', (105, 110))	('LUSC', 'Phenotype', 'HP:0030359', (222, 226))	('SLIT3', 'Gene', (105, 110))	('SEMA5A', 'Gene', '9037', (70, 76))	('RP11', 'Gene', '26121', (124, 128))	('PCNA', 'Gene', '5111', (32, 36))	('WNT2B', 'Gene', '7482', (157, 162))	('TNC', 'Gene', (115, 118))	('ADAMTSL1', 'Gene', (86, 94))	('ADAMTS6', 'Gene', (96, 103))	('SEMA6D', 'Gene', '80031', (78, 84))	('TNC', 'Gene', '3371', (115, 118))
225509	29207598	In contrast, high SerpinB2 was associated with reduced LCSS in stage I squamous cell carcinomas (p = 0.022).	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (71, 95))	('high', 'Var', (13, 17))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (71, 94))	('I squamous cell carcinomas', 'Disease', (69, 95))	('SerpinB2', 'Gene', (18, 26))	('I squamous cell carcinomas', 'Disease', 'MESH:D002294', (69, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('LCSS', 'Disease', (55, 59))	('SerpinB2', 'Gene', '5055', (18, 26))	('reduced', 'NegReg', (47, 54))	('carcinomas', 'Phenotype', 'HP:0030731', (85, 95))
225511	29207598	In multivariate survival analysis of adenocarcinomas, low SerpinB2 demonstrated independent prognostic value (HR 1.8, p = 0.008).	('carcinomas', 'Phenotype', 'HP:0030731', (42, 52))	('adenocarcinomas', 'Disease', (37, 52))	('HR 1.8', 'Gene', '56852', (110, 116))	('low', 'Var', (54, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (42, 51))	('SerpinB2', 'Gene', (58, 66))	('HR 1.8', 'Gene', (110, 116))	('SerpinB2', 'Gene', '5055', (58, 66))	('adenocarcinomas', 'Disease', 'MESH:D000230', (37, 52))
225526	29207598	In smaller studies, low levels of SerpinB2 has been associated with lymph node metastasis and reduced overall survival.	('low levels', 'Var', (20, 30))	('reduced', 'NegReg', (94, 101))	('SerpinB2', 'Gene', (34, 42))	('lymph node metastasis', 'CPA', (68, 89))	('SerpinB2', 'Gene', '5055', (34, 42))	('overall survival', 'CPA', (102, 118))
225544	29207598	In SCC, presence of L1CAM was associated with high histologic grade (p = 0.039).	('SCC', 'Phenotype', 'HP:0002860', (3, 6))	('SCC', 'Gene', '6317', (3, 6))	('presence', 'Var', (8, 16))	('L1CAM', 'Gene', (20, 25))	('L1CAM', 'Gene', '3897', (20, 25))	('high histologic grade', 'CPA', (46, 67))	('SCC', 'Gene', (3, 6))
225558	29207598	When analyzing stage I SCC separately, high SerpinB2 expression (by median value) was associated with reduced LCSS (p = 0.022) (Supplementary Figure 1) and DFS (p = 0.044).	('SerpinB2', 'Gene', (44, 52))	('SCC', 'Gene', '6317', (23, 26))	('high', 'Var', (39, 43))	('SerpinB2', 'Gene', '5055', (44, 52))	('DFS', 'CPA', (156, 159))	('SCC', 'Phenotype', 'HP:0002860', (23, 26))	('LCSS', 'Disease', (110, 114))	('expression', 'MPA', (53, 63))	('SCC', 'Gene', (23, 26))	('reduced', 'NegReg', (102, 109))
225559	29207598	In a multivariate model for AC where sex, histologic grade (high versus low), blood vessel invasion (present versus absent), lymphatic vessel involvement (present versus absent), necrosis (present versus absent), tumor stage (II-IV versus I), and SerpinB2 expression (low versus high) were included, low SerpinB2 demonstrated independent prognostic value for LCSS (HR 1.8 (95% CI 1.17-2.06), p = 0.008) (Table 2).	('tumor', 'Disease', (213, 218))	('necrosis', 'Disease', (179, 187))	('SerpinB2', 'Gene', (304, 312))	('HR 1.8', 'Gene', '56852', (365, 371))	('SerpinB2', 'Gene', '5055', (304, 312))	('necrosis', 'Disease', 'MESH:D009336', (179, 187))	('SerpinB2', 'Gene', (247, 255))	('tumor', 'Disease', 'MESH:D009369', (213, 218))	('SerpinB2', 'Gene', '5055', (247, 255))	('HR 1.8', 'Gene', (365, 371))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('LCSS', 'Disease', (359, 363))	('low', 'Var', (300, 303))
225561	29207598	In stage I squamous cell carcinomas, a multivariate model where variables with p<0.10 in univariate survival analysis (BVI and SerpinB2) were included, showed that high SerpinB2 was an independent prognostic factor for reduced LCSS (HR 3.5 (95 % CI 1.03-11.74), p = 0.044) (Supplementary Table 10B).	('SerpinB2', 'Gene', (169, 177))	('reduced', 'NegReg', (219, 226))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (11, 34))	('SerpinB2', 'Gene', '5055', (169, 177))	('I squamous cell carcinomas', 'Disease', (9, 35))	('SerpinB2', 'Gene', (127, 135))	('high', 'Var', (164, 168))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (11, 35))	('SerpinB2', 'Gene', '5055', (127, 135))	('I squamous cell carcinomas', 'Disease', 'MESH:D002294', (9, 35))	('LCSS', 'Disease', (227, 231))	('carcinoma', 'Phenotype', 'HP:0030731', (25, 34))	('carcinomas', 'Phenotype', 'HP:0030731', (25, 35))
225580	29207598	Whereas high SerpinB2 was related to reduced survival in bladder cancer, endometrial cancer, and esophageal squamous cell carcinoma, low SerpinB2 has been associated with worse survival in breast cancer, hepatocellular carcinoma, and pancreatic cancer.	('endometrial cancer', 'Disease', (73, 91))	('bladder cancer', 'Disease', 'MESH:D001749', (57, 71))	('bladder cancer', 'Disease', (57, 71))	('breast cancer', 'Phenotype', 'HP:0003002', (189, 202))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (204, 228))	('endometrial cancer', 'Disease', 'MESH:D016889', (73, 91))	('esophageal squamous cell carcinoma', 'Disease', (97, 131))	('bladder cancer', 'Phenotype', 'HP:0009725', (57, 71))	('pancreatic cancer', 'Disease', 'MESH:D010190', (234, 251))	('high', 'Var', (8, 12))	('SerpinB2', 'Gene', (13, 21))	('breast cancer', 'Disease', 'MESH:D001943', (189, 202))	('SerpinB2', 'Gene', '5055', (13, 21))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (204, 228))	('breast cancer', 'Disease', (189, 202))	('pancreatic cancer', 'Disease', (234, 251))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (108, 131))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (97, 131))	('hepatocellular carcinoma', 'Disease', (204, 228))	('cancer', 'Phenotype', 'HP:0002664', (245, 251))	('carcinoma', 'Phenotype', 'HP:0030731', (219, 228))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('SerpinB2', 'Gene', (137, 145))	('SerpinB2', 'Gene', '5055', (137, 145))	('low', 'Var', (133, 136))	('endometrial cancer', 'Phenotype', 'HP:0012114', (73, 91))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (234, 251))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('reduced', 'NegReg', (37, 44))
225586	29207598	One study comparing different subgroups where high MMP-9 expression in tumor cells indicated worse outcome in resected lung adenocarcinomas, but not in lung squamous cell carcinomas, has been reported, thus further pointing to differences in biology between the subgroups.	('lung squamous cell carcinomas', 'Disease', (152, 181))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (157, 181))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (152, 180))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (119, 139))	('carcinomas', 'Phenotype', 'HP:0030731', (129, 139))	('expression', 'MPA', (57, 67))	('high', 'Var', (46, 50))	('lung adenocarcinomas', 'Disease', (119, 139))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (157, 180))	('MMP-9', 'Gene', '4318', (51, 56))	('MMP-9', 'Gene', (51, 56))	('carcinoma', 'Phenotype', 'HP:0030731', (171, 180))	('carcinomas', 'Phenotype', 'HP:0030731', (171, 181))	('lung squamous cell carcinomas', 'Disease', 'MESH:D002294', (152, 181))	('tumor', 'Disease', (71, 76))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (119, 139))
225655	25707772	However, the development of drug resistance by cancer cells, despite the use of molecularly targeted drugs for the causal genes, thus obstructing treatment, is a well-known phenomenon.	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('molecularly targeted', 'Var', (80, 100))	('cancer', 'Disease', (47, 53))	('drug resistance', 'Phenotype', 'HP:0020174', (28, 43))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('drug resistance', 'MPA', (28, 43))
225686	25707772	More than 90% of activating mutations of the EGFR gene are L858R mutations and exon 19 deletions.	('L858R', 'Var', (59, 64))	('EGFR', 'Gene', (45, 49))	('activating', 'PosReg', (17, 27))	('L858R', 'Mutation', 'rs121434568', (59, 64))	('mutations', 'Var', (28, 37))
225687	25707772	An additional T790M mutation in exon 20 to these activating mutations causes drug resistance to EGFR-TKIs, which is the most frequent mechanism known for EGFR-TKI-resistant lung tumors.	('lung tumors', 'Phenotype', 'HP:0100526', (173, 184))	('lung tumors', 'Disease', (173, 184))	('drug resistance', 'MPA', (77, 92))	('tumors', 'Phenotype', 'HP:0002664', (178, 184))	('lung tumors', 'Disease', 'MESH:D008175', (173, 184))	('causes', 'Reg', (70, 76))	('T790M', 'Mutation', 'rs121434569', (14, 19))	('lung tumor', 'Phenotype', 'HP:0100526', (173, 183))	('T790M', 'Var', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('drug resistance', 'Phenotype', 'HP:0020174', (77, 92))	('EGFR-TKIs', 'Gene', (96, 105))
225688	25707772	A T790M mutation of EGFR, such as the T315I mutation of ABL in chronic myeloid leukemia patients, is considered to inhibit binding of TKI to the ATP binding site of the kinase domain.	('TKI', 'Protein', (134, 137))	('binding', 'Interaction', (123, 130))	('myeloid leukemia', 'Disease', 'MESH:D007951', (71, 87))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (71, 87))	('T315I', 'Var', (38, 43))	('inhibit', 'NegReg', (115, 122))	('EGFR', 'Gene', (20, 24))	('T790M', 'Mutation', 'rs121434569', (2, 7))	('leukemia', 'Phenotype', 'HP:0001909', (79, 87))	('patients', 'Species', '9606', (88, 96))	('T790M', 'Var', (2, 7))	('ABL', 'Gene', (56, 59))	('chronic myeloid leukemia', 'Phenotype', 'HP:0005506', (63, 87))	('T315I', 'Mutation', 'rs121913459', (38, 43))	('ATP', 'Chemical', 'MESH:D000255', (145, 148))	('myeloid leukemia', 'Disease', (71, 87))
225692	25707772	However, the drug resistance mutation of L1196M of the ALK gene, which corresponds to T790M of EGFR and T315I of ABL mentioned earlier, was previously reported.	('drug resistance', 'Phenotype', 'HP:0020174', (13, 28))	('T790M', 'Var', (86, 91))	('L1196M', 'Mutation', 'rs1057519784', (41, 47))	('L1196M', 'Var', (41, 47))	('T315I', 'Var', (104, 109))	('ABL', 'Gene', (113, 116))	('T790M', 'Mutation', 'rs121434569', (86, 91))	('ALK', 'Gene', (55, 58))	('T315I', 'Mutation', 'rs121913459', (104, 109))	('EGFR', 'Gene', (95, 99))
225702	25707772	Reported Notch activation mechanisms observed in NSCLC include deletion of NUMB expression and gain-of-function mutation of the NOTCH1 gene.	('gain-of-function', 'PosReg', (95, 111))	('activation', 'PosReg', (15, 25))	('mutation', 'Var', (112, 120))	('NSCLC', 'Disease', (49, 54))	('NSCLC', 'Disease', 'MESH:D002289', (49, 54))	('deletion', 'Var', (63, 71))	('NUMB', 'Gene', (75, 79))	('NUMB', 'Gene', '18222', (75, 79))	('NOTCH1', 'Gene', '18128', (128, 134))	('NOTCH1', 'Gene', (128, 134))
225703	25707772	In addition, regarding Notch3 signaling, knockdown of NOTCH3 leads to downregulation of the anti-apoptotic genes BCL-2/BCL-XL and upregulation of the apoptosis-promoting genes BAX/BIM/BAD.	('NOTCH3', 'Gene', (54, 60))	('Notch3', 'Gene', '18131', (23, 29))	('BCL-XL', 'Gene', (119, 125))	('apoptosis-promoting', 'CPA', (150, 169))	('BCL-2', 'Gene', (113, 118))	('Notch3', 'Gene', (23, 29))	('BCL-2', 'Gene', '12043', (113, 118))	('BIM', 'Gene', (180, 183))	('BCL-XL', 'Gene', '12048', (119, 125))	('BIM', 'Gene', '12125', (180, 183))	('upregulation', 'PosReg', (130, 142))	('BAX', 'Gene', (176, 179))	('downregulation', 'NegReg', (70, 84))	('knockdown', 'Var', (41, 50))	('BAX', 'Gene', '12028', (176, 179))	('NOTCH3', 'Gene', '18131', (54, 60))
225711	25707772	Given these events, the tumor-suppressive effect of Notch signaling in SCLC may lie in the induction of differentiation of SCLC stem cells with characteristics similar to those of PNECs.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('Notch signaling', 'Var', (52, 67))	('tumor', 'Disease', (24, 29))	('differentiation', 'CPA', (104, 119))	('SCLC', 'Disease', (71, 75))	('SCLC', 'Disease', 'MESH:D018288', (123, 127))	('SCLC', 'Disease', 'MESH:D018288', (71, 75))	('SCLC', 'Disease', (123, 127))	('tumor', 'Disease', 'MESH:D009369', (24, 29))
225712	25707772	Moreover, Notch signaling is reported to suppress a phosphatase (dual-specificity phosphatase 1) and activate EGFR/ERK1/2 signaling.	('ERK1/2', 'Gene', '26417;26413', (115, 121))	('ERK1/2', 'Gene', (115, 121))	('dual-specificity phosphatase 1', 'Gene', (65, 95))	('dual-specificity phosphatase 1', 'Gene', '19252', (65, 95))	('activate', 'PosReg', (101, 109))	('suppress', 'NegReg', (41, 49))	('phosphatase', 'Enzyme', (52, 63))	('Notch signaling', 'Var', (10, 25))
225716	25707772	In adenocarcinoma, inhibition of SOX2 expression induces apoptosis of tumor cells and downregulation of WNT1/2, NOTCH1, and c-MYC; it also decreases the number of SP cells.	('SOX2', 'Gene', '20674', (33, 37))	('downregulation', 'NegReg', (86, 100))	('MYC', 'Gene', '17869', (126, 129))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('inhibition', 'Var', (19, 29))	('carcinoma', 'Phenotype', 'HP:0030731', (8, 17))	('decreases', 'NegReg', (139, 148))	('SOX2', 'Gene', (33, 37))	('NOTCH1', 'Gene', '18128', (112, 118))	('SP', 'Chemical', 'MESH:C000604007', (163, 165))	('adenocarcinoma', 'Disease', (3, 17))	('WNT1/2', 'Gene', '22410;22408;22413', (104, 110))	('WNT1/2', 'Gene', (104, 110))	('MYC', 'Gene', (126, 129))	('apoptosis', 'CPA', (57, 66))	('tumor', 'Disease', (70, 75))	('NOTCH1', 'Gene', (112, 118))	('induces', 'Reg', (49, 56))	('adenocarcinoma', 'Disease', 'MESH:D000230', (3, 17))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
225717	25707772	reported that inhibition of EGFR/AKT signaling in SP cells of NSCLC induces suppression of SOX2 expression, which in turn suppresses self-renewal of SP cells, indicating the involvement of EGFR signaling and SOX2 expression in stem cell maintenance.	('self-renewal of SP cells', 'CPA', (133, 157))	('SOX2', 'Gene', '20674', (91, 95))	('NSCLC', 'Disease', (62, 67))	('SP', 'Chemical', 'MESH:C000604007', (149, 151))	('SOX2', 'Gene', (91, 95))	('suppression', 'NegReg', (76, 87))	('AKT', 'Gene', '11651', (33, 36))	('NSCLC', 'Disease', 'MESH:D002289', (62, 67))	('expression', 'MPA', (96, 106))	('SOX2', 'Gene', (208, 212))	('SP', 'Chemical', 'MESH:C000604007', (50, 52))	('suppresses', 'NegReg', (122, 132))	('AKT', 'Gene', (33, 36))	('inhibition', 'Var', (14, 24))	('SOX2', 'Gene', '20674', (208, 212))
225726	25707772	In the trachea, where basal, Clara, and ciliated cells exist, SOX2 deletion reduces the numbers of each cell and epithelial cell density, which could suggest involvement of SOX2 in maintenance/regeneration of the trachea epithelium.	('SOX2', 'Gene', (62, 66))	('deletion', 'Var', (67, 75))	('SOX2', 'Gene', '20674', (62, 66))	('SOX2', 'Gene', (173, 177))	('involvement', 'Reg', (158, 169))	('reduces', 'NegReg', (76, 83))	('SOX2', 'Gene', '20674', (173, 177))
225731	25707772	In addition, inhibition of WNT2 signaling leads to downregulation of Survivin, an anti-apoptotic gene; this consequently induces apoptosis.	('WNT2', 'Gene', (27, 31))	('apoptosis', 'CPA', (129, 138))	('inhibition', 'Var', (13, 23))	('Survivin', 'Gene', '11799', (69, 77))	('Survivin', 'Gene', (69, 77))	('induces', 'Reg', (121, 128))	('WNT2', 'Gene', '22413', (27, 31))	('downregulation', 'NegReg', (51, 65))
225732	25707772	In the lung adenocarcinoma mouse model produced by Kras mutation and Wnt signaling activation, enhanced proliferation and EMT of lung cancer cells, as well as downregulation of Sox2 and upregulation of Sox9 and Gata6, were observed, in comparison with the lung adenocarcinoma mouse model produced by Kras mutation only.	('EMT of lung cancer', 'Disease', 'MESH:D008175', (122, 140))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (7, 26))	('Sox9', 'Gene', (202, 206))	('Gata6', 'Gene', (211, 216))	('proliferation', 'CPA', (104, 117))	('mouse', 'Species', '10090', (276, 281))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (7, 26))	('Kras', 'Gene', '16653', (51, 55))	('carcinoma', 'Phenotype', 'HP:0030731', (17, 26))	('enhanced', 'PosReg', (95, 103))	('activation', 'PosReg', (83, 93))	('lung cancer', 'Phenotype', 'HP:0100526', (129, 140))	('Sox2', 'Gene', '20674', (177, 181))	('lung adenocarcinoma', 'Disease', (256, 275))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('Gata6', 'Gene', '14465', (211, 216))	('EMT of lung cancer', 'Disease', (122, 140))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (256, 275))	('mutation', 'Var', (56, 64))	('lung adenocarcinoma', 'Disease', (7, 26))	('Sox9', 'Gene', '20682', (202, 206))	('Kras', 'Gene', (300, 304))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (256, 275))	('upregulation', 'PosReg', (186, 198))	('mouse', 'Species', '10090', (27, 32))	('carcinoma', 'Phenotype', 'HP:0030731', (266, 275))	('Kras', 'Gene', (51, 55))	('Sox2', 'Gene', (177, 181))	('downregulation', 'NegReg', (159, 173))	('Kras', 'Gene', '16653', (300, 304))
225735	25707772	Naphthalene resistance is the characteristic of variant Clara cells.	('Naphthalene', 'Chemical', 'MESH:C031721', (0, 11))	('Naphthalene resistance', 'MPA', (0, 22))	('variant', 'Var', (48, 55))	('variant Clara', 'CellLine', 'CVCL:5U99', (48, 61))
225736	25707772	In addition, deletion of beta-catenin in basal cells suppresses proliferation and leads to apoptosis.	('suppresses', 'NegReg', (53, 63))	('apoptosis', 'CPA', (91, 100))	('deletion', 'Var', (13, 21))	('beta-catenin', 'Gene', '12387', (25, 37))	('proliferation', 'CPA', (64, 77))	('beta-catenin', 'Gene', (25, 37))	('leads to', 'Reg', (82, 90))
225739	25707772	In NSCLC with EGFR mutation, activation of STAT and/or AKT is involved in tumor proliferation.	('activation', 'PosReg', (29, 39))	('mutation', 'Var', (19, 27))	('AKT', 'Gene', (55, 58))	('EGFR', 'Gene', (14, 18))	('NSCLC', 'Disease', (3, 8))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('NSCLC', 'Disease', 'MESH:D002289', (3, 8))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor', 'Disease', (74, 79))	('AT', 'Disease', 'None', (45, 47))	('AKT', 'Gene', '11651', (55, 58))
225743	25707772	In addition, as IL-6 is reported to contribute to survival and maintenance of cancer stem cells through NOTCH3 signaling in breast cancer, Notch signaling may also be involved in the mechanism of proliferation promotion by IL-6 in NSCLC.	('cancer', 'Disease', (131, 137))	('proliferation', 'CPA', (196, 209))	('promotion', 'PosReg', (210, 219))	('involved', 'Reg', (167, 175))	('Notch', 'Var', (139, 144))	('NOTCH3', 'Gene', '18131', (104, 110))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('NSCLC', 'Disease', (231, 236))	('breast cancer', 'Disease', 'MESH:D001943', (124, 137))	('breast cancer', 'Phenotype', 'HP:0003002', (124, 137))	('NOTCH3', 'Gene', (104, 110))	('breast cancer', 'Disease', (124, 137))	('NSCLC', 'Disease', 'MESH:D002289', (231, 236))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (131, 137))
225746	25707772	Because deletion of E-cadherin leads to nuclear translocation of beta-catenin, which binds to the intracellular domain of E-cadherin, the deletion activates the Wnt/beta-catenin signaling.	('activates', 'PosReg', (147, 156))	('beta-catenin', 'Gene', (165, 177))	('E-cadherin', 'Gene', (122, 132))	('beta-catenin', 'Gene', '12387', (65, 77))	('E-cadherin', 'Gene', (20, 30))	('beta-catenin', 'Gene', '12387', (165, 177))	('E-cadherin', 'Gene', '12550', (20, 30))	('deletion', 'Var', (8, 16))	('E-cadherin', 'Gene', '12550', (122, 132))	('nuclear translocation', 'MPA', (40, 61))	('deletion', 'Var', (138, 146))	('beta-catenin', 'Gene', (65, 77))
225751	25707772	DNA methylation is abnormally enhanced in pulmonary precancerous lesions and lung cancer cells.	('lung cancer', 'Phenotype', 'HP:0100526', (77, 88))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('enhanced', 'PosReg', (30, 38))	('pulmonary precancerous lesions', 'Disease', (42, 72))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('pulmonary precancerous lesions', 'Disease', 'MESH:D011230', (42, 72))	('methylation', 'Var', (4, 15))	('lung cancer', 'Disease', 'MESH:D008175', (77, 88))	('DNA', 'MPA', (0, 3))	('lung cancer', 'Disease', (77, 88))
225752	25707772	Methylation of gene regulatory regions is important as an inactivation mechanism of tumor suppressor genes because the methylation strongly suppresses the expression of downstream genes.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('methylation', 'Var', (119, 130))	('suppresses', 'NegReg', (140, 150))	('expression', 'MPA', (155, 165))	('tumor', 'Disease', (84, 89))
225753	25707772	As it is said in the cases of Helicobacter pylori infection in stomach cancer, and hepatitis B and C virus infections in liver cancer, chronic inflammation might lead to cancer development through genomic DNA methylation.	('cancer', 'Disease', (170, 176))	('Helicobacter pylori infection', 'Phenotype', 'HP:0005202', (30, 59))	('Helicobacter pylori infection', 'Disease', (30, 59))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('hepatitis B', 'Disease', (83, 94))	('Helicobacter pylori infection', 'Disease', 'MESH:D016481', (30, 59))	('stomach cancer', 'Disease', 'MESH:D013274', (63, 77))	('C virus infections', 'Disease', (99, 117))	('cancer', 'Disease', (71, 77))	('stomach cancer', 'Phenotype', 'HP:0012126', (63, 77))	('liver cancer', 'Disease', 'MESH:D006528', (121, 133))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('cancer', 'Disease', (127, 133))	('C virus infections', 'Disease', 'MESH:D006526', (99, 117))	('lead to', 'Reg', (162, 169))	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('liver cancer', 'Phenotype', 'HP:0002896', (121, 133))	('hepatitis B', 'Disease', 'MESH:D006509', (83, 94))	('genomic DNA methylation', 'Var', (197, 220))	('inflammation', 'Disease', 'MESH:D007249', (143, 155))	('liver cancer', 'Disease', (121, 133))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('hepatitis', 'Phenotype', 'HP:0012115', (83, 92))	('stomach cancer', 'Disease', (63, 77))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('inflammation', 'Disease', (143, 155))
225755	25707772	In those cases, DNA methylation of pulmonary epithelial cells might be one cause of lung cancer development.	('cause', 'Reg', (75, 80))	('lung cancer', 'Disease', (84, 95))	('lung cancer', 'Phenotype', 'HP:0100526', (84, 95))	('DNA methylation', 'Var', (16, 31))	('lung cancer', 'Disease', 'MESH:D008175', (84, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
225756	25707772	A report also stated that DNA methylation occurs prior to gene mutation and/or deletion, and accumulation of DNA methylation leads to cancer formation.	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('accumulation', 'PosReg', (93, 105))	('leads to', 'Reg', (125, 133))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('deletion', 'Var', (79, 87))
225757	25707772	In stage I lung squamous cell carcinoma, several hundreds of CpG islands are hypermethylated.	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (11, 39))	('hypermethylated', 'Var', (77, 92))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (16, 39))	('I lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (9, 39))	('I lung squamous cell carcinoma', 'Disease', (9, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (30, 39))
225759	25707772	In addition, detection of methylation of P16 or a DNA repair enzyme, the MGMT gene in sputum cells is reported to be useful for early detection of NSCLC.	('MGMT', 'Gene', (73, 77))	('methylation', 'Var', (26, 37))	('MGMT', 'Gene', '17314', (73, 77))	('NSCLC', 'Disease', (147, 152))	('P16', 'Gene', '12578', (41, 44))	('P16', 'Gene', (41, 44))	('NSCLC', 'Disease', 'MESH:D002289', (147, 152))
225762	25707772	Among molecules in the Notch pathway, NOTCH3, JAG1, HES2, HES4, and HES5 have been reported to be hypermethylated in leukemia, but the epigenetic status in the Notch pathway in lung cancer has not been revealed.	('HES5', 'Gene', '15208', (68, 72))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('HES2', 'Gene', (52, 56))	('NOTCH3', 'Gene', '18131', (38, 44))	('NOTCH3', 'Gene', (38, 44))	('lung cancer', 'Disease', 'MESH:D008175', (177, 188))	('leukemia', 'Phenotype', 'HP:0001909', (117, 125))	('Notch pathway', 'Pathway', (23, 36))	('leukemia', 'Disease', 'MESH:D007938', (117, 125))	('hypermethylated', 'Var', (98, 113))	('leukemia', 'Disease', (117, 125))	('HES5', 'Gene', (68, 72))	('JAG1', 'Gene', (46, 50))	('lung cancer', 'Disease', (177, 188))	('JAG1', 'Gene', '16449', (46, 50))	('HES2', 'Gene', '15206', (52, 56))	('lung cancer', 'Phenotype', 'HP:0100526', (177, 188))
225763	25707772	In particular, methylation of Lysin27 of Histone H3 (H3K27) is important as an inactivation mechanism of tumor suppressor genes.	('methylation', 'Var', (15, 26))	('inactivation', 'NegReg', (79, 91))	('Lysin27', 'Chemical', '-', (30, 37))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('H3K27', 'Gene', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumor', 'Disease', (105, 110))
225766	25707772	Although involvement of epigenetics in lung cancer has not been well investigated, WNT signaling could be activated by methylation of APC, SFRP1, SFRP2, SFRP5, and DKK3 in a subset of lung cancer.	('methylation', 'Var', (119, 130))	('SFRP5', 'Gene', (153, 158))	('SFRP2', 'Gene', '20319', (146, 151))	('DKK3', 'Gene', (164, 168))	('lung cancer', 'Disease', (39, 50))	('APC', 'Disease', 'MESH:D011125', (134, 137))	('lung cancer', 'Disease', 'MESH:D008175', (184, 195))	('activated', 'PosReg', (106, 115))	('APC', 'Disease', (134, 137))	('DKK3', 'Gene', '50781', (164, 168))	('SFRP2', 'Gene', (146, 151))	('lung cancer', 'Phenotype', 'HP:0100526', (184, 195))	('SFRP1', 'Gene', '20377', (139, 144))	('SFRP5', 'Gene', '54612', (153, 158))	('lung cancer', 'Disease', 'MESH:D008175', (39, 50))	('SFRP1', 'Gene', (139, 144))	('lung cancer', 'Phenotype', 'HP:0100526', (39, 50))	('WNT signaling', 'MPA', (83, 96))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('lung cancer', 'Disease', (184, 195))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
225767	25707772	Wnt signaling is involved in lung cancer stem cells and lung maintenance/regeneration; therefore, epigenetic modification in Wnt signaling plays some roles in lung cancer and normal lung stem cells.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('lung cancer', 'Disease', 'MESH:D008175', (159, 170))	('epigenetic modification', 'Var', (98, 121))	('lung cancer', 'Disease', 'MESH:D008175', (29, 40))	('lung cancer', 'Disease', (159, 170))	('lung cancer', 'Phenotype', 'HP:0100526', (159, 170))	('lung cancer', 'Disease', (29, 40))	('lung cancer', 'Phenotype', 'HP:0100526', (29, 40))
225770	25707772	Moreover, in lung cancer, miR-34, 199a*, and 7515 targeting c-Met are suppressed.	('lung cancer', 'Disease', (13, 24))	('lung cancer', 'Phenotype', 'HP:0100526', (13, 24))	('c-Met', 'Gene', '17295', (60, 65))	('199a*', 'Var', (34, 39))	('miR-34', 'Var', (26, 32))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('lung cancer', 'Disease', 'MESH:D008175', (13, 24))	('7515', 'Var', (45, 49))	('c-Met', 'Gene', (60, 65))
225772	25707772	In a gastric cancer cell line, miR-126 targets SOX2.	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('gastric cancer', 'Phenotype', 'HP:0012126', (5, 19))	('gastric cancer', 'Disease', (5, 19))	('miR-126', 'Var', (31, 38))	('gastric cancer', 'Disease', 'MESH:D013274', (5, 19))	('SOX2', 'Gene', (47, 51))	('SOX2', 'Gene', '20674', (47, 51))
225774	25707772	A proportion (20-30%) of lung cancer patients with EGFR mutation is primarily resistant to EGFR-TKIs.	('EGFR', 'Gene', (51, 55))	('patients', 'Species', '9606', (37, 45))	('lung cancer', 'Disease', (25, 36))	('lung cancer', 'Phenotype', 'HP:0100526', (25, 36))	('mutation', 'Var', (56, 64))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('lung cancer', 'Disease', 'MESH:D008175', (25, 36))
225775	25707772	In addition, in 50% of lung cancer cases with KRAS mutation, KRAS knockdown exerts no effect on tumor cell proliferation.	('lung cancer', 'Disease', (23, 34))	('lung cancer', 'Phenotype', 'HP:0100526', (23, 34))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('KRAS', 'Gene', '16653', (46, 50))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('KRAS', 'Gene', (46, 50))	('tumor', 'Disease', (96, 101))	('mutation', 'Var', (51, 59))	('KRAS', 'Gene', (61, 65))	('lung cancer', 'Disease', 'MESH:D008175', (23, 34))	('KRAS', 'Gene', '16653', (61, 65))	('tumor', 'Disease', 'MESH:D009369', (96, 101))
225776	25707772	These indicate that development of lung cancers, even those with a mutation of a popular lung cancer-related genes such as EGFR and KRAS, is not necessarily solely dependent on these genes, but another signal pathway is likely to function as survival signaling.	('EGFR', 'Gene', (123, 127))	('lung cancer', 'Disease', 'MESH:D008175', (35, 46))	('KRAS', 'Gene', (132, 136))	('mutation', 'Var', (67, 75))	('lung cancers', 'Disease', (35, 47))	('lung cancer', 'Disease', (89, 100))	('KRAS', 'Gene', '16653', (132, 136))	('lung cancer', 'Phenotype', 'HP:0100526', (89, 100))	('cancers', 'Phenotype', 'HP:0002664', (40, 47))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('lung cancer', 'Phenotype', 'HP:0100526', (35, 46))	('lung cancers', 'Disease', 'MESH:D008175', (35, 47))	('lung cancers', 'Phenotype', 'HP:0100526', (35, 47))	('lung cancer', 'Disease', 'MESH:D008175', (89, 100))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))
225777	25707772	Indeed, in addition to the EGFR gene mutation (T790M mutation), c-MET amplification and HGF overexpression are well-known bypass mechanisms of EGFR signals.	('EGFR', 'Gene', (27, 31))	('T790M', 'Mutation', 'rs121434569', (47, 52))	('HGF', 'Gene', '15234', (88, 91))	('T790M', 'Var', (47, 52))	('c-MET', 'Gene', '17295', (64, 69))	('c-MET', 'Gene', (64, 69))	('HGF', 'Gene', (88, 91))
225779	25707772	Meanwhile, a report stated that in SCLC, Ras mutation occurs in EMT, causing downregulation of Mycl1.	('EMT', 'Gene', (64, 67))	('SCLC', 'Disease', (35, 39))	('downregulation', 'NegReg', (77, 91))	('SCLC', 'Disease', 'MESH:D018288', (35, 39))	('Mycl1', 'Gene', (95, 100))	('Mycl1', 'Gene', '16918', (95, 100))	('EMT', 'Gene', '16428', (64, 67))	('mutation', 'Var', (45, 53))
225786	25707772	In addition, not only genomic mutation but also epigenetic abnormality has been reported as important in the onset of development of lung cancers.	('lung cancers', 'Disease', 'MESH:D008175', (133, 145))	('epigenetic abnormality', 'Var', (48, 70))	('lung cancer', 'Phenotype', 'HP:0100526', (133, 144))	('lung cancers', 'Phenotype', 'HP:0100526', (133, 145))	('cancers', 'Phenotype', 'HP:0002664', (138, 145))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('genomic mutation', 'Var', (22, 38))	('lung cancers', 'Disease', (133, 145))
225788	25707772	From this standpoint, understanding the mechanisms of survival signals and epigenetic abnormalities related to lung cancer/stem cells, which are discussed in this review, should be extremely important.	('epigenetic abnormalities', 'Var', (75, 99))	('lung cancer', 'Disease', 'MESH:D008175', (111, 122))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('lung cancer', 'Disease', (111, 122))	('lung cancer', 'Phenotype', 'HP:0100526', (111, 122))
225795	25125812	The frequency of EGFR mutations was higher among women than men.	('women', 'Species', '9606', (49, 54))	('men', 'Species', '9606', (51, 54))	('mutations', 'Var', (22, 31))	('men', 'Species', '9606', (60, 63))	('EGFR', 'Gene', (17, 21))
225812	25125812	Testing for mutations of the epidermal growth factor receptor (EGFR), EML4-ALK and V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS), BRAF (v raf murine sarcoma viral oncogene homologue B1) have been in progress to identify inhibitors for these receptors for targeted therapy.	('rat', 'Species', '10116', (101, 104))	('murine', 'Species', '10090', (156, 162))	('EGFR', 'Gene', (63, 67))	('mutations', 'Var', (12, 21))	('sarcoma viral', 'Disease', 'MESH:D001102', (163, 176))	('sarcoma viral', 'Disease', 'MESH:D001102', (105, 118))	('sarcoma', 'Phenotype', 'HP:0100242', (163, 170))	('sarcoma', 'Phenotype', 'HP:0100242', (105, 112))	('epidermal growth factor receptor', 'Gene', '24329', (29, 61))	('sarcoma viral', 'Disease', (163, 176))	('sarcoma viral', 'Disease', (105, 118))	('epidermal growth factor receptor', 'Gene', (29, 61))
225833	25125812	For the assessment of biomarkers, specific kits were used such as, EGFR mutation test kit and DxS ARMS-PCR kit for diagnosis of EGFR mutations and Telo TAGGG telomerase PCR kit for detection of telomerase activity using the telomeric repeat amplification protocol (TRAP) method.	('EGFR', 'Gene', (128, 132))	('mutations', 'Var', (133, 142))	('men', 'Species', '9606', (14, 17))
225835	25125812	The frequency of EGFR mutations among women (54%) has been observed to be higher than men (39%).	('men', 'Species', '9606', (86, 89))	('women', 'Species', '9606', (38, 43))	('men', 'Species', '9606', (40, 43))	('mutations', 'Var', (22, 31))	('EGFR', 'Gene', (17, 21))
225836	25125812	investigating 220 patients, the EGFR mutation status was 50.9% in women and 49.1% in men, P = 0.04.	('mutation', 'Var', (37, 45))	('men', 'Species', '9606', (85, 88))	('EGFR', 'Gene', (32, 36))	('patients', 'Species', '9606', (18, 26))	('women', 'Species', '9606', (66, 71))	('men', 'Species', '9606', (68, 71))
225850	25125812	In another study, 21 cases of cytologically diagnosed squamous cell carcinoma showed positivity for p63, followed by 7 cases of adenocarcinoma.	('positivity', 'Var', (85, 95))	('adenocarcinoma', 'Disease', 'MESH:D000230', (128, 142))	('p63', 'Gene', (100, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (54, 77))	('carcinoma', 'Phenotype', 'HP:0030731', (68, 77))	('p63', 'Gene', '8626', (100, 103))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (54, 77))	('adenocarcinoma', 'Disease', (128, 142))	('squamous cell carcinoma', 'Disease', (54, 77))
225865	25125812	The guidelines recommend testing for EGFR mutations and ALK gene rearrangements in select NSCLC patients to predict the treatment response.	('men', 'Species', '9606', (125, 128))	('NSCLC', 'Disease', (90, 95))	('NSCLC', 'Disease', 'MESH:D002289', (90, 95))	('men', 'Species', '9606', (74, 77))	('patients', 'Species', '9606', (96, 104))	('testing', 'Reg', (25, 32))	('EGFR', 'Gene', (37, 41))	('mutations', 'Var', (42, 51))	('ALK gene', 'Gene', (56, 64))	('NSCLC', 'Phenotype', 'HP:0030358', (90, 95))	('men', 'Species', '9606', (20, 23))
225873	25125812	identified EGFR mutation types in stage III or IV NSCLC patients; the authors concluded that screening for EGFR mutations may be useful in deciding response to tyrosine kinase inhibitors (TKI) therapy.	('patients', 'Species', '9606', (56, 64))	('NSCLC', 'Phenotype', 'HP:0030358', (50, 55))	('EGFR', 'Gene', (107, 111))	('mutations', 'Var', (112, 121))	('NSCLC', 'Disease', (50, 55))	('NSCLC', 'Disease', 'MESH:D002289', (50, 55))
225896	25125812	The guidelines recommend testing for EGFR mutations and ALK gene rearrangements in NSCLC patients.	('NSCLC', 'Disease', (83, 88))	('NSCLC', 'Disease', 'MESH:D002289', (83, 88))	('patients', 'Species', '9606', (89, 97))	('NSCLC', 'Phenotype', 'HP:0030358', (83, 88))	('men', 'Species', '9606', (74, 77))	('testing', 'Reg', (25, 32))	('EGFR', 'Gene', (37, 41))	('mutations', 'Var', (42, 51))	('ALK gene', 'Gene', (56, 64))	('men', 'Species', '9606', (20, 23))
225900	25125812	Guideline from the College of American Pathologists (CAP), International Association for the Study of Lung Cancer (IASLC), and Association for Molecular Pathology (AMP) also recommend molecular testing of EGFR and ALK in lung cancer patients.	('men', 'Species', '9606', (179, 182))	('Lung Cancer', 'Disease', 'MESH:D008175', (102, 113))	('lung cancer', 'Phenotype', 'HP:0100526', (221, 232))	('ALK', 'Gene', (214, 217))	('lung cancer', 'Disease', 'MESH:D008175', (221, 232))	('EGFR', 'Gene', (205, 209))	('Lung Cancer', 'Phenotype', 'HP:0100526', (102, 113))	('Cancer', 'Phenotype', 'HP:0002664', (107, 113))	('molecular testing', 'Var', (184, 201))	('Lung Cancer', 'Disease', (102, 113))	('patients', 'Species', '9606', (233, 241))	('lung cancer', 'Disease', (221, 232))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
225902	25125812	This guideline further suggests that formalin-fixed, paraffin-embedded or fresh, frozen or alcohol-fixed specimens should be used for PCR-based EGFR mutation testing.	('EGFR', 'Gene', (144, 148))	('alcohol', 'Chemical', 'MESH:D000438', (91, 98))	('men', 'Species', '9606', (110, 113))	('formalin', 'Chemical', 'MESH:D005557', (37, 45))	('paraffin', 'Chemical', 'MESH:D010232', (53, 61))	('mutation', 'Var', (149, 157))
225998	33635505	To find out whether the modulation of Nrf2 activity by (+)-usnic acid may affect cellular functions, the effect on cell cycle distribution and the markers of apoptosis and autophagy was evaluated.	('modulation', 'Var', (24, 34))	('cell cycle distribution', 'CPA', (115, 138))	('Nrf2', 'Gene', (38, 42))	('usnic acid', 'Chemical', 'MESH:C073339', (59, 69))	('activity', 'MPA', (43, 51))	('affect', 'Reg', (74, 80))	('cellular functions', 'CPA', (81, 99))
226008	33635505	Moreover, in a human intervention trial, xanthohumol caused a significant reduction in DNA damage and a clear induction of alpha-GST (43%), suggesting the involvement of the Keap1-Nrf2 pathway.	('Keap1', 'Gene', '9817', (174, 179))	('Keap1', 'Gene', (174, 179))	('DNA damage', 'MPA', (87, 97))	('xanthohumol', 'Var', (41, 52))	('reduction', 'NegReg', (74, 83))	('xanthohumol', 'Chemical', 'MESH:C104536', (41, 52))	('human', 'Species', '9606', (15, 20))	('alpha-GST', 'Protein', (123, 132))
226036	33635505	Missense mutations in the TP53 gene are extremely widespread in human cancers and give rise to mutant p53 proteins that lose tumor suppressive activities, and some of which exert trans-dominant repression over the wild-type counterpart.	('TP53', 'Gene', (26, 30))	('human', 'Species', '9606', (64, 69))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('TP53', 'Gene', '7157', (26, 30))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('p53', 'Gene', '7157', (102, 105))	('Missense mutations', 'Var', (0, 18))	('tumor', 'Disease', (125, 130))	('lose', 'NegReg', (120, 124))	('cancers', 'Disease', 'MESH:D009369', (70, 77))	('mutant', 'Var', (95, 101))	('p53', 'Gene', (102, 105))	('cancers', 'Phenotype', 'HP:0002664', (70, 77))	('cancers', 'Disease', (70, 77))	('proteins', 'Protein', (106, 114))
226037	33635505	Therefore, assuming that increased expression of the wild-type TP53 gene occurs in cancer cells such as FaDu cells after treatment with (+)-usnic acid, can suggest that (+)-usnic acid may diminish the neoplastic potential of these cells.	('usnic acid', 'Chemical', 'MESH:C073339', (140, 150))	('increased', 'PosReg', (25, 34))	('TP53', 'Gene', '7157', (63, 67))	('TP53', 'Gene', (63, 67))	('+)-usnic acid', 'Var', (170, 183))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('expression', 'MPA', (35, 45))	('diminish', 'NegReg', (188, 196))	('neoplastic potential of these cells', 'CPA', (201, 236))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('usnic acid', 'Chemical', 'MESH:C073339', (173, 183))	('cancer', 'Disease', (83, 89))
226059	33485313	Transcriptional silencing caused by hypermethylation of CpG islands has become a key factor in the occurrence and development of lung cancer.	('lung cancer', 'Disease', (129, 140))	('Transcriptional', 'MPA', (0, 15))	('lung cancer', 'Phenotype', 'HP:0100526', (129, 140))	('men', 'Species', '9606', (121, 124))	('CpG islands', 'Gene', (56, 67))	('hypermethylation', 'Var', (36, 52))	('lung cancer', 'Disease', 'MESH:D008175', (129, 140))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
226061	33485313	The methylation of p16INK4a and MGMT, which can be detected in the sputum of most LUSC patients, could be used to predict the risk of lung cancer in smokers.	('lung cancer', 'Disease', (134, 145))	('lung cancer', 'Phenotype', 'HP:0100526', (134, 145))	('p16INK4a', 'Gene', (19, 27))	('predict', 'Reg', (114, 121))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('MGMT', 'Gene', '4255', (32, 36))	('methylation', 'Var', (4, 15))	('MGMT', 'Gene', (32, 36))	('lung cancer', 'Disease', 'MESH:D008175', (134, 145))	('p16INK4a', 'Gene', '1029', (19, 27))	('LUSC', 'Phenotype', 'HP:0030359', (82, 86))	('patients', 'Species', '9606', (87, 95))
226101	33485313	Then sort the samples by risk score and find that as the score increases, the risk of death is higher (Fig.	('death', 'Disease', 'MESH:D003643', (86, 91))	('higher', 'PosReg', (95, 101))	('score', 'Var', (57, 62))	('death', 'Disease', (86, 91))
226110	33485313	The ADRB3 was altered most often (18%), including deep deletion, amplification, mRNA high, etc.	('mRNA', 'Var', (80, 84))	('altered', 'Reg', (14, 21))	('deep deletion', 'Var', (50, 63))	('amplification', 'Disease', (65, 78))	('ADRB3', 'Gene', '155', (4, 9))	('ADRB3', 'Gene', (4, 9))
226112	33485313	We found that the correlation was most negative, indicating that methylation regulated the mRNA expression of these genes (except for EMX2, LEMD3, ZFP2, ZSCAN1).	('LEMD3', 'Gene', (140, 145))	('ZSCAN1', 'Gene', '284312', (153, 159))	('mRNA expression', 'MPA', (91, 106))	('regulated', 'Reg', (77, 86))	('ZFP2', 'Gene', (147, 151))	('EMX2', 'Gene', '2018', (134, 138))	('EMX2', 'Gene', (134, 138))	('LEMD3', 'Gene', '23592', (140, 145))	('methylation', 'Var', (65, 76))	('ZFP2', 'Gene', '80108', (147, 151))	('ZSCAN1', 'Gene', (153, 159))
226120	33485313	Epigenetic changes affect the entire process of tumorigenesis and development by affecting genomic stability and gene expression.	('affecting', 'Reg', (81, 90))	('tumor', 'Disease', (48, 53))	('men', 'Species', '9606', (73, 76))	('gene expression', 'MPA', (113, 128))	('development', 'CPA', (66, 77))	('affect', 'Reg', (19, 25))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('genomic stability', 'CPA', (91, 108))	('Epigenetic changes', 'Var', (0, 18))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
226121	33485313	Epigenetic changes occur in the early stages of tumor development and can be adjusted by external factors, such as drugs, diet, etc., so the individual's epigenetic analysis may provide valuable information for reducing their risk of cancer.	('tumor', 'Disease', (48, 53))	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('cancer', 'Disease', (234, 240))	('cancer', 'Disease', 'MESH:D009369', (234, 240))	('epigenetic analysis', 'Var', (154, 173))	('men', 'Species', '9606', (61, 64))	('reducing', 'NegReg', (211, 219))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
226123	33485313	It seems clear that the silencing expression of TSG caused by methylation may be the origin of important events in tumorigenesis.	('TSG', 'Gene', (48, 51))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumor', 'Disease', (115, 120))	('methylation', 'Var', (62, 73))	('silencing', 'NegReg', (24, 33))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
226125	33485313	Studies have shown that the incidence of H-cadherin methylation in patients with NSCLC is significantly related to tumor stage.	('H-cadherin', 'Protein', (41, 51))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('patients', 'Species', '9606', (67, 75))	('NSCLC', 'Phenotype', 'HP:0030358', (81, 86))	('tumor', 'Disease', (115, 120))	('methylation', 'Var', (52, 63))	('NSCLC', 'Disease', (81, 86))	('related', 'Reg', (104, 111))	('NSCLC', 'Disease', 'MESH:D002289', (81, 86))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
226127	33485313	GNAS mutations have been found in pancreas, colon and lung tumors, and in up to two-thirds of intraductal papillary mucinous tumors (IPMNs).	('colon', 'Disease', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('lung tumors', 'Phenotype', 'HP:0100526', (54, 65))	('lung tumors', 'Disease', (54, 65))	('pancreas', 'Disease', (34, 42))	('mutations', 'Var', (5, 14))	('GNAS', 'Gene', (0, 4))	('papillary mucinous tumors', 'Disease', (106, 131))	('papillary mucinous tumors', 'Disease', 'MESH:D000077779', (106, 131))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('colon', 'Disease', 'MESH:D003110', (44, 49))	('lung tumors', 'Disease', 'MESH:D008175', (54, 65))	('found', 'Reg', (25, 30))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('GNAS', 'Gene', '2778', (0, 4))
226135	33485313	Our results indicate that DNA methylation plays an important role in the occurrence and development of LUSC and may be proposed as a diagnostic biomarker.	('LUSC', 'Phenotype', 'HP:0030359', (103, 107))	('LUSC', 'Disease', (103, 107))	('methylation', 'Var', (30, 41))	('DNA', 'MPA', (26, 29))	('men', 'Species', '9606', (95, 98))
226138	32684626	Computational analysis of TP53 mutational landscape unveils key prognostic signatures and distinct pathobiological pathways in head and neck squamous cell cancer Mutations of the tumour-suppressor gene TP53 are the most frequent somatic genomic alterations in head and neck squamous cell carcinoma (HNSCC).	('TP53', 'Gene', (26, 30))	('TP53', 'Gene', (202, 206))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (260, 297))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('tumour', 'Phenotype', 'HP:0002664', (179, 185))	('neck squamous cell carcinoma', 'Disease', (269, 297))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (274, 297))	('tumour', 'Disease', 'MESH:D009369', (179, 185))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (269, 297))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (141, 161))	('carcinoma', 'Phenotype', 'HP:0030731', (288, 297))	('TP53', 'Gene', '7157', (26, 30))	('Mutations', 'Var', (162, 171))	('head and neck squamous cell cancer', 'Phenotype', 'HP:0012288', (127, 161))	('neck squamous cell cancer', 'Disease', 'MESH:D002294', (136, 161))	('tumour', 'Disease', (179, 185))	('neck squamous cell cancer', 'Disease', (136, 161))	('TP53', 'Gene', '7157', (202, 206))
226139	32684626	However, it is not yet clear whether specific TP53 mutations bear distinct clinical and pathophysiological significance in different HNSCC subgroups.	('TP53', 'Gene', '7157', (46, 50))	('TP53', 'Gene', (46, 50))	('mutations', 'Var', (51, 60))	('HNSCC', 'Disease', (133, 138))
226140	32684626	A systematic bioinformatics appraisal of TP53 mutations was performed on 415 HNSCC cases available on The Cancer Genome Atlas (TCGA).	('TP53', 'Gene', '7157', (41, 45))	('TP53', 'Gene', (41, 45))	('C', 'Chemical', 'MESH:D003545', (81, 82))	('mutations', 'Var', (46, 55))	('Cancer', 'Disease', (106, 112))	('C', 'Chemical', 'MESH:D003545', (106, 107))	('Cancer', 'Disease', 'MESH:D009369', (106, 112))	('Cancer', 'Phenotype', 'HP:0002664', (106, 112))	('HNSCC', 'Disease', (77, 82))	('C', 'Chemical', 'MESH:D003545', (80, 81))	('C', 'Chemical', 'MESH:D003545', (128, 129))
226143	32684626	TP53 mutations in HNSCCs exhibited distinct differences in different anatomical sites.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))
226144	32684626	The mutational profile of TP53 was an independent prognostic factor in HNSCC.	('mutational profile', 'Var', (4, 22))	('HNSCC', 'Disease', (71, 76))	('TP53', 'Gene', (26, 30))	('TP53', 'Gene', '7157', (26, 30))
226145	32684626	High risk of death mutations, identified by our novel classification algorithm, was an independent prognostic factor in TCGA HNSCC database.	('death', 'Disease', 'MESH:D003643', (13, 18))	('C', 'Chemical', 'MESH:D003545', (129, 130))	('death', 'Disease', (13, 18))	('mutations', 'Var', (19, 28))	('C', 'Chemical', 'MESH:D003545', (121, 122))	('TCGA HNSCC database', 'Disease', (120, 139))	('C', 'Chemical', 'MESH:D003545', (128, 129))
226147	32684626	The mutational profile of TP53 may serve as an independent prognostic factor in HNSCC patients, and is associated with distinctive site-specific biological networks.	('TP53', 'Gene', (26, 30))	('associated', 'Reg', (103, 113))	('HNSCC', 'Disease', (80, 85))	('TP53', 'Gene', '7157', (26, 30))	('mutational', 'Var', (4, 14))	('patients', 'Species', '9606', (86, 94))
226148	32684626	Mutations of the tumour-suppressor gene TP53 are among the most common genomic alterations occurring in malignancy, including head and neck squamous cell carcinoma (HNSCC).	('tumour', 'Phenotype', 'HP:0002664', (17, 23))	('tumour', 'Disease', 'MESH:D009369', (17, 23))	('malignancy', 'Disease', 'MESH:D009369', (104, 114))	('TP53', 'Gene', '7157', (40, 44))	('Mutations', 'Var', (0, 9))	('TP53', 'Gene', (40, 44))	('neck squamous cell carcinoma', 'Disease', (135, 163))	('tumour', 'Disease', (17, 23))	('malignancy', 'Disease', (104, 114))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (140, 163))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (126, 163))	('carcinoma', 'Phenotype', 'HP:0030731', (154, 163))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (135, 163))
226152	32684626	Both tobacco and alcohol cause DNA damage with an increased likelihood of generating mutations in cancer-related genes.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('tobacco', 'Species', '4097', (5, 12))	('alcohol', 'Chemical', 'MESH:D000438', (17, 24))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('mutations', 'Var', (85, 94))	('DNA damage', 'Disease', (31, 41))	('cancer', 'Disease', (98, 104))
226158	32684626	In addition, it plays a central role in the control of cell proliferation and death in response to various urges like DNA damage, hypoxia, oxidative stress, DNA mutations and nutrient deprivation.	('death', 'Disease', 'MESH:D003643', (78, 83))	('death', 'Disease', (78, 83))	('DNA', 'Gene', (157, 160))	('hypoxia', 'Disease', (130, 137))	('hypoxia', 'Disease', 'MESH:D000860', (130, 137))	('cell proliferation', 'CPA', (55, 73))	('mutations', 'Var', (161, 170))	('oxidative stress', 'Phenotype', 'HP:0025464', (139, 155))
226159	32684626	Not surprisingly, TP53 gene alterations are frequent in a large proportion of human cancers, and occur in a tissue-specific manner.	('TP53', 'Gene', '7157', (18, 22))	('alterations', 'Var', (28, 39))	('cancers', 'Disease', 'MESH:D009369', (84, 91))	('cancers', 'Phenotype', 'HP:0002664', (84, 91))	('cancers', 'Disease', (84, 91))	('TP53', 'Gene', (18, 22))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('human', 'Species', '9606', (78, 83))
226160	32684626	For example, TP53 mutation rates vary from 2.2% in renal cell carcinoma to 89% and 94.9% in endometrial carcinoma and serous ovarian cancers, respectively.	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (92, 113))	('TP53', 'Gene', (13, 17))	('endometrial carcinoma and serous ovarian cancers', 'Disease', 'MESH:D010051', (92, 140))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (51, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('cancers', 'Phenotype', 'HP:0002664', (133, 140))	('mutation', 'Var', (18, 26))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (51, 71))	('TP53', 'Gene', '7157', (13, 17))	('ovarian cancers', 'Phenotype', 'HP:0100615', (125, 140))	('renal cell carcinoma', 'Disease', (51, 71))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (62, 71))
226161	32684626	Inherited TP53 mutations lead to a wide spectrum of early-onset cancers.	('TP53', 'Gene', (10, 14))	('mutations', 'Var', (15, 24))	('cancers', 'Disease', 'MESH:D009369', (64, 71))	('cancers', 'Phenotype', 'HP:0002664', (64, 71))	('lead to', 'Reg', (25, 32))	('cancers', 'Disease', (64, 71))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('TP53', 'Gene', '7157', (10, 14))
226162	32684626	In contrast to other tumour-suppressor genes that are mainly altered by truncating mutations, the majority of TP53 mutations are missense substitutions (75%).	('mutations', 'Var', (115, 124))	('TP53', 'Gene', '7157', (110, 114))	('missense substitutions', 'Var', (129, 151))	('TP53', 'Gene', (110, 114))	('tumour', 'Phenotype', 'HP:0002664', (21, 27))	('tumour', 'Disease', 'MESH:D009369', (21, 27))	('tumour', 'Disease', (21, 27))
226163	32684626	However, whether different types of TP53 mutations bear distinct clinical and pathophysiological significance in HNSCC has not been elucidated so far.	('mutations', 'Var', (41, 50))	('HNSCC', 'Disease', (113, 118))	('TP53', 'Gene', '7157', (36, 40))	('TP53', 'Gene', (36, 40))
226168	32684626	The C-terminal domain is characterised of a flexible linker region (residues 293-323), a tetramerisation domain (residues 324-355) and C-terminal regulatory domain (residues 363-393) that undergoes a number of post-translational modifications such as acetylation and phosphorylation.	('residues 324-355', 'Var', (113, 129))	('residues 363-393', 'Var', (165, 181))	('phosphorylation', 'MPA', (267, 282))	('residues 293-323', 'Var', (68, 84))	('C', 'Chemical', 'MESH:D003545', (4, 5))	('acetylation', 'MPA', (251, 262))	('C', 'Chemical', 'MESH:D003545', (135, 136))
226169	32684626	A growing body of evidence now suggests that differential mutational profiles of TP53 gene can influence disease prognosis in several types of tumours; for example, distinct TP53 mutations are independent predictors of survival in CD20+ lymphomas.	('TP53', 'Gene', '7157', (174, 178))	('lymphomas', 'Disease', 'MESH:D008223', (237, 246))	('TP53', 'Gene', (174, 178))	('C', 'Chemical', 'MESH:D003545', (231, 232))	('tumour', 'Phenotype', 'HP:0002664', (143, 149))	('influence', 'Reg', (95, 104))	('lymphomas', 'Phenotype', 'HP:0002665', (237, 246))	('tumours', 'Phenotype', 'HP:0002664', (143, 150))	('tumours', 'Disease', 'MESH:D009369', (143, 150))	('mutations', 'Var', (179, 188))	('tumours', 'Disease', (143, 150))	('lymphomas', 'Disease', (237, 246))	('TP53', 'Gene', '7157', (81, 85))	('TP53', 'Gene', (81, 85))	('mutational', 'Var', (58, 68))
226171	32684626	Whether mutations in p53 subdomains differentially affect disease prognosis, however, has not been elucidated so far.	('affect', 'Reg', (51, 57))	('W', 'Chemical', 'MESH:D014414', (0, 1))	('p53', 'Gene', '7157', (21, 24))	('mutations', 'Var', (8, 17))	('p53', 'Gene', (21, 24))	('disease prognosis', 'CPA', (58, 75))
226174	32684626	The results from this analysis revealed that a wide landscape of TP53 mutations exists in HNSCC and, for the first time, demonstrated that these mutations are associated with distinct clinical behaviour in a site-specific manner.	('mutations', 'Var', (70, 79))	('TP53', 'Gene', '7157', (65, 69))	('HNSCC', 'Disease', (90, 95))	('TP53', 'Gene', (65, 69))	('associated', 'Reg', (159, 169))
226186	32684626	Of 415 patients with HNSCC included in the study (Supplementary Table 1A-D), 129 patients had no mutations in the TP53 gene and were defined as "wild type" (WT); meanwhile, 286 patients had one single mutation in the gene sequence (MUT) (of these, 51 patients had a frameshift mutation, 8 an inframe mutation, 152 a missense mutation, 26 a splice-site mutation and 49 patients had a stop mutation).	('missense mutation', 'Var', (316, 333))	('patients', 'Species', '9606', (177, 185))	('W', 'Chemical', 'MESH:D014414', (157, 158))	('patients', 'Species', '9606', (81, 89))	('TP53', 'Gene', '7157', (114, 118))	('frameshift mutation', 'Var', (266, 285))	('splice-site', 'MPA', (340, 351))	('patients', 'Species', '9606', (251, 259))	('TP53', 'Gene', (114, 118))	('patients', 'Species', '9606', (368, 376))	('patients', 'Species', '9606', (7, 15))
226197	32684626	In particular, residue R175 was affected in 5 patients, G245 in 7 patients, R248 in 11 patients, R273 in 14 patients and R282 in 6 patients (43 hotspot mutations/286 total mutations).	('G245', 'Var', (56, 60))	('patients', 'Species', '9606', (131, 139))	('R', 'Chemical', 'MESH:D001120', (23, 24))	('patients', 'Species', '9606', (46, 54))	('patients', 'Species', '9606', (108, 116))	('R282', 'Var', (121, 125))	('patients', 'Species', '9606', (87, 95))	('patients', 'Species', '9606', (66, 74))	('R', 'Chemical', 'MESH:D001120', (121, 122))	('R273', 'Var', (97, 101))	('R', 'Chemical', 'MESH:D001120', (97, 98))	('affected', 'Reg', (32, 40))	('R', 'Chemical', 'MESH:D001120', (76, 77))	('R248', 'Var', (76, 80))
226198	32684626	In addition to these frequent spots, we decided to include new residues, which were also frequently mutated; only residues involved in at least six patients included in the cohort were also included as new hotspots mutations; such sites were H179 (seven patients), H193 (six patients), R196 (eight patients) and R213 (seven patients).	('patients', 'Species', '9606', (148, 156))	('patients', 'Species', '9606', (324, 332))	('patients', 'Species', '9606', (254, 262))	('R', 'Chemical', 'MESH:D001120', (312, 313))	('H193', 'Chemical', 'MESH:C012111', (265, 269))	('R', 'Chemical', 'MESH:D001120', (286, 287))	('patients', 'Species', '9606', (298, 306))	('R196', 'Var', (286, 290))	('patients', 'Species', '9606', (275, 283))	('H179', 'Var', (242, 246))	('R213', 'Var', (312, 316))	('H193', 'Var', (265, 269))
226199	32684626	The residues involved in the zinc ion ligand, such as C176, H179, C238 and C242, which were involved in 17 on 286 patients.	('C176', 'Var', (54, 58))	('C', 'Chemical', 'MESH:D003545', (75, 76))	('C', 'Chemical', 'MESH:D003545', (54, 55))	('C238', 'Var', (66, 70))	('C', 'Chemical', 'MESH:D003545', (66, 67))	('patients', 'Species', '9606', (114, 122))	('C242', 'Var', (75, 79))	('H179', 'Var', (60, 64))
226202	32684626	Conserved residues were retrieved from their online platform at http://bioinf.org.uk/p53/analysis/index.html#conserved, such as pro98, phe113, lys120, ser121, val122, thr125, ser127, leu130, lys132, leu137, lys139, pro142, pro151, pro152, arg158, ala159, lys164, val172, val173, arg175, pro177, his178, his179, arg196, glu198, gly199, tyr205, asp208, ser215, val216, val218, pro219, tyr220, glu221, pro223, thr230, asn239, ser240, ser241, cys242, met243, gly244, gly245, asn247, arg249, ile251, thr253, leu257, gly262, leu265, gly266, arg267, phe270, glu271, val272, cys275, ala276, cys277, pro278, gly279, arg280, asp281 and arg282.	('leu265', 'Var', (519, 525))	('asp281', 'Var', (615, 621))	('pro278', 'Var', (591, 597))	('arg282', 'Var', (626, 632))	('cys277', 'Var', (583, 589))	('val272', 'Var', (559, 565))	('arg267', 'Var', (535, 541))	('p53', 'Gene', '7157', (85, 88))	('glu271', 'Var', (551, 557))	('gly279', 'Var', (599, 605))	('phe270', 'Var', (543, 549))	('ala276', 'Var', (575, 581))	('gly266', 'Var', (527, 533))	('p53', 'Gene', (85, 88))	('gly262', 'Var', (511, 517))	('C', 'Chemical', 'MESH:D003545', (0, 1))	('leu257', 'Var', (503, 509))	('arg280', 'Var', (607, 613))	('cys275', 'Var', (567, 573))
226203	32684626	also characterised amino-acid substitutions according to their ability to donate or accept hydrogen bonds.	('amino-acid substitutions', 'Var', (19, 43))	('donate', 'MPA', (74, 80))	('accept', 'Reg', (84, 90))	('hydrogen', 'Chemical', 'MESH:D006859', (91, 99))
226205	32684626	Patients were classified as missense-disruptive mutation with substitution of K, R and W with E and D and vice versa, or in the case of forming H+ bond amino acids, substituted by non-forming H+ bonds.	('missense-disruptive mutation', 'Disease', (28, 56))	('R', 'Chemical', 'MESH:D001120', (81, 82))	('Patients', 'Species', '9606', (0, 8))	('W', 'Chemical', 'MESH:D014414', (87, 88))	('substitution', 'Var', (62, 74))
226206	32684626	We also categorised two further amino-acid substitutions, such as (1) mutations resulting in a substitution by proline, and (2) mutations from native glycine in residues at codons 117, 154, 187, 244, 245 and 262.	('mutations', 'Var', (70, 79))	('mutations', 'Var', (128, 137))	('W', 'Chemical', 'MESH:D014414', (0, 1))	('substitution', 'Var', (95, 107))	('proline', 'MPA', (111, 118))	('glycine', 'Chemical', 'MESH:D005998', (150, 157))	('proline', 'Chemical', 'MESH:D011392', (111, 118))
226224	32684626	First, we applied this algorithm to TCGA head and neck cancer, and then we implemented this model in order to highlight patients at high risk of death, according to deleterious missense substitutions in the secondary structure of the protein.	('missense substitutions', 'Var', (177, 199))	('head and neck cancer', 'Phenotype', 'HP:0012288', (41, 61))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('neck cancer', 'Disease', 'MESH:D006258', (50, 61))	('neck cancer', 'Disease', (50, 61))	('death', 'Disease', 'MESH:D003643', (145, 150))	('patients', 'Species', '9606', (120, 128))	('death', 'Disease', (145, 150))	('C', 'Chemical', 'MESH:D003545', (37, 38))
226225	32684626	Mutations were reclassified as disruptive if Mutations were reclassified as conservative if assigned to any other secondary structure, when maintaining their ability to donate or accept hydrogen bonds.	('Mutations', 'Var', (0, 9))	('accept hydrogen bonds', 'MPA', (179, 200))	('donate', 'MPA', (169, 175))	('hydrogen', 'Chemical', 'MESH:D006859', (186, 194))
226227	32684626	We aimed to investigate whether the presence of mutations in the TP53 gene correlated with the prognosis of HNSCC.	('TP53', 'Gene', '7157', (65, 69))	('TP53', 'Gene', (65, 69))	('W', 'Chemical', 'MESH:D014414', (0, 1))	('HNSCC', 'Disease', (108, 113))	('correlated', 'Reg', (75, 85))	('mutations', 'Var', (48, 57))
226228	32684626	By comparing wild-type (WT) HNSCCs with the ones with mutated TP53, univariate survival analysis showed a worse overall survival for patients carrying one mutation in TP53 gene.	('worse', 'NegReg', (106, 111))	('TP53', 'Gene', '7157', (62, 66))	('patients', 'Species', '9606', (133, 141))	('W', 'Chemical', 'MESH:D014414', (24, 25))	('TP53', 'Gene', (62, 66))	('TP53', 'Gene', '7157', (167, 171))	('mutation', 'Var', (155, 163))	('TP53', 'Gene', (167, 171))
226229	32684626	Multivariate Cox regression analysis confirmed that TP53 mutation was an independent prognostic factor in HNSCC patients (multivariate analysis: HR = 1.613; 95% CI: 1.119-2.325; P = 0.010) (Fig.	('mutation', 'Var', (57, 65))	('C', 'Chemical', 'MESH:D003545', (109, 110))	('TP53', 'Gene', '7157', (52, 56))	('C', 'Chemical', 'MESH:D003545', (161, 162))	('patients', 'Species', '9606', (112, 120))	('TP53', 'Gene', (52, 56))	('C', 'Chemical', 'MESH:D003545', (13, 14))	('HNSCC', 'Disease', (106, 111))	('C', 'Chemical', 'MESH:D003545', (110, 111))	('R', 'Chemical', 'MESH:D001120', (146, 147))
226230	32684626	Interestingly, in the OP subgroup, the mutated profile was an independent prognostic factor of overall survival (multivariate analysis: HR = 11.657; 95% CI: 2.668-50.929; P = 0.001) (Fig.	('mutated', 'Var', (39, 46))	('C', 'Chemical', 'MESH:D003545', (153, 154))	('overall', 'MPA', (95, 102))	('R', 'Chemical', 'MESH:D001120', (137, 138))
226233	32684626	When analysing TP53 mutations according to the predicted p53 domains affected (N-terminal, C-terminal or DNA-binding domain), no differences in survival emerged in subgroups, except larynx, where at the univariate analysis, patients with mutations in the DNA-binding domain had a worse overall survival than those with mutations in the N-terminal segment of the gene (multivariate analysis: HR = 0.223; 95% CI: 0.050-0.998; P = 0.050) (Supplementary Fig.	('p53', 'Gene', '7157', (57, 60))	('overall survival', 'MPA', (286, 302))	('W', 'Chemical', 'MESH:D014414', (0, 1))	('C', 'Chemical', 'MESH:D003545', (91, 92))	('mutations', 'Var', (238, 247))	('TP53', 'Gene', '7157', (15, 19))	('TP53', 'Gene', (15, 19))	('p53', 'Gene', (57, 60))	('patients', 'Species', '9606', (224, 232))	('R', 'Chemical', 'MESH:D001120', (392, 393))	('mutations', 'Var', (20, 29))	('C', 'Chemical', 'MESH:D003545', (407, 408))	('worse', 'NegReg', (280, 285))
226234	32684626	TP53 mutations were then analysed according to their occurrence in the predicted secondary structure of the protein.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))
226235	32684626	No differences in survival emerged between WT patients and those with mutations in the helix or in turn region of the protein.	('helix', 'Protein', (87, 92))	('mutations', 'Var', (70, 79))	('patients', 'Species', '9606', (46, 54))	('W', 'Chemical', 'MESH:D014414', (43, 44))
226236	32684626	Patients with mutations in a strand region had a worse overall survival, both in HNSCC (multivariate analysis: HR = 1.559; 95% CI: 1.007-2.413; P = 0.046) (Fig.	('overall survival', 'MPA', (55, 71))	('C', 'Chemical', 'MESH:D003545', (85, 86))	('R', 'Chemical', 'MESH:D001120', (112, 113))	('C', 'Chemical', 'MESH:D003545', (127, 128))	('Patients', 'Species', '9606', (0, 8))	('mutations', 'Var', (14, 23))	('C', 'Chemical', 'MESH:D003545', (84, 85))
226238	32684626	Poor overall survival was also detected for patients with mutations in unknown regions.	('mutations', 'Var', (58, 67))	('patients', 'Species', '9606', (44, 52))	('Poor', 'NegReg', (0, 4))
226241	32684626	Survival analysis was also performed in order to investigate whether particular hotspot mutations could influence patients' prognosis.	('influence', 'Reg', (104, 113))	('patients', 'Species', '9606', (114, 122))	('mutations', 'Var', (88, 97))
226242	32684626	Mutations affecting the residue R175 were associated with a worse overall survival in HNSCC (multivariate analysis: HR = 6.855; 95% CI: 1.635-28.75; P = 0.008) compared with the non-hotspot group.	('C', 'Chemical', 'MESH:D003545', (132, 133))	('R', 'Chemical', 'MESH:D001120', (32, 33))	('HNSCC', 'Disease', (86, 91))	('overall', 'MPA', (66, 73))	('C', 'Chemical', 'MESH:D003545', (89, 90))	('Mutations affecting', 'Var', (0, 19))	('C', 'Chemical', 'MESH:D003545', (90, 91))	('R', 'Chemical', 'MESH:D001120', (117, 118))	('worse', 'NegReg', (60, 65))
226244	32684626	Finally, R213 was linked to poor overall survival in HNSCC (univariate analysis: P = 0.024) (Supplementary Fig.	('HNSCC', 'Disease', (53, 58))	('poor', 'NegReg', (28, 32))	('R', 'Chemical', 'MESH:D001120', (9, 10))	('R213', 'Var', (9, 13))
226245	32684626	In particular, missense (multivariate analysis: HR = 1.688; 95% CI: 1.129-2.526; P = 0.011) and stop (multivariate analysis: HR = 2.016; 95% CI: 1.220-3.332; P = 0.006) mutations were predictive of worse overall survival compared with WT patients in HNSCC.	('C', 'Chemical', 'MESH:D003545', (253, 254))	('C', 'Chemical', 'MESH:D003545', (64, 65))	('overall survival', 'MPA', (204, 220))	('W', 'Chemical', 'MESH:D014414', (235, 236))	('R', 'Chemical', 'MESH:D001120', (126, 127))	('C', 'Chemical', 'MESH:D003545', (254, 255))	('worse', 'NegReg', (198, 203))	('missense', 'Var', (15, 23))	('C', 'Chemical', 'MESH:D003545', (141, 142))	('patients', 'Species', '9606', (238, 246))	('R', 'Chemical', 'MESH:D001120', (49, 50))
226246	32684626	In the last analysis, HNSCC patients with higher VAF, such as those carrying the mutation in homozygous loci, reported a worse overall survival (multivariate analysis: HR = 1.747; 95% CI: 1.055-2.891; P = 0.030) and higher risk of relapse (multivariate analysis: HR = 2.421; 95% CI: 1.168-5.020; P = 0.017) compared with patients with lower VAF (i.e.	('R', 'Chemical', 'MESH:D001120', (169, 170))	('C', 'Chemical', 'MESH:D003545', (26, 27))	('patients', 'Species', '9606', (321, 329))	('worse', 'NegReg', (121, 126))	('mutation', 'Var', (81, 89))	('C', 'Chemical', 'MESH:D003545', (25, 26))	('C', 'Chemical', 'MESH:D003545', (279, 280))	('R', 'Chemical', 'MESH:D001120', (264, 265))	('patients', 'Species', '9606', (28, 36))	('C', 'Chemical', 'MESH:D003545', (184, 185))	('overall', 'MPA', (127, 134))
226249	32684626	Surprisingly, the results failed to show an association between p53 mutations and prognosis.	('mutations', 'Var', (68, 77))	('p53', 'Gene', (64, 67))	('p53', 'Gene', '7157', (64, 67))
226251	32684626	Taken together, these data demonstrate that TP53 mutations are not only predictors of patient survival but, also, that different types of mutations have distinct prognostic significance in HNSCC.	('mutations', 'Var', (49, 58))	('patient', 'Species', '9606', (86, 93))	('TP53', 'Gene', '7157', (44, 48))	('TP53', 'Gene', (44, 48))	('HNSCC', 'Disease', (189, 194))
226259	32684626	Simple main effect analysis showed that mutational status significantly affected mRNA expression (P < 0.001), but there were no differences between anatomical subsites (P = 0.684).	('R', 'Chemical', 'MESH:D001120', (82, 83))	('mRNA expression', 'MPA', (81, 96))	('mutational', 'Var', (40, 50))	('affected', 'Reg', (72, 80))
226260	32684626	Bonferroni-Holm post hoc test showed a differential mRNA expression between OP and the other subsites (O, L and HP; P < 0.001) and a higher mRNA expression in WT, missense and inframe MUT, compared with frameshift, splice and stop MUT (P < 0.001) (Supplementary Fig.	('R', 'Chemical', 'MESH:D001120', (53, 54))	('mRNA expression', 'MPA', (140, 155))	('higher', 'PosReg', (133, 139))	('missense', 'Var', (163, 171))	('mRNA expression', 'MPA', (52, 67))	('W', 'Chemical', 'MESH:D014414', (159, 160))	('R', 'Chemical', 'MESH:D001120', (141, 142))
226264	32684626	In total, 176/246 MUT in OC (Bonferroni post hoc test P = 0.08239), 19/62 in OP (Bonferroni post hoc test P < 0.000001), 5/9 in HP (Bonferroni post hoc test P = 0.40597) and 78/90 in L (Bonferroni post hoc test P = 0.00002); for the HPV status, 3/30 HPV-positive patients were mutated in TP53 gene; meanwhile, 52/64 were mutated in HPV-negative tumours.	('HPV', 'Species', '10566', (233, 236))	('C', 'Chemical', 'MESH:D003545', (26, 27))	('patients', 'Species', '9606', (263, 271))	('TP53', 'Gene', '7157', (288, 292))	('tumour', 'Phenotype', 'HP:0002664', (345, 351))	('HPV-negative tumours', 'Disease', 'MESH:D030361', (332, 352))	('HPV', 'Species', '10566', (250, 253))	('HPV', 'Species', '10566', (332, 335))	('TP53', 'Gene', (288, 292))	('tumours', 'Phenotype', 'HP:0002664', (345, 352))	('HPV-negative tumours', 'Disease', (332, 352))	('mutated', 'Var', (277, 284))
226272	32684626	Mutations in H193 occurred only in males; meanwhile, of 8 patients mutated in R196, 6/8 were female patients (chi-square test P = 0.003).	('H193', 'Gene', (13, 17))	('R', 'Chemical', 'MESH:D001120', (78, 79))	('Mutations', 'Var', (0, 9))	('patients', 'Species', '9606', (100, 108))	('H193', 'Chemical', 'MESH:C012111', (13, 17))	('patients', 'Species', '9606', (58, 66))	('R196', 'Var', (78, 82))
226274	32684626	In the last analysis, R273 mutations were characterised by a missense mutation by a substitution of the R (arginine) amino acid to C (cysteine) or H (histidine).	('substitution', 'Var', (84, 96))	('R273 mutations', 'Var', (22, 36))	('R', 'Chemical', 'MESH:D001120', (22, 23))	('histidine', 'Chemical', 'MESH:D006639', (150, 159))	('cysteine', 'Chemical', 'MESH:D003545', (134, 142))	('C', 'Chemical', 'MESH:D003545', (131, 132))	('R', 'Chemical', 'MESH:D001120', (104, 105))	('R (arginine) amino acid', 'Chemical', '-', (104, 127))
226276	32684626	R273 missense mutations were also linked to alcohol consumption; in particular, of five patients with a change from R to C, four reported alcohol consumption in the anamnesis; meanwhile, 8/9 patients with H change did not report alcohol history (chi-square test P = 0.01); the same result was also detected for the OC subgroup (chi-square test P = 0.044).	('H change', 'Disease', (205, 213))	('alcohol', 'Chemical', 'MESH:D000438', (229, 236))	('patients', 'Species', '9606', (191, 199))	('R273 missense mutations', 'Var', (0, 23))	('alcohol', 'Chemical', 'MESH:D000438', (44, 51))	('patients', 'Species', '9606', (88, 96))	('R', 'Chemical', 'MESH:D001120', (116, 117))	('R', 'Chemical', 'MESH:D001120', (0, 1))	('change', 'Var', (104, 110))	('C', 'Chemical', 'MESH:D003545', (121, 122))	('C', 'Chemical', 'MESH:D003545', (316, 317))	('alcohol', 'Chemical', 'MESH:D000438', (138, 145))	('H change', 'Disease', 'MESH:D009402', (205, 213))
226281	32684626	Indeed, a higher number of smoked cigarettes emerged in patients with transversions, compared with patients with transitions of C-T in CpG islands (Mann-Whitney P = 0.032).	('patients', 'Species', '9606', (56, 64))	('patients', 'Species', '9606', (99, 107))	('higher', 'PosReg', (10, 16))	('transversions', 'Var', (70, 83))	('C', 'Chemical', 'MESH:D003545', (135, 136))	('W', 'Chemical', 'MESH:D014414', (153, 154))	('C', 'Chemical', 'MESH:D003545', (128, 129))
226282	32684626	Patients with mutations in Alpha secondary structure showed lower number of smoked packs of cigarettes, against Turn and Bend (Mann-Whitney P = 0.005), unknown (Mann-Whitney P = 0.03) and beta-strand/bridge patients (P = 0.021).	('patients', 'Species', '9606', (207, 215))	('Alpha secondary structure', 'Protein', (27, 52))	('Patients', 'Species', '9606', (0, 8))	('W', 'Chemical', 'MESH:D014414', (166, 167))	('mutations', 'Var', (14, 23))	('W', 'Chemical', 'MESH:D014414', (132, 133))	('lower', 'NegReg', (60, 65))
226284	32684626	Interactome-genome-transcriptome analysis was undertaken to build a dynamic network that highlighted the TP53 interactors that underwent genomic (mutations, CNA) or translational (mRNA expression) modifications in HNSCC.	('C', 'Chemical', 'MESH:D003545', (157, 158))	('C', 'Chemical', 'MESH:D003545', (218, 219))	('R', 'Chemical', 'MESH:D001120', (181, 182))	('C', 'Chemical', 'MESH:D003545', (217, 218))	('TP53', 'Gene', '7157', (105, 109))	('TP53', 'Gene', (105, 109))	('modifications', 'Var', (197, 210))
226290	32684626	In MUT, changes in NDRG1, GSK3B, SNAI2, BCL6, CCNK, PRKDC and RRM2B affected mainly the intrinsic apoptotic process and the transition of the G1/S cell-cycle phase.	('changes', 'Var', (8, 15))	('GSK3B', 'Gene', '2932', (26, 31))	('BCL6', 'Gene', '604', (40, 44))	('affected', 'Reg', (68, 76))	('GSK3B', 'Gene', (26, 31))	('transition of the G1/S cell-cycle phase', 'CPA', (124, 163))	('NDRG1', 'Gene', (19, 24))	('RRM2B', 'Gene', (62, 67))	('PRKDC', 'Gene', (52, 57))	('CCNK', 'Gene', (46, 50))	('BCL6', 'Gene', (40, 44))	('intrinsic apoptotic process', 'CPA', (88, 115))	('NDRG1', 'Gene', '10397', (19, 24))	('SNAI2', 'Gene', '6591', (33, 38))	('SNAI2', 'Gene', (33, 38))	('CCNK', 'Gene', '8812', (46, 50))	('RRM2B', 'Gene', '50484', (62, 67))	('PRKDC', 'Gene', '5591', (52, 57))
226291	32684626	8, 9, Table 3C/D), both WT and MUT were associated with alterations in BCL6, TP63, GSK3B, CDKN2A, CCNK and DROSHA.	('CDKN2A', 'Gene', '1029', (90, 96))	('BCL6', 'Gene', '604', (71, 75))	('CCNK', 'Gene', '8812', (98, 102))	('alterations', 'Reg', (56, 67))	('TP63', 'Gene', '8626', (77, 81))	('W', 'Chemical', 'MESH:D014414', (24, 25))	('TP63', 'Gene', (77, 81))	('GSK3B', 'Gene', (83, 88))	('BCL6', 'Gene', (71, 75))	('GSK3B', 'Gene', '2932', (83, 88))	('DROSHA', 'Gene', (107, 113))	('CCNK', 'Gene', (98, 102))	('DROSHA', 'Gene', '29102', (107, 113))	('3C/D', 'SUBSTITUTION', 'None', (12, 16))	('CDKN2A', 'Gene', (90, 96))	('3C/D', 'Var', (12, 16))
226292	32684626	Surprisingly, CDKN2A in WT resulted altered only in 18.2% of cases (13.6% reported mRNA upregulation, 2.3% homozygous deletion and 2.3% mutation), whereas in MUT, CDKN2A was affected in 78.9% of cases (57.9% reported homozygous deletion and 21.1% mutation).	('R', 'Chemical', 'MESH:D001120', (84, 85))	('CDKN2A', 'Gene', '1029', (163, 169))	('CDKN2A', 'Gene', '1029', (14, 20))	('mutation', 'Var', (247, 255))	('mutation', 'Var', (136, 144))	('deletion', 'Var', (228, 236))	('W', 'Chemical', 'MESH:D014414', (24, 25))	('upregulation', 'PosReg', (88, 100))	('altered', 'Reg', (36, 43))	('CDKN2A', 'Gene', (163, 169))	('mRNA', 'MPA', (83, 87))	('CDKN2A', 'Gene', (14, 20))
226293	32684626	In particular, WT group resulted affected by deficiencies in both intrinsic and extrinsic apoptotic signals, cell-cycle growth checkpoint at G1/S phase, mismatch repair, positive histone deacetylation, negative regulation of cell-matrix adhesion, fatty acid biosynthetic process, cellular response to starvation, negative regulation of intracellular oestrogen receptor signalling pathway, morphogenesis of embryonic epithelium and negative regulation of phosphatidylinositol 3-kinase signalling.	('negative regulation', 'NegReg', (431, 450))	('affected', 'Reg', (33, 41))	('deficiencies', 'Var', (45, 57))	('mismatch', 'Gene', (153, 161))	('fatty acid', 'Chemical', 'MESH:D005227', (247, 257))	('W', 'Chemical', 'MESH:D014414', (15, 16))
226299	32684626	Noncoding RNA (ncRNA) transcription was linked to alterations in CCNK and CDK9, and in particular, HIF1A and YY1 resulted in a positive regulation of pri-miRNA transcription by RNA polymerase II.	('positive regulation', 'PosReg', (127, 146))	('CCNK', 'Gene', (65, 69))	('R', 'Chemical', 'MESH:D001120', (177, 178))	('CDK9', 'Gene', (74, 78))	('HIF1A', 'Gene', (99, 104))	('YY1', 'Gene', (109, 112))	('R', 'Chemical', 'MESH:D001120', (156, 157))	('HIF1A', 'Gene', '3091', (99, 104))	('alterations', 'Var', (50, 61))	('CCNK', 'Gene', '8812', (65, 69))	('R', 'Chemical', 'MESH:D001120', (10, 11))	('R', 'Chemical', 'MESH:D001120', (17, 18))	('pri-miRNA transcription', 'MPA', (150, 173))	('CDK9', 'Gene', '1025', (74, 78))	('YY1', 'Gene', '7528', (109, 112))
226302	32684626	Notably, alterations resulted in positive regulation of glycolytic process, beta-catenin-TCF complex assembly, regulation of cellular respiration and positive regulation of epithelial cell proliferation, led by TP63, MYC, KAT5 and HIF1A.	('regulation', 'MPA', (111, 121))	('glycolytic process', 'MPA', (56, 74))	('beta-catenin', 'Gene', '1499', (76, 88))	('TP63', 'Gene', (211, 215))	('TP63', 'Gene', '8626', (211, 215))	('MYC', 'Gene', (217, 220))	('HIF1A', 'Gene', '3091', (231, 236))	('beta-catenin', 'Gene', (76, 88))	('C', 'Chemical', 'MESH:D003545', (90, 91))	('alterations', 'Var', (9, 20))	('cellular respiration', 'MPA', (125, 145))	('C', 'Chemical', 'MESH:D003545', (219, 220))	('epithelial cell proliferation', 'CPA', (173, 202))	('positive regulation', 'PosReg', (33, 52))	('HIF1A', 'Gene', (231, 236))	('KAT5', 'Gene', (222, 226))	('MYC', 'Gene', '4609', (217, 220))	('KAT5', 'Gene', '10524', (222, 226))
226305	32684626	10, 11, Table 3E/F), CDKN2A, BCL6, TP63, GSK3B and NDRG1 were altered in both WT and MUT; CSNK2A1 and CREBBP were downregulated in WT, whereas the same resulted upregulated in MUT.	('TP63', 'Gene', (35, 39))	('NDRG1', 'Gene', '10397', (51, 56))	('GSK3B', 'Gene', '2932', (41, 46))	('downregulated', 'NegReg', (114, 127))	('CDKN2A', 'Gene', '1029', (21, 27))	('CREBBP', 'Gene', '1387', (102, 108))	('TP63', 'Gene', '8626', (35, 39))	('BCL6', 'Gene', (29, 33))	('3E/F', 'SUBSTITUTION', 'None', (14, 18))	('W', 'Chemical', 'MESH:D014414', (78, 79))	('NDRG1', 'Gene', (51, 56))	('upregulated', 'PosReg', (161, 172))	('CSNK2A1', 'Gene', (90, 97))	('CSNK2A1', 'Gene', '1457', (90, 97))	('BCL6', 'Gene', '604', (29, 33))	('3E/F', 'Var', (14, 18))	('CREBBP', 'Gene', (102, 108))	('CDKN2A', 'Gene', (21, 27))	('GSK3B', 'Gene', (41, 46))	('W', 'Chemical', 'MESH:D014414', (131, 132))
226306	32684626	In terms of pathways, the main alteration in WT affected the signal transduction by p53-class mediators and downstream stress-activated MAPK cascade, due to modifications affecting MAPK13, UBB, TRAF6, MAPKAPK2 and DYRK1A.	('MAPK13', 'Gene', (181, 187))	('DYRK1A', 'Gene', '1859', (214, 220))	('TRAF6', 'Gene', (194, 199))	('MAPKAPK2', 'Gene', '9261', (201, 209))	('UBB', 'Gene', (189, 192))	('MAPKAPK2', 'Gene', (201, 209))	('TRAF6', 'Gene', '7189', (194, 199))	('signal transduction', 'MPA', (61, 80))	('affected', 'Reg', (48, 56))	('p53', 'Gene', (84, 87))	('DYRK1A', 'Gene', (214, 220))	('p53', 'Gene', '7157', (84, 87))	('W', 'Chemical', 'MESH:D014414', (45, 46))	('MAPK13', 'Gene', '5603', (181, 187))	('UBB', 'Gene', '7314', (189, 192))	('modifications', 'Var', (157, 170))
226308	32684626	Alterations in the hypopharynx subgroups differed between wild-type and mutated TP53 groups (Supplementary Figs.	('mutated', 'Var', (72, 79))	('TP53', 'Gene', '7157', (80, 84))	('TP53', 'Gene', (80, 84))
226322	32684626	CDKN2A mRNA resulted in upregulation in 22.2% of HPV+ tumours, whereas HPV- tumours showed homozygous deletion and mutations in 50% and 33.3%, respectively.	('tumours', 'Disease', 'MESH:D009369', (76, 83))	('mutations', 'Var', (115, 124))	('HPV+ tumours', 'Disease', (49, 61))	('HPV', 'Species', '10566', (49, 52))	('tumours', 'Disease', 'MESH:D009369', (54, 61))	('tumours', 'Disease', (76, 83))	('tumours', 'Disease', (54, 61))	('tumour', 'Phenotype', 'HP:0002664', (76, 82))	('tumours', 'Phenotype', 'HP:0002664', (76, 83))	('HPV', 'Species', '10566', (71, 74))	('HPV+ tumours', 'Disease', 'MESH:D030361', (49, 61))	('CDKN2A', 'Gene', (0, 6))	('upregulation', 'PosReg', (24, 36))	('tumour', 'Phenotype', 'HP:0002664', (54, 60))	('mRNA', 'MPA', (7, 11))	('tumours', 'Phenotype', 'HP:0002664', (54, 61))	('CDKN2A', 'Gene', '1029', (0, 6))	('R', 'Chemical', 'MESH:D001120', (8, 9))
226329	32684626	By applying the Poeta algorithm (PA) on the TCGA database, we found that disruptive mutations had independent prognostic significance in HNSCC, although with small difference between disruptive and conservative mutations (disruptive vs conservative mutations, multivariate analysis: HR = 1.077; 95% CI: 0.753-1.541; P = 0.684); (disruptive vs wild-type, multivariate analysis: HR = 1.663; 95% CI: 1.122-2.466; P = 0.011); (conservative vs wild-type, multivariate analysis: HR = 1.545; 95% CI: 1.013-2.357; P = 0.043) (Fig.	('C', 'Chemical', 'MESH:D003545', (489, 490))	('C', 'Chemical', 'MESH:D003545', (140, 141))	('R', 'Chemical', 'MESH:D001120', (284, 285))	('PA', 'Chemical', '-', (33, 35))	('mutations', 'Var', (84, 93))	('R', 'Chemical', 'MESH:D001120', (378, 379))	('R', 'Chemical', 'MESH:D001120', (474, 475))	('C', 'Chemical', 'MESH:D003545', (45, 46))	('C', 'Chemical', 'MESH:D003545', (299, 300))	('C', 'Chemical', 'MESH:D003545', (141, 142))	('C', 'Chemical', 'MESH:D003545', (393, 394))	('HNSCC', 'Disease', (137, 142))
226331	32684626	Patients were classified as carriers of high-risk death mutations, carriers of low-risk death mutations and wild type.	('mutations', 'Var', (56, 65))	('death', 'Disease', (88, 93))	('death', 'Disease', 'MESH:D003643', (50, 55))	('death', 'Disease', (50, 55))	('Patients', 'Species', '9606', (0, 8))	('death', 'Disease', 'MESH:D003643', (88, 93))
226332	32684626	Our model successfully identified patients at higher risk of death according to the mutational status, depending on the biochemical alterations, characteristics and predicted secondary structure.	('death', 'Disease', (61, 66))	('patients', 'Species', '9606', (34, 42))	('death', 'Disease', 'MESH:D003643', (61, 66))	('mutational', 'Var', (84, 94))
226333	32684626	High risk of death mutations resulted to be an independent prognostic factor in TCGA head and neck database, with greater difference towards low risk of death mutations (high-risk vs low-risk mutations, multivariate analysis: HR = 1.818; 95% CI: 1.153-2.869; P = 0.010); (high-risk vs wild-type, multivariate analysis: HR = 1.857; 95% CI: 1.277-2.702; P = 0.001); (low-risk vs wild-type, multivariate analysis: HR = 1.005; 95% CI: 0.596-1.695; P = 0.986) (Fig.	('C', 'Chemical', 'MESH:D003545', (242, 243))	('C', 'Chemical', 'MESH:D003545', (81, 82))	('C', 'Chemical', 'MESH:D003545', (427, 428))	('death', 'Disease', 'MESH:D003643', (13, 18))	('death', 'Disease', (13, 18))	('C', 'Chemical', 'MESH:D003545', (335, 336))	('mutations', 'Var', (19, 28))	('R', 'Chemical', 'MESH:D001120', (412, 413))	('R', 'Chemical', 'MESH:D001120', (227, 228))	('death', 'Disease', 'MESH:D003643', (153, 158))	('death', 'Disease', (153, 158))	('R', 'Chemical', 'MESH:D001120', (320, 321))
226341	32684626	In OSCC, PA failed to find any significant prognostic class (wild-type vs disruptive, multivariate analysis: HR = 0.771; 95% CI: 0.483-1.232; P = 0.277 and conservative vs disruptive mutations, multivariate analysis: HR = 0.815; 95% CI: 0.520-1.277; P = 0.372); meanwhile, our algorithm found a class of mutation with a better overall survival (wild-type vs high-risk, multivariate analysis: HR = 0.714; 95% CI: 0.458-1.113; P = 0.137); (low-risk vs high-risk, multivariate analysis: HR = 0.499; 95% CI: 0.283-0.878; P = 0.016).	('R', 'Chemical', 'MESH:D001120', (393, 394))	('C', 'Chemical', 'MESH:D003545', (500, 501))	('R', 'Chemical', 'MESH:D001120', (218, 219))	('C', 'Chemical', 'MESH:D003545', (5, 6))	('C', 'Chemical', 'MESH:D003545', (6, 7))	('C', 'Chemical', 'MESH:D003545', (408, 409))	('C', 'Chemical', 'MESH:D003545', (233, 234))	('better', 'PosReg', (320, 326))	('overall', 'MPA', (327, 334))	('R', 'Chemical', 'MESH:D001120', (485, 486))	('C', 'Chemical', 'MESH:D003545', (125, 126))	('PA', 'Chemical', '-', (9, 11))	('OSCC', 'Disease', (3, 7))	('R', 'Chemical', 'MESH:D001120', (110, 111))	('mutation', 'Var', (304, 312))
226343	32684626	Specifically, wild-type p53 was associated with a worse overall survival compared with the whole group of patients carrying mutations (multivariate analysis: HR = 1.572; 95% CI: 1.080-2.287; P = 0.018).	('overall survival', 'MPA', (56, 72))	('p53', 'Gene', (24, 27))	('p53', 'Gene', '7157', (24, 27))	('C', 'Chemical', 'MESH:D003545', (174, 175))	('patients', 'Species', '9606', (106, 114))	('wild-type', 'Var', (14, 23))	('R', 'Chemical', 'MESH:D001120', (159, 160))	('worse', 'NegReg', (50, 55))
226344	32684626	When the PA was applied, it emerged that patients with disruptive mutations had a better overall survival, compared both with wild-type (multivariate analysis: HR = 1.791; 95% CI: 1.186-2.707; P = 0.006) and nondisruptive mutated patients (multivariate analysis: HR = 1.296; 95% CI: 0.939-1.790; P = 0.115).	('mutations', 'Var', (66, 75))	('PA', 'Chemical', '-', (9, 11))	('better', 'PosReg', (82, 88))	('W', 'Chemical', 'MESH:D014414', (0, 1))	('R', 'Chemical', 'MESH:D001120', (161, 162))	('patients', 'Species', '9606', (230, 238))	('patients', 'Species', '9606', (41, 49))	('C', 'Chemical', 'MESH:D003545', (279, 280))	('disruptive', 'Var', (55, 65))	('C', 'Chemical', 'MESH:D003545', (176, 177))	('R', 'Chemical', 'MESH:D001120', (264, 265))	('overall', 'MPA', (89, 96))
226345	32684626	Our algorithm, meanwhile, was able to distinguish a group of high-risk mutations (multivariate analysis: HR = 0.803; 95% CI: 0.537-1.201; P = 0.286), although wild-type patients still reported the worst overall survival compared with low risk of death mutations (multivariate analysis: HR = 1.496; 95% CI: 1.019-2.197; P = 0.040).	('death', 'Disease', 'MESH:D003643', (246, 251))	('death', 'Disease', (246, 251))	('patients', 'Species', '9606', (169, 177))	('R', 'Chemical', 'MESH:D001120', (287, 288))	('R', 'Chemical', 'MESH:D001120', (106, 107))	('mutations', 'Var', (71, 80))	('worst', 'NegReg', (197, 202))	('C', 'Chemical', 'MESH:D003545', (121, 122))	('C', 'Chemical', 'MESH:D003545', (302, 303))	('overall survival', 'MPA', (203, 219))
226346	32684626	Many efforts have been made to classify mutations according to their influence on structural changes, and to investigate if they serve as prognostic factors, but limits have been identified due to the wideness of the mutational landscape of TP53.	('mutations', 'Var', (40, 49))	('TP53', 'Gene', '7157', (241, 245))	('TP53', 'Gene', (241, 245))
226347	32684626	In this study, we propose a new classification method that identifies patients with mutations at high risk of death in squamous cell cancers and, in particular, in tumours from the head and neck district.	('patients', 'Species', '9606', (70, 78))	('tumour', 'Phenotype', 'HP:0002664', (164, 170))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('tumours', 'Phenotype', 'HP:0002664', (164, 171))	('cancers', 'Phenotype', 'HP:0002664', (133, 140))	('mutations', 'Var', (84, 93))	('tumours', 'Disease', 'MESH:D009369', (164, 171))	('tumours', 'Disease', (164, 171))	('squamous cell cancers', 'Disease', (119, 140))	('death', 'Disease', 'MESH:D003643', (110, 115))	('death', 'Disease', (110, 115))	('squamous cell cancers', 'Phenotype', 'HP:0002860', (119, 140))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (119, 139))	('squamous cell cancers', 'Disease', 'MESH:D002294', (119, 140))
226349	32684626	In the HNSCC cohort from TCGA included in this study, 69.9% of patients expressed a mutation in TP53.	('C', 'Chemical', 'MESH:D003545', (26, 27))	('expressed', 'Reg', (72, 81))	('TP53', 'Gene', (96, 100))	('C', 'Chemical', 'MESH:D003545', (10, 11))	('C', 'Chemical', 'MESH:D003545', (11, 12))	('patients', 'Species', '9606', (63, 71))	('TP53', 'Gene', '7157', (96, 100))	('mutation', 'Var', (84, 92))
226351	32684626	Due to the increase in detection of single mutations in TP53 gene, several studies have attempted to elucidate the correlation between mutational status and patients' clinicopathological characteristics, with discordant results.	('increase', 'PosReg', (11, 19))	('single mutations', 'Var', (36, 52))	('TP53', 'Gene', '7157', (56, 60))	('patients', 'Species', '9606', (157, 165))	('TP53', 'Gene', (56, 60))
226352	32684626	This is a reasonable approach, since a broad range of mutations can affect the TP53 gene and its encoded protein; for example, the 286 HNSCC patients included in our study exhibited 129 different kinds of mutation, of which R273 was the most frequent but occurred in only 13 patients.	('TP53', 'Gene', '7157', (79, 83))	('TP53', 'Gene', (79, 83))	('R273', 'Var', (224, 228))	('R', 'Chemical', 'MESH:D001120', (224, 225))	('patients', 'Species', '9606', (275, 283))	('affect', 'Reg', (68, 74))	('patients', 'Species', '9606', (141, 149))
226354	32684626	An extensive analysis of 33 TCGA studies showed that the effects of TP53 mutations on patients' prognosis were statistically significant in nine malignancies (lung adenocarcinoma, hepatocellular carcinoma, HNSCC, acute myeloid leukaemia, clear-cell renal cell carcinoma (RCC), papillary RCC, chromophobe RCC, uterine endometrial carcinoma and thymoma).	('clear-cell renal cell carcinoma', 'Disease', (238, 269))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (317, 338))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (180, 204))	('carcinoma', 'Phenotype', 'HP:0030731', (169, 178))	('malignancies', 'Disease', 'MESH:D009369', (145, 157))	('effects', 'Reg', (57, 64))	('C', 'Chemical', 'MESH:D003545', (29, 30))	('TP53', 'Gene', (68, 72))	('chromophobe RCC', 'Disease', 'MESH:C538614', (292, 307))	('patients', 'Species', '9606', (86, 94))	('malignancies', 'Disease', (145, 157))	('thymoma', 'Disease', (343, 350))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (180, 204))	('thymoma', 'Phenotype', 'HP:0100522', (343, 350))	('clear-cell renal cell carcinoma', 'Disease', 'MESH:C538614', (238, 269))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (249, 269))	('RCC', 'Disease', (304, 307))	('thymoma', 'Disease', 'MESH:D013945', (343, 350))	('C', 'Chemical', 'MESH:D003545', (306, 307))	('acute myeloid leukaemia', 'Disease', 'MESH:D015470', (213, 236))	('RCC', 'Disease', (271, 274))	('myeloid leukaemia', 'Phenotype', 'HP:0012324', (219, 236))	('lung adenocarcinoma', 'Disease', (159, 178))	('HNSCC', 'Disease', (206, 211))	('C', 'Chemical', 'MESH:D003545', (273, 274))	('C', 'Chemical', 'MESH:D003545', (305, 306))	('acute myeloid leukaemia', 'Phenotype', 'HP:0004808', (213, 236))	('endometrial carcinoma', 'Disease', (317, 338))	('C', 'Chemical', 'MESH:D003545', (209, 210))	('hepatocellular carcinoma', 'Disease', (180, 204))	('chromophobe RCC', 'Disease', (292, 307))	('C', 'Chemical', 'MESH:D003545', (272, 273))	('RCC', 'Disease', 'MESH:C538614', (304, 307))	('C', 'Chemical', 'MESH:D003545', (210, 211))	('carcinoma', 'Phenotype', 'HP:0030731', (260, 269))	('RCC', 'Disease', 'MESH:C538614', (271, 274))	('RCC', 'Disease', (287, 290))	('TP53', 'Gene', '7157', (68, 72))	('carcinoma', 'Phenotype', 'HP:0030731', (195, 204))	('C', 'Chemical', 'MESH:D003545', (289, 290))	('papillary RCC', 'Disease', 'MESH:C538614', (277, 290))	('significant', 'Reg', (125, 136))	('papillary RCC', 'Disease', (277, 290))	('clear-cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (238, 269))	('C', 'Chemical', 'MESH:D003545', (288, 289))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (159, 178))	('acute myeloid leukaemia', 'Disease', (213, 236))	('carcinoma', 'Phenotype', 'HP:0030731', (329, 338))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (317, 338))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (159, 178))	('RCC', 'Disease', 'MESH:C538614', (287, 290))	('mutations', 'Var', (73, 82))
226355	32684626	Although this method can be considered "quick and useful", this approach does not take into account some biochemical and functional characteristics of single TP53 mutations.	('TP53', 'Gene', '7157', (158, 162))	('TP53', 'Gene', (158, 162))	('mutations', 'Var', (163, 172))
226357	32684626	After integrating the survival analysis according to the subsite of HNSCC onset, mutated TP53 resulted to be an independent prognostic factor for overall and disease-free survival only in OP.	('mutated', 'Var', (81, 88))	('TP53', 'Gene', '7157', (89, 93))	('TP53', 'Gene', (89, 93))
226358	32684626	These results have salient clinical implications, because, cells with wild-type or higher TP53 expression are more susceptible to radiation therapy, and HPV+ tumours usually display higher radiosensitivity.	('HPV+ tumours', 'Disease', 'MESH:D030361', (153, 165))	('radiosensitivity', 'CPA', (189, 205))	('tumour', 'Phenotype', 'HP:0002664', (158, 164))	('tumours', 'Phenotype', 'HP:0002664', (158, 165))	('TP53', 'Gene', '7157', (90, 94))	('radiation therapy', 'CPA', (130, 147))	('higher', 'PosReg', (182, 188))	('TP53', 'Gene', (90, 94))	('HPV+ tumours', 'Disease', (153, 165))	('higher', 'Var', (83, 89))	('expression', 'MPA', (95, 105))
226359	32684626	Therefore, our data suggest that mutations in TP53 gene have a prognostic role in HNSCC, above all, in HPV+ OP tumours where mutational status of this gene should be investigated before considering treatment options.	('tumours', 'Disease', (111, 118))	('HPV', 'Species', '10566', (103, 106))	('TP53', 'Gene', '7157', (46, 50))	('tumour', 'Phenotype', 'HP:0002664', (111, 117))	('mutations', 'Var', (33, 42))	('TP53', 'Gene', (46, 50))	('HNSCC', 'Disease', (82, 87))	('tumours', 'Phenotype', 'HP:0002664', (111, 118))	('tumours', 'Disease', 'MESH:D009369', (111, 118))
226360	32684626	These findings could let us speculate that mutations affecting TP53 in HPV+ tumours make them more similar to HPV- HNSCCs.	('HPV+ tumours', 'Disease', 'MESH:D030361', (71, 83))	('HPV', 'Species', '10566', (110, 113))	('TP53', 'Gene', (63, 67))	('TP53', 'Gene', '7157', (63, 67))	('tumour', 'Phenotype', 'HP:0002664', (76, 82))	('mutations', 'Var', (43, 52))	('HPV', 'Species', '10566', (71, 74))	('HPV+ tumours', 'Disease', (71, 83))	('tumours', 'Phenotype', 'HP:0002664', (76, 83))
226361	32684626	Although this hypothesis should be analysed in future studies, the results of network analysis showed that MUT OP shared common alterations with other subgroups, in particular homozygous deletions and mutations affecting CDKN2A (78.9% of patients in MUT OP against 13.6% mRNA upregulation in WT OP).	('MUT', 'Var', (250, 253))	('mutations', 'Var', (201, 210))	('CDKN2A', 'Gene', (221, 227))	('CDKN2A', 'Gene', '1029', (221, 227))	('R', 'Chemical', 'MESH:D001120', (272, 273))	('W', 'Chemical', 'MESH:D014414', (292, 293))	('patients', 'Species', '9606', (238, 246))	('deletions', 'Var', (187, 196))
226364	32684626	Loss of pRb leads to the release of E2F with the transcription of S-phase genes.	('pRb', 'Gene', (8, 11))	('pRb', 'Gene', '5925', (8, 11))	('E2F', 'MPA', (36, 39))	('S-phase genes', 'Gene', (66, 79))	('transcription', 'MPA', (49, 62))	('release', 'MPA', (25, 32))	('Loss', 'Var', (0, 4))
226366	32684626	In addition, CX3CL1 and MYB shared common alteration (mRNA upregulation) both in WT OP and HPV+ OP, leading to a positive regulation of transforming growth factor beta production.	('CX3CL1', 'Gene', (13, 19))	('HPV+', 'Var', (91, 95))	('MYB', 'Gene', (24, 27))	('W', 'Chemical', 'MESH:D014414', (81, 82))	('transforming growth factor beta', 'Gene', '7124', (136, 167))	('transforming growth factor beta', 'Gene', (136, 167))	('HPV', 'Species', '10566', (91, 94))	('positive regulation', 'PosReg', (113, 132))	('CX3CL1', 'Gene', '6376', (13, 19))	('MYB', 'Gene', '4602', (24, 27))	('R', 'Chemical', 'MESH:D001120', (55, 56))
226374	32684626	BRCA1 plays a critical role in homologous recombination repair, and cells with deficiency in BRCA1 are more sensible to drugs causing DNA breaks or to ionising radiation.	('BRCA1', 'Gene', (0, 5))	('deficiency', 'Var', (79, 89))	('BRCA1', 'Gene', '672', (93, 98))	('DNA', 'MPA', (134, 137))	('sensible', 'MPA', (108, 116))	('more', 'PosReg', (103, 107))	('BRCA1', 'Gene', (93, 98))	('BRCA1', 'Gene', '672', (0, 5))
226381	32684626	Starting from the findings of Poeta et al, we developed our own algorithm reclassifying mutations in high risk of death according to their homozygous alteration, their zinc ligand and H+-forming bond alteration.	('death', 'Disease', 'MESH:D003643', (114, 119))	('death', 'Disease', (114, 119))	('mutations', 'Var', (88, 97))
226384	32684626	This mutation was reclassified as high risk since tyrosine (Y) is able to create a hydrogen bonding, conversely to what happens when substituted by a cysteine (C).	('C', 'Chemical', 'MESH:D003545', (160, 161))	('tyrosine', 'Chemical', 'MESH:D014443', (50, 58))	('hydrogen', 'Chemical', 'MESH:D006859', (83, 91))	('hydrogen bonding', 'MPA', (83, 99))	('create', 'Reg', (74, 80))	('tyrosine', 'Var', (50, 58))	('cysteine', 'Chemical', 'MESH:D003545', (150, 158))
226388	32684626	Of interest, PA failed to find any significant prognostic class in OSCC, where the new model found a class of mutations with a better overall survival (wild-type vs high-risk, multivariate analysis: HR = 0.714; 95% CI: 0.458-1.113; P = 0.137); (low-risk vs high-risk, multivariate analysis: HR = 0.499; 95% CI: 0.283-0.878; P = 0.016).	('PA', 'Chemical', '-', (13, 15))	('mutations', 'Var', (110, 119))	('C', 'Chemical', 'MESH:D003545', (215, 216))	('better', 'PosReg', (127, 133))	('OSCC', 'Disease', (67, 71))	('R', 'Chemical', 'MESH:D001120', (292, 293))	('overall', 'MPA', (134, 141))	('C', 'Chemical', 'MESH:D003545', (70, 71))	('R', 'Chemical', 'MESH:D001120', (200, 201))	('C', 'Chemical', 'MESH:D003545', (69, 70))	('C', 'Chemical', 'MESH:D003545', (307, 308))
226390	32684626	A meta-analysis, published in 2015, reported the same conflicting results in non-small-cell lung carcinoma, since TP53 mutations emerged to be associated with a worse overall survival compared with wild type.	('overall', 'MPA', (167, 174))	('worse', 'NegReg', (161, 166))	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('lung carcinoma', 'Disease', 'MESH:D008175', (92, 106))	('lung carcinoma', 'Disease', (92, 106))	('TP53', 'Gene', '7157', (114, 118))	('TP53', 'Gene', (114, 118))	('mutations', 'Var', (119, 128))
226401	32684626	To the best of our knowledge, this was the first study to link different molecular aspects of TP53 alterations (mutational profile of TP53, coding gene structure, secondary structure and well-known hotspot mutations) to the clinical variables of HNSCC patients.	('TP53', 'Gene', (134, 138))	('patients', 'Species', '9606', (252, 260))	('TP53', 'Gene', '7157', (94, 98))	('TP53', 'Gene', (94, 98))	('alterations', 'Var', (99, 110))	('HNSCC', 'Disease', (246, 251))	('TP53', 'Gene', '7157', (134, 138))
226403	32684626	Furthermore, this study suggests that there is a broad range of TP53 residues that could be mutated in HNSCC, which may determine differential effects in terms of mRNA and protein expression, secondary structure, apoptosis activity and DNA-binding affinity.	('apoptosis activity', 'CPA', (213, 231))	('mutated', 'Var', (92, 99))	('DNA-binding', 'Interaction', (236, 247))	('R', 'Chemical', 'MESH:D001120', (164, 165))	('TP53', 'Gene', '7157', (64, 68))	('TP53', 'Gene', (64, 68))	('secondary structure', 'MPA', (192, 211))	('effects', 'Reg', (143, 150))
226405	32684626	Finally, whilst this study indicates a prognostic role of TP53 mutations in HNSCC, the influence of TP53 status in cancer prognosis more broadly is still controversial and large, and well-standardised studies are needed.	('mutations', 'Var', (63, 72))	('TP53', 'Gene', '7157', (100, 104))	('cancer', 'Disease', (115, 121))	('HNSCC', 'Disease', (76, 81))	('TP53', 'Gene', '7157', (58, 62))	('TP53', 'Gene', (58, 62))	('TP53', 'Gene', (100, 104))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('cancer', 'Disease', 'MESH:D009369', (115, 121))
226415	32788880	Moreover, we found that MYH9 knock-down led to inhibition of cell migration and invasion.	('invasion', 'CPA', (80, 88))	('MYH9', 'Gene', '4627', (24, 28))	('inhibition', 'NegReg', (47, 57))	('MYH9', 'Gene', (24, 28))	('knock-down', 'Var', (29, 39))
226416	32788880	PCR-array showed MYH9 knockdown led to a significant change of genes expression associated with angiogenesis and epithelial-to-mesenchymal transition (EMT).	('knockdown', 'Var', (22, 31))	('MYH9', 'Gene', (17, 21))	('angiogenesis', 'CPA', (96, 108))	('epithelial-to-mesenchymal transition', 'CPA', (113, 149))	('change', 'Reg', (53, 59))	('genes expression', 'MPA', (63, 79))	('MYH9', 'Gene', '4627', (17, 21))
226418	32788880	Conclusions: Collectively, our study identifies a novel role and mechanism of MYH9, highlights a significance of MYH9 as a metastatic biomarker, and offers potential therapeutic targets for ESCC patients harboring MYH9 mutations.	('ESCC', 'Disease', (190, 194))	('MYH9', 'Gene', (113, 117))	('MYH9', 'Gene', (214, 218))	('MYH9', 'Gene', (78, 82))	('patients', 'Species', '9606', (195, 203))	('MYH9', 'Gene', '4627', (113, 117))	('MYH9', 'Gene', '4627', (214, 218))	('MYH9', 'Gene', '4627', (78, 82))	('mutations', 'Var', (219, 228))
226422	32788880	Over the past decades, researchers have found mutations in several genes, such as TP53 , NOTCH1 , and PIK3CA , show a relatively close relationship with the appearance and development of ESCC by using next-generation sequencing technology.	('ESCC', 'Disease', (187, 191))	('TP53', 'Gene', (82, 86))	('relationship', 'Reg', (135, 147))	('mutations', 'Var', (46, 55))	('PIK3CA', 'Gene', (102, 108))	('NOTCH1', 'Gene', '4851', (89, 95))	('NOTCH1', 'Gene', (89, 95))	('PIK3CA', 'Gene', '5290', (102, 108))	('TP53', 'Gene', '7157', (82, 86))
226423	32788880	Next-generation sequencing technology is able to accurately detect the whole genomic information of cancer cells in great detail, and is especially advantageous for the discovery of new, low frequency mutant genes by bioinformatics analysis of obtained data.	('cancer', 'Disease', (100, 106))	('mutant', 'Var', (201, 207))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))
226424	32788880	In fact, significant mutant genes screened as the "driver genes" in tumorigenesis with the help of bioinformatics and statistical analysis owing to their mutation frequency is not lower than a certain threshold value.	('tumor', 'Disease', (68, 73))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('mutant', 'Var', (21, 27))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))
226432	32788880	Our study identifies a novel role and mechanism of MYH9 contributes to ESCC progression, provide several possible therapeutic targets for ESCC patients harboring MYH9 mutations.	('MYH9', 'Gene', '4627', (51, 55))	('ESCC', 'Disease', (71, 75))	('MYH9', 'Gene', '4627', (162, 166))	('mutations', 'Var', (167, 176))	('patients', 'Species', '9606', (143, 151))	('MYH9', 'Gene', (51, 55))	('contributes', 'Reg', (56, 67))	('MYH9', 'Gene', (162, 166))
226438	32788880	All of the esophageal cancer cell lines, including KYSE140, KYSE180, ECA109, KYSE410, KYSE510, KYSE150, and TE1 were stored at the Translational Medicine Research Center of the Shanxi Medical University (Taiyuan, China).	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('KYSE410', 'Var', (77, 84))	('KYSE510', 'Var', (86, 93))	('KYSE140', 'Var', (51, 58))	('cancer', 'Disease', (22, 28))	('KYSE180', 'Var', (60, 67))	('KYSE150', 'Var', (95, 102))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))
226458	32788880	The analysis result of ICGC database showed that MYH9 was mutated in multiple common tumors (Figure 1).	('MYH9', 'Gene', '4627', (49, 53))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('tumors', 'Disease', (85, 91))	('MYH9', 'Gene', (49, 53))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('mutated', 'Var', (58, 65))	('tumors', 'Disease', 'MESH:D009369', (85, 91))
226459	32788880	Moreover, we found that 90% (223/248) mutations of MYH9 were located in the CDS region in COSMIC database.	('MYH9', 'Gene', '4627', (51, 55))	('CDS', 'Chemical', 'MESH:D002104', (76, 79))	('MYH9', 'Gene', (51, 55))	('mutations', 'Var', (38, 47))	('located', 'Reg', (61, 68))
226460	32788880	Therefore, we hypothesized that the MYH9 mutation is closely related to carcinogenesis.	('MYH9', 'Gene', (36, 40))	('mutation', 'Var', (41, 49))	('related', 'Reg', (61, 68))	('carcinogenesis', 'Disease', 'MESH:D063646', (72, 86))	('MYH9', 'Gene', '4627', (36, 40))	('carcinogenesis', 'Disease', (72, 86))
226465	32788880	In addition, after analyzing the TCGA (The Cancer Genome Atlas) databases of CESC (cervical squamous carcinoma) (Figure 3A) and HNSC (Head and neck squamous cancer) (Figure 3B), we found that high MYH9 expression level was strongly associated with shortened survival period of patients.	('Cancer', 'Disease', (43, 49))	('squamous cancer', 'Phenotype', 'HP:0002860', (148, 163))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('neck squamous cancer', 'Disease', 'MESH:D006258', (143, 163))	('Cancer', 'Disease', 'MESH:D009369', (43, 49))	('MYH9', 'Gene', (197, 201))	('Head and neck squamous cancer', 'Phenotype', 'HP:0012288', (134, 163))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('high', 'Var', (192, 196))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (92, 110))	('shortened', 'NegReg', (248, 257))	('neck squamous cancer', 'Disease', (143, 163))	('patients', 'Species', '9606', (277, 285))	('cervical squamous carcinoma', 'Disease', 'MESH:D002294', (83, 110))	('MYH9', 'Gene', '4627', (197, 201))	('expression level', 'MPA', (202, 218))	('cervical squamous carcinoma', 'Disease', (83, 110))	('Cancer', 'Phenotype', 'HP:0002664', (43, 49))
226466	32788880	Therefore, high MYH9 expression may be one of the most important markers in prognosis of squamous cell carcinoma.	('MYH9', 'Gene', (16, 20))	('expression', 'MPA', (21, 31))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (89, 112))	('MYH9', 'Gene', '4627', (16, 20))	('high', 'Var', (11, 15))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (89, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('squamous cell carcinoma', 'Disease', (89, 112))
226473	32788880	To explore the specific mechanism MYH9 utilizes as an oncogene in ESCC, PCR-array experiments were performed for a comparative analysis between the KYSE140 and KYSE140-MYH9sh cells.	('MYH9', 'Gene', '4627', (168, 172))	('MYH9', 'Gene', (34, 38))	('KYSE140', 'Var', (148, 155))	('ESCC', 'Disease', (66, 70))	('MYH9', 'Gene', (168, 172))	('MYH9', 'Gene', '4627', (34, 38))
226477	32788880	Our results demonstrated that angiogenesis was inhibited after MYH9 knockdown in ESCC cells, directly indicating the promotion effect of MYH9 on angiogenesis (Figure 6B).	('promotion', 'PosReg', (117, 126))	('inhibited', 'NegReg', (47, 56))	('MYH9', 'Gene', '4627', (63, 67))	('MYH9', 'Gene', (137, 141))	('angiogenesis', 'CPA', (30, 42))	('knockdown', 'Var', (68, 77))	('MYH9', 'Gene', '4627', (137, 141))	('MYH9', 'Gene', (63, 67))
226478	32788880	And, we detected with the help of qPCR the changes in expression of angiogenesis and EMT-related markers in knockdown of MYH9 and its control cells of ESCC.	('expression', 'MPA', (54, 64))	('knockdown', 'Var', (108, 117))	('angiogenesis', 'CPA', (68, 80))	('MYH9', 'Gene', '4627', (121, 125))	('MYH9', 'Gene', (121, 125))
226479	32788880	The results showed that after knocking down MYH9, the expression of angiogenesis markers FLT1, KDR, TEK, and VEGFC decreased, and the expression of mesothelial cell markers SNAI2, KRT14 and CDH2 decreased (Figure 6C).	('TEK', 'Gene', '7010', (100, 103))	('KRT14', 'Gene', (180, 185))	('KDR', 'Gene', '3791', (95, 98))	('MYH9', 'Gene', '4627', (44, 48))	('FLT1', 'Gene', (89, 93))	('MYH9', 'Gene', (44, 48))	('FLT1', 'Gene', '2321', (89, 93))	('SNAI2', 'Gene', (173, 178))	('CDH2', 'Gene', (190, 194))	('expression', 'MPA', (134, 144))	('KDR', 'Gene', (95, 98))	('SNAI2', 'Gene', '6591', (173, 178))	('knocking down', 'Var', (30, 43))	('decreased', 'NegReg', (195, 204))	('expression', 'MPA', (54, 64))	('VEGFC', 'Gene', (109, 114))	('CDH2', 'Gene', '1000', (190, 194))	('TEK', 'Gene', (100, 103))	('angiogenesis', 'CPA', (68, 80))	('decreased', 'NegReg', (115, 124))	('VEGFC', 'Gene', '7424', (109, 114))	('KRT14', 'Gene', '3861', (180, 185))
226484	32788880	A series of ESCC-related mutant genes, including some star genes (NOTCH1, TP53, and PIK3C) and some low frequency mutant genes were identified.	('mutant', 'Var', (25, 31))	('ESCC-related', 'Disease', (12, 24))	('TP53', 'Gene', '7157', (74, 78))	('NOTCH1', 'Gene', '4851', (66, 72))	('PIK3C', 'Gene', (84, 89))	('TP53', 'Gene', (74, 78))	('NOTCH1', 'Gene', (66, 72))
226486	32788880	Moreover, the mutant MYH9 was found in a range of common tumors, and 90% (223/248) of the MYH9 mutations were located in the CDS region.	('MYH9', 'Gene', '4627', (21, 25))	('located', 'Reg', (110, 117))	('mutant', 'Var', (14, 20))	('CDS', 'Chemical', 'MESH:D002104', (125, 128))	('found', 'Reg', (30, 35))	('MYH9', 'Gene', '4627', (90, 94))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('MYH9', 'Gene', (21, 25))	('mutations', 'Var', (95, 104))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('tumors', 'Disease', (57, 63))	('MYH9', 'Gene', (90, 94))	('tumors', 'Disease', 'MESH:D009369', (57, 63))
226487	32788880	Therefore, it is reasonable to believe that a mutation of MYH9 plays an important role in the development of cancer.	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('MYH9', 'Gene', '4627', (58, 62))	('cancer', 'Disease', (109, 115))	('mutation', 'Var', (46, 54))	('role', 'Reg', (82, 86))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('MYH9', 'Gene', (58, 62))
226492	32788880	Consistent with our research results, it was reported that expression of MYH9 is closely related to the malignant degree of cancer, and can be regarded as a marker for evaluating lymph node metastasis and poor prognosis in breast cancer, epithelial ovarian cancer and acute myeloid leukemia.	('cancer', 'Phenotype', 'HP:0002664', (257, 263))	('breast cancer', 'Disease', 'MESH:D001943', (223, 236))	('epithelial ovarian cancer', 'Phenotype', 'HP:0025318', (238, 263))	('breast cancer', 'Disease', (223, 236))	('acute myeloid leukemia', 'Disease', (268, 290))	('cancer', 'Disease', 'MESH:D009369', (124, 130))	('epithelial ovarian cancer', 'Disease', (238, 263))	('ovarian cancer', 'Phenotype', 'HP:0100615', (249, 263))	('cancer', 'Disease', 'MESH:D009369', (257, 263))	('cancer', 'Disease', (230, 236))	('expression', 'Var', (59, 69))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (274, 290))	('MYH9', 'Gene', '4627', (73, 77))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (268, 290))	('epithelial ovarian cancer', 'Disease', 'MESH:D000077216', (238, 263))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('related', 'Reg', (89, 96))	('leukemia', 'Phenotype', 'HP:0001909', (282, 290))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (268, 290))	('MYH9', 'Gene', (73, 77))	('cancer', 'Disease', (124, 130))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('breast cancer', 'Phenotype', 'HP:0003002', (223, 236))	('cancer', 'Disease', 'MESH:D009369', (230, 236))	('cancer', 'Disease', (257, 263))
226511	32788880	The aberrant expression of N-cadherin was significantly related to the differentiated degree, histological type, invasion and metastasis of gastric cancer.	('differentiated degree', 'CPA', (71, 92))	('gastric cancer', 'Phenotype', 'HP:0012126', (140, 154))	('invasion', 'CPA', (113, 121))	('N-cadherin', 'Gene', (27, 37))	('aberrant', 'Var', (4, 12))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('metastasis of gastric cancer', 'Disease', (126, 154))	('N-cadherin', 'Gene', '1000', (27, 37))	('related', 'Reg', (56, 63))	('metastasis of gastric cancer', 'Disease', 'MESH:D013274', (126, 154))
226515	32788880	In conclusion, a low frequency mutant gene related to ESCC was found to play an important role in metastasis and angiogenesis of esophageal cancer cells.	('play', 'Reg', (72, 76))	('role', 'Reg', (90, 94))	('angiogenesis', 'CPA', (113, 125))	('metastasis', 'CPA', (98, 108))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('mutant gene', 'Var', (31, 42))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))
226542	30723574	HPV-driven HNSCC show a more favorable clinical outcome and better response to chemoradiation compared to alcohol and smoking induced HNSCC.	('HNSCC', 'Phenotype', 'HP:0012288', (11, 16))	('HNSCC', 'Disease', (11, 16))	('HPV', 'Species', '10566', (0, 3))	('HPV-driven', 'Var', (0, 10))	('alcohol', 'Chemical', 'MESH:D000438', (106, 113))	('HNSCC', 'Phenotype', 'HP:0012288', (134, 139))
226543	30723574	For example, different antitumor immune cell subsets are increased in the TME of HPV+ compared to HPV- HNSCC.	('HNSCC', 'Phenotype', 'HP:0012288', (103, 108))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('HPV+', 'Var', (81, 85))	('tumor', 'Disease', (27, 32))	('increased', 'PosReg', (57, 66))	('HPV', 'Species', '10566', (81, 84))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('HPV', 'Species', '10566', (98, 101))
226547	30723574	This study therefore aimed at providing a detailed characterization of different B cellular components of the TME and comprehensively investigating the humoral immune response against various TAAs in patients with HPV+ and HPV- HNSCC.	('patients', 'Species', '9606', (200, 208))	('HPV', 'Species', '10566', (223, 226))	('HPV-', 'Var', (223, 227))	('HNSCC', 'Phenotype', 'HP:0012288', (228, 233))	('HPV', 'Species', '10566', (214, 217))	('HPV+', 'Var', (214, 218))
226558	30723574	Likewise, percentages of B cells (CD19+/CD20+) were significantly higher in HPV+ HNSCC (1.13 +- 1.72%) compared to HPV- HNSCC (0.17 +- 0.33%; p = 0.024) or mucosa (0.19 +- 0.44%; p = 0.017; Figure 1D).	('HPV+ HNSCC', 'Var', (76, 86))	('HPV', 'Species', '10566', (76, 79))	('CD19', 'Gene', (34, 38))	('HPV', 'Species', '10566', (115, 118))	('HNSCC', 'Phenotype', 'HP:0012288', (81, 86))	('higher', 'PosReg', (66, 72))	('CD19', 'Gene', '930', (34, 38))	('B cells', 'CPA', (25, 32))	('HNSCC', 'Phenotype', 'HP:0012288', (120, 125))	('CD20', 'Gene', (40, 44))	('CD20', 'Gene', '931', (40, 44))
226566	30723574	Of note, the percentage of this antigen-presenting phenotype was significantly lower in the TME of HPV+ HNSCC compared to HPV- HNSCC (7.99 +- 5.33% vs. 3.11 +- 1.56%; p = 0.01; Figure 2B, right).	('HPV', 'Species', '10566', (122, 125))	('HNSCC', 'Phenotype', 'HP:0012288', (104, 109))	('lower', 'NegReg', (79, 84))	('HPV', 'Species', '10566', (99, 102))	('HPV+ HNSCC', 'Var', (99, 109))	('HNSCC', 'Phenotype', 'HP:0012288', (127, 132))
226575	30723574	Regulatory B cells that are characterized by high CD24 and CD38 expression were significantly increased in the CD19+ fraction of PBMC HNSCC compared to PBMC HC (7.11 +- 3.26% vs. 4.60 +- 2.50%; p = 0.016).	('CD38', 'Gene', (59, 63))	('CD19', 'Gene', '930', (111, 115))	('expression', 'MPA', (64, 74))	('CD24', 'Gene', (50, 54))	('increased', 'PosReg', (94, 103))	('Regulatory B cells', 'CPA', (0, 18))	('CD38', 'Gene', '952', (59, 63))	('PBMC', 'Var', (129, 133))	('HNSCC', 'Phenotype', 'HP:0012288', (134, 139))	('CD19', 'Gene', (111, 115))	('CD24', 'Gene', '100133941', (50, 54))
226587	30723574	Similarly, CD27+/CD38hi/CD138hi/CD20- plasma cells were significantly increased in PBMC HNSCC compared to PBMC HC (1.35 +- 1.77% vs. 0.26 +- 0.20%; p = 0.015).	('PBMC', 'Var', (83, 87))	('increased', 'PosReg', (70, 79))	('CD38', 'Gene', '952', (17, 21))	('HNSCC', 'Phenotype', 'HP:0012288', (88, 93))	('CD20', 'Gene', '931', (32, 36))	('CD27', 'Gene', '939', (11, 15))	('CD38', 'Gene', (17, 21))	('CD27', 'Gene', (11, 15))	('CD20', 'Gene', (32, 36))
226603	30723574	Consistent with gene expression results, detection of TAA antibody responses correlated positively with the presence of a HNSCC (rs = 0.41; p = 0.003; Figure 4B/C).	('4B/C', 'Var', (158, 162))	('4B/C', 'SUBSTITUTION', 'None', (158, 162))	('HNSCC', 'Disease', (122, 127))	('HNSCC', 'Phenotype', 'HP:0012288', (122, 127))
226607	30723574	In contrast, 18/27 HPV- HNSCC patients showed antibody responses against at least one TAA (Figure 4B/C).	('HNSCC', 'Phenotype', 'HP:0012288', (24, 29))	('4B/C', 'Var', (98, 102))	('patients', 'Species', '9606', (30, 38))	('antibody responses', 'MPA', (46, 64))	('HPV', 'Species', '10566', (19, 22))	('TAA', 'Protein', (86, 89))	('4B/C', 'SUBSTITUTION', 'None', (98, 102))
226638	30723574	However, we observed stronger humoral TAA antibody responses in patients with tumors that showed high MHC-I expression, suggesting that MHC-I expression in HNSCC does not only influence effector T or NK cell responses, but might also influence B cell function.	('tumors', 'Disease', (78, 84))	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('high MHC', 'Phenotype', 'HP:0025548', (97, 105))	('patients', 'Species', '9606', (64, 72))	('stronger', 'PosReg', (21, 29))	('B cell function', 'CPA', (244, 259))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('MHC-I', 'Gene', (102, 107))	('influence', 'Reg', (234, 243))	('HNSCC', 'Phenotype', 'HP:0012288', (156, 161))	('influence', 'Reg', (176, 185))	('high', 'Var', (97, 101))	('expression', 'Var', (108, 118))
226644	30723574	This might be explained by higher mutational rate in HPV- HNSCC and therefore increased immunogenicity and infiltration by antigen-presenting cells.	('HPV- HNSCC', 'Gene', (53, 63))	('increased', 'PosReg', (78, 87))	('mutational', 'Var', (34, 44))	('higher', 'PosReg', (27, 33))	('HPV', 'Species', '10566', (53, 56))	('HNSCC', 'Phenotype', 'HP:0012288', (58, 63))	('immunogenicity', 'MPA', (88, 102))
226645	30723574	Indeed, the TME of microsatellite-unstable colorectal cancer comprise higher numbers of antigen-presenting cells such as dendritic cells than microsatellite-stable cancers.	('colorectal cancer', 'Disease', (43, 60))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('colorectal cancer', 'Phenotype', 'HP:0003003', (43, 60))	('microsatellite-unstable', 'Var', (19, 42))	('cancers', 'Phenotype', 'HP:0002664', (164, 171))	('colorectal cancer', 'Disease', 'MESH:D015179', (43, 60))	('cancers', 'Disease', (164, 171))	('cancers', 'Disease', 'MESH:D009369', (164, 171))	('higher', 'PosReg', (70, 76))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
226646	30723574	demonstrated increased numbers of antigen-presenting dendritic cells in HPV+ HNSCC and Mansuet-Lupo et al.	('HPV+', 'Var', (72, 76))	('HPV', 'Species', '10566', (72, 75))	('HNSCC', 'Phenotype', 'HP:0012288', (77, 82))	('increased', 'PosReg', (13, 22))
226647	30723574	found tumor-infiltrating dendritic cells irrespective of the number of mutations in lung adenocarcinoma.	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (84, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('tumor', 'Disease', 'MESH:D009369', (6, 11))	('lung adenocarcinoma', 'Disease', (84, 103))	('mutations', 'Var', (71, 80))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (84, 103))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('tumor', 'Disease', (6, 11))
226664	30723574	demonstrated in a murine SCC model that B cells contribute to carcinogenesis by antibodies that form circulating immune complexes and deposits in premalignant lesions, thereby fostering development into malignancy.	('murine', 'Species', '10090', (18, 24))	('malignancy', 'Disease', 'MESH:D009369', (203, 213))	('malignancy', 'Disease', (203, 213))	('fostering', 'PosReg', (176, 185))	('carcinogenesis', 'Disease', 'MESH:D063646', (62, 76))	('circulating immune complexes', 'Phenotype', 'HP:0012224', (101, 129))	('carcinogenesis', 'Disease', (62, 76))	('antibodies', 'Var', (80, 90))
226691	30723574	In short, purified, HEK293T-expressed recombinant human proteins with C-terminal myc-DDK tag or E. coli-overexpressed and purified human protein with N-terminal His tag (E. coli-overexpressed: MAGEC2, NXF2, OIP5) were coupled to Luminex beads.	('OIP5', 'Gene', (207, 211))	('His', 'Chemical', 'MESH:D006639', (161, 164))	('E. coli', 'Species', '562', (170, 177))	('OIP5', 'Gene', '11339', (207, 211))	('human', 'Species', '9606', (131, 136))	('NXF2', 'Gene', '56001', (201, 205))	('HEK293T', 'CellLine', 'CVCL:0063', (20, 27))	('NXF2', 'Gene', (201, 205))	('human', 'Species', '9606', (50, 55))	('E. coli', 'Species', '562', (96, 103))	('HEK293T-expressed', 'Var', (20, 37))
226697	30723574	Conception and study design: AL, HS, MBB, DB Development of methodology: AL, HS, ASV, ST Acquisition of data: AL, HS, SIR, MT, KW, RG, BG, OGS, CUH, MFM, JPK Analysis and interpretation of data: AL, HS, SIR, AQ, MBB Writing and review of the manuscript: AL, KW, MBB, DB Study supervision: MBB, DB Gene expression analysis: EC, JG, AH ANOVA = analysis of variance BAPC = antigen presenting B cell Breg = regulatory B cell CA9 = carbonic anhydrase 9 CDKN2A = cyclin dependent kinase inhibitor 2A CTA = cancer/testis antigen CTAG1A/B = cancer/testis antigen 1A/B CTLA-4 = cytotoxic T-lymphocyte-associated antigen 4 DAB = 3,3'-diaminobenzidine DNA = deoxyribonucleic acid GAGE13 = G antigen 13 GKAP1 = G kinase anchoring protein 1 HC = healthy control HLA = human leukocyte antigen HNSCC = head and neck squamous cell carcinoma HPV = human papillomavirus ICOS = inducible T cell costimulatory MAGE = melanoma antigen MFI = median fluorescence intensity MHC = major histocompatibility complex NXF2 = nuclear RNA export factor 2 NY-ESO-1 = New York Esophageal Squamous Cell Carcinoma 1 OIP5 = opa interacting protein 5 PBMC = peripheral blood mononuclear cells PD-1 = programmed cell death 1 PD-L1 = programmed cell death 1 ligand 1 PRAME = preferentially expressed antigen in melanoma, RNA = ribonucleic acid SSX = synovial sarcoma X breakpoint TAA = tumor associated antigen, TCGA = The Cancer Genome Atlas Tfh = T follicular helper cell TLS = tertiary lymphoid structure TME = tumor microenvironment UICC = Union for International Cancer Control XAGE2 = X antigen family member 2	('melanoma', 'Phenotype', 'HP:0002861', (1272, 1280))	('synovial sarcoma', 'Disease', (1311, 1327))	('Esophageal Squamous Cell Carcinoma', 'Disease', 'MESH:D000077277', (1044, 1078))	('CA9', 'Gene', (421, 424))	('synovial sarcoma', 'Disease', 'MESH:D013584', (1311, 1327))	('cancer', 'Disease', (533, 539))	('GAGE13', 'Gene', (669, 675))	('programmed cell death 1 ligand 1', 'Gene', (1195, 1227))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (1055, 1078))	('Cancer', 'Disease', (1384, 1390))	('HNSCC', 'Phenotype', 'HP:0012288', (779, 784))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (787, 824))	('carcinoma', 'Phenotype', 'HP:0030731', (815, 824))	('programmed cell death 1 ligand 1', 'Gene', '574058', (1195, 1227))	('OIP5', 'Gene', (1081, 1085))	('CTAG1A/B', 'Gene', (522, 530))	('NY-ESO-1', 'Gene', '246100', (1024, 1032))	('Cancer', 'Disease', 'MESH:D009369', (1384, 1390))	('human', 'Species', '9606', (831, 836))	('cancer', 'Disease', 'MESH:D009369', (500, 506))	('tumor', 'Disease', (1475, 1480))	('CTA', 'Chemical', '-', (494, 497))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (796, 824))	('tumor', 'Disease', 'MESH:D009369', (1475, 1480))	('PRAME', 'Gene', '23532', (1228, 1233))	('Cancer', 'Phenotype', 'HP:0002664', (1384, 1390))	('PRAME', 'Gene', (1228, 1233))	('melanoma', 'Phenotype', 'HP:0002861', (897, 905))	('OIP5', 'Gene', '11339', (1081, 1085))	('CTA', 'Chemical', '-', (522, 525))	('NXF2', 'Gene', (989, 993))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (801, 824))	('AH', 'Disease', 'MESH:D007039', (331, 333))	('cancer', 'Phenotype', 'HP:0002664', (533, 539))	('CA9', 'Gene', '768', (421, 424))	('NXF2', 'Gene', '56001', (989, 993))	('GKAP1', 'Gene', '80318', (691, 696))	('melanoma', 'Disease', (1272, 1280))	("3,3'-diaminobenzidine", 'Chemical', 'MESH:D015100', (619, 640))	('GKAP1', 'Gene', (691, 696))	('1A/B', 'Var', (555, 559))	('1A/B', 'SUBSTITUTION', 'None', (555, 559))	('ICOS', 'Gene', '29851', (852, 856))	('tumor', 'Phenotype', 'HP:0002664', (1347, 1352))	('human', 'Species', '9606', (755, 760))	('cancer', 'Disease', (500, 506))	('Esophageal Squamous Cell Carcinoma', 'Disease', (1044, 1078))	('DAB', 'Chemical', 'MESH:C000469', (613, 616))	('BAPC', 'Chemical', '-', (363, 367))	('cancer', 'Disease', 'MESH:D009369', (533, 539))	('XAGE2', 'Gene', (1544, 1549))	('AL', 'Chemical', 'MESH:D000535', (195, 197))	('HPV', 'Species', '10566', (825, 828))	('GAGE13', 'Gene', '645051', (669, 675))	('neck squamous cell carcinoma', 'Disease', (796, 824))	('CDKN2A', 'Gene', (448, 454))	('CTAG1A/B', 'Gene', '246100', (522, 530))	('human papillomavirus', 'Species', '10566', (831, 851))	('Tfh', 'Chemical', '-', (1404, 1407))	('Cancer', 'Disease', (1529, 1535))	('Carcinoma', 'Phenotype', 'HP:0030731', (1069, 1078))	('XAGE2', 'Gene', '9502', (1544, 1549))	('melanoma', 'Disease', (897, 905))	('CDKN2A', 'Gene', '1029', (448, 454))	('ICOS', 'Gene', (852, 856))	('NY-ESO-1', 'Gene', (1024, 1032))	('tumor', 'Phenotype', 'HP:0002664', (1475, 1480))	('Cancer', 'Disease', 'MESH:D009369', (1529, 1535))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (1311, 1327))	('cancer', 'Phenotype', 'HP:0002664', (500, 506))	('AL', 'Chemical', 'MESH:D000535', (73, 75))	('melanoma', 'Disease', 'MESH:D008545', (1272, 1280))	('AL', 'Chemical', 'MESH:D000535', (254, 256))	('melanoma', 'Disease', 'MESH:D008545', (897, 905))	('AL', 'Chemical', 'MESH:D000535', (29, 31))	('AL', 'Chemical', 'MESH:D000535', (110, 112))	('1A/B', 'Var', (526, 530))	('1A/B', 'SUBSTITUTION', 'None', (526, 530))	('tumor', 'Disease', (1347, 1352))	('SSX', 'Chemical', '-', (1305, 1308))	('Cancer', 'Phenotype', 'HP:0002664', (1529, 1535))	('sarcoma', 'Phenotype', 'HP:0100242', (1320, 1327))	('tumor', 'Disease', 'MESH:D009369', (1347, 1352))
226698	27081041	DeltaNp63alpha induces the expression of FAT2 and Slug to promote tumor invasion Tumor invasion can be induced by changes in gene expression that alter cell phenotype.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Disease', (66, 71))	('promote', 'PosReg', (58, 65))	('FAT2', 'Gene', '2196', (41, 45))	('FAT2', 'Gene', (41, 45))	('DeltaNp63alpha', 'Chemical', '-', (0, 14))	('DeltaNp63alpha', 'Var', (0, 14))	('Slug', 'Gene', '6591', (50, 54))	('Slug', 'Gene', (50, 54))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('Tumor', 'Phenotype', 'HP:0002664', (81, 86))
226702	27081041	Notably, lung squamous cell carcinoma migration also required DeltaNp63alpha dependent FAT2 and Slug expression, demonstrating that DeltaNp63alpha promotes migration in multiple tumor types by inducing mesenchymal and non-mesenchymal genes.	('inducing', 'PosReg', (193, 201))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (9, 37))	('DeltaNp63alpha', 'Chemical', '-', (62, 76))	('lung squamous cell carcinoma migration', 'Disease', 'MESH:D002294', (9, 47))	('tumor', 'Disease', (178, 183))	('Slug', 'Gene', '6591', (96, 100))	('promotes', 'PosReg', (147, 155))	('migration', 'CPA', (156, 165))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('DeltaNp63alpha', 'Chemical', '-', (132, 146))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (14, 37))	('DeltaNp63alpha', 'Var', (132, 146))	('lung squamous cell carcinoma migration', 'Disease', (9, 47))	('FAT2', 'Gene', '2196', (87, 91))	('mesenchymal', 'CPA', (202, 213))	('carcinoma', 'Phenotype', 'HP:0030731', (28, 37))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('Slug', 'Gene', (96, 100))	('FAT2', 'Gene', (87, 91))
226704	27081041	Moreover, live-imaging of spheroids in organotypic culture demonstrated that DeltaNp63alpha, FAT2 and Slug were essential for the extension of cellular protrusions that initiate collective invasion.	('Slug', 'Gene', '6591', (102, 106))	('Slug', 'Gene', (102, 106))	('DeltaNp63alpha', 'Chemical', '-', (77, 91))	('DeltaNp63alpha', 'Var', (77, 91))	('FAT2', 'Gene', '2196', (93, 97))	('FAT2', 'Gene', (93, 97))	('collective invasion', 'CPA', (178, 197))
226705	27081041	Importantly, DeltaNp63alpha is co-expressed with FAT2 and Slug in patient tumors and the elevated expression of DeltaNp63alpha, FAT2 and Slug correlated with poor patient outcome.	('Slug', 'Gene', '6591', (137, 141))	('tumors', 'Disease', 'MESH:D009369', (74, 80))	('Slug', 'Gene', '6591', (58, 62))	('tumors', 'Disease', (74, 80))	('FAT2', 'Gene', '2196', (49, 53))	('correlated with', 'Reg', (142, 157))	('FAT2', 'Gene', '2196', (128, 132))	('DeltaNp63alpha', 'Chemical', '-', (13, 27))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('FAT2', 'Gene', (49, 53))	('elevated', 'PosReg', (89, 97))	('FAT2', 'Gene', (128, 132))	('patient', 'Species', '9606', (163, 170))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('DeltaNp63alpha', 'Chemical', '-', (112, 126))	('Slug', 'Gene', (137, 141))	('DeltaNp63alpha', 'Var', (112, 126))	('patient', 'Species', '9606', (66, 73))	('Slug', 'Gene', (58, 62))	('expression', 'MPA', (98, 108))
226706	27081041	Together, these results reveal how DeltaNp63alpha promotes cell migration by directly inducing the expression of a cohort of genes with distinct cellular functions and suggest that FAT2 is a new regulator of collective invasion that may influence patient outcome.	('expression', 'MPA', (99, 109))	('FAT2', 'Gene', '2196', (181, 185))	('patient', 'Species', '9606', (247, 254))	('FAT2', 'Gene', (181, 185))	('cell migration', 'CPA', (59, 73))	('inducing', 'Reg', (86, 94))	('influence', 'Reg', (237, 246))	('DeltaNp63alpha', 'Chemical', '-', (35, 49))	('promotes', 'PosReg', (50, 58))	('DeltaNp63alpha', 'Var', (35, 49))
226707	27081041	During tumor development, the aberrant activation of transcriptional regulatory networks can promote changes in cell state that induce epithelial derived neoplastic cells to invade into the stroma.	('transcriptional regulatory networks', 'Pathway', (53, 88))	('activation', 'PosReg', (39, 49))	('tumor', 'Disease', (7, 12))	('epithelial derived neoplastic cells', 'CPA', (135, 170))	('aberrant', 'Var', (30, 38))	('invade into the stroma', 'CPA', (174, 196))	('cell state', 'CPA', (112, 122))	('tumor', 'Disease', 'MESH:D009369', (7, 12))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
226710	27081041	We focused on defining how the transcription factor DeltaNp63alpha induces neoplastic cell motility.	('neoplastic cell motility', 'Disease', (75, 99))	('neoplastic cell motility', 'Disease', 'MESH:D015835', (75, 99))	('induces', 'Reg', (67, 74))	('DeltaNp63alpha', 'Var', (52, 66))	('DeltaNp63alpha', 'Chemical', '-', (52, 66))
226713	27081041	In human cancer, amplification of the TP63 gene and DeltaNp63alpha expression are defining features of squamous tumors.	('cancer', 'Disease', (9, 15))	('DeltaNp63alpha', 'Gene', (52, 66))	('amplification', 'Var', (17, 30))	('human', 'Species', '9606', (3, 8))	('squamous tumors', 'Disease', (103, 118))	('squamous tumors', 'Disease', 'MESH:D002294', (103, 118))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('TP63', 'Gene', (38, 42))	('expression', 'MPA', (67, 77))	('TP63', 'Gene', '8626', (38, 42))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('DeltaNp63alpha', 'Chemical', '-', (52, 66))
226714	27081041	DeltaNp63alpha is also expressed in invasive bladder cancer and basal-like breast cancer (BLBC) patients with poor outcome.	('invasive bladder cancer', 'Disease', (36, 59))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('breast cancer', 'Disease', (75, 88))	('invasive bladder cancer', 'Disease', 'MESH:D001749', (36, 59))	('breast cancer', 'Phenotype', 'HP:0003002', (75, 88))	('bladder cancer', 'Phenotype', 'HP:0009725', (45, 59))	('DeltaNp63alpha', 'Chemical', '-', (0, 14))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('DeltaNp63alpha', 'Var', (0, 14))	('patients', 'Species', '9606', (96, 104))	('invasive bladder', 'Phenotype', 'HP:0100645', (36, 52))	('breast cancer', 'Disease', 'MESH:D001943', (75, 88))
226718	27081041	DeltaNp63alpha induced invasion is dependent on extrinsic factors.	('DeltaNp63alpha', 'Chemical', '-', (0, 14))	('invasion', 'CPA', (23, 31))	('DeltaNp63alpha', 'Var', (0, 14))
226719	27081041	For example, BLBC cells that express DeltaNp63alpha are reliant upon mammary fibroblasts to initiate ECM reorganization that permits collective invasion.	('DeltaNp63alpha', 'Var', (37, 51))	('collective invasion', 'CPA', (133, 152))	('DeltaNp63alpha', 'Chemical', '-', (37, 51))
226720	27081041	Similarly, Luminal B type breast cancer cells expressing DeltaNp63alpha are limited to invading into regions enriched in collagen I.	('breast cancer', 'Disease', (26, 39))	('breast cancer', 'Phenotype', 'HP:0003002', (26, 39))	('DeltaNp63alpha', 'Chemical', '-', (57, 71))	('DeltaNp63alpha', 'Var', (57, 71))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('breast cancer', 'Disease', 'MESH:D001943', (26, 39))
226721	27081041	Thus, the invasive state induced by DeltaNp63alpha is distinct from other types of invasive states, such as the mesenchymal-like trailblazer state that promotes invasion into a wide range of microenvironments, including those not permissive to DeltaNp63alpha expressing tumor cell invasion.	('DeltaNp63alpha', 'Chemical', '-', (36, 50))	('DeltaNp63alpha', 'Var', (36, 50))	('invasion', 'CPA', (161, 169))	('tumor', 'Disease', 'MESH:D009369', (270, 275))	('tumor', 'Phenotype', 'HP:0002664', (270, 275))	('promotes', 'PosReg', (152, 160))	('DeltaNp63alpha', 'Chemical', '-', (244, 258))	('tumor', 'Disease', (270, 275))
226722	27081041	Together, these results indicate that the DeltaNp63alpha can promote a unique conversion in cell state that confers migratory ability.	('migratory ability', 'CPA', (116, 133))	('promote', 'PosReg', (61, 68))	('DeltaNp63alpha', 'Chemical', '-', (42, 56))	('DeltaNp63alpha', 'Var', (42, 56))	('conversion in cell state', 'MPA', (78, 102))
226723	27081041	DeltaNp63alpha induces migration, in part, by promoting the expression of the transcription factor Slug and the tyrosine kinase Axl in BLBC cells.	('Slug', 'Gene', '6591', (99, 103))	('expression', 'MPA', (60, 70))	('Slug', 'Gene', (99, 103))	('Axl', 'Gene', '558', (128, 131))	('promoting', 'PosReg', (46, 55))	('DeltaNp63alpha', 'Chemical', '-', (0, 14))	('DeltaNp63alpha', 'Var', (0, 14))	('migration', 'CPA', (23, 32))	('induces', 'PosReg', (15, 22))	('Axl', 'Gene', (128, 131))
226725	27081041	During tumor development, the aberrant activation of EMT programs can lead to invasion and metastasis.	('aberrant', 'Var', (30, 38))	('activation', 'PosReg', (39, 49))	('tumor', 'Disease', (7, 12))	('EMT programs', 'CPA', (53, 65))	('lead to', 'Reg', (70, 77))	('tumor', 'Disease', 'MESH:D009369', (7, 12))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
226727	27081041	This retention of epithelial character is potentially due to DeltaNp63alpha simultaneously inducing the expression of miR205, which can silence the E-cadherin suppressors ZEB1/2.	('E-cadherin', 'Gene', (148, 158))	('miR205', 'Gene', (118, 124))	('E-cadherin', 'Gene', '999', (148, 158))	('DeltaNp63alpha', 'Chemical', '-', (61, 75))	('DeltaNp63alpha', 'Var', (61, 75))	('inducing', 'PosReg', (91, 99))	('ZEB1/2', 'Gene', (171, 177))	('expression', 'MPA', (104, 114))	('silence', 'NegReg', (136, 143))	('miR205', 'Gene', '406988', (118, 124))	('ZEB1/2', 'Gene', '6935;9839', (171, 177))
226728	27081041	Thus, DeltaNp63alpha promotes invasion, in part, by inducing a hybrid epithelial/mesenchymal state.	('hybrid epithelial/mesenchymal state', 'CPA', (63, 98))	('promotes', 'PosReg', (21, 29))	('inducing', 'Reg', (52, 60))	('invasion', 'CPA', (30, 38))	('DeltaNp63alpha', 'Chemical', '-', (6, 20))	('DeltaNp63alpha', 'Var', (6, 20))
226729	27081041	While the DeltaNp63alpha dependent induction of Slug and Axl is critical for BLBC motility, exogenous Slug and Axl expression is not sufficient to promote the migration of DeltaNp63alpha depleted BLBC cells.	('Axl', 'Gene', (111, 114))	('Slug', 'Gene', '6591', (102, 106))	('Axl', 'Gene', '558', (57, 60))	('Slug', 'Gene', (102, 106))	('promote', 'PosReg', (147, 154))	('Slug', 'Gene', '6591', (48, 52))	('migration', 'CPA', (159, 168))	('Axl', 'Gene', (57, 60))	('Axl', 'Gene', '558', (111, 114))	('Slug', 'Gene', (48, 52))	('DeltaNp63alpha', 'Chemical', '-', (172, 186))	('DeltaNp63alpha', 'Var', (172, 186))	('DeltaNp63alpha', 'Chemical', '-', (10, 24))
226732	27081041	Further investigation of Slug and the atypical cadherin FAT2 as representative mesenchymal and non-mesenchymal genes revealed that they are co-expressed with DeltaNp63alpha in patient tumors and required for DeltaNp63alpha migration in multiple genetic contexts.	('DeltaNp63alpha', 'Chemical', '-', (208, 222))	('Slug', 'Gene', '6591', (25, 29))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('Slug', 'Gene', (25, 29))	('tumors', 'Disease', 'MESH:D009369', (184, 190))	('tumors', 'Disease', (184, 190))	('DeltaNp63alpha', 'Chemical', '-', (158, 172))	('DeltaNp63alpha', 'Var', (158, 172))	('FAT2', 'Gene', '2196', (56, 60))	('tumors', 'Phenotype', 'HP:0002664', (184, 190))	('FAT2', 'Gene', (56, 60))	('patient', 'Species', '9606', (176, 183))
226733	27081041	Notably, mechanistic analysis determined that DeltaNp63alpha and FAT2, influenced the establishment of cell-cell adhesions and were specifically required for the formation of cellular protrusions that precede collective invasion.	('establishment of cell-cell adhesions', 'CPA', (86, 122))	('DeltaNp63alpha', 'Chemical', '-', (46, 60))	('DeltaNp63alpha', 'Var', (46, 60))	('influenced', 'Reg', (71, 81))	('FAT2', 'Gene', '2196', (65, 69))	('FAT2', 'Gene', (65, 69))
226735	27081041	Together, these results reveal how DeltaNp63alpha promotes cell migration by inducing the expression of a cohort of mesenchymal and non-mesenchymal genes.	('cell migration', 'CPA', (59, 73))	('DeltaNp63alpha', 'Chemical', '-', (35, 49))	('expression', 'MPA', (90, 100))	('inducing', 'PosReg', (77, 85))	('promotes', 'PosReg', (50, 58))	('DeltaNp63alpha', 'Var', (35, 49))
226737	27081041	We previously found that DeltaNp63alpha promotes BLBC migration through the induction of a hybrid epithelial/mesenchymal state.	('DeltaNp63alpha', 'Chemical', '-', (25, 39))	('BLBC migration', 'CPA', (49, 63))	('DeltaNp63alpha', 'Var', (25, 39))	('promotes', 'PosReg', (40, 48))
226739	27081041	To better understand how DeltaNp63alpha promotes migration, we began by analyzing the mRNA content of MCFDCIS and HCC1806 cells depleted of DeltaNp63alpha by siRNAs (Figure 1A and 1B), as we had done previously to identify DeltaNp63alpha-regulated genes.	('DeltaNp63alpha', 'Chemical', '-', (25, 39))	('MCFDCIS', 'CellLine', 'None', (102, 109))	('depleted', 'NegReg', (128, 136))	('DeltaNp63alpha', 'Chemical', '-', (140, 154))	('HCC1806', 'CellLine', 'CVCL:1258', (114, 121))	('DeltaNp63alpha', 'Chemical', '-', (223, 237))	('DeltaNp63alpha', 'Var', (25, 39))	('DeltaNp63alpha', 'Gene', (140, 154))
226740	27081041	We found that DeltaNp63alpha depletion caused a 2-fold decrease (p < 0.05) in the expression of 124 genes in both the MCFDCIS and HCC1806 cells (Figure 1C and Supplementary Table S1).	('HCC1806', 'CellLine', 'CVCL:1258', (130, 137))	('expression of', 'MPA', (82, 95))	('DeltaNp63alpha depletion', 'Var', (14, 38))	('decrease', 'NegReg', (55, 63))	('MCFDCIS', 'CellLine', 'None', (118, 125))	('DeltaNp63alpha', 'Chemical', '-', (14, 28))
226742	27081041	DeltaNp63alpha can also suppress gene expression, as indicated by the elevated expression of 128 genes in response to DeltaNp63alpha depletion (Supplementary Table S2).	('elevated', 'PosReg', (70, 78))	('DeltaNp63alpha', 'Var', (118, 132))	('gene expression', 'MPA', (33, 48))	('expression', 'MPA', (79, 89))	('DeltaNp63alpha', 'Chemical', '-', (118, 132))	('DeltaNp63alpha', 'Chemical', '-', (0, 14))	('DeltaNp63alpha', 'Var', (0, 14))	('suppress', 'NegReg', (24, 32))
226743	27081041	However, we focused on determining how genes reliant on DeltaNp63alpha for expression confer a motile phenotype based on our prior results showing that DeltaNp63alpha promotes migration through the positive regulation of gene expression.	('DeltaNp63alpha', 'Chemical', '-', (152, 166))	('DeltaNp63alpha', 'Var', (152, 166))	('migration', 'CPA', (176, 185))	('promotes', 'PosReg', (167, 175))	('gene', 'Protein', (221, 225))	('positive regulation', 'PosReg', (198, 217))	('DeltaNp63alpha', 'Chemical', '-', (56, 70))
226747	27081041	The DeltaNp63alpha ChIP-seq signal was also enriched in putative enhancer regions (Supplementary Figure S1A).	('DeltaNp63alpha', 'Chemical', '-', (4, 18))	('enhancer', 'PosReg', (65, 73))	('DeltaNp63alpha', 'Var', (4, 18))
226752	27081041	This was consistent with our previous finding that DeltaNp63alpha induced Slug and Axl expression to promote MCFDCIS and HCC1806 migration.	('promote', 'PosReg', (101, 108))	('Slug', 'Gene', (74, 78))	('MCFDCIS', 'CellLine', 'None', (109, 116))	('Axl', 'Gene', '558', (83, 86))	('Slug', 'Gene', '6591', (74, 78))	('induced', 'Reg', (66, 73))	('Axl', 'Gene', (83, 86))	('DeltaNp63alpha', 'Chemical', '-', (51, 65))	('HCC1806', 'CellLine', 'CVCL:1258', (121, 128))	('DeltaNp63alpha', 'Var', (51, 65))
226753	27081041	In addition, the DeltaNp63alpha peak associated with Axl (Figure 1H) was within the same region of the Axl promoter that we had defined as a DeltaNp63alpha binding site using ChIP-qPCR.	('Axl', 'Gene', '558', (53, 56))	('Axl', 'Gene', (53, 56))	('Axl', 'Gene', '558', (103, 106))	('DeltaNp63alpha', 'Var', (17, 31))	('DeltaNp63alpha', 'Chemical', '-', (17, 31))	('Axl', 'Gene', (103, 106))	('DeltaNp63alpha', 'Chemical', '-', (141, 155))
226755	27081041	Notably, this DeltaNp63alpha binding site was located in the putative promoter region within 1 kb of the TSS, indicating that DeltaNp63alpha may directly regulate Slug expression.	('expression', 'MPA', (168, 178))	('regulate', 'Reg', (154, 162))	('DeltaNp63alpha', 'Chemical', '-', (126, 140))	('DeltaNp63alpha', 'Var', (126, 140))	('Slug', 'Gene', '6591', (163, 167))	('Slug', 'Gene', (163, 167))	('DeltaNp63alpha', 'Chemical', '-', (14, 28))
226756	27081041	Conversely, we did not detect DeltaNp63alpha binding proximal to the EMT inducing transcription factors Snail or Twist (Figure 1I), consistent with our previous findings that DeltaNp63alpha selectively regulates Axl and Slug expression to promote a hybrid state.	('Slug', 'Gene', '6591', (220, 224))	('promote', 'PosReg', (239, 246))	('Twist', 'Gene', (113, 118))	('Axl', 'Gene', '558', (212, 215))	('DeltaNp63alpha', 'Chemical', '-', (30, 44))	('Slug', 'Gene', (220, 224))	('regulates', 'Reg', (202, 211))	('DeltaNp63alpha', 'Chemical', '-', (175, 189))	('DeltaNp63alpha', 'Var', (175, 189))	('Snail', 'Gene', (104, 109))	('Axl', 'Gene', (212, 215))	('Snail', 'Gene', '6615', (104, 109))	('expression', 'MPA', (225, 235))	('Twist', 'Gene', '7291', (113, 118))
226759	27081041	We next determined how genes that were potentially regulated by DeltaNp63alpha binding influenced cell motility.	('cell motility', 'CPA', (98, 111))	('DeltaNp63alpha', 'Chemical', '-', (64, 78))	('DeltaNp63alpha', 'Var', (64, 78))	('influenced', 'Reg', (87, 97))
226760	27081041	To do this, we first identified siRNAs that targeted 37 of the 41 genes activated by DeltaNp63alpha in MCFDCIS (Figure 2A) and HCC1806 cells (Supplementary Figure S2) and had associated DeltaNp63alpha binding (Supplementary Table S4).	('DeltaNp63alpha', 'Chemical', '-', (186, 200))	('DeltaNp63alpha', 'MPA', (186, 200))	('HCC1806', 'CellLine', 'CVCL:1258', (127, 134))	('DeltaNp63alpha', 'Chemical', '-', (85, 99))	('DeltaNp63alpha', 'Var', (85, 99))	('binding', 'Interaction', (201, 208))	('activated', 'PosReg', (72, 81))	('MCFDCIS', 'CellLine', 'None', (103, 110))
226769	27081041	Analysis of a published dataset revealed that DeltaNp63alpha binding was detected in similar genomic locations relative to these genes in squamous carcinoma cells (Supplementary Figure S4B), indicating that DeltaNp63alpha had the potential to regulate these pro-migratory genes in multiple genetic contexts.	('regulate', 'Reg', (243, 251))	('DeltaNp63alpha', 'Chemical', '-', (207, 221))	('DeltaNp63alpha', 'Chemical', '-', (46, 60))	('DeltaNp63alpha', 'Var', (207, 221))	('squamous carcinoma', 'Disease', 'MESH:D002294', (138, 156))	('squamous carcinoma', 'Disease', (138, 156))	('carcinoma', 'Phenotype', 'HP:0030731', (147, 156))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (138, 156))
226770	27081041	DeltaNp63alpha binding associated with FAT2 and CPNE8 was additionally confirmed by ChIP-qPCR (Supplementary Figure S4C).	('FAT2', 'Gene', (39, 43))	('CPNE8', 'Gene', (48, 53))	('DeltaNp63alpha', 'Chemical', '-', (0, 14))	('DeltaNp63alpha', 'Var', (0, 14))	('associated', 'Reg', (23, 33))	('binding', 'Interaction', (15, 22))	('CPNE8', 'Gene', '144402', (48, 53))	('FAT2', 'Gene', '2196', (39, 43))
226774	27081041	Moreover, these results indicate that DeltaNp63alpha can promote migration by increasing the expression of genes that function within distinct mesenchymal and non-mesenchymal signaling pathways with unique known functions (Figure 2H).	('migration', 'CPA', (65, 74))	('promote', 'PosReg', (57, 64))	('increasing', 'PosReg', (78, 88))	('expression of genes', 'MPA', (93, 112))	('DeltaNp63alpha', 'Chemical', '-', (38, 52))	('DeltaNp63alpha', 'Var', (38, 52))
226777	27081041	Indeed, there was a strong correlation between DeltaNp63alpha and FAT2 expression across the different tumor types (Figure 3B).	('expression', 'MPA', (71, 81))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor', 'Disease', (103, 108))	('DeltaNp63alpha', 'Chemical', '-', (47, 61))	('DeltaNp63alpha', 'Var', (47, 61))	('FAT2', 'Gene', '2196', (66, 70))	('FAT2', 'Gene', (66, 70))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
226779	27081041	Consistent with our previous finding that DeltaNp63alpha and Slug levels correlated in breast tumors using microarray expression data, a correlation between DeltaNp63alpha and Slug expression was detected in breast tumors using RNA-seq data (Figure 3C).	('breast tumors', 'Phenotype', 'HP:0100013', (208, 221))	('breast tumors', 'Disease', (87, 100))	('breast tumors', 'Disease', 'MESH:D001943', (208, 221))	('Slug', 'Gene', (61, 65))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('breast tumors', 'Disease', (208, 221))	('Slug', 'Gene', '6591', (61, 65))	('Slug', 'Gene', '6591', (176, 180))	('DeltaNp63alpha', 'Chemical', '-', (42, 56))	('breast tumors', 'Phenotype', 'HP:0100013', (87, 100))	('DeltaNp63alpha', 'Chemical', '-', (157, 171))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('DeltaNp63alpha', 'Var', (157, 171))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('tumors', 'Phenotype', 'HP:0002664', (215, 221))	('Slug', 'Gene', (176, 180))	('breast tumors', 'Disease', 'MESH:D001943', (87, 100))	('DeltaNp63alpha', 'MPA', (42, 56))
226782	27081041	To determine if the DeltaNp63alpha dependent induction of FAT2 and Slug was a indeed a mechanism for the control of migration that extended beyond BLBC, we defined the requirement of DeltaNp63alpha, FAT2 and Slug for migration in lung SCC cells.	('Slug', 'Gene', (67, 71))	('DeltaNp63alpha', 'Chemical', '-', (183, 197))	('SCC', 'Gene', '6317', (235, 238))	('DeltaNp63alpha', 'Var', (183, 197))	('FAT2', 'Gene', '2196', (199, 203))	('FAT2', 'Gene', '2196', (58, 62))	('FAT2', 'Gene', (199, 203))	('Slug', 'Gene', '6591', (208, 212))	('FAT2', 'Gene', (58, 62))	('DeltaNp63alpha', 'Chemical', '-', (20, 34))	('SCC', 'Gene', (235, 238))	('Slug', 'Gene', '6591', (67, 71))	('Slug', 'Gene', (208, 212))
226783	27081041	We chose lung SCC because DeltaNp63alpha expression is a defining trait of lung SCC cells and our results indicated that DeltaNp63alpha was co-expressed with FAT2 and Slug in patient lung SCC.	('SCC', 'Gene', '6317', (80, 83))	('SCC', 'Gene', '6317', (188, 191))	('Slug', 'Gene', (167, 171))	('patient', 'Species', '9606', (175, 182))	('FAT2', 'Gene', '2196', (158, 162))	('SCC', 'Gene', (14, 17))	('FAT2', 'Gene', (158, 162))	('DeltaNp63alpha', 'Chemical', '-', (26, 40))	('SCC', 'Gene', '6317', (14, 17))	('SCC', 'Gene', (80, 83))	('SCC', 'Gene', (188, 191))	('DeltaNp63alpha', 'Chemical', '-', (121, 135))	('Slug', 'Gene', '6591', (167, 171))	('DeltaNp63alpha', 'Var', (121, 135))
226785	27081041	Similar to our findings in BLBC cells, DeltaNp63alpha depletion reduced the rate of HCC1313 lung SCC wound closure (Figure 4A), indicating that DeltaNp63alpha can promote lung SCC migration.	('DeltaNp63alpha', 'Chemical', '-', (39, 53))	('DeltaNp63alpha', 'Var', (39, 53))	('SCC', 'Gene', (97, 100))	('HCC1313', 'CellLine', 'CVCL:L087', (84, 91))	('SCC', 'Gene', (176, 179))	('DeltaNp63alpha', 'Var', (144, 158))	('DeltaNp63alpha', 'Chemical', '-', (144, 158))	('SCC', 'Gene', '6317', (176, 179))	('reduced', 'NegReg', (64, 71))	('SCC', 'Gene', '6317', (97, 100))	('promote', 'PosReg', (163, 170))
226787	27081041	Moreover, consistent with the strong correlation in expression detected in patient tumors, DeltaNp63alpha was necessary for FAT2 and Slug expression in lung SCC cells (Figure 4C and 4D).	('SCC', 'Gene', (157, 160))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('Slug', 'Gene', (133, 137))	('DeltaNp63alpha', 'Chemical', '-', (91, 105))	('SCC', 'Gene', '6317', (157, 160))	('DeltaNp63alpha', 'Var', (91, 105))	('tumors', 'Disease', (83, 89))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('FAT2', 'Gene', '2196', (124, 128))	('FAT2', 'Gene', (124, 128))	('tumors', 'Disease', 'MESH:D009369', (83, 89))	('Slug', 'Gene', '6591', (133, 137))	('patient', 'Species', '9606', (75, 82))
226789	27081041	To better understand how DeltaNp63alpha promotes motility, we further investigated how FAT2 and Slug influenced the migratory traits of MCFDCIS cells.	('Slug', 'Gene', '6591', (96, 100))	('MCFDCIS', 'CellLine', 'None', (136, 143))	('FAT2', 'Gene', '2196', (87, 91))	('Slug', 'Gene', (96, 100))	('FAT2', 'Gene', (87, 91))	('DeltaNp63alpha', 'Chemical', '-', (25, 39))	('DeltaNp63alpha', 'Var', (25, 39))
226792	27081041	Indeed, FAT2 depletion reduced MCFDCIS cell displacement and speed (Figure 5A), similar to our prior analysis of DeltaNp63alpha and Slug depleted cells.	('FAT2', 'Gene', (8, 12))	('Slug', 'Gene', '6591', (132, 136))	('depletion', 'Var', (13, 22))	('DeltaNp63alpha', 'Chemical', '-', (113, 127))	('speed', 'CPA', (61, 66))	('MCFDCIS', 'CellLine', 'None', (31, 38))	('Slug', 'Gene', (132, 136))	('FAT2', 'Gene', '2196', (8, 12))	('reduced', 'NegReg', (23, 30))	('MCFDCIS cell displacement', 'CPA', (31, 56))
226793	27081041	The formation of stable cell-cell adhesions can restrict the spontaneous movement of sub-confluent cells, so we next determined how DeltaNp63alpha, FAT2 and Slug influenced the formation of E-cadherin dependent intercellular adhesions.	('spontaneous movement of sub-confluent cells', 'CPA', (61, 104))	('DeltaNp63alpha', 'Chemical', '-', (132, 146))	('restrict the spontaneous movement', 'Phenotype', 'HP:0002375', (48, 81))	('DeltaNp63alpha', 'Var', (132, 146))	('E-cadherin', 'Gene', (190, 200))	('E-cadherin', 'Gene', '999', (190, 200))	('restrict', 'NegReg', (48, 56))	('Slug', 'Gene', (157, 161))	('FAT2', 'Gene', '2196', (148, 152))	('FAT2', 'Gene', (148, 152))	('influenced', 'Reg', (162, 172))	('Slug', 'Gene', '6591', (157, 161))
226794	27081041	The cell-cell contacts formed by DeltaNp63alpha, FAT2 and Slug depleted cells contained greater amounts of E-cadherin compared to the control MCFDCIS cells (Figure 5B), which suggests the presence of more completely assembled adhesion junctions.	('cell-cell contacts', 'CPA', (4, 22))	('DeltaNp63alpha', 'Chemical', '-', (33, 47))	('DeltaNp63alpha', 'Var', (33, 47))	('Slug', 'Gene', '6591', (58, 62))	('FAT2', 'Gene', '2196', (49, 53))	('Slug', 'Gene', (58, 62))	('FAT2', 'Gene', (49, 53))	('E-cadherin', 'Gene', (107, 117))	('greater', 'PosReg', (88, 95))	('MCFDCIS', 'CellLine', 'None', (142, 149))	('E-cadherin', 'Gene', '999', (107, 117))
226797	27081041	Together, these results indicate that the DeltaNp63alpha dependent induction of FAT2 and Slug prevents the establishment of mature cell-cell adhesions.	('prevents', 'NegReg', (94, 102))	('Slug', 'Gene', '6591', (89, 93))	('Slug', 'Gene', (89, 93))	('establishment of mature cell-cell adhesions', 'CPA', (107, 150))	('DeltaNp63alpha', 'Chemical', '-', (42, 56))	('DeltaNp63alpha', 'Var', (42, 56))	('FAT2', 'Gene', '2196', (80, 84))	('FAT2', 'Gene', (80, 84))
226800	27081041	DeltaNp63alpha is also increased in cells that invade in explants derived from mouse polyoma virus middle T antigen (PyMT) mammary tumors.	('mouse', 'Species', '10090', (79, 84))	('polyoma virus middle T', 'Disease', (85, 107))	('polyoma virus middle T', 'Disease', 'MESH:D020244', (85, 107))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('DeltaNp63alpha', 'Chemical', '-', (0, 14))	('DeltaNp63alpha', 'Var', (0, 14))	('increased', 'PosReg', (23, 32))	('tumors', 'Disease', 'MESH:D009369', (131, 137))	('tumors', 'Disease', (131, 137))
226801	27081041	Precisely how DeltaNp63alpha promotes collective invasion is not known.	('DeltaNp63alpha', 'Var', (14, 28))	('collective invasion', 'CPA', (38, 57))	('DeltaNp63alpha', 'Chemical', '-', (14, 28))	('promotes', 'PosReg', (29, 37))
226802	27081041	The invasion of DeltaNp63alpha expressing breast cancer cells is dependent on extrinsic factors, either reorganization of the ECM by fibroblasts or an increased abundance of Collagen I.	('DeltaNp63alpha', 'Var', (16, 30))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('DeltaNp63alpha', 'Chemical', '-', (16, 30))	('breast cancer', 'Disease', 'MESH:D001943', (42, 55))	('breast cancer', 'Phenotype', 'HP:0003002', (42, 55))	('breast cancer', 'Disease', (42, 55))
226803	27081041	Therefore, we investigated how DeltaNp63alpha influenced the collective invasion of MCFDCIS cells into a Collagen I enriched ECM.	('MCFDCIS', 'CellLine', 'None', (84, 91))	('influenced', 'Reg', (46, 56))	('collective invasion', 'CPA', (61, 80))	('DeltaNp63alpha', 'Chemical', '-', (31, 45))	('DeltaNp63alpha', 'Var', (31, 45))
226806	27081041	Conversely, DeltaNp63alpha, Slug and FAT2 depletion reduced the frequency of MCFDCIS collective invasion, with most multicellular lesions forming noninvasive spheroids (Figure 6A and Supplementary Figure S5A).	('MCFDCIS collective', 'Disease', (77, 95))	('FAT2', 'Gene', '2196', (37, 41))	('FAT2', 'Gene', (37, 41))	('MCFDCIS', 'CellLine', 'None', (77, 84))	('reduced', 'NegReg', (52, 59))	('DeltaNp63alpha', 'Chemical', '-', (12, 26))	('DeltaNp63alpha', 'Var', (12, 26))	('Slug', 'Gene', '6591', (28, 32))	('Slug', 'Gene', (28, 32))
226807	27081041	This reduced invasion was further indicated by lower length/width ratio and increased circularity of DeltaNp63alpha, Slug and FAT2 depleted spheroids compared to control spheroids (Figure 6A).	('lower', 'NegReg', (47, 52))	('length/width ratio', 'CPA', (53, 71))	('FAT2', 'Gene', '2196', (126, 130))	('increased', 'PosReg', (76, 85))	('DeltaNp63alpha', 'Var', (101, 115))	('DeltaNp63alpha', 'Chemical', '-', (101, 115))	('FAT2', 'Gene', (126, 130))	('invasion', 'CPA', (13, 21))	('Slug', 'Gene', '6591', (117, 121))	('Slug', 'Gene', (117, 121))	('reduced', 'NegReg', (5, 12))	('circularity', 'MPA', (86, 97))
226811	27081041	Interestingly, we also detected intraspheroid movement in the noninvasive spheroids formed by MCFDCIS cells depleted of DeltaNp63alpha, FAT2 and Slug.	('MCFDCIS', 'CellLine', 'None', (94, 101))	('FAT2', 'Gene', '2196', (136, 140))	('FAT2', 'Gene', (136, 140))	('DeltaNp63alpha', 'Chemical', '-', (120, 134))	('DeltaNp63alpha', 'Var', (120, 134))	('Slug', 'Gene', '6591', (145, 149))	('detected', 'Reg', (23, 31))	('MCFDCIS', 'Gene', (94, 101))	('Slug', 'Gene', (145, 149))
226813	27081041	DeltaNp63alpha and Slug depletion modestly reduced the rate of intraspheroid movement (Figure 6B and Supplementary Video S1).	('depletion', 'Var', (24, 33))	('DeltaNp63alpha', 'Chemical', '-', (0, 14))	('DeltaNp63alpha', 'Var', (0, 14))	('Slug', 'Gene', '6591', (19, 23))	('reduced', 'NegReg', (43, 50))	('Slug', 'Gene', (19, 23))
226814	27081041	However, the DeltaNp63alpha and Slug depleted cells were capable of translocating to new positions in the spheroids independent of cell division (Figure 6B and Supplementary Video S1).	('Slug', 'Gene', '6591', (32, 36))	('translocating', 'MPA', (68, 81))	('DeltaNp63alpha', 'Chemical', '-', (13, 27))	('DeltaNp63alpha', 'Var', (13, 27))	('Slug', 'Gene', (32, 36))
226815	27081041	The reduction in intraspheroid motility speed in DeltaNp63alpha and Slug depleted spheroids was also not as great as the reduction in speed that was observed in MCFDCIS spheroids treated with a MEK1/2 inhibitor (Supplementary Figure S5B).	('Slug', 'Gene', (68, 72))	('S5B', 'Gene', '5711', (233, 236))	('S5B', 'Gene', (233, 236))	('MEK1/2', 'Gene', '5604;5605', (194, 200))	('MEK1/2', 'Gene', (194, 200))	('MCFDCIS', 'CellLine', 'None', (161, 168))	('reduction', 'NegReg', (4, 13))	('Slug', 'Gene', '6591', (68, 72))	('DeltaNp63alpha', 'Chemical', '-', (49, 63))	('DeltaNp63alpha', 'Var', (49, 63))
226816	27081041	There were fluctuations in LifeAct:GFP distribution around the surface of the DeltaNp63alpha, FAT2 and Slug depleted spheroids, indicating that F-actin was being formed and severed in areas of cell contact with the ECM (Figure 6B and Supplementary Video S1).	('Slug', 'Gene', '6591', (103, 107))	('DeltaNp63alpha', 'Chemical', '-', (78, 92))	('Slug', 'Gene', (103, 107))	('DeltaNp63alpha', 'Var', (78, 92))	('FAT2', 'Gene', '2196', (94, 98))	('FAT2', 'Gene', (94, 98))
226817	27081041	Moreover, small transient protrusions into the ECM were detected in DeltaNp63alpha, FAT2 and Slug depleted spheroids (Figure 6B and Supplementary Video S1).	('FAT2', 'Gene', (84, 88))	('detected', 'Reg', (56, 64))	('Slug', 'Gene', '6591', (93, 97))	('DeltaNp63alpha', 'Var', (68, 82))	('DeltaNp63alpha', 'Chemical', '-', (68, 82))	('Slug', 'Gene', (93, 97))	('FAT2', 'Gene', '2196', (84, 88))
226819	27081041	Thus, the depletion of DeltaNp63alpha, FAT2 and Slug does not completely perturb all forms of cell movement or entirely disrupt the dynamics of the cytoskeleton.	('dynamics of the cytoskeleton', 'MPA', (132, 160))	('FAT2', 'Gene', (39, 43))	('DeltaNp63alpha', 'Chemical', '-', (23, 37))	('DeltaNp63alpha', 'Var', (23, 37))	('Slug', 'Gene', '6591', (48, 52))	('depletion', 'Var', (10, 19))	('perturb', 'Reg', (73, 80))	('Slug', 'Gene', (48, 52))	('disrupt', 'Reg', (120, 127))	('FAT2', 'Gene', '2196', (39, 43))
226820	27081041	Together, our results indicate that the DeltaNp63alpha dependent induction of FAT2 and Slug is specifically required for the formation of cellular protrusions that initiate collective invasion.	('FAT2', 'Gene', (78, 82))	('collective invasion', 'CPA', (173, 192))	('Slug', 'Gene', '6591', (87, 91))	('DeltaNp63alpha', 'Chemical', '-', (40, 54))	('DeltaNp63alpha', 'Var', (40, 54))	('Slug', 'Gene', (87, 91))	('FAT2', 'Gene', '2196', (78, 82))
226822	27081041	We previously found that increased DeltaNp63alpha expression correlated with shorter overall survival time in HER2-/ER- breast cancer patients, which are frequently classified as having BLBC.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('breast cancer', 'Disease', (120, 133))	('increased', 'PosReg', (25, 34))	('overall survival', 'MPA', (85, 101))	('breast cancer', 'Disease', 'MESH:D001943', (120, 133))	('breast cancer', 'Phenotype', 'HP:0003002', (120, 133))	('ER', 'Gene', '2099', (111, 113))	('patients', 'Species', '9606', (134, 142))	('HER2', 'Gene', '2064', (110, 114))	('HER2', 'Gene', (110, 114))	('ER', 'Gene', '2099', (116, 118))	('shorter', 'NegReg', (77, 84))	('DeltaNp63alpha', 'Chemical', '-', (35, 49))	('expression', 'MPA', (50, 60))	('DeltaNp63alpha', 'Var', (35, 49))
226826	27081041	Indeed, the DeltaNp63alpha-high, FAT2-high and Slug-high NSCLC patient groups all had a shorter overall survival time (Figure 7B).	('shorter', 'NegReg', (88, 95))	('FAT2', 'Gene', (33, 37))	('Slug', 'Gene', (47, 51))	('DeltaNp63alpha', 'Chemical', '-', (12, 26))	('NSCLC', 'Phenotype', 'HP:0030358', (57, 62))	('FAT2', 'Gene', '2196', (33, 37))	('patient', 'Species', '9606', (63, 70))	('DeltaNp63alpha-high', 'Var', (12, 31))	('overall survival', 'MPA', (96, 112))	('NSCLC', 'Disease', (57, 62))	('Slug', 'Gene', '6591', (47, 51))	('NSCLC', 'Disease', 'MESH:D002289', (57, 62))
226827	27081041	Thus, our results indicate that an elevated expression of DeltaNp63alpha FAT2 and Slug is associated with poor clinical outcome in HER2-/ER- breast cancer and NSCLC patients.	('expression', 'MPA', (44, 54))	('NSCLC', 'Disease', (159, 164))	('patients', 'Species', '9606', (165, 173))	('breast cancer', 'Phenotype', 'HP:0003002', (141, 154))	('elevated', 'PosReg', (35, 43))	('NSCLC', 'Phenotype', 'HP:0030358', (159, 164))	('Slug', 'Gene', '6591', (82, 86))	('HER2', 'Gene', (131, 135))	('FAT2', 'Gene', '2196', (73, 77))	('breast cancer', 'Disease', 'MESH:D001943', (141, 154))	('breast cancer', 'Disease', (141, 154))	('FAT2', 'Gene', (73, 77))	('ER', 'Gene', '2099', (132, 134))	('DeltaNp63alpha', 'Chemical', '-', (58, 72))	('DeltaNp63alpha', 'Var', (58, 72))	('Slug', 'Gene', (82, 86))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('HER2', 'Gene', '2064', (131, 135))	('NSCLC', 'Disease', 'MESH:D002289', (159, 164))	('ER', 'Gene', '2099', (137, 139))
226832	27081041	Our results provide a more detailed understanding of how DeltaNp63alpha induces a hybrid epithelial/mesenchymal state.	('DeltaNp63alpha', 'Chemical', '-', (57, 71))	('induces', 'Reg', (72, 79))	('DeltaNp63alpha', 'Var', (57, 71))	('hybrid epithelial/mesenchymal state', 'CPA', (82, 117))
226833	27081041	Consistent with our previous results, our ChIP-seq experiments indicated that DeltaNp63alpha directly interacts with the proximal promoter of Axl and is necessary for Axl expression.	('Axl', 'Gene', '558', (142, 145))	('Axl', 'Gene', (167, 170))	('interacts', 'Interaction', (102, 111))	('DeltaNp63alpha', 'Chemical', '-', (78, 92))	('DeltaNp63alpha', 'Var', (78, 92))	('Axl', 'Gene', (142, 145))	('Axl', 'Gene', '558', (167, 170))
226836	27081041	These results suggest that the nature of the hybrid state induced by DeltaNp63alpha is a function of DeltaNp63alpha binding specificity that allows for the selective and direct regulation of a subset of mesenchymal genes.	('DeltaNp63alpha', 'Chemical', '-', (101, 115))	('DeltaNp63alpha', 'Chemical', '-', (69, 83))	('DeltaNp63alpha', 'Var', (69, 83))	('DeltaNp63alpha', 'Gene', (101, 115))
226837	27081041	In addition, DeltaNp63alpha and Slug are both expressed in mammary stem cells and required for mammary gland re-populating activity in transplantation assays.	('DeltaNp63alpha', 'Var', (13, 27))	('Slug', 'Gene', '6591', (32, 36))	('Slug', 'Gene', (32, 36))	('DeltaNp63alpha', 'Chemical', '-', (13, 27))
226840	27081041	Our ChIP-seq and ChIP-qPCR experiments have identified DeltaNp63alpha binding sites in putative regulatory regions associated with these genes, which suggests that DeltaNp63alpha directly promotes their expression.	('DeltaNp63alpha', 'Chemical', '-', (55, 69))	('promotes', 'PosReg', (188, 196))	('binding', 'Interaction', (70, 77))	('expression', 'MPA', (203, 213))	('DeltaNp63alpha', 'Gene', (55, 69))	('DeltaNp63alpha', 'Chemical', '-', (164, 178))	('DeltaNp63alpha', 'Var', (164, 178))
226841	27081041	Defining precisely how DeltaNp63alpha binding to these regulatory sites influences pro-migratory expression is an important area of future study.	('influences', 'Reg', (72, 82))	('DeltaNp63alpha', 'Var', (23, 37))	('pro-migratory', 'CPA', (83, 96))	('DeltaNp63alpha', 'Chemical', '-', (23, 37))
226842	27081041	The requirement of FAT2, SNCA, CA12, CPNE8 and NEK1 for DeltaNp63alpha induced motility also suggests new regulatory mechanisms for the control of cell migration.	('NEK1', 'Gene', '4750', (47, 51))	('motility', 'CPA', (79, 87))	('FAT2', 'Gene', (19, 23))	('NEK1', 'Gene', (47, 51))	('CPNE8', 'Gene', '144402', (37, 42))	('SNCA', 'Gene', (25, 29))	('SNCA', 'Gene', '6622', (25, 29))	('FAT2', 'Gene', '2196', (19, 23))	('CA12', 'Gene', (31, 35))	('DeltaNp63alpha', 'Chemical', '-', (56, 70))	('DeltaNp63alpha', 'Var', (56, 70))	('CPNE8', 'Gene', (37, 42))	('CA12', 'Gene', '771', (31, 35))
226853	27081041	Additional factors beyond Axl, Slug, FAT2, SNCA, CPNE8, CA12 and NEK1 expression may also be required for DeltaNp63alpha-induced BLBC migration.	('CPNE8', 'Gene', '144402', (49, 54))	('FAT2', 'Gene', '2196', (37, 41))	('FAT2', 'Gene', (37, 41))	('SNCA', 'Gene', (43, 47))	('SNCA', 'Gene', '6622', (43, 47))	('Axl', 'Gene', (26, 29))	('Slug', 'Gene', '6591', (31, 35))	('DeltaNp63alpha', 'Chemical', '-', (106, 120))	('CPNE8', 'Gene', (49, 54))	('NEK1', 'Gene', '4750', (65, 69))	('Slug', 'Gene', (31, 35))	('DeltaNp63alpha-induced', 'Var', (106, 128))	('NEK1', 'Gene', (65, 69))	('CA12', 'Gene', (56, 60))	('Axl', 'Gene', '558', (26, 29))	('CA12', 'Gene', '771', (56, 60))
226858	27081041	The DeltaNp63alpha dependent suppression of gene expression may be necessary for cell motility as well.	('DeltaNp63alpha', 'Chemical', '-', (4, 18))	('DeltaNp63alpha', 'Var', (4, 18))	('suppression', 'NegReg', (29, 40))
226861	27081041	However, it is possible DeltaNp63alpha may regulate motility through the induction of miRNAs that were not part of the screen or are necessary for migration in other contexts.	('miRNAs', 'CPA', (86, 92))	('regulate', 'Reg', (43, 51))	('motility', 'CPA', (52, 60))	('DeltaNp63alpha', 'Chemical', '-', (24, 38))	('DeltaNp63alpha', 'Var', (24, 38))
226862	27081041	DeltaNp63alpha may also suppress miRNAs that act as inhibitors of migration.	('DeltaNp63alpha', 'Chemical', '-', (0, 14))	('suppress', 'NegReg', (24, 32))	('DeltaNp63alpha', 'Var', (0, 14))	('miRNAs', 'MPA', (33, 39))
226863	27081041	Previous reports have suggested DeltaNp63alpha promotes migration in other cell types by inducing the expression of genes not found in the set of 124 DeltaNp63alpha target genes we identified.	('migration', 'CPA', (56, 65))	('expression', 'MPA', (102, 112))	('promotes', 'PosReg', (47, 55))	('DeltaNp63alpha', 'Var', (32, 46))	('DeltaNp63alpha', 'Chemical', '-', (32, 46))	('DeltaNp63alpha', 'Chemical', '-', (150, 164))	('inducing', 'PosReg', (89, 97))
226866	27081041	Our study showed that DeltaNp63alpha regulates migration through inducing Slug and FAT2 expression in a lung SCC population.	('inducing', 'PosReg', (65, 73))	('SCC', 'Gene', '6317', (109, 112))	('Slug', 'Gene', (74, 78))	('FAT2', 'Gene', '2196', (83, 87))	('DeltaNp63alpha', 'Chemical', '-', (22, 36))	('DeltaNp63alpha', 'Var', (22, 36))	('migration', 'CPA', (47, 56))	('FAT2', 'Gene', (83, 87))	('SCC', 'Gene', (109, 112))	('Slug', 'Gene', '6591', (74, 78))	('expression', 'MPA', (88, 98))
226867	27081041	Notably, DeltaNp63alpha expression also correlated with FAT2 expression across a wide-range of tumors, with Slug also showing a strong correlation in lung SCC, prostate and bladder cancer.	('prostate', 'Disease', (160, 168))	('SCC', 'Gene', (155, 158))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumors', 'Disease', (95, 101))	('correlation', 'Interaction', (135, 146))	('expression', 'MPA', (24, 34))	('Slug', 'Gene', (108, 112))	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('bladder cancer', 'Disease', 'MESH:D001749', (173, 187))	('bladder cancer', 'Disease', (173, 187))	('correlated', 'Reg', (40, 50))	('FAT2', 'Gene', '2196', (56, 60))	('bladder cancer', 'Phenotype', 'HP:0009725', (173, 187))	('DeltaNp63alpha', 'Var', (9, 23))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('DeltaNp63alpha', 'Chemical', '-', (9, 23))	('Slug', 'Gene', '6591', (108, 112))	('SCC', 'Gene', '6317', (155, 158))	('FAT2', 'Gene', (56, 60))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))
226868	27081041	These results suggest that DeltaNp63alpha may promote cell migration through the induction of Slug and FAT2 expression, in multiple tumor lineages.	('promote', 'PosReg', (46, 53))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('induction', 'PosReg', (81, 90))	('FAT2', 'Gene', '2196', (103, 107))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('Slug', 'Gene', '6591', (94, 98))	('tumor', 'Disease', (132, 137))	('FAT2', 'Gene', (103, 107))	('expression', 'MPA', (108, 118))	('Slug', 'Gene', (94, 98))	('cell migration', 'CPA', (54, 68))	('DeltaNp63alpha', 'Chemical', '-', (27, 41))	('DeltaNp63alpha', 'Var', (27, 41))
226870	27081041	It is possible that these genes are specifically required for DeltaNp63alpha induced migration in BLBC, and that an alternative process complements DeltaNp63alpha induced gene expression to promote invasion in additional tumor types.	('promote', 'PosReg', (190, 197))	('invasion', 'CPA', (198, 206))	('DeltaNp63alpha', 'Chemical', '-', (148, 162))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('tumor', 'Disease', (221, 226))	('migration', 'CPA', (85, 94))	('DeltaNp63alpha', 'Chemical', '-', (62, 76))	('DeltaNp63alpha', 'Var', (62, 76))	('tumor', 'Disease', 'MESH:D009369', (221, 226))
226871	27081041	Whether DeltaNp63alpha promotes or represses cell migration is likely dependent on cell context and the type of migratory behavior analyzed.	('DeltaNp63alpha', 'Chemical', '-', (8, 22))	('promotes', 'PosReg', (23, 31))	('represses', 'NegReg', (35, 44))	('DeltaNp63alpha', 'Var', (8, 22))	('cell migration', 'CPA', (45, 59))
226872	27081041	Our results have demonstrated that DeltaNp63alpha promotes the migration of hybrid BLBC cells and lung squamous cancer cells.	('squamous cancer', 'Phenotype', 'HP:0002860', (103, 118))	('lung squamous cancer', 'Phenotype', 'HP:0030359', (98, 118))	('promotes', 'PosReg', (50, 58))	('lung squamous cancer', 'Disease', (98, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('lung squamous cancer', 'Disease', 'MESH:D008175', (98, 118))	('DeltaNp63alpha', 'Chemical', '-', (35, 49))	('migration', 'CPA', (63, 72))	('DeltaNp63alpha', 'Var', (35, 49))
226873	27081041	Conversely DeltaNp63alpha can suppress mesenchymal-like cancer migration through the miR205 dependent suppression of ZEB1/2, and the silencing of FAK.	('FAK', 'Gene', (146, 149))	('FAK', 'Gene', '5747', (146, 149))	('miR205', 'Gene', '406988', (85, 91))	('ZEB1/2', 'Gene', '6935;9839', (117, 123))	('DeltaNp63alpha', 'Chemical', '-', (11, 25))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('miR205', 'Gene', (85, 91))	('silencing', 'NegReg', (133, 142))	('suppress', 'NegReg', (30, 38))	('DeltaNp63alpha', 'Var', (11, 25))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('ZEB1/2', 'Gene', (117, 123))	('suppression', 'NegReg', (102, 113))	('cancer', 'Disease', (56, 62))
226875	27081041	Whether other cell types are dependent on DeltaNp63alpha for migration may also be dependent on DeltaNp63alpha abundance, with cells that express low levels of DeltaNp63alpha likely not requiring it for migration.	('DeltaNp63alpha', 'Chemical', '-', (160, 174))	('DeltaNp63alpha', 'Var', (160, 174))	('DeltaNp63alpha', 'Chemical', '-', (42, 56))	('DeltaNp63alpha', 'Chemical', '-', (96, 110))	('DeltaNp63alpha', 'Var', (96, 110))
226876	27081041	Our live-imaging experiments provided insight into the nature of the DeltaNp63alpha dependent collective invasion.	('collective invasion', 'CPA', (94, 113))	('DeltaNp63alpha', 'Chemical', '-', (69, 83))	('DeltaNp63alpha', 'Var', (69, 83))
226877	27081041	During the initial induction of invasion, DeltaNp63alpha expressing MCFDCIS cells formed F-actin containing protrusions that extended into the ECM.	('F-actin', 'Protein', (89, 96))	('MCFDCIS', 'Gene', (68, 75))	('MCFDCIS', 'CellLine', 'None', (68, 75))	('DeltaNp63alpha', 'Chemical', '-', (42, 56))	('DeltaNp63alpha', 'Var', (42, 56))
226878	27081041	Cells depleted of DeltaNp63alpha, FAT2 or Slug were capable of moving within the spheroids and formed and severed F-actin, which is a key constituent of invasive protrusions.	('DeltaNp63alpha', 'Chemical', '-', (18, 32))	('DeltaNp63alpha', 'Var', (18, 32))	('severed', 'NegReg', (106, 113))	('FAT2', 'Gene', '2196', (34, 38))	('Slug', 'Gene', '6591', (42, 46))	('FAT2', 'Gene', (34, 38))	('Slug', 'Gene', (42, 46))	('F-actin', 'Protein', (114, 121))
226879	27081041	These results extend on our previous finding that distinct cell signaling pathways are required for collective invasion, but not intraspheroid movement by revealing that DeltaNp63alpha, FAT2 and Slug are specifically required for collective invasion in organotypic culture.	('DeltaNp63alpha', 'Var', (170, 184))	('Slug', 'Gene', '6591', (195, 199))	('Slug', 'Gene', (195, 199))	('FAT2', 'Gene', '2196', (186, 190))	('FAT2', 'Gene', (186, 190))	('DeltaNp63alpha', 'Chemical', '-', (170, 184))
226883	27081041	These findings suggest that metastasis may require the activation of migration programs, such as the hybrid state induced by DeltaNp63alpha, which can promote invasion without triggering the full conversion to a mesenchymal state.	('DeltaNp63alpha', 'Var', (125, 139))	('promote', 'PosReg', (151, 158))	('invasion', 'CPA', (159, 167))	('metastasis', 'CPA', (28, 38))	('DeltaNp63alpha', 'Chemical', '-', (125, 139))
226884	27081041	Together, our results suggest that the DeltaNp63alpha dependent expression of Slug and FAT2 can induce collective invasion which promotes local dissemination and can potentially lead to metastatic growth (Figure 7C).	('Slug', 'Gene', (78, 82))	('promotes', 'PosReg', (129, 137))	('DeltaNp63alpha', 'Chemical', '-', (39, 53))	('DeltaNp63alpha', 'Var', (39, 53))	('induce', 'Reg', (96, 102))	('lead to', 'Reg', (178, 185))	('collective invasion', 'CPA', (103, 122))	('FAT2', 'Gene', '2196', (87, 91))	('metastatic growth', 'CPA', (186, 203))	('FAT2', 'Gene', (87, 91))	('local dissemination', 'CPA', (138, 157))	('Slug', 'Gene', '6591', (78, 82))
226885	27081041	NSCLC and BLBC patients classified as DeltaNp63alpha-, Slug- or FAT2-high had a worse odds of survival compared to the DeltaNp63alpha-, Slug- and FAT2-low patients.	('NSCLC', 'Disease', 'MESH:D002289', (0, 5))	('FAT2', 'Gene', (64, 68))	('patients', 'Species', '9606', (15, 23))	('Slug', 'Gene', (136, 140))	('Slug', 'Gene', '6591', (136, 140))	('Slug', 'Gene', '6591', (55, 59))	('survival', 'MPA', (94, 102))	('FAT2', 'Gene', '2196', (146, 150))	('NSCLC', 'Phenotype', 'HP:0030358', (0, 5))	('DeltaNp63alpha', 'Chemical', '-', (119, 133))	('Slug', 'Gene', (55, 59))	('worse', 'NegReg', (80, 85))	('DeltaNp63alpha-', 'Var', (38, 53))	('patients', 'Species', '9606', (155, 163))	('DeltaNp63alpha', 'Chemical', '-', (38, 52))	('FAT2', 'Gene', (146, 150))	('NSCLC', 'Disease', (0, 5))	('FAT2', 'Gene', '2196', (64, 68))
226887	27081041	These combined findings support the further investigation of DeltaNp63alpha, Slug and FAT2 as potential prognostic biomarkers.	('Slug', 'Gene', (77, 81))	('DeltaNp63alpha', 'Chemical', '-', (61, 75))	('DeltaNp63alpha', 'Var', (61, 75))	('FAT2', 'Gene', '2196', (86, 90))	('Slug', 'Gene', '6591', (77, 81))	('FAT2', 'Gene', (86, 90))
226888	27081041	Our functional studies suggest that an enhanced ability to invade may contribute to the poor outcome observed in the DeltaNp63alpha-high, FAT2-high and Slug-high patient groups.	('DeltaNp63alpha-high', 'Var', (117, 136))	('invade', 'CPA', (59, 65))	('FAT2', 'Gene', '2196', (138, 142))	('DeltaNp63alpha', 'Chemical', '-', (117, 131))	('FAT2', 'Gene', (138, 142))	('ability', 'CPA', (48, 55))	('Slug', 'Gene', '6591', (152, 156))	('Slug', 'Gene', (152, 156))	('patient', 'Species', '9606', (162, 169))	('enhanced', 'PosReg', (39, 47))
226889	27081041	The ability of DeltaNp63alpha to promote invasion may also explain the clinical significance of single nucleotide polymorphism that increases DeltaNp63alpha mRNA levels and is associated breast cancer patient poor outcome.	('breast cancer', 'Phenotype', 'HP:0003002', (187, 200))	('DeltaNp63alpha', 'Chemical', '-', (142, 156))	('DeltaNp63alpha', 'Chemical', '-', (15, 29))	('associated', 'Reg', (176, 186))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('single nucleotide polymorphism', 'Var', (96, 126))	('DeltaNp63alpha mRNA levels', 'MPA', (142, 168))	('increases', 'PosReg', (132, 141))	('patient', 'Species', '9606', (201, 208))	('breast cancer', 'Disease', 'MESH:D001943', (187, 200))	('breast cancer', 'Disease', (187, 200))
226890	27081041	In addition, DeltaNp63alpha and Slug can be required for maintaining a pool of cells with tumor initiating ability, which could also contribute to the nature of disease progression and response to treatment.	('contribute', 'Reg', (133, 143))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('Slug', 'Gene', '6591', (32, 36))	('DeltaNp63alpha', 'Chemical', '-', (13, 27))	('DeltaNp63alpha', 'Var', (13, 27))	('Slug', 'Gene', (32, 36))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
226906	27081041	Enhancer regions containing H3K4me1 and H3K4me2 modifications were defined in human mammary epithelial cells (HMECs) by ENCODE and used to further annotate peaks regions by BEDOPS (version 2.4.2).	('human', 'Species', '9606', (78, 83))	('H3K4me2 modifications', 'Var', (40, 61))	('H3K4me1', 'Var', (28, 35))
226908	27081041	To identify genes that are regulated by DeltaNp63alpha expression, we determined which genes were >= 2-fold reduced by DeltaNp63alpha siRNA transfection with a p <=0.05 in MCFDCIS and HCC1806 cells.	('reduced', 'NegReg', (108, 115))	('DeltaNp63alpha', 'Chemical', '-', (40, 54))	('DeltaNp63alpha', 'Chemical', '-', (119, 133))	('DeltaNp63alpha', 'Var', (119, 133))	('genes', 'Gene', (87, 92))	('MCFDCIS', 'CellLine', 'None', (172, 179))	('HCC1806', 'CellLine', 'CVCL:1258', (184, 191))
226939	24672538	VTET: a variable threshold exact test for identifying disease-associated copy number variations enriched in short genomic regions Copy number variations (CNVs) constitute a major source of genetic variations in human populations and have been reported to be associated with complex diseases.	('Copy number variations', 'Var', (130, 152))	('human', 'Species', '9606', (211, 216))	('associated', 'Reg', (258, 268))	('complex diseases', 'Disease', (274, 290))
226942	24672538	Copy number variations (CNVs) are one of the major sources of genetic variations in the human genome (Redon et al.,) and have been reported to be associated with a variety of complex diseases (Sebat et al.,; Consortium,; Stefansson et al.,; Bucan et al.,; Diskin et al.,; Glessner et al.,; McCarthy et al.,; Levinson et al.,).	('Copy number variations', 'Var', (0, 22))	('Diskin', 'Disease', (256, 262))	('associated', 'Reg', (146, 156))	('human', 'Species', '9606', (88, 93))	('Levinson', 'Disease', (308, 316))
226945	24672538	In this manuscript, we consider the scenario that cases are more frequently disrupted by CNVs than controls in a given genomic region while CNVs are randomly distributed in the region with various boundaries (Figure 1), as shown as an example in a GWAS of autism (Glessner et al.,).	('CNVs', 'Var', (89, 93))	('autism', 'Phenotype', 'HP:0000717', (256, 262))	('GWAS of autism', 'Disease', (248, 262))	('GWAS of autism', 'Disease', 'MESH:D001321', (248, 262))
226953	24672538	We will then extend the algorithm to incorporate the BAF information to improve the power, particularly for duplications.	('power', 'MPA', (84, 89))	('improve', 'PosReg', (72, 79))	('BAF', 'Gene', '8815', (53, 56))	('duplications', 'Var', (108, 120))	('BAF', 'Gene', (53, 56))
226956	24672538	When T is sufficiently large, we can use Siegmund's method based on the random walk theory (Siegmund,) to derive a very accurate asymptotic approximation pi   2TU0i lambda-2phi(U0 i)[(s1 -1)es1 - (s2 -1)es2]/8 with lambda = -0.583, s1 = 2lambdaU0i/, s2 = 2lambdaU0i/ and phi as the density function for N(0,1).	('s1 = 2lambdaU0i/', 'Var', (232, 248))	('pi   2', 'Species', '1214577', (154, 160))	('s2 = 2lambdaU0i/', 'Var', (250, 266))
226958	24672538	We define  for detecting CN1 deletions and  for detecting CN3 duplications.	('deletions', 'Var', (29, 38))	('CN1', 'Gene', (25, 28))	('CN1', 'Gene', '84618', (25, 28))
226959	24672538	The p-values are then defined as  for detecting CN1 deletions and  for detecting CN3 duplications.	('CN1', 'Gene', '84618', (48, 51))	('CN1', 'Gene', (48, 51))	('deletions', 'Var', (52, 61))
226960	24672538	Incorporating BAFs can substantially improve the sensitivity of detecting CN3 duplications (Shi and Li,).	('BAF', 'Gene', '8815', (14, 17))	('improve', 'PosReg', (37, 44))	('CN3 duplications', 'Var', (74, 90))	('BAF', 'Gene', (14, 17))	('Shi', 'Disease', (92, 95))
226961	24672538	Briefly, BAFs close to 1/3 or 2/3 support CN3 duplications while BAF close to 0 or 1 are not informative for the inference of CN3 duplications.	('BAF', 'Gene', '8815', (65, 68))	('BAF', 'Gene', '8815', (9, 12))	('BAF', 'Gene', (65, 68))	('CN3', 'Gene', (42, 45))	('BAF', 'Gene', (9, 12))	('duplications', 'Var', (46, 58))
226984	24672538	Thus, as expected, the two-step testing procedure based on PennCNV is more powerful for detecting the association of CN3 duplications but less powerful for CN1 deletions compared to CBS.	('CN1', 'Gene', (156, 159))	('association', 'Interaction', (102, 113))	('CN3', 'Gene', (117, 120))	('CN1', 'Gene', '84618', (156, 159))	('duplications', 'Var', (121, 133))
226985	24672538	Of note, the testing procedure based on CBS has no power for detecting the association of short CN3 duplications while the test based on PennCNV has no power for detecting the association of short CN1 deletions.	('short CN3', 'Gene', (90, 99))	('duplications', 'Var', (100, 112))	('CN1', 'Gene', '84618', (197, 200))	('CN1', 'Gene', (197, 200))
226988	24672538	For short CN3 duplications, CNVtools failed in 10% (>6 probes) -30% (3 or 4 probes) of simulations because it could not converge.	('CN3', 'Gene', (10, 13))	('CNVtools', 'Chemical', '-', (28, 36))	('duplications', 'Var', (14, 26))
226989	24672538	For short CN1 deletions, CNVtools failed in 1-5% simulations.	('CN1', 'Gene', (10, 13))	('deletions', 'Var', (14, 23))	('CNVtools', 'Chemical', '-', (25, 33))	('CN1', 'Gene', '84618', (10, 13))
226990	24672538	CNVtools is slightly more powerful for detecting associations of CN1 deletions.	('associations', 'Interaction', (49, 61))	('deletions', 'Var', (69, 78))	('CN1', 'Gene', '84618', (65, 68))	('CN1', 'Gene', (65, 68))	('CNVtools', 'Chemical', '-', (0, 8))
226991	24672538	However, VTET is more powerful for detecting associations of CN3 duplications because it uses both LRR and BAF information.	('BAF', 'Gene', (107, 110))	('BAF', 'Gene', '8815', (107, 110))	('CN3', 'Gene', (61, 64))	('duplications', 'Var', (65, 77))
226997	24672538	However, even under this unfavorable scenario, VTET is only slightly less powerful than CNVtools for short deletions but more powerful for duplications.	('duplications', 'Var', (139, 151))	('short deletions', 'Var', (101, 116))	('CNVtools', 'Chemical', '-', (88, 96))
227023	33390811	Next, through four databases, miR-525-5P, miR-4640-3p, miR-214-3P, miR-520a-5p all regulated the BAX.	('miR-214', 'Gene', '406996', (55, 62))	('miR-525', 'Gene', (30, 37))	('BAX', 'Gene', (97, 100))	('miR-520a', 'Gene', (67, 75))	('regulated', 'Reg', (83, 92))	('BAX', 'Gene', '581', (97, 100))	('miR-4640-3p', 'Var', (42, 53))	('miR-520a', 'Gene', '574467', (67, 75))	('miR-525', 'Gene', '574470', (30, 37))	('miR-214', 'Gene', (55, 62))
227035	33390811	Then, we showed 8 miRNAs regulating BAX in only four databases by Venn software, such as hsa-miR-3681-3p, hsa-miR-766-5p, hsa-miR-525-5p, hsa-miR-4640-3p, hsa-miR-128-3p, hsa-miR-216a-3p, hsa-miR-520a-5p, hsa-miR-214-3p.	('hsa-miR-766', 'Gene', '768218', (106, 117))	('hsa-miR-3681-3p', 'Var', (89, 104))	('hsa-miR-216a-3p', 'Var', (171, 186))	('hsa-miR-128-3p', 'Var', (155, 169))	('miR-214', 'Gene', (209, 216))	('hsa-miR-766', 'Gene', (106, 117))	('BAX', 'Gene', (36, 39))	('hsa-miR-525', 'Gene', (122, 133))	('hsa-miR-520a', 'Gene', '574467', (188, 200))	('hsa-miR-525', 'Gene', '574470', (122, 133))	('hsa-miR-520a', 'Gene', (188, 200))	('hsa-miR-4640', 'Gene', '100616237', (138, 150))	('hsa-miR-4640', 'Gene', (138, 150))	('miR-214', 'Gene', '406996', (209, 216))	('BAX', 'Gene', '581', (36, 39))
227051	33390811	Besides, according to the differentially expressed miRNAs in the GSE43249 (GPL14613), we found out miRNA520 in NSCLC.	('NSCLC', 'Disease', (111, 116))	('NSCLC', 'Disease', 'MESH:D002289', (111, 116))	('miRNA520', 'Chemical', '-', (99, 107))	('miRNA520', 'Var', (99, 107))	('NSCLC', 'Phenotype', 'HP:0030358', (111, 116))
227072	33390811	8 miRNAs, miR-3681-3p, miR-766-5p, miR-525-5p, miR-4640-3p, miR-128-3p, miR-216a-3p, miR-520a-5p, and miR-214-3p were expressed commonly by the Dram-Venn-Diagram (http://bioinformatics.psb.ugent.be/webtools/Venn/) (Figure 5B).	('miR-214', 'Gene', '406996', (102, 109))	('miR-525', 'Gene', (35, 42))	('miR-128-3p', 'Var', (60, 70))	('miR-520a', 'Gene', '574467', (85, 93))	('miR-4640-3p', 'Var', (47, 58))	('miR-766', 'Gene', (23, 30))	('miR-525', 'Gene', '574470', (35, 42))	('miR-3681-3p', 'Var', (10, 21))	('miR-216a-3p', 'Var', (72, 83))	('miR-766', 'Gene', '768218', (23, 30))	('miR-214', 'Gene', (102, 109))	('miR-520a', 'Gene', (85, 93))
227078	33390811	At the same time, we combined the GSE43249's differentially expressed miRNAs, 2 miRNAs were included, such as miR-520, miR-525.	('miR-525', 'Gene', '574470', (119, 126))	('miR-520', 'Var', (110, 117))	('miR-525', 'Gene', (119, 126))
227080	33390811	MiR-520, miR-525 were targeted miRNAs of lncRNA XIST.	('miR-525', 'Gene', (9, 16))	('MiR-520', 'Var', (0, 7))	('XIST', 'Gene', (48, 52))	('miR-525', 'Gene', '574470', (9, 16))	('XIST', 'Gene', '7503', (48, 52))
227087	33390811	The mutation of TP53 and BAX all influence immune cells; such as the B cell, CD8+ T cell, CD4+ T cell, macrophage, neutrophil, and dendritic cell (P<0.05) (Figure 6D, 6E).	('immune cells', 'CPA', (43, 55))	('CD8', 'Gene', (77, 80))	('influence', 'Reg', (33, 42))	('CD8', 'Gene', '925', (77, 80))	('BAX', 'Gene', (25, 28))	('CD4', 'Gene', (90, 93))	('BAX', 'Gene', '581', (25, 28))	('mutation', 'Var', (4, 12))	('B cell', 'CPA', (69, 75))	('CD4', 'Gene', '920', (90, 93))	('TP53', 'Gene', '7157', (16, 20))	('TP53', 'Gene', (16, 20))
227107	33390811	In addition, cisplatin can induce cell death by engaging endogenous apoptotic signaling that activates mitochondrial apoptosis.	('activates', 'PosReg', (93, 102))	('cell death', 'CPA', (34, 44))	('cisplatin', 'Var', (13, 22))	('mitochondrial apoptosis', 'CPA', (103, 126))	('endogenous apoptotic signaling', 'MPA', (57, 87))	('cisplatin', 'Chemical', 'MESH:D002945', (13, 22))
227108	33390811	We found that induction of p53 promoted apoptosis, autophagy, and cell sensitivity to cisplatin treatment.	('cell sensitivity', 'CPA', (66, 82))	('apoptosis', 'CPA', (40, 49))	('p53', 'Gene', '7157', (27, 30))	('induction', 'Var', (14, 23))	('autophagy', 'CPA', (51, 60))	('cisplatin', 'Chemical', 'MESH:D002945', (86, 95))	('promoted', 'PosReg', (31, 39))	('p53', 'Gene', (27, 30))
227117	33390811	Combining with the GSE43249 and miRcode database, miR520 was a potential molecule by regulating BAX in cisplatin sensitive-resistant NSCLC cells.	('miR520', 'Var', (50, 56))	('cisplatin', 'Chemical', 'MESH:D002945', (103, 112))	('NSCLC', 'Phenotype', 'HP:0030358', (133, 138))	('regulating', 'Reg', (85, 95))	('BAX', 'Gene', (96, 99))	('BAX', 'Gene', '581', (96, 99))	('NSCLC', 'Disease', (133, 138))	('NSCLC', 'Disease', 'MESH:D002289', (133, 138))
227133	33330053	And GPR115 overexpression is an independent prognostic factor for 5-year overall survival of NSCLC patients [hazard ratio (HR)=1.625, P = 0.008].	('NSCLC', 'Disease', (93, 98))	('NSCLC', 'Disease', 'MESH:D002289', (93, 98))	('GPR115', 'Var', (4, 10))	('patients', 'Species', '9606', (99, 107))	('NSCLC', 'Phenotype', 'HP:0030358', (93, 98))	('overexpression', 'PosReg', (11, 25))
227136	33330053	Preliminary bioinformatic analysis confirmed that GPR115 was closely associated with LAMC2 (Spearman correlation coefficient=0.67, P < 0.05), which was accumulated in ECM-receptor interaction and focal adhesion.	('LAMC2', 'Gene', '3918', (85, 90))	('ECM', 'Gene', (167, 170))	('associated', 'Reg', (69, 79))	('ECM', 'Gene', '22915', (167, 170))	('LAMC2', 'Gene', (85, 90))	('GPR115', 'Var', (50, 56))
227137	33330053	Consistent with these findings, deceased of GPR115 was associated with E-cadherin, N-cadherin and Vimentin confirmed by western blot.	('GPR115', 'Gene', (44, 50))	('deceased', 'Var', (32, 40))	('E-cadherin', 'Gene', (71, 81))	('associated', 'Reg', (55, 65))	('E-cadherin', 'Gene', '999', (71, 81))	('Vimentin', 'Gene', (98, 106))	('N-cadherin', 'Gene', (83, 93))	('Vimentin', 'Gene', '7431', (98, 106))	('N-cadherin', 'Gene', '1000', (83, 93))
227138	33330053	In conclusion, these data suggest that GPR115 may play a role in the tumor growth and metastasis and may have utility as a diagnostic and prognostic marker for LUAD, but not LUSC.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('play', 'Reg', (50, 54))	('tumor', 'Disease', (69, 74))	('LUAD', 'Phenotype', 'HP:0030078', (160, 164))	('LUAD', 'Disease', (160, 164))	('GPR115', 'Var', (39, 45))	('LUSC', 'Phenotype', 'HP:0030359', (174, 178))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('metastasis', 'CPA', (86, 96))
227145	33330053	GPCRs play crucial roles in the regulation of many biological functions, and unsurprisingly, dysregulation of their expression and/or activity is associated with numerous diseases.	('numerous diseases', 'Disease', 'MESH:D003141', (162, 179))	('expression', 'MPA', (116, 126))	('numerous diseases', 'Disease', (162, 179))	('dysregulation', 'Var', (93, 106))	('activity', 'MPA', (134, 142))	('associated', 'Reg', (146, 156))
227147	33330053	GPR115 (G protein-coupled receptor 115) is a member of the adhesion GPCR (aGPCR) family, which consists of membrane-bound receptors with a long N-terminus.	('G protein-coupled receptor 115', 'Gene', '221393', (8, 38))	('GPR115', 'Var', (0, 6))	('G protein-coupled receptor 115', 'Gene', (8, 38))
227148	33330053	Some researchers found that GPR115 plays an important role in the pathogenesis of inflammatory skin diseases, and may be related to the treatment of glucocorticoids in these diseases.	('related', 'Reg', (121, 128))	('skin diseases', 'Disease', (95, 108))	('GPR115', 'Var', (28, 34))	('inflammatory skin diseases', 'Phenotype', 'HP:0011123', (82, 108))	('skin diseases', 'Disease', 'MESH:D012871', (95, 108))
227151	33330053	They suggested that GPR115 may have the potential to promote tumor development, but the specific molecular mechanism is still unclear.	('GPR115', 'Var', (20, 26))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Disease', (61, 66))	('promote', 'PosReg', (53, 60))
227152	33330053	It is worth noting that we found that GPR115 mRNA is elevated in NSCLC and is closely related to patient survival.	('elevated', 'PosReg', (53, 61))	('GPR115', 'Var', (38, 44))	('NSCLC', 'Disease', 'MESH:D002289', (65, 70))	('NSCLC', 'Phenotype', 'HP:0030358', (65, 70))	('related', 'Reg', (86, 93))	('patient', 'Species', '9606', (97, 104))	('NSCLC', 'Disease', (65, 70))
227175	33330053	In addition, the higher GPR115 expression, the worse the overall survival of LUAD patients, but not of LUSC ( Figures 1A, B ).	('LUSC', 'Phenotype', 'HP:0030359', (103, 107))	('patients', 'Species', '9606', (82, 90))	('GPR115', 'Var', (24, 30))	('higher', 'PosReg', (17, 23))	('expression', 'MPA', (31, 41))	('LUAD', 'Phenotype', 'HP:0030078', (77, 81))	('worse', 'NegReg', (47, 52))
227176	33330053	Subsequently, IHC analysis of 393 clinical specimens showed that GPR115 was present in both the cytoplasm and membrane of cancer cells ( Figure 1C ).	('cancer', 'Disease', (122, 128))	('GPR115', 'Var', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))
227178	33330053	Correlation analysis (Pearson's chi2) indicated that high GPR115 expression was significantly (P <= 0.05) associated with tumor type, differentiation, tumor size, lymph node metastasis, and tumor-node-metastasis (TNM) stage in NSCLC patients (chi2 = 6.475, 18.473, 7.664, 17.269 and 13.816, respectively; all P < 0.05,  Table 1 ).	('associated', 'Reg', (106, 116))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('tumor', 'Disease', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('NSCLC', 'Disease', 'MESH:D002289', (227, 232))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('expression', 'MPA', (65, 75))	('high', 'Var', (53, 57))	('NSCLC', 'Disease', (227, 232))	('GPR115', 'Gene', (58, 64))	('tumor', 'Disease', (190, 195))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('differentiation', 'CPA', (134, 149))	('patients', 'Species', '9606', (233, 241))	('NSCLC', 'Phenotype', 'HP:0030358', (227, 232))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('lymph node metastasis', 'CPA', (163, 184))	('tumor', 'Disease', (151, 156))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
227180	33330053	Kaplan-Meier survival curve analysis confirmed that the enhanced of GPR115 was associated with poor prognosis in NSCLC patients ( Figure 1E ).	('GPR115', 'Var', (68, 74))	('patients', 'Species', '9606', (119, 127))	('NSCLC', 'Phenotype', 'HP:0030358', (113, 118))	('enhanced', 'PosReg', (56, 64))	('NSCLC', 'Disease', (113, 118))	('NSCLC', 'Disease', 'MESH:D002289', (113, 118))
227188	33330053	The results suggested that GPR115 knockdown significantly suppressed the proliferation of H1650 and SPCA cells, and the efficiency increased with time ( Figure 3C ).	('increased', 'PosReg', (131, 140))	('GPR115', 'Gene', (27, 33))	('SPCA', 'Gene', (100, 104))	('proliferation', 'CPA', (73, 86))	('suppressed', 'NegReg', (58, 68))	('H1650', 'CellLine', 'CVCL:1483', (90, 95))	('SPCA', 'Gene', '2155', (100, 104))	('knockdown', 'Var', (34, 43))
227190	33330053	To examine the effect of GRP115 in metastasis-related phenotype in LUAD, we first measured the cell migration by wound healing assay, which showed that the migration ability of H1650 and SPCA was significantly suppressed compared with NC cells ( Figure 4A ).	('H1650', 'CellLine', 'CVCL:1483', (177, 182))	('SPCA', 'Gene', '2155', (187, 191))	('SPCA', 'Gene', (187, 191))	('suppressed', 'NegReg', (210, 220))	('migration ability', 'CPA', (156, 173))	('LUAD', 'Phenotype', 'HP:0030078', (67, 71))	('H1650', 'Var', (177, 182))
227191	33330053	Similar with the effect of GPR115 regulation on CCK8, silencing of GPR115 significantly inhibited H1650 and SPCA cell invasion ability ( Figure 4B ).	('inhibited', 'NegReg', (88, 97))	('H1650', 'CellLine', 'CVCL:1483', (98, 103))	('SPCA', 'Gene', (108, 112))	('silencing', 'Var', (54, 63))	('GPR115', 'Gene', (67, 73))	('SPCA', 'Gene', '2155', (108, 112))
227200	33330053	In this study, we first confirmed that GPR115 was significantly overexpression in NSCLC tissues than normal lung epithelial tissue, which consistent with the higher expression found in breast cancer and colon cancer.	('NSCLC', 'Phenotype', 'HP:0030358', (82, 87))	('breast cancer', 'Disease', 'MESH:D001943', (185, 198))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('breast cancer', 'Disease', (185, 198))	('overexpression', 'PosReg', (64, 78))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))	('breast cancer', 'Phenotype', 'HP:0003002', (185, 198))	('colon cancer', 'Phenotype', 'HP:0003003', (203, 215))	('GPR115', 'Var', (39, 45))	('NSCLC', 'Disease', (82, 87))	('colon cancer', 'Disease', 'MESH:D015179', (203, 215))	('colon cancer', 'Disease', (203, 215))	('NSCLC', 'Disease', 'MESH:D002289', (82, 87))
227203	33330053	But after further analysis by pathology type, we found that high GPR115 protein expression was significantly associated with the tumor progression and prognosis of LUAD, but not LUSC.	('LUAD', 'Disease', (164, 168))	('LUAD', 'Phenotype', 'HP:0030078', (164, 168))	('high', 'Var', (60, 64))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('GPR115', 'Gene', (65, 71))	('prognosis', 'CPA', (151, 160))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('tumor', 'Disease', (129, 134))	('associated with', 'Reg', (109, 124))	('LUSC', 'Phenotype', 'HP:0030359', (178, 182))
227205	33330053	In summary, our research indicated that GPR115 might be a potential link between tumor progression and prognosis survival, which may serve as a biomarker for LUAD treatment.	('GPR115', 'Var', (40, 46))	('LUAD', 'Phenotype', 'HP:0030078', (158, 162))	('link', 'Reg', (68, 72))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('prognosis', 'CPA', (103, 112))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Disease', (81, 86))
227210	33330053	Similar with other aGPCRs, we further demonstrated that knockdown of GPR115 expression in LUAD cells inhibited proliferation, migration, and invasion, which suggest that GPPR115 was a tumor-promoting gene.	('invasion', 'CPA', (141, 149))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('proliferation', 'CPA', (111, 124))	('LUAD', 'Phenotype', 'HP:0030078', (90, 94))	('GPR115', 'Gene', (69, 75))	('tumor', 'Disease', (184, 189))	('inhibited', 'NegReg', (101, 110))	('knockdown', 'Var', (56, 65))
227227	33330053	We have reason to believe that GPR115 cooperates with the high expression of LAMC2 to induce the mesenchymal changes of LUAD epithelial cells, thereby achieving the purpose of promoting metastasis.	('promoting', 'PosReg', (176, 185))	('metastasis', 'CPA', (186, 196))	('GPR115', 'Var', (31, 37))	('mesenchymal changes of LUAD', 'CPA', (97, 124))	('induce', 'PosReg', (86, 92))	('LAMC2', 'Gene', (77, 82))	('LUAD', 'Phenotype', 'HP:0030078', (120, 124))	('LAMC2', 'Gene', '3918', (77, 82))
227228	33330053	In conclusion, this study was the first to determine GPR115 expression pattern in NSCLC, its value as a prognostic marker for LUAD patients, and its functional role as a tumor promoter.	('patients', 'Species', '9606', (131, 139))	('LUAD', 'Phenotype', 'HP:0030078', (126, 130))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('NSCLC', 'Phenotype', 'HP:0030358', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('tumor', 'Disease', (170, 175))	('GPR115', 'Var', (53, 59))	('NSCLC', 'Disease', (82, 87))	('NSCLC', 'Disease', 'MESH:D002289', (82, 87))
227230	33330053	And GPR115 might activated tumor malignant progression by correlated with LAMC2 to enhanced EMT development.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('EMT development', 'CPA', (92, 107))	('malignant', 'Disease', (33, 42))	('correlated', 'Interaction', (58, 68))	('tumor', 'Disease', (27, 32))	('enhanced', 'PosReg', (83, 91))	('GPR115', 'Var', (4, 10))	('LAMC2', 'Gene', (74, 79))	('activated', 'PosReg', (17, 26))	('LAMC2', 'Gene', '3918', (74, 79))	('malignant', 'Disease', 'MESH:D009369', (33, 42))	('tumor', 'Disease', 'MESH:D009369', (27, 32))
227231	33330053	Next, we will try to construct a GPR115-deletion mouse model to verify that GPR115 regulates tumor proliferation and metastasis, which was important to further promote our results toward clinical applications.	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Disease', (93, 98))	('mouse', 'Species', '10090', (49, 54))	('regulates', 'Reg', (83, 92))	('GPR115', 'Var', (76, 82))	('metastasis', 'CPA', (117, 127))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
227239	27835590	Top genes whose mutations highly occurred in patients with LUSC were identified, most of these genes were shown to be related with tumorigenesis in previous studies.	('related', 'Reg', (118, 125))	('tumorigenesis', 'CPA', (131, 144))	('LUSC', 'Phenotype', 'HP:0030359', (59, 63))	('mutations', 'Var', (16, 25))	('patients', 'Species', '9606', (45, 53))	('LUSC', 'Disease', (59, 63))
227256	27835590	Top genes whose mutations highly occurred in patients with LUSC were identified with the somatic mutations datasets from TCGA.	('patients', 'Species', '9606', (45, 53))	('mutations', 'Var', (16, 25))	('LUSC', 'Phenotype', 'HP:0030359', (59, 63))	('LUSC', 'Disease', (59, 63))
227260	27835590	For example, TTN was mutated in 129 patients and every patient had 2.61 TTN mutations in average.	('TTN', 'Gene', (13, 16))	('mutations', 'Var', (76, 85))	('patients', 'Species', '9606', (36, 44))	('TTN', 'Gene', '7273', (13, 16))	('patient', 'Species', '9606', (55, 62))	('TTN', 'Gene', (72, 75))	('TTN', 'Gene', '7273', (72, 75))	('patient', 'Species', '9606', (36, 43))
227261	27835590	On the other hand, every patient had 1.04 mutations of TP53 in average.	('TP53', 'Gene', (55, 59))	('mutations', 'Var', (42, 51))	('patient', 'Species', '9606', (25, 32))	('TP53', 'Gene', '7157', (55, 59))
227263	27835590	This result also showed that any mutation on TP53, together mutations on other genes, might lead to cancer.	('mutation', 'Var', (33, 41))	('TP53', 'Gene', (45, 49))	('lead to', 'Reg', (92, 99))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('TP53', 'Gene', '7157', (45, 49))
227264	27835590	In this study, MLL2 also had a relative low ratio of non-synonymous mutations and patients.	('low', 'NegReg', (40, 43))	('MLL2', 'Gene', (15, 19))	('patients', 'Species', '9606', (82, 90))	('MLL2', 'Gene', '8085', (15, 19))	('non-synonymous mutations', 'Var', (53, 77))
227265	27835590	However, Gerstung, Pellagatti found that the principal component values of target genes varied widely across the different mutations or indels in patients with myelodysplastic syndromes.	('myelodysplastic syndromes', 'Phenotype', 'HP:0002863', (160, 185))	('myelodysplastic syndromes', 'Disease', (160, 185))	('myelodysplastic syndromes', 'Disease', 'MESH:D009190', (160, 185))	('patients', 'Species', '9606', (146, 154))	('mutations', 'Var', (123, 132))
227269	27835590	This table showed a shared mechanisms and pathways in patients with different gene mutations and suggested the important roles that these pathways played in LUSC.	('mutations', 'Var', (83, 92))	('LUSC', 'Disease', (157, 161))	('patients', 'Species', '9606', (54, 62))	('LUSC', 'Phenotype', 'HP:0030359', (157, 161))
227271	27835590	Among all of the genes that had the most mutations, some of them lack evidence to link them with the cancer.	('mutations', 'Var', (41, 50))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('cancer', 'Disease', (101, 107))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))
227272	27835590	Proteins of TTN and MUC16 are extremely long, respectively 34350 and 22152.	('MUC16', 'Gene', '94025', (20, 25))	('34350', 'Var', (59, 64))	('TTN', 'Gene', (12, 15))	('MUC16', 'Gene', (20, 25))	('TTN', 'Gene', '7273', (12, 15))	('22152', 'Var', (69, 74))
227276	27835590	SYNE1 expressed in skeletal and smooth muscle and localizes to the nuclear membrane, but a lot of studies reported that missense mutations, silent mutations, nonsense mutations, and frameshift deletions on SYNE1 were observed in colon cancer, stomach cancer, breast cancer and so forth.	('SYNE1', 'Gene', (0, 5))	('missense mutations', 'Var', (120, 138))	('colon cancer', 'Disease', (229, 241))	('SYNE1', 'Gene', '23345', (0, 5))	('frameshift deletions', 'Var', (182, 202))	('silent mutations', 'Var', (140, 156))	('breast cancer', 'Phenotype', 'HP:0003002', (259, 272))	('stomach cancer', 'Disease', (243, 257))	('SYNE1', 'Gene', (206, 211))	('breast cancer', 'Disease', 'MESH:D001943', (259, 272))	('breast cancer', 'Disease', (259, 272))	('colon cancer', 'Phenotype', 'HP:0003003', (229, 241))	('SYNE1', 'Gene', '23345', (206, 211))	('stomach cancer', 'Disease', 'MESH:D013274', (243, 257))	('nonsense mutations', 'Var', (158, 176))	('stomach cancer', 'Phenotype', 'HP:0012126', (243, 257))	('colon cancer', 'Disease', 'MESH:D015179', (229, 241))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('cancer', 'Phenotype', 'HP:0002664', (266, 272))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))	('observed', 'Reg', (217, 225))
227281	27835590	This data set contains 504 patients, within which 501 and 497 patients, respectively, had mRNA and mutations information.	('mRNA', 'MPA', (90, 94))	('patients', 'Species', '9606', (27, 35))	('mutations', 'Var', (99, 108))	('patients', 'Species', '9606', (62, 70))
227288	27685326	Association of MicroRNA-149 Polymorphism with Lung Cancer Risk in Chinese Non-Smoking Female: A Case-Control Study Rs2292832 is a single nucleotide polymorphism located in the precursor of mir-149 and was reported to be associated with varieties of malignancies.	('malignancies', 'Disease', (249, 261))	('associated', 'Reg', (220, 230))	('Lung Cancer', 'Disease', (46, 57))	('Rs2292832', 'Mutation', 'Rs2292832', (115, 124))	('Polymorphism', 'Var', (28, 40))	('mir-149', 'Gene', '406941', (189, 196))	('Rs2292832', 'Var', (115, 124))	('Lung Cancer', 'Phenotype', 'HP:0100526', (46, 57))	('Cancer', 'Phenotype', 'HP:0002664', (51, 57))	('Association', 'Interaction', (0, 11))	('MicroRNA-149', 'Gene', (15, 27))	('malignancies', 'Disease', 'MESH:D009369', (249, 261))	('mir-149', 'Gene', (189, 196))
227289	27685326	So far, the effect of miR-149 rs2292832 polymorphism on lung cancer risk was unclear.	('miR-149', 'Gene', (22, 29))	('miR-149', 'Gene', '406941', (22, 29))	('rs2292832', 'Var', (30, 39))	('lung cancer', 'Disease', 'MESH:D008175', (56, 67))	('rs2292832', 'Mutation', 'rs2292832', (30, 39))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('lung cancer', 'Disease', (56, 67))	('lung cancer', 'Phenotype', 'HP:0100526', (56, 67))
227291	27685326	The aim of the present study was to evaluate the associations of rs2292832 polymorphism, cooking oil fume exposure and multiplicative interaction of cooking oil fume exposure and rs2292832 polymorphism with lung cancer risk in Chinese non-smoking female population.	('associations', 'Interaction', (49, 61))	('lung cancer', 'Disease', 'MESH:D008175', (207, 218))	('rs2292832', 'Var', (179, 188))	('cooking oil', 'Chemical', '-', (149, 160))	('lung cancer', 'Phenotype', 'HP:0100526', (207, 218))	('oil fume', 'Chemical', '-', (157, 165))	('rs2292832', 'Gene', (65, 74))	('rs2292832', 'Mutation', 'rs2292832', (179, 188))	('cooking oil', 'Chemical', '-', (89, 100))	('rs2292832', 'Mutation', 'rs2292832', (65, 74))	('lung cancer', 'Disease', (207, 218))	('oil fume', 'Chemical', '-', (97, 105))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))
227294	27685326	Result of Logistic regression showed that the multiplicative interaction of cooking oil fume exposure and rs2292832 polymorphism was not statistically significant (P = 0.063 for lung cancer and P = 0.064 for lung adenocarcinoma).	('lung cancer', 'Disease', (178, 189))	('oil fume', 'Chemical', '-', (84, 92))	('rs2292832', 'Var', (106, 115))	('cooking oil', 'Chemical', '-', (76, 87))	('lung cancer', 'Phenotype', 'HP:0100526', (178, 189))	('carcinoma', 'Phenotype', 'HP:0030731', (218, 227))	('lung adenocarcinoma', 'Disease', (208, 227))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (208, 227))	('rs2292832', 'Mutation', 'rs2292832', (106, 115))	('lung cancer', 'Disease', 'MESH:D008175', (178, 189))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (208, 227))
227295	27685326	MicroRNA-149 rs2292832 polymorphism may not be associated with lung cancer risk in Chinese non-smoking female.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('lung cancer', 'Disease', 'MESH:D008175', (63, 74))	('MicroRNA-149', 'Gene', (0, 12))	('rs2292832', 'Var', (13, 22))	('lung cancer', 'Disease', (63, 74))	('lung cancer', 'Phenotype', 'HP:0100526', (63, 74))	('rs2292832', 'Mutation', 'rs2292832', (13, 22))
227301	27685326	In last decade, accumulating studies focusing on the genetic predisposition of lung cancer observed that SNPs or mutations in microRNAs were associated with lung cancer risk.	('microRNAs', 'Gene', (126, 135))	('lung cancer', 'Disease', 'MESH:D008175', (79, 90))	('lung cancer', 'Disease', (157, 168))	('lung cancer', 'Phenotype', 'HP:0100526', (157, 168))	('SNPs', 'Disease', (105, 109))	('lung cancer', 'Disease', (79, 90))	('lung cancer', 'Phenotype', 'HP:0100526', (79, 90))	('associated', 'Reg', (141, 151))	('mutations', 'Var', (113, 122))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('lung cancer', 'Disease', 'MESH:D008175', (157, 168))
227302	27685326	It was observed that microRNAs were involved in many biological processes including cell proliferation, differentiation, apoptosis and inflammation, the dysfunction of these processes are associated with the carcinogenesis.	('inflammation', 'Disease', 'MESH:D007249', (135, 147))	('associated', 'Reg', (188, 198))	('carcinogenesis', 'Disease', (208, 222))	('cell proliferation', 'CPA', (84, 102))	('differentiation', 'CPA', (104, 119))	('inflammation', 'Disease', (135, 147))	('dysfunction', 'Var', (153, 164))	('apoptosis', 'CPA', (121, 130))	('involved', 'Reg', (36, 44))	('carcinogenesis', 'Disease', 'MESH:D063646', (208, 222))
227304	27685326	Mutations such as single nucleotide polymorphism (SNP) located in microRNA sequence may affect the maturation of miRNAs or the affinity of miRNAs binding to the target mRNAs, thus may modify the regulation of miRNAs on transcription process and alter the expression level of target gene which may be cancer-related, then affect the susceptibility to cancer or the prognosis of the cancer patients.	('single nucleotide polymorphism', 'Var', (18, 48))	('cancer', 'Disease', (350, 356))	('patients', 'Species', '9606', (388, 396))	('cancer', 'Phenotype', 'HP:0002664', (350, 356))	('binding', 'Interaction', (146, 153))	('affinity', 'Interaction', (127, 135))	('Mutations', 'Var', (0, 9))	('affect', 'Reg', (321, 327))	('cancer', 'Disease', (381, 387))	('transcription process', 'MPA', (219, 240))	('cancer', 'Disease', (300, 306))	('alter', 'Reg', (245, 250))	('cancer', 'Phenotype', 'HP:0002664', (381, 387))	('affect', 'Reg', (88, 94))	('cancer', 'Phenotype', 'HP:0002664', (300, 306))	('cancer', 'Disease', 'MESH:D009369', (350, 356))	('maturation', 'MPA', (99, 109))	('modify', 'Reg', (184, 190))	('cancer', 'Disease', 'MESH:D009369', (381, 387))	('regulation', 'MPA', (195, 205))	('cancer', 'Disease', 'MESH:D009369', (300, 306))	('expression level', 'MPA', (255, 271))	('miRNAs', 'MPA', (209, 215))
227305	27685326	Emerging evidence demonstrated that rs2292832 C/T polymorphism in pre-miR-149 is associated with varieties of cancer risk.	('rs2292832 C/T polymorphism', 'Var', (36, 62))	('cancer', 'Disease', (110, 116))	('rs2292832', 'Mutation', 'rs2292832', (36, 45))	('miR-149', 'Gene', (70, 77))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('miR-149', 'Gene', '406941', (70, 77))	('associated', 'Reg', (81, 91))	('cancer', 'Disease', 'MESH:D009369', (110, 116))
227306	27685326	demonstrated that rs2292832 CC/CT genotype carriers have a lower risk of developing liver cancer compared with TT carriers in Korean population.	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('rs2292832 CC/CT', 'Var', (18, 33))	('liver cancer', 'Phenotype', 'HP:0002896', (84, 96))	('liver cancer', 'Disease', 'MESH:D006528', (84, 96))	('rs2292832', 'Mutation', 'rs2292832', (18, 27))	('liver cancer', 'Disease', (84, 96))
227307	27685326	In a population-based case-control study evaluating the associations between miRNA-SNPs and breast cancer risk in Chinese population found that CC genotype carriers of miR-149 rs2292832 have a 0.46-fold decreased risk for breast cancer than TT genotype carriers.	('breast cancer', 'Disease', 'MESH:D001943', (92, 105))	('breast cancer', 'Phenotype', 'HP:0003002', (92, 105))	('breast cancer', 'Disease', (222, 235))	('decreased', 'NegReg', (203, 212))	('breast cancer', 'Disease', (92, 105))	('breast cancer', 'Phenotype', 'HP:0003002', (222, 235))	('miR-149', 'Gene', (168, 175))	('miR-149', 'Gene', '406941', (168, 175))	('rs2292832', 'Var', (176, 185))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('breast cancer', 'Disease', 'MESH:D001943', (222, 235))	('rs2292832', 'Mutation', 'rs2292832', (176, 185))
227308	27685326	There were only two studies focusing on the effect of rs2292832 polymorphism on lung cancer susceptibility carried out in Asian population, but reported negative results.	('lung cancer', 'Disease', 'MESH:D008175', (80, 91))	('rs2292832', 'Mutation', 'rs2292832', (54, 63))	('lung cancer', 'Disease', (80, 91))	('lung cancer', 'Phenotype', 'HP:0100526', (80, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('rs2292832', 'Var', (54, 63))
227309	27685326	Herein, we conduct the present case-control study to investigate the relationship of rs2292832 polymorphism with lung cancer risk in Chinese non-smoking female.	('lung cancer', 'Disease', (113, 124))	('rs2292832', 'Var', (85, 94))	('lung cancer', 'Phenotype', 'HP:0100526', (113, 124))	('rs2292832', 'Mutation', 'rs2292832', (85, 94))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('lung cancer', 'Disease', 'MESH:D008175', (113, 124))
227315	27685326	The odds ratios (OR) and their 95% confidence intervals (CI) were calculated by unconditional logistic regression analysis to evaluate the association between rs2292832 polymorphism and lung cancer risk or pathological subtype of lung cancer risk.	('rs2292832 polymorphism', 'Var', (159, 181))	('rs2292832', 'Mutation', 'rs2292832', (159, 168))	('lung cancer', 'Disease', 'MESH:D008175', (186, 197))	('type of lung cancer', 'Disease', (222, 241))	('lung cancer', 'Phenotype', 'HP:0100526', (230, 241))	('association', 'Interaction', (139, 150))	('polymorphism', 'Var', (169, 181))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('lung cancer', 'Disease', (186, 197))	('type of lung cancer', 'Disease', 'MESH:D008175', (222, 241))	('lung cancer', 'Phenotype', 'HP:0100526', (186, 197))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))	('lung cancer', 'Disease', 'MESH:D008175', (230, 241))
227317	27685326	Multiplicative interaction of cooking oil fume exposure and rs2292832 polymorphism on risk of lung cancer was tested by logistic regression.	('lung cancer', 'Disease', 'MESH:D008175', (94, 105))	('rs2292832', 'Var', (60, 69))	('rs2292832', 'Mutation', 'rs2292832', (60, 69))	('lung cancer', 'Disease', (94, 105))	('lung cancer', 'Phenotype', 'HP:0100526', (94, 105))	('oil fume', 'Chemical', '-', (38, 46))	('cooking oil', 'Chemical', '-', (30, 41))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
227322	27685326	(OR = 1.848, 95%CI = 1.271-2.687, P<0.001) Results of genotype distributions in case and control group and the relationship of genotypes of rs2292832 with lung cancer risk are showed in Table 2.	('rs2292832', 'Var', (140, 149))	('lung cancer', 'Disease', (155, 166))	('rs2292832', 'Mutation', 'rs2292832', (140, 149))	('lung cancer', 'Phenotype', 'HP:0100526', (155, 166))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('lung cancer', 'Disease', 'MESH:D008175', (155, 166))
227323	27685326	There were no statistically significant associations between rs2292832 polymorphism and overall risk of lung cancer.	('rs2292832', 'Var', (61, 70))	('lung cancer', 'Disease', 'MESH:D008175', (104, 115))	('rs2292832', 'Mutation', 'rs2292832', (61, 70))	('lung cancer', 'Disease', (104, 115))	('lung cancer', 'Phenotype', 'HP:0100526', (104, 115))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))
227324	27685326	(TC vs. TT: OR = 1.006, 95%CI = 0.767-1.321, P = 0.963; CC vs. TT: OR = 0.841, 95%CI = 0.532-1.329, P = 0.458; Dominant model: OR = 0.965, 95%CI = 0.745-1.251, P = 0.788; Recessive model: OR = 0.816, 95%CI = 0.528-1.259, P = 0.357, adjusted for age) Subsequently, we performed subgroup analysis stratified by histopathology type of lung cancer to investigate whether polymorphisms of miR-149 rs2292832 relate with risk of non-small cell lung cancer, lung adenocarcinoma or squamous cell carcinoma group.	('lung adenocarcinoma', 'Disease', (450, 469))	('TC', 'Chemical', 'MESH:D013667', (1, 3))	('polymorphisms', 'Var', (367, 380))	('miR-149', 'Gene', '406941', (384, 391))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (422, 448))	('carcinoma', 'Phenotype', 'HP:0030731', (460, 469))	('squamous cell carcinoma', 'Disease', (473, 496))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (450, 469))	('type of lung cancer', 'Disease', 'MESH:D008175', (324, 343))	('non-small cell lung cancer', 'Disease', (422, 448))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (450, 469))	('lung cancer', 'Phenotype', 'HP:0100526', (437, 448))	('rs2292832', 'Mutation', 'rs2292832', (392, 401))	('rs2292832', 'Var', (392, 401))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (473, 496))	('cancer', 'Phenotype', 'HP:0002664', (442, 448))	('type of lung cancer', 'Disease', (324, 343))	('cancer', 'Phenotype', 'HP:0002664', (337, 343))	('miR-149', 'Gene', (384, 391))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (422, 448))	('lung cancer', 'Phenotype', 'HP:0100526', (332, 343))	('carcinoma', 'Phenotype', 'HP:0030731', (487, 496))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (473, 496))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (426, 448))
227327	27685326	Subsequently, we performed a logistic regression to estimate the multiplicative interaction of cooking oil fume exposure with rs2292832 polymorphism in lung cancer and lung adenocarcinoma subgroup, the results showed that the interaction of rs2292832 polymorphism and cooking oil fume exposure in lung cancer and lung adenocarcinoma were not statistically significant (P values were 0.063 in lung cancer and 0.064 in lung adenocarcinoma, respectively).	('cooking oil', 'Chemical', '-', (268, 279))	('lung cancer', 'Disease', 'MESH:D008175', (392, 403))	('lung adenocarcinoma', 'Disease', (417, 436))	('rs2292832', 'Mutation', 'rs2292832', (126, 135))	('lung cancer', 'Phenotype', 'HP:0100526', (392, 403))	('lung adenocarcinoma', 'Disease', (313, 332))	('cancer', 'Phenotype', 'HP:0002664', (302, 308))	('lung cancer', 'Disease', 'MESH:D008175', (152, 163))	('cancer', 'Phenotype', 'HP:0002664', (397, 403))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (417, 436))	('lung adenocarcinoma', 'Disease', (168, 187))	('lung cancer', 'Phenotype', 'HP:0100526', (152, 163))	('lung cancer', 'Disease', (297, 308))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (417, 436))	('carcinoma', 'Phenotype', 'HP:0030731', (323, 332))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (313, 332))	('carcinoma', 'Phenotype', 'HP:0030731', (427, 436))	('cooking oil', 'Chemical', '-', (95, 106))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (313, 332))	('lung cancer', 'Disease', (392, 403))	('rs2292832 polymorphism', 'Var', (241, 263))	('rs2292832', 'Mutation', 'rs2292832', (241, 250))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (168, 187))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('lung cancer', 'Disease', 'MESH:D008175', (297, 308))	('oil fume', 'Chemical', '-', (103, 111))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (168, 187))	('carcinoma', 'Phenotype', 'HP:0030731', (178, 187))	('lung cancer', 'Phenotype', 'HP:0100526', (297, 308))	('polymorphism', 'Var', (251, 263))	('lung cancer', 'Disease', (152, 163))	('oil fume', 'Chemical', '-', (276, 284))
227328	27685326	In the present study, we investigated the associations between miR-149 rs2292832 polymorphism and risk of lung cancer in Chinese non-smoking female population.	('associations', 'Interaction', (42, 54))	('rs2292832', 'Var', (71, 80))	('rs2292832', 'Mutation', 'rs2292832', (71, 80))	('lung cancer', 'Disease', (106, 117))	('lung cancer', 'Phenotype', 'HP:0100526', (106, 117))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('miR-149', 'Gene', (63, 70))	('lung cancer', 'Disease', 'MESH:D008175', (106, 117))	('miR-149', 'Gene', '406941', (63, 70))
227331	27685326	We investigated the relationship of miR-149 rs2292832 polymorphisms with overall lung cancer, but didn't get any statistically significant results.	('miR-149', 'Gene', (36, 43))	('lung cancer', 'Disease', (81, 92))	('miR-149', 'Gene', '406941', (36, 43))	('lung cancer', 'Phenotype', 'HP:0100526', (81, 92))	('rs2292832', 'Var', (44, 53))	('investigated', 'Reg', (3, 15))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('rs2292832', 'Mutation', 'rs2292832', (44, 53))	('lung cancer', 'Disease', 'MESH:D008175', (81, 92))
227332	27685326	Subsequently, in order to elucidate whether miR-149 rs2292832 polymorphisms relate with risk of non-small cell lung cancer, lung adenocarcinoma and squamous cell carcinoma, we carried out a stratified analysis, but didn't get any statistically significant results either.	('small cell lung cancer', 'Phenotype', 'HP:0030357', (100, 122))	('lung adenocarcinoma', 'Disease', (124, 143))	('miR-149', 'Gene', '406941', (44, 51))	('squamous cell carcinoma', 'Disease', (148, 171))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (96, 122))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (124, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (124, 143))	('rs2292832', 'Mutation', 'rs2292832', (52, 61))	('non-small cell lung cancer', 'Disease', (96, 122))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (148, 171))	('polymorphisms', 'Var', (62, 75))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('lung cancer', 'Phenotype', 'HP:0100526', (111, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (162, 171))	('miR-149', 'Gene', (44, 51))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (96, 122))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (148, 171))	('rs2292832 polymorphisms', 'Var', (52, 75))
227333	27685326	Tian et.al conducted a study to evaluate the relationship of rs2292832 polymorphisms with overall lung cancer risk in Chinese Han population and found no statistically significant associations.	('rs2292832', 'Var', (61, 70))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('lung cancer', 'Disease', (98, 109))	('lung cancer', 'Phenotype', 'HP:0100526', (98, 109))	('rs2292832', 'Mutation', 'rs2292832', (61, 70))	('lung cancer', 'Disease', 'MESH:D008175', (98, 109))
227334	27685326	Results of the study conducted in Caucasian population by Vinci S et.al also demonstrated that miR-149 rs2292832 polymorphism were not associated with non-small cell lung cancer risk.	('miR-149', 'Gene', (95, 102))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (151, 177))	('miR-149', 'Gene', '406941', (95, 102))	('rs2292832', 'Var', (103, 112))	('associated', 'Reg', (135, 145))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (151, 177))	('rs2292832', 'Mutation', 'rs2292832', (103, 112))	('lung cancer', 'Phenotype', 'HP:0100526', (166, 177))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('non-small cell lung cancer', 'Disease', (151, 177))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (155, 177))
227345	27685326	MiR-149 was downregulated in tumor tissue of non-small cell lung cancer compared with adjacent non-cancer lung tissue, ectopic expression of miR-149 can inhibit the process of epithelial-to-mesenchymal transition (EMT) in non-small cell lung cancer cells.	('non-small cell lung cancer', 'Disease', (45, 71))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('lung cancer', 'Phenotype', 'HP:0100526', (60, 71))	('non-cancer', 'Disease', (95, 105))	('MiR-149', 'Gene', (0, 7))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (222, 248))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('MiR-149', 'Gene', '406941', (0, 7))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (45, 71))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('miR-149', 'Gene', (141, 148))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (49, 71))	('epithelial-to-mesenchymal transition', 'CPA', (176, 212))	('lung cancer', 'Phenotype', 'HP:0100526', (237, 248))	('non-small cell lung cancer', 'Disease', (222, 248))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (45, 71))	('miR-149', 'Gene', '406941', (141, 148))	('inhibit', 'NegReg', (153, 160))	('non-cancer', 'Disease', 'MESH:D009369', (95, 105))	('ectopic expression', 'Var', (119, 137))	('tumor', 'Disease', (29, 34))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (226, 248))	('cancer', 'Phenotype', 'HP:0002664', (242, 248))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (222, 248))
227348	27685326	The results also showed TT genotype carriers of miR-149 rs2292832 had much more possibility of neck nodal metastasis and had a poorer prognosis compared with CT and CC carriers, which may be associated with the low expression of miR-149 in TT carriers.	('miR-149', 'Gene', (229, 236))	('miR-149', 'Gene', '406941', (229, 236))	('more', 'PosReg', (75, 79))	('neck nodal metastasis', 'CPA', (95, 116))	('miR-149', 'Gene', (48, 55))	('rs2292832', 'Var', (56, 65))	('miR-149', 'Gene', '406941', (48, 55))	('rs2292832', 'Mutation', 'rs2292832', (56, 65))
227349	27685326	It was reported that CC genotype carriers of miR-149 rs2292832 have lower miR-149-5p expression level than CT and TT genotype carriers in papillary thyroid cancer patients and CC genotype carriers were associated with increased risk of papillary thyroid cancer compared with TT genotype carriers and TT/TC combined genotype.	('miR-149', 'Gene', (74, 81))	('papillary thyroid cancer', 'Phenotype', 'HP:0002895', (236, 260))	('thyroid cancer', 'Phenotype', 'HP:0002890', (246, 260))	('papillary thyroid cancer', 'Phenotype', 'HP:0002895', (138, 162))	('cancer', 'Phenotype', 'HP:0002664', (254, 260))	('lower', 'NegReg', (68, 73))	('miR-149', 'Gene', '406941', (74, 81))	('papillary thyroid cancer', 'Disease', 'MESH:D000077273', (236, 260))	('rs2292832', 'Mutation', 'rs2292832', (53, 62))	('papillary thyroid cancer', 'Disease', 'MESH:D000077273', (138, 162))	('rs2292832', 'Var', (53, 62))	('patients', 'Species', '9606', (163, 171))	('thyroid cancer', 'Phenotype', 'HP:0002890', (148, 162))	('miR-149', 'Gene', (45, 52))	('papillary thyroid cancer', 'Disease', (236, 260))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('papillary thyroid cancer', 'Disease', (138, 162))	('miR-149', 'Gene', '406941', (45, 52))	('TC', 'Chemical', 'MESH:D013667', (303, 305))
227350	27685326	The exact effect of miR-149 rs2292832 on expression of miR-149 in lung malignancies need to be elucidated in further studies.	('lung malignancies', 'Phenotype', 'HP:0100526', (66, 83))	('miR-149', 'Gene', '406941', (55, 62))	('miR-149', 'Gene', (20, 27))	('rs2292832', 'Var', (28, 37))	('miR-149', 'Gene', (55, 62))	('miR-149', 'Gene', '406941', (20, 27))	('rs2292832', 'Mutation', 'rs2292832', (28, 37))	('lung malignancies', 'Disease', 'MESH:D009369', (66, 83))	('lung malignancies', 'Disease', (66, 83))
227355	27685326	Herein, we conducted logistic regression analysis to evaluate the multiplicative interaction of cooking oil fume exposure and miR-149 rs2292832 polymorphism on lung cancer risk in Chinese non-smoking female but we didn't achieve any statistically significant results.	('cooking oil', 'Chemical', '-', (96, 107))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('rs2292832', 'Var', (134, 143))	('miR-149', 'Gene', (126, 133))	('rs2292832', 'Mutation', 'rs2292832', (134, 143))	('lung cancer', 'Disease', 'MESH:D008175', (160, 171))	('miR-149', 'Gene', '406941', (126, 133))	('oil fume', 'Chemical', '-', (104, 112))	('lung cancer', 'Disease', (160, 171))	('lung cancer', 'Phenotype', 'HP:0100526', (160, 171))
227358	27685326	Thirdly, the sample size may be a barrier for achieving an enough statistical power to get a significant association, especially the samples size of substratum were too small in the subgroup analysis stratified and the result of the power calculation was 0.7802 for non-exposed of cooking oil fume and 0.5609 for exposed of cooking oil fume subgroup in Table 4.	('cooking oil', 'Chemical', '-', (324, 335))	('oil fume', 'Chemical', '-', (332, 340))	('0.7802', 'Var', (255, 261))	('0.5609', 'Var', (302, 308))	('oil fume', 'Chemical', '-', (289, 297))	('cooking oil', 'Chemical', '-', (281, 292))
227359	27685326	In conclusion, in the present study, we evaluate association between miR-149 rs2292832 polymorphism and susceptibility of lung cancer in Chinese non-smoking female, our result seems to demonstrate that rs2292832 polymorphism was not associated with lung cancer risk.	('cancer', 'Phenotype', 'HP:0002664', (254, 260))	('rs2292832', 'Mutation', 'rs2292832', (202, 211))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('rs2292832', 'Var', (77, 86))	('lung cancer', 'Disease', (122, 133))	('lung cancer', 'Phenotype', 'HP:0100526', (122, 133))	('lung cancer', 'Disease', 'MESH:D008175', (249, 260))	('rs2292832', 'Mutation', 'rs2292832', (77, 86))	('rs2292832', 'Var', (202, 211))	('miR-149', 'Gene', (69, 76))	('lung cancer', 'Disease', 'MESH:D008175', (122, 133))	('miR-149', 'Gene', '406941', (69, 76))	('lung cancer', 'Disease', (249, 260))	('lung cancer', 'Phenotype', 'HP:0100526', (249, 260))
227400	26179909	Summary statistics of the fitted robust linear model was used to identify problematic chips: datasets GSE9844, GSE30784, GSE3524, GSE42743, and GSE2280 contained hybridization artefacts.	('hybridization', 'MPA', (162, 175))	('GSE3524', 'Chemical', '-', (121, 128))	('GSE2280', 'Chemical', '-', (144, 151))	('GSE9844', 'Var', (102, 109))	('GSE30784', 'Var', (111, 119))	('GSE2280', 'Var', (144, 151))	('GSE3524', 'Var', (121, 128))	('GSE9844', 'Chemical', '-', (102, 109))	('contained', 'Reg', (152, 161))	('GSE42743', 'Var', (130, 138))
227421	26179909	To find relations of known associations between the identified hubs and cancers, we obtained a list of genes:for which mutations have been causally implicated in cancer:from the Catalogue of Somatic Mutations in Cancer (COSMIC) database.	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('cancers', 'Disease', 'MESH:D009369', (72, 79))	('cancer', 'Disease', (162, 168))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('hub', 'Gene', '1993', (63, 66))	('Cancer', 'Phenotype', 'HP:0002664', (212, 218))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('cancers', 'Disease', (72, 79))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('mutations', 'Var', (119, 128))	('hub', 'Gene', (63, 66))	('cancer', 'Disease', (72, 78))
227425	26179909	It is worth noting that somatic mutations in seven hub genes:EGFR, MET, MYO5A, PLAG1, PTPRK, SDC4, and HMGA2:have been implicated in cancer.	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('ME', 'Chemical', '-', (67, 69))	('PLAG1', 'Gene', '5324', (79, 84))	('HMGA2', 'Gene', '8091', (103, 108))	('mutations', 'Var', (32, 41))	('EGFR', 'Gene', '1956', (61, 65))	('MYO5A', 'Gene', (72, 77))	('cancer', 'Disease', (133, 139))	('implicated', 'Reg', (119, 129))	('PTPRK', 'Gene', '5796', (86, 91))	('MET', 'Gene', (67, 70))	('hub', 'Gene', (51, 54))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('PLAG1', 'Gene', (79, 84))	('SDC4', 'Gene', '6385', (93, 97))	('hub', 'Gene', '1993', (51, 54))	('SDC4', 'Gene', (93, 97))	('PTPRK', 'Gene', (86, 91))	('HMGA2', 'Gene', (103, 108))	('MYO5A', 'Gene', '4644', (72, 77))	('EGFR', 'Gene', (61, 65))
227431	26179909	The p53 protein regulates the cell cycle and functions as a tumor suppressor, and inhibition of p53's regulatory elements leads to dysregulation of various tumor-suppressing processes, including DNA repair, cell cycle arrest, senescence, and apoptosis.	('p53', 'Gene', (96, 99))	('apoptosis', 'CPA', (242, 251))	('dysregulation', 'MPA', (131, 144))	('p53', 'Gene', '7157', (4, 7))	('tumor', 'Disease', (60, 65))	('p53', 'Gene', '7157', (96, 99))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('inhibition', 'Var', (82, 92))	('DNA repair', 'CPA', (195, 205))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('cell cycle arrest', 'CPA', (207, 224))	('tumor', 'Disease', (156, 161))	('senescence', 'CPA', (226, 236))	('p53', 'Gene', (4, 7))	('cell cycle', 'CPA', (30, 40))
227438	26179909	Furthermore, it is known that dysfunctional integrin signaling is involved in the detachment of tumor cells from neighboring cells, ensuring enhanced survival and proliferative abilities.	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('survival', 'CPA', (150, 158))	('dysfunctional', 'Var', (30, 43))	('tumor', 'Disease', (96, 101))	('proliferative abilities', 'CPA', (163, 186))	('enhanced', 'PosReg', (141, 149))	('tumor', 'Disease', 'MESH:D009369', (96, 101))
227439	26179909	Altogether, our results indicated that the pink module may also be considered as an oncogenic one because it is enriched in well-known cancer-related pathways.	('pink module', 'Var', (43, 54))	('cancer', 'Disease', (135, 141))	('cancer', 'Disease', 'MESH:D009369', (135, 141))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))
227449	26179909	Furthermore, polymorphisms in the VDR gene are associated with prostate cancers; this finding supports the role of VDR in the risk of some type of cancers.	('cancers', 'Disease', (72, 79))	('cancers', 'Disease', 'MESH:D009369', (72, 79))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('VDR', 'Gene', (115, 118))	('VDR', 'Gene', '7421', (34, 37))	('prostate cancers', 'Disease', 'MESH:D011471', (63, 79))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('polymorphisms', 'Var', (13, 26))	('cancers', 'Disease', 'MESH:D009369', (147, 154))	('VDR', 'Gene', '7421', (115, 118))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('prostate cancers', 'Phenotype', 'HP:0012125', (63, 79))	('VDR', 'Gene', (34, 37))	('cancers', 'Disease', (147, 154))	('cancers', 'Phenotype', 'HP:0002664', (147, 154))	('associated', 'Reg', (47, 57))	('prostate cancers', 'Disease', (63, 79))
227455	26179909	Malignant oral keratinocytes express 5-50 times more EGFR than do their healthy counterparts; therefore, activation of EGFR enhances proliferation and the metastatic potential of keratinocytes.	('metastatic potential of keratinocytes', 'CPA', (155, 192))	('EGFR', 'Gene', (53, 57))	('EGFR', 'Gene', '1956', (119, 123))	('proliferation', 'CPA', (133, 146))	('EGFR', 'Gene', '1956', (53, 57))	('activation', 'Var', (105, 115))	('enhances', 'PosReg', (124, 132))	('EGFR', 'Gene', (119, 123))
227470	26179909	Alterations in gene expression correlate with a tumor histotype, grade, and stage.	('tumor', 'Disease', (48, 53))	('Alterations', 'Var', (0, 11))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('gene expression', 'MPA', (15, 30))
227486	26179909	Detailed and systematic literature search suggests that dysregulation of these hub genes is directly involved in OSCC and may play an important role in the development of other cancers.	('cancers', 'Disease', 'MESH:D009369', (177, 184))	('cancers', 'Phenotype', 'HP:0002664', (177, 184))	('cancers', 'Disease', (177, 184))	('OSCC', 'Disease', (113, 117))	('hub', 'Gene', '1993', (79, 82))	('dysregulation', 'Var', (56, 69))	('play', 'Reg', (126, 130))	('involved', 'Reg', (101, 109))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('hub', 'Gene', (79, 82))	('role', 'Reg', (144, 148))
227490	26179909	Some studies have also shown that high expression of CBX3 is associated with other tumors.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumors', 'Disease', (83, 89))	('CBX3', 'Gene', (53, 57))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('high', 'Var', (34, 38))	('tumors', 'Disease', 'MESH:D009369', (83, 89))	('associated', 'Reg', (61, 71))	('CBX3', 'Gene', '11335', (53, 57))
227494	26179909	Furthermore, dysregulation of EGFR is among the most frequently studied molecular events that leads to oral carcinogenesis, and OSCCs show upregulation of EGFR by 42 % to 58 %.	('oral carcinogenesis', 'Disease', (103, 122))	('EGFR', 'Gene', (30, 34))	('EGFR', 'Gene', '1956', (155, 159))	('upregulation', 'PosReg', (139, 151))	('dysregulation', 'Var', (13, 26))	('EGFR', 'Gene', (155, 159))	('leads', 'Reg', (94, 99))	('EGFR', 'Gene', '1956', (30, 34))	('oral carcinogenesis', 'Disease', 'MESH:D063646', (103, 122))
227501	26179909	Furthermore, some reports have suggested that inhibition of GLS slows down the growth of glioblastoma cells and therefore may be therapeutic strategy against such cancers.	('cancers', 'Phenotype', 'HP:0002664', (163, 170))	('cancers', 'Disease', (163, 170))	('inhibition', 'Var', (46, 56))	('glioblastoma', 'Disease', (89, 101))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('glioblastoma', 'Disease', 'MESH:D005909', (89, 101))	('glioblastoma', 'Phenotype', 'HP:0012174', (89, 101))	('slows down', 'NegReg', (64, 74))	('GLS', 'Protein', (60, 63))	('cancers', 'Disease', 'MESH:D009369', (163, 170))
227503	26179909	Altered expression of this gene is also associated with other cancers including urinary bladder cancer, metastatic breast cancer, and gastric cancer.	('gastric cancer', 'Disease', (134, 148))	('bladder cancer', 'Phenotype', 'HP:0009725', (88, 102))	('associated', 'Reg', (40, 50))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('Altered', 'Var', (0, 7))	('gastric cancer', 'Disease', 'MESH:D013274', (134, 148))	('expression', 'MPA', (8, 18))	('cancers', 'Phenotype', 'HP:0002664', (62, 69))	('cancers', 'Disease', (62, 69))	('breast cancer', 'Phenotype', 'HP:0003002', (115, 128))	('urinary bladder cancer', 'Disease', (80, 102))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('breast cancer', 'Disease', 'MESH:D001943', (115, 128))	('gastric cancer', 'Phenotype', 'HP:0012126', (134, 148))	('breast cancer', 'Disease', (115, 128))	('urinary bladder cancer', 'Disease', 'MESH:D001749', (80, 102))	('cancers', 'Disease', 'MESH:D009369', (62, 69))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))
227543	32549297	Similarly, throughout the influenza A virus subtype H1N1 (H1N1) epidemic in 2009, mortality for cancer subjects hospitalized with H1N1 was up to 18.5% higher.	('mortality', 'Disease', 'MESH:D003643', (82, 91))	('H1N1', 'Var', (130, 134))	('H1N1', 'Species', '114727', (130, 134))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('mortality', 'Disease', (82, 91))	('higher', 'PosReg', (151, 157))	('H1N1', 'Species', '114727', (52, 56))	('H1N1', 'Species', '114727', (58, 62))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('influenza A virus', 'Species', '11320', (26, 43))	('cancer', 'Disease', (96, 102))
227637	32549297	It has been reported that patients with augmented concentrations of IL-17 were less likely to survive and had increased angiogenesis with respect to healthy controls.	('increased', 'PosReg', (110, 119))	('concentrations', 'Var', (50, 64))	('patients', 'Species', '9606', (26, 34))	('angiogenesis', 'CPA', (120, 132))	('IL-17', 'Gene', (68, 73))	('less', 'NegReg', (79, 83))
227668	32549297	Other studies will try to evaluate the effects of drugs, such as the myeloma drug thalidomide (NCT04273581), the programmed death-1 (PD-1) inhibitor camrelizumab (NCT04268537), and other anti-TNF tNFkumor drugs in the therapy of SARS-CoV-2 infection.	('TNF', 'Gene', '7124', (192, 195))	('PD-1', 'Gene', '5133', (133, 137))	('TNF', 'Gene', (192, 195))	('NCT04273581', 'Var', (95, 106))	('thalidomide', 'Chemical', 'MESH:D013792', (82, 93))	('myeloma', 'Disease', 'MESH:D009101', (69, 76))	('SARS-CoV-2 infection', 'Disease', 'MESH:C000657245', (229, 249))	('death', 'Disease', 'MESH:D003643', (124, 129))	('death', 'Disease', (124, 129))	('SARS-CoV-2 infection', 'Disease', (229, 249))	('NCT04268537', 'Var', (163, 174))	('myeloma', 'Disease', (69, 76))	('PD-1', 'Gene', (133, 137))
227679	32549297	PD-1 blockade is anticipated to reduce the development of sepsis secondary to severe pneumonia and excessive inflammatory response syndrome in COVID-19 patients, by reversing sepsis-associated T cell depletion.	('sepsis', 'Phenotype', 'HP:0100806', (175, 181))	('reduce', 'NegReg', (32, 38))	('blockade', 'Var', (5, 13))	('sepsis', 'Disease', (58, 64))	('sepsis', 'Disease', 'MESH:D018805', (175, 181))	('pneumonia', 'Disease', (85, 94))	('sepsis', 'Disease', (175, 181))	('PD-1', 'Gene', (0, 4))	('PD-1', 'Gene', '5133', (0, 4))	('COVID-19', 'Disease', 'MESH:C000657245', (143, 151))	('COVID-19', 'Disease', (143, 151))	('patients', 'Species', '9606', (152, 160))	('excessive inflammatory response syndrome', 'Phenotype', 'HP:0012647', (99, 139))	('reversing', 'NegReg', (165, 174))	('sepsis', 'Phenotype', 'HP:0100806', (58, 64))	('excessive inflammatory response', 'Phenotype', 'HP:0012649', (99, 130))	('sepsis', 'Disease', 'MESH:D018805', (58, 64))	('pneumonia', 'Phenotype', 'HP:0002090', (85, 94))	('pneumonia', 'Disease', 'MESH:D011014', (85, 94))
227692	32549297	In a transgenic animal model, stimulation of HCK caused serious pulmonary inflammation and an increase of the innate immune response, especially in older animals.	('HCK', 'Gene', (45, 48))	('increase', 'PosReg', (94, 102))	('pulmonary inflammation', 'Disease', (64, 86))	('innate immune response', 'CPA', (110, 132))	('transgenic', 'Species', '10090', (5, 15))	('stimulation', 'Var', (30, 41))	('pulmonary inflammation', 'Disease', 'MESH:D011014', (64, 86))
227765	32194665	Brim et al determined that ADAM29 is associated with colorectal tumors, and it has also been revealed that the ADAM29 mutation affects the adhesion of melanoma cells to specific extracellular matrix proteins and promotes tumor invasion.	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('promotes', 'PosReg', (212, 220))	('ADAM29', 'Gene', (27, 33))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('melanoma', 'Phenotype', 'HP:0002861', (151, 159))	('melanoma', 'Disease', (151, 159))	('colorectal tumors', 'Disease', (53, 70))	('adhesion', 'MPA', (139, 147))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('ADAM29', 'Gene', '11086', (27, 33))	('ADAM29', 'Gene', (111, 117))	('associated', 'Reg', (37, 47))	('ADAM29', 'Gene', '11086', (111, 117))	('specific extracellular matrix proteins', 'Protein', (169, 207))	('tumor', 'Disease', (221, 226))	('colorectal tumors', 'Disease', 'MESH:D015179', (53, 70))	('mutation', 'Var', (118, 126))	('melanoma', 'Disease', 'MESH:D008545', (151, 159))	('tumor', 'Disease', 'MESH:D009369', (221, 226))	('tumor', 'Disease', (64, 69))	('affects', 'Reg', (127, 134))	('tumor', 'Disease', 'MESH:D009369', (64, 69))
227807	32194665	Furthermore, high ADAM29 expression was significantly associated with the pathological stage (P=0.024) and clinical stage (P=0.016).	('high', 'Var', (13, 17))	('ADAM29', 'Gene', '11086', (18, 24))	('expression', 'MPA', (25, 35))	('clinical stage', 'CPA', (107, 121))	('ADAM29', 'Gene', (18, 24))	('pathological stage', 'CPA', (74, 92))	('associated', 'Reg', (54, 64))
227812	32194665	Furthermore, high FAM135B expression was significantly associated with the pathological stage (P=0.006) and clinical stage (P=0.015).	('expression', 'MPA', (26, 36))	('high', 'Var', (13, 17))	('associated', 'Reg', (55, 65))	('pathological stage', 'CPA', (75, 93))	('clinical stage', 'CPA', (108, 122))	('FAM135B', 'Gene', (18, 25))	('FAM135B', 'Gene', '51059', (18, 25))
227814	32194665	High FAM135B expression occurred in zero cases (0%) in clinical stage I, five cases (22.7%) in clinical stage II: six cases (60%) in clinical stage III.	('expression', 'MPA', (13, 23))	('FAM135B', 'Gene', '51059', (5, 12))	('High', 'Var', (0, 4))	('FAM135B', 'Gene', (5, 12))
227823	32194665	Mutations of the ADAM29 gene predominantly occur in somatic cells, in the prolysin and propeptide domains, and are associated with increased collagen adhesion of types I and IV compared with wild-type ADAM29.	('increased', 'PosReg', (131, 140))	('collagen adhesion', 'CPA', (141, 158))	('propeptide', 'Chemical', '-', (87, 97))	('ADAM29', 'Gene', '11086', (201, 207))	('Mutations', 'Var', (0, 9))	('ADAM29', 'Gene', (201, 207))	('ADAM29', 'Gene', '11086', (17, 23))	('ADAM29', 'Gene', (17, 23))
227844	32194665	Furthermore, high FAM135B expression may be associated with endogenous phosphoglyceraldehyde dehydrogenase.	('associated', 'Reg', (44, 54))	('expression', 'MPA', (26, 36))	('high', 'Var', (13, 17))	('FAM135B', 'Gene', (18, 25))	('endogenous phosphoglyceraldehyde dehydrogenase', 'MPA', (60, 106))	('FAM135B', 'Gene', '51059', (18, 25))
227868	29867084	PTK7 overexpression increased the proliferation of TE-5 and TE-14 cells but decreased the proliferation of TE-6 and TE-10 cells.	('proliferation', 'CPA', (34, 47))	('increased', 'PosReg', (20, 29))	('TE-10', 'CellLine', 'CVCL:1760', (116, 121))	('PTK7', 'Gene', (0, 4))	('proliferation', 'CPA', (90, 103))	('expression', 'Species', '29278', (9, 19))	('decreased', 'NegReg', (76, 85))	('overexpression', 'Var', (5, 19))
227881	29867084	For example, PTK7 increases the proliferation, survival, migration, and invasion of cells and wound healing by activating ERK, JNK, p38, and NF-kappaB signaling pathways, whereas it decreases apoptosis by suppressing the activation of caspase-9 and -10.	('decreases', 'NegReg', (182, 191))	('increases', 'PosReg', (18, 27))	('JNK', 'Pathway', (127, 130))	('p38', 'Gene', (132, 135))	('survival', 'CPA', (47, 55))	('migration', 'CPA', (57, 66))	('activating', 'PosReg', (111, 121))	('apoptosis', 'CPA', (192, 201))	('NF-kappaB', 'Gene', '4790', (141, 150))	('p38', 'Gene', '5594', (132, 135))	('caspase-9 and -10', 'Gene', '842;843', (235, 252))	('proliferation', 'CPA', (32, 45))	('ERK', 'Gene', '5594', (122, 125))	('PTK7', 'Var', (13, 17))	('suppressing', 'NegReg', (205, 216))	('ERK', 'Gene', (122, 125))	('NF-kappaB', 'Gene', (141, 150))
227895	29867084	Ectopic expression of PTK7 increased the proliferation of TE-5 and TE-14 cells (i.e., PTK7-low ESCC cells) (Fig.	('PTK7', 'Gene', (22, 26))	('increased', 'PosReg', (27, 36))	('Ectopic expression', 'Var', (0, 18))	('expression', 'Species', '29278', (8, 18))	('low ESCC', 'Phenotype', 'HP:0025022', (91, 99))	('proliferation', 'CPA', (41, 54))
227896	29867084	2b), whereas the proliferation of the PTK7-high TE-6 and TE-10 cells decreased with ectopic expression (Fig.	('proliferation', 'CPA', (17, 30))	('ectopic expression', 'Var', (84, 102))	('decreased', 'NegReg', (69, 78))	('expression', 'Species', '29278', (92, 102))	('TE-10', 'CellLine', 'CVCL:1760', (57, 62))
227897	29867084	This result was unexpected, as previous evidence showing PTK7 knockdown decreased the proliferation of TE-10 and TE-11 cells indicated that PTK7 is an oncogene in ESCC.	('ESCC', 'Disease', (163, 167))	('decreased', 'NegReg', (72, 81))	('proliferation', 'CPA', (86, 99))	('TE-10', 'CellLine', 'CVCL:1760', (103, 108))	('PTK7', 'Gene', (57, 61))	('knockdown', 'Var', (62, 71))
227902	29867084	The maximal oncogenic effects were found in PTK7-low TE-5 and TE-14 cells transfected with 2 mug or PTK7-high TE-10 and TE-6 cells transfected with 1 mug of the PTK7 expression vector.	('PTK7-high', 'Var', (100, 109))	('oncogenic effects', 'CPA', (12, 29))	('expression', 'Species', '29278', (166, 176))	('TE-10', 'CellLine', 'CVCL:1760', (110, 115))	('PTK7-low', 'Var', (44, 52))
227912	29867084	However, a Kaplan-Meier survival plot showed that ESCC patients in the PTK7-high group had a significantly longer overall survival than those in the PTK7-low group (P = 0.011) (Fig.	('overall survival', 'MPA', (114, 130))	('PTK7-high', 'Var', (71, 80))	('longer', 'PosReg', (107, 113))	('patients', 'Species', '9606', (55, 63))	('ESCC', 'Disease', (50, 54))
227918	29867084	PTK7 knockdown decreased proliferation, survival, wound healing and invasion by inhibiting ERK, JNK, p38, Akt and FAK activation in ESCC TE-10 and TE-11 cells.	('proliferation', 'CPA', (25, 38))	('PTK7', 'Gene', (0, 4))	('p38', 'Gene', (101, 104))	('knockdown', 'Var', (5, 14))	('invasion', 'CPA', (68, 76))	('ERK', 'Gene', (91, 94))	('FAK', 'Gene', (114, 117))	('TE-10', 'CellLine', 'CVCL:1760', (137, 142))	('decreased', 'NegReg', (15, 24))	('FAK', 'Gene', '5747', (114, 117))	('p38', 'Gene', '5594', (101, 104))	('JNK', 'Pathway', (96, 99))	('wound healing', 'CPA', (50, 63))	('inhibiting', 'NegReg', (80, 90))	('Akt', 'Gene', (106, 109))	('activation', 'PosReg', (118, 128))	('ERK', 'Gene', '5594', (91, 94))	('Akt', 'Gene', '207', (106, 109))	('survival', 'CPA', (40, 48))
227920	29867084	Consistently, we found here that overexpression of PTK7 increased proliferation in PTK7-low ESCC TE-5 and TE-14 cells and that PTK7 knockdown decreased it in PTK7-high ESCC TE-6 and TE-10 cells.	('overexpression', 'PosReg', (33, 47))	('low ESCC', 'Phenotype', 'HP:0025022', (88, 96))	('knockdown', 'Var', (132, 141))	('increased', 'PosReg', (56, 65))	('PTK7', 'Gene', (51, 55))	('high ESCC', 'Phenotype', 'HP:0003565', (163, 172))	('proliferation', 'CPA', (66, 79))	('decreased', 'NegReg', (142, 151))	('TE-10', 'CellLine', 'CVCL:1760', (182, 187))	('expression', 'Species', '29278', (37, 47))	('PTK7', 'Gene', (127, 131))
227929	29867084	It appears that when levels of PTK7 are lower than that of KDR, PTK7 helps KDR molecules to oligomerize and activate, whereas high amounts of PTK7 inhibit this.	('KDR', 'Gene', (59, 62))	('KDR', 'Gene', '3791', (75, 78))	('oligomerize', 'MPA', (92, 103))	('activate', 'PosReg', (108, 116))	('PTK7', 'Var', (64, 68))	('KDR', 'Gene', (75, 78))	('KDR', 'Gene', '3791', (59, 62))
227933	29867084	1a and c), and PTK7 overexpression was also shown to decrease oncogenic effects in lung squamous cell carcinoma cells.	('expression', 'Species', '29278', (24, 34))	('overexpression', 'Var', (20, 34))	('decrease', 'NegReg', (53, 61))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (83, 111))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (88, 111))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (83, 111))	('lung squamous cell carcinoma', 'Disease', (83, 111))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('PTK7', 'Gene', (15, 19))	('oncogenic effects', 'CPA', (62, 79))
227934	29867084	Thus, in some cancer types with comparable, or even higher, PTK7 expression, the suppressive effect of PTK7 on oncogenic characteristics may be apparent.	('suppressive effect', 'NegReg', (81, 99))	('oncogenic characteristics', 'CPA', (111, 136))	('cancer', 'Disease', (14, 20))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('expression', 'Species', '29278', (65, 75))	('cancer', 'Disease', 'MESH:D009369', (14, 20))	('expression', 'Var', (65, 75))	('PTK7', 'Gene', (60, 64))
227936	29867084	However, caution should be used with this strategy when considering the evidence showing PTK7 can biphasically regulate tumorigenesis, as the inhibition of PTK7 activity or removal of PTK7-positive cells may induce tumor progression.	('tumor', 'Disease', 'MESH:D009369', (215, 220))	('tumor', 'Disease', (120, 125))	('induce', 'Reg', (208, 214))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('PTK7', 'Gene', (156, 160))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('tumor', 'Disease', (215, 220))	('inhibition', 'Var', (142, 152))	('activity', 'MPA', (161, 169))
227944	29867084	Antibodies against phospho-Src (Tyr416), Src, phospho-Akt (Ser473), and Akt were purchased from Cell Signaling Technology (Danvers, MA, USA).	('Ser473', 'Chemical', '-', (59, 65))	('Akt', 'Gene', (72, 75))	('Akt', 'Gene', '207', (54, 57))	('Src', 'Gene', (27, 30))	('Src', 'Gene', (41, 44))	('Src', 'Gene', '6714', (27, 30))	('Src', 'Gene', '6714', (41, 44))	('Akt', 'Gene', (54, 57))	('Tyr416', 'Chemical', '-', (32, 38))	('Tyr416', 'Var', (32, 38))	('Akt', 'Gene', '207', (72, 75))
227956	26813288	Epigenomic analysis detects aberrant super-enhancer DNA methylation in human cancer One of the hallmarks of cancer is the disruption of gene expression patterns.	('human', 'Species', '9606', (71, 76))	('super-enhancer DNA', 'MPA', (37, 55))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('aberrant', 'Var', (28, 36))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
227957	26813288	Using whole genome bisulfite sequencing to examine uncharted regions of the epigenome, we identify a type of far-reaching DNA methylation alteration in cancer cells of the distal regulatory sequences described as super-enhancers.	('bisulfite', 'Chemical', 'MESH:C042345', (19, 28))	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('alteration', 'Var', (138, 148))	('methylation alteration', 'Var', (126, 148))
227961	26813288	CpG methylation status in normal cells points to locally active regulatory sites at super-enhancers, which are targeted by specific aberrant DNA methylation events in cancer, with putative effects on the expression of downstream genes.	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('effects', 'Reg', (189, 196))	('cancer', 'Disease', (167, 173))	('aberrant', 'Var', (132, 140))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))
227963	26813288	Most importantly, disease-associated variation is especially enriched in the super-enhancers of the corresponding cell types, and new super-enhancers for oncogenes and other transforming genes have been identified in cancer cells.	('variation', 'Var', (37, 46))	('disease-associated', 'Reg', (18, 36))	('cancer', 'Disease', (217, 223))	('cancer', 'Disease', 'MESH:D009369', (217, 223))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))
227964	26813288	Herein, we present human DNA methylomes at single-nucleotide resolution of normal and cancer cells to identify epigenetic shifts in super-enhancers associated with these diseases.	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('associated', 'Reg', (148, 158))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('human', 'Species', '9606', (19, 24))	('epigenetic shifts', 'Var', (111, 128))	('cancer', 'Disease', (86, 92))
227992	26813288	We first used a breast cancer model that included the paired breast cancer cell lines MDA-MB-468PT (derived from the primary tumor) and MDA-MB-468LN (derived from a lymph node metastasis) and the untransformed immortalized breast epithelial cell line MCF10A, associating differential gene expression (RNA sequencing, RNA-seq) with super-enhancer DNA methylation levels.	('MDA-MB-468PT', 'Var', (86, 98))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('breast cancer', 'Disease', (16, 29))	('breast cancer', 'Disease', (61, 74))	('MDA-MB-468LN', 'Var', (136, 148))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('breast cancer', 'Phenotype', 'HP:0003002', (61, 74))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('MDA-MB-468PT', 'CellLine', 'CVCL:0419', (86, 98))	('MDA-MB-468LN', 'CellLine', 'CVCL:M372', (136, 148))	('tumor', 'Disease', (125, 130))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('MCF10A', 'CellLine', 'CVCL:0598', (251, 257))	('breast cancer', 'Disease', 'MESH:D001943', (16, 29))	('breast cancer', 'Disease', 'MESH:D001943', (61, 74))	('breast cancer', 'Phenotype', 'HP:0003002', (16, 29))
227995	26813288	We confirmed the significant association between the DNA methylation gains of super-enhancers identified in our breast cancer cell line data set and gene repression observed in the matched TCGA breast cancer samples (Spearman's correlation test, rho -0.24, p = 0.01; Fig.	('breast cancer', 'Disease', 'MESH:D001943', (112, 125))	('methylation', 'Var', (57, 68))	('breast cancer', 'Disease', (194, 207))	('gene repression', 'MPA', (149, 164))	('breast cancer', 'Phenotype', 'HP:0003002', (112, 125))	('breast cancer', 'Disease', (112, 125))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('breast cancer', 'Disease', 'MESH:D001943', (194, 207))	('gains', 'PosReg', (69, 74))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('breast cancer', 'Phenotype', 'HP:0003002', (194, 207))
227996	26813288	Interestingly, the super-enhancers that became hypermethylated in breast cancer were those that, in normal breast epithelial cells, were the most enriched in the H3K27ac histone mark (Spearman's correlation test, rho 0.2, p < 0.001; Fig.	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('H3K27ac', 'Var', (162, 169))	('breast cancer', 'Disease', 'MESH:D001943', (66, 79))	('breast cancer', 'Disease', (66, 79))	('breast cancer', 'Phenotype', 'HP:0003002', (66, 79))
227997	26813288	We were able to validate the link between cancer-specific super-enhancer hypermethylation and the transcriptional inactivation of the corresponding genes beyond the breast tumor type.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('breast tumor', 'Disease', (165, 177))	('breast tumor', 'Disease', 'MESH:D001943', (165, 177))	('hypermethylation', 'Var', (73, 89))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('breast tumor', 'Phenotype', 'HP:0100013', (165, 177))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('transcriptional', 'MPA', (98, 113))	('super-enhancer', 'PosReg', (58, 72))
227998	26813288	In the lung tumorigenesis samples from the H1437 (lung adenocarcinoma) and H157 (lung squamous cell carcinoma) cancer cell lines, we found evidence that lung super-enhancer gain of DNA methylation was associated with the downregulation of the target genes (linear slope -3.06, p < 0.001 and -2.09, p = 0.004, respectively; Figure S10a, b in Additional file 1) determined by publically available expression microarrays.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (86, 109))	('tumor', 'Disease', (12, 17))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('H157 (lung squamous cell carcinoma) cancer', 'Disease', 'MESH:D002294', (75, 117))	('DNA', 'Gene', (181, 184))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (50, 69))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('downregulation', 'MPA', (221, 235))	('lung adenocarcinoma', 'Disease', (50, 69))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (50, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (60, 69))	('methylation', 'Var', (185, 196))	('gain', 'PosReg', (173, 177))
228000	26813288	In this setting, we observed a significant association between lung super-enhancer hypermethylation identified in our lung cancer cell lines and gene downregulation found in the matched primary lung cancer samples (Spearman's correlation test, rho -0.19, p = 0.012 and rho -0.25, p < 0.001, respectively; Figure S10c, d in Additional file 1).	('lung cancer', 'Phenotype', 'HP:0100526', (194, 205))	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('hypermethylation', 'Var', (83, 99))	('lung cancer', 'Disease', 'MESH:D008175', (118, 129))	('downregulation', 'NegReg', (150, 164))	('lung super-enhancer', 'Gene', (63, 82))	('lung cancer', 'Disease', 'MESH:D008175', (194, 205))	('lung cancer', 'Disease', (118, 129))	('lung cancer', 'Phenotype', 'HP:0100526', (118, 129))	('lung cancer', 'Disease', (194, 205))
228001	26813288	The significant association between cancer-specific DNA methylation of super-enhancers and gene repression was also noted in the glioblastoma cell line U87MG (Spearman correlation test, rho -0.26, p < 0.001; Figure S10e in Additional file 1), in which we performed an expression microarray experiment.	('glioblastoma', 'Disease', (129, 141))	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('glioblastoma', 'Disease', 'MESH:D005909', (129, 141))	('cancer', 'Disease', (36, 42))	('glioblastoma', 'Phenotype', 'HP:0012174', (129, 141))	('gene repression', 'MPA', (91, 106))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('methylation', 'Var', (56, 67))	('U87MG', 'CellLine', 'CVCL:0022', (152, 157))
228002	26813288	Thus, the results overall suggest that a tumor-related gain of DNA methylation in super-enhancers has a transcriptionally repressive effect on the corresponding related genes.	('super-enhancers', 'Gene', (82, 97))	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Disease', (41, 46))	('gain', 'PosReg', (55, 59))	('transcriptionally repressive', 'MPA', (104, 132))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('DNA methylation', 'Var', (63, 78))
228003	26813288	We next considered the commonality among different tumor types within super-enhancer DNA methylation changes, and the type of genes and pathways affected by these aberrant epigenetic shifts.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor', 'Disease', (51, 56))	('methylation changes', 'Var', (89, 108))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
228006	26813288	Interestingly, despite the clear presence of super-enhancer DNA methylation that is associated with the cancer type, there are hypermethylated super-enhancers shared by common epithelial tumors such as the breast and lung samples (Figure S11a in Additional file 1).	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('breast', 'Disease', (206, 212))	('lung', 'Disease', (217, 221))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('hypermethylated', 'Var', (127, 142))	('tumors', 'Phenotype', 'HP:0002664', (187, 193))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('epithelial tumors', 'Disease', (176, 193))	('epithelial tumors', 'Disease', 'MESH:D002277', (176, 193))
228009	26813288	Consistent with the suspected regulatory function, hypermethylation of the MIRLET7-associated super-enhancer region was associated with transcriptional silencing of MIRLET7B and MIRLET7A3, two family members coded within the affected pri-microRNA (Figure S11d in Additional file 1).	('silencing', 'NegReg', (152, 161))	('associated', 'Reg', (120, 130))	('MIRLET7A3', 'Gene', (178, 187))	('hypermethylation', 'Var', (51, 67))	('MIRLET7A3', 'Gene', '406883', (178, 187))	('MIRLET7B', 'Gene', (165, 173))	('MIRLET7B', 'Gene', '406884', (165, 173))	('transcriptional', 'MPA', (136, 151))	('MIRLET7-associated', 'Gene', (75, 93))
228010	26813288	Moreover, microRNAs MIRLET7B and MIRLET7A3 were repressed in primary breast carcinomas (TCGA; Wilcoxon test, p = 0.001 and p = 0.033, respectively) and lung adenocarcinomas (TCGA; Wilcoxon test, p < 0.001 and p < 0.001, respectively) (Figure S11e, f in Additional file 1) and hypermethylation at super-enhancers was significantly correlated with microRNA repression in breast carcinomas (Spearman correlation test, rho -0.4 and -0.42, p < 0.001 and p < 0.001, respectively) and lung adenocarcinomas (Spearman correlation test, rho -0.47 and - 0.3, p < 0.001 and p < 0.001, respectively) (Fig.	('correlated', 'Reg', (330, 340))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (478, 498))	('microRNA', 'Var', (346, 354))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (152, 172))	('carcinomas', 'Phenotype', 'HP:0030731', (376, 386))	('MIRLET7A3', 'Gene', (33, 42))	('lung adenocarcinomas', 'Disease', (478, 498))	('lung adenocarcinomas', 'Disease', (152, 172))	('breast carcinomas', 'Phenotype', 'HP:0003002', (369, 386))	('MIRLET7A3', 'Gene', '406883', (33, 42))	('breast carcinomas', 'Disease', 'MESH:D001943', (69, 86))	('breast carcinomas', 'Disease', (69, 86))	('MIRLET7B', 'Gene', '406884', (20, 28))	('carcinoma', 'Phenotype', 'HP:0030731', (162, 171))	('carcinoma', 'Phenotype', 'HP:0030731', (488, 497))	('carcinomas', 'Phenotype', 'HP:0030731', (488, 498))	('carcinoma', 'Phenotype', 'HP:0030731', (376, 385))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (478, 498))	('carcinomas', 'Phenotype', 'HP:0030731', (76, 86))	('carcinomas', 'Phenotype', 'HP:0030731', (162, 172))	('MIRLET7B', 'Gene', (20, 28))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (152, 172))	('breast carcinomas', 'Phenotype', 'HP:0003002', (69, 86))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (478, 497))	('breast carcinomas', 'Disease', 'MESH:D001943', (369, 386))	('breast carcinomas', 'Disease', (369, 386))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (152, 171))
228019	26813288	Importantly, DNA methylation changes affected solely regions specifically marked by H3K27ac in colon cancer and widely excluded H3K4me3, further indicating that alterations in super-enhancers occur predominantly distal to the core promoter regions (Fig.	('colon cancer', 'Phenotype', 'HP:0003003', (95, 107))	('colon cancer', 'Disease', 'MESH:D015179', (95, 107))	('changes affected', 'Reg', (29, 45))	('colon cancer', 'Disease', (95, 107))	('H3K27ac', 'Var', (84, 91))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))
228025	26813288	Interestingly, the presence of cancer-specific super-enhancer hypomethylation and the tumorigenic effect mediated by the presence of FOXQ1 binding sites could be useful for identifying new candidate oncogenes, such as GPRC5A (G protein-coupled receptor, class C, group 5, member A; Figures.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('hypomethylation', 'Var', (62, 77))	('presence', 'Var', (121, 129))	('GPRC5A', 'Gene', '9052', (218, 224))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('tumor', 'Disease', (86, 91))	('FOXQ1', 'Gene', (133, 138))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('FOXQ1', 'Gene', '94234', (133, 138))	('cancer', 'Disease', (31, 37))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('GPRC5A', 'Gene', (218, 224))
228026	26813288	S13c, d, S15c and S16c in Additional file 1), which, by mediating between retinoid acid and G protein signaling pathways, has a role in epithelial cell differentiation.	('retinoid acid', 'Chemical', '-', (74, 87))	('S16c', 'Var', (18, 22))	('epithelial cell differentiation', 'CPA', (136, 167))
228029	26813288	Furthermore, following small hairpin RNA (shRNA)-mediated knockdown of the TF, we observed significant downregulation of MYC, RNF43 and GPRC5A, suggesting a direct regulatory role of FOXQ1 (Figure S17b in Additional file 1).	('GPRC5A', 'Gene', (136, 142))	('FOXQ1', 'Gene', (183, 188))	('MYC', 'Gene', (121, 124))	('GPRC5A', 'Gene', '9052', (136, 142))	('RNF43', 'Gene', (126, 131))	('downregulation', 'NegReg', (103, 117))	('RNF43', 'Gene', '54894', (126, 131))	('FOXQ1', 'Gene', '94234', (183, 188))	('knockdown', 'Var', (58, 67))	('MYC', 'Gene', '4609', (121, 124))
228030	26813288	In line with the oncogenic role of FOXQ1 targets in colorectal cancer settings, knockdown of the TF reduced cell proliferation of the colorectal cancer cell line (Figure S17c in Additional file 1).	('knockdown', 'Var', (80, 89))	('colorectal cancer', 'Disease', (134, 151))	('reduced', 'NegReg', (100, 107))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('colorectal cancer', 'Phenotype', 'HP:0003003', (52, 69))	('FOXQ1', 'Gene', '94234', (35, 40))	('colorectal cancer', 'Phenotype', 'HP:0003003', (134, 151))	('cell proliferation of the', 'CPA', (108, 133))	('colorectal cancer', 'Disease', 'MESH:D015179', (134, 151))	('colorectal cancer', 'Disease', (52, 69))	('FOXQ1', 'Gene', (35, 40))	('colorectal cancer', 'Disease', 'MESH:D015179', (52, 69))
228033	26813288	Herein, knockdown of the TFs repressed RNF43 and GPRC5A expression (Figure S18c in Additional file 1) and resulted in reduced cell viability (Figure S18d in Additional file 1), further supporting the accuracy of the functional prediction based on super-enhancer DNA methylation levels (Figure S14b in Additional file 1).	('cell viability', 'CPA', (126, 140))	('TFs', 'Gene', (25, 28))	('RNF43', 'Gene', '54894', (39, 44))	('RNF43', 'Gene', (39, 44))	('knockdown', 'Var', (8, 17))	('reduced', 'NegReg', (118, 125))	('expression', 'MPA', (56, 66))	('GPRC5A', 'Gene', (49, 55))	('GPRC5A', 'Gene', '9052', (49, 55))
228035	26813288	Interestingly, although the treatment with JQ1 decreased the expression of super-enhancer gene targets, such as MYC, RNF43 or GPRC5A, we could not detect an effect on DNA methylation levels at super-enhancer-related CpG sites (Figure S19c, d in Additional file 1).	('GPRC5A', 'Gene', (126, 132))	('MYC', 'Gene', '4609', (112, 115))	('GPRC5A', 'Gene', '9052', (126, 132))	('JQ1', 'Var', (43, 46))	('RNF43', 'Gene', '54894', (117, 122))	('RNF43', 'Gene', (117, 122))	('MYC', 'Gene', (112, 115))	('expression', 'MPA', (61, 71))	('decreased', 'NegReg', (47, 56))
228046	26813288	Overall, our findings indicate that super-enhancers, regulatory regions critical for cell identity and function, are partially regulated by their CpG methylation status in normal cells, and that they are targeted by specific aberrant DNA methylation events in cancer, with putative effects for the expression of the downstream-controlled genes.	('cancer', 'Disease', 'MESH:D009369', (260, 266))	('cancer', 'Disease', (260, 266))	('regulated', 'Reg', (127, 136))	('aberrant', 'Var', (225, 233))	('cancer', 'Phenotype', 'HP:0002664', (260, 266))
228047	26813288	In cancer, the perturbed expression of key TFs establishes novel super-enhancers that drive oncogene expression, a scenario that we partially delineated through the identification of FOXQ1 as a putative factor driving the differential DNA methylation at colorectal cancer-specific super-enhancers and the overexpression of key oncogenes, such as MYC and RNF43.	('FOXQ1', 'Gene', (183, 188))	('cancer', 'Phenotype', 'HP:0002664', (265, 271))	('FOXQ1', 'Gene', '94234', (183, 188))	('colorectal cancer', 'Disease', 'MESH:D015179', (254, 271))	('overexpression', 'PosReg', (305, 319))	('colorectal cancer', 'Disease', (254, 271))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('MYC', 'Gene', '4609', (346, 349))	('cancer', 'Disease', 'MESH:D009369', (265, 271))	('RNF43', 'Gene', '54894', (354, 359))	('oncogene expression', 'MPA', (92, 111))	('drive', 'Reg', (86, 91))	('RNF43', 'Gene', (354, 359))	('colorectal cancer', 'Phenotype', 'HP:0003003', (254, 271))	('cancer', 'Disease', (3, 9))	('perturbed', 'Var', (15, 24))	('cancer', 'Disease', (265, 271))	('MYC', 'Gene', (346, 349))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
228052	26813288	The DNA methylation data sets for the two breast cancer cell lines (MDA-MB-468PT and MDA-MB-468LN) were previously published and are available under accession code GSE56763, Gene Expression Omnibus (GEO).	('MDA-MB-468LN', 'CellLine', 'CVCL:M372', (85, 97))	('MDA-MB-468LN', 'Var', (85, 97))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('breast cancer', 'Disease', 'MESH:D001943', (42, 55))	('breast cancer', 'Phenotype', 'HP:0003002', (42, 55))	('breast cancer', 'Disease', (42, 55))	('MDA-MB-468PT', 'CellLine', 'CVCL:0419', (68, 80))
228060	26813288	Subsequently, we fitted a multivariate linear model with H3K27ac signal as response variable, DNA methylation status (hypo/hyper) and CpG density as predictors to assess the impact of CpG density on the association.	('hypo/hyper', 'Disease', (118, 128))	('H3K27ac', 'Var', (57, 64))	('hypo/hyper', 'Disease', 'MESH:D052456', (118, 128))
228064	26813288	Raw RNA sequencing FASTQ reads from the breast cancer cell lines (MCF10A, MDA-MB-468PT and MDA-MB-468LN) were aligned against the human hg19 reference sequence using the TopHat read-mapping algorithm.	('MCF10A', 'CellLine', 'CVCL:0598', (66, 72))	('breast cancer', 'Disease', 'MESH:D001943', (40, 53))	('breast cancer', 'Disease', (40, 53))	('breast cancer', 'Phenotype', 'HP:0003002', (40, 53))	('MDA-MB-468LN', 'Var', (91, 103))	('MDA-MB-468LN', 'CellLine', 'CVCL:M372', (91, 103))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('MDA-MB-468PT', 'CellLine', 'CVCL:0419', (74, 86))	('human', 'Species', '9606', (130, 135))
228085	26813288	Alternatively, for TCGA data set of colorectal adenocarcinomas, we used level 3 CNV data and defined a region to be aberrant if >50 % of the super-enhancer region presented copy numbers <1.5 or >2.5.	('carcinoma', 'Phenotype', 'HP:0030731', (52, 61))	('carcinomas', 'Phenotype', 'HP:0030731', (52, 62))	('colorectal adenocarcinomas', 'Disease', 'MESH:D015179', (36, 62))	('colorectal adenocarcinomas', 'Disease', (36, 62))	('copy numbers <1.5', 'Var', (173, 190))
228091	26813288	5-hmC 5-Hydroxy methylation 5-mC 5-Methylation BS Bisulfite ChIA-PET Chromatin interaction analysis by paired-end tag ChIP Chromatin immunoprecipitation CNV Copy number variation FDR False discovery rate GEO Gene Expression Omnibus HMR Hypomethylated region OR Odds ratio ox-BS Oxidative bisulfite PCR Polymerase chain reaction shRNA Small hairpin RNA SNP Single nucleotide polymorphism TCGA The Cancer Genome Atlas TF Transcription factor TSS Transcription start site WGBS Whole genome bisulfite sequencing	('Cancer Genome Atlas', 'Disease', (396, 415))	('HMR', 'Gene', '3164', (232, 235))	('ChIA', 'Gene', (60, 64))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (396, 415))	('bisulfite', 'Chemical', 'MESH:C042345', (487, 496))	('ChIA', 'Gene', '27159', (60, 64))	('bisulfite', 'Chemical', 'MESH:C042345', (288, 297))	('Bisulfite', 'Chemical', 'MESH:C042345', (50, 59))	('HMR', 'Gene', (232, 235))	('variation', 'Var', (169, 178))	('5-mC', 'Chemical', '-', (28, 32))	('Cancer', 'Phenotype', 'HP:0002664', (396, 402))
228114	24386210	KEAP1 mutations lead to constitutively active Nrf2 and subsequent protection of cancer cells from chemotherapeutic drugs, constitutive activation of Nrf2 is prominently expressed in various kinds of cancers, which has been shown to protect against cancer and leads to progression and poor survival.	('Nrf2', 'Gene', (149, 153))	('cancer', 'Disease', (199, 205))	('KEAP1', 'Gene', '9817', (0, 5))	('cancer', 'Disease', (80, 86))	('poor survival', 'CPA', (284, 297))	('cancer', 'Disease', (248, 254))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('KEAP1', 'Gene', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancer', 'Phenotype', 'HP:0002664', (248, 254))	('Nrf2', 'Gene', '4780', (46, 50))	('cancers', 'Phenotype', 'HP:0002664', (199, 206))	('cancers', 'Disease', (199, 206))	('mutations', 'Var', (6, 15))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('progression', 'CPA', (268, 279))	('Nrf2', 'Gene', '4780', (149, 153))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('cancer', 'Disease', 'MESH:D009369', (248, 254))	('Nrf2', 'Gene', (46, 50))	('cancers', 'Disease', 'MESH:D009369', (199, 206))
228162	24386210	Recently, evidences showed a high incidence occurrence of loss of Keap1 function in cancer, Keap1 mutations affected the repressive activity of Keap1 against Nrf2, the loss of Keap1 function enhanced the nuclear accumulation of Nrf2 and elevated the expression of antioxidative and antixenobiotic stress enzymes and drug efflux pumps.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('Nrf2', 'Gene', (228, 232))	('loss', 'Var', (168, 172))	('Keap1', 'Gene', (144, 149))	('nuclear accumulation', 'MPA', (204, 224))	('enhanced', 'PosReg', (191, 199))	('Keap1', 'Gene', '9817', (92, 97))	('repressive activity', 'MPA', (121, 140))	('affected', 'Reg', (108, 116))	('drug efflux pumps', 'MPA', (316, 333))	('Keap1', 'Gene', (92, 97))	('Nrf2', 'Gene', '4780', (158, 162))	('cancer', 'Disease', (84, 90))	('Keap1', 'Gene', '9817', (66, 71))	('Keap1', 'Gene', '9817', (176, 181))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('Nrf2', 'Gene', '4780', (228, 232))	('Keap1', 'Gene', '9817', (144, 149))	('Keap1', 'Gene', (66, 71))	('Keap1', 'Gene', (176, 181))	('Nrf2', 'Gene', (158, 162))	('mutations', 'Var', (98, 107))	('elevated', 'PosReg', (237, 245))	('expression', 'MPA', (250, 260))
228164	24386210	Furthermore, as the ROS lever was changed all the time in the cancer progression, then the lever of antioxidant enzymes was also changed followed the ROS level, and Nrf2 neutralizes ROS to restore cellular redox balance.	('Nrf2', 'Gene', '4780', (165, 169))	('ROS', 'Chemical', 'MESH:D017382', (150, 153))	('ROS', 'Chemical', 'MESH:D017382', (182, 185))	('ROS', 'Chemical', 'MESH:D017382', (20, 23))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('Nrf2', 'Gene', (165, 169))	('cellular redox balance', 'MPA', (197, 219))	('restore', 'PosReg', (189, 196))	('cancer', 'Disease', (62, 68))	('ROS', 'MPA', (182, 185))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('ROS level', 'MPA', (150, 159))	('lever', 'MPA', (91, 96))	('changed', 'Reg', (34, 41))	('neutralizes', 'Var', (170, 181))
228170	24386210	Ours is the first reported study to determine the frequency of low or high cytoplasmic Keap1 and nuclear Nrf2 expression in OSCC and their association with tumors' clinicopathologic characteristics.	('Nrf2', 'Gene', (105, 109))	('Keap1', 'Gene', '9817', (87, 92))	('Keap1', 'Gene', (87, 92))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumors', 'Disease', 'MESH:D009369', (156, 162))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('Nrf2', 'Gene', '4780', (105, 109))	('low', 'Var', (63, 66))	('tumors', 'Disease', (156, 162))	('OSCC', 'Disease', (124, 128))
228176	24386210	In human lung cancer, tumors showing high levels of Nrf2 protein are associated with a poor outcome and increased resistance to therapy.	('tumors', 'Phenotype', 'HP:0002664', (22, 28))	('lung cancer', 'Phenotype', 'HP:0100526', (9, 20))	('human', 'Species', '9606', (3, 8))	('Nrf2', 'Gene', '4780', (52, 56))	('tumors', 'Disease', 'MESH:D009369', (22, 28))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('lung cancer', 'Disease', 'MESH:D008175', (9, 20))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('Nrf2', 'Gene', (52, 56))	('resistance to therapy', 'CPA', (114, 135))	('lung cancer', 'Disease', (9, 20))	('tumors', 'Disease', (22, 28))	('protein', 'Protein', (57, 64))	('high levels', 'Var', (37, 48))
228210	34032706	Based on immunohistochemistry, there are 4 major categories of amyloidosis: primary or immunoglobulin light chain (AL) disease, hereditary or mutant transthyretin disease, secondary or amyloid protein A disease, and dialysis-associated or beta-2 microglobulin disease.	('hereditary', 'Disease', 'MESH:D030342', (128, 138))	('amyloidosis', 'Disease', (63, 74))	('amyloidosis', 'Phenotype', 'HP:0011034', (63, 74))	('amyloidosis', 'Disease', 'MESH:D000686', (63, 74))	('mutant', 'Var', (142, 148))	('primary or immunoglobulin light chain', 'Disease', (76, 113))	('hereditary', 'Disease', (128, 138))
228231	34032706	Several case reports have described the role of 18F-FDG PET/CT in AL amyloidosis.	('18F-FDG', 'Var', (48, 55))	('amyloidosis', 'Phenotype', 'HP:0011034', (69, 80))	('AL amyloidosis', 'Disease', 'MESH:D000075363', (66, 80))	('AL amyloidosis', 'Disease', (66, 80))	('18F-FDG', 'Chemical', '-', (48, 55))
228245	32296457	LncRNA NEAT1 Interacted With DNMT1 to Regulate Malignant Phenotype of Cancer Cell and Cytotoxic T Cell Infiltration via Epigenetic Inhibition of p53, cGAS, and STING in Lung Cancer Lung cancer is the main cause of cancer-related mortality worldwide.	('cGAS', 'Gene', '115004', (150, 154))	('p53', 'Gene', (145, 148))	('NEAT1', 'Gene', '283131', (7, 12))	('Cancer', 'Disease', 'MESH:D009369', (174, 180))	('Cancer', 'Disease', 'MESH:D009369', (70, 76))	('mortality', 'Disease', 'MESH:D003643', (229, 238))	('cancer', 'Disease', 'MESH:D009369', (186, 192))	('Lung Cancer', 'Disease', (169, 180))	('DNMT1', 'Gene', (29, 34))	('Epigenetic Inhibition', 'Var', (120, 141))	('cancer', 'Disease', (214, 220))	('Cytotoxic T', 'Disease', (86, 97))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('cGAS', 'Gene', (150, 154))	('Lung cancer', 'Disease', 'MESH:D008175', (181, 192))	('Lung cancer', 'Phenotype', 'HP:0100526', (181, 192))	('Cancer', 'Phenotype', 'HP:0002664', (174, 180))	('Lung cancer', 'Disease', (181, 192))	('Lung Cancer', 'Disease', 'MESH:D008175', (169, 180))	('NEAT1', 'Gene', (7, 12))	('Regulate', 'Reg', (38, 46))	('Cancer', 'Phenotype', 'HP:0002664', (70, 76))	('cancer', 'Disease', (186, 192))	('cancer', 'Disease', 'MESH:D009369', (214, 220))	('Lung Cancer', 'Phenotype', 'HP:0100526', (169, 180))	('Cancer', 'Disease', (174, 180))	('mortality', 'Disease', (229, 238))	('p53', 'Gene', '7157', (145, 148))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('DNMT1', 'Gene', '1786', (29, 34))	('Cancer', 'Disease', (70, 76))	('Cytotoxic T', 'Disease', 'MESH:D064420', (86, 97))
228254	32296457	In vitro studies displayed that inhibition of NEAT1 with shRNA resulted in suppression of survival and migration/invasion of lung cancer cells.	('inhibition', 'Var', (32, 42))	('lung cancer', 'Disease', 'MESH:D008175', (125, 136))	('suppression', 'NegReg', (75, 86))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('survival', 'CPA', (90, 98))	('lung cancer', 'Disease', (125, 136))	('shRNA', 'Gene', (57, 62))	('lung cancer', 'Phenotype', 'HP:0100526', (125, 136))
228255	32296457	On the other side, NEAT1 was found to promote tumor growth via inhibiting cytotoxic T cell immunity in syngeneic models.	('NEAT1', 'Var', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Disease', (46, 51))	('inhibiting', 'NegReg', (63, 73))	('promote', 'PosReg', (38, 45))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
228274	32296457	Aberrant methylation, particularly in the promoter regions of tumor suppressor genes, inhibits gene expression and can facilitate human tumorigenesis.	('gene expression', 'MPA', (95, 110))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('inhibits', 'NegReg', (86, 94))	('tumor', 'Disease', (62, 67))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('Aberrant methylation', 'Var', (0, 20))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('facilitate', 'PosReg', (119, 129))	('tumor', 'Disease', (136, 141))	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('human', 'Species', '9606', (130, 135))
228275	32296457	It has been reported that cGAS and STING expression is suppressed by methylation in a pan-tumor analysis, indicating the possibility that cGAS and STING might be inhibited by DNMT1.	('cGAS', 'Gene', '115004', (138, 142))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('cGAS', 'Gene', (26, 30))	('suppressed', 'NegReg', (55, 65))	('DNMT1', 'Gene', (175, 180))	('methylation', 'Var', (69, 80))	('inhibited', 'NegReg', (162, 171))	('cGAS', 'Gene', '115004', (26, 30))	('DNMT1', 'Gene', '1786', (175, 180))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('cGAS', 'Gene', (138, 142))
228278	32296457	Its aberrant expression is closely interrelated with poorer clinicopathological parameters of lung cancer.	('lung cancer', 'Disease', 'MESH:D008175', (94, 105))	('aberrant expression', 'Var', (4, 23))	('lung cancer', 'Disease', (94, 105))	('lung cancer', 'Phenotype', 'HP:0100526', (94, 105))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
228280	32296457	Furthermore, NEAT1 epigenetically suppresses E-cadherin expression through association with G9a-DNMT1-Snail complex, which suggested that NEAT1 might exert protumor effect via DNMT1.	('epigenetically', 'Var', (19, 33))	('Snail', 'Gene', (102, 107))	('DNMT1', 'Gene', '1786', (176, 181))	('DNMT1', 'Gene', '1786', (96, 101))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('Snail', 'Gene', '6615', (102, 107))	('NEAT1', 'Gene', (13, 18))	('DNMT1', 'Gene', (176, 181))	('G9a', 'Gene', (92, 95))	('G9a', 'Gene', '10919', (92, 95))	('tumor', 'Disease', (159, 164))	('expression', 'MPA', (56, 66))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('E-cadherin', 'Gene', (45, 55))	('E-cadherin', 'Gene', '999', (45, 55))	('DNMT1', 'Gene', (96, 101))	('association', 'Interaction', (75, 86))
228327	32296457	Patients with high expression of CD8 showed higher expression level of NEAT1 (Figure 1G).	('CD8', 'Gene', (33, 36))	('CD8', 'Gene', '925', (33, 36))	('higher', 'PosReg', (44, 50))	('Patients', 'Species', '9606', (0, 8))	('high expression', 'Var', (14, 29))	('expression level', 'MPA', (51, 67))
228334	32296457	As observed in Figures 2B,C, knockdown of NEAT1 significantly suppressed the cell viability in A549 cells and SK-MES-1 cells in a time-dependent manner.	('SK-MES-1', 'CellLine', 'CVCL:0630', (110, 118))	('knockdown', 'Var', (29, 38))	('NEAT1', 'Gene', (42, 47))	('suppressed', 'NegReg', (62, 72))	('A549', 'CellLine', 'CVCL:0023', (95, 99))
228335	32296457	Similarly, colony formation assays also displayed that inhibition of NEAT1 dramatically suppressed the ability of colony formation in A549 cells and SK-MES-1 cells (Figures 2D,E).	('suppressed', 'NegReg', (88, 98))	('SK-MES-1', 'CellLine', 'CVCL:0630', (149, 157))	('NEAT1', 'Gene', (69, 74))	('inhibition', 'Var', (55, 65))	('colony formation', 'CPA', (114, 130))	('A549', 'CellLine', 'CVCL:0023', (134, 138))
228337	32296457	Knocking down of NEAT1 was further found to induce the downregulation of ki67, MMP2, and MMP9 expression level (Figures 2H,I).	('MMP9', 'Gene', '4318', (89, 93))	('MMP9', 'Gene', (89, 93))	('Knocking down', 'Var', (0, 13))	('MMP2', 'Gene', (79, 83))	('NEAT1', 'Gene', (17, 22))	('ki67', 'Gene', (73, 77))	('MMP2', 'Gene', '4313', (79, 83))	('downregulation', 'NegReg', (55, 69))
228338	32296457	Given that silencing of NEAT1 could inhibit the cell viability of lung cancer cells in vitro, its function in vivo was also determined.	('silencing', 'Var', (11, 20))	('cell viability of', 'CPA', (48, 65))	('inhibit', 'NegReg', (36, 43))	('lung cancer', 'Disease', (66, 77))	('lung cancer', 'Phenotype', 'HP:0100526', (66, 77))	('NEAT1', 'Gene', (24, 29))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('lung cancer', 'Disease', 'MESH:D008175', (66, 77))
228340	32296457	The data showed that the downregulation of NEAT1 showed antitumor effect in M109 syngeneic models (Figures 3A-C), suggesting that NEAT1 was able to promote lung cancer growth.	('NEAT1', 'Gene', (43, 48))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('NEAT1', 'Var', (130, 135))	('tumor', 'Disease', (60, 65))	('lung cancer', 'Disease', 'MESH:D008175', (156, 167))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('downregulation', 'NegReg', (25, 39))	('promote', 'PosReg', (148, 155))	('lung cancer', 'Disease', (156, 167))	('lung cancer', 'Phenotype', 'HP:0100526', (156, 167))
228341	32296457	To further confirm the antitumor immunity mediated by NEAT1 knockdown, the percentage of tumor-infiltrating cytotoxic T cells was next analyzed.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('NEAT1', 'Gene', (54, 59))	('tumor', 'Disease', (27, 32))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('knockdown', 'Var', (60, 69))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
228342	32296457	The tumors with NEAT1 knockdown M109 cell harvested from mice had intratumoral elevation in CD45+ CD3+ T cells (Figures 3D,E) and CD4- CD8+ T cells (Figures 3F,G) compared to tumor from control mice.	('tumor', 'Disease', (4, 9))	('M109', 'Gene', (32, 36))	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('CD3', 'Gene', (98, 101))	('CD8', 'Gene', '925', (135, 138))	('CD3', 'Gene', '28134', (98, 101))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('mice', 'Species', '10090', (194, 198))	('tumor', 'Disease', (175, 180))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('NEAT1 knockdown', 'Var', (16, 31))	('elevation', 'PosReg', (79, 88))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('CD8', 'Gene', (135, 138))	('tumor', 'Disease', (71, 76))	('mice', 'Species', '10090', (57, 61))	('tumors', 'Disease', (4, 10))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))
228345	32296457	Taken together, these data suggest NEAT1 knockdown drives an adaptive T cell tumor-specific immune response that results in tumor inhibition of lung cancer.	('knockdown', 'Var', (41, 50))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('lung cancer', 'Phenotype', 'HP:0100526', (144, 155))	('tumor inhibition of lung cancer', 'Disease', (124, 155))	('tumor', 'Disease', (124, 129))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('T cell', 'CPA', (70, 76))	('tumor inhibition of lung cancer', 'Disease', 'MESH:D008175', (124, 155))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Disease', (77, 82))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
228347	32296457	Enhanced mRNA and protein levels of CXCL10, CCL5, and IFNbeta were observed following silencing of NEAT1 in human and mouse lung cancer cells as measured by qRT-PCR and Western blot analysis, respectively (Figures 4A-C and Supplementary Figure S2).	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('lung cancer', 'Disease', 'MESH:D008175', (124, 135))	('silencing', 'Var', (86, 95))	('NEAT1', 'Gene', (99, 104))	('CCL5', 'MPA', (44, 48))	('human', 'Species', '9606', (108, 113))	('CXCL10', 'MPA', (36, 42))	('mouse', 'Species', '10090', (118, 123))	('lung cancer', 'Disease', (124, 135))	('lung cancer', 'Phenotype', 'HP:0100526', (124, 135))	('Enhanced', 'PosReg', (0, 8))
228350	32296457	The results indicates that inhibition of NEAT1 results in the increase in cGAS, STING level, and upregulation of phosphorylation of TBK1 and IRF3 in both of cell lines and tumor samples (Figures 4E,F).	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('upregulation', 'PosReg', (97, 109))	('STING level', 'MPA', (80, 91))	('phosphorylation', 'MPA', (113, 128))	('TBK1', 'Gene', '29110', (132, 136))	('tumor', 'Disease', (172, 177))	('IRF3', 'Gene', (141, 145))	('cGAS', 'Gene', (74, 78))	('IRF3', 'Gene', '3661', (141, 145))	('NEAT1', 'Gene', (41, 46))	('inhibition', 'Var', (27, 37))	('TBK1', 'Gene', (132, 136))	('cGAS', 'Gene', '115004', (74, 78))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('increase', 'PosReg', (62, 70))
228355	32296457	Silencing of lncRNA NEAT1 in SK-MES-1 cells obtained the consistent results (Figure 5F).	('Silencing', 'Var', (0, 9))	('SK-MES-1', 'CellLine', 'CVCL:0630', (29, 37))	('lncRNA NEAT1', 'Gene', (13, 25))
228356	32296457	As shown in Figure 5G, the promoter activity of TP53, CGAS, and STING1 was upregulated during inhibition of DNMT1.	('STING1', 'Gene', (64, 70))	('DNMT1', 'Gene', (108, 113))	('upregulated', 'PosReg', (75, 86))	('TP53', 'Gene', '7157', (48, 52))	('promoter activity', 'MPA', (27, 44))	('DNMT1', 'Gene', '1786', (108, 113))	('TP53', 'Gene', (48, 52))	('CGAS', 'Gene', (54, 58))	('inhibition', 'Var', (94, 104))	('CGAS', 'Gene', '115004', (54, 58))
228357	32296457	Taken together, NEAT1 epigenetically inhibits expression of cGAS/STING and P53 via binding to DNMT1.	('DNMT1', 'Gene', (94, 99))	('epigenetically', 'Var', (22, 36))	('DNMT1', 'Gene', '1786', (94, 99))	('P53', 'Gene', '7157', (75, 78))	('binding', 'Interaction', (83, 90))	('cGAS', 'Gene', (60, 64))	('cGAS', 'Gene', '115004', (60, 64))	('expression', 'MPA', (46, 56))	('inhibits', 'NegReg', (37, 45))	('P53', 'Gene', (75, 78))
228368	32296457	For example, LncRNA NEAT1 contributes to paclitaxel resistance of ovarian cancer cells by regulating ZEB1 expression via miR-194.	('ZEB1', 'Gene', '6935', (101, 105))	('paclitaxel', 'Chemical', 'MESH:D017239', (41, 51))	('ZEB1', 'Gene', (101, 105))	('ovarian cancer', 'Phenotype', 'HP:0100615', (66, 80))	('LncRNA NEAT1', 'Gene', (13, 25))	('expression', 'MPA', (106, 116))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('ovarian cancer', 'Disease', 'MESH:D010051', (66, 80))	('miR-194', 'Var', (121, 128))	('regulating', 'Reg', (90, 100))	('ovarian cancer', 'Disease', (66, 80))	('paclitaxel resistance', 'MPA', (41, 62))	('contributes', 'Reg', (26, 37))
228370	32296457	Our results showed that NEAT1 was found to promote cell survival, migration, and invasion in lung cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('migration', 'CPA', (66, 75))	('promote', 'PosReg', (43, 50))	('invasion', 'CPA', (81, 89))	('lung cancer', 'Disease', 'MESH:D008175', (93, 104))	('cell survival', 'CPA', (51, 64))	('NEAT1', 'Var', (24, 29))	('lung cancer', 'Disease', (93, 104))	('lung cancer', 'Phenotype', 'HP:0100526', (93, 104))
228371	32296457	The results showed that knockdown of NEAT1 attenuated the expression of proliferative marker Ki-67 and migrative markers MMP2/MMP9.	('migrative markers', 'MPA', (103, 120))	('NEAT1', 'Gene', (37, 42))	('Ki-67', 'Protein', (93, 98))	('MMP9', 'Gene', '4318', (126, 130))	('expression', 'MPA', (58, 68))	('MMP2', 'Gene', (121, 125))	('attenuated', 'NegReg', (43, 53))	('knockdown', 'Var', (24, 33))	('MMP2', 'Gene', '4313', (121, 125))	('MMP9', 'Gene', (126, 130))	('proliferative marker', 'MPA', (72, 92))
228383	32296457	In order to evade this DNA detection pathway to survive, there are several mechanisms utilized by tumor cells, yielding the defective cGAS-STING signaling in tumors, including decreased the protein level of STING and cGAS, hypermethylation of CGAS and STING1 promoter regions, and defective STING translocation to the Golgi where it normally signals.	('tumors', 'Phenotype', 'HP:0002664', (158, 164))	('defective', 'NegReg', (281, 290))	('decreased', 'NegReg', (176, 185))	('CGAS', 'Gene', (243, 247))	('protein level', 'MPA', (190, 203))	('tumor', 'Disease', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('tumors', 'Disease', (158, 164))	('hypermethylation', 'Var', (223, 239))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('cGAS', 'Gene', (134, 138))	('cGAS', 'Gene', '115004', (217, 221))	('CGAS', 'Gene', '115004', (243, 247))	('tumors', 'Disease', 'MESH:D009369', (158, 164))	('STING', 'MPA', (207, 212))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('defective', 'NegReg', (124, 133))	('tumor', 'Disease', (158, 163))	('STING translocation to the Golgi', 'MPA', (291, 323))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('cGAS', 'Gene', (217, 221))	('cGAS', 'Gene', '115004', (134, 138))
228386	32296457	Moreover, our in vivo study found that when NEAT1 was silenced, the tumor growth was retarded, and more importantly, cytotoxic T cells were elevated.	('tumor', 'Disease', (68, 73))	('cytotoxic T cells', 'CPA', (117, 134))	('NEAT1', 'Gene', (44, 49))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('elevated', 'PosReg', (140, 148))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('silenced', 'Var', (54, 62))
228392	32296457	The aberrant expression was closely associated with tumor stage and lymph node metastasis, suggesting that NEAT1 could be involved in the progression of lung cancer.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('lung cancer', 'Disease', 'MESH:D008175', (153, 164))	('involved', 'Reg', (122, 130))	('tumor', 'Disease', (52, 57))	('aberrant', 'Var', (4, 12))	('lymph node metastasis', 'CPA', (68, 89))	('lung cancer', 'Disease', (153, 164))	('lung cancer', 'Phenotype', 'HP:0100526', (153, 164))	('associated', 'Reg', (36, 46))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
228393	32296457	However, we should admit that there are still obstacles for NEAT1 to be applied in diagnose or treatment of lung cancer due to the limitation of detection of non-coding RNAs.	('lung cancer', 'Disease', 'MESH:D008175', (108, 119))	('lung cancer', 'Disease', (108, 119))	('non-coding RNAs', 'Var', (158, 173))	('lung cancer', 'Phenotype', 'HP:0100526', (108, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
228394	32296457	In vitro studies displayed that inhibition of NEAT1 with shRNA resulted in suppression of survival and migration/invasion of lung cancer cells mediated by targeting DNMT1/P53 signaling.	('DNMT1', 'Gene', (165, 170))	('inhibition', 'Var', (32, 42))	('lung cancer', 'Disease', 'MESH:D008175', (125, 136))	('P53', 'Gene', (171, 174))	('P53', 'Gene', '7157', (171, 174))	('suppression', 'NegReg', (75, 86))	('DNMT1', 'Gene', '1786', (165, 170))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('NEAT1', 'Gene', (46, 51))	('survival', 'CPA', (90, 98))	('lung cancer', 'Disease', (125, 136))	('shRNA', 'Gene', (57, 62))	('lung cancer', 'Phenotype', 'HP:0100526', (125, 136))
228424	30917582	Currently, the best-studied epigenetic event in the mammalian genome is DNA methylation, which is a chemical covalent modification of cytosine.	('DNA', 'Disease', (72, 75))	('mammalian', 'Species', '9606', (52, 61))	('methylation', 'Var', (76, 87))	('cytosine', 'Chemical', 'MESH:D003596', (134, 142))
228425	30917582	In particular, it is the addition of a methyl group (CH 3) at the fifth carbon position of cytosine bases that are located 5' to a guanosine in a CpG dinucleotide; the modification of this region interferes with gene transcription and can eliminate tumor suppressor genes.	('CpG dinucleotide', 'Chemical', 'MESH:C015772', (146, 162))	('guanosine', 'Chemical', 'MESH:D006151', (131, 140))	('gene transcription', 'MPA', (212, 230))	('interferes', 'NegReg', (196, 206))	('tumor', 'Disease', 'MESH:D009369', (249, 254))	('cytosine', 'Chemical', 'MESH:D003596', (91, 99))	('tumor', 'Phenotype', 'HP:0002664', (249, 254))	('carbon', 'Chemical', 'MESH:D002244', (72, 78))	('eliminate', 'NegReg', (239, 248))	('modification', 'Var', (168, 180))	('tumor', 'Disease', (249, 254))
228427	30917582	Both hypomethylation and hypermethylation of well-known cancer-related genes have been found to be a process occurring in the early stages of cancer development.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('hypermethylation', 'Var', (25, 41))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('hypomethylation', 'Var', (5, 20))	('cancer', 'Disease', (142, 148))
228431	30917582	Gene body methylation was found to be involved in the overexpression of inositol-triphosphate 3-kinase A (ITPKA), which regulates the inositol phosphate metabolism and calcium signaling correlated with the increased metastatic potential.	('inositol-triphosphate 3-kinase A', 'Gene', (72, 104))	('inositol-triphosphate 3-kinase A', 'Gene', '3706', (72, 104))	('ITPKA', 'Gene', (106, 111))	('increased', 'PosReg', (206, 215))	('regulates', 'Reg', (120, 129))	('overexpression', 'PosReg', (54, 68))	('involved', 'Reg', (38, 46))	('calcium signaling', 'MPA', (168, 185))	('methylation', 'Var', (10, 21))	('inositol phosphate metabolism', 'MPA', (134, 163))	('calcium', 'Chemical', 'MESH:D002118', (168, 175))	('inositol phosphate', 'Chemical', 'MESH:D007295', (134, 152))	('ITPKA', 'Gene', '3706', (106, 111))	('metastatic potential', 'CPA', (216, 236))
228436	30917582	The results of this study suggested that the methylation of these two genes has the potential to distinguish malignant lung diseases from benign and non-malignant and the combined analysis is able to increase the sensitivity of the cytological examination of lung cancer from 5.7% to 71.5%.	('lung cancer', 'Disease', (259, 270))	('lung cancer', 'Phenotype', 'HP:0100526', (259, 270))	('distinguish', 'Reg', (97, 108))	('lung diseases', 'Disease', (119, 132))	('lung diseases', 'Phenotype', 'HP:0002088', (119, 132))	('increase', 'PosReg', (200, 208))	('lung diseases', 'Disease', 'MESH:D008171', (119, 132))	('lung cancer', 'Disease', 'MESH:D008175', (259, 270))	('cancer', 'Phenotype', 'HP:0002664', (264, 270))	('methylation', 'Var', (45, 56))
228440	30917582	Interestingly, a prognostic risk category based on the methylation status of CD01, HOXAS, PTGDR and AJAP, refined the risk stratification for outcomes as an independent prognostic factor for early-stage diseases.	('HOXAS', 'Gene', (83, 88))	('CD01', 'Gene', (77, 81))	('HOXAS', 'Gene', '100124700', (83, 88))	('early-stage diseases', 'Disease', (191, 211))	('PTGDR', 'Gene', (90, 95))	('methylation', 'Var', (55, 66))	('PTGDR', 'Gene', '5729', (90, 95))
228441	30917582	Angiotensin II type I receptor (AGTR1) promotor methylation was found to be another potential diagnostic biomarker.	('AGTR1', 'Gene', '185', (32, 37))	('methylation', 'Var', (48, 59))	('AGTR1', 'Gene', (32, 37))
228460	30917582	In particular, the most crucial miRNAs in cancer development were miR-205 and miR-3917 (upregulated) and miR-27a-5p, miR-30a-3p, miR-30a-5p, miR-30c-2-3p, and miR-30d-5 (downregulated).	('miR-3917', 'Gene', '100500808', (78, 86))	('upregulated', 'PosReg', (88, 99))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('miR-30a-5p', 'Var', (129, 139))	('miR-30a-3p', 'Var', (117, 127))	('miR-30d-5', 'Var', (159, 168))	('miR-30c-2', 'Gene', (141, 150))	('miR-3917', 'Gene', (78, 86))	('cancer', 'Disease', (42, 48))	('miR-205', 'Gene', (66, 73))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('miR-27a-5p', 'Var', (105, 115))	('miR-205', 'Gene', '406988', (66, 73))	('miR-30c-2', 'Gene', '407032', (141, 150))
228461	30917582	The same group identified aberrantly expressed key miRNAs in lung adenocarcinoma patients.	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (61, 80))	('patients', 'Species', '9606', (81, 89))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('aberrantly', 'Var', (26, 36))	('lung adenocarcinoma', 'Disease', (61, 80))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (61, 80))
228507	30917582	Alteration of the host-bacterial symbiosis is related to several systemic diseases (inflammatory bowel diseases, diabetes, etc.)	('inflammatory bowel diseases', 'Disease', 'MESH:D015212', (84, 111))	('related', 'Reg', (46, 53))	('inflammatory bowel diseases', 'Phenotype', 'HP:0002037', (84, 111))	('Alteration', 'Var', (0, 10))	('inflammatory bowel diseases', 'Disease', (84, 111))	('diabetes', 'Disease', (113, 121))	('systemic', 'Disease', (65, 73))	('diabetes', 'Disease', 'MESH:D003920', (113, 121))
228516	30917582	The authors found an abundance of Acidovarax in squamous cell carcinoma tissue with a TP53 mutation, an association not seen in adenocarcinoma.	('mutation', 'Var', (91, 99))	('Acidovarax', 'MPA', (34, 44))	('adenocarcinoma', 'Disease', 'MESH:D000230', (128, 142))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (48, 71))	('squamous cell carcinoma', 'Disease', (48, 71))	('TP53', 'Gene', '7157', (86, 90))	('Acidovarax', 'Chemical', '-', (34, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('TP53', 'Gene', (86, 90))	('adenocarcinoma', 'Disease', (128, 142))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (48, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (62, 71))
228544	30917582	demonstrated that miR-21 and miR-210 were upregulated and that miR486-5p was downregulated in malignant solitary pulmonary nodules compared with benign solitary pulmonary nodes.	('downregulated', 'NegReg', (77, 90))	('miR-21', 'Gene', '406991', (29, 35))	('malignant solitary pulmonary nodules', 'Disease', (94, 130))	('miR-21', 'Gene', '406991', (18, 24))	('miR-210', 'Gene', (29, 36))	('miR-210', 'Gene', '406992', (29, 36))	('miR-21', 'Gene', (18, 24))	('miR486-5p', 'Var', (63, 72))	('miR-21', 'Gene', (29, 35))	('upregulated', 'PosReg', (42, 53))	('miR486-5p', 'Chemical', '-', (63, 72))
228549	30917582	However, some publications demonstrated that some detectable miRNAs in blood samples (such as miR17-3p, miR21, miR106a, miR146, miR155, miR199, miR203, miR192, miR205, miR210, miR212, and miR214) were present at a high level in lung tumor tissues too.	('miR203', 'Gene', '406986', (144, 150))	('miR214', 'Gene', '406996', (188, 194))	('lung tumor', 'Disease', 'MESH:D008175', (228, 238))	('miR192', 'Gene', (152, 158))	('miR205', 'Gene', (160, 166))	('miR21', 'Gene', (176, 181))	('miR17-3p', 'Gene', (94, 102))	('miR210', 'Gene', '406992', (168, 174))	('miR146', 'Var', (120, 126))	('miR212', 'Gene', '406994', (176, 182))	('miR106a', 'Gene', (111, 118))	('miR21', 'Gene', (168, 173))	('miR21', 'Gene', '406991', (176, 181))	('miR155', 'Gene', (128, 134))	('miR21', 'Gene', (104, 109))	('miR155', 'Gene', '406947', (128, 134))	('miR21', 'Gene', '406991', (168, 173))	('miR212', 'Gene', (176, 182))	('miR21', 'Gene', '406991', (188, 193))	('miR205', 'Gene', '406988', (160, 166))	('miR21', 'Gene', '406991', (104, 109))	('lung tumor', 'Disease', (228, 238))	('miR210', 'Gene', (168, 174))	('miR17-3p', 'Gene', '406952', (94, 102))	('lung tumor', 'Phenotype', 'HP:0100526', (228, 238))	('miR192', 'Gene', '406967', (152, 158))	('miR106a', 'Gene', '406899', (111, 118))	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('miR199', 'Var', (136, 142))	('miR21', 'Gene', (188, 193))	('miR203', 'Gene', (144, 150))	('miR214', 'Gene', (188, 194))
228569	30058293	It is also well acknowledged that patients with HPV-positive OPSCCs have better treatment responses and prognosis than patients with HPV-negative tumors 9, 10, 11, 12, 13.	('better', 'PosReg', (73, 79))	('tumors', 'Phenotype', 'HP:0002664', (146, 152))	('HPV', 'Species', '10566', (48, 51))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('HPV-positive', 'Var', (48, 60))	('treatment responses', 'CPA', (80, 99))	('patients', 'Species', '9606', (119, 127))	('tumors', 'Disease', 'MESH:D009369', (146, 152))	('patients', 'Species', '9606', (34, 42))	('OPSCCs', 'Disease', (61, 67))	('tumors', 'Disease', (146, 152))	('HPV', 'Species', '10566', (133, 136))
228620	30058293	A secondary effect of pRB degradation is that E2F then stimulates the expression of p16, which accumulates in large amounts in the nuclei and cytoplasm of tumor cells (Figure 1).	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('pRB', 'Gene', '5925', (22, 25))	('p16', 'Gene', '1029', (84, 87))	('tumor', 'Disease', (155, 160))	('expression', 'MPA', (70, 80))	('E2F', 'Var', (46, 49))	('pRB', 'Gene', (22, 25))	('degradation', 'Var', (26, 37))	('stimulates', 'PosReg', (55, 65))	('p16', 'Gene', (84, 87))
228691	30319273	Animal xenograft studies indicate that nab-paclitaxel is more rapidly distributed to tumor tissue, and clinical trials in breast and non-small-cell lung cancer have demonstrated increased ORRs in patients treated with nab-paclitaxel/platinum vs solvent-based paclitaxel/platinum.	('tumor', 'Disease', (85, 90))	('ORRs', 'MPA', (188, 192))	('nab', 'Chemical', '-', (39, 42))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (137, 159))	('paclitaxel', 'Chemical', 'MESH:D017239', (43, 53))	('patients', 'Species', '9606', (196, 204))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('platinum', 'Chemical', 'MESH:D010984', (233, 241))	('platinum', 'Chemical', 'MESH:D010984', (270, 278))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('breast', 'Disease', (122, 128))	('increased', 'PosReg', (178, 187))	('nab', 'Chemical', '-', (218, 221))	('paclitaxel', 'Chemical', 'MESH:D017239', (222, 232))	('non-small-cell lung cancer', 'Disease', (133, 159))	('non-small-cell lung cancer', 'Disease', 'MESH:D002289', (133, 159))	('paclitaxel', 'Chemical', 'MESH:D017239', (259, 269))	('lung cancer', 'Phenotype', 'HP:0100526', (148, 159))	('nab-paclitaxel/platinum', 'Var', (218, 241))
228758	30034624	High Numb expression was associated with favorable prognosis in patients with lung adenocarcinoma, but not in those with squamous cell carcinoma.	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (121, 144))	('patients', 'Species', '9606', (64, 72))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (78, 97))	('squamous cell carcinoma', 'Disease', (121, 144))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('High Numb', 'Var', (0, 9))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('lung adenocarcinoma', 'Disease', (78, 97))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (78, 97))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (121, 144))
228764	30034624	KRAS or EGFR gene mutations induce a development of lung ADC in Alveolar type 2 or Clara cells, whereas genomic alteration of TP53, PTEN or SOX2 causes a development of lung SCC in basal, Clara or Alveolar type 2 cells.	('SCC', 'Gene', (174, 177))	('KRAS', 'Gene', '3845', (0, 4))	('mutations', 'Var', (18, 27))	('PTEN', 'Gene', (132, 136))	('SOX2', 'Gene', '6657', (140, 144))	('TP53', 'Gene', (126, 130))	('induce', 'Reg', (28, 34))	('PTEN', 'Gene', '5728', (132, 136))	('SCC', 'Gene', '6317', (174, 177))	('EGFR', 'Gene', '1956', (8, 12))	('lung', 'Disease', (169, 173))	('lung ADC', 'CPA', (52, 60))	('EGFR', 'Gene', (8, 12))	('causes', 'Reg', (145, 151))	('KRAS', 'Gene', (0, 4))	('TP53', 'Gene', '7157', (126, 130))	('SOX2', 'Gene', (140, 144))
228777	30034624	To investigate the role of Numb in lung ADC and SCC, lung ADC cell lines (A549, PC9) and SCC cell lines (H520, H1703) were transfected with Numb small interfering RNA (siRNA).	('SCC', 'Gene', '6317', (89, 92))	('SCC', 'Gene', (48, 51))	('small interfering RNA', 'Var', (145, 166))	('H520', 'CellLine', 'CVCL:1566', (105, 109))	('PC9', 'Gene', '255738', (80, 83))	('A549', 'CellLine', 'CVCL:0023', (74, 78))	('SCC', 'Gene', '6317', (48, 51))	('H1703', 'CellLine', 'CVCL:1490', (111, 116))	('PC9', 'Gene', (80, 83))	('SCC', 'Gene', (89, 92))
228778	30034624	Conversely, Numb knockdown inhibited anchorage-independent proliferation in SCC cells (Figure 1B).	('knockdown', 'Var', (17, 26))	('SCC', 'Gene', (76, 79))	('anchorage-independent proliferation', 'CPA', (37, 72))	('SCC', 'Gene', '6317', (76, 79))	('inhibited', 'NegReg', (27, 36))
228779	30034624	Moreover, Numb inhibition increased the number of migrating and invading ADC cells, whereas it suppressed SCC cell migration and invasion (Figure 1C and 1D).	('suppressed', 'NegReg', (95, 105))	('SCC', 'Gene', '6317', (106, 109))	('invasion', 'CPA', (129, 137))	('increased', 'PosReg', (26, 35))	('Numb', 'Gene', (10, 14))	('inhibition', 'Var', (15, 25))	('SCC', 'Gene', (106, 109))
228784	30034624	In contrast, Numb knockdown augmented Hey1 mRNA levels in both ADC cell lines, but not in SCC cell lines (Figure 2C).	('knockdown', 'Var', (18, 27))	('augmented', 'PosReg', (28, 37))	('Hey1', 'Gene', '23462', (38, 42))	('Hey1', 'Gene', (38, 42))	('SCC', 'Gene', (90, 93))	('SCC', 'Gene', '6317', (90, 93))
228786	30034624	Numb knockdown marginally downregulated the protein levels of E-cadherin, compared to control expression levels in both ADC cell lines.	('downregulated', 'NegReg', (26, 39))	('knockdown', 'Var', (5, 14))	('protein levels', 'MPA', (44, 58))	('E-cadherin', 'Gene', (62, 72))	('E-cadherin', 'Gene', '999', (62, 72))
228789	30034624	In H1703 cells, Numb knockdown did not affect the expression of E-cadherin, Vimentin, or Snail; however, downregulation of E-cadherin was observed and Vimentin was tended to be downregulated by Numb suppression inH520 cells.	('suppression', 'NegReg', (199, 210))	('Vimentin', 'Gene', '7431', (151, 159))	('Snail', 'Gene', (89, 94))	('Vimentin', 'Gene', (76, 84))	('downregulation', 'NegReg', (105, 119))	('Numb', 'Var', (194, 198))	('H520', 'CellLine', 'CVCL:1566', (213, 217))	('Snail', 'Gene', '6615', (89, 94))	('H1703', 'CellLine', 'CVCL:1490', (3, 8))	('E-cadherin', 'Gene', (64, 74))	('E-cadherin', 'Gene', (123, 133))	('E-cadherin', 'Gene', '999', (123, 133))	('Vimentin', 'Gene', '7431', (76, 84))	('E-cadherin', 'Gene', '999', (64, 74))	('Vimentin', 'Gene', (151, 159))	('downregulated', 'NegReg', (177, 190))
228791	30034624	We also attempted the transfections in PC9 and H1703 cells but they failed.	('PC9', 'Gene', (39, 42))	('H1703', 'CellLine', 'CVCL:1490', (47, 52))	('PC9', 'Gene', '255738', (39, 42))	('transfections', 'Var', (22, 35))
228816	30034624	Furthermore, as expected, NICD1 expression in tumors from the Numb-overexpression group was downregulated compared to that in the control group.	('NICD1', 'Gene', (26, 31))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('Numb-overexpression', 'Var', (62, 81))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('tumors', 'Disease', 'MESH:D009369', (46, 52))	('tumors', 'Disease', (46, 52))	('expression', 'MPA', (32, 42))	('downregulated', 'NegReg', (92, 105))
228825	30034624	In ADC patients, high Numb expression significantly correlated with better overall survival (P = 0.004) (Figure 7A).	('high', 'Var', (17, 21))	('patients', 'Species', '9606', (7, 15))	('better', 'PosReg', (68, 74))	('overall survival', 'MPA', (75, 91))
228828	30034624	ADC patients with high NICD1 expression experienced significantly shorter survival compared to those with low NICD1 expression (P = 0.019), whereas SCC patients with high NICD1 expression tended to experience longer survival compared to those with low NICD1 expression (P = 0.083) (Figure 7C and 7D).	('shorter', 'NegReg', (66, 73))	('longer', 'PosReg', (209, 215))	('high NICD1 expression', 'Var', (18, 39))	('survival', 'MPA', (74, 82))	('SCC', 'Gene', (148, 151))	('patients', 'Species', '9606', (4, 12))	('SCC', 'Gene', '6317', (148, 151))	('patients', 'Species', '9606', (152, 160))
228829	30034624	Additionally, ADC patients with high NICD4 expression tended to experience shorter survival compared to those with low NICD4 expression (P = 0.098), whereas SCC patients with high NICD4 expression experienced significantly longer survival compared to those with low NICD4 expression (P = 0.019) (Figure 7E and 7F).	('SCC', 'Gene', (157, 160))	('SCC', 'Gene', '6317', (157, 160))	('ADC', 'Disease', (14, 17))	('longer', 'PosReg', (223, 229))	('patients', 'Species', '9606', (161, 169))	('shorter', 'NegReg', (75, 82))	('patients', 'Species', '9606', (18, 26))	('high NICD4 expression', 'Var', (32, 53))	('survival', 'MPA', (83, 91))
228840	30034624	In contrast, loss-of-function mutations in Notch receptors were found in cutaneous and lung SCC.	('loss-of-function', 'NegReg', (13, 29))	('Notch', 'Protein', (43, 48))	('SCC', 'Gene', '6317', (92, 95))	('mutations', 'Var', (30, 39))	('cutaneous', 'Disease', (73, 82))	('SCC', 'Gene', (92, 95))
228842	30034624	First of all, we found that Numb inhibits tumor proliferation, migration, and invasion of lung ADC cells in this study.	('tumor', 'Disease', (42, 47))	('invasion', 'CPA', (78, 86))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('inhibits', 'NegReg', (33, 41))	('Numb', 'Var', (28, 32))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('migration', 'CPA', (63, 72))
228846	30034624	Moreover, NICD4 was a relative poor prognostic factor in ADC and was a comparatively better prognostic factor in lung SCC.	('SCC', 'Gene', (118, 121))	('SCC', 'Gene', '6317', (118, 121))	('poor', 'NegReg', (31, 35))	('NICD4', 'Var', (10, 15))	('ADC', 'Disease', (57, 60))
228849	30034624	Moreover, our results indicate that Numb might induce switch to oncogenic or tumor suppressor signaling through different Notch receptor which is dependent on the tumor subtype.	('switch', 'Reg', (54, 60))	('Numb', 'Var', (36, 40))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('oncogenic', 'MPA', (64, 73))	('Notch', 'Protein', (122, 127))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Disease', (163, 168))	('tumor', 'Disease', (77, 82))
228852	30034624	E-cadherin is thought to be a dominant mediator of cell interactions, the loss of which results in a switch to mesenchymal phenotype.	('switch', 'Reg', (101, 107))	('results in', 'Reg', (88, 98))	('loss', 'Var', (74, 78))	('E-cadherin', 'Gene', (0, 10))	('E-cadherin', 'Gene', '999', (0, 10))
228880	30034624	Anchorage-independent cell growth was measured by MTT assays using 96-well plates with poly-HEMA coating at 72 h after Numb-siRNA transfection or at 72 h after seeding Numb-overexpressing cells.	('MTT', 'Chemical', 'MESH:C070243', (50, 53))	('Anchorage-independent cell growth', 'CPA', (0, 33))	('poly-HEMA', 'Chemical', '-', (87, 96))	('transfection', 'Var', (130, 142))
228900	29416806	High GLUT-1 expression was significantly associated with poorer prognosis [overall survival: HR = 1.833 (95% CI: 1.597-2.069, P < 0.0001); disease-free survival: HR = 1.838 (95% CI: 1.264-2.673, P < 0.0001); progression-free survival: HR = 2.451 (95% CI: 1.668-3.233, P < 0.0001); disease specific survival: HR = 1.96 (95% CI: 1.05-2.871, P < 0.0001)].	('expression', 'MPA', (12, 22))	('GLUT-1', 'Gene', (5, 11))	('GLUT-1', 'Gene', '6513', (5, 11))	('High', 'Var', (0, 4))
228901	29416806	High GLUT-1 expression may be an independent prognostic marker to predict poor survival in various types of cancers.	('High', 'Var', (0, 4))	('cancers', 'Phenotype', 'HP:0002664', (108, 115))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('cancers', 'Disease', 'MESH:D009369', (108, 115))	('GLUT-1', 'Gene', (5, 11))	('GLUT-1', 'Gene', '6513', (5, 11))	('expression', 'MPA', (12, 22))	('cancers', 'Disease', (108, 115))
228909	29416806	In contrast, anti-Glut-1 antibodies result in cell growth inhibition and apoptosis.	('antibodies', 'Var', (25, 35))	('apoptosis', 'CPA', (73, 82))	('Glut-1', 'Gene', '6513', (18, 24))	('Glut-1', 'Gene', (18, 24))	('cell growth inhibition', 'CPA', (46, 68))
228933	29416806	The overall analysis showed that high GLUT-1 expression was associated with poor OS in cancer (HR = 1.833, 95% CI: 1.597-2.069; P < 0.0001) with no significant heterogeneity (I2 = 0%) (Table 1 and Figure 2).	('high', 'Var', (33, 37))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('OS in cancer', 'Disease', (81, 93))	('expression', 'MPA', (45, 55))	('OS in cancer', 'Disease', 'MESH:C567932', (81, 93))	('GLUT-1', 'Gene', '6513', (38, 44))	('GLUT-1', 'Gene', (38, 44))
228934	29416806	Such results demonstrated that high GLUT-1 expression was an independent predictor for poor OS in multiple cancers.	('multiple cancers', 'Disease', 'MESH:D009369', (98, 114))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('poor OS', 'Disease', (87, 94))	('GLUT-1', 'Gene', '6513', (36, 42))	('GLUT-1', 'Gene', (36, 42))	('multiple cancers', 'Disease', (98, 114))	('OS', 'Chemical', '-', (92, 94))	('high', 'Var', (31, 35))	('expression', 'MPA', (43, 53))	('cancers', 'Phenotype', 'HP:0002664', (107, 114))
228935	29416806	Subgroup analysis indicated high GLUT-1 expression was significantly associated with poor OS in gastric cancer (HR = 1.858, 95%CI: 1.365-2.351; P < 0.0001), urinary carcinoma (HR = 4.589, 95% CI: 1.523-7.655; P = 0.003), ovarian carcinoma (HR = 1.823, 95%CI: 1.163-2.482; P < 0.0001); oral squamous cell carcinomas (HR = 2.224, 95% CI: 1.141-3.306; P < 0.0001); pancreatic adenocarcinoma (HR = 1.729, 95% CI: 1.177-2.282; P < 0.0001); colorectal cancer (HR = 1.473, 95% CI: 0.968-1.979; P < 0.0001); lung cancer (HR = 2.026, 95% CI: 1.278-2.775; P < 0.0002), gallbladder carcinoma (HR = 3.363, 95% CI: 0.218-6.508; P = 0.036), esophageal squamous cell carcinoma (HR = 1.815, 95%CI: 0.779-2.85; P = 0.001).	('oral squamous cell carcinomas', 'Disease', (285, 314))	('lung cancer', 'Disease', (500, 511))	('OS', 'Chemical', '-', (90, 92))	('GLUT-1', 'Gene', (33, 39))	('GLUT-1', 'Gene', '6513', (33, 39))	('carcinomas', 'Phenotype', 'HP:0030731', (304, 314))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (362, 387))	('gastric cancer', 'Disease', 'MESH:D013274', (96, 110))	('urinary carcinoma', 'Disease', 'MESH:D001749', (157, 174))	('colorectal cancer', 'Phenotype', 'HP:0003003', (435, 452))	('carcinoma', 'Phenotype', 'HP:0030731', (571, 580))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (290, 314))	('cancer', 'Phenotype', 'HP:0002664', (446, 452))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('carcinoma', 'Phenotype', 'HP:0030731', (229, 238))	('lung cancer', 'Disease', 'MESH:D008175', (500, 511))	('carcinoma', 'Phenotype', 'HP:0030731', (165, 174))	('urinary carcinoma', 'Disease', (157, 174))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (221, 238))	('esophageal squamous cell carcinoma', 'Disease', (627, 661))	('lung cancer', 'Phenotype', 'HP:0100526', (500, 511))	('gallbladder carcinoma', 'Disease', 'MESH:D005706', (559, 580))	('gastric cancer', 'Phenotype', 'HP:0012126', (96, 110))	('gallbladder carcinoma', 'Disease', (559, 580))	('ovarian carcinoma', 'Disease', (221, 238))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D010190', (362, 387))	('pancreatic adenocarcinoma', 'Disease', (362, 387))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (290, 313))	('colorectal cancer', 'Disease', 'MESH:D015179', (435, 452))	('carcinoma', 'Phenotype', 'HP:0030731', (378, 387))	('high', 'Var', (28, 32))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (638, 661))	('oral squamous cell carcinomas', 'Disease', 'MESH:D002294', (285, 314))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (221, 238))	('colorectal cancer', 'Disease', (435, 452))	('cancer', 'Phenotype', 'HP:0002664', (505, 511))	('carcinoma', 'Phenotype', 'HP:0030731', (304, 313))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (627, 661))	('gastric cancer', 'Disease', (96, 110))
228958	29416806	We performed subgroup analysis and the results revealed that patients with high GLUT-1 expression were more likely to have poor OS in gastric cancer, urinary carcinoma, ovarian carcinoma, oral squamous cell carcinoma, pancreatic adenocarcinoma, colorectal cancer, lung cancer, gallbladder carcinoma, esophageal squamous cell carcinoma.	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (300, 334))	('carcinoma', 'Phenotype', 'HP:0030731', (289, 298))	('gallbladder carcinoma', 'Disease', (277, 298))	('gastric cancer', 'Disease', (134, 148))	('carcinoma', 'Phenotype', 'HP:0030731', (177, 186))	('cancer', 'Phenotype', 'HP:0002664', (256, 262))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (169, 186))	('urinary carcinoma', 'Disease', 'MESH:D001749', (150, 167))	('lung cancer', 'Disease', 'MESH:D008175', (264, 275))	('GLUT-1', 'Gene', (80, 86))	('GLUT-1', 'Gene', '6513', (80, 86))	('OS', 'Chemical', '-', (128, 130))	('patients', 'Species', '9606', (61, 69))	('ovarian carcinoma', 'Disease', (169, 186))	('colorectal cancer', 'Disease', 'MESH:D015179', (245, 262))	('gastric cancer', 'Disease', 'MESH:D013274', (134, 148))	('carcinoma', 'Phenotype', 'HP:0030731', (207, 216))	('lung cancer', 'Phenotype', 'HP:0100526', (264, 275))	('carcinoma', 'Phenotype', 'HP:0030731', (158, 167))	('urinary carcinoma', 'Disease', (150, 167))	('colorectal cancer', 'Disease', (245, 262))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (188, 216))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (218, 243))	('cancer', 'Phenotype', 'HP:0002664', (269, 275))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (169, 186))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('oral squamous cell carcinoma', 'Disease', (188, 216))	('esophageal squamous cell carcinoma', 'Disease', (300, 334))	('carcinoma', 'Phenotype', 'HP:0030731', (234, 243))	('gastric cancer', 'Phenotype', 'HP:0012126', (134, 148))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (193, 216))	('high', 'Var', (75, 79))	('lung cancer', 'Disease', (264, 275))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (311, 334))	('colorectal cancer', 'Phenotype', 'HP:0003003', (245, 262))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D010190', (218, 243))	('pancreatic adenocarcinoma', 'Disease', (218, 243))	('gallbladder carcinoma', 'Disease', 'MESH:D005706', (277, 298))
228964	29416806	In addition, our results demonstrated that high GLUT-1 expression was more closely related to poor DFS in Western patients than in Asian populations, and similar significant predictive value was also seen in OS.	('high', 'Var', (43, 47))	('poor DFS', 'Disease', (94, 102))	('OS', 'Chemical', '-', (208, 210))	('expression', 'MPA', (55, 65))	('related', 'Reg', (83, 90))	('patients', 'Species', '9606', (114, 122))	('GLUT-1', 'Gene', (48, 54))	('GLUT-1', 'Gene', '6513', (48, 54))
228965	29416806	In the light of higher quality paper, the results indicated that high GLUT-1 expression was neither associated with OS, nor with DFS.	('GLUT-1', 'Gene', (70, 76))	('expression', 'MPA', (77, 87))	('DFS', 'Disease', (129, 132))	('GLUT-1', 'Gene', '6513', (70, 76))	('associated', 'Reg', (100, 110))	('high', 'Var', (65, 69))	('OS', 'Chemical', '-', (116, 118))
228975	29416806	Fourthly, there was inevitable bias in our analysis of the association between high GLUT-1 expression and OS, due to the lack of sufficient number of studies.	('expression', 'MPA', (91, 101))	('GLUT-1', 'Gene', '6513', (84, 90))	('GLUT-1', 'Gene', (84, 90))	('high', 'Var', (79, 83))	('OS', 'Chemical', '-', (106, 108))
228979	28849087	Identification of long non-coding RNA 00312 and 00673 in human NSCLC tissues Non-small cell lung cancer (NSCLC) is a fatal disease to human health.	('NSCLC', 'Disease', (63, 68))	('NSCLC', 'Disease', 'MESH:D002289', (105, 110))	('human', 'Species', '9606', (134, 139))	('lung cancer', 'Phenotype', 'HP:0100526', (92, 103))	('NSCLC', 'Disease', 'MESH:D002289', (63, 68))	('human', 'Species', '9606', (57, 62))	('NSCLC', 'Phenotype', 'HP:0030358', (105, 110))	('Non-small cell lung cancer', 'Disease', (77, 103))	('Non-small cell lung cancer', 'Disease', 'MESH:D002289', (77, 103))	('Non-small cell lung cancer', 'Phenotype', 'HP:0030358', (77, 103))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (81, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('NSCLC', 'Phenotype', 'HP:0030358', (63, 68))	('NSCLC', 'Disease', (105, 110))	('00673', 'Var', (48, 53))
228982	28849087	Previous studies identified that long non-coding RNAs, linc00312 and linc00673 are markedly associated with lung cancer.	('linc00312', 'Gene', (55, 64))	('lung cancer', 'Disease', 'MESH:D008175', (108, 119))	('linc00673', 'Gene', '100499467', (69, 78))	('long non-coding RNAs', 'Var', (33, 53))	('lung cancer', 'Disease', (108, 119))	('linc00312', 'Gene', '29931', (55, 64))	('lung cancer', 'Phenotype', 'HP:0100526', (108, 119))	('linc00673', 'Gene', (69, 78))	('associated', 'Reg', (92, 102))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
228987	28849087	In conclusion, lncRNA 00312 and 00673 may serve as potential novel biomarkers for lung cancer early diagnosis, which may play a vital role in treatments of NSCLC.	('lung cancer', 'Phenotype', 'HP:0100526', (82, 93))	('NSCLC', 'Phenotype', 'HP:0030358', (156, 161))	('lung cancer', 'Disease', (82, 93))	('00673', 'Var', (32, 37))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('lung cancer', 'Disease', 'MESH:D008175', (82, 93))	('NSCLC', 'Disease', (156, 161))	('NSCLC', 'Disease', 'MESH:D002289', (156, 161))	('lncRNA 00312', 'Var', (15, 27))
229018	28849087	Based on the previous findings, the authors focused on the two novel lncRNAs (linc00312 and lin00673) and further detected their expression in NSCLC cell lines and tissues.	('lin00673', 'Var', (92, 100))	('linc00312', 'Gene', '29931', (78, 87))	('NSCLC', 'Disease', (143, 148))	('detected', 'Reg', (114, 122))	('linc00312', 'Gene', (78, 87))	('NSCLC', 'Disease', 'MESH:D002289', (143, 148))	('NSCLC', 'Phenotype', 'HP:0030358', (143, 148))
229034	28849087	The ROC curves illustrated strong separation between the tumor tissues and control group, with an AUC of 0.803 (95% CI: 0.732-0.873; P<0.0001) for linc00312 and 0.653 (95% CI: 0.5663-0.7395; P<0.001) for linc00673 respectively (Fig.	('linc00673', 'Gene', (204, 213))	('0.653', 'Var', (161, 166))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('linc00312', 'Gene', '29931', (147, 156))	('linc00673', 'Gene', '100499467', (204, 213))	('tumor', 'Disease', (57, 62))	('linc00312', 'Gene', (147, 156))
229036	28849087	The ROC curves indicated that there was strong separation between LAD and paired normal tissues, with an AUC of 0.717 (95% CI: 0738-0.917; P<0.001) for linc673 (Fig.	('linc673', 'Var', (152, 159))	('LAD', 'Disease', 'MESH:C535887', (66, 69))	('LAD', 'Disease', (66, 69))
229038	28849087	In addition, there was no difference between the LAD and LSCC group, with an AUC of 0.828 (95% CI: 0738-0.917; P<0.0001) and 0.7959 (95% CI: 0.687-0.905; P<0.0001) for linc00312, respectively (Fig.	('LAD', 'Disease', (49, 52))	('SCC', 'Phenotype', 'HP:0002860', (58, 61))	('LSCC', 'Phenotype', 'HP:0030359', (57, 61))	('0.7959', 'Var', (125, 131))	('LAD', 'Disease', 'MESH:C535887', (49, 52))	('LSCC', 'Chemical', '-', (57, 61))	('linc00312', 'Gene', '29931', (168, 177))	('linc00312', 'Gene', (168, 177))
229045	28849087	On average, lncRNAs, which were considered as 'transcription noise' and 'junk', now has been reported to serve important biological functions in various of diseases and cancers such as cardiovascular disease, prostate cancer, thyroid cancer, hepatocellular carcinoma and gastric cancer.	('diseases and cancers', 'Disease', 'MESH:D009369', (156, 176))	('prostate cancer', 'Phenotype', 'HP:0012125', (209, 224))	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (242, 266))	('prostate cancer', 'Disease', (209, 224))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('thyroid cancer', 'Disease', 'MESH:D013964', (226, 240))	('gastric cancer', 'Disease', 'MESH:D013274', (271, 285))	('lncRNAs', 'Var', (12, 19))	('cancer', 'Phenotype', 'HP:0002664', (279, 285))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (242, 266))	('thyroid cancer', 'Phenotype', 'HP:0002890', (226, 240))	('gastric cancer', 'Phenotype', 'HP:0012126', (271, 285))	('hepatocellular carcinoma', 'Disease', (242, 266))	('cardiovascular disease', 'Phenotype', 'HP:0001626', (185, 207))	('carcinoma', 'Phenotype', 'HP:0030731', (257, 266))	('thyroid cancer', 'Disease', (226, 240))	('cardiovascular disease', 'Disease', 'MESH:D002318', (185, 207))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('gastric cancer', 'Disease', (271, 285))	('cardiovascular disease', 'Disease', (185, 207))	('prostate cancer', 'Disease', 'MESH:D011471', (209, 224))	('cancers', 'Phenotype', 'HP:0002664', (169, 176))
229046	28849087	For instance, MALAT-1 generally can be cleaved to small cytoplasmic RNA and large MALAT-1 fragments by RNaseP and RNaseZ, and the latter has the function of epigenetic repression of target genes in cancers through alternative splicing; HOTAIR can silence some tumor suppressor genes through H3K27 and H3K4 methylation with the combination of PCR2 and LSD.	('tumor', 'Disease', (260, 265))	('MALAT-1', 'Gene', (14, 21))	('H3K4', 'Protein', (301, 305))	('silence', 'NegReg', (247, 254))	('HOTAIR', 'Gene', (236, 242))	('MALAT-1', 'Gene', '378938', (82, 89))	('tumor', 'Disease', 'MESH:D009369', (260, 265))	('cancers', 'Disease', (198, 205))	('cancers', 'Phenotype', 'HP:0002664', (198, 205))	('cancers', 'Disease', 'MESH:D009369', (198, 205))	('MALAT-1', 'Gene', (82, 89))	('H3K27', 'Protein', (291, 296))	('HOTAIR', 'Gene', '100124700', (236, 242))	('MALAT-1', 'Gene', '378938', (14, 21))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('tumor', 'Phenotype', 'HP:0002664', (260, 265))	('methylation', 'Var', (306, 317))
229052	28849087	In the present study, the authors mainly focused on two intergenic lncRNA 00312 and 00673 and aimed to establish their regulation pattern in NSCLC.	('00673', 'Var', (84, 89))	('NSCLC', 'Disease', (141, 146))	('NSCLC', 'Disease', 'MESH:D002289', (141, 146))	('00312', 'Var', (74, 79))	('NSCLC', 'Phenotype', 'HP:0030358', (141, 146))
229088	27042229	The eligibility criteria included: (i) histological diagnosis of ESCC; (ii) age > 18 years; (iii) Eastern Cooperative Oncology Group (ECOG) performance status 0-2; (iv) at least one measurable lesion; (v) failure of the initial or second-line chemotherapy; (vi) no prior exposure to irinotecan or 5-fluorouracil (5-FU) as first-line chemotherapy; and (vii) adequate hematologic, hepatic, and renal functions (absolute neutrophil count > 1.5 x 109/l, platelet count > 100 x 109/l, total bilirubin <= 1.5 x upper limit of normal, aspartate transaminase and alanine transaminase <= 2 x upper limit of normal, and creatinine <= 1.5 mg/dl).	('irinotecan', 'Chemical', 'MESH:D000077146', (283, 293))	('platelet count', 'CPA', (450, 464))	('total bilirubin', 'MPA', (480, 495))	('hepatic', 'CPA', (379, 386))	('5-FU', 'Chemical', 'MESH:D005472', (313, 317))	('creatinine', 'MPA', (610, 620))	('hematologic', 'CPA', (366, 377))	('ESCC', 'Disease', (65, 69))	('fluorouracil', 'Chemical', 'MESH:D005472', (299, 311))	('Oncology', 'Phenotype', 'HP:0002664', (118, 126))	('> 100 x 109/l', 'Var', (465, 478))
229175	24571613	Panel 1 consists of five lung cancer cDNA arrays (HLRT101, HLRT102, HLRT103, HLRT104, and HLRT105) purchased from OriGene Technologies (Rockville, MD).	('lung cancer', 'Disease', (25, 36))	('lung cancer', 'Phenotype', 'HP:0100526', (25, 36))	('HLRT103', 'Var', (68, 75))	('HLRT104', 'Var', (77, 84))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('lung cancer', 'Disease', 'MESH:D008175', (25, 36))
229182	24571613	The reference genes ACTB (Hs99999903_m1), GAPDH (Hs99999905_m1) and GUSB (AssyID: Hs99999908_m1) were purchased from Life Technologies.	('GAPDH', 'Gene', '2597', (42, 47))	('Hs99999903_m1', 'Var', (26, 39))	('GAPDH', 'Gene', (42, 47))	('GUSB', 'Gene', '2990', (68, 72))	('ACTB', 'Gene', (20, 24))	('ACTB', 'Gene', '60', (20, 24))	('Hs99999905_m1', 'Var', (49, 62))	('GUSB', 'Gene', (68, 72))
229254	33322698	CDKN2A-Inactivated Pancreatic Ductal Adenocarcinoma Exhibits Therapeutic Sensitivity to Paclitaxel: A Bioinformatics Study The mutation of cyclin dependent kinase inhibitor 2A (CDKN2A) is frequently found in pancreatic ductal adenocarcinoma (PDAC).	('CDKN2A', 'Gene', (177, 183))	('Pancreatic Ductal Adenocarcinoma', 'Disease', 'MESH:D021441', (19, 51))	('Pancreatic Ductal Adenocarcinoma', 'Disease', (19, 51))	('CDKN2A', 'Gene', '1029', (177, 183))	('mutation', 'Var', (127, 135))	('pancreatic ductal adenocarcinoma', 'Disease', (208, 240))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (208, 240))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (208, 240))	('carcinoma', 'Phenotype', 'HP:0030731', (231, 240))	('carcinoma', 'Phenotype', 'HP:0030731', (42, 51))	('CDKN2A', 'Gene', (0, 6))	('found', 'Reg', (199, 204))	('PD', 'Disease', 'MESH:D010300', (242, 244))	('Pancreatic Ductal Adenocarcinoma', 'Phenotype', 'HP:0006725', (19, 51))	('Paclitaxel', 'Chemical', 'MESH:D017239', (88, 98))	('CDKN2A', 'Gene', '1029', (0, 6))
229256	33322698	In this study, we mined and integrated the cancer genomics and chemogenomics data to investigate the roles of CDKN2A genetic alterations in PDAC patients' prognosis and treatment.	('patients', 'Species', '9606', (145, 153))	('CDKN2A', 'Gene', (110, 116))	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('PD', 'Disease', 'MESH:D010300', (140, 142))	('cancer', 'Disease', (43, 49))	('rat', 'Species', '10116', (129, 132))	('rat', 'Species', '10116', (33, 36))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('genetic alterations', 'Var', (117, 136))
229257	33322698	We found that functional CDKN2A inactivation caused by mutations and deep deletions predicted poor prognosis in PDAC patients.	('PD', 'Disease', 'MESH:D010300', (112, 114))	('deep deletions', 'Var', (69, 83))	('mutations', 'Var', (55, 64))	('inactivation', 'NegReg', (32, 44))	('CDKN2A', 'Gene', (25, 31))	('patients', 'Species', '9606', (117, 125))
229258	33322698	CDKN2A inactivation was associated with the upregulation of genes related to estrogen response, which can be overcome by CDKN2A restoration.	('upregulation', 'PosReg', (44, 56))	('inactivation', 'Var', (7, 19))	('rat', 'Species', '10116', (133, 136))	('CDKN2A', 'Gene', (0, 6))
229266	33322698	The major driver gene mutation for PDAC tumorigenesis are Kirsten rat sarcoma 2 viral oncogene homolog (KRAS), tumor protein p53 (TP53), SMAD family member 4 (SMAD4), and cyclin dependent kinase inhibitor 2A (CDKN2A).	('SMAD4', 'Gene', (159, 164))	('KRAS', 'Gene', '24525', (104, 108))	('sarcoma', 'Disease', (70, 77))	('mutation', 'Var', (22, 30))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('SMAD family member 4', 'Gene', (137, 157))	('TP53', 'Gene', '24842', (130, 134))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('sarcoma', 'Phenotype', 'HP:0100242', (70, 77))	('SMAD4', 'Gene', '50554', (159, 164))	('TP53', 'Gene', (130, 134))	('KRAS', 'Gene', (104, 108))	('SMAD family member 4', 'Gene', '50554', (137, 157))	('tumor', 'Disease', (111, 116))	('tumor', 'Disease', (40, 45))	('rat', 'Species', '10116', (66, 69))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('PD', 'Disease', 'MESH:D010300', (35, 37))	('sarcoma', 'Disease', 'MESH:D012509', (70, 77))
229271	33322698	CDKN2A is frequently inactivated in cancers due to genetic alterations by point mutation, homozygous deletion, promoter hypermethylation, and loss of heterozygosity.	('point mutation', 'Var', (74, 88))	('cancers', 'Disease', 'MESH:D009369', (36, 43))	('promoter', 'MPA', (111, 119))	('cancers', 'Phenotype', 'HP:0002664', (36, 43))	('cancers', 'Disease', (36, 43))	('loss of heterozygosity', 'Var', (142, 164))	('homozygous deletion', 'Var', (90, 109))	('CDKN2A', 'Gene', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('rat', 'Species', '10116', (63, 66))
229272	33322698	In this study, we performed a bioinformatics analysis to investigate the prognostic and therapeutic impacts of CDKN2A inactivation in PDAC.	('inactivation', 'Var', (118, 130))	('PD', 'Disease', 'MESH:D010300', (134, 136))	('CDKN2A', 'Gene', (111, 117))
229275	33322698	The genetic (mutation, copy number variation, and mRNA expression) and prognostic (overall survival) data for cancer patients ("TCGA, PanCancer Atlas" data set) were obtained from the cBioPortal (accessed on 27 November 2020).	('copy number variation', 'Var', (23, 44))	('cancer', 'Disease', (110, 116))	('mRNA expression', 'MPA', (50, 65))	('Cancer', 'Phenotype', 'HP:0002664', (137, 143))	('Cancer', 'Disease', (137, 143))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('Cancer', 'Disease', 'MESH:D009369', (137, 143))	('patients', 'Species', '9606', (117, 125))	('cancer', 'Disease', 'MESH:D009369', (110, 116))
229292	33322698	We obtained 168 PDAC patients with complete genomics data (mutations, copy number variations, and mRNA levels).	('patients', 'Species', '9606', (21, 29))	('mRNA levels', 'MPA', (98, 109))	('copy number variations', 'Var', (70, 92))	('PD', 'Disease', 'MESH:D010300', (16, 18))
229293	33322698	As shown in Figure 1a, 29% and 21% of PDAC patients harbored deep deletions and mutations of the CDKN2A gene, respectively.	('CDKN2A', 'Gene', (97, 103))	('mutations', 'Var', (80, 89))	('patients', 'Species', '9606', (43, 51))	('PD', 'Disease', 'MESH:D010300', (38, 40))	('deep deletions', 'Var', (61, 75))	('harbored', 'Reg', (52, 60))
229297	33322698	It has been suggested that the mutant CDKN2A genes may encode functionally inactivated proteins in cancer cells.	('mutant', 'Var', (31, 37))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('cancer', 'Disease', (99, 105))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('CDKN2A', 'Gene', (38, 44))	('functionally', 'MPA', (62, 74))
229298	33322698	The above results implied that CDKN2A mRNA expression itself was not a good prognostic biomarker for PDAC due to the high transcript levels of the mutant CDKN2A gene.	('mutant', 'Var', (147, 153))	('CDKN2A', 'Gene', (154, 160))	('PD', 'Disease', 'MESH:D010300', (101, 103))	('transcript levels', 'MPA', (122, 139))	('high', 'PosReg', (117, 121))
229301	33322698	Interestingly, PDAC patients with CDKN2A mutation (MUT) or deep deletion (DEEP LOSS) had poorer overall survivals compared with those with WT or shallow deletion (LOSS) of the CDKN2A gene (Figure 1d).	('PD', 'Disease', 'MESH:D010300', (15, 17))	('overall', 'MPA', (96, 103))	('poorer', 'NegReg', (89, 95))	('mutation', 'Var', (41, 49))	('CDKN2A', 'Gene', (34, 40))	('patients', 'Species', '9606', (20, 28))	('deep deletion', 'Var', (59, 72))
229302	33322698	Similarly, the primary therapy outcomes for PDAC patients with CDKN2A-MUT and CDKN2A-DEEP LOSS were worse than those with CDKN2A-WT and CDKN2A-LOSS (Figure 1e).	('PD', 'Disease', 'MESH:D010300', (44, 46))	('worse', 'NegReg', (100, 105))	('LOSS', 'NegReg', (90, 94))	('CDKN2A-DEEP', 'Var', (78, 89))	('patients', 'Species', '9606', (49, 57))	('CDKN2A-MUT', 'Var', (63, 73))
229305	33322698	As shown in Figure 1f,g, PDAC patients with inactivated CDKN2A had worse prognostic values in overall survivals and primary therapy outcomes than those with functional CDKN2A.	('overall survivals', 'CPA', (94, 111))	('inactivated', 'Var', (44, 55))	('PD', 'Disease', 'MESH:D010300', (25, 27))	('patients', 'Species', '9606', (30, 38))	('CDKN2A', 'Gene', (56, 62))
229307	33322698	We performed a pan-cancer analysis for CDKN2A alterations using the "TCGA, PanCancer Atlas" data set.	('Cancer', 'Disease', (78, 84))	('CDKN2A', 'Gene', (39, 45))	('cancer', 'Disease', 'MESH:D009369', (19, 25))	('Cancer', 'Disease', 'MESH:D009369', (78, 84))	('rat', 'Species', '10116', (50, 53))	('cancer', 'Disease', (19, 25))	('Cancer', 'Phenotype', 'HP:0002664', (78, 84))	('alterations', 'Var', (46, 57))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))
229309	33322698	The cancer genomics (mutations, copy number variations, and mRNA levels) and patients' survival data (Table S1b-g) in these cancer types were analyzed for the role of CDKN2A.	('cancer', 'Disease', (124, 130))	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('copy number variations', 'Var', (32, 54))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('patients', 'Species', '9606', (77, 85))	('mRNA levels', 'MPA', (60, 71))	('cancer', 'Disease', 'MESH:D009369', (4, 10))	('cancer', 'Disease', (4, 10))	('cancer', 'Disease', 'MESH:D009369', (124, 130))
229310	33322698	CDKN2A mutations also reduced CDKN2A gene levels in GBM and HNSC, but had no effects on the other four cancer types.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('CDKN2A', 'Gene', (30, 36))	('reduced', 'NegReg', (22, 29))	('CDKN2A', 'Gene', (0, 6))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('mutations', 'Var', (7, 16))
229313	33322698	Interestingly, the mutations and copy number variations of the CDKN2A gene did not affect the patients' overall survival in GBM, ESCA, SKCM, LUSC, and BLCA (Figure S4a,c-f).	('affect', 'Reg', (83, 89))	('patients', 'Species', '9606', (94, 102))	('copy number variations', 'Var', (33, 55))	('LUSC', 'Disease', (141, 145))	('SKCM', 'Disease', (135, 139))	('GBM', 'Disease', (124, 127))	('mutations', 'Var', (19, 28))	('BLCA', 'Disease', (151, 155))	('ESCA', 'Disease', (129, 133))	('CDKN2A', 'Gene', (63, 69))
229314	33322698	An exception was that HNSC patients with lower CDKN2A mRNA levels had a poorer overall survival (Figure S3b), which may be resulted from the shallow and deep deletions, and partly mutations, of the CDKN2A gene that exhibited prognostic impact on patients' overall survival (Figure S4b).	('CDKN2A', 'Gene', (198, 204))	('mutations', 'Var', (180, 189))	('patients', 'Species', '9606', (246, 254))	('overall', 'MPA', (79, 86))	('CDKN2A', 'Gene', (47, 53))	('lower', 'NegReg', (41, 46))	('resulted', 'Reg', (123, 131))	('poorer', 'NegReg', (72, 78))	('patients', 'Species', '9606', (27, 35))	('mRNA levels', 'MPA', (54, 65))
229315	33322698	Consistently, HNSC patients with CDKN2A gene mutations and deletions had worse primary therapy outcome (Figure S5).	('mutations', 'Var', (45, 54))	('CDKN2A', 'Gene', (33, 39))	('deletions', 'Var', (59, 68))	('patients', 'Species', '9606', (19, 27))
229316	33322698	Therefore, we conclude that the impact of CDKN2A genetic alterations is cancer type-specific.	('genetic alterations', 'Var', (49, 68))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('rat', 'Species', '10116', (61, 64))	('CDKN2A', 'Gene', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('cancer', 'Disease', (72, 78))
229317	33322698	To further investigate the role of CDKN2A inactivation in PDAC, the gene expression profile in PDAC patients (TCGA-PAAD data set) with CDKN2A mutation and deep deletion (compared to those with CDKN2A wildtype and shallow deletion) were analyzed by GSEA for 50 cancer hallmark enrichment.	('CDKN2A', 'Gene', (135, 141))	('PD', 'Disease', 'MESH:D010300', (95, 97))	('GSEA', 'Chemical', '-', (248, 252))	('deep deletion', 'Var', (155, 168))	('PD', 'Disease', 'MESH:D010300', (58, 60))	('patients', 'Species', '9606', (100, 108))	('cancer hallmark enrichment', 'Disease', 'MESH:D009369', (260, 286))	('mutation', 'Var', (142, 150))	('cancer', 'Phenotype', 'HP:0002664', (260, 266))	('cancer hallmark enrichment', 'Disease', (260, 286))
229318	33322698	We found that 4 cancer hallmarks (TGF-BETA_SIGNALING, NOTCH_SIGNALING, ESTROGEN_RESPONSE_EARLY, and ESTROGEN_RESPONSE_LATE) were significantly associated with CDKN2A inactivation (mutations and deep deletions) in PDAC patients (Figure 2a, the blue bars).	('ESTROGEN_RESPONSE_LATE', 'MPA', (100, 122))	('patients', 'Species', '9606', (218, 226))	('PD', 'Disease', 'MESH:D010300', (213, 215))	('deep deletions', 'Var', (194, 208))	('inactivation', 'NegReg', (166, 178))	('NOTCH_SIGNALING', 'MPA', (54, 69))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('cancer hallmarks', 'Disease', (16, 32))	('cancer hallmarks', 'Disease', 'MESH:D009369', (16, 32))	('ESTROGEN_RESPONSE_EARLY', 'MPA', (71, 94))	('CDKN2A', 'Gene', (159, 165))
229322	33322698	Therefore, CDKN2A inactivation may alter the estrogen response in PDAC.	('inactivation', 'Var', (18, 30))	('estrogen response', 'MPA', (45, 62))	('PD', 'Disease', 'MESH:D010300', (66, 68))	('CDKN2A', 'Gene', (11, 17))	('alter', 'Reg', (35, 40))
229330	33322698	As shown in Figure S7, PDAC cells with copy numbers <-2 (deep deletion) had low CDKN2A expression levels.	('low CDKN2A expression', 'Phenotype', 'HP:0032421', (76, 97))	('PD', 'Disease', 'MESH:D010300', (23, 25))	('copy numbers <-2', 'Var', (39, 55))	('CDKN2A expression levels', 'MPA', (80, 104))	('low CDKN2A', 'Phenotype', 'HP:0032421', (76, 86))	('low', 'NegReg', (76, 79))
229334	33322698	Therefore, CDKN2A inactivation correlates with the increased sensitivity to cell cycle-targeting drugs in PDAC cell lines.	('sensitivity to cell cycle-targeting drugs', 'MPA', (61, 102))	('increased', 'PosReg', (51, 60))	('inactivation', 'Var', (18, 30))	('PD', 'Disease', 'MESH:D010300', (106, 108))	('CDKN2A', 'Gene', (11, 17))
229337	33322698	As shown in Table S2 and Figure 3b, CDKN2A-inactivated (MUT + DEEP LOSS) organoids were more sensitive to paclitaxel, SN-38, 5-FU, bortezomib, and LY2874455, which confirmed the in vitro effects of paclitaxel and SN-38 (Figure 3a).	('LY2874455', 'Chemical', 'MESH:C570663', (147, 156))	('SN-38', 'Chemical', 'MESH:D000077146', (118, 123))	('CDKN2A-inactivated', 'Gene', (36, 54))	('5-FU', 'Chemical', 'MESH:D005472', (125, 129))	('paclitaxel', 'Chemical', 'MESH:D017239', (198, 208))	('SN-38', 'Chemical', 'MESH:D000077146', (213, 218))	('bortezomib', 'Chemical', 'MESH:D000069286', (131, 141))	('LY2874455', 'Var', (147, 156))	('sensitive', 'MPA', (93, 102))	('paclitaxel', 'Chemical', 'MESH:D017239', (106, 116))
229339	33322698	To investigate whether CDKN2A inactivation in GBM, ESCA, SKCM, LUSC, and BLCA also led to the increased sensitivity to paclitaxel and SN-38, the correlation between CDKN2A gene copy number variation and drug sensitivity was analyzed using the data obtained from the CTRP database.	('inactivation', 'Var', (30, 42))	('increased', 'PosReg', (94, 103))	('CDKN2A', 'Gene', (23, 29))	('SN-38', 'Chemical', 'MESH:D000077146', (134, 139))	('paclitaxel', 'Chemical', 'MESH:D017239', (119, 129))	('drug sensitivity', 'Phenotype', 'HP:0020174', (203, 219))
229341	33322698	In contrast, the central nervous system (CNS) cancer cell lines with lower copy numbers were more resistant to both paclitaxel and SN-38.	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('SN-38', 'Chemical', 'MESH:D000077146', (131, 136))	('cancer', 'Disease', (46, 52))	('copy numbers', 'Var', (75, 87))	('paclitaxel', 'Chemical', 'MESH:D017239', (116, 126))	('resistant', 'MPA', (98, 107))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))
229342	33322698	Other cancer types did not exhibit a significant correlation between CDKN2A copy numbers and drug sensitivity.	('drug sensitivity', 'Phenotype', 'HP:0020174', (93, 109))	('copy numbers', 'Var', (76, 88))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('cancer', 'Disease', 'MESH:D009369', (6, 12))	('cancer', 'Disease', (6, 12))	('CDKN2A', 'Gene', (69, 75))
229343	33322698	Therefore, the observations from PDAC may not be applied to other cancer types with a high frequency of CDKN2A alterations.	('rat', 'Species', '10116', (115, 118))	('PD', 'Disease', 'MESH:D010300', (33, 35))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('alterations', 'Var', (111, 122))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('CDKN2A', 'Gene', (104, 110))	('cancer', 'Disease', (66, 72))
229355	33322698	The results suggest that the CDKN2A functional inactivation caused by mutations and deep deletions predicts poor prognosis in PDAC patients.	('CDKN2A', 'Gene', (29, 35))	('patients', 'Species', '9606', (131, 139))	('PD', 'Disease', 'MESH:D010300', (126, 128))	('mutations', 'Var', (70, 79))	('functional', 'MPA', (36, 46))
229356	33322698	Besides, CDKN2A inactivation results in the upregulation of estrogen response-related genes, which can be reversed by paclitaxel.	('estrogen response-related genes', 'Gene', (60, 91))	('paclitaxel', 'Chemical', 'MESH:D017239', (118, 128))	('upregulation', 'PosReg', (44, 56))	('inactivation', 'Var', (16, 28))	('CDKN2A', 'Gene', (9, 15))
229360	33322698	Genes correlated with paclitaxel and SN-38 drug sensitivity in PDAC cell lines, Figure S1: A pan-cancer analysis for the CDKN2A genetic alterations, Figure S2.	('cancer', 'Disease', (97, 103))	('SN-38', 'Chemical', 'MESH:D000077146', (37, 42))	('drug sensitivity', 'Phenotype', 'HP:0020174', (43, 59))	('paclitaxel', 'Chemical', 'MESH:D017239', (22, 32))	('PD', 'Disease', 'MESH:D010300', (63, 65))	('alterations', 'Var', (136, 147))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('rat', 'Species', '10116', (140, 143))	('CDKN2A', 'Gene', (121, 127))	('correlated', 'Reg', (6, 16))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
229361	33322698	Effect of genetic alterations on CDKN2A mRNA expression in cancers, Figure S3.	('genetic alterations', 'Var', (10, 29))	('CDKN2A', 'Gene', (33, 39))	('mRNA expression', 'MPA', (40, 55))	('rat', 'Species', '10116', (22, 25))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('cancers', 'Disease', 'MESH:D009369', (59, 66))	('cancers', 'Phenotype', 'HP:0002664', (59, 66))	('cancers', 'Disease', (59, 66))	('Effect', 'Reg', (0, 6))
229363	33322698	Effect of CDKN2A genetic alterations on cancer patients' overall survival, Figure S5.	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('rat', 'Species', '10116', (29, 32))	('patients', 'Species', '9606', (47, 55))	('cancer', 'Disease', (40, 46))	('genetic alterations', 'Var', (17, 36))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('CDKN2A', 'Gene', (10, 16))	('overall', 'MPA', (57, 64))	('Effect', 'Reg', (0, 6))
229364	33322698	Effect of CDKN2A genetic alterations on cancer patients' primary therapy outcome, Figure S6.	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('rat', 'Species', '10116', (29, 32))	('patients', 'Species', '9606', (47, 55))	('cancer', 'Disease', (40, 46))	('genetic alterations', 'Var', (17, 36))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('CDKN2A', 'Gene', (10, 16))	('Effect', 'Reg', (0, 6))
229365	33322698	The functional impact of CDKN2A inactivation in head and neck squamous cell carcinoma, Figure S7.	('neck squamous cell carcinoma', 'Disease', (57, 85))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (57, 85))	('CDKN2A', 'Gene', (25, 31))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (48, 85))	('inactivation', 'Var', (32, 44))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (62, 85))
229366	33322698	The correlation between CDKN2A copy number variation and mRNA expression levels in pancreatic ductal adenocarcinoma cell lines, Figure S8.	('mRNA expression levels', 'MPA', (57, 79))	('CDKN2A', 'Gene', (24, 30))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (83, 115))	('copy number variation', 'Var', (31, 52))	('pancreatic ductal adenocarcinoma', 'Disease', (83, 115))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (83, 115))
229367	33322698	The correlation between CDKN2A copy number variation and paclitaxel drug activity in cancer cells, Figure S9.	('correlation', 'Interaction', (4, 15))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('paclitaxel drug activity', 'MPA', (57, 81))	('CDKN2A', 'Gene', (24, 30))	('cancer', 'Disease', (85, 91))	('paclitaxel', 'Chemical', 'MESH:D017239', (57, 67))	('copy number variation', 'Var', (31, 52))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
229368	33322698	The correlation between CDKN2A copy number variation and SN-38 drug activity in cancer cells.	('correlation', 'Interaction', (4, 15))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('CDKN2A', 'Gene', (24, 30))	('SN-38', 'Chemical', 'MESH:D000077146', (57, 62))	('SN-38', 'Gene', (57, 62))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('copy number variation', 'Var', (31, 52))	('cancer', 'Disease', (80, 86))
229372	33322698	This research was funded by the Ministry of Science and Technology, grant numbers MOST109-2314-B-038-040 and MOST109-2314-B-195-006; the health and welfare surcharge of tobacco products (WanFang Hospital, Chi-Mei Medical Center, and Hualien Tzu-Chi Hospital Joint Cancer Center Grant-Focus on Colon Cancer Research), grant number MOHW109-TDU-B-212-134020.	('Cancer', 'Phenotype', 'HP:0002664', (299, 305))	('Colon Cancer', 'Phenotype', 'HP:0003003', (293, 305))	('Colon Cancer', 'Disease', 'MESH:D015179', (293, 305))	('Colon Cancer', 'Disease', (293, 305))	('MOST109-2314-B-195-006', 'Var', (109, 131))	('Cancer', 'Phenotype', 'HP:0002664', (264, 270))	('Cancer', 'Disease', (299, 305))	('Cancer', 'Disease', (264, 270))	('tobacco', 'Species', '4097', (169, 176))	('Cancer', 'Disease', 'MESH:D009369', (299, 305))	('Cancer', 'Disease', 'MESH:D009369', (264, 270))
229415	31971940	In other words, knowledge-guided clustering finds groups of patient mutation profiles that have strong correspondence with survival characteristics yet do not simply track tumor types, suggesting alternative levels of molecular similarity.	('patient', 'Species', '9606', (60, 67))	('tumor type', 'Disease', 'MESH:D009369', (172, 182))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('mutation', 'Var', (68, 76))	('tumor type', 'Disease', (172, 182))
229416	31971940	We explored this possibility in detail (Appendix D in S2 File) and found the clusters to be characterized by mutations in genes from specific and distinct pathways, even when they are mixed in terms of tumor type representation.	('tumor type', 'Disease', 'MESH:D009369', (202, 212))	('tumor type', 'Disease', (202, 212))	('mutations', 'Var', (109, 118))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))
229420	31971940	Mimicking their approach, we first clustered the above pan-cancer cohort of patients based on their gene expression, methylation, copy number variation, or protein abundance profiles (Appendix C in S2 File and Table E in S2 Data) separately, using standard clustering.	('gene', 'MPA', (100, 104))	('patients', 'Species', '9606', (76, 84))	('methylation', 'MPA', (117, 128))	('copy number variation', 'Var', (130, 151))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('rat', 'Species', '10116', (234, 237))	('protein abundance profiles', 'MPA', (156, 182))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))
229489	31971940	The most common uses of sample clustering are in identifying subgroups in cancer patients, based on transcriptomic as well as other omics data sets, e.g., identifying breast cancer subgroups from copy number variations, colon cancer subgroups from gene expression data, refinement of breast cancer subtypes based on microRNA expression profiles, subtyping of different cancers from somatic mutation data, to name a few.	('breast cancer', 'Phenotype', 'HP:0003002', (284, 297))	('cancers', 'Phenotype', 'HP:0002664', (369, 376))	('cancers', 'Disease', (369, 376))	('cancer', 'Disease', 'MESH:D009369', (291, 297))	('cancer', 'Disease', (74, 80))	('colon cancer', 'Disease', (220, 232))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('cancer', 'Disease', 'MESH:D009369', (369, 375))	('copy number variations', 'Var', (196, 218))	('cancer', 'Disease', (174, 180))	('cancer', 'Disease', 'MESH:D009369', (226, 232))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('cancer', 'Disease', (291, 297))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancers', 'Disease', 'MESH:D009369', (369, 376))	('colon cancer', 'Phenotype', 'HP:0003003', (220, 232))	('cancer', 'Phenotype', 'HP:0002664', (291, 297))	('cancer', 'Disease', (369, 375))	('breast cancer', 'Phenotype', 'HP:0003002', (167, 180))	('patients', 'Species', '9606', (81, 89))	('cancer', 'Phenotype', 'HP:0002664', (369, 375))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('cancer', 'Disease', (226, 232))	('colon cancer', 'Disease', 'MESH:D015179', (220, 232))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
229517	31971940	In other words, knowledge-guided clustering finds groups of patient mutation profiles that 170 have strong correspondence with survival characteristics yet do not simply track tumor types, 171 suggesting alternative levels of molecular similarity.	('patient', 'Species', '9606', (60, 67))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('tumor type', 'Disease', 'MESH:D009369', (176, 186))	('tumor type', 'Disease', (176, 186))	('mutation', 'Var', (68, 76))
229518	31971940	We explored this possibility in detail 172 (Supplementary Note SN7), and found the clusters to be characterized by mutations in genes 173 from specific and distinct pathways, even when they are mixed in terms of tumor type 174 representation It is not surprising to me that these clusters would not match tumor types, since the KnowENG analysis was not designed to find tumor types (instead, its reliance on large-scale databases makes it unsurprising it clusters according to genes/pathways, since most databases will capture pathway information).	('tumor type', 'Disease', (212, 222))	('mutations', 'Var', (115, 124))	('tumor type', 'Disease', 'MESH:D009369', (212, 222))	('tumor type', 'Disease', (305, 315))	('tumor', 'Phenotype', 'HP:0002664', (305, 310))	('tumor type', 'Disease', 'MESH:D009369', (305, 315))	('tumor', 'Phenotype', 'HP:0002664', (370, 375))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('tumor type', 'Disease', (370, 380))	('tumor type', 'Disease', 'MESH:D009369', (370, 380))
229540	30701028	Knocking down the expression of LOX and especially LOXL2 in melanoma cells almost completely abrogated the invasive growth capability.	('abrogated', 'NegReg', (93, 102))	('melanoma', 'Phenotype', 'HP:0002861', (60, 68))	('melanoma cells', 'Disease', 'MESH:D008545', (60, 74))	('melanoma cells', 'Disease', (60, 74))	('invasive growth capability', 'CPA', (107, 133))	('Knocking', 'Var', (0, 8))
229542	30701028	Thus, our studies reveal that inactive pro-LOX (together with Lox propeptide) functions as a tumor suppressor in ODC- and RAS-transformed murine fibroblasts by inhibiting cell growth and invasion, and active LOX and LOXL2 as tumor promoters in human melanoma cells by promoting their invasive growth.	('LOXL2', 'Var', (216, 221))	('inhibiting', 'NegReg', (160, 170))	('tumor', 'Disease', 'MESH:D009369', (225, 230))	('human', 'Species', '9606', (244, 249))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('promoting', 'PosReg', (268, 277))	('propeptide', 'Chemical', '-', (66, 76))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('melanoma cells', 'Disease', 'MESH:D008545', (250, 264))	('melanoma cells', 'Disease', (250, 264))	('tumor', 'Disease', (93, 98))	('tumor', 'Disease', (225, 230))	('melanoma', 'Phenotype', 'HP:0002861', (250, 258))	('invasive growth', 'CPA', (284, 299))	('murine', 'Species', '10090', (138, 144))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
229546	30701028	c-Jun expression and activity have been found to be elevated in cell lines transformed by many different oncoproteins, such as receptor tyrosine kinases, Src, Ras, Raf, Fos, and Myc, and in human cancers, such as pancreatic cancer, breast cancer, sarcomas, glioblastoma, and melanoma.	('breast cancer', 'Disease', (232, 245))	('Myc', 'Gene', '4609', (178, 181))	('pancreatic cancer', 'Disease', 'MESH:D010190', (213, 230))	('Fos', 'Gene', '2353', (169, 172))	('glioblastoma', 'Disease', 'MESH:D005909', (257, 269))	('oncoproteins', 'Protein', (105, 117))	('cancers', 'Disease', 'MESH:D009369', (196, 203))	('elevated', 'PosReg', (52, 60))	('pancreatic cancer', 'Disease', (213, 230))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('c-Jun expression', 'MPA', (0, 16))	('glioblastoma', 'Disease', (257, 269))	('Fos', 'Gene', (169, 172))	('glioblastoma', 'Phenotype', 'HP:0012174', (257, 269))	('human', 'Species', '9606', (190, 195))	('activity', 'MPA', (21, 29))	('melanoma', 'Phenotype', 'HP:0002861', (275, 283))	('melanoma', 'Disease', (275, 283))	('Ras', 'Var', (159, 162))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))	('Src', 'Gene', (154, 157))	('Myc', 'Gene', (178, 181))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (213, 230))	('Raf', 'Gene', (164, 167))	('cancers', 'Phenotype', 'HP:0002664', (196, 203))	('cancers', 'Disease', (196, 203))	('sarcomas', 'Disease', 'MESH:D012509', (247, 255))	('sarcomas', 'Phenotype', 'HP:0100242', (247, 255))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('Src', 'Gene', '6714', (154, 157))	('breast cancer', 'Phenotype', 'HP:0003002', (232, 245))	('sarcomas', 'Disease', (247, 255))	('breast cancer', 'Disease', 'MESH:D001943', (232, 245))	('melanoma', 'Disease', 'MESH:D008545', (275, 283))	('Raf', 'Gene', '22882', (164, 167))
229563	30701028	To resolve this paradox, we further studied the functions of the encoded proteins by using a universal LOX inhibitor Beta-aminopropionitrile (BAPN) and knocking down of LOX and LOXL2 in melanoma cells.	('melanoma', 'Phenotype', 'HP:0002861', (186, 194))	('melanoma cells', 'Disease', 'MESH:D008545', (186, 200))	('melanoma cells', 'Disease', (186, 200))	('BAPN', 'Chemical', 'MESH:D000629', (142, 146))	('knocking down', 'Var', (152, 165))	('Beta-aminopropionitrile', 'Chemical', 'MESH:D000629', (117, 140))
229565	30701028	Further, we show that high LOXL2 mRNA expression may be correlated with metastasis and poor survival in melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (104, 112))	('melanoma', 'Disease', (104, 112))	('metastasis', 'CPA', (72, 82))	('high', 'Var', (22, 26))	('melanoma', 'Disease', 'MESH:D008545', (104, 112))
229602	30701028	Further, we compared the Kaplan-Meier survival curves of patients with primary melanomas displaying low and high expression of LOXL2 and found a significant association between high expression of LOXL2 and shorter survival time (Figure 6C).	('primary melanomas', 'Disease', 'MESH:D008545', (71, 88))	('high', 'Var', (177, 181))	('shorter', 'NegReg', (206, 213))	('patients', 'Species', '9606', (57, 65))	('primary melanomas', 'Disease', (71, 88))	('melanoma', 'Phenotype', 'HP:0002861', (79, 87))	('melanomas', 'Phenotype', 'HP:0002861', (79, 88))
229607	30701028	Notably, when the melanoma cells were co-cultured in 3D Matrigel with fibroblasts (which we have found to dramatically promote the invasion of melanoma cells), inhibition of LOX activity led to a complete inhibition of the co-invasive growth of fibroblasts and melanoma cells (both WM793 and SK-MEL-147 cells; WM793 already with 250 muM BAPN) (Figures 8 and 9).	('melanoma cells', 'Disease', 'MESH:D008545', (18, 32))	('invasion', 'CPA', (131, 139))	('inhibition', 'Var', (160, 170))	('melanoma cells', 'Disease', (18, 32))	('WM793', 'CellLine', 'CVCL:8787', (282, 287))	('inhibition', 'NegReg', (205, 215))	('promote', 'PosReg', (119, 126))	('WM793', 'CellLine', 'CVCL:8787', (310, 315))	('co-invasive growth', 'CPA', (223, 241))	('BAPN', 'Chemical', 'MESH:D000629', (337, 341))	('SK-MEL-147', 'CellLine', 'CVCL:3876', (292, 302))	('melanoma cells', 'Disease', 'MESH:D008545', (143, 157))	('melanoma', 'Phenotype', 'HP:0002861', (143, 151))	('melanoma cells', 'Disease', 'MESH:D008545', (261, 275))	('melanoma', 'Phenotype', 'HP:0002861', (18, 26))	('melanoma', 'Phenotype', 'HP:0002861', (261, 269))	('melanoma cells', 'Disease', (143, 157))	('melanoma cells', 'Disease', (261, 275))
229613	30701028	We have previously demonstrated that ODC is a downstream effector of mutant HRAS-induced transformation in NIH3T3 cells.	('mutant', 'Var', (69, 75))	('HRAS', 'Gene', '15461', (76, 80))	('NIH3T3', 'CellLine', 'CVCL:0594', (107, 113))	('HRAS', 'Gene', (76, 80))	('transformation', 'CPA', (89, 103))
229614	30701028	In cells that have been transformed by the RAS oncogene or genes signaling through RAS, the tumor suppressive action of LOX has mostly been linked to LOX-PP, which is extracellularly cleaved from pro-LOX and then uptaken by the cells.	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('LOX-PP', 'Var', (150, 156))	('tumor', 'Disease', (92, 97))	('linked', 'Reg', (140, 146))
229615	30701028	In these studies, LOX-PP has been found to reduce cell proliferation and migration in vitro and tumor formation in vivo, through inhibiting Akt, MAPK, and NFkappaB activation.	('reduce', 'NegReg', (43, 49))	('LOX-PP', 'Var', (18, 24))	('inhibiting', 'NegReg', (129, 139))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('MAPK', 'Pathway', (145, 149))	('NFkappaB', 'Protein', (155, 163))	('Akt', 'Gene', '207', (140, 143))	('tumor', 'Disease', (96, 101))	('activation', 'PosReg', (164, 174))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('Akt', 'Gene', (140, 143))	('cell proliferation', 'CPA', (50, 68))
229621	30701028	It is clear, however, that also LOX-PP has tumor suppressive functions, and several lines of evidence show that LOX-PP may be a good pharmacological agent to be used in cancer therapy.	('cancer', 'Disease', (169, 175))	('LOX-PP', 'Var', (32, 38))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('LOX-PP', 'Var', (112, 118))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Disease', (43, 48))	('cancer', 'Disease', 'MESH:D009369', (169, 175))
229623	30701028	Inhibition of LOX activity by BAPN has been found to inhibit invasion and migration of tumor cells in vitro and to reduce metastasis formation in vivo, but no or only a marginal inhibition of cell proliferation by BAPN in standard 2D cultures has usually been observed.	('inhibit', 'NegReg', (53, 60))	('BAPN', 'Chemical', 'MESH:D000629', (30, 34))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Disease', (87, 92))	('metastasis formation', 'CPA', (122, 142))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('Inhibition', 'Var', (0, 10))	('BAPN', 'Chemical', 'MESH:D000629', (214, 218))	('LOX', 'Enzyme', (14, 17))	('BAPN', 'Gene', (30, 34))	('reduce', 'NegReg', (115, 121))
229637	30701028	As a consequence of this, the collagen I content and its crosslinking (and the deposition of fibrillar ECM in general) are reduced in the ODC-transformed cells compared to normal NIH3T3 cells (N1).	('crosslinking', 'MPA', (57, 69))	('ODC-transformed', 'Var', (138, 153))	('NIH3T3', 'CellLine', 'CVCL:0594', (179, 185))	('collagen I content', 'MPA', (30, 48))	('reduced', 'NegReg', (123, 130))	('deposition of fibrillar ECM', 'MPA', (79, 106))
229651	30701028	Likewise, high LOXL2 mRNA expression has been found to associate with lymph node metastasis in esophageal squamous cell carcinoma and with decreased overall survival in lung squamous cell carcinoma and lymph node-negative breast adenocarcinoma, and in colon cancer.	('breast adenocarcinoma', 'Phenotype', 'HP:0003002', (222, 243))	('colon cancer', 'Disease', 'MESH:D015179', (252, 264))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (169, 197))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (174, 197))	('lung squamous cell carcinoma', 'Disease', (169, 197))	('overall survival', 'CPA', (149, 165))	('colon cancer', 'Disease', (252, 264))	('esophageal squamous cell carcinoma', 'Disease', (95, 129))	('lymph node metastasis', 'Disease', 'MESH:D009362', (70, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (234, 243))	('carcinoma', 'Phenotype', 'HP:0030731', (188, 197))	('breast adenocarcinoma', 'Disease', 'MESH:D000230', (222, 243))	('cancer', 'Phenotype', 'HP:0002664', (258, 264))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (169, 197))	('colon cancer', 'Phenotype', 'HP:0003003', (252, 264))	('decreased', 'NegReg', (139, 148))	('breast adenocarcinoma', 'Disease', (222, 243))	('lymph node metastasis', 'Disease', (70, 91))	('high', 'Var', (10, 14))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (95, 129))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (106, 129))
229652	30701028	In addition, high LOXL2 protein expression has been found to associate with poorer overall survival in gastric cancer, laryngeal squamous cell carcinoma, and breast cancer.	('overall survival', 'MPA', (83, 99))	('breast cancer', 'Disease', 'MESH:D001943', (158, 171))	('gastric cancer', 'Phenotype', 'HP:0012126', (103, 117))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('breast cancer', 'Disease', (158, 171))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('poorer', 'NegReg', (76, 82))	('breast cancer', 'Phenotype', 'HP:0003002', (158, 171))	('laryngeal squamous cell carcinoma', 'Disease', 'MESH:D002294', (119, 152))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (129, 152))	('high LOXL2', 'Var', (13, 23))	('gastric cancer', 'Disease', (103, 117))	('carcinoma', 'Phenotype', 'HP:0030731', (143, 152))	('gastric cancer', 'Disease', 'MESH:D013274', (103, 117))	('laryngeal squamous cell carcinoma', 'Disease', (119, 152))
229664	30701028	Odc cells stably transfected with a tetracycline-inducible expression system of the transactivation domain deletion mutant of c-Jun (pLRT-TAM67) or lysyl oxidase (pLRT-LOX) were grown in alpha-MEM containing 50 mug/ml gentamicin (Invitrogen) and 5% TET system approved FBS (Clontech, Laboratories Inc., Mountain View, CA, USA).	('FBS', 'Disease', (269, 272))	('alpha-MEM', 'Chemical', 'MESH:C420642', (187, 196))	('gentamicin', 'Chemical', 'MESH:D005839', (218, 228))	('tetracycline', 'Chemical', 'MESH:D013752', (36, 48))	('FBS', 'Disease', 'MESH:D005198', (269, 272))	('lysyl oxidase', 'Gene', (148, 161))	('lysyl oxidase', 'Gene', '4015', (148, 161))	('deletion mutant', 'Var', (107, 122))	('TET', 'Chemical', 'MESH:C010349', (249, 252))
229669	30701028	WM793, WM115, WM239, MM170, and SK-MEL-28 melanoma cell lines were cultured in RPMI 1640 (Sigma-Aldrich, St. Louis, MO, USA) containing 10% FBS and antibiotics.	('melanoma', 'Disease', (42, 50))	('WM115', 'CellLine', 'CVCL:0040', (7, 12))	('WM793', 'CellLine', 'CVCL:8787', (0, 5))	('RPMI 1640', 'Chemical', '-', (79, 88))	('WM239', 'Var', (14, 19))	('FBS', 'Disease', 'MESH:D005198', (140, 143))	('SK-MEL-28', 'CellLine', 'CVCL:0526', (32, 41))	('melanoma', 'Disease', 'MESH:D008545', (42, 50))	('melanoma', 'Phenotype', 'HP:0002861', (42, 50))	('FBS', 'Disease', (140, 143))
229678	30701028	WM793 cells were grown to 60% confluency and transduced with MISSION  shRNA Lentiviral Transduction Particles (Sigma-Aldrich) targeting LOX (SHCLNV-NM_002317; clone TRCN0000045991), LOXL2 (SHCLNV-NM_002318; clones TRCN0000046195 and TRCN0000046197) or with MISSION  Non-Mammalian shRNA Control Transduction Particles (SHC002V) in the presence of 8 mug/ml polybrene.	('SHCLNV-NM_002317', 'Var', (141, 157))	('Mammalian', 'Species', '9606', (270, 279))	('TRCN0000046197', 'Var', (233, 247))	('WM793', 'CellLine', 'CVCL:8787', (0, 5))
229730	29615105	After removal of LUAD patients with missing values, a total of 1421 LUAD patients and 51 normal controls were analyzed in this study, including 116 patients form GSE50081, 159 patients from GSE31210, 71 patients from GSE30219, 302 patients from GSE72094, 399 patients from TCGA, 342 patients and 19 normal controls from GSE68465, and 32 patients and 32 normal controls from GSE32863.	('patients', 'Species', '9606', (176, 184))	('GSE31210', 'Var', (190, 198))	('patients', 'Species', '9606', (148, 156))	('patients', 'Species', '9606', (259, 267))	('patients', 'Species', '9606', (231, 239))	('LUAD', 'Phenotype', 'HP:0030078', (17, 21))	('patients', 'Species', '9606', (283, 291))	('patients', 'Species', '9606', (22, 30))	('patients', 'Species', '9606', (203, 211))	('GSE72094', 'Var', (245, 253))	('LUAD', 'Phenotype', 'HP:0030078', (68, 72))	('patients', 'Species', '9606', (337, 345))	('patients', 'Species', '9606', (73, 81))	('GSE50081', 'Var', (162, 170))
229740	29615105	Cell lysates from different cell lines were prepared with RIPA buffer in the presence of protease inhibitor cocktails and Phosphatase Inhibitor Cocktail 2 and 3 (P8340, P5726 and P0044; Sigma-Aldrich, St Louis, MO, USA).	('P0044', 'Var', (179, 184))	('P8340', 'Var', (162, 167))	('RIPA buffer', 'Chemical', '-', (58, 69))	('P5726', 'Var', (169, 174))
229755	29615105	We found that patients with high-value expression of TBX21 had significantly higher risk than those with low values (HR = 2.008, 95% CI 1.284-3.396, P = 0.003; Fig.	('high-value expression', 'Var', (28, 49))	('patients', 'Species', '9606', (14, 22))	('TBX21', 'Gene', (53, 58))	('expression', 'Var', (39, 49))
229758	29615105	To assess the reproducibility of the prognostic model, another 1273 patients from five independent datasets (accession numbers GSE31210, GSE30219, GSE68465, GSE72094 and TCGA LUAD) were used to validate its predictive ability.	('GSE30219', 'Var', (137, 145))	('GSE31210', 'Var', (127, 135))	('patients', 'Species', '9606', (68, 76))	('GSE72094', 'Var', (157, 165))	('LUAD', 'Phenotype', 'HP:0030078', (175, 179))	('GSE68465', 'Var', (147, 155))
229760	29615105	In GSE31210, the 3-year OS rates and the 5-year OS rates of patients in the high-risk group were less than the corresponding rates in the low-risk group (88.57% and 74.70% vs 95.59% and 92.71%), respectively (Fig.	('patients', 'Species', '9606', (60, 68))	('GSE31210', 'Var', (3, 11))	('less', 'NegReg', (97, 101))
229761	29615105	The LUAD patients with high-risk scores showed significantly shorter survival than those with low-risk scores (median survival 10.60 years vs 16.10 years (P = 0.030) in GSE30219, 4.18 years vs 9.50 years (P = 2.58 x 10-6) in GSE68465, 3.07 years vs 4.27 years (P = 0.012) in GSE72094, and 5.95 years vs 13.58 years (P = 8.03 x 10-6) in TCGA LUAD) (Fig.	('patients', 'Species', '9606', (9, 17))	('shorter', 'NegReg', (61, 68))	('LUAD', 'Phenotype', 'HP:0030078', (4, 8))	('LUAD', 'Phenotype', 'HP:0030078', (341, 345))	('GSE68465', 'Var', (225, 233))	('GSE30219', 'Var', (169, 177))
229765	29615105	As shown in Additional file 2: Figure S1A, the cutoff value of TBX21 could subdivide patients with stage I into the high-risk group and low-risk group with significant survival time (HR = 2.876, 95% CI 2.087-3.963, P = 7.02 x 10-11).	('patients', 'Species', '9606', (85, 93))	('cutoff value', 'Var', (47, 59))	('TBX21', 'Gene', (63, 68))
229766	29615105	The OS rates of patients with high-risk score were 76.93% and 65.70% at 3 and 5 years, respectively, which were also significantly lower than those from patients with low-risk score whose corresponding proportions were 93.09% and 84.94%.	('patients', 'Species', '9606', (153, 161))	('patients', 'Species', '9606', (16, 24))	('high-risk score', 'Var', (30, 45))	('lower', 'NegReg', (131, 136))
229772	29615105	To confirm the high expression of TBX21 in LUAD, the TBX21 gene was firstly evaluated between adjacent normal and tumor tissues using a microarray assay from 64 samples in GSE32863 and 361 samples in GSE68465.	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumor', 'Disease', (114, 119))	('GSE32863', 'Var', (172, 180))	('LUAD', 'Phenotype', 'HP:0030078', (43, 47))	('TBX21', 'Gene', (53, 58))
229777	29615105	The result summarized the overall landscape of the significantly mutated genes in LUAD, and the patients with mutation (amplification, deep deletion, missense mutation and mRNA upregulation) altered in 154 (30%) of 520 patients (Fig.	('deep deletion', 'Var', (135, 148))	('upregulation', 'PosReg', (177, 189))	('altered', 'Reg', (191, 198))	('patients', 'Species', '9606', (96, 104))	('patients', 'Species', '9606', (219, 227))	('LUAD', 'Phenotype', 'HP:0030078', (82, 86))	('mRNA', 'MPA', (172, 176))	('missense mutation', 'Var', (150, 167))
229778	29615105	We also discovered that the total mean mutation rates of SOX2 and OCT4 (11% and 7%, respectively) were higher than the other three CSC biomarkers (3% for NANOG, 4% for KLF4 and 4% for ALDH1A1, respectively) in these patients, which was close to the TBX21 mutation rates (6%; Fig.	('OCT4', 'Gene', (66, 70))	('mutation', 'Var', (39, 47))	('NANOG', 'Gene', '79923', (154, 159))	('NANOG', 'Gene', (154, 159))	('KLF4', 'Gene', (168, 172))	('ALDH1A1', 'Gene', (184, 191))	('patients', 'Species', '9606', (216, 224))	('SOX2', 'Gene', (57, 61))	('KLF4', 'Gene', '9314', (168, 172))	('higher', 'PosReg', (103, 109))	('ALDH1A1', 'Gene', '216', (184, 191))
229782	29615105	Then, flow cytometry of TBX21-transfected A549 cells was performed to identify side populations and the result showed that the proportion of side-population (SP) cells was significantly depressed by the loss of TBX21 (P < 0.0001; Fig.	('loss', 'Var', (203, 207))	('TBX21', 'Gene', (211, 216))	('depressed', 'NegReg', (186, 195))	('A549', 'CellLine', 'CVCL:0023', (42, 46))	('SP', 'Chemical', '-', (158, 160))
229784	29615105	A549-TBX21-sc cells readily grew spheres in serum-free medium and the presence of TBX21 markedly increased the number and size of spheres compared to that of A549-TBX21-shRNAs (Fig.	('TBX21', 'Gene', (82, 87))	('A549', 'CellLine', 'CVCL:0023', (158, 162))	('presence', 'Var', (70, 78))	('increased', 'PosReg', (97, 106))	('A549', 'CellLine', 'CVCL:0023', (0, 4))
229790	29615105	In agreement, ectopic expression of TBX21 raised remarkably the proportion of SP cells (P < 0.0001; Fig.	('raised', 'PosReg', (42, 48))	('ectopic expression', 'Var', (14, 32))	('TBX21', 'Gene', (36, 41))	('SP', 'Chemical', '-', (78, 80))
229793	29615105	To further identify the role of TBX21 in regulating cancer stemness in vivo, we performed tumor xenograft studies in NOD/SCID mice injected with either A549-shTBX21 or A549-sc cells.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('cancer stemness', 'Disease', (52, 67))	('mice', 'Species', '10090', (126, 130))	('A549-shTBX21', 'Var', (152, 164))	('A549', 'CellLine', 'CVCL:0023', (168, 172))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('A549', 'CellLine', 'CVCL:0023', (152, 156))	('SCID', 'Disease', 'MESH:D053632', (121, 125))	('cancer stemness', 'Disease', 'MESH:D009369', (52, 67))	('SCID', 'Disease', (121, 125))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
229794	29615105	Similarly, the result showed a marked reduction in tumor growth in the A549-shTBX21 group versus the A549-sc control (Fig.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor', 'Disease', (51, 56))	('A549', 'CellLine', 'CVCL:0023', (101, 105))	('A549-shTBX21', 'Var', (71, 83))	('reduction', 'NegReg', (38, 47))	('A549', 'CellLine', 'CVCL:0023', (71, 75))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
229795	29615105	Furthermore, flow cytometry was conducted in the A549-shTBX21 or A549-sc tumors to identify side populations and the result showed that SP cells were significantly depressed by the loss of TBX21 (P < 0.0001; Fig.	('A549-sc tumors', 'Disease', 'MESH:C535687', (65, 79))	('A549', 'CellLine', 'CVCL:0023', (65, 69))	('SP cells', 'CPA', (136, 144))	('TBX21', 'Gene', (189, 194))	('A549', 'CellLine', 'CVCL:0023', (49, 53))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('SP', 'Chemical', '-', (136, 138))	('A549-sc tumors', 'Disease', (65, 79))	('loss', 'Var', (181, 185))	('depressed', 'NegReg', (164, 173))
229805	29615105	4c, mRNA expression of IL-4 was significantly upregulated following the reconstitution of TBX21 expression in A549 cells.	('IL-4', 'Gene', (23, 27))	('reconstitution', 'Var', (72, 86))	('A549', 'CellLine', 'CVCL:0023', (110, 114))	('IL-4', 'Gene', '3565', (23, 27))	('mRNA expression', 'MPA', (4, 19))	('TBX21', 'Gene', (90, 95))	('upregulated', 'PosReg', (46, 57))
229811	29615105	Furthermore, the SP cells were evaluated with flow cytometry, and the result showed that IL-4 gene deficiency significantly abolished the SP cell increase induced by the TBX21 gene (Fig.	('deficiency', 'Var', (99, 109))	('SP', 'Chemical', '-', (138, 140))	('IL-4', 'Gene', (89, 93))	('abolished', 'NegReg', (124, 133))	('gene', 'Var', (176, 180))	('SP cell increase', 'MPA', (138, 154))	('TBX21', 'Gene', (170, 175))	('IL-4', 'Gene', '3565', (89, 93))	('SP', 'Chemical', '-', (17, 19))
229812	29615105	In concordance with the SP, loss of IL-4 expression was discovered to abolish the sphere formation induced by TBX21 (Fig.	('IL-4', 'Gene', (36, 40))	('loss', 'Var', (28, 32))	('abolish', 'NegReg', (70, 77))	('IL-4', 'Gene', '3565', (36, 40))	('SP', 'Chemical', '-', (24, 26))	('sphere formation', 'CPA', (82, 98))	('expression', 'Protein', (41, 51))	('TBX21', 'Gene', (110, 115))
229828	29615105	The OS rates of patients with high-risk score were significantly lower than those with low-risk score at 3 and 5 years, respectively.	('OS rates', 'MPA', (4, 12))	('lower', 'NegReg', (65, 70))	('patients', 'Species', '9606', (16, 24))	('high-risk', 'Var', (30, 39))
229829	29615105	The median survival year was remarkably shorter for patients with high-risk score compared to those with low-risk score.	('shorter', 'NegReg', (40, 47))	('high-risk score', 'Var', (66, 81))	('patients', 'Species', '9606', (52, 60))	('survival', 'MPA', (11, 19))
229834	29615105	Using the LUAD cell line A549, we discovered that TBX21 could promote sphere-forming capacity concomitant with upregulated expression of stemness biomarkers SOX2 and OCT4, suggesting that TBX21 increases the self-renewal of lung CSCs.	('TBX21', 'Gene', (50, 55))	('LUAD', 'Phenotype', 'HP:0030078', (10, 14))	('expression', 'MPA', (123, 133))	('A549', 'CellLine', 'CVCL:0023', (25, 29))	('sphere-forming capacity', 'CPA', (70, 93))	('TBX21', 'Var', (188, 193))	('promote', 'PosReg', (62, 69))	('increases', 'PosReg', (194, 203))	('upregulated', 'PosReg', (111, 122))	('self-renewal of lung CSCs', 'CPA', (208, 233))
229852	26780934	Mutations in TP53 increase the risk of SOX2 copy number alterations and silencing of TP53 reduces SOX2 expression in non-small cell lung cancer Amplifications of the transcription factor, SRY (sex determining region Y)-box 2 (SOX2), are common in non-small cell lung cancer (NSCLC).	('TP53', 'Gene', (13, 17))	('silencing', 'Var', (72, 81))	('cancer', 'Disease', 'MESH:D009369', (267, 273))	('reduces', 'NegReg', (90, 97))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (117, 143))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (247, 273))	('cancer', 'Disease', (137, 143))	('SOX2', 'Gene', '6657', (98, 102))	('SOX2', 'Gene', (98, 102))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (121, 143))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('TP53', 'Gene', (85, 89))	('expression', 'MPA', (103, 113))	('NSCLC', 'Disease', 'MESH:D002289', (275, 280))	('Mutations', 'Var', (0, 9))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (117, 143))	('non-small cell lung cancer', 'Disease', (247, 273))	('TP53', 'Gene', '7157', (13, 17))	('cancer', 'Disease', (267, 273))	('NSCLC', 'Disease', (275, 280))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('cancer', 'Phenotype', 'HP:0002664', (267, 273))	('SOX2', 'Gene', '6657', (39, 43))	('lung cancer', 'Phenotype', 'HP:0100526', (262, 273))	('SOX2', 'Gene', (39, 43))	('TP53', 'Gene', '7157', (85, 89))	('non-small cell lung cancer', 'Disease', (117, 143))	('NSCLC', 'Phenotype', 'HP:0030358', (275, 280))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (247, 273))	('copy number alterations', 'MPA', (44, 67))	('SOX2', 'Gene', (226, 230))	('lung cancer', 'Phenotype', 'HP:0100526', (132, 143))	('SOX2', 'Gene', '6657', (226, 230))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (251, 273))
229855	26780934	The aim of this study was to investigate if TP53 mutational status affected SOX2 copy number variation and gene expression in early-stage NSCLC patients; moreover, to assess if TP53 regulates SOX2 expression in human lung cancer cells.	('lung cancer', 'Phenotype', 'HP:0100526', (217, 228))	('SOX2', 'Gene', (76, 80))	('copy number variation', 'MPA', (81, 102))	('TP53', 'Gene', '7157', (177, 181))	('TP53', 'Gene', (44, 48))	('NSCLC', 'Disease', 'MESH:D002289', (138, 143))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('mutational', 'Var', (49, 59))	('NSCLC', 'Disease', (138, 143))	('lung cancer', 'Disease', (217, 228))	('TP53', 'Gene', '7157', (44, 48))	('NSCLC', 'Phenotype', 'HP:0030358', (138, 143))	('gene expression', 'MPA', (107, 122))	('TP53', 'Gene', (177, 181))	('expression', 'MPA', (197, 207))	('affected', 'Reg', (67, 75))	('regulates', 'Reg', (182, 191))	('patients', 'Species', '9606', (144, 152))	('lung cancer', 'Disease', 'MESH:D008175', (217, 228))	('human', 'Species', '9606', (211, 216))
229860	26780934	The odds ratios (ORs) for associations between copy number variation and lung cancer were estimated by conditional logistic regression, and the correlation between gene status and clinicopathological characteristics was assessed by Chi-square or Fisher's exact test.	('lung cancer', 'Disease', 'MESH:D008175', (73, 84))	('copy number variation', 'Var', (47, 68))	('lung cancer', 'Disease', (73, 84))	('lung cancer', 'Phenotype', 'HP:0100526', (73, 84))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('associations', 'Interaction', (26, 38))
229861	26780934	TP53 mutations were associated with an increased risk of acquiring a SOX2 copy number alteration (OR = 2.08, 95 % CI: 1.14-3.79, p = 0.017), which was more frequently occurring in tumor tissues (34 %) than in adjacent non-tumorous tissues (3 %).	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('SOX2', 'Gene', (69, 73))	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('tumor', 'Disease', 'MESH:D009369', (222, 227))	('mutations', 'Var', (5, 14))	('tumor', 'Disease', (180, 185))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('tumor', 'Disease', (222, 227))
229864	26780934	Furthermore, TP53 knockdown reduced the miRNA hsa-miR-145, which has previously been shown to regulate SOX2 expression.	('knockdown', 'Var', (18, 27))	('TP53', 'Gene', (13, 17))	('miR', 'Gene', (50, 53))	('reduced', 'NegReg', (28, 35))	('miR', 'Gene', '220972', (50, 53))	('miR', 'Gene', (40, 43))	('miR', 'Gene', '220972', (40, 43))	('hsa-miR-145', 'Gene', '406937', (46, 57))	('TP53', 'Gene', '7157', (13, 17))	('hsa-miR-145', 'Gene', (46, 57))
229865	26780934	TP53 signaling may be important in the regulation of SOX2 copy number and expression in NSCLC tumors, and the miRNA hsa-miR-145-5p may be one potential driver.	('expression', 'MPA', (74, 84))	('TP53', 'Gene', '7157', (0, 4))	('hsa-miR-145', 'Gene', '406937', (116, 127))	('TP53', 'Gene', (0, 4))	('NSCLC', 'Phenotype', 'HP:0030358', (88, 93))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('miR', 'Gene', '220972', (120, 123))	('hsa-miR-145', 'Gene', (116, 127))	('miR', 'Gene', (120, 123))	('NSCLC tumors', 'Disease', 'MESH:D009369', (88, 100))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('NSCLC tumors', 'Disease', (88, 100))	('copy', 'Var', (58, 62))	('SOX2', 'Gene', (53, 57))	('miR', 'Gene', '220972', (110, 113))	('miR', 'Gene', (110, 113))
229872	26780934	However, alterations in the TP53 gene are among the most significant genetic events in lung cancers, often occurring as a response to DNA damage caused by exposure to a variety of genotoxic agents such as polycyclic aromatic hydrocarbons (PAHs).	('TP53', 'Gene', '7157', (28, 32))	('cancers', 'Phenotype', 'HP:0002664', (92, 99))	('lung cancers', 'Disease', (87, 99))	('TP53', 'Gene', (28, 32))	('polycyclic aromatic', 'Disease', (205, 224))	('alterations', 'Var', (9, 20))	('lung cancer', 'Phenotype', 'HP:0100526', (87, 98))	('PAHs', 'Chemical', 'MESH:D011084', (239, 243))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('lung cancers', 'Disease', 'MESH:D008175', (87, 99))	('lung cancers', 'Phenotype', 'HP:0100526', (87, 99))	('polycyclic aromatic', 'Disease', 'MESH:C537437', (205, 224))
229873	26780934	Mutations in the TP53 gene increase the risk for chromosomal rearrangements, such as copy number alterations, which are involved in the development and progression of many human malignancies including lung cancer.	('malignancies', 'Disease', 'MESH:D009369', (178, 190))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('copy number alterations', 'Disease', (85, 108))	('lung cancer', 'Disease', 'MESH:D008175', (201, 212))	('chromosomal rearrangements', 'MPA', (49, 75))	('involved', 'Reg', (120, 128))	('malignancies', 'Disease', (178, 190))	('human', 'Species', '9606', (172, 177))	('Mutations', 'Var', (0, 9))	('lung cancer', 'Phenotype', 'HP:0100526', (201, 212))	('lung cancer', 'Disease', (201, 212))	('TP53', 'Gene', '7157', (17, 21))	('TP53', 'Gene', (17, 21))
229874	26780934	Amplifications or deletions in the fragile sites harboring important transcription factors may further advance the process of carcinogenesis.	('carcinogenesis', 'Disease', 'MESH:D063646', (126, 140))	('carcinogenesis', 'Disease', (126, 140))	('Amplifications', 'Var', (0, 14))	('deletions', 'Var', (18, 27))	('advance', 'PosReg', (103, 110))
229877	26780934	In lung cancer, SOX2 gene amplification and consequent increased expression occur most frequently in squamous cell carcinoma and to a lesser extent in adenocarcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (156, 165))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('lung cancer', 'Disease', (3, 14))	('lung cancer', 'Phenotype', 'HP:0100526', (3, 14))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (101, 124))	('increased', 'PosReg', (55, 64))	('amplification', 'Var', (26, 39))	('adenocarcinoma', 'Disease', (151, 165))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (101, 124))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('expression', 'MPA', (65, 75))	('squamous cell carcinoma', 'Disease', (101, 124))	('SOX2', 'Gene', (16, 20))	('lung cancer', 'Disease', 'MESH:D008175', (3, 14))	('adenocarcinoma', 'Disease', 'MESH:D000230', (151, 165))
229880	26780934	This is of interest as a recent study showed that low levels of hsa-miR-145 are associated with unfavorable prognosis in NSCLC.	('hsa-miR-145', 'Gene', (64, 75))	('NSCLC', 'Disease', (121, 126))	('NSCLC', 'Disease', 'MESH:D002289', (121, 126))	('associated', 'Reg', (80, 90))	('NSCLC', 'Phenotype', 'HP:0030358', (121, 126))	('low levels', 'Var', (50, 60))	('hsa-miR-145', 'Gene', '406937', (64, 75))
229883	26780934	Furthermore, effects of TP53 silencing on SOX2 mRNA levels were evaluated and the possibility of miRNAs as downstream regulators was assessed.	('TP53', 'Gene', (24, 28))	('silencing', 'Var', (29, 38))	('miR', 'Gene', '220972', (97, 100))	('SOX2 mRNA levels', 'MPA', (42, 58))	('miR', 'Gene', (97, 100))	('TP53', 'Gene', '7157', (24, 28))
229897	26780934	To assess the frequency of TP53 mutations in tumor tissues DNA was screened either by single-strand conformational polymorphism or denaturating capillary electrophoresis as previously described, covering exons 4 to 9 of the TP53 gene, and DNA samples with alterations were sequenced.	('TP53', 'Gene', '7157', (27, 31))	('TP53', 'Gene', (27, 31))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('TP53', 'Gene', (224, 228))	('tumor', 'Disease', (45, 50))	('mutations', 'Var', (32, 41))	('to 9', 'Species', '1214577', (212, 216))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('TP53', 'Gene', '7157', (224, 228))
229917	26780934	Associations between copy number variation and lung cancer were estimated by odds ratios (ORs) and their 95 % confidence intervals (CIs) from conditional logistic regression adjusted for age, gender, total pack-years and tumor histology.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('Associations', 'Interaction', (0, 12))	('lung cancer', 'Disease', (47, 58))	('lung cancer', 'Phenotype', 'HP:0100526', (47, 58))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('tumor', 'Disease', (221, 226))	('copy number variation', 'Var', (21, 42))	('lung cancer', 'Disease', 'MESH:D008175', (47, 58))	('tumor', 'Disease', 'MESH:D009369', (221, 226))
229921	26780934	Analyses of gene copy numbers were performed on DNA from paired non-tumorous and tumor tissue of the same patient in order to evaluate whether genomic variations in SOX2 may be associated with lung tumor development.	('lung tumor', 'Disease', (193, 203))	('lung tumor', 'Disease', 'MESH:D008175', (193, 203))	('patient', 'Species', '9606', (106, 113))	('non-tumorous and tumor', 'Disease', 'MESH:D009369', (64, 86))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('lung tumor', 'Phenotype', 'HP:0100526', (193, 203))	('genomic variations', 'Var', (143, 161))	('associated with', 'Reg', (177, 192))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('SOX2', 'Gene', (165, 169))
229922	26780934	The SOX2 copy number alterations were more frequent in tumors than in non-tumorous tissues of NSCLC patients (Fig.	('SOX2', 'Gene', (4, 8))	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('NSCLC', 'Phenotype', 'HP:0030358', (94, 99))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('frequent', 'Reg', (43, 51))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('NSCLC', 'Disease', (94, 99))	('tumor', 'Disease', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('patients', 'Species', '9606', (100, 108))	('tumors', 'Disease', (55, 61))	('tumor', 'Disease', (74, 79))	('NSCLC', 'Disease', 'MESH:D002289', (94, 99))	('tumors', 'Disease', 'MESH:D009369', (55, 61))	('copy number alterations', 'Var', (9, 32))
229923	26780934	The odds for acquiring a copy alteration in SOX2 were 12.6-fold higher (95 % CI: 5.8-27.1) in tumors than in non-tumorous tissues.	('tumor', 'Disease', (113, 118))	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('higher', 'PosReg', (64, 70))	('copy alteration', 'Var', (25, 40))	('tumor', 'Disease', (94, 99))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumors', 'Disease', (94, 100))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('SOX2', 'Gene', (44, 48))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))
229927	26780934	1b), and SOX2 copy number alterations were most frequent in squamous cell carcinoma (Fig.	('SOX2', 'Gene', (9, 13))	('copy number alterations', 'Var', (14, 37))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (60, 83))	('frequent', 'Reg', (48, 56))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (60, 83))	('squamous cell carcinoma', 'Disease', (60, 83))
229928	26780934	SOX2 mRNA expression levels were investigated in 15 tumor and 15 non-tumorous tissue samples, and a strong correlation, (r = 0.875, p = 0.001), was observed between the SOX2 copy numbers and the relative SOX2 mRNA expression level (Fig.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor', 'Disease', (52, 57))	('tumor', 'Disease', (69, 74))	('SOX2', 'Gene', (169, 173))	('copy numbers', 'Var', (174, 186))	('SOX2 mRNA expression level', 'MPA', (204, 230))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
229929	26780934	SOX2 copy number alterations did not affect the survival of the patients (data not shown).	('patients', 'Species', '9606', (64, 72))	('SOX2', 'Gene', (0, 4))	('copy number alterations', 'Var', (5, 28))
229932	26780934	Patients with mutated TP53 had a significantly higher odds of acquiring a copy number variation in SOX2 (OR = 2.08, 95 % CI: 1.14-3.79, p = 0.017) than patients without TP53 mutations (Fig.	('mutated', 'Var', (14, 21))	('TP53', 'Gene', '7157', (169, 173))	('Patients', 'Species', '9606', (0, 8))	('TP53', 'Gene', '7157', (22, 26))	('TP53', 'Gene', (169, 173))	('patients', 'Species', '9606', (152, 160))	('copy', 'MPA', (74, 78))	('SOX2', 'Gene', (99, 103))	('TP53', 'Gene', (22, 26))
229934	26780934	TP53 mutations are often occurring as a consequence of DNA-adduct formation following exposure to genotoxic carcinogens such as PAHs in cigarette smoke.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('PAHs', 'Chemical', 'MESH:D011084', (128, 132))	('mutations', 'Var', (5, 14))	('DNA-adduct formation', 'MPA', (55, 75))
229935	26780934	However, increased PAH-adduct levels did not increase the occurrence of SOX2 copy number alterations in our material (data not shown), despite a higher frequency of SOX2 gene alterations in smokers compared to the non-smoking NSCLC patients.	('PAH', 'Gene', '5053', (19, 22))	('SOX2 gene', 'Gene', (165, 174))	('NSCLC', 'Disease', 'MESH:D002289', (226, 231))	('alterations', 'Var', (175, 186))	('patients', 'Species', '9606', (232, 240))	('NSCLC', 'Phenotype', 'HP:0030358', (226, 231))	('NSCLC', 'Disease', (226, 231))	('PAH', 'Gene', (19, 22))
229938	26780934	In TP53 knockdown cells a significant 40 % reduction in SOX2 mRNA and protein expression was observed (p = 0.001, Fig.	('TP53', 'Gene', '7157', (3, 7))	('TP53', 'Gene', (3, 7))	('SOX2', 'Protein', (56, 60))	('knockdown', 'Var', (8, 17))	('reduction', 'NegReg', (43, 52))
229939	26780934	SOX2 knockdown did not affect the expression of TP53 (Fig.	('knockdown', 'Var', (5, 14))	('TP53', 'Gene', '7157', (48, 52))	('TP53', 'Gene', (48, 52))
229940	26780934	Moreover, hsa-miR-145-5p expression was significantly reduced in TP53 knockdown cells (p = 0.004, Fig.	('TP53', 'Gene', '7157', (65, 69))	('knockdown', 'Var', (70, 79))	('TP53', 'Gene', (65, 69))	('hsa-miR-145', 'Gene', '406937', (10, 21))	('hsa-miR-145', 'Gene', (10, 21))	('reduced', 'NegReg', (54, 61))
229941	26780934	In contrast, the levels of hsa-miR-145-3p, hsa-miR-200b and hsa-miR-200c remained unchanged in TP53 knockdown cells, whereas hsa-miR-429 was not expressed in these cells (data not shown).	('knockdown', 'Var', (100, 109))	('hsa-miR-145', 'Gene', '406937', (27, 38))	('miR-200b', 'Gene', '406984', (47, 55))	('hsa-miR-429', 'Gene', '554210', (125, 136))	('miR-200b', 'Gene', (47, 55))	('hsa-miR-429', 'Gene', (125, 136))	('miR-200c', 'Gene', (64, 72))	('hsa-miR-145', 'Gene', (27, 38))	('miR-200c', 'Gene', '406985', (64, 72))	('TP53', 'Gene', '7157', (95, 99))	('TP53', 'Gene', (95, 99))
229944	26780934	Comparison of tumor tissue with non-tumorous tissue obtained from the same patients confirmed that tumor tissues had significantly higher odds of acquiring a copy number alteration in the SOX2 gene.	('tumor', 'Disease', (99, 104))	('copy number alteration', 'Var', (158, 180))	('tumor', 'Disease', (14, 19))	('patients', 'Species', '9606', (75, 83))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('SOX2', 'Gene', (188, 192))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('tumor', 'Disease', (36, 41))
229945	26780934	Surprisingly, SOX2 copy number deletions were detected in a subset of tumor samples in this cohort.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('SOX2', 'Gene', (14, 18))	('copy number deletions', 'Var', (19, 40))	('tumor', 'Disease', (70, 75))	('detected', 'Reg', (46, 54))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
229946	26780934	Deletions in SOX2 copy number have not previously been reported in NSCLC and the importance of this finding remains to be elucidated.	('NSCLC', 'Phenotype', 'HP:0030358', (67, 72))	('NSCLC', 'Disease', (67, 72))	('SOX2', 'Gene', (13, 17))	('NSCLC', 'Disease', 'MESH:D002289', (67, 72))	('Deletions', 'Var', (0, 9))
229948	26780934	SOX2 has been shown to be highly expressed in approximately 90 % of pulmonary squamous cell carcinoma and to a lesser extent in adenocarcinoma and several studies have previously identified SOX2 gene amplifications in lung squamous cell carcinomas with reported frequencies from 20 % to 60 %.	('carcinomas', 'Phenotype', 'HP:0030731', (237, 247))	('pulmonary squamous cell carcinoma', 'Disease', (68, 101))	('lung squamous cell carcinomas', 'Disease', 'MESH:D002294', (218, 247))	('adenocarcinoma', 'Disease', 'MESH:D000230', (128, 142))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('SOX2', 'Gene', (190, 194))	('pulmonary squamous cell carcinoma', 'Disease', 'MESH:D002294', (68, 101))	('lung squamous cell carcinomas', 'Disease', (218, 247))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (78, 101))	('amplifications', 'Var', (200, 214))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (223, 247))	('adenocarcinoma', 'Disease', (128, 142))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (223, 246))	('SOX2', 'Gene', (0, 4))	('carcinoma', 'Phenotype', 'HP:0030731', (237, 246))
229949	26780934	Here, we observed higher frequency of SOX2 copy number amplifications in squamous cell carcinoma tumors (59 %) than in adeno- (20 %) or large cell carcinoma (34 %).	('SOX2', 'Gene', (38, 42))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (73, 96))	('large cell carcinoma', 'Phenotype', 'HP:0030360', (136, 156))	('squamous cell carcinoma tumors', 'Disease', 'MESH:D002294', (73, 103))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('cell carcinoma', 'Disease', 'MESH:C538614', (142, 156))	('squamous cell carcinoma tumors', 'Disease', (73, 103))	('copy number amplifications', 'Var', (43, 69))	('cell carcinoma', 'Disease', 'MESH:C538614', (82, 96))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (147, 156))	('cell carcinoma', 'Disease', (142, 156))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))
229951	26780934	Accordingly, SOX2 affects tumorigenesis and its overexpression increases cell migration and colony formation, while its knockdown impairs cell growth and suppresses metastasis of lung cancer cells.	('cell growth', 'CPA', (138, 149))	('impairs', 'NegReg', (130, 137))	('overexpression increases', 'PosReg', (48, 72))	('colony formation', 'CPA', (92, 108))	('suppresses', 'NegReg', (154, 164))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('lung cancer', 'Phenotype', 'HP:0100526', (179, 190))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('knockdown', 'Var', (120, 129))	('cell migration', 'CPA', (73, 87))	('metastasis of lung cancer', 'Disease', 'MESH:D009362', (165, 190))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('affects', 'Reg', (18, 25))	('SOX2', 'Gene', (13, 17))	('metastasis of lung cancer', 'Disease', (165, 190))
229955	26780934	SOX2 amplifications and overexpression have been reported as predictors of prolonged survival in squamous cell carcinomas.	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (97, 121))	('amplifications', 'Var', (5, 19))	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('prolonged', 'PosReg', (75, 84))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (97, 120))	('carcinomas', 'Phenotype', 'HP:0030731', (111, 121))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (97, 121))	('squamous cell carcinomas', 'Disease', (97, 121))	('SOX2', 'Gene', (0, 4))	('overexpression', 'Var', (24, 38))
229964	26780934	Moreover, a recent report indicated that induction of TP53 led to repressed SOX2 expression in NSCLC cells.	('NSCLC', 'Disease', 'MESH:D002289', (95, 100))	('induction', 'Var', (41, 50))	('SOX2', 'Gene', (76, 80))	('repressed', 'MPA', (66, 75))	('NSCLC', 'Phenotype', 'HP:0030358', (95, 100))	('TP53', 'Gene', '7157', (54, 58))	('TP53', 'Gene', (54, 58))	('NSCLC', 'Disease', (95, 100))	('expression', 'MPA', (81, 91))
229965	26780934	Since genetic alterations in the TP53 gene are significant events in lung cancers, and mutations in the TP53 gene increase the risk for chromosomal rearrangements such as copy number alterations, these early reports open up the possibility of TP53 as an important regulator of SOX2 in NSCLC.	('TP53', 'Gene', '7157', (104, 108))	('TP53', 'Gene', (104, 108))	('lung cancers', 'Disease', (69, 81))	('NSCLC', 'Disease', (285, 290))	('NSCLC', 'Phenotype', 'HP:0030358', (285, 290))	('TP53', 'Gene', '7157', (33, 37))	('cancers', 'Phenotype', 'HP:0002664', (74, 81))	('TP53', 'Gene', '7157', (243, 247))	('NSCLC', 'Disease', 'MESH:D002289', (285, 290))	('lung cancer', 'Phenotype', 'HP:0100526', (69, 80))	('TP53', 'Gene', (33, 37))	('lung cancers', 'Disease', 'MESH:D008175', (69, 81))	('lung cancers', 'Phenotype', 'HP:0100526', (69, 81))	('TP53', 'Gene', (243, 247))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('mutations', 'Var', (87, 96))	('genetic alterations', 'Var', (6, 25))
229967	26780934	Interestingly, patients with at least one mutation in their lung tumors possessed a 2-fold higher risk of having a copy number variation in SOX2.	('patients', 'Species', '9606', (15, 23))	('lung tumors', 'Phenotype', 'HP:0100526', (60, 71))	('lung tumors', 'Disease', (60, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('copy number variation', 'Var', (115, 136))	('lung tumors', 'Disease', 'MESH:D008175', (60, 71))	('lung tumor', 'Phenotype', 'HP:0100526', (60, 70))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('SOX2', 'Gene', (140, 144))
229968	26780934	This is to our knowledge the first study to report an association between TP53 mutations and SOX2 copy number alterations.	('copy number alterations', 'Var', (98, 121))	('SOX2', 'Gene', (93, 97))	('TP53', 'Gene', '7157', (74, 78))	('TP53', 'Gene', (74, 78))	('mutations', 'Var', (79, 88))
229969	26780934	However, individuals carrying TP53 mutations show generally higher levels of germline copy number variation.	('TP53', 'Gene', (30, 34))	('higher', 'PosReg', (60, 66))	('germline copy number variation', 'MPA', (77, 107))	('TP53', 'Gene', '7157', (30, 34))	('mutations', 'Var', (35, 44))
229970	26780934	Furthermore, smoking is known to increase the risk of acquiring TP53 mutations and, similarly, we and others have demonstrated that smokers have a higher risk of acquiring SOX2 copy number alterations in tumors.	('mutations', 'Var', (69, 78))	('SOX2', 'Gene', (172, 176))	('tumors', 'Disease', 'MESH:D009369', (204, 210))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('copy number alterations', 'Var', (177, 200))	('tumors', 'Disease', (204, 210))	('TP53', 'Gene', (64, 68))	('TP53', 'Gene', '7157', (64, 68))	('tumors', 'Phenotype', 'HP:0002664', (204, 210))
229971	26780934	Hence, TP53 mutations may contribute to SOX2 copy number alterations in lung cancer patients.	('TP53', 'Gene', '7157', (7, 11))	('TP53', 'Gene', (7, 11))	('contribute', 'Reg', (26, 36))	('patients', 'Species', '9606', (84, 92))	('mutations', 'Var', (12, 21))	('SOX2', 'Gene', (40, 44))	('copy number alterations', 'Var', (45, 68))	('lung cancer', 'Disease', (72, 83))	('lung cancer', 'Phenotype', 'HP:0100526', (72, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('lung cancer', 'Disease', 'MESH:D008175', (72, 83))
229973	26780934	To further investigate this relationship, silencing of TP53 and SOX2 was performed in the lung adenocarcinoma cell line A427.	('silencing', 'Var', (42, 51))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('lung adenocarcinoma', 'Disease', (90, 109))	('TP53', 'Gene', '7157', (55, 59))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (90, 109))	('TP53', 'Gene', (55, 59))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (90, 109))	('A427', 'CellLine', 'CVCL:1055', (120, 124))
229974	26780934	TP53 knockdown reduced SOX2 mRNA and protein expression, whereas SOX2 knockdown did not affect TP53 expression levels, indicating a regulatory role of TP53 on SOX2 in NSCLC.	('TP53', 'Gene', '7157', (0, 4))	('NSCLC', 'Disease', 'MESH:D002289', (167, 172))	('TP53', 'Gene', (0, 4))	('TP53', 'Gene', (151, 155))	('NSCLC', 'Phenotype', 'HP:0030358', (167, 172))	('knockdown', 'Var', (5, 14))	('reduced', 'NegReg', (15, 22))	('TP53', 'Gene', '7157', (95, 99))	('NSCLC', 'Disease', (167, 172))	('TP53', 'Gene', '7157', (151, 155))	('TP53', 'Gene', (95, 99))
229975	26780934	Considering the role of SOX2 in tumorigenesis it could be expected that TP53 knockdown would increase SOX2 expression.	('increase', 'PosReg', (93, 101))	('TP53', 'Gene', '7157', (72, 76))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('expression', 'MPA', (107, 117))	('knockdown', 'Var', (77, 86))	('TP53', 'Gene', (72, 76))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumor', 'Disease', (32, 37))	('SOX2', 'Gene', (102, 106))
229977	26780934	These discrepancies as well as reports on conflicting effects on NSCLC prognosis following SOX2 copy number amplification indicate that the role of SOX2 in NSCLC is far more complex than can be explained by histology or TP53 status only.	('copy number amplification', 'Var', (96, 121))	('TP53', 'Gene', '7157', (220, 224))	('TP53', 'Gene', (220, 224))	('NSCLC', 'Phenotype', 'HP:0030358', (156, 161))	('NSCLC', 'Disease', 'MESH:D002289', (65, 70))	('NSCLC', 'Phenotype', 'HP:0030358', (65, 70))	('NSCLC', 'Disease', (156, 161))	('SOX2', 'Gene', (91, 95))	('NSCLC', 'Disease', 'MESH:D002289', (156, 161))	('NSCLC', 'Disease', (65, 70))
229983	26780934	demonstrated that TP53 may play a role in modulating hsa-miR-145 expression in NSCLC, and that patients with mutations in TP53 and low hsa-miR-145 levels had lower survival in respect to patients with TP53 wild-type or only mutations in TP53.	('survival', 'MPA', (164, 172))	('TP53', 'Gene', '7157', (18, 22))	('modulating', 'Reg', (42, 52))	('TP53', 'Gene', (237, 241))	('NSCLC', 'Phenotype', 'HP:0030358', (79, 84))	('patients', 'Species', '9606', (187, 195))	('TP53', 'Gene', (201, 205))	('expression', 'MPA', (65, 75))	('hsa-miR-145', 'Gene', '406937', (53, 64))	('hsa-miR-145', 'Gene', '406937', (135, 146))	('hsa-miR-145', 'Gene', (53, 64))	('hsa-miR-145', 'Gene', (135, 146))	('TP53', 'Gene', (122, 126))	('TP53', 'Gene', '7157', (237, 241))	('TP53', 'Gene', (18, 22))	('mutations', 'Var', (109, 118))	('NSCLC', 'Disease', 'MESH:D002289', (79, 84))	('lower', 'NegReg', (158, 163))	('patients', 'Species', '9606', (95, 103))	('TP53', 'Gene', '7157', (201, 205))	('TP53', 'Gene', '7157', (122, 126))	('low', 'NegReg', (131, 134))	('NSCLC', 'Disease', (79, 84))
229993	26780934	TP53 mutations were associated with an increased risk of acquiring a SOX2 copy number amplification in NSCLC.	('TP53', 'Gene', '7157', (0, 4))	('SOX2', 'Gene', (69, 73))	('TP53', 'Gene', (0, 4))	('NSCLC', 'Disease', (103, 108))	('mutations', 'Var', (5, 14))	('NSCLC', 'Disease', 'MESH:D002289', (103, 108))	('NSCLC', 'Phenotype', 'HP:0030358', (103, 108))
230012	32075093	Alteration in the protein structure or in the expression of specific TFs are causative of tumorigenic changes in gene expression.	('Alteration', 'Var', (0, 10))	('protein', 'Protein', (18, 25))	('tumor', 'Disease', (90, 95))	('TFs', 'Gene', (69, 72))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('expression', 'MPA', (46, 56))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
230016	32075093	NF-YC is spliced at the C-terminal, generating multiple isoforms, of which the 37kD and 50kD represent the most abundant, at the mRNA and protein levels.	('37kD', 'Var', (79, 83))	('generating', 'Reg', (36, 46))	('NF-YC', 'Gene', (0, 5))	('NF-YC', 'Gene', '4802', (0, 5))
230017	32075093	The splicings involve the Gln-rich trans-activation domains (TAD) present in both NF-YA and NF-YC, hence generating isoforms with identical HFD and DNA-binding properties, but potentially different activation potential.	('NF-YC', 'Gene', (92, 97))	('Gln-rich', 'Var', (26, 34))	('trans-activation', 'PosReg', (35, 51))	('NF-YA', 'Gene', (82, 87))	('Gln', 'Chemical', 'MESH:D005973', (26, 29))	('NF-YA', 'Gene', '4800', (82, 87))	('activation', 'MPA', (198, 208))	('NF-YC', 'Gene', '4802', (92, 97))
230071	32075093	In pairwise matches, searches of TFBS found a robust enrichment of NF-Y sites only in the PI/PP overexpressed genes, together with E2Fs and Sp1/KLFs DNA motifs (Figure S4A).	('sites', 'Var', (72, 77))	('TFBS', 'Chemical', '-', (33, 37))	('NF-Y', 'Gene', (67, 71))
230078	32075093	A majority of cell lines, 16 in total, had large excess of NF-YAs, four:H1299, RERF.RC.OK, H1819, and H1703:had larger amounts of NF-YAl, and the rest had balanced levels, with a modest prevalence of NF-YAs (Figure 5A).	('H1819', 'CellLine', 'CVCL:1497;-0.02323168141434641', (91, 96))	('NF-YA', 'Gene', (200, 205))	('NF-YA', 'Gene', '4800', (130, 135))	('NF-YA', 'Gene', '4800', (59, 64))	('H1703', 'Var', (102, 107))	('NF-YA', 'Gene', (130, 135))	('larger', 'PosReg', (112, 118))	('NF-YA', 'Gene', '4800', (200, 205))	('NF-YA', 'Gene', (59, 64))	('H1299', 'Var', (72, 77))	('H1819', 'Var', (91, 96))
230079	32075093	Figure 5B shows that H1437 had only NF-YAs, which paralleled the mRNA data (Figure 5A).	('H1437', 'Var', (21, 26))	('NF-YA', 'Gene', '4800', (36, 41))	('NF-YA', 'Gene', (36, 41))
230080	32075093	At the opposite, H1299 had the highest amount of NF-YAl, whereas H2228, H1650, and H1975 had intermediate levels of the two isoforms with a prevalence of NF-YAs.	('NF-YA', 'Gene', (49, 54))	('H1975', 'Var', (83, 88))	('NF-YA', 'Gene', '4800', (49, 54))	('H1650', 'Var', (72, 77))	('NF-YA', 'Gene', (154, 159))	('H1299', 'Var', (17, 22))	('H1650', 'CellLine', 'CVCL:1483;-0.032695502866877064', (72, 77))	('NF-YA', 'Gene', '4800', (154, 159))
230100	32075093	The curves of Figure 8A show a drop in PFI in patients with either high or low ratios, compared to those with intermediate ratios (p-value 0.024).	('PFI', 'MPA', (39, 42))	('low ratios', 'Var', (75, 85))	('patients', 'Species', '9606', (46, 54))	('drop', 'NegReg', (31, 35))
230128	32075093	Thus, differential splicing is predicted to affect activation potential, and data supporting this were reported in mESCs (Mouse Embryonic Stem Cells).	('mESCs', 'Disease', (115, 120))	('differential splicing', 'Var', (6, 27))	('Mouse Embryonic Stem', 'CellLine', 'CVCL:9115;0.04949620346516789', (122, 142))	('activation potential', 'MPA', (51, 71))	('affect', 'Reg', (44, 50))
230142	32075093	(B) NF-YC splicing isoforms in GSE404119.	('NF-YC', 'Gene', '4802', (4, 9))	('GSE404119', 'Var', (31, 40))	('NF-YC', 'Gene', (4, 9))
230162	29333502	Unresectable cutaneous squamous cell carcinoma of the forehead with MLH1 mutation showing dramatic response to Programmed Cell Death Protein 1 Inhibitor Therapy Treatment of refractory, unresectable cutaneous squamous cell carcinoma presents a great challenge in head and neck oncology with poor prognosis.	('cutaneous squamous cell carcinoma', 'Phenotype', 'HP:0006739', (13, 46))	('MLH1', 'Gene', '4292', (68, 72))	('carcinoma', 'Phenotype', 'HP:0030731', (223, 232))	('MLH1', 'Gene', (68, 72))	('cutaneous squamous cell carcinoma', 'Disease', 'MESH:D002294', (13, 46))	('oncology', 'Phenotype', 'HP:0002664', (277, 285))	('cutaneous squamous cell carcinoma', 'Phenotype', 'HP:0006739', (199, 232))	('cutaneous squamous cell carcinoma', 'Disease', 'MESH:D002294', (199, 232))	('carcinoma', 'Phenotype', 'HP:0030731', (37, 46))	('head and neck oncology', 'Phenotype', 'HP:0012288', (263, 285))	('Programmed Cell Death Protein 1', 'Gene', (111, 142))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (209, 232))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (23, 46))	('Unresectable', 'Disease', (0, 12))	('cutaneous squamous cell carcinoma', 'Disease', (13, 46))	('mutation', 'Var', (73, 81))	('Programmed Cell Death Protein 1', 'Gene', '5133', (111, 142))	('cutaneous squamous cell carcinoma', 'Disease', (199, 232))
230164	29333502	In this study we present a severe case of unresectable cutaneous squamous cell carcinoma invading the orbit and cavernous sinus with documented tumor MLH1 mutation.	('cutaneous squamous cell carcinoma', 'Disease', (55, 88))	('tumor', 'Disease', (144, 149))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (65, 88))	('MLH1', 'Gene', '4292', (150, 154))	('MLH1', 'Gene', (150, 154))	('cutaneous squamous cell carcinoma', 'Phenotype', 'HP:0006739', (55, 88))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('cutaneous squamous cell carcinoma', 'Disease', 'MESH:D002294', (55, 88))	('mutation', 'Var', (155, 163))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))
230170	29333502	In this study we present a case of unresectable cutaneous SCC with documented tumor MLH1 mutation invading the orbit and cavernous sinus.	('MLH1', 'Gene', '4292', (84, 88))	('SCC', 'Gene', (58, 61))	('MLH1', 'Gene', (84, 88))	('SCC', 'Phenotype', 'HP:0002860', (58, 61))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('mutation', 'Var', (89, 97))	('SCC', 'Gene', '6317', (58, 61))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Disease', (78, 83))
230177	29333502	The results of profiling were significant for a mutation in MLH1 correlating to loss of function (MLH1 100*).	('MLH1', 'Gene', '4292', (60, 64))	('MLH1', 'Gene', (60, 64))	('MLH1', 'Gene', '4292', (98, 102))	('MLH1', 'Gene', (98, 102))	('mutation', 'Var', (48, 56))	('loss of function', 'NegReg', (80, 96))
230178	29333502	DNA mismatch repair (MMR) deficiency was suspected based on the presence of the MLH1 mutation.	('MLH1', 'Gene', '4292', (80, 84))	('presence', 'Reg', (64, 72))	('MLH1', 'Gene', (80, 84))	('mutation', 'Var', (85, 93))
230203	29333502	Preclinical studies and clinical case reports have shown that the high mutation burden20 coupled with observed immunosuppression in instances of cutaneous SCC progression implicates a utility for targeting immune checkpoint elements such as those in the PD-1 pathway.	('cutaneous', 'Disease', (145, 154))	('SCC', 'Gene', (155, 158))	('PD-1', 'Gene', (254, 258))	('SCC', 'Phenotype', 'HP:0002860', (155, 158))	('PD-1', 'Gene', '5133', (254, 258))	('SCC', 'Gene', '6317', (155, 158))	('mutation burden20', 'Var', (71, 88))
230204	29333502	The present study highlights an application of pembrolizumab in a case of cutaneous SCC with a confirmed gene mutation in MLH1, resulting from loss of DNA mismatch repair (MMR).	('SCC', 'Gene', '6317', (84, 87))	('DNA mismatch repair', 'MPA', (151, 170))	('MLH1', 'Gene', (122, 126))	('MLH1', 'Gene', '4292', (122, 126))	('pembrolizumab', 'Chemical', 'MESH:C582435', (47, 60))	('loss', 'NegReg', (143, 147))	('mutation', 'Var', (110, 118))	('SCC', 'Gene', (84, 87))	('SCC', 'Phenotype', 'HP:0002860', (84, 87))
230205	29333502	The incidence of MLH1 and other mismatch repair gene loss of function mutations in cutaneous SCC are presently unknown.	('mutations', 'Var', (70, 79))	('MLH1', 'Gene', '4292', (17, 21))	('MLH1', 'Gene', (17, 21))	('SCC', 'Gene', (93, 96))	('SCC', 'Phenotype', 'HP:0002860', (93, 96))	('SCC', 'Gene', '6317', (93, 96))	('loss of function', 'NegReg', (53, 69))
230207	29333502	Early efficacy data from studies using DNA MMR deficiency as a biomarker, suggest significant clinical activity when using PD-1 inhibitors.	('PD-1', 'Gene', '5133', (123, 127))	('PD-1', 'Gene', (123, 127))	('clinical activity', 'MPA', (94, 111))	('deficiency', 'Var', (47, 57))
230209	29333502	This case report describes the observation of a dramatic response by a patient with unresectable SCC having documented tumor genome evidence of a significant loss of function MLH1 mutation in the presence of a high mutational burden.	('tumor', 'Disease', (119, 124))	('loss of function', 'NegReg', (158, 174))	('MLH1', 'Gene', '4292', (175, 179))	('MLH1', 'Gene', (175, 179))	('SCC', 'Gene', (97, 100))	('SCC', 'Phenotype', 'HP:0002860', (97, 100))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('SCC', 'Gene', '6317', (97, 100))	('patient', 'Species', '9606', (71, 78))	('mutation', 'Var', (180, 188))
230216	29333502	This study discusses the first case of unresectable cutaneous SCC having documented evidence of an MLH1 mutation and showing complete response to treatment with off-label pembrolizumab.	('SCC', 'Phenotype', 'HP:0002860', (62, 65))	('SCC', 'Gene', '6317', (62, 65))	('MLH1', 'Gene', '4292', (99, 103))	('MLH1', 'Gene', (99, 103))	('mutation', 'Var', (104, 112))	('pembrolizumab', 'Chemical', 'MESH:C582435', (171, 184))	('cutaneous', 'Disease', (52, 61))	('SCC', 'Gene', (62, 65))
230218	29333502	Additionally, the role of DNA MMR deficiency on therapeutic outcomes through additional investigation could prove to be a predictive biomarker to guiding the appropriate selection PD-1 inhibitors in disease management.	('PD-1', 'Gene', (180, 184))	('DNA MMR', 'Gene', (26, 33))	('PD-1', 'Gene', '5133', (180, 184))	('deficiency', 'Var', (34, 44))
230254	27148421	We found that 15 specific plasma miRNAs, let-7d-3p, miR-106b-5p, miR-144-3p, miR-197-3p, miR-19b-3p, miR-211-3p, miR-30e-5p, miR-345-3p, miR-3679-3p, miR-423-5p, miR-451a, miR-4787-5p, miR-5001-5p, miR-5100 and miR-6068, could be promising biomarkers of lung squamous cell carcinoma, and nine specific plasma miRNAs, let-7d-3p, miR-223-3p, miR-21-5p, miR-33b-3p, miR-3613-3p, miR-3675-3p, miR-4728-3p, miR-5571-5p, and miR-575, could be promising biomarkers of lung adenocarcinoma.	('miR', 'Gene', '22877', (65, 68))	('miR', 'Gene', '22877', (389, 392))	('miR', 'Gene', (172, 175))	('miR', 'Gene', (402, 405))	('miR', 'Gene', (419, 422))	('miR-197-3p', 'Gene', '100302290', (77, 87))	('miR', 'Gene', (101, 104))	('miR', 'Gene', '22877', (340, 343))	('miR', 'Gene', '22877', (172, 175))	('miR', 'Gene', (89, 92))	('miR', 'Gene', (137, 140))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (254, 282))	('lung squamous cell carcinoma', 'Disease', (254, 282))	('miR-5100', 'Gene', (198, 206))	('miR-6068', 'Gene', (211, 219))	('miR', 'Gene', '22877', (52, 55))	('miR', 'Gene', '22877', (376, 379))	('miR-197-3p', 'Gene', (77, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (273, 282))	('miR', 'Gene', '22877', (185, 188))	('miR', 'Gene', (77, 80))	('miR-211-3p', 'Gene', '100302164', (101, 111))	('miR', 'Gene', (340, 343))	('miR-144', 'Gene', '406936', (65, 72))	('miR-21-5p', 'Gene', (340, 349))	('miR-5100', 'Gene', '100847014', (198, 206))	('miR', 'Gene', '22877', (77, 80))	('miR', 'Gene', (52, 55))	('miR', 'Gene', (376, 379))	('miR', 'Gene', (328, 331))	('miR', 'Gene', '22877', (211, 214))	('miR', 'Gene', (185, 188))	('miR', 'Gene', (351, 354))	('miR-33b', 'Gene', (351, 358))	('miR', 'Gene', (33, 36))	('miR-6068', 'Gene', '102464823', (211, 219))	('miR', 'Gene', '22877', (328, 331))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (461, 480))	('carcinoma', 'Phenotype', 'HP:0030731', (471, 480))	('miR', 'Gene', '22877', (351, 354))	('miR', 'Gene', '22877', (33, 36))	('miR-211-3p', 'Gene', (101, 111))	('miR', 'Gene', '22877', (309, 312))	('miR', 'Gene', (211, 214))	('miR-21-5p', 'Gene', '406997', (340, 349))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (254, 282))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (259, 282))	('miR-575', 'Gene', '693160', (419, 426))	('miR', 'Gene', (150, 153))	('miR', 'Gene', '22877', (162, 165))	('miR', 'Gene', '22877', (113, 116))	('miR', 'Gene', (309, 312))	('miR', 'Gene', (198, 201))	('miR', 'Gene', (363, 366))	('miR', 'Gene', '22877', (150, 153))	('miR-451a', 'Gene', (162, 170))	('miR', 'Gene', (125, 128))	('miR', 'Gene', '22877', (198, 201))	('miR-575', 'Gene', (419, 426))	('miR-423', 'Gene', '494335', (150, 157))	('miR', 'Gene', '22877', (363, 366))	('miR', 'Gene', '22877', (402, 405))	('miR', 'Gene', '22877', (419, 422))	('miR', 'Gene', (162, 165))	('lung adenocarcinoma', 'Disease', (461, 480))	('miR', 'Gene', '22877', (101, 104))	('miR', 'Gene', (113, 116))	('miR', 'Gene', '22877', (125, 128))	('miR-144', 'Gene', (65, 72))	('miR', 'Gene', (65, 68))	('miR-33b', 'Gene', '693120', (351, 358))	('miR', 'Gene', (389, 392))	('miR-451a', 'Gene', '574411', (162, 170))	('let-7d-3p', 'Var', (317, 326))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (461, 480))	('miR-423', 'Gene', (150, 157))	('miR', 'Gene', '22877', (89, 92))	('miR', 'Gene', '22877', (137, 140))
230257	27148421	Recent reports have revealed that the deregulation of miRNAs correlates with various human cancers and is involved in the initiation and progression of human cancers.	('cancers', 'Disease', 'MESH:D009369', (91, 98))	('miR', 'Gene', (54, 57))	('cancers', 'Phenotype', 'HP:0002664', (91, 98))	('deregulation', 'Var', (38, 50))	('involved', 'Reg', (106, 114))	('cancers', 'Disease', (91, 98))	('cancers', 'Phenotype', 'HP:0002664', (158, 165))	('miR', 'Gene', '22877', (54, 57))	('cancers', 'Disease', (158, 165))	('human', 'Species', '9606', (152, 157))	('cancers', 'Disease', 'MESH:D009369', (158, 165))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('human', 'Species', '9606', (85, 90))
230261	27148421	In recent years, changes in the expression levels of small, non-coding, single-strand RNAs, called miRNAs, have been detected and described.	('miR', 'Gene', (99, 102))	('single-strand', 'Var', (72, 85))	('miR', 'Gene', '22877', (99, 102))	('RNAs', 'Protein', (86, 90))	('expression levels', 'MPA', (32, 49))
230264	27148421	Several miRNAs located in deleted regions demonstrate low expression levels in cancer tissues.12 miRNAs can act as tumor suppressors, the dysfunction of miRNAs can initiate or contribute to the malignant transformation of a normal cell.	('initiate', 'Reg', (164, 172))	('miR', 'Gene', (153, 156))	('miR', 'Gene', '22877', (97, 100))	('miR', 'Gene', '22877', (8, 11))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('miR', 'Gene', '22877', (153, 156))	('miR', 'Gene', (97, 100))	('tumor', 'Disease', (115, 120))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('dysfunction', 'Var', (138, 149))	('malignant transformation of a normal cell', 'CPA', (194, 235))	('contribute', 'Reg', (176, 186))	('cancer', 'Disease', (79, 85))	('miR', 'Gene', (8, 11))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
230269	27148421	Our results determined 15 lung squamous cell carcinoma tissue-specific and plasma miRNAs: let-7d-3p, miR-106b-5p, miR-144-3p, miR-197-3p, miR-19b-3p, miR-211-3p, miR-30e-5p, miR-345-3p, miR-3679-3p, miR-423-5p, miR-451a, miR-4787-5p, miR-5001-5p, miR-5100, and miR-6068; and nine lung adenocarcinoma tissue-specific and plasma miRNAs: let-7d-3p, miR-223-3p, miR-21-5p, miR-33b-3p, miR-3613-3p, miR-3675-3p, miR-4728-3p, miR-5571-5p, and miR-575.	('miR', 'Gene', '22877', (327, 330))	('miR', 'Gene', (394, 397))	('miR', 'Gene', '22877', (174, 177))	('miR', 'Gene', '22877', (199, 202))	('miR', 'Gene', (101, 104))	('miR-144', 'Gene', (114, 121))	('miR', 'Gene', (186, 189))	('miR', 'Gene', (82, 85))	('let-7d-3p', 'Var', (335, 344))	('miR', 'Gene', (327, 330))	('miR', 'Gene', (174, 177))	('miR', 'Gene', (381, 384))	('miR', 'Gene', (199, 202))	('miR', 'Gene', '22877', (82, 85))	('miR-423', 'Gene', (199, 206))	('miR-144', 'Gene', '406936', (114, 121))	('miR', 'Gene', '22877', (358, 361))	('miR-21-5p', 'Gene', (358, 367))	('miR-21-5p', 'Gene', '406997', (358, 367))	('miR-5100', 'Gene', (247, 255))	('miR', 'Gene', '22877', (381, 384))	('miR', 'Gene', '22877', (221, 224))	('miR', 'Gene', (346, 349))	('lung adenocarcinoma', 'Disease', (280, 299))	('miR', 'Gene', (138, 141))	('miR', 'Gene', (407, 410))	('miR-423', 'Gene', '494335', (199, 206))	('miR', 'Gene', '22877', (211, 214))	('miR', 'Gene', '22877', (234, 237))	('miR', 'Gene', '22877', (346, 349))	('miR', 'Gene', (358, 361))	('miR', 'Gene', (437, 440))	('miR', 'Gene', '22877', (138, 141))	('miR-211-3p', 'Gene', (150, 160))	('miR-5100', 'Gene', '100847014', (247, 255))	('miR', 'Gene', '22877', (407, 410))	('miR', 'Gene', '22877', (247, 250))	('miR-451a', 'Gene', (211, 219))	('miR', 'Gene', (221, 224))	('15 lung squamous cell carcinoma', 'Disease', (23, 54))	('miR', 'Gene', '22877', (437, 440))	('miR', 'Gene', (126, 129))	('miR', 'Gene', (211, 214))	('miR', 'Gene', '22877', (420, 423))	('miR-6068', 'Gene', (261, 269))	('miR', 'Gene', (234, 237))	('miR', 'Gene', (114, 117))	('miR-451a', 'Gene', '574411', (211, 219))	('miR', 'Gene', '22877', (126, 129))	('miR-33b', 'Gene', (369, 376))	('miR', 'Gene', (247, 250))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (280, 299))	('carcinoma', 'Phenotype', 'HP:0030731', (45, 54))	('miR', 'Gene', (150, 153))	('miR', 'Gene', '22877', (114, 117))	('miR', 'Gene', '22877', (162, 165))	('15 lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (23, 54))	('miR-575', 'Gene', '693160', (437, 444))	('carcinoma', 'Phenotype', 'HP:0030731', (290, 299))	('miR-197-3p', 'Gene', '100302290', (126, 136))	('miR', 'Gene', (420, 423))	('miR', 'Gene', '22877', (150, 153))	('miR', 'Gene', '22877', (261, 264))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (31, 54))	('miR', 'Gene', '22877', (394, 397))	('miR-33b', 'Gene', '693120', (369, 376))	('miR', 'Gene', (162, 165))	('miR', 'Gene', (369, 372))	('miR-6068', 'Gene', '102464823', (261, 269))	('miR', 'Gene', '22877', (101, 104))	('miR-197-3p', 'Gene', (126, 136))	('miR-211-3p', 'Gene', '100302164', (150, 160))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (280, 299))	('miR', 'Gene', '22877', (186, 189))	('miR', 'Gene', '22877', (369, 372))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (26, 54))	('miR', 'Gene', (261, 264))	('miR-575', 'Gene', (437, 444))
230276	27148421	Interestingly, in all tissues and plasma of lung squamous cell carcinoma, let-7d-3p, miR-106b-5p, miR-197-3p, miR-19b-3p, miR-30e-5p, miR-423-5p, miR-451a, and miR-5100 were down-regulated and miR-144-3p and miR-6068 were up-regulated, which correlated with TNM stage (Fig 3a and Fig 3b).	('miR-197-3p', 'Gene', (98, 108))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (49, 72))	('lung squamous cell carcinoma', 'Disease', (44, 72))	('miR', 'Gene', (85, 88))	('miR', 'Gene', '22877', (208, 211))	('miR', 'Gene', (134, 137))	('miR', 'Gene', '22877', (160, 163))	('up-regulated', 'PosReg', (222, 234))	('miR-451a', 'Gene', (146, 154))	('miR-6068', 'Gene', (208, 216))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))	('miR', 'Gene', '22877', (110, 113))	('down-regulated', 'NegReg', (174, 188))	('let-7d-3p', 'Var', (74, 83))	('miR-5100', 'Gene', (160, 168))	('miR', 'Gene', '22877', (85, 88))	('miR-6068', 'Gene', '102464823', (208, 216))	('miR-197-3p', 'Gene', '100302290', (98, 108))	('miR-423', 'Gene', '494335', (134, 141))	('miR', 'Gene', '22877', (134, 137))	('miR', 'Gene', (146, 149))	('miR-144', 'Gene', (193, 200))	('miR', 'Gene', (193, 196))	('miR', 'Gene', (98, 101))	('miR', 'Gene', (122, 125))	('miR-451a', 'Gene', '574411', (146, 154))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (44, 72))	('miR', 'Gene', (160, 163))	('miR', 'Gene', (208, 211))	('miR', 'Gene', '22877', (193, 196))	('miR-423', 'Gene', (134, 141))	('miR', 'Gene', '22877', (146, 149))	('TNM stage', 'Disease', (258, 267))	('miR', 'Gene', '22877', (98, 101))	('miR', 'Gene', '22877', (122, 125))	('miR-5100', 'Gene', '100847014', (160, 168))	('miR', 'Gene', (110, 113))	('miR-144', 'Gene', '406936', (193, 200))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (44, 72))
230280	27148421	For example, we believed that let-7d-3p was a promising biomarker of NSCLC.	('NSCLC', 'Disease', (69, 74))	('NSCLC', 'Phenotype', 'HP:0030358', (69, 74))	('let-7d-3p', 'Var', (30, 39))	('NSCLC', 'Disease', 'MESH:D002289', (69, 74))
230301	32547321	Silencing ID1 abrogated sphere formation and upregulated expression of stemness genes which were induced by IL-1beta stimulation.	('expression', 'MPA', (57, 67))	('ID1', 'Gene', '15901', (10, 13))	('ID1', 'Gene', (10, 13))	('mul', 'Gene', (120, 123))	('upregulated', 'PosReg', (45, 56))	('sphere formation', 'CPA', (24, 40))	('mul', 'Gene', '68729', (120, 123))	('stemness genes', 'Gene', (71, 85))	('Silencing', 'Var', (0, 9))	('abrogated', 'NegReg', (14, 23))
230316	32547321	Wang et al found that combination of IL-1beta and TGF-beta induced the glioma neurosphere formation and promoted the malignant biological behaviors of glioma cells.	('glioma', 'Disease', 'MESH:D005910', (151, 157))	('glioma', 'Phenotype', 'HP:0009733', (151, 157))	('induced', 'PosReg', (59, 66))	('glioma', 'Disease', (71, 77))	('TGF-beta', 'Gene', (50, 58))	('glioma', 'Disease', 'MESH:D005910', (71, 77))	('glioma', 'Phenotype', 'HP:0009733', (71, 77))	('promoted', 'PosReg', (104, 112))	('combination', 'Var', (22, 33))	('glioma', 'Disease', (151, 157))
230402	32547321	Silencing of ID1 significantly abrogated the tumor sphere formation induced by IL-1beta stimulation (P < 0.05, vs. all other groups, Figure 6A).	('abrogated', 'NegReg', (31, 40))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('mul', 'Gene', '68729', (91, 94))	('tumor', 'Disease', (45, 50))	('ID1', 'Gene', (13, 16))	('Silencing', 'Var', (0, 9))	('ID1', 'Gene', '15901', (13, 16))	('mul', 'Gene', (91, 94))
230404	32547321	As shown in Figure 6B, the sphere formation capability of tumor cells subjected to IL-1beta stimulation and ID1 silence was significantly reduced (P < 0.05, vs. all other groups).	('mul', 'Gene', (95, 98))	('tumor', 'Disease', (58, 63))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('ID1', 'Gene', (108, 111))	('reduced', 'NegReg', (138, 145))	('mul', 'Gene', '68729', (95, 98))	('ID1', 'Gene', '15901', (108, 111))	('sphere formation capability', 'CPA', (27, 54))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('silence', 'Var', (112, 119))
230405	32547321	Furthermore, ID1 knockdown reversed up-regulation of stem cell related markers induced by IL-1beta stimulation in SCC7 cells (P < 0.05, Figure 6C) and B16-F10 tumor cells (P < 0.05, Figure 6D).	('mul', 'Gene', (102, 105))	('SCC7', 'Gene', (114, 118))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('SCC7', 'Gene', '109433', (114, 118))	('B16-F10', 'CellLine', 'CVCL:0159', (151, 158))	('up-regulation', 'PosReg', (36, 49))	('tumor', 'Disease', (159, 164))	('mul', 'Gene', '68729', (102, 105))	('knockdown', 'Var', (17, 26))	('ID1', 'Gene', (13, 16))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('stem cell related', 'CPA', (53, 70))	('ID1', 'Gene', '15901', (13, 16))
230425	32547321	Consistently, Li et al previously reported that IL-1beta can enhance the sphere formation concomitant with up-regulation of stemness markers Bmi1 and nestin in colon cancers.	('enhance', 'PosReg', (61, 68))	('colon cancers', 'Disease', (160, 173))	('up-regulation', 'PosReg', (107, 120))	('IL-1beta', 'Var', (48, 56))	('Bmi1', 'Gene', '12151', (141, 145))	('nestin', 'Gene', '18008', (150, 156))	('nestin', 'Gene', (150, 156))	('Bmi1', 'Gene', (141, 145))	('colon cancers', 'Disease', 'MESH:D015179', (160, 173))	('colon cancers', 'Phenotype', 'HP:0003003', (160, 173))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('sphere formation', 'CPA', (73, 89))	('cancers', 'Phenotype', 'HP:0002664', (166, 173))
230430	32547321	Silencing of ID1 impaired CSC-like capability and inhibited EMT traits in colorectal cancer.	('CSC-like capability', 'CPA', (26, 45))	('colorectal cancer', 'Disease', 'MESH:D015179', (74, 91))	('impaired', 'NegReg', (17, 25))	('colorectal cancer', 'Phenotype', 'HP:0003003', (74, 91))	('EMT traits', 'CPA', (60, 70))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('ID1', 'Gene', (13, 16))	('Silencing', 'Var', (0, 9))	('colorectal cancer', 'Disease', (74, 91))	('ID1', 'Gene', '15901', (13, 16))	('inhibited', 'NegReg', (50, 59))
230434	32547321	Moreover, knockdown of ID1 could abrogate IL-1beta stimulation-prompted stem cell-like properties of HNSCC and melanoma cells.	('melanoma', 'Disease', 'MESH:D008545', (111, 119))	('ID1', 'Gene', '15901', (23, 26))	('melanoma', 'Phenotype', 'HP:0002861', (111, 119))	('melanoma', 'Disease', (111, 119))	('mul', 'Gene', '68729', (54, 57))	('abrogate', 'NegReg', (33, 41))	('ID1', 'Gene', (23, 26))	('knockdown', 'Var', (10, 19))	('mul', 'Gene', (54, 57))
230444	32547321	Our study demonstrated that IL-1beta could enhance the stemness of tumor cells, indicating that blockade of IL-1beta might be an effective strategy to enhance the anti-tumor immunity of CSC-DC.	('tumor', 'Disease', (168, 173))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('enhance', 'PosReg', (151, 158))	('blockade', 'Var', (96, 104))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Disease', (67, 72))	('IL-1beta', 'Gene', (108, 116))	('enhance', 'PosReg', (43, 50))
230445	32547321	Thus, in our future study, we will determine the therapeutical efficacy of IL-1beta neutralization in HNSCC and melanoma.	('neutralization', 'Var', (84, 98))	('IL-1beta', 'Gene', (75, 83))	('melanoma', 'Disease', 'MESH:D008545', (112, 120))	('melanoma', 'Phenotype', 'HP:0002861', (112, 120))	('melanoma', 'Disease', (112, 120))	('HNSCC', 'Disease', (102, 107))
230446	32547321	In conclusion, our study demonstrated that IL-1beta could enhance the stemness of squamous cell carcinoma and melanoma via activating Smad/ID1 pathway.	('enhance', 'PosReg', (58, 65))	('melanoma', 'Disease', 'MESH:D008545', (110, 118))	('melanoma', 'Phenotype', 'HP:0002861', (110, 118))	('melanoma', 'Disease', (110, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('activating', 'PosReg', (123, 133))	('stemness of squamous cell carcinoma', 'Disease', (70, 105))	('ID1', 'Gene', (139, 142))	('stemness of squamous cell carcinoma', 'Disease', 'MESH:D002294', (70, 105))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (82, 105))	('ID1', 'Gene', '15901', (139, 142))	('IL-1beta', 'Var', (43, 51))
230470	26316890	Atypical chemoattractant receptors (Table 1), such as ACKR1 (DARC), ACKR2 (D6), ACKR3 (CXCR7) and ACKR4 (CCRL1), limit the amount of available ligands in the microenvironment due to their ability to internalize and degrade them; for this reason they are also known as "decoy receptors".	('ACKR2', 'Var', (68, 73))	('ACKR3', 'Gene', (80, 85))	('ACKR1', 'Gene', '2532', (54, 59))	('degrade', 'NegReg', (215, 222))	('limit', 'NegReg', (113, 118))	('CCRL1', 'Gene', (105, 110))	('CCRL1', 'Gene', '1524', (105, 110))	('CXCR7', 'Gene', '57007', (87, 92))	('amount of available ligands', 'MPA', (123, 150))	('men', 'Species', '9606', (170, 173))	('ACKR3', 'Gene', '57007', (80, 85))	('ACKR4', 'Gene', (98, 103))	('internalize', 'MPA', (199, 210))	('CXCR7', 'Gene', (87, 92))	('DARC', 'Gene', '2532', (61, 65))	('ACKR4', 'Gene', '51554', (98, 103))	('ACKR1', 'Gene', (54, 59))	('DARC', 'Gene', (61, 65))
230474	26316890	The CXC subfamily is divided into two groups, CXC (ELR+) and CXC (ELR-), according to the presence or absence of the amino acid motif consisting of glutamic acid, leucine and arginine (ELR motif).	('leucine', 'Var', (163, 170))	('glutamic acid', 'Chemical', 'MESH:D018698', (148, 161))	('arginine', 'Chemical', 'MESH:D001120', (175, 183))	('glutamic', 'Protein', (148, 156))	('leucine', 'Chemical', 'MESH:D007930', (163, 170))	('arginine', 'Var', (175, 183))
230520	26316890	First, CCL2 directly activates endothelial cells and induces their migration and the formation of capillary structures.	('endothelial cells', 'CPA', (31, 48))	('rat', 'Species', '10116', (70, 73))	('formation of capillary structures', 'CPA', (85, 118))	('CCL2', 'Var', (7, 11))	('migration', 'CPA', (67, 76))	('induces', 'PosReg', (53, 60))	('activates', 'PosReg', (21, 30))
230523	26316890	It has been demonstrated that tumor tissue homogenates are monocyte chemoattractant, and that the use of neutralizing antibodies against CCL2 significantly reduces this effect.	('neutralizing antibodies', 'Var', (105, 128))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('rat', 'Species', '10116', (19, 22))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('reduces', 'NegReg', (156, 163))	('tumor', 'Disease', (30, 35))	('CCL2', 'Gene', (137, 141))
230525	26316890	However, in vivo murine models of tumorigenesis showed that the neutralization of CCL2 did not alter the number of TAM, although it promoted the polarization of TAM towards the M1 phenotype (associated with an anti-tumor response mediated by CD8+T cells), while the presence of CCL2 favored the polarization towards the M2 phenotype, which produces angiogenic molecules.	('CCL2', 'Gene', (82, 86))	('TAM', 'Chemical', '-', (115, 118))	('tumor', 'Disease', (34, 39))	('M1 phenotype', 'MPA', (177, 189))	('tumor', 'Disease', 'MESH:D009369', (215, 220))	('polarization', 'MPA', (145, 157))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('neutralization', 'Var', (64, 78))	('murine', 'Species', '10090', (17, 23))	('TAM', 'Chemical', '-', (161, 164))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('tumor', 'Disease', (215, 220))	('promoted', 'PosReg', (132, 140))	('CD8', 'Gene', (242, 245))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('CD8', 'Gene', '925', (242, 245))
230530	26316890	Although in vitro studies and humanized animal models indicate that the presence of CCL2 favors the progression of the neoplastic process, a recent clinicopathological study of 65 patients with advanced NSCLC concluded that the expression of CCL2 in tumor tissue is related to greater survival.	('human', 'Species', '9606', (30, 35))	('NSCLC', 'Disease', (203, 208))	('NSCLC', 'Disease', 'MESH:D002289', (203, 208))	('presence', 'Var', (72, 80))	('tumor', 'Disease', (250, 255))	('tumor', 'Disease', 'MESH:D009369', (250, 255))	('SCLC', 'Phenotype', 'HP:0030357', (204, 208))	('progression', 'CPA', (100, 111))	('favors', 'PosReg', (89, 95))	('NSCLC', 'Phenotype', 'HP:0030358', (203, 208))	('tumor', 'Phenotype', 'HP:0002664', (250, 255))	('CCL2', 'Gene', (84, 88))	('neoplastic process', 'Phenotype', 'HP:0002664', (119, 137))	('CCL2', 'Gene', (242, 246))	('patients', 'Species', '9606', (180, 188))	('greater', 'PosReg', (277, 284))
230539	26316890	Contradictorily, it seems that the expression of CCL5 also has a protective effect due to its ability to chemoattract immune effector cells to the tumor.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('protective effect', 'CPA', (65, 82))	('tumor', 'Disease', (147, 152))	('CCL5', 'Gene', (49, 53))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('expression', 'Var', (35, 45))
230545	26316890	In particular, tumor cells expressing CCL5 had a significant decrease in lung metastasis in S100A4-/- mice, indicating that metastasis to this organ is strongly dependent on the interaction between CCL5 and S100A4.	('mice', 'Species', '10090', (102, 106))	('S100A4', 'Gene', (92, 98))	('S100A4', 'Gene', '20198', (92, 98))	('CCL5', 'Var', (38, 42))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('decrease in lung metastasis', 'Disease', (61, 88))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('S100A4', 'Gene', '20198', (207, 213))	('tumor', 'Disease', (15, 20))	('decrease in lung metastasis', 'Disease', 'MESH:D009362', (61, 88))	('S100A4', 'Gene', (207, 213))
230568	26316890	In an in vivo model, silencing of this axis with small interfering RNAs diminished the size of the tumor.	('tumor', 'Disease', (99, 104))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('diminished', 'NegReg', (72, 82))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('silencing', 'Var', (21, 30))	('RNAs', 'Protein', (67, 71))
230578	26316890	Cell lines with mutations in KRAS and EGFR have an increased expression of CXCL8, while the silencing of these molecules and treatment with tyrosine kinase inhibitors, decreases its expression.	('EGFR', 'Gene', '1956', (38, 42))	('decreases', 'NegReg', (168, 177))	('expression', 'MPA', (182, 192))	('increased', 'PosReg', (51, 60))	('EGFR', 'Gene', (38, 42))	('KRAS', 'Gene', (29, 33))	('mutations', 'Var', (16, 25))	('KRAS', 'Gene', '3845', (29, 33))	('silencing', 'MPA', (92, 101))	('CXCL8', 'Gene', '3576', (75, 80))	('men', 'Species', '9606', (130, 133))	('expression', 'MPA', (61, 71))	('CXCL8', 'Gene', (75, 80))
230591	26316890	Studies using tumorigenesis models in CXCR2-/- mice showed that this receptor has a central role in tumor growth, since CXCR2-deficient mice showed a significant decrease in tumor mass (associated with an increase in necrotic tissue), compared to wild type mice, while levels of the chemokines CXCL1-3 were increased.	('tumor', 'Disease', (174, 179))	('CXCR2-deficient', 'Var', (120, 135))	('mice', 'Species', '10090', (136, 140))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Disease', (14, 19))	('mice', 'Species', '10090', (257, 261))	('necrotic', 'Disease', (217, 225))	('tumor', 'Disease', (100, 105))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('necrotic', 'Disease', 'MESH:D009336', (217, 225))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('decrease', 'NegReg', (162, 170))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('mice', 'Species', '10090', (47, 51))
230595	26316890	It has been reported that the neutralization of CXCL10 augments vascularization in lung squamous cell carcinoma.	('CXCL10', 'MPA', (48, 54))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (83, 111))	('neutralization', 'Var', (30, 44))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (83, 111))	('lung squamous cell carcinoma', 'Disease', (83, 111))	('vascularization', 'CPA', (64, 79))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (88, 111))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('augments', 'PosReg', (55, 63))	('men', 'Species', '9606', (58, 61))
230597	26316890	In animal models, the intra-tumoral administration of CXCL10 for 8 weeks has an antineoplastic effect in which the size of the tumor decreases through a reduction in vascularization.	('CXCL10', 'Var', (54, 60))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumor', 'Disease', (28, 33))	('reduction', 'NegReg', (153, 162))	('tumor', 'Disease', (127, 132))	('intra-tumoral', 'Disease', 'MESH:D009369', (22, 35))	('antineoplastic effect', 'CPA', (80, 101))	('rat', 'Species', '10116', (44, 47))	('vascularization', 'CPA', (166, 181))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('intra-tumoral', 'Disease', (22, 35))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('decreases', 'NegReg', (133, 142))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
230600	26316890	Recent studies in Lewis lung carcinoma, colon carcinoma (CT26) and breast carcinoma (4T1) murine models, tested the antitumor effect of a chimeric protein with CXCL10 and CXCL11 domains.	('chimeric', 'Var', (138, 146))	('colon carcinoma', 'Disease', (40, 55))	('CT26', 'CellLine', 'CVCL:7254', (57, 61))	('tested', 'Reg', (105, 111))	('carcinoma', 'Phenotype', 'HP:0030731', (29, 38))	('4T1', 'CellLine', 'CVCL:0125', (85, 88))	('breast carcinoma', 'Phenotype', 'HP:0003002', (67, 83))	('carcinoma', 'Phenotype', 'HP:0030731', (46, 55))	('Lewis lung carcinoma', 'Disease', (18, 38))	('Lewis lung carcinoma', 'Disease', 'MESH:D018827', (18, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('breast carcinoma', 'Disease', (67, 83))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('breast carcinoma', 'Disease', 'MESH:D001943', (67, 83))	('murine', 'Species', '10090', (90, 96))	('colon carcinoma', 'Disease', 'MESH:D015179', (40, 55))	('tumor', 'Disease', (120, 125))
230602	26316890	An important aspect is that in some cancers, such as colorectal carcinoma, CXCL10 has been reported to promote the invasion process through an increase in cell motility, although this does not seem to occur in primary cultures.	('invasion process', 'CPA', (115, 131))	('CXCL10', 'Var', (75, 81))	('cancers', 'Disease', 'MESH:D009369', (36, 43))	('cancers', 'Phenotype', 'HP:0002664', (36, 43))	('cancers', 'Disease', (36, 43))	('colorectal carcinoma', 'Disease', (53, 73))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('cell motility', 'CPA', (155, 168))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (53, 73))	('promote', 'PosReg', (103, 110))	('increase', 'PosReg', (143, 151))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))
230609	26316890	Furthermore, a recent study showed that transgenic mice overexpressing CXCL14 had a diminished increase in the size of transplanted tumor and number of metastases, an effect probably due to NK cells since the depletion of these cells with GM1 antibodies attenuates these effects and partially restores the phenotype of wild type mice.	('mice', 'Species', '10090', (329, 333))	('mice', 'Species', '10090', (51, 55))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('attenuates', 'NegReg', (254, 264))	('CXCL14', 'Var', (71, 77))	('GM1', 'Chemical', 'MESH:D005677', (239, 242))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('metastases', 'Disease', (152, 162))	('transgenic mice', 'Species', '10090', (40, 55))	('metastases', 'Disease', 'MESH:D009362', (152, 162))	('tumor', 'Disease', (132, 137))	('diminished', 'NegReg', (84, 94))
230610	26316890	In lung cancer, the forced expression of CXCL14 in the H23 lung adenocarcinoma cell line through Decitabine (an inhibitor of DNA methylation) treatment, stimulates necrosis and tumor size, and alters the expression pattern of pro-apoptotic genes and genes related to inhibition of cell cycle and, such as caspase 4 and RBP7, respectively  This is one of the most studied chemokines in cancer and has been shown to be important in the angiogenesis, survival and metastasis of the tumor.	('metastasis of the tumor', 'Disease', 'MESH:D009362', (461, 484))	('cancer', 'Phenotype', 'HP:0002664', (385, 391))	('lung cancer', 'Phenotype', 'HP:0100526', (3, 14))	('tumor', 'Disease', (479, 484))	('stimulates', 'PosReg', (153, 163))	('cancer', 'Disease', (8, 14))	('tumor', 'Disease', 'MESH:D009369', (479, 484))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('cancer', 'Disease', 'MESH:D009369', (385, 391))	('expression pattern', 'MPA', (204, 222))	('Decitabine', 'Chemical', 'MESH:D000077209', (97, 107))	('caspase 4', 'Gene', '837', (305, 314))	('tumor', 'Disease', (177, 182))	('alters', 'Reg', (193, 199))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))	('RBP7', 'Gene', '116362', (319, 323))	('lung cancer', 'Disease', (3, 14))	('H23 lung adenocarcinoma', 'Disease', 'MESH:D000077192', (55, 78))	('caspase 4', 'Gene', (305, 314))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('necrosis', 'Disease', 'MESH:D009336', (164, 172))	('tumor', 'Phenotype', 'HP:0002664', (479, 484))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (59, 78))	('Decitabine', 'Gene', (97, 107))	('H23 lung adenocarcinoma', 'Disease', (55, 78))	('RBP7', 'Gene', (319, 323))	('cancer', 'Disease', 'MESH:D009369', (8, 14))	('necrosis', 'Disease', (164, 172))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('CXCL14', 'Var', (41, 47))	('lung cancer', 'Disease', 'MESH:D008175', (3, 14))	('cancer', 'Disease', (385, 391))	('men', 'Species', '9606', (147, 150))	('metastasis of the tumor', 'Disease', (461, 484))
230620	26316890	It has been shown in vitro that CXCL12 induces chemotaxis in lung cancer cell lines, while the neutralization of CXCL12 with antibodies in animal models reduces primary tumor metastasis.	('lung cancer', 'Disease', (61, 72))	('lung cancer', 'Phenotype', 'HP:0100526', (61, 72))	('CXCL12', 'Var', (32, 38))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('reduces', 'NegReg', (153, 160))	('tumor metastasis', 'Disease', 'MESH:D009362', (169, 185))	('lung cancer', 'Disease', 'MESH:D008175', (61, 72))	('chemotaxis', 'CPA', (47, 57))	('tumor metastasis', 'Disease', (169, 185))	('induces', 'Reg', (39, 46))
230621	26316890	Furthermore, human lung adenocarcinoma A549 cells transfected with CXCL12 have greater motility and increased expression of MMP-2 and MMP-9, which are associated with the invasion process.	('MMP-9', 'Gene', (134, 139))	('CXCL12', 'Var', (67, 73))	('increased', 'PosReg', (100, 109))	('MMP-2', 'Gene', '4313', (124, 129))	('human', 'Species', '9606', (13, 18))	('motility', 'CPA', (87, 95))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (19, 38))	('lung adenocarcinoma A549', 'Disease', (19, 43))	('greater', 'PosReg', (79, 86))	('lung adenocarcinoma A549', 'Disease', 'MESH:D000077192', (19, 43))	('carcinoma', 'Phenotype', 'HP:0030731', (29, 38))	('MMP-2', 'Gene', (124, 129))	('expression', 'MPA', (110, 120))	('MMP-9', 'Gene', '4318', (134, 139))
230630	26316890	In this model, the lack of CX3CR1 was associated with larger tumors, neoplastic process-associated cachexia, and a significant reduction of recruitment of NK cells to the lungs of these mice.	('recruitment', 'MPA', (140, 151))	('tumors', 'Disease', (61, 67))	('lack', 'Var', (19, 23))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('neoplastic process', 'Phenotype', 'HP:0002664', (69, 87))	('CX3CR1', 'Var', (27, 33))	('cachexia', 'Phenotype', 'HP:0004326', (99, 107))	('mice', 'Species', '10090', (186, 190))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('cachexia', 'Disease', (99, 107))	('reduction', 'NegReg', (127, 136))	('cachexia', 'Disease', 'MESH:D002100', (99, 107))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('men', 'Species', '9606', (147, 150))
230632	26316890	Using the Lewis Lung Carcinoma (LCC) transfer model with cells expressing CX3CL1 (3LL-FK) or mock transfected cells (3LL-mock) injected into the lung of C57BL/6, it was found that mice that received 3LL-FK cells had smaller tumors, less metastasis (up to 10 times less), and prolonged survival compared with mice inoculated with 3LL-mock cells.	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('3LL-FK', 'Var', (199, 205))	('tumors', 'Disease', (224, 230))	('survival', 'CPA', (285, 293))	('mice', 'Species', '10090', (180, 184))	('metastasis', 'CPA', (237, 247))	('3LL', 'Chemical', '-', (199, 202))	('3LL-FK', 'Chemical', '-', (82, 88))	('3LL-FK', 'Chemical', '-', (199, 205))	('tumors', 'Disease', 'MESH:D009369', (224, 230))	('less', 'NegReg', (232, 236))	('Carcinoma', 'Phenotype', 'HP:0030731', (21, 30))	('Lewis Lung Carcinoma', 'Disease', 'MESH:D018827', (10, 30))	('3LL', 'Chemical', '-', (117, 120))	('prolonged', 'PosReg', (275, 284))	('3LL', 'Chemical', '-', (329, 332))	('smaller', 'NegReg', (216, 223))	('tumors', 'Phenotype', 'HP:0002664', (224, 230))	('Lewis Lung Carcinoma', 'Disease', (10, 30))	('3LL', 'Chemical', '-', (82, 85))	('mice', 'Species', '10090', (308, 312))
230635	26316890	Mice that received 3LL-FK cells had an augmented number of infiltrating DCs and NK cells in the tumor.	('3LL-FK cells', 'Var', (19, 31))	('men', 'Species', '9606', (42, 45))	('NK cells', 'CPA', (80, 88))	('rat', 'Species', '10116', (65, 68))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('infiltrating DCs', 'CPA', (59, 75))	('tumor', 'Disease', (96, 101))	('3LL-FK', 'Chemical', '-', (19, 25))	('Mice', 'Species', '10090', (0, 4))	('augmented', 'PosReg', (39, 48))	('tumor', 'Disease', 'MESH:D009369', (96, 101))
230642	26316890	In vivo assays showed that higher expression of the CX3CL1/CX3CR1 and CCL2/CCR2 axis increases the polarization of TAMs toward an M2 phenotype.	('CX3CL1/CX3CR1', 'Var', (52, 65))	('TAMs', 'Chemical', 'MESH:D013629', (115, 119))	('polarization of TAMs', 'CPA', (99, 119))	('higher', 'PosReg', (27, 33))	('increases', 'PosReg', (85, 94))
230656	26316890	Accumulating evidence indicates that the atypical chemokine receptors may be relevant in cancer.	('chemokine receptor', 'Gene', '7852', (50, 68))	('chemokine receptor', 'Gene', (50, 68))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('atypical', 'Var', (41, 49))	('cancer', 'Disease', (89, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
230658	26316890	In vitro, the overexpression of ACKR2 in breast cancer cells (MDA-MB-231 and MDA-MB-435) inhibits proliferation and invasion; while the chemokine ligands for ACKR2 (CCL2, CCL4, CCL13 and CCL22) decreased in conditioned culture media.	('ACKR2', 'Gene', (32, 37))	('breast cancer', 'Disease', 'MESH:D001943', (41, 54))	('CCL13', 'Gene', '6357', (177, 182))	('inhibits', 'NegReg', (89, 97))	('rat', 'Species', '10116', (105, 108))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (62, 72))	('breast cancer', 'Disease', (41, 54))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('breast cancer', 'Phenotype', 'HP:0003002', (41, 54))	('MDA-MB-435', 'CellLine', 'CVCL:0417', (77, 87))	('MDA-MB-435', 'Var', (77, 87))	('CCL4', 'Gene', '6351', (171, 175))	('CCL13', 'Gene', (177, 182))	('proliferation and invasion', 'CPA', (98, 124))	('CCL4', 'Gene', (171, 175))	('overexpression', 'PosReg', (14, 28))
230662	26316890	In addition, the authors found a decrease in the concentration of CCL2, CCL4 and CCL5 in the conditioned culture medium, while no changes were found in the messenger RNA levels of these chemokines.	('CCL4', 'Gene', '6351', (72, 76))	('rat', 'Species', '10116', (56, 59))	('decrease', 'NegReg', (33, 41))	('CCL4', 'Gene', (72, 76))	('concentration', 'MPA', (49, 62))	('CCL2', 'Var', (66, 70))	('CCL5', 'Var', (81, 85))
230665	26316890	Together, these studies indicate that the ACKR2 receptor controls the local availability of chemokines through the specific sequestration of CCL2, CCL4 and CCL5, suggesting that deregulation of the expression of this receptor could lead to changes in the tumor microenvironment, with important consequences.	('rat', 'Species', '10116', (131, 134))	('tumor', 'Phenotype', 'HP:0002664', (255, 260))	('tumor', 'Disease', (255, 260))	('ACKR2', 'Gene', (42, 47))	('sequestration', 'MPA', (124, 137))	('local availability of chemokines', 'MPA', (70, 102))	('CCL4', 'Gene', '6351', (147, 151))	('men', 'Species', '9606', (273, 276))	('tumor', 'Disease', 'MESH:D009369', (255, 260))	('CCL4', 'Gene', (147, 151))	('lead to changes', 'Reg', (232, 247))	('deregulation', 'Var', (178, 190))
230698	32884895	We found CD68+, CD163+, and CD206+ TAMs distributed in both tumor stroma and tumor islets.	('tumor stroma and tumor', 'Disease', 'MESH:D009369', (60, 82))	('CD68+', 'Var', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('CD163+', 'Var', (16, 22))	('CD206+', 'Var', (28, 34))
230703	32884895	done on 485 samples of colorectal cancer, the higher numbers of CD163+ cells were clearly associated with a good prognosis; a similar study on a cohort of 201 colorectal cancer patients that also demonstrated a tendency of better prognosis is the case of high CD163+ cell count, though these results were not statistically significant.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('colorectal cancer', 'Disease', (23, 40))	('colorectal cancer', 'Disease', 'MESH:D015179', (159, 176))	('colorectal cancer', 'Disease', 'MESH:D015179', (23, 40))	('high', 'Var', (255, 259))	('colorectal cancer', 'Phenotype', 'HP:0003003', (159, 176))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('colorectal cancer', 'Phenotype', 'HP:0003003', (23, 40))	('CD163+ cells', 'Var', (64, 76))	('colorectal cancer', 'Disease', (159, 176))
230704	32884895	At the same time, there are studies demonstrating opposite correlations, i.e., poor prognosis of the colorectal tumors showing high amount of CD163+ cells.	('CD163+ cells', 'Var', (142, 154))	('colorectal tumors', 'Disease', 'MESH:D015179', (101, 118))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('colorectal tumors', 'Disease', (101, 118))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))
230705	32884895	Similarly, for gastric cancer, there are reports of high CD163 as an indicator of good and bad prognosis.	('CD163', 'Gene', (57, 62))	('gastric cancer', 'Disease', (15, 29))	('gastric cancer', 'Disease', 'MESH:D013274', (15, 29))	('gastric cancer', 'Phenotype', 'HP:0012126', (15, 29))	('high', 'Var', (52, 56))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))
230706	32884895	have demonstrated that increased number of CD163+ cells is a marker of good prognosis of signet ring cell carcinoma and mucinous adenocarcinoma, while for other types of gastric cancer, it does not correlated with prognosis or is a marker of poor prognosis.	('ring cell carcinoma', 'Disease', 'MESH:D018279', (96, 115))	('ring cell carcinoma', 'Disease', (96, 115))	('mucinous adenocarcinoma', 'Disease', 'MESH:D002288', (120, 143))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('mucinous adenocarcinoma', 'Disease', (120, 143))	('gastric cancer', 'Phenotype', 'HP:0012126', (170, 184))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('CD163+ cells', 'Var', (43, 55))
230708	32884895	It was reported that high content of CD163+ cells is a marker of good prognosis in estrogen receptor negative breast cancer tumors.	('breast cancer tumors', 'Disease', (110, 130))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('estrogen receptor', 'Gene', (83, 100))	('estrogen receptor', 'Gene', '2099', (83, 100))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('CD163+ cells', 'Var', (37, 49))	('breast cancer tumors', 'Disease', 'MESH:D001943', (110, 130))	('breast cancer', 'Phenotype', 'HP:0003002', (110, 123))
230710	32884895	Particularly, the presence of T cells (CD3+) and T cell subpopulations (e.g., CD4+, CD8+, and CD103+) was established to be markers of a good prognosis.	('CD4', 'Gene', '920', (78, 81))	('CD103', 'Gene', '3682', (94, 99))	('CD8+', 'Var', (84, 88))	('CD103', 'Gene', (94, 99))	('CD4', 'Gene', (78, 81))	('presence of T cells', 'Phenotype', 'HP:0100828', (18, 37))
230744	32580307	In addition, the substitution of Cys by Ser improves the hydrophilicity and solubility of the peptide and its conjugates.	('hydrophilicity', 'MPA', (57, 71))	('improves', 'PosReg', (44, 52))	('Cys', 'Gene', (33, 36))	('Cys', 'Chemical', 'MESH:D003545', (33, 36))	('substitution', 'Var', (17, 29))	('solubility of the peptide', 'MPA', (76, 101))	('Ser', 'Chemical', 'MESH:D012694', (40, 43))	('peptide', 'Chemical', 'MESH:D010455', (94, 101))
230819	32580307	The permission license for breeding and performing experiments with laboratory animals: PEI/001/1738-3/2015 and PEI/001/2574-6/2015.	('PEI/001/2574-6/2015', 'Var', (112, 131))	('rat', 'Species', '10116', (72, 75))	('PEI/001/1738-3/2015', 'Var', (88, 107))
230840	32580307	In our research, the potential homing peptide CKAAKN derived from phage display was modified by the replacement of Cys to Ser.	('Ser', 'Chemical', 'MESH:D012694', (122, 125))	('Cys', 'Chemical', 'MESH:D003545', (115, 118))	('replacement', 'Var', (100, 111))	('Cys', 'MPA', (115, 118))	('peptide', 'Chemical', 'MESH:D010455', (38, 45))
230845	32580307	In addition, the Cys/Ser substitution can increase the hydrophilicity of the peptide that improves the water solubility of the peptide-drug conjugate.	('Cys/Ser', 'Var', (17, 24))	('water solubility of the peptide-drug', 'MPA', (103, 139))	('peptide', 'Chemical', 'MESH:D010455', (77, 84))	('hydrophilicity of the peptide', 'MPA', (55, 84))	('peptide', 'Chemical', 'MESH:D010455', (127, 134))	('Ser', 'Chemical', 'MESH:D012694', (21, 24))	('water', 'Chemical', 'MESH:D014867', (103, 108))	('Cys', 'Chemical', 'MESH:D003545', (17, 20))	('improves', 'PosReg', (90, 98))	('increase', 'PosReg', (42, 50))
230880	32580307	Nevertheless, a similar magnitude of cytotoxicity (viability: 34%) of conjugate 5 was already manifested after 24 h, while, in the case of conjugate 4, only a slight antitumor activity (viability: 91%) was observed (Figure 1A).	('cytotoxicity', 'Disease', (37, 49))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('cytotoxicity', 'Disease', 'MESH:D064420', (37, 49))	('tumor', 'Disease', (170, 175))	('conjugate', 'Var', (70, 79))
230903	32580307	It was also previously reported that conjugation of Dau to a targeting peptide can decrease its fluorescence intensity by 90% compared to the free molecule.	('conjugation', 'Var', (37, 48))	('peptide', 'Chemical', 'MESH:D010455', (71, 78))	('decrease', 'NegReg', (83, 91))	('fluorescence intensity', 'MPA', (96, 118))	('Dau', 'Chemical', 'MESH:D003630', (52, 55))
230948	32580307	Results showed that conjugate 4 inhibited tumor growth significantly under both doses (2 mg/kg Dau-content: 27.3%, 10 mg/kg Dau-content: 30.4%) in comparison with the tumor weight in the control group.	('tumor', 'Disease', (42, 47))	('inhibited', 'NegReg', (32, 41))	('conjugate', 'Var', (20, 29))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('Dau', 'Chemical', 'MESH:D003630', (124, 127))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('tumor', 'Disease', (167, 172))	('Dau', 'Chemical', 'MESH:D003630', (95, 98))
230954	32580307	To summarize the in vivo experiments, the data indicated that conjugate 4 could inhibit the tumor growth of s.c. human pancreatic cancer (PANC-1)-bearing mice significantly without causing any toxic side effects.	('pancreatic cancer', 'Disease', (119, 136))	('mice', 'Species', '10090', (154, 158))	('PANC-1', 'Gene', (138, 144))	('inhibit', 'NegReg', (80, 87))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('conjugate 4', 'Var', (62, 73))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (119, 136))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('tumor', 'Disease', (92, 97))	('PANC-1', 'Gene', '104066', (138, 144))	('human', 'Species', '9606', (113, 118))	('pancreatic cancer', 'Disease', 'MESH:D010190', (119, 136))
230965	32580307	In contrast to the free drug, conjugate 4 did not show any toxicity during the treatment but elicited significant >30% tumor growth inhibition in PANC-1 bearing mice.	('tumor', 'Disease', (119, 124))	('mice', 'Species', '10090', (161, 165))	('PANC-1', 'Gene', '104066', (146, 152))	('conjugate', 'Var', (30, 39))	('toxicity', 'Disease', 'MESH:D064420', (59, 67))	('toxicity', 'Disease', (59, 67))	('PANC-1', 'Gene', (146, 152))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))
231043	30584364	To estimate whether xenografted mice could retain histological features of the patients, we compared the gross morphology and histology types by H&E staining and checking the expression of the biomarkers (eg, CK-7, Naspin A, TTF-1 for adenocarcinoma; P40, P63, and CK56 for squamous carcinoma).	('squamous carcinoma', 'Disease', (274, 292))	('P63', 'Gene', '8626', (256, 259))	('and', 'Var', (261, 264))	('TTF-1', 'Gene', '7270', (225, 230))	('P63', 'Gene', (256, 259))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (274, 292))	('CK-7', 'Gene', '3855', (209, 213))	('squamous carcinoma', 'Disease', 'MESH:D002294', (274, 292))	('adenocarcinoma', 'Disease', (235, 249))	('P40', 'Gene', (251, 254))	('TTF-1', 'Gene', (225, 230))	('carcinoma', 'Phenotype', 'HP:0030731', (283, 292))	('mice', 'Species', '10090', (32, 36))	('CK-7', 'Gene', (209, 213))	('H&E', 'Chemical', 'MESH:D006371', (145, 148))	('adenocarcinoma', 'Disease', 'MESH:D000230', (235, 249))	('P40', 'Gene', '8626', (251, 254))	('patients', 'Species', '9606', (79, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (240, 249))
231050	30584364	The expressions of P40, P63 and CK56 were positive and coincident in the patient tissue and mice tissues.	('CK56', 'Var', (32, 36))	('P63', 'Gene', '8626', (24, 27))	('P40', 'Gene', '8626', (19, 22))	('patient', 'Species', '9606', (73, 80))	('P63', 'Gene', (24, 27))	('P40', 'Gene', (19, 22))	('mice', 'Species', '10090', (92, 96))
231107	29238201	Tissue expression of PCAT6 was systematically evaluated in five Gene Expression Omnibus datasets (GSE19804, GSE18842, GSE30219, GSE19188, and GSE27262).	('GSE19188', 'Var', (128, 136))	('PCAT6', 'Gene', (21, 26))	('GSE30219', 'Var', (118, 126))	('PCAT6', 'Gene', '100506696', (21, 26))	('GSE27262', 'Var', (142, 150))	('GSE18842', 'Var', (108, 116))	('GSE19804', 'Var', (98, 106))
231109	29238201	PCAT6 was significantly increased in lung cancer tissues and could be used to distinguish LUAD from adjacent normal tissues with an area under the receiver operating characteristic curve (AUC) of 0.9210 (p<0.0001; sensitivity, 98.82%; specificity, 78.57%) in GSE30219, 0.9333 (p<0.0001; sensitivity, 86.67%; specificity, 90.77%) in GSE19188, 0.9584 (p<0.0001; sensitivity, 92.00%; specificity, 96.00%) in GSE27262, and 0.9574 (p<0.0001; sensitivity, 95.89%; specificity, 87.67%) in patients from Union Hospital.	('GSE30219', 'Var', (259, 267))	('PCAT6', 'Gene', (0, 5))	('0.9584', 'Var', (342, 348))	('lung cancer', 'Disease', (37, 48))	('0.9333', 'Var', (269, 275))	('PCAT6', 'Gene', '100506696', (0, 5))	('lung cancer', 'Phenotype', 'HP:0100526', (37, 48))	('GSE27262', 'Var', (405, 413))	('0.9210', 'Var', (196, 202))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('patients', 'Species', '9606', (482, 490))	('LUAD', 'Phenotype', 'HP:0030078', (90, 94))	('GSE19188', 'Var', (332, 340))	('lung cancer', 'Disease', 'MESH:D008175', (37, 48))	('0.9574', 'Var', (419, 425))	('increased', 'PosReg', (24, 33))
231110	29238201	As for lung squamous cell carcinoma (LUSC), the AUC of PCAT6 was 0.9567 (p<0.0001; sensitivity, 100%; specificity, 85.71%) in GSE30219, 0.9795 (p<0.0001; sensitivity, 96.30%; specificity, 92.31%) in GSE19188, and 0.9942 (p<0.0001; sensitivity, 100%; specificity, 98.04%) in patients from Union Hospital.	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (7, 35))	('patients', 'Species', '9606', (274, 282))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (7, 35))	('lung squamous cell carcinoma', 'Disease', (7, 35))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (12, 35))	('PCAT6', 'Gene', (55, 60))	('GSE30219', 'Var', (126, 134))	('carcinoma', 'Phenotype', 'HP:0030731', (26, 35))	('0.9567', 'Var', (65, 71))	('LUSC', 'Phenotype', 'HP:0030359', (37, 41))	('0.9795', 'Var', (136, 142))	('PCAT6', 'Gene', '100506696', (55, 60))	('GSE19188', 'Var', (199, 207))	('0.9942', 'Var', (213, 219))
231112	29238201	The AUC of circulating PCAT6 was 0.9213 (p<0.0001; sensitivity, 87.67%; specificity, 97.44%) in LUAD and 0.9583 (p<0.0001; sensitivity, 94.12%; specificity, 100%) in LUSC.	('PCAT6', 'Gene', '100506696', (23, 28))	('LUAD', 'Phenotype', 'HP:0030078', (96, 100))	('LUAD', 'Disease', (96, 100))	('0.9583', 'Var', (105, 111))	('LUSC', 'Phenotype', 'HP:0030359', (166, 170))	('0.9213', 'Var', (33, 39))	('PCAT6', 'Gene', (23, 28))
231124	29238201	During the past decade, mounting evidence has confirmed that dysregulation of lncRNAs, acting either as oncogenes or as tumor suppressors, is an important cause of certain cancers.	('cause', 'Reg', (155, 160))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('dysregulation', 'Var', (61, 74))	('lncRNAs', 'Protein', (78, 85))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('cancers', 'Disease', 'MESH:D009369', (172, 179))	('cancers', 'Phenotype', 'HP:0002664', (172, 179))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('cancers', 'Disease', (172, 179))	('tumor', 'Disease', (120, 125))
231134	29238201	As a result, five panels of lung cancer gene expression datasets, including GSE27262, GSE19804, GSE19188, GSE30219, and GSE18842, were selected to compare PCAT6 expression between lung cancer tissues and normal tissues.	('lung cancer', 'Disease', 'MESH:D008175', (28, 39))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('expression', 'MPA', (161, 171))	('lung cancer', 'Disease', 'MESH:D008175', (180, 191))	('PCAT6', 'Gene', (155, 160))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('GSE27262', 'Var', (76, 84))	('lung cancer', 'Disease', (28, 39))	('lung cancer', 'Phenotype', 'HP:0100526', (28, 39))	('lung cancer', 'Disease', (180, 191))	('lung cancer', 'Phenotype', 'HP:0100526', (180, 191))	('GSE19188', 'Var', (96, 104))	('compare', 'Reg', (147, 154))	('PCAT6', 'Gene', '100506696', (155, 160))
231148	29238201	Then, we further evaluated PCAT6 expression in lung cancer patients from five GEO datasets (GSE19804, GSE18842, GSE30219, GSE19188, and GSE27262).	('evaluated', 'Reg', (17, 26))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('PCAT6', 'Gene', (27, 32))	('lung cancer', 'Disease', (47, 58))	('lung cancer', 'Phenotype', 'HP:0100526', (47, 58))	('GSE30219', 'Var', (112, 120))	('GSE18842', 'Var', (102, 110))	('GSE27262', 'Var', (136, 144))	('PCAT6', 'Gene', '100506696', (27, 32))	('patients', 'Species', '9606', (59, 67))	('GSE19188', 'Var', (122, 130))	('lung cancer', 'Disease', 'MESH:D008175', (47, 58))	('GSE19804', 'Var', (92, 100))
231164	29238201	The diagnostic value of plasma PCAT6 was also evaluated, and the results showed that PCAT6 had an AUC value of 0.9213 (95% CI 0.8663-0.9763; Figure 4B) for LUAD and 0.9583 (95% CI 0.9109-1; Figure 4C) for LUSC.	('LUSC', 'Phenotype', 'HP:0030359', (205, 209))	('PCAT6', 'Gene', (31, 36))	('PCAT6', 'Gene', '100506696', (85, 90))	('LUSC', 'Disease', (205, 209))	('LUAD', 'Disease', (156, 160))	('LUAD', 'Phenotype', 'HP:0030078', (156, 160))	('PCAT6', 'Gene', '100506696', (31, 36))	('0.9583', 'Var', (165, 171))	('PCAT6', 'Gene', (85, 90))
231173	29238201	In this study, the expression and diagnostic value of PCAT6 in cancer tissues was first examined in 349 NSCLC patients from five GEO datasets (GSE19804, GSE18842, GSE30219, GSE19188, and GSE27262).	('GSE19804', 'Var', (143, 151))	('NSCLC', 'Phenotype', 'HP:0030358', (104, 109))	('PCAT6', 'Gene', '100506696', (54, 59))	('GSE30219', 'Var', (163, 171))	('GSE18842', 'Var', (153, 161))	('patients', 'Species', '9606', (110, 118))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('GSE19188', 'Var', (173, 181))	('NSCLC', 'Disease', (104, 109))	('NSCLC', 'Disease', 'MESH:D002289', (104, 109))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('GSE27262', 'Var', (187, 195))	('cancer', 'Disease', (63, 69))	('PCAT6', 'Gene', (54, 59))
231180	29238201	The results showed that plasma PCAT6 had an AUC value of 0.9213 (95% CI 0.8663-0.9763) for LUAD and 0.9583 (95% CI 0.9109-1) for LUSC, significantly higher than GAS5 (0.832, 95% CI 0.754-0.893) and CEA (0.700, 95% CI 0.611-0.779) according to a previous report.	('PCAT6', 'Gene', (31, 36))	('plasma', 'MPA', (24, 30))	('GAS5', 'Gene', '60674', (161, 165))	('AUC', 'MPA', (44, 47))	('GAS5', 'Gene', (161, 165))	('CEA', 'Gene', (198, 201))	('LUSC', 'Phenotype', 'HP:0030359', (129, 133))	('PCAT6', 'Gene', '100506696', (31, 36))	('CEA', 'Gene', '1084', (198, 201))	('higher', 'PosReg', (149, 155))	('0.9583', 'Var', (100, 106))	('LUAD', 'Phenotype', 'HP:0030078', (91, 95))
231243	27549193	TAM numbers have been reported to be a predictor of worse outcome in many cancers.	('TAM numbers', 'Var', (0, 11))	('cancers', 'Disease', 'MESH:D009369', (74, 81))	('cancers', 'Phenotype', 'HP:0002664', (74, 81))	('cancers', 'Disease', (74, 81))	('TAM', 'Chemical', '-', (0, 3))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
231249	27549193	Non-synonymous somatic mutations in the tumor genome can generate immunogenic neoantigens that trigger antitumor response through T-cell activation.	('T-cell', 'CPA', (130, 136))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('Non-synonymous somatic mutations', 'Var', (0, 32))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('tumor', 'Disease', (40, 45))	('immunogenic neoantigens', 'MPA', (66, 89))	('trigger', 'PosReg', (95, 102))
231253	27549193	In addition, we observed that dendritic cell infiltration is correlated with the total mutation load in breast cancer (Spearman's rho = 0.11, q = 0.037), as is B-cell infiltration (rho = 0.13, q = 0.018), suggesting cancer-specific roles for these cell types in antitumor immunity.	('dendritic cell', 'CPA', (30, 44))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('tumor', 'Disease', 'MESH:D009369', (266, 271))	('breast cancer', 'Disease', 'MESH:D001943', (104, 117))	('tumor', 'Phenotype', 'HP:0002664', (266, 271))	('mutation load', 'Var', (87, 100))	('breast cancer', 'Disease', (104, 117))	('cancer', 'Disease', (216, 222))	('cancer', 'Disease', 'MESH:D009369', (216, 222))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('tumor', 'Disease', (266, 271))	('breast cancer', 'Phenotype', 'HP:0003002', (104, 117))
231256	27549193	MSI typically generates small indels across the genome, producing non-self antigens that may be recognized by the host immune system.	('MSI', 'Disease', 'None', (0, 3))	('non-self antigens', 'MPA', (66, 83))	('indels', 'Var', (30, 36))	('MSI', 'Disease', (0, 3))	('producing', 'Reg', (56, 65))
231297	27549193	More importantly, we found that tumors with high TIM3 expression can be divided into two distinct groups with different levels of infiltrating CD8 T cells (Fig.	('TIM3', 'Gene', '84868', (49, 53))	('high', 'Var', (44, 48))	('CD8', 'Gene', (143, 146))	('CD8', 'Gene', '925', (143, 146))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumors', 'Disease', (32, 38))	('TIM3', 'Gene', (49, 53))	('tumors', 'Disease', 'MESH:D009369', (32, 38))
231313	27549193	Systematic exploration of tumor-immune interactions revealed cancer genetic alterations and chemokine/receptor expression networks are potential regulators of immune cell infiltration heterogeneity.	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('cancer', 'Disease', (61, 67))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('genetic alterations', 'Var', (68, 87))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('tumor', 'Disease', (26, 31))
231367	27549193	We investigated the expression levels of the B-cell markers CD19 and CD20 in OV and discovered that tumor purity is not negatively correlated with gene expression levels for both genes, indicating that aneuploid cells in ovarian cancer may also express B-cell markers.	('aneuploid', 'Var', (202, 211))	('express', 'Reg', (245, 252))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('CD19', 'Gene', (60, 64))	('tumor', 'Disease', (100, 105))	('ovarian cancer', 'Disease', (221, 235))	('CD20', 'Gene', '54474', (69, 73))	('CD19', 'Gene', '930', (60, 64))	('CD20', 'Gene', (69, 73))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('ovarian cancer', 'Disease', 'MESH:D010051', (221, 235))	('OV', 'Phenotype', 'HP:0012887', (77, 79))	('ovarian cancer', 'Phenotype', 'HP:0100615', (221, 235))
231402	31157309	Under each correlation structure, consider seven different distributions for the random error epsilon: N(0,1), 0.95N(0,1) + 0.05Cauchy, 0.85N(0,1) + 0.15Cauchy, 0.7N(0,1) + 0.3Cauchy, 0.95N(0,1) + 0.05t(3), 0.85N(0,1) + 0.15t(3), and 0.7N(0,1) + 0.3t(3).	('error epsilon', 'Disease', 'MESH:D001321', (88, 101))	('error epsilon', 'Disease', (88, 101))	('0.95N(0,1) + 0.05t(', 'Var', (184, 203))
231481	24396883	Briefly, four mum thick sections from formalin-fixed, paraffin-embedded lung tissue blocks were immunostained for alpha7 nAChR (AChRalpha7 (319): sc-58607, Santa Cruz Biotechnology, Santa Cruz, CA) with dilutions of 1:50.	('paraffin', 'Chemical', 'MESH:D010232', (54, 62))	('alpha7 nAChR', 'Gene', '11441', (114, 126))	('alpha7 nAChR', 'Gene', (114, 126))	('formalin', 'Chemical', 'MESH:D005557', (38, 46))	('sc-58607', 'Var', (146, 154))
231500	24396883	NNK resulted in various histopathological types of preneoplastic lesions, including squamous metaplasia, squamous dysplasia and atypical adenomatous hyperplasia in ferret lungs (Table 1, Fig.	('squamous metaplasia', 'Disease', (84, 103))	('adenomatous hyperplasia', 'Disease', (137, 160))	('squamous dysplasia', 'Disease', (105, 123))	('neoplastic lesions', 'Phenotype', 'HP:0002664', (54, 72))	('ferret', 'Species', '9669', (164, 170))	('squamous metaplasia', 'Phenotype', 'HP:0002860', (84, 103))	('squamous metaplasia', 'Disease', 'MESH:D008679', (84, 103))	('squamous dysplasia', 'Disease', 'MESH:D002294', (105, 123))	('neoplastic lesions', 'Disease', (54, 72))	('adenomatous hyperplasia', 'Disease', 'MESH:D011125', (137, 160))	('NNK', 'Chemical', 'MESH:C016583', (0, 3))	('neoplastic lesions', 'Disease', 'MESH:D051437', (54, 72))	('squamous dysplasia', 'Phenotype', 'HP:0002860', (105, 123))	('NNK', 'Var', (0, 3))
231502	24396883	Although there were no statistically significant differences in the incidence between the different time points because of the small sample size, these data suggested that NNK could induce lung tumors in a time dependent manner.	('induce', 'Reg', (182, 188))	('lung tumors', 'Disease', 'MESH:D008175', (189, 200))	('lung tumor', 'Phenotype', 'HP:0100526', (189, 199))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('NNK', 'Chemical', 'MESH:C016583', (172, 175))	('tumors', 'Phenotype', 'HP:0002664', (194, 200))	('lung tumors', 'Phenotype', 'HP:0100526', (189, 200))	('NNK', 'Var', (172, 175))	('lung tumors', 'Disease', (189, 200))
231527	24396883	However, there was a previous study indicating that NNK treatment induces lymphomas in vivo.	('induces', 'Reg', (66, 73))	('lymphoma', 'Phenotype', 'HP:0002665', (74, 82))	('lymphomas', 'Disease', (74, 83))	('lymphomas', 'Disease', 'MESH:D008223', (74, 83))	('men', 'Species', '9606', (61, 64))	('lymphomas', 'Phenotype', 'HP:0002665', (74, 83))	('NNK treatment', 'Var', (52, 65))	('NNK', 'Chemical', 'MESH:C016583', (52, 55))
231538	24396883	There were no significantly differences in the body weights between the control and the NNK treated groups at 24 weeks, however, we observed that ferrets exposed to NNK alone had less incidences of lung tumors, as compared with the ferrets treated with the same dose of NNK and exposed to cigarette smoke.	('NNK', 'Chemical', 'MESH:C016583', (88, 91))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('ferrets', 'Species', '9669', (232, 239))	('NNK', 'Var', (165, 168))	('NNK', 'Chemical', 'MESH:C016583', (270, 273))	('tumors', 'Phenotype', 'HP:0002664', (203, 209))	('lung tumors', 'Disease', (198, 209))	('lung tumors', 'Phenotype', 'HP:0100526', (198, 209))	('NNK', 'Chemical', 'MESH:C016583', (165, 168))	('less', 'NegReg', (179, 183))	('lung tumor', 'Phenotype', 'HP:0100526', (198, 208))	('lung tumors', 'Disease', 'MESH:D008175', (198, 209))	('ferrets', 'Species', '9669', (146, 153))
231543	24396883	As we pointed above, NNK is known to be a high-affinity ligand for alpha7 nAChR, we believe that NNK can initiate lung carcinogenesis and also promote lung tumor development by activating alpha7 nAChR.	('NNK', 'Var', (97, 100))	('initiate', 'PosReg', (105, 113))	('men', 'Species', '9606', (169, 172))	('alpha7 nAChR', 'Gene', '11441', (67, 79))	('lung tumor', 'Phenotype', 'HP:0100526', (151, 161))	('alpha7 nAChR', 'Gene', (67, 79))	('promote', 'PosReg', (143, 150))	('lung carcinogenesis', 'Disease', (114, 133))	('alpha7 nAChR', 'Gene', (188, 200))	('alpha7 nAChR', 'Gene', '11441', (188, 200))	('NNK', 'Chemical', 'MESH:C016583', (21, 24))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('lung carcinogenesis', 'Disease', 'MESH:D063646', (114, 133))	('lung tumor', 'Disease', (151, 161))	('activating', 'PosReg', (177, 187))	('lung tumor', 'Disease', 'MESH:D008175', (151, 161))	('NNK', 'Chemical', 'MESH:C016583', (97, 100))
231565	33976747	Moreover, expression of CFP had significant positive correlations with the infiltration levels of CD8+ T cells, CD4+ T cells, macrophages, neutrophils and dendritic cells (DCs) in STAD and LUAD.	('positive', 'PosReg', (44, 52))	('CD8', 'Gene', (98, 101))	('CD4', 'Gene', '920', (112, 115))	('expression', 'Var', (10, 20))	('CD8', 'Gene', '925', (98, 101))	('CD4', 'Gene', (112, 115))	('CFP', 'Gene', (24, 27))
231644	33976747	For instance, the high risk of severe Neisseria meningitides infection is associated with new mutations in the CFP gene.	('severe Neisseria meningitides infection', 'Disease', 'MESH:D045169', (31, 70))	('high risk of severe Neisseria meningitides infection', 'Phenotype', 'HP:0005381', (18, 70))	('CFP', 'Gene', (111, 114))	('mutations', 'Var', (94, 103))	('severe Neisseria meningitides infection', 'Disease', (31, 70))	('associated', 'Reg', (74, 84))
231653	33976747	In six groups of prognostic data, CFP expression level was negatively correlated with breast, lung, ovarian and soft tissue cancer prognosis, suggesting that low CFP expression can serve as an independent risk factor for the above tumors (Figure 3).	('tumors', 'Disease', 'MESH:D009369', (231, 237))	('tumors', 'Phenotype', 'HP:0002664', (231, 237))	('negatively', 'NegReg', (59, 69))	('breast', 'Disease', (86, 92))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('lung', 'Disease', (94, 98))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('low', 'Var', (158, 161))	('soft tissue cancer', 'Phenotype', 'HP:0031459', (112, 130))	('tumors', 'Disease', (231, 237))	('ovarian and soft tissue cancer', 'Disease', 'MESH:D018461', (100, 130))
231679	33976747	Since alternative pathway (AP) accounts for about 80-90% of the terminal pathway activity initiated by classical pathways (CP) and lectin pathways (LP), inhibition of properdin may effectively limit inflammation-mediated injury in diseases in which CP and LP play pathogenic roles.	('LP', 'Chemical', '-', (256, 258))	('inflammation-mediated injury in diseases', 'Disease', (199, 239))	('properdin', 'Gene', (167, 176))	('properdin', 'Gene', '5199', (167, 176))	('LP', 'Chemical', '-', (148, 150))	('terminal pathway', 'Pathway', (64, 80))	('activity', 'MPA', (81, 89))	('inhibition', 'Var', (153, 163))	('inflammation-mediated injury in diseases', 'Disease', 'MESH:D007249', (199, 239))	('limit', 'NegReg', (193, 198))
231680	33976747	There are many experimental evidences support the possibility that inhibiting properdin may be a promising approach for the treatment of inflammatory diseases.	('properdin', 'Gene', (78, 87))	('inhibiting', 'Var', (67, 77))	('inflammatory diseases', 'Disease', (137, 158))	('properdin', 'Gene', '5199', (78, 87))
231689	33976747	Previous studies have shown that CFP is a ligand of NK cell activation receptor NKp46, indicating that CFP can not only remove tumor cells through complement activation, but also promote the removal of tumor cells by promoting phagocytosis and removal of target cells without activated complement.	('complement', 'MPA', (147, 157))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('NKp46', 'Gene', (80, 85))	('phagocytosis', 'CPA', (227, 239))	('tumor', 'Disease', (202, 207))	('tumor', 'Disease', (127, 132))	('remove', 'NegReg', (120, 126))	('NKp46', 'Gene', '9437', (80, 85))	('promote', 'PosReg', (179, 186))	('CFP', 'Var', (103, 106))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('removal', 'MPA', (191, 198))	('promoting', 'PosReg', (217, 226))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))
231692	33976747	On the other hand, CFP may affect the tumor microenvironment through the alternative pathway of complement system.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('alternative pathway of complement system', 'Pathway', (73, 113))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('affect', 'Reg', (27, 33))	('CFP', 'Var', (19, 22))
231703	33679868	The top three of high frequency gene mutations were TP53, EGFR, PIK3CA with rates of 62% (13 cases), 48% (10 cases), and 14% (3 cases), respectively.	('EGFR', 'Gene', '1956', (58, 62))	('PIK3CA', 'Gene', (64, 70))	('TP53', 'Gene', '7157', (52, 56))	('EGFR', 'Gene', (58, 62))	('PIK3CA', 'Gene', '5290', (64, 70))	('TP53', 'Gene', (52, 56))	('mutations', 'Var', (37, 46))
231705	33679868	However, TMB value was not significantly correlated to other clinicopathologic indexes, for examples, age, sex, smoking history, tumor size, as well as TP53 and EGFR mutations in lung ASC.	('EGFR', 'Gene', (161, 165))	('mutations', 'Var', (166, 175))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('lung ASC', 'Disease', (179, 187))	('TP53', 'Gene', '7157', (152, 156))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('TP53', 'Gene', (152, 156))	('TMB', 'Chemical', '-', (9, 12))	('tumor', 'Disease', (129, 134))	('EGFR', 'Gene', '1956', (161, 165))
231707	33679868	In conclusion, this study indicated that lung ASC with high TMB might be associated with the invasion of lymph node and short overall survival.	('invasion of lymph node', 'CPA', (93, 115))	('high TMB', 'Var', (55, 63))	('lung ASC', 'Disease', (41, 49))	('associated', 'Reg', (73, 83))	('TMB', 'Chemical', '-', (60, 63))
231716	33679868	For example, the small molecule tyrosine kinase inhibitors (TKIs) were effective for patients with advanced lung adenocarcinoma with the somatic mutation of epidermal growth factor receptor (EGFR) and the rearrangement of echinoderm microtubule-associated protein-like 4 (EML4) with anaplastic lymphoma kinase (ALK) (Paez et al.,; Soda et al.,; Robichaux et al.,; Ramalingam et al.,).	('lung adenocarcinoma', 'Disease', (108, 127))	('anaplastic lymphoma kinase', 'Gene', (283, 309))	('epidermal growth factor receptor', 'Gene', (157, 189))	('lymphoma', 'Phenotype', 'HP:0002665', (294, 302))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (108, 127))	('EGFR', 'Gene', (191, 195))	('patients', 'Species', '9606', (85, 93))	('ALK', 'Gene', '238', (311, 314))	('epidermal growth factor receptor', 'Gene', '1956', (157, 189))	('echinoderm microtubule-associated protein-like 4', 'Gene', '27436', (222, 270))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (108, 127))	('mutation', 'Var', (145, 153))	('ALK', 'Gene', (311, 314))	('EML4', 'Gene', (272, 276))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('rearrangement', 'Var', (205, 218))	('EML4', 'Gene', '27436', (272, 276))	('echinoderm microtubule-associated protein-like 4', 'Gene', (222, 270))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (283, 302))	('EGFR', 'Gene', '1956', (191, 195))	('anaplastic lymphoma kinase', 'Gene', '238', (283, 309))
231718	33679868	Therefore, besides of EGFR mutation, the continued research is required to identify more cancer-related gene mutations and the corresponding targeted agents or combined therapies to improve outcomes for lung ASC.	('lung ASC', 'Disease', (203, 211))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('cancer', 'Disease', (89, 95))	('EGFR', 'Gene', '1956', (22, 26))	('mutations', 'Var', (109, 118))	('EGFR', 'Gene', (22, 26))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
231730	33679868	Somatic variations were identified with variant allele frequency (cutoff >= 3%) and cancer hotspots were screened with variant allele frequency (cutoff >= 1%) and at least 20 high-quality reads.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('variant', 'Var', (40, 47))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('cancer', 'Disease', (84, 90))
231731	33679868	The tumor mutation burden (TMB) was determined by the number of all the nonsynonymous mutation and indel variants per magabase of coding regions.	('tumor', 'Disease', (4, 9))	('TMB', 'Chemical', '-', (27, 30))	('indel variants', 'Var', (99, 113))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('nonsynonymous mutation', 'Var', (72, 94))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))
231746	33679868	Mutations of the TP53 gene are universal in lung cancer, with mutation rate of about 50% in NSCLC (Mogi and Kuwano,).	('lung cancer', 'Phenotype', 'HP:0100526', (44, 55))	('NSCLC', 'Phenotype', 'HP:0030358', (92, 97))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('lung cancer', 'Disease', 'MESH:D008175', (44, 55))	('Mutations', 'Var', (0, 9))	('NSCLC', 'Disease', (92, 97))	('NSCLC', 'Disease', 'MESH:D002289', (92, 97))	('TP53', 'Gene', '7157', (17, 21))	('TP53', 'Gene', (17, 21))	('lung cancer', 'Disease', (44, 55))
231748	33679868	The hotspot mutations of TP53 p.R248Q and TP53 p.R248W were detected in p11 and p19, respectively, which are the target of APR-246 drug.	('TP53', 'Gene', '7157', (42, 46))	('TP53', 'Gene', (25, 29))	('p11', 'Gene', '6281', (72, 75))	('p.R248W', 'Var', (47, 54))	('p.R248Q', 'Var', (30, 37))	('TP53', 'Gene', (42, 46))	('TP53', 'Gene', '7157', (25, 29))	('p19', 'Gene', (80, 83))	('APR-246', 'Chemical', 'MESH:C533410', (123, 130))	('p11', 'Gene', (72, 75))	('p.R248W', 'Mutation', 'rs121912651', (47, 54))	('p19', 'Gene', '1029', (80, 83))	('p.R248Q', 'Mutation', 'rs11540652', (30, 37))
231749	33679868	At present, FDA has approved APR-246 in combination therapies to treat myelodysplastic syndromes with TP53 mutation, while more clinical trials are required to prove the efficacy of the drug in treating patients with lung cancer.	('TP53', 'Gene', (102, 106))	('lung cancer', 'Disease', (217, 228))	('myelodysplastic syndromes', 'Disease', (71, 96))	('myelodysplastic syndromes', 'Disease', 'MESH:D009190', (71, 96))	('APR-246', 'Chemical', 'MESH:C533410', (29, 36))	('lung cancer', 'Phenotype', 'HP:0100526', (217, 228))	('myelodysplastic syndromes', 'Phenotype', 'HP:0002863', (71, 96))	('patients', 'Species', '9606', (203, 211))	('APR-246', 'Gene', (29, 36))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('lung cancer', 'Disease', 'MESH:D008175', (217, 228))	('TP53', 'Gene', '7157', (102, 106))	('mutation', 'Var', (107, 115))
231750	33679868	For EGFR gene, deletion in exon 19 was the most common mutation (7 cases), and the single nucleotide variation in exon 21 resulting in EGFR p.L858R variant was observed only in one case.	('p.L858R', 'Mutation', 'rs121434568', (140, 147))	('EGFR', 'Gene', '1956', (4, 8))	('EGFR', 'Gene', (4, 8))	('p.L858R', 'Var', (140, 147))	('EGFR', 'Gene', '1956', (135, 139))	('EGFR', 'Gene', (135, 139))	('deletion in', 'Var', (15, 26))
231751	33679868	The drug resistant mutation was detected in one case harboring insertion mutation in exon 20, while none of T790M variant was observed in this study.	('T790M', 'Mutation', 'rs121434569', (108, 113))	('detected', 'Reg', (32, 40))	('case ', 'Gene', (48, 53))	('case ', 'Gene', '100272147', (48, 53))	('insertion mutation in', 'Var', (63, 84))	('drug resistant', 'CPA', (4, 18))
231752	33679868	Two variants of in-frame deletion in exon 19 and single nucleotide variation resulting in EGFR p.E758D were coexisted in one case, as shown in Figure 1 and Supplemental Table 3.	('p.E758D', 'Mutation', 'p.E758D', (95, 102))	('EGFR', 'Gene', '1956', (90, 94))	('p.E758D', 'Var', (95, 102))	('EGFR', 'Gene', (90, 94))
231753	33679868	In addition to EGFR mutations, a set of genes involved in the PI3K signaling pathway were observed in seven lung ACS cases in our study.	('lung ACS', 'Disease', (108, 116))	('EGFR', 'Gene', '1956', (15, 19))	('EGFR', 'Gene', (15, 19))	('mutations', 'Var', (20, 29))	('observed', 'Reg', (90, 98))
231754	33679868	Two cases (p2 and p16) harbored a single nucleotide variation in exon 9 of PIK3CA, resulting in a p.E545K variant in the helical region, and one case (p14) harbored a mutation in exon 21 of PIK3CA which generated a p.H1047L variant in p110alpha catalytic subunit.	('PIK3CA', 'Gene', (75, 81))	('PIK3CA', 'Gene', '5290', (190, 196))	('p14', 'Gene', (151, 154))	('p.E545K', 'Mutation', 'rs104886003', (98, 105))	('PIK3CA', 'Gene', '5290', (75, 81))	('p16', 'Gene', '1029', (18, 21))	('p.H1047L', 'Var', (215, 223))	('p110alpha', 'Gene', (235, 244))	('p14', 'Gene', '1029', (151, 154))	('p110alpha', 'Gene', '5290', (235, 244))	('p16', 'Gene', (18, 21))	('PIK3CA', 'Gene', (190, 196))	('p.E545K', 'Var', (98, 105))	('p.H1047L', 'Mutation', 'rs121913279', (215, 223))	('case ', 'Gene', (145, 150))	('case ', 'Gene', '100272147', (145, 150))
231755	33679868	The variant of PTEN p.H123Y was present in one case (p13).	('p13', 'Gene', '440926', (53, 56))	('case ', 'Gene', (47, 52))	('case ', 'Gene', '100272147', (47, 52))	('PTEN', 'Gene', (15, 19))	('PTEN', 'Gene', '5728', (15, 19))	('p.H123Y', 'Var', (20, 27))	('p13', 'Gene', (53, 56))	('p.H123Y', 'Mutation', 'rs786204931', (20, 27))
231756	33679868	We also found PIK3C2B p.E545K variant in one case (p9), and PIK3C2G p.M1047I variant in another case (p3), both variants belong to class II PI3K.	('p.E545K', 'Var', (22, 29))	('p.E545K', 'Mutation', 'rs104886003', (22, 29))	('PIK3C2G', 'Gene', '5288', (60, 67))	('p.M1047I', 'Var', (68, 76))	('case ', 'Gene', '100272147', (45, 50))	('PIK3C2B', 'Gene', (14, 21))	('p.M1047I', 'Mutation', 'rs1336348464', (68, 76))	('case ', 'Gene', (96, 101))	('case ', 'Gene', '100272147', (96, 101))	('case ', 'Gene', (45, 50))	('PIK3C2B', 'Gene', '5287', (14, 21))	('PIK3C2G', 'Gene', (60, 67))
231757	33679868	In addition, gene mutations were observed in CDKN2A in two cases (p18 and p21), NF1 in two cases (p6 and p20), DDR2 in two cases (p8 and p13), PBRM1 in two cases (p9 and p13), WHSC1L1 in one case (p10), IRF4 in one case (p16), and HRAS in one case (p21).	('case ', 'Gene', (191, 196))	('observed', 'Reg', (33, 41))	('case ', 'Gene', '100272147', (191, 196))	('case ', 'Gene', (215, 220))	('case ', 'Gene', '100272147', (215, 220))	('NF1', 'Gene', '4763', (80, 83))	('p13', 'Gene', (170, 173))	('DDR2', 'Gene', '4921', (111, 115))	('p13', 'Gene', (137, 140))	('CDKN2A', 'Gene', '1029', (45, 51))	('IRF4', 'Gene', (203, 207))	('NF1', 'Gene', (80, 83))	('PBRM1', 'Gene', '55193', (143, 148))	('p21', 'Gene', '1026', (249, 252))	('p21', 'Gene', '1026', (74, 77))	('p18', 'Gene', '1031', (66, 69))	('p13', 'Gene', '440926', (170, 173))	('WHSC1L1', 'Gene', '54904', (176, 183))	('DDR2', 'Gene', (111, 115))	('p10', 'Gene', (197, 200))	('p13', 'Gene', '440926', (137, 140))	('PBRM1', 'Gene', (143, 148))	('HRAS', 'Gene', '3265', (231, 235))	('case ', 'Gene', (243, 248))	('WHSC1L1', 'Gene', (176, 183))	('case ', 'Gene', '100272147', (243, 248))	('HRAS', 'Gene', (231, 235))	('p16', 'Gene', (221, 224))	('p20', 'Gene', '51673', (105, 108))	('gene mutations', 'Var', (13, 27))	('p18', 'Gene', (66, 69))	('p20', 'Gene', (105, 108))	('p16', 'Gene', '1029', (221, 224))	('p10', 'Gene', '6281', (197, 200))	('p21', 'Gene', (74, 77))	('CDKN2A', 'Gene', (45, 51))	('p21', 'Gene', (249, 252))	('IRF4', 'Gene', '3662', (203, 207))
231758	33679868	The rearrangement of anaplastic lymphoma kinase (ALK), c-ros oncogene 1, receptor tyrosine kinase (ROS1), and ret proto-oncogene (RET) play a role on driving the occurrence and development of NSCLC (Takeuchi et al.,; Cancer Genome Atlas Research,).	('NSCLC', 'Disease', (192, 197))	('rearrangement', 'Var', (4, 17))	('anaplastic lymphoma kinase', 'Gene', '238', (21, 47))	('Cancer', 'Phenotype', 'HP:0002664', (217, 223))	('anaplastic lymphoma kinase', 'Gene', (21, 47))	('NSCLC', 'Phenotype', 'HP:0030358', (192, 197))	('lymphoma', 'Phenotype', 'HP:0002665', (32, 40))	('Cancer', 'Disease', (217, 223))	('ROS1', 'Gene', '6098', (99, 103))	('RET', 'Gene', (130, 133))	('ALK', 'Gene', '238', (49, 52))	('Cancer', 'Disease', 'MESH:D009369', (217, 223))	('ALK', 'Gene', (49, 52))	('c-ros oncogene 1, receptor tyrosine kinase', 'Gene', '6098', (55, 97))	('ROS1', 'Gene', (99, 103))	('NSCLC', 'Disease', 'MESH:D002289', (192, 197))	('ret', 'Gene', '5979', (110, 113))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (21, 40))	('ret', 'Gene', (110, 113))	('RET', 'Gene', '5979', (130, 133))
231763	33679868	Among those, the amplification of cyclin dependent kinase 4 (CDK4) was observed in two cases (p7 and p12).	('p12', 'Gene', '56655', (101, 104))	('CDK4', 'Gene', (61, 65))	('CDK4', 'Gene', '1019', (61, 65))	('amplification', 'Var', (17, 30))	('p12', 'Gene', (101, 104))	('cyclin dependent kinase 4', 'Gene', (34, 59))	('cyclin dependent kinase 4', 'Gene', '1019', (34, 59))
231768	33679868	The present study also indicated p1 and p7 cases harboring MDM2 and MYCN with copy number gains, respectively.	('MDM2', 'Gene', '4193', (59, 63))	('MDM2', 'Gene', (59, 63))	('copy number gains', 'Var', (78, 95))	('MYCN', 'Gene', (68, 72))	('MYCN', 'Gene', '4613', (68, 72))
231769	33679868	Overexpression or amplification of MDM2 occurs in a variety of cancer types.	('occurs', 'Reg', (40, 46))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('amplification', 'Var', (18, 31))	('MDM2', 'Gene', '4193', (35, 39))	('cancer', 'Disease', (63, 69))	('MDM2', 'Gene', (35, 39))
231779	33679868	However, there was no significant relationship between TMB and other clinicopathologic indexes, for instances, age, sex, smoking history, as well as TP53 and EGFR mutations in lung ASC (Table 3).	('EGFR', 'Gene', (158, 162))	('mutations', 'Var', (163, 172))	('TP53', 'Gene', '7157', (149, 153))	('TMB', 'Chemical', '-', (55, 58))	('TP53', 'Gene', (149, 153))	('lung ASC', 'Disease', (176, 184))	('EGFR', 'Gene', '1956', (158, 162))
231784	33679868	Among the enrolled patients, one case (p8) harboring EGFR exon 19del and amplification of EGFR, received the EGFR-TKI therapy.	('patients', 'Species', '9606', (19, 27))	('EGFR', 'Gene', '1956', (90, 94))	('exon 19del', 'Var', (58, 68))	('amplification', 'Var', (73, 86))	('EGFR', 'Gene', '1956', (109, 113))	('case (p8)', 'Gene', '100272147', (33, 42))	('EGFR', 'Gene', (90, 94))	('EGFR', 'Gene', '1956', (53, 57))	('EGFR', 'Gene', (53, 57))	('EGFR', 'Gene', (109, 113))	('case (p8', 'Gene', (33, 41))
231792	33679868	Our study showed a high frequency of EGFR mutations in lung ASC, the mutation rate was 48%.	('EGFR', 'Gene', '1956', (37, 41))	('EGFR', 'Gene', (37, 41))	('mutations', 'Var', (42, 51))	('lung ASC', 'Disease', (55, 63))
231793	33679868	However, in contrast to our observation, a lower prevalence of EGFR mutations was reported in lung ASC of Caucasian ethnic group, with a mutation rate of 13% (Tochigi et al.,).	('mutations', 'Var', (68, 77))	('EGFR', 'Gene', (63, 67))	('lung ASC', 'Disease', (94, 102))	('EGFR', 'Gene', '1956', (63, 67))
231794	33679868	Moreover, consistent with the incidence of EGFR mutation in lung adenocarcinoma, the mutation rate was 46.7% in the Asian population and 15% in the white population (Liu et al.,).	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (60, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('EGFR', 'Gene', '1956', (43, 47))	('mutation', 'Var', (48, 56))	('lung adenocarcinoma', 'Disease', (60, 79))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (60, 79))	('EGFR', 'Gene', (43, 47))
231796	33679868	Therefore, considering the similar profile of somatic variations in ASC and lung adenocarcinoma, TKI might be an effective targeted agents for lung ASC with EGFR mutations.	('EGFR', 'Gene', (157, 161))	('mutations', 'Var', (162, 171))	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('lung adenocarcinoma', 'Disease', (76, 95))	('lung ASC', 'Disease', (143, 151))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (76, 95))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (76, 95))	('EGFR', 'Gene', '1956', (157, 161))
231801	33679868	That might be due to the lower prevalence of gene translocations in lung cancers and the small size of enrolled patients with lung ASC.	('lung cancer', 'Phenotype', 'HP:0100526', (68, 79))	('lung cancers', 'Disease', 'MESH:D008175', (68, 80))	('lung cancers', 'Phenotype', 'HP:0100526', (68, 80))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('patients', 'Species', '9606', (112, 120))	('gene translocations', 'Var', (45, 64))	('lung cancers', 'Disease', (68, 80))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))
231807	33679868	The current study displayed that TMB was lower in adenocarcinoma component than in squamous cell carcinoma component, with the median of 6.5 and 7.2 mutations/Mb, respectively (Lin et al.,).	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (83, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (55, 64))	('mutations/Mb', 'Var', (149, 161))	('lower', 'NegReg', (41, 46))	('TMB', 'MPA', (33, 36))	('TMB', 'Chemical', '-', (33, 36))	('adenocarcinoma component than in squamous cell carcinoma component', 'Disease', 'MESH:D002294', (50, 116))
231812	33679868	In line with the results, the previous study indicated that high TMB is a poor prognostic factor for the advanced NSCLC, as well as patient in early stage (Owada-Ozaki et al.,).	('NSCLC', 'Phenotype', 'HP:0030358', (114, 119))	('high', 'Var', (60, 64))	('TMB', 'Chemical', '-', (65, 68))	('NSCLC', 'Disease', (114, 119))	('NSCLC', 'Disease', 'MESH:D002289', (114, 119))	('patient', 'Species', '9606', (132, 139))
231814	33679868	In conclusion, the lung ASC with high TMB might be associated with invasion of lymph node and short overall survival.	('TMB', 'Gene', (38, 41))	('high', 'Var', (33, 37))	('invasion of lymph node', 'CPA', (67, 89))	('TMB', 'Chemical', '-', (38, 41))	('associated', 'Reg', (51, 61))	('lung ASC', 'Disease', (19, 27))
232145	32266120	The data of esophageal squamous cell carcinoma from the Gene Expression Omnibus (GEO) were selected as the research object, processed and analyzed to screen differentially expressed microRNAs (miRNAs) and differential methylation genes.	('carcinoma', 'Phenotype', 'HP:0030731', (37, 46))	('differential methylation', 'Var', (205, 229))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (12, 46))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (23, 46))	('esophageal squamous cell carcinoma', 'Disease', (12, 46))
232164	32266120	In addition to genetic characteristics, scientists have also found that esophageal cancer has a variety of epigenetic changes in recent years.	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('esophageal cancer', 'Disease', (72, 89))	('epigenetic changes', 'Var', (107, 125))	('esophageal cancer', 'Disease', 'MESH:D004938', (72, 89))
232166	32266120	Epigenetic abnormalities not only drive the occurrence and development of tumors, but also affect cell growth, invasion, metastasis, heterogeneity and drug resistance.	('heterogeneity', 'MPA', (133, 146))	('metastasis', 'CPA', (121, 131))	('Epigenetic abnormalities', 'Var', (0, 24))	('drug resistance', 'CPA', (151, 166))	('drug resistance', 'Phenotype', 'HP:0020174', (151, 166))	('drive', 'PosReg', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('affect', 'Reg', (91, 97))	('development', 'CPA', (59, 70))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('cell growth', 'CPA', (98, 109))	('invasion', 'CPA', (111, 119))	('tumors', 'Disease', 'MESH:D009369', (74, 80))	('tumors', 'Disease', (74, 80))
232167	32266120	More importantly, epigenetic changes are often early events in the process of disease occurrence, which provides an opportunity to find tumor specific biomarkers.	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('tumor', 'Disease', (136, 141))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('epigenetic changes', 'Var', (18, 36))
232182	32266120	Finally, three differentially expressed down-regulated miRNAs were obtained, including hsa-mir- 139-5p, hsa-mir-1 and hsa-mir-133b.	('hsa-mir-1', 'Var', (104, 113))	('hsa-mir-133b', 'Gene', (118, 130))	('hsa-mir-133b', 'Gene', '442890', (118, 130))	('down-regulated', 'NegReg', (40, 54))
232183	32266120	There were nine up-regulated miRNAs, including hsa-mir-1246, hsa-mir-34c-5p, hsa-mir-455-5p, hsa-mir-455-3p, hsa-mir-146b-5p, hsa-mir-3651 and hsa-mir-429, as shown in Figs.	('hsa-mir-3651', 'Gene', (126, 138))	('hsa-mir-146b-5p', 'Var', (109, 124))	('hsa-mir-455', 'Gene', '619556', (77, 88))	('hsa-mir-429', 'Gene', '554210', (143, 154))	('hsa-mir-455', 'Gene', (93, 104))	('hsa-mir-34c-5p', 'Var', (61, 75))	('miRNAs', 'MPA', (29, 35))	('hsa-mir-429', 'Gene', (143, 154))	('up-regulated', 'PosReg', (16, 28))	('hsa-mir-455', 'Gene', '619556', (93, 104))	('hsa-mir-3651', 'Gene', '100500918', (126, 138))	('hsa-mir-1246', 'Gene', '100302142', (47, 59))	('hsa-mir-455', 'Gene', (77, 88))	('hsa-mir-1246', 'Gene', (47, 59))
232200	32266120	found that miRNA-338-3p, miRNA-218 and hsa-miRNA-139-5p were up-regulated in esophageal squamous cell carcinoma, while miRNA-183, miRNA-574-5p, miRNA-21 and miRNA-601 were down regulated.	('miRNA-21', 'Gene', (144, 152))	('miRNA-21', 'Gene', (25, 33))	('miRNA-338-3p', 'Var', (11, 23))	('esophageal squamous cell carcinoma', 'Disease', (77, 111))	('miRNA-183', 'Gene', '406959', (119, 128))	('miRNA-183', 'Gene', (119, 128))	('miRNA-21', 'Gene', '406991', (144, 152))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (88, 111))	('miRNA-21', 'Gene', '406991', (25, 33))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (77, 111))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('up-regulated', 'PosReg', (61, 73))
232201	32266120	Kano et al., found that 15 miRNAs were down regulated in esophageal squamous cell carcinoma compared with normal tissues, and 4 miRNAs were able to play an anti-cancer role (miRNA-145, miRNA-30a-3p, miRNA-133a and miRNA-133b), which was consistent with the differential expression miRNAs we analyzed, which proved that our screening method was feasible.	('esophageal squamous cell carcinoma', 'Disease', (57, 91))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('miRNA-133b', 'Gene', '442890', (214, 224))	('miRNA-145', 'Gene', '406937', (174, 183))	('miRNA-145', 'Gene', (174, 183))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('miRNA-30a-3p', 'Var', (185, 197))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('miRNA-133b', 'Gene', (214, 224))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (57, 91))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (68, 91))	('down regulated', 'NegReg', (39, 53))	('cancer', 'Disease', (161, 167))	('miRNA-133a', 'Var', (199, 209))
232209	32266120	The abnormal expression of lncRNAs may play an important role in the occurrence and development of esophageal carcinoma.	('esophageal carcinoma', 'Disease', 'MESH:D004938', (99, 119))	('abnormal', 'Var', (4, 12))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (99, 119))	('expression', 'MPA', (13, 23))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('play', 'Reg', (39, 43))	('lncRNAs', 'Protein', (27, 34))	('esophageal carcinoma', 'Disease', (99, 119))
232213	32266120	FoxO gene changes have been described in a limited number of human cancers such as rhabdomyosarcoma, leukemia and lymphoma.	('human', 'Species', '9606', (61, 66))	('FoxO', 'Gene', (0, 4))	('cancers', 'Phenotype', 'HP:0002664', (67, 74))	('cancers', 'Disease', (67, 74))	('cancers', 'Disease', 'MESH:D009369', (67, 74))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (83, 99))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('lymphoma', 'Disease', (114, 122))	('leukemia', 'Disease', (101, 109))	('rhabdomyosarcoma', 'Disease', (83, 99))	('leukemia', 'Disease', 'MESH:D007938', (101, 109))	('lymphoma', 'Disease', 'MESH:D008223', (114, 122))	('leukemia', 'Phenotype', 'HP:0001909', (101, 109))	('changes', 'Var', (10, 17))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (83, 99))	('described', 'Reg', (28, 37))	('lymphoma', 'Phenotype', 'HP:0002665', (114, 122))
232219	32266120	It can promote the phosphorylation of DNA protein kinase and repair the break of DNA double strand, thus affecting the radiosensitivity of tumor cells.	('DNA protein kinase', 'Enzyme', (38, 56))	('break', 'Var', (72, 77))	('phosphorylation', 'MPA', (19, 34))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('affecting', 'Reg', (105, 114))	('promote', 'PosReg', (7, 14))	('tumor', 'Disease', (139, 144))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))
232237	32251318	However, the functions of the many variants of these proteins in cancer remain incompletely understood.	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('variants', 'Var', (35, 43))
232239	32251318	Although the mutation rate of the netrin family is low in pan-cancer, among the tumor patients with netrin mutations, the highest number are Uterine Corpus Endometrial Carcinoma patients, accounting for 13.6% of cases (54 of 397).	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('netrin', 'Gene', (100, 106))	('mutations', 'Var', (107, 116))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('patients', 'Species', '9606', (178, 186))	('Corpus Endometrial Carcinoma', 'Disease', 'MESH:D016889', (149, 177))	('Carcinoma', 'Phenotype', 'HP:0030731', (168, 177))	('tumor', 'Disease', (80, 85))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('Endometrial Carcinoma', 'Phenotype', 'HP:0012114', (156, 177))	('Corpus Endometrial Carcinoma', 'Disease', (149, 177))	('patients', 'Species', '9606', (86, 94))
232247	32251318	HGF inhibits the treatment of RAF inhibitors of BRAF mutant melanoma.	('inhibits', 'NegReg', (4, 12))	('RAF', 'Gene', '22882', (49, 52))	('HGF', 'Gene', (0, 3))	('RAF', 'Gene', (49, 52))	('treatment of', 'MPA', (17, 29))	('melanoma', 'Disease', 'MESH:D008545', (60, 68))	('melanoma', 'Phenotype', 'HP:0002861', (60, 68))	('HGF', 'Gene', '3082', (0, 3))	('melanoma', 'Disease', (60, 68))	('RAF', 'Gene', '22882', (30, 33))	('mutant', 'Var', (53, 59))	('RAF', 'Gene', (30, 33))	('BRAF', 'Gene', (48, 52))	('BRAF', 'Gene', '673', (48, 52))
232266	32251318	Mutations in the netrins were identified in the 33 cancers included in TCGA (Fig.	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('netrins', 'Gene', (17, 24))	('Mutations', 'Var', (0, 9))	('cancers', 'Phenotype', 'HP:0002664', (51, 58))	('identified', 'Reg', (30, 40))	('cancers', 'Disease', (51, 58))	('cancers', 'Disease', 'MESH:D009369', (51, 58))
232267	32251318	At the cancer level, netrins associated with uterine corpus endometrial carcinoma (UCEC) exhibited the highest number of mutations (54), followed by colon adenocarcinoma (COAD) (49), skin cutaneous melanoma (SKCM) (47), stomach adenocarcinoma (STAD) (42), lung adenocarcinoma (LUAD) (38), and lung squamous cell carcinoma (LUSC)(36).	('mutations', 'Var', (121, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (160, 169))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (60, 81))	('melanoma', 'Phenotype', 'HP:0002861', (198, 206))	('lung adenocarcinoma', 'Disease', (256, 275))	('cancer', 'Disease', (7, 13))	('associated', 'Reg', (29, 39))	('LUAD', 'Phenotype', 'HP:0030078', (277, 281))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (188, 206))	('stomach adenocarcinoma', 'Disease', (220, 242))	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('stomach adenocarcinoma', 'Disease', 'MESH:D013274', (220, 242))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (256, 275))	('corpus endometrial carcinoma', 'Disease', (53, 81))	('corpus endometrial carcinoma', 'Disease', 'MESH:D016889', (53, 81))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (293, 321))	('colon adenocarcinoma (COAD) (49), skin cutaneous melanoma', 'Disease', 'MESH:D029424', (149, 206))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (298, 321))	('lung squamous cell carcinoma', 'Disease', (293, 321))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (256, 275))	('netrins', 'Gene', (21, 28))	('carcinoma', 'Phenotype', 'HP:0030731', (266, 275))	('carcinoma', 'Phenotype', 'HP:0030731', (312, 321))	('cancer', 'Disease', 'MESH:D009369', (7, 13))	('carcinoma', 'Phenotype', 'HP:0030731', (233, 242))
232268	32251318	The total mutation rates of Netrin family members in the above six cancers were 10.19%, 12.28%, 10.06%, 9.61%, 6.70% and 7.32%, respectively.	('cancers', 'Phenotype', 'HP:0002664', (67, 74))	('Netrin family', 'Gene', (28, 41))	('cancers', 'Disease', (67, 74))	('cancers', 'Disease', 'MESH:D009369', (67, 74))	('mutation', 'Var', (10, 18))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))
232270	32251318	However, the hot spot mutation P201Qfs*15 of NTN3 was identified in three patients, each with a different cancer (ESCA, STAD, UCEC), and encodes a truncated protein.	('STAD', 'Disease', (120, 124))	('P201Qfs*15', 'Var', (31, 41))	('NTN3', 'Gene', (45, 49))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('patients', 'Species', '9606', (74, 82))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('ESCA', 'Phenotype', 'HP:0011459', (114, 118))	('cancer', 'Disease', (106, 112))	('NTN3', 'Gene', '4917', (45, 49))
232271	32251318	E59K, one of the hotspot mutations of NTN4, was detected in four patients with three cancers (READ, COAD, and UCEC) and both VEST3 and REVEL algorithms indicated this change was dual-damaging.	('READ', 'Disease', (94, 98))	('detected', 'Reg', (48, 56))	('COAD', 'Disease', (100, 104))	('NTN4', 'Gene', (38, 42))	('cancers', 'Disease', 'MESH:D009369', (85, 92))	('cancers', 'Phenotype', 'HP:0002664', (85, 92))	('E59K', 'Var', (0, 4))	('cancers', 'Disease', (85, 92))	('NTN4', 'Gene', '59277', (38, 42))	('E59K', 'Mutation', 'rs762617558', (0, 4))	('patients', 'Species', '9606', (65, 73))	('READ', 'Disease', '-', (94, 98))	('COAD', 'Disease', 'MESH:D029424', (100, 104))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
232272	32251318	The hot spot mutation X342_splice of NTN5 occurred in two cancers (SKCM and UCEC) in two patients, and also encodes a truncated protein.	('occurred', 'Reg', (42, 50))	('NTN5', 'Gene', '126147', (37, 41))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('cancers', 'Phenotype', 'HP:0002664', (58, 65))	('NTN5', 'Gene', (37, 41))	('patients', 'Species', '9606', (89, 97))	('cancers', 'Disease', 'MESH:D009369', (58, 65))	('cancers', 'Disease', (58, 65))	('X342_splice', 'Var', (22, 33))
232273	32251318	The hot spot mutation R238C/H of NTNG1 was detected in three patients with three cancers (COAD, STAD, and UCEC), and R238C was predicted as damaging in VEST3 and REVEL algorithms.	('STAD', 'Disease', (96, 100))	('COAD', 'Disease', 'MESH:D029424', (90, 94))	('R238C', 'Var', (117, 122))	('R238C', 'SUBSTITUTION', 'None', (117, 122))	('NTNG1', 'Gene', '22854', (33, 38))	('NTNG1', 'Gene', (33, 38))	('R238C', 'Mutation', 'p.R238C', (117, 122))	('cancers', 'Phenotype', 'HP:0002664', (81, 88))	('patients', 'Species', '9606', (61, 69))	('cancers', 'Disease', (81, 88))	('cancers', 'Disease', 'MESH:D009369', (81, 88))	('R238C', 'Var', (22, 27))	('COAD', 'Disease', (90, 94))	('R238C', 'Mutation', 'p.R238C', (22, 27))	('R238C', 'SUBSTITUTION', 'None', (22, 27))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))
232274	32251318	The NTNG2 hotspot mutation D226N/Rfs*141 occurred in three patients with three cancers (LAML, GBM, and COAD), and NTN1 hotspot mutation P459T was detected in three patients with two cancers (STAD, READ).The mutations in NTN1, NTN3, NTN4, NTNG1, and NTNG2 were mainly in the laminin-N domain, and most mutations of NTN5 were concentrated in the laminin_EGF2 domain.	('NTNG1', 'Gene', '22854', (238, 243))	('NTNG2', 'Gene', (249, 254))	('NTN1', 'Gene', '9423', (114, 118))	('P459T', 'Mutation', 'rs376278603', (136, 141))	('NTN4', 'Gene', (232, 236))	('NTN1', 'Gene', (220, 224))	('COAD', 'Disease', (103, 107))	('NTN5', 'Gene', (314, 318))	('D226N', 'SUBSTITUTION', 'None', (27, 32))	('cancers', 'Phenotype', 'HP:0002664', (182, 189))	('mutations', 'Var', (207, 216))	('patients', 'Species', '9606', (59, 67))	('cancers', 'Disease', (182, 189))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('NTN5', 'Gene', '126147', (314, 318))	('patients', 'Species', '9606', (164, 172))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('cancers', 'Disease', (79, 86))	('NTN1', 'Gene', '9423', (220, 224))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('NTN4', 'Gene', '59277', (232, 236))	('NTNG2', 'Gene', '84628', (4, 9))	('D226N', 'Var', (27, 32))	('NTN3', 'Gene', '4917', (226, 230))	('NTNG2', 'Gene', '84628', (249, 254))	('NTNG1', 'Gene', (238, 243))	('NTN1', 'Gene', (114, 118))	('READ', 'Disease', (197, 201))	('cancers', 'Disease', 'MESH:D009369', (182, 189))	('COAD', 'Disease', 'MESH:D029424', (103, 107))	('READ', 'Disease', '-', (197, 201))	('cancers', 'Disease', 'MESH:D009369', (79, 86))	('NTN3', 'Gene', (226, 230))	('NTNG2', 'Gene', (4, 9))
232275	32251318	After screening by genetic ancestry groups and non-synonymous mutations, 62 patients had complete mutation information (64 mutations) for NTN1, 34 patients were included with complete mutation information (37 mutations) for NTN3, and 107 patients had complete mutation information (120 mutations) for NTN4.	('NTN4', 'Gene', (301, 305))	('patients', 'Species', '9606', (76, 84))	('NTN3', 'Gene', '4917', (224, 228))	('NTN1', 'Gene', (138, 142))	('NTN3', 'Gene', (224, 228))	('NTN4', 'Gene', '59277', (301, 305))	('NTN1', 'Gene', '9423', (138, 142))	('patients', 'Species', '9606', (147, 155))	('patients', 'Species', '9606', (238, 246))	('mutations', 'Var', (123, 132))
232276	32251318	Additionally, the data included 33 patients with 33 mutations in NTN5, 152 patient and 161 mutations in NTNG1, and 91 patients with 98 mutations in (Fig.	('mutations', 'Var', (52, 61))	('patient', 'Species', '9606', (75, 82))	('patients', 'Species', '9606', (118, 126))	('patient', 'Species', '9606', (35, 42))	('NTN5', 'Gene', '126147', (65, 69))	('patients', 'Species', '9606', (35, 43))	('NTNG1', 'Gene', '22854', (104, 109))	('patient', 'Species', '9606', (118, 125))	('NTN5', 'Gene', (65, 69))	('NTNG1', 'Gene', (104, 109))
232277	32251318	By comparing the data, we found that up to four netrin family members in individual patients contained mutations in four patients, three UCEC patients and one STAD patient with mutations in both NTN1 and NTNG2.	('mutations', 'Var', (103, 112))	('patients', 'Species', '9606', (84, 92))	('NTNG2', 'Gene', (204, 209))	('patient', 'Species', '9606', (164, 171))	('patient', 'Species', '9606', (121, 128))	('patient', 'Species', '9606', (84, 91))	('patient', 'Species', '9606', (142, 149))	('contained', 'Reg', (93, 102))	('NTN1', 'Gene', (195, 199))	('patients', 'Species', '9606', (142, 150))	('patients', 'Species', '9606', (121, 129))	('NTNG2', 'Gene', '84628', (204, 209))	('NTN1', 'Gene', '9423', (195, 199))
232278	32251318	In cancer studies with at least five mutations in members of netrin genes (Fig.	('netrin genes', 'Gene', (61, 73))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('mutations', 'Var', (37, 46))	('cancer', 'Disease', (3, 9))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
232279	32251318	2b), UCEC patients were one of the two highest among the cancers associated with the netrin family mutations, with most mutations in NTNG1.	('NTNG1', 'Gene', '22854', (133, 138))	('UCEC', 'Disease', (5, 9))	('NTNG1', 'Gene', (133, 138))	('cancers', 'Phenotype', 'HP:0002664', (57, 64))	('cancers', 'Disease', (57, 64))	('cancers', 'Disease', 'MESH:D009369', (57, 64))	('mutations', 'Var', (99, 108))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('mutations', 'Var', (120, 129))	('patients', 'Species', '9606', (10, 18))
232280	32251318	SKCM has the most mutations in NTN4.	('NTN4', 'Gene', '59277', (31, 35))	('NTN4', 'Gene', (31, 35))	('mutations', 'Var', (18, 27))
232281	32251318	2c), the highest number of cancer mutations among the four genetic ancestry groups was UCEC, and the netrin family mutations in STAD were mainly distributed in EAA and NA.	('netrin family', 'Gene', (101, 114))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('mutations', 'Var', (115, 124))	('cancer', 'Disease', (27, 33))	('cancer', 'Disease', 'MESH:D009369', (27, 33))	('mutations', 'Var', (34, 43))
232282	32251318	Most netrin mutations in COAD occur in EA and AA.	('mutations', 'Var', (12, 21))	('COAD', 'Disease', (25, 29))	('COAD', 'Disease', 'MESH:D029424', (25, 29))	('netrin', 'Gene', (5, 11))
232283	32251318	2d,e) revealed that most mutations in netrins were in the laminin N-terminal domain, except for NTN5.	('NTN5', 'Gene', '126147', (96, 100))	('mutations', 'Var', (25, 34))	('netrins', 'Gene', (38, 45))	('NTN5', 'Gene', (96, 100))
232284	32251318	In the laminin EGF domains of NTN1, NTN3, NTN4, and NTN5, most mutations were in the laminin EGF-like 2 domain.	('mutations', 'Var', (63, 72))	('NTN4', 'Gene', (42, 46))	('NTN5', 'Gene', '126147', (52, 56))	('NTN3', 'Gene', '4917', (36, 40))	('NTN4', 'Gene', '59277', (42, 46))	('NTN3', 'Gene', (36, 40))	('NTN1', 'Gene', (30, 34))	('NTN1', 'Gene', '9423', (30, 34))	('NTN5', 'Gene', (52, 56))
232285	32251318	In the NTNG1 laminin EGF domains, the mutation of laminin EGF-like 3 was the most frequent, and in the NTNG2 laminin EGF domains, the mutation of laminin EGF-like 1 was the most frequent.	('NTNG2', 'Gene', (103, 108))	('mutation', 'Var', (134, 142))	('frequent', 'Reg', (82, 90))	('frequent', 'Reg', (178, 186))	('laminin EGF-like 3', 'Gene', (50, 68))	('NTNG1', 'Gene', '22854', (7, 12))	('mutation', 'Var', (38, 46))	('NTNG2', 'Gene', '84628', (103, 108))	('NTNG1', 'Gene', (7, 12))
232286	32251318	The mutations in the NTR domain were mainly concentrated in NTN1 and 4.	('NTR', 'Gene', (21, 24))	('NTN1', 'Gene', (60, 64))	('NTN1', 'Gene', '9423', (60, 64))	('NTR', 'Gene', '4923', (21, 24))	('mutations', 'Var', (4, 13))
232296	32251318	Additionally, MLK1 enhanced cancer cell migration and invasion by epigenetic activation of MMP9 transcription in lung cancer.	('cancer', 'Disease', (118, 124))	('lung cancer', 'Disease', (113, 124))	('invasion', 'CPA', (54, 62))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('MLK1', 'Gene', (14, 18))	('lung cancer', 'Phenotype', 'HP:0100526', (113, 124))	('epigenetic activation', 'Var', (66, 87))	('transcription', 'MPA', (96, 109))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('MLK1', 'Gene', '4293', (14, 18))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('lung cancer', 'Disease', 'MESH:D008175', (113, 124))	('MMP9', 'Gene', (91, 95))	('cancer', 'Disease', (28, 34))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('MMP9', 'Gene', '4318', (91, 95))	('enhanced', 'PosReg', (19, 27))
232331	32251318	5c) showed the survival was worse for hypomethylation of NTN1 in kidney renal papillary cell carcinoma (KIRP) and worse for NTNG1 in kidney renal clear cell carcinoma (KIRC), which is consistent with the correlation of high expression of NTN1 in KIRP and NTNG1 in KIRC with worse survival.	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('kidney renal papillary cell carcinoma', 'Disease', (65, 102))	('hypomethylation', 'Var', (38, 53))	('kidney renal papillary cell carcinoma', 'Disease', 'MESH:D007681', (65, 102))	('kidney renal clear cell carcinoma', 'Disease', 'MESH:C538614', (133, 166))	('NTN1', 'Gene', (238, 242))	('carcinoma', 'Phenotype', 'HP:0030731', (157, 166))	('NTNG1', 'Gene', '22854', (255, 260))	('NTN1', 'Gene', '9423', (238, 242))	('NTN1', 'Gene', (57, 61))	('NTN1', 'Gene', '9423', (57, 61))	('NTNG1', 'Gene', (255, 260))	('NTNG1', 'Gene', '22854', (124, 129))	('kidney renal clear cell carcinoma', 'Disease', (133, 166))	('NTNG1', 'Gene', (124, 129))
232334	32251318	Methylation of NTN1, NTN3, NTN4, NTN5, and NTNG1 was associated with radiation therapy and overall survival of LGG.	('NTN3', 'Gene', (21, 25))	('NTN4', 'Gene', (27, 31))	('NTNG1', 'Gene', '22854', (43, 48))	('Methylation', 'Var', (0, 11))	('NTNG1', 'Gene', (43, 48))	('NTN5', 'Gene', (33, 37))	('NTN1', 'Gene', (15, 19))	('NTN4', 'Gene', '59277', (27, 31))	('radiation therapy', 'CPA', (69, 86))	('NTN1', 'Gene', '9423', (15, 19))	('associated with', 'Reg', (53, 68))	('NTN3', 'Gene', '4917', (21, 25))	('NTN5', 'Gene', '126147', (33, 37))
232336	32251318	In pan-kidney (KIRP and KIRC), methylation of NTN4 was associated with pathology T stage and overall survival of KIRP and KIRC.	('methylation', 'Var', (31, 42))	('associated', 'Reg', (55, 65))	('NTN4', 'Gene', '59277', (46, 50))	('NTN4', 'Gene', (46, 50))
232337	32251318	Methylation of NTN1 and NTNG1 was associated with pathology T stage and pathology N stage of KIRP.	('associated', 'Reg', (34, 44))	('Methylation', 'Var', (0, 11))	('NTN1', 'Gene', (15, 19))	('NTNG1', 'Gene', (24, 29))	('NTN1', 'Gene', '9423', (15, 19))	('NTNG1', 'Gene', '22854', (24, 29))
232339	32251318	Methylation of NTN1 and NTN3 was associated with radiation therapy and pathology T stage of ESCA.	('radiation', 'CPA', (49, 58))	('NTN3', 'Gene', '4917', (24, 28))	('NTN3', 'Gene', (24, 28))	('Methylation', 'Var', (0, 11))	('NTN1', 'Gene', (15, 19))	('associated', 'Reg', (33, 43))	('NTN1', 'Gene', '9423', (15, 19))	('ESCA', 'Phenotype', 'HP:0011459', (92, 96))
232340	32251318	Methylation of NTN3 was associated with pathology T stage, pathology N stage and number of lymph nodes of PRAD.	('Methylation', 'Var', (0, 11))	('NTN3', 'Gene', (15, 19))	('associated', 'Reg', (24, 34))	('NTN3', 'Gene', '4917', (15, 19))
232341	32251318	Methylation of NTN1, NTN3, NTN4, and NTNG1 was associated with PAM50 typing of BRCA, and NTNG1 was also associated with ER.Status and PR.Status.	('NTNG1', 'Gene', (37, 42))	('ER.Status', 'Disease', (120, 129))	('BRCA', 'Gene', (79, 83))	('associated', 'Reg', (104, 114))	('NTN1', 'Gene', (15, 19))	('NTN4', 'Gene', '59277', (27, 31))	('associated', 'Reg', (47, 57))	('NTNG1', 'Gene', '22854', (37, 42))	('Methylation', 'Var', (0, 11))	('NTN1', 'Gene', '9423', (15, 19))	('NTN3', 'Gene', '4917', (21, 25))	('BRCA', 'Phenotype', 'HP:0003002', (79, 83))	('NTNG1', 'Gene', (89, 94))	('PAM50 typing', 'Var', (63, 75))	('NTN3', 'Gene', (21, 25))	('BRCA', 'Gene', '672', (79, 83))	('NTN4', 'Gene', (27, 31))	('PR.Status', 'Disease', (134, 143))	('NTNG1', 'Gene', '22854', (89, 94))
232342	32251318	In UCEC, methylation of NTN3, NTN4, NTNG1, and NTNG2 was associated with MSI phenotype.	('methylation', 'Var', (9, 20))	('NTN3', 'Gene', '4917', (24, 28))	('NTN4', 'Gene', (30, 34))	('MSI', 'Disease', '-', (73, 76))	('NTN3', 'Gene', (24, 28))	('NTNG2', 'Gene', '84628', (47, 52))	('NTNG1', 'Gene', '22854', (36, 41))	('NTN4', 'Gene', '59277', (30, 34))	('NTNG1', 'Gene', (36, 41))	('NTNG2', 'Gene', (47, 52))	('MSI', 'Disease', (73, 76))	('associated', 'Reg', (57, 67))
232346	32251318	Overexpression of EZH2 is also associated with the development of prostate cancer, and phosphorylated EZH2 can act as a co-activator of transcription factors, such as promoting the expression of AR.	('EZH2', 'Gene', (102, 106))	('EZH2', 'Gene', '2146', (102, 106))	('prostate cancer', 'Disease', 'MESH:D011471', (66, 81))	('expression', 'MPA', (181, 191))	('prostate cancer', 'Phenotype', 'HP:0012125', (66, 81))	('EZH2', 'Gene', '2146', (18, 22))	('associated', 'Reg', (31, 41))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('phosphorylated', 'Var', (87, 101))	('EZH2', 'Gene', (18, 22))	('AR', 'Gene', '367', (195, 197))	('prostate cancer', 'Disease', (66, 81))	('promoting', 'PosReg', (167, 176))
232361	32251318	Among the many statistically significant results, hsa-miR-361-3p had the strongest inhibitory effect on NTN1 in TCGT (r = 0.612), hsa-miR-33a-5p had the strongest inhibitory effect on NTN4 in TCGT and ESCA (r = -0.494), and hsa-miR-20b-5p had the strongest inhibitory effect on NTNG1 in DLBC (r = -0.528).	('inhibitory effect', 'MPA', (83, 100))	('NTN4', 'Gene', '59277', (184, 188))	('NTN1', 'Gene', (104, 108))	('hsa-miR-361-3p', 'Gene', '100500908', (50, 64))	('NTN1', 'Gene', '9423', (104, 108))	('inhibitory effect', 'MPA', (163, 180))	('hsa-miR-33a-5p', 'Var', (130, 144))	('ESCA', 'Phenotype', 'HP:0011459', (201, 205))	('NTN4', 'Gene', (184, 188))	('NTNG1', 'Gene', '22854', (278, 283))	('hsa-miR-361-3p', 'Gene', (50, 64))	('NTNG1', 'Gene', (278, 283))	('BC', 'Phenotype', 'HP:0003002', (289, 291))
232367	32251318	The expression of NTN5 was affected by eQTL in BRCA, COAD, KIRC, KIRP, LGG, PRAD, and THCA.	('expression', 'MPA', (4, 14))	('COAD', 'Disease', 'MESH:D029424', (53, 57))	('affected', 'Reg', (27, 35))	('eQTL', 'Var', (39, 43))	('NTN5', 'Gene', '126147', (18, 22))	('BRCA', 'Phenotype', 'HP:0003002', (47, 51))	('THCA', 'Phenotype', 'HP:0002890', (86, 90))	('BRCA', 'Gene', '672', (47, 51))	('COAD', 'Disease', (53, 57))	('NTN5', 'Gene', (18, 22))	('BRCA', 'Gene', (47, 51))
232370	32251318	Of these, 186 (74.4%) NTNG1 eQTLs were associated with AIDS and 57 (22.9%) were associated with non-obstructive azoospermia.	('NTNG1', 'Gene', '22854', (22, 27))	('non-obstructive azoospermia', 'Disease', 'MESH:D053713', (96, 123))	('NTNG1', 'Gene', (22, 27))	('obstructive azoospermia', 'Phenotype', 'HP:0011962', (100, 123))	('azoospermia', 'Phenotype', 'HP:0000027', (112, 123))	('AIDS', 'Disease', (55, 59))	('non-obstructive azoospermia', 'Disease', (96, 123))	('associated', 'Reg', (80, 90))	('associated', 'Reg', (39, 49))	('AIDS', 'Disease', 'MESH:D000163', (55, 59))	('eQTLs', 'Var', (28, 33))	('non-obstructive azoospermia', 'Phenotype', 'HP:0011961', (96, 123))
232373	32251318	Further, three eQTLs (rs9894790, rs9901637, and rs11650713) were found to affect the binding of MYC, TCF12, EBF1, EGR1, and NR2F2.	('rs11650713', 'Var', (48, 58))	('rs11650713', 'Mutation', 'rs11650713', (48, 58))	('MYC', 'Gene', (96, 99))	('EBF1', 'Gene', '1879', (108, 112))	('TCF12', 'Gene', '6938', (101, 106))	('rs9894790', 'Var', (22, 31))	('TCF12', 'Gene', (101, 106))	('EGR1', 'Gene', (114, 118))	('MYC', 'Gene', '4609', (96, 99))	('NR2F2', 'Gene', '7026', (124, 129))	('affect', 'Reg', (74, 80))	('EGR1', 'Gene', '1958', (114, 118))	('rs9894790', 'Mutation', 'rs9894790', (22, 31))	('NR2F2', 'Gene', (124, 129))	('rs9901637', 'Mutation', 'rs9901637', (33, 42))	('rs9901637', 'Var', (33, 42))	('EBF1', 'Gene', (108, 112))	('binding', 'Interaction', (85, 92))
232374	32251318	Additionally, high expression of NTN1 in thyroid carcinoma was correlated with a worse survival.	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (41, 58))	('high', 'Var', (14, 18))	('NTN1', 'Gene', '9423', (33, 37))	('NTN1', 'Gene', (33, 37))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (41, 58))	('thyroid carcinoma', 'Disease', (41, 58))
232382	32251318	Highly expressed NTN4 is more sensitive to SRC inhibitors such as Dasatinib, WH-4-023, and AZD0530.	('NTN4', 'Gene', (17, 21))	('SRC', 'Gene', '6714', (43, 46))	('SRC', 'Gene', (43, 46))	('more', 'PosReg', (25, 29))	('NTN4', 'Gene', '59277', (17, 21))	('WH-4-023', 'Chemical', '-', (77, 85))	('AZD0530', 'Var', (91, 98))	('AZD0530', 'Chemical', 'MESH:C515233', (91, 98))	('Dasatinib', 'Chemical', 'MESH:D000069439', (66, 75))
232394	32251318	In particular, ML162 and ML210 are compounds that target and change the mesenchymal state, inhibit GPX4 activity, and promote apoptosis.	('change', 'Reg', (61, 67))	('GPX4', 'Gene', (99, 103))	('GPX4', 'Gene', '2879', (99, 103))	('activity', 'MPA', (104, 112))	('inhibit', 'NegReg', (91, 98))	('apoptosis', 'CPA', (126, 135))	('ML162', 'Var', (15, 20))	('mesenchymal state', 'CPA', (72, 89))	('promote', 'PosReg', (118, 125))	('ML210', 'Var', (25, 30))
232403	32251318	Our findings are as follows: (1) members of the Netrin family are tightly regulated by multiple mechanisms at the genetic, transcriptional, and post-transcriptional levels; (2) mutations of members of the Netrin family correlate with tumor genetic characteristics; (3) Netrins may play important roles in the occurrence and development of endocrine system-related tumors and sex hormone targeting tumors; (4) Netrin family members may be promising prognostic indicators and potential therapeutic targets for lung and kidney cancer; (5) NTNG1 and NTNG2 are potential diagnostic markers and therapeutic targets that should be further studied systematically.	('tumor', 'Disease', (234, 239))	('tumors', 'Phenotype', 'HP:0002664', (364, 370))	('mutations', 'Var', (177, 186))	('tumor', 'Phenotype', 'HP:0002664', (397, 402))	('tumor', 'Disease', 'MESH:D009369', (234, 239))	('tumors', 'Disease', (397, 403))	('tumor', 'Phenotype', 'HP:0002664', (364, 369))	('kidney cancer', 'Disease', 'MESH:D007680', (517, 530))	('NTNG1', 'Gene', (536, 541))	('tumors', 'Disease', (364, 370))	('lung', 'Disease', (508, 512))	('NTNG2', 'Gene', '84628', (546, 551))	('tumors', 'Disease', 'MESH:D009369', (397, 403))	('cancer', 'Phenotype', 'HP:0002664', (524, 530))	('NTNG1', 'Gene', '22854', (536, 541))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('kidney cancer', 'Phenotype', 'HP:0009726', (517, 530))	('kidney cancer', 'Disease', (517, 530))	('tumors', 'Disease', 'MESH:D009369', (364, 370))	('tumor', 'Disease', (397, 402))	('tumor', 'Disease', (364, 369))	('tumor', 'Disease', 'MESH:D009369', (397, 402))	('NTNG2', 'Gene', (546, 551))	('tumors', 'Phenotype', 'HP:0002664', (397, 403))	('tumor', 'Disease', 'MESH:D009369', (364, 369))
232406	32251318	This study was the first comprehensive analysis of tumor genetic characteristics of mutations in members of the Netrin family.	('mutations', 'Var', (84, 93))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor', 'Disease', (51, 56))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
232407	32251318	We found that tumor mutations of members of the Netrin family showed a unique distribution pattern for cancer type, protein structure, and ethnic group.	('tumor', 'Disease', (14, 19))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('mutations', 'Var', (20, 29))
232408	32251318	It is worth noting that a significant number of missense or truncating mutations have been found in the Laminin N-terminal and EGF domains that interact with related receptors and the regulatory localization of the NTR domain.	('interact', 'Interaction', (144, 152))	('truncating mutations', 'Var', (60, 80))	('NTR', 'Gene', '4923', (215, 218))	('missense', 'Var', (48, 56))	('NTR', 'Gene', (215, 218))
232411	32251318	Our mutation analysis found highly enriched mutation of netrin family genes in uterine corpus endometrial carcinoma.	('corpus endometrial carcinoma', 'Disease', 'MESH:D016889', (87, 115))	('corpus endometrial carcinoma', 'Disease', (87, 115))	('mutation', 'Var', (44, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (94, 115))	('netrin family genes', 'Gene', (56, 75))
232419	32251318	This study found that the NTN family not only has a high overall mutation rate in lung cancer, but that netrin activity is also closely related to the survival and clinical parameters of kidney cancer and non-small cell lung cancer.	('kidney cancer', 'Disease', (187, 200))	('clinical', 'Species', '191496', (164, 172))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (205, 231))	('lung cancer', 'Phenotype', 'HP:0100526', (82, 93))	('related', 'Reg', (136, 143))	('lung cancer', 'Disease', (82, 93))	('non-small cell lung cancer', 'Disease', (205, 231))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('lung cancer', 'Phenotype', 'HP:0100526', (220, 231))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('kidney cancer', 'Disease', 'MESH:D007680', (187, 200))	('mutation', 'Var', (65, 73))	('lung cancer', 'Disease', 'MESH:D008175', (82, 93))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (205, 231))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (209, 231))	('kidney cancer', 'Phenotype', 'HP:0009726', (187, 200))	('lung cancer', 'Disease', 'MESH:D008175', (220, 231))
232427	32251318	Here we find that the expression or methylation of NTNG1 and NTNG2 is associated with survival and other clinical parameters of more than 10 types of cancer.	('NTNG1', 'Gene', (51, 56))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('NTNG2', 'Gene', '84628', (61, 66))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('clinical', 'Species', '191496', (105, 113))	('associated', 'Reg', (70, 80))	('cancer', 'Disease', (150, 156))	('survival', 'CPA', (86, 94))	('NTNG2', 'Gene', (61, 66))	('NTNG1', 'Gene', '22854', (51, 56))	('expression', 'MPA', (22, 32))	('methylation', 'Var', (36, 47))
232428	32251318	There are also important epigenetic and transcriptional modifications of netrins that occur in pan-cancer that are related to the activation of the EMT pathway.	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('activation', 'PosReg', (130, 140))	('EMT', 'Gene', (148, 151))	('cancer', 'Disease', (99, 105))	('EMT', 'Gene', '3702', (148, 151))	('netrins', 'Gene', (73, 80))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('epigenetic', 'Var', (25, 35))
232430	32251318	It is worth noting that the mutations and potential mirRNA targeting of NTNG1 and NTNG2 in cancer exhibit rates that are much higher than those predicted for NTN1 and NTN4.	('NTN4', 'Gene', (167, 171))	('NTN1', 'Gene', '9423', (158, 162))	('NTNG2', 'Gene', '84628', (82, 87))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('higher', 'PosReg', (126, 132))	('NTN4', 'Gene', '59277', (167, 171))	('NTNG2', 'Gene', (82, 87))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('NTNG1', 'Gene', '22854', (72, 77))	('NTNG1', 'Gene', (72, 77))	('mutations', 'Var', (28, 37))	('NTN1', 'Gene', (158, 162))
232431	32251318	TCGA fusion transcripts analysis suggests the presence of fusion transcripts composed of NTNG1 or NTNG2 in multiple cancers.	('multiple cancers', 'Disease', (107, 123))	('NTNG2', 'Gene', '84628', (98, 103))	('NTNG1', 'Gene', '22854', (89, 94))	('multiple cancers', 'Disease', 'MESH:D009369', (107, 123))	('NTNG1', 'Gene', (89, 94))	('fusion transcripts', 'Var', (58, 76))	('cancers', 'Phenotype', 'HP:0002664', (116, 123))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('NTNG2', 'Gene', (98, 103))
232435	32251318	However, in some cancers, the selective inhibition of this receptor-dependent apoptosis pathway depends on the silencing of pro-apoptotic proteins.	('silencing', 'Var', (111, 120))	('receptor-dependent apoptosis pathway', 'Pathway', (59, 95))	('inhibition', 'NegReg', (40, 50))	('cancers', 'Phenotype', 'HP:0002664', (17, 24))	('cancers', 'Disease', (17, 24))	('cancers', 'Disease', 'MESH:D009369', (17, 24))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
232487	32194422	Conversely, if TLR4 is inactivated or deleted, the immune system loses its ability to respond to the tumor, and enters the immune escape mechanism of the tumor.	('ability', 'MPA', (75, 82))	('loses', 'NegReg', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('deleted', 'Var', (38, 45))	('TLR4', 'Gene', '7099', (15, 19))	('tumor', 'Disease', (101, 106))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('TLR4', 'Gene', (15, 19))	('enters', 'Reg', (112, 118))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('tumor', 'Disease', (154, 159))
232547	32194422	As shown in Supplementary Figure 2, LPS and TNF-alpha significantly increased the proportion of CD83-positive cells and the fluorescence intensity of CD83 (Supplementary Figures 2A,B, both P < 0.001).	('TNF-alpha', 'Gene', (44, 53))	('CD83', 'Gene', '9308', (150, 154))	('CD83', 'Gene', '9308', (96, 100))	('fluorescence intensity', 'MPA', (124, 146))	('LPS', 'Chemical', 'MESH:D008070', (36, 39))	('LPS', 'Var', (36, 39))	('CD83', 'Gene', (150, 154))	('TNF-alpha', 'Gene', '7124', (44, 53))	('increased', 'PosReg', (68, 77))	('CD83', 'Gene', (96, 100))
232556	32194422	As shown in Figure 5A, silencing of TLR4 and NF-kappaB p65 using siRNA prevented the inhibition of proliferation of FaDu cells by tilianin at the concentrations used, whereas p38 siRNA and JNK siRNA blocked the cytotoxic effect of tilianin on FaDu cells (Figure 5A, both P < 0.05).	('JNK', 'Gene', '5599', (189, 192))	('tilianin', 'Chemical', 'MESH:C426884', (231, 239))	('TLR4', 'Gene', '7099', (36, 40))	('NF-kappaB p65', 'Gene', (45, 58))	('NF-kappaB p65', 'Gene', '5970', (45, 58))	('p38', 'Gene', '1432', (175, 178))	('silencing', 'Var', (23, 32))	('inhibition', 'NegReg', (85, 95))	('tilianin', 'Chemical', 'MESH:C426884', (130, 138))	('JNK', 'Gene', (189, 192))	('TLR4', 'Gene', (36, 40))	('p38', 'Gene', (175, 178))	('cytotoxic effect', 'CPA', (211, 227))	('prevented', 'NegReg', (71, 80))
232567	32194422	More importantly, the cytotoxic effects of tilianin disappeared after silencing of TLR4 and p65 using siRNA.	('TLR4', 'Gene', '7099', (83, 87))	('p65', 'Gene', (92, 95))	('silencing', 'Var', (70, 79))	('TLR4', 'Gene', (83, 87))	('tilianin', 'Chemical', 'MESH:C426884', (43, 51))	('p65', 'Gene', '5970', (92, 95))	('cytotoxic effects', 'CPA', (22, 39))	('disappeared', 'NegReg', (52, 63))
232574	32194422	Next, flow cytometry results indicated that tilianin increased the apoptosis ratio of FaDu cells and induced cell apoptosis.	('cell apoptosis', 'CPA', (109, 123))	('tilianin', 'Chemical', 'MESH:C426884', (44, 52))	('tilianin', 'Var', (44, 52))	('increased', 'PosReg', (53, 62))	('apoptosis ratio', 'CPA', (67, 82))
232590	32194422	Studies have shown that S. choleraesuis was used as a tumor killing agent and carrier for tumor-targeted gene therapy.	('S. choleraesuis', 'Var', (24, 39))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('S. choleraesuis', 'Species', '28901', (24, 39))	('tumor', 'Disease', (90, 95))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumor', 'Disease', (54, 59))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
232591	32194422	In mechanistic studies, S. choleraesuis was found to cause a strong inflammatory response at the tumor site by acting on TLR4 to recruit a variety of immune cells against tumor cells.	('cause', 'Reg', (53, 58))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('S. choleraesuis', 'Var', (24, 39))	('TLR4', 'Gene', '7099', (121, 125))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('S. choleraesuis', 'Species', '28901', (24, 39))	('TLR4', 'Gene', (121, 125))	('tumor', 'Disease', (97, 102))	('recruit', 'PosReg', (129, 136))	('inflammatory response', 'MPA', (68, 89))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', (171, 176))	('acting', 'Reg', (111, 117))
232617	28631007	Interestingly, nerves also stimulate cancer progression.	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('nerves', 'Var', (15, 21))	('cancer', 'Disease', (37, 43))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('stimulate', 'PosReg', (27, 36))
232678	28631007	In a mouse model of pancreatic ductal adenocarcinoma, the ablation the sensory neurons of the autonomic nervous system reduces the initiation and progression of the cancer.	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('carcinoma', 'Phenotype', 'HP:0030731', (43, 52))	('pancreatic ductal adenocarcinoma', 'Disease', (20, 52))	('initiation', 'CPA', (131, 141))	('cancer', 'Disease', (165, 171))	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (20, 52))	('mouse', 'Species', '10090', (5, 10))	('reduces', 'NegReg', (119, 126))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (20, 52))	('ablation', 'Var', (58, 66))	('progression', 'CPA', (146, 157))
232695	28631007	Furthermore, an older reports similarly proposed that partial gastrectomy and denervation may promote progression of gastric cancer in the gastric remnant.	('partial gastrectomy', 'Var', (54, 73))	('gastric cancer', 'Phenotype', 'HP:0012126', (117, 131))	('progression', 'CPA', (102, 113))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('gastric cancer', 'Disease', (117, 131))	('promote', 'PosReg', (94, 101))	('gastric cancer', 'Disease', 'MESH:D013274', (117, 131))
232699	28631007	These abilities include the conduction of nervous impulses along axons, nerve repair, nerve development, trophic support for neurons, production of extracellular matrix, modulation of neuromuscular synaptic activity, antigen presentation, in addition to the promotion of cancer invasion.	('conduction of nervous impulses', 'CPA', (28, 58))	('cancer', 'Phenotype', 'HP:0002664', (271, 277))	('antigen presentation', 'MPA', (217, 237))	('nerve repair', 'CPA', (72, 84))	('trophic support', 'CPA', (105, 120))	('cancer', 'Disease', 'MESH:D009369', (271, 277))	('modulation', 'Var', (170, 180))	('nerve development', 'CPA', (86, 103))	('cancer', 'Disease', (271, 277))
232770	28631007	Inhibiting the hedgehog signaling in a mice model of PDAC perturbs the tumor microenvironment by reducing the stromal content of the tissue including fibroblasts and leukocytes.	('Inhibiting', 'Var', (0, 10))	('PDAC', 'Phenotype', 'HP:0006725', (53, 57))	('mice', 'Species', '10090', (39, 43))	('stromal content of the tissue', 'CPA', (110, 139))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('hedgehog signaling', 'Pathway', (15, 33))	('perturbs', 'Reg', (58, 66))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('reducing', 'NegReg', (97, 105))	('tumor', 'Disease', (71, 76))	('PDAC', 'Chemical', '-', (53, 57))
232772	28631007	Similarly, depletion of alphaSMA+ myofibroblasts (the pancreatic stellate cells) in a mouse model of pancreatic ductal adenocarcinoma (PDAC) leads to more invasive and undifferentiated tumors and diminished survival.	('pancreatic', 'Disease', 'MESH:D010195', (101, 111))	('PDAC', 'Phenotype', 'HP:0006725', (135, 139))	('pancreatic ductal adenocarcinoma', 'Disease', (101, 133))	('pancreatic', 'Disease', (54, 64))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (101, 133))	('mouse', 'Species', '10090', (86, 91))	('pancreatic', 'Disease', (101, 111))	('depletion', 'Var', (11, 20))	('undifferentiated tumors', 'Disease', 'MESH:D002277', (168, 191))	('more', 'PosReg', (150, 154))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('pancreatic', 'Disease', 'MESH:D010195', (54, 64))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (101, 133))	('tumors', 'Phenotype', 'HP:0002664', (185, 191))	('undifferentiated tumors', 'Disease', (168, 191))	('diminished', 'NegReg', (196, 206))	('PDAC', 'Chemical', '-', (135, 139))	('survival', 'CPA', (207, 215))
232783	28631007	Using cBioPortal we found that a total of 48% of pancreatic cancer patients from a recent study carried on 109 patients show an alteration in genes coding for the neurotrophin family or their receptors (NGF, NGFR coding for p75NTR, NTRK1 coding for TrkA, BDNF, NTRK2 coding for TrkB, NTF3 coding for NF-3, NTRK3 coding for TrkC, NTF4 coding for NF-4).	('NGF', 'Gene', (208, 211))	('NGF', 'Gene', '4803', (203, 206))	('p75NTR', 'Var', (224, 230))	('NTF4', 'Gene', '4909', (329, 333))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (49, 66))	('NTRK2', 'Gene', (261, 266))	('NTF3', 'Gene', '4908', (284, 288))	('TrkA', 'Gene', (249, 253))	('NGFR', 'Gene', '4804', (208, 212))	('neurotrophin', 'Gene', '627', (163, 175))	('NTRK1', 'Gene', '4914', (232, 237))	('NTRK1', 'Gene', (232, 237))	('TrkB', 'Gene', '4915', (278, 282))	('BDNF', 'Gene', (255, 259))	('NGF', 'Gene', '4803', (208, 211))	('NTRK3', 'Gene', '4916', (306, 311))	('pancreatic cancer', 'Disease', 'MESH:D010190', (49, 66))	('rat', 'Species', '10116', (132, 135))	('patients', 'Species', '9606', (67, 75))	('neurotrophin', 'Gene', (163, 175))	('TrkC', 'Gene', (323, 327))	('NTRK3', 'Gene', (306, 311))	('NGF', 'Gene', (203, 206))	('NGFR', 'Gene', (208, 212))	('pancreatic cancer', 'Disease', (49, 66))	('alteration', 'Reg', (128, 138))	('TrkB', 'Gene', (278, 282))	('NTRK2', 'Gene', '4915', (261, 266))	('NTF4', 'Gene', (329, 333))	('TrkA', 'Gene', '4914', (249, 253))	('TrkC', 'Gene', '4916', (323, 327))	('BDNF', 'Gene', '627', (255, 259))	('NTF3', 'Gene', (284, 288))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('patients', 'Species', '9606', (111, 119))
232784	28631007	Similarly, the modification of these genes are seen in 48% of patients with neuroendocrine prostate cancer, in 67% of patients with breast cancer where cells were grown as xenograft in mice and in 27% of patients with breast invasive carcinoma in another study.	('neuroendocrine prostate cancer', 'Disease', 'MESH:D011471', (76, 106))	('patients', 'Species', '9606', (204, 212))	('breast invasive carcinoma', 'Phenotype', 'HP:0003002', (218, 243))	('modification', 'Var', (15, 27))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('mice', 'Species', '10090', (185, 189))	('breast invasive carcinoma', 'Disease', 'MESH:D018270', (218, 243))	('breast cancer', 'Disease', 'MESH:D001943', (132, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (234, 243))	('prostate cancer', 'Phenotype', 'HP:0012125', (91, 106))	('breast cancer', 'Disease', (132, 145))	('patients', 'Species', '9606', (62, 70))	('patients', 'Species', '9606', (118, 126))	('breast cancer', 'Phenotype', 'HP:0003002', (132, 145))	('neuroendocrine prostate cancer', 'Disease', (76, 106))	('breast invasive carcinoma', 'Disease', (218, 243))
232785	28631007	In all these studies, among the different reported gene alterations including mutations, deletions and amplifications, the main gene alteration observed was a gene amplification, and the most affected gene was NTRK1 coding for TrkA.	('gene amplification', 'MPA', (159, 177))	('TrkA', 'Gene', '4914', (227, 231))	('NTRK1', 'Gene', (210, 215))	('deletions', 'Var', (89, 98))	('rat', 'Species', '10116', (60, 63))	('rat', 'Species', '10116', (137, 140))	('NTRK1', 'Gene', '4914', (210, 215))	('TrkA', 'Gene', (227, 231))
232787	28631007	The role of NGF and its high affinity receptor TrkA and low affinity receptor p75NTR in cancer growth is well established.	('NGF', 'Gene', '4803', (12, 15))	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('NGF', 'Gene', (12, 15))	('p75NTR', 'Var', (78, 84))	('TrkA', 'Gene', '4914', (47, 51))	('TrkA', 'Gene', (47, 51))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))
232801	28631007	TrkA is associated with aggressiveness and increased cancer cell proliferation, while p75NTR is associated with a milder prognosis.	('rat', 'Species', '10116', (72, 75))	('aggressiveness', 'Disease', 'MESH:D001523', (24, 38))	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('aggressiveness', 'Disease', (24, 38))	('aggressiveness', 'Phenotype', 'HP:0000718', (24, 38))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('TrkA', 'Gene', '4914', (0, 4))	('TrkA', 'Gene', (0, 4))	('increased', 'PosReg', (43, 52))	('p75NTR', 'Var', (86, 92))
232803	28631007	In specimens of cutaneous squamous cell carcinoma, p75NTR is found in both the perineurium of the nerves and the cancer cells near the nerves.	('cutaneous squamous cell carcinoma', 'Disease', (16, 49))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('found', 'Reg', (61, 66))	('cancer', 'Disease', (113, 119))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (26, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (40, 49))	('cutaneous squamous cell carcinoma', 'Phenotype', 'HP:0006739', (16, 49))	('cutaneous squamous cell carcinoma', 'Disease', 'MESH:D002294', (16, 49))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('p75NTR', 'Var', (51, 57))
232804	28631007	While p75NTR supports tumor development in some of cancer types including glioma and breast cancer, p75NTR also behaves as a tumor suppressor in other cancer types such as gastric, bladder and prostate cancers by blocking cell cycle progression and inducing apoptosis.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('prostate cancer', 'Phenotype', 'HP:0012125', (193, 208))	('bladder and prostate cancers', 'Disease', 'MESH:D001749', (181, 209))	('prostate cancers', 'Phenotype', 'HP:0012125', (193, 209))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('breast cancer', 'Phenotype', 'HP:0003002', (85, 98))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('cancer', 'Disease', 'MESH:D009369', (202, 208))	('glioma', 'Disease', (74, 80))	('cancer', 'Disease', (151, 157))	('apoptosis', 'CPA', (258, 267))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('breast cancer', 'Disease', 'MESH:D001943', (85, 98))	('glioma', 'Disease', 'MESH:D005910', (74, 80))	('cancer', 'Disease', (92, 98))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('breast cancer', 'Disease', (85, 98))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('p75NTR', 'Var', (100, 106))	('glioma', 'Phenotype', 'HP:0009733', (74, 80))	('blocking', 'NegReg', (213, 221))	('gastric', 'Disease', (172, 179))	('tumor', 'Disease', (125, 130))	('cancers', 'Phenotype', 'HP:0002664', (202, 209))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('cancer', 'Disease', (202, 208))	('cell cycle progression', 'CPA', (222, 244))	('tumor', 'Disease', (22, 27))	('inducing', 'Reg', (249, 257))	('cancer', 'Disease', (51, 57))
232806	28631007	Mice embryo lacking p75NTR show a defect in Schwann cell migration with an inhibition of axon growth.	('defect', 'NegReg', (34, 40))	('inhibition', 'NegReg', (75, 85))	('rat', 'Species', '10116', (60, 63))	('p75NTR', 'Var', (20, 26))	('Mice', 'Species', '10090', (0, 4))	('Schwann cell migration', 'CPA', (44, 66))	('axon growth', 'CPA', (89, 100))
232807	28631007	Depleting p75NTR from the Schwann cells and preventing the binding of NGF to p75NTR using the small-molecule inhibitor RO.08.2750 reduce the migration of Schwann cells toward cancer cells.	('reduce', 'NegReg', (130, 136))	('Depleting', 'Var', (0, 9))	('binding', 'Interaction', (59, 66))	('cancer', 'Disease', (175, 181))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('preventing', 'NegReg', (44, 54))	('NGF', 'Gene', '4803', (70, 73))	('rat', 'Species', '10116', (144, 147))	('NGF', 'Gene', (70, 73))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
232808	28631007	This suggests a role for NGF and p75NTR in promoting the nerve infiltration via Schwann cells migration.	('p75NTR', 'Var', (33, 39))	('rat', 'Species', '10116', (97, 100))	('nerve infiltration via Schwann cells migration', 'CPA', (57, 103))	('NGF', 'Gene', '4803', (25, 28))	('promoting', 'PosReg', (43, 52))	('NGF', 'Gene', (25, 28))	('rat', 'Species', '10116', (69, 72))
232824	28631007	Blocking antibody treatment to p75NTR diminishes NGF induced signaling and decreased tumor formation.	('diminishes', 'NegReg', (38, 48))	('decreased tumor', 'Disease', 'MESH:D009369', (75, 90))	('decreased tumor', 'Disease', (75, 90))	('p75NTR', 'Var', (31, 37))	('NGF', 'Gene', '4803', (49, 52))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('NGF', 'Gene', (49, 52))
232825	28631007	Similarly, p75NTR knock-down in melanoma cancer cells prevents tumor formation in a xenograft mouse model.	('tumor', 'Disease', (63, 68))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('prevents', 'NegReg', (54, 62))	('melanoma cancer', 'Disease', (32, 47))	('melanoma cancer', 'Disease', 'MESH:C563985', (32, 47))	('melanoma', 'Phenotype', 'HP:0002861', (32, 40))	('mouse', 'Species', '10090', (94, 99))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('knock-down', 'Var', (18, 28))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('p75NTR knock-down', 'Var', (11, 28))
232826	28631007	The loss of p75NTR in these cells is associated with a loss of stemness marker.	('p75NTR', 'Var', (12, 18))	('loss of stemness', 'Disease', 'MESH:D020295', (55, 71))	('loss of stemness', 'Disease', (55, 71))	('loss', 'Var', (4, 8))
232870	28631007	High expression of EphA2 is associated with a poor prognosis, increased metastasis and decreased survival in other cancer types.	('increased', 'PosReg', (62, 71))	('cancer', 'Disease', (115, 121))	('metastasis', 'CPA', (72, 82))	('High', 'Var', (0, 4))	('decreased', 'NegReg', (87, 96))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('EphA2', 'Gene', (19, 24))	('survival', 'CPA', (97, 105))	('EphA2', 'Gene', '1969', (19, 24))	('cancer', 'Disease', 'MESH:D009369', (115, 121))
232881	28631007	In addition, CCR2 deficient mice have reduced macrophage recruitment and less nerve invasion after cancer cell injection in sciatic nerves.	('macrophage recruitment', 'CPA', (46, 68))	('reduced', 'NegReg', (38, 45))	('mice', 'Species', '10090', (28, 32))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('CCR2', 'Gene', (13, 17))	('cancer', 'Disease', (99, 105))	('deficient', 'Var', (18, 27))	('nerve invasion', 'CPA', (78, 92))	('less', 'NegReg', (73, 77))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
232935	33934696	UALCAN was used to confirm the association between mRNA expressions of Kindlins in NSCLC and clinicopathological parameters.	('NSCLC', 'Disease', (83, 88))	('NSCLC', 'Disease', 'MESH:D002289', (83, 88))	('NSCLC', 'Phenotype', 'HP:0030358', (83, 88))	('mRNA expressions', 'Var', (51, 67))	('Kindlins', 'Protein', (71, 79))
232942	33934696	According to cBioPortal's online instructions, the Kindlins gene alterations information in different cancer types was obtained, including genetic mutations, gene fusions, gene amplifications, deep deletions and multiple alterations.	('Kindlins', 'Gene', (51, 59))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('gene fusions', 'Var', (158, 170))	('genetic mutations', 'Var', (139, 156))	('deep deletions', 'Var', (193, 207))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('gene amplifications', 'Var', (172, 191))	('multiple', 'Var', (212, 220))
232978	33934696	The results showed that gene alterations in Kindlins were present in different types of NSCLC, including LUSC and LUAD, compared with other cancer types (Fig.	('present', 'Reg', (58, 65))	('gene alterations', 'Var', (24, 40))	('NSCLC', 'Phenotype', 'HP:0030358', (88, 93))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('LUSC', 'Phenotype', 'HP:0030359', (105, 109))	('Kindlins', 'Protein', (44, 52))	('NSCLC', 'Disease', (88, 93))	('LUAD', 'Phenotype', 'HP:0030078', (114, 118))	('LUSC', 'Disease', (105, 109))	('LUAD', 'Disease', (114, 118))	('NSCLC', 'Disease', 'MESH:D002289', (88, 93))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))
232980	33934696	The results indicated that 5.45% of the 3025 cases of NSCLC had mutations, amplifications, deep deletions and multiple changes in Kindlins, the frequencies were 2.25% (68 cases), 2.64% (80 cases), 0.53% (16 cases) and 0.03% (1 case), respectively, and gene amplifications and mutations accounted for the majority.	('deep deletions', 'Var', (91, 105))	('NSCLC', 'Phenotype', 'HP:0030358', (54, 59))	('Kindlins', 'Gene', (130, 138))	('mutations', 'Var', (64, 73))	('NSCLC', 'Disease', (54, 59))	('amplifications', 'Var', (75, 89))	('NSCLC', 'Disease', 'MESH:D002289', (54, 59))
232981	33934696	5c, the percentages of gene alterations in individual Kindlins in NSCLC at a range of 1.4-2.5% (FERMT1, 2%; FERMT2, 2.5%; FERMT3, 1.4%;).	('FERMT2', 'Gene', (108, 114))	('NSCLC', 'Disease', (66, 71))	('NSCLC', 'Disease', 'MESH:D002289', (66, 71))	('FERMT3', 'Gene', (122, 128))	('gene alterations', 'Var', (23, 39))	('FERMT2', 'Gene', '10979', (108, 114))	('FERMT1', 'Gene', (96, 102))	('FERMT1', 'Gene', '55612', (96, 102))	('Kindlins', 'Protein', (54, 62))	('FERMT3', 'Gene', '83706', (122, 128))	('NSCLC', 'Phenotype', 'HP:0030358', (66, 71))
232982	33934696	In addition, it was found that gene amplifications made up the majority of gene alterations for FERMT1 and FERMT2, whereas gene mutations made up the majority of genetic alterations for FERMT3 (Fig.	('FERMT3', 'Gene', (186, 192))	('FERMT2', 'Gene', '10979', (107, 113))	('FERMT3', 'Gene', '83706', (186, 192))	('FERMT1', 'Gene', (96, 102))	('FERMT1', 'Gene', '55612', (96, 102))	('FERMT2', 'Gene', (107, 113))	('gene amplifications', 'Var', (31, 50))
233005	33934696	Additionally, a genetic alteration rate of Kindlins (5.9%) was found in patients with NSCLC.	('genetic alteration', 'Var', (16, 34))	('NSCLC', 'Disease', (86, 91))	('NSCLC', 'Disease', 'MESH:D002289', (86, 91))	('Kindlins', 'Protein', (43, 51))	('found', 'Reg', (63, 68))	('NSCLC', 'Phenotype', 'HP:0030358', (86, 91))	('patients', 'Species', '9606', (72, 80))
233031	33934696	found that FERMT3 was obviously upregulated in glioma, and knockdown of FERMT3 effectively suppressed glioma cell proliferation and chemoresistance.	('suppressed', 'NegReg', (91, 101))	('glioma', 'Phenotype', 'HP:0009733', (47, 53))	('glioma', 'Disease', 'MESH:D005910', (102, 108))	('glioma', 'Phenotype', 'HP:0009733', (102, 108))	('FERMT3', 'Gene', '83706', (72, 78))	('chemoresistance', 'CPA', (132, 147))	('FERMT3', 'Gene', '83706', (11, 17))	('glioma', 'Disease', (47, 53))	('knockdown', 'Var', (59, 68))	('glioma', 'Disease', (102, 108))	('FERMT3', 'Gene', (72, 78))	('FERMT3', 'Gene', (11, 17))	('glioma', 'Disease', 'MESH:D005910', (47, 53))	('upregulated', 'PosReg', (32, 43))
233054	33927880	Surgical examination revealed T1bN0M0 lung squamous cell carcinoma.	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (38, 66))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (38, 66))	('carcinoma', 'Phenotype', 'HP:0030731', (57, 66))	('lung squamous cell carcinoma', 'Disease', (38, 66))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (43, 66))	('T1bN0M0', 'Var', (30, 37))
233077	33927880	A variety of onconeural antibodies, including anti-Hu, anti-Ma1 and Ma2 and anti CV2, have been associated with PLE.	('associated', 'Reg', (96, 106))	('Ma1', 'Gene', '9240', (60, 63))	('Ma2', 'Gene', (68, 71))	('Ma2', 'Gene', '10687', (68, 71))	('anti-Hu', 'Var', (46, 53))	('Ma1', 'Gene', (60, 63))	('PLE', 'Disease', (112, 115))
233079	33927880	Gultekin and colleagues also observed neurological improvement by cancer treatment in 38% of patients with anti-Hu antibody and 64% of patients without onconeural antibodies.	('patients', 'Species', '9606', (135, 143))	('neurological improvement', 'CPA', (38, 62))	('anti-Hu antibody', 'Var', (107, 123))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('patients', 'Species', '9606', (93, 101))	('cancer', 'Disease', (66, 72))
233126	32503466	High expression of TRIM44 protein in malignant tissues was found to be strongly associated with poor OS (HR = 1.94, 95% CI: 1.60-2.35, p < 0.0001), and the heterogeneity test revealed a mild heterogeneity (I2 = 32.6%; PQ = 0.139).	('High', 'Var', (0, 4))	('poor OS', 'Disease', (96, 103))	('TRIM44', 'Gene', '54765', (19, 25))	('associated', 'Reg', (80, 90))	('TRIM44', 'Gene', (19, 25))	('PQ', 'Chemical', '-', (218, 220))	('protein', 'Protein', (26, 33))
233140	32503466	When combined with all data from 33 different types of malignant tumors in GEPIA, the Kaplan-Meier analysis suggested that cancer patients with a high expression level of TRIM44 exhibited poorer OS, compared with cases expressing a low level of TRIM44 (Fig.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('TRIM44', 'Gene', '54765', (245, 251))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('TRIM44', 'Gene', '54765', (171, 177))	('patients', 'Species', '9606', (130, 138))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('cancer', 'Disease', (123, 129))	('TRIM44', 'Gene', (245, 251))	('malignant tumors', 'Disease', (55, 71))	('TRIM44', 'Gene', (171, 177))	('malignant tumors', 'Disease', 'MESH:D009369', (55, 71))	('high expression', 'Var', (146, 161))
233148	32503466	TRIM44 amplification is correlated with unfavorable prognosis and advanced clinicopathological parameters of malignancies.	('TRIM44', 'Gene', (0, 6))	('malignancies', 'Disease', (109, 121))	('TRIM44', 'Gene', '54765', (0, 6))	('amplification', 'Var', (7, 20))	('malignancies', 'Disease', 'MESH:D009369', (109, 121))
233158	32503466	Overexpression of TRIM44 has been shown to induce a similar change in hallmark characteristics of EMT in other cancers, such as ICC and HEC.	('cancers', 'Disease', 'MESH:D009369', (111, 118))	('cancers', 'Phenotype', 'HP:0002664', (111, 118))	('ICC', 'Disease', (128, 131))	('HEC', 'CellLine', 'CVCL:N814', (136, 139))	('hallmark characteristics', 'MPA', (70, 94))	('cancers', 'Disease', (111, 118))	('change', 'Reg', (60, 66))	('TRIM44', 'Gene', '54765', (18, 24))	('HEC', 'Disease', (136, 139))	('TRIM44', 'Gene', (18, 24))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('Overexpression', 'Var', (0, 14))
233160	32503466	TRIM44 expression positively affects the expression of cyclins and CDKs, suggesting that TRIM44 is involved in the regulation of cell cycle G1/s transformation.	('TRIM44', 'Gene', (0, 6))	('affects', 'Reg', (29, 36))	('expression', 'MPA', (41, 51))	('involved', 'Reg', (99, 107))	('TRIM44', 'Gene', '54765', (89, 95))	('cyclin', 'Gene', '5111', (55, 61))	('expression', 'Var', (7, 17))	('TRIM44', 'Gene', '54765', (0, 6))	('CDKs', 'Gene', '23097', (67, 71))	('TRIM44', 'Gene', (89, 95))	('cyclin', 'Gene', (55, 61))	('CDKs', 'Gene', (67, 71))
233162	32503466	Indeed, ectopic expression of TRIM44 promotes cell proliferation by accelerating the G1/S-phase transition in HCC.	('accelerating', 'PosReg', (68, 80))	('HCC', 'Gene', '619501', (110, 113))	('ectopic expression', 'Var', (8, 26))	('G1/S-phase transition', 'CPA', (85, 106))	('HCC', 'Gene', (110, 113))	('TRIM44', 'Gene', '54765', (30, 36))	('TRIM44', 'Gene', (30, 36))	('cell proliferation', 'CPA', (46, 64))	('promotes', 'PosReg', (37, 45))
233163	32503466	In colony formation assays, knockdown of TRIM44 in Huh7 cells significantly decreased the expression levels of cyclin D1 and cyclin E, which have been shown to play a crucial role in accelerating the G1/S-phase transition.	('cyclin', 'Gene', (111, 117))	('G1/S-phase transition', 'CPA', (200, 221))	('cyclin D1', 'Gene', (111, 120))	('TRIM44', 'Gene', (41, 47))	('Huh7', 'CellLine', 'CVCL:0336', (51, 55))	('expression levels', 'MPA', (90, 107))	('decreased', 'NegReg', (76, 85))	('cyclin D1', 'Gene', '595', (111, 120))	('cyclin', 'Gene', '5111', (125, 131))	('cyclin', 'Gene', '5111', (111, 117))	('knockdown', 'Var', (28, 37))	('accelerating', 'PosReg', (183, 195))	('TRIM44', 'Gene', '54765', (41, 47))	('cyclin', 'Gene', (125, 131))
233165	32503466	Knock-down of TRIM44 in glioma cells induces an increase in p21/p27 expression,and then it inhibited cell division.	('p27', 'Gene', '10671', (64, 67))	('TRIM44', 'Gene', '54765', (14, 20))	('glioma', 'Disease', 'MESH:D005910', (24, 30))	('cell division', 'CPA', (101, 114))	('glioma', 'Phenotype', 'HP:0009733', (24, 30))	('p21', 'Gene', '644914', (60, 63))	('expression', 'MPA', (68, 78))	('p27', 'Gene', (64, 67))	('TRIM44', 'Gene', (14, 20))	('inhibited', 'NegReg', (91, 100))	('Knock-down', 'Var', (0, 10))	('glioma', 'Disease', (24, 30))	('p21', 'Gene', (60, 63))	('increase', 'PosReg', (48, 56))
233166	32503466	Further, the critical p21/p27 regulator AKT is inactivated after TRIM44 is knocked down, but it is activated in glioma cells that overexpress TRIM44.	('inactivated', 'NegReg', (47, 58))	('TRIM44', 'Gene', '54765', (65, 71))	('glioma', 'Phenotype', 'HP:0009733', (112, 118))	('TRIM44', 'Gene', '54765', (142, 148))	('knocked', 'Var', (75, 82))	('AKT', 'Gene', '207', (40, 43))	('TRIM44', 'Gene', (65, 71))	('TRIM44', 'Gene', (142, 148))	('glioma', 'Disease', (112, 118))	('activated', 'PosReg', (99, 108))	('p21', 'Gene', (22, 25))	('p27', 'Gene', '10671', (26, 29))	('AKT', 'Gene', (40, 43))	('glioma', 'Disease', 'MESH:D005910', (112, 118))	('p21', 'Gene', '644914', (22, 25))	('p27', 'Gene', (26, 29))	('overexpress', 'PosReg', (130, 141))
233167	32503466	TRIM44 overexpression leads to high mTOR activity, which is consistent with observations of reduced mTOR signaling in cancer cell lines after siRNA knockdown of TRIM44.	('TRIM44', 'Gene', (161, 167))	('cancer', 'Disease', (118, 124))	('TRIM44', 'Gene', (0, 6))	('overexpression', 'Var', (7, 21))	('mTOR', 'Gene', (36, 40))	('mTOR', 'Gene', '2475', (36, 40))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('reduced', 'NegReg', (92, 99))	('TRIM44', 'Gene', '54765', (161, 167))	('TRIM44', 'Gene', '54765', (0, 6))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('mTOR', 'Gene', (100, 104))	('mTOR', 'Gene', '2475', (100, 104))
233168	32503466	The phosphorylation of downstream mTOR substrates, including p-Akt (Ser473) and p-p70S6K (Thr389), in TRIM44-knockdown cells was markedly inhibited, indicating that TRIM44 functions upstream of the mTOR signaling pathway by phosphorylating mTOR.	('TRIM44', 'Gene', (102, 108))	('TRIM44', 'Gene', (165, 171))	('p70S6K', 'Gene', (82, 88))	('Ser473', 'Var', (68, 74))	('inhibited', 'NegReg', (138, 147))	('Akt', 'Gene', '207', (63, 66))	('Ser473', 'Chemical', '-', (68, 74))	('mTOR', 'Gene', (34, 38))	('mTOR', 'Gene', (240, 244))	('mTOR', 'Gene', '2475', (34, 38))	('mTOR', 'Gene', '2475', (240, 244))	('Thr389', 'Var', (90, 96))	('p70S6K', 'Gene', '6198', (82, 88))	('mTOR', 'Gene', (198, 202))	('Thr389', 'Chemical', '-', (90, 96))	('phosphorylation', 'MPA', (4, 19))	('mTOR', 'Gene', '2475', (198, 202))	('TRIM44', 'Gene', '54765', (102, 108))	('TRIM44', 'Gene', '54765', (165, 171))	('Akt', 'Gene', (63, 66))
233179	32503466	Microarray analysis showed that TRIM44 knockdown is associated with the dysregulation of NUPR1, CDK19, CADM1, INHBA, TNFSF10, and DDIT4, which could normally activate the apoptotic cell pathways.	('TNFSF10', 'Gene', (117, 124))	('apoptotic cell pathways', 'Pathway', (171, 194))	('INHBA', 'Gene', (110, 115))	('activate', 'PosReg', (158, 166))	('CADM1', 'Gene', (103, 108))	('knockdown', 'Var', (39, 48))	('NUPR1', 'Gene', (89, 94))	('DDIT4', 'Gene', (130, 135))	('TRIM44', 'Gene', '54765', (32, 38))	('TNFSF10', 'Gene', '8743', (117, 124))	('CADM1', 'Gene', '23705', (103, 108))	('TRIM44', 'Gene', (32, 38))	('CDK19', 'Gene', (96, 101))	('INHBA', 'Gene', '3624', (110, 115))	('CDK19', 'Gene', '23097', (96, 101))	('NUPR1', 'Gene', '26471', (89, 94))	('DDIT4', 'Gene', '54541', (130, 135))	('dysregulation', 'MPA', (72, 85))
233188	32503466	A previous report has shown that the silencing of TRIM44 could decrease the c-IAP1, c-IAP2, and XIAP expression levels, especially in the presence of doxorubicin.	('c-IAP1', 'Gene', (76, 82))	('XIAP', 'Gene', '331', (96, 100))	('c-IAP1', 'Gene', '329', (76, 82))	('doxorubicin', 'Chemical', 'MESH:D004317', (150, 161))	('TRIM44', 'Gene', '54765', (50, 56))	('silencing', 'Var', (37, 46))	('decrease', 'NegReg', (63, 71))	('c-IAP2', 'Gene', (84, 90))	('c-IAP2', 'Gene', '330', (84, 90))	('TRIM44', 'Gene', (50, 56))	('XIAP', 'Gene', (96, 100))
233195	32503466	Moreover, miR-26b-5p is the upstream regulatory gene of TRIM44, which acts as a suppressor.	('miR-26b-5p', 'Var', (10, 20))	('TRIM44', 'Gene', '54765', (56, 62))	('TRIM44', 'Gene', (56, 62))
233210	32256710	Risk of brain metastases in T1-3N0 NSCLC: a population-based analysis Several consensus guidelines recommend against routine brain imaging at diagnosis of T1-3N0 non-small cell lung cancer (NSCLC).	('NSCLC', 'Phenotype', 'HP:0030358', (35, 40))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('NSCLC', 'Phenotype', 'HP:0030358', (190, 195))	('NSCLC', 'Disease', (35, 40))	('lung cancer', 'Disease', 'MESH:D008175', (177, 188))	('T1-3N0', 'Var', (155, 161))	('brain metastases', 'Disease', (8, 24))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (162, 188))	('brain metastases', 'Disease', 'MESH:D009362', (8, 24))	('NSCLC', 'Disease', (190, 195))	('NSCLC', 'Disease', 'MESH:D002289', (35, 40))	('lung cancer', 'Disease', (177, 188))	('lung cancer', 'Phenotype', 'HP:0100526', (177, 188))	('NSCLC', 'Disease', 'MESH:D002289', (190, 195))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (166, 188))
233221	32256710	Recent National Comprehensive Cancer Network (NCCN) guidelines for NSCLC have recommended brain imaging during initial staging of patients with T2-3N0 NSCLC (as well as for those with more advanced stages of disease), but not for T1N0 NSCLC.	('NSCLC', 'Phenotype', 'HP:0030358', (151, 156))	('NSCLC', 'Disease', (151, 156))	('NSCLC', 'Phenotype', 'HP:0030358', (235, 240))	('Cancer', 'Disease', 'MESH:D009369', (30, 36))	('Cancer', 'Disease', (30, 36))	('NSCLC', 'Disease', 'MESH:D002289', (151, 156))	('NSCLC', 'Phenotype', 'HP:0030358', (67, 72))	('Cancer', 'Phenotype', 'HP:0002664', (30, 36))	('patients', 'Species', '9606', (130, 138))	('NSCLC', 'Disease', (235, 240))	('NSCLC', 'Disease', (67, 72))	('T2-3N0', 'Var', (144, 150))	('NSCLC', 'Disease', 'MESH:D002289', (235, 240))	('NSCLC', 'Disease', 'MESH:D002289', (67, 72))
233228	32256710	A 1999 study from Japan (with patients treated from 1982 to 1996), also cited by STS, showed low rates of brain metastases (10 of 754) in patients with T1-2N0 NSCLC; while some patients underwent brain MRI, most had had head computed tomography for staging.	('brain metastases', 'Disease', (106, 122))	('brain metastases', 'Disease', 'MESH:D009362', (106, 122))	('NSCLC', 'Disease', (159, 164))	('patients', 'Species', '9606', (177, 185))	('NSCLC', 'Disease', 'MESH:D002289', (159, 164))	('patients', 'Species', '9606', (30, 38))	('NSCLC', 'Phenotype', 'HP:0030358', (159, 164))	('patients', 'Species', '9606', (138, 146))	('T1-2N0', 'Var', (152, 158))
233231	32256710	We hypothesized that the risk of brain metastases would be large enough to warrant consideration of brain imaging for those with T2-3N0 disease (as suggested by NCCN guidelines), and that tumor stage, adenocarcinoma histology and other patient and tumor-related factors (such as age, race, sociodemographic status and tumor grade) would impact these risks.	('tumor', 'Disease', (188, 193))	('impact', 'Reg', (337, 343))	('tumor', 'Disease', (248, 253))	('carcinoma', 'Phenotype', 'HP:0030731', (206, 215))	('adenocarcinoma', 'Disease', 'MESH:D000230', (201, 215))	('tumor', 'Disease', 'MESH:D009369', (318, 323))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('tumor', 'Phenotype', 'HP:0002664', (318, 323))	('brain metastases', 'Disease', (33, 49))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('T2-3N0', 'Var', (129, 135))	('brain metastases', 'Disease', 'MESH:D009362', (33, 49))	('tumor', 'Disease', 'MESH:D009369', (248, 253))	('tumor', 'Phenotype', 'HP:0002664', (248, 253))	('tumor', 'Disease', (318, 323))	('adenocarcinoma', 'Disease', (201, 215))	('patient', 'Species', '9606', (236, 243))
233251	32256710	Among all 49,495 patients with T1-3N0 NSCLC, 2661 (5.4%) had brain metastases at time of initial diagnosis, of whom more than half (57.0%) had no other metastatic sites registered to the SEER program.	('NSCLC', 'Disease', (38, 43))	('NSCLC', 'Disease', 'MESH:D002289', (38, 43))	('T1-3N0', 'Var', (31, 37))	('NSCLC', 'Phenotype', 'HP:0030358', (38, 43))	('patients', 'Species', '9606', (17, 25))	('brain metastases', 'Disease', (61, 77))	('brain metastases', 'Disease', 'MESH:D009362', (61, 77))
233253	32256710	For patients with T1N0, T2N0 and T3N0 NSCLC, 650 of 21,063 (3.0%), 1244 of 19,172 (6.5%) and 767 of 9260 (8.3%) presented with brain metastases, respectively (Figure 1).	('NSCLC', 'Disease', (38, 43))	('T2N0', 'Var', (24, 28))	('T3N0', 'Var', (33, 37))	('presented', 'Reg', (112, 121))	('NSCLC', 'Disease', 'MESH:D002289', (38, 43))	('T1N0', 'Var', (18, 22))	('NSCLC', 'Phenotype', 'HP:0030358', (38, 43))	('patients', 'Species', '9606', (4, 12))	('brain metastases', 'Disease', 'MESH:D009362', (127, 143))	('brain metastases', 'Disease', (127, 143))
233257	32256710	Of 25,357 patients, 217 (0.9%) presented with brain metastases at the time of initial diagnosis; most (181 of 217; 83.4%) had no other sites of metastases; thus approximately 0.7% had T2-3N0M1 with brain metastases and no other apparent (or registered) metastatic sites.	('metastases', 'Disease', (52, 62))	('metastases', 'Disease', (204, 214))	('metastases', 'Disease', 'MESH:D009362', (52, 62))	('T2-3N0M1', 'Var', (184, 192))	('brain metastases', 'Disease', 'MESH:D009362', (198, 214))	('metastases', 'Disease', 'MESH:D009362', (204, 214))	('brain metastases', 'Disease', (46, 62))	('brain metastases', 'Disease', 'MESH:D009362', (46, 62))	('brain metastases', 'Disease', (198, 214))	('patients', 'Species', '9606', (10, 18))	('metastases', 'Disease', (144, 154))	('metastases', 'Disease', 'MESH:D009362', (144, 154))
233259	32256710	Of 23,310 patients, 2444 (10.5%) presented with brain metastases at the time of diagnosis; the majority (1335 of 2444; 54.6%) had no other sites of metastases; thus approximately 5.7% had T1-3N0M1 with brain metastases and no other apparent (or registered) metastatic sites.	('brain metastases', 'Disease', 'MESH:D009362', (202, 218))	('brain metastases', 'Disease', (202, 218))	('metastases', 'Disease', (208, 218))	('brain metastases', 'Disease', (48, 64))	('metastases', 'Disease', (148, 158))	('brain metastases', 'Disease', 'MESH:D009362', (48, 64))	('metastases', 'Disease', (54, 64))	('metastases', 'Disease', 'MESH:D009362', (208, 218))	('metastases', 'Disease', 'MESH:D009362', (148, 158))	('metastases', 'Disease', 'MESH:D009362', (54, 64))	('patients', 'Species', '9606', (10, 18))	('T1-3N0M1', 'Var', (188, 196))
233272	32256710	For patients with T1N0 adenocarcinoma and no nonbrain metastases (for whom the NCCN or STS do not recommend brain imaging in the absence of neurologic symptoms), 268 of 6837 (3.9%) patients <70-year old and 123 of 6273 (2.0%) patients >=70-year old presented with brain metastases at initial diagnosis (although data on possible neurologic symptoms are not available in the SEER program).	('neurologic symptoms', 'Disease', (329, 348))	('neurologic symptoms', 'Disease', 'MESH:D009422', (140, 159))	('adenocarcinoma', 'Disease', 'MESH:D000230', (23, 37))	('brain metastases', 'Disease', (48, 64))	('brain metastases', 'Disease', 'MESH:D009362', (264, 280))	('neurologic symptoms', 'Disease', 'MESH:D009422', (329, 348))	('brain metastases', 'Disease', (264, 280))	('brain metastases', 'Disease', 'MESH:D009362', (48, 64))	('T1N0', 'Var', (18, 22))	('patients', 'Species', '9606', (181, 189))	('patients', 'Species', '9606', (226, 234))	('patients', 'Species', '9606', (4, 12))	('carcinoma', 'Phenotype', 'HP:0030731', (28, 37))	('presented', 'Reg', (249, 258))	('adenocarcinoma', 'Disease', (23, 37))	('neurologic symptoms', 'Disease', (140, 159))
233275	32256710	A greater than threefold risk of presenting with brain metastases was associated with the factors of age younger than 70-year old, adenocarcinoma histology, T2-3 (versus T1) stage and higher histologic grade.	('brain metastases', 'Disease', 'MESH:D009362', (49, 65))	('brain metastases', 'Disease', (49, 65))	('adenocarcinoma', 'Disease', (131, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('T2-3', 'Var', (157, 161))	('adenocarcinoma', 'Disease', 'MESH:D000230', (131, 145))
233277	32256710	It is also notable that patients <70-years in age, with T1N0 adenocarcinoma, had a ~4% risk of having brain metastases; this risk warrants consideration of routine brain imaging for patients who fall within this group, contrary to NCCN and NICE guidelines, and the STS Choosing Wisely statement.	('carcinoma', 'Phenotype', 'HP:0030731', (66, 75))	('fall', 'Phenotype', 'HP:0002527', (195, 199))	('adenocarcinoma', 'Disease', 'MESH:D000230', (61, 75))	('patients', 'Species', '9606', (182, 190))	('patients', 'Species', '9606', (24, 32))	('T1N0', 'Var', (56, 60))	('brain metastases', 'Disease', 'MESH:D009362', (102, 118))	('brain metastases', 'Disease', (102, 118))	('adenocarcinoma', 'Disease', (61, 75))
233281	32256710	In a relatively small retrospective study from Japan, 6 of 46 (13%) patients diagnosed with T1-2aN0 NSCLC (from 2012 to 2016) had brain metastases, with only 1 of 6 being symptomatic.	('NSCLC', 'Disease', (100, 105))	('T1-2aN0', 'Var', (92, 99))	('NSCLC', 'Disease', 'MESH:D002289', (100, 105))	('patients', 'Species', '9606', (68, 76))	('brain metastases', 'Disease', 'MESH:D009362', (130, 146))	('NSCLC', 'Phenotype', 'HP:0030358', (100, 105))	('brain metastases', 'Disease', (130, 146))
233284	32256710	In the NCBD study, compared with squamous cell carcinoma histology, adenocarcinoma was associated with a threefold greater risk of brain metastases; younger age, greater tumor size, node positivity (hazard ratio of ~2) and higher tumor grade were all also significantly (p < 0.001) associated with greater risk of presenting with brain metastases.	('tumor', 'Disease', (230, 235))	('node positivity', 'Var', (182, 197))	('brain metastases', 'Disease', (330, 346))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('brain metastases', 'Disease', 'MESH:D009362', (330, 346))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (33, 56))	('adenocarcinoma', 'Disease', (68, 82))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('brain metastases', 'Disease', (131, 147))	('adenocarcinoma', 'Disease', 'MESH:D000230', (68, 82))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (33, 56))	('brain metastases', 'Disease', 'MESH:D009362', (131, 147))	('tumor', 'Disease', (170, 175))	('squamous cell carcinoma', 'Disease', (33, 56))	('tumor', 'Disease', 'MESH:D009369', (230, 235))	('carcinoma', 'Phenotype', 'HP:0030731', (47, 56))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
233287	32256710	Node positivity also impacts the risk of developing brain metastases in those patients who initially present with nonmetastatic NSCLC.	('positivity', 'Var', (5, 15))	('NSCLC', 'Phenotype', 'HP:0030358', (128, 133))	('brain metastases', 'Disease', 'MESH:D009362', (52, 68))	('brain metastases', 'Disease', (52, 68))	('patients', 'Species', '9606', (78, 86))	('impacts', 'Reg', (21, 28))	('NSCLC', 'Disease', (128, 133))	('NSCLC', 'Disease', 'MESH:D002289', (128, 133))
233288	32256710	A retrospective study of 975 patients with T1-2N0-1M0 NSCLC (using the 6th edition of AJCC staging), showed that the 5-year risk of developing brain metastases is 10%, and that the absence of hilar nodal involvement was associated with approximately 1.2-fold (p < 0.04) decreased risk.	('T1-2N0-1M0', 'Var', (43, 53))	('patients', 'Species', '9606', (29, 37))	('brain metastases', 'Disease', 'MESH:D009362', (143, 159))	('NSCLC', 'Phenotype', 'HP:0030358', (54, 59))	('nodal', 'Gene', (198, 203))	('nodal', 'Gene', '4838', (198, 203))	('NSCLC', 'Disease', (54, 59))	('brain metastases', 'Disease', (143, 159))	('NSCLC', 'Disease', 'MESH:D002289', (54, 59))
233294	32256710	While EGFR positive, anaplastic-lymphoma-kinase rearranged and ROS1-mutated NSCLC (predominantly adenocarcinomas) represent a minority of NSCLC, these oncogene mutations (particularly ALK) are associated with a high incidence of brain metastases, and therefore may impact decision-making for staging with brain imaging.	('mutations', 'Var', (160, 169))	('ROS1', 'Gene', (63, 67))	('anaplastic-lymphoma', 'Disease', 'MESH:D017728', (21, 40))	('associated with', 'Reg', (193, 208))	('anaplastic-lymphoma', 'Phenotype', 'HP:0012193', (21, 40))	('impact', 'Reg', (265, 271))	('EGFR', 'Gene', '1956', (6, 10))	('lymphoma', 'Phenotype', 'HP:0002665', (32, 40))	('NSCLC', 'Disease', 'MESH:D002289', (138, 143))	('brain metastases', 'Disease', 'MESH:D009362', (229, 245))	('NSCLC', 'Disease', 'MESH:D002289', (76, 81))	('brain metastases', 'Disease', (229, 245))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('anaplastic-lymphoma', 'Disease', (21, 40))	('NSCLC', 'Disease', (138, 143))	('NSCLC', 'Disease', (76, 81))	('ALK', 'Gene', '238', (184, 187))	('ROS1', 'Gene', '6098', (63, 67))	('adenocarcinomas', 'Disease', 'MESH:D000230', (97, 112))	('adenocarcinomas', 'Disease', (97, 112))	('NSCLC', 'Phenotype', 'HP:0030358', (138, 143))	('NSCLC', 'Phenotype', 'HP:0030358', (76, 81))	('ALK', 'Gene', (184, 187))	('EGFR', 'Gene', (6, 10))
233310	32256710	While brain metastases may be characterized by different genomic signatures than primary cancers, it is conceivable that certain genomic patterns (single nucleotide polymorphisms or genome-wide association) of the primary cancer can signal a greater risk of brain metastases.	('brain metastases', 'Disease', 'MESH:D009362', (6, 22))	('single nucleotide polymorphisms', 'Var', (147, 178))	('cancer', 'Disease', 'MESH:D009369', (222, 228))	('brain metastases', 'Disease', 'MESH:D009362', (258, 274))	('brain metastases', 'Disease', (6, 22))	('cancers', 'Phenotype', 'HP:0002664', (89, 96))	('cancer', 'Disease', (222, 228))	('brain metastases', 'Disease', (258, 274))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('cancers', 'Disease', 'MESH:D009369', (89, 96))	('cancers', 'Disease', (89, 96))	('cancer', 'Disease', (89, 95))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
233384	29208672	We have previously shown that within the CD44+ population, CD271 marks a more tumorigenic subpopulation in human oral squamous cell carcinoma and that inhibition of CD271 renders cells less tumorigenic, indicating that this is a functional receptor in these cancer cells.	('CD271', 'Gene', '4804', (165, 170))	('oral squamous cell carcinoma', 'Disease', (113, 141))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('cancer', 'Disease', 'MESH:D009369', (258, 264))	('more', 'PosReg', (73, 77))	('less', 'NegReg', (185, 189))	('CD271', 'Gene', '4804', (59, 64))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (118, 141))	('CD271', 'Gene', (165, 170))	('CD271', 'Gene', (59, 64))	('tumor', 'Disease', (190, 195))	('inhibition', 'Var', (151, 161))	('cancer', 'Disease', (258, 264))	('tumor', 'Disease', (78, 83))	('cancer', 'Phenotype', 'HP:0002664', (258, 264))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('human', 'Species', '9606', (107, 112))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (113, 141))
233404	29208672	Furthermore, the effects of rhNGF-beta on Slug expression in HSC3-CD271 cells was abrogated in the presence of antibodies to CD271 (Fig.	('NGF', 'Gene', '4803', (30, 33))	('HSC3', 'Gene', '150353', (61, 65))	('NGF', 'Gene', (30, 33))	('HSC3', 'Gene', (61, 65))	('CD271', 'Gene', '4804', (66, 71))	('abrogated', 'NegReg', (82, 91))	('CD271', 'Gene', '4804', (125, 130))	('Slug', 'Gene', (42, 46))	('antibodies', 'Var', (111, 121))	('CD271', 'Gene', (66, 71))	('CD271', 'Gene', (125, 130))	('expression', 'MPA', (47, 57))
233426	29208672	5), oral tumors with pN+ patients were found to have significantly higher levels of CD271 expression compared to oral tumors without pathologically proven nodal metastases (Fig.	('oral tumors', 'Phenotype', 'HP:0100649', (4, 15))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('expression', 'MPA', (90, 100))	('CD271', 'Gene', '4804', (84, 89))	('oral tumors', 'Disease', 'MESH:D020820', (4, 15))	('metastases', 'Disease', 'MESH:D009362', (161, 171))	('oral tumors', 'Phenotype', 'HP:0100649', (113, 124))	('oral tumors', 'Disease', 'MESH:D020820', (113, 124))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('metastases', 'Disease', (161, 171))	('oral tumors', 'Disease', (4, 15))	('CD271', 'Gene', (84, 89))	('higher', 'PosReg', (67, 73))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('patients', 'Species', '9606', (25, 33))	('oral tumors', 'Disease', (113, 124))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('levels', 'MPA', (74, 80))	('pN+', 'Var', (21, 24))
233428	29208672	The median disease-free survival of patients with high CD271 expression (dichotomized by the median value of percent CD271 positivity within primary tumors) was 9.0 months compared with 64.0 months for patients with low CD271 expression, which was a statistically significant difference (Fig.	('patients', 'Species', '9606', (36, 44))	('primary tumors', 'Disease', (141, 155))	('CD271', 'Gene', '4804', (117, 122))	('CD271', 'Gene', '4804', (220, 225))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('patients', 'Species', '9606', (202, 210))	('disease-free survival', 'CPA', (11, 32))	('primary tumors', 'Disease', 'MESH:D009369', (141, 155))	('CD271', 'Gene', '4804', (55, 60))	('tumors', 'Phenotype', 'HP:0002664', (149, 155))	('CD271', 'Gene', (220, 225))	('CD271', 'Gene', (117, 122))	('CD271', 'Gene', (55, 60))	('high', 'Var', (50, 54))
233429	29208672	More interestingly, even within the pN+ group, patients with high CD271 expression showed a significantly worse disease-free survival compared to patients with low CD271 expression by Kaplan-Meier analysis (Fig.	('worse', 'NegReg', (106, 111))	('CD271', 'Gene', '4804', (164, 169))	('disease-free survival', 'CPA', (112, 133))	('high', 'Var', (61, 65))	('CD271', 'Gene', '4804', (66, 71))	('patients', 'Species', '9606', (47, 55))	('CD271', 'Gene', (164, 169))	('CD271', 'Gene', (66, 71))	('patients', 'Species', '9606', (146, 154))
233457	29208672	This finding is consistent with the observations by Soland et al., in which CD271 positivity at the invasive front of tumor as well as the pattern of invasion were significant prognostic factors of disease-free survival in early stage oral cancer.	('oral cancer', 'Disease', (235, 246))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('positivity', 'Var', (82, 92))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumor', 'Disease', (118, 123))	('CD271', 'Gene', '4804', (76, 81))	('oral cancer', 'Disease', 'MESH:D009062', (235, 246))	('CD271', 'Gene', (76, 81))
233479	29113148	Galectins are classified by the number and structure of CRDs into three major groups: Prototypical galectins, tandem-repeat galectins and chimeric galectins (Fig.	('CRD', 'Disease', 'OMIM:120970', (56, 59))	('CRD', 'Disease', (56, 59))	('tandem-repeat', 'Var', (110, 123))
233481	29113148	Tandem-repeat galectins, including galectins-4, -6, -8, -9 and -12, are characterized by containing at least two distinct CRDs, connected by linker domains, within a single polypeptide.	('galectins-4, -6, -8, -9 and -12', 'Gene', '3960;3964;3965;85329', (35, 66))	('Tandem-repeat', 'Var', (0, 13))	('CRD', 'Disease', (122, 125))	('CRD', 'Disease', 'OMIM:120970', (122, 125))
233489	29113148	For example, galectin-3 ablation in mice is associated with decreased mast cell function, as well as fatty liver disease, liver fibrosis, age-dependent glomerular lesions and lung fibrosis.	('fatty liver disease', 'Disease', (101, 120))	('liver fibrosis', 'Phenotype', 'HP:0001395', (122, 136))	('mast cell function', 'CPA', (70, 88))	('decreased', 'NegReg', (60, 69))	('fatty liver disease', 'Disease', 'MESH:D005234', (101, 120))	('liver disease', 'Phenotype', 'HP:0001392', (107, 120))	('lung fibrosis', 'Phenotype', 'HP:0002206', (175, 188))	('liver fibrosis', 'Disease', (122, 136))	('glomerular lesions', 'Disease', 'MESH:D007674', (152, 170))	('galectin-3', 'Gene', (13, 23))	('glomerular lesions', 'Disease', (152, 170))	('lung fibrosis', 'Disease', 'MESH:D005355', (175, 188))	('liver fibrosis', 'Disease', 'MESH:D008103', (122, 136))	('mice', 'Species', '10090', (36, 40))	('ablation', 'Var', (24, 32))	('lung fibrosis', 'Disease', (175, 188))	('fatty liver', 'Phenotype', 'HP:0001397', (101, 112))
233490	29113148	Galectin-1 is involved in pathfinding and axon regeneration, and its ablation in mice is associated with a decreased sensitivity response to noxious thermal stimuli.	('mice', 'Species', '10090', (81, 85))	('decreased', 'NegReg', (107, 116))	('axon regeneration', 'Phenotype', 'HP:0003450', (42, 59))	('ablation', 'Var', (69, 77))	('Galectin-1', 'Protein', (0, 10))	('sensitivity response to noxious thermal stimuli', 'MPA', (117, 164))
233495	29113148	In the function of mast cells, endogenous galectin-3 is involved in the phagocytosis of macrophages and the promotion of inflammation in the airway.	('inflammation', 'Disease', 'MESH:D007249', (121, 133))	('promotion', 'PosReg', (108, 117))	('inflammation', 'Disease', (121, 133))	('endogenous', 'Var', (31, 41))	('involved', 'Reg', (56, 64))	('phagocytosis of macrophages', 'CPA', (72, 99))
233557	29113148	Overexpression of galectin-3 in A549 cells promotes their sphere-forming capacity (a character of cancer stem cells), and suppression of galectin-3 in H1299 cells in vitro decreases the expression of stemness-associated genes, their sphere-forming capacity, tumorigenicity, chemo-resistance; in vivo, suppression of galectin-3 in H1299 cells also decreases tumor-initiating capacity in NOD/SCID mice.	('mice', 'Species', '10090', (395, 399))	('tumor', 'Disease', (258, 263))	('decreases', 'NegReg', (347, 356))	('cancer', 'Disease', (98, 104))	('A549', 'CellLine', 'CVCL:0023', (32, 36))	('tumor', 'Disease', 'MESH:D009369', (258, 263))	('tumor', 'Phenotype', 'HP:0002664', (357, 362))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('H1299', 'CellLine', 'CVCL:0060', (151, 156))	('decreases', 'NegReg', (172, 181))	('chemo-resistance', 'CPA', (274, 290))	('suppression', 'Var', (122, 133))	('stemness-associated genes', 'Gene', (200, 225))	('SCID', 'Disease', 'MESH:D053632', (390, 394))	('tumor', 'Phenotype', 'HP:0002664', (258, 263))	('H1299', 'CellLine', 'CVCL:0060', (330, 335))	('promotes', 'PosReg', (43, 51))	('sphere-forming capacity', 'CPA', (233, 256))	('sphere-forming capacity', 'CPA', (58, 81))	('suppression', 'Var', (301, 312))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('SCID', 'Disease', (390, 394))	('tumor', 'Disease', (357, 362))	('expression', 'MPA', (186, 196))	('tumor', 'Disease', 'MESH:D009369', (357, 362))
233586	29570800	DNA methylation of microRNA-coding genes in non-small-cell lung cancer patients Deregulated DNA methylation leading to transcriptional inactivation of certain genes occurs frequently in non-small-cell lung cancers (NSCLCs).	('lung cancers', 'Disease', 'MESH:D008175', (201, 213))	('DNA', 'Gene', (92, 95))	('lung cancer', 'Disease', 'MESH:D008175', (59, 70))	('lung cancer', 'Disease', 'MESH:D008175', (201, 212))	('Deregulated', 'Var', (80, 91))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (48, 70))	('lung cancers', 'Disease', (201, 213))	('lung cancer', 'Phenotype', 'HP:0100526', (59, 70))	('transcriptional', 'MPA', (119, 134))	('lung cancer', 'Phenotype', 'HP:0100526', (201, 212))	('NSCLC', 'Disease', (215, 220))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (190, 212))	('lung cancers', 'Phenotype', 'HP:0100526', (201, 213))	('cancers', 'Phenotype', 'HP:0002664', (206, 213))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (186, 212))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (44, 70))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('lung cancer', 'Disease', (59, 70))	('NSCLC', 'Disease', 'MESH:D002289', (215, 220))
233597	29570800	In addition, we found a statistically significant reduction in the growth of NSCLC cells transfected with miR-1179 mimics as compared with control cells.	('NSCLC', 'Disease', 'MESH:D002289', (77, 82))	('miR-1179', 'Gene', (106, 114))	('growth', 'MPA', (67, 73))	('reduction', 'NegReg', (50, 59))	('miR-1179', 'Gene', '100302235', (106, 114))	('mimics', 'Var', (115, 121))	('NSCLC', 'Disease', (77, 82))
233599	29570800	Overall, our findings emphasize the impact of miRNA gene methylation on the pathogenesis of NSCLCs.	('miR', 'Gene', (46, 49))	('methylation', 'Var', (57, 68))	('NSCLC', 'Disease', (92, 97))	('NSCLC', 'Disease', 'MESH:D002289', (92, 97))	('miR', 'Gene', '220972', (46, 49))
233602	29570800	It has been shown that deregulated expression of certain miRNAs may lead to alterations in these processes and to the development of a malignant phenotype 3.	('miR', 'Gene', '220972', (57, 60))	('miR', 'Gene', (57, 60))	('deregulated', 'Var', (23, 34))	('lead to alterations', 'Reg', (68, 87))	('expression', 'MPA', (35, 45))
233631	29570800	Cells were transfected with miRNA mimics, random sequence miRNA mimic controls or miRNA inhibitors (4464066_MC13164, 4464058, 4464084_MH13164; Ambion, Carlsbad, CA, USA) by the use of Lipofectamine RNAiMax Reagent (Invitrogen, Carlsbad, CA, USA).	('Lipofectamine', 'Chemical', 'MESH:C086724', (184, 197))	('miR', 'Gene', '220972', (82, 85))	('miR', 'Gene', (82, 85))	('miR', 'Gene', '220972', (58, 61))	('miR', 'Gene', (58, 61))	('miR', 'Gene', '220972', (28, 31))	('miR', 'Gene', (28, 31))	('4464066_MC13164', 'Var', (100, 115))
233637	29570800	The following miScript Primer Assays (Qiagen) were used: MS00014084 (miR-1179 gene) and MS00003682 (reference, miR-191 gene).	('miR-1179', 'Gene', (69, 77))	('MS00003682', 'Var', (88, 98))	('miR-191', 'Gene', '406966', (111, 118))	('miR-1179', 'Gene', '100302235', (69, 77))	('miR-191', 'Gene', (111, 118))	('MS00014084', 'Var', (57, 67))
233643	29570800	ChIP assays were performed with the Magna Chip A kit (Millipore, Bedford, MA, USA), a Bioruptor (Diagenode, Liege, Belgium), and the following antibodies: anti-acetyl-histone H3 (#06-599; 1:100; Millipore), anti-acetyl-histone H4 (#06-866; 1:100; Millipore), and normal rabbit IgG (2729S; 1:100; Cell Signaling, Frankfurt, Germany).	('anti-acetyl-histone', 'Var', (207, 226))	('acetyl-histone H4', 'Chemical', '-', (212, 229))	('acetyl-histone', 'Chemical', '-', (212, 226))	('rabbit', 'Species', '9986', (270, 276))	('#06-599;', 'Var', (179, 187))	('#06-866', 'Var', (231, 238))	('acetyl-histone', 'Chemical', '-', (160, 174))	('anti-acetyl-histone', 'Var', (155, 174))
233646	29570800	Cells were cotransfected with a luciferase reporter construct containing the 3'-UTR of CCNE1 (SC207262; Origene, Rockville, MD, USA) and with miRNA-1179 mimics (4464066_MC13164; Ambion) or random sequence miRNA mimic controls.	('miR', 'Gene', (205, 208))	('SC207262;', 'Var', (94, 103))	('CCNE1', 'Gene', '898', (87, 92))	('CCNE1', 'Gene', (87, 92))	('miR', 'Gene', (142, 145))	('miR', 'Gene', '220972', (142, 145))	('4464066_MC13164;', 'Var', (161, 177))	('miR', 'Gene', '220972', (205, 208))
233683	29570800	To confirm that miR-1179 regulates CCNE1 expression, we performed a 3'-UTR reporter assay, and detected reduced luciferase activity in cells transfected with miR-1179 mimics as compared with control cells (Figure 4D).	('mimics', 'Var', (167, 173))	('miR-1179', 'Gene', (158, 166))	('luciferase', 'Enzyme', (112, 122))	('reduced', 'NegReg', (104, 111))	('expression', 'MPA', (41, 51))	('miR-1179', 'Gene', '100302235', (16, 24))	('regulates', 'Reg', (25, 34))	('miR-1179', 'Gene', '100302235', (158, 166))	('CCNE1', 'Gene', '898', (35, 40))	('CCNE1', 'Gene', (35, 40))	('miR-1179', 'Gene', (16, 24))	('activity', 'MPA', (123, 131))
233697	29570800	Accordingly, we used a biochemical assay to measure cell viability as followed by cell proliferation of NCI-H2073 cells transfected with either miR-1179 mimics or with random sequence miRNA mimic controls.	('miR-1179', 'Gene', (144, 152))	('miR-1179', 'Gene', '100302235', (144, 152))	('miR', 'Gene', '220972', (144, 147))	('NCI-H2073', 'CellLine', 'CVCL:1521', (104, 113))	('miR', 'Gene', (144, 147))	('miR', 'Gene', '220972', (184, 187))	('mimics', 'Var', (153, 159))	('miR', 'Gene', (184, 187))
233698	29570800	We observed statistically significant reductions of the viability of cells transfected with miR-1179 mimics as compared with control cells after both 96 h and 120 h (p = 0.018 and p = 0.002, respectively; Figure 5B).	('miR-1179', 'Gene', (92, 100))	('miR-1179', 'Gene', '100302235', (92, 100))	('reductions', 'NegReg', (38, 48))	('mimics', 'Var', (101, 107))
233699	29570800	In addition, we measured cell proliferation in real time, and detected significantly reduced proliferation rates of cells transfected with miR-1179 mimics as compared with cells transfected with a control miRNA mimic (Figure 5C).	('miR', 'Gene', (205, 208))	('miR', 'Gene', '220972', (139, 142))	('miR', 'Gene', (139, 142))	('miR-1179', 'Gene', '100302235', (139, 147))	('cell proliferation', 'CPA', (25, 43))	('miR-1179', 'Gene', (139, 147))	('proliferation rates', 'CPA', (93, 112))	('mimics', 'Var', (148, 154))	('reduced', 'NegReg', (85, 92))	('miR', 'Gene', '220972', (205, 208))
233702	29570800	Downregulated miRNA expression caused by methylation of genes encoding these miRNAs may be involved in the pathogenesis of NSCLCs 4, 5, 6, 8, 30, 31.	('miR', 'Gene', (77, 80))	('NSCLC', 'Disease', (123, 128))	('NSCLC', 'Disease', 'MESH:D002289', (123, 128))	('methylation', 'Var', (41, 52))	('Downregulated', 'NegReg', (0, 13))	('miR', 'Gene', '220972', (14, 17))	('miR', 'Gene', (14, 17))	('miR', 'Gene', '220972', (77, 80))
233703	29570800	We reported previously that epigenetically active drugs can upregulate the expression of certain methylated miRNA genes in NSCLC cells.	('NSCLC', 'Disease', (123, 128))	('epigenetically active drugs', 'Var', (28, 55))	('NSCLC', 'Disease', 'MESH:D002289', (123, 128))	('upregulate', 'PosReg', (60, 70))	('miR', 'Gene', '220972', (108, 111))	('miR', 'Gene', (108, 111))	('methylated', 'Var', (97, 107))	('expression', 'MPA', (75, 85))
233708	29570800	those encoding members of the miR-9 and the miR-124 families) it has already been reported that they may be methylated in NSCLCs 32, 33, 34.	('miR', 'Gene', '220972', (30, 33))	('NSCLC', 'Disease', 'MESH:D002289', (122, 127))	('miR', 'Gene', (44, 47))	('miR', 'Gene', (30, 33))	('miR', 'Gene', '220972', (44, 47))	('methylated', 'Var', (108, 118))	('NSCLC', 'Disease', (122, 127))
233709	29570800	For instance, Lujambio et al 32 reported an association between tumour-specific miR-9-3 gene methylation and the appearance of lymph node metastases in NSCLC patients.	('miR-9-3', 'Gene', '407051', (80, 87))	('metastases', 'Disease', (138, 148))	('tumour', 'Phenotype', 'HP:0002664', (64, 70))	('miR-9-3', 'Gene', (80, 87))	('tumour', 'Disease', 'MESH:D009369', (64, 70))	('metastases', 'Disease', 'MESH:D009362', (138, 148))	('NSCLC', 'Disease', (152, 157))	('tumour', 'Disease', (64, 70))	('NSCLC', 'Disease', 'MESH:D002289', (152, 157))	('patients', 'Species', '9606', (158, 166))	('methylation', 'Var', (93, 104))	('association', 'Interaction', (44, 55))
233710	29570800	Methylation of the genes encoding miR-124-1 and miR-124-2 was found to be correlated with shorter OS of NSCLC patients in the study by Kim et al 33.	('miR-124-1', 'Gene', (34, 43))	('shorter OS', 'Disease', (90, 100))	('Methylation', 'Var', (0, 11))	('NSCLC', 'Disease', (104, 109))	('NSCLC', 'Disease', 'MESH:D002289', (104, 109))	('miR-124-2', 'Gene', '406908', (48, 57))	('miR-124-1', 'Gene', '406907', (34, 43))	('miR-124-2', 'Gene', (48, 57))	('patients', 'Species', '9606', (110, 118))
233714	29570800	However, hypomethylation was identified as mechanism for upregulation of only a few miRNA genes (e.g.	('hypomethylation', 'Var', (9, 24))	('miR', 'Gene', (84, 87))	('upregulation', 'PosReg', (57, 69))	('miR', 'Gene', '220972', (84, 87))
233728	29570800	When we compared our miRNA methylation data with clinicopathological characteristics of NSCLC patients, we found that the miR-129-2 gene was more frequently methylated in stage III than in stage I/II patients.	('patients', 'Species', '9606', (94, 102))	('patients', 'Species', '9606', (200, 208))	('methylated', 'Var', (157, 167))	('miR', 'Gene', '220972', (21, 24))	('miR', 'Gene', (21, 24))	('miR-129-2', 'Gene', (122, 131))	('miR', 'Gene', (122, 125))	('miR', 'Gene', '220972', (122, 125))	('NSCLC', 'Disease', (88, 93))	('miR-129-2', 'Gene', '100302138', (122, 131))	('NSCLC', 'Disease', 'MESH:D002289', (88, 93))	('stage III', 'Disease', (171, 180))
233730	29570800	Recently, Torres-Ferreira et al 47 demonstrated that a high level of miR-129-2 gene methylation is associated with shorter DFS of prostate cancer patients, and Liu et al 46 observed an association between low miR-129-2 gene expression in TUs and shorter OS and DFS of hepatocellular carcinoma patients.	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (268, 292))	('prostate cancer', 'Disease', (130, 145))	('miR-129-2', 'Gene', (69, 78))	('miR-129-2', 'Gene', '100302138', (69, 78))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (268, 292))	('shorter OS', 'Disease', (246, 256))	('expression', 'MPA', (224, 234))	('patients', 'Species', '9606', (146, 154))	('low', 'NegReg', (205, 208))	('methylation', 'Var', (84, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (283, 292))	('miR-129-2', 'Gene', (209, 218))	('hepatocellular carcinoma', 'Disease', (268, 292))	('miR-129-2', 'Gene', '100302138', (209, 218))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('prostate cancer', 'Disease', 'MESH:D011471', (130, 145))	('prostate cancer', 'Phenotype', 'HP:0012125', (130, 145))	('patients', 'Species', '9606', (293, 301))	('TU', 'Phenotype', 'HP:0002664', (238, 240))
233733	29570800	Whereas the frequencies of RASSF1A and APC methylation were higher in adenocarcinomas, the frequency of p16 methylation was higher in squamous cell carcinomas [48,49].	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (134, 158))	('APC methylation', 'Var', (39, 54))	('p16', 'Gene', '1029', (104, 107))	('higher', 'Reg', (124, 130))	('RASSF1A', 'Gene', (27, 34))	('squamous cell carcinomas', 'Disease', (134, 158))	('adenocarcinomas', 'Disease', 'MESH:D000230', (70, 85))	('adenocarcinomas', 'Disease', (70, 85))	('carcinomas', 'Phenotype', 'HP:0030731', (148, 158))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('higher', 'Reg', (60, 66))	('p16', 'Gene', (104, 107))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (134, 158))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (134, 157))	('RASSF1A', 'Gene', '11186', (27, 34))	('carcinomas', 'Phenotype', 'HP:0030731', (75, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (148, 157))
233735	29570800	In our analyses, we did not find such differences, indicating that methylation of the six miRNA genes is not specific for either adenocarcinomas or squamous cell carcinomas of the lung.	('adenocarcinomas', 'Disease', (129, 144))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (148, 172))	('carcinoma', 'Phenotype', 'HP:0030731', (162, 171))	('carcinomas', 'Phenotype', 'HP:0030731', (162, 172))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (148, 171))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('squamous cell carcinomas of the lung', 'Disease', (148, 184))	('miR', 'Gene', '220972', (90, 93))	('squamous cell carcinomas of the lung', 'Disease', 'MESH:D002294', (148, 184))	('miR', 'Gene', (90, 93))	('carcinomas', 'Phenotype', 'HP:0030731', (134, 144))	('adenocarcinomas', 'Disease', 'MESH:D000230', (129, 144))	('methylation', 'Var', (67, 78))
233743	29570800	Cyclin E expression is upregulated in several tumour types, and an association between high CCNE1 expression and disease progression/poor prognosis of patients with certain tumour types has been reported [27,28].	('tumour', 'Disease', (173, 179))	('upregulated', 'PosReg', (23, 34))	('CCNE1', 'Gene', (92, 97))	('tumour', 'Phenotype', 'HP:0002664', (46, 52))	('tumour', 'Disease', (46, 52))	('CCNE1', 'Gene', '898', (92, 97))	('patients', 'Species', '9606', (151, 159))	('Cyclin E', 'Protein', (0, 8))	('high', 'Var', (87, 91))	('disease progression/poor', 'CPA', (113, 137))	('expression', 'MPA', (9, 19))	('tumour', 'Phenotype', 'HP:0002664', (173, 179))	('tumour', 'Disease', 'MESH:D009369', (46, 52))	('tumour', 'Disease', 'MESH:D009369', (173, 179))	('expression', 'MPA', (98, 108))
233749	29570800	In in vitro experiments using NSCLC cell line models, we detected upregulated miR-1179 gene expression after treatment of cells with epigenetically active drugs, indicating that expression of this miRNA is indeed affected by methylation.	('miR', 'Gene', '220972', (197, 200))	('NSCLC', 'Disease', 'MESH:D002289', (30, 35))	('miR', 'Gene', (197, 200))	('miR', 'Gene', '220972', (78, 81))	('miR', 'Gene', (78, 81))	('miR-1179', 'Gene', '100302235', (78, 86))	('epigenetically', 'Var', (133, 147))	('upregulated', 'PosReg', (66, 77))	('miR-1179', 'Gene', (78, 86))	('NSCLC', 'Disease', (30, 35))	('expression', 'MPA', (92, 102))
233759	29570800	For many of them, transcriptional regulation by methylation in NSCLCs was previously unknown.	('NSCLC', 'Disease', (63, 68))	('methylation', 'Var', (48, 59))	('NSCLC', 'Disease', 'MESH:D002289', (63, 68))
233762	29570800	In summary, the results of our study stress the importance of methylation of miRNA genes for the pathogenesis of NSCLCs.	('miR', 'Gene', (77, 80))	('NSCLC', 'Disease', 'MESH:D002289', (113, 118))	('methylation', 'Var', (62, 73))	('NSCLC', 'Disease', (113, 118))	('miR', 'Gene', '220972', (77, 80))
233786	25834829	It was tested using an AKT shRNA knockdown of ESCC cell lines and the in vivo tumor suppressive effects of AKT knockdown were observed.	('knockdown', 'Var', (111, 120))	('AKT', 'Gene', (107, 110))	('AKT', 'Gene', '207', (23, 26))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('AKT', 'Gene', (23, 26))	('tumor', 'Disease', (78, 83))	('AKT', 'Gene', '207', (107, 110))
233795	25834829	Accumulation of genetic alterations leads to deregulation of the normal intracellular signaling network and interactions with the extracellular matrix environment, which are important factors associated with cancer development.	('cancer', 'Disease', (208, 214))	('genetic alterations', 'Var', (16, 35))	('deregulation', 'Reg', (45, 57))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('interactions', 'Interaction', (108, 120))	('normal intracellular signaling network', 'MPA', (65, 103))	('cancer', 'Disease', 'MESH:D009369', (208, 214))
233807	25834829	We verified the practicality of this system by studying the changes in a molecular pathway utilizing an AKT (protein kinase B) shRNA knockdown approach in ESCC cell lines to knockdown AKT, which is frequently deregulated in cancers, to confirm its functionality in this in vivo animal model system.	('AKT', 'Gene', '207', (184, 187))	('AKT', 'Gene', (104, 107))	('cancers', 'Phenotype', 'HP:0002664', (224, 231))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('knockdown', 'Var', (174, 183))	('AKT', 'Gene', (184, 187))	('cancers', 'Disease', 'MESH:D009369', (224, 231))	('cancers', 'Disease', (224, 231))	('AKT', 'Gene', '207', (104, 107))
233809	25834829	The 81-T, KYSE30, KYSE150, and SLMT-1 cells were labelled with luciferase and were cultured as previously described.	('KYSE30', 'Var', (10, 16))	('SLMT-1', 'CellLine', 'CVCL:E305', (31, 37))	('KYSE150', 'Var', (18, 25))
233826	25834829	The AKT knockdown oligonucleotide sequences were obtained from The RNAi Consortium/Public TRC portal (http://www.broadinstitute.org/rnai/public/), targeting sequence 984 (construct ID: TRCN0000288787) and sequence 1793 (TRCN0000199454) on AKT.	('AKT', 'Gene', (4, 7))	('oligonucleotide', 'Chemical', 'MESH:D009841', (18, 33))	('AKT', 'Gene', '207', (239, 242))	('AKT', 'Gene', '207', (4, 7))	('sequence 1793', 'Var', (205, 218))	('AKT', 'Gene', (239, 242))
233828	25834829	Western blot analysis was performed to verify efficient knockdown of AKT expression with AKT (Cat number 9272, Cell Signaling, Beverly, MA, USA) and p84 (Cat number GTX70220, Genetex, Irvine, CA, USA) was used as a loading control.	('AKT', 'Gene', (69, 72))	('p84', 'Gene', '9984', (149, 152))	('AKT', 'Gene', '207', (89, 92))	('p84', 'Gene', (149, 152))	('AKT', 'Gene', '207', (69, 72))	('AKT', 'Gene', (89, 92))	('knockdown', 'Var', (56, 65))
233837	25834829	The optimum cell concentrations for producing orthotopic tumors with consistent tumor sizes and survival times for mice, as well as being 100% tumorigenic for the tested ESCC cell lines, KYSE150 luc and SLMT-1 luc, are 1 x 105 cells and for KYSE30 luc and 81-T luc are 2 x 105 cells, each in a volume of 10 muL.	('KYSE150 luc', 'Var', (187, 198))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('orthotopic tumors', 'Disease', (46, 63))	('SLMT-1', 'CellLine', 'CVCL:E305', (203, 209))	('tumor', 'Disease', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Disease', (80, 85))	('orthotopic tumors', 'Disease', 'MESH:D009369', (46, 63))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('mice', 'Species', '10090', (115, 119))	('tumor', 'Disease', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
233842	25834829	Cross sections of the normal mouse esophagus (Figure 3(a)) and the esophagus after inoculation with KYSE150 showing luminal stricture due to the tumor growth (Figure 3(b)) are shown.	('KYSE150', 'Var', (100, 107))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumor', 'Disease', (145, 150))	('mouse', 'Species', '10090', (29, 34))
233846	25834829	Other common characteristics in ESCC, including squamous differentiation and focal keratinization are also observed in orthotopic tumors derived from KYSE150.	('ESCC', 'Disease', (32, 36))	('KYSE150', 'Var', (150, 157))	('focal keratinization', 'CPA', (77, 97))	('orthotopic tumors', 'Disease', (119, 136))	('squamous differentiation', 'Disease', (48, 72))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('orthotopic tumors', 'Disease', 'MESH:D009369', (119, 136))
233849	25834829	Demonstration of the usefulness of the current established ESCC orthotopic model for ESCC studies was shown by shRNA AKT knockdown of this well-known oncogenic signaling pathway for driving cancer.	('knockdown', 'Var', (121, 130))	('cancer', 'Disease', (190, 196))	('AKT', 'Gene', '207', (117, 120))	('cancer', 'Disease', 'MESH:D009369', (190, 196))	('AKT', 'Gene', (117, 120))	('oncogenic signaling pathway', 'Pathway', (150, 177))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))
233853	25834829	Downregulation of well-studied AKT downstream invasion-associated markers including IL8 and VEGFA in the AKT knockdown cell lines was detected, as compared to the control (Figure 4(c)).	('AKT', 'Gene', '207', (105, 108))	('VEGFA', 'Gene', '7422', (92, 97))	('AKT', 'Gene', (31, 34))	('Downregulation', 'NegReg', (0, 14))	('IL8', 'Gene', (84, 87))	('IL8', 'Gene', '3576', (84, 87))	('VEGFA', 'Gene', (92, 97))	('AKT', 'Gene', (105, 108))	('knockdown', 'Var', (109, 118))	('AKT', 'Gene', '207', (31, 34))
233873	25834829	Notably, our previous studies indicated KYSE150 luc requires 1 x 106 cells for subcutaneous inoculation to obtain 100% tumorigenicity in nude mice.	('tumor', 'Disease', (119, 124))	('nude mice', 'Species', '10090', (137, 146))	('KYSE150', 'Var', (40, 47))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))
233886	25834829	The usefulness of this current esophageal orthotopic model as a platform for molecular cancer studies was further demonstrated by silencing of the AKT gene, which is known to play a critical role in ESCC tumorigenesis by regulating invasion, angiogenesis, and metastasis.	('cancer', 'Disease', (87, 93))	('angiogenesis', 'CPA', (242, 254))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('invasion', 'CPA', (232, 240))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('tumor', 'Disease', (204, 209))	('AKT', 'Gene', '207', (147, 150))	('metastasis', 'CPA', (260, 270))	('ESCC', 'Disease', (199, 203))	('regulating', 'PosReg', (221, 231))	('silencing', 'Var', (130, 139))	('AKT', 'Gene', (147, 150))
233887	25834829	The in vivo orthotopic tumor growth, as monitored by bioluminescence, showed a statistically significant tumor growth inhibition after AKT knockdown.	('AKT', 'Gene', '207', (135, 138))	('knockdown', 'Var', (139, 148))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('AKT', 'Gene', (135, 138))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumor', 'Disease', (23, 28))	('tumor', 'Disease', (105, 110))
233888	25834829	An in vitro inhibitory effect upon real-time invasion assay was also observed for AKT knockdown.	('inhibitory', 'NegReg', (12, 22))	('AKT', 'Gene', '207', (82, 85))	('knockdown', 'Var', (86, 95))	('AKT', 'Gene', (82, 85))
233891	25834829	These mutations may result in deregulation of signaling networks intracellularly and pathway activation disrupting the normal cell-cell and cell-matrix interaction in the tumor microenvironment that leads to ESCC tumorigenesis and metastasis.	('tumor', 'Disease', (213, 218))	('activation', 'PosReg', (93, 103))	('ESCC', 'Disease', (208, 212))	('result', 'Reg', (20, 26))	('signaling networks', 'Pathway', (46, 64))	('leads to', 'Reg', (199, 207))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('tumor', 'Disease', 'MESH:D009369', (213, 218))	('deregulation', 'MPA', (30, 42))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', (171, 176))	('disrupting', 'NegReg', (104, 114))	('mutations', 'Var', (6, 15))
233913	32158598	In addition, the complexity of immune landscape of NSCLC arises from molecular subtype, oncogenic drivers, nonsynonymous mutational load, tumor aneuploidy, clonal heterogeneity and tumor evolution.	('tumor aneuploidy', 'Disease', (138, 154))	('tumor', 'Disease', (181, 186))	('nonsynonymous mutational load', 'Var', (107, 136))	('tumor', 'Disease', (138, 143))	('NSCLC', 'Disease', (51, 56))	('NSCLC', 'Disease', 'MESH:D002289', (51, 56))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('tumor aneuploidy', 'Disease', 'MESH:D000782', (138, 154))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
233917	32158598	The role of TMB as a marker predictive of response has been also evaluated in several clinical trials (CheckMate026, CheckMate568, CheckMate227), which showed that patients with high TMB showed enhanced response to immunotherapy, regardless of PD-L1 expression.	('CheckMate568', 'Chemical', '-', (117, 129))	('response to immunotherapy', 'CPA', (203, 228))	('TMB', 'Chemical', '-', (12, 15))	('TMB', 'Gene', (183, 186))	('clinical', 'Species', '191496', (86, 94))	('TMB', 'Chemical', '-', (183, 186))	('PD-L1', 'Gene', (244, 249))	('high', 'Var', (178, 182))	('patients', 'Species', '9606', (164, 172))	('enhanced', 'PosReg', (194, 202))	('PD-L1', 'Gene', '29126', (244, 249))
233919	32158598	Recent pivotal studies have assessed the role of immunotherapy in previously untreated metastatic NSCLCs in both squamous and nonsquamous histology, and 4 studies have shown an OS benefit from adding PD-1 or PD-L1 inhibitor to standard chemotherapy (KEYNOTE-189, IMpower150, IMpower130, KEYNOTE-407).	('IMpower150', 'Var', (263, 273))	('NSCLCs', 'Disease', 'MESH:D002289', (98, 104))	('PD-L1', 'Gene', (208, 213))	('OS', 'Chemical', '-', (177, 179))	('PD-L1', 'Gene', '29126', (208, 213))	('PD-1', 'Gene', (200, 204))	('NSCLCs', 'Disease', (98, 104))	('PD-1', 'Gene', '5133', (200, 204))
233936	32158598	The 3-year OS rates for CheckMate017 and CheckMate057 were 16% and 18% respectively, and among patients who showed response to nivolumab, 26% and 23% showed ongoing responses, respectively.	('OS', 'Chemical', '-', (11, 13))	('patients', 'Species', '9606', (95, 103))	('CheckMate057', 'Var', (41, 53))	('nivolumab', 'Chemical', 'MESH:D000077594', (127, 136))	('CheckMate017', 'Var', (24, 36))
233940	32158598	Patients who expressed PD-L1 expression of >=50% showed greater benefit with pembrolizumab, and the median PFS was also statistically improved in these group of patients.	('improved', 'PosReg', (134, 142))	('expression', 'Var', (29, 39))	('PD-L1', 'Gene', (23, 28))	('PD-L1', 'Gene', '29126', (23, 28))	('Patients', 'Species', '9606', (0, 8))	('PFS', 'MPA', (107, 110))	('patients', 'Species', '9606', (161, 169))	('pembrolizumab', 'Chemical', 'MESH:C582435', (77, 90))	('benefit', 'PosReg', (64, 71))
233948	32158598	Overall, the above trials showed consistent improvement in OS and ORR with PD-L1 or PD-L1 inhibitor monotherapy compared with standard chemotherapy, with less toxicity.	('PD-L1', 'Gene', (84, 89))	('OS', 'Chemical', '-', (59, 61))	('monotherapy', 'Var', (100, 111))	('PD-L1', 'Gene', (75, 80))	('PD-L1', 'Gene', '29126', (84, 89))	('toxicity', 'Disease', 'MESH:D064420', (159, 167))	('toxicity', 'Disease', (159, 167))	('PD-L1', 'Gene', '29126', (75, 80))	('improvement', 'PosReg', (44, 55))	('ORR', 'Disease', (66, 69))
233959	32158598	The KEYNOTE-042 trial assessed the efficacy of pembrolizumab monotherapy in patients with PD-L1 expression on at least 1% of tumor cells.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('patients', 'Species', '9606', (76, 84))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('PD-L1', 'Gene', '29126', (90, 95))	('tumor', 'Disease', (125, 130))	('pembrolizumab', 'Chemical', 'MESH:C582435', (47, 60))	('expression', 'Var', (96, 106))	('PD-L1', 'Gene', (90, 95))
233962	32158598	The magnitude of OS benefit was greatest in the patients with TPS>=50% (20 months vs. 12.2 months; HR, 0.69; 95% CI, 0.56-0.85; p=0.0003), but the OS benefit was not seen patients with TPS >=1%-49%.	('OS', 'Chemical', '-', (147, 149))	('TPS>=50%', 'Var', (62, 70))	('TPS', 'Chemical', 'MESH:C089984', (62, 65))	('TPS', 'Chemical', 'MESH:C089984', (185, 188))	('patients', 'Species', '9606', (171, 179))	('patients', 'Species', '9606', (48, 56))	('>=50%', 'Var', (65, 70))	('OS', 'Chemical', '-', (17, 19))
233967	32158598	Of note, an exploratory analysis was conducted to see the role of TMB, and patients with high TMB (as defined as >=243 missense mutations) showed higher response rate (47% vs. 28%) and prolonged PFS (9.7 months vs. 5.8 months; HR, 0.62; 95% CI, 0.38-1.00).	('higher', 'PosReg', (146, 152))	('response', 'CPA', (153, 161))	('TMB', 'Chemical', '-', (66, 69))	('PFS', 'MPA', (195, 198))	('missense mutations', 'Var', (119, 137))	('patients', 'Species', '9606', (75, 83))	('TMB', 'Chemical', '-', (94, 97))
233969	32158598	MYSTIC trial compared both durvalumab monotherapy and durvalumab in combination with tremelimumab with the platinum-doublet chemotherapy in the first-line setting in patients 25% or greater PD-L1 expression.	('25%', 'Var', (175, 178))	('platinum', 'Chemical', 'MESH:D010984', (107, 115))	('PD-L1', 'Gene', (190, 195))	('durvalumab', 'Chemical', 'MESH:C000613593', (54, 64))	('PD-L1', 'Gene', '29126', (190, 195))	('tremelimumab', 'Chemical', 'MESH:C520704', (85, 97))	('durvalumab', 'Chemical', 'MESH:C000613593', (27, 37))	('patients', 'Species', '9606', (166, 174))
233983	32158598	Of note, patients with EGFR and ALK alterations were included in this trial, and they also had benefit from atezolizumab-containing arm (HR, 0.59; 95% CI, 0.37-0.94).	('patients', 'Species', '9606', (9, 17))	('ALK', 'Gene', (32, 35))	('alterations', 'Var', (36, 47))	('ALK', 'Gene', '238', (32, 35))	('atezolizumab', 'Chemical', 'MESH:C000594389', (108, 120))	('EGFR', 'Gene', '1956', (23, 27))	('EGFR', 'Gene', (23, 27))	('benefit', 'PosReg', (95, 102))
233996	32158598	The study protocol was later modified to include a co-primary endpoint of PFS in patients with high TMB, as defined by >=10 mutations per megabase.	('patients', 'Species', '9606', (81, 89))	('PFS', 'Disease', (74, 77))	('mutations', 'Var', (124, 133))	('TMB', 'Chemical', '-', (100, 103))
233997	32158598	This was due to the previous finding that high TMB was associated with enhanced response rate and PFS, independent of tumor PD-L1 expression.	('PD-L1', 'Gene', (124, 129))	('TMB', 'Chemical', '-', (47, 50))	('enhanced', 'PosReg', (71, 79))	('response rate', 'CPA', (80, 93))	('PFS', 'CPA', (98, 101))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('high TMB', 'Var', (42, 50))	('PD-L1', 'Gene', '29126', (124, 129))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumor', 'Disease', (118, 123))
234003	32158598	Higher response rates and improved PFS were observed in patients with TMB of 10 or more mut/Mb versus TMB of fewer than 10 mut/Mb, irrespective of PD-L1 expression.	('PD-L1', 'Gene', '29126', (147, 152))	('patients', 'Species', '9606', (56, 64))	('TMB', 'Chemical', '-', (70, 73))	('PD-L1', 'Gene', (147, 152))	('mut/Mb', 'Var', (88, 94))	('PFS', 'CPA', (35, 38))	('response', 'CPA', (7, 15))	('improved', 'PosReg', (26, 34))	('TMB', 'Chemical', '-', (102, 105))
234009	32158598	Therefore, clinical trials involving novel checkpoint targets such as V-domain immunoglobulin suppressor of T cell activation /PD-1H (NCT02671955), B7-H3 (NCT01391143, NCT02475213, NCT00844064), LAG-3 (NCT01968109, NCT02460224, NCT00732082, NCT00349934) are ongoing, often in combination with PD-1 inhibitors.	('NCT02460224', 'Var', (215, 226))	('NCT00732082', 'Var', (228, 239))	('clinical', 'Species', '191496', (11, 19))	('PD-1', 'Gene', (127, 131))	('PD-1', 'Gene', '5133', (127, 131))	('NCT00844064', 'Var', (181, 192))	('NCT01391143', 'Var', (155, 166))	('NCT00349934', 'Var', (241, 252))	('LAG-3', 'Gene', (195, 200))	('LAG-3', 'Gene', '3902', (195, 200))	('NCT01968109', 'Var', (202, 213))	('NCT02671955', 'Var', (134, 145))	('PD-1', 'Gene', (293, 297))	('PD-1', 'Gene', '5133', (293, 297))	('NCT02475213', 'Var', (168, 179))
234015	32158598	RO7121661 (bispecific Ab to TIM-3 and PD-1) and LY3415244 (bispecific Ab to TIM-3 and PD-L1) are currently under clinical investigation.	('LY3415244', 'Var', (48, 57))	('TIM-3', 'Gene', (28, 33))	('PD-L1', 'Gene', '29126', (86, 91))	('PD-1', 'Gene', (38, 42))	('TIM-3', 'Gene', '84868', (28, 33))	('TIM-3', 'Gene', (76, 81))	('PD-1', 'Gene', '5133', (38, 42))	('LY3415244', 'Chemical', '-', (48, 57))	('TIM-3', 'Gene', '84868', (76, 81))	('clinical', 'Species', '191496', (113, 121))	('PD-L1', 'Gene', (86, 91))	('RO7121661', 'Var', (0, 9))
234023	32158598	In addition, the CAURAL phase III trial evaluating the combination of osimertinib and durvalumab in EGFR T790M positive patients was also prematurely stopped due to safety concerns.	('EGFR', 'Gene', '1956', (100, 104))	('T790M', 'Mutation', 'rs121434569', (105, 110))	('T790M', 'Var', (105, 110))	('EGFR', 'Gene', (100, 104))	('osimertinib', 'Chemical', 'MESH:C000603933', (70, 81))	('patients', 'Species', '9606', (120, 128))	('durvalumab', 'Chemical', 'MESH:C000613593', (86, 96))
234029	32158598	Other interventional strategies are underway to evaluate the combination of ICIs plus chemotherapy in the resistant setting (NCT02864251, NCT03256136, NCT03515837), as well as combination with anti-CD73 therapies (NCT03454451) based on preclinical rationale.	('CD73', 'Gene', (198, 202))	('NCT02864251', 'Var', (125, 136))	('NCT03515837', 'Var', (151, 162))	('NCT03454451', 'Var', (214, 225))	('NCT03256136', 'Var', (138, 149))	('clinical', 'Species', '191496', (239, 247))	('CD73', 'Gene', '4907', (198, 202))
234047	32158598	There is an emerging evidence that PD-1/PD-L1 inhibitors can lead to hyperprogressive disease (HPD), similar to a flare-up of tumor growth leading to dismal outcome.	('inhibitors', 'Var', (46, 56))	('lead to', 'Reg', (61, 68))	('HPD', 'Disease', (95, 98))	('PD-L1', 'Gene', (40, 45))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('hyperprogressive disease', 'Disease', (69, 93))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('HPD', 'Disease', 'MESH:D030342', (95, 98))	('hyperprogressive disease', 'Disease', 'MESH:D030342', (69, 93))	('PD-L1', 'Gene', '29126', (40, 45))	('PD-1', 'Gene', (35, 39))	('PD-1', 'Gene', '5133', (35, 39))	('tumor', 'Disease', (126, 131))
234051	32158598	In another analysis, genomic alterations in genes such as EGFR, MDM2/4 and DNMT3A were associated with HPD.	('genomic alterations', 'Var', (21, 40))	('EGFR', 'Gene', '1956', (58, 62))	('MDM2', 'Gene', '4193', (64, 68))	('DNMT3A', 'Gene', (75, 81))	('MDM2', 'Gene', (64, 68))	('DNMT3A', 'Gene', '1788', (75, 81))	('EGFR', 'Gene', (58, 62))	('HPD', 'Disease', 'MESH:D030342', (103, 106))	('associated', 'Reg', (87, 97))	('HPD', 'Disease', (103, 106))
234058	32158598	ABCP atezolizumab, bevacizumab, carboplatin, and paclitaxel AE adverse event CI confidence interval HPD hyperprogressive disease HR hazard ratio ICI immune checkpoint inhibitor irAE immune-related adverse event LAG-3 lymphocyte-activation gene-3 NSCLC non-small-cell lung cancer ORR objective response rate OS overall survival PFS progression free survival TIM-3 T cell immunoglobulin- and mucin-domain-containing module 3 TKI tyrosine kinase inhibitor TMB tumor mutational burden	('lung cancer', 'Phenotype', 'HP:0100526', (267, 278))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (256, 278))	('tumor', 'Disease', (457, 462))	('TIM-3', 'Gene', '84868', (357, 362))	('cancer', 'Phenotype', 'HP:0002664', (272, 278))	('LAG-3', 'Gene', (211, 216))	('tyrosine', 'Chemical', 'MESH:D014443', (427, 435))	('NSCLC', 'Disease', (246, 251))	('tumor', 'Disease', 'MESH:D009369', (457, 462))	('mutational', 'Var', (463, 473))	('TIM-3', 'Gene', (357, 362))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (252, 278))	('hyperprogressive disease', 'Disease', (104, 128))	('carboplatin', 'Chemical', 'MESH:D016190', (32, 43))	('tumor', 'Phenotype', 'HP:0002664', (457, 462))	('TMB', 'Gene', (453, 456))	('paclitaxel', 'Chemical', 'MESH:D017239', (49, 59))	('bevacizumab', 'Chemical', 'MESH:D000068258', (19, 30))	('BCP', 'Chemical', '-', (1, 4))	('LAG-3', 'Gene', '3902', (211, 216))	('HPD', 'Disease', (100, 103))	('non-small-cell lung cancer', 'Disease', 'MESH:D002289', (252, 278))	('atezolizumab', 'Chemical', 'MESH:C000594389', (5, 17))	('non-small-cell lung cancer', 'Disease', (252, 278))	('T cell immunoglobulin- and mucin-domain-containing module 3', 'Gene', '84868', (363, 422))	('HPD', 'Disease', 'MESH:D030342', (100, 103))	('OS', 'Chemical', '-', (307, 309))	('TMB', 'Chemical', '-', (453, 456))	('hyperprogressive disease', 'Disease', 'MESH:D030342', (104, 128))	('lymphocyte-activation gene-3', 'Gene', (217, 245))	('NSCLC', 'Disease', 'MESH:D002289', (246, 251))	('lymphocyte-activation gene-3', 'Gene', '3902', (217, 245))
234066	31114375	Moreover, ectopic expression of FRMPD1 significantly inhibited the proliferation and invasion of lung cancer cells, and inhibition of FRMPD1 expression led to opposite effects.	('FRMPD1', 'Gene', '22844', (134, 140))	('invasion of', 'CPA', (85, 96))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('inhibited', 'NegReg', (53, 62))	('lung cancer', 'Disease', 'MESH:D008175', (97, 108))	('FRMPD1', 'Gene', (32, 38))	('inhibition', 'NegReg', (120, 130))	('FRMPD1', 'Gene', (134, 140))	('ectopic expression', 'Var', (10, 28))	('lung cancer', 'Disease', (97, 108))	('lung cancer', 'Phenotype', 'HP:0100526', (97, 108))	('FRMPD1', 'Gene', '22844', (32, 38))
234082	31114375	The main domains include the FERM domain (Leu177-Phe401) and the PDZ domain (Gln67-Thr135).	('Leu177', 'Chemical', '-', (42, 48))	('Phe401', 'Chemical', '-', (49, 55))	('Thr135', 'Chemical', '-', (83, 89))	('FERM', 'Gene', '105369245', (29, 33))	('FERM', 'Gene', (29, 33))	('Gln67', 'Chemical', '-', (77, 82))	('Leu177-Phe401', 'Var', (42, 55))	('Gln67-Thr135', 'Var', (77, 89))
234091	31114375	Finally, we generated mutants of FRMPD1 and WWC3 to detect whether FRMPD1 interacts with WWC3 through its corresponding domains.	('WWC3', 'Gene', '55841', (89, 93))	('WWC3', 'Gene', (44, 48))	('FRMPD1', 'Gene', (33, 39))	('FRMPD1', 'Gene', (67, 73))	('WWC3', 'Gene', '55841', (44, 48))	('WWC3', 'Gene', (89, 93))	('mutants', 'Var', (22, 29))	('FRMPD1', 'Gene', '22844', (33, 39))	('FRMPD1', 'Gene', '22844', (67, 73))
234125	31114375	Four-week-old female BALB/c nude mice were purchased from Charles River (Beijing, China), and the axilla or tail vein of each mouse was subcutaneously or intravenously inoculated with 5x106 or 2x106 tumor cells, respectively, in 0.2 mL of sterile PBS.	('tumor', 'Disease', (199, 204))	('mouse', 'Species', '10090', (126, 131))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('nude mice', 'Species', '10090', (28, 37))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('5x106', 'Var', (184, 189))
234137	31114375	In addition, Kaplan-Meier survival analysis showed that patients with FRMPD1 positive expression (49.540 months +-3.044) survived significantly longer than those (28.178 months +-1.263) with negative expression (P<0.001, Figure 1D).	('FRMPD1', 'Gene', (70, 76))	('patients', 'Species', '9606', (56, 64))	('positive expression', 'Var', (77, 96))	('longer', 'PosReg', (144, 150))	('FRMPD1', 'Gene', '22844', (70, 76))
234142	31114375	To further explore the effects of FRMPD1 on the malignant phenotype of lung cancer cells, we first transfected FRMPD1 into H1299 and H460 cell lines with low expression of FRMPD1, and then carried out colony formation, MTT viability, and Transwell invasion assays.	('H460', 'CellLine', 'CVCL:0459', (133, 137))	('FRMPD1', 'Gene', (111, 117))	('colony formation', 'CPA', (201, 217))	('FRMPD1', 'Gene', '22844', (34, 40))	('lung cancer', 'Disease', 'MESH:D008175', (71, 82))	('lung cancer', 'Phenotype', 'HP:0100526', (71, 82))	('FRMPD1', 'Gene', '22844', (172, 178))	('MTT viability', 'CPA', (219, 232))	('H1299', 'CellLine', 'CVCL:0060', (123, 128))	('FRMPD1', 'Gene', '22844', (111, 117))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('MTT', 'Chemical', 'MESH:C070243', (219, 222))	('Transwell invasion assays', 'CPA', (238, 263))	('transfected', 'Var', (99, 110))	('FRMPD1', 'Gene', (34, 40))	('lung cancer', 'Disease', (71, 82))	('FRMPD1', 'Gene', (172, 178))
234154	31114375	In contrast, the phosphorylation of LATS1 and YAP was decreased; furthermore, the luciferase activity of YAP-TEAD and the expression levels of CTGF and CyclinE in the nucleus of the Hippo pathway were enhanced after silencing of FRMPD1 in A549 and LK2 (Figure 3; Figure S3).	('YAP', 'Gene', '10413', (46, 49))	('YAP', 'Gene', '10413', (105, 108))	('activity', 'MPA', (93, 101))	('A549', 'CellLine', 'CVCL:0023', (239, 243))	('phosphorylation', 'MPA', (17, 32))	('LATS1', 'Gene', (36, 41))	('luciferase', 'Enzyme', (82, 92))	('LATS1', 'Gene', '9113', (36, 41))	('YAP', 'Gene', (46, 49))	('Hippo pathway', 'Pathway', (182, 195))	('YAP', 'Gene', (105, 108))	('FRMPD1', 'Gene', (229, 235))	('enhanced', 'PosReg', (201, 209))	('CTGF', 'Gene', '1490', (143, 147))	('CTGF', 'Gene', (143, 147))	('FRMPD1', 'Gene', '22844', (229, 235))	('expression levels', 'MPA', (122, 139))	('silencing', 'Var', (216, 225))
234155	31114375	In H1299 cell lines, transfection of FRMPD1 inhibited the nuclear translocation of YAP, as demonstrated by nucleus-cytoplasm isolation and immunofluorescence (Figure 3C and D).	('YAP', 'Gene', '10413', (83, 86))	('nuclear translocation', 'MPA', (58, 79))	('YAP', 'Gene', (83, 86))	('inhibited', 'NegReg', (44, 53))	('transfection', 'Var', (21, 33))	('FRMPD1', 'Gene', (37, 43))	('H1299', 'CellLine', 'CVCL:0060', (3, 8))	('FRMPD1', 'Gene', '22844', (37, 43))
234156	31114375	In A549 cells, silencing of FRMPD1 promoted the nuclear translocation of YAP (Figure 3E and F).	('FRMPD1', 'Gene', (28, 34))	('YAP', 'Gene', '10413', (73, 76))	('A549', 'CellLine', 'CVCL:0023', (3, 7))	('nuclear translocation', 'MPA', (48, 69))	('YAP', 'Gene', (73, 76))	('FRMPD1', 'Gene', '22844', (28, 34))	('silencing', 'Var', (15, 24))	('promoted', 'PosReg', (35, 43))
234161	31114375	To determine the binding sites involved in the interactions between FRMPD1 and WWC3, we next constructed a series of FRMPD1 (MYC-FRMPD1-DeltaPDZ) and WWC3 (GFP-WWC3-DeltaADDV) mutant plasmids (Figure 4C).	('FRMPD1', 'Gene', (117, 123))	('GFP-WWC3-DeltaADDV', 'Gene', (156, 174))	('FRMPD1', 'Gene', '22844', (129, 135))	('WWC3', 'Gene', '55841', (79, 83))	('FRMPD1', 'Gene', '22844', (68, 74))	('mutant', 'Var', (176, 182))	('WWC3', 'Gene', '55841', (150, 154))	('FRMPD1', 'Gene', '22844', (117, 123))	('WWC3', 'Gene', (150, 154))	('WWC3', 'Gene', '55841', (160, 164))	('MYC-FRMPD1-DeltaPDZ', 'Gene', (125, 144))	('MYC-FRMPD1-DeltaPDZ', 'Gene', '22844', (125, 144))	('WWC3', 'Gene', (79, 83))	('FRMPD1', 'Gene', (129, 135))	('FRMPD1', 'Gene', (68, 74))	('GFP-WWC3-DeltaADDV', 'Gene', '55841', (156, 174))	('WWC3', 'Gene', (160, 164))
234166	31114375	To answer this question, first we co-transfected wild-type WWC3 and FRMPD1 and their mutants into a H1299 cell line exhibiting low expression of WWC3, as demonstrated in our previous work.	('WWC3', 'Gene', (145, 149))	('FRMPD1', 'Gene', '22844', (68, 74))	('WWC3', 'Gene', (59, 63))	('WWC3', 'Gene', '55841', (59, 63))	('WWC3', 'Gene', '55841', (145, 149))	('mutants', 'Var', (85, 92))	('FRMPD1', 'Gene', (68, 74))	('H1299', 'CellLine', 'CVCL:0060', (100, 105))
234167	31114375	Through a luciferase reporter and WB assays, we found that wild-type FRMPD1 interacted with WWC3 to promote the activity of the Hippo pathway (through downregulation of YAP-TEAD transcriptional activity) and to upregulate the phosphorylation levels of LATS1 and YAP; however, the absence of a PDZ domain in FRMPD1, which hindered the interaction with WWC3, abrogated these effects (Figure 5A and B).	('absence', 'Var', (280, 287))	('YAP', 'Gene', (262, 265))	('phosphorylation levels', 'MPA', (226, 248))	('downregulation', 'NegReg', (151, 165))	('WWC3', 'Gene', '55841', (92, 96))	('activity', 'MPA', (112, 120))	('abrogated', 'NegReg', (357, 366))	('FRMPD1', 'Gene', (69, 75))	('FRMPD1', 'Gene', (307, 313))	('WWC3', 'Gene', (92, 96))	('FRMPD1', 'Gene', '22844', (69, 75))	('FRMPD1', 'Gene', '22844', (307, 313))	('YAP', 'Gene', '10413', (262, 265))	('upregulate', 'PosReg', (211, 221))	('WWC3', 'Gene', '55841', (351, 355))	('YAP', 'Gene', (169, 172))	('promote', 'PosReg', (100, 107))	('WWC3', 'Gene', (351, 355))	('Hippo pathway', 'Pathway', (128, 141))	('LATS1', 'Gene', (252, 257))	('LATS1', 'Gene', '9113', (252, 257))	('YAP', 'Gene', '10413', (169, 172))
234169	31114375	Finally, we transfected the FRMPD1 plasmid into A549 cells with relatively high WWC3 expression and knocked down WWC3 using siRNA.	('WWC3', 'Gene', (80, 84))	('FRMPD1', 'Gene', (28, 34))	('WWC3', 'Gene', (113, 117))	('A549', 'CellLine', 'CVCL:0023', (48, 52))	('FRMPD1', 'Gene', '22844', (28, 34))	('WWC3', 'Gene', '55841', (80, 84))	('WWC3', 'Gene', '55841', (113, 117))	('knocked', 'Var', (100, 107))
234183	31114375	The possibility of methylation or mutation of the FRMPD1 gene or metabolic enhancement in lung cancer cells needs to be explored and verified in subsequent experiments.	('lung cancer', 'Disease', 'MESH:D008175', (90, 101))	('mutation', 'Var', (34, 42))	('lung cancer', 'Disease', (90, 101))	('lung cancer', 'Phenotype', 'HP:0100526', (90, 101))	('FRMPD1', 'Gene', (50, 56))	('FRMPD1', 'Gene', '22844', (50, 56))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))
234189	31114375	We found that there were no significant changes in the activity of the Hippo pathway, phosphorylation index, and expression levels of target genes after transfection of FRMPD1 and silencing of WWC3, and that the transfection of FRMPD1-DeltaPDZ (which could not bind to WWC3) did not stimulate the Hippo pathway.	('WWC3', 'Gene', (269, 273))	('activity', 'MPA', (55, 63))	('phosphorylation index', 'MPA', (86, 107))	('Hippo pathway', 'Pathway', (71, 84))	('Hippo pathway', 'Pathway', (297, 310))	('FRMPD1', 'Gene', (169, 175))	('FRMPD1', 'Gene', (228, 234))	('silencing', 'Var', (180, 189))	('WWC3', 'Gene', '55841', (193, 197))	('WWC3', 'Gene', '55841', (269, 273))	('expression levels', 'MPA', (113, 130))	('FRMPD1', 'Gene', '22844', (169, 175))	('FRMPD1', 'Gene', '22844', (228, 234))	('WWC3', 'Gene', (193, 197))
234191	31114375	For example, LATS1/2 deletion unmasks a malignant cell's immunogenic potential and retains tumor growth due to the induction of anti-tumor immune responses.	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('retains', 'PosReg', (83, 90))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('deletion', 'Var', (21, 29))	('immunogenic potential', 'CPA', (57, 78))	('LATS1', 'Gene', (13, 18))	('unmasks', 'PosReg', (30, 37))	('LATS1', 'Gene', '9113', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor', 'Disease', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumor', 'Disease', (91, 96))
234311	29926557	However, in patients with granulomatous disease such as sarcoidosis, concurrent infectious and inflammatory disease such as tuberculosis, pneumonia and interstitial lung disease (ILD), PET-CT has been shown to increase the rates of false-positive malignancy in mediastinal lymph nodes.	('pneumonia', 'Disease', 'MESH:D011014', (138, 147))	('interstitial lung disease', 'Phenotype', 'HP:0006530', (152, 177))	('malignancy', 'Disease', (247, 257))	('tuberculosis', 'Disease', 'MESH:D014376', (124, 136))	('granulomatous disease', 'Disease', (26, 47))	('interstitial lung disease', 'Disease', 'MESH:D017563', (152, 177))	('sarcoidosis', 'Disease', 'MESH:D012507', (56, 67))	('interstitial lung disease', 'Disease', (152, 177))	('tuberculosis', 'Disease', (124, 136))	('pneumonia', 'Disease', (138, 147))	('patients', 'Species', '9606', (12, 20))	('sarcoidosis', 'Disease', (56, 67))	('PET-CT', 'Var', (185, 191))	('ILD', 'Phenotype', 'HP:0006530', (179, 182))	('lung disease', 'Phenotype', 'HP:0002088', (165, 177))	('granulomatous disease', 'Disease', 'MESH:D006105', (26, 47))	('malignancy', 'Disease', 'MESH:D009369', (247, 257))	('malignancy in mediastinal lymph nodes', 'Phenotype', 'HP:0100721', (247, 284))	('granulomatous disease', 'Phenotype', 'HP:0002955', (26, 47))	('pneumonia', 'Phenotype', 'HP:0002090', (138, 147))
234376	27809802	The ECM metagene was associated with poor prognosis in renal clear cell carcinoma and in lung adenocarcinoma but not in other cancers investigated.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (89, 108))	('ECM metagene', 'Var', (4, 16))	('renal clear cell carcinoma', 'Disease', 'MESH:C538614', (55, 81))	('cancers', 'Phenotype', 'HP:0002664', (126, 133))	('cancers', 'Disease', (126, 133))	('renal clear cell carcinoma', 'Disease', (55, 81))	('cancers', 'Disease', 'MESH:D009369', (126, 133))	('lung adenocarcinoma', 'Disease', (89, 108))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (89, 108))
234477	27809802	Kidney renal clear cell carcinomas are frequently highly vascularized due to deletion or inactivation of the VHL suppressor gene which results in upregulation of hypoxia-inducible factors and angiogenic factors such as VEGF.	('VEGF', 'Gene', (219, 223))	('inactivation', 'Var', (89, 101))	('upregulation', 'PosReg', (146, 158))	('Kidney renal clear cell carcinomas', 'Disease', 'MESH:C538614', (0, 34))	('hypoxia', 'Disease', 'MESH:D000860', (162, 169))	('VHL', 'Gene', (109, 112))	('VEGF', 'Gene', '7422', (219, 223))	('deletion', 'Var', (77, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (24, 33))	('Kidney renal clear cell carcinomas', 'Disease', (0, 34))	('VHL', 'Gene', '7428', (109, 112))	('hypoxia', 'Disease', (162, 169))	('carcinomas', 'Phenotype', 'HP:0030731', (24, 34))
234495	27809802	This may be somewhat counterintuitive given the vast number of reports that have linked beta-catenin/TCF with oncogenic effects following the discovery of Tcf as a component in the mediation of malignancy induced by APC deletion.	('APC', 'Disease', 'MESH:D011125', (216, 219))	('malignancy', 'Disease', 'MESH:D009369', (194, 204))	('APC', 'Disease', (216, 219))	('Tcf', 'Gene', (155, 158))	('deletion', 'Var', (220, 228))	('beta-catenin', 'Gene', (88, 100))	('TCF', 'Gene', (101, 104))	('malignancy', 'Disease', (194, 204))	('Tcf', 'Gene', '3172', (155, 158))	('TCF', 'Gene', '3172', (101, 104))	('beta-catenin', 'Gene', '1499', (88, 100))
234529	27398181	Abnormalities of TJ permeability allow increased diffusion of factors that promote tumor growth.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('promote', 'PosReg', (75, 82))	('Abnormalities', 'Var', (0, 13))	('tumor', 'Disease', (83, 88))	('increased', 'PosReg', (39, 48))	('diffusion of factors', 'MPA', (49, 69))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
234530	27398181	Moreover, changes in TJs have been noted as an early event in tumor metastasis.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('TJs', 'Gene', (21, 24))	('tumor metastasis', 'Disease', 'MESH:D009362', (62, 78))	('tumor metastasis', 'Disease', (62, 78))	('changes', 'Var', (10, 17))
234537	27398181	It has been suggested that a possible mechanism for this is that up-regulation and/or aberrant tissue expression of claudins may directly interfere with TJ formation and function and thereby contribute to neoplasia.	('tissue', 'CPA', (95, 101))	('contribute', 'Reg', (191, 201))	('neoplasia', 'Disease', (205, 214))	('TJ formation', 'CPA', (153, 165))	('claudins', 'Gene', (116, 124))	('aberrant', 'Var', (86, 94))	('neoplasia', 'Disease', 'MESH:D009369', (205, 214))	('function', 'CPA', (170, 178))	('interfere', 'NegReg', (138, 147))	('neoplasia', 'Phenotype', 'HP:0002664', (205, 214))	('up-regulation', 'PosReg', (65, 78))
234560	27398181	For analytical statistical analysis, the clinico-pathologic features were grouped as following: age below or above 65 year-old (the mean age of patients); tumor size (T1-T2 and T2-T4); early TNM stage (I, II) or late TNM stages (III, IV); microscopically well differentiated or moderately/poorly differentiated; the presence of perineural invasion and vascular invasion, local recurrence, regional lymph node involvement and distant metastasis.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('TNM', 'Gene', (191, 194))	('T1-T2', 'Var', (167, 172))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('regional lymph node involvement', 'CPA', (389, 420))	('local recurrence', 'CPA', (371, 387))	('TNM', 'Gene', '10178', (217, 220))	('T2-T4', 'Var', (177, 182))	('tumor', 'Disease', (155, 160))	('microscopically well differentiated', 'CPA', (239, 274))	('vascular invasion', 'CPA', (352, 369))	('patients', 'Species', '9606', (144, 152))	('perineural invasion', 'CPA', (328, 347))	('TNM', 'Gene', '10178', (191, 194))	('TNM', 'Gene', (217, 220))	('distant metastasis', 'CPA', (425, 443))
234595	27398181	Nevertheless, in some studies high claudin-7 expression was significantly associated with a poorer prognosis of the patients with gastric cancer which did not correspond with our study.	('patients', 'Species', '9606', (116, 124))	('gastric cancer', 'Disease', (130, 144))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('high', 'Var', (30, 34))	('expression', 'MPA', (45, 55))	('claudin-7', 'Protein', (35, 44))	('gastric cancer', 'Disease', 'MESH:D013274', (130, 144))	('gastric cancer', 'Phenotype', 'HP:0012126', (130, 144))
234620	32838739	K-means and Spectral Clustering techniques; LRACluster: It is a low-rank approximation based integrative probabilistic model to fast find the shared principal subspace across multiple data types; PINS: Perturbation clustering for data integration and disease subtyping (PINS) is able to address subtype discovery, as well as integration of multiple data types.	('Perturbation', 'Var', (202, 214))	('PINS', 'Gene', (270, 274))	('PINS', 'Gene', '29899', (196, 200))	('PINS', 'Gene', (196, 200))	('PINS', 'Gene', '29899', (270, 274))
234645	32020821	Additionally, mutations in the CDK1 gene were analyzed by using the cBioPortal database.	('CDK1', 'Gene', '983', (31, 35))	('mutations', 'Var', (14, 23))	('CDK1', 'Gene', (31, 35))
234656	32020821	Unrestricted cell proliferation, an indicator of malignancy, is normally driven by alterations in CDK1 activity.	('Unrestricted cell proliferation', 'CPA', (0, 31))	('alterations', 'Var', (83, 94))	('activity', 'MPA', (103, 111))	('malignancy', 'Disease', 'MESH:D009369', (49, 59))	('CDK1', 'Gene', (98, 102))	('malignancy', 'Disease', (49, 59))	('CDK1', 'Gene', '983', (98, 102))
234690	32020821	We also analyzed expression of CDK1 with tumor stage for lung adenocarcinoma and squamous cell lung carcinoma; expression of CDK1 was positively and highly associated (P < 0.05) with advanced cancer stages (Figure 2c).	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('advanced', 'CPA', (183, 191))	('cancer', 'Disease', (192, 198))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('lung adenocarcinoma', 'Disease', (57, 76))	('squamous cell lung carcinoma', 'Phenotype', 'HP:0030359', (81, 109))	('tumor', 'Disease', (41, 46))	('cancer', 'Disease', 'MESH:D009369', (192, 198))	('associated', 'Reg', (156, 166))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (57, 76))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('expression', 'Var', (111, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('squamous cell lung carcinoma', 'Disease', (81, 109))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (57, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('CDK1', 'Gene', (31, 35))	('CDK1', 'Gene', '983', (125, 129))	('CDK1', 'Gene', '983', (31, 35))	('CDK1', 'Gene', (125, 129))	('squamous cell lung carcinoma', 'Disease', 'MESH:D002294', (81, 109))
234697	32020821	cBioPortal provides the frequency of alteration of CDK1 mutations in LC.	('CDK1', 'Gene', (51, 55))	('mutations', 'Var', (56, 65))	('LC', 'Phenotype', 'HP:0100526', (69, 71))	('CDK1', 'Gene', '983', (51, 55))
234699	32020821	CDK1 gene alteration was detected in 1.99% of 502 LUSC patients and 1.16% of 516 LUAD patients (Figure 4b).	('LUAD', 'Phenotype', 'HP:0030078', (81, 85))	('LUSC', 'Phenotype', 'HP:0030359', (50, 54))	('CDK1', 'Gene', (0, 4))	('CDK1', 'Gene', '983', (0, 4))	('patients', 'Species', '9606', (55, 63))	('detected', 'Reg', (25, 33))	('alteration', 'Var', (10, 20))	('patients', 'Species', '9606', (86, 94))
234723	32020821	Kaplan-Meier plots indicated that CDK1 levels were linked to poorer OS, FP, and PPS, in line with an oncogenic role for CDK1.	('CDK1', 'Gene', (120, 124))	('poorer', 'Disease', (61, 67))	('PPS', 'Disease', (80, 83))	('CDK1', 'Gene', '983', (120, 124))	('PPS', 'Disease', 'MESH:C562509', (80, 83))	('CDK1', 'Gene', (34, 38))	('CDK1', 'Gene', '983', (34, 38))	('levels', 'Var', (39, 45))
234729	29622463	In 10,522 cancer genomes from The Cancer Genome Atlas (TCGA), aneuploidy was correlated with TP53 mutation, somatic mutation rate, and expression of proliferation genes.	('aneuploidy', 'Disease', (62, 72))	('mutation', 'Var', (98, 106))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('Cancer', 'Phenotype', 'HP:0002664', (34, 40))	('TP53', 'Gene', '7157', (93, 97))	('TP53', 'Gene', (93, 97))	('Cancer Genome Atlas', 'Disease', (34, 53))	('p', 'Gene', '619493', (137, 138))	('aneuploidy', 'Disease', 'MESH:D000782', (62, 72))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (34, 53))	('cancer', 'Disease', 'MESH:D009369', (10, 16))	('p', 'Gene', '619493', (66, 67))	('cancer', 'Disease', (10, 16))	('p', 'Gene', '619493', (149, 150))
234732	29622463	We applied genome engineering to delete 3p in lung cells, causing decreased proliferation rescued in part by chromosome 3 duplication.	('decreased', 'NegReg', (66, 75))	('delete', 'Var', (33, 39))	('p', 'Gene', '619493', (101, 102))	('p', 'Gene', '619493', (5, 6))	('p', 'Gene', '619493', (4, 5))	('chromosome', 'Var', (109, 119))	('p', 'Gene', '619493', (41, 42))	('p', 'Gene', '619493', (76, 77))	('p', 'Gene', '619493', (124, 125))
234742	29622463	Chromosome arm SCNAs are more common than whole chromosome SCNAs, occurring at higher frequencies in 12 of 16 cancer types analyzed.	('cancer', 'Disease', (110, 116))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('p', 'Gene', '619493', (119, 120))	('Chromosome arm', 'Var', (0, 14))	('cancer', 'Disease', 'MESH:D009369', (110, 116))
234743	29622463	Cancer subtypes are often characterized by tumor-specific patterns of chromosomal arm-level alterations, including squamous subtypes of lung, esophageal, and bladder tumors.	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('alterations', 'Var', (92, 103))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('bladder tumors', 'Disease', (158, 172))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))	('tumor', 'Disease', (43, 48))	('lung', 'Disease', (136, 140))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('bladder tumors', 'Phenotype', 'HP:0009725', (158, 172))	('p', 'Gene', '619493', (12, 13))	('tumor', 'Disease', (166, 171))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('p', 'Gene', '619493', (58, 59))	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('p', 'Gene', '619493', (145, 146))	('p', 'Gene', '619493', (50, 51))	('bladder tumors', 'Disease', 'MESH:D001749', (158, 172))	('Cancer', 'Disease', (0, 6))	('p', 'Gene', '619493', (129, 130))
234744	29622463	Specific chromosome arm level alterations have also defined groups of tumors that are responsive to particular therapies, such as low grade gliomas with 1p/19q co-deletions that have been shown to be responsive to specific chemoradiotherapy regimens.	('glioma', 'Phenotype', 'HP:0009733', (140, 146))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('p', 'Gene', '619493', (238, 239))	('p', 'Gene', '619493', (1, 2))	('p', 'Gene', '619493', (215, 216))	('p', 'Gene', '619493', (116, 117))	('p', 'Gene', '619493', (64, 65))	('tumors', 'Disease', (70, 76))	('p', 'Gene', '619493', (154, 155))	('alterations', 'Var', (30, 41))	('p', 'Gene', '619493', (89, 90))	('tumors', 'Disease', 'MESH:D009369', (70, 76))	('p', 'Gene', '619493', (203, 204))	('gliomas', 'Disease', 'MESH:D005910', (140, 147))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('gliomas', 'Phenotype', 'HP:0009733', (140, 147))	('gliomas', 'Disease', (140, 147))	('p', 'Gene', '619493', (100, 101))
234745	29622463	The functional effect of an individual aneuploidy is often thought to be due to the deletion of a tumor suppressor or overexpression of an oncogene.	('deletion', 'Var', (84, 92))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('aneuploidy', 'Disease', (39, 49))	('p', 'Gene', '619493', (43, 44))	('p', 'Gene', '619493', (106, 107))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('p', 'Gene', '619493', (124, 125))	('tumor', 'Disease', (98, 103))	('aneuploidy', 'Disease', 'MESH:D000782', (39, 49))	('p', 'Gene', '619493', (107, 108))
234749	29622463	Trisomies and monosomies have been extensively modeled in yeast, where they slow proliferation and induce proteosomal stress.	('Trisomies', 'Var', (0, 9))	('p', 'Gene', '619493', (106, 107))	('p', 'Gene', '619493', (81, 82))	('yeast', 'Species', '4932', (58, 63))	('slow', 'NegReg', (76, 80))	('induce', 'Reg', (99, 105))	('monosomies', 'Var', (14, 24))
234757	29622463	By combining analysis of highly annotated cancer genomes and the experimental ability to manipulate chromosomes, we can advance our understanding of the effects of aneuploidy and specific chromosome arm-level alterations in cancer development and progression.	('p', 'Gene', '619493', (180, 181))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('aneuploidy', 'Disease', 'MESH:D000782', (164, 174))	('p', 'Gene', '619493', (67, 68))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('p', 'Gene', '619493', (93, 94))	('p', 'Gene', '619493', (237, 238))	('cancer', 'Disease', 'MESH:D009369', (224, 230))	('p', 'Gene', '619493', (168, 169))	('alterations', 'Var', (209, 220))	('cancer', 'Disease', (224, 230))	('p', 'Gene', '619493', (247, 248))	('aneuploidy', 'Disease', (164, 174))
234780	29622463	To assess whether gene mutations are associated with aneuploidy, we used a multivariable linear regression model that accounts for cancer type and the number of mutations per sample.	('cancer', 'Disease', (131, 137))	('p', 'Gene', '619493', (57, 58))	('p', 'Gene', '619493', (171, 172))	('aneuploidy', 'Disease', (53, 63))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('mutations', 'Var', (23, 32))	('p', 'Gene', '619493', (140, 141))	('p', 'Gene', '619493', (178, 179))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('aneuploidy', 'Disease', 'MESH:D000782', (53, 63))
234781	29622463	In this analysis, TP53 was an outlier, with the highest coefficient in the linear model (towards enrichment of mutations among aneuploid samples) and the highest statistical significance (Figure 2A, Table S3), consistent with previous studies.	('mutations', 'Var', (111, 120))	('p', 'Gene', '619493', (131, 132))	('TP53', 'Gene', '7157', (18, 22))	('TP53', 'Gene', (18, 22))	('p', 'Gene', '619493', (226, 227))	('p', 'Gene', '619493', (140, 141))
234782	29622463	We also detected significant associations between aneuploidy and mutation rate for 34 other genes.	('aneuploidy', 'Disease', (50, 60))	('mutation', 'Var', (65, 73))	('aneuploidy', 'Disease', 'MESH:D000782', (50, 60))
234783	29622463	However, the correlation coefficients for these genes were always negative (towards enrichment of mutations in low aneuploidy samples) and never exceeded a magnitude of 0.027, whereas the coefficient for TP53 was positive 0.13.	('aneuploidy', 'Disease', (115, 125))	('mutations', 'Var', (98, 107))	('TP53', 'Gene', '7157', (204, 208))	('p', 'Gene', '619493', (129, 130))	('p', 'Gene', '619493', (213, 214))	('negative', 'NegReg', (66, 74))	('p', 'Gene', '619493', (119, 120))	('aneuploidy', 'Disease', 'MESH:D000782', (115, 125))	('TP53', 'Gene', (204, 208))	('correlation', 'MPA', (13, 24))
234787	29622463	In contrast, when these hypermutated tumors are excluded, we observed a positive correlation between mutation frequency and aneuploidy score (Spearman's rank correlation coefficient = 0.38), as well as between recurrent SCNAs and recurrent mutations (Spearman's rank correlation coefficient = 0.34).	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('SCNAs', 'Disease', (220, 225))	('p', 'Gene', '619493', (128, 129))	('aneuploidy', 'Disease', (124, 134))	('p', 'Gene', '619493', (26, 27))	('p', 'Gene', '619493', (252, 253))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumors', 'Disease', (37, 43))	('p', 'Gene', '619493', (143, 144))	('aneuploidy', 'Disease', 'MESH:D000782', (124, 134))	('mutation', 'Var', (101, 109))	('p', 'Gene', '619493', (72, 73))	('recurrent SCNAs', 'Phenotype', 'HP:0100776', (210, 225))	('mutations', 'Var', (240, 249))	('tumors', 'Disease', 'MESH:D009369', (37, 43))
234788	29622463	The positive correlation between mutation and aneuploidy was found in most cancer types with the notable exceptions of colorectal carcinoma (COAD and READ) and uterine carcinoma (UCEC and UCS) as well as uveal melanoma (UVM) and stomach adenocarcinoma (STAD) (Figure 2C, Table S4).	('uveal melanoma', 'Phenotype', 'HP:0007716', (204, 218))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('COAD', 'Disease', 'MESH:D029424', (141, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (168, 177))	('p', 'Gene', '619493', (84, 85))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('carcinoma', 'Disease', (168, 177))	('p', 'Gene', '619493', (109, 110))	('carcinoma', 'Disease', 'MESH:D002277', (242, 251))	('stomach adenocarcinoma', 'Disease', (229, 251))	('carcinoma', 'Disease', 'MESH:D002277', (130, 139))	('p', 'Gene', '619493', (4, 5))	('aneuploidy', 'Disease', 'MESH:D000782', (46, 56))	('mutation', 'Var', (33, 41))	('COAD', 'Disease', (141, 145))	('carcinoma', 'Disease', 'MESH:D002277', (168, 177))	('melanoma', 'Phenotype', 'HP:0002861', (210, 218))	('uveal melanoma', 'Disease', 'MESH:C536494', (204, 218))	('stomach adenocarcinoma', 'Disease', 'MESH:D013274', (229, 251))	('p', 'Gene', '619493', (50, 51))	('carcinoma', 'Phenotype', 'HP:0030731', (242, 251))	('uveal melanoma', 'Disease', (204, 218))	('cancer', 'Disease', (75, 81))	('colorectal carcinoma', 'Disease', (119, 139))	('aneuploidy', 'Disease', (46, 56))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('carcinoma', 'Disease', (242, 251))	('uterine carcinoma', 'Phenotype', 'HP:0010784', (160, 177))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (119, 139))	('carcinoma', 'Disease', (130, 139))
234789	29622463	All of these exceptions other than uveal melanoma had some cases of microsatellite instability or POLE mutation.	('uveal melanoma', 'Disease', 'MESH:C536494', (35, 49))	('uveal melanoma', 'Disease', (35, 49))	('P', 'Gene', '619493', (98, 99))	('melanoma', 'Phenotype', 'HP:0002861', (41, 49))	('p', 'Gene', '619493', (17, 18))	('microsatellite instability', 'Var', (68, 94))	('uveal melanoma', 'Phenotype', 'HP:0007716', (35, 49))
234799	29622463	However, the measurement of leukocyte fractions based on methylation signatures, as previously described (; TCGA Immune Subgroup, submitted), showed a negative correlation with aneuploidy (Figure 3B, Table S4).	('aneuploidy', 'Disease', 'MESH:D000782', (177, 187))	('methylation', 'Var', (57, 68))	('p', 'Gene', '619493', (84, 85))	('negative', 'NegReg', (151, 159))	('p', 'Gene', '619493', (181, 182))	('aneuploidy', 'Disease', (177, 187))	('p', 'Gene', '619493', (127, 128))
234819	29622463	Chromosome arms 6p, 12q, 17q, and 19q were gained and lost in equal percentages (difference between gain and loss frequency < 0.03), but others were predominantly gained (1q, 7p, 8q, and 20q) or predominantly lost (3p and 17p).	('lost', 'NegReg', (209, 213))	('gained', 'PosReg', (163, 169))	('p', 'Gene', '619493', (68, 69))	('p', 'Gene', '619493', (17, 18))	('p', 'Gene', '619493', (195, 196))	('p', 'Gene', '619493', (224, 225))	('p', 'Gene', '619493', (216, 217))	('1q', 'Var', (171, 173))	('p', 'Gene', '619493', (149, 150))	('p', 'Gene', '619493', (176, 177))	('lost', 'NegReg', (54, 58))
234833	29622463	A dominant feature of the squamous cancer cluster was chromosome arm 3p loss and chromosome arm 3q gain, which is present in cervical squamous cell carcinomas (CESC) and HPV positive head and neck squamous cell carcinomas (HNSC), and strongest in esophageal squamous cell carcinomas (ESCC), lung squamous cell carcinoma (LUSC) and HPV negative HNSC squamous tumors.	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (291, 319))	('lung squamous cell carcinoma', 'Disease', (291, 319))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (197, 221))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('tumor', 'Phenotype', 'HP:0002664', (358, 363))	('squamous cancer', 'Disease', 'MESH:D002294', (26, 41))	('P', 'Gene', '619493', (171, 172))	('p', 'Gene', '619493', (174, 175))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (134, 158))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (134, 157))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (197, 221))	('gain', 'PosReg', (99, 103))	('p', 'Gene', '619493', (70, 71))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (134, 158))	('carcinoma', 'Phenotype', 'HP:0030731', (310, 319))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (197, 220))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (258, 282))	('neck squamous cell carcinomas', 'Disease', (192, 221))	('carcinoma', 'Phenotype', 'HP:0030731', (148, 157))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (183, 220))	('esophageal squamous cell carcinomas', 'Disease', (247, 282))	('esophageal squamous cell carcinomas', 'Disease', 'MESH:D000077277', (247, 282))	('HNSC squamous tumors', 'Disease', 'MESH:D002294', (344, 364))	('p', 'Gene', '619493', (250, 251))	('squamous cell carcinomas', 'Disease', (134, 158))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (258, 282))	('neck squamous cell carcinomas', 'Disease', 'MESH:D000077195', (192, 221))	('head and neck squamous cell carcinomas', 'Phenotype', 'HP:0012288', (183, 221))	('HNSC squamous tumors', 'Disease', (344, 364))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (291, 319))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (296, 319))	('p', 'Gene', '619493', (114, 115))	('loss', 'NegReg', (72, 76))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (258, 281))	('squamous cancer', 'Phenotype', 'HP:0002860', (26, 41))	('carcinomas', 'Phenotype', 'HP:0030731', (148, 158))	('carcinoma', 'Phenotype', 'HP:0030731', (211, 220))	('P', 'Gene', '619493', (332, 333))	('tumors', 'Phenotype', 'HP:0002664', (358, 364))	('carcinomas', 'Phenotype', 'HP:0030731', (211, 221))	('squamous cancer', 'Disease', (26, 41))	('chromosome arm', 'Var', (81, 95))	('cervical', 'Disease', (125, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (272, 281))	('carcinomas', 'Phenotype', 'HP:0030731', (272, 282))
234834	29622463	Chromosome 3 alterations are a known feature of lung squamous cell carcinoma, with chromosome 3p loss present in preneoplastic lesions in the lung.	('loss', 'NegReg', (97, 101))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (48, 76))	('p', 'Gene', '619493', (102, 103))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (53, 76))	('p', 'Gene', '619493', (95, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('Chromosome 3', 'Gene', (0, 12))	('p', 'Gene', '619493', (113, 114))	('p', 'Gene', '619493', (119, 120))	('lung squamous cell carcinoma', 'Disease', (48, 76))	('alterations', 'Var', (13, 24))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (48, 76))
234835	29622463	In our lung squamous cell carcinoma dataset, chromosome 3p was deleted in almost 80% of tumors and chromosome arm 3q was gained in over 60% of tumors (Figure 4B).	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (7, 35))	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('p', 'Gene', '619493', (57, 58))	('gained', 'PosReg', (121, 127))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (12, 35))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (7, 35))	('tumors', 'Disease', (143, 149))	('lung squamous cell carcinoma', 'Disease', (7, 35))	('tumors', 'Disease', 'MESH:D009369', (143, 149))	('deleted', 'Var', (63, 70))	('carcinoma', 'Phenotype', 'HP:0030731', (26, 35))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('tumors', 'Disease', (88, 94))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
234840	29622463	As expected, deletion of 3p correlated with a reduction of 3p gene expression across TCGA samples (Figure S3B).	('p', 'Gene', '619493', (69, 70))	('reduction', 'NegReg', (46, 55))	('p', 'Gene', '619493', (26, 27))	('p', 'Gene', '619493', (60, 61))	('p', 'Gene', '619493', (5, 6))	('deletion', 'Var', (13, 21))	('p', 'Gene', '619493', (93, 94))
234841	29622463	Based on the linear modeling of gene expression, chr_3p alteration negatively correlated with hallmark sets of cell cycle (E2F targets/G2M Checkpoint, Figure S3C, FWER p value < 0.01), epithelial mesenchymal transition, interferon gamma response, and TNFa signaling (Figures S3D and S3E, FWER p value < 0.01).	('p', 'Gene', '619493', (186, 187))	('p', 'Gene', '619493', (293, 294))	('TNFa', 'Gene', (251, 255))	('p', 'Gene', '619493', (39, 40))	('cell cycle', 'CPA', (111, 121))	('p', 'Gene', '619493', (54, 55))	('p', 'Gene', '619493', (240, 241))	('negatively', 'NegReg', (67, 77))	('TNFa', 'Gene', '7124', (251, 255))	('p', 'Gene', '619493', (144, 145))	('alteration', 'Var', (56, 66))	('correlated', 'Reg', (78, 88))	('p', 'Gene', '619493', (168, 169))
234844	29622463	Given the continuing scientific mystery regarding the function of cancer aneuploidy, and given that deletion of chromosome 3p occurs in almost 80% of squamous cell lung cancers, we wanted to further understand the effect of chr_3p deletion in lung epithelial cells.	('p', 'Gene', '619493', (229, 230))	('p', 'Gene', '619493', (249, 250))	('cancer aneuploidy', 'Disease', 'MESH:D000782', (66, 83))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('squamous cell lung cancers', 'Disease', 'MESH:D002294', (150, 176))	('p', 'Gene', '619493', (77, 78))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('cancer aneuploidy', 'Disease', (66, 83))	('squamous cell lung cancers', 'Disease', (150, 176))	('deletion', 'Var', (100, 108))	('lung cancers', 'Phenotype', 'HP:0100526', (164, 176))	('cancers', 'Phenotype', 'HP:0002664', (169, 176))	('p', 'Gene', '619493', (124, 125))
234867	29622463	We conclude that selection of advantageous alterations or expression changes allow chr_3p deleted cells to overcome the negative growth effects of aneuploidy in this model system (Figure 6F).	('p', 'Gene', '619493', (88, 89))	('p', 'Gene', '619493', (60, 61))	('aneuploidy', 'Disease', 'MESH:D000782', (147, 157))	('p', 'Gene', '619493', (151, 152))	('changes', 'Var', (69, 76))	('aneuploidy', 'Disease', (147, 157))
234871	29622463	By calculating aneuploidy level in 10,522 tumors, we uncovered the correlation of aneuploidy with TP53 mutations, overall somatic mutation rate, and proliferative signatures, and an inverse correlation with leukocyte fraction.	('mutations', 'Var', (103, 112))	('aneuploidy', 'Disease', 'MESH:D000782', (82, 92))	('p', 'Gene', '619493', (149, 150))	('aneuploidy', 'Disease', (15, 25))	('tumors', 'Disease', (42, 48))	('tumors', 'Disease', 'MESH:D009369', (42, 48))	('p', 'Gene', '619493', (19, 20))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('TP53', 'Gene', '7157', (98, 102))	('aneuploidy', 'Disease', 'MESH:D000782', (15, 25))	('p', 'Gene', '619493', (86, 87))	('aneuploidy', 'Disease', (82, 92))	('TP53', 'Gene', (98, 102))
234872	29622463	Our analysis revealed expression changes in cell-cycle and immune hallmarks associated with individual chromosome arm-level alterations, independent of aneuploidy level.	('p', 'Gene', '619493', (141, 142))	('changes', 'Reg', (33, 40))	('cell-cycle', 'CPA', (44, 54))	('p', 'Gene', '619493', (156, 157))	('alterations', 'Var', (124, 135))	('aneuploidy', 'Disease', (152, 162))	('p', 'Gene', '619493', (24, 25))	('chromosome', 'Gene', (103, 113))	('aneuploidy', 'Disease', 'MESH:D000782', (152, 162))
234883	29622463	Once MSI tumors are removed, mutation and aneuploidy are positively correlated (consistent with and).	('aneuploidy', 'Disease', (42, 52))	('MSI tumors', 'Disease', (5, 15))	('mutation', 'Var', (29, 37))	('p', 'Gene', '619493', (57, 58))	('aneuploidy', 'Disease', 'MESH:D000782', (42, 52))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('p', 'Gene', '619493', (46, 47))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('MSI tumors', 'Disease', 'MESH:D009369', (5, 15))
234888	29622463	Deletions of some arms, including 3p, 8p, 13q, or 17p, are positively correlated with immune signatures, whereas deletions of other arms, including 4q, 5q, and 14q, are anti-correlated with immune signatures.	('p', 'Gene', '619493', (35, 36))	('p', 'Gene', '619493', (39, 40))	('immune signatures', 'MPA', (86, 103))	('p', 'Gene', '619493', (59, 60))	('p', 'Gene', '619493', (52, 53))	('Deletions', 'Var', (0, 9))	('correlated', 'Reg', (70, 80))
234889	29622463	The distinct correlations of immune signatures with deletion of different arms also suggest that immune signature changes might be due to specific genes or regions within each affected arm rather than to overall aneuploidy.	('aneuploidy', 'Disease', (212, 222))	('p', 'Gene', '619493', (139, 140))	('changes', 'Reg', (114, 121))	('aneuploidy', 'Disease', 'MESH:D000782', (212, 222))	('immune signature', 'MPA', (97, 113))	('p', 'Gene', '619493', (216, 217))	('deletion', 'Var', (52, 60))
234890	29622463	We have developed a method to generate chromosome arm deletions by initiating centromeric DNA breaks with CRISPR/Cas9 to promote replacement of an arm with a selection cassette and an artificial telomere.	('chromosome arm', 'Disease', (39, 53))	('p', 'Gene', '619493', (131, 132))	('P', 'Gene', '619493', (110, 111))	('p', 'Gene', '619493', (14, 15))	('p', 'Gene', '619493', (121, 122))	('deletions', 'Var', (54, 63))
234892	29622463	Consistent with single chromosome aneuploidy models in human cells, chromosome arm-level deletion of human chr_3p has an anti-proliferative effect that cells can overcome with time.	('aneuploidy', 'Disease', 'MESH:D000782', (34, 44))	('p', 'Gene', '619493', (112, 113))	('human', 'Species', '9606', (55, 60))	('human', 'Species', '9606', (101, 106))	('p', 'Gene', '619493', (126, 127))	('deletion', 'Var', (89, 97))	('p', 'Gene', '619493', (38, 39))	('aneuploidy', 'Disease', (34, 44))
234894	29622463	We initially predicted that deletion of chr_3p would not be as anti-proliferative as other aneuploidies, as it is thought to be an early event in lung tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumor', 'Disease', (151, 156))	('p', 'Gene', '619493', (95, 96))	('p', 'Gene', '619493', (68, 69))	('p', 'Gene', '619493', (13, 14))	('deletion', 'Var', (28, 36))	('p', 'Gene', '619493', (45, 46))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
234901	29622463	Our work here begins to analyze expression changes induced by each arm alteration while controlling for overall aneuploidy level and other confounders.	('alteration', 'Var', (71, 81))	('p', 'Gene', '619493', (116, 117))	('p', 'Gene', '619493', (34, 35))	('aneuploidy', 'Disease', (112, 122))	('aneuploidy', 'Disease', 'MESH:D000782', (112, 122))
234909	29622463	In the case of oncogenic mutations, overexpression in model systems often leads to oncogene-induced senescence; individual aneuploidies may elicit a similar response.	('mutations', 'Var', (25, 34))	('elicit', 'Reg', (140, 146))	('p', 'Gene', '619493', (160, 161))	('p', 'Gene', '619493', (42, 43))	('leads to', 'Reg', (74, 82))	('p', 'Gene', '619493', (127, 128))	('oncogene-induced senescence', 'MPA', (83, 110))
234922	29622463	For amplifications and deletions separately (collectively "alterations"), segments were joined until either the entire chromosome was considered altered or more than 20% of the genomic length between the start and ends were not altered in the same direction; e.g.	('deletions', 'Var', (23, 32))	('p', 'Gene', '619493', (6, 7))	('p', 'Gene', '619493', (35, 36))	('altered', 'Reg', (145, 152))
234924	29622463	For every combination of arm/chromosome and direction of alteration within each TCGA tumor type, the start coordinates, end coordinates, and percentage length of the longest joined segment were clustered across samples using a Gaussian Mixture Model (, Python package SciKit-Learn).	('p', 'Gene', '619493', (141, 142))	('tumor', 'Disease', (85, 90))	('alteration', 'Var', (57, 67))	('p', 'Gene', '619493', (214, 215))	('P', 'Gene', '619493', (253, 254))	('p', 'Gene', '619493', (260, 261))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('p', 'Gene', '619493', (93, 94))
234932	29622463	Recurrent mutation scores are the sum of recurrent mutations, defined in the TCGA MC3 manuscript (TCGA, in preparation).	('p', 'Gene', '619493', (94, 95))	('mutation', 'Var', (10, 18))	('p', 'Gene', '619493', (107, 108))	('MC3', 'Gene', (82, 85))	('MC3', 'Gene', '4159', (82, 85))	('p', 'Gene', '619493', (110, 111))
234965	29622463	Related DNA-sequencing BAM files are available at the Sequence Read Archive as Study PRJNA436953 (SRP133935), Run Numbers SRR6806543-SRR6806552 and SRR6806555-SRR6806558.	('SRR6806543-SRR6806552', 'Var', (122, 143))	('P', 'Gene', '619493', (100, 101))	('P', 'Gene', '619493', (85, 86))	('SRR6806555-SRR6806558', 'Var', (148, 169))
234997	29622463	66160 University of Kansas Medical Center Kansas City KS 66160 University of Michigan 500 S State St, Ann Arbor, MI 48109 University of Montreal 2900 Edouard Mont petit Blvd, Montreal, QC H3T 1J4, Canada University of New Mexico Albuquerque, New Mexico 87131 University of Pennsylvania Philadelphia, PA 19104 University of Pittsburgh, Department of Cardiothoracic Surgery,200 Lothrop St, Suite C-800, Pittsburgh, Pennsylvania 15213 University of Pittsburgh, Department of Pathology, Pittsburgh, Pennsylvania 15213 University of Sheffield Western Bank, Sheffield S10 2TN, UK University of Washington Seattle, WA 98105 UPR Comprehensive Cancer Center Biobank; University of Puerto Rico Comprehensive Cancer Center, Celso Barbosa St. Medical Center Area, San Juan, PR 00936 Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Building 10, Room 1-5940, Bethesda, MD 20892-1107 Valley Health System, 1 Valley Health Plaza, Paramus, NJ 07652 Vanderbilt University Medical Center 1211 Medical Center Dr, Nashville, TN 37232 Washington University School of Medicine, 600 S. Taylor Ave, St. Louis, MO 63110 Weill Cornell Medical College, New York, NY 10065 Aneuploidy, whole chromosome or chromosome-arm imbalance, occurs in 88% of cancers Aneuploidy correlates with cell cycle genes and anti-correlates with immune levels Patterns of aneuploidy alterations are tumor-type specific Engineered chromosome 3p deletion does not promote proliferation in human lung cells Although its universality makes aneuploidy a salient feature of cancer genomes, the functional significance of cancer aneuploidy remains a mystery.	('p', 'Gene', '619493', (1453, 1454))	('P', 'Gene', '619493', (323, 324))	('cancer', 'Disease', 'MESH:D009369', (1252, 1258))	('aneuploidy', 'Disease', (1519, 1529))	('p', 'Gene', '619493', (1181, 1182))	('p', 'Gene', '619493', (294, 295))	('P', 'Gene', '619493', (401, 402))	('Cancer', 'Phenotype', 'HP:0002664', (635, 641))	('p', 'Gene', '619493', (1394, 1395))	('P', 'Gene', '619493', (947, 948))	('p', 'Gene', '619493', (1609, 1610))	('cancer aneuploidy', 'Disease', (1598, 1615))	('p', 'Gene', '619493', (337, 338))	('cancers', 'Phenotype', 'HP:0002664', (1252, 1259))	('Washington Seattle', 'Disease', (588, 606))	('P', 'Gene', '619493', (495, 496))	('cancer', 'Disease', (1252, 1258))	('p', 'Gene', '619493', (1264, 1265))	('P', 'Gene', '619493', (483, 484))	('Pennsylvania Philadelphia', 'Disease', (273, 298))	('p', 'Gene', '619493', (1445, 1446))	('tumor', 'Phenotype', 'HP:0002664', (1382, 1387))	('Cancer', 'Disease', (698, 704))	('cancer', 'Phenotype', 'HP:0002664', (1551, 1557))	('P', 'Gene', '619493', (618, 619))	('Cancer', 'Disease', (808, 814))	('cancer', 'Disease', (1598, 1604))	('Aneuploidy', 'Disease', (1260, 1270))	('P', 'Gene', '619493', (672, 673))	('Cancer', 'Disease', 'MESH:D009369', (698, 704))	('Cancer', 'Disease', 'MESH:D009369', (808, 814))	('P', 'Gene', '619493', (940, 941))	('p', 'Gene', '619493', (1425, 1426))	('p', 'Gene', '619493', (687, 688))	('Aneuploidy', 'Disease', (1177, 1187))	('aneuploidy', 'Disease', 'MESH:D000782', (1355, 1365))	('Cancer', 'Disease', (834, 840))	('cancer', 'Phenotype', 'HP:0002664', (1252, 1258))	('Cancer', 'Phenotype', 'HP:0002664', (698, 704))	('P', 'Gene', '619493', (446, 447))	('Cancer', 'Phenotype', 'HP:0002664', (808, 814))	('p', 'Gene', '619493', (1390, 1391))	('Cancer', 'Disease', 'MESH:D009369', (834, 840))	('aneuploidy', 'Disease', (1355, 1365))	('aneuploidy', 'Disease', 'MESH:D000782', (1605, 1615))	('P', 'Gene', '619493', (762, 763))	('Oncology', 'Phenotype', 'HP:0002664', (780, 788))	('human', 'Species', '9606', (1470, 1475))	('imbalance', 'Phenotype', 'HP:0002172', (1224, 1233))	('p', 'Gene', '619493', (1523, 1524))	('cancer', 'Phenotype', 'HP:0002664', (1598, 1604))	('Washington Seattle', 'Disease', 'MESH:D005955', (588, 606))	('cancer', 'Disease', 'MESH:D009369', (1551, 1557))	('aneuploidy', 'Disease', (1605, 1615))	('P', 'Gene', '619493', (472, 473))	('Cancer', 'Phenotype', 'HP:0002664', (834, 840))	('deletion', 'Var', (1427, 1435))	('P', 'Gene', '619493', (273, 274))	('tumor', 'Disease', (1382, 1387))	('P', 'Gene', '619493', (1343, 1344))	('cancers', 'Disease', (1252, 1259))	('Cancer', 'Disease', (635, 641))	('tumor', 'Disease', 'MESH:D009369', (1382, 1387))	('J4', 'CellLine', 'CVCL:1Q54', (193, 195))	('Cancer', 'Disease', 'MESH:D009369', (635, 641))	('p', 'Gene', '619493', (1359, 1360))	('cancers', 'Disease', 'MESH:D009369', (1252, 1259))	('P', 'Gene', '619493', (300, 301))	('p', 'Gene', '619493', (382, 383))	('Aneuploidy', 'Disease', 'MESH:D000782', (1260, 1270))	('p', 'Gene', '619493', (624, 625))	('cancer', 'Disease', 'MESH:D009369', (1598, 1604))	('p', 'Gene', '619493', (163, 164))	('Aneuploidy', 'Disease', 'MESH:D000782', (1177, 1187))	('aneuploidy alterations', 'Disease', (1355, 1377))	('aneuploidy', 'Disease', 'MESH:D000782', (1519, 1529))	('aneuploidy alterations', 'Disease', 'MESH:D000782', (1355, 1377))	('P', 'Gene', '619493', (286, 287))	('P', 'Gene', '619493', (413, 414))	('cancer', 'Disease', (1551, 1557))	('p', 'Gene', '619493', (460, 461))	('cancer aneuploidy', 'Disease', 'MESH:D000782', (1598, 1615))	('Pennsylvania Philadelphia', 'Disease', 'MESH:D010677', (273, 298))
235051	26433364	Furthermore, a large meta-analysis reported a 24.5 % worldwide incidence of HPV in lung cancer, particularly in China and recently, many Asian studies indicate that longer telomere length may increase lung cancer risk.	('lung cancer', 'Disease', 'MESH:D008175', (83, 94))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('lung cancer', 'Disease', 'MESH:D008175', (201, 212))	('HPV in lung cancer', 'Disease', (76, 94))	('longer telomere length', 'Var', (165, 187))	('lung cancer', 'Phenotype', 'HP:0100526', (83, 94))	('lung cancer', 'Phenotype', 'HP:0100526', (201, 212))	('increase', 'PosReg', (192, 200))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('lung cancer', 'Disease', (201, 212))	('HPV in lung cancer', 'Disease', 'MESH:D030361', (76, 94))
235164	24289720	The incidence of complications in our study was 52.2% and was associated with older age (p < 0.0001), Stage III disease (p < 0.0001), induction chemotherapy (p < 0.0001), non-squamous cell carcinoma (p = 0.0006), N2 status (p < 0.0001) and PA extended resection with bronchus sleeve resection (p < 0.0001).	('non-squamous cell carcinoma', 'Disease', (171, 198))	('Stage III disease', 'Disease', (102, 119))	('non-squamous cell carcinoma', 'Disease', 'MESH:D002294', (171, 198))	('N2 status', 'Var', (213, 222))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (175, 198))	('carcinoma', 'Phenotype', 'HP:0030731', (189, 198))
235229	32461698	To understand the associations of stromal-mediated immunosuppression in the context of the genetic mechanisms of immune evasion, we related fractal dimension to dysfunction in antigen presentation through loss of heterozygosity at the human leukocyte antigen locus (HLA LOH), which has been identified as a potent immune escape mechanism.	('men', 'Species', '9606', (150, 153))	('antigen presentation', 'MPA', (176, 196))	('loss of heterozygosity', 'Var', (205, 227))	('human', 'Species', '9606', (235, 240))
235230	32461698	A significantly higher fractal dimension was found in LUAD tumor regions with intact HLA alleles compared with regions harboring HLA LOH (Fig.	('higher', 'PosReg', (16, 22))	('fractal', 'MPA', (23, 30))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('HLA', 'Gene', (85, 88))	('LUAD tumor', 'Disease', 'MESH:D009369', (54, 64))	('LUAD tumor', 'Disease', (54, 64))	('LUAD', 'Phenotype', 'HP:0030078', (54, 58))	('men', 'Species', '9606', (33, 36))	('alleles', 'Var', (89, 96))
235357	33000243	The dissociation constants (KD) for 5-mG2a-f against SAS and HSC-2 oral cancer cells were determined through flow cytometry to be 2.8x10-10 M and 2.6x10-9 M, respectively, indicating that 5-mG2a-f possesses extremely high binding affinity.	('5-mG2a-f', 'Chemical', '-', (36, 44))	('binding', 'Interaction', (222, 229))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('5-mG2a-f', 'Chemical', '-', (188, 196))	('HSC-2 oral cancer', 'Disease', (61, 78))	('SAS', 'Chemical', 'MESH:C012546', (53, 56))	('5-mG2a-f', 'Var', (188, 196))	('HSC-2 oral cancer', 'Disease', 'MESH:D009369', (61, 78))
235358	33000243	Furthermore, immunohistochemical staining using 5-mG2a-f specifically stained the membranes of oral cancer cells.	('stained', 'Reg', (70, 77))	('oral cancer', 'Disease', (95, 106))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('oral cancer', 'Disease', 'MESH:D009369', (95, 106))	('5-mG2a-f', 'Chemical', '-', (48, 56))	('5-mG2a-f', 'Var', (48, 56))
235359	33000243	In vitro analysis demonstrated that 5-mG2a-f showed moderate ADCC and CDC activities against SAS and HSC-2 oral cancer cells.	('rat', 'Species', '10116', (56, 59))	('5-mG2a-f', 'Chemical', '-', (36, 44))	('CD', 'Gene', '13033', (70, 72))	('HSC-2 oral cancer', 'Disease', (101, 118))	('SAS', 'Chemical', 'MESH:C012546', (93, 96))	('5-mG2a-f', 'Var', (36, 44))	('HSC-2 oral cancer', 'Disease', 'MESH:D009369', (101, 118))	('SAS', 'Disease', (93, 96))	('ADCC', 'CPA', (61, 65))	('rat', 'Species', '10116', (25, 28))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))
235360	33000243	In vivo analysis revealed that 5-mG2a-f significantly reduced tumor development in SAS and HSC-2 xenografts in comparison to control mouse IgG, even after injection seven days post-tumor inoculation.	('tumor', 'Disease', (181, 186))	('SAS', 'Chemical', 'MESH:C012546', (83, 86))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', (62, 67))	('reduced', 'NegReg', (54, 61))	('5-mG2a-f', 'Chemical', '-', (31, 39))	('mouse', 'Species', '10090', (133, 138))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('5-mG2a-f', 'Var', (31, 39))	('IgG', 'Gene', '668542', (139, 142))	('IgG', 'Gene', (139, 142))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
235361	33000243	Collectively, these results suggest that treatment with 5-mG2a-f may represent a useful therapy for patients with CD44-expressing oral cancers.	('5-mG2a-f', 'Chemical', '-', (56, 64))	('cancers', 'Phenotype', 'HP:0002664', (135, 142))	('5-mG2a-f', 'Var', (56, 64))	('oral cancers', 'Disease', 'MESH:D009369', (130, 142))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('patients', 'Species', '9606', (100, 108))	('oral cancers', 'Disease', (130, 142))
235369	33000243	Both CD44s and CD44v are overexpressed in many cancers; however, a pattern of expression remains to be elucidated.	('CD44s', 'Var', (5, 10))	('overexpressed', 'PosReg', (25, 38))	('cancers', 'Disease', 'MESH:D009369', (47, 54))	('cancers', 'Phenotype', 'HP:0002664', (47, 54))	('cancers', 'Disease', (47, 54))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('CD44v', 'Var', (15, 20))
235370	33000243	One of the CD44 variants, CD44v6, was first identified as contributing to cancer metastasis, and CD44v6-specific monoclonal antibodies (mAbs) were found to inhibit metastasis of rat pancreatic cancers.	('cancers', 'Phenotype', 'HP:0002664', (193, 200))	('inhibit', 'NegReg', (156, 163))	('was', 'Gene', '100769113', (34, 37))	('contributing', 'Reg', (58, 70))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (182, 200))	('CD44v6-specific', 'Var', (97, 112))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('pancreatic cancers', 'Disease', 'MESH:D010190', (182, 200))	('pancreatic cancers', 'Disease', (182, 200))	('cancer metastasis', 'Disease', (74, 91))	('was', 'Gene', (34, 37))	('rat', 'Species', '10116', (178, 181))	('cancer metastasis', 'Disease', 'MESH:D009362', (74, 91))	('variants', 'Var', (16, 24))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
235372	33000243	The transfection of CD44v4-7 cDNA confers a metastatic phenotype in non-metastatic cells.	('metastatic phenotype in non-metastatic cells', 'CPA', (44, 88))	('N', 'Chemical', 'MESH:D009584', (31, 32))	('transfection', 'Var', (4, 16))	('CD44v4-7', 'Var', (20, 28))
235373	33000243	Another CD44 variant, CD44v3, binds to several heparan sulfate-binding growth factors such as fibroblast growth factors (FGFs) and heparin-binding epidermal growth factor (HB-EGF), and induces tumor progression.	('heparan sulfate', 'Chemical', 'MESH:D006497', (47, 62))	('epidermal growth factor (HB-', 'Gene', '13645', (147, 175))	('CD44', 'Gene', (8, 12))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('CD44v3', 'Gene', (22, 28))	('induces', 'Reg', (185, 192))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('variant', 'Var', (13, 20))	('tumor', 'Disease', (193, 198))	('binds', 'Interaction', (30, 35))	('heparin', 'Chemical', 'MESH:D006493', (131, 138))
235374	33000243	Several CD44 variants were also reported as prognostic markers in head and neck, lung, colorectal, breast, and hepatocellular cancers.	('hepatocellular cancers', 'Disease', 'MESH:D006528', (111, 133))	('variants', 'Var', (13, 21))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('colorectal', 'Disease', (87, 97))	('CD44', 'Gene', (8, 12))	('cancers', 'Phenotype', 'HP:0002664', (126, 133))	('hepatocellular cancers', 'Disease', (111, 133))	('breast', 'Disease', (99, 105))	('lung', 'Disease', (81, 85))
235376	33000243	Anti-CD44 mAbs were also found to exhibit significant antitumor activity in mouse xenograft models of human cancers.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('cancers', 'Phenotype', 'HP:0002664', (108, 115))	('mouse', 'Species', '10090', (76, 81))	('Anti-CD44', 'Var', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('cancers', 'Disease', 'MESH:D009369', (108, 115))	('cancers', 'Disease', (108, 115))	('human', 'Species', '9606', (102, 107))
235378	33000243	C44Mab-5 recognized both CD44s and CD44v isoforms, and demonstrated high sensitivity for flow cytometry and immunohistochemical analysis in oral cancers.	('rat', 'Species', '10116', (62, 65))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('oral cancers', 'Disease', 'MESH:D009369', (140, 152))	('oral cancers', 'Disease', (140, 152))	('CD44s', 'Var', (25, 30))	('CD44v', 'Var', (35, 40))	('cancers', 'Phenotype', 'HP:0002664', (145, 152))
235381	33000243	We then investigated whether 5-mG2a-f exhibited ADCC, CDC and antitumor activities against oral cancers.	('oral cancers', 'Disease', 'MESH:D009369', (91, 103))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('cancers', 'Phenotype', 'HP:0002664', (96, 103))	('5-mG2a-f', 'Var', (29, 37))	('tumor', 'Disease', (66, 71))	('5-mG2a-f', 'Chemical', '-', (29, 37))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('oral cancers', 'Disease', (91, 103))	('CD', 'Gene', '13033', (54, 56))	('ADCC', 'CPA', (48, 52))	('tumor', 'Disease', 'MESH:D009369', (66, 71))
235423	33000243	The target cells (2x104 cells/well) were plated in 96-well plates and mixed with effector cells, anti-CD44s antibodies, or control IgG (mouse IgG2a) (Sigma-Aldrich Corp.; Merck KGaA).	('anti-CD44s', 'Var', (97, 107))	('IgG', 'Gene', '668542', (142, 145))	('IgG', 'Gene', (142, 145))	('IgG', 'Gene', '668542', (131, 134))	('Sigma-Aldrich Corp', 'Disease', 'MESH:D014923', (150, 168))	('IgG', 'Gene', (131, 134))	('Sigma-Aldrich Corp', 'Disease', (150, 168))	('mouse', 'Species', '10090', (136, 141))
235427	33000243	Cells in DMEM supplemented with 10% FBS were plated in 96-well plates (2x104 cells/well), and incubated for 5 h at 37 C with either anti-CD44s antibodies or control IgG (mouse IgG2a) (Sigma-Aldrich Corp.; Merck KGaA) and 10% rabbit complement (Low-Tox-M Rabbit Complement; Cedarlane Laboratories).	('Sigma-Aldrich Corp', 'Disease', 'MESH:D014923', (184, 202))	('Sigma-Aldrich Corp', 'Disease', (184, 202))	('IgG', 'Gene', '668542', (165, 168))	('anti-CD44s', 'Var', (132, 142))	('IgG', 'Gene', (165, 168))	('IgG', 'Gene', '668542', (176, 179))	('rat', 'Species', '10116', (287, 290))	('mouse', 'Species', '10090', (170, 175))	('DMEM', 'Chemical', '-', (9, 13))	('IgG', 'Gene', (176, 179))
235449	33000243	C44Mab-5, but not 5-mG2a-f, was detected using AAL (Fig.	('was', 'Gene', '100769113', (28, 31))	('5-mG2a-f', 'Chemical', '-', (18, 26))	('was', 'Gene', (28, 31))	('C44Mab-5', 'Var', (0, 8))
235452	33000243	We examined the sensitivity of 5-mG2a-f in CHO cells expressing CD44v3-10 plus N-terminal PA16 tag (CHO/PA16-CD44v3-10) and in oral squamous cell carcinoma (OSCC) cell lines (SAS and HSC-2) using flow cytometry.	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (127, 155))	('CD44v3-10 plus', 'Var', (64, 78))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (132, 155))	('CHO', 'CellLine', 'CVCL:0213', (100, 103))	('N', 'Chemical', 'MESH:D009584', (79, 80))	('oral squamous cell carcinoma', 'Disease', (127, 155))	('PA16', 'Chemical', '-', (104, 108))	('5-mG2a-f', 'Chemical', '-', (31, 39))	('PA16', 'Chemical', '-', (90, 94))	('SAS', 'Chemical', 'MESH:C012546', (175, 178))	('CHO', 'CellLine', 'CVCL:0213', (43, 46))
235455	33000243	Both C44Mab-5 and 5-mG2a-f reacted with SAS cells (Fig.	('C44Mab-5', 'Var', (5, 13))	('reacted', 'Reg', (27, 34))	('5-mG2a-f', 'Chemical', '-', (18, 26))	('SAS', 'Chemical', 'MESH:C012546', (40, 43))
235462	33000243	The sensitivity of 5-mG2a-f was similar with that of C44Mab-5.	('5-mG2a-f', 'Var', (19, 27))	('was', 'Gene', '100769113', (28, 31))	('5-mG2a-f', 'Chemical', '-', (19, 27))	('was', 'Gene', (28, 31))
235463	33000243	Both C44Mab-5 and 5-mG2a-f stained 33/38 cases (86.8%) of OSCCs of the tissue microarray.	('OSCCs', 'Disease', (58, 63))	('C44Mab-5', 'Var', (5, 13))	('5-mG2a-f', 'Chemical', '-', (18, 26))
235470	33000243	The binding affinity of 5-mG2a-f in HSC-2 cells was very similar to that of recC44Mab-5.	('was', 'Gene', '100769113', (48, 51))	('binding', 'Interaction', (4, 11))	('5-mG2a-f', 'Chemical', '-', (24, 32))	('5-mG2a-f', 'Var', (24, 32))	('was', 'Gene', (48, 51))
235471	33000243	The binding affinity of 5-mG2a-f in SAS was 9.3-fold higher than that against HSC-2.	('higher', 'PosReg', (53, 59))	('binding', 'Interaction', (4, 11))	('SAS', 'Chemical', 'MESH:C012546', (36, 39))	('was', 'Gene', (40, 43))	('was', 'Gene', '100769113', (40, 43))	('5-mG2a-f', 'Chemical', '-', (24, 32))	('5-mG2a-f', 'Var', (24, 32))
235472	33000243	Because the mouse IgG1 subclass of C44Mab-5 does not possess ADCC or CDC activities, we synthesized a mouse IgG2a subclass mAb, and further defucosylated it to augment those activities.	('defucosylated', 'Var', (140, 153))	('IgG', 'Gene', '668542', (18, 21))	('CD', 'Gene', '13033', (69, 71))	('IgG', 'Gene', '668542', (108, 111))	('IgG', 'Gene', (18, 21))	('IgG', 'Gene', (108, 111))	('mouse', 'Species', '10090', (12, 17))	('augment', 'PosReg', (160, 167))	('mouse', 'Species', '10090', (102, 107))	('activities', 'MPA', (174, 184))
235473	33000243	In this study, we examined whether the developed 5-mG2a-f induced ADCC and CDC in CD44-expressing oral cancer cell lines, such as SAS and HSC-2 cells.	('induced', 'PosReg', (58, 65))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('oral cancer', 'Disease', (98, 109))	('CD', 'Gene', '13033', (82, 84))	('CD', 'Gene', '13033', (75, 77))	('5-mG2a-f', 'Chemical', '-', (49, 57))	('ADCC', 'CPA', (66, 70))	('5-mG2a-f', 'Var', (49, 57))	('oral cancer', 'Disease', 'MESH:D009369', (98, 109))	('SAS', 'Chemical', 'MESH:C012546', (130, 133))
235474	33000243	5A, 5-mG2a-f exhibited higher ADCC (16% cytotoxicity) in SAS cells compared with that of control PBS (3.4% cytotoxicity; P<0.01) and control mouse IgG2a treatment (4.2% cytotoxicity; P<0.01).	('cytotoxicity', 'Disease', (40, 52))	('cytotoxicity', 'Disease', 'MESH:D064420', (107, 119))	('cytotoxicity', 'Disease', (169, 181))	('IgG', 'Gene', '668542', (147, 150))	('PBS', 'Chemical', '-', (97, 100))	('IgG', 'Gene', (147, 150))	('higher', 'PosReg', (23, 29))	('mouse', 'Species', '10090', (141, 146))	('cytotoxicity', 'Disease', 'MESH:D064420', (40, 52))	('cytotoxicity', 'Disease', 'MESH:D064420', (169, 181))	('cytotoxicity', 'Disease', (107, 119))	('5-mG2a-f', 'Chemical', '-', (4, 12))	('SAS', 'Chemical', 'MESH:C012546', (57, 60))	('5-mG2a-f', 'Var', (4, 12))	('ADCC', 'MPA', (30, 34))
235475	33000243	Similarly, 5-mG2a-f exhibited higher ADCC (18% cytotoxicity) against HSC-2 cells compared with that of control PBS (3.1% cytotoxicity; P<0.01) and control mouse IgG2a treatment (5.2% cytotoxicity; P<0.01), indicating that ADCC in SAS cells is similar with that in HSC-2 cells, despite the binding affinity of 5-mG2a-f in SAS cells being 9.3-fold higher than in HSC-2 cells (Fig.	('PBS', 'Chemical', '-', (111, 114))	('cytotoxicity', 'Disease', (183, 195))	('cytotoxicity', 'Disease', (121, 133))	('IgG', 'Gene', '668542', (161, 164))	('binding affinity', 'Interaction', (289, 305))	('cytotoxicity', 'Disease', 'MESH:D064420', (183, 195))	('higher', 'PosReg', (346, 352))	('IgG', 'Gene', (161, 164))	('cytotoxicity', 'Disease', 'MESH:D064420', (121, 133))	('5-mG2a-f', 'Chemical', '-', (11, 19))	('SAS', 'Chemical', 'MESH:C012546', (230, 233))	('5-mG2a-f', 'Var', (11, 19))	('cytotoxicity', 'Disease', (47, 59))	('mouse', 'Species', '10090', (155, 160))	('ADCC', 'MPA', (37, 41))	('5-mG2a-f', 'Chemical', '-', (309, 317))	('cytotoxicity', 'Disease', 'MESH:D064420', (47, 59))	('5-mG2a-f', 'Var', (309, 317))	('SAS', 'Chemical', 'MESH:C012546', (321, 324))
235476	33000243	5B, 5-mG2a-f exhibited slightly higher CDC (33% cytotoxicity) in SAS cells compared with control PBS (21% cytotoxicity; P<0.01) and control mouse IgG2a treatment (22% cytotoxicity; P<0.01).	('mouse', 'Species', '10090', (140, 145))	('SAS', 'Chemical', 'MESH:C012546', (65, 68))	('PBS', 'Chemical', '-', (97, 100))	('higher', 'PosReg', (32, 38))	('cytotoxicity', 'Disease', 'MESH:D064420', (48, 60))	('cytotoxicity', 'Disease', (167, 179))	('cytotoxicity', 'Disease', (106, 118))	('cytotoxicity', 'Disease', 'MESH:D064420', (106, 118))	('IgG', 'Gene', '668542', (146, 149))	('IgG', 'Gene', (146, 149))	('CD', 'Gene', '13033', (39, 41))	('cytotoxicity', 'Disease', (48, 60))	('5-mG2a-f', 'Chemical', '-', (4, 12))	('cytotoxicity', 'Disease', 'MESH:D064420', (167, 179))	('5-mG2a-f', 'Var', (4, 12))
235477	33000243	Similarly, 5-mG2a-f exhibited slightly higher CDC (30% cytotoxicity) in HSC-2 cells compared with control PBS (18% cytotoxicity; P<0.01) and control mouse IgG2a treatment (19% cytotoxicity; not significant).	('higher', 'PosReg', (39, 45))	('cytotoxicity', 'Disease', 'MESH:D064420', (176, 188))	('cytotoxicity', 'Disease', 'MESH:D064420', (115, 127))	('IgG', 'Gene', '668542', (155, 158))	('IgG', 'Gene', (155, 158))	('cytotoxicity', 'Disease', (55, 67))	('CD', 'Gene', '13033', (46, 48))	('mouse', 'Species', '10090', (149, 154))	('5-mG2a-f', 'Chemical', '-', (11, 19))	('PBS', 'Chemical', '-', (106, 109))	('cytotoxicity', 'Disease', (176, 188))	('cytotoxicity', 'Disease', (115, 127))	('5-mG2a-f', 'Var', (11, 19))	('cytotoxicity', 'Disease', 'MESH:D064420', (55, 67))
235478	33000243	Although ADCC/CDC activities of 5-mG2a-f in oral cancer cells are not outstanding, 5-mG2a-f may exert antitumor activity against oral cancer cells in vivo.	('5-mG2a-f', 'Chemical', '-', (32, 40))	('oral cancer', 'Disease', (44, 55))	('CD', 'Gene', '13033', (14, 16))	('oral cancer', 'Disease', (129, 140))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('oral cancer', 'Disease', 'MESH:D009369', (44, 55))	('oral cancer', 'Disease', 'MESH:D009369', (129, 140))	('5-mG2a-f', 'Chemical', '-', (83, 91))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('5-mG2a-f', 'Var', (83, 91))	('tumor', 'Disease', (106, 111))
235479	33000243	Next, we investigated whether 5-mG2a-f inhibits cell growth of SAS and HSC-2 cells in anchorage-independent condition.	('cell growth', 'CPA', (48, 59))	('SAS', 'Chemical', 'MESH:C012546', (63, 66))	('N', 'Chemical', 'MESH:D009584', (0, 1))	('5-mG2a-f', 'Chemical', '-', (30, 38))	('5-mG2a-f', 'Var', (30, 38))	('inhibits', 'NegReg', (39, 47))
235480	33000243	S2A, both SAS and HSC-2 cells grew in anchorage-independent condition for 48 h. In contrast, an anti-CD44 mAb (5-mG2a-f) did not inhibit the growth of SAS or HSC-2 compared to control mouse IgG2a (Fig.	('anti-CD44', 'Var', (96, 105))	('inhibit', 'NegReg', (129, 136))	('mouse', 'Species', '10090', (184, 189))	('IgG', 'Gene', '668542', (190, 193))	('IgG', 'Gene', (190, 193))	('SAS', 'Chemical', 'MESH:C012546', (151, 154))	('SAS', 'Chemical', 'MESH:C012546', (10, 13))	('5-mG2a-f', 'Chemical', '-', (111, 119))
235486	33000243	Tumor development was significantly reduced in the 5-mG2a-f-treated mice on days 12, 15, and 19 in comparison to the IgG-treated control mice (Fig.	('mice', 'Species', '10090', (68, 72))	('was', 'Gene', (18, 21))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('was', 'Gene', '100769113', (18, 21))	('Tumor development', 'CPA', (0, 17))	('IgG', 'Gene', '668542', (117, 120))	('IgG', 'Gene', (117, 120))	('reduced', 'NegReg', (36, 43))	('5-mG2a-f', 'Chemical', '-', (51, 59))	('5-mG2a-f-treated', 'Var', (51, 67))	('mice', 'Species', '10090', (137, 141))
235488	33000243	Tumors from 5-mG2a-f-treated mice weighed significantly less than tumors from IgG-treated control mice (16.9% reduction, Fig.	('less', 'NegReg', (56, 60))	('5-mG2a-f', 'Chemical', '-', (12, 20))	('IgG', 'Gene', '668542', (78, 81))	('IgG', 'Gene', (78, 81))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('5-mG2a-f-treated', 'Var', (12, 28))	('tumors', 'Disease', (66, 72))	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('mice', 'Species', '10090', (29, 33))	('mice', 'Species', '10090', (98, 102))
235495	33000243	5-mG2a-f-treated mice displayed significantly reduced tumor development on days 22 and 27 in comparison to IgG-treated control mice (Fig.	('mice', 'Species', '10090', (127, 131))	('mice', 'Species', '10090', (17, 21))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('IgG', 'Gene', '668542', (107, 110))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('IgG', 'Gene', (107, 110))	('reduced', 'NegReg', (46, 53))	('5-mG2a-f', 'Chemical', '-', (0, 8))	('tumor', 'Disease', (54, 59))	('5-mG2a-f-treated', 'Var', (0, 16))
235496	33000243	Tumor volume reduction by 5-mG2a-f was 43% on day 27.	('Tumor volume', 'CPA', (0, 12))	('was', 'Gene', (35, 38))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('5-mG2a-f', 'Chemical', '-', (26, 34))	('5-mG2a-f', 'Var', (26, 34))	('reduction', 'NegReg', (13, 22))	('was', 'Gene', '100769113', (35, 38))
235497	33000243	Tumors from the 5-mG2a-f-treated mice weighed significantly less than tumors from the IgG-treated control mice (27.1% reduction, Fig.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('mice', 'Species', '10090', (106, 110))	('IgG', 'Gene', '668542', (86, 89))	('IgG', 'Gene', (86, 89))	('less', 'NegReg', (60, 64))	('5-mG2a-f', 'Chemical', '-', (16, 24))	('5-mG2a-f-treated', 'Var', (16, 32))	('tumors', 'Disease', (70, 76))	('Tumors', 'Disease', (0, 6))	('tumors', 'Disease', 'MESH:D009369', (70, 76))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('mice', 'Species', '10090', (33, 37))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))
235500	33000243	These results indicate that 5-mG2a-f reduced the growth of SAS xenografts effectively, even when 5-mG2a-f was injected 7 days post-SAS cell injections in mice.	('SAS', 'Chemical', 'MESH:C012546', (59, 62))	('mice', 'Species', '10090', (154, 158))	('SAS', 'Chemical', 'MESH:C012546', (131, 134))	('5-mG2a-f', 'Chemical', '-', (97, 105))	('reduced', 'NegReg', (37, 44))	('was', 'Gene', (106, 109))	('5-mG2a-f', 'Chemical', '-', (28, 36))	('was', 'Gene', '100769113', (106, 109))	('growth of SAS xenografts', 'CPA', (49, 73))	('5-mG2a-f', 'Var', (28, 36))
235504	33000243	5-mG2a-f-treated mice displayed significantly reduced tumor development on days 12, 15, and 19 in comparison to IgG-treated control mice (Fig.	('IgG', 'Gene', (112, 115))	('mice', 'Species', '10090', (17, 21))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('5-mG2a-f', 'Chemical', '-', (0, 8))	('mice', 'Species', '10090', (132, 136))	('reduced', 'NegReg', (46, 53))	('tumor', 'Disease', (54, 59))	('5-mG2a-f-treated', 'Var', (0, 16))	('IgG', 'Gene', '668542', (112, 115))
235505	33000243	Tumor volume reduction by 5-mG2a-f was 53% on day 19.	('Tumor volume', 'CPA', (0, 12))	('was', 'Gene', (35, 38))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('5-mG2a-f', 'Chemical', '-', (26, 34))	('5-mG2a-f', 'Var', (26, 34))	('reduction', 'NegReg', (13, 22))	('was', 'Gene', '100769113', (35, 38))
235506	33000243	Tumors from 5-mG2a-f-treated mice weighed significantly less than HSC-2 tumors from IgG-treated control mice (44.1% reduction, Fig.	('less', 'NegReg', (56, 60))	('5-mG2a-f', 'Chemical', '-', (12, 20))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('HSC-2 tumors', 'Disease', (66, 78))	('5-mG2a-f-treated', 'Var', (12, 28))	('HSC-2 tumors', 'Disease', 'MESH:C000657245', (66, 78))	('mice', 'Species', '10090', (104, 108))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('mice', 'Species', '10090', (29, 33))	('IgG', 'Gene', '668542', (84, 87))	('IgG', 'Gene', (84, 87))
235512	33000243	Tumors from 5-mG2a-f-treated mice weighed significantly less than tumors from IgG-treated control mice (27.1% reduction, Fig.	('less', 'NegReg', (56, 60))	('5-mG2a-f', 'Chemical', '-', (12, 20))	('IgG', 'Gene', '668542', (78, 81))	('IgG', 'Gene', (78, 81))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('5-mG2a-f-treated', 'Var', (12, 28))	('tumors', 'Disease', (66, 72))	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('mice', 'Species', '10090', (29, 33))	('mice', 'Species', '10090', (98, 102))
235514	33000243	These results indicate that 5-mG2a-f reduced the growth of HSC-2 xenografts effectively, even when 5-mG2a-f was injected 7 days post-HSC-2 cell injections in mice.	('was', 'Gene', (108, 111))	('mice', 'Species', '10090', (158, 162))	('growth of HSC-2 xenografts', 'CPA', (49, 75))	('5-mG2a-f', 'Chemical', '-', (99, 107))	('reduced', 'NegReg', (37, 44))	('5-mG2a-f', 'Chemical', '-', (28, 36))	('5-mG2a-f', 'Var', (28, 36))	('was', 'Gene', '100769113', (108, 111))
235515	33000243	In the present study, we investigated whether anti-CD44 mAbs are advantageous for the treatment of oral cancers.	('oral cancers', 'Disease', 'MESH:D009369', (99, 111))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('anti-CD44', 'Var', (46, 55))	('oral cancers', 'Disease', (99, 111))	('cancers', 'Phenotype', 'HP:0002664', (104, 111))
235517	33000243	In this study, we developed this antibody into an IgG2a subclass antibody, and augmented ADCC activity using a defucosylated variant.	('ADCC', 'Enzyme', (89, 93))	('augmented', 'PosReg', (79, 88))	('activity', 'MPA', (94, 102))	('defucosylated', 'Var', (111, 124))	('IgG', 'Gene', '668542', (50, 53))	('IgG', 'Gene', (50, 53))
235535	33000243	In vivo analysis revealed that 47-mG2a-f, but not 47-mG2a, exhibited antitumor activity in SAS and HSC-2 xenograft models at a dose of 100 microg/mouse/week administered three times.	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('mouse', 'Species', '10090', (146, 151))	('SAS', 'Chemical', 'MESH:C012546', (91, 94))	('tumor', 'Disease', (73, 78))	('47-mG2a-f', 'Var', (31, 40))
235536	33000243	Although both 47-mG2a and 47-mG2a-f exhibited antitumor activity in HSC-2 xenograft models at a dose of 500 microg/mouse/week administered twice, 47-mG2a-f also demonstrated higher antitumor activity than 47-mG2a, indicating that a core fucose-deficient anti-PODXL mAb could be useful for antibody-based therapy against PODXL-expressing OSCCs.	('tumor', 'Disease', (185, 190))	('47-mG2a-f', 'Var', (26, 35))	('higher', 'PosReg', (174, 180))	('mouse', 'Species', '10090', (115, 120))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('fucose', 'Chemical', 'MESH:D005643', (237, 243))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('rat', 'Species', '10116', (168, 171))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('47-mG2a-f', 'Var', (146, 155))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('tumor', 'Disease', (50, 55))
235538	33000243	In this study, we demonstrated that 5-mG2a-f exerts ADCC/CDC activities in vitro, and antitumor activities in vivo.	('5-mG2a-f', 'Chemical', '-', (36, 44))	('5-mG2a-f', 'Var', (36, 44))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('CD', 'Gene', '13033', (57, 59))	('rat', 'Species', '10116', (25, 28))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
235539	33000243	Importantly, 5-mG2a-f effectively reduced the growth of SAS and HSC-2 xenografts, even when 5-mG2a-f was injected 7 days after cell implantations into the mice.	('reduced', 'NegReg', (34, 41))	('SAS', 'Chemical', 'MESH:C012546', (56, 59))	('was', 'Gene', '100769113', (101, 104))	('5-mG2a-f', 'Chemical', '-', (92, 100))	('was', 'Gene', (101, 104))	('growth', 'CPA', (46, 52))	('5-mG2a-f', 'Chemical', '-', (13, 21))	('mice', 'Species', '10090', (155, 159))	('5-mG2a-f', 'Var', (13, 21))
235541	33000243	One potential reason for this weak antitumor activity is the lower ADCC activity and CDC activity of 5-mG2a-f, despite high binding activity in SAS cells (KD: 2.8x10-10 M) and HSC-2 cells (KD: 2.6x10-9 M).	('5-mG2a-f', 'Chemical', '-', (101, 109))	('ADCC activity', 'MPA', (67, 80))	('lower', 'NegReg', (61, 66))	('5-mG2a-f', 'Var', (101, 109))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('binding', 'Interaction', (124, 131))	('CD', 'Gene', '13033', (85, 87))	('tumor', 'Disease', (39, 44))	('SAS', 'Chemical', 'MESH:C012546', (144, 147))
235548	33000243	In the future study, cancer-specific anti-CD44 mAbs may also be developed that can reduce the adverse effects of traditional antibody therapy.	('cancer', 'Disease', 'MESH:D009369', (21, 27))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('cancer', 'Disease', (21, 27))	('anti-CD44', 'Var', (37, 46))
235550	33000243	JP20am0401013 (YK), JP20am0101078 (YK), and JP20ae0101028 (YK), and by the Japan Society for the Promotion of Science (JSPS) Grants-in-Aid for Scientific Research (KAKENHI) grant nos.	('JP20am0401013', 'Var', (0, 13))	('N', 'Chemical', 'MESH:D009584', (168, 169))	('JP20am0101078', 'Var', (20, 33))	('JP20ae0101028', 'Var', (44, 57))
235577	32089988	In the OCCM intermediate, MCM3 interacts with ORC Cdc6 at CTD and stimulates the ATPase activity.	('ATPase', 'Gene', (81, 87))	('ATPase', 'Gene', '1769', (81, 87))	('Cdc6', 'Gene', '990', (50, 54))	('CTD', 'Gene', (58, 61))	('activity', 'MPA', (88, 96))	('MCM3', 'Var', (26, 30))	('stimulates', 'PosReg', (66, 76))	('ORC', 'Gene', (46, 49))	('interacts', 'Interaction', (31, 40))	('CTD', 'Gene', '1283', (58, 61))	('Cdc6', 'Gene', (50, 54))
235596	32089988	Numerous rearrangements are one of the features of the aggressive cancer genome.	('rearrangements', 'Var', (9, 23))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('aggressive cancer', 'Disease', (55, 72))	('aggressive cancer', 'Disease', 'MESH:D009369', (55, 72))
235601	32089988	The diagnostic values of the individual MCM subunits were identified in various cancers including MCM2 in gastric cardiac cancer and salivary gland tumor, MCM5 in esophageal cancer, MCM7 in meningiomas, and MCM10 in breast cancer.	('cancers', 'Disease', 'MESH:D009369', (80, 87))	('MCM2', 'Var', (98, 102))	('meningiomas', 'Disease', (190, 201))	('esophageal cancer', 'Disease', 'MESH:D004938', (163, 180))	('cardiac cancer', 'Phenotype', 'HP:0100544', (114, 128))	('salivary gland tumor', 'Disease', (133, 153))	('MCM5', 'Gene', '4174', (155, 159))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('MCM7', 'Gene', (182, 186))	('esophageal cancer', 'Disease', (163, 180))	('MCM5', 'Gene', (155, 159))	('gastric cardiac cancer', 'Disease', (106, 128))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('salivary gland tumor', 'Disease', 'MESH:D008949', (133, 153))	('meningioma', 'Phenotype', 'HP:0002858', (190, 200))	('MCM7', 'Gene', '4176', (182, 186))	('cancers', 'Phenotype', 'HP:0002664', (80, 87))	('salivary gland tumor', 'Phenotype', 'HP:0100684', (133, 153))	('cancers', 'Disease', (80, 87))	('breast cancer', 'Phenotype', 'HP:0003002', (216, 229))	('MCM10', 'Gene', (207, 212))	('meningiomas', 'Disease', 'MESH:D008579', (190, 201))	('gastric cardiac cancer', 'Disease', 'MESH:D006338', (106, 128))	('breast cancer', 'Disease', 'MESH:D001943', (216, 229))	('breast cancer', 'Disease', (216, 229))	('MCM10', 'Gene', '55388', (207, 212))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('meningiomas', 'Phenotype', 'HP:0002858', (190, 201))
235606	32089988	Besides, Genistein, BETi, and Breviscapine were reported to, respectively, downregulate MCM2, MCM5, and MCM7.	('MCM7', 'Gene', '4176', (104, 108))	('BETi', 'Chemical', '-', (20, 24))	('MCM5', 'Gene', '4174', (94, 98))	('downregulate', 'NegReg', (75, 87))	('MCM2', 'Gene', (88, 92))	('Breviscapine', 'Var', (30, 42))	('Breviscapine', 'Chemical', 'MESH:C061097', (30, 42))	('MCM7', 'Gene', (104, 108))	('Genistein', 'Chemical', 'MESH:D019833', (9, 18))	('MCM5', 'Gene', (94, 98))
235613	32089988	Univariate and multivariate survival analyses with Cox's regression model present evidence for independent prognostic roles of MCM2 in LUSC prognosis, MCM6 in glioma, MCM5 in lung squamous cell carcinoma, and MCM8 in pancreatic cancer.	('LUSC', 'Disease', (135, 139))	('MCM2', 'Gene', (127, 131))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (217, 234))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (175, 203))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (180, 203))	('glioma', 'Disease', (159, 165))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (175, 203))	('pancreatic cancer', 'Disease', 'MESH:D010190', (217, 234))	('MCM8', 'Var', (209, 213))	('lung squamous cell carcinoma', 'Disease', (175, 203))	('MCM5', 'Gene', '4174', (167, 171))	('glioma', 'Disease', 'MESH:D005910', (159, 165))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('MCM6', 'Gene', '4175', (151, 155))	('MCM5', 'Gene', (167, 171))	('pancreatic cancer', 'Disease', (217, 234))	('carcinoma', 'Phenotype', 'HP:0030731', (194, 203))	('MCM6', 'Gene', (151, 155))	('glioma', 'Phenotype', 'HP:0009733', (159, 165))
235619	32089988	Although initiation might be available at dormant origins, DNA damage would still accumulate because of fork progression obstacle, high frequency of chromosome recombination between nearby stalling forks, deletion of areas with tumor suppressor genes, and other genomic structural abnormalities.	('deletion', 'Var', (205, 213))	('fork', 'CPA', (104, 108))	('chromosome recombination', 'CPA', (149, 173))	('tumor', 'Disease', 'MESH:D009369', (228, 233))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('structural abnormalities', 'Disease', (270, 294))	('tumor', 'Disease', (228, 233))	('structural abnormalities', 'Disease', 'MESH:C536503', (270, 294))
235628	32089988	Cancer cells are produced by accumulated mutations in oncogenes and tumor suppressor genes.	('mutations', 'Var', (41, 50))	('oncogenes', 'Gene', (54, 63))	('tumor', 'Disease', (68, 73))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))
235629	32089988	Genomic variations including mutation, extensive chromosome rearrangement, deletion, and excess amplification of genes are crucial in cancer prognosis.	('mutation', 'Var', (29, 37))	('genes', 'Gene', (113, 118))	('deletion', 'Var', (75, 83))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('excess', 'PosReg', (89, 95))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
235631	32089988	Point mutations in MCM4 (F345I, G364R, and G486D) have been reported to cause dysfunction of MCM2-7 complex, unreplicated DNA in the S phase, and segregation of structurally altered genome to daughter cells, resulting in disrupted DNA replication in daughter cells, malignancy, and relapse of carcinomas.	('MCM4', 'Gene', '4173', (19, 23))	('G364R', 'Var', (32, 37))	('carcinomas', 'Disease', (293, 303))	('cause', 'Reg', (72, 77))	('G486D', 'Mutation', 'p.G486D', (43, 48))	('G364R', 'Mutation', 'rs1485929856', (32, 37))	('disrupted DNA replication', 'MPA', (221, 246))	('MCM4', 'Gene', (19, 23))	('malignancy', 'Disease', 'MESH:D009369', (266, 276))	('dysfunction', 'MPA', (78, 89))	('F345I', 'Mutation', 'p.F345I', (25, 30))	('carcinoma', 'Phenotype', 'HP:0030731', (293, 302))	('carcinomas', 'Phenotype', 'HP:0030731', (293, 303))	('carcinomas', 'Disease', 'MESH:D002277', (293, 303))	('malignancy', 'Disease', (266, 276))	('MCM2-7', 'Gene', '4171;4172;4173;4174;4175;4176', (93, 99))	('MCM2-7', 'Gene', (93, 99))	('G486D', 'Var', (43, 48))	('F345I', 'Var', (25, 30))
235632	32089988	F345I mutation weakens the interaction with MCM6.	('MCM6', 'Gene', (44, 48))	('interaction', 'Interaction', (27, 38))	('MCM6', 'Gene', '4175', (44, 48))	('weakens', 'NegReg', (15, 22))	('F345I', 'Mutation', 'p.F345I', (0, 5))	('F345I mutation', 'Var', (0, 14))
235633	32089988	G364R mutation was detected in skin cancer cells, and G486D mutation was detected in endometrial cancer cells.	('endometrial cancer', 'Disease', 'MESH:D016889', (85, 103))	('detected', 'Reg', (73, 81))	('skin cancer', 'Disease', (31, 42))	('G364R', 'Mutation', 'rs1485929856', (0, 5))	('skin cancer', 'Phenotype', 'HP:0008069', (31, 42))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('G486D', 'Mutation', 'p.G486D', (54, 59))	('skin cancer', 'Disease', 'MESH:D012878', (31, 42))	('endometrial cancer', 'Disease', (85, 103))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('G364R', 'Var', (0, 5))	('endometrial cancer', 'Phenotype', 'HP:0012114', (85, 103))	('G486D', 'Var', (54, 59))
235634	32089988	Copy number variations (CNVs) of MCMs contribute to genomic instability and cancer progression.	('genomic instability', 'CPA', (52, 71))	('Copy number variations', 'Var', (0, 22))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('MCMs', 'Gene', (33, 37))	('contribute', 'Reg', (38, 48))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))
235638	32089988	In the intronic region of MCM7, rs999885 controlled the expression level of miRNA (miR-106b-25) to decrease the death risk in intermediate or advanced HCC , while patients with homozygote genotype (CC) of rs1534309 showed a higher survival rate in acute myeloid leukemia than the patients with other genotypes (CG and GG).	('MCM7', 'Gene', (26, 30))	('leukemia', 'Phenotype', 'HP:0001909', (262, 270))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (248, 270))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (254, 270))	('HCC', 'Gene', '619501', (151, 154))	('MCM7', 'Gene', '4176', (26, 30))	('rs1534309', 'Mutation', 'rs1534309', (205, 214))	('HCC', 'Phenotype', 'HP:0001402', (151, 154))	('CG', 'Chemical', 'MESH:C028505', (311, 313))	('HCC', 'Gene', (151, 154))	('expression level', 'MPA', (56, 72))	('patients', 'Species', '9606', (280, 288))	('patients', 'Species', '9606', (163, 171))	('decrease', 'NegReg', (99, 107))	('acute myeloid leukemia', 'Disease', (248, 270))	('rs999885', 'Var', (32, 40))	('rs999885', 'Mutation', 'rs999885', (32, 40))	('rs1534309', 'Var', (205, 214))	('higher', 'PosReg', (224, 230))	('survival', 'CPA', (231, 239))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (248, 270))
235642	32089988	Survival analysis and joint effect analysis demonstrated that the combination of MCM2 and MCM6 could serve as HCC prognostic predictors.	('HCC', 'Phenotype', 'HP:0001402', (110, 113))	('MCM2', 'Var', (81, 85))	('MCM6', 'Gene', '4175', (90, 94))	('HCC', 'Gene', (110, 113))	('MCM6', 'Gene', (90, 94))	('HCC', 'Gene', '619501', (110, 113))
235671	32089988	IDH1 mutation, a classical biomarker in glioma, was reported to combinate MCM6 overexpressions to improve the prediction of the prognosis in glioblastomas.	('glioblastomas', 'Disease', 'MESH:D005909', (141, 154))	('glioma', 'Disease', 'MESH:D005910', (40, 46))	('improve', 'PosReg', (98, 105))	('glioblastomas', 'Disease', (141, 154))	('MCM6', 'Gene', (74, 78))	('glioma', 'Phenotype', 'HP:0009733', (40, 46))	('glioma', 'Disease', (40, 46))	('MCM6', 'Gene', '4175', (74, 78))	('IDH1', 'Gene', (0, 4))	('glioblastomas', 'Phenotype', 'HP:0012174', (141, 154))	('mutation', 'Var', (5, 13))	('IDH1', 'Gene', '3417', (0, 4))
235679	32089988	Knockdown of MCM6 was related to a delay in S/G2-phase progression with downregulation of CDK2, CDK4, CyclinA, CyclinB1, CyclinD1, and CyclinE in HCC.	('MCM6', 'Gene', (13, 17))	('CyclinA', 'Gene', (102, 109))	('downregulation', 'NegReg', (72, 86))	('CDK2', 'Gene', '1017', (90, 94))	('CyclinD1', 'Gene', '595', (121, 129))	('CDK2', 'Gene', (90, 94))	('delay', 'NegReg', (35, 40))	('CDK4', 'Gene', (96, 100))	('CyclinD1', 'Gene', (121, 129))	('S/G2', 'Var', (44, 48))	('CyclinA', 'Gene', '890', (102, 109))	('S/G2', 'SUBSTITUTION', 'None', (44, 48))	('CyclinB1', 'Gene', '891', (111, 119))	('CDK4', 'Gene', '1019', (96, 100))	('CyclinB1', 'Gene', (111, 119))	('HCC', 'Gene', '619501', (146, 149))	('Knockdown', 'Var', (0, 9))	('HCC', 'Phenotype', 'HP:0001402', (146, 149))	('MCM6', 'Gene', '4175', (13, 17))	('HCC', 'Gene', (146, 149))
235680	32089988	Silencing of MCM7 reduced cyclinD1, cyclinE2, and CDK2, which triggered events in the G1 or G1/S phase.	('MCM7', 'Gene', (13, 17))	('cyclinD1', 'Gene', '595', (26, 34))	('triggered', 'Reg', (62, 71))	('reduced', 'NegReg', (18, 25))	('cyclinD1', 'Gene', (26, 34))	('cyclinE2', 'Gene', (36, 44))	('CDK2', 'Gene', (50, 54))	('MCM7', 'Gene', '4176', (13, 17))	('cyclinE2', 'Gene', '9134', (36, 44))	('Silencing', 'Var', (0, 9))	('CDK2', 'Gene', '1017', (50, 54))
235682	32089988	Besides, results of western blot analysis showed that beta-catenin and cyclin D1 were downregulated in MCM10 knockdown cells, suggesting that downregulated MCM10 suppressed metastasis in breast cancer via the Wnt/beta-catenin pathway.	('breast cancer', 'Phenotype', 'HP:0003002', (187, 200))	('beta-catenin', 'Gene', '1499', (213, 225))	('MCM10', 'Gene', (103, 108))	('MCM10', 'Gene', '55388', (103, 108))	('cyclin D1', 'Gene', '595', (71, 80))	('beta-catenin', 'Gene', '1499', (54, 66))	('metastasis', 'CPA', (173, 183))	('cyclin D1', 'Gene', (71, 80))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('downregulated', 'NegReg', (86, 99))	('beta-catenin', 'Gene', (54, 66))	('MCM10', 'Gene', '55388', (156, 161))	('downregulated', 'Var', (142, 155))	('suppressed', 'NegReg', (162, 172))	('MCM10', 'Gene', (156, 161))	('breast cancer', 'Disease', 'MESH:D001943', (187, 200))	('beta-catenin', 'Gene', (213, 225))	('breast cancer', 'Disease', (187, 200))
235687	32089988	In this research, a protein-protein interaction between overexpressed mutant p53 and MCM2/4 was directly detected.	('MCM2/4', 'Gene', '4171;4173', (85, 91))	('MCM2/4', 'Gene', (85, 91))	('protein-protein', 'Protein', (20, 35))	('mutant', 'Var', (70, 76))	('overexpressed', 'PosReg', (56, 69))	('detected', 'Reg', (105, 113))	('p53', 'Gene', (77, 80))	('p53', 'Gene', '7157', (77, 80))
235688	32089988	Moreover, MCM2-7 was required for synergistic mutant p53-dependent induction of apoptosis by the combination of the poly ADP-ribose polymerase inhibitor talazoparib and the alkylating agent temozolomide, indicating a mutant p53-poly-ADP-ribose polymerase minichromosome maintenance functional axis.	('p53', 'Gene', (224, 227))	('p53', 'Gene', '7157', (224, 227))	('poly ADP-ribose polymerase', 'Gene', '142', (116, 142))	('talazoparib', 'Chemical', 'MESH:C586365', (153, 164))	('poly ADP-ribose polymerase', 'Gene', (116, 142))	('mutant', 'Var', (46, 52))	('p53', 'Gene', (53, 56))	('p53', 'Gene', '7157', (53, 56))	('temozolomide', 'Chemical', 'MESH:D000077204', (190, 202))	('MCM2-7', 'Gene', '4171;4172;4173;4174;4175;4176', (10, 16))	('MCM2-7', 'Gene', (10, 16))
235691	32089988	Silencing of MCM7 inhibited the phosphorylation of AKT1 and mTOR in both esophageal cancer cell lines, suggesting that MCM7 might promote cancer development and poor survival outcomes via activating the AKT1/mTOR signaling pathway.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('cancer', 'Disease', (138, 144))	('MCM7', 'Gene', (119, 123))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('mTOR', 'Gene', '2475', (60, 64))	('MCM7', 'Gene', '4176', (119, 123))	('phosphorylation', 'MPA', (32, 47))	('Silencing', 'Var', (0, 9))	('MCM7', 'Gene', (13, 17))	('AKT1', 'Gene', '207', (51, 55))	('AKT1', 'Gene', '207', (203, 207))	('mTOR', 'Gene', (208, 212))	('esophageal cancer', 'Disease', 'MESH:D004938', (73, 90))	('inhibited', 'NegReg', (18, 27))	('poor survival outcomes', 'CPA', (161, 183))	('MCM7', 'Gene', '4176', (13, 17))	('cancer', 'Disease', 'MESH:D009369', (138, 144))	('activating', 'PosReg', (188, 198))	('AKT1', 'Gene', (51, 55))	('esophageal cancer', 'Disease', (73, 90))	('cancer', 'Disease', (84, 90))	('AKT1', 'Gene', (203, 207))	('mTOR', 'Gene', '2475', (208, 212))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('promote', 'PosReg', (130, 137))	('mTOR', 'Gene', (60, 64))
235694	32089988	Improper modifications might be mechanisms for cancer development and adverse prognosis.	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('Improper modifications', 'Var', (0, 22))	('mechanisms', 'Reg', (32, 42))	('cancer', 'Disease', (47, 53))	('modifications', 'Var', (9, 22))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))
235696	32089988	Dysfunctional phosphorylation of MCMs is suggested to be associated with oncogenesis and cancer development.	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('MCMs', 'Gene', (33, 37))	('cancer', 'Disease', (89, 95))	('oncogenesis', 'CPA', (73, 84))	('Dysfunctional phosphorylation', 'Var', (0, 29))	('associated', 'Reg', (57, 67))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
235708	32089988	A previous study indicated that MCM6 triggered the S/G2 phase transition.	('S/G2', 'Var', (51, 55))	('MCM6', 'Gene', (32, 36))	('S/G2', 'SUBSTITUTION', 'None', (51, 55))	('MCM6', 'Gene', '4175', (32, 36))
235722	32089988	Considering the cross-talk between phosphorylation and sumoylation, as well as the proliferation-promoting effect of restrained ubiquitylation, manipulation of sumoylation and ubiquitylation may be a potential method for MCM-targeted cancer therapy.	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('restrained ubiquitylation', 'MPA', (117, 142))	('proliferation-promoting', 'CPA', (83, 106))	('talk', 'Gene', (22, 26))	('talk', 'Gene', '659', (22, 26))	('cancer', 'Disease', 'MESH:D009369', (234, 240))	('manipulation', 'Var', (144, 156))	('cancer', 'Disease', (234, 240))
235734	30076413	Five-year survival rates range from 67% for patients with T1N0 disease, to 23% for T1-3N2 disease, to about 1-10% for metastatic patients.	('T1N0', 'Var', (58, 62))	('patients', 'Species', '9606', (129, 137))	('T1-3N2', 'Var', (83, 89))	('patients', 'Species', '9606', (44, 52))
235737	30076413	Cis-diamminedichloroplatinum(II) (Cisplatin, CDDP), and its analogues oxaliplatin and carboplatin, cause various types of DNA crosslinks, single and double strand breaks (DSBs), leading to cell cycle arrest and, eventually, cell death.	('Cis-diamminedichloroplatinum', 'Chemical', 'MESH:D002945', (0, 28))	('arrest', 'Disease', 'MESH:D006323', (200, 206))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (70, 81))	('DNA crosslinks', 'MPA', (122, 136))	('Cis-diamminedichloroplatinum', 'Var', (0, 28))	('carboplatin', 'Chemical', 'MESH:D016190', (86, 97))	('arrest', 'Disease', (200, 206))	('leading to', 'Reg', (178, 188))	('DSBs', 'Chemical', '-', (171, 175))	('cell death', 'CPA', (224, 234))	('Cisplatin', 'Chemical', 'MESH:D002945', (34, 43))	('CDDP', 'Chemical', '-', (45, 49))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (189, 206))
235742	30076413	RANBP9 silencing results in reduced activation of the ATM pathway, deficiency of the homology-directed repair (HDR), and enhanced sensitivity to genotoxic treatments.	('reduced', 'NegReg', (28, 35))	('deficiency', 'NegReg', (67, 77))	('sensitivity to genotoxic treatments', 'MPA', (130, 165))	('ATM', 'Gene', (54, 57))	('activation', 'PosReg', (36, 46))	('enhanced', 'PosReg', (121, 129))	('RANBP9', 'Gene', (0, 6))	('ATM', 'Gene', '472', (54, 57))	('silencing', 'Var', (7, 16))
235744	30076413	We also performed in vitro and in vivo experiments showing increased sensitivity to platinum compounds and PARP inhibitors of NSCLC cells in which RANBP9 is genetically ablated.	('NSCLC', 'Disease', 'MESH:D002289', (126, 131))	('PARP', 'Gene', '142', (107, 111))	('sensitivity', 'MPA', (69, 80))	('platinum', 'Chemical', 'MESH:D010984', (84, 92))	('RANBP9', 'Gene', (147, 153))	('NSCLC', 'Phenotype', 'HP:0030358', (126, 131))	('genetically ablated', 'Var', (157, 176))	('LC', 'Phenotype', 'HP:0100526', (129, 131))	('PARP', 'Gene', (107, 111))	('increased', 'PosReg', (59, 68))	('NSCLC', 'Disease', (126, 131))
235762	30076413	To further validate this antibody, we generated subcutaneous xenografts using previously described and validated H460 and H1299 lung cancer cells, stably transduced with an anti-RANBP9 shRNA (shRANBP9) or control vector (shCTRL).	('H1299 lung cancer', 'Disease', 'MESH:D008175', (122, 139))	('lung cancer', 'Phenotype', 'HP:0100526', (128, 139))	('anti-RANBP9', 'Var', (173, 184))	('H1299 lung cancer', 'Disease', (122, 139))	('H460', 'CellLine', 'CVCL:0459', (113, 117))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
235785	30076413	Accordingly, CDDP treatment resulted in a significant reduction of colony formation by RANBP9 KO compared to WT clones (Fig.	('reduction', 'NegReg', (54, 63))	('RANBP9 KO', 'Var', (87, 96))	('colony formation', 'CPA', (67, 83))	('CDDP', 'Chemical', '-', (13, 17))
235789	30076413	To test whether the absence of RANBP9 in NSCLC cells caused an increased sensitivity to cisplatin in vivo, we injected A549 RANBP9 WT and KO cells subcutaneously into athymic nude mice.	('NSCLC', 'Disease', (41, 46))	('NSCLC', 'Disease', 'MESH:D002289', (41, 46))	('sensitivity to cisplatin', 'MPA', (73, 97))	('cisplatin', 'Chemical', 'MESH:D002945', (88, 97))	('RANBP9', 'Gene', (31, 37))	('LC', 'Phenotype', 'HP:0100526', (44, 46))	('nude mice', 'Species', '10090', (175, 184))	('absence', 'Var', (20, 27))	('NSCLC', 'Phenotype', 'HP:0030358', (41, 46))	('A549', 'CellLine', 'CVCL:0023', (119, 123))
235792	30076413	Overall, these results show that the absence of RANBP9 renders NSCLC cells sensitive to platinum-based drugs both in vitro and in vivo.	('NSCLC', 'Disease', (63, 68))	('sensitive to platinum-based drugs', 'MPA', (75, 108))	('NSCLC', 'Disease', 'MESH:D002289', (63, 68))	('LC', 'Phenotype', 'HP:0100526', (66, 68))	('absence', 'Var', (37, 44))	('platinum', 'Chemical', 'MESH:D010984', (88, 96))	('RANBP9', 'Gene', (48, 54))	('NSCLC', 'Phenotype', 'HP:0030358', (63, 68))
235800	30076413	After a median follow-up of 69.8 months, 63.5% of RANBP9low (H-score <= 100 or less than 10% of cells with moderate to strong RANBP9 intensity staining) and 86.1% of patients RANBP9high (H-score > 100 or at least 10% of cells with moderate to strong RANBP9 intensity staining) had died (Table S4C).	('RANBP9low', 'Var', (50, 59))	('RANBP9high', 'Var', (175, 185))	('patients', 'Species', '9606', (166, 174))
235802	30076413	The median progression free survival (PFS, defined as the time from the first-line treatment start to the date of progression or death from any cause, whichever came first) at the platinum-based first-line treatment for RANBP9low patients was 11 months, while for RANBP9high patients was 4.5 months (Table S4D).	('RANBP9low', 'Var', (220, 229))	('platinum', 'Chemical', 'MESH:D010984', (180, 188))	('patients', 'Species', '9606', (230, 238))	('progression', 'CPA', (11, 22))	('patients', 'Species', '9606', (275, 283))
235809	30076413	RANBP9 is a target and a facilitator of the ATM kinase and its silencing in NSCLC cells causes deficits of the HDR after IR exposure.	('HDR', 'MPA', (111, 114))	('ATM', 'Gene', (44, 47))	('NSCLC', 'Disease', (76, 81))	('LC', 'Phenotype', 'HP:0100526', (79, 81))	('RANBP9', 'Gene', (0, 6))	('NSCLC', 'Disease', 'MESH:D002289', (76, 81))	('deficits', 'MPA', (95, 103))	('ATM', 'Gene', '472', (44, 47))	('NSCLC', 'Phenotype', 'HP:0030358', (76, 81))	('silencing', 'Var', (63, 72))
235811	30076413	In comparison to controls, RANBP9 KO cells showed a reduced activation of ATM (S1981), Chk2 (T68) and p53 (S15).	('reduced', 'NegReg', (52, 59))	('ATM', 'Gene', (74, 77))	('p53', 'Gene', '7157', (102, 105))	('S1981', 'Var', (79, 84))	('activation', 'PosReg', (60, 70))	('ATM', 'Gene', '472', (74, 77))	('Chk2', 'Gene', '11200', (87, 91))	('p53', 'Gene', (102, 105))	('Chk2', 'Gene', (87, 91))
235814	30076413	5b) in comparison to RANBP9 WT controls, suggesting that the ablation of RANBP9 causes NSCLC cells to activate different cell-cycle checkpoints to cope with genotoxic stress.	('activate', 'PosReg', (102, 110))	('NSCLC', 'Disease', (87, 92))	('NSCLC', 'Disease', 'MESH:D002289', (87, 92))	('LC', 'Phenotype', 'HP:0100526', (90, 92))	('cell-cycle checkpoints', 'MPA', (121, 143))	('ablation', 'Var', (61, 69))	('NSCLC', 'Phenotype', 'HP:0030358', (87, 92))	('RANBP9', 'Gene', (73, 79))
235815	30076413	We also found that the absence of RANBP9 affects specifically the ATM-dependent but not the insulin-dependent activation of AKT, a well-known regulator of cell survival upon stress (Fig.	('ATM', 'Gene', '472', (66, 69))	('AKT', 'Gene', (124, 127))	('RANBP9', 'Gene', (34, 40))	('absence', 'Var', (23, 30))	('affects', 'Reg', (41, 48))	('ATM', 'Gene', (66, 69))	('AKT', 'Gene', '207', (124, 127))
235821	30076413	These data indicate that the loss of RANBP9 causes an increase of PARylated proteins bound to the chromatin of NSCLC cells.	('bound', 'Interaction', (85, 90))	('NSCLC', 'Disease', (111, 116))	('increase', 'PosReg', (54, 62))	('NSCLC', 'Disease', 'MESH:D002289', (111, 116))	('LC', 'Phenotype', 'HP:0100526', (114, 116))	('loss', 'Var', (29, 33))	('PARylated proteins', 'Protein', (66, 84))	('NSCLC', 'Phenotype', 'HP:0030358', (111, 116))	('RANBP9', 'Gene', (37, 43))
235822	30076413	To investigate whether RANBP9 absence affected NSCLC sensitivity to PARPi, we treated A549 WT and KO clones with AZD2281 (olaparib).	('PARP', 'Gene', (68, 72))	('olaparib', 'Chemical', 'MESH:C531550', (122, 130))	('absence', 'Var', (30, 37))	('NSCLC', 'Phenotype', 'HP:0030358', (47, 52))	('RANBP9', 'Gene', (23, 29))	('A549', 'CellLine', 'CVCL:0023', (86, 90))	('PARP', 'Gene', '142', (68, 72))	('LC', 'Phenotype', 'HP:0100526', (50, 52))	('NSCLC', 'Disease', (47, 52))	('AZD2281', 'Chemical', 'MESH:C531550', (113, 120))	('NSCLC', 'Disease', 'MESH:D002289', (47, 52))
235823	30076413	RANBP9 KO cells were significantly less in numbers and formed also significantly fewer colonies than controls in response to olaparib (Fig.	('less', 'NegReg', (35, 39))	('colonies', 'CPA', (87, 95))	('fewer', 'NegReg', (81, 86))	('olaparib', 'Chemical', 'MESH:C531550', (125, 133))	('RANBP9', 'Var', (0, 6))
235825	30076413	Thus, we evaluated the effect of RANBP9 ablation on H2AX phosphorylation and DNA repair by HDR following exposure of cells to olaparib.	('RANBP9', 'Gene', (33, 39))	('ablation', 'Var', (40, 48))	('H2AX', 'Gene', (52, 56))	('olaparib', 'Chemical', 'MESH:C531550', (126, 134))	('H2AX', 'Gene', '3014', (52, 56))
235826	30076413	6d, e and S6D-E, olaparib was able to induce gammaH2AX foci in RANBP9 WT cells while they were almost absent in KO cells.	('H2AX', 'Gene', '3014', (50, 54))	('induce', 'PosReg', (38, 44))	('olaparib', 'Chemical', 'MESH:C531550', (17, 25))	('S6D-E', 'Var', (10, 15))	('H2AX', 'Gene', (50, 54))
235828	30076413	Overall, RANBP9 KO cells displayed reduced growth and increased late-apoptosis activation in comparison with WT cells upon treatment with CDDP, olaparib or the combination of the two drugs (Fig.	('RANBP9', 'Var', (9, 15))	('CDDP', 'Chemical', '-', (138, 142))	('olaparib', 'Chemical', 'MESH:C531550', (144, 152))	('reduced', 'NegReg', (35, 42))	('late-apoptosis activation', 'MPA', (64, 89))	('increased', 'PosReg', (54, 63))
235830	30076413	Moreover, inhibition of PARP in the absence of RANBP9 results in reduced NSCLC cell proliferation and enhanced apoptosis alone or in combination with CDDP.	('enhanced', 'PosReg', (102, 110))	('reduced', 'NegReg', (65, 72))	('RANBP9', 'Gene', (47, 53))	('LC', 'Phenotype', 'HP:0100526', (76, 78))	('PARP', 'Gene', (24, 28))	('CDDP', 'Chemical', '-', (150, 154))	('NSCLC', 'Disease', (73, 78))	('NSCLC', 'Phenotype', 'HP:0030358', (73, 78))	('NSCLC', 'Disease', 'MESH:D002289', (73, 78))	('inhibition', 'Var', (10, 20))	('PARP', 'Gene', '142', (24, 28))	('apoptosis', 'CPA', (111, 120))
235842	30076413	However, it is tempting to speculate that RANBP9, similarly to other DDR players, might display both pro- and anti-tumorigenic functions, depending on multiple factors such as the cellular context, the molecular partners and the tumorigenesis status.	('tumor', 'Disease', 'MESH:D009369', (229, 234))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('tumor', 'Disease', (115, 120))	('RANBP9', 'Var', (42, 48))	('tumor', 'Disease', (229, 234))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
235844	30076413	Regarding the clinical relevance of our findings, it was previously shown that NSCLC cell lines silenced for RANBP9 were more sensitive to ionizing radiation and CDDP.	('CDDP', 'MPA', (162, 166))	('RANBP9', 'Gene', (109, 115))	('NSCLC', 'Disease', 'MESH:D002289', (79, 84))	('CDDP', 'Chemical', '-', (162, 166))	('silenced', 'Var', (96, 104))	('sensitive', 'MPA', (126, 135))	('NSCLC', 'Phenotype', 'HP:0030358', (79, 84))	('LC', 'Phenotype', 'HP:0100526', (82, 84))	('more', 'PosReg', (121, 125))	('NSCLC', 'Disease', (79, 84))
235850	30076413	Relevant to this limitation in our study, it has been demonstrated that, while abrogation/ deficiency of the ATM-dependent pathways (including the ATM-MDC1-BRCA1/RAP80/ABRAXAS pathway) enhances the sensitivity to platinum-based drugs, the opposite effect is observed in response to microtubule-targeting agents.	('RAP80', 'Gene', '51720', (162, 167))	('RAP80', 'Gene', (162, 167))	('deficiency', 'NegReg', (91, 101))	('platinum', 'Chemical', 'MESH:D010984', (213, 221))	('ATM', 'Gene', (109, 112))	('ATM', 'Gene', (147, 150))	('ATM', 'Gene', '472', (109, 112))	('enhances', 'PosReg', (185, 193))	('MDC1', 'Gene', (151, 155))	('ATM', 'Gene', '472', (147, 150))	('MDC1', 'Gene', '9656', (151, 155))	('abrogation/', 'Var', (79, 90))	('BRCA1', 'Gene', '672', (156, 161))	('sensitivity', 'MPA', (198, 209))	('BRCA1', 'Gene', (156, 161))
235852	30076413	In certain tumor types such as ovarian cancer, somatic alterations in BRCA1 or BRCA2 genes result in a dramatic defect of HDR (frequently reported as "BRCAness phenotype"), making cancer cells dependent on PARP activity.	('BRCA', 'Gene', (151, 155))	('BRCA', 'Gene', (79, 83))	('ovarian cancer', 'Phenotype', 'HP:0100615', (31, 45))	('BRCA', 'Gene', '672', (70, 74))	('BRCA2', 'Gene', (79, 84))	('HDR', 'MPA', (122, 125))	('defect', 'NegReg', (112, 118))	('cancer', 'Disease', (39, 45))	('tumor', 'Disease', (11, 16))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('BRCA', 'Gene', (70, 74))	('tumor', 'Disease', 'MESH:D009369', (11, 16))	('cancer', 'Disease', (180, 186))	('BRCA2', 'Gene', '675', (79, 84))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('ovarian cancer', 'Disease', 'MESH:D010051', (31, 45))	('PARP', 'Gene', '142', (206, 210))	('BRCA', 'Gene', '672', (151, 155))	('BRCA', 'Gene', '672', (79, 83))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('alterations', 'Var', (55, 66))	('BRCA1', 'Gene', '672', (70, 75))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('PARP', 'Gene', (206, 210))	('BRCA1', 'Gene', (70, 75))	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('ovarian cancer', 'Disease', (31, 45))
235863	30076413	Finally, our data also suggest RANBP9 inhibition as a new potential strategy for targeting the DDR in NSCLC patients.	('NSCLC', 'Disease', 'MESH:D002289', (102, 107))	('NSCLC', 'Phenotype', 'HP:0030358', (102, 107))	('RANBP9', 'Gene', (31, 37))	('inhibition', 'Var', (38, 48))	('patients', 'Species', '9606', (108, 116))	('LC', 'Phenotype', 'HP:0100526', (105, 107))	('NSCLC', 'Disease', (102, 107))
235867	31144617	Notably, we show that squamous tumors are dependent NRG1 signaling in vivo, in both genetically engineered mouse models and human xenograft models, and demonstrate that inhibition of NRG1 induces keratinization and terminal squamous differentiation of tumor cells, blocking proliferation and inhibiting tumor growth.	('blocking', 'NegReg', (265, 273))	('tumor', 'Phenotype', 'HP:0002664', (303, 308))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('tumor', 'Disease', 'MESH:D009369', (252, 257))	('NRG1', 'Gene', (183, 187))	('inhibition', 'Var', (169, 179))	('induces', 'Reg', (188, 195))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('keratinization', 'CPA', (196, 210))	('squamous tumors', 'Disease', (22, 37))	('tumor', 'Phenotype', 'HP:0002664', (252, 257))	('squamous tumors', 'Disease', 'MESH:D002294', (22, 37))	('terminal squamous differentiation', 'CPA', (215, 248))	('mouse', 'Species', '10090', (107, 112))	('tumor', 'Disease', (303, 308))	('proliferation', 'CPA', (274, 287))	('tumor', 'Disease', 'MESH:D009369', (303, 308))	('tumor', 'Disease', (31, 36))	('inhibiting', 'NegReg', (292, 302))	('human', 'Species', '9606', (124, 129))	('tumor', 'Disease', (252, 257))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
235870	31144617	Amplifications of master regulators act as oncogenic drivers in cancers arising in the tissues whose development they normally control.	('cancers', 'Phenotype', 'HP:0002664', (64, 71))	('cancers', 'Disease', 'MESH:D009369', (64, 71))	('cancers', 'Disease', (64, 71))	('Amplifications', 'Var', (0, 14))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
235874	31144617	Despite varied anatomic origins, squamous cell cancers (SCCs) share many common properties, including genetic and epigenetic alterations.	('epigenetic alterations', 'Var', (114, 136))	('SCC', 'Gene', (56, 59))	('cancers', 'Phenotype', 'HP:0002664', (47, 54))	('squamous cell cancers', 'Disease', (33, 54))	('squamous cell cancers', 'Phenotype', 'HP:0002860', (33, 54))	('SCC', 'Gene', '6317', (56, 59))	('squamous cell cancers', 'Disease', 'MESH:D002294', (33, 54))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))
235876	31144617	Amplification of TP63 is prevalent in SCCs, and TP63 expression is used to distinguish SCCs from other cancer subtypes in multiple tissues.	('prevalent', 'Reg', (25, 34))	('Amplification', 'Var', (0, 13))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('SCC', 'Gene', (38, 41))	('SCC', 'Gene', (87, 90))	('SCC', 'Gene', '6317', (38, 41))	('TP63', 'Gene', (17, 21))	('SCC', 'Gene', '6317', (87, 90))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))
235878	31144617	Here we show that NRG1 expression is directly regulated by TP63 in SCCs of various organs, and that co-expression of NRG1 and its receptor ERBB3 is prevalent in SCCs.	('regulated', 'Reg', (46, 55))	('SCC', 'Gene', (161, 164))	('TP63', 'Var', (59, 63))	('SCC', 'Gene', '6317', (161, 164))	('SCC', 'Gene', (67, 70))	('NRG1', 'Gene', (117, 121))	('ERBB3', 'Gene', '13867', (139, 144))	('NRG1', 'Gene', (18, 22))	('SCC', 'Gene', '6317', (67, 70))	('ERBB3', 'Gene', (139, 144))	('expression', 'MPA', (23, 33))
235880	31144617	In addition, TP63 acts as a key survival factor and driver of SCCs.	('SCC', 'Gene', '6317', (62, 65))	('TP63', 'Var', (13, 17))	('SCC', 'Gene', (62, 65))
235883	31144617	Despite lacking this domain, deltaN-TP63, the major isoform expressed in SCCs, functions as both a positive and negative transcriptional regulator of different target gene subsets.	('SCC', 'Gene', '6317', (73, 76))	('deltaN-TP63', 'Var', (29, 40))	('SCC', 'Gene', (73, 76))	('lacking', 'NegReg', (8, 15))
235886	31144617	Together, these data suggest that deltaN-TP63 directly regulates NRG1 transcription in SCC.	('SCC', 'Gene', (87, 90))	('NRG1', 'Gene', (65, 69))	('transcription', 'MPA', (70, 83))	('deltaN-TP63', 'Var', (34, 45))	('SCC', 'Gene', '6317', (87, 90))	('regulates', 'Reg', (55, 64))
235887	31144617	Emerging evidence suggest that high ERBB3 or high NRG1 expression is associated with poor clinical outcome in SCCs.	('ERBB3', 'Gene', (36, 41))	('NRG1', 'Gene', (50, 54))	('SCC', 'Gene', '6317', (110, 113))	('SCC', 'Gene', (110, 113))	('expression', 'MPA', (55, 65))	('high', 'Protein', (45, 49))	('high', 'Var', (31, 35))	('ERBB3', 'Gene', '13867', (36, 41))
235889	31144617	Interestingly, NRG1/ERBB3 co-expression appeared prevalent in lung and head and neck SCCs, but was notably rare in lung adenocarcinoma across the various cancer datasets available in TCGA (Figure 2A).	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('prevalent', 'Reg', (49, 58))	('co-expression', 'Var', (26, 39))	('rare', 'Reg', (107, 111))	('ERBB3', 'Gene', (20, 25))	('ERBB3', 'Gene', '13867', (20, 25))	('SCC', 'Gene', '6317', (85, 88))	('lung', 'Disease', (62, 66))	('lung adenocarcinoma', 'Disease', (115, 134))	('cancer', 'Disease', (154, 160))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (115, 134))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('SCC', 'Gene', (85, 88))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (115, 134))
235894	31144617	Importantly, anti-NRG1 treatment markedly inhibited tumor growth in each of these models to an extent that far exceeded that observed in vitro.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumor', 'Disease', (52, 57))	('anti-NRG1', 'Var', (13, 22))	('inhibited', 'NegReg', (42, 51))	('tumor', 'Disease', 'MESH:D009369', (52, 57))
235896	31144617	To further evaluate the NRG1-dependency in ERBB3/NRG1 co-expressing squamous cell cancers, we tested the efficacy of anti-NRG1 in lung SCC PDX models.	('ERBB3', 'Gene', (43, 48))	('tested', 'Reg', (94, 100))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('cancers', 'Phenotype', 'HP:0002664', (82, 89))	('squamous cell cancers', 'Disease', (68, 89))	('SCC', 'Gene', (135, 138))	('squamous cell cancers', 'Phenotype', 'HP:0002860', (68, 89))	('anti-NRG1', 'Var', (117, 126))	('ERBB3', 'Gene', '13867', (43, 48))	('squamous cell cancers', 'Disease', 'MESH:D002294', (68, 89))	('SCC', 'Gene', '6317', (135, 138))
235897	31144617	Again, anti-NRG1 significantly inhibited the tumor growth of three models that co-express NRG1 and ERBB3, resulting in tumor stasis (Figure 3B and Figure 3:figure supplement 1).	('ERBB3', 'Gene', '13867', (99, 104))	('tumor', 'Disease', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('ERBB3', 'Gene', (99, 104))	('tumor', 'Disease', (45, 50))	('anti-NRG1', 'Var', (7, 16))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('inhibited', 'NegReg', (31, 40))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('NRG1', 'Gene', (90, 94))
235899	31144617	Furthermore, mice with Krt5-Cre-driven knockout of Erbb3 in basal progenitor cells are resistant to carcinogen-induced skin tumorigenesis and exhibit defective wound healing, while Krt5-driven overexpression of deltaN-TP63 enhances carcinogen-induced skin tumorigenesis.	('mice', 'Species', '10090', (13, 17))	('Krt5', 'Gene', (23, 27))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('defective wound healing', 'Phenotype', 'HP:0001058', (150, 173))	('knockout', 'Var', (39, 47))	('defective', 'NegReg', (150, 159))	('Krt5', 'Gene', '110308', (23, 27))	('tumor', 'Disease', (124, 129))	('Krt5', 'Gene', (181, 185))	('Krt5', 'Gene', '110308', (181, 185))	('Erbb3', 'Gene', '13867', (51, 56))	('tumor', 'Disease', 'MESH:D009369', (256, 261))	('wound healing', 'CPA', (160, 173))	('tumor', 'Phenotype', 'HP:0002664', (256, 261))	('enhances', 'PosReg', (223, 231))	('Erbb3', 'Gene', (51, 56))	('tumor', 'Disease', (256, 261))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
235901	31144617	In this highly aggressive tumor model, anti-NRG1 dramatically increased the progression free survival (PFS) compared to control treatment, nearly doubling time to progression from 14 to 27 days (p<0.002) (Figure 3C-D).	('increased', 'PosReg', (62, 71))	('anti-NRG1', 'Var', (39, 48))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('tumor', 'Disease', (26, 31))	('progression free survival', 'CPA', (76, 101))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('progression', 'MPA', (163, 174))
235905	31144617	We tested the effect of anti-NRG1 on a panel of ovarian cancer cell lines and indeed proliferation of cell lines expressing both NRG1 and ERBB3 was inhibited by anti-NRG1 in vitro (Figure 3:figure supplement 2A).	('NRG1', 'Gene', (129, 133))	('ERBB3', 'Gene', '13867', (138, 143))	('proliferation', 'CPA', (85, 98))	('anti-NRG1', 'Var', (161, 170))	('ERBB3', 'Gene', (138, 143))	('tested', 'Reg', (3, 9))	('ovarian cancer', 'Disease', 'MESH:D010051', (48, 62))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('ovarian cancer', 'Phenotype', 'HP:0100615', (48, 62))	('inhibited', 'NegReg', (148, 157))	('ovarian cancer', 'Disease', (48, 62))
235910	31144617	Moreover, anti-NRG1-treated tumors showed a dramatic increase in the expression of KRT10, a differentiation-specific keratin normally restricted to the post-mitotic layers of stratified-keratinizing and cornifying epithelia (Figure 4A).	('anti-NRG1-treated', 'Var', (10, 27))	('KRT10', 'Gene', '16661', (83, 88))	('tumors', 'Disease', (28, 34))	('tumors', 'Disease', 'MESH:D009369', (28, 34))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('KRT10', 'Gene', (83, 88))	('expression', 'MPA', (69, 79))	('increase', 'PosReg', (53, 61))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
235911	31144617	Immunoblot analyses of treated tumors showed that anti-NRG1 inhibited ERBB3 activation and decreased the levels of multiple proliferation markers, consistent with a mechanism in which differentiation is induced at the expense of proliferation (Figure 4B and Figure 4:figure supplement 2).	('anti-NRG1', 'Var', (50, 59))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumors', 'Disease', (31, 37))	('ERBB3', 'Gene', '13867', (70, 75))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('inhibited', 'NegReg', (60, 69))	('activation', 'MPA', (76, 86))	('ERBB3', 'Gene', (70, 75))	('tumors', 'Disease', 'MESH:D009369', (31, 37))	('levels of multiple proliferation markers', 'MPA', (105, 145))	('decreased', 'NegReg', (91, 100))
235914	31144617	Treatment of SCC cell lines with anti-NRG1 in vitro also increased expression of the differentiation markers KRT1, KRT10, IVL and KRTDAP (Figure 4:figure supplement 3).	('KRT1', 'Gene', (109, 113))	('anti-NRG1', 'Var', (33, 42))	('KRTDAP', 'Gene', '64661', (130, 136))	('SCC', 'Gene', '6317', (13, 16))	('IVL', 'Gene', '16447', (122, 125))	('KRT10', 'Gene', '16661', (115, 120))	('KRT1', 'Gene', (115, 119))	('KRTDAP', 'Gene', (130, 136))	('KRT10', 'Gene', (115, 120))	('IVL', 'Gene', (122, 125))	('KRT1', 'Gene', '16678', (115, 119))	('increased', 'PosReg', (57, 66))	('expression', 'MPA', (67, 77))	('KRT1', 'Gene', '16678', (109, 113))	('SCC', 'Gene', (13, 16))
235919	31144617	In contrast, although NRG1 and ERBB3 co-expression is prevalent in ovarian tumors, ovarian cancer models did not respond to NRG1 inhibition in vivo.	('NRG1', 'Gene', (22, 26))	('prevalent', 'Reg', (54, 63))	('ovarian tumors', 'Disease', (67, 81))	('ERBB3', 'Gene', '13867', (31, 36))	('ovarian cancer', 'Phenotype', 'HP:0100615', (83, 97))	('ERBB3', 'Gene', (31, 36))	('ovarian tumors', 'Phenotype', 'HP:0100615', (67, 81))	('ovarian cancer', 'Disease', 'MESH:D010051', (83, 97))	('ovarian tumors', 'Disease', 'MESH:D010051', (67, 81))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('ovarian cancer', 'Disease', (83, 97))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('co-expression', 'Var', (37, 50))
235942	31144617	72 hr after siRNA transfection, cells were washed twice with PBS and lysed in RIPA buffer containing protease/phosphatase inhibitors at 4 C. Protein concentrations were determined by BCA (Thermo Scientific).	('transfection', 'Var', (18, 30))	('PBS', 'Disease', 'MESH:D011535', (61, 64))	('PBS', 'Disease', (61, 64))	('RIPA buffer', 'Chemical', '-', (78, 89))
235945	31144617	Antibodies: TP63 alpha (Cell Signaling Technologies, CST 13109), deltaNTP63 (Biolegend 619001), actin (BD Bioscience 612656), p-ERBB3 (CST 4791), ERBB3 (CST 12708), PARP (CST 9542) and Cleaved caspase-3 (CST 9664).	('Cleaved', 'MPA', (185, 192))	('PARP', 'Gene', (165, 169))	('PARP', 'Gene', '11545', (165, 169))	('ERBB3', 'Gene', '13867', (146, 151))	('CST 4791', 'Var', (135, 143))	('ERBB3', 'Gene', (146, 151))	('CST 12708', 'Var', (153, 162))	('caspase-3', 'Protein', (193, 202))	('ERBB3', 'Gene', '13867', (128, 133))	('actin', 'Gene', (96, 101))	('actin', 'Gene', '100342017', (96, 101))	('ERBB3', 'Gene', (128, 133))	('deltaNTP63', 'Gene', (65, 75))
235954	31144617	Although NRG1 has already been established as a TP63 target in breast cells and NRG1/ERBB signaling has already been reported to play a role in squamous cell carcinoma biology, a strength of the work is the use of human material, murine models and cancer cell lines as well as an antibody to block NRG, which suggests that blocking NRG may affect tumor maintenance.	('affect', 'Reg', (340, 346))	('cancer', 'Disease', (248, 254))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (144, 167))	('NRG', 'Gene', (298, 301))	('NRG', 'Gene', (332, 335))	('cancer', 'Disease', 'MESH:D009369', (248, 254))	('tumor', 'Disease', (347, 352))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (144, 167))	('cancer', 'Phenotype', 'HP:0002664', (248, 254))	('blocking', 'Var', (323, 331))	('carcinoma', 'Phenotype', 'HP:0030731', (158, 167))	('murine', 'Species', '10090', (230, 236))	('tumor', 'Disease', 'MESH:D009369', (347, 352))	('human', 'Species', '9606', (214, 219))	('squamous cell carcinoma', 'Disease', (144, 167))	('tumor', 'Phenotype', 'HP:0002664', (347, 352))
235968	31144617	Reviewer #2:  The authors show that NRG1 is a transcriptional target of p63 and argue that anti-NRG1 could be an effective therapy for a wide variety of squamous cell carcinomas.	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (153, 177))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (153, 176))	('anti-NRG1', 'Var', (91, 100))	('p63', 'Gene', '22061', (72, 75))	('carcinoma', 'Phenotype', 'HP:0030731', (167, 176))	('carcinomas', 'Phenotype', 'HP:0030731', (167, 177))	('p63', 'Gene', (72, 75))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (153, 177))	('squamous cell carcinomas', 'Disease', (153, 177))
235971	31144617	In addition, they show that treatment with an anti-NRG1 antibody inhibits the growth of SCC xenograft models and provide evidence that inhibition of NRG1 induces keratinization and terminal squamous differentiation of tumor cells.	('NRG1', 'Gene', (149, 153))	('terminal squamous differentiation', 'CPA', (181, 214))	('induces', 'Reg', (154, 161))	('inhibits', 'NegReg', (65, 73))	('tumor', 'Disease', 'MESH:D009369', (218, 223))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('keratinization', 'CPA', (162, 176))	('SCC', 'Gene', (88, 91))	('inhibition', 'Var', (135, 145))	('tumor', 'Disease', (218, 223))	('SCC', 'Gene', '6317', (88, 91))
235973	31144617	The authors provide some evidence that NRG1 inhibition decreases SCC cell proliferation and promotes cell differentiation.	('promotes', 'PosReg', (92, 100))	('inhibition', 'Var', (44, 54))	('SCC', 'Gene', (65, 68))	('NRG1', 'Gene', (39, 43))	('decreases', 'NegReg', (55, 64))	('SCC', 'Gene', '6317', (65, 68))	('cell differentiation', 'CPA', (101, 121))
235975	31144617	3) In Figure 1, it would be important to perform double IHC/IF to demonstrate co-localization of deltaN-TP63 and NRG1 at the protein level in tumor cells within human SCC tissue samples.	('human', 'Species', '9606', (161, 166))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('deltaN-TP63', 'Var', (97, 108))	('SCC', 'Gene', '6317', (167, 170))	('NRG1', 'Gene', (113, 117))	('tumor', 'Disease', (142, 147))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('SCC', 'Gene', (167, 170))
235983	31144617	As discussed in our final paragraph, EGFR and other signaling pathways also play an important role in driving these tumors and inhibition of NRG1 could drive deeper responses when combined with EGFR inhibition.	('tumors', 'Disease', (116, 122))	('tumors', 'Disease', 'MESH:D009369', (116, 122))	('EGFR', 'Gene', (37, 41))	('inhibition', 'Var', (127, 137))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('EGFR', 'Gene', (194, 198))	('EGFR', 'Gene', '13649', (194, 198))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))	('NRG1', 'Gene', (141, 145))	('EGFR', 'Gene', '13649', (37, 41))
235984	31144617	We carried out qPCR analysis of four differentiation markers in three different squamous cell carcinoma lines treated with anti-NRG1 or control antibody in vitro.	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (80, 103))	('squamous cell carcinoma lines', 'Disease', 'MESH:D002294', (80, 109))	('anti-NRG1', 'Var', (123, 132))	('squamous cell carcinoma lines', 'Disease', (80, 109))
236042	29423024	All three complement activation products were detected in dose-dependent logarithmic standard curves comprising four decades on a log-scale and either ranging from 0.2 to 0.00004 microg/mL for C3a (Figure 3A), 0.03-0.00003 microg/mL for C5a (Figure 3C) or 67-0.019 microg/mL for sC5b-9 (Figure 3E), respectively.	('C5b', 'Gene', (280, 283))	('C3a', 'Gene', (193, 196))	('C5b', 'Gene', '727', (280, 283))	('0.03-0.00003 microg/mL', 'Var', (210, 232))	('men', 'Species', '9606', (16, 19))	('C3a', 'Gene', '718', (193, 196))	('C5a', 'Gene', (237, 240))	('C5a', 'Gene', '728', (237, 240))
236104	29423024	Silencing PI3K/Akt in cancer cells eliminated C5aR and C3aR effects in cancer cells.	('C3aR', 'Gene', (55, 59))	('Akt', 'Gene', '207', (15, 18))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('cancer', 'Disease', (71, 77))	('cancer', 'Disease', (22, 28))	('C5aR', 'Gene', '728', (46, 50))	('Akt', 'Gene', (15, 18))	('C3aR', 'Gene', '719', (55, 59))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('eliminated', 'NegReg', (35, 45))	('Silencing', 'Var', (0, 9))	('C5aR', 'Gene', (46, 50))
236113	29423024	Moreover, knockdown of C3 and CFB markedly inhibited growth of human cSCC xenograft tumors in vivo.	('C3', 'Gene', '718', (23, 25))	('human', 'Species', '9606', (63, 68))	('CFB', 'Gene', (30, 33))	('inhibited', 'NegReg', (43, 52))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('growth of human', 'CPA', (53, 68))	('tumors', 'Disease', (84, 90))	('CFB', 'Gene', '629', (30, 33))	('tumors', 'Disease', 'MESH:D009369', (84, 90))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('knockdown', 'Var', (10, 19))
236172	32961992	We show here that DPT inhibited the kinase activity of epidermal growth factor receptor (EGFR) directly, as well as phosphorylation of its downstream signaling kinases, AKT, GSK-3beta, and ERK.	('DPT', 'Chemical', 'MESH:C014451', (18, 21))	('inhibited', 'NegReg', (22, 31))	('EGFR', 'Gene', (89, 93))	('DPT', 'Var', (18, 21))	('phosphorylation', 'MPA', (116, 131))	('epidermal growth factor receptor', 'Gene', (55, 87))	('kinase activity', 'MPA', (36, 51))	('AKT', 'Gene', (169, 172))	('ERK', 'Gene', '5594', (189, 192))	('epidermal growth factor receptor', 'Gene', '1956', (55, 87))	('GSK-3beta', 'Gene', '2931', (174, 183))	('AKT', 'Gene', '207', (169, 172))	('EGFR', 'Gene', '1956', (89, 93))	('GSK-3beta', 'Gene', (174, 183))	('ERK', 'Gene', (189, 192))
236187	32961992	EGFR phosphorylation specifically triggers the activation of PI3K/AKT and mitogen-activated protein kinase (MAPK) kinase/ERK signaling pathway.	('ERK', 'Gene', '5594', (121, 124))	('ERK', 'Gene', (121, 124))	('EGFR', 'Gene', (0, 4))	('AKT', 'Gene', (66, 69))	('phosphorylation', 'Var', (5, 20))	('activation', 'PosReg', (47, 57))	('AKT', 'Gene', '207', (66, 69))	('EGFR', 'Gene', '1956', (0, 4))
236206	32961992	As shown in Figure 1F, DPT not only inhibited EGFR kinase activity, but also suppressed EGFR and its downstream activation of AKT/GSK-3beta/ERK.	('suppressed', 'NegReg', (77, 87))	('AKT', 'Gene', (126, 129))	('inhibited', 'NegReg', (36, 45))	('activity', 'MPA', (58, 66))	('activation', 'PosReg', (112, 122))	('EGFR', 'Gene', '1956', (46, 50))	('GSK-3beta', 'Gene', '2931', (130, 139))	('ERK', 'Gene', '5594', (140, 143))	('EGFR', 'Gene', '1956', (88, 92))	('DPT', 'Chemical', 'MESH:C014451', (23, 26))	('EGFR', 'Gene', (46, 50))	('AKT', 'Gene', '207', (126, 129))	('DPT', 'Var', (23, 26))	('GSK-3beta', 'Gene', (130, 139))	('ERK', 'Gene', (140, 143))	('EGFR', 'Gene', (88, 92))
236211	32961992	IC50 values for DPT were approximately 7.64 nM (KYSE 30), 8.86 nM (KYSE 70), 8.92 nM (KYSE 410), 8.10 nM (KYSE 450), and 8.88 nM (KYSE 510) after 48 h of treatment, respectively.	('KYSE 450', 'Var', (106, 114))	('DPT', 'Chemical', 'MESH:C014451', (16, 19))	('KYSE 410', 'Var', (86, 94))	('KYSE 70', 'Var', (67, 74))
236214	32961992	Figure 2G,H shows that DPT prominently reduced the number of KYSE 30 and KYSE 450 cell colonies.	('KYSE 450 cell colonies', 'CPA', (73, 95))	('DPT', 'Chemical', 'MESH:C014451', (23, 26))	('reduced', 'NegReg', (39, 46))	('DPT', 'Var', (23, 26))	('KYSE 30', 'CPA', (61, 68))
236223	32961992	Multi-caspase activity in the control group was 5.4% and 3.8% in KYSE 30 and KYSE 450, respectively.	('KYSE', 'Var', (77, 81))	('caspase', 'Gene', (6, 13))	('activity', 'MPA', (14, 22))	('caspase', 'Gene', '834;835;837;838;839;841;842;843', (6, 13))
236238	32961992	The results demonstrated that DPT treatment (10 nM) led to depolarization of the MMP of 50.8 +- 2.7% and 49.2 +- 7.7% in the KYSE 30 and KYSE 450 ESCC cells, respectively (Figure 6A,B).	('depolarization', 'NegReg', (59, 73))	('MMP', 'MPA', (81, 84))	('DPT', 'Chemical', 'MESH:C014451', (30, 33))	('KYSE', 'Var', (137, 141))
236261	32961992	We found that DPT inhibited cell viability and elicited apoptosis in ESCC cells.	('DPT', 'Var', (14, 17))	('elicited', 'Reg', (47, 55))	('cell viability', 'CPA', (28, 42))	('DPT', 'Chemical', 'MESH:C014451', (14, 17))	('inhibited', 'NegReg', (18, 27))	('apoptosis', 'CPA', (56, 65))
236275	32961992	In our experiments, we found that DPT increases intracellular ROS levels in ESCC cells dose-dependently (Figure 5A,B).	('DPT', 'Chemical', 'MESH:C014451', (34, 37))	('increases intracellular ROS levels', 'Phenotype', 'HP:0025464', (38, 72))	('increases', 'PosReg', (38, 47))	('ROS', 'Chemical', 'MESH:D017382', (62, 65))	('DPT', 'Var', (34, 37))	('intracellular ROS levels', 'MPA', (48, 72))
236288	32961992	Based on our findings, DPT induces apoptosis by inhibiting the phosphorylation of EGFR directly in ESCC cells, and thus illustrates the mechanism behind its antitumor effects.	('EGFR', 'Gene', (82, 86))	('inhibiting', 'NegReg', (48, 58))	('DPT', 'Chemical', 'MESH:C014451', (23, 26))	('phosphorylation', 'MPA', (63, 78))	('DPT', 'Var', (23, 26))	('EGFR', 'Gene', '1956', (82, 86))
236297	32961992	Antibodies against p-EGFR (Tyr1068), EGFR, p-GSK-3beta (Ser9), GSK-3beta, p-ERK (Thr202/Tyr204), ERK, p-AKT (Ser473), and AKT were purchased from Cell Signaling Biotechnology (Beverly, MA, USA).	('Ser9', 'Chemical', '-', (56, 60))	('AKT', 'Gene', '207', (122, 125))	('Tyr1068', 'Chemical', '-', (27, 34))	('ERK', 'Gene', '5594', (97, 100))	('AKT', 'Gene', '207', (104, 107))	('EGFR', 'Gene', '1956', (21, 25))	('ERK', 'Gene', (76, 79))	('GSK-3beta', 'Gene', (45, 54))	('EGFR', 'Gene', '1956', (37, 41))	('GSK-3beta', 'Gene', '2931', (63, 72))	('ERK', 'Gene', (97, 100))	('Tyr204', 'Chemical', '-', (88, 94))	('AKT', 'Gene', (122, 125))	('Thr202', 'Chemical', '-', (81, 87))	('EGFR', 'Gene', (21, 25))	('GSK-3beta', 'Gene', (63, 72))	('AKT', 'Gene', (104, 107))	('Tyr1068', 'Var', (27, 34))	('Ser473', 'Chemical', '-', (109, 115))	('EGFR', 'Gene', (37, 41))	('GSK-3beta', 'Gene', '2931', (45, 54))	('ERK', 'Gene', '5594', (76, 79))
236303	32961992	ESCC cells (KYSE 30, KYSE 70, KYSE 410, KYSE 450, and KYSE 510) and JB6 cells were seeded in 96-well plates at 2.75 x 103, 10 x 103, 2.5 x 103, 3.5 x 103, 5.5 x 103, and 8 x 103 per 100 muL and incubated for 24 or 48 h after treatment with DPT (5, 7.5, and 10 nM).	('KYSE 70', 'Var', (21, 28))	('KYSE', 'Var', (12, 16))	('DPT', 'Chemical', 'MESH:C014451', (240, 243))	('KYSE 510', 'Var', (54, 62))	('JB6', 'CellLine', 'CVCL:H633', (68, 71))	('KYSE 450', 'Var', (40, 48))	('KYSE 410', 'Var', (30, 38))
236332	28420414	One particularly important process is the m1A/m1G RNA methylation of the ninth position of different mitochondrial tRNAs, which allows efficient processing of mitochondrial mRNAs and protein translation, and de-regulation of genes involved in these processes has been associated with altered mitochondrial function.	('mitochondrial function', 'MPA', (292, 314))	('mitochondrial mRNAs', 'MPA', (159, 178))	('tRNA', 'Gene', '4563', (115, 119))	('protein translation', 'MPA', (183, 202))	('tRNA', 'Gene', (115, 119))	('genes', 'Gene', (225, 230))	('de-regulation', 'Var', (208, 221))
236335	28420414	We focus on the levels of m1A and m1G RNA methylation in mitochondrial tRNAs in normal and tumor samples and use supervised and unsupervised statistical analysis to compare the levels of these modifications to patient whole genome genotypes, nuclear gene expression, and survival outcomes.	('m1A', 'Var', (26, 29))	('m1G RNA methylation', 'Var', (34, 53))	('tRNA', 'Gene', (71, 75))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('patient', 'Species', '9606', (210, 217))	('methylation', 'Var', (42, 53))	('tumor', 'Disease', (91, 96))	('tRNA', 'Gene', '4563', (71, 75))
236338	28420414	Furthermore, we report 18 gene-by-disease-state interactions where altered RNA methylation levels occur under cancer status conditional on genotype, implicating genes associated with mitochondrial function or cancer (e.g., CACNA2D2, LMO2, and FLT3) and suggesting that nuclear genetic variation can potentially modulate an individual's ability to maintain unaltered rates of mitochondrial RNA processing under cancer status.	('LMO2', 'Gene', '4005', (233, 237))	('LMO2', 'Gene', (233, 237))	('FLT3', 'Gene', (243, 247))	('mitochondrial RNA processing', 'MPA', (375, 403))	('cancer', 'Disease', 'MESH:D009369', (410, 416))	('FLT3', 'Gene', '2322', (243, 247))	('cancer', 'Disease', 'MESH:D009369', (209, 215))	('cancer', 'Disease', (110, 116))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('modulate', 'Reg', (311, 319))	('interactions', 'Var', (48, 60))	('cancer', 'Disease', (410, 416))	('CACNA2D2', 'Gene', (223, 231))	('cancer', 'Disease', (209, 215))	('CACNA2D2', 'Gene', '9254', (223, 231))	('implicating', 'Reg', (149, 160))	('cancer', 'Phenotype', 'HP:0002664', (410, 416))	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
236345	28420414	Second, mutations in nuclear-encoded mitochondrial genes have been identified in patients with cancer, with links to the disease well established in some cases.	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('cancer', 'Disease', (95, 101))	('mutations', 'Var', (8, 17))	('patients', 'Species', '9606', (81, 89))	('mitochondrial genes', 'Gene', (37, 56))	('identified', 'Reg', (67, 77))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))
236346	28420414	Third, increased numbers of mutations are consistently found in the mitochondrial genomes of tumor cells compared to normal samples.	('found', 'Reg', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Disease', (93, 98))	('mitochondrial genomes', 'MPA', (68, 89))	('mutations', 'Var', (28, 37))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
236347	28420414	These mutations may merely tag carcinogenesis, but whether other genetic properties of mitochondrial genomes are important in tumorigenesis remains one of the important unanswered questions in cancer biology.	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('cancer', 'Disease', (193, 199))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('mutations', 'Var', (6, 15))	('tumor', 'Disease', (126, 131))
236351	28420414	The polycistronic nature of mitochondrial transcription means that post-transcriptional events are particularly important: knockdown of RNA processing enzymes influences mitochondrial mRNA and protein levels, and mitochondrial function and the level of m1A and m1G post-transcriptional methylation at the ninth position of mitochondrial tRNAs (p9 sites) can potentially influence downstream metabolic phenotypes.	('mitochondrial function', 'MPA', (213, 235))	('influence', 'Reg', (370, 379))	('influences', 'Reg', (159, 169))	('RNA', 'Gene', (136, 139))	('tRNA', 'Gene', '4563', (337, 341))	('knockdown', 'Var', (123, 132))	('tRNA', 'Gene', (337, 341))
236352	28420414	Indeed, p9 site methylation is thought to influence the correct folding of mitochondrial tRNAs, thus affecting the rate of cleavage within the polycistronic transcript and potentially impacting upon their downstream roles in protein translation.	('p9 site methylation', 'Var', (8, 27))	('cleavage', 'MPA', (123, 131))	('tRNA', 'Gene', '4563', (89, 93))	('tRNA', 'Gene', (89, 93))	('correct folding', 'MPA', (56, 71))	('influence', 'Reg', (42, 51))	('rate', 'MPA', (115, 119))	('affecting', 'Reg', (101, 110))	('impacting', 'Reg', (184, 193))	('protein translation', 'MPA', (225, 244))
236354	28420414	For example, mutations within the mitochondrial processing enzyme RNase Z were found to be segregating with prostate cancer incidence in human pedigrees, and mutations within mitochondrial tRNAs, which are heavily post-transcriptionally modified, have been previously linked with cancer.	('human', 'Species', '9606', (137, 142))	('cancer', 'Disease', 'MESH:D009369', (280, 286))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('cancer', 'Disease', (117, 123))	('cancer', 'Disease', (280, 286))	('prostate cancer', 'Disease', 'MESH:D011471', (108, 123))	('linked', 'Reg', (268, 274))	('tRNA', 'Gene', '4563', (189, 193))	('prostate cancer', 'Phenotype', 'HP:0012125', (108, 123))	('tRNA', 'Gene', (189, 193))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('cancer', 'Phenotype', 'HP:0002664', (280, 286))	('mutations', 'Var', (13, 22))	('mutations', 'Var', (158, 167))	('prostate cancer', 'Disease', (108, 123))
236363	28420414	Recent work by Mercer et al., Sanchez et al., and ourselves has shown that sequence mismatches occur at a high rate at the ninth position of different mitochondrial tRNAs, which are positions that are known to be post-transcriptionally methylated, and subsequent experiments by ourselves have shown that the proportion of mismatches at these sites is systematic and repeatable across replication experiments.	('tRNA', 'Gene', '4563', (165, 169))	('sequence mismatches', 'Var', (75, 94))	('mismatches', 'Var', (84, 94))	('tRNA', 'Gene', (165, 169))
236397	28420414	Next, we investigated whether the observed differences in the levels of p9 site methylation are a general trend in cancer.	('cancer', 'Disease', (115, 121))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('p9 site methylation', 'Var', (72, 91))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))
236402	28420414	Next, for the same sites we tested whether p9 site methylation levels are associated with tRNA expression levels across normal and cancer samples combined.	('cancer', 'Disease', (131, 137))	('methylation', 'MPA', (51, 62))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('p9 site', 'Var', (43, 50))	('tested', 'Reg', (28, 34))	('tRNA', 'Gene', '4563', (90, 94))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('tRNA', 'Gene', (90, 94))	('associated', 'Reg', (74, 84))
236417	28420414	Given the general increase in the levels of p9 methylation in cancers, we assessed whether nuclear genetic variants could modulate the observed changes in mitochondrial RNA processing differentially in tumor relative to normal samples.	('increase', 'PosReg', (18, 26))	('tumor', 'Disease', (202, 207))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('variants', 'Var', (107, 115))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('modulate', 'Reg', (122, 130))	('cancers', 'Disease', 'MESH:D009369', (62, 69))	('cancers', 'Phenotype', 'HP:0002664', (62, 69))	('mitochondrial RNA processing', 'MPA', (155, 183))	('cancers', 'Disease', (62, 69))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))
236422	28420414	In doing so, we found an interaction effect for rs317391 in KIRC at p9 site 12146 (P = 2.16 x 10-5; interaction effect originally observed in BRCA at p9 site 7526, P = 2.46 x 10-9).	('BRCA', 'Phenotype', 'HP:0003002', (142, 146))	('BRCA', 'Gene', '672', (142, 146))	('rs317391', 'Var', (48, 56))	('BRCA', 'Gene', (142, 146))	('rs317391', 'Mutation', 'rs317391', (48, 56))
236424	28420414	We also found that rs341737 is an interaction SNP for the levels of methylation at p9 site 14734 in PRAD (P = 0.000745; interaction effect originally observed in LUAD at p9 site 14734, P = 9.86 x 10-9).	('methylation', 'MPA', (68, 79))	('LUAD', 'Phenotype', 'HP:0030078', (162, 166))	('rs341737', 'Mutation', 'rs341737', (19, 27))	('rs341737', 'Var', (19, 27))	('p9 site 14734', 'Var', (83, 96))
236426	28420414	The fact that these SNPs are also associated with similar effects in other cancer types suggests that our initial observations are robust.	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('SNPs', 'Var', (20, 24))	('cancer', 'Disease', (75, 81))	('cancer', 'Disease', 'MESH:D009369', (75, 81))
236431	28420414	The strongest effect occurs for p9 site 10413 (ninth position of TRNR; P = 0.000476).	('TRNR', 'Gene', '4573', (65, 69))	('p9 site 10413', 'Var', (32, 45))	('TRNR', 'Gene', (65, 69))
236435	28420414	We hypothesize that oncogenic signals trigger these changes, which in turn promote energetic plasticity in tumor cells in a manner that is not dependent on hard-coded mitochondrial genetic changes.	('promote', 'PosReg', (75, 82))	('tumor', 'Disease', (107, 112))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('changes', 'Var', (52, 59))	('energetic plasticity', 'MPA', (83, 103))
236438	28420414	This suggests that the downstream impacts of changes to p9 site methylation levels on mitochondrial gene expression are complex and may vary both along the polycistronic strand and in different cancer types.	('mitochondrial', 'MPA', (86, 99))	('cancer', 'Disease', (194, 200))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('changes', 'Var', (45, 52))	('cancer', 'Disease', 'MESH:D009369', (194, 200))
236444	28420414	Our tests to uncover genotype-by-disease-state interactions revealed 18 peak variants at genome-wide significance and these in vivo interaction effects serve as a promising starting point for a potential method to uncover biomarkers for predictable responses to cancer progression.	('cancer', 'Disease', (262, 268))	('variants', 'Var', (77, 85))	('cancer', 'Disease', 'MESH:D009369', (262, 268))	('cancer', 'Phenotype', 'HP:0002664', (262, 268))
236532	31650027	The crosstalk between BCL-xL and let-7a-5p was then investigated using dual-luciferase reporter assay, and it was found to suppress the migration and invasion of A549 cells.	('BCL-xL', 'Gene', '598', (22, 28))	('suppress', 'NegReg', (123, 131))	('BCL-xL', 'Gene', (22, 28))	('let-7a-5p', 'Var', (33, 42))
236534	31650027	These findings indicate that let-7a-5p is a sensitive initiator for toxic autophagy in A549 lung cancer cells and is an appealing target for lung cancer therapy.	('lung cancer', 'Disease', (92, 103))	('let-7a-5p', 'Var', (29, 38))	('lung cancer', 'Phenotype', 'HP:0100526', (92, 103))	('toxic autophagy', 'CPA', (68, 83))	('lung cancer', 'Disease', (141, 152))	('lung cancer', 'Disease', 'MESH:D008175', (92, 103))	('lung cancer', 'Phenotype', 'HP:0100526', (141, 152))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('lung cancer', 'Disease', 'MESH:D008175', (141, 152))
236547	31650027	A growing number of studies have demonstrated that miRNAs were tightly associated with lung cancer, while dysregulation of miRNAs led to the proliferation, migration, and invasion of lung cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('lung cancer', 'Disease', 'MESH:D008175', (87, 98))	('dysregulation', 'Var', (106, 119))	('invasion of lung cancer', 'Disease', 'MESH:D008175', (171, 194))	('lung cancer', 'Disease', 'MESH:D008175', (183, 194))	('migration', 'CPA', (156, 165))	('proliferation', 'CPA', (141, 154))	('invasion of lung cancer', 'Disease', (171, 194))	('lung cancer', 'Disease', (87, 98))	('led to', 'Reg', (130, 136))	('lung cancer', 'Phenotype', 'HP:0100526', (87, 98))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('lung cancer', 'Phenotype', 'HP:0100526', (183, 194))	('associated', 'Reg', (71, 81))
236549	31650027	Moreover, the expression of a certain number of miRNAs, including miR-146a-5p, miR-324-5p, miR-223-3p, and miR-223-5p, was detected to be altered in the cytologically normal bronchial epithelium of smokers with lung cancer, which may serve as potential targets for the treatment of lung cancer.	('lung cancer', 'Phenotype', 'HP:0100526', (211, 222))	('lung cancer', 'Disease', 'MESH:D008175', (282, 293))	('miR-223-5p', 'Var', (107, 117))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('altered', 'Reg', (138, 145))	('expression', 'MPA', (14, 24))	('miR-223-3p', 'Var', (91, 101))	('lung cancer', 'Disease', 'MESH:D008175', (211, 222))	('men', 'Species', '9606', (274, 277))	('lung cancer', 'Disease', (282, 293))	('cancer', 'Phenotype', 'HP:0002664', (287, 293))	('lung cancer', 'Phenotype', 'HP:0100526', (282, 293))	('miR-324-5p', 'Var', (79, 89))	('miR-146a-5p', 'Var', (66, 77))	('lung cancer', 'Disease', (211, 222))
236550	31650027	Let-7 families are a group of well-studied miRNAs in many diseases, among which downregulation of let-7a-2 was associated with the poor survival of lung cancer, and let-7 was also found to inhibit the growth of multiple human lung cancer cell lines in vitro, as well as the growth of lung cancer xenografts in vivo.	('lung cancer', 'Phenotype', 'HP:0100526', (226, 237))	('let-7a-2', 'Gene', '406882', (98, 106))	('cancer', 'Phenotype', 'HP:0002664', (289, 295))	('growth', 'CPA', (201, 207))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('lung cancer', 'Disease', (284, 295))	('poor', 'NegReg', (131, 135))	('lung cancer', 'Disease', (148, 159))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('inhibit', 'NegReg', (189, 196))	('lung cancer', 'Disease', (226, 237))	('let-7', 'Var', (165, 170))	('lung cancer', 'Disease', 'MESH:D008175', (284, 295))	('let-7a-2', 'Gene', (98, 106))	('lung cancer', 'Phenotype', 'HP:0100526', (284, 295))	('lung cancer', 'Disease', 'MESH:D008175', (148, 159))	('human', 'Species', '9606', (220, 225))	('growth', 'CPA', (274, 280))	('lung cancer', 'Phenotype', 'HP:0100526', (148, 159))	('lung cancer', 'Disease', 'MESH:D008175', (226, 237))	('downregulation', 'NegReg', (80, 94))
236551	31650027	reported that hyperoside and let-7a-5p synergistically repressed lung cancer cell proliferation via inducing G1/S phase arrest.	('arrest', 'Disease', (120, 126))	('let-7a-5p', 'Var', (29, 38))	('lung cancer', 'Disease', 'MESH:D008175', (65, 76))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('repressed', 'NegReg', (55, 64))	('hyperoside', 'Chemical', 'MESH:C021304', (14, 24))	('lung cancer', 'Disease', (65, 76))	('lung cancer', 'Phenotype', 'HP:0100526', (65, 76))	('arrest', 'Disease', 'MESH:D006323', (120, 126))	('inducing', 'PosReg', (100, 108))
236571	31650027	We found that the high expression of BCL-xL adversely affected the survival of lung adenocarcinoma (HR = 1.6, p = 0.024), but dysregulation of BCL-xL did not alter the survival of lung squamous cell carcinoma (HR = 1.4, p = 0.096).	('affected', 'Reg', (54, 62))	('survival', 'CPA', (67, 75))	('BCL-xL', 'Gene', '598', (143, 149))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (185, 208))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('BCL-xL', 'Gene', (143, 149))	('lung squamous cell carcinoma', 'Disease', (180, 208))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (180, 208))	('carcinoma', 'Phenotype', 'HP:0030731', (199, 208))	('high', 'Var', (18, 22))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (79, 98))	('BCL-xL', 'Gene', '598', (37, 43))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (180, 208))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (79, 98))	('BCL-xL', 'Gene', (37, 43))	('lung adenocarcinoma', 'Disease', (79, 98))
236577	31650027	The migration of A549 lung cancer cells was found to be significantly decreased after inducing let-7a-5p mimics but elevated when transfecting with let-7a-5p inhibitors.	('lung cancer', 'Disease', (22, 33))	('lung cancer', 'Phenotype', 'HP:0100526', (22, 33))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('let-7a-5p mimics', 'Var', (95, 111))	('elevated', 'PosReg', (116, 124))	('lung cancer', 'Disease', 'MESH:D008175', (22, 33))	('decreased', 'NegReg', (70, 79))	('inducing', 'Reg', (86, 94))
236586	31650027	For cells co-transfected with let-7a-5p mimics and pmirGLO-BCL-xL-UTR vectors, the expression of BCL-xL was considerably lower in comparing with cells co-transfected with let-7a-5p mimics and mutant vectors (Figure 3D).	('BCL-xL', 'Gene', '598', (59, 65))	('let-7a-5p', 'Var', (30, 39))	('BCL-xL', 'Gene', (59, 65))	('lower', 'NegReg', (121, 126))	('BCL-xL', 'Gene', '598', (97, 103))	('expression', 'MPA', (83, 93))	('BCL-xL', 'Gene', (97, 103))
236590	31650027	These data suggest that let-7a-5p induces apoptosis-independent cell death in A549 lung cancer cells.	('lung cancer', 'Disease', 'MESH:D008175', (83, 94))	('induces', 'Reg', (34, 41))	('let-7a-5p', 'Var', (24, 33))	('apoptosis-independent cell death', 'CPA', (42, 74))	('lung cancer', 'Disease', (83, 94))	('lung cancer', 'Phenotype', 'HP:0100526', (83, 94))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))
236592	31650027	Consistent with the proportion of apoptotic cells detected by flow cytometry, the expressions of caspase-3 and caspase-1 were found to be non-significantly altered among cells treated with let-7a-5p mimics or inhibitors as well as wild-type controls, while the expression of LC3-II was significantly elevated in cells treated with let-7a-5p mimics but downregulated when repressing let-7a-5p in A549 lung cancer cells.	('let-7a-5p mimics', 'Var', (331, 347))	('downregulated', 'NegReg', (352, 365))	('caspase-3', 'Gene', (97, 106))	('caspase-1', 'Gene', (111, 120))	('expressions', 'MPA', (82, 93))	('lung cancer', 'Disease', 'MESH:D008175', (400, 411))	('caspase-3', 'Gene', '836', (97, 106))	('expression', 'MPA', (261, 271))	('mimics', 'Var', (341, 347))	('LC3-II', 'Gene', (275, 281))	('altered', 'Reg', (156, 163))	('let-7a-5p', 'Var', (189, 198))	('caspase-1', 'Gene', '834', (111, 120))	('lung cancer', 'Phenotype', 'HP:0100526', (400, 411))	('cancer', 'Phenotype', 'HP:0002664', (405, 411))	('lung cancer', 'Disease', (400, 411))	('elevated', 'PosReg', (300, 308))
236593	31650027	The morphological characteristics of A549 lung cancer cells were observed under the transmission electron microscope, and we found that cells treated with let-7a-5p mimics showed blurred cell contour and typical autophagosomes, in which undigested organelles were involved, but cells in the control group showed precise cell contour and fewer autophagosomes (Figure 5A).	('lung cancer', 'Disease', 'MESH:D008175', (42, 53))	('cell contour', 'CPA', (187, 199))	('autophagosomes', 'CPA', (212, 226))	('lung cancer', 'Disease', (42, 53))	('lung cancer', 'Phenotype', 'HP:0100526', (42, 53))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('let-7a-5p mimics', 'Var', (155, 171))	('autophagosomes', 'CPA', (343, 357))
236594	31650027	Furthermore, we investigated the mechanism of let-7a-5p promoting autophagy in A549 lung cancer cells.	('lung cancer', 'Disease', (84, 95))	('lung cancer', 'Phenotype', 'HP:0100526', (84, 95))	('autophagy', 'CPA', (66, 75))	('promoting', 'PosReg', (56, 65))	('lung cancer', 'Disease', 'MESH:D008175', (84, 95))	('let-7a-5p', 'Var', (46, 55))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
236596	31650027	These data suggested that autophagy in A549 lung cancer cells was induced by let-7a-5p and tightly associated with the PI3K-signaling pathway.	('lung cancer', 'Phenotype', 'HP:0100526', (44, 55))	('induced', 'PosReg', (66, 73))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('let-7a-5p', 'Var', (77, 86))	('lung cancer', 'Disease', 'MESH:D008175', (44, 55))	('PI3K-signaling pathway', 'Pathway', (119, 141))	('autophagy', 'CPA', (26, 35))	('associated', 'Reg', (99, 109))	('lung cancer', 'Disease', (44, 55))
236604	31650027	In this study, we found that BCL-xL and let-7a-5p showed the opposite effect in deciding the survival of lung adenocarcinoma, while the survival of lung squamous cell carcinoma was not affected by them.	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (105, 124))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (105, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (153, 176))	('let-7a-5p', 'Var', (40, 49))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (148, 176))	('lung adenocarcinoma', 'Disease', (105, 124))	('BCL-xL', 'Gene', '598', (29, 35))	('carcinoma', 'Phenotype', 'HP:0030731', (167, 176))	('BCL-xL', 'Gene', (29, 35))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (148, 176))	('lung squamous cell carcinoma', 'Disease', (148, 176))
236605	31650027	Consistent with the expression patterns of BCL-xL and let-7a-5p, a high expression of BCL-xL was negatively correlated with the survival of lung adenocarcinoma, while a high expression of let-7a-5p prolonged the survival of the lung cancer.	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (140, 159))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (140, 159))	('lung cancer', 'Disease', 'MESH:D008175', (228, 239))	('BCL-xL', 'Gene', '598', (86, 92))	('let-7a-5p', 'Var', (188, 197))	('carcinoma', 'Phenotype', 'HP:0030731', (150, 159))	('negatively', 'NegReg', (97, 107))	('lung adenocarcinoma', 'Disease', (140, 159))	('BCL-xL', 'Gene', (86, 92))	('lung cancer', 'Phenotype', 'HP:0100526', (228, 239))	('BCL-xL', 'Gene', '598', (43, 49))	('prolonged', 'PosReg', (198, 207))	('lung cancer', 'Disease', (228, 239))	('BCL-xL', 'Gene', (43, 49))
236607	31650027	Pan-inhibition of BCL-xL protein family using sabutoclax was found to induce cell death and overcome drug resistance in breast cancer.	('cell death', 'CPA', (77, 87))	('drug resistance', 'MPA', (101, 116))	('breast cancer', 'Disease', (120, 133))	('breast cancer', 'Disease', 'MESH:D001943', (120, 133))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('breast cancer', 'Phenotype', 'HP:0003002', (120, 133))	('Pan-inhibition', 'Var', (0, 14))	('BCL-xL', 'Gene', (18, 24))	('induce', 'PosReg', (70, 76))	('BCL-xL', 'Gene', '598', (18, 24))	('drug resistance', 'Phenotype', 'HP:0020174', (101, 116))
236608	31650027	Utilizing the expressions of miR-769-5p and let-7d-5p in lung cancer, Gasparini et al.	('miR-769-5p', 'Var', (29, 39))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('lung cancer', 'Disease', 'MESH:D008175', (57, 68))	('let-7d-5p', 'Var', (44, 53))	('lung cancer', 'Disease', (57, 68))	('lung cancer', 'Phenotype', 'HP:0100526', (57, 68))
236611	31650027	However, the interaction between BCL-xL and let-7a-5p was seldom reported in lung cancer.	('lung cancer', 'Phenotype', 'HP:0100526', (77, 88))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('let-7a-5p', 'Var', (44, 53))	('lung cancer', 'Disease', 'MESH:D008175', (77, 88))	('BCL-xL', 'Gene', '598', (33, 39))	('BCL-xL', 'Gene', (33, 39))	('lung cancer', 'Disease', (77, 88))
236613	31650027	Collectively, we may conclude that the expression of BCL-xL is negatively correlated with let-7a-5p and dysregulation of BCL-xL/let-7a-5p alters the survival of lung cancer, which is potentially associated with the pathogenesis of lung cancer.	('lung cancer', 'Disease', (231, 242))	('lung cancer', 'Phenotype', 'HP:0100526', (231, 242))	('negatively', 'NegReg', (63, 73))	('survival', 'MPA', (149, 157))	('BCL-xL', 'Gene', '598', (121, 127))	('lung cancer', 'Disease', (161, 172))	('BCL-xL', 'Gene', (121, 127))	('lung cancer', 'Phenotype', 'HP:0100526', (161, 172))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('lung cancer', 'Disease', 'MESH:D008175', (231, 242))	('BCL-xL', 'Gene', '598', (53, 59))	('dysregulation', 'Var', (104, 117))	('alters', 'Reg', (138, 144))	('BCL-xL', 'Gene', (53, 59))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('let-7a-5p', 'Gene', (90, 99))	('lung cancer', 'Disease', 'MESH:D008175', (161, 172))
236614	31650027	Using the lung adenocarcinoma model constructed by the A549 cell line, we explored the role of BCL-xL and let-7a-5p on the migration and invasion of lung cancer cells in vitro.	('lung adenocarcinoma', 'Disease', (10, 29))	('carcinoma', 'Phenotype', 'HP:0030731', (20, 29))	('invasion of lung cancer', 'Disease', 'MESH:D008175', (137, 160))	('let-7a-5p', 'Var', (106, 115))	('lung cancer', 'Phenotype', 'HP:0100526', (149, 160))	('invasion of lung cancer', 'Disease', (137, 160))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (10, 29))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (10, 29))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('BCL-xL', 'Gene', '598', (95, 101))	('BCL-xL', 'Gene', (95, 101))
236616	31650027	Therefore, we adopted the dual-luciferase reporter assay to validate the hypothesis by inducing let-7a-5p putative binding sites or mutation in the 3' UTR of BCL-xL in A549 lung cancer cells.	('mutation in', 'Var', (132, 143))	('BCL-xL', 'Gene', (158, 164))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('lung cancer', 'Disease', 'MESH:D008175', (173, 184))	('binding sites', 'Interaction', (115, 128))	('inducing', 'Reg', (87, 95))	('let-7a-5p', 'Gene', (96, 105))	('lung cancer', 'Disease', (173, 184))	('lung cancer', 'Phenotype', 'HP:0100526', (173, 184))	('BCL-xL', 'Gene', '598', (158, 164))
236617	31650027	As a result, the firefly luciferase activity decreased in cells with putative binding sites but was unchanged in cells with BCL-xL mutant phenotypes as compared to the wild-type control, and the expression of BCL-xL at the protein level further confirmed the hypothesis.	('binding', 'Interaction', (78, 85))	('BCL-xL', 'Gene', '598', (209, 215))	('BCL-xL', 'Gene', (209, 215))	('mutant', 'Var', (131, 137))	('activity', 'MPA', (36, 44))	('decreased', 'NegReg', (45, 54))	('BCL-xL', 'Gene', '598', (124, 130))	('BCL-xL', 'Gene', (124, 130))	('firefly luciferase', 'Enzyme', (17, 35))
236621	31650027	We also investigated the effect of BCL-xL/let-7a-5p crosstalk on the viability of A549 lung cancer cells, and we found that the dysregulation of let-7a-5p altered the cell death rate but did not change the cell apoptosis rate, which seemed to be that the cell death regulated by BCL-xL/let-7a-5p crosstalk was independent of the apoptosis-signaling pathway.	('lung cancer', 'Disease', 'MESH:D008175', (87, 98))	('BCL-xL', 'Gene', '598', (35, 41))	('BCL-xL', 'Gene', (279, 285))	('BCL-xL', 'Gene', (35, 41))	('BCL-xL', 'Gene', '598', (279, 285))	('cell death rate', 'CPA', (167, 182))	('lung cancer', 'Disease', (87, 98))	('lung cancer', 'Phenotype', 'HP:0100526', (87, 98))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('dysregulation', 'Var', (128, 141))	('let-7a-5p', 'Gene', (145, 154))
236623	31650027	Consistent with the result of flow cytometry, the apoptosis represented by caspase-3 was not affected by let-7a-5p or BCL-xL, and a similar phenomenon was also found in pyroptosis detected using caspase-1.	('caspase-3', 'Gene', '836', (75, 84))	('men', 'Species', '9606', (145, 148))	('caspase-1', 'Gene', '834', (195, 204))	('let-7a-5p', 'Var', (105, 114))	('caspase-3', 'Gene', (75, 84))	('BCL-xL', 'Gene', '598', (118, 124))	('BCL-xL', 'Gene', (118, 124))	('caspase-1', 'Gene', (195, 204))
236624	31650027	However, the expression of LC3-II changed with the alteration of let-7a-5p, indicating that BCL-xL/let-7a-5p crosstalk might induce lung cancer cell death through the autophagy-signaling pathway.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('expression', 'MPA', (13, 23))	('lung cancer', 'Disease', 'MESH:D008175', (132, 143))	('autophagy-signaling', 'CPA', (167, 186))	('LC3-II', 'Gene', (27, 33))	('lung cancer', 'Phenotype', 'HP:0100526', (132, 143))	('induce', 'PosReg', (125, 131))	('crosstalk', 'Var', (109, 118))	('alteration', 'Var', (51, 61))	('lung cancer', 'Disease', (132, 143))	('BCL-xL', 'Gene', (92, 98))	('BCL-xL', 'Gene', '598', (92, 98))	('changed', 'Reg', (34, 41))
236626	31650027	For example, it was found that BCL-xL showed a high affinity toward the phosphorylated BECN1, a critical protein in the formation of autophagosomes, and the complex of BECN1-BCL-xL could block macroautophagy/autophagy.	('BCL-xL', 'Gene', (174, 180))	('macroautophagy/autophagy', 'CPA', (193, 217))	('BECN1', 'Gene', '8678', (168, 173))	('BECN1', 'Gene', '8678', (87, 92))	('BCL-xL', 'Gene', '598', (31, 37))	('BCL-xL', 'Gene', (31, 37))	('complex', 'Var', (157, 164))	('block', 'NegReg', (187, 192))	('BECN1', 'Gene', (87, 92))	('BECN1', 'Gene', (168, 173))	('BCL-xL', 'Gene', '598', (174, 180))
236627	31650027	Alternatively, dissociation of BCL-xL with the phosphorylated BECN1 also suppressed the autophagy and resulted in metabolic stress.	('BECN1', 'Gene', '8678', (62, 67))	('BCL-xL', 'Gene', '598', (31, 37))	('metabolic stress', 'CPA', (114, 130))	('BCL-xL', 'Gene', (31, 37))	('autophagy', 'CPA', (88, 97))	('resulted in', 'Reg', (102, 113))	('suppressed', 'NegReg', (73, 83))	('dissociation', 'Var', (15, 27))	('BECN1', 'Gene', (62, 67))
236628	31650027	Moreover, we examined the downstream cascade of BCL-xL in the PI3K-signaling pathway, including Beclin1, NRBF2, PIK3C3, and ATG5, and we found that the suppression of BCL-xL activated those proteins and resulted in macroautophagy in A549 lung cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (243, 249))	('suppression', 'Var', (152, 163))	('BCL-xL', 'Gene', (48, 54))	('lung cancer', 'Disease', 'MESH:D008175', (238, 249))	('BCL-xL', 'Gene', '598', (48, 54))	('activated', 'PosReg', (174, 183))	('proteins', 'Protein', (190, 198))	('lung cancer', 'Disease', (238, 249))	('lung cancer', 'Phenotype', 'HP:0100526', (238, 249))	('resulted in', 'Reg', (203, 214))	('BCL-xL', 'Gene', '598', (167, 173))	('PI3K-signaling pathway', 'Pathway', (62, 84))	('macroautophagy', 'CPA', (215, 229))	('BCL-xL', 'Gene', (167, 173))
236636	31650027	Inspired by the negative correlation between BCL-xL and let-a7-5p, we demonstrated their crosstalk and confirmed its effect on migration and invasion in A549 lung cancer cells.	('effect', 'Reg', (117, 123))	('invasion', 'CPA', (141, 149))	('crosstalk', 'Reg', (89, 98))	('lung cancer', 'Disease', (158, 169))	('lung cancer', 'Phenotype', 'HP:0100526', (158, 169))	('BCL-xL', 'Gene', '598', (45, 51))	('let-a7-5p', 'Var', (56, 65))	('BCL-xL', 'Gene', (45, 51))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('lung cancer', 'Disease', 'MESH:D008175', (158, 169))	('migration', 'CPA', (127, 136))
236655	31650027	Also, the related sequence in 3' UTR of BCL-xL was then mutated by the overlap PCR-based site-directed mutagenesis method.	('BCL-xL', 'Gene', (40, 46))	('mutated', 'Var', (56, 63))	('BCL-xL', 'Gene', '598', (40, 46))
236694	30996049	Lastly, we examined possible links between tRFs and the repeat-element content of genes, and between tRFs and sex disparities.	('tRF', 'Gene', (101, 104))	('tRF', 'Gene', (43, 46))	('tRF', 'Gene', '7200', (101, 104))	('repeat-element content', 'Var', (56, 78))	('tRF', 'Gene', '7200', (43, 46))
236709	30996049	Intuitively, had a modified base at position N of the mature tRNA stopped reverse transcription during library preparation, then tRFs from this tRNA would have appeared to possess a "pseudo-5 " terminus at position N+1.	('stopped', 'NegReg', (66, 73))	('modified', 'Var', (19, 27))	('tRF', 'Gene', (129, 132))	('reverse transcription', 'MPA', (74, 95))	('tRF', 'Gene', '7200', (129, 132))
236711	30996049	Additionally, for 3 -tRFs, we also evaluated whether there is benefit in mapping tRFs after allowing a single nucleotide mismatch.	('single nucleotide mismatch', 'Var', (103, 129))	('tRF', 'Gene', (81, 84))	('tRF', 'Gene', '7200', (81, 84))	('tRF', 'Gene', (21, 24))	('tRF', 'Gene', '7200', (21, 24))
236712	30996049	Such a mismatch would, in principle, alleviate the potential impact on the sequenced reads of the known m1A58 modification (methylated adenine at position 58 of the mature tRNA).	('alleviate', 'NegReg', (37, 46))	('mismatch', 'Var', (7, 15))	('m1A58', 'Gene', (104, 109))	('impact', 'MPA', (61, 67))	('methylated adenine', 'Chemical', '-', (124, 142))
236720	30996049	We kept tRF-mRNA pairs with Spearman correlation <= -0.333 or >= 0.333 and an associated False Discovery Rate (FDR) <= 5%.	('>= 0.333', 'Var', (62, 70))	('<= -0.333', 'Var', (49, 58))	('tRF', 'Gene', (8, 11))	('tRF', 'Gene', '7200', (8, 11))
236748	30996049	In principle, such modifications could hinder the reverse-transcription step during sequencing leading to an artificial 5  endpoint for some tRFs, or, to misreading the nucleotide at the modified location.	('reverse-transcription', 'MPA', (50, 71))	('tRF', 'Gene', '7200', (141, 144))	('artificial 5  endpoint', 'MPA', (109, 131))	('modifications', 'Var', (19, 32))	('tRF', 'Gene', (141, 144))	('hinder', 'NegReg', (39, 45))
236750	30996049	Our analysis also confirmed that permitting nucleotide mismatches when mapping reads to the genome greatly hinders one's ability to distinguish among tRFs and non-tRFs (Supplemental Fig.	('tRF', 'Gene', (163, 166))	('hinders', 'NegReg', (107, 114))	('tRF', 'Gene', (150, 153))	('tRF', 'Gene', '7200', (163, 166))	('tRF', 'Gene', '7200', (150, 153))	('nucleotide mismatches', 'Var', (44, 65))
236754	30996049	Examination of the -1 positions of all 5 -tRFs from tRNAHisGTG across all TCGA samples revealed unexpectedly that His(-1U) is the most abundant modification (Fig.	('tRF', 'Gene', '7200', (42, 45))	('His(-1U', 'Var', (114, 121))	('His', 'Chemical', 'MESH:D006639', (114, 117))	('His', 'Chemical', 'MESH:D006639', (56, 59))	('tRF', 'Gene', (42, 45))	('-1U', 'Var', (118, 121))
236808	30996049	As far as positive correlations are concerned, mRNAs encoding nuclear proteins are significantly enriched in some cancer types, e.g.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('mRNAs', 'Var', (47, 52))	('enriched', 'Reg', (97, 105))	('cancer', 'Disease', (114, 120))
236820	30996049	For example, the KEGG pathway "ribosome" (hsa03010) is significantly overrepresented in 21 cancer types (Supplemental Tables S7 and S8) and the corresponding mRNAs are correlated with both nuclear and MT tRFs (Fig.	('S7', 'Gene', '6264', (125, 127))	('tRF', 'Gene', (204, 207))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('overrepresented', 'PosReg', (69, 84))	('tRF', 'Gene', '7200', (204, 207))	('KEGG pathway', 'Pathway', (17, 29))	('hsa03010', 'Var', (42, 50))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))
236847	30996049	ALU and MIR retrotransposons are most significantly enriched or depleted across multiple cancer types.	('depleted', 'NegReg', (64, 72))	('ALU', 'Var', (0, 3))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('cancer', 'Disease', (89, 95))	('MIR', 'Gene', '220972', (8, 11))	('MIR', 'Gene', (8, 11))	('transposons', 'Species', '2387', (17, 28))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
236854	30996049	These results suggest that the links between tRFs and repeat elements are far-ranging and extend well beyond the recently-reported links with ERVs.	('tRF', 'Gene', (45, 48))	('links', 'Interaction', (31, 36))	('repeat elements', 'Var', (54, 69))	('tRF', 'Gene', '7200', (45, 48))
236859	30996049	On the other hand, the gene set with high repeat density includes G proteins, tyrosine and serine-threonine kinases, as well as proteins with DHR1, DHR2, FERM and/or EF-hand domains.	('G proteins', 'Protein', (66, 76))	('tyrosine', 'MPA', (78, 86))	('proteins', 'Protein', (128, 136))	('DHR2', 'Var', (148, 152))	('DHR1', 'Var', (142, 146))	('serine', 'Chemical', 'MESH:D012694', (91, 97))
236860	30996049	Moreover, genes with high repeat density belong to signaling pathways, including: MAPK, ErbB, Ras, PI3K-Akt, and cGMP-PKG.	('Akt', 'Gene', (104, 107))	('ErbB', 'Gene', (88, 92))	('MAPK', 'Disease', (82, 86))	('ErbB', 'Gene', '1956', (88, 92))	('Ras', 'Disease', (94, 97))	('signaling pathways', 'Pathway', (51, 69))	('belong', 'Reg', (41, 47))	('Akt', 'Gene', '207', (104, 107))	('cGMP', 'Chemical', 'MESH:D006152', (113, 117))	('high repeat density', 'Var', (21, 40))
236893	30996049	From this perspective, the identified links to tRFs could shed light on the molecular events behind their regulation and functions in different tissues and cancer types.	('cancer', 'Disease', (156, 162))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('links', 'Var', (38, 43))	('tRF', 'Gene', (47, 50))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('tRF', 'Gene', '7200', (47, 50))
236909	30996049	In the context of cancer, repeat elements continue to emerge as important components in genomic rearrangements as well as potent regulators of gene expression, and as determinants of overall survival.	('repeat elements', 'Var', (26, 41))	('cancer', 'Disease', (18, 24))	('cancer', 'Disease', 'MESH:D009369', (18, 24))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))
236910	30996049	As repeat elements are also associated with chimeric transcripts involving protein-coding exons, it is conceivable that tRFs can interact with such junctions just like we previously reported for miRNAs.	('chimeric', 'Var', (44, 52))	('associated', 'Reg', (28, 38))	('tRF', 'Gene', (120, 123))	('interact', 'Interaction', (129, 137))	('tRF', 'Gene', '7200', (120, 123))
236918	31049003	The clinical data of lung cancer patients were analyzed to explore the correlation between clinicopathological characteristics and expression level of miRNA-21, miRNA-31, miRNA-let7.	('patients', 'Species', '9606', (33, 41))	('lung cancer', 'Disease', (21, 32))	('miRNA-31', 'Var', (161, 169))	('lung cancer', 'Phenotype', 'HP:0100526', (21, 32))	('miRNA-21', 'Gene', '406991', (151, 159))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('miRNA-let7', 'Var', (171, 181))	('lung cancer', 'Disease', 'MESH:D008175', (21, 32))	('miRNA-21', 'Gene', (151, 159))
236919	31049003	The relative expression levels of miRNA-21 and miRNA-31 in lung cancer group were obviously higher than those in healthy control group, and the relative expression level of miRNA-let7 in lung cancer group was slightly higher than that in healthy control group.	('lung cancer', 'Disease', 'MESH:D008175', (59, 70))	('expression levels', 'MPA', (13, 30))	('miRNA-21', 'Gene', (34, 42))	('higher', 'PosReg', (92, 98))	('higher', 'PosReg', (218, 224))	('lung cancer', 'Disease', 'MESH:D008175', (187, 198))	('miRNA-31', 'Var', (47, 55))	('lung cancer', 'Disease', (59, 70))	('lung cancer', 'Phenotype', 'HP:0100526', (59, 70))	('miRNA-21', 'Gene', '406991', (34, 42))	('expression', 'MPA', (153, 163))	('lung cancer', 'Disease', (187, 198))	('lung cancer', 'Phenotype', 'HP:0100526', (187, 198))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
236947	31049003	The relative expression level of miRNA-let7 in lung cancer group was 0.0016(0.0004,0.1606) and in healthy control group was 0.0010(0,0.0038), suggesting that lung cancer group had a slightly higher level than healthy control group, with a statistically significant difference (P < 0.05).	('higher', 'PosReg', (191, 197))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('lung cancer', 'Disease', (158, 169))	('lung cancer', 'Disease', (47, 58))	('lung cancer', 'Phenotype', 'HP:0100526', (158, 169))	('lung cancer', 'Phenotype', 'HP:0100526', (47, 58))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('miRNA-let7', 'Var', (33, 43))	('expression level', 'MPA', (13, 29))	('lung cancer', 'Disease', 'MESH:D008175', (158, 169))	('lung cancer', 'Disease', 'MESH:D008175', (47, 58))
236952	31049003	For the combined detection of miRNA-31 and miRNA-let7, the AUC, sensitivity and specificity were 0.732, 60% and 75%, respectively, but the combined detection of miRNA-21 and miRNA-let7 showed no statistical difference.	('miRNA-let7', 'Var', (43, 53))	('miRNA-21', 'Gene', (161, 169))	('miRNA-31', 'Var', (30, 38))	('miRNA-21', 'Gene', '406991', (161, 169))
236953	31049003	According to the maximum Youden index of ROC curve, we obtained the optimal diagnostic critical values 2- CT of miRNA-21, miRNA-31 and miRNA-let7, which were 0.065, 0.0025 and 0.0015.	('miRNA-let7', 'Var', (135, 145))	('miRNA-31', 'Var', (122, 130))	('miRNA-21', 'Gene', (112, 120))	('miRNA-21', 'Gene', '406991', (112, 120))
236963	31049003	In addition, lung cancer patients with low expression of miRNA-let7 had shorter survival time than those with high expression, and the high expression of miRNA-let7 inhibited the growth of lung cancer A549 cell line.	('lung cancer', 'Disease', 'MESH:D008175', (189, 200))	('lung cancer', 'Disease', (13, 24))	('lung cancer', 'Phenotype', 'HP:0100526', (13, 24))	('shorter', 'NegReg', (72, 79))	('growth', 'CPA', (179, 185))	('low', 'NegReg', (39, 42))	('A549', 'CellLine', 'CVCL:0023', (201, 205))	('inhibited', 'NegReg', (165, 174))	('lung cancer', 'Phenotype', 'HP:0100526', (189, 200))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('lung cancer', 'Disease', (189, 200))	('survival time', 'CPA', (80, 93))	('patients', 'Species', '9606', (25, 33))	('lung cancer', 'Disease', 'MESH:D008175', (13, 24))	('miRNA-let7', 'Var', (57, 67))	('miRNA-let7', 'Var', (154, 164))	('high expression', 'Var', (135, 150))
236964	31049003	confirmed in the serum of patients with non-small cell lung cancer that miR-125b can be used as an indicator for diagnosis and prediction of chemotherapy efficacy, thus providing a new idea for solving the drug resistance of lung cancer.	('lung cancer', 'Phenotype', 'HP:0100526', (225, 236))	('lung cancer', 'Disease', 'MESH:D008175', (55, 66))	('miR-125b', 'Chemical', '-', (72, 80))	('drug resistance', 'Phenotype', 'HP:0020174', (206, 221))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (40, 66))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('patients', 'Species', '9606', (26, 34))	('non-small cell lung cancer', 'Disease', (40, 66))	('lung cancer', 'Disease', 'MESH:D008175', (225, 236))	('lung cancer', 'Phenotype', 'HP:0100526', (55, 66))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (44, 66))	('miR-125b', 'Var', (72, 80))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (40, 66))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('lung cancer', 'Disease', (225, 236))
236994	27935865	As a consequence of prolonged exposure to environmental toxicants such as cigarette smoke or air pollution, a "field cancerization" effect occurs in the lung resulting in the development of a field of initiated but morphologically normal appearing cells in the damaged bronchial epithelium that contain molecular lesions such as mutations in an oncogene or tumor suppressor gene.	('oncogene', 'Gene', (345, 353))	('tumor', 'Disease', (357, 362))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('mutations', 'Var', (329, 338))	('tumor', 'Disease', 'MESH:D009369', (357, 362))	('cancer', 'Disease', (117, 123))	('tumor', 'Phenotype', 'HP:0002664', (357, 362))
237001	27935865	Modulation of these important pathways would appear to be relevant to prevention or early therapy of SCC.	('Modulation', 'Var', (0, 10))	('SCC', 'Gene', (101, 104))	('SCC', 'Gene', '6317', (101, 104))
237020	27935865	As expected, the PI3K/AKT and Myc pathway were activated in the airway samples of all the 3 groups of lung SCC early-lesion mice treated with NTCU compared to the normal control mice not exposed to any carcinogen.	('NTCU', 'Var', (142, 146))	('mice', 'Species', '10090', (178, 182))	('activated', 'PosReg', (47, 56))	('SCC', 'Gene', (107, 110))	('PI3K/AKT', 'Gene', (17, 25))	('mice', 'Species', '10090', (124, 128))	('PI3K/AKT', 'Gene', '18708;11651', (17, 25))	('SCC', 'Gene', '6317', (107, 110))	('Myc pathway', 'Pathway', (30, 41))	('NTCU', 'Chemical', 'MESH:C572573', (142, 146))
237062	27935865	Moreover, Myc signaling is responsible for the similarities between ESCs (embryonic stem cells) and cancer and Myc can induce a basal stem cell/ESC-like transcriptional profile when transduced into keratinocytes.	('induce', 'PosReg', (119, 125))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('Myc', 'Var', (111, 114))	('basal', 'MPA', (128, 133))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('ESCs', 'Disease', (68, 72))
237065	27935865	As expected, the activated PI3K/AKT signaling was inhibited in bronchial brush samples of lung SCC early-lesion mice by the treatment of XL-147 that is a potent PI3K inhibitor.	('SCC', 'Gene', '6317', (95, 98))	('XL-147', 'Var', (137, 143))	('XL-147', 'Chemical', 'MESH:C581157', (137, 143))	('PI3K/AKT', 'Gene', (27, 35))	('PI3K/AKT', 'Gene', '18708;11651', (27, 35))	('mice', 'Species', '10090', (112, 116))	('SCC', 'Gene', (95, 98))	('inhibited', 'NegReg', (50, 59))
237242	29844511	For gene GAPDH (35905_s_at), it was shown that the levels of GAPDH protein were significantly up-regulated in lung squamous cell carcinoma tissues by clinical tissue studies.	('levels', 'MPA', (51, 57))	('GAPDH', 'Gene', '2597', (9, 14))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('up-regulated', 'PosReg', (94, 106))	('35905_s_at', 'Var', (16, 26))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (110, 138))	('lung squamous cell carcinoma', 'Disease', (110, 138))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (115, 138))	('GAPDH', 'Gene', (9, 14))	('protein', 'Protein', (67, 74))	('GAPDH', 'Gene', '2597', (61, 66))	('GAPDH', 'Gene', (61, 66))
237244	29844511	IGHV4-31 (37864_s_at) has been detected as a candidate gene in peripheral blood mononuclear cells (PBMC) and tumor tissue groups of non-small cell lung cancer.	('non-small cell lung cancer', 'Disease', (132, 158))	('lung cancer', 'Phenotype', 'HP:0100526', (147, 158))	('37864_s_at', 'Var', (10, 20))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (136, 158))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (132, 158))	('IGHV4-31', 'Gene', '28396', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('IGHV4-31', 'Gene', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (132, 158))	('tumor', 'Disease', (109, 114))
237245	29844511	CYAT1 (33273_f_at) is one of the most frequently ranked genes responsible for that clustering through the method proposed by Mondal et al.	('CYAT1', 'Gene', '100290481', (0, 5))	('CYAT1', 'Gene', (0, 5))	('33273_f_at', 'Var', (7, 17))
237246	29844511	reported perfect classification accuracy with only 3 genes: 37947_at, 33499_s_at (IGHA2) and 36528_at on the lung cancer dataset, indicating that these 3 genes are very crucial for lung cancer.	('36528_at', 'Var', (93, 101))	('lung cancer', 'Disease', (109, 120))	('lung cancer', 'Phenotype', 'HP:0100526', (109, 120))	('IGHA2', 'Gene', '3494', (82, 87))	('37947_at', 'Var', (60, 68))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('lung cancer', 'Disease', (181, 192))	('lung cancer', 'Phenotype', 'HP:0100526', (181, 192))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('lung cancer', 'Disease', 'MESH:D008175', (109, 120))	('IGHA2', 'Gene', (82, 87))	('33499_s_at', 'Var', (70, 80))	('lung cancer', 'Disease', 'MESH:D008175', (181, 192))
237255	29844511	FOS (J04130_s_at) has a significant function in regulating cell proliferation, cell differentiation and cell transformation in leukemia and it was detected and validated in the paper.	('J04130_s_at', 'Var', (5, 16))	('FOS', 'Gene', (0, 3))	('leukemia', 'Disease', (127, 135))	('cell differentiation', 'CPA', (79, 99))	('leukemia', 'Disease', 'MESH:D007938', (127, 135))	('cell transformation', 'CPA', (104, 123))	('leukemia', 'Phenotype', 'HP:0001909', (127, 135))	('cell proliferation', 'CPA', (59, 77))	('FOS', 'Gene', '2353', (0, 3))
237256	29844511	Immune-related gene LYZ (U49835_s_at) were highly expressed in THP1 cells in leukemia.	('LYZ', 'Gene', (20, 23))	('leukemia', 'Disease', (77, 85))	('leukemia', 'Phenotype', 'HP:0001909', (77, 85))	('leukemia', 'Disease', 'MESH:D007938', (77, 85))	('LYZ', 'Gene', '4069', (20, 23))	('U49835_s_at', 'Var', (25, 36))	('THP1', 'CellLine', 'CVCL:0006', (63, 67))
237257	29844511	According to, as a direct target of activated NOTCH1, CCND3 (M21624_at) is up-regulated in T-cell acute lymphoblastic leukemia.	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (104, 126))	('NOTCH1', 'Gene', '4851', (46, 52))	('NOTCH1', 'Gene', (46, 52))	('CCND3', 'Gene', '896', (54, 59))	('T-cell acute lymphoblastic leukemia', 'Phenotype', 'HP:0006727', (91, 126))	('CCND3', 'Gene', (54, 59))	('T-cell acute lymphoblastic leukemia', 'Disease', 'MESH:D054218', (91, 126))	('leukemia', 'Phenotype', 'HP:0001909', (118, 126))	('T-cell acute lymphoblastic leukemia', 'Disease', (91, 126))	('up-regulated', 'PosReg', (75, 87))	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (98, 126))	('M21624_at', 'Var', (61, 70))
237258	29844511	By mediating JUNB (X60486_at), miRNA-149 promotes cell proliferation and inhibits apoptosis in T-cell acute lymphoblastic leukemia.	('JUNB', 'Gene', '3726', (13, 17))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (108, 130))	('leukemia', 'Phenotype', 'HP:0001909', (122, 130))	('apoptosis', 'CPA', (82, 91))	('T-cell acute lymphoblastic leukemia', 'Disease', 'MESH:D054218', (95, 130))	('promotes', 'PosReg', (41, 49))	('inhibits', 'NegReg', (73, 81))	('JUNB', 'Gene', (13, 17))	('T-cell acute lymphoblastic leukemia', 'Phenotype', 'HP:0006727', (95, 130))	('T-cell acute lymphoblastic leukemia', 'Disease', (95, 130))	('X60486_at', 'Var', (19, 28))	('miRNA-149', 'Gene', (31, 40))	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (102, 130))	('cell proliferation', 'CPA', (50, 68))
237271	29844511	In GO:0007010 and GO:0034109, SLDSF has the best performance, same as PMD.	('PMD', 'Disease', 'MESH:D020371', (70, 73))	('GO:0007010', 'Var', (3, 13))	('GO:0034109', 'Var', (18, 28))	('PMD', 'Disease', (70, 73))
237274	29844511	In, MUC17, MUC5B and MUC6 gene mutations in tumor region T4A of esophageal squamous cell carcinoma predict the perturbation of O-glycan biosynthesis and processing.	('MUC6', 'Gene', (21, 25))	('MUC17', 'Gene', '140453', (4, 9))	('processing', 'MPA', (153, 163))	('mutations', 'Var', (31, 40))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('esophageal squamous cell carcinoma', 'Disease', (64, 98))	('O-glycan', 'Chemical', '-', (127, 135))	('MUC6', 'Gene', '4588', (21, 25))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('MUC5B', 'Gene', '727897', (11, 16))	('MUC17', 'Gene', (4, 9))	('MUC5B', 'Gene', (11, 16))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (75, 98))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('O-glycan biosynthesis', 'MPA', (127, 148))	('T4A', 'Mutation', 'c.4T>A', (57, 60))	('tumor', 'Disease', (44, 49))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (64, 98))
237281	29844511	Furthermore, expression of certain CD44 variants may be important molecular markers for HNSC progression.	('CD44', 'Gene', (35, 39))	('expression', 'MPA', (13, 23))	('HNSC', 'Disease', (88, 92))	('variants', 'Var', (40, 48))	('CD44', 'Gene', '960', (35, 39))
237291	29844511	Variations in ferritin subunit composition may affect the rates of iron uptake and release in different tissues.	('rates', 'MPA', (58, 63))	('iron uptake', 'MPA', (67, 78))	('ferritin subunit', 'Protein', (14, 30))	('affect', 'Reg', (47, 53))	('Variations', 'Var', (0, 10))	('iron', 'Chemical', 'MESH:D007501', (67, 71))	('release', 'MPA', (83, 90))
237293	29844511	Defects in this light chain ferritin gene are associated with several neurodegenerative diseases and hyperferritinemia-cataract syndrome.	('neurodegenerative diseases', 'Disease', (70, 96))	('neurodegenerative diseases', 'Phenotype', 'HP:0002180', (70, 96))	('cataract', 'Phenotype', 'HP:0000518', (119, 127))	('Defects', 'Var', (0, 7))	('neurodegenerative diseases', 'Disease', 'MESH:D019636', (70, 96))	('associated', 'Reg', (46, 56))	('hyperferritinemia', 'Phenotype', 'HP:0003281', (101, 118))	('hyperferritinemia-cataract syndrome', 'Disease', (101, 136))	('hyperferritinemia-cataract syndrome', 'Disease', 'MESH:C538137', (101, 136))
237298	29844511	Mutations in this gene cause Baraitser-Winter syndrome 1, which is characterized by intellectual disability with a distinctive facial appearance in human patients.	('Baraitser-Winter syndrome', 'Disease', 'OMIM:243310', (29, 54))	('patients', 'Species', '9606', (154, 162))	('human', 'Species', '9606', (148, 153))	('Mutations', 'Var', (0, 9))	('intellectual disability', 'Phenotype', 'HP:0001249', (84, 107))	('cause', 'Reg', (23, 28))	('Baraitser-Winter syndrome', 'Disease', (29, 54))
237300	29844511	Mutations in this gene are associated with osteogenesis imperfecta types I-IV, Ehlers-Danlos syndrome type VIIA, Ehlers-Danlos syndrome Classical type, Caffey Disease and idiopathic osteoporosis.	('Ehlers-Danlos syndrome type VIIA', 'Disease', (79, 111))	('Ehlers-Danlos syndrome Classical type', 'Disease', 'MESH:C536194', (113, 150))	('osteogenesis imperfecta', 'Disease', 'MESH:D010013', (43, 66))	('associated', 'Reg', (27, 37))	('Ehlers-Danlos syndrome type VIIA', 'Disease', 'MESH:C562625', (79, 111))	('Ehlers-Danlos syndrome Classical type', 'Disease', (113, 150))	('idiopathic osteoporosis', 'Disease', 'MESH:C537700', (171, 194))	('osteoporosis', 'Phenotype', 'HP:0000939', (182, 194))	('Mutations', 'Var', (0, 9))	('idiopathic osteoporosis', 'Disease', (171, 194))	('Caffey Disease', 'Disease', (152, 166))	('osteogenesis imperfecta', 'Disease', (43, 66))
237303	29844511	Mutations in this gene and keratin 4 have been associated with the autosomal dominant disorder White Sponge Nevus.	('keratin 4', 'Gene', (27, 36))	('autosomal dominant disorder White Sponge Nevus', 'Disease', (67, 113))	('Mutations', 'Var', (0, 9))	('autosomal dominant disorder White Sponge Nevus', 'Disease', 'MESH:D056784', (67, 113))	('Sponge Nevus', 'Phenotype', 'HP:0025510', (101, 113))	('associated', 'Reg', (47, 57))	('keratin 4', 'Gene', '3851', (27, 36))	('Nevus', 'Phenotype', 'HP:0003764', (108, 113))
237347	25302298	It was already demonstrated in breast cancer cell lines MDAMB-231 that association of SphK1 antagonist FTY720 with IR significantly increased antiproliferative and proapoptotic effects through promoting alterations in MAPK signaling.	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('breast cancer', 'Disease', 'MESH:D001943', (31, 44))	('FTY720', 'Var', (103, 109))	('increased', 'PosReg', (132, 141))	('MDAMB-231', 'CellLine', 'CVCL:0062', (56, 65))	('breast cancer', 'Disease', (31, 44))	('SphK1', 'Gene', '8877', (86, 91))	('promoting', 'PosReg', (193, 202))	('association', 'Interaction', (71, 82))	('MAPK', 'Gene', '5594', (218, 222))	('SphK1', 'Gene', (86, 91))	('breast cancer', 'Phenotype', 'HP:0003002', (31, 44))	('antiproliferative', 'MPA', (142, 159))	('proapoptotic effects', 'MPA', (164, 184))	('MAPK', 'Gene', (218, 222))
237352	25302298	Radiation sensitivity effect of NVP-BEZ235, a dual PI3K/mTOR inhibitor, reveals enhancement of apoptosis in human glioma cells, as well as cell cycle arrest, resulting in striking tumor radiosensitization, which extended the survival of brain tumor-bearing mice.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('enhancement', 'PosReg', (80, 91))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (139, 156))	('apoptosis', 'CPA', (95, 104))	('tumor', 'Disease', (243, 248))	('mice', 'Species', '10090', (257, 261))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('glioma', 'Disease', (114, 120))	('NVP-BEZ235', 'Var', (32, 42))	('tumor', 'Disease', 'MESH:D009369', (243, 248))	('extended', 'PosReg', (212, 220))	('glioma', 'Disease', 'MESH:D005910', (114, 120))	('brain tumor', 'Phenotype', 'HP:0030692', (237, 248))	('brain tumor', 'Disease', (237, 248))	('brain tumor', 'Disease', 'MESH:D001932', (237, 248))	('glioma', 'Phenotype', 'HP:0009733', (114, 120))	('cell cycle arrest', 'CPA', (139, 156))	('BEZ235', 'Chemical', 'MESH:C531198', (36, 42))	('survival', 'CPA', (225, 233))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))	('tumor', 'Disease', (180, 185))	('human', 'Species', '9606', (108, 113))
237353	25302298	Likewise, NVP-BEZ235 prominently improved the radiosensitivity of PC-3 prostate cancer cells through inducing a G2/M arrest and enhanced proapoptotic effect after combined IR.	('prostate cancer', 'Disease', (71, 86))	('NVP-BEZ235', 'Var', (10, 20))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('G2/M arrest', 'MPA', (112, 123))	('inducing', 'PosReg', (101, 109))	('enhanced', 'PosReg', (128, 136))	('prostate cancer', 'Disease', 'MESH:D011471', (71, 86))	('radiosensitivity', 'CPA', (46, 62))	('BEZ235', 'Chemical', 'MESH:C531198', (14, 20))	('prostate cancer', 'Phenotype', 'HP:0012125', (71, 86))	('improved', 'PosReg', (33, 41))	('PC-3', 'CellLine', 'CVCL:0035', (66, 70))	('proapoptotic effect', 'MPA', (137, 156))
237356	25302298	One of the defined mechanisms is that EGFR amplification or Ras activation by mutations results in increased clonogenic cell survival and decreased tumor growth delay following irradiation.	('EGFR', 'Gene', '1956', (38, 42))	('decreased tumor growth delay', 'Disease', 'MESH:D006130', (138, 166))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('EGFR', 'Gene', (38, 42))	('decreased tumor growth delay', 'Disease', (138, 166))	('growth delay', 'Phenotype', 'HP:0001510', (154, 166))	('mutations', 'Var', (78, 87))	('clonogenic cell survival', 'CPA', (109, 133))	('activation', 'PosReg', (64, 74))	('Ras', 'Gene', (60, 63))	('increased', 'PosReg', (99, 108))
237363	25302298	A positive correlation between the presence of a KRAS mutation and radiosensitization after treatment with the EGFR inhibitors erlotinib and cetuximab in several non-small cell lung lineages was lately demonstrated.	('mutation', 'Var', (54, 62))	('KRAS', 'Gene', '3845', (49, 53))	('radiosensitization', 'CPA', (67, 85))	('cetuximab', 'Chemical', 'MESH:D000068818', (141, 150))	('EGFR', 'Gene', '1956', (111, 115))	('EGFR', 'Gene', (111, 115))	('erlotinib', 'Chemical', 'MESH:D000069347', (127, 136))	('KRAS', 'Gene', (49, 53))
237392	25302298	It was suggested that hypermethylation of DR4 CpG island can promote TRAIL radioresistance.	('TRAIL', 'Gene', '8743', (69, 74))	('promote', 'PosReg', (61, 68))	('TRAIL', 'Gene', (69, 74))	('hypermethylation', 'Var', (22, 38))	('DR4', 'Gene', '8797', (42, 45))	('DR4', 'Gene', (42, 45))
237394	25302298	Recent studies showed that miR-193a-3p was able to radiosensitize both U-251 and HeLa cells by accumulation of intracellular reactive oxygen species increasing DNA damage and also apoptosis directly targeting the antiapoptotic Mcl-1 gene, while silencing miR-21 in radioresistant NSCLC A549 cells sensitized them to IR by inhibiting cell proliferation and enhancing cell apoptosis through inhibition of PI3K/Akt signaling pathway.	('inhibiting', 'NegReg', (322, 332))	('inhibition', 'NegReg', (389, 399))	('NSCLC', 'Phenotype', 'HP:0030358', (280, 285))	('silencing', 'Var', (245, 254))	('DNA', 'MPA', (160, 163))	('Mcl-1', 'Gene', '4170', (227, 232))	('enhancing', 'PosReg', (356, 365))	('cell apoptosis', 'CPA', (366, 380))	('A549', 'CellLine', 'CVCL:0023', (286, 290))	('HeLa', 'CellLine', 'CVCL:0030', (81, 85))	('miR-21', 'Gene', '406991', (255, 261))	('Akt', 'Gene', (408, 411))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (125, 148))	('cell proliferation', 'CPA', (333, 351))	('accumulation of intracellular reactive oxygen species', 'Phenotype', 'HP:0025464', (95, 148))	('Akt', 'Gene', '207', (408, 411))	('Mcl-1', 'Gene', (227, 232))	('NSCLC', 'Disease', 'MESH:D002289', (280, 285))	('miR-21', 'Gene', (255, 261))	('NSCLC', 'Disease', (280, 285))
237397	25302298	Inhibition of autophagy could sensitize tumor cells to many cytotoxic drugs or reverse resistance to chemotherapeutic drugs, representing a promising strategy to improve the efficacy of cancer treatment.	('autophagy', 'CPA', (14, 23))	('resistance', 'MPA', (87, 97))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('sensitize', 'Reg', (30, 39))	('Inhibition', 'Var', (0, 10))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('cancer', 'Disease', (186, 192))	('cancer', 'Disease', 'MESH:D009369', (186, 192))
237400	25302298	One of the principal pathways involved in alteration of migratory activities is PI3K/Akt signaling pathway that has been implicated in driving metastatic phenotype in thyroid, breast, and other cancers, and PI3K activity is further increased by radiotherapy in certain tumors.	('cancers', 'Phenotype', 'HP:0002664', (194, 201))	('tumor', 'Phenotype', 'HP:0002664', (269, 274))	('Akt', 'Gene', '207', (85, 88))	('breast', 'Disease', (176, 182))	('cancers', 'Disease', 'MESH:D009369', (194, 201))	('tumors', 'Phenotype', 'HP:0002664', (269, 275))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('cancers', 'Disease', (194, 201))	('PI3K', 'Var', (207, 211))	('tumors', 'Disease', (269, 275))	('Akt', 'Gene', (85, 88))	('tumors', 'Disease', 'MESH:D009369', (269, 275))	('thyroid', 'Disease', (167, 174))
237402	25302298	In a xenograft model of colorectal cancer, knockdown of Akt2 in KM20 cell line inhibits liver metastasis; the converse is observed when constitutively active Myr-Akt2 is expressed.	('Akt2', 'Gene', (56, 60))	('Akt2', 'Gene', '208', (162, 166))	('KM20', 'CellLine', 'CVCL:L095', (64, 68))	('Akt2', 'Gene', '208', (56, 60))	('colorectal cancer', 'Phenotype', 'HP:0003003', (24, 41))	('inhibits', 'NegReg', (79, 87))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('knockdown', 'Var', (43, 52))	('liver metastasis', 'CPA', (88, 104))	('colorectal cancer', 'Disease', (24, 41))	('colorectal cancer', 'Disease', 'MESH:D015179', (24, 41))	('Akt2', 'Gene', (162, 166))
237403	25302298	It has been noticed that activation of Akt2 increases cell invasion and metastasis of breast and ovarian cancer cells through upregulated integrin signaling; its inactivation also inhibits glioma cell invasion and knockdown of Akt2, rather than Akt1, in the cell line A549 dramatically abolishes its invasive potential.	('abolishes', 'NegReg', (286, 295))	('glioma', 'Disease', (189, 195))	('Akt2', 'Gene', (39, 43))	('inactivation', 'NegReg', (162, 174))	('Akt2', 'Gene', '208', (39, 43))	('upregulated', 'PosReg', (126, 137))	('glioma', 'Disease', 'MESH:D005910', (189, 195))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('increases', 'PosReg', (44, 53))	('glioma', 'Phenotype', 'HP:0009733', (189, 195))	('inhibits', 'NegReg', (180, 188))	('Akt1', 'Gene', (245, 249))	('integrin signaling', 'MPA', (138, 156))	('activation', 'PosReg', (25, 35))	('metastasis of breast and ovarian cancer', 'Disease', 'MESH:D009362', (72, 111))	('Akt2', 'Gene', '208', (227, 231))	('Akt2', 'Gene', (227, 231))	('A549', 'CellLine', 'CVCL:0023', (268, 272))	('cell invasion', 'CPA', (54, 67))	('Akt1', 'Gene', '207', (245, 249))	('knockdown', 'Var', (214, 223))	('invasive potential', 'CPA', (300, 318))	('ovarian cancer', 'Phenotype', 'HP:0100615', (97, 111))
237405	25302298	EMT is an embryonic program important for organogenesis in normal development, but its dysfunction can help the survival and dissemination of cancer cells that is characterized by loss of cell-cell contacts, decreased expression of epithelial markers E-cadherin, beta-catenin, and ZO-1, remodeling of the actin cytoskeleton, and increased expression of mesenchymal markers N-cadherin, fibronectin, and vimentin.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('vimentin', 'Gene', '7431', (402, 410))	('loss', 'NegReg', (180, 184))	('vimentin', 'Gene', (402, 410))	('ZO-1', 'Gene', (281, 285))	('beta-catenin', 'Gene', (263, 275))	('fibronectin', 'Gene', '2335', (385, 396))	('E-cadherin', 'Gene', (251, 261))	('E-cadherin', 'Gene', '999', (251, 261))	('beta-catenin', 'Gene', '1499', (263, 275))	('decreased', 'NegReg', (208, 217))	('cell-cell contacts', 'CPA', (188, 206))	('epithelial', 'Protein', (232, 242))	('increased', 'PosReg', (329, 338))	('cancer', 'Disease', (142, 148))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('remodeling', 'Reg', (287, 297))	('cell-cell', 'CellLine', 'CVCL:0320', (188, 197))	('expression', 'MPA', (339, 349))	('fibronectin', 'Gene', (385, 396))	('N-cadherin', 'Gene', (373, 383))	('dysfunction', 'Var', (87, 98))	('N-cadherin', 'Gene', '1000', (373, 383))	('ZO-1', 'Gene', '7082', (281, 285))	('expression', 'MPA', (218, 228))
237413	25302298	Pharmacological inhibition of Akt with GSK690693 blocks the expression of ZEB1 and vimentin and restores the expression of E-cadherin following IR, thus preventing the migration and EMT of nasopharyngeal carcinoma cell lines even as knockdown of Akt2 induces reversion of the EMT process in mammary epithelial cell lines.	('Akt', 'Gene', '207', (246, 249))	('expression', 'MPA', (60, 70))	('migration', 'CPA', (168, 177))	('vimentin', 'Gene', (83, 91))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (189, 213))	('Akt2', 'Gene', (246, 250))	('ZEB1', 'Gene', '6935', (74, 78))	('Akt2', 'Gene', '208', (246, 250))	('Akt', 'Gene', (30, 33))	('Akt', 'Gene', '207', (30, 33))	('GSK690693', 'Var', (39, 48))	('E-cadherin', 'Gene', (123, 133))	('E-cadherin', 'Gene', '999', (123, 133))	('restores', 'PosReg', (96, 104))	('knockdown', 'Var', (233, 242))	('carcinoma', 'Phenotype', 'HP:0030731', (204, 213))	('nasopharyngeal carcinoma', 'Disease', (189, 213))	('ZEB1', 'Gene', (74, 78))	('preventing', 'NegReg', (153, 163))	('blocks', 'NegReg', (49, 55))	('nasopharyngeal carcinoma', 'Disease', 'MESH:D000077274', (189, 213))	('expression', 'MPA', (109, 119))	('Akt', 'Gene', (246, 249))	('EMT process', 'CPA', (276, 287))	('EMT', 'CPA', (182, 185))	('vimentin', 'Gene', '7431', (83, 91))
237416	25302298	Moreover, integrin alpha 2 beta 1 is selectively upregulated in irradiated lung cancer cells and is required for aggressive phenotype and invasion in 3D collagen gels and such invasiveness is mediated via PI3K/Akt signaling pathway and then invasion speed in vitro can be reduced significantly by PI3K inhibitor LY294002.	('lung cancer', 'Disease', (75, 86))	('lung cancer', 'Phenotype', 'HP:0100526', (75, 86))	('reduced', 'NegReg', (272, 279))	('LY294002', 'Chemical', 'MESH:C085911', (312, 320))	('mediated', 'Reg', (192, 200))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('integrin alpha 2 beta 1', 'Protein', (10, 33))	('invasion speed', 'CPA', (241, 255))	('lung cancer', 'Disease', 'MESH:D008175', (75, 86))	('upregulated', 'PosReg', (49, 60))	('Akt', 'Gene', '207', (210, 213))	('LY294002', 'Var', (312, 320))	('Akt', 'Gene', (210, 213))
237419	25302298	Nonreceptor tyrosine kinase Src is often activated in various types of cancer via mutations or growth factor signaling pathways including insulin-like growth factor-1 receptor (IGFR-1), EGFR, and platelet-derived growth factor receptor (PDGFR).	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('IGFR-1', 'Gene', '3480', (177, 183))	('cancer', 'Disease', (71, 77))	('growth factor signaling pathways', 'Pathway', (95, 127))	('platelet-derived growth factor receptor', 'Gene', '5159', (196, 235))	('EGFR', 'Gene', '1956', (186, 190))	('IGFR-1', 'Gene', (177, 183))	('insulin-like growth factor-1 receptor', 'Gene', (138, 175))	('EGFR', 'Gene', (186, 190))	('platelet-derived growth factor receptor', 'Gene', (196, 235))	('mutations', 'Var', (82, 91))	('Src', 'Gene', (28, 31))	('insulin-like growth factor-1 receptor', 'Gene', '3480', (138, 175))	('activated', 'PosReg', (41, 50))	('Src', 'Gene', '6714', (28, 31))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('PDGFR', 'Gene', (237, 242))	('PDGFR', 'Gene', '5159', (237, 242))
237421	25302298	This Src-mediated disruption of focal adhesions leads to a decrease in cell-cell and cell-ECM adhesion and is an important process central to cell migration and invasion.	('Src', 'Gene', (5, 8))	('Src', 'Gene', '6714', (5, 8))	('decrease', 'NegReg', (59, 67))	('disruption', 'Var', (18, 28))	('cell-cell', 'CellLine', 'CVCL:0320', (71, 80))	('focal', 'Protein', (32, 37))
237433	25302298	Additionally, inhibitors of these signaling pathways with specific inhibitors AG1478, U0126, and SB203580 show decrease of uPA levels in both basal and irradiated-IOMM-Lee cells.	('AG1478', 'Chemical', 'MESH:C101044', (78, 84))	('U0126', 'Chemical', 'MESH:C113580', (86, 91))	('uPA', 'Gene', (123, 126))	('uPA', 'Gene', '5328', (123, 126))	('SB203580', 'Chemical', 'MESH:C093642', (97, 105))	('AG1478', 'Var', (78, 84))	('SB203580', 'Var', (97, 105))	('decrease', 'NegReg', (111, 119))	('U0126', 'Var', (86, 91))
237439	25302298	Pretreatment with MG132 followed by irradiation in dose of 4 Gy in vitro is shown to suppress cell migration and invasion abilities in A549 and H1299 cancer cell lines, which is accompanied by decreased expression of MMP-2 and MMP-9 in NSCLC cell lines.	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('NSCLC', 'Disease', 'MESH:D002289', (236, 241))	('MG132', 'Chemical', 'MESH:C072553', (18, 23))	('NSCLC', 'Phenotype', 'HP:0030358', (236, 241))	('MMP-9', 'Gene', (227, 232))	('expression', 'MPA', (203, 213))	('MMP-2', 'Gene', (217, 222))	('MG132', 'Var', (18, 23))	('A549 and H1299 cancer', 'Disease', 'MESH:D009369', (135, 156))	('cell migration', 'CPA', (94, 108))	('MMP-2', 'Gene', '4313', (217, 222))	('NSCLC', 'Disease', (236, 241))	('decreased', 'NegReg', (193, 202))	('suppress', 'NegReg', (85, 93))	('invasion abilities', 'CPA', (113, 131))
237443	25302298	In thyroid carcinoma cells PI3K inhibitor GDC0941 significantly inhibits lung metastasis in mice bearing irradiated follicular thyroid carcinoma cells.	('thyroid carcinoma', 'Disease', (127, 144))	('GDC0941', 'Var', (42, 49))	('lung metastasis', 'Disease', (73, 88))	('thyroid carcinoma', 'Disease', (3, 20))	('lung metastasis', 'Disease', 'MESH:D009362', (73, 88))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (3, 20))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('GDC0941', 'Chemical', 'MESH:C532162', (42, 49))	('follicular thyroid carcinoma', 'Phenotype', 'HP:0006731', (116, 144))	('carcinoma', 'Phenotype', 'HP:0030731', (11, 20))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (127, 144))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (3, 20))	('inhibits', 'NegReg', (64, 72))	('mice', 'Species', '10090', (92, 96))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (127, 144))
237444	25302298	It is of interest that PI3K is not activated in these cells by IR in vitro, which means that tumor microenvironment is involved in antimetastatic activities of GDC0941.	('involved', 'Reg', (119, 127))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Disease', (93, 98))	('antimetastatic activities', 'MPA', (131, 156))	('GDC0941', 'Var', (160, 167))	('GDC0941', 'Chemical', 'MESH:C532162', (160, 167))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
237447	25302298	Inhibition of these signaling pathways in cells of tumor microenvironment can become a promising approach for enhancement of positive effect of radiotherapy.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor', 'Disease', (51, 56))	('Inhibition', 'Var', (0, 10))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
237503	33077915	Given that unchecked interferon signalling and inflammation can result in immunopathology, ISGs are subject to complex regulatory mechanisms.	('unchecked', 'Var', (11, 20))	('result in', 'Reg', (64, 73))	('inflammation', 'Disease', 'MESH:D007249', (47, 59))	('inflammation', 'Disease', (47, 59))	('immunopathology', 'MPA', (74, 89))
237508	33077915	SARS-CoV-2 uses angiotensin-converting enzyme 2 (ACE2) as its primary receptor and recent work suggested that SARS-CoV-2 may hijack the interferon response by inducing ACE2 expression.	('SARS-CoV-2', 'Species', '2697049', (0, 10))	('SARS-CoV-2', 'Var', (110, 120))	('angiotensin-converting enzyme 2', 'Gene', (16, 47))	('SARS-CoV-2', 'Species', '2697049', (110, 120))	('expression', 'Species', '29278', (173, 183))	('ACE2', 'Protein', (168, 172))	('angiotensin-converting enzyme 2', 'Gene', '59272', (16, 47))	('expression', 'MPA', (173, 183))	('interferon', 'CPA', (136, 146))	('inducing', 'PosReg', (159, 167))
237513	33077915	Notably, we find that the truncated MIRb-ACE2 and not full-length ACE2 is the interferon-inducible isoform, and is strongly upregulated in viral infection and following interferon treatment.	('viral infection', 'Disease', (139, 154))	('MIRb', 'Gene', '100124544', (36, 40))	('MIRb', 'Gene', (36, 40))	('viral infection', 'Disease', 'MESH:D001102', (139, 154))	('upregulated', 'PosReg', (124, 135))	('truncated', 'Var', (26, 35))
237569	33077915	The MIRb-ACE2 isoform is predicted to encode a truncated ACE2 product (amino acids 357-805) and exonization exonization of the LTR16A1 element creates a novel 10 amino acid N-terminal sequence (MREAGWDKGG) in the putative translation product (Extended Data Fig.	('LTR16A1', 'Gene', (127, 134))	('MIRb', 'Gene', (4, 8))	('MIRb', 'Gene', '100124544', (4, 8))	('exonization', 'Var', (96, 107))
237583	33077915	Lysine residues 625 and 702 in the full-length ACE2 protein have been described to be ubiquitinated and may contribute to its proteosomal degradation.	('ACE2', 'Gene', (47, 51))	('ubiquitinated', 'MPA', (86, 99))	('Lysine', 'Chemical', 'MESH:D008239', (0, 6))	('proteosomal degradation', 'MPA', (126, 149))	('Lysine residues 625', 'Var', (0, 19))	('contribute', 'Reg', (108, 118))
237584	33077915	We generated a K625R K702R (K2R) mutant of full-length ACE2, which increased protein levels, compared to the wild-type ACE2 (Fig.	('K702R', 'Var', (21, 26))	('K625R', 'SUBSTITUTION', 'None', (15, 20))	('ACE2', 'Gene', (55, 59))	('protein levels', 'MPA', (77, 91))	('K625R', 'Var', (15, 20))	('increased', 'PosReg', (67, 76))	('K702R', 'SUBSTITUTION', 'None', (21, 26))
237585	33077915	We have introduced the same mutations in the corresponding residues of the predicted MIRb-ACE2 protein product, K279R K356R, which were similarly accessible for ubiquitination (Extended Data Fig.	('K279R', 'SUBSTITUTION', 'None', (112, 117))	('K356R', 'Var', (118, 123))	('K279R', 'Var', (112, 117))	('K356R', 'SUBSTITUTION', 'None', (118, 123))	('MIRb', 'Gene', '100124544', (85, 89))	('MIRb', 'Gene', (85, 89))
237588	33077915	Moreover, cycloheximide treatment of HEK293T cells transfected with FLAG tagged ACE2 or MIRb-ACE2 constructs led to the rapid loss of MIRb-ACE2 protein, but did not affect levels of full-length ACE2 in the same time frame (Fig.	('MIRb', 'Gene', (134, 138))	('protein', 'Protein', (144, 151))	('HEK293T', 'CellLine', 'CVCL:0063', (37, 44))	('constructs', 'Var', (98, 108))	('ACE2', 'Gene', (80, 84))	('MIRb', 'Gene', '100124544', (88, 92))	('MIRb', 'Gene', (88, 92))	('loss', 'NegReg', (126, 130))	('MIRb', 'Gene', '100124544', (134, 138))	('cycloheximide', 'Chemical', 'MESH:D003513', (10, 23))
237593	33077915	To examine this possibility, we quantified levels of enzymatically active ACE2, an assay that is considerably more sensitive than Western blotting, and found, as expected, strong enzymatic activity in lysates from ACE2-transfected, but not MIRb-ACE2-transfected cells (Fig.	('MIRb', 'Gene', '100124544', (240, 244))	('ACE2-transfected', 'Var', (214, 230))	('MIRb', 'Gene', (240, 244))
237594	33077915	Furthermore, co-transfection with MIRb-ACE2 did not affect the enzymatic activity conferred by ACE2 transfection (Fig.	('MIRb', 'Gene', (34, 38))	('ACE2', 'Var', (95, 99))	('MIRb', 'Gene', '100124544', (34, 38))
237597	33077915	Whereas SARS-CoV-2 S1 efficiently bound HEK293T cells expressing ACE2, it did not bind those expressing MIRb-ACE2 (Fig.	('HEK293T', 'CellLine', 'CVCL:0063', (40, 47))	('MIRb', 'Gene', '100124544', (104, 108))	('bound', 'Interaction', (34, 39))	('MIRb', 'Gene', (104, 108))	('SARS-CoV-2', 'Species', '2697049', (8, 18))	('ACE2', 'Var', (65, 69))
237605	33077915	LTR and non-LTR retroelements represent an abundant source of promoters, enhancers, and polyadenylation sequences that can modulate the expression and structure of neighboring genes, as with ACE2.	('expression', 'MPA', (136, 146))	('structure', 'MPA', (151, 160))	('polyadenylation sequences', 'Var', (88, 113))	('modulate', 'Reg', (123, 131))	('ACE2', 'Gene', (191, 195))	('expression', 'Species', '29278', (136, 146))
237631	33077915	Based on sequence identity and the human neutral substitution rate estimated at 2.2 x 10-9 substitutions per site per year, the LTR16A1 insertion is expected to be ~131 million years (with 284 nt matches across 399 nt) and the MIRb insertion ~155 million years (with 159 nt matches across 241 nt).	('MIRb', 'Gene', '100124544', (227, 231))	('LTR16A1', 'Gene', (128, 135))	('MIRb', 'Gene', (227, 231))	('insertion', 'Var', (136, 145))	('human', 'Species', '9606', (35, 40))
237651	33077915	Additionally, RNA-seq data from individual studies (GSE147507 and GSE134355) were downloaded from the Gene Expression Omnibus (GEO) database (https://www.ncbi.nlm.nih.gov/geo).	('GSE134355', 'Var', (66, 75))	('GSE147507', 'Var', (52, 61))	('Expression', 'Species', '29278', (107, 117))
237732	30260023	Furthermore, we built mutant reporter vectors containing a mutation in the miR-211 binding site (BIN1 3'-UTR-M).	('BIN1', 'Gene', '274', (97, 101))	('miR-211', 'Gene', '406993', (75, 82))	('miR-211', 'Gene', (75, 82))	('mutation', 'Var', (59, 67))	('BIN1', 'Gene', (97, 101))
237740	30260023	However, as for the HN4 cells which were treated with siR-BIN1, the miR-211 inhibitor did not suppress their invasion and migration ability.	('BIN1', 'Gene', '274', (58, 62))	('HN4', 'Gene', (20, 23))	('suppress', 'NegReg', (94, 102))	('inhibitor', 'Var', (76, 85))	('BIN1', 'Gene', (58, 62))	('miR-211', 'Gene', '406993', (68, 75))	('miR-211', 'Gene', (68, 75))	('HN4', 'Gene', '100463285', (20, 23))
237746	30260023	The deactivation of tumor-suppressing proteins is a frequent cancer hallmark benefiting the progression of OSCC.	('OSCC', 'Disease', (107, 111))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('cancer', 'Disease', (61, 67))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('deactivation', 'Var', (4, 16))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('tumor', 'Disease', (20, 25))
237759	30260023	Overexpression of BIN1 could significantly inhibit the proliferation, migration, and invasion ability of OSCC cells.	('BIN1', 'Gene', '274', (18, 22))	('migration', 'CPA', (70, 79))	('proliferation', 'CPA', (55, 68))	('invasion ability of OSCC cells', 'CPA', (85, 115))	('inhibit', 'NegReg', (43, 50))	('Overexpression', 'Var', (0, 14))	('BIN1', 'Gene', (18, 22))
237765	29617661	Among them, we systematically identify top somatic driver candidates, including mutated FBXW7 with cancer-type-specific patterns and amplified MDM2 showing a mutually exclusive pattern with BRAF mutations.	('FBXW7', 'Gene', (88, 93))	('MDM2', 'Gene', '4193', (143, 147))	('MDM2', 'Gene', (143, 147))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('mutated', 'Var', (80, 87))	('cancer', 'Disease', (99, 105))	('FBXW7', 'Gene', '55294', (88, 93))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
237768	29617661	These samples are consistently associated with the upregulation of cell-cycle and DNA repair pathways, characterized by mutated TP53, MYC/TERT amplification, and APC/PTEN deletion.	('upregulation', 'PosReg', (51, 63))	('APC', 'Disease', (162, 165))	('MYC/TERT', 'Gene', (134, 142))	('PTEN', 'Gene', (166, 170))	('mutated', 'Var', (120, 127))	('PTEN', 'Gene', '5728', (166, 170))	('TERT', 'CellLine', 'CVCL:C452', (138, 142))	('TP53', 'Protein', (128, 132))	('cell-cycle', 'Pathway', (67, 77))	('APC', 'Disease', 'MESH:D011125', (162, 165))	('DNA repair pathways', 'Pathway', (82, 101))
237784	29617661	Overall, across 8,811 non-hypermutated cancer samples, the mutation frequency was low for both UBQ and DUB genes, with an average mutation number per patient of 4.5 and 0.5, respectively.	('patient', 'Species', '9606', (150, 157))	('cancer', 'Disease', (39, 45))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('low', 'NegReg', (82, 85))	('UBQ', 'Gene', (95, 98))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('mutation', 'Var', (59, 67))
237786	29617661	First, we used a ratiometric method for nominating cancer driver genes based on the enrichment of hotspot or loss-of-function (LoF) mutations among all mutations observed in a gene (Figure 1A).	('loss-of-function', 'NegReg', (109, 125))	('mutations', 'Var', (152, 161))	('mutations', 'Var', (132, 141))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))
237787	29617661	In this pan-cancer analysis, we identified 19 UBQ/DUB genes with >30% hotspot mutations and 29 genes with >30% LoF mutations (FBXW7 was identified by both criteria).	('UBQ/DUB genes', 'Gene', (46, 59))	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('LoF', 'NegReg', (111, 114))	('FBXW7', 'Gene', '55294', (126, 131))	('cancer', 'Disease', (12, 18))	('FBXW7', 'Gene', (126, 131))	('mutations', 'Var', (78, 87))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))
237792	29617661	Among 15 driver genes identified by both methods, SPOP, KEAP1, and CHD4 were enriched with hotspot mutations, while BAP1, CDH1, CUL3, EP300, KDM5C, MAP3K1, NSD1, RNF43, TLE1, VHL, and LZTR1 contained excessive LoF mutations.	('BAP1', 'Gene', (116, 120))	('VHL', 'Disease', (175, 178))	('VHL', 'Disease', 'MESH:D006623', (175, 178))	('LZTR1', 'Gene', (184, 189))	('TLE1', 'Gene', (169, 173))	('CHD4', 'Gene', (67, 71))	('NSD1', 'Gene', (156, 160))	('mutations', 'Var', (99, 108))	('MAP3K1', 'Gene', (148, 154))	('SPOP', 'Gene', (50, 54))	('KDM5C', 'Gene', (141, 146))	('RNF43', 'Gene', (162, 167))	('CDH1', 'Gene', (122, 126))	('LoF', 'NegReg', (210, 213))
237793	29617661	Of particular interest, FBXW7 showed enrichment of both hotspot and LoF mutations (Figure 1A).	('mutations', 'Var', (72, 81))	('FBXW7', 'Gene', (24, 29))	('LoF', 'NegReg', (68, 71))	('FBXW7', 'Gene', '55294', (24, 29))
237796	29617661	To gain more insight into its mutational profile, we examined the mutation distributions of FBXW7 in different cancer types and found three distinct patterns (Figure 2A): (1) hotspot mutations were enriched in two uterine cancer types, uterine corpus endometrial carcinoma (UCEC), and uterine carcinosarcoma (UCS); (2) LoF mutations were enriched in skin cutaneous melanoma (SKCM), stomach adenocarcinoma (STAD), lung squamous cell carcinoma (LUSC), lung adenocarcinoma (LUAD), rectum adenocarcinoma (READ), and esophageal carcinoma (ESCA); and (3) the proportions of both hotspot and LoF mutations were high in head and neck squamous cell carcinoma (HNSC), cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), bladder urothelial carcinoma (BLCA), and colon adenocarcinoma (COAD).	('lung adenocarcinoma', 'Disease', (450, 469))	('mutations', 'Var', (589, 598))	('skin cutaneous melanoma', 'Disease', (350, 373))	('carcinoma', 'Phenotype', 'HP:0030731', (263, 272))	('COAD', 'Disease', (794, 798))	('endometrial carcinoma', 'Disease', (251, 272))	('stomach adenocarcinoma', 'Disease', (382, 404))	('carcinosarcoma', 'Disease', 'MESH:D002296', (293, 307))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (413, 441))	('READ', 'Disease', (501, 505))	('bladder urothelial carcinoma', 'Disease', (731, 759))	('carcinoma', 'Phenotype', 'HP:0030731', (460, 469))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (450, 469))	('melanoma', 'Phenotype', 'HP:0002861', (365, 373))	('rectum adenocarcinoma', 'Disease', (478, 499))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (355, 373))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (626, 649))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (731, 759))	('uterine cancer', 'Phenotype', 'HP:0010784', (214, 228))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (418, 441))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (413, 441))	('lung squamous cell carcinoma', 'Disease', (413, 441))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (512, 532))	('colon adenocarcinoma', 'Disease', 'MESH:D003110', (772, 792))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (450, 469))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (285, 307))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('carcinoma', 'Phenotype', 'HP:0030731', (395, 404))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (251, 272))	('stomach adenocarcinoma', 'Disease', 'MESH:D013274', (382, 404))	('FBXW7', 'Gene', (92, 97))	('mutations', 'Var', (323, 332))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (251, 272))	('READ', 'Disease', 'None', (501, 505))	('esophageal carcinoma', 'Disease', (512, 532))	('cancer type', 'Disease', (111, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (490, 499))	('COAD', 'Disease', 'MESH:D029424', (794, 798))	('cervical squamous cell carcinoma', 'Disease', (658, 690))	('endocervical adenocarcinoma', 'Disease', (695, 722))	('cancer type', 'Disease', (222, 233))	('cancer type', 'Disease', 'MESH:D009369', (111, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (432, 441))	('rectum adenocarcinoma', 'Disease', 'MESH:D012004', (478, 499))	('cancer type', 'Disease', 'MESH:D009369', (222, 233))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (512, 532))	('colon adenocarcinoma', 'Disease', (772, 792))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (350, 373))	('FBXW7', 'Gene', '55294', (92, 97))	('carcinosarcoma', 'Disease', (293, 307))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (667, 690))
237797	29617661	Consistent with previous studies, FBXW7 contains three notable missense mutation hotspots (R465, R479, and R505) in the second, third, and fourth WD40 domains that recognize the consensus phospho-motif located in its substrate (Figure 2B).	('FBXW7', 'Gene', '55294', (34, 39))	('R479', 'Var', (97, 101))	('FBXW7', 'Gene', (34, 39))	('R505', 'Var', (107, 111))	('R465', 'Var', (91, 95))
237798	29617661	Figure 2C shows the FBXW7 mutation distributions for the hotspot mutation-enriched cancer types and the LoF mutation-enriched cancer types.	('LoF', 'NegReg', (104, 107))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('FBXW7', 'Gene', '55294', (20, 25))	('mutation', 'Var', (26, 34))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('cancer type', 'Disease', (126, 137))	('cancer type', 'Disease', (83, 94))	('FBXW7', 'Gene', (20, 25))	('cancer type', 'Disease', 'MESH:D009369', (126, 137))	('cancer type', 'Disease', 'MESH:D009369', (83, 94))
237799	29617661	The three missense hotspots accounted for 49% (38 of 77) of the FBXW7 mutations observed in UCEC and UCS.	('FBXW7', 'Gene', '55294', (64, 69))	('mutations', 'Var', (70, 79))	('UCEC', 'Disease', (92, 96))	('FBXW7', 'Gene', (64, 69))	('observed in', 'Reg', (80, 91))	('UCS', 'Disease', (101, 104))
237800	29617661	The contrasting mutation patterns of FBXW7 mutations may reflect tissue-specific roles of FBXW7 substrates or different FBXW7-mediated oncogenic mechanisms in different tumor contexts.	('FBXW7', 'Gene', (37, 42))	('FBXW7', 'Gene', '55294', (120, 125))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('FBXW7', 'Gene', (120, 125))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('FBXW7', 'Gene', '55294', (90, 95))	('mutations', 'Var', (43, 52))	('tumor', 'Disease', (169, 174))	('FBXW7', 'Gene', '55294', (37, 42))	('FBXW7', 'Gene', (90, 95))
237801	29617661	We further assessed the occurrence of FBXW7 mutations with those in clinically actionable cancer genes and revealed that mutations in FBXW7 and PIK3CA showed mutual exclusivity in three cancer types: CESC, BLCA, and LUSC (Figure 2D), suggesting that mutations in these two genes confer similar functional consequences.	('cancer type', 'Disease', 'MESH:D009369', (186, 197))	('mutations', 'Var', (121, 130))	('CESC', 'Disease', (200, 204))	('PIK3CA', 'Gene', (144, 150))	('FBXW7', 'Gene', (134, 139))	('FBXW7', 'Gene', '55294', (38, 43))	('LUSC', 'Disease', (216, 220))	('PIK3CA', 'Gene', '5290', (144, 150))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('FBXW7', 'Gene', (38, 43))	('cancer type', 'Disease', (186, 197))	('BLCA', 'Disease', (206, 210))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('cancer', 'Disease', (90, 96))	('FBXW7', 'Gene', '55294', (134, 139))	('cancer', 'Disease', (186, 192))	('cancer', 'Disease', 'MESH:D009369', (186, 192))
237802	29617661	Patients with FBXW7 or phosphatidylinositol 3-kinase (PI3K) pathway mutations (mutations found in PIK3CA, PTEN, and STK11) had higher PI3K pathway expression activity than patients without such mutations (Figure 2E).	('STK11', 'Gene', (116, 121))	('activity', 'MPA', (158, 166))	('phosphatidylinositol 3-kinase', 'Gene', '5290', (23, 52))	('FBXW7', 'Gene', '55294', (14, 19))	('PIK3CA', 'Gene', (98, 104))	('phosphatidylinositol 3-kinase', 'Gene', (23, 52))	('STK11', 'Gene', '6794', (116, 121))	('PIK3CA', 'Gene', '5290', (98, 104))	('Patients', 'Species', '9606', (0, 8))	('PTEN', 'Gene', '5728', (106, 110))	('PTEN', 'Gene', (106, 110))	('higher', 'PosReg', (127, 133))	('FBXW7', 'Gene', (14, 19))	('PI3K pathway', 'Pathway', (134, 146))	('mutations', 'Var', (68, 77))	('patients', 'Species', '9606', (172, 180))	('mutations', 'Var', (79, 88))
237803	29617661	To infer somatic copy-number alteration (SCNA) drivers, we used GISTIC2 to identify significant focal deletion and amplification peaks in each of 33 cancer types.	('cancer type', 'Disease', 'MESH:D009369', (149, 160))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('deletion', 'Var', (102, 110))	('cancer type', 'Disease', (149, 160))	('amplification', 'MPA', (115, 128))
237804	29617661	UBQ and DUB genes showed similar overall SCNA profiles in terms of the amplification and deletion gene fractions across cancer types (Figures S3A and S3B).	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('cancer type', 'Disease', (120, 131))	('cancer type', 'Disease', 'MESH:D009369', (120, 131))	('deletion', 'Var', (89, 97))	('UBQ', 'Gene', (0, 3))
237806	29617661	Four cancer types (kidney renal clear cell carcinoma [KIRC], SKCM, cholangiocarcinoma [CHOL], and pancreatic adenocarcinoma [PAAD]) showed significant deletion peak enrichments, while no cancer types showed significant amplification peak enrichment (p < 0.01) (Figure 3A).	('pancreatic adenocarcinoma', 'Disease', 'MESH:D010190', (98, 123))	('pancreatic adenocarcinoma', 'Disease', (98, 123))	('cancer type', 'Disease', 'MESH:D009369', (187, 198))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (67, 85))	('cancer type', 'Disease', 'MESH:D009369', (5, 16))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('deletion', 'Var', (151, 159))	('kidney renal clear cell carcinoma', 'Disease', (19, 52))	('cholangiocarcinoma', 'Disease', (67, 85))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (67, 85))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (98, 123))	('SKCM', 'Disease', (61, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (43, 52))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('kidney renal clear cell carcinoma', 'Disease', 'MESH:C538614', (19, 52))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))	('cancer type', 'Disease', (187, 198))	('cancer type', 'Disease', (5, 16))
237810	29617661	Among UBQ and DUB genes, we found a mutually exclusive pattern of MDM2 and SKP2 amplifications in LUAD (Figure S3E), suggesting convergence of their functions on the same downstream effectors.	('amplifications', 'Var', (80, 94))	('MDM2', 'Gene', '4193', (66, 70))	('MDM2', 'Gene', (66, 70))	('UBQ', 'Gene', (6, 9))	('SKP2', 'Gene', (75, 79))	('LUAD', 'Disease', (98, 102))
237812	29617661	For clinically actionable genes, we found that MDM2 amplifications were mutually exclusive to BRAF and ATM mutations in SKCM and BLCA, respectively (Figures 3C and S3F).	('MDM2', 'Gene', '4193', (47, 51))	('mutations', 'Var', (107, 116))	('SKCM', 'Gene', (120, 124))	('MDM2', 'Gene', (47, 51))	('BLCA', 'Gene', (129, 133))
237813	29617661	BRAF kinase domain mutations, such as V600E, result in a constitutively activated form of the protein in around 50% of SKCM patients (45.1% in this study), which then leads to stimulated mitogen-activated protein kinase (MAPK) signaling and induces tumor cell proliferation.	('V600E', 'Var', (38, 43))	('induces', 'PosReg', (241, 248))	('tumor', 'Disease', 'MESH:D009369', (249, 254))	('patients', 'Species', '9606', (124, 132))	('tumor', 'Phenotype', 'HP:0002664', (249, 254))	('SKCM', 'Disease', (119, 123))	('tumor', 'Disease', (249, 254))	('mitogen-activated', 'MPA', (187, 204))	('V600E', 'Mutation', 'rs113488022', (38, 43))	('constitutively', 'MPA', (57, 71))	('stimulated', 'PosReg', (176, 186))
237817	29617661	Furthermore, the mutually exclusive pattern of MDM2 amplification and BRAF mutation suggests that a reduced p53 pathway or induced MAPK signaling can serve as an impetus for aberrant tumor cell proliferation (Figure 3E).	('MDM2', 'Gene', '4193', (47, 51))	('p53', 'Gene', (108, 111))	('p53', 'Gene', '7157', (108, 111))	('MDM2', 'Gene', (47, 51))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('reduced', 'NegReg', (100, 107))	('mutation', 'Var', (75, 83))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('tumor', 'Disease', (183, 188))	('amplification', 'Var', (52, 65))	('MAPK signaling', 'MPA', (131, 145))	('BRAF', 'Gene', (70, 74))
237819	29617661	Studies have shown increased apoptosis and inhibition of melanoma growth by combining a BRAF inhibitor and p53 reactivation.	('apoptosis', 'CPA', (29, 38))	('combining', 'Interaction', (76, 85))	('reactivation', 'Var', (111, 123))	('inhibition', 'NegReg', (43, 53))	('p53', 'Gene', (107, 110))	('p53', 'Gene', '7157', (107, 110))	('melanoma', 'Phenotype', 'HP:0002861', (57, 65))	('melanoma', 'Disease', (57, 65))	('BRAF', 'Protein', (88, 92))	('increased', 'PosReg', (19, 28))	('melanoma', 'Disease', 'MESH:D008545', (57, 65))
237825	29617661	First, in 6 of the 7 cancer types, upregulated genes showed a significantly higher proportion of copy-number amplifications than did neutral genes (chi-square test, q < 0.01) (Figure 4C, top), highlighting the significant role of somatic copy-number gain in increasing UBQ/DUB gene expression in tumor samples.	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('tumor', 'Phenotype', 'HP:0002664', (296, 301))	('cancer type', 'Disease', (21, 32))	('tumor', 'Disease', (296, 301))	('expression', 'MPA', (282, 292))	('increasing', 'PosReg', (258, 268))	('copy-number', 'Var', (238, 249))	('UBQ/DUB', 'Gene', (269, 276))	('copy-number', 'Var', (97, 108))	('upregulated', 'PosReg', (35, 46))	('cancer type', 'Disease', 'MESH:D009369', (21, 32))	('gain', 'PosReg', (250, 254))	('tumor', 'Disease', 'MESH:D009369', (296, 301))
237845	29617661	Then we examined SCNA drivers by focusing on known oncogenes and tumor suppressors residing in amplification or deletion peaks (identified by GISTIC2) in each cancer type.	('tumor', 'Disease', (65, 70))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('deletion', 'Var', (112, 120))	('amplification', 'Var', (95, 108))	('cancer type', 'Disease', (159, 170))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('cancer type', 'Disease', 'MESH:D009369', (159, 170))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
237846	29617661	We found that COCA2 was associated with the amplifications of MYC and TERT and the deletions of PTEN and APC in multiple cancer types (q < 0.001) (Figure 6D).	('PTEN', 'Gene', '5728', (96, 100))	('amplifications', 'Var', (44, 58))	('APC', 'Disease', (105, 108))	('MYC', 'Protein', (62, 65))	('multiple cancer', 'Disease', (112, 127))	('associated', 'Reg', (24, 34))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('COCA', 'Species', '289672', (14, 18))	('cancer type', 'Disease', (121, 132))	('deletions', 'Var', (83, 92))	('multiple cancer', 'Disease', 'MESH:D009369', (112, 127))	('TERT', 'CellLine', 'CVCL:C452', (70, 74))	('TERT', 'Gene', (70, 74))	('cancer type', 'Disease', 'MESH:D009369', (121, 132))	('COCA2', 'Disease', (14, 19))	('APC', 'Disease', 'MESH:D011125', (105, 108))	('PTEN', 'Gene', (96, 100))
237848	29617661	Deletion or low expression of the tumor suppressor PTEN has been shown to drive cell-cycle progression, proliferation, and cell survival.	('cell survival', 'CPA', (123, 136))	('drive', 'PosReg', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('tumor', 'Disease', (34, 39))	('PTEN', 'Gene', '5728', (51, 55))	('proliferation', 'CPA', (104, 117))	('expression', 'MPA', (16, 26))	('low', 'NegReg', (12, 15))	('cell-cycle progression', 'CPA', (80, 102))	('PTEN', 'Gene', (51, 55))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('Deletion', 'Var', (0, 8))
237851	29617661	Therefore, we put forward a model in which mutated TP53 and amplified MYC are closely associated with primarily an upregulation of key ubiquitin-related enzymes, leading to an uncontrolled cell cycle, elevated DNA damage response, and ultimately poor survival for COCA2 patients (Figure 7).	('elevated', 'PosReg', (201, 209))	('TP53', 'Gene', (51, 55))	('upregulation', 'PosReg', (115, 127))	('patients', 'Species', '9606', (270, 278))	('uncontrolled', 'MPA', (176, 188))	('COCA', 'Species', '289672', (264, 268))	('MYC', 'Protein', (70, 73))	('amplified', 'Gene', (60, 69))	('DNA damage response', 'MPA', (210, 229))	('mutated', 'Var', (43, 50))
237853	29617661	For example, substrates of FBXW7 are oncoproteins, such as cyclin E, c-Myc, and Notch, while substrates of SKP2 are tumor suppressors, such as p21, p27, and p57.	('c-Myc', 'MPA', (69, 74))	('SKP2', 'Gene', (107, 111))	('cyclin E', 'Protein', (59, 67))	('FBXW7', 'Gene', '55294', (27, 32))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('Notch', 'MPA', (80, 85))	('FBXW7', 'Gene', (27, 32))	('p21', 'Var', (143, 146))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('p57', 'Var', (157, 160))	('tumor', 'Disease', (116, 121))	('p27', 'Var', (148, 151))
237856	29617661	For example, BAP1 and VHL are frequently mutated in mesothelioma (MESO) and KIRC, respectively, whereas FBXW7 is enriched with hotspot mutations in UCEC and UCS but enriched with LoF mutations in ESCA, LUAD, LUSC, READ, SKCM, and STAD.	('BAP1', 'Gene', (13, 17))	('ESCA', 'Disease', (196, 200))	('mutations', 'Var', (183, 192))	('READ', 'Disease', (214, 218))	('mutated', 'Reg', (41, 48))	('mutations', 'Var', (135, 144))	('VHL', 'Disease', 'MESH:D006623', (22, 25))	('mesothelioma', 'Disease', (52, 64))	('FBXW7', 'Gene', '55294', (104, 109))	('VHL', 'Disease', (22, 25))	('LoF', 'NegReg', (179, 182))	('mesothelioma', 'Disease', 'MESH:D008654', (52, 64))	('READ', 'Disease', 'None', (214, 218))	('FBXW7', 'Gene', (104, 109))
237857	29617661	Second, we show that compared to matched normal tissues, genes in the ubiquitin pathway tend to be overexpressed in a range of cancer types, and collectively, 71% of the upregulated genes are contributed by one of three mechanisms: somatic copy-number gain, reduced methylation-mediated gene silencing, and reduced miRNA-mediated gene regulation in tumors.	('cancer type', 'Disease', (127, 138))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('tumors', 'Disease', (349, 355))	('tumors', 'Disease', 'MESH:D009369', (349, 355))	('tumors', 'Phenotype', 'HP:0002664', (349, 355))	('reduced', 'NegReg', (258, 265))	('copy-number', 'Var', (240, 251))	('miRNA-mediated', 'MPA', (315, 329))	('reduced', 'NegReg', (307, 314))	('methylation-mediated gene', 'MPA', (266, 291))	('cancer type', 'Disease', 'MESH:D009369', (127, 138))	('genes', 'Var', (182, 187))	('tumor', 'Phenotype', 'HP:0002664', (349, 354))	('gain', 'PosReg', (252, 256))	('upregulated', 'PosReg', (170, 181))
237859	29617661	These tumor samples are associated with differential UBQ/DUB expression underlying the perturbation of many fundamental signaling pathways, notably cell-cycle progression and DNA damage repair, likely resulting from key molecular drivers such as TP53, MYC, TERT, PTEN, and APC.	('APC', 'Disease', 'MESH:D011125', (273, 276))	('TERT', 'Disease', (257, 261))	('APC', 'Disease', (273, 276))	('TERT', 'CellLine', 'CVCL:C452', (257, 261))	('DNA damage repair', 'MPA', (175, 192))	('MYC', 'Disease', (252, 255))	('PTEN', 'Gene', (263, 267))	('tumor', 'Disease', 'MESH:D009369', (6, 11))	('TP53', 'Var', (246, 250))	('PTEN', 'Gene', '5728', (263, 267))	('perturbation', 'NegReg', (87, 99))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('UBQ/DUB', 'Gene', (53, 60))	('cell-cycle progression', 'CPA', (148, 170))	('tumor', 'Disease', (6, 11))	('fundamental signaling pathways', 'Pathway', (108, 138))
237862	29617661	This could be largely due to the lack of systemic characterization of significant driver mutations, SCNA patterns, and dysregulated expression profiles in the ubiquitin pathway across cancer types through an integrated genomic analysis that would provide clinically relevant drug candidates to the pharmaceutical industry.	('cancer type', 'Disease', 'MESH:D009369', (184, 195))	('ubiquitin pathway', 'Pathway', (159, 176))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('mutations', 'Var', (89, 98))	('dysregulated', 'Var', (119, 131))	('expression', 'MPA', (132, 142))	('cancer type', 'Disease', (184, 195))
237864	29617661	Moreover, the deubiquitinase USP7 has been shown to deubiquitinate several key cancer proteins, and P5091, a highly specific inhibitor of USP7, induced apoptosis in multiple myeloma cells.	('multiple myeloma', 'Disease', (165, 181))	('multiple myeloma', 'Disease', 'MESH:D009101', (165, 181))	('induced', 'PosReg', (144, 151))	('USP7', 'Gene', (29, 33))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('cancer', 'Disease', (79, 85))	('multiple myeloma', 'Phenotype', 'HP:0006775', (165, 181))	('apoptosis', 'CPA', (152, 161))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('deubiquitinate', 'MPA', (52, 66))	('P5091', 'Var', (100, 105))
237872	29617661	Across the pan-cancer cohort, hotspot mutations were defined as missense or in-frame mutations at the same protein amino acid in > 2 patient samples.	('cancer', 'Disease', (15, 21))	('cancer', 'Disease', 'MESH:D009369', (15, 21))	('patient', 'Species', '9606', (133, 140))	('in-frame', 'Reg', (76, 84))	('missense', 'Var', (64, 72))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))
237873	29617661	Mutual exclusivity for FBXW7 mutations and mutations in clinically actionable genes (annotated as in OncoKB, http://oncokb.org) was performed with the R package "cometExactTest."	('FBXW7', 'Gene', (23, 28))	('mutations', 'Var', (29, 38))	('FBXW7', 'Gene', '55294', (23, 28))
237874	29617661	To study the effects of FBXW7 mutations, PI3K pathway expression was calculated from protein levels of the PI3K/Akt pathway components as measured by RPPA with the following formula where E means expression:   We obtained SCNA data of 9,125 patient samples from Genomic Data Commons and applied GISTIC2.	('FBXW7', 'Gene', (24, 29))	('mutations', 'Var', (30, 39))	('patient', 'Species', '9606', (241, 248))	('FBXW7', 'Gene', '55294', (24, 29))
237894	29360512	Histologic Lung Cancer Incidence Rates and Trends vary by Race/Ethnicity and Residential County Lung cancer incidence is higher among NH blacks compared with NH white and Hispanic populations in the U.S.	('Cancer', 'Phenotype', 'HP:0002664', (16, 22))	('Cancer', 'Disease', (16, 22))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('NH blacks', 'Var', (134, 143))	('cancer', 'Disease', (101, 107))	('Cancer', 'Disease', 'MESH:D009369', (16, 22))	('Lung cancer', 'Phenotype', 'HP:0100526', (96, 107))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('higher', 'PosReg', (121, 127))	('Lung Cancer', 'Phenotype', 'HP:0100526', (11, 22))
237924	29360512	Lung cancer histology groups were defined using International Classification of Diseases for Oncology version 3 (ICD-0-3): Small cell (8002-8005, 8041-8045); Non-small cell (8046); Squamous (8052, 8070-8076, 8078, 8083-8084, 8094, 8120, 8123); Adenocarcinoma (8050, 8140-8141, 8144, 8201, 8250-8255, 8260, 8290, 8310, 8320, 8323, 8333, 8470, 8480, 8481, 8490, 8507, 8550, 8570, 8572, 8574, 8576); Large cell (8012-8014, 8021, 8082); Carcinoma, NOS (8000, 8001, 8010, 8020, 8230); Other specified types (8022, 8030, 8031-8033, 8200, 8240, 8241, 8244-8246, 8249,8430, 8560, 8562, 8575); Sarcoma (8800-8805, 8810, 8811, 8815, 8830, 8890, 8900, 8940, 9040, 9041, 9043, 9120, 9133, 9220, 9231, 9473, 9540) (Supplementary Table 1).	('Sarcoma', 'Disease', 'MESH:D012509', (585, 592))	('cancer', 'Disease', 'MESH:D009369', (5, 11))	('men', 'Species', '9606', (708, 711))	('Adenocarcinoma', 'Disease', (244, 258))	('Lung cancer', 'Phenotype', 'HP:0100526', (0, 11))	('Carcinoma', 'Phenotype', 'HP:0030731', (433, 442))	('Sarcoma', 'Disease', (585, 592))	('Oncology', 'Phenotype', 'HP:0002664', (93, 101))	('Sarcoma', 'Phenotype', 'HP:0100242', (585, 592))	('8815', 'Var', (617, 621))	('8800-8805', 'Var', (594, 603))	('Carcinoma', 'Disease', (433, 442))	('8830', 'Var', (623, 627))	('8022', 'Var', (503, 507))	('cancer', 'Disease', (5, 11))	('carcinoma', 'Phenotype', 'HP:0030731', (249, 258))	('Carcinoma', 'Disease', 'MESH:D002277', (433, 442))	('Adenocarcinoma', 'Disease', 'MESH:D000230', (244, 258))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))	('8811', 'Var', (611, 615))	('8900', 'Var', (635, 639))	('8000', 'Var', (449, 453))
237947	29360512	The incidence of lung adenocarcinoma in metropolitan counties and counties not adjacent to metropolitan counties were significantly higher among NH black men compared with NH white men (Table 3).	('higher', 'PosReg', (132, 138))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (17, 36))	('carcinoma', 'Phenotype', 'HP:0030731', (27, 36))	('NH black', 'Var', (145, 153))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (17, 36))	('men', 'Species', '9606', (154, 157))	('lung adenocarcinoma', 'Disease', (17, 36))	('men', 'Species', '9606', (181, 184))
237966	29360512	Interestingly, studies where the association between exposure to carcinogens and lung cancer risk have been examined in different racial/ethnic groups show that the effect of the relationship was stronger in NH blacks, compared with NH whites and stronger in rural counties.	('lung cancer', 'Phenotype', 'HP:0100526', (81, 92))	('stronger', 'PosReg', (196, 204))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('carcinogens and lung cancer', 'Disease', 'MESH:D008175', (65, 92))	('NH blacks', 'Var', (208, 217))
237979	29360512	However, studies do not support the hypothesis that menthol cigarettes are associated with a greater risk of lung cancer compared with other tobacco types.	('lung cancer', 'Disease', (109, 120))	('lung cancer', 'Phenotype', 'HP:0100526', (109, 120))	('menthol cigarettes', 'Var', (52, 70))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('menthol', 'Chemical', 'MESH:D008610', (52, 59))	('lung cancer', 'Disease', 'MESH:D008175', (109, 120))	('tobacco', 'Species', '4097', (141, 148))
237996	29360512	There is perhaps one exception in that the incidence of carcinoma NOS seemed to be higher in Hispanics, compared with NH whites.	('carcinoma NOS', 'Disease', (56, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (56, 65))	('carcinoma NOS', 'Disease', 'MESH:D002277', (56, 69))	('Hispanics', 'Var', (93, 102))
238018	28652248	Inhibition of GLI1 in human lung SCC cell lines suppressed tumor cell clonogenicity and proliferation in culture and in vivo.	('SCC', 'Gene', '6317', (33, 36))	('GLI1', 'Gene', (14, 18))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Disease', (59, 64))	('suppressed', 'NegReg', (48, 58))	('Inhibition', 'Var', (0, 10))	('SCC', 'Gene', (33, 36))	('proliferation', 'CPA', (88, 101))	('human', 'Species', '9606', (22, 27))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
238020	28652248	Furthermore, in vivo growth of SCC harboring amplifications of the PI3K gene PIK3CA was attenuated by antagonizing GLI1 and PI3K.	('PIK3CA', 'Gene', (77, 83))	('SCC', 'Gene', (31, 34))	('antagonizing', 'NegReg', (102, 114))	('PIK3CA', 'Gene', '5290', (77, 83))	('SCC', 'Gene', '6317', (31, 34))	('amplifications', 'Var', (45, 59))	('attenuated', 'NegReg', (88, 98))
238023	28652248	Recent genome-wide analyses of lung SCC revealed a number of frequent genetic aberrations in FGFR1, DDR2, components of the PI3K/mTOR and CDKN2A/RB1 pathways that represent promising targets for the development of small molecule antagonists.	('CDKN2A', 'Gene', (138, 144))	('RB1', 'Gene', (145, 148))	('CDKN2A', 'Gene', '1029', (138, 144))	('RB1', 'Gene', '5925', (145, 148))	('mTOR', 'Gene', '2475', (129, 133))	('SCC', 'Gene', (36, 39))	('mTOR', 'Gene', (129, 133))	('aberrations', 'Var', (78, 89))	('DDR2', 'Gene', '4921', (100, 104))	('FGFR1', 'Gene', (93, 98))	('DDR2', 'Gene', (100, 104))	('SCC', 'Gene', '6317', (36, 39))	('FGFR1', 'Gene', '2260', (93, 98))
238026	28652248	Non-classical activation of GLI1 and GLI2 by pathways orthogonal to the classical Hh pathway has been reported in a number of tumors including loss of SMARCB1 (SNF5) in malignant rhabdoid tumors, K-ras and TGFbeta in pancreatic cancer, TNFalpha via mTOR in esophageal cancer, PI3K in glioblastoma, and aPKCiota/lambda in drug-resistant basal cell carcinomas.	('basal cell carcinoma', 'Disease', (336, 356))	('malignant rhabdoid tumors', 'Disease', 'MESH:D018335', (169, 194))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('carcinomas', 'Disease', (347, 357))	('glioblastoma', 'Phenotype', 'HP:0012174', (284, 296))	('mTOR', 'Gene', (249, 253))	('TGFbeta', 'Gene', (206, 213))	('SNF5', 'Gene', '6598', (160, 164))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (217, 234))	('K-ras', 'Gene', (196, 201))	('TGFbeta', 'Gene', '7040', (206, 213))	('TNFalpha', 'Gene', '7124', (236, 244))	('tumors', 'Disease', (126, 132))	('tumors', 'Phenotype', 'HP:0002664', (188, 194))	('esophageal cancer', 'Disease', 'MESH:D004938', (257, 274))	('mTOR', 'Gene', '2475', (249, 253))	('malignant rhabdoid tumors', 'Disease', (169, 194))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('basal cell carcinoma', 'Disease', 'MESH:D002280', (336, 356))	('carcinoma', 'Phenotype', 'HP:0030731', (347, 356))	('carcinomas', 'Phenotype', 'HP:0030731', (347, 357))	('tumors', 'Disease', 'MESH:D009369', (126, 132))	('tumors', 'Disease', (188, 194))	('carcinomas', 'Disease', 'MESH:D002277', (347, 357))	('pancreatic cancer', 'Disease', 'MESH:D010190', (217, 234))	('basal cell carcinomas', 'Phenotype', 'HP:0002671', (336, 357))	('esophageal cancer', 'Disease', (257, 274))	('SNF5', 'Gene', (160, 164))	('GLI2', 'Gene', (37, 41))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('GLI2', 'Gene', '2736', (37, 41))	('SMARCB1', 'Gene', '6598', (151, 158))	('TNFalpha', 'Gene', (236, 244))	('SMARCB1', 'Gene', (151, 158))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (336, 356))	('K-ras', 'Gene', '3845', (196, 201))	('pancreatic cancer', 'Disease', (217, 234))	('glioblastoma', 'Disease', 'MESH:D005909', (284, 296))	('tumors', 'Disease', 'MESH:D009369', (188, 194))	('cancer', 'Phenotype', 'HP:0002664', (268, 274))	('loss', 'Var', (143, 147))	('glioblastoma', 'Disease', (284, 296))
238044	28652248	BEZ235, LY294002, UO126 (Sigma-Aldrich), BKM120 (Selleckchem, Houston, TX), GDC-0449 (LC Labs, Woburn, MA), LDE225 (Collagen Technology, San Diego, CA), KAAD-cyclopamine (Millipore, Billerica, MA), and SAG (Xcessbio, San Diego, CA) were prepared in DMSO.	('DMSO', 'Chemical', 'MESH:D004121', (249, 253))	('KAAD-cyclopamine', 'Chemical', 'MESH:C542465', (153, 169))	('LY294002', 'Var', (8, 16))	('BKM120', 'Chemical', 'MESH:C571178', (41, 47))	('BEZ235', 'Chemical', 'MESH:C531198', (0, 6))	('UO126', 'Chemical', 'MESH:C113580', (18, 23))	('SAG', 'Gene', (202, 205))	('GDC-0449', 'Chemical', 'MESH:C538724', (76, 84))	('SAG', 'Gene', '6295', (202, 205))	('LY294002', 'Chemical', 'MESH:C085911', (8, 16))
238059	28652248	One million HCC95 cells stably transduced with TRC2-pLKO-shNT (non-target control) or TRC2-pLKO-shGLI1 were subcutaneously injected into the flanks of female NOD/SCID mouse.	('HCC95', 'CellLine', 'CVCL:5137', (12, 17))	('TRC2-pLKO-shNT', 'Var', (47, 61))	('NOD', 'Gene', '1822', (158, 161))	('NOD', 'Gene', (158, 161))	('mouse', 'Species', '10090', (167, 172))	('TRC2-pLKO-shGLI1', 'Var', (86, 102))
238072	28652248	High GLI1 mRNA expression was significantly correlated with worse overall survival of all NSCLC patients (P = 0.0141) with a trend toward worse survival in AD (P = 0.0561) and SCC patients (P = 0.2800) (Fig.	('overall survival', 'MPA', (66, 82))	('AD', 'Disease', 'MESH:D000544', (156, 158))	('AD', 'Disease', (156, 158))	('NSCLC', 'Disease', (90, 95))	('NSCLC', 'Disease', 'MESH:D002289', (90, 95))	('SCC', 'Gene', (176, 179))	('patients', 'Species', '9606', (96, 104))	('High GLI1', 'Var', (0, 9))	('SCC', 'Gene', '6317', (176, 179))	('patients', 'Species', '9606', (180, 188))	('worse', 'NegReg', (60, 65))
238087	28652248	GLI1 levels robustly increased with active N-terminal SHHN conditioned medium (CM) treatment and then decreased to baseline levels after the addition of KAAD-cyclopamine 200 nM, a potent SMO antagonist (Supplementary Fig.	('increased', 'PosReg', (21, 30))	('SHH', 'Gene', '6469', (54, 57))	('active N-terminal', 'Var', (36, 53))	('SMO', 'Gene', '6608', (187, 190))	('SMO', 'Gene', (187, 190))	('SHH', 'Gene', (54, 57))	('KAAD-cyclopamine', 'Chemical', 'MESH:C542465', (153, 169))	('GLI1 levels', 'MPA', (0, 11))
238095	28652248	GLI1 knockdown also significantly decreased GLI2 mRNA (Supplementary Fig.	('GLI1', 'Gene', (0, 4))	('decreased', 'NegReg', (34, 43))	('knockdown', 'Var', (5, 14))	('GLI2', 'Gene', (44, 48))	('GLI2', 'Gene', '2736', (44, 48))
238098	28652248	C911 oligonucleotides lose the siRNA's "on-target" effects while retaining many of its "off-target" effects.	('siRNA', 'MPA', (31, 36))	('C911', 'Var', (0, 4))	('C911 oligonucleotides', 'Chemical', '-', (0, 21))	('lose', 'NegReg', (22, 26))	('off-target', 'MPA', (88, 98))
238099	28652248	C911 oligonucleotides of siGLI1-2 and siGLI1-3 had little effect on GLI1 mRNA and protein levels of HCC2814 cells whereas C911-siGLI1-1 reduced GLI1 mRNA by almost 70% compared to controls (Supplementary Fig.	('C911-siGLI1-1', 'Var', (122, 135))	('GLI1 mRNA', 'MPA', (144, 153))	('HCC2814', 'CellLine', 'CVCL:V586', (100, 107))	('C911 oligonucleotides', 'Chemical', '-', (0, 21))	('reduced', 'NegReg', (136, 143))
238101	28652248	Knock down of GLI1 significantly inhibited anchorage-dependent liquid colony forming ability in both HCC95 and HCC2814 cells (Fig.	('GLI1', 'Gene', (14, 18))	('HCC95', 'CellLine', 'CVCL:5137', (101, 106))	('anchorage-dependent liquid colony forming ability', 'CPA', (43, 92))	('HCC2814', 'CellLine', 'CVCL:V586', (111, 118))	('Knock down', 'Var', (0, 10))	('inhibited', 'NegReg', (33, 42))
238104	28652248	Subcutaneous xenograft tumors of shGLI1 HCC95 cells grew significantly slower than tumors expressing shNT and exhibited decreased expression of GLI1 mRNA (Fig.	('decreased', 'NegReg', (120, 129))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('slower', 'NegReg', (71, 77))	('expression', 'MPA', (130, 140))	('tumors', 'Disease', (23, 29))	('grew', 'CPA', (52, 56))	('Subcutaneous xenograft tumors', 'Disease', 'MESH:D013352', (0, 29))	('tumors', 'Disease', 'MESH:D009369', (23, 29))	('tumors', 'Disease', (83, 89))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('HCC95', 'CellLine', 'CVCL:5137', (40, 45))	('shGLI1', 'Var', (33, 39))	('GLI1 mRNA', 'Protein', (144, 153))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('tumors', 'Disease', 'MESH:D009369', (83, 89))	('Subcutaneous xenograft tumors', 'Disease', (0, 29))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))
238111	28652248	PI3K and MAPK pathways were considered first as genetic aberrations in these pathways are frequently found in lung SCC.	('genetic aberrations', 'Var', (48, 67))	('SCC', 'Gene', (115, 118))	('found', 'Reg', (101, 106))	('SCC', 'Gene', '6317', (115, 118))
238112	28652248	Using a pharmacologic approach, SCC cells were treated with BEZ235 (PI3K/mTOR dual inhibitor), LY294002 (PI3K inhibitor), and U0126 (MEK1/2 inhibitor).	('MEK1/2', 'Gene', (133, 139))	('mTOR', 'Gene', '2475', (73, 77))	('LY294002', 'Chemical', 'MESH:C085911', (95, 103))	('U0126', 'Chemical', 'MESH:C113580', (126, 131))	('mTOR', 'Gene', (73, 77))	('U0126', 'Var', (126, 131))	('LY294002', 'Var', (95, 103))	('SCC', 'Gene', (32, 35))	('MEK1/2', 'Gene', '5604;5605', (133, 139))	('SCC', 'Gene', '6317', (32, 35))	('BEZ235', 'Chemical', 'MESH:C531198', (60, 66))
238115	28652248	GLI1 protein is destabilized by U0126 in skin keratinocytes and pancreatic adenocarcinoma cells.	('GLI1', 'Gene', (0, 4))	('destabilized', 'NegReg', (16, 28))	('U0126', 'Var', (32, 37))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (64, 89))	('U0126', 'Chemical', 'MESH:C113580', (32, 37))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D010190', (64, 89))	('protein', 'Protein', (5, 12))	('pancreatic adenocarcinoma', 'Disease', (64, 89))
238121	28652248	Indeed, BEZ235 significantly inhibited clonogenicity and proliferation (Fig.	('inhibited', 'NegReg', (29, 38))	('BEZ235', 'Var', (8, 14))	('BEZ235', 'Chemical', 'MESH:C531198', (8, 14))
238132	28652248	Inhibition of PI3K pathway by BKM120, as evidenced by decreased pAKT and pS6K protein, led to decreased GLI1 protein and mRNA expression (Fig.	('pS6K', 'Gene', '6198', (73, 77))	('BKM120', 'Chemical', 'MESH:C571178', (30, 36))	('pS6K', 'Gene', (73, 77))	('AKT', 'Gene', (65, 68))	('decreased', 'NegReg', (94, 103))	('mRNA expression', 'MPA', (121, 136))	('decreased', 'NegReg', (54, 63))	('BKM120', 'Var', (30, 36))	('AKT', 'Gene', '207', (65, 68))	('PI3K pathway', 'Pathway', (14, 26))	('GLI1 protein', 'Protein', (104, 116))
238136	28652248	ATO or BKM120 alone had little effect on tumor growth compared to control.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('BKM120', 'Var', (7, 13))	('tumor', 'Disease', (41, 46))	('BKM120', 'Chemical', 'MESH:C571178', (7, 13))	('ATO', 'Chemical', 'MESH:D000077237', (0, 3))	('tumor', 'Disease', 'MESH:D009369', (41, 46))
238142	28652248	7E) only in tumors treated with combination BKM120 and ATO.	('BKM120', 'Chemical', 'MESH:C571178', (44, 50))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('BKM120', 'Var', (44, 50))	('ATO', 'Chemical', 'MESH:D000077237', (55, 58))	('tumors', 'Disease', (12, 18))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('tumors', 'Disease', 'MESH:D009369', (12, 18))
238152	28652248	We also demonstrated the in vivo efficacy of combinatorial GLI1 and PI3K antagonism as an effective therapeutic strategy for PI3K-activated lung cancers.	('lung cancer', 'Phenotype', 'HP:0100526', (140, 151))	('PI3K', 'Gene', (68, 72))	('combinatorial', 'Var', (45, 58))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('lung cancers', 'Disease', 'MESH:D008175', (140, 152))	('lung cancers', 'Phenotype', 'HP:0100526', (140, 152))	('cancers', 'Phenotype', 'HP:0002664', (145, 152))	('antagonism', 'Var', (73, 83))	('lung cancers', 'Disease', (140, 152))
238153	28652248	Many other tumor types have high frequency of genetic aberrations in the PI3K pathway (Supplementary Fig.	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('PI3K pathway', 'Pathway', (73, 85))	('tumor', 'Disease', (11, 16))	('genetic aberrations', 'Var', (46, 65))	('tumor', 'Disease', 'MESH:D009369', (11, 16))
238156	28652248	The phase II BASALT-1 trial used BKM120 as second-line therapy for metastatic lung SCC and AD patients with PIK3CA or PTEN mutations.	('patients', 'Species', '9606', (94, 102))	('AD', 'Disease', 'MESH:D000544', (91, 93))	('AD', 'Disease', (91, 93))	('SCC', 'Gene', (83, 86))	('PTEN', 'Gene', '5728', (118, 122))	('PTEN', 'Gene', (118, 122))	('SCC', 'Gene', '6317', (83, 86))	('PIK3CA', 'Gene', (108, 114))	('BKM120', 'Chemical', 'MESH:C571178', (33, 39))	('mutations', 'Var', (123, 132))	('PIK3CA', 'Gene', '5290', (108, 114))
238159	28652248	Analogous to the human trials, we did not see tumor responses with ATO or BKM120 alone whereas the combination significantly inhibited tumor growth (Fig.	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('BKM120', 'Chemical', 'MESH:C571178', (74, 80))	('human', 'Species', '9606', (17, 22))	('tumor', 'Disease', (46, 51))	('tumor', 'Disease', (135, 140))	('tumor', 'Disease', 'MESH:D009369', (135, 140))	('ATO', 'Chemical', 'MESH:D000077237', (67, 70))	('BKM120', 'Var', (74, 80))	('inhibited', 'NegReg', (125, 134))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
238160	28652248	HCC2814 xenografts contain both PIK3CA amplifications and PTEN loss.	('PTEN', 'Gene', '5728', (58, 62))	('PTEN', 'Gene', (58, 62))	('PIK3CA', 'Gene', '5290', (32, 38))	('HCC2814', 'CellLine', 'CVCL:V586', (0, 7))	('loss', 'NegReg', (63, 67))	('amplifications', 'Var', (39, 53))	('PIK3CA', 'Gene', (32, 38))
238161	28652248	The loss of PTEN removes the primary restraint to PI3K activity in HCC2814 cells.	('PTEN', 'Gene', '5728', (12, 16))	('HCC2814', 'CellLine', 'CVCL:V586', (67, 74))	('loss', 'Var', (4, 8))	('PTEN', 'Gene', (12, 16))
238163	28652248	7A) - ~63x and ~125x IC50 for pAKT suppression in A2780 cancer cells.	('AKT', 'Gene', (31, 34))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('A2780', 'CellLine', 'CVCL:0134', (50, 55))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('AKT', 'Gene', '207', (31, 34))	('IC50', 'Var', (21, 25))
238168	28652248	Thus, BKM120 and ATO concentrations in the tumors may not have reached adequate levels to completely inhibit their targets as single agents.	('BKM120', 'Var', (6, 12))	('ATO', 'Chemical', 'MESH:D000077237', (17, 20))	('BKM120', 'Chemical', 'MESH:C571178', (6, 12))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumors', 'Disease', (43, 49))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('tumors', 'Disease', 'MESH:D009369', (43, 49))
238171	27462775	An integrative framework to identify cell death-related microRNAs in esophageal squamous cell carcinoma Cell death is a critical biological process involved in many important functions, and defects in this system are usually linked with numerous human diseases including cancers.	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (69, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (80, 103))	('cancer', 'Phenotype', 'HP:0002664', (271, 277))	('esophageal squamous cell carcinoma', 'Disease', (69, 103))	('numerous human diseases', 'Disease', (237, 260))	('defects', 'Var', (190, 197))	('numerous human diseases', 'Disease', 'MESH:D015658', (237, 260))	('linked', 'Reg', (225, 231))	('cancers', 'Disease', 'MESH:D009369', (271, 278))	('cancers', 'Phenotype', 'HP:0002664', (271, 278))	('cancers', 'Disease', (271, 278))
238173	27462775	Follow-up experimental verification of 7 miRNAs indicated at least 3 miRNAs (MIR20b, MIR498 and MIR196) were involved in both apoptosis and autophagy processes.	('MIR20b', 'Gene', (77, 83))	('MIR20b', 'Gene', '574032', (77, 83))	('MIR498', 'Gene', '574460', (85, 91))	('MIR498', 'Gene', (85, 91))	('apoptosis', 'CPA', (126, 135))	('MIR196', 'Var', (96, 102))	('involved', 'Reg', (109, 117))	('autophagy processes', 'CPA', (140, 159))
238175	27462775	This integrative framework can also be easily extended to identify miRNAs in other key cellular signaling pathways or may find conditional specific miRNAs in other cancer types.	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('cancer', 'Disease', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('miRNAs', 'Var', (67, 73))
238200	27462775	In esophageal cancers cell line KYSE150, as shown in the up panel of Figure 2A, over-expression of MIR30e, MIR363, MIR498, MIR196, MIR422, MIR337 or MIR202 remarkably increase the LC3-I to LC3-II conversion whereas miR-20b modestly decrease.	('MIR202', 'Gene', (149, 155))	('esophageal cancers', 'Disease', (3, 21))	('MIR337', 'Gene', '442905', (139, 145))	('MIR363', 'Gene', (107, 113))	('MIR422', 'Var', (131, 137))	('miR-20b', 'Gene', '574032', (215, 222))	('LC3', 'Gene', (189, 192))	('esophageal cancers', 'Disease', 'MESH:D004938', (3, 21))	('LC3', 'Gene', (180, 183))	('MIR498', 'Gene', '574460', (115, 121))	('MIR498', 'Gene', (115, 121))	('MIR30e', 'Gene', (99, 105))	('MIR202', 'Gene', '574448', (149, 155))	('over-expression', 'PosReg', (80, 95))	('MIR196', 'Var', (123, 129))	('MIR337', 'Gene', (139, 145))	('cancers', 'Phenotype', 'HP:0002664', (14, 21))	('MIR30e', 'Gene', '407034', (99, 105))	('LC3', 'Gene', '84557', (189, 192))	('MIR363', 'Gene', '574031', (107, 113))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('miR-20b', 'Gene', (215, 222))	('LC3', 'Gene', '84557', (180, 183))	('increase', 'PosReg', (167, 175))
238201	27462775	In addition to LC3, the sequestosome 1(SQSTM1/P62) protein were accumulated when MIR30e, MIR363, MIR498 or MIR196 were transfected whereas MIR20b significantly decreased (up panel of Figure 2B).	('SQSTM1', 'Gene', (39, 45))	('MIR498', 'Gene', (97, 103))	('MIR196', 'Var', (107, 113))	('P62', 'Gene', (46, 49))	('MIR363', 'Gene', (89, 95))	('P62', 'Gene', '8878', (46, 49))	('MIR20b', 'Gene', '574032', (139, 145))	('SQSTM1', 'Gene', '8878', (39, 45))	('MIR363', 'Gene', '574031', (89, 95))	('decreased', 'NegReg', (160, 169))	('MIR20b', 'Gene', (139, 145))	('accumulated', 'PosReg', (64, 75))	('LC3', 'Gene', (15, 18))	('LC3', 'Gene', '84557', (15, 18))	('MIR30e', 'Gene', (81, 87))	('sequestosome', 'MPA', (24, 36))	('MIR498', 'Gene', '574460', (97, 103))	('MIR30e', 'Gene', '407034', (81, 87))
238202	27462775	In another esophageal cancers cell line TE3, transfection of MIR20b, MIR363, MIR498 or MIR196 affected the autophagy when monitoring both LC3 and p62 (down panel of Figure 2A and Figure 2B).	('MIR196', 'Var', (87, 93))	('MIR20b', 'Gene', (61, 67))	('MIR363', 'Gene', (69, 75))	('cancers', 'Phenotype', 'HP:0002664', (22, 29))	('esophageal cancers', 'Disease', (11, 29))	('autophagy', 'CPA', (107, 116))	('MIR498', 'Gene', '574460', (77, 83))	('MIR20b', 'Gene', '574032', (61, 67))	('MIR498', 'Gene', (77, 83))	('LC3', 'Gene', (138, 141))	('LC3', 'Gene', '84557', (138, 141))	('esophageal cancers', 'Disease', 'MESH:D004938', (11, 29))	('p62', 'Gene', '8878', (146, 149))	('MIR363', 'Gene', '574031', (69, 75))	('p62', 'Gene', (146, 149))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('affected', 'Reg', (94, 102))
238204	27462775	The cleaved PARP were modestly but significantly increased when transfection of MIR20b, MIR30e, MIR498 or MIR196 in both cell lines (Figure 2B).	('increased', 'PosReg', (49, 58))	('PARP', 'Gene', '142', (12, 16))	('cleaved', 'MPA', (4, 11))	('MIR196', 'Var', (106, 112))	('MIR20b', 'Gene', (80, 86))	('MIR30e', 'Gene', '407034', (88, 94))	('MIR30e', 'Gene', (88, 94))	('MIR20b', 'Gene', '574032', (80, 86))	('MIR498', 'Gene', '574460', (96, 102))	('PARP', 'Gene', (12, 16))	('MIR498', 'Gene', (96, 102))
238206	27462775	Collectively, above results suggested that the four predicted miRNAs, MIR20b, MIR30e, MIR498 and MIR196 may be involved in the apoptotic pathway in esophageal cancers cells.	('MIR196', 'Var', (97, 103))	('MIR30e', 'Gene', (78, 84))	('apoptotic pathway', 'Pathway', (127, 144))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('MIR20b', 'Gene', (70, 76))	('involved', 'Reg', (111, 119))	('esophageal cancers', 'Disease', (148, 166))	('MIR498', 'Gene', '574460', (86, 92))	('MIR20b', 'Gene', '574032', (70, 76))	('MIR498', 'Gene', (86, 92))	('cancers', 'Phenotype', 'HP:0002664', (159, 166))	('esophageal cancers', 'Disease', 'MESH:D004938', (148, 166))	('MIR30e', 'Gene', '407034', (78, 84))
238208	27462775	At one hand, dysfunction in apoptotic machinery hampered damaged cells into apoptotic suicides; at the other hand, cytotoxic stress, for example chemotherapy, will elevate level of autophagy to protect cells from environmental stress or even promote the cancer cell proliferation.	('autophagy', 'CPA', (181, 190))	('elevate', 'PosReg', (164, 171))	('cancer', 'Phenotype', 'HP:0002664', (254, 260))	('cancer', 'Disease', 'MESH:D009369', (254, 260))	('cancer', 'Disease', (254, 260))	('cytotoxic', 'Var', (115, 124))	('promote', 'PosReg', (242, 249))
238212	27462775	In addition to genetic defects, alterations in genes in cell death pathways also contribute to the disease.	('genetic defects', 'Disease', 'MESH:D030342', (15, 30))	('genes', 'Gene', (47, 52))	('genetic defects', 'Disease', (15, 30))	('contribute', 'Reg', (81, 91))	('alterations', 'Var', (32, 43))	('disease', 'Disease', (99, 106))	('cell death pathways', 'Pathway', (56, 75))
238213	27462775	For example, pharmacological and genetic inhibition of autophagy enhanced the resveratrol-induced cytotoxicity to the ESCC cells.	('cytotoxicity', 'Disease', (98, 110))	('resveratrol', 'Chemical', 'MESH:D000077185', (78, 89))	('autophagy', 'CPA', (55, 64))	('enhanced', 'PosReg', (65, 73))	('cytotoxicity', 'Disease', 'MESH:D064420', (98, 110))	('resveratrol-induced', 'MPA', (78, 97))	('genetic inhibition', 'Var', (33, 51))
238214	27462775	A recent study also indicated that AZD2281, Novel poly (ADP-ribose) polymerase inhibitor enhances radio-sensitivity in esophageal squamous cancer cells.	('AZD2281', 'Chemical', 'MESH:C531550', (35, 42))	('AZD2281', 'Var', (35, 42))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('squamous cancer', 'Phenotype', 'HP:0002860', (130, 145))	('radio-sensitivity', 'CPA', (98, 115))	('esophageal squamous cancer', 'Disease', 'MESH:D004938', (119, 145))	('esophageal squamous cancer', 'Disease', (119, 145))	('enhances', 'PosReg', (89, 97))
238218	27462775	Follow-up experiments indicated transfection of MIR20b, MIR30e, MIR498 and MIR196 affected the apoptotic pathway in esophageal cancers cells.	('esophageal cancers', 'Disease', (116, 134))	('esophageal cancers', 'Disease', 'MESH:D004938', (116, 134))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('MIR196', 'Var', (75, 81))	('affected', 'Reg', (82, 90))	('MIR20b', 'Gene', (48, 54))	('MIR498', 'Gene', '574460', (64, 70))	('MIR498', 'Gene', (64, 70))	('MIR30e', 'Gene', (56, 62))	('MIR30e', 'Gene', '407034', (56, 62))	('cancers', 'Phenotype', 'HP:0002664', (127, 134))	('MIR20b', 'Gene', '574032', (48, 54))	('apoptotic pathway', 'Pathway', (95, 112))
238220	27462775	The results indicated at least 3 miRNAs (MIR20b, MIR498 and MIR196) were involved in cell death in two esophageal cancers cell lines.	('cancers', 'Phenotype', 'HP:0002664', (114, 121))	('cell death', 'CPA', (85, 95))	('MIR196', 'Var', (60, 66))	('MIR20b', 'Gene', (41, 47))	('esophageal cancers', 'Disease', (103, 121))	('esophageal cancers', 'Disease', 'MESH:D004938', (103, 121))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('MIR20b', 'Gene', '574032', (41, 47))	('involved', 'Reg', (73, 81))	('MIR498', 'Gene', '574460', (49, 55))	('MIR498', 'Gene', (49, 55))
238221	27462775	Interestingly, three out of the four apoptotic related miRNAs (MIR20b, MIR498 and MIR196), can modulate both autophagy and apoptosis processes.	('MIR498', 'Gene', '574460', (71, 77))	('MIR498', 'Gene', (71, 77))	('modulate', 'Reg', (95, 103))	('autophagy', 'CPA', (109, 118))	('MIR196', 'Var', (82, 88))	('MIR20b', 'Gene', (63, 69))	('MIR20b', 'Gene', '574032', (63, 69))	('apoptosis processes', 'CPA', (123, 142))
238222	27462775	For example, MIR101 can modulate MCL1 (myeloid cell leukemia sequence 1) therefore promotes apoptosis.	('myeloid cell leukemia sequence 1', 'Gene', (39, 71))	('MCL1', 'Gene', (33, 37))	('myeloid cell leukemia sequence 1', 'Gene', '4170', (39, 71))	('apoptosis', 'CPA', (92, 101))	('promotes', 'PosReg', (83, 91))	('leukemia', 'Phenotype', 'HP:0001909', (52, 60))	('myeloid cell leukemia', 'Phenotype', 'HP:0012324', (39, 60))	('MIR101', 'Var', (13, 19))	('MCL1', 'Gene', '4170', (33, 37))	('modulate', 'Reg', (24, 32))
238223	27462775	On the other hand, MIR101 can also negatively modulate the autophagy flux via inhibiting autophagy-related protein RAB5A.	('autophagy-related', 'Protein', (89, 106))	('modulate', 'Reg', (46, 54))	('MIR101', 'Var', (19, 25))	('inhibiting', 'NegReg', (78, 88))	('negatively', 'NegReg', (35, 45))	('autophagy flux', 'CPA', (59, 73))	('RAB5A', 'Gene', (115, 120))	('RAB5A', 'Gene', '5868', (115, 120))
238228	27462775	GSE13937 includes 76 US and Japanese patients enrolled in 3 distinct cohorts; GSE6188 for 104 normal and 151 disease samples; and GSE43732 for 119 normal and 119 cancer samples.	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('GSE6188', 'Chemical', '-', (78, 85))	('cancer', 'Disease', (162, 168))	('patients', 'Species', '9606', (37, 45))	('GSE43732', 'Var', (130, 138))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('GSE6188', 'Gene', (78, 85))
238240	27462775	The membranes were blocked in 5% nonfat milk for 1 h, incubated with antibodies against PARP (1:1000, CST, USA), p62 and LC3 (1:1000, CST, USA) and beta-actin (1:1000, Santa Cruz Biotechnology, USA), respectively, according to the manufacturer's recommendations.	('beta-actin', 'Gene', '728378', (148, 158))	('p62', 'Gene', (113, 116))	('beta-actin', 'Gene', (148, 158))	('LC3', 'Gene', '84557', (121, 124))	('PARP', 'Gene', '142', (88, 92))	('LC3', 'Gene', (121, 124))	('1:1000', 'Var', (160, 166))	('1:1000', 'Var', (126, 132))	('p62', 'Gene', '8878', (113, 116))	('PARP', 'Gene', (88, 92))
238253	26300886	For a long time, tumors were considered as highly homogenous entities resulting from the clonal expansion of a single cell with specific genetic or epigenetic defects.	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('tumors', 'Disease', (17, 23))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('epigenetic defects', 'Var', (148, 166))
238275	26300886	In particular, ICD is etiologically associated with the phosphorylation of EIF2A on S51, and this appears to be required for the exposure of CALR and HSPs on the surface of dying cells.	('HSP', 'Gene', '7190', (150, 153))	('CALR', 'Gene', '811', (141, 145))	('ICD', 'Disease', 'OMIM:252500', (15, 18))	('S51', 'Var', (84, 87))	('EIF2A', 'Gene', '83939', (75, 80))	('EIF2A', 'Gene', (75, 80))	('ICD', 'Disease', (15, 18))	('HSP', 'Gene', (150, 153))	('phosphorylation', 'MPA', (56, 71))	('CALR', 'Gene', (141, 145))	('associated', 'Reg', (36, 46))
238303	26300886	Of note, both CALR and GRP78 expression levels are also indirect manifestations of the activation of another branch of the ER stress response, i.e., the derepression of activating transcription factor 6 (ATF6).	('activation', 'PosReg', (87, 97))	('derepression', 'Var', (153, 165))	('ATF6', 'Gene', '22926', (204, 208))	('CALR', 'Gene', (14, 18))	('GRP78', 'Gene', (23, 28))	('CALR', 'Gene', '811', (14, 18))	('ATF6', 'Gene', (204, 208))	('expression levels', 'MPA', (29, 46))	('GRP78', 'Gene', '3309', (23, 28))	('activating transcription factor 6', 'Gene', '22926', (169, 202))	('activating transcription factor 6', 'Gene', (169, 202))
238308	26300886	For instance, high CD47 levels have been reported to constitute an independent negative prognostic factor in cohorts of 86 patients with ovarian clear cell carcinoma, 102 individuals with esophageal squamous cell carcinoma, and 137 subjects with karyotypically normal AML.	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (188, 222))	('carcinoma', 'Phenotype', 'HP:0030731', (156, 165))	('AML', 'Disease', (268, 271))	('ovarian clear cell carcinoma', 'Disease', (137, 165))	('AML', 'Phenotype', 'HP:0004808', (268, 271))	('negative', 'NegReg', (79, 87))	('esophageal squamous cell carcinoma', 'Disease', (188, 222))	('patients', 'Species', '9606', (123, 131))	('high', 'Var', (14, 18))	('CD47', 'Gene', '961', (19, 23))	('ovarian clear cell carcinoma', 'Disease', 'MESH:D008649', (137, 165))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (199, 222))	('CD47', 'Gene', (19, 23))	('carcinoma', 'Phenotype', 'HP:0030731', (213, 222))	('AML', 'Disease', 'MESH:D015470', (268, 271))
238310	26300886	Moreover, single nucleotide polymorphisms (SNPs) affecting HSPA1A have been linked to an increased incidence of gastric carcinoma (as determined in a cohort of 39 patients and 186 controls), a SNP affecting THBS1 has been correlated with gastric cancer occurrence and progression in a cohort of 275 patients and 275 healthy individuals, while a SNP in LMAN1 as well as the consequent decrease in LMAN1 levels appear to be associated with an increased risk for ovarian carcinoma (as determined in a cohort of 289 women seen in gynecologic oncology practice and 126 healthy volunteers).	('gastric cancer', 'Disease', (238, 252))	('HSPA1A', 'Gene', '3303', (59, 65))	('gastric carcinoma', 'Disease', (112, 129))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('SNP', 'Var', (345, 348))	('patients', 'Species', '9606', (299, 307))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (112, 129))	('carcinoma', 'Phenotype', 'HP:0030731', (468, 477))	('gastric cancer', 'Disease', 'MESH:D013274', (238, 252))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (460, 477))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))	('ovarian carcinoma', 'Disease', (460, 477))	('THBS1', 'Gene', (207, 212))	('levels', 'MPA', (402, 408))	('patients', 'Species', '9606', (163, 171))	('THBS1', 'Gene', '7057', (207, 212))	('LMAN1', 'Gene', '3998', (352, 357))	('single nucleotide polymorphisms', 'Var', (10, 41))	('decrease', 'NegReg', (384, 392))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (460, 477))	('gastric cancer', 'Phenotype', 'HP:0012126', (238, 252))	('LMAN1', 'Gene', '3998', (396, 401))	('LMAN1', 'Gene', (352, 357))	('women', 'Species', '9606', (512, 517))	('HSPA1A', 'Gene', (59, 65))	('linked', 'Reg', (76, 82))	('oncology', 'Phenotype', 'HP:0002664', (538, 546))	('LMAN1', 'Gene', (396, 401))	('gastric carcinoma', 'Disease', 'MESH:D013274', (112, 129))
238329	26300886	SNPs affecting TLR3 have been shown to influence prognosis in cohorts of 582 patients with CRC, especially among untreated individuals with Stage II disease and 568 NSCLC patients.	('Stage II disease', 'Disease', (140, 156))	('influence', 'Reg', (39, 48))	('NSCLC', 'Disease', 'MESH:D002289', (165, 170))	('CRC', 'Disease', (91, 94))	('CRC', 'Phenotype', 'HP:0030731', (91, 94))	('patients', 'Species', '9606', (171, 179))	('SNPs', 'Var', (0, 4))	('TLR3', 'Gene', (15, 19))	('patients', 'Species', '9606', (77, 85))	('prognosis', 'MPA', (49, 58))	('NSCLC', 'Phenotype', 'HP:0030358', (165, 170))	('TLR3', 'Gene', '7098', (15, 19))	('Stage II disease', 'Disease', 'MESH:D058625', (140, 156))	('NSCLC', 'Disease', (165, 170))
238330	26300886	Along similar lines, TLR3 SNPs have been associated with an altered risk for cervical cancer amongst 330 Tunisian women, breast carcinoma amongst 174 African-American women, oral squamous cell carcinoma amongst 197 individuals HCC amongst 948 subjects, and CRC amongst more than 5,000 individuals.	('women', 'Species', '9606', (114, 119))	('associated', 'Reg', (41, 51))	('carcinoma', 'Phenotype', 'HP:0030731', (193, 202))	('women', 'Species', '9606', (167, 172))	('breast carcinoma', 'Disease', 'MESH:D001943', (121, 137))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (174, 202))	('cervical cancer', 'Disease', (77, 92))	('cervical cancer', 'Disease', 'MESH:D002583', (77, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('oral squamous cell carcinoma', 'Disease', (174, 202))	('CRC', 'Phenotype', 'HP:0030731', (257, 260))	('breast carcinoma', 'Phenotype', 'HP:0003002', (121, 137))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('breast carcinoma', 'Disease', (121, 137))	('HCC', 'Gene', '619501', (227, 230))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (179, 202))	('HCC', 'Phenotype', 'HP:0001402', (227, 230))	('TLR3', 'Gene', '7098', (21, 25))	('SNPs', 'Var', (26, 30))	('HCC', 'Gene', (227, 230))	('TLR3', 'Gene', (21, 25))
238332	26300886	Moreover, SNPs affecting interferon (alpha, beta and omega) receptor 1 (IFNAR1) have been associated with an increased risk for the development of CRC amongst 2085 individuals, as well as with significantly reduced overall survival in a cohort of 304 glioma patients.	('IFNAR1', 'Gene', (72, 78))	('glioma', 'Phenotype', 'HP:0009733', (251, 257))	('interferon (alpha, beta and omega) receptor 1', 'Gene', '3454', (25, 70))	('overall survival', 'MPA', (215, 231))	('glioma', 'Disease', 'MESH:D005910', (251, 257))	('IFNAR1', 'Gene', '3454', (72, 78))	('reduced', 'NegReg', (207, 214))	('SNPs affecting', 'Var', (10, 24))	('CRC', 'Disease', (147, 150))	('patients', 'Species', '9606', (258, 266))	('CRC', 'Phenotype', 'HP:0030731', (147, 150))	('glioma', 'Disease', (251, 257))
238340	26300886	In line with this notion, the administration of CD39 inhibitors or CD39-neutralizing monoclonal antibodies reportedly relieves tumor-mediated immunosuppression, and (at least in some models) allows autophagy-deficient cells treated with anthracyclines to elicit normal immune responses upon inoculation in immunocompetent mice.	('inhibitors', 'Var', (53, 63))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumor', 'Disease', (127, 132))	('immune responses', 'CPA', (269, 285))	('relieves', 'NegReg', (118, 126))	('CD39-neutralizing', 'Gene', (67, 84))	('autophagy-deficient', 'Disease', (198, 217))	('CD39', 'Gene', (48, 52))	('anthracyclines', 'Chemical', 'MESH:D018943', (237, 251))	('elicit', 'PosReg', (255, 261))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('mice', 'Species', '10090', (322, 326))	('autophagy-deficient', 'Disease', 'MESH:C564093', (198, 217))
238344	26300886	A SNP compromising the function of P2RX7 has been associated with decreased time-to-metastasis in a cohort of 225 breast carcinoma patients treated with adjuvant anthracycline-based chemotherapy, with worsened clinicopathological parameters amongst 121 subjects with papillary thyroid cancer, and with an increased risk for the development of chronic lymphocytic leukemia (CLL), as determined in a cohort of 40 patients and 46 age-matched healthy individuals.	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('chronic lymphocytic leukemia', 'Disease', (343, 371))	('papillary thyroid cancer', 'Phenotype', 'HP:0002895', (267, 291))	('decreased', 'NegReg', (66, 75))	('SNP', 'Var', (2, 5))	('thyroid cancer', 'Phenotype', 'HP:0002890', (277, 291))	('patients', 'Species', '9606', (411, 419))	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (343, 371))	('leukemia', 'Phenotype', 'HP:0001909', (363, 371))	('breast carcinoma', 'Phenotype', 'HP:0003002', (114, 130))	('papillary thyroid cancer', 'Disease', 'MESH:D000077273', (267, 291))	('time-to-metastasis', 'CPA', (76, 94))	('anthracycline', 'Chemical', 'MESH:D018943', (162, 175))	('P2RX7', 'Gene', '5027', (35, 40))	('compromising', 'NegReg', (6, 18))	('breast carcinoma', 'Disease', (114, 130))	('function', 'MPA', (23, 31))	('patients', 'Species', '9606', (131, 139))	('cancer', 'Phenotype', 'HP:0002664', (285, 291))	('CLL', 'Phenotype', 'HP:0005550', (373, 376))	('papillary thyroid cancer', 'Disease', (267, 291))	('P2RX7', 'Gene', (35, 40))	('breast carcinoma', 'Disease', 'MESH:D001943', (114, 130))	('chronic lymphocytic leukemia', 'Disease', 'MESH:D015451', (343, 371))
238345	26300886	Contrasting with these latter findings, however, the same SNP has been associated with increased overall survival in a cohort of 170 subjects with CLL, or found to have no correlation with disease incidence and/or outcome in independent cohorts of 144 CLL patients and 348 healthy controls, 121 individuals with CLL 111 CLL patients and 97 controls, and 136 subjects with multiple myeloma.	('increased', 'PosReg', (87, 96))	('patients', 'Species', '9606', (324, 332))	('multiple myeloma', 'Phenotype', 'HP:0006775', (372, 388))	('CLL', 'Phenotype', 'HP:0005550', (320, 323))	('multiple myeloma', 'Disease', 'MESH:D009101', (372, 388))	('overall survival', 'MPA', (97, 113))	('patients', 'Species', '9606', (256, 264))	('CLL', 'Phenotype', 'HP:0005550', (252, 255))	('multiple myeloma', 'Disease', (372, 388))	('CLL', 'Disease', (252, 255))	('CLL', 'Phenotype', 'HP:0005550', (312, 315))	('SNP', 'Var', (58, 61))	('CLL', 'Phenotype', 'HP:0005550', (147, 150))
238351	26300886	At stark contrast with these findings, high levels of CD39 mRNA have been linked to improved disease outcome in a cohort of 28 pancreatic cancer patients treated with surgery.	('patients', 'Species', '9606', (145, 153))	('pancreatic cancer', 'Disease', (127, 144))	('CD39', 'Gene', (54, 58))	('high', 'Var', (39, 43))	('pancreatic cancer', 'Disease', 'MESH:D010190', (127, 144))	('disease', 'Disease', (93, 100))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('mRNA', 'Var', (59, 63))	('improved', 'PosReg', (84, 92))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (127, 144))
238354	26300886	For instance, LC3 expression has been associated with prolonged overall survival in a cohort of 190 HCC patients, but with lymph node involvement and high TNM score amongst 79 individuals with head and neck cancer.	('TNM', 'Gene', '10178', (155, 158))	('LC3', 'Gene', '84557', (14, 17))	('HCC', 'Gene', (100, 103))	('overall survival', 'MPA', (64, 80))	('LC3', 'Gene', (14, 17))	('head and neck cancer', 'Phenotype', 'HP:0012288', (193, 213))	('TNM', 'Gene', (155, 158))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('HCC', 'Gene', '619501', (100, 103))	('prolonged', 'PosReg', (54, 63))	('patients', 'Species', '9606', (104, 112))	('expression', 'Var', (18, 28))	('HCC', 'Phenotype', 'HP:0001402', (100, 103))	('head and neck cancer', 'Disease', 'MESH:D006258', (193, 213))
238362	26300886	Rather, oxidized HMGB1 signal via TLR2, TLR4 and advanced glycosylation end product-specific receptor (AGER, best known as RAGE) to stimulate the production of pro-inflammatory cytokines.	('production of pro-inflammatory cytokines', 'MPA', (146, 186))	('AGER', 'Gene', (103, 107))	('RAGE', 'Gene', (123, 127))	('TLR4', 'Gene', '7099', (40, 44))	('HMGB1', 'Gene', (17, 22))	('HMGB1', 'Gene', '3146', (17, 22))	('TLR2', 'Gene', '7097', (34, 38))	('TLR4', 'Gene', (40, 44))	('AGER', 'Gene', '177', (103, 107))	('RAGE', 'Gene', '177', (123, 127))	('TLR2', 'Gene', (34, 38))	('stimulate', 'PosReg', (132, 141))	('oxidized', 'Var', (8, 16))
238368	26300886	High expression levels of HMGB1 in malignant cells have been shown to correlate with improved overall survival in 88 patients with esophageal squamous cell carcinoma subjected to neo-adjuvant chemoradiotherapy and surgical resection, as well as in 76 subjects with reseactable gastric adenocarcinoma.	('gastric adenocarcinoma', 'Disease', 'MESH:D013274', (277, 299))	('HMGB1', 'Gene', (26, 31))	('improved', 'PosReg', (85, 93))	('gastric adenocarcinoma', 'Disease', (277, 299))	('High', 'Var', (0, 4))	('HMGB1', 'Gene', '3146', (26, 31))	('overall survival', 'MPA', (94, 110))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (142, 165))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (131, 165))	('carcinoma', 'Phenotype', 'HP:0030731', (156, 165))	('esophageal squamous cell carcinoma', 'Disease', (131, 165))	('carcinoma', 'Phenotype', 'HP:0030731', (290, 299))	('patients', 'Species', '9606', (117, 125))
238369	26300886	In a cohort of 232 breast carcinoma patients treated with anthracycline-based adjuvant chemotherapy, loss of nuclear HMGB1 has been positively associated with tumor size.	('breast carcinoma', 'Disease', 'MESH:D001943', (19, 35))	('associated', 'Reg', (143, 153))	('patients', 'Species', '9606', (36, 44))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('loss', 'Var', (101, 105))	('HMGB1', 'Gene', (117, 122))	('breast carcinoma', 'Phenotype', 'HP:0003002', (19, 35))	('tumor', 'Disease', (159, 164))	('carcinoma', 'Phenotype', 'HP:0030731', (26, 35))	('HMGB1', 'Gene', '3146', (117, 122))	('breast carcinoma', 'Disease', (19, 35))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('anthracycline', 'Chemical', 'MESH:D018943', (58, 71))
238370	26300886	Along similar lines, the co-expression of HMGB1 in the nucleus and in the cytoplasm of malignant cells has been shown to inversely correlate with tumor infiltration by CD45RO+ memory T cells and 5-year survival rate in 72 individuals with Stage IIIB CRC.	('CD4', 'Gene', (168, 171))	('CD4', 'Gene', '920', (168, 171))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('correlate with', 'Reg', (131, 145))	('tumor', 'Disease', (146, 151))	('co-expression', 'Var', (25, 38))	('HMGB1', 'Gene', (42, 47))	('HMGB1', 'Gene', '3146', (42, 47))	('CRC', 'Phenotype', 'HP:0030731', (250, 253))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
238380	26300886	SNPs in TLR2, TLR4 and AGER, as well as the circulating levels of a soluble RAGE variant have been shown to affect cancer susceptibility as well as disease outcome in several studies.	('TLR2', 'Gene', '7097', (8, 12))	('cancer', 'Disease', (115, 121))	('AGER', 'Gene', '177', (23, 27))	('TLR4', 'Gene', (14, 18))	('affect', 'Reg', (108, 114))	('TLR2', 'Gene', (8, 12))	('circulating levels', 'MPA', (44, 62))	('RAGE', 'Gene', '177', (76, 80))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('SNPs', 'Var', (0, 4))	('variant', 'Var', (81, 88))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('AGER', 'Gene', (23, 27))	('RAGE', 'Gene', (76, 80))	('TLR4', 'Gene', '7099', (14, 18))
238381	26300886	In particular, TLR2 polymorphisms have been linked to an increased risk for lymphoma (as determined in 710 patients and as many healthy subjects), gastric carcinoma (as assessed in 289 patients and more than 400 controls), prostate carcinoma (as investigated in 195 patients and 250 healthy individuals), HCC (as tested in 211 patients and 232 controls), and CRC (as assessed in 2,309 patients and 2,915 healthy individuals).	('prostate carcinoma', 'Disease', (223, 241))	('lymphoma', 'Phenotype', 'HP:0002665', (76, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (232, 241))	('patients', 'Species', '9606', (266, 274))	('lymphoma', 'Disease', (76, 84))	('patients', 'Species', '9606', (385, 393))	('lymphoma', 'Disease', 'MESH:D008223', (76, 84))	('patients', 'Species', '9606', (107, 115))	('gastric carcinoma', 'Disease', 'MESH:D013274', (147, 164))	('CRC', 'Disease', (359, 362))	('prostate carcinoma', 'Disease', 'MESH:D011472', (223, 241))	('HCC', 'Gene', '619501', (305, 308))	('HCC', 'Phenotype', 'HP:0001402', (305, 308))	('gastric carcinoma', 'Disease', (147, 164))	('patients', 'Species', '9606', (185, 193))	('prostate carcinoma', 'Phenotype', 'HP:0012125', (223, 241))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (147, 164))	('patients', 'Species', '9606', (327, 335))	('HCC', 'Gene', (305, 308))	('carcinoma', 'Phenotype', 'HP:0030731', (155, 164))	('TLR2', 'Gene', '7097', (15, 19))	('CRC', 'Phenotype', 'HP:0030731', (359, 362))	('TLR2', 'Gene', (15, 19))	('polymorphisms', 'Var', (20, 33))	('linked', 'Reg', (44, 50))
238382	26300886	Loss-of-function variants of TLR4 have been associated with decreased time-to-metastasis amongst 280 women with non-metastatic breast carcinoma treated with surgery followed by anthracycline-based chemotherapy and local irradiation, with reduced disease-free and overall survival amongst 188 head and neck cancer patients receiving adjuvant systemic therapy, amongst 72 melanoma patients vaccinated with a heat-shocked allogeneic melanoma cell line, and amongst 622 melanoma patients subjected to various treatment modalities.	('decreased', 'NegReg', (60, 69))	('time-to-metastasis', 'CPA', (70, 88))	('head and neck cancer', 'Phenotype', 'HP:0012288', (292, 312))	('melanoma', 'Disease', 'MESH:D008545', (466, 474))	('shocked', 'Phenotype', 'HP:0031273', (411, 418))	('melanoma', 'Disease', 'MESH:D008545', (370, 378))	('patients', 'Species', '9606', (475, 483))	('patients', 'Species', '9606', (379, 387))	('variants', 'Var', (17, 25))	('breast carcinoma', 'Disease', 'MESH:D001943', (127, 143))	('reduced', 'NegReg', (238, 245))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('shock', 'Phenotype', 'HP:0031273', (411, 416))	('melanoma', 'Disease', 'MESH:D008545', (430, 438))	('patients', 'Species', '9606', (313, 321))	('head and neck cancer', 'Disease', 'MESH:D006258', (292, 312))	('women', 'Species', '9606', (101, 106))	('TLR4', 'Gene', '7099', (29, 33))	('melanoma', 'Phenotype', 'HP:0002861', (466, 474))	('melanoma', 'Disease', (466, 474))	('anthracycline', 'Chemical', 'MESH:D018943', (177, 190))	('breast carcinoma', 'Phenotype', 'HP:0003002', (127, 143))	('TLR4', 'Gene', (29, 33))	('melanoma', 'Phenotype', 'HP:0002861', (370, 378))	('melanoma', 'Disease', (370, 378))	('Loss-of-function', 'NegReg', (0, 16))	('breast carcinoma', 'Disease', (127, 143))	('cancer', 'Phenotype', 'HP:0002664', (306, 312))	('melanoma', 'Phenotype', 'HP:0002861', (430, 438))	('disease-free', 'CPA', (246, 258))	('melanoma', 'Disease', (430, 438))
238383	26300886	Along similar lines, SNPs affecting TLR4 or AGER have been linked to an increased risk for prostate cancer (as determined in multiple studies collectively testing more than 1,000 patients and as many age-matched controls), ovarian cancer (as assessed in a study testing 190 patients and 210 controls), breast carcinoma (as investigated in 509 patients and 504 healthy women), CRC (as determined in a large cohort encompassing 2,309 patients and 2,915 healthy individuals), and NSCLC (as tested in 562 patients and 764 controls).	('linked', 'Reg', (59, 65))	('prostate cancer', 'Disease', (91, 106))	('NSCLC', 'Disease', (477, 482))	('SNPs', 'Var', (21, 25))	('carcinoma', 'Phenotype', 'HP:0030731', (309, 318))	('NSCLC', 'Phenotype', 'HP:0030358', (477, 482))	('CRC', 'Disease', (376, 379))	('patients', 'Species', '9606', (274, 282))	('ovarian cancer', 'Disease', 'MESH:D010051', (223, 237))	('patients', 'Species', '9606', (432, 440))	('patients', 'Species', '9606', (179, 187))	('breast carcinoma', 'Disease', 'MESH:D001943', (302, 318))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('AGER', 'Gene', (44, 48))	('patients', 'Species', '9606', (343, 351))	('TLR4', 'Gene', '7099', (36, 40))	('CRC', 'Phenotype', 'HP:0030731', (376, 379))	('patients', 'Species', '9606', (501, 509))	('women', 'Species', '9606', (368, 373))	('TLR4', 'Gene', (36, 40))	('ovarian cancer', 'Disease', (223, 237))	('AGER', 'Gene', '177', (44, 48))	('breast carcinoma', 'Phenotype', 'HP:0003002', (302, 318))	('ovarian cancer', 'Phenotype', 'HP:0100615', (223, 237))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('NSCLC', 'Disease', 'MESH:D002289', (477, 482))	('prostate cancer', 'Disease', 'MESH:D011471', (91, 106))	('breast carcinoma', 'Disease', (302, 318))	('prostate cancer', 'Phenotype', 'HP:0012125', (91, 106))
238386	26300886	Along similar lines, activating mutations in MYD88 have been linked to the pathogenesis of primary central nervous system lymphomas.	('lymphomas', 'Phenotype', 'HP:0002665', (122, 131))	('MYD88', 'Gene', '4615', (45, 50))	('primary central nervous system lymphomas', 'Phenotype', 'HP:0030069', (91, 131))	('MYD88', 'Gene', (45, 50))	('lymphoma', 'Phenotype', 'HP:0002665', (122, 130))	('activating mutations', 'Var', (21, 41))	('primary central nervous system lymphomas', 'Disease', 'MESH:D016543', (91, 131))	('linked', 'Reg', (61, 67))	('primary central nervous system lymphomas', 'Disease', (91, 131))
238388	26300886	Finally, distinct SNPs affecting caspase-7 (CASP7) and one affecting caspase-3 (CASP3) have been associated with an altered risk for endometrial carcinoma (as investigated in a cohort of 1,028 patients and 1,003 healthy women), whereas SNPs affecting caspase-9 (CASP9) have been linked to reduced CRC incidence or improved disease outcome (as determined in a cohort of 402 patients and 480 healthy controls).	('CRC', 'Disease', (297, 300))	('carcinoma', 'Phenotype', 'HP:0030731', (145, 154))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (133, 154))	('reduced', 'NegReg', (289, 296))	('caspase-9', 'Gene', '842', (251, 260))	('associated', 'Reg', (97, 107))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (133, 154))	('caspase-3', 'Gene', '836', (69, 78))	('CRC', 'Phenotype', 'HP:0030731', (297, 300))	('CASP3', 'Gene', (80, 85))	('caspase-3', 'Gene', (69, 78))	('caspase-7', 'Gene', '840', (33, 42))	('caspase-9', 'Gene', (251, 260))	('CASP7', 'Gene', (44, 49))	('patients', 'Species', '9606', (193, 201))	('CASP3', 'Gene', '836', (80, 85))	('CASP7', 'Gene', '840', (44, 49))	('SNPs', 'Var', (18, 22))	('endometrial carcinoma', 'Disease', (133, 154))	('women', 'Species', '9606', (220, 225))	('CASP9', 'Gene', (262, 267))	('CASP9', 'Gene', '842', (262, 267))	('improved', 'PosReg', (314, 322))	('patients', 'Species', '9606', (373, 381))	('caspase-7', 'Gene', (33, 42))
238389	26300886	It remains to be determined whether these SNPs truly compromise the ability of cancer cells to emit DAMPs (and hence trigger immunosurveillance mechanisms).	('compromise', 'NegReg', (53, 63))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('emit', 'CPA', (95, 99))	('ability', 'MPA', (68, 75))	('AMP', 'Chemical', 'MESH:D000249', (101, 104))	('SNPs', 'Var', (42, 46))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('trigger', 'Reg', (117, 124))
238396	26300886	Upon binding to formyl peptide receptor 1 (FPR1), N-formylated peptides reportedly attract neutrophils, stimulate their degranulation, activate monocytes and favor the production of pro-inflammatory cytokines.	('formyl peptide receptor 1', 'Gene', '2357', (16, 41))	('FPR1', 'Gene', '2357', (43, 47))	('degranulation', 'MPA', (120, 133))	('monocytes', 'CPA', (144, 153))	('neutrophils', 'MPA', (91, 102))	('FPR1', 'Gene', (43, 47))	('production of pro-inflammatory cytokines', 'MPA', (168, 208))	('activate', 'PosReg', (135, 143))	('attract', 'PosReg', (83, 90))	('N-formylated peptides', 'Var', (50, 71))	('favor', 'PosReg', (158, 163))	('formyl peptide receptor 1', 'Gene', (16, 41))	('stimulate', 'PosReg', (104, 113))	('binding', 'Interaction', (5, 12))
238409	33572595	The development of novel technologies, such as revolutionary next-generation sequencing, enables the identification of cancer biomarkers, gene signatures, and their aberrant expression affecting oncogenesis, as well as the discovery of molecular targets for anticancer therapies.	('cancer', 'Disease', (262, 268))	('aberrant', 'Var', (165, 173))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('cancer', 'Phenotype', 'HP:0002664', (262, 268))	('oncogenesis', 'CPA', (195, 206))	('affecting', 'Reg', (185, 194))	('cancer', 'Disease', (119, 125))	('cancer', 'Disease', 'MESH:D009369', (262, 268))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
238420	33572595	The development of cancer is always associated with genetic and epigenetic changes accumulated within the cell, through which it acquires aberrant biological features specific for cancer cells (e.g., loss of apoptosis, insensitivity to regulatory factors, uncontrolled growth and cell division).	('apoptosis', 'CPA', (208, 217))	('cancer', 'Disease', 'MESH:D009369', (19, 25))	('epigenetic changes', 'Var', (64, 82))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('loss', 'NegReg', (200, 204))	('cancer', 'Disease', (19, 25))	('insensitivity', 'CPA', (219, 232))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('associated', 'Reg', (36, 46))	('cancer', 'Disease', (180, 186))
238446	33572595	It enables the analysis of epigenetic modifications and elements playing role in mechanisms, such as ncRNAs.	('epigenetic modifications', 'Var', (27, 51))	('ncRNA', 'Gene', (101, 106))	('ncRNA', 'Gene', '54719', (101, 106))
238458	33572595	The clusters distinguished in this study correspond closely to immunohistochemistry markers of breast tumors: estrogen receptors, Her-2 and Ki-67, and thus, should be treated as distinct diseases.	('breast tumors', 'Phenotype', 'HP:0100013', (95, 108))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('breast tumors', 'Disease', 'MESH:D001943', (95, 108))	('estrogen receptor', 'Gene', (110, 127))	('Her-2', 'Gene', '2064', (130, 135))	('estrogen receptor', 'Gene', '2099', (110, 127))	('breast tumors', 'Disease', (95, 108))	('Her-2', 'Gene', (130, 135))	('Ki-67', 'Var', (140, 145))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))
238481	33572595	Currently, the most commonly used biomarkers in esophageal squamous cell carcinoma (ESCC) diagnosis are: cytokeratin 19 fragment antigen 21-1 (Cyfra21-1), carbohydrate antigen 19-9 (CA19-9), carbohydrate antigen 72-4 (CA72-4), carcinoembryonic antigen (CEA), and squamous cell carcinoma antigen (SCC-Ag).	('carcinoembryonic antigen', 'Gene', (227, 251))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (59, 82))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (48, 82))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (263, 286))	('carcinoma', 'Phenotype', 'HP:0030731', (277, 286))	('CEA', 'Gene', (253, 256))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (263, 286))	('esophageal squamous cell carcinoma', 'Disease', (48, 82))	('CEA', 'Gene', '1084', (253, 256))	('squamous cell carcinoma', 'Disease', (263, 286))	('carcinoembryonic antigen', 'Gene', '1084', (227, 251))	('CA72-4', 'Var', (218, 224))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (59, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
238540	33572595	Inhibition of oncomiRs' expressions can be achieved through the use of antisense oligonucleotides with 2'-O-methyl groups, 2'-O-methoxyethyl groups and other linkages blocking exonuclease degradation, such as N,N-diethyl-4-(4-nitronaphthalen-1-ylazo)-phenylamine.	('exonuclease', 'Enzyme', (176, 187))	('antisense', 'Var', (71, 80))	('oligonucleotides', 'Chemical', 'MESH:D009841', (81, 97))	('miR', 'Gene', '220972', (18, 21))	('miR', 'Gene', (18, 21))	('N,N-diethyl-4-(4-nitronaphthalen-1-ylazo)-phenylamine', 'Chemical', '-', (209, 262))	('degradation', 'MPA', (188, 199))	('blocking', 'NegReg', (167, 175))
238636	33107706	22  Consistent with these results, patients who were 40-60 years old, female sex, black race, and high grade were more likely to have a distant metastasis in our study.	('high grade', 'Var', (98, 108))	('distant metastasis', 'CPA', (136, 154))	('patients', 'Species', '9606', (35, 43))
238659	32545247	Increasing evidence suggests dysregulated post-transcriptional gene expression as an important mechanism in the pathogenesis of cancer.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('post-transcriptional', 'Protein', (42, 62))	('dysregulated', 'Var', (29, 41))	('cancer', 'Disease', (128, 134))
238675	32545247	The consensus sequence of AREs in the 3'UTRs of the target mRNAs is UUAUUUAUU, although some variations of this sequence still mediate high affinity binding.	('AU', 'Chemical', 'MESH:D006046', (74, 76))	('mediate', 'Reg', (127, 134))	('binding', 'Interaction', (149, 156))	('variations', 'Var', (93, 103))	('AU', 'Chemical', 'MESH:D006046', (70, 72))
238677	32545247	Interestingly, germline gene knockouts of the three TTP family RBPs in mice resulted in vastly different phenotypes.	('mice', 'Species', '10090', (71, 75))	('RBP', 'Gene', (63, 66))	('knockouts', 'Var', (29, 38))	('RBP', 'Gene', '57794', (63, 66))
238678	32545247	For instance, while germline deletion of TTP resulted in a systemic inflammatory syndrome, germline deletion of ZFP36L1 was embryonically lethal, and germline deletion of ZFP36L2 resulted in post-natal mortality within two weeks post-birth due to defects in hematopoiesis.	('ZFP36L1', 'Gene', (112, 119))	('systemic inflammatory syndrome', 'MPA', (59, 89))	('hematopoiesis', 'Disease', (258, 271))	('resulted in', 'Reg', (179, 190))	('mortality', 'Disease', 'MESH:D003643', (202, 211))	('ZFP36L2', 'Gene', (171, 178))	('hematopoiesis', 'Disease', 'MESH:C536227', (258, 271))	('resulted in', 'Reg', (45, 56))	('deletion', 'Var', (100, 108))	('mortality', 'Disease', (202, 211))	('TTP', 'Gene', (41, 44))
238690	32545247	Alterations in the expression/activity of the TTP family RBPs have been reported to be associated with multiple cancers (Table 2).	('RBP', 'Gene', (57, 60))	('RBP', 'Gene', '57794', (57, 60))	('cancers', 'Phenotype', 'HP:0002664', (112, 119))	('Alterations', 'Var', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('associated', 'Reg', (87, 97))	('cancers', 'Disease', 'MESH:D009369', (112, 119))	('cancers', 'Disease', (112, 119))	('expression/activity', 'MPA', (19, 38))
238693	32545247	Three different mechanisms for loss of expression/activity of the TTP family RBPs have been reported: (1) MicroRNA-mediated regulation; (2) epigenetic silencing via DNA methylation; and (3) modulation of protein activity through post-translational modifications, particularly phosphorylation.	('post-translational modifications', 'Var', (229, 261))	('RBP', 'Gene', '57794', (77, 80))	('epigenetic silencing', 'Var', (140, 160))	('MicroRNA-mediated regulation', 'MPA', (106, 134))	('phosphorylation', 'Var', (276, 291))	('loss', 'NegReg', (31, 35))	('protein', 'Protein', (204, 211))	('activity', 'MPA', (212, 220))	('expression/activity', 'MPA', (39, 58))	('RBP', 'Gene', (77, 80))	('modulation', 'Reg', (190, 200))
238698	32545247	Dysregulation of the cell cycle is a characteristic feature of all cancers.	('cancers', 'Phenotype', 'HP:0002664', (67, 74))	('cancers', 'Disease', (67, 74))	('Dysregulation', 'Var', (0, 13))	('cell cycle', 'CPA', (21, 31))	('cancers', 'Disease', 'MESH:D009369', (67, 74))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('Dysregulation of the cell cycle', 'Phenotype', 'HP:0011018', (0, 31))
238705	32545247	Aberrant expression of E2F1 is associated with high-grade tumors, metastases, and unfavorable patient prognosis.	('metastases', 'Disease', (66, 76))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('Aberrant expression', 'Var', (0, 19))	('metastases', 'Disease', 'MESH:D009362', (66, 76))	('tumors', 'Disease', (58, 64))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('E2F1', 'Gene', '1869', (23, 27))	('E2F1', 'Gene', (23, 27))	('associated', 'Reg', (31, 41))	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('patient', 'Species', '9606', (94, 101))
238707	32545247	reported that TTP inhibits cellular proliferation in breast tumor cells in vitro and breast tumor growth in vivo by inducing cell cycle arrest at the S phase.	('inducing', 'Reg', (116, 124))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (125, 142))	('inhibits', 'NegReg', (18, 26))	('breast tumor', 'Disease', 'MESH:D001943', (53, 65))	('breast tumor', 'Phenotype', 'HP:0100013', (85, 97))	('breast tumor', 'Phenotype', 'HP:0100013', (53, 65))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('breast tumor', 'Disease', (53, 65))	('breast tumor', 'Disease', 'MESH:D001943', (85, 97))	('arrest', 'Disease', 'MESH:D006323', (136, 142))	('cellular proliferation', 'CPA', (27, 49))	('TTP', 'Var', (14, 17))	('breast tumor', 'Disease', (85, 97))	('arrest', 'Disease', (136, 142))
238715	32545247	Accordingly, levels of ZFP36L1 were found to be significantly reduced in acute myeloid leukemia patients.	('acute myeloid leukemia', 'Disease', (73, 95))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (73, 95))	('leukemia', 'Phenotype', 'HP:0001909', (87, 95))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (73, 95))	('levels', 'MPA', (13, 19))	('patients', 'Species', '9606', (96, 104))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (79, 95))	('ZFP36L1', 'Var', (23, 30))	('reduced', 'NegReg', (62, 69))
238719	32545247	Furthermore, these authors found that ZFP36L1 is epigenetically silenced through hypermethylation of the second exon and is downregulated in several patient cohorts of bladder and breast cancers.	('cancers', 'Phenotype', 'HP:0002664', (187, 194))	('breast cancers', 'Phenotype', 'HP:0003002', (180, 194))	('downregulated', 'NegReg', (124, 137))	('silenced', 'NegReg', (64, 72))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('breast cancers', 'Disease', 'MESH:D001943', (180, 194))	('ZFP36L1', 'Gene', (38, 45))	('breast cancers', 'Disease', (180, 194))	('patient', 'Species', '9606', (149, 156))	('breast cancer', 'Phenotype', 'HP:0003002', (180, 193))	('bladder', 'Disease', (168, 175))	('hypermethylation', 'Var', (81, 97))
238720	32545247	Functionally, silencing ZFP36L1 enhanced tumor cell growth while overexpression of ZFP36L1 suppressed cell proliferation and migration in bladder and breast cancer cell lines.	('suppressed', 'NegReg', (91, 101))	('silencing', 'Var', (14, 23))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('breast cancer', 'Disease', 'MESH:D001943', (150, 163))	('breast cancer', 'Phenotype', 'HP:0003002', (150, 163))	('tumor', 'Disease', (41, 46))	('breast cancer', 'Disease', (150, 163))	('enhanced', 'PosReg', (32, 40))	('ZFP36L1', 'Gene', (24, 31))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('cell proliferation', 'CPA', (102, 120))
238721	32545247	Finally, both ZFP36L1 and ZFP36L2 were shown to inhibit cellular proliferation through downregulation of cyclin D expression, resulting in cell cycle arrest at the G1 phase.	('cyclin D', 'Protein', (105, 113))	('ZFP36L2', 'Var', (26, 33))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (139, 156))	('ZFP36L1', 'Var', (14, 21))	('downregulation', 'NegReg', (87, 101))	('arrest', 'Disease', (150, 156))	('arrest', 'Disease', 'MESH:D006323', (150, 156))	('cellular proliferation', 'CPA', (56, 78))	('inhibit', 'NegReg', (48, 55))
238724	32545247	The authors suggested that TTP was unique and somewhat different from the two other family members, ZFP36L1 and ZFP36L2, because TTP, but not ZFP36L1 and ZFP36L2, could also sensitize the cells to apoptosis by inducing TNFalpha.	('apoptosis', 'CPA', (197, 206))	('TNFalpha', 'Gene', (219, 227))	('inducing', 'Reg', (210, 218))	('TNFalpha', 'Gene', '7124', (219, 227))	('TTP', 'Var', (129, 132))	('sensitize', 'Reg', (174, 183))
238726	32545247	Mechanistically, this study showed that TTP phosphorylation and inactivation through the p38 MAPK pathway resulted in increased TNFalpha-induced apoptosis.	('inactivation', 'Var', (64, 76))	('p38 MAPK pathway', 'Pathway', (89, 105))	('phosphorylation', 'Var', (44, 59))	('TNFalpha', 'Gene', (128, 136))	('increased', 'PosReg', (118, 127))	('TNFalpha', 'Gene', '7124', (128, 136))	('TTP phosphorylation', 'Var', (40, 59))
238731	32545247	In fact, ectopic TTP expression impaired the viability and invasiveness of glioblastoma multiforme cancer cells by destabilizing the PIM1, PIM2, and X-linked inhibitor of apoptosis proteins (XIAP) in these cells.	('ectopic', 'Var', (9, 16))	('TTP', 'Gene', (17, 20))	('PIM2', 'Gene', '11040', (139, 143))	('destabilizing', 'NegReg', (115, 128))	('invasiveness of glioblastoma multiforme cancer', 'Disease', 'MESH:D005909', (59, 105))	('impaired', 'NegReg', (32, 40))	('PIM1', 'Gene', '5292', (133, 137))	('viability', 'CPA', (45, 54))	('PIM2', 'Gene', (139, 143))	('PIM1', 'Gene', (133, 137))	('glioblastoma', 'Phenotype', 'HP:0012174', (75, 87))	('invasiveness of glioblastoma multiforme cancer', 'Disease', (59, 105))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
238732	32545247	recently reported that TTP enhances cisplatin sensitivity in head and neck squamous cell carcinoma (SCCHN) cells by reducing the levels of BCL-2, an anti-apoptotic protein, which is overexpressed in cancer and confers resistance to cisplatin.	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('reducing', 'NegReg', (116, 124))	('neck squamous cell carcinoma', 'Disease', (70, 98))	('SCC', 'Phenotype', 'HP:0002860', (100, 103))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (70, 98))	('TTP', 'Var', (23, 26))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (75, 98))	('enhances', 'PosReg', (27, 35))	('cancer', 'Disease', (199, 205))	('cisplatin', 'Chemical', 'MESH:D002945', (232, 241))	('BCL-2', 'Gene', '596', (139, 144))	('cisplatin', 'Chemical', 'MESH:D002945', (36, 45))	('cisplatin sensitivity', 'MPA', (36, 57))	('BCL-2', 'Gene', (139, 144))
238733	32545247	had showed that ZFP36L1 enhanced cisplatin sensitivity in SCCHN cells by inhibiting the human inhibitor of apoptosis protein-2 (cIAP2) and resulting in increased caspase-3 activity.	('activity', 'MPA', (172, 180))	('SCC', 'Phenotype', 'HP:0002860', (58, 61))	('increased', 'PosReg', (152, 161))	('ZFP36L1', 'Var', (16, 23))	('enhanced', 'PosReg', (24, 32))	('human', 'Species', '9606', (88, 93))	('cisplatin', 'Chemical', 'MESH:D002945', (33, 42))	('caspase-3', 'Gene', '836', (162, 171))	('inhibitor of apoptosis protein-2', 'Gene', '329', (94, 126))	('inhibiting', 'NegReg', (73, 83))	('cisplatin sensitivity', 'MPA', (33, 54))	('cIAP2', 'Gene', (128, 133))	('cIAP2', 'Gene', '330', (128, 133))	('caspase-3', 'Gene', (162, 171))	('inhibitor of apoptosis protein-2', 'Gene', (94, 126))
238742	32545247	Subsequent studies showed that a number of other pro-inflammatory cytokines and chemokines, including IL-23, IL-17, IL-1beta, CXCL1, and CXCL2, are also directly regulated by TTP.	('regulated', 'Reg', (162, 171))	('CXCL1', 'Gene', '2919', (126, 131))	('IL-1beta', 'Gene', '3552', (116, 124))	('IL-1beta', 'Gene', (116, 124))	('CXCL2', 'Gene', (137, 142))	('CXCL1', 'Gene', (126, 131))	('TTP', 'Var', (175, 178))	('CXCL2', 'Gene', '2920', (137, 142))	('IL-17', 'Gene', (109, 114))	('IL-17', 'Gene', '3605', (109, 114))	('IL-23', 'MPA', (102, 107))
238753	32545247	Additionally, TTP reduced the cloning efficiency in vitro when transfected into a fully established tumor cell line and the growth of the inoculated cells in vivo.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Disease', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('reduced', 'NegReg', (18, 25))	('cloning efficiency', 'CPA', (30, 48))	('TTP', 'Var', (14, 17))
238757	32545247	Most importantly, TTP levels were inversely correlated with the levels of the full-length transcript, and TTP transfection resulted in a reduction in the levels of the full-length transcript, indicating TTP regulation of COX-2 in these cells.	('TTP levels', 'MPA', (18, 28))	('COX-2', 'Gene', (221, 226))	('COX-2', 'Gene', '5743', (221, 226))	('reduction', 'NegReg', (137, 146))	('levels', 'MPA', (64, 70))	('transfection', 'Var', (110, 122))	('levels', 'MPA', (154, 160))	('TTP transfection', 'Var', (106, 122))
238760	32545247	Similarly, TTP was shown to destabilize interleukin 8 (IL-8) and vascular endothelial growth factor (VEGF) mRNAs in malignant glioma cells, resulting in a dose-dependent decrease in cellular proliferation, loss of cell viability, and apoptosis.	('glioma', 'Phenotype', 'HP:0009733', (126, 132))	('cell viability', 'CPA', (214, 228))	('vascular endothelial growth factor', 'Gene', (65, 99))	('malignant glioma', 'Disease', (116, 132))	('apoptosis', 'CPA', (234, 243))	('interleukin 8', 'Gene', '3576', (40, 53))	('malignant glioma', 'Disease', 'MESH:D005910', (116, 132))	('destabilize', 'NegReg', (28, 39))	('vascular endothelial growth factor', 'Gene', '7422', (65, 99))	('cellular proliferation', 'CPA', (182, 204))	('interleukin 8', 'Gene', (40, 53))	('decrease', 'NegReg', (170, 178))	('IL-8', 'Gene', (55, 59))	('TTP', 'Var', (11, 14))	('IL-8', 'Gene', '3576', (55, 59))	('loss', 'NegReg', (206, 210))
238762	32545247	showed that TTP expression is significantly lower in invasive breast cancer cells compared to normal breast cells, and that the genes involved in cellular growth, invasion, and metastasis, namely matrix metalloproteinase 1 (MMP1), urokinase-type plasminogen activator (uPA), and urokinase plasminogen activator receptor (uPAR), were directly regulated by TTP in breast cancer cells.	('MMP1', 'Gene', '4312', (224, 228))	('breast cancer', 'Phenotype', 'HP:0003002', (62, 75))	('uPAR', 'Gene', '5329', (321, 325))	('invasive breast cancer', 'Disease', (53, 75))	('uPA', 'Gene', (269, 272))	('MMP1', 'Gene', (224, 228))	('invasion', 'CPA', (163, 171))	('uPA', 'Gene', '5328', (269, 272))	('lower', 'NegReg', (44, 49))	('invasive breast cancer', 'Disease', 'MESH:D001943', (53, 75))	('regulated', 'Reg', (342, 351))	('breast cancer', 'Disease', 'MESH:D001943', (62, 75))	('TTP', 'Gene', (12, 15))	('expression', 'MPA', (16, 26))	('breast cancer', 'Phenotype', 'HP:0003002', (362, 375))	('uPA', 'Gene', (321, 324))	('TTP', 'Var', (355, 358))	('urokinase-type plasminogen activator', 'Gene', (231, 267))	('uPA', 'Gene', '5328', (321, 324))	('matrix metalloproteinase 1', 'Gene', '4312', (196, 222))	('breast cancer', 'Disease', 'MESH:D001943', (362, 375))	('breast cancer', 'Disease', (362, 375))	('urokinase-type plasminogen activator', 'Gene', '5328', (231, 267))	('uPAR', 'Gene', (321, 325))	('urokinase plasminogen activator receptor', 'Gene', (279, 319))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('cancer', 'Phenotype', 'HP:0002664', (369, 375))	('metastasis', 'CPA', (177, 187))	('urokinase plasminogen activator receptor', 'Gene', '5329', (279, 319))	('matrix metalloproteinase 1', 'Gene', (196, 222))	('cellular growth', 'CPA', (146, 161))
238766	32545247	TTP was also shown to directly regulate hypoxia-inducible factor 1 (HIF-1), a factor critically required for survival in hypoxic conditions, indicating that a low TTP poses a significant advantage to cancer cells by increasing HIF-1 and allowing adaptation to hypoxia.	('TTP', 'MPA', (163, 166))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('hypoxia', 'Disease', (40, 47))	('hypoxic conditions', 'Disease', 'MESH:D000071069', (121, 139))	('hypoxic conditions', 'Disease', (121, 139))	('hypoxia-inducible factor 1', 'Gene', '3091', (40, 66))	('cancer', 'Disease', 'MESH:D009369', (200, 206))	('low', 'Var', (159, 162))	('hypoxia', 'Disease', (260, 267))	('hypoxia', 'Disease', 'MESH:D000860', (40, 47))	('hypoxia-inducible factor 1', 'Gene', (40, 66))	('HIF-1', 'Gene', (68, 73))	('HIF-1', 'Gene', '3091', (227, 232))	('cancer', 'Disease', (200, 206))	('hypoxia', 'Disease', 'MESH:D000860', (260, 267))	('HIF-1', 'Gene', (227, 232))	('HIF-1', 'Gene', '3091', (68, 73))	('increasing', 'PosReg', (216, 226))	('advantage', 'PosReg', (187, 196))
238770	32545247	Squamous cell carcinoma of the head and neck (SCCHN) patients with low interleukin 6 (IL-6) and high MMP9, or with high IL-6 and low MMP9, were found to have the poorest outcomes followed by patients with both high IL-6 and high MMP9.	('carcinoma', 'Phenotype', 'HP:0030731', (14, 23))	('Squamous cell carcinoma', 'Disease', 'MESH:D002294', (0, 23))	('patients', 'Species', '9606', (191, 199))	('patients', 'Species', '9606', (53, 61))	('Squamous cell carcinoma', 'Phenotype', 'HP:0002860', (0, 23))	('interleukin 6', 'Gene', '3569', (71, 84))	('Squamous cell carcinoma', 'Disease', (0, 23))	('SCC', 'Phenotype', 'HP:0002860', (46, 49))	('high MMP9', 'Var', (96, 105))	('low', 'NegReg', (67, 70))	('interleukin 6', 'Gene', (71, 84))
238771	32545247	In comparison, patients with low IL-6 and low MMP9 had the best outcomes with respect to tumor recurrence, surgery, or death.	('patients', 'Species', '9606', (15, 23))	('IL-6', 'Gene', (33, 37))	('low', 'NegReg', (29, 32))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('MMP9', 'Gene', (46, 50))	('surgery', 'CPA', (107, 114))	('low', 'Var', (42, 45))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
238777	32545247	In this particular study, TTP inversely correlated with IL-13 levels in glioma tissues and TTP inhibited the growth, migration, and invasion of glioma cells through downregulation of IL-13 and attenuation of the PI3K/Akt/mTOR pathway.	('IL-13', 'Gene', '3596', (56, 61))	('downregulation', 'NegReg', (165, 179))	('glioma', 'Disease', (144, 150))	('IL-13', 'Gene', '3596', (183, 188))	('glioma', 'Disease', (72, 78))	('attenuation', 'NegReg', (193, 204))	('glioma', 'Disease', 'MESH:D005910', (144, 150))	('mTOR', 'Gene', (221, 225))	('TTP', 'Var', (91, 94))	('glioma', 'Disease', 'MESH:D005910', (72, 78))	('growth', 'CPA', (109, 115))	('Akt', 'Gene', (217, 220))	('glioma', 'Phenotype', 'HP:0009733', (144, 150))	('mTOR', 'Gene', '2475', (221, 225))	('IL-13', 'Gene', (56, 61))	('inhibited', 'NegReg', (95, 104))	('glioma', 'Phenotype', 'HP:0009733', (72, 78))	('IL-13', 'Gene', (183, 188))	('Akt', 'Gene', '207', (217, 220))	('invasion', 'CPA', (132, 140))
238782	32545247	showed innately immunoresistant RAS mutant tumors are characterized by the upregulation of immunosuppressive protein programmed death-ligand 1 (PD-L1) through RAS-MEK-MK2-induced TTP phosphorylation/inactivation, resulting in increased PD-L1 mRNA stability.	('MK2', 'Gene', '9261', (167, 170))	('MK2', 'Gene', (167, 170))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('programmed death-ligand 1', 'Gene', (117, 142))	('programmed death-ligand 1', 'Gene', '29126', (117, 142))	('PD-L1 mRNA stability', 'MPA', (236, 256))	('increased PD', 'Phenotype', 'HP:0008151', (226, 238))	('upregulation', 'PosReg', (75, 87))	('MEK', 'Gene', (163, 166))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('RAS', 'Gene', (32, 35))	('mutant', 'Var', (36, 42))	('MEK', 'Gene', '5609', (163, 166))	('tumors', 'Disease', (43, 49))	('increased', 'PosReg', (226, 235))	('TTP', 'MPA', (179, 182))	('tumors', 'Disease', 'MESH:D009369', (43, 49))
238787	32545247	Similar to TTP, ZFP36L1 phosphorylation and inactivation by the p38-MK2 axis has been shown to stabilize Nanog and Klf4 in triple-negative breast cancer cells, resulting in breast cancer stem cell phenotype, a feature of chemotherapy-resistance in triple-negative breast cancer.	('ZFP36L1 phosphorylation', 'Var', (16, 39))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('inactivation', 'Var', (44, 56))	('Klf4', 'Gene', '9314', (115, 119))	('breast cancer', 'Phenotype', 'HP:0003002', (173, 186))	('cancer', 'Phenotype', 'HP:0002664', (271, 277))	('breast cancer', 'Disease', 'MESH:D001943', (173, 186))	('breast cancer', 'Phenotype', 'HP:0003002', (139, 152))	('MK2', 'Gene', '9261', (68, 71))	('breast cancer', 'Disease', (173, 186))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('breast cancer', 'Disease', 'MESH:D001943', (139, 152))	('breast cancer', 'Phenotype', 'HP:0003002', (264, 277))	('breast cancer', 'Disease', (139, 152))	('phosphorylation', 'Var', (24, 39))	('breast cancer', 'Disease', 'MESH:D001943', (264, 277))	('Nanog', 'Gene', '79923', (105, 110))	('breast cancer', 'Disease', (264, 277))	('Klf4', 'Gene', (115, 119))	('Nanog', 'Gene', (105, 110))	('MK2', 'Gene', (68, 71))
238788	32545247	Cellular senescence is characterized by cells undergoing growth arrest in response to a wide variety of extrinsic and intrinsic insults, including DNA damage, loss of telomeres, and oncogenic activation.	('arrest', 'Disease', (64, 70))	('Cellular senescence', 'Disease', (0, 19))	('growth arrest', 'Phenotype', 'HP:0001510', (57, 70))	('loss', 'Var', (159, 163))	('oncogenic activation', 'CPA', (182, 202))	('DNA damage', 'MPA', (147, 157))	('arrest', 'Disease', 'MESH:D006323', (64, 70))	('telomeres', 'Protein', (167, 176))
238790	32545247	For instance, human papilloma virus-18 (HPV-18)-positive HeLa cells were used to show that TTP promoted cellular senescence through rapid decay of E6-associated protein (E6-AP) mRNA, resulting in p53 stabilization and inhibition of human telomerase reverse transcription gene (hTERT) transcription.	('promoted', 'PosReg', (95, 103))	('human', 'MPA', (232, 237))	('decay', 'NegReg', (138, 143))	('cellular', 'MPA', (104, 112))	('hTERT', 'Gene', '7015', (277, 282))	('human', 'Species', '9606', (232, 237))	('E6-associated protein', 'Gene', '7337', (147, 168))	('E6-associated protein', 'Gene', (147, 168))	('HeLa', 'CellLine', 'CVCL:0030', (57, 61))	('papilloma', 'Phenotype', 'HP:0012740', (20, 29))	('E6-AP', 'Gene', (170, 175))	('hTERT', 'Gene', (277, 282))	('p53', 'Gene', '7157', (196, 199))	('E6-AP', 'Gene', '7337', (170, 175))	('inhibition', 'NegReg', (218, 228))	('human', 'Species', '9606', (14, 19))	('TTP', 'Var', (91, 94))	('human papilloma virus', 'Species', '10566', (14, 35))	('p53', 'Gene', (196, 199))	('stabilization', 'MPA', (200, 213))
238801	32545247	GALR2, a pro-survival G-protein coupled receptor promoted angiogenesis via p38-mediated phosphorylation/inactivation of TTP, resulting in increased VEGF and IL-6 levels both in vitro in SCCHN cancer cells and in vivo in murine tumor xenografts and chorioallantoic membrane models.	('TTP', 'Gene', (120, 123))	('increased', 'PosReg', (138, 147))	('phosphorylation/inactivation', 'Var', (88, 116))	('tumor', 'Disease', (227, 232))	('SCCHN cancer', 'Phenotype', 'HP:0100280', (186, 198))	('GALR2', 'Gene', '14428', (0, 5))	('SCCHN cancer', 'Disease', 'MESH:D009369', (186, 198))	('promoted', 'PosReg', (49, 57))	('SCCHN cancer', 'Disease', (186, 198))	('tumor', 'Disease', 'MESH:D009369', (227, 232))	('SCC', 'Phenotype', 'HP:0002860', (186, 189))	('GALR2', 'Gene', (0, 5))	('murine', 'Species', '10090', (220, 226))	('angiogenesis', 'CPA', (58, 70))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))
238808	32545247	demonstrated that ZFP36L1 was markedly suppressed in breast cancer cells and patient tissues and that a derivative of ZFP36L1 fused to cell-penetrating peptide inhibited the proliferation, migration, invasion, and anchorage-independent growth in vitro and impaired the tumor growth and EMT markers, including Snail, Vimentin, and N-cadherin, in vivo.	('anchorage-independent growth', 'CPA', (214, 242))	('Snail', 'Gene', '6615', (309, 314))	('impaired the tumor', 'Disease', 'MESH:D060825', (256, 274))	('impaired the tumor', 'Disease', (256, 274))	('N-cadherin', 'Gene', (330, 340))	('N-cadherin', 'Gene', '1000', (330, 340))	('EMT markers', 'CPA', (286, 297))	('fused', 'Var', (126, 131))	('suppressed', 'NegReg', (39, 49))	('proliferation', 'CPA', (174, 187))	('migration', 'CPA', (189, 198))	('breast cancer', 'Phenotype', 'HP:0003002', (53, 66))	('tumor', 'Phenotype', 'HP:0002664', (269, 274))	('Vimentin', 'Gene', '7431', (316, 324))	('breast cancer', 'Disease', 'MESH:D001943', (53, 66))	('inhibited', 'NegReg', (160, 169))	('ZFP36L1', 'Gene', (18, 25))	('patient', 'Species', '9606', (77, 84))	('breast cancer', 'Disease', (53, 66))	('invasion', 'CPA', (200, 208))	('Vimentin', 'Gene', (316, 324))	('Snail', 'Gene', (309, 314))	('derivative', 'Var', (104, 114))	('ZFP36L1', 'Gene', (118, 125))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
238810	32545247	This study showed that while the loss of ZFP36L1 in the neural lineage resulted in myelination deficits due to the oligodendrocyte-astrocyte switch, in tumorigenesis this process was in fact beneficial by preventing gliomagenesis, thus enhancing survival.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('survival', 'CPA', (246, 254))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('myelination deficits', 'Disease', 'MESH:D003711', (83, 103))	('glioma', 'Disease', 'MESH:D005910', (216, 222))	('glioma', 'Phenotype', 'HP:0009733', (216, 222))	('myelination deficits', 'Phenotype', 'HP:0012448', (83, 103))	('tumor', 'Disease', (152, 157))	('ZFP36L1', 'Gene', (41, 48))	('preventing', 'NegReg', (205, 215))	('loss', 'Var', (33, 37))	('myelination deficits', 'Disease', (83, 103))	('enhancing', 'PosReg', (236, 245))	('glioma', 'Disease', (216, 222))
238811	32545247	Tumorigenesis is a consequence of mutations in oncogenes and tumor-suppressor genes that frequently result in either an overexpression of oncogenes or loss of tumor suppressors.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('loss of tumor', 'Disease', (151, 164))	('overexpression', 'PosReg', (120, 134))	('tumor-suppressor', 'Gene', '7248', (61, 77))	('Tumorigenesis', 'CPA', (0, 13))	('oncogenes', 'Gene', (47, 56))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('tumor-suppressor', 'Gene', (61, 77))	('oncogenes', 'MPA', (138, 147))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('loss of tumor', 'Disease', 'MESH:D009369', (151, 164))	('mutations', 'Var', (34, 43))
238819	32545247	The epigenetic inactivation of TTP resulted in an increased half-life of c-Myc, causing cancer cells to undergo selective resistance to TGFbeta1 antiproliferative signaling.	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('c-Myc', 'Gene', '4609', (73, 78))	('TTP', 'Gene', (31, 34))	('TGFbeta1', 'Gene', '7040', (136, 144))	('increased', 'PosReg', (50, 59))	('epigenetic inactivation', 'Var', (4, 27))	('TGFbeta1', 'Gene', (136, 144))	('c-Myc', 'Gene', (73, 78))	('causing', 'Reg', (80, 87))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('half-life', 'MPA', (60, 69))
238823	32545247	Interestingly, ZFP36L1 was found to be downregulated due to enhancer hypermethylation within the second exon in myelofibrosis, which conversely led to an increased expression of its target mRNAs.	('ZFP36L1', 'Gene', (15, 22))	('hypermethylation', 'Var', (69, 85))	('expression', 'MPA', (164, 174))	('myelofibrosis', 'Disease', 'MESH:D055728', (112, 125))	('myelofibrosis', 'Disease', (112, 125))	('enhancer', 'PosReg', (60, 68))	('myelofibrosis', 'Phenotype', 'HP:0011974', (112, 125))	('increased', 'PosReg', (154, 163))	('downregulated', 'NegReg', (39, 52))
238825	32545247	Similar to TTP and ZFP36L1, ZFP36L2 also functions as a tumor suppressor.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Disease', (56, 61))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('ZFP36L2', 'Var', (28, 35))
238826	32545247	Hypermethylation of a super-enhancer site in ZFP36L2 resulted in epigenetic silencing in a large data set of esophageal squamous cell carcinoma (SCC) whole-exome sequenced tissues.	('esophageal squamous cell carcinoma', 'Disease', (109, 143))	('Hypermethylation', 'Var', (0, 16))	('SCC', 'Phenotype', 'HP:0002860', (145, 148))	('resulted', 'Reg', (53, 61))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (120, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('ZFP36L2', 'Gene', (45, 52))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (109, 143))	('epigenetic silencing', 'MPA', (65, 85))
238828	32545247	The strongest evidence for the role of ZFP36L1 and ZFP36L2 as tumor suppressors came from studies done by Hodson et al..	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', (62, 67))	('ZFP36L1', 'Var', (39, 46))	('ZFP36L2', 'Var', (51, 58))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
238829	32545247	These authors demonstrated that loss of both ZFP36L1 and ZFP36L2 in mouse thymocytes resulted in the development of T cell acute lymphoblastic leukemia (T-ALL) due to stabilization of an oncogenic transcriptional regulator, Notch 1.	('Notch 1', 'Gene', (224, 231))	('mouse', 'Species', '10090', (68, 73))	('leukemia', 'Phenotype', 'HP:0001909', (143, 151))	('stabilization', 'MPA', (167, 180))	('ZFP36L2', 'Var', (57, 64))	('Notch 1', 'Gene', '18128', (224, 231))	('ZFP36L1', 'Gene', (45, 52))	('T cell acute lymphoblastic leukemia', 'Disease', (116, 151))	('loss', 'Var', (32, 36))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (129, 151))	('T cell acute lymphoblastic leukemia', 'Disease', 'MESH:D054218', (116, 151))	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (123, 151))
238830	32545247	Recently, genomic mutation in ZFP36L1 was identified as a potential driver of tumorigenesis in patients with concomitant diffuse large B-cell lymphoma and hepatitis B virus (HBV) infection.	('ZFP36L1', 'Gene', (30, 37))	('patients', 'Species', '9606', (95, 103))	('genomic mutation', 'Var', (10, 26))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('hepatitis', 'Phenotype', 'HP:0012115', (155, 164))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('B-cell lymphoma and hepatitis B virus (HBV) infection', 'Disease', 'MESH:D006509', (135, 188))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (135, 150))	('tumor', 'Disease', (78, 83))	('lymphoma', 'Phenotype', 'HP:0002665', (142, 150))
238831	32545247	The authors showed that tandem duplication induced amplification of the super enhancers and were associated with an increase in ZFP36L2 expression in ~10% of gastric cancers.	('expression', 'MPA', (136, 146))	('gastric cancers', 'Disease', 'MESH:D013274', (158, 173))	('gastric cancers', 'Disease', (158, 173))	('super', 'Protein', (72, 77))	('gastric cancers', 'Phenotype', 'HP:0012126', (158, 173))	('tandem duplication', 'Var', (24, 42))	('increase', 'PosReg', (116, 124))	('amplification', 'MPA', (51, 64))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('ZFP36L2', 'Gene', (128, 135))	('gastric cancer', 'Phenotype', 'HP:0012126', (158, 172))	('cancers', 'Phenotype', 'HP:0002664', (166, 173))
238846	32545247	Men with low TTP-expressing primary prostate cancer had significantly increased chances of biochemical reoccurrence in this study.	('prostate cancer', 'Disease', (36, 51))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('low TTP-expressing', 'Var', (9, 27))	('biochemical', 'Disease', (91, 102))	('prostate cancer', 'Disease', 'MESH:D011471', (36, 51))	('prostate cancer', 'Phenotype', 'HP:0012125', (36, 51))	('Men', 'Species', '9606', (0, 3))
238848	32545247	Another study that also investigated prostate cancers, showed that low-TTP tumors had faster reoccurrence or metastasis versus high-TTP tumors.	('tumors', 'Disease', (136, 142))	('tumors', 'Disease', 'MESH:D009369', (136, 142))	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('cancers', 'Phenotype', 'HP:0002664', (46, 53))	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('prostate cancers', 'Phenotype', 'HP:0012125', (37, 53))	('low-TTP', 'Var', (67, 74))	('faster', 'PosReg', (86, 92))	('prostate cancers', 'Disease', (37, 53))	('metastasis', 'CPA', (109, 119))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('reoccurrence', 'CPA', (93, 105))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('prostate cancers', 'Disease', 'MESH:D011471', (37, 53))	('tumors', 'Disease', (75, 81))	('prostate cancer', 'Phenotype', 'HP:0012125', (37, 52))
238849	32545247	Additionally, the low time to reoccurrence in low-TTP tumors was more pronounced in low-grade tumors.	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('low-TTP', 'Var', (46, 53))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('tumors', 'Disease', (94, 100))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('tumors', 'Disease', (54, 60))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('tumors', 'Disease', 'MESH:D009369', (54, 60))
238859	32545247	The TTP-low gene signature was also a feature of several other cancers, including pancreatic, bladder, and prostate from non-TCGA datasets.	('bladder', 'Disease', (94, 101))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('pancreatic', 'Disease', 'MESH:D010195', (82, 92))	('TTP-low', 'Var', (4, 11))	('cancers', 'Phenotype', 'HP:0002664', (63, 70))	('prostate', 'Disease', (107, 115))	('pancreatic', 'Disease', (82, 92))	('cancers', 'Disease', (63, 70))	('cancers', 'Disease', 'MESH:D009369', (63, 70))
238860	32545247	Low TTP expression was a poor prognostic indicator in breast cancer and lung adenocarcinoma patients and was associated with decreased survival and more aggressive necrotic tumors.	('breast cancer', 'Disease', (54, 67))	('lung adenocarcinoma', 'Disease', (72, 91))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (72, 91))	('Low', 'Var', (0, 3))	('decreased', 'NegReg', (125, 134))	('TTP', 'Protein', (4, 7))	('patients', 'Species', '9606', (92, 100))	('breast cancer', 'Disease', 'MESH:D001943', (54, 67))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (72, 91))	('tumors', 'Phenotype', 'HP:0002664', (173, 179))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('survival', 'CPA', (135, 143))	('aggressive necrotic tumors', 'Disease', 'MESH:D001523', (153, 179))	('breast cancer', 'Phenotype', 'HP:0003002', (54, 67))	('aggressive necrotic tumors', 'Disease', (153, 179))
238861	32545247	ZFP36L1 was found to be one of the genes with variants that was associated with an increased risk of subtype-specific epithelial ovarian cancers.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('associated', 'Reg', (64, 74))	('epithelial ovarian cancers', 'Disease', (118, 144))	('ovarian cancers', 'Phenotype', 'HP:0100615', (129, 144))	('ZFP36L1', 'Gene', (0, 7))	('cancers', 'Phenotype', 'HP:0002664', (137, 144))	('epithelial ovarian cancers', 'Disease', 'MESH:D000077216', (118, 144))	('variants', 'Var', (46, 54))
238863	32545247	This was further supported by silencing ZFP36L2 in vitro, which inhibited cancer cell aggressiveness in PDAC cells.	('aggressiveness', 'Phenotype', 'HP:0000718', (86, 100))	('cancer cell aggressiveness', 'Disease', 'MESH:D009369', (74, 100))	('ZFP36L2', 'Gene', (40, 47))	('inhibited', 'NegReg', (64, 73))	('silencing', 'Var', (30, 39))	('PDAC', 'Phenotype', 'HP:0006725', (104, 108))	('cancer cell aggressiveness', 'Disease', (74, 100))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
238867	32545247	showed the presence of a synonymous polymorphism (rs3746083) in the TTP gene in an aggressive TTP-negative breast cancer cell line.	('rs3746083', 'Mutation', 'rs3746083', (50, 59))	('presence', 'Reg', (11, 19))	('breast cancer', 'Disease', 'MESH:D001943', (107, 120))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('breast cancer', 'Disease', (107, 120))	('rs3746083', 'Var', (50, 59))	('breast cancer', 'Phenotype', 'HP:0003002', (107, 120))	('TTP', 'Gene', (68, 71))
238868	32545247	Interestingly, this mutation did not change the corresponding amino acid but affected the protein translation and was significantly associated with a lack of response to Herceptin treatment in HER2-positive breast cancer patients.	('patients', 'Species', '9606', (221, 229))	('HER2', 'Gene', (193, 197))	('HER2', 'Gene', '2064', (193, 197))	('affected', 'Reg', (77, 85))	('mutation', 'Var', (20, 28))	('Herceptin', 'Chemical', 'MESH:D000068878', (170, 179))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('breast cancer', 'Disease', 'MESH:D001943', (207, 220))	('protein translation', 'MPA', (90, 109))	('breast cancer', 'Phenotype', 'HP:0003002', (207, 220))	('breast cancer', 'Disease', (207, 220))
238870	32545247	Finally, the antitumor activity of curcumin analogue DM-1 in melanoma was shown to be mediated by multiple targets, which included TTP, ZFP36L1, and ZFP36L2, among others.	('ZFP36L2', 'Var', (149, 156))	('DM-1', 'Gene', (53, 57))	('tumor', 'Disease', (17, 22))	('melanoma', 'Phenotype', 'HP:0002861', (61, 69))	('melanoma', 'Disease', (61, 69))	('ZFP36L1', 'Var', (136, 143))	('melanoma', 'Disease', 'MESH:D008545', (61, 69))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('curcumin', 'Chemical', 'MESH:D003474', (35, 43))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('DM-1', 'Gene', '1760', (53, 57))
238873	32545247	Therefore, it is not clear whether the loss of TTP family RBPs is an early event that initiates tumor development or is a consequence of tumor development.	('RBP', 'Gene', (58, 61))	('tumor', 'Disease', (137, 142))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('RBP', 'Gene', '57794', (58, 61))	('tumor', 'Disease', (96, 101))	('loss', 'Var', (39, 43))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
238896	29145449	Also CT operation increased inference performances of the estimators for synthetic datasets.	('inference performances', 'MPA', (28, 50))	('increased', 'PosReg', (18, 27))	('operation', 'Var', (8, 17))	('synthetic', 'Species', '2005392', (73, 82))
238948	29145449	It was observed that ADAR (ADAR1), CCNE2 (CYCLINE2), BID, CDKN1B (P27_Pt198), and PRKCA (PKCALPHA) hub genes (proteins) may have significant effects on KIRC as a result of the WGCNA analysis with Shrink association estimator.	('KIRC', 'Disease', (152, 156))	('effects', 'Reg', (141, 148))	('ADAR1', 'Gene', (27, 32))	('CDKN1B', 'Gene', (58, 64))	('ADAR', 'Gene', (21, 25))	('ADAR', 'Gene', (27, 31))	('BID', 'Gene', '637', (53, 56))	('PRKCA', 'Gene', '5578', (82, 87))	('PKCALPHA', 'Gene', (89, 97))	('PRKCA', 'Gene', (82, 87))	('P27_Pt198', 'Var', (66, 75))	('PKCALPHA', 'Gene', '5578', (89, 97))	('BID', 'Gene', (53, 56))	('ADAR1', 'Gene', '103', (27, 32))	('CDKN1B', 'Gene', '1027', (58, 64))	('ADAR', 'Gene', '103', (21, 25))	('ADAR', 'Gene', '103', (27, 31))
238966	28878296	Genetic variants in ERCC1 and XPC predict survival outcome of non-small cell lung cancer patients treated with platinum-based therapy Nucleotide excision repair (NER) plays a vital role in platinum-induced DNA damage during chemotherapy.	('lung cancer', 'Phenotype', 'HP:0100526', (77, 88))	('ERCC1', 'Gene', '2067', (20, 25))	('ERCC1', 'Gene', (20, 25))	('predict', 'Reg', (34, 41))	('platinum', 'Chemical', 'MESH:D010984', (111, 119))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (66, 88))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (62, 88))	('XPC', 'Gene', (30, 33))	('variants', 'Var', (8, 16))	('patients', 'Species', '9606', (89, 97))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (62, 88))	('XPC', 'Gene', '7508', (30, 33))	('non-small cell lung cancer', 'Disease', (62, 88))	('Genetic variants', 'Var', (0, 16))	('platinum', 'Chemical', 'MESH:D010984', (189, 197))
238967	28878296	We hypothesize that regulatory single nucleotide polymorphisms (rSNPs) of the core NER genes modulate clinical outcome of patients with advanced non-small cell lung cancer (NSCLC) treated with platinum-based chemotherapy (PBS).	('non-small cell lung cancer', 'Disease', (145, 171))	('NSCLC', 'Phenotype', 'HP:0030358', (173, 178))	('modulate', 'Reg', (93, 101))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (149, 171))	('single nucleotide polymorphisms', 'Var', (31, 62))	('platinum', 'Chemical', 'MESH:D010984', (193, 201))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (145, 171))	('PBS', 'Chemical', '-', (222, 225))	('NSCLC', 'Disease', (173, 178))	('lung cancer', 'Phenotype', 'HP:0100526', (160, 171))	('patients', 'Species', '9606', (122, 130))	('NSCLC', 'Disease', 'MESH:D002289', (173, 178))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (145, 171))	('NER genes', 'Gene', (83, 92))
238968	28878296	We investigated associations of 25 rSNPs in eight NER genes with progression free survival (PFS) and overall survival (OS) in 710 NSCLC patients.	('NSCLC', 'Disease', 'MESH:D002289', (130, 135))	('progression', 'Disease', (65, 76))	('associations', 'Interaction', (16, 28))	('NER genes', 'Gene', (50, 59))	('rSNPs', 'Var', (35, 40))	('overall', 'MPA', (101, 108))	('NSCLC', 'Phenotype', 'HP:0030358', (130, 135))	('patients', 'Species', '9606', (136, 144))	('NSCLC', 'Disease', (130, 135))	('OS', 'Chemical', '-', (119, 121))
238969	28878296	We found that ERCC1 rs3212924 AG/GG and XPC rs2229090 GC/CC genotypes were associated with patients' PFS (HRadj = 1.21, 95% CI = 1.03-1.43, P adj = 0.021 for ERCC1 and HRadj = 0.80, 95% CI = 0.68-0.94, P adj = 0.007 for XPC), compared with the AA and GG genotypes, respectively.	('patients', 'Species', '9606', (91, 99))	('ERCC1', 'Gene', '2067', (158, 163))	('ERCC1', 'Gene', (158, 163))	('ERCC1', 'Gene', '2067', (14, 19))	('ERCC1', 'Gene', (14, 19))	('XPC', 'Gene', '7508', (220, 223))	('rs3212924', 'Mutation', 'rs3212924', (20, 29))	('PFS', 'Disease', (101, 104))	('rs2229090', 'Mutation', 'rs2229090', (44, 53))	('XPC', 'Gene', (40, 43))	('rs2229090 GC/CC', 'Var', (44, 59))	('rs3212924 AG/GG', 'Var', (20, 35))	('XPC', 'Gene', '7508', (40, 43))	('XPC', 'Gene', (220, 223))
238970	28878296	The association of XPC rs2229090 was more apparent in adenocarcinoma than in squamous cell carcinoma patients.	('adenocarcinoma', 'Disease', (54, 68))	('patients', 'Species', '9606', (101, 109))	('adenocarcinoma', 'Disease', 'MESH:D000230', (54, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (59, 68))	('rs2229090', 'Mutation', 'rs2229090', (23, 32))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (77, 100))	('XPC', 'Gene', (19, 22))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (77, 100))	('rs2229090', 'Var', (23, 32))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('squamous cell carcinoma', 'Disease', (77, 100))	('XPC', 'Gene', '7508', (19, 22))
238971	28878296	Additionally, ERCC4 rs1799798 GA/AA genotypes were associated with poorer OS (HRadj = 1.32, 95% CI = 1.04-1.69, P adj = 0.026), compared with the GG genotype.	('rs1799798', 'Mutation', 'rs1799798', (20, 29))	('rs1799798', 'Var', (20, 29))	('ERCC4', 'Gene', '2072', (14, 19))	('ERCC4', 'Gene', (14, 19))	('poorer', 'NegReg', (67, 73))	('OS', 'Chemical', '-', (74, 76))
238972	28878296	The expression quantitative trait loci analysis revealed that ERCC1 rs3212924 and XPC rs2229090 might regulate transcription of their genes, which is consistent with their associations with survival.	('rs2229090', 'Mutation', 'rs2229090', (86, 95))	('rs2229090', 'Var', (86, 95))	('rs3212924', 'Mutation', 'rs3212924', (68, 77))	('regulate', 'Reg', (102, 110))	('ERCC1', 'Gene', (62, 67))	('rs3212924', 'Var', (68, 77))	('transcription', 'MPA', (111, 124))	('XPC', 'Gene', (82, 85))	('ERCC1', 'Gene', '2067', (62, 67))	('XPC', 'Gene', '7508', (82, 85))
238977	28878296	Platinum-based regimes are the standard first-line chemotherapy for NSCLC patients, although recent targeted therapies have presented benefits for a small portion of the patients who have activating EGFR mutations or EML-ALK translocations.	('patients', 'Species', '9606', (170, 178))	('ALK', 'Gene', (221, 224))	('Platinum', 'Chemical', 'MESH:D010984', (0, 8))	('NSCLC', 'Disease', 'MESH:D002289', (68, 73))	('activating', 'PosReg', (188, 198))	('EGFR', 'Gene', (199, 203))	('mutations', 'Var', (204, 213))	('patients', 'Species', '9606', (74, 82))	('EGFR', 'Gene', '1956', (199, 203))	('ALK', 'Gene', '238', (221, 224))	('NSCLC', 'Phenotype', 'HP:0030358', (68, 73))	('NSCLC', 'Disease', (68, 73))
238985	28878296	The XPE/DDB1 protein has been studied for its auxiliary role for the recognition of cyclobutane pyrimidine lesions, due to its affinity for UV-damaged DNA.	('cyclobutane', 'Var', (84, 95))	('XPE', 'Gene', (4, 7))	('affinity', 'MPA', (127, 135))	('cyclobutane pyrimidine', 'Chemical', '-', (84, 106))	('XPE', 'Gene', '1642', (4, 7))	('DDB1', 'Gene', '1642', (8, 12))	('DDB1', 'Gene', (8, 12))
238996	28878296	Call rates of the majority of the SNPs were >95%, except for three rSNPs (rs2607735, rs1007616 and rs7507745), which were then excluded from further analysis.	('rs7507745', 'Mutation', 'rs7507745', (99, 108))	('rs2607735', 'Var', (74, 83))	('rs2607735', 'Mutation', 'rs2607735', (74, 83))	('rs7507745', 'Var', (99, 108))	('rs1007616', 'Mutation', 'rs1007616', (85, 94))	('rs1007616', 'Var', (85, 94))
238997	28878296	In the univariate analysis without and multivariate analysis with adjustment for clinical variables, three rSNPs (ERCC1 rs3212924, XPC rs2229090 and ERCC4 rs1799798) consistently showed a significant association with either PFS or OS in NSCLC patients (Tables 2).	('PFS', 'Disease', (224, 227))	('NSCLC', 'Disease', (237, 242))	('rs3212924', 'Mutation', 'rs3212924', (120, 129))	('rs2229090', 'Mutation', 'rs2229090', (135, 144))	('rs2229090', 'Var', (135, 144))	('XPC', 'Gene', (131, 134))	('NSCLC', 'Disease', 'MESH:D002289', (237, 242))	('patients', 'Species', '9606', (243, 251))	('rs3212924', 'Var', (120, 129))	('rs1799798', 'Mutation', 'rs1799798', (155, 164))	('XPC', 'Gene', '7508', (131, 134))	('ERCC1', 'Gene', (114, 119))	('rs1799798', 'Var', (155, 164))	('ERCC1', 'Gene', '2067', (114, 119))	('OS', 'Chemical', '-', (231, 233))	('ERCC4', 'Gene', '2072', (149, 154))	('NSCLC', 'Phenotype', 'HP:0030358', (237, 242))	('ERCC4', 'Gene', (149, 154))
238999	28878296	Specifically, the ERCC1 rs3212924 G allele was found to be significantly associated with a poor PFS [AG/GG vs. AA: median survival time (MST) 6.5 vs. 7.6 months, P log-rank = 0.030; adjusted hazards ratio (HRadj) = 1.21, 95% CI = 1.03-1.43, P adj = 0.021, under a dominant model] (Table 2).	('ERCC1', 'Gene', '2067', (18, 23))	('ERCC1', 'Gene', (18, 23))	('rs3212924', 'Mutation', 'rs3212924', (24, 33))	('rs3212924 G', 'Var', (24, 35))
239000	28878296	This variant was not significantly associated with PFS in patients with adenocarcinoma, nor in patients with squamous cell carcinoma alone in our dataset (Supplemental Table S3).	('patients', 'Species', '9606', (95, 103))	('associated', 'Reg', (35, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('variant', 'Var', (5, 12))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (109, 132))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('adenocarcinoma', 'Disease', (72, 86))	('adenocarcinoma', 'Disease', 'MESH:D000230', (72, 86))	('patients', 'Species', '9606', (58, 66))	('squamous cell carcinoma', 'Disease', (109, 132))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (109, 132))	('PFS', 'Disease', (51, 54))
239001	28878296	The XPC rs2229090 C allele was associated with a longer PFS for all patients (GC/CC vs. GG: MST 7.4 vs. 6.5 months, P log-rank = 0.063; HRadj = 0.80, 95% CI = 0.68-0.94, P adj = 0.007, under a dominant model) (Table 2).	('XPC', 'Gene', '7508', (4, 7))	('rs2229090', 'Mutation', 'rs2229090', (8, 17))	('patients', 'Species', '9606', (68, 76))	('rs2229090 C', 'Var', (8, 19))	('longer', 'PosReg', (49, 55))	('PFS', 'MPA', (56, 59))	('XPC', 'Gene', (4, 7))
239002	28878296	In the stratified analysis by histological type and treatment, this variant was significantly associated with a longer PFS only in adenocarcinoma patients alone and squamous cell carcinoma patients who had received docetaxel-cisplatin (GC/CC vs. GG: MST 7.4 vs.6.1 and 10.3 vs. 6.5, P log-rank = 0.109 and 0.030, HRadj = 0.79 and 0.44, 95% CI = 0.65-0.96 and 0.22-0.90, P adj = 0.021 and 0.025, respectively) (Supplemental Tables S3 and S4).	('PFS', 'MPA', (119, 122))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (165, 188))	('squamous cell carcinoma', 'Disease', (165, 188))	('cisplatin', 'Chemical', 'MESH:D002945', (225, 234))	('variant', 'Var', (68, 75))	('adenocarcinoma', 'Disease', (131, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (179, 188))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('docetaxel', 'Chemical', 'MESH:D000077143', (215, 224))	('patients', 'Species', '9606', (189, 197))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (165, 188))	('patients', 'Species', '9606', (146, 154))	('adenocarcinoma', 'Disease', 'MESH:D000230', (131, 145))
239003	28878296	Patients carrying ERCC4 rs1799798 GA/AA genotypes showed a significantly increased risk of death, compared with those with the GG genotype (MST 24 vs. 29.3 months, P log-rank = 0.032; HRadj = 1.32, 95% CI = 1.04-1.69, P adj = 0.026, also under a dominant model) (Table 2; Fig.	('death', 'Disease', 'MESH:D003643', (91, 96))	('death', 'Disease', (91, 96))	('rs1799798', 'Mutation', 'rs1799798', (24, 33))	('ERCC4', 'Gene', '2072', (18, 23))	('ERCC4', 'Gene', (18, 23))	('rs1799798', 'Var', (24, 33))	('Patients', 'Species', '9606', (0, 8))
239004	28878296	This variant has a borderline association with OS in adenocarcinoma patients, but not in squamous cell lung cancer patients, which is likely due to sample size reduction in the subgroup analysis (Supplemental Table S3).	('adenocarcinoma', 'Disease', (53, 67))	('patients', 'Species', '9606', (115, 123))	('adenocarcinoma', 'Disease', 'MESH:D000230', (53, 67))	('variant', 'Var', (5, 12))	('squamous cell lung cancer', 'Disease', 'MESH:D002294', (89, 114))	('patients', 'Species', '9606', (68, 76))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('lung cancer', 'Phenotype', 'HP:0100526', (103, 114))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))	('OS', 'Chemical', '-', (47, 49))	('squamous cell lung cancer', 'Disease', (89, 114))
239005	28878296	When we combined all risk genotypes into the number of risk genotypes (NRGs, i.e., the number of ERCC1 rs3212924 GG/AG and XPC rs2229090 GG genotypes) for assessing their joint effect on PFS, the frequencies of patients with a score of 0, 1 or 2 for NRGs were 205, 347 and 156, respectively (Table 2).	('patients', 'Species', '9606', (211, 219))	('PFS', 'Disease', (187, 190))	('ERCC1', 'Gene', (97, 102))	('rs3212924', 'Mutation', 'rs3212924', (103, 112))	('rs2229090 GG', 'Var', (127, 139))	('rs3212924 GG/AG', 'Var', (103, 118))	('rs2229090', 'Mutation', 'rs2229090', (127, 136))	('XPC', 'Gene', (123, 126))	('ERCC1', 'Gene', '2067', (97, 102))	('XPC', 'Gene', '7508', (123, 126))
239009	28878296	Overall, the risk genotype group carriers (ERCC1 rs3212924 AG/GG and XPC rs2229090 GG) tended to have a significantly increased risk of disease progression in subgroups of younger (<=58 years old), males, current smokers, TNM stage III, no radiotherapy, ECOG status 2, poorly differentiated, platinum-docetaxel/paclitaxel recipients.	('XPC', 'Gene', (69, 72))	('platinum-docetaxel', 'Chemical', '-', (292, 310))	('TNM', 'Gene', (222, 225))	('XPC', 'Gene', '7508', (69, 72))	('ERCC1', 'Gene', '2067', (43, 48))	('disease progression', 'CPA', (136, 155))	('rs3212924', 'Mutation', 'rs3212924', (49, 58))	('paclitaxel', 'Chemical', 'MESH:D017239', (311, 321))	('rs2229090', 'Mutation', 'rs2229090', (73, 82))	('rs3212924 AG/GG', 'Var', (49, 64))	('TNM', 'Gene', '10178', (222, 225))	('rs2229090 GG', 'Var', (73, 85))	('ERCC1', 'Gene', (43, 48))
239010	28878296	For ERCC4 rs1799798 GA/AA carriers, an increased risk of death was observed in older patients (>58 years), non-smokers or former smokers, well-moderately differentiated tumours, and recipients of carboplatin-based or TKI chemotherapies, compared with the GG carriers (Supplemental Table S5).	('death', 'Disease', 'MESH:D003643', (57, 62))	('death', 'Disease', (57, 62))	('ERCC4', 'Gene', (4, 9))	('tumours', 'Disease', (169, 176))	('rs1799798', 'Mutation', 'rs1799798', (10, 19))	('carboplatin', 'Chemical', 'MESH:D016190', (196, 207))	('ERCC4', 'Gene', '2072', (4, 9))	('rs1799798', 'Var', (10, 19))	('patients', 'Species', '9606', (85, 93))	('tumour', 'Phenotype', 'HP:0002664', (169, 175))	('tumours', 'Phenotype', 'HP:0002664', (169, 176))	('tumours', 'Disease', 'MESH:D009369', (169, 176))
239011	28878296	One included the GTEx samples of normal lung tissues, in which the ERCC1 rs3212924 G allele was associated with a significantly higher ERCC1 mRNA expression level (P = 0.038, effect size = 0.13) (Fig.	('rs3212924 G', 'Var', (73, 84))	('ERCC1', 'Gene', '2067', (135, 140))	('ERCC1', 'Gene', (135, 140))	('rs3212924', 'Mutation', 'rs3212924', (73, 82))	('ERCC1', 'Gene', '2067', (67, 72))	('ERCC1', 'Gene', (67, 72))	('higher', 'PosReg', (128, 134))
239012	28878296	The XPC rs2229090 protective C allele was associated with a lower expression level of XPC (z-score = -6.83, P = 8.39E-12) and a nearby gene TMEM43 in peripheral blood cells (z-score = -6.29, P = 3.17E-10, Fig.	('expression level', 'MPA', (66, 82))	('XPC', 'Gene', '7508', (4, 7))	('XPC', 'Gene', '7508', (86, 89))	('TMEM43', 'Gene', (140, 146))	('TMEM43', 'Gene', '79188', (140, 146))	('rs2229090', 'Mutation', 'rs2229090', (8, 17))	('rs2229090 protective', 'Var', (8, 28))	('XPC', 'Gene', (86, 89))	('XPC', 'Gene', (4, 7))	('lower', 'NegReg', (60, 65))
239013	28878296	Therefore, it is biologically plausible that the associations between those variants and NSCLC survival may be explained by the difference in gene expression levels regulated by those variants.	('NSCLC', 'Disease', 'MESH:D002289', (89, 94))	('associations', 'Interaction', (49, 61))	('NSCLC', 'Phenotype', 'HP:0030358', (89, 94))	('variants', 'Var', (76, 84))	('NSCLC', 'Disease', (89, 94))
239023	28878296	In the present study, we found that two rSNPs (ERCC1 rs3212924 and XPC rs2229090) were associated with PFS and one rSNP (ERCC4 rs1799798) associated with OS of NSCLC patients, and these associations were not previously reported for lung cancer.	('PFS', 'Disease', (103, 106))	('rs3212924', 'Var', (53, 62))	('rs2229090', 'Var', (71, 80))	('lung cancer', 'Disease', 'MESH:D008175', (232, 243))	('XPC', 'Gene', '7508', (67, 70))	('NSCLC', 'Disease', (160, 165))	('lung cancer', 'Phenotype', 'HP:0100526', (232, 243))	('XPC', 'Gene', (67, 70))	('rs2229090', 'Mutation', 'rs2229090', (71, 80))	('NSCLC', 'Phenotype', 'HP:0030358', (160, 165))	('associated', 'Reg', (87, 97))	('ERCC1', 'Gene', '2067', (47, 52))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('rs1799798', 'Mutation', 'rs1799798', (127, 136))	('ERCC4', 'Gene', (121, 126))	('ERCC4', 'Gene', '2072', (121, 126))	('ERCC1', 'Gene', (47, 52))	('lung cancer', 'Disease', (232, 243))	('rs3212924', 'Mutation', 'rs3212924', (53, 62))	('associated', 'Reg', (138, 148))	('OS', 'Chemical', '-', (154, 156))	('patients', 'Species', '9606', (166, 174))	('NSCLC', 'Disease', 'MESH:D002289', (160, 165))
239024	28878296	The rs3212924 variant resides at the upstream or an intron of different ERCC1 transcripts, with a predicted function of altering transcription factor binding, which may further affect gene expression.	('altering', 'Reg', (120, 128))	('gene expression', 'MPA', (184, 199))	('transcription factor', 'MPA', (129, 149))	('ERCC1', 'Gene', '2067', (72, 77))	('ERCC1', 'Gene', (72, 77))	('rs3212924', 'Mutation', 'rs3212924', (4, 13))	('affect', 'Reg', (177, 183))	('rs3212924', 'Var', (4, 13))	('binding', 'Interaction', (150, 157))
239026	28878296	Difference in gene expression by the rs3212924 G allele has been observed not only in lung tissue, but also in artery, skin, and ovary tissues, suggesting a genetically determined regulatory role of this variant in its gene expression.	('rs3212924', 'Mutation', 'rs3212924', (37, 46))	('rs3212924 G', 'Var', (37, 48))	('gene expression', 'MPA', (14, 29))
239027	28878296	In the rs3212924 LD block, none of the other SNPs in high LD (r2 > 0.8) have been previously reported to be associated with cancer survival (Fig.	('cancer', 'Disease', (124, 130))	('rs3212924 LD', 'Var', (7, 19))	('rs3212924', 'Mutation', 'rs3212924', (7, 16))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('associated with', 'Reg', (108, 123))	('cancer', 'Disease', 'MESH:D009369', (124, 130))
239028	28878296	Taken together, the associations between this variant with high tumour tissue levels of ERCC1 mRNA may have led to cisplatin resistance, which may have independently affected disease progression in NSCLC patients.	('patients', 'Species', '9606', (204, 212))	('associations', 'Interaction', (20, 32))	('NSCLC', 'Phenotype', 'HP:0030358', (198, 203))	('variant', 'Var', (46, 53))	('led to', 'Reg', (108, 114))	('tumour', 'Disease', 'MESH:D009369', (64, 70))	('cisplatin', 'Chemical', 'MESH:D002945', (115, 124))	('tumour', 'Disease', (64, 70))	('ERCC1', 'Gene', '2067', (88, 93))	('cisplatin resistance', 'MPA', (115, 135))	('NSCLC', 'Disease', (198, 203))	('ERCC1', 'Gene', (88, 93))	('affected', 'Reg', (166, 174))	('NSCLC', 'Disease', 'MESH:D002289', (198, 203))	('tumour', 'Phenotype', 'HP:0002664', (64, 70))
239029	28878296	The rs2229090 variant is located at the 3'UTR of XPC, and the G to C allele substitution is predicted to affect miRNA binding.	('XPC', 'Gene', '7508', (49, 52))	('miRNA', 'Protein', (112, 117))	('affect', 'Reg', (105, 111))	('rs2229090', 'Mutation', 'rs2229090', (4, 13))	('rs2229090', 'Var', (4, 13))	('XPC', 'Gene', (49, 52))
239030	28878296	In fact, the eQTL analysis indicated a genotypic effect of rs2229090 on expression of a pseudogene (Vomeronasal 1 Receptor 20 Pseudogene, VN1R20P) downstream of XPC in tibial artery tissues (Fig.	('XPC', 'Gene', '7508', (161, 164))	('VN1R20P', 'Gene', '100312775', (138, 145))	('Vomeronasal 1 Receptor 20 Pseudogene', 'Gene', (100, 136))	('expression', 'MPA', (72, 82))	('Vomeronasal 1 Receptor 20 Pseudogene', 'Gene', '100312775', (100, 136))	('VN1R20P', 'Gene', (138, 145))	('rs2229090', 'Mutation', 'rs2229090', (59, 68))	('rs2229090', 'Var', (59, 68))	('XPC', 'Gene', (161, 164))
239033	28878296	Prior evidence indicated that subjects carrying rs2228000 CT/TT genotypes exhibited a better DNA repair capacity, and a poorer survival or risk of recurrence in oropharynx squamous cell carcinoma and acute myeloid leukaemia.	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (172, 195))	('rs2228000', 'Mutation', 'rs2228000', (48, 57))	('squamous cell carcinoma', 'Disease', (172, 195))	('carcinoma', 'Phenotype', 'HP:0030731', (186, 195))	('poorer', 'NegReg', (120, 126))	('acute myeloid leukaemia', 'Phenotype', 'HP:0004808', (200, 223))	('better', 'PosReg', (86, 92))	('acute myeloid leukaemia', 'Disease', (200, 223))	('DNA repair capacity', 'MPA', (93, 112))	('acute myeloid leukaemia', 'Disease', 'MESH:D007938', (200, 223))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (172, 195))	('myeloid leukaemia', 'Phenotype', 'HP:0012324', (206, 223))	('rs2228000', 'Var', (48, 57))
239035	28878296	It is likely that the phenotypic change of XPC function associated with rs2228000 may have been responsible for the observed association with rs2229090 that is within the same LD block (Fig.	('rs2228000', 'Var', (72, 81))	('rs2229090', 'Var', (142, 151))	('rs2228000', 'Mutation', 'rs2228000', (72, 81))	('XPC', 'Gene', '7508', (43, 46))	('XPC', 'Gene', (43, 46))	('rs2229090', 'Mutation', 'rs2229090', (142, 151))
239036	28878296	Because XPC plays a key role in recognizing DNA damage and initiation of the NER process, these collective findings suggest that XPC variants at the rs2229090 block may have an impact on PFS in NSCLC patients treated with PBC by affecting PBC outcome through changing XPC expression and thus the DNA repair capacity.	('changing', 'Reg', (259, 267))	('expression', 'MPA', (272, 282))	('XPC', 'Gene', '7508', (268, 271))	('XPC', 'Gene', (268, 271))	('impact', 'Reg', (177, 183))	('PFS', 'Disease', (187, 190))	('NSCLC', 'Disease', 'MESH:D002289', (194, 199))	('XPC', 'Gene', '7508', (129, 132))	('rs2229090', 'Mutation', 'rs2229090', (149, 158))	('XPC', 'Gene', '7508', (8, 11))	('NSCLC', 'Disease', (194, 199))	('XPC', 'Gene', (129, 132))	('PBC', 'Chemical', '-', (239, 242))	('variants', 'Var', (133, 141))	('NSCLC', 'Phenotype', 'HP:0030358', (194, 199))	('patients', 'Species', '9606', (200, 208))	('XPC', 'Gene', (8, 11))	('PBC', 'Chemical', '-', (222, 225))	('DNA', 'MPA', (296, 299))	('PBC', 'Disease', (239, 242))	('affecting', 'Reg', (229, 238))
239037	28878296	In the subgroup analysis by histological type and chemotherapy treatment, XPC rs2229090 GC/CC exhibited a significant association with a longer PFS, while ERCC4 rs1799798 GA genotype was significantly associated with a shorter OS in 477 adenocarcinoma patients, but not in 138 squamous cell carcinoma patients, suggesting a potential histological difference in genetic regulation of lung cancer survival outcome in response to the treatments.	('rs1799798', 'Mutation', 'rs1799798', (161, 170))	('lung cancer', 'Disease', 'MESH:D008175', (383, 394))	('adenocarcinoma', 'Disease', (237, 251))	('rs1799798 GA', 'Var', (161, 173))	('patients', 'Species', '9606', (301, 309))	('rs2229090 GC/CC', 'Var', (78, 93))	('lung cancer', 'Phenotype', 'HP:0100526', (383, 394))	('rs2229090', 'Mutation', 'rs2229090', (78, 87))	('patients', 'Species', '9606', (252, 260))	('adenocarcinoma', 'Disease', 'MESH:D000230', (237, 251))	('ERCC4', 'Gene', '2072', (155, 160))	('ERCC4', 'Gene', (155, 160))	('XPC', 'Gene', '7508', (74, 77))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (277, 300))	('cancer', 'Phenotype', 'HP:0002664', (388, 394))	('carcinoma', 'Phenotype', 'HP:0030731', (291, 300))	('XPC', 'Gene', (74, 77))	('lung cancer', 'Disease', (383, 394))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (277, 300))	('OS', 'Chemical', '-', (227, 229))	('carcinoma', 'Phenotype', 'HP:0030731', (242, 251))	('PFS', 'MPA', (144, 147))	('squamous cell carcinoma', 'Disease', (277, 300))
239038	28878296	Although XPC rs2229090 GC/CC genotypes were significantly associated with PFS in squamous cell carcinoma patients who received docetaxel-cisplatin, the sample size of this treatment group was relatively small (n = 56); hence, this result needs to be interpreted with caution (Supplemental Table S4).	('docetaxel', 'Chemical', 'MESH:D000077143', (127, 136))	('patients', 'Species', '9606', (105, 113))	('associated', 'Reg', (58, 68))	('XPC', 'Gene', (9, 12))	('rs2229090 GC/CC', 'Var', (13, 28))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('rs2229090', 'Mutation', 'rs2229090', (13, 22))	('PFS', 'Disease', (74, 77))	('XPC', 'Gene', '7508', (9, 12))	('cisplatin', 'Chemical', 'MESH:D002945', (137, 146))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (81, 104))	('squamous cell carcinoma', 'Disease', (81, 104))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (81, 104))
239041	28878296	Second, with the aim of studying potentially functional SNPs in the regulatory regions of eight NER core genes, we did not incorporate the other known effect of non-synonymous SNPs on survival outcome of NSCLC patients, although they are not in the LD block with the ones under investigation in the present study (except for rs2228080).	('NSCLC', 'Disease', (204, 209))	('patients', 'Species', '9606', (210, 218))	('rs2228080', 'Mutation', 'rs2228080', (325, 334))	('NSCLC', 'Disease', 'MESH:D002289', (204, 209))	('NSCLC', 'Phenotype', 'HP:0030358', (204, 209))	('SNPs', 'Var', (56, 60))
239042	28878296	The present study provided evidence that rSNPs in the core NER genes may modulate PBC-related survival outcome in Chinese NSCLC patients with an advanced stage disease.	('PBC-related survival', 'Gene', (82, 102))	('NSCLC', 'Disease', 'MESH:D002289', (122, 127))	('modulate', 'Reg', (73, 81))	('NSCLC', 'Phenotype', 'HP:0030358', (122, 127))	('rSNPs', 'Var', (41, 46))	('PBC', 'Chemical', '-', (82, 85))	('patients', 'Species', '9606', (128, 136))	('NSCLC', 'Disease', (122, 127))	('NER genes', 'Gene', (59, 68))
239043	28878296	Potential gene regulation by rSNPs of two NER genes associated with outcomes of patients with NSCLC call for further functional studies to unravel the molecular mechanisms underlying the observed associations, which will also allow for further development of predictive biomarkers to facilitate personalized chemotherapy regime.	('NER genes', 'Gene', (42, 51))	('NSCLC', 'Phenotype', 'HP:0030358', (94, 99))	('patients', 'Species', '9606', (80, 88))	('gene', 'Reg', (10, 14))	('associated', 'Reg', (52, 62))	('NSCLC', 'Disease', (94, 99))	('NSCLC', 'Disease', 'MESH:D002289', (94, 99))	('rSNPs', 'Var', (29, 34))
239093	32216776	No abnormalities were observed in limb color ultrasonography, tumor antigen testing, or surrogate markers of autoimmune diseases (anti-nuclear antibody, anti-RNP antibody, anti-CCP antibody, c-ANCA, p-ANCA, anti-SS-A antibody, and anti-SS-B antibody).	('anti-CCP', 'Var', (172, 180))	('autoimmune diseases', 'Disease', (109, 128))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('c-ANCA', 'Gene', '5657', (191, 197))	('autoimmune diseases', 'Phenotype', 'HP:0002960', (109, 128))	('tumor', 'Disease', (62, 67))	('SS-A', 'Gene', '6737', (212, 216))	('c-ANCA', 'Gene', (191, 197))	('p-ANCA', 'Disease', (199, 205))	('SS-B', 'Gene', '6741', (236, 240))	('autoimmune diseases', 'Disease', 'MESH:D001327', (109, 128))	('SS-B', 'Gene', (236, 240))	('SS-A', 'Gene', (212, 216))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
239167	30410612	In the subgroup analysis, a significant relationship was observed between cytoplasmic p62 accumulation and both overall survival (HR 1.53, 95% CI: 1.03-2.27, P < 0.05) and disease-specific survival (HR 1.60, 95% CI: 1.15-2.24, P < 0.01).	('p62', 'Gene', '8878', (86, 89))	('p62', 'Gene', (86, 89))	('disease-specific survival', 'CPA', (172, 197))	('cytoplasmic', 'Var', (74, 85))	('accumulation', 'PosReg', (90, 102))	('overall survival', 'CPA', (112, 128))
239175	30410612	The dysregulation of autophagy is involved in a broad spectrum of diseases, such as cancer, heart diseases and neurodegeneration diseases.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('heart diseases', 'Disease', 'MESH:D006331', (92, 106))	('autophagy', 'CPA', (21, 30))	('cancer', 'Disease', (84, 90))	('involved', 'Reg', (34, 42))	('dysregulation', 'Var', (4, 17))	('heart diseases', 'Disease', (92, 106))	('neurodegeneration diseases', 'Disease', (111, 137))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('neurodegeneration', 'Phenotype', 'HP:0002180', (111, 128))	('neurodegeneration diseases', 'Disease', 'MESH:D019636', (111, 137))
239230	30410612	In esophageal cancer, high p62 level indicated a better OS (HR 0.55, 95% CI: 0.33-0.91, P < 0.05) with only one study included.	('OS', 'Chemical', '-', (56, 58))	('p62', 'Gene', '8878', (27, 30))	('esophageal cancer', 'Disease', (3, 20))	('p62', 'Gene', (27, 30))	('high', 'Var', (22, 26))	('esophageal cancer', 'Disease', 'MESH:D004938', (3, 20))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))
239291	29212307	During recent decades, a growing body of evidence suggests that NRF2 is frequently activated in many types of cancer by multiple mechanisms, including the genetic mutations in the KEAP1-NRF2 pathway.	('cancer', 'Disease', (110, 116))	('mutations', 'Var', (163, 172))	('KEAP1', 'Gene', '9817', (180, 185))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('KEAP1', 'Gene', (180, 185))	('NRF2', 'Gene', (64, 68))	('activated', 'PosReg', (83, 92))	('cancer', 'Disease', 'MESH:D009369', (110, 116))
239293	29212307	Recently, several NRF2 inhibitors have been reported with anti-tumor efficacy.	('tumor', 'Disease', (63, 68))	('NRF2', 'Gene', (18, 22))	('inhibitors', 'Var', (23, 33))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
239306	29212307	The IVR domain contains highly reactive cysteine residues, such as Cys273, Cys288, and Cys297, which are easily oxidized and are thus responsible for sensing oxidative stress.	('Cys288', 'Var', (75, 81))	('Cys288', 'Chemical', '-', (75, 81))	('oxidative stress', 'Phenotype', 'HP:0025464', (158, 174))	('Cys273', 'Var', (67, 73))	('cysteine', 'Chemical', 'MESH:D003545', (40, 48))	('Cys297', 'Var', (87, 93))	('Cys297', 'Chemical', '-', (87, 93))	('Cys273', 'Chemical', '-', (67, 73))
239312	29212307	Thus, promoting anti-oxidant defense in normal cells by activating NRF2 has been considered an attractive and promising strategy to prevent cancer development.	('promoting', 'PosReg', (6, 15))	('anti-oxidant defense', 'MPA', (16, 36))	('activating', 'Var', (56, 66))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('rat', 'Species', '10116', (122, 125))	('NRF2', 'Gene', (67, 71))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))
239314	29212307	Analysis in The Cancer Genome Atlas (TCGA) showed that genetic mutations leading to the activation of NRF2 were found in more than 20% of lung adenocarcinomas (LUAD) and 34% of lung squamous cell carcinomas (LUSC).	('mutations', 'Var', (63, 72))	('Cancer', 'Phenotype', 'HP:0002664', (16, 22))	('carcinomas', 'Phenotype', 'HP:0030731', (196, 206))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (16, 35))	('activation', 'PosReg', (88, 98))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (138, 158))	('carcinoma', 'Phenotype', 'HP:0030731', (148, 157))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (138, 158))	('carcinomas', 'Phenotype', 'HP:0030731', (148, 158))	('LUAD', 'Phenotype', 'HP:0030078', (160, 164))	('lung squamous cell carcinomas', 'Disease', (177, 206))	('lung squamous cell carcinomas', 'Disease', 'MESH:D002294', (177, 206))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (182, 206))	('carcinoma', 'Phenotype', 'HP:0030731', (196, 205))	('NRF2', 'Gene', (102, 106))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (182, 205))	('lung adenocarcinomas', 'Disease', (138, 158))	('Cancer Genome Atlas', 'Disease', (16, 35))
239316	29212307	Thus, these data strongly suggest that inhibition of NRF2, either alone or in combination, could be a promising therapeutic strategy for cancer.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('inhibition', 'Var', (39, 49))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('cancer', 'Disease', (137, 143))	('NRF2', 'Gene', (53, 57))	('rat', 'Species', '10116', (126, 129))
239317	29212307	In this review, we summarize the currently-known mechanisms of NRF2 dysregulation in cancer.	('NRF2', 'Gene', (63, 67))	('dysregulation', 'Var', (68, 81))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('cancer', 'Disease', (85, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
239322	29212307	In Lung Adenocarcinoma (LUAD), loss of function mutations in KEAP1 and CUL3 leading to the activation of NRF2 were found in 19% and less than 1%, respectively, while gain of function mutations in NRF2 were found in 3% of patients with cancer.	('KEAP1', 'Gene', (61, 66))	('CUL3', 'Gene', '8452', (71, 75))	('patients', 'Species', '9606', (221, 229))	('Lung Adenocarcinoma', 'Disease', (3, 22))	('CUL3', 'Gene', (71, 75))	('LUAD', 'Phenotype', 'HP:0030078', (24, 28))	('loss of', 'NegReg', (31, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (13, 22))	('cancer', 'Disease', (235, 241))	('cancer', 'Disease', 'MESH:D009369', (235, 241))	('activation', 'PosReg', (91, 101))	('Lung Adenocarcinoma', 'Phenotype', 'HP:0030078', (3, 22))	('Lung Adenocarcinoma', 'Disease', 'MESH:D000077192', (3, 22))	('NRF2', 'Gene', (105, 109))	('KEAP1', 'Gene', '9817', (61, 66))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))	('mutations', 'Var', (48, 57))	('gain of function', 'PosReg', (166, 182))
239323	29212307	By contrast, in lung squamous cell carcinoma (LUSC), loss of function mutations in KEAP1 and CUL3 leading to the activation of NRF2 were found in 12% and 7% respectively, while gain of function mutations in NRF2 were found in 19% of patients with cancer.	('lung squamous cell carcinoma', 'Disease', (16, 44))	('KEAP1', 'Gene', '9817', (83, 88))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (21, 44))	('mutations', 'Var', (70, 79))	('gain of function', 'PosReg', (177, 193))	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('carcinoma', 'Phenotype', 'HP:0030731', (35, 44))	('cancer', 'Disease', (247, 253))	('activation', 'PosReg', (113, 123))	('loss', 'NegReg', (53, 57))	('KEAP1', 'Gene', (83, 88))	('CUL3', 'Gene', '8452', (93, 97))	('cancer', 'Disease', 'MESH:D009369', (247, 253))	('patients', 'Species', '9606', (233, 241))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (16, 44))	('NRF2', 'Gene', (127, 131))	('CUL3', 'Gene', (93, 97))
239324	29212307	In addition to lung cancer, mutations in KEAP1 or NRF2 have been found in diverse cancer types, such as breast cancer, gastric cancer, colorectal cancer, prostate cancer, gall bladder cancer, ovarian cancer, liver cancer, and esophageal carcinoma.	('cancer', 'Disease', (184, 190))	('cancer', 'Disease', (146, 152))	('bladder cancer', 'Phenotype', 'HP:0009725', (176, 190))	('prostate cancer', 'Disease', (154, 169))	('gastric cancer', 'Disease', (119, 133))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (20, 26))	('breast cancer', 'Disease', 'MESH:D001943', (104, 117))	('breast cancer', 'Disease', (104, 117))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('found', 'Reg', (65, 70))	('cancer', 'Disease', (111, 117))	('lung cancer', 'Disease', (15, 26))	('cancer', 'Disease', 'MESH:D009369', (163, 169))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (226, 246))	('cancer', 'Disease', (214, 220))	('colorectal cancer', 'Disease', 'MESH:D015179', (135, 152))	('KEAP1', 'Gene', '9817', (41, 46))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('ovarian cancer', 'Disease', 'MESH:D010051', (192, 206))	('NRF2', 'Gene', (50, 54))	('KEAP1', 'Gene', (41, 46))	('gastric cancer', 'Disease', 'MESH:D013274', (119, 133))	('cancer', 'Disease', (127, 133))	('cancer', 'Disease', 'MESH:D009369', (200, 206))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('liver cancer', 'Disease', 'MESH:D006528', (208, 220))	('colorectal cancer', 'Disease', (135, 152))	('gall bladder cancer', 'Disease', 'MESH:D005706', (171, 190))	('carcinoma', 'Phenotype', 'HP:0030731', (237, 246))	('esophageal carcinoma', 'Disease', (226, 246))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('lung cancer', 'Disease', 'MESH:D008175', (15, 26))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('cancer', 'Disease', (20, 26))	('prostate cancer', 'Disease', 'MESH:D011471', (154, 169))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('liver cancer', 'Phenotype', 'HP:0002896', (208, 220))	('ovarian cancer', 'Disease', (192, 206))	('mutations', 'Var', (28, 37))	('cancer', 'Disease', (163, 169))	('lung cancer', 'Phenotype', 'HP:0100526', (15, 26))	('liver cancer', 'Disease', (208, 220))	('cancer', 'Disease', 'MESH:D009369', (214, 220))	('gastric cancer', 'Phenotype', 'HP:0012126', (119, 133))	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('ovarian cancer', 'Phenotype', 'HP:0100615', (192, 206))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (226, 246))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('colorectal cancer', 'Phenotype', 'HP:0003003', (135, 152))	('breast cancer', 'Phenotype', 'HP:0003002', (104, 117))	('gall bladder cancer', 'Disease', (171, 190))	('prostate cancer', 'Phenotype', 'HP:0012125', (154, 169))	('cancer', 'Disease', (200, 206))
239325	29212307	Notably, in contrast to the KEAP1 mutations, which occur throughout the gene and are either missense or nonsense mutations, all the mutations in NRF2 are found exclusively within regions encoding the DLG/ETGE motifs, which prevent KEAP1 binding.	('KEAP1', 'Gene', '9817', (28, 33))	('binding', 'Interaction', (237, 244))	('mutations', 'Var', (132, 141))	('KEAP1', 'Gene', (28, 33))	('KEAP1', 'Gene', '9817', (231, 236))	('NRF2', 'Gene', (145, 149))	('prevent', 'NegReg', (223, 230))	('KEAP1', 'Gene', (231, 236))
239328	29212307	In addition, the loss of function mutations in CUL3 and RBX1 leading to the activation of NRF2 have been reported frequently in sporadic papillary renal cell carcinoma (PRCC) and serous ovarian cancer, respectively.	('PRCC', 'Gene', '5546', (169, 173))	('papillary renal cell carcinoma', 'Disease', (137, 167))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (147, 167))	('serous ovarian cancer', 'Disease', 'MESH:D010051', (179, 200))	('CUL3', 'Gene', '8452', (47, 51))	('loss of function', 'NegReg', (17, 33))	('ovarian cancer', 'Phenotype', 'HP:0100615', (186, 200))	('carcinoma', 'Phenotype', 'HP:0030731', (158, 167))	('papillary renal cell carcinoma', 'Phenotype', 'HP:0006766', (137, 167))	('NRF2', 'Gene', (90, 94))	('RBX1', 'Gene', '9978', (56, 60))	('PRCC', 'Gene', (169, 173))	('serous ovarian cancer', 'Disease', (179, 200))	('papillary renal cell carcinoma', 'Disease', 'MESH:C538614', (137, 167))	('PRCC', 'Phenotype', 'HP:0006766', (169, 173))	('CUL3', 'Gene', (47, 51))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('RBX1', 'Gene', (56, 60))	('activation', 'PosReg', (76, 86))	('mutations', 'Var', (34, 43))
239329	29212307	Epigenetic modifications in KEAP1 and NRF2 promoter regions contribute to the activation of NRF2 in cancer.	('KEAP1', 'Gene', '9817', (28, 33))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('KEAP1', 'Gene', (28, 33))	('activation', 'PosReg', (78, 88))	('NRF2', 'Gene', (92, 96))	('Epigenetic modifications', 'Var', (0, 24))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))
239331	29212307	Importantly, methylation within the KEAP1 promoter region in patients with glioma is associated with poor prognosis.	('KEAP1', 'Gene', (36, 41))	('glioma', 'Phenotype', 'HP:0009733', (75, 81))	('methylation', 'Var', (13, 24))	('patients', 'Species', '9606', (61, 69))	('glioma', 'Disease', (75, 81))	('KEAP1', 'Gene', '9817', (36, 41))	('glioma', 'Disease', 'MESH:D005910', (75, 81))
239332	29212307	Recently, demethylation of NRF2 promoter regions resulting in the overexpression of NRF2 was also reported in drug-resistant colon cancer cells.	('colon cancer', 'Disease', 'MESH:D015179', (125, 137))	('NRF2', 'Gene', (27, 31))	('colon cancer', 'Disease', (125, 137))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('demethylation', 'Var', (10, 23))	('NRF2', 'Gene', (84, 88))	('colon cancer', 'Phenotype', 'HP:0003003', (125, 137))	('overexpression', 'PosReg', (66, 80))
239333	29212307	These observations suggest that reversal of KEAP1 methylation or NRF2 demethylation would inhibit NRF2 expression, which might contribute to a better outcome of chemotherapy.	('inhibit', 'NegReg', (90, 97))	('NRF2', 'Gene', (65, 69))	('KEAP1', 'Gene', (44, 49))	('expression', 'MPA', (103, 113))	('contribute', 'Reg', (127, 137))	('KEAP1', 'Gene', '9817', (44, 49))	('demethylation', 'Var', (70, 83))	('NRF2', 'Gene', (98, 102))
239342	29212307	In addition, p21 and breast cancer 1 (BRCA1) were shown to compete with KEAP1 for binding to the ETGE and/or DLG motifs of NRF2.	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('KEAP1', 'Gene', '9817', (72, 77))	('breast cancer 1', 'Gene', '672', (21, 36))	('DLG', 'Var', (109, 112))	('BRCA1', 'Gene', (38, 43))	('breast cancer', 'Phenotype', 'HP:0003002', (21, 34))	('breast cancer 1', 'Gene', (21, 36))	('KEAP1', 'Gene', (72, 77))	('p21', 'Gene', '1026', (13, 16))	('p21', 'Gene', (13, 16))	('binding', 'Interaction', (82, 89))	('BRCA1', 'Gene', '672', (38, 43))	('NRF2', 'Gene', (123, 127))
239344	29212307	Deficiency of the tricarboxylic acid cycle enzyme, fumarate hydratase (FH), in type 2 PRCC induces the accumulation of fumarate, which induces succinylation of cysteine residues in KEAP1, resulting in the accumulation of NRF2.	('NRF2', 'MPA', (221, 225))	('succinylation of cysteine residues', 'MPA', (143, 177))	('KEAP1', 'Gene', (181, 186))	('fumarate', 'Chemical', 'MESH:D005650', (119, 127))	('PRCC', 'Gene', '5546', (86, 90))	('cysteine', 'Chemical', 'MESH:D003545', (160, 168))	('FH', 'Gene', '2271', (71, 73))	('fumarate', 'Chemical', 'MESH:D005650', (51, 59))	('PRCC', 'Phenotype', 'HP:0006766', (86, 90))	('PRCC', 'Gene', (86, 90))	('accumulation', 'PosReg', (205, 217))	('fumarate hydratase', 'Gene', '2271', (51, 69))	('fumarate hydratase', 'Gene', (51, 69))	('induces', 'Reg', (135, 142))	('KEAP1', 'Gene', '9817', (181, 186))	('tricarboxylic acid', 'Chemical', 'MESH:D014233', (18, 36))	('Deficiency', 'Var', (0, 10))
239350	29212307	Importantly, this activation of NRF2 was shown to be critical for tumor growth and enhanced chemoresistance of K-Ras mutant cancer cells.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('cancer', 'Disease', (124, 130))	('tumor', 'Disease', (66, 71))	('mutant', 'Var', (117, 123))	('enhanced', 'PosReg', (83, 91))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('chemoresistance', 'CPA', (92, 107))	('NRF2', 'Gene', (32, 36))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('K-Ras mutant', 'Var', (111, 123))	('cancer', 'Disease', 'MESH:D009369', (124, 130))	('activation', 'PosReg', (18, 28))
239360	29212307	Collectively, considering that oxidative stress, inflammation, and nutrient deficiency in tumor microenvironment are activators of NRF2 as well as AMPK in tumors, hyperactivation of NRF2 would be a common phenomenon in most tumors in vivo, even in the absence of other alterations in the KEAP1-NRF2 pathway.	('NRF2', 'Gene', (182, 186))	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('tumors', 'Disease', (224, 230))	('AMPK', 'Gene', (147, 151))	('oxidative stress', 'Phenotype', 'HP:0025464', (31, 47))	('KEAP1', 'Gene', '9817', (288, 293))	('deficiency in tumor', 'Disease', 'MESH:D009369', (76, 95))	('KEAP1', 'Gene', (288, 293))	('tumors', 'Disease', 'MESH:D009369', (224, 230))	('tumors', 'Phenotype', 'HP:0002664', (155, 161))	('inflammation', 'Disease', 'MESH:D007249', (49, 61))	('deficiency in tumor', 'Disease', (76, 95))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('AMPK', 'Gene', '5562', (147, 151))	('tumors', 'Disease', (155, 161))	('inflammation', 'Disease', (49, 61))	('hyperactivation', 'Var', (163, 178))	('tumors', 'Phenotype', 'HP:0002664', (224, 230))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('rat', 'Species', '10116', (273, 276))	('tumors', 'Disease', 'MESH:D009369', (155, 161))
239362	29212307	Among the downregulated miRNAs in esophageal squamous cell carcinoma (ESCC), four miRNAs, miR-507, miR-634, miR-450a, and miR-129-5p, directly target and inhibit the expression of NRF2 and are associated with poor prognosis.	('miR-507', 'Gene', (90, 97))	('miR-634', 'Gene', '693219', (99, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (59, 68))	('downregulated', 'NegReg', (10, 23))	('miR-507', 'Gene', '574512', (90, 97))	('esophageal squamous cell carcinoma', 'Disease', (34, 68))	('inhibit', 'NegReg', (154, 161))	('NRF2', 'Gene', (180, 184))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (45, 68))	('miR-129-5p', 'Gene', '100302178', (122, 132))	('miR-634', 'Gene', (99, 106))	('miR-129-5p', 'Gene', (122, 132))	('expression', 'MPA', (166, 176))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (34, 68))	('miR-450a', 'Var', (108, 116))
239364	29212307	In addition, abnormal splicing of KEAP1 mRNA, resulting in nonfunctional KEAP1 protein that is unable to restrain NRF2, was reported in colon cancer cells.	('KEAP1', 'Gene', (34, 39))	('nonfunctional', 'MPA', (59, 72))	('KEAP1', 'Gene', '9817', (73, 78))	('colon cancer', 'Phenotype', 'HP:0003003', (136, 148))	('colon cancer', 'Disease', 'MESH:D015179', (136, 148))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('reported', 'Reg', (124, 132))	('KEAP1', 'Gene', (73, 78))	('abnormal splicing', 'Var', (13, 30))	('colon cancer', 'Disease', (136, 148))	('KEAP1', 'Gene', '9817', (34, 39))
239372	29212307	Although no inhibitors are currently clinically available or under clinical trial, some effective NRF2 inhibitors with potential antitumor efficacy have been reported.	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('inhibitors', 'Var', (103, 113))	('tumor', 'Disease', (133, 138))	('NRF2', 'Gene', (98, 102))
239381	29212307	Recently, it has been shown that K-RAS and B-RAF proto-oncogene, serine/threonine kinase (BRAF) mutant colorectal cancer cells are selectively sensitive to AA by overexpressing glucose transporter type 1 (GLUT1), which is responsible for the uptake of DHA.	('BRAF', 'Gene', (90, 94))	('GLUT1', 'Gene', (205, 210))	('glucose transporter type 1', 'Gene', '6513', (177, 203))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('K-RAS', 'Gene', (33, 38))	('colorectal cancer', 'Disease', 'MESH:D015179', (103, 120))	('mutant', 'Var', (96, 102))	('K-RAS', 'Gene', '3845', (33, 38))	('colorectal cancer', 'Disease', (103, 120))	('overexpressing', 'PosReg', (162, 176))	('RAF', 'Gene', '22882', (45, 48))	('GLUT1', 'Gene', '6513', (205, 210))	('DHA', 'Chemical', '-', (252, 255))	('serine', 'Chemical', 'MESH:D012694', (65, 71))	('RAF', 'Gene', '22882', (91, 94))	('RAF', 'Gene', (45, 48))	('colorectal cancer', 'Phenotype', 'HP:0003003', (103, 120))	('glucose transporter type 1', 'Gene', (177, 203))	('RAF', 'Gene', (91, 94))	('BRAF', 'Gene', '673', (90, 94))
239404	29212307	In the Hep3B hepatoma cell line, INH prevented nuclear translocation of NRF2 by inhibition of extracellular signal-regulated kinase 1 (ERK1) phosphorylation, which leads to the oxidative stress and apoptosis.	('ERK1', 'Gene', (135, 139))	('extracellular signal-regulated kinase 1', 'Gene', (94, 133))	('inhibition', 'NegReg', (80, 90))	('leads to', 'Reg', (164, 172))	('Hep3B', 'CellLine', 'CVCL:0326', (7, 12))	('extracellular signal-regulated kinase 1', 'Gene', '5595', (94, 133))	('NRF2', 'Gene', (72, 76))	('oxidative stress', 'MPA', (177, 193))	('hepatoma', 'Disease', (13, 21))	('ERK1', 'Gene', '5595', (135, 139))	('phosphorylation', 'MPA', (141, 156))	('nuclear translocation', 'MPA', (47, 68))	('hepatoma', 'Disease', 'MESH:D006528', (13, 21))	('prevented', 'NegReg', (37, 46))	('INH', 'Var', (33, 36))	('oxidative stress', 'Phenotype', 'HP:0025464', (177, 193))
239409	29212307	The anti-diabetic effects of metformin can be attributed, at least in part, to the activation of AMPK by inducing energetic stress caused by inhibition of mitochondrial metabolism.	('mitochondrial metabolism', 'MPA', (155, 179))	('diabetic', 'Disease', (9, 17))	('inhibition', 'NegReg', (141, 151))	('metformin', 'Chemical', 'MESH:D008687', (29, 38))	('energetic stress', 'MPA', (114, 130))	('inducing', 'PosReg', (105, 113))	('diabetic', 'Disease', 'MESH:D003920', (9, 17))	('metformin', 'Var', (29, 38))	('AMPK', 'Gene', '5562', (97, 101))	('AMPK', 'Gene', (97, 101))
239418	29212307	In contrast, a recent study showed that another class of anti-diabetic drug, dipeptidyl peptidase-4 (DPP-4) inhibitors, might potentially induce NRF2 activation, contributing to acceleration of cancer metastasis.	('rat', 'Species', '10116', (184, 187))	('diabetic', 'Disease', 'MESH:D003920', (62, 70))	('activation', 'PosReg', (150, 160))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('cancer metastasis', 'Disease', (194, 211))	('dipeptidyl peptidase-4', 'Gene', '1803', (77, 99))	('DPP-4', 'Gene', (101, 106))	('dipeptidyl peptidase-4', 'Gene', (77, 99))	('diabetic', 'Disease', (62, 70))	('DPP-4', 'Gene', '1803', (101, 106))	('acceleration', 'PosReg', (178, 190))	('inhibitors', 'Var', (108, 118))	('NRF2', 'Protein', (145, 149))	('cancer metastasis', 'Disease', 'MESH:D009362', (194, 211))
239419	29212307	DPP-4 inhibitors reduce blood glucose levels by increasing bioactive incretins, which promote glucose-dependent insulin secretion and inhibit glucagon secretion from the pancreas to maintain blood glucose homeostasis.	('reduce blood glucose', 'Phenotype', 'HP:0001943', (17, 37))	('DPP-4', 'Gene', '1803', (0, 5))	('glucose', 'Chemical', 'MESH:D005947', (94, 101))	('DPP-4', 'Gene', (0, 5))	('blood glucose homeostasis', 'Disease', (191, 216))	('bioactive incretins', 'MPA', (59, 78))	('glucose', 'Chemical', 'MESH:D005947', (197, 204))	('inhibit', 'NegReg', (134, 141))	('reduce', 'NegReg', (17, 23))	('glucose', 'Chemical', 'MESH:D005947', (30, 37))	('promote', 'PosReg', (86, 93))	('blood glucose levels', 'MPA', (24, 44))	('increasing', 'PosReg', (48, 58))	('inhibitors', 'Var', (6, 16))	('blood glucose homeostasis', 'Disease', 'MESH:D006402', (191, 216))	('glucagon secretion from the pancreas', 'MPA', (142, 178))	('glucose-dependent insulin secretion', 'Disease', (94, 129))	('glucose-dependent insulin secretion', 'Disease', 'MESH:D003922', (94, 129))
239420	29212307	However, the mechanisms by which DPP-4 inhibitors induce NRF2 activity are largely unknown.	('inhibitors', 'Var', (39, 49))	('NRF2', 'Protein', (57, 61))	('activity', 'MPA', (62, 70))	('DPP-4', 'Gene', (33, 38))	('DPP-4', 'Gene', '1803', (33, 38))	('induce', 'PosReg', (50, 56))
239437	29212307	Furthermore, CP, alone or in combination with the mTORC1 inhibitor rapamycin, strongly inhibited the in vitro and in vivo growth of tumors harboring mutations in KEAP1 or in both KEAP1 and liver kinase B1 (LKB1) that are frequently observed in lung cancer.	('rapamycin', 'Chemical', 'MESH:D020123', (67, 76))	('cancer', 'Phenotype', 'HP:0002664', (249, 255))	('mTORC1', 'Gene', (50, 56))	('LKB1', 'Gene', '6794', (206, 210))	('lung cancer', 'Disease', (244, 255))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('liver kinase B1', 'Gene', '6794', (189, 204))	('mTORC1', 'Gene', '382056', (50, 56))	('liver kinase B1', 'Gene', (189, 204))	('mutations', 'Var', (149, 158))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('inhibited', 'NegReg', (87, 96))	('tumors', 'Disease', (132, 138))	('KEAP1', 'Gene', '9817', (179, 184))	('lung cancer', 'Disease', 'MESH:D008175', (244, 255))	('KEAP1', 'Gene', (179, 184))	('LKB1', 'Gene', (206, 210))	('KEAP1', 'Gene', '9817', (162, 167))	('lung cancer', 'Phenotype', 'HP:0100526', (244, 255))	('KEAP1', 'Gene', (162, 167))	('tumors', 'Disease', 'MESH:D009369', (132, 138))	('growth', 'CPA', (122, 128))
239441	29212307	A growing body of evidence has revealed frequent activation of NRF2 via diverse mechanisms in most cancers; therefore, inhibition of NRF2 should be a promising therapeutic strategy to treat cancer.	('cancer', 'Disease', (190, 196))	('cancer', 'Disease', 'MESH:D009369', (190, 196))	('NRF2', 'Gene', (63, 67))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('cancers', 'Disease', 'MESH:D009369', (99, 106))	('inhibition', 'Var', (119, 129))	('cancers', 'Phenotype', 'HP:0002664', (99, 106))	('cancer', 'Disease', (99, 105))	('cancers', 'Disease', (99, 106))	('rat', 'Species', '10116', (174, 177))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('NRF2', 'Gene', (133, 137))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('activation', 'PosReg', (49, 59))
239464	27966459	Aberration and abnormal expression of proteasome subunits have been demonstrated in many tumors including breast cancer, lung cancer, hepatocellular carcinoma and colorectal cancer.	('tumors', 'Disease', (89, 95))	('lung cancer', 'Disease', 'MESH:D008175', (121, 132))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('abnormal', 'Var', (15, 23))	('lung cancer', 'Phenotype', 'HP:0100526', (121, 132))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (134, 158))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('expression', 'MPA', (24, 34))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('demonstrated', 'Reg', (68, 80))	('colorectal cancer', 'Phenotype', 'HP:0003003', (163, 180))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('Aberration', 'Var', (0, 10))	('proteasome subunits', 'Protein', (38, 57))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('hepatocellular carcinoma', 'Disease', (134, 158))	('carcinoma', 'Phenotype', 'HP:0030731', (149, 158))	('breast cancer', 'Phenotype', 'HP:0003002', (106, 119))	('lung cancer', 'Disease', (121, 132))	('breast cancer', 'Disease', 'MESH:D001943', (106, 119))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('breast cancer', 'Disease', (106, 119))	('colorectal cancer', 'Disease', 'MESH:D015179', (163, 180))	('colorectal cancer', 'Disease', (163, 180))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (134, 158))
239470	27966459	Polymorphisms in PSMA4 contribute to lung cancer susceptibility, and upregulated PSMA4 in lung cancer plays an important role in regulating cell proliferation and apoptosis.	('apoptosis', 'CPA', (163, 172))	('cell proliferation', 'CPA', (140, 158))	('lung cancer', 'Disease', (37, 48))	('lung cancer', 'Disease', 'MESH:D008175', (90, 101))	('lung cancer', 'Phenotype', 'HP:0100526', (37, 48))	('PSMA4', 'Gene', '5685', (17, 22))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('Polymorphisms', 'Var', (0, 13))	('PSMA4', 'Gene', (81, 86))	('contribute', 'Reg', (23, 33))	('lung cancer', 'Disease', (90, 101))	('lung cancer', 'Phenotype', 'HP:0100526', (90, 101))	('PSMA4', 'Gene', (17, 22))	('upregulated', 'PosReg', (69, 80))	('lung cancer', 'Disease', 'MESH:D008175', (37, 48))	('PSMA4', 'Gene', '5685', (81, 86))
239498	27966459	The results showed that high expression of PSMA1 (HR = 1.48; 95% CI: 1.32-1.67; p < 0.001), PSMA2 ( HR = 1.14; 95% CI: 1.02-1.28; p = 0.021), PSMA3 (HR = 1.34, 95% CI: 1.19-1.50; p < 0.001), PSMA4 (HR = 1.53; 95% CI: 1.36-1.71; p < 0.001), PSMA5 (HR = 0.71; 95% CI: 0.60-0.84; p < 0.001), PSMA6 (HR = 1.39; 95% CI: 1.24-1.56; p < 0.001) and PSMA7 (HR = 1.50; 95% CI: 1.33-1.68; p < 0.001) were all significantly associated with relapse free survival (RFS) (Table 2).	('PSMA7', 'Gene', '5688', (341, 346))	('PSMA6', 'Var', (289, 294))	('associated with', 'Reg', (412, 427))	('PSMA3', 'Gene', (142, 147))	('PSMA5', 'Gene', (240, 245))	('PSMA4', 'Gene', (191, 196))	('PSMA2', 'Gene', '5683', (92, 97))	('PSMA3', 'Gene', '5684', (142, 147))	('PSMA7', 'Gene', (341, 346))	('FS', 'Chemical', 'MESH:D005461', (452, 454))	('PSMA5', 'Gene', '5686', (240, 245))	('PSMA1', 'Gene', (43, 48))	('relapse free', 'Disease', (428, 440))	('PSMA4', 'Gene', '5685', (191, 196))	('PSMA2', 'Gene', (92, 97))	('PSMA1', 'Gene', '5682', (43, 48))
239502	27966459	In addition, high expression of PSMA5 was associated with better prognosis in patients with the luminal A or basal-like types, which was consistent with the overall cohort.	('basal-like types', 'CPA', (109, 125))	('better', 'PosReg', (58, 64))	('PSMA5', 'Gene', '5686', (32, 37))	('high expression', 'Var', (13, 28))	('patients', 'Species', '9606', (78, 86))	('PSMA5', 'Gene', (32, 37))	('prognosis', 'CPA', (65, 74))	('luminal', 'Disease', (96, 103))
239521	27966459	In addition, high mRNA level of PSMA4 was significantly associated with FP (HR = 0.80; 95% CI: 0.66-0.97; p = 0.021) but not OS or PPS.	('PSMA4', 'Gene', (32, 37))	('OS', 'Chemical', '-', (125, 127))	('high', 'Var', (13, 17))	('mRNA level', 'MPA', (18, 28))	('associated', 'Reg', (56, 66))	('PSMA4', 'Gene', '5685', (32, 37))	('PPS', 'Chemical', '-', (131, 134))
239523	27966459	On the contrary, high PSMA6 expression was associated with worse OS (HR = 1.33; 95% CI: 0.1.17-1.51; p < 0.001) and FP (HR = 1.37; 95% CI: 1.13-1.66; p = 0.001) but not PPS for lung cancer patients.	('worse OS', 'Disease', (59, 67))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('OS', 'Chemical', '-', (65, 67))	('lung cancer', 'Disease', 'MESH:D008175', (177, 188))	('high PSMA6 expression', 'Var', (17, 38))	('lung cancer', 'Disease', (177, 188))	('patients', 'Species', '9606', (189, 197))	('PPS', 'Chemical', '-', (169, 172))	('lung cancer', 'Phenotype', 'HP:0100526', (177, 188))
239539	27966459	In line with the overall cohort, the expression of all PSMAs was significantly correlated with better prognosis in the HER2-negative group.	('HER2', 'Gene', '2064', (119, 123))	('expression', 'Var', (37, 47))	('HER2', 'Gene', (119, 123))	('PSMAs', 'Gene', (55, 60))
239560	27966459	The expression levels of PSMA1-3 and PSMA6 were higher in kidney clear cell carcinoma than in normal samples.	('expression levels', 'MPA', (4, 21))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('PSMA1', 'Gene', (25, 30))	('PSMA6', 'Var', (37, 42))	('PSMA1', 'Gene', '5682', (25, 30))	('higher', 'PosReg', (48, 54))	('kidney clear cell carcinoma', 'Disease', 'MESH:C538614', (58, 85))	('kidney clear cell carcinoma', 'Disease', (58, 85))
239586	27966459	In ovarian cancer, high expression of PSMB4 was closely related to tumor grade, tumor stage, lymph node, ascites and Ki-67, as well as worse OS.	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('ovarian cancer', 'Disease', 'MESH:D010051', (3, 17))	('tumor', 'Disease', (67, 72))	('ascites', 'Disease', (105, 112))	('expression', 'MPA', (24, 34))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('ovarian cancer', 'Disease', (3, 17))	('ascites', 'Disease', 'MESH:D001201', (105, 112))	('ovarian cancer', 'Phenotype', 'HP:0100615', (3, 17))	('OS', 'Chemical', '-', (141, 143))	('tumor', 'Disease', (80, 85))	('worse OS', 'Disease', (135, 143))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('high', 'Var', (19, 23))	('ascites', 'Phenotype', 'HP:0001541', (105, 112))	('PSMB4', 'Gene', (38, 43))	('lymph node', 'Disease', (93, 103))	('related', 'Reg', (56, 63))
239588	27966459	demonstrated that positive expression of PSMD9 was significantly correlated with higher rates of local recurrence after radiotherapy in breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('breast cancer', 'Disease', 'MESH:D001943', (136, 149))	('breast cancer', 'Disease', (136, 149))	('breast cancer', 'Phenotype', 'HP:0003002', (136, 149))	('positive', 'Var', (18, 26))	('PSMD9', 'Gene', (41, 46))	('local recurrence', 'CPA', (97, 113))	('PSMD9', 'Gene', '5715', (41, 46))	('correlated', 'Reg', (65, 75))
239593	27966459	In the present study, we found that high expression of PSMA1-4 and PSMA6-7 was significantly associated with worse prognosis in breast cancer, while PSMA5 was related to better OS, RFS and DMFS.	('high expression', 'Var', (36, 51))	('FS', 'Chemical', 'MESH:D005461', (182, 184))	('PSMA5', 'Gene', '5686', (149, 154))	('PSMA6-7', 'Gene', '5687;5688', (67, 74))	('DMFS', 'Chemical', '-', (189, 193))	('OS', 'Chemical', '-', (177, 179))	('PSMA6-7', 'Gene', (67, 74))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('PSMA5', 'Gene', (149, 154))	('PSMA1-4', 'Gene', '5682;5683;5684;5685', (55, 62))	('FS', 'Chemical', 'MESH:D005461', (191, 193))	('breast cancer', 'Disease', (128, 141))	('breast cancer', 'Disease', 'MESH:D001943', (128, 141))	('breast cancer', 'Phenotype', 'HP:0003002', (128, 141))	('PSMA1-4', 'Gene', (55, 62))
239595	27966459	In lung cancer, PSMA1-2, PSMA4 and PSMA5 were correlated with better prognosis, whereas PSMA6 and PSMA7 predicted worse survival outcomes.	('PSMA1-2', 'Gene', (16, 23))	('lung cancer', 'Disease', (3, 14))	('lung cancer', 'Phenotype', 'HP:0100526', (3, 14))	('PSMA1-2', 'Gene', '5682;5683', (16, 23))	('PSMA6', 'Var', (88, 93))	('PSMA5', 'Gene', (35, 40))	('PSMA7', 'Gene', '5688', (98, 103))	('PSMA4', 'Gene', '5685', (25, 30))	('lung cancer', 'Disease', 'MESH:D008175', (3, 14))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('PSMA4', 'Gene', (25, 30))	('PSMA7', 'Gene', (98, 103))	('PSMA5', 'Gene', '5686', (35, 40))
239604	27966459	Although PMSA7 knockdown in colorectal cancer cell line RKO showed no impact on proliferation or cell cycle, depletion of PSMA7 was demonstrated to significantly suppress tumor formation in vitro and in vivo, as well as inhibit RKO cell invasion and migration.	('colorectal cancer', 'Phenotype', 'HP:0003003', (28, 45))	('suppress', 'NegReg', (162, 170))	('RKO', 'CellLine', 'CVCL:0504', (56, 59))	('RKO cell invasion', 'CPA', (228, 245))	('depletion', 'Var', (109, 118))	('colorectal cancer', 'Disease', (28, 45))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('migration', 'CPA', (250, 259))	('PSMA7', 'Gene', '5688', (122, 127))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('inhibit', 'NegReg', (220, 227))	('cell cycle', 'CPA', (97, 107))	('tumor', 'Disease', (171, 176))	('colorectal cancer', 'Disease', 'MESH:D015179', (28, 45))	('PSMA7', 'Gene', (122, 127))	('RKO', 'CellLine', 'CVCL:0504', (228, 231))
239635	26008846	Urobasal A (UroA) tumors show papillary growth, good prognosis and frequent mutation and expression of FGFR3.	('expression', 'MPA', (89, 99))	('FGFR3', 'Gene', '2261', (103, 108))	('papillary growth', 'Phenotype', 'HP:0007482', (30, 46))	('UroA', 'Chemical', '-', (12, 16))	('FGFR3', 'Gene', (103, 108))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('tumors', 'Disease', (18, 24))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('mutation', 'Var', (76, 84))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
239637	26008846	Genomically Unstable (GU) tumors are undifferentiated, highly proliferative and characterized by frequent E2F3/SOX4 amplifications, RB1 deletions, TP53 mutations and ERBB2 expression.	('SOX4', 'Gene', (111, 115))	('TP53', 'Gene', (147, 151))	('mutations', 'Var', (152, 161))	('SOX4', 'Gene', '6659', (111, 115))	('deletions', 'Var', (136, 145))	('RB1', 'Gene', (132, 135))	('ERBB2', 'Gene', '2064', (166, 171))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('ERBB2', 'Gene', (166, 171))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('RB1', 'Gene', '5925', (132, 135))	('E2F3', 'Gene', '1871', (106, 110))	('TP53', 'Gene', '7157', (147, 151))	('E2F3', 'Gene', (106, 110))	('tumors', 'Disease', (26, 32))	('Genomically Unstable', 'Disease', (0, 20))
239639	26008846	We identify loss of PPARG and ADIRF, a novel regulator of fatty acid metabolism, as well as upregulation of STAT3 expression, as putative mediators of the SCCL phenotype.	('STAT3 expression', 'MPA', (108, 124))	('ADIRF', 'Gene', '10974', (30, 35))	('upregulation', 'PosReg', (92, 104))	('loss', 'Var', (12, 16))	('PPARG', 'Gene', (20, 25))	('ADIRF', 'Gene', (30, 35))	('fatty acid', 'Chemical', 'MESH:D005227', (58, 68))
239657	26008846	PPARG and RXRA cooperate as heterodimers and induce differentiation though the transcription factors ELF3, FOXA1 and members of the GATA transcription factor family (Additional file 2: Figure S1).	('GATA', 'Gene', '55278', (132, 136))	('ELF3', 'Gene', (101, 105))	('ELF3', 'Gene', '1999', (101, 105))	('FOXA1', 'Gene', (107, 112))	('induce', 'PosReg', (45, 51))	('differentiation', 'CPA', (52, 67))	('PPARG', 'Var', (0, 5))	('GATA', 'Gene', (132, 136))
239724	26008846	Methylation of TBX2 and TBX3 has been found to be associated with urothelial tumor progression, however their full role in urothelial carcinoma is not yet clear.	('urothelial tumor', 'Disease', 'MESH:D001749', (66, 82))	('Methylation', 'Var', (0, 11))	('TBX3', 'Gene', '6926', (24, 28))	('urothelial carcinoma', 'Disease', (123, 143))	('TBX2', 'Gene', '6909', (15, 19))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('TBX3', 'Gene', (24, 28))	('urothelial tumor', 'Disease', (66, 82))	('TBX2', 'Gene', (15, 19))	('associated', 'Reg', (50, 60))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (123, 143))
239778	32143735	Further stratification analyses revealed that this 10 immune-related gene signature was still an effective tool for predicting prognosis in smoking or nonsmoking patients, patients with KRAS mutation or KRAS wild-type, and patients with EGFR mutation or EGFR wild-type.	('KRAS', 'Gene', (203, 207))	('patients', 'Species', '9606', (162, 170))	('EGFR', 'Gene', '1956', (237, 241))	('KRAS', 'Gene', '3845', (203, 207))	('EGFR', 'Gene', (254, 258))	('KRAS', 'Gene', (186, 190))	('EGFR', 'Gene', (237, 241))	('KRAS', 'Gene', '3845', (186, 190))	('patients', 'Species', '9606', (172, 180))	('patients', 'Species', '9606', (223, 231))	('mutation', 'Var', (191, 199))	('EGFR', 'Gene', '1956', (254, 258))
239785	32143735	For example, epidermal growth factor receptor (EGFR) mutations are more frequent in LUAD than in LUSC.	('epidermal growth factor receptor', 'Gene', (13, 45))	('epidermal growth factor receptor', 'Gene', '1956', (13, 45))	('mutations', 'Var', (53, 62))	('LUAD', 'Phenotype', 'HP:0030078', (84, 88))	('EGFR', 'Gene', '1956', (47, 51))	('LUAD', 'Disease', (84, 88))	('LUAD', 'Disease', 'MESH:C538231', (84, 88))	('frequent', 'Reg', (72, 80))	('EGFR', 'Gene', (47, 51))
239790	32143735	For example, PD-L1 expression is a predictive biomarker for worse prognosis of NSCLC and the probability of clinical benefit from immune-modulating drugs is greater in NSCLC patients expressing PD-L1.	('PD-L1', 'Var', (194, 199))	('expression', 'MPA', (19, 29))	('NSCLC', 'Disease', 'MESH:D002289', (79, 84))	('greater', 'PosReg', (157, 164))	('NSCLC', 'Disease', 'MESH:D002289', (168, 173))	('NSCLC', 'Disease', (79, 84))	('patients', 'Species', '9606', (174, 182))	('NSCLC', 'Phenotype', 'HP:0030358', (168, 173))	('NSCLC', 'Phenotype', 'HP:0030358', (79, 84))	('PD-L1', 'Gene', (13, 18))	('NSCLC', 'Disease', (168, 173))
239801	32143735	Finally, 226 patients from GSE31210 (validation set 1) and 398 cases from GSE72094 (validation set 2) were included.	('set 1', 'Gene', '9739', (48, 53))	('set 2', 'Gene', (95, 100))	('patients', 'Species', '9606', (13, 21))	('GSE31210', 'Var', (27, 35))	('set 1', 'Gene', (48, 53))	('set 2', 'Gene', '29072', (95, 100))
239825	32143735	The results demonstrated that high-risk LUAD patients in each stratum of age, gender, smoking behavior, KRAS mutation, and EGFR mutation status presented worse survival than low-risk LUAD patients (all P values < 0.05) (Figs.	('EGFR', 'Gene', (123, 127))	('EGFR', 'Gene', '1956', (123, 127))	('LUAD', 'Disease', (183, 187))	('KRAS', 'Gene', '3845', (104, 108))	('LUAD', 'Disease', 'MESH:C538231', (183, 187))	('survival', 'MPA', (160, 168))	('LUAD', 'Phenotype', 'HP:0030078', (183, 187))	('patients', 'Species', '9606', (188, 196))	('LUAD', 'Disease', (40, 44))	('LUAD', 'Disease', 'MESH:C538231', (40, 44))	('patients', 'Species', '9606', (45, 53))	('LUAD', 'Phenotype', 'HP:0030078', (40, 44))	('KRAS', 'Gene', (104, 108))	('mutation', 'Var', (128, 136))	('worse', 'NegReg', (154, 159))	('mutation', 'Var', (109, 117))
239846	32143735	reported that high ImmuneScore was associated with favorable prognosis in LUAD.	('high', 'Var', (14, 18))	('LUAD', 'Phenotype', 'HP:0030078', (74, 78))	('LUAD', 'Disease', (74, 78))	('LUAD', 'Disease', 'MESH:C538231', (74, 78))	('ImmuneScore', 'MPA', (19, 30))
239867	32143735	CD40LG polymorphism is related to various immunological disorders such as tumors.	('polymorphism', 'Var', (7, 19))	('related', 'Reg', (23, 30))	('immunological disorders', 'Disease', 'MESH:D007154', (42, 65))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('immunological disorders', 'Phenotype', 'HP:0002715', (42, 65))	('CD40LG', 'Gene', '959', (0, 6))	('CD40LG', 'Gene', (0, 6))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('tumors', 'Disease', 'MESH:D009369', (74, 80))	('immunological disorders', 'Disease', (42, 65))	('tumors', 'Disease', (74, 80))
239883	32143735	reported that EGFR mutations were closely correlated with therapeutic efficacy and progression-free survival in LUAD.	('LUAD', 'Disease', 'MESH:C538231', (112, 116))	('EGFR', 'Gene', '1956', (14, 18))	('EGFR', 'Gene', (14, 18))	('mutations', 'Var', (19, 28))	('therapeutic efficacy', 'CPA', (58, 78))	('correlated', 'Reg', (42, 52))	('LUAD', 'Phenotype', 'HP:0030078', (112, 116))	('LUAD', 'Disease', (112, 116))
239905	31666604	The recent studies have shown that the disorder in the function of miRNA leads to a variety of diseases, involving cancer, cardiovascular complications and neurological disorders, etc.	('neurological disorders', 'Disease', 'MESH:D009422', (156, 178))	('cancer', 'Disease', (115, 121))	('disorder', 'Var', (39, 47))	('neurological disorders', 'Disease', (156, 178))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('leads to', 'Reg', (73, 81))	('function', 'MPA', (55, 63))	('cardiovascular complications', 'Phenotype', 'HP:0001626', (123, 151))	('miRNA', 'Gene', (67, 72))	('cardiovascular complications', 'Disease', (123, 151))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('cardiovascular complications', 'Disease', 'MESH:D002318', (123, 151))
239925	31666604	However, the expression of crg-miR-504 (0.3235 +- 0.01582 vs 1.254 +- 0.04585) and Novel-117 (0.3891 +- 0.05357 vs 1.2450 +- 0.05247) were significant lower than the normal group (p < 0.001), and Novel-135 (0.7811 +- 0.02293 vs 1.097 +- 0.1015) was also lower (p < 0.05).	('miR-504', 'Gene', '102464946', (31, 38))	('expression', 'MPA', (13, 23))	('lower', 'NegReg', (254, 259))	('0.3891 +- 0.05357', 'Var', (94, 111))	('lower', 'NegReg', (151, 156))	('0.3235 +- 0.01582', 'Var', (40, 57))	('miR-504', 'Gene', (31, 38))
239927	31666604	The mutation or deletion of PTEN causes the continuous activation of AKT, which enhances the transcriptional and expressive activity of the anti-apoptotic gene.	('PTEN', 'Gene', (28, 32))	('enhances', 'PosReg', (80, 88))	('transcriptional', 'MPA', (93, 108))	('deletion', 'Var', (16, 24))	('mutation', 'Var', (4, 12))	('PTEN', 'Gene', '100764294', (28, 32))	('expressive activity', 'MPA', (113, 132))	('AKT', 'Pathway', (69, 72))	('activation', 'PosReg', (55, 65))
239946	31666604	revealed that the expression of exogenous miR-146a-5p could activate the downstream JNK of its target, further has an impact on apoptosis and proliferation of cells with OSCC.	('proliferation', 'CPA', (142, 155))	('OSCC', 'Disease', (170, 174))	('miR-146a', 'Gene', '102466527', (42, 50))	('exogenous', 'Var', (32, 41))	('miR-146a', 'Gene', (42, 50))	('OSCC', 'Disease', 'MESH:D002294', (170, 174))	('activate', 'PosReg', (60, 68))	('impact', 'Reg', (118, 124))	('apoptosis', 'CPA', (128, 137))
239948	31666604	Meanwhile, miRNAs can also affect the occurrence and development of OSCC by regulating the specific cellular components in OSCC cells.	('specific cellular', 'MPA', (91, 108))	('OSCC', 'Disease', 'MESH:D002294', (123, 127))	('affect', 'Reg', (27, 33))	('OSCC', 'Disease', (123, 127))	('OSCC', 'Disease', (68, 72))	('OSCC', 'Disease', 'MESH:D002294', (68, 72))	('occurrence', 'CPA', (38, 48))	('regulating', 'Reg', (76, 86))	('miRNAs', 'Var', (11, 17))	('development', 'CPA', (53, 64))
239949	31666604	found that miRNA-10a could cause GLUT1 high expression, which leads to the acceleration of glucose metabolism, and further promotes the growth of OSCC cells.	('OSCC', 'Disease', (146, 150))	('promotes', 'PosReg', (123, 131))	('growth', 'MPA', (136, 142))	('glucose metabolism', 'Disease', (91, 109))	('OSCC', 'Disease', 'MESH:D002294', (146, 150))	('cause', 'Reg', (27, 32))	('GLUT1', 'Gene', '100753506', (33, 38))	('miRNA-10a', 'Var', (11, 20))	('acceleration', 'PosReg', (75, 87))	('glucose metabolism', 'Disease', 'MESH:D044882', (91, 109))	('GLUT1', 'Gene', (33, 38))
239953	31666604	were up-regulated, while miR-133a, miR-376c, and miR-411, et al., were down-regulated in OSCC.	('down-regulated', 'NegReg', (71, 85))	('OSCC', 'Disease', 'MESH:D002294', (89, 93))	('miR-411', 'Gene', (49, 56))	('miR-133a', 'Gene', (25, 33))	('up-regulated', 'PosReg', (5, 17))	('miR-376c', 'Var', (35, 43))	('OSCC', 'Disease', (89, 93))
239958	31666604	demonstrated that knockdown of miR-21 could significantly inhibit the migration of breast cancer cells in vitro and the growth of transplanted tumors in vivo.	('knockdown', 'Var', (18, 27))	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('migration of', 'CPA', (70, 82))	('breast cancer', 'Disease', 'MESH:D001943', (83, 96))	('tumors', 'Disease', (143, 149))	('tumors', 'Disease', 'MESH:D009369', (143, 149))	('miR-21', 'Gene', (31, 37))	('breast cancer', 'Disease', (83, 96))	('breast cancer', 'Phenotype', 'HP:0003002', (83, 96))	('inhibit', 'NegReg', (58, 65))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
239960	31666604	According to the previous report and our prediction, plenty of tumor suppressor genes including PDCD4 and PTEN were confirmed as targets of miR-21.	('PTEN', 'Gene', '100764294', (106, 110))	('tumor', 'Disease', (63, 68))	('miR-21', 'Var', (140, 146))	('PDCD4', 'Gene', '100766922', (96, 101))	('PDCD4', 'Gene', (96, 101))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('PTEN', 'Gene', (106, 110))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
239962	31666604	The mutation or deletion of PTEN causes the continuous activation of AKT, which enhances the transcriptional and expressive activity of Bcl-2, at the same time Serl84 residue of Bax was deactivated, thereby suppressing apoptosis and promoting cell survival.	('Bax', 'Gene', '100689032', (178, 181))	('mutation', 'Var', (4, 12))	('expressive activity', 'MPA', (113, 132))	('Bcl-2', 'Gene', '100774873', (136, 141))	('PTEN', 'Gene', (28, 32))	('deletion', 'Var', (16, 24))	('PTEN', 'Gene', '100764294', (28, 32))	('deactivated', 'NegReg', (186, 197))	('apoptosis', 'CPA', (219, 228))	('enhances', 'PosReg', (80, 88))	('promoting', 'PosReg', (233, 242))	('transcriptional', 'MPA', (93, 108))	('Serl84', 'MPA', (160, 166))	('Bcl-2', 'Gene', (136, 141))	('suppressing', 'NegReg', (207, 218))	('activation', 'PosReg', (55, 65))	('Bax', 'Gene', (178, 181))	('AKT', 'Pathway', (69, 72))	('cell survival', 'CPA', (243, 256))
239967	31666604	These results supported the opinion that the miR-21 may affect the occurrence of oral cancer by restraining the expression of PTEN, which regulated the expression of apoptotic protein through the PI3K/Akt signal pathway.	('affect', 'Reg', (56, 62))	('expression', 'MPA', (112, 122))	('oral cancer', 'Disease', (81, 92))	('PI3K/Akt signal pathway', 'Pathway', (196, 219))	('PTEN', 'Gene', '100764294', (126, 130))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('miR-21', 'Var', (45, 51))	('regulated', 'Reg', (138, 147))	('expression of', 'MPA', (152, 165))	('PTEN', 'Gene', (126, 130))	('oral cancer', 'Disease', 'MESH:D009062', (81, 92))	('restraining', 'NegReg', (96, 107))
239994	31383000	Characterisation of DNA methylation changes in EBF3 and TBC1D16 associated with tumour progression and metastasis in multiple cancer types Characteristic DNA methylation differences have been identified between primary and metastatic melanomas at EBF3 and/or TBC1D16 gene loci.	('EBF3', 'Gene', '253738', (47, 51))	('melanomas', 'Disease', (234, 243))	('TBC1D16', 'Gene', (56, 63))	('associated', 'Reg', (64, 74))	('changes', 'Var', (36, 43))	('cancer', 'Disease', (126, 132))	('TBC1D16', 'Gene', (259, 266))	('melanomas', 'Phenotype', 'HP:0002861', (234, 243))	('EBF3', 'Gene', (247, 251))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('TBC1D16', 'Gene', '125058', (56, 63))	('EBF3', 'Gene', '253738', (247, 251))	('tumour', 'Phenotype', 'HP:0002664', (80, 86))	('tumour', 'Disease', 'MESH:D009369', (80, 86))	('melanoma', 'Phenotype', 'HP:0002861', (234, 242))	('tumour', 'Disease', (80, 86))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('TBC1D16', 'Gene', '125058', (259, 266))	('melanomas', 'Disease', 'MESH:D008545', (234, 243))	('EBF3', 'Gene', (47, 51))
239998	31383000	These findings suggest characteristic DNA methylation changes in EBF3 and TBC1D16 are relatively common tumour-associated epigenetic events in multiple tumour types, which is consistent with a potential role as more general drivers of tumour progression.	('tumour', 'Disease', 'MESH:D009369', (152, 158))	('EBF3', 'Gene', (65, 69))	('tumour', 'Disease', (152, 158))	('tumour', 'Disease', 'MESH:D009369', (235, 241))	('tumour', 'Disease', (235, 241))	('DNA methylation changes', 'Var', (38, 61))	('tumour', 'Phenotype', 'HP:0002664', (104, 110))	('tumour', 'Disease', 'MESH:D009369', (104, 110))	('TBC1D16', 'Gene', '125058', (74, 81))	('tumour', 'Phenotype', 'HP:0002664', (152, 158))	('EBF3', 'Gene', '253738', (65, 69))	('tumour', 'Phenotype', 'HP:0002664', (235, 241))	('TBC1D16', 'Gene', (74, 81))	('tumour', 'Disease', (104, 110))
240000	31383000	Over the recent decades, many mutations have been identified that promote tumour growth (i.e.	('promote', 'PosReg', (66, 73))	('mutations', 'Var', (30, 39))	('tumour growth', 'Disease', (74, 87))	('tumour', 'Phenotype', 'HP:0002664', (74, 80))	('tumour growth', 'Disease', 'MESH:D006130', (74, 87))
240001	31383000	However, evidence for the existence of unique or metastasis-specific genetic mutations that drive cancer metastasis has remained elusive.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('mutations', 'Var', (77, 86))	('cancer metastasis', 'Disease', (98, 115))	('cancer metastasis', 'Disease', 'MESH:D009362', (98, 115))
240002	31383000	Although metastatic tumour cells are responsible for at least 90% of cancer-related deaths, which is in part due to their ability to spread to distant organs via the lymphatics or circulatory systems, recently, Vogelstein and colleagues have suggested that due to the lack of metastasis-specific mutations being identified from large-scale next-generation sequencing approaches, specific driver gene mutations causing metastasis do not exist.	('tumour', 'Disease', 'MESH:D009369', (20, 26))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('tumour', 'Disease', (20, 26))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('death', 'Disease', 'MESH:D003643', (84, 89))	('death', 'Disease', (84, 89))	('mutations', 'Var', (296, 305))	('cancer', 'Disease', (69, 75))	('tumour', 'Phenotype', 'HP:0002664', (20, 26))
240003	31383000	It is now well established that epigenetic changes are associated with tumour growth.	('tumour growth', 'Disease', 'MESH:D006130', (71, 84))	('epigenetic changes', 'Var', (32, 50))	('associated', 'Reg', (55, 65))	('tumour', 'Phenotype', 'HP:0002664', (71, 77))	('tumour growth', 'Disease', (71, 84))
240006	31383000	However, to date, relatively few studies have investigated whether characteristic epigenetic alterations, that involve one or more loci, are epigenetic drivers (epi-drivers) of metastasis and possess critical roles in advanced stages of tumourigenesis in multiple different cancer types.	('tumour', 'Phenotype', 'HP:0002664', (237, 243))	('cancer', 'Disease', 'MESH:D009369', (274, 280))	('roles', 'Reg', (209, 214))	('cancer', 'Disease', (274, 280))	('metastasis', 'CPA', (177, 187))	('tumour', 'Disease', 'MESH:D009369', (237, 243))	('tumour', 'Disease', (237, 243))	('epigenetic alterations', 'Var', (82, 104))	('cancer', 'Phenotype', 'HP:0002664', (274, 280))
240007	31383000	We defined epi-drivers to be epigenetic alterations that can definitively be shown to be required for at least one of the cancer hallmarks.	('cancer hallmarks', 'Disease', 'MESH:D009369', (122, 138))	('epi-drivers', 'Var', (11, 22))	('cancer hallmarks', 'Disease', (122, 138))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))
240008	31383000	An epi-driver change would be heritable in daughter cancer cells, dependent on the cancer hallmark, with generalised epi-drivers hypothesised to occur across multiple cancer types, and tumour-specific epi-drivers confined to just one cancer type.	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('cancer', 'Disease', (167, 173))	('cancer', 'Disease', (234, 240))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('tumour', 'Phenotype', 'HP:0002664', (185, 191))	('tumour', 'Disease', 'MESH:D009369', (185, 191))	('cancer', 'Disease', 'MESH:D009369', (234, 240))	('change', 'Var', (14, 20))	('cancer', 'Disease', (83, 89))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('cancer hallmark', 'Disease', (83, 98))	('cancer hallmark', 'Disease', 'MESH:D009369', (83, 98))	('tumour', 'Disease', (185, 191))
240009	31383000	In contrast, epigenetic passengers (epi-passengers) would not be required for a hallmark feature of cancer.	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('epigenetic', 'Var', (13, 23))
240016	31383000	In another study, Vizoso and colleagues analysed primary and metastatic cell line pairs from melanoma, breast and colorectal cancer to identify common DNA methylation-associated changes involved in the formation of metastasis.	('melanoma', 'Phenotype', 'HP:0002861', (93, 101))	('melanoma', 'Disease', (93, 101))	('melanoma', 'Disease', 'MESH:D008545', (93, 101))	('breast and colorectal cancer', 'Disease', 'MESH:D015179', (103, 131))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('colorectal cancer', 'Phenotype', 'HP:0003003', (114, 131))	('methylation-associated', 'Var', (155, 177))
240018	31383000	Loss of TBC1D16 methylation was associated with activation of an alternative cryptic transcript, TBC1D16-47KD, which was shown to promote melanoma proliferation and metastasis.	('metastasis', 'CPA', (165, 175))	('melanoma', 'Phenotype', 'HP:0002861', (138, 146))	('promote', 'PosReg', (130, 137))	('melanoma proliferation', 'Disease', (138, 160))	('cryptic', 'Gene', '55997', (77, 84))	('melanoma proliferation', 'Disease', 'MESH:D008545', (138, 160))	('cryptic', 'Gene', (77, 84))	('TBC1D16', 'Gene', '125058', (97, 104))	('TBC1D16', 'Gene', '125058', (8, 15))	('TBC1D16', 'Gene', (97, 104))	('TBC1D16', 'Gene', (8, 15))	('Loss', 'NegReg', (0, 4))	('activation', 'PosReg', (48, 58))	('methylation', 'Var', (16, 27))
240020	31383000	Hypomethylation of TBC1D16 was also shown to increase sensitivity to BRAF and MEK inhibitors but predicted poorer clinical outcome for melanoma patients.	('MEK', 'Gene', (78, 81))	('MEK', 'Gene', '5609', (78, 81))	('melanoma', 'Disease', 'MESH:D008545', (135, 143))	('melanoma', 'Phenotype', 'HP:0002861', (135, 143))	('melanoma', 'Disease', (135, 143))	('Hypomethylation', 'Var', (0, 15))	('poorer', 'NegReg', (107, 113))	('TBC1D16', 'Gene', '125058', (19, 26))	('patients', 'Species', '9606', (144, 152))	('TBC1D16', 'Gene', (19, 26))	('BRAF', 'Gene', '673', (69, 73))	('BRAF', 'Gene', (69, 73))	('increase', 'PosReg', (45, 53))
240021	31383000	identified significant hypermethylation of 5808 Illumina 450k probes (1533 genes) and significant hypomethylation of 4151 probes (1722) in both primary melanomas and metastases compared to benign nevi.	('melanomas', 'Disease', 'MESH:D008545', (152, 161))	('melanoma', 'Phenotype', 'HP:0002861', (152, 160))	('melanomas', 'Phenotype', 'HP:0002861', (152, 161))	('metastases', 'Disease', (166, 176))	('hypermethylation', 'MPA', (23, 39))	('metastases', 'Disease', 'MESH:D009362', (166, 176))	('melanomas', 'Disease', (152, 161))	('primary melanoma', 'Disease', (144, 160))	('primary melanoma', 'Disease', 'MESH:D008545', (144, 160))	('nevi', 'Phenotype', 'HP:0003764', (196, 200))	('hypomethylation', 'Var', (98, 113))
240022	31383000	In their analysis, seven CpGs in the gene body of EBF3 (chr10:131636622-131671489, GRCh37; cg03774288, cg07890827, cg09121772, cg09371530, cg09649486, cg16803064 and cg25866634) showed significant loss of methylation in metastases compared to benign nevi, and one of these CpG sites showed the same degree of hypomethylation in metastases compared to primary melanoma.	('cg25866634', 'Chemical', '-', (166, 176))	('melanoma', 'Phenotype', 'HP:0002861', (359, 367))	('metastases', 'Disease', (328, 338))	('loss', 'NegReg', (197, 201))	('cg16803064', 'Var', (151, 161))	('cg09371530', 'Var', (127, 137))	('primary melanoma', 'Disease', (351, 367))	('primary melanoma', 'Disease', 'MESH:D008545', (351, 367))	('cg03774288', 'Var', (91, 101))	('EBF3', 'Gene', (50, 54))	('cg07890827', 'Var', (103, 113))	('cg25866634', 'Var', (166, 176))	('EBF3', 'Gene', '253738', (50, 54))	('chr10:131636622-131671489', 'STRUCTURAL_ABNORMALITY', 'None', (56, 81))	('nevi', 'Phenotype', 'HP:0003764', (250, 254))	('cg09649486', 'Var', (139, 149))	('metastases', 'Disease', 'MESH:D009362', (220, 230))	('cg09121772', 'Var', (115, 125))	('methylation', 'MPA', (205, 216))	('metastases', 'Disease', 'MESH:D009362', (328, 338))	('metastases', 'Disease', (220, 230))
240028	31383000	Evaluation of EBF3 CpG sites (at chr10:131636622-131671489, GRCh37; cg03774288, cg07890827, cg09121772, cg09371530, cg09649486, cg16803064 and cg25866634), in a cohort of 450k data of melanocytes (n = 3), primary melanomas (n = 4) and melanoma metastases (n = 33 in total) (Fig.	('EBF3', 'Gene', (14, 18))	('cg09371530', 'Var', (104, 114))	('EBF3', 'Gene', '253738', (14, 18))	('melanoma metastases', 'Disease', (235, 254))	('melanomas', 'Phenotype', 'HP:0002861', (213, 222))	('cg03774288', 'Var', (68, 78))	('cg25866634', 'Var', (143, 153))	('chr10:131636622-131671489', 'STRUCTURAL_ABNORMALITY', 'None', (33, 58))	('cg07890827', 'Var', (80, 90))	('melanoma', 'Phenotype', 'HP:0002861', (213, 221))	('primary melanoma', 'Disease', (205, 221))	('primary melanoma', 'Disease', 'MESH:D008545', (205, 221))	('cg09649486', 'Var', (116, 126))	('melanoma', 'Phenotype', 'HP:0002861', (235, 243))	('cg09121772', 'Var', (92, 102))	('melanomas', 'Disease', 'MESH:D008545', (213, 222))	('melanoma metastases', 'Disease', 'MESH:D009362', (235, 254))	('melanomas', 'Disease', (213, 222))	('cg25866634', 'Chemical', '-', (143, 153))	('cg16803064', 'Var', (128, 138))
240030	31383000	We also evaluated methylation of TBC1D16 CpG sites (at chr17: 77924371-77925136, GRCh37; cg18749563, cg07618085, cg17295878, cg23651872 and cg19004465) in the same melanoma dataset (Fig.	('melanoma', 'Phenotype', 'HP:0002861', (164, 172))	('cg17295878', 'Var', (113, 123))	('cg07618085', 'Var', (101, 111))	('cg17295878', 'Chemical', '-', (113, 123))	('methylation', 'MPA', (18, 29))	('melanoma', 'Disease', 'MESH:D008545', (164, 172))	('TBC1D16', 'Gene', '125058', (33, 40))	('TBC1D16', 'Gene', (33, 40))	('cg23651872', 'Var', (125, 135))	('cg18749563', 'Var', (89, 99))	('cg19004465', 'Var', (140, 150))	('melanoma', 'Disease', (164, 172))
240032	31383000	In general, melanocytes were also hypomethylated in TBC1D16.	('TBC1D16', 'Gene', '125058', (52, 59))	('hypomethylated', 'Var', (34, 48))	('TBC1D16', 'Gene', (52, 59))
240035	31383000	No major differences were observed for methylation in TBC1D16, except in a primary and metastatic melanoma cell line pair and a primary melanoma cell line, which exhibited hypermethylation in both the TBC1D16 gene body and TBC1D16-47KD cryptic promoter regions (Fig.	('primary melanoma', 'Disease', (128, 144))	('primary melanoma', 'Disease', 'MESH:D008545', (128, 144))	('TBC1D16', 'Gene', '125058', (223, 230))	('cryptic', 'Gene', '55997', (236, 243))	('cryptic', 'Gene', (236, 243))	('hypermethylation', 'Var', (172, 188))	('TBC1D16', 'Gene', (223, 230))	('TBC1D16', 'Gene', '125058', (201, 208))	('melanoma', 'Disease', 'MESH:D008545', (98, 106))	('TBC1D16', 'Gene', (201, 208))	('TBC1D16', 'Gene', '125058', (54, 61))	('melanoma', 'Disease', (98, 106))	('melanoma', 'Disease', 'MESH:D008545', (136, 144))	('melanoma', 'Phenotype', 'HP:0002861', (136, 144))	('melanoma', 'Phenotype', 'HP:0002861', (98, 106))	('melanoma', 'Disease', (136, 144))	('TBC1D16', 'Gene', (54, 61))
240041	31383000	2a), CpG sites in the gene bodies of EBF3 (cg09649486, cg25866634) and TBC1D16 (cg07618085) were significantly differentially methylated (+ 17% and - 14%, respectively) in lymph node metastases compared to primary tumours (green vs red boxplots).	('tumours', 'Phenotype', 'HP:0002664', (214, 221))	('EBF3', 'Gene', '253738', (37, 41))	('metastases', 'Disease', (183, 193))	('cg07618085', 'Var', (80, 90))	('cg09649486', 'Var', (43, 53))	('methylated', 'MPA', (126, 136))	('TBC1D16', 'Gene', '125058', (71, 78))	('primary tumours', 'Disease', (206, 221))	('primary tumours', 'Disease', 'MESH:D009369', (206, 221))	('metastases', 'Disease', 'MESH:D009362', (183, 193))	('cg25866634', 'Var', (55, 65))	('TBC1D16', 'Gene', (71, 78))	('EBF3', 'Gene', (37, 41))	('tumour', 'Phenotype', 'HP:0002664', (214, 220))	('cg25866634', 'Chemical', '-', (55, 65))
240042	31383000	A similar significant loss of methylation was also observed in the TBC1D16-47KD cryptic promoter (cg23651872).	('cryptic', 'Gene', '55997', (80, 87))	('cryptic', 'Gene', (80, 87))	('TBC1D16', 'Gene', '125058', (67, 74))	('cg23651872', 'Var', (98, 108))	('loss', 'NegReg', (22, 26))	('TBC1D16', 'Gene', (67, 74))	('methylation', 'MPA', (30, 41))
240043	31383000	One of the EBF3 CpG sites (cg25866634) also gained methylation (+ 17%) in abdominal metastases (black vs red boxplots).	('abdominal metastases', 'Disease', 'MESH:D009362', (74, 94))	('abdominal metastases', 'Disease', (74, 94))	('EBF3', 'Gene', (11, 15))	('methylation', 'MPA', (51, 62))	('cg25866634', 'Var', (27, 37))	('cg25866634', 'Chemical', '-', (27, 37))	('EBF3', 'Gene', '253738', (11, 15))	('gained', 'PosReg', (44, 50))
240044	31383000	Furthermore, three EBF3 gene body CpG sites (cg09649486, cg25866634, cg03774288) showed a 19% gain of methylation in endometrial hyperplasia compared to primary endometrial tumours (blue vs red boxplots).	('methylation', 'MPA', (102, 113))	('endometrial tumours', 'Disease', 'MESH:D016889', (161, 180))	('EBF3', 'Gene', '253738', (19, 23))	('cg25866634', 'Var', (57, 67))	('endometrial hyperplasia', 'Disease', (117, 140))	('cg25866634', 'Chemical', '-', (57, 67))	('endometrial hyperplasia', 'Disease', 'MESH:D004714', (117, 140))	('gain', 'PosReg', (94, 98))	('endometrial hyperplasia', 'Phenotype', 'HP:0040298', (117, 140))	('EBF3', 'Gene', (19, 23))	('endometrial tumours', 'Disease', (161, 180))	('tumour', 'Phenotype', 'HP:0002664', (173, 179))	('tumours', 'Phenotype', 'HP:0002664', (173, 180))	('cg03774288', 'Var', (69, 79))	('cg09649486', 'Var', (45, 55))
240046	31383000	2b) significant hypermethylation of one EBF3 (cg03774288) gene body CpG and four TBC1D16 (cg07618085, cg17295878, cg23651872, cg19004465) CpG sites (both + 16%) were observed compared to normal prostate tissue (red vs blue boxplots).	('cg23651872', 'Var', (114, 124))	('cg07618085', 'Var', (90, 100))	('hypermethylation', 'MPA', (16, 32))	('cg17295878', 'Chemical', '-', (102, 112))	('EBF3', 'Gene', '253738', (40, 44))	('EBF3', 'Gene', (40, 44))	('cg17295878', 'Var', (102, 112))	('TBC1D16', 'Gene', '125058', (81, 88))	('TBC1D16', 'Gene', (81, 88))	('cg19004465', 'Var', (126, 136))
240048	31383000	2c), there were no significant metastasis-related methylation changes in either the EBF3 promoter or TBC1D16, but five CpG sites (cg07890827, cg16803064, cg09649486, cg25866634, cg09121772) in the EBF3 gene body showed 12% loss of methylation in primary tumours compared to normal tissue (red vs blue boxplots).	('cg25866634', 'Chemical', '-', (166, 176))	('cg09121772', 'Var', (178, 188))	('EBF3', 'Gene', '253738', (84, 88))	('cg07890827', 'Var', (130, 140))	('EBF3', 'Gene', '253738', (197, 201))	('cg09649486', 'Var', (154, 164))	('TBC1D16', 'Gene', '125058', (101, 108))	('tumours', 'Phenotype', 'HP:0002664', (254, 261))	('EBF3', 'Gene', (197, 201))	('TBC1D16', 'Gene', (101, 108))	('EBF3', 'Gene', (84, 88))	('methylation', 'MPA', (231, 242))	('primary tumours', 'Disease', 'MESH:D009369', (246, 261))	('tumour', 'Phenotype', 'HP:0002664', (254, 260))	('cg25866634', 'Var', (166, 176))	('cg16803064', 'Var', (142, 152))	('primary tumours', 'Disease', (246, 261))	('loss', 'NegReg', (223, 227))
240054	31383000	In the RRBS dataset, all EBF3 promoter CpG sites and one TBC1D16 site in the gene body were significantly hypermethylated (+ 26% and + 17%, respectively) in aberrant crypt foci compared to normal colonic crypt (green vs red boxplots).	('RRBS', 'Chemical', '-', (7, 11))	('EBF3', 'Gene', (25, 29))	('hypermethylated', 'PosReg', (106, 121))	('TBC1D16', 'Gene', (57, 64))	('aberrant', 'Var', (157, 165))	('EBF3', 'Gene', '253738', (25, 29))	('TBC1D16', 'Gene', '125058', (57, 64))
240062	31383000	With the exception of the normal brain tissue and the metastatic breast cancer cell line, TBC1D16 was largely methylated (median = 0.94) in all of the cell lines and samples.	('TBC1D16', 'Gene', '125058', (90, 97))	('breast cancer', 'Disease', 'MESH:D001943', (65, 78))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('TBC1D16', 'Gene', (90, 97))	('breast cancer', 'Disease', (65, 78))	('breast cancer', 'Phenotype', 'HP:0003002', (65, 78))	('methylated', 'Var', (110, 120))
240063	31383000	In the breast cancer cell lines, TBC1D16 methylation showed high discrimination between the primary (median = 0.96) and the metastatic (median = 0) breast cancer cell line pair (Fig.	('breast cancer', 'Disease', 'MESH:D001943', (7, 20))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('breast cancer', 'Disease', 'MESH:D001943', (148, 161))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('breast cancer', 'Disease', (7, 20))	('TBC1D16', 'Gene', '125058', (33, 40))	('methylation', 'Var', (41, 52))	('breast cancer', 'Phenotype', 'HP:0003002', (7, 20))	('breast cancer', 'Disease', (148, 161))	('breast cancer', 'Phenotype', 'HP:0003002', (148, 161))	('TBC1D16', 'Gene', (33, 40))
240066	31383000	5a, median = 0.57), but comparatively hypomethylated in four tumour samples, glioblastoma multiforme, lung adenocarcinoma, colon adenocarcinoma and breast invasive carcinoma (median = 0.17).	('glioblastoma multiforme', 'Disease', (77, 100))	('tumour', 'Disease', 'MESH:D009369', (61, 67))	('colon adenocarcinoma and breast invasive carcinoma', 'Disease', 'MESH:D003110', (123, 173))	('tumour', 'Disease', (61, 67))	('breast invasive carcinoma', 'Phenotype', 'HP:0003002', (148, 173))	('glioblastoma', 'Phenotype', 'HP:0012174', (77, 89))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (77, 100))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (102, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('tumour', 'Phenotype', 'HP:0002664', (61, 67))	('carcinoma', 'Phenotype', 'HP:0030731', (164, 173))	('hypomethylated', 'Var', (38, 52))	('lung adenocarcinoma', 'Disease', (102, 121))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (102, 121))
240067	31383000	The EBF3 gene body was comparatively highly methylated on average in all of the tumour samples (median = 0.75).	('methylated', 'Var', (44, 54))	('tumour', 'Disease', (80, 86))	('EBF3', 'Gene', (4, 8))	('tumour', 'Phenotype', 'HP:0002664', (80, 86))	('EBF3', 'Gene', '253738', (4, 8))	('tumour', 'Disease', 'MESH:D009369', (80, 86))
240073	31383000	Hypomethylation in the EBF3 gene body was also observed in squamous cell carcinoma of the lung, adenocarcinoma of the lung, glioma and in colorectal cancer tissue or cell lines in comparison to normal colon tissues or cell lines.	('squamous cell carcinoma of the lung', 'Disease', 'MESH:D002294', (59, 94))	('glioma', 'Disease', (124, 130))	('colorectal cancer', 'Phenotype', 'HP:0003003', (138, 155))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('Hypomethylation', 'Var', (0, 15))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (59, 82))	('EBF3', 'Gene', '253738', (23, 27))	('colorectal cancer', 'Disease', (138, 155))	('observed', 'Reg', (47, 55))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('glioma', 'Phenotype', 'HP:0009733', (124, 130))	('adenocarcinoma of the lung', 'Disease', (96, 122))	('glioma', 'Disease', 'MESH:D005910', (124, 130))	('EBF3', 'Gene', (23, 27))	('adenocarcinoma of the lung', 'Disease', 'MESH:D000077192', (96, 122))	('squamous cell carcinoma of the lung', 'Disease', (59, 94))	('colorectal cancer', 'Disease', 'MESH:D015179', (138, 155))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
240075	31383000	Increased methylation of a CpG site in the EBF3 promoter in primary and metastatic tumours (cg02700606, which is 396 bp from the RRBS fragment previously analysed and additional sites examined) was consistent with previously published data showing significant hypermethylation of the EBF3 promoter in metastatic melanoma cell lines.	('EBF3', 'Gene', '253738', (284, 288))	('methylation', 'MPA', (10, 21))	('cg02700606', 'Var', (92, 102))	('metastatic tumours', 'Disease', (72, 90))	('metastatic tumours', 'Disease', 'MESH:C538445', (72, 90))	('EBF3', 'Gene', '253738', (43, 47))	('melanoma', 'Disease', 'MESH:D008545', (312, 320))	('melanoma', 'Phenotype', 'HP:0002861', (312, 320))	('RRBS', 'Chemical', '-', (129, 133))	('melanoma', 'Disease', (312, 320))	('EBF3', 'Gene', (284, 288))	('tumours', 'Phenotype', 'HP:0002664', (83, 90))	('tumour', 'Phenotype', 'HP:0002664', (83, 89))	('EBF3', 'Gene', (43, 47))
240080	31383000	Taken altogether, these results suggest that the EBF3 promoter hypermethylation and gene body hypomethylation is associated with tumour progression and metastasis, and it might be a characteristic aggressive change shared by both melanoma and colorectal cancer.	('cancer', 'Phenotype', 'HP:0002664', (254, 260))	('tumour', 'Phenotype', 'HP:0002664', (129, 135))	('EBF3', 'Gene', (49, 53))	('metastasis', 'CPA', (152, 162))	('tumour', 'Disease', 'MESH:D009369', (129, 135))	('promoter hypermethylation', 'Var', (54, 79))	('hypomethylation', 'Var', (94, 109))	('tumour', 'Disease', (129, 135))	('melanoma and colorectal cancer', 'Disease', 'MESH:D015179', (230, 260))	('aggressive change', 'Phenotype', 'HP:0000718', (197, 214))	('EBF3', 'Gene', '253738', (49, 53))	('melanoma', 'Phenotype', 'HP:0002861', (230, 238))	('colorectal cancer', 'Phenotype', 'HP:0003003', (243, 260))	('associated', 'Reg', (113, 123))
240081	31383000	We also observed characteristic TBC1D16 methylation changes in both melanoma and breast cancer (hypomethylation of the TBC1D16 gene body, including the cryptic TBC1D16-47KD cryptic promoter (75%), in metastatic melanoma compared to primary melanoma and also hypomethylation (94%) in metastatic vs primary paired breast cancer samples).	('cryptic', 'Gene', '55997', (173, 180))	('methylation', 'Var', (40, 51))	('cryptic', 'Gene', (173, 180))	('breast cancer', 'Disease', (81, 94))	('melanoma', 'Disease', 'MESH:D008545', (211, 219))	('melanoma', 'Disease', 'MESH:D008545', (68, 76))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('cancer', 'Phenotype', 'HP:0002664', (319, 325))	('melanoma and breast cancer', 'Disease', 'MESH:D001943', (68, 94))	('TBC1D16', 'Gene', '125058', (160, 167))	('TBC1D16', 'Gene', '125058', (32, 39))	('primary melanoma', 'Disease', (232, 248))	('primary melanoma', 'Disease', 'MESH:D008545', (232, 248))	('TBC1D16', 'Gene', '125058', (119, 126))	('melanoma', 'Disease', 'MESH:D008545', (240, 248))	('breast cancer', 'Phenotype', 'HP:0003002', (312, 325))	('melanoma', 'Phenotype', 'HP:0002861', (211, 219))	('melanoma', 'Disease', (211, 219))	('melanoma', 'Phenotype', 'HP:0002861', (68, 76))	('melanoma', 'Disease', (68, 76))	('changes', 'Reg', (52, 59))	('breast cancer', 'Disease', 'MESH:D001943', (312, 325))	('cryptic', 'Gene', (152, 159))	('cryptic', 'Gene', '55997', (152, 159))	('breast cancer', 'Disease', (312, 325))	('breast cancer', 'Phenotype', 'HP:0003002', (81, 94))	('TBC1D16', 'Gene', (160, 167))	('TBC1D16', 'Gene', (32, 39))	('melanoma', 'Phenotype', 'HP:0002861', (240, 248))	('melanoma', 'Disease', (240, 248))	('TBC1D16', 'Gene', (119, 126))	('breast cancer', 'Disease', 'MESH:D001943', (81, 94))
240083	31383000	Hypomethylation of TBC1D16 was previously reported in metastatic vs primary melanoma, breast cancer and other tumour types.	('Hypomethylation', 'Var', (0, 15))	('reported', 'Reg', (42, 50))	('primary melanoma', 'Disease', 'MESH:D008545', (68, 84))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('TBC1D16', 'Gene', '125058', (19, 26))	('primary melanoma', 'Disease', (68, 84))	('breast cancer', 'Disease', 'MESH:D001943', (86, 99))	('tumour', 'Phenotype', 'HP:0002664', (110, 116))	('breast cancer', 'Phenotype', 'HP:0003002', (86, 99))	('TBC1D16', 'Gene', (19, 26))	('breast cancer', 'Disease', (86, 99))	('tumour', 'Disease', 'MESH:D009369', (110, 116))	('tumour', 'Disease', (110, 116))	('melanoma', 'Phenotype', 'HP:0002861', (76, 84))
240086	31383000	cohort and in the WGBS data, which support the notion that methylation changes in TBC1D16 are a potential epigenetic driver of tumour metastasis.	('tumour metastasis', 'Disease', (127, 144))	('tumour', 'Phenotype', 'HP:0002664', (127, 133))	('methylation changes', 'Var', (59, 78))	('TBC1D16', 'Gene', '125058', (82, 89))	('TBC1D16', 'Gene', (82, 89))	('tumour metastasis', 'Disease', 'MESH:D009362', (127, 144))
240087	31383000	However, epigenetic changes in EBF3, or TBC1D16, were not identified in all tumour samples, or in all primary/metastasis cancer pairs.	('tumour', 'Disease', 'MESH:D009369', (76, 82))	('EBF3', 'Gene', (31, 35))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('tumour', 'Phenotype', 'HP:0002664', (76, 82))	('TBC1D16', 'Gene', '125058', (40, 47))	('metastasis cancer', 'Disease', 'MESH:D009362', (110, 127))	('metastasis cancer', 'Disease', (110, 127))	('TBC1D16', 'Gene', (40, 47))	('epigenetic changes', 'Var', (9, 27))	('tumour', 'Disease', (76, 82))	('EBF3', 'Gene', '253738', (31, 35))
240089	31383000	In addition, the direction of methylation changes in EBF3 and TBC1D16 was not necessarily conserved across different cancer types, since endometrial cancer and prostate cancer in our data showed opposite patterns of methylation changes in EBF3 gene body and promoter regions compared to melanoma and colorectal cancer.	('cancer', 'Disease', (169, 175))	('TBC1D16', 'Gene', (62, 69))	('endometrial cancer', 'Disease', 'MESH:D016889', (137, 155))	('cancer', 'Disease', (311, 317))	('colorectal cancer', 'Phenotype', 'HP:0003003', (300, 317))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('melanoma', 'Phenotype', 'HP:0002861', (287, 295))	('EBF3', 'Gene', (53, 57))	('cancer', 'Phenotype', 'HP:0002664', (311, 317))	('EBF3', 'Gene', '253738', (53, 57))	('prostate cancer', 'Disease', 'MESH:D011471', (160, 175))	('prostate cancer', 'Phenotype', 'HP:0012125', (160, 175))	('cancer', 'Disease', (117, 123))	('cancer', 'Disease', 'MESH:D009369', (169, 175))	('TBC1D16', 'Gene', '125058', (62, 69))	('cancer', 'Disease', (149, 155))	('melanoma and colorectal cancer', 'Disease', 'MESH:D015179', (287, 317))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('prostate cancer', 'Disease', (160, 175))	('cancer', 'Disease', 'MESH:D009369', (311, 317))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('EBF3', 'Gene', (239, 243))	('endometrial cancer', 'Phenotype', 'HP:0012114', (137, 155))	('EBF3', 'Gene', '253738', (239, 243))	('methylation', 'Var', (216, 227))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('endometrial cancer', 'Disease', (137, 155))	('cancer', 'Disease', 'MESH:D009369', (149, 155))
240090	31383000	We show here that in several cancer types, characteristic methylation changes in both EBF3 and TBC1D16 were associated with tumour metastasis, which is responsible for the majority of cancer-related deaths.	('cancer', 'Disease', (184, 190))	('cancer', 'Disease', (29, 35))	('tumour metastasis', 'Disease', 'MESH:D009362', (124, 141))	('death', 'Disease', 'MESH:D003643', (199, 204))	('methylation changes', 'Var', (58, 77))	('death', 'Disease', (199, 204))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('EBF3', 'Gene', (86, 90))	('tumour metastasis', 'Disease', (124, 141))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('tumour', 'Phenotype', 'HP:0002664', (124, 130))	('TBC1D16', 'Gene', '125058', (95, 102))	('associated with', 'Reg', (108, 123))	('cancer', 'Disease', 'MESH:D009369', (29, 35))	('TBC1D16', 'Gene', (95, 102))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('EBF3', 'Gene', '253738', (86, 90))
240093	31383000	Furthermore, if the identified methylation changes are causal, they may have significant relevance to early diagnosis of cancer and possibly as a therapeutic target.	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('methylation changes', 'Var', (31, 50))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('cancer', 'Disease', (121, 127))	('relevance', 'Reg', (89, 98))
240102	31383000	Overall, the findings presented strengthen the view that methylation changes in EBF3 and TBC1D16 are potential epi-drivers of aggressive tumourigenic changes in multiple cancer types.	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('EBF3', 'Gene', '253738', (80, 84))	('cancer', 'Disease', (170, 176))	('EBF3', 'Gene', (80, 84))	('aggressive tumour', 'Disease', (126, 143))	('aggressive tumour', 'Disease', 'MESH:D001523', (126, 143))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('TBC1D16', 'Gene', '125058', (89, 96))	('methylation changes', 'Var', (57, 76))	('TBC1D16', 'Gene', (89, 96))	('tumour', 'Phenotype', 'HP:0002664', (137, 143))
240104	31383000	An RRBS dataset was obtained from the GEO database (accession number GSE95654, data retrieved on 10/7/2018) of four normal colon, eight normal colonic crypt, nine9 aberrant crypt foci and ten primary colorectal cancer tumours.	('primary colorectal cancer', 'Disease', (192, 217))	('tumours', 'Phenotype', 'HP:0002664', (218, 225))	('primary colorectal cancer', 'Disease', 'MESH:D015179', (192, 217))	('colorectal cancer tumours', 'Disease', 'MESH:D015179', (200, 225))	('aberrant', 'Var', (164, 172))	('colorectal cancer tumours', 'Disease', (200, 225))	('colorectal cancer', 'Phenotype', 'HP:0003003', (200, 217))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('tumour', 'Phenotype', 'HP:0002664', (218, 224))	('RRBS', 'Chemical', '-', (3, 7))
240106	31383000	The cell lines analysed were Hs688(A).T (primary melanoma) and Hs688(B).T (matching metastatic melanoma), WM75 (primary melanoma) and WM373 (matching metastatic melanoma), WM115 (primary melanoma) and WM-266-4 (matching metastatic melanoma) and six additional primary melanoma cell lines, WM793, WM853-2, WM278, WM39, WM1341D and WM15552C.	('melanoma', 'Disease', 'MESH:D008545', (187, 195))	('melanoma', 'Phenotype', 'HP:0002861', (95, 103))	('melanoma', 'Disease', (231, 239))	('melanoma', 'Disease', (95, 103))	('melanoma', 'Phenotype', 'HP:0002861', (120, 128))	('melanoma', 'Disease', (120, 128))	('primary melanoma', 'Disease', (41, 57))	('primary melanoma', 'Disease', 'MESH:D008545', (41, 57))	('WM39', 'Var', (312, 316))	('WM15552C', 'Var', (330, 338))	('primary melanoma', 'Disease', 'MESH:D008545', (112, 128))	('WM793', 'CellLine', 'CVCL:8787', (289, 294))	('primary melanoma', 'Disease', (112, 128))	('melanoma', 'Disease', 'MESH:D008545', (161, 169))	('WM-266-4', 'CellLine', 'CVCL:2765', (201, 209))	('melanoma', 'Disease', (268, 276))	('melanoma', 'Disease', 'MESH:D008545', (49, 57))	('melanoma', 'Phenotype', 'HP:0002861', (187, 195))	('melanoma', 'Disease', (187, 195))	('melanoma', 'Disease', 'MESH:D008545', (231, 239))	('melanoma', 'Disease', 'MESH:D008545', (95, 103))	('WM278', 'CellLine', 'CVCL:6473', (305, 310))	('WM1341D', 'Var', (318, 325))	('melanoma', 'Disease', 'MESH:D008545', (120, 128))	('primary melanoma', 'Disease', 'MESH:D008545', (260, 276))	('primary melanoma', 'Disease', (179, 195))	('primary melanoma', 'Disease', (260, 276))	('primary melanoma', 'Disease', 'MESH:D008545', (179, 195))	('melanoma', 'Disease', (161, 169))	('melanoma', 'Phenotype', 'HP:0002861', (161, 169))	('melanoma', 'Phenotype', 'HP:0002861', (49, 57))	('melanoma', 'Disease', (49, 57))	('melanoma', 'Disease', 'MESH:D008545', (268, 276))
240111	31383000	The 450k (GSE44661, GSE67116, GSE38240, GSE78758, GSE77954), RRBS (GSE95654, GSE70621) and WGBS (GSE52271, GSE56763) methylation datasets analysed during the current study are available in the NCBI GEO repository, https://www.ncbi.nlm.nih.gov/geo/.	('GSE70621', 'Var', (77, 85))	('GSE78758', 'Var', (40, 48))	('GSE67116', 'Var', (20, 28))	('GSE77954', 'Var', (50, 58))	('GSE44661', 'Var', (10, 18))	('GSE95654', 'Var', (67, 75))	('GSE38240', 'Var', (30, 38))	('RRBS', 'Chemical', '-', (61, 65))
240112	31383000	The additional RRBS data generated during the current study (primary melanoma cell lines WM793, WM853-2, WM278, WM39, WM1341D and WM15552C) are available from the corresponding author on reasonable request.	('WM793', 'CellLine', 'CVCL:8787', (89, 94))	('WM39', 'Var', (112, 116))	('WM15552C', 'Var', (130, 138))	('WM1341D', 'Var', (118, 125))	('RRBS', 'Chemical', '-', (15, 19))	('primary melanoma', 'Disease', 'MESH:D008545', (61, 77))	('WM278', 'CellLine', 'CVCL:6473', (105, 110))	('primary melanoma', 'Disease', (61, 77))	('WM278', 'Var', (105, 110))	('melanoma', 'Phenotype', 'HP:0002861', (69, 77))
240152	30922393	In other control experiments, primary antibodies: 1) were not added, 2) were detected by alternative secondary antibodies, 3) were tested on a TMA containing 14 cancer cell lines (e.g., prostate, breast, ovarian, kidney, cervical cancer cells and Jurkat), and 4) were replaced with isotype control antibodies (MOPC-31C, G155-178, MPC-11) (BD Pharminogen).	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('G155-178', 'Var', (320, 328))	('MOPC-31C', 'Var', (310, 318))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('breast, ovarian, kidney, cervical cancer', 'Disease', 'MESH:D001943', (196, 236))	('TMA', 'Chemical', '-', (143, 146))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('cancer', 'Disease', (230, 236))	('cancer', 'Disease', 'MESH:D009369', (230, 236))	('cancer', 'Disease', (161, 167))	('Jurkat', 'CellLine', 'CVCL:0065', (247, 253))
240185	30922393	Ki-67 was associated with positive OS (P = 0.0068) (Fig.	('Ki-67', 'Var', (0, 5))	('positive OS', 'Disease', (26, 37))	('OS', 'Chemical', '-', (35, 37))
240188	30922393	The same was observed for TILs, where association of CD3 with OS was enhanced by Ki-67 co-labeling (P = 0.0297 to P = 0.0044) (Fig.	('association', 'Interaction', (38, 49))	('OS', 'Chemical', '-', (62, 64))	('enhanced', 'PosReg', (69, 77))	('Ki-67', 'Var', (81, 86))	('CD3', 'Gene', (53, 56))
240204	30922393	IFN-gamma marks adaptive immune activation, and is central to anti-tumor immunity, and absence of HLA-DR is associated with metastasis.	('HLA-DR', 'Protein', (98, 104))	('metastasis', 'CPA', (124, 134))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('adaptive immune activation', 'CPA', (16, 42))	('associated', 'Reg', (108, 118))	('tumor', 'Disease', (67, 72))	('IFN-gamma', 'Gene', '3458', (0, 9))	('IFN-gamma', 'Gene', (0, 9))	('absence', 'Var', (87, 94))
240210	30922393	Altogether, these results demonstrate that proliferating Ki-67+ IIC; CD3+, CD8+, and CD4+ TILs; CD20+ TIL-Bs; and HLA-DR and IFN-gamma are positive prognostic markers for NSCLC patients.	('CD8', 'Gene', '925', (75, 78))	('CD20', 'Gene', '54474', (96, 100))	('IFN-gamma', 'Gene', (125, 134))	('rat', 'Species', '10116', (50, 53))	('patients', 'Species', '9606', (177, 185))	('IFN-gamma', 'Gene', '3458', (125, 134))	('CD3+', 'Var', (69, 73))	('CD20', 'Gene', (96, 100))	('Ki-67+ IIC', 'Var', (57, 67))	('rat', 'Species', '10116', (33, 36))	('NSCLC', 'Disease', (171, 176))	('CD8', 'Gene', (75, 78))	('CD4', 'Gene', (85, 88))	('NSCLC', 'Disease', 'MESH:D002289', (171, 176))	('CD4', 'Gene', '920', (85, 88))
240216	30922393	The only ICP associated with positive OS independently of TILs was TIM-3 (P = 0.0448), and this was augmented by it co-labeling CD3+ TILs (P = 0.0151) (Fig.	('CD3+ TILs', 'Chemical', '-', (128, 137))	('TIM-3', 'Gene', (67, 72))	('OS', 'Chemical', '-', (38, 40))	('CD3+', 'Var', (128, 132))	('TIM-3', 'Gene', '84868', (67, 72))
240224	30922393	Only three ICPs showed discrepancies using the second method, where PD-1 (P = 0.0121), CD3-PD-L1 (P = 0.0155), CD26 (P = 0.0052), and CD3-CD26 (P = 0.0017) were positively associated with OS, but CD3-TIGIT was not (P = 0.4830).	('PD-1', 'Var', (68, 72))	('CD3-CD26', 'Gene', (134, 142))	('PD-L1', 'Gene', (91, 96))	('TIGIT', 'Gene', (200, 205))	('associated with', 'Reg', (172, 187))	('PD-L1', 'Gene', '29126', (91, 96))	('CD3-CD26', 'Gene', '1803', (134, 142))	('CD26', 'Gene', '1803', (138, 142))	('OS', 'Chemical', '-', (188, 190))	('CD26', 'Gene', '1803', (111, 115))	('CD26', 'Gene', (138, 142))	('TIGIT', 'Gene', '201633', (200, 205))	('CD26', 'Gene', (111, 115))
240227	30922393	CD3+ TILs were highly correlated with CD45+ IICs (P < 0.0001, r = 0.3428), but global ICP expression was not (Fig.	('CD3+ TILs', 'Var', (0, 9))	('CD3+ TILs', 'Chemical', '-', (0, 9))	('CD45', 'Gene', (38, 42))	('CD45', 'Gene', '5788', (38, 42))
240244	30922393	The positive effect on OS was maintained with ICPs and CD3-ICPs co-labeling for TIM-3/BTLA/LAG-3 combinations (P = 0.0018 to P = 0.0033), as it was for the 2B4/PD-1/CD57 combination (Fig.	('LAG-3', 'Gene', (91, 96))	('2B4/PD-1', 'Gene', (156, 164))	('CD57', 'Gene', (165, 169))	('CD57', 'Gene', '27087', (165, 169))	('LAG-3', 'Gene', '3902', (91, 96))	('2B4/PD-1', 'Gene', '51744;5133', (156, 164))	('TIM-3', 'Gene', '84868', (80, 85))	('TIM-3', 'Gene', (80, 85))	('combinations', 'Var', (97, 109))	('OS', 'Chemical', '-', (23, 25))	('BTLA', 'Gene', (86, 90))	('BTLA', 'Gene', '151888', (86, 90))
240252	30922393	The relationship between PC1 and OS was increased using CD3-ICP values (P = 1.4 x 10- 5).	('relationship', 'Interaction', (4, 16))	('CD3-ICP values', 'Var', (56, 70))	('PC1', 'Gene', '5167', (25, 28))	('OS', 'Chemical', '-', (33, 35))	('increased', 'PosReg', (40, 49))	('PC1', 'Gene', (25, 28))
240357	30498189	Therefore, the study result that showed the incidence of GP resistance in the ADC group was higher than that in the SqCC group was reliable (71 out of 90 cases versus 51 out of 79 cases, P=0.038 at <0.05, Table 1).	('GP resistance', 'MPA', (57, 70))	('GP', 'Chemical', '-', (57, 59))	('higher', 'PosReg', (92, 98))	('ADC', 'Var', (78, 81))
240364	30498189	We found that the presence of GP resistance was an independent factor associated with MPV (>=10.85) factors [odds ratio (OR): 5.81, 95% confidence interval (CI): 1.082-31.195, P=0.004] eventually (Tables 6, 7).	('presence', 'Var', (18, 26))	('GP', 'Chemical', '-', (30, 32))	('associated', 'Reg', (70, 80))
240372	30498189	We found the presence of GP resistance was an independent factor associated with PCT MPV (>=0.235) factors (OR: 3.517, 95% CI: 1.087-11.387, P=0.036), and CA125 (>=16.9) factors (OR: 4.862, 95% CI: 1.437-16.448, P=0.011) (Table 11).	('CA125', 'Gene', (155, 160))	('PCT MPV', 'Disease', (81, 88))	('CA125', 'Gene', '94025', (155, 160))	('GP', 'Chemical', '-', (25, 27))	('presence', 'Var', (13, 21))
240391	30498189	In this study, we found that PCT >=0.235 had no significant link with outcomes but was a main risk factor for GP resistance for lung squamous cell carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (147, 156))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (128, 156))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (128, 156))	('PCT >=0.235', 'Var', (29, 40))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (133, 156))	('lung squamous cell carcinoma', 'Disease', (128, 156))	('GP', 'Chemical', '-', (110, 112))
240393	30498189	Simultaneously, we found that MPV >=10.85 was the only main risk factor with GP resistance for lung adenocarcinoma cell carcinoma.	('GP', 'Chemical', '-', (77, 79))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (95, 114))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('lung adenocarcinoma cell carcinoma', 'Disease', 'MESH:D000077192', (95, 129))	('lung adenocarcinoma cell carcinoma', 'Disease', (95, 129))	('MPV', 'Var', (30, 33))
240403	30498189	In our study, MPV >=10.85 was significantly related to GP resistance for lung adenocarcinoma cell carcinoma, and PCT >=0.235 was significantly related to GP resistance for lung squamous cell carcinoma.	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (172, 200))	('GP resistance', 'MPA', (55, 68))	('lung adenocarcinoma cell carcinoma', 'Disease', (73, 107))	('MPV >=10.85', 'Var', (14, 25))	('lung adenocarcinoma cell carcinoma', 'Disease', 'MESH:D000077192', (73, 107))	('related', 'Reg', (44, 51))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (177, 200))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (172, 200))	('lung squamous cell carcinoma', 'Disease', (172, 200))	('GP', 'Chemical', '-', (154, 156))	('carcinoma', 'Phenotype', 'HP:0030731', (191, 200))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('related', 'Reg', (143, 150))	('GP', 'Chemical', '-', (55, 57))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (73, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))
240411	28960030	GAB2 Amplification in Squamous Cell Lung Cancer of Non-Smokers Lung squamous cell cancer (SCC) is typically found in smokers and has a very low incidence in non-smokers, indicating differences in the tumor biology of lung SCC in smokers and non-smokers.	('Squamous Cell Lung Cancer', 'Phenotype', 'HP:0030359', (22, 47))	('SCC', 'Gene', '6317', (90, 93))	('Squamous Cell Lung Cancer', 'Disease', (22, 47))	('Amplification', 'Var', (5, 18))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('SCC', 'Gene', (90, 93))	('tumor', 'Disease', (200, 205))	('Cancer', 'Phenotype', 'HP:0002664', (41, 47))	('SCC', 'Phenotype', 'HP:0002860', (222, 225))	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('Lung Cancer', 'Phenotype', 'HP:0100526', (36, 47))	('Lung squamous cell cancer', 'Phenotype', 'HP:0030359', (63, 88))	('GAB2', 'Gene', '9846', (0, 4))	('squamous cell cancer', 'Disease', (68, 88))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (68, 88))	('Squamous Cell Lung Cancer', 'Disease', 'MESH:D002294', (22, 47))	('GAB2', 'Gene', (0, 4))	('SCC', 'Gene', '6317', (222, 225))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('SCC', 'Phenotype', 'HP:0002860', (90, 93))	('squamous cell cancer', 'Disease', 'MESH:D002294', (68, 88))	('Squamous Cell Lung Cancer of Non-Smokers', 'Phenotype', 'HP:0030358', (22, 62))	('SCC', 'Gene', (222, 225))
240413	28960030	To identify mutations in lung SCC of non-smokers, we performed a genetic analysis using arrays comparative genomic hybridization (ArrayCGH).	('SCC', 'Gene', '6317', (30, 33))	('mutations', 'Var', (12, 21))	('SCC', 'Phenotype', 'HP:0002860', (30, 33))	('SCC', 'Gene', (30, 33))
240421	28960030	GAB2 amplification may have an important role in the development of lung SCC in non-smokers.	('amplification', 'Var', (5, 18))	('SCC', 'Gene', (73, 76))	('SCC', 'Phenotype', 'HP:0002860', (73, 76))	('GAB2', 'Gene', '9846', (0, 4))	('SCC', 'Gene', '6317', (73, 76))	('GAB2', 'Gene', (0, 4))
240424	28960030	Over 85% of lung cancer cases are attributed to smoking, which contributes to the accumulation of genetic alterations that cause lung cancer.	('lung cancer', 'Disease', (129, 140))	('lung cancer', 'Phenotype', 'HP:0100526', (129, 140))	('lung cancer', 'Disease', 'MESH:D008175', (12, 23))	('lung cancer', 'Disease', 'MESH:D008175', (129, 140))	('lung cancer', 'Disease', (12, 23))	('lung cancer', 'Phenotype', 'HP:0100526', (12, 23))	('genetic alterations', 'Var', (98, 117))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
240429	28960030	Genetic alterations associated with lung cancer have been identified mainly in adenocarcinoma patients and have led to the development of targeted treatment strategies.	('lung cancer', 'Disease', (36, 47))	('Genetic alterations', 'Var', (0, 19))	('associated', 'Reg', (20, 30))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('patients', 'Species', '9606', (94, 102))	('lung cancer', 'Disease', 'MESH:D008175', (36, 47))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('adenocarcinoma', 'Disease', (79, 93))	('led', 'Reg', (112, 115))	('adenocarcinoma', 'Disease', 'MESH:D000230', (79, 93))	('lung cancer', 'Phenotype', 'HP:0100526', (36, 47))
240431	28960030	Several candidate genes with a potential role in the pathogenesis of lung SCC have been investigated but no genetic mutations have been specifically associated with lung SCC, especially in non-smokers.	('associated', 'Reg', (149, 159))	('SCC', 'Gene', (170, 173))	('mutations', 'Var', (116, 125))	('SCC', 'Gene', (74, 77))	('SCC', 'Phenotype', 'HP:0002860', (170, 173))	('SCC', 'Gene', '6317', (170, 173))	('SCC', 'Phenotype', 'HP:0002860', (74, 77))	('SCC', 'Gene', '6317', (74, 77))
240433	28960030	We analyzed tissue samples from these patients to identify common genetic mutations associated with lung SCC in non-smokers.	('mutations', 'Var', (74, 83))	('associated', 'Reg', (84, 94))	('SCC', 'Gene', (105, 108))	('patients', 'Species', '9606', (38, 46))	('SCC', 'Phenotype', 'HP:0002860', (105, 108))	('SCC', 'Gene', '6317', (105, 108))
240445	28960030	To identify genomic regions that were significantly amplified or deleted, Genomic Identification of Significant Targets in Cancer (GISTIC, version 2.0.1) was used.	('Cancer', 'Disease', 'MESH:D009369', (123, 129))	('Cancer', 'Phenotype', 'HP:0002664', (123, 129))	('Cancer', 'Disease', (123, 129))	('deleted', 'Var', (65, 72))
240452	28960030	Three gain (5p15.33, 8q24.21, and 11q13.3) and four loss regions (4q35.2, 9p21.3, 10q23.31, and 15q11.2) overlapped with the GISTIC analysis of TCGA LUSC patients.	('gain', 'PosReg', (6, 10))	('4q35.2', 'Var', (66, 72))	('patients', 'Species', '9606', (154, 162))	('LUSC', 'Phenotype', 'HP:0030359', (149, 153))	('TCGA LUSC', 'Disease', (144, 153))	('5p15.33', 'Var', (12, 19))
240458	28960030	A multiple logistic regression model with adjustment for age and sex was used to test copy number associations between nine lifelong non-smokers and 187 smokers to determine whether SCC depends on the smoking status in the TCGA LUSC dataset.	('SCC', 'Gene', (182, 185))	('SCC', 'Phenotype', 'HP:0002860', (182, 185))	('SCC', 'Gene', '6317', (182, 185))	('LUSC', 'Phenotype', 'HP:0030359', (228, 232))	('copy', 'Var', (86, 90))	('test', 'Reg', (81, 85))
240463	28960030	Tumors are caused by mutations in genes that affect cell proliferation and regulation.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('caused by', 'Reg', (11, 20))	('mutations', 'Var', (21, 30))
240464	28960030	Activation of oncogenes, inactivation of tumor suppressor genes, and increased instability of various genes comprise the genetic changes that affect the growth, differentiation, and survival of cells and ultimately lead to lung cancer.	('differentiation', 'CPA', (161, 176))	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('lead to', 'Reg', (215, 222))	('instability', 'MPA', (79, 90))	('inactivation', 'Var', (25, 37))	('tumor', 'Disease', (41, 46))	('lung cancer', 'Disease', (223, 234))	('affect', 'Reg', (142, 148))	('increased', 'PosReg', (69, 78))	('lung cancer', 'Phenotype', 'HP:0100526', (223, 234))	('growth', 'CPA', (153, 159))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('survival', 'CPA', (182, 190))	('Activation', 'PosReg', (0, 10))	('oncogenes', 'Gene', (14, 23))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('lung cancer', 'Disease', 'MESH:D008175', (223, 234))
240466	28960030	Genomic alterations in lung cancer are related to the progression and determine the optimal treatment of the disease.	('lung cancer', 'Disease', (23, 34))	('lung cancer', 'Phenotype', 'HP:0100526', (23, 34))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('related', 'Reg', (39, 46))	('lung cancer', 'Disease', 'MESH:D008175', (23, 34))	('Genomic alterations', 'Var', (0, 19))
240475	28960030	Amplification of GAB2 has been reported in several cancers, including melanoma, ovarian cancer, breast cancer, gliomas, and gastic cancer.	('melanoma', 'Disease', 'MESH:D008545', (70, 78))	('gliomas', 'Disease', 'MESH:D005910', (111, 118))	('gastic cancer', 'Disease', (124, 137))	('breast cancer', 'Disease', 'MESH:D001943', (96, 109))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('breast cancer', 'Disease', (96, 109))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('gastic cancer', 'Disease', 'MESH:D009369', (124, 137))	('gliomas', 'Phenotype', 'HP:0009733', (111, 118))	('GAB2', 'Gene', '9846', (17, 21))	('GAB2', 'Gene', (17, 21))	('gastic cancer', 'Phenotype', 'HP:0012126', (124, 137))	('ovarian cancer', 'Disease', 'MESH:D010051', (80, 94))	('cancers', 'Disease', 'MESH:D009369', (51, 58))	('melanoma', 'Phenotype', 'HP:0002861', (70, 78))	('melanoma', 'Disease', (70, 78))	('reported', 'Reg', (31, 39))	('ovarian cancer', 'Disease', (80, 94))	('Amplification', 'Var', (0, 13))	('gliomas', 'Disease', (111, 118))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('ovarian cancer', 'Phenotype', 'HP:0100615', (80, 94))	('cancers', 'Phenotype', 'HP:0002664', (51, 58))	('breast cancer', 'Phenotype', 'HP:0003002', (96, 109))	('cancers', 'Disease', (51, 58))
240477	28960030	Increased PI3K signaling and abberation of the PI3K pathway genes PIK3CA, PKB, and PTEN have been implicated in several types of cancer including lung cancer.	('lung cancer', 'Disease', 'MESH:D008175', (146, 157))	('cancer', 'Disease', (129, 135))	('implicated', 'Reg', (98, 108))	('PKB', 'Gene', '207', (74, 77))	('lung cancer', 'Phenotype', 'HP:0100526', (146, 157))	('PKB', 'Gene', (74, 77))	('PTEN', 'Gene', (83, 87))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('PIK3CA', 'Gene', (66, 72))	('cancer', 'Disease', (151, 157))	('PTEN', 'Gene', '5728', (83, 87))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('PI3K', 'Gene', (47, 51))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('Increased', 'PosReg', (0, 9))	('abberation', 'Var', (29, 39))	('lung cancer', 'Disease', (146, 157))	('PI3K signaling', 'Pathway', (10, 24))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('PIK3CA', 'Gene', '5290', (66, 72))
240479	28960030	In addition, ablation of GAB2 severely suppressed lung metastasis, implicating GAB2 as an important therapeutic target.	('GAB2', 'Gene', (79, 83))	('ablation', 'Var', (13, 21))	('lung metastasis', 'CPA', (50, 65))	('GAB2', 'Gene', '9846', (25, 29))	('GAB2', 'Gene', '9846', (79, 83))	('suppressed', 'NegReg', (39, 49))	('GAB2', 'Gene', (25, 29))
240494	28960030	In summary, we identified a GAB2 genetic variation that was associated with lung cancer in non-smokers by ArrayCGH and this result was validated by TCGA data.	('lung cancer', 'Disease', 'MESH:D008175', (76, 87))	('GAB2', 'Gene', (28, 32))	('genetic variation', 'Var', (33, 50))	('lung cancer', 'Disease', (76, 87))	('lung cancer', 'Phenotype', 'HP:0100526', (76, 87))	('GAB2', 'Gene', '9846', (28, 32))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('associated', 'Reg', (60, 70))
240496	28960030	Smoking is a major risk factor for lung cancer, but specific genetic alterations affect the development of lung cancer in non-smokers.	('lung cancer', 'Disease', 'MESH:D008175', (35, 46))	('lung cancer', 'Disease', 'MESH:D008175', (107, 118))	('genetic alterations', 'Var', (61, 80))	('lung cancer', 'Disease', (35, 46))	('affect', 'Reg', (81, 87))	('lung cancer', 'Phenotype', 'HP:0100526', (35, 46))	('lung cancer', 'Disease', (107, 118))	('lung cancer', 'Phenotype', 'HP:0100526', (107, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))
240497	28960030	Identification of these specific genetic alterations may uncover new biomarkers to identify individuals at high risk of developing lung cancer.	('lung cancer', 'Disease', 'MESH:D008175', (131, 142))	('genetic alterations', 'Var', (33, 52))	('lung cancer', 'Disease', (131, 142))	('lung cancer', 'Phenotype', 'HP:0100526', (131, 142))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
240509	26880895	It has been reported that the deactivation of the CADM1/TSLC1 gene, partly through promoter hypermethylation, is associated with the occurrence and development of a wide variety of tumors, including non-small cell lung cancer, ovarian cancer, breast cancer, colon cancer, and laryngeal squamous cell carcinoma.	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (199, 225))	('laryngeal squamous cell carcinoma', 'Disease', (276, 309))	('colon cancer', 'Disease', 'MESH:D015179', (258, 270))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('ovarian cancer', 'Disease', (227, 241))	('breast cancer', 'Phenotype', 'HP:0003002', (243, 256))	('tumors', 'Phenotype', 'HP:0002664', (181, 187))	('ovarian cancer', 'Phenotype', 'HP:0100615', (227, 241))	('cancer', 'Phenotype', 'HP:0002664', (264, 270))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (203, 225))	('non-small cell lung cancer', 'Disease', (199, 225))	('breast cancer', 'Disease', 'MESH:D001943', (243, 256))	('colon cancer', 'Disease', (258, 270))	('CADM1/TSLC1', 'Gene', (50, 61))	('breast cancer', 'Disease', (243, 256))	('carcinoma', 'Phenotype', 'HP:0030731', (300, 309))	('laryngeal squamous cell carcinoma', 'Disease', 'MESH:D002294', (276, 309))	('deactivation', 'Var', (30, 42))	('lung cancer', 'Phenotype', 'HP:0100526', (214, 225))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (199, 225))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('colon cancer', 'Phenotype', 'HP:0003003', (258, 270))	('ovarian cancer', 'Disease', 'MESH:D010051', (227, 241))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))	('associated', 'Reg', (113, 123))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (286, 309))
240510	26880895	Ito and colleagues reported that loss of CADM1/TSLC1 expression plays an important role in tumor growth, cell motility, and invasion and is associated with aggressive tumor behavior in ESCC.	('tumor growth', 'CPA', (91, 103))	('associated with', 'Reg', (140, 155))	('aggressive tumor behavior', 'Disease', (156, 181))	('CADM1/TSLC1', 'Gene', (41, 52))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('loss', 'Var', (33, 37))	('ESCC', 'Disease', (185, 189))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('aggressive tumor behavior', 'Disease', 'MESH:D001523', (156, 181))	('invasion', 'CPA', (124, 132))	('cell motility', 'CPA', (105, 118))
240524	26880895	Furthermore, Lee and colleagues reported that cohypermethylation of CADM1 in combination with p14 may be an independent prognostic factor for recurrence in patients with stage I ESCC.	('CADM1', 'Gene', (68, 73))	('cohypermethylation', 'Var', (46, 64))	('p14', 'Gene', (94, 97))	('stage I ESCC', 'Disease', (170, 182))	('p14', 'Gene', '1029', (94, 97))
240535	25876000	125 (14 %) out of 893 R/M SCCHN patients received palliative, non-trial first-line systemic treatment, mainly platinum + 5FU + cetuximab (32 %), other platinum-based combination therapy (13 %), methotrexate monotherapy (27 %) and capecitabine monotherapy (14 %).	('cetuximab', 'Chemical', 'MESH:D000068818', (127, 136))	('platinum', 'Chemical', 'MESH:D010984', (110, 118))	('893 R/M', 'SUBSTITUTION', 'None', (18, 25))	('SCC', 'Gene', '6317', (26, 29))	('patients', 'Species', '9606', (32, 40))	('capecitabine', 'Chemical', 'MESH:D000069287', (230, 242))	('5FU', 'Chemical', 'MESH:D005472', (121, 124))	('platinum', 'Chemical', 'MESH:D010984', (151, 159))	('methotrexate', 'Chemical', 'MESH:D008727', (194, 206))	('SCC', 'Gene', (26, 29))	('893 R/M', 'Var', (18, 25))
240563	25876000	Medical charts were reviewed for patients diagnosed with recurrent and/or metastatic (M+) squamous cell carcinoma of the head and neck (ICD-O C01-C14 and C30-C32) between January 1, 2006 and July 3, 2013.	('C30-C32', 'Var', (154, 161))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (90, 113))	('patients', 'Species', '9606', (33, 41))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('squamous cell carcinoma', 'Disease', (90, 113))	('C01-C14', 'Var', (142, 149))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (90, 113))	('carcinoma of the head and neck', 'Phenotype', 'HP:0012288', (104, 134))
240664	25961911	The relative standard deviation (RSD) was obtained by measuring the abundance of ions at m/z 782.5, 808.5 and 832.5 (MS stage) of the tumor tissues, and the RSDs were 18.17%, 18.84% and 17.83%, respectively (Table S-1).	('m/z 782.5', 'Var', (89, 98))	('808.5', 'Var', (100, 105))	('832.5', 'Var', (110, 115))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('RSDs', 'Disease', (157, 161))	('RSDs', 'Disease', 'MESH:D012019', (157, 161))	('RSD', 'Disease', 'MESH:D012019', (33, 36))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('RSD', 'Disease', 'MESH:D012019', (157, 160))	('RSD', 'Disease', (33, 36))	('RSD', 'Disease', (157, 160))	('abundance', 'MPA', (68, 77))	('tumor', 'Disease', (134, 139))
240670	25961911	The relative abundances of m/z 154.03 (5.75 +- 2.39 vs 3.26 +- 1.53, P < 0.05), m/z 170.06 (3.65 +- 2.37 vs 1.21 +- 0.56, P < 0.05), m/z 798.90 (4.69 +- 2.31 vs 2.35 +- 0.87, P < 0.05), m/z 808.49 (4.95 +- 1.56 vs 3.82 +- 1.36, P < 0.05), and m/z 832.43 (3.96 +- 1.53vs 2.61 +- 1.15, P < 0.05) were greater in cancerous tissue, and the relative abundances of m/z 203.08 (1.59 +- 0.84 vs 3.56 +- 2.43, P < 0.05), m/z 757.47 (2.59 +- 1.08 vs 6.97 +- 2.34, P < 0.05) and m/z 782.52 (3.39 +- 1.54 vs 4.67 +- 1.26, P < 0.05) were higher in normal tissue (Fig.	('m/z 782.52', 'Var', (468, 478))	('cancerous', 'Disease', (310, 319))	('greater', 'PosReg', (299, 306))	('cancer', 'Phenotype', 'HP:0002664', (310, 316))	('cancerous', 'Disease', 'MESH:D009369', (310, 319))	('m/z 808.49', 'Var', (186, 196))	('m/z', 'Var', (133, 136))	('m/z 203.08', 'Var', (359, 369))	('m/z 757.47', 'Var', (412, 422))
240678	25961911	observed the composition of pulmonary surfactant phospholipids and fatty acids of lung cancer patients, and, as it is well known that smoking is the leading correlated condition of lung cancer, he found that smoking lowered PC and phosphatidylglycerol in lung tissue.	('patients', 'Species', '9606', (94, 102))	('fatty acids of lung cancer', 'Disease', (67, 93))	('lung cancer', 'Phenotype', 'HP:0100526', (82, 93))	('smoking', 'Var', (208, 215))	('PC', 'Chemical', 'MESH:D010713', (224, 226))	('phospholipids', 'Chemical', 'MESH:D010743', (49, 62))	('lowered', 'NegReg', (216, 223))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('lung cancer', 'Disease', (181, 192))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('fatty acids of lung cancer', 'Disease', 'MESH:D000326', (67, 93))	('lung cancer', 'Phenotype', 'HP:0100526', (181, 192))	('condition of lung', 'Phenotype', 'HP:0002088', (168, 185))	('lung cancer', 'Disease', 'MESH:D008175', (82, 93))	('phosphatidylglycerol', 'Chemical', 'MESH:D010715', (231, 251))	('lung cancer', 'Disease', 'MESH:D008175', (181, 192))
240680	25961911	Also, the association between genetic variations in surfactant protein D and lung cancer was found in a Japanese patient cohort.	('lung cancer', 'Phenotype', 'HP:0100526', (77, 88))	('patient', 'Species', '9606', (113, 120))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('association', 'Interaction', (10, 21))	('lung cancer', 'Disease', 'MESH:D008175', (77, 88))	('genetic variations', 'Var', (30, 48))	('lung cancer', 'Disease', (77, 88))
240713	32190688	EGFR knockdown with shRNA in ESCC cell significantly reduced the sensitivity of cancer cells to ILQ.	('EGFR', 'Gene', (0, 4))	('ILQ', 'Chemical', 'MESH:C040920', (96, 99))	('knockdown', 'Var', (5, 14))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('reduced', 'NegReg', (53, 60))	('sensitivity', 'MPA', (65, 76))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('EGFR', 'Gene', '1956', (0, 4))	('cancer', 'Disease', (80, 86))
240714	32190688	Moreover, it was found that ILQ had a significantly inhibitory effect on AP-1 family, the protein of Jun and Fos subfamilies was substantially downregulated, and the transcriptional activity of AP-1 family was dramatically suppressed by ILQ.	('AP-1', 'Gene', (194, 198))	('AP-1', 'Gene', '2353', (194, 198))	('ILQ', 'Chemical', 'MESH:C040920', (237, 240))	('AP-1', 'Gene', '2353', (73, 77))	('downregulated', 'NegReg', (143, 156))	('ILQ', 'Chemical', 'MESH:C040920', (28, 31))	('suppressed', 'NegReg', (223, 233))	('inhibitory effect', 'NegReg', (52, 69))	('transcriptional activity', 'MPA', (166, 190))	('ILQ', 'Var', (237, 240))	('Fos', 'Gene', '2353', (109, 112))	('AP-1', 'Gene', (73, 77))	('ILQ', 'Var', (28, 31))	('Fos', 'Gene', (109, 112))
240716	32190688	Finally, the antitumor potency of ILQ was validated in xenograft models and the tumor growth was prominently restrained by ILQ.	('ILQ', 'Chemical', 'MESH:C040920', (123, 126))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor', 'Disease', (17, 22))	('ILQ', 'Chemical', 'MESH:C040920', (34, 37))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('ILQ', 'Var', (123, 126))	('tumor', 'Disease', (80, 85))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('restrained', 'NegReg', (109, 119))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
240726	32190688	Owing to its importance, in some tumor types such as lung adenocarcinoma, the somatic mutations of EGFR can act as a driver to accelerate tumor growth.	('mutations', 'Var', (86, 95))	('EGFR', 'Gene', (99, 103))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (53, 72))	('tumor', 'Disease', (138, 143))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('lung adenocarcinoma', 'Disease', (53, 72))	('accelerate', 'PosReg', (127, 137))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (53, 72))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumor', 'Disease', (33, 38))	('EGFR', 'Gene', '1956', (99, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
240727	32190688	And the tumors with EGFR mutations have shown great response to EGFR inhibitors.	('mutations', 'Var', (25, 34))	('EGFR', 'Gene', (20, 24))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('tumors', 'Disease', (8, 14))	('tumors', 'Disease', 'MESH:D009369', (8, 14))	('EGFR', 'Gene', '1956', (64, 68))	('tumors', 'Phenotype', 'HP:0002664', (8, 14))	('EGFR', 'Gene', (64, 68))	('EGFR', 'Gene', '1956', (20, 24))	('response', 'MPA', (52, 60))
240730	32190688	In addition to overexpression, gene amplification of EGFR was also identified in ESCC tissue.	('EGFR', 'Gene', (53, 57))	('gene amplification', 'Var', (31, 49))	('ESCC', 'Disease', (81, 85))	('EGFR', 'Gene', '1956', (53, 57))
240731	32190688	The analysis of survival demonstrated that the patients with low copy number had longer survival in contrast with those of high EGFR amplification.	('longer', 'PosReg', (81, 87))	('EGFR', 'Gene', '1956', (128, 132))	('EGFR', 'Gene', (128, 132))	('patients', 'Species', '9606', (47, 55))	('survival', 'MPA', (88, 96))	('low copy number', 'Var', (61, 76))
240735	32190688	Recently, multiple studies had investigated the effect of ILQ on cancers, and ILQ has exhibited profound antitumor abilities against breast cancer, hepatocellular carcinoma, colon cancer, cervical cancer, prostate cancer, endometrial cancer, and so on.	('breast cancer', 'Phenotype', 'HP:0003002', (133, 146))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (148, 172))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('endometrial cancer', 'Disease', (222, 240))	('cancers', 'Phenotype', 'HP:0002664', (65, 72))	('cancers', 'Disease', (65, 72))	('endometrial cancer', 'Disease', 'MESH:D016889', (222, 240))	('breast cancer', 'Disease', 'MESH:D001943', (133, 146))	('ILQ', 'Chemical', 'MESH:C040920', (78, 81))	('breast cancer', 'Disease', (133, 146))	('colon cancer', 'Phenotype', 'HP:0003003', (174, 186))	('cervical cancer', 'Disease', (188, 203))	('ILQ', 'Var', (78, 81))	('cervical cancer', 'Disease', 'MESH:D002583', (188, 203))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (148, 172))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('ILQ', 'Chemical', 'MESH:C040920', (58, 61))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('colon cancer', 'Disease', 'MESH:D015179', (174, 186))	('prostate cancer', 'Disease', 'MESH:D011471', (205, 220))	('hepatocellular carcinoma', 'Disease', (148, 172))	('cancers', 'Disease', 'MESH:D009369', (65, 72))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('prostate cancer', 'Phenotype', 'HP:0012125', (205, 220))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('prostate cancer', 'Disease', (205, 220))	('endometrial cancer', 'Phenotype', 'HP:0012114', (222, 240))	('carcinoma', 'Phenotype', 'HP:0030731', (163, 172))	('colon cancer', 'Disease', (174, 186))	('tumor', 'Disease', (109, 114))
240748	32190688	The primary antibodies used in this study including anti-p-EGFR (Tyr1068) (#3777), anti-EGFR (#4267), anti-p-Akt (S473) (#4060), anti-Akt (#4691), anti-p-ERK1/2 (Thr202/Tyr204) (#4370), anti-ERK1/2(#4695), anti-c-Jun (#9165), anti-JunB (#3746), anti-JunD (#5000), anti-FosB(#4691), anti-c-Fos (#2251), anti-Fra1(#5281), anti-Cyclin D1(#55506), anti-beta-actin (#3700), and anti-Histone H3 Ser10 (#53348) were products of Cell Signaling Technology (Danvers, MA).	('EGFR', 'Gene', (59, 63))	('FosB', 'Gene', (269, 273))	('Fra1', 'Gene', '8061', (307, 311))	('FosB', 'Gene', '2354', (269, 273))	('#4370', 'Var', (178, 183))	('Akt', 'Gene', (109, 112))	('Akt', 'Gene', (134, 137))	('#3746', 'Var', (237, 242))	('JunD', 'Gene', (250, 254))	('#2251', 'Var', (294, 299))	('Akt', 'Gene', '207', (109, 112))	('Cyclin D1', 'Gene', '595', (325, 334))	('Akt', 'Gene', '207', (134, 137))	('#3700', 'Var', (361, 366))	('ERK1/2', 'Gene', (191, 197))	('ERK1/2', 'Gene', '5595;5594', (191, 197))	('Cyclin D1', 'Gene', (325, 334))	('EGFR', 'Gene', (88, 92))	('EGFR', 'Gene', '1956', (59, 63))	('#53348', 'Var', (396, 402))	('c-Fos', 'Gene', (287, 292))	('JunB', 'Gene', (231, 235))	('#5000', 'Var', (256, 261))	('c-Fos', 'Gene', '2353', (287, 292))	('ERK1/2', 'Gene', '5595;5594', (154, 160))	('JunB', 'Gene', '3726', (231, 235))	('Fra1', 'Gene', (307, 311))	('c-Jun', 'Gene', '3725', (211, 216))	('JunD', 'Gene', '3727', (250, 254))	('c-Jun', 'Gene', (211, 216))	('EGFR', 'Gene', '1956', (88, 92))	('ERK1/2', 'Gene', (154, 160))
240765	32190688	To generate lentiviral particles, the plasmid pLKO.1-sh-EGFR, psPAX2 (#12260, Addgene), or pMD2.G (#12259, Addgene) was cotransfected into HEK-293T cells with PSPAX2 and PMD2.G.	('EGFR', 'Gene', '1956', (56, 60))	('#12260', 'Var', (70, 76))	('EGFR', 'Gene', (56, 60))	('HEK-293T', 'CellLine', 'CVCL:0063;0.1213289305524951', (139, 147))	('#12259', 'Var', (99, 105))
240779	32190688	As shown in Figures 1(b)-1(d), in three tested ESCC cells KYSE-140, KYSE-520, and TE-1, ILQ had demonstrated profound antitumor activity, and the cell viability was significantly decreased in a dose- and time-dependent manner.	('ILQ', 'Chemical', 'MESH:C040920', (88, 91))	('decreased', 'NegReg', (179, 188))	('KYSE-520', 'Var', (68, 76))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('KYSE-140', 'Var', (58, 66))	('cell viability', 'CPA', (146, 160))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumor', 'Disease', (122, 127))
240784	32190688	Moreover, with EGFR inhibition, the phosphorylation of ERK and AKT, two major downstream signaling molecules, were both significantly reduced.	('AKT', 'Gene', (63, 66))	('ERK', 'Gene', '5594', (55, 58))	('inhibition', 'Var', (20, 30))	('EGFR', 'Gene', '1956', (15, 19))	('EGFR', 'Gene', (15, 19))	('reduced', 'NegReg', (134, 141))	('AKT', 'Gene', '207', (63, 66))	('phosphorylation', 'MPA', (36, 51))	('ERK', 'Gene', (55, 58))
240790	32190688	After transfection with EGFR-shRNA, the ability of colony formation had been affected in contrast with GFP-shRNA.	('EGFR', 'Gene', '1956', (24, 28))	('EGFR', 'Gene', (24, 28))	('colony formation', 'CPA', (51, 67))	('transfection', 'Var', (6, 18))
240795	32190688	Meanwhile, other proteins in the Fos subfamily, including FosB, c-Fos, and Fra1, were also substantially decreased after ILQ treatment (Figures 3(a) and 3(b)).	('Fos', 'Gene', (33, 36))	('FosB', 'Gene', (58, 62))	('Fra1', 'Gene', '8061', (75, 79))	('Fos', 'Gene', (58, 61))	('c-Fos', 'Gene', (64, 69))	('Fos', 'Gene', (66, 69))	('Fra1', 'Gene', (75, 79))	('FosB', 'Gene', '2354', (58, 62))	('Fos', 'Gene', '2353', (66, 69))	('Fos', 'Gene', '2353', (33, 36))	('ILQ', 'Chemical', 'MESH:C040920', (121, 124))	('Fos', 'Gene', '2353', (58, 61))	('c-Fos', 'Gene', '2353', (64, 69))	('ILQ', 'Var', (121, 124))	('decreased', 'NegReg', (105, 114))	('proteins', 'Protein', (17, 25))
240802	32190688	Next, we analyzed the cell phase distribution in ILQ-treated cells, as shown in Figure 4(b), after the treatment of ILQ, the proportion of cells in the G0/G1 phase increased in a dose-dependent manner, suggesting ILQ could cause cell cycle arrest.	('ILQ', 'Chemical', 'MESH:C040920', (213, 216))	('ILQ', 'Var', (213, 216))	('ILQ', 'Chemical', 'MESH:C040920', (116, 119))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (229, 246))	('ILQ', 'Chemical', 'MESH:C040920', (49, 52))	('cell cycle arrest', 'CPA', (229, 246))	('increased', 'PosReg', (164, 173))
240821	32190688	It is consolidated that the dysregulation of EGFR activity is closely associated with tumor development.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('EGFR', 'Gene', (45, 49))	('tumor', 'Disease', (86, 91))	('dysregulation', 'Var', (28, 41))	('associated', 'Reg', (70, 80))	('activity', 'MPA', (50, 58))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('EGFR', 'Gene', '1956', (45, 49))
240828	32190688	With the inactivation of EGFR, two key downstream molecules, ERK and Akt, were inhibited.	('Akt', 'Gene', (69, 72))	('EGFR', 'Gene', (25, 29))	('ERK', 'Gene', '5594', (61, 64))	('inhibited', 'NegReg', (79, 88))	('inactivation', 'Var', (9, 21))	('Akt', 'Gene', '207', (69, 72))	('ERK', 'Gene', (61, 64))	('EGFR', 'Gene', '1956', (25, 29))
240830	32190688	Moreover, in EGFR deficient cells, the sensitivities to ILQ were reduced significantly.	('sensitivities to ILQ', 'MPA', (39, 59))	('reduced', 'NegReg', (65, 72))	('ILQ', 'Chemical', 'MESH:C040920', (56, 59))	('deficient', 'Var', (18, 27))	('EGFR', 'Gene', '1956', (13, 17))	('EGFR', 'Gene', (13, 17))
240835	32190688	Genomic profiling showed that CCND1 amplification was present in 57% tumor tissue and often coordinated with EGFR amplification to accelerate tumor progression.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('tumor', 'Disease', (69, 74))	('tumor', 'Disease', (142, 147))	('amplification', 'Var', (36, 49))	('EGFR', 'Gene', '1956', (109, 113))	('CCND1', 'Gene', (30, 35))	('accelerate', 'PosReg', (131, 141))	('EGFR', 'Gene', (109, 113))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('CCND1', 'Gene', '595', (30, 35))
240836	32190688	Some studies also indicated that dysregulated cyclin D1 expression is the reason for the reduced efficacy of EGFR inhibitors.	('cyclin D1', 'Gene', '595', (46, 55))	('cyclin D1', 'Gene', (46, 55))	('EGFR', 'Gene', '1956', (109, 113))	('dysregulated', 'Var', (33, 45))	('expression', 'MPA', (56, 66))	('reduced', 'NegReg', (89, 96))	('EGFR', 'Gene', (109, 113))	('efficacy', 'MPA', (97, 105))
240843	32190688	Western blotting also confirmed that the expression of proteins in Jun and Fos family was decreased after ILQ treatment.	('expression of proteins', 'MPA', (41, 63))	('ILQ', 'Chemical', 'MESH:C040920', (106, 109))	('decreased', 'NegReg', (90, 99))	('Fos', 'Gene', '2353', (75, 78))	('treatment', 'Var', (110, 119))	('Fos', 'Gene', (75, 78))	('Jun', 'Protein', (67, 70))
240850	25152695	We determined P53, epidermal growth factor receptor, microsatellite instability, human papilloma virus infection and loss of heterozygosity status at several tumor suppressor loci in one hundred and twenty one oral SCCT (SSCOT) samples and analyzed their association with clinico-pathological features and patient survival.	('loss of heterozygosity status', 'Var', (117, 146))	('papilloma virus infection', 'Disease', 'MESH:D010212', (87, 112))	('tumor', 'Disease', (158, 163))	('P53', 'Gene', '7157', (14, 17))	('epidermal growth factor receptor', 'Gene', '1956', (19, 51))	('P53', 'Gene', (14, 17))	('papilloma', 'Phenotype', 'HP:0012740', (87, 96))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('epidermal growth factor receptor', 'Gene', (19, 51))	('papilloma virus infection', 'Disease', (87, 112))	('microsatellite', 'MPA', (53, 67))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('patient', 'Species', '9606', (306, 313))
240851	25152695	FHIT loss was significantly associated with p53 nuclear stabilization and the association was stronger in patients with no history of tobacco use.	('tobacco', 'Species', '4097', (134, 141))	('p53', 'Var', (44, 47))	('FHIT loss', 'Disease', 'MESH:D015431', (0, 9))	('FHIT loss', 'Disease', (0, 9))	('patients', 'Species', '9606', (106, 114))
240872	25152695	Samples exhibiting nuclear stain in more than 20% tumor epithelium were considered as positive for p53.	('p53', 'Var', (99, 102))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('positive', 'Reg', (86, 94))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Disease', (50, 55))
240873	25152695	For EGFR, staining intensity (negative, weak, moderate and strong) and fractional epithelium positivity (<=25%, 25 <= 50%, 50 <= 75% and 75 <= 100%) were scored as 0-3.	('EGFR', 'Gene', (4, 8))	('<=25%', 'Var', (105, 110))	('EGFR', 'Gene', '1956', (4, 8))
240881	25152695	D2S123, D5S346 and D17S250) using FFPE DNA as template as described earlier.	('D5S346', 'Gene', '7905', (8, 14))	('D2S123', 'Var', (0, 6))	('D5S346', 'Gene', (8, 14))	('D17S250', 'Var', (19, 26))
240882	25152695	LOH analysis was performed (only for fresh samples) based on polymorphic microsatellites located close to putative tongue cancer tumor suppressor genes including tp53CA (TP53-17pl3.1), D3S1300 (FHIT-3p14.2) and D9S1748 (CDKN2A-9p21).	('tp53CA', 'Var', (162, 168))	('FHIT', 'Gene', (194, 198))	('FHIT', 'Gene', '2272', (194, 198))	('D3S1300', 'Var', (185, 192))	('D9S1748', 'Var', (211, 218))	('TP53', 'Gene', '7157', (170, 174))	('p21', 'Gene', (228, 231))	('TP53', 'Gene', (170, 174))	('tongue cancer tumor', 'Disease', 'MESH:D014062', (115, 134))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('p21', 'Gene', '644914', (228, 231))	('tongue cancer tumor', 'Phenotype', 'HP:0100648', (115, 134))	('tongue cancer tumor', 'Disease', (115, 134))	('CDKN2A', 'Gene', (220, 226))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('CDKN2A', 'Gene', '1029', (220, 226))
240883	25152695	LOH status was also assessed for all three dinucleotide microsatellites of the NCI panel namely D2S123 (hMSH2-2p15-16), D5S346 (APC-5q21) and D17S250 (BRCA1-17q11.2).	('dinucleotide', 'Chemical', 'MESH:D015226', (43, 55))	('BRCA1', 'Gene', '672', (151, 156))	('D5S346', 'Gene', (120, 126))	('BRCA1', 'Gene', (151, 156))	('hMSH2', 'Gene', '4436', (104, 109))	('D5S346', 'Gene', '7905', (120, 126))	('hMSH2', 'Gene', (104, 109))	('D2S123', 'Var', (96, 102))	('D17S250', 'Var', (142, 149))
240888	25152695	There was no significant association however between p53 stabilization and tobacco use (data not shown).	('tobacco', 'Species', '4097', (75, 82))	('p53', 'Var', (53, 56))	('tobacco use', 'Disease', (75, 86))
240889	25152695	We next screened mutations in exons 5-8 of TP53 that encode the DNA binding domain and are known to harbor majority of mutations.	('TP53', 'Gene', '7157', (43, 47))	('TP53', 'Gene', (43, 47))	('binding', 'Interaction', (68, 75))	('mutations', 'Var', (17, 26))
240890	25152695	Mutations (listed in Additional file 3: Table S3), were detected in fifteen of thirty five tumor samples that exhibited p53 nuclear stabilization and in three of twenty six that did not.	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('Mutations', 'Var', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('p53', 'Gene', (120, 123))	('tumor', 'Disease', (91, 96))
240892	25152695	Proportion of transitions, transversions and indels were similar to previous reports for SCCT as per the International Agency for Research on Cancer TP53 database (Additional file 4: Figure S1) and were not significantly different between the two age groups (data not shown).	('TP53', 'Gene', '7157', (149, 153))	('TP53', 'Gene', (149, 153))	('transversions', 'Var', (27, 40))	('indels', 'Var', (45, 51))	('Cancer', 'Phenotype', 'HP:0002664', (142, 148))	('transitions', 'Var', (14, 25))
240893	25152695	We identified a novel 33 bp deletion, c.616-648del33 (Additional file 5: Figure S2), located in exon 5 in a p53 positive tumor sample obtained from a chronic tobacco chewer that is expected to result in loss of eleven amino acids (143-153).	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tobacco', 'Species', '4097', (158, 165))	('143-153', 'Var', (231, 238))	('tumor', 'Disease', (121, 126))	('c.616-648del33', 'Mutation', 'c.616_648del33', (38, 52))	('c.616-648del33', 'Var', (38, 52))	('eleven amino acids', 'MPA', (211, 229))	('loss', 'NegReg', (203, 207))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
240894	25152695	Majority of p53 positive tumors harboring mutation (12/15) exhibited p53 positivity in greater than 50% tumor cells (Additional file 3: Table S3).	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumors', 'Disease', (25, 31))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('tumor', 'Disease', (25, 30))	('tumor', 'Disease', (104, 109))	('p53', 'Gene', (12, 15))	('tumors', 'Disease', 'MESH:D009369', (25, 31))	('mutation', 'Var', (42, 50))	('p53 positivity', 'MPA', (69, 83))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
240896	25152695	In addition, of the three p53 negative tumors that harbored p53 mutation, two exhibited complete absence of staining.	('tumors', 'Disease', (39, 45))	('mutation', 'Var', (64, 72))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('p53', 'Gene', (60, 63))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))
240897	25152695	Interestingly, missense/inframe mutations were predominantly identified in tumors exhibiting p53 stabilization whereas frameshift mutations resulting in protein truncation were identified exclusively in p53 negative tumors (Additional file 3: Table S3).	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('p53', 'Gene', (93, 96))	('protein truncation', 'MPA', (153, 171))	('tumors', 'Disease', (216, 222))	('tumors', 'Disease', 'MESH:D009369', (216, 222))	('tumors', 'Phenotype', 'HP:0002664', (216, 222))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('missense/inframe mutations', 'Var', (15, 41))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('frameshift mutations', 'Var', (119, 139))	('tumors', 'Disease', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))
240903	25152695	PCR based screening revealed low proportion of HPV infection (14/106; 13.2%) (Additional file 6: Table S4) and MSI 14/106 (13.2%) (Additional file 7: Figure S3A-E) in our sample cohort.	('MSI', 'Var', (111, 114))	('HPV infection', 'Disease', 'MESH:D030361', (47, 60))	('HPV infection', 'Disease', (47, 60))
240904	25152695	Dinucleotide microsatellites exhibited frequent instability (40/318; 12.58%) compared to mononucleotide microsatellites (13/212; 6.13%) (data not shown).	('Dinucleotide', 'Chemical', 'MESH:D015226', (0, 12))	('instability', 'MPA', (48, 59))	('Dinucleotide microsatellites', 'Var', (0, 28))	('mononucleotide', 'Chemical', '-', (89, 103))
240910	25152695	As expected, patients with tumors harboring p53 DNA binding domain mutation were significantly associated with poor survival (p = 0.0117) (Figure 2B and Table 5).	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('patients', 'Species', '9606', (13, 21))	('p53 DNA', 'Var', (44, 51))	('tumors', 'Disease', (27, 33))	('tumors', 'Disease', 'MESH:D009369', (27, 33))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('binding', 'Interaction', (52, 59))	('poor', 'NegReg', (111, 115))
240912	25152695	Abrogation of p53 tumor suppressor activity is a frequent event in many cancers, including HNSCC.	('p53', 'Protein', (14, 17))	('Abrogation', 'Var', (0, 10))	('tumor', 'Disease', (18, 23))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('HNSCC', 'Disease', (91, 96))	('cancers', 'Disease', (72, 79))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('cancers', 'Disease', 'MESH:D009369', (72, 79))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
240913	25152695	Interestingly, frequency of p53 nuclear stabilization was high in young patients (Table 1), suggesting possible role of genetic factors.	('p53', 'Var', (28, 31))	('patients', 'Species', '9606', (72, 80))	('nuclear stabilization', 'CPA', (32, 53))
240917	25152695	The distinct occurrence of TP53 mutation exclusively in samples exhibiting strong or absent p53 immunostain has been observed earlier in ovarian cancer.	('TP53', 'Gene', '7157', (27, 31))	('TP53', 'Gene', (27, 31))	('ovarian cancer', 'Phenotype', 'HP:0100615', (137, 151))	('occurrence', 'Reg', (13, 23))	('ovarian cancer', 'Disease', 'MESH:D010051', (137, 151))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('p53 immunostain', 'Protein', (92, 107))	('ovarian cancer', 'Disease', (137, 151))	('absent', 'NegReg', (85, 91))	('mutation', 'Var', (32, 40))
240918	25152695	Interestingly, we observed that young patients with p53 nuclear stabilization also exhibited DNA binding domain mutation similar to older SCCOT patients.	('exhibited', 'Reg', (83, 92))	('p53', 'Gene', (52, 55))	('domain mutation', 'Var', (105, 120))	('patients', 'Species', '9606', (144, 152))	('patients', 'Species', '9606', (38, 46))	('DNA', 'MPA', (93, 96))
240922	25152695	In this study, dinucleotide microsatellites exhibited frequent instability compared to mononucleotide microsatellites perhaps suggesting the occurrence of a distinct form of instability than the one observed in classical mismatch repair (MMR) deficient tumors.	('deficient tumors', 'Disease', (243, 259))	('instability', 'MPA', (63, 74))	('deficient tumors', 'Disease', 'MESH:D009369', (243, 259))	('tumors', 'Phenotype', 'HP:0002664', (253, 259))	('tumor', 'Phenotype', 'HP:0002664', (253, 258))	('mononucleotide', 'Chemical', '-', (87, 101))	('dinucleotide microsatellites', 'Var', (15, 43))	('dinucleotide', 'Chemical', 'MESH:D015226', (15, 27))
240923	25152695	A significant proportion (one-third) of tumors exhibited LOH at D9S1748 (CDKN2A) consistent with earlier reports.	('LOH', 'Var', (57, 60))	('CDKN2A', 'Gene', '1029', (73, 79))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('tumors', 'Disease', 'MESH:D009369', (40, 46))	('D9S1748', 'Var', (64, 71))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumors', 'Disease', (40, 46))	('CDKN2A', 'Gene', (73, 79))
240924	25152695	LOH frequency of D2S123 (hMSH2), D5S346 (APC) and D17S250 (BRCA1) observed in our patient cohort appeared to be lower than previous reports.	('BRCA1', 'Gene', '672', (59, 64))	('D5S346', 'Gene', (33, 39))	('D17S250', 'Var', (50, 57))	('patient', 'Species', '9606', (82, 89))	('BRCA1', 'Gene', (59, 64))	('D5S346', 'Gene', '7905', (33, 39))	('D2S123', 'Var', (17, 23))	('hMSH2', 'Gene', '4436', (25, 30))	('hMSH2', 'Gene', (25, 30))
240925	25152695	An earlier report from India revealed marginally higher frequency of LOH at TP53 locus in oral cancer, probably due to influence of tumors other than SCCOT.	('TP53', 'Gene', '7157', (76, 80))	('oral cancer', 'Disease', 'MESH:D009062', (90, 101))	('LOH', 'Var', (69, 72))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('oral cancer', 'Disease', (90, 101))	('TP53', 'Gene', (76, 80))	('tumors', 'Disease', (132, 138))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('tumors', 'Disease', 'MESH:D009369', (132, 138))
240927	25152695	P53 inactivation induced genomic instability could be one cause for the association of p53 nuclear stabilization with FHIT loss though a similar association with CDKN2A LOH was not identified.	('inactivation', 'Var', (4, 16))	('FHIT loss', 'Disease', 'MESH:D015431', (118, 127))	('CDKN2A', 'Gene', (162, 168))	('FHIT loss', 'Disease', (118, 127))	('p53', 'Gene', (87, 90))	('CDKN2A', 'Gene', '1029', (162, 168))	('genomic instability', 'MPA', (25, 44))	('P53', 'Gene', (0, 3))	('P53', 'Gene', '7157', (0, 3))	('nuclear', 'MPA', (91, 98))
240929	25152695	Strong association of loss of FHIT and p53 inactivation in nonsmokers (Table 4) suggests that tumors occurring in tobacco never users with and without p53 inactivation could be distinct entities.	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('FHIT', 'Gene', (30, 34))	('loss', 'NegReg', (22, 26))	('p53', 'Gene', (39, 42))	('tumors', 'Disease', (94, 100))	('FHIT', 'Gene', '2272', (30, 34))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('tobacco', 'Species', '4097', (114, 121))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('inactivation', 'Var', (43, 55))
240931	25152695	Therefore, inactivation of FHIT and p53 may facilitate tumor cells to evade apoptosis and escape G0/G1 arrest.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('escape', 'NegReg', (90, 96))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('G0/G1 arrest', 'CPA', (97, 109))	('p53', 'Gene', (36, 39))	('inactivation', 'Var', (11, 23))	('tumor', 'Disease', (55, 60))	('FHIT', 'Gene', (27, 31))	('FHIT', 'Gene', '2272', (27, 31))	('evade apoptosis', 'CPA', (70, 85))	('facilitate', 'PosReg', (44, 54))
240932	25152695	A recent report suggests that inactivation of both FHIT and p53 may have possible synergistic effect resulting in deregulation of proliferation related genes in lung cancer cell lines and tumors, particularly in squamous cell carcinoma subtype of non-small cell lung cancer.	('lung cancer', 'Disease', (262, 273))	('proliferation related genes', 'Gene', (130, 157))	('lung cancer', 'Disease', 'MESH:D008175', (161, 172))	('deregulation', 'MPA', (114, 126))	('tumors', 'Phenotype', 'HP:0002664', (188, 194))	('inactivation', 'Var', (30, 42))	('lung cancer', 'Phenotype', 'HP:0100526', (161, 172))	('FHIT', 'Gene', (51, 55))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (212, 235))	('tumors', 'Disease', (188, 194))	('lung cancer', 'Disease', 'MESH:D008175', (262, 273))	('cancer', 'Phenotype', 'HP:0002664', (267, 273))	('carcinoma', 'Phenotype', 'HP:0030731', (226, 235))	('FHIT', 'Gene', '2272', (51, 55))	('lung cancer', 'Phenotype', 'HP:0100526', (262, 273))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('squamous cell carcinoma subtype of non-small cell lung cancer', 'Disease', 'MESH:D002289', (212, 273))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (247, 273))	('tumors', 'Disease', 'MESH:D009369', (188, 194))	('lung cancer', 'Disease', (161, 172))	('p53', 'Gene', (60, 63))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (251, 273))
240936	25152695	However, this is the most comprehensive molecular genetic study undertaken on Indian SCCOT patients and has identified frequent mutational inactivation of p53 and its significant association with loss of FHIT.	('FHIT', 'Gene', (204, 208))	('mutational inactivation', 'Var', (128, 151))	('p53', 'Gene', (155, 158))	('patients', 'Species', '9606', (91, 99))	('association', 'Interaction', (179, 190))	('FHIT', 'Gene', '2272', (204, 208))	('loss', 'Gene', (196, 200))
240938	25152695	It would be interesting to study tumorigenesis pathways contributing to SCCOT in the absence of p53 and FHIT inactivation.	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('FHIT', 'Gene', (104, 108))	('SCCOT', 'Disease', (72, 77))	('FHIT', 'Gene', '2272', (104, 108))	('tumor', 'Disease', (33, 38))	('inactivation', 'Var', (109, 121))
240959	33218162	An integrative analysis identified that enrichment of F. nucleatum was associated with host gene promoter methylation, including hypermethylation of tumor suppressor genes LXN and SMARCA2, for which gene expressions were downregulated in the HNSCC cohort from The Cancer Genome Atlas.	('LXN', 'Gene', (172, 175))	('F. nucleatum', 'Species', '851', (54, 66))	('tumor suppressor', 'Gene', (149, 165))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('Cancer', 'Phenotype', 'HP:0002664', (264, 270))	('tumor suppressor', 'Gene', '7248', (149, 165))	('HNSCC', 'Phenotype', 'HP:0012288', (242, 247))	('Cancer', 'Disease', 'MESH:D009369', (264, 270))	('Cancer', 'Disease', (264, 270))	('downregulated', 'NegReg', (221, 234))	('LXN', 'Gene', '56925', (172, 175))	('hypermethylation', 'Var', (129, 145))	('SMARCA2', 'Gene', (180, 187))	('SMARCA2', 'Gene', '6595', (180, 187))
240964	33218162	The bacterial microbiome has also been proposed to interact with the host and play a role in carcinogenesis through host epigenetic alterations in the gut mucosa that are seen in ulcerative colitis and colorectal cancer.	('colitis', 'Phenotype', 'HP:0002583', (190, 197))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('epigenetic alterations', 'Var', (121, 143))	('colorectal cancer', 'Phenotype', 'HP:0003003', (202, 219))	('play', 'Reg', (78, 82))	('colorectal cancer', 'Disease', (202, 219))	('ulcerative colitis', 'Phenotype', 'HP:0100279', (179, 197))	('ulcerative colitis', 'Disease', (179, 197))	('ulcerative colitis', 'Disease', 'MESH:D003093', (179, 197))	('colorectal cancer', 'Disease', 'MESH:D015179', (202, 219))
241012	33218162	The most significant enrichments (p <= 0.05) involved the plant-pathogen interaction (ko04626) and epithelial cell signaling (ko05120), which were mainly contributed by Fusobacterium and Leptotrichia (Table S4).	('ko04626', 'Var', (86, 93))	('ko05120', 'Var', (126, 133))	('plant-pathogen interaction', 'CPA', (58, 84))	('Fusobacterium', 'Species', '851', (169, 182))	('epithelial', 'MPA', (99, 109))
241013	33218162	In contrast, depletions in abundance of Rothia, Lautropia, Neisseria, and several commensal bacteria were largely responsible for the suppression of pathways related to proteasome (ko03050), p53 signaling pathway (ko04115), and ribosome biogenesis in eukaryotes (ko03008).	('ko03050', 'Var', (181, 188))	('proteasome', 'Protein', (169, 179))	('suppression', 'NegReg', (134, 145))	('p53 signaling pathway', 'Pathway', (191, 212))	('pathways', 'Pathway', (149, 157))	('Lautropia, Neisseria', 'Disease', 'MESH:D006069', (48, 68))
241014	33218162	We also observed enriched pathways related to bacterial cell motility (ko02030: bacterial chemotaxis, ko02040: flagellar assembly) in tumor tissues, implying a favorable microenvironment of niche adaptation for periodontal pathogens such as Treponema2, Fusobacterium, and Catonella.	('ko02030', 'Var', (71, 78))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('ko02040', 'Var', (102, 109))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('Fusobacterium', 'Species', '851', (253, 266))	('tumor', 'Disease', (134, 139))
241025	33218162	Depletions of Neisseria, Haemophilus, and Rothia in HNSCC cases were associated with worse cancer-specific survival.	('HNSCC', 'Disease', (52, 57))	('Depletions', 'Var', (0, 10))	('HNSCC', 'Phenotype', 'HP:0012288', (52, 57))	('Rothia', 'Gene', (42, 48))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('Neisseria', 'Disease', 'MESH:D006069', (14, 23))	('Neisseria', 'Disease', (14, 23))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('worse', 'NegReg', (85, 90))
241036	33218162	Interestingly, 20 (20) hyper- and 63 (61) hypo-methylated DMRs (genes) were positively and negatively related to Fusobacterium enrichment (>=15% methylation difference, adjusted p <= 0.01), respectively, which was further confirmed by a negative binomial generalized linear regression model test (glm.nb) and a Spearman's rank-order correlation test (p <= 0.05) (Figure 5A and Figure S7, Table S5).	('DMR', 'Chemical', '-', (58, 61))	('Fusobacterium', 'Species', '851', (113, 126))	('hyper-', 'Var', (23, 29))	('Fusobacterium', 'Disease', (113, 126))	('negatively', 'NegReg', (91, 101))	('hypo-methylated', 'Var', (42, 57))
241037	33218162	We further compared gene expression profiles in the TCGA HNSCC cohort and found consistent associations between hypermethylation and downregulation in genes LXN, IRX5, NRIP2, and SMARCA2 (log2FC <= -0.5, adjusted p <= 0.01).	('HNSCC', 'Phenotype', 'HP:0012288', (57, 62))	('NRIP2', 'Gene', (168, 173))	('LXN', 'Gene', '56925', (157, 160))	('SMARCA2', 'Gene', (179, 186))	('SMARCA2', 'Gene', '6595', (179, 186))	('IRX5', 'Gene', (162, 166))	('downregulation', 'NegReg', (133, 147))	('hypermethylation', 'Var', (112, 128))	('LXN', 'Gene', (157, 160))
241038	33218162	Tumor suppressor gene (TSG) latexin (LXN) expression negatively correlates with the prognosis of several human cancers and plays significant roles in inflammatory response, tumor cell migration, invasion and apoptosis (Figure 5B); and TSG-SMARCA2 is involved in ATP-dependent chromatin remodeling related to DNA repair and replication (Figure 5C), implying a potential role of F. nucleatum infection in gene dysregulation related to the inflammatory response and cell proliferation through epigenetic silencing.	('cancers', 'Disease', 'MESH:D009369', (111, 118))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('LXN', 'Gene', '56925', (37, 40))	('infection', 'Disease', (390, 399))	('Tumor suppressor', 'Gene', '7248', (0, 16))	('infection', 'Disease', 'MESH:D007239', (390, 399))	('human', 'Species', '9606', (105, 110))	('latexin', 'Gene', '56925', (28, 35))	('F. nucleatum', 'Species', '851', (377, 389))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('latexin', 'Gene', (28, 35))	('cancers', 'Phenotype', 'HP:0002664', (111, 118))	('cancers', 'Disease', (111, 118))	('Tumor suppressor', 'Gene', (0, 16))	('SMARCA2', 'Gene', (239, 246))	('SMARCA2', 'Gene', '6595', (239, 246))	('LXN', 'Gene', (37, 40))	('tumor', 'Disease', (173, 178))	('epigenetic', 'Var', (490, 500))	('ATP', 'Chemical', 'MESH:D000255', (262, 265))
241053	33218162	This is in broad agreement with our observation of loss of LXN expression likely by F. nucleatum-associated epigenetic silencing in the HNSCC tumor microenvironment, where bacterial invasion may interfere with the pro-inflammatory immunomodulatory gene signature of LXN in blocking tumor immune cell evasion.	('F. nucleatum', 'Species', '851', (84, 96))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('LXN', 'Gene', (59, 62))	('tumor', 'Phenotype', 'HP:0002664', (282, 287))	('LXN', 'Gene', '56925', (266, 269))	('HNSCC tumor', 'Disease', 'MESH:D000077195', (136, 147))	('tumor', 'Disease', (142, 147))	('tumor', 'Disease', (282, 287))	('interfere', 'NegReg', (195, 204))	('epigenetic silencing', 'Var', (108, 128))	('HNSCC tumor', 'Disease', (136, 147))	('LXN', 'Gene', (266, 269))	('LXN', 'Gene', '56925', (59, 62))	('blocking', 'NegReg', (273, 281))	('HNSCC', 'Phenotype', 'HP:0012288', (136, 141))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('tumor', 'Disease', 'MESH:D009369', (282, 287))
241054	33218162	We also observed a similar association between F. nucleatum enrichment and TSG-SMARCA2 promoter hypermethylation.	('F. nucleatum', 'Species', '851', (47, 59))	('promoter', 'MPA', (87, 95))	('SMARCA2', 'Gene', (79, 86))	('SMARCA2', 'Gene', '6595', (79, 86))	('hypermethylation', 'Var', (96, 112))
241058	33218162	In contrast to hypermethylation, hypomethylation of sulfatase 1 (SULF1) and matrix metalloproteinase 2 (MMP2) promoters was observed to be associated with the enrichment of F. nucleatum in our HNSCC tumor tissues.	('F. nucleatum', 'Species', '851', (173, 185))	('HNSCC tumor', 'Disease', (193, 204))	('HNSCC tumor', 'Disease', 'MESH:D000077195', (193, 204))	('F. nucleatum', 'Disease', (173, 185))	('associated', 'Reg', (139, 149))	('HNSCC', 'Phenotype', 'HP:0012288', (193, 198))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('hypomethylation', 'Var', (33, 48))
241060	33218162	Whether F. nucleatum directly up-regulates SULF1 and/or MMP2 through epigenetic mechanisms or ECM remodeling by gene degradation plays a role in initial HNSCC tumor growth remains an interesting question warranting further investigations.	('HNSCC tumor', 'Disease', (153, 164))	('up-regulates', 'PosReg', (30, 42))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('HNSCC', 'Phenotype', 'HP:0012288', (153, 158))	('MMP2', 'Gene', (56, 60))	('gene degradation', 'Var', (112, 128))	('F. nucleatum', 'Species', '851', (8, 20))	('HNSCC tumor', 'Disease', 'MESH:D000077195', (153, 164))	('SULF1', 'Gene', (43, 48))
241061	33218162	Given the prominent role of somatic mutations in TP53 in smoking-related HNSCCs, for example, dramatic enrichment of F. nucleatum in nonsmokers, may explain it in part as a pathogen causing DNA damage in patients without traditional high-risk factors.	('patients', 'Species', '9606', (204, 212))	('TP53', 'Gene', (49, 53))	('HNSCC', 'Phenotype', 'HP:0012288', (73, 78))	('HNSCCs', 'Disease', (73, 79))	('mutations', 'Var', (36, 45))	('F. nucleatum', 'Species', '851', (117, 129))	('DNA damage', 'Disease', (190, 200))	('HNSCCs', 'Disease', 'MESH:D000077195', (73, 79))
241063	33218162	Furthermore, F. nucleatum may regulate host gene transcriptome profiles through epigenetic mechanisms and act as a pro-inflammatory driver involving multiple cell signaling pathways.	('F. nucleatum', 'Species', '851', (13, 25))	('epigenetic', 'Var', (80, 90))	('host gene transcriptome profiles', 'MPA', (39, 71))	('regulate', 'Reg', (30, 38))
241092	31367271	Cisplatin induces severe nausea and vomiting, i.e., it is highly emetogenic, and it also has strong nephrotoxicity, in which a large amount infusion is necessary to prevent renal impairment.	('vomiting', 'Disease', 'MESH:D014839', (36, 44))	('renal impairment', 'Disease', (173, 189))	('nephrotoxicity', 'Disease', 'MESH:D007674', (100, 114))	('nephrotoxicity', 'Disease', (100, 114))	('renal impairment', 'Disease', 'MESH:D007674', (173, 189))	('nausea', 'Phenotype', 'HP:0002018', (25, 31))	('nausea', 'Disease', (25, 31))	('nausea', 'Disease', 'MESH:D009325', (25, 31))	('Cisplatin', 'Chemical', 'MESH:D002945', (0, 9))	('renal impairment', 'Phenotype', 'HP:0000083', (173, 189))	('nausea and vomiting', 'Phenotype', 'HP:0002017', (25, 44))	('Cisplatin', 'Var', (0, 9))	('vomiting', 'Phenotype', 'HP:0002013', (36, 44))	('vomiting', 'Disease', (36, 44))
241093	31367271	In contrast, oxaliplatin is moderately emetogenic and less nephrotoxic than cisplatin.	('oxaliplatin', 'Var', (13, 24))	('emetogenic', 'MPA', (39, 49))	('cisplatin', 'Chemical', 'MESH:D002945', (76, 85))	('nephrotoxic', 'Disease', 'MESH:D007674', (59, 70))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (13, 24))	('nephrotoxic', 'Disease', (59, 70))
241109	31367271	In a study with docetaxel, cisplatin and S-1 (DCS) as neoadjuvant chemotherapy (JCOG1002), the response rate was 57.7%, and R0 resection was achieved in 84.6% of patients.	('patients', 'Species', '9606', (162, 170))	('cisplatin', 'Chemical', 'MESH:D002945', (27, 36))	('S-1', 'Gene', '5707', (41, 44))	('docetaxel', 'Chemical', 'MESH:D000077143', (16, 25))	('S-1', 'Gene', (41, 44))	('cisplatin', 'Var', (27, 36))	('DCS', 'Chemical', '-', (46, 49))
241126	31367271	Trifluridine/tipiracil improved the overall survival compared with the placebo in patients who had previously received two or more regimens.	('overall survival', 'MPA', (36, 52))	('patients', 'Species', '9606', (82, 90))	('Trifluridine/tipiracil', 'Var', (0, 22))	('improved', 'PosReg', (23, 31))	('tipiracil', 'Chemical', 'MESH:C000613754', (13, 22))	('Trifluridine', 'Chemical', 'MESH:D014271', (0, 12))
241133	31367271	Although pembrolizumab did not significantly improve overall survival compared with paclitaxel as a second-line therapy for advanced gastric or gastroesophageal junction cancer, pembrolizumab had a better safety profile than paclitaxel.	('pembrolizumab', 'Chemical', 'MESH:C582435', (178, 191))	('pembrolizumab', 'Chemical', 'MESH:C582435', (9, 22))	('gastric or gastroesophageal junction cancer', 'Disease', (133, 176))	('paclitaxel', 'Chemical', 'MESH:D017239', (84, 94))	('paclitaxel', 'Chemical', 'MESH:D017239', (225, 235))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('gastric or gastroesophageal junction cancer', 'Disease', 'MESH:D013274', (133, 176))	('pembrolizumab', 'Var', (178, 191))
241177	31367271	The Cancer Genome Atlas (TCGA) project proposes a molecular classification dividing gastric cancer into four subtypes: Tumors positive for Epstein-Barr virus, which display PIK3CA mutations, DNA hypermethylation, and an amplification of JAK2, PD-L1 and PD-L2; microsatellite unstable tumors, which show elevated mutation rates; genomically stable tumors, which are enriched for the diffuse histological variant and mutations of RhoA or fusions involving RHO-family GTPase-activating proteins; and tumors with chromosomal instability, which show aneuploidy and the focal amplification of receptor tyrosine kinases.	('Tumors', 'Phenotype', 'HP:0002664', (119, 125))	('tumors', 'Phenotype', 'HP:0002664', (347, 353))	('mutation', 'MPA', (312, 320))	('unstable tumors', 'Disease', 'MESH:D000789', (275, 290))	('Cancer', 'Phenotype', 'HP:0002664', (4, 10))	('chromosomal instability', 'Phenotype', 'HP:0040012', (509, 532))	('tumors', 'Phenotype', 'HP:0002664', (497, 503))	('tumors', 'Phenotype', 'HP:0002664', (284, 290))	('tumor', 'Phenotype', 'HP:0002664', (347, 352))	('gastric cancer', 'Disease', (84, 98))	('Tumors', 'Disease', (119, 125))	('tumors', 'Disease', (347, 353))	('tumor', 'Phenotype', 'HP:0002664', (497, 502))	('tumor', 'Phenotype', 'HP:0002664', (284, 289))	('tumors', 'Disease', (497, 503))	('receptor tyrosine kinases', 'Enzyme', (587, 612))	('tumors', 'Disease', (284, 290))	('aneuploidy', 'Disease', 'MESH:D000782', (545, 555))	('gastric cancer', 'Disease', 'MESH:D013274', (84, 98))	('Tumors', 'Disease', 'MESH:D009369', (119, 125))	('tumors', 'Disease', 'MESH:D009369', (347, 353))	('tumors', 'Disease', 'MESH:D009369', (497, 503))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (4, 23))	('tumors', 'Disease', 'MESH:D009369', (284, 290))	('unstable tumors', 'Disease', (275, 290))	('PD-L1', 'Gene', (243, 248))	('gastric cancer', 'Phenotype', 'HP:0012126', (84, 98))	('Cancer Genome Atlas', 'Disease', (4, 23))	('aneuploidy', 'Disease', (545, 555))	('mutations', 'Var', (415, 424))	('PD-L1', 'Gene', '29126', (243, 248))
241184	31423177	CA916798 gene expression is associated with multidrug resistance and predicts progression-free survival in patients with lung cancer CA916798 has been identified as a novel multidrug resistance gene in lung cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('CA916798', 'Var', (133, 141))	('lung cancer', 'Disease', 'MESH:D008175', (121, 132))	('lung cancer', 'Disease', 'MESH:D008175', (202, 213))	('drug resistance', 'Phenotype', 'HP:0020174', (178, 193))	('associated', 'Reg', (28, 38))	('CA916798', 'Gene', (0, 8))	('lung cancer', 'Disease', (202, 213))	('CA916798', 'Chemical', '-', (133, 141))	('lung cancer', 'Phenotype', 'HP:0100526', (202, 213))	('drug resistance', 'Phenotype', 'HP:0020174', (49, 64))	('lung cancer', 'Disease', (121, 132))	('CA916798', 'Chemical', '-', (0, 8))	('multidrug resistance', 'MPA', (44, 64))	('lung cancer', 'Phenotype', 'HP:0100526', (121, 132))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('predicts', 'Reg', (69, 77))	('patients', 'Species', '9606', (107, 115))
241185	31423177	However, the expression patterns of CA916798 in tumor tissues prior and subsequent to chemotherapy remain unclear.	('tumor', 'Disease', (48, 53))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('CA916798', 'Var', (36, 44))	('CA916798', 'Chemical', '-', (36, 44))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
241186	31423177	In the present study, CA916798 expression levels in tumor tissues prior and subsequent to chemotherapy were detected by reverse transcription-quantitative polymerase chain reaction and immunohistochemistry analysis.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('CA916798', 'Var', (22, 30))	('tumor', 'Disease', (52, 57))	('CA916798', 'Chemical', '-', (22, 30))	('tumor', 'Disease', 'MESH:D009369', (52, 57))
241187	31423177	The prognostic significance of CA916798 expression in tumor tissues was explored by Kaplan-Meier survival analysis and Cox proportional hazards regression analysis.	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('CA916798', 'Var', (31, 39))	('CA916798', 'Chemical', '-', (31, 39))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumor', 'Disease', (54, 59))
241188	31423177	The messenger RNA (mRNA) and protein expression levels of CA916798 in tumor tissues were downregulated post-chemotherapy in chemotherapy-sensitive patients with lung cancer, but not in chemotherapy-resistant patients.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('patients', 'Species', '9606', (208, 216))	('tumor', 'Disease', (70, 75))	('lung cancer', 'Disease', (161, 172))	('downregulated', 'NegReg', (89, 102))	('lung cancer', 'Phenotype', 'HP:0100526', (161, 172))	('CA916798', 'Var', (58, 66))	('patients', 'Species', '9606', (147, 155))	('CA916798', 'Chemical', '-', (58, 66))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('lung cancer', 'Disease', 'MESH:D008175', (161, 172))
241189	31423177	Downregulation of CA916798 mRNA and protein expression post-chemotherapy was significantly associated with improved progression-free survival time.	('improved', 'PosReg', (107, 115))	('progression-free survival time', 'CPA', (116, 146))	('Downregulation', 'NegReg', (0, 14))	('CA916798', 'Var', (18, 26))	('CA916798', 'Chemical', '-', (18, 26))
241190	31423177	The findings from the present study suggest that platinum-based chemotherapy may induce the expression of CA916798, and CA916798 may be a promising biomarker to predict chemotherapy resistance and improve therapies for patients with lung cancer.	('induce', 'PosReg', (81, 87))	('lung cancer', 'Phenotype', 'HP:0100526', (233, 244))	('CA916798', 'Chemical', '-', (120, 128))	('CA916798', 'Var', (120, 128))	('lung cancer', 'Disease', (233, 244))	('CA916798', 'Chemical', '-', (106, 114))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('lung cancer', 'Disease', 'MESH:D008175', (233, 244))	('patients', 'Species', '9606', (219, 227))	('improve', 'PosReg', (197, 204))	('platinum', 'Chemical', 'MESH:D010984', (49, 57))	('CA916798', 'Protein', (106, 114))	('expression', 'MPA', (92, 102))
241201	31423177	CA916798 has been identified as a novel multidrug resistance gene in cis-dichlorodiamine platinum (CDDP)-resistant lung adenocarcinoma cells.	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('cis-dichlorodiamine platinum', 'Chemical', 'MESH:D002945', (69, 97))	('CA916798', 'Var', (0, 8))	('lung adenocarcinoma', 'Disease', (115, 134))	('drug resistance', 'Phenotype', 'HP:0020174', (45, 60))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (115, 134))	('CA916798', 'Chemical', '-', (0, 8))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (115, 134))	('CDDP', 'Chemical', 'MESH:D002945', (99, 103))
241202	31423177	Overexpression of CA916798 in lung cancer cells enhances resistance to multiple chemotherapeutic agents by regulating CDDP-induced cell growth and apoptosis.	('lung cancer', 'Phenotype', 'HP:0100526', (30, 41))	('lung cancer', 'Disease', (30, 41))	('cell growth', 'CPA', (131, 142))	('CDDP-induced', 'MPA', (118, 130))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('CA916798', 'Var', (18, 26))	('regulating', 'Reg', (107, 117))	('CDDP', 'Chemical', 'MESH:D002945', (118, 122))	('lung cancer', 'Disease', 'MESH:D008175', (30, 41))	('CA916798', 'Chemical', '-', (18, 26))	('resistance to multiple chemotherapeutic agents', 'MPA', (57, 103))	('apoptosis', 'CPA', (147, 156))	('enhances', 'PosReg', (48, 56))
241203	31423177	Mechanistically, CA916798 may exert its multidrug resistance functions via the phosphoinositide 3-kinase/AKT signaling pathway.	('AKT', 'Gene', '207', (105, 108))	('CA916798', 'Chemical', '-', (17, 25))	('CA916798', 'Var', (17, 25))	('drug resistance', 'Phenotype', 'HP:0020174', (45, 60))	('AKT', 'Gene', (105, 108))	('multidrug resistance functions', 'MPA', (40, 70))
241204	31423177	However, the majority of previous studies have focused on the molecular characteristics, biological functions and molecular mechanism of CA916798 in lung cancer.	('lung cancer', 'Disease', 'MESH:D008175', (149, 160))	('CA916798', 'Chemical', '-', (137, 145))	('CA916798', 'Var', (137, 145))	('lung cancer', 'Phenotype', 'HP:0100526', (149, 160))	('lung cancer', 'Disease', (149, 160))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))
241205	31423177	It is still unknown whether CA916798 expression is associated with platinum-based chemotherapy in tumor tissues from patients with lung cancer.	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('lung cancer', 'Disease', 'MESH:D008175', (131, 142))	('associated', 'Reg', (51, 61))	('CA916798', 'Var', (28, 36))	('CA916798', 'Chemical', '-', (28, 36))	('platinum', 'Chemical', 'MESH:D010984', (67, 75))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('platinum-based chemotherapy', 'CPA', (67, 94))	('tumor', 'Disease', (98, 103))	('patients', 'Species', '9606', (117, 125))	('lung cancer', 'Disease', (131, 142))	('lung cancer', 'Phenotype', 'HP:0100526', (131, 142))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
241206	31423177	The present study evaluated the messenger RNA (mRNA) and protein expression levels of CA916798 in tumor tissues prior and subsequent to chemotherapy in patients with advanced lung cancer.	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('lung cancer', 'Disease', (175, 186))	('lung cancer', 'Phenotype', 'HP:0100526', (175, 186))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('CA916798', 'Var', (86, 94))	('lung cancer', 'Disease', 'MESH:D008175', (175, 186))	('tumor', 'Disease', (98, 103))	('CA916798', 'Chemical', '-', (86, 94))	('patients', 'Species', '9606', (152, 160))
241207	31423177	Both the mRNA and protein expression levels of CA916798 were altered in chemotherapy-sensitive lung cancer tissues.	('lung cancer', 'Disease', (95, 106))	('CA916798', 'Var', (47, 55))	('lung cancer', 'Phenotype', 'HP:0100526', (95, 106))	('CA916798', 'Chemical', '-', (47, 55))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('lung cancer', 'Disease', 'MESH:D008175', (95, 106))	('altered', 'Reg', (61, 68))
241208	31423177	The present study further evaluated the prognostic implications of CA916798 mRNA and protein expression levels in patients with lung cancer.	('CA916798', 'Chemical', '-', (67, 75))	('lung cancer', 'Disease', 'MESH:D008175', (128, 139))	('lung cancer', 'Disease', (128, 139))	('lung cancer', 'Phenotype', 'HP:0100526', (128, 139))	('patients', 'Species', '9606', (114, 122))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('CA916798', 'Var', (67, 75))
241219	31423177	Quantification cycle (Cq) values of GAPDH mRNA <25 and Cq values of CA916798 mRNA <35 were considered of good quality.	('mRNA <25', 'Var', (42, 50))	('CA916798', 'Chemical', '-', (68, 76))	('GAPDH', 'Gene', '2597', (36, 41))	('CA916798 mRNA <35', 'Var', (68, 85))	('GAPDH', 'Gene', (36, 41))
241220	31423177	The 2-DeltaDeltaCq method was used to calculate the relative expression of CA916798 as follows: DeltaCq=Cq(CA916798)-Cq(GAPDH), where DeltaDeltaCq=DeltaCq(post-chemotherapy)-DeltaCq(pre-chemotherapy) and fold-change=2-DeltaDeltaCq.	('GAPDH', 'Gene', (120, 125))	('CA916798', 'Var', (75, 83))	('DeltaDeltaCq=DeltaCq', 'Var', (134, 154))	('DeltaDeltaCq', 'Chemical', '-', (218, 230))	('DeltaCq', 'Chemical', '-', (139, 146))	('CA916798', 'Chemical', '-', (75, 83))	('DeltaDeltaCq', 'Chemical', '-', (134, 146))	('DeltaCq', 'Chemical', '-', (174, 181))	('DeltaDeltaCq', 'Chemical', '-', (6, 18))	('DeltaCq', 'Chemical', '-', (147, 154))	('2-DeltaDeltaCq', 'Chemical', '-', (216, 230))	('GAPDH', 'Gene', '2597', (120, 125))	('DeltaCq', 'Chemical', '-', (11, 18))	('DeltaCq', 'Chemical', '-', (96, 103))	('CA916798', 'Chemical', '-', (107, 115))	('2-DeltaDeltaCq', 'Chemical', '-', (4, 18))	('DeltaCq', 'Chemical', '-', (223, 230))	('DeltaCq=Cq(CA916798)-Cq', 'Var', (96, 119))
241221	31423177	The primers used in RT-qPCR analysis were synthesized by Sangon Biotech Co., Ltd., and the sequences are as follows: CA916798 forward, 5'-GCTTCCTCCTCAACCTCGTCCT-3' and reverse, 5'-GTAGCCCACTTATCCACCTTCTCC-3'; and GAPDH forward, 5'-AAGGTGAAGGTCGGAGTCAAC-3' and reverse, 5'-GGGGTCATTGATGGCAACAATA-3'.	('CA916798', 'Var', (117, 125))	('GAPDH', 'Gene', (213, 218))	('CA916798', 'Chemical', '-', (117, 125))	('GAPDH', 'Gene', '2597', (213, 218))
241237	31423177	Progression-free survival was analyzed by the Kaplan-Meier method with upregulated and downregulated expression of CA916798.	('upregulated', 'PosReg', (71, 82))	('downregulated', 'NegReg', (87, 100))	('expression', 'MPA', (101, 111))	('CA916798', 'Var', (115, 123))	('CA916798', 'Chemical', '-', (115, 123))
241248	31423177	CA916798 mRNA expression levels were significantly downregulated in post-chemotherapy tumor tissues compared with those in pre-chemotherapy tissues in chemotherapy-sensitive patients (P<0.05) (Fig.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Disease', (86, 91))	('CA916798', 'Var', (0, 8))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('CA916798', 'Chemical', '-', (0, 8))	('patients', 'Species', '9606', (174, 182))	('downregulated', 'NegReg', (51, 64))	('mRNA expression levels', 'MPA', (9, 31))
241249	31423177	However, CA916798 mRNA expression levels did not significantly change in chemotherapy-resistant lung cancer samples (P>0.05) (Fig.	('lung cancer', 'Disease', 'MESH:D008175', (96, 107))	('lung cancer', 'Disease', (96, 107))	('lung cancer', 'Phenotype', 'HP:0100526', (96, 107))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('CA916798', 'Var', (9, 17))	('CA916798', 'Chemical', '-', (9, 17))
241250	31423177	The fold-change in CA916798 mRNA levels following chemotherapy, normalized to GAPDH and relative to the expression levels prior to chemotherapy, was calculated for each patient.	('CA916798', 'Chemical', '-', (19, 27))	('patient', 'Species', '9606', (169, 176))	('GAPDH', 'Gene', '2597', (78, 83))	('GAPDH', 'Gene', (78, 83))	('CA916798', 'Var', (19, 27))
241251	31423177	The fold-change in CA916798 mRNA expression levels in the chemotherapy-sensitive lung cancer group of patients was significantly lower compared with those in the chemotherapy-resistant group (P<0.05) (Fig.	('lung cancer', 'Disease', (81, 92))	('CA916798', 'Chemical', '-', (19, 27))	('lung cancer', 'Phenotype', 'HP:0100526', (81, 92))	('patients', 'Species', '9606', (102, 110))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('lung cancer', 'Disease', 'MESH:D008175', (81, 92))	('CA916798', 'Var', (19, 27))	('lower', 'NegReg', (129, 134))
241253	31423177	CA916798 protein was positively detected in nearly all biopsy specimens from the patients with lung cancer prior to chemotherapy.	('lung cancer', 'Disease', (95, 106))	('lung cancer', 'Phenotype', 'HP:0100526', (95, 106))	('CA916798', 'Var', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('patients', 'Species', '9606', (81, 89))	('protein', 'Protein', (9, 16))	('CA916798', 'Chemical', '-', (0, 8))	('lung cancer', 'Disease', 'MESH:D008175', (95, 106))
241254	31423177	However, the IHC staining after 2 cycles of chemotherapy showed that CA916798 protein was only positively stained in 42.1% (8/19) of samples from chemotherapy-sensitive patients, which was significantly lower than the percentage exhibited by chemotherapy-resistant patients (P<0.05) (Table II).	('patients', 'Species', '9606', (169, 177))	('lower', 'NegReg', (203, 208))	('CA916798', 'Var', (69, 77))	('patients', 'Species', '9606', (265, 273))	('CA916798', 'Chemical', '-', (69, 77))	('protein', 'Protein', (78, 85))
241256	31423177	In chemotherapy-sensitive patients, the expression of CA916798 was significantly decreased post-chemotherapy in 89.5% (17/19) of lung cancer cases compared with that in chemotherapy-resistant patients (P<0.05) (Table II).	('CA916798', 'Var', (54, 62))	('expression', 'MPA', (40, 50))	('lung cancer', 'Disease', (129, 140))	('decreased', 'NegReg', (81, 90))	('lung cancer', 'Phenotype', 'HP:0100526', (129, 140))	('patients', 'Species', '9606', (192, 200))	('patients', 'Species', '9606', (26, 34))	('lung cancer', 'Disease', 'MESH:D008175', (129, 140))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('CA916798', 'Chemical', '-', (54, 62))
241261	31423177	The downregulated expression of CA916798 mRNA post-chemotherapy was significantly associated with improved progression-free survival time (P=0.009) (Fig.	('CA916798', 'Chemical', '-', (32, 40))	('downregulated', 'NegReg', (4, 17))	('expression', 'MPA', (18, 28))	('CA916798', 'Var', (32, 40))	('improved', 'PosReg', (98, 106))	('progression-free survival time', 'CPA', (107, 137))
241263	31423177	Consistent with the results of CA916798 mRNA expression, Kaplan-Meier analysis also indicated that downregulated protein expression of CA916798 post-chemotherapy was significantly associated with improved progression-free survival time (P<0.001) (Fig.	('CA916798', 'Chemical', '-', (135, 143))	('protein expression', 'MPA', (113, 131))	('progression-free survival time', 'CPA', (205, 235))	('downregulated', 'NegReg', (99, 112))	('CA916798', 'Chemical', '-', (31, 39))	('CA916798', 'Var', (135, 143))	('improved', 'PosReg', (196, 204))
241264	31423177	Upon adjusting for age, gender, histological type, pathological stage, smoking status and maximum tumor diameter, the Cox proportional hazard model indicated that downregulated protein expression of CA916798 was an independent prognostic factor for lung cancer (n=30; HR, 0.145; 95% CI, 0.050-0.418; P<0.001).	('cancer', 'Phenotype', 'HP:0002664', (254, 260))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('CA916798', 'Var', (199, 207))	('lung cancer', 'Disease', 'MESH:D008175', (249, 260))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('CA916798', 'Chemical', '-', (199, 207))	('downregulated', 'NegReg', (163, 176))	('protein expression', 'MPA', (177, 195))	('tumor', 'Disease', (98, 103))	('lung cancer', 'Disease', (249, 260))	('lung cancer', 'Phenotype', 'HP:0100526', (249, 260))
241269	31423177	The present study demonstrated that CA916798, a novel multidrug resistance gene, was downregulated following 2 cycles of chemotherapy in chemotherapy-sensitive patients with lung cancer.	('downregulated', 'NegReg', (85, 98))	('lung cancer', 'Disease', (174, 185))	('patients', 'Species', '9606', (160, 168))	('lung cancer', 'Phenotype', 'HP:0100526', (174, 185))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('drug resistance', 'Phenotype', 'HP:0020174', (59, 74))	('lung cancer', 'Disease', 'MESH:D008175', (174, 185))	('CA916798', 'Chemical', '-', (36, 44))	('CA916798', 'Var', (36, 44))
241270	31423177	In addition, CA916798 expression level was demonstrated to be an independent predictor for progression-free survival time in patients with advanced lung cancer.	('CA916798', 'Var', (13, 21))	('lung cancer', 'Disease', 'MESH:D008175', (148, 159))	('CA916798', 'Chemical', '-', (13, 21))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('lung cancer', 'Disease', (148, 159))	('lung cancer', 'Phenotype', 'HP:0100526', (148, 159))	('patients', 'Species', '9606', (125, 133))
241274	31423177	For patients receiving chemotherapy, multidrug resistance limits the ability to treat advanced lung cancer effectively.	('limits', 'NegReg', (58, 64))	('lung cancer', 'Disease', (95, 106))	('lung cancer', 'Phenotype', 'HP:0100526', (95, 106))	('drug resistance', 'Phenotype', 'HP:0020174', (42, 57))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('multidrug resistance', 'Var', (37, 57))	('lung cancer', 'Disease', 'MESH:D008175', (95, 106))	('patients', 'Species', '9606', (4, 12))
241281	31423177	Gain- and loss-of-function of CA916798 in lung cancer cell lines were investigated, which revealed that CA916798 could enhance cell resistance to chemotherapeutic agents.	('enhance', 'PosReg', (119, 126))	('cell resistance to chemotherapeutic agents', 'CPA', (127, 169))	('CA916798', 'Chemical', '-', (30, 38))	('CA916798', 'Var', (104, 112))	('lung cancer', 'Disease', (42, 53))	('lung cancer', 'Phenotype', 'HP:0100526', (42, 53))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('CA916798', 'Chemical', '-', (104, 112))	('lung cancer', 'Disease', 'MESH:D008175', (42, 53))
241284	31423177	Dynamic changes in CA916798 mRNA and protein expression levels were observed in tumor tissues following 2 cycles of standard chemotherapy.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('CA916798', 'Chemical', '-', (19, 27))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumor', 'Disease', (80, 85))	('CA916798', 'Var', (19, 27))
241285	31423177	In the chemotherapy-sensitive patients, both the CA916798 mRNA and protein expression levels were downregulated following 2 cycles of chemotherapy.	('downregulated', 'NegReg', (98, 111))	('patients', 'Species', '9606', (30, 38))	('CA916798', 'Chemical', '-', (49, 57))	('CA916798', 'Var', (49, 57))
241286	31423177	However, the CA916798 mRNA and protein expression levels were upregulated following chemotherapy in chemotherapy-resistant patients.	('upregulated', 'PosReg', (62, 73))	('CA916798', 'Chemical', '-', (13, 21))	('patients', 'Species', '9606', (123, 131))	('CA916798', 'Var', (13, 21))
241291	31423177	Thus, the expression of CA916798 may be a predictive and prognostic biomarker for chemotherapy sensitivity in patients with advanced lung cancer.	('lung cancer', 'Disease', (133, 144))	('lung cancer', 'Phenotype', 'HP:0100526', (133, 144))	('CA916798', 'Var', (24, 32))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('CA916798', 'Chemical', '-', (24, 32))	('lung cancer', 'Disease', 'MESH:D008175', (133, 144))	('patients', 'Species', '9606', (110, 118))
241293	31423177	Downregulated CA916798 mRNA and protein expression levels were associated with improved progression-free survival in lung cancer.	('improved', 'PosReg', (79, 87))	('lung cancer', 'Disease', (117, 128))	('lung cancer', 'Phenotype', 'HP:0100526', (117, 128))	('CA916798', 'Var', (14, 22))	('Downregulated', 'NegReg', (0, 13))	('progression-free survival', 'CPA', (88, 113))	('CA916798', 'Chemical', '-', (14, 22))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('lung cancer', 'Disease', 'MESH:D008175', (117, 128))
241294	31423177	Thus, if CA916798 expression in tumor tissue is downregulated following 2 cycles of chemotherapy, the patient will have an improved prognosis.	('patient', 'Species', '9606', (102, 109))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('downregulated', 'NegReg', (48, 61))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('expression', 'MPA', (18, 28))	('CA916798', 'Var', (9, 17))	('tumor', 'Disease', (32, 37))	('improved', 'PosReg', (123, 131))	('CA916798', 'Chemical', '-', (9, 17))
241295	31423177	Conversely, if CA916798 expression is upregulated following 2 cycles of chemotherapy, the patient will have a poor prognosis.	('expression', 'MPA', (24, 34))	('upregulated', 'PosReg', (38, 49))	('patient', 'Species', '9606', (90, 97))	('CA916798', 'Var', (15, 23))	('CA916798', 'Chemical', '-', (15, 23))
241296	31423177	These results suggested that CA916798 expression could be a novel biomarker for predicting progression of lung cancer following platinum-based chemotherapy.	('platinum', 'Chemical', 'MESH:D010984', (128, 136))	('lung cancer', 'Disease', (106, 117))	('lung cancer', 'Phenotype', 'HP:0100526', (106, 117))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('lung cancer', 'Disease', 'MESH:D008175', (106, 117))	('CA916798 expression', 'Var', (29, 48))	('CA916798', 'Chemical', '-', (29, 37))
241299	31423177	Of these, 8 patients with upregulated CA916798 protein expression were resistant to continued chemotherapy.	('protein', 'Protein', (47, 54))	('patients', 'Species', '9606', (12, 20))	('upregulated', 'PosReg', (26, 37))	('CA916798', 'Var', (38, 46))	('CA916798', 'Chemical', '-', (38, 46))
241300	31423177	However, 3 patients with downregulated (or unchanged) CA916798 protein expression were sensitive to continued chemotherapy.	('CA916798', 'Var', (54, 62))	('protein', 'Protein', (63, 70))	('downregulated', 'NegReg', (25, 38))	('patients', 'Species', '9606', (11, 19))	('CA916798', 'Chemical', '-', (54, 62))
241301	31423177	The results suggested that, if CA916798 expression was upregulated following 2 cycles of chemotherapy, patients with SD may remain resistant to continued chemotherapy and the type of treatment should be changed.	('expression', 'MPA', (40, 50))	('CA916798', 'Var', (31, 39))	('CA916798', 'Chemical', '-', (31, 39))	('upregulated', 'PosReg', (55, 66))	('patients', 'Species', '9606', (103, 111))	('SD', 'Disease', 'MESH:D029461', (117, 119))
241302	31423177	Firstly, in order to explore the dynamic changes in CA916798 expression, tumor tissues should be collected from patients prior to chemotherapy and following 2 cycles of chemotherapy.	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('patients', 'Species', '9606', (112, 120))	('tumor', 'Disease', (73, 78))	('CA916798', 'Var', (52, 60))	('CA916798', 'Chemical', '-', (52, 60))
241306	31423177	In conclusion, the present study demonstrated that both CA916798 mRNA and protein expression levels are downregulated post-chemotherapy in chemotherapy-sensitive patients with lung cancer, but not in chemotherapy-resistant patients.	('patients', 'Species', '9606', (162, 170))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('lung cancer', 'Disease', 'MESH:D008175', (176, 187))	('downregulated', 'NegReg', (104, 117))	('CA916798', 'Chemical', '-', (56, 64))	('CA916798', 'Var', (56, 64))	('patients', 'Species', '9606', (223, 231))	('lung cancer', 'Disease', (176, 187))	('lung cancer', 'Phenotype', 'HP:0100526', (176, 187))
241307	31423177	Furthermore, the dynamic change in CA916798 mRNA or protein expression level post-chemotherapy is an independent prognostic factor for lung cancer.	('CA916798', 'Var', (35, 43))	('lung cancer', 'Disease', 'MESH:D008175', (135, 146))	('CA916798', 'Chemical', '-', (35, 43))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('lung cancer', 'Disease', (135, 146))	('lung cancer', 'Phenotype', 'HP:0100526', (135, 146))
241308	31423177	These findings suggest that CA916798 may be a promising biomarker to predict chemotherapy resistance and optimize therapy for patients with lung cancer.	('lung cancer', 'Disease', (140, 151))	('lung cancer', 'Phenotype', 'HP:0100526', (140, 151))	('predict', 'Reg', (69, 76))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('CA916798', 'Var', (28, 36))	('lung cancer', 'Disease', 'MESH:D008175', (140, 151))	('patients', 'Species', '9606', (126, 134))	('CA916798', 'Chemical', '-', (28, 36))	('chemotherapy resistance', 'CPA', (77, 100))
241315	30576338	In comparison, the high EMX2 or EMX2OS group were associated with better RFS compared with their respective low expression group in classical PTC (p = 0.007 and 0.004 respectively).	('PTC', 'Phenotype', 'HP:0002895', (142, 145))	('high EMX2', 'Var', (19, 28))	('EMX2OS', 'Var', (32, 38))	('RFS', 'MPA', (73, 76))	('better', 'PosReg', (66, 72))	('PTC', 'Gene', '8030', (142, 145))	('RFS', 'Chemical', '-', (73, 76))	('PTC', 'Gene', (142, 145))
241317	30576338	By performing stepwise regression, we found that EMX2OS was better than EMX2 in predicting RFS in classical PTC.	('RFS', 'Chemical', '-', (91, 94))	('PTC', 'Gene', '8030', (108, 111))	('EMX2OS', 'Var', (49, 55))	('PTC', 'Gene', (108, 111))	('RFS', 'Disease', (91, 94))	('PTC', 'Phenotype', 'HP:0002895', (108, 111))
241318	30576338	Multivariate analysis confirmed that high EMX2OS expression was an independent indicator of favorable RFS in classical PTC (HR: 0.239, 95%CI: 0.100 = 0.569, p = 0.001), after adjustment of pathological stages and residual tumors.	('tumors', 'Disease', 'MESH:D009369', (222, 228))	('high', 'Var', (37, 41))	('PTC', 'Gene', (119, 122))	('PTC', 'Gene', '8030', (119, 122))	('RFS', 'Chemical', '-', (102, 105))	('expression', 'MPA', (49, 59))	('PTC', 'Phenotype', 'HP:0002895', (119, 122))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('tumors', 'Phenotype', 'HP:0002664', (222, 228))	('tumors', 'Disease', (222, 228))	('EMX2OS', 'Gene', (42, 48))
241347	30576338	In comparison, the classical PTC patients with high EMX2 or EMX2OS expression had significantly better RFS compared with their respective low expression group (p = 0.004 and 0.007 respectively, Fig 2B and 2D).	('PTC', 'Gene', '8030', (29, 32))	('PTC', 'Gene', (29, 32))	('patients', 'Species', '9606', (33, 41))	('RFS', 'MPA', (103, 106))	('high EMX2', 'Var', (47, 56))	('better', 'PosReg', (96, 102))	('PTC', 'Phenotype', 'HP:0002895', (29, 32))	('EMX2OS', 'Gene', (60, 66))	('RFS', 'Chemical', '-', (103, 106))
241352	30576338	By performing stepwise regression, we found that EMX2OS is better than EMX2 in predicting RFS in classical PTC (S1 Fig).	('PTC', 'Phenotype', 'HP:0002895', (107, 110))	('RFS', 'Chemical', '-', (90, 93))	('RFS', 'Disease', (90, 93))	('PTC', 'Gene', '8030', (107, 110))	('PTC', 'Gene', (107, 110))	('EMX2OS', 'Var', (49, 55))
241354	30576338	Results showed that the high EMX2OS expression group had older age (47.89+-1.13 vs. 43.83+-1.34, p = 0.02) and a higher proportion of patients with pathological III/IV stage disease (36% vs. 25%, p = 0.044) and the presence of residual tumors (16% vs. 7%, p = 0.011), compared to the low EMX2OS expression group (Table 2).	('IV stage disease', 'Disease', 'MESH:D058625', (165, 181))	('IV stage disease', 'Disease', (165, 181))	('high EMX2OS expression', 'Var', (24, 46))	('patients', 'Species', '9606', (134, 142))	('tumors', 'Phenotype', 'HP:0002664', (236, 242))	('tumor', 'Phenotype', 'HP:0002664', (236, 241))	('tumors', 'Disease', (236, 242))	('tumors', 'Disease', 'MESH:D009369', (236, 242))
241355	30576338	In multivariate analysis, we confirmed that high EMX2OS expression was an independent indicator of favorable RFS in classical PTC (HR: 0.239, 95%CI: 0.100 = 0.569, p = 0.001), after adjustment of pathological stages and residual tumors (Table 3).	('tumors', 'Disease', 'MESH:D009369', (229, 235))	('high', 'Var', (44, 48))	('RFS', 'Chemical', '-', (109, 112))	('EMX2OS', 'Gene', (49, 55))	('PTC', 'Gene', '8030', (126, 129))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('PTC', 'Gene', (126, 129))	('PTC', 'Phenotype', 'HP:0002895', (126, 129))	('tumors', 'Phenotype', 'HP:0002664', (229, 235))	('tumors', 'Disease', (229, 235))
241369	30576338	In univariate analysis, we confirmed that both high EMX2 and EMX2OS expression were associated with better RFS (HR: 0.332, 95%CI: 0.152-0.728, p = 0.006; HR: 0.343, 95%CI: 0.151-0.776, p = 0.010 respectively).	('RFS', 'MPA', (107, 110))	('high', 'Var', (47, 51))	('better', 'PosReg', (100, 106))	('EMX2OS', 'Gene', (61, 67))	('RFS', 'Chemical', '-', (107, 110))	('EMX2', 'Gene', (52, 56))
241373	30576338	The results of stepwise regression showed that EMX2OS is better than EMX2 in predicting RFS in classical PTC.	('RFS', 'Disease', (88, 91))	('RFS', 'Chemical', '-', (88, 91))	('PTC', 'Gene', (105, 108))	('EMX2OS', 'Var', (47, 53))	('PTC', 'Phenotype', 'HP:0002895', (105, 108))	('PTC', 'Gene', '8030', (105, 108))
241378	30576338	Therefore, EMX2OS might be a specific biomarker in classical PTC.	('EMX2OS', 'Var', (11, 17))	('PTC', 'Phenotype', 'HP:0002895', (61, 64))	('PTC', 'Gene', '8030', (61, 64))	('PTC', 'Gene', (61, 64))
241398	27278367	Genomic driver aberrations, such as mutations, amplifications and translocations of FGFR1-4 genes dysregulate FGFR signaling pathways and promote tumor development.	('translocations', 'Var', (66, 80))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('FGFR signaling pathways', 'Pathway', (110, 133))	('dysregulate', 'Reg', (98, 109))	('FGFR1-4', 'Gene', '2260;2263;2261;2264', (84, 91))	('tumor', 'Disease', (146, 151))	('mutations', 'Var', (36, 45))	('FGFR1-4', 'Gene', (84, 91))	('promote', 'PosReg', (138, 145))	('amplifications', 'Var', (47, 61))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
241415	27278367	Next, sets of slides were incubated with 150 microL anti-FGFR1 antibody (ab10646, 1:2000 dilution) (Abcam, Cambridge, UK), anti-FGFR2 antibody (ab10648, 1:1000 dilution) (Abcam), anti-FGFR3 antibody (sc-13121, 1:25 dilution) (Santa Cruz Biotechnology, Dallas, TX, USA) or anti-FGFR4 antibody (PAB3044, 1:200 dilution) (Abnova, Taipei City, Taiwan) for 32 min.	('FGFR1', 'Gene', (57, 62))	('FGFR1', 'Gene', '2260', (57, 62))	('FGFR2', 'Gene', (128, 133))	('FGFR3', 'Gene', '2261', (184, 189))	('FGFR2', 'Gene', '2263', (128, 133))	('FGFR4', 'Gene', '2264', (277, 282))	('ab10648', 'Var', (144, 151))	('FGFR4', 'Gene', (277, 282))	('FGFR3', 'Gene', (184, 189))
241460	27278367	Therapeutic value has already been observed for the FGFR1-inhibitor PD173074 in HNSCC cell lines and a clinical trial on HNSCC patients with the FGFR-inhibitor ponatinib has been completed (ClinicalTrials.gov Identifier: NCT01761747).	('ponatinib', 'Chemical', 'MESH:C545373', (160, 169))	('PD173074', 'Var', (68, 76))	('PD173074', 'Chemical', 'MESH:C115711', (68, 76))	('HNSCC', 'Phenotype', 'HP:0012288', (121, 126))	('HNSCC', 'Phenotype', 'HP:0012288', (80, 85))	('patients', 'Species', '9606', (127, 135))	('FGFR1', 'Gene', (52, 57))	('FGFR1', 'Gene', '2260', (52, 57))
241464	27278367	In these studies, they observed that FGFR1 amplification was much more common in HPV-negative HNSCC, while FGFR2 and FGFR3 aberrations were much more common in HPV-positive HNSCC.	('FGFR2', 'Gene', (107, 112))	('FGFR1', 'Gene', (37, 42))	('FGFR1', 'Gene', '2260', (37, 42))	('FGFR3', 'Gene', '2261', (117, 122))	('HPV-negative HNSCC', 'Disease', (81, 99))	('FGFR2', 'Gene', '2263', (107, 112))	('HNSCC', 'Phenotype', 'HP:0012288', (94, 99))	('amplification', 'Var', (43, 56))	('HNSCC', 'Phenotype', 'HP:0012288', (173, 178))	('common', 'Reg', (71, 77))	('FGFR3', 'Gene', (117, 122))	('HPV', 'Species', '10566', (160, 163))	('HPV', 'Species', '10566', (81, 84))
241465	27278367	Also in cervical squamous cell carcinoma, all tumors harboring FGFR3 mutations were HPV-positive.	('mutations', 'Var', (69, 78))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (17, 40))	('FGFR3', 'Gene', '2261', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('HPV', 'Species', '10566', (84, 87))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('FGFR3', 'Gene', (63, 68))	('tumors', 'Disease', (46, 52))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (17, 40))	('squamous cell carcinoma', 'Disease', (17, 40))	('carcinoma', 'Phenotype', 'HP:0030731', (31, 40))	('tumors', 'Disease', 'MESH:D009369', (46, 52))
241537	25245141	Deregulations of either one of these members could affect the progression of human and canine OSCC.	('Deregulations', 'Var', (0, 13))	('affect', 'Reg', (51, 57))	('canine', 'Species', '9615', (87, 93))	('progression', 'CPA', (62, 73))	('human', 'Species', '9606', (77, 82))
241564	25245141	In summary, the Lin28 - let-7 -HMGA regulatory pathway and deregulations of either one of these members or of all involved proteins and miRNAs could have an effect on the progression and pathogeneses of human and canine OSCC.	('human', 'Species', '9606', (203, 208))	('Lin28', 'Gene', (16, 21))	('canine', 'Species', '9615', (213, 219))	('human', 'Disease', (203, 208))	('effect', 'Reg', (157, 163))	('deregulations', 'Var', (59, 72))
241632	25245141	Further, multivariate risk factor analysis demonstrated that HMGA2 expression was found to be a significant independent predictor of death of carcinoma and as an independent prognostic marker for disease-specific overall survival.	('expression', 'Var', (67, 77))	('death of carcinoma', 'Disease', 'MESH:D003643', (133, 151))	('HMGA2', 'Gene', (61, 66))	('death of carcinoma', 'Disease', (133, 151))	('carcinoma', 'Phenotype', 'HP:0030731', (142, 151))
241652	25245141	These results strongly fortify the described Lin28 to let-7 to HMGA2 axis hypothesis drawn by Hammond et al.. Further, increased levels of Lin28b could be associated with poor prognosis OSCCs.	('levels', 'Var', (129, 135))	('associated', 'Reg', (155, 165))	('Lin28b', 'Gene', (139, 145))	('Lin28b', 'Gene', '389421', (139, 145))	('increased', 'PosReg', (119, 128))
241658	25245141	Let-7a was over expressed within the cell line samples while mir-98 was over expressed in the tumour samples.	('tumour', 'Disease', (94, 100))	('mir-98', 'Var', (61, 67))	('over', 'PosReg', (11, 15))	('Let-7a', 'Gene', (0, 6))	('tumour', 'Phenotype', 'HP:0002664', (94, 100))	('tumour', 'Disease', 'MESH:D009369', (94, 100))
241668	33953608	In this study, we evaluated the clinicopathologic significance of miR-183-3p and miR-182-5p, and the role of miR-183-3p in non-small-cell lung cancer (NSCLC) progression.	('NSCLC', 'Phenotype', 'HP:0030358', (151, 156))	('lung cancer', 'Disease', 'MESH:D008175', (138, 149))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('NSCLC', 'Disease', (151, 156))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (123, 149))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (127, 149))	('lung cancer', 'Disease', (138, 149))	('NSCLC', 'Disease', 'MESH:D002289', (151, 156))	('miR-183-3p', 'Chemical', '-', (109, 119))	('miR-183-3p', 'Chemical', '-', (66, 76))	('miR-183-3p', 'Var', (66, 76))	('lung cancer', 'Phenotype', 'HP:0100526', (138, 149))	('miR-182-5p', 'Gene', '100302183', (81, 91))	('miR-182-5p', 'Gene', (81, 91))
241671	33953608	miR-183-3p and miR-182-5p were significantly increased in NSCLC tumor tissues (both P < 0.0001) and were positively correlated (r = 0.8519, P < 0.0001).	('NSCLC tumor', 'Disease', (58, 69))	('increased', 'PosReg', (45, 54))	('miR-182-5p', 'Gene', (15, 25))	('miR-183-3p', 'Var', (0, 10))	('miR-183-3p', 'Chemical', '-', (0, 10))	('NSCLC', 'Phenotype', 'HP:0030358', (58, 63))	('miR-182-5p', 'Gene', '100302183', (15, 25))	('correlated', 'Interaction', (116, 126))	('NSCLC tumor', 'Disease', 'MESH:D009369', (58, 69))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
241672	33953608	miR-183-3p (P = 0.0444) and miR-182-5p (P = 0.0132) were correlated with tumor size.	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('miR-182-5p', 'Gene', '100302183', (28, 38))	('miR-182-5p', 'Gene', (28, 38))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('correlated', 'Reg', (57, 67))	('miR-183-3p', 'Var', (0, 10))	('tumor', 'Disease', (73, 78))	('miR-183-3p', 'Chemical', '-', (0, 10))
241673	33953608	In addition, miR-183-3p (P = 0.0135) and miR-182-5p (P = 0.0009) were upregulated in normal lung tissues from smokers.	('miR-182-5p', 'Gene', (41, 51))	('miR-183-3p', 'Var', (13, 23))	('miR-182-5p', 'Gene', '100302183', (41, 51))	('miR-183-3p', 'Chemical', '-', (13, 23))	('upregulated', 'PosReg', (70, 81))
241674	33953608	In vitro, miR-183-3p was correlated with cell proliferation.	('cell proliferation', 'CPA', (41, 59))	('correlated', 'Reg', (25, 35))	('miR-183-3p', 'Chemical', '-', (10, 20))	('miR-183-3p', 'Var', (10, 20))
241675	33953608	In addition, bioinformatics analysis indicated that miR-183-3p was correlated with poor prognosis (P = 0.0466) and tumor size (P = 0.0017).	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumor', 'Disease', (115, 120))	('miR-183-3p', 'Chemical', '-', (52, 62))	('miR-183-3p', 'Var', (52, 62))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
241676	33953608	In addition, miR-183-3p was higher in lung squamous carcinoma (LUSC) tissue (P < 0.0001) than in lung adenocarcinoma (LUAD) tissue, and miR-183-3p was higher in the tumor tissue of smokers (P = 0.0053) than in that of nonsmokers.	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (97, 116))	('lung squamous carcinoma', 'Phenotype', 'HP:0030359', (38, 61))	('higher', 'PosReg', (151, 157))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('LUSC', 'Phenotype', 'HP:0030359', (63, 67))	('miR-183-3p', 'Var', (13, 23))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (43, 61))	('miR-183-3p', 'Chemical', '-', (136, 146))	('higher', 'PosReg', (28, 34))	('lung squamous carcinoma', 'Disease', (38, 61))	('lung adenocarcinoma', 'Disease', (97, 116))	('lung squamous carcinoma', 'Disease', 'MESH:D002294', (38, 61))	('LUAD', 'Phenotype', 'HP:0030078', (118, 122))	('tumor', 'Disease', (165, 170))	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('carcinoma', 'Phenotype', 'HP:0030731', (52, 61))	('miR-183-3p', 'Var', (136, 146))	('miR-183-3p', 'Chemical', '-', (13, 23))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (97, 116))
241677	33953608	Upregulation of miR-183-3p and miR-182-5p may play an oncogenic role in NSCLC.	('Upregulation', 'PosReg', (0, 12))	('miR-183-3p', 'Var', (16, 26))	('miR-183-3p', 'Chemical', '-', (16, 26))	('NSCLC', 'Disease', (72, 77))	('miR-182-5p', 'Gene', '100302183', (31, 41))	('miR-182-5p', 'Gene', (31, 41))	('NSCLC', 'Disease', 'MESH:D002289', (72, 77))	('NSCLC', 'Phenotype', 'HP:0030358', (72, 77))
241678	33953608	miR-183-3p could be used as a potential prognostic biomarker and therapeutic target to manage lung cancer.	('lung cancer', 'Disease', 'MESH:D008175', (94, 105))	('miR-183-3p', 'Chemical', '-', (0, 10))	('miR-183-3p', 'Var', (0, 10))	('lung cancer', 'Disease', (94, 105))	('lung cancer', 'Phenotype', 'HP:0100526', (94, 105))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
241694	33953608	In this study, we focused on the clinicopathological significance of miR-183-3p and miR-182-5p in NSCLC.	('NSCLC', 'Phenotype', 'HP:0030358', (98, 103))	('miR-182-5p', 'Gene', '100302183', (84, 94))	('miR-182-5p', 'Gene', (84, 94))	('miR-183-3p', 'Var', (69, 79))	('NSCLC', 'Disease', (98, 103))	('miR-183-3p', 'Chemical', '-', (69, 79))	('NSCLC', 'Disease', 'MESH:D002289', (98, 103))
241702	33953608	The correlation between the expression of miR-183-3p or miR-182-5p and clinicopathological factors (age, sex, histological type, smoking, tumor size, lymphatic metastasis, distant metastasis, pleura invasion, vessel carcinoma embolus) was evaluated.	('tumor', 'Disease', (138, 143))	('miR-182-5p', 'Gene', (56, 66))	('vessel carcinoma embolus', 'Disease', 'MESH:D004617', (209, 233))	('miR-183-3p', 'Var', (42, 52))	('vessel carcinoma embolus', 'Disease', (209, 233))	('miR-182-5p', 'Gene', '100302183', (56, 66))	('miR-183-3p', 'Chemical', '-', (42, 52))	('lymphatic metastasis', 'CPA', (150, 170))	('carcinoma', 'Phenotype', 'HP:0030731', (216, 225))	('distant metastasis', 'CPA', (172, 190))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
241713	33953608	The assay IDs of microRNA-specific stem-loop RT primers (Thermo Fisher Scientific, Pleasanton, CA, USA) were as follows: hsa-miR-183-3p 002270, hsa-miR-182-5p 002334, and U6 snRNA 001973.	('hsa-miR-182', 'Gene', (144, 155))	('hsa-miR-182', 'Gene', '406958', (144, 155))	('hsa-miR-183-3p 002270', 'Var', (121, 142))	('miR-182-5p', 'Gene', '100302183', (148, 158))	('miR-182-5p', 'Gene', (148, 158))	('miR-183-3p', 'Chemical', '-', (125, 135))	('U6 snRNA 001973', 'Var', (171, 186))
241714	33953608	The assay IDs of microRNA-specific TaqMan  MGB probes (Thermo Fisher Scientific, Pleasanton, CA, USA) were as follows: hsa-miR-183-3p 002270, hsa-miR-182-5p 002334, and U6 snRNA 001973.	('U6 snRNA 001973', 'Var', (169, 184))	('miR-183-3p', 'Chemical', '-', (123, 133))	('hsa-miR-182', 'Gene', (142, 153))	('miR-182-5p', 'Gene', '100302183', (146, 156))	('miR-182-5p', 'Gene', (146, 156))	('hsa-miR-183-3p 002270', 'Var', (119, 140))	('hsa-miR-182', 'Gene', '406958', (142, 153))
241727	33953608	The top 10% and the bottom 10% miR-183-3p or miR-182-5p expression was defined as the cutoff value between the high and low expression groups.	('miR-183-3p', 'Chemical', '-', (31, 41))	('miR-183-3p', 'Var', (31, 41))	('miR-182-5p', 'Gene', '100302183', (45, 55))	('miR-182-5p', 'Gene', (45, 55))
241731	33953608	The expression levels of miR-183-3p and miR-182-5p in 76 paired NSCLC tissues and adjacent noncancerous tissues were quantified by RT-qPCR.	('NSCLC', 'Disease', 'MESH:D002289', (64, 69))	('NSCLC', 'Phenotype', 'HP:0030358', (64, 69))	('miR-183-3p', 'Var', (25, 35))	('miR-183-3p', 'Chemical', '-', (25, 35))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('miR-182-5p', 'Gene', '100302183', (40, 50))	('NSCLC', 'Disease', (64, 69))	('miR-182-5p', 'Gene', (40, 50))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
241733	33953608	The median miR-183-3p expression was 4.097 (25-75 percentile, 2.365-7.361) in lung cancer tissues and 0.5592 (25-75 percentile, 0.3859-0.9922) in adjacent noncancerous tissues.	('lung cancer', 'Disease', (78, 89))	('lung cancer', 'Phenotype', 'HP:0100526', (78, 89))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('0.5592', 'Var', (102, 108))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('miR-183-3p', 'Gene', (11, 21))	('cancer', 'Disease', (158, 164))	('miR-183-3p', 'Chemical', '-', (11, 21))	('lung cancer', 'Disease', 'MESH:D008175', (78, 89))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('expression', 'MPA', (22, 32))	('cancer', 'Disease', (83, 89))
241735	33953608	Remarkably, miR-183-3p and miR-182-5p were higher in lung cancer tissues than in adjacent noncancerous tissues (both P < 0.0001) (Figure 1A and B).	('miR-183-3p', 'Var', (12, 22))	('miR-183-3p', 'Chemical', '-', (12, 22))	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('miR-182-5p', 'Gene', (27, 37))	('higher', 'PosReg', (43, 49))	('miR-182-5p', 'Gene', '100302183', (27, 37))	('lung cancer', 'Disease', 'MESH:D008175', (53, 64))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('cancer', 'Disease', (58, 64))	('lung cancer', 'Disease', (53, 64))	('lung cancer', 'Phenotype', 'HP:0100526', (53, 64))
241737	33953608	In addition, the RT-qPCR results of cell lines also showed that the relative expression of miR-183-3p and miR-182-5p was significantly increased in all NSCLC cell lines except A549 (Figure 2A and B).	('miR-183-3p', 'Var', (91, 101))	('miR-182-5p', 'Gene', '100302183', (106, 116))	('miR-182-5p', 'Gene', (106, 116))	('miR-183-3p', 'Chemical', '-', (91, 101))	('A549', 'CellLine', 'CVCL:0023', (176, 180))	('NSCLC', 'Disease', (152, 157))	('increased', 'PosReg', (135, 144))	('NSCLC', 'Disease', 'MESH:D002289', (152, 157))	('NSCLC', 'Phenotype', 'HP:0030358', (152, 157))
241740	33953608	We further evaluated the correlation between miR-183-3p or miR-182-5p expression and the clinicopathological characteristics of 76 included patients.	('miR-182-5p', 'Gene', (59, 69))	('evaluated', 'Reg', (11, 20))	('miR-182-5p', 'Gene', '100302183', (59, 69))	('miR-183-3p', 'Var', (45, 55))	('patients', 'Species', '9606', (140, 148))	('miR-183-3p', 'Chemical', '-', (45, 55))
241741	33953608	In tumor tissues, the results showed that miR-183-3p (P = 0.0444) and miR-182-5p (P = 0.0132) were correlated with tumor size (maximum diameter > 2 cm).	('tumor', 'Disease', (3, 8))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('miR-182-5p', 'Gene', (70, 80))	('miR-183-3p', 'Var', (42, 52))	('tumor', 'Disease', (115, 120))	('miR-182-5p', 'Gene', '100302183', (70, 80))	('miR-183-3p', 'Chemical', '-', (42, 52))	('correlated', 'Reg', (99, 109))	('tumor', 'Disease', 'MESH:D009369', (3, 8))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
241743	33953608	Interestingly, we also found that miR-183-3p and miR-182-5p were upregulation in nonmalignant tissues of smokers (Figure 1G and H).	('miR-182-5p', 'Gene', (49, 59))	('miR-183-3p', 'Var', (34, 44))	('miR-183-3p', 'Chemical', '-', (34, 44))	('miR-182-5p', 'Gene', '100302183', (49, 59))	('upregulation', 'PosReg', (65, 77))
241746	33953608	We further explored the relationship between the expression of miR-183-3p and miR-182-5p.	('miR-182-5p', 'Gene', '100302183', (78, 88))	('miR-182-5p', 'Gene', (78, 88))	('miR-183-3p', 'Chemical', '-', (63, 73))	('miR-183-3p', 'Var', (63, 73))
241747	33953608	The linear correlation analysis of miR-183-3p and miR-182-5p expression in tumor tissues showed a strong positive correlation with each other (r = 0.8519, P < 0.001) (Figure 3A).	('miR-182-5p', 'Gene', '100302183', (50, 60))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('miR-183-3p', 'Var', (35, 45))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('miR-182-5p', 'Gene', (50, 60))	('miR-183-3p', 'Chemical', '-', (35, 45))	('tumor', 'Disease', (75, 80))
241748	33953608	Furthermore, we also found that the expression level of miR-182-5p presented a coincident change in miR-183-3p artificially up- or down-regulated cell models (Figure 3B).	('miR-182-5p', 'Gene', (56, 66))	('miR-182-5p', 'Gene', '100302183', (56, 66))	('miR-183-3p', 'Chemical', '-', (100, 110))	('down-regulated', 'NegReg', (131, 145))	('up-', 'PosReg', (124, 127))	('miR-183-3p', 'Var', (100, 110))	('expression', 'MPA', (36, 46))
241751	33953608	The CCK-8 assay results showed that the proliferation of the A549, H226 and BEAS-2B cell lines transfected with the miR-183-3p mimics was significantly promoted compared with that of the cells transfected with the negative control (Figure 4A-C).	('H226', 'CellLine', 'CVCL:J621', (67, 71))	('miR-183-3p', 'Chemical', '-', (116, 126))	('miR-183-3p mimics', 'Var', (116, 133))	('promoted', 'PosReg', (152, 160))	('proliferation', 'CPA', (40, 53))	('BEAS-2B', 'CellLine', 'CVCL:0168', (76, 83))	('A549', 'CellLine', 'CVCL:0023', (61, 65))
241752	33953608	Moreover, the proliferation ability of the H1395 cell line transfected with miR-183-3p inhibitors was significantly reduced (Figure 4D).	('reduced', 'NegReg', (116, 123))	('miR-183-3p inhibitors', 'Var', (76, 97))	('miR-183-3p', 'Chemical', '-', (76, 86))	('proliferation ability of the H1395 cell line', 'CPA', (14, 58))	('H1395', 'CellLine', 'CVCL:1467', (43, 48))
241753	33953608	Consistent with this outcome, the colony formation assay revealed that the colony numbers, colony formation rates and colony sizes of A549, H226 and BEAS-2B cell lines transfected with miR-183-3p mimics were significantly increased (Figure 4E-G).	('BEAS-2B', 'CellLine', 'CVCL:0168', (149, 156))	('colony numbers', 'CPA', (75, 89))	('miR-183-3p', 'Chemical', '-', (185, 195))	('H226', 'CellLine', 'CVCL:J621', (140, 144))	('colony formation rates', 'CPA', (91, 113))	('colony sizes', 'CPA', (118, 130))	('increased', 'PosReg', (222, 231))	('miR-183-3p mimics', 'Var', (185, 202))	('A549', 'CellLine', 'CVCL:0023', (134, 138))
241754	33953608	In addition, those of the H1395 cell line transfected with miR-183-3p inhibitors were significantly reduced (Figure 4H-J).	('reduced', 'NegReg', (100, 107))	('H1395', 'CellLine', 'CVCL:1467', (26, 31))	('miR-183-3p inhibitors', 'Var', (59, 80))	('miR-183-3p', 'Chemical', '-', (59, 69))
241756	33953608	In addition, miR-183-3p was found to be relatively higher in LUSC tumor tissue than in LUAD tumor tissue (P < 0.0001) (Figure 5B).	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('LUAD tumor', 'Disease', (87, 97))	('LUAD', 'Phenotype', 'HP:0030078', (87, 91))	('tumor', 'Disease', (66, 71))	('miR-183-3p', 'Var', (13, 23))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('LUAD tumor', 'Disease', 'MESH:D009369', (87, 97))	('miR-183-3p', 'Chemical', '-', (13, 23))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('LUSC', 'Phenotype', 'HP:0030359', (61, 65))	('tumor', 'Disease', (92, 97))	('higher', 'PosReg', (51, 57))	('tumor', 'Disease', 'MESH:D009369', (66, 71))
241757	33953608	In addition, miR-183-3p was also higher in the tumor tissues of smokers than in that of nonsmokers (P = 0.0057) (Figure 5C).	('higher', 'PosReg', (33, 39))	('miR-183-3p', 'Var', (13, 23))	('miR-183-3p', 'Chemical', '-', (13, 23))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor', 'Disease', (47, 52))
241758	33953608	We further carried out a prognostic analysis of miR-183-3p and miR-182-5p using cases in TCGA database.	('miR-182-5p', 'Gene', '100302183', (63, 73))	('miR-183-3p', 'Var', (48, 58))	('miR-183-3p', 'Chemical', '-', (48, 58))	('miR-182-5p', 'Gene', (63, 73))
241759	33953608	For miR-183-3p, 192 NSCLC cases were included for OS analysis.	('NSCLC', 'Disease', 'MESH:D002289', (20, 25))	('NSCLC', 'Phenotype', 'HP:0030358', (20, 25))	('miR-183-3p', 'Var', (4, 14))	('miR-183-3p', 'Chemical', '-', (4, 14))	('NSCLC', 'Disease', (20, 25))
241762	33953608	Further subgroup analysis indicated that miR-183-3p expression was closely related to poor prognosis in LUAD (P = 0.0147) (Figure 5E).	('related', 'Reg', (75, 82))	('LUAD', 'Disease', (104, 108))	('LUAD', 'Phenotype', 'HP:0030078', (104, 108))	('miR-183-3p expression', 'Var', (41, 62))	('miR-183-3p', 'Chemical', '-', (41, 51))
241771	33953608	The miR-183-5p expression characteristics in various cancers are inconsistent.	('cancers', 'Phenotype', 'HP:0002664', (53, 60))	('miR-183-5p', 'Chemical', '-', (4, 14))	('cancers', 'Disease', (53, 60))	('cancers', 'Disease', 'MESH:D009369', (53, 60))	('miR-183-5p', 'Var', (4, 14))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))
241772	33953608	For example, miR-183-5p expression is upregulated in several cancer types, but it decreases in osteosarcoma.	('miR-183-5p', 'Chemical', '-', (13, 23))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('expression', 'MPA', (24, 34))	('miR-183-5p', 'Var', (13, 23))	('cancer', 'Disease', (61, 67))	('upregulated', 'PosReg', (38, 49))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('decreases', 'NegReg', (82, 91))	('osteosarcoma', 'Disease', (95, 107))	('osteosarcoma', 'Disease', 'MESH:D012516', (95, 107))	('osteosarcoma', 'Phenotype', 'HP:0002669', (95, 107))
241774	33953608	Zhang and colleagues reported that miR-183-5p was upregulated in tumors and promoted the growth of NSCLC cells through FoxO1 inhibition.	('upregulated', 'PosReg', (50, 61))	('NSCLC', 'Disease', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('miR-183-5p', 'Chemical', '-', (35, 45))	('growth', 'MPA', (89, 95))	('NSCLC', 'Phenotype', 'HP:0030358', (99, 104))	('tumors', 'Disease', (65, 71))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('FoxO1', 'Gene', (119, 124))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('miR-183-5p', 'Var', (35, 45))	('promoted', 'PosReg', (76, 84))	('FoxO1', 'Gene', '2308', (119, 124))	('inhibition', 'NegReg', (125, 135))	('NSCLC', 'Disease', 'MESH:D002289', (99, 104))
241775	33953608	However, Meng reported in their recent study that miR-183-5p was downregulated in lung cancer and may function as a tumor suppressor.	('lung cancer', 'Phenotype', 'HP:0100526', (82, 93))	('miR-183-5p', 'Var', (50, 60))	('lung cancer', 'Disease', (82, 93))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('downregulated', 'NegReg', (65, 78))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('lung cancer', 'Disease', 'MESH:D008175', (82, 93))	('miR-183-5p', 'Chemical', '-', (50, 60))	('tumor', 'Disease', (116, 121))
241776	33953608	As the reverse complement of miR-183-5p, miR-183-3p has only been reported by a few studies on cancer.	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('cancer', 'Disease', (95, 101))	('miR-183-3p', 'Var', (41, 51))	('miR-183-5p', 'Chemical', '-', (29, 39))	('miR-183-3p', 'Chemical', '-', (41, 51))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))
241777	33953608	For lung cancer, only F. Xu focused on miR-183-3p expression, but the types of cases included in their study were limited.	('miR-183-3p', 'Chemical', '-', (39, 49))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('lung cancer', 'Disease', (4, 15))	('lung cancer', 'Phenotype', 'HP:0100526', (4, 15))	('lung cancer', 'Disease', 'MESH:D008175', (4, 15))	('miR-183-3p', 'Var', (39, 49))
241778	33953608	In this study, we included different kinds of histological types of NSCLC patients and paid attention to the clinicopathological significance of miR-183-3p and miR-182-5p in NSCLC.	('NSCLC', 'Disease', 'MESH:D002289', (174, 179))	('NSCLC', 'Disease', 'MESH:D002289', (68, 73))	('miR-183-3p', 'Chemical', '-', (145, 155))	('patients', 'Species', '9606', (74, 82))	('NSCLC', 'Phenotype', 'HP:0030358', (174, 179))	('NSCLC', 'Phenotype', 'HP:0030358', (68, 73))	('miR-182-5p', 'Gene', (160, 170))	('miR-183-3p', 'Var', (145, 155))	('NSCLC', 'Disease', (68, 73))	('miR-182-5p', 'Gene', '100302183', (160, 170))	('NSCLC', 'Disease', (174, 179))
241779	33953608	In tumor tissues, we found that miR-183-3p and miR-182-5p expression was significantly increased compared with that in corresponding nonmalignant tissues (Figure 1A and B) and correlated with tumor size (Table 1).	('miR-182-5p', 'Gene', '100302183', (47, 57))	('miR-183-3p', 'Var', (32, 42))	('increased', 'PosReg', (87, 96))	('tumor', 'Disease', (192, 197))	('tumor', 'Disease', (3, 8))	('miR-183-3p', 'Chemical', '-', (32, 42))	('expression', 'MPA', (58, 68))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('tumor', 'Disease', 'MESH:D009369', (3, 8))	('miR-182-5p', 'Gene', (47, 57))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))	('correlated', 'Reg', (176, 186))
241780	33953608	Thus, we speculate that miR-183-3p and miR-182-5p may correlate with tumor growth.	('correlate', 'Reg', (54, 63))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor', 'Disease', (69, 74))	('miR-183-3p', 'Var', (24, 34))	('miR-183-3p', 'Chemical', '-', (24, 34))	('miR-182-5p', 'Gene', (39, 49))	('miR-182-5p', 'Gene', '100302183', (39, 49))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
241786	33953608	Only one study reported that the upregulation of miR-183-5p was observed in the infected abdominal aortic aneurysm tumor tissues of smokers.	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('miR-183-5p', 'Chemical', '-', (49, 59))	('abdominal aortic aneurysm', 'Phenotype', 'HP:0005112', (89, 114))	('upregulation', 'PosReg', (33, 45))	('infected abdominal aortic aneurysm tumor', 'Disease', (80, 120))	('miR-183-5p', 'Var', (49, 59))	('aortic aneurysm', 'Phenotype', 'HP:0004942', (99, 114))	('infected abdominal aortic aneurysm tumor', 'Disease', 'MESH:D017544', (80, 120))	('aneurysm', 'Phenotype', 'HP:0002617', (106, 114))
241787	33953608	We further explored the relationship between miR-183-3p or miR-182-5p expression in tumor tissues and smoking history in TCGA database, and the results showed that miR-183-3p was also relatively higher in NSCLC cancer tissue of smokers than that of nonsmokers.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('NSCLC', 'Phenotype', 'HP:0030358', (205, 210))	('NSCLC cancer', 'Disease', (205, 217))	('miR-182-5p', 'Gene', (59, 69))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('higher', 'PosReg', (195, 201))	('miR-183-3p', 'Var', (164, 174))	('miR-182-5p', 'Gene', '100302183', (59, 69))	('NSCLC cancer', 'Disease', 'MESH:D009369', (205, 217))	('tumor', 'Disease', (84, 89))	('miR-183-3p', 'Chemical', '-', (164, 174))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('miR-183-3p', 'Chemical', '-', (45, 55))
241788	33953608	We speculate that the upregulation of miR-183-3p may be caused by smoking, and the increase in miR-183-3p may further promote the proliferation of lung cancer cells.	('increase', 'PosReg', (83, 91))	('miR-183-3p', 'Var', (95, 105))	('miR-183-3p', 'Chemical', '-', (95, 105))	('lung cancer', 'Disease', (147, 158))	('proliferation', 'CPA', (130, 143))	('miR-183-3p', 'Gene', (38, 48))	('miR-183-3p', 'Chemical', '-', (38, 48))	('lung cancer', 'Phenotype', 'HP:0100526', (147, 158))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('upregulation', 'PosReg', (22, 34))	('promote', 'PosReg', (118, 125))	('lung cancer', 'Disease', 'MESH:D008175', (147, 158))
241793	33953608	For miR-183-3p, we performed growth curve assays and colony formation assays in several NSCLC cell lines, and the results indicated that miR-183-3p was positively correlated with cell proliferation (Figure 4A-J).	('cell proliferation', 'CPA', (179, 197))	('NSCLC', 'Phenotype', 'HP:0030358', (88, 93))	('correlated', 'Reg', (163, 173))	('miR-183-3p', 'Var', (137, 147))	('NSCLC', 'Disease', (88, 93))	('miR-183-3p', 'Chemical', '-', (137, 147))	('miR-183-3p', 'Chemical', '-', (4, 14))	('NSCLC', 'Disease', 'MESH:D002289', (88, 93))
241794	33953608	The in vitro experimental results in our study and in previous studies may support the hypothesis that miR-183-3p and miR-182-5p are correlated with tumor growth to some extent.	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('miR-183-3p', 'Var', (103, 113))	('tumor', 'Disease', (149, 154))	('correlated', 'Reg', (133, 143))	('miR-182-5p', 'Gene', '100302183', (118, 128))	('miR-182-5p', 'Gene', (118, 128))	('miR-183-3p', 'Chemical', '-', (103, 113))
241795	33953608	In addition to the above findings, we also noticed that the expression of miR-183-3p and miR-182-5p in tumor tissues was closely positively correlated (Figure 3A).	('miR-182-5p', 'Gene', '100302183', (89, 99))	('miR-182-5p', 'Gene', (89, 99))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('miR-183-3p', 'Var', (74, 84))	('miR-183-3p', 'Chemical', '-', (74, 84))	('tumor', 'Disease', (103, 108))	('correlated', 'Reg', (140, 150))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
241796	33953608	At present, the relationship between miR-183-3p and miR-182-5p has not been reported before.	('miR-183-3p', 'Var', (37, 47))	('miR-182-5p', 'Gene', '100302183', (52, 62))	('miR-182-5p', 'Gene', (52, 62))	('miR-183-3p', 'Chemical', '-', (37, 47))
241800	33953608	The clinicopathological analysis results indicated that miR-183-3p was highly expressed in tumor tissues (Figure 5A-5C).	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('miR-183-3p', 'Var', (56, 66))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('miR-183-3p', 'Chemical', '-', (56, 66))	('tumor', 'Disease', (91, 96))
241801	33953608	In addition, miR-183-3p in LUSC tumors was relatively higher than that in LUAD tumors (Figure 5B), which indicates its potential value for distinguishing LUSC from LUAD and thus may influence treatment options.	('LUAD tumors', 'Disease', 'MESH:D009369', (74, 85))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('LUAD tumors', 'Disease', (74, 85))	('tumors', 'Disease', (32, 38))	('higher', 'PosReg', (54, 60))	('miR-183-3p', 'Var', (13, 23))	('tumors', 'Disease', (79, 85))	('influence', 'Reg', (182, 191))	('tumors', 'Disease', 'MESH:D009369', (32, 38))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('LUSC', 'Phenotype', 'HP:0030359', (27, 31))	('LUSC', 'Disease', (154, 158))	('LUAD', 'Phenotype', 'HP:0030078', (164, 168))	('miR-183-3p', 'Chemical', '-', (13, 23))	('LUAD', 'Phenotype', 'HP:0030078', (74, 78))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('LUSC', 'Phenotype', 'HP:0030359', (154, 158))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
241802	33953608	Furthermore, the correlation between miR-183-3p expression and tumor size could also be verified in TCGA database (Figure 5A).	('miR-183-3p', 'Var', (37, 47))	('tumor', 'Disease', (63, 68))	('miR-183-3p', 'Chemical', '-', (37, 47))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
241803	33953608	The survival analysis results indicate that patients with high expression of miR-183-3p have a relatively shorter overall survival time, which means that this gene is a meaningful indicator of poor prognosis in NSCLC patients (Figure 5D-5F).	('miR-183-3p', 'Var', (77, 87))	('overall survival', 'MPA', (114, 130))	('shorter', 'NegReg', (106, 113))	('patients', 'Species', '9606', (44, 52))	('NSCLC', 'Phenotype', 'HP:0030358', (211, 216))	('miR-183-3p', 'Chemical', '-', (77, 87))	('high expression', 'Var', (58, 73))	('NSCLC', 'Disease', (211, 216))	('patients', 'Species', '9606', (217, 225))	('NSCLC', 'Disease', 'MESH:D002289', (211, 216))
241807	33953608	In summary, we evaluated the clinical and prognostic values of miR-183-3p and miR-182-5p and further explored the effect of miR-183-3p on NSCLC progression and its relationship with miR-182-5p from different aspects.	('miR-182-5p', 'Gene', '100302183', (78, 88))	('miR-182-5p', 'Gene', (78, 88))	('miR-182-5p', 'Gene', (182, 192))	('NSCLC', 'Disease', (138, 143))	('miR-182-5p', 'Gene', '100302183', (182, 192))	('NSCLC', 'Disease', 'MESH:D002289', (138, 143))	('miR-183-3p', 'Chemical', '-', (124, 134))	('miR-183-3p', 'Var', (63, 73))	('miR-183-3p', 'Chemical', '-', (63, 73))	('NSCLC', 'Phenotype', 'HP:0030358', (138, 143))	('miR-183-3p', 'Var', (124, 134))
241808	33953608	First, as miR-183-3p is correlated with malignant biological properties, this gene may also have meaningful diagnostic value, and subsequent studies will explore this further.	('malignant biological properties', 'CPA', (40, 71))	('correlated', 'Reg', (24, 34))	('miR-183-3p', 'Chemical', '-', (10, 20))	('miR-183-3p', 'Var', (10, 20))
241812	33953608	This study confirmed that miR-183-3p and miR-182-5p are highly expressed in NSCLC tumor tissues and correlated with tumor size.	('miR-182-5p', 'Gene', (41, 51))	('miR-183-3p', 'Var', (26, 36))	('miR-183-3p', 'Chemical', '-', (26, 36))	('NSCLC tumor', 'Disease', (76, 87))	('miR-182-5p', 'Gene', '100302183', (41, 51))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumor', 'Disease', (82, 87))	('tumor', 'Disease', (116, 121))	('correlated', 'Reg', (100, 110))	('NSCLC', 'Phenotype', 'HP:0030358', (76, 81))	('NSCLC tumor', 'Disease', 'MESH:D009369', (76, 87))
241813	33953608	In addition, the expression levels of miR-183-3p and miR-182-5p were closely positively correlated with each other.	('expression', 'MPA', (17, 27))	('miR-183-3p', 'Chemical', '-', (38, 48))	('miR-183-3p', 'Var', (38, 48))	('miR-182-5p', 'Gene', (53, 63))	('miR-182-5p', 'Gene', '100302183', (53, 63))
241814	33953608	An increase in miR-183-3p may play an oncogenic role by promoting proliferation and have meaningful prognostic value in NSCLC.	('miR-183-3p', 'Chemical', '-', (15, 25))	('NSCLC', 'Disease', 'MESH:D002289', (120, 125))	('promoting', 'PosReg', (56, 65))	('proliferation', 'CPA', (66, 79))	('NSCLC', 'Phenotype', 'HP:0030358', (120, 125))	('miR-183-3p', 'Var', (15, 25))	('NSCLC', 'Disease', (120, 125))	('increase', 'PosReg', (3, 11))
241949	27847826	Hence, when compared to oral squamous cell carcinomas with different grades of differentiation, the low and the moderate differentiated carcinoma are known to be more aggressive and invasive and, in these cases, MCs may play a double role in promoting angiogenesis and invasion, while their cytotoxic function may be inefficient in such situations.	('invasion', 'CPA', (269, 277))	('MCs', 'Var', (212, 215))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (29, 53))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (29, 52))	('angiogenesis', 'CPA', (252, 264))	('carcinoma', 'Disease', 'MESH:D002277', (43, 52))	('carcinoma', 'Disease', 'MESH:D002277', (136, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (43, 52))	('carcinomas', 'Phenotype', 'HP:0030731', (43, 53))	('promoting', 'PosReg', (242, 251))	('rat', 'Species', '10116', (116, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('oral squamous cell carcinomas', 'Disease', 'MESH:D002294', (24, 53))	('oral squamous cell carcinomas', 'Disease', (24, 53))	('carcinoma', 'Disease', (43, 52))	('carcinoma', 'Disease', (136, 145))
241953	27847826	It is difficult to explain these discordant results regarding mast cell density and, thus, the hypothesis according to which the lower density observed in low differentiated oral SCC is possible due to massive mast cell degranulation may be stated, an aspect that makes their identification difficult.	('low', 'Var', (155, 158))	('SCC', 'Gene', '6317', (179, 182))	('SCC', 'Gene', (179, 182))
241963	27847826	The results of this study are consistent with the idea that MCs may promote tumor progression through the regulation of angiogenesis.	('promote', 'PosReg', (68, 75))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('angiogenesis', 'CPA', (120, 132))	('MCs', 'Var', (60, 63))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
241994	33681201	CPT1A can promote the proliferation of breast cancer cells by succinylation of enolase 1 and enhance metastasis of gastric cancer (GC) cells by succinylation of S100A10.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('breast cancer', 'Phenotype', 'HP:0003002', (39, 52))	('CPT1A', 'Gene', (0, 5))	('succinyl', 'Chemical', '-', (144, 152))	('gastric cancer', 'Phenotype', 'HP:0012126', (115, 129))	('S100A10', 'Gene', '6281', (161, 168))	('enolase 1', 'Gene', '2023', (79, 88))	('promote', 'PosReg', (10, 17))	('breast cancer', 'Disease', 'MESH:D001943', (39, 52))	('enolase 1', 'Gene', (79, 88))	('breast cancer', 'Disease', (39, 52))	('succinyl', 'Chemical', '-', (62, 70))	('enhance', 'PosReg', (93, 100))	('proliferation', 'CPA', (22, 35))	('GC', 'Phenotype', 'HP:0012126', (131, 133))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('succinylation', 'MPA', (62, 75))	('metastasis of gastric cancer', 'Disease', (101, 129))	('succinylation', 'Var', (144, 157))	('CPT1A', 'Gene', '1374', (0, 5))	('metastasis of gastric cancer', 'Disease', 'MESH:D013274', (101, 129))	('S100A10', 'Gene', (161, 168))
242003	33681201	Compared to acetylation, succinylation can cause larger mass changes in substrate proteins due to the higher molecular weight of succinyl and can also have a greater effect on the charge of lysine residues from +1 to -1, resulting in more significant influences on the structure and function of target proteins.	('succinyl', 'Chemical', '-', (25, 33))	('lysine', 'Chemical', 'MESH:D008239', (190, 196))	('mass changes', 'MPA', (56, 68))	('influences', 'Reg', (251, 261))	('higher', 'PosReg', (102, 108))	('effect', 'Reg', (166, 172))	('succinylation', 'Var', (25, 38))	('charge', 'MPA', (180, 186))	('structure', 'MPA', (269, 278))	('molecular weight', 'MPA', (109, 125))	('function', 'MPA', (283, 291))	('succinyl', 'Chemical', '-', (129, 137))
242005	33681201	For example, succinylation of S100A10 or GLS can increase the stability of these proteins by antagonizing ubiquitination and proteasome-dependent degradation.	('ubiquitination', 'MPA', (106, 120))	('increase', 'PosReg', (49, 57))	('stability', 'MPA', (62, 71))	('S100A10', 'Gene', '6281', (30, 37))	('succinylation', 'Var', (13, 26))	('S100A10', 'Gene', (30, 37))	('GLS', 'Gene', '2744', (41, 44))	('antagonizing', 'NegReg', (93, 105))	('GLS', 'Gene', (41, 44))	('proteasome-dependent degradation', 'MPA', (125, 157))	('succinyl', 'Chemical', '-', (13, 21))
242042	33681201	However, univariate Cox regression analysis showed that the overall survival (OS) of patients with KIRC (also named ccRCC), but not other tumor types, was associated with all four regulators (P < 0.05) (Figure 1B and Supplementary Table S4).	('RCC', 'Disease', 'MESH:C538614', (118, 121))	('ccRCC', 'Phenotype', 'HP:0006770', (116, 121))	('RCC', 'Disease', (118, 121))	('tumor', 'Disease', (138, 143))	('RCC', 'Phenotype', 'HP:0005584', (118, 121))	('Cox', 'Gene', '1351', (20, 23))	('Cox', 'Gene', (20, 23))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('patients', 'Species', '9606', (85, 93))	('associated', 'Interaction', (155, 165))	('KIRC', 'Var', (99, 103))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
242062	33681201	Interestingly, we found that most of the up-regulated pathways were related to immune regulation and part of the pathways overlapped between clusters 1 and 2, suggesting that succinylation regulators might promote the ccRCC by regulating immune pathways (Figures 4B,E).	('succinyl', 'Chemical', '-', (175, 183))	('ccRCC', 'Phenotype', 'HP:0006770', (218, 223))	('succinylation', 'Var', (175, 188))	('immune pathways', 'Pathway', (238, 253))	('regulating', 'Reg', (227, 237))	('promote', 'PosReg', (206, 213))	('RCC', 'Phenotype', 'HP:0005584', (220, 223))	('RCC', 'Disease', 'MESH:C538614', (220, 223))	('RCC', 'Disease', (220, 223))
242067	33681201	Kaplan-Meier analysis indicated that infiltration of Tregs was associated with the poor prognosis of OS (HR = 1.820, 95%CI = 1.140-2.906, P = 0.011) and infiltration of resting mast cells was associated with longer OS (HR = 0.462, 95%CI = 0.286-0.747, P = 0.001).	('longer OS', 'Disease', (208, 217))	('infiltration', 'Var', (37, 49))	('Tregs', 'Chemical', '-', (53, 58))	('infiltration', 'Var', (153, 165))
242080	33681201	N6-methyladenosine (m6A) methylation, one of the most common RNA-related modifications, is catalyzed by m6A regulators.	('m6A', 'Gene', '56339', (20, 23))	('m6A', 'Gene', '56339', (104, 107))	('N6-methyladenosine', 'Chemical', 'MESH:C010223', (0, 18))	('N6-methyladenosine', 'Var', (0, 18))	('m6A', 'Gene', (20, 23))	('m6A', 'Gene', (104, 107))
242094	33681201	From these data, we inferred that succinylation modification might promote malignant progression in ccRCC by regulating m6A regulators, at least partially by influencing protein expression levels.	('succinylation modification', 'Var', (34, 60))	('succinyl', 'Chemical', '-', (34, 42))	('protein expression levels', 'MPA', (170, 195))	('m6A', 'Gene', '56339', (120, 123))	('regulating', 'Reg', (109, 119))	('malignant progression', 'CPA', (75, 96))	('RCC', 'Disease', 'MESH:C538614', (102, 105))	('ccRCC', 'Phenotype', 'HP:0006770', (100, 105))	('RCC', 'Disease', (102, 105))	('RCC', 'Phenotype', 'HP:0005584', (102, 105))	('m6A', 'Gene', (120, 123))	('influencing', 'Reg', (158, 169))	('promote', 'PosReg', (67, 74))
242106	33681201	Further validation was performed in the ACHN cell line by Western blotting, showing that LRPPRC was down-regulated following the silencing of CPT1A while EIF3B was prominently up-regulated by the knockdown of SIRT5 (Figure 9C).	('SIRT5', 'Gene', (209, 214))	('LRPPRC', 'Gene', '10128', (89, 95))	('up-regulated', 'PosReg', (176, 188))	('SIRT5', 'Gene', '23408', (209, 214))	('EIF3B', 'Gene', (154, 159))	('CPT1A', 'Gene', (142, 147))	('silencing', 'Var', (129, 138))	('down-regulated', 'NegReg', (100, 114))	('LRPPRC', 'Gene', (89, 95))	('EIF3B', 'Gene', '8662', (154, 159))	('CPT1A', 'Gene', '1374', (142, 147))	('knockdown', 'Var', (196, 205))
242116	33681201	SIRT5 has been reported to desuccinylate SDHA to promote ccRCC tumorigenesis.	('SIRT5', 'Gene', (0, 5))	('tumor', 'Disease', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('ccRCC', 'Phenotype', 'HP:0006770', (57, 62))	('desuccinylate', 'Var', (27, 40))	('SDHA', 'Gene', (41, 45))	('SIRT5', 'Gene', '23408', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('promote', 'PosReg', (49, 56))	('succinyl', 'Chemical', '-', (29, 37))	('SDHA', 'Gene', '6389', (41, 45))	('RCC', 'Disease', 'MESH:C538614', (59, 62))	('RCC', 'Disease', (59, 62))	('RCC', 'Phenotype', 'HP:0005584', (59, 62))
242124	33681201	Furthermore, our pathway enrichment analyses of the three clusters suggested that succinylation regulators might play a role in the immune cell infiltration and m6A methylation in ccRCC.	('m6A', 'Gene', '56339', (161, 164))	('ccRCC', 'Phenotype', 'HP:0006770', (180, 185))	('play', 'Reg', (113, 117))	('methylation', 'Var', (165, 176))	('RCC', 'Phenotype', 'HP:0005584', (182, 185))	('RCC', 'Disease', 'MESH:C538614', (182, 185))	('RCC', 'Disease', (182, 185))	('m6A', 'Gene', (161, 164))	('succinyl', 'Chemical', '-', (82, 90))
242134	33681201	Loss of SIRT5 promotes the transcription of IL-1beta in macrophages by increasing the succinylation level of PKM2 and forcing it to be translocated into the nucleus for the formation of the PKM2-HIF1alpha complex on the IL-1beta promoter.	('increasing', 'PosReg', (71, 81))	('HIF1alpha', 'Gene', (195, 204))	('promotes', 'PosReg', (14, 22))	('IL-1beta', 'Gene', (220, 228))	('PKM2', 'Gene', (109, 113))	('PKM2', 'Gene', (190, 194))	('PKM2', 'Gene', '5315', (190, 194))	('PKM2', 'Gene', '5315', (109, 113))	('IL-1beta', 'Gene', (44, 52))	('succinyl', 'Chemical', '-', (86, 94))	('forcing', 'Reg', (118, 125))	('IL-1beta', 'Gene', '3552', (220, 228))	('Loss', 'Var', (0, 4))	('IL-1beta', 'Gene', '3552', (44, 52))	('HIF1alpha', 'Gene', '3091', (195, 204))	('transcription', 'MPA', (27, 40))	('SIRT5', 'Gene', (8, 13))	('succinylation level', 'MPA', (86, 105))	('SIRT5', 'Gene', '23408', (8, 13))
242154	33681201	For example, succinylation modification of GLS could inhibit ubiquitination via competition for same lysine residues leading to decrescent protein degradation and increscent protein stability.	('decrescent protein degradation', 'MPA', (128, 158))	('succinylation modification', 'Var', (13, 39))	('inhibit', 'NegReg', (53, 60))	('GLS', 'Gene', '2744', (43, 46))	('lysine', 'Chemical', 'MESH:D008239', (101, 107))	('GLS', 'Gene', (43, 46))	('increscent', 'NegReg', (163, 173))	('ubiquitination', 'MPA', (61, 75))	('succinyl', 'Chemical', '-', (13, 21))
242236	31412811	Dysregulation of lncRNA expression has been reported for different cancer types and may contribute to tumor development and progression.	('lncRNA expression', 'Protein', (17, 34))	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('contribute', 'Reg', (88, 98))	('cancer', 'Disease', (67, 73))	('Dysregulation', 'Var', (0, 13))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('progression', 'CPA', (124, 135))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))
242271	31412811	The HNSCC cell line panel consisted of UM (University of Michigan) -SCC 10A/ B, -11B, -14A/ B, -17A/ B, - 47, - 104 and UT (University of Turku) -SCC -14, - 24A/ B, - 33, as well as UD (University of Duesseldorf) -SCC 1, - 2, - 3, - 5, - 6, -7A, - 8, and FaDu.	('SCC', 'Phenotype', 'HP:0002860', (68, 71))	('SCC', 'Gene', '6317', (68, 71))	('SCC', 'Gene', (6, 9))	('HNSCC', 'Phenotype', 'HP:0012288', (4, 9))	('SCC', 'Gene', '6317', (214, 217))	('SCC', 'Phenotype', 'HP:0002860', (6, 9))	('10A/ B', 'Var', (72, 78))	('SCC', 'Gene', (146, 149))	('SCC', 'Gene', '6317', (6, 9))	('24A/ B', 'SUBSTITUTION', 'None', (157, 163))	('SCC', 'Phenotype', 'HP:0002860', (146, 149))	('SCC', 'Gene', '6317', (146, 149))	('24A/ B', 'Var', (157, 163))	('SCC', 'Gene', (68, 71))	('SCC', 'Gene', (214, 217))	('SCC', 'Phenotype', 'HP:0002860', (214, 217))	('10A/ B', 'SUBSTITUTION', 'None', (72, 78))
242317	31412811	Patients with high expression of either CASC9 (p = 0.002) or HOTAIR (p < 0.001) experienced poor overall survival (Fig.	('overall survival', 'MPA', (97, 113))	('HOTAIR', 'Gene', (61, 67))	('poor', 'NegReg', (92, 96))	('Patients', 'Species', '9606', (0, 8))	('HOTAIR', 'Gene', '100124700', (61, 67))	('high expression', 'Var', (14, 29))	('CASC9', 'Gene', (40, 45))	('CASC9', 'Gene', '101805492', (40, 45))
242333	31412811	Finally, overexpressed CASC9 has been reported in recent publications to influence proliferation, migration and invasion of tumor cell lines from cancers of esophagus, lung, stomach, and liver.	('liver', 'Disease', (187, 192))	('cancers', 'Disease', (146, 153))	('cancers', 'Disease', 'MESH:D009369', (146, 153))	('lung', 'Disease', (168, 172))	('proliferation', 'CPA', (83, 96))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('invasion', 'CPA', (112, 120))	('esophagus', 'Disease', (157, 166))	('tumor', 'Disease', (124, 129))	('overexpressed', 'Var', (9, 22))	('CASC9', 'Gene', (23, 28))	('CASC9', 'Gene', '101805492', (23, 28))	('migration', 'CPA', (98, 107))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('influence', 'Reg', (73, 82))	('stomach', 'Disease', (174, 181))	('cancers', 'Phenotype', 'HP:0002664', (146, 153))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
242354	31412811	CASC9 expression had excellent tumor specificity according to ROC curve analysis, comparable to results reported in ESCC, and high CASC9 expression was significantly associated with high AJCC stage and extracapsular spread, indicating further diagnostic power.	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('expression', 'MPA', (137, 147))	('CASC9', 'Gene', (131, 136))	('CASC9', 'Gene', '101805492', (131, 136))	('SCC', 'Gene', (117, 120))	('tumor', 'Disease', (31, 36))	('CASC9', 'Gene', '101805492', (0, 5))	('high AJCC', 'Disease', (182, 191))	('high', 'Var', (126, 130))	('SCC', 'Gene', '6317', (117, 120))	('extracapsular spread', 'CPA', (202, 222))	('SCC', 'Phenotype', 'HP:0002860', (117, 120))	('associated', 'Reg', (166, 176))	('CASC9', 'Gene', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
242369	31412811	Since previous studies with cell lines from other cancer types reported stimulating effects of CASC9 expression on proliferation, migration and invasion or inhibitory effects on apoptosis, we modulated CASC9 expression by either stable overexpression or shRNA-mediated knock down in suitable HNSCC cell lines and in the benign HaCaT cell line.	('SCC', 'Phenotype', 'HP:0002860', (294, 297))	('knock down', 'Var', (269, 279))	('cancer', 'Disease', (50, 56))	('CASC9', 'Gene', (202, 207))	('SCC', 'Gene', '6317', (294, 297))	('CASC9', 'Gene', '101805492', (202, 207))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('HNSCC', 'Phenotype', 'HP:0012288', (292, 297))	('invasion', 'CPA', (144, 152))	('proliferation', 'CPA', (115, 128))	('HaCaT', 'CellLine', 'CVCL:0038', (327, 332))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('migration', 'CPA', (130, 139))	('CASC9', 'Gene', '101805492', (95, 100))	('modulated', 'Reg', (192, 201))	('SCC', 'Gene', (294, 297))	('CASC9', 'Gene', (95, 100))
242394	30867734	The present paper reviews previous studies of the molecular signaling pathways by which CAFs promote tumor neo-angiogenesis and highlights therapeutic response targets.	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('promote', 'PosReg', (93, 100))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('CAFs', 'Var', (88, 92))
242416	30867734	Studies have indicated that tumor progression is associated with the microenvironment of the tumor-host interface, which comprises tumor and stromal cells, as well as genetic mutations and the unlimited proliferation of tumor cells.	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('tumor', 'Disease', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('unlimited proliferation', 'CPA', (193, 216))	('tumor', 'Disease', (220, 225))	('associated', 'Reg', (49, 59))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('tumor', 'Disease', (93, 98))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('genetic mutations', 'Var', (167, 184))	('tumor', 'Disease', (131, 136))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('tumor', 'Disease', 'MESH:D009369', (220, 225))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
242422	30867734	Research indicates that CAF inhibition prolongs the survival of patients with pancreatic cancer compared with chemotherapy alone, and that anti-CAFs prevent tumor progression prior to tumor invasion.	('tumor', 'Disease', (157, 162))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('patients', 'Species', '9606', (64, 72))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (78, 95))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('prolongs', 'PosReg', (39, 47))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('inhibition', 'Var', (28, 38))	('anti-CAFs', 'Var', (139, 148))	('tumor', 'Disease', (184, 189))	('survival', 'CPA', (52, 60))	('pancreatic cancer', 'Disease', (78, 95))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('CAF', 'Protein', (24, 27))	('prevent', 'NegReg', (149, 156))	('pancreatic cancer', 'Disease', 'MESH:D010190', (78, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
242430	30867734	As such, antibodies against MMP-2 and MT1-MMP, PI3K inhibitors and Ln-5gamma2 target short interfering RNA are able to inhibit VM formation.	('PI3', 'Gene', '5266', (47, 50))	('MMP-2', 'Gene', (28, 33))	('MT1-MMP', 'Gene', '4323', (38, 45))	('inhibit', 'NegReg', (119, 126))	('MT1-MMP', 'Gene', (38, 45))	('VM formation', 'CPA', (127, 139))	('PI3', 'Gene', (47, 50))	('antibodies', 'Var', (9, 19))	('MMP-2', 'Gene', '4313', (28, 33))	('short interfering RNA', 'MPA', (85, 106))
242443	30867734	AGM has been reported to be overexpressed by CAFs in breast, colon, lung and uterus carcinomas, and so is considered to be a marker of cancer vasculature permeability.	('colon', 'Disease', (61, 66))	('cancer', 'Disease', (135, 141))	('overexpressed', 'PosReg', (28, 41))	('AGM', 'Gene', '3490', (0, 3))	('CAFs', 'Var', (45, 49))	('uterus carcinomas', 'Disease', (77, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('carcinomas', 'Phenotype', 'HP:0030731', (84, 94))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('uterus carcinomas', 'Disease', 'MESH:D014594', (77, 94))	('breast', 'Disease', (53, 59))	('uterus carcinomas', 'Phenotype', 'HP:0010784', (77, 94))	('lung', 'Disease', (68, 72))	('AGM', 'Gene', (0, 3))	('cancer', 'Disease', 'MESH:D009369', (135, 141))
242446	30867734	GPER knockdown eliminates VEGF expression in activated CAFs under hypoxic conditions, and it has been identified that breast CAFs promote hypoxia-dependent tumor angiogenesis in a HIF-1alpha/GPER-dependent manner by mediating the expression of VEGF.	('GPER', 'Gene', '2852', (0, 4))	('HIF-1alpha', 'Gene', (180, 190))	('promote', 'PosReg', (130, 137))	('hypoxia-dependent tumor', 'Disease', 'MESH:D000860', (138, 161))	('hypoxia-dependent tumor', 'Disease', (138, 161))	('knockdown', 'Var', (5, 14))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('VEGF', 'Gene', (26, 30))	('expression', 'MPA', (31, 41))	('GPER', 'Gene', (0, 4))	('GPER', 'Gene', '2852', (191, 195))	('eliminates', 'NegReg', (15, 25))	('HIF-1alpha', 'Gene', '3091', (180, 190))	('GPER', 'Gene', (191, 195))
242507	30867734	In a transgenic adenocarcinoma mouse prostate (TRAMP) mouse model, increased vascularization occurred was observed in eng+/+ mice compared with in eng+/- mice, suggesting that eng is required for multiple aspects of CAF function.	('adenocarcinoma', 'Disease', 'MESH:D000230', (16, 30))	('mice', 'Species', '10090', (154, 158))	('carcinoma', 'Phenotype', 'HP:0030731', (21, 30))	('mouse', 'Species', '10090', (31, 36))	('mice', 'Species', '10090', (125, 129))	('vascularization', 'CPA', (77, 92))	('increased', 'PosReg', (67, 76))	('eng+/+', 'Var', (118, 124))	('mouse', 'Species', '10090', (54, 59))	('AM', 'Gene', '133', (49, 51))	('adenocarcinoma', 'Disease', (16, 30))
242509	30867734	Such agents include SU5416 and Z24, which act as inhibitors of VEGFR and FGFR, respectively.	('FGFR', 'Gene', '39564', (73, 77))	('VEGFR', 'Gene', '3791', (63, 68))	('SU5416', 'Chemical', 'MESH:C116890', (20, 26))	('FGFR', 'Gene', (73, 77))	('Z24', 'Chemical', '-', (31, 34))	('VEGFR', 'Gene', (63, 68))	('SU5416', 'Var', (20, 26))
242549	33091876	Immunotherapies such as programmed cell death-1 (PD1) / programmed cell death ligand-1 (PD-L1) inhibitors have become standard-of-care treatment options for NSCLC patients.	('men', 'Species', '9606', (140, 143))	('programmed cell death ligand-1', 'Gene', (56, 86))	('PD1', 'Gene', (49, 52))	('programmed cell death ligand-1', 'Gene', '574058', (56, 86))	('patients', 'Species', '9606', (163, 171))	('inhibitors', 'Var', (95, 105))	('PD-L1', 'Gene', (88, 93))	('NSCLC', 'Disease', (157, 162))	('NSCLC', 'Disease', 'MESH:D002289', (157, 162))
242573	33091876	We also evaluated the DEGs between patients with high and low immune scores (Figure 3B), and found that 1,278 genes were upregulated in the group with high immune scores, while 278 genes were upregulated in the group with low immune scores.	('low immune scores', 'Phenotype', 'HP:0002721', (222, 239))	('high immune scores', 'Var', (151, 169))	('upregulated', 'PosReg', (192, 203))	('upregulated', 'PosReg', (121, 132))	('low immune scores', 'Phenotype', 'HP:0002721', (58, 75))	('patients', 'Species', '9606', (35, 43))
242583	33091876	The significant increase in TRIM28 expression in LUAD was further validated in four independent data sets, including GSE32863, GSE7670, GSE19188 and the Beer Lund dataset (Figure 4C-4F).	('TRIM28', 'Gene', (28, 34))	('TRIM28', 'Gene', '10155', (28, 34))	('expression', 'MPA', (35, 45))	('increase', 'PosReg', (16, 24))	('GSE7670', 'Var', (127, 134))	('GSE7670', 'Chemical', '-', (127, 134))
242587	33091876	Notably, TRIM28 expression significantly impacted the prognosis of seven cancer types, including breast, lung, ovarian, brain, skin, prostate and blood cancers (Figure 5A-5L).	('impacted', 'Reg', (41, 49))	('brain', 'Disease', (120, 125))	('blood cancers', 'Phenotype', 'HP:0001909', (146, 159))	('skin', 'Disease', (127, 131))	('TRIM28', 'Gene', '10155', (9, 15))	('cancers', 'Phenotype', 'HP:0002664', (152, 159))	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', (152, 158))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('ovarian', 'Disease', 'MESH:D010049', (111, 118))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('blood cancer', 'Phenotype', 'HP:0001909', (146, 158))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('expression', 'Var', (16, 26))	('TRIM28', 'Gene', (9, 15))	('breast', 'Disease', (97, 103))	('ovarian', 'Disease', (111, 118))	('lung', 'Disease', (105, 109))	('prostate and blood cancers', 'Disease', 'MESH:D011471', (133, 159))
242588	33091876	In three cohorts (GSE4922-GPL96, GSE3494-GPL96 and GSE7378) that respectively included 249 samples, 236 samples and 54 cases at different stages of breast cancer, higher TRIM28 expression was marginally associated with poorer DFS or disease-specific survival (DSS) (DFS hazard ratio [HR] = 3.62, 95% confidence interval [CI] = 2.03 to 6.44, Cox p < 0.001; DSS HR = 3.76, 95% CI = 1.77 to 7.98, Cox p < 0.001; DFS HR = 104.71, 95% CI = 6.95 to 1577.65, Cox p < 0.001; Respectively; Figure 5A-5C).	('Cox', 'Gene', '1351', (394, 397))	('poorer', 'NegReg', (219, 225))	('higher', 'Var', (163, 169))	('breast cancer', 'Phenotype', 'HP:0003002', (148, 161))	('TRIM28', 'Gene', '10155', (170, 176))	('Cox', 'Gene', (341, 344))	('expression', 'MPA', (177, 187))	('DSS', 'Chemical', '-', (260, 263))	('DFS HR', 'Disease', (409, 415))	('DSS', 'Chemical', '-', (356, 359))	('Cox', 'Gene', (452, 455))	('Cox', 'Gene', (394, 397))	('breast cancer', 'Disease', 'MESH:D001943', (148, 161))	('breast cancer', 'Disease', (148, 161))	('disease-specific survival', 'CPA', (233, 258))	('DFS', 'MPA', (226, 229))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('TRIM28', 'Gene', (170, 176))	('DFS HR', 'Disease', 'MESH:D001919', (409, 415))	('GSE3494-GPL96', 'Var', (33, 46))	('Cox', 'Gene', '1351', (341, 344))	('GSE7378', 'Var', (51, 58))	('Cox', 'Gene', '1351', (452, 455))
242590	33091876	In one cohort (GSE31210) that included 204 samples at different stages of LUAD, higher TRIM28 expression was marginally associated with poorer recurrence-free survival (RFS) and OS (RFS HR = 5.44, 95% CI = 2.73 to 10.87, Cox p < 0.001; OS HR = 3.59, 95% CI = 1.33 to 9.68, Cox p = 0.012; Figure 5F and 5G).	('RFS', 'Disease', 'MESH:D005198', (169, 172))	('poorer', 'NegReg', (136, 142))	('Cox', 'Gene', (273, 276))	('RFS', 'Disease', (182, 185))	('TRIM28', 'Gene', (87, 93))	('RFS', 'Disease', 'MESH:D005198', (182, 185))	('recurrence-free survival', 'CPA', (143, 167))	('TRIM28', 'Gene', '10155', (87, 93))	('RFS', 'Disease', (169, 172))	('Cox', 'Gene', '1351', (221, 224))	('Cox', 'Gene', (221, 224))	('Cox', 'Gene', '1351', (273, 276))	('expression', 'Var', (94, 104))
242598	33091876	Higher TRIM28 levels were associated with poorer OS in adrenocortical carcinoma, brain lower grade glioma, LUAD, mesothelioma, skin cutaneous melanoma, etc.	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (127, 150))	('glioma', 'Disease', 'MESH:D005910', (99, 105))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('mesothelioma', 'Disease', 'MESH:D008654', (113, 125))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (55, 79))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (55, 79))	('skin cutaneous melanoma', 'Disease', (127, 150))	('LUAD', 'Disease', (107, 111))	('glioma', 'Phenotype', 'HP:0009733', (99, 105))	('Higher', 'Var', (0, 6))	('TRIM28', 'Gene', '10155', (7, 13))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (132, 150))	('glioma', 'Disease', (99, 105))	('adrenocortical carcinoma', 'Disease', (55, 79))	('mesothelioma', 'Disease', (113, 125))	('melanoma', 'Phenotype', 'HP:0002861', (142, 150))	('TRIM28', 'Gene', (7, 13))
242602	33091876	Overexpression of TRIM28 was associated with worse OS and worse first progression (FP), regardless of gender and smoking history (p < 0.001).	('TRIM28', 'Gene', '10155', (18, 24))	('TRIM28', 'Gene', (18, 24))	('Overexpression', 'Var', (0, 14))	('first progression', 'MPA', (64, 81))
242619	33091876	We also downloaded two mRNA expression datasets (GSE43580 and GSE7670) from the Gene Expression Omnibus (GEO).	('GSE7670', 'Chemical', '-', (62, 69))	('GSE43580', 'Var', (49, 57))	('GSE7670', 'Var', (62, 69))
242621	33091876	The volcano graphs in Figures 7B and 7C display the DEGs in GSE43580 and GSE7670, respectively.	('GSE7670', 'Var', (73, 80))	('GSE43580', 'Var', (60, 68))	('GSE7670', 'Chemical', '-', (73, 80))
242630	33091876	We then performed a correlation analysis, which indicated that TRIM28 expression correlated negatively with IRF5 and IRF8 expression in TCGA (R = -0.210, p < 0.001; R = -0.302, p < 0.001; Figure 8C and 8D), GSE43580 (R = -0.371, p < 0.001; R = -0.420, p < 0.001; Figure 8E and 8F) and GSE7670 (R = -0.491, p = 0.004; R = -0.430, p = 0.014; Figure 8G and 8H), respectively.	('IRF8', 'Gene', (117, 121))	('expression', 'MPA', (122, 132))	('TRIM28', 'Gene', (63, 69))	('IRF8', 'Gene', '3394', (117, 121))	('IRF5', 'Gene', (108, 112))	('GSE7670', 'Chemical', '-', (285, 292))	('IRF5', 'Gene', '3663', (108, 112))	('GSE43580', 'Var', (207, 215))	('TRIM28', 'Gene', '10155', (63, 69))	('negatively', 'NegReg', (92, 102))
242632	33091876	To verify our hypothesis that TRIM28 downregulates IRF5 and IRF8, we knocked down TRIM28 in two different LUAD cell lines (PC9 and H1299).	('IRF5', 'Gene', '3663', (51, 55))	('knocked', 'Var', (69, 76))	('downregulates', 'NegReg', (37, 50))	('IRF5', 'Gene', (51, 55))	('TRIM28', 'Gene', '10155', (30, 36))	('H1299', 'CellLine', 'CVCL:0060', (131, 136))	('TRIM28', 'Gene', '10155', (82, 88))	('PC9', 'CellLine', 'CVCL:B260', (123, 126))	('IRF8', 'Gene', (60, 64))	('IRF8', 'Gene', '3394', (60, 64))	('TRIM28', 'Gene', (30, 36))	('TRIM28', 'Gene', (82, 88))
242647	33091876	Tumor cells adopt a variety of mechanisms to avoid immune recognition and destruction, including: 1) downregulating human leukocyte antigen (HLA) class I molecules such as HLA-A, HLA-B, HLA-C and B2M on the cancer cell surface; 2) altering the antigen-presenting cell number or function; 3) lacking costimulation molecules such as B7-1, B7-2 and CD40; 4) promoting negative immune regulation by regulatory T cells and mesenchymal stem cells; 5) secreting immunosuppressive cytokines such as interleukin (IL)-10, transforming growth factor beta and IL-6; 6) aberrantly expressing apoptosis-related molecules such as Fas, Fas ligand, tumor necrosis factor-related apoptosis inducing ligand and BAX; and 7) inhibiting effector cells via inhibitory ligands such as PD-L1, cytotoxic T-lymphocyte associated protein 4 and lymphocyte activation gene 3.	('cytotoxic T-lymphocyte associated protein 4', 'Gene', '1493', (768, 811))	('HLA-B', 'Gene', '3106', (179, 184))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('interleukin (IL)-10', 'Gene', (491, 510))	('HLA', 'Gene', '3123', (179, 182))	('transforming growth factor beta', 'Gene', (512, 543))	('inhibiting', 'NegReg', (704, 714))	('HLA', 'Gene', (141, 144))	('tumor necrosis', 'Disease', 'MESH:D009336', (632, 646))	('HLA', 'Gene', '3123', (186, 189))	('CD4', 'Gene', '920', (346, 349))	('B7-2', 'Gene', '942', (337, 341))	('cancer', 'Disease', (207, 213))	('lymphocyte activation gene 3', 'Gene', (816, 844))	('tumor necrosis', 'Disease', (632, 646))	('HLA', 'Gene', (172, 175))	('lymphocyte activation gene 3', 'Gene', '3902', (816, 844))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('transforming growth factor beta', 'Gene', '7124', (512, 543))	('HLA-B', 'Gene', (179, 184))	('Fas', 'Gene', (615, 618))	('B7-2', 'Gene', (337, 341))	('CD4', 'Gene', (346, 349))	('tumor', 'Phenotype', 'HP:0002664', (632, 637))	('apoptosis-related molecules', 'Gene', (579, 606))	('B2M', 'Gene', (196, 199))	('B7-1', 'Gene', '941', (331, 335))	('IL-6', 'Gene', '3569', (548, 552))	('HLA', 'Gene', (179, 182))	('HLA', 'Gene', '3123', (141, 144))	('interleukin (IL)-10', 'Gene', '3586', (491, 510))	('human', 'Species', '9606', (116, 121))	('Fas ligand', 'Gene', '356', (620, 630))	('cytotoxic T-lymphocyte associated protein 4', 'Gene', (768, 811))	('B7-1', 'Gene', (331, 335))	('cancer', 'Disease', 'MESH:D009369', (207, 213))	('aberrantly', 'Var', (557, 567))	('HLA', 'Gene', (186, 189))	('B2M', 'Gene', '567', (196, 199))	('Fas ligand', 'Gene', (620, 630))	('IL-6', 'Gene', (548, 552))	('HLA', 'Gene', '3123', (172, 175))	('PD-L1', 'Protein', (761, 766))	('BAX', 'Gene', (692, 695))	('BAX', 'Gene', '581', (692, 695))
242676	33091876	The TRIM28 expression data from GSE32863, GSE7670, GSE19188 and the Beer Lund dataset were downloaded from Oncomine (https://www.oncomine.org/resource/main.html).	('GSE19188', 'Var', (51, 59))	('TRIM28', 'Gene', (4, 10))	('GSE7670', 'Chemical', '-', (42, 49))	('Oncomine', 'Chemical', '-', (107, 115))	('TRIM28', 'Gene', '10155', (4, 10))	('GSE7670', 'Var', (42, 49))	('GSE32863', 'Var', (32, 40))
242677	33091876	Two mRNA expression datasets (GSE43580 and GSE7670) were downloaded from the GEO database (https://www.ncbi.nlm.nih.gov/geo/), and were based on the GPL570 (Affymetrix Human Genome U133 Plus 2.0 Array) and GPL96 (Affymetrix Human Genome U133A Array) platforms, respectively.	('Human', 'Species', '9606', (168, 173))	('GSE7670', 'Var', (43, 50))	('Human', 'Species', '9606', (224, 229))	('GSE7670', 'Chemical', '-', (43, 50))	('GSE43580', 'Var', (30, 38))
242699	33091876	The cells were transfected using jetPRIME reagent (Polyplus transfection) with 110 pmol of ON-TARGETplus SMARTpool-Human TRIM28 (L-005046-00-0020, Dharmacon) according to the manufacturers' protocols.	('TRIM28', 'Gene', (121, 127))	('jetPRIME', 'Chemical', '-', (33, 41))	('TRIM28', 'Gene', '10155', (121, 127))	('Human', 'Species', '9606', (115, 120))	('L-005046-00-0020', 'Var', (129, 145))
242728	33050576	PTENP1 upregulates PTEN expression by sponging PTEN-targeting miRNAs (e.g., miR-17, miR-21, miR-214, miR-19, and miR-26), leading to tumor suppression.	('miR-17', 'Gene', (76, 82))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('miR-21', 'Gene', (84, 90))	('PTEN', 'Gene', '5728', (47, 51))	('miR-21', 'Gene', (92, 98))	('expression', 'MPA', (24, 34))	('PTEN', 'Gene', (19, 23))	('miR-214', 'Gene', (92, 99))	('upregulates', 'PosReg', (7, 18))	('miR-17', 'Gene', '406952', (76, 82))	('PTEN', 'Gene', '5728', (19, 23))	('miR-19', 'Var', (101, 107))	('tumor', 'Disease', (133, 138))	('PTEN', 'Gene', (0, 4))	('miR-26', 'Var', (113, 119))	('PTENP1', 'Gene', (0, 6))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('miR-21', 'Gene', '406991', (84, 90))	('miR-21', 'Gene', '406991', (92, 98))	('PTEN', 'Gene', (47, 51))	('miR-214', 'Gene', '406996', (92, 99))	('PTEN', 'Gene', '5728', (0, 4))	('PTENP1', 'Gene', '11191', (0, 6))
242730	33050576	It was shown that the 5'-domain of HOTAIR binds to PRC2 to promote gene repression, and the 3'-domain binds to the LSD1/coREST/REST complex, which demethylates lysine 4 of histone H3 (H3K4) to repress gene activation.	('PRC2', 'Gene', (51, 55))	('coREST', 'Gene', (120, 126))	('HOTAIR', 'Gene', (35, 41))	('HOTAIR', 'Gene', '100124700', (35, 41))	('demethylates', 'Var', (147, 159))	('LSD1', 'Gene', (115, 119))	('gene repression', 'MPA', (67, 82))	('coREST', 'Gene', '23186', (120, 126))	('LSD1', 'Gene', '23028', (115, 119))	('lysine', 'Chemical', 'MESH:D008239', (160, 166))	('promote', 'PosReg', (59, 66))	('gene activation', 'MPA', (201, 216))	('H3K4', 'Protein', (184, 188))	('repress', 'PosReg', (193, 200))
242732	33050576	Moreover, antisense non-coding RNA at the INK4 locus (ANRIL) is upregulated in adult T-cell leukemia and associates with EZH2 and the RelA/p65 subunit of NFkappaB, which enhances NFkappaB signaling and promotes cancer cell proliferation.	('enhances', 'PosReg', (170, 178))	('INK4', 'Gene', (42, 46))	('EZH2', 'Gene', '2146', (121, 125))	('adult T-cell leukemia', 'Disease', 'MESH:D015459', (79, 100))	('EZH2', 'Gene', (121, 125))	('NFkappaB', 'Gene', '4790', (179, 187))	('ANRIL', 'Gene', '100048912', (54, 59))	('cancer', 'Disease', 'MESH:D009369', (211, 217))	('NFkappaB', 'Gene', '4790', (154, 162))	('promotes', 'PosReg', (202, 210))	('NFkappaB', 'Gene', (179, 187))	('leukemia', 'Phenotype', 'HP:0001909', (92, 100))	('antisense non-coding RNA', 'Var', (10, 34))	('NFkappaB', 'Gene', (154, 162))	('ANRIL', 'Gene', (54, 59))	('upregulated', 'PosReg', (64, 75))	('cancer', 'Disease', (211, 217))	('associates', 'Interaction', (105, 115))	('INK4', 'Gene', '1029', (42, 46))	('adult T-cell leukemia', 'Disease', (79, 100))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))
242735	33050576	In mouse placenta, antisense of the IGF2R non-protein coding RNA (AIRN) has been shown to silence the transcription of cis-linked genes via chromatin interaction at their promoter regions.	('transcription', 'MPA', (102, 115))	('chromatin interaction', 'MPA', (140, 161))	('mouse', 'Species', '10090', (3, 8))	('antisense', 'Var', (19, 28))	('cis-linked genes', 'Gene', (119, 135))	('silence', 'NegReg', (90, 97))	('IGF2R', 'Gene', (36, 41))
242740	33050576	Quiescent fibroblasts can differentiate into CAFs upon stimulation by diverse external cues such as cytokines/chemokines, growth factors, reactive oxygen species, hypoxia, and non-coding RNAs.	('reactive oxygen species', 'Chemical', 'MESH:D017382', (138, 161))	('hypoxia', 'Disease', (163, 170))	('non-coding RNAs', 'Var', (176, 191))	('CAF', 'Gene', (45, 48))	('hypoxia', 'Disease', 'MESH:D000860', (163, 170))	('CAF', 'Gene', '8850', (45, 48))
242776	33050576	Downregulation of focal adhesion kinase in CAFs increases CCL6 and CCL12 expression, leading to elevated glycolysis in cancer cells.	('CCL6', 'Gene', (58, 62))	('increases', 'PosReg', (48, 57))	('CAF', 'Gene', (43, 46))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('glycolysis', 'MPA', (105, 115))	('Downregulation', 'Var', (0, 14))	('cancer', 'Disease', (119, 125))	('expression', 'MPA', (73, 83))	('CCL12', 'Gene', (67, 72))	('CAF', 'Gene', '8850', (43, 46))	('elevated', 'PosReg', (96, 104))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
242778	33050576	Epigenetic changes in prostate CAFs drive the synthesis of glutamine, which is then transported to adjacent cancer cells to promote energy production, differentiation, and the aggressiveness of prostate cancer cells.	('drive', 'Reg', (36, 41))	('synthesis', 'MPA', (46, 55))	('cancer', 'Disease', 'MESH:D009369', (203, 209))	('prostate cancer', 'Phenotype', 'HP:0012125', (194, 209))	('aggressiveness', 'Phenotype', 'HP:0000718', (176, 190))	('aggressiveness of prostate cancer', 'Disease', (176, 209))	('cancer', 'Disease', 'MESH:D009369', (108, 114))	('aggressiveness of prostate cancer', 'Disease', 'MESH:D011471', (176, 209))	('cancer', 'Disease', (203, 209))	('promote', 'PosReg', (124, 131))	('CAF', 'Gene', '8850', (31, 34))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('cancer', 'Disease', (108, 114))	('differentiation', 'CPA', (151, 166))	('prostate', 'Gene', (22, 30))	('energy production', 'MPA', (132, 149))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('CAF', 'Gene', (31, 34))	('glutamine', 'Chemical', 'MESH:D005973', (59, 68))	('Epigenetic changes', 'Var', (0, 18))
242802	33050576	Using microarrays and Kaplan-Meier survival analysis, they identified ten CAF-specific lncRNAs: nine lncRNAs (CRNDE, DANCR, LOC642852, MALAT1, MEG3, MGC2752, NEAT1, TP73-AS1, and XIST) were associated with shorter survival, and one (MIR155HG) was associated with longer survival.	('DANCR', 'Gene', (117, 122))	('NEAT1', 'Gene', '283131', (158, 163))	('AS1', 'Gene', '5729', (170, 173))	('MALAT1', 'Gene', (135, 141))	('MEG3', 'Gene', (143, 147))	('TP73', 'Gene', '7161', (165, 169))	('MALAT1', 'Gene', '378938', (135, 141))	('DANCR', 'Gene', '57291', (117, 122))	('MIR155HG', 'Gene', '114614', (233, 241))	('MIR155HG', 'Gene', (233, 241))	('CAF', 'Gene', '8850', (74, 77))	('XIST', 'Gene', (179, 183))	('MEG3', 'Gene', '55384', (143, 147))	('MGC2752', 'Var', (149, 156))	('TP73', 'Gene', (165, 169))	('CAF', 'Gene', (74, 77))	('AS1', 'Gene', (170, 173))	('XIST', 'Gene', '7503', (179, 183))	('NEAT1', 'Gene', (158, 163))	('LOC642852', 'Var', (124, 133))	('CRNDE', 'Gene', (110, 115))	('CRNDE', 'Gene', '643911', (110, 115))	('shorter', 'NegReg', (206, 213))
242804	33050576	Gene clusters involving DANCR, LOC642852, MALAT1, MEG3, MGC2752, TP73-AS1, and XIST are associated with metabolic processes and autophagy.	('AS1', 'Gene', '5729', (70, 73))	('AS1', 'Gene', (70, 73))	('DANCR', 'Gene', (24, 29))	('TP73', 'Gene', '7161', (65, 69))	('TP73', 'Gene', (65, 69))	('MGC2752', 'Gene', (56, 63))	('MEG3', 'Gene', (50, 54))	('MALAT1', 'Gene', (42, 48))	('DANCR', 'Gene', '57291', (24, 29))	('autophagy', 'CPA', (128, 137))	('MEG3', 'Gene', '55384', (50, 54))	('LOC642852', 'Var', (31, 40))	('XIST', 'Gene', '7503', (79, 83))	('XIST', 'Gene', (79, 83))	('associated', 'Reg', (88, 98))	('metabolic processes', 'CPA', (104, 123))	('MALAT1', 'Gene', '378938', (42, 48))
242811	33050576	In terms of clinical relevance, high FLJ22447 expression was associated with a high TNM stage and poor patient survival.	('high', 'Var', (32, 36))	('FLJ22447', 'Gene', (37, 45))	('FLJ22447', 'Gene', '400221', (37, 45))	('TNM', 'Gene', (84, 87))	('poor', 'NegReg', (98, 102))	('patient survival', 'CPA', (103, 119))	('patient', 'Species', '9606', (103, 110))	('TNM', 'Gene', '10178', (84, 87))	('expression', 'MPA', (46, 56))
242816	33050576	The shRNA-mediated knockdown of HIPK1-AS blocked the activation of CAFs by HeLa conditioned medium.	('CAF', 'Gene', (67, 70))	('knockdown', 'Var', (19, 28))	('CAF', 'Gene', '8850', (67, 70))	('HIPK1', 'Gene', '204851', (32, 37))	('HIPK1', 'Gene', (32, 37))	('HeLa', 'CellLine', 'CVCL:0030', (75, 79))	('blocked', 'NegReg', (41, 48))	('activation', 'MPA', (53, 63))
242824	33050576	Patients with high TIRY expression had poorer overall and progression-free survival than those with low TIRY expression.	('high TIRY expression', 'Var', (14, 34))	('overall', 'CPA', (46, 53))	('progression-free survival', 'CPA', (58, 83))	('Patients', 'Species', '9606', (0, 8))	('poorer', 'NegReg', (39, 45))
242826	33050576	Interestingly, TIRY in CAFs suppressed exosomal delivery of miR-14 to neighboring cancer cells, which caused the upregulation of WNT3A, a miR-14 target, and activation of Wnt/beta-catenin signaling in cancer cells.	('miR-14', 'Chemical', '-', (60, 66))	('cancer', 'Disease', (201, 207))	('CAF', 'Gene', (23, 26))	('cancer', 'Disease', (82, 88))	('miR-14', 'Chemical', '-', (138, 144))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('beta-catenin', 'Gene', (175, 187))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('beta-catenin', 'Gene', '1499', (175, 187))	('TIRY', 'Var', (15, 19))	('WNT3A', 'Gene', '89780', (129, 134))	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('suppressed', 'NegReg', (28, 38))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('miR-14', 'Gene', (60, 66))	('upregulation', 'PosReg', (113, 125))	('WNT3A', 'Gene', (129, 134))	('CAF', 'Gene', '8850', (23, 26))	('exosomal delivery', 'MPA', (39, 56))	('activation', 'PosReg', (157, 167))
242843	33050576	LINC00092 knockdown also causes a reduction in glycolysis metabolites, such as lactate.	('lactate', 'MPA', (79, 86))	('glycolysis metabolites', 'MPA', (47, 69))	('LINC00092', 'Gene', '100188953', (0, 9))	('reduction', 'NegReg', (34, 43))	('lactate', 'Chemical', 'MESH:D019344', (79, 86))	('LINC00092', 'Gene', (0, 9))	('knockdown', 'Var', (10, 19))
242862	33050576	HOTAIR, in turn, activates the EMT, migration, and invasion of breast cancer cells by the epigenetic suppression of EGR1 and CDK5RAP1 promoters.	('EMT', 'CPA', (31, 34))	('EGR1', 'Gene', '1958', (116, 120))	('HOTAIR', 'Gene', '100124700', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('CDK5RAP1', 'Gene', (125, 133))	('breast cancer', 'Disease', 'MESH:D001943', (63, 76))	('CDK5RAP1', 'Gene', '51654', (125, 133))	('breast cancer', 'Disease', (63, 76))	('migration', 'CPA', (36, 45))	('breast cancer', 'Phenotype', 'HP:0003002', (63, 76))	('EGR1', 'Gene', (116, 120))	('HOTAIR', 'Gene', (0, 6))	('invasion', 'CPA', (51, 59))	('epigenetic suppression', 'Var', (90, 112))	('activates', 'PosReg', (17, 26))
242870	33050576	Moreover, high ANRIL expression is associated with high TNM stage and lymph node metastasis in patients with oral squamous cell carcinoma.	('lymph node metastasis', 'CPA', (70, 91))	('oral squamous cell carcinoma', 'Disease', (109, 137))	('patients', 'Species', '9606', (95, 103))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (114, 137))	('ANRIL', 'Gene', (15, 20))	('associated', 'Reg', (35, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('expression', 'MPA', (21, 31))	('TNM', 'Gene', '10178', (56, 59))	('high', 'Var', (10, 14))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (109, 137))	('ANRIL', 'Gene', '100048912', (15, 20))	('TNM', 'Gene', (56, 59))
242904	33050576	In melanoma-derived exosomes, the lncRNA Gm26809 was significantly enriched.	('Gm26809', 'Var', (41, 48))	('Gm26809', 'Chemical', '-', (41, 48))	('melanoma', 'Phenotype', 'HP:0002861', (3, 11))	('melanoma', 'Disease', (3, 11))	('melanoma', 'Disease', 'MESH:D008545', (3, 11))
242907	33050576	Supplemented with further investigation on the exact working mechanisms, exosomal Gm26809 could be a good target for melanoma treatment.	('Gm26809', 'Var', (82, 89))	('melanoma', 'Disease', 'MESH:D008545', (117, 125))	('Gm26809', 'Chemical', '-', (82, 89))	('melanoma', 'Disease', (117, 125))	('melanoma', 'Phenotype', 'HP:0002861', (117, 125))	('exosomal Gm26809', 'Var', (73, 89))
242929	32886690	Furthermore, P. gingivalis augmented secretion and bioactivity of TGFbeta through glycoprotein A repetitions predominant (GARP) up-regulation.	('GARP', 'Gene', '2615', (122, 126))	('P. gingivalis', 'Var', (13, 26))	('bioactivity', 'MPA', (51, 62))	('augmented', 'PosReg', (27, 36))	('up-regulation', 'PosReg', (128, 141))	('P. gingivalis', 'Species', '837', (13, 26))	('GARP', 'Gene', (122, 126))	('TGFbeta', 'Gene', (66, 73))	('glycoprotein', 'MPA', (82, 94))	('secretion', 'MPA', (37, 46))
242930	32886690	Accordingly, disruption of either the GARP/TGFbeta axis or its activated Smads/YAP/TAZ complex abrogated the tumor-promoting role of P. gingivalis.	('Smad', 'Gene', (73, 77))	('YAP', 'Gene', (79, 82))	('GARP', 'Gene', '2615', (38, 42))	('Smad', 'Gene', '33529', (73, 77))	('disruption', 'Var', (13, 23))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('GARP', 'Gene', (38, 42))	('abrogated', 'NegReg', (95, 104))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('YAP', 'Gene', '10413', (79, 82))	('tumor', 'Disease', (109, 114))	('P. gingivalis', 'Species', '837', (133, 146))
242933	32886690	Microbial dysbiosis in the upper digestive tract is linked to an increased risk of esophageal squamous cell carcinoma (ESCC); this study shows that invasion of the bacterium Porphyromonas gingivalis enhances the aggressive progression of ESCC via the TGFbeta/Smad and TGFbeta/YAP/TAZ pathways.	('ESCC', 'Disease', (238, 242))	('aggressive progression', 'CPA', (212, 234))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (83, 117))	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (94, 117))	('invasion', 'Var', (148, 156))	('YAP', 'Gene', '10413', (276, 279))	('Porphyromonas gingivalis', 'Species', '837', (174, 198))	('Smad', 'Gene', (259, 263))	('esophageal squamous cell carcinoma', 'Disease', (83, 117))	('YAP', 'Gene', (276, 279))	('enhances', 'PosReg', (199, 207))	('Microbial dysbiosis', 'Disease', (0, 19))	('Smad', 'Gene', '33529', (259, 263))	('Microbial dysbiosis', 'Disease', 'MESH:D064806', (0, 19))
242939	32886690	Previous studies reported that the amount of P. gingivalis in saliva was associated with the progression of oral cancer and ESCC.	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('oral cancer', 'Disease', 'MESH:D009369', (108, 119))	('P. gingivalis', 'Species', '837', (45, 58))	('P. gingivalis', 'Var', (45, 58))	('associated with', 'Reg', (73, 88))	('oral cancer', 'Disease', (108, 119))	('ESCC', 'Disease', (124, 128))
242942	32886690	All of these findings support the notion that P. gingivalis is one of the key factors implicated in ESCC and may causatively influence the development, progression, and response to treatment of ESCC.	('ESCC', 'Disease', (194, 198))	('ESCC', 'Disease', (100, 104))	('P. gingivalis', 'Var', (46, 59))	('P. gingivalis', 'Species', '837', (46, 59))	('influence', 'Reg', (125, 134))
242946	32886690	Long-term infection by P. gingivalis has been shown to increase the invasiveness of oral cancer cells via induction of EMT-like changes and cell surface expression of cancer stem cell (CSC) markers cluster of differentiation (CD)44 and CD133.	('increase', 'PosReg', (55, 63))	('infection', 'Disease', (10, 19))	('infection', 'Disease', 'MESH:D007239', (10, 19))	('cancer', 'Disease', (167, 173))	('cancer', 'Disease', (89, 95))	('CD', 'Chemical', 'MESH:D002104', (226, 228))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('P. gingivalis', 'Species', '837', (23, 36))	('invasiveness of oral cancer', 'Disease', (68, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('EMT-like changes', 'CPA', (119, 135))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('expression', 'Species', '29278', (153, 163))	('invasiveness of oral cancer', 'Disease', 'MESH:D009362', (68, 95))	('CD133', 'Gene', (236, 241))	('cell surface expression', 'CPA', (140, 163))	('CD', 'Chemical', 'MESH:D002104', (236, 238))	('P. gingivalis', 'Var', (23, 36))
242948	32886690	In this study, we analyzed the influence of P. gingivalis on the prognosis of ESCC patients and revealed infection of P. gingivalis as a risk factor for the first time, to our knowledge.	('infection', 'Disease', (105, 114))	('ESCC', 'Disease', (78, 82))	('infection', 'Disease', 'MESH:D007239', (105, 114))	('P. gingivalis', 'Species', '837', (44, 57))	('P. gingivalis', 'Species', '837', (118, 131))	('P. gingivalis', 'Var', (118, 131))	('patients', 'Species', '9606', (83, 91))
242950	32886690	Up-regulation of glycoprotein A repetitions predominant (GARP) induced by intracellular colonization of P. gingivalis accelerates TGFbeta bioactivity, driving ESCC progression and metastasis.	('GARP', 'Gene', '2615', (57, 61))	('GARP', 'Gene', (57, 61))	('TGFbeta', 'Gene', (130, 137))	('metastasis', 'CPA', (180, 190))	('bioactivity', 'MPA', (138, 149))	('driving', 'PosReg', (151, 158))	('P. gingivalis', 'Var', (104, 117))	('P. gingivalis', 'Species', '837', (104, 117))	('Up-regulation', 'PosReg', (0, 13))	('glycoprotein A repetitions', 'Protein', (17, 43))	('accelerates', 'PosReg', (118, 129))	('ESCC', 'Disease', (159, 163))
242953	32886690	Both immunohistochemistry (IHC) and RNA in situ hybridization (RNAscope) detected P. gingivalis in the cytoplasm of cancer cells and stroma (Fig 1A).	('P. gingivalis', 'Species', '837', (82, 95))	('detected', 'Reg', (73, 81))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('P. gingivalis', 'Var', (82, 95))
242954	32886690	Consistent with our previous results, the amount of P. gingivalis in ESCC was positively associated with invasion depth, lymphatic metastasis, and tumor-node metastasis (TNM) stage (S1A Fig).	('associated', 'Reg', (89, 99))	('tumor', 'Disease', (147, 152))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('lymphatic metastasis', 'CPA', (121, 141))	('P. gingivalis', 'Var', (52, 65))	('P. gingivalis', 'Species', '837', (52, 65))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('invasion depth', 'CPA', (105, 119))	('ESCC', 'Disease', (69, 73))
242956	32886690	Univariate (S1B Fig) and multivariate (S1C Fig) Cox regression analysis revealed that the amount of P. gingivalis was an independent predictor of clinical outcome for ESCC patients.	('patients', 'Species', '9606', (172, 180))	('ESCC', 'Disease', (167, 171))	('P. gingivalis', 'Var', (100, 113))	('P. gingivalis', 'Species', '837', (100, 113))
242958	32886690	P. gingivalis treatment significantly increased the proliferation (Fig 1C), migration, and invasion (Fig 1D) of ESCC cells in vitro compared with treatments with heat-killed P. gingivalis, Lipopolysaccharide (LPS), and untreated controls.	('P. gingivalis', 'Species', '837', (174, 187))	('proliferation', 'CPA', (52, 65))	('Lipopolysaccharide', 'Chemical', 'MESH:D008070', (189, 207))	('invasion', 'CPA', (91, 99))	('migration', 'CPA', (76, 85))	('P. gingivalis', 'Var', (0, 13))	('P. gingivalis', 'Species', '837', (0, 13))	('increased', 'PosReg', (38, 47))
242962	32886690	Although E. coli DH5alpha had no enhancing effect on growth of NE6-T and KYSE30 cells, resembling the effect of E. coli DH5alpha on HCT-116 cells (S1E Fig), E. coli DH5alpha significantly augmented the abilities of migration and invasion in NE6-T and KYSE30 cells (S1F Fig).	('E. coli DH5alpha', 'Species', '668369', (9, 25))	('augmented', 'PosReg', (188, 197))	('E. coli DH5alpha', 'Var', (157, 173))	('invasion', 'CPA', (229, 237))	('HCT-116', 'CellLine', 'CVCL:0291', (132, 139))	('E. coli DH5alpha', 'Species', '668369', (112, 128))	('E. coli DH5alpha', 'Species', '668369', (157, 173))	('KYSE30', 'CellLine', 'CVCL:1351', (251, 257))	('migration', 'CPA', (215, 224))	('KYSE30', 'CellLine', 'CVCL:1351', (73, 79))
242964	32886690	Interestingly, neither did we observe the tumorigenic effect of P. gingivalis on HCT-116 cells (S1E and S1F Fig).	('tumor', 'Disease', (42, 47))	('HCT-116', 'CellLine', 'CVCL:0291', (81, 88))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('P. gingivalis', 'Species', '837', (64, 77))	('P. gingivalis', 'Var', (64, 77))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
242966	32886690	Remarkably, NE6-T cells infected by P. gingivalis displayed an enhanced tumor growth in vivo compared with untreated controls (Fig 1F).	('P. gingivalis', 'Species', '837', (36, 49))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('infected', 'Disease', 'MESH:D007239', (24, 32))	('enhanced', 'PosReg', (63, 71))	('tumor', 'Disease', (72, 77))	('infected', 'Disease', (24, 32))	('P. gingivalis', 'Var', (36, 49))	('tumor', 'Disease', 'MESH:D009369', (72, 77))
242968	32886690	In the mouse tail vein injection lung metastasis model, P. gingivalis significantly increased KYSE30 cell lung metastasis after 40 days compared with the control mice, evidenced by quantitative bioluminescence imaging and histological examination (Fig 1G).	('mouse', 'Species', '10090', (7, 12))	('P. gingivalis', 'Var', (56, 69))	('mice', 'Species', '10090', (162, 166))	('KYSE30', 'CellLine', 'CVCL:1351', (94, 100))	('increased', 'PosReg', (84, 93))	('P. gingivalis', 'Species', '837', (56, 69))	('KYSE30 cell lung metastasis', 'CPA', (94, 121))
242972	32886690	Together, these data demonstrate that P. gingivalis potentiates the aggressive progression of ESCC but has no malignant transformation potential.	('aggressive progression', 'CPA', (68, 90))	('potentiates', 'PosReg', (52, 63))	('P. gingivalis', 'Species', '837', (38, 51))	('P. gingivalis', 'Var', (38, 51))	('ESCC', 'Disease', (94, 98))
242978	32886690	Additionally, P. gingivalis increased the activation of a TGFbeta-responsive Smad-binding element (SBE) luciferase reporter in NE6-T and KYSE30 cells at 24 h postinfection.	('KYSE30', 'CellLine', 'CVCL:1351', (137, 143))	('gingivalis increased', 'Phenotype', 'HP:0000212', (17, 37))	('P. gingivalis', 'Var', (14, 27))	('infection', 'Disease', (162, 171))	('P. gingivalis', 'Species', '837', (14, 27))	('Smad', 'Gene', (77, 81))	('activation', 'PosReg', (42, 52))	('infection', 'Disease', 'MESH:D007239', (162, 171))	('Smad', 'Gene', '33529', (77, 81))	('SB', 'Chemical', 'MESH:D000965', (99, 101))
242982	32886690	Consistent with the notion that activated TGFbeta signaling induces EMT and stem-like features during later stages of tumorigenesis, P. gingivalis treatment of NE6-T and KYSE30 cells caused down-regulation of E-cadherin and simultaneous overexpression of N-cadherin and EMT inducer Snail (Fig 2F).	('P. gingivalis', 'Var', (133, 146))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('expression', 'Species', '29278', (241, 251))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('E-cadherin', 'Gene', (209, 219))	('down-regulation', 'NegReg', (190, 205))	('N-cadherin', 'Gene', (255, 265))	('tumor', 'Disease', (118, 123))	('KYSE30', 'CellLine', 'CVCL:1351', (170, 176))	('overexpression', 'PosReg', (237, 251))	('N-cadherin', 'Gene', '1000', (255, 265))	('induces', 'PosReg', (60, 67))	('E-cadherin', 'Gene', '999', (209, 219))	('P. gingivalis', 'Species', '837', (133, 146))
242983	32886690	Accordingly, either western blotting (Fig 2F) or immunofluorescence microscopy (Fig 2G) demonstrated that P. gingivalis treatment caused increased expression of pluripotency marker Oct4, which was abolished by TGFbeta1-N, SB-431542, and tinidazole pretreatment.	('P. gingivalis', 'Species', '837', (106, 119))	('P. gingivalis', 'Var', (106, 119))	('expression', 'Species', '29278', (147, 157))	('Oct4', 'Gene', (181, 185))	('tinidazole', 'Chemical', 'MESH:D014011', (237, 247))	('expression', 'MPA', (147, 157))	('pluripotency marker', 'MPA', (161, 180))	('TGFbeta1', 'Gene', '7040', (210, 218))	('TGFbeta1', 'Gene', (210, 218))	('SB-431542', 'Chemical', 'MESH:C459179', (222, 231))	('Oct4', 'Gene', '5460', (181, 185))	('increased', 'PosReg', (137, 146))
242985	32886690	Interestingly, P. gingivalis also induced up-regulation of cell-cycle inhibitors and apoptosis-related genes (S2C Fig), suggesting TGFbeta signaling as a mediator.	('apoptosis-related genes', 'Gene', (85, 108))	('P. gingivalis', 'Species', '837', (15, 28))	('P. gingivalis', 'Var', (15, 28))	('cell-cycle inhibitors', 'Gene', (59, 80))	('up-regulation', 'PosReg', (42, 55))
242988	32886690	The augmented xenograft tumor growth and weight of NE6-T (Fig 2H) and KYSE30 (S2H Fig) cells instigated by P. gingivalis treatment were significantly reduced by SB-431542 compared with P. gingivalis-treated NE6-T cells.	('SB-431542', 'Var', (161, 170))	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('weight', 'CPA', (41, 47))	('tumor', 'Disease', (24, 29))	('P. gingivalis', 'Species', '837', (185, 198))	('KYSE30', 'CellLine', 'CVCL:1351', (70, 76))	('P. gingivalis', 'Species', '837', (107, 120))	('reduced', 'NegReg', (150, 157))	('SB-431542', 'Chemical', 'MESH:C459179', (161, 170))	('tumor', 'Disease', 'MESH:D009369', (24, 29))
242990	32886690	Real-time PCR analyses showed that P. gingivalis induced increased mRNA levels of PAI-1, Smad7, Snail, and Oct4, which were rescued by SB-431542 or tinidazole in xenograft tumors, with the exception of Smad7 (S2I Fig).	('Smad', 'Gene', '33529', (89, 93))	('Oct4', 'Gene', (107, 111))	('tumors', 'Phenotype', 'HP:0002664', (172, 178))	('Snail', 'MPA', (96, 101))	('Smad', 'Gene', '33529', (202, 206))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('Smad', 'Gene', (89, 93))	('tumors', 'Disease', (172, 178))	('SB-431542', 'Chemical', 'MESH:C459179', (135, 144))	('P. gingivalis', 'Var', (35, 48))	('PAI-1', 'Gene', '5054', (82, 87))	('tinidazole', 'Chemical', 'MESH:D014011', (148, 158))	('increased', 'PosReg', (57, 66))	('Oct4', 'Gene', '5460', (107, 111))	('PAI-1', 'Gene', (82, 87))	('tumors', 'Disease', 'MESH:D009369', (172, 178))	('mRNA levels', 'MPA', (67, 78))	('P. gingivalis', 'Species', '837', (35, 48))	('Smad', 'Gene', (202, 206))
242991	32886690	Again, IHC of pSmad2, PAI-1, Snail, and Oct4 showed significantly increased proteins induced by P. gingivalis (S2J Fig).	('increased', 'PosReg', (66, 75))	('Oct4', 'Gene', '5460', (40, 44))	('PAI-1', 'Gene', '5054', (22, 27))	('P. gingivalis', 'Species', '837', (96, 109))	('Smad', 'Gene', (15, 19))	('P. gingivalis', 'Var', (96, 109))	('Oct4', 'Gene', (40, 44))	('Smad', 'Gene', '33529', (15, 19))	('proteins induced', 'MPA', (76, 92))	('PAI-1', 'Gene', (22, 27))
242997	32886690	Immunofluorescence staining revealed that P. gingivalis exposure caused increased YAP/TAZ nuclear accumulation in NE6-T cells (Fig 3B) and KYSE30 cells (S3A Fig).	('increased', 'PosReg', (72, 81))	('P. gingivalis', 'Var', (42, 55))	('P. gingivalis', 'Species', '837', (42, 55))	('YAP', 'Gene', '10413', (82, 85))	('KYSE30', 'CellLine', 'CVCL:1351', (139, 145))	('YAP', 'Gene', (82, 85))
242998	32886690	Analysis of YAP/TAZ target genes further demonstrated that P. gingivalis-treated ESCC cells expressed significantly increased levels of mRNA and protein of connective tissue growth factor (CTGF) and cysteine-rich angiogenic inducer 61 (CYR61) (S3B Fig and Fig 3A).	('CTGF', 'Gene', '1490', (189, 193))	('cysteine', 'Chemical', 'MESH:D003545', (199, 207))	('CTGF', 'Gene', (189, 193))	('YAP', 'Gene', '10413', (12, 15))	('P. gingivalis-treated', 'Var', (59, 80))	('P. gingivalis', 'Species', '837', (59, 72))	('CYR61', 'Gene', (236, 241))	('YAP', 'Gene', (12, 15))	('connective tissue growth factor', 'Gene', '1490', (156, 187))	('CYR61', 'Gene', '3491', (236, 241))	('increased', 'PosReg', (116, 125))	('connective tissue growth factor', 'Gene', (156, 187))
242999	32886690	Pretreatment of ESCC cells with TGFbeta1-N, SB-431542, and tinidazole resulted in hyperphosphorylation of YAP/TAZ (Fig 3A) and YAP/TAZ cytoplasmic localization (Fig 3B and S3A Fig) and abolished the up-regulation of CTGF and CYR61 expression in response to P. gingivalis (Fig 3A and S3B Fig).	('abolished', 'NegReg', (185, 194))	('YAP', 'Gene', (127, 130))	('YAP', 'Gene', '10413', (106, 109))	('SB-431542', 'Chemical', 'MESH:C459179', (44, 53))	('CTGF', 'Gene', '1490', (216, 220))	('hyperphosphorylation', 'MPA', (82, 102))	('up-regulation', 'PosReg', (199, 212))	('CYR61', 'Gene', '3491', (225, 230))	('YAP', 'Gene', '10413', (127, 130))	('TGFbeta1', 'Gene', '7040', (32, 40))	('CTGF', 'Gene', (216, 220))	('tinidazole', 'Var', (59, 69))	('SB-431542', 'Var', (44, 53))	('TGFbeta1', 'Gene', (32, 40))	('YAP', 'Gene', (106, 109))	('CYR61', 'Gene', (225, 230))	('tinidazole', 'Chemical', 'MESH:D014011', (59, 69))	('P. gingivalis', 'Species', '837', (257, 270))	('expression', 'Species', '29278', (231, 241))
243005	32886690	Interestingly, P. gingivalis induced hyperphosphorylation of moesin-ezrin-radixin-like protein (Merlin), which is an upstream negative regulator of Hippo signaling (Fig 3D).	('P. gingivalis', 'Var', (15, 28))	('moesin-ezrin-radixin-like protein', 'Gene', (61, 94))	('P. gingivalis', 'Species', '837', (15, 28))	('moesin-ezrin-radixin-like protein', 'Gene', '32979', (61, 94))	('hyperphosphorylation', 'MPA', (37, 57))	('Merlin', 'Gene', '32979', (96, 102))	('Merlin', 'Gene', (96, 102))
243007	32886690	Overexpression of Lats1/2 or S518A Merlin in ESCC cells strongly and significantly inhibited the P. gingivalis-induced activation of YAP/TAZ (Fig 3E) and enhancement of migration and invasion (S3D Fig).	('Merlin', 'Gene', '32979', (35, 41))	('Lats1/2', 'Gene', (18, 25))	('expression', 'Species', '29278', (4, 14))	('YAP', 'Gene', '10413', (133, 136))	('S518A', 'Mutation', 'p.S518A', (29, 34))	('inhibited', 'NegReg', (83, 92))	('activation', 'PosReg', (119, 129))	('enhancement', 'PosReg', (154, 165))	('P. gingivalis', 'Species', '837', (97, 110))	('S518A', 'Var', (29, 34))	('Lats1/2', 'Gene', '8140', (18, 25))	('YAP', 'Gene', (133, 136))	('Merlin', 'Gene', (35, 41))
243008	32886690	Taken together, these results show that inactivation of Merlin and Lats1/2 by P. gingivalis is involved in the malignant progression of ESCC.	('Lats1/2', 'Gene', '8140', (67, 74))	('ESCC', 'Disease', (136, 140))	('Lats1/2', 'Gene', (67, 74))	('Merlin', 'Gene', (56, 62))	('P. gingivalis', 'Species', '837', (78, 91))	('involved', 'Reg', (95, 103))	('inactivation', 'Var', (40, 52))	('Merlin', 'Gene', '32979', (56, 62))	('malignant progression', 'CPA', (111, 132))
243010	32886690	Therefore, we tested whether P. gingivalis-induced activation of YAP/TAZ controls Smad2/3 nuclear accumulation by siRNA-mediated knocking down of YAP/TAZ in ESCC cells.	('YAP', 'Gene', '10413', (146, 149))	('YAP', 'Gene', (65, 68))	('YAP', 'Gene', (146, 149))	('Smad2/3', 'Gene', (82, 89))	('knocking down', 'Var', (129, 142))	('Smad2/3', 'Gene', '4088', (82, 89))	('P. gingivalis', 'Species', '837', (29, 42))	('tested', 'Reg', (14, 20))	('YAP', 'Gene', '10413', (65, 68))
243011	32886690	While phosphorylation of Smad2/3 was unaffected by deletion of YAP/TAZ (Fig 4A), YAP/TAZ knockdown abrogated the increase of transcriptional activity of Smad2/3 stimulated by P. gingivalis in an SBE luciferase reporter assay (Fig 4B).	('Smad2/3', 'Gene', (153, 160))	('Smad2/3', 'Gene', '4088', (153, 160))	('P. gingivalis', 'Species', '837', (175, 188))	('YAP', 'Gene', (63, 66))	('YAP', 'Gene', '10413', (81, 84))	('knockdown', 'Var', (89, 98))	('transcriptional activity', 'MPA', (125, 149))	('YAP', 'Gene', (81, 84))	('YAP', 'Gene', '10413', (63, 66))	('abrogated', 'NegReg', (99, 108))	('Smad2/3', 'Gene', (25, 32))	('deletion', 'Var', (51, 59))	('SB', 'Chemical', 'MESH:D000965', (195, 197))	('Smad2/3', 'Gene', '4088', (25, 32))
243013	32886690	In addition, knockdown of YAP/TAZ repressed the protein levels of Snail and Oct4 and caused a reversal of EMT markers (Fig 4A).	('Oct4', 'Gene', '5460', (76, 80))	('reversal', 'MPA', (94, 102))	('EMT', 'MPA', (106, 109))	('YAP', 'Gene', '10413', (26, 29))	('Oct4', 'Gene', (76, 80))	('knockdown', 'Var', (13, 22))	('YAP', 'Gene', (26, 29))	('Snail', 'MPA', (66, 71))	('protein levels', 'MPA', (48, 62))
243014	32886690	Furthermore, nuclear accumulation of Smad2/3 induced by P. gingivalis was markedly inhibited by YAP/TAZ knockdown (S4B Fig).	('YAP', 'Gene', (96, 99))	('Smad2/3', 'Gene', (37, 44))	('inhibited', 'NegReg', (83, 92))	('P. gingivalis', 'Var', (56, 69))	('Smad2/3', 'Gene', '4088', (37, 44))	('P. gingivalis', 'Species', '837', (56, 69))	('nuclear accumulation', 'MPA', (13, 33))	('YAP', 'Gene', '10413', (96, 99))	('knockdown', 'Var', (104, 113))
243018	32886690	After transfection with the pGL3-CTGF/CYR61 vectors, ESCC cells in the presence of P. gingivalis displayed an increase in CTGF or CYR61 promoter activities (Fig 4C).	('pGL3', 'Gene', (28, 32))	('increase', 'PosReg', (110, 118))	('CYR61', 'Gene', '3491', (38, 43))	('CTGF', 'Gene', '1490', (33, 37))	('P. gingivalis', 'Var', (83, 96))	('P. gingivalis', 'Species', '837', (83, 96))	('pGL3', 'Gene', '6391', (28, 32))	('CYR61', 'Gene', (130, 135))	('CYR61', 'Gene', '3491', (130, 135))	('CTGF', 'Gene', (33, 37))	('CYR61', 'Gene', (38, 43))	('CTGF', 'Gene', '1490', (122, 126))	('CTGF', 'Gene', (122, 126))
243019	32886690	Putative binding elements for TEAD1 (-1,794 to -1,781 nucleotides) and Smad (-1,745 to -1,732 nucleotides) were identified in the CYR61 promoter.	('TEAD', 'Disease', (30, 34))	('Smad', 'Gene', (71, 75))	('CYR61', 'Gene', (130, 135))	('-1,745', 'Var', (77, 83))	('CYR61', 'Gene', '3491', (130, 135))	('Smad', 'Gene', '33529', (71, 75))	('-1,794', 'Var', (37, 43))	('TEAD', 'Disease', 'None', (30, 34))
243022	32886690	P. gingivalis triggered stronger binding of YAP/TAZ, TEAD1, and Smad2/3 to CTGF (Fig 4D) and CYR61 (S4D Fig) promoters relative to control treatment in NE6-T cells.	('TEAD', 'Disease', 'None', (53, 57))	('TEAD', 'Disease', (53, 57))	('P. gingivalis', 'Var', (0, 13))	('P. gingivalis', 'Species', '837', (0, 13))	('CYR61', 'Gene', '3491', (93, 98))	('Smad2/3', 'Gene', (64, 71))	('YAP', 'Gene', '10413', (44, 47))	('Smad2/3', 'Gene', '4088', (64, 71))	('stronger', 'PosReg', (24, 32))	('YAP', 'Gene', (44, 47))	('CYR61', 'Gene', (93, 98))	('binding', 'Interaction', (33, 40))	('CTGF', 'Gene', '1490', (75, 79))	('CTGF', 'Gene', (75, 79))
243027	32886690	This assay demonstrated that Smad2/3 binding to the YAP/TAZ/TEAD1 complex was significantly increased following P. gingivalis challenge, and this was accompanied by decreased association with 14-3-3.	('decreased', 'NegReg', (165, 174))	('binding', 'Interaction', (37, 44))	('P. gingivalis', 'Species', '837', (112, 125))	('association', 'Interaction', (175, 186))	('Smad2/3', 'Gene', (29, 36))	('Smad2/3', 'Gene', '4088', (29, 36))	('YAP', 'Gene', (52, 55))	('increased', 'PosReg', (92, 101))	('TEAD', 'Disease', 'None', (60, 64))	('TEAD', 'Disease', (60, 64))	('P. gingivalis', 'Var', (112, 125))	('YAP', 'Gene', '10413', (52, 55))
243029	32886690	Because S94A YAP/S51A TAZ mutants lost the abilities to interact with TEAD, we transfected ESCC cells with S94A YAP/S51A TAZ mutants.	('abilities', 'MPA', (43, 52))	('S94A', 'Mutation', 'p.S94A', (107, 111))	('interact', 'Interaction', (56, 64))	('lost', 'NegReg', (34, 38))	('S51A', 'Mutation', 'p.S51A', (17, 21))	('S51A', 'Mutation', 'p.S51A', (116, 120))	('TEAD', 'Disease', 'None', (70, 74))	('YAP', 'Gene', '10413', (112, 115))	('S94A', 'Var', (107, 111))	('S94A', 'Mutation', 'p.S94A', (8, 12))	('mutants', 'Var', (26, 33))	('TEAD', 'Disease', (70, 74))	('YAP', 'Gene', '10413', (13, 16))	('S94A', 'Var', (8, 12))	('YAP', 'Gene', (13, 16))	('YAP', 'Gene', (112, 115))
243030	32886690	S94A YAP/S51A TAZ diminished migration and invasion in response to P. gingivalis (S4G Fig).	('S51A', 'Mutation', 'p.S51A', (9, 13))	('S94A', 'Var', (0, 4))	('YAP', 'Gene', '10413', (5, 8))	('migration', 'CPA', (29, 38))	('YAP', 'Gene', (5, 8))	('diminished', 'NegReg', (18, 28))	('P. gingivalis', 'Species', '837', (67, 80))	('S94A', 'Mutation', 'p.S94A', (0, 4))
243038	32886690	In line with this, we found that GARP protein levels were increased in NE6-T and KYSE30 cells in response to P. gingivalis (Fig 5A).	('P. gingivalis', 'Species', '837', (109, 122))	('P. gingivalis', 'Var', (109, 122))	('increased', 'PosReg', (58, 67))	('KYSE30', 'CellLine', 'CVCL:1351', (81, 87))	('GARP', 'Gene', '2615', (33, 37))	('GARP', 'Gene', (33, 37))
243040	32886690	Interestingly, P. gingivalis induced predominant membranous and paramembranous distributions of GARP in ESCC cells (Fig 5C).	('GARP', 'Gene', '2615', (96, 100))	('GARP', 'Gene', (96, 100))	('P. gingivalis', 'Species', '837', (15, 28))	('P. gingivalis', 'Var', (15, 28))	('membranous', 'CPA', (49, 59))
243042	32886690	GARP knockdown abrogated the P. gingivalis-induced increase of active TGFbeta in NE6-T and KYSE30 cells (S5A Fig).	('knockdown', 'Var', (5, 14))	('increase of active TGFbeta', 'Disease', 'MESH:D006940', (51, 77))	('abrogated', 'NegReg', (15, 24))	('GARP', 'Gene', '2615', (0, 4))	('GARP', 'Gene', (0, 4))	('P. gingivalis', 'Species', '837', (29, 42))	('increase of active TGFbeta', 'Disease', (51, 77))	('KYSE30', 'CellLine', 'CVCL:1351', (91, 97))
243044	32886690	Western blotting showed that GARP depletion abrogated the elevated levels of Smad2/3 phosphorylation, CTGF, PAI-1, Snail, and Oct4 induced by P. gingivalis treatment (Fig 5A).	('Oct4', 'Gene', (126, 130))	('PAI-1', 'Gene', '5054', (108, 113))	('Smad2/3', 'Gene', '4088', (77, 84))	('Smad2/3', 'Gene', (77, 84))	('levels', 'MPA', (67, 73))	('GARP', 'Gene', '2615', (29, 33))	('P. gingivalis', 'Var', (142, 155))	('P. gingivalis', 'Species', '837', (142, 155))	('Oct4', 'Gene', '5460', (126, 130))	('abrogated', 'NegReg', (44, 53))	('PAI-1', 'Gene', (108, 113))	('CTGF', 'Gene', '1490', (102, 106))	('elevated', 'PosReg', (58, 66))	('CTGF', 'Gene', (102, 106))	('GARP', 'Gene', (29, 33))	('Snail', 'MPA', (115, 120))
243045	32886690	In addition, knockdown of GARP expression also blocked P. gingivalis-induced ESCC cell migration and invasion (S5B Fig).	('ESCC', 'Disease', (77, 81))	('GARP', 'Gene', (26, 30))	('expression', 'Species', '29278', (31, 41))	('blocked', 'NegReg', (47, 54))	('P. gingivalis', 'Species', '837', (55, 68))	('knockdown', 'Var', (13, 22))	('invasion', 'CPA', (101, 109))	('GARP', 'Gene', '2615', (26, 30))
243048	32886690	Furthermore, knockdown of TLR4 or MYD88 markedly reduced the up-regulation of GARP and the enhanced activity of Smad2/3 induced by P. gingivalis (Fig 5E).	('GARP', 'Gene', (78, 82))	('reduced', 'NegReg', (49, 56))	('GARP', 'Gene', '2615', (78, 82))	('Smad2/3', 'Gene', (112, 119))	('TLR4', 'Gene', '34235', (26, 30))	('Smad2/3', 'Gene', '4088', (112, 119))	('P. gingivalis', 'Species', '837', (131, 144))	('MYD88', 'Gene', '35956', (34, 39))	('up-regulation', 'PosReg', (61, 74))	('TLR4', 'Gene', (26, 30))	('knockdown', 'Var', (13, 22))	('enhanced', 'PosReg', (91, 99))	('activity', 'MPA', (100, 108))	('MYD88', 'Gene', (34, 39))
243049	32886690	Although P. gingivalis induced activation of YAP/TAZ, as evidenced by decreased phosphorylation of S127YAP and S89TAZ and nuclear accumulation of YAP/TAZ, silencing of YAP/TAZ or overexpression of S127A mutant YAP had no effect on the expression of GARP (S5C and S5D Fig).	('YAP', 'Gene', '10413', (146, 149))	('YAP', 'Gene', (103, 106))	('YAP', 'Gene', '10413', (168, 171))	('phosphorylation', 'MPA', (80, 95))	('GARP', 'Gene', '2615', (249, 253))	('GARP', 'Gene', (249, 253))	('YAP', 'Gene', (45, 48))	('S127A', 'Var', (197, 202))	('expression', 'Species', '29278', (235, 245))	('YAP', 'Gene', '10413', (103, 106))	('silencing', 'Var', (155, 164))	('S89TAZ', 'Var', (111, 117))	('YAP', 'Gene', (210, 213))	('YAP', 'Gene', (146, 149))	('decreased', 'NegReg', (70, 79))	('YAP', 'Gene', '10413', (45, 48))	('YAP', 'Gene', (168, 171))	('S5C', 'Mutation', 'p.S5C', (255, 258))	('expression', 'Species', '29278', (183, 193))	('nuclear accumulation', 'CPA', (122, 142))	('P. gingivalis', 'Species', '837', (9, 22))	('YAP', 'Gene', '10413', (210, 213))	('S127A', 'Mutation', 'rs762471803', (197, 202))
243053	32886690	The protein levels of GARP, pSmad2, YAP/TAZ, Snail, and Oct4 were increased significantly in ESCC tissues with a high amount of P. gingivalis (Fig 6A).	('protein levels', 'MPA', (4, 18))	('increased', 'PosReg', (66, 75))	('GARP', 'Gene', '2615', (22, 26))	('GARP', 'Gene', (22, 26))	('YAP', 'Gene', '10413', (36, 39))	('YAP', 'Gene', (36, 39))	('Smad', 'Gene', (29, 33))	('Oct4', 'Gene', (56, 60))	('Smad', 'Gene', '33529', (29, 33))	('P. gingivalis', 'Var', (128, 141))	('P. gingivalis', 'Species', '837', (128, 141))	('Oct4', 'Gene', '5460', (56, 60))
243061	32886690	The risk score was calculated as follows: risk score = (-0.3918 x differential expression of E-cadherin + (-0.0443 x differential expression of Snail).	('expression', 'Species', '29278', (79, 89))	('E-cadherin', 'Gene', (93, 103))	('-0.0443', 'Var', (107, 114))	('E-cadherin', 'Gene', '999', (93, 103))	('-0.3918', 'Var', (56, 63))	('Snail', 'Protein', (144, 149))	('expression', 'Species', '29278', (130, 140))
243066	32886690	In addition, numerous studies have reported that P. gingivalis is an important risk factor for development and progression of a variety of cancers, including ESCC.	('cancers', 'Disease', 'MESH:D009369', (139, 146))	('cancers', 'Phenotype', 'HP:0002664', (139, 146))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('cancers', 'Disease', (139, 146))	('ESCC', 'Disease', (158, 162))	('P. gingivalis', 'Species', '837', (49, 62))	('P. gingivalis', 'Var', (49, 62))
243067	32886690	Here, we show that P. gingivalis exacerbates the aggressive progression of ESCC.	('P. gingivalis', 'Species', '837', (19, 32))	('ESCC', 'Disease', (75, 79))	('aggressive progression', 'CPA', (49, 71))	('exacerbates', 'PosReg', (33, 44))	('P. gingivalis', 'Var', (19, 32))
243070	32886690	Thus, ESCC patients with high levels of P. gingivalis and its downstream activated molecules have worse clinical outcomes.	('patients', 'Species', '9606', (11, 19))	('ESCC', 'Disease', (6, 10))	('P. gingivalis', 'Var', (40, 53))	('P. gingivalis', 'Species', '837', (40, 53))
243074	32886690	As a keystone periodontal pathogen, P. gingivalis enrichment in the oral cavity contributes to a dysbiotic microbial community, resulting in the onset of chronic periodontal disease and the possible subsequent development of oral cancer.	('P. gingivalis', 'Species', '837', (36, 49))	('oral cancer', 'Disease', (225, 236))	('chronic periodontal disease', 'Disease', (154, 181))	('dysbiotic microbial community', 'MPA', (97, 126))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('oral cancer', 'Disease', 'MESH:D009369', (225, 236))	('chronic periodontal disease', 'Disease', 'MESH:D055113', (154, 181))	('P. gingivalis', 'Var', (36, 49))	('periodontal disease', 'Phenotype', 'HP:0000704', (162, 181))
243075	32886690	Upon interaction with host cells, P. gingivalis induces cytoskeleton remodeling to allow its entry via activation of multiple signaling cascades and subsequently enhances invasiveness of oral cancer cells.	('P. gingivalis', 'Var', (34, 47))	('P. gingivalis', 'Species', '837', (34, 47))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('invasiveness of oral cancer', 'Disease', 'MESH:D009362', (171, 198))	('cytoskeleton', 'MPA', (56, 68))	('induces', 'Reg', (48, 55))	('invasiveness of oral cancer', 'Disease', (171, 198))	('activation', 'PosReg', (103, 113))	('enhances', 'PosReg', (162, 170))
243079	32886690	Fimbriae play a crucial role in mediating the attachment of P. gingivalis to tooth surface, other bacteria, and host cells for its internalization.	('P. gingivalis', 'Var', (60, 73))	('gingivalis to tooth surface', 'Phenotype', 'HP:0012292', (63, 90))	('P. gingivalis', 'Species', '837', (60, 73))	('attachment', 'Interaction', (46, 56))
243081	32886690	These data suggest that there are other mechanisms, such as LPS- or exosome-mediated signaling, imparting the oncogenic effect of P. gingivalis apart from intracellular invasion of P. gingivalis mediated by FimA.	('LPS-', 'MPA', (60, 64))	('P. gingivalis', 'Species', '837', (181, 194))	('oncogenic effect', 'MPA', (110, 126))	('P. gingivalis', 'Species', '837', (130, 143))	('P. gingivalis', 'Var', (130, 143))
243085	32886690	Deregulation of the TGFbeta signaling pathway has been demonstrated in multiple types of human cancers.	('human', 'Species', '9606', (89, 94))	('TGFbeta signaling pathway', 'Pathway', (20, 45))	('Deregulation', 'Var', (0, 12))	('cancers', 'Phenotype', 'HP:0002664', (95, 102))	('cancers', 'Disease', (95, 102))	('cancers', 'Disease', 'MESH:D009369', (95, 102))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))
243087	32886690	In line with this, we report that P. gingivalis induced increased secretion of TGFbeta1 and activation of TGFbeta1 and subsequently stimulated TGFbeta-dependent R-Smad phosphorylation.	('P. gingivalis', 'Var', (34, 47))	('stimulated', 'PosReg', (132, 142))	('activation', 'PosReg', (92, 102))	('TGFbeta-dependent', 'Protein', (143, 160))	('increased', 'PosReg', (56, 65))	('P. gingivalis', 'Species', '837', (34, 47))	('Smad', 'Gene', (163, 167))	('TGFbeta1', 'Gene', '7040', (106, 114))	('TGFbeta1', 'Gene', (106, 114))	('increased secretion of TGFbeta1', 'Phenotype', 'HP:0030269', (56, 87))	('Smad', 'Gene', '33529', (163, 167))	('TGFbeta1', 'Gene', '7040', (79, 87))	('secretion', 'MPA', (66, 75))	('TGFbeta1', 'Gene', (79, 87))
243089	32886690	Unexpectedly, downstream target genes of TGFbeta signaling involving cell-cycle suppression and apoptosis promotion were up-regulated in response to P. gingivalis.	('cell-cycle suppression', 'CPA', (69, 91))	('up-regulated', 'PosReg', (121, 133))	('apoptosis promotion', 'CPA', (96, 115))	('P. gingivalis', 'Var', (149, 162))	('TGFbeta signaling', 'Gene', (41, 58))	('P. gingivalis', 'Species', '837', (149, 162))
243092	32886690	We found that GARP, a TGFbeta-docking receptor on the cell surface, was markedly up-regulated in response to P. gingivalis and promoted TGFbeta bioactivity through the TLR4-MYD88 pathway.	('P. gingivalis', 'Species', '837', (109, 122))	('P. gingivalis', 'Var', (109, 122))	('TGFbeta', 'Gene', (136, 143))	('TLR4', 'Gene', (168, 172))	('MYD88', 'Gene', '35956', (173, 178))	('GARP', 'Gene', '2615', (14, 18))	('promoted', 'PosReg', (127, 135))	('MYD88', 'Gene', (173, 178))	('GARP', 'Gene', (14, 18))	('up-regulated', 'PosReg', (81, 93))	('TLR4', 'Gene', '34235', (168, 172))
243093	32886690	Chemical or genetic inhibition of GARP or TGFbeta blocked P. gingivalis-induced invasion and metastasis.	('inhibition', 'Var', (20, 30))	('blocked', 'NegReg', (50, 57))	('GARP', 'Gene', '2615', (34, 38))	('P. gingivalis', 'Species', '837', (58, 71))	('GARP', 'Gene', (34, 38))	('TGFbeta', 'Gene', (42, 49))	('genetic inhibition', 'Var', (12, 30))
243100	32886690	Furthermore, YAP/TAZ was required for P. gingivalis-associated oncogenic roles in ESCC because deletion of YAP/TAZ or overexpression of YAP S94A/TAZ S51A mutants abrogated the increased migration, invasion, and metastasis induced by P. gingivalis.	('invasion', 'CPA', (197, 205))	('S94A', 'Var', (140, 144))	('S51A', 'Var', (149, 153))	('YAP', 'Gene', (136, 139))	('abrogated', 'NegReg', (162, 171))	('deletion', 'Var', (95, 103))	('YAP', 'Gene', '10413', (107, 110))	('ESCC', 'Disease', (82, 86))	('migration', 'CPA', (186, 195))	('YAP', 'Gene', (107, 110))	('P. gingivalis', 'Species', '837', (233, 246))	('S94A', 'SUBSTITUTION', 'None', (140, 144))	('P. gingivalis', 'Species', '837', (38, 51))	('YAP', 'Gene', '10413', (13, 16))	('YAP', 'Gene', '10413', (136, 139))	('YAP', 'Gene', (13, 16))	('expression', 'Species', '29278', (122, 132))	('S51A', 'Mutation', 'p.S51A', (149, 153))
243106	32886690	We discovered that the mechanisms by which P. gingivalis induced suppression of Hippo signaling activity and YAP/TAZ activation involve inactivation of LATS1/2 and its upstream negative regulator Merlin.	('inactivation', 'NegReg', (136, 148))	('suppression', 'NegReg', (65, 76))	('Hippo signaling activity', 'MPA', (80, 104))	('YAP', 'Gene', '10413', (109, 112))	('Merlin', 'Gene', '32979', (196, 202))	('Merlin', 'Gene', (196, 202))	('YAP', 'Gene', (109, 112))	('LATS1/2', 'Gene', '8140', (152, 159))	('activation', 'PosReg', (117, 127))	('LATS1/2', 'Gene', (152, 159))	('P. gingivalis', 'Species', '837', (43, 56))	('P. gingivalis', 'Var', (43, 56))
243107	32886690	Upon exposure to P. gingivalis, Merlin was phosphorylated and thus inactivated, and this could be rescued by TGFbeta receptor inhibition.	('Merlin', 'Gene', '32979', (32, 38))	('P. gingivalis', 'Species', '837', (17, 30))	('Merlin', 'Gene', (32, 38))	('P. gingivalis', 'Var', (17, 30))	('inactivated', 'NegReg', (67, 78))
243108	32886690	Overexpression of S518A Merlin significantly reduced the invasive potential induced by P. gingivalis.	('reduced', 'NegReg', (45, 52))	('expression', 'Species', '29278', (4, 14))	('S518A', 'Var', (18, 23))	('P. gingivalis', 'Species', '837', (87, 100))	('Merlin', 'Gene', (24, 30))	('Merlin', 'Gene', '32979', (24, 30))	('S518A', 'Mutation', 'p.S518A', (18, 23))	('invasive potential', 'CPA', (57, 75))
243109	32886690	YAP/TAZ inactivation by Lats1/2 overexpression resembled the inhibitory effects of S518A Merlin.	('YAP', 'Gene', (0, 3))	('S518A', 'Mutation', 'p.S518A', (83, 88))	('Merlin', 'Gene', '32979', (89, 95))	('overexpression', 'Var', (32, 46))	('Merlin', 'Gene', (89, 95))	('YAP', 'Gene', '10413', (0, 3))	('Lats1/2', 'Gene', '8140', (24, 31))	('expression', 'Species', '29278', (36, 46))	('Lats1/2', 'Gene', (24, 31))
243115	32886690	It has been demonstrated that alterations in the oral microbiota or salivary composition represent promising noninvasive biomarkers for surveillance and early detection for high-risk subjects, as well as therapeutic response and prognosis for ESCC patients.	('patients', 'Species', '9606', (248, 256))	('alterations', 'Var', (30, 41))	('ESCC', 'Disease', (243, 247))
243123	32886690	In summary, the present study defines a complex circuitry underlying P. gingivalis-induced aggressive progression of ESCC, which orchestrates TGFbeta canonical and noncanonical signaling cascades.	('P. gingivalis-induced', 'Var', (69, 90))	('P. gingivalis', 'Species', '837', (69, 82))	('ESCC', 'Disease', (117, 121))
243174	32886690	Overexpression of Last1/2 or S518A Merlin in ESCC 209 cells affect the migration phenotypes.	('Merlin', 'Gene', '32979', (35, 41))	('expression', 'Species', '29278', (4, 14))	('S518A', 'Mutation', 'p.S518A', (29, 34))	('S518A', 'Var', (29, 34))	('affect', 'Reg', (60, 66))	('migration phenotypes', 'CPA', (71, 91))	('Merlin', 'Gene', (35, 41))
243179	32886690	A number of abbreviations are used in the manuscript, which should be explained, if they are used for the first time (especially if included in the abstract) Some minor things have been marked in the ms. Reviewer #3: In this manuscript, authors explore how P. gingivalis affects esophageal squamous cancer cells (ESCC).	('P. gingivalis', 'Var', (257, 270))	('squamous cancer', 'Phenotype', 'HP:0002860', (290, 305))	('P. gingivalis', 'Species', '837', (257, 270))	('cancer', 'Phenotype', 'HP:0002664', (299, 305))	('affects', 'Reg', (271, 278))	('squamous cancer', 'Disease', 'MESH:D002294', (290, 305))	('squamous cancer', 'Disease', (290, 305))
243180	32886690	Results show that P. gingivalis promotes proliferation, migration and invasion.	('migration', 'CPA', (56, 65))	('P. gingivalis', 'Var', (18, 31))	('P. gingivalis', 'Species', '837', (18, 31))	('promotes', 'PosReg', (32, 40))	('invasion', 'CPA', (70, 78))	('proliferation', 'CPA', (41, 54))
243182	32886690	Authors provide evidence that P. gingivalis increases TGF-beta bioactivity in tumor cells, which results in activation of TGF-beta signaling pathway, ultimately leading to EMT activation.	('P. gingivalis', 'Var', (30, 43))	('EMT activation', 'CPA', (172, 186))	('P. gingivalis', 'Species', '837', (30, 43))	('bioactivity', 'MPA', (63, 74))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('TGF-beta', 'Gene', '7039', (122, 130))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('gingivalis increases', 'Phenotype', 'HP:0000212', (33, 53))	('TGF-beta', 'Gene', (54, 62))	('tumor', 'Disease', (78, 83))	('leading to', 'Reg', (161, 171))	('TGF-beta', 'Gene', '7039', (54, 62))	('increases', 'PosReg', (44, 53))	('TGF-beta', 'Gene', (122, 130))	('activation', 'PosReg', (108, 118))
243184	32886690	However, in figure 2 authors show that P. gingivalis indeed increases not only active TGF-beta but also total TGF-beta.	('increases', 'PosReg', (60, 69))	('active', 'MPA', (79, 85))	('TGF-beta', 'Gene', (110, 118))	('TGF-beta', 'Gene', (86, 94))	('TGF-beta', 'Gene', '7039', (110, 118))	('TGF-beta', 'Gene', '7039', (86, 94))	('P. gingivalis', 'Species', '837', (39, 52))	('P. gingivalis', 'Var', (39, 52))
243187	32886690	Authors show that infection with P. gingivalis in ESCC tumor cells promotes a more aggresive phenotype, and it is correlated with a poor prognosis, so P. gingivalis seems to be important for progression.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('promotes', 'PosReg', (67, 75))	('more aggresive phenotype', 'MPA', (78, 102))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('infection', 'Disease', (18, 27))	('tumor', 'Disease', (55, 60))	('P. gingivalis', 'Species', '837', (151, 164))	('infection', 'Disease', 'MESH:D007239', (18, 27))	('P. gingivalis', 'Species', '837', (33, 46))	('P. gingivalis', 'Var', (33, 46))
243190	32886690	Authors claim that inactivation of Merlin is involved in the P. gingivalis-induced mechanism driving malignant progression of ESSC cells.	('ESSC', 'Disease', (126, 130))	('Merlin', 'Gene', '32979', (35, 41))	('P. gingivalis', 'Species', '837', (61, 74))	('involved', 'Reg', (45, 53))	('inactivation', 'Var', (19, 31))	('malignant progression', 'CPA', (101, 122))	('Merlin', 'Gene', (35, 41))
243191	32886690	However, the downregulation of Merlin provoked by P. gingivalis (fig.	('downregulation', 'NegReg', (13, 27))	('P. gingivalis', 'Var', (50, 63))	('Merlin', 'Gene', '32979', (31, 37))	('Merlin', 'Gene', (31, 37))	('P. gingivalis', 'Species', '837', (50, 63))
243200	32886690	4A (since it is not fully clear that phosphorylation is actually unaffected by deleting YAP/TAZ).	('YAP', 'Gene', (88, 91))	('deleting', 'Var', (79, 87))	('YAP', 'Gene', '10413', (88, 91))
243204	32886690	Figure S3: Controls for the overexpression of Lats1/2 and S518A Merlin should be included.	('Lats1/2', 'Gene', '8140', (46, 53))	('S518A', 'Var', (58, 63))	('Lats1/2', 'Gene', (46, 53))	('Merlin', 'Gene', (64, 70))	('Merlin', 'Gene', '32979', (64, 70))	('expression', 'Species', '29278', (32, 42))	('S518A', 'Mutation', 'p.S518A', (58, 63))
243209	32886690	Figure S3: revisit text (S518A Merlin) and figure (S51A Merlin).	('S518A', 'Mutation', 'p.S518A', (25, 30))	('S518A', 'Var', (25, 30))	('S51A', 'Mutation', 'p.S51A', (51, 55))	('Merlin', 'Gene', (56, 62))	('Merlin', 'Gene', '32979', (31, 37))	('Merlin', 'Gene', (31, 37))	('S51A', 'Var', (51, 55))	('Merlin', 'Gene', '32979', (56, 62))
243220	32886690	While fimA mutant P. gingivalis led to markedly decreased Smad2/3, this may be due to the simple reason of poor adherence.	('mutant P. gingivalis', 'Var', (11, 31))	('decreased', 'NegReg', (48, 57))	('P. gingivalis', 'Species', '837', (18, 31))	('Smad2/3', 'Gene', (58, 65))	('Smad2/3', 'Gene', '4088', (58, 65))
243245	32235701	It has been hypothesized that XPC-HR23B initially binds to DNA non-specifically and only then searches for the presence of DNA damage, encircling the undamaged DNA strand and sensing single-stranded structures induced by the lesion without interacting with the lesion directly.	('HR23B', 'Gene', '5887', (34, 39))	('sensing single-stranded structures', 'MPA', (175, 209))	('XPC', 'Gene', (30, 33))	('XPC', 'Gene', '7508', (30, 33))	('binds', 'Interaction', (50, 55))	('lesion', 'Var', (225, 231))	('HR23B', 'Gene', (34, 39))	('encircling', 'Reg', (135, 145))
243273	32235701	XPA binds both the ssDNA-dsDNA (5' and 3' flaps) junction and Y junction via direct interaction with the residues K168 and K179 (located within MBD) and K221, K222, K224, and K236 (located within the wider DNA binding domain).	('K168', 'Var', (114, 118))	('K222', 'Var', (159, 163))	('K179', 'Var', (123, 127))	('MBD', 'Disease', 'MESH:D012080', (144, 147))	('K224', 'Var', (165, 169))	('K221', 'Var', (153, 157))	('MBD', 'Disease', (144, 147))	('interaction', 'Interaction', (84, 95))	('K236', 'Var', (175, 179))
243285	32235701	Consequently, deletion of the first 15 aa of TTDA abolishes XPA binding and strongly decreases the repair function of TFIIH.	('repair function', 'MPA', (99, 114))	('decreases', 'NegReg', (85, 94))	('abolishes', 'NegReg', (50, 59))	('TTDA', 'Gene', '404672', (45, 49))	('TTDA', 'Gene', (45, 49))	('XPA', 'Protein', (60, 63))	('TFIIH', 'Gene', '2068', (118, 123))	('deletion', 'Var', (14, 22))	('TFIIH', 'Gene', (118, 123))
243289	32235701	Accordingly, mutating the APIM increases UV sensitivity, reduces repair of CPDs and 6-4 PPs, and induces cell cycle arrest in S phase.	('CPDs', 'Disease', (75, 79))	('PPs', 'Chemical', '-', (88, 91))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (105, 122))	('increases', 'PosReg', (31, 40))	('arrest', 'Disease', 'MESH:D006323', (116, 122))	('CPDs', 'Disease', 'MESH:C565866', (75, 79))	('mutating', 'Var', (13, 21))	('induces', 'Reg', (97, 104))	('UV sensitivity', 'MPA', (41, 55))	('APIM', 'Gene', (26, 30))	('arrest', 'Disease', (116, 122))	('reduces', 'NegReg', (57, 64))
243293	32235701	XPA interacts physically with DDB2 through aa residues 185-226 and this interaction can be seen both in vitro and in vivo (Figure 1B).	('DDB2', 'Gene', '1643', (30, 34))	('DDB2', 'Gene', (30, 34))	('interacts', 'Interaction', (4, 13))	('aa residues 185-226', 'Var', (43, 62))
243298	32235701	In particular, three highly conserved glycines of XPA, Gly72-74, have been shown to be essential for ERCC1 binding and UV resistance.	('ERCC1', 'Gene', '2067', (101, 106))	('ERCC1', 'Gene', (101, 106))	('RC', 'Phenotype', 'HP:0100743', (102, 104))	('glycines', 'Chemical', 'MESH:D005998', (38, 46))	('binding', 'Interaction', (107, 114))	('UV resistance', 'MPA', (119, 132))	('Gly72', 'Chemical', '-', (55, 60))	('Gly72-74', 'Var', (55, 63))
243300	32235701	NMR and molecular dynamic simulation identified hydrogen bonding between Gly74, Gly73, and Asp70 of XPA; and Ser142, Gln107, and His149 of ERCC1, respectively.	('Asp70', 'Chemical', '-', (91, 96))	('His149', 'Chemical', '-', (129, 135))	('XPA', 'Gene', (100, 103))	('Gly74', 'Chemical', '-', (73, 78))	('Ser142', 'Chemical', '-', (109, 115))	('Gln107', 'Var', (117, 123))	('Ser142', 'Var', (109, 115))	('Gly74', 'Var', (73, 78))	('Gly73', 'Chemical', '-', (80, 85))	('RC', 'Phenotype', 'HP:0100743', (140, 142))	('ERCC1', 'Gene', '2067', (139, 144))	('ERCC1', 'Gene', (139, 144))	('hydrogen', 'Chemical', 'MESH:D006859', (48, 56))	('His149', 'Var', (129, 135))	('hydrogen bonding', 'MPA', (48, 64))	('Asp70', 'Var', (91, 96))	('Gly73', 'Var', (80, 85))	('Gln107', 'Chemical', '-', (117, 123))
243309	32235701	A study associating DNA repair gene polymorphisms with DNA double-strand break (DSB) repair found that levels of phosphorylated histone H2AX 1 h post ionizing radiation was significantly lower in subjects heterozygous for the XPA single nucleotide polymorphism (SNP) rs3176683 (for further details on XPA SNPs, see text below), suggesting that XPA may also influence DSB repair.	('DSB repair', 'CPA', (367, 377))	('rs3176683', 'Var', (267, 276))	('influence', 'Reg', (357, 366))	('levels of phosphorylated histone H2AX', 'MPA', (103, 140))	('lower', 'NegReg', (187, 192))	('rs3176683', 'Mutation', 'rs3176683', (267, 276))	('XPA', 'Gene', (226, 229))
243315	32235701	In particular, XPA Lys188 was found to influence the interaction by modulating the stability of the helix.	('modulating', 'Reg', (68, 78))	('influence', 'Reg', (39, 48))	('stability of the helix', 'CPA', (83, 105))	('XPA Lys188', 'Var', (15, 25))	('interaction', 'Interaction', (53, 64))	('Lys188', 'Chemical', '-', (19, 25))
243362	32235701	In lung cancer (LC) cell lines, in which endogenous XPA levels are higher, inhibition of HIF-1alpha reduces the expression of XPA, while in LC cell lines with lower endogenous XPA, hypoxia elevates expression of HIF-1alpha and XPA.	('inhibition', 'Var', (75, 85))	('lung cancer', 'Phenotype', 'HP:0100526', (3, 14))	('XPA', 'Protein', (126, 129))	('LC', 'Phenotype', 'HP:0100526', (140, 142))	('expression', 'MPA', (112, 122))	('HIF-1alpha', 'Gene', (212, 222))	('HIF-1alpha', 'Gene', '3091', (89, 99))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('expression', 'MPA', (198, 208))	('higher', 'PosReg', (67, 73))	('lung cancer', 'Disease', (3, 14))	('hypoxia', 'Disease', (181, 188))	('HIF-1alpha', 'Gene', (89, 99))	('elevates', 'PosReg', (189, 197))	('reduces', 'NegReg', (100, 107))	('hypoxia', 'Disease', 'MESH:D000860', (181, 188))	('HIF-1alpha', 'Gene', '3091', (212, 222))	('LC', 'Phenotype', 'HP:0100526', (16, 18))	('lung cancer', 'Disease', 'MESH:D008175', (3, 14))
243373	32235701	CLEC4M knockdown inhibits XPA expression and leads to increased sensitivity to CDDP, while CLEC4M overexpression upregulates XPA.	('inhibits', 'NegReg', (17, 25))	('CDDP', 'Chemical', '-', (79, 83))	('CLEC4M', 'Gene', (91, 97))	('XPA', 'Protein', (26, 29))	('upregulates', 'PosReg', (113, 124))	('increased', 'PosReg', (54, 63))	('XPA', 'MPA', (125, 128))	('CLEC4M', 'Gene', '10332', (91, 97))	('knockdown', 'Var', (7, 16))	('CLEC4M', 'Gene', '10332', (0, 6))	('CLEC4M', 'Gene', (0, 6))	('sensitivity to CDDP', 'MPA', (64, 83))
243377	32235701	XPA is phosphorylated at Ser196, located in DNA binding domain, by ATR in a UV dose-dependent manner.	('Ser196', 'Chemical', '-', (25, 31))	('ATR', 'Gene', '545', (67, 70))	('ATR', 'Gene', (67, 70))	('Ser196', 'Var', (25, 31))
243378	32235701	Phosphorylation of XPA is required to allow XPA to complex with the RPA subunit RPA70 and a Ser196 substitution decreased the affinity of XPA for RPA70.	('RPA70', 'Gene', '6118', (80, 85))	('RPA70', 'Gene', (146, 151))	('RPA70', 'Gene', (80, 85))	('affinity', 'MPA', (126, 134))	('Ser196 substitution', 'Var', (92, 111))	('complex', 'Interaction', (51, 58))	('RPA', 'Protein', (68, 71))	('decreased', 'NegReg', (112, 121))	('Ser196', 'Chemical', '-', (92, 98))	('RPA70', 'Gene', '6118', (146, 151))
243383	32235701	It has been shown that the loss of the SIRT1 expression significantly reduces the repair rate of CPDs and 6-4PPs in UV-irradiated cells and is associated with downregulation of XPC.	('loss', 'Var', (27, 31))	('XPC', 'Gene', (177, 180))	('CPDs', 'Disease', (97, 101))	('reduces', 'NegReg', (70, 77))	('6-4PPs', 'MPA', (106, 112))	('SIRT1', 'Gene', (39, 44))	('XPC', 'Gene', '7508', (177, 180))	('6-4PPs', 'Chemical', '-', (106, 112))	('downregulation', 'NegReg', (159, 173))	('repair', 'MPA', (82, 88))	('SIRT1', 'Gene', '23411', (39, 44))	('CPDs', 'Disease', 'MESH:C565866', (97, 101))
243384	32235701	While only a small fraction of XPA is subject to acetylation, as observed in mouse liver, it has been reported that acetylation on Lys63 and Lys67 reduces XPA activity by interfering with the XPA-RPA interaction and, possibly, interactions with other NER factors.	('reduces', 'NegReg', (147, 154))	('interfering', 'NegReg', (171, 182))	('Lys67', 'Chemical', '-', (141, 146))	('XPA-RPA', 'Enzyme', (192, 199))	('interactions', 'Interaction', (227, 239))	('Lys67', 'Var', (141, 146))	('Lys63', 'Var', (131, 136))	('acetylation', 'Var', (116, 127))	('mouse', 'Species', '10090', (77, 82))	('Lys63', 'Chemical', '-', (131, 136))	('XPA', 'Enzyme', (155, 158))
243385	32235701	SIRT1 deacetylates XPA at residues Lys63, Lys67, and Lys215 to promote the interaction of ATR with XPA, and the subsequent phosphorylation of XPA Ser196.	('phosphorylation', 'MPA', (123, 138))	('Lys67', 'Var', (42, 47))	('Lys63', 'Chemical', '-', (35, 40))	('SIRT1', 'Gene', '23411', (0, 5))	('SIRT1', 'Gene', (0, 5))	('Lys67', 'Chemical', '-', (42, 47))	('Lys63', 'Var', (35, 40))	('promote', 'PosReg', (63, 70))	('ATR', 'Gene', '545', (90, 93))	('ATR', 'Gene', (90, 93))	('Lys215', 'Var', (53, 59))	('Ser196', 'Chemical', '-', (146, 152))	('interaction', 'Interaction', (75, 86))	('Lys215', 'Chemical', '-', (53, 59))
243386	32235701	Accordingly, it has been shown that increased levels of SIRT1 result in an increase in deacetylated XPA that persists in chromatin-bound state and facilitates repair of UV- and CDDP-induced DNA lesions.	('repair', 'MPA', (159, 165))	('facilitates', 'PosReg', (147, 158))	('CDDP', 'Chemical', '-', (177, 181))	('increased', 'PosReg', (36, 45))	('deacetylated', 'MPA', (87, 99))	('levels', 'Var', (46, 52))	('SIRT1', 'Gene', '23411', (56, 61))	('increase', 'PosReg', (75, 83))	('SIRT1', 'Gene', (56, 61))
243391	32235701	It has been demonstrated that XPA phosphorylation on Ser196 enhances the XPA protein level by inhibiting HERC2-mediated ubiquitination upon UV exposure, indicating an antagonizing effect of ATR-mediated phosphorylation on HERC2-mediated XPA degradation.	('ATR', 'Gene', '545', (190, 193))	('ATR', 'Gene', (190, 193))	('enhances', 'PosReg', (60, 68))	('HERC2', 'Gene', (105, 110))	('HERC2', 'Gene', (222, 227))	('RC', 'Phenotype', 'HP:0100743', (107, 109))	('HERC2', 'Gene', '8924', (105, 110))	('HERC2', 'Gene', '8924', (222, 227))	('inhibiting', 'NegReg', (94, 104))	('Ser196', 'Chemical', '-', (53, 59))	('RC', 'Phenotype', 'HP:0100743', (224, 226))	('Ser196', 'Var', (53, 59))	('XPA protein level', 'MPA', (73, 90))
243411	32235701	Docking simulations revealed that the binding between ERCC1 and XPA is primarily mediated by five residues on XPA (Gly72, Gly73, Gly74, Phe75, and Ile76) and 10 residues on ERCC1 (Arg106, Gln107, Gly109, Asn110, Pro111, Phe140, Leu141, Ser142, Tyr145, and Tyr152).	('Gly72', 'Chemical', '-', (115, 120))	('Asn110', 'Chemical', '-', (204, 210))	('binding', 'Interaction', (38, 45))	('Phe140', 'Chemical', '-', (220, 226))	('Gln107', 'Chemical', '-', (188, 194))	('Gln107', 'Var', (188, 194))	('XPA', 'Gene', (110, 113))	('Leu141', 'Chemical', '-', (228, 234))	('Gly74', 'Chemical', '-', (129, 134))	('RC', 'Phenotype', 'HP:0100743', (174, 176))	('Gly73', 'Var', (122, 127))	('Ile76', 'Var', (147, 152))	('Tyr152', 'Var', (256, 262))	('RC', 'Phenotype', 'HP:0100743', (55, 57))	('Ser142', 'Chemical', '-', (236, 242))	('Phe140', 'Var', (220, 226))	('mediated', 'Reg', (81, 89))	('Phe75', 'Var', (136, 141))	('Pro111', 'Var', (212, 218))	('Gly74', 'Var', (129, 134))	('Phe75', 'Chemical', '-', (136, 141))	('Gly72', 'Var', (115, 120))	('Gly109', 'Chemical', '-', (196, 202))	('ERCC1', 'Gene', '2067', (173, 178))	('Leu141', 'Var', (228, 234))	('ERCC1', 'Gene', '2067', (54, 59))	('Gly109', 'Var', (196, 202))	('Gly73', 'Chemical', '-', (122, 127))	('Pro111', 'Chemical', '-', (212, 218))	('Arg106', 'Var', (180, 186))	('Ser142', 'Var', (236, 242))	('Tyr145', 'Chemical', '-', (244, 250))	('Tyr145', 'Var', (244, 250))	('Arg106', 'Chemical', '-', (180, 186))	('ERCC1', 'Gene', (173, 178))	('Ile76', 'Chemical', '-', (147, 152))	('Tyr152', 'Chemical', '-', (256, 262))	('ERCC1', 'Gene', (54, 59))
243412	32235701	NERI01 binding is mediated by a hydrogen bond network within the binding site, making six hydrogen bonds with ERCC1 and stabilizing the interaction between the side chains of Phe140 and Asn110.	('Asn110', 'Var', (186, 192))	('hydrogen bonds', 'MPA', (90, 104))	('Asn110', 'Chemical', '-', (186, 192))	('binding', 'Interaction', (7, 14))	('RC', 'Phenotype', 'HP:0100743', (111, 113))	('NERI01', 'Chemical', '-', (0, 6))	('Phe140', 'Chemical', '-', (175, 181))	('ERCC1', 'Gene', '2067', (110, 115))	('ERCC1', 'Gene', (110, 115))	('interaction', 'Interaction', (136, 147))	('hydrogen', 'Chemical', 'MESH:D006859', (90, 98))	('hydrogen', 'Chemical', 'MESH:D006859', (32, 40))	('Phe140', 'Var', (175, 181))
243414	32235701	Further screens of structurally similar molecules identified AB-00027849 and AB-00026258 as more potent inhibitors of the XPA-ERCC1 interaction.	('ERCC1', 'Gene', '2067', (126, 131))	('ERCC1', 'Gene', (126, 131))	('AB-00026258', 'Chemical', '-', (77, 88))	('interaction', 'Interaction', (132, 143))	('AB-00027849', 'Chemical', '-', (61, 72))	('RC', 'Phenotype', 'HP:0100743', (127, 129))	('AB-00027849', 'Var', (61, 72))	('AB-00026258', 'Gene', (77, 88))
243416	32235701	SNPs may alter numerous cellular functions, including DDR, through regulation of transcription or protein expression of the related DDR factors, thereby playing critical roles in altering an individual's susceptibility to cancer risk.	('cellular functions', 'MPA', (24, 42))	('altering', 'Reg', (179, 187))	('cancer', 'Disease', 'MESH:D009369', (222, 228))	('cancer', 'Disease', (222, 228))	('alter', 'Reg', (9, 14))	('DDR', 'Chemical', '-', (132, 135))	('SNPs', 'Var', (0, 4))	('regulation', 'Reg', (67, 77))	('DDR', 'Chemical', '-', (54, 57))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('protein expression', 'MPA', (98, 116))	('transcription', 'MPA', (81, 94))
243418	32235701	The XPA rs2808668 and rs10817938 SNPs cause T to C transitions in the 5'-untranslated region (UTR) in the nucleotides -2718 and -514 from the transcriptional start site, respectively.	('cause', 'Reg', (38, 43))	('rs2808668', 'Mutation', 'rs2808668', (8, 17))	('rs10817938', 'Var', (22, 32))	('rs2808668', 'Var', (8, 17))	('rs10817938', 'Mutation', 'rs10817938', (22, 32))
243420	32235701	Indeed, rs10817938 heterozygous CT and homozygous TT genotypes have been associated with longer overall survival (OS) in colorectal cancer (CRC) patients receiving oxaliplatin-based chemotherapy.	('patients', 'Species', '9606', (145, 153))	('CRC', 'Phenotype', 'HP:0003003', (140, 143))	('longer', 'PosReg', (89, 95))	('colorectal cancer', 'Phenotype', 'HP:0003003', (121, 138))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('rs10817938', 'Var', (8, 18))	('rectal cancer', 'Phenotype', 'HP:0100743', (125, 138))	('colorectal cancer', 'Disease', (121, 138))	('overall survival', 'MPA', (96, 112))	('rs10817938', 'Mutation', 'rs10817938', (8, 18))	('colorectal cancer', 'Disease', 'MESH:D015179', (121, 138))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (164, 175))	('RC', 'Phenotype', 'HP:0100743', (141, 143))
243421	32235701	In addition, these SNPs have been shown to be associated with the risk and development of numerous cancers and display significant gene-environment interactions (see below).	('numerous cancers', 'Disease', (90, 106))	('SNPs', 'Var', (19, 23))	('cancers', 'Phenotype', 'HP:0002664', (99, 106))	('interactions', 'Interaction', (148, 160))	('numerous cancers', 'Disease', 'MESH:D009369', (90, 106))	('associated with', 'Reg', (46, 61))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
243422	32235701	Recently, the most comprehensive meta-analysis for rs10817938 and rs2808668 and cancer risk (33 types of cancer were examined) showed that harbouring rs10817938 homozygous CC genotype, C allele, and CC/CT genotype in a dominant setting associates with an increased overall cancer risk, with a specific association with digestive system cancers.	('rs10817938', 'Mutation', 'rs10817938', (150, 160))	('cancer', 'Disease', (105, 111))	('cancers', 'Phenotype', 'HP:0002664', (336, 343))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('cancer', 'Disease', (336, 342))	('cancers', 'Disease', (336, 343))	('cancer', 'Disease', (80, 86))	('cancer', 'Phenotype', 'HP:0002664', (336, 342))	('cancer', 'Disease', 'MESH:D009369', (273, 279))	('rs2808668', 'Mutation', 'rs2808668', (66, 75))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('rs10817938', 'Mutation', 'rs10817938', (51, 61))	('cancer', 'Disease', 'MESH:D009369', (336, 342))	('cancers', 'Disease', 'MESH:D009369', (336, 343))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('rs10817938', 'Var', (150, 160))	('increased', 'PosReg', (255, 264))	('cancer', 'Disease', (273, 279))	('cancer', 'Phenotype', 'HP:0002664', (273, 279))
243423	32235701	In contrast, there was no association with overall cancer risk for rs2808668, albeit subgroup analysis revealed a decreased risk in the majority of cancers examined, with the exception of digestive system cancer.	('rs2808668', 'Var', (67, 76))	('cancer', 'Disease', (148, 154))	('cancers', 'Disease', 'MESH:D009369', (148, 155))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (205, 211))	('cancers', 'Phenotype', 'HP:0002664', (148, 155))	('cancers', 'Disease', (148, 155))	('cancer', 'Disease', (205, 211))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('decreased', 'NegReg', (114, 123))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('rs2808668', 'Mutation', 'rs2808668', (67, 76))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))
243426	32235701	This might partially be explained by the environmental factors or clinical-pathological parameters that interact with the XPA genetic variants synergistically, contributing to the process of carcinogenesis.	('variants', 'Var', (134, 142))	('carcinogenesis', 'Disease', (191, 205))	('XPA', 'Gene', (122, 125))	('contributing', 'Reg', (160, 172))	('carcinogenesis', 'Disease', 'MESH:D063646', (191, 205))
243427	32235701	Meta-analysis examining rs1800975 and the risk of developing breast cancer (BC) suggests a decreased risk of developing this malignity in non-Asian populations in a recessive setting.	('breast cancer', 'Disease', 'MESH:D001943', (61, 74))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('breast cancer', 'Disease', (61, 74))	('breast cancer', 'Phenotype', 'HP:0003002', (61, 74))	('BC', 'Phenotype', 'HP:0003002', (76, 78))	('rs1800975', 'Var', (24, 33))	('rs1800975', 'Mutation', 'rs1800975', (24, 33))
243428	32235701	Individuals carrying the TC and CC genotypes at rs10817938 had significantly greater risk of developing oral squamous cell carcinoma (OSCC) compared to the TT genotype.	('rs10817938', 'Var', (48, 58))	('rs10817938', 'Mutation', 'rs10817938', (48, 58))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (104, 132))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (109, 132))	('TC', 'Chemical', 'MESH:D013667', (25, 27))	('SCC', 'Phenotype', 'HP:0002860', (135, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('oral squamous cell carcinoma', 'Disease', (104, 132))
243429	32235701	Moreover, OSCC patients with the C allele at this SNP were more susceptible to lymph metastases, poor pathological differentiation and late tumour node metastasis (TNM) stage.	('tumour', 'Phenotype', 'HP:0002664', (140, 146))	('late tumour node metastasis', 'Disease', 'MESH:D009362', (135, 162))	('patients', 'Species', '9606', (15, 23))	('SCC', 'Phenotype', 'HP:0002860', (11, 14))	('C allele at', 'Var', (33, 44))	('susceptible', 'Reg', (64, 75))	('lymph metastases', 'Disease', (79, 95))	('late tumour node metastasis', 'Disease', (135, 162))	('lymph metastases', 'Disease', 'MESH:D009362', (79, 95))	('poor pathological differentiation', 'CPA', (97, 130))
243430	32235701	This indicates that rs10817938 is a useful biomarker for poor prognosis in OSCC patients.	('patients', 'Species', '9606', (80, 88))	('rs10817938', 'Mutation', 'rs10817938', (20, 30))	('OSCC', 'Disease', (75, 79))	('SCC', 'Phenotype', 'HP:0002860', (76, 79))	('rs10817938', 'Var', (20, 30))
243432	32235701	In contrast with rs10817938, no significant association of rs2808668 with OSCC risk or prognosis was observed.	('rs2808668', 'Var', (59, 68))	('rs10817938', 'Mutation', 'rs10817938', (17, 27))	('OSCC', 'Disease', (74, 78))	('SCC', 'Phenotype', 'HP:0002860', (75, 78))	('rs2808668', 'Mutation', 'rs2808668', (59, 68))
243433	32235701	The XPA rs10817938 SNP was also associated with hepatocellular cancer (HCC) risk in stage 1, where the CC genotype displays an increased risk compared with the TT wild-type and TT plus TC genotype.	('hepatocellular cancer', 'Phenotype', 'HP:0001402', (48, 69))	('HCC', 'Phenotype', 'HP:0001402', (71, 74))	('rs10817938 SNP', 'Var', (8, 22))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('TC', 'Chemical', 'MESH:D013667', (185, 187))	('hepatocellular cancer', 'Disease', 'MESH:D006528', (48, 69))	('associated with', 'Reg', (32, 47))	('hepatocellular cancer', 'Disease', (48, 69))	('rs10817938', 'Mutation', 'rs10817938', (8, 18))
243434	32235701	Another SNP present in 5'-UTR of XPA, rs1800975 (A23G), is A to G transition in the nucleotide -4 from ATG start codon having an implication for the binding of the 40S ribosomal subunit and, consequently, the level of XPA protein in the cell.	('implication', 'Reg', (129, 140))	('A23G', 'Mutation', 'rs1800975', (49, 53))	('binding', 'Interaction', (149, 156))	('rs1800975', 'Var', (38, 47))	('rs1800975', 'Mutation', 'rs1800975', (38, 47))
243437	32235701	A23G has been shown to contribute to the risk of developing LC, basal and squamous cell carcinoma (SCC), esophageal SCC (ESCC), OSCC, and OC, but not testicular, prostate, colorectal, and gastric cancers, SCC of the oropharynx, or melanoma.	('OSCC', 'Disease', (128, 132))	('gastric cancer', 'Phenotype', 'HP:0012126', (188, 202))	('SCC', 'Phenotype', 'HP:0002860', (129, 132))	('SCC', 'Phenotype', 'HP:0002860', (122, 125))	('melanoma', 'Phenotype', 'HP:0002861', (231, 239))	('melanoma', 'Disease', (231, 239))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('esophageal SCC', 'Disease', (105, 119))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (74, 97))	('SCC', 'Phenotype', 'HP:0002860', (205, 208))	('basal', 'Disease', (64, 69))	('LC', 'Phenotype', 'HP:0100526', (60, 62))	('squamous cell carcinoma', 'Disease', (74, 97))	('OC', 'Phenotype', 'HP:0100615', (138, 140))	('melanoma', 'Disease', 'MESH:D008545', (231, 239))	('cancers', 'Phenotype', 'HP:0002664', (196, 203))	('SCC', 'Phenotype', 'HP:0002860', (99, 102))	('A23G', 'Var', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('SCC', 'Phenotype', 'HP:0002860', (116, 119))	('gastric cancers', 'Disease', 'MESH:D013274', (188, 203))	('gastric cancers', 'Disease', (188, 203))	('A23G', 'Mutation', 'rs1800975', (0, 4))	('gastric cancers', 'Phenotype', 'HP:0012126', (188, 203))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (74, 97))
243439	32235701	The A23G SNP was also included in a screen for genetic factors predisposing to TP53 mutations in LC patients and was found to be significantly associated with the prevalence of mutations in this gene, suggesting that it may modulate the occurrence of the TP53 mutations, thereby contributing to LC.	('TP53', 'Gene', (255, 259))	('associated', 'Reg', (143, 153))	('TP53', 'Gene', '7157', (79, 83))	('TP53', 'Gene', (79, 83))	('contributing', 'Reg', (279, 291))	('mutations', 'Var', (177, 186))	('A23G', 'Mutation', 'rs1800975', (4, 8))	('LC', 'Phenotype', 'HP:0100526', (97, 99))	('mutations', 'Var', (84, 93))	('patients', 'Species', '9606', (100, 108))	('modulate', 'Reg', (224, 232))	('mutations', 'Var', (260, 269))	('LC', 'Phenotype', 'HP:0100526', (295, 297))	('TP53', 'Gene', '7157', (255, 259))
243440	32235701	A23G has been associated with chemoresistance in acute myeloblastic leukaemia (AML), where individuals with the AA genotype had a probability of resistant disease 2- and 5-times lower than those with heterozygous AG and homozygous GG variant genotype, respectively.	('AML', 'Disease', (79, 82))	('chemoresistance', 'MPA', (30, 45))	('AML', 'Phenotype', 'HP:0004808', (79, 82))	('acute myeloblastic leukaemia', 'Disease', (49, 77))	('myeloblastic leukaemia', 'Phenotype', 'HP:0012324', (55, 77))	('lower', 'NegReg', (178, 183))	('A23G', 'Mutation', 'rs1800975', (0, 4))	('acute myeloblastic leukaemia', 'Phenotype', 'HP:0004808', (49, 77))	('AML', 'Disease', 'MESH:D015470', (79, 82))	('acute myeloblastic leukaemia', 'Disease', 'MESH:D015470', (49, 77))	('A23G', 'Var', (0, 4))
243442	32235701	G709A SNP (rs number not available) resides in the protein coding region of XPA and leads to a G to A transition in exon 6, and thus Arg to Gln substitution at position 228 in the protein sequence.	('G to', 'Reg', (95, 99))	('G709A', 'Var', (0, 5))	('Arg to Gln', 'Var', (133, 143))	('G709A', 'Mutation', 'rs766009752', (0, 5))	('Arg to Gln substitution at position 228', 'Mutation', 'rs1805160', (133, 172))	('leads to', 'Reg', (84, 92))
243443	32235701	In contrast to A23G SNP, the G709A SNP has virtually no impact on the repair of UV- and benzo(a)pyrene diol epoxide-induced DNA damage compared to wild-type XPA, and appears to have a protective effect for LC patients.	('benzo', 'Chemical', '-', (88, 93))	('LC', 'Phenotype', 'HP:0100526', (206, 208))	('G709A', 'Mutation', 'rs766009752', (29, 34))	('repair', 'MPA', (70, 76))	('pyrene diol epoxide', 'Chemical', '-', (96, 115))	('G709A', 'Var', (29, 34))	('patients', 'Species', '9606', (209, 217))	('A23G', 'Mutation', 'rs1800975', (15, 19))
243444	32235701	Three further SNPs reside in intron sequences of XPA: rs3176658, which causes C to T transition, rs3176721, a C to A transversion, and rs2808667, a T to C transition .	('rs3176658', 'Mutation', 'rs3176658', (54, 63))	('rs2808667', 'Var', (135, 144))	('rs3176721', 'Mutation', 'rs3176721', (97, 106))	('rs3176721', 'Var', (97, 106))	('rs3176658', 'Var', (54, 63))	('C to T transition', 'MPA', (78, 95))	('causes', 'Reg', (71, 77))	('rs2808667', 'Mutation', 'rs2808667', (135, 144))
243445	32235701	rs3176658 and rs3176721 are associated with efficacy of platinum-based chemotherapy in LC, while rs3176658 alone has been shown to be significantly associated with LC risk and with response to neoadjuvant radiochemotherapy treatment of locally advanced rectal cancer (RC).	('rs3176658', 'Var', (0, 9))	('LC', 'Phenotype', 'HP:0100526', (164, 166))	('rectal cancer', 'Phenotype', 'HP:0100743', (253, 266))	('rs3176658', 'Mutation', 'rs3176658', (97, 106))	('platinum', 'Chemical', 'MESH:D010984', (56, 64))	('rs3176721', 'Mutation', 'rs3176721', (14, 23))	('cancer', 'Disease', 'MESH:D009369', (260, 266))	('LC', 'Phenotype', 'HP:0100526', (87, 89))	('cancer', 'Disease', (260, 266))	('rs3176721', 'Var', (14, 23))	('rs3176658', 'Var', (97, 106))	('associated', 'Reg', (148, 158))	('rs3176658', 'Mutation', 'rs3176658', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (260, 266))	('RC', 'Phenotype', 'HP:0100743', (268, 270))
243446	32235701	Changes in the expression level of XPA are assumed to significantly contribute to cancer risk, disease prognosis and treatment outcome.	('XPA', 'Gene', (35, 38))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('expression level', 'MPA', (15, 31))	('cancer', 'Disease', (82, 88))	('contribute', 'Reg', (68, 78))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('Changes', 'Var', (0, 7))
243451	32235701	Furthermore, XPA protein expression has been reported to be significantly decreased in CRC tissues, and patients with high XPA protein expression had longer OS, though contradictory data also exist.	('high', 'Var', (118, 122))	('CRC', 'Phenotype', 'HP:0003003', (87, 90))	('RC', 'Phenotype', 'HP:0100743', (88, 90))	('XPA protein', 'Protein', (13, 24))	('decreased', 'NegReg', (74, 83))	('patients', 'Species', '9606', (104, 112))
243457	32235701	However, subsite analysis revealed that high XPA expression showed a significantly increased OS in patients with SCC of the oropharynx, indicating that it may function as a predictive marker for increased OS in these patients.	('high', 'Var', (40, 44))	('XPA', 'Protein', (45, 48))	('increased', 'PosReg', (83, 92))	('SCC of the oropharynx', 'Disease', (113, 134))	('patients', 'Species', '9606', (99, 107))	('patients', 'Species', '9606', (217, 225))	('SCC', 'Phenotype', 'HP:0002860', (113, 116))
243467	32235701	Recently, we have brought evidence that TGCT patients with low XPA expression have significantly better OS than patients with high expression.	('GC', 'Phenotype', 'HP:0012126', (41, 43))	('patients', 'Species', '9606', (112, 120))	('patients', 'Species', '9606', (45, 53))	('better', 'PosReg', (97, 103))	('low', 'Var', (59, 62))	('TGCT', 'Disease', (40, 44))	('XPA', 'Protein', (63, 66))
243472	32235701	In a personal context, XPA genetic variations and expression level might once be screened for predicting cancer prognosis leading to additional improvement and a precise approach in cancer treatment.	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('XPA', 'Gene', (23, 26))	('cancer', 'Disease', (182, 188))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('genetic variations', 'Var', (27, 45))
243511	31956375	The Cox model showed that 5376 genes were statistically significantly correlated with overall survival at the p value less than 0.05.	('Cox', 'Gene', '1351', (4, 7))	('overall', 'MPA', (86, 93))	('Cox', 'Gene', (4, 7))	('5376 genes', 'Var', (26, 36))	('correlated', 'Reg', (70, 80))
243523	31956375	In addition, the C-index of the RSF model was larger than that of the Cox model.	('RSF', 'Var', (32, 35))	('larger', 'PosReg', (46, 52))	('C-index', 'MPA', (17, 24))	('Cox', 'Gene', '1351', (70, 73))	('Cox', 'Gene', (70, 73))
243561	25916205	Dysregulation of zinc finger protein, X-linked (ZFX) impairs cell proliferation and induces apoptosis in human oral squamous cell carcinorma Zinc finger protein, X-linked (ZFX) is a transcriptional factor involved in many physiological processes such as embryonic stem cell survival and self-renewal.	('impairs', 'NegReg', (53, 60))	('human', 'Species', '9606', (105, 110))	('Zinc finger protein, X-linked', 'Gene', '7543', (141, 170))	('zinc finger protein, X-linked', 'Gene', '7543', (17, 46))	('apoptosis', 'CPA', (92, 101))	('squamous cell carcinorma', 'Phenotype', 'HP:0002860', (116, 140))	('Dysregulation', 'Var', (0, 13))	('oral squamous cell carcinorma', 'Disease', 'MESH:D002294', (111, 140))	('ZFX', 'Gene', '7543', (172, 175))	('cell proliferation', 'CPA', (61, 79))	('oral squamous cell carcinorma', 'Disease', (111, 140))	('ZFX', 'Gene', (172, 175))	('ZFX', 'Gene', (48, 51))	('ZFX', 'Gene', '7543', (48, 51))	('induces', 'Reg', (84, 91))
243562	25916205	Though ZFX dysfunctions have been identified in variant human diseases and especially in cancers, its pathological roles have not been fully addressed.	('cancers', 'Phenotype', 'HP:0002664', (89, 96))	('cancers', 'Disease', 'MESH:D009369', (89, 96))	('human', 'Species', '9606', (56, 61))	('cancers', 'Disease', (89, 96))	('dysfunctions', 'Var', (11, 23))	('ZFX', 'Gene', '7543', (7, 10))	('identified', 'Reg', (34, 44))	('ZFX', 'Gene', (7, 10))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
243565	25916205	Furthermore, ZFX knockdown impeded cell proliferation, impaired colony formation ability, and lead to cell cycle arrest while induced cell apoptosis in human tongue squamous cell carcinoma cell line Tca-8113.	('colony formation ability', 'CPA', (64, 88))	('cell proliferation', 'CPA', (35, 53))	('human', 'Species', '9606', (152, 157))	('tongue squamous cell carcinoma', 'Disease', (158, 188))	('cell cycle arrest', 'CPA', (102, 119))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (165, 188))	('cell apoptosis', 'CPA', (134, 148))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (102, 119))	('tongue squamous cell carcinoma', 'Phenotype', 'HP:0030413', (158, 188))	('induced', 'Reg', (126, 133))	('ZFX', 'Gene', (13, 16))	('knockdown', 'Var', (17, 26))	('carcinoma', 'Phenotype', 'HP:0030731', (179, 188))	('impaired', 'NegReg', (55, 63))	('Tca', 'Chemical', 'MESH:D014238', (199, 202))	('ZFX', 'Gene', '7543', (13, 16))	('impeded', 'NegReg', (27, 34))	('lead to', 'Reg', (94, 101))	('tongue squamous cell carcinoma', 'Disease', 'MESH:D002294', (158, 188))
243572	25916205	Cys2His2 zinc finger (C2H2-ZF) proteins are the major class of DNA-binding proteins and have been implicated in diverse biological processes such as cell proliferation differentiation and cell survival while their dysfunctions have been linked to multiple human diseases including variant types of cancer.	('human', 'Species', '9606', (256, 261))	('dysfunctions', 'Var', (214, 226))	('linked', 'Reg', (237, 243))	('cancer', 'Disease', 'MESH:D009369', (298, 304))	('implicated', 'Reg', (98, 108))	('cancer', 'Disease', (298, 304))	('cell proliferation differentiation', 'CPA', (149, 183))	('cell survival', 'CPA', (188, 201))	('cancer', 'Phenotype', 'HP:0002664', (298, 304))
243621	25916205	Appropriate protein lysates were mixed with 2x loading buffer, separated on 10-12 % SDS-PAGE and transferred to PVDF membranes (Amersham), which was further blocked with 5 % dissolved milk buffer for 2 h at room temperature and incubated overnight with specific primary antibodies including anti-cleaved caspase 3 (Cell Signaling #9664), anti-cleaved PARP (Cell Signaling #5625), and anti-GAPDH.	('GAPDH', 'Gene', '2597', (389, 394))	('anti-cleaved', 'Var', (291, 303))	('SDS', 'Chemical', 'MESH:D012967', (84, 87))	('PARP', 'Gene', '1302', (351, 355))	('GAPDH', 'Gene', (389, 394))	('anti-cleaved', 'Var', (338, 350))	('PARP', 'Gene', (351, 355))	('caspase 3', 'Protein', (304, 313))	('PVDF', 'Chemical', 'MESH:C024865', (112, 116))
243646	25916205	These results revealed that ZFX knockdown inhibited clone formation in Tca-8113 cells, which indicated that ZFX is essential for clonogenic ability of human tongue squamous cell carcinoma cells.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (164, 187))	('ZFX', 'Gene', '7543', (108, 111))	('clone formation', 'CPA', (52, 67))	('human', 'Species', '9606', (151, 156))	('knockdown', 'Var', (32, 41))	('tongue squamous cell carcinoma', 'Phenotype', 'HP:0030413', (157, 187))	('inhibited', 'NegReg', (42, 51))	('carcinoma', 'Phenotype', 'HP:0030731', (178, 187))	('tongue squamous cell carcinoma', 'Disease', 'MESH:D002294', (157, 187))	('tongue squamous cell carcinoma', 'Disease', (157, 187))	('ZFX', 'Gene', (28, 31))	('Tca', 'Chemical', 'MESH:D014238', (71, 74))	('ZFX', 'Gene', '7543', (28, 31))	('ZFX', 'Gene', (108, 111))
243649	25916205	Results showed that significant cell cycle arrest at the G2/M phase was induced by ZFX knockdown, as the percentage of G2/M phase cells increased from 7.59 to 12.27 % with ZFX-siRNA treatment.	('ZFX', 'Gene', '7543', (83, 86))	('ZFX', 'Gene', (83, 86))	('cell cycle arrest at the G2/M phase', 'CPA', (32, 67))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (32, 49))	('increased', 'PosReg', (136, 145))	('ZFX', 'Gene', (172, 175))	('ZFX', 'Gene', '7543', (172, 175))	('knockdown', 'Var', (87, 96))
243650	25916205	Taken together, these data showed that cell cycle progression was disrupted by ZFX knockdown and indicated that ZFX knockdown-induced cell proliferation impairment might be partially attributed to cell cycle arrest.	('cell proliferation', 'CPA', (134, 152))	('ZFX', 'Gene', (79, 82))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (197, 214))	('ZFX', 'Gene', (112, 115))	('impairment', 'NegReg', (153, 163))	('ZFX', 'Gene', '7543', (112, 115))	('cell cycle progression', 'CPA', (39, 61))	('disrupted', 'NegReg', (66, 75))	('cell cycle', 'CPA', (197, 207))	('knockdown', 'Var', (83, 92))	('ZFX', 'Gene', '7543', (79, 82))
243656	25916205	It was shown that ZFX knockdown led to the upregulation of cleaved caspase 3 and PARP proteins (Fig.	('PARP', 'Gene', (81, 85))	('ZFX', 'Gene', '7543', (18, 21))	('knockdown', 'Var', (22, 31))	('upregulation', 'PosReg', (43, 55))	('cleaved', 'MPA', (59, 66))	('ZFX', 'Gene', (18, 21))	('PARP', 'Gene', '1302', (81, 85))
243661	25916205	Studies from our lab also showed that ZFX is involved in human laryngeal squamous cell carcinoma (LSCC), a subgroup of cancer of HNSCC, and ZFX knockdown impaired the cell proliferation and induced apoptosis in LSCC Hep-2 cells.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (73, 96))	('SCC', 'Gene', (212, 215))	('apoptosis', 'CPA', (198, 207))	('SCC', 'Gene', '6317', (99, 102))	('laryngeal squamous cell carcinoma', 'Disease', (63, 96))	('HNSCC', 'Phenotype', 'HP:0012288', (129, 134))	('ZFX', 'Gene', '7543', (140, 143))	('SCC', 'Phenotype', 'HP:0002860', (131, 134))	('SCC', 'Gene', '6317', (131, 134))	('SCC', 'Gene', (99, 102))	('human', 'Species', '9606', (57, 62))	('cell proliferation', 'CPA', (167, 185))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))	('Hep-2', 'CellLine', 'CVCL:1906', (216, 221))	('SCC', 'Gene', (131, 134))	('cancer', 'Disease', (119, 125))	('impaired', 'NegReg', (154, 162))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('laryngeal squamous cell carcinoma', 'Disease', 'MESH:D002294', (63, 96))	('induced', 'Reg', (190, 197))	('SCC', 'Phenotype', 'HP:0002860', (212, 215))	('knockdown', 'Var', (144, 153))	('SCC', 'Phenotype', 'HP:0002860', (99, 102))	('ZFX', 'Gene', (38, 41))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('SCC', 'Gene', '6317', (212, 215))	('ZFX', 'Gene', (140, 143))	('ZFX', 'Gene', '7543', (38, 41))
243669	25916205	However, the underlying mechanisms about colony formation ability impairment by ZFX knockdown remain elusive, though it was shown in this study that ZFX expression is essential for colony formation.	('ZFX', 'Gene', (80, 83))	('colony formation ability', 'CPA', (41, 65))	('impairment', 'NegReg', (66, 76))	('ZFX', 'Gene', '7543', (80, 83))	('knockdown', 'Var', (84, 93))	('ZFX', 'Gene', (149, 152))	('ZFX', 'Gene', '7543', (149, 152))
243674	25916205	It has been reported that ZFX knockdown in diverse tumor types including gliomas, NSCLC, LSCC, breast cancers, and gastric cancer all led to hypophosphorylation of Akt, extracellular signal-regulated kinase 1/2 (ERK1/2), or MEK1/2 except for ERK2 hyperphosphorylation in breast cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('gliomas', 'Phenotype', 'HP:0009733', (73, 80))	('breast cancer', 'Phenotype', 'HP:0003002', (95, 108))	('ERK2', 'Gene', '5594', (242, 246))	('gastric cancer', 'Phenotype', 'HP:0012126', (115, 129))	('ZFX', 'Gene', (26, 29))	('knockdown', 'Var', (30, 39))	('SCC', 'Gene', '6317', (90, 93))	('Akt', 'Gene', (164, 167))	('breast cancer', 'Disease', 'MESH:D001943', (95, 108))	('ERK2', 'Gene', (242, 246))	('cancer', 'Phenotype', 'HP:0002664', (278, 284))	('Akt', 'Gene', '207', (164, 167))	('ZFX', 'Gene', '7543', (26, 29))	('tumor', 'Disease', (51, 56))	('SCC', 'Gene', (90, 93))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('gastric cancer', 'Disease', (115, 129))	('NSCLC', 'Disease', 'MESH:D002289', (82, 87))	('gliomas', 'Disease', (73, 80))	('breast cancer', 'Phenotype', 'HP:0003002', (271, 284))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))	('NSCLC', 'Disease', (82, 87))	('extracellular signal-regulated kinase 1/2', 'Gene', (169, 210))	('ERK1/2', 'Gene', (212, 218))	('ERK1/2', 'Gene', '5595;5594', (212, 218))	('extracellular signal-regulated kinase 1/2', 'Gene', '5594', (169, 210))	('gastric cancer', 'Disease', 'MESH:D013274', (115, 129))	('MEK1/2', 'Gene', (224, 230))	('gliomas', 'Disease', 'MESH:D005910', (73, 80))	('breast cancers', 'Disease', (95, 109))	('breast cancers', 'Disease', 'MESH:D001943', (95, 109))	('breast cancer', 'Disease', 'MESH:D001943', (271, 284))	('MEK1/2', 'Gene', '5604;5605', (224, 230))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('breast cancer', 'Disease', (271, 284))	('SCC', 'Phenotype', 'HP:0002860', (90, 93))	('hypophosphorylation', 'MPA', (141, 160))	('breast cancers', 'Phenotype', 'HP:0003002', (95, 109))
243676	25916205	What's more, ZFX knockdown resulted in the downregulation of anti-apoptotic factor such as bcl-2 and upregulation of apoptotic factors including bax, caspase1, 3, 9 in diverse cancers.	('cancers', 'Disease', (176, 183))	('bcl-2', 'Gene', (91, 96))	('caspase1', 'Gene', (150, 158))	('cancers', 'Disease', 'MESH:D009369', (176, 183))	('upregulation', 'PosReg', (101, 113))	('downregulation', 'NegReg', (43, 57))	('bax', 'Gene', (145, 148))	('bcl-2', 'Gene', '596', (91, 96))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('apoptotic', 'CPA', (117, 126))	('caspase1', 'Gene', '834', (150, 158))	('ZFX', 'Gene', (13, 16))	('ZFX', 'Gene', '7543', (13, 16))	('knockdown', 'Var', (17, 26))	('cancers', 'Phenotype', 'HP:0002664', (176, 183))	('bax', 'Gene', '581', (145, 148))	('anti-apoptotic factor', 'MPA', (61, 82))
243678	25916205	These results were all in consistent with the phenomenon that ZFX knockdown induces cell apoptosis in Tca-8113 cells and provided valuable insights for the underlying mechanisms of ZFX-mediated cell apoptosis.	('Tca', 'Chemical', 'MESH:D014238', (102, 105))	('induces', 'Reg', (76, 83))	('ZFX', 'Gene', (62, 65))	('ZFX', 'Gene', '7543', (62, 65))	('ZFX', 'Gene', (181, 184))	('knockdown', 'Var', (66, 75))	('ZFX', 'Gene', '7543', (181, 184))	('cell apoptosis', 'CPA', (84, 98))
243679	25916205	Furthermore, it has been revealed that cell cyle factors such as cyclin D1 and cyclin B1 was downregulated by ZFX knockdown in multiple cancer types, which might account for the cell cycle disruption in Tca-8113 cells treated with ZFX-siRNA.	('cyclin B1', 'Gene', '891', (79, 88))	('cyclin D1', 'Gene', (65, 74))	('ZFX', 'Gene', (231, 234))	('cyclin B1', 'Gene', (79, 88))	('ZFX', 'Gene', '7543', (231, 234))	('knockdown', 'Var', (114, 123))	('Tca', 'Chemical', 'MESH:D014238', (203, 206))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('cancer', 'Disease', (136, 142))	('downregulated', 'NegReg', (93, 106))	('cyclin D1', 'Gene', '595', (65, 74))	('cell cyle', 'MPA', (39, 48))	('ZFX', 'Gene', (110, 113))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('ZFX', 'Gene', '7543', (110, 113))
243680	25916205	Indeed, ZFX knockdown induced G1 phase cell cycle arrest in Tca-8113 cells, which is in consistent with previous cell cycle results in PC-3 cells, SGC7901 cells, H1299 cells, MDA-MB-231 cells, U87, and U373 cells, and in contrast to results in MGC803 cells and Hep-2 cells, in which S phase cell cycle arrest was induced by ZFX knockdown.	('H1299', 'CellLine', 'CVCL:0060', (162, 167))	('ZFX', 'Gene', '7543', (8, 11))	('ZFX', 'Gene', (324, 327))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (175, 185))	('SGC7901', 'CellLine', 'CVCL:0520', (147, 154))	('PC-3', 'CellLine', 'CVCL:0035', (135, 139))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (39, 56))	('knockdown', 'Var', (12, 21))	('U373', 'CellLine', 'CVCL:2219', (202, 206))	('MGC803', 'CellLine', 'CVCL:5334', (244, 250))	('U87', 'CellLine', 'CVCL:0022', (193, 196))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (291, 308))	('Hep-2', 'CellLine', 'CVCL:1906', (261, 266))	('G1 phase cell cycle arrest', 'CPA', (30, 56))	('Tca', 'Chemical', 'MESH:D014238', (60, 63))	('ZFX', 'Gene', '7543', (324, 327))	('ZFX', 'Gene', (8, 11))
243681	25916205	It has been demonstrated that cyclin D1 and cyclin E1 were essential for G1/S phase transition while cyclin A2 was involved in S-phase process, so it is quite likely that cyclin E1 or cyclin D1 function was disrupted in Tca-8113 cells by ZFX knockdown, which has been confirmed in SGC7901 cells, U87, and U373 cells treated with ZFX-siRNA.	('Tca', 'Chemical', 'MESH:D014238', (220, 223))	('cyclin D1', 'Gene', (184, 193))	('cyclin A2', 'Gene', (101, 110))	('SGC7901', 'CellLine', 'CVCL:0520', (281, 288))	('ZFX', 'Gene', '7543', (329, 332))	('cyclin E1', 'Gene', (44, 53))	('cyclin D1', 'Gene', '595', (184, 193))	('ZFX', 'Gene', (238, 241))	('knockdown', 'Var', (242, 251))	('cyclin A2', 'Gene', '890', (101, 110))	('ZFX', 'Gene', '7543', (238, 241))	('disrupted', 'NegReg', (207, 216))	('cyclin E1', 'Gene', '898', (171, 180))	('cyclin D1', 'Gene', (30, 39))	('cyclin E1', 'Gene', '898', (44, 53))	('U87', 'CellLine', 'CVCL:0022', (296, 299))	('ZFX', 'Gene', (329, 332))	('U373', 'CellLine', 'CVCL:2219', (305, 309))	('cyclin D1', 'Gene', '595', (30, 39))	('cyclin E1', 'Gene', (171, 180))
243701	33306121	In addition, with respect to the mutations of Fam20C gene lead to Raine syndrome, which is characterized by generalized osteosclerosis, periosteal bone formation, and a unique facial phenotype.	('Raine syndrome', 'Disease', 'MESH:C535282', (66, 80))	('osteosclerosis', 'Disease', 'MESH:D010026', (120, 134))	('osteosclerosis', 'Phenotype', 'HP:0011001', (120, 134))	('osteosclerosis', 'Disease', (120, 134))	('periosteal bone formation', 'Phenotype', 'HP:0031485', (136, 161))	('mutations', 'Var', (33, 42))	('lead to', 'Reg', (58, 65))	('Fam20C', 'Gene', '56975', (46, 52))	('Raine syndrome', 'Disease', (66, 80))	('Fam20C', 'Gene', (46, 52))	('generalized osteosclerosis', 'Phenotype', 'HP:0005789', (108, 134))
243762	33306121	In general, the expression of Fam20C showed a detrimental role in pan-cancer.	('Fam20C', 'Gene', (30, 36))	('expression', 'Var', (16, 26))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('Fam20C', 'Gene', '56975', (30, 36))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))
243765	33306121	Consequently, a strong association of the Fam20C high expression with worse OS, FP (first progression), and PPS (post-progression survival) in female and male patients was found.	('PPS', 'Disease', (108, 111))	('Fam20C', 'Gene', (42, 48))	('PPS', 'Disease', 'MESH:C562509', (108, 111))	('worse OS', 'Disease', (70, 78))	('high expression', 'Var', (49, 64))	('patients', 'Species', '9606', (159, 167))	('Fam20C', 'Gene', '56975', (42, 48))
243797	33306121	Macrophages secrete a large number of chemokines such as CC-like chemokines CCL22 and CCL20, which induce Tregs to recruit to the tumor site, similarly DCs also induce Treg generation, and then promote the metastasis of cancer cells.	('CCL20', 'Gene', '6364', (86, 91))	('promote', 'PosReg', (194, 201))	('induce', 'Reg', (161, 167))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('Tregs', 'Chemical', '-', (106, 111))	('DCs', 'Var', (152, 155))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('Treg', 'Chemical', '-', (106, 110))	('CCL22', 'Gene', '6367', (76, 81))	('cancer', 'Disease', 'MESH:D009369', (220, 226))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('Treg', 'Chemical', '-', (168, 172))	('CCL20', 'Gene', (86, 91))	('cancer', 'Disease', (220, 226))	('tumor', 'Disease', (130, 135))	('Treg generation', 'CPA', (168, 183))	('CCL22', 'Gene', (76, 81))
243807	33306121	Therefore, it is desirable to speculate that the expression of Fam20C may affect the survival of patients through the progression of tumor cells.	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('Fam20C', 'Gene', '56975', (63, 69))	('Fam20C', 'Gene', (63, 69))	('survival', 'CPA', (85, 93))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumor', 'Disease', (133, 138))	('affect', 'Reg', (74, 80))	('expression', 'Var', (49, 59))	('patients', 'Species', '9606', (97, 105))
243817	33306121	Here, we present an integrated study on the Fam20C expression levels in pan-cancer, the association of Fam20C variations with prognosis among different cancers and the potential mechanisms underlying different clinicopathological features.	('Fam20C', 'Gene', (44, 50))	('cancers', 'Disease', (152, 159))	('cancer', 'Disease', (152, 158))	('Fam20C', 'Gene', '56975', (103, 109))	('cancers', 'Disease', 'MESH:D009369', (152, 159))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('Fam20C', 'Gene', (103, 109))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('variations', 'Var', (110, 120))	('Fam20C', 'Gene', '56975', (44, 50))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('cancer', 'Disease', (76, 82))	('association', 'Interaction', (88, 99))	('cancers', 'Phenotype', 'HP:0002664', (152, 159))
243925	30421444	The TRA2B-DNAH5 fusion has been identified as a novel oncogenic driver in lung cancer.	('lung cancer', 'Disease', (74, 85))	('TRA2B', 'Gene', '6434', (4, 9))	('DNAH5', 'Gene', '1767', (10, 15))	('lung cancer', 'Phenotype', 'HP:0100526', (74, 85))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('lung cancer', 'Disease', 'MESH:D008175', (74, 85))	('TRA2B', 'Gene', (4, 9))	('fusion', 'Var', (16, 22))	('DNAH5', 'Gene', (10, 15))
243926	30421444	The top three genes that only have strong signals in stage I are DKFZP434B094, AK3, and ANKS1A.	('ANKS1A', 'Gene', (88, 94))	('DKFZP434B094', 'Var', (65, 77))	('AK3', 'Gene', (79, 82))	('ANKS1A', 'Gene', '23294', (88, 94))	('AK3', 'Gene', '50808', (79, 82))
243942	30421444	One genetic variant of CMLKLR1, rs1878022, is found to be significantly associated with poorer survival in advanced stage non-small cell lung cancer.	('rs1878022', 'Var', (32, 41))	('lung cancer', 'Phenotype', 'HP:0100526', (137, 148))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (122, 148))	('associated', 'Reg', (72, 82))	('rs1878022', 'Mutation', 'rs1878022', (32, 41))	('non-small cell lung cancer', 'Disease', (122, 148))	('CMLKLR1', 'Gene', (23, 30))	('poorer', 'NegReg', (88, 94))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (126, 148))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (122, 148))
243950	30421444	The genetic variant of BTBD3 is also found to be significantly associated with survival in non-small cell lung cancer patients.	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (91, 117))	('lung cancer', 'Phenotype', 'HP:0100526', (106, 117))	('non-small cell lung cancer', 'Disease', (91, 117))	('patients', 'Species', '9606', (118, 126))	('BTBD3', 'Gene', '22903', (23, 28))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (95, 117))	('associated with', 'Reg', (63, 78))	('genetic variant', 'Var', (4, 19))	('BTBD3', 'Gene', (23, 28))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (91, 117))
243958	28430625	Previous evidence suggests that post-transcriptional deregulation of p53 by microRNAs contributes to tumorigenesis, tumor progression and therapeutic resistance.	('microRNAs', 'Var', (76, 85))	('therapeutic resistance', 'CPA', (138, 160))	('p53', 'Gene', (69, 72))	('p53', 'Gene', '7157', (69, 72))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('contributes', 'Reg', (86, 97))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('deregulation', 'Var', (53, 65))	('tumor', 'Disease', (116, 121))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
243968	28430625	Indeed, mutation of this gene occurs in over 50% of cancers, enabling malignant cells to escape wild-type p53-dependent growth inhibition and cell death.	('p53', 'Gene', '7157', (106, 109))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('cancers', 'Disease', (52, 59))	('cancers', 'Phenotype', 'HP:0002664', (52, 59))	('enabling', 'PosReg', (61, 69))	('mutation', 'Var', (8, 16))	('p53', 'Gene', (106, 109))	('cancers', 'Disease', 'MESH:D009369', (52, 59))
243987	28430625	Compared to tumors with wild-type p53, miR-766 was elevated in mutant p53 tumor samples (Supplementary Figure 1A).	('p53', 'Gene', (34, 37))	('p53', 'Gene', '7157', (34, 37))	('mutant', 'Var', (63, 69))	('p53', 'Gene', (70, 73))	('p53', 'Gene', '7157', (70, 73))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('miR-766', 'Gene', '768218', (39, 46))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('tumor', 'Disease', (74, 79))	('elevated', 'PosReg', (51, 59))	('tumors', 'Disease', (12, 18))	('miR-766', 'Gene', (39, 46))	('tumor', 'Disease', (12, 17))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('tumors', 'Disease', 'MESH:D009369', (12, 18))
243988	28430625	More data was collected from TCGA across different cancer types (including hepatocellular carcinoma, lung squamous cell carcinoma, lung adenocarcinoma, colon adenocarcinoma, stomach adenocarcinoma and ovarian serous cystadenocarcinoma), and a trend of increased miR-766 expression in p53 mutant groups was found (Supplementary Figure 1B).	('lung adenocarcinoma', 'Disease', (131, 150))	('miR-766', 'Gene', '768218', (262, 269))	('colon adenocarcinoma', 'Disease', (152, 172))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (75, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('stomach adenocarcinoma', 'Disease', (174, 196))	('increased', 'PosReg', (252, 261))	('Supplementary Figure 1B', 'Disease', 'MESH:D017034', (313, 336))	('mutant', 'Var', (288, 294))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (131, 150))	('p53', 'Gene', '7157', (284, 287))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (75, 99))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (131, 150))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('expression', 'MPA', (270, 280))	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('miR-766', 'Gene', (262, 269))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (101, 129))	('cancer', 'Disease', (51, 57))	('Supplementary Figure 1B', 'Disease', (313, 336))	('p53', 'Gene', (284, 287))	('hepatocellular carcinoma', 'Disease', (75, 99))	('ovarian serous cystadenocarcinoma', 'Phenotype', 'HP:0012887', (201, 234))	('carcinoma', 'Phenotype', 'HP:0030731', (163, 172))	('carcinoma', 'Phenotype', 'HP:0030731', (187, 196))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (106, 129))	('lung squamous cell carcinoma', 'Disease', (101, 129))
243999	28430625	Conversely, inhibition of miR-766 using an LNA inhibitor increased cell proliferation and colony formation of SBC3 and U2OS cells (Figure 1E).	('U2OS', 'CellLine', 'CVCL:0042', (119, 123))	('inhibition', 'Var', (12, 22))	('miR-766', 'Gene', (26, 33))	('miR-766', 'Gene', '768218', (26, 33))	('increased', 'PosReg', (57, 66))	('cell proliferation', 'CPA', (67, 85))	('colony formation', 'CPA', (90, 106))
244003	28430625	We observed a significantly increased proportion of cells in G2 phase 48 hours after miR-766 mimic transfection in U2OS and SBC3 cells (Figure 2A).	('transfection', 'Var', (99, 111))	('increased', 'PosReg', (28, 37))	('cells', 'CPA', (52, 57))	('increased proportion of cells in G2 phase', 'Phenotype', 'HP:0003214', (28, 69))	('G2 phase', 'CPA', (61, 69))	('miR-766', 'Gene', '768218', (85, 92))	('U2OS', 'CellLine', 'CVCL:0042', (115, 119))	('miR-766', 'Gene', (85, 92))
244006	28430625	To detect molecular alterations in the p53 pathway associated with changes in miR-766 expression, we characterized the mRNA levels of GADD45A, SFN and GEST1 genes (as these genes are p53 downstream targets involved in cell cycle regulation) following transfection of miR-766 mimic.	('changes', 'Var', (67, 74))	('GADD45A', 'Gene', (134, 141))	('SFN', 'Gene', (143, 146))	('p53', 'Gene', (183, 186))	('p53', 'Gene', '7157', (183, 186))	('GEST1 genes', 'Gene', (151, 162))	('SFN', 'Gene', '25996', (143, 146))	('p53', 'Gene', (39, 42))	('p53', 'Gene', '7157', (39, 42))	('miR-766', 'Gene', '768218', (267, 274))	('miR-766', 'Gene', '768218', (78, 85))	('miR-766', 'Gene', (267, 274))	('miR-766', 'Gene', (78, 85))	('GADD45A', 'Gene', '1647', (134, 141))
244025	28430625	Consistent with our hypothesis, knockdown of MDM4 (Figure 4A) pheno-copied miR-766 over expression: more specifically, it induced significant cell growth repression (Figure 4B), decreased soft agar clonogenicity (Figure 4C) and caused an increase in G2/M phase cells (Figure 4D).	('MDM4', 'Gene', '4194', (45, 49))	('cell growth repression', 'CPA', (142, 164))	('G2/M phase cells', 'CPA', (250, 266))	('decreased', 'NegReg', (178, 187))	('increase', 'PosReg', (238, 246))	('MDM4', 'Gene', (45, 49))	('soft agar clonogenicity', 'CPA', (188, 211))	('induced', 'Reg', (122, 129))	('knockdown', 'Var', (32, 41))	('miR-766', 'Gene', '768218', (75, 82))	('agar', 'Chemical', 'MESH:D000362', (193, 197))	('miR-766', 'Gene', (75, 82))
244045	28430625	The frequency of p53 mutations in colorectal cancer is over 50%, and the cell line SW480 is p53 mutant.	('colorectal cancer', 'Phenotype', 'HP:0003003', (34, 51))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('colorectal cancer', 'Disease', (34, 51))	('SW480', 'CellLine', 'CVCL:0546', (83, 88))	('p53', 'Gene', (92, 95))	('colorectal cancer', 'Disease', 'MESH:D015179', (34, 51))	('p53', 'Gene', '7157', (92, 95))	('p53', 'Gene', (17, 20))	('p53', 'Gene', '7157', (17, 20))	('mutations', 'Var', (21, 30))
244049	28430625	The status of p53 and MDM4 was not specified in those studies but it is known that the frequency of p53 mutations is high in both cutaneous squamous cell carcinoma (40%-50%) and lung adenocarcinoma (63%).	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (178, 197))	('MDM4', 'Gene', (22, 26))	('cutaneous squamous cell carcinoma', 'Phenotype', 'HP:0006739', (130, 163))	('mutations', 'Var', (104, 113))	('MDM4', 'Gene', '4194', (22, 26))	('cutaneous squamous cell carcinoma', 'Disease', 'MESH:D002294', (130, 163))	('p53', 'Gene', (14, 17))	('p53', 'Gene', '7157', (14, 17))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (178, 197))	('carcinoma', 'Phenotype', 'HP:0030731', (154, 163))	('p53', 'Gene', '7157', (100, 103))	('lung adenocarcinoma', 'Disease', (178, 197))	('not specified', 'Species', '32644', (31, 44))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (140, 163))	('cutaneous squamous cell carcinoma', 'Disease', (130, 163))	('carcinoma', 'Phenotype', 'HP:0030731', (188, 197))	('p53', 'Gene', (100, 103))
244058	28430625	Thus, in contexts where MDM4 levels are low, or in mutant p53 tumors where the normal transactivation activities of p53 are compromised, miR-766 may potentially exhibit oncogenic behaviour.	('exhibit', 'Reg', (161, 168))	('p53', 'Gene', (116, 119))	('MDM4', 'Gene', '4194', (24, 28))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumors', 'Disease', (62, 68))	('mutant', 'Var', (51, 57))	('MDM4', 'Gene', (24, 28))	('tumors', 'Disease', 'MESH:D009369', (62, 68))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('p53', 'Gene', '7157', (116, 119))	('p53', 'Gene', (58, 61))	('miR-766', 'Gene', '768218', (137, 144))	('oncogenic behaviour', 'CPA', (169, 188))	('miR-766', 'Gene', (137, 144))	('p53', 'Gene', '7157', (58, 61))
244062	28430625	Thus, we speculate that in addition to the known mechanism of p53 stabalization via MDM2 due to its activation of DNA damage pathways, miR-766 is up-regulated and this also contributes to stabilization of p53 via modulation of MDM4.	('modulation', 'Var', (213, 223))	('MDM2', 'Gene', (84, 88))	('stabilization', 'MPA', (188, 201))	('p53', 'Gene', (205, 208))	('up-regulated', 'PosReg', (146, 158))	('DNA damage pathways', 'Pathway', (114, 133))	('MDM4', 'Gene', '4194', (227, 231))	('miR-766', 'Gene', '768218', (135, 142))	('stabalization', 'MPA', (66, 79))	('p53', 'Gene', '7157', (205, 208))	('MDM4', 'Gene', (227, 231))	('miR-766', 'Gene', (135, 142))	('activation', 'PosReg', (100, 110))	('p53', 'Gene', (62, 65))	('p53', 'Gene', '7157', (62, 65))	('MDM2', 'Gene', '4193', (84, 88))
244091	28418860	ROC1 knockdown significantly inhibited the growth of esophageal cancer cells in vitro and in vivo.	('inhibited', 'NegReg', (29, 38))	('ROC1', 'Gene', (0, 4))	('knockdown', 'Var', (5, 14))	('esophageal cancer', 'Disease', (53, 70))	('ROC1', 'Gene', '9978', (0, 4))	('growth', 'CPA', (43, 49))	('esophageal cancer', 'Disease', 'MESH:D004938', (53, 70))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
244092	28418860	Mechanistically, ROC1 silencing induced G2 cell cycle arrest and triggered apoptosis by accumulating the pro-apoptotic protein NOXA.	('arrest', 'Disease', (54, 60))	('apoptosis', 'CPA', (75, 84))	('ROC1', 'Gene', '9978', (17, 21))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (43, 60))	('silencing', 'Var', (22, 31))	('arrest', 'Disease', 'MESH:D006323', (54, 60))	('accumulating', 'PosReg', (88, 100))	('NOXA', 'Gene', (127, 131))	('ROC1', 'Gene', (17, 21))	('NOXA', 'Gene', '5366', (127, 131))
244093	28418860	Consistently, the downregulation of NOXA expression via siRNA substantially attenuated apoptosis induced by ROC1 silencing.	('ROC1', 'Gene', (108, 112))	('expression', 'MPA', (41, 51))	('attenuated', 'NegReg', (76, 86))	('NOXA', 'Gene', (36, 40))	('apoptosis', 'CPA', (87, 96))	('NOXA', 'Gene', '5366', (36, 40))	('silencing', 'Var', (113, 122))	('ROC1', 'Gene', '9978', (108, 112))	('downregulation', 'NegReg', (18, 32))
244100	28418860	Dysfunction of ROC1 induced embryonic death and abnormal meiosis.	('abnormal meiosis', 'Disease', (48, 64))	('embryonic death', 'Disease', (28, 43))	('ROC1', 'Gene', '9978', (15, 19))	('Dysfunction', 'Var', (0, 11))	('ROC1', 'Gene', (15, 19))	('embryonic death', 'Disease', 'MESH:D003643', (28, 43))	('induced', 'Reg', (20, 27))	('abnormal meiosis', 'Disease', 'MESH:C536875', (48, 64))	('abnormal meiosis', 'Phenotype', 'HP:0031515', (48, 64))
244105	28418860	These findings revealed the detailed mechanism for proliferation-inhibition effect of ROC1 knockdown and suggested that ROC1 was an appealing drug target for esophageal cancer.	('ROC1', 'Gene', (86, 90))	('esophageal cancer', 'Disease', 'MESH:D004938', (158, 175))	('knockdown', 'Var', (91, 100))	('proliferation-inhibition', 'CPA', (51, 75))	('ROC1', 'Gene', '9978', (120, 124))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('ROC1', 'Gene', '9978', (86, 90))	('ROC1', 'Gene', (120, 124))	('esophageal cancer', 'Disease', (158, 175))
244109	28418860	To further assess the role of ROC1 on cell proliferation of esophageal cancer, ROC1 was knockdown by two specific siRNA oligoes, named siROC1-1 and siROC1-2.	('ROC1', 'Gene', (79, 83))	('ROC1', 'Gene', (150, 154))	('ROC1', 'Gene', '9978', (137, 141))	('ROC1', 'Gene', '9978', (30, 34))	('knockdown', 'Var', (88, 97))	('ROC1', 'Gene', '9978', (150, 154))	('esophageal cancer', 'Disease', (60, 77))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('ROC1', 'Gene', (137, 141))	('ROC1', 'Gene', '9978', (79, 83))	('esophageal cancer', 'Disease', 'MESH:D004938', (60, 77))	('ROC1', 'Gene', (30, 34))
244110	28418860	Results showed that ROC1 silencing significantly inhibited cell proliferation of both Kyse450 and TE1 cells (Figure 2A-2C).	('silencing', 'Var', (25, 34))	('inhibited', 'NegReg', (49, 58))	('cell proliferation', 'CPA', (59, 77))	('ROC1', 'Gene', '9978', (20, 24))	('ROC1', 'Gene', (20, 24))
244111	28418860	Besides, knockdown of ROC1 also effectively inhibited the cell colony formation in both cell lines (Figure 2D and 2E).	('knockdown', 'Var', (9, 18))	('ROC1', 'Gene', '9978', (22, 26))	('inhibited', 'NegReg', (44, 53))	('ROC1', 'Gene', (22, 26))	('cell colony formation in', 'CPA', (58, 82))
244114	28418860	As shown in Figure 3A, knockdown of ROC1 triggered G2/M cell cycle arrest in both Kyse450 and TE1 cells.	('ROC1', 'Gene', '9978', (36, 40))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (56, 73))	('arrest', 'Disease', 'MESH:D006323', (67, 73))	('knockdown', 'Var', (23, 32))	('ROC1', 'Gene', (36, 40))	('arrest', 'Disease', (67, 73))
244115	28418860	Furthermore, ROC1 silencing induced significant accumulation of WEE1, an inhibitor of G2-M phase transition, while a decrease of p-H3, a hallmark of M phase cells, indicating that ROC1-silencing cells were arrested at the G2 phase (Figure 3B).	('silencing', 'Var', (18, 27))	('ROC1', 'Gene', (13, 17))	('ROC1', 'Gene', (180, 184))	('arrest', 'Disease', (206, 212))	('accumulation', 'PosReg', (48, 60))	('ROC1', 'Gene', '9978', (13, 17))	('WEE1', 'Gene', (64, 68))	('WEE1', 'Gene', '7465', (64, 68))	('decrease', 'NegReg', (117, 125))	('p-H3', 'MPA', (129, 133))	('arrest', 'Disease', 'MESH:D006323', (206, 212))	('ROC1', 'Gene', '9978', (180, 184))
244116	28418860	Next we examined whether apoptosis was also responsible for the anti-proliferative effects of ROC1 silencing.	('ROC1', 'Gene', '9978', (94, 98))	('ROC1', 'Gene', (94, 98))	('silencing', 'Var', (99, 108))
244117	28418860	Results showed that knockdown of ROC1 led to a significant increase in Annexin V-positive cells (Figure 4A) and caspase-3-actived cells (Figure 4B).	('ROC1', 'Gene', '9978', (33, 37))	('ROC1', 'Gene', (33, 37))	('caspase-3', 'Gene', (112, 121))	('knockdown', 'Var', (20, 29))	('Annexin V', 'Gene', (71, 80))	('Annexin V', 'Gene', '308', (71, 80))	('caspase-3', 'Gene', '836', (112, 121))	('increase', 'PosReg', (59, 67))
244119	28418860	Furthermore, we found that knockdown of ROC1 led to the loss of mitochondrial membrane potential (DeltaPsim) (Figure 5A), a classical marker of the activation of intrinsic apoptosis, which suggested that knockdown of ROC1 triggered mitochondrial apoptosis.	('ROC1', 'Gene', (217, 221))	('knockdown', 'Var', (27, 36))	('ROC1', 'Gene', '9978', (40, 44))	('knockdown', 'Var', (204, 213))	('loss', 'NegReg', (56, 60))	('ROC1', 'Gene', (40, 44))	('ROC1', 'Gene', '9978', (217, 221))	('mitochondrial apoptosis', 'CPA', (232, 255))
244120	28418860	To explore the potential mechanism of apoptosis, we investigated systematically the effect of ROC1 knockdown on the expression of the pro-apoptotic and anti-apoptotic proteins.	('ROC1', 'Gene', '9978', (94, 98))	('knockdown', 'Var', (99, 108))	('ROC1', 'Gene', (94, 98))
244123	28418860	NOXA knockdown significantly reduced the induction of apoptosis (Figure 6A) and the cleavage of PARP in ROC1-silencing cells (Figure 6B).	('apoptosis', 'CPA', (54, 63))	('NOXA', 'Gene', (0, 4))	('cleavage', 'MPA', (84, 92))	('NOXA', 'Gene', '5366', (0, 4))	('ROC1', 'Gene', (104, 108))	('knockdown', 'Var', (5, 14))	('PARP', 'Gene', (96, 100))	('reduced', 'NegReg', (29, 36))	('ROC1', 'Gene', '9978', (104, 108))	('PARP', 'Gene', '142', (96, 100))
244125	28418860	After demonstrating the inhibition efficacy of ROC1 silencing in vitro, we further investigated the growth-suppressive effect of ROC1 knockdown in subcutaneous-transplantation tumor model of human esophageal cancer in mice.	('esophageal cancer', 'Disease', 'MESH:D004938', (197, 214))	('ROC1', 'Gene', '9978', (129, 133))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('silencing', 'Var', (52, 61))	('ROC1', 'Gene', '9978', (47, 51))	('tumor', 'Disease', (176, 181))	('ROC1', 'Gene', (129, 133))	('knockdown', 'Var', (134, 143))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('growth-suppressive', 'MPA', (100, 118))	('ROC1', 'Gene', (47, 51))	('human', 'Species', '9606', (191, 196))	('esophageal cancer', 'Disease', (197, 214))	('mice', 'Species', '10090', (218, 222))	('tumor', 'Disease', 'MESH:D009369', (176, 181))
244126	28418860	Results showed that ROC1 silencing significantly suppressed tumor growth over time while control tumors grew rapidly, as revealed by the tumor growth curve (Figure 7A, **P<0.01), tumor size (Figure 7B, top panel) and tumor weight analysis (Figure 7B, bottom panel, **P<0.01).	('silencing', 'Var', (25, 34))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('suppressed', 'NegReg', (49, 59))	('tumors', 'Disease', (97, 103))	('tumor', 'Disease', (60, 65))	('ROC1', 'Gene', (20, 24))	('tumor', 'Disease', (217, 222))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Disease', (97, 102))	('tumor', 'Disease', 'MESH:D009369', (217, 222))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('tumors', 'Disease', 'MESH:D009369', (97, 103))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor', 'Disease', (137, 142))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('ROC1', 'Gene', '9978', (20, 24))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('tumor', 'Disease', (179, 184))
244128	28418860	As shown in Figure 7C, ROC1 was effectively downregulated and the expression of NOXA and cleaved PARP were significantly induced upon ROC1 silencing.	('PARP', 'Gene', '142', (97, 101))	('downregulated', 'NegReg', (44, 57))	('ROC1', 'Gene', '9978', (23, 27))	('NOXA', 'Gene', (80, 84))	('silencing', 'Var', (139, 148))	('expression', 'MPA', (66, 76))	('ROC1', 'Gene', '9978', (134, 138))	('induced', 'PosReg', (121, 128))	('NOXA', 'Gene', '5366', (80, 84))	('PARP', 'Gene', (97, 101))	('ROC1', 'Gene', (23, 27))	('ROC1', 'Gene', (134, 138))
244129	28418860	These observations indicated that ROC1 silencing inhibited esophageal tumor growth both in vitro and in vivo by accumulating the expression of NOXA.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('expression', 'MPA', (129, 139))	('inhibited', 'NegReg', (49, 58))	('esophageal tumor', 'Disease', 'MESH:D004938', (59, 75))	('ROC1', 'Gene', '9978', (34, 38))	('esophageal tumor', 'Disease', (59, 75))	('silencing', 'Var', (39, 48))	('NOXA', 'Gene', (143, 147))	('esophageal tumor', 'Phenotype', 'HP:0100751', (59, 75))	('accumulating', 'PosReg', (112, 124))	('ROC1', 'Gene', (34, 38))	('NOXA', 'Gene', '5366', (143, 147))
244131	28418860	Results showed that ROC1 silencing significantly enhanced the cytotoxity of CDDP and inhibited cell viability (Figure 8A).	('silencing', 'Var', (25, 34))	('cytotoxity', 'Disease', 'MESH:D064420', (62, 72))	('inhibited', 'NegReg', (85, 94))	('enhanced', 'PosReg', (49, 57))	('CDDP', 'Chemical', 'MESH:D002945', (76, 80))	('cytotoxity', 'Disease', (62, 72))	('ROC1', 'Gene', '9978', (20, 24))	('ROC1', 'Gene', (20, 24))	('cell viability', 'CPA', (95, 109))
244132	28418860	Moreover, knockdown of ROC1 significantly enhanced CDDP-induced apoptosis, which is evident by the increased expression of cleaved-PARP (Figure 8B).	('CDDP', 'Chemical', 'MESH:D002945', (51, 55))	('expression', 'MPA', (109, 119))	('PARP', 'Gene', '142', (131, 135))	('ROC1', 'Gene', '9978', (23, 27))	('enhanced', 'PosReg', (42, 50))	('increased', 'PosReg', (99, 108))	('ROC1', 'Gene', (23, 27))	('knockdown', 'Var', (10, 19))	('PARP', 'Gene', (131, 135))	('CDDP-induced', 'Disease', (51, 63))
244134	28418860	RBX1/ROC1 disruption results in early embryonic lethality, cancer cell death or the inhibition of tumor cell migration.	('RBX1', 'Gene', '9978', (0, 4))	('inhibition', 'NegReg', (84, 94))	('ROC1', 'Gene', '9978', (5, 9))	('disruption', 'Var', (10, 20))	('embryonic lethality', 'Disease', 'MESH:D020964', (38, 57))	('embryonic lethality', 'Disease', (38, 57))	('cancer cell death', 'Disease', 'MESH:D003643', (59, 76))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('RBX1', 'Gene', (0, 4))	('ROC1', 'Gene', (5, 9))	('tumor', 'Disease', (98, 103))	('cancer cell death', 'Disease', (59, 76))
244136	28418860	Moreover, knockdown of ROC1 significantly inhibited cell proliferation in vitro and in vivo, and enhanced the cytotoxity of CDDP to ESCC cells.	('cytotoxity', 'Disease', 'MESH:D064420', (110, 120))	('cell proliferation', 'CPA', (52, 70))	('ROC1', 'Gene', '9978', (23, 27))	('CDDP', 'Chemical', 'MESH:D002945', (124, 128))	('enhanced', 'PosReg', (97, 105))	('inhibited', 'NegReg', (42, 51))	('ROC1', 'Gene', (23, 27))	('cytotoxity', 'Disease', (110, 120))	('knockdown', 'Var', (10, 19))
244138	28418860	Previous reports showed that knockdown of ROC1 destroy CRL/SCF complexes and thus disrupt CRL/SCF E3 ligase activity.	('SCF', 'Gene', (94, 97))	('CRL', 'Gene', '133396', (90, 93))	('ROC1', 'Gene', (42, 46))	('SCF', 'Gene', '4254', (59, 62))	('activity', 'MPA', (108, 116))	('knockdown', 'Var', (29, 38))	('SCF', 'Gene', '4254', (94, 97))	('CRL', 'Gene', (55, 58))	('CRL', 'Gene', (90, 93))	('ROC1', 'Gene', '9978', (42, 46))	('destroy', 'NegReg', (47, 54))	('CRL', 'Gene', '133396', (55, 58))	('SCF', 'Gene', (59, 62))	('disrupt', 'NegReg', (82, 89))
244140	28418860	In terms of apoptosis induction, Jia's finding showed that proapoptotic protein PUMA are involved in RBX1 (ROC1) silencing-induced apoptosis, whereas NOXA is associated with RBX2 silencing.	('NOXA', 'Gene', (150, 154))	('NOXA', 'Gene', '5366', (150, 154))	('RBX2', 'Gene', (174, 178))	('involved', 'Reg', (89, 97))	('RBX1', 'Gene', '9978', (101, 105))	('RBX2', 'Gene', '9616', (174, 178))	('ROC1', 'Gene', (107, 111))	('silencing-induced', 'Var', (113, 130))	('apoptosis', 'CPA', (131, 140))	('RBX1', 'Gene', (101, 105))	('ROC1', 'Gene', '9978', (107, 111))
244141	28418860	Here we found that knockdown of ROC1 led to the accumulation of NOXA and NOXA knockdown afforded significant protection against apoptosis, implying that NOXA also play an important role in ROC1 silencing-induced apoptosis for ESCC cells.	('ROC1', 'Gene', (189, 193))	('NOXA', 'Gene', (73, 77))	('silencing-induced', 'Var', (194, 211))	('knockdown', 'Var', (19, 28))	('ROC1', 'Gene', (32, 36))	('knockdown', 'Var', (78, 87))	('accumulation', 'PosReg', (48, 60))	('NOXA', 'Gene', (153, 157))	('NOXA', 'Gene', '5366', (73, 77))	('NOXA', 'Gene', (64, 68))	('ROC1', 'Gene', '9978', (189, 193))	('NOXA', 'Gene', '5366', (153, 157))	('NOXA', 'Gene', '5366', (64, 68))	('apoptosis', 'CPA', (128, 137))	('ROC1', 'Gene', '9978', (32, 36))
244146	28418860	Treatment ESCC or acute myelogenous leukemia cells with MLN4924, a neddylation inhibitor, lead to inactivation of CRL/SCF E3 ubiquitin ligase and transactivation of NOXA in a cell-type-specific manner to induce cell apoptosis.	('cell apoptosis', 'CPA', (211, 225))	('myelogenous leukemia', 'Phenotype', 'HP:0012324', (24, 44))	('SCF', 'Gene', '4254', (118, 121))	('acute myelogenous leukemia', 'Phenotype', 'HP:0004808', (18, 44))	('myelogenous leukemia', 'Disease', (24, 44))	('inactivation', 'NegReg', (98, 110))	('SCF', 'Gene', (118, 121))	('E3 ubiquitin ligase', 'Gene', '79594', (122, 141))	('CRL', 'Gene', (114, 117))	('leukemia', 'Phenotype', 'HP:0001909', (36, 44))	('MLN4924', 'Var', (56, 63))	('myelogenous leukemia', 'Disease', 'MESH:D007951', (24, 44))	('induce', 'PosReg', (204, 210))	('CRL', 'Gene', '133396', (114, 117))	('E3 ubiquitin ligase', 'Gene', (122, 141))	('NOXA', 'Gene', '5366', (165, 169))	('transactivation', 'MPA', (146, 161))	('NOXA', 'Gene', (165, 169))	('MLN4924', 'Chemical', 'MESH:C539933', (56, 63))
244170	28418860	ROC1 regulator of Cullins-1 EC Esophageal cancer ESCC Esophageal squamous cell carcinoma RBX1 RING box protein-1 IHC immunohistochemistry CDDP cisplatin UPS ubiquitin proteasome system TNM tumor-node-metastasis MMP mitochondrial membrane potential S.D.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (65, 88))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('ROC1', 'Gene', '9978', (0, 4))	('CDDP', 'Var', (138, 142))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('RING box protein-1', 'Gene', '9978', (94, 112))	('tumor-node-metastasis', 'Disease', (189, 210))	('regulator of Cullins-1', 'Gene', (5, 27))	('tumor-node-metastasis', 'Disease', 'MESH:D009362', (189, 210))	('Esophageal squamous cell carcinoma', 'Disease', (54, 88))	('cancer ESCC Esophageal squamous cell carcinoma', 'Phenotype', 'HP:0011459', (42, 88))	('regulator of Cullins-1', 'Gene', '9978', (5, 27))	('RBX1', 'Gene', '9978', (89, 93))	('cisplatin', 'Chemical', 'MESH:D002945', (143, 152))	('Esophageal cancer', 'Disease', (31, 48))	('CDDP', 'Chemical', 'MESH:D002945', (138, 142))	('RING box protein-1', 'Gene', (94, 112))	('UPS', 'Disease', (153, 156))	('ROC1', 'Gene', (0, 4))	('UPS', 'Disease', 'MESH:D017118', (153, 156))	('Esophageal cancer', 'Disease', 'MESH:D004938', (31, 48))	('RBX1', 'Gene', (89, 93))	('Esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (54, 88))
244176	28160555	A total of 9,947 participants across 40 cohorts, followed-up for about 5 years on average, were analyzed comparing patients showing SALL4 presence (SALL4+, n = 1,811) or absence (SALL4-, n = 8,136).	('presence', 'Var', (138, 146))	('patients', 'Species', '9606', (115, 123))	('SALL4', 'Gene', (132, 137))	('SALL4', 'Gene', '57167', (179, 184))	('participants', 'Species', '9606', (17, 29))	('SALL4', 'Gene', (179, 184))	('SALL4', 'Gene', '57167', (148, 153))	('SALL4', 'Gene', '57167', (132, 137))	('SALL4', 'Gene', (148, 153))
244180	28160555	These results suggest that SALL4 expression increases both mortality and recurrence of cancer, confirming this gene as an important prognostic marker and a potential target for personalized medicine.	('recurrence', 'CPA', (73, 83))	('cancer', 'Disease', (87, 93))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('expression', 'Var', (33, 43))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('SALL4', 'Gene', '57167', (27, 32))	('mortality', 'CPA', (59, 68))	('SALL4', 'Gene', (27, 32))	('increases', 'PosReg', (44, 53))
244181	28160555	The stem-like phenotype in cancer is the result of epigenetic and genetic alterations leading to the expression of genes involved in cell migration, invasion, angiogenesis, self-renewal, anti-apoptosis, and immune-escape, which are fundamental for the embryo-fetal development.	('epigenetic', 'Var', (51, 61))	('cell migration', 'CPA', (133, 147))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('immune-escape', 'CPA', (207, 220))	('anti-apoptosis', 'CPA', (187, 201))	('stem-like phenotype', 'CPA', (4, 23))	('angiogenesis', 'CPA', (159, 171))	('cancer', 'Disease', (27, 33))	('cancer', 'Disease', 'MESH:D009369', (27, 33))	('expression', 'MPA', (101, 111))	('genetic alterations', 'Var', (66, 85))	('self-renewal', 'CPA', (173, 185))	('leading', 'Reg', (86, 93))	('invasion', 'CPA', (149, 157))
244197	28160555	The presence of SALL4 resulted significantly associated with higher death rate (55.2% SALL4+ vs. 39.8% SALL4- on average, RR=1.34; 95%CI: 1.21-1.48, p<0.0001; I2=66%) (Figure 1a).	('SALL4', 'Gene', (16, 21))	('death', 'Disease', 'MESH:D003643', (68, 73))	('higher', 'PosReg', (61, 67))	('death', 'Disease', (68, 73))	('SALL4', 'Gene', '57167', (86, 91))	('SALL4', 'Gene', '57167', (103, 108))	('presence', 'Var', (4, 12))	('SALL4', 'Gene', (86, 91))	('SALL4', 'Gene', (103, 108))	('SALL4', 'Gene', '57167', (16, 21))
244207	28160555	Homozygous loss-of function mutation of SALL4 are lethal for the embryo, while heterozygous mutations cause renal-ocular syndrome and the Okihiro syndrome, associated with multi limbs defects, deficient eye movements, renal malformations, and deafness.	('renal malformations', 'Disease', (218, 237))	('loss-of function', 'NegReg', (11, 27))	('SALL4', 'Gene', '57167', (40, 45))	('renal-ocular syndrome and the Okihiro syndrome', 'Disease', 'MESH:D004370', (108, 154))	('multi limbs defects', 'Disease', 'MESH:D015140', (172, 191))	('SALL4', 'Gene', (40, 45))	('deficient eye movements', 'Disease', (193, 216))	('deafness', 'Disease', 'MESH:D003638', (243, 251))	('mutation', 'Var', (28, 36))	('multi limbs defects', 'Disease', (172, 191))	('renal malformations', 'Disease', 'MESH:D007674', (218, 237))	('deafness', 'Phenotype', 'HP:0000365', (243, 251))	('deficient eye movements', 'Disease', 'MESH:D015835', (193, 216))	('deafness', 'Disease', (243, 251))	('renal malformations', 'Phenotype', 'HP:0012210', (218, 237))
244213	28160555	Epigenetic regulation of SALL4 has also been proposed, but it needs further confirmation.	('Epigenetic regulation', 'Var', (0, 21))	('SALL4', 'Gene', '57167', (25, 30))	('SALL4', 'Gene', (25, 30))
244216	28160555	In cancers where aberrantly reactivated, SALL4 has been associated with the expression of many stemness-related genes (i.e.	('stemness-related genes', 'Gene', (95, 117))	('cancers', 'Phenotype', 'HP:0002664', (3, 10))	('associated', 'Reg', (56, 66))	('SALL4', 'Gene', '57167', (41, 46))	('cancers', 'Disease', (3, 10))	('expression', 'MPA', (76, 86))	('cancers', 'Disease', 'MESH:D009369', (3, 10))	('aberrantly', 'Var', (17, 27))	('SALL4', 'Gene', (41, 46))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
244224	28160555	Results showed that the expression of SALL4 was significantly associated with increased cancer mortality and recurrence, also after adjusting for potential confounders in the survival analyses.	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('associated', 'Reg', (62, 72))	('SALL4', 'Gene', '57167', (38, 43))	('recurrence', 'CPA', (109, 119))	('increased', 'PosReg', (78, 87))	('SALL4', 'Gene', (38, 43))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('expression', 'Var', (24, 34))
244239	28160555	Despite these limitations, our meta-analysis suggests that SALL4 expression shortens overall survival as well as increases the rate of recurrences, even taking in consideration potential confounders.	('shortens', 'NegReg', (76, 84))	('SALL4', 'Gene', '57167', (59, 64))	('SALL4', 'Gene', (59, 64))	('overall survival', 'MPA', (85, 101))	('increases', 'PosReg', (113, 122))	('expression', 'Var', (65, 75))	('recurrences', 'MPA', (135, 146))
244240	28160555	Since many epithelial cancers are characterized by SALL4 reactivation, this gene should be considered for developing future targeted therapeutic strategies.	('cancers', 'Phenotype', 'HP:0002664', (22, 29))	('epithelial cancers', 'Disease', 'MESH:D000077216', (11, 29))	('reactivation', 'Var', (57, 69))	('SALL4', 'Gene', '57167', (51, 56))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('epithelial cancers', 'Disease', (11, 29))	('SALL4', 'Gene', (51, 56))
244242	28160555	Two investigators independently conducted a literature search using PubMed and SCOPUS with no language restriction, from database inception to 1st September 2016, for perspective studies comparing relevant outcomes (i.e., all-cause mortality, cancer mortality and recurrence of disease/cancer) in patients with a diagnosis of cancer with loss vs. presence of expression of SALL4.	('loss', 'NegReg', (338, 342))	('patients', 'Species', '9606', (297, 305))	('cancer', 'Phenotype', 'HP:0002664', (286, 292))	('SALL4', 'Gene', '57167', (373, 378))	('cancer', 'Disease', (243, 249))	('cancer', 'Disease', 'MESH:D009369', (243, 249))	('cancer', 'Disease', 'MESH:D009369', (326, 332))	('cancer', 'Disease', (326, 332))	('SALL4', 'Gene', (373, 378))	('cancer', 'Disease', 'MESH:D009369', (286, 292))	('cancer', 'Phenotype', 'HP:0002664', (243, 249))	('presence of', 'Var', (347, 358))	('cancer', 'Disease', (286, 292))	('cancer', 'Phenotype', 'HP:0002664', (326, 332))
244253	28160555	SALL4 expression was classified in a binary way: one class of patients was identified by the presence of SALL4 (SALL4+) according to an over-expression quantified by a z-score>=2 and the other class was characterized by samples reporting a z-score<2 (SALL4-).	('SALL4', 'Gene', '57167', (112, 117))	('SALL4', 'Gene', '57167', (105, 110))	('presence', 'Var', (93, 101))	('SALL4', 'Gene', (105, 110))	('SALL4', 'Gene', '57167', (0, 5))	('SALL4', 'Gene', (112, 117))	('SALL4', 'Gene', '57167', (251, 256))	('SALL4', 'Gene', (0, 5))	('SALL4', 'Gene', (251, 256))	('over-expression', 'PosReg', (136, 151))	('patients', 'Species', '9606', (62, 70))
244394	26425690	IL-6 levels have previously been shown to be associated with lung toxicity and so it would be interesting to see if CRP and LRG1 modulation in plasma could indicate radiotherapy linked toxicity.	('indicate', 'Reg', (156, 164))	('LRG1', 'Gene', '116844', (124, 128))	('LRG1', 'Gene', (124, 128))	('lung toxicity', 'Disease', (61, 74))	('toxicity', 'Disease', 'MESH:D064420', (185, 193))	('toxicity', 'Disease', (185, 193))	('associated', 'Reg', (45, 55))	('IL-6', 'Gene', (0, 4))	('toxicity', 'Disease', 'MESH:D064420', (66, 74))	('CRP', 'Gene', (116, 119))	('toxicity', 'Disease', (66, 74))	('IL-6', 'Gene', '3569', (0, 4))	('modulation', 'Var', (129, 139))	('CRP', 'Gene', '1401', (116, 119))	('lung toxicity', 'Disease', 'MESH:D008171', (61, 74))
244397	26425690	Wang and colleagues have also shown that angiogenesis can be reduced by the inhibition of LRG1 and so it is a possible therapeutic target for regulation of angiogenesis.	('LRG1', 'Gene', '116844', (90, 94))	('LRG1', 'Gene', (90, 94))	('angiogenesis', 'CPA', (41, 53))	('inhibition', 'Var', (76, 86))	('reduced', 'NegReg', (61, 68))
244502	26352260	The effects of those alterations on the fitness of somatic cells lead to evolutionary adaptations such as increased cell proliferation, angiogenesis, and altered anticancer drug responses.	('cancer', 'Disease', (166, 172))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('alterations', 'Var', (21, 32))	('angiogenesis', 'CPA', (136, 148))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('increased', 'PosReg', (106, 115))	('altered', 'Reg', (154, 161))	('cell proliferation', 'CPA', (116, 134))
244505	26352260	We found that somatic mutations of a cancer driver gene may drive cancer genome evolution by inducing mutations in other genes.	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('drive', 'Reg', (60, 65))	('cancer', 'Disease', (37, 43))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('mutations', 'MPA', (102, 111))	('inducing', 'Reg', (93, 101))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('mutations', 'Var', (22, 31))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('cancer', 'Disease', (66, 72))
244507	26352260	The tumor genomes harboring the nonsynonymous somatic mutations in these genes had a higher mutation density at the genome level compared to the wild-type groups.	('tumor', 'Disease', (4, 9))	('mutation density', 'MPA', (92, 108))	('higher', 'PosReg', (85, 91))	('nonsynonymous somatic mutations', 'Var', (32, 63))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))
244508	26352260	Furthermore, we provided statistical evidence that hypermutation of cancer driver genes on inactive X chromosomes is a general feature in female cancer genomes.	('hypermutation', 'Var', (51, 64))	('cancer', 'Disease', (145, 151))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('cancer', 'Disease', (68, 74))	('cancer', 'Disease', 'MESH:D009369', (145, 151))
244509	26352260	In summary, this study sheds light on the functional consequences and evolutionary characteristics of somatic mutations during tumorigenesis by propelling adaptive cancer genome evolution, which would provide new perspectives for cancer research and therapeutics.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('mutations', 'Var', (110, 119))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('tumor', 'Disease', (127, 132))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('cancer', 'Disease', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('propelling', 'PosReg', (144, 154))	('cancer', 'Disease', (230, 236))	('cancer', 'Disease', 'MESH:D009369', (230, 236))	('tumor', 'Disease', 'MESH:D009369', (127, 132))
244514	26352260	We found that cancer driver genes may shape somatic genome evolution by inducing mutations in other genes in cancer.	('cancer', 'Disease', (14, 20))	('shape', 'Reg', (38, 43))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('cancer', 'Disease', (109, 115))	('inducing', 'Reg', (72, 80))	('mutations', 'Var', (81, 90))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('cancer', 'Disease', 'MESH:D009369', (14, 20))
244515	26352260	Moreover, we provided statistical evidence that hypermutation of cancer driver genes on inactive X chromosomes is a general feature in female cancer genomes and found a putative X-inactive specific gene STAG2 in uterine cancer.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('STAG2', 'Gene', (203, 208))	('STAG2', 'Gene', '10735', (203, 208))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (220, 226))	('cancer', 'Disease', (220, 226))	('cancer', 'Disease', (65, 71))	('hypermutation', 'Var', (48, 61))	('uterine cancer', 'Phenotype', 'HP:0010784', (212, 226))	('cancer', 'Disease', (142, 148))
244516	26352260	In summary, this work illustrates the functional consequences and evolutionary characteristics of somatic mutations during tumorigenesis through driving adaptive cancer genome evolution.	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('driving', 'Reg', (145, 152))	('tumor', 'Disease', (123, 128))	('cancer', 'Disease', (162, 168))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('mutations', 'Var', (106, 115))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
244517	26352260	Cancer development and progression are mediated by the accumulation of genomic alterations, including point mutations, insertions and deletions, gene fusions, amplifications, and chromosomal rearrangements.	('insertions', 'Var', (119, 129))	('mediated', 'Reg', (39, 47))	('deletions', 'Var', (134, 143))	('point mutations', 'Var', (102, 117))	('progression', 'CPA', (23, 34))	('gene fusions', 'Var', (145, 157))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('amplifications', 'Var', (159, 173))	('chromosomal rearrangements', 'Var', (179, 205))
244518	26352260	The majority of the somatic mutations found in tumor cells are 'passenger' rather than 'driver' mutations.	('mutations', 'Var', (28, 37))	('tumor', 'Disease', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor', 'Disease', 'MESH:D009369', (47, 52))
244521	26352260	He also noted that genetic instability, occurring in tumor cells during disease progression, might enhance this process.	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('genetic instability', 'Var', (19, 38))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Disease', (53, 58))	('enhance', 'PosReg', (99, 106))
244525	26352260	found that in yeast a mutation on a single gene may cause genomic instability, leading to adaptive genetic changes.	('mutation', 'Var', (22, 30))	('genomic instability', 'MPA', (58, 77))	('adaptive genetic changes', 'CPA', (90, 114))	('cause', 'Reg', (52, 57))	('yeast', 'Species', '4932', (14, 19))	('leading to', 'Reg', (79, 89))
244527	26352260	found an amplification of PIP4K2B in HER-2/Neu-positive breast cancer with its co-occurrence with mutations in TP53.	('amplification', 'Reg', (9, 22))	('PIP4K2B', 'Gene', '8396', (26, 33))	('HER-2', 'Gene', '2064', (37, 42))	('Neu', 'Gene', (43, 46))	('TP53', 'Gene', '7157', (111, 115))	('Neu', 'Gene', '2064', (43, 46))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('HER-2', 'Gene', (37, 42))	('TP53', 'Gene', (111, 115))	('mutations', 'Var', (98, 107))	('PIP4K2B', 'Gene', (26, 33))	('breast cancer', 'Disease', 'MESH:D001943', (56, 69))	('breast cancer', 'Phenotype', 'HP:0003002', (56, 69))	('breast cancer', 'Disease', (56, 69))
244529	26352260	found that POLR2A (encoding the largest and catalytic subunit of the RNA polymerase II complex) was deleted together with TP53 in cancer cell lines and primary tumors in human colon cancer.	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('colon cancer', 'Phenotype', 'HP:0003003', (176, 188))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('POLR2A', 'Gene', '5430', (11, 17))	('cancer', 'Disease', (182, 188))	('primary tumors', 'Disease', (152, 166))	('colon cancer', 'Disease', 'MESH:D015179', (176, 188))	('POLR2A', 'Gene', (11, 17))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('TP53', 'Gene', (122, 126))	('primary tumors', 'Disease', 'MESH:D009369', (152, 166))	('colon cancer', 'Disease', (176, 188))	('deleted', 'Var', (100, 107))	('cancer', 'Disease', (130, 136))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('human', 'Species', '9606', (170, 175))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('TP53', 'Gene', '7157', (122, 126))
244531	26352260	These lines of evidence show that single gene alterations may induce the mutations of other genes in a cancer genome that drive tumorigenesis and tumor progression.	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('single gene alterations', 'Var', (34, 57))	('induce', 'Reg', (62, 68))	('drive', 'PosReg', (122, 127))	('tumor', 'Disease', (146, 151))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('alterations', 'Var', (46, 57))	('tumor', 'Disease', (128, 133))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('mutations', 'Var', (73, 82))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
244536	26352260	The development of a mathematical model will be helpful to understand how genetic aberrations perturb the molecular network architecture and manifest the effects during tumorigenesis.	('molecular network', 'Pathway', (106, 123))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('perturb', 'Reg', (94, 101))	('tumor', 'Disease', (169, 174))	('genetic aberrations', 'Var', (74, 93))
244544	26352260	The gene gravity model postulates that if two genes have high mutation density and strong gene co-expression in a given cancer type, they should have a higher G score and related to a higher risk of inducing mutations to other genes; this postulation is based on several previous observations.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('higher', 'PosReg', (152, 158))	('inducing', 'Reg', (199, 207))	('G score', 'MPA', (159, 166))	('mutations', 'Var', (208, 217))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('mutation density', 'Var', (62, 78))
244555	26352260	We found that PIN is significantly more enriched for high mutation density than random pairs across the 9 cancer types (q < 2.2 x 10-16, Wilcoxon rank-sum test corrected by Benjamini-Hochberg multiple testing, S1 Fig).	('PIN', 'Gene', '8655', (14, 17))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('high mutation', 'Var', (53, 66))	('cancer', 'Disease', (106, 112))	('PIN', 'Gene', (14, 17))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
244566	26352260	These observations suggest that cancer driver mutations may increase subsequent genetic changes based on the previous studies.	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('mutations', 'Var', (46, 55))	('cancer', 'Disease', (32, 38))	('increase', 'PosReg', (60, 68))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('genetic changes', 'MPA', (80, 95))
244570	26352260	A previous study indicated that an average mutation frequency in smokers is more than 10-fold higher in never-smokers in non-small cell lung cancer.	('lung cancer', 'Phenotype', 'HP:0100526', (136, 147))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (125, 147))	('non-small cell lung cancer', 'Disease', (121, 147))	('mutation', 'Var', (43, 51))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (121, 147))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (121, 147))	('higher', 'PosReg', (94, 100))
244575	26352260	Tumorigenesis is dependent on the accumulation of one or multiple driver mutations that activate oncogenic pathways or inactivate tumor suppressors.	('oncogenic pathways', 'Pathway', (97, 115))	('tumor', 'Disease', (130, 135))	('Tumorigenesis', 'CPA', (0, 13))	('inactivate', 'NegReg', (119, 129))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('activate', 'PosReg', (88, 96))	('mutations', 'Var', (73, 82))
244590	26352260	We further investigated whether genetic or epigenetic alterations have combinatorial effects that shape cancer genome evolution.	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('epigenetic alterations', 'Var', (43, 65))	('shape', 'Reg', (98, 103))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))
244606	26352260	We found CGC genes are significantly enriched in DNA repair genes as well (p = 2.7 x 10-18, Fisher's exact test, S16B Fig).	('S16B', 'SUBSTITUTION', 'None', (113, 117))	('S16B', 'Var', (113, 117))	('CGC genes', 'Gene', (9, 18))
244614	26352260	By examining mutation density data of ~3,000 tumor exomes from Kandoth et al., we found that patients having nonsynonymous somatic mutations on any of four genes (FAT4, SYNE1, AHNAK, or COL11A1) often showed a higher cancer genome mutation density at the whole genome level compared to that of wild-type (WT) patients in 4 cancer types: COAD, LUAD, LUSC, and UCEC (Fig 4B).	('LUAD', 'Phenotype', 'HP:0030078', (343, 347))	('FAT4', 'Gene', '79633', (163, 167))	('tumor', 'Disease', (45, 50))	('SYNE1', 'Gene', '23345', (169, 174))	('LUSC', 'Phenotype', 'HP:0030359', (349, 353))	('LUAD', 'Disease', (343, 347))	('patients', 'Species', '9606', (93, 101))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('cancer', 'Disease', 'MESH:D009369', (323, 329))	('cancer', 'Disease', 'MESH:D009369', (217, 223))	('COAD', 'Disease', 'MESH:D029424', (337, 341))	('AHNAK', 'Gene', '79026', (176, 181))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('FAT4', 'Gene', (163, 167))	('COL11A1', 'Gene', '1301', (186, 193))	('higher', 'PosReg', (210, 216))	('AHNAK', 'Gene', (176, 181))	('mutations', 'Var', (131, 140))	('cancer', 'Disease', (323, 329))	('UCEC', 'Disease', (359, 363))	('COAD', 'Disease', (337, 341))	('SYNE1', 'Gene', (169, 174))	('cancer', 'Disease', (217, 223))	('cancer', 'Phenotype', 'HP:0002664', (323, 329))	('COL11A1', 'Gene', (186, 193))	('patients', 'Species', '9606', (309, 317))	('LUSC', 'Disease', (349, 353))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))
244617	26352260	The average number of mutations per Mb for 40 FAT4 mutated COAD samples (43.3 +- 12.8) are significantly higher than that of FAT4 WT samples (5.0 +- 0.57, q = 1.1 x 10-5, Fig 4B).	('FAT4', 'Gene', (125, 129))	('COAD', 'Disease', (59, 63))	('FAT4', 'Gene', '79633', (125, 129))	('higher', 'PosReg', (105, 111))	('FAT4', 'Gene', '79633', (46, 50))	('FAT4', 'Gene', (46, 50))	('mutations', 'Var', (22, 31))	('COAD', 'Disease', 'MESH:D029424', (59, 63))
244618	26352260	Similarly, the average number of mutations per Mb for 43 FAT4 mutated LUAD samples (26.3 +- 8.4) are significantly higher than that of FAT4 WT samples (7.5 +- 0.48, q = 2.8 x 10-9, Fig 4B).	('FAT4', 'Gene', '79633', (135, 139))	('FAT4', 'Gene', (135, 139))	('mutations', 'Var', (33, 42))	('LUAD', 'Phenotype', 'HP:0030078', (70, 74))	('FAT4', 'Gene', (57, 61))	('FAT4', 'Gene', '79633', (57, 61))	('higher', 'PosReg', (115, 121))
244623	26352260	Herein, we found that the average number of mutations per Mb for 49 SYNE1 mutated COAD samples (35.8 +- 8.4) are significantly higher than that of SYNE1 WT samples (7.5 +- 0.48, q = 6.8 x 10-9, Fig 5B).	('COAD', 'Disease', (82, 86))	('SYNE1', 'Gene', (68, 73))	('SYNE1', 'Gene', (147, 152))	('COAD', 'Disease', 'MESH:D029424', (82, 86))	('mutated', 'Var', (74, 81))	('higher', 'PosReg', (127, 133))	('mutations', 'Var', (44, 53))	('SYNE1', 'Gene', '23345', (68, 73))	('SYNE1', 'Gene', '23345', (147, 152))
244624	26352260	found that SYNE1 polymorphism relates to an increased risk of invasive ovarian cancer.	('SYNE1', 'Gene', '23345', (11, 16))	('invasive ovarian cancer', 'Disease', 'MESH:D010051', (62, 85))	('SYNE1', 'Gene', (11, 16))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('invasive ovarian cancer', 'Phenotype', 'HP:0025318', (62, 85))	('invasive ovarian cancer', 'Disease', (62, 85))	('ovarian cancer', 'Phenotype', 'HP:0100615', (71, 85))	('polymorphism', 'Var', (17, 29))
244627	26352260	In this study, the average number of mutations per Mb (12.1 +- 2.6) for 22 AHNAK mutated samples is significantly higher than that of AHNAK WT samples in HNSC (4.5 +- 0.21, q = 1.5 x 10-5, Fig 4B).	('AHNAK', 'Gene', (75, 80))	('AHNAK', 'Gene', (134, 139))	('mutated', 'Var', (81, 88))	('mutations', 'Var', (37, 46))	('AHNAK', 'Gene', '79026', (75, 80))	('AHNAK', 'Gene', '79026', (134, 139))	('higher', 'PosReg', (114, 120))
244630	26352260	In LUAD, the average number of mutations per Mb (25.3 +- 7.9) for 46 COL11A1 mutated samples is significantly higher than that of COL11A1 WT samples (7.4 +- 0.47, q = 1.1 x 10-9, Fig 5B).	('COL11A1', 'Gene', '1301', (69, 76))	('mutations', 'Var', (31, 40))	('LUAD', 'Phenotype', 'HP:0030078', (3, 7))	('COL11A1', 'Gene', (69, 76))	('mutated', 'Var', (77, 84))	('COL11A1', 'Gene', '1301', (130, 137))	('COL11A1', 'Gene', (130, 137))	('higher', 'PosReg', (110, 116))
244631	26352260	Additionally, for LUSC, the average number of mutations per Mb (16.5 +- 0.59) for 32 COL11A1 mutated samples is significantly higher than that of COL11A1 WT samples as well (8.5 +- 0.40, q = 4.9 x 10-5).	('LUSC', 'Phenotype', 'HP:0030359', (18, 22))	('mutations', 'Var', (46, 55))	('mutated', 'Var', (93, 100))	('COL11A1', 'Gene', '1301', (146, 153))	('higher', 'PosReg', (126, 132))	('COL11A1', 'Gene', (146, 153))	('COL11A1', 'Gene', '1301', (85, 92))	('COL11A1', 'Gene', (85, 92))
244632	26352260	Furthermore, COL6A3 (q = 3.1 x 10-4, COAD) and COL5A2 (q = 1.5 x 10-4, LUAD) mutations are significantly associated with a high mutation density in colorectal and lung cancer, respectively.	('COL5A2', 'Gene', '1290', (47, 53))	('COL6A3', 'Gene', (13, 19))	('COL5A2', 'Gene', (47, 53))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('COL6A3', 'Gene', '1293', (13, 19))	('high mutation density', 'MPA', (123, 144))	('COAD', 'Disease', 'MESH:D029424', (37, 41))	('lung cancer', 'Phenotype', 'HP:0100526', (163, 174))	('mutations', 'Var', (77, 86))	('LUAD', 'Phenotype', 'HP:0030078', (71, 75))	('associated', 'Reg', (105, 115))	('colorectal and lung cancer', 'Disease', 'MESH:D015179', (148, 174))	('COAD', 'Disease', (37, 41))
244643	26352260	A recent study showed that hypermutation of the inactive X chromosome is a frequent event in cancer.	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('inactive X chromosome', 'Protein', (48, 69))	('hypermutation', 'Var', (27, 40))
244650	26352260	We found that the patients harboring DDX3X or STAG2 nonsynonymous mutations have a higher genome mutation density in uterine cancer during the genome-wide mutation rate analysis (Fig 6D).	('nonsynonymous mutations', 'Var', (52, 75))	('uterine cancer', 'Phenotype', 'HP:0010784', (117, 131))	('DDX3X', 'Gene', (37, 42))	('STAG2', 'Gene', (46, 51))	('STAG2', 'Gene', '10735', (46, 51))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('genome mutation density', 'MPA', (90, 113))	('DDX3X', 'Gene', '1654', (37, 42))	('patients', 'Species', '9606', (18, 26))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('higher', 'PosReg', (83, 89))
244651	26352260	For instance, the average number of mutations per Mb for 15 DDX3X mutated uterine tumors is 144.1 +- 34.0, 11-fold higher than that of DDX3X WT tumors (13.1 +- 2.8, q = 2.5 x 10-5).	('tumors', 'Disease', (144, 150))	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('mutated', 'Var', (66, 73))	('DDX3X', 'Gene', (135, 140))	('tumors', 'Disease', (82, 88))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('tumors', 'Disease', 'MESH:D009369', (144, 150))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('DDX3X', 'Gene', '1654', (135, 140))	('mutations', 'Var', (36, 45))	('WT tumors', 'Disease', 'MESH:C536751', (141, 150))	('DDX3X', 'Gene', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('uterine tumors', 'Phenotype', 'HP:0010784', (74, 88))	('DDX3X', 'Gene', '1654', (60, 65))	('higher', 'PosReg', (115, 121))	('WT tumors', 'Disease', (141, 150))
244653	26352260	Additionally, the average number of mutations per Mb for 26 STAG2 mutated uterine tumors (144.5 +- 26.0) is significantly higher than that for STAG2 WT samples (10.2 +- 2.2, q = 1.9 x 10-10).	('tumors', 'Disease', (82, 88))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('STAG2', 'Gene', '10735', (60, 65))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('higher', 'PosReg', (122, 128))	('mutations', 'Var', (36, 45))	('STAG2', 'Gene', '10735', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('uterine tumors', 'Phenotype', 'HP:0010784', (74, 88))	('STAG2', 'Gene', (60, 65))	('STAG2', 'Gene', (143, 148))
244655	26352260	found that the inactivation of STAG2 causes aneuploidy in human glioblastoma cell lines.	('aneuploidy', 'Disease', 'MESH:D000782', (44, 54))	('STAG2', 'Gene', (31, 36))	('glioblastoma', 'Disease', (64, 76))	('glioblastoma', 'Disease', 'MESH:D005909', (64, 76))	('human', 'Species', '9606', (58, 63))	('STAG2', 'Gene', '10735', (31, 36))	('glioblastoma', 'Phenotype', 'HP:0012174', (64, 76))	('aneuploidy', 'Disease', (44, 54))	('causes', 'Reg', (37, 43))	('inactivation', 'Var', (15, 27))
244657	26352260	Taken together, we provided statistical evidence in that hypermutation of the cancer driver genes on the inactive X chromosome may be a general feature in the female cancer genomes.	('cancer', 'Disease', (166, 172))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('hypermutation', 'Var', (57, 70))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))
244658	26352260	Several previous studies showed several lines of strong biological evidences in that a single gene may shape subsequent evolution of the human cancer genome.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('human', 'Species', '9606', (137, 142))	('shape', 'Reg', (103, 108))	('single', 'Var', (87, 93))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))
244661	26352260	connectivity), high mutation rate on the cancer driver genes, and high PCC value for the particular genes, may affect the performance of the gene gravity model.	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('affect', 'Reg', (111, 117))	('PCC', 'MPA', (71, 74))	('mutation', 'Var', (20, 28))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('performance', 'MPA', (122, 133))
244662	26352260	Longer genes would be more likely to harbor mutations, increasing the false positive rate during cancer genomic analysis.	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('mutations', 'Var', (44, 53))	('cancer', 'Disease', (97, 103))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
244673	26352260	Thus, the current observation is consistent with our previous study that network-attacking perturbations due to somatic mutations occurring in the network hubs of the cancer interactome play important roles during tumor emergence and evolution.	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('tumor', 'Disease', 'MESH:D009369', (214, 219))	('cancer', 'Disease', (167, 173))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('tumor', 'Disease', (214, 219))	('mutations', 'Var', (120, 129))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))
244695	26352260	We used a network smoothing method to spread the mutations across the whole network for each cancer type.	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('mutations', 'Var', (49, 58))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))
244697	26352260	For alpha = 1, the stationary solution of  is ki/2N L (N L is the total edges in PIN), which is determined only by the network structure.	('PIN', 'Gene', (81, 84))	('ki/2N L', 'Var', (46, 53))	('PIN', 'Gene', '8655', (81, 84))
244704	26352260	identified 224 significantly mutated genes from 4,742 human cancer exomes in 21 cancer types using the MutSig method.	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancer', 'Disease', (60, 66))	('mutated', 'Var', (29, 36))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('human', 'Species', '9606', (54, 59))	('cancer', 'Disease', (80, 86))
244705	26352260	identified 125 mutated cancer genes from the genome-wide sequencing studies of 3,284 tumors using the 20/20 rule.	('cancer', 'Disease', (23, 29))	('cancer', 'Disease', 'MESH:D009369', (23, 29))	('mutated', 'Var', (15, 22))	('tumors', 'Disease', (85, 91))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('tumors', 'Disease', 'MESH:D009369', (85, 91))
244706	26352260	identified 127 significantly mutated genes from 3,281 tumors across 12 cancer types.	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('mutated genes', 'Var', (29, 42))	('cancer', 'Disease', (71, 77))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('tumors', 'Disease', (54, 60))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('tumors', 'Disease', 'MESH:D009369', (54, 60))
244710	26352260	CRFs regulate chromatin structure using three distinct processes: the post-translational modification of histone tails, the replacement of core histones by histone variants, and direct structural remodeling by ATP-dependent chromatin-remodeling enzymes.	('post-translational modification', 'MPA', (70, 101))	('variants', 'Var', (164, 172))	('regulate', 'Reg', (5, 13))	('ATP', 'Chemical', 'MESH:D000255', (210, 213))
244712	26352260	Essential genes, whose knockouts result in lethality or infertility, are important for studying the robustness of a biological system.	('result in', 'Reg', (33, 42))	('infertility', 'Disease', 'MESH:D007247', (56, 67))	('infertility', 'Phenotype', 'HP:0000789', (56, 67))	('knockouts', 'Var', (23, 32))	('lethality', 'CPA', (43, 52))	('infertility', 'Disease', (56, 67))
244717	33671513	These findings have been strongly buttressed by demonstration of increased tumorigenesis in tissue-specific AEG-1 transgenic mouse models, and profound resistance of multiple types of cancer development and progression in total and conditional AEG-1 knockout mouse models.	('cancer', 'Disease', (184, 190))	('increased', 'PosReg', (65, 74))	('transgenic', 'Var', (114, 124))	('mouse', 'Species', '10090', (125, 130))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('AEG-1', 'Gene', (108, 113))	('mouse', 'Species', '10090', (259, 264))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('rat', 'Species', '10116', (55, 58))	('tumor', 'Disease', (75, 80))
244738	33671513	Indeed, overexpression of AEG-1 promotes all hallmarks of cancer and inhibition of AEG-1 reverses these phenotypes and tissue-specific AEG-1 transgenic mouse display augmented tumorigenesis and AEG-1 knockout mouse show resistance to the development and progression of multiple cancer types, such as those of liver, breast, prostate and colon, indicating that AEG-1 plays a pivotal role in regulating tumorigenesis.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('AEG-1', 'Gene', (83, 88))	('tumor', 'Disease', 'MESH:D009369', (401, 406))	('cancer', 'Disease', (278, 284))	('cancer', 'Phenotype', 'HP:0002664', (278, 284))	('tumor', 'Disease', (176, 181))	('augmented', 'PosReg', (166, 175))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('tumor', 'Phenotype', 'HP:0002664', (401, 406))	('tumor', 'Disease', 'MESH:D009369', (176, 181))	('AEG-1', 'Gene', (135, 140))	('cancer', 'Disease', 'MESH:D009369', (278, 284))	('mouse', 'Species', '10090', (209, 214))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('resistance', 'CPA', (220, 230))	('liver', 'Disease', (309, 314))	('mouse', 'Species', '10090', (152, 157))	('cancer', 'Disease', (58, 64))	('inhibition', 'Var', (69, 79))	('tumor', 'Disease', (401, 406))
244746	33671513	In both squamous cell carcinoma and adenocarcinoma, significant difference in survival time between low and high AEG-1 expression groups was observed in poorly differentiated cases (p < 0.001), but not in well-differentiated cases.	('expression', 'MPA', (119, 129))	('AEG-1', 'Gene', (113, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (41, 50))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (8, 31))	('adenocarcinoma', 'Disease', 'MESH:D000230', (36, 50))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (8, 31))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('squamous cell carcinoma', 'Disease', (8, 31))	('high', 'Var', (108, 112))	('adenocarcinoma', 'Disease', (36, 50))
244758	33671513	OS (p = 0.014) and DFS (p = 0.009) were longer in low AEG-1 expressing group versus high expressing group in patients who received postoperative chemotherapy.	('rat', 'Species', '10116', (138, 141))	('patients', 'Species', '9606', (109, 117))	('low', 'Var', (50, 53))	('DFS', 'CPA', (19, 22))	('AEG-1', 'Protein', (54, 59))
244759	33671513	Similarly, in patients receiving postoperative radiotherapy recurrence free survival was significantly shorter in high AEG-1 expressing group (p = 0.016).	('high', 'Var', (114, 118))	('rat', 'Species', '10116', (40, 43))	('shorter', 'NegReg', (103, 110))	('patients', 'Species', '9606', (14, 22))	('AEG-1', 'Protein', (119, 124))
244763	33671513	While 6.8% normal tissues showed AEG-1 expression, in NSCLC cases it was 61.3% (p < 0.001) which showed significant association with TNM stage (p = 0.021), dedifferentiation (p = 0.034), vascular invasion (p = 0.035), lymph node metastasis (p < 0.001) and poor overall survival (p = 0.024).	('TNM', 'Gene', (133, 136))	('AEG-1', 'Var', (33, 38))	('vascular invasion', 'CPA', (187, 204))	('lymph node metastasis', 'CPA', (218, 239))	('association', 'Reg', (116, 127))	('NSCLC', 'Disease', (54, 59))	('TNM', 'Gene', '10178', (133, 136))	('NSCLC', 'Disease', 'MESH:D002289', (54, 59))	('dedifferentiation', 'CPA', (156, 173))
244767	33671513	This analysis revealed that high AEG-1 expression significantly correlated with higher mortality and metastasis in breast, ovarian and cervical cancers.	('high', 'Var', (28, 32))	('mortality', 'Disease', 'MESH:D003643', (87, 96))	('cancers', 'Phenotype', 'HP:0002664', (144, 151))	('expression', 'MPA', (39, 49))	('AEG-1', 'Gene', (33, 38))	('mortality', 'Disease', (87, 96))	('higher', 'PosReg', (80, 86))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('metastasis in breast, ovarian and cervical cancers', 'Disease', 'MESH:D009362', (101, 151))
244768	33671513	In addition, polymorphisms in AEG-1 gene, such as a C/T variant in exon 11 or a G>A variant in exon 9, have been shown to confer susceptibility to breast and ovarian cancers in women from specific ethnic groups in China, which needs to be validated in more extensive studies in other patient cohorts.	('susceptibility', 'Reg', (129, 143))	('ovarian cancer', 'Phenotype', 'HP:0100615', (158, 172))	('C/T', 'Var', (52, 55))	('women', 'Species', '9606', (177, 182))	('breast and ovarian cancers', 'Disease', 'MESH:D001943', (147, 173))	('G>A', 'Var', (80, 83))	('ovarian cancers', 'Phenotype', 'HP:0100615', (158, 173))	('polymorphisms', 'Var', (13, 26))	('cancers', 'Phenotype', 'HP:0002664', (166, 173))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('patient', 'Species', '9606', (284, 291))	('AEG-1', 'Gene', (30, 35))
244782	33671513	These breast cancer patients also showed correlation between AEG-1 and proliferation marker Ki-67 (p = 0.003) in a subsequent study indicating that AEG-1 is associated with highly proliferative breast cancers.	('cancers', 'Phenotype', 'HP:0002664', (201, 208))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('rat', 'Species', '10116', (187, 190))	('breast cancer', 'Disease', 'MESH:D001943', (6, 19))	('AEG-1', 'Var', (148, 153))	('associated with', 'Reg', (157, 172))	('correlation', 'Interaction', (41, 52))	('breast cancer', 'Disease', (6, 19))	('breast cancer', 'Phenotype', 'HP:0003002', (6, 19))	('rat', 'Species', '10116', (78, 81))	('breast cancers', 'Phenotype', 'HP:0003002', (194, 208))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('patients', 'Species', '9606', (20, 28))	('breast cancer', 'Disease', 'MESH:D001943', (194, 207))	('breast cancers', 'Disease', 'MESH:D001943', (194, 208))	('breast cancers', 'Disease', (194, 208))	('breast cancer', 'Phenotype', 'HP:0003002', (194, 207))
244783	33671513	However, knocking down AEG-1 in breast cancer cells did not affect proliferation, although there was marked inhibition in migration, invasion and metastasis, arguing against the clinicopathologic study.	('breast cancer', 'Disease', (32, 45))	('rat', 'Species', '10116', (125, 128))	('inhibition', 'NegReg', (108, 118))	('breast cancer', 'Phenotype', 'HP:0003002', (32, 45))	('breast cancer', 'Disease', 'MESH:D001943', (32, 45))	('knocking down', 'Var', (9, 22))	('rat', 'Species', '10116', (74, 77))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('migration', 'CPA', (122, 131))	('AEG-1', 'Gene', (23, 28))
244784	33671513	Copy number alterations (CNA) of oncogenes is widely observed in human cancers.	('human', 'Species', '9606', (65, 70))	('cancers', 'Disease', 'MESH:D009369', (71, 78))	('cancers', 'Phenotype', 'HP:0002664', (71, 78))	('rat', 'Species', '10116', (16, 19))	('cancers', 'Disease', (71, 78))	('Copy number alterations', 'Var', (0, 23))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))
244787	33671513	Kaplan-Meier curves constructed to determine the effect of 8q22 gain on survival revealed significantly (p < 0.05) lower metastasis- and cancer-free survival in breast cancer patients with high 8q22 gain compared with low 8q22 gain, further validating the importance of AEG-1 expression in breast cancer prognosis.	('lower', 'NegReg', (115, 120))	('cancer', 'Disease', (137, 143))	('cancer', 'Disease', (168, 174))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('breast cancer', 'Phenotype', 'HP:0003002', (290, 303))	('cancer', 'Disease', 'MESH:D009369', (297, 303))	('breast cancer', 'Disease', 'MESH:D001943', (290, 303))	('breast cancer', 'Disease', (290, 303))	('high 8q22', 'Var', (189, 198))	('breast cancer', 'Phenotype', 'HP:0003002', (161, 174))	('gain', 'PosReg', (199, 203))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('cancer', 'Disease', (297, 303))	('breast cancer', 'Disease', 'MESH:D001943', (161, 174))	('breast cancer', 'Disease', (161, 174))	('patients', 'Species', '9606', (175, 183))	('cancer', 'Phenotype', 'HP:0002664', (297, 303))
244792	33671513	Microarray analysis of AEG-1-knockdown cells demonstrated that genes such as ALDH3A1 and MET contribute to the multidrug chemoresistance that is seen in AEG-1-positive specimens and it was hypothesized that AEG-1 may promote chemoresistance by improving survival of metastatic lesions.	('rat', 'Species', '10116', (52, 55))	('MET', 'Gene', (89, 92))	('ALDH3A1', 'Gene', (77, 84))	('chemoresistance', 'CPA', (225, 240))	('multidrug chemoresistance', 'MPA', (111, 136))	('survival of metastatic lesions', 'CPA', (254, 284))	('promote', 'PosReg', (217, 224))	('AEG-1', 'Var', (207, 212))	('MET', 'Gene', '79811', (89, 92))	('improving', 'PosReg', (244, 253))	('ALDH3A1', 'Gene', '218', (77, 84))
244793	33671513	In a subsequent study, it was documented that expression of AEG-1 was implicated in progression of precancerous breast lesions into cancerous ones.	('cancerous', 'Disease', 'MESH:D009369', (102, 111))	('precancerous breast lesions', 'Disease', (99, 126))	('expression', 'Var', (46, 56))	('precancerous breast lesions', 'Disease', 'MESH:D001943', (99, 126))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('cancerous', 'Disease', (132, 141))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('cancerous', 'Disease', (102, 111))	('cancerous', 'Disease', 'MESH:D009369', (132, 141))	('implicated', 'Reg', (70, 80))	('AEG-1', 'Gene', (60, 65))
244797	33671513	Additionally, AEG-1 overexpression was significantly associated with age (p = 0.042), Ki-67 status (p = 0.036), ER status (p = 0.018) and p53 status (p = 0.001) in invasive cancer patients, which was not observed in other previous studies.	('AEG-1', 'Protein', (14, 19))	('p53', 'Gene', (138, 141))	('ER', 'Gene', '2069', (112, 114))	('p53', 'Gene', '7157', (138, 141))	('invasive cancer', 'Disease', (164, 179))	('overexpression', 'PosReg', (20, 34))	('invasive cancer', 'Disease', 'MESH:D009362', (164, 179))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('associated', 'Reg', (53, 63))	('Ki-67 status', 'Var', (86, 98))	('patients', 'Species', '9606', (180, 188))
244800	33671513	High MVD was observed in 59 cases out of which 42 displayed high AEG-1 expression (p = 0.002) indicating that AEG-1 is associated with increased angiogenesis.	('expression', 'MPA', (71, 81))	('angiogenesis', 'CPA', (145, 157))	('High MVD', 'Disease', 'MESH:D052456', (0, 8))	('High MVD', 'Disease', (0, 8))	('AEG-1', 'Gene', (65, 70))	('AEG-1', 'Var', (110, 115))	('increased', 'PosReg', (135, 144))
244801	33671513	Poor disease-free and overall survivals were associated with high AEG-1 and VEGF levels in Kaplan-Meier 5-year survival analysis.	('AEG-1', 'Protein', (66, 71))	('VEGF', 'Gene', (76, 80))	('high', 'Var', (61, 65))	('Poor', 'NegReg', (0, 4))	('VEGF', 'Gene', '7422', (76, 80))	('overall survivals', 'CPA', (22, 39))	('disease-free', 'CPA', (5, 17))
244805	33671513	AEG-1 levels did not correlate with ER, PR or HER2 levels indicating that AEG-1 might promote all types of breast cancers.	('cancers', 'Phenotype', 'HP:0002664', (114, 121))	('HER2', 'Gene', (46, 50))	('ER', 'Gene', '2069', (36, 38))	('breast cancers', 'Phenotype', 'HP:0003002', (107, 121))	('AEG-1', 'Var', (74, 79))	('HER2', 'Gene', '2064', (46, 50))	('ER', 'Gene', '2069', (47, 49))	('PR', 'Gene', '140738', (40, 42))	('promote', 'PosReg', (86, 93))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('breast cancers', 'Disease', 'MESH:D001943', (107, 121))	('breast cancers', 'Disease', (107, 121))	('breast cancer', 'Phenotype', 'HP:0003002', (107, 120))
244818	33671513	Overexpression of AEG-1 was found to be associated with poorer overall survival and lower 5-year survival in these patients.	('patients', 'Species', '9606', (115, 123))	('overall', 'MPA', (63, 70))	('AEG-1', 'Gene', (18, 23))	('poorer', 'NegReg', (56, 62))	('5-year survival', 'CPA', (90, 105))	('Overexpression', 'Var', (0, 14))	('lower', 'NegReg', (84, 89))
244824	33671513	Five-year survival curves demonstrated significantly shorter PFS (p < 0.001) as well as OS (p < 0.001) in patients with high expression of AEG-1, compared with those patients with low expression of AEG-1.	('PFS', 'MPA', (61, 64))	('rat', 'Species', '10116', (33, 36))	('high expression', 'Var', (120, 135))	('AEG-1', 'Gene', (139, 144))	('patients', 'Species', '9606', (106, 114))	('shorter', 'NegReg', (53, 60))	('patients', 'Species', '9606', (166, 174))
244825	33671513	In patients with high-expressing AEG-1 tumors, the median PFS was only 30.4 months, whereas PFS was 63.6 months for patients with low-expressing AEG-1 tumors.	('high-expressing', 'Var', (17, 32))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumors', 'Disease', (151, 157))	('tumors', 'Disease', 'MESH:D009369', (151, 157))	('patients', 'Species', '9606', (116, 124))	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('patients', 'Species', '9606', (3, 11))	('AEG-1', 'Gene', (33, 38))	('tumors', 'Disease', (39, 45))
244826	33671513	Univariate analysis demonstrated that high AEG-1 expression was significantly associated with shorter OS (35.55 + 1.46 months, p < 0.0001) and shorter PFS (27.28 + 3.27 months, p < 0.0001).	('PFS', 'MPA', (151, 154))	('high', 'Var', (38, 42))	('expression', 'MPA', (49, 59))	('rat', 'Species', '10116', (27, 30))	('AEG-1', 'Gene', (43, 48))
244827	33671513	Notably, there was a 5-year OS of only 34.25% for patients with high AEG-1 expression.	('AEG-1', 'Gene', (69, 74))	('high', 'Var', (64, 68))	('patients', 'Species', '9606', (50, 58))
244831	33671513	Among 102 such patients, 77 were categorized as high AEG-1 expression, which was significantly associated with poor prognosis (p < 0.01).	('high', 'Var', (48, 52))	('patients', 'Species', '9606', (15, 23))	('AEG-1', 'Protein', (53, 58))
244832	33671513	Patients with high AEG-1 expression were significantly associated with shorter median survival time in years (1.13056 for high, 2.32156 for low AEG-1 expression) and 3-year survival rates (0.1436 for high, 0.3816 for low AEG-1 expression) when compared to those of low AEG-1 expression (p = 0.0028).	('high', 'Var', (14, 18))	('rat', 'Species', '10116', (182, 185))	('Patients', 'Species', '9606', (0, 8))	('AEG-1', 'Gene', (19, 24))	('0.1436', 'Var', (189, 195))	('shorter', 'NegReg', (71, 78))
244852	33671513	Tissue microarray of 90 cervical cancer samples, including 74 squamous cervical carcinoma and 16 adenocarcinoma) demonstrated that high AEG-1 expression was significantly associated with tumor size (>4 cm, p = 0.010) and metastasis to lymph nodes (p = 0.004).	('AEG-1', 'Protein', (136, 141))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('adenocarcinoma', 'Disease', 'MESH:D000230', (97, 111))	('cancer', 'Disease', (33, 39))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('squamous cervical carcinoma', 'Disease', (62, 89))	('squamous cervical carcinoma', 'Disease', 'MESH:D002294', (62, 89))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('metastasis to lymph nodes', 'CPA', (221, 246))	('tumor', 'Disease', (187, 192))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('rat', 'Species', '10116', (120, 123))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('expression', 'MPA', (142, 152))	('adenocarcinoma', 'Disease', (97, 111))	('associated', 'Reg', (171, 181))	('high', 'Var', (131, 135))
244853	33671513	IHC staining of normal cervical squamous epithelium revealed absence of AEG-1, while AEG-1 staining was positive in cervical intraepithelial neoplasia (CIN) I, II and III samples, indicating AEG-1 expression may necessitate progression of CIN to cervical carcinoma.	('CIN', 'Disease', 'MESH:D007674', (152, 155))	('CIN', 'Disease', (239, 242))	('carcinoma', 'Phenotype', 'HP:0030731', (255, 264))	('necessitate', 'Reg', (212, 223))	('intraepithelial neoplasia', 'Phenotype', 'HP:0032187', (125, 150))	('CIN', 'Disease', 'MESH:D007674', (239, 242))	('CIN to cervical carcinoma', 'Disease', (239, 264))	('neoplasia', 'Phenotype', 'HP:0002664', (141, 150))	('neoplasia', 'Disease', 'MESH:D009369', (141, 150))	('AEG-1', 'Var', (191, 196))	('cervical intraepithelial neoplasia', 'Phenotype', 'HP:0032242', (116, 150))	('CIN to cervical carcinoma', 'Disease', 'MESH:D002583', (239, 264))	('CIN', 'Disease', (152, 155))	('neoplasia', 'Disease', (141, 150))
244856	33671513	High AEG-1 expression was associated with tumor size (AUC = 0.826, p = 0.000) and lymph node metastasis (AUC = 0.745, p = 0.004) and showed significantly lower OS (p < 0.05) compared with low AEG-1 expression.	('lower', 'NegReg', (154, 159))	('tumor', 'Disease', (42, 47))	('High', 'Var', (0, 4))	('lymph node metastasis', 'CPA', (82, 103))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('AEG-1', 'Gene', (5, 10))	('expression', 'Var', (11, 21))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('associated', 'Reg', (26, 36))
244857	33671513	High AEG-1 expression was identified as an independent prognostic factor for poor OS (hazard ratio = 4.021, p = 0.027).	('rat', 'Species', '10116', (93, 96))	('poor OS', 'Disease', (77, 84))	('High', 'Var', (0, 4))	('AEG-1 expression', 'Protein', (5, 21))
244865	33671513	A Pearson correlation found a significant positive association between AEG-1 levels and VEGF and NF-kappaB levels (p = 0) and MVD (p = 0) suggesting that AEG-1 as a potential inducer of angiogenesis which could potentially contribute to invasion and metastasis by cervical cancer.	('inducer', 'PosReg', (175, 182))	('angiogenesis', 'CPA', (186, 198))	('cancer', 'Disease', (273, 279))	('cancer', 'Disease', 'MESH:D009369', (273, 279))	('MVD', 'Gene', (126, 129))	('VEGF', 'Gene', (88, 92))	('positive', 'PosReg', (42, 50))	('metastasis', 'CPA', (250, 260))	('contribute', 'Reg', (223, 233))	('AEG-1', 'Var', (154, 159))	('NF-kappaB', 'Gene', '4790', (97, 106))	('invasion', 'CPA', (237, 245))	('cancer', 'Phenotype', 'HP:0002664', (273, 279))	('VEGF', 'Gene', '7422', (88, 92))	('MVD', 'Gene', '4597', (126, 129))	('NF-kappaB', 'Gene', (97, 106))
244870	33671513	Although not statistically significant, AEG-1 expression showed a trend of higher level in patients with low Gleason score versus in patients with high Gleason score.	('level', 'MPA', (82, 87))	('patients', 'Species', '9606', (91, 99))	('low', 'Var', (105, 108))	('higher', 'PosReg', (75, 81))	('patients', 'Species', '9606', (133, 141))	('expression', 'MPA', (46, 56))	('AEG-1', 'Gene', (40, 45))
244881	33671513	Additionally, recurrence rate, determined by prostate-specific antigen (PSA) levels, was significantly higher in AEG-1-high patients compared to AEG-1-low patients.	('AEG-1-high', 'Var', (113, 123))	('recurrence', 'MPA', (14, 24))	('prostate-specific antigen', 'Gene', '354', (45, 70))	('PSA', 'Gene', (72, 75))	('PSA', 'Gene', '354', (72, 75))	('patients', 'Species', '9606', (155, 163))	('rat', 'Species', '10116', (25, 28))	('higher', 'PosReg', (103, 109))	('prostate-specific antigen', 'Gene', (45, 70))	('patients', 'Species', '9606', (124, 132))
244883	33671513	Interestingly, in this study, the authors showed that knocking out AEG-1 in the transgenic adenocarcinoma of mouse prostate (TRAMP) model prolonged tumor latency and abrogated tumor progression and metastasis further establishing the importance of AEG-1 in prostate cancer.	('abrogated', 'NegReg', (166, 175))	('prostate cancer', 'Phenotype', 'HP:0012125', (257, 272))	('prostate cancer', 'Disease', (257, 272))	('AEG-1', 'Gene', (67, 72))	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('knocking out', 'Var', (54, 66))	('tumor', 'Disease', (176, 181))	('tumor', 'Disease', 'MESH:D009369', (176, 181))	('adenocarcinoma', 'Disease', (91, 105))	('mouse', 'Species', '10090', (109, 114))	('prolonged', 'PosReg', (138, 147))	('TRAMP', 'Gene', '85030', (125, 130))	('TRAMP', 'Gene', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('adenocarcinoma', 'Disease', 'MESH:D000230', (91, 105))	('tumor', 'Disease', (148, 153))	('cancer', 'Phenotype', 'HP:0002664', (266, 272))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('prostate cancer', 'Disease', 'MESH:D011471', (257, 272))
244886	33671513	It was identified that high AEG-1 staining index was associated with tumor progression and poor survival status in all types of GI cancers thus establishing the importance of AEG-1 as a prognostic marker for GI cancers.	('AEG-1', 'Protein', (28, 33))	('cancers', 'Phenotype', 'HP:0002664', (131, 138))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('high', 'Var', (23, 27))	('GI cancers', 'Disease', 'MESH:D009369', (208, 218))	('GI cancer', 'Phenotype', 'HP:0007378', (128, 137))	('tumor', 'Disease', (69, 74))	('GI cancers', 'Disease', 'MESH:D009369', (128, 138))	('GI cancer', 'Phenotype', 'HP:0007378', (208, 217))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('cancers', 'Phenotype', 'HP:0002664', (211, 218))	('associated', 'Reg', (53, 63))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('GI cancers', 'Disease', (128, 138))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('GI cancers', 'Disease', (208, 218))
244930	33671513	Both nuclear and cytoplasmic AEG-1 expression significantly correlated with phosphorylated NF-kappaB (Ser 536), p73 and Rad50 in primary tumors.	('tumors', 'Disease', (137, 143))	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('NF-kappaB', 'Gene', '4790', (91, 100))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('NF-kappaB', 'Gene', (91, 100))	('Ser 536', 'Var', (102, 109))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('Rad50', 'Gene', '10111', (120, 125))	('correlated', 'Reg', (60, 70))	('AEG-1', 'Gene', (29, 34))	('Rad50', 'Gene', (120, 125))	('p73', 'Gene', '7161', (112, 115))	('p73', 'Gene', (112, 115))	('Ser', 'Chemical', 'MESH:D012694', (102, 105))
244931	33671513	It was hypothesized that AEG-1 might be involved in p73-mediated DNA damage-induced apoptosis since cytoplasmic:but not nuclear:AEG-1 associated with increased apoptosis.	('apoptosis', 'CPA', (160, 169))	('DN', 'Chemical', '-', (65, 67))	('p73', 'Gene', '7161', (52, 55))	('AEG-1', 'Var', (128, 133))	('p73', 'Gene', (52, 55))	('increased', 'PosReg', (150, 159))
244933	33671513	Rectal cancer patients showed higher AEG-1 expression than colon cancer patients (p = 0.047) and in a follow-up study of 158 rectal cancer patients treated with radiotherapy (RT), the authors documented that high AEG-1 expression in primary tumors independently correlated with higher risk of distant recurrence (p = 0.009) and worse DFS (p = 0.007), indicating that AEG-1 might be a marker to identify patients who might develop distant relapse.	('high', 'Var', (208, 212))	('tumors', 'Disease', 'MESH:D009369', (241, 247))	('colon cancer', 'Disease', 'MESH:D015179', (59, 71))	('patients', 'Species', '9606', (14, 22))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('patients', 'Species', '9606', (403, 411))	('higher', 'PosReg', (30, 36))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('cancer', 'Disease', (7, 13))	('AEG-1', 'Protein', (213, 218))	('rectal cancer', 'Phenotype', 'HP:0100743', (125, 138))	('Rectal cancer', 'Phenotype', 'HP:0100743', (0, 13))	('AEG-1 expression', 'MPA', (37, 53))	('colon cancer', 'Disease', (59, 71))	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('patients', 'Species', '9606', (139, 147))	('tumors', 'Phenotype', 'HP:0002664', (241, 247))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))	('cancer', 'Disease', (132, 138))	('expression', 'MPA', (219, 229))	('tumors', 'Disease', (241, 247))	('colon cancer', 'Phenotype', 'HP:0003003', (59, 71))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('cancer', 'Disease', 'MESH:D009369', (7, 13))	('distant recurrence', 'CPA', (293, 311))	('patients', 'Species', '9606', (72, 80))
244941	33671513	AEG-1 and SND1 co-expression negatively correlated with postoperative overall survival and positively correlated with mortality (p = 0.009) in cox multivariate analysis, strongly indicating that AEG-1 and SND1 can serve as prognostic factors for colon cancer.	('SND1', 'Gene', (205, 209))	('colon cancer', 'Disease', 'MESH:D015179', (246, 258))	('rat', 'Species', '10116', (63, 66))	('colon cancer', 'Disease', (246, 258))	('mortality', 'Disease', (118, 127))	('SND1', 'Gene', '27044', (205, 209))	('negatively', 'NegReg', (29, 39))	('correlated', 'Reg', (102, 112))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('SND1', 'Gene', (10, 14))	('AEG-1', 'Var', (195, 200))	('mortality', 'Disease', 'MESH:D003643', (118, 127))	('colon cancer', 'Phenotype', 'HP:0003003', (246, 258))	('SND1', 'Gene', '27044', (10, 14))	('co-expression', 'Var', (15, 28))	('AEG-1', 'Gene', (0, 5))
244949	33671513	This A>C SNP alters AP2 binding site in AEG-1 promoter and was suggested to be associated with HCC susceptibility in Iranian patients.	('A>C SNP', 'Var', (5, 12))	('AP2', 'Gene', '7020', (20, 23))	('associated', 'Reg', (79, 89))	('AP2', 'Gene', (20, 23))	('HCC', 'Disease', (95, 98))	('alters', 'Reg', (13, 19))	('patients', 'Species', '9606', (125, 133))
244954	33671513	Genomic amplification of AEG-1 in HCC patients was shown in additional studies.	('Genomic amplification', 'Var', (0, 21))	('AEG-1', 'Gene', (25, 30))	('HCC', 'Disease', (34, 37))	('patients', 'Species', '9606', (38, 46))
244958	33671513	Additionally, the 1-, 3- and 5-year OS in high AEG-1-expressing group were significantly lower than those in low AEG-1-expressing group (83.0% vs. 89.7%, 52.0% vs. 75.3%, 37.4% vs. 66.9%, respectively); and the 1-, 3- and 5-year cumulative recurrence rates were markedly higher in high AEG-1-expressing group than those in low AEG-1-expressing group (32.4% vs. 16.8%, 61.2% vs. 38.2%, 70.7% vs. 47.8%, respectively).	('lower', 'NegReg', (89, 94))	('high AEG-1-expressing', 'Var', (281, 302))	('high AEG-1-expressing', 'Var', (42, 63))	('higher', 'PosReg', (271, 277))	('rat', 'Species', '10116', (251, 254))
244971	33671513	High AEG-1 levels were associated with worse OS and RFS (p < 0.001 and p = 0.01, respectively) and cox regression analysis identified that TNM stage, surgery margin and high AEG-1 expression were independent factors for OS and RFS in PCCA.	('high', 'Var', (169, 173))	('TNM', 'Gene', (139, 142))	('PCCA', 'Disease', (234, 238))	('RFS', 'Disease', (227, 230))	('RFS', 'Disease', (52, 55))	('TNM', 'Gene', '10178', (139, 142))	('RFS', 'Disease', 'MESH:D005198', (227, 230))	('RFS', 'Disease', 'MESH:D005198', (52, 55))
244988	33671513	Average survival time in EphA7 and AEG-1 positive cases was 8.1 months versus 13.2 months in EphA7 and AEG-1 negative cases (p < 0.001).	('EphA7', 'Gene', (25, 30))	('EphA7', 'Gene', '2045', (25, 30))	('EphA7', 'Gene', '2045', (93, 98))	('positive', 'Var', (41, 49))	('AEG-1', 'Gene', (35, 40))	('EphA7', 'Gene', (93, 98))
244994	33671513	Additionally, in 105 PDAC patients, 98.09% showed AEG-1 expression by IHC which was associated with advanced clinical stage (p = 0.004), T (p = 0.006), N (p = 0.003) and M (p = 0.007) classifications, lymph node involvement (p = 0.003) and distant metastasis (p = 0.007).	('lymph node involvement', 'CPA', (201, 223))	('IHC', 'Gene', (70, 73))	('patients', 'Species', '9606', (26, 34))	('distant metastasis', 'CPA', (240, 258))	('associated', 'Reg', (84, 94))	('AEG-1 expression', 'Var', (50, 66))
245000	33671513	IHC analysis in 102 RCC patients that included 86 clear cell carcinomas, 10 papillary carcinomas, 3 chromophobe cell types and three cases of cancer of the collecting duct of Bellini as well as 6 matched lymph node metastases and seven cases of neoplastic embolus in the renal vein showed high AEG-1 expression in 96 cases, especially in lymph node metastases and neoplastic emboli with weak AEG-1 expression in normal tubular epithelium and no expression in normal glomeruli.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('carcinomas', 'Disease', (86, 96))	('carcinomas', 'Disease', (61, 71))	('RCC', 'Disease', (20, 23))	('neoplastic embolus', 'Disease', (245, 263))	('metastases', 'Disease', 'MESH:D009362', (215, 225))	('cell carcinoma', 'Disease', (56, 70))	('RCC', 'Disease', 'MESH:C538614', (20, 23))	('metastases', 'Disease', 'MESH:D009362', (349, 359))	('carcinomas', 'Disease', 'MESH:D009369', (86, 96))	('cancer', 'Disease', (142, 148))	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('carcinomas', 'Phenotype', 'HP:0030731', (86, 96))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('metastases', 'Disease', (349, 359))	('metastases', 'Disease', (215, 225))	('neoplastic embolus', 'Disease', 'MESH:D004617', (245, 263))	('carcinomas', 'Disease', 'MESH:D009369', (61, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('carcinomas', 'Phenotype', 'HP:0030731', (61, 71))	('papillary carcinomas', 'Disease', 'MESH:D002291', (76, 96))	('cell carcinoma', 'Disease', 'MESH:C538614', (56, 70))	('papillary carcinomas', 'Disease', (76, 96))	('patients', 'Species', '9606', (24, 32))	('AEG-1', 'Var', (294, 299))
245002	33671513	The cumulative 5-year survival rate was 91.3% and 52.4% in low and high AEG-1 expression groups, respectively.	('high', 'Var', (67, 71))	('AEG-1', 'Protein', (72, 77))	('rat', 'Species', '10116', (31, 34))
245003	33671513	The mean survival time was 76.98 and 60.94 months in low and high AEG-1 expression groups, respectively, indicating a potential role of AEG-1 in regulating advanced progression of RCC.	('RCC', 'Disease', 'MESH:C538614', (180, 183))	('AEG-1', 'Gene', (66, 71))	('high', 'Var', (61, 65))	('RCC', 'Disease', (180, 183))
245005	33671513	Similarly, p53 levels correlated with tumor diameter (p = 0.028), renal sinal invasion (p = 0.05) and Fuhrman grade (p = 0.026) indicating that AEG-1 and p53 might serve as prognostic markers for RCC.	('p53', 'Gene', (11, 14))	('tumor', 'Disease', (38, 43))	('p53', 'Gene', '7157', (11, 14))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('Fuhrman grade', 'CPA', (102, 115))	('renal sinal invasion', 'CPA', (66, 86))	('correlated', 'Reg', (22, 32))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('p53', 'Gene', (154, 157))	('p53', 'Gene', '7157', (154, 157))	('AEG-1', 'Var', (144, 149))	('RCC', 'Disease', 'MESH:C538614', (196, 199))	('RCC', 'Disease', (196, 199))
245012	33671513	In a multivariate survival analysis, patients with high SI (SI > 6) had a shorter OS compared to patients with low SI (SI < 6) (p < 0.001).	('shorter', 'NegReg', (74, 81))	('high SI (SI > 6', 'Var', (51, 66))	('patients', 'Species', '9606', (37, 45))	('patients', 'Species', '9606', (97, 105))
245032	33671513	These patients were also classified into those who had either high- or low-AEG-1 expression.	('low-AEG-1', 'NegReg', (71, 80))	('patients', 'Species', '9606', (6, 14))	('high-', 'Var', (62, 67))
245035	33671513	IHC analysis of 204 tissues, including 32 normal brain tissues, 80 Low-malignant astrocytomas (LMAs) and 92 High-Malignant astrocytomas (HMAs) showed AEG-1 positivity in 74.4% tumor samples which significantly correlated with histological grades (p < 0.001).	('correlated', 'Reg', (210, 220))	('High-Malignant astrocytomas', 'Disease', (108, 135))	('astrocytoma', 'Phenotype', 'HP:0009592', (123, 134))	('astrocytoma', 'Phenotype', 'HP:0009592', (81, 92))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('High-Malignant astrocytomas', 'Disease', 'MESH:D020339', (108, 135))	('tumor', 'Disease', (176, 181))	('Low-malignant astrocytomas', 'Disease', 'MESH:D020339', (67, 93))	('Low-malignant astrocytomas', 'Disease', (67, 93))	('AEG-1 positivity', 'Var', (150, 166))	('tumor', 'Disease', 'MESH:D009369', (176, 181))
245040	33671513	IHC analysis of 75 oligodendroglioma patients, including 52 well-differentiated and 23 anaplatic tumors, showed AEG-1 expression in 68% cases with correlated with tumor grade and Ki-67 levels (p = 0) but not with age and sex.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('patients', 'Species', '9606', (37, 45))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('AEG-1', 'Var', (112, 117))	('tumor', 'Disease', (97, 102))	('oligodendroglioma', 'Disease', (19, 36))	('Ki-67 levels', 'MPA', (179, 191))	('tumor', 'Disease', (163, 168))	('tumors', 'Disease', (97, 103))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('tumors', 'Disease', 'MESH:D009369', (97, 103))	('oligodendroglioma', 'Disease', 'MESH:D009837', (19, 36))	('glioma', 'Phenotype', 'HP:0009733', (30, 36))
245041	33671513	In high AEG-1 expressing patients, median survival time was 28 months (95% confidence interval, 25.54-30.46) and cumulative 3-year survival rate was 19.69%, while in low AEG-1 expressing patients these values were 57 months (95% confidence interval, 46.37-67.63) (p = 0) and 88.05%, respectively.	('patients', 'Species', '9606', (187, 195))	('high', 'Var', (3, 7))	('AEG-1', 'Protein', (8, 13))	('patients', 'Species', '9606', (25, 33))	('rat', 'Species', '10116', (140, 143))
245049	33671513	Although in clinical stage I-II no significant difference between low or high AEG-1 levels and OS was observed, in stages III-IV high AEG-1 levels correlated with poor survival and patients with distant metastasis and high AEG-1 levels showed shorter OS compared to patients without distant metastases.	('poor', 'NegReg', (163, 167))	('patients', 'Species', '9606', (266, 274))	('high', 'Var', (218, 222))	('high', 'Var', (129, 133))	('AEG-1', 'MPA', (134, 139))	('metastases', 'Disease', (291, 301))	('distant metastasis', 'CPA', (195, 213))	('patients', 'Species', '9606', (181, 189))	('metastases', 'Disease', 'MESH:D009362', (291, 301))	('shorter', 'NegReg', (243, 250))
245054	33671513	AEG-1 is also targeted by tumor suppressor miR-30e-5p, which is downregulated in HNSCC, and low levels of miR-30e-5p correlated with poor overall survival (p < 0.05).	('miR-30e-5p', 'Chemical', '-', (43, 53))	('overall', 'MPA', (138, 145))	('poor', 'NegReg', (133, 137))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('low', 'Var', (92, 95))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('miR-30e-5p', 'Chemical', '-', (106, 116))
245063	33671513	Additionally, 5-year survival rate in high AEG-1 expressing TSCC patients (16.98%, 95% CI: 32.04-50.13%) was significantly lower than low AEG-1 expressing patients (36.73%, 95% CI: 58.68-73.08%).	('high AEG-1 expressing', 'Var', (38, 59))	('lower', 'NegReg', (123, 128))	('rat', 'Species', '10116', (30, 33))	('patients', 'Species', '9606', (65, 73))	('patients', 'Species', '9606', (155, 163))	('TSCC', 'Disease', (60, 64))
245066	33671513	IHC analysis of 62 osteosarcoma patients and 20 normal bone samples revealed 82.3% AEG-1 positivity in cancer samples out of which 32 cases showed high expression and barely detectable expression in normal bone.	('positivity', 'Var', (89, 99))	('patients', 'Species', '9606', (32, 40))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('AEG-1', 'Gene', (83, 88))	('osteosarcoma', 'Disease', 'MESH:D012516', (19, 31))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('osteosarcoma', 'Phenotype', 'HP:0002669', (19, 31))	('cancer', 'Disease', (103, 109))	('osteosarcoma', 'Disease', (19, 31))	('expression', 'MPA', (152, 162))
245072	33671513	Additionally, IHC analysis of samples from 30 DLBCL patients and 15 reactive hyperplasia of the lymph nodes showed AEG-1 positivity with variable levels of expression in 76.67% DLBCL cases while little to no AEG-1 expression was detected in the controls.	('DLBCL', 'Disease', (177, 182))	('positivity', 'Var', (121, 131))	('AEG-1', 'Gene', (115, 120))	('hyperplasia', 'Disease', (77, 88))	('hyperplasia of the lymph', 'Phenotype', 'HP:0002716', (77, 101))	('hyperplasia', 'Disease', 'MESH:D006965', (77, 88))	('patients', 'Species', '9606', (52, 60))
245082	33671513	At titers of >=1:50 anti-AEG-1 antibody was detected in 49% of these patients, including 45% breast cancer, 50% HCC, 49% colorectal cancer, 45% lung cancer and 49% gastric cancer patients, with none of 230 normal individuals displaying positivity (p < 0.01).	('gastric cancer', 'Phenotype', 'HP:0012126', (164, 178))	('anti-AEG-1', 'Var', (20, 30))	('HCC', 'Disease', (112, 115))	('detected', 'Reg', (44, 52))	('colorectal cancer', 'Disease', (121, 138))	('lung cancer', 'Disease', 'MESH:D008175', (144, 155))	('patients', 'Species', '9606', (69, 77))	('breast cancer', 'Phenotype', 'HP:0003002', (93, 106))	('lung cancer', 'Phenotype', 'HP:0100526', (144, 155))	('breast cancer', 'Disease', 'MESH:D001943', (93, 106))	('breast cancer', 'Disease', (93, 106))	('patients', 'Species', '9606', (179, 187))	('gastric cancer', 'Disease', (164, 178))	('rectal cancer', 'Phenotype', 'HP:0100743', (125, 138))	('colorectal cancer', 'Phenotype', 'HP:0003003', (121, 138))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('gastric cancer', 'Disease', 'MESH:D013274', (164, 178))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('lung cancer', 'Disease', (144, 155))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('colorectal cancer', 'Disease', 'MESH:D015179', (121, 138))
245087	33671513	Even though AEG-1 is an established diagnostic/prognostic marker for cancer, its use is limited by the availability of tumor biopsy samples and as such anti-AEG-1 antibody might serve as an important surrogate for AEG-1.	('tumor', 'Disease', (119, 124))	('anti-AEG-1', 'Var', (152, 162))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('cancer', 'Disease', (69, 75))
245099	33671513	The present study was supported in part by The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Grant 1R01DK107451-01A1, National Cancer Institute (NCI) Grants 1R01CA230561-01A1, 1R01CA240004-01 and 1R01CA244993-01, and Department of Defense (DOD) Grant CA170048.	('Diabetes', 'Disease', (69, 77))	('R01CA230561-01A1', 'CellLine', 'CVCL:X698', (185, 201))	('Cancer', 'Disease', (154, 160))	('Cancer', 'Disease', 'MESH:D009369', (154, 160))	('Cancer', 'Phenotype', 'HP:0002664', (154, 160))	('R01CA244993-01', 'CellLine', 'CVCL:9726', (224, 238))	('Kidney Diseases', 'Disease', 'MESH:D007674', (96, 111))	('Diabetes', 'Disease', 'MESH:D003920', (69, 77))	('1R01CA244993-01', 'Var', (223, 238))	('Kidney Diseases', 'Phenotype', 'HP:0000112', (96, 111))	('Kidney Diseases', 'Disease', (96, 111))
245106	31878938	132 patients (32.0%) had TC >= 25% PD-L1 expression; 199 patients (48.3%) and 85 patients (20.6%) had TC >= 10% and >= 50%, respectively.	('TC >= 25%', 'Var', (25, 34))	('TC', 'Chemical', '-', (102, 104))	('patients', 'Species', '9606', (57, 65))	('patients', 'Species', '9606', (81, 89))	('TC', 'Chemical', '-', (25, 27))	('patients', 'Species', '9606', (4, 12))	('PD-L1', 'Gene', (35, 40))
245118	31878938	Evidence is building that PD-L1 expression on TCs is associated with improved survival in patients with HNSCC treated with IO agents and yet the role of PD-L1 in outcomes irrespective of treatment (i.e.	('NS', 'Disease', 'MESH:D009404', (105, 107))	('TCs', 'Chemical', '-', (46, 49))	('improved', 'PosReg', (69, 77))	('IO agents', 'Chemical', '-', (123, 132))	('HNSCC', 'Phenotype', 'HP:0012288', (104, 109))	('expression', 'Var', (32, 42))	('PD-L1', 'Gene', (26, 31))	('survival', 'MPA', (78, 86))	('patients', 'Species', '9606', (90, 98))
245120	31878938	Here, we describe patient characteristics, OS, and other clinical outcomes related to PD-L1 expression independent of treatment choice.	('PD-L1', 'Gene', (86, 91))	('patient', 'Species', '9606', (18, 25))	('expression', 'Var', (92, 102))
245123	31878938	Patients with locally advanced disease amenable to curative local therapy were excluded as were patients who had received prior IO treatment with anti-cytotoxic T-lymphocyte-associated antigen 4, or anti-PD-1, anti-PD-L1, or anti-PD-L2 antibodies for HNSCC.	('anti-PD-L1', 'Var', (210, 220))	('HNSCC', 'Phenotype', 'HP:0012288', (251, 256))	('Patients', 'Species', '9606', (0, 8))	('IO', 'Chemical', '-', (128, 130))	('PD-L2', 'Gene', (230, 235))	('PD-L2', 'Gene', '80380', (230, 235))	('patients', 'Species', '9606', (96, 104))	('PD-1', 'Gene', '5133', (204, 208))	('PD-1', 'Gene', (204, 208))	('NS', 'Disease', 'MESH:D009404', (252, 254))
245135	31878938	OS and PFS were compared between patients with PD-L1 high and low/negative expression for the different cutoffs using a log-rank test at a 5% level of significance.	('high', 'Var', (53, 57))	('patients', 'Species', '9606', (33, 41))	('PD-L1', 'Gene', (47, 52))	('low/negative', 'NegReg', (62, 74))	('expression', 'MPA', (75, 85))
245144	31878938	There were 132 patients (32.0%) who were found to have TC >= 25% PD-L1 expression (Table 1).	('PD-L1', 'Gene', (65, 70))	('patients', 'Species', '9606', (15, 23))	('TC >= 25%', 'Var', (55, 64))	('TC', 'Chemical', '-', (55, 57))
245168	31878938	The OS for patients with oral cavity tumors was numerically lower in the PD-L1 TC >= 25% population than in the PD-L1 TC < 25% population (median 6.9 months vs 9.7 months; log-rank test; P = 0.15).	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('TC', 'Chemical', '-', (118, 120))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('TC', 'Chemical', '-', (79, 81))	('oral cavity tumors', 'Phenotype', 'HP:0100649', (25, 43))	('tumors', 'Disease', (37, 43))	('patients', 'Species', '9606', (11, 19))	('PD-L1 TC >= 25%', 'Var', (73, 88))	('tumors', 'Disease', 'MESH:D009369', (37, 43))	('lower', 'NegReg', (60, 65))
245169	31878938	Similarly, for oropharyngeal primary site patients, those in the PD-L1 TC >= 25% population had a median OS of 6.3 months versus 14.8 months for patients in the PD-L1 TC < 25% population (log-rank test; P = 0.03) (Fig.	('patients', 'Species', '9606', (145, 153))	('TC', 'Chemical', '-', (71, 73))	('TC', 'Chemical', '-', (167, 169))	('oropharyngeal primary', 'Disease', (15, 36))	('PD-L1 TC >= 25%', 'Var', (65, 80))	('patients', 'Species', '9606', (42, 50))
245170	31878938	In contrast, numerically longer survival was seen in the PD-L1 TC >= 25% population than in the PD-L1 TC < 25% population with hypopharyngeal primary tumors (median 21 months vs 12.2 months; log-rank test; P = 0.35).	('tumors', 'Phenotype', 'HP:0002664', (150, 156))	('TC', 'Chemical', '-', (102, 104))	('survival', 'MPA', (32, 40))	('PD-L1', 'Var', (57, 62))	('longer', 'PosReg', (25, 31))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('TC', 'Chemical', '-', (63, 65))	('hypopharyngeal primary tumors', 'Disease', 'MESH:D007012', (127, 156))	('hypopharyngeal primary tumors', 'Disease', (127, 156))
245171	31878938	The PFS from the start of first-line chemotherapy did not differ significantly among patients with TC >= 25% PD-L1 expression versus TC < 25% (median: 4.2 vs 4.8 months, P = 0.37) (Fig.	('TC', 'Chemical', '-', (99, 101))	('TC', 'Chemical', '-', (133, 135))	('patients', 'Species', '9606', (85, 93))	('PD-L1', 'Gene', (109, 114))	('TC >= 25%', 'Var', (99, 108))
245173	31878938	However, median PFS from the start of second-line chemotherapy was significantly different between patients with TC >= 25% PD-L1 (n = 25) expression versus those with TC < 25% (n = 58) (4.1 months vs 2.2 months, P = 0.04).	('TC', 'Chemical', '-', (113, 115))	('TC', 'Chemical', '-', (167, 169))	('patients', 'Species', '9606', (99, 107))	('PD-L1', 'Gene', (123, 128))	('different', 'Reg', (81, 90))	('TC >= 25%', 'Var', (113, 122))
245174	31878938	The difference was also significant for patients with TC >= 10% PD-L1 (n = 38) expression versus those with TC < 10% (n = 45) (4.1 vs 2.1 months, P = 0.04) and those patients with TC >= 50% PD-L1 (n = 13) expression versus those with TC < 50% (n = 70) (6.3 vs 2.4 months, P = 0.03).	('TC', 'Chemical', '-', (54, 56))	('TC >= 10%', 'Var', (54, 63))	('patients', 'Species', '9606', (40, 48))	('PD-L1', 'Gene', (64, 69))	('TC', 'Chemical', '-', (234, 236))	('TC', 'Chemical', '-', (180, 182))	('expression', 'Var', (79, 89))	('TC', 'Chemical', '-', (108, 110))	('patients', 'Species', '9606', (166, 174))
245208	31878938	The median OS for patients with oral cavity carcinoma was lower in PD-L1 TC >= 25% than PD-L1 TC < 25% patients; poor prognosis in PD-L1 TC >= 25% oral cavity patients has been observed by others.	('lower', 'NegReg', (58, 63))	('TC', 'Chemical', '-', (73, 75))	('TC', 'Chemical', '-', (137, 139))	('oral cavity carcinoma', 'Disease', (32, 53))	('patients', 'Species', '9606', (18, 26))	('TC', 'Chemical', '-', (94, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (44, 53))	('patients', 'Species', '9606', (103, 111))	('patients', 'Species', '9606', (159, 167))	('oral cavity carcinoma', 'Disease', 'MESH:D009062', (32, 53))	('PD-L1 TC >= 25%', 'Var', (67, 82))
245209	31878938	Likewise, for oropharyngeal primary site patients, median OS in patients with PD-L1 TC >= 25% was less than that seen for patients with PD-L1 TC < 25% (log-rank test; P = 0.03; Fig.	('patients', 'Species', '9606', (64, 72))	('PD-L1 TC >= 25%', 'Var', (78, 93))	('less', 'NegReg', (98, 102))	('patients', 'Species', '9606', (41, 49))	('patients', 'Species', '9606', (122, 130))	('TC', 'Chemical', '-', (142, 144))	('TC', 'Chemical', '-', (84, 86))
245210	31878938	Conversely, longer survival was seen in PD-L1 TC >= 25% than PD-L1 TC < 25% patients with hypopharyngeal primary tumors (21 months vs 12.2 months).	('longer', 'PosReg', (12, 18))	('TC', 'Chemical', '-', (46, 48))	('patients', 'Species', '9606', (76, 84))	('hypopharyngeal primary tumors', 'Disease', 'MESH:D007012', (90, 119))	('PD-L1', 'Var', (40, 45))	('hypopharyngeal primary tumors', 'Disease', (90, 119))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('TC', 'Chemical', '-', (67, 69))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
245217	31878938	The variety of scoring methods used for determining PD-L1 positivity (TCs and/or ICs) may also contribute to the apparent contradictory publications regarding its prognostic value.	('positivity', 'Var', (58, 68))	('TCs', 'Chemical', '-', (70, 73))	('PD-L1', 'Gene', (52, 57))
245239	30643111	Here, we report that RTHF inhibits cell proliferation and induces apoptosis in cutaneous squamous cell carcinoma A431 cells and is a potential strategy for cancer therapy.	('RTHF', 'Var', (21, 25))	('inhibits', 'NegReg', (26, 34))	('cutaneous squamous cell carcinoma', 'Disease', (79, 112))	('cancer', 'Disease', (156, 162))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('induces', 'Reg', (58, 65))	('cutaneous squamous cell carcinoma', 'Phenotype', 'HP:0006739', (79, 112))	('cell proliferation', 'CPA', (35, 53))	('cutaneous squamous cell carcinoma', 'Disease', 'MESH:D002294', (79, 112))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (89, 112))	('apoptosis', 'CPA', (66, 75))	('RTHF', 'Chemical', '-', (21, 25))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('A431', 'CellLine', 'CVCL:0037', (113, 117))
245244	30643111	Enzyme proteasome assay show that the RTHF treatment of activity of proteasome and DUB was significantly lower than in control.	('lower', 'NegReg', (105, 110))	('activity', 'MPA', (56, 64))	('proteasome', 'Protein', (68, 78))	('RTHF', 'Chemical', '-', (38, 42))	('RTHF treatment', 'Var', (38, 52))
245254	30643111	Here, we found that RTHF inhibits proliferation and induces apoptosis of cutaneous squamous cell carcinoma A431 cells.	('proliferation', 'CPA', (34, 47))	('cutaneous squamous cell carcinoma', 'Disease', (73, 106))	('RTHF', 'Var', (20, 24))	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('inhibits', 'NegReg', (25, 33))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (83, 106))	('cutaneous squamous cell carcinoma', 'Phenotype', 'HP:0006739', (73, 106))	('apoptosis', 'CPA', (60, 69))	('A431', 'CellLine', 'CVCL:0037', (107, 111))	('cutaneous squamous cell carcinoma', 'Disease', 'MESH:D002294', (73, 106))	('induces', 'Reg', (52, 59))	('RTHF', 'Chemical', '-', (20, 24))
245272	30643111	As shown in Figure 1, RTHF dramatically inhibited A431 cell growth in a dose-dependent manner (P<0.05).	('A431', 'CellLine', 'CVCL:0037', (50, 54))	('RTHF', 'Chemical', '-', (22, 26))	('RTHF', 'Var', (22, 26))	('inhibited', 'NegReg', (40, 49))
245278	30643111	After incubation for 48 h, RTHF dramatically inhibited the CT-like activity (p<0.05) (Figure 5).	('RTHF', 'Chemical', '-', (27, 31))	('inhibited', 'NegReg', (45, 54))	('RTHF', 'Var', (27, 31))	('CT-like activity', 'CPA', (59, 75))
245279	30643111	As shown in Figure 6, RTHF caused a dose-dependent decrease of DUB activity in A431 cancer cells (p<0.05).	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('cancer', 'Disease', (84, 90))	('A431', 'CellLine', 'CVCL:0037', (79, 83))	('RTHF', 'Chemical', '-', (22, 26))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('decrease', 'NegReg', (51, 59))	('RTHF', 'Var', (22, 26))	('DUB activity', 'MPA', (63, 75))
245283	30643111	As shown in Figure 8, RTHF increased the level of ub-prs but decreased levels of USP14, UCHL5, and POH1 in a concentration-dependent manner.	('POH1', 'Gene', '10213', (99, 103))	('UCHL5', 'Gene', (88, 93))	('increased', 'PosReg', (27, 36))	('ub-prs', 'MPA', (50, 56))	('USP14', 'Gene', '9097', (81, 86))	('UCHL5', 'Gene', '51377', (88, 93))	('RTHF', 'Chemical', '-', (22, 26))	('USP14', 'Gene', (81, 86))	('decreased', 'NegReg', (61, 70))	('POH1', 'Gene', (99, 103))	('RTHF', 'Var', (22, 26))
245288	30643111	In this study, we showed that RTHF significantly inhibited the growth and induced cell apoptosis of A431 cells.	('RTHF', 'Var', (30, 34))	('growth', 'CPA', (63, 69))	('A431', 'CellLine', 'CVCL:0037', (100, 104))	('induced', 'Reg', (74, 81))	('cell apoptosis', 'CPA', (82, 96))	('RTHF', 'Chemical', '-', (30, 34))	('inhibited', 'NegReg', (49, 58))
245291	30643111	In this study, we showed the ability of RTHF to significantly decrease the chymotrypsin-like activity.	('RTHF', 'Var', (40, 44))	('decrease', 'NegReg', (62, 70))	('chymotrypsin-like activity', 'MPA', (75, 101))	('RTHF', 'Chemical', '-', (40, 44))
245293	30643111	In this report, we showed that RTHF significantly inhibits the activity of DUB compared to control.	('inhibits', 'NegReg', (50, 58))	('RTHF', 'Var', (31, 35))	('activity', 'MPA', (63, 71))	('RTHF', 'Chemical', '-', (31, 35))
245295	30643111	In humans, 19S RP is associated with 3 deubiquitinases (DUBs), USP14/Ubp6, and UCHL5/Uch37, which belong to the ubiquitin-specific proteases (USP) and ubiquitin C-terminal hydrolases (UCH) families, respectively.	('Uch37', 'Gene', (85, 90))	('UCHL5', 'Gene', (79, 84))	('USP14', 'Gene', '9097', (63, 68))	('humans', 'Species', '9606', (3, 9))	('19S RP', 'Var', (11, 17))	('Uch37', 'Gene', '51377', (85, 90))	('UCHL5', 'Gene', '51377', (79, 84))	('USP14', 'Gene', (63, 68))
245303	30643111	POH1 is essential for viability, and POH1 knockdown inhibits proteasome activity and reduces cell survival.	('POH1', 'Gene', '10213', (37, 41))	('POH1', 'Gene', '10213', (0, 4))	('cell survival', 'CPA', (93, 106))	('inhibits', 'NegReg', (52, 60))	('POH1', 'Gene', (37, 41))	('proteasome activity', 'MPA', (61, 80))	('reduces', 'NegReg', (85, 92))	('POH1', 'Gene', (0, 4))	('knockdown', 'Var', (42, 51))
245305	30643111	Indeed, it has been reported that knockdown of both UCHL5 and USP14 but (not either one alone) leads to defects in UPS and impairs proteasome activity.	('defects', 'NegReg', (104, 111))	('USP14', 'Gene', (62, 67))	('UCHL5', 'Gene', '51377', (52, 57))	('impairs', 'NegReg', (123, 130))	('UPS', 'Disease', 'MESH:D017118', (115, 118))	('proteasome activity', 'MPA', (131, 150))	('UPS', 'Disease', (115, 118))	('UCHL5', 'Gene', (52, 57))	('knockdown', 'Var', (34, 43))	('USP14', 'Gene', '9097', (62, 67))
245307	30643111	We found that RTHF significant mediates inhibition of growth and induction of apoptosis in A431 cells, and showed that inhibition of DUBs might be one of the major mechanisms by which RTHF inhibits tumor cells.	('RTHF', 'Var', (14, 18))	('apoptosis', 'CPA', (78, 87))	('RTHF', 'Chemical', '-', (184, 188))	('A431', 'CellLine', 'CVCL:0037', (91, 95))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('inhibition', 'NegReg', (40, 50))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('growth', 'CPA', (54, 60))	('tumor', 'Disease', (198, 203))	('RTHF', 'Chemical', '-', (14, 18))
245318	30107644	The results showed that recurrent mutations in MUC genes were significantly associated with better survival prognosis.	('better', 'PosReg', (92, 98))	('MUC', 'Gene', '100508689', (47, 50))	('MUC', 'Gene', (47, 50))	('associated', 'Reg', (76, 86))	('mutations', 'Var', (34, 43))
245319	30107644	Only a small part of RMGs was differentially expressed due to their own mutations and most of them were downregulated.	('RMGs', 'Chemical', '-', (21, 25))	('mutations', 'Var', (72, 81))	('RMGs', 'Gene', (21, 25))	('downregulated', 'NegReg', (104, 117))
245326	30107644	Mutations in cancer genome can influence molecular function of genes and signaling pathways, leading to cell differentiation, proliferation, and survival (Hanahan & Weinberg Robert, 2011; Watson, Takahashi, Futreal, & Chin, 2013).	('genes', 'Pathway', (63, 68))	('proliferation', 'CPA', (126, 139))	('leading to', 'Reg', (93, 103))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('cell differentiation', 'CPA', (104, 124))	('influence', 'Reg', (31, 40))	('cancer', 'Disease', (13, 19))	('cancer', 'Disease', 'MESH:D009369', (13, 19))	('Mutations', 'Var', (0, 9))	('signaling pathways', 'Pathway', (73, 91))	('survival', 'CPA', (145, 153))	('molecular function', 'MPA', (41, 59))
245330	30107644	TP53 (OMIM *191170) was reported as the most frequently mutated gene in diverse cancers, and patients with TP53 mutation tend to have worse prognosis (Wang & Sun, 2017).	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('mutation', 'Var', (112, 120))	('cancers', 'Disease', 'MESH:D009369', (80, 87))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancers', 'Disease', (80, 87))	('TP53', 'Gene', '7157', (107, 111))	('TP53', 'Gene', (107, 111))	('patients', 'Species', '9606', (93, 101))	('cancers', 'Phenotype', 'HP:0002664', (80, 87))
245331	30107644	investigated 127 significantly mutated genes in 12 cancers and categorized them into 20 cellular processes, including Wnt/beta-catenin, MAPK, and PI3K signaling pathways (Kandoth et al., 2013).	('PI3K signaling pathways', 'Pathway', (146, 169))	('beta-catenin', 'Gene', (122, 134))	('beta-catenin', 'Gene', '1499', (122, 134))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('MAPK', 'Pathway', (136, 140))	('cancers', 'Phenotype', 'HP:0002664', (51, 58))	('cancers', 'Disease', (51, 58))	('cancers', 'Disease', 'MESH:D009369', (51, 58))	('mutated', 'Var', (31, 38))
245333	30107644	For instance, 10 RMGs including KRAS (* 190070), TP53, CDKN2A (* 600160), and RREB1 (* 602209) were identified in Pancreatic Ductal Adenocarcinoma (PDAC), and it was revealed that the frequent disruptions in RAS-MAPK pathway played a pivotal role in this cancer (Network, 2014).	('CDKN2A', 'Gene', '1029', (55, 61))	('TP53', 'Gene', '7157', (49, 53))	('RMGs', 'Chemical', '-', (17, 21))	('cancer', 'Disease', (255, 261))	('* 600160', 'Var', (63, 71))	('PDAC', 'Phenotype', 'HP:0006725', (148, 152))	('disruptions', 'Reg', (193, 204))	('Pancreatic Ductal Adenocarcinoma', 'Disease', (114, 146))	('cancer', 'Phenotype', 'HP:0002664', (255, 261))	('KRAS', 'Gene', '3845', (32, 36))	('Pancreatic Ductal Adenocarcinoma', 'Phenotype', 'HP:0006725', (114, 146))	('TP53', 'Gene', (49, 53))	('KRAS', 'Gene', (32, 36))	('cancer', 'Disease', 'MESH:D009369', (255, 261))	('RREB1', 'Gene', '6239', (78, 83))	('Pancreatic Ductal Adenocarcinoma', 'Disease', 'MESH:D021441', (114, 146))	('CDKN2A', 'Gene', (55, 61))	('RAS-MAPK pathway', 'Pathway', (208, 224))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('RREB1', 'Gene', (78, 83))	('* 602209', 'Var', (85, 93))
245334	30107644	Besides, dozens of significantly mutated genes in various canonical signaling pathways were identified in Muscle-Invasive Bladder Cancer (BLCA), which highlighted the importance of these pathways in the disease (Robertson et al., 2017).	('Muscle-Invasive Bladder Cancer', 'Disease', 'MESH:D001749', (106, 136))	('Invasive Bladder', 'Phenotype', 'HP:0100645', (113, 129))	('Cancer', 'Phenotype', 'HP:0002664', (130, 136))	('Bladder Cancer', 'Phenotype', 'HP:0009725', (122, 136))	('mutated', 'Var', (33, 40))	('Muscle-Invasive Bladder Cancer', 'Disease', (106, 136))	('BLCA', 'Phenotype', 'HP:0009725', (138, 142))
245337	30107644	Besides, it was reported that the mutations of six RMGs including TP53, KDR (* 191306), PIK3CA (* 171834), ATM (* 607585), AKT1 (* 164730), and KIT (* 164920) were associated with a poor prognosis in sporadic triple negative breast cancer (Pop et al., 2018).	('PIK3CA', 'Gene', '5290', (88, 94))	('TP53', 'Gene', '7157', (66, 70))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('* 191306', 'Var', (77, 85))	('AKT1', 'Gene', '207', (123, 127))	('KDR', 'Gene', '3791', (72, 75))	('* 164730', 'Var', (129, 137))	('* 171834', 'Var', (96, 104))	('PIK3CA', 'Gene', (88, 94))	('breast cancer', 'Phenotype', 'HP:0003002', (225, 238))	('* 164920', 'Var', (149, 157))	('AKT1', 'Gene', (123, 127))	('associated', 'Reg', (164, 174))	('TP53', 'Gene', (66, 70))	('ATM', 'Gene', '472', (107, 110))	('* 607585', 'Var', (112, 120))	('breast cancer', 'Disease', 'MESH:D001943', (225, 238))	('breast cancer', 'Disease', (225, 238))	('KIT', 'Gene', (144, 147))	('KDR', 'Gene', (72, 75))	('RMGs', 'Chemical', '-', (51, 55))	('ATM', 'Gene', (107, 110))
245338	30107644	The diagnostic and prognostic impacts of RMGs (e.g., EZH2 (* 601573), ELP3 (* 612722), and IDH2 (* 147650)) in lymphoma were surveyed for better clinical decision making (Rosenquist et al., 2016).	('* 601573', 'Var', (59, 67))	('* 147650', 'Var', (97, 105))	('ELP3', 'Gene', '55140', (70, 74))	('lymphoma', 'Phenotype', 'HP:0002665', (111, 119))	('IDH2', 'Gene', (91, 95))	('lymphoma', 'Disease', 'MESH:D008223', (111, 119))	('lymphoma', 'Disease', (111, 119))	('RMGs', 'Chemical', '-', (41, 45))	('IDH2', 'Gene', '3418', (91, 95))	('ELP3', 'Gene', (70, 74))	('* 612722', 'Var', (76, 84))	('EZH2', 'Gene', (53, 57))	('EZH2', 'Gene', '2146', (53, 57))
245339	30107644	Moreover, RMGs (e.g., TET2 (* 612839), DNMT3A (* 602769), BAP1 (* 603089), and ASXL1 (* 612990)) involved in histone modification, chromatin remodeling and DNA methylation were associated with adverse outcome in thymic carcinoma (Wang et al., 2014).	('DNMT3A', 'Gene', (39, 45))	('DNMT3A', 'Gene', '1788', (39, 45))	('* 612839', 'Var', (28, 36))	('BAP1', 'Gene', (58, 62))	('TET2', 'Gene', '54790', (22, 26))	('thymic carcinoma', 'Disease', 'MESH:D013945', (212, 228))	('thymic carcinoma', 'Disease', (212, 228))	('* 602769', 'Var', (47, 55))	('ASXL1', 'Gene', '171023', (79, 84))	('RMGs', 'Chemical', '-', (10, 14))	('carcinoma', 'Phenotype', 'HP:0030731', (219, 228))	('associated', 'Reg', (177, 187))	('TET2', 'Gene', (22, 26))	('BAP1', 'Gene', '8314', (58, 62))	('* 603089', 'Var', (64, 72))	('ASXL1', 'Gene', (79, 84))	('* 612990', 'Var', (86, 94))
245355	30107644	The differences of overall survival time between RMG-mutation, RMG-MS or RMG-NS patients and RMG wild-type patients were shown by KM survival curves (log-rank test).	('RMG-NS', 'Disease', (73, 79))	('patients', 'Species', '9606', (80, 88))	('RMG-mutation', 'Var', (49, 61))	('RMG-NS', 'Disease', 'MESH:D009404', (73, 79))	('RMG-MS', 'Disease', (63, 69))	('patients', 'Species', '9606', (107, 115))
245358	30107644	As a result, we identified 897 unique RMGs across 31 cancer types (Supporting Information Table S1).	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('RMGs', 'Var', (38, 42))	('RMGs', 'Chemical', '-', (38, 42))
245360	30107644	There were more than 100 RMGs in SKCM, STAD, LUSC, LUAD, ACC, and DLBC (see the abbreviations of cancer types in method section), indicating that these cancers were closely related to gene recurrent mutations.	('LUAD', 'Phenotype', 'HP:0030078', (51, 55))	('cancers', 'Disease', (152, 159))	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', (97, 103))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('cancers', 'Disease', 'MESH:D009369', (152, 159))	('LUSC', 'Phenotype', 'HP:0030359', (45, 49))	('ACC', 'Phenotype', 'HP:0006744', (57, 60))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('RMGs', 'Chemical', '-', (25, 29))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('mutations', 'Var', (199, 208))	('cancers', 'Phenotype', 'HP:0002664', (152, 159))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
245373	30107644	In addition, we identified 624 specifically mutated RMGs (smRMGs) that were only in a single cancer type (Figure 1d and Supporting Information Table S2).	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('RMGs', 'Chemical', '-', (60, 64))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('mutated', 'Var', (44, 51))	('RMGs', 'Chemical', '-', (52, 56))
245377	30107644	We also detected another five smRMGs that mutated in nearly half of the samples in corresponding cancers, including PCDHAC2 in SKCM (53%), ZFPM1 in ACC (52%), VHL in KIRC (49%), GNAQ in UVM (49%), and ADAM6 in LUSC (45%).	('PCDHAC2', 'Gene', '56134', (116, 123))	('UVM', 'Phenotype', 'HP:0007716', (186, 189))	('ADAM6', 'Gene', '8755', (201, 206))	('PCDHAC2', 'Gene', (116, 123))	('cancers', 'Phenotype', 'HP:0002664', (97, 104))	('RMGs', 'Chemical', '-', (32, 36))	('cancers', 'Disease', (97, 104))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('VHL', 'Disease', (159, 162))	('GNAQ', 'Gene', '2776', (178, 182))	('GNAQ', 'Gene', (178, 182))	('ZFPM1', 'Gene', '161882', (139, 144))	('cancers', 'Disease', 'MESH:D009369', (97, 104))	('LUSC', 'Phenotype', 'HP:0030359', (210, 214))	('ACC', 'Phenotype', 'HP:0006744', (148, 151))	('mutated', 'Var', (42, 49))	('ADAM6', 'Gene', (201, 206))	('VHL', 'Disease', 'MESH:D006623', (159, 162))	('ZFPM1', 'Gene', (139, 144))
245380	30107644	PI3K-Akt signaling pathway had the most number of RMGs (n = 47) and were disrupted in 23 cancer types.	('Akt', 'Gene', '207', (5, 8))	('RMGs', 'Var', (50, 54))	('RMGs', 'Chemical', '-', (50, 54))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('cancer', 'Disease', (89, 95))	('Akt', 'Gene', (5, 8))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
245384	30107644	It was also shown that BLCA had the greatest proportion of RMGs in cell cycle.	('cell cycle', 'CPA', (67, 77))	('RMGs', 'Var', (59, 63))	('BLCA', 'Phenotype', 'HP:0009725', (23, 27))	('RMGs', 'Chemical', '-', (59, 63))
245390	30107644	For most cRMGs, missense mutation accounts for the largest proportion (>50%), especially for PIK3CA.	('PIK3CA', 'Gene', (93, 99))	('PIK3CA', 'Gene', '5290', (93, 99))	('RMGs', 'Chemical', '-', (10, 14))	('missense mutation', 'Var', (16, 33))
245391	30107644	Specially, KMT2C in LUSC and CHOL as well as DNAH5 in CHOL were more frequently disrupted by nonsense mutation.	('DNAH5', 'Gene', (45, 50))	('DNAH5', 'Gene', '1767', (45, 50))	('disrupted', 'Reg', (80, 89))	('CHOL', 'Phenotype', 'HP:0030153', (29, 33))	('KMT2C', 'Gene', (11, 16))	('nonsense mutation', 'Var', (93, 110))	('KMT2C', 'Gene', '58508', (11, 16))	('CHOL', 'Phenotype', 'HP:0030153', (54, 58))	('LUSC', 'Phenotype', 'HP:0030359', (20, 24))
245392	30107644	In addition, frame shift insertion was also found to be a key mutation for MUC5B in KICH, which occupied a relatively large proportion.	('MUC5B', 'Gene', '727897', (75, 80))	('frame shift insertion', 'Var', (13, 34))	('MUC5B', 'Gene', (75, 80))
245395	30107644	It was observed that TP53 was more frequently disrupted by nonsense mutations, frame-shift indels and splice site mutations compared with other cRMGs (Figure 3a), which results in the initiation and progression of cancers (Payne & Kemp, 2005; Wojnarowicz et al., 2012).	('TP53', 'Gene', (21, 25))	('RMGs', 'Chemical', '-', (145, 149))	('frame-shift indels', 'Var', (79, 97))	('cancers', 'Phenotype', 'HP:0002664', (214, 221))	('splice site mutations', 'Var', (102, 123))	('results in', 'Reg', (169, 179))	('nonsense mutations', 'Var', (59, 77))	('cancers', 'Disease', (214, 221))	('cancers', 'Disease', 'MESH:D009369', (214, 221))	('progression', 'PosReg', (199, 210))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('disrupted', 'Reg', (46, 55))	('TP53', 'Gene', '7157', (21, 25))
245397	30107644	To assess the functional impacts of TP53 mutations, we identified 87 DEGs shared by more than one-quarter of the 21 cancer types.	('mutations', 'Var', (41, 50))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('TP53', 'Gene', '7157', (36, 40))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('TP53', 'Gene', (36, 40))
245403	30107644	Surprisingly, patients with MUC3A, MUC4, MUC5B, MUC6, and MUC16 mutations had significantly better OS prognoses compared with those without mutations in several cancer types (Figure 4a).	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('MUC6', 'Gene', (48, 52))	('patients', 'Species', '9606', (14, 22))	('MUC4', 'Gene', '4585', (35, 39))	('MUC16', 'Gene', '94025', (58, 63))	('MUC4', 'Gene', (35, 39))	('MUC6', 'Gene', '4588', (48, 52))	('MUC5B', 'Gene', '727897', (41, 46))	('mutations', 'Var', (64, 73))	('MUC5B', 'Gene', (41, 46))	('OS prognoses', 'CPA', (99, 111))	('cancer', 'Disease', (161, 167))	('MUC3A', 'Gene', '4584', (28, 33))	('MUC3A', 'Gene', (28, 33))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('better', 'PosReg', (92, 98))	('MUC16', 'Gene', (58, 63))
245405	30107644	Results showed that there was a greater proportion of in-frame deletion of MUC4 in KIPAN and KIRC (Figure 3a), where the mutations of MUC4 were significantly associated with prognosis.	('MUC4', 'Gene', (75, 79))	('MUC4', 'Gene', (134, 138))	('mutations', 'Var', (121, 130))	('associated with', 'Reg', (158, 173))	('MUC4', 'Gene', '4585', (134, 138))	('in-frame deletion', 'Var', (54, 71))	('MUC4', 'Gene', '4585', (75, 79))
245406	30107644	Similarly, we found a greater proportion of frame-shift deletion of MUC5B in STAD and STES.	('STES', 'Chemical', '-', (86, 90))	('MUC5B', 'Gene', '727897', (68, 73))	('MUC5B', 'Gene', (68, 73))	('STAD', 'Disease', (77, 81))	('frame-shift deletion', 'Var', (44, 64))	('STES', 'Disease', (86, 90))
245410	30107644	There were more recurrently mutated MUC family genes in SKCM, DLBC, CHOL, ACC, ESCA, KICH, and STAD compared with other cancer types.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('STAD', 'Disease', (95, 99))	('KICH', 'Disease', (85, 89))	('mutated', 'Var', (28, 35))	('SKCM', 'Disease', (56, 60))	('CHOL', 'Disease', (68, 72))	('ESCA', 'Phenotype', 'HP:0011459', (79, 83))	('DLBC', 'Disease', (62, 66))	('ESCA', 'Disease', (79, 83))	('ACC', 'Phenotype', 'HP:0006744', (74, 77))	('cancer', 'Disease', (120, 126))	('ACC', 'Disease', (74, 77))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('MUC', 'Gene', '100508689', (36, 39))	('CHOL', 'Phenotype', 'HP:0030153', (68, 72))	('MUC', 'Gene', (36, 39))
245412	30107644	As a result, the better OS prognosis were observed in SKCM and STAD (Supporting Information Figure S3), which further suggested that mutations of MUC family genes were frequently associated with better survival prognosis in cancers.	('better', 'PosReg', (195, 201))	('associated', 'Reg', (179, 189))	('cancers', 'Phenotype', 'HP:0002664', (224, 231))	('cancers', 'Disease', (224, 231))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('mutations', 'Var', (133, 142))	('cancers', 'Disease', 'MESH:D009369', (224, 231))	('MUC', 'Gene', '100508689', (146, 149))	('MUC', 'Gene', (146, 149))
245413	30107644	To explore the impacts of mutation types on gene expression, we firstly identified 37 RMGs which were differentially expressed caused by their own mutations (Supporting Information Table S3).	('RMGs', 'Chemical', '-', (86, 90))	('mutations', 'Var', (147, 156))	('caused', 'Reg', (127, 133))
245416	30107644	We further categorized the mutations into two groups: MS (including missense and in-frame mutations) and NS (including nonsense, frame-shift, and splice site mutations).	('NS', 'Disease', 'MESH:D009404', (105, 107))	('frame-shift', 'Var', (129, 140))	('nonsense', 'Var', (119, 127))	('splice site mutations', 'Var', (146, 167))	('missense', 'Var', (68, 76))
245419	30107644	When comparing RMG-NS cancers to RMG wild-type cancers, we found all the 20 differentially expressed RMGs are downregulated (Supporting Information Figure S4), which may mainly due to nonsense-mediated mRNA decay (Noensie & Dietz, 2001).	('RMGs', 'Chemical', '-', (101, 105))	('cancers', 'Disease', 'MESH:D009369', (22, 29))	('cancers', 'Phenotype', 'HP:0002664', (22, 29))	('RMG-NS cancers', 'Disease', 'MESH:D009369', (15, 29))	('downregulated', 'NegReg', (110, 123))	('cancers', 'Disease', (22, 29))	('cancers', 'Disease', 'MESH:D009369', (47, 54))	('cancers', 'Phenotype', 'HP:0002664', (47, 54))	('cancers', 'Disease', (47, 54))	('RMG-NS cancers', 'Disease', (15, 29))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('nonsense-mediated mRNA decay', 'Var', (184, 212))	('RMGs', 'Gene', (101, 105))
245424	30107644	Similarly, to study the influences of mutation types on prognosis, we identified 13 cRMGs that mutated in sufficient samples (n >= 5) in each respective group (MS and NS) excluding TP53 that have been widely explored (Freed-Pastor & Prives, 2012).	('NS', 'Disease', 'MESH:D009404', (167, 169))	('TP53', 'Gene', (181, 185))	('mutated', 'Var', (95, 102))	('RMGs', 'Chemical', '-', (85, 89))	('TP53', 'Gene', '7157', (181, 185))
245426	30107644	The results showed that six cRMGs including OBSCN, CDKN2A, CSMD3, DMD, DNAH5, and KMT2Cwith MS or NS mutations have significant associations with prognosis in several cancer types (Figure 5c).	('CDKN2A', 'Gene', '1029', (51, 57))	('DMD', 'Gene', '1756', (66, 69))	('RMGs', 'Chemical', '-', (29, 33))	('mutations', 'Var', (101, 110))	('NS', 'Disease', 'MESH:D009404', (98, 100))	('OBSCN', 'Gene', (44, 49))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('OBSCN', 'Gene', '84033', (44, 49))	('cancer', 'Disease', (167, 173))	('KMT2C', 'Gene', (82, 87))	('DNAH5', 'Gene', '1767', (71, 76))	('KMT2C', 'Gene', '58508', (82, 87))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('DNAH5', 'Gene', (71, 76))	('DMD', 'Gene', (66, 69))	('CDKN2A', 'Gene', (51, 57))	('CSMD3', 'Gene', (59, 64))	('CSMD3', 'Gene', '114788', (59, 64))
245427	30107644	Patients with NS mutations in CDKN2A (PAAD), CSMD3 (STAD), and DMD (STAD and STES) had worse survival.	('CSMD3', 'Gene', (45, 50))	('CSMD3', 'Gene', '114788', (45, 50))	('DMD', 'Gene', '1756', (63, 66))	('CDKN2A', 'Gene', (30, 36))	('NS', 'Disease', 'MESH:D009404', (14, 16))	('CDKN2A', 'Gene', '1029', (30, 36))	('Patients', 'Species', '9606', (0, 8))	('PAAD', 'Phenotype', 'HP:0006725', (38, 42))	('STES', 'Chemical', '-', (77, 81))	('DMD', 'Gene', (63, 66))	('mutations', 'Var', (17, 26))
245430	30107644	The NS mutations downregulated its mRNA expression, therefore, dysregulated transcription, chromatin architecture or cellular differentiation.	('downregulated', 'NegReg', (17, 30))	('cellular differentiation', 'CPA', (117, 141))	('NS', 'Disease', 'MESH:D009404', (4, 6))	('transcription', 'MPA', (76, 89))	('mRNA expression', 'MPA', (35, 50))	('dysregulated', 'Reg', (63, 75))	('chromatin architecture', 'CPA', (91, 113))	('mutations', 'Var', (7, 16))
245431	30107644	Whereas, both OBSCN (in STAD) and DNAH5 (in SKCM) with MS mutations had better survival.	('OBSCN', 'Gene', '84033', (14, 19))	('mutations', 'Var', (58, 67))	('DNAH5', 'Gene', '1767', (34, 39))	('OBSCN', 'Gene', (14, 19))	('better', 'PosReg', (72, 78))	('DNAH5', 'Gene', (34, 39))
245436	30107644	Of which, mutations in ARID1A and PIK3CA were co-occurred (p-value < 0.01), which was consistent with the previous study (Liang et al., 2012).	('PIK3CA', 'Gene', (34, 40))	('ARID1A', 'Gene', '8289', (23, 29))	('ARID1A', 'Gene', (23, 29))	('PIK3CA', 'Gene', '5290', (34, 40))	('mutations', 'Var', (10, 19))
245439	30107644	Mutations in ARID1A could activate the PI3K pathway activity, and the concordance of mutations in ARID1A and PI3K pathway contributed to tumorigenesis (Liang et al., 2012).	('ARID1A', 'Gene', '8289', (98, 104))	('tumor', 'Disease', (137, 142))	('ARID1A', 'Gene', (98, 104))	('activate', 'PosReg', (26, 34))	('ARID1A', 'Gene', '8289', (13, 19))	('ARID1A', 'Gene', (13, 19))	('activity', 'MPA', (52, 60))	('PI3K pathway', 'Pathway', (39, 51))	('PI3K pathway', 'Pathway', (109, 121))	('mutations', 'Var', (85, 94))	('Mutations', 'Var', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('contributed', 'Reg', (122, 133))
245442	30107644	The co-occurred mutations in RNF43 and FAT3/FAT4 disrupted the Wnt signaling and thus promoted the development of cancer.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('RNF43', 'Gene', (29, 34))	('FAT3', 'Gene', (39, 43))	('RNF43', 'Gene', '54894', (29, 34))	('FAT3', 'Gene', '120114', (39, 43))	('mutations', 'Var', (16, 25))	('FAT4', 'Gene', (44, 48))	('Wnt signaling', 'Pathway', (63, 76))	('FAT4', 'Gene', '79633', (44, 48))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('disrupted', 'NegReg', (49, 58))	('promoted', 'PosReg', (86, 94))	('cancer', 'Disease', (114, 120))
245447	30107644	Moreover, we found MUC family genes were enriched in RMGs, and mutations of five MUC family genes were associated with better OS prognosis.	('mutations', 'Var', (63, 72))	('MUC', 'Gene', (81, 84))	('MUC', 'Gene', '100508689', (19, 22))	('MUC', 'Gene', '100508689', (81, 84))	('MUC', 'Gene', (19, 22))	('associated', 'Reg', (103, 113))	('RMGs', 'Chemical', '-', (53, 57))	('RMGs', 'Disease', (53, 57))
245448	30107644	In addition, we assessed the impacts of mutations in RMGs on gene expression and survival, as well as the pairwise mutation patterns among RMGs.	('mutations', 'Var', (40, 49))	('gene expression', 'MPA', (61, 76))	('RMGs', 'Chemical', '-', (139, 143))	('RMGs', 'Chemical', '-', (53, 57))
245449	30107644	In this study, we showed that the RMGs with mutation rates greater than 25% were enriched in hydrolases.	('mutation', 'Var', (44, 52))	('RMGs', 'Chemical', '-', (34, 38))	('hydrolases', 'Enzyme', (93, 103))
245450	30107644	Among these genes, PTEN was a tumor suppressor gene encoding a phosphatase and its mutation may lead to decreased sensitivity to apoptosis stimulating thus promote tumorigenesis (Farrow & Mark Evers, 2003; Stambolic et al., 1998; Zhong et al., 2000).	('tumor', 'Disease', (164, 169))	('sensitivity to apoptosis stimulating', 'MPA', (114, 150))	('PTEN', 'Gene', (19, 23))	('decreased', 'NegReg', (104, 113))	('PTEN', 'Gene', '5728', (19, 23))	('mutation', 'Var', (83, 91))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('tumor', 'Disease', (30, 35))	('promote', 'PosReg', (156, 163))
245452	30107644	Mutations in PTPRD abrogated its function to regulate STAT3 and promoted cancer progression (Funato, Yamazumi, Oda, & Akiyama, 2011; Zhao et al., 2010).	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('PTPRD', 'Gene', '5789', (13, 18))	('promoted', 'PosReg', (64, 72))	('PTPRD', 'Gene', (13, 18))	('STAT3', 'Gene', '6774', (54, 59))	('abrogated', 'NegReg', (19, 28))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('Mutations', 'Var', (0, 9))	('STAT3', 'Gene', (54, 59))	('function', 'MPA', (33, 41))
245453	30107644	In addition, the alterations in cathepsins may disrupt lysosomal trafficking and autophagy, thus led to tumor invasion (Dielschneider, Henson, & Gibson, 2017; White, Mehnert, & Chan, 2015).	('disrupt', 'NegReg', (47, 54))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('led to', 'Reg', (97, 103))	('cathepsins', 'Protein', (32, 42))	('tumor', 'Disease', (104, 109))	('autophagy', 'CPA', (81, 90))	('lysosomal trafficking', 'CPA', (55, 76))	('alterations', 'Var', (17, 28))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
245454	30107644	Recurrent mutations in hydrolases may cause uncontrolled proliferation, differentiation and metastasis, so target tumor cell hydrolases is a good way to treat cancer.	('cancer', 'Disease', (159, 165))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('differentiation', 'CPA', (72, 87))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('cause', 'Reg', (38, 43))	('metastasis', 'CPA', (92, 102))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('tumor', 'Disease', (114, 119))	('uncontrolled', 'MPA', (44, 56))	('hydrolases', 'Gene', (23, 33))	('mutations', 'Var', (10, 19))	('cancer', 'Disease', 'MESH:D009369', (159, 165))
245458	30107644	The recurrent mutations of MUC4 were detected only in ESCA (16%), whereas not in STAD.	('MUC4', 'Gene', (27, 31))	('detected', 'Reg', (37, 45))	('ESCA', 'Phenotype', 'HP:0011459', (54, 58))	('ESCA', 'Disease', (54, 58))	('MUC4', 'Gene', '4585', (27, 31))	('mutations', 'Var', (14, 23))
245461	30107644	Our results suggested recurrent mutations of MUC family genes are closely associated with survival in diverse cancers, so the mutations of MUC4 may cause the increase in mRNA expression and further protect epithelial surfaces in ESCA and STAD.	('cancers', 'Disease', (110, 117))	('MUC', 'Gene', '100508689', (139, 142))	('MUC4', 'Gene', '4585', (139, 143))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('MUC', 'Gene', '100508689', (45, 48))	('MUC', 'Gene', (45, 48))	('mutations', 'Var', (126, 135))	('MUC4', 'Gene', (139, 143))	('ESCA', 'Disease', (229, 233))	('protect', 'PosReg', (198, 205))	('STAD', 'Disease', (238, 242))	('cancers', 'Phenotype', 'HP:0002664', (110, 117))	('ESCA', 'Phenotype', 'HP:0011459', (229, 233))	('increase', 'PosReg', (158, 166))	('mRNA expression', 'MPA', (170, 185))	('cancers', 'Disease', 'MESH:D009369', (110, 117))	('MUC', 'Gene', (139, 142))
245462	30107644	Similarly, PTEN was frequently mutated in GBM and the combined data, GBMLGG, which could also indicate the mutated PTEN lost its cancer suppressing property thus promote tumorigenesis in GBM.	('PTEN', 'Gene', (11, 15))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('lost', 'NegReg', (120, 124))	('PTEN', 'Gene', '5728', (11, 15))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('PTEN', 'Gene', (115, 119))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('PTEN', 'Gene', '5728', (115, 119))	('mutated', 'Var', (107, 114))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('tumor', 'Disease', (170, 175))	('promote', 'PosReg', (162, 169))
245464	30107644	Mutant p53 protein encoded by TP53 with MS mutations could inactivate p53-related proteins and acquire new oncogenic functions (Freed-Pastor & Prives, 2012), so the upregulation of TP53 helped the tumor cells evade apoptosis and senescence.	('oncogenic functions', 'CPA', (107, 126))	('TP53', 'Gene', (30, 34))	('TP53', 'Gene', (181, 185))	('inactivate', 'NegReg', (59, 69))	('TP53', 'Gene', '7157', (181, 185))	('p53', 'Gene', (70, 73))	('protein', 'Protein', (11, 18))	('p53', 'Gene', '7157', (70, 73))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('cells evade apoptosis and', 'CPA', (203, 228))	('p53', 'Gene', '7157', (7, 10))	('mutations', 'Var', (43, 52))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('Mutant', 'Var', (0, 6))	('TP53', 'Gene', '7157', (30, 34))	('the', 'PosReg', (161, 164))	('tumor', 'Disease', (197, 202))	('p53', 'Gene', (7, 10))
245466	30107644	The mutated CDKN2A proteins failed to bind to cdk4, which promoted the development of cancer (Lilischkis, Sarcevic, Kennedy, Warlters, & Sutherland, 1996; Liu et al., 1995; Ranade et al., 1995).	('mutated', 'Var', (4, 11))	('CDKN2A', 'Gene', (12, 18))	('cdk4', 'Gene', '1019', (46, 50))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('CDKN2A', 'Gene', '1029', (12, 18))	('cdk4', 'Gene', (46, 50))	('promoted', 'PosReg', (58, 66))	('proteins', 'Protein', (19, 27))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('cancer', 'Disease', (86, 92))
245469	30107644	Whereas NS mutations could only downregulate gene expression (Supporting Information Figure S4).	('downregulate', 'NegReg', (32, 44))	('gene expression', 'MPA', (45, 60))	('mutations', 'Var', (11, 20))	('NS', 'Disease', 'MESH:D009404', (8, 10))
245475	30107644	Strong correlation between recurrently mutated MUC family genes and human survival were revealed.	('human survival', 'CPA', (68, 82))	('human', 'Species', '9606', (68, 73))	('MUC', 'Gene', '100508689', (47, 50))	('MUC', 'Gene', (47, 50))	('mutated', 'Var', (39, 46))
245538	33680908	Down-Regulation of MiR-181c-5p Promotes Epithelial-to-Mesenchymal Transition in Laryngeal Squamous Cell Carcinoma via Targeting SERPINE1 Laryngeal squamous cell carcinoma (LSCC) arises from the squamous epithelium of the larynx and is associated with a high incidence of cervical lymph node metastasis.	('squamous cell carcinoma', 'Disease', (147, 170))	('Squamous Cell Carcinoma', 'Disease', (90, 113))	('Epithelial-to-Mesenchymal Transition', 'CPA', (40, 76))	('MiR-181c', 'Gene', (19, 27))	('Promotes', 'PosReg', (31, 39))	('Targeting', 'Var', (118, 127))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (147, 170))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (90, 113))	('Down-Regulation', 'NegReg', (0, 15))	('SERPINE1', 'Protein', (128, 136))	('cervical lymph node metastasis', 'Phenotype', 'HP:0025289', (271, 301))	('Carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (161, 170))	('MiR-181c', 'Gene', '406957', (19, 27))	('Squamous Cell Carcinoma', 'Disease', 'MESH:D002294', (90, 113))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (147, 170))
245542	33680908	Silencing of miR-181c-5p expression promoted cell migration and invasion in cell lines, whereas the overexpression of miR-181c-5p suppressed cell migration and epithelial-to-mesenchymal transition (EMT) through the downregulation of SERPINE1.	('SERPINE1', 'Gene', (233, 241))	('miR-181c', 'Gene', '406957', (13, 21))	('-181c-5p', 'Chemical', '-', (121, 129))	('downregulation', 'NegReg', (215, 229))	('suppressed', 'NegReg', (130, 140))	('cell migration', 'CPA', (45, 59))	('cell migration', 'CPA', (141, 155))	('-181c-5p', 'Chemical', '-', (16, 24))	('miR-181c', 'Gene', (118, 126))	('miR-181c', 'Gene', '406957', (118, 126))	('epithelial-to-mesenchymal transition', 'CPA', (160, 196))	('invasion in cell lines', 'CPA', (64, 86))	('Silencing', 'Var', (0, 9))	('promoted', 'PosReg', (36, 44))	('miR-181c', 'Gene', (13, 21))	('SERPINE1', 'Gene', '5054', (233, 241))
245543	33680908	Further analysis showed that the enhancement effect on EMT and metastasis induced by silencing miR-181c-5p could be rescued through knockdown of SERPINE1 expression in vitro.	('SERPINE1', 'Gene', '5054', (145, 153))	('enhancement', 'PosReg', (33, 44))	('-181c-5p', 'Chemical', '-', (98, 106))	('SERPINE1', 'Gene', (145, 153))	('silencing', 'Var', (85, 94))	('miR-181c', 'Gene', (95, 103))	('miR-181c', 'Gene', '406957', (95, 103))
245563	33680908	The GSE51985 and GSE59102 datasets, based on the Illumina HumanHT-12 V4.0 expression BeadChip platform, and the Agilent-014850 Whole Human Genome Microarray 4x44K G4112F platform, respectively contained a total of 62 tissue samples (39 LSCC tissues and 23 adjacent cancer tissues).	('cancer', 'Disease', 'MESH:D009369', (265, 271))	('LSCC', 'Disease', (236, 240))	('GSE59102', 'Var', (17, 25))	('Human', 'Species', '9606', (58, 63))	('cancer', 'Phenotype', 'HP:0002664', (265, 271))	('Human', 'Species', '9606', (133, 138))	('cancer', 'Disease', (265, 271))	('G4112F', 'Mutation', 'p.G4112F', (163, 169))
245577	33680908	The 3'-UTR sequences of SERPINE1 that including wild-type (WT) or mutant-type (Mut) miR-181c-5p binding sites were synthesized by Genecopoeia, Guangzhou, China.	('mutant-type', 'Var', (66, 77))	('SERPINE1', 'Gene', '5054', (24, 32))	('SERPINE1', 'Gene', (24, 32))	('miR-181c', 'Gene', (84, 92))	('miR-181c', 'Gene', '406957', (84, 92))	('-181c-5p', 'Chemical', '-', (87, 95))
245578	33680908	Fadu cells were co-transfected with SERPINE1 3'-UTR reporter plasmids [wild type (wt) or mutant (mut)] luciferase plasmids and miR-181c-5p mimic or mimic NC.	('miR-181c', 'Gene', (127, 135))	('miR-181c', 'Gene', '406957', (127, 135))	('SERPINE1', 'Gene', '5054', (36, 44))	('SERPINE1', 'Gene', (36, 44))	('-181c-5p', 'Chemical', '-', (130, 138))	('mutant', 'Var', (89, 95))
245592	33680908	Primary antibodies anti-PAI1 (A6211), anti-E-cadherin (A3044), anti-N-cadherin (A3055), and anti-Vimentin (A2584) were all purchased from Abclonal, Wuhan, China.	('Vimentin', 'Gene', (97, 105))	('A6211', 'Var', (30, 35))	('E-cadherin', 'Gene', (43, 53))	('PAI1', 'Gene', '5054', (24, 28))	('N-cadherin', 'Gene', (68, 78))	('A3055', 'Var', (80, 85))	('E-cadherin', 'Gene', '999', (43, 53))	('Vimentin', 'Gene', '7431', (97, 105))	('N-cadherin', 'Gene', '1000', (68, 78))	('A3044', 'Var', (55, 60))	('A2584', 'Var', (107, 112))	('PAI1', 'Gene', (24, 28))
245603	33680908	It is known that miRNAs can suppress the expression levels of their target genes by acting as oncogenes or tumor suppressors, and thus play important roles in the regulation of cancer pathogenesis and metastasis.	('suppress', 'NegReg', (28, 36))	('expression levels', 'MPA', (41, 58))	('cancer', 'Disease', (177, 183))	('play', 'Reg', (135, 139))	('cancer', 'Disease', 'MESH:D009369', (177, 183))	('tumor', 'Disease', (107, 112))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('roles', 'Reg', (150, 155))	('miRNAs', 'Var', (17, 23))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('tumor', 'Disease', 'MESH:D009369', (107, 112))
245606	33680908	Among these six miRNAs, Kaplan-Meier survival analysis showed that only the low miR-181c-5p expression LSCC patient group exhibited poorer prognosis than the higher miR-181c-5p group (P = 0.021) (Figures 5C-H).	('low', 'Var', (76, 79))	('miR-181c', 'Gene', (165, 173))	('miR-181c', 'Gene', '406957', (165, 173))	('-181c-5p', 'Chemical', '-', (83, 91))	('miR-181c', 'Gene', (80, 88))	('patient', 'Species', '9606', (108, 115))	('miR-181c', 'Gene', '406957', (80, 88))	('-181c-5p', 'Chemical', '-', (168, 176))
245617	33680908	In contrast, SCC-4 cells transfected with inhibitor markedly promoted cell invasion when compared with the negative control transfection (Figure 6E).	('SCC-4', 'CellLine', 'CVCL:1684', (13, 18))	('promoted', 'PosReg', (61, 69))	('cell invasion', 'CPA', (70, 83))	('inhibitor', 'Var', (42, 51))
245623	33680908	Then, in order to measure the potential effects of SERPINE1 on LSCC, we transfected SERPINE1 siRNAs to knockdown its expression in Fadu cells.	('SERPINE1', 'Gene', '5054', (51, 59))	('SERPINE1', 'Gene', (51, 59))	('expression', 'MPA', (117, 127))	('SERPINE1', 'Gene', '5054', (84, 92))	('SERPINE1', 'Gene', (84, 92))	('knockdown', 'Var', (103, 112))
245624	33680908	Silencing of SERPINE1 was confirmed by qPCR and western blotting (Figure 7B).	('SERPINE1', 'Gene', '5054', (13, 21))	('SERPINE1', 'Gene', (13, 21))	('Silencing', 'Var', (0, 9))
245625	33680908	The cell viability assay showed that silencing SERPINE1 significantly inhibited Fadu cell proliferation at 72 h (Figure 7C).	('silencing', 'Var', (37, 46))	('Fadu cell proliferation at 72 h', 'CPA', (80, 111))	('inhibited', 'NegReg', (70, 79))	('SERPINE1', 'Gene', '5054', (47, 55))	('SERPINE1', 'Gene', (47, 55))
245626	33680908	In addition, transwell assays (Figure 7E) and wound healing (Figure 7F) results demonstrated that SERPINE1 knockdown slowed down migration and mitigated the invasion of Fadu cells.	('knockdown', 'Var', (107, 116))	('mitigated', 'NegReg', (143, 152))	('invasion of Fadu cells', 'CPA', (157, 179))	('slowed down', 'NegReg', (117, 128))	('migration', 'CPA', (129, 138))	('SERPINE1', 'Gene', '5054', (98, 106))	('SERPINE1', 'Gene', (98, 106))
245627	33680908	Altogether, these data suggest that the silencing of SERPINE1expression attenuates tumorigenicity and metastasis in HNSCC cells.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumor', 'Disease', (83, 88))	('attenuates', 'NegReg', (72, 82))	('HNSCC', 'Disease', (116, 121))	('silencing', 'Var', (40, 49))	('SERPINE1', 'Gene', (53, 61))	('SERPINE1', 'Gene', '5054', (53, 61))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
245630	33680908	Luciferase reporter assays showed that transfection of miR-181c-5p mimic remarkably inhibited the luciferase activities of SERPINE1-3'UTR-WT compared with the negative control, whereas the mimic did not alter the luciferase activities of the SERPINE1 3'UTR-Mut (Figure 7G).	('mimic', 'Var', (67, 72))	('luciferase', 'Enzyme', (98, 108))	('-181c-5p', 'Chemical', '-', (58, 66))	('miR-181c', 'Gene', (55, 63))	('miR-181c', 'Gene', '406957', (55, 63))	('SERPINE1', 'Gene', (242, 250))	('SERPINE1', 'Gene', '5054', (242, 250))	('SERPINE1', 'Gene', '5054', (123, 131))	('SERPINE1', 'Gene', (123, 131))	('activities', 'MPA', (109, 119))	('inhibited', 'NegReg', (84, 93))
245637	33680908	The dysregulation of miRNAs has been reported to be involved in the tumorigenesis and progression of HNSCC, and to mediate cellular biological processes such as cell cycle regulation, differentiation, apoptosis, and migration in the epigenetic level.	('tumor', 'Disease', (68, 73))	('HNSCC', 'Disease', (101, 106))	('dysregulation', 'Var', (4, 17))	('cell cycle regulation', 'CPA', (161, 182))	('miRNAs', 'Protein', (21, 27))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('involved', 'Reg', (52, 60))	('differentiation', 'CPA', (184, 199))	('migration', 'CPA', (216, 225))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('apoptosis', 'CPA', (201, 210))	('mediate', 'Reg', (115, 122))
245646	33680908	miR-181b-5p, is a member of the miR-181 family, and has been reported to act as a tumor suppressor in a variety of tumors.	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumor', 'Disease', (115, 120))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumors', 'Disease', (115, 121))	('tumors', 'Disease', 'MESH:D009369', (115, 121))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('miR-181b-5p', 'Var', (0, 11))	('tumor', 'Disease', (82, 87))	('miR-181b-5p', 'Chemical', '-', (0, 11))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
245649	33680908	Our in vitro experiments showed that miR-181b-5p is a key regulator of EMT and inhibits the cell invasion-metastasis cascade but not proliferation.	('inhibits', 'NegReg', (79, 87))	('miR-181b-5p', 'Var', (37, 48))	('miR-181b-5p', 'Chemical', '-', (37, 48))	('cell invasion-metastasis', 'CPA', (92, 116))
245650	33680908	Bioinformatics analysis demonstrated there was a negative correlation between miR-181b-5p and SERPINE1 expression in LSCC, and the knockdown of SERPINE1 attenuated tumor growth, EMT, and metastasis of cells, supporting its activity as an oncogene.	('SERPINE1', 'Gene', '5054', (144, 152))	('SERPINE1', 'Gene', (144, 152))	('knockdown', 'Var', (131, 140))	('negative', 'NegReg', (49, 57))	('SERPINE1', 'Gene', (94, 102))	('miR-181b-5p', 'Var', (78, 89))	('attenuated tumor', 'Disease', (153, 169))	('SERPINE1', 'Gene', '5054', (94, 102))	('miR-181b-5p', 'Chemical', '-', (78, 89))	('attenuated tumor', 'Disease', 'MESH:C538265', (153, 169))	('LSCC', 'Disease', (117, 121))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))
245651	33680908	Moreover, the downregulation of miR-181b-5p led to an elevated expression of SERPINE1, while up-regulation of miR-181b-5p resulted in the opposite tendency.	('miR-181b-5p', 'Var', (32, 43))	('up-regulation', 'PosReg', (93, 106))	('miR-181b-5p', 'Chemical', '-', (32, 43))	('elevated', 'PosReg', (54, 62))	('miR-181b-5p', 'Chemical', '-', (110, 121))	('expression', 'MPA', (63, 73))	('downregulation', 'NegReg', (14, 28))	('SERPINE1', 'Gene', '5054', (77, 85))	('SERPINE1', 'Gene', (77, 85))	('miR-181b-5p', 'Var', (110, 121))
245652	33680908	These results revealed that miR-181b-5p repressed the mesenchymal phenotype in LSCC, at least in part, via directly targeting SERPINE1.	('targeting', 'Reg', (116, 125))	('repressed', 'PosReg', (40, 49))	('LSCC', 'Disease', (79, 83))	('miR-181b-5p', 'Chemical', '-', (28, 39))	('mesenchymal phenotype', 'CPA', (54, 75))	('miR-181b-5p', 'Var', (28, 39))	('SERPINE1', 'Gene', '5054', (126, 134))	('SERPINE1', 'Gene', (126, 134))
245658	33680908	Further SERPINE1 mediates the effects of miR-181b-5p on EMT and migration of LSCC cells.	('SERPINE1', 'Gene', '5054', (8, 16))	('SERPINE1', 'Gene', (8, 16))	('effects', 'Reg', (30, 37))	('miR-181b-5p', 'Chemical', '-', (41, 52))	('miR-181b-5p', 'Var', (41, 52))
245659	33680908	Our findings revealed that miR-181c-5p/SERPINE1 regulatory signaling was strongly associated with migration and invasion of LSCC, and miR-181b-5p acts as suppressor during the regulation of EMT progression.	('associated', 'Reg', (82, 92))	('miR-181c', 'Gene', (27, 35))	('miR-181c', 'Gene', '406957', (27, 35))	('invasion', 'CPA', (112, 120))	('miR-181b-5p', 'Var', (134, 145))	('miR-181b-5p', 'Chemical', '-', (134, 145))	('migration', 'CPA', (98, 107))	('SERPINE1', 'Gene', '5054', (39, 47))	('SERPINE1', 'Gene', (39, 47))	('-181c-5p', 'Chemical', '-', (30, 38))
245665	33680908	The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fonc.2020.544476/full#supplementary-material LSCC, laryngeal squamous cell carcinoma; miRNAs, microRNAs; GEO, Gene Expression Omnibus; TCGA, The Cancer Genome Atlas; EMT, epithelial-to-mesenchymal transition; LC, laryngeal cancer; OS, overall survival; EMT-TF, epithelial-to-mesenchymal transition transcription factors; HNSCC, head and neck squamous cell carcinoma; DE miRNAs, differentially expressed miRNAs; DE mRNAs, differentially expressed mRNAs; FC, fold-change; GO, Gene Ontology; MF, molecular function; BP, biological process; CC, cellular component; STRING, Search Tool for the Retrieval of Interacting Genes; PPI, protein-protein interaction; FBS, fetal bovine serum; WT, wild-type; Mut, mutant-type; U6, small RNA RNU6; CCK8, Cell Counting Kit-8; OD, optical density; HR, hazard ratio.	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (441, 478))	('carcinoma', 'Phenotype', 'HP:0030731', (469, 478))	('Cancer', 'Disease', (258, 264))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (174, 197))	('cancer', 'Disease', (336, 342))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (455, 478))	('cancer', 'Phenotype', 'HP:0002664', (336, 342))	('Kit', 'Gene', (866, 869))	('Kit', 'Gene', '3815', (866, 869))	('Cancer', 'Disease', 'MESH:D009369', (258, 264))	('RNU6', 'Gene', (840, 844))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (174, 197))	('neck squamous cell carcinoma', 'Disease', (450, 478))	('RNU6', 'Gene', '26827', (840, 844))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (450, 478))	('cancer', 'Disease', 'MESH:D009369', (336, 342))	('carcinoma', 'Phenotype', 'HP:0030731', (188, 197))	('squamous cell carcinoma', 'Disease', (174, 197))	('laryngeal cancer', 'Phenotype', 'HP:0012118', (326, 342))	('Cancer', 'Phenotype', 'HP:0002664', (258, 264))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (455, 478))	('mutant-type', 'Var', (813, 824))
245669	31778279	A series of in vitro and in vivo experiments were applied to determine the effects of miR-30e-5p and its target AEG-1 on SCCHN metastasis.	('AEG-1', 'Gene', '92140', (112, 117))	('SCCHN metastasis', 'Disease', (121, 137))	('miR-30e-5p', 'Var', (86, 96))	('SCCHN metastasis', 'Disease', 'MESH:C535575', (121, 137))	('AEG-1', 'Gene', (112, 117))
245670	31778279	A mechanism investigation further revealed that AEG-1 was implicated in the angiogenesis and metastasis mediated by miR-30e-5p.	('angiogenesis', 'CPA', (76, 88))	('AEG-1', 'Gene', '92140', (48, 53))	('AEG-1', 'Gene', (48, 53))	('metastasis', 'CPA', (93, 103))	('miR-30e-5p', 'Var', (116, 126))	('implicated', 'Reg', (58, 68))
245671	31778279	Overall, our study confirms that miR-30e-5p is a valuable predictive biomarker and potential therapeutic target in SCCHN metastasis.	('miR-30e-5p', 'Var', (33, 43))	('SCCHN metastasis', 'Disease', 'MESH:C535575', (115, 131))	('SCCHN metastasis', 'Disease', (115, 131))
245676	31778279	MiRNA bind to the 3'- or 5'-untranslated regions (UTR) of target mRNA, leading to the degradation of mRNA and repression of protein translation.13, 14, 15 It is well established that miRNA play key roles in diverse biopathological behaviors, including malignant growth, metastasis and resistance to chemotherapy and radiotherapy.13, 14 Abundant studies have shown that miRNA are dysregulated in numerous cancers, including SCCHN, contributing to cancer progression.16, 17 Therefore, modulation of specific miRNA activities represents a potential therapeutic avenue.13, 15  Here, the Cancer Genome Atlas (TCGA) data and a validation patient cohort were used to determine that miR-30e-5p was closely associated with the aggressive traits of SCCHN, including metastasis.	('metastasis', 'Disease', (756, 766))	('cancers', 'Phenotype', 'HP:0002664', (404, 411))	('cancers', 'Disease', (404, 411))	('miR-30e-5p', 'Var', (675, 685))	('SCCHN', 'Disease', (739, 744))	('cancers', 'Disease', 'MESH:D009369', (404, 411))	('patient', 'Species', '9606', (632, 639))	('cancer', 'Disease', 'MESH:D009369', (404, 410))	('cancer', 'Phenotype', 'HP:0002664', (446, 452))	('cancer', 'Disease', (404, 410))	('Cancer', 'Phenotype', 'HP:0002664', (583, 589))	('associated with', 'Reg', (698, 713))	('cancer', 'Disease', 'MESH:D009369', (446, 452))	('cancer', 'Phenotype', 'HP:0002664', (404, 410))	('cancer', 'Disease', (446, 452))
245677	31778279	Survival analysis revealed that patients with low expression of miR-30e-5p displayed a worse prognosis, and miR-30e-5p was an independent factor for the survival prognosis in patients with SCCHN.	('low', 'NegReg', (46, 49))	('expression', 'MPA', (50, 60))	('patients', 'Species', '9606', (32, 40))	('SCCHN', 'Disease', (189, 194))	('miR-30e-5p', 'Var', (64, 74))	('patients', 'Species', '9606', (175, 183))	('miR-30e-5p', 'Var', (108, 118))
245678	31778279	Mechanistically, miR-30e-5p inhibited the occurrence of EMT of SCCHN cells, and also blocked SCCHN angiogenesis through downregulating multiple proangiogenic factors, including vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF).	('vascular endothelial growth factor', 'Gene', '7422', (177, 211))	('HGF', 'Gene', '3082', (249, 252))	('SCCHN', 'Disease', (93, 98))	('hepatocyte growth factor', 'Gene', (223, 247))	('VEGF', 'Gene', '7422', (213, 217))	('blocked', 'NegReg', (85, 92))	('occurrence of EMT of SCCHN cells', 'CPA', (42, 74))	('inhibited', 'NegReg', (28, 37))	('miR-30e-5p', 'Var', (17, 27))	('hepatocyte growth factor', 'Gene', '3082', (223, 247))	('vascular endothelial growth factor', 'Gene', (177, 211))	('downregulating', 'NegReg', (120, 134))	('HGF', 'Gene', (249, 252))	('VEGF', 'Gene', (213, 217))
245679	31778279	More importantly, we found that oncogene AEG-1 was directly targeted by miR-30e-5p and partially involved in the angiogenesis and metastasis mediated by miR-30e-5p.	('AEG-1', 'Gene', '92140', (41, 46))	('AEG-1', 'Gene', (41, 46))	('angiogenesis', 'CPA', (113, 125))	('involved', 'Reg', (97, 105))	('targeted', 'Reg', (60, 68))	('miR-30e-5p', 'Var', (72, 82))	('miR-30e-5p', 'Var', (153, 163))
245680	31778279	Our data suggest that miR-30e-5p is a valuable prognosis biomarker and a potential therapeutic target for SCCHN metastasis.	('SCCHN metastasis', 'Disease', (106, 122))	('SCCHN metastasis', 'Disease', 'MESH:C535575', (106, 122))	('miR-30e-5p', 'Var', (22, 32))
245702	31778279	Finally, 2 miRNA (miR-30e-5p and miR-3187-3p) were ultimately analyzed and found to be associated with SCCHN metastasis (Figure S1B).	('SCCHN metastasis', 'Disease', (103, 119))	('miR-3187-3p', 'Var', (33, 44))	('associated with', 'Reg', (87, 102))	('SCCHN metastasis', 'Disease', 'MESH:C535575', (103, 119))	('miR-30e-5p', 'Var', (18, 28))
245704	31778279	To further validate the clinical significance of miR-30e-5p in patients with SCCHN, the relative expression of miR-30e-5p was quantified in 113 cases of SCCHN via quantitative PCR (qPCR).	('patients', 'Species', '9606', (63, 71))	('SCCHN', 'Disease', (153, 158))	('SCCHN', 'Disease', (77, 82))	('miR-30e-5p', 'Var', (111, 121))
245705	31778279	Our data revealed that miR-30e-5p was dramatically decreased in SCCHN samples compared with corresponding adjacent noncancerous tissues (Figure 1A; P < 0.01).	('SCCHN', 'Disease', (64, 69))	('cancer', 'Disease', (118, 124))	('miR-30e-5p', 'Var', (23, 33))	('decreased', 'NegReg', (51, 60))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('cancer', 'Disease', 'MESH:D009369', (118, 124))
245706	31778279	For further analysis, our SCCHN patient cohort was divided into two groups: high miR-30e-5p (n = 56) and low miR-30e-5p (n = 57) expression groups, in which the expression level of miR-30e-5p was greater than or less than the median value in 113 patients with SCCHN.	('patient', 'Species', '9606', (246, 253))	('patients', 'Species', '9606', (246, 254))	('expression', 'MPA', (161, 171))	('miR-30e-5p', 'Var', (181, 191))	('less', 'NegReg', (212, 216))	('patient', 'Species', '9606', (32, 39))	('SCCHN', 'Disease', (260, 265))
245707	31778279	As summarized in Table 1 via Student's t test, low expression of miR-30e-5p was closely associated with high T classification, advanced clinical stage and cervical lymph node metastasis in patients with SCCHN (Table 1; all P < 0.05).	('SCCHN', 'Disease', (203, 208))	('cervical lymph node metastasis', 'CPA', (155, 185))	('high', 'CPA', (104, 108))	('low', 'NegReg', (47, 50))	('advanced clinical stage', 'CPA', (127, 150))	('associated', 'Reg', (88, 98))	('patients', 'Species', '9606', (189, 197))	('miR-30e-5p', 'Var', (65, 75))	('cervical lymph node metastasis', 'Phenotype', 'HP:0025289', (155, 185))
245708	31778279	Importantly, survival analysis further indicated that patients with low expression of miR-30e-5p displayed a worse prognosis than that in patients with high expression of miR-30e-5p (Figure 1B; P < 0.001).	('patients', 'Species', '9606', (54, 62))	('patients', 'Species', '9606', (138, 146))	('low', 'NegReg', (68, 71))	('miR-30e-5p', 'Var', (86, 96))
245709	31778279	Furthermore, histological stage, metastasis and miR-30e-5p expression were determined to be independent factors with prognostic value for the overall survival in patients with SCCHN in the multivariate Cox regression analyses (Table 2).	('patients', 'Species', '9606', (162, 170))	('miR-30e-5p expression', 'Var', (48, 69))	('SCCHN', 'Disease', (176, 181))
245710	31778279	Taken together, these data suggest that miR-30e-5p is a valuable biomarker for prognosis in patients with SCCHN.	('SCCHN', 'Disease', (106, 111))	('patients', 'Species', '9606', (92, 100))	('miR-30e-5p', 'Var', (40, 50))
245711	31778279	We also stably overexpressed miR-30e-5p in Fadu cells and established the xenograft tumors in nude mice (Figure S2E).	('miR-30e-5p', 'Var', (29, 39))	('nude mice', 'Species', '10090', (94, 103))	('xenograft tumors', 'Disease', (74, 90))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('xenograft tumors', 'Disease', 'MESH:D009369', (74, 90))
245712	31778279	The in vivo experiments further confirmed that miR-30e-5p had no effects on the growth pattern of SCCHN cells (Figure S2F-H).	('S2F-H', 'Chemical', 'MESH:C042345', (118, 123))	('miR-30e-5p', 'Var', (47, 57))	('growth pattern', 'CPA', (80, 94))
245713	31778279	Based on the results that miR-30e-5p was closely associated with SCCHN metastasis in clinical patient samples, both wound-healing and Transwell assays were used to check the effects of miR-30e-5p on migration and invasion in vitro.	('SCCHN metastasis', 'Disease', (65, 81))	('associated', 'Reg', (49, 59))	('miR-30e-5p', 'Var', (26, 36))	('invasion', 'CPA', (213, 221))	('SCCHN metastasis', 'Disease', 'MESH:C535575', (65, 81))	('patient', 'Species', '9606', (94, 101))	('migration', 'CPA', (199, 208))
245715	31778279	Both the size and number of lung metastatic tumors were reduced in Fadu cells with miR-30e-5p overexpression (Figure 2H,I).	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('reduced', 'NegReg', (56, 63))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('lung metastatic tumors', 'Disease', 'MESH:D008175', (28, 50))	('miR-30e-5p overexpression', 'Var', (83, 108))	('lung metastatic tumors', 'Disease', (28, 50))
245716	31778279	Notably, no liver metastatic lesions were observed in mice after the delivery of lenti-miR-30e-5p or lenti-miR-ctrl (Figure S2I).	('liver metastatic lesions', 'CPA', (12, 36))	('lenti-miR-30e-5p', 'Var', (81, 97))	('mice', 'Species', '10090', (54, 58))	('lenti-miR-ctrl', 'Var', (101, 115))
245717	31778279	Cancer malignant progression is determined by both endogenous changes of oncogenes and/or suppressors, and its surrounding tumor microenvironment (TME).7, 8 In the aspect of cancer cells, EMT is a complicated reprogramming process, which is characterized by the inhibition of epithelial markers and upregulation of mesenchymal markers.6, 16 Therefore, we used multiple methods to evaluate the effects of miR-30e-5p on the alterations of EMT markers.	('miR-30e-5p', 'Var', (404, 414))	('tumor', 'Disease', (123, 128))	('cancer', 'Disease', (174, 180))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
245718	31778279	As shown in Figure 3A, the qPCR results revealed that miR-30e-5p overexpression in Fadu and JHU011 obviously increased the mRNA expression of E-cadherin and reduced the mRNA expression of vimentin, which was accompanied by the inhibition of EMT transcription factor including mRNA of Twist 1 and Twist 2 (Figure 3A).	('Twist 2', 'Gene', (296, 303))	('E-cadherin', 'Gene', (142, 152))	('E-cadherin', 'Gene', '999', (142, 152))	('Twist 1', 'Gene', (284, 291))	('miR-30e-5p', 'Var', (54, 64))	('mRNA expression', 'MPA', (123, 138))	('JHU011', 'Var', (92, 98))	('vimentin', 'Gene', '7431', (188, 196))	('Twist 1', 'Gene', '7291', (284, 291))	('overexpression', 'PosReg', (65, 79))	('Twist 2', 'Gene', '117581', (296, 303))	('increased', 'PosReg', (109, 118))	('mRNA expression', 'MPA', (169, 184))	('inhibition', 'NegReg', (227, 237))	('vimentin', 'Gene', (188, 196))	('reduced', 'NegReg', (157, 164))
245719	31778279	Western blotting and immunofluorescence staining confirmed that miR-30e-5p overexpression in Fadu and JHU011 also upregulated E-cadherin and reduced vimentin (Figure 3B,C).	('JHU011', 'Gene', (102, 108))	('overexpression', 'PosReg', (75, 89))	('reduced', 'NegReg', (141, 148))	('vimentin', 'Gene', '7431', (149, 157))	('vimentin', 'Gene', (149, 157))	('E-cadherin', 'Gene', (126, 136))	('miR-30e-5p', 'Var', (64, 74))	('E-cadherin', 'Gene', '999', (126, 136))	('upregulated', 'PosReg', (114, 125))
245721	31778279	Angiogenesis has an important function in cancer metastasis, which provides a vessel for cancer cells to migrate into the blood system.9, 12, 27 In examining the exact role of miR-30e-5p in SCCHN angiogenesis, the migratory ability of HUVEC was found to be significantly suppressed when cocultured with Fadu cells that upregulated miR-30e-5p (Figure 4A,B).	('miR-30e-5p', 'Var', (331, 341))	('migratory ability', 'CPA', (214, 231))	('upregulated', 'PosReg', (319, 330))	('cancer metastasis', 'Disease', (42, 59))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('suppressed', 'NegReg', (271, 281))	('cancer metastasis', 'Disease', 'MESH:D009362', (42, 59))	('cancer', 'Disease', (89, 95))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
245722	31778279	To answer the question of how miR-30e-5p represses SCCHN angiogenesis, we quantified a panel of cytokines and chemokines involved in cancer angiogenesis, which revealed that miR-30e-5p overexpression significantly inhibited the mRNA expression of VEGF, HGF, FGF1, CSF1/2/3, FGF2, IL-8, IGF1 and IGF2 (Figure 4E,F).	('IL-8', 'Gene', (280, 284))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('IGF2', 'Gene', '3481', (295, 299))	('IGF1', 'Gene', '3479', (286, 290))	('CSF1/2/3', 'Gene', '1435;1437;1440', (264, 272))	('VEGF', 'Gene', '7422', (247, 251))	('FGF1', 'Gene', (258, 262))	('miR-30e-5p', 'Var', (174, 184))	('overexpression', 'PosReg', (185, 199))	('FGF2', 'Gene', '2247', (274, 278))	('VEGF', 'Gene', (247, 251))	('FGF1', 'Gene', '2246', (258, 262))	('IGF1', 'Gene', (286, 290))	('IL-8', 'Gene', '3576', (280, 284))	('HGF', 'Gene', '3082', (253, 256))	('cancer', 'Disease', (133, 139))	('CSF1/2/3', 'Gene', (264, 272))	('IGF2', 'Gene', (295, 299))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('FGF2', 'Gene', (274, 278))	('HGF', 'Gene', (253, 256))	('mRNA expression', 'MPA', (228, 243))	('inhibited', 'NegReg', (214, 223))
245723	31778279	In examining the role of miR-30e-5p in cancer angiogenesis, in vivo Matrigel angiogenesis plug assay revealed that miR-30e-5p overexpression in Fadu cells reduced the tumors' newly formed blood vessels in Matrigel (Figure 5A,B), which was accompanied by the decline of proangiogenic factors including VEGF, FGF1, CSF1/2/3 and HGF (Figure 5C).	('FGF1', 'Gene', (307, 311))	('tumors', 'Disease', 'MESH:D009369', (167, 173))	('FGF1', 'Gene', '2246', (307, 311))	('cancer', 'Disease', (39, 45))	('HGF', 'Gene', '3082', (326, 329))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('CSF1/2/3', 'Gene', (313, 321))	('HGF', 'Gene', (326, 329))	('miR-30e-5p', 'Var', (115, 125))	('tumors', 'Phenotype', 'HP:0002664', (167, 173))	('VEGF', 'Gene', '7422', (301, 305))	('decline', 'NegReg', (258, 265))	('reduced', 'NegReg', (155, 162))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('overexpression', 'PosReg', (126, 140))	('VEGF', 'Gene', (301, 305))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('CSF1/2/3', 'Gene', '1435;1437;1440', (313, 321))	('tumors', 'Disease', (167, 173))
245725	31778279	In addition, immunostaining of proangiogenic factor VEGF and blood vessel epithelial marker CD31 were also significantly decreased in the miR-30e-5p overexpression group (Figure 5D-J).	('VEGF', 'Gene', (52, 56))	('CD31', 'Gene', (92, 96))	('VEGF', 'Gene', '7422', (52, 56))	('miR-30e-5p', 'Var', (138, 148))	('decreased', 'NegReg', (121, 130))	('CD31', 'Gene', '5175', (92, 96))	('immunostaining', 'MPA', (13, 27))	('overexpression', 'PosReg', (149, 163))
245726	31778279	Finally, the chick chorioallantoic membrane vascular assay indicated that miR-30e-5p overexpression in Fadu cells similarly reduced the vascular density (Figure 5K,L).	('reduced', 'NegReg', (124, 131))	('miR-30e-5p', 'Var', (74, 84))	('overexpression', 'PosReg', (85, 99))	('vascular density', 'CPA', (136, 152))	('chick', 'Species', '9031', (13, 18))
245727	31778279	Collectively, these data clearly indicate that miR-30e-5p represses EMT in cancer cells themselves and also impedes the formation of cancer angiogenesis.	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('represses', 'NegReg', (58, 67))	('miR-30e-5p', 'Var', (47, 57))	('cancer', 'Disease', (75, 81))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('cancer', 'Disease', (133, 139))	('impedes', 'NegReg', (108, 115))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
245729	31778279	Therefore, we used luciferase reporter assays to determine whether AEG-1 was a direct binding target of miR-30e-5p.	('AEG-1', 'Gene', '92140', (67, 72))	('AEG-1', 'Gene', (67, 72))	('miR-30e-5p', 'Var', (104, 114))
245730	31778279	Luciferase reporter plasmids encoding the wild-type (WT) or mutant (MU) 3'-UTR domain of AEG-1 mRNA were designed (Figure 6C), and then miR-30e-5p mimic was cotransfected with the reporter plasmid into SCCHN Fadu and JHU011 cells.	('mutant', 'Var', (60, 66))	('AEG-1', 'Gene', '92140', (89, 94))	('AEG-1', 'Gene', (89, 94))
245731	31778279	As shown in Figure6D, luciferase activities in Fadu and JHU011 cells cotransfected with AEG-1 3'-UTR-WT and miR-30e-5p mimic were significantly lower than those cells cotransfected with AEG-1 3'-UTR-WT and NC (Figure6D; P < 0.01).	('lower', 'NegReg', (144, 149))	('luciferase', 'Enzyme', (22, 32))	('AEG-1', 'Gene', '92140', (186, 191))	('AEG-1', 'Gene', (186, 191))	('activities', 'MPA', (33, 43))	('AEG-1', 'Gene', '92140', (88, 93))	('miR-30e-5p mimic', 'Var', (108, 124))	('AEG-1', 'Gene', (88, 93))
245732	31778279	These data meant that miR-30e-5p reduced the expression of AEG-1 by directly binding to its 3'-UTR region of AEG-1 mRNA.	('AEG-1', 'Gene', (109, 114))	('AEG-1', 'Gene', '92140', (59, 64))	('miR-30e-5p', 'Var', (22, 32))	('AEG-1', 'Gene', (59, 64))	('expression', 'MPA', (45, 55))	('reduced', 'NegReg', (33, 40))	('binding', 'Interaction', (77, 84))	('AEG-1', 'Gene', '92140', (109, 114))
245733	31778279	Consistent with the result of luciferase reporter assays, miR-30e-5p mimic also greatly inhibited the expression of AEG-1 mRNA (Figure 6E) and protein (Figure 6F).	('inhibited', 'NegReg', (88, 97))	('expression', 'MPA', (102, 112))	('miR-30e-5p mimic', 'Var', (58, 74))	('AEG-1', 'Gene', (116, 121))	('AEG-1', 'Gene', '92140', (116, 121))	('protein', 'Protein', (143, 150))
245736	31778279	Our data revealed that knockdown of AEG-1 mitigated the repression of migration, invasion and angiogenesis in Tu686 cells (Figure 6G-I).	('angiogenesis', 'CPA', (94, 106))	('mitigated', 'NegReg', (42, 51))	('migration', 'CPA', (70, 79))	('invasion', 'CPA', (81, 89))	('knockdown', 'Var', (23, 32))	('AEG-1', 'Gene', '92140', (36, 41))	('AEG-1', 'Gene', (36, 41))
245738	31778279	Therefore, our data clearly suggest that AEG-1 is involved in miR-30e-5p-mediated angiogenesis and metastasis.	('AEG-1', 'Gene', '92140', (41, 46))	('AEG-1', 'Gene', (41, 46))	('angiogenesis', 'CPA', (82, 94))	('miR-30e-5p-mediated', 'Var', (62, 81))	('metastasis', 'CPA', (99, 109))	('involved', 'Reg', (50, 58))
245739	31778279	In this study, we found that miR-30e-5p was correlated with the aggressive characteristics in patients with SCCHN, which was an independent factor for prognosis in patients with SCCHN.	('miR-30e-5p', 'Var', (29, 39))	('aggressive characteristics', 'CPA', (64, 90))	('patients', 'Species', '9606', (94, 102))	('correlated', 'Reg', (44, 54))	('SCCHN', 'Disease', (108, 113))	('patients', 'Species', '9606', (164, 172))
245740	31778279	A series of in vitro and in vivo experiments further identified that miR-30e-5p impeded the invasion and metastasis of SCCHN via the modulation of both EMT occurrence and cancer angiogenesis.	('impeded', 'NegReg', (80, 87))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('modulation', 'Reg', (133, 143))	('cancer', 'Disease', (171, 177))	('EMT occurrence', 'CPA', (152, 166))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('miR-30e-5p', 'Var', (69, 79))	('SCCHN', 'Disease', (119, 124))
245741	31778279	Our study provides solid evidence demonstrating that miR-30e-5p is a valuable prognosis biomarker and a critical inhibitor for SCCHN metastasis.	('miR-30e-5p', 'Var', (53, 63))	('SCCHN metastasis', 'Disease', (127, 143))	('SCCHN metastasis', 'Disease', 'MESH:C535575', (127, 143))
245742	31778279	As a metastasis suppressor, miR-30e-5p has been reported to be downregulated in several malignant carcinomas, such as bladder cancer,28 colorectal cancer,29 nasopharyngeal carcinoma30 and head and neck cancer.31 In the available clinical studies based on tumor samples, low expression of miR-30e-5p always exists in patients with more aggressive clinical characteristics, including advanced TNM stages and metastasis, which is consistent with our conclusion.	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('tumor', 'Phenotype', 'HP:0002664', (255, 260))	('miR-30e-5p', 'Var', (288, 298))	('nasopharyngeal carcinoma30', 'Phenotype', 'HP:0100630', (157, 183))	('metastasis', 'CPA', (406, 416))	('colorectal cancer', 'Disease', 'MESH:D015179', (136, 153))	('malignant carcinomas', 'Disease', 'MESH:D002277', (88, 108))	('patients', 'Species', '9606', (316, 324))	('low', 'NegReg', (270, 273))	('colorectal cancer', 'Disease', (136, 153))	('TNM', 'Gene', '10178', (391, 394))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('bladder cancer', 'Disease', 'MESH:D001749', (118, 132))	('bladder cancer', 'Disease', (118, 132))	('tumor', 'Disease', (255, 260))	('carcinoma30 and head and neck cancer', 'Disease', 'MESH:D006258', (172, 208))	('TNM', 'Gene', (391, 394))	('tumor', 'Disease', 'MESH:D009369', (255, 260))	('carcinoma', 'Phenotype', 'HP:0030731', (172, 181))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('carcinomas', 'Phenotype', 'HP:0030731', (98, 108))	('malignant carcinomas', 'Disease', (88, 108))
245744	31778279	Metastasis is a critical malignant behavior for SCCHN cells, which tremendously influences the treatment strategy decisions and final prognosis of patients, including SCCHN.2 Consistent with the clinical results, loss and gain of functional experiments clearly indicated the critical role of miR-30e-5p in SCCHN metastasis.	('SCCHN metastasis', 'Disease', (306, 322))	('influences', 'Reg', (80, 90))	('patients', 'Species', '9606', (147, 155))	('miR-30e-5p', 'Var', (292, 302))	('SCCHN metastasis', 'Disease', 'MESH:C535575', (306, 322))
245745	31778279	Several studies have confirmed that miR-30e-5p is a microRNA that is closely associated with metastasis in vitro28, 29, 30; however, how miR-30e-5p blocks cancer metastasis and its exact molecular mechanisms remain largely unknown.	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('miR-30e-5p', 'Var', (137, 147))	('blocks cancer metastasis', 'Disease', (148, 172))	('blocks cancer metastasis', 'Disease', 'MESH:D009362', (148, 172))
245746	31778279	In the process of metastasis, metastatic cancer cells are required to detach the primary lesion and enhance the migratory and invasive abilities, in which EMT is indispensable in the initiation of metastasis.5 Our data clearly demonstrated that miR-30e-5p, as an endogenous metastasis suppressor, together with its target AEG-1, inhibited EMT and then impeded SCCHN metastasis.	('impeded', 'NegReg', (352, 359))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('inhibited', 'NegReg', (329, 338))	('SCCHN metastasis', 'Disease', 'MESH:C535575', (360, 376))	('AEG-1', 'Gene', '92140', (322, 327))	('cancer', 'Disease', (41, 47))	('EMT', 'CPA', (339, 342))	('SCCHN metastasis', 'Disease', (360, 376))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('AEG-1', 'Gene', (322, 327))	('miR-30e-5p', 'Var', (245, 255))
245747	31778279	In addition, mounting evidence has indicated that AEG-1, as an oncogene, has an important function in the process of EMT and metastasis in diverse human solid cancers.32, 33, 34 miR-30e-5p and AEG-1 can form an miR-30e-5p/AEG-1 axis pathway, which regulates the metastasis and EMT of SCCHN.	('cancers', 'Disease', (159, 166))	('AEG-1', 'Gene', '92140', (50, 55))	('SCCHN', 'Disease', (284, 289))	('human', 'Species', '9606', (147, 152))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('miR-30e-5p', 'Var', (178, 188))	('cancers', 'Phenotype', 'HP:0002664', (159, 166))	('regulates', 'Reg', (248, 257))	('AEG-1', 'Gene', '92140', (222, 227))	('AEG-1', 'Gene', (222, 227))	('metastasis', 'CPA', (262, 272))	('AEG-1', 'Gene', '92140', (193, 198))	('AEG-1', 'Gene', (193, 198))	('cancers', 'Disease', 'MESH:D009369', (159, 166))	('AEG-1', 'Gene', (50, 55))
245749	31778279	In our study, data from coculture system initially revealed that miR-30e-5p repressed the migration of blood vessel epithelial cells (HUVEC), indicating the potential role of miR-30e-5p in cancer angiogenesis.	('migration of blood vessel epithelial cells', 'CPA', (90, 132))	('repressed', 'NegReg', (76, 85))	('miR-30e-5p', 'Var', (175, 185))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('miR-30e-5p', 'Var', (65, 75))	('cancer', 'Disease', (189, 195))
245751	31778279	As expected, both experimental models verified that miR-30e-5p overexpression dramatically reduced the microvessel density in cancer angiogenesis, which suggests the pivotal function of miR-30e-5p in the regulation of SCCHN angiogenesis.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('microvessel density', 'CPA', (103, 122))	('reduced', 'NegReg', (91, 98))	('miR-30e-5p', 'Var', (52, 62))
245753	31778279	Our data showed that miR-30e-5p overexpression obviously reduced the expression of multiple proangiogenic factors, including VEGF and HGF, both of which are the main stimulators for tumor blood vessel formation.9, 12, 27, 36 Apart from VEGF and HGF, IL-8,37 FGF12 and CSF/1/2/338 are also potent proangiogenic factors, which were correspondingly decreased after miR-30e-5p overexpression.	('VEGF', 'Gene', (125, 129))	('VEGF', 'Gene', '7422', (236, 240))	('IL-8', 'Gene', (250, 254))	('CSF/1/2', 'Gene', (268, 275))	('VEGF', 'Gene', (236, 240))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))	('proangiogenic', 'MPA', (296, 309))	('HGF', 'Gene', '3082', (245, 248))	('IL-8', 'Gene', '3576', (250, 254))	('HGF', 'Gene', '3082', (134, 137))	('FGF12', 'Gene', (258, 263))	('HGF', 'Gene', (245, 248))	('decreased', 'NegReg', (346, 355))	('miR-30e-5p', 'Var', (362, 372))	('tumor', 'Disease', (182, 187))	('CSF/1/2', 'Gene', '1435;1437', (268, 275))	('HGF', 'Gene', (134, 137))	('VEGF', 'Gene', '7422', (125, 129))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('FGF12', 'Gene', '2257', (258, 263))
245754	31778279	In addition, as a direct target of miR-30e-5p, AEG-1 overexpression restored the level of part of the proangiogenic factors, revealing that AEG-1, indeed, participated in miR-30e-5p-mediated angiogenesis.	('angiogenesis', 'CPA', (191, 203))	('AEG-1', 'Gene', (140, 145))	('AEG-1', 'Gene', '92140', (140, 145))	('miR-30e-5p-mediated', 'Var', (171, 190))	('level of part of the proangiogenic factors', 'MPA', (81, 123))	('participated', 'Reg', (155, 167))	('AEG-1', 'Gene', '92140', (47, 52))	('AEG-1', 'Gene', (47, 52))
245755	31778279	However, some other proangiogenic factors, including FGF, were not changed following AEG-1 overexpression, which suggests that other potential signaling pathways may be affected by miR-30e-5p.	('AEG-1', 'Gene', '92140', (85, 90))	('AEG-1', 'Gene', (85, 90))	('affected', 'Reg', (169, 177))	('FGF', 'Gene', (53, 56))	('miR-30e-5p', 'Var', (181, 191))	('FGF', 'Gene', '2246;2247;2257', (53, 56))
245756	31778279	Micro RNA regulate the malignant behaviors of cancer cells by controlling distinct gene expression, including that of oncogenes and/or suppressors.39 Specific miRNA synchronously inhibits multiple target genes by directly binding to the 3'-UTR or 5'-UTR region of mRNA.40 Based on review of the literature (present study), miR-30e-5p modulates diverse mRNA targets in different disease situations, including cancer.	('cancer', 'Phenotype', 'HP:0002664', (408, 414))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('cancer', 'Disease', (46, 52))	('modulates', 'Reg', (334, 343))	('cancer', 'Disease', 'MESH:D009369', (408, 414))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('cancer', 'Disease', (408, 414))	('miR-30e-5p', 'Var', (323, 333))
245758	31778279	In our current study, miR-30e-5p was found to directly link to the 3'-UTR domain of AEG-1 mRNA, which accelerates the degradation of AEG-1 mRNA and eventually reduces the level of AEG-1 protein.	('miR-30e-5p', 'Var', (22, 32))	('AEG-1', 'Gene', '92140', (180, 185))	('degradation', 'MPA', (118, 129))	('accelerates', 'PosReg', (102, 113))	('reduces', 'NegReg', (159, 166))	('AEG-1', 'Gene', (180, 185))	('AEG-1', 'Gene', '92140', (84, 89))	('AEG-1', 'Gene', (84, 89))	('AEG-1', 'Gene', '92140', (133, 138))	('AEG-1', 'Gene', (133, 138))
245759	31778279	In addition, TCGA data analysis revealed that miR-30e-5p and AEG-1 mRNA display an opposite expression status in SCCHN samples.	('miR-30e-5p', 'Var', (46, 56))	('AEG-1', 'Gene', '92140', (61, 66))	('SCCHN', 'Disease', (113, 118))	('expression', 'MPA', (92, 102))	('AEG-1', 'Gene', (61, 66))
245760	31778279	Taken together, these data reveal that AEG-1 is a direct downstream target of miR-3e-5p.	('AEG-1', 'Gene', '92140', (39, 44))	('AEG-1', 'Gene', (39, 44))	('miR-3e-5p', 'Var', (78, 87))
245761	31778279	AEG-1, as a multifunctional oncogene, have been reported to play critical roles in several cancer biological malignant behaviors, including transformation, metastasis, angiogenesis and therapeutic resistance.46 More importantly, restoration of AEG-1 level abolished the enhancement of metastasis capability caused by miR-30e-5p downexpression, which suggests that AEG-1 is involved in the effects mediated by miR-30e-5p, although we have to acknowledge that other potential targets of miR-30e-5p may also participate in this process.	('AEG-1', 'Gene', '92140', (244, 249))	('AEG-1', 'Gene', '92140', (364, 369))	('AEG-1', 'Gene', (364, 369))	('downexpression', 'NegReg', (328, 342))	('cancer', 'Disease', (91, 97))	('AEG-1', 'Gene', (244, 249))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('enhancement', 'PosReg', (270, 281))	('restoration', 'Var', (229, 240))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('AEG-1', 'Gene', (0, 5))	('AEG-1', 'Gene', '92140', (0, 5))	('metastasis capability', 'CPA', (285, 306))
245763	31778279	Most importantly, in vitro and in vivo evidence revealed that miR-30e-5p directly targeted oncogene AEG-1, and repressed the invasion and metastasis by blocking EMT and angiogenesis.	('repressed', 'NegReg', (111, 120))	('AEG-1', 'Gene', '92140', (100, 105))	('AEG-1', 'Gene', (100, 105))	('blocking', 'NegReg', (152, 160))	('miR-30e-5p', 'Var', (62, 72))
245764	31778279	Therefore, miR-30e-5p and AEG-1 represent promising molecular treatment targets to conquer metastatic SCCHN cancer.	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('SCCHN cancer', 'Phenotype', 'HP:0100280', (102, 114))	('miR-30e-5p', 'Var', (11, 21))	('AEG-1', 'Gene', '92140', (26, 31))	('AEG-1', 'Gene', (26, 31))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
245839	28417598	The endometrioid carcinoma and the associated high-grade components shared copy number alterations and four clonal mutations, including SMARCA4 mutations, which resulted in loss of BRG1 protein expression.	('BRG1', 'Gene', '6597', (181, 185))	('endometrioid carcinoma', 'Disease', 'MESH:D016889', (4, 26))	('endometrioid carcinoma', 'Disease', (4, 26))	('BRG1', 'Gene', (181, 185))	('protein', 'Protein', (186, 193))	('loss', 'NegReg', (173, 177))	('expression', 'MPA', (194, 204))	('carcinoma', 'Phenotype', 'HP:0030731', (17, 26))	('mutations', 'Var', (144, 153))	('SMARCA4', 'Gene', (136, 143))	('SMARCA4', 'Gene', '6597', (136, 143))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (4, 26))
245840	28417598	Subclonal mutations and mutations restricted to single components were also identified, such as distinct TP53 mutations restricted to each histologic component.	('TP53', 'Gene', '7157', (105, 109))	('mutations', 'Var', (110, 119))	('TP53', 'Gene', (105, 109))
245842	28417598	In the present case, SMARCA4 mutations were likely early events, whereas TP53 somatic mutations were acquired later in evolution.	('TP53', 'Gene', '7157', (73, 77))	('SMARCA4', 'Gene', (21, 28))	('SMARCA4', 'Gene', '6597', (21, 28))	('mutations', 'Var', (29, 38))	('TP53', 'Gene', (73, 77))
245848	28417598	Bioinformatics analyses for the identification of somatic mutations, their potential functional effect, copy number alterations (CNAs), cancer cell fractions (CCFs) and mutational signatures, and for assessing clonal relatedness were performed as previously described (Supplementary Methods).	('mutations', 'Var', (58, 67))	('cancer', 'Disease', (136, 142))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
245855	28417598	Amplification of 17q, encompassing the ERBB2 locus, was identified in the endometrioid carcinoma, whereas the anaplastic carcinoma and squamous cell carcinoma harbored gains of 17q (Figure 1B, Supplementary Figure S1).	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('ERBB2', 'Gene', '2064', (39, 44))	('Amplification', 'Var', (0, 13))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (135, 158))	('anaplastic carcinoma', 'Disease', (110, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (149, 158))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (135, 158))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))	('squamous cell carcinoma', 'Disease', (135, 158))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (74, 96))	('anaplastic carcinoma', 'Disease', 'MESH:D002277', (110, 130))	('endometrioid carcinoma', 'Disease', 'MESH:D016889', (74, 96))	('gains', 'PosReg', (168, 173))	('endometrioid carcinoma', 'Disease', (74, 96))	('ERBB2', 'Gene', (39, 44))
245859	28417598	A clonal somatic missense POLE mutation (E349K) was identified by MSK-IMPACT in both high-grade carcinoma components, however it did not target a hotspot and was predicted to be non-pathogenic.	('MSK', 'Gene', (66, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('carcinoma', 'Disease', (96, 105))	('E349K', 'Mutation', 'p.E349K', (41, 46))	('E349K', 'Var', (41, 46))	('MSK', 'Gene', '150094', (66, 69))	('carcinoma', 'Disease', 'MESH:D002277', (96, 105))
245863	28417598	All samples harboring somatic mutations displayed the mutational signature 2 (Figure 2B), which has been linked to tumors with a high mutation burden and is associated with the APOBEC cytidine deaminase activity.	('associated', 'Reg', (157, 167))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumors', 'Disease', 'MESH:D009369', (115, 121))	('tumors', 'Disease', (115, 121))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('mutations', 'Var', (30, 39))	('linked', 'Reg', (105, 111))
245866	28417598	These likely early genetic events included missense mutations targeting NOTCH3 and MDC1, and concurrent nonsense and missense mutations affecting SMARCA4 (Y439* and K1390N, Figure 2A, Supplementary Figure S2, Supplementary Table S6), suggesting an early bi-allelic inactivation of SMARCA4.	('MDC1', 'Gene', '9656', (83, 87))	('missense mutations', 'Var', (43, 61))	('SMARCA4', 'Gene', (281, 288))	('Y439*', 'SUBSTITUTION', 'None', (155, 160))	('Y439*', 'Var', (155, 160))	('SMARCA4', 'Gene', '6597', (281, 288))	('K1390N', 'Mutation', 'p.K1390N', (165, 171))	('K1390N', 'Var', (165, 171))	('NOTCH3', 'Gene', (72, 78))	('SMARCA4', 'Gene', (146, 153))	('missense mutations', 'Var', (117, 135))	('SMARCA4', 'Gene', '6597', (146, 153))	('NOTCH3', 'Gene', '4854', (72, 78))	('MDC1', 'Gene', (83, 87))
245868	28417598	Of the 101 non-synonymous mutations identified, 9%, 12% and 52% were restricted to the squamous cell, anaplastic and endometrioid carcinoma components, respectively, some of which may contribute to the distinct phenotype of each specific component of this case (Figure 2A, Supplementary Figure S2, Supplementary Table S6).	('contribute', 'Reg', (184, 194))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (117, 139))	('endometrioid carcinoma', 'Disease', 'MESH:D016889', (117, 139))	('mutations', 'Var', (26, 35))	('endometrioid carcinoma', 'Disease', (117, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))
245869	28417598	Nineteen mutations were shared solely by the high-grade squamous cell and anaplastic carcinomas, including likely-pathogenic mutations affecting CDKN2A, PTEN, PIK3R1 and APC.	('APC', 'Disease', (170, 173))	('mutations', 'Var', (125, 134))	('CDKN2A', 'Gene', '1029', (145, 151))	('anaplastic carcinomas', 'Disease', 'MESH:D002277', (74, 95))	('PTEN', 'Gene', (153, 157))	('PIK3R1', 'Gene', '5295', (159, 165))	('PTEN', 'Gene', '5728', (153, 157))	('APC', 'Disease', 'MESH:D011125', (170, 173))	('PIK3R1', 'Gene', (159, 165))	('anaplastic carcinomas', 'Disease', (74, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('carcinomas', 'Phenotype', 'HP:0030731', (85, 95))	('CDKN2A', 'Gene', (145, 151))
245871	28417598	TP53 was inactivated in the endometrioid, anaplastic and squamous cell carcinoma components by distinct clonal somatic mutations (E180K, Q331*, and E285K mutations, respectively), all coupled with LOH of the wild-type allele (Figure 2A, Supplementary Table S6), providing evidence of convergent evolution.	('E180K', 'Var', (130, 135))	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('E180K', 'Mutation', 'rs879253911', (130, 135))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (57, 80))	('Q331*', 'SUBSTITUTION', 'None', (137, 142))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (57, 80))	('squamous cell carcinoma', 'Disease', (57, 80))	('Q331*', 'Var', (137, 142))	('E285K', 'Mutation', 'rs112431538', (148, 153))	('E285K', 'Var', (148, 153))
245873	28417598	A formal clonal relatedness analysis based on all somatic mutations demonstrated that the endometrioid, anaplastic and squamous cell carcinoma components were clonally related (p<0.05, Supplementary Figure S4).	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (119, 142))	('mutations', 'Var', (58, 67))	('endometrioid', 'Disease', (90, 102))	('anaplastic', 'Disease', (104, 114))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (119, 142))	('squamous cell carcinoma', 'Disease', (119, 142))
245874	28417598	Given the clonal nature of the components, we next performed a clonal decomposition analysis (Figure 2D), which suggested that SMARCA4 mutations were among the earliest genetic events.	('SMARCA4', 'Gene', (127, 134))	('SMARCA4', 'Gene', '6597', (127, 134))	('mutations', 'Var', (135, 144))
245875	28417598	The endometrioid carcinoma evolved separately with the acquisition of clonal mutations affecting CDK12, MLH1 and MAPK1, whereas the anaplastic and squamous cell carcinomas stemmed from a common ancestor, sharing several clonal mutations, including those affecting CDKN2A, POLE and ERBB2.	('ERBB2', 'Gene', '2064', (281, 286))	('endometrioid carcinoma', 'Disease', (4, 26))	('MAPK1', 'Gene', '5594', (113, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (17, 26))	('CDK12', 'Gene', '51755', (97, 102))	('carcinomas', 'Phenotype', 'HP:0030731', (161, 171))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (147, 171))	('CDKN2A', 'Gene', (264, 270))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (4, 26))	('MAPK1', 'Gene', (113, 118))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (147, 171))	('MLH1', 'Gene', (104, 108))	('mutations', 'Var', (77, 86))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (147, 170))	('CDK12', 'Gene', (97, 102))	('CDKN2A', 'Gene', '1029', (264, 270))	('endometrioid carcinoma', 'Disease', 'MESH:D016889', (4, 26))	('ERBB2', 'Gene', (281, 286))	('squamous cell carcinomas', 'Disease', (147, 171))	('MLH1', 'Gene', '4292', (104, 108))	('carcinoma', 'Phenotype', 'HP:0030731', (161, 170))
245876	28417598	TP53 mutations and ERBB2 amplification likely constituted later events in the tumor evolution.	('ERBB2', 'Gene', '2064', (19, 24))	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('ERBB2', 'Gene', (19, 24))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('mutations', 'Var', (5, 14))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Disease', (78, 83))	('amplification', 'Var', (25, 38))
245878	28417598	In the present case, bi-allelic inactivation of SMARCA4 associated with lack of BRG1 expression was a truncal genetic event, potentially driving its early development.	('expression', 'MPA', (85, 95))	('BRG1', 'Gene', (80, 84))	('bi-allelic inactivation', 'Var', (21, 44))	('BRG1', 'Gene', '6597', (80, 84))	('SMARCA4', 'Gene', (48, 55))	('SMARCA4', 'Gene', '6597', (48, 55))	('driving', 'Reg', (137, 144))
245880	28417598	SMARCA4 encodes for BRG1, a catalytic unit of the ATP-dependent switching and sucrose non-fermenting (SWI/SNF) chromatin regulators complex, frequently mutated in human malignancies.	('SMARCA4', 'Gene', (0, 7))	('BRG1', 'Gene', '6597', (20, 24))	('malignancies', 'Disease', (169, 181))	('mutated', 'Var', (152, 159))	('SMARCA4', 'Gene', '6597', (0, 7))	('human', 'Species', '9606', (163, 168))	('malignancies', 'Disease', 'MESH:D009369', (169, 181))	('BRG1', 'Gene', (20, 24))	('sucrose', 'Chemical', 'MESH:D013395', (78, 85))	('ATP', 'Chemical', 'MESH:D000255', (50, 53))
245881	28417598	Somatic and germline SMARCA4 mutations underpin a panoply of carcinomas, often displaying a rhabdoid phenotype, such as ovarian small cell carcinoma, hypercalcemic type.	('small cell carcinoma', 'Phenotype', 'HP:0030357', (128, 148))	('ovarian small cell carcinoma', 'Disease', (120, 148))	('SMARCA4', 'Gene', (21, 28))	('SMARCA4', 'Gene', '6597', (21, 28))	('carcinoma', 'Phenotype', 'HP:0030731', (139, 148))	('mutations', 'Var', (29, 38))	('rhabdoid', 'Disease', 'MESH:D018335', (92, 100))	('rhabdoid', 'Disease', (92, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('hypercalcemic type', 'Disease', (150, 168))	('underpin', 'Reg', (39, 47))	('carcinomas', 'Phenotype', 'HP:0030731', (61, 71))	('carcinomas', 'Disease', 'MESH:D002277', (61, 71))	('ovarian small', 'Phenotype', 'HP:0008724', (120, 133))	('ovarian small cell carcinoma', 'Disease', 'MESH:D018288', (120, 148))	('carcinomas', 'Disease', (61, 71))
245883	28417598	Our observation of bi-allelic inactivation of SMARCA4 in this case illustrates that loss of function of this gene is not necessarily restricted to tumors with a rhabdoid phenotype.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumors', 'Disease', (147, 153))	('tumors', 'Phenotype', 'HP:0002664', (147, 153))	('tumors', 'Disease', 'MESH:D009369', (147, 153))	('rhabdoid', 'Disease', 'MESH:D018335', (161, 169))	('bi-allelic inactivation', 'Var', (19, 42))	('rhabdoid', 'Disease', (161, 169))	('SMARCA4', 'Gene', (46, 53))	('SMARCA4', 'Gene', '6597', (46, 53))
245890	28417598	CCF Cancer cell fraction CNA copy number alteration FISH fluorescence in situ hybridization LOH loss of heterozygosity MSKCC Memorial Sloan Kettering Cancer Center MSK-IMPACT Integrated Mutation Profiling of Actionable Cancer Targets	('copy', 'Var', (29, 33))	('Cancer', 'Phenotype', 'HP:0002664', (150, 156))	('MSK', 'Gene', '150094', (164, 167))	('Cancer', 'Phenotype', 'HP:0002664', (219, 225))	('alteration', 'Var', (41, 51))	('MSK', 'Gene', (119, 122))	('Memorial Sloan Kettering Cancer', 'Disease', 'MESH:D008569', (125, 156))	('Cancer', 'Phenotype', 'HP:0002664', (4, 10))	('MSK', 'Gene', '150094', (119, 122))	('Memorial Sloan Kettering Cancer', 'Disease', (125, 156))	('MSK', 'Gene', (164, 167))
245896	28393072	More interesting, the racial differences of COL11A1 were consistent across multiple molecular levels, with higher mutation frequency, higher methylation, and lower expression in White patients.	('methylation', 'MPA', (141, 152))	('lower', 'NegReg', (158, 163))	('patients', 'Species', '9606', (184, 192))	('mutation', 'Var', (114, 122))	('expression', 'MPA', (164, 174))	('higher', 'PosReg', (134, 140))	('COL11A1', 'Gene', '1301', (44, 51))	('COL11A1', 'Gene', (44, 51))	('higher', 'PosReg', (107, 113))
245910	28393072	Genome sequencing of liver cancer found that AXIN1 was more frequently mutated in patients with HBV infection, while mutations of its downstream gene CTNNB1 majorly occurred in HCV-associated cases.	('mutations', 'Var', (117, 126))	('AXIN1', 'Gene', '8312', (45, 50))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('liver cancer', 'Disease', 'MESH:D006528', (21, 33))	('CTNNB1', 'Gene', (150, 156))	('patients', 'Species', '9606', (82, 90))	('liver cancer', 'Disease', (21, 33))	('AXIN1', 'Gene', (45, 50))	('mutated', 'Var', (71, 78))	('CTNNB1', 'Gene', '1499', (150, 156))	('HBV infection', 'Disease', (96, 109))	('occurred', 'Reg', (165, 173))	('HBV infection', 'Disease', 'MESH:D006509', (96, 109))	('liver cancer', 'Phenotype', 'HP:0002896', (21, 33))
245913	28393072	Except cancer genomes, racial specificity was also observed in other molecular features, such as gene expression in pediatric B-Precursor acute lymphoblastic leukemia and methylation in prostate cancer.	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('prostate cancer', 'Disease', (186, 201))	('leukemia', 'Phenotype', 'HP:0001909', (158, 166))	('cancer', 'Disease', (195, 201))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('methylation', 'Var', (171, 182))	('prostate cancer', 'Disease', 'MESH:D011471', (186, 201))	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (138, 166))	('prostate cancer', 'Phenotype', 'HP:0012125', (186, 201))	('acute lymphoblastic leukemia', 'Disease', (138, 166))	('cancer', 'Disease', (7, 13))	('cancer', 'Disease', 'MESH:D009369', (7, 13))	('B-Precursor acute lymphoblastic leukemia', 'Phenotype', 'HP:0004812', (126, 166))	('acute lymphoblastic leukemia', 'Disease', 'MESH:D054198', (138, 166))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (144, 166))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
245943	28393072	The majority of mutations were found in TP53 (80.1%); other SMGs included KMT2B (13.2%), NOTCH1 (12.8%), and PIK3CA (9.6%).	('PIK3CA', 'Gene', (109, 115))	('PIK3CA', 'Gene', '5290', (109, 115))	('KMT2B', 'Gene', (74, 79))	('mutations', 'Var', (16, 25))	('NOTCH1', 'Gene', '4851', (89, 95))	('NOTCH1', 'Gene', (89, 95))	('TP53', 'Gene', '7157', (40, 44))	('TP53', 'Gene', (40, 44))	('KMT2B', 'Gene', '9757', (74, 79))
245946	28393072	Tumors from White patients were more significantly associated with harboring a KEAP1 mutation (Figure 2(c)).	('KEAP1', 'Gene', (79, 84))	('harboring', 'Var', (67, 76))	('EA', 'Phenotype', 'HP:0011459', (80, 82))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('patients', 'Species', '9606', (18, 26))	('KEAP1', 'Gene', '9817', (79, 84))
245949	28393072	For example, TP53 mutations were more frequent in White patients, while the mutation frequencies of its upstream genes EP300 and CDKN2A were higher in Asian patients.	('patients', 'Species', '9606', (56, 64))	('TP53', 'Gene', (13, 17))	('EP300', 'Gene', (119, 124))	('EP300', 'Gene', '2033', (119, 124))	('CDKN2A', 'Gene', (129, 135))	('patients', 'Species', '9606', (157, 165))	('CDKN2A', 'Gene', '1029', (129, 135))	('TP53', 'Gene', '7157', (13, 17))	('frequent', 'Reg', (38, 46))	('mutations', 'Var', (18, 27))
245950	28393072	Another example is the Keap1-Nrf2 pathway and White patients harbored more KEAP1 mutations, while Asian people had more NFE2L2 (also called NRF2) mutations.	('Nrf2', 'Gene', (29, 33))	('KEAP1', 'Gene', (75, 80))	('NFE2L2', 'Gene', '4780', (120, 126))	('people', 'Species', '9606', (104, 110))	('mutations', 'Var', (146, 155))	('NFE2L2', 'Gene', (120, 126))	('EA', 'Phenotype', 'HP:0011459', (76, 78))	('Nrf2', 'Gene', '4780', (29, 33))	('Keap1', 'Gene', (23, 28))	('mutations', 'Var', (81, 90))	('patients', 'Species', '9606', (52, 60))	('Keap1', 'Gene', '9817', (23, 28))	('KEAP1', 'Gene', '9817', (75, 80))	('NRF2', 'Gene', '4780', (140, 144))	('NRF2', 'Gene', (140, 144))
245952	28393072	Somatic mutations in NRF2 or KEAP1 disrupt the interaction of these two proteins and activate the NRF2 signaling.	('NRF2', 'Gene', (21, 25))	('interaction', 'Interaction', (47, 58))	('disrupt', 'NegReg', (35, 42))	('these two proteins', 'Protein', (62, 80))	('activate', 'PosReg', (85, 93))	('proteins', 'Protein', (72, 80))	('mutations', 'Var', (8, 17))	('KEAP1', 'Gene', '9817', (29, 34))	('NRF2', 'Gene', '4780', (98, 102))	('NRF2', 'Gene', '4780', (21, 25))	('EA', 'Phenotype', 'HP:0011459', (30, 32))	('KEAP1', 'Gene', (29, 34))	('NRF2', 'Gene', (98, 102))
245965	28393072	Mutated COL11A1 had higher expression than the wide-type gene (P = 0.03, Figure 5(d)).	('COL11A1', 'Gene', '1301', (8, 15))	('higher', 'PosReg', (20, 26))	('expression', 'MPA', (27, 37))	('COL11A1', 'Gene', (8, 15))	('Mutated', 'Var', (0, 7))
245966	28393072	In summary, COL11A1 had higher mutation frequency and higher methylation level in White people, which may decrease gene expression.	('COL11A1', 'Gene', '1301', (12, 19))	('higher', 'PosReg', (54, 60))	('mutation', 'Var', (31, 39))	('decrease', 'NegReg', (106, 114))	('higher', 'PosReg', (24, 30))	('people', 'Species', '9606', (88, 94))	('COL11A1', 'Gene', (12, 19))	('methylation level', 'MPA', (61, 78))	('gene expression', 'MPA', (115, 130))
245977	28393072	Taken the breast cancer-susceptible gene BRCA1 as an example, genetic BRCA1 mutations were significantly more common in Jewish (10.2%) versus non-Jewish (2.0%) cases.	('mutations', 'Var', (76, 85))	('BRCA1', 'Gene', '672', (41, 46))	('BRCA1', 'Gene', '672', (70, 75))	('breast cancer', 'Disease', 'MESH:D001943', (10, 23))	('common', 'Reg', (110, 116))	('breast cancer', 'Phenotype', 'HP:0003002', (10, 23))	('BRCA1', 'Gene', (41, 46))	('breast cancer', 'Disease', (10, 23))	('BRCA1', 'Gene', (70, 75))	('Jewish', 'Disease', (120, 126))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
245978	28393072	Recently, the larger-scale tumor sequencing projects revealed that pattern and frequency of oncogene mutations might vary by race.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('mutations', 'Var', (101, 110))	('tumor', 'Disease', (27, 32))	('oncogene', 'Gene', (92, 100))	('tumor', 'Disease', 'MESH:D009369', (27, 32))
245979	28393072	For example, the mutation rate of EGFR in non-small-cell lung cancer is 16-18% in North Americans and Europeans, 19% in African-Americans, 22% in Indians, 29% in Koreans, 40% in Japanese, and around 50% in Chinese; such variability in EGFR mutation rate led to different effectiveness of tyrosine kinase inhibitors in the given population.	('EGFR', 'Gene', (34, 38))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (42, 68))	('mutation', 'Var', (17, 25))	('EGFR', 'Gene', '1956', (34, 38))	('effectiveness', 'MPA', (271, 284))	('lung cancer', 'Disease', 'MESH:D008175', (57, 68))	('EGFR', 'Gene', '1956', (235, 239))	('EGFR', 'Gene', (235, 239))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (46, 68))	('lung cancer', 'Disease', (57, 68))	('lung cancer', 'Phenotype', 'HP:0100526', (57, 68))
245984	28393072	Some differences might be important for tumorigenesis and personalized treatment, such as KEAP1 mutation, TFPI methylation, and COL11A1 expression.	('TFPI', 'Gene', (106, 110))	('COL11A1', 'Gene', '1301', (128, 135))	('TFPI', 'Gene', '7035', (106, 110))	('KEAP1', 'Gene', '9817', (90, 95))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('mutation', 'Var', (96, 104))	('COL11A1', 'Gene', (128, 135))	('KEAP1', 'Gene', (90, 95))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('EA', 'Phenotype', 'HP:0011459', (91, 93))
245992	33376383	Screening and Identifying Cisplatin-Related Gene Mutations in Lung Squamous Cell Carcinoma Platinum-based chemotherapy is the cornerstone of treatment for patients with LUSC, but cisplatin resistance greatly restricts its clinical application.	('Cisplatin-Related Gene', 'Gene', (26, 48))	('Lung Squamous Cell Carcinoma', 'Phenotype', 'HP:0030359', (62, 90))	('Carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('Lung Squamous Cell Carcinoma', 'Disease', (62, 90))	('Lung Squamous Cell Carcinoma', 'Disease', 'MESH:D002294', (62, 90))	('Cisplatin', 'Chemical', 'MESH:D002945', (26, 35))	('Platinum', 'Chemical', 'MESH:D010984', (91, 99))	('patients', 'Species', '9606', (155, 163))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (67, 90))	('cisplatin', 'Chemical', 'MESH:D002945', (179, 188))	('Mutations', 'Var', (49, 58))
245993	33376383	Data for 15 LUSC cell lines were downloaded from the Genomics of Drug Sensitivity in Cancer (GDSC) Project database to screen for mutations related to cisplatin susceptibility.	('cisplatin', 'Chemical', 'MESH:D002945', (151, 160))	('Drug Sensitivity', 'Phenotype', 'HP:0020174', (65, 81))	('Cancer', 'Disease', (85, 91))	('Cancer', 'Phenotype', 'HP:0002664', (85, 91))	('Cancer', 'Disease', 'MESH:D009369', (85, 91))	('mutations', 'Var', (130, 139))
245995	33376383	Subsequently, the clinical prognostic value of these mutations was verified by using The Cancer Genome Atlas (TCGA)-LUSC cohort and our cohort (n=58).	('Cancer', 'Disease', 'MESH:D009369', (89, 95))	('Cancer', 'Phenotype', 'HP:0002664', (89, 95))	('Cancer', 'Disease', (89, 95))	('mutations', 'Var', (53, 62))
245996	33376383	Based on the cisplatin sensitivity data of GDSC-LUSC and survival analysis of TCGA-LUSC and Local-LUSC cohorts, we found that only mutation of IGF2R was associated with cisplatin sensitivity, better overall survival [OS; P=0.04, HR (95% CI): 0.42 (0.23-0.78)] and progression-free survival [PFS; P =0.016, HR (95% CI): 0.26 (0.12-0.59)].	('overall survival', 'MPA', (199, 215))	('better', 'PosReg', (192, 198))	('progression-free survival', 'CPA', (264, 289))	('IGF2R', 'Gene', '3482', (143, 148))	('cisplatin', 'Chemical', 'MESH:D002945', (169, 178))	('cisplatin sensitivity', 'MPA', (169, 190))	('cisplatin', 'Chemical', 'MESH:D002945', (13, 22))	('IGF2R', 'Gene', (143, 148))	('mutation', 'Var', (131, 139))
245999	33376383	The results suggest that IGF2R mutations are a potential biomarker for screening LUSC patients suitable for cisplatin treatment.	('IGF2R', 'Gene', (25, 30))	('mutations', 'Var', (31, 40))	('cisplatin', 'Chemical', 'MESH:D002945', (108, 117))	('IGF2R', 'Gene', '3482', (25, 30))	('LUSC', 'Disease', (81, 85))	('patients', 'Species', '9606', (86, 94))
246011	33376383	Muller et al showed that p53 mutation upregulates expression of endogenous p53, binds to caspase-9 and ultimately inhibits apoptosis and mediates cisplatin resistance.	('p53', 'Gene', (25, 28))	('mutation', 'Var', (29, 37))	('p53', 'Gene', '7157', (25, 28))	('caspase-9', 'Gene', '842', (89, 98))	('cisplatin', 'Chemical', 'MESH:D002945', (146, 155))	('inhibits', 'NegReg', (114, 122))	('binds', 'Interaction', (80, 85))	('upregulates', 'PosReg', (38, 49))	('caspase-9', 'Gene', (89, 98))	('apoptosis', 'CPA', (123, 132))	('p53', 'Gene', (75, 78))	('p53', 'Gene', '7157', (75, 78))	('cisplatin resistance', 'MPA', (146, 166))	('mediates', 'Reg', (137, 145))	('expression', 'MPA', (50, 60))
246012	33376383	BRCA2 mutations can increase the DNA damage repair ability of tumor cells and mediate cisplatin resistance.	('BRCA2', 'Gene', '675', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('mediate', 'Reg', (78, 85))	('cisplatin resistance', 'MPA', (86, 106))	('tumor', 'Disease', (62, 67))	('increase', 'PosReg', (20, 28))	('cisplatin', 'Chemical', 'MESH:D002945', (86, 95))	('BRCA2', 'Gene', (0, 5))	('mutations', 'Var', (6, 15))	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('DNA damage repair', 'MPA', (33, 50))
246013	33376383	Mutations in DNA mismatch repair (MMR) genes, such as MLH1 or MSH2, have also been shown to be associated with acquired resistance to cisplatin.	('MLH1', 'Gene', '4292', (54, 58))	('MLH1', 'Gene', (54, 58))	('MSH2', 'Gene', (62, 66))	('Mutations', 'Var', (0, 9))	('MSH2', 'Gene', '4436', (62, 66))	('acquired resistance to cisplatin', 'MPA', (111, 143))	('MMR', 'Gene', (34, 37))	('cisplatin', 'Chemical', 'MESH:D002945', (134, 143))	('associated with', 'Reg', (95, 110))
246015	33376383	In this study, gene mutations associated with cisplatin sensitivity were identified by analyzing the mRNA and cisplatin response data of LUSC cell lines in public databases, and clinical prognosis was analyzed by The Cancer Genome Atlas (TCGA)-LUSC cohort.	('associated', 'Reg', (30, 40))	('Cancer', 'Disease', (217, 223))	('cisplatin', 'Chemical', 'MESH:D002945', (110, 119))	('Cancer', 'Disease', 'MESH:D009369', (217, 223))	('cisplatin', 'Chemical', 'MESH:D002945', (46, 55))	('Cancer', 'Phenotype', 'HP:0002664', (217, 223))	('mutations', 'Var', (20, 29))
246021	33376383	We used the Mann-Whitney U-test to examine the difference between the 896 mutations (mutation frequency > 10%) and cisplatin's IC50 values, and mutations with an adjusted P value less than 0.05 were included in downstream analysis.	('IC50 values', 'MPA', (127, 138))	('mutations', 'Var', (74, 83))	('cisplatin', 'Chemical', 'MESH:D002945', (115, 124))
246022	33376383	Finally, we obtained one gene mutation that was associated with cisplatin sensitivity and clinical prognosis.	('associated', 'Reg', (48, 58))	('mutation', 'Var', (30, 38))	('cisplatin', 'Chemical', 'MESH:D002945', (64, 73))
246031	33376383	Ultimately, we found only the IGF2R mutation to be related to cisplatin response and survival, mainly manifesting as significantly increased cisplatin sensitivity and better overall survival (OS) [log-rank P = 0.04, hazard ratio (HR) (95% confidence interval (CI)): 0.42 (0.23-0.78); Figure 2A and B].	('cisplatin', 'Chemical', 'MESH:D002945', (62, 71))	('IGF2R', 'Gene', '3482', (30, 35))	('increased', 'PosReg', (131, 140))	('cisplatin', 'Chemical', 'MESH:D002945', (141, 150))	('overall survival', 'MPA', (174, 190))	('cisplatin sensitivity', 'MPA', (141, 162))	('related', 'Reg', (51, 58))	('IGF2R', 'Gene', (30, 35))	('cisplatin response', 'MPA', (62, 80))	('better', 'PosReg', (167, 173))	('mutation', 'Var', (36, 44))
246032	33376383	Next (Kaplan-Meier) KM analysis was used to evaluate associations with IGF2R mutations and the prognosis of LUSC.	('IGF2R', 'Gene', '3482', (71, 76))	('LUSC', 'Disease', (108, 112))	('IGF2R', 'Gene', (71, 76))	('mutations', 'Var', (77, 86))	('associations', 'Interaction', (53, 65))
246033	33376383	In TCGA-LUSC/Local-LUSC cohorts, only alterations in IGF2R were associated with significantly favorable OS/PFS; other clinical features conferred no survival benefit (Figure 2D).	('favorable', 'PosReg', (94, 103))	('IGF2R', 'Gene', (53, 58))	('OS/PFS', 'Disease', (104, 110))	('alterations', 'Var', (38, 49))	('IGF2R', 'Gene', '3482', (53, 58))
246035	33376383	In the GDSC-LUSC dataset (Figure 3A), we identified the top 20 mutations, among which the top 5 were TP53 (100% vs 91%), TTN (100% vs 64%), CSMD3 (100% vs 55%), HYDIN (75% vs 45%), and LRP1B (50% vs 55%).	('mutations', 'Var', (63, 72))	('LRP1B', 'Gene', '53353', (185, 190))	('LRP1B', 'Gene', (185, 190))	('HYDIN', 'Gene', '54768', (161, 166))	('TTN', 'Gene', '7273', (121, 124))	('TP53', 'Gene', '7157', (101, 105))	('HYDIN', 'Gene', (161, 166))	('TP53', 'Gene', (101, 105))	('TTN', 'Gene', (121, 124))	('CSMD3', 'Gene', (140, 145))	('CSMD3', 'Gene', '114788', (140, 145))
246038	33376383	In Local-LUSC (Figure 3C; Supplementary Table S3), the mutation frequencies of several genes were higher in IGF2R-MT than in IGF2R-WT, such as MUC16 (60% vs 29%; P < 0.05); TP53 (60% vs 29%; P < 0.05); KMT2C (50% vs 13%; P < 0.01); PRUNE2 (40% vs 13%; P < 0.05); SYNE1 (60% vs 8%; P < 0.001); ZFHX3 (50% vs 11%; P < 0.01); FAT4 (40% vs 11%; P < 0.05); NEB (50% vs 8%; P < 0.01); and PCNT (50% vs 8%; P < 0.01).	('IGF2R', 'Gene', (125, 130))	('SYNE1', 'Gene', '23345', (263, 268))	('TP53', 'Gene', (173, 177))	('KMT2C', 'Gene', '58508', (202, 207))	('KMT2C', 'Gene', (202, 207))	('PCNT', 'Gene', '5116', (383, 387))	('FAT4', 'Gene', (323, 327))	('IGF2R', 'Gene', (108, 113))	('PRUNE2', 'Gene', (232, 238))	('ZFHX3', 'Gene', '463', (293, 298))	('IGF2R', 'Gene', '3482', (125, 130))	('ZFHX3', 'Gene', (293, 298))	('MUC16', 'Gene', '94025', (143, 148))	('TP53', 'Gene', '7157', (173, 177))	('IGF2R', 'Gene', '3482', (108, 113))	('mutation', 'Var', (55, 63))	('PRUNE2', 'Gene', '158471', (232, 238))	('PCNT', 'Gene', (383, 387))	('FAT4', 'Gene', '79633', (323, 327))	('higher', 'PosReg', (98, 104))	('SYNE1', 'Gene', (263, 268))	('MUC16', 'Gene', (143, 148))
246057	33376383	This finding suggests that IGF2R mutations reduce the metabolism of NADPH and NADP, downregulating the synthesis of GSH and eventually promoting cisplatin resistance.	('GSH', 'Chemical', 'MESH:D005978', (116, 119))	('reduce', 'NegReg', (43, 49))	('GSH', 'MPA', (116, 119))	('NADPH', 'Gene', (68, 73))	('synthesis', 'MPA', (103, 112))	('NADPH', 'Gene', '1666', (68, 73))	('cisplatin', 'Chemical', 'MESH:D002945', (145, 154))	('mutations', 'Var', (33, 42))	('downregulating', 'NegReg', (84, 98))	('metabolism', 'MPA', (54, 64))	('promoting', 'PosReg', (135, 144))	('IGF2R', 'Gene', '3482', (27, 32))	('NADP', 'Chemical', 'MESH:D009249', (78, 82))	('cisplatin resistance', 'MPA', (145, 165))	('NADP', 'Chemical', 'MESH:D009249', (68, 72))	('IGF2R', 'Gene', (27, 32))
246064	33376383	Studies have also shown that inhibitors of AKT1, mTOR, PI3K and MAPK signaling can significantly increase cisplatin's cytotoxicity in breast cancer.	('mTOR', 'Gene', (49, 53))	('increase', 'PosReg', (97, 105))	('inhibitors', 'Var', (29, 39))	('breast cancer', 'Disease', (134, 147))	('AKT1', 'Gene', (43, 47))	('mTOR', 'Gene', '2475', (49, 53))	('breast cancer', 'Phenotype', 'HP:0003002', (134, 147))	('cytotoxicity', 'Disease', 'MESH:D064420', (118, 130))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('cisplatin', 'MPA', (106, 115))	('PI3K', 'Var', (55, 59))	('AKT1', 'Gene', '207', (43, 47))	('cisplatin', 'Chemical', 'MESH:D002945', (106, 115))	('MAPK', 'Gene', (64, 68))	('cytotoxicity', 'Disease', (118, 130))	('breast cancer', 'Disease', 'MESH:D001943', (134, 147))
246065	33376383	Cisplatin activates MAPK signaling and the production of multidrug resistance, and the Wnt/beta-catenin pathway is closely related to the MAPK pathway.	('drug resistance', 'Phenotype', 'HP:0020174', (62, 77))	('beta-catenin', 'Gene', (91, 103))	('Cisplatin', 'Chemical', 'MESH:D002945', (0, 9))	('production of multidrug resistance', 'MPA', (43, 77))	('Cisplatin', 'Var', (0, 9))	('activates', 'PosReg', (10, 19))	('beta-catenin', 'Gene', '1499', (91, 103))	('MAPK signaling', 'Pathway', (20, 34))
246069	33376383	In contrast, IGF2R mutations increased the sensitivity of tumor cells to cisplatin by reducing autophagy, MAPK3, VEGFR, and WNT/beta-catenin signaling activity, mediating cisplatin sensitivity.	('cisplatin', 'Chemical', 'MESH:D002945', (73, 82))	('tumor', 'Disease', (58, 63))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('beta-catenin', 'Gene', (128, 140))	('IGF2R', 'Gene', '3482', (13, 18))	('VEGFR', 'Gene', (113, 118))	('increased', 'PosReg', (29, 38))	('mutations', 'Var', (19, 28))	('beta-catenin', 'Gene', '1499', (128, 140))	('MAPK3', 'Gene', (106, 111))	('reducing', 'NegReg', (86, 94))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('MAPK3', 'Gene', '5595', (106, 111))	('IGF2R', 'Gene', (13, 18))	('autophagy', 'CPA', (95, 104))	('cisplatin', 'Chemical', 'MESH:D002945', (171, 180))	('sensitivity', 'MPA', (43, 54))	('VEGFR', 'Gene', '3791', (113, 118))
246072	33376383	Second, we used only the GSEA and ssGSEA algorithms to evaluate the differences in cell signatures between the mutant group and wild-type group and did not use employ cell experiments or animal experiments for subsequent validation.	('cell signatures', 'MPA', (83, 98))	('mutant', 'Var', (111, 117))	('GSEA', 'Chemical', '-', (25, 29))	('GSEA', 'Chemical', '-', (36, 40))
246075	33376383	In conclusion, IGF2R mutations are potential biomarker for screening cisplatin sensitivity in patients with LUSC.	('IGF2R', 'Gene', '3482', (15, 20))	('cisplatin', 'Chemical', 'MESH:D002945', (69, 78))	('patients', 'Species', '9606', (94, 102))	('IGF2R', 'Gene', (15, 20))	('mutations', 'Var', (21, 30))
246076	33376383	IGF2R mutations are associated with cisplatin sensitivity and better survival prognoses, while wild-type IGF2R promotes the development of cisplatin resistance in LUSC.	('associated', 'Reg', (20, 30))	('IGF2R', 'Gene', '3482', (105, 110))	('IGF2R', 'Gene', '3482', (0, 5))	('cisplatin', 'Chemical', 'MESH:D002945', (139, 148))	('IGF2R', 'Gene', (105, 110))	('promotes', 'PosReg', (111, 119))	('development of cisplatin resistance', 'MPA', (124, 159))	('cisplatin', 'Chemical', 'MESH:D002945', (36, 45))	('cisplatin sensitivity', 'MPA', (36, 57))	('IGF2R', 'Gene', (0, 5))	('mutations', 'Var', (6, 15))
246077	33376383	Additionally, mechanistic analysis suggests that IGF2R mutations increase the intracellular detoxification of drugs and reduce the activity of abnormal signaling pathways, which may reverse cisplatin tolerance and significantly improve clinical benefit in LUSC populations.	('increase', 'PosReg', (65, 73))	('reverse', 'NegReg', (182, 189))	('IGF2R', 'Gene', (49, 54))	('mutations', 'Var', (55, 64))	('reduce', 'NegReg', (120, 126))	('intracellular detoxification of drugs', 'MPA', (78, 115))	('activity', 'MPA', (131, 139))	('cisplatin', 'Chemical', 'MESH:D002945', (190, 199))	('abnormal signaling pathways', 'Pathway', (143, 170))	('IGF2R', 'Gene', '3482', (49, 54))	('clinical benefit', 'CPA', (236, 252))	('improve', 'PosReg', (228, 235))	('cisplatin tolerance', 'MPA', (190, 209))
246082	33376383	LUSC, lung squamous cell carcinoma; GDSC, Genomics of Drug Sensitivity in Cancer; TCGA, The Cancer Genome Atlas; MT, mutant; WT, wild-type; GSEA, Gene set enrichment analysis; ssGSEA, single-sample GSEA; NSCLC, non-small cell lung cancer; LUAD, lung adenocarcinoma; DDR, DNA damage repair; MMR, Mutations in DNA mismatch repair; WES, whole exome sequencing; IC50, the half maximal inhibitory concentration; GO, Gene Ontology; KEGG, Kyoto Encyclopedia of Genes and Genomes; MSigDB, Molecular Signatures Database; OS, overall survival; HR, hazard ratio; CI, confidence interval; UPR, unfolded protein response; HSP, heat shock proteins.	('Cancer', 'Disease', (92, 98))	('lung cancer', 'Phenotype', 'HP:0100526', (226, 237))	('non-small cell lung cancer', 'Disease', (211, 237))	('Drug Sensitivity', 'Phenotype', 'HP:0020174', (54, 70))	('heat shock proteins', 'Disease', (614, 633))	('NSCLC', 'Disease', 'MESH:D002289', (204, 209))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (245, 264))	('carcinoma', 'Phenotype', 'HP:0030731', (25, 34))	('carcinoma', 'Phenotype', 'HP:0030731', (255, 264))	('GSEA', 'Chemical', '-', (178, 182))	('Cancer', 'Disease', 'MESH:D009369', (92, 98))	('Cancer', 'Phenotype', 'HP:0002664', (74, 80))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (245, 264))	('Mutations', 'Var', (295, 304))	('heat shock proteins', 'Disease', 'MESH:D012769', (614, 633))	('shock', 'Phenotype', 'HP:0031273', (619, 624))	('NSCLC', 'Disease', (204, 209))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (211, 237))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('NSCLC', 'Phenotype', 'HP:0030358', (204, 209))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (6, 34))	('Cancer', 'Disease', (74, 80))	('GSEA', 'Chemical', '-', (198, 202))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (215, 237))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (11, 34))	('Cancer', 'Phenotype', 'HP:0002664', (92, 98))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (211, 237))	('Cancer', 'Disease', 'MESH:D009369', (74, 80))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (6, 34))	('lung squamous cell carcinoma', 'Disease', (6, 34))	('lung adenocarcinoma', 'Disease', (245, 264))	('GSEA', 'Chemical', '-', (140, 144))
246108	32933105	In many studies the presence of a large number of CD3+ and CD8+ cells has been associated with a favorable prognosis and improved survival, while the presence of a large number of Treg (FOXP3+) has been often associated with a worse prognosis.	('CD3+', 'Var', (50, 54))	('survival', 'CPA', (130, 138))	('improved', 'PosReg', (121, 129))	('FOXP3', 'Gene', (186, 191))	('CD8', 'Gene', (59, 62))	('CD8', 'Gene', '925', (59, 62))	('FOXP3', 'Gene', '50943', (186, 191))
246123	32933105	Sections were incubated with primary antibodies at room temperature: anti-CD206 (Sigma-Aldrich, St. Louis, MO, USA HPA004114), anti-CD68 (Genemed, South San Francisco, CA, USA 61-0184), anti-CD163 (Clone 10D6; BIOCARE, USA), anti-iNOS (Sigma, St. Louis, MO, USA SAB5500152), anti-CD8 (Genemed, South San Francisco, CA, USA 61-0124), anti-CD3 (Genemed, South San Francisco, CA, USA 61-0011) and anti-FOXP3 (Cell Signaling, Denvers, MA, USA #98377).	('iNOS', 'Gene', (230, 234))	('CD8', 'Gene', '925', (280, 283))	('CD163', 'Gene', (191, 196))	('anti-CD3', 'Var', (333, 341))	('CD206', 'Gene', '4360', (74, 79))	('CD206', 'Gene', (74, 79))	('FOXP3', 'Gene', (399, 404))	('FOXP3', 'Gene', '50943', (399, 404))	('CD163', 'Gene', '9332', (191, 196))	('iNOS', 'Gene', '4843', (230, 234))	('CD8', 'Gene', (280, 283))
246173	32933105	It is interesting to note that the relative abundance of the genus Staphylococcus was higher in low-grade tumors compared to high-grade ones (Table S3).	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('low-grade', 'Var', (96, 105))	('tumors', 'Disease', (106, 112))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('higher', 'PosReg', (86, 92))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))
246176	32933105	An analysis of tumor stroma was done using CD68 for macrophages, iNOS for type 1 macrophages (M1), CD206 and CD163 for type 2 macrophages (M2), CD3 for T-cells, CD8 for cytotoxic T-cells and FoxP3 for Treg.	('CD163', 'Gene', '9332', (109, 114))	('CD3', 'Var', (144, 147))	('tumor stroma', 'Disease', (15, 27))	('iNOS', 'Gene', '4843', (65, 69))	('iNOS', 'Gene', (65, 69))	('CD8', 'Gene', (161, 164))	('CD163', 'Gene', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('CD68', 'Var', (43, 47))	('CD8', 'Gene', '925', (161, 164))	('FoxP3', 'Gene', '50943', (191, 196))	('FoxP3', 'Gene', (191, 196))	('CD206', 'Gene', '4360', (99, 104))	('CD206', 'Gene', (99, 104))	('tumor stroma', 'Disease', 'MESH:D009369', (15, 27))
246192	32933105	We found that high iNOS expression accompanied by increased bacterial load is a marker of a good prognosis compared to the group of patients with high bacterial load and low iNOS expression (HR 0.1824 (0.05563-0.5983); p = 0.0123).	('increased bacterial load', 'Phenotype', 'HP:0002718', (50, 74))	('iNOS', 'Gene', (174, 178))	('expression', 'MPA', (24, 34))	('increased', 'PosReg', (50, 59))	('high', 'Var', (14, 18))	('iNOS', 'Gene', '4843', (19, 23))	('iNOS', 'Gene', (19, 23))	('bacterial load', 'MPA', (60, 74))	('patients', 'Species', '9606', (132, 140))	('iNOS', 'Gene', '4843', (174, 178))
246201	32933105	An increase in the Shannon and Simpson indices in the group with a low level of iNOS expression was found to be accompanied by an increase in the relative abundance of the only genus Propionibacterium (Figure 9).	('low', 'Var', (67, 70))	('iNOS', 'Gene', '4843', (80, 84))	('iNOS', 'Gene', (80, 84))	('relative abundance', 'MPA', (146, 164))	('increase', 'PosReg', (130, 138))	('increase', 'PosReg', (3, 11))
246204	32933105	Commensal bacteria play an important role in maintaining the immune homeostasis of various organs and tissues, and disturbances in their balance can affect the susceptibility of the body to carcinogenesis or tumor progression.	('disturbances', 'Var', (115, 127))	('carcinogenesis', 'Disease', (190, 204))	('immune homeostasis', 'MPA', (61, 79))	('tumor', 'Disease', 'MESH:D009369', (208, 213))	('affect', 'Reg', (149, 155))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('balance', 'MPA', (137, 144))	('tumor', 'Disease', (208, 213))	('susceptibility', 'MPA', (160, 174))	('carcinogenesis', 'Disease', 'MESH:D063646', (190, 204))
246235	32933105	Assessing the bacterial load in tumor samples with different stromal phenotypes showed that an increased bacterial content is typical for tumors with high iNOS (p = 0.0170) and FOXP3 (p = 0.0292) expression.	('FOXP3', 'Gene', '50943', (177, 182))	('tumor', 'Disease', (138, 143))	('bacterial content', 'MPA', (105, 122))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('iNOS', 'Gene', '4843', (155, 159))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('iNOS', 'Gene', (155, 159))	('high', 'Var', (150, 154))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('tumors', 'Disease', (138, 144))	('tumors', 'Disease', 'MESH:D009369', (138, 144))	('FOXP3', 'Gene', (177, 182))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumor', 'Disease', (32, 37))	('increased', 'PosReg', (95, 104))	('bacterial load', 'MPA', (14, 28))
246263	31579115	Expression of HIFs in cancer cells contributes to metastasis, but inactivation of HIFs decreases metastasis of cancer cells.	('decreases', 'NegReg', (87, 96))	('HIFs', 'Gene', (82, 86))	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('cancer', 'Disease', (22, 28))	('inactivation', 'Var', (66, 78))	('metastasis', 'CPA', (50, 60))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))
246283	31579115	Multivariate analysis showed that HIF-1alpha expression was associated with worse OS in tissue samples (n = 17 studies with 2027 cases, HR = 1.61, 95% CI = 1.28-2.03, p < 0.001), but was not correlated with OS in blood samples (n = two studies with 315 cases, HR = 0.79, 95% CI = 0.15-4.07, p = 0.774) (Figure 2).	('HIF-1alpha', 'Gene', (34, 44))	('expression', 'Var', (45, 55))	('worse OS', 'Disease', (76, 84))	('HIF-1alpha', 'Gene', '3091', (34, 44))
246286	31579115	Subgroup analysis by survival status showed that HIF-1alpha expression was significantly associated with worse prognosis for 5-year OS (n = 10 studies with 1566 cases, HR = 1.36, p < 0.001) and <3-year OS (n = two studies with 95 cases, HR = 3.47, p = 0.007) subgroups, but no relationship was found between the HR of the 3-year OS (n = four studies with 204 cases, p = 0.064).	('HIF-1alpha', 'Gene', '3091', (49, 59))	('expression', 'Var', (60, 70))	('HIF-1alpha', 'Gene', (49, 59))
246310	31579115	The pooled data indicated that the expression of HIF-1alpha was associated with reduced OS (HR = 1.61, p < 0.001), DFS (HR = 1.61, p < 0.001), PFS (HR = 1.49, p = 0.01), CSS (HR = 1.65, p = 0.056), RFS (HR = 2.10, p = 0.015), or MFS (HR = 2.36, p = 0.002).	('CSS', 'Disease', (170, 173))	('HIF-1alpha', 'Gene', (49, 59))	('reduced', 'NegReg', (80, 87))	('DFS', 'CPA', (115, 118))	('HIF-1alpha', 'Gene', '3091', (49, 59))	('PFS', 'Disease', (143, 146))	('MFS', 'CPA', (229, 232))	('expression', 'Var', (35, 45))	('RFS', 'Disease', (198, 201))
246325	31579115	First, HIF-1alpha expression is associated with worse outcomes, which suggests that HIF-1alpha may be a key druggable therapeutic target.	('HIF-1alpha', 'Gene', (7, 17))	('HIF-1alpha', 'Gene', (84, 94))	('HIF-1alpha', 'Gene', '3091', (7, 17))	('HIF-1alpha', 'Gene', '3091', (84, 94))	('expression', 'Var', (18, 28))
246327	31579115	Third, HIF-1alpha expression is linked to poor OS in European and Asian subjects, which suggests that HIF-1alpha may play important roles in different ethnic populations.	('HIF-1alpha', 'Gene', (7, 17))	('poor OS', 'Disease', (42, 49))	('HIF-1alpha', 'Gene', '3091', (102, 112))	('HIF-1alpha', 'Gene', (102, 112))	('HIF-1alpha', 'Gene', '3091', (7, 17))	('expression', 'Var', (18, 28))
246347	29636832	Seven out of the 12 mgmiRs, i.e., mgmiR9-1, mgmiR124-1, mgmiR124-2, mgmiR124-3, mgmiR129-2, mgmiR137, and mgmiR148a, were further found to significantly increase in HNSCC tumor tissues compared to control tissues.	('mgmiR124-1', 'Var', (44, 54))	('miR137', 'Gene', (94, 100))	('mgmiR124-3', 'Var', (68, 78))	('HNSCC', 'Phenotype', 'HP:0012288', (165, 170))	('miR129-2', 'Gene', '100302138', (82, 90))	('miR148a', 'Gene', (108, 115))	('mgmiR9-1', 'Var', (34, 42))	('increase', 'PosReg', (153, 161))	('miR148a', 'Gene', '406940', (108, 115))	('miR137', 'Gene', '406928', (94, 100))	('HNSCC tumor', 'Disease', 'MESH:D000077195', (165, 176))	('HNSCC tumor', 'Disease', (165, 176))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('mgmiR124-2', 'Var', (56, 66))	('miR129-2', 'Gene', (82, 90))
246357	29636832	Development of cancer-specific biomarkers for detection of initial HNSCC and recurrence has been widely explored using DNA-based (loss of heterozygosity, mutation, and DNA methylation), RNA-based, and protein-based assays in both patient tissues and saliva.	('cancer', 'Disease', (15, 21))	('SCC', 'Gene', (69, 72))	('cancer', 'Disease', 'MESH:D009369', (15, 21))	('mutation', 'Var', (154, 162))	('patient', 'Species', '9606', (230, 237))	('SCC', 'Gene', '6317', (69, 72))	('HNSCC', 'Phenotype', 'HP:0012288', (67, 72))	('loss of', 'NegReg', (130, 137))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))
246364	29636832	We have reported that DNA methylation of miR9 specifically occurred in a subset of human HNSCC tissue samples.	('methylation', 'Var', (26, 37))	('human', 'Species', '9606', (83, 88))	('SCC', 'Gene', (91, 94))	('miR9', 'Gene', (41, 45))	('HNSCC', 'Phenotype', 'HP:0012288', (89, 94))	('occurred', 'Reg', (59, 67))	('SCC', 'Gene', '6317', (91, 94))
246368	29636832	We then investigated panel of seven mgmiRs, i.e., 9-1, 124-1, 124-2, 124-3, 129-2, 137, and 148a, in an expanded patient's cohort, including 189 HNSCC tissues and 92 control tissues.	('patient', 'Species', '9606', (113, 120))	('SCC', 'Gene', (147, 150))	('HNSCC', 'Phenotype', 'HP:0012288', (145, 150))	('SCC', 'Gene', '6317', (147, 150))	('148a', 'Var', (92, 96))	('9-1', 'Var', (50, 53))
246408	29636832	Based on the comparison of relative methylation levels, seven mgmiRs, i.e., 9-1, 124-1, 124-2, 124-3, 129, 137, and 148a, showed significant elevation in HNSCC tissue compared to non-HNSCC control tissues and were selected for further study (Additional file 1: Figure S3).	('SCC', 'Gene', (185, 188))	('HNSCC', 'Phenotype', 'HP:0012288', (183, 188))	('SCC', 'Gene', (156, 159))	('SCC', 'Gene', '6317', (185, 188))	('SCC', 'Gene', '6317', (156, 159))	('148a', 'Var', (116, 120))	('elevation', 'PosReg', (141, 150))	('HNSCC', 'Phenotype', 'HP:0012288', (154, 159))
246416	29636832	Notably, mgmiR124-2 and mgmiR129-2 were found to detect significantly more HPV-positive than HPV-negative HNSCC cases (88.0 vs. 65.9%, p = 0.04; 84.0 vs. 56.1%, p = 0.02, respectively).	('HPV', 'Species', '10566', (75, 78))	('miR129-2', 'Gene', (26, 34))	('SCC', 'Gene', (108, 111))	('HPV', 'Species', '10566', (93, 96))	('miR129-2', 'Gene', '100302138', (26, 34))	('SCC', 'Gene', '6317', (108, 111))	('HPV-positive', 'Gene', (75, 87))	('mgmiR124-2', 'Var', (9, 19))	('HNSCC', 'Phenotype', 'HP:0012288', (106, 111))
246424	29636832	Similar to the tissue sample results, the associations between the mgmiRs and location of HNSCC, smoking status, tumor size, node status, and stage were generally stronger for the combination of the seven mgmiRs compared to their individual assessments (Table 5).	('tumor', 'Disease', (113, 118))	('associations', 'Interaction', (42, 54))	('SCC', 'Gene', '6317', (92, 95))	('HNSCC', 'Phenotype', 'HP:0012288', (90, 95))	('combination', 'Var', (180, 191))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('stronger', 'PosReg', (163, 171))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('SCC', 'Gene', (92, 95))
246437	29636832	In contrast with examining expression level of mRNA, miRNA itself, or protein, which can be either positive (increased) or negative (decreased), DNA methylation converts a negative signal (reduced or loss of expression) into a positive signal, which can be used for the detection of cancer-specific signal in a high background of normal non-cancer cells.	('DNA', 'Var', (145, 148))	('cancer', 'Disease', 'MESH:D009369', (283, 289))	('cancer', 'Phenotype', 'HP:0002664', (341, 347))	('cancer', 'Disease', (283, 289))	('loss', 'NegReg', (200, 204))	('methylation', 'Var', (149, 160))	('expression', 'MPA', (208, 218))	('cancer', 'Disease', 'MESH:D009369', (341, 347))	('cancer', 'Phenotype', 'HP:0002664', (283, 289))	('cancer', 'Disease', (341, 347))
246546	28747140	The pathological T classifications of the 151 OTSCC patients were T1 in 41 (27%) patients, T2 in 51 (34%) patients, T3 in 12 (8%) patients, T4a in 42 (28%) patients, and T4b in five (3%) patients.	('patients', 'Species', '9606', (156, 164))	('patients', 'Species', '9606', (187, 195))	('T4a', 'Var', (140, 143))	('patients', 'Species', '9606', (81, 89))	('patients', 'Species', '9606', (130, 138))	('patients', 'Species', '9606', (106, 114))	('patients', 'Species', '9606', (52, 60))	('T4b', 'Var', (170, 173))
246559	28747140	Univariate analyses demonstrated that MasR overexpression (p=0.012, Figure 2(a)), pathological T classification, T1/2 (p=0.001), pathological N classification, N0 (p<0.001), pathological 7th AJCC Stage I/II (p<0.001), absence of vascular invasion (p=0.045), absence of perineural invasion (p=0.018), absence of extracapsular spread (p<0.001), negative surgical margin (p=0.024), and absence of smoking history (p=0.047) were significantly associated with superior overall survival.	('overall survival', 'CPA', (464, 480))	('perineural invasion', 'CPA', (269, 288))	('superior', 'PosReg', (455, 463))	('pathological', 'Var', (174, 186))	('MasR', 'Gene', (38, 42))	('vascular invasion', 'CPA', (229, 246))	('MasR', 'Gene', '116511', (38, 42))
246560	28747140	Additionally, MasR overexpression (p=0.007, Figure 2(b)), pathological T classification, T1/2 (p=0.008), pathological N classification, N0 (p<0.001), pathological 7th AJCC Stage I/II (p<0.001), histologic grade 1 (p=0.04), absence of perineural invasion (p=0.003), and absence of extracapsular spread (p<0.001) were significantly associated with superior disease-free survival.	('MasR', 'Gene', '116511', (14, 18))	('perineural invasion', 'CPA', (234, 253))	('extracapsular spread', 'CPA', (280, 300))	('MasR', 'Gene', (14, 18))	('pathological', 'Var', (150, 162))	('superior', 'PosReg', (346, 354))	('disease-free survival', 'CPA', (355, 376))
246583	28747140	In the current study, low MasR expression was highly representative of biological aggressiveness and independently associated with poor overall survival and disease-free survival.	('MasR', 'Gene', (26, 30))	('poor', 'NegReg', (131, 135))	('disease-free survival', 'CPA', (157, 178))	('aggressiveness', 'Disease', (82, 96))	('low', 'Var', (22, 25))	('associated', 'Reg', (115, 125))	('aggressiveness', 'Phenotype', 'HP:0000718', (82, 96))	('MasR', 'Gene', '116511', (26, 30))	('aggressiveness', 'Disease', 'MESH:D001523', (82, 96))	('overall survival', 'CPA', (136, 152))
246588	28747140	reported that cell growth was suppressed by angiotensin-(1-7) treatment and enhanced by MasR knockdown in breast cancer cell lines.	('knockdown', 'Var', (93, 102))	('MasR', 'Gene', (88, 92))	('breast cancer', 'Disease', (106, 119))	('suppressed', 'NegReg', (30, 40))	('breast cancer', 'Phenotype', 'HP:0003002', (106, 119))	('men', 'Species', '9606', (67, 70))	('enhanced', 'PosReg', (76, 84))	('MasR', 'Gene', '116511', (88, 92))	('cell growth', 'CPA', (14, 25))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('breast cancer', 'Disease', 'MESH:D001943', (106, 119))
246643	29221167	By immunohistochemistry, BSCC expresses cytokeratins (AK1, AK3, LP34) and epithelial membrane antigen EMA.	('AK3', 'Gene', '50808', (59, 62))	('LP34', 'Var', (64, 68))	('AK3', 'Gene', (59, 62))	('AK1', 'Gene', '203', (54, 57))	('BSCC', 'Chemical', '-', (25, 29))	('SCC', 'Phenotype', 'HP:0002860', (26, 29))	('BSCC', 'Phenotype', 'HP:0002671', (25, 29))	('AK1', 'Gene', (54, 57))
246707	26590264	Protein domain analysis enhances the statistical power to detect cancer-relevant mutations and links mutations to the specific biological functions encoded in domains.	('cancer', 'Disease', (65, 71))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('mutations', 'Var', (81, 90))	('enhances', 'PosReg', (24, 32))	('cancer', 'Disease', 'MESH:D009369', (65, 71))
246709	26590264	We believe that MutationAligner will be an important resource for the cancer research community by providing detailed clues for the functional importance of particular mutations, as well as for the design of functional genomics experiments and for decision support in precision medicine.	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('MutationAligner', 'Var', (16, 31))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('mutations', 'Var', (168, 177))
246714	26590264	Enhancing the computational-analytic methods for establishing the identity of infrequent mutations that play causative roles in cancer is not only an important scientific question for understanding tumorigenesis, but is also essential to the development of personalized cancer therapies.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('cancer', 'Disease', (270, 276))	('cancer', 'Disease', 'MESH:D009369', (270, 276))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('mutations', 'Var', (89, 98))	('cancer', 'Phenotype', 'HP:0002664', (270, 276))	('tumor', 'Disease', (198, 203))	('cancer', 'Disease', (128, 134))
246715	26590264	To address the critical challenge of associating function with rare mutations in cancer, we present a comprehensive web-based resource of the analysis of mutations in protein domains in cancer.	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('cancer', 'Disease', (81, 87))	('mutations', 'Var', (154, 163))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('cancer', 'Disease', (186, 192))	('cancer', 'Disease', 'MESH:D009369', (186, 192))
246716	26590264	This resource, called 'MutationAligner', is associated with our recent work describing a new analytical framework that uses domains, rather than individual genes, as the basis for the discovery of functionally relevant mutations in cancer.	('cancer', 'Disease', (232, 238))	('mutations', 'Var', (219, 228))	('cancer', 'Disease', 'MESH:D009369', (232, 238))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))
246717	26590264	In the MutationAligner approach, we systematically analyzed nearly 500 000 missense mutations from 22 TCGA-profiled tumor types deposited in the cBioPortal by tallying mutations across sequence alignments of protein domains.	('tumor', 'Disease', (116, 121))	('missense mutations', 'Var', (75, 93))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))
246718	26590264	developed the 'mCluster' approach (http://research-pub.gene.com/mcluster) in which around 9000 somatic cancer mutations, 19 000 germline disease mutations and 17 000 other annotations of amino acid residues were analyzed in the context of sequence alignments of domains.	('mutations', 'Var', (110, 119))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('mutations', 'Var', (145, 154))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('germline disease', 'Disease', (128, 144))
246721	26590264	In this work, we (i) describe the MutationAligner database and how other resources are combined and integrated (Pfam-A, cBioPortal and TCGA), (ii) provide technical details about the database construction and software architecture and (iii) provide guidelines and illustrate with an example of how exploring the database can reveal biological insights of mutations in domains in cancer.	('cancer', 'Disease', (379, 385))	('mutations', 'Var', (355, 364))	('cancer', 'Phenotype', 'HP:0002664', (379, 385))	('reveal', 'Reg', (325, 331))	('cancer', 'Disease', 'MESH:D009369', (379, 385))
246724	26590264	Briefly, around 460 000 missense mutations from 5496 exome-sequenced tumor-normal pairs of 22 different tumor types studied by the TGCA consortium were obtained from the cBioPortal in the format of TCGA level 3 variant data.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('missense mutations', 'Var', (24, 42))	('tumor', 'Disease', (69, 74))	('tumor', 'Disease', (104, 109))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
246728	26590264	Typing into the search box dynamically updates the table to display positions that contain mutations in particular genes, cancer types or domains of interest.	('cancer', 'Disease', (122, 128))	('mutations', 'Var', (91, 100))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))
246732	26590264	KEAP1 is cysteine-rich, and modification of cysteine residues due to oxidative stress can induce a conformational change in KEAP1, leading to the nuclear translocation of NRF2 and up-regulation of anti-oxidant stress response genes.	('anti-oxidant stress response genes', 'Gene', (197, 231))	('oxidant stress', 'Phenotype', 'HP:0025464', (202, 216))	('conformational change', 'MPA', (99, 120))	('up-regulation', 'PosReg', (180, 193))	('KEAP1', 'Gene', (0, 5))	('cysteine', 'Chemical', 'MESH:D003545', (9, 17))	('KEAP1', 'Gene', '9817', (124, 129))	('induce', 'Reg', (90, 96))	('nuclear translocation', 'MPA', (146, 167))	('cysteine', 'Chemical', 'MESH:D003545', (44, 52))	('NRF2', 'Gene', '4780', (171, 175))	('oxidative stress', 'Phenotype', 'HP:0025464', (69, 85))	('modification', 'Var', (28, 40))	('KEAP1', 'Gene', (124, 129))	('KEAP1', 'Gene', '9817', (0, 5))	('NRF2', 'Gene', (171, 175))
246733	26590264	KEAP1 is composed of a series of six repeated Kelch_1 domains, and the mutation of residues in this domain have been shown to lead to dysregulated activation of NRF2.	('Kelch', 'Gene', '11275', (46, 51))	('NRF2', 'Gene', (161, 165))	('dysregulated', 'MPA', (134, 146))	('mutation of', 'Var', (71, 82))	('Kelch', 'Gene', (46, 51))	('KEAP1', 'Gene', (0, 5))	('lead to', 'Reg', (126, 133))	('NRF2', 'Gene', '4780', (161, 165))	('activation', 'PosReg', (147, 157))	('KEAP1', 'Gene', '9817', (0, 5))
246736	26590264	On the mutationaligner.org homepage, users can query a searchable and sortable table with all mutations analyzed in the context of protein domains, providing an effective way of identifying domain mutations in specific genes or tumor types of interest (Figure 2A).	('tumor', 'Disease', 'MESH:D009369', (228, 233))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('domain mutations', 'Var', (190, 206))	('tumor', 'Disease', (228, 233))
246737	26590264	The table of all analyzed positions (positions tab) is dynamically updated to show matching search results of the >17K domain mutations analyzed and provides the user with information about (i) the specific position in the multiple sequence alignment that is mutated; (ii) the hotspot significance level (-log10 of the P-value); (iii) the entropy score that estimates how uniformly mutations are spread across domain-containing genes, where a high score indicates that multiple genes are mutated in the particular position (the entropy score is normalized to the domain family size, with a maximum score of 1 signifying that mutation counts are the same for all genes); (iv) the number of identified mutations; (v) information on which genes are mutated; (vi) information on which cancer types are mutated.	('cancer', 'Disease', (781, 787))	('cancer', 'Disease', 'MESH:D009369', (781, 787))	('cancer', 'Phenotype', 'HP:0002664', (781, 787))	('mutations', 'Var', (700, 709))
246740	26590264	In the Kelch_1 domain, for example, position 12 is found as the most significant hotspot with mutations in multiple genes including KEAP1.	('Kelch', 'Gene', (7, 12))	('mutations', 'Var', (94, 103))	('KEAP1', 'Gene', '9817', (132, 137))	('Kelch', 'Gene', '11275', (7, 12))	('KEAP1', 'Gene', (132, 137))
246741	26590264	To explore the mutations in Kelch_1 further, users can click on the domain name or chart icon (Figure 2A, bottom), bringing the user to the domain details page.	('mutations', 'Var', (15, 24))	('Kelch', 'Gene', (28, 33))	('Kelch', 'Gene', '11275', (28, 33))
246742	26590264	The details page of user-selected domains visualizes mutations in the context of domain sequence alignments and allows users to analyze mutations across selected genes and tumor types.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('tumor', 'Disease', (172, 177))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('mutations', 'Var', (53, 62))
246743	26590264	Figure 2B depicts a typical domain details page summarizing information for mutations in the selected Kelch_1 domain.	('mutations', 'Var', (76, 85))	('Kelch', 'Gene', (102, 107))	('Kelch', 'Gene', '11275', (102, 107))
246744	26590264	A summary histogram at the top of the page depicts the distribution of aligned mutations, summed across all cancer types over all genes containing the Kelch_1 domain (occurs 116 times in 43 genes).	('mutations', 'Var', (79, 88))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('Kelch', 'Gene', '11275', (151, 156))	('Kelch', 'Gene', (151, 156))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
246745	26590264	For example, in the tallest peak (position 12), a large proportion of the new amino acids generated by mutations are positively charged, basic amino acids (R and K, red) and cysteines (C, yellow).	('mutations', 'Var', (103, 112))	('basic amino acids', 'Chemical', 'MESH:D024361', (137, 154))	('positively charged', 'MPA', (117, 135))	('cysteines', 'MPA', (174, 183))	('basic amino acids', 'MPA', (137, 154))	('amino acids', 'MPA', (78, 89))	('cysteines', 'Chemical', 'MESH:D003545', (174, 183))
246748	26590264	The peak at position 12 is an aggregate of homologous mutations of the Kelch_1 domain across multiple genes.	('mutations', 'Var', (54, 63))	('Kelch', 'Gene', (71, 76))	('Kelch', 'Gene', '11275', (71, 76))
246749	26590264	Among eight genes that have mutations in position 12, KEAP1 has the most mutations, which can be displayed in more detail using the 'Select gene' option (note that only five of the six Kelch_1 domains in KEAP1 were analyzed as the first instance was excluded based on high e-value).	('KEAP1', 'Gene', (54, 59))	('KEAP1', 'Gene', '9817', (204, 209))	('Kelch', 'Gene', '11275', (185, 190))	('KEAP1', 'Gene', '9817', (54, 59))	('Kelch', 'Gene', (185, 190))	('mutations', 'Var', (28, 37))	('mutations', 'Var', (73, 82))	('KEAP1', 'Gene', (204, 209))
246750	26590264	Displaying KEAP1's fourth Kelch_1 domain, which spans amino acid positions 459-504, shows six mutations in residue R470 with four being R470C mutations.	('KEAP1', 'Gene', '9817', (11, 16))	('R470C', 'Var', (136, 141))	('mutations in', 'Var', (94, 106))	('Kelch', 'Gene', '11275', (26, 31))	('KEAP1', 'Gene', (11, 16))	('Kelch', 'Gene', (26, 31))	('R470C', 'Mutation', 'rs762451424', (136, 141))
246751	26590264	The KEAP1 R470C mutation has been reported as a 'super-binder' in the literature, leading to enhanced KEAP1 and NRF2 interaction and hypomorphic regulation of NRF2 by KEAP1.	('KEAP1', 'Gene', (167, 172))	('KEAP1', 'Gene', (102, 107))	('NRF2', 'Gene', '4780', (159, 163))	('R470C', 'Mutation', 'rs762451424', (10, 15))	('interaction', 'Interaction', (117, 128))	('KEAP1', 'Gene', (4, 9))	('R470C', 'Var', (10, 15))	('NRF2', 'Gene', (159, 163))	('hypomorphic regulation', 'MPA', (133, 155))	('NRF2', 'Gene', '4780', (112, 116))	('enhanced', 'PosReg', (93, 101))	('KEAP1', 'Gene', '9817', (167, 172))	('KEAP1', 'Gene', '9817', (102, 107))	('NRF2', 'Gene', (112, 116))	('KEAP1', 'Gene', '9817', (4, 9))
246752	26590264	Interestingly, two mutations occur in KEAP1 at position G423 in the third Kelch_1 repeat (residues 412-457), and these align precisely with the R470 mutation hotspot.	('KEAP1', 'Gene', '9817', (38, 43))	('Kelch', 'Gene', '11275', (74, 79))	('KEAP1', 'Gene', (38, 43))	('G423', 'Var', (56, 60))	('Kelch', 'Gene', (74, 79))
246753	26590264	As these two repeats are mutated at analogous positions and multiple repeats are needed to form the functional Kelch_1 beta-propeller, these observations indicate that G423 mutations are likely functionally relevant despite being rare mutation events.	('Kelch', 'Gene', (111, 116))	('Kelch', 'Gene', '11275', (111, 116))	('G423 mutations', 'Var', (168, 182))
246754	26590264	have reported that the non-canonical G423 mutation in KEAP1 has an identical 'super-binder' effect as the R470C mutation.	("'super-binder'", 'PosReg', (77, 91))	('KEAP1', 'Gene', (54, 59))	('R470C', 'Var', (106, 111))	('KEAP1', 'Gene', '9817', (54, 59))	('G423', 'Var', (37, 41))	('R470C', 'Mutation', 'rs762451424', (106, 111))
246756	26590264	For Kelch_1 this view shows that lung cancers in general have many mutations distributed over the domain.	('lung cancer', 'Phenotype', 'HP:0100526', (33, 44))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('lung cancers', 'Disease', 'MESH:D008175', (33, 45))	('lung cancers', 'Phenotype', 'HP:0100526', (33, 45))	('Kelch', 'Gene', '11275', (4, 9))	('mutations', 'Var', (67, 76))	('lung cancers', 'Disease', (33, 45))	('cancers', 'Phenotype', 'HP:0002664', (38, 45))	('Kelch', 'Gene', (4, 9))
246759	26590264	Analyzing mutations across different user-selected tumor types also offers the ability to transfer knowledge from one context to another, particularly when recurrent mutations in one cancer type overlaps with more infrequent mutations in other cancer types.	('cancer', 'Disease', (183, 189))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('mutations', 'Var', (166, 175))	('cancer type overlaps', 'Disease', 'MESH:D009369', (183, 203))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('tumor', 'Disease', (51, 56))	('cancer', 'Disease', 'MESH:D009369', (183, 189))	('cancer type overlaps', 'Disease', (183, 203))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('mutations', 'Var', (10, 19))	('cancer', 'Disease', (244, 250))	('cancer', 'Disease', 'MESH:D009369', (244, 250))
246760	26590264	For example, in the case of Kelch_1, while most mutations at position 12 were in lung cancer, using MutationAligner it is clear that melanomas (SKCM) also contain mutations in the same position (five mutations, Figure 2B).	('lung cancer', 'Disease', (81, 92))	('lung cancer', 'Phenotype', 'HP:0100526', (81, 92))	('melanomas', 'Disease', (133, 142))	('mutations', 'Var', (163, 172))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('melanomas', 'Disease', 'MESH:D008545', (133, 142))	('melanoma', 'Phenotype', 'HP:0002861', (133, 141))	('melanomas', 'Phenotype', 'HP:0002861', (133, 142))	('lung cancer', 'Disease', 'MESH:D008175', (81, 92))	('Kelch', 'Gene', '11275', (28, 33))	('mutations', 'Var', (48, 57))	('Kelch', 'Gene', (28, 33))
246761	26590264	Interestingly, out of the five mutations found in melanoma in position 12, none of the mutations occur in KEAP1, but rather these mutations are spread across KLHL4 (three mutations), KLHL18 and KLHL20 (see box in Figure 2B).	('KLHL4', 'Gene', (158, 163))	('KEAP1', 'Gene', (106, 111))	('KLHL18', 'Gene', '23276', (183, 189))	('melanoma', 'Phenotype', 'HP:0002861', (50, 58))	('melanoma', 'Disease', (50, 58))	('KLHL20', 'Gene', '27252', (194, 200))	('melanoma', 'Disease', 'MESH:D008545', (50, 58))	('KLHL20', 'Gene', (194, 200))	('mutations', 'Var', (130, 139))	('KLHL4', 'Gene', '56062', (158, 163))	('KLHL18', 'Gene', (183, 189))	('KEAP1', 'Gene', '9817', (106, 111))
246765	26590264	KLHL4 G523R) could alter Kelch_1-mediated function as they affect equivalent positions to the canonical KEAP1 hotspot mutations reported in lung cancer.	('affect', 'Reg', (59, 65))	('alter', 'Reg', (19, 24))	('lung cancer', 'Disease', (140, 151))	('Kelch', 'Gene', (25, 30))	('lung cancer', 'Phenotype', 'HP:0100526', (140, 151))	('KEAP1', 'Gene', '9817', (104, 109))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('G523R', 'Var', (6, 11))	('lung cancer', 'Disease', 'MESH:D008175', (140, 151))	('KEAP1', 'Gene', (104, 109))	('Kelch', 'Gene', '11275', (25, 30))	('KLHL4', 'Gene', '56062', (0, 5))	('G523R', 'Mutation', 'p.G523R', (6, 11))	('KLHL4', 'Gene', (0, 5))
246766	26590264	Taken together, the observation that mutations in the Kelch_1 domain of KLHL4 align precisely with hotspot mutations in KEAP1, in tandem with a lack of reports of oncogenic mutations in KLHL4 in melanoma, make these mutations an appealing subject for future investigation.	('KLHL4', 'Gene', '56062', (186, 191))	('KEAP1', 'Gene', '9817', (120, 125))	('KEAP1', 'Gene', (120, 125))	('KLHL4', 'Gene', (72, 77))	('Kelch', 'Gene', '11275', (54, 59))	('melanoma', 'Disease', 'MESH:D008545', (195, 203))	('KLHL4', 'Gene', (186, 191))	('mutations', 'Var', (37, 46))	('Kelch', 'Gene', (54, 59))	('melanoma', 'Phenotype', 'HP:0002861', (195, 203))	('melanoma', 'Disease', (195, 203))	('KLHL4', 'Gene', '56062', (72, 77))
246767	26590264	The end-product of tumor sequencing pipelines is a list of mutations of putatively unknown consequence.	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('mutations', 'Var', (59, 68))	('tumor', 'Disease', (19, 24))
246768	26590264	Distilling meaning from this list, by annotating variants with their likely contribution to the malignancy, is critical to understanding cancer biology and designing therapeutic protocols.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('malignancy', 'Disease', 'MESH:D009369', (96, 106))	('variants', 'Var', (49, 57))	('malignancy', 'Disease', (96, 106))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('cancer', 'Disease', (137, 143))
246769	26590264	While the TCGA has succeeded in identifying many recurrent alterations in tumors, a number of studies have highlighted the 'long tail' phenomenon in cancer where many genes are infrequently mutated, making it difficult to distinguish between non-functional passenger mutations and true oncogenic driver mutations.	('alterations', 'Var', (59, 70))	('cancer', 'Disease', (149, 155))	('long tail', 'Phenotype', 'HP:0002831', (124, 133))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumors', 'Disease', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	("'long tail'", 'Phenotype', 'HP:0002831', (123, 134))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('cancer', 'Disease', 'MESH:D009369', (149, 155))	('tumors', 'Disease', 'MESH:D009369', (74, 80))
246771	26590264	By taking a domain-centric approach, we identify new mutation hotspots in domains of genes not previously associated with cancer and predict the functional role of many rare mutations.	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('mutation', 'Var', (53, 61))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))
246774	26590264	As an example of the utility of the resource, we show how canonical hotspot mutations in KEAP1 in lung cancer align with rare, and putatively functional, mutations in other Kelch_1-containing genes in melanoma.	('melanoma', 'Disease', (201, 209))	('mutations', 'Var', (76, 85))	('hotspot', 'PosReg', (68, 75))	('Kelch', 'Gene', '11275', (173, 178))	('KEAP1', 'Gene', (89, 94))	('lung cancer', 'Disease', (98, 109))	('melanoma', 'Disease', 'MESH:D008545', (201, 209))	('lung cancer', 'Phenotype', 'HP:0100526', (98, 109))	('Kelch', 'Gene', (173, 178))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('lung cancer', 'Disease', 'MESH:D008175', (98, 109))	('KEAP1', 'Gene', '9817', (89, 94))	('melanoma', 'Phenotype', 'HP:0002861', (201, 209))
246775	26590264	As more cancers are sequenced this framework will help point to new alterations in domains with potential functional impact.	('cancers', 'Disease', 'MESH:D009369', (8, 15))	('cancers', 'Phenotype', 'HP:0002664', (8, 15))	('cancers', 'Disease', (8, 15))	('domains', 'MPA', (83, 90))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('alterations', 'Var', (68, 79))
246865	33616759	Pathological biopsy indicated ypT2N0M0 with tumor-free resection margins.	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumor', 'Disease', (44, 49))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('ypT2N0M0', 'Var', (30, 38))
246977	33616759	On subgroup analysis smoking mostly affected outcomes in the minimally invasive approach increasing the odds of wound complications (OR: 1.54, p-value: 0.005) and anastomotic leaks (OR: 1.70, p-value: 0.003).	('anastomotic leaks', 'Disease', 'MESH:D057868', (163, 180))	('wound complications', 'CPA', (112, 131))	('anastomotic leaks', 'Disease', (163, 180))	('increasing', 'PosReg', (89, 99))	('minimally', 'Var', (61, 70))
247133	33616759	Despite the afore mentioned, it has been proved that mild and moderate inflammation of the stump is more frequent when using Hem-o-lok clips than conventional stapler and cases of reaction to a foreign body have been reported when using Hem-olok clips.	('men', 'Species', '9606', (18, 21))	('inflammation', 'Disease', 'MESH:D007249', (71, 83))	('Hem-o-lok', 'Var', (125, 134))	('inflammation', 'Disease', (71, 83))
247241	33616759	Overall anastomotic complication rate was around 3.60% (1 patient (1.08%) with ICG A group vs 6 patient (6.06%) with control group).	('anastomotic complication', 'CPA', (8, 32))	('ICG', 'Chemical', 'MESH:D007208', (79, 82))	('patient', 'Species', '9606', (58, 65))	('patient', 'Species', '9606', (96, 103))	('ICG A', 'Var', (79, 84))
247334	33616759	The aim of this study is to evaluate whether patients with HPVs 16/18, or other high-risk subtypes have increased risk of progression to or recurrence of high-grade squamous intraepithelial lesions (HSIL).	('HPVs 16/18', 'Var', (59, 69))	('patients', 'Species', '9606', (45, 53))	('squamous intraepithelial lesions', 'Disease', (165, 197))	('squamous intraepithelial lesions', 'Disease', 'MESH:D000081483', (165, 197))
247348	33616759	We report a rare case of IMFT causing ileocolic intussusception leading to acute intestinal obstruction in an adult.	('intestinal obstruction', 'Disease', 'MESH:D007415', (81, 103))	('intussusception', 'Phenotype', 'HP:0002576', (48, 63))	('intestinal obstruction', 'Phenotype', 'HP:0005214', (81, 103))	('intestinal obstruction', 'Disease', (81, 103))	('IMFT', 'Var', (25, 29))	('ileocolic intussusception', 'Disease', (38, 63))
247474	33616759	Interestingly, PD-L1 expression was significantly higher in patients exhibiting high microsatellite instability (p = 0.0169).	('high microsatellite instability', 'Var', (80, 111))	('higher', 'PosReg', (50, 56))	('PD-L1', 'Gene', (15, 20))	('patients', 'Species', '9606', (60, 68))	('expression', 'MPA', (21, 31))	('PD-L1', 'Gene', '29126', (15, 20))
247533	33616759	Survival analysis highlighted that patients with a tumoral volume at diagnosis >= 30 cm3 had a lower disease-free survival (DFS) than patients with lower volume (p = 0.04).	('>= 30 cm3', 'Var', (79, 88))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('patients', 'Species', '9606', (134, 142))	('tumoral', 'Disease', (51, 58))	('tumoral', 'Disease', 'MESH:D009369', (51, 58))	('patients', 'Species', '9606', (35, 43))	('lower disease-free', 'Disease', 'MESH:D008569', (95, 113))	('lower disease-free', 'Disease', (95, 113))
247669	33616759	Samples were collected by Helsinki University Hospital and Jyvaskyla Central Hospital, Finland and represented a wide range of MSH2 and MSH6 pathogenic variants (n = 27) and non-pathogenic controls (n = 90).	('MSH6', 'Gene', '2956', (136, 140))	('MSH2', 'Gene', (127, 131))	('MSH2', 'Gene', '4436', (127, 131))	('variants', 'Var', (152, 160))	('MSH6', 'Gene', (136, 140))
247708	33616759	The level of NT-proBNP:1641.8 +- 47 pg/ml, cTnI < 0.01 g/mL, LDL-cholesterol 3.69 +- 0.4 m/l, CKD 53.5 +- 3.1 ml/min/1.73 m2.	('cTnI', 'Gene', '7137', (43, 47))	('NT-proBNP:1641.8', 'Var', (13, 29))	('LDL-cholesterol', 'MPA', (61, 76))	('cTnI', 'Gene', (43, 47))
247728	33616759	The aim of this poster is to expose a clinical case of a patient with acute gastrointestinal bleeding due to Dieulafoy's lesion in the cecum.	('post', 'Gene', '159371', (16, 20))	('post', 'Gene', (16, 20))	('patient', 'Species', '9606', (57, 64))	('acute gastrointestinal bleeding', 'Disease', (70, 101))	('lesion', 'Var', (121, 127))	('gastrointestinal bleeding', 'Phenotype', 'HP:0002239', (76, 101))	('acute gastrointestinal bleeding', 'Disease', 'MESH:D005767', (70, 101))
247927	33616759	Results Overall, SSI occurred in 2854/26,087 patients (10.9%) receiving C + M vs. 278/1835 (15.1%) receiving A/C (p < 0.001).	('SSI', 'Disease', (17, 20))	('C + M', 'Var', (72, 77))	('patients', 'Species', '9606', (45, 53))
247998	33616759	Data from observational studies and randomized trials show that ERAS protocols in colorectal (CR) surgery are associated with reduced length of stay (LOS) and morbidity, faster recovery and comparable or reduced readmission rates compared to traditional care.	('colo', 'Species', '307630', (82, 86))	('ERAS', 'Var', (64, 68))	('colorectal', 'Disease', (82, 92))	('length of', 'MPA', (134, 143))	('reduced', 'NegReg', (126, 133))
248341	33616759	Incidence rates were extracted from the Scottish Heath and Social care platform under the following ICD 10 codes: C18, C19-20, C18-20.	('C18', 'Gene', '27241', (127, 130))	('C19-20', 'Var', (119, 125))	('C18', 'Gene', (114, 117))	('C18', 'Gene', '27241', (114, 117))	('C18', 'Gene', (127, 130))
248499	33616759	The genetic study showed the rearrangement of FOXO1 gene.	('FOXO1', 'Gene', (46, 51))	('rearrangement', 'Var', (29, 42))	('FOXO1', 'Gene', '2308', (46, 51))	('men', 'Species', '9606', (38, 41))
248539	33363208	reported that KLHL5 knockdown inhibited proliferation in ovarian adenocarcinoma and renal carcinoma cell lines, and sensitized tumor cells to anticancer agents.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('sensitized', 'Reg', (116, 126))	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('ovarian adenocarcinoma and renal carcinoma', 'Disease', 'MESH:C538614', (57, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('tumor', 'Disease', (127, 132))	('KLHL5', 'Gene', '51088', (14, 19))	('inhibited', 'NegReg', (30, 39))	('KLHL5', 'Gene', (14, 19))	('renal carcinoma', 'Phenotype', 'HP:0005584', (84, 99))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('ovarian adenocarcinoma', 'Phenotype', 'HP:0025318', (57, 79))	('knockdown', 'Var', (20, 29))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('proliferation', 'CPA', (40, 53))
248573	33363208	What is more, KLHL5 expression was associated with the immunocyte level of B cell in 21 types, CD8+ T cell in 27 types, CD4+ T cell in 25 types, macrophage in 33 types, dendritic cell in 31 types, and neutrophil in 33 cancer types (Supplementary Figures 2A-2AK).	('CD4', 'Gene', (120, 123))	('cancer', 'Disease', 'MESH:D009369', (218, 224))	('CD8', 'Gene', '925', (95, 98))	('cancer', 'Disease', (218, 224))	('KLHL5', 'Gene', '51088', (14, 19))	('CD4', 'Gene', '920', (120, 123))	('associated', 'Reg', (35, 45))	('KLHL5', 'Gene', (14, 19))	('expression', 'Var', (20, 30))	('immunocyte level of B cell', 'MPA', (55, 81))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('CD8', 'Gene', (95, 98))
248591	33363208	Although its full functions remain uncertain, it is clear that KLHL5 knockdown inhibits cell proliferation in certain cancer cell lines (Schleifer et al.,).	('cancer', 'Disease', (118, 124))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('KLHL5', 'Gene', '51088', (63, 68))	('KLHL5', 'Gene', (63, 68))	('inhibits', 'NegReg', (79, 87))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('cell proliferation in', 'CPA', (88, 109))	('knockdown', 'Var', (69, 78))
248673	30585254	In addition, induction of IKKbeta/NF-kappaB by EGFR inhibitors required HER2 and HER3 expression.	('HER2', 'Gene', (72, 76))	('HER2', 'Gene', '2064', (72, 76))	('induction', 'Reg', (13, 22))	('NF-kappaB', 'Gene', '4790', (34, 43))	('NF-kappaB', 'Gene', (34, 43))	('inhibitors', 'Var', (52, 62))	('IKKbeta', 'Gene', '1147', (26, 33))	('HER3', 'Gene', (81, 85))	('IKKbeta', 'Gene', (26, 33))	('EGFR', 'Gene', (47, 51))	('HER3', 'Gene', '2065', (81, 85))
248674	30585254	In keeping with these, IKKbeta inhibitor CmpdA synergistically enhanced the efficacy of EGFR inhibitors to further inhibit in vitro HNSCC cell growth.	('CmpdA', 'Chemical', '-', (41, 46))	('inhibit', 'NegReg', (115, 122))	('enhanced', 'PosReg', (63, 71))	('HNSCC', 'Phenotype', 'HP:0012288', (132, 137))	('in vitro HNSCC cell growth', 'CPA', (123, 149))	('IKKbeta', 'Gene', '1147', (23, 30))	('IKKbeta', 'Gene', (23, 30))	('inhibitors', 'Var', (93, 103))	('EGFR', 'Gene', (88, 92))
248676	30585254	Our data demonstrated that co-targeting EGFR and IKKbeta with Gefitinib and IKKbeta inhibitors could provide a potential novel therapy for head and neck squamous cell cancer.	('neck squamous cell cancer', 'Disease', 'MESH:D002294', (148, 173))	('neck squamous cell cancer', 'Disease', (148, 173))	('IKKbeta', 'Gene', '1147', (49, 56))	('IKKbeta', 'Gene', (49, 56))	('head and neck squamous cell cancer', 'Phenotype', 'HP:0012288', (139, 173))	('co-targeting', 'Var', (27, 39))	('IKKbeta', 'Gene', '1147', (76, 83))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (153, 173))	('EGFR', 'Gene', (40, 44))	('IKKbeta', 'Gene', (76, 83))	('Gefitinib', 'Chemical', 'MESH:D000077156', (62, 71))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))
248701	30585254	Furthermore, the IKK inhibitor CmpdA enhanced the efficacy of EGFR inhibitors in HNSCC cell growth inhibition in vitro and in vivo.	('inhibitors', 'Var', (67, 77))	('efficacy', 'MPA', (50, 58))	('CmpdA', 'Gene', (31, 36))	('EGFR', 'Gene', (62, 66))	('HNSCC', 'Phenotype', 'HP:0012288', (81, 86))	('HNSCC', 'Disease', (81, 86))	('enhanced', 'PosReg', (37, 45))	('CmpdA', 'Chemical', '-', (31, 36))
248702	30585254	Our findings indicate that IKKbeta plays an essential role in the regulation of EGFR inhibitor resistance, and, therefore, co-targeting of EGFR and IKKbeta may be an effective treatment strategy for refractory HNSCC.	('refractory HNSCC', 'Disease', (199, 215))	('co-targeting', 'Var', (123, 135))	('IKKbeta', 'Gene', '1147', (27, 34))	('IKKbeta', 'Gene', (27, 34))	('HNSCC', 'Phenotype', 'HP:0012288', (210, 215))	('EGFR', 'Gene', (80, 84))	('IKKbeta', 'Gene', '1147', (148, 155))	('IKKbeta', 'Gene', (148, 155))	('EGFR', 'Gene', (139, 143))
248741	30585254	When tumours reached approximately 200 mm3, mice were randomised to one of four treatment groups: vehicle control (n = 7), 15 mg/kg, Gefitinib by per os (PO) (n = 7), 15 mg/kg CmpdA by IP (n = 7) or a combination of Gefitinib and CmpdA (n = 7).	('tumours', 'Phenotype', 'HP:0002664', (5, 12))	('Gefitinib', 'Chemical', 'MESH:D000077156', (133, 142))	('Gefitinib', 'Var', (133, 142))	('Gefitinib', 'Chemical', 'MESH:D000077156', (216, 225))	('tumours', 'Disease', 'MESH:D009369', (5, 12))	('CmpdA', 'Chemical', '-', (230, 235))	('tumours', 'Disease', (5, 12))	('CmpdA', 'Chemical', '-', (176, 181))	('mice', 'Species', '10090', (44, 48))	('tumour', 'Phenotype', 'HP:0002664', (5, 11))
248761	30585254	We also treated Cal27 cells with similar doses of Gefitinib for 4 or 48 h and found that treatment with Gefitinib for 4 h could also inhibit EGFR, Akt, S6K and ERK phosphorylation, but, conversely, induced p65 phosphorylation (data not shown).	('ERK', 'Gene', '5594', (160, 163))	('induced', 'Reg', (198, 205))	('p65', 'Gene', '5970', (206, 209))	('inhibit', 'NegReg', (133, 140))	('ERK', 'Gene', (160, 163))	('S6K', 'Gene', (152, 155))	('EGFR', 'Pathway', (141, 145))	('Akt', 'Gene', '207', (147, 150))	('p65', 'Gene', (206, 209))	('Gefitinib', 'Chemical', 'MESH:D000077156', (104, 113))	('Akt', 'Gene', (147, 150))	('S6K', 'Gene', '6198', (152, 155))	('Gefitinib', 'Var', (104, 113))	('Gefitinib', 'Chemical', 'MESH:D000077156', (50, 59))
248765	30585254	Our data demonstrated that EGFR inhibitors induced the IKK/NF-kappaB pathway in HNSCC cells.	('inhibitors', 'Var', (32, 42))	('EGFR', 'Gene', (27, 31))	('NF-kappaB', 'Gene', '4790', (59, 68))	('induced', 'Reg', (43, 50))	('HNSCC', 'Phenotype', 'HP:0012288', (80, 85))	('NF-kappaB', 'Gene', (59, 68))
248768	30585254	These data further confirm that NF-kappaB signalling was up-regulated by EGFR inhibitor treatment in HNSCC cells.	('NF-kappaB', 'Gene', (32, 41))	('HNSCC', 'Phenotype', 'HP:0012288', (101, 106))	('EGFR', 'Gene', (73, 77))	('up-regulated', 'PosReg', (57, 69))	('inhibitor', 'Var', (78, 87))	('NF-kappaB', 'Gene', '4790', (32, 41))
248796	30585254	The cells were incubated in media that contained serum and growth factors for 24 h, followed by treatment with DMSO, Gefitinib, CmpdA or a combination for an additional 24 h. Results from Western blot analyses of cell lysates showed that Gefitinib inhibited EGFR, Akt, S6K and ERK pathways, but increased IKK and NF-kappaB phosphorylation (Supplementary Figure 6A).	('Akt', 'Gene', (264, 267))	('Gefitinib', 'Chemical', 'MESH:D000077156', (238, 247))	('Gefitinib', 'Var', (238, 247))	('CmpdA', 'Chemical', '-', (128, 133))	('S6K', 'Gene', (269, 272))	('IKK', 'Pathway', (305, 308))	('EGFR', 'Pathway', (258, 262))	('ERK', 'Gene', '5594', (277, 280))	('Gefitinib', 'Chemical', 'MESH:D000077156', (117, 126))	('NF-kappaB', 'Gene', '4790', (313, 322))	('S6K', 'Gene', '6198', (269, 272))	('inhibited', 'NegReg', (248, 257))	('NF-kappaB', 'Gene', (313, 322))	('ERK', 'Gene', (277, 280))	('Akt', 'Gene', '207', (264, 267))	('increased', 'PosReg', (295, 304))	('DMSO', 'Chemical', 'MESH:D004121', (111, 115))
248803	30585254	Gene expression profiles showed that the mRNA levels of IKKbeta in Cal27GR cells were much higher than that of Cal27 cells, whereas mRNA levels of both IKKalpha and NF-kappaB were equal (Fig.	('IKKalpha', 'Gene', (152, 160))	('IKKalpha', 'Gene', '1147', (152, 160))	('higher', 'PosReg', (91, 97))	('NF-kappaB', 'Gene', '4790', (165, 174))	('IKKbeta', 'Gene', '1147', (56, 63))	('IKKbeta', 'Gene', (56, 63))	('NF-kappaB', 'Gene', (165, 174))	('Cal27GR', 'Var', (67, 74))	('mRNA levels', 'MPA', (41, 52))
248809	30585254	Our data indicated that inhibition of IKK/NF-kappaB could overcome Gefitinib resistance in HNSCC cells.	('Gefitinib', 'Chemical', 'MESH:D000077156', (67, 76))	('NF-kappaB', 'Gene', '4790', (42, 51))	('overcome', 'NegReg', (58, 66))	('inhibition', 'Var', (24, 34))	('HNSCC', 'Phenotype', 'HP:0012288', (91, 96))	('NF-kappaB', 'Gene', (42, 51))	('Gefitinib resistance', 'MPA', (67, 87))
248814	30585254	EGFR inhibition increased HER2 and HER3 levels, and also suppressed HER2 and HER3 phosphorylation.	('EGFR', 'Gene', (0, 4))	('inhibition', 'Var', (5, 15))	('HER2', 'Gene', (68, 72))	('HER3', 'Gene', (35, 39))	('HER3', 'Gene', '2065', (35, 39))	('HER2', 'Gene', (26, 30))	('increased', 'PosReg', (16, 25))	('HER2', 'Gene', '2064', (68, 72))	('HER2', 'Gene', '2064', (26, 30))	('HER3', 'Gene', (77, 81))	('HER3', 'Gene', '2065', (77, 81))	('suppressed', 'NegReg', (57, 67))
248818	30585254	Our data implied that co-targeting EGFR and IKKbeta/NF-kappaB signalling could be a potential novel therapy for head and neck squamous cell cancer for a subset of patients.	('squamous cell cancer', 'Phenotype', 'HP:0002860', (126, 146))	('patients', 'Species', '9606', (163, 171))	('co-targeting', 'Var', (22, 34))	('neck squamous cell cancer', 'Disease', 'MESH:D002294', (121, 146))	('neck squamous cell cancer', 'Disease', (121, 146))	('EGFR', 'Gene', (35, 39))	('NF-kappaB', 'Gene', '4790', (52, 61))	('head and neck squamous cell cancer', 'Phenotype', 'HP:0012288', (112, 146))	('IKKbeta', 'Gene', '1147', (44, 51))	('NF-kappaB', 'Gene', (52, 61))	('IKKbeta', 'Gene', (44, 51))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))
248819	30585254	The mechanisms by which EGFR inhibitors induce IKK/NF-kappaB are complicated.	('NF-kappaB', 'Gene', (51, 60))	('inhibitors', 'Var', (29, 39))	('induce', 'Reg', (40, 46))	('NF-kappaB', 'Gene', '4790', (51, 60))
248820	30585254	It has been reported, both here and previously, that HER2 plays an important role in EGFR inhibitor resistance, and that EGFR inhibitors upregulate HER2 and HER3.	('HER3', 'Gene', '2065', (157, 161))	('HER2', 'Gene', (148, 152))	('HER2', 'Gene', '2064', (148, 152))	('inhibitors', 'Var', (126, 136))	('HER2', 'Gene', (53, 57))	('EGFR', 'Gene', (121, 125))	('upregulate', 'PosReg', (137, 147))	('HER2', 'Gene', '2064', (53, 57))	('HER3', 'Gene', (157, 161))
248824	30585254	We found that while single depletion of HER2 or HER3 did not significantly impair Gefitinib induction of IKK/NF-kappaB, double depletion of HER2 and HER3 could do so.	('NF-kappaB', 'Gene', '4790', (109, 118))	('HER3', 'Gene', (48, 52))	('Gefitinib', 'Chemical', 'MESH:D000077156', (82, 91))	('HER2', 'Gene', (40, 44))	('double depletion', 'Var', (120, 136))	('HER3', 'Gene', '2065', (48, 52))	('HER2', 'Gene', '2064', (40, 44))	('NF-kappaB', 'Gene', (109, 118))	('HER3', 'Gene', '2065', (149, 153))	('HER3', 'Gene', (149, 153))	('HER2', 'Gene', '2064', (140, 144))	('HER2', 'Gene', (140, 144))	('Gefitinib', 'MPA', (82, 91))	('impair', 'NegReg', (75, 81))
248833	30585254	We found that HER2 and HER3 knockdown impaired Gefitinib-mediated IKK/NF-kappaB up-regulation, although the detailed mechanisms remain unclear.	('HER2', 'Gene', '2064', (14, 18))	('Gefitinib', 'Chemical', 'MESH:D000077156', (47, 56))	('up-regulation', 'PosReg', (80, 93))	('NF-kappaB', 'Gene', '4790', (70, 79))	('HER3', 'Gene', (23, 27))	('knockdown', 'Var', (28, 37))	('Gefitinib-mediated', 'MPA', (47, 65))	('HER3', 'Gene', '2065', (23, 27))	('HER2', 'Gene', (14, 18))	('impaired', 'NegReg', (38, 46))	('NF-kappaB', 'Gene', (70, 79))
248850	30585254	It may also be important to examine whether the partial rebound of Akt phosphorylation caused by CmpdA attenuates the efficacy of a Gefitinib/CmpdA combination to inhibit cell proliferation and induction of apoptosis.	('inhibit', 'NegReg', (163, 170))	('cell proliferation', 'CPA', (171, 189))	('Gefitinib', 'Chemical', 'MESH:D000077156', (132, 141))	('attenuates', 'NegReg', (103, 113))	('apoptosis', 'CPA', (207, 216))	('Akt', 'Gene', (67, 70))	('Akt', 'Gene', '207', (67, 70))	('CmpdA', 'Chemical', '-', (142, 147))	('CmpdA', 'Chemical', '-', (97, 102))	('CmpdA', 'Var', (97, 102))
248851	30585254	It should be mentioned that although the combination of Gefitinib and CmpdA was able to obviously suppress the tumour growth in vivo, the inhibitory efficacy for tumour volume in vivo was not as strong as in the in vitro clonogenic assay.	('CmpdA', 'Chemical', '-', (70, 75))	('tumour', 'Disease', (162, 168))	('combination', 'Var', (41, 52))	('tumour', 'Phenotype', 'HP:0002664', (111, 117))	('tumour growth', 'Disease', (111, 124))	('tumour growth', 'Disease', 'MESH:D006130', (111, 124))	('Gefitinib', 'Gene', (56, 65))	('suppress', 'NegReg', (98, 106))	('Gefitinib', 'Chemical', 'MESH:D000077156', (56, 65))	('tumour', 'Disease', 'MESH:D009369', (111, 117))	('tumour', 'Phenotype', 'HP:0002664', (162, 168))	('CmpdA', 'Gene', (70, 75))	('tumour', 'Disease', (111, 117))	('tumour', 'Disease', 'MESH:D009369', (162, 168))
248858	30585254	We would like to determine whether radiotherapy induces IKKbeta kinase activity and whether CmpdA-induced inhibition of IKKbeta improves the efficacy of radiotherapy in HNSCC.	('CmpdA', 'Chemical', '-', (92, 97))	('IKKbeta', 'Gene', '1147', (56, 63))	('HNSCC', 'Phenotype', 'HP:0012288', (169, 174))	('IKKbeta', 'Gene', (56, 63))	('inhibition', 'Var', (106, 116))	('HNSCC', 'Disease', (169, 174))	('activity', 'MPA', (71, 79))	('improves', 'PosReg', (128, 136))	('IKKbeta', 'Gene', '1147', (120, 127))	('IKKbeta', 'Gene', (120, 127))
248866	30542513	Of 7 patients receiving the 100 mug dose, 2 (29%) showed immune responses, compared with 3 of the 14 (21%) patients who received the 300 mug dose.	('patients', 'Species', '9606', (107, 115))	('immune', 'MPA', (57, 63))	('patients', 'Species', '9606', (5, 13))	('100 mug', 'Var', (28, 35))
248903	30542513	Six of the 22 (27%) patients had pre-existing antibodies to MAGE-A4, including 5 with high optical density (OD) (at least twice the cut-off level) and 1 with low OD (below twice the cut-off level) value.	('antibodies', 'Var', (46, 56))	('patients', 'Species', '9606', (20, 28))	('MAGE-A4', 'Gene', (60, 67))	('MAGE-A4', 'Gene', '4103', (60, 67))
248911	30542513	As shown in Tables 2 and 3, 11 of the 22 (50%) patients had pre-existing antibodies to NY-ESO-1, including 6 with high OD values.	('antibodies', 'Var', (73, 83))	('NY-ESO-1', 'Gene', (87, 95))	('patients', 'Species', '9606', (47, 55))	('NY-ESO-1', 'Gene', '246100', (87, 95))
248927	30542513	Survival time was significantly longer in NY-ESO-1 seronegative patients, including those with low titers of the antibody, than in those with high levels of pre-existing NY-ESO-1 antibodies (p = 0.0007) (Supplementary Figure 1, Figure 2B).	('longer', 'PosReg', (32, 38))	('NY-ESO-1', 'Gene', (42, 50))	('seronegative', 'Var', (51, 63))	('patients', 'Species', '9606', (64, 72))	('NY-ESO-1', 'Gene', '246100', (170, 178))	('Survival time', 'CPA', (0, 13))	('NY-ESO-1', 'Gene', (170, 178))	('NY-ESO-1', 'Gene', '246100', (42, 50))
248950	30542513	In the current trial, of the 16 patients with either refractory esophageal cancer (n = 14) or head/neck squamous cell carcinoma (n = 2), the 3 patients who demonstrated antigen spreading survived for a median of 7.5 months, while the 12 patients without spreading survived for 7.7 months.	('patients', 'Species', '9606', (32, 40))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (104, 127))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (99, 127))	('refractory esophageal cancer', 'Disease', (53, 81))	('head/neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (94, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('patients', 'Species', '9606', (143, 151))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('neck squamous cell carcinoma', 'Disease', (99, 127))	('antigen spreading', 'Var', (169, 186))	('refractory esophageal cancer', 'Disease', 'MESH:D004938', (53, 81))	('patients', 'Species', '9606', (237, 245))
248954	30542513	One study found that 31% of esophageal cancer patients had NY-ESO-1 auto-antibodies, and the positive rate increased with tumor stage progression.	('NY-ESO-1', 'Gene', '246100', (59, 67))	('esophageal cancer', 'Disease', (28, 45))	('patients', 'Species', '9606', (46, 54))	('NY-ESO-1', 'Gene', (59, 67))	('esophageal cancer', 'Disease', 'MESH:D004938', (28, 45))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('auto-antibodies', 'Var', (68, 83))	('tumor', 'Disease', (122, 127))
248957	30542513	For the first time, we demonstrated that patients with refractory esophageal or head/neck squamous cell carcinoma that co-expressed MAGE-A4 and NY-ESO-1 had significantly worse prognosis than patients with tumors expressing MAGE-A4 alone.	('tumors', 'Phenotype', 'HP:0002664', (206, 212))	('head/neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (80, 113))	('MAGE-A4', 'Gene', '4103', (132, 139))	('MAGE-A4', 'Gene', (224, 231))	('NY-ESO-1', 'Gene', (144, 152))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('tumors', 'Disease', (206, 212))	('neck squamous cell carcinoma', 'Disease', (85, 113))	('NY-ESO-1', 'Gene', '246100', (144, 152))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (85, 113))	('MAGE-A4', 'Gene', '4103', (224, 231))	('esophageal', 'Disease', (66, 76))	('patients', 'Species', '9606', (192, 200))	('tumors', 'Disease', 'MESH:D009369', (206, 212))	('patients', 'Species', '9606', (41, 49))	('MAGE-A4', 'Gene', (132, 139))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (90, 113))	('co-expressed', 'Var', (119, 131))
249003	30542513	Clinical trials conducted at Mie University Hospital/Nagasaki Medical Center and Kitano Hospital were registered in the UMIN Clinical Trials Registry as UMIN000001599 and UMIN000002153, started on December 25, 2008 and July 2, 2009, and ended on November 23, 2012 and July 31, 2014, respectively.	('UMIN000001599', 'Disease', 'None', (153, 166))	('Clinical', 'Species', '191496', (0, 8))	('UMIN000001599', 'Disease', (153, 166))	('Clinical', 'Species', '191496', (125, 133))	('UMIN000002153', 'Var', (171, 184))
249024	28904817	High cytoplasmic expression of tumoral (but not stromal) FLIP was associated with a 2.5-fold increased risk of death in lung adenocarcinoma patients, even when adjusted for known confounders (HR 2.47, 95% CI 1.14-5.35).	('death in lung adenocarcinoma', 'Disease', (111, 139))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (120, 139))	('tumoral', 'Disease', (31, 38))	('tumoral', 'Disease', 'MESH:D009369', (31, 38))	('death in lung adenocarcinoma', 'Disease', 'MESH:D000077192', (111, 139))	('patients', 'Species', '9606', (140, 148))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('High cytoplasmic', 'Var', (0, 16))
249025	28904817	Neither nuclear nor cytoplasmic tumoral procaspase-8 expression was associated with overall survival in lung adenocarcinoma patients; however, there was a significant trend (P for trend=0.03) for patients with adenocarcinomas with both high cytoplasmic FLIP and high cytoplasmic procaspase-8 to have a multiplicative increased risk of death.	('tumoral', 'Disease', 'MESH:D009369', (32, 39))	('caspase-8', 'Gene', (282, 291))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('patients', 'Species', '9606', (196, 204))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('caspase-8', 'Gene', (43, 52))	('patients', 'Species', '9606', (124, 132))	('adenocarcinomas', 'Disease', 'MESH:D000230', (210, 225))	('high cytoplasmic', 'Var', (262, 278))	('adenocarcinomas', 'Disease', (210, 225))	('carcinoma', 'Phenotype', 'HP:0030731', (215, 224))	('carcinomas', 'Phenotype', 'HP:0030731', (215, 225))	('lung adenocarcinoma', 'Disease', (104, 123))	('caspase-8', 'Gene', '841', (282, 291))	('caspase-8', 'Gene', '841', (43, 52))	('high cytoplasmic', 'Var', (236, 252))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (104, 123))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (104, 123))	('tumoral', 'Disease', (32, 39))
249026	28904817	Notably, high stromal nuclear procaspase-8 expression was associated with a reduced risk of death in lung adenocarcinoma patients (adjusted HR 0.31, 95% CI 0.15-0.66).	('death in lung adenocarcinoma', 'Disease', 'MESH:D000077192', (92, 120))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (101, 120))	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('death in lung adenocarcinoma', 'Disease', (92, 120))	('caspase-8', 'Gene', (33, 42))	('reduced', 'NegReg', (76, 83))	('high stromal', 'Var', (9, 21))	('expression', 'MPA', (43, 53))	('caspase-8', 'Gene', '841', (33, 42))	('patients', 'Species', '9606', (121, 129))
249047	28904817	Moreover, we unexpectedly found that high nuclear expression of procaspase-8 in the stromal compartment is strongly associated with improved prognosis.	('prognosis', 'CPA', (141, 150))	('high', 'Var', (37, 41))	('improved', 'PosReg', (132, 140))	('caspase-8', 'Gene', (67, 76))	('caspase-8', 'Gene', '841', (67, 76))
249064	28904817	High cytoplasmic expression of tumoral FLIP (H-score >172.5) was associated with a two-fold increased risk of death in lung adenocarcinoma patients, which strengthened further when adjusted for known confounders (HR 2.47, 95% CI 1.14-5.35; Table 2; Figure 2a).	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('patients', 'Species', '9606', (139, 147))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (119, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('tumoral', 'Disease', (31, 38))	('tumoral', 'Disease', 'MESH:D009369', (31, 38))	('death in lung adenocarcinoma', 'Disease', 'MESH:D000077192', (110, 138))	('death in lung adenocarcinoma', 'Disease', (110, 138))	('High cytoplasmic', 'Var', (0, 16))
249067	28904817	Unexpectedly, however, high stromal nuclear procaspase-8 expression (H-score>90.5) was associated with a reduced risk of death in lung adenocarcinoma patients, which was significant when considering nuclear expression (adjusted HR 0.31, 95% CI 0.15-0.66; Table 2, Figure 2b).	('caspase-8', 'Gene', '841', (47, 56))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (130, 149))	('patients', 'Species', '9606', (150, 158))	('reduced', 'NegReg', (105, 112))	('caspase-8', 'Gene', (47, 56))	('death in lung adenocarcinoma', 'Disease', 'MESH:D000077192', (121, 149))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))	('high stromal', 'Var', (23, 35))	('death in lung adenocarcinoma', 'Disease', (121, 149))
249075	28904817	Although, no significant associations between individual combined categories and death were observed, there was a significant trend (P for trend=0.03) for patients with adenocarcinomas with both high cytoplasmic FLIP and high cytoplasmic procaspase-8 having a multiplicative increased risk of death; however, no such association was observed in the squamous histology subgroup (Figure 3b).	('high cytoplasmic FLIP', 'Var', (195, 216))	('caspase-8', 'Gene', (241, 250))	('high cytoplasmic', 'Var', (221, 237))	('patients', 'Species', '9606', (155, 163))	('caspase-8', 'Gene', '841', (241, 250))	('adenocarcinomas', 'Disease', 'MESH:D000230', (169, 184))	('adenocarcinomas', 'Disease', (169, 184))	('carcinoma', 'Phenotype', 'HP:0030731', (174, 183))	('carcinomas', 'Phenotype', 'HP:0030731', (174, 184))
249079	28904817	By defining H-score cutoffs using the ROC approach and by performing multivariate analyses that demonstrate that cytoplasmic FLIP expression is an independent prognostic factor in adenocarcinoma patients but not in squamous cell carcinoma patients, this study refines our previous findings that high cytoplasmic FLIP expression is a biomarker of poor prognosis in NSCLC.	('NSCLC', 'Disease', (364, 369))	('NSCLC', 'Disease', 'MESH:D002289', (364, 369))	('high cytoplasmic', 'Var', (295, 311))	('patients', 'Species', '9606', (239, 247))	('carcinoma', 'Phenotype', 'HP:0030731', (229, 238))	('carcinoma', 'Phenotype', 'HP:0030731', (185, 194))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (215, 238))	('SCLC', 'Phenotype', 'HP:0030357', (365, 369))	('patients', 'Species', '9606', (195, 203))	('NSCLC', 'Phenotype', 'HP:0030358', (364, 369))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (215, 238))	('adenocarcinoma', 'Disease', (180, 194))	('squamous cell carcinoma', 'Disease', (215, 238))	('adenocarcinoma', 'Disease', 'MESH:D000230', (180, 194))
249082	28904817	As a major inhibitor of cell death induced by death ligands expressed by immune effector cells, high FLIP expression has been shown to promote immune escape of tumors in mouse models.	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('promote', 'PosReg', (135, 142))	('high FLIP expression', 'Var', (96, 116))	('mouse', 'Species', '10090', (170, 175))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('tumors', 'Disease', (160, 166))	('tumors', 'Disease', 'MESH:D009369', (160, 166))
249093	28904817	Although predominantly expressed in the cytoplasm, sumoylated caspase-8 translocates to the nucleus.	('caspase-8', 'Gene', '841', (62, 71))	('caspase-8', 'Gene', (62, 71))	('sumoylated', 'Var', (51, 61))	('translocates', 'MPA', (72, 84))
249094	28904817	Moreover, caspase-8 has been reported to have a broad role in the activation of immune cells; for example, caspase-8 has been shown to be essential for T-cell proliferation, as specific deletion of the gene encoding caspase-8 (CASP8) in T cells results in depletion of the peripheral T-cell population, thereby impairing immune responses.	('caspase-8', 'Gene', (10, 19))	('deletion', 'Var', (186, 194))	('caspase-8', 'Gene', '841', (216, 225))	('caspase-8', 'Gene', (107, 116))	('CASP8', 'Gene', (227, 232))	('caspase-8', 'Gene', '841', (10, 19))	('CASP8', 'Gene', '841', (227, 232))	('caspase-8', 'Gene', '841', (107, 116))	('depletion', 'MPA', (256, 265))	('caspase-8', 'Gene', (216, 225))	('immune responses', 'CPA', (321, 337))	('impairing', 'NegReg', (311, 320))
249095	28904817	It is possible that lymphoid cells with high nuclear caspase-8 promote antitumor immunity, which could explain the association between high nuclear procaspase-8 in the stromal compartment and good prognosis.	('high nuclear', 'Var', (40, 52))	('caspase-8', 'Gene', (151, 160))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('caspase-8', 'Gene', '841', (151, 160))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('promote', 'PosReg', (63, 70))	('caspase-8', 'Gene', (53, 62))	('caspase-8', 'Gene', '841', (53, 62))	('high nuclear', 'Var', (135, 147))	('tumor', 'Disease', (75, 80))
249126	27981249	The Cyclin D1, EGFR and p53 expressions also showed significant (P < 0.001) poor survivals (OS, DFS and RFS) in patients with positive/strong positive expressions than negative expression suggesting their prognosis in OSCC.	('positive/strong', 'Var', (126, 141))	('poor', 'NegReg', (76, 80))	('p53', 'Gene', (24, 27))	('p53', 'Gene', '7157', (24, 27))	('OSCC', 'Disease', (218, 222))	('patients', 'Species', '9606', (112, 120))	('EGFR', 'Gene', '1956', (15, 19))	('RFS', 'Disease', (104, 107))	('EGFR', 'Gene', (15, 19))	('Cyclin D1', 'Gene', '595', (4, 13))	('RFS', 'Disease', 'MESH:D005198', (104, 107))	('Cyclin D1', 'Gene', (4, 13))
249133	27981249	Therefore heterogeneity of tumor cells introduces significant threat in the management of OSCC.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('OSCC', 'Disease', (90, 94))	('tumor', 'Disease', (27, 32))	('heterogeneity', 'Var', (10, 23))	('tumor', 'Disease', 'MESH:D009369', (27, 32))
249215	27981249	These genetic alterations includes mutations or amplification of oncogenes as well as inactivation of tumor suppressor genes evident by expression of various molecular markers, leading to tumorogenesis which acquire self sufficient unexceptional growth and escape growth inhibitory signals, making the cells immortal resulting in uncontrolled tumor growth.	('alterations', 'Var', (14, 25))	('tumor', 'Disease', (188, 193))	('escape growth inhibitory signals', 'MPA', (257, 289))	('leading to', 'Reg', (177, 187))	('oncogenes', 'Gene', (65, 74))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('tumor', 'Disease', 'MESH:D009369', (343, 348))	('amplification', 'Var', (48, 61))	('inactivation', 'Var', (86, 98))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('tumor', 'Phenotype', 'HP:0002664', (343, 348))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('tumor', 'Disease', (343, 348))	('mutations', 'Var', (35, 44))
249216	27981249	Over a period of time and with further exposure to carcinogens, the cancer cells accumulate further mutations and acquire more evil characteristics such as ability to invade and move into adjoining tissues, progress to lymphatics and blood vessels, tumor angiogenesis and may reside and grow to distant sites.	('mutations', 'Var', (100, 109))	('grow', 'CPA', (287, 291))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('tumor', 'Disease', 'MESH:D009369', (249, 254))	('tumor', 'Phenotype', 'HP:0002664', (249, 254))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('tumor', 'Disease', (249, 254))	('progress', 'CPA', (207, 215))	('cancer', 'Disease', (68, 74))
249217	27981249	While on conventional treatment regimen or in the post treatment follow up period some cancer cells due to genetic instability may acquire further mutations and become resistant or refractory to the treatment delivered, leading to progression or recurrence of cancer.	('mutations', 'Var', (147, 156))	('cancer', 'Disease', (87, 93))	('genetic instability', 'Var', (107, 126))	('cancer', 'Phenotype', 'HP:0002664', (260, 266))	('cancer', 'Disease', 'MESH:D009369', (260, 266))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cancer', 'Disease', (260, 266))	('leading to', 'Reg', (220, 230))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('acquire', 'Reg', (131, 138))
249225	27981249	Although some of the studies have documented that p53 mutation can estimates disease prognosis more accurately than clinical staging in HNSCC, and could stratify patients according to their risk of locoregional recurrence but have not reached to a significant conclusion.	('mutation', 'Var', (54, 62))	('patients', 'Species', '9606', (162, 170))	('p53', 'Gene', (50, 53))	('p53', 'Gene', '7157', (50, 53))	('HNSCC', 'Disease', (136, 141))	('estimates', 'Reg', (67, 76))
249233	27981249	p53 gene mutation frequently occurs in recurrent ovarian cancer and influences salvage chemotherapy thereby impacting upon the prognosis of recurrent disease.	('mutation', 'Var', (9, 17))	('influences', 'Reg', (68, 78))	('p53', 'Gene', (0, 3))	('p53', 'Gene', '7157', (0, 3))	('salvage', 'CPA', (79, 86))	('ovarian cancer', 'Phenotype', 'HP:0100615', (49, 63))	('ovarian cancer', 'Disease', 'MESH:D010051', (49, 63))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('occurs', 'Reg', (29, 35))	('impacting', 'Reg', (108, 117))	('ovarian cancer', 'Disease', (49, 63))
249238	27981249	Cyclin D1 genetic alteration was found to be an early event in the carcinogenesis of transitional cell carcinoma of bladder and resulted in the rapid recurrence of a subset of superficial bladder cancer.	('carcinoma of bladder', 'Disease', (103, 123))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('bladder cancer', 'Phenotype', 'HP:0009725', (188, 202))	('carcinoma of bladder', 'Disease', 'MESH:D001749', (103, 123))	('Cyclin D1', 'Gene', '595', (0, 9))	('genetic alteration', 'Var', (10, 28))	('bladder cancer', 'Disease', 'MESH:D001749', (188, 202))	('bladder cancer', 'Disease', (188, 202))	('resulted in', 'Reg', (128, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('Cyclin D1', 'Gene', (0, 9))
249241	27981249	In nasopharyngeal carcinoma, early local recurrence rate were significantly higher in patients with high levels of Cyclin D1 evaluated before initiation of radiation therapy when compared with patients with low or no expression.	('carcinoma', 'Phenotype', 'HP:0030731', (18, 27))	('patients', 'Species', '9606', (193, 201))	('nasopharyngeal carcinoma', 'Disease', 'MESH:D000077274', (3, 27))	('nasopharyngeal carcinoma', 'Disease', (3, 27))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (3, 27))	('Cyclin D1', 'Gene', (115, 124))	('high levels', 'Var', (100, 111))	('higher', 'PosReg', (76, 82))	('Cyclin D1', 'Gene', '595', (115, 124))	('patients', 'Species', '9606', (86, 94))
249265	25341494	Although previous research has shown that the etiology of breast cancer includes heritable factors and genetic mutations -, the molecular mechanism is poorly understood.	('mutations -', 'Var', (111, 122))	('breast cancer', 'Disease', 'MESH:D001943', (58, 71))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('breast cancer', 'Disease', (58, 71))	('breast cancer', 'Phenotype', 'HP:0003002', (58, 71))
249271	25341494	TBLR1 also functions as an E3-ligase by recruiting UbcH5 ubiquitin conjugating enzymes/19S proteasome, leading to the replacement of corepressors with coactivators in a ligand-dependent manner,,.	('UbcH5', 'Gene', (51, 56))	('corepressors', 'MPA', (133, 145))	('recruiting', 'PosReg', (40, 50))	('TBLR1', 'Gene', (0, 5))	('replacement', 'Var', (118, 129))	('UbcH5', 'Gene', '7321', (51, 56))	('enzymes/19S proteasome', 'MPA', (79, 101))
249285	25341494	Stable cell lines expressing TBLR1 and TBLR1-shRNA were generated via retroviral infection using HEK293T cells as previously described and selected with 0.5 mug/mL puromycin for 10 days.	('HEK293T', 'CellLine', 'CVCL:0063', (97, 104))	('retroviral infection', 'Disease', (70, 90))	('retroviral infection', 'Disease', 'MESH:D000071297', (70, 90))	('puromycin', 'Chemical', 'MESH:D011691', (164, 173))	('TBLR1-shRNA', 'Var', (39, 50))
249286	25341494	Western blot analysis was carried out according to standard methods as described previously, using anti-TBLR1 (Sigma, Saint Louis, MI, USA), anti-cyclin D1, anti-pRb, anti-Rb (Cell Signaling, Danvers, MA, USA).	('cyclin D1', 'Gene', (146, 155))	('pRb', 'Gene', (162, 165))	('pRb', 'Gene', '5925', (162, 165))	('Rb', 'Chemical', 'MESH:D012413', (172, 174))	('anti-TBLR1', 'Var', (99, 109))	('anti-Rb', 'Var', (167, 174))	('cyclin D1', 'Gene', '595', (146, 155))	('Rb', 'Chemical', 'MESH:D012413', (163, 165))
249303	25341494	For tumor cell implantation, MCF-7-TBLR1 or MCF-7-TBLR1-RNAi or their respective control cells (1 x 107) in 100 muL of the mixture were subcutaneously injected into the mice.	('tumor', 'Disease', (4, 9))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('mice', 'Species', '10090', (169, 173))	('MCF-7', 'CellLine', 'CVCL:0031', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('MCF-7-TBLR1', 'Var', (29, 40))	('MCF-7', 'CellLine', 'CVCL:0031', (44, 49))
249316	25341494	As shown in Table 2, detailed analyses revealed that expression of TBLR1was significantly associated with clinical stage (P <0.001), tumor (T) classification (P <0.001), node (N) classification (P = 0.024), metastasis (M) classification (P = 0.004), pathological differentiation (P = 0.044), c-erbB-2 expression (P = 0.036) and Ki-67 expression (P <0.001).	('pathological differentiation', 'CPA', (250, 278))	('Ki-67', 'CPA', (328, 333))	('expression', 'Var', (53, 63))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('c-erbB-2', 'Gene', (292, 300))	('c-erbB-2', 'Gene', '2064', (292, 300))	('TBLR1was', 'Gene', (67, 75))	('associated', 'Reg', (90, 100))	('expression', 'MPA', (334, 344))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumor', 'Disease', (133, 138))	('clinical stage', 'CPA', (106, 120))	('expression', 'MPA', (301, 311))
249320	25341494	Kaplan-Meier survival curves showed that patients with high levels of TBLR1 had significantly shorter overall survival (OS) rates than those with low levels of TBLR1 (P <0.001; Figure 2C).	('high levels', 'Var', (55, 66))	('shorter', 'NegReg', (94, 101))	('patients', 'Species', '9606', (41, 49))	('TBLR1', 'Gene', (70, 75))	('overall survival', 'MPA', (102, 118))	('OS', 'Chemical', '-', (120, 122))
249324	25341494	We found that the patients with high TBLR1 expression had significantly lower OS rates compared with those with a low level of TBLR1 expression in the early clinical subgroup (stages I to II, n = 128; log-rank, P <0.001; Figure 2D, left panel) and the advanced disease subgroup (stages III to IV, n = 86; log-rank, P <0.001; Figure 2D, right panel).	('TBLR1', 'Gene', (37, 42))	('high', 'Var', (32, 36))	('OS rates', 'MPA', (78, 86))	('expression', 'Var', (43, 53))	('lower', 'NegReg', (72, 77))	('patients', 'Species', '9606', (18, 26))	('OS', 'Chemical', '-', (78, 80))
249329	25341494	MTT assays showed an approximately two-fold increase in the number of TBLR1-overexpressing cells relative to vector control cells after four days of culture (Figure 3B), indicating that ectopic expression of TBLR1 increased the proliferative capacity of breast cancer cells.	('TBLR1', 'Gene', (208, 213))	('proliferative capacity', 'CPA', (228, 250))	('breast cancer', 'Disease', 'MESH:D001943', (254, 267))	('cancer', 'Phenotype', 'HP:0002664', (261, 267))	('breast cancer', 'Disease', (254, 267))	('breast cancer', 'Phenotype', 'HP:0003002', (254, 267))	('increased', 'PosReg', (214, 223))	('MTT', 'Chemical', '-', (0, 3))	('ectopic expression', 'Var', (186, 204))
249334	25341494	Anchorage-independent growth assays demonstrated that the growth capacity of SKBR3 and MCF-7 breast cancer cell lines was significantly enhanced by TBLR1-overexpression, as shown by the increased number and size of colonies (Figure 5A).	('TBLR1-overexpression', 'Var', (148, 168))	('enhanced', 'PosReg', (136, 144))	('TBLR1-overexpression', 'Gene', (148, 168))	('increased', 'PosReg', (186, 195))	('SKBR3', 'CellLine', 'CVCL:0033', (77, 82))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('breast cancer', 'Phenotype', 'HP:0003002', (93, 106))	('growth capacity', 'CPA', (58, 73))	('MCF-7 breast cancer', 'Disease', 'MESH:D001943', (87, 106))	('MCF-7 breast cancer', 'Disease', (87, 106))
249340	25341494	Consistent with the aforementioned results, the phosphorylated Rb was also increased in the TBLR1 overexpressing-cells and decreased in the TBLR1 silencing cells, further demonstrating that TBLR1 plays an important role in the proliferation of HCC cells (Figure 6A).	('phosphorylated', 'MPA', (48, 62))	('TBLR1', 'Gene', (92, 97))	('decreased', 'NegReg', (123, 132))	('Rb', 'Chemical', 'MESH:D012413', (63, 65))	('increased', 'PosReg', (75, 84))	('overexpressing-cells', 'Var', (98, 118))	('silencing', 'NegReg', (146, 155))
249341	25341494	Interestingly, we found that both transcriptional and translational levels of CDK regulator cyclin D1 were upregulated by TBLR1 overexpression, but supressed by TBLR1 silencing, as compared with that in control cells (Figure 6A and B).	('translational levels', 'MPA', (54, 74))	('cyclin D1', 'Gene', '595', (92, 101))	('TBLR1', 'Gene', (122, 127))	('overexpression', 'Var', (128, 142))	('silencing', 'NegReg', (167, 176))	('cyclin D1', 'Gene', (92, 101))	('CDK regulator', 'MPA', (78, 91))	('upregulated', 'PosReg', (107, 118))
249342	25341494	Importantly, the stimulatory effect of TBLR1 on the cyclin D1 expression was abolished by the inhibition of Wnt/beta-catenin signaling via TCF4 dominant-negative mutant (TCF4-dn) transfection, suggesting that TBLR1 might activate Wnt/beta-catenin signaling.	('beta-catenin', 'Gene', (234, 246))	('cyclin D1', 'Gene', (52, 61))	('beta-catenin', 'Gene', '1499', (234, 246))	('beta-catenin', 'Gene', '1499', (112, 124))	('transfection', 'Var', (179, 191))	('expression', 'MPA', (62, 72))	('TCF4', 'Gene', (139, 143))	('TCF4', 'Gene', (170, 174))	('TCF4', 'Gene', '6925', (170, 174))	('TCF4', 'Gene', '6925', (139, 143))	('beta-catenin', 'Gene', (112, 124))	('activate', 'PosReg', (221, 229))	('abolished', 'NegReg', (77, 86))	('cyclin D1', 'Gene', '595', (52, 61))
249345	25341494	We further examined whether inhibiting wnt/beta-catenin signaling has a similar effect to knocking down TBLR1 expression.	('knocking', 'Var', (90, 98))	('expression', 'MPA', (110, 120))	('beta-catenin', 'Gene', (43, 55))	('TBLR1', 'Gene', (104, 109))	('beta-catenin', 'Gene', '1499', (43, 55))
249346	25341494	As shown in Figure 7A-C, knocking down of TBLR1 or blocking wnt/beta-catenin signaling by ectopically expressing TCF4-dn, drastically reduced Rb phosphorylation, TOP/FOP activity and transcription of Cyclin D1, MYC and AXIN2 in TBLR1-overexpressing cells.	('MYC', 'Gene', '4609', (211, 214))	('knocking down', 'Var', (25, 38))	('Cyclin D1', 'Gene', (200, 209))	('blocking', 'NegReg', (51, 59))	('AXIN2', 'Gene', (219, 224))	('AXIN2', 'Gene', '8313', (219, 224))	('reduced', 'NegReg', (134, 141))	('MYC', 'Gene', (211, 214))	('TBLR1', 'Gene', (42, 47))	('transcription', 'MPA', (183, 196))	('TCF4', 'Gene', (113, 117))	('beta-catenin', 'Gene', (64, 76))	('TOP/FOP activity', 'MPA', (162, 178))	('Rb', 'Chemical', 'MESH:D012413', (142, 144))	('TCF4', 'Gene', '6925', (113, 117))	('beta-catenin', 'Gene', '1499', (64, 76))	('Cyclin D1', 'Gene', '595', (200, 209))
249347	25341494	Moreover, both knocking down of TBLR1 and inhibition of wnt/beta-catenin signaling, abrogated the stimulatory effect of TBLR1 overexpression on breast cancer cell growth and proliferation (Additional file 5: Figure S5 and Figure 7D-F).	('TBLR1', 'Gene', (32, 37))	('breast cancer', 'Disease', 'MESH:D001943', (144, 157))	('TBLR1', 'Gene', (120, 125))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('breast cancer', 'Disease', (144, 157))	('overexpression', 'PosReg', (126, 140))	('breast cancer', 'Phenotype', 'HP:0003002', (144, 157))	('knocking down', 'Var', (15, 28))	('abrogated', 'NegReg', (84, 93))	('beta-catenin', 'Gene', (60, 72))	('stimulatory effect', 'MPA', (98, 116))	('beta-catenin', 'Gene', '1499', (60, 72))	('inhibition', 'NegReg', (42, 52))
249354	25341494	Overexpression of TBLR1 promotes the proliferation and tumorigenicity of breast cancer cells in vitro and in vivo.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('breast cancer', 'Disease', 'MESH:D001943', (73, 86))	('tumor', 'Disease', (55, 60))	('TBLR1', 'Gene', (18, 23))	('breast cancer', 'Disease', (73, 86))	('promotes', 'PosReg', (24, 32))	('proliferation', 'CPA', (37, 50))	('Overexpression', 'Var', (0, 14))	('breast cancer', 'Phenotype', 'HP:0003002', (73, 86))
249358	25341494	Reports have shown that tumorigenesis is associated with the progressive accumulation of genetic and epigenetic alterations in genes and proteins that regulate cell proliferation, cell death and genomic instability,.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('genetic', 'Var', (89, 96))	('epigenetic alterations', 'Var', (101, 123))	('tumor', 'Disease', (24, 29))	('proteins', 'Protein', (137, 145))	('tumor', 'Disease', 'MESH:D009369', (24, 29))
249362	25341494	Importantly, knocking down of TBLR1 markedly reduced breast cancer cell proliferation and tumorigenicity.	('breast cancer', 'Phenotype', 'HP:0003002', (53, 66))	('knocking down', 'Var', (13, 26))	('reduced', 'NegReg', (45, 52))	('TBLR1', 'Gene', (30, 35))	('tumor', 'Disease', (90, 95))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('breast cancer', 'Disease', 'MESH:D001943', (53, 66))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('breast cancer', 'Disease', (53, 66))
249367	25341494	Thus, it would be of great interest and importance to investigate whether TBLR1 upregulates C-erbB-2 expression via beta-catenin/TCF4 transcription complex or others, and whether knocking down of TBLR1 could reduce the tumorigencity of C-erbB-2-overexpressing breast tumors.	('tumor', 'Disease', (219, 224))	('tumor', 'Disease', 'MESH:D009369', (267, 272))	('tumor', 'Disease', 'MESH:D009369', (219, 224))	('tumors', 'Phenotype', 'HP:0002664', (267, 273))	('upregulates', 'PosReg', (80, 91))	('tumor', 'Phenotype', 'HP:0002664', (267, 272))	('C-erbB-2', 'Gene', '2064', (92, 100))	('TBLR1', 'Gene', (196, 201))	('C-erbB-2', 'Gene', '2064', (236, 244))	('C-erbB-2', 'Gene', (236, 244))	('C-erbB-2', 'Gene', (92, 100))	('TBLR1', 'Gene', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('breast tumors', 'Disease', 'MESH:D001943', (260, 273))	('TCF4', 'Gene', '6925', (129, 133))	('breast tumors', 'Disease', (260, 273))	('beta-catenin', 'Gene', (116, 128))	('reduce', 'NegReg', (208, 214))	('beta-catenin', 'Gene', '1499', (116, 128))	('knocking down', 'Var', (179, 192))	('breast tumors', 'Phenotype', 'HP:0100013', (260, 273))	('TCF4', 'Gene', (129, 133))	('tumor', 'Disease', (267, 272))	('expression', 'MPA', (101, 111))
249413	25541719	We also tested for the effect of deregulation of CK2 expression on patient overall survival using Kaplan-Meier Plotter.	('tested', 'Reg', (8, 14))	('CK2', 'Gene', '13000', (49, 52))	('deregulation', 'Var', (33, 45))	('CK2', 'Gene', (49, 52))	('patient', 'Species', '9606', (67, 74))
249497	25541719	Kaplan-Meier plotter analysis revealed that high-levels of expression of CK2alpha correlated with lower patients survival rates.	('high-levels of', 'Var', (44, 58))	('patients survival rates', 'CPA', (104, 127))	('patients', 'Species', '9606', (104, 112))	('CK2alpha', 'Gene', '1459', (73, 81))	('CK2alpha', 'Gene', (73, 81))	('lower', 'NegReg', (98, 103))
249530	25541719	Together with our study, these data suggest that deregulated CK2 gene transcript expression may be a mechanism underlying the increase in CK2 activity and protein levels detected in human tumors.	('CK2', 'Gene', (138, 141))	('protein levels', 'MPA', (155, 169))	('tumors', 'Disease', (188, 194))	('tumors', 'Disease', 'MESH:D009369', (188, 194))	('tumors', 'Phenotype', 'HP:0002664', (188, 194))	('human', 'Species', '9606', (182, 187))	('CK2', 'Gene', '13000', (138, 141))	('CK2', 'Gene', (61, 64))	('deregulated', 'Var', (49, 60))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('increase', 'PosReg', (126, 134))	('CK2', 'Gene', '13000', (61, 64))
249537	25541719	Our data indicates that deregulated CK2 expression is an important factor during tumorigenesis.	('expression', 'MPA', (40, 50))	('CK2', 'Gene', (36, 39))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('CK2', 'Gene', '13000', (36, 39))	('deregulated', 'Var', (24, 35))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Disease', (81, 86))
249553	25541719	Our analysis of Kaplan-Meier Plotter also found correlations between CK2 gene deregulation and survival rates (Table 9).	('CK2', 'Gene', '13000', (69, 72))	('correlations', 'Interaction', (48, 60))	('survival rates', 'CPA', (95, 109))	('deregulation', 'Var', (78, 90))	('CK2', 'Gene', (69, 72))
249574	25541719	Sixth, additional research on the impact on patient survival of changes in the CK2 genes in additional cancer types.	('patient', 'Species', '9606', (44, 51))	('CK2', 'Gene', '13000', (79, 82))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('changes', 'Var', (64, 71))	('cancer', 'Disease', (103, 109))	('CK2', 'Gene', (79, 82))	('cancer', 'Disease', 'MESH:D009369', (103, 109))
249596	33931671	Whole exome sequencing analysis of 15 archival OSCC samples with history of shammah exposure reported mutation in genes previously associated with OSCC along with novel mutational driver events including CSMD3, TRPM2 and NOTCH3.	('NOTCH3', 'Gene', '4854', (221, 227))	('mutation', 'Var', (102, 110))	('CSMD3', 'Gene', (204, 209))	('TRPM2', 'Gene', '7226', (211, 216))	('CSMD3', 'Gene', '114788', (204, 209))	('NOTCH3', 'Gene', (221, 227))	('TRPM2', 'Gene', (211, 216))
249597	33931671	Copy number alteration (CNAs) analysis of these samples revealed amplification of genes categorized as oncogenic such as MDM2 and BAG1 and deletion of potential tumor suppressor gene SMARCC1.	('SMARCC1', 'Gene', '6599', (183, 190))	('deletion', 'Var', (139, 147))	('BAG1', 'Gene', (130, 134))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('amplification', 'MPA', (65, 78))	('BAG1', 'Gene', '573', (130, 134))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('MDM2', 'Gene', '4193', (121, 125))	('tumor', 'Disease', (161, 166))	('MDM2', 'Gene', (121, 125))	('SMARCC1', 'Gene', (183, 190))
249606	33931671	Six months of chronic exposure to shammah resulted in cellular morphological changes in OKF6/TERT1-Shammah as compared to OKF6/TERT1-Parental cells.	('OKF6/TERT1-Shammah', 'Var', (88, 106))	('OKF6/TERT1', 'CellLine', 'CVCL:L224', (88, 98))	('OKF6/TERT1-Shammah', 'CellLine', 'CVCL:L224', (88, 106))	('OKF6/TERT1', 'CellLine', 'CVCL:L224', (122, 132))	('cellular morphological changes', 'CPA', (54, 84))
249607	33931671	We further observed significant increase in colony formation capability and the invasive ability of OKF6/TERT1-Shammah cells in comparison to OKF6/TERT1-Parental cells (Fig.	('OKF6/TERT1', 'CellLine', 'CVCL:L224', (100, 110))	('invasive ability', 'CPA', (80, 96))	('OKF6/TERT1-Shammah', 'CellLine', 'CVCL:L224', (100, 118))	('increase', 'PosReg', (32, 40))	('OKF6/TERT1', 'CellLine', 'CVCL:L224', (142, 152))	('colony formation capability', 'CPA', (44, 71))	('OKF6/TERT1-Shammah', 'Var', (100, 118))
249616	33931671	Higher expression of ECM components such as expression of fibronectin (FN1) (3.60-fold; p-value <= 0.05), thrombospondin 1 (THBS1) (3.26-fold; p-value <= 0.05) and heparan sulfate proteoglycan 2 (HSPG2) (1.95-fold; p-value <= 0.05) were identified in OKF6/TERT1-Shammah cells compared to OKF6/TERT1-Parental cells.	('FN1', 'Gene', (71, 74))	('OKF6/TERT1-Shammah', 'CellLine', 'CVCL:L224', (251, 269))	('HSPG2', 'Gene', '3339', (196, 201))	('heparan sulfate proteoglycan 2', 'Gene', (164, 194))	('expression', 'MPA', (7, 17))	('thrombospondin 1', 'Gene', (106, 122))	('THBS1', 'Gene', (124, 129))	('fibronectin', 'Gene', '2335', (58, 69))	('OKF6/TERT1', 'CellLine', 'CVCL:L224', (288, 298))	('OKF6/TERT1-Shammah', 'Var', (251, 269))	('Higher', 'PosReg', (0, 6))	('heparan sulfate proteoglycan 2', 'Gene', '3339', (164, 194))	('OKF6/TERT1', 'CellLine', 'CVCL:L224', (251, 261))	('thrombospondin 1', 'Gene', '7057', (106, 122))	('THBS1', 'Gene', '7057', (124, 129))	('HSPG2', 'Gene', (196, 201))	('FN1', 'Gene', '2335', (71, 74))	('fibronectin', 'Gene', (58, 69))
249620	33931671	Our data shows an increased expression of proteins involved in peroxisome mediated catabolism of long chain fatty acids such as peroxisomal biogenesis factor 14 (PEX14) (2.2-fold; p-value <= 0.05), acyl-CoA oxidase 1 (ACOX1) (2.42-fold; p-value <= 0.05), sterol carrier protein 2 (SCP2) (2.59-fold; p-value <= 0.05), enoyl-CoA hydratase 1 (ECH1) (1.98-fold; p-value <= 0.05), carnitine O-acetyltransferase (CRAT) (2.02-fold; p-value <= 0.05), isocitrate dehydrogenase (IDH2) (1.96-fold; p-value <= 0.05), isocitrate dehydrogenase [NAD] subunit gamma (IDH3G) (2.00-fold; p-value <= 0.05) and hydroxymethylglutaryl-CoA lyas (HMGCL) (1.95-fold; p-value <= 0.05) in OKF6/TERT1-Shammah compared to OKF6/TERT1-Parental cells.	('OKF6/TERT1', 'CellLine', 'CVCL:L224', (662, 672))	('long chain fatty acids', 'Chemical', '-', (97, 119))	('peroxisomal biogenesis factor 14', 'Gene', '5195', (128, 160))	('peroxisomal biogenesis factor 14', 'Gene', (128, 160))	('SCP2', 'Gene', (281, 285))	('OKF6/TERT1', 'CellLine', 'CVCL:L224', (693, 703))	('OKF6/TERT1-Shammah', 'Var', (662, 680))	('ACOX1', 'Gene', '51', (218, 223))	('acyl-CoA oxidase 1', 'Gene', '51', (198, 216))	('IDH3G', 'Gene', '3421', (551, 556))	('OKF6/TERT1-Shammah', 'CellLine', 'CVCL:L224', (662, 680))	('HMGCL', 'Gene', '3155', (623, 628))	('ECH1', 'Gene', '1891', (340, 344))	('CRAT', 'Gene', '1384', (407, 411))	('CRAT', 'Gene', (407, 411))	('carnitine O-acetyltransferase', 'Gene', '1384', (376, 405))	('ACOX1', 'Gene', (218, 223))	('ECH1', 'Gene', (340, 344))	('IDH3G', 'Gene', (551, 556))	('enoyl-CoA hydratase 1', 'Gene', '1891', (317, 338))	('increased', 'PosReg', (18, 27))	('PEX14', 'Gene', '5195', (162, 167))	('HMGCL', 'Gene', (623, 628))	('sterol carrier protein 2', 'Gene', '6342', (255, 279))	('PEX14', 'Gene', (162, 167))	('acyl-CoA oxidase 1', 'Gene', (198, 216))	('SCP2', 'Gene', '6342', (281, 285))	('IDH2', 'Gene', (469, 473))	('expression', 'MPA', (28, 38))	('enoyl-CoA hydratase 1', 'Gene', (317, 338))	('sterol carrier protein 2', 'Gene', (255, 279))	('IDH2', 'Gene', '3418', (469, 473))	('carnitine O-acetyltransferase', 'Gene', (376, 405))
249627	33931671	Aberrant regulation of kinase activity leads to dysregulation of key cell signaling pathways which are responsible for multiple disease conditions including cancer.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('Aberrant regulation', 'Var', (0, 19))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('multiple disease conditions', 'Disease', 'MESH:D000071069', (119, 146))	('multiple disease conditions', 'Disease', (119, 146))	('cancer', 'Disease', (157, 163))	('key cell signaling pathways', 'Pathway', (65, 92))	('leads to', 'Reg', (39, 47))	('dysregulation', 'MPA', (48, 61))
249631	33931671	HIPK2 (p = 0.018; z-score = 2.07) was predicted to be activated upstream kinase of substrates HNRNPH1 (S104), H2AFX (S140), LMNA (S392), NCL (S563) and PKD2 (S812).	('HNRNPH1', 'Gene', (94, 101))	('S392', 'Var', (130, 134))	('LMNA', 'Gene', '4000', (124, 128))	('S140', 'Var', (117, 121))	('HIPK2', 'Gene', '28996', (0, 5))	('NCL', 'Gene', (137, 140))	('S104', 'Var', (103, 107))	('NCL', 'Gene', '4691', (137, 140))	('PKD2', 'Gene', '5311', (152, 156))	('H2AFX', 'Gene', '3014', (110, 115))	('HIPK2', 'Gene', (0, 5))	('H2AFX', 'Gene', (110, 115))	('LMNA', 'Gene', (124, 128))	('HNRNPH1', 'Gene', '3187', (94, 101))	('PKD2', 'Gene', (152, 156))
249633	33931671	Genomic studies have identified driver mutations associated with oral cancer in shammah users.	('oral cancer', 'Disease', 'MESH:D009369', (65, 76))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('associated', 'Reg', (49, 59))	('mutations', 'Var', (39, 48))	('oral cancer', 'Disease', (65, 76))
249637	33931671	Frequently disorganised and dysregulation of ECM proteins have been reported in multiple cancer types which stimulates tumor progression and metastasis.	('tumor', 'Disease', (119, 124))	('ECM proteins', 'Protein', (45, 57))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('dysregulation', 'Var', (28, 41))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('cancer', 'Disease', (89, 95))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('stimulates', 'PosReg', (108, 118))	('disorganised', 'Var', (11, 23))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
249644	33931671	We observed an overexpression of LAMC2 (3.51-fold; p-value <= 0.05) in OKF6/TERT1-Shammah compared to OKF6/TERT1-Parental cells.	('OKF6/TERT1-Shammah', 'Var', (71, 89))	('overexpression', 'PosReg', (15, 29))	('OKF6/TERT1-Shammah', 'CellLine', 'CVCL:L224', (71, 89))	('LAMC2', 'Gene', (33, 38))	('OKF6/TERT1', 'CellLine', 'CVCL:L224', (71, 81))	('LAMC2', 'Gene', '3918', (33, 38))	('OKF6/TERT1', 'CellLine', 'CVCL:L224', (102, 112))
249671	33931671	Nevertheless, PRKCE activation has a protective role in cardiac and brain ischemia while its aberrant activation induces cell proliferation, disruption of cell-cell contacts, tumor progression and metastasis.	('tumor', 'Disease', (175, 180))	('PRKCE', 'Gene', '5581', (14, 19))	('brain ischemia', 'Phenotype', 'HP:0002637', (68, 82))	('brain ischemia', 'Disease', 'MESH:D002545', (68, 82))	('cell proliferation', 'CPA', (121, 139))	('aberrant', 'Var', (93, 101))	('activation', 'PosReg', (102, 112))	('metastasis', 'CPA', (197, 207))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('brain ischemia', 'Disease', (68, 82))	('cardiac', 'Disease', (56, 63))	('PRKCE', 'Gene', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))
249674	33931671	Moreover, invasive property of lung cancer cells A549 was significantly increased on RAF1 transfection.	('lung cancer', 'Disease', 'MESH:D008175', (31, 42))	('increased', 'PosReg', (72, 81))	('A549', 'CellLine', 'CVCL:0023', (49, 53))	('RAF1', 'Gene', (85, 89))	('RAF1', 'Gene', '5894', (85, 89))	('lung cancer', 'Disease', (31, 42))	('lung cancer', 'Phenotype', 'HP:0100526', (31, 42))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('transfection', 'Var', (90, 102))
249678	33931671	Phosphorylation of MLF2 at serine 24 plays an essential role in the proliferation and oncogenicity in chronic myelogenous leukemia (CML).	('chronic myelogenous leukemia', 'Disease', (102, 130))	('MLF2', 'Gene', '8079', (19, 23))	('chronic myelogenous leukemia', 'Disease', 'MESH:D015464', (102, 130))	('chronic myelogenous leukemia', 'Phenotype', 'HP:0005506', (102, 130))	('leukemia', 'Phenotype', 'HP:0001909', (122, 130))	('Phosphorylation', 'Var', (0, 15))	('serine', 'Chemical', 'MESH:D012694', (27, 33))	('myelogenous leukemia', 'Phenotype', 'HP:0012324', (110, 130))	('CML', 'Disease', 'MESH:D015464', (132, 135))	('CML', 'Disease', (132, 135))	('MLF2', 'Gene', (19, 23))
249776	33665167	Besides, the second mitochondria-derived activator of caspase (SMAC) mimetics can representatively cause the auto-degradation of cIAPs.	('cIAPs', 'Disease', (129, 134))	('mimetics', 'Var', (69, 77))	('auto-degradation', 'MPA', (109, 125))	('SMAC', 'Gene', (63, 67))	('cause', 'Reg', (99, 104))	('second mitochondria-derived activator of caspase', 'Gene', '56616', (13, 61))	('SMAC', 'Gene', '56616', (63, 67))	('second mitochondria-derived activator of caspase', 'Gene', (13, 61))
249777	33665167	In general, when the activity of caspase-8 is present, FLIPL and caspase-8 combine with each other to form a heterodimer to cleave RIPK1, RIPK3 and CYLD, which prevents the initiation of necroptosis.	('prevents', 'NegReg', (160, 168))	('cleave', 'Var', (124, 130))	('necroptosis', 'CPA', (187, 198))	('RIPK1', 'Gene', (131, 136))	('CYLD', 'Gene', (148, 152))	('CYLD', 'Gene', '1540', (148, 152))	('RIPK3', 'Gene', (138, 143))
249779	33665167	It has been reported that RIPK1 phosphorylates signal transducer and activator of transcription 3 (STAT3), which leads to the interaction of STAT3 with gene associated with retinoic and interferon-induced mortality 19 and subsequent translocation of STAT3 to the mitochondria to promote reactive oxygen species (ROS) generation and cell death.	('ROS', 'Chemical', 'MESH:D017382', (312, 315))	('RIPK1', 'Gene', (26, 31))	('interaction', 'Interaction', (126, 137))	('STAT3', 'Gene', '6774', (141, 146))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (287, 310))	('STAT3', 'Gene', '6774', (250, 255))	('STAT3', 'Gene', (141, 146))	('translocation', 'MPA', (233, 246))	('cell death', 'CPA', (332, 342))	('STAT3', 'Gene', '6774', (99, 104))	('signal transducer and activator of transcription 3', 'Gene', '6774', (47, 97))	('promote', 'PosReg', (279, 286))	('phosphorylates', 'Var', (32, 46))	('STAT3', 'Gene', (99, 104))	('STAT3', 'Gene', (250, 255))	('leads to', 'Reg', (113, 121))
249780	33665167	What's more, mitochondria may promote the translocation of necrosomes to mitochondria-associated membranes, which probably induces ROS generation and related necroptosis.	('promote', 'PosReg', (30, 37))	('induces', 'Reg', (123, 130))	('necroptosis', 'Disease', (158, 169))	('ROS', 'Chemical', 'MESH:D017382', (131, 134))	('ROS generation', 'MPA', (131, 145))	('mitochondria', 'Var', (13, 25))
249799	33665167	Moreover, ferroptosis is the exclusive mode of regulated necrosis that can be repressed by iron chelators (such as deferoxamine), lipophilic antioxidants (such as alpha-tocopherol and coenzyme Q10), and depletion of PUFA.	('coenzyme Q10', 'Chemical', 'MESH:C024989', (184, 196))	('depletion', 'Var', (203, 212))	('PUFA', 'Chemical', 'MESH:D005231', (216, 220))	('deferoxamine', 'Chemical', 'MESH:D003676', (115, 127))	('necrosis', 'Disease', (57, 65))	('ferroptosis', 'Disease', (10, 21))	('alpha-tocopherol', 'Chemical', 'MESH:D024502', (163, 179))	('lipophilic', 'MPA', (130, 140))	('iron', 'Chemical', 'MESH:D007501', (91, 95))	('necrosis', 'Disease', 'MESH:D009336', (57, 65))
249806	33665167	There are some conditions that can cause DNA damage and activate PARP1, such as ultraviolet light, alkylating agents, the Ca2+ signaling pathway, posttranslational modifications through acetylation, ROS, hypoxia, hypoglycemia.	('hypoxia', 'Disease', (204, 211))	('hypoxia', 'Disease', 'MESH:D000860', (204, 211))	('hypoglycemia', 'Disease', 'MESH:D007003', (213, 225))	('ROS', 'Chemical', 'MESH:D017382', (199, 202))	('ROS', 'Protein', (199, 202))	('acetylation', 'Var', (186, 197))	('posttranslational', 'Var', (146, 163))	('activate', 'PosReg', (56, 64))	('hypoglycemia', 'Disease', (213, 225))	('hypoglycemia', 'Phenotype', 'HP:0001943', (213, 225))	('PARP1', 'Gene', (65, 70))	('Ca2+', 'Chemical', 'MESH:D000069285', (122, 126))
249808	33665167	Then, NAD+ and ATP depletion cause energy depletion, which brings about cell death.	('energy depletion', 'MPA', (35, 51))	('NAD+', 'Var', (6, 10))	('NAD+', 'Chemical', 'MESH:D009243', (6, 10))	('cell death', 'CPA', (72, 82))	('brings about', 'Reg', (59, 71))	('ATP', 'Chemical', 'MESH:D000255', (15, 18))
249810	33665167	For instance, PAR polymer leads to the depolarization of the mitochondrial outer membrane and the release of active apoptosis-inducing factor (AIF) from the mitochondria into the nucleus, which results in chromatin condensation and large-scale (about 50 kb) DNA fragmentation, followed by regulated necrosis.	('results in', 'Reg', (194, 204))	('chromatin condensation', 'CPA', (205, 227))	('necrosis', 'Disease', (299, 307))	('PAR polymer', 'Var', (14, 25))	('apoptosis-inducing factor', 'Gene', '9131', (116, 141))	('apoptosis-inducing factor', 'Gene', (116, 141))	('release', 'MPA', (98, 105))	('depolarization', 'NegReg', (39, 53))	('necrosis', 'Disease', 'MESH:D009336', (299, 307))	('mitochondrial outer membrane', 'MPA', (61, 89))	('polymer', 'Chemical', 'MESH:D011108', (18, 25))	('DNA fragmentation', 'CPA', (258, 275))
249813	33665167	Notably, PAR glycohydrolase (PARG) can reverse all of the above processes and protect cells from PAR-mediated parthanatos via catalyzing the degradation of PAR, and knockout of PARG can markedly increase the toxicity of PAR and enhance the occurrence of parthanatos.	('occurrence', 'MPA', (240, 250))	('toxicity', 'Disease', 'MESH:D064420', (208, 216))	('PARG', 'Gene', (29, 33))	('PARG', 'Gene', (177, 181))	('enhance', 'PosReg', (228, 235))	('PAR glycohydrolase', 'Gene', '8505', (9, 27))	('knockout', 'Var', (165, 173))	('PARG', 'Gene', '8505', (177, 181))	('PAR glycohydrolase', 'Gene', (9, 27))	('toxicity', 'Disease', (208, 216))	('PARG', 'Gene', '8505', (29, 33))	('increase', 'PosReg', (195, 203))
249816	33665167	Thus far, a new definition of pyroptosis has been proposed as a type of regulated necrosis that mainly depends on the activation of caspase-1 and the cleavage of gasdermin D (GSDMD).	('activation', 'PosReg', (118, 128))	('cleavage', 'Var', (150, 158))	('GSDMD', 'Gene', '79792', (175, 180))	('caspase-1', 'Gene', (132, 141))	('necrosis', 'Disease', 'MESH:D009336', (82, 90))	('gasdermin D', 'Gene', '79792', (162, 173))	('necrosis', 'Disease', (82, 90))	('GSDMD', 'Gene', (175, 180))	('gasdermin D', 'Gene', (162, 173))	('caspase-1', 'Gene', '834', (132, 141))
249845	33665167	Accordingly, both loss of RIPK3 in the tumor microenvironment and loss of the kinase activity in RIPK1 have been reported to reduce tumor nodules in the lung in murine B16.F10 primary melanoma tumors, which further implies that RIPK3 and RIPK1 are fundamental for cancer growth and metastasis.	('melanoma', 'Phenotype', 'HP:0002861', (184, 192))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('reduce', 'NegReg', (125, 131))	('tumor', 'Disease', (132, 137))	('melanoma tumors', 'Disease', 'MESH:D008545', (184, 199))	('cancer', 'Disease', (264, 270))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('cancer', 'Phenotype', 'HP:0002664', (264, 270))	('melanoma tumors', 'Disease', (184, 199))	('RIPK1', 'Gene', (97, 102))	('tumor', 'Disease', (193, 198))	('iron', 'Chemical', 'MESH:D007501', (53, 57))	('loss', 'NegReg', (66, 70))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('B16.F10', 'CellLine', 'CVCL:0159', (168, 175))	('tumor', 'Disease', (39, 44))	('RIPK3', 'Gene', (26, 31))	('tumors', 'Phenotype', 'HP:0002664', (193, 199))	('cancer', 'Disease', 'MESH:D009369', (264, 270))	('loss', 'Var', (18, 22))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('murine', 'Species', '10090', (161, 167))
249868	33665167	Reportedly, the small-molecule SMAC mimetic BV6 could antagonize cIAPs to overcome apoptosis resistance by inducing necroptosis upon caspase inhibition and sensitize acute myeloid leukemia (AML) cells to cytarabine-induced cell death, which could be significantly inhibited by NEC1 or MLKL inhibitor necrosulfonamide but not by caspases inhibitor Z-VAD-FMK.	('cytarabine', 'Chemical', 'MESH:D003561', (204, 214))	('caspase', 'Gene', '834;837;838;841;12370', (133, 140))	('caspase', 'Gene', (328, 335))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (166, 188))	('SMAC', 'Gene', (31, 35))	('leukemia', 'Phenotype', 'HP:0001909', (180, 188))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (166, 188))	('cell death', 'CPA', (223, 233))	('AML', 'Disease', 'MESH:D015470', (190, 193))	('caspases', 'Gene', (328, 336))	('necrosulfonamide', 'Chemical', 'MESH:C570695', (300, 316))	('AML', 'Disease', (190, 193))	('caspases', 'Gene', '834;837;838;841;12370', (328, 336))	('AML', 'Phenotype', 'HP:0004808', (190, 193))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (172, 188))	('SMAC', 'Gene', '56616', (31, 35))	('caspase', 'Gene', '834;837;838;841;12370', (328, 335))	('sensitize', 'Reg', (156, 165))	('small-molecule', 'Var', (16, 30))	('BV6', 'Chemical', '-', (44, 47))	('necroptosis', 'MPA', (116, 127))	('inducing', 'Reg', (107, 115))	('caspase', 'Gene', (133, 140))	('Z-VAD-FMK', 'Chemical', 'MESH:C096713', (347, 356))	('BV6', 'Var', (44, 47))	('acute myeloid leukemia', 'Disease', (166, 188))
249870	33665167	Besides, 1, 2-Diarachidonoyl-sn-glycero-3-phosphoethanolamine (DAPE) has been found to induce RIPK1-dependent necroptosis in malignant pleural mesothelioma cells, mainly in NCI-H28 cell line, in a concentration (1-100 muM)-dependent manner.	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (135, 155))	('1, 2-Diarachidonoyl-sn-glycero-3-phosphoethanolamine', 'Chemical', '-', (9, 61))	('necroptosis', 'CPA', (110, 121))	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (125, 155))	('malignant pleural mesothelioma', 'Disease', (125, 155))	('RIPK1-dependent', 'Var', (94, 109))	('NCI-H28', 'CellLine', 'CVCL:1555', (173, 180))	('DAPE', 'Chemical', '-', (63, 67))
249871	33665167	What's more, BI2536, an inhibitor of serine/threonine protein kinase Polo-like Kinase 1 (PLK1), has been reported to induce necroptosis in androgen-insensitive prostate cancer cells (LNCaP-AI) to overcome castration-resistance.	('Polo-like Kinase 1', 'Gene', '5347', (69, 87))	('LNCaP', 'CellLine', 'CVCL:0395', (183, 188))	('BI2536', 'Var', (13, 19))	('prostate cancer', 'Disease', (160, 175))	('Polo-like Kinase 1', 'Gene', (69, 87))	('necroptosis', 'CPA', (124, 135))	('induce', 'PosReg', (117, 123))	('BI2536', 'Chemical', 'MESH:C518477', (13, 19))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('prostate cancer', 'Disease', 'MESH:D011471', (160, 175))	('PLK1', 'Gene', (89, 93))	('prostate cancer', 'Phenotype', 'HP:0012125', (160, 175))	('serine', 'Chemical', 'MESH:D012694', (37, 43))	('PLK1', 'Gene', '5347', (89, 93))
249872	33665167	Moreover, a multicentric parallel phase II trial has demonstrated that intravenous BI2536 has limited anti-cancer activity in five different cancer types, including advanced head and neck, breast, and ovarian cancer, soft tissue sarcoma and melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (241, 249))	('melanoma', 'Disease', (241, 249))	('limited', 'NegReg', (94, 101))	('soft tissue sarcoma', 'Disease', (217, 236))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('ovarian cancer', 'Disease', 'MESH:D010051', (201, 215))	('breast', 'Disease', (189, 195))	('cancer', 'Disease', 'MESH:D009369', (209, 215))	('sarcoma', 'Phenotype', 'HP:0100242', (229, 236))	('cancer', 'Disease', (141, 147))	('melanoma', 'Disease', 'MESH:D008545', (241, 249))	('ovarian cancer', 'Disease', (201, 215))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('BI2536', 'Var', (83, 89))	('ovarian cancer', 'Phenotype', 'HP:0100615', (201, 215))	('cancer', 'Disease', (107, 113))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('cancer', 'Disease', (209, 215))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (217, 236))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (217, 236))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('BI2536', 'Chemical', 'MESH:C518477', (83, 89))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
249873	33665167	In addition, intravenous BI2536 also exhibited modest efficacy in relapsed non-small-cell lung cancer in an open-label, randomized phase II clinical trial, while BI2536 failed to inhibit the progression of relapsed small-cell lung cancer.	('small-cell lung cancer', 'Disease', (215, 237))	('small-cell lung cancer', 'Disease', 'MESH:D055752', (79, 101))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (79, 101))	('lung cancer', 'Phenotype', 'HP:0100526', (226, 237))	('BI2536', 'Var', (25, 31))	('lung cancer', 'Phenotype', 'HP:0100526', (90, 101))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (215, 237))	('BI2536', 'Chemical', 'MESH:C518477', (25, 31))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('non-small-cell lung cancer', 'Disease', (75, 101))	('non-small-cell lung cancer', 'Disease', 'MESH:D002289', (75, 101))	('small-cell lung cancer', 'Disease', 'MESH:D055752', (215, 237))	('BI2536', 'Chemical', 'MESH:C518477', (162, 168))
249875	33665167	Also, Compound C (also called dorsomorphin) has been found to induce glioma cell death via necroptosis.	('glioma cell death via necroptosis', 'Disease', 'MESH:D003643', (69, 102))	('dorsomorphin', 'Chemical', 'MESH:C516138', (30, 42))	('induce', 'PosReg', (62, 68))	('glioma cell death via necroptosis', 'Disease', (69, 102))	('glioma', 'Phenotype', 'HP:0009733', (69, 75))	('Compound', 'Var', (6, 14))
249876	33665167	Last but not least, aurora kinase inhibitor CCT137690 can indirectly activate RIPK1, RIPK3, and MLKL in PDAC in vivo, which leads to the initiation of necroptosis and the inhibition of cancer growth and metastasis.	('RIPK1', 'Gene', (78, 83))	('initiation', 'PosReg', (137, 147))	('necroptosis', 'CPA', (151, 162))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('activate', 'PosReg', (69, 77))	('MLKL', 'Gene', (96, 100))	('leads to', 'Reg', (124, 132))	('CCT137690', 'Var', (44, 53))	('inhibition', 'NegReg', (171, 181))	('PDAC', 'Phenotype', 'HP:0006725', (104, 108))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('RIPK3', 'Gene', (85, 90))	('CCT137690', 'Chemical', 'MESH:C551619', (44, 53))	('cancer', 'Disease', (185, 191))
249895	33665167	The recognition that GPX4 plays such an important role in ferroptosis in various cancers suggests that the inhibitors of GPX4 could point the way for cancer treatment.	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('cancers', 'Phenotype', 'HP:0002664', (81, 88))	('GPX4', 'Gene', (21, 25))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('cancer', 'Disease', (81, 87))	('cancers', 'Disease', (81, 88))	('cancers', 'Disease', 'MESH:D009369', (81, 88))	('GPX4', 'Gene', (121, 125))	('GPX4', 'Gene', '2879', (21, 25))	('cancer', 'Disease', (150, 156))	('GPX4', 'Gene', '2879', (121, 125))	('inhibitors', 'Var', (107, 117))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
249898	33665167	Accumulation of NRF2 inhibits ferroptosis by promoting the expression of antioxidant proteins, such as quinone oxidoreductase 1 and heme oxygenase-1, and ferritin heavy chain 1, while knockdown of NRF2 enhances ferroptosis in HCC cells.	('heme oxygenase-1', 'Gene', (132, 148))	('inhibits', 'NegReg', (21, 29))	('knockdown', 'Var', (184, 193))	('promoting', 'PosReg', (45, 54))	('HCC', 'Phenotype', 'HP:0001402', (226, 229))	('NRF2', 'Gene', '4780', (197, 201))	('NRF2', 'Gene', '4780', (16, 20))	('expression', 'MPA', (59, 69))	('ferroptosis', 'CPA', (211, 222))	('NRF2', 'Gene', (197, 201))	('enhances', 'PosReg', (202, 210))	('ferritin heavy chain 1', 'Gene', '2495', (154, 176))	('ferritin heavy chain 1', 'Gene', (154, 176))	('heme oxygenase-1', 'Gene', '3162', (132, 148))	('ferroptosis', 'CPA', (30, 41))	('NRF2', 'Gene', (16, 20))
249902	33665167	Thus, CD44v may be a biomarker for cancers that can be effectively treated with system  inhibitors.	('cancers', 'Disease', 'MESH:D009369', (35, 42))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('CD44v', 'Var', (6, 11))	('cancers', 'Phenotype', 'HP:0002664', (35, 42))	('cancers', 'Disease', (35, 42))
249913	33665167	The activation of p53, a common tumor suppressor gene, can trigger ferroptosis in certain cancer cells, as p53 directly inhibits the transcription of SLC7A11, an essential component of the system .	('inhibits', 'NegReg', (120, 128))	('ferroptosis', 'Disease', (67, 78))	('SLC7A11', 'Gene', (150, 157))	('p53', 'Gene', (18, 21))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('SLC7A11', 'Gene', '23657', (150, 157))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('trigger', 'Reg', (59, 66))	('p53', 'Var', (107, 110))	('tumor', 'Disease', (32, 37))	('cancer', 'Disease', (90, 96))	('transcription', 'MPA', (133, 146))	('activation', 'PosReg', (4, 14))
249914	33665167	P533KR, an acetylation-defective mutant, is a representative case because it specifically inhibits the expression of SLC7A11 rather than other target genes related to anti-proliferative and pro-apoptotic activity.	('expression', 'MPA', (103, 113))	('P533KR', 'Var', (0, 6))	('inhibits', 'NegReg', (90, 98))	('SLC7A11', 'Gene', (117, 124))	('SLC7A11', 'Gene', '23657', (117, 124))
249915	33665167	Moreover, p533KR fails to trigger cell-cycle arrest, senescence, and apoptosis but retains the tumor suppression function by inducing ferroptosis in vivo.	('arrest', 'Disease', (45, 51))	('inducing', 'Reg', (125, 133))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('p533KR', 'Var', (10, 16))	('ferroptosis', 'CPA', (134, 145))	('tumor', 'Disease', (95, 100))	('arrest', 'Disease', 'MESH:D006323', (45, 51))
249916	33665167	However, p53 has been found to limit erastin-induced ferroptosis and protect CRC cells from cell death in a transcription-independent manner.	('p53', 'Var', (9, 12))	('erastin-induced ferroptosis', 'MPA', (37, 64))	('CRC', 'Disease', (77, 80))	('limit', 'NegReg', (31, 36))	('erastin', 'Chemical', 'MESH:C477224', (37, 44))	('CRC', 'Phenotype', 'HP:0003003', (77, 80))	('CRC', 'Disease', 'MESH:D015179', (77, 80))	('cell death', 'CPA', (92, 102))
249917	33665167	Further research has indicated that p53 blocks dipeptidyl-peptidase-4 (DPP4) activity by inducing nuclear accumulation of DPP4, which inhibits DPP4-dependent lipid peroxidation and consequent ferroptosis.	('inhibits', 'NegReg', (134, 142))	('blocks', 'NegReg', (40, 46))	('ferroptosis', 'CPA', (192, 203))	('DPP4', 'Gene', (71, 75))	('lipid', 'Chemical', 'MESH:D008055', (158, 163))	('p53', 'Var', (36, 39))	('DPP4', 'Gene', (143, 147))	('dipeptidyl-peptidase-4', 'Gene', '1803', (47, 69))	('DPP4', 'Gene', '1803', (122, 126))	('DPP4', 'Gene', (122, 126))	('nuclear accumulation', 'MPA', (98, 118))	('activity', 'MPA', (77, 85))	('DPP4', 'Gene', '1803', (71, 75))	('dipeptidyl-peptidase-4', 'Gene', (47, 69))	('DPP4', 'Gene', '1803', (143, 147))	('inducing', 'PosReg', (89, 97))
249930	33665167	Similarly, artesunate-induced ferroptosis has been observed only in K-Ras-mutant PDAC cell lines, but not in human pancreatic ductal epithelial cells or wild-type K-Ras PDAC cells, which indicates that the anti-cancer activity of artesunate depends on K-Ras mutation.	('human', 'Species', '9606', (109, 114))	('PDAC', 'Phenotype', 'HP:0006725', (169, 173))	('cancer', 'Disease', 'MESH:D009369', (211, 217))	('K-Ras-mutant', 'Var', (68, 80))	('artesunate', 'Chemical', 'MESH:D000077332', (230, 240))	('cancer', 'Disease', (211, 217))	('artesunate', 'Chemical', 'MESH:D000077332', (11, 21))	('PDAC', 'Disease', (81, 85))	('PDAC', 'Phenotype', 'HP:0006725', (81, 85))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))
249935	33665167	In addition, phenethyl isothiocyanate (PEITC) has been identified as a dietary anti-cancer compound by inducing ROS production.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('ROS', 'Chemical', 'MESH:D017382', (112, 115))	('phenethyl isothiocyanate', 'Chemical', 'MESH:C058305', (13, 37))	('inducing', 'PosReg', (103, 111))	('PEITC', 'Chemical', 'MESH:C058305', (39, 44))	('cancer', 'Disease', (84, 90))	('phenethyl', 'Var', (13, 22))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('ROS production', 'MPA', (112, 126))
249942	33665167	However, another study has found that erastin selectively targets certain genotypes in Ras-mutant cell lines, including H-Ras-mutant-engineered cells, N-Ras-mutant HT1080 human fibrosarcoma cells, and K-Ras-mutant Calu-1 non-small-cell lung cancer cells.	('Ras-mutant', 'Gene', (87, 97))	('erastin', 'Chemical', 'MESH:C477224', (38, 45))	('lung cancer', 'Phenotype', 'HP:0100526', (236, 247))	('sarcoma', 'Phenotype', 'HP:0100242', (182, 189))	('N-Ras', 'Gene', (151, 156))	('fibrosarcoma', 'Disease', (177, 189))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (177, 189))	('non-small-cell lung cancer', 'Disease', (221, 247))	('HT1080', 'CellLine', 'CVCL:0317', (164, 170))	('H-Ras', 'Gene', '3265', (120, 125))	('H-Ras', 'Gene', (120, 125))	('fibrosarcoma', 'Disease', 'MESH:D005354', (177, 189))	('non-small-cell lung cancer', 'Disease', 'MESH:D002289', (221, 247))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (225, 247))	('N-Ras', 'Gene', '4893', (151, 156))	('Ras-mutant', 'Var', (87, 97))	('human', 'Species', '9606', (171, 176))
249948	33665167	And it has been demonstrated that RSL3 can enhance the sensitivity of resistant cancer cells to chemotherapeutic drugs in certain types of cancers.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('cancer', 'Disease', (80, 86))	('cancers', 'Disease', 'MESH:D009369', (139, 146))	('cancers', 'Phenotype', 'HP:0002664', (139, 146))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('sensitivity', 'MPA', (55, 66))	('cancers', 'Disease', (139, 146))	('cancer', 'Disease', (139, 145))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('RSL3', 'Chemical', '-', (34, 38))	('enhance', 'PosReg', (43, 50))	('RSL3', 'Var', (34, 38))
249949	33665167	Buthionine sulfoximine (BSO), an irreversible inhibitor of gamma-glutamyl cysteine synthetase, has been found to reduce GPX4 activity by inhibiting GSH synthesis, and subsequently increase ROS levels, which selectively triggers ferroptosis in BJ cells with oncogenic Ras mutation.	('GPX4', 'Gene', (120, 124))	('Ras', 'Gene', (267, 270))	('GPX4', 'Gene', '2879', (120, 124))	('Buthionine sulfoximine', 'Chemical', 'MESH:D019328', (0, 22))	('GSH synthesis', 'MPA', (148, 161))	('increase', 'PosReg', (180, 188))	('ROS levels', 'MPA', (189, 199))	('reduce', 'NegReg', (113, 119))	('inhibiting', 'NegReg', (137, 147))	('ROS', 'Chemical', 'MESH:D017382', (189, 192))	('mutation', 'Var', (271, 279))	('BJ', 'CellLine', 'CVCL:6573', (243, 245))	('increase ROS levels', 'Phenotype', 'HP:0025464', (180, 199))	('GSH', 'Chemical', 'MESH:D005978', (148, 151))	('cysteine', 'Chemical', 'MESH:D003545', (74, 82))	('triggers', 'Reg', (219, 227))	('BSO', 'Chemical', 'MESH:D019328', (24, 27))	('ferroptosis', 'Disease', (228, 239))
249954	33665167	APR246, a mutant-p53 reactivator, has been found to directly bind to and deplete GSH in oesophageal cancer cells, which results in the accumulation of lipid peroxidation and consequent ferroptosis.	('ferroptosis', 'CPA', (185, 196))	('deplete', 'NegReg', (73, 80))	('APR246', 'Var', (0, 6))	('APR246', 'Chemical', 'MESH:C533410', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('lipid', 'Chemical', 'MESH:D008055', (151, 156))	('bind', 'Interaction', (61, 65))	('accumulation', 'PosReg', (135, 147))	('GSH', 'Chemical', 'MESH:D005978', (81, 84))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('GSH', 'MPA', (81, 84))	('lipid peroxidation', 'MPA', (151, 169))
249955	33665167	Lanperisone, which is commonly used as a muscle relaxant, can induce ROS generation to selectively kill K-Ras-mutant mouse embryonic fibroblasts via ferroptosis signaling in vitro, and it can also inhibit tumor growth through inducing ferroptosis in a K-Ras-driven mouse model of lung cancer in vivo.	('K-Ras-mutant', 'Gene', (104, 116))	('inducing', 'Reg', (226, 234))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('inhibit', 'NegReg', (197, 204))	('ferroptosis signaling', 'MPA', (149, 170))	('mouse', 'Species', '10090', (117, 122))	('ROS', 'Chemical', 'MESH:D017382', (69, 72))	('mouse', 'Species', '10090', (265, 270))	('cancer', 'Phenotype', 'HP:0002664', (285, 291))	('lung cancer', 'Disease', 'MESH:D008175', (280, 291))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumor', 'Disease', (205, 210))	('K-Ras-mutant', 'Var', (104, 116))	('ferroptosis', 'CPA', (235, 246))	('ROS generation', 'MPA', (69, 83))	('Lanperisone', 'Chemical', '-', (0, 11))	('lung cancer', 'Disease', (280, 291))	('lung cancer', 'Phenotype', 'HP:0100526', (280, 291))
249973	33665167	Compared with traditional administration methods, nano-DDS has the advantages of promoted drug availability and targeting ability, high solubility, and enhanced permeability and retention effect, especially in early-stage solid tumors.	('nano-DDS', 'Var', (50, 58))	('permeability', 'MPA', (161, 173))	('promoted', 'PosReg', (81, 89))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('tumors', 'Disease', (228, 234))	('drug availability', 'CPA', (90, 107))	('enhanced', 'PosReg', (152, 160))	('tumors', 'Phenotype', 'HP:0002664', (228, 234))	('tumors', 'Disease', 'MESH:D009369', (228, 234))	('retention', 'MPA', (178, 187))	('targeting ability', 'CPA', (112, 129))
249984	33665167	When inhibitions of PARP1 and BRCA1/2 coexist, the persistent DNA breaks can induce cell cycle arrest and apoptosis.	('BRCA1/2', 'Gene', '672;675', (30, 37))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (84, 101))	('apoptosis', 'CPA', (106, 115))	('BRCA1/2', 'Gene', (30, 37))	('inhibitions', 'Var', (5, 16))	('arrest', 'Disease', 'MESH:D006323', (95, 101))	('arrest', 'Disease', (95, 101))	('persistent', 'Var', (51, 61))	('PARP1', 'Gene', (20, 25))	('induce', 'Reg', (77, 83))
249990	33665167	One of the views is that inhibitors of parthanatos, such as PARP1 inhibitors, could facilitate cancer cell death via inhibiting the DNA repair needed for cell survival, while other ideas are that inducers of parthanatos could directly promote cancer cell death ( Table 3 ).	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('promote', 'PosReg', (235, 242))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('cancer', 'Disease', (95, 101))	('cancer', 'Disease', (243, 249))	('cancer', 'Disease', 'MESH:D009369', (243, 249))	('DNA repair needed for cell survival', 'MPA', (132, 167))	('facilitate', 'PosReg', (84, 94))	('inhibiting', 'NegReg', (117, 127))	('inhibitors', 'Var', (25, 35))	('PARP1', 'Gene', (60, 65))	('cancer', 'Phenotype', 'HP:0002664', (243, 249))
249991	33665167	It has been found that inhibition of PARP1 and deficiency of BRCA1/2 synergistically kill BRCA1/2-deficient breast and other cancer cells via inhibiting DNA repair.	('DNA repair', 'MPA', (153, 163))	('BRCA1/2', 'Gene', '672;675', (61, 68))	('BRCA1/2', 'Gene', (90, 97))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('BRCA1/2', 'Gene', '672;675', (90, 97))	('breast', 'Disease', (108, 114))	('PARP1', 'Gene', (37, 42))	('BRCA1/2', 'Gene', (61, 68))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('deficient breast', 'Phenotype', 'HP:0003187', (98, 114))	('inhibiting', 'NegReg', (142, 152))	('deficiency', 'Var', (47, 57))
249993	33665167	What's more, as it is mentioned above that PARP1 can protect tumor cells from radiation and chemotherapeutic drugs, PARP1 inhibitors, such as 3-AB, GPI 15427, and nicotinamide, have been utilized as radiosensitizers or chemosensitizer.	('GPI 15427', 'Chemical', 'MESH:C502278', (148, 157))	('inhibitors', 'Var', (122, 132))	('nicotinamide', 'Chemical', 'MESH:D009536', (163, 175))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('3-AB', 'Chemical', 'MESH:C025160', (142, 146))	('PARP1', 'Gene', (116, 121))	('tumor', 'Disease', (61, 66))
249996	33665167	Sepantronium bromide (YM155), a survivin suppressant, has been found to induce parthanatos in cultured KYSE410 and KYSE150 esophageal carcinoma cell lines in vitro and relatedly inhibit esophageal squamous-cell carcinoma growth in mice, which can be abrogated by genetic knockdown of PARP1 or AIF.	('squamous-cell carcinoma growth', 'Disease', 'MESH:D002294', (197, 227))	('KYSE150', 'Var', (115, 122))	('survivin', 'Gene', (32, 40))	('survivin', 'Gene', '11799', (32, 40))	('squamous-cell carcinoma', 'Phenotype', 'HP:0002860', (197, 220))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (123, 143))	('squamous-cell carcinoma growth', 'Disease', (197, 227))	('YM155', 'Chemical', 'MESH:C523798', (22, 27))	('induce', 'PosReg', (72, 78))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('Sepantronium bromide', 'Chemical', 'MESH:C523798', (0, 20))	('esophageal carcinoma', 'Disease', (123, 143))	('KYSE410', 'Var', (103, 110))	('YM155', 'Var', (22, 27))	('inhibit', 'NegReg', (178, 185))	('mice', 'Species', '10090', (231, 235))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (123, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (211, 220))	('PARP1', 'Gene', (284, 289))	('parthanatos', 'MPA', (79, 90))
250011	33665167	Moreover, the combination of pyroptosis-targeted therapy and conventional remedies seems to enhance therapeutic efficacy, reduce off-target toxicity, and promote patient outcomes ( Table 4 ).	('toxicity', 'Disease', 'MESH:D064420', (140, 148))	('reduce', 'NegReg', (122, 128))	('toxicity', 'Disease', (140, 148))	('promote', 'PosReg', (154, 161))	('pyroptosis-targeted', 'Var', (29, 48))	('therapeutic efficacy', 'CPA', (100, 120))	('patient outcomes', 'CPA', (162, 178))	('patient', 'Species', '9606', (162, 169))	('enhance', 'PosReg', (92, 99))
250017	33665167	Furthermore, mechanistic studies have revealed that dioscin can induce pyroptosis through the caspase-3/GSDME pathway.	('caspase-3', 'Gene', (94, 103))	('induce', 'PosReg', (64, 70))	('pyroptosis', 'MPA', (71, 81))	('caspase-3', 'Gene', '836', (94, 103))	('dioscin', 'Var', (52, 59))	('GSDME', 'Chemical', '-', (104, 109))	('dioscin', 'Chemical', 'MESH:C019357', (52, 59))
250023	33665167	Compound L61H10, a heterocyclic ketone derivative, has been observed to kill cancer cells without apparent side effects in lung cancer cell lines and mice bearing lung cancer xenografts by inducing pyroptosis.	('mice', 'Species', '10090', (150, 154))	('lung cancer', 'Phenotype', 'HP:0100526', (123, 134))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('cancer', 'Disease', (168, 174))	('cancer', 'Disease', (128, 134))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('lung cancer', 'Disease', (163, 174))	('lung cancer', 'Disease', (123, 134))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('L61H10', 'Var', (9, 15))	('L61H10', 'Chemical', '-', (9, 15))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('ketone', 'Chemical', 'MESH:D007659', (32, 38))	('inducing', 'PosReg', (189, 197))	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('lung cancer', 'Disease', 'MESH:D008175', (163, 174))	('pyroptosis', 'MPA', (198, 208))	('lung cancer', 'Phenotype', 'HP:0100526', (163, 174))	('lung cancer', 'Disease', 'MESH:D008175', (123, 134))
250024	33665167	Further studies have revealed that compound L61H10 can arrest the cell cycle in the G2/M phase and switch apoptosis to caspase-3/GSDME-mediated pyroptosis.	('switch', 'Reg', (99, 105))	('arrest', 'Disease', 'MESH:D006323', (55, 61))	('caspase-3', 'Gene', '836', (119, 128))	('L61H10', 'Chemical', '-', (44, 50))	('arrest', 'Disease', (55, 61))	('caspase-3', 'Gene', (119, 128))	('GSDME', 'Chemical', '-', (129, 134))	('L61H10', 'Var', (44, 50))	('cell cycle in the G2/M phase', 'CPA', (66, 94))
250027	33665167	In addition, a phase 1 dose-finding study of metformin has demonstrated that metformin can promote the efficiency of chemoradiotherapy and elevate the rates of overall survival and progression-free survival in patients with locally advanced head and neck squamous cell carcinoma.	('metformin', 'Var', (77, 86))	('elevate', 'Disease', (139, 146))	('promote', 'PosReg', (91, 98))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (241, 278))	('metformin', 'Chemical', 'MESH:D008687', (77, 86))	('carcinoma', 'Phenotype', 'HP:0030731', (269, 278))	('overall survival', 'CPA', (160, 176))	('head and neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (241, 278))	('elevate', 'Disease', 'MESH:D006973', (139, 146))	('metformin', 'Chemical', 'MESH:D008687', (45, 54))	('patients', 'Species', '9606', (210, 218))	('chemoradiotherapy', 'CPA', (117, 134))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (255, 278))	('progression-free survival', 'CPA', (181, 206))
250033	33665167	Recent studies have found that small-molecule DPP8/9 inhibitors can induce pyroptosis in human AML cell lines and primary AML samples by activating the caspase-1/GSDMD pathway, which represents a brand-new therapeutic strategy for AML.	('activating', 'PosReg', (137, 147))	('induce', 'PosReg', (68, 74))	('AML', 'Disease', 'MESH:D015470', (122, 125))	('AML', 'Phenotype', 'HP:0004808', (122, 125))	('AML', 'Disease', (122, 125))	('AML', 'Disease', 'MESH:D015470', (231, 234))	('human', 'Species', '9606', (89, 94))	('AML', 'Disease', 'MESH:D015470', (95, 98))	('pyroptosis', 'MPA', (75, 85))	('DPP8/9', 'Gene', (46, 52))	('AML', 'Phenotype', 'HP:0004808', (95, 98))	('AML', 'Phenotype', 'HP:0004808', (231, 234))	('AML', 'Disease', (231, 234))	('AML', 'Disease', (95, 98))	('caspase-1', 'Gene', '834', (152, 161))	('inhibitors', 'Var', (53, 63))	('caspase-1', 'Gene', (152, 161))	('GSDMD', 'Gene', '79792', (162, 167))	('DPP8/9', 'Gene', '54878;91039', (46, 52))	('GSDMD', 'Gene', (162, 167))
250040	33665167	Recent studies have shown that, in addition to inducing necroptosis in prostate cancer cells, the PLK1 inhibitor BI2536 sensitizes esophageal squamous cell carcinoma cells to cisplatin in vivo and in vitro by inhibiting the DNA damage repair and promoting pyroptosis.	('BI2536', 'Chemical', 'MESH:C518477', (113, 119))	('DNA damage repair', 'MPA', (224, 241))	('PLK1', 'Gene', (98, 102))	('necroptosis in prostate cancer', 'Disease', 'MESH:D011471', (56, 86))	('sensitizes', 'Reg', (120, 130))	('cisplatin', 'Chemical', 'MESH:D002945', (175, 184))	('necroptosis in prostate cancer', 'Disease', (56, 86))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (142, 165))	('inhibiting', 'NegReg', (209, 219))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (131, 165))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('prostate cancer', 'Phenotype', 'HP:0012125', (71, 86))	('PLK1', 'Gene', '5347', (98, 102))	('inducing', 'Reg', (47, 55))	('carcinoma', 'Phenotype', 'HP:0030731', (156, 165))	('pyroptosis', 'MPA', (256, 266))	('inhibitor BI2536', 'Var', (103, 119))	('BI2536', 'Var', (113, 119))	('promoting', 'PosReg', (246, 255))	('esophageal squamous cell carcinoma', 'Disease', (131, 165))
250041	33665167	Mechanistic studies have demonstrated that the combination of BI2536 and cisplatin can significantly increase the expression of caspase-3 and ensuing cleaved GSDME, which results in the pyroptosis of esophageal squamous cell carcinoma cells.	('cisplatin', 'Chemical', 'MESH:D002945', (73, 82))	('GSDME', 'Chemical', '-', (158, 163))	('pyroptosis of esophageal squamous cell carcinoma', 'Disease', (186, 234))	('cleaved', 'MPA', (150, 157))	('BI2536', 'Var', (62, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (225, 234))	('caspase-3', 'Gene', (128, 137))	('results in', 'Reg', (171, 181))	('GSDME', 'Protein', (158, 163))	('increase', 'PosReg', (101, 109))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (211, 234))	('pyroptosis of esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (186, 234))	('BI2536', 'Chemical', 'MESH:C518477', (62, 68))	('caspase-3', 'Gene', '836', (128, 137))	('expression', 'MPA', (114, 124))
250047	33665167	In addition to the above various compounds, nano-DDS has also been applied to induce pyroptosis in cancer cells, which is similar to its application in ferroptosis mentioned above.	('induce', 'PosReg', (78, 84))	('nano-DDS', 'Var', (44, 52))	('pyroptosis', 'Disease', (85, 95))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('cancer', 'Disease', (99, 105))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
250063	33665167	Moreover, nano-DDS, an emerging administration method that can greatly enhance the drug targeting property and anti-cancer efficacy, has only been applied to deliver ferroptosis and pyroptosis inducers.	('drug', 'CPA', (83, 87))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('nano-DDS', 'Var', (10, 18))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('enhance', 'PosReg', (71, 78))
250085	33323542	Furthermore, aberrant expression of miRNAs leads to a variety of diseases, including cancer, by interacting with the 3'-untranslated region of target mRNAs and altering protein translation.	('miRNAs', 'Protein', (36, 42))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('protein translation', 'MPA', (169, 188))	('cancer', 'Disease', (85, 91))	('diseases', 'Disease', (65, 73))	('altering', 'Reg', (160, 168))	('interacting', 'Interaction', (96, 107))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('expression', 'MPA', (22, 32))	('leads to', 'Reg', (43, 51))	('aberrant', 'Var', (13, 21))
250104	33323542	Real-time reverse transcription polymerase chain reaction (RT-PCR) analysis revealed significantly increased expression of CXCL5, CXCL9, and CXCL10 in MNK28 and SGC7901 cells after transfection with miR-588 mimics compared with mimic negative control (NC)-transfected cells (P < 0.05, Figure 2D).	('SGC7901', 'Gene', (161, 168))	('expression', 'MPA', (109, 119))	('SGC7901', 'CellLine', 'CVCL:0520', (161, 168))	('CXCL5', 'Gene', (123, 128))	('CXCL5', 'Gene', '6374', (123, 128))	('CXCL9', 'Gene', '4283', (130, 135))	('MNK28', 'Gene', (151, 156))	('miR-588', 'Gene', (199, 206))	('CXCL10', 'Gene', '3627', (141, 147))	('increased', 'PosReg', (99, 108))	('CXCL10', 'Gene', (141, 147))	('GC', 'Phenotype', 'HP:0012126', (162, 164))	('miR-588', 'Gene', '693173', (199, 206))	('CXCL9', 'Gene', (130, 135))	('mimics', 'Var', (207, 213))
250117	33323542	Next, we analyzed the infiltration levels of different somatic copy number alterations for CXCL5, CXCL9, and CXCL10.	('CXCL5', 'Gene', (91, 96))	('CXCL5', 'Gene', '6374', (91, 96))	('CXCL10', 'Gene', '3627', (109, 115))	('CXCL10', 'Gene', (109, 115))	('CXCL9', 'Gene', '4283', (98, 103))	('alterations', 'Var', (75, 86))	('CXCL9', 'Gene', (98, 103))
250154	33323542	The antibodies used were CXCL5 (D263012-0025, BBI), CXCL9 (ab202961, Abcam), CXCL10 (D220389-0025, BBI), and antitubulin (#T8203, Sigma-Aldrich, St. Louis, MO).	('#T8203', 'Var', (122, 128))	('CXCL10', 'Gene', '3627', (77, 83))	('CXCL9', 'Gene', (52, 57))	('D263012-0025', 'Var', (32, 44))	('CXCL10', 'Gene', (77, 83))	('CXCL5', 'Gene', (25, 30))	('CXCL5', 'Gene', '6374', (25, 30))	('D220389-0025', 'Var', (85, 97))	('CXCL9', 'Gene', '4283', (52, 57))
250168	33323542	Then, a primary CXCL5 (D263012-0025, BBI), CXCL9 (ab202961, Abcam), or CXCL10 (D220389-0025, BBI) (1:500) was added to each section for 2 hours at room temperature.	('CXCL5', 'Gene', (16, 21))	('CXCL5', 'Gene', '6374', (16, 21))	('CXCL10', 'Gene', (71, 77))	('CXCL9', 'Gene', '4283', (43, 48))	('CXCL9', 'Gene', (43, 48))	('D263012-0025', 'Var', (23, 35))	('CXCL10', 'Gene', '3627', (71, 77))
250206	33081066	ED-st exerted a greater effect on the tumor parenchyma in proliferation and invasion than EX-st. Morphological analysis showed that ED-st changed the morphology of HSC-2 cells to the invasive type of OSCC, and EX-st altered the morphology of HSC-2 cells to verrucous OSCC.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('changed', 'Reg', (138, 145))	('tumor parenchyma', 'Disease', 'MESH:D010195', (38, 54))	('ED-st', 'Var', (132, 137))	('tumor parenchyma', 'Disease', (38, 54))	('altered', 'Reg', (216, 223))
250218	33081066	Although tumorigenesis is caused by accumulation of mutations, clinical tumorigenesis that cannot be explained by this mechanism occurs.	('mutations', 'Var', (52, 61))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('tumor', 'Disease', (72, 77))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumor', 'Disease', (9, 14))	('tumor', 'Disease', 'MESH:D009369', (72, 77))
250233	33081066	The proliferative activity was in the order of HSC-2/ED-st, HSC-2/EX-st, and HSC-2/HDF, and the proliferative activity was significantly higher in the HSC-2/ED-st group than in the other groups (Figure 2b).	('HDF', 'Disease', (83, 86))	('higher', 'PosReg', (137, 143))	('proliferative activity', 'CPA', (4, 26))	('HDF', 'Disease', 'None', (83, 86))	('HSC-2/ED-st', 'Var', (151, 162))	('proliferative activity', 'CPA', (96, 118))
250236	33081066	The total number of invading cells including tumor cells and stromal cells in the HSC-2/ED-st group was significantly higher than in the other groups (Figure 3a).	('higher', 'PosReg', (118, 124))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumor', 'Disease', (45, 50))	('HSC-2/ED-st', 'Var', (82, 93))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
250267	33081066	Some researchers have reported that alpha-SMA is widely expressed in CAFs or myofibroblasts and that expression of alpha-SMA is associated with poor prognosis of patients with various types of cancers, including OSCC.	('patients', 'Species', '9606', (162, 170))	('cancers', 'Disease', 'MESH:D009369', (193, 200))	('cancers', 'Phenotype', 'HP:0002664', (193, 200))	('cancers', 'Disease', (193, 200))	('expression', 'Var', (101, 111))	('OSCC', 'Disease', (212, 216))	('associated', 'Reg', (128, 138))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('alpha-SMA', 'Var', (115, 124))
250274	33081066	In our previous study comparing EX-st and ED-st in human tissues, the alpha-SMA-positive rate was significantly higher in ED-st than in EX-st, consistent with the results of this study.	('human', 'Species', '9606', (51, 56))	('alpha-SMA-positive', 'MPA', (70, 88))	('ED-st', 'Var', (122, 127))	('higher', 'PosReg', (112, 118))
250277	33081066	In particular, EX-st CM increased tumor cell proliferation in a concentration-dependent manner at day 7 (Figure 2a).	('tumor', 'Disease', (34, 39))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('increased', 'PosReg', (24, 33))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('EX-st CM', 'Var', (15, 23))
250280	33081066	A comparison of the HSC-2/ED-st co-culture group and HSC-2/EX-st co-culture group in vitro and in vivo showed that ED-st more strongly promoted tumor cell growth and more dramatically stimulated the invasive ability of tumor cells than EX-st.	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('promoted', 'PosReg', (135, 143))	('tumor', 'Disease', (144, 149))	('stimulated', 'PosReg', (184, 194))	('tumor', 'Disease', (219, 224))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('ED-st', 'Var', (115, 120))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('tumor', 'Disease', 'MESH:D009369', (219, 224))
250343	30003189	Based on the genetic alteration of esophageal SCC, p53 is reportedly one of the key molecules in the diagnosis and in the treatment of esophageal SCC.7 The most frequently mutated gene identified in esophageal SCC is the p53 gene, and its mutation and/or protein overexpression are observed in 40%-60% of patients with esophageal cancer:even in the early phase of carcinogenesis.8, 9 Because p53 alteration was a good predictor for treatment response and survival in esophageal SCC, the 5-year survival rate in the p53-normal group was significantly higher than that in the p53-alteration group.10, 11, 12 The overexpression of p53 protein usually results from genetic alterations modifying protein conformation and stability.7, 8 Such p53 protein alteration frequently induces p53 autoantibodies (s-p53 Abs) in esophageal SCC.	('esophageal SCC', 'Disease', (35, 49))	('p53', 'Gene', (51, 54))	('p53', 'Gene', (574, 577))	('p53', 'Gene', (392, 395))	('carcinogenesis', 'Disease', 'MESH:D063646', (364, 378))	('esophageal SCC', 'Disease', (812, 826))	('esophageal SCC', 'Disease', 'MESH:D004941', (35, 49))	('SCC', 'Phenotype', 'HP:0002860', (478, 481))	('esophageal SCC', 'Disease', 'MESH:D004941', (812, 826))	('esophageal SCC', 'Disease', (199, 213))	('induces', 'Reg', (770, 777))	('p53', 'Gene', '7157', (778, 781))	('p53', 'Gene', (628, 631))	('esophageal SCC', 'Disease', 'MESH:D004941', (199, 213))	('p53', 'Gene', '7157', (515, 518))	('esophageal SCC', 'Disease', (135, 149))	('p53', 'Gene', '7157', (221, 224))	('esophageal SCC', 'Disease', 'MESH:D004941', (135, 149))	('p53', 'Gene', (778, 781))	('SCC', 'Phenotype', 'HP:0002860', (46, 49))	('esophageal SCC', 'Disease', (467, 481))	('p53', 'Gene', '7157', (800, 803))	('SCC', 'Phenotype', 'HP:0002860', (823, 826))	('p53', 'Gene', (515, 518))	('esophageal cancer', 'Disease', 'MESH:D004938', (319, 336))	('esophageal SCC', 'Disease', 'MESH:D004941', (467, 481))	('p53', 'Gene', '7157', (736, 739))	('alteration', 'Var', (748, 758))	('p53', 'Gene', (221, 224))	('patients', 'Species', '9606', (305, 313))	('p53', 'Gene', (800, 803))	('esophageal cancer', 'Disease', (319, 336))	('p53', 'Gene', '7157', (51, 54))	('p53', 'Gene', '7157', (574, 577))	('p53', 'Gene', (736, 739))	('cancer', 'Phenotype', 'HP:0002664', (330, 336))	('SCC', 'Phenotype', 'HP:0002860', (210, 213))	('p53', 'Gene', '7157', (392, 395))	('carcinogenesis', 'Disease', (364, 378))	('SCC', 'Phenotype', 'HP:0002860', (146, 149))	('protein', 'Protein', (740, 747))	('p53', 'Gene', '7157', (628, 631))
250354	30003189	Clinical impact of s-p53 Abs in surveillance of high-risk patients was reported.18 Cawley et al detected s-p53 Abs in four patients with Barrett's esophagus, including one with dysplasia that later progressed to adenocarcinoma.	('Abs', 'Var', (111, 114))	("Barrett's esophagus", 'Disease', 'MESH:D001471', (137, 156))	('p53', 'Gene', (107, 110))	('progressed', 'Reg', (198, 208))	('p53', 'Gene', '7157', (21, 24))	('p53', 'Gene', '7157', (107, 110))	('adenocarcinoma', 'Disease', (212, 226))	('dysplasia', 'Disease', (177, 186))	('patients', 'Species', '9606', (123, 131))	('carcinoma', 'Phenotype', 'HP:0030731', (217, 226))	("Barrett's esophagus", 'Disease', (137, 156))	('adenocarcinoma', 'Disease', 'MESH:D000230', (212, 226))	('dysplasia', 'Disease', 'MESH:D004476', (177, 186))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (137, 156))	('patients', 'Species', '9606', (58, 66))	('p53', 'Gene', (21, 24))
250372	30003189	Generally, the genetic alteration of p53 could induce s-p53 Abs in patients with other gastroenterological cancers.	('gastroenterological cancers', 'Disease', (87, 114))	('patients', 'Species', '9606', (67, 75))	('p53', 'Gene', (56, 59))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('p53', 'Gene', '7157', (56, 59))	('gastroenterological cancers', 'Disease', 'MESH:D009369', (87, 114))	('p53', 'Gene', (37, 40))	('p53', 'Gene', '7157', (37, 40))	('induce', 'Reg', (47, 53))	('cancers', 'Phenotype', 'HP:0002664', (107, 114))	('genetic alteration', 'Var', (15, 33))
250377	30003189	Further analysis on such patients with very high titers should be carried out to evaluate the anti-tumoral effects of the presence of s-p53 Abs.	('tumor', 'Disease', (99, 104))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('patients', 'Species', '9606', (25, 33))	('p53', 'Gene', (136, 139))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('presence', 'Var', (122, 130))	('p53', 'Gene', '7157', (136, 139))
250383	30003189	Eight patients had tumors with p53 mutations among exons 5 to 8.	('p53', 'Gene', '7157', (31, 34))	('p53', 'Gene', (31, 34))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('tumors', 'Disease', (19, 25))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('patients', 'Species', '9606', (6, 14))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('mutations', 'Var', (35, 44))
250412	33936872	Squamous Cell Carcinoma of the Lung in McCune-Albright Syndrome McCune Albright Syndrome (MAS) is caused by a mutation in the GNAS gene that results in multiple endocrinopathies such as Cushing syndrome, acromegaly, hyperthyroidism, and precocious puberty.	('hyperthyroidism', 'Disease', (216, 231))	('caused by', 'Reg', (98, 107))	('endocrinopathies', 'Disease', 'MESH:C567425', (161, 177))	('Cushing syndrome', 'Disease', 'MESH:D003480', (186, 202))	('precocious puberty', 'Disease', (237, 255))	('Carcinoma', 'Phenotype', 'HP:0030731', (14, 23))	('hyperthyroidism', 'Disease', 'MESH:D006980', (216, 231))	('Cushing syndrome', 'Phenotype', 'HP:0003118', (186, 202))	('Carcinoma of the Lung', 'Phenotype', 'HP:0100526', (14, 35))	('Cushing syndrome', 'Disease', (186, 202))	('endocrinopathies', 'Disease', (161, 177))	('McCune Albright Syndrome', 'Disease', 'MESH:D005357', (64, 88))	('Squamous Cell Carcinoma', 'Disease', 'MESH:D002294', (0, 23))	('GNAS', 'Gene', (126, 130))	('McCune-Albright Syndrome', 'Disease', (39, 63))	('precocious puberty', 'Phenotype', 'HP:0000826', (237, 255))	('Squamous Cell Carcinoma of the Lung', 'Phenotype', 'HP:0030359', (0, 35))	('hyperthyroidism', 'Phenotype', 'HP:0000836', (216, 231))	('GNAS', 'Gene', '2778', (126, 130))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (0, 23))	('McCune-Albright Syndrome', 'Disease', 'MESH:D005357', (39, 63))	('mutation', 'Var', (110, 118))	('acromegaly', 'Disease', 'MESH:D000172', (204, 214))	('Squamous Cell Carcinoma', 'Disease', (0, 23))	('results in', 'Reg', (141, 151))	('acromegaly', 'Phenotype', 'HP:0000845', (204, 214))	('acromegaly', 'Disease', (204, 214))	('McCune Albright Syndrome', 'Disease', (64, 88))
250413	33936872	Despite the presence of pleiotropy coupled with a GNAS gene mutation, malignancy is a rare occurrence in MAS.	('mutation', 'Var', (60, 68))	('malignancy', 'Disease', 'MESH:D009369', (70, 80))	('malignancy', 'Disease', (70, 80))	('GNAS', 'Gene', '2778', (50, 54))	('GNAS', 'Gene', (50, 54))
250419	33936872	Current literature shows that the GNAS mutation is an oncogenic driver in many tumor types such as pancreatic adenocarcinoma, adrenocortical carcinoma, and thyroid carcinoma; however, current data are limited on the role of GNAS mutations in SCC of the lung.	('GNAS', 'Gene', '2778', (224, 228))	('pancreatic adenocarcinoma', 'Disease', (99, 124))	('thyroid carcinoma', 'Disease', (156, 173))	('adrenocortical carcinoma', 'Disease', (126, 150))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (156, 173))	('mutations', 'Var', (229, 238))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D000230', (99, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('tumor', 'Disease', (79, 84))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (99, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (164, 173))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('SCC', 'Phenotype', 'HP:0002860', (242, 245))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (126, 150))	('mutation', 'Var', (39, 47))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('GNAS', 'Gene', (34, 38))	('GNAS', 'Gene', (224, 228))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (156, 173))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (126, 150))	('GNAS', 'Gene', '2778', (34, 38))
250424	33936872	Patients with MAS exhibit somatic mosaicism of the GNAS gene, more specifically mutations in the Gs alpha subunit of the cyclic adenosine monophosphate (cAMP) regulating protein.	('GNAS', 'Gene', '2778', (51, 55))	('phosphate', 'Chemical', 'MESH:D010710', (142, 151))	('cAMP', 'Chemical', 'MESH:D000242', (153, 157))	('mutations', 'Var', (80, 89))	('adenosine', 'Chemical', 'MESH:D000241', (128, 137))	('MAS', 'Disease', (14, 17))	('GNAS', 'Gene', (51, 55))	('Patients', 'Species', '9606', (0, 8))
250425	33936872	Patients with MAS have a gain-of-function mutation in the GNAS gene causing adenylate cyclase to be constitutively activated thus ultimately creating an overproduction of hormones and intracellular signals.	('adenylate cyclase', 'Enzyme', (76, 93))	('GNAS', 'Gene', '2778', (58, 62))	('MAS', 'Disease', (14, 17))	('gain-of-function', 'PosReg', (25, 41))	('Patients', 'Species', '9606', (0, 8))	('mutation', 'Var', (42, 50))	('GNAS', 'Gene', (58, 62))
250426	33936872	GNAS mutations have been shown to play an oncogenic role in the pathogenesis of thyroid, pituitary, and pancreatic carcinomas.	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('carcinomas', 'Phenotype', 'HP:0030731', (115, 125))	('mutations', 'Var', (5, 14))	('GNAS', 'Gene', (0, 4))	('pancreatic carcinomas', 'Disease', (104, 125))	('thyroid', 'Disease', (80, 87))	('pituitary', 'Disease', (89, 98))	('pancreatic carcinomas', 'Disease', 'MESH:D010190', (104, 125))	('GNAS', 'Gene', '2778', (0, 4))
250454	33936872	Patients with MAS have a GNAS mutation, which has been known to play a role in the pathogenesis of many endocrine cancers such as pancreatic adenocarcinoma, gastric carcinoma, and thyroid carcinoma.	('cancers', 'Phenotype', 'HP:0002664', (114, 121))	('thyroid carcinoma', 'Disease', (180, 197))	('mutation', 'Var', (30, 38))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('role', 'Reg', (71, 75))	('gastric carcinoma', 'Disease', 'MESH:D013274', (157, 174))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (180, 197))	('endocrine cancers', 'Disease', (104, 121))	('gastric carcinoma', 'Disease', (157, 174))	('Patients', 'Species', '9606', (0, 8))	('GNAS', 'Gene', '2778', (25, 29))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (157, 174))	('carcinoma', 'Phenotype', 'HP:0030731', (165, 174))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D000230', (130, 155))	('endocrine cancers', 'Disease', 'MESH:D004701', (104, 121))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (130, 155))	('carcinoma', 'Phenotype', 'HP:0030731', (188, 197))	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('GNAS', 'Gene', (25, 29))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (180, 197))	('pancreatic adenocarcinoma', 'Disease', (130, 155))
250455	33936872	Patients with MAS have mosaicism of the GNAS mutation, thus the mutation is only present in some of the body's cells but not others.	('MAS', 'Disease', (14, 17))	('GNAS', 'Gene', '2778', (40, 44))	('Patients', 'Species', '9606', (0, 8))	('mutation', 'Var', (45, 53))	('mosaicism', 'Var', (23, 32))	('GNAS', 'Gene', (40, 44))
250456	33936872	If the mutation in GNAS is ubiquitous throughout the body, the mutation would be lethal and lead to loss of the zygote in utero.	('GNAS', 'Gene', (19, 23))	('mutation', 'Var', (63, 71))	('GNAS', 'Gene', '2778', (19, 23))	('mutation', 'Var', (7, 15))	('loss', 'NegReg', (100, 104))
250457	33936872	The presence of the GNAS mutation can lead to a significant tissue burden in several organs, but interestingly, the prevalence of malignancy in MAS is extremely rare.	('malignancy', 'Disease', (130, 140))	('tissue burden in several organs', 'MPA', (60, 91))	('mutation', 'Var', (25, 33))	('GNAS', 'Gene', (20, 24))	('lead to', 'Reg', (38, 45))	('malignancy', 'Disease', 'MESH:D009369', (130, 140))	('presence', 'Var', (4, 12))	('GNAS', 'Gene', '2778', (20, 24))
250458	33936872	It is postulated this may be due to the weak cumulative oncogenic effect of GNAS mutations; the ratio of cells with the GNAS mutation to the normal variant in cells is extremely small thus suggesting the interaction of external oncogenic pathways may be necessary for cancer pathogenesis.	('cancer', 'Disease', (268, 274))	('GNAS', 'Gene', (120, 124))	('GNAS', 'Gene', '2778', (76, 80))	('cancer', 'Phenotype', 'HP:0002664', (268, 274))	('mutations', 'Var', (81, 90))	('GNAS', 'Gene', '2778', (120, 124))	('cancer', 'Disease', 'MESH:D009369', (268, 274))	('GNAS', 'Gene', (76, 80))	('mutation', 'Var', (125, 133))
250459	33936872	The weak cumulative oncogenic effect of the GNAS mutation can also be a potential explanation for why the patient presented with malignancy at the age of 72 and not earlier on in her life.	('GNAS', 'Gene', (44, 48))	('malignancy', 'Disease', (129, 139))	('patient', 'Species', '9606', (106, 113))	('mutation', 'Var', (49, 57))	('GNAS', 'Gene', '2778', (44, 48))	('malignancy', 'Disease', 'MESH:D009369', (129, 139))
250463	33936872	Smoking may have been the necessary extrinsic factor that amplified the initially weak cumulative effect of the GNAS mutation to develop into squamous cell carcinoma of the lung.	('develop', 'Reg', (129, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (156, 165))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (142, 165))	('GNAS', 'Gene', (112, 116))	('squamous cell carcinoma of the lung', 'Phenotype', 'HP:0030359', (142, 177))	('squamous cell carcinoma', 'Disease', (142, 165))	('carcinoma of the lung', 'Phenotype', 'HP:0100526', (156, 177))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (142, 165))	('mutation', 'Var', (117, 125))	('GNAS', 'Gene', '2778', (112, 116))
250464	33936872	Further research comparing individuals who smoke and have the GNAS mutation to individuals who are just smokers can help quantify the role smoking has on patients with a GNAS mutation.	('mutation', 'Var', (67, 75))	('GNAS', 'Gene', '2778', (62, 66))	('GNAS', 'Gene', '2778', (170, 174))	('patients', 'Species', '9606', (154, 162))	('GNAS', 'Gene', (62, 66))	('GNAS', 'Gene', (170, 174))
250486	33936872	Overall, in this case report, we highlight the importance of investigating the oncogenic effects of GNAS mutations and their potential for squamous cell carcinoma.	('GNAS', 'Gene', '2778', (100, 104))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (139, 162))	('carcinoma', 'Phenotype', 'HP:0030731', (153, 162))	('squamous cell carcinoma', 'Disease', (139, 162))	('GNAS', 'Gene', (100, 104))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (139, 162))	('mutations', 'Var', (105, 114))
250493	31908889	Smohaze exert hazardous effects on exposed populations, including induction of a large amount of mutations in the genome, alternative splicing of mRNAs, abnormalities in epigenomics, initiation of tumor-promoting chronic inflammation, and facilitating immune escape of transformed cells.	('mutations', 'Var', (97, 106))	('immune escape of transformed cells', 'CPA', (252, 286))	('mRNAs', 'Gene', (146, 151))	('tumor-promoting chronic inflammation', 'Disease', (197, 233))	('induction', 'Reg', (66, 75))	('abnormalities', 'Var', (153, 166))	('alternative splicing', 'Var', (122, 142))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('epigenomics', 'Gene', (170, 181))	('tumor-promoting chronic inflammation', 'Disease', 'MESH:D007249', (197, 233))
250500	31908889	Targeted therapies include inhibitors of tyrosine kinases EGFR, MET, HER2, and BRAF V600, inhibitors of fusion proteins involved ALK, ROS1, RET, and TRK, antibodies against VEGF, and others.	('antibodies', 'Var', (154, 164))	('VEGF', 'Gene', (173, 177))	('RET', 'Gene', (140, 143))	('BRAF', 'Gene', '673', (79, 83))	('BRAF', 'Gene', (79, 83))	('ROS1', 'Gene', (134, 138))	('EGFR', 'Gene', (58, 62))	('tyrosine kinases', 'Enzyme', (41, 57))	('fusion proteins', 'Protein', (104, 119))	('tyrosine', 'Chemical', 'None', (41, 49))	('ALK', 'Gene', '238', (129, 132))	('HER2', 'Gene', '2064', (69, 73))	('ALK', 'Gene', (129, 132))	('inhibitors', 'Var', (90, 100))	('TRK', 'Gene', (149, 152))	('RET', 'Gene', '5979', (140, 143))	('ROS1', 'Gene', '6098', (134, 138))	('HER2', 'Gene', (69, 73))	('TRK', 'Gene', '4914', (149, 152))	('VEGF', 'Gene', '7422', (173, 177))
250526	31908889	These findings had been cited in the IARC monograph classifying HAP as "carcinogenic to humans (group 1)".	('carcinogenic', 'Disease', 'MESH:D063646', (72, 84))	('HAP', 'Var', (64, 67))	('humans', 'Species', '9606', (88, 94))	('carcinogenic', 'Disease', (72, 84))
250533	31908889	PM2.5 are inhaled, and cause diseases such as respiratory infections, cardiovascular disease, chronic obstructive pulmonary disease (COPD), and cancers.	('COPD', 'Disease', 'MESH:D029424', (133, 137))	('COPD', 'Disease', (133, 137))	('cause', 'Reg', (23, 28))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('PM2.5', 'Var', (0, 5))	('cardiovascular disease', 'Phenotype', 'HP:0001626', (70, 92))	('respiratory infections', 'Phenotype', 'HP:0011947', (46, 68))	('chronic obstructive pulmonary disease', 'Phenotype', 'HP:0006510', (94, 131))	('cancers', 'Phenotype', 'HP:0002664', (144, 151))	('cardiovascular disease', 'Disease', 'MESH:D002318', (70, 92))	('cancers', 'Disease', (144, 151))	('chronic obstructive pulmonary disease', 'Disease', 'MESH:D029424', (94, 131))	('cardiovascular disease', 'Disease', (70, 92))	('chronic obstructive pulmonary disease', 'Disease', (94, 131))	('respiratory infections', 'Disease', (46, 68))	('obstructive pulmonary disease', 'Phenotype', 'HP:0006536', (102, 131))	('respiratory infections', 'Disease', 'MESH:D012141', (46, 68))	('cancers', 'Disease', 'MESH:D009369', (144, 151))	('COPD', 'Phenotype', 'HP:0006510', (133, 137))
250544	31908889	As compared with counterpart normal controls, cancer genomes usually have six types of nucleotide changes, C T/G A, C A/G T, C G/G C, A G/T C, A T/T A, and A C/T G. Smohaze carcinogens can cause characteristic mutations (or signature) in the genome.	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('C A/G T', 'Var', (116, 123))	('C G/G', 'Var', (125, 130))	('cancer', 'Disease', (46, 52))	('T/T A', 'Var', (145, 150))	('cause', 'Reg', (189, 194))	('C/T G. Smohaze', 'Var', (158, 172))	('C T/G A', 'Var', (107, 114))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('mutations', 'MPA', (210, 219))	('G/T C', 'Var', (136, 141))
250545	31908889	For example, the G to T transversions have been described as a mutational fingerprint of tobacco smoke mutagens in smoking-associated lung cancers, and smokers more frequently show G T transversions, whereas never-smokers have more G A transitions.	('lung cancer', 'Phenotype', 'HP:0100526', (134, 145))	('tobacco', 'Species', '4097', (89, 96))	('cancers', 'Phenotype', 'HP:0002664', (139, 146))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('lung cancers', 'Disease', 'MESH:D008175', (134, 146))	('G to T', 'Var', (17, 23))	('lung cancers', 'Phenotype', 'HP:0100526', (134, 146))	('G T transversions', 'Var', (181, 198))	('lung cancers', 'Disease', (134, 146))
250547	31908889	NNK may induce both G T and G A mutations, and 4-aminobiphenyl and 1,3-butadiene cause the A T transversions.	('G T', 'Gene', (20, 23))	('4-aminobiphenyl', 'Chemical', 'MESH:C006757', (47, 62))	('induce', 'Reg', (8, 14))	('mutations', 'Var', (32, 41))	('NNK', 'Chemical', 'MESH:C016583', (0, 3))	('1,3-butadiene', 'Chemical', 'MESH:C031763', (67, 80))	('G A', 'Gene', (28, 31))
250548	31908889	These mutations were firstly reported in genes such as TP53, RAS, and others.	('RAS', 'Disease', (61, 64))	('TP53', 'Gene', (55, 59))	('mutations', 'Var', (6, 15))	('TP53', 'Gene', '7157', (55, 59))
250550	31908889	showed that the rate of TP53 mutations increased from 47.5% in never-smokers to 77.4% in active smokers, and the risk of having a TP53 mutation was significantly proportional to the amount of tobacco consumed.	('TP53', 'Gene', (24, 28))	('tobacco', 'Species', '4097', (192, 199))	('mutations', 'Var', (29, 38))	('TP53', 'Gene', '7157', (130, 134))	('TP53', 'Gene', (130, 134))	('TP53', 'Gene', '7157', (24, 28))
250551	31908889	KRAS mutations are much more frequent in smokers, in that in active smokers and never-smokers the KRAS mutation rates were 34% and 5%, respectively.	('mutations', 'Var', (5, 14))	('KRAS', 'Gene', (98, 102))	('KRAS', 'Gene', '3845', (98, 102))	('KRAS', 'Gene', (0, 4))	('KRAS', 'Gene', '3845', (0, 4))
250552	31908889	BRAF mutations are significantly more frequent in smokers (active or former).	('smokers', 'Disease', (50, 57))	('mutations', 'Var', (5, 14))	('BRAF', 'Gene', '673', (0, 4))	('BRAF', 'Gene', (0, 4))	('frequent', 'Reg', (38, 46))
250553	31908889	On the contrary, EGFR mutations and ALK rearrangements are much more frequent in never-smokers compared to active smokers.	('ALK', 'Gene', '238', (36, 39))	('frequent', 'Reg', (69, 77))	('mutations', 'Var', (22, 31))	('rearrangements', 'Var', (40, 54))	('ALK', 'Gene', (36, 39))	('EGFR', 'Gene', (17, 21))
250554	31908889	further reported significant differences between smokers and never-smokers for mutations in EGFR (4.5% vs. 36.3%), ALK (3.5% vs. 9.7%), KRAS (31.7% vs. 9.6%), BRAF (1.6% vs. 1.8%), and HER2 (0.2% vs. 3.8%), respectively (Table 2).	('ALK', 'Gene', (115, 118))	('KRAS', 'Gene', '3845', (136, 140))	('BRAF', 'Gene', (159, 163))	('ALK', 'Gene', '238', (115, 118))	('KRAS', 'Gene', (136, 140))	('HER2', 'Gene', (185, 189))	('EGFR', 'Gene', (92, 96))	('BRAF', 'Gene', '673', (159, 163))	('HER2', 'Gene', '2064', (185, 189))	('mutations', 'Var', (79, 88))
250561	31908889	Whole genome sequencing revealed a mean of 289 somatic exonic mutations per tumor and the C:G A:T nucleotide substitutions in XW NSCLCs.	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('C:G A:T nucleotide substitutions', 'Var', (90, 122))	('NSCLC', 'Disease', (129, 134))	('NSCLC', 'Disease', 'MESH:D002289', (129, 134))	('SCLC', 'Phenotype', 'HP:0030357', (130, 134))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
250564	31908889	The mutation rates of 70 genes (e.g., RYR2, MYH3, GPR144, CACNA1E) were associated with patients' lifetime BaP exposure.	('MYH3', 'Gene', '4621', (44, 48))	('RYR2', 'Gene', '6262', (38, 42))	('patients', 'Species', '9606', (88, 96))	('associated', 'Reg', (72, 82))	('mutation', 'Var', (4, 12))	('GPR144', 'Gene', '347088', (50, 56))	('GPR144', 'Gene', (50, 56))	('CACNA1E', 'Gene', (58, 65))	('RYR2', 'Gene', (38, 42))	('MYH3', 'Gene', (44, 48))	('CACNA1E', 'Gene', '777', (58, 65))
250568	31908889	The C:G T:A transitions, a signature of tobacco carcinogen N-methyl-N-nitro-N-nitrosoguanidine, were the predominant nucleotide changes in counterpart normal controls (CNCs) of LUAD and LUSC.	('tobacco', 'Species', '4097', (40, 47))	('N-methyl-N-nitro-N-nitrosoguanidine', 'Chemical', 'MESH:D008769', (59, 94))	('LUSC', 'Disease', 'MESH:D002294', (186, 190))	('LUSC', 'Phenotype', 'HP:0030359', (186, 190))	('LUSC', 'Disease', (186, 190))	('C:G T:A transitions', 'Var', (4, 23))	('LUAD', 'Phenotype', 'HP:0030078', (177, 181))	('LUAD', 'Disease', (177, 181))	('LUAD', 'Disease', 'MESH:C538231', (177, 181))
250569	31908889	One possibility was that some of the mutated genes were pro-oncogenes (e.g., MUC4 and CDC27) or tumor suppressors (e.g., NCOR1), cells harboring these variations were in a "precancerous" stage, and accumulation of other mutations would result in transformation and development of malignant neoplasms.	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('result in', 'Reg', (236, 245))	('cancerous', 'Disease', 'MESH:D009369', (176, 185))	('MUC4', 'Gene', '4585', (77, 81))	('transformation', 'CPA', (246, 260))	('genes', 'Gene', (45, 50))	('MUC4', 'Gene', (77, 81))	('NCOR1', 'Gene', (121, 126))	('malignant neoplasms', 'Disease', (280, 299))	('malignant neoplasms', 'Disease', 'MESH:D009369', (280, 299))	('NCOR1', 'Gene', '9611', (121, 126))	('neoplasms', 'Phenotype', 'HP:0002664', (290, 299))	('mutated', 'Var', (37, 44))	('mutations', 'Var', (220, 229))	('CDC27', 'Gene', '996', (86, 91))	('cancerous', 'Disease', (176, 185))	('variations', 'Var', (151, 161))	('tumor', 'Disease', (96, 101))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('CDC27', 'Gene', (86, 91))	('development', 'CPA', (265, 276))
250571	31908889	Alternative splicing, the process by which splice sites are differentially utilized to produce different mRNA isoforms, contributes to oncogenic activation in several types of cancers.	('cancers', 'Disease', (176, 183))	('cancers', 'Disease', 'MESH:D009369', (176, 183))	('oncogenic activation', 'MPA', (135, 155))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('Alternative splicing', 'Var', (0, 20))	('cancers', 'Phenotype', 'HP:0002664', (176, 183))
250573	31908889	showed that of the 117 lung cancer tissue samples analyzed, 31 (26.5%) had splice variants for the MDM2 gene, with 26 samples bearing a splice variant lacking exons 3-11.	('lung cancer', 'Disease', (23, 34))	('lung cancer', 'Phenotype', 'HP:0100526', (23, 34))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('MDM2', 'Gene', '4193', (99, 103))	('MDM2', 'Gene', (99, 103))	('lung cancer', 'Disease', 'MESH:D008175', (23, 34))	('splice variants', 'Var', (75, 90))
250577	31908889	BPDE-induced MDM2 mRNA alternative splicing in H1355 cells may occur through the PI3K or MAPK pathway.	('mRNA alternative splicing', 'Var', (18, 43))	('BPDE', 'Chemical', 'MESH:D015123', (0, 4))	('MDM2', 'Gene', '4193', (13, 17))	('MDM2', 'Gene', (13, 17))	('PI3K', 'Pathway', (81, 85))	('H1355', 'CellLine', 'CVCL:1464', (47, 52))
250578	31908889	We recently reported a splicing variant of Focal adhesion kinase (FAK), FAK, that contains alternatively spliced exons of 18 bp (Box 6) and 21 bp (Box 7) on either side of codon for Y397 in 4 (4.4%) of 91 patients with NSCLC.	('NSCLC', 'Disease', (219, 224))	('SCLC', 'Phenotype', 'HP:0030357', (220, 224))	('patients', 'Species', '9606', (205, 213))	('NSCLC', 'Disease', 'MESH:D002289', (219, 224))	('FAK', 'Gene', '5747', (72, 75))	('FAK', 'Gene', (66, 69))	('FAK', 'Gene', '5747', (66, 69))	('FAK', 'Gene', (72, 75))	('Y397', 'Var', (182, 186))
250580	31908889	In TCGA RNA-seq data, Box 6/7-containing FAK variants were positive in 42 (8.3%) of 508 LUADs and 37 (7.4%) of 501 LUSCs, and current smokers had higher expression of Box 6/7 (+) FAK than reformed and never smokers.	('higher', 'PosReg', (146, 152))	('variants', 'Var', (45, 53))	('LUSC', 'Disease', 'MESH:D002294', (115, 119))	('LUSC', 'Disease', (115, 119))	('LUSC', 'Phenotype', 'HP:0030359', (115, 119))	('FAK', 'Gene', (41, 44))	('FAK', 'Gene', '5747', (41, 44))	('FAK', 'Gene', (179, 182))	('FAK', 'Gene', '5747', (179, 182))	('LUAD', 'Phenotype', 'HP:0030078', (88, 92))	('expression', 'MPA', (153, 163))	('LUAD', 'Disease', (88, 92))	('LUAD', 'Disease', 'MESH:C538231', (88, 92))
250582	31908889	Cancer has been considered as a disease of the genome, and genomic mutations have been shown to be critical to tumorigenesis and served as targets for drug development.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('mutations', 'Var', (67, 76))	('Cancer', 'Disease', (0, 6))	('tumor', 'Disease', (111, 116))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))
250589	31908889	We recently found that AhR mediated smohaze-induced PD-L1 expression on lung epithelial cells, and deficiency in AhR significantly suppresses BaP-induced lung cancer.	('lung cancer', 'Disease', (154, 165))	('deficiency', 'Var', (99, 109))	('lung cancer', 'Phenotype', 'HP:0100526', (154, 165))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('AhR', 'Gene', (113, 116))	('lung cancer', 'Disease', 'MESH:D008175', (154, 165))	('suppresses', 'NegReg', (131, 141))
250590	31908889	AhR inhibitors alpha-naphthoflavone (ANF) and CH223191 exert significant antitumor activity in lung cancer mouse models.	('lung cancer', 'Disease', (95, 106))	('ANF', 'Chemical', 'MESH:C011512', (37, 40))	('CH223191', 'Chemical', 'MESH:C511621', (46, 54))	('lung cancer', 'Phenotype', 'HP:0100526', (95, 106))	('alpha-naphthoflavone', 'Chemical', 'MESH:C011512', (15, 35))	('mouse', 'Species', '10090', (107, 112))	('CH223191', 'Var', (46, 54))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('lung cancer', 'Disease', 'MESH:D008175', (95, 106))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Disease', (77, 82))
250596	31908889	Silencing CIP2A inhibited the proliferation and clonogenic activity of lung cancer cells.	('inhibited', 'NegReg', (16, 25))	('CIP2A', 'Gene', (10, 15))	('clonogenic activity', 'CPA', (48, 67))	('lung cancer', 'Disease', 'MESH:D008175', (71, 82))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('CIP2A', 'Gene', '57650', (10, 15))	('Silencing', 'Var', (0, 9))	('lung cancer', 'Disease', (71, 82))	('lung cancer', 'Phenotype', 'HP:0100526', (71, 82))
250599	31908889	Silencing IRX5 significantly inhibited tumor growth in nude mice.	('inhibited', 'NegReg', (29, 38))	('nude mice', 'Species', '10090', (55, 64))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('IRX5', 'Gene', (10, 14))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumor', 'Disease', (39, 44))	('Silencing', 'Var', (0, 9))
250601	31908889	In EGFR-L858R and EGFR-T790M/Del(exon 19)-driven lung cancer in mice, knockdown of CDC34 significantly inhibited tumor formation.	('tumor', 'Disease', (113, 118))	('L858R', 'Mutation', 'rs121434568', (8, 13))	('T790M', 'SUBSTITUTION', 'None', (23, 28))	('lung cancer', 'Disease', 'MESH:D008175', (49, 60))	('T790M', 'Var', (23, 28))	('CDC34', 'Gene', (83, 88))	('inhibited', 'NegReg', (103, 112))	('lung cancer', 'Disease', (49, 60))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('lung cancer', 'Phenotype', 'HP:0100526', (49, 60))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('EGFR-L858R', 'Var', (3, 13))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('mice', 'Species', '10090', (64, 68))
250606	31908889	CDKN2A hypermethylation was significantly associated with cigarette smoking in Japanese, Chinese and Americans, whereas RARB hypermethylation was associated with smoking status in Chinese patients.	('hypermethylation', 'Var', (7, 23))	('CDKN2A', 'Gene', '1029', (0, 6))	('cigarette smoking', 'Disease', (58, 75))	('associated', 'Reg', (42, 52))	('patients', 'Species', '9606', (188, 196))	('RARB', 'Gene', (120, 124))	('CDKN2A', 'Gene', (0, 6))	('RARB', 'Gene', '5915', (120, 124))
250609	31908889	BaP-induced DKK2 and EN1 promoter hypermethylation and LPAR2 promoter hypomethylation led to down-regulation and up-regulation of the genes, respectively; the down-regulation of DKK2 and EN1 promoted cellular proliferation.	('down-regulation', 'NegReg', (159, 174))	('EN1', 'Gene', (187, 190))	('down-regulation', 'NegReg', (93, 108))	('promoted', 'PosReg', (191, 199))	('cellular proliferation', 'CPA', (200, 222))	('LPAR2', 'Gene', '9170', (55, 60))	('EN1', 'Gene', '2019', (187, 190))	('DKK2', 'Gene', (178, 182))	('DKK2', 'Gene', '27123', (178, 182))	('LPAR2', 'Gene', (55, 60))	('EN1', 'Gene', (21, 24))	('EN1', 'Gene', '2019', (21, 24))	('up-regulation', 'PosReg', (113, 126))	('DKK2', 'Gene', (12, 16))	('DKK2', 'Gene', '27123', (12, 16))	('promoter hypermethylation', 'Var', (25, 50))
250614	31908889	analyzed the expression of 484 miRNAs in the lungs of rats exposed to environmental cigarette smoke (ECS), and found that ECS down-regulated 126 miRNAs (26.0%) at least 2-fold and 24 miRNAs more than 3-fold.	('miR', 'Gene', '22877', (183, 186))	('down-regulated', 'NegReg', (126, 140))	('miR', 'Gene', (31, 34))	('ECS', 'Var', (122, 125))	('miR', 'Gene', (145, 148))	('miR', 'Gene', (183, 186))	('rats', 'Species', '10116', (54, 58))	('miR', 'Gene', '22877', (145, 148))	('miR', 'Gene', '22877', (31, 34))
250617	31908889	showed that cigarette smoke upregulates miR-25-3p maturation via N6-methyladenosine and inhibits PHLPP2 to activate AKT, leading to promotion of pancreatic cancer progression.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (145, 162))	('miR-25', 'Gene', '407014', (40, 46))	('PHLPP2', 'Gene', '23035', (97, 103))	('miR-25', 'Gene', (40, 46))	('pancreatic cancer', 'Disease', (145, 162))	('promotion', 'PosReg', (132, 141))	('pancreatic cancer', 'Disease', 'MESH:D010190', (145, 162))	('AKT', 'Gene', '207', (116, 119))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('activate', 'PosReg', (107, 115))	('N6-methyladenosine', 'Chemical', 'MESH:C010223', (65, 83))	('PHLPP2', 'Gene', (97, 103))	('inhibits', 'NegReg', (88, 96))	('N6-methyladenosine', 'Var', (65, 83))	('AKT', 'Gene', (116, 119))	('upregulates', 'PosReg', (28, 39))
250624	31908889	Cigarette smoke or BaP can induce the expression of several lncRNAs, such as lncRNA-1 (SCAL1), DQ786227, and LOC728228, in cells.	('lncRNA-1', 'Gene', (77, 85))	('expression', 'MPA', (38, 48))	('SCAL1', 'Gene', (87, 92))	('induce', 'PosReg', (27, 33))	('DQ786227', 'Var', (95, 103))	('LOC728228', 'Chemical', 'MESH:C492399', (109, 118))	('LOC728228', 'Var', (109, 118))	('SCAL1', 'Gene', '100505994', (87, 92))	('DQ786227', 'Chemical', 'MESH:D006683', (95, 103))
250634	31908889	Tumor promotion is due to induction of inflammation that results in enhanced pneumocyte proliferation and is abrogated by IKKbeta ablation in myeloid cells or inactivation of JNK1.	('enhanced', 'PosReg', (68, 76))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('IKKbeta', 'Gene', (122, 129))	('IKKbeta', 'Gene', '3551', (122, 129))	('inflammation', 'Disease', 'MESH:D007249', (39, 51))	('inactivation', 'Var', (159, 171))	('ablation', 'Var', (130, 138))	('JNK1', 'Gene', (175, 179))	('pneumocyte proliferation', 'CPA', (77, 101))	('inflammation', 'Disease', (39, 51))	('JNK1', 'Gene', '5599', (175, 179))	('promotion', 'PosReg', (6, 15))
250640	31908889	Deficiency in Cxcl13 or its receptor, Cxcr5, attenuated BaP-induced lung cancer in mice, demonstrating CXCL13's critical role in PAH-induced lung carcinogenesis.	('lung cancer', 'Disease', (68, 79))	('lung cancer', 'Phenotype', 'HP:0100526', (68, 79))	('PAH', 'Chemical', 'MESH:D010130', (129, 132))	('attenuated', 'NegReg', (45, 55))	('lung carcinogenesis', 'Disease', (141, 160))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('mice', 'Species', '10090', (83, 87))	('Cxcl13', 'Gene', (14, 20))	('lung carcinogenesis', 'Disease', 'MESH:D063646', (141, 160))	('Cxcr5', 'Gene', (38, 43))	('lung cancer', 'Disease', 'MESH:D008175', (68, 79))	('Cxcl13', 'Gene', '55985', (14, 20))	('Cxcr5', 'Gene', '12145', (38, 43))	('Deficiency', 'Var', (0, 10))
250644	31908889	Anti-PD-L1 antibody or deficiency in AhR significantly suppresses BaP-induced lung cancer.	('lung cancer', 'Disease', (78, 89))	('deficiency', 'Var', (23, 33))	('lung cancer', 'Phenotype', 'HP:0100526', (78, 89))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('Anti-PD-L1 antibody', 'Protein', (0, 19))	('AhR', 'Gene', (37, 40))	('lung cancer', 'Disease', 'MESH:D008175', (78, 89))	('suppresses', 'NegReg', (55, 65))
250659	31908889	Of course, the less mutated genes usually play important roles in physiological settings, targeting these genes may possibly induce side effects in the patients.	('targeting', 'Var', (90, 99))	('induce', 'Reg', (125, 131))	('patients', 'Species', '9606', (152, 160))
250661	31908889	Inhibition of EGFR gain-of-function mutations marks a revolution in the history of lung cancer treatment, and while resistance occurred the second, third, and even fourth generations of EGFR inhibitors were developed, though drug resistance may develop again.	('lung cancer', 'Disease', 'MESH:D008175', (83, 94))	('EGFR', 'Gene', (14, 18))	('gain-of-function', 'PosReg', (19, 35))	('mutations', 'Var', (36, 45))	('lung cancer', 'Disease', (83, 94))	('lung cancer', 'Phenotype', 'HP:0100526', (83, 94))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('drug resistance', 'Phenotype', 'HP:0020174', (225, 240))
250665	31908889	The discoveries that deficiency in AhR significantly inhibited BaP-induced lung  and skin cancers indicate that inhibition of AhR may exert beneficial effects in prevention and treatment of lung cancer.	('inhibited', 'NegReg', (53, 62))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('skin cancers', 'Phenotype', 'HP:0008069', (85, 97))	('BaP-induced', 'Disease', (63, 74))	('lung cancer', 'Disease', 'MESH:D008175', (190, 201))	('skin cancers', 'Disease', (85, 97))	('deficiency', 'Var', (21, 31))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('skin cancers', 'Disease', 'MESH:D012878', (85, 97))	('lung cancer', 'Disease', (190, 201))	('lung cancer', 'Phenotype', 'HP:0100526', (190, 201))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('AhR', 'Gene', (35, 38))
250666	31908889	Moreover, deficiency in CXCL13 or suppression of PD-L1, both of which are AhR target genes, inhibited BaP-induced lung cancer, further confirming the critical roles of AhR in smohaze-induced lung carcinogenesis.	('inhibited', 'NegReg', (92, 101))	('lung cancer', 'Disease', 'MESH:D008175', (114, 125))	('CXCL13', 'MPA', (24, 30))	('lung carcinogenesis', 'Disease', (191, 210))	('lung cancer', 'Disease', (114, 125))	('lung cancer', 'Phenotype', 'HP:0100526', (114, 125))	('deficiency', 'Var', (10, 20))	('lung carcinogenesis', 'Disease', 'MESH:D063646', (191, 210))	('PD-L1', 'Gene', (49, 54))	('suppression', 'NegReg', (34, 45))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
250678	31827637	In particular, understaging might lead to recurrence or even death after surgery; conversely, overstaging is likely to subject a patient to needless adjuvant chemoradiotherapy.	('death', 'Disease', (61, 66))	('lead to', 'Reg', (34, 41))	('death', 'Disease', 'MESH:D003643', (61, 66))	('understaging', 'Var', (15, 27))
250684	31827637	Finally, the LASSO algorithm was used to shrink and pick out the OS-related lncRNAs (Figure 1), which were AC007907.1, AC025419.1, AC078993.1, AC090241.2, AL158166.1, AL355974.2, AL596330.1, HOXB-AS4, KLHL6-AS1, LHX1-DT, LINC00528, LINC01436, and TTTY14, to build a lncRNA-based signature.	('LINC00528', 'Gene', '200298', (221, 230))	('LINC00528', 'Gene', (221, 230))	('AS1', 'Gene', '5729', (207, 210))	('AL158166.1', 'Var', (155, 165))	('AS1', 'Gene', (207, 210))	('KLHL6', 'Gene', '89857', (201, 206))	('HOXB-AS4', 'Gene', '100874351', (191, 199))	('LHX1', 'Gene', (212, 216))	('KLHL6', 'Gene', (201, 206))	('LINC01436', 'Gene', (232, 241))	('TTTY14', 'Gene', (247, 253))	('LHX1', 'Gene', '3975', (212, 216))	('HOXB-AS4', 'Gene', (191, 199))	('LINC01436', 'Gene', '100996609', (232, 241))	('TTTY14', 'Gene', '83869', (247, 253))	('AL596330.1', 'Var', (179, 189))
250690	31827637	Among the thirteen OS-related lncRNAs, LINC01436 and TTTY14 have been previously reported to be related with cancers, such as in non-small-cell lung cancer (NSCLC), oral squamous cell carcinoma (OSCC), and gastric cancer.	('carcinoma', 'Phenotype', 'HP:0030731', (184, 193))	('gastric cancer', 'Disease', (206, 220))	('NSCLC', 'Disease', (157, 162))	('non-small-cell lung cancer', 'Disease', (129, 155))	('non-small-cell lung cancer', 'Disease', 'MESH:D002289', (129, 155))	('lung cancer', 'Phenotype', 'HP:0100526', (144, 155))	('TTTY14', 'Gene', (53, 59))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (133, 155))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (165, 193))	('cancers', 'Phenotype', 'HP:0002664', (109, 116))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('related', 'Reg', (96, 103))	('oral squamous cell carcinoma', 'Disease', (165, 193))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('LINC01436', 'Var', (39, 48))	('gastric cancer', 'Phenotype', 'HP:0012126', (206, 220))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (170, 193))	('NSCLC', 'Disease', 'MESH:D002289', (157, 162))
250691	31827637	In terms of mechanisms, LINC01436, acting as a microRNA- (miR-) 30a-3p sponge, regulated the expression level of its target gene EPAS1.	('LINC01436', 'Var', (24, 33))	('EPAS1', 'Gene', (129, 134))	('expression level', 'MPA', (93, 109))	('regulated', 'Reg', (79, 88))	('EPAS1', 'Gene', '2034', (129, 134))
250694	31827637	On account of the anonymous database, we cannot extend our database with variables such as race, insurance status, comorbidity, hemoglobin level, albumin, tumor hypoxia, and TP53 mutation, which were frequently reported prognostic factors of patients with LSCC.	('LSCC', 'Disease', (256, 260))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('TP53', 'Gene', (174, 178))	('mutation', 'Var', (179, 187))	('tumor hypoxia', 'Disease', (155, 168))	('albumin', 'Gene', (146, 153))	('tumor hypoxia', 'Disease', 'MESH:D000860', (155, 168))	('albumin', 'Gene', '213', (146, 153))	('TP53', 'Gene', '7157', (174, 178))
250799	26498363	At 4 years, the 5FU/MMC arm had higher colostomy free and disease free survival rates.	('5FU', 'Chemical', 'MESH:D005472', (16, 19))	('higher', 'PosReg', (32, 38))	('colostomy free and disease', 'Disease', 'MESH:D015673', (39, 65))	('MMC', 'Chemical', 'MESH:D016685', (20, 23))	('5FU/MMC', 'Var', (16, 23))
250813	26498363	Separately, a Danish study suggests that mutations of the KRAS, NRAS, or BRAF genes are rare in anal squamous cell carcinoma.	('KRAS', 'Gene', (58, 62))	('mutations', 'Var', (41, 50))	('BRAF', 'Gene', '673', (73, 77))	('KRAS', 'Gene', '3845', (58, 62))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (101, 124))	('NRAS', 'Gene', (64, 68))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (101, 124))	('squamous cell carcinoma', 'Disease', (101, 124))	('NRAS', 'Gene', '4893', (64, 68))	('BRAF', 'Gene', (73, 77))
250830	26498363	Additionally, amplification of EGFR was identified in 7.4% of tumors evaluated.	('EGFR', 'Gene', '1956', (31, 35))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumors', 'Disease', (62, 68))	('tumors', 'Disease', 'MESH:D009369', (62, 68))	('EGFR', 'Gene', (31, 35))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('amplification', 'Var', (14, 27))
250832	26498363	amplification or rearrangement) detected.	('rearrangement', 'Var', (17, 30))	('men', 'Species', '9606', (26, 29))	('amplification', 'Var', (0, 13))
250833	26498363	Next generation gene sequencing identified several mutations involving the PIK3CA/AKT pathway, including PIK3CA PTEN AKT1, and FBXW7.	('PIK3CA', 'Gene', (105, 111))	('AKT', 'Gene', '207', (117, 120))	('PIK3CA', 'Gene', (75, 81))	('PIK3CA PTEN AKT1', 'Gene', '5294', (105, 121))	('mutations', 'Var', (51, 60))	('FBXW7', 'Gene', '55294', (127, 132))	('PIK3CA', 'Gene', '5290', (75, 81))	('PIK3CA PTEN AKT1', 'Gene', (105, 121))	('PIK3CA', 'Gene', '5290', (105, 111))	('AKT', 'Gene', (117, 120))	('AKT', 'Gene', '207', (82, 85))	('FBXW7', 'Gene', (127, 132))	('AKT', 'Gene', (82, 85))
250834	26498363	In specimens evaluated by NGS, KRAS was mutated in 2%.	('KRAS', 'Gene', (31, 35))	('mutated', 'Var', (40, 47))	('men', 'Species', '9606', (8, 11))	('KRAS', 'Gene', '3845', (31, 35))
250845	26498363	ISH analysis suggested few tumors had EGFR mutations.	('EGFR', 'Gene', '1956', (38, 42))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('EGFR', 'Gene', (38, 42))	('tumors', 'Disease', (27, 33))	('tumors', 'Disease', 'MESH:D009369', (27, 33))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('mutations', 'Var', (43, 52))
250846	26498363	Moreover, only 2 tumors demonstrated mutations, which, as is the case in colorectal adenocarcinoma, has been suggested to confer resistance to anti-EGFR antibody therapy in ASCC.	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('tumors', 'Disease', (17, 23))	('EGFR', 'Gene', '1956', (148, 152))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('EGFR', 'Gene', (148, 152))	('colorectal adenocarcinoma', 'Disease', (73, 98))	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (73, 98))	('mutations', 'Var', (37, 46))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
250852	26498363	Although individually occurring in smaller numbers, cumulatively, dysregulation of the PI3K/ATK/mTOR pathway was identified in 60% of the anal squamous cell carcinomas evaluated, consistent with what is being reported.	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (143, 167))	('squamous cell carcinomas', 'Disease', (143, 167))	('carcinomas', 'Phenotype', 'HP:0030731', (157, 167))	('PI3K/ATK/mTOR pathway', 'Pathway', (87, 108))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (143, 167))	('dysregulation', 'Var', (66, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (157, 166))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (143, 166))
250854	26498363	In a transgenic mouse model, Sun has evaluated the role that mTOR plays in anal carcinogenesis, finding that mTOR knockout led to a delay in carcinoma onset, and thus suggesting this as a potential therapeutic target, too.	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('carcinoma onset', 'Disease', (141, 156))	('mTOR', 'Gene', (109, 113))	('carcinoma onset', 'Disease', 'MESH:D002277', (141, 156))	('mouse', 'Species', '10090', (16, 21))	('delay', 'NegReg', (132, 137))	('carcinogenesis', 'Disease', 'MESH:D063646', (80, 94))	('knockout', 'Var', (114, 122))	('carcinogenesis', 'Disease', (80, 94))
250856	26498363	Almost a third of tumors evaluated were non-expressers of methylguanine-DNA-methyltransferase (MGMT) by IHC, suggesting a possible susceptibility to temozolomide.	('methylguanine-DNA-methyltransferase', 'Gene', '4255', (58, 93))	('non-expressers', 'Var', (40, 54))	('tumors', 'Disease', (18, 24))	('susceptibility', 'Reg', (131, 145))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('MGMT', 'Gene', '4255', (95, 99))	('methylguanine-DNA-methyltransferase', 'Gene', (58, 93))	('MGMT', 'Gene', (95, 99))	('temozolomide', 'Chemical', 'MESH:D000077204', (149, 161))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
250860	26498363	However, while not therapeutically evaluated, a retrospective study of PD-L1 positivity was associated with a non-statistically significant trend towards a poorer RFS in ASCC, consistent with what has been observed with other cancer types.	('ASCC', 'Disease', (170, 174))	('RFS', 'MPA', (163, 166))	('PD-L1', 'Gene', (71, 76))	('PD-L1', 'Gene', '29126', (71, 76))	('cancer', 'Disease', (226, 232))	('cancer', 'Disease', 'MESH:D009369', (226, 232))	('poorer', 'NegReg', (156, 162))	('positivity', 'Var', (77, 87))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
250921	31932491	In TCGA cohort, the expression of CNR1 and CNR2 was elevated in HPV positive HNSCC compared with HPV negative HNSCC, and knockdown of CNR1/CNR2 expression inhibited proliferation in HPV positive HNSCC cell lines.	('knockdown', 'Var', (121, 130))	('HPV', 'Species', '10566', (182, 185))	('expression', 'Species', '29278', (144, 154))	('CNR1/CNR2', 'Gene', (134, 143))	('expression', 'MPA', (20, 30))	('HPV', 'Disease', (64, 67))	('HPV', 'Species', '10566', (97, 100))	('HNSCC', 'Phenotype', 'HP:0012288', (110, 115))	('CNR2', 'Gene', (43, 47))	('expression', 'Species', '29278', (20, 30))	('inhibited', 'NegReg', (155, 164))	('CNR1', 'Gene', (34, 38))	('HNSCC', 'Phenotype', 'HP:0012288', (77, 82))	('HNSCC', 'Phenotype', 'HP:0012288', (195, 200))	('proliferation', 'CPA', (165, 178))	('HPV', 'Species', '10566', (64, 67))	('elevated', 'PosReg', (52, 60))
250954	31932491	Rimonabant, SR144528 and SB203580 were dissolved in DMSO.	('SB203580', 'Var', (25, 33))	('Rimonabant', 'Chemical', 'MESH:D000077285', (0, 10))	('SR144528', 'Chemical', 'MESH:C110630', (12, 20))	('SB203580', 'Chemical', 'MESH:C093642', (25, 33))	('SR144528', 'Var', (12, 20))	('DMSO', 'Chemical', 'MESH:D004121', (52, 56))
250956	31932491	The pooled siRNAs for knockdown the expression of CNR1 and CNR2 were purchased from GE Dharmacon (Lafayette, CO, USA), utilizing ON-TARGETplus SMART-pool for CNR1 (L-004711-00-0005) and CNR2 (L-005469-00-0005), and ON-TARGETplus Non-targeting pool siRNA (i.e.	('CNR1', 'Gene', (50, 54))	('siRNAs', 'Disease', (11, 17))	('knockdown', 'Var', (22, 31))	('siRNAs', 'Disease', 'None', (11, 17))	('expression', 'Species', '29278', (36, 46))	('CNR2', 'Gene', (59, 63))	('L-004711-00-0005', 'Var', (164, 180))
250960	31932491	UM-SCC-47 and UD-SCC-2 cells were infected with viral supernatants containing CNR1 or CNR2 shRNA with Polybrene, followed by selection using 1 mug/ml Puromycin (InvivoGen, San Diego, CA, USA).	('infected', 'Disease', 'MESH:D007239', (34, 42))	('SCC-2', 'Gene', (17, 22))	('Polybrene', 'Chemical', 'MESH:D006583', (102, 111))	('Puromycin', 'Chemical', 'MESH:D011691', (150, 159))	('infected', 'Disease', (34, 42))	('CNR1', 'Var', (78, 82))	('SCC-2', 'Gene', '25836', (17, 22))	('CNR2 shRNA', 'Var', (86, 96))	('UM-SCC-47', 'CellLine', 'CVCL:7759', (0, 9))
250990	31932491	For the UD-SCC-2 xenografts, when tumors had reached an average size of 50 mm3, animals were divided randomly into various groups and injected intraperitoneally with THC (3 mg/kg) and control vehicle every day, or Rimonabant (1 mg/kg), SR144528 (1 mg/kg), SB203580 (5 mg/kg) and control vehicle every other day.	('tumors', 'Disease', (34, 40))	('THC', 'Chemical', 'MESH:D013759', (166, 169))	('tumors', 'Disease', 'MESH:D009369', (34, 40))	('SB203580', 'Chemical', 'MESH:C093642', (256, 264))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('SB203580', 'Var', (256, 264))	('SCC-2', 'Gene', (11, 16))	('SR144528', 'Chemical', 'MESH:C110630', (236, 244))	('Rimonabant', 'Chemical', 'MESH:D000077285', (214, 224))	('SCC-2', 'Gene', '25836', (11, 16))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
250994	31932491	This analysis showed that the CNR1 and CNR2 expression were both up-regulated in HPV positive HNSCC compared with HPV negative HNSCC (Fig.	('expression', 'MPA', (44, 54))	('up-regulated', 'PosReg', (65, 77))	('HPV positive', 'Var', (81, 93))	('CNR2', 'Gene', (39, 43))	('HPV', 'Species', '10566', (114, 117))	('HNSCC', 'Phenotype', 'HP:0012288', (94, 99))	('CNR1', 'Gene', (30, 34))	('HPV', 'Species', '10566', (81, 84))	('expression', 'Species', '29278', (44, 54))	('HNSCC', 'Phenotype', 'HP:0012288', (127, 132))
251006	31932491	In addition, higher concentrations of ACEA and Hu308 (10 muM) could inhibit cell growth in UM-SCC-47 cells (Supplemental Fig.	('Hu308', 'Var', (47, 52))	('cell growth in UM-SCC-47 cells', 'CPA', (76, 106))	('inhibit', 'NegReg', (68, 75))	('ACEA', 'Chemical', '-', (38, 42))	('Hu308', 'Chemical', 'MESH:C402416', (47, 52))	('UM-SCC-47', 'CellLine', 'CVCL:7759', (91, 100))
251013	31932491	In UD-SCC-2, UPCI:SCC090 and 93VU147T cells, 1 nM to 1 muM SR144528 also suppressed cell growth (Fig.	('SR144528', 'Var', (59, 67))	('SR144528', 'Chemical', 'MESH:C110630', (59, 67))	('SCC-2', 'Gene', (6, 11))	('SCC-2', 'Gene', '25836', (6, 11))	('cell growth', 'CPA', (84, 95))	('93VU147T', 'CellLine', 'CVCL:L895', (29, 37))	('suppressed', 'NegReg', (73, 83))
251017	31932491	4A-C), while CNR1 or CNR2 antagonist Rimonabant (1 muM) and SR144528 (1 muM) could induce cell apoptosis in HPV positive HNSCC (Fig.	('HPV', 'Species', '10566', (108, 111))	('HNSCC', 'Phenotype', 'HP:0012288', (121, 126))	('induce', 'PosReg', (83, 89))	('SR144528', 'Chemical', 'MESH:C110630', (60, 68))	('Rimonabant', 'Chemical', 'MESH:D000077285', (37, 47))	('SR144528', 'Var', (60, 68))	('cell apoptosis', 'CPA', (90, 104))
251019	31932491	Our results demonstrated that CNR1 or CNR2 agonist ACEA, Hu308 and THC could increase cell migration ability across multiple cell lines (Fig.	('THC', 'Chemical', 'MESH:D013759', (67, 70))	('Hu308', 'Var', (57, 62))	('ACEA', 'Chemical', '-', (51, 55))	('cell migration ability across', 'CPA', (86, 115))	('CNR2', 'Gene', (38, 42))	('increase', 'PosReg', (77, 85))	('Hu308', 'Chemical', 'MESH:C402416', (57, 62))
251028	31932491	As expected, in UD-SCC-2, UPCI:SCC090 and UM-SCC104 cells, inactivation of p38 MAPK pathway significantly inhibited the proliferative ability triggered by CNR1 agonist ACEA (Supplemental Fig.	('UM-SCC104', 'CellLine', 'CVCL:7712', (42, 51))	('SCC-2', 'Gene', '25836', (19, 24))	('inactivation', 'Var', (59, 71))	('p38 MAPK', 'Gene', '26416', (75, 83))	('inhibited', 'NegReg', (106, 115))	('ACEA', 'Chemical', '-', (168, 172))	('p38 MAPK', 'Gene', (75, 83))	('SCC-2', 'Gene', (19, 24))	('proliferative ability', 'CPA', (120, 141))
251030	31932491	In UD-SCC-2, UPCI:SCC090 and UM-SCC-47 cells, inhibition of p38 MAPK could also attenuate the pro-proliferative effect caused by non-selective cannabinoid receptor agonist THC (Supplemental Fig.	('cannabinoid', 'Chemical', 'MESH:D002186', (143, 154))	('p38 MAPK', 'Gene', '26416', (60, 68))	('inhibition', 'Var', (46, 56))	('SCC-2', 'Gene', (6, 11))	('pro-proliferative effect', 'CPA', (94, 118))	('SCC-2', 'Gene', '25836', (6, 11))	('p38 MAPK', 'Gene', (60, 68))	('UM-SCC-47', 'CellLine', 'CVCL:7759', (29, 38))	('attenuate', 'NegReg', (80, 89))	('THC', 'Chemical', 'MESH:D013759', (172, 175))
251037	31932491	The results revealed that compared with the control group, the growth of tumor was significantly decreased in the Rimonabant, SR144528, and SB203580 treated group (Fig.	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('SB203580', 'Chemical', 'MESH:C093642', (140, 148))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('SB203580', 'Var', (140, 148))	('Rimonabant', 'Chemical', 'MESH:D000077285', (114, 124))	('tumor', 'Disease', (73, 78))	('decreased', 'NegReg', (97, 106))	('SR144528', 'Var', (126, 134))	('SR144528', 'Chemical', 'MESH:C110630', (126, 134))
251041	31932491	The growth of tumor was significantly decreased in the shCNR1 and shCNR2 group than control group (Fig.	('decreased', 'NegReg', (38, 47))	('tumor', 'Disease', (14, 19))	('shCNR1', 'Var', (55, 61))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('shCNR2', 'Gene', (66, 72))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
251059	31932491	Recently, in vitro and in vivo experiments suggest that CNR1 and CNR2 agonists are potential options for treatment of a variety of cancer types.	('cancer', 'Disease', (131, 137))	('CNR1', 'Gene', (56, 60))	('agonists', 'Var', (70, 78))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('CNR2', 'Gene', (65, 69))	('cancer', 'Disease', 'MESH:D009369', (131, 137))
251065	31932491	In addition, cannabinoids may exert activity via immune modulation, as THC enhances breast cancer growth and metastasis by suppressing antitumor immune response in in vitro and in vivo models.	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('breast cancer', 'Phenotype', 'HP:0003002', (84, 97))	('suppressing', 'NegReg', (123, 134))	('THC', 'Chemical', 'MESH:D013759', (71, 74))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('enhances', 'PosReg', (75, 83))	('cannabinoids', 'Chemical', 'MESH:D002186', (13, 25))	('metastasis', 'CPA', (109, 119))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('breast cancer', 'Disease', 'MESH:D001943', (84, 97))	('THC', 'Var', (71, 74))	('breast cancer', 'Disease', (84, 97))
251066	31932491	As the main cannabinoid receptor in central nervous system, CNR1 was also found to be elevated in a series of cancers, which indicated that CNR1 may be pro-tumorigenic.	('elevated', 'PosReg', (86, 94))	('cancers', 'Disease', (110, 117))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('CNR1', 'Gene', (60, 64))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('cannabinoid', 'Chemical', 'MESH:D002186', (12, 23))	('cancers', 'Phenotype', 'HP:0002664', (110, 117))	('tumor', 'Disease', (156, 161))	('CNR1', 'Var', (140, 144))	('cancers', 'Disease', 'MESH:D009369', (110, 117))
251067	31932491	In support of this, CNR1 immunoreactivity was associated with disease severity and outcome in esophageal cancer, prostate cancer, pancreatic cancer, ovarian cancer and others.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('prostate cancer', 'Disease', 'MESH:D011471', (113, 128))	('ovarian cancer', 'Disease', (149, 163))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('esophageal cancer', 'Disease', (94, 111))	('prostate cancer', 'Disease', (113, 128))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (130, 147))	('immunoreactivity', 'Var', (25, 41))	('esophageal cancer', 'Disease', 'MESH:D004938', (94, 111))	('CNR1', 'Gene', (20, 24))	('associated', 'Reg', (46, 56))	('prostate cancer', 'Phenotype', 'HP:0012125', (113, 128))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('ovarian cancer', 'Disease', 'MESH:D010051', (149, 163))	('pancreatic cancer', 'Disease', (130, 147))	('ovarian cancer', 'Phenotype', 'HP:0100615', (149, 163))	('pancreatic cancer', 'Disease', 'MESH:D010190', (130, 147))
251069	31932491	In this study, although TCGA data showed that the expression of CNR1 mRNA was downregulated in HNSCC compared with normal samples, CNR1 mRNA was highly expressed in HPV positive HNSCC compared with HPV negative HNSCC (Fig.	('HNSCC', 'Phenotype', 'HP:0012288', (178, 183))	('CNR1', 'Gene', (131, 135))	('HPV', 'Species', '10566', (165, 168))	('HPV', 'Var', (165, 168))	('CNR1', 'Gene', (64, 68))	('HNSCC', 'Phenotype', 'HP:0012288', (211, 216))	('HPV', 'Species', '10566', (198, 201))	('expression', 'Species', '29278', (50, 60))	('HNSCC', 'Disease', (95, 100))	('HNSCC', 'Phenotype', 'HP:0012288', (95, 100))	('expression', 'MPA', (50, 60))	('downregulated', 'NegReg', (78, 91))
251077	31932491	Meanwhile, knockdown the expression of CNR2 inhibited the proliferation of HPV positive HNSCC in vitro and in vivo.	('expression', 'Species', '29278', (25, 35))	('CNR2', 'Gene', (39, 43))	('inhibited', 'NegReg', (44, 53))	('proliferation of HPV positive HNSCC', 'CPA', (58, 93))	('HNSCC', 'Phenotype', 'HP:0012288', (88, 93))	('HPV', 'Species', '10566', (75, 78))	('knockdown', 'Var', (11, 20))
251078	31932491	In addition, selective CNR2 agonist Hu308 increased the growth, migration and inhibited the apoptosis of HPV positive HNSCC cells while the selective CNR2 antagonist SR144528 exhibited an opposite effect.	('increased', 'PosReg', (42, 51))	('apoptosis', 'CPA', (92, 101))	('inhibited', 'NegReg', (78, 87))	('Hu308', 'Var', (36, 41))	('growth', 'CPA', (56, 62))	('CNR2', 'Gene', (23, 27))	('SR144528', 'Chemical', 'MESH:C110630', (166, 174))	('HNSCC', 'Phenotype', 'HP:0012288', (118, 123))	('Hu308', 'Chemical', 'MESH:C402416', (36, 41))	('HPV', 'Species', '10566', (105, 108))	('migration', 'CPA', (64, 73))
251081	31932491	Indeed, when cannabinoid receptors were activated by the agonists ACEA, Hu308 and THC, the expression of p-p38 MAPK was elevated and the downstream molecules of p38 MAPK signaling pathway, such as p-MAPKAPK2 and p-HSP27, increased correspondingly.	('expression', 'MPA', (91, 101))	('MAPKAPK2', 'Gene', (199, 207))	('THC', 'Chemical', 'MESH:D013759', (82, 85))	('HSP27', 'Gene', '3315', (214, 219))	('cannabinoid receptors', 'Protein', (13, 34))	('Hu308', 'Chemical', 'MESH:C402416', (72, 77))	('p38 MAPK', 'Gene', '26416', (107, 115))	('expression', 'Species', '29278', (91, 101))	('MAPKAPK2', 'Gene', '9261', (199, 207))	('p38 MAPK', 'Gene', (107, 115))	('p38 MAPK', 'Gene', '26416', (161, 169))	('ACEA', 'Chemical', '-', (66, 70))	('HSP27', 'Gene', (214, 219))	('elevated', 'PosReg', (120, 128))	('p38 MAPK', 'Gene', (161, 169))	('Hu308', 'Var', (72, 77))	('cannabinoid', 'Chemical', 'MESH:D002186', (13, 24))	('activated', 'PosReg', (40, 49))	('increased', 'PosReg', (221, 230))
251082	31932491	These were further confirmed by inhibition of p38 MAPK with SB203580, while the pro-proliferative effect caused by cannabinoid receptors agonists were largely attenuated.	('SB203580', 'Var', (60, 68))	('inhibition', 'NegReg', (32, 42))	('p38 MAPK', 'Gene', (46, 54))	('p38 MAPK', 'Gene', '26416', (46, 54))	('cannabinoid', 'Chemical', 'MESH:D002186', (115, 126))	('SB203580', 'Chemical', 'MESH:C093642', (60, 68))
251103	31973134	The highest mutation was found in the R321*/Q amino acid of BMP5 corresponding to colorectal and breast cancer whereas the alteration frequency was higher in lung squamous carcinoma datasets (>4%).	('R321*', 'Var', (38, 43))	('lung squamous carcinoma', 'Disease', 'MESH:D002294', (158, 181))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (163, 181))	('R321*', 'SUBSTITUTION', 'None', (38, 43))	('lung squamous carcinoma', 'Phenotype', 'HP:0030359', (158, 181))	('BMP5', 'Gene', (60, 64))	('colorectal and breast cancer', 'Disease', 'MESH:D001943', (82, 110))	('breast cancer', 'Phenotype', 'HP:0003002', (97, 110))	('lung squamous carcinoma', 'Disease', (158, 181))	('carcinoma', 'Phenotype', 'HP:0030731', (172, 181))
251109	31973134	One of the most dominant causes of oncogenesis is the accumulation of gene alterations which has a positive correlation to the prognosis of cancer patients.	('gene alterations', 'Var', (70, 86))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('patients', 'Species', '9606', (147, 155))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))
251112	31973134	Mutation in BMP5 is associated with a wide range of skeletal defects such as reduction in the long bone width and the size of the vertebral processes as well as the reduction of lower body mass.	('associated', 'Reg', (20, 30))	('skeletal defects', 'Phenotype', 'HP:0000924', (52, 68))	('BMP5', 'Gene', (12, 16))	('reduction', 'NegReg', (77, 86))	('Mutation', 'Var', (0, 8))	('skeletal defects', 'Disease', 'MESH:D009358', (52, 68))	('long bone width', 'CPA', (94, 109))	('lower body mass', 'Phenotype', 'HP:0004325', (178, 193))	('reduction', 'NegReg', (165, 174))	('lower body mass', 'CPA', (178, 193))	('skeletal defects', 'Disease', (52, 68))	('long bone width', 'Phenotype', 'HP:0005622', (94, 109))
251114	31973134	Previous studies on colorectal cancer showed a significant correlation between BMP5 down-expression and mutation and the prognostic value of colorectal cancer (CRC), triggering the initiation and development of tumors.	('tumors', 'Disease', 'MESH:D009369', (211, 217))	('colorectal cancer', 'Phenotype', 'HP:0003003', (20, 37))	('colorectal cancer', 'Disease', 'MESH:D015179', (141, 158))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('CRC', 'Phenotype', 'HP:0003003', (160, 163))	('tumors', 'Phenotype', 'HP:0002664', (211, 217))	('colorectal cancer', 'Disease', (20, 37))	('colorectal cancer', 'Phenotype', 'HP:0003003', (141, 158))	('down-expression', 'NegReg', (84, 99))	('mutation', 'Var', (104, 112))	('colorectal cancer', 'Disease', 'MESH:D015179', (20, 37))	('colorectal cancer', 'Disease', (141, 158))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('tumors', 'Disease', (211, 217))	('triggering', 'Reg', (166, 176))	('BMP5', 'Gene', (79, 83))
251115	31973134	One study reported that 13 cases of BMP5 mutation across seven cancers where gastrointestinal cancers (GICs) were the most influenced by recurrent hotspot mutations.	('cancers', 'Disease', 'MESH:D009369', (94, 101))	('gastrointestinal cancers', 'Disease', 'MESH:D004067', (77, 101))	('BMP5', 'Gene', (36, 40))	('gastrointestinal cancers', 'Disease', (77, 101))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('mutation', 'Var', (41, 49))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('cancers', 'Phenotype', 'HP:0002664', (63, 70))	('cancers', 'Phenotype', 'HP:0002664', (94, 101))	('cancers', 'Disease', (63, 70))	('cancers', 'Disease', (94, 101))	('cancers', 'Disease', 'MESH:D009369', (63, 70))
251162	31973134	In Figure 3C,E-G the GSE17536 and GSE17333 datasets exhibited that the patient group with low level of BMP5 mRNA expression (n = 93, 101, 118 and 146, respectively) reported significantly poor overall survival compared to the high expression group (n = 84, 76, 108 and 31, respectively), whereas one alteration reported by dataset GSE17537 contradicted the association of BMP5 low expression with overall survival of colorectal cancer patients (Figure 3D).	('colorectal cancer', 'Disease', (417, 434))	('overall survival', 'MPA', (193, 209))	('poor', 'NegReg', (188, 192))	('colorectal cancer', 'Disease', 'MESH:D015179', (417, 434))	('patients', 'Species', '9606', (435, 443))	('cancer', 'Phenotype', 'HP:0002664', (428, 434))	('colorectal cancer', 'Phenotype', 'HP:0003003', (417, 434))	('patient', 'Species', '9606', (71, 78))	('low', 'Var', (90, 93))	('patient', 'Species', '9606', (435, 442))
251163	31973134	Analysis of GSE31210 and Jacob-00182-MSK datasets of PrognoScan showed significantly (p-value) lower survival of lung cancer patients in the low BMP5 mRNA expression group (n = 35, 42, 12, 39 and 24, respectively) compared to their higher expression counterparts (n = 169, 162, 92, 65 and 180, respectively; Figure 3H-L and Supplementary Table S3).	('lower', 'NegReg', (95, 100))	('lung cancer', 'Disease', (113, 124))	('lung cancer', 'Phenotype', 'HP:0100526', (113, 124))	('survival', 'MPA', (101, 109))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('low BMP5', 'Var', (141, 149))	('lung cancer', 'Disease', 'MESH:D008175', (113, 124))	('patients', 'Species', '9606', (125, 133))
251164	31973134	High survival ratio was exhibited in low BMP5 expression group (n = 70 and 90, respectively) of ovarian cancer compared to the high expression group (n = 63 and 43, respectively), according to the DUKE-OC dataset (Figure 3M,N and Supplementary Table S3).	('low BMP5', 'Var', (37, 45))	('ovarian cancer', 'Phenotype', 'HP:0100615', (96, 110))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('ovarian cancer', 'Disease', 'MESH:D010051', (96, 110))	('ovarian cancer', 'Disease', (96, 110))
251173	31973134	The database queried for the BMP5 gene mutations in 15,405 number of samples from 26 cancer studies of breast, colorectal, lung, bladder, and ovarian cancer.	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('colorectal', 'Disease', (111, 121))	('ovarian cancer', 'Disease', (142, 156))	('breast', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('bladder', 'Disease', (129, 136))	('BMP5', 'Gene', (29, 33))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('mutations', 'Var', (39, 48))	('cancer', 'Disease', (85, 91))	('ovarian cancer', 'Phenotype', 'HP:0100615', (142, 156))	('cancer', 'Disease', (150, 156))	('ovarian cancer', 'Disease', 'MESH:D010051', (142, 156))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('lung', 'Disease', (123, 127))
251176	31973134	Highest mutations were reported in breast invasive ductal and colorectal carcinoma and occurred in a hotspot in R321*/Q.	('R321*', 'SUBSTITUTION', 'None', (112, 117))	('occurred', 'Reg', (87, 95))	('breast invasive ductal', 'Disease', (35, 57))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (62, 82))	('mutations', 'Var', (8, 17))	('R321*', 'Var', (112, 117))	('colorectal carcinoma', 'Disease', (62, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
251177	31973134	Total fourmutations were reported in R321*/Q site, among which missense mutations were found in total 5397 breast invasive ductal carcinoma samples whereas, 837 samples of colorectal adenocarcinoma showed nonsense mutation (Table 1).	('carcinoma', 'Phenotype', 'HP:0030731', (188, 197))	('breast invasive ductal carcinoma', 'Disease', (107, 139))	('colorectal adenocarcinoma', 'Disease', (172, 197))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (123, 139))	('breast invasive ductal carcinoma', 'Disease', 'MESH:D001943', (107, 139))	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (172, 197))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('R321*', 'Var', (37, 42))	('R321*', 'SUBSTITUTION', 'None', (37, 42))
251178	31973134	Total 3 cases of mutation were reported in the hotspot V5A/L/S in lung squamous carcinoma datasets (Figure 5A).	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (71, 89))	('mutation', 'Var', (17, 25))	('lung squamous carcinoma', 'Phenotype', 'HP:0030359', (66, 89))	('lung squamous carcinoma', 'Disease', 'MESH:D002294', (66, 89))	('lung squamous carcinoma', 'Disease', (66, 89))
251179	31973134	Alteration frequency was found highest in lung squamous carcinoma samples (>4%) among five cancer types (Figure 5B).	('squamous carcinoma', 'Phenotype', 'HP:0002860', (47, 65))	('Alteration', 'Var', (0, 10))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('lung squamous carcinoma', 'Disease', 'MESH:D002294', (42, 65))	('highest', 'Reg', (31, 38))	('lung squamous carcinoma', 'Phenotype', 'HP:0030359', (42, 65))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (56, 65))	('lung squamous carcinoma', 'Disease', (42, 65))
251182	31973134	Mutated BMP5 proteins were profiled in 11 cases of breast and colorectal cancers, whereas only a single missense mutation was reported in ovarian cancer.	('BMP5', 'Gene', (8, 12))	('colorectal cancer', 'Phenotype', 'HP:0003003', (62, 79))	('breast', 'Disease', (51, 57))	('colorectal cancers', 'Disease', 'MESH:D015179', (62, 80))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('ovarian cancer', 'Phenotype', 'HP:0100615', (138, 152))	('colorectal cancers', 'Disease', (62, 80))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('ovarian cancer', 'Disease', 'MESH:D010051', (138, 152))	('Mutated', 'Var', (0, 7))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('ovarian cancer', 'Disease', (138, 152))
251226	31973134	observed the down-regulation of BMP5 in colorectal cancer due to the miR-32 deregulation.	('BMP5', 'Gene', (32, 36))	('colorectal cancer', 'Disease', (40, 57))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('down-regulation', 'NegReg', (13, 28))	('colorectal cancer', 'Disease', 'MESH:D015179', (40, 57))	('deregulation', 'Var', (76, 88))	('miR-32', 'Gene', '407036', (69, 75))	('miR-32', 'Gene', (69, 75))	('colorectal cancer', 'Phenotype', 'HP:0003003', (40, 57))
251234	31973134	Somatic loss-of-function or gain-of-function alterations ensue in particular genomic regions which engaged in potential inhibitory or carcinogenic effects, respectively.	('alterations', 'Var', (45, 56))	('carcinogenic', 'Disease', 'MESH:D063646', (134, 146))	('carcinogenic', 'Disease', (134, 146))	('gain-of-function', 'PosReg', (28, 44))	('loss-of-function', 'NegReg', (8, 24))
251235	31973134	The G-to-A mutation at nucleotide 932 cleaves the nucleotides encoding arginine (CGA) residue and thus destroys the Taq I polymerase restriction site resulting in the blockage of the post-translational processing of the BMP5 protein.	('arginine', 'Chemical', 'MESH:D001120', (71, 79))	('post-translational processing of the', 'MPA', (183, 219))	('cleaves', 'Reg', (38, 45))	('Taq', 'Protein', (116, 119))	('destroys', 'NegReg', (103, 111))	('blockage', 'NegReg', (167, 175))	('G-to-A mutation at nucleotide 932', 'Mutation', 'c.932G>A', (4, 37))	('BMP5', 'Protein', (220, 224))	('mutation', 'Var', (11, 19))
251236	31973134	In our analysis, we found diverse missense and truncating mutations in the BMP5 protein-coding sequence while exposed to cancer cells.	('missense', 'Var', (34, 42))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('truncating mutations', 'Var', (47, 67))	('BMP5', 'Gene', (75, 79))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('cancer', 'Disease', (121, 127))
251237	31973134	This study revealed mutations in breast invasive ductal and colorectal carcinoma in a hotspot at position R321*/Q and position V5A/L/S in lung squamous carcinoma between BMP5-propeptide and BMP5 domain.	('carcinoma', 'Phenotype', 'HP:0030731', (152, 161))	('R321*', 'SUBSTITUTION', 'None', (106, 111))	('lung squamous carcinoma', 'Disease', (138, 161))	('colorectal carcinoma', 'Disease', (60, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (143, 161))	('lung squamous carcinoma', 'Phenotype', 'HP:0030359', (138, 161))	('breast invasive ductal', 'Disease', (33, 55))	('propeptide', 'Chemical', '-', (175, 185))	('lung squamous carcinoma', 'Disease', 'MESH:D002294', (138, 161))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (60, 80))	('R321*', 'Var', (106, 111))	('mutations', 'Var', (20, 29))
251238	31973134	Similar results of mutation at R321*/Q stop-codon (4 cases) was also found in a previous study which may impact cleavage of the protein to the mature secreted form.	('R321*', 'SUBSTITUTION', 'None', (31, 36))	('cleavage of the protein', 'MPA', (112, 135))	('impact', 'Reg', (105, 111))	('R321*', 'Var', (31, 36))
251240	31973134	Another BMP5 mRNA expression (RNA Seq V2) analysis via cBioPortal web found a higher mutation rate in lung cancer and then in bladder cancers.	('bladder cancer', 'Phenotype', 'HP:0009725', (126, 140))	('lung cancer', 'Phenotype', 'HP:0100526', (102, 113))	('bladder cancers', 'Phenotype', 'HP:0009725', (126, 141))	('cancers', 'Phenotype', 'HP:0002664', (134, 141))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('lung cancer', 'Disease', (102, 113))	('bladder cancers', 'Disease', 'MESH:D001749', (126, 141))	('mutation', 'Var', (85, 93))	('lung cancer', 'Disease', 'MESH:D008175', (102, 113))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('bladder cancers', 'Disease', (126, 141))
251241	31973134	These mutations may have played an essential role in cancer progression and prognosis.	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('played', 'Reg', (25, 31))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('mutations', 'Var', (6, 15))
251280	32029792	Our in vitro experiments demonstrated that GPNCA silencing inhibited tumor growth via inhibiting its nearby gene GSK3B.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('silencing', 'Var', (49, 58))	('tumor', 'Disease', (69, 74))	('GSK3B', 'Gene', (113, 118))	('inhibited', 'NegReg', (59, 68))	('GSK3B', 'Gene', '2932', (113, 118))	('inhibiting', 'NegReg', (86, 96))	('GPNCA', 'Gene', (43, 48))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
251291	32029792	Finally, we confirmed that GPNCA silencing could inhibit HepG2 and HCT116 tumor cell growth via regulating its nearby gene GSK3B.	('GPNCA', 'Gene', (27, 32))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('silencing', 'Var', (33, 42))	('HepG2', 'CellLine', 'CVCL:0027', (57, 62))	('GSK3B', 'Gene', (123, 128))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('regulating', 'Reg', (96, 106))	('GSK3B', 'Gene', '2932', (123, 128))	('tumor', 'Disease', (74, 79))	('inhibit', 'NegReg', (49, 56))	('HCT116', 'CellLine', 'CVCL:0291', (67, 73))
251295	32029792	Here, we termed LncRNA GPNCA whose gene Ensembl ID was ENSG00000242622.1 and was upregulated in the Chr3q13.33 (120094895-120136783) region next to GSK3B.	('GSK3B', 'Gene', (148, 153))	('120094895-120136783', 'Var', (112, 131))	('upregulated', 'PosReg', (81, 92))	('GSK3B', 'Gene', '2932', (148, 153))
251313	32029792	The results from liver cancer patients showed that those with GPNCA expression (FPKM value) > 0.295 were of high-risk and had poor survival (HR = 1.890, 95% CI, 1.278-2.795, P = 0.0012), (Fig.	('liver cancer', 'Phenotype', 'HP:0002896', (17, 29))	('liver cancer', 'Disease', 'MESH:D006528', (17, 29))	('survival', 'MPA', (131, 139))	('liver cancer', 'Disease', (17, 29))	('patients', 'Species', '9606', (30, 38))	('poor', 'NegReg', (126, 130))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('> 0.295', 'Var', (92, 99))
251314	32029792	S1B); whilst renal clear cell cancer patients with GPNCA expression (FPKM value) > 0.421 were of high-risk resulting in poor OS (AUC value > 0.5, HR = 2.166, 95% CI, 1.269-3.698, P = 0.0002)(Fig.	('renal clear cell cancer', 'Disease', (13, 36))	('renal clear cell cancer', 'Disease', 'MESH:D002292', (13, 36))	('clear cell cancer', 'Phenotype', 'HP:0006770', (19, 36))	('patients', 'Species', '9606', (37, 45))	('> 0.421', 'Var', (81, 88))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
251315	32029792	The results of breast cancer patients with GPNCA expression (FPKM value) >= 0.417 were of high-risk leading to poor OS (HR = 1.392, 95% CI, 1.032-1.959, P = 0.0324) (Fig.	('patients', 'Species', '9606', (29, 37))	('GPNCA', 'Var', (43, 48))	('>= 0.417', 'Var', (73, 81))	('breast cancer', 'Disease', 'MESH:D001943', (15, 28))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('breast cancer', 'Disease', (15, 28))	('poor OS', 'MPA', (111, 118))	('breast cancer', 'Phenotype', 'HP:0003002', (15, 28))
251316	32029792	These data suggested that high GPNCA expression was indeed associated with poor OS in several cancers but not enough sensitive to be an independent clinical biomarker for prognosis.	('cancers', 'Disease', 'MESH:D009369', (94, 101))	('high', 'Var', (26, 30))	('GPNCA expression', 'Protein', (31, 47))	('associated', 'Reg', (59, 69))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('poor OS', 'Disease', (75, 82))	('cancers', 'Phenotype', 'HP:0002664', (94, 101))	('cancers', 'Disease', (94, 101))
251328	32029792	In intro ChIP (Chromatin immunoprecipitation) assays revealed that H3k27ac enrichment was markedly higher in HepG2 cells (liver cancer cells) compared to LO2 cells (normal liver cells) on the GPNCA promoter region (Fig.	('liver cancer', 'Phenotype', 'HP:0002896', (122, 134))	('liver cancer', 'Disease', 'MESH:D006528', (122, 134))	('liver cancer', 'Disease', (122, 134))	('higher', 'PosReg', (99, 105))	('H3k27ac', 'Protein', (67, 74))	('HepG2', 'Var', (109, 114))	('HepG2', 'CellLine', 'CVCL:0027', (109, 114))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('LO2', 'CellLine', 'CVCL:6926', (154, 157))	('enrichment', 'MPA', (75, 85))
251344	32029792	The results showed that GPNCA silencing inhibited cell proliferation both in HepG2 and HCT116 cells (Fig.	('inhibited', 'NegReg', (40, 49))	('HepG2', 'CellLine', 'CVCL:0027', (77, 82))	('HCT116', 'CellLine', 'CVCL:0291', (87, 93))	('GPNCA', 'Protein', (24, 29))	('silencing', 'Var', (30, 39))	('cell proliferation', 'CPA', (50, 68))
251346	32029792	Taken together, these data demonstrate that GPNCA silencing inhibits tumor cell growth.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor', 'Disease', (69, 74))	('silencing', 'Var', (50, 59))	('inhibits', 'NegReg', (60, 68))	('GPNCA', 'Gene', (44, 49))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
251360	32029792	However, the expressions of GPNCA were not influenced by GSK3B knockdown both in HCT116 and HepG2 cells (Fig.	('HCT116', 'CellLine', 'CVCL:0291', (81, 87))	('GSK3B', 'Gene', '2932', (57, 62))	('HepG2', 'CellLine', 'CVCL:0027', (92, 97))	('GSK3B', 'Gene', (57, 62))	('knockdown', 'Var', (63, 72))
251368	32029792	Furthermore, we found that the upregulation of GPNCA was associated with the high enrichment of H3k27ac on the GPNCA promoter region via EP300 and GCN5, implicating GPNCA as an oncogene.	('GPNCA', 'Disease', (47, 52))	('H3k27ac', 'Var', (96, 103))	('EP300', 'Gene', (137, 142))	('EP300', 'Gene', '2033', (137, 142))	('GCN5', 'Gene', (147, 151))	('GCN5', 'Gene', '2648', (147, 151))	('upregulation', 'PosReg', (31, 43))
251384	32029792	In vitro experiments revealed that GPNCA silencing markedly inhibits tumor cell proliferation via regulation of GSK3B, suggesting that drugs targeted to GPNCA may hold potential considerable value for anti-cancer therapy.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('GSK3B', 'Gene', '2932', (112, 117))	('silencing', 'Var', (41, 50))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('GSK3B', 'Gene', (112, 117))	('tumor', 'Disease', (69, 74))	('GPNCA', 'Gene', (35, 40))	('regulation', 'MPA', (98, 108))	('inhibits', 'NegReg', (60, 68))	('cancer', 'Disease', (206, 212))	('cancer', 'Disease', 'MESH:D009369', (206, 212))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
251400	32029792	Primary antibodies were showed as follows: EP300 (Abcam, ab14984), KAT2A/GCN5 (Abcam, ab208097), H3k27ac (Abcam, ab177178), beta-actin (Proteintech, 60008-1-lg), Lamin B1 (CST, #13435) and Histone 3 (Abcam, ab1791).	('beta-actin', 'Gene', (124, 134))	('Lamin B1', 'Gene', (162, 170))	('EP300', 'Gene', '2033', (43, 48))	('EP300', 'Gene', (43, 48))	('KAT2A', 'Gene', '2648', (67, 72))	('Lamin B1', 'Gene', '4001', (162, 170))	('Histone 3', 'Protein', (189, 198))	('H3k27ac', 'Var', (97, 104))	('KAT2A', 'Gene', (67, 72))	('GCN5', 'Gene', (73, 77))	('beta-actin', 'Gene', '728378', (124, 134))	('GCN5', 'Gene', '2648', (73, 77))
251415	31118798	Results: MiR-145 inhibited LSCC growth in a dose-dependent manner, as tumor growth was significantly inhibited in mice injected intratumorally with high-dose miR-145 compared with both the untreated and low-dose miR-145 groups (p<0.05).	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumor', 'Disease', (70, 75))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('miR-145', 'Var', (158, 165))	('inhibited', 'NegReg', (17, 26))	('tumor', 'Disease', (133, 138))	('mice', 'Species', '10090', (114, 118))	('LSCC growth', 'CPA', (27, 38))	('inhibited', 'NegReg', (101, 110))	('MiR-145', 'Gene', (9, 16))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
251417	31118798	PI3K and Akt protein expression were significantly lower in tumors treated with high-dose miR-145 group compared with those in the untreated and low-dose miR-145 groups (p<0.05).	('high-dose miR-145 group', 'Var', (80, 103))	('tumors', 'Disease', 'MESH:D009369', (60, 66))	('lower', 'NegReg', (51, 56))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('Akt', 'Pathway', (9, 12))	('PI3K', 'Pathway', (0, 4))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('tumors', 'Disease', (60, 66))
251418	31118798	Conclusions: MiR-145 was associated with inhibited tumor growth in a nude mouse model of LSCC.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor', 'Disease', (51, 56))	('LSCC', 'Disease', (89, 93))	('mouse', 'Species', '10090', (74, 79))	('inhibited', 'NegReg', (41, 50))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('MiR-145', 'Var', (13, 20))
251423	31118798	Epigenetic control networks based on non-coding RNA recognition have become an important area of research, with a significant focus on the role of microRNAs (miRNAs) in carcinogenesis.	('non-coding RNA', 'Var', (37, 51))	('carcinogenesis', 'Disease', (169, 183))	('miR', 'Gene', '220972', (158, 161))	('miR', 'Gene', (158, 161))	('carcinogenesis', 'Disease', 'MESH:D063646', (169, 183))
251433	31118798	Recent studies of miR-145 in LSCC were limited to laryngeal carcinoma tissues and cell lines and indicated that miR-145 inhibited the growth of most tumors.	('laryngeal carcinoma', 'Disease', (50, 69))	('inhibited', 'NegReg', (120, 129))	('laryngeal carcinoma', 'Disease', 'MESH:D007827', (50, 69))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('laryngeal carcinoma', 'Phenotype', 'HP:0012118', (50, 69))	('tumors', 'Disease', 'MESH:D009369', (149, 155))	('tumors', 'Disease', (149, 155))	('miR-145', 'Var', (112, 119))	('tumors', 'Phenotype', 'HP:0002664', (149, 155))	('carcinoma', 'Phenotype', 'HP:0030731', (60, 69))
251444	31118798	Tumors were allowed to grow to more than 100 mm3, and the mice were randomly divided into six groups (n=8 each): 1) unmanipulated control, 2) glucose solution control, 3) transfection reagent control, 4) non-specific gene sequence control, 5) miR-145 high-dose (1.0 OD) treatment , and 6) miR-145 low-dose (0.5 OD) treatment.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('glucose', 'Chemical', 'MESH:D005947', (142, 149))	('mice', 'Species', '10090', (58, 62))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('miR-145', 'Var', (243, 250))
251461	31118798	The solid tumors in the treatment groups were smaller than those in the control groups, and this reduction in size was more conspicuous in the high-dose miR-145 treatment group.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('miR-145', 'Gene', (153, 160))	('high-dose', 'Var', (143, 152))	('solid tumors', 'Disease', (4, 16))	('tumors', 'Phenotype', 'HP:0002664', (10, 16))	('solid tumors', 'Disease', 'MESH:D009369', (4, 16))	('smaller', 'NegReg', (46, 53))
251469	31118798	Disruption in the normal expression of these molecules can lead to tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('expression', 'MPA', (25, 35))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('lead to', 'Reg', (59, 66))	('tumor', 'Disease', (67, 72))	('Disruption', 'Var', (0, 10))
251493	31118798	Moreover, miR-145 silencing suppressed E-cadherin expression and enhanced N-cadherin and vimentin expression in Hep2 cells.	('vimentin', 'Gene', (89, 97))	('N-cadherin', 'Gene', (74, 84))	('silencing', 'Var', (18, 27))	('E-cadherin', 'Gene', (39, 49))	('E-cadherin', 'Gene', '999', (39, 49))	('N-cadherin', 'Gene', '1000', (74, 84))	('enhanced', 'PosReg', (65, 73))	('suppressed', 'NegReg', (28, 38))	('Hep2', 'CellLine', 'CVCL:1906', (112, 116))	('vimentin', 'Gene', '7431', (89, 97))	('miR-145', 'Gene', (10, 17))	('expression', 'MPA', (98, 108))
251494	31118798	Gao et al, indicated that miR-145-5p plays a critical role in inhibiting the progression of LSCC by suppressing FSCN1.	('LSCC', 'Disease', (92, 96))	('progression', 'CPA', (77, 88))	('miR-145-5p', 'Var', (26, 36))	('inhibiting', 'NegReg', (62, 72))	('suppressing', 'NegReg', (100, 111))	('FSCN1', 'Gene', (112, 117))	('FSCN1', 'Gene', '6624', (112, 117))
251495	31118798	Both miR-145-5p and FSCN1 are important potential prognostic markers and therapeutic targets for the treatment of LSCC.	('LSCC', 'Disease', (114, 118))	('miR-145-5p', 'Var', (5, 15))	('FSCN1', 'Gene', (20, 25))	('FSCN1', 'Gene', '6624', (20, 25))
251503	31118798	Moreover, curcumin treatment reversed anti-miR-145-mediated increases in cell viability, migration, and invasion, and reversed inhibition of apoptosis in LSCC cells.	('increases', 'PosReg', (60, 69))	('anti-miR-145-mediated', 'Var', (38, 59))	('LSCC', 'Disease', (154, 158))	('cell viability', 'CPA', (73, 87))	('curcumin', 'Chemical', 'MESH:D003474', (10, 18))	('invasion', 'CPA', (104, 112))	('migration', 'CPA', (89, 98))	('apoptosis', 'CPA', (141, 150))
251504	31118798	Curcumin treatment increased miR-145-induced inhibition of the PI3K/Akt/mTOR pathway, and reversed anti-miR-145-mediated activation of the PI3K/Akt/mTOR pathway in LSCC cells.	('inhibition', 'NegReg', (45, 55))	('Curcumin', 'Chemical', 'MESH:D003474', (0, 8))	('mTOR', 'Gene', (148, 152))	('mTOR', 'Gene', '2475', (72, 76))	('mTOR', 'Gene', '2475', (148, 152))	('anti-miR-145-mediated', 'Var', (99, 120))	('mTOR', 'Gene', (72, 76))	('miR-145-induced', 'Gene', (29, 44))	('increased', 'PosReg', (19, 28))	('activation', 'PosReg', (121, 131))
251512	31118798	MiR-145 directly inhibits the expression of p70S6K1 in pancreatic cancer, making it an effective therapeutic agent for the treatment of pancreatic cancer.	('inhibits', 'NegReg', (17, 25))	('pancreatic cancer', 'Disease', 'MESH:D010190', (136, 153))	('expression', 'MPA', (30, 40))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('p70S6K1', 'Var', (44, 51))	('MiR-145', 'Gene', (0, 7))	('pancreatic cancer', 'Disease', 'MESH:D010190', (55, 72))	('pancreatic cancer', 'Disease', (55, 72))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (136, 153))	('pancreatic cancer', 'Disease', (136, 153))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (55, 72))
251513	31118798	In ovarian cancer, miR-145 was imported into SKOV3/PTX ovarian cancer cells, resulting in decreased intracellular cyclin-dependent kinase 6 and Sp1 levels.	('Sp1 levels', 'MPA', (144, 154))	('PTX ovarian cancer', 'Disease', 'MESH:D010051', (51, 69))	('PTX ovarian cancer', 'Disease', (51, 69))	('cyclin-dependent kinase 6', 'Gene', (114, 139))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('ovarian cancer', 'Phenotype', 'HP:0100615', (3, 17))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('miR-145', 'Var', (19, 26))	('cyclin-dependent kinase 6', 'Gene', '1021', (114, 139))	('decreased', 'NegReg', (90, 99))	('ovarian cancer', 'Disease', 'MESH:D010051', (3, 17))	('ovarian cancer', 'Phenotype', 'HP:0100615', (55, 69))	('ovarian cancer', 'Disease', (3, 17))	('ovarian cancer', 'Disease', 'MESH:D010051', (55, 69))	('SKOV3', 'CellLine', 'CVCL:0532', (45, 50))
251515	31118798	These changes may induce aggregation of antitumor drugs in cells, in addition to G1 cell cycle blockade, consequently improving the sensitivity of tumor cells to taxols both in vitro and in vivo.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('improving', 'PosReg', (118, 127))	('taxols', 'Chemical', 'MESH:D017239', (162, 168))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('sensitivity', 'MPA', (132, 143))	('induce', 'Reg', (18, 24))	('changes', 'Var', (6, 13))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('aggregation', 'MPA', (25, 36))	('tumor', 'Disease', (44, 49))
251516	31118798	Reactivation of miR-145 expression by demethylation mediated by the DNA methylase inhibitor 5-azos-2-deoxycytidine may also increase the susceptibility of tumor cells to taxols.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('increase', 'PosReg', (124, 132))	('miR-145', 'Gene', (16, 23))	('5-azos-2-deoxycytidine', 'Chemical', '-', (92, 114))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('expression', 'MPA', (24, 34))	('taxols', 'Chemical', 'MESH:D017239', (170, 176))	('tumor', 'Disease', (155, 160))	('Reactivation', 'MPA', (0, 12))	('demethylation', 'Var', (38, 51))	('susceptibility', 'MPA', (137, 151))
251517	31118798	As a result, the etiology and biological mechanisms underlying the proliferation of tumor cells are complex and include inactivation of cancer suppressor genes, overexpression of oncogenes, uncontrolled cell cycling, and tolerance to apoptosis.	('inactivation', 'Var', (120, 132))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('tumor', 'Disease', (84, 89))	('cancer', 'Disease', (136, 142))	('overexpression', 'PosReg', (161, 175))	('oncogenes', 'Gene', (179, 188))	('tolerance to apoptosis', 'CPA', (221, 243))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
251538	31118798	Similarly, miR-145 was also shown to enhance the resistance of SK-GT-4 cells to cisplatin.	('cisplatin', 'Chemical', 'MESH:D002945', (80, 89))	('SK-GT-4', 'CellLine', 'CVCL:2195', (63, 70))	('miR-145', 'Var', (11, 18))	('enhance', 'PosReg', (37, 44))	('resistance', 'MPA', (49, 59))
251558	30607140	Despite the fact that tremendous somatic mutations in a variety of cancer types can give chances for personalized treatment targeting at patients' specific mutations, these mutations can eventually translate into new antigens for possible anti-tumor immune response.	('mutations', 'Var', (41, 50))	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('tumor', 'Phenotype', 'HP:0002664', (244, 249))	('translate', 'Reg', (198, 207))	('cancer', 'Disease', (67, 73))	('tumor', 'Disease', (244, 249))	('mutations', 'Var', (156, 165))	('patients', 'Species', '9606', (137, 145))	('mutations', 'Var', (173, 182))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('tumor', 'Disease', 'MESH:D009369', (244, 249))
251564	30607140	Thus, monoclonal antibodies blocking PD-1 have arisen as an impressive treatment strategy for cancer patients and have been approved by the U.S. Food and Drug Administration (FDA) for human use.	('patients', 'Species', '9606', (101, 109))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('human', 'Species', '9606', (184, 189))	('monoclonal', 'Var', (6, 16))	('PD-1', 'Gene', (37, 41))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
251633	30607140	The combination of PD-1 and CTLA-4 blockade has demonstrated higher response rates in advanced melanoma, while combination with LAG3 blockade are still carrying on clinical trials (NCT03250832, NCT02658981, NCT01968109, NCT03005782).	('LAG3', 'Gene', '3902', (128, 132))	('advanced melanoma', 'Disease', 'MESH:D008545', (86, 103))	('higher', 'PosReg', (61, 67))	('melanoma', 'Phenotype', 'HP:0002861', (95, 103))	('advanced melanoma', 'Disease', (86, 103))	('NCT03250832', 'Var', (181, 192))	('CTLA-4', 'Gene', '1493', (28, 34))	('PD-1', 'Gene', (19, 23))	('LAG3', 'Gene', (128, 132))	('CTLA-4', 'Gene', (28, 34))
251637	30607140	Therefore, we can infer that the high expression of LFA-1 may improve the efficacy of T cells that have been released from the "brake" of PD-1 by PD-1 blockade.	('LFA-1', 'Gene', (52, 57))	('high expression', 'Var', (33, 48))	('improve', 'PosReg', (62, 69))	('efficacy', 'CPA', (74, 82))	('LFA-1', 'Gene', '3689', (52, 57))
251654	27038552	Dysregulation of SOCS protein expression in cancers can be one of the mechanisms that maintain STAT activation, but this mechanism is still poorly understood in oral squamous cell carcinoma (OSCC).	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (161, 189))	('STAT activation', 'MPA', (95, 110))	('cancers', 'Phenotype', 'HP:0002664', (44, 51))	('Dysregulation', 'Var', (0, 13))	('SOCS', 'Gene', (17, 21))	('carcinoma', 'Phenotype', 'HP:0030731', (180, 189))	('cancers', 'Disease', (44, 51))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (166, 189))	('SOCS', 'Gene', '1154', (17, 21))	('cancers', 'Disease', 'MESH:D009369', (44, 51))	('oral squamous cell carcinoma', 'Disease', (161, 189))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
251659	27038552	Antagomir-mediated inactivation of miR-424-5p prevented the IL-8-induced cell migration and invasion, indicating that miR-424-5p is required for IL-8-induced cellular invasiveness.	('IL-8', 'Gene', (145, 149))	('miR-424', 'Gene', (35, 42))	('miR-424', 'Gene', (118, 125))	('Antagomir-mediated', 'Var', (0, 18))	('miR-424', 'Gene', '494336', (35, 42))	('IL-8', 'Gene', (60, 64))	('-424-5p', 'Chemical', '-', (38, 45))	('-424-5p', 'Chemical', '-', (121, 128))	('prevented', 'NegReg', (46, 55))	('miR-424', 'Gene', '494336', (118, 125))	('inactivation', 'Var', (19, 31))	('IL-8', 'Gene', '3576', (145, 149))	('IL-8', 'Gene', '3576', (60, 64))
251660	27038552	Taken together, these data indicate that STAT5-dependent expression of miR-424-5p plays an important role in mediating IL-8/STAT5/SOCS2 feedback loop, and scavenging miR-424-5p function using antagomir may have therapeutic potential for the treatment of OSCC.	('STAT5', 'Gene', '6776', (41, 46))	('STAT5', 'Gene', '6776', (124, 129))	('IL-8', 'Gene', '3576', (119, 123))	('miR-424', 'Gene', (166, 173))	('STAT5', 'Gene', (41, 46))	('IL-8', 'Gene', (119, 123))	('miR-424', 'Gene', (71, 78))	('STAT5', 'Gene', (124, 129))	('scavenging', 'Var', (155, 165))	('miR-424', 'Gene', '494336', (71, 78))	('miR-424', 'Gene', '494336', (166, 173))	('OSCC', 'Disease', (254, 258))
251673	27038552	Therefore, dysregulation of SOCS proteins could be one of the important mechanisms of abnormal STAT activation (Inagaki-Ohara et al., 2013).	('dysregulation', 'Var', (11, 24))	('SOCS', 'Gene', '1154', (28, 32))	('STAT activation', 'MPA', (95, 110))	('SOCS', 'Gene', (28, 32))
251674	27038552	Several mechanisms that lead to abnormal expression of SOCS proteins in cancer have been reported, such as abnormal subcellular localization (Rossa et al., 2012), genetic variations (Zhang et al., 2014), epigenetic modifications (Sutherland et al., 2004; Zhang et al., 2013), and microRNA (miRNA) regulation (Huang et al., 2013; Ru et al., 2011).	('epigenetic modifications', 'MPA', (204, 228))	('miR', 'Gene', '220972', (290, 293))	('miR', 'Gene', (290, 293))	('genetic variations', 'Var', (163, 181))	('subcellular localization', 'MPA', (116, 140))	('expression', 'MPA', (41, 51))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('SOCS', 'Gene', (55, 59))	('SOCS', 'Gene', '1154', (55, 59))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('cancer', 'Disease', (72, 78))
251677	27038552	Alterations in miRNA expression can cause various human diseases such as cancer (Calin and Croce, 2006).	('cancer', 'Disease', (73, 79))	('Calin', 'Disease', (81, 86))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('cause', 'Reg', (36, 41))	('Alterations', 'Var', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('miR', 'Gene', (15, 18))	('human', 'Species', '9606', (50, 55))	('miR', 'Gene', '220972', (15, 18))	('Croce', 'Disease', (91, 96))
251715	27038552	DOK and SCC-15 cells were cultured in 24-well plates and co-transfected with 300 ng of SOCS2 3'-untranslated region (UTR) wild-type or mutant-type pmirGLO reporter plasmid and with 25 nM of miR-424-5p mimics (PM) or control oligonucleotide (NC) with Lipofectamine 2000 according to the manufacturer's instructions.	('Lipofectamine 2000', 'Chemical', 'MESH:C086724', (250, 268))	('oligonucleotide', 'Chemical', 'MESH:D009841', (224, 239))	('mutant-type', 'Var', (135, 146))	('miR-424', 'Gene', (190, 197))	('SCC-15', 'CellLine', 'CVCL:1681', (8, 14))	('miR-424', 'Gene', '494336', (190, 197))
251727	27038552	After 16 h, the cells were treated with 10 mug/ml of cycloheximide (cat# C7698, Sigma, MO, USA) or 10 muM of MG132 (cat# M7449, Sigma, MO, USA) for indicated times.	('muM', 'Gene', (102, 105))	('cycloheximide', 'Chemical', 'MESH:D003513', (53, 66))	('muM', 'Gene', '56925', (102, 105))	('MG132', 'Chemical', 'MESH:C072553', (109, 114))	('cat# M7449', 'Var', (116, 126))
251738	27038552	The results showed that SOCS2 protein expression was significantly elevated in OEC-M1 and SCC-9 cells, and the expression of SOCS2 strongly reduced STAT5 phosphorylation (Figure 2A) and its transcriptional activity (Figure 2B).	('expression', 'Var', (111, 121))	('SCC-9', 'CellLine', 'CVCL:1685', (90, 95))	('SOCS2', 'Gene', (24, 29))	('elevated', 'PosReg', (67, 75))	('expression', 'MPA', (38, 48))	('SOCS2', 'Gene', (125, 130))	('STAT5', 'Gene', (148, 153))	('transcriptional activity', 'MPA', (190, 214))	('protein', 'Protein', (30, 37))	('STAT5', 'Gene', '6776', (148, 153))	('reduced', 'NegReg', (140, 147))
251739	27038552	Complementarily, we silenced SOCS2 in DOK and SCC-15 cells using SOCS2-specific lentiviral shRNA construct (shSOCS2) and found that shRNA-mediated silencing of ectopic SOCS2 increased STAT5 protein level and its phosphorylation (Figure 2C).	('SOCS2', 'Gene', (168, 173))	('STAT5', 'Gene', '6776', (184, 189))	('phosphorylation', 'MPA', (212, 227))	('STAT5', 'Gene', (184, 189))	('SCC-15', 'CellLine', 'CVCL:1681', (46, 52))	('increased', 'PosReg', (174, 183))	('silencing', 'Var', (147, 156))
251749	27038552	The Renilla luciferase activity of the reporter that contained SOCS2 3'-UTR was significantly suppressed by miR-424-5p mimic (PM) transfection, but the activity of the reporter that contained SOCS2 mutant 3'-UTR had no significant change (Figure 3D).	('miR-424', 'Gene', (108, 115))	('SOCS2', 'Gene', (63, 68))	('transfection', 'Var', (130, 142))	('miR-424', 'Gene', '494336', (108, 115))	('suppressed', 'NegReg', (94, 104))	('activity', 'MPA', (23, 31))	('Renilla luciferase', 'Enzyme', (4, 22))	('-424-5p', 'Chemical', '-', (111, 118))
251755	27038552	SCC-15 (high expression of SOCS2) and OEC-M1 (low expression of SOCS2) cells were treated with or without proteasome inhibitor MG132 and collected protein lysate at 12 h. The protein level of SOCS2 was accumulated in the presence of MG132 (Supplementary Figure 4A), indicating that the proteasome is required for degradation of SOCS2.	('SOCS2', 'Gene', (192, 197))	('MG132', 'Var', (233, 238))	('MG132', 'Chemical', 'MESH:C072553', (233, 238))	('MG132', 'Chemical', 'MESH:C072553', (127, 132))	('SCC-15', 'CellLine', 'CVCL:1681', (0, 6))	('protein', 'MPA', (175, 182))	('accumulated', 'PosReg', (202, 213))
251766	27038552	Moreover, SOCS2 restoration was able to reduce the expression of canonical STAT5-transcriptional targets, such as MMP-2 and MMP-9 (Figure 4B and Supplementary Figure 2B).	('MMP-2', 'Gene', '4313', (114, 119))	('SOCS2', 'Gene', (10, 15))	('MMP-9', 'Gene', '4318', (124, 129))	('reduce', 'NegReg', (40, 46))	('restoration', 'Var', (16, 27))	('MMP-9', 'Gene', (124, 129))	('STAT5', 'Gene', '6776', (75, 80))	('expression', 'MPA', (51, 61))	('MMP-2', 'Gene', (114, 119))	('STAT5', 'Gene', (75, 80))
251768	27038552	As expected, the restoration of SOCS2 potently suppressed the migration and invasion activities induced by miR-424-5p overexpression (Figure 4C and D).	('suppressed', 'NegReg', (47, 57))	('overexpression', 'PosReg', (118, 132))	('miR-424', 'Gene', (107, 114))	('SOCS2', 'Gene', (32, 37))	('miR-424', 'Gene', '494336', (107, 114))	('restoration', 'Var', (17, 28))
251780	27038552	Interestingly, suppression of NF-kappaB activity only resulted in a moderate decrease of IL-8-induced miR-424-5p expression, however, suppression of STAT5 activity dramatically reduced the IL-8-induced miR-424-5p expression (Figure 5H), suggesting that STAT5 is a major downstream effector for mature miR-424-5p formation.	('miR-424', 'Gene', '494336', (102, 109))	('reduced', 'NegReg', (177, 184))	('IL-8', 'Gene', '3576', (189, 193))	('miR-424', 'Gene', (202, 209))	('STAT5', 'Gene', '6776', (253, 258))	('decrease', 'NegReg', (77, 85))	('miR-424', 'Gene', '494336', (202, 209))	('STAT5', 'Gene', (253, 258))	('IL-8', 'Gene', (89, 93))	('suppression', 'NegReg', (15, 26))	('STAT5', 'Gene', '6776', (149, 154))	('miR-424', 'Gene', (301, 308))	('suppression', 'Var', (134, 145))	('STAT5', 'Gene', (149, 154))	('NF-kappaB', 'Gene', (30, 39))	('IL-8', 'Gene', (189, 193))	('miR-424', 'Gene', '494336', (301, 308))	('NF-kappaB', 'Gene', '4790', (30, 39))	('IL-8', 'Gene', '3576', (89, 93))	('miR-424', 'Gene', (102, 109))
251787	27038552	However, the JAK/STAT pathway requires precise cellular control and loss of the tightly regulation can promote the inflammatory disease and tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('promote', 'PosReg', (103, 110))	('loss', 'Var', (68, 72))	('inflammatory disease', 'Disease', (115, 135))	('tumor', 'Disease', (140, 145))
251799	27038552	Functional studies have shown that transgenic mice with SOCS2 alleles disruption exert an increase in the spontaneous development of tumors (Newton et al., 2010), strongly suggesting the tumor suppressive activity of SOCS2.	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('transgenic mice', 'Species', '10090', (35, 50))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('alleles', 'Var', (62, 69))	('increase', 'PosReg', (90, 98))	('tumors', 'Disease', (133, 139))	('SOCS2', 'Gene', (56, 61))	('tumors', 'Disease', 'MESH:D009369', (133, 139))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumor', 'Disease', (187, 192))	('tumor', 'Disease', (133, 138))
251810	27038552	One possibility is that SOCS2 gene is epigenetic silencing by hypermethylation of CpG dinucleotides in its promoter region in various cancer cells and cancer cell lines (Fiegl et al., 2004; Liu et al., 2008; Sutherland et al., 2004).	('hypermethylation', 'Var', (62, 78))	('SOCS2', 'Gene', (24, 29))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('dinucleotides', 'Chemical', 'MESH:D015226', (86, 99))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('cancer', 'Disease', (151, 157))	('epigenetic', 'Var', (38, 48))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
251811	27038552	Treatment of colon cancer cells with 5-aza-dC (a DNA methyltransferase inhibitor) has been shown to increase the basal SOCS2 expression, demonstrating that the DNA methylation is responsible for the reduced SOCS2 expression (Letellier et al., 2014).	('5-aza-dC', 'Chemical', 'MESH:D000077209', (37, 45))	('expression', 'MPA', (213, 223))	('basal', 'MPA', (113, 118))	('colon cancer', 'Phenotype', 'HP:0003003', (13, 25))	('colon cancer', 'Disease', 'MESH:D015179', (13, 25))	('SOCS2', 'Gene', (119, 124))	('expression', 'MPA', (125, 135))	('5-aza-dC', 'Var', (37, 45))	('colon cancer', 'Disease', (13, 25))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('increase', 'PosReg', (100, 108))	('reduced', 'NegReg', (199, 206))
251821	27038552	Furthermore, restoration of SOCS2 expression could block miR-424-5p-induced migration and invasion in oral cancer cells, indicating that miR-424-5p-mediated tumor malignancy is SOCS2 dependent.	('oral cancer', 'Disease', 'MESH:D009062', (102, 113))	('SOCS2', 'Gene', (28, 33))	('miR-424', 'Gene', '494336', (137, 144))	('tumor malignancy', 'Disease', 'MESH:D018198', (157, 173))	('expression', 'MPA', (34, 44))	('miR-424', 'Gene', '494336', (57, 64))	('oral cancer', 'Disease', (102, 113))	('migration', 'CPA', (76, 85))	('block', 'NegReg', (51, 56))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('tumor malignancy', 'Disease', (157, 173))	('miR-424', 'Gene', (57, 64))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('restoration', 'Var', (13, 24))	('miR-424', 'Gene', (137, 144))	('invasion', 'CPA', (90, 98))
251831	27038552	Furthermore, antagomir-mediated inactivation of miR-424-5p prevented the IL-8-induced cell migration and invasion, demonstrating the essential role of miR-424-5p in IL-8-induced cellular invasiveness.	('miR-424', 'Gene', (151, 158))	('prevented', 'NegReg', (59, 68))	('miR-424', 'Gene', (48, 55))	('miR-424', 'Gene', '494336', (151, 158))	('IL-8', 'Gene', '3576', (165, 169))	('antagomir-mediated inactivation', 'Var', (13, 44))	('-424-5p', 'Chemical', '-', (154, 161))	('-424-5p', 'Chemical', '-', (51, 58))	('miR-424', 'Gene', '494336', (48, 55))	('IL-8', 'Gene', (165, 169))	('IL-8', 'Gene', '3576', (73, 77))	('IL-8', 'Gene', (73, 77))
251832	27038552	Besides IL-8 and STAT5, which are well established targets for cancer treatment, here we propose that scavenging miR-424-5p expression and function using antagomir may have therapeutic potential for the treatment of invasive OSCC.	('IL-8', 'Gene', '3576', (8, 12))	('IL-8', 'Gene', (8, 12))	('scavenging', 'Var', (102, 112))	('STAT5', 'Gene', (17, 22))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('expression', 'MPA', (124, 134))	('STAT5', 'Gene', '6776', (17, 22))	('miR-424', 'Gene', (113, 120))	('invasive OSCC', 'Disease', (216, 229))	('cancer', 'Disease', (63, 69))	('miR-424', 'Gene', '494336', (113, 120))
251871	33061814	Genetic landscape of mutations in ACE2, TMPRSS2 and IFITM3 were analyzed by the cBioCancer Genomics Portal (c-BioPortal, https://www.cbioportal.org/) based on The Cancer Genome Atlas (TCGA).	('Cancer', 'Disease', 'MESH:D009369', (84, 90))	('IFITM3', 'Gene', (52, 58))	('ACE2', 'Gene', (34, 38))	('IFITM3', 'Gene', '10410', (52, 58))	('Cancer', 'Phenotype', 'HP:0002664', (163, 169))	('TMPRSS2', 'Gene', '7113', (40, 47))	('ACE2', 'Gene', '59272', (34, 38))	('Cancer', 'Disease', 'MESH:D009369', (163, 169))	('Cancer', 'Disease', (163, 169))	('TMPRSS2', 'Gene', (40, 47))	('Cancer', 'Phenotype', 'HP:0002664', (84, 90))	('Cancer', 'Disease', (84, 90))	('mutations', 'Var', (21, 30))
251895	33061814	The top 3 cancers with mutated ACE2 were undifferentiated stomach adenocarcinoma, esophageal squamous cell carcinoma and endometrial carcinoma and those with TMPRSS2 were prostate adenocarcinoma, undifferentiated stomach adenocarcinoma and melanoma.	('ACE2', 'Gene', '59272', (31, 35))	('TMPRSS2', 'Gene', (158, 165))	('esophageal squamous cell carcinoma', 'Disease', (82, 116))	('mutated', 'Var', (23, 30))	('ACE2', 'Gene', (31, 35))	('cancers', 'Phenotype', 'HP:0002664', (10, 17))	('cancers', 'Disease', (10, 17))	('undifferentiated stomach adenocarcinoma', 'Disease', 'MESH:D002277', (41, 80))	('prostate adenocarcinoma', 'Disease', 'MESH:D011471', (171, 194))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('undifferentiated stomach adenocarcinoma', 'Disease', (196, 235))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (82, 116))	('endometrial carcinoma', 'Disease', (121, 142))	('melanoma', 'Disease', 'MESH:D008545', (240, 248))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (93, 116))	('carcinoma', 'Phenotype', 'HP:0030731', (226, 235))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (121, 142))	('cancers', 'Disease', 'MESH:D009369', (10, 17))	('undifferentiated stomach adenocarcinoma', 'Disease', 'MESH:D002277', (196, 235))	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (121, 142))	('carcinoma', 'Phenotype', 'HP:0030731', (185, 194))	('melanoma', 'Phenotype', 'HP:0002861', (240, 248))	('undifferentiated stomach adenocarcinoma', 'Disease', (41, 80))	('TMPRSS2', 'Gene', '7113', (158, 165))	('melanoma', 'Disease', (240, 248))	('prostate adenocarcinoma', 'Disease', (171, 194))
251897	33061814	The main mutation type of ACE2 and IFITM3 was deep deletion and that of TMPRSS2 was fusion.	('deep deletion', 'Var', (46, 59))	('ACE2', 'Gene', (26, 30))	('TMPRSS2', 'Gene', (72, 79))	('IFITM3', 'Gene', (35, 41))	('ACE2', 'Gene', '59272', (26, 30))	('IFITM3', 'Gene', '10410', (35, 41))	('fusion', 'Var', (84, 90))	('TMPRSS2', 'Gene', '7113', (72, 79))
251899	33061814	Database results also showed that these mutated genes could up-regulate their expression levels in cancers.	('cancers', 'Disease', 'MESH:D009369', (99, 106))	('cancers', 'Phenotype', 'HP:0002664', (99, 106))	('cancers', 'Disease', (99, 106))	('mutated', 'Var', (40, 47))	('expression levels', 'MPA', (78, 95))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('up-regulate', 'PosReg', (60, 71))
251901	33061814	TMPRSS2 and IFITM3 mutations exhibited mutual exclusivity (Table S4).	('TMPRSS2', 'Gene', '7113', (0, 7))	('TMPRSS2', 'Gene', (0, 7))	('mutations', 'Var', (19, 28))	('IFITM3', 'Gene', '10410', (12, 18))	('IFITM3', 'Gene', (12, 18))
251906	33061814	The high expression of TMPRSS2 might indicate a poor prognosis in BRCA (p = 0.014), but reveal a favorable prognosis in LUAD (p = 0.0016).	('BRCA', 'Phenotype', 'HP:0003002', (66, 70))	('TMPRSS2', 'Gene', (23, 30))	('BRCA', 'Gene', (66, 70))	('BRCA', 'Gene', '672', (66, 70))	('TMPRSS2', 'Gene', '7113', (23, 30))	('high', 'Var', (4, 8))	('LUAD', 'Phenotype', 'HP:0030078', (120, 124))
251925	33061814	The genetic variants of IFITM3 were associated with disease severity in COVID-19 patients.	('IFITM3', 'Gene', (24, 30))	('COVID-19', 'Disease', (72, 80))	('IFITM3', 'Gene', '10410', (24, 30))	('disease', 'Disease', (52, 59))	('patients', 'Species', '9606', (81, 89))	('genetic variants', 'Var', (4, 20))	('COVID-19', 'Disease', 'MESH:C000657245', (72, 80))	('associated', 'Reg', (36, 46))
251937	33061814	The profiling data on mutation status in ACE2, TMPRSS2 and IFITM3 indicated that low-frequency mutations may have little effect on the protein crystal structure and gene expression.	('mutation', 'Var', (22, 30))	('TMPRSS2', 'Gene', (47, 54))	('IFITM3', 'Gene', (59, 65))	('ACE2', 'Gene', (41, 45))	('IFITM3', 'Gene', '10410', (59, 65))	('gene expression', 'MPA', (165, 180))	('TMPRSS2', 'Gene', '7113', (47, 54))	('mutations', 'Var', (95, 104))	('ACE2', 'Gene', '59272', (41, 45))
251955	31802951	Comparison of 37 cases with epidermal growth factor receptor (EGFR) gene mutation versus 26 cases without mutations showed that there was no correlation between the distribution of brain metastasis and gene mutation.	('EGFR', 'Gene', '1956', (62, 66))	('epidermal growth factor receptor', 'Gene', (28, 60))	('EGFR', 'Gene', (62, 66))	('mutation', 'Var', (73, 81))	('epidermal growth factor receptor', 'Gene', '1956', (28, 60))
251980	31802951	Of those, 43 patients had gene mutations, including epidermal growth factor receptor (EGFR) gene mutations and anaplastic lymphoma kinase (ALK) gene mutations.	('mutations', 'Var', (97, 106))	('ALK', 'Gene', (139, 142))	('EGFR', 'Gene', '1956', (86, 90))	('patients', 'Species', '9606', (13, 21))	('anaplastic lymphoma kinase', 'Gene', '238', (111, 137))	('epidermal growth factor receptor', 'Gene', (52, 84))	('EGFR', 'Gene', (86, 90))	('ALK', 'Gene', '238', (139, 142))	('lymphoma', 'Phenotype', 'HP:0002665', (122, 130))	('epidermal growth factor receptor', 'Gene', '1956', (52, 84))	('anaplastic lymphoma kinase', 'Gene', (111, 137))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (111, 130))
251995	31802951	Among the 43 patients with a mutated gene, 37 patients had EGFR gene mutations and four patients had ALK gene mutations.	('ALK', 'Gene', (101, 104))	('mutations', 'Var', (69, 78))	('patients', 'Species', '9606', (46, 54))	('EGFR', 'Gene', (59, 63))	('patients', 'Species', '9606', (88, 96))	('patients', 'Species', '9606', (13, 21))	('ALK', 'Gene', '238', (101, 104))	('mutated gene', 'Var', (29, 41))	('EGFR', 'Gene', '1956', (59, 63))
251996	31802951	Among those with mutated EGFR, two patients had mutations at exon 18; 14 patients at exon 19; one patient at exon 20; 17 patients at exon 21; and three patients had dual mutations (one at exon 18 and 20; one at exons 19 and 20; and one at exons 19 and 21).	('EGFR', 'Gene', (25, 29))	('patient', 'Species', '9606', (98, 105))	('patient', 'Species', '9606', (35, 42))	('patient', 'Species', '9606', (152, 159))	('patient', 'Species', '9606', (73, 80))	('patients', 'Species', '9606', (152, 160))	('patients', 'Species', '9606', (35, 43))	('patient', 'Species', '9606', (121, 128))	('patients', 'Species', '9606', (73, 81))	('patients', 'Species', '9606', (121, 129))	('mutations', 'Var', (48, 57))	('mutated', 'Var', (17, 24))	('EGFR', 'Gene', '1956', (25, 29))
252009	31802951	In patients with EGFR gene mutations, the left frontal lobe (62%; 23/37 patients), right frontal lobe (62%; 23/37 patients) and cerebellum (57%; 21/37 patients) had the highest rate of metastasis.	('mutations', 'Var', (27, 36))	('right frontal lobe', 'Disease', 'MESH:D001927', (83, 101))	('patients', 'Species', '9606', (72, 80))	('patients', 'Species', '9606', (151, 159))	('patients', 'Species', '9606', (3, 11))	('right frontal lobe', 'Disease', (83, 101))	('EGFR', 'Gene', '1956', (17, 21))	('patients', 'Species', '9606', (114, 122))	('metastasis', 'CPA', (185, 195))	('EGFR', 'Gene', (17, 21))
252010	31802951	However, there was no statistically significant difference (P=0.998>0.05) between patients with EGFR gene mutations and those with wild-type EGFR (26 patients).	('EGFR', 'Gene', '1956', (141, 145))	('EGFR', 'Gene', (96, 100))	('patients', 'Species', '9606', (82, 90))	('EGFR', 'Gene', (141, 145))	('patients', 'Species', '9606', (150, 158))	('mutations', 'Var', (106, 115))	('EGFR', 'Gene', '1956', (96, 100))
252011	31802951	The highest incidence of metastasis with ALK gene mutations was reported in the right parietal lobe (75%; 3/4 patients) and right frontal lobe (75%; 3/4 patients).	('right frontal lobe', 'Disease', (124, 142))	('patients', 'Species', '9606', (153, 161))	('mutations', 'Var', (50, 59))	('patients', 'Species', '9606', (110, 118))	('right frontal lobe', 'Disease', 'MESH:D001927', (124, 142))	('ALK', 'Gene', (41, 44))	('ALK', 'Gene', '238', (41, 44))	('metastasis', 'CPA', (25, 35))
252032	31802951	In lung cancer, patients with mutant EGFR had a higher frequency of brain metastasis than those with wild-type EGFR Furthermore, among patients with EGFR mutations, the incidence of brain metastasis was significantly higher in patients with mutation at exon 19 than in those with mutation at other sites.	('patients', 'Species', '9606', (135, 143))	('EGFR', 'Gene', '1956', (111, 115))	('lung cancer', 'Phenotype', 'HP:0100526', (3, 14))	('patients', 'Species', '9606', (16, 24))	('mutation at exon 19', 'Var', (241, 260))	('EGFR', 'Gene', '1956', (149, 153))	('EGFR', 'Gene', '1956', (37, 41))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('patients', 'Species', '9606', (227, 235))	('brain metastasis', 'CPA', (182, 198))	('lung cancer', 'Disease', (3, 14))	('higher', 'PosReg', (217, 223))	('EGFR', 'Gene', (111, 115))	('mutant', 'Var', (30, 36))	('EGFR', 'Gene', (149, 153))	('mutations', 'Var', (154, 163))	('lung cancer', 'Disease', 'MESH:D008175', (3, 14))	('EGFR', 'Gene', (37, 41))	('brain metastasis', 'CPA', (68, 84))
252033	31802951	Takano et al reported that brain metastasis from lung cancer in patients with an EGFR L858R mutation occurred more often in the caudate nucleus, cerebellum, and temporal lobe than those with an EGFR exon 19 deletion.	('lung cancer', 'Disease', 'MESH:D008175', (49, 60))	('brain metastasis', 'CPA', (27, 43))	('patients', 'Species', '9606', (64, 72))	('L858R', 'Var', (86, 91))	('lung cancer', 'Disease', (49, 60))	('lung cancer', 'Phenotype', 'HP:0100526', (49, 60))	('EGFR', 'Gene', '1956', (194, 198))	('L858R', 'Mutation', 'rs121434568', (86, 91))	('EGFR', 'Gene', (194, 198))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('EGFR', 'Gene', '1956', (81, 85))	('EGFR', 'Gene', (81, 85))
252035	31802951	However, our results showed that there was no statistical significance in the distribution of brain metastasis between patients with EGFR gene mutations and those without mutations (P=0.998).	('patients', 'Species', '9606', (119, 127))	('brain metastasis', 'CPA', (94, 110))	('EGFR', 'Gene', '1956', (133, 137))	('EGFR', 'Gene', (133, 137))	('mutations', 'Var', (143, 152))
252036	31802951	A possible explanation for this difference is that Takano et al compared various types of EGFR mutations, while we compared mutated and wild-type subgroups.	('EGFR', 'Gene', '1956', (90, 94))	('EGFR', 'Gene', (90, 94))	('mutations', 'Var', (95, 104))
252038	31802951	The roles of molecules related to the EGFR mutation status will be studied further in the near future.	('mutation', 'Var', (43, 51))	('EGFR', 'Gene', (38, 42))	('EGFR', 'Gene', '1956', (38, 42))
252041	31802951	Secondly, we only compared patients with EGFR gene mutations, while those with ALK gene mutations were not analyzed due to the small sample size.	('ALK', 'Gene', '238', (79, 82))	('EGFR', 'Gene', (41, 45))	('mutations', 'Var', (51, 60))	('patients', 'Species', '9606', (27, 35))	('ALK', 'Gene', (79, 82))	('EGFR', 'Gene', '1956', (41, 45))
252054	31030664	In recent years, it has been reported that epidermal growth factor receptor (EGFR) mutations and the echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) fusion gene are involved in the diagnosis of lung cancer, and it is known that the presence or absence of these also affect treatment.	('echinoderm microtubule-associated protein-like 4', 'Gene', (101, 149))	('anaplastic lymphoma', 'Disease', (157, 176))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('affect', 'Reg', (307, 313))	('involved', 'Reg', (206, 214))	('EGFR', 'Gene', '1956', (77, 81))	('lymphoma', 'Phenotype', 'HP:0002665', (168, 176))	('lung cancer', 'Disease', (235, 246))	('ALK', 'Gene', '238', (185, 188))	('ALK', 'Gene', (185, 188))	('epidermal growth factor receptor', 'Gene', (43, 75))	('anaplastic lymphoma', 'Disease', 'MESH:D017728', (157, 176))	('mutations', 'Var', (83, 92))	('epidermal growth factor receptor', 'Gene', '1956', (43, 75))	('EML4', 'Gene', (151, 155))	('lung cancer', 'Disease', 'MESH:D008175', (235, 246))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (157, 176))	('echinoderm microtubule-associated protein-like 4', 'Gene', '27436', (101, 149))	('EML4', 'Gene', '27436', (151, 155))	('EGFR', 'Gene', (77, 81))	('lung cancer', 'Phenotype', 'HP:0100526', (235, 246))
252117	30050312	Silencing of MMP-7 significantly decreased cervical cancer cell proliferation, migration, and invasion.	('invasion', 'CPA', (94, 102))	('migration', 'CPA', (79, 88))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('cervical cancer', 'Disease', 'MESH:D002583', (43, 58))	('MMP-7', 'Gene', (13, 18))	('cervical cancer', 'Disease', (43, 58))	('MMP-7', 'Gene', '4316', (13, 18))	('decreased', 'NegReg', (33, 42))	('Silencing', 'Var', (0, 9))
252186	30050312	Further functional studies demonstrated that knockdown of MMP-7 significantly decreased the proliferation of Hela and Caski cells (Figure 3).	('MMP-7', 'Gene', (58, 63))	('Hela', 'CellLine', 'CVCL:0030', (109, 113))	('decreased', 'NegReg', (78, 87))	('MMP-7', 'Gene', '4316', (58, 63))	('knockdown', 'Var', (45, 54))
252188	30050312	Moreover, knockdown of MMP-7 also suppressed cervical cancer cell invasion in vitro, as demonstrated by the transwell invasion assay (Figure 5).	('suppressed', 'NegReg', (34, 44))	('MMP-7', 'Gene', '4316', (23, 28))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('transwell invasion assay', 'CPA', (108, 132))	('cervical cancer', 'Disease', (45, 60))	('cervical cancer', 'Disease', 'MESH:D002583', (45, 60))	('knockdown', 'Var', (10, 19))	('MMP-7', 'Gene', (23, 28))
252189	30050312	Taken together, these data indicated that silencing of MMP-7 in cervical cancer cells suppressed cell proliferation, migration, and invasion in vitro.	('MMP-7', 'Gene', '4316', (55, 60))	('silencing', 'Var', (42, 51))	('migration', 'CPA', (117, 126))	('cervical cancer', 'Disease', (64, 79))	('cervical cancer', 'Disease', 'MESH:D002583', (64, 79))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('MMP-7', 'Gene', (55, 60))	('suppressed', 'NegReg', (86, 96))	('cell proliferation', 'CPA', (97, 115))	('invasion', 'CPA', (132, 140))
252206	30050312	Since E6/E7 play a key role in the development of cervical cancer, to further investigate the relationship between E6/E7 and MMP-7, we silenced E6/E7 in Caski and Hela cells and then performed a whole-genome microarray analysis in siRNA-E6/E7 and siRNA-control cells (the details are described in Supplementary materials).	('MMP-7', 'Gene', '4316', (125, 130))	('cervical cancer', 'Disease', 'MESH:D002583', (50, 65))	('cervical cancer', 'Disease', (50, 65))	('E6/E7', 'Gene', (144, 149))	('Hela cells', 'CellLine', 'CVCL:0030', (163, 173))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('MMP-7', 'Gene', (125, 130))	('silenced', 'Var', (135, 143))
252238	30050312	This is consistent with our study, as we also found that silencing of MMP-7 suppressed cell proliferation, migration, and invasion in vitro and that serum MMP-7 concentrations were much higher in cervical cancer patients compared with normal controls.	('MMP-7', 'Gene', '4316', (70, 75))	('migration', 'CPA', (107, 116))	('invasion in vitro', 'CPA', (122, 139))	('cervical cancer', 'Disease', 'MESH:D002583', (196, 211))	('cell proliferation', 'CPA', (87, 105))	('patients', 'Species', '9606', (212, 220))	('silencing', 'Var', (57, 66))	('suppressed', 'NegReg', (76, 86))	('cervical cancer', 'Disease', (196, 211))	('serum', 'MPA', (149, 154))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('MMP-7', 'Gene', (70, 75))	('MMP-7', 'Gene', (155, 160))	('higher', 'PosReg', (186, 192))	('MMP-7', 'Gene', '4316', (155, 160))
252243	30050312	HPV16 and HPV18 are the most carcinogenic HPVs.	('HPV', 'Species', '10566', (10, 13))	('HPV', 'Species', '10566', (42, 45))	('HPV', 'Species', '10566', (0, 3))	('HPV16', 'Species', '333760', (0, 5))	('carcinogenic HPVs', 'Disease', 'MESH:D063646', (29, 46))	('HPV18', 'Gene', (10, 15))	('HPV16', 'Var', (0, 5))	('carcinogenic HPVs', 'Disease', (29, 46))
252256	30050312	Our study confirmed the aberrant expression and clinical significance of MMP-7 in cervical cancer.	('MMP-7', 'Gene', '4316', (73, 78))	('clinical', 'Species', '191496', (48, 56))	('cervical cancer', 'Disease', (82, 97))	('cervical cancer', 'Disease', 'MESH:D002583', (82, 97))	('aberrant expression', 'Var', (24, 43))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('MMP-7', 'Gene', (73, 78))
252257	30050312	Moreover, we found that MMP-7 knockdown suppressed cervical cancer cell proliferation, invasion, and migration.	('suppressed', 'NegReg', (40, 50))	('migration', 'CPA', (101, 110))	('MMP-7', 'Gene', '4316', (24, 29))	('MMP-7', 'Gene', (24, 29))	('knockdown', 'Var', (30, 39))	('invasion', 'CPA', (87, 95))	('cervical cancer', 'Disease', (51, 66))	('cervical cancer', 'Disease', 'MESH:D002583', (51, 66))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
252264	29796170	The majority of cSCC cell lines are more sensitive than normal skin cells to death induced by the SF3B1 inhibitor pladienolide B. Knockdown of SF3B1 and a range of other splicing factors with diverse roles in the spliceosome can also selectively kill cSCC cells.	('pladienolide B', 'Chemical', 'MESH:C522342', (114, 128))	('Knockdown', 'Var', (130, 139))	('cSCC', 'Phenotype', 'HP:0006739', (16, 20))	('splicing factor', 'Gene', (170, 185))	('SF3B1', 'Gene', '23451', (98, 103))	('SF3B1', 'Gene', (143, 148))	('cSCC', 'Phenotype', 'HP:0006739', (251, 255))	('SF3B1', 'Gene', '23451', (143, 148))	('splicing factor', 'Gene', '10569', (170, 185))	('cSCC', 'Disease', (251, 255))	('SF3B1', 'Gene', (98, 103))
252266	29796170	c-MYC expression is elevated in cSCC lines and its knockdown reduces alterations in mRNA splicing and attenuates cell death caused by interference with the spliceosome.	('attenuates', 'NegReg', (102, 112))	('mRNA splicing', 'MPA', (84, 97))	('cell death', 'CPA', (113, 123))	('expression', 'MPA', (6, 16))	('c-MYC', 'Gene', '4609', (0, 5))	('interference', 'MPA', (134, 146))	('c-MYC', 'Gene', (0, 5))	('reduces', 'NegReg', (61, 68))	('alterations', 'MPA', (69, 80))	('cSCC', 'Phenotype', 'HP:0006739', (32, 36))	('knockdown', 'Var', (51, 60))
252267	29796170	SF3B1 inhibition causes wild-type p53 upregulation associated with altered mRNA splicing and reduced protein expression of both principal p53 negative regulators MDMX/MDM4 and MDM2.	('p53', 'Gene', (34, 37))	('MDM4', 'Gene', (167, 171))	('SF3B1', 'Gene', (0, 5))	('mRNA splicing', 'MPA', (75, 88))	('reduced', 'NegReg', (93, 100))	('SF3B1', 'Gene', '23451', (0, 5))	('protein expression', 'MPA', (101, 119))	('altered', 'Reg', (67, 74))	('inhibition', 'Var', (6, 16))	('MDM4', 'Gene', '4194', (167, 171))	('upregulation', 'PosReg', (38, 50))
252269	29796170	However, p53 is commonly inactivated by mutation in cSCCs and p53 participates in killing normal skin cells at high concentrations of pladienolide B.	('mutation', 'Var', (40, 48))	('participates', 'Reg', (66, 78))	('cSCCs', 'Gene', (52, 57))	('p53', 'Gene', (9, 12))	('pladienolide B', 'Chemical', 'MESH:C522342', (134, 148))	('killing normal skin cells', 'CPA', (82, 107))	('cSCC', 'Phenotype', 'HP:0006739', (52, 56))	('p53', 'Gene', (62, 65))
252271	29796170	We provide evidence that, while suppression of SF3B1 has promise for treating cSCCs with mutant p53, inhibitors which target the spliceosome through SF3B1-independent mechanisms could have greater cSCC selectivity as a consequence of reduced p53 upregulation in normal cells.	('p53', 'Gene', (96, 99))	('SF3B1', 'Gene', (47, 52))	('cSCC', 'Phenotype', 'HP:0006739', (197, 201))	('upregulation', 'PosReg', (246, 258))	('SF3B1', 'Gene', '23451', (149, 154))	('cSCC', 'Phenotype', 'HP:0006739', (78, 82))	('p53', 'Gene', (242, 245))	('SF3B1', 'Gene', '23451', (47, 52))	('cSCCs', 'Disease', (78, 83))	('SF3B1', 'Gene', (149, 154))	('mutant', 'Var', (89, 95))
252286	29796170	Importantly, only a subset of splicing events is affected by knockdown of a particular core splicing factor: there are alterations in splice site selection rather than generalised inhibition of splicing and the effects of suppressing different core splicing factors can be divergent.	('splicing factor', 'Gene', '10569', (249, 264))	('splicing factor', 'Gene', '10569', (92, 107))	('knockdown', 'Var', (61, 70))	('splice site selection', 'MPA', (134, 155))	('splicing factor', 'Gene', (249, 264))	('splicing factor', 'Gene', (92, 107))	('alterations', 'Reg', (119, 130))
252293	29796170	A point mutation in SF3B1 has been shown to decrease the binding of pladienolide B to the spliceosome and to dramatically reduce the potency of its effects on cell viability.	('binding', 'Interaction', (57, 64))	('SF3B1', 'Gene', (20, 25))	('reduce', 'NegReg', (122, 128))	('decrease', 'NegReg', (44, 52))	('potency', 'MPA', (133, 140))	('spliceosome', 'Protein', (90, 101))	('SF3B1', 'Gene', '23451', (20, 25))	('pladienolide B', 'Chemical', 'MESH:C522342', (68, 82))	('cell viability', 'CPA', (159, 173))	('point mutation', 'Var', (2, 16))	('effects on', 'MPA', (148, 158))
252294	29796170	SF3B1 inhibitors have good pre-clinical anti-tumour activity in model systems.	('SF3B1', 'Gene', (0, 5))	('tumour', 'Phenotype', 'HP:0002664', (45, 51))	('SF3B1', 'Gene', '23451', (0, 5))	('tumour', 'Disease', 'MESH:D009369', (45, 51))	('inhibitors', 'Var', (6, 16))	('tumour', 'Disease', (45, 51))	('clinical', 'Species', '191496', (31, 39))
252302	29796170	Altered splicing of the mRNAs coding for the anti-apoptotic proteins BCL-X and MCL-1 can also contribute to the anti-tumour activity of targeting the spliceosome.	('BCL-X', 'Gene', '598', (69, 74))	('MCL-1', 'Gene', '4170', (79, 84))	('tumour', 'Phenotype', 'HP:0002664', (117, 123))	('BCL-X', 'Gene', (69, 74))	('tumour', 'Disease', 'MESH:D009369', (117, 123))	('Altered splicing', 'Var', (0, 16))	('contribute', 'Reg', (94, 104))	('tumour', 'Disease', (117, 123))	('spliceosome', 'Protein', (150, 161))	('MCL-1', 'Gene', (79, 84))
252308	29796170	Consistent with previous observations, suppression of SF3B1 reduces the expression of MDM2 as well as MDMX and causes strong upregulation of wild-type p53.	('SF3B1', 'Gene', (54, 59))	('upregulation', 'PosReg', (125, 137))	('SF3B1', 'Gene', '23451', (54, 59))	('suppression', 'Var', (39, 50))	('expression', 'MPA', (72, 82))	('reduces', 'NegReg', (60, 67))	('MDM2', 'Gene', (86, 90))	('MDMX', 'Gene', (102, 106))
252309	29796170	We show that small molecule inhibition of the splicing factor SF3B1 has promise for treating cSCCs with mutant p53.	('cSCCs', 'Disease', (93, 98))	('mutant', 'Var', (104, 110))	('p53', 'Gene', (111, 114))	('splicing factor', 'Gene', (46, 61))	('SF3B1', 'Gene', (62, 67))	('cSCC', 'Phenotype', 'HP:0006739', (93, 97))	('SF3B1', 'Gene', '23451', (62, 67))	('splicing factor', 'Gene', '10569', (46, 61))
252321	29796170	Splicing factor knockdown caused a greater reduction in the viability of cSCC cell lines than normal skin cells (Figure 1, left panels).	('viability', 'CPA', (60, 69))	('reduction', 'NegReg', (43, 52))	('knockdown', 'Var', (16, 25))	('Splicing factor', 'Gene', (0, 15))	('cSCC', 'Phenotype', 'HP:0006739', (73, 77))	('Splicing factor', 'Gene', '10569', (0, 15))	('cSCC cell lines', 'CPA', (73, 88))
252326	29796170	Suppression of PRPF19 killed SCCRDEB4 and SCCTMet cell lines but it did not increase cell death in SCCRDEBMet cells.	('PRPF19', 'Gene', '27339', (15, 21))	('Suppression', 'Var', (0, 11))	('PRPF19', 'Gene', (15, 21))
252335	29796170	Overall these results indicate that small-molecule inhibition of SF3B1 has potential for cSCC therapy.	('SF3B1', 'Gene', (65, 70))	('cSCC', 'Phenotype', 'HP:0006739', (89, 93))	('small-molecule inhibition', 'Var', (36, 61))	('SF3B1', 'Gene', '23451', (65, 70))	('cSCC', 'Disease', (89, 93))
252337	29796170	Alterations in mRNA splicing of BCL-2 family members can promote cell death brought about by targeting the spliceosome.	('mRNA splicing', 'MPA', (15, 28))	('spliceosome', 'MPA', (107, 118))	('promote', 'PosReg', (57, 64))	('Alterations', 'Var', (0, 11))	('cell death', 'CPA', (65, 75))	('BCL-2', 'Gene', '596', (32, 37))	('BCL-2', 'Gene', (32, 37))
252341	29796170	Knockdown of c-MYC attenuated cell death caused by depletion of PRPF8 or SF3B1 in SCCRDEBMet cells and depletion of PRPF8 in SCCRDEB4 cells (Figure 3).	('depletion', 'MPA', (51, 60))	('cell death', 'CPA', (30, 40))	('SF3B1', 'Gene', '23451', (73, 78))	('c-MYC', 'Gene', '4609', (13, 18))	('PRPF8', 'Gene', '10594', (116, 121))	('PRPF8', 'Gene', (116, 121))	('PRPF8', 'Gene', '10594', (64, 69))	('PRPF8', 'Gene', (64, 69))	('c-MYC', 'Gene', (13, 18))	('depletion', 'Var', (103, 112))	('SF3B1', 'Gene', (73, 78))	('attenuated', 'NegReg', (19, 29))
252344	29796170	There was little or no effect of PRPF8 or SF3B1 knockdown on the level of MCL-1 or BCL-X under circumstances where cell death was dependent on c-MYC.	('PRPF8', 'Gene', '10594', (33, 38))	('BCL-X', 'Gene', '598', (83, 88))	('c-MYC', 'Gene', (143, 148))	('PRPF8', 'Gene', (33, 38))	('SF3B1', 'Gene', (42, 47))	('BCL-X', 'Gene', (83, 88))	('c-MYC', 'Gene', '4609', (143, 148))	('MCL-1', 'Gene', '4170', (74, 79))	('MCL-1', 'Gene', (74, 79))	('SF3B1', 'Gene', '23451', (42, 47))	('knockdown', 'Var', (48, 57))
252346	29796170	Similarly, c-MYC knockdown reduced the sensitivity of SCCRDEBMet and SCCRDEB4 lines to death induced by the SF3B1 inhibitor pladienolide B (Figure 4A).	('reduced', 'NegReg', (27, 34))	('sensitivity', 'MPA', (39, 50))	('SF3B1', 'Gene', '23451', (108, 113))	('c-MYC', 'Gene', '4609', (11, 16))	('SF3B1', 'Gene', (108, 113))	('knockdown', 'Var', (17, 26))	('pladienolide B', 'Chemical', 'MESH:C522342', (124, 138))	('c-MYC', 'Gene', (11, 16))
252359	29796170	SF3B1 depletion resulted in exon skipping in MDM2 and RBM5 mRNAs and intron retention in separase mRNA.	('exon skipping', 'MPA', (28, 41))	('SF3B1', 'Gene', (0, 5))	('resulted in', 'Reg', (16, 27))	('intron retention', 'MPA', (69, 85))	('separase', 'Gene', '9700', (89, 97))	('SF3B1', 'Gene', '23451', (0, 5))	('depletion', 'Var', (6, 15))	('separase', 'Gene', (89, 97))	('RBM5', 'Gene', '10181', (54, 58))	('RBM5', 'Gene', (54, 58))
252360	29796170	PRPF8 depletion caused an increase in separase mRNA intron retention.	('PRPF8', 'Gene', '10594', (0, 5))	('PRPF8', 'Gene', (0, 5))	('separase', 'Gene', '9700', (38, 46))	('depletion', 'Var', (6, 15))	('increase', 'PosReg', (26, 34))	('separase', 'Gene', (38, 46))
252361	29796170	c-MYC knockdown reduced the severity of these alterations in splicing.	('c-MYC', 'Gene', '4609', (0, 5))	('splicing', 'MPA', (61, 69))	('reduced', 'NegReg', (16, 23))	('knockdown', 'Var', (6, 15))	('c-MYC', 'Gene', (0, 5))
252365	29796170	These data indicate that endogenous c-MYC can promote alterations in splicing caused by targeting the spliceosome.	('c-MYC', 'Gene', '4609', (36, 41))	('alterations', 'Reg', (54, 65))	('splicing', 'MPA', (69, 77))	('endogenous', 'Var', (25, 35))	('c-MYC', 'Gene', (36, 41))
252371	29796170	We confirmed that knockdown of mutant p53 in cSCC cells did not attenuate pladienolide B-induced death (Supplementary Figure 3).	('attenuate', 'NegReg', (64, 73))	('mutant', 'Var', (31, 37))	('p53', 'Gene', (38, 41))	('pladienolide B-induced death', 'MPA', (74, 102))	('cSCC', 'Phenotype', 'HP:0006739', (45, 49))	('pladienolide B', 'Chemical', 'MESH:C522342', (74, 88))
252372	29796170	Pladienolide B and SF3B1 knockdown reduced MDMX and MDM2 protein expression in cSCC lines, indicating that these effects can occur independently of wild-type p53 (Supplementary Figures 4 and 5).	('reduced', 'NegReg', (35, 42))	('SF3B1', 'Gene', '23451', (19, 24))	('SF3B1', 'Gene', (19, 24))	('MDMX', 'MPA', (43, 47))	('cSCC', 'Phenotype', 'HP:0006739', (79, 83))	('Pladienolide B', 'Chemical', 'MESH:C522342', (0, 14))	('MDM2', 'Gene', (52, 56))	('knockdown', 'Var', (25, 34))
252374	29796170	Consistent with this, pladienolide B-dependent expression of short MDM2 protein isoforms was attenuated by knockdown of wild-type p53 in NHF and loss of full-length wild-type p53 in HCT116 cells (Figure 6B and Supplementary Figure 6B).	('MDM2', 'Gene', (67, 71))	('HCT116', 'CellLine', 'CVCL:0291', (182, 188))	('attenuated', 'NegReg', (93, 103))	('pladienolide B', 'Chemical', 'MESH:C522342', (22, 36))	('loss', 'Var', (145, 149))	('expression', 'MPA', (47, 57))
252376	29796170	This is consistent with the high protein stability of mutant p53 in tumours.	('tumour', 'Phenotype', 'HP:0002664', (68, 74))	('tumours', 'Phenotype', 'HP:0002664', (68, 75))	('tumours', 'Disease', 'MESH:D009369', (68, 75))	('tumours', 'Disease', (68, 75))	('mutant', 'Var', (54, 60))	('protein stability', 'MPA', (33, 50))	('p53', 'Gene', (61, 64))
252377	29796170	On the contrary, we observed that 3 to 30 nM pladienolide B and SF3B1 knockdown actually decreased mutant p53 protein expression to some extent in cSCC cells.	('SF3B1', 'Gene', (64, 69))	('protein', 'Protein', (110, 117))	('cSCC', 'Phenotype', 'HP:0006739', (147, 151))	('SF3B1', 'Gene', '23451', (64, 69))	('mutant', 'Var', (99, 105))	('p53', 'Gene', (106, 109))	('cSCC', 'Disease', (147, 151))	('pladienolide B', 'Chemical', 'MESH:C522342', (45, 59))	('decreased', 'NegReg', (89, 98))
252378	29796170	This is unlikely to make a major contribution to death caused by SF3B1 suppression through attenuation of mutant p53 gain of function activity because p53 could be robustly knocked down in cSCC cell lines without causing marked cell death (Supplementary Figure 3).	('mutant', 'Var', (106, 112))	('knocked down', 'NegReg', (173, 185))	('SF3B1', 'Gene', (65, 70))	('cSCC', 'Phenotype', 'HP:0006739', (189, 193))	('p53', 'Gene', (113, 116))	('SF3B1', 'Gene', '23451', (65, 70))	('activity', 'MPA', (134, 142))
252379	29796170	We have previously observed in tumour cells that MDMX protein levels are reduced by suppression of a range of splicing factors but that MDM2 mRNA splicing is selectively sensitive to knockdown of SF3B1.	('splicing factor', 'Gene', (110, 125))	('knockdown', 'Var', (183, 192))	('reduced', 'NegReg', (73, 80))	('tumour', 'Phenotype', 'HP:0002664', (31, 37))	('SF3B1', 'Gene', (196, 201))	('tumour', 'Disease', 'MESH:D009369', (31, 37))	('MDMX protein levels', 'MPA', (49, 68))	('SF3B1', 'Gene', '23451', (196, 201))	('splicing factor', 'Gene', '10569', (110, 125))	('tumour', 'Disease', (31, 37))
252380	29796170	Consistent with this, PRPF8 knockdown in cSCC cells reduced full-length MDMX protein expression but it did not diminish MDM2 protein levels (Supplementary Figure 5B).	('PRPF8', 'Gene', '10594', (22, 27))	('reduced', 'NegReg', (52, 59))	('PRPF8', 'Gene', (22, 27))	('MDMX protein expression', 'MPA', (72, 95))	('MDM2 protein levels', 'MPA', (120, 139))	('cSCC', 'Phenotype', 'HP:0006739', (41, 45))	('knockdown', 'Var', (28, 37))
252382	29796170	In contrast, knockdown of SF3B1 but not the other splicing factors disrupted MDM2 mRNA splicing (Figure 7B).	('SF3B1', 'Gene', (26, 31))	('splicing factor', 'Gene', '10569', (50, 65))	('disrupted', 'NegReg', (67, 76))	('SF3B1', 'Gene', '23451', (26, 31))	('MDM2', 'Gene', (77, 81))	('splicing factor', 'Gene', (50, 65))	('knockdown', 'Var', (13, 22))
252385	29796170	SF3B1 knockdown altered MDM2 splicing in NHF but this did not change MDM2 protein expression and p53 levels were not strongly upregulated by SF3B1 knockdown (Figure 7A).	('SF3B1', 'Gene', '23451', (141, 146))	('SF3B1', 'Gene', (0, 5))	('SF3B1', 'Gene', '23451', (0, 5))	('altered', 'Reg', (16, 23))	('MDM2 splicing', 'MPA', (24, 37))	('SF3B1', 'Gene', (141, 146))	('knockdown', 'Var', (6, 15))
252386	29796170	This presumably reflects partial depletion of SF3B1 and is consistent with the relatively low level of death induced by SF3B1 knockdown in NHF and a requirement for stronger suppression of the spliceosome to have effects on splicing in normal skin cells.	('SF3B1', 'Gene', (120, 125))	('depletion', 'MPA', (33, 42))	('SF3B1', 'Gene', '23451', (120, 125))	('SF3B1', 'Gene', (46, 51))	('knockdown', 'Var', (126, 135))	('SF3B1', 'Gene', '23451', (46, 51))
252389	29796170	The absence of full-length p53 markedly reduced cell death caused by pladienolide B (Supplementary Figure 6A).	('pladienolide B', 'Chemical', 'MESH:C522342', (69, 83))	('cell death', 'CPA', (48, 58))	('reduced', 'NegReg', (40, 47))	('absence', 'Var', (4, 11))	('p53', 'Gene', (27, 30))
252395	29796170	Small molecule inhibition of SF3B1 can selectively kill cSCC cells.	('SF3B1', 'Gene', '23451', (29, 34))	('cSCC', 'Disease', (56, 60))	('SF3B1', 'Gene', (29, 34))	('cSCC', 'Phenotype', 'HP:0006739', (56, 60))	('inhibition', 'Var', (15, 25))
252408	29796170	There are often widespread/global changes in splicing during tumour development which can be linked with aberrant expression of splicing factors and to splicing factor mutations.	('splicing factor', 'Gene', '10569', (152, 167))	('tumour', 'Disease', 'MESH:D009369', (61, 67))	('splicing factor', 'Gene', (128, 143))	('splicing factor', 'Gene', (152, 167))	('tumour', 'Disease', (61, 67))	('changes', 'Reg', (34, 41))	('tumour', 'Phenotype', 'HP:0002664', (61, 67))	('splicing', 'MPA', (45, 53))	('splicing factor', 'Gene', '10569', (128, 143))	('mutations', 'Var', (168, 177))
252412	29796170	Of the splicing factors that we have targeted to date only SF3B1 knockdown results in an alteration in MDM2 splicing.	('splicing factor', 'Gene', (7, 22))	('SF3B1', 'Gene', '23451', (59, 64))	('SF3B1', 'Gene', (59, 64))	('splicing factor', 'Gene', '10569', (7, 22))	('MDM2 splicing', 'MPA', (103, 116))	('alteration', 'Reg', (89, 99))	('knockdown', 'Var', (65, 74))
252413	29796170	The convergence on SF3B1 is intriguing, in that: MDM2 splicing appears to be particularly sensitive to SF3B1 suppression, SF3B1 is the target for multiple families of naturally occurring splicing modulators and there is an elevated SF3B1 mutation rate in cancer.	('SF3B1', 'Gene', (232, 237))	('cancer', 'Phenotype', 'HP:0002664', (255, 261))	('SF3B1', 'Gene', (122, 127))	('elevated', 'Reg', (223, 231))	('SF3B1', 'Gene', '23451', (19, 24))	('SF3B1', 'Gene', '23451', (232, 237))	('SF3B1', 'Gene', '23451', (122, 127))	('SF3B1', 'Gene', (103, 108))	('suppression', 'NegReg', (109, 120))	('cancer', 'Disease', (255, 261))	('cancer', 'Disease', 'MESH:D009369', (255, 261))	('mutation', 'Var', (238, 246))	('SF3B1', 'Gene', '23451', (103, 108))	('SF3B1', 'Gene', (19, 24))
252417	29796170	This is consistent with the severity of p53-dependent effects on normal tissues in mouse knockout models in which loss of MDM2 is more deleterious than loss of MDMX and targeting MDMX and MDM2 simultaneously has the greatest impact.	('mouse', 'Species', '10090', (83, 88))	('MDM2', 'Gene', (122, 126))	('loss', 'Var', (114, 118))
252418	29796170	We confirmed that missense mutant p53 depletion did not attenuate pladienolide B-induced cell death in cSCC cells.	('p53', 'Gene', (34, 37))	('attenuate', 'NegReg', (56, 65))	('missense mutant', 'Var', (18, 33))	('cSCC', 'Phenotype', 'HP:0006739', (103, 107))	('pladienolide B', 'Chemical', 'MESH:C522342', (66, 80))
252419	29796170	Knockdown of splicing factors outwith the SF3B complex can kill cSCC cells expressing mutant p53 without altering MDM2 splicing.	('splicing factor', 'Gene', '10569', (13, 28))	('cSCC', 'Phenotype', 'HP:0006739', (64, 68))	('mutant', 'Var', (86, 92))	('p53', 'Gene', (93, 96))	('splicing factor', 'Gene', (13, 28))
252420	29796170	This raises the possibility that by not depleting both MDM2 and MDMX and thus avoiding strong p53 upregulation in normal cells small-molecules that target the spliceosome through SF3B1-independent mechanisms could have even greater selectivity than SF3B1 inhibitors for cSCCs with mutant p53.	('cSCC', 'Phenotype', 'HP:0006739', (270, 274))	('SF3B1', 'Gene', '23451', (249, 254))	('SF3B1', 'Gene', (179, 184))	('p53', 'Gene', (288, 291))	('SF3B1', 'Gene', '23451', (179, 184))	('upregulation', 'PosReg', (98, 110))	('SF3B1', 'Gene', (249, 254))	('mutant', 'Var', (281, 287))
252421	29796170	Furthermore, it may be advantageous to treat cSCCs where p53 is mutated with an SF3B1-independent inhibitor because a reduction in MDMX and MDM2 levels could enhance the gain of function activity of mutant p53.	('p53', 'Gene', (206, 209))	('enhance', 'PosReg', (158, 165))	('MDM2 levels', 'MPA', (140, 151))	('SF3B1', 'Gene', '23451', (80, 85))	('reduction', 'NegReg', (118, 127))	('activity', 'MPA', (187, 195))	('cSCC', 'Phenotype', 'HP:0006739', (45, 49))	('gain', 'PosReg', (170, 174))	('SF3B1', 'Gene', (80, 85))	('mutant', 'Var', (199, 205))
252427	29796170	However, there are also agents with different mechanisms of action including inhibitors of MDMX/MDM2 heterodimerisation and antisense oligonucleotides that promote MDMX exon skipping.	('MDMX/MDM2', 'Gene', (91, 100))	('MDMX exon skipping', 'Var', (164, 182))	('heterodimerisation', 'Interaction', (101, 119))	('inhibitors', 'Reg', (77, 87))	('oligonucleotides', 'Chemical', 'MESH:D009841', (134, 150))	('promote', 'PosReg', (156, 163))
252428	29796170	Although not specific for the p53 pathway, modulation of SF3B1 is another way of suppressing MDMX and MDM2.	('SF3B1', 'Gene', (57, 62))	('suppressing', 'NegReg', (81, 92))	('MDMX', 'Disease', (93, 97))	('SF3B1', 'Gene', '23451', (57, 62))	('modulation', 'Var', (43, 53))	('MDM2', 'Disease', (102, 106))
252449	29796170	This was extended to 120 and 96 hours respectively for experiments investigating the effect of c-MYC and p53 knockdown in SCCRDEBMet cells.	('knockdown', 'Var', (109, 118))	('p53', 'Gene', (105, 108))	('c-MYC', 'Gene', (95, 100))	('c-MYC', 'Gene', '4609', (95, 100))
252469	29728663	Alterations at the genetic and epigenetic levels in the complex enzymatic machinery involved in miRNA biogenesis can result in aberrant miRNA expression.	('Alterations', 'Var', (0, 11))	('miR', 'Gene', '220972', (136, 139))	('miR', 'Gene', (136, 139))	('miR', 'Gene', '220972', (96, 99))	('miR', 'Gene', (96, 99))	('result in', 'Reg', (117, 126))
252483	29728663	miRNA dysregulation is in turn known to affect expression of their target proteins leading to diverse functional consequences.	('miR', 'Gene', '220972', (0, 3))	('dysregulation', 'Var', (6, 19))	('miR', 'Gene', (0, 3))	('affect', 'Reg', (40, 46))	('expression', 'MPA', (47, 57))
252487	29728663	We observed an increase in proliferative capability of both OKF6/TERT1-Tobacco and OKF6/TERT1-Smoke cells compared to OKF6/TERT1-Parental cells (Fig.	('OKF6/TERT1-Smoke', 'Var', (83, 99))	('proliferative capability', 'CPA', (27, 51))	('OKF6/TERT1', 'CellLine', 'CVCL:L224', (83, 93))	('Tobacco', 'Species', '4097', (71, 78))	('OKF6/TERT1', 'CellLine', 'CVCL:L224', (118, 128))	('increase', 'PosReg', (15, 23))	('OKF6/TERT1', 'CellLine', 'CVCL:L224', (60, 70))	('OKF6/TERT1-Tobacco', 'Var', (60, 78))
252491	29728663	We also observed change in expression levels of markers associated with EMT in both chewing tobacco treated and cigarette smoke exposed cells compared to parental cells.There was a decrease in expression of E-Cadherin (processed band, lower) and a increase in vimentin expression in OKF6/TERT1-Tobacco and OKF6/TERT1-Smoke cells compared to OKF6/TERT1-Parental cells (Fig.	('OKF6/TERT1', 'CellLine', 'CVCL:L224', (306, 316))	('tobacco', 'Species', '4097', (92, 99))	('increase', 'PosReg', (248, 256))	('OKF6/TERT1', 'CellLine', 'CVCL:L224', (341, 351))	('OKF6/TERT1-Smoke', 'Var', (306, 322))	('decrease', 'NegReg', (181, 189))	('E-Cadherin', 'Protein', (207, 217))	('expression', 'MPA', (269, 279))	('OKF6/TERT1', 'CellLine', 'CVCL:L224', (283, 293))	('Tobacco', 'Species', '4097', (294, 301))	('vimentin', 'Protein', (260, 268))	('OKF6/TERT1-Tobacco', 'Var', (283, 301))	('expression', 'MPA', (193, 203))
252499	29728663	Amongst the 311 significantly dysregulated proteins in OKF6/TERT1-Tobacco, 197 were overexpressed (>=1.5-fold, p-value <= 0.05) and 114 proteins were downregulated (<=0.6-fold, p-value <= 0.05).	('downregulated', 'NegReg', (150, 163))	('OKF6/TERT1', 'CellLine', 'CVCL:L224', (55, 65))	('OKF6/TERT1-Tobacco', 'Var', (55, 73))	('overexpressed', 'PosReg', (84, 97))	('proteins', 'Protein', (43, 51))	('Tobacco', 'Species', '4097', (66, 73))	('proteins', 'Protein', (136, 144))
252506	29728663	Our proteomics data revealed downregulation of superoxidase dismutase, SOD2, in tobacco treated OKF6/TERT1 cells and in conjunction with this we observed a significant decrease in SOD2 expression in OKF6/TERT1-Tobacco cells compared to OKF6/TERT1-Parental cells (Supplementary Fig.	('downregulation', 'NegReg', (29, 43))	('OKF6/TERT1-Tobacco', 'Var', (199, 217))	('OKF6/TERT1', 'CellLine', 'CVCL:L224', (96, 106))	('expression', 'MPA', (185, 195))	('SOD2', 'Gene', '6648', (180, 184))	('SOD2', 'Gene', (180, 184))	('OKF6/TERT1', 'CellLine', 'CVCL:L224', (236, 246))	('SOD2', 'Gene', '6648', (71, 75))	('SOD2', 'Gene', (71, 75))	('decrease', 'NegReg', (168, 176))	('OKF6/TERT1', 'CellLine', 'CVCL:L224', (199, 209))	('Tobacco', 'Species', '4097', (210, 217))	('tobacco', 'Species', '4097', (80, 87))
252521	29728663	Conversely, miRNA NM-OKF6-ST-02-5p showed higher expression in smoke exposed cells with 532 reads compared to tobacco treated cells with 53 reads.	('expression', 'MPA', (49, 59))	('higher', 'PosReg', (42, 48))	('tobacco', 'Species', '4097', (110, 117))	('532 reads', 'Var', (88, 97))	('miR', 'Gene', '220972', (12, 15))	('miR', 'Gene', (12, 15))
252552	29728663	STAT1 is a target protein of miR-146a-5p (significantly upregulated in tobacco treated cells) and is reported to be downregulated due to promoter methylation in HNSCC.	('tobacco', 'Species', '4097', (71, 78))	('downregulated', 'NegReg', (116, 129))	('HNSCC', 'Protein', (161, 166))	('miR-146a', 'Gene', '406938', (29, 37))	('promoter methylation', 'Var', (137, 157))	('upregulated', 'PosReg', (56, 67))	('miR-146a', 'Gene', (29, 37))
252562	29728663	It is suggested that the ability of OSCC cells to secrete TGF-beta2 could contribute to clinical progression by maintaining a microenvironment conducive for tumor growth and proliferation.	('tumor', 'Disease', (157, 162))	('secrete', 'Var', (50, 57))	('contribute', 'Reg', (74, 84))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('TGF-beta2', 'Gene', (58, 67))	('proliferation', 'CPA', (174, 187))
252567	29728663	Hypomethylation of inositol monophosphatase domain containing 1 (IMPAD1) has been associated with its overexpression in breast carcinoma.	('breast carcinoma', 'Disease', (120, 136))	('associated', 'Reg', (82, 92))	('breast carcinoma', 'Disease', 'MESH:D001943', (120, 136))	('Hypomethylation', 'Var', (0, 15))	('overexpression', 'PosReg', (102, 116))	('breast carcinoma', 'Phenotype', 'HP:0003002', (120, 136))	('IMPAD1', 'Gene', (65, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))
252575	29728663	Mutations in several components of chromatin remodelling complex, SWI/SNF have been linked to malignant transformation and progression of cancer.	('cancer', 'Disease', (138, 144))	('malignant transformation', 'CPA', (94, 118))	('SWI/SNF', 'Gene', (66, 73))	('linked to', 'Reg', (84, 93))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('Mutations', 'Var', (0, 9))	('cancer', 'Disease', 'MESH:D009369', (138, 144))
252581	29728663	Overexpression of DNMT1 in lung cancer is associated with increased expression of histone deacetylases (HDACs) which increases the stability of DNMT1 and in turn stimulates cancer progression.	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('increased', 'PosReg', (58, 67))	('expression', 'MPA', (68, 78))	('cancer', 'Disease', (173, 179))	('cancer', 'Disease', (32, 38))	('lung cancer', 'Disease', (27, 38))	('increases', 'PosReg', (117, 126))	('lung cancer', 'Phenotype', 'HP:0100526', (27, 38))	('stability', 'MPA', (131, 140))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('Overexpression', 'Var', (0, 14))	('stimulates', 'PosReg', (162, 172))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('DNMT1', 'Gene', (18, 23))	('lung cancer', 'Disease', 'MESH:D008175', (27, 38))
252583	29728663	It has been unveiled that nicotine induces binding of Sp1 on alpha7-nAChR promoter, leading to transcriptional activation of alpha7-nAChR in lung cancer, which in turn facilitates tumor growth and progression.	('activation', 'PosReg', (111, 121))	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('binding', 'Interaction', (43, 50))	('facilitates', 'PosReg', (168, 179))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('tumor', 'Disease', (180, 185))	('nicotine', 'Chemical', 'MESH:D009538', (26, 34))	('transcriptional', 'MPA', (95, 110))	('lung cancer', 'Disease', (141, 152))	('lung cancer', 'Phenotype', 'HP:0100526', (141, 152))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('alpha7-nAChR', 'Var', (125, 137))	('lung cancer', 'Disease', 'MESH:D008175', (141, 152))
252638	27403438	Our study suggests that miR-149 expression in laryngeal squamous cell carcinoma tissues is critically associated with the prognosis of patients, and the ectopic expression of miR-149 in Hep-2 cells inhibits proliferation and cell cycle progression.	('ectopic expression', 'Var', (153, 171))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (56, 79))	('patients', 'Species', '9606', (135, 143))	('associated', 'Reg', (102, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('cell cycle progression', 'CPA', (225, 247))	('miR-149', 'Gene', (175, 182))	('laryngeal squamous cell carcinoma', 'Disease', 'MESH:D002294', (46, 79))	('proliferation', 'CPA', (207, 220))	('miR-149', 'Gene', '406941', (175, 182))	('miR-149', 'Gene', (24, 31))	('inhibits', 'NegReg', (198, 206))	('miR-149', 'Gene', '406941', (24, 31))	('laryngeal squamous cell carcinoma', 'Disease', (46, 79))	('Hep-2', 'CellLine', 'CVCL:1906', (186, 191))
252665	27403438	The relative expression of microRNA-149 was calculated by methods mentioned by Schmittgen: F = 2 - DeltaDeltaCT and DeltaDeltaCT = ctmiRNA-149 - ctmiRNA - U6.	('DeltaDeltaCT', 'Var', (116, 128))	('microRNA-149', 'Gene', (27, 39))	('microRNA-149', 'Gene', '406941', (27, 39))	('miRNA-149', 'Chemical', '-', (133, 142))
252700	27403438	Results revealed that the apoptosis of transfected Hep-2 cells was significantly different from that in untransfected cells: the apoptosis rate of Hep-2 cells was significantly enhanced by miRNA-149 transfection (48.91 +- 3.52% versus 9.8 +- 0.41%, resp.	('miRNA-149 transfection', 'Var', (189, 211))	('transfection', 'Var', (199, 211))	('Hep-2', 'CellLine', 'CVCL:1906', (147, 152))	('apoptosis rate', 'CPA', (129, 143))	('Hep-2', 'CellLine', 'CVCL:1906', (51, 56))	('enhanced', 'PosReg', (177, 185))	('miRNA-149', 'Chemical', '-', (189, 198))
252702	27403438	miR-149 locates on chromosome 2, and studies have indicated that single nucleotide polymorphisms of miR-149 might be associated with head and neck cancer, as well as the occurrence of pneumoconiosis.	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('neck cancer', 'Disease', 'MESH:D006258', (142, 153))	('pneumoconiosis', 'Disease', 'MESH:D011009', (184, 198))	('associated', 'Reg', (117, 127))	('single nucleotide polymorphisms', 'Var', (65, 96))	('neck cancer', 'Disease', (142, 153))	('pneumoconiosis', 'Disease', (184, 198))	('miR-149', 'Gene', (0, 7))	('miR-149', 'Gene', '406941', (0, 7))	('miR-149', 'Gene', (100, 107))	('miR-149', 'Gene', '406941', (100, 107))	('head and neck cancer', 'Phenotype', 'HP:0012288', (133, 153))
252703	27403438	found that the combined polymorphism effect of four microRNAs (HSA-146A, HSA-196A, HSA-149, and HSA-499) has a dose-response relationship with head and neck squamous cell carcinoma (HNSCC).	('HSA-196A', 'Var', (73, 81))	('HSA-146A', 'Var', (63, 71))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (152, 180))	('HSA', 'Chemical', 'MESH:D006585', (96, 99))	('HSA', 'Chemical', 'MESH:D006585', (63, 66))	('carcinoma', 'Phenotype', 'HP:0030731', (171, 180))	('neck squamous cell carcinoma', 'Disease', (152, 180))	('HSA', 'Chemical', 'MESH:D006585', (83, 86))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (157, 180))	('HSA-499', 'Var', (96, 103))	('HSA', 'Chemical', 'MESH:D006585', (73, 76))	('HSA-149', 'Var', (83, 90))
252706	27403438	Results revealed that the expression of miRNA-149 in HNSCC carcinoma tissues was significantly lower, and that the expression of miRNA-149 could inhibit the migration of HNSCC cells.	('expression', 'MPA', (26, 36))	('lower', 'NegReg', (95, 100))	('miRNA-149', 'Gene', (40, 49))	('HNSCC carcinoma', 'Disease', (53, 68))	('HNSCC carcinoma', 'Disease', 'MESH:D000077195', (53, 68))	('miRNA-149', 'Chemical', '-', (129, 138))	('miRNA-149', 'Chemical', '-', (40, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (59, 68))	('miRNA-149', 'Var', (129, 138))	('migration of HNSCC cells', 'CPA', (157, 181))	('inhibit', 'NegReg', (145, 152))
252707	27403438	After further studies, they found that the single nucleotide polymorphism of T/T (pre-miRNA-149) was associated with the expression of miR-149 in HNSCC, while miRNA-149 was determined by miRNA-149 and the prognosis of patients with HNSCC.	('miR-149', 'Gene', '406941', (135, 142))	('HNSCC', 'Disease', (146, 151))	('patients', 'Species', '9606', (218, 226))	('miRNA-149', 'Chemical', '-', (86, 95))	('miRNA-149', 'Chemical', '-', (159, 168))	('expression', 'MPA', (121, 131))	('miRNA-149', 'Chemical', '-', (187, 196))	('associated', 'Reg', (101, 111))	('T/T', 'Gene', (77, 80))	('miR-149', 'Gene', (135, 142))	('single nucleotide polymorphism', 'Var', (43, 73))
252709	27403438	indicated that miRNA-149 was epigenetically silenced in colorectal cancer (CRC) and the downregulation of miRNA-149 was associated with the hypermethylation of the neighboring CpG island (CGI).	('downregulation', 'NegReg', (88, 102))	('colorectal cancer', 'Disease', 'MESH:D015179', (56, 73))	('miRNA-149', 'Gene', (15, 24))	('colorectal cancer', 'Phenotype', 'HP:0003003', (56, 73))	('miRNA-149', 'Gene', (106, 115))	('miRNA-149', 'Chemical', '-', (15, 24))	('silenced', 'NegReg', (44, 52))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('colorectal cancer', 'Disease', (56, 73))	('CRC', 'Phenotype', 'HP:0003003', (75, 78))	('miRNA-149', 'Chemical', '-', (106, 115))	('epigenetically', 'Var', (29, 43))	('hypermethylation', 'Var', (140, 156))
252710	27403438	They concluded that, as a methylation-sensitive miRNA, miRNA-149 may play an important role as a tumor suppressor in CRC, which has prognostic and therapeutic implications.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('miRNA-149', 'Chemical', '-', (55, 64))	('tumor', 'Disease', (97, 102))	('CRC', 'Phenotype', 'HP:0003003', (117, 120))	('miRNA-149', 'Var', (55, 64))	('CRC', 'Disease', (117, 120))
252712	27403438	Thus, we speculate that DNA methylation is also regulated by miRNA-149 methylation in LC tissues.	('methylation', 'Var', (71, 82))	('miRNA-149', 'Gene', (61, 70))	('miRNA-149', 'Chemical', '-', (61, 70))	('LC', 'Phenotype', 'HP:0012118', (86, 88))	('regulated', 'Reg', (48, 57))
252721	27403438	These results revealed that miRNA-149 inhibits the proliferation of human Hep-2 cells, and the ectopic expression of miR-149 in Hep-2 cells inhibits proliferation and cell cycle progression.	('inhibits', 'NegReg', (140, 148))	('human', 'Species', '9606', (68, 73))	('inhibits', 'NegReg', (38, 46))	('miRNA-149', 'Var', (28, 37))	('proliferation', 'CPA', (51, 64))	('proliferation', 'CPA', (149, 162))	('miR-149', 'Gene', (117, 124))	('cell cycle progression', 'CPA', (167, 189))	('Hep-2', 'CellLine', 'CVCL:1906', (128, 133))	('miR-149', 'Gene', '406941', (117, 124))	('miRNA-149', 'Chemical', '-', (28, 37))	('Hep-2', 'CellLine', 'CVCL:1906', (74, 79))
252723	27403438	In vitro experiments revealed that miRNA-149 has a significant impact on the proliferation and apoptosis of human Hep-2 cells, and related molecular biology mechanisms need further research.	('miRNA-149', 'Chemical', '-', (35, 44))	('apoptosis', 'CPA', (95, 104))	('miRNA-149', 'Var', (35, 44))	('human', 'Species', '9606', (108, 113))	('impact', 'Reg', (63, 69))	('Hep-2', 'CellLine', 'CVCL:1906', (114, 119))	('proliferation', 'CPA', (77, 90))
252727	32777161	Inhibition of glycolysis has been considered as a therapeutic approach in aggressive cancers including lung cancer.	('aggressive cancers', 'Disease', 'MESH:D009369', (74, 92))	('lung cancer', 'Disease', 'MESH:D008175', (103, 114))	('cancers', 'Phenotype', 'HP:0002664', (85, 92))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('lung cancer', 'Disease', (103, 114))	('Inhibition', 'Var', (0, 10))	('lung cancer', 'Phenotype', 'HP:0100526', (103, 114))	('aggressive cancers', 'Disease', (74, 92))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
252735	32777161	In lung adenocarcinoma, PCK2 expression was associated with significantly improved overall survival, while the opposite was found for GLUT1.	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (3, 22))	('overall survival', 'MPA', (83, 99))	('expression', 'Var', (29, 39))	('GLUT1', 'Gene', (134, 139))	('GLUT1', 'Gene', '6513', (134, 139))	('PCK2', 'Gene', '5106', (24, 28))	('PCK2', 'Gene', (24, 28))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (3, 22))	('improved', 'PosReg', (74, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (13, 22))	('lung adenocarcinoma', 'Disease', (3, 22))
252759	32777161	Of note, PEPCK inhibition or silencing reduced the growth of tumors in different in vivo models [11, 12, 13, 20].	('tumors', 'Disease', (61, 67))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('silencing', 'Var', (29, 38))	('PEPCK', 'Enzyme', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('reduced', 'NegReg', (39, 46))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('inhibition', 'Var', (15, 25))
252851	32777161	Conversely, in LUAD patients whose tumors were positive for GLUT1, overall survival was significantly worse (Fig.	('worse', 'NegReg', (102, 107))	('positive', 'Var', (47, 55))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('GLUT1', 'Gene', (60, 65))	('overall survival', 'MPA', (67, 83))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('GLUT1', 'Gene', '6513', (60, 65))	('tumors', 'Disease', (35, 41))	('tumors', 'Disease', 'MESH:D009369', (35, 41))	('patients', 'Species', '9606', (20, 28))
252854	32777161	PCK2 expression was significantly associated with a favorable outcome in LUAD also in multivariate survival analysis including tumor stage, grade, age at diagnosis, and gender (Table S3).	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('associated with', 'Reg', (34, 49))	('tumor', 'Disease', (127, 132))	('PCK2', 'Gene', (0, 4))	('expression', 'Var', (5, 15))	('PCK2', 'Gene', '5106', (0, 4))	('LUAD also', 'Disease', (73, 82))	('tumor', 'Disease', 'MESH:D009369', (127, 132))
252864	32777161	In the large LUAD TCGA cohort, KRAS mutant tumors displayed a slightly but significantly reduced PCK2 expression, while GLUT1 expression was reduced in LKB1 (STK11) mutant tumors and enhanced in TP53 mutant tumors (Fig.	('KRAS', 'Gene', (31, 35))	('GLUT1', 'Gene', '6513', (120, 125))	('mutant', 'Var', (200, 206))	('enhanced', 'PosReg', (183, 191))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('STK11', 'Gene', '6794', (158, 163))	('reduced', 'NegReg', (89, 96))	('tumors', 'Disease', (207, 213))	('LKB1', 'Gene', '6794', (152, 156))	('TP53', 'Gene', (195, 199))	('tumors', 'Phenotype', 'HP:0002664', (172, 178))	('tumors', 'Disease', 'MESH:D009369', (207, 213))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('GLUT1', 'Gene', (120, 125))	('expression', 'MPA', (126, 136))	('reduced', 'NegReg', (141, 148))	('tumors', 'Disease', (172, 178))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('LKB1', 'Gene', (152, 156))	('PCK2', 'Gene', (97, 101))	('tumors', 'Disease', (43, 49))	('TP53', 'Gene', '7157', (195, 199))	('mutant', 'Var', (165, 171))	('tumors', 'Disease', 'MESH:D009369', (172, 178))	('expression', 'MPA', (102, 112))	('STK11', 'Gene', (158, 163))	('KRAS', 'Gene', '3845', (31, 35))	('mutant', 'Var', (36, 42))	('tumors', 'Phenotype', 'HP:0002664', (207, 213))	('PCK2', 'Gene', '5106', (97, 101))	('tumors', 'Disease', 'MESH:D009369', (43, 49))
252865	32777161	The overall effect of cancer driver mutations on GLUT1 and PCK2 expression appeared limited and may only partially explain the observed interpatient variability.	('expression', 'MPA', (64, 74))	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('PCK2', 'Gene', (59, 63))	('cancer', 'Disease', (22, 28))	('mutations', 'Var', (36, 45))	('patient', 'Species', '9606', (141, 148))	('PCK2', 'Gene', '5106', (59, 63))	('GLUT1', 'Gene', (49, 54))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('GLUT1', 'Gene', '6513', (49, 54))
252866	32777161	It is well known that besides cell-intrinsic factors, like oncogenic driver mutations or tumor histology, the metabolic microenvironment and the availability of nutrients and oxygen are critical regulators of cancer cell metabolism [31].	('mutations', 'Var', (76, 85))	('cancer', 'Disease', 'MESH:D009369', (209, 215))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))	('cancer', 'Disease', (209, 215))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))	('oxygen', 'Chemical', 'MESH:D010100', (175, 181))
252903	32777161	High PCK2 expression predicted a worse overall survival in prostate cancer [19].	('PCK2', 'Gene', '5106', (5, 9))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('prostate cancer', 'Disease', 'MESH:D011471', (59, 74))	('High', 'Var', (0, 4))	('prostate cancer', 'Phenotype', 'HP:0012125', (59, 74))	('prostate cancer', 'Disease', (59, 74))	('PCK2', 'Gene', (5, 9))
252904	32777161	Here, we show that the mixed phenotype, exhibiting GLUT1 as well as PCK1/2 expression was significantly associated with a worse overall survival in LUAD compared to the purely gluconeogenic phenotype, while no significant difference was found between the mixed and the purely glycolytic phenotypes (Fig.	('PCK1/2', 'Gene', '5105;5106', (68, 74))	('worse', 'NegReg', (122, 127))	('gluconeogenic phenotype', 'Phenotype', 'HP:0005959', (176, 199))	('LUAD', 'Disease', (148, 152))	('expression', 'Var', (75, 85))	('associated', 'Reg', (104, 114))	('GLUT1', 'Gene', (51, 56))	('PCK1/2', 'Gene', (68, 74))	('GLUT1', 'Gene', '6513', (51, 56))
252911	32777161	Accordingly, tumor-initiating cells (TICs) from prostate cancer showed higher PCK2 levels than the parental cells and PCK2 silencing reduced TIC numbers by affecting levels of reactive oxygen species and protein acetylation [19].	('higher', 'PosReg', (71, 77))	('tumor', 'Disease', (13, 18))	('TIC', 'Phenotype', 'HP:0100033', (141, 144))	('TIC', 'Disease', (37, 40))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('affecting', 'Reg', (156, 165))	('PCK2', 'Gene', (118, 122))	('TICs', 'Phenotype', 'HP:0100033', (37, 41))	('PCK2', 'Gene', '5106', (78, 82))	('protein acetylation', 'MPA', (204, 223))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('TIC', 'Disease', 'None', (141, 144))	('TIC', 'Phenotype', 'HP:0100033', (37, 40))	('PCK2', 'Gene', '5106', (118, 122))	('prostate cancer', 'Disease', 'MESH:D011471', (48, 63))	('prostate cancer', 'Phenotype', 'HP:0012125', (48, 63))	('prostate cancer', 'Disease', (48, 63))	('silencing', 'Var', (123, 132))	('TIC', 'Disease', (141, 144))	('reduced', 'NegReg', (133, 140))	('TIC', 'Disease', 'None', (37, 40))	('oxygen', 'Chemical', 'MESH:D010100', (185, 191))	('levels of reactive oxygen species', 'MPA', (166, 199))	('PCK2', 'Gene', (78, 82))
252917	32777161	This mechanism is known to be activated by mutant KRAS in lung tumors [47].	('lung tumors', 'Disease', 'MESH:D008175', (58, 69))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('KRAS', 'Gene', (50, 54))	('mutant', 'Var', (43, 49))	('KRAS', 'Gene', '3845', (50, 54))	('lung tumors', 'Disease', (58, 69))	('lung tumors', 'Phenotype', 'HP:0100526', (58, 69))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
252926	32777161	Inhibition of glycolysis and gluconeogenesis simultaneously would potentially allow to target different tumor niches and compartments.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('gluconeogenesis', 'MPA', (29, 44))	('tumor', 'Disease', (104, 109))	('Inhibition', 'Var', (0, 10))	('glycolysis', 'MPA', (14, 24))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
252955	30241505	Unfortunately, sustained chronic injury or congenital defects, especially genes related to DNA repair and cell cycle check points, break the balance between damage and repair and contribute to structural or numerical changes in DNA molecules such as point mutations, insertions, deletions, rearrangements, DNA double-stranded breaks gene amplification and aneuploidy, namely chromosomal instability.	('rearrangements', 'Var', (290, 304))	('point mutations', 'Var', (250, 265))	('chronic injury', 'Disease', (25, 39))	('aneuploidy', 'Disease', 'MESH:D000782', (356, 366))	('congenital defects', 'Disease', 'MESH:D005124', (43, 61))	('congenital defects', 'Disease', (43, 61))	('deletions', 'Var', (279, 288))	('chronic injury', 'Disease', 'MESH:D020208', (25, 39))	('chromosomal instability', 'Phenotype', 'HP:0040012', (375, 398))	('chromosomal instability', 'Disease', (375, 398))	('DNA', 'Gene', (306, 309))	('insertions', 'Var', (267, 277))	('aneuploidy', 'Disease', (356, 366))	('balance', 'MPA', (141, 148))	('break', 'NegReg', (131, 136))
252959	30241505	MSI has been identified as an inactivation mechanism of some of the tumor suppressor genes (TSGs) by causing the accumulation of frameshift mutations in the protein-coding sequence of those TSGs.	('tumor', 'Disease', (68, 73))	('MSI', 'Disease', 'None', (0, 3))	('TSG', 'Gene', (190, 193))	('MSI', 'Disease', (0, 3))	('TSG', 'Gene', (92, 95))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('frameshift mutations', 'Var', (129, 149))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('TSG', 'Gene', '57045', (190, 193))	('TSG', 'Gene', '57045', (92, 95))
252963	30241505	Loss of heterozygosity (LOH) is another TSG inactivation mechanism by which the loss of the corresponding wild-type allele of one chromosome turns a heterozygous somatic cell into a hemizygous one.	('TSG', 'Gene', (40, 43))	('loss', 'Var', (80, 84))	('turns', 'Reg', (141, 146))	('TSG', 'Gene', '57045', (40, 43))	('Loss', 'Var', (0, 4))
252974	30241505	To discover biomarkers in genomics, it is important to determine which tool would be suitable for the effective and accurate detection of mutated DNA from a large number of genes of OSCC patients.	('DNA', 'Gene', (146, 149))	('patients', 'Species', '9606', (187, 195))	('OSCC', 'Disease', (182, 186))	('mutated', 'Var', (138, 145))
252982	30241505	Transcriptomic research on biomarkers, just similar to genomics, also requires a high-throughput technique to screen the whole transcriptome of patients to find cancer-specific mutations or genes with altered expression.	('expression', 'MPA', (209, 219))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('mutations', 'Var', (177, 186))	('altered', 'Reg', (201, 208))	('patients', 'Species', '9606', (144, 152))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('cancer', 'Disease', (161, 167))
252983	30241505	successfully screened more than 70,000 tumor-related mutations in open reading frames (ORFs) of transcripts and identified six OSCC-specific mutations (ANKRA2, GTF2H5, STOML1, NUP37, PPP1R26, and TAF1L).	('ANKRA2', 'Gene', (152, 158))	('ANKRA2', 'Gene', '57763', (152, 158))	('TAF1L', 'Gene', '138474', (196, 201))	('OSCC-specific', 'Disease', (127, 140))	('TAF1L', 'Gene', (196, 201))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('PPP1R26', 'Gene', '9858', (183, 190))	('STOML1', 'Gene', '9399', (168, 174))	('mutations', 'Var', (53, 62))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('GTF2H5', 'Gene', '404672', (160, 166))	('GTF2H5', 'Gene', (160, 166))	('tumor', 'Disease', (39, 44))	('STOML1', 'Gene', (168, 174))	('NUP37', 'Gene', '79023', (176, 181))	('PPP1R26', 'Gene', (183, 190))	('NUP37', 'Gene', (176, 181))
253000	30241505	Other salivary biomarkers such as transferrin, myosin, actin, and truncated cystatin SA-I were subsequently discovered and preliminarily identified by different teams utilizing MS and immunochemical technologies.	('myosin', 'Gene', (47, 53))	('transferrin', 'Gene', (34, 45))	('cystatin SA-I', 'Gene', '1469', (76, 89))	('myosin', 'Gene', '79784', (47, 53))	('truncated', 'Var', (66, 75))	('transferrin', 'Gene', '7018', (34, 45))	('cystatin SA-I', 'Gene', (76, 89))
253004	30241505	Cytosines of the CpGs, shores, or shelves can be modified by methylation or demethylation (5hmc) owing to chronic harmful stimulation, such as that resulting from smoking or betel quid chewing.	('5hmc', 'Chemical', '-', (91, 95))	('modified', 'Reg', (49, 57))	('methylation', 'Var', (61, 72))	('demethylation', 'Var', (76, 89))
253006	30241505	According to Knudson's two-hit hypothesis, DNA methylation constitutes a second hit to TSGs following gene alteration (mutation, MSI, LOH).	('TSG', 'Gene', (87, 90))	('mutation', 'Var', (119, 127))	('MSI', 'Disease', (129, 132))	('TSG', 'Gene', '57045', (87, 90))	('MSI', 'Disease', 'None', (129, 132))
253009	30241505	Differentially methylated regions (DMRs), as epigenetic biomarkers, can be screened out by NGS by comparison between cancer tissues and NCMT or PMDs.	('PMD', 'Disease', (144, 147))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('PMD', 'Disease', 'MESH:D020371', (144, 147))	('DMRs', 'Chemical', '-', (35, 39))	('Differentially', 'Var', (0, 14))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('cancer', 'Disease', (117, 123))
253013	30241505	Methyl Cap-seq and MeDIP-seq not only "avoid" 5hmc but also provide coverage of more than 80% of methylation sites, via enrichment of methylated CpG by methyl CpG binding protein and anti-5-methylcytosine antibodies, respectively.	('methylated', 'Var', (134, 144))	('cytosine', 'Chemical', 'MESH:D003596', (196, 204))	('5hmc', 'Chemical', '-', (46, 50))	('methylation', 'MPA', (97, 108))
253016	30241505	Notably, three genes (TRHDE, ZNF454, and KCNAB3) with a high frequency (90-100%) of methylation specific to OSCC were identified.	('KCNAB3', 'Gene', '9196', (41, 47))	('methylation', 'Var', (84, 95))	('TRHDE', 'Gene', (22, 27))	('TRHDE', 'Gene', '29953', (22, 27))	('ZNF454', 'Gene', (29, 35))	('ZNF454', 'Gene', '285676', (29, 35))	('KCNAB3', 'Gene', (41, 47))
253038	30241505	As early as 2000, LOH on 3p, 9p21, or 17p was identified as an early event that drives the malignant transformation of PMDs.	('LOH', 'Var', (18, 21))	('malignant transformation', 'CPA', (91, 115))	('PMD', 'Disease', 'MESH:D020371', (119, 122))	('PMD', 'Disease', (119, 122))
253042	30241505	A double-blind multicenter prospective study also unequivocally showed that P16 gene methylation as an initiating event of OSCC is a remarkable predictor of the malignant transformation of PMDs.	('methylation', 'Var', (85, 96))	('PMD', 'Disease', (189, 192))	('predictor', 'Reg', (144, 153))	('P16', 'Gene', (76, 79))	('PMD', 'Disease', 'MESH:D020371', (189, 192))	('P16', 'Gene', '1029', (76, 79))
253043	30241505	Notably, research at Johns Hopkins Medical Institutions indicated that detecting hypermethylation of EDNRB and DCC has the same performance as an expert clinical examination for the early diagnosis of OSCC, which indicates that limited expert health care resources need not be an obstacle to the early and precise diagnosis and screening of OSCC.	('OSCC', 'Disease', (201, 205))	('EDNRB', 'Gene', '1910', (101, 106))	('DCC', 'Gene', (111, 114))	('detecting hypermethylation', 'Var', (71, 97))	('DCC', 'Gene', '1630', (111, 114))	('EDNRB', 'Gene', (101, 106))	('hypermethylation', 'Var', (81, 97))
253045	30241505	In addition, miR-31, miR-16, let-7b, miR-338-3p, miR-223, and miR-29a are considered as potential noninvasive biomarkers for early diagnosis of OSCC.	('let-7b', 'Gene', (29, 35))	('miR-31', 'Gene', (13, 19))	('miR-338-3p', 'Var', (37, 47))	('miR-223', 'Gene', (49, 56))	('miR-16', 'Gene', (21, 27))	('miR-29a', 'Gene', (62, 69))	('miR-29a', 'Gene', '407021', (62, 69))	('miR-16', 'Gene', '51573', (21, 27))	('miR-31', 'Gene', '407035', (13, 19))	('let-7b', 'Gene', '406884', (29, 35))	('miR-223', 'Gene', '407008', (49, 56))	('OSCC', 'Disease', (144, 148))
253087	30241505	performed LCM to collect intratumoral cell subgroups from different parts of the tumor (ITF, center, surface) and found that LOH on 9p21 (RPS6) was more frequently detected in ITF than at the center and surface.	('RPS6', 'Gene', (138, 142))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('LOH on 9p21', 'Var', (125, 136))	('tumor', 'Disease', (30, 35))	('tumor', 'Disease', (81, 86))	('RPS6', 'Gene', '6194', (138, 142))
253095	30241505	also identified a set of hypomethylated genes that are specific to OSCC tissues of Indian patients.	('hypomethylated', 'Var', (25, 39))	('patients', 'Species', '9606', (90, 98))	('OSCC', 'Disease', (67, 71))
253214	29499051	Mechanistically, ST2, a well-defined receptor of IL-33, is expressed on CD8+ T cells, Th1 cells, NK and NKT cells and IFN-gamma production by tumoral CD8+ T cells and NK cells was significantly increased by IL-33.	('CD8', 'Gene', (150, 153))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('CD8', 'Gene', '925', (150, 153))	('Th1', 'Gene', (86, 89))	('tumor', 'Disease', (142, 147))	('increased', 'PosReg', (194, 203))	('IFN-gamma', 'Gene', (118, 127))	('IFN-gamma', 'Gene', '3458', (118, 127))	('CD8', 'Gene', (72, 75))	('Th1', 'Gene', '51497', (86, 89))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('IL-33', 'Var', (207, 212))	('ST2', 'Gene', (17, 20))	('CD8', 'Gene', '925', (72, 75))
253235	29499051	In the same vein, another study shows that ST2 deficiency does not affect polyposis in large intestine but does reduce polyposis in small intestine in the APC Min/+ model.	('polyposis', 'Disease', (74, 83))	('polyposis', 'Disease', (119, 128))	('reduce', 'NegReg', (112, 118))	('polyposis', 'Disease', 'MESH:D011125', (74, 83))	('affect polyposis in large intestine', 'Phenotype', 'HP:0200008', (67, 102))	('ST2', 'Gene', (43, 46))	('polyposis', 'Disease', 'MESH:D011125', (119, 128))	('polyposis in small intestine', 'Phenotype', 'HP:0200008', (119, 147))	('deficiency', 'Var', (47, 57))
253236	29499051	IL-33 primarily targets Treg, mast cells and M2 rather than CD8+ T cells in the APC Min/+ model, because APC mutation results in activation of the WNT pathway, which inhibits CD8+ T cell recruitment.	('WNT pathway', 'Pathway', (147, 158))	('CD8', 'Gene', (175, 178))	('CD8', 'Gene', '925', (60, 63))	('mutation', 'Var', (109, 117))	('activation', 'PosReg', (129, 139))	('inhibits', 'NegReg', (166, 174))	('CD8', 'Gene', '925', (175, 178))	('APC', 'Gene', (105, 108))	('CD8', 'Gene', (60, 63))
253249	24602385	The baseline tumour FDG uptake decreased significantly at PET2 (p < 0.0001).	('FDG', 'Chemical', 'MESH:D019788', (20, 23))	('tumour', 'Phenotype', 'HP:0002664', (13, 19))	('PET2', 'Var', (58, 62))	('decreased', 'NegReg', (31, 40))	('tumour', 'Disease', 'MESH:D009369', (13, 19))	('tumour', 'Disease', (13, 19))
253256	24602385	variations in FDG uptake, provided additional prognostic information in multivariate analyses ClinicalTrials.gov NCT 00934505.	('variations', 'Var', (0, 10))	('FDG', 'Chemical', 'MESH:D019788', (14, 17))	('FDG', 'Protein', (14, 17))
253269	24602385	An automatic method using parametric imaging (PI) has been proposed to quantify FDG uptake variations in metastatic colorectal cancers.	('variations', 'Var', (91, 101))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('colorectal cancers', 'Disease', (116, 134))	('FDG', 'Chemical', 'MESH:D019788', (80, 83))	('cancers', 'Phenotype', 'HP:0002664', (127, 134))	('colorectal cancers', 'Disease', 'MESH:D015179', (116, 134))
253322	24602385	In this prospective, multicentre study, an automated parametric method was successfully used to investigate the prognostic value of variations in FDG uptake during curative-intent RCT in oesophageal squamous cell carcinoma.	('oesophageal squamous cell carcinoma', 'Disease', 'MESH:D002294', (187, 222))	('FDG', 'Gene', (146, 149))	('FDG', 'Chemical', 'MESH:D019788', (146, 149))	('oesophageal squamous cell carcinoma', 'Disease', (187, 222))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (199, 222))	('variations', 'Var', (132, 142))	('carcinoma', 'Phenotype', 'HP:0030731', (213, 222))
253334	24602385	However, we failed to demonstrate a prognostic value for Delta%SUVmax, Delta%SUVmean or Delta%TV, showing similar evolution of these quantitative parameters whatever the tumour response to treatment.	('tumour', 'Disease', (170, 176))	('tumour', 'Phenotype', 'HP:0002664', (170, 176))	('Delta', 'Var', (57, 62))	('tumour', 'Disease', 'MESH:D009369', (170, 176))
253371	31481083	Knocking down of MINCR greatly inhibited the growth of NSCLC cell lines PC9 and A549.	('Knocking down', 'Var', (0, 13))	('NSCLC', 'Disease', (55, 60))	('growth', 'CPA', (45, 51))	('PC9', 'Gene', '255738', (72, 75))	('NSCLC', 'Disease', 'MESH:D002289', (55, 60))	('A549', 'CellLine', 'CVCL:0023', (80, 84))	('PC9', 'Gene', (72, 75))	('MINCR', 'Gene', (17, 22))	('inhibited', 'NegReg', (31, 40))	('MINCR', 'Gene', '100507316', (17, 22))
253372	31481083	In addition, silencing of MINCR induced cell cycle arrest and apoptosis.	('arrest', 'Disease', 'MESH:D006323', (51, 57))	('MINCR', 'Gene', (26, 31))	('arrest', 'Disease', (51, 57))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (40, 57))	('apoptosis', 'CPA', (62, 71))	('MINCR', 'Gene', '100507316', (26, 31))	('silencing', 'Var', (13, 22))
253373	31481083	Furthermore, silencing of MINCR reduced the expression levels of oncogene c-Myc and its downstream cyclin A, cyclin D, CD4, and CDK2, as well as apoptosis-associated Bcl-2, while significantly increased the expression levels of cleaved PARP-1.	('Bcl-2', 'Gene', '596', (166, 171))	('MINCR', 'Gene', (26, 31))	('c-Myc', 'Gene', '4609', (74, 79))	('CDK2', 'Gene', '1017', (128, 132))	('cleaved', 'MPA', (228, 235))	('cyclin', 'Gene', '5111', (109, 115))	('reduced', 'NegReg', (32, 39))	('CDK2', 'Gene', (128, 132))	('PARP-1', 'Gene', (236, 242))	('cyclin A', 'Gene', '890', (99, 107))	('silencing', 'Var', (13, 22))	('cyclin', 'Gene', '5111', (99, 105))	('cyclin A', 'Gene', (99, 107))	('cyclin', 'Gene', (109, 115))	('MINCR', 'Gene', '100507316', (26, 31))	('increased', 'PosReg', (193, 202))	('expression levels', 'MPA', (44, 61))	('CD4', 'Gene', '920', (119, 122))	('Bcl-2', 'Gene', (166, 171))	('cyclin', 'Gene', (99, 105))	('expression levels', 'MPA', (207, 224))	('PARP-1', 'Gene', '142', (236, 242))	('c-Myc', 'Gene', (74, 79))	('CD4', 'Gene', (119, 122))
253412	31481083	Cells were cultured in 6-cm plates at 1x 106 cells/dish and cultured for 72 h. Silencing the MINCR to measure cell cycle and apoptosis requires siRNA reverse transfection while seeding cells.	('MINCR', 'Gene', '100507316', (93, 98))	('Silencing', 'Var', (79, 88))	('MINCR', 'Gene', (93, 98))	('cell cycle', 'CPA', (110, 120))
253423	31481083	Furthermore, silencing of MINCR greatly inhibited cell viabilities and reduced the expression levels of Ki-67 (Fig.	('inhibited', 'NegReg', (40, 49))	('MINCR', 'Gene', (26, 31))	('expression levels', 'MPA', (83, 100))	('Ki-67', 'Protein', (104, 109))	('cell viabilities', 'CPA', (50, 66))	('reduced', 'NegReg', (71, 78))	('MINCR', 'Gene', '100507316', (26, 31))	('silencing', 'Var', (13, 22))
253425	31481083	These data indicated that silencing of MINCR suppressed the proliferation of NSCLC cells.	('NSCLC', 'Disease', 'MESH:D002289', (77, 82))	('suppressed', 'NegReg', (45, 55))	('MINCR', 'Gene', '100507316', (39, 44))	('silencing', 'Var', (26, 35))	('NSCLC', 'Disease', (77, 82))	('MINCR', 'Gene', (39, 44))
253426	31481083	To further dissect the underlying mechanisms by which MINCR silencing inhibited growth of PC9 cells, flow-cytometer was used to analyze the proportions of cells in different cell cycle stages as well as the status of cell appoptosis.	('MINCR', 'Gene', (54, 59))	('PC9', 'Gene', '255738', (90, 93))	('growth', 'CPA', (80, 86))	('PC9', 'Gene', (90, 93))	('MINCR', 'Gene', '100507316', (54, 59))	('silencing', 'Var', (60, 69))	('inhibited', 'NegReg', (70, 79))
253441	31481083	Furthermore, silencing of MINCR greatly reduced cell growth by inducing cell cycle arrest and apoptosis of NSCLC cells, while over-expressing MINCR remarkably enhanced cell proliferation, part of which are consistent with a previous report by Wang et al.. For the mechanism studies, Wang et al.	('cell cycle arrest', 'Phenotype', 'HP:0011018', (72, 89))	('cell growth', 'CPA', (48, 59))	('arrest', 'Disease', 'MESH:D006323', (83, 89))	('NSCLC', 'Disease', (107, 112))	('MINCR', 'Gene', '100507316', (142, 147))	('inducing', 'Reg', (63, 71))	('MINCR', 'Gene', (26, 31))	('arrest', 'Disease', (83, 89))	('NSCLC', 'Disease', 'MESH:D002289', (107, 112))	('reduced', 'NegReg', (40, 47))	('MINCR', 'Gene', '100507316', (26, 31))	('MINCR', 'Gene', (142, 147))	('apoptosis', 'CPA', (94, 103))	('silencing', 'Var', (13, 22))
253448	31481083	As expected, we found that silencing of MINCR reduced the expression of c-Myc and its target effectors, while over-expression of MINCR activated the expression of c-Myc and its target genes, indicating that MINCR was capable of promoting c-Myc transcription network in NSCLC cells.	('c-Myc', 'Gene', '4609', (163, 168))	('expression', 'MPA', (58, 68))	('promoting', 'PosReg', (228, 237))	('NSCLC', 'Disease', 'MESH:D002289', (269, 274))	('MINCR', 'Gene', (207, 212))	('MINCR', 'Gene', (40, 45))	('c-Myc', 'Gene', (72, 77))	('NSCLC', 'Disease', (269, 274))	('MINCR', 'Gene', '100507316', (129, 134))	('c-Myc', 'Gene', (238, 243))	('c-Myc', 'Gene', '4609', (72, 77))	('c-Myc', 'Gene', '4609', (238, 243))	('reduced', 'NegReg', (46, 53))	('expression', 'MPA', (149, 159))	('MINCR', 'Gene', (129, 134))	('activated', 'PosReg', (135, 144))	('silencing', 'Var', (27, 36))	('c-Myc', 'Gene', (163, 168))	('MINCR', 'Gene', '100507316', (207, 212))	('MINCR', 'Gene', '100507316', (40, 45))
253460	30201948	MM gene expression studies GSE6477, GSE31162, GSE24080, and GSE19784 were obtained and analyzed.	('GSE6477', 'Chemical', '-', (27, 34))	('GSE19784', 'Var', (60, 68))	('GSE31162', 'Var', (36, 44))	('GSE6477', 'Var', (27, 34))	('GSE24080', 'Var', (46, 54))
253466	30201948	Meanwhile, ARPC5 was significantly increased in relapsed MM cells compared to baseline MM cells (P<0.0001).	('ARPC5', 'Gene', (11, 16))	('increased', 'PosReg', (35, 44))	('ARPC5', 'Gene', '10092', (11, 16))	('relapsed', 'Var', (48, 56))
253468	30201948	Meanwhile, patients in the ARPC5 high expression group were associated with poor overall survival (P=0.0027) and event-free survival (P=0.0102) compared to those in the ARPC5 low expression group.	('ARPC5', 'Gene', '10092', (27, 32))	('poor', 'NegReg', (76, 80))	('ARPC5', 'Gene', (27, 32))	('high expression', 'Var', (33, 48))	('ARPC5', 'Gene', (169, 174))	('ARPC5', 'Gene', '10092', (169, 174))	('overall', 'MPA', (81, 88))	('patients', 'Species', '9606', (11, 19))
253508	30201948	Patients in GSE20480 were divided into ARPC5 low expression group and ARPC5 high expression group based on the median of ARPC5 expression in GSE24080.	('GSE20480', 'Var', (12, 20))	('ARPC5', 'Gene', '10092', (70, 75))	('ARPC5', 'Gene', '10092', (121, 126))	('ARPC5', 'Gene', (70, 75))	('ARPC5', 'Gene', (121, 126))	('ARPC5', 'Gene', '10092', (39, 44))	('Patients', 'Species', '9606', (0, 8))	('ARPC5', 'Gene', (39, 44))
253526	30201948	suggested that the knockdown of microRNA-133a was associated with downregulation of APRC5, knockdown of ARPC5 inhibited the proliferation of lung squamous cell carcinoma and they concluded that ARPC5 might function as oncogenes in the development of lung squamous cell carcinoma.	('lung squamous cell carcinoma', 'Disease', (250, 278))	('carcinoma', 'Phenotype', 'HP:0030731', (160, 169))	('APRC5', 'Gene', (84, 89))	('ARPC5', 'Gene', '10092', (194, 199))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (141, 169))	('knockdown', 'Var', (19, 28))	('proliferation', 'CPA', (124, 137))	('ARPC5', 'Gene', (194, 199))	('knockdown', 'Var', (91, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (269, 278))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (141, 169))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (250, 278))	('lung squamous cell carcinoma', 'Disease', (141, 169))	('downregulation', 'NegReg', (66, 80))	('ARPC5', 'Gene', '10092', (104, 109))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (146, 169))	('ARPC5', 'Gene', (104, 109))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (250, 278))	('inhibited', 'NegReg', (110, 119))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (255, 278))
253535	30201948	demonstrated that MK2206 combined with bufalin inhibited the proliferation and stimulated apoptosis of myeloma cells through the inhibition of the AKT/mTOR pathway.	('proliferation', 'CPA', (61, 74))	('inhibited', 'NegReg', (47, 56))	('myeloma', 'Disease', 'MESH:D009101', (103, 110))	('mTOR', 'Gene', (151, 155))	('bufalin', 'Chemical', 'MESH:C022777', (39, 46))	('MK2206', 'Chemical', 'MESH:C548887', (18, 24))	('AKT', 'Gene', '207', (147, 150))	('inhibition', 'NegReg', (129, 139))	('stimulated', 'PosReg', (79, 89))	('apoptosis', 'CPA', (90, 99))	('mTOR', 'Gene', '2475', (151, 155))	('MK2206', 'Var', (18, 24))	('myeloma', 'Disease', (103, 110))	('AKT', 'Gene', (147, 150))
253536	30201948	demonstrated that polydatin inhibited cell proliferation and induced apoptosis and autophagy of myeloma cells through the mTOR/p70s6k signaling pathway.	('induced', 'PosReg', (61, 68))	('autophagy of myeloma', 'Disease', (83, 103))	('polydatin', 'Var', (18, 27))	('cell proliferation', 'CPA', (38, 56))	('p70s6k', 'Gene', (127, 133))	('autophagy of myeloma', 'Disease', 'MESH:C564093', (83, 103))	('inhibited', 'NegReg', (28, 37))	('apoptosis', 'CPA', (69, 78))	('mTOR', 'Gene', (122, 126))	('mTOR', 'Gene', '2475', (122, 126))	('p70s6k', 'Gene', '6198', (127, 133))	('polydatin', 'Chemical', 'MESH:C058229', (18, 27))
253538	30201948	Our GSEA results indicated that APCR5 might inhibit the proliferation of MM cells through regulation of mTORC1 signaling pathway.	('APCR5', 'Var', (32, 37))	('inhibit', 'NegReg', (44, 51))	('mTORC1', 'Gene', '382056', (104, 110))	('mTORC1', 'Gene', (104, 110))	('GSEA', 'Chemical', '-', (4, 8))
253572	33841579	The silencing of Klotho gene expression is mainly mediated through promoter hypermethylation and histone deacetylation in cancer.	('Klotho gene', 'Gene', (17, 28))	('cancer', 'Disease', (122, 128))	('promoter hypermethylation', 'Var', (67, 92))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('histone', 'MPA', (97, 104))	('deacetylation', 'Var', (105, 118))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('silencing', 'NegReg', (4, 13))	('expression', 'MPA', (29, 39))
253614	33841579	The expression of the mesenchymal marker N-cadherin was completely inhibited in the Klotho-overexpressing A549/KL-1 cells compared with the parental A549 cells and Klotho overexpression did not affect the regulation of other mesenchymal markers including vimentin or the epithelial marker E-cadherin (Fig.	('E-cadherin', 'Gene', (289, 299))	('E-cadherin', 'Gene', '999', (289, 299))	('inhibited', 'NegReg', (67, 76))	('N-cadherin', 'Gene', (41, 51))	('KL-1', 'Gene', '4254', (111, 115))	('KL-1', 'Gene', (111, 115))	('expression', 'MPA', (4, 14))	('N-cadherin', 'Gene', '1000', (41, 51))	('Klotho-overexpressing', 'Var', (84, 105))	('A549', 'CellLine', 'CVCL:0023', (149, 153))	('vimentin', 'Gene', '7431', (255, 263))	('vimentin', 'Gene', (255, 263))	('A549', 'CellLine', 'CVCL:0023', (106, 110))
253634	33841579	The top 30 genes with high-fold change values were assessed and the results demonstrated that the expression of EMT-related genes [discoidin I-like domain-containing protein 3 (EDIL3), pentraxin-3 (PTX3), fibrillin-2 (FBN2), interleukin-6 (IL-6)] and genes related to pemetrexed [dihydropyrimidine dehydrogenase (DPYD), lipocalin-2 (LCN2)] was upregulated by the introduction of the Klotho gene (Fig.	('LCN2', 'Gene', (333, 337))	('interleukin-6', 'Gene', (225, 238))	('DPYD', 'Gene', (313, 317))	('lipocalin-2', 'Gene', (320, 331))	('EDIL3', 'Gene', (177, 182))	('EDIL3', 'Gene', '10085', (177, 182))	('fibrillin-2', 'Gene', '2201', (205, 216))	('fibrillin-2', 'Gene', (205, 216))	('Klotho gene', 'Gene', (383, 394))	('EMT-related genes', 'Gene', (112, 129))	('upregulated', 'PosReg', (344, 355))	('FBN2', 'Gene', (218, 222))	('pentraxin-3', 'Gene', '5806', (185, 196))	('IL-6', 'Gene', '3569', (240, 244))	('lipocalin-2', 'Gene', '3934', (320, 331))	('DPYD', 'Gene', '1806', (313, 317))	('FBN2', 'Gene', '2201', (218, 222))	('interleukin-6', 'Gene', '3569', (225, 238))	('introduction', 'Var', (363, 375))	('IL-6', 'Gene', (240, 244))	('dihydropyrimidine dehydrogenase', 'Gene', (280, 311))	('PTX3', 'Gene', (198, 202))	('dihydropyrimidine dehydrogenase', 'Gene', '1806', (280, 311))	('pentraxin-3', 'Gene', (185, 196))	('PTX3', 'Gene', '5806', (198, 202))	('LCN2', 'Gene', '3934', (333, 337))	('pemetrexed', 'Chemical', 'MESH:D000068437', (268, 278))	('expression', 'MPA', (98, 108))
253641	33841579	The results of the present study demonstrated that the expression of EMT-related genes (EDIL3, PTX3, FBN2 and IL-6) and genes related to pemetrexed [DPYD, lipocalin-2 (LCN2)] was upregulated by the introduction of the Klotho gene.	('lipocalin-2', 'Gene', (155, 166))	('FBN2', 'Gene', (101, 105))	('DPYD', 'Gene', (149, 153))	('lipocalin-2', 'Gene', '3934', (155, 166))	('FBN2', 'Gene', '2201', (101, 105))	('EDIL3', 'Gene', (88, 93))	('EDIL3', 'Gene', '10085', (88, 93))	('DPYD', 'Gene', '1806', (149, 153))	('upregulated', 'PosReg', (179, 190))	('Klotho gene', 'Gene', (218, 229))	('pemetrexed', 'Chemical', 'MESH:D000068437', (137, 147))	('expression', 'MPA', (55, 65))	('introduction', 'Var', (198, 210))	('LCN2', 'Gene', '3934', (168, 172))	('IL-6', 'Gene', (110, 114))	('IL-6', 'Gene', '3569', (110, 114))	('PTX3', 'Gene', (95, 99))	('PTX3', 'Gene', '5806', (95, 99))	('LCN2', 'Gene', (168, 172))
253660	33841579	Wu et al demonstrated that pemetrexed caused cell cycle arrest in the G1 phase and S phase of A549 cells, and they noted a high expression of LCN2 proteins in A549 cells after pemetrexed exposure.	('LCN2', 'Gene', (142, 146))	('arrest', 'Disease', (56, 62))	('pemetrexed', 'Chemical', 'MESH:D000068437', (27, 37))	('A549', 'CellLine', 'CVCL:0023', (94, 98))	('pemetrexed', 'Var', (27, 37))	('A549', 'CellLine', 'CVCL:0023', (159, 163))	('S phase', 'CPA', (83, 90))	('expression', 'MPA', (128, 138))	('pemetrexed', 'Chemical', 'MESH:D000068437', (176, 186))	('LCN2', 'Gene', '3934', (142, 146))	('arrest', 'Disease', 'MESH:D006323', (56, 62))
253674	33664821	ERalpha and ERRalpha have 69% (70% with ERRalpha-1) and 34% (35% with ERRalpha-1) identity, respectively; ERRalpha and ERRbeta, have 92 and 61% identity, respectively.	('ERalpha', 'Gene', '2099', (0, 7))	('ERRalpha-1', 'Var', (40, 50))	('ERalpha', 'Gene', (0, 7))
253694	33664821	In non-smokers with NSCLC, biomarkers including epidermal growth factor receptor (EGFR), ELK (Ets like transcription factor-1; highly expressed in NSCLC, irrespective of patient's age, sex, smoking status and histology) and KRAS mutations are more frequently observed in women compared with men.	('ELK', 'Gene', (89, 92))	('epidermal growth factor receptor', 'Gene', (48, 80))	('men', 'Species', '9606', (273, 276))	('epidermal growth factor receptor', 'Gene', '1956', (48, 80))	('women', 'Species', '9606', (271, 276))	('EGFR', 'Gene', (82, 86))	('NSCLC', 'Disease', 'MESH:D002289', (20, 25))	('KRAS', 'Gene', '3845', (224, 228))	('mutations', 'Var', (229, 238))	('NSCLC', 'Disease', (20, 25))	('KRAS', 'Gene', (224, 228))	('NSCLC', 'Disease', 'MESH:D002289', (147, 152))	('ELK', 'Gene', '2047', (89, 92))	('NSCLC', 'Phenotype', 'HP:0030358', (20, 25))	('EGFR', 'Gene', '1956', (82, 86))	('NSCLC', 'Disease', (147, 152))	('NSCLC', 'Phenotype', 'HP:0030358', (147, 152))	('men', 'Species', '9606', (291, 294))	('patient', 'Species', '9606', (170, 177))
253695	33664821	These mutations mostly occur in adenocarcinoma.	('adenocarcinoma', 'Disease', 'MESH:D000230', (32, 46))	('carcinoma', 'Phenotype', 'HP:0030731', (37, 46))	('occur', 'Reg', (23, 28))	('adenocarcinoma', 'Disease', (32, 46))	('mutations', 'Var', (6, 15))
253704	33664821	Also, female smokers have a higher frequency of TP53 gene mutations compared to non-smoking females or males.	('mutations', 'Var', (58, 67))	('TP53', 'Gene', '7157', (48, 52))	('TP53', 'Gene', (48, 52))
253706	33664821	Women are also more likely to have mutations in the GSTM1 (Glutathione S-transferase Mu 1) gene, which normally inactivates toxic metabolites and has been linked to lung cancer development in smokers.	('linked to', 'Reg', (155, 164))	('Women', 'Species', '9606', (0, 5))	('Glutathione S-transferase Mu 1', 'Gene', (59, 89))	('lung cancer', 'Disease', (165, 176))	('lung cancer', 'Phenotype', 'HP:0100526', (165, 176))	('Glutathione S-transferase Mu 1', 'Gene', '2944', (59, 89))	('men', 'Species', '9606', (2, 5))	('men', 'Species', '9606', (184, 187))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('inactivates', 'NegReg', (112, 123))	('lung cancer', 'Disease', 'MESH:D008175', (165, 176))	('GSTM1', 'Gene', '2944', (52, 57))	('GSTM1', 'Gene', (52, 57))	('mutations', 'Var', (35, 44))
253741	33664821	Inspection of the ERRalpha and ERRgamma LBD conformations reveals the importance of amino acids that have bulky side chains occupying the ligand binding pocket, hence mimicking a ligand bound conformation that facilitates cofactor binding.	('ERRgamma', 'Gene', (31, 39))	('ERRgamma', 'Gene', '2104', (31, 39))	('facilitates', 'PosReg', (210, 221))	('ligand', 'MPA', (179, 185))	('cofactor binding', 'Interaction', (222, 238))	('mimicking', 'Reg', (167, 176))	('bulky side', 'Var', (106, 116))
253742	33664821	As one example, the ERRalpha LBD crystal structure revealed a significant Phe328 hold of the ligand binding pocket that confers an agonist conformation to the LBD, which further binds the PPARgamma co-activator-1alpha peptide.	('binds', 'Interaction', (178, 183))	('Phe328', 'Chemical', '-', (74, 80))	('agonist conformation', 'MPA', (131, 151))	('PPARgamma co-activator-1alpha', 'Gene', (188, 217))	('Phe328 hold', 'Var', (74, 85))	('PPARgamma co-activator-1alpha', 'Gene', '10891', (188, 217))
253770	33664821	ERRalpha KO mice also exhibit cardiac defects in bioenergetics and functional adaptation to pressure overload, but their development and function under normal, unstressed conditions is unaffected.	('cardiac defects', 'Disease', (30, 45))	('functional adaptation to pressure overload', 'MPA', (67, 109))	('ERRalpha', 'Var', (0, 8))	('men', 'Species', '9606', (128, 131))	('cardiac defects', 'Disease', 'MESH:D006331', (30, 45))	('mice', 'Species', '10090', (12, 16))	('bioenergetics', 'MPA', (49, 62))
253792	33664821	It was also noticed that XCT-790 modulated the p53 and pRB signaling pathways (via ROS involvement) and consequently suppressed cell replication.	('pRB', 'Gene', '5925', (55, 58))	('modulated', 'Reg', (33, 42))	('men', 'Species', '9606', (94, 97))	('suppressed', 'NegReg', (117, 127))	('XCT-790', 'Var', (25, 32))	('pRB', 'Gene', (55, 58))	('ROS', 'Chemical', 'MESH:D017382', (83, 86))	('cell replication', 'CPA', (128, 144))	('p53', 'Gene', (47, 50))	('p53', 'Gene', '7157', (47, 50))
253800	33664821	NSCLC cell culture-based investigations demonstrated ERRalpha specific inverse agonists/small interfering (si)RNA/shRNA effect cell cycle regulation.	('NSCLC', 'Disease', 'MESH:D002289', (0, 5))	('agonists/small interfering', 'Var', (79, 105))	('rat', 'Species', '10116', (47, 50))	('cell cycle regulation', 'CPA', (127, 148))	('NSCLC', 'Phenotype', 'HP:0030358', (0, 5))	('ERRalpha', 'Protein', (53, 61))	('NSCLC', 'Disease', (0, 5))
253804	33664821	Modulation of multiple signaling pathways by ERRalpha presents implicit cell-division acceleration strategies, which collectively result in tumor progression (Fig.	('Modulation', 'Var', (0, 10))	('rat', 'Species', '10116', (101, 104))	('cell-division', 'CPA', (72, 85))	('result in', 'Reg', (130, 139))	('ERRalpha', 'Gene', (45, 53))	('rat', 'Species', '10116', (92, 95))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('tumor', 'Disease', (140, 145))
253806	33664821	The results demonstrated that ERRalpha knockdown in LUAD leads to cell synchronization at the G2-M phase transition, but the LSCC cells continued with cell cycle progression.	('ERRalpha', 'Gene', (30, 38))	('knockdown', 'Var', (39, 48))	('LUAD', 'Phenotype', 'HP:0030078', (52, 56))	('cell synchronization', 'CPA', (66, 86))	('rat', 'Species', '10116', (19, 22))
253813	33664821	The EMT phenotype in NSCLC is associated with EGFR mutations, drug resistance and formation of cancer stem cells.	('associated', 'Reg', (30, 40))	('mutations', 'Var', (51, 60))	('drug resistance', 'CPA', (62, 77))	('NSCLC', 'Disease', (21, 26))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('drug resistance', 'Phenotype', 'HP:0020174', (62, 77))	('EGFR', 'Gene', '1956', (46, 50))	('cancer', 'Disease', (95, 101))	('NSCLC', 'Disease', 'MESH:D002289', (21, 26))	('NSCLC', 'Phenotype', 'HP:0030358', (21, 26))	('EGFR', 'Gene', (46, 50))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))
253829	33664821	In a subsequent investigation, Zhang et al observed ERRalpha induces pro-inflammatory transcription factor NF-kappaB activation and translocation from cytoplasm to nucleus, which in turn led to the expression of the pro-inflammatory cytokine, IL-6.	('expression', 'MPA', (198, 208))	('led to', 'Reg', (187, 193))	('IL-6', 'Gene', (243, 247))	('NF-kappaB', 'Gene', '4790', (107, 116))	('IL-6', 'Gene', '3569', (243, 247))	('ERRalpha', 'Var', (52, 60))	('translocation', 'MPA', (132, 145))	('activation', 'PosReg', (117, 127))	('NF-kappaB', 'Gene', (107, 116))
253977	32607829	Eradication of HP decreases the risk of ulcers and may prevent stomach cancer.	('stomach cancer', 'Disease', 'MESH:D013274', (63, 77))	('decreases', 'NegReg', (18, 27))	('stomach cancer', 'Phenotype', 'HP:0012126', (63, 77))	('HP', 'Species', '210', (15, 17))	('stomach cancer', 'Disease', (63, 77))	('ulcers', 'Disease', (40, 46))	('Eradication', 'Var', (0, 11))	('prevent', 'NegReg', (55, 62))	('ulcers', 'Disease', 'MESH:D014456', (40, 46))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))
254013	31823521	EGFR signaling inhibition decreases SOX2 expression by promoting its autophagic degradation.	('autophagic degradation', 'CPA', (69, 91))	('EGFR', 'Gene', (0, 4))	('expression', 'MPA', (41, 51))	('promoting', 'PosReg', (55, 64))	('SOX2', 'Gene', '6657', (36, 40))	('SOX2', 'Gene', (36, 40))	('decreases', 'NegReg', (26, 35))	('EGFR', 'Gene', '1956', (0, 4))	('inhibition', 'Var', (15, 25))
254019	31823521	EGFR activation induces SOX2 phosphorylation at Y277 site and reduces its ubiquitination, which inhibit its associated with p62 and subsequent autophagic degradation.	('SOX2', 'Gene', (24, 28))	('reduces', 'NegReg', (62, 69))	('ubiquitination', 'MPA', (74, 88))	('EGFR', 'Gene', (0, 4))	('Y277 site', 'Var', (48, 57))	('inhibit', 'NegReg', (96, 103))	('p62', 'Gene', '8878', (124, 127))	('activation', 'PosReg', (5, 15))	('p62', 'Gene', (124, 127))	('associated', 'Interaction', (108, 118))	('autophagic degradation', 'CPA', (143, 165))	('EGFR', 'Gene', '1956', (0, 4))	('SOX2', 'Gene', '6657', (24, 28))
254028	31823521	Inhibiting EGFR signaling decreases the proliferation, invasion, and tumor sphere-forming capacity of CAL-27 cells, a human tongue squamous cell carcinoma cell line.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (131, 154))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tongue squamous cell carcinoma', 'Phenotype', 'HP:0030413', (124, 154))	('Inhibiting', 'Var', (0, 10))	('carcinoma', 'Phenotype', 'HP:0030731', (145, 154))	('tumor', 'Disease', (69, 74))	('EGFR', 'Gene', '1956', (11, 15))	('EGFR', 'Gene', (11, 15))	('tongue squamous cell carcinoma', 'Disease', (124, 154))	('tongue squamous cell carcinoma', 'Disease', 'MESH:D002294', (124, 154))	('CAL-27', 'CellLine', 'CVCL:1107', (102, 108))	('invasion', 'CPA', (55, 63))	('human', 'Species', '9606', (118, 123))	('decreases', 'NegReg', (26, 35))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('proliferation', 'CPA', (40, 53))
254033	31823521	SOX2 mutants (Y277A and Y277D) were established using the Fast Mutagenesis System (TransGen Biotech).	('SOX2', 'Gene', '6657', (0, 4))	('Y277D', 'Var', (24, 29))	('Y277A', 'Var', (14, 19))	('Y277D', 'Mutation', 'p.Y277D', (24, 29))	('Y277A', 'Mutation', 'p.Y277A', (14, 19))	('SOX2', 'Gene', (0, 4))
254056	31823521	The sources of the antibodies are as follows: anti-EPCAM (ab223582), anti-Nanog (ab109250), anti-OCT4 (ab181557), anti-SOX2 (ab92494), anti-KLF4 (ab215036), anti-p62 (ab109012), anti-EGFR (ab52894), anti-phosphotyrosine (ab10321), anti-LC3 (ab48394), anti-Beclin1 (ab210498), and anti-PI3KC3 (ab40776).	('ab48394', 'Var', (241, 248))	('OCT4', 'Gene', (97, 101))	('KLF4', 'Gene', '9314', (140, 144))	('ab210498', 'Var', (265, 273))	('ab10321', 'Var', (221, 228))	('Beclin1', 'Gene', (256, 263))	('ab215036', 'Var', (146, 154))	('ab181557', 'Var', (103, 111))	('EPCAM', 'Gene', '4072', (51, 56))	('EGFR', 'Gene', (183, 187))	('SOX2', 'Gene', (119, 123))	('SOX2', 'Gene', '6657', (119, 123))	('ab52894', 'Var', (189, 196))	('ab92494', 'Var', (125, 132))	('Nanog', 'Gene', '79923', (74, 79))	('KLF4', 'Gene', (140, 144))	('Nanog', 'Gene', (74, 79))	('p62', 'Gene', (162, 165))	('p62', 'Gene', '8878', (162, 165))	('EPCAM', 'Gene', (51, 56))	('ab109012', 'Var', (167, 175))	('phosphotyrosine', 'Chemical', 'MESH:C117571', (204, 219))	('ab40776', 'Var', (293, 300))	('OCT4', 'Gene', '5460', (97, 101))	('EGFR', 'Gene', '1956', (183, 187))	('Beclin1', 'Gene', '8678', (256, 263))
254061	31823521	As reported, EGFR is overexpressed in over 90% of HNSCC patients, and we analyzed the relationship between EGFR expression and HNSCC survival using the GEPIA platform.20 A high level of EGFR is correlated with a decreased overall survival rate of patients with HNSCC (Figure 1A).	('patients', 'Species', '9606', (56, 64))	('HNSCC', 'Disease', 'MESH:C535575', (261, 266))	('EGFR', 'Gene', (107, 111))	('EGFR', 'Gene', (186, 190))	('HNSCC', 'Disease', (50, 55))	('EGFR', 'Gene', '1956', (13, 17))	('HNSCC', 'Phenotype', 'HP:0012288', (50, 55))	('HNSCC', 'Disease', (127, 132))	('decreased', 'NegReg', (212, 221))	('HNSCC', 'Disease', (261, 266))	('EGFR', 'Gene', '1956', (107, 111))	('EGFR', 'Gene', '1956', (186, 190))	('patients', 'Species', '9606', (247, 255))	('HNSCC', 'Disease', 'MESH:C535575', (50, 55))	('high', 'Var', (172, 176))	('EGFR', 'Gene', (13, 17))	('HNSCC', 'Phenotype', 'HP:0012288', (127, 132))	('HNSCC', 'Phenotype', 'HP:0012288', (261, 266))	('overall survival rate', 'CPA', (222, 243))	('HNSCC', 'Disease', 'MESH:C535575', (127, 132))
254075	31823521	Instead, gefitinib-treated CAL-27 cells displayed a much shorter SOX2 half-life (~2.5 hours) than did the control cells (~5.5 hours) (Figure 2B), indicating that gefitinib treatment reduced SOX2 stability.	('SOX2', 'Gene', '6657', (65, 69))	('SOX2', 'Gene', (65, 69))	('gefitinib', 'Chemical', 'MESH:C419708', (162, 171))	('SOX2', 'Gene', (190, 194))	('gefitinib', 'Chemical', 'MESH:C419708', (9, 18))	('SOX2', 'Gene', '6657', (190, 194))	('CAL-27', 'CellLine', 'CVCL:1107', (27, 33))	('gefitinib-treated', 'Var', (9, 26))	('reduced', 'NegReg', (182, 189))	('shorter', 'NegReg', (57, 64))
254077	31823521	The proteasome inhibitor MG132 extended the half-life of SOX2 in both control (~3.8 hours) and gefitinib-treated (~7.4 hours) CAL-27 cells without changing the SOX2 stability in either group (Figure 2C).	('half-life', 'MPA', (44, 53))	('CAL-27', 'CellLine', 'CVCL:1107', (126, 132))	('SOX2', 'Gene', '6657', (160, 164))	('SOX2', 'Gene', (160, 164))	('MG132', 'Var', (25, 30))	('extended', 'PosReg', (31, 39))	('SOX2', 'Gene', (57, 61))	('SOX2', 'Gene', '6657', (57, 61))	('gefitinib', 'Chemical', 'MESH:C419708', (95, 104))
254084	31823521	Additionally, silencing Beclin-1 increased the level of SOX2 in gefitinib-treated CAL-27 cells without enhancing the SOX2 tyrosine phosphorylation level (Figure 3B).	('silencing', 'Var', (14, 23))	('SOX2', 'Gene', '6657', (117, 121))	('SOX2', 'Gene', '6657', (56, 60))	('CAL-27', 'CellLine', 'CVCL:1107', (82, 88))	('SOX2', 'Gene', (117, 121))	('SOX2', 'Gene', (56, 60))	('tyrosine', 'Chemical', 'None', (122, 130))	('increased', 'PosReg', (33, 42))	('Beclin-1', 'Gene', (24, 32))	('Beclin-1', 'Gene', '8678', (24, 32))	('gefitinib', 'Chemical', 'MESH:C419708', (64, 73))	('level', 'MPA', (47, 52))
254085	31823521	In addition, we found that gefitinib induced autophagy in CAL-27 cells (Figure 3C).	('CAL-27', 'CellLine', 'CVCL:1107', (58, 64))	('gefitinib', 'Chemical', 'MESH:C419708', (27, 36))	('gefitinib', 'Var', (27, 36))	('autophagy', 'CPA', (45, 54))
254087	31823521	Kinase prediction algorithms22 showed that SOX2 Tyr277 was a putative EGFR phosphorylation site (Figure 3D).	('EGFR', 'Gene', '1956', (70, 74))	('SOX2', 'Gene', (43, 47))	('EGFR', 'Gene', (70, 74))	('SOX2', 'Gene', '6657', (43, 47))	('Tyr277', 'Var', (48, 54))
254090	31823521	These data indicate that EGFR-induced SOX2 Tyr277 phosphorylation prevents the autophagic degradation of SOX2 and enhances its stability.	('SOX2', 'Gene', '6657', (38, 42))	('SOX2', 'Gene', (38, 42))	('stability', 'MPA', (127, 136))	('EGFR', 'Gene', (25, 29))	('Tyr277', 'Var', (43, 49))	('SOX2', 'Gene', (105, 109))	('SOX2', 'Gene', '6657', (105, 109))	('autophagic degradation', 'CPA', (79, 101))	('prevents', 'NegReg', (66, 74))	('enhances', 'PosReg', (114, 122))	('EGFR', 'Gene', '1956', (25, 29))
254091	31823521	p62 is one of the cargo receptors that mediates the degradation of ubiquitinated substrates.23 We found that ubiquitinated SOX2 was increased when blocking EGFR activity with gefitinib, suggesting that inhibition of EGFR activity increases SOX2 ubiquitination (Figure 4A,B).	('SOX2', 'Gene', '6657', (240, 244))	('EGFR', 'Gene', (216, 220))	('gefitinib', 'Chemical', 'MESH:C419708', (175, 184))	('p62', 'Gene', '8878', (0, 3))	('SOX2', 'Gene', (240, 244))	('increases', 'PosReg', (230, 239))	('EGFR', 'Gene', '1956', (156, 160))	('p62', 'Gene', (0, 3))	('increased', 'PosReg', (132, 141))	('inhibition', 'Var', (202, 212))	('EGFR', 'Gene', (156, 160))	('SOX2', 'Gene', '6657', (123, 127))	('SOX2', 'Gene', (123, 127))	('EGFR', 'Gene', '1956', (216, 220))	('ubiquitinated', 'MPA', (109, 122))	('blocking', 'NegReg', (147, 155))	('activity', 'MPA', (161, 169))
254093	31823521	To further determine whether Y277 phosphorylation mediated the disassociation of SOX2 from p62, the interaction of p62 with wild-type SOX2 and its Y277A and Y277D (a phosphorylation-mimic mutant) mutants was detected.	('Y277 phosphorylation', 'Var', (29, 49))	('p62', 'Gene', '8878', (91, 94))	('disassociation', 'MPA', (63, 77))	('interaction', 'Interaction', (100, 111))	('SOX2', 'Gene', '6657', (134, 138))	('Y277D', 'Mutation', 'p.Y277D', (157, 162))	('Y277A', 'Var', (147, 152))	('Y277A', 'Mutation', 'p.Y277A', (147, 152))	('SOX2', 'Gene', '6657', (81, 85))	('p62', 'Gene', '8878', (115, 118))	('SOX2', 'Gene', (81, 85))	('Y277D', 'Var', (157, 162))	('p62', 'Gene', (115, 118))	('p62', 'Gene', (91, 94))	('SOX2', 'Gene', (134, 138))
254094	31823521	Our data showed that the Y277D mutant had a decreased binding ability with p62 in comparison with that of wild-type SOX2 and the Y277A mutant (Figure 4E).	('Y277A', 'Var', (129, 134))	('Y277A', 'Mutation', 'p.Y277A', (129, 134))	('Y277D', 'Mutation', 'p.Y277D', (25, 30))	('Y277D', 'Var', (25, 30))	('p62', 'Gene', (75, 78))	('SOX2', 'Gene', '6657', (116, 120))	('p62', 'Gene', '8878', (75, 78))	('SOX2', 'Gene', (116, 120))	('binding', 'Interaction', (54, 61))	('decreased', 'NegReg', (44, 53))
254095	31823521	These results demonstrate that EGFR-induced Tyr277 phosphorylation of SOX2 reduces its binding activity with p62 and enhances its stability.	('EGFR', 'Gene', '1956', (31, 35))	('SOX2', 'Gene', '6657', (70, 74))	('SOX2', 'Gene', (70, 74))	('EGFR', 'Gene', (31, 35))	('binding', 'Interaction', (87, 94))	('reduces', 'NegReg', (75, 82))	('Tyr277', 'Var', (44, 50))	('p62', 'Gene', '8878', (109, 112))	('stability', 'MPA', (130, 139))	('enhances', 'PosReg', (117, 125))	('p62', 'Gene', (109, 112))
254096	31823521	Since inhibiting EGFR activity promotes autophagic degradation of SOX2, we wondered whether the tumor inhibiting effect of gefitinib could be reversed by blocking autophagy.	('gefitinib', 'Chemical', 'MESH:C419708', (123, 132))	('SOX2', 'Gene', '6657', (66, 70))	('autophagic degradation', 'MPA', (40, 62))	('inhibiting', 'Var', (6, 16))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('SOX2', 'Gene', (66, 70))	('promotes', 'PosReg', (31, 39))	('tumor', 'Disease', (96, 101))	('EGFR', 'Gene', '1956', (17, 21))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('EGFR', 'Gene', (17, 21))
254100	31823521	Fewer oncospheres and smaller oncospheres were observed in the gefitinib treatment group than in the nontreated group, while 3-MA treatment reversed the oncosphere-inhibiting effect of gefitinib (Figure 5C).	('gefitinib', 'Chemical', 'MESH:C419708', (63, 72))	('oncospheres', 'CPA', (6, 17))	('3-MA', 'Chemical', 'MESH:D008694', (125, 129))	('oncosphere-inhibiting', 'CPA', (153, 174))	('Fewer', 'NegReg', (0, 5))	('gefitinib', 'Var', (63, 72))	('gefitinib', 'Chemical', 'MESH:C419708', (185, 194))	('oncospheres', 'CPA', (30, 41))
254105	31823521	In addition, gefitinib reduced the p-EGFR level in tumor tissue, and this effect was not reversed by 3-MA treatment (Figure 5H).	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor', 'Disease', (51, 56))	('3-MA', 'Chemical', 'MESH:D008694', (101, 105))	('EGFR', 'Gene', '1956', (37, 41))	('gefitinib', 'Var', (13, 22))	('reduced', 'NegReg', (23, 30))	('EGFR', 'Gene', (37, 41))	('gefitinib', 'Chemical', 'MESH:C419708', (13, 22))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
254118	31823521	Ubiquitin-conjugating enzyme E2S (Ube2s) mediates K11-linked polyubiquitination at the Sox2-K123 residue and facilitates proteasome-mediated degradation.16 In embryonic stem cells, the precise level of SOX2 protein is regulated by a balanced methylation and phosphorylation switch.17 Here, we provide evidence to show that EGFR-mediated Y277 phosphorylation is a critical modification for maintaining SOX2 stability by avoiding its autophagic degradation.	('Ubiquitin-conjugating enzyme E2S', 'Gene', '27338', (0, 32))	('Sox2', 'Gene', '6657', (87, 91))	('SOX2', 'Gene', '6657', (202, 206))	('Sox2', 'Gene', (87, 91))	('EGFR', 'Gene', '1956', (323, 327))	('Ube2s', 'Gene', (34, 39))	('autophagic degradation', 'MPA', (432, 454))	('stability', 'MPA', (406, 415))	('EGFR', 'Gene', (323, 327))	('Ube2s', 'Gene', '27338', (34, 39))	('Y277 phosphorylation', 'Var', (337, 357))	('SOX2', 'Gene', '6657', (401, 405))	('SOX2', 'Gene', (202, 206))	('Ubiquitin-conjugating enzyme E2S', 'Gene', (0, 32))	('avoiding', 'NegReg', (419, 427))	('SOX2', 'Gene', (401, 405))
254122	31823521	However, the exact relationship between Y277 phosphorylation and the ubiquitination of SOX2 remains to be determined.	('SOX2', 'Gene', '6657', (87, 91))	('ubiquitination', 'MPA', (69, 83))	('SOX2', 'Gene', (87, 91))	('Y277', 'Var', (40, 44))
254123	31823521	Collectively, our study provides evidence that EGFR signaling induces SOX2 phosphorylation at Y277 and decreases SOX2 ubiquitination, which inhibits the binding of SOX2 with p62 and prohibits the autophagic degradation of SOX2.	('p62', 'Gene', (174, 177))	('induces', 'Reg', (62, 69))	('SOX2', 'Gene', '6657', (113, 117))	('SOX2', 'Gene', (113, 117))	('EGFR', 'Gene', '1956', (47, 51))	('Y277', 'Var', (94, 98))	('binding', 'Interaction', (153, 160))	('SOX2', 'Gene', (164, 168))	('inhibits', 'NegReg', (140, 148))	('prohibits', 'NegReg', (182, 191))	('SOX2', 'Gene', (222, 226))	('SOX2', 'Gene', '6657', (222, 226))	('EGFR', 'Gene', (47, 51))	('autophagic degradation', 'CPA', (196, 218))	('SOX2', 'Gene', '6657', (70, 74))	('decreases', 'NegReg', (103, 112))	('SOX2', 'Gene', (70, 74))	('p62', 'Gene', '8878', (174, 177))	('SOX2', 'Gene', '6657', (164, 168))
254131	31823521	Thus, treatments using a combination of EGFR inhibitors with surgery or conventional chemotherapy will target both the bulk of the tumor and the cancer stem cell subpopulation, thereby reducing the possibility of relapse and metastasis.	('cancer', 'Disease', (145, 151))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('reducing', 'NegReg', (185, 193))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('tumor', 'Disease', (131, 136))	('EGFR', 'Gene', '1956', (40, 44))	('EGFR', 'Gene', (40, 44))	('inhibitors', 'Var', (45, 55))	('cancer', 'Disease', 'MESH:D009369', (145, 151))
254144	31391030	As a class of endogenous non coding RNA, long noncoding RNA (lncRNA) has a broad range of molecular and cellular functions, including chromatin modification, gene imprinting, alternative splicing, dosage compensation, nuclear-cytoplasmic trafficking, and inactivation of major tumor suppressor genes etc..	('nuclear-cytoplasmic trafficking', 'CPA', (218, 249))	('inactivation', 'Var', (255, 267))	('tumor', 'Disease', 'MESH:D009369', (277, 282))	('tumor', 'Phenotype', 'HP:0002664', (277, 282))	('tumor', 'Disease', (277, 282))
254145	31391030	Accumulating evidences of dysregulated lncRNAs in various cancers suggested that these greater than 200 nucleotides RNAs may contribute to cancer development and progression.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('cancers', 'Phenotype', 'HP:0002664', (58, 65))	('cancers', 'Disease', (58, 65))	('greater than 200 nucleotides', 'Var', (87, 115))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('cancers', 'Disease', 'MESH:D009369', (58, 65))	('cancer', 'Disease', (58, 64))	('RNAs', 'Gene', (116, 120))	('progression', 'CPA', (162, 173))	('contribute', 'Reg', (125, 135))	('cancer', 'Disease', (139, 145))
254174	31391030	For example, the dysregulation of LncRNA SNHG1 has been demonstrated to participate in Notch and Wnt/beta-catenin signaling pathways in osteosarcoma and colorectal cancer.	('osteosarcoma', 'Disease', (136, 148))	('osteosarcoma', 'Phenotype', 'HP:0002669', (136, 148))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('colorectal cancer', 'Disease', 'MESH:D015179', (153, 170))	('osteosarcoma', 'Disease', 'MESH:D012516', (136, 148))	('SNHG1', 'Gene', (41, 46))	('beta-catenin', 'Gene', (101, 113))	('dysregulation', 'Var', (17, 30))	('colorectal cancer', 'Phenotype', 'HP:0003003', (153, 170))	('beta-catenin', 'Gene', '1499', (101, 113))	('participate', 'Reg', (72, 83))	('SNHG1', 'Gene', '23642', (41, 46))	('colorectal cancer', 'Disease', (153, 170))
254178	31391030	These encouraged evidences urged us investigating the relationship between lncRNA SNHG1 and cancer prognosis, and our analysis firstly demonstrated that high expression level of lncRNA SNHG1 was an unfavorable predictor for the clinical outcomes of various cancer patients.	('SNHG1', 'Gene', (185, 190))	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('cancer', 'Phenotype', 'HP:0002664', (257, 263))	('SNHG1', 'Gene', '23642', (82, 87))	('SNHG1', 'Gene', '23642', (185, 190))	('cancer', 'Disease', 'MESH:D009369', (257, 263))	('SNHG1', 'Gene', (82, 87))	('patients', 'Species', '9606', (264, 272))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('cancer', 'Disease', (257, 263))	('high', 'Var', (153, 157))
254198	30766750	The knockdown of Flot1 decreased the growth, migration, and invasiveness of SCLC cells and reversed EMT phenotype in vitro and in vivo, while enhanced Flot1 expression exhibited the opposite behavior.	('reversed', 'Reg', (91, 99))	('expression', 'MPA', (157, 167))	('migration', 'CPA', (45, 54))	('EMT phenotype', 'CPA', (100, 113))	('SCLC', 'Gene', '7864', (76, 80))	('SCLC', 'Gene', (76, 80))	('Flot1', 'Gene', (17, 22))	('enhanced', 'PosReg', (142, 150))	('Flot1', 'Gene', (151, 156))	('growth', 'CPA', (37, 43))	('invasiveness of', 'CPA', (60, 75))	('knockdown', 'Var', (4, 13))	('decreased', 'NegReg', (23, 32))
254260	30766750	Total RNA from human NCI-H446 cells, in which Flot1 was stably knocked down, and wild type NCI-H446 cells was isolated and quantified.	('knocked down', 'Var', (63, 75))	('NCI-H446', 'CellLine', 'CVCL:1562', (91, 99))	('Flot1', 'Gene', (46, 51))	('human', 'Species', '9606', (15, 20))	('NCI-H446', 'CellLine', 'CVCL:1562', (21, 29))
254265	30766750	We found that high Flot1 expression was correlated with poor survival probability in LUSC patients, but not in patients LUAD (Figure 1A and 1B).	('poor', 'NegReg', (56, 60))	('survival', 'CPA', (61, 69))	('expression', 'MPA', (25, 35))	('high', 'Var', (14, 18))	('patients', 'Species', '9606', (90, 98))	('Flot1', 'Gene', (19, 24))	('patients', 'Species', '9606', (111, 119))
254278	30766750	The median survival of patients with SCLC with high Flot1 expression and low Flot1 expression was 13 and 18 months, respectively.	('SCLC', 'Gene', (37, 41))	('Flot1', 'Gene', (77, 82))	('patients', 'Species', '9606', (23, 31))	('high', 'Var', (47, 51))	('Flot1', 'Gene', (52, 57))	('expression', 'MPA', (83, 93))	('SCLC', 'Gene', '7864', (37, 41))	('low', 'NegReg', (73, 76))
254279	30766750	Notably, high Flot1 expression was also significantly correlated with shorter progression-free survival in the limited stage of SCLC patients (PFS, P = 0.002, Figure 3E) and extensive stage of SCLC patients (PFS, P < 0.001, Figure 3E).	('expression', 'MPA', (20, 30))	('patients', 'Species', '9606', (198, 206))	('SCLC', 'Gene', '7864', (128, 132))	('SCLC', 'Gene', (128, 132))	('shorter', 'NegReg', (70, 77))	('SCLC', 'Gene', (193, 197))	('Flot1', 'Gene', (14, 19))	('patients', 'Species', '9606', (133, 141))	('SCLC', 'Gene', '7864', (193, 197))	('progression-free survival', 'CPA', (78, 103))	('high', 'Var', (9, 13))
254282	30766750	We examined the role of Flot1 in cell proliferation using the xCELLigence System and found that knockdown of Flot1 expression inhibited the proliferation of NCI-H446 and NCI-H1688 cells (Figure 4B), whereas overexpression of Flot1 promoted proliferation of NCI-H446 and NCI-H1688 cells (Supplementary Figure S2A and S2B).	('knockdown', 'Var', (96, 105))	('NCI-H1688', 'CellLine', 'CVCL:1487', (170, 179))	('proliferation', 'CPA', (140, 153))	('Flot1', 'Gene', (109, 114))	('NCI-H1688', 'CellLine', 'CVCL:1487', (270, 279))	('inhibited', 'NegReg', (126, 135))	('NCI-H1688 cells', 'CPA', (170, 185))	('NCI-H446', 'CellLine', 'CVCL:1562', (257, 265))	('NCI-H446', 'CellLine', 'CVCL:1562', (157, 165))
254283	30766750	In addition, cell cycle analysis by flow cytometry showed that the knockdown of Flot1 with siRNA resulted in an increase in the percentage of cells in G1 phase from 55.89% to 69.80% or 71.80% for two sequence of siRNA for Flot1 in NCI-H446, respectively (Figure 4E and 4F), suggesting that inhibiting Flot1 could arrest the SCLC cells to G1 phase.	('knockdown', 'Var', (67, 76))	('cells in G1 phase', 'CPA', (142, 159))	('NCI-H446', 'CellLine', 'CVCL:1562', (231, 239))	('SCLC', 'Gene', '7864', (324, 328))	('SCLC', 'Gene', (324, 328))	('increase', 'PosReg', (112, 120))	('Flot1', 'Gene', (80, 85))	('inhibiting', 'Var', (290, 300))
254290	30766750	Morphological changes were observed in the cells overexpressing Flot1, showing an elongated, mesenchymal morphology as compared to the parental NCI-H446 and NCI-H1688 cells (Figure 5B), which suggests that Flot1 may be involved in the progression of EMT in SCLC.	('overexpressing', 'Var', (49, 63))	('NCI-H446', 'CellLine', 'CVCL:1562', (144, 152))	('NCI-H1688', 'CellLine', 'CVCL:1487', (157, 166))	('Flot1', 'Gene', (64, 69))	('involved', 'Reg', (219, 227))	('SCLC', 'Gene', '7864', (257, 261))	('SCLC', 'Gene', (257, 261))
254292	30766750	In contrast, Flot1 knockdown impaired the migration of SCLC cells (Figure 5E).	('migration of', 'CPA', (42, 54))	('SCLC', 'Gene', '7864', (55, 59))	('impaired', 'NegReg', (29, 37))	('Flot1', 'Gene', (13, 18))	('knockdown', 'Var', (19, 28))	('SCLC', 'Gene', (55, 59))
254293	30766750	Furthermore, the silencing of Flot1 substantially increased the levels of the epithelial marker E-cadherin but decreased the levels of the mesenchymal marker vimentin in NCI-H446 and NCI-H1688 cells (Figure 5F).	('Flot1', 'Gene', (30, 35))	('NCI-H1688', 'CellLine', 'CVCL:1487', (183, 192))	('vimentin', 'Gene', (158, 166))	('decreased', 'NegReg', (111, 120))	('increased', 'PosReg', (50, 59))	('NCI-H446', 'CellLine', 'CVCL:1562', (170, 178))	('E-cadherin', 'Gene', (96, 106))	('vimentin', 'Gene', '7431', (158, 166))	('silencing', 'Var', (17, 26))	('E-cadherin', 'Gene', '999', (96, 106))
254296	30766750	Taken together, our results revealed that Flot1 was involved in EMT phenotype of SCLC and high expression of Flot1 was able to promote the progression of EMT.	('Flot1', 'Gene', (109, 114))	('promote', 'PosReg', (127, 134))	('high expression', 'Var', (90, 105))	('SCLC', 'Gene', '7864', (81, 85))	('SCLC', 'Gene', (81, 85))	('progression of EMT', 'CPA', (139, 157))
254298	30766750	Three representative genes were confirmed by qRT-PCR and the result indicated that the genes twist2, CDC42, and Sox11, which are all related to tumor progression, were downregulated in cells in the shFlot1 group (Figure 6B).	('Sox11', 'Gene', (112, 117))	('tumor', 'Disease', (144, 149))	('Sox11', 'Gene', '6664', (112, 117))	('twist2', 'Gene', (93, 99))	('twist2', 'Gene', '117581', (93, 99))	('downregulated', 'NegReg', (168, 181))	('CDC42', 'Gene', '998', (101, 106))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('shFlot1', 'Var', (198, 205))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('CDC42', 'Gene', (101, 106))
254300	30766750	Specifically, we further found that the knockdown of Flot1 led to a pronounced decrease in the activity of the TGF-beta-smad2/3 and AKT signaling pathways, which has been reported to be responsible for Flot1 function.	('TGF-beta', 'Gene', '7040', (111, 119))	('AKT', 'Gene', '207', (132, 135))	('TGF-beta', 'Gene', (111, 119))	('knockdown', 'Var', (40, 49))	('decrease', 'NegReg', (79, 87))	('AKT', 'Gene', (132, 135))	('activity', 'MPA', (95, 103))	('Flot1', 'Gene', (53, 58))
254309	30766750	After 9 weeks, the Flot1 shRNA-injected mice displayed significantly lower number of lung metastases than those injected with control shRNA cells, as shown in Figure 7F.	('lung metastases', 'Disease', (85, 100))	('lower', 'NegReg', (69, 74))	('Flot1 shRNA-injected', 'Var', (19, 39))	('lung metastases', 'Disease', 'MESH:D009362', (85, 100))	('mice', 'Species', '10090', (40, 44))
254316	30766750	We further demonstrated that Flot1 knockdown affected the expression of EMT biomarkers in cultured SCLC cells and xenograft mouse models.	('knockdown', 'Var', (35, 44))	('expression', 'MPA', (58, 68))	('mouse', 'Species', '10090', (124, 129))	('affected', 'Reg', (45, 53))	('SCLC', 'Gene', (99, 103))	('Flot1', 'Gene', (29, 34))	('SCLC', 'Gene', '7864', (99, 103))
254323	30766750	The present study showed that Flot1 was highly expressed in SCLC compared to other types of lung cancer, and that high Flot1 expression was positively correlated with tumor progression and tumor stage in SCLC.	('lung cancer', 'Phenotype', 'HP:0100526', (92, 103))	('Flot1', 'Gene', (30, 35))	('high', 'Var', (114, 118))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('correlated with', 'Reg', (151, 166))	('SCLC', 'Gene', '7864', (204, 208))	('SCLC', 'Gene', (204, 208))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('SCLC', 'Gene', (60, 64))	('SCLC', 'Gene', '7864', (60, 64))	('tumor', 'Disease', (167, 172))	('lung cancer', 'Disease', (92, 103))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('expression', 'MPA', (125, 135))	('tumor', 'Disease', (189, 194))	('Flot1', 'Gene', (119, 124))	('lung cancer', 'Disease', 'MESH:D008175', (92, 103))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))
254333	30766750	In our present study, it was observed that Flot1 knockdown downregulated the genes that mapped to TGF-beta signaling pathway, which is involved in the EMT process.	('knockdown', 'Var', (49, 58))	('Flot1', 'Gene', (43, 48))	('downregulated', 'NegReg', (59, 72))	('TGF-beta', 'Gene', '7040', (98, 106))	('TGF-beta', 'Gene', (98, 106))	('genes', 'MPA', (77, 82))
254336	30766750	Our results showed that the silencing of Flot1 substantially enhanced the levels of the epithelial marker E-cadherin and decreased the levels of vimentin.	('enhanced', 'PosReg', (61, 69))	('vimentin', 'Gene', '7431', (145, 153))	('vimentin', 'Gene', (145, 153))	('Flot1', 'Gene', (41, 46))	('decreased', 'NegReg', (121, 130))	('E-cadherin', 'Gene', (106, 116))	('E-cadherin', 'Gene', '999', (106, 116))	('silencing', 'Var', (28, 37))
254343	30766750	We also found that the knockdown of the Flot1 decreased the activity of the TGF-beta-smad2/3 and AKT signaling pathways in vitro and in vivo.	('Flot1', 'Gene', (40, 45))	('AKT', 'Gene', '207', (97, 100))	('TGF-beta', 'Gene', '7040', (76, 84))	('AKT', 'Gene', (97, 100))	('knockdown', 'Var', (23, 32))	('TGF-beta', 'Gene', (76, 84))	('activity', 'MPA', (60, 68))	('decreased', 'NegReg', (46, 55))
254345	30766750	In addition, it has been reported that Curcumin could regulate the expression of Flot1 and some microRNA such as miR-485-5p, miR-506, microRNA-34a, and microRNA-124 could inhibit the expression of Flot1, so some small molecular compounds or microRNAs could target Flot1, and could be used as a therapeutic strategy for targeting Flot1 in SCLC treatment, which need further research.	('Flot1', 'Gene', (197, 202))	('miR-506', 'Gene', '574511', (125, 132))	('miR-506', 'Gene', (125, 132))	('Flot1', 'Gene', (81, 86))	('SCLC', 'Gene', (338, 342))	('regulate', 'Reg', (54, 62))	('SCLC', 'Gene', '7864', (338, 342))	('inhibit', 'NegReg', (171, 178))	('expression', 'MPA', (183, 193))	('expression', 'MPA', (67, 77))	('miR-485-5p', 'Var', (113, 123))	('Curcumin', 'Chemical', 'MESH:D003474', (39, 47))
254353	33276627	AGTPBP1 knockdown increased the proliferation, migration, sphere formation, and drug resistance of A549 cells.	('A549', 'CellLine', 'CVCL:0023', (99, 103))	('increased', 'PosReg', (18, 27))	('knockdown', 'Var', (8, 17))	('AGTPBP1', 'Gene', (0, 7))	('drug resistance', 'CPA', (80, 95))	('drug resistance', 'Phenotype', 'HP:0020174', (80, 95))	('migration', 'CPA', (47, 56))	('sphere formation', 'CPA', (58, 74))
254360	33276627	Furthermore, AGTPBP1 expression has been detected at high levels in the motor neurons and testis of mice, and loss-of-function of CCP1 is associated with neurodegeneration and defective spermatogenesis in Purkinje cell degeneration (pcd) mice.	('defective spermatogenesis', 'Phenotype', 'HP:0008669', (176, 201))	('loss-of-function', 'Var', (110, 126))	('CCP1', 'Gene', (130, 134))	('mice', 'Species', '10090', (100, 104))	('AGTPBP1', 'Gene', (13, 20))	('defective spermatogenesis in Purkinje cell', 'Phenotype', 'HP:0007001', (176, 218))	('Purkinje cell degeneration', 'Gene', '67269', (205, 231))	('associated', 'Reg', (138, 148))	('spermatogenesis', 'CPA', (186, 201))	('mice', 'Species', '10090', (238, 242))	('neurodegeneration', 'Phenotype', 'HP:0002180', (154, 171))	('defective', 'NegReg', (176, 185))	('Purkinje cell degeneration', 'Gene', (205, 231))	('neurodegeneration', 'Disease', (154, 171))	('neurodegeneration', 'Disease', 'MESH:D019636', (154, 171))
254362	33276627	Thus, the expression of AGTPBP1 modulates the organization of microtubules and cellular dynamics and has direct effects on cell function and cilia wellness.	('organization of microtubules', 'MPA', (46, 74))	('cilia wellness', 'Disease', (141, 155))	('cilia wellness', 'Disease', 'MESH:C536693', (141, 155))	('AGTPBP1', 'Gene', (24, 31))	('cellular dynamics', 'CPA', (79, 96))	('cell function', 'CPA', (123, 136))	('modulates', 'Reg', (32, 41))	('effects', 'Reg', (112, 119))	('expression', 'Var', (10, 20))
254363	33276627	Since microtubules are essential components for cell division and migration, altered polyglutamylation of alpha- and beta-tubulins is associated with tumorigenesis and drug resistance in patients with prostate cancer and neuroblastoma.	('drug resistance', 'CPA', (168, 183))	('associated with', 'Reg', (134, 149))	('patients', 'Species', '9606', (187, 195))	('drug resistance', 'Phenotype', 'HP:0020174', (168, 183))	('polyglutamylation', 'MPA', (85, 102))	('neuroblastoma', 'Disease', (221, 234))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('prostate cancer', 'Disease', 'MESH:D011471', (201, 216))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('prostate cancer', 'Phenotype', 'HP:0012125', (201, 216))	('neuroblastoma', 'Phenotype', 'HP:0003006', (221, 234))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('altered', 'Var', (77, 84))	('tumor', 'Disease', (150, 155))	('neuroblastoma', 'Disease', 'MESH:D009447', (221, 234))	('prostate cancer', 'Disease', (201, 216))
254375	33276627	In this study, we examined the effect of AGTPBP1 on the proliferation, migration, and cancer stemness of lung cancer cells in vitro by silencing AGTPBP1 with short-hairpin RNA (shRNA).	('lung cancer', 'Phenotype', 'HP:0100526', (105, 116))	('cancer stemness of lung cancer', 'Disease', 'MESH:D009369', (86, 116))	('silencing', 'Var', (135, 144))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('AGTPBP1', 'Gene', (145, 152))	('examined', 'Reg', (18, 26))	('cancer stemness of lung cancer', 'Disease', (86, 116))
254423	33276627	Overall, knockdown of AGTPBP1 enhanced the oncogenic characteristics, including proliferation, migration, self-renewal, and drug-resistance, of A549 lung cancer cells, suggesting that AGTPBP1 had a tumor-suppressing ability and could modulate the progression of LUAD.	('AGTPBP1', 'Gene', (22, 29))	('drug-resistance', 'CPA', (124, 139))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('modulate', 'Reg', (234, 242))	('lung cancer', 'Disease', (149, 160))	('migration', 'CPA', (95, 104))	('A549', 'CellLine', 'CVCL:0023', (144, 148))	('LUAD', 'Phenotype', 'HP:0030078', (262, 266))	('lung cancer', 'Disease', 'MESH:D008175', (149, 160))	('knockdown', 'Var', (9, 18))	('self-renewal', 'CPA', (106, 118))	('LUAD', 'Disease', (262, 266))	('lung cancer', 'Phenotype', 'HP:0100526', (149, 160))	('tumor', 'Disease', (198, 203))	('AGTPBP1', 'Var', (184, 191))	('enhanced', 'PosReg', (30, 38))	('oncogenic characteristics', 'CPA', (43, 68))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('drug-resistance', 'Phenotype', 'HP:0020174', (124, 139))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))
254443	33276627	ROS1 alteration patient samples were significantly counted in the AGTPBP1 altered group, whereas EGFR and BRAF mutated patients was predominant in AGTPBP1 unaltered group.	('patient', 'Species', '9606', (119, 126))	('ROS1', 'Gene', (0, 4))	('EGFR', 'Gene', '1956', (97, 101))	('BRAF', 'Gene', '673', (106, 110))	('ROS1', 'Gene', '6098', (0, 4))	('patients', 'Species', '9606', (119, 127))	('EGFR', 'Gene', (97, 101))	('BRAF', 'Gene', (106, 110))	('AGTPBP1', 'Gene', (66, 73))	('alteration', 'Reg', (5, 15))	('patient', 'Species', '9606', (16, 23))	('altered', 'Var', (74, 81))
254444	33276627	Overall, these results suggested that alteration of AGTPBP1 could be associated with lung cancer.	('lung cancer', 'Disease', (85, 96))	('lung cancer', 'Phenotype', 'HP:0100526', (85, 96))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('associated', 'Reg', (69, 79))	('lung cancer', 'Disease', 'MESH:D008175', (85, 96))	('alteration', 'Var', (38, 48))	('AGTPBP1', 'Gene', (52, 59))
254445	33276627	The effects of AGTPBP1 knockdown suggest the suppressive role of AGTPBP1 in tumor progression.	('suppressive role', 'NegReg', (45, 61))	('AGTPBP1', 'Gene', (15, 22))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('knockdown', 'Var', (23, 32))	('tumor', 'Disease', (76, 81))	('AGTPBP1', 'Gene', (65, 72))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
254449	33276627	Four different datasets, including GSE19188, GSE3141, GSE31210, and GSE30219, also displayed positive correlation between overall survival and AGTPBP1 expression (Figure 5b-e).	('GSE31210', 'Var', (54, 62))	('positive', 'PosReg', (93, 101))	('GSE30219', 'Var', (68, 76))	('expression', 'MPA', (151, 161))	('AGTPBP1', 'Gene', (143, 150))	('GSE3141', 'Chemical', '-', (45, 52))	('GSE3141', 'Var', (45, 52))	('GSE19188', 'Var', (35, 43))	('overall survival', 'CPA', (122, 138))
254452	33276627	To elucidate the potential signaling mechanism related to AGTPBP1 expression in lung cancer, we acquired the correlation gene sets from the following five different transcriptome datasets of lung cancer using the R2 data tool: GSE63074, GSE19804, GSE33532, GSE19188, and LUAD-TCGA.	('LUAD', 'Phenotype', 'HP:0030078', (271, 275))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('lung cancer', 'Disease', 'MESH:D008175', (80, 91))	('lung cancer', 'Disease', 'MESH:D008175', (191, 202))	('GSE63074', 'Var', (227, 235))	('GSE33532', 'Var', (247, 255))	('AGTPBP1', 'Gene', (58, 65))	('GSE19804', 'Var', (237, 245))	('lung cancer', 'Disease', (80, 91))	('lung cancer', 'Phenotype', 'HP:0100526', (80, 91))	('lung cancer', 'Disease', (191, 202))	('GSE19188', 'Var', (257, 265))	('lung cancer', 'Phenotype', 'HP:0100526', (191, 202))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
254459	33276627	Higher AGTPBP1 expression in LUAD tissues notably increased the infiltrated level of certain types of immune cells, including B cells, CD8+ T cells, CD4+ T cells, macrophages, neutrophils, and dendritic cells (DCs), whereas AGTPBP1 expression in LUSC was not significantly correlated with tumor purity and the infiltration of macrophages and neutrophils (Figure 7a and Table 1).	('tumor', 'Disease', 'MESH:D009369', (289, 294))	('CD8', 'Gene', '925', (135, 138))	('expression', 'Var', (15, 25))	('tumor', 'Phenotype', 'HP:0002664', (289, 294))	('CD4', 'Gene', (149, 152))	('increased', 'PosReg', (50, 59))	('tumor', 'Disease', (289, 294))	('AGTPBP1', 'Gene', (7, 14))	('CD4', 'Gene', '920', (149, 152))	('LUSC', 'Phenotype', 'HP:0030359', (246, 250))	('LUAD', 'Phenotype', 'HP:0030078', (29, 33))	('CD8', 'Gene', (135, 138))	('infiltrated level of certain types of immune cells', 'MPA', (64, 114))
254470	33276627	Mutations in human and mouse AGTPBP1 genes are closely related to childhood-onset neurodegeneration.	('AGTPBP1', 'Gene', (29, 36))	('human', 'Species', '9606', (13, 18))	('neurodegeneration', 'Phenotype', 'HP:0002180', (82, 99))	('Mutations', 'Var', (0, 9))	('mouse', 'Species', '10090', (23, 28))	('neurodegeneration', 'Disease', (82, 99))	('neurodegeneration', 'Disease', 'MESH:D019636', (82, 99))	('related', 'Reg', (55, 62))
254476	33276627	CNA analysis showed that a significant proportion of the lung cancer tissues displayed shallow deletion, and AGTPBP1 expression was significantly reduced in cells with shallow deletion as compared to diploid cells.	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('AGTPBP1', 'Gene', (109, 116))	('expression', 'MPA', (117, 127))	('reduced', 'NegReg', (146, 153))	('lung cancer', 'Disease', 'MESH:D008175', (57, 68))	('shallow deletion', 'Var', (87, 103))	('shallow deletion', 'Var', (168, 184))	('lung cancer', 'Disease', (57, 68))	('lung cancer', 'Phenotype', 'HP:0100526', (57, 68))
254492	33276627	Our results suggested that lower expressions of AGTPBP1 were associated with low cytotoxicity in LUAD, and AGTPBP1 might be a prognostic factor for lung cancer.	('low cytotoxicity', 'Disease', 'MESH:D064420', (77, 93))	('lung cancer', 'Disease', 'MESH:D008175', (148, 159))	('low cytotoxicity', 'Disease', (77, 93))	('LUAD', 'Phenotype', 'HP:0030078', (97, 101))	('lower', 'NegReg', (27, 32))	('AGTPBP1', 'Gene', (48, 55))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('lung cancer', 'Disease', (148, 159))	('lung cancer', 'Phenotype', 'HP:0100526', (148, 159))	('expressions', 'MPA', (33, 44))	('AGTPBP1', 'Var', (107, 114))
254495	33276627	Higher level of XBP1 correlates with lower survival rate and poor prognosis of patients with glioblastoma; conversely, ovarian cancer mouse treated with XBP1-silencing nanoparticles exhibited better prognosis, as compared to control.	('glioblastoma', 'Phenotype', 'HP:0012174', (93, 105))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('ovarian cancer', 'Phenotype', 'HP:0100615', (119, 133))	('ovarian cancer', 'Disease', 'MESH:D010051', (119, 133))	('better', 'PosReg', (192, 198))	('XBP1-silencing', 'Gene', (153, 167))	('glioblastoma', 'Disease', (93, 105))	('ovarian cancer', 'Disease', (119, 133))	('patients', 'Species', '9606', (79, 87))	('glioblastoma', 'Disease', 'MESH:D005909', (93, 105))	('nanoparticles', 'Var', (168, 181))	('mouse', 'Species', '10090', (134, 139))
254500	33276627	alluded to a crucial role of polyglutamylation in tumorigenesis and cancer cell resistance.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('polyglutamylation', 'Var', (29, 46))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('cancer', 'Disease', (68, 74))	('tumor', 'Disease', (50, 55))
254501	33276627	Polyglutamylation contributes negative charge to the C-terminal that is required on neuronal differentiation, but increased abundance leads to both carcinogenesis and chemo-resistance.	('carcinogenesis', 'Disease', (148, 162))	('leads to', 'Reg', (134, 142))	('negative charge', 'MPA', (30, 45))	('chemo-resistance', 'CPA', (167, 183))	('Polyglutamylation', 'Var', (0, 17))	('carcinogenesis', 'Disease', 'MESH:D063646', (148, 162))
254502	33276627	Therefore, modulation of AGTPBP1 expression could be a potential therapeutic approach for lung cancer.	('lung cancer', 'Disease', 'MESH:D008175', (90, 101))	('modulation', 'Var', (11, 21))	('lung cancer', 'Disease', (90, 101))	('lung cancer', 'Phenotype', 'HP:0100526', (90, 101))	('AGTPBP1', 'Gene', (25, 32))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))
254506	33276627	Enhanced survival of AGTPBP1 knockdown cell in the single use of doxorubicin and cisplatin treatment in Figure 1f meant that AGTPBP1 function could be involved in death-inducing mechanism such as oxidative stress, which is induced by both doxorubicin and cisplatin in A549 cells.	('AGTPBP1', 'Gene', (125, 132))	('cisplatin', 'Chemical', 'MESH:D002945', (255, 264))	('knockdown', 'Var', (29, 38))	('doxorubicin', 'Chemical', 'MESH:D004317', (239, 250))	('oxidative stress', 'Disease', (196, 212))	('involved', 'Reg', (151, 159))	('oxidative stress', 'Phenotype', 'HP:0025464', (196, 212))	('A549', 'CellLine', 'CVCL:0023', (268, 272))	('AGTPBP1', 'Gene', (21, 28))	('doxorubicin', 'Chemical', 'MESH:D004317', (65, 76))	('cisplatin', 'Chemical', 'MESH:D002945', (81, 90))	('survival', 'CPA', (9, 17))	('Enhanced', 'PosReg', (0, 8))
254508	33276627	Advances in DNA sequencing technology revealed the driver mutations in lung cancers at the genes including EGFR, ROS1, BRAF, ALK, and KRAS.	('KRAS', 'Gene', '3845', (134, 138))	('mutations', 'Var', (58, 67))	('ROS1', 'Gene', '6098', (113, 117))	('cancers', 'Phenotype', 'HP:0002664', (76, 83))	('EGFR', 'Gene', '1956', (107, 111))	('lung cancers', 'Disease', 'MESH:D008175', (71, 83))	('BRAF', 'Gene', '673', (119, 123))	('lung cancers', 'Phenotype', 'HP:0100526', (71, 83))	('ALK', 'Gene', '238', (125, 128))	('EGFR', 'Gene', (107, 111))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('BRAF', 'Gene', (119, 123))	('lung cancers', 'Disease', (71, 83))	('ROS1', 'Gene', (113, 117))	('KRAS', 'Gene', (134, 138))	('ALK', 'Gene', (125, 128))	('lung cancer', 'Phenotype', 'HP:0100526', (71, 82))
254509	33276627	A significant association of mutations in some relevant genes, including BRAF, EGFR, and ROS1 with AGTPBP1 (Figure 4d), suggested the possible combinatorial effect of mutations in AGTPBP1 and other driver genes, which should be perused in further study.	('BRAF', 'Gene', '673', (73, 77))	('AGTPBP1', 'Gene', (99, 106))	('EGFR', 'Gene', '1956', (79, 83))	('ROS1', 'Gene', (89, 93))	('EGFR', 'Gene', (79, 83))	('mutations', 'Var', (29, 38))	('ROS1', 'Gene', '6098', (89, 93))	('mutations', 'Var', (167, 176))	('BRAF', 'Gene', (73, 77))	('AGTPBP1', 'Gene', (180, 187))
254511	33276627	Activating KRAS mutation rate is around 10-30% in human lung adenocarcinoma.	('KRAS', 'Gene', (11, 15))	('Activating', 'PosReg', (0, 10))	('mutation', 'Var', (16, 24))	('carcinoma', 'Phenotype', 'HP:0030731', (66, 75))	('lung adenocarcinoma', 'Disease', (56, 75))	('KRAS', 'Gene', '3845', (11, 15))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (56, 75))	('human', 'Species', '9606', (50, 55))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (56, 75))
254525	32668390	By conducting 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT), scratch test, and Transwell and flow cytometric analyses, miR-203 was witnessed to restrain SCL-1 cell proliferation, migration, and invasion while accelerating their apoptosis.	('migration', 'CPA', (201, 210))	('restrain', 'NegReg', (166, 174))	('apoptosis', 'CPA', (250, 259))	('invasion', 'CPA', (216, 224))	('SCL-1', 'CellLine', 'CVCL:A789', (175, 180))	('SCL-1 cell proliferation', 'CPA', (175, 199))	('accelerating', 'PosReg', (231, 243))	('3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide', 'Chemical', 'MESH:C022616', (14, 75))	('MTT', 'Chemical', 'MESH:C070243', (77, 80))	('miR-203', 'Var', (141, 148))
254526	32668390	The rescue experiments addressed that inhibition of the Wnt/beta-catenin signaling pathway conferred the anti-tumor effect of miR-203.	('Wnt', 'Gene', '7479', (56, 59))	('tumor', 'Disease', 'MESH:D009369', (110, 115))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('beta-catenin', 'Gene', (60, 72))	('miR-203', 'Var', (126, 133))	('beta-catenin', 'Gene', '1499', (60, 72))	('Wnt', 'Gene', (56, 59))
254538	32668390	The Wnt/beta-catenin signaling pathway is one of the typical pathways involved in cell signal transduction, in which the phosphorylation of beta-catenin is important for the signaling transduction, influencing tumorigenesis, cell multiplication, and differentiation.	('beta-catenin', 'Gene', '1499', (140, 152))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('beta-catenin', 'Gene', (8, 20))	('tumor', 'Disease', (210, 215))	('Wnt', 'Gene', '7479', (4, 7))	('differentiation', 'CPA', (250, 265))	('Wnt', 'Gene', (4, 7))	('beta-catenin', 'Gene', '1499', (8, 20))	('cell multiplication', 'CPA', (225, 244))	('influencing', 'Reg', (198, 209))	('phosphorylation', 'Var', (121, 136))	('beta-catenin', 'Gene', (140, 152))	('tumor', 'Disease', 'MESH:D009369', (210, 215))
254542	32668390	The present study was conducted to examine the potential role of miR-203 in the growth, migration, invasion, and apoptosis of CSCC cells, and whether miR-203 could interact with PRC1 gene and the Wnt/beta-catenin signaling pathway.	('PRC1 gene', 'Gene', (178, 187))	('apoptosis', 'CPA', (113, 122))	('miR-203', 'Var', (150, 157))	('beta-catenin', 'Gene', (200, 212))	('CSCC', 'Phenotype', 'HP:0006739', (126, 130))	('migration', 'CPA', (88, 97))	('Wnt', 'Gene', '7479', (196, 199))	('interact', 'Reg', (164, 172))	('invasion', 'CPA', (99, 107))	('Wnt', 'Gene', (196, 199))	('beta-catenin', 'Gene', '1499', (200, 212))	('miR-203', 'Gene', (65, 72))
254547	32668390	A previous study found that the abnormal expression of PRC1 may predict recurrence of male prostate cancer, which can be used as a marker of prognosis for this malignancy.	('malignancy', 'Disease', (160, 170))	('expression', 'MPA', (41, 51))	('PRC1', 'Gene', (55, 59))	('recurrence', 'Disease', (72, 82))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('prostate cancer', 'Phenotype', 'HP:0012125', (91, 106))	('abnormal', 'Var', (32, 40))	('malignancy', 'Disease', 'MESH:D009369', (160, 170))	('predict', 'Reg', (64, 71))	('male prostate cancer', 'Disease', (86, 106))	('male prostate cancer', 'Disease', 'MESH:D018567', (86, 106))
254558	32668390	The results depicted in Figures 5 and 6 displayed that compared with the blank group, the expression of miR-203 was markedly increased in the miR-203 mimic group, miR-203 mimic + XAV-939 group, and miR-203 mimic + oe-PRC1 group, while miR-203 expression was remarkably reduced in the miR-203 inhibitor group, miR-203 inhibitor + XAV-939 group, and miR-203 inhibitor + sh-PRC1 group (p < 0.05).	('XAV-939', 'Chemical', 'MESH:C544261', (179, 186))	('increased', 'PosReg', (125, 134))	('miR-203', 'Var', (163, 170))	('miR-203', 'Var', (198, 205))	('expression', 'MPA', (90, 100))	('XAV-939', 'Chemical', 'MESH:C544261', (329, 336))	('miR-203', 'Gene', (104, 111))
254559	32668390	Compared with the blank group, the mRNA and protein expression of PRC1 was decreased in the miR-203 mimic and miR-203 mimic + XAV-939 groups, whereas PRC1 mRNA and protein expression was elevated in the miR-203 inhibitor and miR-203 inhibitor + XAV-939 groups (p < 0.05), with no significant difference observed in the XAV-939 and negative control (NC) groups (p > 0.05).	('miR-203', 'Var', (203, 210))	('elevated', 'PosReg', (187, 195))	('PRC1', 'Gene', (150, 154))	('XAV-939', 'Chemical', 'MESH:C544261', (126, 133))	('miR-203', 'Var', (225, 232))	('PRC1', 'Gene', (66, 70))	('XAV-939', 'Chemical', 'MESH:C544261', (245, 252))	('XAV-939', 'Chemical', 'MESH:C544261', (319, 326))	('decreased', 'NegReg', (75, 84))
254560	32668390	Compared with the blank group, the mRNA and protein expression of beta-catenin, Wnt8b, c-Jun, FZD3, Bcl-2, and c-Myc was elevated in the miR-203 inhibitor and oe-PRC1 groups but lowered in the miR-203 mimic, XAV-939, sh-PRC1, and miR-203 mimic + XAV-939 groups (p < 0.05).	('c-Jun', 'Gene', (87, 92))	('Wnt8b', 'Gene', '7479', (80, 85))	('Bcl-2', 'Gene', (100, 105))	('c-Myc', 'Gene', '4609', (111, 116))	('lowered', 'NegReg', (178, 185))	('beta-catenin', 'Gene', (66, 78))	('FZD3', 'Gene', (94, 98))	('Bcl-2', 'Gene', '596', (100, 105))	('c-Myc', 'Gene', (111, 116))	('beta-catenin', 'Gene', '1499', (66, 78))	('Wnt8b', 'Gene', (80, 85))	('c-Jun', 'Gene', '3725', (87, 92))	('miR-203', 'Var', (137, 144))	('FZD3', 'Gene', '7976', (94, 98))	('XAV-939', 'Chemical', 'MESH:C544261', (208, 215))	('XAV-939', 'Chemical', 'MESH:C544261', (246, 253))	('elevated', 'PosReg', (121, 129))
254562	32668390	The expression of beta-catenin, Wnt8b, c-Jun, FZD3, Bcl-2, and c-Myc mRNAs and proteins was reduced in the miR-203 mimic + XAV-939 group while that of those mRNAs and proteins was elevated in the miR-203 mimic + oe-PRC1 group when compared with those in the miR-203 mimic group (p < 0.05).	('Wnt8b', 'Gene', (32, 37))	('XAV-939', 'Chemical', 'MESH:C544261', (123, 130))	('c-Myc', 'Gene', (63, 68))	('Bcl-2', 'Gene', (52, 57))	('beta-catenin', 'Gene', (18, 30))	('Bcl-2', 'Gene', '596', (52, 57))	('Wnt8b', 'Gene', '7479', (32, 37))	('beta-catenin', 'Gene', '1499', (18, 30))	('c-Jun', 'Gene', (39, 44))	('FZD3', 'Gene', (46, 50))	('expression', 'MPA', (4, 14))	('c-Myc', 'Gene', '4609', (63, 68))	('reduced', 'NegReg', (92, 99))	('miR-203 mimic + XAV-939', 'Var', (107, 130))	('FZD3', 'Gene', '7976', (46, 50))	('c-Jun', 'Gene', '3725', (39, 44))
254563	32668390	As compared to the miR-203 inhibitor group, the miR-203 inhibitor + XAV-939 group and miR-203 inhibitor + sh-PRC1 group exhibited reductions in the expression of beta-catenin, Wnt8b, c-Jun, FZD3, Bcl-2, and c-Myc mRNAs and proteins (p < 0.05).	('Wnt8b', 'Gene', '7479', (176, 181))	('FZD3', 'Gene', '7976', (190, 194))	('Bcl-2', 'Gene', (196, 201))	('Bcl-2', 'Gene', '596', (196, 201))	('beta-catenin', 'Gene', (162, 174))	('FZD3', 'Gene', (190, 194))	('c-Jun', 'Gene', (183, 188))	('c-Myc', 'Gene', '4609', (207, 212))	('reductions', 'NegReg', (130, 140))	('beta-catenin', 'Gene', '1499', (162, 174))	('expression', 'MPA', (148, 158))	('Wnt8b', 'Gene', (176, 181))	('miR-203', 'Var', (86, 93))	('c-Myc', 'Gene', (207, 212))	('c-Jun', 'Gene', '3725', (183, 188))	('XAV-939', 'Chemical', 'MESH:C544261', (68, 75))
254566	32668390	Compared with the miR-203 mimic group, upregulated p16 mRNA and protein expression was determined in the miR-203 mimic + XAV-939 group, while lower p16 mRNA and protein expression was determined in the miR-203 mimic + oe-PRC1 group (p < 0.05).	('p16', 'Gene', '1029', (51, 54))	('p16', 'Gene', '1029', (148, 151))	('upregulated', 'PosReg', (39, 50))	('miR-203', 'Var', (105, 112))	('lower', 'NegReg', (142, 147))	('XAV-939', 'Chemical', 'MESH:C544261', (121, 128))	('p16', 'Gene', (51, 54))	('p16', 'Gene', (148, 151))
254576	32668390	Scratch test was used for the evaluation of migration potential of SCL-1 cells, the results of which (Figure 8) illustrated that with the prolongation of time, there was no statistical difference regarding cell migration in the NC, miR-203 mimic + oe-PRC1, miR-203 inhibitor + sh-PRC1, and miR-203 inhibitor + XAV-939 groups, relative to the blank group (p > 0.05).	('cell migration', 'CPA', (206, 220))	('SCL-1', 'CellLine', 'CVCL:A789', (67, 72))	('miR-203 mimic + oe-PRC1', 'Var', (232, 255))	('XAV-939', 'Chemical', 'MESH:C544261', (310, 317))	('miR-203 inhibitor + sh-PRC1', 'Var', (257, 284))
254580	32668390	The aforementioned results indicated that the overexpression of miR-203 can repress the migration of the CSCC cells through downregulation of PRC1 and inhibition of the Wnt/beta-catenin signaling pathway.	('migration of the CSCC cells', 'CPA', (88, 115))	('overexpression', 'PosReg', (46, 60))	('beta-catenin', 'Gene', '1499', (173, 185))	('PRC1', 'Gene', (142, 146))	('Wnt', 'Gene', '7479', (169, 172))	('beta-catenin', 'Gene', (173, 185))	('CSCC', 'Phenotype', 'HP:0006739', (105, 109))	('miR-203', 'Var', (64, 71))	('repress', 'NegReg', (76, 83))	('inhibition', 'NegReg', (151, 161))	('downregulation', 'NegReg', (124, 138))	('Wnt', 'Gene', (169, 172))
254582	32668390	As illustrated in Figure 9, compared with the blank group, there was no significant difference in the NC, miR-203 mimic + oe-PRC1, miR-203 inhibitor + sh-PRC1, and miR-203 inhibitor + XAV-939 groups (p > 0.05).	('miR-203', 'Var', (131, 138))	('XAV-939', 'Chemical', 'MESH:C544261', (184, 191))	('miR-203', 'Var', (164, 171))
254585	32668390	The invasive ability of cells in the miR-203 mimic + XAV-939 group was reduced when compared with that in the miR-203 mimic and XAV-939 groups (p < 0.05).	('XAV-939', 'Chemical', 'MESH:C544261', (128, 135))	('miR-203', 'Var', (37, 44))	('invasive ability of cells', 'CPA', (4, 29))	('reduced', 'NegReg', (71, 78))	('XAV-939', 'Chemical', 'MESH:C544261', (53, 60))
254586	32668390	Thus, miR-203 was able to suppress invasion of the CSCC cells by targeting PRC1 and blocking the Wnt/beta-catenin signaling pathway.	('Wnt', 'Gene', (97, 100))	('Wnt', 'Gene', '7479', (97, 100))	('beta-catenin', 'Gene', (101, 113))	('CSCC', 'Phenotype', 'HP:0006739', (51, 55))	('invasion of the CSCC cells', 'CPA', (35, 61))	('blocking', 'NegReg', (84, 92))	('targeting', 'Reg', (65, 74))	('suppress', 'NegReg', (26, 34))	('beta-catenin', 'Gene', '1499', (101, 113))	('miR-203', 'Var', (6, 13))	('PRC1', 'Gene', (75, 79))
254587	32668390	The results from Annexin V/propidium iodide (PI) double staining (Figure 10) revealed that the apoptosis rates in the blank, NC, miR-203 inhibitor, miR-203 mimic, XAV-939, miR-203 mimic + XAV-939, miR-203 inhibitor + XAV-939, miR-203 mimic + oe-PRC1, and miR-203 inhibitor + sh-PRC1 groups at 48 h after transfection were 9.83% +- 0.91%, 9.71% +- 0.94%, 5.52% +- 0.47%, 17.54% +- 1.16%, 18.81% +- 1.21%, 32.31% +- 2.91%, 9.90% +- 0.87%, 9.85% +- 0.89%, and 9.82% +- 0.90%, respectively.	('XAV-939', 'Chemical', 'MESH:C544261', (217, 224))	('Annexin V', 'Gene', '308', (17, 26))	('mimic + XAV-939', 'Var', (180, 195))	('Annexin V', 'Gene', (17, 26))	('miR-203', 'Var', (197, 204))	('apoptosis', 'CPA', (95, 104))	('XAV-939', 'Chemical', 'MESH:C544261', (163, 170))	('miR-203', 'Var', (226, 233))	('miR-203', 'Var', (255, 262))	('miR-203', 'Var', (172, 179))	('XAV-939', 'Chemical', 'MESH:C544261', (188, 195))
254597	32668390	Deregulation of PRC1 results in cytokinesis defects that facilitates chromosomal instability thereby contributing to tumor heterogeneity and cancer evolution.	('chromosomal instability', 'MPA', (69, 92))	('contributing to', 'Reg', (101, 116))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('cytokinesis defects', 'Disease', (32, 51))	('Deregulation', 'Var', (0, 12))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('tumor', 'Disease', (117, 122))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('chromosomal instability', 'Phenotype', 'HP:0040012', (69, 92))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('results in', 'Reg', (21, 31))	('facilitates', 'PosReg', (57, 68))	('PRC1', 'Gene', (16, 20))	('cancer', 'Disease', (141, 147))	('cytokinesis defects', 'Disease', 'MESH:D000014', (32, 51))
254604	32668390	We also found that the Wnt/beta-catenin signaling pathway was activated in the presence of miR-203.	('Wnt', 'Gene', (23, 26))	('beta-catenin', 'Gene', '1499', (27, 39))	('miR-203', 'Var', (91, 98))	('Wnt', 'Gene', '7479', (23, 26))	('beta-catenin', 'Gene', (27, 39))	('activated', 'PosReg', (62, 71))
254607	32668390	Therefore, miR-203 might play a role as a cancer suppressor in CSCC cell line SCL-1 by targeting PRC1 and blocking the Wnt signaling pathway.	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('Wnt', 'Gene', (119, 122))	('targeting', 'NegReg', (87, 96))	('CSCC', 'Phenotype', 'HP:0006739', (63, 67))	('PRC1', 'Gene', (97, 101))	('SCL-1', 'CellLine', 'CVCL:A789', (78, 83))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('Wnt', 'Gene', '7479', (119, 122))	('CSCC', 'Disease', (63, 67))	('miR-203', 'Var', (11, 18))	('blocking', 'NegReg', (106, 114))
254642	32668390	Tankyrase inhibitor, XAV-939 (MedChemExpress, NJ, USA), has been reported to induce Axin stabilization and to cause subsequent destruction of the beta-catenin complex and dephosphorylation of beta-catenin.	('induce', 'PosReg', (77, 83))	('beta-catenin', 'Gene', '1499', (192, 204))	('Tankyrase', 'Gene', (0, 9))	('XAV-939', 'Chemical', 'MESH:C544261', (21, 28))	('Tankyrase', 'Gene', '8658', (0, 9))	('beta-catenin', 'Gene', (146, 158))	('Axin', 'Gene', '8312', (84, 88))	('stabilization', 'MPA', (89, 102))	('beta-catenin', 'Gene', '1499', (146, 158))	('beta-catenin', 'Gene', (192, 204))	('XAV-939', 'Var', (21, 28))	('destruction', 'MPA', (127, 138))	('dephosphorylation', 'MPA', (171, 188))	('Axin', 'Gene', (84, 88))
254653	32668390	The membrane underwent incubation overnight at 4 C with the following primary antibodies diluted at ratio of 1:1,000 and purchased from Abcam, Cambridge, MA, USA: rabbit anti-human PRC1 (ab140033), beta-actin (ab8226), beta-catenin (ab16051), Wnt8b (ab66307), c-Jun (ab31367), FZD3 (ab75233), p16 (ab151303), Bcl-2 (ab32124), and c-myc (ab32072).	('Bcl-2', 'Gene', '596', (309, 314))	('c-myc', 'Gene', '4609', (330, 335))	('ab75233', 'Var', (283, 290))	('Wnt8b', 'Gene', '7479', (243, 248))	('human', 'Species', '9606', (175, 180))	('beta-actin', 'Gene', '728378', (198, 208))	('Wnt8b', 'Gene', (243, 248))	('ab66307', 'Var', (250, 257))	('c-Jun', 'Gene', '3725', (260, 265))	('c-myc', 'Gene', (330, 335))	('c-Jun', 'Gene', (260, 265))	('ab16051', 'Var', (233, 240))	('p16', 'Gene', (293, 296))	('ab151303', 'Var', (298, 306))	('Bcl-2', 'Gene', (309, 314))	('beta-catenin', 'Gene', (219, 231))	('FZD3', 'Gene', '7976', (277, 281))	('beta-actin', 'Gene', (198, 208))	('ab140033', 'Var', (187, 195))	('p16', 'Gene', '1029', (293, 296))	('beta-catenin', 'Gene', '1499', (219, 231))	('FZD3', 'Gene', (277, 281))	('ab31367', 'Var', (267, 274))	('ab8226', 'Var', (210, 216))
254712	31814767	made a propensity score-matched analysis that including 1497 patients with T1N0M0 lung ADC.	('T1N0M0', 'Var', (75, 81))	('lung ADC', 'Disease', (82, 90))	('patients', 'Species', '9606', (61, 69))	('lung ADC', 'Disease', 'MESH:C538231', (82, 90))
254716	31814767	In multivariable models, STAS was an independent predictor for both recurrence and lung cancer-specific death.	('lung cancer', 'Disease', 'MESH:D008175', (83, 94))	('STAS', 'Var', (25, 29))	('lung cancer', 'Disease', (83, 94))	('lung cancer', 'Phenotype', 'HP:0100526', (83, 94))	('death', 'Disease', 'MESH:D003643', (104, 109))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('death', 'Disease', (104, 109))
254732	31814767	found STAS was associated with lower rates of EGFR but higher rates of BRAF mutations, and not associated with KRASmutations, TTF1, napsin or CK7 expression.	('higher rates', 'PosReg', (55, 67))	('mutations', 'Var', (76, 85))	('KRAS', 'Gene', (111, 115))	('TTF1', 'Gene', (126, 130))	('BRAF', 'Gene', '673', (71, 75))	('CK7', 'Gene', '3855', (142, 145))	('KRAS', 'Gene', '3845', (111, 115))	('EGFR', 'Gene', '1956', (46, 50))	('BRAF', 'Gene', (71, 75))	('TTF1', 'Gene', '7270', (126, 130))	('lower', 'NegReg', (31, 36))	('EGFR', 'Gene', (46, 50))	('CK7', 'Gene', (142, 145))
254734	31814767	concluded that STAS was not significantly associated with EGFR mutations or PD-L1 expression.	('mutations', 'Var', (63, 72))	('EGFR', 'Gene', '1956', (58, 62))	('EGFR', 'Gene', (58, 62))	('PD-L1', 'Gene', '29126', (76, 81))	('STAS', 'Disease', (15, 19))	('PD-L1', 'Gene', (76, 81))
254735	31814767	concluded that STAS was frequently observed in tumors with wild-type EGFR and ALK rearrangement, and they found no association with KRAS mutation.	('rearrangement', 'Var', (82, 95))	('tumors', 'Disease', (47, 53))	('EGFR', 'Gene', '1956', (69, 73))	('KRAS', 'Gene', (132, 136))	('ALK', 'Gene', (78, 81))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('KRAS', 'Gene', '3845', (132, 136))	('EGFR', 'Gene', (69, 73))	('STAS', 'Disease', (15, 19))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('ALK', 'Gene', '238', (78, 81))	('observed', 'Reg', (35, 43))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))
254736	31814767	Although there was no statistical significance with ROS1 rearrangement, when combined with ALK rearrangements, STAS was frequently found in tumors with ALK or ROS1 rearrangements.	('ALK', 'Gene', (91, 94))	('tumors', 'Disease', (140, 146))	('rearrangements', 'Var', (164, 178))	('tumors', 'Disease', 'MESH:D009369', (140, 146))	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('ALK', 'Gene', '238', (152, 155))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('ALK', 'Gene', '238', (91, 94))	('ROS1', 'Gene', (52, 56))	('ROS1', 'Gene', (159, 163))	('ROS1', 'Gene', '6098', (52, 56))	('ROS1', 'Gene', '6098', (159, 163))	('ALK', 'Gene', (152, 155))
254737	31814767	concluded that STAS was associated with a lower incidence of EGFR mutation and a higher incidence of ALK rearrangement.	('ALK', 'Gene', (101, 104))	('lower', 'NegReg', (42, 47))	('ALK', 'Gene', '238', (101, 104))	('STAS', 'Disease', (15, 19))	('mutation', 'Var', (66, 74))	('EGFR', 'Gene', '1956', (61, 65))	('EGFR', 'Gene', (61, 65))
254744	31814767	The magnitude of STAS is so small that this phenomenon may not reliably be detected on CT, as many other factors may contribute to a change in CT. We still hope the above results will be helpful in identifying STAS-positive ADC by CT before surgical resection someday.	('ADC', 'Disease', 'MESH:D000230', (224, 227))	('STAS-positive', 'Var', (210, 223))	('ADC', 'Disease', (224, 227))
254784	29681454	However, a large mutational burden also increases the probability that NSCLCs will contain vulnerabilities, not found in normal cells, which might be exploited therapeutically.	('NSCLC', 'Phenotype', 'HP:0030358', (71, 76))	('contain', 'Reg', (83, 90))	('mutational burden', 'Var', (17, 34))	('NSCLC', 'Disease', (71, 76))	('vulnerabilities', 'MPA', (91, 106))	('NSCLC', 'Disease', 'MESH:D002289', (71, 76))
254804	29681454	As compelling proof of concept, these methods linked high ALK expression as predicting sensitivity to the ALK inhibitor crizotinib (Figure 1G) and EGFR mutations and amplifications to predict sensitivity to the EGFR inhibitor erlotinib (Figure 1H).	('ALK', 'Gene', '238', (106, 109))	('predicting', 'Reg', (76, 86))	('si', 'Chemical', 'MESH:D012825', (90, 92))	('EGFR', 'Gene', (147, 151))	('mutations', 'Var', (152, 161))	('ALK', 'Gene', (58, 61))	('ALK', 'Gene', (106, 109))	('EGFR', 'Gene', '1956', (211, 215))	('sensitivity', 'MPA', (87, 98))	('si', 'Chemical', 'MESH:D012825', (68, 70))	('crizotinib', 'Chemical', 'MESH:D000077547', (120, 130))	('erlotinib', 'Chemical', 'MESH:D000069347', (226, 235))	('si', 'Chemical', 'MESH:D012825', (195, 197))	('EGFR', 'Gene', (211, 215))	('EGFR', 'Gene', '1956', (147, 151))	('ALK', 'Gene', '238', (58, 61))
254805	29681454	As expected, the EGFR mutant, erlotinib-sensitive cell lines have mutations in the kinase domain known to affect EGFR function.	('mutations', 'Var', (66, 75))	('si', 'Chemical', 'MESH:D012825', (43, 45))	('erlotinib', 'Chemical', 'MESH:D000069347', (30, 39))	('EGFR', 'Gene', '1956', (113, 117))	('function', 'MPA', (118, 126))	('mutant', 'Var', (22, 28))	('EGFR', 'Gene', (113, 117))	('EGFR', 'Gene', '1956', (17, 21))	('affect', 'Reg', (106, 112))	('EGFR', 'Gene', (17, 21))
254806	29681454	Notably, among the EGFR mutant non-responders, 2 cell lines harbored preexisting T790M mutations (Figure S1U), a known cell-autonomous adaptive mechanism promoting inhibitor resistance not detected by related chemical profiling efforts (Figure S1V).	('mutant', 'Var', (24, 30))	('promoting', 'PosReg', (154, 163))	('T790M', 'Mutation', 'rs121434569', (81, 86))	('EGFR', 'Gene', '1956', (19, 23))	('inhibitor resistance', 'MPA', (164, 184))	('T790M mutations', 'Var', (81, 96))	('EGFR', 'Gene', (19, 23))	('si', 'Chemical', 'MESH:D012825', (176, 178))
254813	29681454	We further examined SW157765 as a member of a cluster of compounds associated with activity in cytochrome p450 family member, CYP4F11, expressing cells.	('SW157765', 'Var', (20, 28))	('CYP4F11', 'Gene', '57834', (126, 133))	('CYP4F11', 'Gene', (126, 133))	('si', 'Chemical', 'MESH:D012825', (141, 143))
254814	29681454	Notably, the CYP4F family inhibitor, HET0016, reversed metabolism of the compound (Figure 2F), and CRISPR-mediated knockout of CYP4F11 reversed toxicity in otherwise sensitive cell lines (Figure 2G, S2K-M).	('knockout', 'Var', (115, 123))	('metabolism', 'MPA', (55, 65))	('si', 'Chemical', 'MESH:D012825', (169, 171))	('toxicity', 'Disease', 'MESH:D064420', (144, 152))	('toxicity', 'Disease', (144, 152))	('CYP4F11', 'Gene', '57834', (127, 134))	('CYP4F11', 'Gene', (127, 134))	('reversed', 'Reg', (135, 143))
254815	29681454	We next predicted the activity of SW001286 and SW126788, within a panel of 26 previously untested NSCLC cells, using the weighted elastic net models.	('SW126788', 'Var', (47, 55))	('NSCLC', 'Phenotype', 'HP:0030358', (98, 103))	('si', 'Chemical', 'MESH:D012825', (112, 114))	('SW001286', 'Var', (34, 42))	('SW126788', 'CellLine', 'CVCL:R777', (47, 55))	('NSCLC', 'Disease', (98, 103))	('activity', 'MPA', (22, 30))	('NSCLC', 'Disease', 'MESH:D002289', (98, 103))
254817	29681454	However, prediction accuracy of SW001286 sensitivities was lower due to 4 unanticipated non-responders (Figure S2O).	('SW001286', 'Var', (32, 40))	('lower', 'NegReg', (59, 64))	('si', 'Chemical', 'MESH:D012825', (44, 46))
254818	29681454	Like SW157756, HET0016 rescued SW001286 toxicity in two sensitive cell lines (Figure 2H).	('SW157756', 'CellLine', 'CVCL:R777', (5, 13))	('toxicity', 'Disease', (40, 48))	('SW001286', 'Var', (31, 39))	('toxicity', 'Disease', 'MESH:D064420', (40, 48))	('si', 'Chemical', 'MESH:D012825', (59, 61))
254819	29681454	Thus, the metabolic products of SW001286 in CYP4F11-expressing cells may not be behaving as a general toxin(s), but rather may be targeting a selective vulnerability in sensitive cell lines.	('SW001286', 'Var', (32, 40))	('CYP4F11', 'Gene', '57834', (44, 51))	('CYP4F11', 'Gene', (44, 51))	('si', 'Chemical', 'MESH:D012825', (58, 60))	('si', 'Chemical', 'MESH:D012825', (172, 174))
254820	29681454	In line with this possibility, a manual examination of the KS test output indicated mutations in LKB1 as an additional marker that, together with CYP4F11 expression, better stratify response (Figure 2I, S2P).	('stratify', 'Reg', (173, 181))	('CYP4F11', 'Gene', '57834', (146, 153))	('CYP4F11', 'Gene', (146, 153))	('si', 'Chemical', 'MESH:D012825', (160, 162))	('LKB1', 'Gene', (97, 101))	('mutations', 'Var', (84, 93))	('KS', 'Chemical', 'MESH:D011188', (59, 61))	('LKB1', 'Gene', '6794', (97, 101))	('si', 'Chemical', 'MESH:D012825', (21, 23))	('better', 'PosReg', (166, 172))
254822	29681454	A mechanistic connection between SW001286 sensitivity and loss-of-function LKB1 mutations was supported by the observation that depletion of ACC1 (Figure 2J), or addition of a ROS scavenger (Figure S2Q), partially rescued SW001286-sensitivity.	('LKB1', 'Gene', (75, 79))	('SW001286-sensitivity', 'MPA', (222, 242))	('mutations', 'Var', (80, 89))	('depletion', 'MPA', (128, 137))	('LKB1', 'Gene', '6794', (75, 79))	('ACC1', 'Gene', '597', (141, 145))	('ROS', 'Chemical', '-', (176, 179))	('loss-of-function', 'NegReg', (58, 74))	('ACC1', 'Gene', (141, 145))	('si', 'Chemical', 'MESH:D012825', (234, 236))	('si', 'Chemical', 'MESH:D012825', (45, 47))
254827	29681454	Consistent with the possibility that protein/small molecule conjugation might be at play, 72 hour ED50's were similar following either transient or sustained exposure to SW157765 (Figure S2S).	('si', 'Chemical', 'MESH:D012825', (110, 112))	('SW157765', 'Var', (170, 178))	('ED50', 'Gene', (98, 102))	('si', 'Chemical', 'MESH:D012825', (139, 141))	('si', 'Chemical', 'MESH:D012825', (23, 25))	('si', 'Chemical', 'MESH:D012825', (3, 5))	("50's", 'Species', '1214577', (100, 104))
254828	29681454	In an effort to identify structural components of the molecule required for biological activity, we designed and synthesized a series of analogs of SW157765, of which analog 500-01 (Figure S2T) was found to be completely inert when tested for viability in a NSCLC cell line panel (Figure S2U).	('NSCLC', 'Disease', (258, 263))	('SW157765', 'Var', (148, 156))	('NSCLC', 'Disease', 'MESH:D002289', (258, 263))	('si', 'Chemical', 'MESH:D012825', (119, 121))	('NSCLC', 'Phenotype', 'HP:0030358', (258, 263))	('si', 'Chemical', 'MESH:D012825', (102, 104))
254829	29681454	Interestingly, 500-01 differs from the parent molecule in only the hydrogenation of its internal alkene, suggesting SW157765 requires this functional group for biological activity.	('alkene', 'Chemical', 'MESH:D000475', (97, 103))	('hydrogenation of', 'MPA', (67, 83))	('SW157765', 'Var', (116, 124))
254831	29681454	Mass spectrometry-based evaluation of metabolites produced by H2122 cells treated with either SW157765 or 500-1 for eight hours identified an oxidized metabolite, unique to SW157765 (Figures S2V-S2Y), potentially containing an epoxide at the site of the internal alkene (Figure S2Z).	('epoxide', 'Chemical', 'MESH:D004852', (227, 234))	('SW157765', 'Var', (94, 102))	('epoxide', 'MPA', (227, 234))	('si', 'Chemical', 'MESH:D012825', (242, 244))	('SW157765', 'Var', (173, 181))	('alkene', 'Chemical', 'MESH:D000475', (263, 269))	('H2122', 'CellLine', 'CVCL:1531', (62, 67))	('containing', 'Reg', (213, 223))
254835	29681454	RNAi-mediated depletion of ABCG2 sensitized resistant cells to THZ1, suggesting it is an ABCG2 substrate (Figure 2L).	('ABCG2', 'Gene', '9429', (89, 94))	('ABCG2', 'Gene', (27, 32))	('ABCG2', 'Gene', '9429', (27, 32))	('si', 'Chemical', 'MESH:D012825', (46, 48))	('si', 'Chemical', 'MESH:D012825', (36, 38))	('depletion', 'Var', (14, 23))	('sensitized', 'Reg', (33, 43))	('ABCG2', 'Gene', (89, 94))
254839	29681454	The "dispersed" pattern of Notch2 alleles detected among the NSCLC cell lines is reminiscent of loss-of-function alterations typically associated with a tumor suppressor (Figure S3A) and the glucocorticoid-sensitive cell lines harboring these mutations display downregulation of Notch pathway genes as compared to wild-type counterparts.	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('loss-of-function', 'NegReg', (96, 112))	('Notch', 'Gene', '4851;4853;18129', (27, 32))	('NSCLC', 'Phenotype', 'HP:0030358', (61, 66))	('Notch', 'Gene', '4851;4853;18129', (279, 284))	('Notch', 'Gene', (27, 32))	('tumor', 'Disease', (153, 158))	('mutations', 'Var', (243, 252))	('Notch', 'Gene', (279, 284))	('si', 'Chemical', 'MESH:D012825', (209, 211))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('NSCLC', 'Disease', (61, 66))	('downregulation', 'NegReg', (261, 275))	('NSCLC', 'Disease', 'MESH:D002289', (61, 66))
254840	29681454	Depletion of the ubiquitously expressed GC receptor, NR3C1, was sufficient to reduce cellular sensitivity to GC exposure, suggesting the selective toxicity phenotype is receptor-dependent (Figure 3D).	('si', 'Chemical', 'MESH:D012825', (97, 99))	('reduce', 'NegReg', (78, 84))	('toxicity', 'Disease', 'MESH:D064420', (147, 155))	('toxicity', 'Disease', (147, 155))	('Depletion', 'Var', (0, 9))	('cellular sensitivity to GC exposure', 'MPA', (85, 120))	('NR3C1', 'Gene', (53, 58))
254844	29681454	Consistent with these observations, we found significantly higher basal expression levels of NR3C1 mRNA in Notch2 mutant, GC responsive cell lines (Figure 3E).	('si', 'Chemical', 'MESH:D012825', (131, 133))	('expression levels', 'MPA', (72, 89))	('NR3C1', 'Gene', (93, 98))	('Notch2', 'Gene', (107, 113))	('mutant', 'Var', (114, 120))	('si', 'Chemical', 'MESH:D012825', (3, 5))	('si', 'Chemical', 'MESH:D012825', (78, 80))	('higher', 'PosReg', (59, 65))	('si', 'Chemical', 'MESH:D012825', (45, 47))
254855	29681454	We therefore suspect that Notch2 mutations, in NSCLC cells, result in reduced Notch signaling and higher basal NR3C1 expression, priming cells to respond to GC with G1 cell cycle arrest (Figure S3G).	('Notch', 'Gene', (26, 31))	('Notch', 'Gene', '4851;4853;18129', (26, 31))	('arrest', 'Disease', 'MESH:D006323', (179, 185))	('reduced', 'NegReg', (70, 77))	('si', 'Chemical', 'MESH:D012825', (84, 86))	('arrest', 'Disease', (179, 185))	('respond to GC', 'MPA', (146, 159))	('expression', 'MPA', (117, 127))	('NSCLC', 'Phenotype', 'HP:0030358', (47, 52))	('mutations', 'Var', (33, 42))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (168, 185))	('NR3C1', 'Gene', (111, 116))	('higher', 'PosReg', (98, 104))	('si', 'Chemical', 'MESH:D012825', (123, 125))	('NSCLC', 'Disease', (47, 52))	('Notch', 'Gene', '4851;4853;18129', (78, 83))	('NSCLC', 'Disease', 'MESH:D002289', (47, 52))	('Notch', 'Gene', (78, 83))
254856	29681454	While GC therapy is not commonly used in therapeutic doses to treat patients with lung cancer, 5.9% of LUAD tumors and 5.1% of LUSC's in the TCGA have mutations or deletions in Notch2, corresponding to thousands of patients a year that could be treated with a FDA approved therapy.	('patients', 'Species', '9606', (215, 223))	('LUAD tumors', 'Disease', (103, 114))	('LUAD tumors', 'Disease', 'MESH:D009369', (103, 114))	('lung cancer', 'Phenotype', 'HP:0100526', (82, 93))	('LUAD', 'Phenotype', 'HP:0030078', (103, 107))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('lung cancer', 'Disease', (82, 93))	('deletions', 'Var', (164, 173))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('patients', 'Species', '9606', (68, 76))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('lung cancer', 'Disease', 'MESH:D008175', (82, 93))	('LUSC', 'Phenotype', 'HP:0030359', (127, 131))	('mutations', 'Var', (151, 160))	('Notch2', 'Gene', (177, 183))
254863	29681454	4 chemicals passing one or both criteria were selected for additional functional characterization (SW036310, SW151511, SW140154, SW208097).	('SW208097', 'Var', (129, 137))	('SW208097', 'CellLine', 'CVCL:R777', (129, 137))	('SW036310', 'Chemical', '-', (99, 107))	('si', 'Chemical', 'MESH:D012825', (15, 17))	('SW140154', 'Var', (119, 127))	('SW036310', 'Var', (99, 107))	('SW151511', 'Var', (109, 117))
254864	29681454	The automated scanning KS analysis indicated that mutations in TTC21B correspond to sensitivity to the benzothiazole-containing small molecule SW036310 (Figure 4C), in which selective efficacy was preserved in spheroid assays (Figure 4D).	('sensitivity', 'MPA', (84, 95))	('si', 'Chemical', 'MESH:D012825', (87, 89))	('mutations', 'Var', (50, 59))	('KS', 'Chemical', 'MESH:D011188', (23, 25))	('SW036310', 'Chemical', '-', (143, 151))	('TTC21B', 'Gene', (63, 69))	('si', 'Chemical', 'MESH:D012825', (31, 33))	('benzothiazole', 'Chemical', 'MESH:C005465', (103, 116))
254865	29681454	Somatic mutations in TTC21B have not been characterized in the setting of cancer, however, loss of function TTC21B mutations upregulate cilia dependent processes in mice and are causal mutations in human developmental diseases driven by primary cilia malfunction (ciliopathies).	('primary cilia malfunction', 'Disease', (237, 262))	('mutations', 'Var', (115, 124))	('mice', 'Species', '10090', (165, 169))	('developmental diseases', 'Disease', (204, 226))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('primary cilia malfunction', 'Disease', 'MESH:C536287', (237, 262))	('cancer', 'Disease', (74, 80))	('human', 'Species', '9606', (198, 203))	('TTC21B', 'Gene', (108, 114))	('cilia dependent processes', 'CPA', (136, 161))	('upregulate', 'PosReg', (125, 135))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('loss of function', 'NegReg', (91, 107))	('developmental diseases', 'Disease', 'MESH:D001848', (204, 226))
254867	29681454	Indeed, whole genome transcript profiles indicated that gene signatures associated with activation of these pathways were selectively enriched (Figure S4B) and primary cilia were selectively detectable (Figure S4C) in TTC21B mutant, SW036310-sensitive cell lines (Figure S4B).	('si', 'Chemical', 'MESH:D012825', (61, 63))	('si', 'Chemical', 'MESH:D012825', (245, 247))	('primary cilia', 'CPA', (160, 173))	('TTC21B mutant', 'Var', (218, 231))	('SW036310', 'Chemical', '-', (233, 241))
254868	29681454	Given these associations, we suspect that SW036310 may perturb a target(s) associated with primary cilia biology that supports survival of TTC21B mutant cells.	('survival', 'CPA', (127, 135))	('perturb', 'NegReg', (55, 62))	('mutant', 'Var', (146, 152))	('SW036310', 'Chemical', '-', (42, 50))	('TTC21B', 'Gene', (139, 145))	('SW036310', 'Var', (42, 50))
254869	29681454	Consistently, SW036310 sensitivity almost perfectly correlated sensitivity to the cytoplasmic dynein inhibitor, ciliobrevin, known to disrupt primary cilia by perturbing anterograde trafficking to that organelle (Figure 4E).	('SW036310', 'Chemical', '-', (14, 22))	('primary cilia', 'CPA', (142, 155))	('anterograde trafficking to that organelle', 'MPA', (170, 211))	('si', 'Chemical', 'MESH:D012825', (26, 28))	('si', 'Chemical', 'MESH:D012825', (3, 5))	('ciliobrevin', 'Chemical', '-', (112, 123))	('si', 'Chemical', 'MESH:D012825', (66, 68))	('perturbing', 'NegReg', (159, 169))	('disrupt', 'NegReg', (134, 141))	('SW036310', 'Var', (14, 22))
254871	29681454	Using the derived weighted sum elastic net model, we found SW140154 sensitivity was accurately predicted outside the training set by a combination of high expression of the negative regulator of Toll like receptor signaling (TLR) pathway, SARM1, and low expression of the cytokine receptor, IL18R1 (Figure 4H, S4D) while SW151511 sensitivity could be predicted by high expression of the positive regulator of the TLR pathway, PELI2 (Figure 4H, S4E).	('SW140154', 'Var', (59, 67))	('si', 'Chemical', 'MESH:D012825', (214, 216))	('IL18R1', 'Gene', '8809', (291, 297))	('si', 'Chemical', 'MESH:D012825', (389, 391))	('si', 'Chemical', 'MESH:D012825', (375, 377))	('si', 'Chemical', 'MESH:D012825', (71, 73))	('si', 'Chemical', 'MESH:D012825', (108, 110))	('expression', 'MPA', (254, 264))	('si', 'Chemical', 'MESH:D012825', (1, 3))	('si', 'Chemical', 'MESH:D012825', (260, 262))	('si', 'Chemical', 'MESH:D012825', (333, 335))	('SARM1', 'Gene', '23098', (239, 244))	('TLR pathway', 'Pathway', (413, 424))	('si', 'Chemical', 'MESH:D012825', (161, 163))	('PELI2', 'Gene', (426, 431))	('SARM1', 'Gene', (239, 244))	('IL18R1', 'Gene', (291, 297))	('PELI2', 'Gene', '57161', (426, 431))
254872	29681454	We compared cell lines on opposing ends of the sensitivity spectrum and noted that high expression of TLR pathway genes was associated with sensitivity to SW151511 and resistance to SW140154 (Figure 4I).	('sensitivity', 'MPA', (140, 151))	('si', 'Chemical', 'MESH:D012825', (170, 172))	('si', 'Chemical', 'MESH:D012825', (30, 32))	('expression', 'MPA', (88, 98))	('SW151511', 'Var', (155, 163))	('si', 'Chemical', 'MESH:D012825', (50, 52))	('TLR pathway genes', 'Gene', (102, 119))	('associated', 'Reg', (124, 134))	('si', 'Chemical', 'MESH:D012825', (143, 145))	('resistance', 'MPA', (168, 178))	('high', 'PosReg', (83, 87))	('si', 'Chemical', 'MESH:D012825', (94, 96))
254878	29681454	Finally, low nanomolar sensitivity to SW208097 was predicted and validated to correspond to co-occuring mutations in TP53 and KEAP1 (Figure 4K,L).	('mutations', 'Var', (104, 113))	('TP53', 'Gene', '7157', (117, 121))	('KEAP1', 'Gene', (126, 131))	('TP53', 'Gene', (117, 121))	('si', 'Chemical', 'MESH:D012825', (26, 28))	('SW208097', 'Var', (38, 46))	('SW208097', 'CellLine', 'CVCL:R777', (38, 46))	('KEAP1', 'Gene', '9817', (126, 131))
254881	29681454	Co-occurring TP53 and KEAP1 mutations are detected in 9.6% of LUAD in the TCGA, which extrapolates to ~17,000 patients/year potentially harboring GSK923295-responsive disease.	('KEAP1', 'Gene', (22, 27))	('TP53', 'Gene', (13, 17))	('GSK923295', 'Chemical', 'MESH:C571460', (146, 155))	('si', 'Chemical', 'MESH:D012825', (162, 164))	('LUAD', 'Phenotype', 'HP:0030078', (62, 66))	('LUAD', 'Disease', (62, 66))	('KEAP1', 'Gene', '9817', (22, 27))	('TP53', 'Gene', '7157', (13, 17))	('mutations', 'Var', (28, 37))	('patients', 'Species', '9606', (110, 118))
254883	29681454	We previously reported the overarching phenotypic diversity among KRAS mutant lung cancer cell lines is essentially equivalent to the global phenotypic variation found across all characterized NSCLC cell lines.	('lung cancer', 'Disease', (78, 89))	('lung cancer', 'Phenotype', 'HP:0100526', (78, 89))	('NSCLC', 'Phenotype', 'HP:0030358', (193, 198))	('KRAS', 'Gene', '3845', (66, 70))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('si', 'Chemical', 'MESH:D012825', (55, 57))	('mutant', 'Var', (71, 77))	('lung cancer', 'Disease', 'MESH:D008175', (78, 89))	('NSCLC', 'Disease', (193, 198))	('NSCLC', 'Disease', 'MESH:D002289', (193, 198))	('KRAS', 'Gene', (66, 70))
254885	29681454	This genomic mRNA expression diversity was mirrored by a diversity of sensitivity of KRAS mutant cell lines to the POPs collection (Figure 5B,C).	('si', 'Chemical', 'MESH:D012825', (73, 75))	('mutant', 'Var', (90, 96))	('si', 'Chemical', 'MESH:D012825', (34, 36))	('KRAS', 'Gene', (85, 89))	('si', 'Chemical', 'MESH:D012825', (62, 64))	('KRAS', 'Gene', '3845', (85, 89))	('si', 'Chemical', 'MESH:D012825', (24, 26))
254886	29681454	However, automated scanning KS analyses returned 4 chemical associations with KRAS mutant subtypes that passed p-value thresholds (p<2E-4).	('KS', 'Chemical', 'MESH:D011188', (28, 30))	('KRAS', 'Gene', '3845', (78, 82))	('KRAS', 'Gene', (78, 82))	('mutant', 'Var', (83, 89))
254887	29681454	These subtypes were defined by co-occurring mutations in KEAP1, NUP214, PTPRT, and TTC21B (Figure S5A, 5D).	('KEAP1', 'Gene', (57, 62))	('KEAP1', 'Gene', '9817', (57, 62))	('TTC21B', 'Gene', (83, 89))	('mutations', 'Var', (44, 53))	('PTPRT', 'Gene', '11122', (72, 77))	('PTPRT', 'Gene', (72, 77))	('NUP214', 'Gene', (64, 70))	('NUP214', 'Gene', '8021', (64, 70))
254888	29681454	Among these, the association of KRAS/KEAP1 double mutant cell lines with sensitivity to SW157765 (Figure 5D) was verifiable in a test set of NSCLC lines distinct from the training set (Figure 5E) and selective efficacy was preserved in spheroid models of lung cancer (Figure 5F, S5B).	('si', 'Chemical', 'MESH:D012825', (76, 78))	('association', 'Interaction', (17, 28))	('SW157765', 'Var', (88, 96))	('S5B', 'Gene', '5711', (279, 282))	('cancer', 'Phenotype', 'HP:0002664', (260, 266))	('lung cancer', 'Disease', (255, 266))	('KRAS', 'Gene', (32, 36))	('lung cancer', 'Phenotype', 'HP:0100526', (255, 266))	('NSCLC', 'Disease', (141, 146))	('KRAS', 'Gene', '3845', (32, 36))	('KEAP1', 'Gene', '9817', (37, 42))	('NSCLC', 'Disease', 'MESH:D002289', (141, 146))	('S5B', 'Gene', (279, 282))	('lung cancer', 'Disease', 'MESH:D008175', (255, 266))	('NSCLC', 'Phenotype', 'HP:0030358', (141, 146))	('KEAP1', 'Gene', (37, 42))
254891	29681454	Upon stress, KEAP1 inactivation facilitates NRF2 nuclear translocation and consequent activation of the NRF2-dependent anti-oxidant and cytoprotective transcriptional responses.	('KEAP1', 'Gene', '9817', (13, 18))	('nuclear translocation', 'MPA', (49, 70))	('NRF2', 'Gene', (104, 108))	('NRF2', 'Gene', '4780', (44, 48))	('KEAP1', 'Gene', (13, 18))	('inactivation', 'Var', (19, 31))	('NRF2', 'Gene', (44, 48))	('activation', 'PosReg', (86, 96))	('facilitates', 'PosReg', (32, 43))	('NRF2', 'Gene', '4780', (104, 108))
254892	29681454	Deleterious mutations or deletions in KEAP1 are present in ~19% of LUAD's and ~12% of LUSC's corresponding to constitutive NRF2 activity.	('KEAP1', 'Gene', '9817', (38, 43))	('activity', 'MPA', (128, 136))	('mutations', 'Var', (12, 21))	('KEAP1', 'Gene', (38, 43))	('LUSC', 'Phenotype', 'HP:0030359', (86, 90))	('deletions', 'Var', (25, 34))	('NRF2', 'Gene', '4780', (123, 127))	('LUAD', 'Disease', (67, 71))	('LUAD', 'Phenotype', 'HP:0030078', (67, 71))	('NRF2', 'Gene', (123, 127))
254893	29681454	Co-occurring mutations in KEAP1 and KRAS are present in ~6% of LUADs (www.tcga.org); significantly more than expected by chance (p=.007), suggesting they are under positive selective pressure during disease development.	('KEAP1', 'Gene', (26, 31))	('LUAD', 'Phenotype', 'HP:0030078', (63, 67))	('si', 'Chemical', 'MESH:D012825', (166, 168))	('KRAS', 'Gene', (36, 40))	('si', 'Chemical', 'MESH:D012825', (85, 87))	('KRAS', 'Gene', '3845', (36, 40))	('KEAP1', 'Gene', '9817', (26, 31))	('mutations', 'Var', (13, 22))
254894	29681454	There were, however, a few KEAP1 wild-type cell lines that were responsive to SW157765 (Figure 5G).	('KEAP1', 'Gene', '9817', (27, 32))	('SW157765', 'Var', (78, 86))	('KEAP1', 'Gene', (27, 32))	('si', 'Chemical', 'MESH:D012825', (70, 72))
254895	29681454	These included the only cell line in the panel that harbors a KEAP1 homozygous deletion (Figure S5C) resulting in undetectable KEAP1 mRNA (Figure 5G).	('KEAP1', 'Gene', '9817', (127, 132))	('KEAP1', 'Gene', '9817', (62, 67))	('undetectable', 'NegReg', (114, 126))	('KEAP1', 'Gene', (127, 132))	('KEAP1', 'Gene', (62, 67))	('deletion', 'Var', (79, 87))
254896	29681454	These also included cell lines (2/2) with amino acid substitutions in the degron domain of NRF2 (Figure 5G), corresponding to hotspot NRF2 mutations detected in LUAD tumors lacking functional KEAP1 degradation motifs producing constitutively activated variants (Figure S5D).	('KEAP1', 'Gene', '9817', (192, 197))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('mutations', 'Var', (139, 148))	('KEAP1', 'Gene', (192, 197))	('LUAD', 'Phenotype', 'HP:0030078', (161, 165))	('NRF2', 'Gene', '4780', (91, 95))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))	('LUAD tumors', 'Disease', (161, 172))	('LUAD tumors', 'Disease', 'MESH:D009369', (161, 172))	('NRF2', 'Gene', '4780', (134, 138))	('NRF2', 'Gene', (91, 95))	('NRF2', 'Gene', (134, 138))	('amino acid substitutions in', 'Var', (42, 69))
254897	29681454	We did not detect additional variants in known NRF2 pathway genes among the 8 remaining sensitive cell lines that were KRAS/KEAP1 wild type.	('si', 'Chemical', 'MESH:D012825', (91, 93))	('KEAP1', 'Gene', '9817', (124, 129))	('NRF2', 'Gene', '4780', (47, 51))	('variants', 'Var', (29, 37))	('KRAS', 'Gene', (119, 123))	('KEAP1', 'Gene', (124, 129))	('NRF2', 'Gene', (47, 51))	('KRAS', 'Gene', '3845', (119, 123))
254899	29681454	High expression of this NRF2 gene signature (Figure S5F) was predictive of sensitivity to SW157765 when applied to cell lines outside the training set (Figure 5H).	('NRF2', 'Gene', (24, 28))	('si', 'Chemical', 'MESH:D012825', (129, 131))	('si', 'Chemical', 'MESH:D012825', (78, 80))	('si', 'Chemical', 'MESH:D012825', (34, 36))	('si', 'Chemical', 'MESH:D012825', (11, 13))	('NRF2', 'Gene', '4780', (24, 28))	('SW157765', 'Var', (90, 98))
254900	29681454	SW157765 is found as a member of the 'prodrug' compounds in which high expression of CYP4F11 is predictive of, and required for, cellular response (Figure 2 A,G).	('CYP4F11', 'Gene', '57834', (85, 92))	('CYP4F11', 'Gene', (85, 92))	('si', 'Chemical', 'MESH:D012825', (77, 79))	('SW157765', 'Var', (0, 8))
254902	29681454	Given this association, we assessed NRF2 dependent regulation of CYP4F11 in an SW157765-sensitive cell line and found that siRNA-mediated depletion of NRF2 resulted in depletion of CYP4F11 (Figure 5I, S5G) and reduction of sensitivity to SW157765 (Figure 5J).	('NRF2', 'Gene', '4780', (151, 155))	('si', 'Chemical', 'MESH:D012825', (91, 93))	('reduction', 'NegReg', (210, 219))	('NRF2', 'Gene', '4780', (36, 40))	('NRF2', 'Gene', (36, 40))	('si', 'Chemical', 'MESH:D012825', (226, 228))	('depletion', 'Var', (138, 147))	('CYP4F11', 'Gene', '57834', (65, 72))	('si', 'Chemical', 'MESH:D012825', (123, 125))	('CYP4F11', 'Gene', '57834', (181, 188))	('sensitivity to SW157765', 'MPA', (223, 246))	('depletion', 'MPA', (168, 177))	('CYP4F11', 'Gene', (181, 188))	('NRF2', 'Gene', (151, 155))	('CYP4F11', 'Gene', (65, 72))
254903	29681454	This suggests that NRF2 pathway activity leads to selective production of a toxic SW157765 metabolite.	('SW157765', 'Var', (82, 90))	('production', 'MPA', (60, 70))	('NRF2', 'Gene', '4780', (19, 23))	('NRF2', 'Gene', (19, 23))
254905	29681454	Consistent with this, we found siRNA-mediated depletion of KRAS completely rescued cellular sensitivity to SW157765 even though metabolism of the compound was unaffected (Figure 5K,L).	('SW157765', 'Var', (107, 115))	('depletion', 'Var', (46, 55))	('KRAS', 'Gene', '3845', (59, 63))	('rescued', 'PosReg', (75, 82))	('cellular sensitivity', 'MPA', (83, 103))	('si', 'Chemical', 'MESH:D012825', (95, 97))	('si', 'Chemical', 'MESH:D012825', (3, 5))	('si', 'Chemical', 'MESH:D012825', (31, 33))	('KRAS', 'Gene', (59, 63))
254906	29681454	Thus, KRAS and NRF2 pathway activation combine to produce a selective cellular vulnerability to SW157765 intervention.	('KRAS', 'Gene', '3845', (6, 10))	('SW157765 intervention', 'Var', (96, 117))	('NRF2', 'Gene', '4780', (15, 19))	('NRF2', 'Gene', (15, 19))	('activation', 'PosReg', (28, 38))	('KRAS', 'Gene', (6, 10))
254909	29681454	As an alternate approach, we undertook docking studies to assess binding of SW157765 to GLUT8 in comparison to the predicted metabolite (Figure S2Z).	('GLUT8', 'Gene', (88, 93))	('SW157765', 'Var', (76, 84))	('GLUT8', 'Gene', '29988', (88, 93))	('binding', 'Interaction', (65, 72))
254912	29681454	SW157765 and the epoxide metabolite were predicted to dock on top of one another, except for a deviation near the epoxide region.	('epoxide', 'Chemical', 'MESH:D004852', (17, 24))	('dock', 'Interaction', (54, 58))	('epoxide', 'Chemical', 'MESH:D004852', (114, 121))	('SW157765', 'Var', (0, 8))
254915	29681454	In aggregate, these analyses are consistent with interaction of both SW157765 and its oxidized metabolite with GLUT8.	('GLUT8', 'Gene', '29988', (111, 116))	('interaction', 'Interaction', (49, 60))	('si', 'Chemical', 'MESH:D012825', (36, 38))	('SW157765', 'Var', (69, 77))	('GLUT8', 'Gene', (111, 116))
254916	29681454	Enhanced GLUT8 thermal stability in cells treated with SW157765, but not 500-1, provided orthogonal evidence for this interaction (Figure S6C).	('Enhanced', 'PosReg', (0, 8))	('GLUT8', 'Gene', '29988', (9, 14))	('SW157765', 'Var', (55, 63))	('GLUT8', 'Gene', (9, 14))
254921	29681454	Notably, we found SW157765-sensitive NSCLC cell lines were also selectively sensitive to glucose deprivation (Figure S6D) and to GLUT8 depletion (Figure 6B).	('si', 'Chemical', 'MESH:D012825', (79, 81))	('SW157765-sensitive', 'Var', (18, 36))	('NSCLC', 'Phenotype', 'HP:0030358', (37, 42))	('GLUT8', 'Gene', (129, 134))	('glucose deprivation', 'Disease', 'MESH:D012892', (89, 108))	('GLUT8', 'Gene', '29988', (129, 134))	('si', 'Chemical', 'MESH:D012825', (30, 32))	('glucose deprivation', 'Disease', (89, 108))	('NSCLC', 'Disease', (37, 42))	('sensitive', 'Reg', (76, 85))	('NSCLC', 'Disease', 'MESH:D002289', (37, 42))
254922	29681454	Furthermore, SW157765 selectively inhibited fluorescent 2-deoxyglucose (2DG) uptake in SW157765-sensitive cells in a dose-dependent manner (Figure 6C).	('SW157765-sensitive', 'Var', (87, 105))	('inhibited', 'NegReg', (34, 43))	('SW157765', 'Var', (13, 21))	('si', 'Chemical', 'MESH:D012825', (99, 101))	('2-deoxyglucose', 'Chemical', 'MESH:D003847', (56, 70))	('2DG', 'Chemical', 'MESH:D003847', (72, 75))
254924	29681454	These observations are consistent with action of SW157765 at the level of GLUT8 inhibition, and a selective dependence of KRAS/KEAP1 mutant cells on GLUT8 for glucose consumption.	('KEAP1', 'Gene', '9817', (127, 132))	('GLUT8', 'Gene', (149, 154))	('glucose', 'Chemical', 'MESH:D005947', (159, 166))	('GLUT8', 'Gene', '29988', (74, 79))	('GLUT8', 'Gene', '29988', (149, 154))	('GLUT8', 'Gene', (74, 79))	('KEAP1', 'Gene', (127, 132))	('dependence', 'Reg', (108, 118))	('si', 'Chemical', 'MESH:D012825', (26, 28))	('glucose consumption', 'MPA', (159, 178))	('mutant', 'Var', (133, 139))	('KRAS', 'Gene', (122, 126))	('SW157765', 'Var', (49, 57))	('KRAS', 'Gene', '3845', (122, 126))
254926	29681454	Of relevance to this study, high NRF2 activity was recently demonstrated to promote serine/glycine biosynthesis, in some NSCLC cell types, through ATF4-dependent expression of rate-limiting serine biosynthetic enzymes (PHGDH, PSAT1, PSPH, SHMT1, and SHMT2).	('promote', 'PosReg', (76, 83))	('ATF4', 'Gene', (147, 151))	('si', 'Chemical', 'MESH:D012825', (168, 170))	('ATF4', 'Gene', '468', (147, 151))	('NRF2', 'Gene', '4780', (33, 37))	('PHGDH', 'Gene', '26227', (219, 224))	('PSAT1', 'Gene', (226, 231))	('PSAT1', 'Gene', '29968', (226, 231))	('PHGDH', 'Gene', (219, 224))	('activity', 'MPA', (38, 46))	('SHMT2', 'Gene', '6472', (250, 255))	('SHMT1', 'Gene', (239, 244))	('NSCLC', 'Disease', 'MESH:D002289', (121, 126))	('NRF2', 'Gene', (33, 37))	('serine/glycine biosynthesis', 'MPA', (84, 111))	('PSPH', 'Gene', '5723', (233, 237))	('high', 'Var', (28, 32))	('serine', 'Chemical', 'MESH:D012694', (190, 196))	('si', 'Chemical', 'MESH:D012825', (108, 110))	('NSCLC', 'Disease', (121, 126))	('PSPH', 'Gene', (233, 237))	('SHMT1', 'Gene', '6470', (239, 244))	('glycine', 'Chemical', 'MESH:D005998', (91, 98))	('serine', 'Chemical', 'MESH:D012694', (84, 90))	('SHMT2', 'Gene', (250, 255))	('NSCLC', 'Phenotype', 'HP:0030358', (121, 126))
254928	29681454	When we examined carbon flux from uniformly labeled [13C6] glucose into serine (SerM3) and glycine (GlyM2) mass isotopomers across 63 NSCLC cell lines, we found significant enrichment of heavy carbons in the SW157765 sensitive cell lines (Figure 6E), corresponding to significantly higher expression of serine biosynthetic pathway genes (Figure S6I) and selective consequences on cell survival upon depletion of the ATF4 transcription factor (Figure 6F) and PHGDH (Figure 6G), the enzyme that catalyzes the first committed step in the serine biosynthetic pathway.	('NSCLC', 'Disease', 'MESH:D002289', (134, 139))	('si', 'Chemical', 'MESH:D012825', (295, 297))	('expression', 'MPA', (289, 299))	('si', 'Chemical', 'MESH:D012825', (161, 163))	('depletion', 'NegReg', (399, 408))	('PHGDH', 'Gene', '26227', (458, 463))	('NSCLC', 'Disease', (134, 139))	('serine biosynthetic pathway genes', 'Gene', (303, 336))	('serine', 'Chemical', 'MESH:D012694', (535, 541))	('PHGDH', 'Gene', (458, 463))	('NSCLC', 'Phenotype', 'HP:0030358', (134, 139))	('higher', 'PosReg', (282, 288))	('13C6', 'Chemical', '-', (53, 57))	('ATF4', 'Gene', (416, 420))	('glucose', 'Chemical', 'MESH:D005947', (59, 66))	('ATF4', 'Gene', '468', (416, 420))	('serine', 'Chemical', 'MESH:D012694', (303, 309))	('serine', 'Chemical', 'MESH:D012694', (72, 78))	('consequences', 'Reg', (364, 376))	('carbon', 'Chemical', 'MESH:D002244', (193, 199))	('si', 'Chemical', 'MESH:D012825', (220, 222))	('cell survival', 'CPA', (380, 393))	('si', 'Chemical', 'MESH:D012825', (268, 270))	('carbon', 'Chemical', 'MESH:D002244', (17, 23))	('SW157765', 'Var', (208, 216))	('glycine', 'Chemical', 'MESH:D005998', (91, 98))
254929	29681454	Taken together, these findings indicate a dependence of KRAS/KEAP1 mutant NSCLC cells on consumption of glucose to support serine biosynthetic pathway activity.	('KEAP1', 'Gene', (61, 66))	('dependence', 'Reg', (42, 52))	('NSCLC', 'Phenotype', 'HP:0030358', (74, 79))	('serine biosynthetic pathway activity', 'MPA', (123, 159))	('serine', 'Chemical', 'MESH:D012694', (123, 129))	('KRAS', 'Gene', (56, 60))	('KRAS', 'Gene', '3845', (56, 60))	('consumption of glucose', 'MPA', (89, 111))	('NSCLC', 'Disease', (74, 79))	('KEAP1', 'Gene', '9817', (61, 66))	('mutant', 'Var', (67, 73))	('NSCLC', 'Disease', 'MESH:D002289', (74, 79))	('glucose', 'Chemical', 'MESH:D005947', (104, 111))
254930	29681454	These cumulative observations led us to consider that SW157765 may be acting to reduce carbon flux through the serine biosynthetic pathway, leading to selective targeting of cancer cells dependent on this pathway.	('SW157765', 'Var', (54, 62))	('si', 'Chemical', 'MESH:D012825', (43, 45))	('serine', 'Chemical', 'MESH:D012694', (111, 117))	('cancer', 'Disease', (174, 180))	('reduce', 'NegReg', (80, 86))	('serine biosynthetic pathway', 'Pathway', (111, 138))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('carbon', 'Chemical', 'MESH:D002244', (87, 93))	('carbon flux', 'MPA', (87, 98))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))
254931	29681454	To test this, we pretreated H647 (KRAS/KEAP1 mutant) with SW157765 for 24 hours, an interval where we do not observe significant induction of cell death (Figure S6J), followed by exposure to glucose ([13C2]) (Figure S6O).	('KRAS', 'Gene', '3845', (34, 38))	('KEAP1', 'Gene', (39, 44))	('glucose', 'Chemical', 'MESH:D005947', (191, 198))	('KEAP1', 'Gene', '9817', (39, 44))	('H647', 'CellLine', 'CVCL:1574', (28, 32))	('13C', 'Chemical', '-', (201, 204))	('si', 'Chemical', 'MESH:D012825', (117, 119))	('SW157765', 'Var', (58, 66))	('KRAS', 'Gene', (34, 38))
254932	29681454	Heavy carbon labeling of serine reached steady-state after 2 hrs (SerM2), which was reduced 5-fold by SW157765 (Figure 6H).	('carbon', 'Chemical', 'MESH:D002244', (6, 12))	('Heavy carbon labeling of serine', 'MPA', (0, 31))	('serine', 'Chemical', 'MESH:D012694', (25, 31))	('SW157765', 'Var', (102, 110))
254933	29681454	Iteration of this approach within a panel of NSCLC cell lines, indicated basal carbon flux through the serine biosynthetic pathway was higher in SW157765-sensitive cell lines, as expected, and exposure to SW157765 selectively reduced serine labeling in these cell lines (Figure 6I).	('serine labeling', 'MPA', (234, 249))	('SW157765', 'Var', (205, 213))	('SW157765-sensitive', 'Var', (145, 163))	('NSCLC', 'Disease', (45, 50))	('NSCLC', 'Phenotype', 'HP:0030358', (45, 50))	('serine', 'Chemical', 'MESH:D012694', (103, 109))	('serine', 'Chemical', 'MESH:D012694', (234, 240))	('carbon', 'Chemical', 'MESH:D002244', (79, 85))	('NSCLC', 'Disease', 'MESH:D002289', (45, 50))	('carbon flux', 'MPA', (79, 90))	('si', 'Chemical', 'MESH:D012825', (157, 159))	('serine', 'Pathway', (103, 109))	('higher', 'PosReg', (135, 141))	('reduced', 'NegReg', (226, 233))
254934	29681454	Notably, carbon flux from glucose through the pentose phosphate pathway (PPP; LacM1) or the citric acid cycle (TCA; CitM2) (Figure S6K-L; Figure S6O) was not affected by SW157765.	('SW157765', 'Var', (170, 178))	('citric acid cycle', 'MPA', (92, 109))	('carbon flux from glucose', 'MPA', (9, 33))	('citric acid', 'Chemical', 'MESH:D019343', (92, 103))	('glucose', 'Chemical', 'MESH:D005947', (26, 33))	('carbon', 'Chemical', 'MESH:D002244', (9, 15))	('pentose phosphate', 'Chemical', 'MESH:D010428', (46, 63))	('pentose', 'Enzyme', (46, 53))
254936	29681454	Thus, the selective consequences of SW157765 exposure on serine/glycine metabolism suggests a dominant routing of available glucose to the PPP and TCA.	('glucose', 'Chemical', 'MESH:D005947', (124, 131))	('SW157765', 'Var', (36, 44))	('routing', 'MPA', (103, 110))	('serine/glycine metabolism', 'MPA', (57, 82))	('serine', 'Chemical', 'MESH:D012694', (57, 63))	('glycine', 'Chemical', 'MESH:D005998', (64, 71))
254937	29681454	GLUT8 may therefore support supplementary glucose consumption to an extent that provides for serine/glycine biosynthetic demands of the KRAS/KEAP1 mutant cellular context.	('mutant', 'Var', (147, 153))	('KEAP1', 'Gene', '9817', (141, 146))	('glycine', 'Chemical', 'MESH:D005998', (100, 107))	('GLUT8', 'Gene', '29988', (0, 5))	('GLUT8', 'Gene', (0, 5))	('KRAS', 'Gene', (136, 140))	('serine/glycine biosynthetic demands', 'MPA', (93, 128))	('serine', 'Chemical', 'MESH:D012694', (93, 99))	('KEAP1', 'Gene', (141, 146))	('glucose', 'Chemical', 'MESH:D005947', (42, 49))	('KRAS', 'Gene', '3845', (136, 140))
254938	29681454	While KEAP1 and KRAS mutation status was robustly predictive of sensitivity to SW157765, we noted 4 unanticipated non-responders (DFCI024, HCC44, H2030, HCC4019) with co-occurring mutations in KEAP1 and KRAS and high expression of CYP4F11(Figure S6M).	('KRAS', 'Gene', (203, 207))	('HCC4019', 'CellLine', 'CVCL:V581', (153, 160))	('KEAP1', 'Gene', (193, 198))	('KRAS', 'Gene', '3845', (203, 207))	('mutations', 'Var', (180, 189))	('si', 'Chemical', 'MESH:D012825', (67, 69))	('KEAP1', 'Gene', (6, 11))	('CYP4F11', 'Gene', '57834', (231, 238))	('CYP4F11', 'Gene', (231, 238))	('HCC44', 'CellLine', 'CVCL:2060', (139, 144))	('KEAP1', 'Gene', '9817', (193, 198))	('KRAS', 'Gene', (16, 20))	('KRAS', 'Gene', '3845', (16, 20))	('H20', 'Chemical', '-', (146, 149))	('SW157765', 'Var', (79, 87))	('si', 'Chemical', 'MESH:D012825', (223, 225))	('KEAP1', 'Gene', '9817', (6, 11))
254941	29681454	These cells may be resistant to SW157765 due to a pre-existing adaptation that reduces contributions of glycolysis to serine/glycine biosynthesis.	('si', 'Chemical', 'MESH:D012825', (111, 113))	('si', 'Chemical', 'MESH:D012825', (142, 144))	('SW157765', 'Var', (32, 40))	('reduces', 'NegReg', (79, 86))	('glycine', 'Chemical', 'MESH:D005998', (125, 132))	('si', 'Chemical', 'MESH:D012825', (21, 23))	('serine', 'Chemical', 'MESH:D012694', (118, 124))
254944	29681454	In summary, we have shown co-occurring mutations in KEAP1 and KRAS define a vulnerability to continued function of GLUT8.	('GLUT8', 'Gene', (115, 120))	('KRAS', 'Gene', (62, 66))	('KRAS', 'Gene', '3845', (62, 66))	('KEAP1', 'Gene', '9817', (52, 57))	('mutations', 'Var', (39, 48))	('KEAP1', 'Gene', (52, 57))	('GLUT8', 'Gene', '29988', (115, 120))	('vulnerability', 'MPA', (76, 89))
254945	29681454	Inhibition of GLUT8 is associated with a reduction of glucose intake leading to a selective shunting of glucose from serine biosynthesis.	('glucose', 'Chemical', 'MESH:D005947', (104, 111))	('glucose', 'Chemical', 'MESH:D005947', (54, 61))	('serine', 'Chemical', 'MESH:D012694', (117, 123))	('si', 'Chemical', 'MESH:D012825', (133, 135))	('Inhibition', 'Var', (0, 10))	('GLUT8', 'Gene', '29988', (14, 19))	('GLUT8', 'Gene', (14, 19))	('glucose intake', 'MPA', (54, 68))	('reduction', 'NegReg', (41, 50))
254946	29681454	We found overexpression of wild-type PHGDH can re-sensitize HCC44 cells to SW157765.	('PHGDH', 'Gene', (37, 42))	('overexpression', 'PosReg', (9, 23))	('si', 'Chemical', 'MESH:D012825', (53, 55))	('si', 'Chemical', 'MESH:D012825', (19, 21))	('SW157765', 'Var', (75, 83))	('HCC44', 'CellLine', 'CVCL:2060', (60, 65))	('PHGDH', 'Gene', '26227', (37, 42))
254947	29681454	Perhaps most intriguingly, re-introduction of PHGDH also can sensitize cells to GLUT8 inhibition.	('GLUT8', 'Gene', '29988', (80, 85))	('GLUT8', 'Gene', (80, 85))	('sensitize', 'Reg', (61, 70))	('PHGDH', 'Gene', '26227', (46, 51))	('si', 'Chemical', 'MESH:D012825', (64, 66))	('PHGDH', 'Gene', (46, 51))	('re-introduction', 'Var', (27, 42))
254948	29681454	These findings suggest that shunting cellular consumption of glucose to serine biosynthesis generates a dependency on GLUT8 that can be selectively targeted with SW157765.	('GLUT8', 'Gene', '29988', (118, 123))	('SW157765', 'Var', (162, 170))	('GLUT8', 'Gene', (118, 123))	('dependency', 'MPA', (104, 114))	('si', 'Chemical', 'MESH:D012825', (88, 90))	('serine', 'Chemical', 'MESH:D012694', (72, 78))	('glucose', 'Chemical', 'MESH:D005947', (61, 68))
254949	29681454	To potentially help assess the generality of this relationship, we profiled SW157765 for toxicity in a panel of 27 breast cancer cell lines with publically available genomics data.	('toxicity', 'Disease', 'MESH:D064420', (89, 97))	('toxicity', 'Disease', (89, 97))	('breast cancer', 'Disease', 'MESH:D001943', (115, 128))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('breast cancer', 'Disease', (115, 128))	('breast cancer', 'Phenotype', 'HP:0003002', (115, 128))	('SW157765', 'Var', (76, 84))
254950	29681454	Importantly, we found that copy number-driven amplification of PHGDH expression together with high expression of CYP4F11 significantly corresponded to SW157765 sensitivity (Figure 6L).	('si', 'Chemical', 'MESH:D012825', (163, 165))	('corresponded', 'Reg', (135, 147))	('si', 'Chemical', 'MESH:D012825', (105, 107))	('PHGDH', 'Gene', '26227', (63, 68))	('si', 'Chemical', 'MESH:D012825', (75, 77))	('CYP4F11', 'Gene', (113, 120))	('CYP4F11', 'Gene', '57834', (113, 120))	('copy', 'Var', (27, 31))	('PHGDH', 'Gene', (63, 68))	('amplification', 'PosReg', (46, 59))	('si', 'Chemical', 'MESH:D012825', (121, 123))
254953	29681454	This included the association of erlotinib-sensitivity with EGFR mutation status and the association of crizotinib-sensitivity with EML4-ALK translocations.	('si', 'Chemical', 'MESH:D012825', (118, 120))	('si', 'Chemical', 'MESH:D012825', (46, 48))	('erlotinib', 'Chemical', 'MESH:D000069347', (33, 42))	('ALK', 'Gene', (137, 140))	('association', 'Interaction', (18, 29))	('EML4', 'Gene', (132, 136))	('EGFR', 'Gene', '1956', (60, 64))	('mutation', 'Var', (65, 73))	('ALK', 'Gene', '238', (137, 140))	('EML4', 'Gene', '27436', (132, 136))	('EGFR', 'Gene', (60, 64))	('crizotinib', 'Chemical', 'MESH:D000077547', (104, 114))
254958	29681454	However, significant chemical/genetic associations were detected upon segmentation of cell models according to mutations in additional genes that co-occurred with KRAS mutations at a reasonable frequency.	('mutations', 'Var', (111, 120))	('KRAS', 'Gene', (163, 167))	('si', 'Chemical', 'MESH:D012825', (9, 11))	('KRAS', 'Gene', '3845', (163, 167))	('mutations', 'Var', (168, 177))
254960	29681454	Most notably, KRAS/KEAP1 double mutant NSCLC cells were selectively sensitive to the benzothiozole, SW157765, due to the convergent consequences of dual KRAS and NRF2 modulation of metabolic and xenobiotic gene regulatory programs.	('KEAP1', 'Gene', (19, 24))	('NSCLC', 'Phenotype', 'HP:0030358', (39, 44))	('KRAS', 'Gene', '3845', (14, 18))	('sensitive', 'Reg', (68, 77))	('modulation', 'Reg', (167, 177))	('xenobiotic', 'Disease', (195, 205))	('NRF2', 'Gene', (162, 166))	('si', 'Chemical', 'MESH:D012825', (71, 73))	('KRAS', 'Gene', (153, 157))	('KEAP1', 'Gene', '9817', (19, 24))	('benzothiozole', 'Chemical', '-', (85, 98))	('KRAS', 'Gene', '3845', (153, 157))	('NSCLC', 'Disease', (39, 44))	('SW157765', 'Var', (100, 108))	('xenobiotic', 'Disease', 'None', (195, 205))	('KRAS', 'Gene', (14, 18))	('NSCLC', 'Disease', 'MESH:D002289', (39, 44))	('NRF2', 'Gene', '4780', (162, 166))
254961	29681454	Glut8 was identified as a mechanistic target of SW157765, and is selectively required to support the diversion of glucose to serine biosynthesis in this genetic background.	('diversion', 'MPA', (101, 110))	('glucose', 'Chemical', 'MESH:D005947', (114, 121))	('Glut8', 'Gene', '29988', (0, 5))	('serine', 'Chemical', 'MESH:D012694', (125, 131))	('si', 'Chemical', 'MESH:D012825', (106, 108))	('Glut8', 'Gene', (0, 5))	('si', 'Chemical', 'MESH:D012825', (141, 143))	('SW157765', 'Var', (48, 56))
254962	29681454	Modulation of these regulatory programs by orthogonal means was sufficient to modulate SW157765 responsiveness.	('Modulation', 'Var', (0, 10))	('SW157765', 'Gene', (87, 95))	('modulate', 'Reg', (78, 86))	('si', 'Chemical', 'MESH:D012825', (102, 104))
254964	29681454	Of note, parallel analysis within a large cohort of breast cancer cell lines returned sensitivity-associated biomarkers indicative of a conserved biological mode-of-action for SW155765, but there was no relationship with KRAS/KEAP1 mutation status, an oncogenotype that is exceedingly rare in breast.	('KEAP1', 'Gene', (226, 231))	('breast cancer', 'Disease', 'MESH:D001943', (52, 65))	('KRAS', 'Gene', (221, 225))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('si', 'Chemical', 'MESH:D012825', (23, 25))	('breast cancer', 'Disease', (52, 65))	('KRAS', 'Gene', '3845', (221, 225))	('breast cancer', 'Phenotype', 'HP:0003002', (52, 65))	('si', 'Chemical', 'MESH:D012825', (89, 91))	('KEAP1', 'Gene', '9817', (226, 231))	('SW155765', 'Var', (176, 184))
254967	29681454	Furthermore, it is clear that chemical vulnerabilities can be revealed that are linked to recurrent mutations in lung cancer patients that are not currently "actionable".	('mutations', 'Var', (100, 109))	('lung cancer', 'Disease', (113, 124))	('lung cancer', 'Phenotype', 'HP:0100526', (113, 124))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('lung cancer', 'Disease', 'MESH:D008175', (113, 124))	('patients', 'Species', '9606', (125, 133))
254969	29681454	Further information and requests for resources and reagents should be directed to and will be fulfilled by the Lead Contact, Michael White (michael.white@utsouthwestern.edu) Most NSCLC lines used in this study were part of the NCI and HCC (Hamon Cancer Center at UT Southwestern) series of cell lines, with the exception of THLE-2, THLE-3, A427, A549, Calu.1, Calu.6 (American Type Culture Collection; ATCC), Cal.12T (Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH; DSMZ), DFCI.024, DFCI.032 (Dana Farber Cancer Institute, courtesy of Pasi Janne), EKVX, Hop62 (NCI-60 panel), PC9 (Johns Hopkins University School of Medicine, courtesy of Bert Vogelstein).	('A549', 'CellLine', 'CVCL:0023', (346, 350))	('Cancer', 'Disease', (518, 524))	('NSCLC', 'Disease', 'MESH:D002289', (179, 184))	('Cancer', 'Disease', 'MESH:D009369', (246, 252))	('DFCI.032', 'Var', (496, 504))	('von', 'Disease', (436, 439))	('Cancer', 'Disease', 'MESH:D009369', (518, 524))	('Cancer', 'Phenotype', 'HP:0002664', (518, 524))	('PC9', 'Gene', '255738', (589, 592))	('si', 'Chemical', 'MESH:D012825', (614, 616))	('NSCLC', 'Phenotype', 'HP:0030358', (179, 184))	('Cancer', 'Phenotype', 'HP:0002664', (246, 252))	('PC9', 'Gene', (589, 592))	('si', 'Chemical', 'MESH:D012825', (550, 552))	('von', 'Disease', 'MESH:D014842', (436, 439))	('NSCLC', 'Disease', (179, 184))	('Cancer', 'Disease', (246, 252))
254988	29681454	Media was then removed and cells were rinsed with PBS prior to treatment with SW157765 in media containing glucose-free RPMI supplemented with 5% FBS and 13C glucose.	('glucose-free RPMI', 'Disease', 'MESH:D000072662', (107, 124))	('glucose-free RPMI', 'Disease', (107, 124))	('PBS', 'Chemical', '-', (50, 53))	('SW157765', 'Var', (78, 86))	('13C glucose', 'Chemical', '-', (154, 165))
255049	29681454	Cell lines were plated at a density of either 2000 (H2122, A549, HCC95, HCC44, H1792, H460, H322, HCC1171, H920, HCC2108, H226, H647, H2086, HCC4011) or 4000 (DFCI.032, HCC3051, H3255, H1395, H2073, H1437, HCC2814, HCC515, H596, H3122) cells per well in 96 well plates.	('HCC1171', 'Var', (98, 105))	('H2073', 'CellLine', 'CVCL:1521', (192, 197))	('H1437', 'Var', (199, 204))	('HCC1171', 'CellLine', 'CVCL:5126', (98, 105))	('H460', 'CellLine', 'CVCL:0459', (86, 90))	('H647', 'CellLine', 'CVCL:1574', (128, 132))	('H2086', 'Var', (134, 139))	('H1792', 'Var', (79, 84))	('HCC3051', 'Var', (169, 176))	('H1437', 'CellLine', 'CVCL:1472', (199, 204))	('H3122', 'CellLine', 'CVCL:5160', (229, 234))	('H647', 'Var', (128, 132))	('HCC4011', 'CellLine', 'CVCL:S700', (141, 148))	('HCC44', 'CellLine', 'CVCL:2060', (72, 77))	('H226', 'Var', (122, 126))	('H3255', 'Var', (178, 183))	('H322', 'Var', (92, 96))	('H2122', 'CellLine', 'CVCL:1531', (52, 57))	('H460', 'Var', (86, 90))	('si', 'Chemical', 'MESH:D012825', (31, 33))	('H920', 'Var', (107, 111))	('H1395', 'Var', (185, 190))	('HCC2814', 'CellLine', 'CVCL:V586', (206, 213))	('H3255', 'CellLine', 'CVCL:6831', (178, 183))	('H2086', 'CellLine', 'CVCL:A524', (134, 139))	('H596', 'Var', (223, 227))	('A549', 'CellLine', 'CVCL:0023', (59, 63))	('H2073', 'Var', (192, 197))	('HCC515', 'CellLine', 'CVCL:5136', (215, 221))	('H226', 'CellLine', 'CVCL:J621', (122, 126))	('HCC2108', 'Var', (113, 120))	('HCC515', 'Var', (215, 221))	('HCC95', 'CellLine', 'CVCL:5137', (65, 70))	('HCC3051', 'CellLine', 'CVCL:V582', (169, 176))	('HCC2108', 'CellLine', 'CVCL:A352', (113, 120))
255050	29681454	After overnight adherence, media was removed and replaced with fresh media containing either 100 nM (SW027951, SW098382, SW126788, SW153609, SW157765, and SW159580) or 200 nM (SW103675, SW115205, and SW167255) compound.	('SW157765', 'Var', (141, 149))	('SW027951', 'Var', (101, 109))	('SW126788', 'CellLine', 'CVCL:R777', (121, 129))	('SW153609', 'Var', (131, 139))	('SW159580', 'Var', (155, 163))	('SW115205', 'Var', (186, 194))	('SW098382', 'Var', (111, 119))	('SW103675', 'Var', (176, 184))	('SW167255', 'Var', (200, 208))	('SW126788', 'Var', (121, 129))
255054	29681454	In experiments involving the compound SW153609, proteins were pre-cleared by addition of a two-fold volume of methanol containing 2 mM NH4 formate and 100 ng/mg of IS.	('NH4 formate', 'Chemical', '-', (135, 146))	('methanol', 'Chemical', 'MESH:D000432', (110, 118))	('SW153609', 'Var', (38, 46))	('proteins', 'Protein', (48, 56))
255057	29681454	Transitions utilized in positive mode were as follows: SW098382: 459.149/121.2; SW103675: 329.045/91.1; SW115205: 309.119/107.0; SW126788: 395.197/349.1; SW153609: 408.098/125.0; SW155765: 332.071/211.1; SW167255: 411.032/125.0; n-benzylbenzamide: 212.1/91.1.	('SW155765: 332.071/211.1', 'Var', (179, 202))	('SW153609: 408.098/125.0', 'Var', (154, 177))	('SW098382', 'Var', (55, 63))	('SW167255: 411.032/125.0', 'Var', (204, 227))	('SW126788', 'CellLine', 'CVCL:R777', (129, 137))	('si', 'Chemical', 'MESH:D012825', (26, 28))	('n-benzylbenzamide', 'Chemical', '-', (229, 246))	('SW103675', 'Var', (80, 88))	('si', 'Chemical', 'MESH:D012825', (4, 6))	('SW126788: 395.197/349.1', 'Var', (129, 152))
255058	29681454	Transitions utilized in negative mode were as follows: SW027951: 331.02/125.9; SW134963: 299.862/240.9; SW147739: 376.203/166.7; tolbutamide: 269.9/169.9.	('SW147739', 'Var', (104, 112))	('tolbutamide', 'Chemical', 'MESH:D014044', (129, 140))	('SW134963', 'Var', (79, 87))	('SW027951', 'Var', (55, 63))	('si', 'Chemical', 'MESH:D012825', (4, 6))
255060	29681454	Several compounds (SW134963, SW153609, and SW167255) showed such chemical instability with the amount of compound lost in media only by 24 hr equivalent to that lost in the presence of both sensitive and resistant cell lines.	('SW134963', 'Var', (19, 27))	('SW153609', 'Var', (29, 37))	('si', 'Chemical', 'MESH:D012825', (193, 195))	('chemical instability', 'MPA', (65, 85))	('si', 'Chemical', 'MESH:D012825', (206, 208))	('SW167255', 'Var', (43, 51))
255134	29681454	In addition to single mutations, we also annotated a 'RAS_Class' metaclass in which we assigned a cell line a value of '1' if it contained a mutation in either KRAS, NRAS, HRAS, PIK3C1, or BRAF.	('HRAS', 'Gene', '3265', (172, 176))	('BRAF', 'Gene', '673', (189, 193))	('NRAS', 'Gene', (166, 170))	('PIK3C1', 'Gene', '5291', (178, 184))	('HRAS', 'Gene', (172, 176))	('KRAS', 'Gene', (160, 164))	('NRAS', 'Gene', '4893', (166, 170))	('PIK3C1', 'Gene', (178, 184))	('si', 'Chemical', 'MESH:D012825', (15, 17))	('KRAS', 'Gene', '3845', (160, 164))	('si', 'Chemical', 'MESH:D012825', (89, 91))	('BRAF', 'Gene', (189, 193))	('mutation', 'Var', (141, 149))	('contained', 'Reg', (129, 138))
255135	29681454	For each chemical, we reasoned that if a mutation combination is conferring a selective sensitivity, then the ED50 or AUC values for cell lines that are mutated will be lower than those that are wild-type.	('mutated', 'Var', (153, 160))	('si', 'Chemical', 'MESH:D012825', (91, 93))	('mutation combination', 'Var', (41, 61))	('AUC values', 'MPA', (118, 128))	('ED50', 'MPA', (110, 114))	('lower', 'NegReg', (169, 174))
255158	29681454	The resulting p-value was determined to be:  Cell lines were dichotomized based on sensitivities to SW140154 and SW151511.	('SW151511', 'Var', (113, 121))	('SW140154', 'Var', (100, 108))	('si', 'Chemical', 'MESH:D012825', (86, 88))
255159	29681454	We selected cell lines that were sensitive (ED50 < 10 microM) to SW151511 and resistant to SW140154 (ED50 > 20 microM) and compared them to cells resistant to SW151511 (ED50 > 20 microM) and sensitive to SW140154 (ED50 < 10 microM) using a GSEA analysis.	('si', 'Chemical', 'MESH:D012825', (148, 150))	('SW151511', 'Var', (65, 73))	('si', 'Chemical', 'MESH:D012825', (36, 38))	('si', 'Chemical', 'MESH:D012825', (250, 252))	('SW151511', 'Var', (159, 167))	('si', 'Chemical', 'MESH:D012825', (194, 196))	('si', 'Chemical', 'MESH:D012825', (233, 235))	('si', 'Chemical', 'MESH:D012825', (80, 82))
255160	29681454	For SW036310, we compared sensitive (ED50 <2 microM), TTC21B mutant cell lines to resistant lines (ED50 > 40 microM) with a GSEA analysis.	('si', 'Chemical', 'MESH:D012825', (29, 31))	('TTC21B', 'Gene', (54, 60))	('si', 'Chemical', 'MESH:D012825', (84, 86))	('si', 'Chemical', 'MESH:D012825', (134, 136))	('SW036310', 'Chemical', '-', (4, 12))	('mutant', 'Var', (61, 67))
255166	29681454	Sensitivity to SW001286 and SW126788 was predicted based on RNAseq based expression of CYP4F11 and CES1/CES1P1, respectively.	('si', 'Chemical', 'MESH:D012825', (79, 81))	('CYP4F11', 'Gene', (87, 94))	('CES1', 'Gene', (99, 103))	('CES1P1', 'Gene', (104, 110))	('CES1', 'Gene', (104, 108))	('SW126788', 'Var', (28, 36))	('si', 'Chemical', 'MESH:D012825', (3, 5))	('CES1', 'Gene', '1066', (99, 103))	('CES1', 'Gene', '1066', (104, 108))	('SW126788', 'CellLine', 'CVCL:R777', (28, 36))	('CYP4F11', 'Gene', '57834', (87, 94))	('CES1P1', 'Gene', '51716', (104, 110))	('SW001286', 'Var', (15, 23))
255167	29681454	Sensitivity to SW151511 and SW140154 was predicted based on expression of PELI2 and SARM1/IL18R1.	('SW140154', 'Var', (28, 36))	('PELI2', 'Gene', (74, 79))	('IL18R1', 'Gene', '8809', (90, 96))	('IL18R1', 'Gene', (90, 96))	('PELI2', 'Gene', '57161', (74, 79))	('SARM1', 'Gene', '23098', (84, 89))	('si', 'Chemical', 'MESH:D012825', (3, 5))	('SARM1', 'Gene', (84, 89))	('si', 'Chemical', 'MESH:D012825', (66, 68))	('SW151511', 'Var', (15, 23))
255169	29681454	Cells predicted to be sensitive to SW151511 and resistant to SW140154 were confirmed to have high TLR pathway expression levels.	('TLR pathway', 'Pathway', (98, 109))	('si', 'Chemical', 'MESH:D012825', (116, 118))	('si', 'Chemical', 'MESH:D012825', (50, 52))	('SW151511', 'Var', (35, 43))	('expression levels', 'MPA', (110, 127))	('si', 'Chemical', 'MESH:D012825', (25, 27))	('SW140154', 'Var', (61, 69))
255180	29681454	RNAseq and illumina BeadChip features were further reduced by selecting features that were above a minimal expression cutoff in at least one cell line (RNAseq FPKM value of 1 and illumina BeadChip value of 6), resulting in 5075 and 5047 features, respectively.	('si', 'Chemical', 'MESH:D012825', (113, 115))	('5075', 'Var', (223, 227))	('5047', 'Var', (232, 236))
255184	29681454	Recent work has also annotated a non-small cell lung cancer specific set of genes that are upregulated in cells with gain of function mutations in the NRF2 pathway.	('upregulated', 'PosReg', (91, 102))	('NRF2', 'Gene', '4780', (151, 155))	('non-small cell lung cancer', 'Disease', (33, 59))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (37, 59))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('mutations', 'Var', (134, 143))	('lung cancer', 'Phenotype', 'HP:0100526', (48, 59))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (33, 59))	('gain of function', 'PosReg', (117, 133))	('NRF2', 'Gene', (151, 155))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (33, 59))
255186	29681454	SW157765 sensitive cell lines were defined to have an AUC < 400 and an ED50 value <1microM while resistant cells had an ED50 >30 microM.	('ED50 value', 'MPA', (71, 81))	('si', 'Chemical', 'MESH:D012825', (12, 14))	('AUC', 'MPA', (54, 57))	('si', 'Chemical', 'MESH:D012825', (99, 101))	('SW157765', 'Var', (0, 8))
255190	29681454	Using the 509 genes, we used a Pearson correlation to compare each tumor in the TCGA with each cell line in our dataset with the stats package in R. p-values for the correlation are plotted (Figure 1A, S1A) TCGA mutation data for the LUAD and LUSC subtypes was retrieved using the cgdsr package in R. Somatic mutations characterized as either 'missense' or 'nonsense' were plotted according to amino acid position.	('si', 'Chemical', 'MESH:D012825', (407, 409))	('si', 'Chemical', 'MESH:D012825', (272, 274))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('si', 'Chemical', 'MESH:D012825', (1, 3))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('LUSC', 'Phenotype', 'HP:0030359', (243, 247))	('tumor', 'Disease', (67, 72))	("'missense'", 'Var', (343, 353))	('LUAD', 'Phenotype', 'HP:0030078', (234, 238))
255194	29566644	The characteristics of ctDNA reveal the high complexity in matching the corresponding tumor tissues Next-generation sequencing (NGS) is an efficient and sensitive method to detect mutations from ctDNA.	('tumor', 'Disease', (86, 91))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('mutations', 'Var', (180, 189))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))
255199	29566644	Considering mutations detected from NGS of tumor tissues as golden standard, UC-Seq achieved overall 93.6% sensitivity for SNVs and Indels, and 0.8 Pearson correlation between tumor TMB and bTMB.	('Indels', 'Var', (132, 138))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('Indel', 'Chemical', '-', (132, 137))	('TMB', 'Chemical', '-', (182, 185))	('tumor', 'Disease', (176, 181))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('SNVs', 'Var', (123, 127))	('TMB', 'Chemical', '-', (191, 194))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('bTMB', 'Chemical', '-', (190, 194))	('tumor', 'Disease', (43, 48))	('tumor', 'Disease', 'MESH:D009369', (176, 181))
255201	29566644	About 84% mutations showed shorter mutant fragment length than that of wild-type fragments, and the AFs of mutations could be significantly enriched in small-size ctDNA.	('mutations', 'Var', (107, 116))	('shorter', 'NegReg', (27, 34))	('AF', 'Disease', 'MESH:D001281', (100, 102))	('mutant fragment length', 'MPA', (35, 57))	('mutations', 'Var', (10, 19))
255209	29566644	Targeted drugs usually target one or several DNA aberrations, which requires appropriate biopsies and technology to identify relevant biomarkers, including single nucleotide variations (SNVs), insertion and deletions (Indels), gene fusions, copy number variations (CNVs) and abnormal expressions.	('gene fusions', 'Var', (227, 239))	('Indel', 'Chemical', '-', (218, 223))	('abnormal expressions', 'Phenotype', 'HP:0100022', (275, 295))	('copy number variations', 'Var', (241, 263))	('abnormal expressions', 'MPA', (275, 295))	('single nucleotide variations', 'Var', (156, 184))
255212	29566644	ctDNAs from late-stage lung cancer generally have higher sensitivity (from 74% to 85%) to detect tissue-matched mutations than that from early stages (53.8%) by targeted next generation sequencing (NGS) in the past 2 years.	('higher', 'PosReg', (50, 56))	('lung cancer', 'Phenotype', 'HP:0100526', (23, 34))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('late-stage lung cancer', 'Disease', (12, 34))	('mutations', 'Var', (112, 121))	('late-stage lung cancer', 'Disease', 'MESH:D008175', (12, 34))
255213	29566644	Recently, AM Newman proposed a digital error suppression process with barcoding technique to further increase the sensitivity of mutation detection from ctDNA to 93%.	('digital error suppression', 'Disease', 'OMIM:146850', (31, 56))	('digital error suppression', 'Disease', (31, 56))	('mutation', 'Var', (129, 137))
255225	29566644	The CNVs of tumor tissues were calculated by BIC-seq2 with default parameters, and the CNVs of ctDNA samples were called by a method reported by Jacob J. Chabon et al.. All mutations were manually reviewed using IGV to further eliminate false-positive results.	('BIC', 'Chemical', 'MESH:C100119', (45, 48))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('mutations', 'Var', (173, 182))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('tumor', 'Disease', (12, 17))
255233	29566644	Both ctDNA and tumor tissues were sequenced by UC-Seq of a customized panel comprising 63 full-length targeted-therapy related genes, which could simultaneously detect single nucleotide variations (SNVs), small insertions and deletions (Indels), copy number variations (CNVs) and gene fusions.	('small insertions', 'Var', (205, 221))	('deletions', 'Var', (226, 235))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('copy number variations', 'Var', (246, 268))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('single nucleotide variations', 'Var', (168, 196))	('tumor', 'Disease', (15, 20))	('Indel', 'Chemical', '-', (237, 242))
255237	29566644	A total of 145 single nucleotide variations (SNVs), 34 short insertions/deletions (Indels), 2 fusions and 12 copy number gains whose gain ratios were larger than 3.5, were identified in tumor tissue samples.	('single nucleotide variations', 'Var', (15, 43))	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('tumor', 'Disease', (186, 191))	('Indel', 'Chemical', '-', (83, 88))
255238	29566644	The sensitivity of detecting those SNVs and Indels from tumor tissues in ctDNA significantly increases from 63.5% to 83.2% (p value < 0.01) (Additional file 1: Figure S1A) from non-barcoding technique to barcoding technique.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('SNVs', 'Var', (35, 39))	('tumor', 'Disease', (56, 61))	('Indel', 'Chemical', '-', (44, 49))	('increases', 'PosReg', (93, 102))	('Indels', 'Var', (44, 50))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
255242	29566644	The AFs of SNVs and Indels in ctDNA didn't have strong correlation with those in tumor tissues (Fig.	('SNVs', 'Var', (11, 15))	('AF', 'Disease', 'MESH:D001281', (4, 6))	('Indel', 'Chemical', '-', (20, 25))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('Indels', 'Var', (20, 26))	('ctDNA', 'Gene', (30, 35))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Disease', (81, 86))
255243	29566644	The sensitivity of tumor-matched mutation detection in ctDNA was affected by their mutant AFs in the tissues (Fig.	('mutant', 'Var', (83, 89))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('AF', 'Disease', 'MESH:D001281', (90, 92))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('affected', 'Reg', (65, 73))	('tumor', 'Disease', (19, 24))
255246	29566644	We found that ctDNA from lung squamous cell carcinoma showed slightly higher sensitivity (95.5%) to detect tumor-matched mutations than that from lung adenocarcinoma (91.7%), but it was not statistically significant (p-value = 1.0).	('carcinoma', 'Phenotype', 'HP:0030731', (156, 165))	('mutations', 'Var', (121, 130))	('tumor', 'Disease', (107, 112))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (25, 53))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('lung adenocarcinoma', 'Disease', (146, 165))	('lung squamous cell carcinoma', 'Disease', (25, 53))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (25, 53))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (146, 165))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (30, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (44, 53))	('higher', 'PosReg', (70, 76))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (146, 165))
255247	29566644	Mutations detected in ctDNA had slightly higher concordance with the tumor tissues from metastatic sites (98.1%) than those from primary sites (91.3%) without significant p-value (0.17).	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor', 'Disease', (69, 74))	('Mutations', 'Var', (0, 9))	('higher', 'PosReg', (41, 47))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
255248	29566644	And ctDNA had slightly better sensitivity (93.7%) to detect tumor-matched mutations in IIIB patients than that in IV patients (93.3%) without significant p-value (1.00).	('mutations', 'Var', (74, 83))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('patients', 'Species', '9606', (92, 100))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('IIIB', 'Disease', (87, 91))	('patients', 'Species', '9606', (117, 125))	('tumor', 'Disease', (60, 65))
255249	29566644	The receiver operating characteristic (ROC) curve whose area under curve (AUC) was 0.94, indicated an exceptional overall prediction power of tumor-matched mutations detected in ctDNA (Fig.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('mutations', 'Var', (156, 165))	('tumor', 'Disease', (142, 147))	('ctDNA', 'Disease', (178, 183))	('tumor', 'Disease', 'MESH:D009369', (142, 147))
255251	29566644	The detection of EGFR hotspots (L858R and exon 19 deletion) can reached over 90% sensitivity and 100% specificity.	('EGFR', 'Gene', (17, 21))	('exon 19 deletion', 'Var', (42, 58))	('EGFR', 'Gene', '1956', (17, 21))	('L858R', 'Var', (32, 37))	('L858R', 'Mutation', 'rs121434568', (32, 37))
255253	29566644	From the results above, SNVs and Indels detected from ctDNA by UC-Seq are highly concordant with its corresponding tumor tissues.	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('Indel', 'Chemical', '-', (33, 38))	('Indels', 'Var', (33, 39))	('tumor', 'Disease', (115, 120))	('ctDNA', 'Gene', (54, 59))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
255254	29566644	We used the maximum mutant AF of somatic mutations in a sample to approximate the proportions of ctDNAs in cfDNAs, and the result showed that the copy gain events from tumors can be effectively detected at high copy gain ratios or at high proportions of ctDNAs in cfDNAs.	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('copy', 'MPA', (146, 150))	('tumors', 'Disease', 'MESH:D009369', (168, 174))	('tumors', 'Disease', (168, 174))	('AF', 'Disease', 'MESH:D001281', (27, 29))	('mutant', 'Var', (20, 26))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
255265	29566644	As the data showed in the previous session, the cutoff of mutant AFs in tumor tissues was set to larger or equal to 5%.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('mutant', 'Var', (58, 64))	('tumor', 'Disease', (72, 77))	('AF', 'Disease', 'MESH:D001281', (65, 67))	('tumor', 'Disease', 'MESH:D009369', (72, 77))
255266	29566644	We took different cutoffs of mutant AFs in ctDNA and plot a curve on their Pearson correlations of TMB with tumor tissues (Fig.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('mutant', 'Var', (29, 35))	('tumor', 'Disease', (108, 113))	('AF', 'Disease', 'MESH:D001281', (36, 38))	('TMB', 'Chemical', '-', (99, 102))
255271	29566644	Besides the standard group of samples, we also collected 75 samples with various clinical conditions and compared their concordance of SNVs and Indels whose AFs were higher than 5% in tumor tissues between ctDNA and tumor tissues.	('tumor', 'Disease', (216, 221))	('AF', 'Disease', 'MESH:D001281', (157, 159))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('SNVs', 'Var', (135, 139))	('Indels', 'Var', (144, 150))	('tumor', 'Disease', (184, 189))	('tumor', 'Disease', 'MESH:D009369', (216, 221))	('Indel', 'Chemical', '-', (144, 149))	('clinical', 'Species', '191496', (81, 89))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))
255283	29566644	Though there were only three IIIB patients in this category, all mutations from tumor tissues could be detected in ctDNA.	('ctDNA', 'Disease', (115, 120))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('detected', 'Reg', (103, 111))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumor', 'Disease', (80, 85))	('patients', 'Species', '9606', (34, 42))	('mutations', 'Var', (65, 74))
255288	29566644	However, considering mutations detected in the paired tumor tissues as golden standard, ctDNA samples from the patients with high cfDNA concentrations showed better sensitivity to detect tumor-matched mutations than those from the patients with low cfDNA concentrations (p-value < 0.01) (Fig.	('mutations', 'Var', (201, 210))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('patients', 'Species', '9606', (231, 239))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor', 'Disease', (187, 192))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumor', 'Disease', (54, 59))	('patients', 'Species', '9606', (111, 119))
255289	29566644	Besides, the AFs of tumor-matched mutations in cfDNA samples with high concentrations (> = 30 ng/ml) were significantly higher than those in cfDNA samples with low concentrations (< 9 ng/ml) (p < 0.01) (Fig.	('AF', 'Disease', 'MESH:D001281', (13, 15))	('higher', 'PosReg', (120, 126))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('mutations', 'Var', (34, 43))	('tumor', 'Disease', (20, 25))
255294	29566644	Moreover, we respectively performed Gaussian smoothing to the mutant and wild-type fragments of each SNV and Indel, whose numbers of mutant fragments were larger than 20, and identified their peak lengths where the maximum probability densities were achieved (Fig.	('mutant', 'Var', (62, 68))	('Indel', 'Chemical', '-', (109, 114))	('SNV', 'Gene', (101, 104))	('mutant', 'Var', (133, 139))	('Indel', 'Gene', (109, 114))
255298	29566644	UC-Seq significantly improves the sensitivity of ctDNA detection on SNVs and Indels.	('sensitivity', 'MPA', (34, 45))	('ctDNA', 'Disease', (49, 54))	('Indel', 'Chemical', '-', (77, 82))	('Indels', 'Var', (77, 83))	('SNVs', 'Var', (68, 72))	('improves', 'PosReg', (21, 29))
255300	29566644	However, the AFs of tumor-matched mutations in ctDNAs are affected by many variables and are poorly correlated with their AFs in tumor tissues.	('AF', 'Disease', 'MESH:D001281', (13, 15))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('affected', 'Reg', (58, 66))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('AF', 'Disease', 'MESH:D001281', (122, 124))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('tumor', 'Disease', (129, 134))	('ctDNAs', 'Gene', (47, 53))	('mutations', 'Var', (34, 43))	('tumor', 'Disease', (20, 25))
255301	29566644	Since tumors are usually heterogenic, mutations with low AFs may come from minor sub-clones, and these mutations might thus drop below the detection limit in ctDNA.	('drop', 'NegReg', (124, 128))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('tumors', 'Disease', (6, 12))	('mutations', 'Var', (38, 47))	('AF', 'Disease', 'MESH:D001281', (57, 59))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))
255302	29566644	Usually the cutoff of AFs for actionable mutations in tumor tissues is practically set between 5% to 10%.	('mutations', 'Var', (41, 50))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('AF', 'Disease', 'MESH:D001281', (22, 24))	('tumor', 'Disease', (54, 59))
255303	29566644	In addition, the patients, whose tumor sequencing showed the L858R mutation with AFs over 9%, were more sensitive to EGFR-TKIs than those whose AFs were below.	('AF', 'Disease', 'MESH:D001281', (81, 83))	('AF', 'Disease', 'MESH:D001281', (144, 146))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('EGFR', 'Gene', '1956', (117, 121))	('L858R', 'Mutation', 'rs121434568', (61, 66))	('EGFR', 'Gene', (117, 121))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('patients', 'Species', '9606', (17, 25))	('tumor', 'Disease', (33, 38))	('sensitive', 'MPA', (104, 113))	('L858R', 'Var', (61, 66))
255305	29566644	Hence the sensitivity of UC-Seq at a depth of 10,000x is sufficient to detect the actionable mutations for late-stage lung cancer patients.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('late-stage lung cancer', 'Disease', 'MESH:D008175', (107, 129))	('mutations', 'Var', (93, 102))	('patients', 'Species', '9606', (130, 138))	('lung cancer', 'Phenotype', 'HP:0100526', (118, 129))	('late-stage lung cancer', 'Disease', (107, 129))
255308	29566644	The detection of copy number variations is determined by the ratios of gene copy numbers in tumor and the ctDNA proportions in cfDNA.	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('copy number variations', 'Var', (17, 39))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Disease', (92, 97))
255319	29566644	Since the tissue samples contained only part of the clones of tumors while ctDNA could theoretically detect the mutations from all clones as long as their DNAs are released to the blood stream.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumors', 'Disease', (62, 68))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('tumors', 'Disease', 'MESH:D009369', (62, 68))	('mutations', 'Var', (112, 121))
255333	29566644	In both cases of low concordance, the status of tumors may dynamically change.	('tumors', 'Disease', 'MESH:D009369', (48, 54))	('tumors', 'Disease', (48, 54))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('low concordance', 'Var', (17, 32))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
255337	29566644	Moreover, the mutant AFs in ctDNA samples with high concentrations are generally higher (Fig.	('mutant', 'Var', (14, 20))	('AF', 'Disease', 'MESH:D001281', (21, 23))	('higher', 'PosReg', (81, 87))
255341	29566644	Besides, the advanced NSCLC patients with low cfDNA concentrations have better overall survival than those with high cfDNA concentrations.	('NSCLC', 'Phenotype', 'HP:0030358', (22, 27))	('overall', 'MPA', (79, 86))	('better', 'PosReg', (72, 78))	('low', 'Var', (42, 45))	('NSCLC', 'Disease', (22, 27))	('patients', 'Species', '9606', (28, 36))	('NSCLC', 'Disease', 'MESH:D002289', (22, 27))
255345	29566644	Two studies have reported that the mutant fragments from tumors were generally shorter than those of wild-type fragments.	('shorter', 'NegReg', (79, 86))	('mutant', 'Var', (35, 41))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('tumors', 'Disease', (57, 63))	('tumors', 'Disease', 'MESH:D009369', (57, 63))
255348	29566644	86% of SNVs and Indels had higher mutant AFs in small fragments (< 145 nt), including important actionable mutations such as L858R and exon 19 deletion in EGFR.	('Indel', 'Chemical', '-', (16, 21))	('EGFR', 'Gene', '1956', (155, 159))	('AF', 'Disease', 'MESH:D001281', (41, 43))	('EGFR', 'Gene', (155, 159))	('L858R', 'Var', (125, 130))	('higher', 'PosReg', (27, 33))	('exon 19 deletion', 'Var', (135, 151))	('L858R', 'Mutation', 'rs121434568', (125, 130))	('mutant', 'Var', (34, 40))
255349	29566644	However, the shortening effect of mutant fragments from tumors is likely to be gene-specific or even position-specific.	('shortening', 'NegReg', (13, 23))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumors', 'Disease', (56, 62))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('mutant', 'Var', (34, 40))
255350	29566644	The length distribution of mutant fragments from tumors might be affected by the DNA accessibility of the loci in the tumor tissues.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('mutant', 'Var', (27, 33))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('tumor', 'Disease', (49, 54))	('tumor', 'Disease', (118, 123))	('tumors', 'Disease', (49, 55))	('affected', 'Reg', (65, 73))	('tumors', 'Disease', 'MESH:D009369', (49, 55))	('length', 'MPA', (4, 10))
255351	29566644	The shortening extent of mutant fragments from tumors might reflect the transcriptional activity of genes in the tumors, especially in a panel that genes are selected from known drug targets and cancer drivers.	('tumors', 'Disease', (47, 53))	('mutant', 'Var', (25, 31))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('tumors', 'Disease', (113, 119))	('cancer', 'Disease', (195, 201))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
255352	29566644	This finding offers a plausible way to further increase the sensitivity of detecting mutations in ctDNA, and also a theoretical guide for deducing the expressions of genes in tumors.	('tumors', 'Disease', (175, 181))	('tumors', 'Disease', 'MESH:D009369', (175, 181))	('tumors', 'Phenotype', 'HP:0002664', (175, 181))	('deducing', 'NegReg', (138, 146))	('expressions', 'MPA', (151, 162))	('ctDNA', 'Gene', (98, 103))	('mutations', 'Var', (85, 94))	('increase', 'PosReg', (47, 55))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))
255354	29566644	Considering tumor tissues as golden standard of mutation detection, our UC-seq method achieved overall 93.6% sensitivity for SNVs and Indels, and 0.8 Pearson correlation between tumor TMB and bTMB.	('SNVs', 'Var', (125, 129))	('bTMB', 'Chemical', '-', (192, 196))	('tumor', 'Disease', (178, 183))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('Indel', 'Chemical', '-', (134, 139))	('TMB', 'Chemical', '-', (193, 196))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('Indels', 'Var', (134, 140))	('TMB', 'Chemical', '-', (184, 187))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('tumor', 'Disease', (12, 17))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))
255369	32158698	For SqCLC, the EGFR gene mutation rate is <4% and the rearrangement rate of the ALK gene is <3%.	('mutation', 'Var', (25, 33))	('ALK', 'Gene', '238', (80, 83))	('EGFR', 'Gene', '1956', (15, 19))	('SqCLC', 'Disease', (4, 9))	('EGFR', 'Gene', (15, 19))	('SqCLC', 'Disease', 'MESH:D018307', (4, 9))	('SqCLC', 'Phenotype', 'HP:0030359', (4, 9))	('ALK', 'Gene', (80, 83))
255381	32158698	High hTERT expression is associated with advanced stages and unfavorable prognoses in different types of malignancies.	('malignancies', 'Disease', (105, 117))	('High', 'Var', (0, 4))	('associated', 'Reg', (25, 35))	('hTERT', 'Gene', '7015', (5, 10))	('hTERT', 'Gene', (5, 10))	('malignancies', 'Disease', 'MESH:D009369', (105, 117))
255384	32158698	We showed that the modified adenovirus has a significant killing effect on several tumor cells.	('adenovirus', 'Protein', (28, 38))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumor', 'Disease', (83, 88))	('modified', 'Var', (19, 27))	('killing effect', 'CPA', (57, 71))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
255436	32158698	We found that Ad-VP3, Ad-T, and Ad-VT could significantly inhibit the proliferation of NCI-H226 cells when compared with Ad-Mock and in a time and dose dependent manner.	('NCI-H226', 'CellLine', 'CVCL:1544', (87, 95))	('proliferation', 'CPA', (70, 83))	('Ad-VP3', 'Var', (14, 20))	('inhibit', 'NegReg', (58, 65))	('Ad-T', 'Var', (22, 26))	('VT', 'Disease', 'MESH:D017180', (35, 37))
255437	32158698	The strongest inhibitory effect was mediated by Ad-VT, followed by Ad-T and Ad-VP3 (Figures 1A-C).	('inhibitory effect', 'MPA', (14, 31))	('VT', 'Disease', 'MESH:D017180', (51, 53))	('Ad-VP3', 'Var', (76, 82))
255439	32158698	At 10 MOI, Ad-VP3, Ad-T and Ad-VT increased the inhibition ratio of NCI-H226 proliferation with time.	('inhibition', 'NegReg', (48, 58))	('NCI-H226', 'Gene', (68, 76))	('VT increased', 'Phenotype', 'HP:0008151', (31, 43))	('Ad-VP3', 'Var', (11, 17))	('Ad-T', 'Var', (19, 23))	('NCI-H226', 'CellLine', 'CVCL:1544', (68, 76))	('increased', 'PosReg', (34, 43))	('VT', 'Disease', 'MESH:D017180', (31, 33))
255441	32158698	At 100 MOI, the inhibitory effect of Ad-VP3, Ad-T, and Ad-VT on NCI-H226 cells significantly increased with time (P < 0.05).	('Ad-T', 'Var', (45, 49))	('increased', 'PosReg', (93, 102))	('inhibitory effect', 'MPA', (16, 33))	('NCI-H226', 'CellLine', 'CVCL:1544', (64, 72))	('VT', 'Disease', 'MESH:D017180', (58, 60))	('Ad-VP3', 'Var', (37, 43))
255442	32158698	In the process of infection, the inhibition rate of Ad-VT, Ad-T, and Ad-VP3 on cells, reached the maximum at 72 h with 69.69, 57.91, and 30.16%, respectively (p < 0.01) (Figure 1D).	('VT', 'Disease', 'MESH:D017180', (55, 57))	('inhibition', 'NegReg', (33, 43))	('infection', 'Disease', (18, 27))	('Ad-VP3', 'Var', (69, 75))	('infection', 'Disease', 'MESH:D007239', (18, 27))
255443	32158698	The above results suggested that recombinant adenovirus Ad-VP3, Ad-T, and Ad-VT showed different degrees of inhibition on NCI-H226 cells and in a time and dose dependence fashion.	('inhibition', 'NegReg', (108, 118))	('VT', 'Disease', 'MESH:D017180', (77, 79))	('Ad-VP3', 'Var', (56, 62))	('NCI-H226', 'CellLine', 'CVCL:1544', (122, 130))	('Ad-T', 'Var', (64, 68))
255466	32158698	Above all, the combination of gemcitabine and Ad-VT 5 nM + 5 MOI, 10 nM + 10 MOI, and 15 nM + 15 MOI had synergistic inhibitory effects (CI < 1) at 72 h post-treatments, with inhibition rates of 50.09, 75.38, and 82.34%, respectively.	('5 nM + 5 MOI', 'Var', (52, 64))	('gemcitabine', 'Chemical', 'MESH:C056507', (30, 41))	('10 nM + 10 MOI', 'Var', (66, 80))	('VT', 'Disease', 'MESH:D017180', (49, 51))
255522	32158698	It was reported that dl922-947 (an oncolytic adenovirus with a 24-bp deletion in E1A CR2) and low-dose paclitaxel induce aberrant, multipolar mitoses, mitotic slippage and multinucleation, triggering an apoptotic cell death.	('multipolar mitoses', 'CPA', (131, 149))	('paclitaxel', 'Chemical', 'MESH:D017239', (103, 113))	('multinucleation', 'CPA', (172, 187))	('aberrant', 'CPA', (121, 129))	('mitotic slippage', 'CPA', (151, 167))	('triggering', 'Reg', (189, 199))	('induce', 'Reg', (114, 120))	('E1A CR2', 'Gene', (81, 88))	('deletion', 'Var', (69, 77))
255524	32158698	We observed that although Ad-VP3 does not have the ability to self-replicate in tumor cells, the apoptin protein expression by Ad-VP3 plays an important role in tumor suppression.	('expression', 'MPA', (113, 123))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('apoptin', 'Gene', '1494446', (97, 104))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('Ad-VP3', 'Var', (127, 133))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('tumor', 'Disease', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('tumor', 'Disease', (161, 166))	('apoptin', 'Gene', (97, 104))
255558	30216655	Recent studies have reported that the genetic alteration of some lncRNAs conferred a selective growth advantage to the cancer cells in which it occurs, playing an important role in the initiation and progression of cancer (Schmitt and Chang, 2016; Yan et al., 2015).	('cancer', 'Disease', (215, 221))	('cancer', 'Disease', 'MESH:D009369', (215, 221))	('growth advantage', 'CPA', (95, 111))	('genetic alteration', 'Var', (38, 56))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('cancer', 'Disease', (119, 125))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
255563	30216655	Therefore, comprehensive identification of genetically altered driver lncRNAs across distinct tumor types is not only urgently needed, but also may promote new diagnostic and therapeutic strategies for cancer (Yan et al., 2015).	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('genetically', 'Var', (43, 54))	('tumor', 'Disease', (94, 99))	('cancer', 'Disease', 'MESH:D009369', (202, 208))	('cancer', 'Disease', (202, 208))	('promote', 'PosReg', (148, 155))
255565	30216655	Some passenger lncRNAs also show random or hitchhiking somatic mutations, which can confound the analysis of cancer drivers (Garraway and Lander, 2013; Marx, 2014; Pon and Marra, 2015).	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('hitchhiking', 'Var', (43, 54))	('Pon', 'Gene', (164, 167))	('cancer', 'Disease', (109, 115))	('Pon', 'Gene', '5444', (164, 167))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))
255568	30216655	Interestingly, such genetically altered lncRNAs were found to be mutually exclusive with well-known cancer driver genes.	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('genetically altered', 'Var', (20, 39))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))
255578	30216655	Next, we screened for PCGs/lncRNAs whose copy number significantly affected their expression levels using a one-tailed Wilcoxon signed rank test with P < 0.05.	('expression levels', 'MPA', (82, 99))	('PCGs', 'Chemical', 'MESH:D010400', (22, 26))	('affected', 'Reg', (67, 75))	('copy number', 'Var', (41, 52))
255579	30216655	On average, 231 lncRNAs and 1425 PCGs per cancer type were found to be altered (with amplifications or deletions) (Table S2).	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('altered', 'Reg', (71, 78))	('deletions', 'Var', (103, 112))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('PCGs', 'Chemical', 'MESH:D010400', (33, 37))
255602	30216655	In detail, for each cancer type, only copy number affected PCGs that were recorded in the known driver PCG category downloaded from Cancer Gene Census (CGC) (Futreal et al., 2004) were regarded as driver PCGs according to the following criteria: (i) the copy number alteration of drivers occurred in more than 2.5% of samples; (ii) the copy number alteration showed detectable RNA expression (RPKM > 0.3 in at least 30% of the samples); and (iii) the copy number alteration significantly affected RNA expression levels by one-tailed Wilcoxon signed rank test with P < 0.05.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('PCG', 'Chemical', '-', (204, 207))	('PCGs', 'Chemical', 'MESH:D010400', (204, 208))	('PCGs', 'Chemical', 'MESH:D010400', (59, 63))	('copy number alteration', 'Var', (451, 473))	('cancer', 'Disease', 'MESH:D009369', (20, 26))	('affected', 'Reg', (488, 496))	('cancer', 'Disease', (20, 26))	('RNA expression levels', 'MPA', (497, 518))	('PCG', 'Chemical', '-', (59, 62))	('PCG', 'Chemical', '-', (103, 106))	('Cancer', 'Phenotype', 'HP:0002664', (132, 138))	('Cancer', 'Disease', (132, 138))	('copy number alteration', 'Var', (336, 358))	('RNA expression', 'MPA', (377, 391))	('Cancer', 'Disease', 'MESH:D009369', (132, 138))
255624	30216655	Patients were stratified based on continuous copy number alteration or expression above or below the median.	('expression', 'MPA', (71, 81))	('continuous copy number alteration', 'Var', (34, 67))	('Patients', 'Species', '9606', (0, 8))
255632	30216655	(ii) lncRNAs were amplified in corresponding cells at log2 ratio > 0 (i.e., A549 for LUAD and MCF-7 for BRCA).	('BRCA', 'Gene', '672', (104, 108))	('BRCA', 'Gene', (104, 108))	('A549', 'CellLine', 'CVCL:0023', (76, 80))	('MCF-7', 'CellLine', 'CVCL:0031', (94, 99))	('A549', 'Var', (76, 80))	('LUAD', 'Phenotype', 'HP:0030078', (85, 89))	('BRCA', 'Phenotype', 'HP:0003002', (104, 108))
255633	30216655	Here, copy number alterations of lncRNAs in cell lines were obtained from the Cancer Cell Line Encyclopedia (Barretina et al., 2012) (https://portals.broadinstitute.org/ccle/home).	('Cancer Cell Line Encyclopedia', 'Disease', (78, 107))	('Cancer Cell Line Encyclopedia', 'Disease', 'MESH:C538614', (78, 107))	('copy number alterations', 'Var', (6, 29))	('Cancer', 'Phenotype', 'HP:0002664', (78, 84))
255647	30216655	Copy number alterations affected a large fraction of cancer genomes, activating oncogenes and inactivating tumor suppressors, and consequently contributed to tumorigenesis.	('inactivating', 'NegReg', (94, 106))	('tumor', 'Disease', (158, 163))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('cancer', 'Disease', (53, 59))	('oncogenes', 'Protein', (80, 89))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('Copy number alterations', 'Var', (0, 23))	('activating', 'PosReg', (69, 79))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('affected', 'Reg', (24, 32))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('contributed to', 'Reg', (143, 157))
255650	30216655	An average of 3080 lncRNAs (and 4038 PCGs) per cancer type showed copy number alterations.	('PCGs', 'Chemical', 'MESH:D010400', (37, 41))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('copy number alterations', 'Var', (66, 89))	('cancer', 'Disease', (47, 53))	('showed', 'Reg', (59, 65))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))
255659	30216655	1D), implying that copy number alteration was a potent contributor to lncRNA dysregulation in cancer.	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('cancer', 'Disease', (94, 100))	('copy number alteration', 'Var', (19, 41))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
255660	30216655	For example, lncRNA RP11-745C15.2 was amplified in 39.1% of samples in GBM, resulting in an almost 50-fold increase in the expression compared to wild-type (Fig.	('RP11', 'Gene', '26121', (20, 24))	('expression', 'MPA', (123, 133))	('increase', 'PosReg', (107, 115))	('lncRNA', 'Var', (13, 19))	('RP11', 'Gene', (20, 24))
255689	30216655	Although CRISPRd identified functional lncRNAs in the liver cancer cell line Huh7.5OC, we only found two candidates identified in our results (amplification of lncRNA LINC00885 and AC084809.2 in HNSC and BRCA, respectively; P = 0.30, hypergeometric test), which may be a result of the tissue specificity of lncRNAs.	('LINC00885', 'Gene', '401109', (167, 176))	('LINC00885', 'Gene', (167, 176))	('BRCA', 'Phenotype', 'HP:0003002', (204, 208))	('AC084809.2', 'Var', (181, 191))	('Huh7.5OC', 'CellLine', 'CVCL:7927', (77, 85))	('HNSC', 'Phenotype', 'HP:0012288', (195, 199))	('BRCA', 'Gene', '672', (204, 208))	('liver cancer', 'Phenotype', 'HP:0002896', (54, 66))	('liver cancer', 'Disease', 'MESH:D006528', (54, 66))	('BRCA', 'Gene', (204, 208))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('liver cancer', 'Disease', (54, 66))
255691	30216655	For example, deletion of lncRNA ANRIL and CDK4 constituted a mutually exclusive module associated with the hallmark 'Self Sufficiency in Growth Signals' in GBM (Fig.	('CDK4', 'Gene', '1019', (42, 46))	('lncRNA', 'Gene', (25, 31))	("hallmark 'Self Sufficiency", 'Disease', (107, 133))	('ANRIL', 'Gene', (32, 37))	('associated', 'Reg', (87, 97))	('deletion', 'Var', (13, 21))	('Sufficiency in Growth', 'Phenotype', 'HP:0001510', (122, 143))	("hallmark 'Self Sufficiency", 'Disease', 'MESH:D012652', (107, 133))	('ANRIL', 'Gene', '100048912', (32, 37))	('CDK4', 'Gene', (42, 46))
255696	30216655	The inactivation of NORAD was sufficient to produce a chromosomal instability phenotype (Lee et al., 2016).	('inactivation', 'Var', (4, 16))	('produce', 'Reg', (44, 51))	('chromosomal instability phenotype', 'MPA', (54, 87))	('NORAD', 'Gene', '647979', (20, 25))	('chromosomal instability', 'Phenotype', 'HP:0040012', (54, 77))	('NORAD', 'Gene', (20, 25))
255697	30216655	In LUSC, deletion of lncRNA MIR31HG was identified to form a mutually exclusive module affecting hallmark 'Genome Instability and Mutation' (Fig.	("Mutation'", 'MPA', (130, 139))	('deletion', 'Var', (9, 17))	("'Genome Instability", 'MPA', (106, 125))	('affecting', 'Reg', (87, 96))	('MIR31HG', 'Gene', (28, 35))	('MIR31HG', 'Gene', '554202', (28, 35))	('LUSC', 'Phenotype', 'HP:0030359', (3, 7))
255704	30216655	Similarly, these lncRNAs and cancer driver PCGs were both significantly enriched in sensitive/ultra-sensitive regions, which exhibit depletion of common polymorphisms and strong enrichment in disease-causing mutations (Khurana et al., 2013) (P < 0.001, hypergeometric test) (Fig.	('PCGs', 'Chemical', 'MESH:D010400', (43, 47))	('cancer', 'Disease', (29, 35))	('mutations', 'Var', (208, 217))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('disease-causing', 'Reg', (192, 207))	('cancer', 'Disease', 'MESH:D009369', (29, 35))
255722	30216655	For example, in GBM, amplification of RP11-745C15.2 and deletion of CDKN2B-AS1 were both associated with the hallmark pathway of 'ceramide biosynthetic process', which was reported to promote apoptosis in glioblastoma (Sordillo et al., 2016), whereas, in PRAD, deletion of lncRNA AC003102.3, RGMB-AS1, and DLG5-AS1 was all related to the hallmark pathway of 'Urogenital System Development', during which the dysfunction in cell lineage specification predisposed prostate epithelia to hyperplasia and cancer (Brechka et al., 2016).	('deletion', 'Var', (56, 64))	('associated', 'Reg', (89, 99))	('glioblastoma', 'Phenotype', 'HP:0012174', (205, 217))	('RGMB-AS1', 'Gene', '503569', (292, 300))	('RP11', 'Gene', '26121', (38, 42))	('prostate epithelia to hyperplasia and cancer', 'Disease', 'MESH:D011470', (462, 506))	('CDKN2B-AS1', 'Gene', '100048912', (68, 78))	('cancer', 'Phenotype', 'HP:0002664', (500, 506))	('glioblastoma', 'Disease', (205, 217))	('CDKN2B-AS1', 'Gene', (68, 78))	('RGMB-AS1', 'Gene', (292, 300))	('DLG5-AS1', 'Gene', '100128292;9231;5729', (306, 314))	('RP11', 'Gene', (38, 42))	('amplification', 'Var', (21, 34))	('DLG5-AS1', 'Gene', (306, 314))	('glioblastoma', 'Disease', 'MESH:D005909', (205, 217))	("'Urogenital System", 'Phenotype', 'HP:0000119', (358, 376))	('promote', 'PosReg', (184, 191))
255729	30216655	6E,F) and deregulation of CCNE1 expression led to genomic instability via mitotic delay (Caldon et al., 2013).	('mitotic delay', 'CPA', (74, 87))	('CCNE1', 'Gene', '898', (26, 31))	('deregulation', 'Var', (10, 22))	('CCNE1', 'Gene', (26, 31))	('genomic instability', 'CPA', (50, 69))	('led to', 'Reg', (43, 49))
255736	30216655	Specifically, in LGG, amplification of candidate driver lncRNA AC000123.4 conferred a poor prognosis to patients with glioma (P < 0.001 for DFS, log-rank test) (Fig.	('glioma', 'Disease', (118, 124))	('amplification', 'Var', (22, 35))	('glioma', 'Disease', 'MESH:D005910', (118, 124))	('glioma', 'Phenotype', 'HP:0009733', (118, 124))	('AC000123.4', 'Gene', (63, 73))	('patients', 'Species', '9606', (104, 112))	('poor', 'NegReg', (86, 90))
255737	30216655	The median recurrence-free interval of AC000123.4 amplification patients was 39.6 months [95% confidence interval (CI) = 35.6-63.8], whereas that of AC000123.4 diploid patients was 68.9 months (95% CI = 44.5-100.9).	('AC000123.4 amplification', 'Var', (39, 63))	('amplification', 'Var', (50, 63))	('patients', 'Species', '9606', (168, 176))	('patients', 'Species', '9606', (64, 72))
255738	30216655	Multivariate Cox proportional hazards models further showed that AC000123.4 amplification had a poor effect on DFS (hazard ratio (HR), 1.99, 95% CI = 1.38-2.88) (Table S7) independent of the patient's age, gender and pathologic stages.	('AC000123.4 amplification', 'Var', (65, 89))	('Cox', 'Gene', (13, 16))	('DFS', 'Disease', (111, 114))	('patient', 'Species', '9606', (191, 198))	('Cox', 'Gene', '1351', (13, 16))
255739	30216655	Moreover, its expression was significantly up-regulated in tumors with AC000123.4 amplification (P = 0.002, Student's t test) (Fig.	('AC000123.4 amplification', 'Var', (71, 95))	('expression', 'MPA', (14, 24))	('tumors', 'Disease', (59, 65))	('tumors', 'Disease', 'MESH:D009369', (59, 65))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('up-regulated', 'PosReg', (43, 55))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
255740	30216655	Likewise, we observed that up-expression of AC000123.4 in LGG was also significantly associated with decreased survival in patients (P < 0.001 for DFS, log-rank test) (Fig.	('AC000123.4', 'Var', (44, 54))	('survival', 'MPA', (111, 119))	('up-expression', 'PosReg', (27, 40))	('patients', 'Species', '9606', (123, 131))	('decreased', 'NegReg', (101, 110))
255743	30216655	Activated EGFR increased the production of tumor-derived VEGF that acts on endothelial cells in a paracrine manner to promote angiogenesis (Larsen et al., 2011) and amplification of EGFR also indicated poor prognosis in glioma (Sun et al., 2014) (Fig.	('EGFR', 'Gene', '1956', (10, 14))	('promote', 'PosReg', (118, 125))	('EGFR', 'Gene', '1956', (182, 186))	('EGFR', 'Gene', (182, 186))	('production', 'MPA', (29, 39))	('EGFR', 'Gene', (10, 14))	('glioma', 'Disease', 'MESH:D005910', (220, 226))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('glioma', 'Phenotype', 'HP:0009733', (220, 226))	('angiogenesis', 'CPA', (126, 138))	('amplification', 'Var', (165, 178))	('VEGF', 'Gene', (57, 61))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Disease', (43, 48))	('glioma', 'Disease', (220, 226))	('VEGF', 'Gene', '7422', (57, 61))
255744	30216655	Interestingly, in EGFR wild-type samples, amplification of AC000123.4 is associated with a worse prognosis (DFS: HR = 1.86, 95% CI = 1.26-2.76, P = 0.0018) (Fig.	('amplification', 'Var', (42, 55))	('EGFR', 'Gene', '1956', (18, 22))	('AC000123.4', 'Gene', (59, 69))	('EGFR', 'Gene', (18, 22))
255746	30216655	The median recurrence-free interval of AC000123.4 amplification patients without EGFR amplification was 42.9 months (95% CI = 38.90-74.8), whereas that of AC000123.4 diploid patients without EGFR amplification was 72.0 months (95% CI = 44.55-not reached), suggesting a complementary prognostic role of AC000123.4 to EGFR.	('amplification', 'Var', (50, 63))	('patients', 'Species', '9606', (64, 72))	('EGFR', 'Gene', '1956', (316, 320))	('EGFR', 'Gene', '1956', (191, 195))	('EGFR', 'Gene', (316, 320))	('EGFR', 'Gene', (191, 195))	('patients', 'Species', '9606', (174, 182))	('AC000123.4 amplification', 'Var', (39, 63))	('EGFR', 'Gene', '1956', (81, 85))	('EGFR', 'Gene', (81, 85))
255747	30216655	Our above observations indicated that these genetically altered lncRNAs may substantially contribute to tumorigenesis by inducing similar functional effects with known cancer driver PCGs in a mutually exclusive manner, suggesting their cancer-driving roles.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('cancer', 'Disease', 'MESH:D009369', (236, 242))	('cancer', 'Disease', (236, 242))	('tumor', 'Disease', (104, 109))	('inducing', 'Reg', (121, 129))	('genetically altered', 'Var', (44, 63))	('PCGs', 'Chemical', 'MESH:D010400', (182, 186))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('cancer', 'Disease', (168, 174))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('contribute', 'Reg', (90, 100))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
255752	30216655	As a result, cell migration was significantly reduced by depletion of five of these lncRNAs in lung adenocarcinoma and breast cancer cell lines, as shown by a Transwell migration assay (P < 0.05, unpaired Student's test) (Fig.	('cell migration', 'CPA', (13, 27))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('breast cancer', 'Disease', 'MESH:D001943', (119, 132))	('Transwell migration assay', 'CPA', (159, 184))	('depletion', 'Var', (57, 66))	('breast cancer', 'Disease', (119, 132))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (95, 114))	('breast cancer', 'Phenotype', 'HP:0003002', (119, 132))	('lung adenocarcinoma', 'Disease', (95, 114))	('reduced', 'NegReg', (46, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (95, 114))
255762	30216655	For example, lncRNA FAL1 amplified in ovarian cancers could promote cell proliferation by recruiting the chromatin repressor protein BMI-1 and inhibiting the expression of CDKN1A (Hu et al., 2014).	('promote', 'PosReg', (60, 67))	('amplified', 'Var', (25, 34))	('cancers', 'Phenotype', 'HP:0002664', (46, 53))	('expression', 'MPA', (158, 168))	('cell proliferation', 'CPA', (68, 86))	('FAL1', 'Gene', (20, 24))	('inhibiting', 'NegReg', (143, 153))	('ovarian cancers', 'Disease', (38, 53))	('BMI-1', 'Gene', (133, 138))	('FAL1', 'Gene', '100874054', (20, 24))	('CDKN1A', 'Gene', (172, 178))	('ovarian cancers', 'Phenotype', 'HP:0100615', (38, 53))	('ovarian cancers', 'Disease', 'MESH:D010051', (38, 53))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('CDKN1A', 'Gene', '1026', (172, 178))	('recruiting', 'PosReg', (90, 100))	('BMI-1', 'Gene', '648', (133, 138))
255766	30216655	Recurrence is considered as one potential sign of positive selection among tumors (Dees et al., 2012; Fu et al., 2014); therefore, functional lncRNAs with recurrent genetic alterations are more likely to be driver lncRNAs, instead of non-driver cancer lncRNAs.	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('cancer', 'Disease', 'MESH:D009369', (245, 251))	('cancer', 'Disease', (245, 251))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('cancer', 'Phenotype', 'HP:0002664', (245, 251))	('tumors', 'Disease', (75, 81))	('genetic alterations', 'Var', (165, 184))
255767	30216655	With the aim of identifying driver lncRNAs, our method considers lncRNAs that show recurrent copy number alteration, exhibit mutually exclusive patterns with known cancer drivers, and affect various cancer hallmarks.	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('copy number alteration', 'Var', (93, 115))	('affect', 'Reg', (184, 190))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('cancer hallmarks', 'Disease', (199, 215))	('cancer hallmarks', 'Disease', 'MESH:D009369', (199, 215))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('cancer', 'Disease', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('cancer', 'Disease', (199, 205))
255777	30216655	When damage of a driver gene is sufficient to disturb the activity of certain key pathways, other gene alterations with similar functional consequences will offer no further selective advantage on that clone; that is the selection pressure on these other alterations could be diminished or even nullified during tumor evolution (Ciriello et al., 2012; Remy et al., 2015).	('activity', 'MPA', (58, 66))	('tumor', 'Disease', 'MESH:D009369', (312, 317))	('disturb', 'Reg', (46, 53))	('key pathways', 'Pathway', (78, 90))	('tumor', 'Phenotype', 'HP:0002664', (312, 317))	('tumor', 'Disease', (312, 317))	('damage', 'Var', (5, 11))
255788	30216655	For example, in the hallmark 'Evading Immune Detection', we found that GO term 'regulation of defense response to virus' was only affected by mutually exclusive modules in HNSC, which is consistent with the prevalence and the roles of human papillomavirus in directly inhibiting innate immune system for this cancer type (Bodily and Laimins, 2011; Maxwell et al., 2016).	('human papillomavirus', 'Species', '10566', (235, 255))	('affected', 'Reg', (130, 138))	('cancer', 'Phenotype', 'HP:0002664', (309, 315))	('inhibiting', 'NegReg', (268, 278))	('HNSC', 'Gene', (172, 176))	('modules', 'Var', (161, 168))	('cancer', 'Disease', 'MESH:D009369', (309, 315))	('HNSC', 'Phenotype', 'HP:0012288', (172, 176))	('cancer', 'Disease', (309, 315))
255794	30216655	A previous study has demonstrated that PVT1 epigenetically repressed the expression of CDKN2A by binding to the EZH2 (Kong et al., 2015); therefore, amplification of PVT1 and deletion of CDKN2A could consistently trigger the expression abnormality of CDKN2A and in turn lead to genomic instability.	('PVT1', 'Gene', (39, 43))	('lead to', 'Reg', (270, 277))	('PVT1', 'Gene', '5820', (166, 170))	('CDKN2A', 'Gene', (187, 193))	('EZH2', 'Gene', (112, 116))	('amplification', 'Var', (149, 162))	('CDKN2A', 'Gene', '1029', (187, 193))	('CDKN2A', 'Gene', '1029', (87, 93))	('EZH2', 'Gene', '2146', (112, 116))	('CDKN2A', 'Gene', '1029', (251, 257))	('PVT1', 'Gene', '5820', (39, 43))	('trigger', 'Reg', (213, 220))	('expression abnormality', 'MPA', (225, 247))	('deletion', 'Var', (175, 183))	('genomic', 'MPA', (278, 285))	('CDKN2A', 'Gene', (251, 257))	('PVT1', 'Gene', (166, 170))	('CDKN2A', 'Gene', (87, 93))
255797	30216655	Interestingly, CCNE1 suffered much more frequent CNA (24.6%) than CDKN2A (4.5%) in OV, whereas the opposite trend was observed in LUAD (5.8% and 19.0% for CCNE1 and CDKN2A, respectively), indicating that amplification of PVT1 may dysregulate different downstream genes, which in turn contribute to cancer development.	('PVT1', 'Gene', '5820', (221, 225))	('CCNE1', 'Gene', (15, 20))	('contribute', 'Reg', (284, 294))	('amplification', 'Var', (204, 217))	('dysregulate', 'Reg', (230, 241))	('cancer', 'Disease', 'MESH:D009369', (298, 304))	('CDKN2A', 'Gene', '1029', (66, 72))	('CCNE1', 'Gene', (155, 160))	('CDKN2A', 'Gene', (165, 171))	('cancer', 'Disease', (298, 304))	('OV', 'Phenotype', 'HP:0012887', (83, 85))	('CCNE1', 'Gene', '898', (155, 160))	('PVT1', 'Gene', (221, 225))	('CDKN2A', 'Gene', '1029', (165, 171))	('CCNE1', 'Gene', '898', (15, 20))	('CDKN2A', 'Gene', (66, 72))	('LUAD', 'Phenotype', 'HP:0030078', (130, 134))	('cancer', 'Phenotype', 'HP:0002664', (298, 304))
255800	30216655	These findings suggest that both of these lncRNAs and derived miRNAs contribute to tumorigenesis, although, for lncRNAs LINC00969, U47924.29 and LINC00669, we did not find evidence of oncogenic roles recorded in literature.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('LINC00969', 'Gene', '440993', (120, 129))	('tumor', 'Disease', (83, 88))	('LINC00969', 'Gene', (120, 129))	('LINC00669', 'Gene', '647946', (145, 154))	('LINC00669', 'Gene', (145, 154))	('U47924.29', 'Var', (131, 140))	('contribute', 'Reg', (69, 79))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
255805	30216655	XXZ performed copy number analysis and pan-cancer analysis.	('cancer', 'Disease', (43, 49))	('copy number analysis', 'Var', (14, 34))	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))
255815	32117295	In the classical sense, cancer pathogenesis is explained by mutations affecting proto-oncogenes and tumor suppressors, a paradigm that has proven rather simplistic particularly with the emergence of host immune deregulation as an important hallmark in cancer pathogenesis.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('cancer', 'Disease', 'MESH:D009369', (252, 258))	('reg', 'Gene', (213, 216))	('reg', 'Gene', '5967', (213, 216))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('tumor', 'Disease', (100, 105))	('cancer', 'Disease', (252, 258))	('cancer', 'Disease', (24, 30))	('cancer', 'Disease', 'MESH:D009369', (24, 30))	('proto-oncogenes', 'Gene', (80, 95))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('mutations', 'Var', (60, 69))	('tumor', 'Disease', 'MESH:D009369', (100, 105))
255823	32117295	The malignancy, which frequently arises among female non-smokers, adopts a histologically glandular pattern with activating mutations affecting driver genes such as KRAS, EGFR, and BRAF, as well as ALK fusions and other genetic alterations.	('malignancy', 'Disease', 'MESH:D009369', (4, 14))	('EGFR', 'Gene', (171, 175))	('activating', 'PosReg', (113, 123))	('KRAS', 'Gene', '3845', (165, 169))	('mutations', 'Var', (124, 133))	('ALK', 'Gene', (198, 201))	('malignancy', 'Disease', (4, 14))	('BRAF', 'Gene', (181, 185))	('BRAF', 'Gene', '673', (181, 185))	('ALK', 'Gene', '238', (198, 201))	('EGFR', 'Gene', '1956', (171, 175))	('KRAS', 'Gene', (165, 169))
255847	32117295	TSAs result from the accumulation of mutations within a tumor cell line.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Disease', (56, 61))	('mutations', 'Var', (37, 46))	('TSAs', 'Disease', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
255885	32117295	Despite its promise, the success of ACT was primarily restricted to melanoma patients, which was later attributed to the disease's inherent immunogenomic landscape; melanomas exhibit high mutation rates which produce tumor-specific antigens, or neoantigens, highly recognizable by TILs.	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('tumor', 'Disease', (217, 222))	('mutation', 'Var', (188, 196))	('melanomas', 'Disease', (165, 174))	('melanoma', 'Phenotype', 'HP:0002861', (165, 173))	('melanoma', 'Phenotype', 'HP:0002861', (68, 76))	('melanoma', 'Disease', (68, 76))	('patients', 'Species', '9606', (77, 85))	('melanoma', 'Disease', 'MESH:D008545', (68, 76))	('melanomas', 'Phenotype', 'HP:0002861', (165, 174))	('tumor', 'Disease', 'MESH:D009369', (217, 222))	('melanomas', 'Disease', 'MESH:D008545', (165, 174))	('melanoma', 'Disease', (165, 173))	('melanoma', 'Disease', 'MESH:D008545', (165, 173))
255898	32117295	Additionally, one study reported, in mice, an anti-tumor effect of CAR-NK cells differentiated from induced pluripotent stem cells in vitro, with significantly reduced adverse effects compared to CAR-T cell therapy.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor', 'Disease', (51, 56))	('CAR-NK', 'Var', (67, 73))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('mice', 'Species', '10090', (37, 41))
255914	32117295	OVs can also induce viral infection cascades known to elicit a type 1 interferon response thereby stimulating cytokine release, cancer cell lysis, and apoptosis.	('infection', 'Disease', (26, 35))	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('interferon', 'Gene', (70, 80))	('infection', 'Disease', 'MESH:D007239', (26, 35))	('induce', 'Reg', (13, 19))	('stimulating', 'PosReg', (98, 109))	('cytokine release', 'MPA', (110, 126))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('OVs', 'Var', (0, 3))	('interferon', 'Gene', '3439', (70, 80))	('viral', 'MPA', (20, 25))	('apoptosis', 'CPA', (151, 160))	('cancer', 'Disease', (128, 134))
255916	32117295	TG4010, an attenuated poxvirus engineered to express MUC-1 and IL-2 prolonged the survival of patients with advanced NSCLC when administered with first-line chemotherapy and is now being tested in phase III clinical trials.	('NSCLC', 'Disease', (117, 122))	('MUC-1', 'Gene', (53, 58))	('patients', 'Species', '9606', (94, 102))	('prolonged', 'PosReg', (68, 77))	('IL-2', 'Gene', (63, 67))	('IL-2', 'Gene', '3558', (63, 67))	('MUC-1', 'Gene', '4582', (53, 58))	('NSCLC', 'Disease', 'MESH:D002289', (117, 122))	('TG4010', 'Var', (0, 6))	('SCLC', 'Phenotype', 'HP:0030357', (118, 122))	('NSCLC', 'Phenotype', 'HP:0030358', (117, 122))	('survival', 'MPA', (82, 90))
255938	32117295	Additionally, tumors with high PD-L1 expression, defined as at least 50% of expression specific to tumor cells, exhibited improved response to anti-PD-1 monotherapy in NSCLC patients.	('high', 'Var', (26, 30))	('response', 'MPA', (131, 139))	('NSCLC', 'Phenotype', 'HP:0030358', (168, 173))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('tumor', 'Disease', (99, 104))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('PD-L1', 'Gene', (31, 36))	('tumors', 'Disease', (14, 20))	('SCLC', 'Phenotype', 'HP:0030357', (169, 173))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('expression', 'MPA', (37, 47))	('tumor', 'Disease', (14, 19))	('NSCLC', 'Disease', 'MESH:D002289', (168, 173))	('patients', 'Species', '9606', (174, 182))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('NSCLC', 'Disease', (168, 173))	('improved', 'PosReg', (122, 130))
255940	32117295	Patients expressing at least 50% of PD-L1 on tumor cells achieved superior progression-free survival with anti-PD-1 compared to chemotherapy, with a durable overall survival of 60.6% for 24 months.	('anti-PD-1', 'Var', (106, 115))	('superior', 'PosReg', (66, 74))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('PD-L1', 'Gene', (36, 41))	('tumor', 'Disease', (45, 50))	('Patients', 'Species', '9606', (0, 8))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('progression-free survival', 'CPA', (75, 100))
255947	32117295	In fact, targeting the PD-1/PD-L1 axis showed variable levels of efficacy across multiple tumor types and among patients with the same type of cancer, due to several factors such as gender, driver mutations, genomic instability (such as translocations in ALK, KRAS, EGFRI in lung cancer patients), and the degree of tumor metastases.	('KRAS', 'Gene', '3845', (260, 264))	('tumor metastases', 'Disease', (316, 332))	('type of cancer', 'Disease', (135, 149))	('KRAS', 'Gene', (260, 264))	('cancer', 'Phenotype', 'HP:0002664', (280, 286))	('tumor', 'Phenotype', 'HP:0002664', (316, 321))	('lung cancer', 'Disease', (275, 286))	('tumor', 'Disease', (90, 95))	('EGFR', 'Gene', '1956', (266, 270))	('ALK', 'Gene', '238', (255, 258))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('translocations', 'Var', (237, 251))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('type of cancer', 'Disease', 'MESH:D009369', (135, 149))	('mutations', 'Var', (197, 206))	('ALK', 'Gene', (255, 258))	('tumor metastases', 'Disease', 'MESH:D009362', (316, 332))	('lung cancer', 'Disease', 'MESH:D008175', (275, 286))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (316, 321))	('patients', 'Species', '9606', (112, 120))	('patients', 'Species', '9606', (287, 295))	('lung cancer', 'Phenotype', 'HP:0100526', (275, 286))	('EGFR', 'Gene', (266, 270))	('tumor', 'Disease', 'MESH:D009369', (316, 321))
255953	32117295	Indeed, a smoker molecular signature correlates with higher prevalence of somatic non-synonymous point mutations, an increased TMB, and elevated neoantigen production.	('increased', 'PosReg', (117, 126))	('TMB', 'Chemical', '-', (127, 130))	('non-synonymous point mutations', 'Var', (82, 112))	('neoantigen production', 'MPA', (145, 166))	('elevated', 'PosReg', (136, 144))	('TMB', 'MPA', (127, 130))
255959	32117295	Building on this, any failure to deliver survival benefits in PD-L1-high/TMB-high/MSI-high patients receiving ICB therapies could be attributed to insufficient CD8+ T cells infiltrating the tumor bed, hypoxia, mutation variability in oncogenic pathways, intratumoral heterogeneity of cytotoxic T cells populations, or specific human leukocyte antigen (HLA)-restricted neoantigens (Figure 1).	('ICB', 'Chemical', '-', (110, 113))	('hypoxia', 'Disease', (201, 208))	('CD8', 'Gene', '925', (160, 163))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('patients', 'Species', '9606', (91, 99))	('tumor', 'Disease', 'MESH:D009369', (259, 264))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('mutation', 'Var', (210, 218))	('tumor', 'Phenotype', 'HP:0002664', (259, 264))	('failure', 'Disease', 'MESH:D017093', (22, 29))	('human', 'Species', '9606', (327, 332))	('tumor', 'Disease', (190, 195))	('TMB', 'Chemical', '-', (73, 76))	('tumor', 'Disease', (259, 264))	('failure', 'Disease', (22, 29))	('hypoxia', 'Disease', 'MESH:D000860', (201, 208))	('CD8', 'Gene', (160, 163))
255964	32117295	Indeed, the two best-studied ICBs, anti-CTLA-4 and anti-PD-1 mAbs, mediate distinct yet complementary antitumor responses despite both having a suppressive effect on T cells.	('T cells', 'CPA', (166, 173))	('anti-PD-1', 'Gene', (51, 60))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('ICBs', 'Chemical', '-', (29, 33))	('anti-CTLA-4', 'Var', (35, 46))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Disease', (106, 111))
255968	32117295	It was also reported that combination immunotherapies could not deliver survival benefit among NSCLC patients with low TMB, which is consistent with data from gastrointestinal cancers.	('TMB', 'Chemical', '-', (119, 122))	('gastrointestinal cancers', 'Disease', 'MESH:D005770', (159, 183))	('patients', 'Species', '9606', (101, 109))	('low', 'Var', (115, 118))	('NSCLC', 'Disease', 'MESH:D002289', (95, 100))	('SCLC', 'Phenotype', 'HP:0030357', (96, 100))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('NSCLC', 'Phenotype', 'HP:0030358', (95, 100))	('gastrointestinal cancers', 'Disease', (159, 183))	('not', 'NegReg', (60, 63))	('cancers', 'Phenotype', 'HP:0002664', (176, 183))	('NSCLC', 'Disease', (95, 100))
255969	32117295	While some combinations were showing reduced toxicities compared to single-agents, other immune-related adverse effects were being reported, which may be reversed if properly addressed.	('reduced', 'NegReg', (37, 44))	('toxicities', 'Disease', 'MESH:D064420', (45, 55))	('toxicities', 'Disease', (45, 55))	('combinations', 'Var', (11, 23))
255973	32117295	In one cohort, anti-CTLA-4 increased expression of PD-1 and VISTA inhibitory checkpoints in prostate tumors, which makes targeting CTLA-4, PD-1, and VISTA an appealing combinatorial approach.	('anti-CTLA-4', 'Var', (15, 26))	('increased', 'PosReg', (27, 36))	('prostate tumors', 'Disease', (92, 107))	('VISTA', 'Gene', (60, 65))	('PD-1', 'Gene', (51, 55))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('VISTA', 'Gene', '64115', (149, 154))	('prostate tumors', 'Disease', 'MESH:D011471', (92, 107))	('VISTA', 'Gene', '64115', (60, 65))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('expression', 'MPA', (37, 47))	('VISTA', 'Gene', (149, 154))
255983	32117295	As previously mentioned, studies have repeatedly shown that tumors with a high mutational load possess a high number of neoantigens and are more responsive to ICB.	('high mutational load', 'Var', (74, 94))	('responsive', 'Interaction', (145, 155))	('more', 'PosReg', (140, 144))	('tumors', 'Disease', 'MESH:D009369', (60, 66))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('neoantigens', 'MPA', (120, 131))	('ICB', 'Chemical', '-', (159, 162))	('tumors', 'Disease', (60, 66))
255986	32117295	This makes ICB a more logical approach for tumors with a high mutational load, and tumors with a low mutational load may best be addressed with more conventional forms of cancer treatment or other forms of immunotherapy.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('mutational', 'Var', (62, 72))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('tumors', 'Disease', (83, 89))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('cancer', 'Disease', (171, 177))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumors', 'Disease', 'MESH:D009369', (83, 89))	('ICB', 'Chemical', '-', (11, 14))	('tumors', 'Disease', (43, 49))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('tumors', 'Disease', 'MESH:D009369', (43, 49))
255987	32117295	Yet, some tumors with high mutational load are surprisingly unresponsive to ICB treatment, and a deeper investigation revealed additional factors that influence neoantigen presentation and response to ICB.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('high mutational load', 'Var', (22, 42))	('ICB', 'Chemical', '-', (201, 204))	('ICB', 'Chemical', '-', (76, 79))	('tumors', 'Disease', 'MESH:D009369', (10, 16))	('tumors', 'Disease', (10, 16))	('tumors', 'Phenotype', 'HP:0002664', (10, 16))	('neoantigen presentation', 'MPA', (161, 184))	('influence', 'Reg', (151, 160))
255989	32117295	For instance, long-term survival of patients with pancreatic cancer correlated with neoantigen "foreignness," an attribute of their homology to antigens derived from infectious diseases, rather than the actual number of neoantigens, a timely observation given the emerging roles of tumor microbiomes (further discussed below).	('tumor', 'Phenotype', 'HP:0002664', (282, 287))	('patients', 'Species', '9606', (36, 44))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (50, 67))	('tumor', 'Disease', (282, 287))	('pancreatic cancer', 'Disease', (50, 67))	('foreignness', 'Disease', (96, 107))	('foreignness', 'Disease', 'MESH:D005547', (96, 107))	('pancreatic cancer', 'Disease', 'MESH:D010190', (50, 67))	('neoantigen', 'Var', (84, 94))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('correlated', 'Reg', (68, 78))	('tumor', 'Disease', 'MESH:D009369', (282, 287))
256000	32117295	Mutations that survive this phase evade immune surveillance by being poorly presented on HLA molecules and are thus more likely be found in the tumor later on.	('tumor', 'Disease', (144, 149))	('poorly', 'NegReg', (69, 75))	('Mutations', 'Var', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))
256006	32117295	They identified that 40% of early stage NSCLCs harbor HLA LOH and that this is significantly associated with a high subclonal neoantigen burden, APOBEC-mediated mutagenesis, upregulation of cytolytic activity, and PD-L1 positivity.	('SCLC', 'Phenotype', 'HP:0030357', (41, 45))	('HLA', 'Gene', (54, 57))	('NSCLC', 'Phenotype', 'HP:0030358', (40, 45))	('cytolytic activity', 'MPA', (190, 208))	('reg', 'Gene', (176, 179))	('reg', 'Gene', '5967', (176, 179))	('NSCLC', 'Disease', (40, 45))	('NSCLC', 'Disease', 'MESH:D002289', (40, 45))	('mutagenesis', 'Var', (161, 172))
256009	32117295	Somatic mutations generate neoantigens and may also influence response to ICB in a gene-specific manner, and next generation sequencing has been instrumental in identifying the somatic alterations that influence the immunogenomic landscape of tumors (see Table 1).	('response to ICB', 'MPA', (62, 77))	('tumors', 'Disease', (243, 249))	('tumors', 'Disease', 'MESH:D009369', (243, 249))	('tumors', 'Phenotype', 'HP:0002664', (243, 249))	('mutations', 'Var', (8, 17))	('ICB', 'Chemical', '-', (74, 77))	('influence', 'Reg', (202, 211))	('influence', 'Reg', (52, 61))	('neoantigens', 'MPA', (27, 38))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))	('generate', 'Reg', (18, 26))
256010	32117295	In a recent study, researchers established that KRAS-mutant LUADs harboring additional mutations in STK11/LKB1 were unaffected by PD-1/PD-L1 inhibition.	('LKB1', 'Gene', (106, 110))	('KRAS', 'Gene', (48, 52))	('KRAS', 'Gene', '3845', (48, 52))	('LKB1', 'Gene', '6794', (106, 110))	('STK11', 'Gene', (100, 105))	('LUAD', 'Phenotype', 'HP:0030078', (60, 64))	('STK11', 'Gene', '6794', (100, 105))	('LUAD', 'Disease', (60, 64))	('LUAD', 'Disease', 'MESH:C538231', (60, 64))	('mutations', 'Var', (87, 96))
256012	32117295	LUAD patients harboring STK11 mutations were shown to have low densities of CD8+ TILs in tumor beds, in contrast to STK11 wildtype LUAD patients who displayed high levels of CD4+ and CD8+ T cells.	('STK11', 'Gene', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('LUAD', 'Disease', (131, 135))	('CD8', 'Gene', (76, 79))	('LUAD', 'Phenotype', 'HP:0030078', (0, 4))	('patients', 'Species', '9606', (5, 13))	('STK11', 'Gene', '6794', (116, 121))	('LUAD', 'Disease', 'MESH:C538231', (131, 135))	('CD8', 'Gene', (183, 186))	('tumor', 'Disease', (89, 94))	('LUAD', 'Disease', (0, 4))	('STK11', 'Gene', (24, 29))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('mutations', 'Var', (30, 39))	('CD8', 'Gene', '925', (76, 79))	('CD4', 'Gene', '920', (174, 177))	('LUAD', 'Disease', 'MESH:C538231', (0, 4))	('low', 'NegReg', (59, 62))	('patients', 'Species', '9606', (136, 144))	('LUAD', 'Phenotype', 'HP:0030078', (131, 135))	('densities', 'MPA', (63, 72))	('STK11', 'Gene', '6794', (24, 29))	('CD4', 'Gene', (174, 177))	('CD8', 'Gene', '925', (183, 186))
256013	32117295	Mechanistically, inactivating mutations in the tumor suppressor STK11 were able to reprogram the TME into so-called "immune-deserts," which support a "cold" tumor.	('tumor', 'Disease', (157, 162))	('inactivating mutations', 'Var', (17, 39))	('STK11', 'Gene', (64, 69))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('STK11', 'Gene', '6794', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('tumor', 'Disease', (47, 52))
256014	32117295	When treated with anti-PD-1 therapy, KRAS-mutant LUAD tumors with co-occurring mutations in STK11 had an objective response rate of 7.4%, compared to the highly responsive subgroup of KRAS-mutant LUADs with p53 mutations showing 35.7% objective response rate.	('LUAD', 'Disease', 'MESH:C538231', (196, 200))	('LUAD', 'Phenotype', 'HP:0030078', (49, 53))	('p53', 'Gene', '7157', (207, 210))	('KRAS', 'Gene', (37, 41))	('mutations', 'Var', (79, 88))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('LUAD', 'Disease', (49, 53))	('STK11', 'Gene', '6794', (92, 97))	('KRAS', 'Gene', '3845', (184, 188))	('p53', 'Gene', (207, 210))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('LUAD', 'Phenotype', 'HP:0030078', (196, 200))	('tumors', 'Disease', (54, 60))	('KRAS', 'Gene', (184, 188))	('LUAD', 'Disease', 'MESH:C538231', (49, 53))	('tumors', 'Disease', 'MESH:D009369', (54, 60))	('LUAD', 'Disease', (196, 200))	('KRAS', 'Gene', '3845', (37, 41))	('STK11', 'Gene', (92, 97))
256039	32117295	Enterocolitis is particularly frequent and severe following CTLA-4 inhibition, and appears to resemble, and even cause inflammatory bowel diseases.	('inhibition', 'Var', (67, 77))	('Enterocolitis', 'Disease', (0, 13))	('Enterocolitis', 'Phenotype', 'HP:0004387', (0, 13))	('Enterocolitis', 'Disease', 'MESH:D004760', (0, 13))	('CTLA-4', 'Gene', (60, 66))	('inflammatory bowel diseases', 'Disease', 'MESH:D015212', (119, 146))	('inflammatory bowel diseases', 'Phenotype', 'HP:0002037', (119, 146))	('inflammatory bowel diseases', 'Disease', (119, 146))
256043	32117295	In animal models, modulation of the lung microbiome using probiotics or antibiotics decreased tumor seeding in the lung and improved the effect of chemotherapy against experimental metastases.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('metastases', 'Disease', 'MESH:D009362', (181, 191))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('improved', 'PosReg', (124, 132))	('modulation', 'Var', (18, 28))	('tumor', 'Disease', (94, 99))	('effect', 'MPA', (137, 143))	('metastases', 'Disease', (181, 191))	('decreased', 'NegReg', (84, 93))
256052	32117295	In one report, LUSCs with somatic mutations affecting TP53, the most commonly mutated tumor suppressor gene in lung cancers, were enriched with tissue-specific microbial consortia, a subset of which was highly abundant among smokers.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Disease', (86, 91))	('LUSC', 'Disease', 'MESH:D002294', (15, 19))	('LUSC', 'Phenotype', 'HP:0030359', (15, 19))	('lung cancers', 'Disease', (111, 123))	('TP53', 'Gene', '7157', (54, 58))	('cancers', 'Phenotype', 'HP:0002664', (116, 123))	('lung cancer', 'Phenotype', 'HP:0100526', (111, 122))	('LUSC', 'Disease', (15, 19))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('TP53', 'Gene', (54, 58))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('mutations', 'Var', (34, 43))	('lung cancers', 'Disease', 'MESH:D008175', (111, 123))	('lung cancers', 'Phenotype', 'HP:0100526', (111, 123))
256061	32117295	Further, PD-1 blockade in a carcinogen-induced leukoplakia mouse model reduced the number of OPLs and their frequency of transforming to oral squamous cell carcinomas.	('leukoplakia', 'Disease', 'MESH:D007971', (47, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (156, 165))	('mouse', 'Species', '10090', (59, 64))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (142, 165))	('OPLs', 'Disease', (93, 97))	('oral squamous cell carcinomas', 'Disease', 'MESH:D002294', (137, 166))	('leukoplakia', 'Disease', (47, 58))	('blockade', 'Var', (14, 22))	('oral squamous cell carcinomas', 'Disease', (137, 166))	('reduced', 'NegReg', (71, 78))	('carcinomas', 'Phenotype', 'HP:0030731', (156, 166))	('PD-1', 'Gene', (9, 13))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (142, 166))
256068	32117295	Interestingly, early-stage LUADs treated with standard adjuvant therapy exhibited mutations in genes involved in immune regulation that are also associated with smoking.	('LUAD', 'Disease', (27, 31))	('LUAD', 'Disease', 'MESH:C538231', (27, 31))	('LUAD', 'Phenotype', 'HP:0030078', (27, 31))	('reg', 'Gene', (120, 123))	('exhibited', 'Reg', (72, 81))	('reg', 'Gene', '5967', (120, 123))	('associated', 'Reg', (145, 155))	('mutations', 'Var', (82, 91))
256069	32117295	Early-stage LUSC patients also revealed immune marker mutation profiles based on their somatic mutational burdens, which may justify a personalized immunotherapeutic approach to target cancers at early stages of disease progression.	('mutation', 'Var', (54, 62))	('immune marker', 'MPA', (40, 53))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('revealed', 'Reg', (31, 39))	('LUSC', 'Phenotype', 'HP:0030359', (12, 16))	('cancers', 'Phenotype', 'HP:0002664', (185, 192))	('LUSC', 'Disease', 'MESH:D002294', (12, 16))	('LUSC', 'Disease', (12, 16))	('patients', 'Species', '9606', (17, 25))	('cancers', 'Disease', 'MESH:D009369', (185, 192))	('cancers', 'Disease', (185, 192))
256072	32117295	This effect was further intensified by additional blockade of PD-1, whereby T cell activation in the lymph nodes promoted CD8+ T cell infiltration as well as neoantigen-specific T cell clonal expansion in peripheral blood and subsequent infiltration of TILs into tumor beds.	('tumor', 'Disease', 'MESH:D009369', (263, 268))	('promoted', 'PosReg', (113, 121))	('neoantigen-specific', 'Var', (158, 177))	('tumor', 'Phenotype', 'HP:0002664', (263, 268))	('CD8', 'Gene', (122, 125))	('PD-1', 'Gene', (62, 66))	('CD8', 'Gene', '925', (122, 125))	('tumor', 'Disease', (263, 268))
256078	32117295	The mutagenized airway profiles were pertinent to the step-wise progression into invasive tumors, as well as evolutionarily conserved and evident among cancer-free smokers where the field effect is also prominent.	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('invasive tumors', 'Disease', (81, 96))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('mutagenized', 'Var', (4, 15))	('invasive tumors', 'Disease', 'MESH:D009361', (81, 96))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))
256080	32117295	Using other mouse models with genetically induced Kras-mutations, the same variants that are implicated as drivers of human LUAD in smokers, researchers have shown that inhibition of IL-6, whose pleiotropic roles include promoting inflammation as well as growth and differentiation of B and T cells, restricted the development of lung oncogenesis.	('restricted', 'NegReg', (300, 310))	('Kras', 'Gene', '16653', (50, 54))	('inflammation', 'Disease', 'MESH:D007249', (231, 243))	('LUAD', 'Phenotype', 'HP:0030078', (124, 128))	('inflammation', 'Disease', (231, 243))	('promoting', 'PosReg', (221, 230))	('LUAD', 'Disease', (124, 128))	('development of lung oncogenesis', 'CPA', (315, 346))	('LUAD', 'Disease', 'MESH:C538231', (124, 128))	('mouse', 'Species', '10090', (12, 17))	('human', 'Species', '9606', (118, 123))	('variants', 'Var', (75, 83))	('IL-6', 'Gene', (183, 187))	('Kras', 'Gene', (50, 54))	('inhibition', 'Var', (169, 179))
256083	32117295	Further investigation revealed that Stat3 appears to play diverse roles that are cell-type specific (e.g., epithelial vs. immune cell) as well as gender-specific, whereby female mice with additional deletion of Stat3 conferred antitumor immunity, compared to a Stat3-deletion-mediated pro-tumor immune responses in male littermates.	('Stat3', 'Gene', (261, 266))	('tumor', 'Disease', 'MESH:D009369', (289, 294))	('tumor', 'Disease', 'MESH:D009369', (231, 236))	('tumor', 'Phenotype', 'HP:0002664', (289, 294))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('mice', 'Species', '10090', (178, 182))	('Stat3', 'Gene', '20848', (261, 266))	('Stat3', 'Gene', (211, 216))	('tumor', 'Disease', (289, 294))	('tumor', 'Disease', (231, 236))	('Stat3', 'Gene', (36, 41))	('deletion', 'Var', (199, 207))	('Stat3', 'Gene', '20848', (211, 216))	('Stat3', 'Gene', '20848', (36, 41))	('conferred', 'Reg', (217, 226))
256101	32117295	Field-associated gradients have been described at the level of somatic point mutations in cancer driver genes such as EGFR and KRAS, LOH of 3p and 9p chromosomal regions, epigenetic modulation of CDKN2A, copy number alterations, in addition to gene expression profiles across tumor tissue and nearby normal-appearing airway of injury.	('tumor', 'Disease', 'MESH:D009369', (276, 281))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('tumor', 'Phenotype', 'HP:0002664', (276, 281))	('tumor', 'Disease', (276, 281))	('KRAS', 'Gene', (127, 131))	('copy number alterations', 'Var', (204, 227))	('EGFR', 'Gene', (118, 122))	('reg', 'Gene', (162, 165))	('epigenetic modulation', 'Var', (171, 192))	('CDKN2A', 'Gene', (196, 202))	('reg', 'Gene', '5967', (162, 165))	('EGFR', 'Gene', '1956', (118, 122))	('CDKN2A', 'Gene', '1029', (196, 202))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('KRAS', 'Gene', '3845', (127, 131))	('LOH', 'Var', (133, 136))
256105	32117295	Common chromosomal aberrations had been previously described as early events in AAHs, such as 17p chromosomal arm loss which arises prior to TP53 mutation (see Table 1).	('17p chromosomal arm', 'Disease', (94, 113))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (7, 30))	('TP53', 'Gene', '7157', (141, 145))	('AAHs', 'Disease', (80, 84))	('TP53', 'Gene', (141, 145))	('AAHs', 'Disease', 'MESH:D011125', (80, 84))	('mutation', 'Var', (146, 154))	('AAHs', 'Phenotype', 'HP:0040261', (80, 84))
256117	32117295	In another cohort, somatic mutations in AAHs that progressed and persisted in LUADs were not only shown to be highly heterogeneous between PMLs of different patients, but they also produced putative progressive neoantigens that were expressed in the earliest pulmonary PMLs and persisted throughout tumor progression.	('mutations', 'Var', (27, 36))	('AAHs', 'Phenotype', 'HP:0040261', (40, 44))	('tumor', 'Disease', (299, 304))	('neoantigens', 'MPA', (211, 222))	('patients', 'Species', '9606', (157, 165))	('PMLs', 'Disease', (269, 273))	('AAHs', 'Disease', (40, 44))	('PMLs', 'Disease', (139, 143))	('PMLs', 'Disease', 'MESH:D051437', (139, 143))	('AAHs', 'Disease', 'MESH:D011125', (40, 44))	('LUAD', 'Disease', (78, 82))	('PMLs', 'Disease', 'MESH:D051437', (269, 273))	('LUAD', 'Disease', 'MESH:C538231', (78, 82))	('LUAD', 'Phenotype', 'HP:0030078', (78, 82))	('tumor', 'Disease', 'MESH:D009369', (299, 304))	('tumor', 'Phenotype', 'HP:0002664', (299, 304))
256229	27570459	In addition, the ROC curve revealed that the AUC of DcR3 was 0.726 (95% CI 0.644-0.788) for lung adenocarcinoma patients and 0.647 (95% CI 0.566-0.728) for squamous cell carcinoma patients, which was applied to analyze the diagnostic value of DcR3 level in lung cancer.	('DcR3', 'Gene', '8771', (52, 56))	('0.647', 'Var', (125, 130))	('lung cancer', 'Phenotype', 'HP:0100526', (257, 268))	('squamous cell carcinoma', 'Disease', (156, 179))	('lung adenocarcinoma', 'Disease', (92, 111))	('patients', 'Species', '9606', (180, 188))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (92, 111))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (92, 111))	('cancer', 'Phenotype', 'HP:0002664', (262, 268))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (156, 179))	('lung cancer', 'Disease', (257, 268))	('DcR3', 'Gene', (243, 247))	('carcinoma', 'Phenotype', 'HP:0030731', (170, 179))	('DcR3', 'Gene', (52, 56))	('patients', 'Species', '9606', (112, 120))	('DcR3', 'Gene', '8771', (243, 247))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (156, 179))	('lung cancer', 'Disease', 'MESH:D008175', (257, 268))
256247	27570459	They found that high expression of DcR3 could predict the prognosis of pancreatic carcinoma and that the DcR3 level in sera could be used for the early diagnosis and prognostic judgment of pancreatic carcinoma.	('pancreatic carcinoma', 'Disease', (189, 209))	('DcR3', 'Gene', '8771', (35, 39))	('high', 'Var', (16, 20))	('pancreatic carcinoma', 'Disease', (71, 91))	('pancreatic carcinoma', 'Disease', 'MESH:C562463', (189, 209))	('carcinoma', 'Phenotype', 'HP:0030731', (200, 209))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('DcR3', 'Gene', '8771', (105, 109))	('predict', 'Reg', (46, 53))	('DcR3', 'Gene', (35, 39))	('pancreatic carcinoma', 'Disease', 'MESH:C562463', (71, 91))	('DcR3', 'Gene', (105, 109))
256269	33522072	Prognostic significance of genetic variants in GLUT1 in stage III non-small cell lung cancer treated with radiotherapy To examine the impact of polymorphisms of glucose transporter 1 (GLUT1) gene on the prognosis of patients with stage III non-small cell lung cancer (NSCLC) who received radiotherapy.	('variants', 'Var', (35, 43))	('NSCLC', 'Disease', 'MESH:D002289', (268, 273))	('lung cancer', 'Disease', 'MESH:D008175', (81, 92))	('lung cancer', 'Disease', 'MESH:D008175', (255, 266))	('lung cancer', 'Phenotype', 'HP:0100526', (81, 92))	('GLUT1', 'Gene', '6513', (47, 52))	('NSCLC', 'Disease', (268, 273))	('lung cancer', 'Phenotype', 'HP:0100526', (255, 266))	('NSCLC', 'Phenotype', 'HP:0030358', (268, 273))	('GLUT1', 'Gene', (184, 189))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (240, 266))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (66, 92))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('patients', 'Species', '9606', (216, 224))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (244, 266))	('glucose transporter 1', 'Gene', '6513', (161, 182))	('cancer', 'Phenotype', 'HP:0002664', (260, 266))	('lung cancer', 'Disease', (81, 92))	('GLUT1', 'Gene', (47, 52))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (70, 92))	('lung cancer', 'Disease', (255, 266))	('glucose transporter 1', 'Gene', (161, 182))	('GLUT1', 'Gene', '6513', (184, 189))
256270	33522072	Five single nucleotide polymorphisms (SNPs) (rs4658C>G, rs1385129G>A, rs3820589A>T, rs3806401A>C and rs3806400C>T) in GLUT1 gene were evaluated in 90 patients with pathologically confirmed stage III NSCLC.	('rs1385129G>A', 'Var', (56, 68))	('NSCLC', 'Disease', 'MESH:D002289', (199, 204))	('rs4658C>G', 'DBSNP_MENTION', 'None', (45, 54))	('rs3806401A>C', 'Var', (84, 96))	('GLUT1', 'Gene', '6513', (118, 123))	('rs4658C>G', 'Var', (45, 54))	('patients', 'Species', '9606', (150, 158))	('rs3806400C>T', 'Var', (101, 113))	('rs3806401A>C', 'DBSNP_MENTION', 'None', (84, 96))	('NSCLC', 'Phenotype', 'HP:0030358', (199, 204))	('rs3820589A>T', 'Var', (70, 82))	('rs3820589A>T', 'DBSNP_MENTION', 'None', (70, 82))	('GLUT1', 'Gene', (118, 123))	('rs3806400C>T', 'DBSNP_MENTION', 'None', (101, 113))	('rs1385129G>A', 'DBSNP_MENTION', 'None', (56, 68))	('NSCLC', 'Disease', (199, 204))
256272	33522072	Two SNPs (rs1385129 and rs3806401) were significant risk factors for OS.	('rs1385129', 'Var', (10, 19))	('rs3806401', 'Mutation', 'rs3806401', (24, 33))	('rs1385129', 'Mutation', 'rs1385129', (10, 19))	('rs3806401', 'Var', (24, 33))
256273	33522072	Three SNPs (rs1385129, rs3820589 and rs3806401) were in linkage disequilibrium.	('rs1385129', 'Var', (12, 21))	('rs3806401', 'Mutation', 'rs3806401', (37, 46))	('rs1385129', 'Mutation', 'rs1385129', (12, 21))	('rs3820589', 'Var', (23, 32))	('rs3820589', 'Mutation', 'rs3820589', (23, 32))	('rs3806401', 'Var', (37, 46))
256274	33522072	In Cox proportional hazard models, GAA haplotype was a good prognostic factor for OS (hazard ratio [HR] = 0.57, 95% confidence interval [CI]: 0.39-0.81, p = 0.002) and PFS (HR = 0.68, 95% CI: 0.47-0.99, p = 0.043), compared to variant haplotypes.	('PFS', 'Disease', (168, 171))	('GAA', 'Gene', (35, 38))	('GAA', 'Gene', '2548', (35, 38))	('haplotype', 'Var', (39, 48))
256276	33522072	These results suggest that polymorphisms of GLUT1 gene could be used as a prognostic marker for patients with stage III NSCLC treated with radiotherapy.	('GLUT1', 'Gene', (44, 49))	('NSCLC', 'Disease', 'MESH:D002289', (120, 125))	('GLUT1', 'Gene', '6513', (44, 49))	('NSCLC', 'Phenotype', 'HP:0030358', (120, 125))	('patients', 'Species', '9606', (96, 104))	('polymorphisms', 'Var', (27, 40))	('NSCLC', 'Disease', (120, 125))
256277	33522072	Genetic variants of GLUT1 had prognostic significance in NSCLC treated with RT with or without chemotherapy.	('significance', 'Reg', (41, 53))	('GLUT1', 'Gene', (20, 25))	('NSCLC', 'Phenotype', 'HP:0030358', (57, 62))	('prognostic', 'Reg', (30, 40))	('GLUT1', 'Gene', '6513', (20, 25))	('NSCLC', 'Disease', (57, 62))	('Genetic variants', 'Var', (0, 16))	('NSCLC', 'Disease', 'MESH:D002289', (57, 62))
256278	33522072	A haplotype of rs1385129G-rs3820589A-rs3806401A was related to better survival.	('rs3806401', 'Mutation', 'rs3806401', (37, 46))	('better', 'PosReg', (63, 69))	('rs1385129G-rs3820589A-rs3806401A', 'Var', (15, 47))	('rs3820589', 'Mutation', 'rs3820589', (26, 35))	('rs1385129', 'Mutation', 'rs1385129', (15, 24))
256291	33522072	It is plausible that its genetic variations may affect glucose uptake and the consequent glycolytic metabolism in cancer cells, which may impact the post-treatment prognosis of cancer patients.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('affect', 'Reg', (48, 54))	('glucose', 'Chemical', 'MESH:D005947', (55, 62))	('cancer', 'Disease', (177, 183))	('cancer', 'Disease', 'MESH:D009369', (177, 183))	('post-treatment prognosis', 'CPA', (149, 173))	('patients', 'Species', '9606', (184, 192))	('glycolytic metabolism', 'MPA', (89, 110))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('genetic variations', 'Var', (25, 43))	('impact', 'Reg', (138, 144))	('glucose uptake', 'MPA', (55, 69))	('cancer', 'Disease', (114, 120))
256293	33522072	In a recent study, GLUT1 genetic variations were found to be predictive biomarkers for NSCLC treated with surgery.	('GLUT1', 'Gene', '6513', (19, 24))	('NSCLC', 'Disease', (87, 92))	('genetic variations', 'Var', (25, 43))	('NSCLC', 'Disease', 'MESH:D002289', (87, 92))	('NSCLC', 'Phenotype', 'HP:0030358', (87, 92))	('GLUT1', 'Gene', (19, 24))
256294	33522072	12   Therefore, we investigated the clinical implications of the genetic variations of GLUT1 gene on the survival outcomes of patients with stage III NSCLC treated with RT.	('NSCLC', 'Disease', 'MESH:D002289', (150, 155))	('NSCLC', 'Phenotype', 'HP:0030358', (150, 155))	('GLUT1', 'Gene', (87, 92))	('patients', 'Species', '9606', (126, 134))	('investigated', 'Reg', (19, 31))	('GLUT1', 'Gene', '6513', (87, 92))	('NSCLC', 'Disease', (150, 155))	('genetic variations', 'Var', (65, 83))
256298	33522072	12  To identify potentially functional polymorphisms in GLUT1, we first searched the public single nucleotide polymorphism (SNP) database of the National Institutes of Health (http://www.ncbi.nlm.nih.gov/SNP) for all SNPs in GLUT1 gene with minor allele frequency >=0.05, based on the HapMap JPT data.	('GLUT1', 'Gene', (56, 61))	('GLUT1', 'Gene', (225, 230))	('SNPs', 'Var', (217, 221))	('GLUT1', 'Gene', '6513', (56, 61))	('GLUT1', 'Gene', '6513', (225, 230))
256299	33522072	Next, using the FuncPred utility for prediction of functional SNPs and the TagSNP utility for linkage disequilibrium (LD) tag SNP selection in the SNPinfo web server (https://snpinfo.niehs.nih.gov), five SNPs in GLUT1 (rs4658C>G, rs1385129G>A, rs3820589A>T, rs3806401A>C, and rs3806400C>T) were identified after excluding those in LD (r2 >= 0.8).	('rs4658C>G', 'DBSNP_MENTION', 'None', (219, 228))	('GLUT1', 'Gene', (212, 217))	('rs3806401A>C', 'DBSNP_MENTION', 'None', (258, 270))	('rs3806400C>T', 'Var', (276, 288))	('rs4658C>G', 'Var', (219, 228))	('GLUT1', 'Gene', '6513', (212, 217))	('rs3820589A>T', 'Var', (244, 256))	('rs1385129G>A', 'DBSNP_MENTION', 'None', (230, 242))	('rs3820589A>T', 'DBSNP_MENTION', 'None', (244, 256))	('rs3806401A>C', 'Var', (258, 270))	('rs1385129G>A', 'Var', (230, 242))	('rs3806400C>T', 'DBSNP_MENTION', 'None', (276, 288))
256308	33522072	As for rs3820589, the AT genotype was associated with higher stage than AA genotype (p = 0.032), with no association with other factors.	('rs3820589', 'Mutation', 'rs3820589', (7, 16))	('rs3820589', 'Var', (7, 16))	('higher', 'PosReg', (54, 60))
256309	33522072	Among the five SNPs studied, the rs1385129G>A and rs3806401A>C were significant prognostic factors for OS under both codominant and dominant models.	('rs1385129G>A', 'DBSNP_MENTION', 'None', (33, 45))	('rs1385129G>A', 'Var', (33, 45))	('rs3806401A>C', 'DBSNP_MENTION', 'None', (50, 62))	('rs3806401A>C', 'Var', (50, 62))
256310	33522072	Among the five SNPs, three SNPs (rs1385129G>A, rs3820589A>T and rs3806401A>C) were in LD.	('rs3820589A>T', 'Var', (47, 59))	('rs1385129G>A', 'DBSNP_MENTION', 'None', (33, 45))	('rs3820589A>T', 'DBSNP_MENTION', 'None', (47, 59))	('rs3806401A>C', 'Var', (64, 76))	('rs1385129G>A', 'Var', (33, 45))	('rs3806401A>C', 'DBSNP_MENTION', 'None', (64, 76))
256316	33522072	On haplotype and diplotype analyses for the three SNPs with LD (rs1385129G>A, rs3820589A>T and rs3806401A>C), presence of wild-type haplotype of the three SNPs was an independent predictor of favorable OS and PFS.	('rs3820589A>T', 'Var', (78, 90))	('favorable OS', 'Disease', (192, 204))	('rs3820589A>T', 'DBSNP_MENTION', 'None', (78, 90))	('rs1385129G>A', 'DBSNP_MENTION', 'None', (64, 76))	('rs3806401A>C', 'Var', (95, 107))	('rs1385129G>A', 'Var', (64, 76))	('rs3806401A>C', 'DBSNP_MENTION', 'None', (95, 107))	('PFS', 'Disease', (209, 212))
256321	33522072	17  conducted gene set enrichment analysis and found significant enrichment of 11 hallmark pathways (including, glycolysis, G2M checkpoint, mTORC1 signaling, and hypoxia) in lung adenocarcinoma with high GLUT1 expression.	('carcinoma', 'Phenotype', 'HP:0030731', (184, 193))	('mTORC1', 'Gene', '382056', (140, 146))	('glycolysis', 'MPA', (112, 122))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (174, 193))	('hypoxia', 'Disease', 'MESH:D000860', (162, 169))	('mTORC1', 'Gene', (140, 146))	('G2M checkpoint', 'MPA', (124, 138))	('high', 'Var', (199, 203))	('GLUT1', 'Gene', (204, 209))	('lung adenocarcinoma', 'Disease', (174, 193))	('hypoxia', 'Disease', (162, 169))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (174, 193))	('GLUT1', 'Gene', '6513', (204, 209))
256322	33522072	Therefore, it is plausible that functional polymorphisms in GLUT1 gene may modulate the effect of GLUT1 on the prognosis of NSCLC.	('polymorphisms', 'Var', (43, 56))	('GLUT1', 'Gene', '6513', (98, 103))	('effect', 'MPA', (88, 94))	('GLUT1', 'Gene', (60, 65))	('NSCLC', 'Disease', (124, 129))	('GLUT1', 'Gene', '6513', (60, 65))	('NSCLC', 'Disease', 'MESH:D002289', (124, 129))	('modulate', 'Reg', (75, 83))	('GLUT1', 'Gene', (98, 103))	('NSCLC', 'Phenotype', 'HP:0030358', (124, 129))
256323	33522072	The prognostic impact of polymorphisms of various cancer-related genes has been reported in NSCLC patients treated with RT.	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('NSCLC', 'Phenotype', 'HP:0030358', (92, 97))	('patients', 'Species', '9606', (98, 106))	('polymorphisms', 'Var', (25, 38))	('NSCLC', 'Disease', (92, 97))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('NSCLC', 'Disease', 'MESH:D002289', (92, 97))
256324	33522072	18 ,  19 ,  20  However, the impact of GLUT1 polymorphisms on the prognosis of patients with stage III NSCLC treated with RT has not been reported, even though metabolic reprogramming is a common phenomenon in NSCLC.	('GLUT1', 'Gene', '6513', (39, 44))	('NSCLC', 'Disease', (103, 108))	('NSCLC', 'Disease', (210, 215))	('NSCLC', 'Disease', 'MESH:D002289', (103, 108))	('polymorphisms', 'Var', (45, 58))	('NSCLC', 'Disease', 'MESH:D002289', (210, 215))	('patients', 'Species', '9606', (79, 87))	('NSCLC', 'Phenotype', 'HP:0030358', (103, 108))	('GLUT1', 'Gene', (39, 44))	('NSCLC', 'Phenotype', 'HP:0030358', (210, 215))
256325	33522072	Among the five SNPs (rs4658, rs1385129, rs3820589, rs3806401, and rs3806400) of the GLUT1 gene, the rs1385129 and rs3806401 were associated with OS of patients with stage III NSCLC treated with RT in the current study, while rs4658 and rs3820589 were associated with OS in early-stage NSCLC treated with surgery in the study by Do et al.	('associated', 'Reg', (129, 139))	('NSCLC', 'Phenotype', 'HP:0030358', (175, 180))	('NSCLC', 'Disease', 'MESH:D002289', (285, 290))	('rs3820589', 'Mutation', 'rs3820589', (236, 245))	('rs3806401', 'Var', (51, 60))	('NSCLC', 'Disease', (285, 290))	('rs4658', 'Mutation', 'rs4658', (225, 231))	('rs3806401', 'Var', (114, 123))	('rs1385129', 'Var', (29, 38))	('rs1385129', 'Mutation', 'rs1385129', (29, 38))	('NSCLC', 'Phenotype', 'HP:0030358', (285, 290))	('GLUT1', 'Gene', '6513', (84, 89))	('rs3806400', 'Mutation', 'rs3806400', (66, 75))	('rs3820589', 'Var', (40, 49))	('rs3806400', 'Var', (66, 75))	('rs1385129', 'Var', (100, 109))	('rs1385129', 'Mutation', 'rs1385129', (100, 109))	('NSCLC', 'Disease', 'MESH:D002289', (175, 180))	('rs3820589', 'Var', (236, 245))	('patients', 'Species', '9606', (151, 159))	('rs3820589', 'Mutation', 'rs3820589', (40, 49))	('rs3806401', 'Mutation', 'rs3806401', (51, 60))	('GLUT1', 'Gene', (84, 89))	('rs4658', 'Var', (21, 27))	('rs3806401', 'Mutation', 'rs3806401', (114, 123))	('NSCLC', 'Disease', (175, 180))	('rs4658', 'Mutation', 'rs4658', (21, 27))
256327	33522072	18 ,  22  In the current study, a wild-type haplotype of rs1385129G-rs3820589A-rs3806401A was associated with better OS and PFS, even though individual SNPs of rs1385129 and rs3806401 were risk factors only for OS.	('rs1385129', 'Mutation', 'rs1385129', (57, 66))	('PFS', 'Disease', (124, 127))	('rs3806401', 'Mutation', 'rs3806401', (174, 183))	('rs3806401', 'Mutation', 'rs3806401', (79, 88))	('better', 'PosReg', (110, 116))	('rs1385129G-rs3820589A-rs3806401A', 'Var', (57, 89))	('rs3820589', 'Mutation', 'rs3820589', (68, 77))	('rs1385129', 'Mutation', 'rs1385129', (160, 169))
256330	33522072	These findings suggest that testing diplotypes of these three SNPs may help predict the prognosis of patients with stage III NSCLC.	('patients', 'Species', '9606', (101, 109))	('NSCLC', 'Disease', (125, 130))	('NSCLC', 'Disease', 'MESH:D002289', (125, 130))	('diplotypes', 'Var', (36, 46))	('NSCLC', 'Phenotype', 'HP:0030358', (125, 130))
256331	33522072	In the current study, the minor allele frequencies of the three SNPs (rs1385129G>A, rs3820589A>T, and rs3806401A>C) were 15%-22%, and a GAA/GAA diplotype with all major alleles was observed in 46.7% of patients.	('rs1385129G>A', 'Var', (70, 82))	('GAA', 'Gene', '2548', (136, 139))	('GAA', 'Gene', '2548', (140, 143))	('GAA', 'Gene', (136, 139))	('patients', 'Species', '9606', (202, 210))	('rs3806401A>C', 'Var', (102, 114))	('GAA', 'Gene', (140, 143))	('rs3820589A>T', 'DBSNP_MENTION', 'None', (84, 96))	('rs3820589A>T', 'Var', (84, 96))	('rs1385129G>A', 'DBSNP_MENTION', 'None', (70, 82))	('rs3806401A>C', 'DBSNP_MENTION', 'None', (102, 114))
256336	33522072	11  GLUT1 polymorphisms were associated with the prognosis of early-stage NSCLC undergoing surgical resection only for squamous cell carcinoma, not for adenocarcinoma.	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (119, 142))	('adenocarcinoma', 'Disease', 'MESH:D000230', (152, 166))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (119, 142))	('GLUT1', 'Gene', (4, 9))	('NSCLC', 'Phenotype', 'HP:0030358', (74, 79))	('GLUT1', 'Gene', '6513', (4, 9))	('polymorphisms', 'Var', (10, 23))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('NSCLC', 'Disease', (74, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (157, 166))	('adenocarcinoma', 'Disease', (152, 166))	('NSCLC', 'Disease', 'MESH:D002289', (74, 79))	('associated with', 'Reg', (29, 44))	('squamous cell carcinoma', 'Disease', (119, 142))
256338	33522072	The following evidence supports that GLUT1 polymorphisms could be a predictive marker for adenocarcinoma as well as squamous cell carcinoma in stage III NSCLC treated with RT.	('polymorphisms', 'Var', (43, 56))	('NSCLC', 'Phenotype', 'HP:0030358', (153, 158))	('GLUT1', 'Gene', '6513', (37, 42))	('NSCLC', 'Disease', (153, 158))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (116, 139))	('adenocarcinoma', 'Disease', (90, 104))	('squamous cell carcinoma', 'Disease', (116, 139))	('NSCLC', 'Disease', 'MESH:D002289', (153, 158))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (116, 139))	('adenocarcinoma', 'Disease', 'MESH:D000230', (90, 104))	('GLUT1', 'Gene', (37, 42))
256342	33522072	Moreover, we did not investigate the relationships between GLUT1 polymorphisms and the expression level or functionality of GLUT1 protein.	('GLUT1', 'Gene', '6513', (124, 129))	('expression level', 'MPA', (87, 103))	('GLUT1', 'Gene', (59, 64))	('polymorphisms', 'Var', (65, 78))	('GLUT1', 'Gene', '6513', (59, 64))	('GLUT1', 'Gene', (124, 129))
256343	33522072	In conclusion, among patients with stage III NSCLC who received RT with or without chemotherapy, those with a homozygous pair of rs1385129G-rs3820589A-rs3806401A haplotype of GLUT1 gene showed better survival outcomes compared to those with at least one variant haplotype.	('rs3820589', 'Mutation', 'rs3820589', (140, 149))	('rs1385129', 'Mutation', 'rs1385129', (129, 138))	('survival outcomes', 'CPA', (200, 217))	('GLUT1', 'Gene', (175, 180))	('NSCLC', 'Disease', (45, 50))	('rs3806401', 'Mutation', 'rs3806401', (151, 160))	('GLUT1', 'Gene', '6513', (175, 180))	('patients', 'Species', '9606', (21, 29))	('NSCLC', 'Disease', 'MESH:D002289', (45, 50))	('better', 'PosReg', (193, 199))	('rs1385129G-rs3820589A-rs3806401A', 'Var', (129, 161))	('NSCLC', 'Phenotype', 'HP:0030358', (45, 50))
256344	33522072	This is the first study to report the prognostic impact of GLUT1 polymorphisms on the post-RT survival outcomes of patients with stage III NSCLC.	('patients', 'Species', '9606', (115, 123))	('NSCLC', 'Phenotype', 'HP:0030358', (139, 144))	('GLUT1', 'Gene', (59, 64))	('polymorphisms', 'Var', (65, 78))	('NSCLC', 'Disease', (139, 144))	('GLUT1', 'Gene', '6513', (59, 64))	('NSCLC', 'Disease', 'MESH:D002289', (139, 144))
256368	32209727	The statistical analyses revealed that for patients with LUAD, high immune scores were associated with an earlier clinical TNM stage (P = 0.008) and T stage (P = 0.003), and high stromal scores were associated with an earlier M stage (P = 0.007).	('patients', 'Species', '9606', (43, 51))	('TNM', 'Gene', (123, 126))	('high', 'Var', (63, 67))	('T stage', 'CPA', (149, 156))	('LUAD', 'Phenotype', 'HP:0030078', (57, 61))	('M stage', 'CPA', (226, 233))	('TNM', 'Gene', '10178', (123, 126))
256370	32209727	The results showed that for the patients with LUAD, high immune scores were associated with a favorable prognosis (P = 0.022), whereas the stromal scores did not have any statistically significant association with prognosis (P = 0.092).	('LUAD', 'Phenotype', 'HP:0030078', (46, 50))	('LUAD', 'Disease', (46, 50))	('high', 'Var', (52, 56))	('patients', 'Species', '9606', (32, 40))
256401	32209727	Aside from the immune infiltration, tumors' response to the immune treatment was also determined by the expression level of PD-L1, tumor mutation burden, EGFR mutation and other unknown factors.	('EGFR', 'Gene', (154, 158))	('PD-L1', 'Gene', (124, 129))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('tumors', 'Disease', 'MESH:D009369', (36, 42))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('PD-L1', 'Gene', '29126', (124, 129))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('tumor', 'Disease', (131, 136))	('mutation', 'Var', (159, 167))	('determined', 'Reg', (86, 96))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumors', 'Disease', (36, 42))	('tumor', 'Disease', (36, 41))	('EGFR', 'Gene', '1956', (154, 158))	('expression level', 'MPA', (104, 120))
256406	32209727	Consistent with this, the association between neutrophil infiltration and poor survival was also reported in gallbladder carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('gallbladder carcinoma', 'Disease', (109, 130))	('neutrophil', 'Var', (46, 56))	('gallbladder carcinoma', 'Disease', 'MESH:D005706', (109, 130))
256450	31485443	TCGA currently collects and maintains genome-wide data, including encoded and noncoding RNA expression, somatic mutations, copy number changes, and promoter methylation, etc.. Tumor development is a complex pathological process involving multiple genetic alterations, including overexpression of oncogenes and/or inactivation of tumor suppressor genes.	('Tumor', 'Phenotype', 'HP:0002664', (176, 181))	('inactivation', 'Var', (313, 325))	('tumor', 'Disease', 'MESH:D009369', (329, 334))	('tumor', 'Phenotype', 'HP:0002664', (329, 334))	('Tumor development', 'CPA', (176, 193))	('overexpression', 'PosReg', (278, 292))	('tumor', 'Disease', (329, 334))
256472	31485443	When using GEPIA to analyze the correlation between hub gene expression and the prognosis of HNSCC, we found that the overall survival rate of high-expressing TGFBI was lower than that of low-expressing TGFBI (p=0.013); compared with low-expressing SPP1, the overall survival rate of high-expressing SPP1 was lower (p=0.045); compared with low-expressing LAMB3, the overall survival rate of high-expression group of LAMB3 was lower (p=0.011).	('TGFBI', 'Gene', (159, 164))	('HNSCC', 'Phenotype', 'HP:0012288', (93, 98))	('hub', 'Gene', (52, 55))	('LAMB3', 'Gene', (416, 421))	('SPP1', 'Gene', '6696', (249, 253))	('LAMB3', 'Gene', (355, 360))	('SPP1', 'Gene', '6696', (300, 304))	('TGFBI', 'Gene', '7045', (203, 208))	('TGFBI', 'Gene', '7045', (159, 164))	('LAMB3', 'Gene', '3914', (416, 421))	('hub', 'Gene', '1993', (52, 55))	('lower', 'NegReg', (169, 174))	('LAMB3', 'Gene', '3914', (355, 360))	('TGFBI', 'Gene', (203, 208))	('SPP1', 'Gene', (300, 304))	('high-expressing', 'Var', (143, 158))	('SPP1', 'Gene', (249, 253))
256505	31485443	In addition, inhibition of LAMB3 increases cisplatin cytotoxicity of HNSCC cells.	('cytotoxicity', 'Disease', (53, 65))	('HNSCC', 'Phenotype', 'HP:0012288', (69, 74))	('inhibition', 'Var', (13, 23))	('LAMB3', 'Gene', (27, 32))	('increases', 'PosReg', (33, 42))	('LAMB3', 'Gene', '3914', (27, 32))	('cytotoxicity', 'Disease', 'MESH:D064420', (53, 65))	('cisplatin', 'Chemical', 'MESH:D002945', (43, 52))
256515	31485443	These DEGs were significantly enriched in the GOs and KEGG pathways of mitosis, cell cycle, Wnt, JAK/STAT and TLR signaling pathways.	('STAT', 'Disease', 'None', (101, 105))	('mitosis', 'Disease', (71, 78))	('STAT', 'Disease', (101, 105))	('mitosis', 'Disease', 'None', (71, 78))	('cell cycle', 'CPA', (80, 90))	('KEGG', 'Var', (54, 58))	('TLR signaling pathways', 'Pathway', (110, 132))	('Wnt', 'Pathway', (92, 95))
256527	30149601	Aberrant Regulation of mRNA m6A Modification in Cancer Development N6-methyladenosine (m6A) is the most prevalent internal modification of eukaryotic messenger RNAs (mRNAs).	('m6A', 'Gene', (28, 31))	('m6A', 'Gene', (87, 90))	('N6-methyladenosine', 'Var', (67, 85))	('m6A', 'Gene', '56339', (28, 31))	('m6A', 'Gene', '56339', (87, 90))	('Cancer', 'Phenotype', 'HP:0002664', (48, 54))	('N6-methyladenosine', 'Chemical', 'MESH:C010223', (67, 85))
256531	30149601	Accumulating evidence strongly supports the correlation between aberrant cellular m6A level and cancer.	('aberrant cellular', 'Var', (64, 81))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('m6A', 'Gene', (82, 85))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('m6A', 'Gene', '56339', (82, 85))	('cancer', 'Disease', (96, 102))
256532	30149601	We summarize here that deregulation of m6A modification, resulting from aberrant expression or function of m6A writers, erasers, readers or some other protein factors, is associated with carcinogenesis and cancer progression.	('m6A', 'Gene', (107, 110))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('carcinogenesis', 'Disease', (187, 201))	('m6A', 'Gene', '56339', (107, 110))	('m6A', 'Gene', (39, 42))	('aberrant', 'Var', (72, 80))	('carcinogenesis', 'Disease', 'MESH:D063646', (187, 201))	('cancer', 'Disease', 'MESH:D009369', (206, 212))	('m6A', 'Gene', '56339', (39, 42))	('function', 'MPA', (95, 103))	('cancer', 'Disease', (206, 212))	('deregulation', 'Var', (23, 35))	('associated', 'Reg', (171, 181))
256533	30149601	Understanding the regulation and functional mechanism of mRNA m6A modification in cancer development may help in developing novel and efficient strategies for the diagnosis, prognosis and treatment of human cancers.	('cancer', 'Disease', 'MESH:D009369', (207, 213))	('cancers', 'Disease', 'MESH:D009369', (207, 214))	('cancers', 'Phenotype', 'HP:0002664', (207, 214))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('cancers', 'Disease', (207, 214))	('cancer', 'Disease', (207, 213))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('human', 'Species', '9606', (201, 206))	('m6A', 'Gene', (62, 65))	('modification', 'Var', (66, 78))	('m6A', 'Gene', '56339', (62, 65))
256534	30149601	N6-methyladenosine (m6A) is the most abundant modification in eukaryotic mRNAs.	('m6A', 'Gene', (20, 23))	('m6A', 'Gene', '56339', (20, 23))	('N6-methyladenosine', 'Chemical', 'MESH:C010223', (0, 18))	('N6-methyladenosine', 'Var', (0, 18))
256538	30149601	N6-methyladenosine influences almost every stage of mRNA metabolism, including RNA folding and structure, maturation, nuclear export, translation, and decay, as well as other RNA modifications, such as adenosine-to-inosine editing.	('decay', 'MPA', (151, 156))	('adenosine', 'Chemical', 'MESH:D000241', (202, 211))	('structure', 'MPA', (95, 104))	('adenosine', 'Chemical', 'MESH:D000241', (9, 18))	('inosine', 'Chemical', 'MESH:D007288', (215, 222))	('N6-methyladenosine', 'Chemical', 'MESH:C010223', (0, 18))	('N6-methyladenosine', 'Var', (0, 18))	('translation', 'MPA', (134, 145))	('nuclear export', 'MPA', (118, 132))	('maturation', 'MPA', (106, 116))	('influences', 'Reg', (19, 29))	('mRNA metabolism', 'MPA', (52, 67))	('RNA folding', 'MPA', (79, 90))
256539	30149601	As the most common internal mRNA modification found in eukaryotes, m6A modification is widely implicated in multiple biological processes, such as circadian rhythm, adipogenesis, spermatogenesis, embryonic stem cell self-renewal and differentiation, cortical neurogenesis, and so on.	('modification', 'Var', (71, 83))	('cortical neurogenesis', 'Disease', 'MESH:D001750', (250, 271))	('spermatogenesis', 'CPA', (179, 194))	('m6A', 'Gene', (67, 70))	('m6A', 'Gene', '56339', (67, 70))	('cortical neurogenesis', 'Disease', (250, 271))	('implicated', 'Reg', (94, 104))	('adipogenesis', 'MPA', (165, 177))
256540	30149601	However, increasing evidence shows a correlation between aberrant cellular m6A level and cancer.	('aberrant cellular', 'Var', (57, 74))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('m6A', 'Gene', (75, 78))	('cancer', 'Disease', (89, 95))	('m6A', 'Gene', '56339', (75, 78))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
256545	30149601	The effect of aberrant m6A level on cancer development has also been addressed.	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('cancer', 'Disease', (36, 42))	('aberrant', 'Var', (14, 22))	('m6A', 'Gene', (23, 26))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('m6A', 'Gene', '56339', (23, 26))
256551	30149601	We summarize the function and regulatory mechanism of mRNA m6A in carcinogenesis and cancer progression, which highlights m6A regulatory factors as potential targets for the diagnosis, prognosis and treatment of human cancers.	('cancer', 'Disease', 'MESH:D009369', (218, 224))	('m6A', 'Gene', '56339', (122, 125))	('human', 'Species', '9606', (212, 217))	('m6A', 'Gene', '56339', (59, 62))	('cancer', 'Disease', (218, 224))	('mRNA', 'Var', (54, 58))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('cancers', 'Disease', 'MESH:D009369', (218, 225))	('cancers', 'Phenotype', 'HP:0002664', (218, 225))	('cancers', 'Disease', (218, 225))	('cancer', 'Disease', (85, 91))	('carcinogenesis', 'Disease', 'MESH:D063646', (66, 80))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('carcinogenesis', 'Disease', (66, 80))	('m6A', 'Gene', (122, 125))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('m6A', 'Gene', (59, 62))
256569	30149601	Proteins that selectively bind m6A can be defined as m6A "readers" that exert regulatory functions by selective recognition of methylated RNA.	('m6A', 'Gene', '56339', (31, 34))	('m6A', 'Gene', '56339', (53, 56))	('methylated', 'Var', (127, 137))	('regulatory', 'MPA', (78, 88))	('m6A', 'Gene', (53, 56))	('RNA', 'Protein', (138, 141))	('m6A', 'Gene', (31, 34))
256575	30149601	It presents a dynamic and multi-dimensional mechanism of m6A modification in regulating gene expression.	('modification', 'Var', (61, 73))	('m6A', 'Gene', (57, 60))	('regulating gene expression', 'MPA', (77, 103))	('m6A', 'Gene', '56339', (57, 60))
256588	30149601	Moreover, m6A modulated by METTL3 promotes leukemogenesis.	('m6A', 'Gene', '56339', (10, 13))	('METTL3', 'Gene', '56339', (27, 33))	('promotes', 'PosReg', (34, 42))	('METTL3', 'Gene', (27, 33))	('m6A', 'Gene', (10, 13))	('modulated', 'Var', (14, 23))	('leukemogenesis', 'Disease', (43, 57))
256590	30149601	Furthermore, depletion of METTL3 in human myeloid leukemia cell lines facilitates differentiation and apoptosis and delays leukemia development in recipient mice in vivo.	('METTL3', 'Gene', (26, 32))	('leukemia', 'Phenotype', 'HP:0001909', (123, 131))	('delays leukemia', 'Disease', 'MESH:D007938', (116, 131))	('mice', 'Species', '10090', (157, 161))	('apoptosis', 'CPA', (102, 111))	('facilitates', 'PosReg', (70, 81))	('myeloid leukemia', 'Disease', (42, 58))	('depletion', 'Var', (13, 22))	('myeloid leukemia', 'Disease', 'MESH:D007951', (42, 58))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (42, 58))	('delays leukemia', 'Disease', (116, 131))	('METTL3', 'Gene', '56339', (26, 32))	('leukemia', 'Phenotype', 'HP:0001909', (50, 58))	('human', 'Species', '9606', (36, 41))	('differentiation', 'CPA', (82, 97))
256592	30149601	METTL3 depletion in AML cells reduces the translation of such transcripts, resulting in AKT activation, increased cell differentiation and apoptosis.	('activation', 'PosReg', (92, 102))	('AKT', 'Pathway', (88, 91))	('cell differentiation', 'CPA', (114, 134))	('increased', 'PosReg', (104, 113))	('METTL3', 'Gene', '56339', (0, 6))	('METTL3', 'Gene', (0, 6))	('depletion', 'Var', (7, 16))	('AML', 'Disease', 'MESH:D015470', (20, 23))	('translation', 'MPA', (42, 53))	('reduces', 'NegReg', (30, 37))	('AML', 'Phenotype', 'HP:0004808', (20, 23))	('apoptosis', 'CPA', (139, 148))	('AML', 'Disease', (20, 23))
256593	30149601	One recent study demonstrated a vital role of METTL3-regulated m6A modification in the maintenance and radioresistance of glioma stem-like cells.	('m6A', 'Gene', (63, 66))	('glioma', 'Disease', 'MESH:D005910', (122, 128))	('m6A', 'Gene', '56339', (63, 66))	('modification', 'Var', (67, 79))	('glioma', 'Disease', (122, 128))	('METTL3', 'Gene', '56339', (46, 52))	('METTL3', 'Gene', (46, 52))	('maintenance', 'CPA', (87, 98))	('glioma', 'Phenotype', 'HP:0009733', (122, 128))
256594	30149601	METTL3 was upregulated in glioma stem-like cells over the matched differentiated glioma cells and its silencing suppressed tumor growth in vivo.	('glioma', 'Phenotype', 'HP:0009733', (81, 87))	('suppressed', 'NegReg', (112, 122))	('tumor', 'Disease', (123, 128))	('METTL3', 'Gene', '56339', (0, 6))	('glioma', 'Disease', (81, 87))	('upregulated', 'PosReg', (11, 22))	('glioma', 'Disease', (26, 32))	('METTL3', 'Gene', (0, 6))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('silencing', 'Var', (102, 111))	('glioma', 'Disease', 'MESH:D005910', (26, 32))	('glioma', 'Phenotype', 'HP:0009733', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('glioma', 'Disease', 'MESH:D005910', (81, 87))
256595	30149601	SOX2, one of the glioma reprogramming factors, was methylated in its specific sites of mRNA 3' UTR by METTL3.	('SOX2', 'Gene', '6657', (0, 4))	('glioma', 'Disease', 'MESH:D005910', (17, 23))	('glioma', 'Phenotype', 'HP:0009733', (17, 23))	('METTL3', 'Gene', (102, 108))	('methylated', 'Var', (51, 61))	('glioma', 'Disease', (17, 23))	('SOX2', 'Gene', (0, 4))	('METTL3', 'Gene', '56339', (102, 108))
256599	30149601	A sphere formation assay revealed that pancreatic cancer cells with METTL3 knockdown showed significantly lower self-renewal abilities than control cells.	('lower', 'NegReg', (106, 111))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (39, 56))	('METTL3', 'Gene', (68, 74))	('self-renewal abilities', 'CPA', (112, 134))	('knockdown', 'Var', (75, 84))	('pancreatic cancer', 'Disease', (39, 56))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('pancreatic cancer', 'Disease', 'MESH:D010190', (39, 56))	('METTL3', 'Gene', '56339', (68, 74))
256600	30149601	Moreover, METTL3 depletion enhanced chemo- and radiosensitivity of cancer cells, which suggests that METTL3 has an important role in the acquisition of resistance to anticancer drugs and irradiation.	('METTL3', 'Gene', (101, 107))	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('cancer', 'Disease', (170, 176))	('cancer', 'Disease', (67, 73))	('enhanced', 'PosReg', (27, 35))	('METTL3', 'Gene', '56339', (10, 16))	('METTL3', 'Gene', (10, 16))	('depletion', 'Var', (17, 26))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('METTL3', 'Gene', '56339', (101, 107))
256606	30149601	In 2017, one study found that m6A modification decreased in hepatocellular carcinoma (HCC), especially in metastatic HCC, and METTL14 was responsible for the aberrant m6A modification in this kind of cancer.	('HCC', 'Phenotype', 'HP:0001402', (117, 120))	('metastatic HCC', 'Disease', (106, 120))	('METTL14', 'Gene', '57721', (126, 133))	('METTL14', 'Gene', (126, 133))	('cancer', 'Disease', 'MESH:D009369', (200, 206))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('HCC', 'Phenotype', 'HP:0001402', (86, 89))	('m6A', 'Gene', (30, 33))	('modification', 'Var', (34, 46))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (60, 84))	('m6A', 'Gene', (167, 170))	('m6A', 'Gene', '56339', (30, 33))	('hepatocellular carcinoma', 'Disease', (60, 84))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (60, 84))	('m6A', 'Gene', '56339', (167, 170))	('cancer', 'Disease', (200, 206))	('decreased', 'NegReg', (47, 56))
256607	30149601	It was also found that METTL14 knockdown raised the metastatic capacity of HCC, but METTL14 overexpression restrained invasiveness and metastasis in HCC.	('restrained', 'NegReg', (107, 117))	('METTL14', 'Gene', '57721', (23, 30))	('HCC', 'Phenotype', 'HP:0001402', (149, 152))	('overexpression', 'PosReg', (92, 106))	('HCC', 'Phenotype', 'HP:0001402', (75, 78))	('METTL14', 'Gene', '57721', (84, 91))	('metastatic capacity of HCC', 'CPA', (52, 78))	('METTL14', 'Gene', (84, 91))	('METTL14', 'Gene', (23, 30))	('raised', 'PosReg', (41, 47))	('knockdown', 'Var', (31, 40))
256608	30149601	Mechanistically, METTL14-dependent m6A methylation promoted the recognition and binding of DGCR8 to pri-miR-126 and enhanced its processing to mature miR-126.	('m6A', 'Gene', (35, 38))	('miR-126', 'Gene', (150, 157))	('enhanced', 'PosReg', (116, 124))	('methylation', 'Var', (39, 50))	('METTL14', 'Gene', '57721', (17, 24))	('METTL14', 'Gene', (17, 24))	('m6A', 'Gene', '56339', (35, 38))	('DGCR8', 'Gene', (91, 96))	('miR-126', 'Gene', '406913', (104, 111))	('miR-126', 'Gene', (104, 111))	('promoted', 'PosReg', (51, 59))	('DGCR8', 'Gene', '54487', (91, 96))	('binding', 'Interaction', (80, 87))	('recognition', 'Interaction', (64, 75))	('miR-126', 'Gene', '406913', (150, 157))
256614	30149601	Recently, high expression of METTL14 was observed in acute myeloid leukemia (AML) cells with t(11q23), t(15;17), or t(8;21), as well as in hematopoietic stem/progenitor cells (HSPCs).	('AML', 'Disease', 'MESH:D015470', (77, 80))	('acute myeloid leukemia', 'Disease', (53, 75))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (53, 75))	('t(11q23', 'Var', (93, 100))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (59, 75))	('AML', 'Disease', (77, 80))	('t(15;17', 'Var', (103, 110))	('expression', 'MPA', (15, 25))	('observed', 'Reg', (41, 49))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (53, 75))	('AML', 'Phenotype', 'HP:0004808', (77, 80))	('t(8;21', 'Var', (116, 122))	('leukemia', 'Phenotype', 'HP:0001909', (67, 75))	('METTL14', 'Gene', '57721', (29, 36))	('METTL14', 'Gene', (29, 36))
256616	30149601	Moreover, METTL14 depletion inhibited AML cell proliferation or survival and promoted terminal myeloid differentiation of normal HSPCs and AML cells.	('AML', 'Disease', (38, 41))	('survival', 'CPA', (64, 72))	('AML', 'Disease', 'MESH:D015470', (139, 142))	('promoted', 'PosReg', (77, 85))	('METTL14', 'Gene', (10, 17))	('AML', 'Phenotype', 'HP:0004808', (139, 142))	('METTL14', 'Gene', '57721', (10, 17))	('AML', 'Disease', (139, 142))	('inhibited', 'NegReg', (28, 37))	('terminal myeloid differentiation', 'CPA', (86, 118))	('depletion', 'Var', (18, 27))	('AML', 'Disease', 'MESH:D015470', (38, 41))	('AML', 'Phenotype', 'HP:0004808', (38, 41))
256619	30149601	As the first identified RNA m6A eraser, FTO has been demonstrated to promote leukemic oncogene-mediated cell transformation and leukemogenesis.	('m6A', 'Gene', (28, 31))	('leukemic', 'Disease', (77, 85))	('FTO', 'Var', (40, 43))	('m6A', 'Gene', '56339', (28, 31))	('leukemogenesis', 'Disease', (128, 142))	('promote', 'PosReg', (69, 76))	('leukemic', 'Disease', 'MESH:D007938', (77, 85))
256620	30149601	FTO is activated by several leukemic oncoproteins, and therefore is highly expressed in several AML subtypes (e.g., t(11q23)/MLL-rearranged, t(15;17), FLT3-ITD, and/or NPM1-mutated AMLs).	('AML', 'Disease', (96, 99))	('NPM1', 'Gene', '4869', (168, 172))	('AML', 'Phenotype', 'HP:0004808', (181, 184))	('leukemic oncoproteins', 'Disease', 'MESH:D007938', (28, 49))	('t(15;17', 'Var', (141, 148))	('leukemic oncoproteins', 'Disease', (28, 49))	('AML', 'Phenotype', 'HP:0004808', (96, 99))	('FLT3', 'Gene', '2322', (151, 155))	('FTO', 'Gene', (0, 3))	('AML', 'Disease', 'MESH:D015470', (181, 184))	('NPM1', 'Gene', (168, 172))	('MLL', 'Gene', '4297', (125, 128))	('AML', 'Disease', 'MESH:D015470', (96, 99))	('MLL', 'Gene', (125, 128))	('AML', 'Disease', (181, 184))	('FLT3', 'Gene', (151, 155))
256628	30149601	Moreover, there is a positive correlation between FTO and beta-catenin expression in human CSCC samples, and the combination of FTO and beta-catenin confers better prognostic value for overall survival of CSCC than FTO alone.	('beta-catenin', 'Gene', '1499', (136, 148))	('beta-catenin', 'Gene', (58, 70))	('better', 'PosReg', (157, 163))	('beta-catenin', 'Gene', '1499', (58, 70))	('FTO', 'Gene', (128, 131))	('beta-catenin', 'Gene', (136, 148))	('human', 'Species', '9606', (85, 90))	('combination', 'Var', (113, 124))
256630	30149601	R-2-hydroxyglutarate (R-2HG), which is generated by mutant isocitrate dehydrogenase 1/2 (IDH1/2) and is regarded as an oncometabolite, also possesses anti-tumor effect in leukemia.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('IDH1/2', 'Gene', '3417;3418', (89, 95))	('leukemia', 'Phenotype', 'HP:0001909', (171, 179))	('leukemia', 'Disease', 'MESH:D007938', (171, 179))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('mutant', 'Var', (52, 58))	('leukemia', 'Disease', (171, 179))	('IDH1/2', 'Gene', (89, 95))	('tumor', 'Disease', (155, 160))	('R-2-hydroxyglutarate', 'Chemical', '-', (0, 20))
256631	30149601	By directly binding and restraining the demethylase activity of FTO, R-2HG promotes overall m6A modification in R-2HG-sensitive leukemia cells.	('demethylase activity', 'MPA', (40, 60))	('R-2HG', 'Var', (69, 74))	('promotes', 'PosReg', (75, 83))	('leukemia', 'Phenotype', 'HP:0001909', (128, 136))	('leukemia', 'Disease', 'MESH:D007938', (128, 136))	('m6A', 'Gene', (92, 95))	('leukemia', 'Disease', (128, 136))	('binding', 'Interaction', (12, 19))	('restraining', 'NegReg', (24, 35))	('m6A', 'Gene', '56339', (92, 95))
256633	30149601	Therefore, R-2HG displays anti-leukemia activity by suppressing FTO/m6A/MYC/CEBPA signaling, as well as relevant pathways.	('m6A/MYC', 'Gene', '56339;4609', (68, 75))	('leukemia', 'Disease', (31, 39))	('R-2HG', 'Var', (11, 16))	('CEBPA', 'Gene', '1050', (76, 81))	('leukemia', 'Disease', 'MESH:D007938', (31, 39))	('leukemia', 'Phenotype', 'HP:0001909', (31, 39))	('m6A/MYC', 'Gene', (68, 75))	('suppressing', 'NegReg', (52, 63))	('CEBPA', 'Gene', (76, 81))
256634	30149601	ALKBH5-mediated demethylation of mRNA N6-methyladenosine has been linked to cancer stem cell phenotypes.	('ALKBH5', 'Gene', (0, 6))	('mRNA', 'Var', (33, 37))	('demethylation', 'MPA', (16, 29))	('linked', 'Reg', (66, 72))	('N6-methyladenosine', 'Chemical', 'MESH:C010223', (38, 56))	('ALKBH5', 'Gene', '54890', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))
256640	30149601	Furthermore, ALKBH5 demethylates FOXM1 pre-mRNA and increases its stability by interaction with HuR.	('HuR', 'Gene', (96, 99))	('HuR', 'Gene', '1994', (96, 99))	('FOXM1', 'Gene', (33, 38))	('interaction', 'Interaction', (79, 90))	('stability', 'MPA', (66, 75))	('increases', 'PosReg', (52, 61))	('FOXM1', 'Gene', '2305', (33, 38))	('demethylates', 'Var', (20, 32))	('ALKBH5', 'Gene', '54890', (13, 19))	('ALKBH5', 'Gene', (13, 19))
256642	30149601	Recently, another study also reported that RNA m6A modification regulated the self-renewal and tumorigenesis of glioblastoma stem cells.	('self-renewal', 'CPA', (78, 90))	('glioblastoma', 'Disease', (112, 124))	('glioblastoma', 'Disease', 'MESH:D005909', (112, 124))	('glioblastoma', 'Phenotype', 'HP:0012174', (112, 124))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('modification', 'Var', (51, 63))	('regulated', 'Reg', (64, 73))	('m6A', 'Gene', (47, 50))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('m6A', 'Gene', '56339', (47, 50))	('tumor', 'Disease', (95, 100))
256643	30149601	It was found that knockdown of METTL3 or METTL14 expression enhanced, but overexpression of METTL3 inhibited, GSC growth and self-renewal.	('knockdown', 'Var', (18, 27))	('METTL14', 'Gene', '57721', (41, 48))	('METTL3', 'Gene', '56339', (31, 37))	('METTL14', 'Gene', (41, 48))	('GSC growth', 'CPA', (110, 120))	('METTL3', 'Gene', (31, 37))	('METTL3', 'Gene', '56339', (92, 98))	('self-renewal', 'CPA', (125, 137))	('enhanced', 'PosReg', (60, 68))	('METTL3', 'Gene', (92, 98))
256644	30149601	Likewise, inhibition of the RNA demethylase FTO with its inhibitor MA2 reduced GSC-initiated tumor growth and prolonged the lifespan of GSC-grafted mice substantially.	('FTO', 'Enzyme', (44, 47))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Disease', (93, 98))	('mice', 'Species', '10090', (148, 152))	('reduced', 'NegReg', (71, 78))	('GSC-initiated', 'Disease', (79, 92))	('prolonged', 'PosReg', (110, 119))	('inhibition', 'Var', (10, 20))	('lifespan', 'CPA', (124, 132))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
256660	30149601	Considering the accumulating evidence that ZNF217 plays an essential role in tumor progression, metastasis, and chemoresistance, it is predictable that ZNF217-regulated m6A modification, possibly by interaction with METTL3, is relevant in human cancers.	('modification', 'Var', (173, 185))	('METTL3', 'Gene', '56339', (216, 222))	('m6A', 'Gene', (169, 172))	('cancers', 'Disease', 'MESH:D009369', (245, 252))	('cancers', 'Phenotype', 'HP:0002664', (245, 252))	('cancers', 'Disease', (245, 252))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('METTL3', 'Gene', (216, 222))	('m6A', 'Gene', '56339', (169, 172))	('ZNF217', 'Gene', (152, 158))	('ZNF217', 'Gene', '7764', (152, 158))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('ZNF217', 'Gene', (43, 49))	('ZNF217', 'Gene', '7764', (43, 49))	('human', 'Species', '9606', (239, 244))	('tumor', 'Disease', (77, 82))	('cancer', 'Phenotype', 'HP:0002664', (245, 251))
256664	30149601	Thus, the TGFbeta pathway may be involved in cancer development by affecting m6A epigenetic modification.	('involved', 'Reg', (33, 41))	('epigenetic modification', 'Var', (81, 104))	('affecting', 'Reg', (67, 76))	('TGFbeta', 'Gene', '7040', (10, 17))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('m6A', 'Gene', (77, 80))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('m6A', 'Gene', '56339', (77, 80))	('TGFbeta', 'Gene', (10, 17))	('cancer', 'Disease', (45, 51))
256669	30149601	Therefore, overexpression or depletion of these m6A-related factors may alter m6A modification in tumors and interfere with cancer progression.	('depletion', 'Var', (29, 38))	('tumors', 'Disease', (98, 104))	('cancer', 'Disease', (124, 130))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('tumors', 'Disease', 'MESH:D009369', (98, 104))	('m6A', 'Gene', '56339', (48, 51))	('interfere', 'NegReg', (109, 118))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('alter', 'Reg', (72, 77))	('m6A', 'Gene', (78, 81))	('cancer', 'Disease', 'MESH:D009369', (124, 130))	('overexpression', 'PosReg', (11, 25))	('modification', 'MPA', (82, 94))	('m6A', 'Gene', (48, 51))	('m6A', 'Gene', '56339', (78, 81))
256679	30149601	Elucidating the regulatory mechanism of mRNA m6A modification in carcinogenesis and cancer progression would serve to develop m6A-related factors as valuable targets for the treatment of human cancers.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('cancers', 'Disease', 'MESH:D009369', (193, 200))	('cancers', 'Phenotype', 'HP:0002664', (193, 200))	('m6A', 'Gene', '56339', (45, 48))	('cancer', 'Disease', (84, 90))	('cancers', 'Disease', (193, 200))	('cancer', 'Disease', (193, 199))	('modification', 'Var', (49, 61))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('human', 'Species', '9606', (187, 192))	('carcinogenesis', 'Disease', 'MESH:D063646', (65, 79))	('m6A', 'Gene', (126, 129))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('carcinogenesis', 'Disease', (65, 79))	('m6A', 'Gene', (45, 48))	('m6A', 'Gene', '56339', (126, 129))
256689	26219895	Patients with highly expressed C14ORF166 showed a tendency to receive postoperative chemotherapy (P = 0.005) and postoperative radiation (P = 0.008).	('C14ORF166', 'Gene', '51637', (31, 40))	('highly expressed', 'Var', (14, 30))	('C14ORF166', 'Gene', (31, 40))	('postoperative', 'CPA', (70, 83))	('Patients', 'Species', '9606', (0, 8))
256700	26219895	Patients with lymph node metastasis have a higher rate of mortality than patients without lymph node metastasis, and assessment of lymph node metastasis provides important information for determining the appropriate treatment approach.	('Patients', 'Species', '9606', (0, 8))	('mortality', 'CPA', (58, 67))	('lymph node metastasis', 'Var', (14, 35))	('patients', 'Species', '9606', (73, 81))
256741	26219895	The proportion of tumor cells was scored as follows: 1 (<10 % positive tumor cells), 2 (10-50 % positive tumor cells), 3 (50-75 % positive tumor cells), and 4 (>75 % positive tumor cells).	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('tumor', 'Disease', (175, 180))	('10-50', 'Var', (88, 93))	('tumor', 'Disease', (18, 23))	('50-75', 'Var', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumor', 'Disease', (71, 76))	('tumor', 'Disease', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
256744	26219895	An optimal cut-off value was identified as follows: a staining index score of >6 was utilized to define tumors with high C14ORF166 expression and <=6 suggested low C14ORF166 expression.	('low', 'NegReg', (160, 163))	('C14ORF166', 'Gene', '51637', (121, 130))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('C14ORF166', 'Gene', (121, 130))	('expression', 'MPA', (174, 184))	('high', 'Var', (116, 120))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('expression', 'MPA', (131, 141))	('tumors', 'Disease', (104, 110))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('C14ORF166', 'Gene', '51637', (164, 173))	('C14ORF166', 'Gene', (164, 173))
256763	26219895	In addition, patients with highly expressed C14ORF166 showed a tendency to receive postoperative chemotherapy (0.224; P = 0.005) and postoperative radiation (0.213; P = 0.008).	('highly expressed', 'Var', (27, 43))	('postoperative', 'CPA', (83, 96))	('patients', 'Species', '9606', (13, 21))	('C14ORF166', 'Gene', '51637', (44, 53))	('C14ORF166', 'Gene', (44, 53))
256778	26219895	In this cohort, we showed that aberrant expression of C14ORF166 protein was associated with significantly poorer 5-year OS and DFS.	('DFS', 'CPA', (127, 130))	('poorer', 'NegReg', (106, 112))	('C14ORF166', 'Gene', '51637', (54, 63))	('5-year OS', 'CPA', (113, 122))	('C14ORF166', 'Gene', (54, 63))	('aberrant expression', 'Var', (31, 50))	('protein', 'Protein', (64, 71))
256779	26219895	Multivariate Cox regression analysis revealed that a high level of C14ORF166 was an independent prognostic marker for cervical cancer.	('cervical cancer', 'Disease', (118, 133))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('Cox', 'Gene', (13, 16))	('high level', 'Var', (53, 63))	('C14ORF166', 'Gene', '51637', (67, 76))	('C14ORF166', 'Gene', (67, 76))	('cervical cancer', 'Disease', 'MESH:D002583', (118, 133))	('Cox', 'Gene', '1351', (13, 16))
256789	26219895	Hyperactivation of inflammatory pathways plays an important role in cervical cancer tumorgenesis, and promotes progression from low-grade lesions to invasive cervical cancer.	('cervical cancer tumorgenesis', 'Disease', (68, 96))	('invasive cervical cancer', 'Disease', (149, 173))	('promotes', 'PosReg', (102, 110))	('invasive cervical cancer', 'Disease', 'MESH:D002583', (149, 173))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('cervical cancer tumorgenesis', 'Disease', 'MESH:D002583', (68, 96))	('inflammatory pathways', 'Pathway', (19, 40))	('Hyperactivation', 'Var', (0, 15))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))
256815	26219895	Patients with highly expressed C14ORF166 showed a tendency to receive postoperative chemotherapy and postoperative radiation.	('C14ORF166', 'Gene', '51637', (31, 40))	('highly expressed', 'Var', (14, 30))	('C14ORF166', 'Gene', (31, 40))	('postoperative', 'CPA', (70, 83))	('Patients', 'Species', '9606', (0, 8))
256824	33658304	Patients with high YES1 tumor levels also showed high infiltration of CD4+/FOXP3+ cells (regulatory T cells (Tregs)), suggesting an immunosuppressive phenotype.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumor', 'Disease', (24, 29))	('Tregs', 'Chemical', '-', (109, 114))	('YES1', 'Gene', (19, 23))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('high', 'Var', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('CD4+/FOXP3+', 'MPA', (70, 81))
256844	33658304	In preclinical murine models of melanoma, sarcoma, breast and colorectal cancer, dasatinib has been shown to cause antitumor effects by increasing the number of tumor-infiltrating CD8+ cells and decreasing that of Tregs.	('sarcoma', 'Phenotype', 'HP:0100242', (42, 49))	('dasatinib', 'Chemical', 'MESH:D000069439', (81, 90))	('melanoma', 'Phenotype', 'HP:0002861', (32, 40))	('melanoma', 'Disease', (32, 40))	('colorectal cancer', 'Phenotype', 'HP:0003003', (62, 79))	('decreasing', 'NegReg', (195, 205))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('Tregs', 'CPA', (214, 219))	('tumor', 'Disease', (161, 166))	('murine', 'Species', '10090', (15, 21))	('dasatinib', 'Var', (81, 90))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('CD8', 'Gene', '925', (180, 183))	('Tregs', 'Chemical', '-', (214, 219))	('colorectal cancer', 'Disease', 'MESH:D015179', (62, 79))	('melanoma', 'Disease', 'MESH:D008545', (32, 40))	('breast', 'Disease', (51, 57))	('colorectal cancer', 'Disease', (62, 79))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('sarcoma', 'Disease', 'MESH:D012509', (42, 49))	('sarcoma', 'Disease', (42, 49))	('tumor', 'Disease', (119, 124))	('increasing', 'PosReg', (136, 146))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('CD8', 'Gene', (180, 183))
256851	33658304	We herein demonstrate that YES1 expression is found, among other SFK members, as the strongest predictor of poor prognosis in patients with NSCLC, and that high YES1 protein levels are associated with increased number of tumor-infiltrating Tregs.	('YES1', 'Gene', (27, 31))	('NSCLC', 'Disease', 'MESH:D002289', (140, 145))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('tumor', 'Disease', (221, 226))	('high', 'Var', (156, 160))	('tumor', 'Disease', 'MESH:D009369', (221, 226))	('protein', 'Protein', (166, 173))	('Tregs', 'Chemical', '-', (240, 245))	('NSCLC', 'Phenotype', 'HP:0030358', (140, 145))	('patients', 'Species', '9606', (126, 134))	('YES1', 'Gene', (161, 165))	('NSCLC', 'Disease', (140, 145))
256862	33658304	The following primary antibodies were used: anti-FOXP3, anti-CK, anti-CD31, anti-CD4, anti-CD8 and anti-F4/80.	('CD8', 'Gene', (91, 94))	('CD8', 'Gene', '925', (91, 94))	('anti-FOXP3', 'Var', (44, 54))	('anti-F4/80', 'Var', (99, 109))	('anti-CK', 'Var', (56, 63))	('CD31', 'Gene', '18613', (70, 74))	('anti-CD4', 'Var', (76, 84))	('CD31', 'Gene', (70, 74))
256866	33658304	Previously characterized murine cell lines used for functional experiments were 393P and UNSCC680AJ (from now on referred to as UN680).	('UNSCC680AJ', 'Var', (89, 99))	('393P', 'Var', (80, 84))	('murine', 'Species', '10090', (25, 31))
256877	33658304	The effect of knocking down YES1 in tumor cells, in combination with anti-PD-1, was studied in an in vivo experiment with 393P-shRNA-transduced cells.	('YES1', 'Gene', (28, 32))	('knocking down', 'Var', (14, 27))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumor', 'Disease', (36, 41))
256884	33658304	On day 14, tumors and spleens were surgically excised, mechanically disaggregated and digested with collagenase (400 MandL units/mL, Roche) and DNase (10 mg/mL, Roche).	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('tumors', 'Phenotype', 'HP:0002664', (11, 17))	('tumors', 'Disease', 'MESH:D009369', (11, 17))	('tumors', 'Disease', (11, 17))	('400', 'Var', (113, 116))
256905	33658304	SRC expression was not related to prognosis and low FYN levels predicted worse outcome (not shown).	('FYN', 'Gene', (52, 55))	('SRC', 'Gene', (0, 3))	('FYN', 'Gene', '14360', (52, 55))	('low', 'Var', (48, 51))	('SRC', 'Gene', '20779', (0, 3))
256906	33658304	Therefore, we conclude that YES1 is the strongest predictor of reduced OS in NSCLC, among all these SFKs.	('NSCLC', 'Disease', 'MESH:D002289', (77, 82))	('YES1', 'Var', (28, 32))	('reduced', 'NegReg', (63, 70))	('NSCLC', 'Phenotype', 'HP:0030358', (77, 82))	('OS in', 'MPA', (71, 76))	('NSCLC', 'Disease', (77, 82))
256907	33658304	Based on these results, we hypothesized that high YES1 levels could be associated with a more immunosuppressive TME, which could explain the worse outcome of patients with high levels of YES1.	('more', 'PosReg', (89, 93))	('patients', 'Species', '9606', (158, 166))	('high', 'Var', (45, 49))	('YES1', 'Gene', (50, 54))
256916	33658304	This analysis showed that patients with LUAD with high YES1 expression tended to have a higher number of Treg cells, although this difference did not reach statistical significance (p=0.055, figure 1I).	('YES1', 'Gene', (55, 59))	('higher', 'PosReg', (88, 94))	('Treg', 'Chemical', '-', (105, 109))	('Treg cells', 'CPA', (105, 115))	('patients', 'Species', '9606', (26, 34))	('LUAD', 'Disease', (40, 44))	('LUAD', 'Phenotype', 'HP:0030078', (40, 44))	('high', 'Var', (50, 54))
256926	33658304	As shown in figure 2D, a decrease in phospho(p)-SFKs was observed on dasatinib administration (20 nM-15microM).	('phospho', 'MPA', (37, 44))	('dasatinib', 'Chemical', 'MESH:D000069439', (69, 78))	('decrease', 'NegReg', (25, 33))	('20 nM-15microM', 'Var', (95, 109))
256942	33658304	To ascertain to what extent expression of YES1 in cancer cells was mediating the therapeutic effect, we silenced YES1 in 393 P cells using shRNA and performed an in vivo experiment with or without combination with anti-PD-1 (online supplemental figure 2C, D).	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('silenced', 'Var', (104, 112))	('YES1', 'Gene', (113, 117))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))
256943	33658304	As expected, YES1 knockdown improved anti-PD-1 efficacy, obtaining a 52% reduction in the tumor volume for the shYES1+ anti-PD-1 group compared with the untreated controls (sh-scramble) and 41% with respect to the sh-scramble +anti-PD-1 treated group (online supplemental figure 2C, D).	('knockdown', 'Var', (18, 27))	('improved', 'PosReg', (28, 36))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('YES1', 'Gene', (13, 17))	('reduction', 'NegReg', (73, 82))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
256945	33658304	Dasatinib and/or combination treatments led to a very significant decrease in the number of Tregs (CD4+CD25+FOXP3+) and levels of PD-1 in CD8+ and in CD4+ cells (the latter ones likely reflecting exhausted T lymphocytes) (figure 4B-D).	('combination', 'Var', (17, 28))	('levels of PD-1', 'MPA', (120, 134))	('Tregs', 'Chemical', '-', (92, 97))	('Dasatinib', 'Chemical', 'MESH:D000069439', (0, 9))	('CD8', 'Gene', (138, 141))	('CD8', 'Gene', '925', (138, 141))	('decrease', 'NegReg', (66, 74))	('Tregs', 'CPA', (92, 97))
256947	33658304	None of the treatments alone or in combination modified the frequency of CD45+, CD4+, CD8+, NK cells or macrophages (figure 4F-H and online supplemental figure 3B-I).	('CD45', 'Gene', (73, 77))	('CD45', 'Gene', '19264', (73, 77))	('CD8', 'Gene', (86, 89))	('CD8', 'Gene', '925', (86, 89))	('CD4+', 'Var', (80, 84))
256952	33658304	Representative images of FOXP3+/CD4+ cells are shown in figure 5B and a representative picture of a wide-field tumor where all seven markers are merged, in figure 5C.	('tumor', 'Disease', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('FOXP3+/CD4+ cells', 'Var', (25, 42))
256953	33658304	A lower number of CD31+ cells was also detected in animals administered with anti-PD-1 and the combination treatment, suggesting an impaired angiogenesis in these groups.	('angiogenesis', 'CPA', (141, 153))	('impaired', 'NegReg', (132, 140))	('CD31', 'Gene', '18613', (18, 22))	('CD31', 'Gene', (18, 22))	('anti-PD-1', 'Var', (77, 86))
256968	33658304	A strong inhibition of pLCK levels was found in the Treg cells treated with dasatinib (10 nM) compared with untreated cells (figure 6E).	('inhibition', 'NegReg', (9, 19))	('dasatinib (10 nM', 'Var', (76, 92))	('LCK', 'Gene', (24, 27))	('LCK', 'Gene', '16818', (24, 27))	('dasatinib', 'Chemical', 'MESH:D000069439', (76, 85))	('Treg', 'Chemical', '-', (52, 56))
256972	33658304	We next evaluated whether the decrease in the percentage of Tregs observed in 393P tumors could be due not only to an inhibition of Treg cell proliferation but also to a blockade of the conversion of effector CD4+ T cells into Tregs.	('Treg cell proliferation', 'CPA', (132, 155))	('393P', 'Var', (78, 82))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('Treg', 'Chemical', '-', (60, 64))	('inhibition', 'NegReg', (118, 128))	('decrease', 'NegReg', (30, 38))	('tumors', 'Disease', (83, 89))	('Tregs', 'Chemical', '-', (60, 65))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('blockade', 'NegReg', (170, 178))	('Tregs', 'Chemical', '-', (227, 232))	('tumors', 'Disease', 'MESH:D009369', (83, 89))	('Treg', 'Chemical', '-', (227, 231))	('Treg', 'Chemical', '-', (132, 136))	('Tregs', 'CPA', (60, 65))
256983	33658304	For example, the coexistence of KRAS and STK11 (LKB1) mutations, which is estimated in 8%-30% of patients with NSCLC, is associated with an immunosuppressive TME characterized by high infiltration of tumor-associated neutrophils that secrete IL-6 and CXCL-10.	('NSCLC', 'Disease', (111, 116))	('associated with', 'Reg', (121, 136))	('NSCLC', 'Phenotype', 'HP:0030358', (111, 116))	('mutations', 'Var', (54, 63))	('tumor', 'Disease', (200, 205))	('LKB1', 'Gene', '6794', (48, 52))	('IL-6', 'Gene', '3569', (242, 246))	('KRAS', 'Gene', '3845', (32, 36))	('CXCL-10', 'Gene', '3627', (251, 258))	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('IL-6', 'Gene', (242, 246))	('KRAS', 'Gene', (32, 36))	('STK11', 'Gene', (41, 46))	('CXCL-10', 'Gene', (251, 258))	('patients', 'Species', '9606', (97, 105))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('LKB1', 'Gene', (48, 52))	('NSCLC', 'Disease', 'MESH:D002289', (111, 116))	('STK11', 'Gene', '6794', (41, 46))
256984	33658304	On the contrary, concurrent KRAS-TP53 mutations are associated with infiltration of effector CD8+ T lymphocytes and responsiveness to anti-PD-1 therapy.	('KRAS', 'Gene', (28, 32))	('KRAS', 'Gene', '3845', (28, 32))	('associated', 'Reg', (52, 62))	('TP53', 'Gene', '22059', (33, 37))	('TP53', 'Gene', (33, 37))	('CD8', 'Gene', (93, 96))	('mutations', 'Var', (38, 47))	('CD8', 'Gene', '925', (93, 96))
256987	33658304	Here we show that expression of the SFK member YES1 in ADC is significantly associated with an increase in the number of Tregs in patients with NSCLC.	('NSCLC', 'Disease', (144, 149))	('NSCLC', 'Disease', 'MESH:D002289', (144, 149))	('increase', 'PosReg', (95, 103))	('patients', 'Species', '9606', (130, 138))	('YES1', 'Gene', (47, 51))	('NSCLC', 'Phenotype', 'HP:0030358', (144, 149))	('Tregs', 'Chemical', '-', (121, 126))	('expression', 'Var', (18, 28))
256989	33658304	In our lung cancer models, we have shown, using shRNA strategies, that abrogation of YES1 in tumor cells is responsible for ~50% of tumor reduction when combined with anti-PD-1.	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('lung cancer', 'Disease', (7, 18))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('lung cancer', 'Phenotype', 'HP:0100526', (7, 18))	('tumor', 'Disease', (93, 98))	('abrogation', 'Var', (71, 81))	('tumor', 'Disease', (132, 137))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('YES1', 'Gene', (85, 89))	('lung cancer', 'Disease', 'MESH:D008175', (7, 18))	('reduction', 'NegReg', (138, 147))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
256994	33658304	Dasatinib causes cell growth inhibition and apoptosis in NSCLC cells with high expression of YES1, whereas in low-expressing or negative cells, the effect is much less pronounced.	('high expression', 'Var', (74, 89))	('apoptosis', 'CPA', (44, 53))	('YES1', 'Gene', (93, 97))	('NSCLC', 'Phenotype', 'HP:0030358', (57, 62))	('cell growth inhibition', 'CPA', (17, 39))	('Dasatinib', 'Chemical', 'MESH:D000069439', (0, 9))	('NSCLC', 'Disease', (57, 62))	('NSCLC', 'Disease', 'MESH:D002289', (57, 62))
257007	33658304	Complex mechanisms may account for the intratumoral accumulation of CD4+/FOXP3+/CD25+ Tregs, including recruitment, expansion and differentiation from conventional effector CD4+ T lymphocytes.	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('CD4+/FOXP3+/CD25+', 'Var', (68, 85))	('expansion', 'CPA', (116, 125))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('Tregs', 'Chemical', '-', (86, 91))	('tumor', 'Disease', (44, 49))
257011	33658304	Interestingly, Dyck et al have shown that anti-PD-1 inhibits Tregs conversion to unleash intratumoral effector T cells.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('anti-PD-1', 'Var', (42, 51))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('Tregs', 'Chemical', '-', (61, 66))	('Tregs conversion', 'CPA', (61, 77))	('tumor', 'Disease', (94, 99))	('inhibits', 'NegReg', (52, 60))
257029	33466167	Patients with LUSC and known smoking habits show a high rate of genetic alteration, and thus, are potentially immunogenic and show promise for treatment with novel immunotherapeutic agents.	('genetic alteration', 'Var', (64, 82))	('Patients', 'Species', '9606', (0, 8))	('LUSC', 'Disease', (14, 18))	('LUSC', 'Phenotype', 'HP:0030359', (14, 18))
257062	33466167	A previous study has shown that SEMA4C knockdown inhibits NSCLC cell proliferation and reverses epithelial-mesenchymal transition.	('NSCLC', 'Disease', (58, 63))	('SEMA4C', 'Gene', (32, 38))	('NSCLC', 'Disease', 'MESH:D002289', (58, 63))	('epithelial-mesenchymal transition', 'CPA', (96, 129))	('inhibits', 'NegReg', (49, 57))	('reverses', 'NegReg', (87, 95))	('knockdown', 'Var', (39, 48))	('NSCLC', 'Phenotype', 'HP:0030358', (58, 63))	('SEMA4C', 'Gene', '54910', (32, 38))
257074	32214092	A common MET polymorphism harnesses HER2 signaling to drive aggressive squamous cell carcinoma c-MET receptors are activated in cancers through genomic events like tyrosine kinase domain mutations, juxtamembrane splicing mutation and amplified copy numbers, which can be inhibited by c-MET small molecule inhibitors.	('cancers', 'Disease', 'MESH:D009369', (128, 135))	('cancers', 'Phenotype', 'HP:0002664', (128, 135))	('c-MET', 'Gene', '4233', (284, 289))	('c-MET', 'Gene', '4233', (95, 100))	('cancers', 'Disease', (128, 135))	('tyrosine', 'Var', (164, 172))	('amplified copy numbers', 'Var', (234, 256))	('HER2', 'Gene', (36, 40))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (71, 94))	('aggressive squamous cell carcinoma', 'Disease', 'MESH:D002294', (60, 94))	('HER2', 'Gene', '2064', (36, 40))	('c-MET', 'Gene', (284, 289))	('aggressive squamous cell carcinoma', 'Disease', (60, 94))	('c-MET', 'Gene', (95, 100))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('juxtamembrane splicing mutation', 'Var', (198, 229))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('activated', 'PosReg', (115, 124))
257075	32214092	Here, we discover that the most common polymorphism known to affect MET gene (N375S), involving the semaphorin domain, confers exquisite binding affinity for HER2 and enables METN375S to interact with HER2 in a ligand-independent fashion.	('N375S', 'SUBSTITUTION', 'None', (78, 83))	('N375S', 'SUBSTITUTION', 'None', (178, 183))	('interact', 'Interaction', (187, 195))	('HER2', 'Protein', (201, 205))	('METN375S', 'Chemical', '-', (175, 183))	('binding affinity', 'Interaction', (137, 153))	('N375S', 'Var', (78, 83))	('MET gene', 'Gene', (68, 76))	('HER2', 'Protein', (158, 162))	('N375S', 'Var', (178, 183))
257076	32214092	The resultant METN375S/HER2 dimer transduces potent proliferative, pro-invasive and pro-metastatic cues through the HER2 signaling axis to drive aggressive squamous cell carcinomas of the head and neck (HNSCC) and lung (LUSC), and is associated with poor prognosis.	('carcinoma', 'Phenotype', 'HP:0030731', (170, 179))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (156, 180))	('aggressive squamous cell carcinomas', 'Disease', (145, 180))	('METN375S', 'Chemical', '-', (14, 22))	('carcinomas of the head and neck', 'Phenotype', 'HP:0012288', (170, 201))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (156, 179))	('carcinomas', 'Phenotype', 'HP:0030731', (170, 180))	('SCC', 'Gene', (205, 208))	('METN375S/HER2', 'Var', (14, 27))	('SCC', 'Gene', '6317', (205, 208))	('drive', 'PosReg', (139, 144))	('aggressive squamous cell carcinomas', 'Disease', 'MESH:D002294', (145, 180))
257077	32214092	Accordingly, HER2 blockers, but not c-MET inhibitors, are paradoxically effective at restraining in vivo and in vitro models expressing METN375S.	('METN375S', 'Chemical', '-', (136, 144))	('c-MET', 'Gene', '4233', (36, 41))	('c-MET', 'Gene', (36, 41))	('restraining', 'CPA', (85, 96))	('HER2 blockers', 'Protein', (13, 26))	('METN375S', 'Var', (136, 144))
257078	32214092	These results establish METN375S as a biologically distinct and clinically actionable molecular subset of SCCs that are uniquely amenable to HER2 blocking therapies.	('METN375S', 'Chemical', '-', (24, 32))	('SCC', 'Gene', '6317', (106, 109))	('METN375S', 'Var', (24, 32))	('SCC', 'Gene', (106, 109))
257080	32214092	Here, the authors show that in head and neck and lung squamous carcinoma, a polymorphic MET variant enhances binding to HER2, resulting in activation of HER2 signalling and progression of the cancers.	('lung squamous carcinoma', 'Disease', (49, 72))	('lung squamous carcinoma', 'Phenotype', 'HP:0030359', (49, 72))	('HER2 signalling', 'Pathway', (153, 168))	('activation', 'PosReg', (139, 149))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (54, 72))	('cancers', 'Disease', 'MESH:D009369', (192, 199))	('cancers', 'Phenotype', 'HP:0002664', (192, 199))	('variant', 'Var', (92, 99))	('lung squamous carcinoma', 'Disease', 'MESH:D002294', (49, 72))	('cancers', 'Disease', (192, 199))	('enhances', 'PosReg', (100, 108))	('HER2', 'Protein', (120, 124))	('binding', 'Interaction', (109, 116))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))	('MET', 'Gene', (88, 91))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))
257083	32214092	Many human carcinomas have been found to constitutively activate MET via protein overexpression or gene amplification, which is associated with poorer survival and resistance to EGFR tyrosine kinase inhibitors (TKIs) in EGFR mutant lung adenocarcinoma.	('carcinomas', 'Disease', 'MESH:D002277', (11, 21))	('protein', 'Protein', (73, 80))	('mutant', 'Var', (225, 231))	('EGFR', 'Gene', '1956', (220, 224))	('EGFR', 'Gene', (178, 182))	('lung adenocarcinoma', 'Disease', (232, 251))	('carcinomas', 'Disease', (11, 21))	('overexpression', 'PosReg', (81, 95))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (232, 251))	('human', 'Species', '9606', (5, 10))	('gene amplification', 'Var', (99, 117))	('EGFR', 'Gene', '1956', (178, 182))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (232, 251))	('EGFR', 'Gene', (220, 224))	('carcinoma', 'Phenotype', 'HP:0030731', (242, 251))	('activate', 'PosReg', (56, 64))	('MET', 'MPA', (65, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (11, 20))	('carcinomas', 'Phenotype', 'HP:0030731', (11, 21))
257086	32214092	A germinal MET polymorphism, Asn375Ser (N375S) residing in the Sema domain, has been found in ~10% of individuals of east and south Asian descent.	('N375S', 'SUBSTITUTION', 'None', (40, 45))	('N375S', 'Var', (40, 45))	('Sema', 'Gene', '57556', (63, 67))	('Sema', 'Gene', (63, 67))	('Asn375Ser', 'SUBSTITUTION', 'None', (29, 38))	('Asn375Ser', 'Var', (29, 38))
257087	32214092	To our knowledge, the METN375S polymorphism has not been definitively shown to increase cancer susceptibility, despite causing conformational changes at the ligand-binding site.	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('conformational changes', 'MPA', (127, 149))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('METN375S', 'Var', (22, 30))	('causing', 'Reg', (119, 126))	('METN375S', 'Chemical', '-', (22, 30))
257088	32214092	However, the lack of a clear association with cancer risk appears to belie the true pathogenic potential of METN375S, as we demonstrate in this study that the oncogenic effects of METN375S are primarily manifested only in patients with active malignancies.	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('malignancies', 'Disease', (243, 255))	('cancer', 'Disease', (46, 52))	('METN375S', 'Var', (180, 188))	('METN375S', 'Chemical', '-', (108, 116))	('patients', 'Species', '9606', (222, 230))	('METN375S', 'Chemical', '-', (180, 188))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('malignancies', 'Disease', 'MESH:D009369', (243, 255))
257089	32214092	In this study, we characterize the biologically- and clinically aggressive phenotype driven by METN375S in LUSC and HNSCC, elucidate the intriguing mechanism by which METN375S co-opts HER2 signaling to drive SCCs, and crucially, translate our findings into therapeutically cogent interventions with the successful therapy of tumor-bearing animals using commercially-available HER2 inhibitors.	('SCC', 'Gene', (118, 121))	('tumor', 'Disease', 'MESH:D009369', (325, 330))	('METN375S', 'Var', (95, 103))	('SCC', 'Gene', (208, 211))	('SCC', 'Gene', '6317', (118, 121))	('METN375S', 'Chemical', '-', (95, 103))	('METN375S', 'Var', (167, 175))	('tumor', 'Phenotype', 'HP:0002664', (325, 330))	('tumor', 'Disease', (325, 330))	('METN375S', 'Chemical', '-', (167, 175))	('SCC', 'Gene', '6317', (208, 211))
257090	32214092	Our results therefore provide a strong clinical foundation for treating METN375S SCC patients with HER2-targeted therapies.	('SCC', 'Gene', '6317', (81, 84))	('METN375S', 'Var', (72, 80))	('METN375S', 'Chemical', '-', (72, 80))	('patients', 'Species', '9606', (85, 93))	('SCC', 'Gene', (81, 84))
257091	32214092	We genotyped the METN375S variant in germline DNA (gDNA) of several cohorts of patients (n = 1076) diagnosed with common cancers in the East Asian population in relation to healthy cancer-free controls, and determined the prevalence of the N375S polymorphism to be comparable in cancer patients relative to healthy, cancer-free controls (Fig.	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('N375S', 'SUBSTITUTION', 'None', (20, 25))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('N375S', 'Var', (20, 25))	('cancer', 'Disease', (279, 285))	('cancers', 'Phenotype', 'HP:0002664', (121, 128))	('cancers', 'Disease', (121, 128))	('N375S', 'SUBSTITUTION', 'None', (240, 245))	('cancer', 'Phenotype', 'HP:0002664', (279, 285))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('cancer', 'Disease', (316, 322))	('N375S', 'Var', (240, 245))	('cancer', 'Phenotype', 'HP:0002664', (316, 322))	('cancer', 'Disease', (181, 187))	('cancer', 'Disease', 'MESH:D009369', (279, 285))	('cancers', 'Disease', 'MESH:D009369', (121, 128))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('patients', 'Species', '9606', (79, 87))	('cancer', 'Disease', 'MESH:D009369', (316, 322))	('cancer', 'Disease', (121, 127))	('patients', 'Species', '9606', (286, 294))
257097	32214092	The RFS was significantly shorter in patients with the METN375S polymorphism in both the SCC cohorts (Fig.	('METN375S', 'Var', (55, 63))	('patients', 'Species', '9606', (37, 45))	('METN375S', 'Chemical', '-', (55, 63))	('SCC', 'Gene', '6317', (89, 92))	('shorter', 'NegReg', (26, 33))	('RFS', 'MPA', (4, 7))	('SCC', 'Gene', (89, 92))
257098	32214092	To confirm that the poor prognosis in these SCC cohorts were attributable to METN375S polymorphism, amplicon-enriched next-generation sequencing was performed on 45 archival FFPE LUSC tissues that were retrieved from the Department of Pathology, National University of Singapore.	('SCC', 'Gene', '6317', (44, 47))	('METN375S polymorphism', 'Var', (77, 98))	('polymorphism', 'Var', (86, 98))	('SCC', 'Gene', (44, 47))	('METN375S', 'Chemical', '-', (77, 85))
257100	32214092	While N375S was the most prevalent alteration in these samples (9/45, 20%) (Supplementary Fig.	('prevalent', 'Reg', (25, 34))	('N375S', 'SUBSTITUTION', 'None', (6, 11))	('N375S', 'Var', (6, 11))
257104	32214092	To characterize the phenotype associated with METN375S in SCC, we generated isogenic cell lines expressing either wild-type or variant MET with turboGFP tag (tGFP) (METwt-tGFP and METN375S-tGFP) in two LUSC lines (the epithelial H2170 cells and the p53-null mesenchymal Calu-1 cells) and two HNSCC lines (the cutaneous SCC13 cells and oral SCC UMSCC-1 cells).	('SCC', 'Gene', (58, 61))	('SCC', 'Gene', (340, 343))	('SCC', 'Gene', '6317', (294, 297))	('METN375S-tGFP', 'Var', (180, 193))	('SCC', 'Gene', '6317', (319, 322))	('SCC', 'Gene', '6317', (346, 349))	('SCC', 'Gene', '6317', (58, 61))	('METN375S', 'Chemical', '-', (180, 188))	('SCC', 'Gene', '6317', (340, 343))	('variant', 'Var', (127, 134))	('METN375S', 'Chemical', '-', (46, 54))	('SCC', 'Gene', (319, 322))	('p53', 'Gene', (249, 252))	('p53', 'Gene', '7157', (249, 252))	('SCC UMSCC-1', 'CellLine', 'CVCL:7707;-0.023556843741700854', (340, 351))	('SCC', 'Gene', (294, 297))	('SCC', 'Gene', (346, 349))
257106	32214092	Introduction of METN375S in LUSC cells significantly enhanced cell motility (Fig.	('METN375S', 'Var', (16, 24))	('METN375S', 'Chemical', '-', (16, 24))	('cell motility', 'CPA', (62, 75))	('enhanced', 'PosReg', (53, 61))
257107	32214092	These oncogenic properties were attributable to the exogenous METN375S protein, as silencing of MET was able to ablate the observed phenotypes (Fig.	('METN375S', 'Chemical', '-', (62, 70))	('METN375S', 'Var', (62, 70))	('ablate', 'NegReg', (112, 118))	('MET', 'Gene', (96, 99))	('silencing', 'Var', (83, 92))
257108	32214092	These findings were corroborated by in vivo subcutaneous H2170 xenograft models where the METN375S variant tumors exhibited steeper growth gradients compared with their METwt counterparts (Fig.	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('METN375S', 'Var', (90, 98))	('tumors', 'Disease', (107, 113))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('tumors', 'Disease', 'MESH:D009369', (107, 113))	('steeper growth gradients', 'MPA', (124, 148))
257109	32214092	In addition, while tail vein engraftment of both METwt-tGFP and METN375S-tGFP Calu-1 clones developed significant lung metastases compared with EV control (Fig.	('EV', 'Chemical', '-', (144, 146))	('METN375S-tGFP', 'Var', (64, 77))	('developed', 'PosReg', (92, 101))	('metastases', 'Disease', (119, 129))	('Calu-1', 'Gene', (78, 84))	('METN375S', 'Chemical', '-', (64, 72))	('metastases', 'Disease', 'MESH:D009362', (119, 129))
257110	32214092	2h), METN375S-tGFP clones demonstrated enhanced metastatic potential by forming large "cannonball" metastatic nodules compared to METwt-tGFP (Fig.	('METN375S-tGFP', 'Var', (5, 18))	('metastatic potential', 'CPA', (48, 68))	('METN375S', 'Chemical', '-', (5, 13))	('enhanced', 'PosReg', (39, 47))
257112	32214092	These observations collectively demonstrate enhanced functional MET activity of the N375S variant, and are concordant with the shorter RFS observed in patients with HNSCC and LUSC harboring this variant.	('MET activity', 'MPA', (64, 76))	('N375S', 'SUBSTITUTION', 'None', (84, 89))	('SCC', 'Gene', '6317', (167, 170))	('N375S', 'Var', (84, 89))	('patients', 'Species', '9606', (151, 159))	('SCC', 'Gene', (167, 170))	('enhanced', 'PosReg', (44, 52))
257115	32214092	Both H2170 and Calu-1 clones with homozygous N375S (METN375S/N375S) demonstrated spindle-shaped morphology (Supplementary Fig.	('N375S', 'SUBSTITUTION', 'None', (61, 66))	('N375S', 'Var', (45, 50))	('N375S', 'Var', (55, 60))	('spindle-shaped morphology', 'CPA', (81, 106))	('H2170', 'Gene', (5, 10))	('N375S', 'Var', (61, 66))	('N375S', 'SUBSTITUTION', 'None', (45, 50))	('METN375S', 'Chemical', '-', (52, 60))	('Calu-1', 'Gene', (15, 21))	('N375S', 'SUBSTITUTION', 'None', (55, 60))
257116	32214092	To compare the downstream signaling profiles between METN375S and METwt, a human phospho-kinase antibody array analysis was conducted on the whole-cell lysates and showed that METN375S-tGFP cells activated dissimilar signaling pathways compared to METwt-tGFP, specifically the activation of Src (Fig.	('METN375S-tGFP', 'Var', (176, 189))	('Src', 'Gene', (291, 294))	('activation', 'PosReg', (277, 287))	('Src', 'Gene', '6714', (291, 294))	('METN375S', 'Chemical', '-', (176, 184))	('dissimilar signaling pathways', 'Pathway', (206, 235))	('activated', 'PosReg', (196, 205))	('METN375S', 'Chemical', '-', (53, 61))	('human', 'Species', '9606', (75, 80))
257117	32214092	In concordance, higher expression of phosphorylated Src (Fig.	('higher', 'PosReg', (16, 22))	('Src', 'Gene', (52, 55))	('Src', 'Gene', '6714', (52, 55))	('phosphorylated', 'Var', (37, 51))	('expression', 'MPA', (23, 33))
257118	32214092	3d, e) were detected in METN375S tumors.	('METN375S', 'Var', (24, 32))	('METN375S', 'Chemical', '-', (24, 32))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('tumors', 'Disease', 'MESH:D009369', (33, 39))	('tumors', 'Disease', (33, 39))
257120	32214092	As shown, METN375S-tGFP cells did not exhibit differential half-maximal inhibitory concentration (IC50) values compared with METwt-tGFP cells, with the exception of tivantinib, which may have additional off-target effects.	('METN375S', 'Chemical', '-', (10, 18))	('METN375S-tGFP', 'Var', (10, 23))	('half-maximal', 'MPA', (59, 71))	('tivantinib', 'Chemical', 'MESH:C551661', (165, 175))
257122	32214092	Moreover, both crizotinib and INC280:two tyrosine kinase inhibitors (TKIs) of MET:failed to elicit significant growth inhibition in METwt-tGFP and METN375S-tGFP tumors (Supplementary Fig.	('METN375S', 'Chemical', '-', (147, 155))	('tumors', 'Disease', (161, 167))	('tumors', 'Phenotype', 'HP:0002664', (161, 167))	('INC280', 'Chemical', 'MESH:C000613976', (30, 36))	('tumors', 'Disease', 'MESH:D009369', (161, 167))	('METwt-tGFP', 'Var', (132, 142))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('METN375S-tGFP', 'Var', (147, 160))	('crizotinib', 'Chemical', 'MESH:D000077547', (15, 25))
257123	32214092	Importantly, the GOF of METN375S could not be abrogated by crizotinib (1 muM) (Supplementary Fig.	('METN375S', 'Var', (24, 32))	('METN375S', 'Chemical', '-', (24, 32))	('muM', 'Gene', '56925', (73, 76))	('muM', 'Gene', (73, 76))	('crizotinib', 'Chemical', 'MESH:D000077547', (59, 69))
257125	32214092	We extended our analyses to inhibitors of EGFR (gefitinib), Src (saracatinib), PI3K (copanlisib), and ERK1/2 (trametinib), but none of these treatments induced significant growth inhibition of H2170 METN375S clones (Supplementary Fig.	('EGFR', 'Gene', '1956', (42, 46))	('saracatinib', 'Chemical', 'MESH:C515233', (65, 76))	('Src', 'Gene', '6714', (60, 63))	('gefitinib', 'Chemical', 'MESH:D000077156', (48, 57))	('EGFR', 'Gene', (42, 46))	('growth', 'MPA', (172, 178))	('H2170 METN375S', 'Var', (193, 207))	('trametinib', 'Chemical', 'MESH:C560077', (110, 120))	('Src', 'Gene', (60, 63))
257127	32214092	We postulated that the increased functional activity of METN375S may be related to either enhanced MET activity, or alternative pathway signaling through crosstalk with other growth factor receptors.	('MET activity', 'MPA', (99, 111))	('crosstalk', 'Interaction', (154, 163))	('functional activity', 'MPA', (33, 52))	('METN375S', 'Chemical', '-', (56, 64))	('METN375S', 'Var', (56, 64))	('alternative pathway', 'Pathway', (116, 135))	('enhanced', 'PosReg', (90, 98))	('increased', 'PosReg', (23, 32))
257130	32214092	In addition, detailed analysis of the epithelial-mesenchymal transition (EMT) signature genes revealed identical EMT scores between the two MET variants (-0.59606 in METwt, -0.62169 in METN375S) (Supplementary Fig.	('epithelial-mesenchymal transition', 'CPA', (38, 71))	('METN375S', 'Var', (185, 193))	('-0.59606', 'Var', (154, 162))	('METN375S', 'Chemical', '-', (185, 193))
257131	32214092	4B), indicating that the oncogenic signaling and phenotypic aggressiveness of METN375S occur independently of transcriptomic alterations.	('oncogenic signaling', 'CPA', (25, 44))	('aggressiveness', 'Disease', (60, 74))	('aggressiveness', 'Phenotype', 'HP:0000718', (60, 74))	('METN375S', 'Var', (78, 86))	('aggressiveness', 'Disease', 'MESH:D001523', (60, 74))	('METN375S', 'Chemical', '-', (78, 86))
257133	32214092	We hypothesized that the variant Sema domain may acquire conformational changes that alter receptor dynamics at the cell membrane, leading to aberrant cell signaling culminating in gain-of-function of MET.	('Sema', 'Gene', '57556', (33, 37))	('dynamics at the', 'MPA', (100, 115))	('Sema', 'Gene', (33, 37))	('cell signaling', 'MPA', (151, 165))	('alter', 'Reg', (85, 90))	('gain-of-function', 'PosReg', (181, 197))	('leading to aberrant', 'Reg', (131, 150))	('variant', 'Var', (25, 32))	('MET', 'MPA', (201, 204))
257136	32214092	Here, background binders as well as common interaction partners between METwt and METN375S have 1:1 SILAC ratios, while specific binders to either variant display differential SILAC ratios after normalization with MET protein expressions.	('SILAC ratios', 'MPA', (100, 112))	('METN375S', 'Var', (82, 90))	('METN375S', 'Chemical', '-', (82, 90))	('SILAC ratios', 'MPA', (176, 188))	('binders', 'Interaction', (17, 24))	('interaction', 'Interaction', (43, 54))
257138	32214092	This preferential interaction was further substantiated with in situ proximity ligation assay (PLA) and fluorescent confocal imaging, that confirmed the proximal co-localization and possible heterodimerization of METN375S and HER2 (Fig.	('METN375S', 'Var', (213, 221))	('co-localization', 'Interaction', (162, 177))	('METN375S', 'Chemical', '-', (213, 221))	('heterodimerization', 'MPA', (191, 209))	('HER2', 'Protein', (226, 230))
257139	32214092	We further demonstrated the specificity of this receptor dimerization by confirming the lack of receptor-binding preference of METN375S to other TKs, such as EGFR and Src (Supplementary Fig.	('METN375S', 'Chemical', '-', (127, 135))	('EGFR', 'Gene', (158, 162))	('Src', 'Gene', (167, 170))	('Src', 'Gene', '6714', (167, 170))	('EGFR', 'Gene', '1956', (158, 162))	('METN375S', 'Var', (127, 135))
257140	32214092	5A); whereas other prevalent MET variants of the Sema/juxtamembrane domains (E168D, S323G, R988C, and T1010I) did not preferentially co-immunoprecipitate with HER2 as compared to the N375S variant (Supplementary Fig.	('N375S', 'Var', (183, 188))	('R988C', 'Var', (91, 96))	('T1010I', 'Mutation', 'p.T1010I', (102, 108))	('HER2', 'Protein', (159, 163))	('S323G', 'Var', (84, 89))	('R988C', 'Mutation', 'p.R988C', (91, 96))	('S323G', 'Mutation', 'p.S323G', (84, 89))	('E168D', 'Var', (77, 82))	('Sema', 'Gene', '57556', (49, 53))	('E168D', 'Mutation', 'p.E168D', (77, 82))	('N375S', 'SUBSTITUTION', 'None', (183, 188))	('T1010I', 'Var', (102, 108))	('Sema', 'Gene', (49, 53))
257141	32214092	As H2170 is a HER2-amplified (HER2+) cell line, we further studied this binding between HER2 and METN375S in HER2-non-amplified isogenic Calu-1 cells (Supplementary Fig.	('METN375S', 'Chemical', '-', (97, 105))	('H2170', 'Var', (3, 8))	('METN375S', 'Var', (97, 105))
257143	32214092	These substantiated the preferential interaction between METN375S and HER2, as did similar assays in METwt-tGFP and METN375S-tGFP xenograft tumors (Fig.	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('xenograft tumors', 'Disease', (130, 146))	('HER2', 'Protein', (70, 74))	('METN375S-tGFP', 'Var', (116, 129))	('METN375S', 'Var', (57, 65))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('xenograft tumors', 'Disease', 'MESH:D009369', (130, 146))	('METN375S', 'Chemical', '-', (57, 65))	('METN375S', 'Chemical', '-', (116, 124))	('interaction', 'Interaction', (37, 48))
257144	32214092	Collectively, the co-localization and strong binding affinity of both receptors in our assay models indicated that HER2 is a preferred interacting partner of METN375S.	('METN375S', 'Chemical', '-', (158, 166))	('HER2', 'Protein', (115, 119))	('METN375S', 'Var', (158, 166))	('binding affinity', 'Interaction', (45, 61))
257152	32214092	Notably, rSemaN375S profoundly repressed HER2 phosphorylation in METN375S-tGFP cells, together with the decrease of p-ERK1/2 and p-Akt (Fig.	('METN375S', 'Chemical', '-', (65, 73))	('Akt', 'Gene', (131, 134))	('METN375S-tGFP', 'Var', (65, 78))	('phosphorylation', 'MPA', (46, 61))	('rSemaN375S', 'Chemical', '-', (9, 19))	('decrease', 'NegReg', (104, 112))	('rSemaN375S', 'Var', (9, 19))	('p-ERK1/2', 'Pathway', (116, 124))	('HER2', 'Protein', (41, 45))	('Akt', 'Gene', '207', (131, 134))	('repressed', 'PosReg', (31, 40))
257153	32214092	These were concordant with the more profound attenuation of HER2-binding to METN375S by co-incubation with rSemaN375S as compared to that with rSemawt (Fig.	('rSemaN375S', 'Chemical', '-', (107, 117))	('METN375S', 'Chemical', '-', (76, 84))	('METN375S', 'Var', (76, 84))	('Sema', 'Gene', '57556', (144, 148))	('attenuation', 'NegReg', (45, 56))	('Sema', 'Gene', (144, 148))	('Sema', 'Gene', '57556', (108, 112))	('HER2-binding', 'Protein', (60, 72))	('Sema', 'Gene', (108, 112))	('HER2-binding', 'Interaction', (60, 72))
257154	32214092	4k), signifying the avid interaction in the presence of the N375S Sema-domain variant.	('N375S', 'SUBSTITUTION', 'None', (60, 65))	('avid interaction', 'Interaction', (20, 36))	('N375S', 'Var', (60, 65))	('Sema', 'Gene', '57556', (66, 70))	('Sema', 'Gene', (66, 70))
257155	32214092	We next asked if a single substitution of asparagine at 375 by serine at the Sema domain is sufficient to foster the MET-HER2 interaction.	('interaction', 'Interaction', (126, 137))	('asparagine at 375 by serine', 'Mutation', 'rs33917957', (42, 69))	('Sema', 'Gene', '57556', (77, 81))	('asparagine at 375', 'Var', (42, 59))	('foster', 'PosReg', (106, 112))	('Sema', 'Gene', (77, 81))	('MET-HER2', 'Protein', (117, 125))
257156	32214092	It has been previously demonstrated that the conformational changes at METN375S receptor reduced affinity to HGF, and we showed that HGF-depletion through serum starvation barely influenced the association of MET and HER2 (Fig.	('HGF', 'Gene', (133, 136))	('affinity', 'Interaction', (97, 105))	('HGF', 'Gene', (109, 112))	('HGF', 'Gene', '3082', (133, 136))	('HGF', 'Gene', '3082', (109, 112))	('conformational', 'MPA', (45, 59))	('reduced', 'NegReg', (89, 96))	('METN375S', 'Var', (71, 79))	('METN375S', 'Chemical', '-', (71, 79))	('HER2', 'Protein', (217, 221))	('association', 'Interaction', (194, 205))
257157	32214092	We next transfected WT, N375S,  SEMA (Sema domain deleted), N375Q (amino acid substitution), M1268T (somatic activating), Y1248H (somatic activating)-mutant MET together with HER2 protein in HEK293 cells, and evaluated the receptor-binding preference to HER2.	('N375Q', 'Mutation', 'p.N375Q', (60, 65))	('M1268T', 'Var', (93, 99))	('N375Q', 'Var', (60, 65))	('M1268T', 'SUBSTITUTION', 'None', (93, 99))	('Y1248H', 'Var', (122, 128))	('N375S', 'SUBSTITUTION', 'None', (24, 29))	('Sema', 'Gene', '57556', (38, 42))	('SEMA', 'Gene', (32, 36))	('Sema', 'Gene', (38, 42))	('Y1248H', 'Mutation', 'p.Y1248H', (122, 128))	('receptor-binding', 'Interaction', (223, 239))	('N375S', 'Var', (24, 29))	('SEMA', 'Gene', '57556', (32, 36))
257158	32214092	As compared with METwt, METN375S variant profoundly co-immunoprecipitated with HER2, while Sema deletion ( SEMA) or modification (N375Q) substantially reduced this association (Fig.	('N375Q', 'Mutation', 'p.N375Q', (130, 135))	('METN375S', 'Var', (24, 32))	('association', 'Interaction', (164, 175))	('reduced', 'NegReg', (151, 158))	('Sema', 'Gene', '57556', (91, 95))	('Sema', 'Gene', (91, 95))	('SEMA', 'Gene', (107, 111))	('co-immunoprecipitated', 'Interaction', (52, 73))	('modification (N375Q', 'Var', (116, 135))	('SEMA', 'Gene', '57556', (107, 111))	('HER2', 'Protein', (79, 83))
257159	32214092	These observations strongly support an enhanced affinity for HER2 through Asn375Ser Sema modification, and explains the greater decoy effect of rSemaN375S on cell viability and HER2 signaling in METN375S-tGFP cells (Fig.	('Sema modification', 'Disease', (84, 101))	('Asn375Ser', 'Var', (74, 83))	('HER2', 'MPA', (177, 181))	('METN375S', 'Chemical', '-', (195, 203))	('rSemaN375S', 'Var', (144, 154))	('Asn375Ser', 'SUBSTITUTION', 'None', (74, 83))	('HER2', 'Protein', (61, 65))	('rSemaN375S', 'Chemical', '-', (144, 154))	('affinity', 'Interaction', (48, 56))	('METN375S-tGFP', 'Var', (195, 208))	('Sema modification', 'Disease', '-', (84, 101))	('enhanced', 'PosReg', (39, 47))
257160	32214092	Interestingly, oncogenic MET (M1268T and Y1248H) displayed weakest binding to HER2 but possessed elevated MET phosphorylation (Fig.	('elevated', 'PosReg', (97, 105))	('Y1248H', 'Mutation', 'p.Y1248H', (41, 47))	('M1268T', 'Var', (30, 36))	('HER2', 'Protein', (78, 82))	('MET phosphorylation', 'MPA', (106, 125))	('weakest', 'NegReg', (59, 66))	('M1268T', 'SUBSTITUTION', 'None', (30, 36))	('Y1248H', 'Var', (41, 47))	('binding', 'Interaction', (67, 74))
257162	32214092	In concordance, xenograft METN375S-tGFP tumors expressed substantial amounts of p-HER2 compared with METwt-tGFP (Fig.	('METN375S', 'Chemical', '-', (26, 34))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('p-HER2', 'Protein', (80, 86))	('METN375S-tGFP', 'Var', (26, 39))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumors', 'Disease', (40, 46))	('tumors', 'Disease', 'MESH:D009369', (40, 46))
257164	32214092	Recent findings implicate the role of MET in the phosphorylation of PARP1 toimpart insensitivity to PARP inhibitors through its kinase-dependent association to PARP1; therefore, we examined the relevance of kinase activities on the association of METN375S and HER2.	('METN375S', 'Chemical', '-', (247, 255))	('PARP', 'Gene', (68, 72))	('PARP', 'Gene', '142', (160, 164))	('PARP', 'Gene', '142', (100, 104))	('PARP', 'Gene', (100, 104))	('PARP1', 'Gene', (160, 165))	('PARP', 'Gene', '142', (68, 72))	('association', 'Interaction', (145, 156))	('phosphorylation', 'MPA', (49, 64))	('PARP1', 'Gene', '142', (160, 165))	('PARP', 'Gene', (160, 164))	('HER2', 'Protein', (260, 264))	('PARP1', 'Gene', '142', (68, 73))	('association', 'Interaction', (232, 243))	('METN375S', 'Var', (247, 255))	('PARP1', 'Gene', (68, 73))
257165	32214092	Single or combination treatment of METN375S-tGFP cells with crizotinib and lapatinib (HER2 TKI) effectively impaired METN375S/HER2 interaction as confirmed by co-immunoprecipitation and PLA (Fig.	('METN375S', 'Chemical', '-', (35, 43))	('METN375S', 'Chemical', '-', (117, 125))	('crizotinib', 'Chemical', 'MESH:D000077547', (60, 70))	('interaction', 'Interaction', (131, 142))	('METN375S/HER2', 'Var', (117, 130))	('impaired', 'NegReg', (108, 116))	('lapatinib', 'Chemical', 'MESH:D000077341', (75, 84))
257166	32214092	In agreement with this observation, prolonged treatment of xenograft tumors with crizotinib abrogated MET phosphorylation and METN375S/HER2 interaction (Fig.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('xenograft tumors', 'Disease', 'MESH:D009369', (59, 75))	('crizotinib', 'Chemical', 'MESH:D000077547', (81, 91))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('MET phosphorylation', 'MPA', (102, 121))	('abrogated', 'NegReg', (92, 101))	('xenograft tumors', 'Disease', (59, 75))	('METN375S/HER2', 'Var', (126, 139))	('crizotinib', 'Gene', (81, 91))	('interaction', 'Interaction', (140, 151))	('METN375S', 'Chemical', '-', (126, 134))
257167	32214092	This suggests that upon its activation by METN375S, HER2 remains hyperphosphorylated to continually promulgate oncogenic growth signals, further indicating that once activated by heterodimerization, HER2 remains constitutively active despite kinase inhibition of its partner receptor.	('METN375S', 'Chemical', '-', (42, 50))	('activation', 'PosReg', (28, 38))	('METN375S', 'Var', (42, 50))
257169	32214092	As shown, METN375S-tGFP clones were more sensitive to lapatinib and afatinib (HER2 TKIs), with significantly lower IC50 (Supplementary Fig.	('lapatinib', 'MPA', (54, 63))	('METN375S', 'Chemical', '-', (10, 18))	('lower', 'NegReg', (109, 114))	('IC50', 'MPA', (115, 119))	('lapatinib', 'Chemical', 'MESH:D000077341', (54, 63))	('sensitive', 'MPA', (41, 50))	('METN375S-tGFP', 'Var', (10, 23))	('afatinib', 'Chemical', 'MESH:D000077716', (68, 76))	('more', 'PosReg', (36, 40))
257173	32214092	In addition, HER2 knockdown cells showed greater reduction of the invasion front (99% and 94%) as compared with MET knockdown cells (90% and 70%) in Calu-1 METN375S-tGFP cells, as opposed to the observations in METwt-tGFP cells (96% and 94% inhibition in siMET cells; 77% and 91% in siERBB2 cells) (Fig.	('knockdown', 'Var', (18, 27))	('reduction', 'NegReg', (49, 58))	('METN375S', 'Chemical', '-', (156, 164))	('HER2', 'Gene', (13, 17))	('ERBB2', 'Gene', '2064', (285, 290))	('invasion front', 'CPA', (66, 80))	('ERBB2', 'Gene', (285, 290))
257174	32214092	6g), indicating that knockdown of either MET or HER2 could repress the oncogenic phenotype of the N375S variant.	('N375S', 'SUBSTITUTION', 'None', (98, 103))	('HER2', 'Protein', (48, 52))	('repress', 'NegReg', (59, 66))	('oncogenic phenotype', 'CPA', (71, 90))	('N375S', 'Var', (98, 103))
257175	32214092	Collectively, these data suggest that METN375S-tGFP cells attain the aggressive phenotype through interactions between intact MET and HER2 receptors, leading to HER2 phosphorylation that once activated is constitutively active and is irrepressible by MET kinase inhibition.	('interactions', 'Interaction', (98, 110))	('METN375S', 'Chemical', '-', (38, 46))	('phosphorylation', 'MPA', (166, 181))	('HER2', 'Protein', (161, 165))	('METN375S-tGFP', 'Var', (38, 51))
257181	32214092	Nonetheless, METN375S-tGFP tumors were more sensitive, particularly to trastuzumab where tumor regression was attained at tolerable doses with significant dephosphorylation of MET in addition to the ablation of HER2 activity (Fig.	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumor', 'Disease', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('sensitive', 'MPA', (44, 53))	('tumors', 'Disease', (27, 33))	('tumors', 'Disease', 'MESH:D009369', (27, 33))	('HER2', 'Protein', (211, 215))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('dephosphorylation', 'MPA', (155, 172))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('trastuzumab', 'Chemical', 'MESH:D000068878', (71, 82))	('METN375S-tGFP', 'Var', (13, 26))	('METN375S', 'Chemical', '-', (13, 21))	('activity', 'MPA', (216, 224))	('tumor', 'Disease', (89, 94))
257182	32214092	8H, I), likely due to the interference with heterodimerization between HER2 and METN375S.	('heterodimerization', 'MPA', (44, 62))	('METN375S', 'Var', (80, 88))	('HER2', 'Protein', (71, 75))	('METN375S', 'Chemical', '-', (80, 88))
257183	32214092	To evaluate the structural basis of HER2 dimerization with METN375S, HEK293 cells transfected with MET-N375S vector and either one of the HER2-mutant constructs (WT,  D1,  D2,  D3,  D4, or  TK) were studied with co-immunoprecipitation assays; intact HER2 subdomain IV was shown to be necessary for binding to METN375S, and that HER2 TK activation facilitates this interaction (Fig.	('binding', 'Interaction', (298, 305))	('N375S', 'Var', (103, 108))	('METN375S', 'Chemical', '-', (309, 317))	('N375S', 'SUBSTITUTION', 'None', (312, 317))	('interaction', 'Interaction', (364, 375))	('METN375S', 'Chemical', '-', (59, 67))	('activation facilitates', 'PosReg', (336, 358))	('N375S', 'SUBSTITUTION', 'None', (103, 108))	('N375S', 'Var', (312, 317))	('N375S', 'SUBSTITUTION', 'None', (62, 67))	('HER2', 'Protein', (328, 332))	('N375S', 'Var', (62, 67))
257184	32214092	This also explains the sensitivity of METN375S-tGFP xenografts to trastuzumab, which complexes with subdomain IV of HER2.	('METN375S', 'Chemical', '-', (38, 46))	('trastuzumab', 'Chemical', 'MESH:D000068878', (66, 77))	('METN375S-tGFP', 'Var', (38, 51))	('complexes', 'Interaction', (85, 94))
257185	32214092	Using a primary culture derived from a HER2-non-amplified MET (N375S) heterozygous tongue SCC tumor (NCC-NPC7), we confirmed the increased susceptibility to HER2 inhibitors (lapatinib and afatinib), but not to crizotinib as compared to a HER2-non-amplified MET wild-type HNSCC cell line (SCC13) (Supplementary Fig.	('NCC-NPC7', 'CellLine', 'CVCL:1444;-0.01020063762965161', (101, 109))	('SCC', 'Gene', '6317', (273, 276))	('SCC', 'Gene', '6317', (288, 291))	('N375S', 'Var', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('SCC', 'Gene', '6317', (90, 93))	('SCC', 'Gene', (90, 93))	('N375S', 'SUBSTITUTION', 'None', (63, 68))	('susceptibility', 'MPA', (139, 153))	('tongue SCC tumor', 'Disease', 'MESH:D014062', (83, 99))	('SCC', 'Gene', (273, 276))	('crizotinib', 'Chemical', 'MESH:D000077547', (210, 220))	('HER2', 'Protein', (157, 161))	('SCC', 'Gene', (288, 291))	('lapatinib', 'Chemical', 'MESH:D000077341', (174, 183))	('afatinib', 'Chemical', 'MESH:D000077716', (188, 196))	('tongue SCC tumor', 'Disease', (83, 99))
257188	32214092	In addition, we confirmed that METN375S variant in NCC-NPC7 cells co-immunoprecipitated with HER2, and similar to that in isogenic H2170 cells (Fig.	('METN375S', 'Var', (31, 39))	('NCC-NPC7', 'Gene', (51, 59))	('NCC-NPC7', 'CellLine', 'CVCL:1444;-0.01020063762965161', (51, 59))
257191	32214092	In contrast, mice engrafted with METwt-tGFP cells survived longer and did not benefit from afatinib treatment (Fig.	('afatinib', 'Chemical', 'MESH:D000077716', (91, 99))	('mice', 'Species', '10090', (13, 17))	('longer', 'PosReg', (59, 65))	('METwt-tGFP', 'Var', (33, 43))
257192	32214092	6n), thereby confirming the aggressiveness of N375S tumors as well as the therapeutic potential of pharmacological HER2 inhibition in these tumors.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumors', 'Disease', (140, 146))	('tumors', 'Disease', 'MESH:D009369', (140, 146))	('N375S', 'Var', (46, 51))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('HER2', 'Protein', (115, 119))	('tumors', 'Disease', (52, 58))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('aggressiveness', 'Phenotype', 'HP:0000718', (28, 42))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('N375S', 'SUBSTITUTION', 'None', (46, 51))
257196	32214092	Concordant with our in vivo observations, the METN375S-positive tumors were demonstrated to have strong p-HER2 (9/9 with score >= 2+) and p-MET (8/9 with score >= 2+) (Supplementary Fig.	('tumors', 'Disease', (64, 70))	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('METN375S-positive', 'Var', (46, 63))	('p-HER2', 'Protein', (104, 110))	('METN375S', 'Chemical', '-', (46, 54))	('p-MET', 'Var', (138, 143))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
257197	32214092	10F), indicative of increased HER2 activation in tumors with activated METN375S, and these METN375S-positive patients had significantly shorter RFS compared to METwt patients (Supplementary Fig.	('increased', 'PosReg', (20, 29))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('patients', 'Species', '9606', (109, 117))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('patients', 'Species', '9606', (166, 174))	('tumors', 'Disease', (49, 55))	('tumors', 'Disease', 'MESH:D009369', (49, 55))	('METN375S', 'Chemical', '-', (91, 99))	('METN375S-positive', 'Var', (91, 108))	('METN375S', 'Chemical', '-', (71, 79))	('shorter', 'NegReg', (136, 143))	('HER2', 'Protein', (30, 34))	('METN375S', 'Var', (71, 79))	('activation', 'PosReg', (35, 45))	('RFS', 'MPA', (144, 147))
257198	32214092	This is in concordance with our postulation that METN375S phosphorylation is essential for HER2 activation that promotes the aggressiveness of SCC.	('SCC', 'Gene', (143, 146))	('METN375S', 'Var', (49, 57))	('promotes', 'PosReg', (112, 120))	('METN375S', 'Chemical', '-', (49, 57))	('SCC', 'Gene', '6317', (143, 146))	('aggressiveness', 'Disease', 'MESH:D001523', (125, 139))	('aggressiveness', 'Disease', (125, 139))	('aggressiveness', 'Phenotype', 'HP:0000718', (125, 139))
257201	32214092	This likely explains the tissue- and context-specificity of METN375S on LUSC and HNSCC.	('SCC', 'Gene', (83, 86))	('SCC', 'Gene', '6317', (83, 86))	('METN375S', 'Chemical', '-', (60, 68))	('METN375S', 'Var', (60, 68))
257205	32214092	Patients with HNSCC and LUSC who carry the METN375S polymorphism have higher risk of disease recurrence, mediated by a novel mechanism of oncogenicity that involves enhanced dimerization to another oncogenic membrane-bound RTK receptor HER2 without HGF ligand activation (Supplementary Fig.	('RTK', 'Gene', (223, 226))	('HGF', 'Gene', '3082', (249, 252))	('enhanced', 'PosReg', (165, 173))	('SCC', 'Gene', (16, 19))	('RTK', 'Gene', '5979', (223, 226))	('Patients', 'Species', '9606', (0, 8))	('dimerization', 'MPA', (174, 186))	('METN375S', 'Var', (43, 51))	('disease', 'Disease', (85, 92))	('SCC', 'Gene', '6317', (16, 19))	('METN375S', 'Chemical', '-', (43, 51))	('HGF', 'Gene', (249, 252))
257206	32214092	This mechanism of Sema-domain activation due to a single amino acid substitution adds to the other more established molecular mechanisms of oncogenic MET signaling, which mostly revolve around constitutive and persistent kinase activity.	('Sema', 'Gene', (18, 22))	('activation', 'PosReg', (30, 40))	('Sema', 'Gene', '57556', (18, 22))	('single amino acid substitution', 'Var', (50, 80))
257208	32214092	Based on molecular modeling and simulations, we postulate that the asparagine-to-serine substitution could induce significant localized conformational changes (Supplementary Fig.	('serine', 'Chemical', 'MESH:D012694', (81, 87))	('asparagine-to-serine substitution', 'Var', (67, 100))	('induce', 'Reg', (107, 113))	('asparagine', 'Chemical', 'MESH:D001216', (67, 77))	('localized conformational changes', 'MPA', (126, 158))
257209	32214092	12A, B), which improve surface interactions between METN375S and HER2 (Supplementary Fig.	('METN375S', 'Var', (52, 60))	('METN375S', 'Chemical', '-', (52, 60))	('surface interactions', 'MPA', (23, 43))	('improve', 'PosReg', (15, 22))	('HER2', 'Protein', (65, 69))
257210	32214092	Taken together with the imaging and biochemical characterization, our data collectively implicate that the N375S modification may reconfigure the Sema domain for MET interaction with HER2.	('reconfigure', 'Reg', (130, 141))	('Sema', 'Gene', (146, 150))	('MET', 'MPA', (162, 165))	('HER2', 'Protein', (183, 187))	('interaction', 'Interaction', (166, 177))	('N375S', 'SUBSTITUTION', 'None', (107, 112))	('Sema', 'Gene', '57556', (146, 150))	('N375S', 'Var', (107, 112))
257211	32214092	The resulting METN375S phosphorylation is necessary for HER2 activation, as rSemaN375S proteins lacking the tyrosine kinase domain could inhibit HER2 phosphorylation.	('phosphorylation', 'MPA', (150, 165))	('rSemaN375S', 'Chemical', '-', (76, 86))	('HER2', 'Protein', (145, 149))	('METN375S', 'Chemical', '-', (14, 22))	('lacking', 'NegReg', (96, 103))	('rSemaN375S', 'Var', (76, 86))	('tyrosine kinase domain', 'MPA', (108, 130))	('inhibit', 'NegReg', (137, 144))
257212	32214092	HER2 is rarely amplified or mutated in HNSCC/LUSC, but this activation through polymorphic MET may lead to constitutive HER2 signaling and drive these cancers.	('polymorphic MET', 'Var', (79, 94))	('SCC', 'Gene', (41, 44))	('lead to', 'Reg', (99, 106))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('SCC', 'Gene', '6317', (41, 44))	('constitutive', 'MPA', (107, 119))	('activation', 'PosReg', (60, 70))	('cancers', 'Disease', 'MESH:D009369', (151, 158))	('HER2', 'Protein', (120, 124))	('cancers', 'Phenotype', 'HP:0002664', (151, 158))	('cancers', 'Disease', (151, 158))	('drive', 'PosReg', (139, 144))
257213	32214092	Our data further demonstrates that the heterodimeric signal between METN375S and HER2 is specifically dependent on an intact subdomain IV on HER2, which is the binding site of trastuzumab, explaining the enhanced sensitivity of METN375S tumors to trastuzumab relative to HER2 TKIs.	('trastuzumab', 'Chemical', 'MESH:D000068878', (247, 258))	('sensitivity', 'MPA', (213, 224))	('tumors', 'Disease', (237, 243))	('heterodimeric signal', 'MPA', (39, 59))	('tumors', 'Disease', 'MESH:D009369', (237, 243))	('tumors', 'Phenotype', 'HP:0002664', (237, 243))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))	('trastuzumab', 'Chemical', 'MESH:D000068878', (176, 187))	('METN375S', 'Chemical', '-', (228, 236))	('METN375S', 'Var', (228, 236))	('enhanced', 'PosReg', (204, 212))	('METN375S', 'Chemical', '-', (68, 76))
257214	32214092	While MET has been previously demonstrated to be a heterodimeric partner of HER2, our work on SCC shows a strong addiction of METN375S tumors to HER2 signaling.	('METN375S', 'Var', (126, 134))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('SCC', 'Gene', (94, 97))	('tumors', 'Disease', (135, 141))	('SCC', 'Gene', '6317', (94, 97))	('tumors', 'Disease', 'MESH:D009369', (135, 141))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))	('METN375S', 'Chemical', '-', (126, 134))
257216	32214092	Our findings strongly indicate that phosphorylated METN375S leads to constitutively active HER2 that mediates signaling regardless of MET inhibition.	('METN375S', 'Var', (51, 59))	('phosphorylated', 'Var', (36, 50))	('METN375S', 'Chemical', '-', (51, 59))	('constitutively active', 'MPA', (69, 90))	('signaling', 'MPA', (110, 119))	('leads to', 'Reg', (60, 68))	('HER2', 'Protein', (91, 95))
257217	32214092	Conversely, HER2 inhibitors effectively suppress oncogenic METN375S signaling in SCC tumors, as evidenced by their strong anti-proliferative activity both in vitro and in vivo.	('METN375S', 'Chemical', '-', (59, 67))	('suppress', 'NegReg', (40, 48))	('SCC tumors', 'Disease', 'MESH:D009369', (81, 91))	('HER2', 'Protein', (12, 16))	('oncogenic METN375S signaling', 'MPA', (49, 77))	('inhibitors', 'Var', (17, 27))	('anti-proliferative activity', 'MPA', (122, 149))	('SCC tumors', 'Disease', (81, 91))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))
257218	32214092	This adds on to the growing recognition that HER2 inhibition could be effective in TKI-relapsed MET-driven tumors, and METN375S exemplifies emerging evidence that germline polymorphisms can drive malignancy and represent bona fide biomarkers to select therapeutic agents clinically.	('malignancy', 'Disease', 'MESH:D009369', (196, 206))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('inhibition', 'NegReg', (50, 60))	('malignancy', 'Disease', (196, 206))	('tumors', 'Disease', (107, 113))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('tumors', 'Disease', 'MESH:D009369', (107, 113))	('METN375S', 'Chemical', '-', (119, 127))	('METN375S', 'Var', (119, 127))	('drive', 'PosReg', (190, 195))	('germline polymorphisms', 'Var', (163, 185))	('HER2', 'Protein', (45, 49))
257219	32214092	Although HER2-amplified H2170 was primarily used in the study which may influence sensitivity to HER2 inhibitors, we recapitulated the experimental findings in non-HER2 overexpressing cells like Calu-1 and patient-derived NPC7 cells.	('H2170', 'Var', (24, 29))	('patient', 'Species', '9606', (206, 213))	('influence', 'Reg', (72, 81))
257222	32214092	To address this substantial unmet therapeutic need, we are currently conducting a clinical trial to treat patients with metastatic HNSCC and LUSC who screened positive for the METN375S polymorphism with HER2 blockade (NCT03938012).	('HER2', 'Protein', (203, 207))	('SCC', 'Gene', '6317', (133, 136))	('METN375S', 'Chemical', '-', (176, 184))	('METN375S', 'Var', (176, 184))	('patients', 'Species', '9606', (106, 114))	('SCC', 'Gene', (133, 136))	('NCT03938012', 'Var', (218, 229))
257224	32214092	Currently, the oncogenic role of the N375S variant in other cancers remains unclear.	('cancers', 'Phenotype', 'HP:0002664', (60, 67))	('cancers', 'Disease', (60, 67))	('cancers', 'Disease', 'MESH:D009369', (60, 67))	('N375S', 'Var', (37, 42))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('N375S', 'SUBSTITUTION', 'None', (37, 42))
257225	32214092	Theoretically, tumors overexpressing MET should be subjected to the similar aggressive influences of the polymorphic receptor, notwithstanding, our data demonstrated the ineffectiveness of HER2 inhibition in METN375S-positive HCC, suggesting that this strategy is tumor-context dependent, and is effective particularly in tumors with activated METN375S.	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumor', 'Disease', 'MESH:D009369', (322, 327))	('tumors', 'Phenotype', 'HP:0002664', (322, 328))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('tumor', 'Disease', (264, 269))	('METN375S', 'Var', (344, 352))	('tumor', 'Phenotype', 'HP:0002664', (322, 327))	('tumors', 'Disease', (322, 328))	('tumor', 'Disease', 'MESH:D009369', (264, 269))	('tumors', 'Disease', (15, 21))	('HER2', 'Protein', (189, 193))	('METN375S', 'Chemical', '-', (344, 352))	('tumor', 'Disease', (15, 20))	('tumors', 'Disease', 'MESH:D009369', (15, 21))	('tumors', 'Disease', 'MESH:D009369', (322, 328))	('tumor', 'Phenotype', 'HP:0002664', (264, 269))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('METN375S', 'Chemical', '-', (208, 216))	('tumor', 'Disease', (322, 327))
257226	32214092	Our data do not suggest that the METN375S polymorphism increases cancer susceptibility; however, whether the risks are elevated in the homozygous state needs further clarification, as the majority of the individuals in our study were heterozygotes.	('increases cancer', 'Disease', 'MESH:D009369', (55, 71))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('METN375S', 'Var', (33, 41))	('METN375S', 'Chemical', '-', (33, 41))	('increases cancer', 'Disease', (55, 71))
257227	32214092	In the clinical context, HER2 amplification is common in a variety of cancers: such as breast and hepatocellular carcinoma:and how this potentially cooperates with METN375S to promote malignancy is unclear, though our experimental models have shown that HER2 amplification is not essential for the oncogenic phenotype conferred by the MET variant.	('METN375S', 'Chemical', '-', (164, 172))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('malignancy', 'Disease', 'MESH:D009369', (184, 194))	('malignancy', 'Disease', (184, 194))	('variant', 'Var', (339, 346))	('cancers', 'Disease', 'MESH:D009369', (70, 77))	('cancers', 'Phenotype', 'HP:0002664', (70, 77))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (98, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('cancers', 'Disease', (70, 77))	('breast and hepatocellular carcinoma', 'Disease', 'MESH:D006528', (87, 122))
257228	32214092	Nonetheless, the lack of efficacy of HER2 inhibitors in METN375S HCC tumors with low p-HER2 expression suggest that other mechanisms are more dominant in HCC, and that HER2 activation is necessary for therapeutic impact.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('HCC', 'Disease', (154, 157))	('METN375S', 'Chemical', '-', (56, 64))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('METN375S', 'Var', (56, 64))	('HCC tumors', 'Disease', (65, 75))	('HCC tumors', 'Disease', 'MESH:D006528', (65, 75))
257229	32214092	Our current work contributes to the emerging notion that germline genetic events could impact the selection of oncotherapeutic agents, and in this case, specifically in SCC.	('selection of oncotherapeutic agents', 'MPA', (98, 133))	('SCC', 'Gene', (169, 172))	('germline genetic events', 'Var', (57, 80))	('SCC', 'Gene', '6317', (169, 172))	('impact', 'Reg', (87, 93))
257231	32214092	For inhibitor studies, crizotinib (#S1068), INC280 (#2788), gefitinib (#S1025), saracatinib (#S1066), copanlisib (#S2802), trametinib (#S2673), lapatinib (#S2111), and afatinib (#S1011) were purchased from Selleckchem.	('saracatinib', 'Chemical', 'MESH:C515233', (80, 91))	('#S1068', 'Var', (35, 41))	('#S1066', 'Var', (93, 99))	('#S2673', 'Var', (135, 141))	('#S1025', 'Var', (71, 77))	('#S2802', 'Var', (114, 120))	('INC280', 'Chemical', 'MESH:C000613976', (44, 50))	('#S2111', 'Var', (155, 161))	('crizotinib', 'Chemical', 'MESH:D000077547', (23, 33))	('trametinib', 'Chemical', 'MESH:C560077', (123, 133))	('afatinib', 'Chemical', 'MESH:D000077716', (168, 176))	('#2788', 'Var', (52, 57))	('#S1011', 'Var', (178, 184))	('lapatinib', 'Chemical', 'MESH:D000077341', (144, 153))	('gefitinib', 'Chemical', 'MESH:D000077156', (60, 69))
257235	32214092	For immunoblotting, p-MET (Tyr1234/1235, #3077), total MET (#8198), p-HER2 (Tyr1221/1222, #2243), total HER2 (#2165), p-p38 (Thr180/Tyr182, #4511), total p38 (#8690), p-Src (Tyr416, #2101), total Src (#2108), p-ERK1/2 (Thr202/Tyr204, #4377), total ERK1/2 (#4695), p-mTOR (Ser2448, #2971), total mTOR (#2172), p-Stat3 (Tyr705, #9131), total Stat3 (#4904), p-EGFR (Tyr1068, #2234), total EGFR (#2646), p-Akt (Ser473, #4060), total Akt (#9272), alpha-tubulin (#2125), horseradish peroxidase (HRP)-conjugated MET (#24294), HER2 (#60388), HSP90 (#4874), and beta-actin (#5125) antibodies were purchased from Cell Signaling Technology; turboGFP antibody was from Origene (#TA150041); pan-Cadherin antibody (#ab22744) from Abcam.	('mTOR', 'Gene', '2475', (266, 270))	('Akt', 'Gene', '207', (429, 432))	('Stat3', 'Gene', (311, 316))	('Akt', 'Gene', (402, 405))	('beta-actin', 'Gene', (553, 563))	('#TA150041', 'Var', (666, 675))	('Src', 'Gene', (196, 199))	('beta-actin', 'Gene', '11461', (553, 563))	('EGFR', 'Gene', '1956', (386, 390))	('Stat3', 'Gene', '6774', (311, 316))	('Akt', 'Gene', '207', (402, 405))	('Stat3', 'Gene', (340, 345))	('mTOR', 'Gene', (295, 299))	('#2646', 'Var', (392, 397))	('#24294', 'Var', (510, 516))	('EGFR', 'Gene', (357, 361))	('Src', 'Gene', '6714', (196, 199))	('Stat3', 'Gene', '6774', (340, 345))	('Src', 'Gene', (169, 172))	('mTOR', 'Gene', '2475', (295, 299))	('mTOR', 'Gene', (266, 270))	('#ab22744', 'Var', (701, 709))	('EGFR', 'Gene', (386, 390))	('EGFR', 'Gene', '1956', (357, 361))	('Src', 'Gene', '6714', (169, 172))	('Akt', 'Gene', (429, 432))
257236	32214092	Anti-mouse (#7076) and -rabbit (#7074) HRP-conjugated secondary antibodies were obtained from Cell Signaling Technologies.	('mouse', 'Species', '10090', (5, 10))	('#7074', 'Var', (32, 37))	('rabbit', 'Species', '9986', (24, 30))	('#7076', 'Var', (12, 17))
257240	32214092	Recombinant Sema proteins (rSema) were designed as described previously with modifications (WT and N375S) (Supplementary Table 1), and generated by MyBioSource.	('N375S', 'SUBSTITUTION', 'None', (99, 104))	('Sema', 'Gene', '57556', (12, 16))	('Sema', 'Gene', '57556', (28, 32))	('Sema proteins', 'Disease', (12, 25))	('Sema', 'Gene', (12, 16))	('Sema proteins', 'Disease', 'MESH:D011488', (12, 25))	('N375S', 'Var', (99, 104))	('Sema', 'Gene', (28, 32))
257244	32214092	For SILAC labeling, cells were incubated in RPMI 1640 (-Arg, -Lys) medium containing 10% dialyzed fetal bovine serum (Thermo) supplemented with 84 mg/l 13C615N4 L-arginine and 50 mg/l 13C615N2 L-lysine (Cambridge Isotope) or the corresponding non-labeled amino acids, respectively.	('13C615N4', 'Chemical', '-', (152, 160))	('13C615N4 L-arginine', 'Var', (152, 171))	('13C615N2 L-lysine', 'Var', (184, 201))	('RPMI', 'Chemical', '-', (44, 48))	('L-arginine', 'Chemical', '-', (161, 171))	('Arg', 'Chemical', 'MESH:D001120', (56, 59))	('bovine', 'Species', '9913', (104, 110))	('L-lysine', 'Chemical', '-', (193, 201))	('Lys', 'Chemical', 'MESH:D008239', (62, 65))	('13C615N2', 'Chemical', '-', (184, 192))
257247	32214092	Isogenic cell lines stably expressing pCMV6-AC-GFP vector, pCMV6-MET (wt), and pCMV6-MET (N375S) plasmids, respectively, were generated by transfection and single-cell clonal selection.	('N375S', 'SUBSTITUTION', 'None', (90, 95))	('pCMV6-AC-GFP', 'Var', (38, 50))	('N375S', 'Var', (90, 95))
257248	32214092	Cell lines homozygous of METN375S/N375S were established using CRISPR-Cas9 genome-editing technique, as previously described.	('METN375S', 'Chemical', '-', (25, 33))	('N375S', 'SUBSTITUTION', 'None', (34, 39))	('N375S', 'SUBSTITUTION', 'None', (28, 33))	('N375S', 'Var', (28, 33))	('N375S', 'Var', (34, 39))
257249	32214092	pCMV6-AC-turboGFP (tGFP) vector, pCMV6-MET-tGFP, and pCMV6-ERBB2-DDK plasmids were obtained from Origene (#PS100010, #RG217003, and #RC12583).	('#PS100010', 'Var', (106, 115))	('#RG217003', 'Var', (117, 126))	('#RC12583', 'Var', (132, 140))	('ERBB2', 'Gene', (59, 64))	('ERBB2', 'Gene', '2064', (59, 64))
257250	32214092	Site-directed mutagenesis was performed on pCMV6-MET-tGFP for substitution of glutamate-to-aspartate at 168 (E168D), serine-to-glycine at 323 (S323G), asparagine-to-serine at 375 (MET-N375S), asparagine-to-glutamine at 375 (N375Q), arginine-to-cysteine at 988 (R988C), threonine-to-isoleucine at 1010 (T1010I), methionine-to-threonine at 1268 (M1268T), tyrosine-to-histidine at 1248 (Y1248H), and deletion of Sema domain (( Sema); as well as on pCMV6-ERBB2-DDK for deletion of L domain 1 ( D1), furin-like domain ( D2), L domain 3 ( D3), growth factor receptor domain IV ( D4) and tyrosine kinase domain ( TK) using QuikChange Lightning Kit (Agilent, #210519) according to the manufacturer's protocol.	('Sema', 'Gene', (424, 428))	('Sema', 'Gene', '57556', (409, 413))	('E168D', 'Mutation', 'p.E168D', (109, 114))	('ERBB2', 'Gene', (451, 456))	('Sema', 'Gene', '57556', (424, 428))	('R988C', 'Mutation', 'p.R988C', (261, 266))	('deletion', 'Var', (397, 405))	('S323G', 'Mutation', 'p.S323G', (143, 148))	('N375Q', 'Mutation', 'p.N375Q', (224, 229))	('T1010I', 'Mutation', 'p.T1010I', (302, 308))	('N375S', 'SUBSTITUTION', 'None', (184, 189))	('asparagine-to-serine at 375', 'Mutation', 'rs33917957', (151, 178))	('ERBB2', 'Gene', '2064', (451, 456))	('M1268T', 'Var', (344, 350))	('M1268T', 'SUBSTITUTION', 'None', (344, 350))	('N375S', 'Var', (184, 189))	('deletion', 'Var', (465, 473))	('tyrosine kinase domain', 'MPA', (581, 603))	('Y1248H', 'Mutation', 'p.Y1248H', (384, 390))	('tyrosine-to-histidine at 1248', 'Mutation', 'p.Y1248H', (353, 382))	('arginine-to-cysteine at 988', 'Mutation', 'p.R988C', (232, 259))	('threonine-to-isoleucine at 1010', 'Mutation', 'p.T1010I', (269, 300))	('growth factor receptor domain IV', 'MPA', (538, 570))	('Sema', 'Gene', (409, 413))	('asparagine-to-glutamine at 375', 'Mutation', 'p.N375Q', (192, 222))	('glutamate-to-aspartate at 168', 'Mutation', 'p.E168D', (78, 107))	('serine-to-glycine at 323', 'Mutation', 'p.S323G', (117, 141))	('methionine-to-threonine at 1268', 'Mutation', 'p.M1268T', (311, 342))
257258	32214092	For in vivo metastases model, 1 x 106 of cancer cells (empty vector control, METwt-tGFP and METN375S-tGFP) were injected intravenously into tail vein of each mice.	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('mice', 'Species', '10090', (158, 162))	('metastases', 'Disease', (12, 22))	('METN375S-tGFP', 'Var', (92, 105))	('metastases', 'Disease', 'MESH:D009362', (12, 22))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('METN375S', 'Chemical', '-', (92, 100))
257266	32214092	For xenograft study, 5 x 106 isogenic H2170 cells (empty vector control, METwt-tGFP and METN375S-tGFP) in 100 microL of PBS or 1-2 mm3 dices of PDX tumors (HCC26-0808B and HCC13-0109) were injected subcutaneously into both flanks of each mice.	('PDX tumors', 'Disease', (144, 154))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('METN375S-tGFP', 'Var', (88, 101))	('METN375S', 'Chemical', '-', (88, 96))	('PDX tumors', 'Disease', 'MESH:D009369', (144, 154))	('HCC26', 'CellLine', 'CVCL:8806;-0.09280399198030526', (156, 161))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('mice', 'Species', '10090', (238, 242))
257273	32214092	Fold change for each target spots was analyzed in relative to METwt-tGFP cells, and presented as fold regulation (positive fold regulation indicates relative fold increase in METN375S-tGFP cells; negative fold regulation indicates relative fold decrease in METwt-tGFP cells).	('METN375S', 'Chemical', '-', (175, 183))	('METN375S-tGFP', 'Var', (175, 188))	('increase', 'PosReg', (163, 171))
257283	32214092	Immunostaining was performed with anti-MET (mouse) and anti-HER2 (rabbit) overnight at 4  C, followed by incubation with Alexa Fluor-488 or -594 secondary antibodies (1:1000, Molecular Probes, Life Technologies, A28175 and A-11012) for 2 h at 25  C, and by DAPI nuclear staining for 10 min.	('DAPI', 'Chemical', 'MESH:C007293', (257, 261))	('Alexa Fluor-488', 'Chemical', '-', (121, 136))	('anti-HER2', 'Var', (55, 64))	('A28175', 'Var', (212, 218))	('anti-MET', 'Var', (34, 42))	('mouse', 'Species', '10090', (44, 49))	('rabbit', 'Species', '9986', (66, 72))
257293	25679763	Cancer cells can occasionally suppress the growth restrictive AMPK pathway by mutation of an upstream regulatory kinase.	('suppress', 'NegReg', (30, 38))	('mutation', 'Var', (78, 86))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('AMPK', 'Gene', (62, 66))	('AMPK', 'Gene', '5564', (62, 66))
257300	25679763	AMPK is a hetero-trimeric kinase comprised of catalytic alpha and regulatory beta and gamma subunits that is regulated by the cellular concentrations of ATP, ADP, and AMP.	('AMPK', 'Gene', '5564', (0, 4))	('ATP', 'Chemical', 'MESH:D000255', (153, 156))	('AMP', 'Chemical', 'MESH:D000249', (167, 170))	('AMPK', 'Gene', (0, 4))	('ADP', 'Chemical', 'MESH:D000244', (158, 161))	('ADP', 'Var', (158, 161))	('AMP', 'Chemical', 'MESH:D000249', (0, 3))	('AMP', 'Var', (167, 170))
257306	25679763	For example, knockout of AMPKalpha1 in the mouse accelerates development of c-Myc-driven lymphomas.	('Myc', 'Gene', '4609', (78, 81))	('development', 'CPA', (61, 72))	('Myc', 'Gene', (78, 81))	('lymphomas', 'Phenotype', 'HP:0002665', (89, 98))	('knockout', 'Var', (13, 21))	('lymphomas', 'Disease', (89, 98))	('AMPKalpha1', 'Gene', (25, 35))	('accelerates', 'PosReg', (49, 60))	('mouse', 'Species', '10090', (43, 48))	('lymphomas', 'Disease', 'MESH:D008223', (89, 98))
257311	25679763	For example, in approximately 20% of lung adenocarcinomas and cervical cancers, signaling through this axis is reduced by loss of function mutation or deletion of Lkb1/Stk11.	('deletion', 'Var', (151, 159))	('Lkb1', 'Gene', '6794', (163, 167))	('Stk11', 'Gene', (168, 173))	('loss of function', 'NegReg', (122, 138))	('mutation', 'Var', (139, 147))	('cancers', 'Phenotype', 'HP:0002664', (71, 78))	('carcinoma', 'Phenotype', 'HP:0030731', (47, 56))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (37, 57))	('carcinomas', 'Phenotype', 'HP:0030731', (47, 57))	('signaling', 'MPA', (80, 89))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('Stk11', 'Gene', '6794', (168, 173))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (37, 56))	('reduced', 'NegReg', (111, 118))	('cervical cancers', 'Disease', (62, 78))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (37, 57))	('cervical cancers', 'Disease', 'MESH:D002583', (62, 78))	('lung adenocarcinomas', 'Disease', (37, 57))	('Lkb1', 'Gene', (163, 167))
257312	25679763	Additionally, AMPK levels have been shown to be reduced in some cases of hepatocellular carcinomas and B-RAF V600E can downregulate AMPK signaling through inhibition of Lkb1/Stk11 in melanomas.	('AMPK', 'Gene', (132, 136))	('melanomas', 'Phenotype', 'HP:0002861', (183, 192))	('hepatocellular carcinomas', 'Disease', 'MESH:D006528', (73, 98))	('V600E', 'Mutation', 'rs113488022', (109, 114))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('carcinomas', 'Phenotype', 'HP:0030731', (88, 98))	('Lkb1', 'Gene', (169, 173))	('hepatocellular carcinomas', 'Phenotype', 'HP:0001402', (73, 98))	('B-RAF', 'Gene', '673', (103, 108))	('hepatocellular carcinomas', 'Disease', (73, 98))	('Stk11', 'Gene', (174, 179))	('Lkb1', 'Gene', '6794', (169, 173))	('V600E', 'Var', (109, 114))	('inhibition', 'NegReg', (155, 165))	('melanomas', 'Disease', 'MESH:D008545', (183, 192))	('reduced', 'NegReg', (48, 55))	('melanomas', 'Disease', (183, 192))	('B-RAF', 'Gene', (103, 108))	('Stk11', 'Gene', '6794', (174, 179))	('downregulate', 'NegReg', (119, 131))	('AMPK', 'Gene', (14, 18))	('AMPK', 'Gene', '5564', (14, 18))	('AMPK', 'Gene', '5564', (132, 136))
257317	25679763	For example, knockdown of MAGE-A3/6 impairs tumor growth in mice, whereas expression of MAGE-A3 in MAGE-negative cells drives tumor growth and metastasis in vivo.	('drives', 'PosReg', (119, 125))	('MAGE', 'Gene', (99, 103))	('metastasis', 'CPA', (143, 153))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('MAGE', 'Gene', '51152', (88, 92))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('MAGE', 'Gene', '51152', (26, 30))	('MAGE', 'Gene', '51152', (99, 103))	('impairs', 'NegReg', (36, 43))	('MAGE', 'Gene', (88, 92))	('mice', 'Species', '10090', (60, 64))	('knockdown', 'Var', (13, 22))	('tumor', 'Disease', (44, 49))	('MAGE', 'Gene', (26, 30))	('tumor', 'Disease', (126, 131))
257327	25679763	Additionally, expression of MAGE-A3 and MAGE-A6 was significantly correlated in breast invasive carcinomas, colon adenocarcinomas, and lung squamous cell carcinomas (Figure 1F-H).	('breast invasive carcinomas', 'Disease', (80, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('correlated', 'Reg', (66, 76))	('carcinomas', 'Phenotype', 'HP:0030731', (96, 106))	('lung squamous cell carcinomas', 'Disease', (135, 164))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (140, 164))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (135, 163))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('colon adenocarcinomas', 'Disease', (108, 129))	('carcinomas', 'Phenotype', 'HP:0030731', (119, 129))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (140, 163))	('colon adenocarcinomas', 'Disease', 'MESH:D003110', (108, 129))	('breast invasive carcinomas', 'Disease', 'MESH:D018270', (80, 106))	('breast invasive carcinoma', 'Phenotype', 'HP:0003002', (80, 105))	('MAGE-A6', 'Var', (40, 47))	('expression', 'MPA', (14, 24))	('lung squamous cell carcinomas', 'Disease', 'MESH:D002294', (135, 164))	('carcinoma', 'Phenotype', 'HP:0030731', (154, 163))	('carcinomas', 'Phenotype', 'HP:0030731', (154, 164))
257330	25679763	Indeed, patients with lung squamous cell carcinomas expressing MAGE-A3 or MAGE-A6 have a significant decrease in overall survival time (Figure 1I-J).	('lung squamous cell carcinomas', 'Disease', 'MESH:D002294', (22, 51))	('MAGE-A3', 'Var', (63, 70))	('carcinoma', 'Phenotype', 'HP:0030731', (41, 50))	('carcinomas', 'Phenotype', 'HP:0030731', (41, 51))	('overall survival', 'MPA', (113, 129))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (27, 51))	('MAGE-A6', 'Var', (74, 81))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (22, 50))	('lung squamous cell carcinomas', 'Disease', (22, 51))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (27, 50))	('decrease', 'NegReg', (101, 109))	('patients', 'Species', '9606', (8, 16))
257331	25679763	Patients with tumors expressing MAGE-A3 had a >50% reduced overall survival time compared to patients with MAGE-A3-negative tumors (30 versus 69 months, respectively; 2.0 hazard ratio; Supplemental Table 1).	('overall survival time', 'MPA', (59, 80))	('reduced', 'NegReg', (51, 58))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('MAGE-A3', 'Var', (32, 39))	('tumors', 'Disease', (14, 20))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('Patients', 'Species', '9606', (0, 8))	('tumors', 'Disease', (124, 130))	('tumors', 'Disease', 'MESH:D009369', (124, 130))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('patients', 'Species', '9606', (93, 101))
257332	25679763	Similarly, patients with tumors expressing MAGE-A6 had a >50% reduced survival time (33 vs 71 months; hazard ratio of 1.9; Supplemental Table 1).	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('survival', 'MPA', (70, 78))	('tumors', 'Disease', (25, 31))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('tumors', 'Disease', 'MESH:D009369', (25, 31))	('MAGE-A6', 'Var', (43, 50))	('patients', 'Species', '9606', (11, 19))	('reduced', 'NegReg', (62, 69))
257337	25679763	Indeed, knockdown of MAGE-A3/6 using two independent siRNAs (Figure S2A-B) in multiple lung (HCC193, H1648, and H2126), breast (HCC1806 and SK-BR-3), and colon (HCT116 and HT29) cancer cells resulted in a significant decrease in cell viability and clonogenic survival (Figures 2A-C and S2C-D).	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('knockdown', 'Var', (8, 17))	('H2126', 'CellLine', 'CVCL:1532', (112, 117))	('HCT116', 'CellLine', 'CVCL:0291', (161, 167))	('HCC193', 'CellLine', 'CVCL:5130', (93, 99))	('clonogenic survival', 'CPA', (248, 267))	('decrease', 'NegReg', (217, 225))	('cancer', 'Disease', (178, 184))	('SK-BR-3', 'CellLine', 'CVCL:0033', (140, 147))	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('HCC1806', 'CellLine', 'CVCL:1258', (128, 135))	('cell viability', 'CPA', (229, 243))	('HT29', 'CellLine', 'CVCL:0320', (172, 176))
257339	25679763	First, expression of either MAGE-A3 or MAGE-A6 significantly stimulated foci formation of NIH3T3 cells (Figure 2D).	('foci formation', 'CPA', (72, 86))	('NIH3T3', 'CellLine', 'CVCL:0594', (90, 96))	('stimulated', 'PosReg', (61, 71))	('expression', 'Var', (7, 17))	('MAGE-A6', 'Gene', (39, 46))	('MAGE-A3', 'Gene', (28, 35))
257341	25679763	Finally, to more stringently assay the oncogenic activity of MAGE-A3/6, we determined the ability of MAGE-A6 to promote tumorigenic phenotypes in non-transformed, human colonic epithelial cells (HCECs) derived from normal colon biopsies and immortalized with CDK4 and hTERT.	('promote', 'PosReg', (112, 119))	('CDK4', 'Gene', '1019', (259, 263))	('MAGE-A6', 'Var', (101, 108))	('CDK4', 'Gene', (259, 263))	('HCEC', 'CellLine', 'CVCL:2064', (195, 199))	('hTERT', 'Gene', (268, 273))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('human', 'Species', '9606', (163, 168))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('tumor', 'Disease', (120, 125))	('hTERT', 'Gene', '7015', (268, 273))
257343	25679763	Additionally, even in the context of mutant K-Rasv12 expression, MAGE-A6 was still competent to drive anchorage-independent growth of HCEC cells to a similar degree as the Apcmin oncogene (Figure 2G).	('anchorage-independent growth', 'CPA', (102, 130))	('mutant', 'Var', (37, 43))	('HCEC', 'CellLine', 'CVCL:2064', (134, 138))
257348	25679763	However, several of the cell lines dependent on MAGE-A3/6 for viability (Figure 2A-C) are p53 null (HCC1806 and H1648) or mutant (HCC193, SK-BR-3, and HT-29).	('HCC193', 'Var', (130, 136))	('p53', 'Gene', (90, 93))	('SK-BR-3', 'CellLine', 'CVCL:0033', (138, 145))	('p53', 'Gene', '7157', (90, 93))	('HCC1806', 'CellLine', 'CVCL:1258', (100, 107))	('HCC193', 'CellLine', 'CVCL:5130', (130, 136))	('HT-29', 'CellLine', 'CVCL:0320', (151, 156))
257349	25679763	Additionally, MAGE-A3/6 stimulated anchorage-independent growth in p53 mutant DLD1 colon cancer cells (Figure 2E).	('colon cancer', 'Disease', (83, 95))	('p53', 'Gene', (67, 70))	('p53', 'Gene', '7157', (67, 70))	('mutant', 'Var', (71, 77))	('stimulated', 'PosReg', (24, 34))	('anchorage-independent growth', 'CPA', (35, 63))	('DLD1', 'Gene', (78, 82))	('colon cancer', 'Phenotype', 'HP:0003003', (83, 95))	('colon cancer', 'Disease', 'MESH:D015179', (83, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
257350	25679763	Furthermore, expression of MAGE-A3/6 did not inversely correlate with p53 mutational status (chi2=0.17; p=0.98).	('mutational', 'Var', (74, 84))	('p53', 'Gene', '7157', (70, 73))	('p53', 'Gene', (70, 73))
257356	25679763	Next, we determined whether modulation of AMPK protein levels by MAGE-A3/6-TRIM28 had a functional impact on AMPK activity and the cellular metabolic processes it controls.	('AMPK', 'Gene', '5564', (42, 46))	('AMPK', 'Gene', (109, 113))	('AMPK', 'Gene', '5564', (109, 113))	('impact', 'Reg', (99, 105))	('MAGE-A3/6-TRIM28', 'Var', (65, 81))	('AMPK', 'Gene', (42, 46))	('cellular metabolic processes', 'CPA', (131, 159))
257357	25679763	Furthermore, the knockdown of MAGE-A3/6 or TRIM28 resulted in increased phosphorylation of ACC1 (Figure 4B), a prototypical target of AMPK.	('increased', 'PosReg', (62, 71))	('ACC1', 'Gene', (91, 95))	('phosphorylation', 'MPA', (72, 87))	('AMPK', 'Gene', (134, 138))	('TRIM28', 'Gene', (43, 49))	('AMPK', 'Gene', '5564', (134, 138))	('knockdown', 'Var', (17, 26))	('ACC1', 'Gene', '597', (91, 95))	('MAGE-A3/6', 'Gene', (30, 39))
257360	25679763	Furthermore, knockdown of TRIM28 increased glucose consumption (Figure 4D) and correspondingly increased lactate production (Figure 4E) in MAGE-A3/6-positive cells.	('increased lactate production', 'Phenotype', 'HP:0003128', (95, 123))	('glucose consumption', 'MPA', (43, 62))	('lactate', 'Chemical', 'MESH:D019344', (105, 112))	('increased glucose', 'Phenotype', 'HP:0003074', (33, 50))	('TRIM28', 'Gene', (26, 32))	('increased', 'PosReg', (33, 42))	('lactate production', 'MPA', (105, 123))	('glucose', 'Chemical', 'MESH:D005947', (43, 50))	('increased', 'PosReg', (95, 104))	('knockdown', 'Var', (13, 22))
257363	25679763	Upon knockdown of MAGE-A3/6 or TRIM28, mTOR signaling was severely inhibited and phosphorylation of both p70 ribosomal S6 kinase and ribosomal S6 protein were reduced (Figure 4F).	('TRIM28', 'Gene', (31, 37))	('phosphorylation', 'MPA', (81, 96))	('p70', 'Gene', (105, 108))	('inhibited', 'NegReg', (67, 76))	('knockdown', 'Var', (5, 14))	('reduced', 'NegReg', (159, 166))	('ribosomal S6 protein', 'MPA', (133, 153))	('mTOR', 'Gene', (39, 43))	('mTOR', 'Gene', '2475', (39, 43))	('p70', 'Gene', '84959', (105, 108))
257364	25679763	Similarly, amino acid-induced mTOR activity was significantly reduced upon depletion of MAGE-A3/6 (Figure 4G).	('depletion', 'Var', (75, 84))	('MAGE-A3/6 (Figure 4G', 'Gene', '4102;4105', (88, 108))	('mTOR', 'Gene', '2475', (30, 34))	('mTOR', 'Gene', (30, 34))	('reduced', 'NegReg', (62, 69))
257365	25679763	Importantly, reduction in basal mTOR activity was rescued by treatment with the AMPK inhibitor, compound c (Figure 4H) or co-depeltion of AMPKalpha1 (Figure 4I).	('AMPK', 'Gene', (80, 84))	('AMPK', 'Gene', '5564', (80, 84))	('mTOR', 'Gene', '2475', (32, 36))	('mTOR', 'Gene', (32, 36))	('co-depeltion', 'Var', (122, 134))	('reduction', 'NegReg', (13, 22))	('AMPK', 'Gene', (138, 142))	('AMPK', 'Gene', '5564', (138, 142))
257369	25679763	AMPK phosphorylation of ULK1 S555 promotes ULK1 activity and autophagy, whereas mTOR phosphorylation of ULK1 S757 inhibits ULK1 activity and autophagy.	('ULK1', 'Gene', '8408', (104, 108))	('ULK1', 'Gene', '8408', (43, 47))	('activity', 'MPA', (48, 56))	('mTOR', 'Gene', (80, 84))	('autophagy', 'CPA', (141, 150))	('promotes', 'PosReg', (34, 42))	('inhibits', 'NegReg', (114, 122))	('mTOR', 'Gene', '2475', (80, 84))	('ULK1', 'Gene', (123, 127))	('ULK1', 'Gene', (43, 47))	('AMPK', 'Gene', '5564', (0, 4))	('ULK1', 'Gene', '8408', (123, 127))	('AMPK', 'Gene', (0, 4))	('autophagy', 'CPA', (61, 70))	('ULK1', 'Gene', (24, 28))	('S555', 'Var', (29, 33))	('ULK1', 'Gene', '8408', (24, 28))	('ULK1', 'Gene', (104, 108))
257371	25679763	Changes in ULK1 phosphorylation by MAGE-A3/6 or TRIM28 knockdown were accompanied by the expected increase in GFP-LC3 puncta, a marker of autophagy (Figures 5B and S3A-C).	('knockdown', 'Var', (55, 64))	('ULK1', 'Gene', (11, 15))	('TRIM28', 'Gene', (48, 54))	('ULK1', 'Gene', '8408', (11, 15))	('LC3', 'Gene', '84557', (114, 117))	('LC3', 'Gene', (114, 117))	('increase', 'PosReg', (98, 106))	('phosphorylation', 'CPA', (16, 31))
257373	25679763	The magnitude of increased GFP-LC3 puncta upon MAGE-A3/6 or TRIM28 knockdown was similar to knockdown of mTOR, an established potent inhibitor of autophagy (Figure 5B).	('increased', 'PosReg', (17, 26))	('LC3', 'Gene', '84557', (31, 34))	('knockdown', 'Var', (67, 76))	('LC3', 'Gene', (31, 34))	('mTOR', 'Gene', (105, 109))	('mTOR', 'Gene', '2475', (105, 109))	('MAGE-A3/6', 'Gene', (47, 56))	('increased GFP', 'Phenotype', 'HP:0012214', (17, 30))	('TRIM28', 'Gene', (60, 66))
257375	25679763	Similarly to GFP-LC3, siRNAs targeting MAGE-A3/6 induced the accumulation of endogenous LC3 puncta in MAGE-A3/6-positive cells, but had no effect in MAGE-A3/6-negative cells (Figure 5D-E).	('LC3', 'Gene', '84557', (17, 20))	('LC3', 'Gene', (17, 20))	('MAGE-A3/6', 'Var', (39, 48))	('LC3', 'Gene', '84557', (88, 91))	('LC3', 'Gene', (88, 91))	('accumulation', 'PosReg', (61, 73))
257378	25679763	We observed a significant decrease in GFP-LC3 fluorescence upon knockdown of MAGE-A3/6 or TRIM28 and this was again similar to the degree of GFP-LC3 consumption upon mTOR depletion (Figures 5G and S3D).	('TRIM28', 'Gene', (90, 96))	('LC3', 'Gene', '84557', (145, 148))	('decrease', 'NegReg', (26, 34))	('mTOR', 'Gene', (166, 170))	('LC3', 'Gene', (42, 45))	('LC3', 'Gene', '84557', (42, 45))	('mTOR', 'Gene', '2475', (166, 170))	('LC3', 'Gene', (145, 148))	('MAGE-A3/6', 'Gene', (77, 86))	('knockdown', 'Var', (64, 73))
257379	25679763	These results were further confirmed by western blotting where knockdown of MAGE-A3/6 or TRIM28 promoted a marked decrease in GFP-LC3 protein levels (Figure 5H).	('LC3', 'Gene', (130, 133))	('decrease', 'NegReg', (114, 122))	('knockdown', 'Var', (63, 72))	('TRIM28', 'Gene', (89, 95))	('LC3', 'Gene', '84557', (130, 133))
257382	25679763	Short-term treatment of cells with bafilomycin A1 blocked consumption of GFP-LC3 by knockdown of MAGE-A3/6 or TRIM28 (Figure 5I).	('consumption', 'MPA', (58, 69))	('MAGE-A3/6', 'Gene', (97, 106))	('blocked', 'NegReg', (50, 57))	('knockdown', 'Var', (84, 93))	('TRIM28', 'Gene', (110, 116))	('LC3', 'Gene', '84557', (77, 80))	('LC3', 'Gene', (77, 80))
257384	25679763	Similarly to LC3, endogenous p62/ SQSTM1 was consumed upon knockdown of MAGE-A3/6 or TRIM28 (Figure 5J) and this could be rescued by bafilomycin A1 (Figure 5K).	('LC3', 'Gene', (13, 16))	('MAGE-A3/6', 'Gene', (72, 81))	('SQSTM1', 'Gene', '8878', (34, 40))	('consumed', 'MPA', (45, 53))	('SQSTM1', 'Gene', (34, 40))	('knockdown', 'Var', (59, 68))	('TRIM28', 'Gene', (85, 91))	('p62', 'Gene', (29, 32))	('p62', 'Gene', '8878', (29, 32))	('LC3', 'Gene', '84557', (13, 16))
257387	25679763	Indeed, breast invasive carcinoma (Figure S4A), colon adenocarcinoma (Figure 6A), and lung squamous cell carcinoma (Figure 6B) tumors expressing MAGE-A3/6 had significantly reduced total and active (phospho-T172) AMPKalpha protein levels.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('total', 'MPA', (181, 186))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (86, 114))	('colon adenocarcinoma', 'Disease', (48, 68))	('MAGE-A3/6', 'Var', (145, 154))	('colon adenocarcinoma', 'Disease', 'MESH:D003110', (48, 68))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('reduced', 'NegReg', (173, 180))	('breast invasive carcinoma', 'Disease', 'MESH:D018270', (8, 33))	('lung squamous cell carcinoma (Figure 6B) tumors', 'Disease', 'MESH:D002294', (86, 133))	('AMPK', 'Gene', (213, 217))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (91, 114))	('breast invasive carcinoma', 'Disease', (8, 33))	('AMPK', 'Gene', '5564', (213, 217))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('carcinoma', 'Phenotype', 'HP:0030731', (59, 68))	('breast invasive carcinoma', 'Phenotype', 'HP:0003002', (8, 33))	('carcinoma', 'Phenotype', 'HP:0030731', (24, 33))
257396	25679763	MAGE-A6-induced, but not Apcmin- or MAGE-B10-induced anchorage-independent growth of HCEC and DLD1 cells was significantly impaired by A769662 in a dose-dependent manner (Figures 6C and S4G).	('A769662', 'Var', (135, 142))	('anchorage-independent growth', 'CPA', (53, 81))	('HCEC', 'CellLine', 'CVCL:2064', (85, 89))	('MAGE-B10', 'Gene', (36, 44))	('impaired', 'NegReg', (123, 131))	('MAGE-B10', 'Gene', '139422', (36, 44))
257400	25679763	One known mechanism of reducing AMPK activity in cancer is mutation/deletion of its upstream regulatory kinase Lkb1/Stk11.	('AMPK', 'Gene', (32, 36))	('AMPK', 'Gene', '5564', (32, 36))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('Stk11', 'Gene', (116, 121))	('Stk11', 'Gene', '6794', (116, 121))	('Lkb1', 'Gene', '6794', (111, 115))	('mutation/deletion', 'Var', (59, 76))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('Lkb1', 'Gene', (111, 115))	('reducing', 'NegReg', (23, 31))	('cancer', 'Disease', (49, 55))
257403	25679763	Consistent with this, expression of MAGE-A3/6 and mutation of Lkb1/Stk11 are rarely found in the same lung adenocarcinoma tumors (Figure S4C, p<0.01).	('Stk11', 'Gene', (67, 72))	('Lkb1', 'Gene', '6794', (62, 66))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (102, 121))	('lung adenocarcinoma tumors', 'Disease', (102, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('lung adenocarcinoma tumors', 'Disease', 'MESH:D000077192', (102, 128))	('Lkb1', 'Gene', (62, 66))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('Stk11', 'Gene', '6794', (67, 72))	('tumors', 'Phenotype', 'HP:0002664', (122, 128))	('mutation', 'Var', (50, 58))
257405	25679763	In combination with previous studies, our findings suggest that activation of MAGE-A3/6 in cancer cells is not a by-product, passenger event during cellular transformation and tumorigenesis, but rather MAGE-A3/6 are driver genes that support multiple phenotypes associated with tumors, including metabolic dysregulation.	('tumor', 'Phenotype', 'HP:0002664', (278, 283))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('tumors', 'Disease', (278, 284))	('tumors', 'Phenotype', 'HP:0002664', (278, 284))	('tumor', 'Disease', (278, 283))	('cancer', 'Disease', (91, 97))	('tumor', 'Disease', (176, 181))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('tumors', 'Disease', 'MESH:D009369', (278, 284))	('MAGE-A3/6', 'Gene', (78, 87))	('activation', 'PosReg', (64, 74))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('metabolic dysregulation', 'Disease', (296, 319))	('MAGE-A3/6', 'Var', (202, 211))	('tumor', 'Disease', 'MESH:D009369', (278, 283))	('tumor', 'Disease', 'MESH:D009369', (176, 181))
257410	25679763	Our results suggest that aberrant activation of MAGE-A3/6 in tumors may provide a unique mechanism for inhibition of tumor-suppressive autophagy during tumor initiation.	('MAGE-A3/6', 'Protein', (48, 57))	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('tumors', 'Disease', (61, 67))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('aberrant', 'Var', (25, 33))	('tumor', 'Disease', (117, 122))	('tumor initiation', 'Disease', 'MESH:D009369', (152, 168))	('tumor', 'Disease', (152, 157))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor initiation', 'Disease', (152, 168))	('activation', 'PosReg', (34, 44))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('tumor', 'Disease', (61, 66))	('inhibition', 'NegReg', (103, 113))
257414	25679763	However, simple demethylation of MAGEs is not sufficient to drive expression.	('drive', 'Reg', (60, 65))	('demethylation', 'Var', (16, 29))	('expression', 'MPA', (66, 76))	('MAGE', 'Gene', '51152', (33, 37))	('MAGE', 'Gene', (33, 37))
257419	25679763	Our findings on the molecular and cellular functions of MAGE-A3/6-TRIM28 in cancer provide intriguing insights into their normal physiological function during spermatogenesis.	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('cancer', 'Disease', (76, 82))	('MAGE-A3/6-TRIM28', 'Var', (56, 72))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))
257424	25679763	Consistent with these ideas, we have found that mouse MAGE-A genes are highly expressed in pre-pachytene spermatocytes (data not shown) where these regulator events are occurring and previous studies have shown that testis-specific knockout of TRIM28 blocks spermatocyte differentiation, resulting in testis degeneration.	('TRIM28', 'Gene', (244, 250))	('mouse', 'Species', '10090', (48, 53))	('knockout', 'Var', (232, 240))	('testis degeneration', 'Disease', (301, 320))	('blocks', 'NegReg', (251, 257))	('MAGE', 'Gene', '51152', (54, 58))	('testis degeneration', 'Phenotype', 'HP:0000029', (301, 320))	('spermatocyte differentiation', 'CPA', (258, 286))	('testis degeneration', 'Disease', 'MESH:D013736', (301, 320))	('MAGE', 'Gene', (54, 58))
257443	27077485	In multivariate Cox proportional hazards analysis, moderate to severe comorbidity was associated with an increased risk of death from any cause (adjusted hazards ratio [aHR], 1.52 [95% CI, 0.99-2.32]) and increased risk of death or recurrence (aHR, 1.71 [95% CI, 1.13-2.59]).	('death', 'Disease', 'MESH:D003643', (223, 228))	('death', 'Disease', 'MESH:D003643', (123, 128))	('death', 'Disease', (223, 228))	('death', 'Disease', (123, 128))	('moderate to severe', 'Var', (51, 69))
257503	27077485	Among p16-negative patients, moderate to severe comorbidity was associated with a statistically significant and clinically meaningful 1.9-fold increased risk of death (aHR, 1.90 [95% CI, 1.03-3.50]) and a 2.1-foldincreased risk of death or recurrence (aHR, 2.07 [95% CI, 1.13-3.80]) compared with no comorbidity to mild comorbidity after controlling for age, race, clinical T stage, and treatment.	('moderate', 'Var', (29, 37))	('death', 'Disease', 'MESH:D003643', (161, 166))	('patients', 'Species', '9606', (19, 27))	('death', 'Disease', (161, 166))	('p16', 'Gene', (6, 9))	('death', 'Disease', 'MESH:D003643', (231, 236))	('p16', 'Gene', '1029', (6, 9))	('death', 'Disease', (231, 236))
257508	27077485	Furthermore, given the upper bound of the 95% CI, it is plausible that moderate to severe comorbidity may increase the risk of death from any cause or recurrence by more than 2-fold compared with no comorbidity to mild comorbidity.	('death', 'Disease', 'MESH:D003643', (127, 132))	('death', 'Disease', (127, 132))	('comorbidity', 'Var', (90, 101))
257531	27077485	After controlling for other factors, including p16 status, moderate to severe comorbidity is associated with a statistically insignificant yet clinically relevant increased risk of death from any cause.	('p16', 'Gene', (47, 50))	('death', 'Disease', 'MESH:D003643', (181, 186))	('death', 'Disease', (181, 186))	('p16', 'Gene', '1029', (47, 50))	('moderate to severe comorbidity', 'Var', (59, 89))
257535	27077485	In this retrospective cohort study of 300 patients, moderate to severe comorbidity was associated with significantly worse survival than none to mild comorbidity after controlling for other variables including p16 status.	('worse', 'NegReg', (117, 122))	('p16', 'Gene', (210, 213))	('survival', 'MPA', (123, 131))	('moderate', 'Var', (52, 60))	('patients', 'Species', '9606', (42, 50))	('p16', 'Gene', '1029', (210, 213))
257542	24478461	Large deletions encompassing both BRCA1 and BECN1, and deletions of only BRCA1 but not BECN1, were found in breast and ovarian cancers, consistent with BRCA1 loss being a primary driver mutation in these cancers.	('ovarian cancer', 'Phenotype', 'HP:0100615', (119, 133))	('found', 'Reg', (99, 104))	('BRCA', 'Phenotype', 'HP:0003002', (34, 38))	('BRCA1', 'Gene', '672', (34, 39))	('BRCA', 'Phenotype', 'HP:0003002', (73, 77))	('BRCA', 'Phenotype', 'HP:0003002', (152, 156))	('cancers', 'Disease', 'MESH:D009369', (204, 211))	('BRCA1', 'Gene', '672', (152, 157))	('BECN1', 'Gene', (44, 49))	('BRCA1', 'Gene', (34, 39))	('cancers', 'Phenotype', 'HP:0002664', (127, 134))	('BRCA1', 'Gene', (152, 157))	('cancers', 'Disease', (127, 134))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('BRCA1 loss', 'Disease', 'MESH:D015431', (152, 162))	('ovarian cancers', 'Phenotype', 'HP:0100615', (119, 134))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('BRCA1', 'Gene', '672', (73, 78))	('BRCA1', 'Gene', (73, 78))	('cancers', 'Phenotype', 'HP:0002664', (204, 211))	('cancers', 'Disease', (204, 211))	('breast and ovarian cancers', 'Disease', 'MESH:D010051', (108, 134))	('cancers', 'Disease', 'MESH:D009369', (127, 134))	('deletions', 'Var', (55, 64))	('BRCA1 loss', 'Disease', (152, 162))
257543	24478461	Furthermore, there was no evidence for BECN1 mutation or loss in any other cancer, casting doubt on whether BECN1 is a tumor suppressor in most human cancers.	('tumor', 'Disease', (119, 124))	('BECN1', 'Gene', (39, 44))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('human', 'Species', '9606', (144, 149))	('cancers', 'Phenotype', 'HP:0002664', (150, 157))	('cancers', 'Disease', (150, 157))	('cancer', 'Disease', (75, 81))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('cancers', 'Disease', 'MESH:D009369', (150, 157))	('cancer', 'Disease', (150, 156))	('mutation', 'Var', (45, 53))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('loss', 'NegReg', (57, 61))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
257546	24478461	Monoallelic disruption of BECN1 on chromosome 17q21 has been reported in 40 to 75% of human breast, ovarian, and prostate tumors, suggesting that autophagy is a tumor suppression mechanism.	('prostate tumors', 'Disease', (113, 128))	('ovarian', 'Disease', (100, 107))	('BECN1', 'Gene', (26, 31))	('autophagy', 'CPA', (146, 155))	('tumor', 'Disease', (122, 127))	('Monoallelic disruption', 'Var', (0, 22))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('human', 'Species', '9606', (86, 91))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('breast', 'Disease', (92, 98))	('prostate tumors', 'Disease', 'MESH:D011471', (113, 128))	('tumors', 'Phenotype', 'HP:0002664', (122, 128))	('tumor', 'Disease', (161, 166))	('reported', 'Reg', (61, 69))
257547	24478461	BECN1 allelic loss was also found in 9 out of 22 breast cancer cell lines by fluorescence in situ hybridization (FISH) analysis, although no coding or splice site mutations were found.	('BECN1', 'Gene', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('breast cancer', 'Disease', 'MESH:D001943', (49, 62))	('allelic', 'Var', (6, 13))	('breast cancer', 'Disease', (49, 62))	('breast cancer', 'Phenotype', 'HP:0003002', (49, 62))	('loss', 'NegReg', (14, 18))
257550	24478461	BRCA1 is a critical regulator of DNA repair by homologous recombination (HR) and its loss causes DNA repair defects and cancer predisposition.	('loss', 'Var', (85, 89))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('BRCA1', 'Gene', (0, 5))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('causes', 'Reg', (90, 96))	('BRCA1', 'Gene', '672', (0, 5))	('BRCA', 'Phenotype', 'HP:0003002', (0, 4))	('DNA repair', 'MPA', (97, 107))
257553	24478461	In support of the concept that autophagy is a tumor suppression mechanism and that allelic loss of BECN1 promotes cancer, Beclin1+/- mice are prone to mammary hyperplasia, liver and lung carcinomas and lymphomas.	('hyperplasia', 'Disease', (159, 170))	('liver and lung carcinomas and lymphomas', 'Disease', 'MESH:D006528', (172, 211))	('mice', 'Species', '10090', (133, 137))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('hyperplasia', 'Disease', 'MESH:D006965', (159, 170))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('Beclin1', 'Gene', '56208', (122, 129))	('Beclin1', 'Gene', (122, 129))	('BECN1', 'Gene', (99, 104))	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('promotes', 'PosReg', (105, 113))	('mammary hyperplasia', 'Phenotype', 'HP:0010313', (151, 170))	('tumor', 'Disease', (46, 51))	('lymphomas', 'Phenotype', 'HP:0002665', (202, 211))	('loss', 'Var', (91, 95))	('tumor', 'Disease', 'MESH:D009369', (46, 51))	('prone', 'Reg', (142, 147))	('carcinoma', 'Phenotype', 'HP:0030731', (187, 196))	('carcinomas', 'Phenotype', 'HP:0030731', (187, 197))	('lymphoma', 'Phenotype', 'HP:0002665', (202, 210))	('cancer', 'Disease', (114, 120))
257554	24478461	However, mosaic whole body knock out of the essential autophagy gene Atg5, or liver-specific knock out of the essential autophagy gene Atg7, produces only benign liver hepatomas and no other neoplasms.	('benign liver hepatomas', 'Disease', (155, 177))	('neoplasms', 'Phenotype', 'HP:0002664', (191, 200))	('Atg5', 'Gene', (69, 73))	('Atg7', 'Gene', (135, 139))	('benign liver hepatomas', 'Disease', 'MESH:D018248', (155, 177))	('knock out', 'Var', (27, 36))	('neoplasm', 'Phenotype', 'HP:0002664', (191, 199))	('neoplasms', 'Disease', 'MESH:D009369', (191, 200))	('neoplasms', 'Disease', (191, 200))	('knock out', 'Var', (93, 102))
257557	24478461	The vast majority of germline mutations in BRCA1 are loss-of-function mutations (frameshift, indels, nonsense mutations, or missense), or focal deletions, not gross deletions in the BRCA1 locus at 17q21 that extend to encompass BECN1.	('BRCA1', 'Gene', (43, 48))	('BRCA1', 'Gene', '672', (182, 187))	('deletions', 'Var', (144, 153))	('missense', 'Var', (124, 132))	('BRCA1', 'Gene', (182, 187))	('frameshift', 'Var', (81, 91))	('nonsense mutations', 'Var', (101, 119))	('germline mutations', 'Var', (21, 39))	('BRCA', 'Phenotype', 'HP:0003002', (43, 47))	('BRCA1', 'Gene', '672', (43, 48))	('BRCA', 'Phenotype', 'HP:0003002', (182, 186))	('loss-of-function', 'NegReg', (53, 69))
257561	24478461	Without autophagy tumors accumulate defective mitochondria, have growth and metabolic defects, and progresses to a more benign fate.	('defective', 'Var', (36, 45))	('progresses', 'PosReg', (99, 109))	('growth', 'CPA', (65, 71))	('metabolic defects', 'Disease', (76, 93))	('autophagy tumors', 'Disease', (8, 24))	('more benign fate', 'CPA', (115, 131))	('autophagy tumors', 'Disease', 'MESH:C564093', (8, 24))	('metabolic defects', 'Disease', 'MESH:D008659', (76, 93))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
257563	24478461	Germline mutations in BRCA1, BRCA2, and PALB2, predispose to hereditary breast cancer and the three proteins function together to maintain genome stability by promoting faithful repair of double strand breaks by HR.	('Germline mutations', 'Var', (0, 18))	('PALB2', 'Gene', (40, 45))	('PALB2', 'Gene', '79728', (40, 45))	('hereditary breast cancer', 'Disease', 'MESH:D001943', (61, 85))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('genome', 'MPA', (139, 145))	('maintain', 'PosReg', (130, 138))	('faithful repair', 'MPA', (169, 184))	('BRCA2', 'Gene', (29, 34))	('predispose', 'Reg', (47, 57))	('hereditary breast cancer', 'Disease', (61, 85))	('promoting', 'PosReg', (159, 168))	('BRCA', 'Phenotype', 'HP:0003002', (29, 33))	('function', 'Reg', (109, 117))	('BRCA1', 'Gene', '672', (22, 27))	('BRCA2', 'Gene', '675', (29, 34))	('BRCA', 'Phenotype', 'HP:0003002', (22, 26))	('breast cancer', 'Phenotype', 'HP:0003002', (72, 85))	('BRCA1', 'Gene', (22, 27))
257564	24478461	Mammary epithelial cell-specific knockout of Palb2 causes mammary tumorigenesis with long latency that is suppressed by allelic loss of Becnl, suggesting that autophagy is tumor-promoting.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('knockout', 'Var', (33, 41))	('tumor', 'Disease', (66, 71))	('tumor', 'Disease', (172, 177))	('Palb2', 'Gene', '79728', (45, 50))	('causes', 'Reg', (51, 57))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('Palb2', 'Gene', (45, 50))
257565	24478461	Deletion of Trp53 abrogates tumorigenesis impairment upon allelic loss of Becnl in Pa/fr2-deficient mammary tumors, thus the combination of autophagy defect and loss of a critical DNA repair mechanism augments the p53 anti-tumor response.	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('tumor', 'Disease', (28, 33))	('tumor', 'Disease', (108, 113))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('Pa/fr2-deficient mammary tumors', 'Disease', (83, 114))	('impairment', 'NegReg', (42, 52))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('Pa/fr2-deficient mammary tumors', 'Disease', 'MESH:D015674', (83, 114))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('p53', 'Gene', '7157', (214, 217))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('augments', 'PosReg', (201, 209))	('abrogates', 'NegReg', (18, 27))	('Deletion', 'Var', (0, 8))	('tumor', 'Disease', (223, 228))	('p53', 'Gene', '7157', (14, 17))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('p53', 'Gene', (214, 217))	('Trp53', 'Gene', (12, 17))	('tumor', 'Disease', 'MESH:D009369', (223, 228))	('Trp53', 'Gene', '7157', (12, 17))	('p53', 'Gene', (14, 17))	('autophagy defect and loss', 'Disease', 'MESH:C564093', (140, 165))
257566	24478461	Since loss of both Palb2 and autophagy promote DNA damage and p53 activation,, this explains enhanced p53 activity and why autophagy suppresses the p53 response and mammary tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('p53', 'Gene', '7157', (62, 65))	('activation', 'PosReg', (66, 76))	('loss', 'Var', (6, 10))	('autophagy', 'CPA', (29, 38))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('p53', 'Gene', '7157', (102, 105))	('p53', 'Gene', (62, 65))	('promote', 'PosReg', (39, 46))	('Palb2', 'Gene', (19, 24))	('p53', 'Gene', '7157', (148, 151))	('DNA damage', 'MPA', (47, 57))	('enhanced', 'PosReg', (93, 101))	('Palb2', 'Gene', '79728', (19, 24))	('p53', 'Gene', (102, 105))	('p53', 'Gene', (148, 151))	('suppresses', 'NegReg', (133, 143))	('tumor', 'Disease', (173, 178))	('activity', 'MPA', (106, 114))
257567	24478461	The important unanswered question here is whether mutations in essential autophagy genes are found in human cancers using current genomic information, and if they are found, are they loss- or gain-of-function mutations?	('loss-', 'NegReg', (183, 188))	('mutations', 'Var', (50, 59))	('cancers', 'Phenotype', 'HP:0002664', (108, 115))	('gain-of-function', 'PosReg', (192, 208))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('autophagy genes', 'Gene', (73, 88))	('cancers', 'Disease', 'MESH:D009369', (108, 115))	('cancers', 'Disease', (108, 115))	('human', 'Species', '9606', (102, 107))
257570	24478461	We first assessed BECN1 for single nucleotide variations (SNVs) and copy number variations (CNVs) in human breast, ovarian and prostate cancer genome sequences.	('prostate cancer', 'Phenotype', 'HP:0012125', (127, 142))	('human', 'Species', '9606', (101, 106))	('single nucleotide variations', 'Var', (28, 56))	('copy number variations', 'Var', (68, 90))	('ovarian and prostate cancer', 'Disease', 'MESH:D010051', (115, 142))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
257571	24478461	Since BECN1 is adjacent to BRCA1, we specifically looked for deletions of BECN1 that do not encompass BRCA1.	('BRCA1', 'Gene', (102, 107))	('BECN1', 'Gene', (74, 79))	('BRCA1', 'Gene', '672', (27, 32))	('deletions', 'Var', (61, 70))	('BRCA1', 'Gene', (27, 32))	('BRCA', 'Phenotype', 'HP:0003002', (102, 106))	('BRCA1', 'Gene', '672', (102, 107))	('BRCA', 'Phenotype', 'HP:0003002', (27, 31))
257572	24478461	We found enrichment for truncating mutations of BRCA1, deletion of the chromosomal region that included BRCA1 only, and deletions affecting both BRCA1 and BECN1, but not truncating mutations of BECN1 or deletions of only BECN1.	('BRCA1', 'Gene', '672', (48, 53))	('deletions', 'Var', (120, 129))	('BRCA', 'Phenotype', 'HP:0003002', (48, 52))	('BRCA1', 'Gene', '672', (104, 109))	('BRCA', 'Phenotype', 'HP:0003002', (145, 149))	('BRCA1', 'Gene', (48, 53))	('BRCA1', 'Gene', '672', (145, 150))	('BRCA1', 'Gene', (104, 109))	('BRCA1', 'Gene', (145, 150))	('truncating', 'MPA', (24, 34))	('deletion', 'Var', (55, 63))	('BECN1', 'Gene', (155, 160))	('BRCA', 'Phenotype', 'HP:0003002', (104, 108))
257573	24478461	Analysis of all other cancers that lack BRCA1 deletion indicated no significant recurrence of SNVs or CNVs in BECN1.	('deletion', 'Var', (46, 54))	('cancers', 'Disease', 'MESH:D009369', (22, 29))	('cancers', 'Phenotype', 'HP:0002664', (22, 29))	('cancers', 'Disease', (22, 29))	('BRCA', 'Phenotype', 'HP:0003002', (40, 44))	('BRCA1', 'Gene', '672', (40, 45))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('SNVs', 'Disease', (94, 98))	('BRCA1', 'Gene', (40, 45))
257580	24478461	We test the sensitivity of our method by finding the previously reported CNV (amplifications in PIK3CA, EGFR, FOXA1 and HER2; de/etions in MLL3, PTEN, RB1 and MAP2K4) in breast invasive cancer.	('MAP2K4', 'Gene', '6416', (159, 165))	('MAP2K4', 'Gene', (159, 165))	('HER2', 'Gene', '2064', (120, 124))	('PIK3CA', 'Gene', '5290', (96, 102))	('FOXA1', 'Gene', '3169', (110, 115))	('EGFR', 'Gene', (104, 108))	('RB1', 'Gene', '5925', (151, 154))	('MLL3', 'Gene', '58508', (139, 143))	('FOXA1', 'Gene', (110, 115))	('de/etions', 'Var', (126, 135))	('PTEN', 'Gene', (145, 149))	('HER2', 'Gene', (120, 124))	('PIK3CA', 'Gene', (96, 102))	('EGFR', 'Gene', '1956', (104, 108))	('MLL3', 'Gene', (139, 143))	('PTEN', 'Gene', '5728', (145, 149))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('breast invasive cancer', 'Disease', 'MESH:D001943', (170, 192))	('breast invasive cancer', 'Disease', (170, 192))	('RB1', 'Gene', (151, 154))
257585	24478461	We extracted the somatic mutations for BECN1 and BRCA1 and indicated their type as missense, nonsense, silent, splice site, and insertion or deletion resulting in frame shift or in frame (Table S3 and Table S4).	('BRCA', 'Phenotype', 'HP:0003002', (49, 53))	('nonsense', 'Var', (93, 101))	('deletion', 'Var', (141, 149))	('BECN1', 'Gene', (39, 44))	('missense', 'Var', (83, 91))	('BRCA1', 'Gene', '672', (49, 54))	('frame', 'MPA', (163, 168))	('BRCA1', 'Gene', (49, 54))	('insertion', 'Var', (128, 137))
257589	24478461	CNVs were classified into three groups defined by whether the CNV overlapped with BECN1 but not BRCA1, overlapped with BRCA1 but not BECN1, or overlapped with both BECN1 and BRCA1 (Table 1).	('BRCA', 'Phenotype', 'HP:0003002', (96, 100))	('BRCA1', 'Gene', (174, 179))	('BRCA1', 'Gene', (119, 124))	('BRCA1', 'Gene', '672', (96, 101))	('BRCA1', 'Gene', (96, 101))	('BRCA', 'Phenotype', 'HP:0003002', (119, 123))	('BRCA', 'Phenotype', 'HP:0003002', (174, 178))	('BRCA1', 'Gene', '672', (174, 179))	('BRCA1', 'Gene', '672', (119, 124))	('overlapped', 'Var', (103, 113))
257591	24478461	As expected, breast and ovarian tumors were significantly enriched for having deletions in the locus containing both BECN1 and BRCA1 (Table 1).	('BRCA1', 'Gene', '672', (127, 132))	('breast and ovarian tumors', 'Disease', 'MESH:D001943', (13, 38))	('BRCA1', 'Gene', (127, 132))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('BRCA', 'Phenotype', 'HP:0003002', (127, 131))	('ovarian tumor', 'Phenotype', 'HP:0100615', (24, 37))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('BECN1', 'Gene', (117, 122))	('ovarian tumors', 'Phenotype', 'HP:0100615', (24, 38))	('deletions', 'Var', (78, 87))
257592	24478461	Other tumor types that exhibited significant enrichment for deletions in both BECN1 and BRCA1 include kidney chromophobe and uterine corpus endometrioid carcinoma (Table 1).	('BRCA1', 'Gene', (88, 93))	('kidney chromophobe', 'Disease', 'MESH:D000238', (102, 120))	('corpus endometrioid carcinoma', 'Disease', (133, 162))	('corpus endometrioid carcinoma', 'Disease', 'MESH:D016889', (133, 162))	('BECN1', 'Gene', (78, 83))	('deletions', 'Var', (60, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (153, 162))	('tumor', 'Disease', 'MESH:D009369', (6, 11))	('BRCA', 'Phenotype', 'HP:0003002', (88, 92))	('kidney chromophobe', 'Disease', (102, 120))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('BRCA1', 'Gene', '672', (88, 93))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (140, 162))	('tumor', 'Disease', (6, 11))
257594	24478461	Closer examination found that the CNVs in kidney chromophobe and kidney renal papillary cell carcinoma are whole chromosome deletions and amplifications, respectively, which are consistent with known loss and gain of chromosome 17 for these two types of tumors.	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('tumors', 'Disease', (254, 260))	('tumors', 'Phenotype', 'HP:0002664', (254, 260))	('tumors', 'Disease', 'MESH:D009369', (254, 260))	('tumor', 'Phenotype', 'HP:0002664', (254, 259))	('renal papillary cell carcinoma', 'Phenotype', 'HP:0006766', (72, 102))	('CNVs', 'Var', (34, 38))	('kidney chromophobe and kidney renal papillary cell carcinoma', 'Disease', 'MESH:D007674', (42, 102))
257595	24478461	CNVs that overlap BRCA1 but not BECN1 were enriched for deletions in breast and ovarian tumors, while CNVs that overlap BECN1 but not BRCA1 were not enriched for deletions in any tumor (Table 1).	('BRCA', 'Phenotype', 'HP:0003002', (18, 22))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('BRCA1', 'Gene', '672', (18, 23))	('BRCA1', 'Gene', (134, 139))	('ovarian tumors', 'Phenotype', 'HP:0100615', (80, 94))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('ovarian tumor', 'Phenotype', 'HP:0100615', (80, 93))	('BECN1', 'Gene', (120, 125))	('BRCA1', 'Gene', (18, 23))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('deletions', 'Var', (56, 65))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('BRCA', 'Phenotype', 'HP:0003002', (134, 138))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('breast and ovarian tumors', 'Disease', 'MESH:D001943', (69, 94))	('BRCA1', 'Gene', '672', (134, 139))	('tumor', 'Disease', (88, 93))	('tumor', 'Disease', (179, 184))
257596	24478461	These results are consistent with the loss of BRCA1 being the driver mutation in breast and ovarian tumors.	('loss', 'Var', (38, 42))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('BRCA1', 'Gene', '672', (46, 51))	('ovarian tumors', 'Phenotype', 'HP:0100615', (92, 106))	('ovarian tumor', 'Phenotype', 'HP:0100615', (92, 105))	('BRCA', 'Phenotype', 'HP:0003002', (46, 50))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('breast and ovarian tumors', 'Disease', 'MESH:D001943', (81, 106))	('BRCA1', 'Gene', (46, 51))
257598	24478461	Loss of chromosome 17q21 and BRCA1 has been reported in prostate cancer only very infrequently (0.45%).	('prostate cancer', 'Disease', 'MESH:D011471', (56, 71))	('BRCA', 'Phenotype', 'HP:0003002', (29, 33))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('BRCA1', 'Gene', '672', (29, 34))	('prostate cancer', 'Phenotype', 'HP:0012125', (56, 71))	('BRCA1', 'Gene', (29, 34))	('Loss', 'Var', (0, 4))	('prostate cancer', 'Disease', (56, 71))
257599	24478461	For prostate adenocarcinoma, we found 9 deletions (covering both BECN1 and BRCA1) and no amplifications (Table 1).	('carcinoma', 'Phenotype', 'HP:0030731', (18, 27))	('BRCA1', 'Gene', (75, 80))	('prostate adenocarcinoma', 'Disease', (4, 27))	('deletions', 'Var', (40, 49))	('prostate adenocarcinoma', 'Disease', 'MESH:D011471', (4, 27))	('BECN1', 'Gene', (65, 70))	('BRCA', 'Phenotype', 'HP:0003002', (75, 79))	('BRCA1', 'Gene', '672', (75, 80))
257600	24478461	Prostate adenocarcinoma is a heterogeneous disease and the fraction of this disease where loss of 17q21 is a driver mutation is small compared to breast or ovarian cancer.	('breast or ovarian cancer', 'Disease', 'MESH:D010051', (146, 170))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('Prostate adenocarcinoma', 'Disease', 'MESH:D011471', (0, 23))	('17q21', 'Gene', (98, 103))	('breast or ovarian cancer', 'Disease', (146, 170))	('Prostate adenocarcinoma', 'Disease', (0, 23))	('ovarian cancer', 'Phenotype', 'HP:0100615', (156, 170))	('loss of', 'Var', (90, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (14, 23))
257601	24478461	It is clear, however, that in contrast to previous reports, BECN1 deletions do not significantly occur in the absence of BRCA1 deletion.	('BRCA', 'Phenotype', 'HP:0003002', (121, 125))	('BECN1', 'Gene', (60, 65))	('BRCA1', 'Gene', '672', (121, 126))	('BRCA1', 'Gene', (121, 126))	('deletions', 'Var', (66, 75))
257602	24478461	There are 169 and 32 (ratio of 5.28) mutations found in BRCA1 and BECN1 respectively across all tumor samples (6632) and the numbers are 137 and 31 (ratio of 4.42) if we exclude breast and ovarian tumors where BRCA1 is known to be a tumor suppressor (Table S2).	('BRCA', 'Phenotype', 'HP:0003002', (210, 214))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('ovarian tumor', 'Phenotype', 'HP:0100615', (189, 202))	('tumors', 'Phenotype', 'HP:0002664', (197, 203))	('ovarian tumors', 'Phenotype', 'HP:0100615', (189, 203))	('tumor', 'Disease', (233, 238))	('BRCA1', 'Gene', '672', (210, 215))	('BRCA1', 'Gene', (210, 215))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('BECN1', 'Gene', (66, 71))	('tumor', 'Disease', 'MESH:D009369', (233, 238))	('BRCA1', 'Gene', '672', (56, 61))	('BRCA', 'Phenotype', 'HP:0003002', (56, 60))	('tumor', 'Disease', (96, 101))	('mutations', 'Var', (37, 46))	('BRCA1', 'Gene', (56, 61))	('breast and ovarian tumors', 'Disease', 'MESH:D001943', (178, 203))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('tumor', 'Disease', (197, 202))
257604	24478461	None of the mutations found in BECN1 were nonsense or splice site mutations (Table S3) with the potential to alter function and that are frequently found tumor suppressor mutations.	('alter', 'Reg', (109, 114))	('mutations', 'Var', (12, 21))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('function', 'MPA', (115, 123))	('BECN1', 'Gene', (31, 36))	('tumor', 'Disease', (154, 159))
257605	24478461	If we restrict analysis to breast and ovarian cancer, there is only one mutation found in BECN1 and it is a missense mutation in an ovarian tumor.	('breast and ovarian cancer', 'Disease', 'MESH:D010051', (27, 52))	('ovarian cancer', 'Phenotype', 'HP:0100615', (38, 52))	('ovarian tumor', 'Phenotype', 'HP:0100615', (132, 145))	('ovarian tumor', 'Disease', 'MESH:D010051', (132, 145))	('missense mutation', 'Var', (108, 125))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('BECN1', 'Gene', (90, 95))	('ovarian tumor', 'Disease', (132, 145))
257606	24478461	In contrast, there are 32 mutations in BRCA1 of which 23 are nonsense, splice site or frame shift mutations all of which lead to truncation of BRCA1 (Table S4).	('BRCA1', 'Gene', '672', (143, 148))	('truncation', 'MPA', (129, 139))	('BRCA1', 'Gene', (143, 148))	('BRCA', 'Phenotype', 'HP:0003002', (143, 147))	('BRCA', 'Phenotype', 'HP:0003002', (39, 43))	('mutations', 'Var', (26, 35))	('BRCA1', 'Gene', '672', (39, 44))	('lead to', 'Reg', (121, 128))	('frame shift', 'Var', (86, 97))	('BRCA1', 'Gene', (39, 44))
257607	24478461	Across all cancer data from TCGA, there are 30 missense, 0 nonsense, 0 splice site and 11 silent mutations for BECN1 and 135 missense, 20 nonsense, 12 splice site and 39 silent mutations for BRCA1.	('BRCA1', 'Gene', (191, 196))	('missense', 'Var', (47, 55))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('BRCA', 'Phenotype', 'HP:0003002', (191, 195))	('cancer', 'Disease', 'MESH:D009369', (11, 17))	('missense', 'Var', (125, 133))	('BRCA1', 'Gene', '672', (191, 196))	('cancer', 'Disease', (11, 17))	('BECN1', 'Gene', (111, 116))
257608	24478461	To find statistical enrichment of missense, nonsense or splice site mutations compared to silent mutations, we use as null model the aggregate of mutations across all samples in breast cancer (778 tumors) yielding 31861 missense, 2339 nonsense, 1075 splice site and 11677 silent mutations.	('tumors', 'Disease', 'MESH:D009369', (197, 203))	('missense', 'Var', (220, 228))	('nonsense', 'Var', (235, 243))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('breast cancer', 'Disease', 'MESH:D001943', (178, 191))	('breast cancer', 'Phenotype', 'HP:0003002', (178, 191))	('tumors', 'Phenotype', 'HP:0002664', (197, 203))	('breast cancer', 'Disease', (178, 191))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('tumors', 'Disease', (197, 203))
257609	24478461	Since the vast majority of mutations detected in tumors are passenger mutations with little or no selective advantage to the tumors, the ratio of missense to silent mutations (2.73), nonsense to silent mutations (0.20), and splice site to silent mutations (0.09) are good approximations for little or no selection of missense, nonsense or splice site over silent mutations.	('mutations', 'Var', (27, 36))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('tumors', 'Disease', 'MESH:D009369', (125, 131))	('tumors', 'Disease', (125, 131))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('tumors', 'Disease', (49, 55))	('tumors', 'Disease', 'MESH:D009369', (49, 55))
257611	24478461	There is statistically significant enrichment for ratio of nonsense to silent and splice site to silent mutations for BRCA1 (2.6 and 3.4 fold enrichment with p-value of 0.0008 and 0.0003 using two-tailed Chi-square test with Yate's correction).	('BRCA1', 'Gene', (118, 123))	('nonsense', 'Var', (59, 67))	('BRCA', 'Phenotype', 'HP:0003002', (118, 122))	('BRCA1', 'Gene', '672', (118, 123))
257612	24478461	There is no significant enrichment for missense over silent mutations for BRCA1 and BECN1, and no enrichment of nonsense and splice site over silent mutations in BECN1.	('BECN1', 'Gene', (84, 89))	('BRCA1', 'Gene', '672', (74, 79))	('BRCA', 'Phenotype', 'HP:0003002', (74, 78))	('BRCA1', 'Gene', (74, 79))	('missense', 'Var', (39, 47))	('BECN1', 'Gene', (162, 167))
257616	24478461	Despite reports indicating allelic loss of BECN1 in some human cancers, this appears to be explained solely by the proximity of BECN1 to BRCA1.	('BRCA1', 'Gene', '672', (137, 142))	('loss', 'NegReg', (35, 39))	('BECN1', 'Gene', (43, 48))	('BRCA1', 'Gene', (137, 142))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('allelic', 'Var', (27, 34))	('BRCA', 'Phenotype', 'HP:0003002', (137, 141))	('cancers', 'Phenotype', 'HP:0002664', (63, 70))	('cancers', 'Disease', (63, 70))	('human', 'Species', '9606', (57, 62))	('cancers', 'Disease', 'MESH:D009369', (63, 70))
257619	24478461	Furthermore, there is no finding of nonsense or splice site mutations in BECN1 in any other cancers.	('nonsense or splice site mutations', 'Var', (36, 69))	('BECN1', 'Gene', (73, 78))	('cancers', 'Phenotype', 'HP:0002664', (92, 99))	('cancers', 'Disease', 'MESH:D009369', (92, 99))	('cancers', 'Disease', (92, 99))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
257621	24478461	In these cancers, the majority of the deletions are large and take out both genes and a hundred others.	('cancers', 'Disease', 'MESH:D009369', (9, 16))	('cancers', 'Phenotype', 'HP:0002664', (9, 16))	('cancers', 'Disease', (9, 16))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('deletions', 'Var', (38, 47))
257622	24478461	While focal deletions and somatic, predicted loss of function mutations (missense, nonsense, frame shift and splice site mutations) are found in BRCA1, they are not found in BECN1.	('nonsense', 'Var', (83, 91))	('BRCA', 'Phenotype', 'HP:0003002', (145, 149))	('BRCA1', 'Gene', '672', (145, 150))	('loss of function', 'NegReg', (45, 61))	('BRCA1', 'Gene', (145, 150))	('frame shift', 'Var', (93, 104))
257623	24478461	Furthermore, there are no significant germline mutation or allelic loss of BECN1 in breast and ovarian cancer patients, nor are there inactivating mutations in the absence of BRCA1 mutation or loss.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('BRCA1', 'Gene', (175, 180))	('BECN1', 'Gene', (75, 80))	('ovarian cancer', 'Phenotype', 'HP:0100615', (95, 109))	('loss', 'NegReg', (67, 71))	('mutation', 'Var', (181, 189))	('breast and ovarian cancer', 'Disease', 'MESH:D010051', (84, 109))	('BRCA', 'Phenotype', 'HP:0003002', (175, 179))	('patients', 'Species', '9606', (110, 118))	('BRCA1', 'Gene', '672', (175, 180))
257625	24478461	Indeed, allelic loss of Becnl suppresses rather than promotes mammary tumorgenesis mediated by Palb2 deficiency.	('promotes', 'PosReg', (53, 61))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('Palb2', 'Gene', '79728', (95, 100))	('Becnl', 'Gene', (24, 29))	('suppresses', 'NegReg', (30, 40))	('tumor', 'Disease', (70, 75))	('Palb2', 'Gene', (95, 100))	('deficiency', 'Var', (101, 111))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
257628	24478461	Mice with allelic loss of Becnl, or bi-allelic deletion of Atg5 or Atg7 in liver are prone to liver tumors.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('bi-allelic deletion', 'Var', (36, 55))	('loss', 'NegReg', (18, 22))	('Atg5', 'Gene', (59, 63))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('Atg7', 'Gene', (67, 71))	('liver tumors', 'Disease', 'MESH:D008113', (94, 106))	('Mice', 'Species', '10090', (0, 4))	('prone', 'Reg', (85, 90))	('liver tumors', 'Phenotype', 'HP:0002896', (94, 106))	('liver tumors', 'Disease', (94, 106))
257630	24478461	Indeed, deletion of Atg7 diverts progression of lung adenocarcinomas to benign oncocytomas.	('lung adenocarcinomas to benign oncocytomas', 'Disease', (48, 90))	('carcinomas', 'Phenotype', 'HP:0030731', (58, 68))	('progression', 'MPA', (33, 44))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (48, 68))	('diverts', 'NegReg', (25, 32))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (48, 67))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))	('lung adenocarcinomas to benign oncocytomas', 'Disease', 'MESH:D018249', (48, 90))	('deletion', 'Var', (8, 16))	('Atg7', 'Gene', (20, 24))
257639	33339347	Moreover, we identify specific topics that are enriched in genes known to play a role in the corresponding disease and are strongly related to the survival probability of patients.	('related', 'Reg', (132, 139))	('genes', 'Var', (59, 64))	('patients', 'Species', '9606', (171, 179))
257682	33339347	Breast cancer samples are usually divided in 5 different subtypes: Luminal A, Luminal B, Triple-Negative/Basal, HER2 and Normal-like.	('Luminal', 'Chemical', 'MESH:D010634', (78, 85))	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('Breast cancer', 'Phenotype', 'HP:0003002', (0, 13))	('Triple-Negative/Basal', 'Var', (89, 110))	('Breast cancer', 'Disease', 'MESH:D001943', (0, 13))	('HER2', 'Gene', (112, 116))	('HER2', 'Gene', '2064', (112, 116))	('Breast cancer', 'Disease', (0, 13))	('Luminal', 'Chemical', 'MESH:D010634', (67, 74))
257689	33339347	Triple-negative/Basal (which we shall simply denote as Basal in the following) are both hormone-receptor negative and HER2 negative.	('HER2', 'Gene', (118, 122))	('hormone-receptor', 'Gene', '3164', (88, 104))	('HER2', 'Gene', '2064', (118, 122))	('Triple-negative/Basal', 'Var', (0, 21))	('hormone-receptor', 'Gene', (88, 104))
257812	28977965	Genetic polymorphisms of non-coding RNAs associated with increased head and neck cancer susceptibility: a systematic review and meta-analysis Genetic polymorphisms, including single nucleotide polymorphisms (SNP) and nucleotide repeat expansions, can occur in regions that transcribe non-coding RNAs (ncRNA), such as, but not limited to, micro RNA and long non-coding RNA.	('associated', 'Reg', (41, 51))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('cancer', 'Disease', (81, 87))	('micro RNA', 'Disease', (338, 347))	('head and neck cancer', 'Phenotype', 'HP:0012288', (67, 87))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('polymorphisms', 'Var', (8, 21))
257813	28977965	An association between genetic polymorphisms of ncRNA and increasing head and neck cancer (HNC) risk has been identified by several studies.	('genetic polymorphisms', 'Var', (23, 44))	('head and neck cancer', 'Phenotype', 'HP:0012288', (69, 89))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('neck cancer', 'Disease', 'MESH:D006258', (78, 89))	('neck cancer', 'Disease', (78, 89))	('ncRNA', 'Gene', (48, 53))
257814	28977965	Our analysis revealed that HOTAIR rs920778, uc003opf.1 rs11752942, and miR-196a2 rs11614913 were related to HNC susceptibility, while let-7 rs10877887, miR-124-1rs531564, and miR-608 rs4919510 were considered as protective factors.	('rs920778', 'Mutation', 'rs920778', (34, 42))	('miR-608', 'Gene', (175, 182))	('rs11752942', 'Mutation', 'rs11752942', (55, 65))	('related', 'Reg', (97, 104))	('miR-196a2', 'Gene', (71, 80))	('rs11614913', 'Mutation', 'rs11614913', (81, 91))	('HNC', 'Disease', (108, 111))	('rs10877887', 'Mutation', 'rs10877887', (140, 150))	('rs920778', 'Var', (34, 42))	('miR-608', 'Gene', '693193', (175, 182))	('rs11752942', 'Var', (55, 65))	('miR-196a2', 'Gene', '406973', (71, 80))	('rs11614913', 'Var', (81, 91))	('HOTAIR', 'Gene', (27, 33))	('rs4919510', 'Mutation', 'rs4919510', (183, 192))	('HOTAIR', 'Gene', '100124700', (27, 33))
257829	28977965	Most of these genetic polymorphisms are due to SNPs caused by single nucleotide mutations that occur on average approximately once in 100 to 300 base pairs in the human genome.	('human', 'Species', '9606', (163, 168))	('due', 'Reg', (40, 43))	('SNPs', 'Disease', (47, 51))	('single nucleotide mutations', 'Var', (62, 89))
257830	28977965	in 2005 firstly demonstrated the association between SNPs in miRNA-related genes and Tourette's syndrome, SNPs in genes encoding ncRNAs have been widely investigated, especially in the field of cancer susceptibility.	('cancer', 'Disease', (194, 200))	('miR', 'Gene', '220972', (61, 64))	('miR', 'Gene', (61, 64))	('SNPs', 'Var', (53, 57))	("Tourette's syndrome", 'Disease', (85, 104))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('cancer', 'Disease', 'MESH:D009369', (194, 200))	("Tourette's syndrome", 'Disease', 'MESH:D005879', (85, 104))	('association', 'Interaction', (33, 44))
257836	28977965	Except all the three cohorts of miR-219-1 rs213210 and two of the four cohorts of miR-26a-1: rs7372209, the rest cohorts were of different SNPs (listed in detail in Supplementary Table 1).	('miR-26a-1', 'Gene', '407015', (82, 91))	('miR-219-1', 'Gene', (32, 41))	('miR-219-1', 'Gene', '407002', (32, 41))	('rs213210', 'Var', (42, 50))	('miR-26a-1', 'Gene', (82, 91))	('rs7372209', 'Mutation', 'rs7372209', (93, 102))	('rs213210', 'Mutation', 'rs213210', (42, 50))
257837	28977965	Meta-analysis results are listed in Supplementary Table 4. lncRNA SNPs, HOTAIR rs920778 (C/T) and uc003opf.1 rs11752942 (A/G) were considered eligible for meta-analysis.	('HOTAIR', 'Gene', '100124700', (72, 78))	('rs920778', 'Mutation', 'rs920778', (79, 87))	('rs11752942', 'Mutation', 'rs11752942', (109, 119))	('HOTAIR', 'Gene', (72, 78))	('rs11752942', 'Var', (109, 119))
257838	28977965	For HOTAIR rs920778, three comparisons were found in a single study including 2098 cases and 2150 controls, and for uc003opf.1 rs11752942, two comparisons were found also in a single study including 1493 cases and 1553 controls, respectively.	('HOTAIR', 'Gene', '100124700', (4, 10))	('rs11752942', 'Var', (127, 137))	('rs920778', 'Mutation', 'rs920778', (11, 19))	('rs920778', 'Var', (11, 19))	('rs11752942', 'Mutation', 'rs11752942', (127, 137))	('HOTAIR', 'Gene', (4, 10))
257839	28977965	A significant association was found in all genetic models between oesophageal squamous cell carcinoma (abbreviated to ESCC to differentiate it from oral squamous cell carcinoma) susceptibility and both HOTAIR rs920778 (C allele vs. T allele: OR = 1.46, 95% CI = 1.32-1.61, P-H = 0.37; CC vs. CT + TT: OR = 1.44, 95% CI = 1.27-1.62, P-H = 0.40; CC + CT vs. TT:OR = 2.54, 95% CI = 1.93-3.34, P-H = 0.37; CC vs. CT:OR = 1.29, 95% CI = 1.14-1.47, P-H = 0.43; CC vs. TT:OR = 2.81, 95% CI = 2.13-3.71, P-H = 0.36) and uc003opf.1 rs11752942 (A allele vs. G allele: OR = 0.75, 95% CI = 0.68-0.83, P-H = 0.57; AA vs. AG + GG: OR = 0.72, 95% CI = 0.62-0.83, P-H = 0.50; AA + AG vs. GG: OR = 0.62, 95% CI = 0.50-0.78, P-H = 0.91; AA vs. AG: OR = 0.77, 95% CI = 0.66-0.89, P-H = 0.53; AA vs. GG: OR = 0.54, 95% CI = 0.43-0.69, P-H = 0.74).	('oral squamous cell carcinoma', 'Disease', (148, 176))	('oesophageal squamous cell carcinoma', 'Disease', (66, 101))	('rs920778', 'Mutation', 'rs920778', (209, 217))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (153, 176))	('rs11752942', 'Mutation', 'rs11752942', (523, 533))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('uc003opf.1', 'Gene', (512, 522))	('carcinoma', 'Phenotype', 'HP:0030731', (167, 176))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (148, 176))	('oesophageal squamous cell carcinoma', 'Disease', 'MESH:D002294', (66, 101))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (78, 101))	('HOTAIR', 'Gene', (202, 208))	('rs11752942', 'Var', (523, 533))	('HOTAIR', 'Gene', '100124700', (202, 208))
257842	28977965	Furthermore, we found that several SNPs acted as protective factors according to the overall pooled result in certain genetic models, such as let-7 rs10877887 (T/C; TT vs. TC + CC: OR = 0.80, 95% CI = 0.68-0.95, P-H = 0.81;TT vs. TC: OR = 0.77, 95% CI = 0.64-0.92, P-H = 0.54),miR-124-1 rs531564(C/G; CC + CG vs. GG: OR = 0.46, 95% CI = 0.28-0.75, P-H = 0.31; CC vs. GG: OR = 0.45, 95% CI = 0.27, 0.75, P-H = 0.34), and miR-608 rs4919510(G/C; GG + GC vs. CC: OR = 0.82, 95% CI = 0.68-0.98, P-H = 0.07), which were supported by two comparisons (1002 cases and 1293 controls), two comparisons (1738 cases and 1961 controls), and four comparisons (3191 cases and 3899 controls), respectively.	('rs531564', 'Var', (287, 295))	('rs531564', 'Mutation', 'rs531564', (287, 295))	('TC', 'Chemical', 'MESH:D013667', (230, 232))	('miR-124-1', 'Gene', '406907', (277, 286))	('TC', 'Chemical', 'MESH:D013667', (172, 174))	('rs10877887', 'Mutation', 'rs10877887', (148, 158))	('miR-608', 'Gene', (420, 427))	('rs10877887', 'Var', (148, 158))	('miR-124-1', 'Gene', (277, 286))	('let-7', 'Var', (142, 147))	('rs4919510', 'Mutation', 'rs4919510', (428, 437))	('miR-608', 'Gene', '693193', (420, 427))
257843	28977965	Eight SNPs underwent subgroup analysis to detect the source of heterogeneity, while miR-218-2 rs11134527 (G/A), and miR-27a rs895819 (T/C), miR-449b rs10061133 (A/G) were not subjected to subgroup analysis because the number of included studies was too small(n = 2).	('miR', 'Gene', '220972', (84, 87))	('miR', 'Gene', (84, 87))	('rs10061133', 'Mutation', 'rs10061133', (149, 159))	('miR-27a', 'Gene', '407018', (116, 123))	('miR', 'Gene', '220972', (140, 143))	('miR', 'Gene', (140, 143))	('miR', 'Gene', '220972', (116, 119))	('rs895819', 'Var', (124, 132))	('miR', 'Gene', (116, 119))	('rs10061133', 'Var', (149, 159))	('miR-27a', 'Gene', (116, 123))	('rs11134527', 'Mutation', 'rs11134527', (94, 104))	('rs895819', 'Mutation', 'rs895819', (124, 132))
257845	28977965	The forest plots of subgroup analysis of four SNPs, such as mir-26a-1 rs7372209 (C/T), miR-34b/c rs4938723 (T/C), miR-423 rs6505162 (C/A), and miR-608 rs4919510 (G/C), were shown in Figures 2-5.	('miR-423', 'Gene', (114, 121))	('rs7372209', 'Mutation', 'rs7372209', (70, 79))	('rs4919510', 'Var', (151, 160))	('mir-26a-1', 'Gene', '407015', (60, 69))	('miR-608', 'Gene', '693193', (143, 150))	('miR-423', 'Gene', '494335', (114, 121))	('mir-26a-1', 'Gene', (60, 69))	('rs4919510', 'Mutation', 'rs4919510', (151, 160))	('rs4938723', 'Mutation', 'rs4938723', (97, 106))	('rs6505162', 'Mutation', 'rs6505162', (122, 131))	('miR-34b', 'Gene', (87, 94))	('miR-34b', 'Gene', '407041', (87, 94))	('miR-608', 'Gene', (143, 150))
257847	28977965	We also found that miR-196a2 rs11614913T allele could significantly increase HNC risk in Asian populations (CC + CT vs. TT: OR = 1.14, 95% CI = 1.01-1.22, P-H = 0.04) supported by 10 comparisons (5189 cases and 5213 controls).	('miR-196a2', 'Gene', (19, 28))	('rs11614913T', 'Var', (29, 40))	('miR-196a2', 'Gene', '406973', (19, 28))	('increase', 'PosReg', (68, 76))	('HNC', 'Disease', (77, 80))	('rs11614913', 'Mutation', 'rs11614913', (29, 39))
257848	28977965	SNP miR-196a2 rs11614913 was also found to be related to OSCC susceptibility by pooled result of four comparisons (1561 cases and 1304 controls).	('related', 'Reg', (46, 53))	('rs11614913', 'Var', (14, 24))	('OSCC', 'Disease', (57, 61))	('miR-196a2', 'Gene', (4, 13))	('miR-196a2', 'Gene', '406973', (4, 13))	('rs11614913', 'Mutation', 'rs11614913', (14, 24))
257850	28977965	SNP miR-608 rs4919510 (G/C) showed protective effect on NPC susceptibility (G allele vs. C allele: OR = 0.83, 95% CI = 0.75-0.91, P-H = 0.8; GG vs. GC + CC: OR = 0.81, 95% CI = 0.70-0.94, P-H = 0.73; GG + GC vs. CC: OR = 0.74, 95% CI = 0.63-0.86, P-H = 0.92; GG vs. CC: OR = 0.68, 95% CI = 0.57-0.82, P-H = 0.77), while only two comparisons (1590 cases and 1979 controls) were included in this subgroup.	('rs4919510', 'Mutation', 'rs4919510', (12, 21))	('miR-608', 'Gene', (4, 11))	('NPC', 'Gene', (56, 59))	('miR-608', 'Gene', '693193', (4, 11))	('NPC', 'Gene', '4864', (56, 59))	('rs4919510', 'Var', (12, 21))
257851	28977965	In addition, miR-499a rs3746444 (T/C) was found to be a protective factor in Caucasian populations (CC vs. CT + TT: OR = 0.80, 95% CI = 0.69-0.94, P-H = 0.54), and contributed to ESCC (C allele vs. T allele: OR = 0.80, 95% CI = 0.66-0.98, P-H = 0.75), as supported by the pooled result of two comparisons (669 cases and 688 controls).	('ESCC', 'Disease', (179, 183))	('miR-499a', 'Gene', '574501', (13, 21))	('rs3746444', 'Var', (22, 31))	('rs3746444', 'Mutation', 'rs3746444', (22, 31))	('miR-499a', 'Gene', (13, 21))
257852	28977965	Interestingly, the overall pooled result for miR-34b/c rs4938723 (T/C) differed from the subgroup analysis result.	('rs4938723', 'Var', (55, 64))	('miR-34b', 'Gene', '407041', (45, 52))	('rs4938723', 'Mutation', 'rs4938723', (55, 64))	('miR-34b', 'Gene', (45, 52))
257854	28977965	Publication bias of the two SNPs, such as miR-146a rs2910164 and miR-196a2 rs11614913 was detected by funnel plots (Supplementary Figure 2).	('rs2910164', 'Var', (51, 60))	('miR-146a', 'Gene', '406938', (42, 50))	('miR-196a2', 'Gene', '406973', (65, 74))	('rs11614913', 'Mutation', 'rs11614913', (75, 85))	('miR-146a', 'Gene', (42, 50))	('miR-196a2', 'Gene', (65, 74))	('rs11614913', 'Var', (75, 85))	('rs2910164', 'Mutation', 'rs2910164', (51, 60))
257860	28977965	Regarding uc003opf.1 rs11752942, a change from A allele to G allele could significantly decrease lncRNA expression and directly suppress tumour development.	('rs11752942', 'Mutation', 'rs11752942', (21, 31))	('decrease', 'NegReg', (88, 96))	('rs11752942', 'Var', (21, 31))	('tumour', 'Disease', 'MESH:D009369', (137, 143))	('tumour', 'Disease', (137, 143))	('uc003opf.1', 'Gene', (10, 20))	('tumour', 'Phenotype', 'HP:0002664', (137, 143))	('lncRNA', 'Protein', (97, 103))	('suppress', 'NegReg', (128, 136))
257861	28977965	In accordance with its biological functions, our meta-analysis results demonstrated that HOTAIR rs920778 (C/T) and uc003opf.1 rs11752942 (A/G) could significantly increase and decrease, respectively, ESCC risk in Chinese populations.	('rs920778', 'Mutation', 'rs920778', (96, 104))	('rs920778', 'Var', (96, 104))	('HOTAIR', 'Gene', (89, 95))	('rs11752942', 'Mutation', 'rs11752942', (126, 136))	('decrease', 'NegReg', (176, 184))	('HOTAIR', 'Gene', '100124700', (89, 95))	('ESCC', 'Disease', (200, 204))
257862	28977965	However, it is noteworthy that 3 comparisons investigating HOTAIR rs920778, as well as 2 comparisons investigating uc003opf.1 rs11752942, were provided by one single study.	('HOTAIR', 'Gene', (59, 65))	('HOTAIR', 'Gene', '100124700', (59, 65))	('rs920778', 'Mutation', 'rs920778', (66, 74))	('rs920778', 'Var', (66, 74))	('rs11752942', 'Mutation', 'rs11752942', (126, 136))
257868	28977965	On the basis of the above process, SNPs residing in miRNA gene loci may affect one, two or all three steps, such as transcription of the primary transcript, processing of pri-miRNAs and pre-miRNAs, and miRNA-mRNA interactions.	('transcription', 'MPA', (116, 129))	('affect', 'Reg', (72, 78))	('miR', 'Gene', '220972', (202, 205))	('miR', 'Gene', (202, 205))	('miR', 'Gene', '220972', (175, 178))	('miR', 'Gene', (175, 178))	('processing', 'MPA', (157, 167))	('miR', 'Gene', '220972', (52, 55))	('miR', 'Gene', (52, 55))	('miR', 'Gene', '220972', (190, 193))	('miR', 'Gene', (190, 193))	('SNPs residing', 'Var', (35, 48))
257870	28977965	As miRNAs are functionally associated with oncogenesis and have the ability to simultaneously affect many genes, SNPs in miRNAs could theoretically lead to phenotypic variations that contribute to cancer susceptibility.	('cancer', 'Disease', 'MESH:D009369', (197, 203))	('SNPs', 'Var', (113, 117))	('miR', 'Gene', (3, 6))	('affect', 'Reg', (94, 100))	('cancer', 'Disease', (197, 203))	('associated', 'Reg', (27, 37))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('miR', 'Gene', '220972', (3, 6))	('oncogenesis', 'Disease', (43, 54))	('miR', 'Gene', '220972', (121, 124))	('miR', 'Gene', (121, 124))	('lead to', 'Reg', (148, 155))
257873	28977965	Compared to a recently published systematic review, a certain number of new studies were added in the meta-analysis of the present systematic review, including 11 new studies investigating mir-146a rs2910164, eight new studies investigating mir-196a rs11614913, six new studies investigating mir-499a rs3746444, and two new studies investigating mir-149 rs2292832.	('rs11614913', 'Mutation', 'rs11614913', (250, 260))	('mir', 'Gene', (346, 349))	('mir', 'Gene', (241, 244))	('mir-499a', 'Gene', (292, 300))	('mir-146a', 'Gene', (189, 197))	('mir-146a', 'Gene', '406938', (189, 197))	('mir', 'Gene', '220972', (292, 295))	('rs2910164', 'Var', (198, 207))	('rs3746444', 'Mutation', 'rs3746444', (301, 310))	('rs2292832', 'Mutation', 'rs2292832', (354, 363))	('rs2910164', 'Mutation', 'rs2910164', (198, 207))	('mir', 'Gene', '220972', (189, 192))	('mir-149', 'Gene', (346, 353))	('mir', 'Gene', (292, 295))	('mir-149', 'Gene', '406941', (346, 353))	('mir-499a', 'Gene', '574501', (292, 300))	('mir', 'Gene', '220972', (346, 349))	('mir', 'Gene', '220972', (241, 244))	('rs11614913', 'Var', (250, 260))	('mir', 'Gene', (189, 192))
257877	28977965	The miRNA-146a rs2910164 (G/C) polymorphism is the most widely investigated miRNA SNP related to HNC.	('miRNA-146a', 'Gene', (4, 14))	('rs2910164', 'Mutation', 'rs2910164', (15, 24))	('miR', 'Gene', (4, 7))	('miRNA-146a', 'Gene', '406938', (4, 14))	('HNC', 'Disease', (97, 100))	('miR', 'Gene', '220972', (4, 7))	('miR', 'Gene', '220972', (76, 79))	('miR', 'Gene', (76, 79))	('rs2910164 (G/C', 'Var', (15, 29))
257878	28977965	In contrast to a previous meta-analysis which found that miR-146a rs2910164 gene polymorphism contributed to HNC risk in Asian populations, our meta-analysis did not show any correlation when subgroup analyses among ethnic backgrounds were performed.	('miR-146a', 'Gene', '406938', (57, 65))	('HNC', 'Disease', (109, 112))	('rs2910164', 'Mutation', 'rs2910164', (66, 75))	('rs2910164', 'Var', (66, 75))	('miR-146a', 'Gene', (57, 65))
257879	28977965	In regards to cancer types, only increased NPC risk associated with this SNP was found in several comparative models (G vs. C, GG + GC vs. CC and GG vs. CC), suggesting that C allele or CC genotype represented NPC risk factors.	('cancer', 'Disease', (14, 20))	('NPC', 'Gene', '4864', (210, 213))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('C allele', 'Var', (174, 182))	('NPC', 'Gene', (43, 46))	('cancer', 'Disease', 'MESH:D009369', (14, 20))	('NPC', 'Gene', (210, 213))	('NPC', 'Gene', '4864', (43, 46))
257881	28977965	Rs11614913 is located in the mature sequence of miR-196a-3P, thus, a change from C allele to T allele could lead to less efficient processing of the miRNA precursor to its mature form, as well as diminished capacity to regulate target genes.	('regulate', 'MPA', (219, 227))	('capacity', 'MPA', (207, 215))	('Rs11614913', 'Var', (0, 10))	('diminished', 'NegReg', (196, 206))	('less', 'NegReg', (116, 120))	('change', 'Var', (69, 75))	('miR', 'Gene', (149, 152))	('miR', 'Gene', '220972', (149, 152))	('miR', 'Gene', '220972', (48, 51))	('miR', 'Gene', (48, 51))	('processing', 'MPA', (131, 141))	('Rs11614913', 'Mutation', 'Rs11614913', (0, 10))
257882	28977965	Our systematic review highlighted a significant association between miR-196a2 rs11614913 T allele and increased HNC risk in the co-dominant models.	('HNC', 'Disease', (112, 115))	('miR-196a2', 'Gene', (68, 77))	('rs11614913', 'Mutation', 'rs11614913', (78, 88))	('miR-196a2', 'Gene', '406973', (68, 77))	('rs11614913 T', 'Var', (78, 90))
257883	28977965	The results above were consistent with the results of a recently published meta-analysis, which also indicated that the miRNA-196a2 rs11614913 (C/T) may play a risk role in the development of HNC.	('miR', 'Gene', '220972', (120, 123))	('miR', 'Gene', (120, 123))	('rs11614913', 'Var', (132, 142))	('rs11614913', 'Mutation', 'rs11614913', (132, 142))	('HNC', 'Disease', (192, 195))
257884	28977965	Hence, our meta-analysis confirmed that the detection of miR-196a2 rs11614913 polymorphism could be useful in HNC prediction and prevention.	('rs11614913', 'Mutation', 'rs11614913', (67, 77))	('miR-196a2', 'Gene', (57, 66))	('rs11614913', 'Var', (67, 77))	('HNC', 'Disease', (110, 113))	('miR-196a2', 'Gene', '406973', (57, 66))
257885	28977965	SNPs resident in miRNAs gene loci could not only increase cancer risk, but also play protective roles in cancer development.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('miR', 'Gene', '220972', (17, 20))	('cancer', 'Disease', (105, 111))	('miR', 'Gene', (17, 20))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('SNPs', 'Var', (0, 4))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('increase cancer', 'Disease', (49, 64))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('cancer', 'Disease', (58, 64))	('increase cancer', 'Disease', 'MESH:D009369', (49, 64))
257887	28977965	The correlation between SNP rs3746444 in miR-499a and HNC susceptibility was broadly investigated, thus a total of 9 studies were included into our meta-analysis.	('rs3746444', 'Mutation', 'rs3746444', (28, 37))	('miR-499a', 'Gene', '574501', (41, 49))	('SNP rs3746444', 'Var', (24, 37))	('miR-499a', 'Gene', (41, 49))
257888	28977965	The rs4919510 is located in the miR-608 mature sequence, thus the mutant C-allelic mir-608 exerts a significantly lower colony formation in vitro.	('rs4919510', 'Var', (4, 13))	('colony formation in vitro', 'CPA', (120, 145))	('mutant', 'Var', (66, 72))	('mir-608', 'Gene', (83, 90))	('mir-608', 'Gene', '693193', (83, 90))	('rs4919510', 'Mutation', 'rs4919510', (4, 13))	('miR-608', 'Gene', (32, 39))	('lower', 'NegReg', (114, 119))	('miR-608', 'Gene', '693193', (32, 39))
257889	28977965	In accordance with the functional assay, the overall and subgroup pooled results of the present meta-analysis also indicated that the G > C variation of miR-608 rs4919510 was protective against HNC development.	('rs4919510', 'Mutation', 'rs4919510', (161, 170))	('G > C', 'Var', (134, 139))	('miR-608', 'Gene', (153, 160))	('HNC', 'Disease', (194, 197))	('miR-608', 'Gene', '693193', (153, 160))	('rs4919510', 'Var', (161, 170))
257891	28977965	Similarly, miR-124-1 rs531564 GG genotype may promote miR-124 expression, which can directly suppress the expression of its targeting oncogene PTBP1, thus acting as a tumour suppressor.	('miR-124-1', 'Gene', '406907', (11, 20))	('suppress', 'NegReg', (93, 101))	('PTBP1', 'Gene', (143, 148))	('promote', 'PosReg', (46, 53))	('miR-124-1', 'Gene', (11, 20))	('miR', 'Gene', (54, 57))	('tumour', 'Disease', (167, 173))	('tumour', 'Disease', 'MESH:D009369', (167, 173))	('miR', 'Gene', '220972', (54, 57))	('expression', 'MPA', (106, 116))	('expression', 'MPA', (62, 72))	('rs531564 GG', 'Var', (21, 32))	('miR', 'Gene', '220972', (11, 14))	('miR', 'Gene', (11, 14))	('tumour', 'Phenotype', 'HP:0002664', (167, 173))	('rs531564', 'Mutation', 'rs531564', (21, 29))	('PTBP1', 'Gene', '5725', (143, 148))
257892	28977965	Accordingly, our meta-analysis suggested that the SNPs located in let-7 and miR-124 were both associated with decreased HNC risk.	('SNPs located', 'Var', (50, 62))	('decreased', 'NegReg', (110, 119))	('miR', 'Gene', '220972', (76, 79))	('miR', 'Gene', (76, 79))	('let-7', 'Gene', (66, 71))	('HNC', 'Disease', (120, 123))
257900	28977965	If only one of the five genetic models showed positive result, such as miR-34b/c rs4938723, miR-196a2 rs11614913 and miR-608 rs4919510, the reliability of the result should be considered.	('miR-34b', 'Gene', (71, 78))	('miR-196a2', 'Gene', (92, 101))	('rs4938723', 'Mutation', 'rs4938723', (81, 90))	('miR-608', 'Gene', (117, 124))	('rs4919510', 'Var', (125, 134))	('rs4919510', 'Mutation', 'rs4919510', (125, 134))	('rs11614913', 'Mutation', 'rs11614913', (102, 112))	('miR-34b', 'Gene', '407041', (71, 78))	('miR-196a2', 'Gene', '406973', (92, 101))	('miR-608', 'Gene', '693193', (117, 124))	('rs4938723', 'Var', (81, 90))	('rs11614913', 'Var', (102, 112))
257901	28977965	Studies that met the following inclusion criteria were included in the present systematic review: (1) cohort study or case-control study as study design; (2) patients with diagnosed HNC; (3) controls without any cancer history; (4) study that evaluated the association between ncRNAs polymorphisms and HNC susceptibility; and (5) collect an amount of sufficient data to calculate odds ratios (OR) and 95% confidence intervals (95% CI).	('association', 'Interaction', (257, 268))	('HNC', 'Disease', (302, 305))	('cancer', 'Disease', (212, 218))	('cancer', 'Disease', 'MESH:D009369', (212, 218))	('patients', 'Species', '9606', (158, 166))	('polymorphisms', 'Var', (284, 297))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))
257917	26783151	The sensitivity of detection by ELISA of one HP peptide (HP216) was 70% of SCC patients, 40% of COPDs patients and 13% of healthy controls.	('SCC', 'Gene', '6317', (75, 78))	('HP216', 'Chemical', '-', (57, 62))	('COPD', 'Phenotype', 'HP:0006510', (96, 100))	('COPD', 'Disease', 'MESH:D029424', (96, 100))	('patients', 'Species', '9606', (102, 110))	('HP216', 'Var', (57, 62))	('COPD', 'Disease', (96, 100))	('patients', 'Species', '9606', (79, 87))	('SCC', 'Gene', (75, 78))	('SCC', 'Phenotype', 'HP:0002860', (75, 78))
257919	26783151	However, when the measurement of HP216 was combined with that of CYFRA, 100% (10 of 10 patients) of SCC cases were detected.	('HP216', 'Chemical', '-', (33, 38))	('SCC', 'Gene', (100, 103))	('SCC', 'Phenotype', 'HP:0002860', (100, 103))	('SCC', 'Gene', '6317', (100, 103))	('HP216', 'Var', (33, 38))	('patients', 'Species', '9606', (87, 95))	('men', 'Species', '9606', (25, 28))
257920	26783151	Our proteomic profiling demonstrates that the SCC-specific HP peptide HP216 may potentially be used as a diagnostic biomarker for SCC.	('SCC', 'Gene', (130, 133))	('HP216', 'Var', (70, 75))	('SCC', 'Phenotype', 'HP:0002860', (130, 133))	('SCC', 'Gene', '6317', (130, 133))	('SCC', 'Gene', (46, 49))	('HP216', 'Chemical', '-', (70, 75))	('SCC', 'Phenotype', 'HP:0002860', (46, 49))	('SCC', 'Gene', '6317', (46, 49))
257990	26783151	The HP216 peptide sequence was also increased by 21.3-fold in SCC compared to COPD samples (Fig.	('COPD', 'Disease', 'MESH:D029424', (78, 82))	('SCC', 'Phenotype', 'HP:0002860', (62, 65))	('COPD', 'Disease', (78, 82))	('SCC', 'Gene', '6317', (62, 65))	('HP216', 'Chemical', '-', (4, 9))	('increased', 'PosReg', (36, 45))	('HP216', 'Var', (4, 9))	('COPD', 'Phenotype', 'HP:0006510', (78, 82))	('SCC', 'Gene', (62, 65))
257996	26783151	We first established novel polyclonal antibodies for HP60 and HP216 and then developed a sandwich ELISA for the quantification of these specific peptides using samples from 10 SCC and 10 COPD patients, and eight healthy control smokers.	('HP216', 'Var', (62, 67))	('HP60', 'Var', (53, 57))	('patients', 'Species', '9606', (192, 200))	('COPD', 'Phenotype', 'HP:0006510', (187, 191))	('SCC', 'Gene', (176, 179))	('SCC', 'Gene', '6317', (176, 179))	('COPD', 'Disease', 'MESH:D029424', (187, 191))	('SCC', 'Phenotype', 'HP:0002860', (176, 179))	('peptides', 'Chemical', 'MESH:D010455', (145, 153))	('HP216', 'Chemical', '-', (62, 67))	('COPD', 'Disease', (187, 191))
257998	26783151	In contrast, significantly high levels of HP216 peptide were found in sera from SCC patients when compared with those of healthy smoker controls (Fig.	('SCC', 'Gene', '6317', (80, 83))	('patients', 'Species', '9606', (84, 92))	('HP216', 'Chemical', '-', (42, 47))	('high', 'PosReg', (27, 31))	('SCC', 'Gene', (80, 83))	('SCC', 'Phenotype', 'HP:0002860', (80, 83))	('HP216', 'Var', (42, 47))
257999	26783151	The sensitivity of HP216 (cut-off value of 0.13) was 70% (7 of 10) of SCC patients, 40% (4 of 10) of COPD patients and 13% (1 of 8) of smoker controls (Fig.	('HP216', 'Chemical', '-', (19, 24))	('patients', 'Species', '9606', (74, 82))	('SCC', 'Gene', (70, 73))	('HP216', 'Var', (19, 24))	('COPD', 'Phenotype', 'HP:0006510', (101, 105))	('SCC', 'Phenotype', 'HP:0002860', (70, 73))	('patients', 'Species', '9606', (106, 114))	('COPD', 'Disease', 'MESH:D029424', (101, 105))	('SCC', 'Gene', '6317', (70, 73))	('COPD', 'Disease', (101, 105))
258000	26783151	These results suggest that HP216 is a novel candidate serum biomarker of SCC patients.	('SCC', 'Gene', (73, 76))	('SCC', 'Phenotype', 'HP:0002860', (73, 76))	('patients', 'Species', '9606', (77, 85))	('HP216', 'Chemical', '-', (27, 32))	('SCC', 'Gene', '6317', (73, 76))	('HP216', 'Var', (27, 32))
258003	26783151	Interestingly, the detection of HP216 peptides was positive in three CYFRA false-negative SCC cases (Table IV).	('HP216', 'Chemical', '-', (32, 37))	('peptides', 'Chemical', 'MESH:D010455', (38, 46))	('HP216', 'Var', (32, 37))	('SCC', 'Gene', (90, 93))	('SCC', 'Phenotype', 'HP:0002860', (90, 93))	('SCC', 'Gene', '6317', (90, 93))
258004	26783151	When the detection of HP216 was combined with that of CYFRA, 100% (10 of 10 patients) of SCC cases were detected (Table IV).	('patients', 'Species', '9606', (76, 84))	('HP216', 'Chemical', '-', (22, 27))	('SCC', 'Gene', '6317', (89, 92))	('HP216', 'Var', (22, 27))	('SCC', 'Gene', (89, 92))	('SCC', 'Phenotype', 'HP:0002860', (89, 92))
258005	26783151	These findings suggest that the SCC-specific peptide HP216 may be used as a diagnostic biomarker for SCC.	('HP216', 'Chemical', '-', (53, 58))	('HP216', 'Var', (53, 58))	('SCC', 'Gene', (101, 104))	('SCC', 'Gene', (32, 35))	('SCC', 'Phenotype', 'HP:0002860', (101, 104))	('SCC', 'Phenotype', 'HP:0002860', (32, 35))	('SCC', 'Gene', '6317', (101, 104))	('SCC', 'Gene', '6317', (32, 35))
258006	26783151	A combination of detecting HP216 with CYFRA protein fragment levels in patient sera may be applicable to diagnose SCC.	('SCC', 'Gene', (114, 117))	('men', 'Species', '9606', (56, 59))	('CYFRA protein fragment levels', 'MPA', (38, 67))	('HP216', 'Chemical', '-', (27, 32))	('SCC', 'Phenotype', 'HP:0002860', (114, 117))	('SCC', 'Gene', '6317', (114, 117))	('patient', 'Species', '9606', (71, 78))	('HP216', 'Var', (27, 32))
258015	26783151	Several cases of COPD were reported to be associated with mutations and polymorphisms in the AACT gene.	('mutations', 'Var', (58, 67))	('COPD', 'Disease', 'MESH:D029424', (17, 21))	('associated', 'Reg', (42, 52))	('COPD', 'Disease', (17, 21))	('AACT', 'Gene', '12', (93, 97))	('polymorphisms', 'Var', (72, 85))	('AACT', 'Gene', (93, 97))	('COPD', 'Phenotype', 'HP:0006510', (17, 21))
258019	26783151	Furthermore, SCC was predicted in all ten SCC patients only when using the detection of HP216 combined with CYFRA.	('patients', 'Species', '9606', (46, 54))	('SCC', 'Phenotype', 'HP:0002860', (13, 16))	('SCC', 'Gene', '6317', (13, 16))	('HP216', 'Chemical', '-', (88, 93))	('HP216', 'Var', (88, 93))	('SCC', 'Gene', (42, 45))	('SCC', 'Phenotype', 'HP:0002860', (42, 45))	('SCC', 'Gene', '6317', (42, 45))	('SCC', 'Gene', (13, 16))
258024	26783151	Abnormal HP glycosylation was found to interfere with tumor metastasis, while fucosylated HP was shown to be a novel biomarker for colorectal cancer.	('interfere', 'NegReg', (39, 48))	('colorectal cancer', 'Disease', 'MESH:D015179', (131, 148))	('Abnormal HP glycosylation', 'Disease', 'MESH:C537262', (0, 25))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('colorectal cancer', 'Phenotype', 'HP:0003003', (131, 148))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('fucosylated', 'Var', (78, 89))	('colorectal cancer', 'Disease', (131, 148))	('Abnormal HP glycosylation', 'Disease', (0, 25))	('tumor metastasis', 'Disease', 'MESH:D009362', (54, 70))	('tumor metastasis', 'Disease', (54, 70))
258027	26783151	By processing serum samples after the removal of high-abundance proteins, we finally identified HP216 peptide as a candidate SCC biomarker.	('HP216 peptide', 'Var', (96, 109))	('SCC', 'Gene', (125, 128))	('SCC', 'Phenotype', 'HP:0002860', (125, 128))	('HP216', 'Chemical', '-', (96, 101))	('SCC', 'Gene', '6317', (125, 128))
258028	26783151	Both the origin and function of HP216 are still unknown; however, serum levels of a two-residue longer peptide, HP216-230, were also significantly higher in SCC the patient samples in the present study (data not shown).	('SCC', 'Gene', (157, 160))	('SCC', 'Phenotype', 'HP:0002860', (157, 160))	('HP216', 'Chemical', '-', (112, 117))	('HP216', 'Chemical', '-', (32, 37))	('SCC', 'Gene', '6317', (157, 160))	('patient', 'Species', '9606', (165, 172))	('HP216-230', 'Var', (112, 121))	('higher', 'PosReg', (147, 153))	('serum levels of', 'MPA', (66, 81))
258029	26783151	CYFRA21-1 is a fragment of cytokeratin 19 that has been extensively studied in patients with SCC and has been demonstrated to be clinically useful.	('men', 'Species', '9606', (19, 22))	('SCC', 'Gene', (93, 96))	('SCC', 'Phenotype', 'HP:0002860', (93, 96))	('patients', 'Species', '9606', (79, 87))	('SCC', 'Gene', '6317', (93, 96))	('CYFRA21-1', 'Var', (0, 9))
258034	26783151	In the present study, all SCC cases were detected by the measurement of HP216 combined with CYFRA.	('HP216', 'Var', (72, 77))	('SCC', 'Gene', '6317', (26, 29))	('HP216', 'Chemical', '-', (72, 77))	('men', 'Species', '9606', (64, 67))	('SCC', 'Gene', (26, 29))	('SCC', 'Phenotype', 'HP:0002860', (26, 29))	('detected', 'Reg', (41, 49))
258035	26783151	A combination of detecting serum HP216 with CYFRA levels may be applicable to diagnose SCC.	('HP216', 'Chemical', '-', (33, 38))	('SCC', 'Gene', (87, 90))	('HP216', 'Var', (33, 38))	('SCC', 'Phenotype', 'HP:0002860', (87, 90))	('CYFRA levels', 'MPA', (44, 56))	('SCC', 'Gene', '6317', (87, 90))
258036	26783151	Taken together, the HP peptide HP216, is a promising cancer biomarker for the early detection of SCC in high-risk lung cancer populations, including COPD patients and heavy smokers.	('HP216', 'Var', (31, 36))	('lung cancer', 'Disease', 'MESH:D008175', (114, 125))	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('patients', 'Species', '9606', (154, 162))	('SCC', 'Gene', (97, 100))	('cancer', 'Disease', (119, 125))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('lung cancer', 'Disease', (114, 125))	('SCC', 'Phenotype', 'HP:0002860', (97, 100))	('HP216', 'Chemical', '-', (31, 36))	('COPD', 'Disease', 'MESH:D029424', (149, 153))	('lung cancer', 'Phenotype', 'HP:0100526', (114, 125))	('COPD', 'Phenotype', 'HP:0006510', (149, 153))	('SCC', 'Gene', '6317', (97, 100))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('COPD', 'Disease', (149, 153))
258037	26783151	Combined with CYFRA determinations, the measurement of serum HP216 may lead to the earlier detection of SCC in at-risk patients and become a novel diagnostic tool for SCC.	('SCC', 'Phenotype', 'HP:0002860', (167, 170))	('SCC', 'Gene', '6317', (167, 170))	('HP216', 'Chemical', '-', (61, 66))	('patients', 'Species', '9606', (119, 127))	('SCC', 'Gene', (104, 107))	('HP216', 'Var', (61, 66))	('men', 'Species', '9606', (47, 50))	('SCC', 'Phenotype', 'HP:0002860', (104, 107))	('SCC', 'Gene', '6317', (104, 107))	('SCC', 'Gene', (167, 170))
258077	33494458	Eleven molecules were excluded (M27, ethane, formaldehyde, methanol, ethylene, nitric oxide (NO), M31, M32, hydrogen sulfide (H2S), M46 and M49) because of their significantly higher concentration in environmental air (in a t-test) if compared to that in the corresponding alveolar air.	('ethylene', 'Chemical', 'MESH:C036216', (69, 77))	('methanol', 'Chemical', 'MESH:D000432', (59, 67))	('M46', 'Var', (132, 135))	('H2S', 'Chemical', 'MESH:D003903', (126, 129))	('M31', 'Var', (98, 101))	('formaldehyde', 'Chemical', 'MESH:D005557', (45, 57))	('M32', 'Var', (103, 106))	('ethane', 'Chemical', 'MESH:D004980', (37, 43))	('hydrogen sulfide', 'Chemical', 'MESH:D006862', (108, 124))	('M49', 'Var', (140, 143))	('higher', 'PosReg', (176, 182))	('nitric oxide', 'Chemical', 'MESH:D009569', (79, 91))	('environmental', 'Species', '1275957', (200, 213))
258123	33494458	Based on the molecular weight, we can assume that M48 could be methanethiol and M62 and M76 could be, respectively, dimethyl sulfide and carbon disulfide.	('M76', 'Var', (88, 91))	('M62', 'Var', (80, 83))	('carbon disulfide', 'Chemical', 'MESH:D002246', (137, 153))	('methanethiol', 'Chemical', 'MESH:C005231', (63, 75))	('dimethyl sulfide', 'Chemical', 'MESH:C004784', (116, 132))	('M48', 'Var', (50, 53))
258124	33494458	M74 could be 1-Hydroxy-2-propanone, M98 could be methylcyclohexane and M121 could be ethylaniline.	('ethylaniline', 'Chemical', 'MESH:C056400', (85, 97))	('M121', 'Var', (71, 75))	('M98', 'Var', (36, 39))	('M74', 'Var', (0, 3))	('methylcyclohexane', 'Chemical', 'MESH:C521475', (49, 66))	('1-Hydroxy-2-propanone', 'Chemical', 'MESH:C004433', (13, 34))
258128	33494458	Some products (acetic acid, ammonia, acetaldehyde, M43, M103) were selected by algorithms as discriminants of lung cancer, but other molecules show concentrations which differentiate the two kinds of lung cancer.	('lung cancer', 'Disease', 'MESH:D008175', (110, 121))	('acetaldehyde', 'Chemical', 'MESH:D000079', (37, 49))	('ammonia', 'Chemical', 'MESH:D000641', (28, 35))	('lung cancer', 'Disease', 'MESH:D008175', (200, 211))	('ammonia', 'MPA', (28, 35))	('M103', 'Var', (56, 60))	('lung cancer', 'Disease', (110, 121))	('acetaldehyde', 'MPA', (37, 49))	('lung cancer', 'Disease', (200, 211))	('lung cancer', 'Phenotype', 'HP:0100526', (110, 121))	('lung cancer', 'Phenotype', 'HP:0100526', (200, 211))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('M43', 'Var', (51, 54))	('acetic acid', 'Chemical', 'MESH:D019342', (15, 26))
258136	33494458	Among the volatile products selected by the algorithm and identified exclusively by the molecular weight, we can hypothesize that M106 could be xylene (1,3- and 1,4-dimethylbenzene), which was also found in the breath of patients with colon cancer by Altomare et al.	('M106', 'Var', (130, 134))	('patients', 'Species', '9606', (221, 229))	('colon cancer', 'Disease', 'MESH:D015179', (235, 247))	('colon cancer', 'Phenotype', 'HP:0003003', (235, 247))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('xylene', 'Chemical', 'MESH:D014992', (144, 150))	('colon cancer', 'Disease', (235, 247))	('1,4-dimethylbenzene', 'Chemical', 'MESH:C031286', (161, 180))
258210	33494458	Some biomarkers (acetic acid, ammonia, acetaldehyde, M43, M103) have a similar behavior in the alveolar air, but others show concentrations which differentiate the two kinds of cancers.	('acetaldehyde', 'Chemical', 'MESH:D000079', (39, 51))	('M103', 'Var', (58, 62))	('cancers', 'Disease', 'MESH:D009369', (177, 184))	('cancers', 'Phenotype', 'HP:0002664', (177, 184))	('cancers', 'Disease', (177, 184))	('acetic acid', 'Chemical', 'MESH:D019342', (17, 28))	('M43', 'Var', (53, 56))	('acetaldehyde', 'MPA', (39, 51))	('ammonia', 'Chemical', 'MESH:D000641', (30, 37))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('ammonia', 'MPA', (30, 37))
258216	30701024	Pan-cancer analysis of intratumor heterogeneity associated with patient prognosis using multidimensional measures Human cancers accumulate various mutations during development and consist of highly heterogeneous cell populations.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('mutations', 'Var', (147, 156))	('patient', 'Species', '9606', (64, 71))	('Pan-cancer', 'Disease', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('cancers', 'Phenotype', 'HP:0002664', (120, 127))	('Pan-cancer', 'Disease', 'MESH:C537931', (0, 10))	('cancers', 'Disease', (120, 127))	('Human', 'Species', '9606', (114, 119))	('cancers', 'Disease', 'MESH:D009369', (120, 127))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
258224	30701024	Cancer is indicated via dysregulated cell growth, proliferation, and cell cycle progression.	('dysregulated', 'Var', (24, 36))	('cell cycle progression', 'CPA', (69, 91))	('proliferation', 'CPA', (50, 63))	('cell growth', 'CPA', (37, 48))	('Cancer', 'Disease', (0, 6))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))
258225	30701024	Cancer cells often consist of heterogeneous populations with various mutations rather than composed of homogeneous populations.	('Cancer', 'Disease', (0, 6))	('mutations', 'Var', (69, 78))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))
258226	30701024	Previous studies demonstrated that cancer develops from mutations in certain driver genes and eventually accumulates various genetic mutations through cell growth, leading to intratumor heterogeneity (ITH).	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('mutations', 'Var', (56, 65))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('tumor', 'Disease', (180, 185))	('leading to', 'Reg', (164, 174))	('mutations', 'Var', (133, 142))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('cancer', 'Disease', (35, 41))
258230	30701024	VAFs are able to estimate the fraction of tumor populations containing mutations in cancer cells.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('tumor', 'Disease', (42, 47))	('cancer', 'Disease', (84, 90))	('mutations', 'Var', (71, 80))	('VAF', 'Chemical', '-', (0, 3))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
258233	30701024	Moreover, mutant-allele tumor heterogeneity (MATH) scores represent the variance of VAFs, and the entropy-based mutation allele fraction (EMAF) represents uncertainty of somatic mutation patterns.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('mutant-allele', 'Var', (10, 23))	('VAF', 'Chemical', '-', (84, 87))	('tumor', 'Disease', (24, 29))	('tumor', 'Disease', 'MESH:D009369', (24, 29))
258242	30701024	Since correlation coefficients were -0.44, 0.03, and 0.00, which were observed between m_Peaks vs. m_MATH, m_Peak vs. m_Count, and m_Count vs. m_MATH, respectively, we considered the parameters could be used as independent variables representing the characteristics of VAF distributions.	('VAF', 'Chemical', '-', (269, 272))	('m_Peak', 'Var', (107, 113))	('m_Peaks', 'Var', (87, 94))
258248	30701024	We drew histograms of VAFs assembled from all mutations in samples belonging to each cluster and created trunk-branch models of mutations in tumors (Figure 2A).	('mutations', 'Var', (46, 55))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumors', 'Disease', 'MESH:D009369', (141, 147))	('tumors', 'Disease', (141, 147))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('trunk-branch', 'Disease', (105, 117))	('trunk-branch', 'Disease', 'MESH:D016750', (105, 117))	('VAF', 'Chemical', '-', (22, 25))
258250	30701024	Since the VAF distributions showed that samples in cluster 1 had more MF mutations with higher VAF than lower VAF, while the samples in cluster 2 had more MF mutations with lower VAF than higher VAF, they were predicted to have accumulated clonal mutations in cluster 1 and subclonal mutations in cluster 2, respectively.	('VAF', 'Chemical', '-', (95, 98))	('VAF', 'Chemical', '-', (10, 13))	('VAF', 'Chemical', '-', (195, 198))	('VAF', 'Chemical', '-', (179, 182))	('lower', 'NegReg', (173, 178))	('VAF', 'Chemical', '-', (110, 113))	('mutations', 'Var', (73, 82))
258251	30701024	This observation was consistent with a recent study by McGranahan and colleagues, which indicated that, in some cancer types, including melanoma and lung cancer, mutations accumulated prior to carcinogenesis.	('mutations', 'Var', (162, 171))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('carcinogenesis', 'Disease', (193, 207))	('cancer', 'Disease', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('lung cancer', 'Phenotype', 'HP:0100526', (149, 160))	('melanoma', 'Phenotype', 'HP:0002861', (136, 144))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('carcinogenesis', 'Disease', 'MESH:D063646', (193, 207))	('melanoma and lung cancer', 'Disease', 'MESH:D008175', (136, 160))
258254	30701024	This trend can be interpreted as MF mutations occurring in the early stages of cancer development and maintained through cancer progression, without further accumulating a large number of MF mutations among samples in cluster 3.	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('mutations', 'Var', (36, 45))	('cancer', 'Disease', (121, 127))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))
258255	30701024	In cluster 4, expansion of some subclones with certain MF mutations might occur during cancer progression under strong positive selection.	('cancer', 'Disease', (87, 93))	('mutations', 'Var', (58, 67))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))
258256	30701024	In contrast, samples in cluster 5 had MF mutations that possibly occurred under neutral cancer evolution.	('mutations', 'Var', (41, 50))	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))
258257	30701024	To evaluate the clusters' genetic characteristics, we calculated MF mutation frequencies of each gene for 16 cancer types and examined the 10 genes with the highest frequency of mutations in each cluster (Supplementary Figure 2).	('mutation', 'Var', (68, 76))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('cancer', 'Disease', (109, 115))	('cancer', 'Disease', 'MESH:D009369', (109, 115))
258258	30701024	In BRCA, the frequencies of MF mutation in PIK3CA in clusters 3, 4, and 5 (35.5%, 40.5%, and 32.5%, respectively), in which the m_Count was small, were relatively high.	('PIK3CA', 'Gene', '5290', (43, 49))	('BRCA', 'Gene', '672', (3, 7))	('BRCA', 'Gene', (3, 7))	('mutation', 'Var', (31, 39))	('BRCA', 'Phenotype', 'HP:0003002', (3, 7))	('PIK3CA', 'Gene', (43, 49))
258259	30701024	Once mutations in PIK3CA occurred, without a striking increase in the number of other mutations, cells may remain genetically stable.	('PIK3CA', 'Gene', (18, 24))	('PIK3CA', 'Gene', '5290', (18, 24))	('mutations', 'Var', (5, 14))
258261	30701024	This result suggests that liver cancer cells with mutations in the driver gene CTNNB1, which have been generated in the earlier stage of cancer development, occupied in the cancer cell population.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('CTNNB1', 'Gene', '1499', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('cancer', 'Disease', (173, 179))	('mutations', 'Var', (50, 59))	('cancer', 'Disease', (32, 38))	('liver cancer', 'Disease', (26, 38))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('cancer', 'Disease', (137, 143))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('CTNNB1', 'Gene', (79, 85))	('liver cancer', 'Phenotype', 'HP:0002896', (26, 38))	('liver cancer', 'Disease', 'MESH:D006528', (26, 38))
258264	30701024	In our study, the samples in cluster 2 was predicted to have the highest ITH level due to a large number of mutations with lower VAF.	('VAF', 'Chemical', '-', (129, 132))	('ITH level', 'MPA', (73, 82))	('lower', 'NegReg', (123, 128))	('mutations', 'Var', (108, 117))
258266	30701024	In melanoma, the frequency of C>T transitions decreases, and the frequency of T>G transversions increases among branch mutations compared to trunk mutations.	('T>G transversions', 'Var', (78, 95))	('increases', 'PosReg', (96, 105))	('C>T transitions', 'Var', (30, 45))	('decreases', 'NegReg', (46, 55))	('melanoma', 'Phenotype', 'HP:0002861', (3, 11))	('melanoma', 'Disease', (3, 11))	('melanoma', 'Disease', 'MESH:D008545', (3, 11))
258267	30701024	Therefore, most mutations in samples with fewer mutations were proposed to occur in later, rather than earlier, stages of cancer development.	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('mutations', 'Var', (16, 25))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))
258271	30701024	As mentioned above, samples in clusters 1 and 2 supposedly accumulated a large number of MF mutations during cancer development.	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('cancer', 'Disease', (109, 115))	('mutations', 'Var', (92, 101))
258290	30701024	This suggested more mutations are associated with worse prognosis in these cancer types.	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('cancer', 'Disease', (75, 81))	('mutations', 'Var', (20, 29))	('cancer', 'Disease', 'MESH:D009369', (75, 81))
258291	30701024	Cancer cells occupied by a lower number of mutations occurring early in cancer development might be associated with worse prognosis in BLCA and UCEC.	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('BLCA', 'Disease', (135, 139))	('Cancer', 'Disease', (0, 6))	('UCEC', 'Disease', (144, 148))	('mutations', 'Var', (43, 52))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('cancer', 'Disease', (72, 78))
258292	30701024	Thus, samples were associated with poor prognosis when fewer mutations occurred at carcinogenesis and survived during cancer development.	('cancer', 'Disease', (118, 124))	('carcinogenesis', 'Disease', 'MESH:D063646', (83, 97))	('mutations', 'Var', (61, 70))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('carcinogenesis', 'Disease', (83, 97))	('cancer', 'Disease', 'MESH:D009369', (118, 124))
258293	30701024	Since frequencies of MF mutations in IDH1, which is one of the driver genes in LGG, were higher among samples in clusters 3, 4, and 5 (69.5%, 54.5%, and 59.5%, respectively), it was expected that other factors that increase the number of mutations from the early to mid-stage of cancer development may affect patient prognosis.	('affect', 'Reg', (302, 308))	('patient prognosis', 'CPA', (309, 326))	('IDH1', 'Gene', (37, 41))	('cancer', 'Phenotype', 'HP:0002664', (279, 285))	('patient', 'Species', '9606', (309, 316))	('higher', 'PosReg', (89, 95))	('IDH1', 'Gene', '3417', (37, 41))	('mutations', 'Var', (24, 33))	('cancer', 'Disease', (279, 285))	('cancer', 'Disease', 'MESH:D009369', (279, 285))
258306	30701024	Previous studies have shown that melanoma is a highly malignant cancer and harbors various mutations in the early stages of cancer development.	('cancer', 'Disease', (124, 130))	('melanoma', 'Phenotype', 'HP:0002861', (33, 41))	('melanoma', 'Disease', (33, 41))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('melanoma', 'Disease', 'MESH:D008545', (33, 41))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('mutations', 'Var', (91, 100))	('cancer', 'Disease', 'MESH:D009369', (124, 130))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
258308	30701024	Our results consistently showed that most samples have a large number of mutations accumulated prior to carcinogenesis.	('carcinogenesis', 'Disease', 'MESH:D063646', (104, 118))	('carcinogenesis', 'Disease', (104, 118))	('mutations', 'Var', (73, 82))
258309	30701024	Taking the mutation spectrum into consideration, most mutations in the samples with fewer mutations were considered to occur in the later rather than earlier stages of cancer development.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('mutations', 'Var', (54, 63))	('cancer', 'Disease', (168, 174))	('cancer', 'Disease', 'MESH:D009369', (168, 174))
258311	30701024	From these results, we proposed the following hypothesis of the genetic evolution of melanoma: melanoma is generated by a large number of genetic mutations, including those in BRAF (clusters 1 and 2), and only those cells with certain mutations are selected under selective pressure.	('mutations', 'Var', (146, 155))	('melanoma', 'Disease', 'MESH:D008545', (95, 103))	('melanoma', 'Phenotype', 'HP:0002861', (95, 103))	('melanoma', 'Disease', (95, 103))	('generated by', 'Reg', (107, 119))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('BRAF', 'Gene', '673', (176, 180))	('melanoma', 'Disease', (85, 93))	('melanoma', 'Disease', 'MESH:D008545', (85, 93))	('BRAF', 'Gene', (176, 180))
258313	30701024	Other mutated genes may be involved in evolutionary process of melanoma because of the low frequency of driver gene mutations in samples with few mutations.	('melanoma', 'Disease', 'MESH:D008545', (63, 71))	('involved', 'Reg', (27, 35))	('mutations', 'Var', (116, 125))	('melanoma', 'Phenotype', 'HP:0002861', (63, 71))	('melanoma', 'Disease', (63, 71))
258316	30701024	Previous studies showed that high TMB in NSCLC was associated with worse prognosis.	('high', 'Var', (29, 33))	('NSCLC', 'Disease', (41, 46))	('TMB', 'Chemical', '-', (34, 37))	('NSCLC', 'Disease', 'MESH:D002289', (41, 46))	('TMB', 'MPA', (34, 37))	('NSCLC', 'Phenotype', 'HP:0030358', (41, 46))
258317	30701024	In LUAD, the mutations partially attributable to smoking may gradually accumulate in cells during cancer progression, leading to more aggressive cancer cells.	('more', 'PosReg', (129, 133))	('cancer', 'Disease', (145, 151))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('leading to', 'Reg', (118, 128))	('LUAD', 'Phenotype', 'HP:0030078', (3, 7))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('aggressive cancer', 'Disease', 'MESH:D009369', (134, 151))	('cancer', 'Disease', (98, 104))	('mutations', 'Var', (13, 22))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('aggressive cancer', 'Disease', (134, 151))
258318	30701024	Conversely, in LUSC, once mutations are occupied in cancer cells under selective pressure (cluster 4), those samples were predicted to have a worse prognosis than cancer cells with a large number of clonal mutations (cluster 1).	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('LUSC', 'Phenotype', 'HP:0030359', (15, 19))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('mutations', 'Var', (26, 35))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('cancer', 'Disease', (163, 169))	('cancer', 'Disease', 'MESH:D009369', (163, 169))
258323	30701024	In this study, we analyzed 16 cancer types using only single nucleotide substitutions in genes.	('cancer', 'Disease', (30, 36))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('single nucleotide substitutions', 'Var', (54, 85))
258329	30701024	The MF mutations of amino acid substitution may have an impact on protein structures and/or functions, suggesting their possible involvement in cancer development or progression.	('mutations of amino acid substitution', 'Var', (7, 43))	('protein', 'Protein', (66, 73))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('involvement', 'Reg', (129, 140))	('cancer', 'Disease', (144, 150))	('functions', 'MPA', (92, 101))	('impact', 'Reg', (56, 62))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
258343	27402115	Notably, high ANXA2 and ANXA4 expression was significantly associated with shorter disease-free survival (p = 0.004 and p = 0.033, respectively).	('expression', 'MPA', (30, 40))	('ANXA2', 'Gene', (14, 19))	('ANXA4', 'Gene', '307', (24, 29))	('disease-free survival', 'CPA', (83, 104))	('shorter', 'NegReg', (75, 82))	('ANXA4', 'Gene', (24, 29))	('ANXA2', 'Gene', '302', (14, 19))	('high', 'Var', (9, 13))
258360	27402115	These data suggest that changes in ANXA2 and ANXA4 expression are associated with a particular tumor type, indicating that ANXs may be useful clinical biomarkers.	('ANXA2', 'Gene', '302', (35, 40))	('associated', 'Reg', (66, 76))	('ANXA2', 'Gene', (35, 40))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('expression', 'MPA', (51, 61))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('ANXA4', 'Gene', '307', (45, 50))	('changes', 'Var', (24, 31))	('ANXA4', 'Gene', (45, 50))	('tumor', 'Disease', (95, 100))
258405	27402115	Patients with high ANXA4 mRNA expression showed significantly poorer OS (p = 0.027) (Additional file 1: Figure S2).	('ANXA4', 'Gene', (19, 24))	('OS', 'Chemical', '-', (69, 71))	('poorer', 'NegReg', (62, 68))	('high', 'Var', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('ANXA4', 'Gene', '307', (19, 24))
258418	27402115	ANXA2 expression was associated with a more aggressive cancer phenotype (Table 1).	('ANXA2', 'Gene', (0, 5))	('associated with', 'Reg', (21, 36))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('aggressive cancer', 'Disease', 'MESH:D009369', (44, 61))	('ANXA2', 'Gene', '302', (0, 5))	('aggressive cancer', 'Disease', (44, 61))	('expression', 'Var', (6, 16))
258425	27402115	The 5-year DFS rates were 80 and 81 % in patients with positive ANXA2 and ANXA4 expression, respectively, compared with 92 and 91 % in patients with negative expression.	('ANXA4', 'Gene', '307', (74, 79))	('ANXA2', 'Gene', (64, 69))	('patients', 'Species', '9606', (135, 143))	('ANXA4', 'Gene', (74, 79))	('DFS', 'MPA', (11, 14))	('patients', 'Species', '9606', (41, 49))	('ANXA2', 'Gene', '302', (64, 69))	('expression', 'Var', (80, 90))
258426	27402115	Similarly, 5-year OS rates were 94 and 94 % in patients with positive ANXA2 and ANXA4 expression respectively, compared with 97 and 97 % for patients with negative expressions.	('ANXA4', 'Gene', (80, 85))	('ANXA2', 'Gene', '302', (70, 75))	('patients', 'Species', '9606', (47, 55))	('OS', 'Chemical', '-', (18, 20))	('ANXA2', 'Gene', (70, 75))	('expression', 'Var', (86, 96))	('ANXA4', 'Gene', '307', (80, 85))	('patients', 'Species', '9606', (141, 149))
258440	27402115	Furthermore, we demonstrated that high ANXA2 and ANXA4 expression predicted poor survival in patients with cervical cancer, which was supported by the improved predictive power of a model using combined clinical-ANXA2/ANXA4-variables.	('ANXA4', 'Gene', (49, 54))	('cervical cancer', 'Disease', (107, 122))	('poor', 'NegReg', (76, 80))	('ANXA2', 'Gene', (212, 217))	('ANXA4', 'Gene', (218, 223))	('expression', 'MPA', (55, 65))	('ANXA2', 'Gene', '302', (39, 44))	('high', 'Var', (34, 38))	('ANXA4', 'Gene', '307', (49, 54))	('ANXA2', 'Gene', '302', (212, 217))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cervical cancer', 'Disease', 'MESH:D002583', (107, 122))	('patients', 'Species', '9606', (93, 101))	('ANXA2', 'Gene', (39, 44))	('ANXA4', 'Gene', '307', (218, 223))
258456	27402115	They confirmed the role of ANXA2 in HPV16 infection by showing that (i) early HPV16 binding results in extracellular translocation of ANXA2, (ii) ANXA2 cointernalizes and mediates intracellular trafficking of HPV16 and (iii) anti-A2 and anti-S100A10 antibodies block HPV16 infection at different stages of HPV16 infection.	('ANXA2', 'Gene', '302', (27, 32))	('HPV16', 'Gene', (267, 272))	('HPV16', 'Species', '333760', (267, 272))	('ANXA2', 'Gene', (134, 139))	('HPV16', 'Species', '333760', (78, 83))	('anti-A2', 'Var', (225, 232))	('extracellular translocation', 'MPA', (103, 130))	('ANXA2', 'Gene', '302', (146, 151))	('HPV16', 'Species', '333760', (36, 41))	('anti-S100A10', 'Var', (237, 249))	('block', 'NegReg', (261, 266))	('ANXA2', 'Gene', (27, 32))	('HPV16', 'Species', '333760', (209, 214))	('ANXA2', 'Gene', (146, 151))	('ANXA2', 'Gene', '302', (134, 139))	('binding', 'Interaction', (84, 91))	('HPV16', 'Species', '333760', (306, 311))	('mediates intracellular trafficking', 'MPA', (171, 205))
258489	27198045	Structural alterations to complex carbohydrate (glycans) structures represent a key signature in the development of neoplastic character in the proliferation cells.	('Structural alterations', 'Var', (0, 22))	('carbohydrate', 'Chemical', 'MESH:D002241', (34, 46))	('neoplastic character', 'CPA', (116, 136))	('glycans', 'Chemical', 'MESH:D011134', (48, 55))
258516	27198045	The expression levels of the four main families of sialyltransferases (ST3Gal (alpha2,3 linkage), ST6Gal (alpha2,6 linkage), ST6GalNAc (alpha2,6 linkage), and ST8Sia (alpha2,8 linkage)) can vary between different tumor cases and tumor types.	('tumor', 'Disease', (213, 218))	('tumor', 'Disease', 'MESH:D009369', (229, 234))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('expression', 'MPA', (4, 14))	('ST6GalNAc', 'Gene', '27090', (125, 134))	('tumor', 'Disease', (229, 234))	('tumor', 'Disease', 'MESH:D009369', (213, 218))	('ST6GalNAc', 'Gene', (125, 134))	('vary', 'Reg', (190, 194))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('ST6Gal', 'Var', (98, 104))
258521	27198045	Generally O-linked glycans are frequently truncated in tumours, often as a result of premature sialylation where the sialyltransferase ST3Gal-I transfers N-acetylneuraminic acid (SA) via alpha2-3 linkage to the galactose residue in core 1 to form sialyl core-1 or sialyl T. ST3Gal-I sialyltransferase is required for core 1 O-glycan sialylation on CD8+ T cells and its deficiency induces core 2 O-glycan biosynthesis.	('tumours', 'Disease', (55, 62))	('induces', 'Reg', (380, 387))	('O-glycan', 'Chemical', '-', (324, 332))	('ST3Gal-I', 'Gene', (274, 282))	('ST3Gal-I', 'Gene', (135, 143))	('core 2 O-glycan biosynthesis', 'MPA', (388, 416))	('galactose', 'Chemical', 'MESH:D005690', (211, 220))	('glycans', 'Chemical', 'MESH:D011134', (19, 26))	('tumour', 'Phenotype', 'HP:0002664', (55, 61))	('O-glycan', 'Chemical', '-', (395, 403))	('tumours', 'Phenotype', 'HP:0002664', (55, 62))	('ST3Gal-I', 'Gene', '6482', (135, 143))	('tumours', 'Disease', 'MESH:D009369', (55, 62))	('deficiency', 'Var', (369, 379))	('ST3Gal-I', 'Gene', '6482', (274, 282))
258525	27198045	Aberrant sialylation during the biosynthesis glycosphingolipids (gangliosides) in the Golgi apparatus is important to cell adhesion and motility in many cancers.	('Aberrant', 'Var', (0, 8))	('motility in many cancers', 'Disease', 'MESH:D009369', (136, 160))	('motility in many cancers', 'Disease', (136, 160))	('sialylation', 'MPA', (9, 20))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('gangliosides', 'Chemical', 'MESH:D005732', (65, 77))	('glycosphingolipids', 'Chemical', 'MESH:D006028', (45, 63))	('important', 'Reg', (105, 114))	('cancers', 'Phenotype', 'HP:0002664', (153, 160))
258575	27198045	Furthermore, the rate of GATA3 mutations in luminal subtypes (G2: 13%, G3: 14% and G4: 15%) is in line with the results of other studies.	('GATA3', 'Gene', (25, 30))	('mutations', 'Var', (31, 40))	('GATA3', 'Gene', '2625', (25, 30))
258576	27198045	The combined effect of differential expression leading to cancer segregation and highly ranked importance of GT genes in cancer identification emphasizes that the biochemical pathways underlying key phenotypes across cancers differ significantly.	('differential', 'Var', (23, 35))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('cancers', 'Phenotype', 'HP:0002664', (217, 224))	('cancer', 'Disease', (217, 223))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('cancer', 'Disease', 'MESH:D009369', (217, 223))	('cancers', 'Disease', 'MESH:D009369', (217, 224))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('cancer', 'Disease', (58, 64))	('cancers', 'Disease', (217, 224))	('cancer', 'Disease', (121, 127))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))
258597	25608466	Plasma POU3F3 could serve as a potential biomarker for diagnosis of ESCC, and the combination of POU3F3 and SCCA was more efficient for ESCC detection, in particular for early tumor screening.	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('POU3F3', 'Gene', (97, 103))	('ESCC', 'Disease', (68, 72))	('POU3F3', 'Gene', '5455', (97, 103))	('ESCC', 'Disease', (136, 140))	('tumor', 'Disease', (176, 181))	('SCCA', 'Gene', (108, 112))	('POU3F3', 'Gene', (7, 13))	('POU3F3', 'Gene', '5455', (7, 13))	('tumor', 'Disease', 'MESH:D009369', (176, 181))	('combination', 'Var', (82, 93))
258605	25608466	The aberrant expression of lncRNAs have been reported to serve as potential diagnostic or prognostic biomarkers for many human malignancies such as breast, lung, liver, and colon cancers.	('malignancies', 'Disease', 'MESH:D009369', (127, 139))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('colon cancers', 'Disease', (173, 186))	('malignancies', 'Disease', (127, 139))	('breast', 'Disease', (148, 154))	('aberrant expression', 'Var', (4, 23))	('lung', 'Disease', (156, 160))	('human', 'Species', '9606', (121, 126))	('colon cancers', 'Phenotype', 'HP:0003003', (173, 186))	('liver', 'Disease', (162, 167))	('lncRNAs', 'Protein', (27, 34))	('cancers', 'Phenotype', 'HP:0002664', (179, 186))	('colon cancers', 'Disease', 'MESH:D015179', (173, 186))
258611	25608466	In gastric cancer patients, plasma AA174084 levels dropped markedly on day 15 after surgery compared with preoperative levels and were associated with invasion and lymphatic metastasis.	('AA174084', 'Var', (35, 43))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('gastric cancer', 'Phenotype', 'HP:0012126', (3, 17))	('lymphatic metastasis', 'CPA', (164, 184))	('gastric cancer', 'Disease', (3, 17))	('dropped', 'NegReg', (51, 58))	('associated with', 'Reg', (135, 150))	('patients', 'Species', '9606', (18, 26))	('gastric cancer', 'Disease', 'MESH:D013274', (3, 17))
258621	25608466	On the basis of previous study, 10 lncRNAs (HOTAIR, AFAP1-AS1, POU3F3, HNF1A-AS1, PlncRNA1, SPRY4-IT1, ENST00000435885.1, ENST00000547963.1, 91H and XLOC_013104) which have been reported to be differently expressed in esophageal cancer were selected in the present study.	('POU3F3', 'Gene', '5455', (63, 69))	('PlncRNA1', 'Gene', (82, 90))	('HOTAIR', 'Gene', (44, 50))	('HNF1A-AS1', 'Gene', '283460', (71, 80))	('ENST00000435885.1', 'Var', (103, 120))	('XLOC_013104', 'Var', (149, 160))	('esophageal cancer', 'Disease', 'MESH:D004938', (218, 235))	('POU3F3', 'Gene', (63, 69))	('AFAP1-AS1', 'Gene', (52, 61))	('PlncRNA1', 'Gene', '100506428', (82, 90))	('esophageal cancer', 'Disease', (218, 235))	('AFAP1-AS1', 'Gene', '84740;60312;5729', (52, 61))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('91H', 'Var', (141, 144))	('SPRY4-IT1', 'Gene', '100642175;81848;79441', (92, 101))	('ENST00000547963.1', 'Var', (122, 139))	('HNF1A-AS1', 'Gene', (71, 80))	('HOTAIR', 'Gene', '100124700', (44, 50))	('SPRY4-IT1', 'Gene', (92, 101))
258623	25608466	Among them, HOTAIR, AFAP1-AS1, POU3F3, HNF1A-AS1, PlncRNA1, SPRY4-IT1, ENST00000435885.1 and ENST00000547963.1 were significantly higher in most of ESCC tumor tissues compared with paired adjacent normal tissues (Figure 1).	('ENST00000547963.1', 'Var', (93, 110))	('PlncRNA1', 'Gene', (50, 58))	('HOTAIR', 'Gene', (12, 18))	('higher', 'PosReg', (130, 136))	('SPRY4-IT1', 'Gene', (60, 69))	('ENST00000435885.1', 'Var', (71, 88))	('PlncRNA1', 'Gene', '100506428', (50, 58))	('ESCC tumor', 'Disease', 'MESH:D004938', (148, 158))	('AFAP1-AS1', 'Gene', '84740;60312;5729', (20, 29))	('SPRY4-IT1', 'Gene', '100642175;81848;79441', (60, 69))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('HOTAIR', 'Gene', '100124700', (12, 18))	('HNF1A-AS1', 'Gene', (39, 48))	('AFAP1-AS1', 'Gene', (20, 29))	('HNF1A-AS1', 'Gene', '283460', (39, 48))	('ESCC tumor', 'Disease', (148, 158))	('POU3F3', 'Gene', (31, 37))	('POU3F3', 'Gene', '5455', (31, 37))
258692	25608466	provided the pioneering evidence that blood cells were the major contributor to the circulating miRNAs and that perturbations in blood cell counts and hemolysis could alter plasma miRNAs levels by up to 50-fold.	('hemolysis', 'Disease', (151, 160))	('hemolysis', 'Disease', 'MESH:D006461', (151, 160))	('perturbations', 'Var', (112, 125))	('alter', 'Reg', (167, 172))	('circulating miRNAs', 'MPA', (84, 102))	('plasma miRNAs levels', 'MPA', (173, 193))
258733	33643802	It is widely accepted that the development of advanced non-small cell lung cancer (NSCLC) relies on gene mutations and some of them act as drivers of neoplastic transformation.	('small cell lung cancer', 'Disease', 'MESH:D055752', (59, 81))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (59, 81))	('gene mutations', 'Var', (100, 114))	('NSCLC', 'Disease', (83, 88))	('NSCLC', 'Disease', 'MESH:D002289', (83, 88))	('lung cancer', 'Phenotype', 'HP:0100526', (70, 81))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (55, 81))	('small cell lung cancer', 'Disease', (59, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))
258734	33643802	[  1 ,  2 ,  3 ,  4  ] Patients with mutations of epidermal growth factor receptor (EGFR) and translocations of anaplastic lymphoma kinase (ALK) can be treated with tyrosine kinase inhibitor (TKI)-based target therapy whose efficacy has been fully demonstrated and many guidelines suggest the TKIs are the first line treatment for these patients.	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (112, 131))	('translocations', 'Var', (94, 108))	('anaplastic lymphoma kinase', 'Gene', (112, 138))	('epidermal growth factor receptor', 'Gene', '1956', (50, 82))	('ALK', 'Gene', (140, 143))	('Patients', 'Species', '9606', (23, 31))	('lymphoma', 'Phenotype', 'HP:0002665', (123, 131))	('EGFR', 'Gene', '1956', (84, 88))	('mutations', 'Var', (37, 46))	('epidermal growth factor receptor', 'Gene', (50, 82))	('EGFR', 'Gene', (84, 88))	('ALK', 'Gene', '238', (140, 143))	('anaplastic lymphoma kinase', 'Gene', '238', (112, 138))	('patients', 'Species', '9606', (337, 345))
258747	33643802	The proportion of male patients in the group without mutations/translocations in EGFR or ALK genes was higher compared to that of patients harboring a driver gene alteration.	('ALK', 'Gene', (89, 92))	('patients', 'Species', '9606', (23, 31))	('EGFR', 'Gene', '1956', (81, 85))	('patients', 'Species', '9606', (130, 138))	('ALK', 'Gene', '238', (89, 92))	('mutations/translocations', 'Var', (53, 77))	('EGFR', 'Gene', (81, 85))
258750	33643802	TP53, DPP6, DEAF1, SP8, and ATXN2 had the highest frequency of mutations in the whole cohort (Figure 1A).	('mutations', 'Var', (63, 72))	('ATXN2', 'Gene', '6311', (28, 33))	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('DEAF1', 'Gene', '10522', (12, 17))	('DPP6', 'Gene', '1804', (6, 10))	('ATXN2', 'Gene', (28, 33))	('DEAF1', 'Gene', (12, 17))	('DPP6', 'Gene', (6, 10))	('SP8', 'Gene', '221833', (19, 22))	('SP8', 'Gene', (19, 22))
258751	33643802	For example, KRAS mutations were common in LADC (27.6%) while its frequency was significantly lower in LUSC (5.6%, P < 0.001, FDR = 0.010) and absent in SCLC (0.0%, P < 0.001, FDR = 0.009) (Figure 1B-E, Table S2, Supporting Information).	('SCLC', 'Disease', (153, 157))	('SCLC', 'Disease', 'MESH:D018288', (153, 157))	('LADC', 'Disease', (43, 47))	('lower', 'NegReg', (94, 99))	('KRAS', 'Gene', (13, 17))	('KRAS', 'Gene', '3845', (13, 17))	('mutations', 'Var', (18, 27))
258752	33643802	RB1 mutations were frequent in SCLC (39.0%) but much less frequent in LADC (10.3%, P < 0.001, FDR = 0.011) and LUSC (1.4%, P < 0.001, FDR < 0.001) (Figure 1B-E, Table S2, Supporting Information).	('SCLC', 'Disease', 'MESH:D018288', (31, 35))	('RB1', 'Gene', '5925', (0, 3))	('frequent', 'Reg', (19, 27))	('mutations', 'Var', (4, 13))	('RB1', 'Gene', (0, 3))	('SCLC', 'Disease', (31, 35))
258754	33643802	By comparing mutational signatures of our data with 30 known COSMIC cancer signatures, we found four similar mutational signatures (Figure  2A,B), which suggested that mutation in our data were similar to those caused by age, smoking, function of APOBEC family, and dysfunction of DNA mismatch repair.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('APOBEC', 'Gene', (247, 253))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('caused', 'Reg', (211, 217))	('cancer', 'Disease', (68, 74))	('dysfunction', 'Var', (266, 277))
258755	33643802	Both NSCLC and SCLC can be subdivided into four groups according to their mutation signature (C1-C4 for NSCLC, C5-C8 for SCLC).	('SCLC', 'Disease', (121, 125))	('SCLC', 'Disease', 'MESH:D018288', (121, 125))	('SCLC', 'Disease', (15, 19))	('C5-C8', 'Var', (111, 116))	('SCLC', 'Disease', (105, 109))	('SCLC', 'Disease', 'MESH:D018288', (15, 19))	('SCLC', 'Disease', 'MESH:D018288', (105, 109))	('NSCLC', 'Disease', (104, 109))	('C1-C4', 'Var', (94, 99))	('NSCLC', 'Disease', 'MESH:D002289', (104, 109))	('NSCLC', 'Disease', (5, 10))	('SCLC', 'Disease', (6, 10))	('SCLC', 'Disease', 'MESH:D018288', (6, 10))	('NSCLC', 'Disease', 'MESH:D002289', (5, 10))
258756	33643802	C1 of NSCLC and C5 of SCLC had enriched mutational signature 15 whose potential cause was dysfunction of DNA mismatch repair.	('NSCLC', 'Disease', 'MESH:D002289', (6, 11))	('SCLC', 'Disease', (22, 26))	('SCLC', 'Disease', 'MESH:D018288', (22, 26))	('mutational', 'Var', (40, 50))	('SCLC', 'Disease', (7, 11))	('SCLC', 'Disease', 'MESH:D018288', (7, 11))	('NSCLC', 'Disease', (6, 11))
258757	33643802	C2 of NSCLC and C8 of SCLC had enriched mutational signature 1 which was correlated with age.	('NSCLC', 'Disease', 'MESH:D002289', (6, 11))	('SCLC', 'Disease', (22, 26))	('SCLC', 'Disease', 'MESH:D018288', (22, 26))	('mutational', 'Var', (40, 50))	('SCLC', 'Disease', (7, 11))	('SCLC', 'Disease', 'MESH:D018288', (7, 11))	('NSCLC', 'Disease', (6, 11))
258758	33643802	C3 of NSCLC and C6 of SCLC had enriched mutational signature 13 which might have relationship with the activity of enzymes of APOBEC family.	('NSCLC', 'Disease', 'MESH:D002289', (6, 11))	('SCLC', 'Disease', (22, 26))	('SCLC', 'Disease', 'MESH:D018288', (22, 26))	('mutational', 'Var', (40, 50))	('SCLC', 'Disease', (7, 11))	('SCLC', 'Disease', 'MESH:D018288', (7, 11))	('NSCLC', 'Disease', (6, 11))
258759	33643802	C4 of NSCLC and C7 of SCLC had enriched mutational signature 4 which might be caused by smoking.	('NSCLC', 'Disease', 'MESH:D002289', (6, 11))	('SCLC', 'Disease', (22, 26))	('SCLC', 'Disease', 'MESH:D018288', (22, 26))	('mutational', 'Var', (40, 50))	('SCLC', 'Disease', (7, 11))	('caused', 'Reg', (78, 84))	('SCLC', 'Disease', 'MESH:D018288', (7, 11))	('NSCLC', 'Disease', (6, 11))
258761	33643802	In NSCLC, we found patients with smoking history were more likely to have mutational signature 4 (P = 0.006).	('mutational', 'Var', (74, 84))	('NSCLC', 'Disease', 'MESH:D002289', (3, 8))	('NSCLC', 'Disease', (3, 8))	('patients', 'Species', '9606', (19, 27))
258762	33643802	Although C7 subtype of SCLC also had enriched mutational signature 4, we did not find the proportion of patient with smoking history was different between C7 subtype and non-C7 subtype (P = 0.807).	('mutational', 'Var', (46, 56))	('patient', 'Species', '9606', (104, 111))	('SCLC', 'Disease', (23, 27))	('SCLC', 'Disease', 'MESH:D018288', (23, 27))
258763	33643802	Figure 3B shows the correlation of subtype with the specific gene mutations in NSCLC.	('mutations', 'Var', (66, 75))	('NSCLC', 'Disease', 'MESH:D002289', (79, 84))	('NSCLC', 'Disease', (79, 84))
258767	33643802	A) Mutational signatures for the four NSCLC molecular subtypes (C1-C4) and four SCLC subtypes (C5-C8).	('NSCLC', 'Disease', (38, 43))	('SCLC', 'Disease', (80, 84))	('Mutational', 'Var', (3, 13))	('SCLC', 'Disease', 'MESH:D018288', (80, 84))	('NSCLC', 'Disease', 'MESH:D002289', (38, 43))	('SCLC', 'Disease', (39, 43))	('SCLC', 'Disease', 'MESH:D018288', (39, 43))
258768	33643802	B) The association between NSCLC molecular subtype and specific gene mutations.	('mutations', 'Var', (69, 78))	('association', 'Reg', (7, 18))	('NSCLC', 'Disease', 'MESH:D002289', (27, 32))	('NSCLC', 'Disease', (27, 32))
258786	33643802	The distribution of TMB had not been fully characterized in Chinese lung cancer patients with no EGFR or ALK mutations.	('ALK', 'Gene', (105, 108))	('lung cancer', 'Disease', (68, 79))	('patients', 'Species', '9606', (80, 88))	('lung cancer', 'Phenotype', 'HP:0100526', (68, 79))	('EGFR', 'Gene', '1956', (97, 101))	('TMB', 'Chemical', '-', (20, 23))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('ALK', 'Gene', '238', (105, 108))	('EGFR', 'Gene', (97, 101))	('lung cancer', 'Disease', 'MESH:D008175', (68, 79))	('mutations', 'Var', (109, 118))
258796	33643802	C) Mutational frequency for cancer-related genes within NSCLC TMB subtype S1, S2, and S3.	('Mutational', 'Var', (3, 13))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('NSCLC TMB', 'Disease', 'MESH:D002289', (56, 65))	('cancer', 'Disease', (28, 34))	('NSCLC TMB', 'Disease', (56, 65))
258799	33643802	F) Mutational frequency for most frequently mutated genes within NSCLC TMB subtype S1, S2, and S3.	('Mutational', 'Var', (3, 13))	('NSCLC TMB', 'Disease', (65, 74))	('NSCLC TMB', 'Disease', 'MESH:D002289', (65, 74))
258802	33643802	I) Comparison of OS between NSCLC TMB subtype S1+S2 and S3 (P = 0.29).	('NSCLC TMB', 'Disease', 'MESH:D002289', (28, 37))	('NSCLC TMB', 'Disease', (28, 37))	('S1+S2', 'Var', (46, 51))
258805	33643802	L) Comparison of PFS between NSCLC TMB subtype S1+S2 and S3 (P = 0.12).	('NSCLC TMB', 'Disease', 'MESH:D002289', (29, 38))	('NSCLC TMB', 'Disease', (29, 38))	('S1+S2', 'Var', (47, 52))
258810	33643802	The mutational frequency for most genes in S3 was higher than that in S1 and S2, and the frequency of the SP8 mutations in S3 was significantly higher than that in S1 (P < 0.001, FDR = 0.008), which had a strong correlation with high TMB.	('SP8', 'Gene', '221833', (106, 109))	('higher', 'PosReg', (50, 56))	('mutations', 'Var', (110, 119))	('TMB', 'Chemical', '-', (234, 237))	('high TMB', 'Disease', (229, 237))	('SP8', 'Gene', (106, 109))	('higher', 'PosReg', (144, 150))	('mutational', 'Var', (4, 14))
258811	33643802	The mutational frequency for each gene in S2 and S3 was higher than that in S1, and the frequency of the TP53 and TTN mutations in S2 and S3 was higher than that in S1 (Figure 4F).	('higher', 'Reg', (145, 151))	('TTN', 'Gene', '7273', (114, 117))	('TTN', 'Gene', (114, 117))	('TP53', 'Gene', '7157', (105, 109))	('TP53', 'Gene', (105, 109))	('higher', 'PosReg', (56, 62))	('mutational', 'Var', (4, 14))
258816	33643802	Figure  5  indicated that the TMB of patients with TP53, TTN, RYR2, LRP1B, FSIP2, and SPTA1 mutations was significantly higher than that of patients without these mutations for both NSCLC and SCLC.	('FSIP2', 'Gene', '401024', (75, 80))	('NSCLC', 'Disease', 'MESH:D002289', (182, 187))	('TTN', 'Gene', '7273', (57, 60))	('SPTA1', 'Gene', (86, 91))	('TTN', 'Gene', (57, 60))	('NSCLC', 'Disease', (182, 187))	('TP53', 'Gene', (51, 55))	('patients', 'Species', '9606', (37, 45))	('SCLC', 'Disease', (192, 196))	('patients', 'Species', '9606', (140, 148))	('FSIP2', 'Gene', (75, 80))	('RYR2', 'Gene', (62, 66))	('SCLC', 'Disease', (183, 187))	('LRP1B', 'Gene', (68, 73))	('RYR2', 'Gene', '6262', (62, 66))	('mutations', 'Var', (92, 101))	('TMB', 'MPA', (30, 33))	('TP53', 'Gene', '7157', (51, 55))	('higher', 'PosReg', (120, 126))	('SCLC', 'Disease', 'MESH:D018288', (192, 196))	('SPTA1', 'Gene', '6708', (86, 91))	('LRP1B', 'Gene', '53353', (68, 73))	('TMB', 'Chemical', '-', (30, 33))	('SCLC', 'Disease', 'MESH:D018288', (183, 187))
258818	33643802	These high-frequency mutations are closely related to the higher TMB (Figure 5).	('mutations', 'Var', (21, 30))	('TMB', 'Chemical', '-', (65, 68))	('related', 'Reg', (43, 50))	('higher TMB', 'Disease', (58, 68))
258819	33643802	Moreover, observation on correlation between high-frequency mutations and TMB also suggested that TMB was not correlated with mutations of individual genes but multiple genes.	('TMB', 'Chemical', '-', (74, 77))	('mutations', 'Var', (60, 69))	('TMB', 'Chemical', '-', (98, 101))	('TMB', 'Disease', (98, 101))
258823	33643802	In this study, we found that the frequency of TP53 and DPP6 gene mutations in all lung cancer were higher than that of other genes, and the frequency of TP53 mutations in SCLC was particularly high (85.4%) and significantly higher than that in LUSC.	('lung cancer', 'Phenotype', 'HP:0100526', (82, 93))	('higher', 'PosReg', (99, 105))	('lung cancer', 'Disease', (82, 93))	('TP53', 'Gene', '7157', (46, 50))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('DPP6', 'Gene', (55, 59))	('TP53', 'Gene', '7157', (153, 157))	('SCLC', 'Disease', (171, 175))	('TP53', 'Gene', (46, 50))	('DPP6', 'Gene', '1804', (55, 59))	('lung cancer', 'Disease', 'MESH:D008175', (82, 93))	('TP53', 'Gene', (153, 157))	('SCLC', 'Disease', 'MESH:D018288', (171, 175))	('mutations', 'Var', (158, 167))	('mutations', 'Var', (65, 74))
258824	33643802	The mutation rate of RB1 was 39.0% in SCLC, while it was only 10.3% and 1.4% in LADC and LUSC, respectively.	('RB1', 'Gene', '5925', (21, 24))	('mutation', 'Var', (4, 12))	('SCLC', 'Disease', (38, 42))	('SCLC', 'Disease', 'MESH:D018288', (38, 42))	('RB1', 'Gene', (21, 24))
258825	33643802	In addition, NKX2-3, DEAF1, and SP8 were found to have high mutation frequencies in LADC, LUSC, and SCLC, respectively.	('mutation', 'Var', (60, 68))	('NKX2-3', 'Gene', '159296;4824', (13, 19))	('LADC', 'Disease', (84, 88))	('NKX2-3', 'Gene', (13, 19))	('DEAF1', 'Gene', (21, 26))	('LUSC', 'Disease', (90, 94))	('SP8', 'Gene', '221833', (32, 35))	('SCLC', 'Disease', (100, 104))	('SCLC', 'Disease', 'MESH:D018288', (100, 104))	('DEAF1', 'Gene', '10522', (21, 26))	('SP8', 'Gene', (32, 35))
258831	33643802	[  16  ] This may be due to the exclusion of EGFR or ALK-related driver gene mutations, as a considerable proportion of patients with TKI-related driver gene mutations were nonsmoking patients.	('ALK', 'Gene', (53, 56))	('EGFR', 'Gene', (45, 49))	('patients', 'Species', '9606', (184, 192))	('ALK', 'Gene', '238', (53, 56))	('patients', 'Species', '9606', (120, 128))	('mutations', 'Var', (158, 167))	('EGFR', 'Gene', '1956', (45, 49))
258832	33643802	Therefore, the therapeutic response and long-term prognosis of LUSC and male patients with no EGFR or ALK-related driver gene mutations are worth further investigation.	('EGFR', 'Gene', '1956', (94, 98))	('ALK', 'Gene', (102, 105))	('EGFR', 'Gene', (94, 98))	('patients', 'Species', '9606', (77, 85))	('ALK', 'Gene', '238', (102, 105))	('mutations', 'Var', (126, 135))
258848	33643802	These observations strongly suggested that high TMB might be a potential indicator of worse survival in NSCLC patients treated with first-line chemotherapy.	('TMB', 'MPA', (48, 51))	('high', 'Var', (43, 47))	('TMB', 'Chemical', '-', (48, 51))	('NSCLC', 'Disease', (104, 109))	('NSCLC', 'Disease', 'MESH:D002289', (104, 109))	('patients', 'Species', '9606', (110, 118))
258872	33643802	EGFR mutations in exons 18-21 and EML4-ALK rearrangement were detected by AmoyDx EGFR 29 Mutations Detection Kit (Amoy, Xiamen, China) and AmoyDx EML4-ALK Fusion Gene Detection Kit (Amoy, Xiamen, China) separately according to the protocols.	('ALK', 'Gene', (39, 42))	('EGFR', 'Gene', (0, 4))	('Kit', 'Gene', (177, 180))	('EML4', 'Gene', (34, 38))	('ALK', 'Gene', (151, 154))	('mutations', 'Var', (5, 14))	('Kit', 'Gene', '3815', (177, 180))	('EML4', 'Gene', (146, 150))	('ALK', 'Gene', '238', (39, 42))	('Kit', 'Gene', (109, 112))	('EML4', 'Gene', '27436', (34, 38))	('Kit', 'Gene', '3815', (109, 112))	('ALK', 'Gene', '238', (151, 154))	('EML4', 'Gene', '27436', (146, 150))	('EGFR', 'Gene', '1956', (0, 4))	('EGFR', 'Gene', '1956', (81, 85))	('EGFR', 'Gene', (81, 85))
258873	33643802	Patients with 19del, L858R, T790M, 20ins, G719X (X = A, C, or S), S768I, or L861Q would be classified as EGFR mutated.	('L861Q', 'Mutation', 'rs121913444', (76, 81))	('20ins', 'Mutation', 'c.20ins', (35, 40))	('L858R', 'Var', (21, 26))	('G719X', 'Mutation', 'p.G719X', (42, 47))	('L861Q', 'Var', (76, 81))	('EGFR', 'Gene', '1956', (105, 109))	('Patients', 'Species', '9606', (0, 8))	('L858R', 'Mutation', 'rs121434568', (21, 26))	('T790M', 'Mutation', 'rs121434569', (28, 33))	('S768I', 'Var', (66, 71))	('EGFR', 'Gene', (105, 109))	('T790M', 'Var', (28, 33))	('19del', 'Mutation', 'c.19del', (14, 19))	('S768I', 'Mutation', 'rs121913465', (66, 71))
258875	33643802	The cutoff DeltaCt values for 19del, L858R, T790M, 20ins, G719X, S768I, and L861Q were 13, 14, 12.5, 13, 13, 12, and 12, respectively.	('L861Q', 'Mutation', 'rs121913444', (76, 81))	('20ins', 'Mutation', 'c.20ins', (51, 56))	('L861Q', 'Var', (76, 81))	('S768I', 'Var', (65, 70))	('G719X', 'Mutation', 'p.G719X', (58, 63))	('T790M', 'Mutation', 'rs121434569', (44, 49))	('T790M', 'Var', (44, 49))	('19del', 'Mutation', 'c.19del', (30, 35))	('G719X', 'Var', (58, 63))	('S768I', 'Mutation', 'rs121913465', (65, 70))	('L858R', 'Var', (37, 42))	('L858R', 'Mutation', 'rs121434568', (37, 42))
258896	33482859	Patients with low GSTM3 expression tended to exhibit an increased rate of poor differentiation in both the mRNA cohort (p = 0.024) and protein cohort (p = 0.004).	('GSTM3', 'Gene', '2947', (18, 23))	('expression', 'MPA', (24, 34))	('poor differentiation', 'CPA', (74, 94))	('Patients', 'Species', '9606', (0, 8))	('GSTM3', 'Gene', (18, 23))	('low', 'Var', (14, 17))
258911	33482859	At least five mammalian GST gene families have been identified as polymorphic, and mutations or deletions of these genes contribute to the predisposition of several diseases, including cancer.	('mutations', 'Var', (83, 92))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('deletions', 'Var', (96, 105))	('contribute', 'Reg', (121, 131))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('diseases', 'Disease', (165, 173))	('cancer', 'Disease', (185, 191))	('mammalian', 'Species', '9606', (14, 23))
258916	33482859	GSTM3 polymorphisms may increase lung cancer and esophageal cancer susceptibility.	('lung cancer', 'Phenotype', 'HP:0100526', (33, 44))	('increase', 'PosReg', (24, 32))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('polymorphisms', 'Var', (6, 19))	('GSTM3', 'Gene', (0, 5))	('cancer', 'Disease', (60, 66))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('lung cancer', 'Disease', 'MESH:D008175', (33, 44))	('GSTM3', 'Gene', '2947', (0, 5))	('cancer', 'Disease', (38, 44))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('lung cancer', 'Disease', (33, 44))
258952	33482859	Then, GSTM3 mRNA expression in the mRNA cohort was divided into two groups: the low-expression group (<= 0.662, n = 91) and the high-expression group (>0.662, n = 93).	('<= 0.662', 'Var', (102, 110))	('GSTM3', 'Gene', '2947', (6, 11))	('GSTM3', 'Gene', (6, 11))
258966	33482859	Cox's proportional hazards regression confirmed that high GSTM3 expression was significantly associated with lower risk of disease recurrence in the mRNA cohort (hazard ratio, HR: 0.635, 95 % confidence interval, CI: 0.435-0.927, p = 0.019) and protein cohort (HR: 0.659, 95 % CI: 0.484-0.898, p = 0.008) (Tables 5 and 6).	('lower', 'NegReg', (109, 114))	('high', 'Var', (53, 57))	('disease recurrence', 'CPA', (123, 141))	('GSTM3', 'Gene', (58, 63))	('GSTM3', 'Gene', '2947', (58, 63))
258972	33482859	High GSTM3 expression levels indeed decreased the risk of disease recurrence for patients with resected ESCC compared with those with low GSTM3 expression levels.	('High', 'Var', (0, 4))	('GSTM3', 'Gene', (5, 10))	('GSTM3', 'Gene', '2947', (5, 10))	('patients', 'Species', '9606', (81, 89))	('GSTM3', 'Gene', '2947', (138, 143))	('ESCC', 'Disease', (104, 108))	('disease', 'Disease', (58, 65))	('SCC', 'Phenotype', 'HP:0002860', (105, 108))	('GSTM3', 'Gene', (138, 143))	('decreased', 'NegReg', (36, 45))
258977	33482859	Epigenetic inactivation of GSTM3 has been reported in Barrett's adenocarcinoma.	('adenocarcinoma', 'Disease', (64, 78))	('GSTM3', 'Gene', (27, 32))	('reported', 'Reg', (42, 50))	('adenocarcinoma', 'Disease', 'MESH:D000230', (64, 78))	('GSTM3', 'Gene', '2947', (27, 32))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))	('Epigenetic inactivation', 'Var', (0, 23))
258983	33482859	Some studies have noted that high GSTM3 expression is a poor prognostic factor, whereas others have noted that low GSTM3 expression is a poor prognostic factor.	('high', 'Var', (29, 33))	('GSTM3', 'Gene', '2947', (115, 120))	('GSTM3', 'Gene', '2947', (34, 39))	('GSTM3', 'Gene', (34, 39))	('GSTM3', 'Gene', (115, 120))
258985	33482859	Meding S reported that high GSTM3 expression correlated with lymph node metastasis and advanced stage of colon cancer, and low GSTM3 expression was associated with better survival.	('expression', 'MPA', (34, 44))	('high', 'Var', (23, 27))	('colon cancer', 'Disease', 'MESH:D015179', (105, 117))	('colon cancer', 'Disease', (105, 117))	('better', 'PosReg', (164, 170))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('lymph node metastasis', 'CPA', (61, 82))	('low', 'Var', (123, 126))	('GSTM3', 'Gene', (127, 132))	('correlated with', 'Reg', (45, 60))	('GSTM3', 'Gene', (28, 33))	('GSTM3', 'Gene', '2947', (127, 132))	('GSTM3', 'Gene', '2947', (28, 33))	('colon cancer', 'Phenotype', 'HP:0003003', (105, 117))
258993	33482859	Univariate analysis demonstrated that patients with high GSTM3 expression tended to have better 3- and 5-year DSS compared with those with low-expression in the mRNA cohort (64.6 % vs. 56.2 % and 52.8 % vs. 46.0 %, p = 0.132) and the protein cohort (42.4 % vs. 31.0 % and 37.1 % vs. 22.3 %, p = 0.070); however, the difference was not statistically significant.	('DSS', 'Gene', '5376', (110, 113))	('better', 'PosReg', (89, 95))	('GSTM3', 'Gene', (57, 62))	('GSTM3', 'Gene', '2947', (57, 62))	('high', 'Var', (52, 56))	('patients', 'Species', '9606', (38, 46))	('DSS', 'Gene', (110, 113))
258998	33482859	Our present study showed that the difference of DFS between low and high expression of GSTM3 was statistically significant, but the difference in DSS did not reach statistical significance.	('DSS', 'Gene', '5376', (146, 149))	('high expression', 'Var', (68, 83))	('low', 'Var', (60, 63))	('GSTM3', 'Gene', (87, 92))	('DSS', 'Gene', (146, 149))	('GSTM3', 'Gene', '2947', (87, 92))
259003	33482859	Both low- and high-expression of GSTM3 cohorts received no neoadjuvant or adjuvant treatment until disease recurrence.	('low-', 'NegReg', (5, 9))	('GSTM3', 'Gene', '2947', (33, 38))	('high-expression', 'Var', (14, 29))	('GSTM3', 'Gene', (33, 38))
259011	33482859	Patients with low GSTM3 expression tended to exhibit an increased rate of poor differentiation in patients with resectable ESCC.	('GSTM3', 'Gene', '2947', (18, 23))	('poor differentiation', 'CPA', (74, 94))	('ESCC', 'Disease', (123, 127))	('patients', 'Species', '9606', (98, 106))	('SCC', 'Phenotype', 'HP:0002860', (124, 127))	('Patients', 'Species', '9606', (0, 8))	('GSTM3', 'Gene', (18, 23))	('low', 'Var', (14, 17))
259022	30843252	In summary, our study reveals that HOXA9 promoter hypermethylation contributes to the risk of HNSCC and its progression and metastasis.	('HNSCC', 'Disease', (94, 99))	('metastasis', 'CPA', (124, 134))	('HOXA9', 'Gene', '3205', (35, 40))	('HNSCC', 'Phenotype', 'HP:0012288', (94, 99))	('promoter hypermethylation', 'Var', (41, 66))	('risk', 'Reg', (86, 90))	('HOXA9', 'Gene', (35, 40))	('progression', 'CPA', (108, 119))
259023	30843252	Additionally, HOXA9 hypermethylation is a potential biomarker for the early diagnosis and screening of patients with HNSCC.	('HNSCC', 'Phenotype', 'HP:0012288', (117, 122))	('HNSCC', 'Disease', (117, 122))	('hypermethylation', 'Var', (20, 36))	('HOXA9', 'Gene', '3205', (14, 19))	('HOXA9', 'Gene', (14, 19))	('patients', 'Species', '9606', (103, 111))
259027	30843252	Recent studies have revealed that hypermethylation of the HOXA9 promoter leads to its transcriptional inactivation in several of cancers, including those of the lung,28 breast,29 cervix,25 and bladder30; however, the relationship between HOXA9 and HNSCC remains unclear.	('HNSCC', 'Phenotype', 'HP:0012288', (248, 253))	('HOXA9', 'Gene', (238, 243))	('transcriptional', 'MPA', (86, 101))	('hypermethylation', 'Var', (34, 50))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('HOXA9', 'Gene', '3205', (58, 63))	('cancers', 'Disease', 'MESH:D009369', (129, 136))	('cancers', 'Phenotype', 'HP:0002664', (129, 136))	('cancers', 'Disease', (129, 136))	('HOXA9', 'Gene', (58, 63))	('HOXA9', 'Gene', '3205', (238, 243))
259043	30843252	The average beta values of two Illumina Human Methylation 450K BeadChip probes (cg02643054 on chr7:27206544 and cg00905524 on chr7:27206907), close to the qMSP amplification fragment (chr7:27206577-27206704), were used to evaluate HOXA9 methylation in this dataset.	('Human', 'Species', '9606', (40, 45))	('cg02643054', 'Var', (80, 90))	('chr7:27206577-27206704', 'STRUCTURAL_ABNORMALITY', 'None', (184, 206))	('HOXA9', 'Gene', '3205', (231, 236))	('HOXA9', 'Gene', (231, 236))	('cg00905524 on', 'Var', (112, 125))
259046	30843252	Illumina Human Methylation 450K data from 528 patients with histologically confirmed HNSCC, including tumor tissues in all cases and matched adjacent normal tissues in 50 cases, were available from TCGA project, and two Methylation 450K CpG sites (cg02643054 and cg00905524) located near the tested fragment (chr7:27206577-27206704) were chosen to verify our findings (Figure 1).	('patients', 'Species', '9606', (46, 54))	('cg00905524', 'Var', (263, 273))	('tumor', 'Disease', (102, 107))	('cg02643054', 'Var', (248, 258))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('Human', 'Species', '9606', (9, 14))	('HNSCC', 'Phenotype', 'HP:0012288', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('HNSCC', 'Disease', (85, 90))	('chr7:27206577-27206704', 'STRUCTURAL_ABNORMALITY', 'None', (309, 331))
259047	30843252	In our study cohort, we found that the HOXA9 methylation levels in tumor tissues were significantly higher than those in paired adjacent normal tissues: median PMR with interquartile range, 0.359 (0.221, 0.556) vs 0.075 (0.043, 0.116), P = 1.06E-35 (Figure 2A).	('0.359', 'Var', (190, 195))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('HOXA9', 'Gene', '3205', (39, 44))	('higher', 'PosReg', (100, 106))	('tumor', 'Disease', (67, 72))	('0.075', 'Var', (214, 219))	('HOXA9', 'Gene', (39, 44))
259051	30843252	As shown in Table 1, HOXA9 hypermethylation in human HNSCC tissues was associated with T classification (P = 0.008), lymph metastasis (P = 0.012), and tumor stage (P = 0.004).	('hypermethylation', 'Var', (27, 43))	('lymph metastasis', 'CPA', (117, 133))	('T classification', 'CPA', (87, 103))	('HOXA9', 'Gene', '3205', (21, 26))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumor', 'Disease', (151, 156))	('HNSCC', 'Phenotype', 'HP:0012288', (53, 58))	('tumor', 'Disease', 'MESH:D009369', (151, 156))	('HOXA9', 'Gene', (21, 26))	('human', 'Species', '9606', (47, 52))	('associated', 'Reg', (71, 81))
259058	30843252	Hypermethylation, causing the transcriptional silencing of the promoters of tumor suppressor genes (TSGs), occurs in various malignancies as part of the process of carcinogenesis.34 Compared with other molecular markers, DNA hypermethylation is a common and early event during the progression of various tumors and it is chemically and biologically more stable than RNA or the majority of proteins.35 Given these advantages and the development of technology for their detection, methylation biomarkers have great potential for use in early screening and diagnosis of cancer.36 HOXA9 functions as a tumor suppressor gene that suppresses breast tumor growth and metastasis.23 Furthermore, methylation of the HOXA9 promoter is associated with progression and prognosis in numerous cancers.	('tumors', 'Disease', (304, 310))	('tumor', 'Disease', (76, 81))	('tumor', 'Phenotype', 'HP:0002664', (643, 648))	('carcinogenesis', 'Disease', (164, 178))	('cancer', 'Disease', 'MESH:D009369', (567, 573))	('tumor', 'Disease', (304, 309))	('breast tumor', 'Phenotype', 'HP:0100013', (636, 648))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('associated with', 'Reg', (724, 739))	('HOXA9', 'Gene', (706, 711))	('tumors', 'Disease', 'MESH:D009369', (304, 310))	('tumor', 'Disease', 'MESH:D009369', (304, 309))	('carcinogenesis', 'Disease', 'MESH:D063646', (164, 178))	('breast tumor', 'Disease', (636, 648))	('methylation', 'Var', (687, 698))	('cancers', 'Phenotype', 'HP:0002664', (778, 785))	('cancer', 'Disease', (778, 784))	('cancers', 'Disease', (778, 785))	('HOXA9', 'Gene', '3205', (706, 711))	('tumor', 'Disease', (598, 603))	('cancer', 'Phenotype', 'HP:0002664', (778, 784))	('tumor', 'Disease', 'MESH:D009369', (598, 603))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('HOXA9', 'Gene', (577, 582))	('tumor', 'Disease', (643, 648))	('breast tumor', 'Disease', 'MESH:D061325', (636, 648))	('tumor', 'Phenotype', 'HP:0002664', (304, 309))	('malignancies', 'Disease', 'MESH:D009369', (125, 137))	('tumors', 'Phenotype', 'HP:0002664', (304, 310))	('cancer', 'Disease', (567, 573))	('malignancies', 'Disease', (125, 137))	('tumor', 'Disease', 'MESH:D009369', (643, 648))	('HOXA9', 'Gene', '3205', (577, 582))	('cancer', 'Phenotype', 'HP:0002664', (567, 573))	('tumor', 'Phenotype', 'HP:0002664', (598, 603))	('cancer', 'Disease', 'MESH:D009369', (778, 784))	('cancers', 'Disease', 'MESH:D009369', (778, 785))
259059	30843252	28, 29  In the current study, we recruited 145 HNSCC patients to investigate the association of HOXA9 methylation with HNSCC and its potential for use in detection of HNSCC.	('association', 'Interaction', (81, 92))	('patients', 'Species', '9606', (53, 61))	('methylation', 'Var', (102, 113))	('HOXA9', 'Gene', '3205', (96, 101))	('HNSCC', 'Phenotype', 'HP:0012288', (47, 52))	('HNSCC', 'Phenotype', 'HP:0012288', (167, 172))	('HOXA9', 'Gene', (96, 101))	('HNSCC', 'Phenotype', 'HP:0012288', (119, 124))	('HNSCC', 'Disease', (119, 124))
259072	30843252	In addition, emerging evidence indicates that a panel of several methylation genes could improve cancer diagnosis,51 while our study focused on a single gene, which may not completely satisfy the requirements for clinical application.	('improve', 'PosReg', (89, 96))	('cancer', 'Disease', (97, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('methylation genes', 'Var', (65, 82))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
259074	30843252	In conclusion, HOXA9 promoter hypermethylation is associated with the risk for HNSCC and its progression and metastasis.	('HNSCC', 'Disease', (79, 84))	('HOXA9', 'Gene', (15, 20))	('metastasis', 'CPA', (109, 119))	('promoter hypermethylation', 'Var', (21, 46))	('HOXA9', 'Gene', '3205', (15, 20))	('associated', 'Reg', (50, 60))	('HNSCC', 'Phenotype', 'HP:0012288', (79, 84))	('progression', 'CPA', (93, 104))
259075	30843252	Additionally, HOXA9 hypermethylation has potential for use as a biomarker for the early diagnosis and screening of patients with HNSCC.	('patients', 'Species', '9606', (115, 123))	('hypermethylation', 'Var', (20, 36))	('HOXA9', 'Gene', '3205', (14, 19))	('HNSCC', 'Phenotype', 'HP:0012288', (129, 134))	('HOXA9', 'Gene', (14, 19))	('HNSCC', 'Disease', (129, 134))
259124	31001524	Our method (MDRANBL+DRANBD) achieved 0.862 DICE_1, 0.703 DICE_2, and the average score of 0.783.	('DICE_1', 'Gene', (43, 49))	('0.703', 'Var', (51, 56))	('0.862', 'Var', (37, 42))	('DICE_1', 'Gene', '26512', (43, 49))
259125	31001524	Using a single scale nuclei segmentation method (DRANBL+DRANBD), we obtained 0.853 DICE_1, 0.701 DICE_2, and the average score of 0.777, worse than those of the multiscale aggregation.	('DICE_1', 'Gene', '26512', (83, 89))	('DICE_1', 'Gene', (83, 89))	('0.701', 'Var', (91, 96))
259173	30519046	A study of different targetable mutations, such as KARS, EGFR, HER2, MET, PI3KA, as well as ROS1 and ALK rearrangements, represents a critical junction for the therapy of lung carcinoma, paving the way to the era of personalized medicine.	('PI3KA', 'Var', (74, 79))	('ALK', 'Gene', (101, 104))	('ROS1', 'Gene', (92, 96))	('MET', 'Var', (69, 72))	('ROS1', 'Gene', '6098', (92, 96))	('HER2', 'Gene', '2064', (63, 67))	('ALK', 'Gene', '238', (101, 104))	('lung carcinoma', 'Disease', (171, 185))	('lung carcinoma', 'Disease', 'MESH:D008175', (171, 185))	('KARS', 'Gene', '3735', (51, 55))	('EGFR', 'Gene', '1956', (57, 61))	('KARS', 'Gene', (51, 55))	('HER2', 'Gene', (63, 67))	('EGFR', 'Gene', (57, 61))	('rearrangements', 'Var', (105, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (176, 185))
259218	30519046	For instance, HOTAIR silencing through RNAi has been shown to reduce invasiveness and viability in breast, pancreatic, as well as lung cancer; it also contributed to cisplatin resistance in lung adenocarcinoma cells via the downregulation of p21 expression.	('lung cancer', 'Phenotype', 'HP:0100526', (130, 141))	('contributed', 'Reg', (151, 162))	('carcinoma', 'Phenotype', 'HP:0030731', (200, 209))	('p21', 'Gene', '1026', (242, 245))	('reduce', 'NegReg', (62, 68))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (190, 209))	('pancreatic', 'Disease', (107, 117))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (190, 209))	('RNAi', 'Gene', (39, 43))	('cisplatin', 'Chemical', 'MESH:D002945', (166, 175))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('viability', 'CPA', (86, 95))	('cisplatin resistance', 'MPA', (166, 186))	('breast', 'Disease', (99, 105))	('expression', 'MPA', (246, 256))	('silencing', 'Var', (21, 30))	('lung cancer', 'Disease', (130, 141))	('p21', 'Gene', (242, 245))	('invasiveness', 'CPA', (69, 81))	('HOTAIR', 'Gene', '100124700', (14, 20))	('lung cancer', 'Disease', 'MESH:D008175', (130, 141))	('lung adenocarcinoma', 'Disease', (190, 209))	('downregulation', 'NegReg', (224, 238))	('pancreatic', 'Disease', 'MESH:D010195', (107, 117))	('HOTAIR', 'Gene', (14, 20))
259219	30519046	In addition, MALAT1 shRNA-mediated knockdown has been shown to significantly reduce cell invasiveness and migration in NSCLC.	('cell invasiveness', 'CPA', (84, 101))	('knockdown', 'Var', (35, 44))	('NSCLC', 'Disease', 'MESH:D002289', (119, 124))	('MALAT1', 'Gene', (13, 19))	('reduce', 'NegReg', (77, 83))	('NSCLC', 'Phenotype', 'HP:0030358', (119, 124))	('MALAT1', 'Gene', '378938', (13, 19))	('NSCLC', 'Disease', (119, 124))
259225	30519046	In some cases, ASOs were shown to target lncRNA MALAT1 and the inhibition of MALAT1 weakened malignant phenotypes via cycle arrest in cervical and lung cancer cells.	('weakened', 'NegReg', (84, 92))	('MALAT1', 'Gene', (48, 54))	('malignant phenotypes', 'CPA', (93, 113))	('arrest', 'Disease', 'MESH:D006323', (124, 130))	('lung cancer', 'Disease', (147, 158))	('ASO', 'Chemical', 'MESH:D016376', (15, 18))	('lung cancer', 'Phenotype', 'HP:0100526', (147, 158))	('arrest', 'Disease', (124, 130))	('MALAT1', 'Gene', '378938', (77, 83))	('lung cancer', 'Disease', 'MESH:D008175', (147, 158))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('inhibition', 'Var', (63, 73))	('MALAT1', 'Gene', (77, 83))	('MALAT1', 'Gene', '378938', (48, 54))
259228	30519046	Thus, inhibition via MALAT1 ASOs prevented NSCLC metastasis, revealing a novel therapeutic approach for NSCLC patients' treatment.	('MALAT1', 'Gene', '378938', (21, 27))	('ASO', 'Chemical', 'MESH:D016376', (28, 31))	('MALAT1', 'Gene', (21, 27))	('NSCLC metastasis', 'Disease', (43, 59))	('NSCLC', 'Disease', (104, 109))	('NSCLC metastasis', 'Disease', 'MESH:D009362', (43, 59))	('NSCLC', 'Phenotype', 'HP:0030358', (43, 48))	('NSCLC', 'Disease', 'MESH:D002289', (104, 109))	('inhibition', 'Var', (6, 16))	('prevented', 'NegReg', (33, 42))	('NSCLC', 'Disease', (43, 48))	('patients', 'Species', '9606', (110, 118))	('NSCLC', 'Phenotype', 'HP:0030358', (104, 109))	('NSCLC', 'Disease', 'MESH:D002289', (43, 48))
259242	30519046	In a study by Schmidt et al, it was found that high expression of MALAT1 were often associated with poor prognosis in squamous cell carcinoma of the lung.	('MALAT1', 'Gene', '378938', (66, 72))	('squamous cell carcinoma of the lung', 'Disease', (118, 153))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('carcinoma of the lung', 'Phenotype', 'HP:0100526', (132, 153))	('MALAT1', 'Gene', (66, 72))	('high', 'Var', (47, 51))	('squamous cell carcinoma of the lung', 'Disease', 'MESH:D002294', (118, 153))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (118, 141))	('squamous cell carcinoma of the lung', 'Phenotype', 'HP:0030359', (118, 153))	('associated', 'Reg', (84, 94))
259258	30519046	The association between the expression of MEG3 and prognosis in NSCLC found using the Gene Expression Omnibus database showed that low expression of MEG3 experienced an unfavorable prognosis in NSCLC (Table 2).	('NSCLC', 'Phenotype', 'HP:0030358', (194, 199))	('NSCLC', 'Disease', 'MESH:D002289', (64, 69))	('MEG3', 'Gene', '55384', (42, 46))	('MEG3', 'Gene', (149, 153))	('MEG3', 'Gene', '55384', (149, 153))	('NSCLC', 'Disease', (194, 199))	('NSCLC', 'Phenotype', 'HP:0030358', (64, 69))	('NSCLC', 'Disease', 'MESH:D002289', (194, 199))	('low expression', 'Var', (131, 145))	('MEG3', 'Gene', (42, 46))	('NSCLC', 'Disease', (64, 69))
259284	33038921	Finally, the concurrent re-expression of DIRAS3 and p53 significantly decreased the tumor volume compared with the control group in a HNSCC xenograft mouse model [(3.12 +- 0.75) mm3 vs. (189.02 +- 17.54) mm3, P < 0.001].	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('DIRAS3', 'Gene', (41, 47))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('DIRAS3', 'Gene', '9077', (41, 47))	('decreased', 'NegReg', (70, 79))	('tumor', 'Disease', (84, 89))	('HNSCC', 'Phenotype', 'HP:0012288', (134, 139))	('mouse', 'Species', '10090', (150, 155))	('p53', 'Var', (52, 55))
259290	33038921	The mutation of the p53 tumor suppressor gene, which plays crucial functions in genomic stability, cell cycle regulation, stress-induced reaction and DNA repair, arises in 60-80% of patients with HNSCC.	('HNSCC', 'Disease', (196, 201))	('p53', 'Gene', (20, 23))	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('arises', 'Reg', (162, 168))	('HNSCC', 'Phenotype', 'HP:0012288', (196, 201))	('tumor', 'Disease', (24, 29))	('mutation', 'Var', (4, 12))	('patients', 'Species', '9606', (182, 190))	('tumor', 'Disease', 'MESH:D009369', (24, 29))
259291	33038921	p53-based cancer therapies, including wild-type p53 gene transfer, p53 vaccines, MDM2 antagonist, and mutant p53 re-activation, are used clinically or are currently undergoing trials.	('mutant', 'Var', (102, 108))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('MDM2', 'Gene', '4193', (81, 85))	('MDM2', 'Gene', (81, 85))	('p53', 'Gene', (109, 112))	('cancer', 'Disease', 'MESH:D009369', (10, 16))	('cancer', 'Disease', (10, 16))
259299	33038921	The re-expression of DIRAS3 led to retarded cell growth, angiogenesis, migration and invasion in breast, ovarian and liver cancer.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('DIRAS3', 'Gene', (21, 27))	('liver cancer', 'Phenotype', 'HP:0002896', (117, 129))	('DIRAS3', 'Gene', '9077', (21, 27))	('angiogenesis', 'CPA', (57, 69))	('breast', 'Disease', (97, 103))	('migration', 'CPA', (71, 80))	('ovarian and liver cancer', 'Disease', 'MESH:D017093', (105, 129))	('invasion', 'CPA', (85, 93))	('cell growth', 'CPA', (44, 55))	('re-expression', 'Var', (4, 17))	('retarded', 'NegReg', (35, 43))
259350	33038921	For adenovirus infection, the mice were intratumorally injected every 3 days with 200 mul of PBS containing Ad-DIRAS3, rAd-p53, Ad-DIRAS3 plus rAd-p53, or control adenovirus.	('adenovirus infection', 'Disease', (4, 24))	('adenovirus infection', 'Disease', 'MESH:D000257', (4, 24))	('mice', 'Species', '10090', (30, 34))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('adenovirus', 'Species', '10508', (163, 173))	('rAd-p53', 'Var', (119, 126))	('tumor', 'Disease', (45, 50))	('DIRAS3', 'Gene', '9077', (111, 117))	('DIRAS3', 'Gene', (111, 117))	('DIRAS3', 'Gene', (131, 137))	('DIRAS3', 'Gene', '9077', (131, 137))	('adenovirus', 'Species', '10508', (4, 14))	('PBS', 'Chemical', 'MESH:D007854', (93, 96))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
259357	33038921	To address the effects of DIRAS3 and p53 in HNSCC, CAL-27 and SCC-25 cells were treated with Ad-GFP, Ad-DIRAS3, or rAd-p53 alone or with a combination of Ad-DIRAS3 and rAd-p53.	('DIRAS3', 'Gene', (157, 163))	('SCC-25', 'CellLine', 'CVCL:1682', (62, 68))	('DIRAS3', 'Gene', '9077', (157, 163))	('DIRAS3', 'Gene', (104, 110))	('DIRAS3', 'Gene', '9077', (104, 110))	('CAL-27', 'CellLine', 'CVCL:1107', (51, 57))	('DIRAS3', 'Gene', (26, 32))	('HNSCC', 'Phenotype', 'HP:0012288', (44, 49))	('DIRAS3', 'Gene', '9077', (26, 32))	('Ad-GFP', 'Var', (93, 99))
259362	33038921	Significant increases in early apoptotic cells (Annexin V+/7-AAD-) were detected in Ad-DIRAS3 (12.35%), rAd-p53 (17.40%) and the combination group (25.87%) compared with the control group (1.33%) (Fig.	('Annexin V', 'Gene', '308', (48, 57))	('early apoptotic cells', 'CPA', (25, 46))	('Annexin V', 'Gene', (48, 57))	('7-AAD', 'Chemical', 'MESH:C025942', (59, 64))	('DIRAS3', 'Gene', (87, 93))	('increases', 'PosReg', (12, 21))	('DIRAS3', 'Gene', '9077', (87, 93))	('rAd-p53', 'Var', (104, 111))
259366	33038921	Conversely, only a slight increase in DIRAS3 expression was observed in response to rAd-p53 infection (Fig.	('infection', 'Disease', 'MESH:D007239', (92, 101))	('rAd-p53', 'Var', (84, 91))	('DIRAS3', 'Gene', (38, 44))	('DIRAS3', 'Gene', '9077', (38, 44))	('expression', 'MPA', (45, 55))	('infection', 'Disease', (92, 101))
259373	33038921	Western blotting analysis showed that the re-expression of DIRAS3 suppressed the phosphorylation of Akt at Ser473 but not at Thr308, while p53 inhibited Akt phosphorylation at both Thr308 and Ser473.	('Akt', 'Gene', (100, 103))	('phosphorylation', 'MPA', (81, 96))	('Akt', 'Gene', '207', (153, 156))	('p53', 'Var', (139, 142))	('Thr308', 'Chemical', '-', (181, 187))	('DIRAS3', 'Gene', (59, 65))	('Thr308', 'Chemical', '-', (125, 131))	('inhibited', 'NegReg', (143, 152))	('Akt', 'Gene', (153, 156))	('DIRAS3', 'Gene', '9077', (59, 65))	('Akt', 'Gene', '207', (100, 103))	('suppressed', 'NegReg', (66, 76))	('Ser473', 'Chemical', '-', (192, 198))	('Ser473', 'Chemical', '-', (107, 113))
259374	33038921	The concurrent re-expression of DIRAS3 and p53 nearly abolished the activity of Akt, as evidenced by the significantly decreased Akt phosphorylation at both residues (Fig.	('Akt', 'Gene', '207', (80, 83))	('decreased', 'NegReg', (119, 128))	('Akt', 'Gene', '207', (129, 132))	('p53', 'Var', (43, 46))	('Akt', 'Gene', (80, 83))	('abolished', 'NegReg', (54, 63))	('activity', 'MPA', (68, 76))	('Akt', 'Gene', (129, 132))	('DIRAS3', 'Gene', (32, 38))	('DIRAS3', 'Gene', '9077', (32, 38))
259377	33038921	The phosphorylation of 4E-BP1 at Ser65, Thr70 and Thr37/46 was significantly inhibited by DIRAS3 or p53 re-expression.	('Thr37/46', 'Var', (50, 58))	('4E-BP1', 'Gene', '1978', (23, 29))	('inhibited', 'NegReg', (77, 86))	('DIRAS3', 'Gene', (90, 96))	('phosphorylation', 'MPA', (4, 19))	('DIRAS3', 'Gene', '9077', (90, 96))	('Ser65', 'Var', (33, 38))	('Thr37', 'Chemical', '-', (50, 55))	('Ser65', 'Chemical', '-', (33, 38))	('Thr70', 'Chemical', '-', (40, 45))	('4E-BP1', 'Gene', (23, 29))	('p53 re-expression', 'Var', (100, 117))	('Thr70', 'Var', (40, 45))
259379	33038921	Moreover, increased interaction of 4E-BP1 with eIF4E was observed in the DIRAS3 or p53 group, but the maximal amount of eIF4E bound to 4E-BP1 was observed in the combination treatment group (Fig.	('4E-BP1', 'Gene', (135, 141))	('4E-BP1', 'Gene', (35, 41))	('eIF4E', 'Gene', '1977', (47, 52))	('eIF4E', 'Gene', '1977', (120, 125))	('interaction', 'Interaction', (20, 31))	('DIRAS3', 'Gene', (73, 79))	('4E-BP1', 'Gene', '1978', (135, 141))	('4E-BP1', 'Gene', '1978', (35, 41))	('eIF4E', 'Gene', (47, 52))	('eIF4E', 'Gene', (120, 125))	('DIRAS3', 'Gene', '9077', (73, 79))	('p53', 'Var', (83, 86))
259386	33038921	A significantly increased accumulation of autophagic vacuoles (AVs) was observed in cells re-expressed with DIRAS3, p53, and the combination as compared with that in the control adenovirus-treated cells, which suggested that DIRAS3 and p53 could induce autophagy in CAL-27 cells (Fig.	('accumulation', 'PosReg', (26, 38))	('CAL-27', 'CellLine', 'CVCL:1107', (266, 272))	('p53', 'Var', (236, 239))	('AVs', 'Phenotype', 'HP:0003736', (63, 66))	('DIRAS3', 'Gene', (108, 114))	('autophagic vacuoles', 'CPA', (42, 61))	('autophagic vacuoles', 'Phenotype', 'HP:0003736', (42, 61))	('DIRAS3', 'Gene', '9077', (108, 114))	('autophagy', 'CPA', (253, 262))	('adenovirus', 'Species', '10508', (178, 188))	('autophagic vacuole', 'Phenotype', 'HP:0003736', (42, 60))	('DIRAS3', 'Gene', (225, 231))	('DIRAS3', 'Gene', '9077', (225, 231))	('induce', 'PosReg', (246, 252))
259388	33038921	We found that the percentage of cells with GFP-LC3 puncta was increased after DIRAS3 or p53 re-expression.	('LC3', 'Gene', '84557', (47, 50))	('increased', 'PosReg', (62, 71))	('LC3', 'Gene', (47, 50))	('re-expression', 'Var', (92, 105))	('p53', 'Gene', (88, 91))	('DIRAS3', 'Gene', (78, 84))	('DIRAS3', 'Gene', '9077', (78, 84))
259398	33038921	A weaker inhibition of tumor growth was observed after rAd-p53 injection.	('tumor', 'Disease', (23, 28))	('rAd-p53', 'Var', (55, 62))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))
259404	33038921	Moreover, H&E staining of different organs (heart, lung, liver, kidney and spleen) showed that there were no obvious histopathological lesions in mice treated with Ad-DIRAS3, rAd-p53 or Ad-DIRAS3 plus rAd-p53 compared with those treated with control adenovirus (Fig.	('DIRAS3', 'Gene', '9077', (189, 195))	('adenovirus', 'Species', '10508', (250, 260))	('DIRAS3', 'Gene', (189, 195))	('H&E', 'Gene', '15139', (10, 13))	('mice', 'Species', '10090', (146, 150))	('with', 'Var', (159, 163))	('H&E', 'Gene', (10, 13))	('DIRAS3', 'Gene', (167, 173))	('DIRAS3', 'Gene', '9077', (167, 173))
259409	33038921	These results suggest that the concurrent targeting of DIRAS3 and p53 represents a more effective approach for the treatment of HNSCC than the targeting of a single gene.	('HNSCC', 'Disease', (128, 133))	('DIRAS3', 'Gene', (55, 61))	('HNSCC', 'Phenotype', 'HP:0012288', (128, 133))	('DIRAS3', 'Gene', '9077', (55, 61))	('targeting', 'Var', (42, 51))	('p53', 'Gene', (66, 69))
259418	33038921	Bax is directly activated by p53, allowing for further mitochondrial membrane permeabilization and apoptosis.	('Bax', 'Gene', '581', (0, 3))	('p53', 'Var', (29, 32))	('apoptosis', 'CPA', (99, 108))	('mitochondrial membrane permeabilization', 'MPA', (55, 94))	('Bax', 'Gene', (0, 3))
259422	33038921	Therefore, the combination treatment of DIRAS3 and p53 was far more effective for inhibiting HNSCC tumor growth than either single agent.	('DIRAS3', 'Gene', '9077', (40, 46))	('HNSCC', 'Phenotype', 'HP:0012288', (93, 98))	('HNSCC tumor', 'Disease', (93, 104))	('inhibiting', 'NegReg', (82, 92))	('p53', 'Var', (51, 54))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('DIRAS3', 'Gene', (40, 46))	('HNSCC tumor', 'Disease', 'MESH:D000077195', (93, 104))
259425	33038921	We showed that the concurrent re-expression of DIRAS3 and p53 significantly inhibited the phosphorylation of Akt and 4E-BP1.	('4E-BP1', 'Gene', (117, 123))	('Akt', 'Gene', '207', (109, 112))	('4E-BP1', 'Gene', '1978', (117, 123))	('phosphorylation', 'MPA', (90, 105))	('p53', 'Var', (58, 61))	('Akt', 'Gene', (109, 112))	('inhibited', 'NegReg', (76, 85))	('DIRAS3', 'Gene', (47, 53))	('DIRAS3', 'Gene', '9077', (47, 53))
259429	33038921	The genetic silencing of eIF4E, or pharmacologic inhibition using ribavirin, reduces the growth, invasion and metastasis of breast cancer.	('metastasis of breast cancer', 'Disease', (110, 137))	('eIF4E', 'Gene', (25, 30))	('ribavirin', 'Chemical', 'MESH:D012254', (66, 75))	('growth', 'CPA', (89, 95))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('breast cancer', 'Phenotype', 'HP:0003002', (124, 137))	('metastasis of breast cancer', 'Disease', 'MESH:D001943', (110, 137))	('eIF4E', 'Gene', '1977', (25, 30))	('genetic silencing', 'Var', (4, 21))	('reduces', 'NegReg', (77, 84))
259430	33038921	eIF4E silencing also increases Bax/Bcl-2 ratio and sensitizes breast cancer to cisplatin, adriamycin, paclitaxel and docetaxel.	('increases', 'PosReg', (21, 30))	('sensitizes', 'Reg', (51, 61))	('Bcl-2', 'Gene', (35, 40))	('paclitaxel', 'Chemical', 'MESH:D017239', (102, 112))	('cisplatin', 'Chemical', 'MESH:D002945', (79, 88))	('Bcl-2', 'Gene', '596', (35, 40))	('Bax', 'Gene', '581', (31, 34))	('docetaxel', 'Chemical', 'MESH:D000077143', (117, 126))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('breast cancer', 'Disease', 'MESH:D001943', (62, 75))	('eIF4E', 'Gene', '1977', (0, 5))	('breast cancer', 'Phenotype', 'HP:0003002', (62, 75))	('breast cancer', 'Disease', (62, 75))	('eIF4E', 'Gene', (0, 5))	('Bax', 'Gene', (31, 34))	('silencing', 'Var', (6, 15))	('adriamycin', 'Chemical', 'MESH:D004317', (90, 100))
259446	33038921	The re-expression of DIRAS3 was reported to induce autophagic cell death in ovarian and breast cancer cells.	('induce', 'PosReg', (44, 50))	('DIRAS3', 'Gene', (21, 27))	('DIRAS3', 'Gene', '9077', (21, 27))	('death in ovarian and breast cancer', 'Disease', 'MESH:D003643', (67, 101))	('re-expression', 'Var', (4, 17))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('breast cancer', 'Phenotype', 'HP:0003002', (88, 101))
259447	33038921	showed that p53 induces autophagy in a DRAM-dependent manner, and DRAM is essential for p53-mediated apoptosis.	('p53', 'Var', (12, 15))	('DRAM', 'Gene', '55332', (39, 43))	('DRAM', 'Gene', (66, 70))	('induces', 'Reg', (16, 23))	('DRAM', 'Gene', '55332', (66, 70))	('DRAM', 'Gene', (39, 43))	('autophagy', 'CPA', (24, 33))
259448	33038921	However, another study showed that p53 re-activation by CP-31398 and RITA induces protective autophagy.	('re-activation', 'PosReg', (39, 52))	('autophagy', 'CPA', (93, 102))	('RITA', 'Chemical', '-', (69, 73))	('CP-31398', 'Var', (56, 64))	('CP-31398', 'Chemical', 'MESH:C402665', (56, 64))	('p53', 'Protein', (35, 38))
259449	33038921	It is unclear whether the impaired autophagy induced by DIRAS3 and p53 re-expression in our study plays a pro-survival or pro-apoptotic role.	('DIRAS3', 'Gene', (56, 62))	('autophagy', 'CPA', (35, 44))	('re-expression', 'Var', (71, 84))	('p53', 'Gene', (67, 70))	('DIRAS3', 'Gene', '9077', (56, 62))
259609	26048572	To study the role of Lmo4 in embryonic lung development, lung repair and tumorigenesis, we used conditional knock-out mice to delete Lmo4 in lung epithelial cells from the first stages of lung development.	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('Lmo4', 'Gene', (133, 137))	('tumor', 'Disease', (73, 78))	('embryonic lung', 'Disease', 'MESH:D008171', (29, 43))	('embryonic lung', 'Disease', (29, 43))	('mice', 'Species', '10090', (118, 122))	('delete', 'Var', (126, 132))
259611	26048572	The role of Lmo4 in lung tumorigenesis was measured using a mouse model of lung adenocarcinoma in which the oncogenic K-Ras protein has been knocked into the K-Ras locus.	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (75, 94))	('lung tumor', 'Phenotype', 'HP:0100526', (20, 30))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('K-Ras', 'Gene', (118, 123))	('K-Ras', 'Gene', '16653', (118, 123))	('lung adenocarcinoma', 'Disease', (75, 94))	('lung tumor', 'Disease', (20, 30))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (75, 94))	('K-Ras', 'Gene', (158, 163))	('K-Ras', 'Gene', '16653', (158, 163))	('lung tumor', 'Disease', 'MESH:D008175', (20, 30))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('knocked', 'Var', (141, 148))	('mouse', 'Species', '10090', (60, 65))
259615	26048572	In the adult lung, loss of Lmo4 reduced epithelial cell proliferation and delayed repair of the lung following naphthalene or flu-mediated injury, suggesting that Lmo4 participates in the regulation of epithelial cell expansion in response to cellular damage.	('repair', 'CPA', (82, 88))	('reduced', 'NegReg', (32, 39))	('naphthalene', 'Chemical', 'MESH:C031721', (111, 122))	('loss', 'Var', (19, 23))	('Lmo4', 'Gene', (27, 31))	('rat', 'Species', '10116', (63, 66))	('epithelial cell proliferation', 'CPA', (40, 69))	('delayed', 'NegReg', (74, 81))
259623	26048572	Deregulation of LMO4 has been described in several tumor types including breast, prostate, pancreas, lung and squamous cell carcinoma of the oral cavity.	('LMO4', 'Gene', (16, 20))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (110, 133))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('Deregulation', 'Var', (0, 12))	('squamous cell carcinoma', 'Disease', (110, 133))	('pancreas', 'Disease', 'MESH:D010190', (91, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (110, 133))	('tumor', 'Disease', (51, 56))	('prostate', 'Disease', (81, 89))	('breast', 'Disease', (73, 79))	('lung', 'Disease', (101, 105))	('carcinoma of the oral cavity', 'Phenotype', 'HP:0100649', (124, 152))	('pancreas', 'Disease', (91, 99))	('described', 'Reg', (30, 39))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('squamous cell carcinoma of the oral cavity', 'Phenotype', 'HP:0030413', (110, 152))
259630	26048572	Specifically, administration of H1N1 flu virus to animals leads to broad damage of epithelial cell types in the lung including club cells, ciliated cells, as well as alveolar cells.	('H1N1', 'Species', '114727', (32, 36))	('rat', 'Species', '10116', (22, 25))	('damage', 'NegReg', (73, 79))	('H1N1', 'Var', (32, 36))	('club', 'Phenotype', 'HP:0001217', (127, 131))
259637	26048572	Naphthalene injury has also been shown to accelerate tumour growth when combined with oncogenic alterations such as expression of K-RasG12D.	('Naphthalene injury', 'Disease', (0, 18))	('tumour', 'Phenotype', 'HP:0002664', (53, 59))	('accelerate', 'PosReg', (42, 52))	('tumour', 'Disease', (53, 59))	('K-RasG12D', 'Var', (130, 139))	('Naphthalene injury', 'Disease', 'MESH:D058186', (0, 18))	('tumour', 'Disease', 'MESH:D009369', (53, 59))	('rat', 'Species', '10116', (100, 103))	('rat', 'Species', '10116', (48, 51))
259639	26048572	We used conditional knock-out mice to ablate Lmo4 expression in the lung epithelium from E9.5 and found that Shh-cre;Lmo4fl/fl mice were viable and healthy.	('mice', 'Species', '10090', (127, 131))	('mice', 'Species', '10090', (30, 34))	('Shh', 'Gene', (109, 112))	('Shh', 'Gene', '20423', (109, 112))	('Lmo4', 'Gene', (45, 49))	('ablate', 'Var', (38, 44))
259641	26048572	We then examined the role of Lmo4 in lung tumorigenesis by deleting Lmo4 in mice expressing the oncogenic K-RasG12D.	('lung tumor', 'Disease', (37, 47))	('lung tumor', 'Disease', 'MESH:D008175', (37, 47))	('Lmo4', 'Gene', (68, 72))	('mice', 'Species', '10090', (76, 80))	('deleting', 'Var', (59, 67))	('lung tumor', 'Phenotype', 'HP:0100526', (37, 47))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
259642	26048572	Our results showed that in the context of naphthalene-induced sensitization of K-RasG12D-driven carcinogenesis, loss of Lmo4 reduced cell proliferation and delayed the onset of transformation but did not affect overall survival or tumor latency.	('tumor', 'Disease', 'MESH:D009369', (231, 236))	('cell proliferation', 'CPA', (133, 151))	('naphthalene', 'Chemical', 'MESH:C031721', (42, 53))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('reduced', 'NegReg', (125, 132))	('tumor', 'Disease', (231, 236))	('Lmo4', 'Gene', (120, 124))	('loss', 'Var', (112, 116))	('delayed', 'NegReg', (156, 163))	('rat', 'Species', '10116', (145, 148))
259693	26048572	Since the cre allele was knocked into the Shh locus resulting in loss of one Shh allele, Shh-cre;Lmo4fl/+ animals were used as controls.	('loss', 'NegReg', (65, 69))	('Shh', 'Gene', '20423', (42, 45))	('Shh', 'Gene', (77, 80))	('Shh', 'Gene', '20423', (77, 80))	('Shh', 'Gene', (89, 92))	('Shh', 'Gene', '20423', (89, 92))	('knocked', 'Var', (25, 32))	('Shh', 'Gene', (42, 45))
259699	26048572	These results suggested that loss of Lmo4 does not affect CD104+ progenitor cells colony forming capacity in vitro.	('loss', 'Var', (29, 33))	('CD104', 'Gene', (58, 63))	('Lmo4', 'Gene', (37, 41))	('CD104', 'Gene', '192897', (58, 63))
259703	26048572	Interestingly, Lmo4 is expressed in these regions of active proliferation with keratin 5-positive cells expressing Lmo4 (Fig.	('Lmo4', 'Var', (115, 119))	('rat', 'Species', '10116', (67, 70))	('rat', 'Species', '10116', (81, 84))	('keratin 5', 'Gene', (79, 88))	('keratin 5', 'Gene', '110308', (79, 88))
259707	26048572	Reduced animal recovery (68 %) and lower proliferation in Lmo4-depleted animals that survive the injury, suggest that Lmo4 is required for the proliferation of lung epithelial cells for the repair of the injured lung but is not essential for progenitor cells activity after flu-mediated injury.	('Lmo4', 'Var', (118, 122))	('rat', 'Species', '10116', (48, 51))	('proliferation', 'CPA', (41, 54))	('rat', 'Species', '10116', (150, 153))
259719	26048572	These results were confirmed using Scgb1a1-creER;Lmo4fl/fl mice in which deletion of Lmo4 occurs specifically in club cells after tamoxifen administration (Additional file 2: Figure S2A).	('rat', 'Species', '10116', (148, 151))	('mice', 'Species', '10090', (59, 63))	('tamoxifen', 'Chemical', 'MESH:D013629', (130, 139))	('Scgb1a1', 'Gene', (35, 42))	('Scgb1a1', 'Gene', '22287', (35, 42))	('Lmo4', 'Gene', (85, 89))	('club', 'Phenotype', 'HP:0001217', (113, 117))	('deletion', 'Var', (73, 81))
259725	26048572	Given that Lmo4 is involved in the regulation of the proliferation of epithelial cells after naphthalene injury, we assessed whether loss of Lmo4 would affect initiation of tumor growth in naphthalene-mediated sensitization of K-RasG12D-driven tumors.	('tumor', 'Phenotype', 'HP:0002664', (244, 249))	('Lmo4', 'Gene', (141, 145))	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('naphthalene', 'Chemical', 'MESH:C031721', (189, 200))	('naphthalene injury', 'Disease', 'MESH:D058186', (93, 111))	('tumor', 'Disease', (244, 249))	('naphthalene', 'Chemical', 'MESH:C031721', (93, 104))	('rat', 'Species', '10116', (60, 63))	('affect', 'Reg', (152, 158))	('tumor', 'Disease', (173, 178))	('naphthalene injury', 'Disease', (93, 111))	('tumors', 'Disease', (244, 250))	('tumors', 'Disease', 'MESH:D009369', (244, 250))	('tumors', 'Phenotype', 'HP:0002664', (244, 250))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumor', 'Disease', 'MESH:D009369', (244, 249))	('loss', 'Var', (133, 137))
259726	26048572	We used K-RasLSL-G12D model in which cre-mediated excision of the "STOP" cassette by intranasal administration of cre-expressing adenoviruses leads to activation of the oncogenic K-RasG12D in the lung.	('G12D', 'Mutation', 'rs121913529', (184, 188))	('K-Ras', 'Gene', '16653', (8, 13))	('K-Ras', 'Gene', (8, 13))	('rat', 'Species', '10116', (104, 107))	('K-Ras', 'Gene', (179, 184))	('G12D', 'Mutation', 'rs121913529', (17, 21))	('K-Ras', 'Gene', '16653', (179, 184))	('oncogenic', 'MPA', (169, 178))	('activation', 'PosReg', (151, 161))	('excision', 'Var', (50, 58))
259727	26048572	Upon Ad5-CMV-Cre infection, these mice initially develop adenomatous hyperplasia, which progresses to adenomas and adenocarcinomas.	('mice', 'Species', '10090', (34, 38))	('adenomatous hyperplasia', 'Disease', 'MESH:D011125', (57, 80))	('develop', 'PosReg', (49, 56))	('adenomas and adenocarcinomas', 'Disease', 'MESH:D000236', (102, 130))	('infection', 'Disease', (17, 26))	('infection', 'Disease', 'MESH:D007239', (17, 26))	('Ad5-CMV-Cre', 'Var', (5, 16))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('adenomatous hyperplasia', 'Disease', (57, 80))	('carcinomas', 'Phenotype', 'HP:0030731', (120, 130))
259728	26048572	K-RasLSL-G12D/+;Lmo4fl/fl, K-RasLSL-G12D/+;Lmo4fl/+ and K-RasLSL-G12D/+;Lmo4+/+ mice were infected with Ad5-CMV-cre resulting in activation of K-RasG12D and excision of Lmo4 alleles in lung cells, followed one week later by naphthalene administration.	('G12D', 'Mutation', 'rs121913529', (65, 69))	('naphthalene', 'Chemical', 'MESH:C031721', (224, 235))	('G12D', 'Mutation', 'rs121913529', (148, 152))	('excision', 'Var', (157, 165))	('Lmo4', 'Gene', (169, 173))	('G12D', 'Mutation', 'rs121913529', (36, 40))	('G12D', 'Mutation', 'rs121913529', (9, 13))	('K-Ras', 'Gene', (0, 5))	('activation', 'PosReg', (129, 139))	('K-Ras', 'Gene', (143, 148))	('K-Ras', 'Gene', (27, 32))	('K-Ras', 'Gene', '16653', (0, 5))	('mice', 'Species', '10090', (80, 84))	('K-Ras', 'Gene', '16653', (143, 148))	('K-Ras', 'Gene', '16653', (27, 32))	('rat', 'Species', '10116', (244, 247))	('K-Ras', 'Gene', '16653', (56, 61))	('K-Ras', 'Gene', (56, 61))
259734	26048572	These results indicate that loss of Lmo4 delays initiation of hyperplasia after naphthalene injury but this effect is rapidly overcome by signaling pathways activated by K-RasG12D.	('delays initiation of hyperplasia', 'Disease', 'MESH:D006965', (41, 73))	('loss', 'Var', (28, 32))	('naphthalene injury', 'Disease', 'MESH:D058186', (80, 98))	('Lmo4', 'Gene', (36, 40))	('naphthalene injury', 'Disease', (80, 98))	('delays initiation of hyperplasia', 'Disease', (41, 73))
259736	26048572	K-RasLSL-G12D/+, K-RasLSL-G12D/+;Lmo4fl/+ and K-RasLSL-G12D/+;Lmo4fl/fl mice were infected intra-nasally with Ad5-CMV-cre resulting in activation of K-RasG12D expression and excision of Lmo4 alleles in lung cells.	('K-Ras', 'Gene', (46, 51))	('activation', 'PosReg', (135, 145))	('K-Ras', 'Gene', '16653', (46, 51))	('K-Ras', 'Gene', '16653', (149, 154))	('excision', 'MPA', (174, 182))	('Lmo4', 'Gene', (186, 190))	('Lmo4fl/fl', 'Var', (62, 71))	('G12D', 'Mutation', 'rs121913529', (9, 13))	('K-Ras', 'Gene', (0, 5))	('expression', 'MPA', (159, 169))	('K-Ras', 'Gene', '16653', (0, 5))	('K-Ras', 'Gene', (17, 22))	('mice', 'Species', '10090', (72, 76))	('G12D', 'Mutation', 'rs121913529', (26, 30))	('G12D', 'Mutation', 'rs121913529', (154, 158))	('K-Ras', 'Gene', '16653', (17, 22))	('G12D', 'Mutation', 'rs121913529', (55, 59))	('K-Ras', 'Gene', (149, 154))
259738	26048572	Histological examination and analysis of lung weight upon collection at ethical endpoint showed no significant difference in tumor burden in Lmo4-depleted lungs compared to control mice (Fig.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('mice', 'Species', '10090', (181, 185))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumor', 'Disease', (125, 130))	('Lmo4-depleted', 'Var', (141, 154))
259742	26048572	To evaluate whether loss of Lmo4 could affect tumour initiation, we collected mice of each genotype 12 weeks after Ad5-CMV-cre administration.	('loss', 'Var', (20, 24))	('rat', 'Species', '10116', (135, 138))	('tumour initiation', 'Disease', 'MESH:D009369', (46, 63))	('affect', 'Reg', (39, 45))	('tumour initiation', 'Disease', (46, 63))	('tumour', 'Phenotype', 'HP:0002664', (46, 52))	('mice', 'Species', '10090', (78, 82))	('Lmo4', 'Gene', (28, 32))
259762	26048572	Lmo4 has been implicated in the proliferation of progenitor cells in normal neural crest development where knockdown of Lmo4 leads to loss of neural crest precursor formation at the neural plate border prompting us to evaluate the role of Lmo4 in lung progenitor cell activity.	('knockdown', 'Var', (107, 116))	('loss', 'NegReg', (134, 138))	('Lmo4', 'Gene', (120, 124))	('rat', 'Species', '10116', (39, 42))
259764	26048572	Following naphthalene administration, a rare population of variant club cells that do not express Cyp2f2 is maintained and responsible for the repopulation of the cells lining the airways.	('naphthalene', 'Chemical', 'MESH:C031721', (10, 21))	('rat', 'Species', '10116', (30, 33))	('variant', 'Var', (59, 66))	('club', 'Phenotype', 'HP:0001217', (67, 71))	('Cyp2f2', 'Gene', '13107', (98, 104))	('Cyp2f2', 'Gene', (98, 104))
259768	26048572	Knock-down of Lmo4 has been shown to potentiate TGFbeta signaling in HEK293 cells.	('Knock-down', 'Var', (0, 10))	('TGFbeta signaling', 'MPA', (48, 65))	('HEK293', 'CellLine', 'CVCL:0045', (69, 75))	('potentiate', 'PosReg', (37, 47))	('Lmo4', 'Gene', (14, 18))
259769	26048572	We previously showed that TGFbeta inhibited lung epithelial cell colony formation capacity in vitro while SB431542, an inhibitor of TGFbeta signaling, increased colony forming capacity in vitro.	('increased', 'PosReg', (151, 160))	('TGFbeta', 'Gene', (26, 33))	('lung epithelial cell colony formation capacity', 'CPA', (44, 90))	('colony forming capacity', 'CPA', (161, 184))	('inhibited', 'NegReg', (34, 43))	('SB431542', 'Chemical', 'MESH:C459179', (106, 114))	('SB431542', 'Var', (106, 114))
259770	26048572	Loss of Lmo4 in Shh-cre;Lmo4fl/fl mice may therefore increase TGFbeta signaling resulting in reduced epithelial cell proliferation.	('rat', 'Species', '10116', (124, 127))	('Shh', 'Gene', (16, 19))	('mice', 'Species', '10090', (34, 38))	('Lmo4', 'Gene', (8, 12))	('TGFbeta signaling', 'MPA', (62, 79))	('reduced', 'NegReg', (93, 100))	('Shh', 'Gene', '20423', (16, 19))	('increase', 'PosReg', (53, 61))	('epithelial cell proliferation', 'CPA', (101, 130))	('increase TGFbeta', 'Phenotype', 'HP:0030269', (53, 69))	('Loss', 'Var', (0, 4))
259772	26048572	Stabilisation of beta-catenin has also been shown to accelerate repair and increase CC10 expression three days following naphthalene injury.	('naphthalene injury', 'Disease', 'MESH:D058186', (121, 139))	('CC10', 'Gene', '22287', (84, 88))	('naphthalene injury', 'Disease', (121, 139))	('CC10', 'Gene', (84, 88))	('beta-catenin', 'Gene', '12387', (17, 29))	('Stabilisation', 'Var', (0, 13))	('repair', 'MPA', (64, 70))	('increase', 'PosReg', (75, 83))	('rat', 'Species', '10116', (59, 62))	('accelerate', 'PosReg', (53, 63))	('beta-catenin', 'Gene', (17, 29))
259779	26048572	Interestingly, Lmo4 deletion reduced cell proliferation after naphthalene injury in K-RasLSL-G12D/+ mice, suggesting that upon K-RasG12D expression, Lmo4 is required for optimal proliferation of CC10-positive cells resistant to naphthalene injury.	('mice', 'Species', '10090', (100, 104))	('Lmo4', 'Gene', (15, 19))	('naphthalene injury', 'Disease', (62, 80))	('K-Ras', 'Gene', (127, 132))	('naphthalene injury', 'Disease', (228, 246))	('deletion', 'Var', (20, 28))	('CC10', 'Gene', (195, 199))	('K-Ras', 'Gene', '16653', (127, 132))	('cell proliferation', 'CPA', (37, 55))	('naphthalene injury', 'Disease', 'MESH:D058186', (62, 80))	('G12D', 'Mutation', 'rs121913529', (93, 97))	('K-Ras', 'Gene', (84, 89))	('G12D', 'Mutation', 'rs121913529', (132, 136))	('naphthalene injury', 'Disease', 'MESH:D058186', (228, 246))	('K-Ras', 'Gene', '16653', (84, 89))	('CC10', 'Gene', '22287', (195, 199))	('reduced', 'NegReg', (29, 36))	('rat', 'Species', '10116', (185, 188))	('rat', 'Species', '10116', (49, 52))
259781	26048572	Using CMV-cre adenoviruses to activate K-RasG12D expression and deplete Lmo4 expression, we targeted all cell types in the lung, including alveolar type II cells that are the predominant cell of origin in K-RasG12D-induced adenocarcinoma but do not express Lmo4.	('activate', 'PosReg', (30, 38))	('deplete', 'MPA', (64, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (228, 237))	('K-RasG12D-induced', 'Var', (205, 222))	('adenocarcinoma', 'Disease', (223, 237))	('adenocarcinoma', 'Disease', 'MESH:D000230', (223, 237))	('K-RasG12D', 'Gene', (39, 48))
259783	26048572	Deletion of Lmo4 and activation of K-RasG12D exclusively in CC10-positive cell would enable to resolve this hypothesis.	('CC10', 'Gene', '22287', (60, 64))	('K-RasG12D', 'Protein', (35, 44))	('Lmo4', 'Gene', (12, 16))	('CC10', 'Gene', (60, 64))	('activation', 'PosReg', (21, 31))	('Deletion', 'Var', (0, 8))
259788	26048572	High LMO4 expression is associated with worse outcome in breast cancer while in pancreatic adenocarcinoma, low LMO4 expression is associated with poor outcome.	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('breast cancer', 'Disease', (57, 70))	('breast cancer', 'Phenotype', 'HP:0003002', (57, 70))	('High', 'Var', (0, 4))	('expression', 'MPA', (10, 20))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D010190', (80, 105))	('pancreatic adenocarcinoma', 'Disease', (80, 105))	('LMO4', 'Gene', (5, 9))	('breast cancer', 'Disease', 'MESH:D001943', (57, 70))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (80, 105))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
259794	26048572	Our results show that loss of Lmo4 delays repair in acute models of lung damage such as naphthalene and H1N1 injury.	('lung damage', 'Disease', (68, 79))	('delays', 'NegReg', (35, 41))	('lung damage', 'Disease', 'MESH:D008171', (68, 79))	('H1N1', 'Species', '114727', (104, 108))	('naphthalene', 'Chemical', 'MESH:C031721', (88, 99))	('Lmo4', 'Gene', (30, 34))	('loss', 'Var', (22, 26))	('repair', 'MPA', (42, 48))
259813	25588631	The squamous cells showed unequivocal pleomorphism and extensive keratinization, resulting in a diagnosis of squamous cell carcinoma with cystic degeneration (Fig.	('cystic degeneration', 'Disease', 'MESH:C538364', (138, 157))	('cystic degeneration', 'Phenotype', 'HP:0007667', (138, 157))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (109, 132))	('cystic degeneration', 'Disease', (138, 157))	('pleomorphism', 'Var', (38, 50))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('squamous cell carcinoma', 'Disease', (109, 132))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (109, 132))
259849	30853705	CS is known to cause oxidative DNA damage and mutation of tumor-related genes, and these factors are involved in carcinogenesis.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('carcinogenesis', 'Disease', 'MESH:D063646', (113, 127))	('carcinogenesis', 'Disease', (113, 127))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('involved', 'Reg', (101, 109))	('mutation', 'Var', (46, 54))	('cause', 'Reg', (15, 20))	('oxidative DNA damage', 'MPA', (21, 41))
259851	30853705	Increased levels of 8-OHdG are associated with a number of pathological conditions, including cancer.	('8-OHdG', 'Chemical', 'MESH:C067134', (20, 26))	('associated', 'Reg', (31, 41))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('8-OHdG', 'Var', (20, 26))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
259856	30853705	The aberrant expression of p53 significantly correlated with smoking, male, squamous cell carcinoma, and Ki-67 positivity (p < .05).	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (76, 99))	('p53', 'Gene', '7157', (27, 30))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('squamous cell carcinoma', 'Disease', (76, 99))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (76, 99))	('aberrant expression', 'Var', (4, 23))	('male', 'Disease', (70, 74))	('correlated', 'Reg', (45, 55))	('p53', 'Gene', (27, 30))
259862	30853705	Smoking is known as a major inducer of oxidative stress, which in turn is known to cause DNA damage and mutation of tumor-related genes, and these factors are involved in carcinogenesis.	('carcinogenesis', 'Disease', 'MESH:D063646', (171, 185))	('oxidative stress', 'Phenotype', 'HP:0025464', (39, 55))	('carcinogenesis', 'Disease', (171, 185))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('involved', 'Reg', (159, 167))	('DNA damage', 'MPA', (89, 99))	('cause', 'Reg', (83, 88))	('mutation', 'Var', (104, 112))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumor', 'Disease', (116, 121))
259864	30853705	Increased levels of 8-OHdG are associated with the aging process as well as a number of pathological conditions, including cancer, diabetes, and hypertension.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('hypertension', 'Disease', (145, 157))	('hypertension', 'Phenotype', 'HP:0000822', (145, 157))	('diabetes', 'Disease', (131, 139))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('associated', 'Reg', (31, 41))	('8-OHdG', 'Chemical', 'MESH:C067134', (20, 26))	('hypertension', 'Disease', 'MESH:D006973', (145, 157))	('cancer', 'Disease', (123, 129))	('8-OHdG', 'Var', (20, 26))	('diabetes', 'Disease', 'MESH:D003920', (131, 139))
259867	30853705	Negative 8-OHdG expression was associated with an aggressive cancer phenotype.	('8-OHdG', 'Chemical', 'MESH:C067134', (9, 15))	('aggressive cancer', 'Disease', 'MESH:D009369', (50, 67))	('Negative 8-OHdG expression', 'Var', (0, 26))	('associated', 'Reg', (31, 41))	('aggressive cancer', 'Disease', (50, 67))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))
259871	30853705	TP53 mutations are one of the most common mutations found in lung cancers and occur more frequently in smoking-related lung cancer.	('TP53', 'Gene', '7157', (0, 4))	('lung cancer', 'Phenotype', 'HP:0100526', (61, 72))	('TP53', 'Gene', (0, 4))	('lung cancer', 'Disease', (119, 130))	('lung cancer', 'Phenotype', 'HP:0100526', (119, 130))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('lung cancers', 'Disease', 'MESH:D008175', (61, 73))	('lung cancers', 'Phenotype', 'HP:0100526', (61, 73))	('mutations', 'Var', (5, 14))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('lung cancer', 'Disease', 'MESH:D008175', (61, 72))	('cancers', 'Phenotype', 'HP:0002664', (66, 73))	('lung cancer', 'Disease', 'MESH:D008175', (119, 130))	('lung cancers', 'Disease', (61, 73))
259872	30853705	It is known that the common types of cancer-associated TP53 mutations not only lose tumor suppression function but acquire a function related to tumor progression, such as cell-cycle progression or cell migration.	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('TP53', 'Gene', '7157', (55, 59))	('cancer', 'Disease', (37, 43))	('TP53', 'Gene', (55, 59))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumor', 'Disease', (84, 89))	('tumor', 'Disease', (145, 150))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('cell-cycle progression', 'CPA', (172, 194))	('cell migration', 'CPA', (198, 212))	('mutations', 'Var', (60, 69))	('lose', 'NegReg', (79, 83))	('acquire', 'Reg', (115, 122))
259874	30853705	Oxidative stress is known to play an important role in p53 mutations caused by smoking.	('p53', 'Gene', '7157', (55, 58))	('caused', 'Reg', (69, 75))	('p53', 'Gene', (55, 58))	('Oxidative stress', 'Phenotype', 'HP:0025464', (0, 16))	('mutations', 'Var', (59, 68))
259875	30853705	It is known that impaired capability of mutant p53 to promote DNA repair leads to cancer development.	('promote', 'PosReg', (54, 61))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('cancer', 'Disease', (82, 88))	('leads to', 'Reg', (73, 81))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('DNA repair', 'MPA', (62, 72))	('mutant', 'Var', (40, 46))	('p53', 'Gene', (47, 50))	('p53', 'Gene', '7157', (47, 50))
259883	30853705	The primary antibodies for 8-OHdG (1:200, N45.1, JaiCA, Shizuoka, Japan), p53 (1:800, DO-7, Leica, London, UK), and Ki-67 (1:100, MIB-1, Dako, Glustrup, Denmark) were used for immunohistochemical staining.	('MIB-1', 'Gene', (130, 135))	('1:800', 'Var', (79, 84))	('MIB-1', 'Gene', '57534', (130, 135))	('p53', 'Gene', (74, 77))	('p53', 'Gene', '7157', (74, 77))	('8-OHdG', 'Chemical', 'MESH:C067134', (27, 33))
259889	30853705	Complete negative and high expression showed strong correlation with TP53 mutation.	('mutation', 'Var', (74, 82))	('TP53', 'Gene', '7157', (69, 73))	('TP53', 'Gene', (69, 73))	('high expression', 'MPA', (22, 37))	('negative', 'NegReg', (9, 17))
259899	30853705	Expression of 8-OHdG was found exclusively in nuclei of tumor cells and was positive in 83.3% (169/203) of NSCLC samples (Table 1, Fig.	('8-OHdG', 'Var', (14, 20))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('NSCLC', 'Disease', (107, 112))	('NSCLC', 'Disease', 'MESH:D002289', (107, 112))	('tumor', 'Disease', (56, 61))	('NSCLC', 'Phenotype', 'HP:0030358', (107, 112))	('8-OHdG', 'Chemical', 'MESH:C067134', (14, 20))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
259900	30853705	The positive expression of 8-OHdG was significantly associated with female, adenocarcinoma, smaller tumor size, lower T group, negative lymph node status, and never-smoker (p < .05) (Table 1).	('8-OHdG', 'Var', (27, 33))	('adenocarcinoma', 'Disease', 'MESH:D000230', (76, 90))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Disease', (100, 105))	('female', 'Disease', (68, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('adenocarcinoma', 'Disease', (76, 90))	('8-OHdG', 'Chemical', 'MESH:C067134', (27, 33))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('lower', 'NegReg', (112, 117))
259901	30853705	The expression of 8-OHdG was high in never-smoker (89.5%) compared to smoker (73.4%) (p = .003).	('expression', 'MPA', (4, 14))	('8-OHdG', 'Chemical', 'MESH:C067134', (18, 24))	('8-OHdG', 'Var', (18, 24))
259903	30853705	Analysis was performed on the correlations between p53 staining pattern and clinicopathological features of NSCLC patients, and p53 aberrant expression was significantly correlated with male, smoker, squamous cell carcinoma, and Ki-67 positivity (p < .05) (Table 2).	('NSCLC', 'Phenotype', 'HP:0030358', (108, 113))	('p53', 'Gene', (51, 54))	('p53', 'Gene', '7157', (51, 54))	('p53', 'Gene', (128, 131))	('p53', 'Gene', '7157', (128, 131))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (200, 223))	('carcinoma', 'Phenotype', 'HP:0030731', (214, 223))	('squamous cell carcinoma', 'Disease', (200, 223))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (200, 223))	('NSCLC', 'Disease', (108, 113))	('correlated', 'Reg', (170, 180))	('NSCLC', 'Disease', 'MESH:D002289', (108, 113))	('aberrant expression', 'Var', (132, 151))	('patients', 'Species', '9606', (114, 122))
259904	30853705	The p53 wild-type expression was high in never-smoker (39.5%) compared to smoker (13.9%), and p53 aberrant expression was 86.1% (68/79) in smoker and 60.5% (75/124) in never-smoker (p < .001).	('p53', 'Gene', '7157', (4, 7))	('p53', 'Gene', '7157', (94, 97))	('p53', 'Gene', (94, 97))	('aberrant expression', 'Var', (98, 117))	('p53', 'Gene', (4, 7))
259905	30853705	The p53 aberrant expression rate was 87.2% in squamous cell carcinoma and 56% in lung adenocarcinoma.	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (81, 100))	('p53', 'Gene', '7157', (4, 7))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (46, 69))	('lung adenocarcinoma', 'Disease', (81, 100))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (81, 100))	('squamous cell carcinoma', 'Disease', (46, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (60, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (46, 69))	('aberrant expression', 'Var', (8, 27))	('p53', 'Gene', (4, 7))
259907	30853705	Comparing the p53 wild-type and the p53 aberrant patients, there was no significant difference in tumor stage or lymph node stage.	('p53', 'Gene', (14, 17))	('p53', 'Gene', '7157', (14, 17))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('p53', 'Gene', (36, 39))	('p53', 'Gene', '7157', (36, 39))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('lymph node stage', 'CPA', (113, 129))	('patients', 'Species', '9606', (49, 57))	('tumor', 'Disease', (98, 103))	('aberrant', 'Var', (40, 48))
259908	30853705	When univariate Cox proportional regression analysis was performed for the survival of NSCLC patients, older age (>= 65), male, smoker, higher tumor stage, presence of lymph node metastasis, 8-OHdG negativity and p53 aberrant expression, and Ki-67 positivity showed significant association with shorter OS of NSCLC patients by univariate analysis (Table 3).	('NSCLC', 'Disease', (309, 314))	('NSCLC', 'Disease', (87, 92))	('NSCLC', 'Phenotype', 'HP:0030358', (309, 314))	('p53', 'Gene', '7157', (213, 216))	('NSCLC', 'Phenotype', 'HP:0030358', (87, 92))	('patients', 'Species', '9606', (93, 101))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('patients', 'Species', '9606', (315, 323))	('p53', 'Gene', (213, 216))	('presence', 'Var', (156, 164))	('Cox', 'Gene', '1351', (16, 19))	('8-OHdG', 'Chemical', 'MESH:C067134', (191, 197))	('tumor', 'Disease', (143, 148))	('NSCLC', 'Disease', 'MESH:D002289', (309, 314))	('NSCLC', 'Disease', 'MESH:D002289', (87, 92))	('positivity', 'Var', (248, 258))	('Ki-67', 'Gene', (242, 247))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('Cox', 'Gene', (16, 19))
259909	30853705	The patients with 8-OHdG negativity showed 1.847-fold (95% confidence interval [95% CI], 1.054 to 3.236; p = .032) greater risk of death.	('8-OHdG negativity', 'Var', (18, 35))	('patients', 'Species', '9606', (4, 12))	('death', 'Disease', 'MESH:D003643', (131, 136))	('death', 'Disease', (131, 136))	('8-OHdG', 'Chemical', 'MESH:C067134', (18, 24))
259917	30853705	Our results show that (1) expression of 8-OHdG was observed in 83.3% of NSCLC tissue; (2) expression of 8-OHdG was significantly associated with low T category, negative lymph node status, and never-smoker; (3) expression of 8-OHdG was significantly associated with longer OS by univariate and Kaplan-Meier survival analysis; (4) p53 aberrant expression closely correlated with smoker, male, squamous cell carcinoma, and Ki-67 positivity.	('p53', 'Gene', (330, 333))	('p53', 'Gene', '7157', (330, 333))	('8-OHdG', 'Chemical', 'MESH:C067134', (225, 231))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (392, 415))	('smoker', 'Disease', (378, 384))	('NSCLC', 'Disease', (72, 77))	('correlated', 'Reg', (362, 372))	('8-OHdG', 'Chemical', 'MESH:C067134', (40, 46))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (392, 415))	('carcinoma', 'Phenotype', 'HP:0030731', (406, 415))	('NSCLC', 'Disease', 'MESH:D002289', (72, 77))	('squamous cell carcinoma', 'Disease', (392, 415))	('aberrant expression', 'Var', (334, 353))	('male', 'Disease', (386, 390))	('NSCLC', 'Phenotype', 'HP:0030358', (72, 77))	('8-OHdG', 'Chemical', 'MESH:C067134', (104, 110))
259922	30853705	Increased levels of 8-OHdG are associated with the aging process as well as with a number of pathological conditions including cancer, diabetes, and hypertension.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('hypertension', 'Disease', (149, 161))	('hypertension', 'Phenotype', 'HP:0000822', (149, 161))	('8-OHdG', 'Chemical', 'MESH:C067134', (20, 26))	('associated', 'Reg', (31, 41))	('diabetes', 'Disease', (135, 143))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('diabetes', 'Disease', 'MESH:D003920', (135, 143))	('8-OHdG', 'Var', (20, 26))	('cancer', 'Disease', (127, 133))	('hypertension', 'Disease', 'MESH:D006973', (149, 161))
259923	30853705	The overexpression of 8-OHdG has been reported in a variety of cancers, including breast cancer, lung cancer, bladder cancer, colorectal cancer, renal cell carcinoma, prostate cancer, and gastric adenocarcinoma.	('8-OHdG', 'Chemical', 'MESH:C067134', (22, 28))	('gastric adenocarcinoma', 'Disease', (188, 210))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (145, 165))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('lung cancer', 'Disease', 'MESH:D008175', (97, 108))	('colorectal cancer', 'Disease', 'MESH:D015179', (126, 143))	('overexpression', 'PosReg', (4, 18))	('cancers', 'Phenotype', 'HP:0002664', (63, 70))	('lung cancer', 'Phenotype', 'HP:0100526', (97, 108))	('prostate cancer', 'Disease', 'MESH:D011471', (167, 182))	('cancers', 'Disease', (63, 70))	('bladder cancer', 'Disease', 'MESH:D001749', (110, 124))	('bladder cancer', 'Disease', (110, 124))	('prostate cancer', 'Phenotype', 'HP:0012125', (167, 182))	('breast cancer', 'Phenotype', 'HP:0003002', (82, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (156, 165))	('renal cell carcinoma', 'Disease', (145, 165))	('colorectal cancer', 'Disease', (126, 143))	('gastric adenocarcinoma', 'Disease', 'MESH:D013274', (188, 210))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (145, 165))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('prostate cancer', 'Disease', (167, 182))	('bladder cancer', 'Phenotype', 'HP:0009725', (110, 124))	('breast cancer', 'Disease', 'MESH:D001943', (82, 95))	('breast cancer', 'Disease', (82, 95))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('carcinoma', 'Phenotype', 'HP:0030731', (201, 210))	('reported', 'Reg', (38, 46))	('8-OHdG', 'Var', (22, 28))	('lung cancer', 'Disease', (97, 108))	('colorectal cancer', 'Phenotype', 'HP:0003003', (126, 143))	('cancers', 'Disease', 'MESH:D009369', (63, 70))
259924	30853705	Reports have predominantly indicated that overexpression of 8-OHdG is associated with unfavorable prognostic factors and/or poor patient prognosis.	('8-OHdG', 'Var', (60, 66))	('8-OHdG', 'Chemical', 'MESH:C067134', (60, 66))	('overexpression', 'PosReg', (42, 56))	('patient', 'Species', '9606', (129, 136))
259931	30853705	We detected 8-OHdG expression using immunohistochemistry because immunohistochemical procedures allow detection of 8-OHdG at the single-cell level, which has the advantage of directly confirming its expression in cancer cells in tissues composed of different cell populations.	('8-OHdG', 'Chemical', 'MESH:C067134', (12, 18))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('8-OHdG', 'Var', (115, 121))	('cancer', 'Disease', 'MESH:D009369', (213, 219))	('cancer', 'Disease', (213, 219))	('8-OHdG', 'Chemical', 'MESH:C067134', (115, 121))
259935	30853705	Overproduction of antioxidant enzymes would prevent ROS interaction with DNA, leading to decreased formation of 8-OHdG at the tissue level, as suggested by their results.	('8-OHdG', 'Chemical', 'MESH:C067134', (112, 118))	('interaction', 'Interaction', (56, 67))	('ROS', 'Chemical', 'MESH:D017382', (52, 55))	('Overproduction', 'Var', (0, 14))	('formation of 8-OHdG at the', 'MPA', (99, 125))	('decreased', 'NegReg', (89, 98))
259938	30853705	Although there was no statistical significance, the association between positive 8-OHdG and negative Ki-67 (p = .084) in this study may support this hypothesis.	('Ki-67', 'Gene', (101, 106))	('negative', 'NegReg', (92, 100))	('8-OHdG', 'Chemical', 'MESH:C067134', (81, 87))	('positive 8-OHdG', 'Var', (72, 87))
259940	30853705	The expression of 8-OHdG decreased significantly in invasive breast carcinomas compared to non-invasive lesions, namely usual ductal hyperplasia, atypical ductal hyperplasia, and ductal carcinoma in situ.	('breast carcinomas', 'Disease', 'MESH:D001943', (61, 78))	('breast carcinomas', 'Disease', (61, 78))	('8-OHdG', 'Var', (18, 24))	('ductal hyperplasia', 'Disease', 'MESH:D002285', (155, 173))	('ductal carcinoma', 'Disease', 'MESH:D044584', (179, 195))	('ductal hyperplasia', 'Disease', (155, 173))	('ductal carcinoma', 'Disease', (179, 195))	('carcinoma', 'Phenotype', 'HP:0030731', (186, 195))	('decreased', 'NegReg', (25, 34))	('expression', 'MPA', (4, 14))	('breast carcinomas', 'Phenotype', 'HP:0003002', (61, 78))	('usual', 'Disease', (120, 125))	('carcinoma', 'Phenotype', 'HP:0030731', (68, 77))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (179, 203))	('ductal hyperplasia', 'Disease', 'MESH:D002285', (126, 144))	('ductal hyperplasia', 'Disease', (126, 144))	('carcinomas', 'Phenotype', 'HP:0030731', (68, 78))	('8-OHdG', 'Chemical', 'MESH:C067134', (18, 24))
259942	30853705	In this study, expression of 8-OHdG was significantly associated with never-smoker (p = .003).	('8-OHdG', 'Var', (29, 35))	('8-OHdG', 'Chemical', 'MESH:C067134', (29, 35))	('associated', 'Reg', (54, 64))	('never-smoker', 'Disease', (70, 82))
259949	30853705	TP53 mutation is an important mutation associated with CS exposure, and loss of wild-type p53 function and increased mutant p53 function due to TP53 mutation are important in NSCLC carcinogenesis.	('TP53', 'Gene', '7157', (144, 148))	('TP53', 'Gene', (144, 148))	('p53', 'Gene', (124, 127))	('TP53', 'Gene', (0, 4))	('loss', 'NegReg', (72, 76))	('p53', 'Gene', (90, 93))	('NSCLC carcinogenesis', 'Disease', 'MESH:D063646', (175, 195))	('TP53', 'Gene', '7157', (0, 4))	('increased', 'PosReg', (107, 116))	('mutant', 'Var', (117, 123))	('p53', 'Gene', '7157', (90, 93))	('p53', 'Gene', '7157', (124, 127))	('NSCLC', 'Phenotype', 'HP:0030358', (175, 180))	('function', 'MPA', (128, 136))	('function', 'MPA', (94, 102))	('NSCLC carcinogenesis', 'Disease', (175, 195))	('mutation', 'Var', (149, 157))
259951	30853705	The p53 aberrant expression rate was 87.2% in squamous cell carcinoma and 56% in lung adenocarcinoma (data not shown).	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (81, 100))	('p53', 'Gene', '7157', (4, 7))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (46, 69))	('lung adenocarcinoma', 'Disease', (81, 100))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (81, 100))	('squamous cell carcinoma', 'Disease', (46, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (60, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (46, 69))	('aberrant expression', 'Var', (8, 27))	('p53', 'Gene', (4, 7))
259952	30853705	Our results are consistent with another report that found p53 mutations in 46% of lung adenocarcinomas and 81% of squamous cell carcinomas.	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (82, 102))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (114, 137))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (82, 101))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (114, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('carcinomas', 'Phenotype', 'HP:0030731', (128, 138))	('lung adenocarcinomas', 'Disease', (82, 102))	('carcinomas', 'Phenotype', 'HP:0030731', (92, 102))	('squamous cell carcinomas', 'Disease', (114, 138))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (114, 138))	('p53', 'Gene', (58, 61))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (82, 102))	('mutations', 'Var', (62, 71))	('p53', 'Gene', '7157', (58, 61))
259953	30853705	The p53 aberrant expression is closely correlated with smoker (p = .000), male (p = .000), squamous cell carcinoma (p = .000), and Ki-67 positivity (p = .003).	('p53', 'Gene', '7157', (4, 7))	('correlated', 'Reg', (39, 49))	('Ki-67', 'Var', (131, 136))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (91, 114))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (91, 114))	('smoker', 'Disease', (55, 61))	('squamous cell carcinoma', 'Disease', (91, 114))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('aberrant expression', 'Var', (8, 27))	('p53', 'Gene', (4, 7))
259954	30853705	Further studies are needed to determine the concordance of p53 immunohistochemistry with TP53 mutations in NSCLC to confirm our assertion.	('p53', 'Gene', (59, 62))	('TP53', 'Gene', '7157', (89, 93))	('p53', 'Gene', '7157', (59, 62))	('TP53', 'Gene', (89, 93))	('NSCLC', 'Disease', (107, 112))	('mutations', 'Var', (94, 103))	('NSCLC', 'Disease', 'MESH:D002289', (107, 112))	('NSCLC', 'Phenotype', 'HP:0030358', (107, 112))
259955	30853705	In conclusion, this study has demonstrated the expression of 8-OHdG and p53 in NSCLC and its relationship with clinicopathologic factors and patient survival.	('NSCLC', 'Disease', 'MESH:D002289', (79, 84))	('8-OHdG', 'Chemical', 'MESH:C067134', (61, 67))	('p53', 'Gene', (72, 75))	('p53', 'Gene', '7157', (72, 75))	('patient', 'Species', '9606', (141, 148))	('NSCLC', 'Phenotype', 'HP:0030358', (79, 84))	('8-OHdG', 'Var', (61, 67))	('relationship', 'Reg', (93, 105))	('NSCLC', 'Disease', (79, 84))
259956	30853705	Univariate analysis revealed that expression of 8-OHdG was significantly associated with longer OS.	('expression', 'Var', (34, 44))	('associated', 'Reg', (73, 83))	('8-OHdG', 'Chemical', 'MESH:C067134', (48, 54))	('longer OS', 'Disease', (89, 98))	('8-OHdG', 'Var', (48, 54))
259958	30853705	The aberrant expression patterns of p53 immunohistochemical staining showed significant associations with smoking status.	('aberrant', 'Var', (4, 12))	('p53', 'Gene', (36, 39))	('p53', 'Gene', '7157', (36, 39))	('smoking status', 'Disease', (106, 120))	('associations', 'Interaction', (88, 100))
259961	29056726	The average age of cats with FOSCC with high p16 immunoreactivity was significantly lower than the average age in the low p16 group.	('cats', 'Species', '9685', (19, 23))	('high p16', 'Var', (40, 48))	('lower', 'NegReg', (84, 89))
259963	29056726	Five of 6 (83%) of the high p16 FOSCC had low p53, but only 1/6 (17%) had low pRb immunoreactivity.	('p53', 'Gene', (46, 49))	('high p16 FOSCC', 'Var', (23, 37))	('pRb', 'Gene', (78, 81))	('p53', 'Gene', '7157', (46, 49))	('pRb', 'Gene', '5925', (78, 81))	('low', 'NegReg', (42, 45))
259964	29056726	In summary, the staining pattern of p16, p53, and pRb in FOSCC was different from human head and neck squamous cell carcinoma and feline cutaneous squamous cell carcinoma.	('p53', 'Gene', '7157', (41, 44))	('cutaneous squamous cell carcinoma', 'Disease', 'MESH:D002294', (137, 170))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (88, 125))	('pRb', 'Gene', '5925', (50, 53))	('human', 'Species', '9606', (82, 87))	('neck squamous cell carcinoma', 'Disease', (97, 125))	('pRb', 'Gene', (50, 53))	('p16', 'Var', (36, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('cutaneous squamous cell carcinoma', 'Disease', (137, 170))	('carcinoma', 'Phenotype', 'HP:0030731', (161, 170))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (102, 125))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (147, 170))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (97, 125))	('p53', 'Gene', (41, 44))	('cutaneous squamous cell carcinoma', 'Phenotype', 'HP:0006739', (137, 170))
259971	29056726	Inactivation or mutation of tumor suppressor genes, especially CDKN2A and TP53, were reported in more than 60% of non-viral associated HNSCC patients (pp.	('mutation', 'Var', (16, 24))	('tumor', 'Disease', (28, 33))	('patients', 'Species', '9606', (141, 149))	('non-viral associated HNSCC', 'Disease', (114, 140))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('Inactivation', 'Var', (0, 12))	('CDKN2A', 'Gene', (63, 69))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('TP53', 'Gene', (74, 78))
259973	29056726	More than 50% of HNSCC patients were reported to have either TP53 mutations or increased p53 protein (usually due to mutations) detected by immunohistochemistry, which were associated with a poor clinical outcome and opposing tumor progression (pp.	('mutations', 'Var', (66, 75))	('increased', 'PosReg', (79, 88))	('patients', 'Species', '9606', (23, 31))	('protein', 'Protein', (93, 100))	('tumor', 'Disease', (226, 231))	('tumor', 'Disease', 'MESH:D009369', (226, 231))	('p53', 'Gene', (89, 92))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('p53', 'Gene', '7157', (89, 92))	('TP53', 'Gene', (61, 65))	('HNSCC', 'Disease', (17, 22))
259974	29056726	High p53 immunostaining was reported in 43% (10/23) of FOSCCs, while 35% (8/23) of FOSCCs did not have high p53 staining (pp.	('p53', 'Gene', '7157', (108, 111))	('p53', 'Gene', (108, 111))	('High', 'Var', (0, 4))	('p53', 'Gene', '7157', (5, 8))	('p53', 'Gene', (5, 8))
259977	29056726	Loss of p16 protein immunoreactivity in human HNSCC correlated with CDKN2A inactivation, especially point mutations, promoter hypermethylation, or homozygous deletion (pp.	('promoter', 'MPA', (117, 125))	('p16 protein', 'Protein', (8, 19))	('CDKN2A', 'Gene', (68, 74))	('point mutations', 'Var', (100, 115))	('Loss', 'NegReg', (0, 4))	('inactivation', 'MPA', (75, 87))	('human', 'Species', '9606', (40, 45))
259980	29056726	In high-risk human PVs (HPV), including HPV-16, -18 and -31, E6 and E7 are oncogenic and cause degradation of p53 and pRb during the cell cycle (pp.	('p53', 'Gene', (110, 113))	('human', 'Species', '9606', (13, 18))	('pRb', 'Gene', (118, 121))	('cause', 'Reg', (89, 94))	('HPV', 'Species', '10566', (24, 27))	('HPV-16', 'Species', '333760', (40, 46))	('pRb', 'Gene', '5925', (118, 121))	('p53', 'Gene', '7157', (110, 113))	('HPV', 'Species', '10566', (40, 43))	('degradation', 'MPA', (95, 106))	('HPV-16', 'Var', (40, 46))
260008	29056726	P16 mRNA was reduced in the SCCF3 cells compared to normal gingiva (p = 0.027).	('reduced', 'NegReg', (13, 20))	('P16', 'Gene', (0, 3))	('P16', 'Gene', '101089220', (0, 3))	('SCCF3 cells', 'Var', (28, 39))
260020	29056726	The average age of FOSCC cats with high intensity p16 staining (mean = 10.6 years, SD = 4.0) was significantly lower than cats in the low intensity group (mean = 14.6 years, SD = 4.3), (p < 0.05) (Figure 6).	('cats', 'Species', '9685', (122, 126))	('p16 staining', 'Var', (50, 62))	('lower', 'NegReg', (111, 116))	('cats', 'Species', '9685', (25, 29))
260027	29056726	In humans, high intensity p16 staining was associated with high-risk HPV infection and a better prognosis, while loss of p16 immunostaining was associated with CDKN2A inactivation and a worse clinical outcome (pp.	('HPV infection', 'Disease', 'MESH:D030361', (69, 82))	('associated', 'Reg', (144, 154))	('CDKN2A', 'Gene', (160, 166))	('HPV infection', 'Disease', (69, 82))	('high intensity', 'Var', (11, 25))	('loss', 'Var', (113, 117))	('humans', 'Species', '9606', (3, 9))	('p16', 'Protein', (26, 29))	('inactivation', 'NegReg', (167, 179))
260030	29056726	Therefore, we speculate that the pathogenesis of FOSCC in younger cats with high p16 staining intensity may differ from FOSCC in older cats with low p16.	('high', 'Var', (76, 80))	('cats', 'Species', '9685', (135, 139))	('FOSCC', 'Disease', (49, 54))	('cats', 'Species', '9685', (66, 70))
260031	29056726	It is also possible that FOSCC with high p16 intensity may be associated with a feline papillomavirus infection that has not been discovered yet.	('p16', 'Var', (41, 44))	('papillomavirus infection', 'Disease', 'MESH:D030361', (87, 111))	('associated', 'Reg', (62, 72))	('papillomavirus infection', 'Phenotype', 'HP:0012740', (87, 111))	('papilloma', 'Phenotype', 'HP:0012740', (87, 96))	('papillomavirus infection', 'Disease', (87, 111))
260039	29056726	A lack of pRb correlated with high p16 and FcaPV2 infection in feline cutaneous squamous cell carcinoma (pp.	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('FcaPV2', 'Gene', (43, 49))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (80, 103))	('cutaneous squamous cell carcinoma', 'Disease', (70, 103))	('p16', 'Gene', (35, 38))	('high', 'Var', (30, 34))	('cutaneous squamous cell carcinoma', 'Phenotype', 'HP:0006739', (70, 103))	('infection', 'Disease', 'MESH:D007239', (50, 59))	('cutaneous squamous cell carcinoma', 'Disease', 'MESH:D002294', (70, 103))	('infection', 'Disease', (50, 59))	('pRb', 'Gene', (10, 13))	('pRb', 'Gene', '5925', (10, 13))
260040	29056726	In this study, high p16 immunoreactivity was associated with low p53 in 5 out of 6 samples; however, only 1 of 6 FOSCC with high p16 had low pRb.	('high', 'Var', (15, 19))	('pRb', 'Gene', (141, 144))	('p53', 'Gene', (65, 68))	('p53', 'Gene', '7157', (65, 68))	('p16', 'Protein', (20, 23))	('low', 'NegReg', (61, 64))	('pRb', 'Gene', '5925', (141, 144))
260041	29056726	Instead, FOSCC samples with high p16 were more likely to have moderate pRb (4 out of 6 samples).	('pRb', 'Gene', '5925', (71, 74))	('pRb', 'Gene', (71, 74))	('high p16', 'Var', (28, 36))
260047	29056726	Hypermethylation of a CpG island in the CDKN2A promoter region and homozygous deletion mutation of p16 has been reported in various cancers, particularly HNSCC (pp.	('p16', 'Gene', (99, 102))	('cancers', 'Disease', (132, 139))	('cancers', 'Disease', 'MESH:D009369', (132, 139))	('Hypermethylation', 'Var', (0, 16))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('HNSCC', 'Disease', (154, 159))	('cancers', 'Phenotype', 'HP:0002664', (132, 139))	('deletion mutation', 'Var', (78, 95))	('reported', 'Reg', (112, 120))
260048	29056726	It is possible that many FOSCCs are associated with mutation or inactivation of the CDKN2A tumor suppressor gene.	('FOSCCs', 'Disease', (25, 31))	('CDKN2A', 'Gene', (84, 90))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('mutation', 'Var', (52, 60))	('associated', 'Reg', (36, 46))	('tumor', 'Disease', (91, 96))	('inactivation', 'NegReg', (64, 76))
260050	29056726	p16 protein expression was suggested to possess prognostic utility in squamous cell carcinoma of the nasal planum in cats, since cats with high p16 had a longer survival compared to those with loss of p16 (pp.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (70, 93))	('longer', 'PosReg', (154, 160))	('squamous cell carcinoma of the nasal planum', 'Disease', 'MESH:D002294', (70, 113))	('cats', 'Species', '9685', (129, 133))	('squamous cell carcinoma of the nasal planum', 'Disease', (70, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('p16', 'Gene', (144, 147))	('cats', 'Species', '9685', (117, 121))	('high', 'Var', (139, 143))
260051	29056726	In addition, transfection of wild-type p16 into HNSCC cell lines decreased cancer cell proliferation in vitro (pp.	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('transfection', 'Var', (13, 25))	('decreased', 'NegReg', (65, 74))	('cancer', 'Disease', (75, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))
260052	29056726	Increased p53 is the predictor of TP53 mutation in various cancers including HNSCC (pp.	('p53', 'Gene', '7157', (10, 13))	('mutation', 'Var', (39, 47))	('TP53', 'Gene', (34, 38))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('HNSCC', 'Disease', (77, 82))	('cancers', 'Disease', 'MESH:D009369', (59, 66))	('cancers', 'Phenotype', 'HP:0002664', (59, 66))	('cancers', 'Disease', (59, 66))	('p53', 'Gene', (10, 13))
260056	29056726	Lack of or low p53 immunostaining can be found in cells with TP53 inactivation as well as normal p53 expression.	('p53', 'Gene', (97, 100))	('p53', 'Gene', '7157', (97, 100))	('p53', 'Gene', (15, 18))	('low', 'NegReg', (11, 14))	('p53', 'Gene', '7157', (15, 18))	('inactivation', 'Var', (66, 78))	('TP53', 'Gene', (61, 65))
260057	29056726	However, a subset of FOSCCs with low p53 immunostaining might be associated with TP53 inactivation, since 24%-53% of HNSCC in humans with low p53 immunostaining were related to TP53 mutations (pp.	('related', 'Reg', (166, 173))	('p53', 'Gene', (142, 145))	('p53', 'Gene', '7157', (142, 145))	('humans', 'Species', '9606', (126, 132))	('p53', 'Gene', (37, 40))	('p53', 'Gene', '7157', (37, 40))	('TP53', 'Gene', (177, 181))	('mutations', 'Var', (182, 191))
260059	29056726	Since CDKN2A encodes both the p16 and p14 proteins, inactivation of CDKN2A may also lead to loss of p14 if one of the common exons is inactivated or deleted.	('p14', 'Gene', (100, 103))	('p14', 'Gene', (38, 41))	('CDKN2A', 'Gene', (68, 74))	('p14', 'Gene', '1029', (38, 41))	('p14', 'Gene', '1029', (100, 103))	('inactivation', 'Var', (52, 64))	('loss', 'NegReg', (92, 96))	('CDKN2A', 'Gene', (6, 12))
260062	29056726	There is still no evidence that CDKN2A inactivation causes both p16 and p14 loss in HNSCC.	('loss', 'NegReg', (76, 80))	('CDKN2A', 'Gene', (32, 38))	('HNSCC', 'Disease', (84, 89))	('p14', 'Gene', (72, 75))	('p14', 'Gene', '1029', (72, 75))	('inactivation', 'Var', (39, 51))	('p16', 'Var', (64, 67))
260063	29056726	However, the loss of both p16 and p14 IHC was found in 30% (9/30) of non-small cell lung cancers (NSCLC) and 67% (19/28) of pancreatic cancers (pp.	('cancers', 'Phenotype', 'HP:0002664', (89, 96))	('lung cancers', 'Phenotype', 'HP:0100526', (84, 96))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('non-small cell lung cancers', 'Disease', (69, 96))	('p14', 'Gene', '1029', (34, 37))	('non-small cell lung cancers', 'Phenotype', 'HP:0030358', (69, 96))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (124, 142))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('p16', 'Var', (26, 29))	('NSCLC', 'Disease', 'MESH:D002289', (98, 103))	('p14', 'Gene', (34, 37))	('pancreatic cancers', 'Disease', (124, 142))	('cancers', 'Phenotype', 'HP:0002664', (135, 142))	('NSCLC', 'Disease', (98, 103))	('small cell lung cancers', 'Phenotype', 'HP:0030357', (73, 96))	('pancreatic cancers', 'Disease', 'MESH:D010190', (124, 142))	('NSCLC', 'Phenotype', 'HP:0030358', (98, 103))	('non-small cell lung cancers', 'Disease', 'MESH:D002289', (69, 96))	('loss', 'NegReg', (13, 17))
260064	29056726	Inactivation of CDKN2A is a potential mechanism to indirectly inhibit p53 protein expression.	('p53', 'Gene', '7157', (70, 73))	('p53', 'Gene', (70, 73))	('CDKN2A', 'Gene', (16, 22))	('inhibit', 'NegReg', (62, 69))	('Inactivation', 'Var', (0, 12))
260067	29056726	Our data suggests that inactivation of the TP53 or CDKN2A may occur in FOSCC to directly or indirectly silence p53 expression.	('p53', 'Gene', (111, 114))	('p53', 'Gene', '7157', (111, 114))	('silence', 'NegReg', (103, 110))	('expression', 'MPA', (115, 125))	('CDKN2A', 'Gene', (51, 57))	('TP53', 'Gene', (43, 47))	('inactivation', 'Var', (23, 35))
260069	29056726	The immunohistochemistry patterns of p16, p53, and pRb in FOSCC were different from human HNSCC and feline cutaneous SCC.	('p53', 'Gene', (42, 45))	('p53', 'Gene', '7157', (42, 45))	('human', 'Species', '9606', (84, 89))	('p16', 'Var', (37, 40))	('pRb', 'Gene', '5925', (51, 54))	('pRb', 'Gene', (51, 54))
260078	33753723	In a mouse oral squamous cell carcinoma model induced by 4-nitroquinolin-1-oxide, ceramide synthase 1 knockout was associated with the severity of oral malignant transformation.	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (11, 39))	('knockout', 'Var', (102, 110))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (16, 39))	('associated', 'Reg', (115, 125))	('oral squamous cell carcinoma', 'Disease', (11, 39))	('4-nitroquinolin-1-oxide', 'Chemical', '-', (57, 80))	('mouse', 'Species', '10090', (5, 10))	('carcinoma', 'Phenotype', 'HP:0030731', (30, 39))	('oral malignant transformation', 'CPA', (147, 176))
260080	33753723	Ceramide synthase 1 knockdown caused endoplasmic reticulum stress and induced the VEGFA upregulation.	('VEGFA', 'Protein', (82, 87))	('upregulation', 'PosReg', (88, 100))	('Ceramide synthase 1', 'Gene', (0, 19))	('endoplasmic reticulum stress', 'MPA', (37, 65))	('Ceramide synthase 1', 'Gene', '93898', (0, 19))	('knockdown', 'Var', (20, 29))	('caused', 'Reg', (30, 36))
260081	33753723	Activating transcription factor 4 is responsible for ceramide synthase 1 knockdown caused VEGFA transcriptional upregulation.	('VEGFA transcriptional', 'Gene', (90, 111))	('Activating transcription factor 4', 'Gene', (0, 33))	('upregulation', 'PosReg', (112, 124))	('Activating transcription factor 4', 'Gene', '468', (0, 33))	('knockdown', 'Var', (73, 82))
260082	33753723	In addition, mild endoplasmic reticulum stress caused by ceramide synthase 1 knockdown could induce cisplatin resistance.	('cisplatin', 'Chemical', 'MESH:D002945', (100, 109))	('ceramide', 'Gene', (57, 65))	('cisplatin resistance', 'MPA', (100, 120))	('knockdown', 'Var', (77, 86))	('induce', 'PosReg', (93, 99))
260100	33753723	Similarly, Senkal found that knock-down of CERS1 in HNSCC cells resulted in attenuation of apoptosis due to the repression of casepase-3 and caspase-9 activity.Moreover, CERS1 is also linked to chemotherapy resistance.	('caspase-9', 'Gene', (141, 150))	('HNSCC', 'Phenotype', 'HP:0012288', (52, 57))	('linked', 'Reg', (184, 190))	('caspase-9', 'Gene', '842', (141, 150))	('CERS1', 'Var', (170, 175))	('chemotherapy resistance', 'CPA', (194, 217))
260101	33753723	It has been consistently reported that knockdown of CERS1 significantly protected HNSCC cells from chemotherapeutic agents, including gemcitabine, doxorubicin, and cisplatin, induced apoptosis.	('knockdown', 'Var', (39, 48))	('doxorubicin', 'Chemical', 'MESH:D004317', (147, 158))	('HNSCC', 'Phenotype', 'HP:0012288', (82, 87))	('CERS1', 'Gene', (52, 57))	('gemcitabine', 'Chemical', 'MESH:C056507', (134, 145))	('cisplatin', 'Chemical', 'MESH:D002945', (164, 173))
260102	33753723	In response to cisplatin, CERS1 localized to mitochondria and induced mitophagy to promote cell death.	('cell death', 'CPA', (91, 101))	('CERS1', 'Var', (26, 31))	('cisplatin', 'Chemical', 'MESH:D002945', (15, 24))	('induced', 'Reg', (62, 69))	('mitophagy', 'CPA', (70, 79))	('promote', 'PosReg', (83, 90))
260109	33753723	Therefore, the expression of CERS1 might also influence oral cancer.	('influence', 'Reg', (46, 55))	('expression', 'Var', (15, 25))	('CERS1', 'Gene', (29, 34))	('oral cancer', 'Disease', 'MESH:D009369', (56, 67))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('oral cancer', 'Disease', (56, 67))
260113	33753723	In addition, the patients with high CERS1 expression survived longer (P = 0.049, Fig.	('high', 'Var', (31, 35))	('patients', 'Species', '9606', (17, 25))	('longer', 'PosReg', (62, 68))	('CERS1', 'Gene', (36, 41))
260125	33753723	Based on the gross appearance of the tongue, more mice developed obvious precancerous and cancerous lesions in the Cers1-/- group (22/25, 88%) than that in the Cers1 + /+ group (16/25, 64%) (Fig.	('cancerous lesions', 'Disease', 'MESH:D009369', (90, 107))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('Cers1-/-', 'Var', (115, 123))	('cancerous lesions', 'Disease', (90, 107))	('cancer', 'Disease', (90, 96))	('mice', 'Species', '10090', (50, 54))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))
260126	33753723	The average tumor lesion size in the Cers1-/- group was (7.82 +- 7.69) mm2.	('tumor', 'Disease', (12, 17))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('Cers1-/-', 'Var', (37, 45))
260127	33753723	However, the average tumor lesion size in the Cers1 + /+ group was smaller at (3.5 +- 5.6) mm2 (P = 0.033, Fig.	('tumor', 'Disease', (21, 26))	('smaller', 'NegReg', (67, 74))	('Cers1 + /+', 'Var', (46, 56))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
260128	33753723	In addition, the number of lesions per mouse in the Cers1-/- group was significantly higher than that in the Cers1 + /+ group (2.23 +- 1.02 vs. 1.88 +- 0.72, P = 0.017, Fig.	('mouse', 'Species', '10090', (39, 44))	('Cers1-/-', 'Var', (52, 60))	('higher', 'PosReg', (85, 91))
260129	33753723	The results showed that knocking out Cers1 contributed to the formation of tongue lesions induced by 4NQO.	('knocking out', 'Var', (24, 36))	('Cers1', 'Gene', (37, 42))	('4NQO', 'Var', (101, 105))	('tongue lesions', 'Disease', (75, 89))	('4NQO', 'Chemical', 'MESH:D015112', (101, 105))
260130	33753723	H&E staining showed that after treatment with 4NQO, the Cers1-/- mice exhibited different stages of oral carcinogenesis than the Cers1 + /+ mice.	('mice', 'Reg', (65, 69))	('the', 'Var', (52, 55))	('carcinogenesis', 'Disease', 'MESH:D063646', (105, 119))	('mice', 'Species', '10090', (140, 144))	('carcinogenesis', 'Disease', (105, 119))	('mice', 'Species', '10090', (65, 69))	('H&E', 'Chemical', '-', (0, 3))	('of oral', 'CPA', (97, 104))	('4NQO', 'Chemical', 'MESH:D015112', (46, 50))
260132	33753723	A total of 36% (9/25) of mice in the Cers1-/- group developed tongue squamous cell carcinoma compared with 12% (3/25) of mice in the Cers1 + /+ group.	('mice', 'Species', '10090', (25, 29))	('tongue squamous cell carcinoma', 'Disease', (62, 92))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (69, 92))	('developed', 'Reg', (52, 61))	('mice', 'Species', '10090', (121, 125))	('Cers1-/-', 'Var', (37, 45))	('tongue squamous cell carcinoma', 'Disease', 'MESH:D002294', (62, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))
260133	33753723	These results indicated that Cers1 knockout enhanced 4NQO-induced tongue carcinogenesis.	('4NQO', 'Chemical', 'MESH:D015112', (53, 57))	('Cers1', 'Gene', (29, 34))	('tongue carcinogenesis', 'Disease', 'MESH:D063646', (66, 87))	('tongue carcinogenesis', 'Disease', (66, 87))	('knockout', 'Var', (35, 43))	('enhanced', 'PosReg', (44, 52))
260145	33753723	The expression levels of Bax in the Cers1-/- group were lower than those in the Cers1 + /+ group (P < 0.05, Fig.	('expression levels', 'MPA', (4, 21))	('Bax', 'Gene', '581', (25, 28))	('Cers1-/-', 'Var', (36, 44))	('lower', 'NegReg', (56, 61))	('Bax', 'Gene', (25, 28))
260148	33753723	ER stress is a kind of cellular stress state caused by protein folding dysfunction of the endoplasmic reticulum that is induced endogenously or exogenously.	('dysfunction', 'Var', (71, 82))	('ER', 'Gene', '2069', (0, 2))	('caused by', 'Reg', (45, 54))	('protein folding', 'Protein', (55, 70))
260151	33753723	The expression of BIP in CERS1 knockdown cells was higher than that in the control group (P < 0.05, Fig.	('BIP', 'Gene', (18, 21))	('expression', 'MPA', (4, 14))	('BIP', 'Gene', '3309', (18, 21))	('higher', 'PosReg', (51, 57))	('CERS1', 'Gene', (25, 30))	('knockdown', 'Var', (31, 40))
260153	33753723	ATF4 was significantly upregulated after CERS1 knockdown (P < 0.05, Fig.	('upregulated', 'PosReg', (23, 34))	('knockdown', 'Var', (47, 56))	('ATF4', 'Gene', (0, 4))	('CERS1', 'Gene', (41, 46))	('ATF4', 'Gene', '468', (0, 4))
260155	33753723	Consistent with the expression of other ER stress markers, CHOP was also highly expressed in CERS1 knockdown cells (P < 0.05, Fig.	('ER', 'Gene', '2069', (94, 96))	('highly expressed', 'PosReg', (73, 89))	('CHOP', 'Gene', '1649', (59, 63))	('ER', 'Gene', '2069', (40, 42))	('knockdown', 'Var', (99, 108))	('CHOP', 'Gene', (59, 63))
260164	33753723	To prove that CERS1 knockdown led to increased VEGFA expression through ATF4, we used a luciferase reporter plasmid in which a VEGFA 5'-flanking sequence (-2304 to +65 relative to the transcription initiation site) was fused to the firefly luciferase coding sequences in the pEZX-FR01 vector.	('ATF4', 'Gene', '468', (72, 76))	('-2304 to +65', 'Var', (155, 167))	('VEGFA', 'Protein', (47, 52))	('increased', 'PosReg', (37, 46))	('expression', 'MPA', (53, 63))	('knockdown', 'Var', (20, 29))	('ATF4', 'Gene', (72, 76))	('CERS1', 'Gene', (14, 19))
260170	33753723	Recent studies have shown that high CERS1 expression renders cells more sensitive to cisplatin.	('more', 'PosReg', (67, 71))	('sensitive to cisplatin', 'MPA', (72, 94))	('expression', 'MPA', (42, 52))	('CERS1', 'Gene', (36, 41))	('high', 'Var', (31, 35))	('cisplatin', 'Chemical', 'MESH:D002945', (85, 94))
260177	33753723	There were four groups in the experiment that underwent various treatments as follows: siNC group, transfected with NC siRNA and treated with 1% DMSO; siNC+DDP group, transfected with NC siRNA and treated with cisplatin (40 nmol L-1, Sigma) for 12 h; siNC+TM + DDP group, transfected with NC siRNA, pretreated with TM (1 mug mL-1) for 2 h and then treated with cisplatin for 12 h; and siCERS1+DDP group, with CERS1 knockdown and then treated with cisplatin for 12 h. The expression of BIP, ATF4, and CHOP was higher in the siNC+TM + DDP and siCERS1+DDP groups than in the siNC and siNC+DDP groups (P < 0.05, Fig.	('CHOP', 'Gene', '1649', (500, 504))	('cisplatin', 'Chemical', 'MESH:D002945', (447, 456))	('siNC', 'Disease', (151, 155))	('siNC+DDP', 'Disease', 'MESH:C535808', (151, 159))	('cisplatin', 'Chemical', 'MESH:D002945', (210, 219))	('NC siRNA', 'Disease', 'OMIM:617025', (116, 124))	('expression', 'MPA', (471, 481))	('siNC', 'Disease', (87, 91))	('siNC+TM', 'Disease', 'None', (523, 530))	('siNC', 'Disease', (523, 527))	('ATF4', 'Gene', (490, 494))	('NC siRNA', 'Disease', (116, 124))	('siCERS1+DDP', 'Var', (541, 552))	('NC siRNA', 'Disease', 'OMIM:617025', (289, 297))	('siNC', 'Disease', 'None', (581, 585))	('BIP', 'Gene', '3309', (485, 488))	('ATF4', 'Gene', '468', (490, 494))	('NC siRNA', 'Disease', (289, 297))	('siNC+TM', 'Disease', 'None', (251, 258))	('siNC', 'Disease', (251, 255))	('DDP', 'Chemical', 'MESH:D002945', (549, 552))	('TM', 'Chemical', 'MESH:D014415', (315, 317))	('CHOP', 'Gene', (500, 504))	('siNC', 'Disease', 'None', (572, 576))	('siNC', 'Disease', 'None', (151, 155))	('L-1', 'Gene', '23961', (326, 329))	('siNC', 'Disease', 'None', (87, 91))	('DDP', 'Chemical', 'MESH:D002945', (533, 536))	('mL-1', 'Gene', '23961', (325, 329))	('siNC', 'Disease', 'None', (523, 527))	('L-1', 'Gene', (326, 329))	('BIP', 'Gene', (485, 488))	('NC siRNA', 'Disease', 'OMIM:617025', (184, 192))	('TM', 'Chemical', 'MESH:D014415', (528, 530))	('NC siRNA', 'Disease', (184, 192))	('DDP', 'Chemical', 'MESH:D002945', (261, 264))	('siNC', 'Disease', 'None', (251, 255))	('L-1', 'Gene', '23961', (229, 232))	('L-1', 'Gene', (229, 232))	('siNC+TM', 'Disease', (523, 530))	('mL-1', 'Gene', (325, 329))	('TM', 'Chemical', 'MESH:D014415', (256, 258))	('siNC+DDP', 'Disease', (581, 589))	('siNC+TM', 'Disease', (251, 258))	('cisplatin', 'Chemical', 'MESH:D002945', (361, 370))	('siNC', 'Disease', (581, 585))	('siNC+DDP', 'Disease', 'MESH:C535808', (581, 589))	('DDP', 'Chemical', 'MESH:D002945', (586, 589))	('DDP', 'Chemical', 'MESH:D002945', (393, 396))	('siNC+DDP', 'Disease', (151, 159))	('higher', 'PosReg', (509, 515))	('DDP', 'Chemical', 'MESH:D002945', (156, 159))	('siNC', 'Disease', (572, 576))
260181	33753723	Similar to the anti-apoptosis effect of TM, knock-down of CERS1 significantly decreased the apoptosis ratio after DDP treatment.	('TM', 'Chemical', 'MESH:D014415', (40, 42))	('apoptosis ratio', 'CPA', (92, 107))	('CERS1', 'Gene', (58, 63))	('DDP', 'Chemical', 'MESH:D002945', (114, 117))	('decreased', 'NegReg', (78, 87))	('knock-down', 'Var', (44, 54))
260183	33753723	Also, cell viability test supported that knock-down of CERS1 resulted in cisplatin resistance, whereas overexpression of CERS1 obtained the opposite effect (Supplementary Fig.	('cisplatin', 'Chemical', 'MESH:D002945', (73, 82))	('CERS1', 'Gene', (55, 60))	('resulted in', 'Reg', (61, 72))	('knock-down', 'Var', (41, 51))	('cisplatin resistance', 'MPA', (73, 93))
260184	33753723	These findings indicated that knockdown of CERS1 could trigger mild ER stress and induce cisplatin resistance.	('induce', 'Reg', (82, 88))	('cisplatin resistance', 'MPA', (89, 109))	('ER', 'Gene', '2069', (44, 46))	('ER', 'Gene', '2069', (68, 70))	('knockdown', 'Var', (30, 39))	('cisplatin', 'Chemical', 'MESH:D002945', (89, 98))	('trigger', 'Reg', (55, 62))
260195	33753723	Cers1 knockout mice were more likely to develop oral cancer, which was consistent with the vitro experiments and other studies.	('oral cancer', 'Disease', 'MESH:D009369', (48, 59))	('Cers1', 'Gene', (0, 5))	('mice', 'Species', '10090', (15, 19))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('knockout', 'Var', (6, 14))	('develop', 'PosReg', (40, 47))	('oral cancer', 'Disease', (48, 59))
260201	33753723	Reducing CERS1 inhibits the synthesis of C18 CER, AKT, and BCL2 to inhibit apoptosis.	('BCL2', 'Gene', '596', (59, 63))	('C18', 'Gene', (41, 44))	('C18', 'Gene', '27241', (41, 44))	('synthesis', 'MPA', (28, 37))	('inhibit', 'NegReg', (67, 74))	('CER', 'Chemical', 'MESH:D002518', (9, 12))	('AKT', 'Gene', '207', (50, 53))	('apoptosis', 'CPA', (75, 84))	('BCL2', 'Gene', (59, 63))	('AKT', 'Gene', (50, 53))	('inhibits', 'NegReg', (15, 23))	('CER', 'Chemical', 'MESH:D002518', (45, 48))	('CERS1', 'Var', (9, 14))
260208	33753723	In our study, after knocking down/out CERS1, the expression of BIP, ATF4, CHOP, and VEGFA was higher than that in the control group.	('CHOP', 'Gene', '1649', (74, 78))	('knocking down/out', 'Var', (20, 37))	('BIP', 'Gene', (63, 66))	('VEGFA', 'Protein', (84, 89))	('CHOP', 'Gene', (74, 78))	('ATF4', 'Gene', (68, 72))	('expression', 'MPA', (49, 59))	('CERS1', 'Gene', (38, 43))	('ATF4', 'Gene', '468', (68, 72))	('BIP', 'Gene', '3309', (63, 66))	('higher', 'PosReg', (94, 100))
260209	33753723	However, ATF4 knockdown abolished this relationship.	('ATF4', 'Gene', (9, 13))	('ATF4', 'Gene', '468', (9, 13))	('knockdown', 'Var', (14, 23))
260210	33753723	Therefore, downregulation of CERS1 promotes migration through ER stress, the PERK-ATF4 pathway and VEGFA.	('ATF4', 'Gene', (82, 86))	('downregulation', 'Var', (11, 25))	('promotes', 'PosReg', (35, 43))	('ER', 'Gene', '2069', (30, 32))	('ER', 'Gene', '2069', (78, 80))	('VEGFA', 'Protein', (99, 104))	('ER', 'Gene', '2069', (62, 64))	('migration', 'CPA', (44, 53))	('PERK', 'Gene', (77, 81))	('ATF4', 'Gene', '468', (82, 86))	('PERK', 'Gene', '9451', (77, 81))
260213	33753723	Junxia Min's research showed that CERS1 expression rendered cells more sensitive to cisplatin, carboplatin, doxorubicin, and vincristine.	('carboplatin', 'Chemical', 'MESH:D016190', (95, 106))	('carboplatin', 'MPA', (95, 106))	('expression', 'Var', (40, 50))	('sensitive to cisplatin', 'MPA', (71, 93))	('cisplatin', 'Chemical', 'MESH:D002945', (84, 93))	('more', 'PosReg', (66, 70))	('CERS1', 'Gene', (34, 39))	('vincristine', 'Chemical', 'MESH:D014750', (125, 136))	('doxorubicin', 'Chemical', 'MESH:D004317', (108, 119))
260215	33753723	As our study, CERS1 knockdown induced ER stress, which is a process that can remove misfolded proteins in the ER through the unfolded protein response to maintain ER homeostasis.	('induced', 'Reg', (30, 37))	('ER', 'Gene', '2069', (163, 165))	('ER', 'Gene', '2069', (15, 17))	('ER', 'Gene', '2069', (38, 40))	('knockdown', 'Var', (20, 29))	('ER', 'Gene', '2069', (110, 112))
260219	33753723	Similar to the result of low-dose TM, CERS1 knockdown caused mild ER stress and then reduce the apoptosis caused by cisplatin.	('ER', 'Gene', '2069', (39, 41))	('reduce', 'NegReg', (85, 91))	('TM', 'Chemical', 'MESH:D014415', (34, 36))	('apoptosis', 'CPA', (96, 105))	('knockdown', 'Var', (44, 53))	('cisplatin', 'Chemical', 'MESH:D002945', (116, 125))	('ER', 'Gene', '2069', (66, 68))
260257	33753723	Then, the sections were incubated overnight at 4  C with anti-Bax antibody (1:1 000), anti-Bcl2 antibody (1:100), anti-Mmp2 antibody (1:1 000), anti-Mmp9 antibody (1:800), anti-Pcna antibody (1:500), and anti-Vegfa antibody (1:500).	('Mmp2', 'Gene', '4313', (119, 123))	('Mmp2', 'Gene', (119, 123))	('Bax', 'Gene', '581', (62, 65))	('Pcna', 'Gene', (177, 181))	('Pcna', 'Gene', '5111', (177, 181))	('Bcl2', 'Gene', '596', (91, 95))	('Bax', 'Gene', (62, 65))	('Bcl2', 'Gene', (91, 95))	('Mmp9', 'Gene', '4318', (149, 153))	('Mmp9', 'Gene', (149, 153))	('1:800', 'Var', (164, 169))
260265	33753723	Anti-CERS1 (#ab98062, Abcam, United States), anti-GDF1(#bs-1794R, Bioss, China) anti-ATF4 (#11815, Cell Signaling Technology, United States), anti-VEGFA (#ab46154, Abcam, United States), anti-BIP (#ER40402, Huabio, China), anti-CHOP (#5554, Cell Signaling Technology, United States), anti-BAX (#5023, Cell Signaling Technology, United States), and anti-BCL2 (#4223, Cell Signaling Technology, United States) were used.	('#5554', 'Var', (234, 239))	('BCL2', 'Gene', (353, 357))	('CHOP', 'Gene', (228, 232))	('BAX', 'Gene', '581', (289, 292))	('ER', 'Gene', '2069', (198, 200))	('ER', 'Gene', '2069', (6, 8))	('ATF4', 'Gene', (85, 89))	('#ab46154', 'Var', (154, 162))	('BCL2', 'Gene', '596', (353, 357))	('GDF1', 'Gene', '2657', (50, 54))	('BIP', 'Gene', '3309', (192, 195))	('BAX', 'Gene', (289, 292))	('GDF1', 'Gene', (50, 54))	('BIP', 'Gene', (192, 195))	('CHOP', 'Gene', '1649', (228, 232))	('ATF4', 'Gene', '468', (85, 89))
260283	33428598	In recent years, targeted therapy has improved the survival and quality of life of nearly 60% of lung adenocarcinoma patients that carry the corresponding driver gene mutations.	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (97, 116))	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('improved', 'PosReg', (38, 46))	('lung adenocarcinoma', 'Disease', (97, 116))	('mutations', 'Var', (167, 176))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (97, 116))	('patients', 'Species', '9606', (117, 125))
260284	33428598	However, majority of the advanced lung squamous cell carcinoma (LUSC) patients do not harbor mutations in the driver genes that are amenable for the currently available targeted therapeutics and are therefore treated by traditional chemotherapies.	('patients', 'Species', '9606', (70, 78))	('mutations', 'Var', (93, 102))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (34, 62))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (34, 62))	('lung squamous cell carcinoma', 'Disease', (34, 62))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (39, 62))	('carcinoma', 'Phenotype', 'HP:0030731', (53, 62))	('LUSC', 'Phenotype', 'HP:0030359', (64, 68))	('LUSC', 'Chemical', '-', (64, 68))
260327	33428598	Although survival analysis showed no significant differences in OS between the three LUSC subtypes (Figure 3G), TOX mRNA expression levels were significantly higher in the high immunity group of LUSC samples compared to the low immunity group (Supplementary Figure 3A).	('LUSC', 'Chemical', '-', (85, 89))	('TOX', 'Gene', '9760', (112, 115))	('LUSC', 'Chemical', '-', (195, 199))	('high immunity', 'Var', (172, 185))	('TOX', 'Gene', (112, 115))	('higher', 'PosReg', (158, 164))	('LUSC', 'Phenotype', 'HP:0030359', (195, 199))	('LUSC', 'Phenotype', 'HP:0030359', (85, 89))
260332	33428598	The gene sets related to the complement receptor mediated signaling and MHC class II protein complex were significantly enriched in the LUSC patients with high LAPTM5, C1QC, SLCO2B1 and CSF1R expression (Figure 9A).	('LAPTM5', 'Gene', (160, 166))	('SLCO2B1', 'Gene', (174, 181))	('C1QC', 'Gene', '714', (168, 172))	('LUSC', 'Chemical', '-', (136, 140))	('CSF1R', 'Gene', (186, 191))	('patients', 'Species', '9606', (141, 149))	('C1QC', 'Gene', (168, 172))	('SLCO2B1', 'Gene', '11309', (174, 181))	('LUSC', 'Phenotype', 'HP:0030359', (136, 140))	('high', 'Var', (155, 159))	('LAPTM5', 'Gene', '7805', (160, 166))	('LUSC', 'Disease', (136, 140))
260366	33428598	In fact, the proportion of cluster 2 samples was significantly higher in the high immunity LUSC samples compared to the medium immunity and low immunity LUSC samples (Supplementary Figure 3B).	('LUSC', 'Chemical', '-', (91, 95))	('LUSC', 'Phenotype', 'HP:0030359', (153, 157))	('LUSC', 'Phenotype', 'HP:0030359', (91, 95))	('LUSC', 'Chemical', '-', (153, 157))	('higher', 'PosReg', (63, 69))	('high immunity', 'Var', (77, 90))
260379	33428598	Not only that, a recent literature reported that treatment with anti-CSF1R preferentially depleted macrophages with an inflammatory signature but spared macrophage populations that in mouse and human expresses pro-angiogenic/tumorigenic genes.	('tumor', 'Disease', 'MESH:D009369', (225, 230))	('inflammatory signature', 'MPA', (119, 141))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('tumor', 'Disease', (225, 230))	('anti-CSF1R', 'Var', (64, 74))	('mouse', 'Species', '10090', (184, 189))	('human', 'Species', '9606', (194, 199))	('depleted', 'NegReg', (90, 98))
260468	32064753	The curves of Kaplan-Meier method and logarithmic-rank test displayed that miR-99a-3p was a positive factor for OS; on the contrary, miR-4652-5p was a negative one (Figure 3).	('miR-4652', 'Gene', '100616206', (133, 141))	('OS', 'Disease', (112, 114))	('miR-4652', 'Gene', (133, 141))	('miR-99a-3p', 'Chemical', '-', (75, 85))	('miR-99a-3p', 'Var', (75, 85))
260469	32064753	Correlation analysis of 2 kinds of SDEMs with clinical information displayed that miR-99a-3p was significantly correlated with histologic grade (P = .028), T stage (P = .02), and N stage (P = .05) and miR-4652-5p was related to M stage (P = .03) and T stage (P = .046) (Table 1).	('N stage', 'CPA', (179, 186))	('correlated', 'Reg', (111, 121))	('T stage', 'CPA', (250, 257))	('miR-99a-3p', 'Var', (82, 92))	('M stage', 'CPA', (228, 235))	('miR-99a-3p', 'Chemical', '-', (82, 92))	('related', 'Reg', (217, 224))	('SDEMs', 'Chemical', '-', (35, 40))	('miR-4652', 'Gene', '100616206', (201, 209))	('miR-4652', 'Gene', (201, 209))	('histologic grade', 'CPA', (127, 143))	('T stage', 'CPA', (156, 163))
260484	32064753	According to Wong et al, miR-193b-3p, miR-455-5p, miR-92a-3p, and miR-497-5p were associated with survival in OPSCC.	('SCC', 'Phenotype', 'HP:0002860', (112, 115))	('associated with', 'Reg', (82, 97))	('miR-497', 'Gene', '574456', (66, 73))	('miR-497', 'Gene', (66, 73))	('miR-92a-3p', 'Var', (50, 60))	('OPSCC', 'Disease', (110, 115))	('miR-193b-3p', 'Var', (25, 36))	('miR-455-5p', 'Var', (38, 48))
260487	32064753	Dysregulation of genic expression could have an impact on tumorigenesis and evolvement through the maladjusted molecular mechanism and signaling pathways.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('evolvement', 'CPA', (76, 86))	('Dysregulation', 'Var', (0, 13))	('genic expression', 'Protein', (17, 33))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('impact', 'Reg', (48, 54))
260498	30210237	With regard to survival, we found that ESCC patients with high SOX2 expression had significantly better survival time than those with low SOX2 expression (p=0.021).	('SOX2', 'Gene', (63, 67))	('SOX2', 'Gene', '6657', (138, 142))	('SOX2', 'Gene', '6657', (63, 67))	('ESCC', 'Disease', (39, 43))	('patients', 'Species', '9606', (44, 52))	('SOX2', 'Gene', (138, 142))	('better', 'PosReg', (97, 103))	('high', 'Var', (58, 62))	('survival time', 'CPA', (104, 117))
260500	30210237	Furthermore, higher T stage, clinical stage (pTNM), venous invasion, and high p53 expression were independent predictors of a worse progression-free survival.	('venous invasion', 'CPA', (52, 67))	('expression', 'MPA', (82, 92))	('pTNM', 'Chemical', '-', (45, 49))	('clinical stage', 'CPA', (29, 43))	('T stage', 'CPA', (20, 27))	('p53', 'Gene', (78, 81))	('high', 'Var', (73, 77))	('p53', 'Gene', '7157', (78, 81))
260519	30210237	Ki-67 labeling index was found to be significantly associated with poor prognosis in many malignancies, such as lymphoma, neuroendocrine tumors, and bladder cancer.	('bladder cancer', 'Disease', 'MESH:D001749', (149, 163))	('lymphoma', 'Disease', (112, 120))	('Ki-67', 'Var', (0, 5))	('malignancies', 'Disease', (90, 102))	('neuroendocrine tumors', 'Disease', 'MESH:D018358', (122, 143))	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (122, 143))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('bladder cancer', 'Disease', (149, 163))	('lymphoma', 'Disease', 'MESH:D008223', (112, 120))	('lymphoma', 'Phenotype', 'HP:0002665', (112, 120))	('associated', 'Reg', (51, 61))	('neuroendocrine tumors', 'Disease', (122, 143))	('bladder cancer', 'Phenotype', 'HP:0009725', (149, 163))	('malignancies', 'Disease', 'MESH:D009369', (90, 102))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
260521	30210237	Yao et al reported that high expression of p53 was associated with poor prognosis in patients with early-stage ESCC.	('early-stage ESCC', 'Disease', (99, 115))	('patients', 'Species', '9606', (85, 93))	('high', 'Var', (24, 28))	('p53', 'Gene', '7157', (43, 46))	('p53', 'Gene', (43, 46))
260555	30210237	Notably, high Cyclin D1 was correlated with increased p53 expression (p=0.015).	('expression', 'MPA', (58, 68))	('p53', 'Gene', (54, 57))	('Cyclin D1', 'Gene', '595', (14, 23))	('p53', 'Gene', '7157', (54, 57))	('increased', 'PosReg', (44, 53))	('Cyclin D1', 'Gene', (14, 23))	('high', 'Var', (9, 13))
260561	30210237	Univariate analysis showed that N stage (p=0.014), higher pTNM (p=0.006), adjuvant therapy (p=0.044), presence of venous invasion (p=0.015), lymph node metastasis (p=0.007), and high expression of P53 (p=0.018) were associated with OS (Table 3).	('lymph node metastasis', 'CPA', (141, 162))	('P53', 'Gene', '7157', (197, 200))	('high expression', 'Var', (178, 193))	('pTNM', 'Chemical', '-', (58, 62))	('P53', 'Gene', (197, 200))
260565	30210237	We found that therapy (hazard ratio [HR]: 0.490, 95% confidence interval [CI]: 0.249-0.964, p=0.039), high expression of p53 (HR: 2.697, 95% CI: 1.373-5.299, p=0.004), and venous invasion (HR: 2.373, 95% CI: 1.129-4.987, p=0.023) were significant independent predictors of OS.	('high', 'Var', (102, 106))	('p53', 'Gene', (121, 124))	('p53', 'Gene', '7157', (121, 124))	('venous invasion', 'CPA', (172, 187))
260567	30210237	In the multivariate analysis, higher T stage, pTNM stage, venous invasion, and high p53 expression were also found to be independent factors affecting PFS (Table 4).	('high', 'Var', (79, 83))	('p53', 'Gene', (84, 87))	('p53', 'Gene', '7157', (84, 87))	('expression', 'MPA', (88, 98))	('pTNM', 'Chemical', '-', (46, 50))	('PFS', 'Disease', (151, 154))
260572	30210237	SOX2 expression was significantly correlated with favorable prognosis in the group with age <65 years (p=0.020), tumor size <4 cm (p=0.031), moderate differentiation (p=0.018), T2 pathological stage (p=0.032), no lymph node metastasis (p=0.017), the combination of radical surgery and chemotherapy (p=0.017), LNR >0.2 (p=0.026), lower p53 expression (p=0.029), and higher Cyclin D1 expression (p=0.031).	('SOX2', 'Gene', '6657', (0, 4))	('tumor', 'Disease', (113, 118))	('Cyclin D1', 'Gene', (372, 381))	('lower', 'NegReg', (329, 334))	('expression', 'Var', (5, 15))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('p53', 'Gene', (335, 338))	('Cyclin D1', 'Gene', '595', (372, 381))	('p53', 'Gene', '7157', (335, 338))	('expression', 'MPA', (382, 392))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('LNR', 'Var', (309, 312))	('moderate differentiation', 'CPA', (141, 165))	('SOX2', 'Gene', (0, 4))	('higher', 'PosReg', (365, 371))
260574	30210237	The Kaplan-Meier survival analysis with log-rank test showed that high p53 expression was associated with shorter OS and PFS (p=0.018 and p=0.006, respectively) in ESCC.	('shorter', 'NegReg', (106, 113))	('p53', 'Gene', (71, 74))	('ESCC', 'Disease', (164, 168))	('p53', 'Gene', '7157', (71, 74))	('high', 'Var', (66, 70))	('PFS', 'CPA', (121, 124))	('expression', 'MPA', (75, 85))
260578	30210237	Next, we found that the combination of p53 and Cyclin D1 was significantly correlated with poor prognosis in radical surgery (p=0.020) and in the chemotherapy (p=0.020) after stratification.	('radical', 'Disease', (109, 116))	('Cyclin D1', 'Gene', '595', (47, 56))	('combination', 'Var', (24, 35))	('Cyclin D1', 'Gene', (47, 56))	('p53', 'Gene', (39, 42))	('p53', 'Gene', '7157', (39, 42))
260584	30210237	As previously described, high level of SOX2 is associated with poor prognosis in human oral squamous cell carcinomas.	('carcinomas', 'Phenotype', 'HP:0030731', (106, 116))	('oral squamous cell carcinomas', 'Disease', (87, 116))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (92, 116))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('SOX2', 'Gene', '6657', (39, 43))	('human', 'Species', '9606', (81, 86))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (92, 115))	('SOX2', 'Gene', (39, 43))	('oral squamous cell carcinomas', 'Disease', 'MESH:D002294', (87, 116))	('high level', 'Var', (25, 35))
260590	30210237	With regard to survival, we found that ESCC patients with high SOX2 expression had significantly better survival time than those with low SOX2 expression (p=0.021) by Kaplan-Meier analysis.	('SOX2', 'Gene', (63, 67))	('SOX2', 'Gene', '6657', (138, 142))	('SOX2', 'Gene', '6657', (63, 67))	('ESCC', 'Disease', (39, 43))	('patients', 'Species', '9606', (44, 52))	('SOX2', 'Gene', (138, 142))	('better', 'PosReg', (97, 103))	('high', 'Var', (58, 62))	('survival time', 'CPA', (104, 117))
260591	30210237	Subgroup analysis found that in the low SOX2 expression group, receiving both radical surgery and chemotherapy did not lead to any significant survival benefit.	('SOX2', 'Gene', '6657', (40, 44))	('SOX2', 'Gene', (40, 44))	('low', 'Var', (36, 39))
260603	30210237	With regard to survival, our study revealed that ESCC patients with p53 overexpression had lower OS and PFS rates than patient without p53 expression.	('lower', 'NegReg', (91, 96))	('patient', 'Species', '9606', (54, 61))	('patient', 'Species', '9606', (119, 126))	('overexpression', 'Var', (72, 86))	('patients', 'Species', '9606', (54, 62))	('p53', 'Gene', (135, 138))	('p53', 'Gene', '7157', (135, 138))	('PFS rates', 'CPA', (104, 113))	('p53', 'Gene', (68, 71))	('ESCC', 'Disease', (49, 53))	('p53', 'Gene', '7157', (68, 71))
260612	30210237	In conclusion, our study found that treatment modality, high expression of p53, and venous invasion were significant independent predictors of OS.	('p53', 'Gene', (75, 78))	('high expression', 'Var', (56, 71))	('venous invasion', 'CPA', (84, 99))	('p53', 'Gene', '7157', (75, 78))
260613	30210237	We also found that higher T stage, pTNM, venous invasion, and high p53 expression were significantly associated with worse PFS.	('expression', 'MPA', (71, 81))	('T stage', 'CPA', (26, 33))	('p53', 'Gene', (67, 70))	('p53', 'Gene', '7157', (67, 70))	('pTNM', 'Chemical', '-', (35, 39))	('high', 'Var', (62, 66))	('venous invasion', 'CPA', (41, 56))
260626	29587142	Comprehensive integrated analyses have identified distinct patterns of genomic mutations, epigenetic alterations, and expression signatures that have been used to classify lung cancers.	('genomic mutations', 'Var', (71, 88))	('cancers', 'Phenotype', 'HP:0002664', (177, 184))	('lung cancers', 'Disease', (172, 184))	('rat', 'Species', '10116', (105, 108))	('lung cancer', 'Phenotype', 'HP:0100526', (172, 183))	('rat', 'Species', '10116', (19, 22))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('lung cancers', 'Disease', 'MESH:D008175', (172, 184))	('lung cancers', 'Phenotype', 'HP:0100526', (172, 184))	('expression', 'MPA', (118, 128))	('epigenetic alterations', 'Var', (90, 112))
260630	29587142	In the absence of the lung lineage-specifying factor NKX2-1, mutant KRAS engenders the development of a particular form of lung adenocarcinoma, mucinous adenocarcinoma, that remarkably manifests elements of gastric differentiation.	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (123, 142))	('mucinous adenocarcinoma', 'Disease', 'MESH:D002288', (144, 167))	('mucinous adenocarcinoma', 'Disease', (144, 167))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (123, 142))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('KRAS', 'Gene', (68, 72))	('KRAS', 'Gene', '16653', (68, 72))	('mutant', 'Var', (61, 67))	('carcinoma', 'Phenotype', 'HP:0030731', (158, 167))	('lung adenocarcinoma', 'Disease', (123, 142))	('absence of the lung', 'Phenotype', 'HP:0005944', (7, 26))
260669	29587142	Taken together, our results indicate that NSCLCs without NKX2-1 expression have lost their lung identity and transformed into cells that reflect other organ lineages; namely, SCCs resemble the esophagus, whereas MADs resemble midgut/hindgut epithelial tissues.	('NSCLC', 'Disease', (42, 47))	('SCC', 'Gene', (175, 178))	('without', 'Var', (49, 56))	('NSCLC', 'Disease', 'MESH:D002289', (42, 47))	('SCCs', 'Phenotype', 'HP:0002860', (175, 179))	('SCC', 'Gene', '6317', (175, 178))	('NKX2-1', 'Gene', (57, 63))	('transformed', 'Reg', (109, 120))	('lost', 'NegReg', (80, 84))	('lung identity', 'CPA', (91, 104))
260670	29587142	To better understand the molecular mechanism underlying the role of developmental regulators in NSCLC tumor subtype heterogeneity, we generated 12 inducible genetic murine models that allowed the production of various combinations of Nkx2-1 loss of function alleles, Sox2 overexpression alleles, and a gain of function oncogenic Kras allele in either the airway or the alveoli (Table S1).	('rat', 'Species', '10116', (138, 141))	('alleles', 'Var', (258, 265))	('Sox2', 'Gene', '20674', (267, 271))	('NSCLC tumor', 'Disease', (96, 107))	('Kras', 'Gene', (329, 333))	('Nkx2-1', 'Gene', (234, 240))	('loss of function', 'NegReg', (241, 257))	('murine', 'Species', '10090', (165, 171))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('overexpression', 'PosReg', (272, 286))	('Sox2', 'Gene', (267, 271))	('gain of function', 'PosReg', (302, 318))	('NSCLC tumor', 'Disease', 'MESH:D009369', (96, 107))
260671	29587142	To begin, we specifically deleted Nkx2-1 in lung airway cells (Sox2-creER; Nkx2-1f/f, hereafter referred to as Sox2-Nkx2-1f/f).	('Nkx2-1', 'Gene', (34, 40))	('Sox2', 'Gene', '20674', (111, 115))	('Sox2', 'Gene', (63, 67))	('Sox2', 'Gene', (111, 115))	('Sox2', 'Gene', '20674', (63, 67))	('deleted', 'Var', (26, 33))
260673	29587142	Similarly, we deleted Nkx2-1 in alveolar type 2 progenitor cells (Sftpc-creER; Nkx2-1f/f, hereafter referred to as Sftpc-Nkx2-1f/f) of an otherwise normal mouse (Fig.	('deleted', 'Var', (14, 21))	('mouse', 'Species', '10090', (155, 160))	('Sftpc', 'Gene', '20389', (66, 71))	('Sftpc', 'Gene', (66, 71))	('Sftpc', 'Gene', '20389', (115, 120))	('Sftpc', 'Gene', (115, 120))	('Nkx2-1', 'Gene', (22, 28))
260677	29587142	In aggregate, lung alveolar cells, but not airway cells, converted into tissues that resemble multiple distinct gut lineages after loss of Nkx2-1; however, no tumors formed.	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('tumors', 'Phenotype', 'HP:0002664', (159, 165))	('loss', 'Var', (131, 135))	('tumors', 'Disease', (159, 165))	('Nkx2-1', 'Gene', (139, 145))	('tumors', 'Disease', 'MESH:D009369', (159, 165))
260678	29587142	Activating Kras mutations are frequently observed in human MADs, and loss of Nkx2-1 coupled with mutant Kras activation has previously been shown to drive the production of MADs in mice using Scgb1a1 secretory cell promoter-driven Cre or a ubiquitous Rosa26 promoter-driven CreER.	('mice', 'Species', '10090', (181, 185))	('Scgb1a1', 'Gene', (192, 199))	('Scgb1a1', 'Gene', '22287', (192, 199))	('loss', 'Var', (69, 73))	('mutant', 'Var', (97, 103))	('activation', 'PosReg', (109, 119))	('Kras', 'Gene', (104, 108))	('human', 'Species', '9606', (53, 58))	('drive', 'Reg', (149, 154))	('Nkx2-1', 'Gene', (77, 83))
260679	29587142	To systematically dissect whether the loss of lung identity (through deletion of NKX2-1) in an oncogenic environment will result in adenocarcinomas that resemble histological and molecular features of multiple neighboring gut organs, we generated mouse models to concomitantly delete NKX2-1 and to constitutively express mutant Kras in pan-airway epithelial cells or specifically in alveolar type 2 cells.	('carcinomas', 'Phenotype', 'HP:0030731', (137, 147))	('mouse', 'Species', '10090', (247, 252))	('result', 'Reg', (122, 128))	('express', 'Reg', (313, 320))	('delete', 'NegReg', (277, 283))	('NKX2-1', 'Gene', (81, 87))	('adenocarcinomas', 'Disease', 'MESH:D000230', (132, 147))	('NKX2-1', 'Gene', (284, 290))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('mutant', 'Var', (321, 327))	('deletion', 'Var', (69, 77))	('rat', 'Species', '10116', (241, 244))	('adenocarcinomas', 'Disease', (132, 147))
260681	29587142	In these mice, tamoxifen administration concomitantly triggers a homozygous deletion of Nkx2-1 and simultaneously activates oncogenic KrasG12D.	('deletion', 'Var', (76, 84))	('tamoxifen', 'Chemical', 'MESH:D013629', (15, 24))	('activates', 'PosReg', (114, 123))	('oncogenic KrasG12D', 'CPA', (124, 142))	('rat', 'Species', '10116', (33, 36))	('Nkx2-1', 'Gene', (88, 94))	('mice', 'Species', '10090', (9, 13))
260688	29587142	In contrast, in the setting of oncogenic and ontogenetic transcription factor modulation, alveoli with concurrent oncogenic Kras and Nkx2-1 deletion (n = 4) were replete with MAD-like nodules that expressed TFF2, HNF4alpha and PDX1 (Fig.	('PDX1', 'Gene', '18609', (227, 231))	('Nkx2-1', 'Gene', (133, 139))	('TFF2', 'Gene', '21785', (207, 211))	('TFF2', 'Gene', (207, 211))	('deletion', 'Var', (140, 148))	('Kras', 'Gene', (124, 128))	('PDX1', 'Gene', (227, 231))	('HNF4alpha', 'Gene', '15378', (213, 222))	('HNF4alpha', 'Gene', (213, 222))
260689	29587142	Of note, Nkx2-1 deletion and Kras activation did not cause a cellular conversion of epithelial lineages into mesenchymal or endothelial lineages (as assessed by the expression of Fibroblast Specific Protein (FSP1) and CD31, respectively, in YFP+ lineage-traced cells) (Fig.	('CD31', 'Gene', '18613', (218, 222))	('CD31', 'Gene', (218, 222))	('deletion', 'Var', (16, 24))	('FSP1', 'Gene', '20198', (208, 212))	('Nkx2-1', 'Gene', (9, 15))	('FSP1', 'Gene', (208, 212))
260690	29587142	To assess whether loss of Nkx2-1 has any effect on the growth properties of these tumor cells, we performed immunofluorescence analysis for the proliferation marker Ki67 and found that there is a modest but statistically insignificant increase in the number of proliferating cells in mice with mutant Kras activation combined with Nkx2-1 loss as compared to mice with mutant Kras activation alone (14% +-2.05 in Kras vs 19.6% +-3.6 in Kras-Nkx2-1f/f; p >0.05) (Fig.	('Ki67', 'Gene', '17345', (165, 169))	('loss', 'NegReg', (338, 342))	('Kras', 'Gene', (301, 305))	('rat', 'Species', '10116', (268, 271))	('Nkx2-1', 'Gene', (331, 337))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('mice', 'Species', '10090', (358, 362))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('increase', 'PosReg', (235, 243))	('Ki67', 'Gene', (165, 169))	('mutant', 'Var', (294, 300))	('rat', 'Species', '10116', (151, 154))	('proliferating cells', 'CPA', (261, 280))	('tumor', 'Disease', (82, 87))	('mice', 'Species', '10090', (284, 288))
260697	29587142	Indeed, mice treated with adeno-cre virus to cause Nkx2-1 loss and Sox2 gain (n = 3) developed SCCs, which expressed CK5, CK14, p63, and CK6 (Fig.	('SCC', 'Gene', '6317', (95, 98))	('SCCs', 'Phenotype', 'HP:0002860', (95, 99))	('CK6', 'Var', (137, 140))	('p63', 'Gene', '22061', (128, 131))	('p63', 'Gene', (128, 131))	('CK14', 'Gene', (122, 126))	('CK5', 'Gene', '110308', (117, 120))	('Nkx2-1 loss and Sox2 gain', 'Disease', 'MESH:D015430', (51, 76))	('CK5', 'Gene', (117, 120))	('SCC', 'Gene', (95, 98))	('CK14', 'Gene', '16664', (122, 126))	('mice', 'Species', '10090', (8, 12))
260701	29587142	We reasoned that the lack of SCC formation following Sox2 ectopic expression could be due to the presence of NKX2-1, which was maintaining the lung cell identity.	('SCC', 'Gene', '6317', (29, 32))	('Sox2', 'Gene', '20674', (53, 57))	('NKX2-1', 'Gene', (109, 115))	('Sox2', 'Gene', (53, 57))	('ectopic expression', 'Var', (58, 76))	('SCC', 'Gene', (29, 32))
260702	29587142	We therefore generated Sox2-SIGf/+-Nkx2-1f/f mice (n = 3), with which we could concomitantly delete Nkx2-1 and ectopically express Sox2.	('Sox2', 'Gene', '20674', (131, 135))	('mice', 'Species', '10090', (45, 49))	('delete', 'Var', (93, 99))	('Sox2', 'Gene', '20674', (23, 27))	('Nkx2-1', 'Gene', (100, 106))	('Sox2', 'Gene', (131, 135))	('Sox2', 'Gene', (23, 27))	('rat', 'Species', '10116', (17, 20))
260704	29587142	Instead, airways were enriched for FOXJ1+ ciliated cells and depleted of SCGB1A1+ secretory club cells (Fig.	('SCGB1A1', 'Gene', '7356', (73, 80))	('club', 'Phenotype', 'HP:0001217', (92, 96))	('SCGB1A1', 'Gene', (73, 80))	('FOXJ1+', 'Var', (35, 41))
260707	29587142	In this setting, we indeed observed large lung SCCs in 6 out of 8 mice, which were positive for esophageal and forestomach squamous markers, including CK6, CK14, p63 and PAX9 (Fig.	('SCCs', 'Phenotype', 'HP:0002860', (47, 51))	('CK6', 'Var', (151, 154))	('CK14', 'Gene', (156, 160))	('SCC', 'Gene', '6317', (47, 50))	('CK14', 'Gene', '16664', (156, 160))	('p63', 'Gene', '22061', (162, 165))	('forestomach squamous', 'Disease', (111, 131))	('mice', 'Species', '10090', (66, 70))	('PAX9', 'Gene', '18511', (170, 174))	('forestomach squamous', 'Disease', 'MESH:D013274', (111, 131))	('p63', 'Gene', (162, 165))	('PAX9', 'Gene', (170, 174))	('SCC', 'Gene', (47, 50))
260712	29587142	Through quantitative analysis of Ki67 expression we found that there is a significant increase (31% +-1.9 SIGf/f-Nkx2-1f/f vs 17% +-2.62 in SIGf/f mouse models; P< 0.05) in the number of proliferating cells, indicating that the loss of Nkx2-1 alters not only lung cell identity, but also increases tumor cell propagation (Fig.	('mouse', 'Species', '10090', (147, 152))	('tumor', 'Disease', (298, 303))	('Ki67', 'Gene', (33, 37))	('rat', 'Species', '10116', (194, 197))	('alters', 'Reg', (243, 249))	('loss', 'Var', (228, 232))	('tumor', 'Disease', 'MESH:D009369', (298, 303))	('Ki67', 'Gene', '17345', (33, 37))	('increases', 'PosReg', (288, 297))	('tumor', 'Phenotype', 'HP:0002664', (298, 303))	('lung cell identity', 'CPA', (259, 277))	('Nkx2-1', 'Gene', (236, 242))
260713	29587142	Taken together, our results demonstrate that loss of the lung lineage-specifying transcription factor NKX2-1 coupled with high levels of the foregut-specifying transcription factor SOX2 is sufficient to drive the conversion of lung epithelial cells into foregut-like squamous tissues.	('loss', 'Var', (45, 49))	('drive', 'Reg', (203, 208))	('conversion', 'CPA', (213, 223))	('rat', 'Species', '10116', (35, 38))	('NKX2-1', 'Gene', (102, 108))
260725	29587142	Marker analysis indicated that cultured cells expressed markers of SCC and MAD in the respective genotypes but only when Nkx2-1 is deleted (Fig.	('SCC', 'Gene', '6317', (67, 70))	('Nkx2-1', 'Gene', (121, 127))	('deleted', 'Var', (131, 138))	('SCC', 'Gene', (67, 70))	('MAD', 'Disease', (75, 78))
260727	29587142	Our conditional mouse models indicate that the loss of Nkx2-1 influences tumor cell lineage plasticity, and additionally suggests that loss of Nkx2-1 promotes tumor cell replication and progression in vivo in certain contexts (Fig.	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('promotes', 'PosReg', (150, 158))	('Nkx2-1', 'Gene', (143, 149))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('influences', 'Reg', (62, 72))	('tumor', 'Disease', (159, 164))	('Nkx2-1', 'Gene', (55, 61))	('loss', 'Var', (135, 139))	('tumor', 'Disease', (73, 78))	('loss', 'Var', (47, 51))	('mouse', 'Species', '10090', (16, 21))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('progression', 'CPA', (186, 197))
260729	29587142	Since the presence of Nkx2-1 restricts Sox2 from driving a squamous differentiation program in the airway epithelium, we hypothesized that the presence or absence of Nkx2.1 might alter Sox2 genomic occupancy.	('Sox2', 'Gene', (185, 189))	('squamous differentiation program', 'CPA', (59, 91))	('Sox2', 'Gene', '20674', (39, 43))	('Sox2', 'Gene', '20674', (185, 189))	('alter', 'Reg', (179, 184))	('Nkx2.1', 'Gene', '21869', (166, 172))	('restricts', 'NegReg', (29, 38))	('Nkx2-1', 'Gene', (22, 28))	('presence', 'Var', (10, 18))	('Sox2', 'Gene', (39, 43))	('Nkx2.1', 'Gene', (166, 172))	('driving', 'Reg', (49, 56))
260730	29587142	We thus performed Sox2 chromatin immunoprecipitation followed by deep sequencing (ChIP-seq) on SIG Nkx2-1+/+ and SIG Nkx2-1-/- primary lung epithelial cells.	('Sox2', 'Gene', '20674', (18, 22))	('Sox2', 'Gene', (18, 22))	('Nkx2-1+/+', 'Var', (99, 108))	('SIG Nkx2-1+/+', 'Var', (95, 108))
260732	29587142	Of note, 72 regions were depleted of Sox2 binding upon Nkx2-1 deletion, while 1185 regions were exclusively bound by Sox2 in the absence of Nkx2-1 (Fig.	('Sox2', 'Gene', (117, 121))	('Sox2', 'Gene', '20674', (37, 41))	('depleted', 'NegReg', (25, 33))	('binding', 'Interaction', (42, 49))	('Nkx2-1', 'Gene', (55, 61))	('Sox2', 'Gene', (37, 41))	('deletion', 'Var', (62, 70))	('Sox2', 'Gene', '20674', (117, 121))
260734	29587142	For instance, we found that Sox2 acquired several new binding sites in the Trp63 locus after Nkx2-1 deletion (Fig.	('Trp63', 'Gene', (75, 80))	('Sox2', 'Gene', (28, 32))	('Sox2', 'Gene', '20674', (28, 32))	('Nkx2-1', 'Gene', (93, 99))	('deletion', 'Var', (100, 108))	('binding', 'Interaction', (54, 61))	('Trp63', 'Gene', '22061', (75, 80))
260742	29587142	Taken together, these results indicate that Nkx2-1 deletion dramatically alters the binding profile of Sox2 in lung epithelial cells allowing an activation of a squamous differentiation program.	('activation', 'PosReg', (145, 155))	('Sox2', 'Gene', '20674', (103, 107))	('Sox2', 'Gene', (103, 107))	('binding profile', 'MPA', (84, 99))	('deletion', 'Var', (51, 59))	('alters', 'Reg', (73, 79))	('Nkx2-1', 'Gene', (44, 50))	('squamous differentiation program', 'CPA', (161, 193))
260743	29587142	As transcription factors generally work in multi-factor complexes to drive specific differentiation programs, we wondered whether Nkx2-1 deletion alters the binding partners of Sox2.	('binding', 'Interaction', (157, 164))	('Sox2', 'Gene', '20674', (177, 181))	('deletion', 'Var', (137, 145))	('Sox2', 'Gene', (177, 181))	('alters', 'Reg', (146, 152))	('Nkx2-1', 'Gene', (130, 136))
260748	29587142	To explicitly delineate possible changes in Sox2 binding partners with or without Nkx2-1, we next performed differential motif analysis between SIG Nkx2-1+/+ and SIG Nkx2-1-/- specific regions.	('Sox2', 'Gene', (44, 48))	('Sox2', 'Gene', '20674', (44, 48))	('SIG Nkx2-1+/+', 'Var', (144, 157))
260750	29587142	This finding suggests that the Sox2 binding sites which are lost upon Nkx2-1 deletion are likely due to the loss of direct interactions between Sox2 and Nkx2-1 at these specific sites.	('lost', 'NegReg', (60, 64))	('direct interactions', 'Interaction', (116, 135))	('loss', 'NegReg', (108, 112))	('Sox2', 'Gene', (31, 35))	('Nkx2-1', 'Gene', (70, 76))	('deletion', 'Var', (77, 85))	('Sox2', 'Gene', '20674', (144, 148))	('Sox2', 'Gene', '20674', (31, 35))	('Sox2', 'Gene', (144, 148))
260754	29587142	Using previously published H3K27ac ChIP-seq data in mouse MADs, we also found that Nkx2-1 deletion led to a gain of H3K27ac signal around Cdx2 and Tff2, in addition to the previously reported gain of H3K27ac signal around Hnf4a (Fig.	('deletion', 'Var', (90, 98))	('Tff2', 'Gene', (147, 151))	('Cdx2', 'Gene', (138, 142))	('H3K27ac signal', 'MPA', (116, 130))	('Tff2', 'Gene', '21785', (147, 151))	('gain', 'PosReg', (108, 112))	('mouse', 'Species', '10090', (52, 57))	('Hnf4a', 'Gene', '15378', (222, 227))	('Nkx2-1', 'Gene', (83, 89))	('Cdx2', 'Gene', '12591', (138, 142))	('Hnf4a', 'Gene', (222, 227))
260783	29587142	The following antibodies were used: goat anti-CC10 (1:200; sc-9772, Santa Cruz Biotechnology), rabbit anti-CDX2 (1:100; 12306S, Cell Signaling Technology), rabbit anti-CK1 (1:400; PRB-149P, Covance), mouse anti-CK14 (1:400; ab7800, Abcam), rabbit anti-CK5 (1:1000; ab53121, Abcam), rabbit anti-CK6 (1:500; ab24646, Abcam), rabbit anti-CPS1 (1:400; ab3682, Abcam), goat anti-FOXA2 (1:250; sc6554, Santa Cruz Biotechnology), mouse anti-FOXJ1 (1:500; 14-9965, eBioscience), chicken anti-GFP (1:500; GFP-1020, Aves Labs); goat anti-GFP (1:100; NB-100-1770, Novus Biologicals), goat anti-HNF4alpha isoform 7-9 (1:250; PP-H6939-00, R&D Systems), rabbit anti-MUC2 (1:200; sc-15334, Santa Cruz Biotechnology), mouse IgG1 anti-MUC5AC (1:250; MS-145, Thermo Scientific), goat anti-MUC6 (1:200; sc-16914, Santa Cruz Biotechnology), mouse IgG1 anti-MUC6 (1:200; MUC-6-CE-S, Leica Biosystems), rabbit anti-NKX2-1 (1:500; ab76013, Abcam), mouse IgG2a anti-p63 (1:100; 790-4509, Ventana), rat anti-PAX9 (1:500; ab28538, Abcam), goat anti-PDX1 (1:200; AF2419, R&D Systems), sheep anti-PRSS1 (1:250; AF3848, R&D Systems), goat anti-SOX2 (1:200; AF2018, R&D Systems), goat anti-SOX9 (1:200; AF3075, R&D Systems), and rabbit anti-TFF2 (1:400; 13681-1-AP, ProteinTech).	('MUC5AC', 'Gene', (718, 724))	('rabbit', 'Species', '9986', (323, 329))	('goat', 'Species', '9925', (518, 522))	('chicken', 'Species', '9031', (471, 478))	('rabbit', 'Species', '9986', (156, 162))	('CK14', 'Gene', '16664', (211, 215))	('goat', 'Species', '9925', (1105, 1109))	('rabbit', 'Species', '9986', (640, 646))	('TFF2', 'Gene', (1211, 1215))	('IgG1', 'Gene', (827, 831))	('rabbit', 'Species', '9986', (282, 288))	('MUC6', 'Gene', (771, 775))	('CDX2', 'Gene', (107, 111))	('CPS1', 'Gene', '227231', (335, 339))	('MUC6', 'Gene', '353328', (837, 841))	('IgG1', 'Gene', (708, 712))	('PAX9', 'Gene', '18511', (983, 987))	('CK1', 'Gene', '666937', (211, 214))	('CK1', 'Gene', (211, 214))	('rat', 'Species', '10116', (974, 977))	('goat', 'Species', '9925', (573, 577))	('goat', 'Species', '9925', (1150, 1154))	('mouse', 'Species', '10090', (925, 930))	('SOX9', 'Gene', '20682', (1160, 1164))	('MUC2', 'Gene', '17831', (652, 656))	('PRSS1', 'Gene', '114228', (1069, 1074))	('rabbit', 'Species', '9986', (240, 246))	('anti-NKX2-1', 'Var', (888, 899))	('rabbit', 'Species', '9986', (1199, 1205))	('CDX2', 'Gene', '12591', (107, 111))	('CK14', 'Gene', (211, 215))	('rabbit', 'Species', '9986', (95, 101))	('p63', 'Gene', (942, 945))	('rabbit', 'Species', '9986', (881, 887))	('goat', 'Species', '9925', (761, 765))	('goat', 'Species', '9925', (364, 368))	('FOXA2', 'Gene', '15376', (374, 379))	('CK1', 'Gene', '666937', (168, 171))	('TFF2', 'Gene', '21785', (1211, 1215))	('CK1', 'Gene', (168, 171))	('mouse', 'Species', '10090', (702, 707))	('MUC6', 'Gene', (837, 841))	('HNF4alpha', 'Gene', (583, 592))	('IgG2a', 'Gene', '668478', (931, 936))	('FOXA2', 'Gene', (374, 379))	('goat', 'Species', '9925', (36, 40))	('CK5', 'Gene', (252, 255))	('MUC6', 'Gene', '353328', (771, 775))	('SOX9', 'Gene', (1160, 1164))	('MUC5AC', 'Gene', '17833', (718, 724))	('mouse', 'Species', '10090', (423, 428))	('IgG2a', 'Gene', (931, 936))	('IgG1', 'Gene', '16017', (827, 831))	('mouse', 'Species', '10090', (821, 826))	('p63', 'Gene', '22061', (942, 945))	('PDX1', 'Gene', (1023, 1027))	('CPS1', 'Gene', (335, 339))	('mouse', 'Species', '10090', (200, 205))	('PAX9', 'Gene', (983, 987))	('goat', 'Species', '9925', (1013, 1017))	('IgG1', 'Gene', '16017', (708, 712))	('HNF4alpha', 'Gene', '15378', (583, 592))	('sheep', 'Species', '9940', (1058, 1063))	('CK5', 'Gene', '110308', (252, 255))	('PDX1', 'Gene', '18609', (1023, 1027))	('PRSS1', 'Gene', (1069, 1074))	('MUC2', 'Gene', (652, 656))
260785	29587142	Lung epithelial cells were isolated from KrasLSL-G12D/+ mice, KrasLSL-G12D/+; Nkx2-1f/f mice, SIGf/f mice, and SIGf/f-Nkx2-1f/f mice and cultured as previously described.	('G12D', 'Mutation', 'rs121913529', (70, 74))	('Nkx2-1f/f', 'Var', (78, 87))	('KrasLSL-G12D/+', 'Var', (62, 76))	('mice', 'Species', '10090', (128, 132))	('mice', 'Species', '10090', (56, 60))	('mice', 'Species', '10090', (101, 105))	('mice', 'Species', '10090', (88, 92))	('G12D', 'Mutation', 'rs121913529', (49, 53))
260786	29587142	Cells were infected with Adeno-cre virus (Signagen laboratories, Cat# SL100706) to activate KrasG12D or SOX2 and to delete Nkx2-1.	('Nkx2-1', 'Gene', (123, 129))	('KrasG12D', 'Gene', (92, 100))	('activate', 'PosReg', (83, 91))	('delete', 'Var', (116, 122))	('rat', 'Species', '10116', (55, 58))	('SOX2', 'Gene', (104, 108))
260833	29587142	H3K27ac ChIP-seq signal tracks in Nkx2-1+/+ and Nkx2-1-/- lung tumors were created using a previously published dataset.	('H3K27ac', 'Var', (0, 7))	('lung tumors', 'Disease', 'MESH:D008175', (58, 69))	('lung tumor', 'Phenotype', 'HP:0100526', (58, 68))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('lung tumors', 'Phenotype', 'HP:0100526', (58, 69))	('lung tumors', 'Disease', (58, 69))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
260834	29587142	A framework for considering tumor plasticity through the lens of normal development Loss of Nkx2.1 leads to the acquisition of gut fates in mucinous adenocarcinoma A model of lung squamous cancer driven solely by transcription factor modulation Loss of Nkx2-1 rewires Sox2 genomic occupancy towards a squamous program	('Nkx2-1', 'Gene', (253, 259))	('tumor', 'Disease', (28, 33))	('squamous cancer', 'Phenotype', 'HP:0002860', (180, 195))	('Loss', 'Var', (245, 249))	('Loss', 'Var', (84, 88))	('Sox2', 'Gene', (268, 272))	('mucinous adenocarcinoma', 'Disease', (140, 163))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('mucinous adenocarcinoma', 'Disease', 'MESH:D002288', (140, 163))	('lung squamous cancer', 'Disease', 'MESH:D008175', (175, 195))	('lung squamous cancer', 'Disease', (175, 195))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('Nkx2.1', 'Gene', '21869', (92, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (154, 163))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('Sox2', 'Gene', '20674', (268, 272))	('Nkx2.1', 'Gene', (92, 98))
260848	29184450	Alterations in these signaling molecules and other cytokines play a key role in the pathophysiologic mechanism of multiple myeloma.	('multiple myeloma', 'Phenotype', 'HP:0006775', (114, 130))	('multiple myeloma', 'Disease', 'MESH:D009101', (114, 130))	('Alterations', 'Var', (0, 11))	('multiple myeloma', 'Disease', (114, 130))
260907	27043631	The most common high-risk HPV types are HPV16, HPV18, HPV31, HPV33 and HPV35.	('HPV31', 'Var', (54, 59))	('HPV18', 'Var', (47, 52))	('HPV16', 'Species', '333760', (40, 45))	('HPV16', 'Var', (40, 45))	('HPV33', 'Var', (61, 66))	('HPV', 'Species', '10566', (40, 43))	('HPV', 'Species', '10566', (71, 74))	('HPV', 'Species', '10566', (26, 29))	('HPV', 'Species', '10566', (54, 57))	('HPV35', 'Var', (71, 76))	('HPV', 'Species', '10566', (61, 64))	('HPV', 'Species', '10566', (47, 50))	('HPV35', 'Species', '10587', (71, 76))
260915	27043631	Furthermore, HPV+ HNSCC are characterized by poorly differentiated or basaloid histology compared to the HPV- HNSCC with a generally keratinized histology.	('HNSCC', 'Phenotype', 'HP:0012288', (18, 23))	('basaloid histology', 'CPA', (70, 88))	('HNSCC', 'Phenotype', 'HP:0012288', (110, 115))	('HPV', 'Species', '10566', (105, 108))	('poorly differentiated', 'CPA', (45, 66))	('HPV+ HNSCC', 'Var', (13, 23))	('HPV', 'Species', '10566', (13, 16))
260924	27043631	Cancerous lesions are recognized by an increased risk of viral DNA integration into the host genome.	('Cancerous lesions', 'Disease', (0, 17))	('viral DNA', 'Var', (57, 66))	('Cancerous lesions', 'Disease', 'MESH:D009062', (0, 17))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))
260931	27043631	Before the knowledge of HPV infections and widespread use of (next generation) sequencing, HNSCC progression was also seen as an accumulation of stepwise (epi)-genetic alterations such as loss of chromosome 9p21 (CDKN2A loss), acquisition of TP53 mutations, 11q13 amplification (CCDN1), EGFR overexpression and PTEN inactivation.	('HPV infections', 'Disease', 'MESH:D030361', (24, 38))	('inactivation', 'NegReg', (316, 328))	('loss', 'Var', (188, 192))	('HPV infections', 'Disease', (24, 38))	('overexpression', 'PosReg', (292, 306))	('TP53', 'Gene', '7157', (242, 246))	('HNSCC', 'Disease', (91, 96))	('p21', 'Gene', (208, 211))	('TP53', 'Gene', (242, 246))	('PTEN', 'Gene', (311, 315))	('mutations', 'Var', (247, 256))	('EGFR', 'Gene', (287, 291))	('PTEN', 'Gene', '5728', (311, 315))	('EGFR', 'Gene', '1956', (287, 291))	('p21', 'Gene', '644914', (208, 211))	('HNSCC', 'Phenotype', 'HP:0012288', (91, 96))
260934	27043631	Nonetheless, it was shown that HPV+ tumors have less chromosomal copy number alterations compared to the HPV- HNSCC.	('HPV', 'Species', '10566', (31, 34))	('tumors', 'Disease', 'MESH:D009369', (36, 42))	('HNSCC', 'Phenotype', 'HP:0012288', (110, 115))	('chromosomal copy number alterations', 'MPA', (53, 88))	('HPV+', 'Var', (31, 35))	('HPV', 'Species', '10566', (105, 108))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('less', 'NegReg', (48, 52))	('tumors', 'Disease', (36, 42))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))
260940	27043631	These studies showed a 2 to 5 fold increase in mutation rates between HPV- and HPV+ HNSCC.	('increase', 'PosReg', (35, 43))	('HPV', 'Species', '10566', (79, 82))	('HPV', 'Species', '10566', (70, 73))	('HPV+', 'Var', (79, 83))	('HNSCC', 'Phenotype', 'HP:0012288', (84, 89))	('mutation', 'MPA', (47, 55))
260945	27043631	Interestingly, several retrospective and prospective trials have shown that HPV+ HNSCC patients have better overall survival (OS), disease free survival (DFS) and locoregional control (LRC) compared to the HPV- patients and this is independent of the treatment modality.	('HPV', 'Species', '10566', (206, 209))	('locoregional control', 'CPA', (163, 183))	('patients', 'Species', '9606', (211, 219))	('disease free survival', 'CPA', (131, 152))	('overall survival', 'CPA', (108, 124))	('HNSCC', 'Gene', (81, 86))	('HPV', 'Species', '10566', (76, 79))	('HPV+', 'Var', (76, 80))	('HNSCC', 'Phenotype', 'HP:0012288', (81, 86))	('patients', 'Species', '9606', (87, 95))	('better', 'PosReg', (101, 107))
260954	27043631	One of the interesting observations about the performed studies involving RT is that HPV positivity results primarily in an improved LRC, but no statistically significant difference can be seen in distant metastasis rates.	('positivity', 'Var', (89, 99))	('improved', 'PosReg', (124, 132))	('LRC', 'CPA', (133, 136))	('HPV', 'Species', '10566', (85, 88))	('HPV', 'Gene', (85, 88))
260970	27043631	One of the first studies that not only showed the increased radiation sensitivity of HPV+ HNSCC cells but also investigated the possible influence of HPV on cell cycle progression and apoptosis was performed by Kimple et al.	('radiation sensitivity', 'CPA', (60, 81))	('HNSCC', 'Phenotype', 'HP:0012288', (90, 95))	('increased', 'PosReg', (50, 59))	('HPV', 'Species', '10566', (150, 153))	('HPV', 'Species', '10566', (85, 88))	('HPV+ HNSCC', 'Var', (85, 95))
260972	27043631	demonstrated that indeed introduction of E6 expression in HPV- HNSCC resulted in increased RT response by cell cycle regulation and cell death, but in a TP53 independent manner.	('HPV- HNSCC', 'Gene', (58, 68))	('cell cycle regulation', 'CPA', (106, 127))	('TP53', 'Gene', '7157', (153, 157))	('E6 expression', 'Var', (41, 54))	('increased RT', 'Phenotype', 'HP:0008151', (81, 93))	('TP53', 'Gene', (153, 157))	('increased', 'PosReg', (81, 90))	('cell death', 'CPA', (132, 142))	('HPV', 'Species', '10566', (58, 61))	('RT response', 'MPA', (91, 102))	('HNSCC', 'Phenotype', 'HP:0012288', (63, 68))
260978	27043631	showed that HPV+ tumors have not only impaired DNA damage response, but also showed that this response was related to the expression of p16INK4A.	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('tumors', 'Disease', (17, 23))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('p16INK4A', 'Gene', '1029', (136, 144))	('p16INK4A', 'Gene', (136, 144))	('DNA damage response', 'MPA', (47, 66))	('HPV', 'Species', '10566', (12, 15))	('HPV+', 'Var', (12, 16))	('impaired', 'NegReg', (38, 46))
260983	27043631	Currently, HPV positivity in HNSCC cancers is accepted to be a prognostic marker for outcome and is currently assessed in several institutions.	('HNSCC cancers', 'Disease', 'MESH:D000077195', (29, 42))	('HPV', 'Species', '10566', (11, 14))	('HPV', 'Gene', (11, 14))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('HNSCC', 'Phenotype', 'HP:0012288', (29, 34))	('positivity', 'Var', (15, 25))	('cancers', 'Phenotype', 'HP:0002664', (35, 42))	('HNSCC cancers', 'Disease', (29, 42))
260999	27043631	Of note, the cause of p16INK4a expression in HPV- cases is still unclear but likely to be due to mutations in p16INK4a/RB pathway.	('mutations', 'Var', (97, 106))	('HPV', 'Species', '10566', (45, 48))	('p16INK4a', 'Gene', '1029', (110, 118))	('p16INK4a', 'Gene', (22, 30))	('due to', 'Reg', (90, 96))	('p16INK4a', 'Gene', '1029', (22, 30))	('p16INK4a', 'Gene', (110, 118))
261012	27043631	Although several laboratory studies show that targeting of aberrant oncogenic/mitogenic signal transduction pathways can result in radiation sensitization of tumors, translation of this combination treatment strategy to clinical trial settings is rare.	('tumors', 'Disease', (158, 164))	('radiation sensitization', 'Phenotype', 'HP:0011133', (131, 154))	('tumors', 'Phenotype', 'HP:0002664', (158, 164))	('oncogenic/mitogenic signal transduction pathways', 'Pathway', (68, 116))	('radiation sensitization', 'MPA', (131, 154))	('tumors', 'Disease', 'MESH:D009369', (158, 164))	('aberrant', 'Var', (59, 67))	('result', 'Reg', (121, 127))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))
261014	27043631	Until recently, EGFR amplification or overexpression was seen as one of the most important aberrations in HNSCC patients leading to the development of EGFR inhibitors including monoclonal antibodies (mAb) as well as tyrosine kinase inhibitors (TKI).	('EGFR', 'Gene', (151, 155))	('monoclonal', 'Var', (177, 187))	('patients', 'Species', '9606', (112, 120))	('EGFR', 'Gene', '1956', (16, 20))	('HNSCC', 'Disease', (106, 111))	('HNSCC', 'Phenotype', 'HP:0012288', (106, 111))	('EGFR', 'Gene', (16, 20))	('EGFR', 'Gene', '1956', (151, 155))
261027	27043631	Aberration and subsequent activation of PI3K pathway is one the most frequent events seen in HNSCC patients (34% in HPV- and 56% in HPV+).	('HNSCC', 'Disease', (93, 98))	('HPV', 'Species', '10566', (116, 119))	('HNSCC', 'Phenotype', 'HP:0012288', (93, 98))	('PI3K pathway', 'Pathway', (40, 52))	('HPV', 'Species', '10566', (132, 135))	('activation', 'PosReg', (26, 36))	('patients', 'Species', '9606', (99, 107))	('Aberration', 'Var', (0, 10))
261028	27043631	Activating mutations of the PIK3CA gene have been reported in 8%-21% of head and neck tumors, with an enrichment of mutations in HPV+ (37%) patients in comparison with HPV- patient population (18%).	('HPV', 'Species', '10566', (168, 171))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('Activating', 'PosReg', (0, 10))	('PIK3CA', 'Gene', (28, 34))	('neck tumors', 'Disease', 'MESH:D006258', (81, 92))	('patient', 'Species', '9606', (140, 147))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('mutations', 'Var', (116, 125))	('neck tumors', 'Disease', (81, 92))	('patients', 'Species', '9606', (140, 148))	('patient', 'Species', '9606', (173, 180))	('HPV', 'Species', '10566', (129, 132))	('head and neck tumors', 'Phenotype', 'HP:0012288', (72, 92))
261030	27043631	This suggests that PIK3CA mutations may have an important role in the development of HPV+ HNSCC as it has been hypothesized for cervical cancers.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('PIK3CA', 'Gene', (19, 25))	('HNSCC', 'Phenotype', 'HP:0012288', (90, 95))	('cancers', 'Phenotype', 'HP:0002664', (137, 144))	('HPV+ HNSCC', 'Disease', (85, 95))	('mutations', 'Var', (26, 35))	('cervical cancers', 'Disease', (128, 144))	('cervical cancers', 'Disease', 'MESH:D002583', (128, 144))	('HPV', 'Species', '10566', (85, 88))
261032	27043631	Although, the activity of PI3K inhibitors as single agents in lung squamous cell cancer patients with PTEN/PIK3CA mutations are disappointing.	('lung squamous cell cancer', 'Disease', 'MESH:D002294', (62, 87))	('mutations', 'Var', (114, 123))	('lung squamous cell cancer', 'Phenotype', 'HP:0030359', (62, 87))	('patients', 'Species', '9606', (88, 96))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (67, 87))	('lung squamous cell cancer', 'Disease', (62, 87))	('PTEN', 'Gene', (102, 106))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('PTEN', 'Gene', '5728', (102, 106))
261033	27043631	A preclinical study performed in HNSCC mouse model showed selective efficiency of PI3K inhibition in PIK3CA mutated samples.	('inhibition', 'NegReg', (87, 97))	('mutated', 'Var', (108, 115))	('HNSCC', 'Phenotype', 'HP:0012288', (33, 38))	('PI3K', 'Pathway', (82, 86))	('mouse', 'Species', '10090', (39, 44))	('PIK3CA', 'Gene', (101, 107))
261041	27043631	Thus, the choice of repair is cell cycle dependent with NHEJ preferred in G0/G1 phase of cell cycle and HRR taking place during S/G2/M cell-cycle phases.	('NHEJ', 'Gene', (56, 60))	('S/G2', 'Var', (128, 132))	('S/G2', 'SUBSTITUTION', 'None', (128, 132))
261050	27043631	Annealing of DNA is mediated by RAD52 leading to the deletion of one of the repeats and the DNA sequences between the repeats or to translocations when 2 DSB occur in different chromosomes.	('RAD52', 'Gene', '5893', (32, 37))	('translocations', 'Var', (132, 146))	('deletion', 'Var', (53, 61))	('RAD52', 'Gene', (32, 37))
261052	27043631	For example inhibitors of important molecules in DSB repair, such as DNA-PKcs and PARP inhibitors have been shown to sensitize cancer cells to RT.	('inhibitors', 'Var', (12, 22))	('DNA-PKcs', 'Gene', (69, 77))	('sensitize', 'Reg', (117, 126))	('PARP', 'Gene', (82, 86))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('PARP', 'Gene', '142', (82, 86))	('cancer', 'Disease', (127, 133))	('DNA-PKcs', 'Gene', '5591', (69, 77))
261056	27043631	The best example of a synthetic lethality approach is the use of Poly (ADP ribose) polymerase (PARP1) in BRCA1/2 mutated breast and ovarian cancers.	('breast and ovarian cancers', 'Disease', 'MESH:D010051', (121, 147))	('cancers', 'Phenotype', 'HP:0002664', (140, 147))	('BRCA1/2', 'Gene', (105, 112))	('mutated', 'Var', (113, 120))	('Poly (ADP ribose) polymerase (PARP1', 'Gene', '142', (65, 100))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('BRCA1/2', 'Gene', '672;675', (105, 112))	('ovarian cancers', 'Phenotype', 'HP:0100615', (132, 147))
261058	27043631	In line with this, cancer cells with aberrations in their repair mechanisms are expected to shift their repair to less common used back-up DNA repair pathways in response to IR, this compared to normal cells where the common used DNA repair mechanism is still intact.	('back-up DNA repair pathways', 'Pathway', (131, 158))	('cancer', 'Disease', 'MESH:D009369', (19, 25))	('shift', 'Reg', (92, 97))	('cancer', 'Disease', (19, 25))	('aberrations', 'Var', (37, 48))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('repair', 'MPA', (104, 110))
261059	27043631	Inhibition of the back-up DNA repair pathway used by the tumor cells can result in a relative tumor selective radiation sensitization.	('back-up', 'Pathway', (18, 25))	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('radiation sensitization', 'Phenotype', 'HP:0011133', (110, 133))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Disease', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('Inhibition', 'Var', (0, 10))	('tumor', 'Disease', (57, 62))
261060	27043631	Since synthetic lethal drugs inhibit DNA repair components, it will also result in an increased mutation rate of the repair pathways and as a consequence the cancer cell can activate the repressed DNA repair pathways by additional mutations as it is noted for BRCA2 and PARP inhibition.	('activate', 'PosReg', (174, 182))	('DNA repair components', 'Protein', (37, 58))	('increased', 'PosReg', (86, 95))	('mutations', 'Var', (231, 240))	('PARP', 'Gene', '142', (270, 274))	('repair pathways', 'Pathway', (117, 132))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('inhibit', 'NegReg', (29, 36))	('BRCA2', 'Gene', (260, 265))	('cancer', 'Disease', (158, 164))	('DNA repair pathways', 'Pathway', (197, 216))	('PARP', 'Gene', (270, 274))	('BRCA2', 'Gene', '675', (260, 265))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('mutation rate', 'MPA', (96, 109))
261063	28550687	Tanshinone Suppresses Arecoline-Induced Epithelial-Mesenchymal Transition in Oral Submucous Fibrosis by Epigenetically Reactivating the p53 Pathway Oral submucous fibrosis (OSF) induced by chewing of the areca nut has been considered to be a precancerous lesion with a high probability of developing oral squamous cell carcinoma.	('areca nut', 'Species', '184783', (204, 213))	('Arecoline', 'Chemical', 'MESH:D001115', (22, 31))	('precancerous lesion', 'Disease', (242, 261))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (300, 328))	('p53', 'Gene', '7157', (136, 139))	('Fibrosis', 'Disease', (92, 100))	('Tanshinone', 'Chemical', 'MESH:C021751', (0, 10))	('carcinoma', 'Phenotype', 'HP:0030731', (319, 328))	('precancerous lesion', 'Disease', 'MESH:D011230', (242, 261))	('Fibrosis', 'Disease', 'MESH:D005355', (92, 100))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (305, 328))	('Suppresses', 'NegReg', (11, 21))	('Epigenetically Reactivating', 'Var', (104, 131))	('oral squamous cell carcinoma', 'Disease', (300, 328))	('fibrosis', 'Disease', 'MESH:D005355', (163, 171))	('fibrosis', 'Disease', (163, 171))	('cancer', 'Phenotype', 'HP:0002664', (245, 251))	('p53', 'Gene', (136, 139))
261070	28550687	Furthermore, we identified that LSD1 could epigenetically activate TP53 by recruiting H3K27me1 and H3K4m2 to its promoter.	('recruiting', 'PosReg', (75, 85))	('H3K4m2', 'Var', (99, 105))	('epigenetically', 'Var', (43, 57))	('H3K27me1', 'Protein', (86, 94))	('activate', 'PosReg', (58, 66))	('TP53', 'Gene', '7157', (67, 71))	('TP53', 'Gene', (67, 71))
261076	28550687	For example, chronic arecoline exposure (found in the areca nut) of human oral epithelial cells resulted in increased cluster of differentiation 44 (CD44) positivity and epithelial-mesenchymal transition (EMT) traits, a crucial event in the formation of oral squamous cell carcinoma and OSF.	('areca nut', 'Species', '184783', (54, 63))	('human', 'Species', '9606', (68, 73))	('CD44', 'Gene', (149, 153))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (259, 282))	('cluster of', 'CPA', (118, 128))	('increased', 'PosReg', (108, 117))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (254, 282))	('positivity', 'Var', (155, 165))	('arecoline', 'Chemical', 'MESH:D001115', (21, 30))	('carcinoma', 'Phenotype', 'HP:0030731', (273, 282))	('oral squamous cell carcinoma', 'Disease', (254, 282))	('epithelial-mesenchymal transition', 'CPA', (170, 203))
261082	28550687	For example, TSN IIA can inhibit the growth of human gastric cancer cells through increasing the protein expression of phosphorylated mitogen-activated protein kinase (p-p38) and phosphorylated C-Jun N-terminal kinase (p-JNK) and activating tumor protein p53 (p53), followed by increasing the protein expression of cyclin-dependent kinase inhibitor 1A (p21).	('tumor', 'Disease', (241, 246))	('JNK', 'Gene', (221, 224))	('gastric cancer', 'Disease', (53, 67))	('TSN IIA', 'Chemical', 'MESH:C021751', (13, 20))	('cyclin-dependent kinase inhibitor 1A', 'Gene', (315, 351))	('activating', 'PosReg', (230, 240))	('p38', 'Gene', (170, 173))	('JNK', 'Gene', '5599', (221, 224))	('cyclin-dependent kinase inhibitor 1A', 'Gene', '1026', (315, 351))	('tumor', 'Disease', 'MESH:D009369', (241, 246))	('human', 'Species', '9606', (47, 52))	('gastric cancer', 'Disease', 'MESH:D013274', (53, 67))	('growth', 'CPA', (37, 43))	('protein expression', 'MPA', (97, 115))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))	('p38', 'Gene', '1432', (170, 173))	('increasing', 'PosReg', (82, 92))	('increasing', 'PosReg', (278, 288))	('TSN', 'Var', (13, 16))	('protein expression', 'MPA', (293, 311))	('inhibit', 'NegReg', (25, 32))	('gastric cancer', 'Phenotype', 'HP:0012126', (53, 67))
261111	28550687	The primers used were unmethylated TP53, 5'-GGTTTTAGGATTAGAGGATAGATTGA-3' (forward) and 5'-CCTTCCTACAAAA AAAACAAACAAA-3' (reverse); and methylated TP53, 5'-GGGTTTTAGGATTAGAG GATAGATC-3' (forward) and 5'-CTTCCTACAAAAAAAACAAACGAA-3' (reverse).	('methylated', 'Var', (136, 146))	('TP53', 'Gene', (147, 151))	('TP53', 'Gene', '7157', (35, 39))	('TP53', 'Gene', (35, 39))	('TP53', 'Gene', '7157', (147, 151))
261146	28550687	Notably, TSN treatment abolished arecoline-induced fibroblast proliferation, and this effect was attenuated by knockdown of TP53 by shRNA (Fig.	('arecoline-induced', 'MPA', (33, 50))	('knockdown', 'Var', (111, 120))	('TSN', 'Chemical', 'MESH:C021751', (9, 12))	('TP53', 'Gene', '7157', (124, 128))	('TP53', 'Gene', (124, 128))	('arecoline', 'Chemical', 'MESH:D001115', (33, 42))	('abolished', 'NegReg', (23, 32))
261148	28550687	We found that knockdown of LSD1 could significantly increase the protein levels of p53 under the arecoline challenge (Fig.	('LSD1', 'Gene', (27, 31))	('increase', 'PosReg', (52, 60))	('arecoline', 'Chemical', 'MESH:D001115', (97, 106))	('arecoline challenge', 'MPA', (97, 116))	('knockdown', 'Var', (14, 23))	('protein levels of p53', 'MPA', (65, 86))
261151	28550687	In addition, the promoter region of TP53 was inserted into a PGL3 luciferase reporter vector, and Dual-Luciferase Reporter analysis showed that knockdown of LSD1 could activate luciferase (Fig.	('TP53', 'Gene', (36, 40))	('luciferase', 'Enzyme', (177, 187))	('PGL3', 'Gene', '6391', (61, 65))	('activate', 'PosReg', (168, 176))	('TP53', 'Gene', '7157', (36, 40))	('PGL3', 'Gene', (61, 65))	('knockdown', 'Var', (144, 153))	('LSD1', 'Gene', (157, 161))
261152	28550687	Moreover, we found that knockdown of LSD1 could increase the binding of H3K27me1 and H3K4m2 on the TP53 promoter, which was similar to the TSN treatment (Fig.	('TP53', 'Gene', (99, 103))	('H3K4m2', 'Var', (85, 91))	('H3K27me1', 'Protein', (72, 80))	('TSN', 'Chemical', 'MESH:C021751', (139, 142))	('LSD1', 'Gene', (37, 41))	('TP53', 'Gene', '7157', (99, 103))	('knockdown', 'Var', (24, 33))	('binding', 'Interaction', (61, 68))	('increase', 'PosReg', (48, 56))
261153	28550687	These results indicate that TSN may epigenetically activate p53 in OSF by inhibiting LSD1.	('LSD1', 'CPA', (85, 89))	('inhibiting', 'NegReg', (74, 84))	('epigenetically', 'Var', (36, 50))	('activate', 'PosReg', (51, 59))	('p53', 'Gene', (60, 63))	('OSF', 'Disease', (67, 70))	('TSN', 'Chemical', 'MESH:C021751', (28, 31))
261173	28550687	Notably, TSN IIA exerted a strong radiosensitizing effect on oral squamous carcinoma cells compared with the simple drug or single radiation treatment by enhancing reactive oxygen species (ROS) generation and autophagy.	('enhancing', 'PosReg', (154, 163))	('TSN', 'Var', (9, 12))	('ROS', 'Chemical', 'MESH:D017382', (189, 192))	('squamous carcinoma', 'Disease', 'MESH:D002294', (66, 84))	('squamous carcinoma', 'Disease', (66, 84))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (164, 187))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (66, 84))	('autophagy', 'CPA', (209, 218))	('TSN IIA', 'Chemical', 'MESH:C021751', (9, 16))
261178	28550687	p53, one of the most frequently mutated and deleted tumor suppressors in a multitude of tumor types, has been frequently reported to be downregulated or deleted in oral squamous cell carcinoma, suggesting other mechanisms in OSF, the precancerous lesion likely responsible for the downregulation of p53.	('p53', 'Gene', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('precancerous lesion', 'Disease', 'MESH:D011230', (234, 253))	('downregulated', 'NegReg', (136, 149))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (169, 192))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('tumor', 'Disease', (52, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (183, 192))	('oral squamous cell carcinoma', 'Disease', (164, 192))	('deleted', 'Var', (153, 160))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('OSF', 'Disease', (225, 228))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('tumor', 'Disease', (88, 93))	('precancerous lesion', 'Disease', (234, 253))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (164, 192))
261182	28550687	Importantly, TSN treatment can epigenetically demethylate the promoter of TP53 and upregulate the p53 levels by inhibiting LSD1 expression.	('upregulate', 'PosReg', (83, 93))	('promoter', 'MPA', (62, 70))	('epigenetically demethylate', 'Var', (31, 57))	('p53 levels', 'MPA', (98, 108))	('TSN', 'Chemical', 'MESH:C021751', (13, 16))	('LSD1 expression', 'MPA', (123, 138))	('TP53', 'Gene', '7157', (74, 78))	('demethylate', 'Var', (46, 57))	('TP53', 'Gene', (74, 78))	('inhibiting', 'NegReg', (112, 122))
261183	28550687	One of the early genetic studies found a statistically significant increase in the size of C-band heteromorphism patterns on chromosome 1 in OSF and oral squamous cell carcinoma patients when compared with healthy subjects.	('carcinoma', 'Phenotype', 'HP:0030731', (168, 177))	('size', 'MPA', (83, 87))	('C-band', 'Var', (91, 97))	('patients', 'Species', '9606', (178, 186))	('OSF', 'Disease', (141, 144))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (149, 177))	('increase', 'PosReg', (67, 75))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (154, 177))	('oral squamous cell carcinoma', 'Disease', (149, 177))
261190	28550687	Here our results demonstrated a novel mechanism that TSN epigenetically activates the p53 pathway by inhibiting LSD1.	('activates', 'PosReg', (72, 81))	('LSD1', 'MPA', (112, 116))	('epigenetically', 'Var', (57, 71))	('p53 pathway', 'Pathway', (86, 97))	('TSN', 'Chemical', 'MESH:C021751', (53, 56))	('inhibiting', 'NegReg', (101, 111))
261197	28550687	This effect was reversed by increasing the binding of H3K27me1 and H3K4m2 on the TP53 promoter with TSN treatment.	('binding', 'Interaction', (43, 50))	('TP53', 'Gene', (81, 85))	('increasing', 'PosReg', (28, 38))	('TSN', 'Chemical', 'MESH:C021751', (100, 103))	('H3K27me1', 'Var', (54, 62))	('TP53', 'Gene', '7157', (81, 85))	('H3K4m2', 'Var', (67, 73))
261198	28550687	These results indicate that TSN may epigenetically activate TP53 in OSF by inhibiting LSD1.	('epigenetically', 'Var', (36, 50))	('OSF', 'Disease', (68, 71))	('inhibiting', 'NegReg', (75, 85))	('activate', 'PosReg', (51, 59))	('LSD1', 'MPA', (86, 90))	('TP53', 'Gene', '7157', (60, 64))	('TP53', 'Gene', (60, 64))	('TSN', 'Chemical', 'MESH:C021751', (28, 31))
261214	32831192	Recent studies have focused increasing attention on the potential of long non-coding RNAs (lncRNAs) in cancer etiology .	('long non-coding RNAs', 'Var', (69, 89))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))
261215	32831192	Significantly, it has been suggested that aberrant expression of lncRNAs is implicated in the development and progression of lung cancer .	('lung cancer', 'Disease', 'MESH:D008175', (125, 136))	('aberrant expression', 'Var', (42, 61))	('lung cancer', 'Phenotype', 'HP:0100526', (125, 136))	('lung cancer', 'Disease', (125, 136))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('lncRNAs', 'Gene', (65, 72))	('implicated', 'Reg', (76, 86))
261217	32831192	indicated that high expression of MALAT-1 was correlated with tumor metastasis and a poor prognosis, in patients with NSCLC.	('high', 'Var', (15, 19))	('MALAT-1', 'Gene', (34, 41))	('NSCLC', 'Phenotype', 'HP:0030358', (118, 123))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor metastasis', 'Disease', 'MESH:D009362', (62, 78))	('NSCLC', 'Disease', (118, 123))	('MALAT-1', 'Gene', '378938', (34, 41))	('tumor metastasis', 'Disease', (62, 78))	('NSCLC', 'Disease', 'MESH:D002289', (118, 123))	('correlated with', 'Reg', (46, 61))	('patients', 'Species', '9606', (104, 112))
261243	32831192	Then these predictive lncRNAs underwent a stepwise multivariate Cox's regression analysis, and 14 lncRNAs were constructed for clinical prognostic prediction, including C20orf197, LINC00319, AC090286.1, AC004485.1, AL355916.1, LINC00941, AC119150.1, AC025419.1, AC034223.2, AC073651.1, AC007406.4, LINC02320, AC097504.2, and AL161431.1.	('AC007406.4', 'Var', (286, 296))	('Cox', 'Gene', (64, 67))	('LINC02320', 'Var', (298, 307))	('AC097504.2', 'Var', (309, 319))	('AL161431.1', 'Var', (325, 335))	('LINC00941', 'Gene', '100287314', (227, 236))	('AC119150.1', 'Var', (238, 248))	('C20orf197', 'Gene', '284756', (169, 178))	('AC073651.1', 'Var', (274, 284))	('C20orf197', 'Gene', (169, 178))	('AL355916.1', 'Var', (215, 225))	('AL355916', 'Chemical', '-', (215, 223))	('Cox', 'Gene', '1351', (64, 67))	('AC004485.1', 'Var', (203, 213))	('LINC00319', 'Gene', '284836', (180, 189))	('AC090286.1', 'Var', (191, 201))	('AC025419.1', 'Var', (250, 260))	('LINC00319', 'Gene', (180, 189))	('AC034223.2', 'Var', (262, 272))	('LINC00941', 'Gene', (227, 236))
261256	32831192	Compared with normal tissues, of these 14 lncRNAs, nine (AC034223.2, AC073651.1, AC119150.1, AL161431.1, AL355916.1, C20orf197, LINC00319, LINC00941 and LINC02320) were up-regulated in tumor tissues, and the other 5 (AC090286.1, AC004485.1, AC025419.1, AC007406.4 and AC097504.2,) showed a lower expression in tumor tissues ( 0.0001, Fig.	('C20orf197', 'Gene', (117, 126))	('tumor', 'Phenotype', 'HP:0002664', (310, 315))	('expression', 'MPA', (296, 306))	('LINC02320', 'Var', (153, 162))	('AC119150.1', 'Var', (81, 91))	('tumor', 'Disease', (185, 190))	('lower', 'NegReg', (290, 295))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('AC007406.4', 'Var', (253, 263))	('AC073651.1', 'Var', (69, 79))	('AL355916.1', 'Var', (105, 115))	('LINC00941', 'Gene', '100287314', (139, 148))	('AL161431.1', 'Var', (93, 103))	('AL355916', 'Chemical', '-', (105, 113))	('LINC00319', 'Gene', '284836', (128, 137))	('tumor', 'Disease', (310, 315))	('LINC00319', 'Gene', (128, 137))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('tumor', 'Disease', 'MESH:D009369', (310, 315))	('AC034223.2', 'Var', (57, 67))	('up-regulated', 'PosReg', (169, 181))	('C20orf197', 'Gene', '284756', (117, 126))	('AC025419.1', 'Var', (241, 251))	('LINC00941', 'Gene', (139, 148))
261257	32831192	Of these 14 lncRNAs, nine lncRNAs (LINC00319, AC090286.1, AL355916.1, LINC00941, AC025419.1, AC034223.2, LINC02320, AC097504.2, and AL161431.1) were highly expressed in high-risk group suggesting a risk role, and five lncRNAs were highly expressed in low-risk group (C20orf197, AC004485.1, AC007406.4, AC073651.1 and AC119150.1) suggesting a protective role ( 0.0001, Fig.	('C20orf197', 'Gene', '284756', (267, 276))	('AC097504.2', 'Var', (116, 126))	('AC034223.2', 'Var', (93, 103))	('AC004485.1', 'Var', (278, 288))	('LINC00319', 'Gene', '284836', (35, 44))	('AL355916.1', 'Var', (58, 68))	('LINC00319', 'Gene', (35, 44))	('C20orf197', 'Gene', (267, 276))	('AC025419.1', 'Var', (81, 91))	('AC090286.1', 'Var', (46, 56))	('AL355916', 'Chemical', '-', (58, 66))	('AC119150.1', 'Var', (317, 327))	('AC007406.4', 'Var', (290, 300))	('AC073651.1', 'Var', (302, 312))	('LINC00941', 'Gene', '100287314', (70, 79))	('LINC00941', 'Gene', (70, 79))	('LINC02320', 'Var', (105, 114))	('AL161431.1', 'Var', (132, 142))
261276	32831192	LncRNA expression profile analyses have reported disrupted expression of lncRNAs in various malignancies, and dysregulated expression of lncRNAs have been involved in physiologic and pathologic processes of lung cancer .	('dysregulated', 'Var', (110, 122))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))	('expression', 'MPA', (123, 133))	('malignancies', 'Disease', (92, 104))	('lung cancer', 'Disease', 'MESH:D008175', (207, 218))	('expression', 'MPA', (59, 69))	('involved', 'Reg', (155, 163))	('lncRNAs', 'Gene', (137, 144))	('malignancies', 'Disease', 'MESH:D009369', (92, 104))	('disrupted', 'NegReg', (49, 58))	('lung cancer', 'Disease', (207, 218))	('lung cancer', 'Phenotype', 'HP:0100526', (207, 218))	('lncRNAs', 'Gene', (73, 80))
261278	32831192	Moreover, the aberrant expressions of specific lncRNAs could be served as diagnostic markers to distinguish tumors from normal subjects .	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('aberrant', 'Var', (14, 22))	('tumors', 'Disease', 'MESH:D009369', (108, 114))	('tumors', 'Disease', (108, 114))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))
261296	32831192	LncRNA expression profile analysis found that AL355916.1 was up-regulated in patients with hypopharyngeal squamous cell carcinoma .	('hypopharyngeal squamous cell carcinoma', 'Disease', (91, 129))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (106, 129))	('hypopharyngeal squamous cell carcinoma', 'Disease', 'MESH:D002294', (91, 129))	('patients', 'Species', '9606', (77, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('AL355916', 'Chemical', '-', (46, 54))	('AL355916.1', 'Var', (46, 56))	('up-regulated', 'PosReg', (61, 73))
261298	32831192	revealed that AC025419.1 displayed a high diagnostic value for papillary thyroid carcinoma.	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (73, 90))	('papillary thyroid carcinoma', 'Disease', 'MESH:D000077273', (63, 90))	('papillary thyroid carcinoma', 'Phenotype', 'HP:0002895', (63, 90))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('papillary thyroid carcinoma', 'Disease', (63, 90))	('AC025419.1', 'Var', (14, 24))
261359	33061645	The clinical cases with positive integrin beta6 expression demonstrated a higher probability of lymph node metastasis compared with those with negative expression (P<0.001).	('expression', 'MPA', (48, 58))	('positive', 'Var', (24, 32))	('lymph node metastasis', 'CPA', (96, 117))	('integrin beta6', 'Gene', (33, 47))	('integrin beta6', 'Gene', '3694', (33, 47))
261362	33061645	More importantly, patients with positive integrin beta6 expression had worse outcomes compared with those with negative integrin beta6 expression (Figure 3A; P<0.001).	('integrin beta6', 'Gene', '3694', (120, 134))	('integrin beta6', 'Gene', (41, 55))	('integrin beta6', 'Gene', '3694', (41, 55))	('expression', 'MPA', (56, 66))	('patients', 'Species', '9606', (18, 26))	('positive', 'Var', (32, 40))	('integrin beta6', 'Gene', (120, 134))
261364	33061645	ESCC specimens with high HAX-1 expression were more likely to demonstrate late pT stage (P<0.001) and lymph node metastasis (P=0.024) compared with those with low HAX-1 expression.	('HAX-1', 'Gene', '10456', (25, 30))	('HAX-1', 'Gene', '10456', (163, 168))	('lymph node metastasis', 'CPA', (102, 123))	('high', 'Var', (20, 24))	('HAX-1', 'Gene', (25, 30))	('late pT stage', 'CPA', (74, 87))	('HAX-1', 'Gene', (163, 168))	('expression', 'Var', (31, 41))
261367	33061645	Additionally, patients with high HAX-1 expression had worse outcomes compared with those with low HAX-1 expression (Figure 3B; P=0.004).	('HAX-1', 'Gene', (33, 38))	('HAX-1', 'Gene', (98, 103))	('expression', 'Var', (39, 49))	('HAX-1', 'Gene', '10456', (98, 103))	('HAX-1', 'Gene', '10456', (33, 38))	('high', 'Var', (28, 32))	('patients', 'Species', '9606', (14, 22))
261370	33061645	The 137 ESCC cases enrolled in the present study were classified into four different groups based on integrin beta6 and HAX-1 expression levels for Kaplan-Meier analysis, and the results indicated that patients with positive integrin beta6 and high HAX-1 expression had worst outcomes compared with the other groups (Figure 4; P=0.003).	('HAX-1', 'Gene', '10456', (120, 125))	('ESCC', 'Disease', (8, 12))	('positive', 'Var', (216, 224))	('HAX-1', 'Gene', (120, 125))	('expression', 'MPA', (255, 265))	('patients', 'Species', '9606', (202, 210))	('HAX-1', 'Gene', '10456', (249, 254))	('integrin beta6', 'Gene', (225, 239))	('integrin beta6', 'Gene', (101, 115))	('integrin beta6', 'Gene', '3694', (101, 115))	('integrin beta6', 'Gene', '3694', (225, 239))	('HAX-1', 'Gene', (249, 254))
261403	33061645	Furthermore, patients with positive integrin beta6 and high HAX-1 expression demonstrated worst outcomes, which is in accordance with the involvement of integrin beta6 and HAX-1 in tumor progression.	('tumor', 'Disease', (181, 186))	('HAX-1', 'Gene', (60, 65))	('HAX-1', 'Gene', '10456', (172, 177))	('patients', 'Species', '9606', (13, 21))	('integrin beta6', 'Gene', (153, 167))	('HAX-1', 'Gene', (172, 177))	('high', 'Var', (55, 59))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('integrin beta6', 'Gene', '3694', (153, 167))	('HAX-1', 'Gene', '10456', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('integrin beta6', 'Gene', (36, 50))	('integrin beta6', 'Gene', '3694', (36, 50))
261447	30104402	In addition, these datasets provided clinical data, including histology, grade, stage, TP53 mutation status, debulk, and applied chemotherapy for the ovarian cancer patients.	('TP53', 'Gene', '7157', (87, 91))	('mutation', 'Var', (92, 100))	('ovarian cancer', 'Disease', 'MESH:D010051', (150, 164))	('TP53', 'Gene', (87, 91))	('ovarian cancer', 'Disease', (150, 164))	('ovarian cancer', 'Phenotype', 'HP:0100615', (150, 164))	('patients', 'Species', '9606', (165, 173))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
261456	30104402	In comparison, among 12 cases of ovarian cancer tissues examined, medium staining of PRDX1 was detected in the majority of cancerous tissues (ten cases), while the rest two cases had low PRDX1 staining.	('ovarian cancer', 'Disease', 'MESH:D010051', (33, 47))	('PRDX1', 'Gene', '5052', (187, 192))	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('cancerous', 'Disease', 'MESH:D009369', (123, 132))	('PRDX1', 'Gene', (85, 90))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('ovarian cancer', 'Disease', (33, 47))	('PRDX1', 'Gene', '5052', (85, 90))	('medium', 'Var', (66, 72))	('detected', 'Reg', (95, 103))	('PRDX1', 'Gene', (187, 192))	('ovarian cancer', 'Phenotype', 'HP:0100615', (33, 47))	('cancerous', 'Disease', (123, 132))
261460	30104402	However, among the examined 9 ovarian cancer tissues, 8 cases had medium PRDX3 staining and 1 case had low PRDX3 staining (Figure 3).	('PRDX3', 'Gene', (73, 78))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('ovarian cancer', 'Disease', 'MESH:D010051', (30, 44))	('PRDX3', 'Gene', (107, 112))	('ovarian cancer', 'Disease', (30, 44))	('medium', 'Var', (66, 72))	('PRDX3', 'Gene', '10935', (107, 112))	('PRDX3', 'Gene', '10935', (73, 78))	('ovarian cancer', 'Phenotype', 'HP:0100615', (30, 44))
261469	30104402	The desired Affymetrix ID for PRDX1 is 208680_at.	('208680_at', 'Var', (39, 48))	('PRDX1', 'Gene', '5052', (30, 35))	('PRDX1', 'Gene', (30, 35))
261471	30104402	As shown in Table 2, high mRNA expression of PRDX1 showed a null association with OS or PFS among all ovarian cancer patients, serous ovarian cancer patients, and endometrioid ovarian cancer patients.	('serous ovarian cancer', 'Disease', 'MESH:D010051', (127, 148))	('endometrioid ovarian cancer', 'Disease', 'MESH:D010051', (163, 190))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('ovarian cancer', 'Disease', 'MESH:D010051', (176, 190))	('patients', 'Species', '9606', (117, 125))	('OS', 'Chemical', '-', (82, 84))	('patients', 'Species', '9606', (149, 157))	('PRDX1', 'Gene', (45, 50))	('PRDX1', 'Gene', '5052', (45, 50))	('serous ovarian cancer', 'Disease', (127, 148))	('ovarian cancer', 'Disease', 'MESH:D010051', (102, 116))	('ovarian cancer', 'Disease', 'MESH:D010051', (134, 148))	('high mRNA', 'Var', (21, 30))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('ovarian cancer', 'Phenotype', 'HP:0100615', (176, 190))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('patients', 'Species', '9606', (191, 199))	('ovarian cancer', 'Disease', (102, 116))	('PFS', 'Disease', (88, 91))	('endometrioid ovarian cancer', 'Disease', (163, 190))	('ovarian cancer', 'Phenotype', 'HP:0100615', (102, 116))	('ovarian cancer', 'Phenotype', 'HP:0100615', (134, 148))
261473	30104402	Analysis indicated that a high expression of PRDX1 was correlated with a better OS in grade I or II ovarian cancer patients.	('patients', 'Species', '9606', (115, 123))	('high', 'Var', (26, 30))	('OS', 'Chemical', '-', (80, 82))	('II ovarian cancer', 'Disease', (97, 114))	('PRDX1', 'Gene', (45, 50))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('expression', 'MPA', (31, 41))	('grade I', 'Disease', (86, 93))	('PRDX1', 'Gene', '5052', (45, 50))	('II ovarian cancer', 'Disease', 'MESH:D010051', (97, 114))	('ovarian cancer', 'Phenotype', 'HP:0100615', (100, 114))
261475	30104402	However, the clinical stage results showed that high levels of PRDX1 mRNA were associated with a poorer PFS in stages I and II ovarian cancer patients.	('ovarian cancer', 'Phenotype', 'HP:0100615', (127, 141))	('II ovarian cancer', 'Disease', (124, 141))	('PRDX1', 'Gene', (63, 68))	('high levels', 'Var', (48, 59))	('II ovarian cancer', 'Disease', 'MESH:D010051', (124, 141))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('PRDX1', 'Gene', '5052', (63, 68))	('PFS', 'MPA', (104, 107))	('poorer', 'NegReg', (97, 103))	('patients', 'Species', '9606', (142, 150))	('mRNA', 'MPA', (69, 73))
261478	30104402	The desired Affymetrix ID for PRDX2 is 39729_at.	('PRDX2', 'Gene', '7001', (30, 35))	('39729_at', 'Var', (39, 47))	('PRDX2', 'Gene', (30, 35))
261481	30104402	In addition, high expression of PRDX2 mRNA was correlated with a better PFS in grade II or III ovarian cancer patients.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('high', 'Var', (13, 17))	('PRDX2', 'Gene', '7001', (32, 37))	('PFS', 'MPA', (72, 75))	('PRDX2', 'Gene', (32, 37))	('II or III ovarian cancer', 'Disease', 'MESH:D010051', (85, 109))	('II or III ovarian cancer', 'Disease', (85, 109))	('patients', 'Species', '9606', (110, 118))	('ovarian cancer', 'Phenotype', 'HP:0100615', (95, 109))
261484	30104402	For PRDX3, its desired Affymetrix ID is 201619_at (Figures 7C and 8C, and Table 4).	('PRDX3', 'Gene', '10935', (4, 9))	('201619_at', 'Var', (40, 49))	('PRDX3', 'Gene', (4, 9))
261486	30104402	However, high mRNA expression of PRDX3 showed no effect on PFS in different histological types of ovarian cancer patients.	('PRDX3', 'Gene', '10935', (33, 38))	('ovarian cancer', 'Disease', 'MESH:D010051', (98, 112))	('PRDX3', 'Gene', (33, 38))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('ovarian cancer', 'Disease', (98, 112))	('PFS', 'MPA', (59, 62))	('patients', 'Species', '9606', (113, 121))	('mRNA expression', 'MPA', (14, 29))	('ovarian cancer', 'Phenotype', 'HP:0100615', (98, 112))	('high', 'Var', (9, 13))
261488	30104402	Furthermore, the clinical stage results showed that high expression of PRDX3 mRNA was associated with a poorer OS in stages III and IV ovarian cancer patients.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('IV ovarian cancer', 'Disease', 'MESH:D010051', (132, 149))	('PRDX3', 'Gene', (71, 76))	('PRDX3', 'Gene', '10935', (71, 76))	('poorer', 'NegReg', (104, 110))	('associated', 'Reg', (86, 96))	('OS', 'Chemical', '-', (111, 113))	('IV ovarian cancer', 'Disease', (132, 149))	('patients', 'Species', '9606', (150, 158))	('ovarian cancer', 'Phenotype', 'HP:0100615', (135, 149))	('high expression', 'Var', (52, 67))
261491	30104402	The desired Affymetrix ID for PRDX4 is 201923_at.	('PRDX4', 'Gene', (30, 35))	('201923_at', 'Var', (39, 48))	('PRDX4', 'Gene', '10549', (30, 35))
261495	30104402	The clinical stage results showed that high mRNA expression of PRDX4 was related to a positive OS in stages I and II ovarian cancer patients.	('high', 'Var', (39, 43))	('mRNA expression', 'MPA', (44, 59))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('PRDX4', 'Gene', '10549', (63, 68))	('II ovarian cancer', 'Disease', (114, 131))	('ovarian cancer', 'Phenotype', 'HP:0100615', (117, 131))	('PRDX4', 'Gene', (63, 68))	('II ovarian cancer', 'Disease', 'MESH:D010051', (114, 131))	('OS', 'Chemical', '-', (95, 97))	('patients', 'Species', '9606', (132, 140))	('related', 'Reg', (73, 80))
261499	30104402	The desired Affymetrix ID for PRDX5 is 1560587_s_at.	('PRDX5', 'Gene', '25824', (30, 35))	('PRDX5', 'Gene', (30, 35))	('1560587_s_at', 'Var', (39, 51))
261500	30104402	High PRDX5 mRNA expression was associated with a poorer OS for serous ovarian cancer patients and endometrioid cancer patients.	('OS', 'Chemical', '-', (56, 58))	('High', 'Var', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('PRDX5', 'Gene', '25824', (5, 10))	('serous ovarian cancer', 'Disease', 'MESH:D010051', (63, 84))	('poorer', 'NegReg', (49, 55))	('ovarian cancer', 'Phenotype', 'HP:0100615', (70, 84))	('mRNA expression', 'MPA', (11, 26))	('patients', 'Species', '9606', (85, 93))	('endometrioid cancer', 'Disease', 'MESH:D016889', (98, 117))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('endometrioid cancer', 'Phenotype', 'HP:0012114', (98, 117))	('patients', 'Species', '9606', (118, 126))	('endometrioid cancer', 'Disease', (98, 117))	('PRDX5', 'Gene', (5, 10))	('serous ovarian cancer', 'Disease', (63, 84))
261504	30104402	Further studies revealed that high PRDX5 mRNA expression was associated with a poor PFS in stages III and IV ovarian cancer patients.	('IV ovarian cancer', 'Disease', (106, 123))	('PRDX5', 'Gene', '25824', (35, 40))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('patients', 'Species', '9606', (124, 132))	('high', 'Var', (30, 34))	('PRDX5', 'Gene', (35, 40))	('IV ovarian cancer', 'Disease', 'MESH:D010051', (106, 123))	('PFS', 'MPA', (84, 87))	('stages III', 'Disease', (91, 101))	('ovarian cancer', 'Phenotype', 'HP:0100615', (109, 123))
261508	30104402	The desired Affymetrix ID for PRDX6 is 200845_s_at.	('PRDX6', 'Gene', (30, 35))	('PRDX6', 'Gene', '9588', (30, 35))	('200845_s_at', 'Var', (39, 50))
261510	30104402	Meanwhile, the curves showed that high PRDX6 mRNA expression was associated with poorer PFS for all ovarian cancer patients and endometrioid cancer patients.	('PFS', 'MPA', (88, 91))	('ovarian cancer', 'Disease', (100, 114))	('PRDX6', 'Gene', (39, 44))	('endometrioid cancer', 'Disease', 'MESH:D016889', (128, 147))	('patients', 'Species', '9606', (148, 156))	('patients', 'Species', '9606', (115, 123))	('PRDX6', 'Gene', '9588', (39, 44))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('endometrioid cancer', 'Phenotype', 'HP:0012114', (128, 147))	('endometrioid cancer', 'Disease', (128, 147))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('high', 'Var', (34, 38))	('ovarian cancer', 'Disease', 'MESH:D010051', (100, 114))	('ovarian cancer', 'Phenotype', 'HP:0100615', (100, 114))	('mRNA expression', 'MPA', (45, 60))	('poorer', 'NegReg', (81, 87))
261511	30104402	Furthermore, high PRDX6 mRNA expression was found to be correlated with poorer OS in grade III ovarian cancer patients.	('III ovarian cancer', 'Disease', (91, 109))	('OS', 'Chemical', '-', (79, 81))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('high', 'Var', (13, 17))	('PRDX6', 'Gene', (18, 23))	('III ovarian cancer', 'Disease', 'MESH:D010051', (91, 109))	('mRNA expression', 'MPA', (24, 39))	('PRDX6', 'Gene', '9588', (18, 23))	('poorer', 'Disease', (72, 78))	('patients', 'Species', '9606', (110, 118))	('ovarian cancer', 'Phenotype', 'HP:0100615', (95, 109))
261515	30104402	It has been demonstrated that an imbalance between the generation of ROS and PRDXs in cancer cells could cause oxidative stress and the induction of apoptosis.	('PRDXs', 'Gene', (77, 82))	('apoptosis', 'CPA', (149, 158))	('cause', 'Reg', (105, 110))	('oxidative stress', 'MPA', (111, 127))	('imbalance', 'Var', (33, 42))	('ROS', 'Chemical', 'MESH:D017382', (69, 72))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('imbalance', 'Phenotype', 'HP:0002172', (33, 42))	('ROS', 'Protein', (69, 72))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('oxidative stress', 'Phenotype', 'HP:0025464', (111, 127))	('cancer', 'Disease', (86, 92))
261532	30104402	However, further analysis via KM plotter database indicated that high levels of PRDX1 showed no effect on OS or PFS among all ovarian cancer patients, serous ovarian cancer patients, or endometrioid ovarian cancer patients.	('ovarian cancer', 'Phenotype', 'HP:0100615', (126, 140))	('ovarian cancer', 'Phenotype', 'HP:0100615', (158, 172))	('patients', 'Species', '9606', (214, 222))	('high levels', 'Var', (65, 76))	('endometrioid ovarian cancer', 'Disease', 'MESH:D010051', (186, 213))	('patients', 'Species', '9606', (141, 149))	('OS', 'Chemical', '-', (106, 108))	('serous ovarian cancer', 'Disease', (151, 172))	('patients', 'Species', '9606', (173, 181))	('ovarian cancer', 'Disease', 'MESH:D010051', (199, 213))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('PFS', 'Disease', (112, 115))	('ovarian cancer', 'Disease', 'MESH:D010051', (126, 140))	('ovarian cancer', 'Disease', 'MESH:D010051', (158, 172))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('ovarian cancer', 'Phenotype', 'HP:0100615', (199, 213))	('serous ovarian cancer', 'Disease', 'MESH:D010051', (151, 172))	('ovarian cancer', 'Disease', (126, 140))	('PRDX1', 'Gene', (80, 85))	('PRDX1', 'Gene', '5052', (80, 85))	('endometrioid ovarian cancer', 'Disease', (186, 213))
261546	30104402	In addition, high expression of PRDX2 predicted a better PFS in grade II or III patients and stages III and IV patients.	('patients', 'Species', '9606', (80, 88))	('PFS', 'CPA', (57, 60))	('high', 'Var', (13, 17))	('PRDX2', 'Gene', '7001', (32, 37))	('PRDX2', 'Gene', (32, 37))	('patients', 'Species', '9606', (111, 119))
261551	30104402	demonstrated that high cytoplasmic expression of PRDX3 was linked with poor prognosis in breast cancer patients.	('linked', 'Reg', (59, 65))	('breast cancer', 'Disease', 'MESH:D001943', (89, 102))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('breast cancer', 'Disease', (89, 102))	('breast cancer', 'Phenotype', 'HP:0003002', (89, 102))	('high', 'Var', (18, 22))	('PRDX3', 'Gene', '10935', (49, 54))	('patients', 'Species', '9606', (103, 111))	('PRDX3', 'Gene', (49, 54))
261553	30104402	Furthermore, PRDX3 overexpression was strongly associated with the progression of hepatocellular carcinoma; patients with high serum PRDX3 levels had a shorter median survival time when compared to those with low serum PRDX3 level.	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('PRDX3', 'Gene', '10935', (133, 138))	('high', 'Var', (122, 126))	('PRDX3', 'Gene', (133, 138))	('PRDX3', 'Gene', (13, 18))	('PRDX3', 'Gene', '10935', (13, 18))	('shorter', 'NegReg', (152, 159))	('PRDX3', 'Gene', '10935', (219, 224))	('PRDX3', 'Gene', (219, 224))	('patients', 'Species', '9606', (108, 116))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (82, 106))	('associated', 'Reg', (47, 57))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (82, 106))	('hepatocellular carcinoma', 'Disease', (82, 106))
261555	30104402	observed that the expression of PRDX3 was significantly higher in cancer tissues than the adjacent non-cancerous tissues, and high PRDX3 levels in serous ovarian carcinoma were related to poorly differentiated cancer cells, FIGO stages III and IV, which suggests that aberrant expression of PRDX3 is significantly associated with the progression of ovarian cancer.	('ovarian cancer', 'Phenotype', 'HP:0100615', (349, 363))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('PRDX3', 'Gene', (291, 296))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('PRDX3', 'Gene', '10935', (291, 296))	('cancer', 'Disease', (103, 109))	('PRDX3', 'Gene', '10935', (131, 136))	('PRDX3', 'Gene', (131, 136))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('serous ovarian carcinoma', 'Disease', (147, 171))	('cancerous', 'Disease', 'MESH:D009369', (103, 112))	('cancer', 'Disease', (357, 363))	('expression', 'MPA', (18, 28))	('cancer', 'Disease', 'MESH:D009369', (210, 216))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (154, 171))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('cancer', 'Phenotype', 'HP:0002664', (357, 363))	('related', 'Reg', (177, 184))	('ovarian cancer', 'Disease', 'MESH:D010051', (349, 363))	('serous ovarian carcinoma', 'Disease', 'MESH:D010051', (147, 171))	('aberrant', 'Var', (268, 276))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('cancerous', 'Disease', (103, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (162, 171))	('PRDX3', 'Gene', '10935', (32, 37))	('PRDX3', 'Gene', (32, 37))	('associated with', 'Reg', (314, 329))	('cancer', 'Disease', 'MESH:D009369', (357, 363))	('ovarian cancer', 'Disease', (349, 363))	('higher', 'PosReg', (56, 62))	('cancer', 'Disease', (210, 216))	('cancer', 'Disease', (66, 72))
261560	30104402	In addition, high PRDX3 levels predicted a poorer OS in grade III patients, stages III and IV patients, while PRDX3 predicted a better PFS in 37 patients with grade I ovarian cancer; this finding might have been due to the small and unbalanced sample sizes.	('patients', 'Species', '9606', (145, 153))	('I ovarian cancer', 'Disease', 'MESH:D010051', (165, 181))	('PRDX3', 'Gene', (110, 115))	('patients', 'Species', '9606', (94, 102))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('high', 'Var', (13, 17))	('I ovarian cancer', 'Disease', (165, 181))	('patients', 'Species', '9606', (66, 74))	('ovarian cancer', 'Phenotype', 'HP:0100615', (167, 181))	('PRDX3', 'Gene', (18, 23))	('OS', 'Chemical', '-', (50, 52))	('PRDX3', 'Gene', '10935', (18, 23))	('poorer', 'NegReg', (43, 49))	('PRDX3', 'Gene', '10935', (110, 115))
261563	30104402	Several previous studies reported that high expression of PRDX4 demonstrated an unfavorable prognosis in colorectal cancer, lung squamous cell carcinoma, oral cavity squamous cell carcinoma, and urinary bladder carcinoma.	('urinary bladder carcinoma', 'Disease', (195, 220))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (129, 152))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (166, 189))	('PRDX4', 'Gene', '10549', (58, 63))	('colorectal cancer', 'Phenotype', 'HP:0003003', (105, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (143, 152))	('urinary bladder carcinoma', 'Disease', 'MESH:D001749', (195, 220))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (124, 152))	('carcinoma', 'Phenotype', 'HP:0030731', (180, 189))	('rectal cancer', 'Phenotype', 'HP:0100743', (109, 122))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (166, 189))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (203, 220))	('colorectal cancer', 'Disease', 'MESH:D015179', (105, 122))	('high expression', 'Var', (39, 54))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (129, 152))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (124, 152))	('lung squamous cell carcinoma', 'Disease', (124, 152))	('carcinoma', 'Phenotype', 'HP:0030731', (211, 220))	('PRDX4', 'Gene', (58, 63))	('squamous cell carcinoma', 'Disease', (166, 189))	('colorectal cancer', 'Disease', (105, 122))
261570	30104402	Our results showed that high PRDX4 level was related to a favorable OS for endometrioid cancer patients and a better PFS for all ovarian cancer patients, serous cancer patients, and endometrioid cancer patients.	('endometrioid cancer', 'Disease', (182, 201))	('endometrioid cancer', 'Disease', 'MESH:D016889', (75, 94))	('PFS', 'MPA', (117, 120))	('high', 'Var', (24, 28))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('endometrioid cancer', 'Phenotype', 'HP:0012114', (182, 201))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('ovarian cancer', 'Disease', 'MESH:D010051', (129, 143))	('serous cancer', 'Disease', (154, 167))	('patients', 'Species', '9606', (202, 210))	('endometrioid cancer', 'Disease', (75, 94))	('PRDX4', 'Gene', (29, 34))	('ovarian cancer', 'Disease', (129, 143))	('endometrioid cancer', 'Phenotype', 'HP:0012114', (75, 94))	('serous cancer', 'Disease', 'MESH:D009369', (154, 167))	('endometrioid cancer', 'Disease', 'MESH:D016889', (182, 201))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('ovarian cancer', 'Phenotype', 'HP:0100615', (129, 143))	('patients', 'Species', '9606', (95, 103))	('patients', 'Species', '9606', (144, 152))	('patients', 'Species', '9606', (168, 176))	('OS', 'Chemical', '-', (68, 70))	('PRDX4', 'Gene', '10549', (29, 34))
261579	30104402	But so far, there is only one study that has previously reported the role of PRDX5 in ovarian cancer, and it merely revealed that high PRDX5 cytoplasmic expression was correlated with a higher stage in ovarian cancer, but did not further analyze the prognostic value of PRDX5 in ovarian cancer patients.	('ovarian cancer', 'Disease', (86, 100))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('ovarian cancer', 'Disease', 'MESH:D010051', (202, 216))	('cancer', 'Phenotype', 'HP:0002664', (287, 293))	('ovarian cancer', 'Phenotype', 'HP:0100615', (86, 100))	('PRDX5', 'Gene', (135, 140))	('PRDX5', 'Gene', (270, 275))	('PRDX5', 'Gene', '25824', (135, 140))	('PRDX5', 'Gene', '25824', (270, 275))	('ovarian cancer', 'Disease', 'MESH:D010051', (279, 293))	('ovarian cancer', 'Disease', (202, 216))	('higher', 'PosReg', (186, 192))	('PRDX5', 'Gene', (77, 82))	('ovarian cancer', 'Phenotype', 'HP:0100615', (202, 216))	('PRDX5', 'Gene', '25824', (77, 82))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('ovarian cancer', 'Disease', 'MESH:D010051', (86, 100))	('ovarian cancer', 'Disease', (279, 293))	('high', 'Var', (130, 134))	('patients', 'Species', '9606', (294, 302))	('ovarian cancer', 'Phenotype', 'HP:0100615', (279, 293))
261582	30104402	Our results showed that high PRDX5 expression was associated with poorer OS for serous ovarian cancer patients, endometrioid ovarian cancer patients, and grade II or III ovarian cancer patients.	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('patients', 'Species', '9606', (102, 110))	('expression', 'MPA', (35, 45))	('ovarian cancer', 'Phenotype', 'HP:0100615', (125, 139))	('high', 'Var', (24, 28))	('endometrioid ovarian cancer', 'Disease', (112, 139))	('OS', 'Chemical', '-', (73, 75))	('serous ovarian cancer', 'Disease', (80, 101))	('II or III ovarian cancer', 'Disease', 'MESH:D010051', (160, 184))	('poorer', 'NegReg', (66, 72))	('ovarian cancer', 'Phenotype', 'HP:0100615', (170, 184))	('patients', 'Species', '9606', (140, 148))	('endometrioid ovarian cancer', 'Disease', 'MESH:D010051', (112, 139))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('PRDX5', 'Gene', (29, 34))	('II or III ovarian cancer', 'Disease', (160, 184))	('PRDX5', 'Gene', '25824', (29, 34))	('patients', 'Species', '9606', (185, 193))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('ovarian cancer', 'Phenotype', 'HP:0100615', (87, 101))	('serous ovarian cancer', 'Disease', 'MESH:D010051', (80, 101))
261589	30104402	showed that high PRDX6 expression was related to shortened biochemical recurrence-free survival and OS in prostate cancer patients after radical prostatectomy.	('prostate cancer', 'Phenotype', 'HP:0012125', (106, 121))	('high', 'Var', (12, 16))	('OS', 'Chemical', '-', (100, 102))	('PRDX6', 'Gene', (17, 22))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('prostate cancer', 'Disease', (106, 121))	('patients', 'Species', '9606', (122, 130))	('biochemical recurrence-free survival', 'CPA', (59, 95))	('PRDX6', 'Gene', '9588', (17, 22))	('shortened', 'NegReg', (49, 58))	('prostate cancer', 'Disease', 'MESH:D011471', (106, 121))	('expression', 'MPA', (23, 33))
261590	30104402	Another study suggested that high level of PRDX6 was correlated with shorter 5-year disease-specific survival in patients with diffuse large B-cell lymphoma.	('lymphoma', 'Phenotype', 'HP:0002665', (148, 156))	('PRDX6', 'Gene', (43, 48))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (141, 156))	('PRDX6', 'Gene', '9588', (43, 48))	('patients', 'Species', '9606', (113, 121))	('shorter', 'NegReg', (69, 76))	('high level', 'Var', (29, 39))	('diffuse large B-cell lymphoma', 'Disease', (127, 156))	('disease-specific survival', 'CPA', (84, 109))
261600	30104402	PRDX3 expression was associated with platinum resistance in ovarian cancer, and siRNA targeting of PRDX3 triggered cisplatin-induced apoptosis in SKOV3 ovarian cancer cells through suppression of the NF-kappaB signaling pathway.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('ovarian cancer', 'Disease', 'MESH:D010051', (60, 74))	('triggered', 'PosReg', (105, 114))	('apoptosis in SKOV3 ovarian cancer', 'Disease', (133, 166))	('PRDX3', 'Gene', '10935', (99, 104))	('PRDX3', 'Gene', (99, 104))	('ovarian cancer', 'Disease', (60, 74))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('ovarian cancer', 'Disease', 'MESH:D010051', (152, 166))	('suppression', 'NegReg', (181, 192))	('ovarian cancer', 'Phenotype', 'HP:0100615', (60, 74))	('cisplatin-induced', 'MPA', (115, 132))	('associated', 'Reg', (21, 31))	('PRDX3', 'Gene', '10935', (0, 5))	('apoptosis in SKOV3 ovarian cancer', 'Disease', 'MESH:D010051', (133, 166))	('PRDX3', 'Gene', (0, 5))	('targeting', 'Var', (86, 95))	('NF-kappaB signaling pathway', 'Pathway', (200, 227))	('cisplatin', 'Chemical', 'MESH:D002945', (115, 124))	('platinum', 'Chemical', 'MESH:D010984', (37, 45))	('ovarian cancer', 'Phenotype', 'HP:0100615', (152, 166))
261625	29930174	Furthermore, we report that copy number variation at the LIMD1 locus occurs in 47.1% of lung adenocarcinoma patients, correlates with enhanced expression of a HIF target gene signature and is a negative prognostic indicator.	('LIMD1', 'Gene', '8994', (57, 62))	('LIMD1', 'Gene', (57, 62))	('enhanced', 'PosReg', (134, 142))	('expression', 'MPA', (143, 153))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (88, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('copy number variation', 'Var', (28, 49))	('lung adenocarcinoma', 'Disease', (88, 107))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (88, 107))	('patients', 'Species', '9606', (108, 116))
261627	29930174	HIF-alpha is regulated by intracellular oxygen levels; at physiological oxygen tension (normoxia), two highly conserved proline residues within the oxygen-dependent degradation domain of the HIF-alpha subunit (P402/564 on HIF-1alpha; P405/531 on HIF-2alpha) are hydroxylated by prolyl hydroxylase domain (PHD) proteins.	('PHD', 'Disease', (305, 308))	('HIF-1alpha', 'Gene', '3091', (222, 232))	('oxygen', 'Chemical', 'MESH:D010100', (40, 46))	('proline', 'Chemical', 'MESH:D011392', (120, 127))	('P402/564', 'Var', (210, 218))	('HIF-2alpha', 'Gene', (246, 256))	('P405/531', 'Var', (234, 242))	('HIF-1alpha', 'Gene', (222, 232))	('oxygen', 'Chemical', 'MESH:D010100', (72, 78))	('pen', 'Gene', (157, 160))	('oxygen', 'Chemical', 'MESH:D010100', (148, 154))	('HIF-2alpha', 'Gene', '2034', (246, 256))	('pen', 'Gene', '27344', (157, 160))	('PHD', 'Disease', 'MESH:D011547', (305, 308))
261632	29930174	This is exemplified by VHL mutations in clear cell renal carcinomas, leading to sustained HIF-alpha expression and activity (Rechsteiner et al, 2011).	('mutations', 'Var', (27, 36))	('renal carcinomas', 'Phenotype', 'HP:0005584', (51, 67))	('VHL', 'Gene', (23, 26))	('carcinoma', 'Phenotype', 'HP:0030731', (57, 66))	('activity', 'MPA', (115, 123))	('expression', 'MPA', (100, 110))	('VHL', 'Gene', '7428', (23, 26))	('clear cell renal carcinomas', 'Phenotype', 'HP:0006770', (40, 67))	('carcinomas', 'Phenotype', 'HP:0030731', (57, 67))	('clear cell renal carcinomas', 'Disease', (40, 67))	('HIF-alpha', 'Protein', (90, 99))	('clear cell renal carcinomas', 'Disease', 'MESH:C538614', (40, 67))
261637	29930174	Furthermore, it has been reported that silencing of LIMD1 in multidrug-resistant colorectal carcinoma cells increased their chemosensitivity in vitro (Chen et al, 2014).	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('increased', 'PosReg', (108, 117))	('colorectal carcinoma', 'Disease', (81, 101))	('silencing', 'Var', (39, 48))	('LIMD1', 'Gene', '8994', (52, 57))	('chemosensitivity', 'MPA', (124, 140))	('LIMD1', 'Gene', (52, 57))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (81, 101))
261642	29930174	Our recent work has shown that LIMD1 is a critical effector of microRNA (miRNA)-mediated gene silencing, a process generally considered to be a global tumour-suppressive mechanism (James et al, 2010; Bridge et al, 2017).	('gene', 'Var', (89, 93))	('tumour', 'Phenotype', 'HP:0002664', (151, 157))	('LIMD1', 'Gene', '8994', (31, 36))	('tumour', 'Disease', 'MESH:D009369', (151, 157))	('LIMD1', 'Gene', (31, 36))	('tumour', 'Disease', (151, 157))	('microRNA', 'MPA', (63, 71))
261648	29930174	In vivo, inhibition of hypoxia-driven LIMD1 expression results in larger and more vascularised xenograft tumours.	('tumours', 'Phenotype', 'HP:0002664', (105, 112))	('hypoxia', 'Disease', 'MESH:D000860', (23, 30))	('xenograft tumours', 'Disease', (95, 112))	('hypoxia', 'Disease', (23, 30))	('more', 'PosReg', (77, 81))	('LIMD1', 'Gene', '8994', (38, 43))	('xenograft tumours', 'Disease', 'MESH:D009369', (95, 112))	('LIMD1', 'Gene', (38, 43))	('tumour', 'Phenotype', 'HP:0002664', (105, 111))	('inhibition', 'Var', (9, 19))
261655	29930174	Within this construct, we created a series of ten consecutive small internal deletions within the CpG Island that have previously been identified as containing transcriptional regulatory elements (Foxler et al, 2011; Fig EV1I).	('small internal deletions', 'Var', (62, 86))	('containing', 'Reg', (149, 159))	('transcriptional regulatory elements', 'MPA', (160, 195))	('EV1', 'Gene', (221, 224))	('EV1', 'Gene', '11322', (221, 224))	('CpG', 'Gene', (98, 101))
261657	29930174	However, deletion of the 31-bp Delta3 region that encompasses the predicted HRE3 ablated any hypoxia-induced increase in luciferase activity (Fig EV1J).	('deletion', 'Var', (9, 17))	('activity', 'MPA', (132, 140))	('EV1', 'Gene', '11322', (146, 149))	('hypoxia', 'Disease', (93, 100))	('EV1', 'Gene', (146, 149))	('Delta3', 'Gene', '10683', (31, 37))	('hypoxia', 'Disease', 'MESH:D000860', (93, 100))	('Delta3', 'Gene', (31, 37))	('luciferase', 'Enzyme', (121, 131))	('ablated', 'NegReg', (81, 88))
261658	29930174	Furthermore, internal deletion of the three predicted HREs confirmed HRE3 to be the active hypoxia-responsive element within the LIMD1 promoter (Fig 1E).	('LIMD1', 'Gene', (129, 134))	('hypoxia', 'Disease', (91, 98))	('HRE3', 'Gene', (69, 73))	('internal deletion', 'Var', (13, 30))	('hypoxia', 'Disease', 'MESH:D000860', (91, 98))	('LIMD1', 'Gene', '8994', (129, 134))
261662	29930174	siRNA-mediated depletion of HIF-1alpha reduced LIMD1 protein and mRNA expression under hypoxic and, to a lesser extent, normoxic conditions in all cell lines examined (Figs 2C and D, and EV2B-E).	('depletion', 'Var', (15, 24))	('mRNA expression', 'MPA', (65, 80))	('HIF-1alpha reduced LIMD1 protein', 'Disease', (28, 60))	('HIF-1alpha reduced LIMD1 protein', 'Disease', 'MESH:D015354', (28, 60))
261672	29930174	Thus, in hypoxia, LIMD1 expression facilitates formation of an active PHD2-LIMD1-VHL HIF-degradation complex.	('hypoxia', 'Disease', (9, 16))	('LIMD1', 'Gene', '8994', (75, 80))	('LIMD1', 'Gene', (75, 80))	('LIMD1', 'Gene', '8994', (18, 23))	('facilitates', 'PosReg', (35, 46))	('PHD2-LIMD1-VHL HIF-degradation', 'Disease', 'MESH:D006623', (70, 100))	('LIMD1', 'Gene', (18, 23))	('expression', 'Var', (24, 34))	('PHD2-LIMD1-VHL HIF-degradation', 'Disease', (70, 100))	('hypoxia', 'Disease', 'MESH:D000860', (9, 16))
261674	29930174	This led us to hypothesise that a decrease in the normal levels of LIMD1 protein expression as a result of LIMD1 loss of heterozygosity (LOH) or promoter methylation (Sharp et al, 2008) may disrupt the hypoxic PHD-LIMD1-VHL complex, and exacerbate HIF-mediated gene expression and pro-transforming effects in the context of a hypoxic tumour microenvironment.	('LIMD1', 'Gene', '8994', (67, 72))	('hypoxic PHD-LIMD1-VHL', 'Disease', (202, 223))	('hypoxic tumour', 'Disease', 'MESH:D009369', (326, 340))	('LIMD1', 'Gene', (214, 219))	('hypoxic tumour', 'Disease', (326, 340))	('hypoxic PHD-LIMD1-VHL', 'Disease', 'MESH:D006623', (202, 223))	('LIMD1', 'Gene', '8994', (214, 219))	('tumour', 'Phenotype', 'HP:0002664', (334, 340))	('decrease', 'NegReg', (34, 42))	('LIMD1', 'Gene', (107, 112))	('HIF-mediated', 'CPA', (248, 260))	('exacerbate', 'PosReg', (237, 247))	('LIMD1', 'Gene', (67, 72))	('promoter methylation', 'Var', (145, 165))	('levels', 'MPA', (57, 63))	('LIMD1', 'Gene', '8994', (107, 112))	('loss of', 'NegReg', (113, 120))	('pro-transforming effects', 'CPA', (281, 305))	('disrupt', 'NegReg', (190, 197))
261679	29930174	In contrast, mutation of the HRE within the LIMD1 promoter (HREmut) significantly impaired hypoxic induction of LIMD1 in these lines.	('LIMD1', 'Gene', (112, 117))	('LIMD1', 'Gene', '8994', (44, 49))	('LIMD1', 'Gene', (44, 49))	('impaired hypoxic', 'Disease', (82, 98))	('mutation', 'Var', (13, 21))	('impaired hypoxic', 'Disease', 'MESH:D009422', (82, 98))	('HRE', 'Protein', (29, 32))	('LIMD1', 'Gene', '8994', (112, 117))
261685	29930174	Furthermore, siRNA depletion of HIF-1alpha ablated the differential gene expression of VEGF-A between the lines (Fig 4C and D).	('HIF-1alpha', 'Gene', '3091', (32, 42))	('depletion', 'Var', (19, 28))	('differential gene expression', 'MPA', (55, 83))	('HIF-1alpha', 'Gene', (32, 42))	('VEGF-A', 'Gene', '7422', (87, 93))	('VEGF-A', 'Gene', (87, 93))	('ablated', 'NegReg', (43, 50))
261690	29930174	Together, these data reveal that inhibition of the HIF-1/LIMD1 feedback loop causes an increased cellular hypoxic HIF phenotype in vitro, demonstrating that increased LIMD1 protein expression in hypoxia is necessary for correct modulation of HIF-1 expression and signalling in a hypoxic environment.	('inhibition', 'Var', (33, 43))	('LIMD1', 'Gene', '8994', (57, 62))	('LIMD1', 'Gene', '8994', (167, 172))	('LIMD1', 'Gene', (57, 62))	('LIMD1', 'Gene', (167, 172))	('HIF-1', 'Gene', '3091', (242, 247))	('HIF-1', 'Gene', (51, 56))	('hypoxia', 'Disease', 'MESH:D000860', (195, 202))	('HIF-1', 'Gene', (242, 247))	('hypoxia', 'Disease', (195, 202))	('hypoxic HIF', 'Disease', (106, 117))	('hypoxic HIF', 'Disease', 'MESH:D000860', (106, 117))	('HIF-1', 'Gene', '3091', (51, 56))
261695	29930174	The transduced cell lines were validated in vitro, where ablation of the hypoxic induction in LIMD1 expression in the HREmut line increased synthetic HIF-1-driven luciferase activity, HIF-1-responsive genes and secreted VEGF (Fig 5A-C).	('HIF-1', 'Gene', '3091', (184, 189))	('VEGF', 'Gene', '7422', (220, 224))	('ablation', 'Var', (57, 65))	('activity', 'MPA', (174, 182))	('HIF-1', 'Gene', (184, 189))	('HIF-1', 'Gene', '3091', (150, 155))	('LIMD1', 'Gene', '8994', (94, 99))	('increased', 'PosReg', (130, 139))	('LIMD1', 'Gene', (94, 99))	('HIF-1', 'Gene', (150, 155))	('VEGF', 'Gene', (220, 224))
261698	29930174	Xenografts from A549 HREmut cells (which have an impaired HIF-LIMD1 negative feedback loop) had increased age-matched endpoint tumour volumes compared to A459 HREwt cells (which have an intact HIF-LIMD1 negative feedback loop; Fig 5D).	('increased', 'PosReg', (96, 105))	('A549 HREmut', 'CellLine', 'CVCL:0023', (16, 27))	('A549', 'Var', (16, 20))	('HIF-LIMD1', 'Disease', 'None', (193, 202))	('HIF-LIMD1', 'Disease', (193, 202))	('tumour', 'Phenotype', 'HP:0002664', (127, 133))	('HIF-LIMD1', 'Disease', (58, 67))	('tumour', 'Disease', 'MESH:D009369', (127, 133))	('impaired HIF-LIMD1', 'Disease', 'MESH:D009422', (49, 67))	('impaired HIF-LIMD1', 'Disease', (49, 67))	('HIF-LIMD1', 'Disease', 'None', (58, 67))	('tumour', 'Disease', (127, 133))
261702	29930174	Together, these data indicate that ablation of this HIF-1-LIMD1 negative regulatory feedback mechanism in vivo increases tumour growth and vascularisation.	('increases tumour growth', 'Disease', 'MESH:D006130', (111, 134))	('HIF-1-LIMD1', 'Disease', (52, 63))	('tumour', 'Phenotype', 'HP:0002664', (121, 127))	('increases tumour growth', 'Disease', (111, 134))	('HIF-1-LIMD1', 'Disease', 'MESH:C565162', (52, 63))	('ablation', 'Var', (35, 43))
261706	29930174	Immunohistochemical analysis of HIF-1alpha and downstream angiogenic marker VEGF-A was not significantly correlated with LIMD1 expression in this cohort; however, high VEGF expression was correlated with poor patient prognosis (P = 0.045; Appendix Fig S1, Fig EV5A-C).	('high', 'Var', (163, 167))	('pen', 'Gene', '27344', (241, 244))	('VEGF', 'Gene', (76, 80))	('patient', 'Species', '9606', (209, 216))	('VEGF', 'Gene', '7422', (168, 172))	('VEGF-A', 'Gene', '7422', (76, 82))	('HIF-1alpha', 'Gene', (32, 42))	('VEGF', 'Gene', '7422', (76, 80))	('LIMD1', 'Gene', '8994', (121, 126))	('VEGF-A', 'Gene', (76, 82))	('pen', 'Gene', (241, 244))	('LIMD1', 'Gene', (121, 126))	('VEGF', 'Gene', (168, 172))	('HIF-1alpha', 'Gene', '3091', (32, 42))
261708	29930174	First, gene copy number analysis of LIMD1 and a number of other well-characterised tumour suppressor genes in lung adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC) cohorts (n = 512 and n = 498, respectively) demonstrated that single (shallow) or bi-allele (Ghosh et al, 2008) deletion of the LIMD1 gene occurred in 47.1% (LUAD) and 85.4% of patients (LUSC; Figs 6D and EV5D).	('LIMD1', 'Gene', '8994', (36, 41))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (110, 129))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (110, 129))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (141, 164))	('deletion', 'Var', (284, 292))	('tumour', 'Phenotype', 'HP:0002664', (83, 89))	('tumour', 'Disease', 'MESH:D009369', (83, 89))	('LIMD1', 'Gene', (300, 305))	('tumour', 'Disease', (83, 89))	('LUAD', 'Phenotype', 'HP:0030078', (330, 334))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (141, 164))	('LIMD1', 'Gene', '8994', (300, 305))	('carcinoma', 'Phenotype', 'HP:0030731', (155, 164))	('LIMD1', 'Gene', (36, 41))	('lung adenocarcinoma', 'Disease', (110, 129))	('squamous cell carcinoma', 'Disease', (141, 164))	('patients', 'Species', '9606', (349, 357))	('LUAD', 'Phenotype', 'HP:0030078', (131, 135))
261709	29930174	Regression analysis demonstrated correlation between LIMD1 copy number and reduced mRNA expression (Fig EV5E and F); therefore, lung adenocarcinoma patients were stratified into risk groups (quartiles) based on mRNA abundance intensities, and patient survival was determined using a Cox proportional hazards model.	('LIMD1', 'Gene', (53, 58))	('patients', 'Species', '9606', (148, 156))	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('patient', 'Species', '9606', (243, 250))	('lung adenocarcinoma', 'Disease', (128, 147))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (128, 147))	('reduced', 'NegReg', (75, 82))	('copy number', 'Var', (59, 70))	('mRNA expression', 'MPA', (83, 98))	('patient', 'Species', '9606', (148, 155))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (128, 147))	('LIMD1', 'Gene', '8994', (53, 58))
261715	29930174	We used siRNA to knock down LIMD1 in primary human lung bronchial epithelial cells (HBEC) and performed micro-array analysis to identify the resultant gene ontology changes.	('LIMD1', 'Gene', (28, 33))	('human', 'Species', '9606', (45, 50))	('LIMD1', 'Gene', '8994', (28, 33))	('changes', 'Reg', (165, 172))	('knock down', 'Var', (17, 27))
261719	29930174	This is the first example of the main scaffold protein LIMD1 within the regulatory PHD2-LIMD1-VHL complex being itself regulated by HIF and therefore providing this regulatory triad with an intrinsic homeostatic negative regulatory functionality, which when deregulated contributes to lung adenocarcinoma tumour growth.	('LIMD1', 'Gene', '8994', (88, 93))	('tumour growth', 'Disease', 'MESH:D006130', (305, 318))	('lung adenocarcinoma tumour', 'Disease', 'MESH:D000077192', (285, 311))	('LIMD1', 'Gene', (88, 93))	('PHD2-LIMD1-VHL', 'Disease', 'MESH:D006623', (83, 97))	('PHD2-LIMD1-VHL', 'Disease', (83, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (295, 304))	('homeostatic negative regulatory functionality', 'MPA', (200, 245))	('contributes to', 'Reg', (270, 284))	('deregulated', 'Var', (258, 269))	('LIMD1', 'Gene', '8994', (55, 60))	('lung adenocarcinoma tumour', 'Disease', (285, 311))	('LIMD1', 'Gene', (55, 60))	('tumour', 'Phenotype', 'HP:0002664', (305, 311))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (285, 304))	('tumour growth', 'Disease', (305, 318))
261723	29930174	In a xenograft model for tumorigenesis, ablation of the hypoxic inducibility of LIMD1 expression and subsequent loss of hypoxic HIF-1alpha protein regulation caused increased tumour vasculature and growth.	('ablation', 'Var', (40, 48))	('loss of hypoxic HIF-1alpha', 'Disease', (112, 138))	('growth', 'CPA', (198, 204))	('loss of hypoxic HIF-1alpha', 'Disease', 'MESH:D015431', (112, 138))	('tumour vasculature', 'Disease', (175, 193))	('tumour vasculature', 'Disease', 'MESH:C565633', (175, 193))	('LIMD1', 'Gene', (80, 85))	('increased', 'PosReg', (165, 174))	('LIMD1', 'Gene', '8994', (80, 85))	('tumour', 'Phenotype', 'HP:0002664', (175, 181))
261726	29930174	HIF-alpha is post-transcriptionally regulated (Gorospe et al, 2011), including by microRNA-20b, microRNA-199a and microRNA-424 (Rane et al, 2009; Cascio et al, 2010; Ghosh et al, 2010a).	('microRNA-424', 'Gene', (114, 126))	('microRNA-199a', 'Var', (96, 109))	('microRNA-20b', 'Gene', (82, 94))	('microRNA-424', 'Gene', '494336', (114, 126))	('microRNA-20b', 'Gene', '574032', (82, 94))
261727	29930174	Therefore to rule out the possibility that the miRNA-silencing function of LIMD1 (James et al, 2010) was contributing to the observations made, we identified that loss of LIMD1 does not affect the stability nor silencing of HIF1A/HIF2A mRNA.	('LIMD1', 'Gene', '8994', (75, 80))	('HIF2A', 'Gene', '2034', (230, 235))	('LIMD1', 'Gene', '8994', (171, 176))	('LIMD1', 'Gene', (75, 80))	('LIMD1', 'Gene', (171, 176))	('loss', 'Var', (163, 167))	('HIF2A', 'Gene', (230, 235))	('HIF1A', 'Gene', (224, 229))	('HIF1A', 'Gene', '3091', (224, 229))	('stability', 'MPA', (197, 206))	('silencing', 'MPA', (211, 220))
261745	29930174	In our small cohort of 276 NSCLC, high VEGF expression was correlated with poor survival, with 80% of the cohort demonstrating high VEGF expression.	('VEGF', 'Gene', (132, 136))	('NSCLC', 'Disease', (27, 32))	('NSCLC', 'Disease', 'MESH:D002289', (27, 32))	('VEGF', 'Gene', (39, 43))	('high', 'Var', (34, 38))	('VEGF', 'Gene', '7422', (132, 136))	('NSCLC', 'Phenotype', 'HP:0030358', (27, 32))	('VEGF', 'Gene', '7422', (39, 43))
261748	29930174	Correlative studies have also determined upregulation or de novo expression of the IGF2BP family of oncofetal proteins across a number of solid tumours to be associated with tumour aggressiveness, metastasis and poorer overall survival (Bell et al, 2013).	('solid tumours', 'Disease', (138, 151))	('overall survival', 'CPA', (219, 235))	('tumour', 'Phenotype', 'HP:0002664', (144, 150))	('poorer', 'NegReg', (212, 218))	('tumour', 'Phenotype', 'HP:0002664', (174, 180))	('associated', 'Reg', (158, 168))	('tumour aggressiveness', 'Disease', (174, 195))	('tumours', 'Phenotype', 'HP:0002664', (144, 151))	('aggressiveness', 'Phenotype', 'HP:0000718', (181, 195))	('metastasis', 'CPA', (197, 207))	('tumour aggressiveness', 'Disease', 'MESH:D001523', (174, 195))	('solid tumours', 'Disease', 'MESH:D009369', (138, 151))	('expression', 'Var', (65, 75))	('IGF2BP', 'Gene', (83, 89))	('upregulation', 'PosReg', (41, 53))
261751	29930174	Taken together, our findings hold significant impact for the aetiology of LIMD1-negative lung cancers and hold the potential for advances in the diagnosis and prognosis of such cancers with respect to deregulated HIF regulation and associated oncogenic phenotypes, and subsequently hypoxia-targeted therapies.	('cancers', 'Disease', 'MESH:D009369', (94, 101))	('cancers', 'Phenotype', 'HP:0002664', (177, 184))	('cancers', 'Disease', (177, 184))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('hypoxia', 'Disease', 'MESH:D000860', (282, 289))	('deregulated', 'Var', (201, 212))	('HIF regulation', 'MPA', (213, 227))	('lung cancer', 'Phenotype', 'HP:0100526', (89, 100))	('lung cancers', 'Disease', 'MESH:D008175', (89, 101))	('cancers', 'Phenotype', 'HP:0002664', (94, 101))	('cancers', 'Disease', (94, 101))	('lung cancers', 'Disease', (89, 101))	('cancers', 'Disease', 'MESH:D009369', (177, 184))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('lung cancers', 'Phenotype', 'HP:0100526', (89, 101))	('LIMD1', 'Gene', (74, 79))	('impact', 'Reg', (46, 52))	('LIMD1', 'Gene', '8994', (74, 79))	('hypoxia', 'Disease', (282, 289))
261805	29930174	A549 HRE wild-type and mutant cells were seeded into 6-cm plates at 5 x 104 cells per plate.	('A549', 'CellLine', 'CVCL:0023', (0, 4))	('mutant', 'Var', (23, 29))	('A549 HRE', 'Var', (0, 8))
261839	29296124	TFF1 hypermethylation and decreased expression in esophageal squamous cell carcinoma and histologically normal tumor surrounding esophageal cells Esophageal squamous cell carcinoma (ESCC) is one of the 10 most incident cancer types in the world, and it is mainly associated with tobacco and alcohol consumption.	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('cancer', 'Disease', 'MESH:D009369', (219, 225))	('decreased', 'NegReg', (26, 35))	('Esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (146, 180))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (61, 84))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (50, 84))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (157, 180))	('esophageal squamous cell carcinoma', 'Disease', (50, 84))	('alcohol', 'Chemical', 'MESH:D000438', (291, 298))	('tumor', 'Disease', (111, 116))	('tobacco', 'Species', '4097', (279, 286))	('carcinoma', 'Phenotype', 'HP:0030731', (171, 180))	('hypermethylation', 'Var', (5, 21))	('cancer', 'Disease', (219, 225))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('TFF1', 'Gene', '7031', (0, 4))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('Esophageal squamous cell carcinoma', 'Disease', (146, 180))	('TFF1', 'Gene', (0, 4))	('expression', 'MPA', (36, 46))
261894	29296124	TFF1 promoter was hypermethylated in tumor and histologically normal tumor surrounding tissue in comparison with healthy esophagus (Fig.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('tumor', 'Disease', (69, 74))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('TFF1', 'Gene', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('hypermethylated', 'Var', (18, 33))
261897	29296124	Taken together, our results suggest that a TFF1 promoter methylation increase of less than 20% can result in a reduction of gene expression greater than 80% and total absence of protein expression, as observed when comparing healthy esophagus and non-tumor adjacent mucosa from ESCC patients.	('reduction', 'NegReg', (111, 120))	('methylation', 'Var', (57, 68))	('increase', 'PosReg', (69, 77))	('promoter', 'MPA', (48, 56))	('protein expression', 'MPA', (178, 196))	('absence', 'NegReg', (167, 174))	('TFF1', 'Gene', (43, 47))	('patients', 'Species', '9606', (283, 291))	('non-tumor', 'Disease', 'MESH:D009369', (247, 256))	('gene expression greater', 'MPA', (124, 147))	('ESCC', 'Disease', (278, 282))	('tumor', 'Phenotype', 'HP:0002664', (251, 256))	('non-tumor', 'Disease', (247, 256))
261899	29296124	These findings are consistent with the hypothesis that methylation-dependent silencing of TFF1 may occur in both ESCC and tumor adjacent normal-appearing mucosa.	('ESCC', 'Disease', (113, 117))	('silencing', 'NegReg', (77, 86))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('methylation-dependent', 'Var', (55, 76))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumor', 'Disease', (122, 127))	('TFF1', 'Gene', (90, 94))
261900	29296124	However, we found no association between TFF1 expression levels or promoter methylation rate in normal esophageal cells and tobacco smoking or alcohol drinking, two well-recognized risk factors for this cancer type (Additional file 1: Table S1), suggesting that methylation-mediated silencing of TFF1 is independent of these risk factors.	('alcohol drinking', 'Phenotype', 'HP:0030955', (143, 159))	('alcohol', 'Chemical', 'MESH:D000438', (143, 150))	('methylation-mediated', 'Var', (262, 282))	('TFF1', 'Gene', (41, 45))	('tobacco', 'Species', '4097', (124, 131))	('cancer', 'Disease', (203, 209))	('TFF1', 'Gene', (296, 300))	('cancer', 'Disease', 'MESH:D009369', (203, 209))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))
261912	29296124	Finally, we show that silencing of TFF1 expression by promoter hypermethylation is a specific feature of ESCC, since the same profile was not observed in esophageal adenocarcinoma.	('expression', 'MPA', (40, 50))	('ESCC', 'Disease', (105, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (170, 179))	('promoter hypermethylation', 'Var', (54, 79))	('silencing', 'NegReg', (22, 31))	('esophageal adenocarcinoma', 'Disease', (154, 179))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (154, 179))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (154, 179))	('TFF1', 'Gene', (35, 39))
261919	29296124	In gastric cancer, the loss of TFF1 can contribute to the induction of pro-inflammatory and anti-apoptotic genes through activation of NF-kappaB pathway.	('NF-kappaB', 'Gene', (135, 144))	('gastric cancer', 'Phenotype', 'HP:0012126', (3, 17))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('pro-inflammatory and', 'MPA', (71, 91))	('induction', 'MPA', (58, 67))	('gastric cancer', 'Disease', (3, 17))	('anti-apoptotic genes', 'Gene', (92, 112))	('loss', 'Var', (23, 27))	('NF-kappaB', 'Gene', '4790', (135, 144))	('gastric cancer', 'Disease', 'MESH:D013274', (3, 17))	('TFF1', 'Gene', (31, 35))	('activation', 'PosReg', (121, 131))
261921	29296124	For example, the absence of TFF1 enhances the tumorigenic abilities of MCF7, a breast cancer cell line, in vitro and in vivo.	('MCF7', 'Gene', (71, 75))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('breast cancer', 'Disease', 'MESH:D001943', (79, 92))	('enhances', 'PosReg', (33, 41))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('breast cancer', 'Disease', (79, 92))	('tumor', 'Disease', (46, 51))	('absence', 'Var', (17, 24))	('MCF7', 'CellLine', 'CVCL:0031', (71, 75))	('breast cancer', 'Phenotype', 'HP:0003002', (79, 92))	('TFF1', 'Gene', (28, 32))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
261922	29296124	Similarly, TFF1-KO also enhances tumor formation in ovary and lung using a 7,12-dimethylbenz[a]anthracene (DMBA)-induced carcinogenesis model.	('anthracene', 'Chemical', 'MESH:C034020', (95, 105))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('ovary', 'Disease', (52, 57))	('ovary', 'Disease', 'MESH:D010051', (52, 57))	('tumor', 'Disease', (33, 38))	('DMBA', 'Chemical', 'MESH:D015127', (107, 111))	('enhances', 'PosReg', (24, 32))	('7,12-dimethylbenz', 'Chemical', '-', (75, 92))	('TFF1-KO', 'Var', (11, 18))
261926	29296124	However, it is important to mention that EAC is closely related to gastric cancers with chromosomal instability and these two tumors clearly differ from gastric adenocarcinoma related to Epstein-Barr infection, microsatellite instability, and genomic stability.	('related', 'Reg', (56, 63))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('men', 'Species', '9606', (28, 31))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('gastric cancer', 'Phenotype', 'HP:0012126', (67, 81))	('EAC', 'Disease', (41, 44))	('chromosomal instability', 'Var', (88, 111))	('chromosomal instability', 'Phenotype', 'HP:0040012', (88, 111))	('tumors', 'Disease', (126, 132))	('carcinoma', 'Phenotype', 'HP:0030731', (166, 175))	('Epstein-Barr infection', 'Disease', (187, 209))	('gastric adenocarcinoma', 'Disease', (153, 175))	('tumors', 'Disease', 'MESH:D009369', (126, 132))	('Epstein-Barr infection', 'Disease', 'MESH:D020031', (187, 209))	('gastric cancers', 'Phenotype', 'HP:0012126', (67, 82))	('differ', 'Reg', (141, 147))	('cancers', 'Phenotype', 'HP:0002664', (75, 82))	('EAC', 'Phenotype', 'HP:0011459', (41, 44))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('gastric cancers', 'Disease', (67, 82))	('gastric cancers', 'Disease', 'MESH:D013274', (67, 82))	('gastric adenocarcinoma', 'Disease', 'MESH:D013274', (153, 175))
261992	28977904	The sensitivity and specificity of CK4 protein positivity by immunohistochemical staining for predicting high KRT4 gene expression and low PI were 46% and 92%, and 38% and 85%, respectively.	('al', 'Chemical', 'MESH:D000535', (78, 80))	('high', 'Var', (105, 109))	('expression', 'MPA', (120, 130))	('CK4', 'Gene', (35, 38))	('KRT4', 'Gene', (110, 114))	('low PI', 'Disease', (135, 141))	('KRT4', 'Gene', '3851', (110, 114))	('CK4', 'Gene', '3851', (35, 38))
261996	28977904	Multivariate Cox regression analysis in 127 TSCC patients revealed that CK4 positivity was an independent favorable prognostic factor in TSCC patients for RFS (HR 0.591, 95% CI: 0.354-0.988) and DSS (HR 0.333, 95%CI: 0.159-0.697) (Table 4).	('CK4', 'Gene', '3851', (72, 75))	('Cox', 'Gene', (13, 16))	('al', 'Chemical', 'MESH:D000535', (62, 64))	('positivity', 'Var', (76, 86))	('RFS', 'Disease', (155, 158))	('CK4', 'Gene', (72, 75))	('DSS', 'Gene', (195, 198))	('patients', 'Species', '9606', (49, 57))	('DSS', 'Gene', '5376', (195, 198))	('al', 'Chemical', 'MESH:D000535', (30, 32))	('patients', 'Species', '9606', (142, 150))	('TSCC', 'Disease', (137, 141))	('Cox', 'Gene', '1351', (13, 16))
262028	28977904	Mutation of the KRT4 gene leads to the development of white sponge nevus, which is characterized by oral leukoplakia.	('KRT4', 'Gene', (16, 20))	('leads to', 'Reg', (26, 34))	('KRT4', 'Gene', '3851', (16, 20))	('white sponge nevus', 'Disease', (54, 72))	('oral leukoplakia', 'Phenotype', 'HP:0002745', (100, 116))	('Mutation', 'Var', (0, 8))	('oral leukoplakia', 'Disease', 'MESH:D007972', (100, 116))	('nevus', 'Phenotype', 'HP:0003764', (67, 72))	('sponge nevus', 'Phenotype', 'HP:0025510', (60, 72))	('oral leukoplakia', 'Disease', (100, 116))
262079	28977904	After endogenous peroxidase activity was blocked with 0.3% H2O2 in methanol, antigen retrieval was performed by immersion in buffer (S2367, Target Retrieval Solution, pH 9; Dako) in a microwave oven for 10 minutes at 95 C. The anti-CK4 antibody (ab9004; Abcom) was diluted at 1:500 in antibody diluent (S3022, Antibody Dilution with Background Reducing Components; Dako) and the sections were incubated with the antibody overnight at 4 C. The slides were then reacted with a peroxidase-labeled secondary antibody (K4000, EnVision/HRP system; Dako) and visualized as a brown reaction product by applying 3,3'-diaminobenzidine (DAB) solution (K3467, DAB+ Liquid; Dako).	('DAB', 'Chemical', 'MESH:D015100', (648, 651))	('CK4', 'Gene', '3851', (232, 235))	('S3022', 'Var', (303, 308))	('diaminobenzidine', 'Chemical', '-', (608, 624))	('CK4', 'Gene', (232, 235))	('DAB', 'Chemical', 'MESH:D015100', (626, 629))	('al', 'Chemical', 'MESH:D000535', (92, 94))	('al', 'Chemical', 'MESH:D000535', (154, 156))	('al', 'Chemical', 'MESH:D000535', (556, 558))
262104	33834191	Higher RBP4 expression was associated with better overall survival time in HCC patients, and we identified a deletion-mutation rate of 1.4% in RBP4.	('deletion-mutation', 'Var', (109, 126))	('RBP4', 'Gene', (143, 147))	('HCC', 'Gene', '619501', (75, 78))	('RBP4', 'Gene', '5950', (143, 147))	('RBP4', 'Gene', '5950', (7, 11))	('RBP4', 'Gene', (7, 11))	('patients', 'Species', '9606', (79, 87))	('expression', 'MPA', (12, 22))	('HCC', 'Gene', (75, 78))
262126	33834191	Studies have indicated that high serum RBP4 in HCC combined with metabolic syndrome patients were closely associated with poor prognosis.	('RBP4', 'Gene', '5950', (39, 43))	('HCC', 'Gene', (47, 50))	('metabolic syndrome', 'Disease', (65, 83))	('associated', 'Reg', (106, 116))	('patients', 'Species', '9606', (84, 92))	('HCC', 'Gene', '619501', (47, 50))	('metabolic syndrome', 'Disease', 'MESH:D024821', (65, 83))	('high', 'Var', (28, 32))	('RBP4', 'Gene', (39, 43))
262138	33834191	The online CBioPortal site (https://www.cbioportal.org/) and LinkedOmics were used to access data for RBP4 gene mutations, co-expressed genes, and mutations related to protein expression.	('mutations', 'Var', (112, 121))	('RBP4', 'Gene', '5950', (102, 106))	('RBP4', 'Gene', (102, 106))
262153	33834191	For DSS, high RBP4 expression was also associated with better outcomes (HR = 0.32, 95% CI: 0.2-0.51), (log rank P = 2.8e-07, Figure 2J).	('expression', 'MPA', (19, 29))	('RBP4', 'Gene', (14, 18))	('DSS', 'Chemical', '-', (4, 7))	('RBP4', 'Gene', '5950', (14, 18))	('high', 'Var', (9, 13))
262155	33834191	Deletion mutations accounted for 1.4% of total RBP4 mutations, and five proteins were changed because of RBP4 related somatic mutations (T41l, RBP4-GPC3, IGHG1-RBP4, AMBP-RBP4, and CLU-RBP4) (Figure 3A).	('RBP4', 'Gene', (143, 147))	('CLU', 'Gene', (181, 184))	('RBP4', 'Gene', (47, 51))	('RBP4', 'Gene', '5950', (171, 175))	('CLU', 'Gene', '1191', (181, 184))	('IGHG1', 'Gene', '3500', (154, 159))	('Deletion mutations', 'Var', (0, 18))	('T41l', 'Var', (137, 141))	('RBP4', 'Gene', '5950', (105, 109))	('RBP4', 'Gene', (171, 175))	('RBP4', 'Gene', '5950', (185, 189))	('IGHG1', 'Gene', (154, 159))	('GPC3', 'Gene', (148, 152))	('RBP4', 'Gene', '5950', (160, 164))	('RBP4', 'Gene', (105, 109))	('AMBP', 'Gene', '259', (166, 170))	('mutations', 'Var', (52, 61))	('RBP4', 'Gene', '5950', (143, 147))	('changed', 'Reg', (86, 93))	('GPC3', 'Gene', '2719', (148, 152))	('AMBP', 'Gene', (166, 170))	('RBP4', 'Gene', (185, 189))	('proteins', 'Protein', (72, 80))	('RBP4', 'Gene', (160, 164))	('RBP4', 'Gene', '5950', (47, 51))
262156	33834191	The different types of RBP4 mutations also affected RBP4 m RNA expression (F-value = 9.969, P<0.001, Figure 3B).	('affected', 'Reg', (43, 51))	('RBP4', 'Gene', '5950', (23, 27))	('RBP4', 'Gene', (52, 56))	('RBP4', 'Gene', '5950', (52, 56))	('RBP4', 'Gene', (23, 27))	('mutations', 'Var', (28, 37))
262157	33834191	The RBP4 mutation types were also correlated with immune cell infiltration levels, especially for neutrophils with deep-deletion and arm-level gain types of mutations (Figure 3C).	('deep-deletion', 'Var', (115, 128))	('RBP4', 'Gene', '5950', (4, 8))	('RBP4', 'Gene', (4, 8))	('mutations', 'Var', (157, 166))	('arm-level', 'MPA', (133, 142))	('immune cell infiltration levels', 'MPA', (50, 81))	('gain', 'PosReg', (143, 147))
262159	33834191	Collectively, RBP4 expression and mutations were associated with immune cell infiltration characteristics.	('RBP4', 'Gene', (14, 18))	('associated', 'Reg', (49, 59))	('RBP4', 'Gene', '5950', (14, 18))	('mutations', 'Var', (34, 43))	('immune cell infiltration characteristics', 'CPA', (65, 105))
262190	33834191	We determined that RBP4 mutations were negatively correlated with immune cell infiltration, indicating that RBP4 expression is closely related to immune cell bioactivity in preclinical and clinical models.	('RBP4', 'Gene', (108, 112))	('mutations', 'Var', (24, 33))	('negatively', 'NegReg', (39, 49))	('RBP4', 'Gene', '5950', (108, 112))	('RBP4', 'Gene', '5950', (19, 23))	('RBP4', 'Gene', (19, 23))	('immune cell infiltration', 'CPA', (66, 90))
262202	32668393	Homozygous deletion of six genes in 9p21.3 characterized an LGG subtype with poor prognosis and contributed to the dysfunction of cancer-associated pathways in a complementary way.	('contributed', 'Reg', (96, 107))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('cancer', 'Disease', (130, 136))	('Homozygous', 'Var', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('dysfunction', 'MPA', (115, 126))	('LGG', 'Disease', (60, 63))
262211	32668393	Somatic copy-number alterations (SCNAs), one important type of somatic genetic alterations, have been reported to activate oncogenes and inactivate tumor suppressors, which further made contributions to cancer progression.	('alterations', 'Var', (79, 90))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('tumor', 'Disease', (148, 153))	('inactivate', 'NegReg', (137, 147))	('activate', 'PosReg', (114, 122))	('cancer', 'Disease', (203, 209))	('cancer', 'Disease', 'MESH:D009369', (203, 209))	('copy-number alterations', 'Var', (8, 31))	('oncogenes', 'Protein', (123, 132))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))
262216	32668393	showed that the co-amplifications and co-deletions of cancer-causing genes and metabolic genes contributed to reprogram cancer cell metabolism.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('co-amplifications', 'Var', (16, 33))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', (54, 60))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('co-deletions', 'Var', (38, 50))	('contributed', 'Reg', (95, 106))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
262218	32668393	The driver genetic alterations could induce the dysregulation of multilayer factor-mediated regulatory networks of gene expression and further cause disorder of cancer-associated functions.	('cancer', 'Disease', (161, 167))	('disorder', 'MPA', (149, 157))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('multilayer factor-mediated regulatory networks of', 'Pathway', (65, 114))	('cause', 'Reg', (143, 148))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('induce', 'Reg', (37, 43))	('dysregulation', 'MPA', (48, 61))	('genetic alterations', 'Var', (11, 30))
262224	32668393	Copy number loss of both CNOT6LA and VAPA may downregulate PTEN in a miRNA-dependent manner.	('downregulate', 'NegReg', (46, 58))	('VAPA', 'Gene', '9218', (37, 41))	('VAPA', 'Gene', (37, 41))	('CNOT6LA', 'Gene', (25, 32))	('PTEN', 'Gene', (59, 63))	('PTEN', 'Gene', '5728', (59, 63))	('Copy number loss', 'Var', (0, 16))
262226	32668393	vIRF1 deletion increased miR-218-5p expression level and reduced the level of lnc-OIP5-AS1.	('OIP5-AS1', 'Gene', '729082;11339;5729', (82, 90))	('increased', 'PosReg', (15, 24))	('deletion', 'Var', (6, 14))	('OIP5-AS1', 'Gene', (82, 90))	('reduced', 'NegReg', (57, 64))	('vIRF1', 'Gene', (0, 5))	('miR-218-5p expression level', 'MPA', (25, 52))
262229	32668393	Homozygous deletion of six genes in 9p21.3 could characterize a LGG subtype with poor prognosis and contribute to the dysfunction of cancer-associated pathways in a complementary way.	('contribute', 'Reg', (100, 110))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('dysfunction', 'MPA', (118, 129))	('cancer', 'Disease', (133, 139))	('Homozygous deletion', 'Var', (0, 19))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('LGG', 'Disease', (64, 67))
262239	32668393	The knocking down of COMMD9 was reported to inhibit cell proliferation and migration, and it arrested the cell cycle at the G1/S transition.	('knocking down', 'Var', (4, 17))	('cell cycle at the G1/S transition', 'CPA', (106, 139))	('arrest', 'Disease', 'MESH:D006323', (93, 99))	('inhibit', 'NegReg', (44, 51))	('cell proliferation', 'CPA', (52, 70))	('COMMD9', 'Gene', (21, 27))	('arrest', 'Disease', (93, 99))	('COMMD9', 'Gene', '29099', (21, 27))
262240	32668393	The depletion of CPSF1 suppressed cell viability and promoted cell apoptosis by inducing cell cycle arrest at the G0/G1 phase.	('promoted', 'PosReg', (53, 61))	('suppressed', 'NegReg', (23, 33))	('arrest', 'Disease', 'MESH:D006323', (100, 106))	('arrest', 'Disease', (100, 106))	('depletion', 'Var', (4, 13))	('CPSF1', 'Gene', '29894', (17, 22))	('CPSF1', 'Gene', (17, 22))	('cell apoptosis', 'CPA', (62, 76))	('inducing', 'Reg', (80, 88))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (89, 106))	('cell viability', 'CPA', (34, 48))
262242	32668393	HSF1 knockdown reduced cell migration and invasive ability, which were restored by HSF1 overexpression.	('invasive ability', 'CPA', (42, 58))	('knockdown', 'Var', (5, 14))	('HSF1', 'Gene', (0, 4))	('HSF1', 'Gene', '3297', (0, 4))	('HSF1', 'Gene', (83, 87))	('reduced', 'NegReg', (15, 22))	('cell migration', 'CPA', (23, 37))	('HSF1', 'Gene', '3297', (83, 87))
262247	32668393	To investigate whether dysregulated ceRNA networks were associated with cancer hallmarks, we downloaded 50 hallmark signatures from MSigDB and identified the significantly enriched hallmark signatures by the deregulated ceRNA networks using R package clusterProfiler at a false discovery rate (FDR) of 0.05.	('deregulated', 'Var', (208, 219))	('MSigDB', 'Gene', (132, 138))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('cancer hallmarks', 'Disease', (72, 88))	('cancer hallmarks', 'Disease', 'MESH:D009369', (72, 88))
262248	32668393	For example, the dysregulated ceRNA networks caused by lncRNA ZNF252P-AS1 amplification were significantly enriched in a DNA damage signature (DNA_REPAIR), proliferation signatures (E2F_TARGETS, G2M_CHECKPOINT, MITOTIC_SPINDLE, MYC_TARGETS_V1, and MYC_TARGETS_V2), and a pathway signature (UNFOLDED_PROTEIN_RESPONSE).	('ZNF252P-AS1', 'Gene', (62, 73))	('MYC', 'Gene', '4609', (228, 231))	('amplification', 'Var', (74, 87))	('MYC', 'Gene', (248, 251))	('DNA damage signature', 'MPA', (121, 141))	('proliferation', 'MPA', (156, 169))	('ZNF252P-AS1', 'Gene', '286103', (62, 73))	('MYC', 'Gene', (228, 231))	('ceRNA', 'Gene', (30, 35))	('MYC', 'Gene', '4609', (248, 251))
262249	32668393	The most frequently enriched hallmark signatures across 37 dysregulated ceRNA networks were proliferation signatures, including E2F_TARGETS (30/37), G2M_CHECKPOINT (29/37), and MYC_TARGETS_V1 (25/37).	('MYC', 'Gene', '4609', (177, 180))	('E2F_TARGETS', 'Var', (128, 139))	('proliferation', 'CPA', (92, 105))	('MYC', 'Gene', (177, 180))
262254	32668393	To further analyze the association of 9p21.3 deletions with LGG poor prognosis in spite of alterations in the rest of the driver genes, we classified the LGG patients into three subgroups based on the SCNA status of the 44 driver genes as follows: subgroup I, including patients without any SCNAs of the 44 driver genes; subgroup II, including patients with homozygous deletions of at least one of the six genes in 9p21.3; and subgroup III, including patients without homozygous deletions of the six genes but with homozygous deletions or high-level amplifications of the rest of the 38 driver genes.	('patients', 'Species', '9606', (270, 278))	('deletions', 'Var', (45, 54))	('patients', 'Species', '9606', (158, 166))	('deletions', 'Var', (369, 378))	('patients', 'Species', '9606', (344, 352))	('patients', 'Species', '9606', (451, 459))
262255	32668393	By preforming function enrichment analysis, we found that these six dysregulated ceRNA networks were consistently and significantly enriched in the proliferation hallmark signatures, including E2F_TARGETS, G2M_CHECKPOINT and MYC_TARGETS_V1 (Figure 4F).	('MYC', 'Gene', '4609', (225, 228))	('MYC', 'Gene', (225, 228))	('E2F_TARGETS', 'Var', (193, 204))	('G2M_CHECKPOINT', 'Var', (206, 220))
262266	32668393	We found that amplification of lncRNA PVT1 could destroy its ceRNA networks in six cancer types, including OV, head and neck squamous cell carcinoma (HNSC), lung adenocarcinoma (LUAD), stomach adenocarcinoma (STAD), BRCA, and bladder urothelial carcinoma (BLCA) (Figures S5-S10).	('LUAD', 'Phenotype', 'HP:0030078', (178, 182))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('carcinoma', 'Phenotype', 'HP:0030731', (167, 176))	('BRCA', 'Phenotype', 'HP:0003002', (216, 220))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (157, 176))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (125, 148))	('neck squamous cell carcinoma', 'Disease', (120, 148))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (120, 148))	('carcinoma', 'Phenotype', 'HP:0030731', (245, 254))	('carcinoma', 'Phenotype', 'HP:0030731', (198, 207))	('PVT1', 'Gene', (38, 42))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (157, 176))	('ceRNA networks', 'CPA', (61, 75))	('PVT1', 'Gene', '5820', (38, 42))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('BRCA', 'Gene', '672', (216, 220))	('destroy', 'NegReg', (49, 56))	('stomach adenocarcinoma', 'Disease', 'MESH:D000230', (185, 207))	('OV', 'Phenotype', 'HP:0012887', (107, 109))	('stomach adenocarcinoma', 'Disease', (185, 207))	('bladder urothelial carcinoma', 'Disease', (226, 254))	('BRCA', 'Gene', (216, 220))	('carcinoma', 'Phenotype', 'HP:0030731', (139, 148))	('cancer', 'Disease', (83, 89))	('lung adenocarcinoma', 'Disease', (157, 176))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (226, 254))	('amplification', 'Var', (14, 27))
262269	32668393	Amplification of PVT1 could contribute to the development ovarian and breast cancer.	('Amplification', 'Var', (0, 13))	('PVT1', 'Gene', (17, 21))	('ovarian and breast cancer', 'Disease', 'MESH:D001943', (58, 83))	('PVT1', 'Gene', '5820', (17, 21))	('breast cancer', 'Phenotype', 'HP:0003002', (70, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('contribute to', 'Reg', (28, 41))
262270	32668393	Knockdown of PVT1 could inhibit cell migration and proliferation.	('PVT1', 'Gene', (13, 17))	('PVT1', 'Gene', '5820', (13, 17))	('inhibit', 'NegReg', (24, 31))	('Knockdown', 'Var', (0, 9))
262272	32668393	Compared with non-alteration status, amplification significantly elevated the expression levels of PVT1 (Figure 6B).	('PVT1', 'Gene', (99, 103))	('amplification', 'Var', (37, 50))	('PVT1', 'Gene', '5820', (99, 103))	('elevated', 'PosReg', (65, 73))	('expression levels', 'MPA', (78, 95))
262275	32668393	The amplification of PVT1 completely destroyed the active ceRNA networks, and the numbers of active ceRNA triples dropped to 0.	('active ceRNA networks', 'CPA', (51, 72))	('destroyed', 'NegReg', (37, 46))	('PVT1', 'Gene', (21, 25))	('amplification', 'Var', (4, 17))	('PVT1', 'Gene', '5820', (21, 25))
262285	32668393	Comparative analysis showed that MTAP deletion also disturbed distinct ceRNA triples in different cancers (Figure S11).	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('MTAP', 'Gene', (33, 37))	('disturbed', 'Reg', (52, 61))	('cancers', 'Phenotype', 'HP:0002664', (98, 105))	('ceRNA triples', 'MPA', (71, 84))	('MTAP', 'Gene', '4507', (33, 37))	('cancers', 'Disease', 'MESH:D009369', (98, 105))	('cancers', 'Disease', (98, 105))	('deletion', 'Var', (38, 46))
262290	32668393	However, the significant inverse relationships between hsa-miR-326 and both PVT1 and NEAT1 were destroyed by PVT1 amplification in HNSC.	('PVT1', 'Gene', '5820', (76, 80))	('amplification', 'Var', (114, 127))	('NEAT1', 'Gene', '283131', (85, 90))	('PVT1', 'Gene', '5820', (109, 113))	('NEAT1', 'Gene', (85, 90))	('hsa-miR-326', 'Gene', '442900', (55, 66))	('hsa-miR-326', 'Gene', (55, 66))	('PVT1', 'Gene', (76, 80))	('PVT1', 'Gene', (109, 113))
262301	32668393	EGFR amplification was associated with poor prognosis in both GBM and HNSC (p = 0.0242 for GBM, p = 0.0314 for HNSC; Figure S13).	('GBM', 'Disease', (62, 65))	('EGFR', 'Gene', (0, 4))	('amplification', 'Var', (5, 18))	('HNSC', 'Disease', (70, 74))	('EGFR', 'Gene', '1956', (0, 4))
262302	32668393	Compared with non-alteration, amplification significantly elevated EGFR expression levels in both GBM and HNSC (p = 3.6e-16 for GBM and p = 1.3e-9 for HNSC; Figure 8F).	('expression levels', 'MPA', (72, 89))	('amplification', 'Var', (30, 43))	('EGFR', 'Gene', '1956', (67, 71))	('EGFR', 'Gene', (67, 71))	('elevated', 'PosReg', (58, 66))
262303	32668393	However, EGFR did not participate in the ceRNA regulatory mechanism in spite of non-alteration or amplification in GBM (FDR = 0.05, PCC < 0; Figure 8G).	('GBM', 'Gene', (115, 118))	('EGFR', 'Gene', '1956', (9, 13))	('amplification', 'Var', (98, 111))	('EGFR', 'Gene', (9, 13))	('non-alteration', 'Var', (80, 94))
262304	32668393	Under non-alteration of EGFR in HNSC, four miRNAs showed significant inverse correlations with EGFR while no inverse correlations were identified between any miRNA and EGFR under EGFR amplifications (FDR = 0.05, PCC < 0; Figure 8H; Figure S14).	('EGFR', 'Gene', (179, 183))	('EGFR', 'Gene', '1956', (24, 28))	('EGFR', 'Gene', '1956', (168, 172))	('EGFR', 'Gene', (168, 172))	('EGFR', 'Gene', (24, 28))	('non-alteration', 'Var', (6, 20))	('correlations', 'Interaction', (77, 89))	('EGFR', 'Gene', '1956', (95, 99))	('inverse', 'NegReg', (69, 76))	('EGFR', 'Gene', '1956', (179, 183))	('EGFR', 'Gene', (95, 99))
262308	32668393	Due to the less frequent SCNAs of known cancer genes, we re-identified the driver genes in LGG for the threshold of alteration frequencies at 0.08, 0.06, 0.04, and 0.02, which also could significantly capture known cancer genes.	('cancer', 'Disease', (215, 221))	('cancer', 'Disease', 'MESH:D009369', (215, 221))	('0.02', 'Var', (164, 168))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('LGG', 'Gene', (91, 94))	('cancer', 'Disease', (40, 46))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))
262317	32668393	Analysis of ceRNA networks in previous studies explored ceRNA partners of PGs (PTEN) based on mRNA-mRNA ceRNA networks or predicted lncRNA functions based on lncRNA-mRNA ceRNA networks.	('PGs', 'Var', (74, 77))	('PTEN', 'Gene', '5728', (79, 83))	('PTEN', 'Gene', (79, 83))	('lncRNA functions', 'MPA', (132, 148))
262325	32668393	Amplification of EGFR could elevate EGFR expression levels in both HNSC and GBM.	('expression levels', 'MPA', (41, 58))	('Amplification', 'Var', (0, 13))	('elevate', 'PosReg', (28, 35))	('EGFR', 'Gene', '1956', (36, 40))	('EGFR', 'Gene', '1956', (17, 21))	('EGFR', 'Gene', (36, 40))	('EGFR', 'Gene', (17, 21))
262326	32668393	EGFR amplification dysregulated the EGFR-associated ceRNA network in HNSC, while EGFR did not participate in the ceRNA regulatory mechanism in GBM.	('dysregulated', 'Reg', (19, 31))	('EGFR', 'Gene', (0, 4))	('HNSC', 'Disease', (69, 73))	('amplification', 'Var', (5, 18))	('EGFR', 'Gene', '1956', (36, 40))	('EGFR', 'Gene', (36, 40))	('EGFR', 'Gene', '1956', (0, 4))	('EGFR', 'Gene', '1956', (81, 85))	('EGFR', 'Gene', (81, 85))
262327	32668393	In other case, SCNAs of genes or lncRNAs could disturb their associated ceRNA networks through different miRNAs and different ceRNA partners in different cancer types.	('SCNAs', 'Var', (15, 20))	('cancer', 'Disease', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('miRNAs', 'MPA', (105, 111))	('disturb', 'Reg', (47, 54))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('ceRNA networks', 'Pathway', (72, 86))
262332	32668393	The copy number profiles of 12 cancer types involved 5,814 cancer samples in TCGA.	('cancer', 'Disease', (31, 37))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('copy', 'Var', (4, 8))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))
262348	32668393	According to copy number status of each candidate gene, we grouped cancer samples into subgroups and deleted the subgroups with fewer than five samples.	('copy', 'Var', (13, 17))	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('cancer', 'Disease', (67, 73))
262349	32668393	For a given PG or lncRNA, three SCNA status levels may be present across cancer populations: heterozygous deletion (-2), high-level amplification (2), and non-alterations (0).	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('non-alterations', 'Var', (155, 170))
262350	32668393	According to SCNA status of the PG or lncRNA, the cancer patients were divided into subgroups as follows: one subgroup of patients with heterozygous deletion (-2) of the PG or lncRNA, one subgroup of patients with high-level amplification (2) of the PG or lncRNA, and one subgroup of patients with non-alteration (0) of the PG or lncRNA.	('deletion', 'Var', (149, 157))	('patients', 'Species', '9606', (200, 208))	('cancer', 'Disease', (50, 56))	('patients', 'Species', '9606', (284, 292))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('patients', 'Species', '9606', (57, 65))	('patients', 'Species', '9606', (122, 130))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))
262373	31798724	TP53 tumor suppressor has mutations in 40-60% of the HNSCC cases.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('HNSCC', 'Disease', (53, 58))	('mutations', 'Var', (26, 35))	('tumor', 'Disease', (5, 10))
262418	31798724	Some studies have shown that the number of cells that present with polysomy at the level of the 17th chromosome is raised in oral cavity squamous carcinomas and this may be correlated with the process of carcinogenesis.	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('carcinogenesis', 'Disease', (204, 218))	('oral cavity squamous carcinomas', 'Disease', (125, 156))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (137, 155))	('oral cavity squamous carcinomas', 'Disease', 'MESH:D002294', (125, 156))	('carcinomas', 'Phenotype', 'HP:0030731', (146, 156))	('carcinogenesis', 'Disease', 'MESH:D063646', (204, 218))	('polysomy', 'Var', (67, 75))
262420	31798724	Thereby, it has been tried to identify some possible numeric aberrations of chromosome 17, such as deletion or amplification of TP53 gene in the FaDu and PE/CA-PJ49 cells.	('TP53', 'Gene', '7157', (128, 132))	('TP53', 'Gene', (128, 132))	('amplification', 'Var', (111, 124))	('deletion', 'Var', (99, 107))
262425	31798724	1B) suggesting a deletion of the TP53 gene, without modification at the level of chromosome 17 which presented only two signals for the 17(D17Z1) centromere (green dots Fig.	('deletion', 'Var', (17, 25))	('TP53', 'Gene', '7157', (33, 37))	('TP53', 'Gene', (33, 37))
262443	31798724	FaDu having a TP53 deletion and constitutively a lower expression of phospho ERK1/2, does not respond to any of the treatments (Fig.	('TP53', 'Gene', '7157', (14, 18))	('TP53', 'Gene', (14, 18))	('deletion', 'Var', (19, 27))	('lower', 'NegReg', (49, 54))	('expression of', 'MPA', (55, 68))
262451	31798724	Thus, the tumor cells were pretreated for 2 h with a specific ERK1/2 inhibitor, 25 microM PD98059 (concentration determined after sketching the dose-effect curve) was used for pretreatments, and then the cells were treated with CisPt and/or CRM for another 24 h. FaDu cells have a TP53 deletion (Fig.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('TP53', 'Gene', (281, 285))	('tumor', 'Disease', (10, 15))	('CisPt', 'Chemical', 'MESH:D002945', (228, 233))	('CRM', 'Chemical', 'MESH:D003474', (241, 244))	('PD98059', 'Chemical', 'MESH:C093973', (90, 97))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('TP53', 'Gene', '7157', (281, 285))	('deletion', 'Var', (286, 294))
262455	31798724	Pretreating with the PD98059 inhibitor of the PE-CA/PJ49 cells induced an increase of the proliferative activity in the case of treated cells with CisPt (d; P=0.005) or CRM (e; P=0.007).	('CRM', 'Chemical', 'MESH:D003474', (169, 172))	('PD98059', 'Var', (21, 28))	('increase', 'PosReg', (74, 82))	('PD98059', 'Chemical', 'MESH:C093973', (21, 28))	('CisPt', 'Chemical', 'MESH:D002945', (147, 152))	('proliferative activity', 'CPA', (90, 112))
262469	31798724	In the case of cells treated with CisPt alone the process of phosphorylation seems to be less affected by the presence of PD98059, the phosphorylated form of protein p53 being expressed in 65% (a; P=0.0007).	('PD98059', 'Var', (122, 129))	('p53', 'Gene', (166, 169))	('p53', 'Gene', '7157', (166, 169))	('PD98059', 'Chemical', 'MESH:C093973', (122, 129))	('CisPt', 'Chemical', 'MESH:D002945', (34, 39))
262471	31798724	In the PE/CA-PJ49 untreated cells, the presence of PD98059 reduced the phospho-p53 expression to 53% (Fig.	('p53', 'Gene', '7157', (79, 82))	('p53', 'Gene', (79, 82))	('reduced', 'NegReg', (59, 66))	('PD98059', 'Var', (51, 58))	('PD98059', 'Chemical', 'MESH:C093973', (51, 58))
262473	31798724	The combined CisPt and CRM treatment in the presence of PD98059 kept the phosphorylated form of protein p53 to 30% (c; P=0.007) since the effect of the two agents was not additive (Fig.	('p53', 'Gene', (104, 107))	('p53', 'Gene', '7157', (104, 107))	('CRM', 'Chemical', 'MESH:D003474', (23, 26))	('PD98059', 'Var', (56, 63))	('CisPt', 'Chemical', 'MESH:D002945', (13, 18))	('phosphorylated form', 'MPA', (73, 92))	('PD98059', 'Chemical', 'MESH:C093973', (56, 63))
262487	31798724	6C, the PD98059 inhibition of ERK1/2 protein kinase led to a decrease of the apoptotic cell percentage in both cell lines compared to untreated cells.	('PD98059', 'Chemical', 'MESH:C093973', (8, 15))	('decrease', 'NegReg', (61, 69))	('PD98059 inhibition', 'Var', (8, 26))	('ERK1/2 protein kinase', 'Enzyme', (30, 51))	('apoptotic cell percentage', 'CPA', (77, 102))
262491	31798724	The genotypic abnormalities such as polysomy of chromosome 17 may be associated with the development of an early recurrence or second primary tumors and can influence the therapy response.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('influence', 'Reg', (157, 166))	('associated', 'Reg', (69, 79))	('tumors', 'Disease', (142, 148))	('tumors', 'Disease', 'MESH:D009369', (142, 148))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))	('early recurrence', 'CPA', (107, 123))	('polysomy of chromosome', 'Var', (36, 58))	('therapy response', 'CPA', (171, 187))
262494	31798724	Abnormalities in the p53 gene cause an inefficient checkpoint system for the repair and destruction of mutant cells.	('mutant', 'Var', (103, 109))	('p53', 'Gene', '7157', (21, 24))	('p53', 'Gene', (21, 24))	('Abnormalities', 'Var', (0, 13))
262496	31798724	PE/CA-PJ49 cell line had an amplification of the TP53 gene associated with polysomy in chromosome 17.	('TP53', 'Gene', '7157', (49, 53))	('TP53', 'Gene', (49, 53))	('associated', 'Reg', (59, 69))	('polysomy in chromosome 17', 'Disease', (75, 100))	('amplification', 'Var', (28, 41))
262497	31798724	FaDu tumor line presented a deletion in gene TP53, without chromosome 17 modifications.	('FaDu tumor', 'Disease', 'MESH:D009369', (0, 10))	('TP53', 'Gene', (45, 49))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('FaDu tumor', 'Disease', (0, 10))	('deletion', 'Var', (28, 36))	('TP53', 'Gene', '7157', (45, 49))
262499	31798724	Genetic modifications, as well as p53 protein expression alterations could influence the activation of several intracellular signaling pathways, such as ERK1/2 and therefore it could contribute to the modulation of the response to therapy.	('p53', 'Gene', (34, 37))	('intracellular signaling pathways', 'Pathway', (111, 143))	('p53', 'Gene', '7157', (34, 37))	('protein', 'Protein', (38, 45))	('contribute', 'Reg', (183, 193))	('influence', 'Reg', (75, 84))	('alterations', 'Var', (57, 68))	('expression', 'MPA', (46, 56))	('modulation', 'Reg', (201, 211))	('ERK1/2', 'Pathway', (153, 159))	('Genetic modifications', 'Var', (0, 21))
262509	31798724	In untreated cells, the expression of total and phosphorylated p53 was higher in FaDu compared to PE/CA-PJ49 cells (Fig.	('higher', 'PosReg', (71, 77))	('p53', 'Gene', '7157', (63, 66))	('p53', 'Gene', (63, 66))	('expression', 'MPA', (24, 34))	('FaDu', 'Var', (81, 85))
262510	31798724	This difference can be associated with the amplification of p53 gene in PE/CA-PJ49 cells and the p53 deletion in tumor cells FaDu (Fig.	('deletion', 'Var', (101, 109))	('tumor', 'Disease', (113, 118))	('p53', 'Gene', (97, 100))	('p53', 'Gene', '7157', (97, 100))	('p53', 'Gene', (60, 63))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('p53', 'Gene', '7157', (60, 63))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))
262521	31798724	The results showed that the tumor cell line FaDu presented a deletion of the TP53 gene, while cell line PE-CA/PJ49 presented polysomy.	('tumor', 'Disease', (28, 33))	('deletion', 'Var', (61, 69))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('TP53', 'Gene', '7157', (77, 81))	('TP53', 'Gene', (77, 81))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
262574	31059033	miR-1 was upregulated in the GSE47525 study and downregulated in other previous studies (Table I; Fig.	('GSE47525', 'Var', (29, 37))	('downregulated', 'NegReg', (48, 61))	('miR', 'Gene', '220972', (0, 3))	('miR', 'Gene', (0, 3))	('upregulated', 'PosReg', (10, 21))
262605	31059033	A number of previous studies demonstrated that miRNAs may be a key effector of p53 tumor-suppressor function; mediating the biological effects of p53 and inactivating this molecule may contribute to specific cancer types, suggesting that miRNAs may serve a vital role in the p53 gene signaling pathway.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('p53', 'Gene', (79, 82))	('p53', 'Gene', '7157', (79, 82))	('cancer', 'Disease', (208, 214))	('p53', 'Gene', '7157', (275, 278))	('miR', 'Gene', '220972', (47, 50))	('p53', 'Gene', (146, 149))	('tumor', 'Disease', (83, 88))	('miR', 'Gene', (47, 50))	('p53', 'Gene', '7157', (146, 149))	('contribute', 'Reg', (185, 195))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('cancer', 'Disease', 'MESH:D009369', (208, 214))	('inactivating', 'Var', (154, 166))	('miR', 'Gene', '220972', (238, 241))	('miR', 'Gene', (238, 241))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('p53', 'Gene', (275, 278))
262620	25586059	Patients were divided into two subgroups according to expression (54 high-expression and 53 low-expression patients); the high-expression group was associated with a better disease-free survival (DFS) rate (P=0.042, log-rank test).	('Patients', 'Species', '9606', (0, 8))	('high-expression', 'Var', (122, 137))	('better', 'PosReg', (166, 172))	('patients', 'Species', '9606', (107, 115))	('disease-free survival', 'CPA', (173, 194))
262628	25586059	In addition, discovery of biomarkers such as recurrent mutations in the epidermal growth factor receptor (EGFR) kinase and a fusion gene of EML4-anaplastic lymphoma kinase has led to a marked change in lung adenocarcinoma treatment.	('lung adenocarcinoma', 'Disease', (202, 221))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (202, 221))	('mutations', 'Var', (55, 64))	('change', 'Reg', (192, 198))	('epidermal growth factor receptor', 'Gene', (72, 104))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (202, 221))	('carcinoma', 'Phenotype', 'HP:0030731', (212, 221))	('lymphoma', 'Phenotype', 'HP:0002665', (156, 164))	('EML4-anaplastic lymphoma', 'Disease', (140, 164))	('EML4-anaplastic lymphoma', 'Disease', 'MESH:D017728', (140, 164))	('EGFR', 'Gene', '1956', (106, 110))	('epidermal growth factor receptor', 'Gene', '1956', (72, 104))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (145, 164))	('EGFR', 'Gene', (106, 110))
262629	25586059	However, these mutations occur only in adenocarcinoma patients who have never smoked, but are not present in SCC cases that are invariably associated with tobacco smoking.	('SCC', 'Gene', '6317', (109, 112))	('adenocarcinoma', 'Disease', 'MESH:D000230', (39, 53))	('patients', 'Species', '9606', (54, 62))	('mutations', 'Var', (15, 24))	('tobacco', 'Species', '4097', (155, 162))	('carcinoma', 'Phenotype', 'HP:0030731', (44, 53))	('SCC', 'Gene', (109, 112))	('adenocarcinoma', 'Disease', (39, 53))
262631	25586059	Recently, some studies have reported several genetic changes related to SCC, such as amplification of TP63, PIK3CA, PDGFRA, SOX2, or FGFR1 and mutations in TP53, EGFR, PIK3CA, NRE2L2, PTEN, and DDR2.	('DDR2', 'Gene', (194, 198))	('EGFR', 'Gene', (162, 166))	('PIK3CA', 'Gene', '5290', (168, 174))	('TP53', 'Gene', (156, 160))	('amplification', 'Var', (85, 98))	('PDGFRA', 'Gene', (116, 122))	('PIK3CA', 'Gene', (108, 114))	('PDGFRA', 'Gene', '5156', (116, 122))	('FGFR1', 'Gene', (133, 138))	('TP63', 'Gene', (102, 106))	('mutations', 'Var', (143, 152))	('PTEN', 'Gene', (184, 188))	('EGFR', 'Gene', '1956', (162, 166))	('PIK3CA', 'Gene', (168, 174))	('TP53', 'Gene', '7157', (156, 160))	('TP63', 'Gene', '8626', (102, 106))	('SCC', 'Gene', '6317', (72, 75))	('DDR2', 'Gene', '4921', (194, 198))	('PIK3CA', 'Gene', '5290', (108, 114))	('SOX2', 'Gene', '6657', (124, 128))	('FGFR1', 'Gene', '2260', (133, 138))	('SOX2', 'Gene', (124, 128))	('PTEN', 'Gene', '5728', (184, 188))	('SCC', 'Gene', (72, 75))	('NRE2L2', 'Gene', (176, 182))
262637	25586059	Therefore, we conducted western blotting and immunohistochemical analyses and found that FAM83B protein was also increased in lung SCC compared with lung adenocarcinoma or adjacent normal tissues, and that high-expression levels of FAM83B were associated with a high disease-free survival (DFS) rate.	('FAM83B', 'Gene', (232, 238))	('protein', 'Protein', (96, 103))	('FAM83B', 'Gene', '222584', (89, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (159, 168))	('lung adenocarcinoma', 'Disease', (149, 168))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (149, 168))	('FAM83B', 'Gene', (89, 95))	('SCC', 'Gene', (131, 134))	('high-expression', 'Var', (206, 221))	('increased', 'PosReg', (113, 122))	('FAM83B', 'Gene', '222584', (232, 238))	('SCC', 'Gene', '6317', (131, 134))	('disease-free survival', 'CPA', (267, 288))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (149, 168))
262657	25586059	The membranes were blocked with 5% skim milk in T-PBS (0.137 M NaCl, 2.6 mM KCl, 1.8 mM KH2PO4, 8.1 mM Na2HPO4 12H2O, and 0.005% Tween-20) and incubated with primary antibodies overnight at 4 C. The membranes were incubated with anti-FAM83B (1:2,000, HPA031464; Atlas Antibodies AB, Stockholm, Sweden) or anti-GAPDH (1:2,500, no.	('T-PBS', 'Disease', 'MESH:D011535', (48, 53))	('Atlas Antibodies AB', 'Disease', (262, 281))	('T-PBS', 'Disease', (48, 53))	('GAPDH', 'Gene', '2597', (310, 315))	('FAM83B', 'Gene', '222584', (234, 240))	('Atlas Antibodies AB', 'Disease', 'MESH:D049290', (262, 281))	('GAPDH', 'Gene', (310, 315))	('FAM83B', 'Gene', (234, 240))	('HPA031464', 'Var', (251, 260))
262711	25586059	Our data demonstrated that patients with high FAM83B expression tended to exhibit longer DFS (P=0.042), indicating that FAM83B is a candidate biomarker that can predict prognosis of SCC.	('SCC', 'Gene', (182, 185))	('FAM83B', 'Gene', (46, 52))	('FAM83B', 'Gene', (120, 126))	('DFS', 'MPA', (89, 92))	('FAM83B', 'Gene', '222584', (120, 126))	('SCC', 'Gene', '6317', (182, 185))	('high', 'Var', (41, 45))	('patients', 'Species', '9606', (27, 35))	('FAM83B', 'Gene', '222584', (46, 52))
262720	25586059	The most plausible explanation would be that SOX2 expression might promote squamous differentiation rather than malignant dedifferentiation.	('squamous differentiation', 'CPA', (75, 99))	('expression', 'Var', (50, 60))	('SOX2', 'Gene', '6657', (45, 49))	('SOX2', 'Gene', (45, 49))	('promote', 'PosReg', (67, 74))
262727	33613558	Among nutrients obtained from foods, omega-3 polyunsaturated fatty acids (PUFAs) have various beneficial effects on inflammatory diseases.	('PUFAs', 'Chemical', 'MESH:D005231', (74, 79))	('beneficial effects', 'PosReg', (94, 112))	('inflammatory diseases', 'Disease', (116, 137))	('omega-3', 'Var', (37, 44))	('omega-3 polyunsaturated fatty acids', 'Chemical', 'MESH:D015525', (37, 72))
262744	33613558	For apoptotic cells, the macrophage phagocytosis is enhanced by RvE1, PD1, and RvD1.	('RvD1', 'Var', (79, 83))	('macrophage phagocytosis', 'CPA', (25, 48))	('enhanced', 'PosReg', (52, 60))	('PD', 'Disease', 'MESH:D010300', (70, 72))	('RvE1', 'Gene', (64, 68))
262745	33613558	RvE1, RvD1, and RvD2 suppress chemokine (C-C motif) ligand 4 (CCL4), CCL5, interleukin (IL)-6, IL-8, and tumor necrosis factor (TNF)-alpha induced by human monocyte-derived macrophages co-cultured with tumor cell debris, IL-12 by DCs stimulated with pathogen extract, and superoxide production by macrophages stimulated with cigarette smoke.	('interleukin (IL)-6', 'Gene', '3569', (75, 93))	('CCL5', 'Gene', (69, 73))	('IL-8', 'Gene', '3576', (95, 99))	('RvD2', 'Var', (16, 20))	('superoxide production', 'MPA', (272, 293))	('CCL4', 'Gene', (62, 66))	('tumor', 'Disease', (202, 207))	('tumor necrosis factor (TNF)-alpha', 'Gene', '7124', (105, 138))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('tumor', 'Disease', (105, 110))	('chemokine', 'MPA', (30, 39))	('human', 'Species', '9606', (150, 155))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('IL-8', 'Gene', (95, 99))	('suppress', 'NegReg', (21, 29))	('CCL5', 'Gene', '6352', (69, 73))	('superoxide', 'Chemical', 'MESH:D013481', (272, 282))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('interleukin (IL)-6', 'Gene', (75, 93))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('CCL4', 'Gene', '6351', (62, 66))
262748	33613558	RvD1 suppresses antigen presentation by suppressing major histocompatibility complex (MHC) class II and CD40 expression.	('RvD1', 'Var', (0, 4))	('expression', 'MPA', (109, 119))	('CD4', 'Gene', (104, 107))	('suppresses', 'NegReg', (5, 15))	('CD4', 'Gene', '920', (104, 107))	('antigen presentation', 'MPA', (16, 36))	('suppressing', 'NegReg', (40, 51))
262759	33613558	RvD1, RvD2, and PD1 are known to contribute to the inhibition of immune reactions by increasing Tregs.	('RvD1', 'Var', (0, 4))	('increasing', 'PosReg', (85, 95))	('Tregs', 'CPA', (96, 101))	('immune reactions', 'CPA', (65, 81))	('Tregs', 'Chemical', '-', (96, 101))	('RvD2', 'Var', (6, 10))	('PD', 'Disease', 'MESH:D010300', (16, 18))
262761	33613558	Furthermore, reactive oxygen species (ROS) generation in neutrophils is promoted by RvE1 and RvD3.	('ROS', 'Chemical', 'MESH:D017382', (38, 41))	('RvD3', 'Var', (93, 97))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (13, 36))	('RvE1', 'Gene', (84, 88))	('promoted', 'PosReg', (72, 80))
262762	33613558	In addition, neutrophil migration is suppressed by RvE1, RvE3, RvD1, RvD2, RvD3, PD1, and MaR1.	('PD', 'Disease', 'MESH:D010300', (81, 83))	('RvD2', 'Var', (69, 73))	('RvD3', 'Var', (75, 79))	('RvE1', 'Gene', (51, 55))	('RvD1', 'Gene', (63, 67))	('RvE3', 'Gene', (57, 61))	('neutrophil migration', 'CPA', (13, 33))	('suppressed', 'NegReg', (37, 47))
262764	33613558	RvD1 decreases CXCR4 expression.	('CXCR4', 'Gene', '7852', (15, 20))	('CXCR4', 'Gene', (15, 20))	('RvD1', 'Var', (0, 4))	('decreases', 'NegReg', (5, 14))
262781	33613558	Consequently, MaR1 attenuates IL-23 receptor expression on CD4+ and gammadeltaTCRmid+ cells by inhibiting retinoic acid-related orphan receptor gamma t (RORgammat) in clathrin-dependent IL-23 receptor internalization.	('MaR1', 'Var', (14, 18))	('inhibiting', 'NegReg', (95, 105))	('IL-23 receptor', 'Gene', '149233', (186, 200))	('CD4', 'Gene', (59, 62))	('IL-23 receptor', 'Gene', (30, 44))	('CD4', 'Gene', '920', (59, 62))	('IL-23 receptor', 'Gene', '149233', (30, 44))	('expression', 'MPA', (45, 55))	('IL-23 receptor', 'Gene', (186, 200))	('attenuates', 'NegReg', (19, 29))
262783	33613558	Furthermore, IL-17-producing cells and neutrophils are reduced in the skin following RvE1 treatment.	('reduced', 'NegReg', (55, 62))	('treatment', 'Var', (90, 99))	('IL-17', 'Gene', (13, 18))	('IL-17', 'Gene', '3605', (13, 18))	('RvE1 treatment', 'Var', (85, 99))
262787	33613558	Consistently, IL-17, IL-23, and TNF-alpha are decreased by RvD1.	('IL-17', 'Gene', '3605', (14, 19))	('RvD1', 'Var', (59, 63))	('TNF-alpha', 'Protein', (32, 41))	('IL-23', 'Gene', '51561', (21, 26))	('IL-23', 'Gene', (21, 26))	('decreased', 'NegReg', (46, 55))	('IL-17', 'Gene', (14, 19))
262794	33613558	During the sensitization phase, RvE1-treated mice exhibit significantly reduced DC migration into draining lymph nodes, subsequently reducing the number of central and effector memory T cells.	('memory T', 'Disease', (177, 185))	('reduced', 'NegReg', (72, 79))	('mice', 'Species', '10090', (45, 49))	('RvE1-treated', 'Var', (32, 44))	('DC migration into draining lymph nodes', 'CPA', (80, 118))	('memory T', 'Disease', 'MESH:D008569', (177, 185))	('reducing', 'NegReg', (133, 141))
262796	33613558	In the elicitation phase, RvE1 impairs DC cluster formation, which is essential for the development of elicitation phase inflammation, subsequently suppressing the number of IFN-gamma-producing CD8+ T cells in the skin.	('CD8', 'Gene', (194, 197))	('inflammation', 'Disease', 'MESH:D007249', (121, 133))	('CD8', 'Gene', '925', (194, 197))	('DC cluster formation', 'CPA', (39, 59))	('inflammation', 'Disease', (121, 133))	('RvE1', 'Var', (26, 30))	('impairs', 'NegReg', (31, 38))	('suppressing', 'NegReg', (148, 159))	('IFN-gamma', 'Gene', '3458', (174, 183))	('IFN-gamma', 'Gene', (174, 183))
262808	33613558	RvD2 suppresses squamous cell carcinoma development and decreases inflammatory chemokines and cytokines, including CXCL10, IL-6, monocyte chemoattractant protein-1 (MCP-1), and TNF-alpha, by cancer cells.	('CXCL10', 'Gene', (115, 121))	('cancer', 'Disease', (191, 197))	('cancer', 'Disease', 'MESH:D009369', (191, 197))	('suppresses', 'NegReg', (5, 15))	('decreases', 'NegReg', (56, 65))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (16, 39))	('monocyte chemoattractant protein-1', 'Gene', '20296', (129, 163))	('inflammatory chemokines', 'MPA', (66, 89))	('CXCL10', 'Gene', '15945', (115, 121))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (16, 39))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('squamous cell carcinoma', 'Disease', (16, 39))	('monocyte chemoattractant protein-1', 'Gene', (129, 163))	('carcinoma', 'Phenotype', 'HP:0030731', (30, 39))	('RvD2', 'Var', (0, 4))
262809	33613558	In squamous cell carcinoma, RvD2 decreases the infiltration of neutrophils and suppresses myeloperoxidase (MPO) activity.	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (3, 26))	('MPO', 'Gene', (107, 110))	('myeloperoxidase', 'Gene', (90, 105))	('myeloperoxidase', 'Gene', '4353', (90, 105))	('suppresses', 'NegReg', (79, 89))	('decreases', 'NegReg', (33, 42))	('MPO', 'Gene', '4353', (107, 110))	('activity', 'MPA', (112, 120))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (3, 26))	('carcinoma', 'Phenotype', 'HP:0030731', (17, 26))	('RvD2', 'Var', (28, 32))	('infiltration of neutrophils', 'MPA', (47, 74))	('squamous cell carcinoma', 'Disease', (3, 26))
262810	33613558	Additionally, RvD2 enhances the M2 macrophage population and their efferocytosis.	('M2 macrophage population', 'CPA', (32, 56))	('enhances', 'PosReg', (19, 27))	('efferocytosis', 'Disease', 'None', (67, 80))	('efferocytosis', 'Disease', (67, 80))	('RvD2', 'Var', (14, 18))
262813	33613558	Furthermore, RvD1 or RvD2 inhibit lung metastasis of melanoma cells and regulate the production of chemokines and cytokines, including CCL4, CCL5, IL-6, IL-8, and TNF-alpha, by human macrophages, providing antitumor immunity.	('IL-8', 'Gene', (153, 157))	('RvD1', 'Var', (13, 17))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('CCL4', 'Gene', '6351', (135, 139))	('CCL5', 'Gene', (141, 145))	('CCL4', 'Gene', (135, 139))	('melanoma', 'Disease', (53, 61))	('inhibit', 'NegReg', (26, 33))	('tumor', 'Disease', (210, 215))	('melanoma', 'Phenotype', 'HP:0002861', (53, 61))	('melanoma', 'Disease', 'MESH:D008545', (53, 61))	('human', 'Species', '9606', (177, 182))	('production of chemokines', 'MPA', (85, 109))	('RvD2', 'Var', (21, 25))	('IL-8', 'Gene', '3576', (153, 157))	('CCL5', 'Gene', '6352', (141, 145))	('tumor', 'Disease', 'MESH:D009369', (210, 215))
262836	31438464	This correlation suggests coordinated deregulated mechanisms in all cancer types through aberrant activation of a bidirectional p14-ARF/ANRIL promoter.	('ANRIL', 'Gene', '100048912', (136, 141))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('p14-ARF', 'Gene', (128, 135))	('activation', 'PosReg', (98, 108))	('aberrant', 'Var', (89, 97))	('p14-ARF', 'Gene', '1029', (128, 135))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('ANRIL', 'Gene', (136, 141))	('cancer', 'Disease', (68, 74))	('bidirectional', 'MPA', (114, 127))
262843	31438464	ANRIL intervenes mainly at the transcriptional level through epigenetic mechanisms.	('epigenetic', 'Var', (61, 71))	('ANRIL', 'Gene', '100048912', (0, 5))	('ANRIL', 'Gene', (0, 5))	('intervenes', 'Reg', (6, 16))
262846	31438464	The PRC2 complex mainly comprises subunits JARID2, EED, SUZ12, and EZH2, which maintain chromatin repression by catalyzing mono-, di-, and trimethylation of histone H3 lysine 27 (H3K27me1, H3K27me2, and H3K27me3).	('PRC2', 'Gene', (4, 8))	('EZH2', 'Gene', (67, 71))	('JARID2', 'Gene', (43, 49))	('JARID2', 'Gene', '3720', (43, 49))	('SUZ12', 'Gene', '23512', (56, 61))	('SUZ12', 'Gene', (56, 61))	('EED', 'Gene', '8726', (51, 54))	('H3K27me3', 'Var', (203, 211))	('lysine', 'Chemical', 'MESH:C114808', (168, 174))	('EED', 'Gene', (51, 54))	('chromatin repression', 'MPA', (88, 108))	('EZH2', 'Gene', '2146', (67, 71))	('H3K27me2', 'Var', (189, 197))
262851	31438464	Mounting data from the literature suggests that this lncRNA could function as an oncogenic driver, consistent with the association of multiple single nucleotide polymorphisms (SNPs) in 9p21.3 with numerous cancers.	('single nucleotide polymorphisms', 'Var', (143, 174))	('association', 'Interaction', (119, 130))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('9p21.3', 'Gene', (185, 191))	('cancers', 'Disease', 'MESH:D009369', (206, 213))	('cancers', 'Phenotype', 'HP:0002664', (206, 213))	('cancers', 'Disease', (206, 213))
262852	31438464	Structural alterations of ANRIL (deletions and translocations) were described in neurofibromas and gliomas, and MTAP-ANRIL fusion transcripts were observed in melanomas.	('melanomas', 'Disease', 'MESH:D008545', (159, 168))	('melanomas', 'Phenotype', 'HP:0002861', (159, 168))	('neurofibromas and gliomas', 'Disease', 'MESH:D009455', (81, 106))	('ANRIL', 'Gene', '100048912', (117, 122))	('neurofibromas', 'Phenotype', 'HP:0001067', (81, 94))	('MTAP', 'Gene', (112, 116))	('ANRIL', 'Gene', (26, 31))	('translocations', 'Var', (47, 61))	('ANRIL fusion', 'Phenotype', 'HP:0003191', (117, 129))	('ANRIL', 'Gene', (117, 122))	('observed', 'Reg', (147, 155))	('gliomas', 'Phenotype', 'HP:0009733', (99, 106))	('MTAP', 'Gene', '4507', (112, 116))	('melanomas', 'Disease', (159, 168))	('ANRIL', 'Gene', '100048912', (26, 31))
262853	31438464	During carcinogenesis, DNA alterations favor activation of the ATM-E2F1 pathway and induce ANRIL dysregulation, resulting in its aberrant chronic overexpression.	('overexpression', 'PosReg', (146, 160))	('E2F1', 'Gene', '1869', (67, 71))	('ANRIL', 'Gene', (91, 96))	('carcinogenesis', 'Disease', 'MESH:D063646', (7, 21))	('E2F1', 'Gene', (67, 71))	('induce', 'Reg', (84, 90))	('carcinogenesis', 'Disease', (7, 21))	('ANRIL', 'Gene', '100048912', (91, 96))	('activation', 'PosReg', (45, 55))	('alterations', 'Var', (27, 38))
262854	31438464	Aberrant ANRIL overexpression causes inefficiency of DNA damage repair mechanisms, leading to genomic instability and tumor progression via cell cycle progression, inhibition of apoptosis and senescence, tumor proliferation, and angiogenesis.	('ANRIL', 'Gene', (9, 14))	('overexpression', 'PosReg', (15, 29))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('Aberrant', 'Var', (0, 8))	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('angiogenesis', 'CPA', (229, 241))	('genomic instability', 'CPA', (94, 113))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('apoptosis', 'CPA', (178, 187))	('ANRIL', 'Gene', '100048912', (9, 14))	('tumor', 'Disease', (204, 209))	('inefficiency', 'NegReg', (37, 49))	('tumor', 'Disease', (118, 123))	('inhibition', 'NegReg', (164, 174))	('senescence', 'CPA', (192, 202))	('cell cycle progression', 'CPA', (140, 162))
262891	31438464	In invasive breast carcinomas, ANRIL overexpression was higher in triple-negative (25%) and HER2+ (24%) subtypes than in luminal carcinomas (12%).	('ANRIL', 'Gene', (31, 36))	('overexpression', 'PosReg', (37, 51))	('breast carcinomas', 'Phenotype', 'HP:0003002', (12, 29))	('luminal carcinomas', 'Disease', 'MESH:D002277', (121, 139))	('invasive breast carcinomas', 'Disease', 'MESH:D001943', (3, 29))	('luminal carcinomas', 'Disease', (121, 139))	('invasive breast carcinomas', 'Disease', (3, 29))	('carcinoma', 'Phenotype', 'HP:0030731', (19, 28))	('HER2', 'Gene', '2064', (92, 96))	('triple-negative', 'Var', (66, 81))	('HER2', 'Gene', (92, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('carcinomas', 'Phenotype', 'HP:0030731', (19, 29))	('ANRIL', 'Gene', '100048912', (31, 36))	('higher', 'PosReg', (56, 62))	('carcinomas', 'Phenotype', 'HP:0030731', (129, 139))
262905	31438464	Concerning CDKN2A-B locus deregulation in cancers, literature data provided contradictory results.	('cancers', 'Disease', (42, 49))	('deregulation', 'Var', (26, 38))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('cancers', 'Phenotype', 'HP:0002664', (42, 49))	('CDKN2A', 'Gene', (11, 17))	('cancers', 'Disease', 'MESH:D009369', (42, 49))	('CDKN2A', 'Gene', '1029', (11, 17))
262915	31438464	Splicing was recently implicated in ANRIL deregulation, and ANRIL transcript stability seems to be influenced by miRNAs and proteins.	('ANRIL', 'Gene', '100048912', (60, 65))	('Splicing', 'Var', (0, 8))	('implicated', 'Reg', (22, 32))	('ANRIL', 'Gene', (36, 41))	('ANRIL', 'Gene', (60, 65))	('influenced', 'Reg', (99, 109))	('ANRIL', 'Gene', '100048912', (36, 41))
262927	29725421	Furthermore, immunohistochemical staining of Bcl-2 expression was performed in a tissue microarray of 72 patients with LUSC and survival analysis demonstrated that patients with high expression Bcl-2 exhibited significantly more improved overall survival rates compared with those with low Bcl-2 expression.	('patients', 'Species', '9606', (105, 113))	('Bcl-2', 'Gene', (45, 50))	('Bcl-2', 'Gene', '596', (45, 50))	('Bcl-2', 'Gene', (194, 199))	('Bcl-2', 'Gene', '596', (194, 199))	('high expression', 'Var', (178, 193))	('overall survival rates', 'CPA', (238, 260))	('Bcl-2', 'Gene', (290, 295))	('improved', 'PosReg', (229, 237))	('Bcl-2', 'Gene', '596', (290, 295))	('LUSC', 'Phenotype', 'HP:0030359', (119, 123))	('patients', 'Species', '9606', (164, 172))
262928	29725421	Multivariate Cox regression revealed that high expression of Bcl-2 is an independent favorable prognostic factor (hazard ratio, 0.295; confidence interval, 0.097-0.904; P<0.05).	('Bcl-2', 'Gene', (61, 66))	('Bcl-2', 'Gene', '596', (61, 66))	('high expression', 'Var', (42, 57))
262934	29725421	At present, the individualized molecular targeted therapy for clinical application is primarily for epidermal growth factor mutation and anaplastic lymphoma kinase fusion genotypes in lung cancer, both of which have clear molecular targets, and targeted drug has significantly improved the clinical efficacy.	('lymphoma', 'Phenotype', 'HP:0002665', (148, 156))	('epidermal growth factor', 'Gene', (100, 123))	('anaplastic', 'Gene', (137, 147))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('lung cancer', 'Disease', 'MESH:D008175', (184, 195))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (137, 156))	('epidermal growth factor', 'Gene', '1950', (100, 123))	('mutation', 'Var', (124, 132))	('lung cancer', 'Disease', (184, 195))	('lung cancer', 'Phenotype', 'HP:0100526', (184, 195))	('improved', 'PosReg', (277, 285))
262977	29725421	Considering the overall positive rate of Bcl-2 expression observed in this study, patients with LUSC were divided into two groups as follows: Score <=1 as the low expression group and score >1 as the high expression group.	('LUSC', 'Phenotype', 'HP:0030359', (96, 100))	('Bcl-2', 'Gene', (41, 46))	('Bcl-2', 'Gene', '596', (41, 46))	('Score <=1', 'Var', (142, 151))	('patients', 'Species', '9606', (82, 90))
262983	29725421	The Kaplan-Meier survival curves demonstrated that patients with LUSC with high Bcl-2 expression had a significantly favorable OS time (Fig.	('LUSC', 'Phenotype', 'HP:0030359', (65, 69))	('high', 'Var', (75, 79))	('Bcl-2', 'Gene', (80, 85))	('OS time', 'CPA', (127, 134))	('Bcl-2', 'Gene', '596', (80, 85))	('patients', 'Species', '9606', (51, 59))	('favorable', 'PosReg', (117, 126))
262996	29725421	Since Bcl-2 has anti-apoptotic effects based on in vitro and in vivo experiments, it is expected that high Bcl-2 expression may lead to worse prognosis, rather than prolonged survival.	('anti-apoptotic', 'CPA', (16, 30))	('expression', 'MPA', (113, 123))	('Bcl-2', 'Gene', (107, 112))	('Bcl-2', 'Gene', '596', (107, 112))	('high', 'Var', (102, 106))	('Bcl-2', 'Gene', (6, 11))	('Bcl-2', 'Gene', '596', (6, 11))	('lead to', 'Reg', (128, 135))
263000	27669890	Epidermal growth factor (EGF) receptor-ligand based molecular staging predicts prognosis in head and neck squamous cell carcinoma partly due to deregulated EGF- induced amphiregulin expression Increased expression of epidermal growth factor receptor (EGFR) and its ligands is associated with poor prognosis and chemoresistance in many carcinoma types, but its role in head and neck squamous cell carcinoma (HNSCC) is unclear.	('EGF', 'Gene', '1950', (156, 159))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (382, 405))	('SCC', 'Gene', '6317', (409, 412))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (92, 129))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('carcinoma', 'Phenotype', 'HP:0030731', (335, 344))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (368, 405))	('EGFR', 'Gene', '1956', (251, 255))	('carcinoma', 'Disease', (120, 129))	('carcinoma', 'Disease', (335, 344))	('SCC', 'Gene', (409, 412))	('carcinoma', 'Phenotype', 'HP:0030731', (396, 405))	('deregulated', 'Var', (144, 155))	('EGF', 'Gene', (251, 254))	('carcinoma', 'Disease', (396, 405))	('EGF', 'Gene', '1950', (25, 28))	('EGF', 'Gene', (156, 159))	('Epidermal growth factor (EGF) receptor', 'Gene', '1956', (0, 38))	('epidermal growth factor receptor', 'Gene', (217, 249))	('Increased', 'PosReg', (193, 202))	('amphiregulin', 'Gene', (169, 181))	('epidermal growth factor receptor', 'Gene', '1956', (217, 249))	('carcinoma', 'Disease', 'MESH:D002277', (120, 129))	('carcinoma', 'Disease', 'MESH:D002277', (335, 344))	('neck squamous cell carcinoma', 'Disease', (101, 129))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (101, 129))	('carcinoma', 'Disease', 'MESH:D002277', (396, 405))	('neck squamous cell carcinoma', 'Disease', (377, 405))	('EGFR', 'Gene', (251, 255))	('expression', 'MPA', (203, 213))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (377, 405))	('EGF', 'Gene', (25, 28))	('EGF', 'Gene', '1950', (251, 254))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (106, 129))	('amphiregulin', 'Gene', '374', (169, 181))
263024	27669890	Despite conflicting results on cell lines, increased cancerous AREG expression has been associated with radiotherapy resistance in pancreatic cancer cell lines and in K-RAS mutated cancer cells, probably by activating the PI3K-Akt survival pathway.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (131, 148))	('expression', 'MPA', (68, 78))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('mutated', 'Var', (173, 180))	('cancerous', 'Disease', (53, 62))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('activating', 'PosReg', (207, 217))	('K-RAS', 'Gene', (167, 172))	('AREG', 'Protein', (63, 67))	('pancreatic cancer', 'Disease', 'MESH:D010190', (131, 148))	('increased', 'PosReg', (43, 52))	('K-RAS', 'Gene', '3845', (167, 172))	('cancer', 'Disease', (142, 148))	('radiotherapy resistance', 'CPA', (104, 127))	('Akt', 'Gene', (227, 230))	('cancer', 'Disease', (53, 59))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('pancreatic cancer', 'Disease', (131, 148))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('cancer', 'Disease', (181, 187))	('Akt', 'Gene', '207', (227, 230))	('cancerous', 'Disease', 'MESH:D009369', (53, 62))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('associated', 'Reg', (88, 98))
263040	27669890	Anti-human phospho-Erk1/2, phospho-p38, phospho-JNK, phospho-ErbB2 (Tyr1248), Erk1/2, p38, JNK, Akt, ErbB2 and EGFR antibodies were obtained from Cell signaling (Beverly, Massachusetts, USA).	('ErbB2', 'Gene', (61, 66))	('EGFR', 'Gene', '1956', (111, 115))	('p38', 'Gene', '5594', (86, 89))	('p38', 'Gene', (35, 38))	('JNK', 'Gene', (48, 51))	('JNK', 'Gene', '5599', (48, 51))	('Tyr1248', 'Chemical', '-', (68, 75))	('ErbB2', 'Gene', '2064', (101, 106))	('JNK', 'Gene', (91, 94))	('EGFR', 'Gene', (111, 115))	('p38', 'Gene', '5594', (35, 38))	('ErbB2', 'Gene', '2064', (61, 66))	('JNK', 'Gene', '5599', (91, 94))	('human', 'Species', '9606', (5, 10))	('Tyr1248', 'Var', (68, 75))	('Akt', 'Gene', (96, 99))	('p38', 'Gene', (86, 89))	('ErbB2', 'Gene', (101, 106))	('Akt', 'Gene', '207', (96, 99))
263044	27669890	EGFR inhibitor AG1478 and ErbB2 inhibitor AG825 were obtained from Sigma-Aldrich; MEK inhibitor PD98059, p38 inhibitor SB203580, JNK inhibitor SP600125, and PI3K inhibitor LY294002 were obtained from Calbiochem (Billerica, MA, USA).	('LY294002', 'Var', (172, 180))	('SP600125', 'Chemical', 'MESH:C432165', (143, 151))	('ErbB2', 'Gene', '2064', (26, 31))	('AG1478', 'Chemical', 'MESH:C101044', (15, 21))	('PD98059', 'Chemical', 'MESH:C093973', (96, 103))	('p38', 'Gene', (105, 108))	('LY294002', 'Chemical', 'MESH:C085911', (172, 180))	('AG825', 'Chemical', 'MESH:C098214', (42, 47))	('EGFR', 'Gene', (0, 4))	('SB203580', 'Chemical', 'MESH:C093642', (119, 127))	('MEK', 'Gene', '5609', (82, 85))	('ErbB2', 'Gene', (26, 31))	('PD98059', 'Var', (96, 103))	('SP600125', 'Var', (143, 151))	('MEK', 'Gene', (82, 85))	('p38', 'Gene', '5594', (105, 108))	('SB203580', 'Var', (119, 127))	('JNK', 'Gene', (129, 132))	('JNK', 'Gene', '5599', (129, 132))	('EGFR', 'Gene', '1956', (0, 4))
263047	27669890	The selective EGFR inhibitor AG1478 may, in addition inhibit HER4, however, this did not influence our results as HER4 is not expressed in the cell lines.	('EGFR', 'Gene', '1956', (14, 18))	('inhibit', 'NegReg', (53, 60))	('EGFR', 'Gene', (14, 18))	('AG1478', 'Var', (29, 35))	('HER4', 'Gene', (61, 65))	('HER4', 'Gene', '2066', (61, 65))	('AG1478', 'Chemical', 'MESH:C101044', (29, 35))	('HER4', 'Gene', (114, 118))	('HER4', 'Gene', '2066', (114, 118))
263050	27669890	The cisplatin resistant subclones, C12cis and D2cis, were selected by exposure to sequential cycles of cisplatin for eight months, which mimic the way the drug is used in the clinic.	('D2cis', 'Var', (46, 51))	('C12cis', 'Var', (35, 41))	('cisplatin', 'Chemical', 'MESH:D002945', (4, 13))	('cisplatin', 'Chemical', 'MESH:D002945', (103, 112))
263087	27669890	Whereas the MAPK/ERK kinase (MEK) inhibitor (PD98050) reduced EGF-induced AREG mRNA expression, the PI3K inhibitor (LY294002) increased it in all three cell lines.	('MEK', 'Gene', '5609', (29, 32))	('EGF-induced', 'Disease', (62, 73))	('LY294002', 'Chemical', 'MESH:C085911', (116, 124))	('PD98050', 'Chemical', '-', (45, 52))	('PD98050', 'Var', (45, 52))	('ERK', 'Gene', '5594', (17, 20))	('reduced', 'NegReg', (54, 61))	('ERK', 'Gene', (17, 20))	('increased', 'PosReg', (126, 135))	('MEK', 'Gene', (29, 32))
263089	27669890	The JNK-inhibition (SP600125) had similar effect but only in the two conventional OSCC cell lines D2 and E10.	('SCC', 'Gene', (83, 86))	('SCC', 'Gene', '6317', (83, 86))	('SP600125', 'Var', (20, 28))	('JNK', 'Gene', (4, 7))	('SP600125', 'Chemical', 'MESH:C432165', (20, 28))	('JNK', 'Gene', '5599', (4, 7))
263092	27669890	PI3K-inhibition partly blocked EGF-induced AREG protein secretion in the two conventional OSCC cell lines, but not in the basaloid C12 cell line.	('AREG protein secretion', 'MPA', (43, 65))	('blocked', 'NegReg', (23, 30))	('PI3K-inhibition', 'Var', (0, 15))	('SCC', 'Gene', (91, 94))	('SCC', 'Gene', '6317', (91, 94))
263093	27669890	Patients with high AREG expression had poor clinical response to cisplatin treatment (Fig.	('cisplatin', 'Chemical', 'MESH:D002945', (65, 74))	('men', 'Species', '9606', (80, 83))	('high', 'Var', (14, 18))	('AREG', 'Protein', (19, 23))	('Patients', 'Species', '9606', (0, 8))
263117	27669890	Both EGF- and HBEGF- induced AREG may increase cell proliferation, anchorage-independent growth, and reduce apoptosis in an almost autocrine manner, as shown for hepatocellular carcinoma.	('cell proliferation', 'CPA', (47, 65))	('increase', 'PosReg', (38, 46))	('HBEGF', 'Gene', (14, 19))	('reduce', 'NegReg', (101, 107))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (162, 186))	('carcinoma', 'Phenotype', 'HP:0030731', (177, 186))	('hepatocellular carcinoma', 'Disease', (162, 186))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (162, 186))	('HBEGF', 'Gene', '1839', (14, 19))	('apoptosis', 'CPA', (108, 117))	('anchorage-independent growth', 'CPA', (67, 95))	('AREG', 'Var', (29, 33))
263120	27669890	MEK inhibition substantially reduced EGF-induced AREG mRNA and protein expression in all three cell lines, illustrating a more total ERK1/2 pathway dependency than previously observed in human skin organ cultures.	('MEK', 'Gene', (0, 3))	('MEK', 'Gene', '5609', (0, 3))	('inhibition', 'Var', (4, 14))	('reduced', 'NegReg', (29, 36))	('human', 'Species', '9606', (187, 192))	('ERK1/2', 'Gene', (133, 139))	('ERK1/2', 'Gene', '5595;5594', (133, 139))
263121	27669890	In contrast to insulin-induced AREG mRNA expression in RT4 bladder cancer cells, PI3K inhibition increased EGF-induced AREG mRNA expression, but not protein secretion.	('increased', 'PosReg', (97, 106))	('insulin', 'Gene', '3630', (15, 22))	('insulin', 'Gene', (15, 22))	('PI3K', 'Gene', (81, 85))	('EGF-induced AREG mRNA expression', 'MPA', (107, 139))	('bladder cancer', 'Phenotype', 'HP:0009725', (59, 73))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('inhibition', 'Var', (86, 96))	('bladder cancer', 'Disease', 'MESH:D001749', (59, 73))	('bladder cancer', 'Disease', (59, 73))
263127	27669890	Furthermore, exogenous AREG did not increase cisplatin resistance in the sensitive cell lines, and the two in house made cisplatin-resistant cell lines had either increased (C12cis) or decreased (D2cis) AREG mRNA expression.	('decreased', 'NegReg', (185, 194))	('cisplatin', 'Chemical', 'MESH:D002945', (45, 54))	('increased', 'PosReg', (163, 172))	('cisplatin', 'Chemical', 'MESH:D002945', (121, 130))	('C12cis', 'Var', (174, 180))	('AREG', 'Gene', (203, 207))
263129	27669890	Although most of the cis-/carbo-platin treated patients had advanced disease (TNM stage IV), patients with high AREG expressing tumors had, in particular, perineural, lymphovascular and nodal extracapsular infiltration.	('high AREG expressing', 'Var', (107, 127))	('perineural', 'CPA', (155, 165))	('TNM', 'Gene', (78, 81))	('patients', 'Species', '9606', (47, 55))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('cis-/carbo-platin', 'Chemical', '-', (21, 38))	('tumors', 'Disease', (128, 134))	('tumors', 'Disease', 'MESH:D009369', (128, 134))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('patients', 'Species', '9606', (93, 101))	('TNM', 'Gene', '10178', (78, 81))
263134	27669890	Inhibiting EGF-induced AREG expression may be a novel strategy in HNSCC treatment.	('EGF-induced AREG expression', 'Protein', (11, 38))	('Inhibiting', 'Var', (0, 10))	('SCC', 'Gene', '6317', (68, 71))	('men', 'Species', '9606', (77, 80))	('SCC', 'Gene', (68, 71))
263166	34011038	Cytological examination of the pancreatic mass was highlighted by immunohistochemical staining for PCK, P63, P40, and CK7, and it was presumed to be derived from primary ESCC (Fig.	('CK7', 'Gene', (118, 121))	('CK7', 'Gene', '3855', (118, 121))	('PCK', 'Var', (99, 102))	('pancreatic mass', 'Disease', (31, 46))	('P63', 'Var', (104, 107))	('P40', 'Var', (109, 112))
263169	34011038	The TMB was determined to be 5.26 mutations/Mb, and a total of 20 nonsynonymous mutations were detected in the whole genome, including 6 insertion-deletion mutations, 9 single-nucleotide variants, and 5 copy number variations.	('single-nucleotide variants', 'Var', (169, 195))	('copy number variations', 'Var', (203, 225))	('TMB', 'Chemical', '-', (4, 7))	('insertion-deletion mutations', 'Var', (137, 165))
263170	34011038	The tumor harbored clinically relevant mutations in CDKN2A, CCND1, and FGF19.	('tumor', 'Disease', (4, 9))	('FGF19', 'Gene', '9965', (71, 76))	('mutations', 'Var', (39, 48))	('CCND1', 'Gene', (60, 65))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('CDKN2A', 'Gene', (52, 58))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('CCND1', 'Gene', '595', (60, 65))	('CDKN2A', 'Gene', '1029', (52, 58))	('FGF19', 'Gene', (71, 76))
263230	32194861	Dysregulations of Functional RNA Modifications in Cancer, Cancer Stemness and Cancer Therapeutics More than a hundred chemical modifications in coding and non-coding RNAs have been identified so far.	('Cancer', 'Disease', 'MESH:D009369', (50, 56))	('Cancer', 'Disease', (50, 56))	('Cancer', 'Disease', (78, 84))	('Cancer Stemness and Cancer', 'Disease', 'MESH:D009369', (58, 84))	('N', 'Chemical', 'MESH:D009584', (167, 168))	('Cancer', 'Phenotype', 'HP:0002664', (50, 56))	('Cancer', 'Disease', 'MESH:D009369', (78, 84))	('Modifications', 'Var', (33, 46))	('Cancer', 'Phenotype', 'HP:0002664', (78, 84))	('N', 'Chemical', 'MESH:D009584', (30, 31))	('Cancer', 'Phenotype', 'HP:0002664', (58, 64))	('Cancer', 'Disease', (58, 64))	('Cancer', 'Disease', 'MESH:D009369', (58, 64))
263233	32194861	Modified RNA bases and their regulators form intricate networks which are associated with a vast array of diverse biological functions.	('RNA bases', 'Protein', (9, 18))	('N', 'Chemical', 'MESH:D009584', (10, 11))	('Modified', 'Var', (0, 8))	('associated', 'Reg', (74, 84))
263234	32194861	RNA modifications are not only essential for maintaining the stability and structural integrity of the RNA molecules themselves, they are also associated with the functional outcomes and phenotypic attributes of cells.	('associated', 'Reg', (143, 153))	('modifications', 'Var', (4, 17))	('N', 'Chemical', 'MESH:D009584', (1, 2))	('stability', 'MPA', (61, 70))	('N', 'Chemical', 'MESH:D009584', (104, 105))
263235	32194861	In addition to their normal biological roles, many of the RNA modifications also play important roles in various diseases particularly in cancer as evidenced that the modified RNA transcripts and their regulatory proteins are aberrantly expressed in many cancer types.	('modifications', 'Var', (62, 75))	('RNA', 'Gene', (176, 179))	('cancer', 'Disease', (138, 144))	('N', 'Chemical', 'MESH:D009584', (177, 178))	('cancer', 'Phenotype', 'HP:0002664', (255, 261))	('cancer', 'Disease', 'MESH:D009369', (255, 261))	('N', 'Chemical', 'MESH:D009584', (59, 60))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('modified', 'Var', (167, 175))	('roles', 'Reg', (96, 101))	('cancer', 'Disease', (255, 261))	('cancer', 'Disease', 'MESH:D009369', (138, 144))
263237	32194861	It is concluded that, while advanced technologies have uncovered the contributions of many of RNA modifications in cancer, the underlying mechanisms are still poorly understood.	('cancer', 'Disease', (115, 121))	('N', 'Chemical', 'MESH:D009584', (95, 96))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('modifications', 'Var', (98, 111))	('cancer', 'Disease', 'MESH:D009369', (115, 121))
263239	32194861	Further studies are needed to elucidate the mechanism of how RNA modifications promote cell malignant transformation and generation of cancer stem cells, which will lead to the development of new strategies for cancer prevention and treatment.	('modifications', 'Var', (65, 78))	('cancer', 'Disease', (135, 141))	('rat', 'Species', '10116', (125, 128))	('cancer', 'Disease', 'MESH:D009369', (211, 217))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('cancer', 'Disease', (211, 217))	('RNA', 'Gene', (61, 64))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('rat', 'Species', '10116', (198, 201))	('promote', 'PosReg', (79, 86))	('N', 'Chemical', 'MESH:D009584', (62, 63))	('cell malignant transformation', 'CPA', (87, 116))	('cancer', 'Disease', 'MESH:D009369', (135, 141))
263244	32194861	It is now clear that the transcriptional outputs of the genes not only produce the messenger RNAs (mRNAs) but also produce non-coding RNAs that are not translated into proteins.	('non-coding RNAs', 'MPA', (123, 138))	('produce', 'Reg', (115, 122))	('messenger RNAs', 'MPA', (83, 97))	('produce', 'Reg', (71, 78))	('genes', 'Var', (56, 61))	('N', 'Chemical', 'MESH:D009584', (101, 102))	('N', 'Chemical', 'MESH:D009584', (135, 136))	('N', 'Chemical', 'MESH:D009584', (94, 95))
263247	32194861	Precursor mRNA (pre-mRNA) undergoes a series of intricate processing of capping, splicing, polyadenylation to become mature mRNA and transport to cytoplasm in order for a gene to be translated into protein.	('N', 'Chemical', 'MESH:D009584', (12, 13))	('N', 'Chemical', 'MESH:D009584', (22, 23))	('capping', 'MPA', (72, 79))	('splicing', 'MPA', (81, 89))	('N', 'Chemical', 'MESH:D009584', (126, 127))	('polyadenylation', 'Var', (91, 106))
263250	32194861	Modifications of these nucleotides not only change the identity of the molecule but also bring about changes in the biological role of the modified RNAs.	('change', 'Reg', (44, 50))	('modified', 'Var', (139, 147))	('RNAs', 'Protein', (148, 152))	('Modifications', 'Var', (0, 13))	('identity of the molecule', 'MPA', (55, 79))	('biological role', 'MPA', (116, 131))	('N', 'Chemical', 'MESH:D009584', (149, 150))	('changes', 'Reg', (101, 108))
263251	32194861	These modifications occurring post-transcriptionally also affect the folding patterns of RNAs which are especially important for tRNAs and rRNAs to maintain their functional structures.	('modifications', 'Var', (6, 19))	('RNAs', 'Protein', (89, 93))	('folding patterns', 'MPA', (69, 85))	('N', 'Chemical', 'MESH:D009584', (141, 142))	('N', 'Chemical', 'MESH:D009584', (131, 132))	('N', 'Chemical', 'MESH:D009584', (90, 91))	('affect', 'Reg', (58, 64))
263252	32194861	For mRNAs and long non-coding RNAs (lncRNAs), the modifications determine their stability and binding specificity for the proteins while for the small regulatory RNAs such as siRNA and microRNAs (miRNAs) modifications are important to maintain their regulatory role by limiting the accessibility to their binding sites.	('N', 'Chemical', 'MESH:D009584', (191, 192))	('N', 'Chemical', 'MESH:D009584', (40, 41))	('limiting', 'NegReg', (269, 277))	('binding', 'Interaction', (94, 101))	('modifications', 'Var', (50, 63))	('regulatory', 'MPA', (250, 260))	('modifications', 'Var', (204, 217))	('N', 'Chemical', 'MESH:D009584', (6, 7))	('stability', 'MPA', (80, 89))	('N', 'Chemical', 'MESH:D009584', (199, 200))	('N', 'Chemical', 'MESH:D009584', (178, 179))	('N', 'Chemical', 'MESH:D009584', (31, 32))	('binding', 'Interaction', (305, 312))	('accessibility', 'MPA', (282, 295))	('N', 'Chemical', 'MESH:D009584', (163, 164))	('proteins', 'Protein', (122, 130))
263255	32194861	The dynamicity of RNA modification facilitates the cells to respond rapidly for adaptation to the changes in their microenvironment.	('modification', 'Var', (22, 34))	('N', 'Chemical', 'MESH:D009584', (19, 20))	('facilitates', 'PosReg', (35, 46))
263259	32194861	We will also highlight on how changes in RNA modification landscape are critically involved in generation of cancer stem cells (CSCs) and the potential of RNA modification machinery as cancer therapeutic targets.	('N', 'Chemical', 'MESH:D009584', (156, 157))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('changes', 'Var', (30, 37))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('involved', 'Reg', (83, 91))	('cancer', 'Disease', (109, 115))	('rat', 'Species', '10116', (99, 102))	('C', 'Chemical', 'MESH:D003596', (128, 129))	('N', 'Chemical', 'MESH:D009584', (42, 43))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('C', 'Chemical', 'MESH:D003596', (130, 131))	('cancer', 'Disease', (185, 191))
263270	32194861	The m6A RNA methylation is the most abundant mRNA modification in eukaryotic cells (about 0.1 to 0.4% of the total number of adenosine), which plays crucial roles in RNA fate and metabolism.	('N', 'Chemical', 'MESH:D009584', (47, 48))	('N', 'Chemical', 'MESH:D009584', (167, 168))	('adenosine', 'Chemical', 'MESH:D000241', (125, 134))	('m6A', 'Var', (4, 7))	('methylation', 'Var', (12, 23))	('N', 'Chemical', 'MESH:D009584', (9, 10))
263290	32194861	Other methods developed to quantify m6A in individual level include the use of m6A-sensitive reverse transcriptase, substitution of the allyl for methyl group with methyltransferase enzymes followed by mutagenesis and use of deoxythymidine triphosphate (dTTP) analog 4SedTTP.	('dTTP', 'Chemical', 'MESH:C024157', (270, 274))	('substitution', 'Var', (116, 128))	('dTTP', 'Chemical', 'MESH:C024157', (254, 258))	('mutagenesis', 'Var', (202, 213))	('deoxythymidine triphosphate', 'Chemical', 'MESH:C024157', (225, 252))
263321	32194861	In substitution of UV crosslinking, a site-specific mutation is carried out on the target RNA which stabilizes the methyltransferase-m5C RNA complex and is immunoprecipitated that can be detected by western blotting.	('N', 'Chemical', 'MESH:D009584', (91, 92))	('m5C', 'Chemical', '-', (133, 136))	('mutation', 'Var', (52, 60))	('N', 'Chemical', 'MESH:D009584', (138, 139))	('methyltransferase-m5C', 'Enzyme', (115, 136))
263324	32194861	Based on these findings from sequencing, the m5C modified bases are more abundantly found near the UTRs (Figure 2), particularly near the Argonaute proteins I-IV binding sites compared to other locations.	('m5C modified bases', 'Var', (45, 63))	('m5C', 'Chemical', '-', (45, 48))	('Argonaute proteins', 'Protein', (138, 156))
263327	32194861	Methylation on the N1 position of adenosine produces the modified nucleotide m1A which diminishes the Watson-Crick base pairing of A to T or U because of the steric hindrance by the methyl group.	('Watson-Crick base pairing', 'MPA', (102, 127))	('N', 'Chemical', 'MESH:D009584', (19, 20))	('Methylation', 'Var', (0, 11))	('diminishes', 'NegReg', (87, 97))	('C', 'Chemical', 'MESH:D003596', (109, 110))	('m1A', 'Gene', (77, 80))	('m1A', 'Chemical', '-', (77, 80))	('adenosine', 'Chemical', 'MESH:D000241', (34, 43))
263328	32194861	This hindrance of base pairing in the m1A-T/U interface may result in a misincorporation of the base by unstable Hoogsteen base pairing with other nucleotides or truncation of the nucleotide chain.	('truncation', 'Var', (162, 172))	('base pairing', 'MPA', (18, 30))	('m1A', 'Chemical', '-', (38, 41))	('result in', 'Reg', (60, 69))	('rat', 'Species', '10116', (82, 85))	('misincorporation of the base', 'MPA', (72, 100))	('Hoogsteen base pairing', 'MPA', (113, 135))
263329	32194861	N1-methylation of A produces a positive charge on the m1A molecule which can dramatically alter the RNA structure or alter the RNA-protein interaction.	('N', 'Chemical', 'MESH:D009584', (128, 129))	('m1A', 'Chemical', '-', (54, 57))	('RNA structure', 'MPA', (100, 113))	('N1-methylation', 'Var', (0, 14))	('N', 'Chemical', 'MESH:D009584', (0, 1))	('interaction', 'Interaction', (139, 150))	('alter', 'Reg', (117, 122))	('RNA-protein', 'Protein', (127, 138))	('N', 'Chemical', 'MESH:D009584', (101, 102))	('alter', 'Reg', (90, 95))
263335	32194861	Also there is lack of methods that could adequately detect and quantify the extent of m1A methylation in the transcriptome with adequate sensitivity and reproducibility.	('m1A', 'Chemical', '-', (86, 89))	('methylation', 'Var', (90, 101))	('m1A', 'Gene', (86, 89))
263338	32194861	They characterized the m1A-carrying mRNA by the nature of the modification to introduce mismatched nucleotide and truncation and identified the mismatch rate created by m1A using Dimroth rearrangement (m1A converted to m6A).	('m1A', 'Chemical', '-', (23, 26))	('mismatch', 'Var', (144, 152))	('introduce', 'Reg', (78, 87))	('rat', 'Species', '10116', (153, 156))	('m1A', 'Chemical', '-', (202, 205))	('N', 'Chemical', 'MESH:D009584', (38, 39))	('m1A', 'Chemical', '-', (169, 172))	('truncation', 'MPA', (114, 124))	('mismatched nucleotide', 'MPA', (88, 109))
263354	32194861	The adenosine usually base-pairs with uridine, but modification to inosine confers it structural similarity to guanosine (G).	('uridine', 'Chemical', 'MESH:D014529', (38, 45))	('guanosine', 'Chemical', 'MESH:D006151', (111, 120))	('uridine', 'MPA', (38, 45))	('inosine', 'Chemical', 'MESH:D007288', (67, 74))	('modification', 'Var', (51, 63))	('adenosine', 'Chemical', 'MESH:D000241', (4, 13))
263357	32194861	This mismatched base pairing also brings about structural conformational changes of the edited RNA, creating additional bulge or removing the existing ones from the dsRNA.	('ones', 'MPA', (151, 155))	('removing', 'NegReg', (129, 137))	('structural conformational changes', 'MPA', (47, 80))	('N', 'Chemical', 'MESH:D009584', (168, 169))	('bulge', 'MPA', (120, 125))	('N', 'Chemical', 'MESH:D009584', (96, 97))	('mismatched', 'Var', (5, 15))
263358	32194861	This is because the modification can increase or decrease the base pairing through misreading of I as G. A-to-I RNA editing can occur in both coding and noncoding regions of any double stranded RNA (small regulatory RNA, mRNA etc.).	('base pairing', 'MPA', (62, 74))	('N', 'Chemical', 'MESH:D009584', (113, 114))	('N', 'Chemical', 'MESH:D009584', (195, 196))	('modification', 'Var', (20, 32))	('decrease', 'NegReg', (49, 57))	('increase', 'PosReg', (37, 45))	('N', 'Chemical', 'MESH:D009584', (223, 224))	('N', 'Chemical', 'MESH:D009584', (217, 218))
263359	32194861	Since A-to-I modification is widespread in living organisms ranging from metazoans to humans and plays vital biological roles, it is important to map the locations of the editing sites to better understand the implications of this editing.	('modification', 'Var', (13, 25))	('A-to-I modification', 'Var', (6, 25))	('humans', 'Species', '9606', (86, 92))
263360	32194861	Bioinformatic studies have predicted several locations of A-to-I modification in all over the human transcriptome including intronic, exonic or even untranslated regions.	('A-to-I', 'Gene', (58, 64))	('modification', 'Var', (65, 77))	('human', 'Species', '9606', (94, 99))
263362	32194861	As I is read as G during the reverse transcription instead of A, the conventional method for detecting A-to-I modification site involved identification of A-to-G mismatch sites on the cDNA after the reverse transcription and comparing it with the genomic DNA sequence.	('N', 'Chemical', 'MESH:D009584', (186, 187))	('mismatch sites', 'Var', (162, 176))	('N', 'Chemical', 'MESH:D009584', (256, 257))	('A-to-G', 'Var', (155, 161))
263365	32194861	Another approach for A-to-I identification was to knockdown or knockout of ADARs by RNAi.	('ADAR', 'Gene', (75, 79))	('knockdown', 'Var', (50, 59))	('N', 'Chemical', 'MESH:D009584', (85, 86))	('ADAR', 'Gene', '103', (75, 79))	('knockout', 'Var', (63, 71))
263367	32194861	However, knockdown or knockout of ADARs caused alteration in gene expression, phenotypic changes or even lethality in experimental animals rendering this method impracticable.	('ADAR', 'Gene', '103', (34, 38))	('gene expression', 'MPA', (61, 76))	('knockdown', 'Var', (9, 18))	('ADAR', 'Gene', (34, 38))	('knockout', 'Var', (22, 30))	('phenotypic changes', 'CPA', (78, 96))	('alteration', 'Reg', (47, 57))	('lethality', 'CPA', (105, 114))	('rat', 'Species', '10116', (51, 54))
263372	32194861	With the help of this method they were able to identify ~20,000 novel A-to-I modification sites in human transcriptome.	('A-to-I', 'Gene', (70, 76))	('sites', 'Var', (90, 95))	('human', 'Species', '9606', (99, 104))	('modification sites', 'Var', (77, 95))
263381	32194861	Although these differences between the uridine and Psi do not affect the base-pairing specificity; they significantly affect the base-pairing stability, base stacking and the tertiary structure of the RNA molecule carrying this modification.	('affect', 'Reg', (118, 124))	('tertiary structure', 'MPA', (175, 193))	('base-pairing stability', 'MPA', (129, 151))	('base stacking', 'MPA', (153, 166))	('uridine', 'Chemical', 'MESH:D014529', (39, 46))	('N', 'Chemical', 'MESH:D009584', (202, 203))	('differences', 'Var', (15, 26))
263391	32194861	Base pairing between Psi on snRNA and A on the pre-mRNA intronic junction stabilizes the snRNA/pre-mRNA complex to facilitate mRNA splicing.	('N', 'Chemical', 'MESH:D009584', (128, 129))	('N', 'Chemical', 'MESH:D009584', (53, 54))	('snRNA/pre-mRNA complex', 'MPA', (89, 111))	('N', 'Chemical', 'MESH:D009584', (92, 93))	('facilitate', 'PosReg', (115, 125))	('mRNA splicing', 'MPA', (126, 139))	('N', 'Chemical', 'MESH:D009584', (31, 32))	('N', 'Chemical', 'MESH:D009584', (101, 102))	('Base pairing', 'Var', (0, 12))
263400	32194861	This modified CMC-Psi based method utilizes a new RT condition that can read both the mutation and deletion on the cDNA products.	('CMC', 'Chemical', '-', (14, 17))	('N', 'Chemical', 'MESH:D009584', (117, 118))	('deletion', 'Var', (99, 107))	('mutation', 'Var', (86, 94))
263406	32194861	Besides N6-methyladenosine (m6A), 5-methylcytosine (m5C), N1-methyladenosine (m1A), Adenosine to Inosine (A to I) and pseudouridine (Psi) modifications that are sparse and versatile in the entire transcriptome, there are hundreds of other RNA modifications and more are likely to be identified.	('pseudouridine', 'Chemical', 'MESH:D011560', (118, 131))	('5-methylcytosine', 'Chemical', 'MESH:D044503', (34, 50))	('N1-methyladenosine', 'Var', (58, 76))	('Inosine', 'Chemical', 'MESH:D007288', (97, 104))	('m5C', 'Chemical', '-', (52, 55))	('m1A', 'Chemical', '-', (78, 81))	('N', 'Chemical', 'MESH:D009584', (240, 241))	('N', 'Chemical', 'MESH:D009584', (58, 59))	('N1-methyladenosine', 'Chemical', 'MESH:C002230', (58, 76))	('N', 'Chemical', 'MESH:D009584', (8, 9))	('Adenosine', 'Chemical', 'MESH:D000241', (84, 93))	('N6-methyladenosine', 'Chemical', 'MESH:C010223', (8, 26))	('N6-methyladenosine', 'Var', (8, 26))
263411	32194861	The nucleotides next to the m7G of the transcribed mRNA are usually methylated on the ribose sugar at the 2'-OH position.	('N', 'Chemical', 'MESH:D009584', (53, 54))	('m7G', 'Var', (28, 31))	('methylated', 'Var', (68, 78))	("2'-O", 'Chemical', 'MESH:C030514', (106, 110))	('ribose sugar', 'Chemical', '-', (86, 98))
263414	32194861	While m6A is identified as the most common internal modification of mRNA, m6Am is discovered as the second nucleotide from beginning of the 5' UTR of mRNA (m7GpppNm).	('N', 'Chemical', 'MESH:D009584', (152, 153))	('m6Am', 'Chemical', '-', (74, 78))	('N', 'Chemical', 'MESH:D009584', (70, 71))	('m6Am', 'Var', (74, 78))	('N', 'Chemical', 'MESH:D009584', (162, 163))	('m6A', 'Var', (6, 9))
263419	32194861	Similar to iCLIP, this method uses UV crosslinking of anti-m6A antibodies to RNA and a miCLIP library is prepared which is then used for subsequent steps to map m6A and m6Am residues in a single nucleotide resolution level.	('m6Am', 'Chemical', '-', (169, 173))	('N', 'Chemical', 'MESH:D009584', (78, 79))	('C', 'Chemical', 'MESH:D003596', (12, 13))	('m6Am', 'Var', (169, 173))	('m6A', 'Var', (161, 164))	('C', 'Chemical', 'MESH:D003596', (89, 90))
263420	32194861	Without miCLIP the peak signal within the 5' UTR would refer to m6A instead of m6Am which is found only in the transcription start site.	('m6Am', 'Chemical', '-', (79, 83))	('C', 'Chemical', 'MESH:D003596', (10, 11))	('m6Am', 'Var', (79, 83))	('m6A', 'Var', (64, 67))
263423	32194861	m7G is present in the cap structure of almost all eukaryotic mRNAs which is installed during the transcription initiation and is involved in regulating mRNA stabilization, transport and splicing.	('mRNA stabilization', 'MPA', (152, 170))	('N', 'Chemical', 'MESH:D009584', (63, 64))	('m7G', 'Var', (0, 3))	('N', 'Chemical', 'MESH:D009584', (154, 155))
263429	32194861	This method, although emerged as an efficient technique in recent years for detecting m6A and m5C in the RNA transcriptome globally, however; is associated with major drawbacks and is not immune to error.	('m5C', 'Var', (94, 97))	('N', 'Chemical', 'MESH:D009584', (106, 107))	('m6A', 'Var', (86, 89))	('m5C', 'Chemical', '-', (94, 97))
263431	32194861	Another drawback for this method is the non-specific binding to the modified nucleotides that possess structural similarity, such as misrecognition of m6A for m6Am by m6A specific antibody.	('m6A', 'Var', (151, 154))	('binding', 'Interaction', (53, 60))	('m6Am', 'Chemical', '-', (159, 163))	('misrecognition', 'Var', (133, 147))
263440	32194861	Elucidation of the crystal structure of methyltransferase domain of the METT3-METTL14 complex revealed that, METTL3 is the main component of the complex playing the catalytic function; whereas METTL14 acts as a pseudo-methyltransferase by binding to RNA and stabilizing the METTL3-RNA interaction.	('RNA', 'Protein', (250, 253))	('interaction', 'Interaction', (285, 296))	('stabilizing', 'Reg', (258, 269))	('N', 'Chemical', 'MESH:D009584', (251, 252))	('N', 'Chemical', 'MESH:D009584', (282, 283))	('METTL14', 'Var', (193, 200))	('METTL3-RNA', 'Protein', (274, 284))	('binding', 'Interaction', (239, 246))
263444	32194861	With photoactivable ribonucleoside-enhanced crosslinking (PARCLIP) assay it was found that METTL3, METTL14 and WTAP share the same RNA binding motif by which all of them recognize the same m6A consensus sequence on RNA.	('C', 'Chemical', 'MESH:D003596', (61, 62))	('METTL3', 'Gene', (91, 97))	('N', 'Chemical', 'MESH:D009584', (132, 133))	('WTAP', 'Gene', '9589', (111, 115))	('ribonucleoside', 'Chemical', 'MESH:D012263', (20, 34))	('WTAP', 'Gene', (111, 115))	('N', 'Chemical', 'MESH:D009584', (216, 217))	('m6A', 'Var', (189, 192))	('METTL14', 'Gene', (99, 106))
263448	32194861	Disruption of any one component of the complex leads to a reduction in the m6A level in mRNA.	('reduction', 'NegReg', (58, 67))	('m6A level in mRNA', 'MPA', (75, 92))	('N', 'Chemical', 'MESH:D009584', (90, 91))	('Disruption', 'Var', (0, 10))
263459	32194861	In this study they showed that, the methylation of adenosine is dependent on the presence of m7G in the adjacent position.	('adenosine', 'Chemical', 'MESH:D000241', (51, 60))	('m7G', 'Var', (93, 96))	('methylation', 'MPA', (36, 47))	('dependent', 'Reg', (64, 73))
263462	32194861	Another research group almost at the same time using both in vitro and in vivo models discovered PCIF1 as the only methyl transferase for generating m6Am .	('m6Am', 'Chemical', '-', (149, 153))	('PCIF1', 'Gene', '63935', (97, 102))	('m6Am', 'Var', (149, 153))	('rat', 'Species', '10116', (142, 145))	('PCIF1', 'Gene', (97, 102))
263463	32194861	m5C modification in E. coli rRNA is catalyzed by SAM-dependent methyltransferase enzyme, RsmB and RsmF.	('m5C modification', 'Var', (0, 16))	('N', 'Chemical', 'MESH:D009584', (30, 31))	('SAM-dependent methyltransferase', 'Gene', (49, 80))	('SAM-dependent methyltransferase', 'Gene', '80745', (49, 80))	('m5C', 'Chemical', '-', (0, 3))	('E. coli', 'Species', '562', (20, 27))
263464	32194861	In higher eukaryotes DNA methyltransferaselike protein 2 (DNMT2) and members of the Nol1/Nop2/SUN (NSUN) family proteins play role as methyltransferases to catalyze the m5C modification.	('N', 'Chemical', 'MESH:D009584', (84, 85))	('DNA methyltransferaselike protein 2', 'Gene', '1787', (21, 56))	('m5C', 'Chemical', '-', (169, 172))	('N', 'Chemical', 'MESH:D009584', (22, 23))	('m5C', 'Var', (169, 172))	('DNMT2', 'Gene', '1787', (58, 63))	('N', 'Chemical', 'MESH:D009584', (99, 100))	('N', 'Chemical', 'MESH:D009584', (102, 103))	('DNA methyltransferaselike protein 2', 'Gene', (21, 56))	('N', 'Chemical', 'MESH:D009584', (89, 90))	('DNMT2', 'Gene', (58, 63))	('N', 'Chemical', 'MESH:D009584', (59, 60))	('Nol1', 'Gene', (84, 88))	('Nol1', 'Gene', '4839', (84, 88))	('N', 'Chemical', 'MESH:D009584', (96, 97))
263466	32194861	In yeast, the methyltransferase enzymes Trm4 (Ncl1), Nop2 and Rcm1 was reported to catalyze the m5C modification; whereas in humans, several other related proteins (e.g.	('Ncl1', 'Gene', (46, 50))	('Nop2', 'Gene', (53, 57))	('Trm4', 'Gene', '852257', (40, 44))	('Ncl1', 'Gene', '852257', (46, 50))	('humans', 'Species', '9606', (125, 131))	('Rcm1', 'Gene', (62, 66))	('Trm4', 'Gene', (40, 44))	('Rcm1', 'Gene', '855709', (62, 66))	('yeast', 'Species', '4932', (3, 8))	('m5C', 'Chemical', '-', (96, 99))	('m5C', 'Var', (96, 99))
263467	32194861	p120, NSUN1/NOL1, NSUN2-7) are found to mediate the m5C modification.	('NSUN2', 'Gene', (18, 23))	('mediate', 'Reg', (40, 47))	('NOL1', 'Gene', (12, 16))	('m5C', 'Chemical', '-', (52, 55))	('m5C', 'Var', (52, 55))	('NSUN2', 'Gene', '54888', (18, 23))	('p120', 'Gene', '4839', (0, 4))	('NOL1', 'Gene', '4839', (12, 16))	('NSUN1', 'Gene', (6, 11))	('p120', 'Gene', (0, 4))	('NSUN1', 'Gene', '4839', (6, 11))
263470	32194861	NSUN1 and NSUN5 are the human orthologues of yeast Nop2 and Rcm1which catalyze the methylation of cytoplasmic rRNA 28S subunit at cytosin4413 and 3761 respectively.	('Rcm1', 'Gene', '855709', (60, 64))	('human', 'Species', '9606', (24, 29))	('methylation', 'MPA', (83, 94))	('N', 'Chemical', 'MESH:D009584', (112, 113))	('N', 'Chemical', 'MESH:D009584', (0, 1))	('N', 'Chemical', 'MESH:D009584', (3, 4))	('cytosin4413', 'Var', (130, 141))	('3761', 'Var', (146, 150))	('N', 'Chemical', 'MESH:D009584', (10, 11))	('NSUN1', 'Gene', (0, 5))	('yeast', 'Species', '4932', (45, 50))	('N', 'Chemical', 'MESH:D009584', (13, 14))	('NSUN5', 'Gene', (10, 15))	('NSUN5', 'Gene', '55695', (10, 15))	('NSUN1', 'Gene', '4839', (0, 5))	('N', 'Chemical', 'MESH:D009584', (51, 52))	('Rcm1', 'Gene', (60, 64))
263475	32194861	In mRNA, m5C modification was found to be catalyzed mainly by NSUN2 and is localized close to the translation initiation sites.	('N', 'Chemical', 'MESH:D009584', (5, 6))	('NSUN2', 'Gene', (62, 67))	('m5C', 'Chemical', '-', (9, 12))	('NSUN2', 'Gene', '54888', (62, 67))	('m5C', 'Var', (9, 12))	('N', 'Chemical', 'MESH:D009584', (62, 63))	('N', 'Chemical', 'MESH:D009584', (65, 66))
263511	32194861	The common eukaryotic mRNA cap modification m7G is carried out by the heterodimeric enzyme complex METTL1-WDR4 in mammals which is the yeast homolog of Trm8 and Trm82 enzyme complex.	('METTL1', 'Gene', (99, 105))	('Trm8', 'Gene', '851326', (152, 156))	('Trm8', 'Gene', (152, 156))	('yeast', 'Species', '4932', (135, 140))	('Trm8', 'Gene', (161, 165))	('m7G', 'Var', (44, 47))	('N', 'Chemical', 'MESH:D009584', (24, 25))	('Trm82', 'Gene', (161, 166))	('Trm8', 'Gene', '851326', (161, 165))	('METTL1', 'Gene', '4234', (99, 105))	('Trm82', 'Gene', '851743', (161, 166))	('modification m7G', 'Var', (31, 47))
263512	32194861	The internal m7G modification in the tRNA and rRNA is carried out by the enzyme, WBSCR22.	('internal m7G', 'Var', (4, 16))	('N', 'Chemical', 'MESH:D009584', (39, 40))	('N', 'Chemical', 'MESH:D009584', (48, 49))	('WBSCR22', 'Gene', '114049', (81, 88))	('WBSCR22', 'Gene', (81, 88))
263516	32194861	The demethylating ALKB enzyme family recognizes the methylation on adenine and cytosine nucleotide bases in both single stranded DNA and RNA and to a smaller extent in the double stranded DNA which block DNA replication.	('DNA replication', 'MPA', (204, 219))	('cytosine nucleotide', 'Chemical', 'MESH:D003597', (79, 98))	('N', 'Chemical', 'MESH:D009584', (205, 206))	('N', 'Chemical', 'MESH:D009584', (130, 131))	('ALKB', 'Gene', (18, 22))	('ALKB', 'Gene', '8846', (18, 22))	('adenine', 'Chemical', 'MESH:D000225', (67, 74))	('N', 'Chemical', 'MESH:D009584', (189, 190))	('methylation', 'Var', (52, 63))	('N', 'Chemical', 'MESH:D009584', (138, 139))
263526	32194861	m6Am is demethylated by FTO in the same way as m6A and reverted to Am .	('FTO', 'Gene', (24, 27))	('FTO', 'Gene', '79068', (24, 27))	('m6Am', 'Var', (0, 4))	('m6Am', 'Chemical', '-', (0, 4))
263528	32194861	They also found that, m6Am transcripts have more stability compared to mRNA transcripts with their non-methylated counterpart Am or any other nucleotide.	('m6Am', 'Chemical', '-', (22, 26))	('N', 'Chemical', 'MESH:D009584', (73, 74))	('m6Am', 'Var', (22, 26))	('stability', 'MPA', (49, 58))
263539	32194861	These proteins were identified for the first time using the antibodies targeting the methylated RNA and co-immunoprecipitation followed by mass spectrometry analysis.	('RNA', 'Protein', (96, 99))	('N', 'Chemical', 'MESH:D009584', (97, 98))	('methylated', 'Var', (85, 95))
263541	32194861	Other proteins of YTH family (such as YTHDC1) were found to localize in the nucleus and recognize m6A in the nuclear region.	('m6A', 'Var', (98, 101))	('YTHDC1', 'Gene', (38, 44))	('localize', 'MPA', (60, 68))	('YTHDC1', 'Gene', '91746', (38, 44))
263544	32194861	YTHDF1 and 3 coordinate each other in processing the m6A bearing mRNA for translation.	('N', 'Chemical', 'MESH:D009584', (67, 68))	('translation', 'MPA', (74, 85))	('m6A', 'Var', (53, 56))	('YTHDF1', 'Gene', '54915', (0, 6))	('YTHDF1', 'Gene', (0, 6))
263547	32194861	One such protein hnRNPC was found to bind to an m6A altered stem-loop RNA structure which subsequently directs an alternative splicing of RNA.	('N', 'Chemical', 'MESH:D009584', (139, 140))	('directs', 'Reg', (103, 110))	('N', 'Chemical', 'MESH:D009584', (71, 72))	('hnRNPC', 'Gene', (17, 23))	('N', 'Chemical', 'MESH:D009584', (20, 21))	('hnRNPC', 'Gene', '3183', (17, 23))	('m6A altered', 'Var', (48, 59))	('alternative splicing', 'MPA', (114, 134))
263552	32194861	Three members of this family, IGF2BP 1-3 have been identified which can recognize the m6A consensus sequence in mRNA.	('N', 'Chemical', 'MESH:D009584', (114, 115))	('IGF2BP 1', 'Gene', (30, 38))	('m6A', 'Var', (86, 89))	('IGF2BP 1', 'Gene', '10642', (30, 38))
263561	32194861	In normal tissue development, the role of DNA methylation as a vital epigenetic factor is well established; however, association of m6A RNA modification as an epigenetic regulator in cancer is emerging now.	('N', 'Chemical', 'MESH:D009584', (43, 44))	('cancer', 'Disease', (183, 189))	('m6A', 'Var', (132, 135))	('N', 'Chemical', 'MESH:D009584', (137, 138))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('cancer', 'Disease', 'MESH:D009369', (183, 189))
263563	32194861	Alternative splice variants produced from pre-mRNA splicing are frequently observed in many cancer types, some of which are found to be mediated by m6A modification.	('Alternative', 'Var', (0, 11))	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('observed', 'Reg', (75, 83))	('N', 'Chemical', 'MESH:D009584', (48, 49))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
263565	32194861	In acute myeloid leukemia (AML), METTL14 is also found to be highly expressed, silencing of which led to inhibition of cellular proliferation and reduced survival of AML cells.	('myeloid leukemia', 'Phenotype', 'HP:0012324', (9, 25))	('rat', 'Species', '10116', (135, 138))	('leukemia', 'Phenotype', 'HP:0001909', (17, 25))	('AML', 'Disease', (166, 169))	('inhibition', 'NegReg', (105, 115))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (3, 25))	('survival', 'CPA', (154, 162))	('reduced', 'NegReg', (146, 153))	('METTL14', 'Gene', (33, 40))	('AML', 'Disease', 'MESH:D015470', (27, 30))	('cellular proliferation', 'CPA', (119, 141))	('acute myeloid leukemia', 'Disease', (3, 25))	('silencing', 'Var', (79, 88))	('AML', 'Disease', (27, 30))	('AML', 'Disease', 'MESH:D015470', (166, 169))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (3, 25))
263566	32194861	METTL14 knockdown also reduced the self-renewal capacity of leukemia stem cells.	('leukemia', 'Phenotype', 'HP:0001909', (60, 68))	('METTL14', 'Gene', (0, 7))	('knockdown', 'Var', (8, 17))	('reduced', 'NegReg', (23, 30))	('leukemia', 'Disease', (60, 68))	('leukemia', 'Disease', 'MESH:D007938', (60, 68))
263569	32194861	Overexpression of WTAP was found in almost 32% of the AML cases where the patients are found to carry mutation in the NPM1 and FTL3-ITD genes.	('NPM1', 'Gene', (118, 122))	('AML', 'Disease', 'MESH:D015470', (54, 57))	('WTAP', 'Gene', '9589', (18, 22))	('mutation', 'Var', (102, 110))	('patients', 'Species', '9606', (74, 82))	('NPM1', 'Gene', '4869', (118, 122))	('WTAP', 'Gene', (18, 22))	('AML', 'Disease', (54, 57))	('FTL3-ITD', 'Gene', (127, 135))
263579	32194861	The incorporation of m6A in p53 pre-mRNA transcript was observed in the p53 mutant colon cancer cells.	('p53', 'Gene', (28, 31))	('observed', 'Reg', (56, 64))	('colon cancer', 'Disease', (83, 95))	('incorporation', 'MPA', (4, 17))	('p53', 'Gene', '7157', (28, 31))	('mutant', 'Var', (76, 82))	('p53', 'Gene', (72, 75))	('p53', 'Gene', '7157', (72, 75))	('N', 'Chemical', 'MESH:D009584', (38, 39))	('rat', 'Species', '10116', (11, 14))	('colon cancer', 'Phenotype', 'HP:0003003', (83, 95))	('colon cancer', 'Disease', 'MESH:D015179', (83, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
263584	32194861	Ovarian cancer cells with METTL3 overexpression exhibited increased cellular proliferation, invasiveness, metastasis and tumorigenicity in nude mice; which upon METTL3 silencing showed the opposite effects.	('METTL3', 'Gene', (26, 32))	('nude mice', 'Species', '10090', (139, 148))	('increased', 'PosReg', (58, 67))	('cancer', 'Disease', (8, 14))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('rat', 'Species', '10116', (84, 87))	('Ovarian cancer', 'Phenotype', 'HP:0100615', (0, 14))	('tumor', 'Disease', (121, 126))	('cellular proliferation', 'CPA', (68, 90))	('tumor', 'Disease', 'MESH:D009369', (121, 126))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('overexpression', 'Var', (33, 47))	('invasiveness', 'CPA', (92, 104))	('metastasis', 'CPA', (106, 116))	('cancer', 'Disease', 'MESH:D009369', (8, 14))
263596	32194861	The possible mechanism behind it is that, FTO caused demethylation of m6A in mRNA transcript and downregulation of Ankyrin repeat and SOCS box-containing 2 (ASB2) and retinoic acid receptor-alpha (RARA).	('retinoic acid receptor-alpha', 'Gene', '5914', (167, 195))	('m6A', 'Gene', (70, 73))	('mRNA transcript', 'MPA', (77, 92))	('ASB2', 'Gene', '51676', (157, 161))	('FTO', 'Gene', '79068', (42, 45))	('retinoic acid receptor-alpha', 'Gene', (167, 195))	('demethylation', 'Var', (53, 66))	('ASB2', 'Gene', (157, 161))	('Ankyrin repeat and SOCS box-containing 2', 'Gene', '51676', (115, 155))	('downregulation', 'NegReg', (97, 111))	('N', 'Chemical', 'MESH:D009584', (79, 80))	('RARA', 'Gene', '5914', (197, 201))	('FTO', 'Gene', (42, 45))	('RARA', 'Gene', (197, 201))
263605	32194861	Increased expression of FTO and m6A demethylation of the protumorigenic mRNA transcripts (PD-1, CXCR4, and SOX10) accelerates the growth of melanoma cells and leads to reduced sensitivity against anti-PD-1 blockade immunotherapy.	('CXCR4', 'Gene', (96, 101))	('rat', 'Species', '10116', (120, 123))	('melanoma', 'Disease', 'MESH:D008545', (140, 148))	('tumor', 'Disease', (60, 65))	('sensitivity', 'CPA', (176, 187))	('SOX10', 'Gene', (107, 112))	('reduced', 'NegReg', (168, 175))	('N', 'Chemical', 'MESH:D009584', (74, 75))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('FTO', 'Gene', '79068', (24, 27))	('melanoma', 'Phenotype', 'HP:0002861', (140, 148))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('melanoma', 'Disease', (140, 148))	('FTO', 'Gene', (24, 27))	('demethylation', 'Var', (36, 49))	('CXCR4', 'Gene', '7852', (96, 101))	('SOX10', 'Gene', '6663', (107, 112))	('growth', 'CPA', (130, 136))	('accelerates', 'PosReg', (114, 125))
263608	32194861	FTO-induced demethylation of the tumor suppressor BNIP3 mRNA in its 3'UTR causes degradation of the transcript thus eliminating the tumor suppressive effect of BNIP3 in breast cancer.	('BNIP3', 'Gene', '664', (160, 165))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('tumor', 'Disease', (132, 137))	('eliminating', 'NegReg', (116, 127))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('N', 'Chemical', 'MESH:D009584', (161, 162))	('N', 'Chemical', 'MESH:D009584', (58, 59))	('tumor', 'Disease', (33, 38))	('N', 'Chemical', 'MESH:D009584', (51, 52))	('BNIP3', 'Gene', (50, 55))	('degradation of the transcript', 'MPA', (81, 110))	('FTO', 'Gene', '79068', (0, 3))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('FTO', 'Gene', (0, 3))	('breast cancer', 'Phenotype', 'HP:0003002', (169, 182))	('demethylation', 'Var', (12, 25))	('BNIP3', 'Gene', (160, 165))	('BNIP3', 'Gene', '664', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('breast cancer', 'Disease', 'MESH:D001943', (169, 182))	('breast cancer', 'Disease', (169, 182))
263613	32194861	In one study it has been shown that, METTL14 knockdown in hepatocellular carcinoma (HCC) enhances the metastatic tumor progression by decreasing m6A mRNA level both in vivo and in vitro.	('hepatocellular carcinoma', 'Disease', (58, 82))	('tumor', 'Disease', (113, 118))	('METTL14', 'Gene', (37, 44))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (58, 82))	('decreasing', 'NegReg', (134, 144))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('N', 'Chemical', 'MESH:D009584', (151, 152))	('enhances', 'PosReg', (89, 97))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('m6A mRNA level', 'MPA', (145, 159))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (58, 82))	('knockdown', 'Var', (45, 54))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
263616	32194861	METTL3 and METTL14 knockdown was observed to upregulate the expression of several oncogenes such as ADAM19, EPHA3 and KLF4 in glioblastoma stem cells (GBCs).	('expression', 'MPA', (60, 70))	('ADAM19', 'Gene', '8728', (100, 106))	('METTL14', 'Gene', (11, 18))	('knockdown', 'Var', (19, 28))	('glioblastoma', 'Disease', (126, 138))	('ADAM19', 'Gene', (100, 106))	('glioblastoma', 'Disease', 'MESH:D005909', (126, 138))	('C', 'Chemical', 'MESH:D003596', (153, 154))	('METTL3', 'Gene', (0, 6))	('EPHA3', 'Gene', '2042', (108, 113))	('glioblastoma', 'Phenotype', 'HP:0012174', (126, 138))	('EPHA3', 'Gene', (108, 113))	('upregulate', 'PosReg', (45, 55))	('KLF4', 'Gene', (118, 122))	('KLF4', 'Gene', '9314', (118, 122))
263620	32194861	Silencing of ALKBH5 also altered the expression level of several ALKBH5 target genes which was evidenced from the integrated transcriptome and m6A immunoprecipitation followed by the sequence analysis of the mRNAs.	('altered', 'Reg', (25, 32))	('ALKBH5', 'Gene', (65, 71))	('rat', 'Species', '10116', (119, 122))	('expression level', 'MPA', (37, 53))	('ALKBH5', 'Gene', '54890', (13, 19))	('N', 'Chemical', 'MESH:D009584', (210, 211))	('ALKBH5', 'Gene', (13, 19))	('Silencing', 'Var', (0, 9))	('ALKBH5', 'Gene', '54890', (65, 71))
263622	32194861	At the same time ALKBH5 knockdown increases m6A level in FOXM1 mRNA which lacks the regulation by HuR thus decreased FOXM1 expression.	('FOXM1', 'Gene', '2305', (117, 122))	('expression', 'MPA', (123, 133))	('N', 'Chemical', 'MESH:D009584', (65, 66))	('FOXM1', 'Gene', (57, 62))	('m6A level', 'MPA', (44, 53))	('decreased', 'NegReg', (107, 116))	('HuR', 'Gene', '1994', (98, 101))	('FOXM1', 'Gene', '2305', (57, 62))	('ALKBH5', 'Gene', '54890', (17, 23))	('HuR', 'Gene', (98, 101))	('knockdown', 'Var', (24, 33))	('ALKBH5', 'Gene', (17, 23))	('FOXM1', 'Gene', (117, 122))	('increases', 'PosReg', (34, 43))
263628	32194861	The genes associated with proliferation, migration and cell-cell adhesion were also affected by the NSUN2 knockdown.	('genes', 'MPA', (4, 9))	('NSUN2', 'Gene', (100, 105))	('migration', 'CPA', (41, 50))	('NSUN2', 'Gene', '54888', (100, 105))	('rat', 'Species', '10116', (33, 36))	('rat', 'Species', '10116', (44, 47))	('knockdown', 'Var', (106, 115))	('cell-cell adhesion', 'CPA', (55, 73))	('proliferation', 'CPA', (26, 39))	('affected', 'Reg', (84, 92))
263629	32194861	In another study NSUN2 was found to methylate the C1733 in the 3'UTR of the CDK1 mRNA thus elevating the CDK1 translational activity.	('CDK1', 'Gene', (105, 109))	('CDK1', 'Gene', '983', (105, 109))	('NSUN2', 'Gene', '54888', (17, 22))	('methylate', 'Var', (36, 45))	('CDK1', 'Gene', (76, 80))	('C', 'Chemical', 'MESH:D003596', (76, 77))	('N', 'Chemical', 'MESH:D009584', (20, 21))	('N', 'Chemical', 'MESH:D009584', (83, 84))	('C1733', 'Var', (50, 55))	('N', 'Chemical', 'MESH:D009584', (17, 18))	('elevating', 'PosReg', (91, 100))	('NSUN2', 'Gene', (17, 22))	('C', 'Chemical', 'MESH:D003596', (50, 51))	('C', 'Chemical', 'MESH:D003596', (105, 106))	('CDK1', 'Gene', '983', (76, 80))	('translational activity', 'MPA', (110, 132))
263631	32194861	Association of m5C modification is reported in human urothelial carcinoma of bladder (UCB).	('C', 'Chemical', 'MESH:D003596', (17, 18))	('C', 'Chemical', 'MESH:D003596', (87, 88))	('m5C', 'Chemical', '-', (15, 18))	('urothelial carcinoma of bladder', 'Disease', 'MESH:D001749', (53, 84))	('urothelial carcinoma of bladder', 'Phenotype', 'HP:0006740', (53, 84))	('Association', 'Reg', (0, 11))	('urothelial carcinoma of bladder', 'Disease', (53, 84))	('human', 'Species', '9606', (47, 52))	('m5C modification', 'Var', (15, 31))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))
263632	32194861	Increased m5C methylation in several oncogenes is identified in UCB.	('m5C', 'Var', (10, 13))	('oncogenes', 'Gene', (37, 46))	('C', 'Chemical', 'MESH:D003596', (65, 66))	('Increased', 'PosReg', (0, 9))	('C', 'Chemical', 'MESH:D003596', (12, 13))	('m5C', 'Chemical', '-', (10, 13))
263633	32194861	The methylation is carried out by NSUN2 and is recognized by the m5C reader YBX1 which stabilizes the modified oncogenic mRNAs.	('NSUN2', 'Gene', (34, 39))	('N', 'Chemical', 'MESH:D009584', (37, 38))	('YBX1', 'Gene', (76, 80))	('NSUN2', 'Gene', '54888', (34, 39))	('modified', 'Var', (102, 110))	('N', 'Chemical', 'MESH:D009584', (34, 35))	('N', 'Chemical', 'MESH:D009584', (123, 124))	('YBX1', 'Gene', '4904', (76, 80))	('m5C', 'Chemical', '-', (65, 68))
263634	32194861	Thus, NSUN2 and YBX1 in cooperation drive the tumorigenesis in UCB by hypermethylation of the mRNA targets.	('drive', 'PosReg', (36, 41))	('YBX1', 'Gene', '4904', (16, 20))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('NSUN2', 'Gene', '54888', (6, 11))	('hypermethylation', 'Var', (70, 86))	('rat', 'Species', '10116', (29, 32))	('tumor', 'Disease', (46, 51))	('N', 'Chemical', 'MESH:D009584', (6, 7))	('C', 'Chemical', 'MESH:D003596', (64, 65))	('N', 'Chemical', 'MESH:D009584', (96, 97))	('YBX1', 'Gene', (16, 20))	('NSUN2', 'Gene', (6, 11))	('UCB', 'Disease', (63, 66))	('N', 'Chemical', 'MESH:D009584', (9, 10))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
263637	32194861	The inhibitory effect of TRDMT1 knockdown was associated with the alteration of genes controlling cell cycle progression, RNA transport and degradation.	('alteration', 'Reg', (66, 76))	('rat', 'Species', '10116', (70, 73))	('TRDMT1', 'Gene', (25, 31))	('inhibitory effect', 'NegReg', (4, 21))	('RNA transport', 'MPA', (122, 135))	('knockdown', 'Var', (32, 41))	('N', 'Chemical', 'MESH:D009584', (123, 124))	('degradation', 'MPA', (140, 151))	('cell cycle progression', 'CPA', (98, 120))	('TRDMT1', 'Gene', '1787', (25, 31))
263638	32194861	Since A-to-I modification is more abundant in human brain than any other organs, the modification itself and the modification machinery are associated with various human neurological disorders including cancer.	('associated', 'Reg', (140, 150))	('human', 'Species', '9606', (164, 169))	('neurological disorders', 'Disease', (170, 192))	('modification', 'Var', (13, 25))	('A-to-I modification', 'Var', (6, 25))	('human', 'Species', '9606', (46, 51))	('cancer', 'Disease', (203, 209))	('cancer', 'Disease', 'MESH:D009369', (203, 209))	('neurological disorders', 'Disease', 'MESH:D009422', (170, 192))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))
263645	32194861	Increased A-to-I editing in breast cancer was found to confer breast cancer cells resistance to methotrexate, an inhibitor of folate metabolism in cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('breast cancer', 'Phenotype', 'HP:0003002', (62, 75))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('resistance to methotrexate', 'MPA', (82, 108))	('breast cancer', 'Disease', 'MESH:D001943', (62, 75))	('breast cancer', 'Phenotype', 'HP:0003002', (28, 41))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('breast cancer', 'Disease', (62, 75))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('breast cancer', 'Disease', 'MESH:D001943', (28, 41))	('breast cancer', 'Disease', (28, 41))	('folate', 'Chemical', 'MESH:D005492', (126, 132))	('cancer', 'Disease', (69, 75))	('A-to-I editing', 'Var', (10, 24))	('methotrexate', 'Chemical', 'MESH:D008727', (96, 108))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('cancer', 'Disease', (147, 153))	('cancer', 'Disease', (35, 41))
263647	32194861	Overexpression of ADAR1 was also reported in oral squamous cell carcinoma (OSCC) and esophageal squamous cell carcinoma (ESCC) which is associated with the rapid tumor growth and poor disease prognosis in OSCC and ESCC patients.	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('ADAR1', 'Gene', (18, 23))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (45, 73))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (96, 119))	('esophageal squamous cell carcinoma', 'Disease', (85, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('tumor', 'Disease', (162, 167))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (50, 73))	('oral squamous cell carcinoma', 'Disease', (45, 73))	('ADAR1', 'Gene', '103', (18, 23))	('Overexpression', 'Var', (0, 14))	('reported', 'Reg', (33, 41))	('patients', 'Species', '9606', (219, 227))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (85, 119))	('tumor', 'Disease', 'MESH:D009369', (162, 167))
263654	32194861	Knockdown of ALKBH3 was found to decrease the proliferation of prostate cancer cell proliferation and tumor growth in vivo.	('ALKBH3', 'Gene', (13, 19))	('ALKBH3', 'Gene', '221120', (13, 19))	('decrease', 'NegReg', (33, 41))	('Knockdown', 'Var', (0, 9))	('rat', 'Species', '10116', (91, 94))	('prostate cancer', 'Disease', 'MESH:D011471', (63, 78))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('prostate cancer', 'Phenotype', 'HP:0012125', (63, 78))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('proliferation', 'CPA', (46, 59))	('rat', 'Species', '10116', (53, 56))	('prostate cancer', 'Disease', (63, 78))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))
263655	32194861	ALKBH3 has also been found to be highly expressed in other cancer types such as pancreatic cancer, renal cell carcinoma and non-small-cell lung carcinoma etc.. Mutation in the snoRNA-dependent pseudouridine synthase DKC1 is associated with a heriditary bone marrow failure syndrome Dyskeratosis Congenita (DC) which leads to various cutaneous and noncutaneous abnormalities including premature ageing and cancer.	('pseudouridine', 'Chemical', 'MESH:D011560', (193, 206))	('non-small-cell lung carcinoma etc', 'Disease', 'MESH:D002289', (124, 157))	('ALKBH3', 'Gene', '221120', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('premature ageing', 'Phenotype', 'HP:0007495', (384, 400))	('cancer', 'Disease', (405, 411))	('pancreatic cancer', 'Disease', (80, 97))	('renal cell carcinoma', 'Disease', (99, 119))	('non-small-cell lung carcinoma etc', 'Disease', (124, 157))	('associated', 'Reg', (224, 234))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (99, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('cancer', 'Phenotype', 'HP:0002664', (405, 411))	('C', 'Chemical', 'MESH:D003596', (295, 296))	('ALKBH3', 'Gene', (0, 6))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('heriditary bone marrow failure syndrome Dyskeratosis Congenita', 'Disease', 'MESH:D000080983', (242, 304))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('snoRNA', 'Gene', '6079', (176, 182))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (80, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('cancer', 'Disease', 'MESH:D009369', (405, 411))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (99, 119))	('snoRNA', 'Gene', (176, 182))	('Mutation', 'Var', (160, 168))	('cancer', 'Disease', (91, 97))	('bone marrow failure', 'Phenotype', 'HP:0005528', (253, 272))	('DKC1', 'Gene', (216, 220))	('C', 'Chemical', 'MESH:D003596', (307, 308))	('pancreatic cancer', 'Disease', 'MESH:D010190', (80, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('DKC1', 'Gene', '1736', (216, 220))	('C', 'Chemical', 'MESH:D003596', (218, 219))	('cancer', 'Disease', (59, 65))
263657	32194861	Loss of an H/ACA snoRNA, SNORA which directs site specific Psi modification in 18s rRNA subunit results in RAS-induced development of liver cancer in mice.	('mice', 'Species', '10090', (150, 154))	('liver cancer', 'Disease', 'MESH:D006528', (134, 146))	('C', 'Chemical', 'MESH:D003596', (14, 15))	('liver cancer', 'Phenotype', 'HP:0002896', (134, 146))	('liver cancer', 'Disease', (134, 146))	('Psi modification', 'Var', (59, 75))	('N', 'Chemical', 'MESH:D009584', (85, 86))	('N', 'Chemical', 'MESH:D009584', (26, 27))	('RAS-induced development of', 'CPA', (107, 133))	('snoRNA', 'Gene', (17, 23))	('snoRNA', 'Gene', '6079', (17, 23))	('ACA snoRNA', 'Phenotype', 'HP:0025267', (13, 23))	('N', 'Chemical', 'MESH:D009584', (21, 22))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))
263662	32194861	METTL1, writer of the common 5'-cap modification m7G in mRNA and internal modification in other non-coding RNAs, is found upregulated in hepatocellular carcinoma (HCC).	('carcinoma', 'Phenotype', 'HP:0030731', (152, 161))	('upregulated', 'PosReg', (122, 133))	('m7G', 'Var', (49, 52))	('METTL1', 'Gene', (0, 6))	('N', 'Chemical', 'MESH:D009584', (58, 59))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (137, 161))	('METTL1', 'Gene', '4234', (0, 6))	('hepatocellular carcinoma', 'Disease', (137, 161))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (137, 161))	('N', 'Chemical', 'MESH:D009584', (108, 109))
263663	32194861	Overexpression of METTL1 is correlated with poor overall survival in HCC patients.	('METTL1', 'Gene', '4234', (18, 24))	('METTL1', 'Gene', (18, 24))	('Overexpression', 'Var', (0, 14))	('HCC', 'Disease', (69, 72))	('patients', 'Species', '9606', (73, 81))
263664	32194861	METTL1 overexpression also showed increased cell proliferation and migration in in vitro studies.	('rat', 'Species', '10116', (70, 73))	('overexpression', 'Var', (7, 21))	('cell proliferation', 'CPA', (44, 62))	('rat', 'Species', '10116', (56, 59))	('METTL1', 'Gene', (0, 6))	('increased', 'PosReg', (34, 43))	('METTL1', 'Gene', '4234', (0, 6))
263669	32194861	The writers of m5C and m7G, NSUN2 and METTL1 are both tRNA modifiers which are found concurrently overexpressed in human cancers.	('cancers', 'Disease', (121, 128))	('cancers', 'Disease', 'MESH:D009369', (121, 128))	('NSUN2', 'Gene', '54888', (28, 33))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('m5C', 'Chemical', '-', (15, 18))	('METTL1', 'Gene', (38, 44))	('m7G', 'Var', (23, 26))	('human', 'Species', '9606', (115, 120))	('m5C', 'Var', (15, 18))	('METTL1', 'Gene', '4234', (38, 44))	('cancers', 'Phenotype', 'HP:0002664', (121, 128))	('NSUN2', 'Gene', (28, 33))
263670	32194861	Combined knockdown of both NSUN2 and METTL1 in HeLa cells increased their sensitivity to chemotherapeutic drug 5-fluorouracil (5-FU).	('METTL1', 'Gene', (37, 43))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (111, 125))	('5-FU', 'Chemical', 'MESH:D005472', (127, 131))	('NSUN2', 'Gene', (27, 32))	('increased', 'PosReg', (58, 67))	('knockdown', 'Var', (9, 18))	('METTL1', 'Gene', '4234', (37, 43))	('NSUN2', 'Gene', '54888', (27, 32))	('C', 'Chemical', 'MESH:D003596', (0, 1))
263674	32194861	Thus, lack of METTL3 maintains the pluripotency in naive ESCs.	('METTL3', 'Gene', (14, 20))	('lack', 'Var', (6, 10))	('pluripotency', 'MPA', (35, 47))	('C', 'Chemical', 'MESH:D003596', (59, 60))
263675	32194861	In this case METT3 depletion diminished self-renewal capability and accelerated the stem cell differentiation.	('depletion', 'Var', (19, 28))	('stem cell differentiation', 'CPA', (84, 109))	('rat', 'Species', '10116', (74, 77))	('accelerated', 'PosReg', (68, 79))	('METT3', 'Gene', (13, 18))	('self-renewal capability', 'CPA', (40, 63))	('diminished', 'NegReg', (29, 39))
263679	32194861	METTL3 mediates the m6A modification in both JAK2 and the negative regulator of the JAK2-STAT3 pathway, SOCS3 which causes decreased SOCS3 expression resulting in rescue of the repressive effect of SOCS3 on this pathway.	('SOCS3', 'Gene', (198, 203))	('SOCS3', 'Gene', (133, 138))	('JAK2', 'Gene', (84, 88))	('decreased', 'NegReg', (123, 132))	('SOCS3', 'Gene', '9021', (133, 138))	('JAK2', 'Gene', '16452', (84, 88))	('rescue', 'PosReg', (163, 169))	('SOCS3', 'Gene', '9021', (104, 109))	('repressive effect', 'MPA', (177, 194))	('JAK2', 'Gene', (45, 49))	('SOCS3', 'Gene', '9021', (198, 203))	('STAT3', 'Gene', '20848', (89, 94))	('expression', 'MPA', (139, 149))	('JAK2', 'Gene', '16452', (45, 49))	('STAT3', 'Gene', (89, 94))	('SOCS3', 'Gene', (104, 109))	('m6A', 'Var', (20, 23))
263680	32194861	In this case, m6A modified JAK2 mRNA is recognized and stabilized by YTHDF1, whereas the SOCS3 mRNA is degraded by YTHDF2.	('SOCS3', 'Gene', '9021', (89, 94))	('YTHDF1', 'Gene', (69, 75))	('m6A', 'Var', (14, 17))	('N', 'Chemical', 'MESH:D009584', (97, 98))	('SOCS3', 'Gene', (89, 94))	('N', 'Chemical', 'MESH:D009584', (34, 35))	('YTHDF2', 'Gene', '51441', (115, 121))	('JAK2', 'Gene', (27, 31))	('YTHDF2', 'Gene', (115, 121))	('YTHDF1', 'Gene', '54915', (69, 75))	('JAK2', 'Gene', '16452', (27, 31))
263682	32194861	In absence of FTO, the m6A modified JAK2 mRNA is recognized and degraded by YTHDF2.	('N', 'Chemical', 'MESH:D009584', (43, 44))	('JAK2', 'Gene', (36, 40))	('FTO', 'Gene', '79068', (14, 17))	('JAK2', 'Gene', '16452', (36, 40))	('YTHDF2', 'Gene', '51441', (76, 82))	('m6A modified', 'Var', (23, 35))	('YTHDF2', 'Gene', (76, 82))	('FTO', 'Gene', (14, 17))
263693	32194861	Ablation of METTL14 reduced the immortalization of the cells in vitro and decreased the tumorigenicity of the AML cells in vivo.	('reduced', 'NegReg', (20, 27))	('AML', 'Disease', 'MESH:D015470', (110, 113))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('AML', 'Disease', (110, 113))	('Ablation', 'Var', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('METTL14', 'Gene', (12, 19))	('immortalization of the cells in vitro', 'CPA', (32, 69))	('decreased', 'NegReg', (74, 83))	('tumor', 'Disease', (88, 93))
263694	32194861	The tumorigenicity and stemness of AML cells were due to METTL14-mediated methylation and increased stability of the MYB and MYC mRNA transcripts.	('tumor', 'Disease', (4, 9))	('METTL14-mediated', 'Gene', (57, 73))	('methylation', 'Var', (74, 85))	('AML', 'Disease', (35, 38))	('MYB', 'Gene', '4602', (117, 120))	('MYB', 'Gene', (117, 120))	('MYC', 'Gene', '4609', (125, 128))	('increased', 'PosReg', (90, 99))	('MYC', 'Gene', (125, 128))	('stability', 'MPA', (100, 109))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('AML', 'Disease', 'MESH:D015470', (35, 38))	('N', 'Chemical', 'MESH:D009584', (131, 132))	('stemness', 'CPA', (23, 31))
263700	32194861	In this study, three specific locations in the 3'-UTR of SOX2 mRNA was found to be the target for m6A modification.	('N', 'Chemical', 'MESH:D009584', (64, 65))	('modification', 'Var', (102, 114))	('SOX2', 'Gene', (57, 61))	('SOX2', 'Gene', '6657', (57, 61))	('m6A', 'Var', (98, 101))
263701	32194861	Silencing METTL3 sensitized the GSCs to gamma-irradiation and reduced the neurosphere formation.	('sensitized', 'Reg', (17, 27))	('neurosphere formation', 'CPA', (74, 95))	('METTL3', 'Gene', (10, 16))	('C', 'Chemical', 'MESH:D003596', (34, 35))	('Silencing', 'Var', (0, 9))	('reduced', 'NegReg', (62, 69))
263702	32194861	The opposite effect of m6A methylation in glioblastoma was observed in other studies.	('glioblastoma', 'Disease', (42, 54))	('glioblastoma', 'Phenotype', 'HP:0012174', (42, 54))	('m6A', 'Var', (23, 26))	('glioblastoma', 'Disease', 'MESH:D005909', (42, 54))
263704	32194861	This is evidenced by knockdown of METTL3 and METTL14 and subsequent increase in several oncogenes (ADAM19, EPHA3, and KLF4) and a decrease in tumor suppressor genes (CDKN2A, BRCA2, and TP53I11).	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('CDKN2A', 'Gene', '1029', (166, 172))	('ADAM19', 'Gene', '8728', (99, 105))	('knockdown', 'Var', (21, 30))	('ADAM19', 'Gene', (99, 105))	('EPHA3', 'Gene', (107, 112))	('increase', 'PosReg', (68, 76))	('BRCA2', 'Gene', (174, 179))	('KLF4', 'Gene', (118, 122))	('METTL3', 'Gene', (34, 40))	('EPHA3', 'Gene', '2042', (107, 112))	('tumor', 'Disease', (142, 147))	('decrease', 'NegReg', (130, 138))	('TP53I11', 'Gene', (185, 192))	('TP53I11', 'Gene', '9537', (185, 192))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('CDKN2A', 'Gene', (166, 172))	('BRCA2', 'Gene', '675', (174, 179))	('METTL14', 'Gene', (45, 52))	('KLF4', 'Gene', '9314', (118, 122))
263706	32194861	ALKBH5 mediated the cancer progression and stemness behavior of GSCs through demethylation of the transcription factor FOXM1 nascent transcripts, thus increasing FOXM1 expression.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('ALKBH5', 'Gene', (0, 6))	('FOXM1', 'Gene', '2305', (162, 167))	('expression', 'MPA', (168, 178))	('C', 'Chemical', 'MESH:D003596', (66, 67))	('demethylation', 'Var', (77, 90))	('cancer', 'Disease', 'MESH:D009369', (20, 26))	('stemness behavior', 'Disease', 'MESH:D020295', (43, 60))	('increasing', 'PosReg', (151, 161))	('FOXM1', 'Gene', (119, 124))	('cancer', 'Disease', (20, 26))	('stemness behavior', 'Disease', (43, 60))	('FOXM1', 'Gene', '2305', (119, 124))	('ALKBH5', 'Gene', '54890', (0, 6))	('FOXM1', 'Gene', (162, 167))
263710	32194861	Inhibition of ALKBH5 expression can be a potential therapeutic strategy to downregulate the NANOG expression and block the recurrence of breast cancer by BCSCs.	('breast cancer', 'Disease', 'MESH:D001943', (137, 150))	('ALKBH5', 'Gene', (14, 20))	('breast cancer', 'Phenotype', 'HP:0003002', (137, 150))	('breast cancer', 'Disease', (137, 150))	('NANOG', 'Gene', (92, 97))	('rat', 'Species', '10116', (65, 68))	('downregulate', 'NegReg', (75, 87))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('recurrence', 'CPA', (123, 133))	('C', 'Chemical', 'MESH:D003596', (155, 156))	('Inhibition', 'Var', (0, 10))	('C', 'Chemical', 'MESH:D003596', (157, 158))	('ALKBH5', 'Gene', '54890', (14, 20))	('NANOG', 'Gene', '79923', (92, 97))	('block', 'NegReg', (113, 118))
263715	32194861	The m5C and pseudouridine modifications in mRNA are also reported to be associated with pluripotency of the mammalian cells.	('mammalian', 'Species', '9606', (108, 117))	('pseudouridine', 'Chemical', 'MESH:D011560', (12, 25))	('pseudouridine modifications', 'Var', (12, 39))	('associated', 'Reg', (72, 82))	('pluripotency of the mammalian cells', 'MPA', (88, 123))	('mRNA', 'Gene', (43, 47))	('N', 'Chemical', 'MESH:D009584', (45, 46))	('m5C', 'Chemical', '-', (4, 7))	('m5C', 'Var', (4, 7))
263724	32194861	Impaired PUS7 function retards ESC differentiation and promotes malignant transformation to generate aggressive acute myeloid leukemia (AML) stem cells.	('retards', 'Disease', (23, 30))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (112, 134))	('PUS7', 'Gene', (9, 13))	('leukemia', 'Phenotype', 'HP:0001909', (126, 134))	('ESC differentiation', 'CPA', (31, 50))	('promotes', 'PosReg', (55, 63))	('PUS7', 'Gene', '54517', (9, 13))	('retards', 'Disease', 'MESH:D008607', (23, 30))	('aggressive acute myeloid leukemia', 'Disease', (101, 134))	('AML', 'Disease', 'MESH:D015470', (136, 139))	('aggressive acute myeloid leukemia', 'Disease', 'MESH:D015470', (101, 134))	('C', 'Chemical', 'MESH:D003596', (33, 34))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (118, 134))	('rat', 'Species', '10116', (96, 99))	('malignant transformation', 'CPA', (64, 88))	('Impaired', 'Var', (0, 8))	('AML', 'Disease', (136, 139))
263731	32194861	The approaches for targeting the RNA modification machinery as anticancer drug targets are still in its infancy and most of the effort is focused mainly on the proteins involved in RNA methylations (methyltransferases, demethylators and other RNA binding proteins).	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('cancer', 'Disease', (67, 73))	('N', 'Chemical', 'MESH:D009584', (34, 35))	('N', 'Chemical', 'MESH:D009584', (182, 183))	('demethylators', 'Var', (219, 232))	('N', 'Chemical', 'MESH:D009584', (244, 245))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))
263734	32194861	The methyltransferases responsible for m6A, m1A, m5C, m7G and other methylations fall under Class I category which is the largest among all other groups.	('m5C', 'Var', (49, 52))	('methyltransferases', 'Enzyme', (4, 22))	('fall', 'Phenotype', 'HP:0002527', (81, 85))	('responsible', 'Reg', (23, 34))	('C', 'Chemical', 'MESH:D003596', (51, 52))	('m6A', 'Var', (39, 42))	('m7G', 'Var', (54, 57))	('C', 'Chemical', 'MESH:D003596', (92, 93))	('m1A', 'Var', (44, 47))	('m1A', 'Chemical', '-', (44, 47))	('m5C', 'Chemical', '-', (49, 52))
263751	32194861	Since the RNA modifying enzymes can incorporate modifications in both coding and non-coding RNA moieties, many of these modifications contribute to additional binding capabilities with diverse cellular components expanding their arrays of regulation.	('modifications', 'Var', (48, 61))	('rat', 'Species', '10116', (43, 46))	('binding', 'Interaction', (159, 166))	('N', 'Chemical', 'MESH:D009584', (11, 12))	('N', 'Chemical', 'MESH:D009584', (93, 94))	('modifications', 'Var', (120, 133))
263752	32194861	In addition to their roles in regulating normal cellular processes, RNA modifications are also found to play roles in carcinogenesis and confer stemness to the cancerous cell sub populations.	('carcinogenesis', 'Disease', (118, 132))	('modifications', 'Var', (72, 85))	('stemness to the cancerous', 'Disease', (144, 169))	('carcinogenesis', 'Disease', 'MESH:D063646', (118, 132))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('N', 'Chemical', 'MESH:D009584', (69, 70))	('play roles', 'Reg', (104, 114))	('stemness to the cancerous', 'Disease', 'MESH:D009369', (144, 169))
263753	32194861	On one hand, RNA modifications can contribute to cancer progression by decreasing the stability of the suppressors of the oncogenes thereby eliminating their inhibitory effects, on the other hand they can enhance the stability and expression of the protooncogenic transcripts.	('modifications', 'Var', (17, 30))	('stability', 'MPA', (217, 226))	('decreasing', 'NegReg', (71, 81))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('inhibitory effects', 'MPA', (158, 176))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('stability', 'MPA', (86, 95))	('enhance', 'PosReg', (205, 212))	('eliminating', 'NegReg', (140, 151))	('N', 'Chemical', 'MESH:D009584', (14, 15))	('expression', 'MPA', (231, 241))	('cancer', 'Disease', (49, 55))
263755	32194861	In many cases the oncogenic effects of the RNA modifications are due to incorporation of the modified nucleotides in the non-coding RNAs such as miRs and lncRNAs affecting their binding interactions with the target mRNA transcripts.	('N', 'Chemical', 'MESH:D009584', (133, 134))	('N', 'Chemical', 'MESH:D009584', (44, 45))	('affecting', 'Reg', (162, 171))	('N', 'Chemical', 'MESH:D009584', (158, 159))	('N', 'Chemical', 'MESH:D009584', (217, 218))	('modified', 'Var', (93, 101))	('miR', 'Gene', '220972', (145, 148))	('binding interactions', 'Interaction', (178, 198))	('miR', 'Gene', (145, 148))	('rat', 'Species', '10116', (79, 82))	('modifications', 'Var', (47, 60))
263756	32194861	These modifications may increase or decrease their binding affinity with specific sequence motifs on the target mRNAs which may determine their stability or contribute to their transcriptional activation/ repression contributing to tumorigenesis and/or stemness.	('N', 'Chemical', 'MESH:D009584', (114, 115))	('modifications', 'Var', (6, 19))	('increase', 'PosReg', (24, 32))	('stability', 'MPA', (144, 153))	('stemness', 'CPA', (253, 261))	('repression', 'NegReg', (205, 215))	('transcriptional', 'MPA', (177, 192))	('tumor', 'Disease', 'MESH:D009369', (232, 237))	('determine', 'Reg', (128, 137))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('contribute', 'Reg', (157, 167))	('activation/', 'PosReg', (193, 204))	('binding affinity', 'Interaction', (51, 67))	('tumor', 'Disease', (232, 237))	('decrease', 'NegReg', (36, 44))
263761	32194861	Another big challenge in this field is that, the occurrence and contributions of many of the modifications in cancers although identified, their molecular targets in pathogenesis of cancers are yet to be revealed.	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('cancers', 'Disease', (110, 117))	('modifications', 'Var', (93, 106))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('cancers', 'Phenotype', 'HP:0002664', (182, 189))	('cancers', 'Disease', (182, 189))	('cancers', 'Phenotype', 'HP:0002664', (110, 117))	('cancers', 'Disease', 'MESH:D009369', (182, 189))	('cancers', 'Disease', 'MESH:D009369', (110, 117))
263819	30557376	In these two models, both personal history of cancer and family history of lung cancer are regarded as important risk factors of IPLC.These results suggest that some cancer-related genetic driver mutations seemingly play an important role in the tumorigenesis and progression of lung cancer.	('lung cancer', 'Phenotype', 'HP:0100526', (75, 86))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('cancer', 'Disease', 'MESH:D009369', (284, 290))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('cancer', 'Disease', (80, 86))	('lung cancer', 'Disease', 'MESH:D008175', (279, 290))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('lung cancer', 'Phenotype', 'HP:0100526', (279, 290))	('lung cancer', 'Disease', (75, 86))	('cancer', 'Disease', (166, 172))	('cancer', 'Disease', (46, 52))	('cancer', 'Disease', (284, 290))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('tumor', 'Disease', (246, 251))	('cancer', 'Phenotype', 'HP:0002664', (284, 290))	('mutations', 'Var', (196, 205))	('tumor', 'Disease', 'MESH:D009369', (246, 251))	('lung cancer', 'Disease', (279, 290))	('lung cancer', 'Disease', 'MESH:D008175', (75, 86))
263826	30557376	The participants whose histology were malignant neoplasm(8000/3), or malignant tumor cell (8001/3),carcinoma (8010/3), or non small cell lung cancer (8046/3) were not incorporated into this study.	('non small cell lung cancer', 'Disease', 'MESH:D002289', (122, 148))	('malignant tumor', 'Disease', (69, 84))	('malignant neoplasm', 'Disease', 'MESH:D009369', (38, 56))	('lung cancer', 'Phenotype', 'HP:0100526', (137, 148))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('neoplasm', 'Phenotype', 'HP:0002664', (48, 56))	('participants', 'Species', '9606', (4, 16))	('non small cell lung cancer', 'Disease', (122, 148))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (126, 148))	('malignant tumor', 'Disease', 'MESH:D018198', (69, 84))	('carcinoma', 'Disease', 'MESH:D002277', (99, 108))	('non small cell lung cancer', 'Phenotype', 'HP:0030358', (122, 148))	('malignant neoplasm', 'Disease', (38, 56))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('8001/3', 'Var', (91, 97))	('carcinoma', 'Disease', (99, 108))	('8010/3', 'Var', (110, 116))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
263876	30557376	Whether neuroendocrine-related driver mutations regulate the development of metachronous SPLC with the histology of squamous cell carcinoma and adenocarcinoma deserves further investigation.	('carcinoma', 'Phenotype', 'HP:0030731', (149, 158))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (116, 139))	('adenocarcinoma', 'Disease', (144, 158))	('adenocarcinoma', 'Disease', 'MESH:D000230', (144, 158))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (116, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('squamous cell carcinoma', 'Disease', (116, 139))	('regulate', 'Reg', (48, 56))	('mutations', 'Var', (38, 47))
263894	27041574	PRR14 is a novel activator of the PI3K pathway promoting lung carcinogenesis Chromosomal focal amplifications often cause an increase in gene copy number contributing to the pathogenesis of cancer.	('cancer', 'Disease', (190, 196))	('cancer', 'Disease', 'MESH:D009369', (190, 196))	('increase', 'PosReg', (125, 133))	('Chromosomal focal amplifications', 'Var', (77, 109))	('PRR14', 'Gene', '78994', (0, 5))	('PRR14', 'Gene', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('gene copy number', 'MPA', (137, 153))	('lung carcinogenesis', 'Disease', (57, 76))	('lung carcinogenesis', 'Disease', 'MESH:D063646', (57, 76))
263899	27041574	Significantly, 2 cancer patient-derived PRR14 mutants displayed considerably augmented GRB2-binding and enhanced ability of promoting cell proliferation.	('cell proliferation', 'CPA', (134, 152))	('promoting', 'PosReg', (124, 133))	('GRB2', 'Gene', '2885', (87, 91))	('PRR14', 'Gene', (40, 45))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('enhanced', 'PosReg', (104, 112))	('patient', 'Species', '9606', (24, 31))	('cancer', 'Disease', (17, 23))	('mutants', 'Var', (46, 53))	('GRB2', 'Gene', (87, 91))	('augmented', 'PosReg', (77, 86))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
263900	27041574	Together with the in vivo data demonstrating a strong tumor-promoting activity of PRR14 and the mutants, our work uncovered this proline-rich protein as a novel activator of the PI3K pathway that promoted tumorigenesis in lung cancer.	('proline-rich protein', 'Gene', '722', (129, 149))	('lung cancer', 'Disease', (222, 233))	('PRR14', 'Gene', (82, 87))	('PI3', 'Gene', '5266', (178, 181))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('lung cancer', 'Phenotype', 'HP:0100526', (222, 233))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('proline-rich protein', 'Gene', (129, 149))	('promoted', 'PosReg', (196, 204))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumor', 'Disease', (205, 210))	('PI3', 'Gene', (178, 181))	('lung cancer', 'Disease', 'MESH:D008175', (222, 233))	('tumor', 'Disease', (54, 59))	('mutants', 'Var', (96, 103))
263908	27041574	Indeed, mTOR phosphorylation increased with the malignant progression and blocking mTOR was sufficient to block lung tumor progression.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('mTOR', 'Gene', (83, 87))	('phosphorylation', 'MPA', (13, 28))	('block lung tumor', 'Disease', 'MESH:D008175', (106, 122))	('mTOR', 'Gene', '2475', (8, 12))	('increased', 'PosReg', (29, 38))	('mTOR', 'Gene', (8, 12))	('block lung tumor', 'Disease', (106, 122))	('lung tumor', 'Phenotype', 'HP:0100526', (112, 122))	('blocking', 'Var', (74, 82))	('mTOR', 'Gene', '2475', (83, 87))
263913	27041574	Data mining from TCGA (The Cancer Genome Atlas) shows consistent copy number increase in lung cancer (Fig 1 A), which correlates with significantly enhanced PRR14 transcription in both adenocarcinoma and squamous cell carcinoma (Fig 1 B).	('carcinoma', 'Phenotype', 'HP:0030731', (190, 199))	('lung cancer', 'Disease', (89, 100))	('adenocarcinoma and squamous cell carcinoma', 'Disease', 'MESH:D002294', (185, 227))	('lung cancer', 'Phenotype', 'HP:0100526', (89, 100))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (204, 227))	('PRR14', 'Gene', (157, 162))	('carcinoma', 'Phenotype', 'HP:0030731', (218, 227))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('Cancer Genome Atlas', 'Disease', (27, 46))	('enhanced', 'PosReg', (148, 156))	('transcription', 'MPA', (163, 176))	('increase', 'PosReg', (77, 85))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (27, 46))	('Cancer', 'Phenotype', 'HP:0002664', (27, 33))	('lung cancer', 'Disease', 'MESH:D008175', (89, 100))	('copy number', 'Var', (65, 76))
263916	27041574	The high expression of PRR14 in lung cancer cases significantly associates with worse 5 year survival in all lung cancers (SCLC, LUSC and LUAD) (p=0.05) especially LUAD (p=0.0043) and LUSC (p=0.02) (Fig 1 D).	('cancers', 'Phenotype', 'HP:0002664', (114, 121))	('LUAD', 'Disease', (164, 168))	('LUSC', 'Phenotype', 'HP:0030359', (184, 188))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('SCLC', 'Phenotype', 'HP:0030357', (123, 127))	('lung cancer', 'Disease', 'MESH:D008175', (32, 43))	('SCLC', 'Gene', (123, 127))	('SCLC', 'Gene', '7864', (123, 127))	('lung cancer', 'Phenotype', 'HP:0100526', (32, 43))	('lung cancers', 'Disease', 'MESH:D008175', (109, 121))	('lung cancer', 'Disease', 'MESH:D008175', (109, 120))	('high', 'Var', (4, 8))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('lung cancers', 'Disease', (109, 121))	('lung cancer', 'Phenotype', 'HP:0100526', (109, 120))	('PRR14', 'Gene', (23, 28))	('LUAD', 'Phenotype', 'HP:0030078', (164, 168))	('lung cancers', 'Phenotype', 'HP:0100526', (109, 121))	('LUAD', 'Phenotype', 'HP:0030078', (138, 142))	('LUSC', 'Disease', (184, 188))	('LUSC', 'Phenotype', 'HP:0030359', (129, 133))	('worse', 'NegReg', (80, 85))	('lung cancer', 'Disease', (32, 43))
263919	27041574	The high-PRR14 expression level associated with increased gene expression in both LUAD and LUSC types of cancer.	('increased', 'PosReg', (48, 57))	('high-PRR14', 'Var', (4, 14))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('gene expression', 'MPA', (58, 73))	('expression', 'MPA', (15, 25))	('LUSC', 'Phenotype', 'HP:0030359', (91, 95))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('LUAD', 'Disease', (82, 86))	('LUAD', 'Phenotype', 'HP:0030078', (82, 86))
263937	27041574	It has been shown that the PI3K inhibitor LY294002 alone rendered cells with highly activated Akt more sensitive to apoptosis and growth inhibition.	('more', 'PosReg', (98, 102))	('Akt', 'Gene', (94, 97))	('LY294002', 'Var', (42, 50))	('PI3', 'Gene', '5266', (27, 30))	('sensitive', 'MPA', (103, 112))	('LY294002', 'Chemical', 'MESH:C085911', (42, 50))	('Akt', 'Gene', '207', (94, 97))	('PI3', 'Gene', (27, 30))
263938	27041574	We assessed the contribution of PI3K/Akt/mTOR to PRR14-mediated cell proliferation by treating cells with 10uM LY294002.	('Akt', 'Gene', '207', (37, 40))	('PI3', 'Gene', (32, 35))	('LY294002', 'Var', (111, 119))	('Akt', 'Gene', (37, 40))	('PI3', 'Gene', '5266', (32, 35))	('LY294002', 'Chemical', 'MESH:C085911', (111, 119))	('mTOR', 'Gene', (41, 45))	('mTOR', 'Gene', '2475', (41, 45))
263939	27041574	The PRR14 over-expressing cells were considerably more sensitive to LY294002-induced inhibition of cell proliferation (Fig 5 B).	('cell proliferation', 'CPA', (99, 117))	('LY294002', 'Chemical', 'MESH:C085911', (68, 76))	('PRR14', 'Gene', (4, 9))	('inhibition', 'NegReg', (85, 95))	('over-expressing', 'PosReg', (10, 25))	('LY294002-induced', 'Var', (68, 84))	('more', 'PosReg', (50, 54))
263940	27041574	To complement with the treatment with LY294002, we treated cells with two additional inhibitors, Torin2 (Fig 5 C) and U0126 (Fig 5 D).	('Torin', 'Gene', '7001', (97, 102))	('U0126', 'Var', (118, 123))	('Torin', 'Gene', (97, 102))	('U0126', 'Chemical', 'MESH:C113580', (118, 123))	('LY294002', 'Chemical', 'MESH:C085911', (38, 46))
263941	27041574	Consistently, PRR14 showed a heightened sensitivity to PI3K/Akt/mTOR signal pathway inhibitors, LY294002 and Torin2.	('PI3', 'Gene', (55, 58))	('LY294002', 'Var', (96, 104))	('Akt', 'Gene', '207', (60, 63))	('mTOR', 'Gene', (64, 68))	('Torin', 'Gene', (109, 114))	('Akt', 'Gene', (60, 63))	('heightened', 'PosReg', (29, 39))	('PI3', 'Gene', '5266', (55, 58))	('Torin', 'Gene', '7001', (109, 114))	('PRR14', 'Gene', (14, 19))	('mTOR', 'Gene', '2475', (64, 68))	('LY294002', 'Chemical', 'MESH:C085911', (96, 104))	('sensitivity', 'MPA', (40, 51))
263942	27041574	Of note, the cells did not show significantly different sensitivity to U0126 treatment (Fig 5 D), indicative of an effect specific to the PI3K/Akt/mTOR signaling pathway.	('U0126', 'Var', (71, 76))	('U0126', 'Chemical', 'MESH:C113580', (71, 76))	('Akt', 'Gene', '207', (143, 146))	('PI3', 'Gene', '5266', (138, 141))	('Akt', 'Gene', (143, 146))	('mTOR', 'Gene', '2475', (147, 151))	('mTOR', 'Gene', (147, 151))	('PI3', 'Gene', (138, 141))
263944	27041574	To explore how PRR14 activated Ras as well as PI3K, we focused on GRB2, a protein functioning upstream of both.	('PI3', 'Gene', (46, 49))	('GRB2', 'Gene', '2885', (66, 70))	('PRR14', 'Var', (15, 20))	('PI3', 'Gene', '5266', (46, 49))	('GRB2', 'Gene', (66, 70))
263949	27041574	We generated GST-fusion proteins of full-length, N-terminal SH3, middle part SH2, or C-terminal SH3 of GRB2 (Fig 6 A).	('GRB2', 'Gene', (103, 107))	('GRB2', 'Gene', '2885', (103, 107))	('N-terminal', 'Var', (49, 59))	('C-terminal SH3', 'Var', (85, 99))
263953	27041574	We next asked whether the binding of PRR14 to GRB2 mediated its stimulation of Akt/mTOR activity.	('GRB2', 'Gene', (46, 50))	('stimulation', 'PosReg', (64, 75))	('mTOR', 'Gene', (83, 87))	('GRB2', 'Gene', '2885', (46, 50))	('Akt', 'Gene', '207', (79, 82))	('PRR14', 'Var', (37, 42))	('binding', 'Interaction', (26, 33))	('Akt', 'Gene', (79, 82))	('mTOR', 'Gene', '2475', (83, 87))
263959	27041574	We compared the mutants with wild-type PRR14 for their ability to bind to GRB2.	('bind', 'Interaction', (66, 70))	('GRB2', 'Gene', (74, 78))	('GRB2', 'Gene', '2885', (74, 78))	('mutants', 'Var', (16, 23))
263960	27041574	As a consequence to this increased GRB2-binding, these 2 PRR14 mutants displayed a significantly greater potential of enhancing Ras (Fig 7 C, D) and AKT activity (Fig 7 E, F) than the wild-type counterpart.	('GRB2', 'Gene', (35, 39))	('PRR14', 'Gene', (57, 62))	('mutants', 'Var', (63, 70))	('increased', 'PosReg', (25, 34))	('AKT', 'Gene', (149, 152))	('GRB2', 'Gene', '2885', (35, 39))	('Ras', 'CPA', (128, 131))	('enhancing', 'PosReg', (118, 127))	('AKT', 'Gene', '207', (149, 152))
263961	27041574	At a comparable expression level (Fig 7 G), these 2 mutants induced a greater increase in cell proliferation (Fig 7 H) and colony formation (Fig 7 I) than wild-type PRR14, indicating an augmented ability of these 2 PRR14 mutants in promoting cancer formation.	('cancer', 'Disease', (242, 248))	('cancer', 'Disease', 'MESH:D009369', (242, 248))	('PRR14', 'Gene', (215, 220))	('cell proliferation', 'CPA', (90, 108))	('mutants', 'Var', (52, 59))	('augmented', 'PosReg', (186, 195))	('increase', 'PosReg', (78, 86))	('mutants', 'Var', (221, 228))	('colony formation', 'CPA', (123, 139))	('promoting', 'PosReg', (232, 241))	('cancer', 'Phenotype', 'HP:0002664', (242, 248))
263967	27041574	Consistent with the in vitro data, proline-rich domain of PRR14 itself is sufficient to promote tumor formation in mice (Fig 8 F, G).	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('proline-rich domain', 'Var', (35, 54))	('promote', 'PosReg', (88, 95))	('tumor', 'Disease', (96, 101))	('proline', 'Chemical', 'MESH:D011392', (35, 42))	('PRR14', 'Gene', (58, 63))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('mice', 'Species', '10090', (115, 119))
263968	27041574	We also tested the tumorigenicity of the 2 PRR14 mutants that exhibited an enhanced ability of stimulating cell proliferation.	('tested', 'Reg', (8, 14))	('enhanced', 'PosReg', (75, 83))	('PRR14', 'Gene', (43, 48))	('mutants', 'Var', (49, 56))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('cell proliferation', 'CPA', (107, 125))	('tumor', 'Disease', (19, 24))
263969	27041574	H1299 M1 (Fig 8 H) or H1299 M2 (Fig 8 J) cells, together with wild-type PRR14 expressing H1299 cells, were subcutaneously injected into nude mice to induce tumor formation.	('H1299', 'Var', (22, 27))	('H1299 M1', 'CellLine', 'CVCL:0060', (0, 8))	('H1299 M2', 'CellLine', 'CVCL:0060', (22, 30))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('H1299', 'Var', (0, 5))	('H1299', 'CellLine', 'CVCL:0060', (22, 27))	('nude mice', 'Species', '10090', (136, 145))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('H1299', 'CellLine', 'CVCL:0060', (89, 94))	('tumor', 'Disease', (156, 161))	('H1299', 'CellLine', 'CVCL:0060', (0, 5))
263970	27041574	In agreement with the in vitro data, both PRR14 mutants showed greater tumorigenicity than wild-type PRR14.	('mutants', 'Var', (48, 55))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('greater', 'PosReg', (63, 70))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('PRR14', 'Gene', (42, 47))	('tumor', 'Disease', (71, 76))
263979	27041574	Of interest is that we also identified two PRR14 mutations from cancer patients, one in proline-rich region and the other at PRR14's C-terminal.	('proline', 'Chemical', 'MESH:D011392', (88, 95))	('mutations', 'Var', (49, 58))	('PRR14', 'Gene', (43, 48))	('patients', 'Species', '9606', (71, 79))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
263980	27041574	These two mutations enhance PRR14's ability to interact with GRB2, and consequently further stimulate its activity.	('stimulate', 'PosReg', (92, 101))	('ability', 'MPA', (36, 43))	('enhance', 'PosReg', (20, 27))	('GRB2', 'Gene', '2885', (61, 65))	('activity', 'MPA', (106, 114))	('GRB2', 'Gene', (61, 65))	('PRR14', 'Gene', (28, 33))	('mutations', 'Var', (10, 19))	('interact', 'Interaction', (47, 55))
263981	27041574	While it is unclear why the mutations at such distinct sites caused a similar increase in GRB2-binding, the data suggests that the conformation of PRR14 protein is very critical for its interaction with GRB2.	('GRB2', 'Gene', (90, 94))	('GRB2', 'Gene', '2885', (203, 207))	('protein', 'Protein', (153, 160))	('increase', 'PosReg', (78, 86))	('GRB2', 'Gene', '2885', (90, 94))	('interaction', 'Interaction', (186, 197))	('PRR14', 'Gene', (147, 152))	('GRB2', 'Gene', (203, 207))	('mutations', 'Var', (28, 37))
263988	27041574	siRNA (SASI_Hs01_00196781, SASI_Hs01_00196782, SASI_Hs01_00196783, Sigma) transfection was mediated by Lipofectamine  RNAiMAX Transfection Reagent (Invitrogen).	('Lipofectamine', 'Chemical', 'MESH:C086724', (103, 116))	('Sigma', 'MPA', (67, 72))	('SASI_Hs01_00196783', 'Var', (47, 65))	('transfection', 'MPA', (74, 86))	('SASI_Hs01_00196781', 'Var', (7, 25))
264075	28418897	N2-3 was a risk factor for OS and PFS in the univariate analysis, but not significant in the multivariate analysis, which can be explained by small number of patients.	('patients', 'Species', '9606', (158, 166))	('N2-3', 'Var', (0, 4))	('PFS', 'Disease', (34, 37))
264076	28418897	But it cannot be totally eliminated that the chemotherapy adapted in current study improved the survival of patients with N2-3 so that the survival difference between N0-1 and N2-3 become too small to be tested in multivariate analysis.	('patients', 'Species', '9606', (108, 116))	('N2-3', 'Var', (122, 126))	('improved', 'PosReg', (83, 91))	('survival', 'MPA', (96, 104))
264111	30847302	Of note, P. gingivalis is now accepted as a risk factor of cancer such as oral squamous cell carcinoma (OSCC), the most common type of head and neck squamous cell carcinoma (HNSCC).	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (79, 102))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (149, 172))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (135, 172))	('carcinoma', 'Phenotype', 'HP:0030731', (163, 172))	('neck squamous cell carcinoma', 'Disease', (144, 172))	('oral squamous cell carcinoma', 'Disease', (74, 102))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (144, 172))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('P. gingivalis', 'Var', (9, 22))	('P. gingivalis', 'Species', '837', (9, 22))	('cancer', 'Disease', (59, 65))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (74, 102))	('HNSCC', 'Phenotype', 'HP:0012288', (174, 179))
264115	30847302	Furthermore, we reported the promoting effect of chronic infection by P. gingivalis on cellular morphology, cell proliferation, migration and invasion of HIOECs.	('chronic infection', 'Disease', 'MESH:D006505', (49, 66))	('chronic infection', 'Phenotype', 'HP:0031035', (49, 66))	('migration', 'CPA', (128, 137))	('chronic infection', 'Disease', (49, 66))	('P. gingivalis', 'Var', (70, 83))	('promoting effect', 'PosReg', (29, 45))	('cellular morphology', 'CPA', (87, 106))	('P. gingivalis', 'Species', '837', (70, 83))	('cell proliferation', 'CPA', (108, 126))	('invasion', 'CPA', (142, 150))
264116	30847302	Also, using microarray analysis and relevant validation of changes in expression, we identified genes that may be involved in the tumorigenic-like transformation of HIOECs induced by P. gingivalis.	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('involved', 'Reg', (114, 122))	('HIOECs', 'Disease', (165, 171))	('P. gingivalis', 'Species', '837', (183, 196))	('P. gingivalis', 'Var', (183, 196))	('tumor', 'Disease', (130, 135))
264126	30847302	When the HIOECs infected by P. gingivalis showed significantly increased tumorigenic properties after 15 weeks, the total RNA of non-infected HIOECs and infected HIOECs was extracted with an RNAiso Plus kit (TaKaRa, Dalian, China).	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('increased', 'PosReg', (63, 72))	('P. gingivalis', 'Var', (28, 41))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('P. gingivalis', 'Species', '837', (28, 41))	('tumor', 'Disease', (73, 78))
264146	30847302	To be consistent with a previous study, CD274 and PDCD1LG2 are shown as B7H1 and B7DC, respectively, in Figure 8.	('B7H1', 'CellLine', 'CVCL:0I14', (72, 76))	('CD274', 'Var', (40, 45))	('PDCD1LG2', 'Gene', (50, 58))
264153	30847302	To date, several studies have reported the promoting effects of P. gingivalis on OSCC initiation and progression.	('OSCC', 'Disease', (81, 85))	('promoting', 'PosReg', (43, 52))	('P. gingivalis', 'Species', '837', (64, 77))	('P. gingivalis', 'Var', (64, 77))	('progression', 'CPA', (101, 112))
264180	30847302	The presence of LYN kinase in the tumor microenvironment was regarded as a key component for tumor progression.	('tumor', 'Disease', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Disease', (93, 98))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('presence', 'Var', (4, 12))	('LYN', 'Protein', (16, 19))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
264185	30847302	Taken together, we hypothesized that chronic infection by P. gingivalis contributed to an immunosuppressive microenvironment by targeting CD274 and PDCD1LG2 through the activation of STAT1.	('activation', 'PosReg', (169, 179))	('STAT1', 'MPA', (183, 188))	('P. gingivalis', 'Species', '837', (58, 71))	('P. gingivalis', 'Var', (58, 71))	('chronic infection', 'Disease', 'MESH:D006505', (37, 54))	('chronic infection', 'Phenotype', 'HP:0031035', (37, 54))	('CD274', 'Gene', (138, 143))	('PDCD1LG2', 'Gene', (148, 156))	('immunosuppressive microenvironment', 'MPA', (90, 124))	('targeting', 'Reg', (128, 137))	('chronic infection', 'Disease', (37, 54))
264205	30847302	However, similar to the present cellular model, chemokines such as CXCL9, CXCL10, CXCL11 secreted in an autocrine manner by tumor cells were considered to contribute to a pro-tumoral microenvironment.	('tumor', 'Disease', (175, 180))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('tumor', 'Disease', (124, 129))	('CXCL11', 'Var', (82, 88))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('CXCL10', 'MPA', (74, 80))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
264208	30847302	As reported previously, CXCL10 was associated with tumor cell motility and metastasis in various type of cancer.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('type of cancer', 'Disease', 'MESH:D009369', (97, 111))	('CXCL10', 'Var', (24, 30))	('associated', 'Reg', (35, 45))	('tumor', 'Disease', (51, 56))	('metastasis', 'CPA', (75, 85))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('type of cancer', 'Disease', (97, 111))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
264230	25997063	Among all these extrapulmonary carcinomas, 93.7% of adenocarcinomas exhibited TFF3 positivity, whereas only 2.9% of squamous cell carcinomas were TFF3-positive.	('carcinoma', 'Phenotype', 'HP:0030731', (57, 66))	('carcinomas', 'Phenotype', 'HP:0030731', (57, 67))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (116, 140))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (116, 139))	('adenocarcinomas', 'Disease', 'MESH:D000230', (52, 67))	('extrapulmonary carcinomas', 'Disease', (16, 41))	('adenocarcinomas', 'Disease', (52, 67))	('extrapulmonary carcinomas', 'Phenotype', 'HP:0032271', (16, 41))	('TFF3', 'Gene', (78, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (31, 40))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (116, 140))	('carcinomas', 'Phenotype', 'HP:0030731', (31, 41))	('TFF3', 'Gene', '7033', (78, 82))	('positivity', 'Var', (83, 93))	('squamous cell carcinomas', 'Disease', (116, 140))	('extrapulmonary carcinomas', 'Disease', 'MESH:D002277', (16, 41))	('TFF3', 'Gene', (146, 150))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('carcinomas', 'Phenotype', 'HP:0030731', (130, 140))	('TFF3', 'Gene', '7033', (146, 150))
264231	25997063	Totally, 92.9% of both pulmonary and extrapulmonary adenocarcinomas exhibited TFF3 positivity, whereas only 1.5% of squamous cell carcinomas were TFF3-positive.	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (116, 140))	('squamous cell carcinomas', 'Disease', (116, 140))	('TFF3', 'Gene', '7033', (78, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (57, 66))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (116, 140))	('carcinomas', 'Phenotype', 'HP:0030731', (130, 140))	('TFF3', 'Gene', (146, 150))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (116, 139))	('adenocarcinomas', 'Disease', 'MESH:D000230', (52, 67))	('positivity', 'Var', (83, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('adenocarcinomas', 'Disease', (52, 67))	('carcinomas', 'Phenotype', 'HP:0030731', (57, 67))	('exhibited', 'Reg', (68, 77))	('TFF3', 'Gene', (78, 82))	('TFF3', 'Gene', '7033', (146, 150))
264296	25997063	We next examined the mRNA levels of TFF3 by qPCR in 16 NSCLC cell lines, 11 of which have been reported to be derived from lung ADC, 4 of which have been reported to be derived from lung SCC and 1 of which has been reported to be derived from lung ASC.	('TFF3', 'Gene', '7033', (36, 40))	('NSCLC', 'Disease', (55, 60))	('SCC', 'Gene', (187, 190))	('NSCLC', 'Disease', 'MESH:D002289', (55, 60))	('SCC', 'Phenotype', 'HP:0002860', (187, 190))	('SCC', 'Gene', '6317', (187, 190))	('qPCR', 'Var', (44, 48))	('NSCLC', 'Phenotype', 'HP:0030358', (55, 60))	('TFF3', 'Gene', (36, 40))
264299	25997063	The mRNAs of the 4 markers of the squamous lineage (KRT5, KRT6A, KRT6B, and TP63) were all highly expressed in the NSCLC lines identified to be of squamous origin (H697, H1270, LC-1/sq, and LC-1F) and adenosquamous origin (H596) (Figure 2A, Supplemental Digital Content 3, http://links.lww.com/MD/A268).	('H697', 'Var', (164, 168))	('TP63', 'Gene', (76, 80))	('KRT5', 'Gene', '3852', (52, 56))	('TP63', 'Gene', '8626', (76, 80))	('NSCLC', 'Phenotype', 'HP:0030358', (115, 120))	('H1270', 'Var', (170, 175))	('KRT6B', 'Gene', '3854', (65, 70))	('NSCLC', 'Disease', (115, 120))	('KRT6A', 'Gene', '3853', (58, 63))	('NSCLC', 'Disease', 'MESH:D002289', (115, 120))	('KRT5', 'Gene', (52, 56))	('H697', 'CellLine', 'CVCL:0079', (164, 168))	('H1270', 'CellLine', 'CVCL:9E87', (170, 175))	('KRT6B', 'Gene', (65, 70))	('KRT6A', 'Gene', (58, 63))
264306	25997063	siRNA-mediated depletion of TFF3 expression in NCI-H1975 or HCC-2935 cells resulted in decreased mRNA levels of TTF-1 relative to their vector control cells.	('depletion', 'Var', (15, 24))	('decreased', 'NegReg', (87, 96))	('NCI-H1975', 'CellLine', 'CVCL:1511', (47, 56))	('TFF3', 'Gene', (28, 32))	('TTF-1', 'Gene', '7080', (112, 117))	('TTF-1', 'Gene', (112, 117))	('HCC-2935', 'CellLine', 'CVCL:1265', (60, 68))	('TFF3', 'Gene', '7033', (28, 32))
264307	25997063	mRNA levels of KRT7 were slightly increased in NCI-H1975 and slightly decreased in HCC-2935 cells upon siRNA-mediated depletion of TFF3 (Figure 3A).	('TFF3', 'Gene', '7033', (131, 135))	('NCI-H1975', 'CellLine', 'CVCL:1511', (47, 56))	('depletion', 'MPA', (118, 127))	('decreased', 'NegReg', (70, 79))	('HCC-2935', 'CellLine', 'CVCL:1265', (83, 91))	('NCI-H1975', 'Var', (47, 56))	('TFF3', 'Gene', (131, 135))	('mRNA levels of', 'MPA', (0, 14))	('KRT7', 'Gene', '3855', (15, 19))	('increased', 'PosReg', (34, 43))	('KRT7', 'Gene', (15, 19))
264342	25997063	We observed a high frequency of TFF3 positivity in cervical ADC (31/35, 88.6%), esophageal ADC (19/20, 95%), colorectal ADC (29/29, 100%), and gastric ADC (25/27, 92.6%).	('TFF3', 'Gene', '7033', (32, 36))	('cervical ADC', 'Disease', (51, 63))	('esophageal ADC', 'Disease', (80, 94))	('gastric ADC', 'Disease', (143, 154))	('positivity', 'Var', (37, 47))	('TFF3', 'Gene', (32, 36))	('colorectal ADC', 'Disease', (109, 123))
264385	31848368	Tucker and his colleagues claimed that the risk of developing SPLC of the patients with chest radiotherapy was approximately two fold higher than those without chest radiotherapy in small cell lung cancer.	('chest radiotherapy', 'Var', (88, 106))	('small cell lung cancer', 'Disease', (182, 204))	('patients', 'Species', '9606', (74, 82))	('higher', 'PosReg', (134, 140))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('small cell lung cancer', 'Disease', 'MESH:D055752', (182, 204))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (182, 204))	('lung cancer', 'Phenotype', 'HP:0100526', (193, 204))
264393	31848368	The IPLC individual was not considered when a patient's histological characteristics were unclear and could not be classified into the aforementioned five categories, such as malignant neoplasm (8000/3), malignant tumor cell(8001/3), carcinoma(8010/3), etc.	('men', 'Species', '9606', (140, 143))	('patient', 'Species', '9606', (46, 53))	('8000/3', 'Var', (195, 201))	('carcinoma', 'Disease', (234, 243))	('neoplasm', 'Phenotype', 'HP:0002664', (185, 193))	('malignant tumor', 'Disease', (204, 219))	('carcinoma', 'Disease', 'MESH:D009369', (234, 243))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('malignant neoplasm', 'Disease', (175, 193))	('malignant tumor', 'Disease', 'MESH:D009369', (204, 219))	('carcinoma', 'Phenotype', 'HP:0030731', (234, 243))	('8001/3', 'Var', (225, 231))	('malignant neoplasm', 'Disease', 'MESH:D009369', (175, 193))
264416	31848368	On account of more early stage patients in the nonradiotherapy group, their survival time was significantly longer(HR = 0.33, 95% CI: 0.32-0.35, P < 0.001) than that in the radiotherapy group(see Fig.	('nonradiotherapy', 'Var', (47, 62))	('patients', 'Species', '9606', (31, 39))	('longer', 'PosReg', (108, 114))	('survival time', 'CPA', (76, 89))
264418	31848368	The estimated survival time was longer among patients with metachronous SPLC than that among patients without metachronous SPLC in the radiotherapy group(HR = 1.54, 95% CI:1.36-1.74, see Fig.	('longer', 'PosReg', (32, 38))	('metachronous SPLC', 'Var', (59, 76))	('survival time', 'CPA', (14, 27))	('patients', 'Species', '9606', (45, 53))	('patients', 'Species', '9606', (93, 101))
264421	31848368	When considering the competing risk of all cause death, the patients with radiotherapy still were associated with lower 5 year incidence of metachronous SPLC compared with those without radiotherapy (2.28% vs 4.47%, HR = 0.49, 95% CI:0.43-0.57).	('metachronous SPLC', 'Disease', (140, 157))	('radiotherapy', 'Var', (74, 86))	('patients', 'Species', '9606', (60, 68))	('lower', 'NegReg', (114, 119))	('death', 'Disease', 'MESH:D003643', (49, 54))	('death', 'Disease', (49, 54))
264430	31848368	Our study demonstrated that the 5-year incidence of small cell lung cancer in radiotherapy group was similar to that in non-radiotherapy group(3.1% vs 2.8%, sbHR = 0.87, 95% CI: 0.33-2.07).	('small cell lung cancer', 'Disease', 'MESH:D055752', (52, 74))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (52, 74))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('radiotherapy', 'Var', (78, 90))	('small cell lung cancer', 'Disease', (52, 74))	('lung cancer', 'Phenotype', 'HP:0100526', (63, 74))
264440	31848368	However, our study suggested that the risk of developing metachronous SPLC for IPLC patients with radiotherapy was lower compared with that of patients without radiotherapy in the first 5 years follow-up period, which was consistent with the study of Abdel-Rahman et al..	('lower', 'NegReg', (115, 120))	('patients', 'Species', '9606', (84, 92))	('radiotherapy', 'Var', (98, 110))	('patients', 'Species', '9606', (143, 151))
264458	29369779	However, dysregulation of the Eph/ephrin interactions is implicated in cancer contributing to tumour growth, metastasis, and angiogenesis.	('angiogenesis', 'CPA', (125, 137))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('implicated', 'Reg', (57, 67))	('cancer', 'Disease', (71, 77))	('tumour', 'Phenotype', 'HP:0002664', (94, 100))	('metastasis', 'CPA', (109, 119))	('tumour growth', 'Disease', (94, 107))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('Eph', 'Gene', '2041', (30, 33))	('tumour growth', 'Disease', 'MESH:D006130', (94, 107))	('Eph', 'Gene', (30, 33))	('dysregulation', 'Var', (9, 22))
264471	29369779	However, crosstalk between elevated Eph receptors and other oncogenes, such as the ErbB family of receptor tyrosine kinases is thought to result in enhanced cell proliferation and tumorigenesis, presumably independent of ephrin stimulation (reviewed,) (Fig.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('ErbB', 'Gene', '1956;2064', (83, 87))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('cell proliferation', 'CPA', (157, 175))	('crosstalk', 'Var', (9, 18))	('tyrosine', 'Chemical', 'MESH:D014443', (107, 115))	('tumor', 'Disease', (180, 185))	('Eph', 'Gene', '2041', (36, 39))	('elevated', 'PosReg', (27, 35))	('enhanced', 'PosReg', (148, 156))	('ErbB', 'Gene', (83, 87))	('Eph', 'Gene', (36, 39))
264479	29369779	The EphB4-ephrinB2 structural analysis suggested that L95 plays a particularly important role in defining ligand selectivity of EphB4.	('L95', 'Var', (54, 57))	('ephrinB2', 'Gene', '1948', (10, 18))	('EphB4', 'Gene', (128, 133))	('ephrinB2', 'Gene', (10, 18))
264480	29369779	Furthermore, amino acid changes in the EphB4 ligand binding cavity when designed based on comparison with the crystal structure of the more promiscuous EphB2 receptor, yielded EphB4 variants with altered binding affinity for ephrinB2 and TNYL-RAW.	('EphB2', 'Gene', '2048', (152, 157))	('ephrinB2', 'Gene', (225, 233))	('altered', 'Reg', (196, 203))	('variants', 'Var', (182, 190))	('amino acid changes', 'Var', (13, 31))	('binding', 'Interaction', (204, 211))	('EphB4', 'Gene', (176, 181))	('ephrinB2', 'Gene', '1948', (225, 233))	('TNYL-RAW', 'MPA', (238, 246))	('EphB2', 'Gene', (152, 157))
264481	29369779	Finally, binding studies employing isothermal titration calorimetry with the EphB4 L95R mutant confirmed the importance of this amino acid in conferring high affinity binding to both ephrinB2 and TNYL-RAW.	('ephrinB2', 'Gene', (183, 191))	('EphB4', 'Gene', (77, 82))	('L95R', 'Mutation', 'p.L95R', (83, 87))	('ephrinB2', 'Gene', '1948', (183, 191))	('mutant', 'Var', (88, 94))	('L95R mutant', 'Var', (83, 94))	('TNYL-RAW', 'Protein', (196, 204))	('binding', 'Interaction', (167, 174))
264491	29369779	However, overexpression of EphB4 or that of an inactive mutant EphB4 kinase in esophageal squamous cell carcinoma cells promoted cell growth and migration, suggesting EphB4 promoted cell growth and migration independently of its kinase activity and that repressed tumourigenesis.	('tumour', 'Disease', (264, 270))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (90, 113))	('promoted', 'PosReg', (173, 181))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('promoted', 'PosReg', (120, 128))	('esophageal squamous cell carcinoma', 'Disease', (79, 113))	('migration', 'CPA', (145, 154))	('EphB4', 'Gene', (63, 68))	('cell growth', 'CPA', (129, 140))	('tumour', 'Phenotype', 'HP:0002664', (264, 270))	('tumour', 'Disease', 'MESH:D009369', (264, 270))	('cell growth', 'CPA', (182, 193))	('EphB4', 'Var', (167, 172))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (79, 113))
264493	29369779	Furthermore, similar to the situation with forward signaling, reverse signaling has also been observed to result in both tumour suppression as well as progression.	('tumour', 'Phenotype', 'HP:0002664', (121, 127))	('tumour suppression', 'Disease', (121, 139))	('reverse signaling', 'Var', (62, 79))	('progression', 'CPA', (151, 162))	('tumour suppression', 'Disease', 'OMIM:146850', (121, 139))
264494	29369779	For example, tumour cells expressing dominant negative EphB4 are incapable of forward signaling, but remain able to stimulate ephrinB2 reverse signaling, that in turn promotes cell invasion and proliferation.	('tumour', 'Phenotype', 'HP:0002664', (13, 19))	('ephrinB2', 'Gene', '1948', (126, 134))	('promotes', 'PosReg', (167, 175))	('stimulate', 'PosReg', (116, 125))	('dominant negative', 'Var', (37, 54))	('tumour', 'Disease', 'MESH:D009369', (13, 19))	('proliferation', 'CPA', (194, 207))	('tumour', 'Disease', (13, 19))	('cell invasion', 'CPA', (176, 189))	('ephrinB2', 'Gene', (126, 134))	('reverse signaling', 'MPA', (135, 152))	('EphB4', 'Gene', (55, 60))
264497	29369779	Furthermore, mutations dysregulating Eph function likely also play a role in cancer progression.	('play', 'Reg', (62, 66))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('Eph', 'Gene', '2041', (37, 40))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('mutations', 'Var', (13, 22))	('Eph', 'Gene', (37, 40))
264500	29369779	Three potentially relevant EphB6 mutations were identified in NSCLC patients (3.8%) that included two point mutations and an in-frame deletion mutation (del915-917).	('NSCLC', 'Disease', (62, 67))	('EphB6', 'Gene', (27, 32))	('NSCLC', 'Disease', 'MESH:D002289', (62, 67))	('patients', 'Species', '9606', (68, 76))	('del915-917', 'Mutation', 'c.915_917del', (153, 163))	('del915-917', 'Var', (153, 163))
264501	29369779	Furthermore, the del915-917 mutation also increased the metastatic capability of NSCLC cells in an in vivo mouse model suggesting that EphB6 mutations promote metastasis in a subset of patients with non-small cell lung cancer (NSCLC) cells.	('metastasis', 'CPA', (159, 169))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (199, 225))	('del915-917', 'Var', (17, 27))	('NSCLC', 'Disease', 'MESH:D002289', (227, 232))	('promote', 'PosReg', (151, 158))	('non-small cell lung cancer', 'Disease', (199, 225))	('increased', 'PosReg', (42, 51))	('mutations', 'Var', (141, 150))	('NSCLC', 'Disease', (227, 232))	('mouse', 'Species', '10090', (107, 112))	('patients', 'Species', '9606', (185, 193))	('NSCLC', 'Disease', 'MESH:D002289', (81, 86))	('lung cancer', 'Phenotype', 'HP:0100526', (214, 225))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (199, 225))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('del915-917', 'Mutation', 'c.915_917del', (17, 27))	('EphB6', 'Gene', (135, 140))	('NSCLC', 'Disease', (81, 86))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (203, 225))	('metastatic capability', 'CPA', (56, 77))
264503	29369779	While mutations in EphA3 appear to have pro-tumourigenic effects thereby transforming tumour suppressor function of the WT protein in the lung, the functional significance of these alterations in EphA5 is unknown.	('EphA3', 'Gene', (19, 24))	('tumour', 'Disease', 'MESH:D009369', (44, 50))	('tumour', 'Phenotype', 'HP:0002664', (86, 92))	('tumour', 'Disease', (44, 50))	('tumour', 'Phenotype', 'HP:0002664', (44, 50))	('tumour', 'Disease', 'MESH:D009369', (86, 92))	('EphA3', 'Gene', '2042', (19, 24))	('EphA5', 'Gene', (196, 201))	('EphA5', 'Gene', '2044', (196, 201))	('tumour', 'Disease', (86, 92))	('mutations', 'Var', (6, 15))	('transforming', 'PosReg', (73, 85))
264506	29369779	Several non-synonymous mutations in EphB4 have also been identified, in human tumour tissues and cell lines.	('tumour', 'Disease', 'MESH:D009369', (78, 84))	('EphB4', 'Gene', (36, 41))	('human', 'Species', '9606', (72, 77))	('non-synonymous mutations', 'Var', (8, 32))	('tumour', 'Disease', (78, 84))	('tumour', 'Phenotype', 'HP:0002664', (78, 84))
264507	29369779	Thus, a mutation resulting in an R564K substitution occurring in the intracellular juxtamembrane (JM) domain was detected in one multiple myeloma cell line, and an R889W substitution was detected in one gastric carcinoma tissue sample.	('R889W', 'Mutation', 'rs762016655', (164, 169))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (203, 220))	('gastric carcinoma', 'Disease', 'MESH:D013274', (203, 220))	('R564K', 'Var', (33, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (211, 220))	('multiple myeloma', 'Disease', 'MESH:D009101', (129, 145))	('gastric carcinoma', 'Disease', (203, 220))	('multiple myeloma', 'Phenotype', 'HP:0006775', (129, 145))	('R564K', 'Mutation', 'rs767980355', (33, 38))	('multiple myeloma', 'Disease', (129, 145))
264508	29369779	A detailed genetic analysis of small cell lung cancer (SCLC) also identified several mutations in the ephrin receptor family including EphB4 (Rudin et al, 2012).	('small cell lung cancer', 'Disease', 'MESH:D055752', (31, 53))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (31, 53))	('small cell lung cancer', 'Disease', (31, 53))	('mutations', 'Var', (85, 94))	('lung cancer', 'Phenotype', 'HP:0100526', (42, 53))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('EphB4', 'Gene', (135, 140))	('SCLC', 'Disease', (55, 59))	('SCLC', 'Disease', 'MESH:D018288', (55, 59))
264509	29369779	Another comprehensive study by revealed EphB4 can be mutated in lung cancer and that they lead to putative structural alterations as well as increased cellular proliferation and motility.	('lung cancer', 'Disease', (64, 75))	('lung cancer', 'Phenotype', 'HP:0100526', (64, 75))	('EphB4', 'Gene', (40, 45))	('structural', 'MPA', (107, 117))	('increased', 'PosReg', (141, 150))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('mutated', 'Var', (53, 60))	('lung cancer', 'Disease', 'MESH:D008175', (64, 75))	('cellular proliferation', 'CPA', (151, 173))	('motility', 'CPA', (178, 186))
264510	29369779	Notably, the authors detected eight NS EphB4 mutations with one (A230V) in an extracellular linker region, two (A371V and P381S) in the first extracellular fibronectin III repeat, two (W534* and E536K) in the extracellular juxtamembrane domain, two (G723S and A742V) in the tyrosine kinase domain, and one (P881S) in an intracellular linker region just C-terminal to the tyrosine kinase domain.	('P881S', 'Var', (307, 312))	('E536K', 'Var', (195, 200))	('P381S', 'Mutation', 'p.P381S', (122, 127))	('tyrosine', 'Chemical', 'MESH:D014443', (371, 379))	('P881S', 'Mutation', 'p.P881S', (307, 312))	('A371V', 'Mutation', 'rs55720981', (112, 117))	('tyrosine', 'Chemical', 'MESH:D014443', (274, 282))	('EphB4', 'Gene', (39, 44))	('W534*', 'SUBSTITUTION', 'None', (185, 190))	('A230V', 'Mutation', 'p.A230V', (65, 70))	('A371V', 'Var', (112, 117))	('A742V', 'Var', (260, 265))	('W534*', 'Var', (185, 190))	('G723S', 'Mutation', 'p.G723S', (250, 255))	('P381S', 'Var', (122, 127))	('mutations', 'Var', (45, 54))	('A742V', 'Mutation', 'p.A742V', (260, 265))	('E536K', 'Mutation', 'p.E536K', (195, 200))	('G723S', 'Var', (250, 255))	('A230V', 'Var', (65, 70))
264511	29369779	Three of these (A230V, A371V, and P381S) occurred in adenocarcinoma, one (A742V) occurred in SCC, and four (W534*, E536K, G723S, and P881S) occurred in SCLC.	('A742V', 'Mutation', 'p.A742V', (74, 79))	('SCLC', 'Disease', 'MESH:D018288', (152, 156))	('SCC', 'Gene', (93, 96))	('E536K', 'Var', (115, 120))	('occurred', 'Reg', (41, 49))	('P381S', 'Mutation', 'p.P381S', (34, 39))	('adenocarcinoma', 'Disease', (53, 67))	('A230V', 'Var', (16, 21))	('W534*', 'SUBSTITUTION', 'None', (108, 113))	('SCLC', 'Disease', (152, 156))	('W534*', 'Var', (108, 113))	('adenocarcinoma', 'Disease', 'MESH:D000230', (53, 67))	('A371V', 'Mutation', 'rs55720981', (23, 28))	('P881S', 'Var', (133, 138))	('G723S', 'Mutation', 'p.G723S', (122, 127))	('P381S', 'Var', (34, 39))	('A371V', 'Var', (23, 28))	('P881S', 'Mutation', 'p.P881S', (133, 138))	('A230V', 'Mutation', 'p.A230V', (16, 21))	('SCC', 'Gene', '6317', (93, 96))	('G723S', 'Var', (122, 127))	('E536K', 'Mutation', 'p.E536K', (115, 120))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))
264515	29369779	Interestingly, of the 16 sites with EphB4 mutations in adenocarcinoma tissues identified by, 12.5% were located in the kinase domain underscoring the functional implications.	('EphB4', 'Gene', (36, 41))	('carcinoma', 'Phenotype', 'HP:0030731', (60, 69))	('adenocarcinoma', 'Disease', (55, 69))	('mutations', 'Var', (42, 51))	('adenocarcinoma', 'Disease', 'MESH:D000230', (55, 69))
264516	29369779	Furthermore, a bioinformatics analysis of these mutations revealed that a) they are mutually exclusive from other common RTK variants in lung cancer, b) they correspond to analogous sites of other RTK's variations in cancers, c) they are predicted to be oncogenic based on biochemical, evolutionary, and domain-function constraints, and d) EPHB4 mutations can induce broad changes in the kinome signature of lung cancer cells.	('lung cancer', 'Disease', (137, 148))	('lung cancer', 'Disease', (408, 419))	('lung cancer', 'Phenotype', 'HP:0100526', (137, 148))	('EPHB4', 'Gene', (340, 345))	('EPHB4', 'Gene', '2050', (340, 345))	('lung cancer', 'Phenotype', 'HP:0100526', (408, 419))	('cancers', 'Phenotype', 'HP:0002664', (217, 224))	('mutations', 'Var', (346, 355))	('changes', 'Reg', (373, 380))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('lung cancer', 'Disease', 'MESH:D008175', (137, 148))	('cancers', 'Disease', 'MESH:D009369', (217, 224))	('cancer', 'Phenotype', 'HP:0002664', (413, 419))	('kinome signature', 'MPA', (388, 404))	('cancers', 'Disease', (217, 224))	('lung cancer', 'Disease', 'MESH:D008175', (408, 419))	('mutations', 'Var', (48, 57))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))
264518	29369779	However, thus far, no non-synonymous EphB4 mutations have been reported in HNSCC or pleural mesothelioma tissues.	('pleural mesothelioma', 'Disease', 'MESH:D008654', (84, 104))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (84, 104))	('EphB4', 'Gene', (37, 42))	('pleural mesothelioma', 'Disease', (84, 104))	('mutations', 'Var', (43, 52))	('SCC', 'Gene', (77, 80))	('SCC', 'Gene', '6317', (77, 80))
264521	29369779	assessed a single-nucleotide polymorphism in EphB4 to determine its effect on protein expression in NSCLC.	('single-nucleotide polymorphism', 'Var', (11, 41))	('NSCLC', 'Disease', (100, 105))	('NSCLC', 'Disease', 'MESH:D002289', (100, 105))	('EphB4', 'Gene', (45, 50))	('effect', 'Reg', (68, 74))	('protein expression', 'MPA', (78, 96))
264533	29369779	Furthermore, EphB4 siRNA and AS-ODN significantly inhibited tumour cell viability, induced apoptosis, activated caspase-8, and sensitized cells to TRAIL-induced cell death.	('EphB4', 'Var', (13, 18))	('TRAIL', 'Gene', '8743', (147, 152))	('caspase-8', 'Gene', '841', (112, 121))	('tumour', 'Disease', 'MESH:D009369', (60, 66))	('sensitized', 'Reg', (127, 137))	('apoptosis', 'CPA', (91, 100))	('activated', 'PosReg', (102, 111))	('tumour', 'Disease', (60, 66))	('TRAIL', 'Gene', (147, 152))	('caspase-8', 'Gene', (112, 121))	('AS-ODN', 'Chemical', 'MESH:D016376', (29, 35))	('induced', 'Reg', (83, 90))	('inhibited', 'NegReg', (50, 59))	('tumour', 'Phenotype', 'HP:0002664', (60, 66))
264557	29369779	Knocking down EphB4 initiated caspase-8-mediated apoptosis and down-regulation of the anti-apoptotic protein bcl-xl.	('bcl-xl', 'Gene', (109, 115))	('Knocking down', 'Var', (0, 13))	('caspase-8', 'Gene', '841', (30, 39))	('bcl-xl', 'Gene', '598', (109, 115))	('EphB4', 'Gene', (14, 19))	('caspase-8', 'Gene', (30, 39))	('down-regulation', 'NegReg', (63, 78))
264558	29369779	EphB4 knockdown also resulted in reduced phosphorylation of Akt and down-regulation of matrix metalloproteinase-2 transcription.	('Akt', 'Gene', '207', (60, 63))	('EphB4', 'Gene', (0, 5))	('phosphorylation', 'MPA', (41, 56))	('Akt', 'Gene', (60, 63))	('reduced', 'NegReg', (33, 40))	('down-regulation', 'NegReg', (68, 83))	('knockdown', 'Var', (6, 15))	('matrix metalloproteinase-2', 'Gene', (87, 113))	('matrix metalloproteinase-2', 'Gene', '4313', (87, 113))
264559	29369779	In addition, murine tumour xenograft studies showed a marked reduction in tumour growth that was accompanied by a decline in EphB4 protein expression, reduced cell division, apoptosis in tumour tissue, and decreased microvascular density upon EphB4 silencing.	('tumour', 'Disease', 'MESH:D009369', (20, 26))	('reduction', 'NegReg', (61, 70))	('microvascular density', 'CPA', (216, 237))	('tumour', 'Disease', (20, 26))	('apoptosis', 'CPA', (174, 183))	('EphB4', 'Gene', (243, 248))	('tumour', 'Phenotype', 'HP:0002664', (187, 193))	('tumour growth', 'Disease', 'MESH:D006130', (74, 87))	('tumour', 'Disease', 'MESH:D009369', (187, 193))	('tumour', 'Disease', (187, 193))	('murine', 'Species', '10090', (13, 19))	('tumour', 'Phenotype', 'HP:0002664', (74, 80))	('cell division', 'CPA', (159, 172))	('reduced', 'NegReg', (151, 158))	('tumour', 'Disease', 'MESH:D009369', (74, 80))	('tumour', 'Disease', (74, 80))	('decreased', 'NegReg', (206, 215))	('silencing', 'Var', (249, 258))	('tumour growth', 'Disease', (74, 87))	('EphB4', 'Gene', (125, 130))	('decline', 'NegReg', (114, 121))	('protein', 'Protein', (131, 138))	('tumour', 'Phenotype', 'HP:0002664', (20, 26))
264567	29369779	This inhibitor was tested in an open-label, multi-institutional Phase II trial to investigate efficacy and safety of XL647 in treatment-naive non-small-cell lung cancer patients clinically enriched for the presence of EGFR mutations and is currently in a Phase III trial (XL647 versus erlotinib), in patients with stage IIIB-IV NSCLC with progression after first- or second-line chemotherapy.	('patients', 'Species', '9606', (169, 177))	('lung cancer', 'Disease', 'MESH:D008175', (157, 168))	('erlotinib', 'Chemical', 'MESH:D000069347', (285, 294))	('lung cancer', 'Disease', (157, 168))	('men', 'Species', '9606', (131, 134))	('lung cancer', 'Phenotype', 'HP:0100526', (157, 168))	('EGFR', 'Gene', '1956', (218, 222))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('NSCLC', 'Disease', (328, 333))	('NSCLC', 'Disease', 'MESH:D002289', (328, 333))	('EGFR', 'Gene', (218, 222))	('mutations', 'Var', (223, 232))	('patients', 'Species', '9606', (300, 308))
264584	29369779	Furthermore, a combination of MAb47 and another anti-angiogenesis mAb, bevacizumab, enhances the antitumour activity and induces tumour regression.	('tumour', 'Phenotype', 'HP:0002664', (129, 135))	('enhances', 'PosReg', (84, 92))	('combination', 'Interaction', (15, 26))	('bevacizumab', 'Chemical', 'MESH:D000068258', (71, 82))	('tumour', 'Disease', (101, 107))	('MAb47', 'Var', (30, 35))	('tumour', 'Disease', 'MESH:D009369', (129, 135))	('tumour regression', 'Disease', (129, 146))	('induces', 'PosReg', (121, 128))	('tumour', 'Disease', (129, 135))	('tumour regression', 'Disease', 'MESH:D009365', (129, 146))	('tumour', 'Phenotype', 'HP:0002664', (101, 107))	('tumour', 'Disease', 'MESH:D009369', (101, 107))
264588	29369779	sEphB4-HSA has full-length human serum albumin fused to the C-terminus of sEphB4 to improve half-life and delivery, and both variants of the protein, sEphB4 alone and sEphB4-HAS, have anti-tumour activities in multiple tumour models.	('tumour', 'Phenotype', 'HP:0002664', (219, 225))	('sEphB4', 'Gene', (74, 80))	('tumour', 'Phenotype', 'HP:0002664', (189, 195))	('human', 'Species', '9606', (27, 32))	('tumour', 'Disease', 'MESH:D009369', (219, 225))	('sEphB4', 'Chemical', '-', (150, 156))	('tumour', 'Disease', (219, 225))	('tumour', 'Disease', 'MESH:D009369', (189, 195))	('sEphB4', 'Chemical', '-', (0, 6))	('tumour', 'Disease', (189, 195))	('multiple tumour', 'Disease', 'MESH:D009369', (210, 225))	('multiple tumour', 'Disease', (210, 225))	('delivery', 'MPA', (106, 114))	('improve', 'PosReg', (84, 91))	('half-life', 'MPA', (92, 101))	('sEphB4-HSA', 'Chemical', '-', (0, 10))	('sEphB4', 'Chemical', '-', (167, 173))	('sEphB4', 'Chemical', '-', (74, 80))	('variants', 'Var', (125, 133))
264598	29369779	Interestingly, a mutation in EphA3 identified in lung cancer enhances cis interaction with ephrin-A3.	('ephrin-A3', 'Gene', '1944', (91, 100))	('EphA3', 'Gene', (29, 34))	('lung cancer', 'Disease', 'MESH:D008175', (49, 60))	('mutation', 'Var', (17, 25))	('cis interaction', 'MPA', (70, 85))	('ephrin-A3', 'Gene', (91, 100))	('lung cancer', 'Disease', (49, 60))	('enhances', 'PosReg', (61, 69))	('lung cancer', 'Phenotype', 'HP:0100526', (49, 60))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('EphA3', 'Gene', '2042', (29, 34))
264599	29369779	Taken together, these tantalizing observations suggest that modulating Eph receptor, more specifically EphB4 activity in cis may be a novel therapeutic approach for upper aerodigestive malignancies.	('Eph', 'Gene', '2041', (103, 106))	('upper aerodigestive malignancies', 'Disease', (165, 197))	('Eph', 'Gene', (103, 106))	('Eph', 'Gene', '2041', (71, 74))	('cis', 'Disease', (121, 124))	('activity', 'MPA', (109, 117))	('modulating', 'Var', (60, 70))	('Eph', 'Gene', (71, 74))	('upper aerodigestive malignancies', 'Disease', 'MESH:D006258', (165, 197))
264608	29369779	In two established SCC xenograft models, CARgpc3 T cells almost completely eliminated the growth of GPC3-positive cells.	('eliminated', 'NegReg', (75, 85))	('SCC', 'Gene', '6317', (19, 22))	('CARgpc3 T', 'Var', (41, 50))	('GPC3', 'Gene', (100, 104))	('SCC', 'Gene', (19, 22))	('growth', 'MPA', (90, 96))	('GPC3', 'Gene', '2719', (100, 104))
264610	29369779	Taken together, these findings indicate that CARgpc3 T cells might be a novel potential therapeutic agent for the treatment of patients with SCC.	('SCC', 'Gene', (141, 144))	('CARgpc3', 'Var', (45, 52))	('patients', 'Species', '9606', (127, 135))	('SCC', 'Gene', '6317', (141, 144))	('men', 'Species', '9606', (119, 122))
264635	28245875	Human leukocyte antigen (HLA) typing revealed HLA-A*0201 homozygosity, which is the prevalent HLA class I allele that has been used to develop universal cancer vaccine targeting TERT-derived peptides.	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('Human', 'Species', '9606', (0, 5))	('HLA-A*', 'Var', (46, 52))	('cancer', 'Disease', (153, 159))	('TERT', 'Gene', (178, 182))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('TERT', 'Gene', '7015', (178, 182))
264646	28245875	Biopsy of the recurrent right axillary mass and RLL lung mass confirmed recurrent, moderately differentiated SCC of most likely lung primary by immunohistochemistry stains (p40: positive and TTF1: negative).	('SCC', 'Phenotype', 'HP:0002860', (109, 112))	('SCC', 'Gene', '6317', (109, 112))	('p40', 'Var', (173, 176))	('lung primary', 'Disease', (128, 140))	('TTF1', 'Gene', (191, 195))	('SCC', 'Gene', (109, 112))	('TTF1', 'Gene', '7270', (191, 195))
264690	28245875	Variable clinicopathological factors, such as preexisting lung damage due to tumor burden, smoking, chronic obstructive pulmonary disease, pulmonary fibrosis, and variable expression of PD-L1 on normal lung tissues, have all been associated with a higher incidence of pneumonitis in NSCLC patients compared to other tumor types.	('pulmonary fibrosis', 'Disease', (139, 157))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('pneumonitis', 'Disease', 'MESH:D011014', (268, 279))	('pulmonary fibrosis', 'Phenotype', 'HP:0002206', (139, 157))	('NSCLC', 'Disease', 'MESH:D002289', (283, 288))	('pulmonary fibrosis', 'Disease', 'MESH:D011658', (139, 157))	('pneumonitis', 'Disease', (268, 279))	('tumor', 'Phenotype', 'HP:0002664', (316, 321))	('chronic obstructive pulmonary disease', 'Phenotype', 'HP:0006510', (100, 137))	('lung damage', 'Disease', (58, 69))	('associated', 'Reg', (230, 240))	('chronic obstructive pulmonary disease', 'Disease', 'MESH:D029424', (100, 137))	('NSCLC', 'Disease', (283, 288))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('patients', 'Species', '9606', (289, 297))	('NSCLC', 'Phenotype', 'HP:0030358', (283, 288))	('chronic obstructive pulmonary disease', 'Disease', (100, 137))	('lung damage', 'Disease', 'MESH:D008171', (58, 69))	('PD-L1', 'Gene', (186, 191))	('variable', 'Var', (163, 171))	('tumor', 'Disease', (316, 321))	('obstructive pulmonary disease', 'Phenotype', 'HP:0006536', (108, 137))	('tumor', 'Disease', (77, 82))	('tumor', 'Disease', 'MESH:D009369', (316, 321))
264704	28245875	Except for one mutation (CDC73 G28*), 13 "functional" genomic alterations, which are defined as known or likely oncogenic genomic alterations, detected in the post-treatment, relapsed tumor (column D) were identical to those of the initial (column A) and recurrent metastatic (columns B and C) tumors.	('tumor', 'Disease', (294, 299))	('CDC73', 'Gene', (25, 30))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('tumors', 'Phenotype', 'HP:0002664', (294, 300))	('CDC73', 'Gene', '79577', (25, 30))	('tumors', 'Disease', 'MESH:D009369', (294, 300))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('tumor', 'Disease', (184, 189))	('tumor', 'Disease', 'MESH:D009369', (294, 299))	('G28*', 'SUBSTITUTION', 'None', (31, 35))	('G28*', 'Var', (31, 35))	('tumor', 'Phenotype', 'HP:0002664', (294, 299))	('tumors', 'Disease', (294, 300))
264705	28245875	Of note, the mutation allele frequency (MAF) of the identified genomic mutations was usually higher in the recurrent (columns B and C) and progressive (column D) tumors than those of the initial tumor (column A) (Fig.	('higher', 'PosReg', (93, 99))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('tumor', 'Disease', (195, 200))	('tumor', 'Disease', (162, 167))	('mutations', 'Var', (71, 80))	('tumors', 'Disease', (162, 168))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('tumors', 'Disease', 'MESH:D009369', (162, 168))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))	('mutation allele', 'MPA', (13, 28))	('tumor', 'Disease', 'MESH:D009369', (162, 167))
264709	28245875	Third, all tumors harbored a PIK3CA Q661K mutation and mutations in several DNA damage response genes (Table 1) that have been associated with increased clinical responses to PD-1 or PD-L1 inhibitors.	('Q661K', 'Mutation', 'p.Q661K', (36, 41))	('increased', 'PosReg', (143, 152))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('associated', 'Reg', (127, 137))	('PD-1', 'Gene', (175, 179))	('Q661K', 'Var', (36, 41))	('mutations', 'Var', (55, 64))	('PD-1', 'Gene', '5133', (175, 179))	('tumors', 'Phenotype', 'HP:0002664', (11, 17))	('tumors', 'Disease', (11, 17))	('tumors', 'Disease', 'MESH:D009369', (11, 17))	('PIK3CA', 'Gene', (29, 35))	('PIK3CA', 'Gene', '5290', (29, 35))
264710	28245875	Fourth, among all the functional genomic alterations detected, telomerase reverse transcriptase (TERT or hTERT) promoter -146C>T mutation had incrementally increased in MAF% over time (Fig.	('MAF%', 'MPA', (169, 173))	('promoter -146C>T', 'Var', (112, 128))	('telomerase reverse transcriptase', 'Gene', (63, 95))	('TERT', 'Gene', (106, 110))	('TERT', 'Gene', '7015', (106, 110))	('telomerase reverse transcriptase', 'Gene', '7015', (63, 95))	('increased', 'PosReg', (156, 165))	('hTERT', 'Gene', '7015', (105, 110))	('-146C>T', 'Mutation', 'rs200775326', (121, 128))	('TERT', 'Gene', (97, 101))	('hTERT', 'Gene', (105, 110))	('TERT', 'Gene', '7015', (97, 101))
264772	27822875	Immunohistochemically, the carcinoma cells were positive for AE1/AE3, CAM5.2, p40, p63, CK34betaE12, CD5, and bcl-2 but negative for CK5/6, TTF-1, c-kit, AFP, and CD30.	('TTF-1', 'Gene', '7270', (140, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (27, 36))	('AFP', 'Gene', (154, 157))	('CD30', 'Gene', (163, 167))	('carcinoma', 'Disease', (27, 36))	('AFP', 'Gene', '174', (154, 157))	('CD5', 'Gene', (101, 104))	('AE1', 'Gene', (61, 64))	('c-kit', 'Gene', (147, 152))	('CK5/6', 'Gene', '3852', (133, 138))	('CD30', 'Gene', '943', (163, 167))	('CD5', 'Gene', '921', (101, 104))	('bcl-2', 'Gene', (110, 115))	('TTF-1', 'Gene', (140, 145))	('p40', 'Gene', (78, 81))	('CK34betaE12', 'Var', (88, 99))	('carcinoma', 'Disease', 'MESH:D002277', (27, 36))	('AE3', 'Gene', (65, 68))	('p40', 'Gene', '8626', (78, 81))	('positive', 'Reg', (48, 56))	('CK5/6', 'Gene', (133, 138))	('CAM5.2', 'Var', (70, 76))	('bcl-2', 'Gene', '596', (110, 115))	('c-kit', 'Gene', '3815', (147, 152))	('p63', 'Gene', (83, 86))	('AE3', 'Gene', '6508', (65, 68))	('p63', 'Gene', '8626', (83, 86))	('AE1', 'Gene', '6521', (61, 64))
264817	25816356	RNAi is the process of silencing genes by the sequence specific double-stranded RNA (dsRNA).	('double-stranded', 'Var', (64, 79))	('silencing', 'NegReg', (23, 32))	('double', 'Chemical', '-', (64, 70))	('p', 'Gene', '23436', (56, 57))	('p', 'Gene', '23436', (12, 13))
264832	25816356	Therefore, gene silencing HIF-1alpha by RNAi may be an effective method to control the malignancy of tumors and improve the survival of patients.	('malignancy of tumors', 'Disease', 'MESH:D018198', (87, 107))	('HIF-1alpha', 'Gene', '3091', (26, 36))	('p', 'Gene', '23436', (136, 137))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('control', 'CPA', (75, 82))	('malignancy of tumors', 'Disease', (87, 107))	('survival', 'CPA', (124, 132))	('patients', 'Species', '9606', (136, 144))	('HIF-1alpha', 'Gene', (26, 36))	('gene silencing', 'Var', (11, 25))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('RNAi', 'Gene', (40, 44))	('p', 'Gene', '23436', (33, 34))	('p', 'Gene', '23436', (114, 115))
264843	25816356	The target gene sequence of HIF-1alpha (NM_001530) is GATGAAAGAATTACCGAAT.	('HIF-1alpha', 'Gene', (28, 38))	('NM_001530', 'Var', (40, 49))	('HIF-1alpha', 'Gene', '3091', (28, 38))
264851	25816356	Forty-eight hours later, the medium containing lentivirus was centrifuged at 4000 g for 10 min at 4 C to pellet cell debris, and to concentrate the lentivirus at 4000 g for 15 min and stored at -80 C. SCC-15 cells (2x105) were collected and seeded in each well of a 6-well plate with 1 ml of complete media and transduced by lentiviral vectors at a MOI (Manual Optical Inspector) 10.	('p', 'Gene', '23436', (105, 106))	('p', 'Gene', '23436', (295, 296))	('p', 'Gene', '23436', (273, 274))	('transduced by', 'Reg', (311, 324))	('SCC-15', 'CellLine', 'CVCL:1681', (201, 207))	('p', 'Gene', '23436', (372, 373))	('lentiviral', 'Var', (325, 335))	('p', 'Gene', '23436', (362, 363))
264903	25816356	The three groups of cells were cultured with or without DFO for 24, 48, or 72 h. When SCC-15 cells were treated with DFO, the proliferation of hypoxic cells was significantly inhibited compared with the normoxic cells (Fig.	('DFO', 'Var', (117, 120))	('inhibited', 'NegReg', (175, 184))	('SCC-15', 'CellLine', 'CVCL:1681', (86, 92))	('p', 'Gene', '23436', (126, 127))	('p', 'Gene', '23436', (188, 189))	('DFO', 'Chemical', 'MESH:D003676', (117, 120))	('DFO', 'Chemical', 'MESH:D003676', (56, 59))	('p', 'Gene', '23436', (14, 15))	('p', 'Gene', '23436', (145, 146))
264907	25816356	DFO can induce a significant increase of SCC-15 cells in G1 phase and a decrease of cells in the S/G2 phase compared to normoxic cells (Fig.	('p', 'Gene', '23436', (102, 103))	('S/G2', 'Var', (97, 101))	('S/G2', 'SUBSTITUTION', 'None', (97, 101))	('p', 'Gene', '23436', (60, 61))	('DFO', 'Chemical', 'MESH:D003676', (0, 3))	('SCC-15', 'CellLine', 'CVCL:1681', (41, 47))	('increase', 'PosReg', (29, 37))	('SCC-15 cells', 'CPA', (41, 53))	('p', 'Gene', '23436', (111, 112))	('DFO', 'Var', (0, 3))	('decrease', 'NegReg', (72, 80))
264908	25816356	SCC-15 cells treated with lentiviral vector targeting HIF-1alpha showed a significant decrease of G1 phase cells and an increase of S/G2 phase cells compared to Mock and Con cells after treated with DFO for 24 h (Fig.	('p', 'Gene', '23436', (101, 102))	('p', 'Gene', '23436', (152, 153))	('p', 'Gene', '23436', (61, 62))	('HIF-1alpha', 'Gene', '3091', (54, 64))	('S/G2', 'SUBSTITUTION', 'None', (132, 136))	('DFO', 'Chemical', 'MESH:D003676', (199, 202))	('p', 'Gene', '23436', (137, 138))	('SCC-15', 'CellLine', 'CVCL:1681', (0, 6))	('HIF-1alpha', 'Gene', (54, 64))	('increase', 'PosReg', (120, 128))	('decrease', 'NegReg', (86, 94))	('S/G2', 'Var', (132, 136))
264923	25816356	After treated with DFO, the proliferation of SCC-15 cells was inhibited, which was like the other cell types.	('p', 'Gene', '23436', (105, 106))	('SCC-15', 'CellLine', 'CVCL:1681', (45, 51))	('DFO', 'Var', (19, 22))	('p', 'Gene', '23436', (28, 29))	('inhibited', 'NegReg', (62, 71))	('DFO', 'Chemical', 'MESH:D003676', (19, 22))
264924	25816356	We observed a significant increase of cells in G1 phase and a decrease of cells in the S/G2 phase in DFO-treated SCC-15 cells, which indicated the G1 arrest.	('S/G2', 'SUBSTITUTION', 'None', (87, 91))	('SCC-15', 'CellLine', 'CVCL:1681', (113, 119))	('p', 'Gene', '23436', (50, 51))	('p', 'Gene', '23436', (92, 93))	('G1 arrest', 'CPA', (147, 156))	('decrease', 'NegReg', (62, 70))	('DFO', 'Chemical', 'MESH:D003676', (101, 104))	('increase', 'PosReg', (26, 34))	('S/G2', 'Var', (87, 91))
264927	25816356	The invasion ability of SCC-15 cells was significantly increased after treated with DFO.	('SCC-15', 'CellLine', 'CVCL:1681', (24, 30))	('increased', 'PosReg', (55, 64))	('invasion ability of SCC-15 cells', 'CPA', (4, 36))	('DFO', 'Var', (84, 87))	('DFO', 'Chemical', 'MESH:D003676', (84, 87))
264938	25816356	We demonstrated that the level of HIF-1alpha mRNA was not significantly changed between DFO treated and normal SCC-15 cells.	('DFO treated', 'Var', (88, 99))	('SCC-15', 'CellLine', 'CVCL:1681', (111, 117))	('HIF-1alpha', 'Gene', '3091', (34, 44))	('DFO', 'Chemical', 'MESH:D003676', (88, 91))	('HIF-1alpha', 'Gene', (34, 44))
264941	25816356	We used RNAi technique to suppress the expression of HIF-1alpha, and found that silencing HIF-1alpha can significantly decrease the aggressive potential for SCC-15 cells in hypoxia.	('HIF-1alpha', 'Gene', '3091', (53, 63))	('decrease', 'NegReg', (119, 127))	('silencing', 'Var', (80, 89))	('p', 'Gene', '23436', (60, 61))	('HIF-1alpha', 'Gene', (90, 100))	('p', 'Gene', '23436', (175, 176))	('SCC-15', 'CellLine', 'CVCL:1681', (157, 163))	('HIF-1alpha', 'Gene', (53, 63))	('p', 'Gene', '23436', (143, 144))	('p', 'Gene', '23436', (41, 42))	('p', 'Gene', '23436', (28, 29))	('p', 'Gene', '23436', (97, 98))	('hypoxia', 'Disease', 'MESH:D000860', (173, 180))	('HIF-1alpha', 'Gene', '3091', (90, 100))	('p', 'Gene', '23436', (29, 30))	('hypoxia', 'Disease', (173, 180))
264959	25816356	RNAi technique was used to evaluate the effect of HIF-1alpha on apoptosis of cultured human SCC-15 cells under normaxia and hypoxia, and we found the number of apoptotic cells was significantly increased in RNAi cells compared to that of Mock or Con cells under normoxic and hypoxic condition.	('p', 'Gene', '23436', (57, 58))	('HIF-1alpha', 'Gene', '3091', (50, 60))	('hypoxia', 'Disease', 'MESH:D000860', (124, 131))	('p', 'Gene', '23436', (221, 222))	('p', 'Gene', '23436', (277, 278))	('p', 'Gene', '23436', (161, 162))	('p', 'Gene', '23436', (126, 127))	('human', 'Species', '9606', (86, 91))	('p', 'Gene', '23436', (163, 164))	('increased', 'PosReg', (194, 203))	('HIF-1alpha', 'Gene', (50, 60))	('hypoxic condition', 'Disease', 'MESH:D009135', (275, 292))	('hypoxic condition', 'Disease', (275, 292))	('hypoxia', 'Disease', (124, 131))	('SCC-15', 'CellLine', 'CVCL:1681', (92, 98))	('p', 'Gene', '23436', (65, 66))	('RNAi', 'Var', (207, 211))	('p', 'Gene', '23436', (67, 68))
264963	25816356	In a glioma cell line, gene silencing of HIF-1alpha can downregulate MMP-2/MMP-9 to suppress cell migration and invasion into adjacent normal tissue.	('HIF-1alpha', 'Gene', (41, 51))	('MMP-2', 'Gene', '4313', (69, 74))	('glioma', 'Disease', (5, 11))	('suppress', 'NegReg', (84, 92))	('MMP-2', 'Gene', (69, 74))	('cell migration', 'CPA', (93, 107))	('HIF-1alpha', 'Gene', '3091', (41, 51))	('downregulate', 'NegReg', (56, 68))	('MMP-9', 'Gene', (75, 80))	('MMP-9', 'Gene', '4318', (75, 80))	('invasion into adjacent normal tissue', 'CPA', (112, 148))	('glioma', 'Disease', 'MESH:D005910', (5, 11))	('gene silencing', 'Var', (23, 37))	('glioma', 'Phenotype', 'HP:0009733', (5, 11))
264970	25816356	Hence gene silencing HIF-1alpha can consequently reduce the malignant potential of SCC-15 cells.	('HIF-1alpha', 'Gene', (21, 31))	('gene silencing', 'Var', (6, 20))	('p', 'Gene', '23436', (28, 29))	('SCC-15', 'CellLine', 'CVCL:1681', (83, 89))	('HIF-1alpha', 'Gene', '3091', (21, 31))	('reduce', 'NegReg', (49, 55))	('p', 'Gene', '23436', (70, 71))
264995	29108335	Analysing the TCGA data, three amplicons (11q13, 3q22-29, 5p15) were associated with a number of genes for which expression data was prognostic in head and neck and in either breast or lung cancers (requiring p < 0 05).	('cancers', 'Phenotype', 'HP:0002664', (190, 197))	('3q22-29', 'Var', (49, 56))	('breast or lung cancers', 'Disease', (175, 197))	('breast or lung cancers', 'Disease', 'MESH:D001943', (175, 197))	('11q13', 'Var', (42, 47))	('p15', 'Gene', (59, 62))	('lung cancer', 'Phenotype', 'HP:0100526', (185, 196))	('p15', 'Gene', '1030', (59, 62))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('lung cancers', 'Phenotype', 'HP:0100526', (185, 197))
264999	29108335	Dysregulation of ATP13A3, SSR3 and ANO1 showed a significantly increased HR of 1 45 (CI: 1 09 to 1 93; p = 0 01), 1 82 (CI: 1 2 to 2 78; p < 0 01) and 1 72 (CI: 1 21 to 2 46; p < 0 01) respectively (Supplementary Table 1).	('SSR3', 'Gene', (26, 30))	('ATP13A3', 'Gene', (17, 24))	('increased', 'PosReg', (63, 72))	('Dysregulation', 'Var', (0, 13))	('SSR3', 'Gene', '6747', (26, 30))	('ATP13A3', 'Gene', '79572', (17, 24))	('ANO1', 'Gene', (35, 39))	('HR of 1 45', 'MPA', (73, 83))	('ANO1', 'Gene', '55107', (35, 39))
265095	26801987	reported that HPV and EBV infections were mutually exclusive in a low NPC incidence population; however, HPV positivity was significantly associated with WHO grade 2 tumors.	('EBV infections', 'Disease', 'MESH:D020031', (22, 36))	('NPC', 'Phenotype', 'HP:0100630', (70, 73))	('tumors', 'Disease', 'MESH:D009369', (166, 172))	('HPV', 'Species', '10566', (14, 17))	('NPC', 'Gene', (70, 73))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('NPC', 'Gene', '4864', (70, 73))	('associated', 'Reg', (138, 148))	('HPV', 'Species', '10566', (105, 108))	('HPV', 'Gene', (105, 108))	('tumors', 'Disease', (166, 172))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))	('positivity', 'Var', (109, 119))	('EBV infections', 'Disease', (22, 36))
265120	26801987	It is well known that there is a strong association between high-risk HPVs and cervical cancer.	('HPV', 'Species', '10566', (70, 73))	('high-risk', 'Var', (60, 69))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('cervical cancer', 'Disease', (79, 94))	('cervical cancer', 'Disease', 'MESH:D002583', (79, 94))
265141	26801987	Interestingly, HPV-16 E6/E7, the genotype that is most frequently detected in cervical uterine cancer, was the only genotype identified in HPV-positive breast cancer and integrated into the host genome in all cases.	('cancer', 'Disease', (159, 165))	('HPV-positive breast cancer', 'Disease', 'MESH:D030361', (139, 165))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('HPV-16', 'Species', '333760', (15, 21))	('detected', 'Reg', (66, 74))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('cancer', 'Disease', (95, 101))	('HPV-positive breast cancer', 'Disease', (139, 165))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('breast cancer', 'Phenotype', 'HP:0003002', (152, 165))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('E6/E7', 'Var', (22, 27))	('HPV-16', 'Gene', (15, 21))	('uterine cancer', 'Phenotype', 'HP:0010784', (87, 101))
265149	26801987	The Glenn group reported that HPV and EBV co-exist in several human cancers, and the presence of these viruses in breast cancer is associated with young age at diagnosis and, possibly, an increased breast cancer grade.	('EBV', 'Species', '10376', (38, 41))	('breast cancer', 'Phenotype', 'HP:0003002', (198, 211))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('human', 'Species', '9606', (62, 67))	('cancers', 'Phenotype', 'HP:0002664', (68, 75))	('associated', 'Reg', (131, 141))	('cancers', 'Disease', (68, 75))	('cancers', 'Disease', 'MESH:D009369', (68, 75))	('breast cancer', 'Phenotype', 'HP:0003002', (114, 127))	('HPV', 'Species', '10566', (30, 33))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('breast cancer', 'Disease', 'MESH:D001943', (114, 127))	('breast cancer', 'Disease', 'MESH:D001943', (198, 211))	('presence', 'Var', (85, 93))	('breast cancer', 'Disease', (114, 127))	('breast cancer', 'Disease', (198, 211))
265151	26801987	To clarify whether the co-infection of EBV and HPV promotes the development of breast cancer, further studies are needed.	('HPV', 'Gene', (47, 50))	('EBV', 'Gene', (39, 42))	('breast cancer', 'Disease', 'MESH:D001943', (79, 92))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('breast cancer', 'Disease', (79, 92))	('men', 'Species', '9606', (71, 74))	('co-infection', 'Var', (23, 35))	('EBV', 'Species', '10376', (39, 42))	('breast cancer', 'Phenotype', 'HP:0003002', (79, 92))	('promotes', 'PosReg', (51, 59))	('HPV', 'Species', '10566', (47, 50))
265180	26801987	In one study of early-stage breast carcinogenesis, HPV type 18 infection induced APOBEC3B activity, leading to genome instability, whereas in another study APOBEC3 induced E2 hypermutation in HPV16 DNA upon beta interferon stimulation in cervical keratinocytes.	('HPV type 18 infection', 'Disease', (51, 72))	('activity', 'MPA', (90, 98))	('genome instability', 'MPA', (111, 129))	('APOBEC3B', 'Gene', (81, 89))	('E2 hypermutation', 'Var', (172, 188))	('breast carcinogenesis', 'Disease', (28, 49))	('APOBEC3', 'Gene', (156, 163))	('HPV16', 'Species', '333760', (192, 197))	('breast carcinogenesis', 'Disease', 'MESH:D063646', (28, 49))	('leading to', 'Reg', (100, 110))	('HPV type 18 infection', 'Disease', 'MESH:D030361', (51, 72))	('induced', 'Reg', (73, 80))
265181	26801987	In HPV-induced tumorigenesis, APOBEC3 also mutated other host genomic regions, including those of phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) helical domain.	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('phosphatidylinositol-4,5-bisphosphate', 'Chemical', 'MESH:D019269', (98, 135))	('APOBEC3', 'Gene', (30, 37))	('tumor', 'Disease', (15, 20))	('mutated', 'Var', (43, 50))	('HPV', 'Species', '10566', (3, 6))
265182	26801987	Interestingly, EBV-positive gastric cancer displayed recurrent PIK3CA mutations.	('mutations', 'Var', (70, 79))	('gastric cancer', 'Phenotype', 'HP:0012126', (28, 42))	('EBV', 'Species', '10376', (15, 18))	('PIK3CA', 'Gene', (63, 69))	('gastric cancer', 'Disease', (28, 42))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('gastric cancer', 'Disease', 'MESH:D013274', (28, 42))
265195	26801987	Interestingly, DZ1 is regarded as a phosphorothioate-modified "10-23," DNAzymes were specifically targeted to the LMP1 mRNA, and DZ1 treatment increases the radiosensitivity of NPC to standard radiotherapy.	('increases', 'PosReg', (143, 152))	('LMP1', 'Gene', '9260', (114, 118))	('NPC', 'Phenotype', 'HP:0100630', (177, 180))	('men', 'Species', '9606', (138, 141))	('NPC', 'Gene', (177, 180))	('LMP1', 'Gene', (114, 118))	('NPC', 'Gene', '4864', (177, 180))	('phosphorothioate', 'Chemical', 'MESH:D010278', (36, 52))	('DZ1 treatment', 'Var', (129, 142))	('radiosensitivity', 'CPA', (157, 173))
265197	31828152	Inclusion of hnRNP L Alternative Exon 7 Is Associated with Good Prognosis and Inhibited by Oncogene SRSF3 in Head and Neck Squamous Cell Carcinoma Alternative splicing is increasingly associated with cancers.	('cancers', 'Disease', 'MESH:D009369', (200, 207))	('SRSF3', 'Gene', '6428', (100, 105))	('Carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('cancers', 'Phenotype', 'HP:0002664', (200, 207))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('cancers', 'Disease', (200, 207))	('hnRNP L', 'Gene', (13, 20))	('Alternative splicing', 'Var', (147, 167))	('hnRNP L', 'Gene', '3191', (13, 20))	('Head and Neck Squamous Cell Carcinoma', 'Phenotype', 'HP:0012288', (109, 146))	('Neck Squamous Cell Carcinoma', 'Disease', (118, 146))	('Neck Squamous Cell Carcinoma', 'Disease', 'MESH:D000077195', (118, 146))	('cancer', 'Disease', 'MESH:D009369', (200, 206))	('SRSF3', 'Gene', (100, 105))	('associated with', 'Reg', (184, 199))	('cancer', 'Disease', (200, 206))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (123, 146))
265201	31828152	SRSF3 exon 4 inclusion was correlated with hnRNP L exon 7 inclusion in both HNSCC and breast cancer.	('HNSCC', 'Phenotype', 'HP:0012288', (76, 81))	('SRSF3', 'Gene', (0, 5))	('hnRNP L', 'Gene', (43, 50))	('HNSCC and breast cancer', 'Disease', 'MESH:D001943', (76, 99))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('breast cancer', 'Disease', 'MESH:D001943', (86, 99))	('inclusion', 'Var', (13, 22))	('breast cancer', 'Phenotype', 'HP:0003002', (86, 99))	('breast cancer', 'Disease', (86, 99))	('correlated', 'Reg', (27, 37))
265205	31828152	Knockout of hnRNP L alters hematopoiesis and is lethal in mice.	('hnRNP L', 'Gene', (12, 19))	('alters', 'Reg', (20, 26))	('hematopoiesis', 'Disease', (27, 40))	('mice', 'Species', '10090', (58, 62))	('Knockout', 'Var', (0, 8))	('hematopoiesis', 'Disease', 'MESH:C536227', (27, 40))
265207	31828152	Overexpression of SRSF3 induces varied cancerous phenotypes, such as cell cycle progression, antiapoptosis, and cell proliferation.	('cell proliferation', 'CPA', (112, 130))	('antiapoptosis', 'CPA', (93, 106))	('cell cycle progression', 'CPA', (69, 91))	('induces', 'Reg', (24, 31))	('cancerous', 'Disease', (39, 48))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('Overexpression', 'Var', (0, 14))	('SRSF3', 'Gene', (18, 23))	('cancerous', 'Disease', 'MESH:D009369', (39, 48))
265218	31828152	showed that knockdown of hnRNP L suppresses prostate cancer cell growth but exerts no effect on normal-like prostate cell growth.	('L suppresses prostate cancer', 'Disease', 'MESH:D011471', (31, 59))	('knockdown', 'Var', (12, 21))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('prostate cancer', 'Disease', 'MESH:D011471', (44, 59))	('prostate cancer', 'Phenotype', 'HP:0012125', (44, 59))	('L suppresses prostate cancer', 'Disease', (31, 59))
265229	29643973	In addition to point mutations, epigenetic abnormalities, as aberrant promoter methylation, and microRNA (miRNA) and long noncoding RNA (lncRNA) deregulation were reported as emerging mechanisms of KEAP1/NRF2 axis modulation.	('aberrant', 'Var', (61, 69))	('deregulation', 'MPA', (145, 157))	('epigenetic abnormalities', 'Var', (32, 56))	('promoter methylation', 'MPA', (70, 90))	('KEAP1', 'Gene', '9817', (198, 203))	('microRNA', 'MPA', (96, 104))	('KEAP1', 'Gene', (198, 203))
265230	29643973	This review will summarize the current knowledge about the epigenetic mechanisms that deregulate the KEAP1/NRF2 cascade in solid tumors and their potential usefulness as prognostic and predictive molecular markers.	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('solid tumors', 'Disease', (123, 135))	('KEAP1', 'Gene', '9817', (101, 106))	('solid tumors', 'Disease', 'MESH:D009369', (123, 135))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('KEAP1', 'Gene', (101, 106))	('epigenetic', 'Var', (59, 69))
265231	29643973	Oncogenes and tumor suppressor genes are deregulated in cancer and modify their expression through heterogeneous genetic and epigenetic modifications.	('tumor', 'Disease', (14, 19))	('modify', 'Reg', (67, 73))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('deregulated', 'PosReg', (41, 52))	('expression', 'MPA', (80, 90))	('epigenetic modifications', 'Var', (125, 149))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('Oncogenes', 'Gene', (0, 9))
265232	29643973	All these alterations exert their effects on several cellular processes in which transient modifications of redox balance might occur, such as cell cycle and apoptosis.	('effects', 'Reg', (34, 41))	('alterations', 'Var', (10, 21))	('cell cycle', 'CPA', (143, 153))	('apoptosis', 'CPA', (158, 167))	('modifications', 'Reg', (91, 104))	('rat', 'Species', '10116', (14, 17))	('redox balance', 'MPA', (108, 121))
265241	29643973	The final effect is in any case the disruption of protein-protein interaction of the KEAP1/NRF2 crosstalk and its imbalance in expression levels, with a consequent upregulation of cellular detoxifying proteins.	('KEAP1', 'Gene', (85, 90))	('crosstalk', 'Var', (96, 105))	('imbalance in expression levels', 'MPA', (114, 144))	('imbalance', 'Phenotype', 'HP:0002172', (114, 123))	('disruption', 'NegReg', (36, 46))	('protein-protein interaction', 'MPA', (50, 77))	('cellular detoxifying proteins', 'MPA', (180, 209))	('KEAP1', 'Gene', '9817', (85, 90))	('upregulation', 'PosReg', (164, 176))
265242	29643973	Genetic alterations were the first reported mechanisms of KEAP1/NRF2 axis deregulation.	('Genetic alterations', 'Var', (0, 19))	('KEAP1', 'Gene', (58, 63))	('rat', 'Species', '10116', (12, 15))	('KEAP1', 'Gene', '9817', (58, 63))
265243	29643973	Biallelic changes of the tumor suppressor KEAP1 gene (by point mutations and loss of heterozygosity) were described for the first time in NSCLC and, immediately after, in other several malignancies together with NFE2L2 mutations, the gene that codifies for the NRF2 protein.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('KEAP1', 'Gene', '9817', (42, 47))	('NSCLC', 'Disease', (138, 143))	('NFE2L2', 'Gene', '4780', (212, 218))	('tumor', 'Disease', (25, 30))	('malignancies', 'Disease', 'MESH:D009369', (185, 197))	('NSCLC', 'Disease', 'MESH:D002289', (138, 143))	('KEAP1', 'Gene', (42, 47))	('malignancies', 'Disease', (185, 197))	('NFE2L2', 'Gene', (212, 218))	('mutations', 'Var', (219, 228))	('tumor', 'Disease', 'MESH:D009369', (25, 30))
265244	29643973	More recently, the discovery of hypermethylation of the KEAP1 promoter and noncoding RNAs linked to cell-detoxifying network added a new important dimension in the complex regulation of the KEAP1/NRF2 system (Figure 1).	('KEAP1', 'Gene', '9817', (56, 61))	('KEAP1', 'Gene', '9817', (190, 195))	('hypermethylation', 'Var', (32, 48))	('KEAP1', 'Gene', (56, 61))	('KEAP1', 'Gene', (190, 195))
265245	29643973	This minireview describes the recent updates about the deregulation mechanisms of the KEAP1/NRF2 pathway, with a particular focus on the epigenetic modulation of KEAP1 and NFE2L2 and their cellular significance and potential impact on cancer patient management.	('cancer', 'Disease', (235, 241))	('cancer', 'Disease', 'MESH:D009369', (235, 241))	('KEAP1', 'Gene', '9817', (162, 167))	('NFE2L2', 'Gene', '4780', (172, 178))	('KEAP1', 'Gene', '9817', (86, 91))	('KEAP1', 'Gene', (86, 91))	('epigenetic modulation', 'Var', (137, 158))	('KEAP1', 'Gene', (162, 167))	('NFE2L2', 'Gene', (172, 178))	('patient', 'Species', '9606', (242, 249))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))
265246	29643973	Among the genetic lesions that affect the KEAP1/NRF2 activity, point mutations are the most frequently investigated ones in solid tumors.	('solid tumors', 'Disease', 'MESH:D009369', (124, 136))	('KEAP1', 'Gene', '9817', (42, 47))	('investigated', 'Reg', (103, 115))	('KEAP1', 'Gene', (42, 47))	('solid tumors', 'Disease', (124, 136))	('point mutations', 'Var', (63, 78))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))
265249	29643973	Moreover, since the KEAP1 is able to negatively modulate the BCL-2 and p62 degradation, the KEAP1 point mutations also lead to an accumulation of these proteins with a general deregulation of apoptosis, autophagy, and inflammation.	('accumulation', 'PosReg', (130, 142))	('inflammation', 'Disease', 'MESH:D007249', (218, 230))	('autophagy', 'CPA', (203, 212))	('point mutations', 'Var', (98, 113))	('proteins', 'Protein', (152, 160))	('inflammation', 'Disease', (218, 230))	('KEAP1', 'Gene', '9817', (92, 97))	('modulate', 'Reg', (48, 56))	('KEAP1', 'Gene', '9817', (20, 25))	('BCL-2', 'Gene', '596', (61, 66))	('BCL-2', 'Gene', (61, 66))	('KEAP1', 'Gene', (92, 97))	('lead to', 'Reg', (119, 126))	('KEAP1', 'Gene', (20, 25))	('apoptosis', 'CPA', (192, 201))	('p62', 'Gene', '23636', (71, 74))	('negatively', 'NegReg', (37, 47))	('p62', 'Gene', (71, 74))	('deregulation', 'Reg', (176, 188))
265250	29643973	Loss-of-function mutations of the human KEAP1 gene have been firstly reported in NSCLC with a prevalence of about 20-25%.	('Loss-of-function', 'NegReg', (0, 16))	('human', 'Species', '9606', (34, 39))	('KEAP1', 'Gene', (40, 45))	('NSCLC', 'Disease', 'MESH:D002289', (81, 86))	('NSCLC', 'Disease', (81, 86))	('KEAP1', 'Gene', '9817', (40, 45))	('mutations', 'Var', (17, 26))
265251	29643973	These mutations were frequently observed in the lung papillary subtype and in TTF-1 negative lung adenocarcinoma.	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (93, 112))	('lung adenocarcinoma', 'Disease', (93, 112))	('observed', 'Reg', (32, 40))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (93, 112))	('lung papillary subtype', 'Disease', (48, 70))	('TTF-1', 'Gene', (78, 83))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('mutations', 'Var', (6, 15))	('TTF-1', 'Gene', '7270', (78, 83))
265252	29643973	Moreover, KEAP1 point mutations were identified in several human cancers such as gastric (11.1%), liver (2-8%), colorectal (7.8%), prostate (1.3%), gallbladder (30.7%), ovarian (37%), glioma (1.7%), head and neck (42%), and clear renal cell carcinoma (4.7%).	('KEAP1', 'Gene', '9817', (10, 15))	('carcinoma', 'Phenotype', 'HP:0030731', (241, 250))	('KEAP1', 'Gene', (10, 15))	('colorectal', 'Disease', (112, 122))	('gallbladder', 'Disease', (148, 159))	('cancers', 'Phenotype', 'HP:0002664', (65, 72))	('cancers', 'Disease', (65, 72))	('gastric', 'Disease', (81, 88))	('glioma', 'Disease', (184, 190))	('clear renal cell carcinoma', 'Disease', 'MESH:C538614', (224, 250))	('ovarian', 'Disease', (169, 176))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('glioma', 'Disease', 'MESH:D005910', (184, 190))	('colorectal', 'Disease', 'MESH:D015179', (112, 122))	('liver', 'Disease', (98, 103))	('glioma', 'Phenotype', 'HP:0009733', (184, 190))	('identified', 'Reg', (37, 47))	('cancers', 'Disease', 'MESH:D009369', (65, 72))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (230, 250))	('clear renal cell carcinoma', 'Phenotype', 'HP:0006770', (224, 250))	('clear renal cell carcinoma', 'Disease', (224, 250))	('point mutations', 'Var', (16, 31))	('human', 'Species', '9606', (59, 64))	('prostate', 'Disease', (131, 139))
265254	29643973	This last finding was also confirmed by a different group which reported a prevalence of KEAP1-NFE2L2 (31%) alterations in tumors with high neuroendocrine gene expression, mainly cooccurrent with gene mutations.	('NFE2L2', 'Gene', '4780', (95, 101))	('high neuroendocrine gene expression', 'MPA', (135, 170))	('tumors', 'Disease', (123, 129))	('tumors', 'Disease', 'MESH:D009369', (123, 129))	('alterations', 'Var', (108, 119))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('KEAP1', 'Gene', (89, 94))	('NFE2L2', 'Gene', (95, 101))	('rat', 'Species', '10116', (112, 115))	('KEAP1', 'Gene', '9817', (89, 94))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
265255	29643973	Gain-of-function NFE2L2 mutations are generally mutually exclusive with respect to KEAP1 mutations and are frequently located into the DLG or ETGE motifs.	('KEAP1', 'Gene', '9817', (83, 88))	('NFE2L2', 'Gene', '4780', (17, 23))	('NFE2L2', 'Gene', (17, 23))	('Gain-of-function', 'PosReg', (0, 16))	('KEAP1', 'Gene', (83, 88))	('mutations', 'Var', (89, 98))	('mutations', 'Var', (24, 33))
265256	29643973	NFE2L2 point mutations were identified in several tumors with squamous histological features, such as esophageal, skin, lung, and laryngeal carcinomas.	('identified', 'Reg', (28, 38))	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('esophageal', 'Disease', (102, 112))	('skin', 'Disease', (114, 118))	('point mutations', 'Var', (7, 22))	('NFE2L2', 'Gene', '4780', (0, 6))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))	('laryngeal carcinomas', 'Disease', 'MESH:D007827', (130, 150))	('laryngeal carcinomas', 'Phenotype', 'HP:0012118', (130, 150))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('NFE2L2', 'Gene', (0, 6))	('laryngeal carcinomas', 'Disease', (130, 150))	('esophageal', 'Disease', 'MESH:D004941', (102, 112))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('tumors', 'Disease', (50, 56))	('lung', 'Disease', (120, 124))	('carcinomas', 'Phenotype', 'HP:0030731', (140, 150))
265258	29643973	All of these mutations are generally missense changes that interfere with the KEAP1 ability to bind to NRF2, thus inducing an escape of NRF2 degradation without changing its gene functionality.	('KEAP1', 'Gene', (78, 83))	('escape', 'MPA', (126, 132))	('interfere', 'NegReg', (59, 68))	('NRF2 degradation', 'MPA', (136, 152))	('inducing', 'Reg', (114, 122))	('NRF2', 'Protein', (103, 107))	('bind', 'Interaction', (95, 99))	('KEAP1', 'Gene', '9817', (78, 83))	('mutations', 'Var', (13, 22))
265259	29643973	Somatic lesions linked to KEAP1/NRF2 axis deregulation were also reported in the CUL3 gene, the component of the E3 ligase complex KEAP1/CUL3/RBX1 that marks NRF2 for proteasomal degradation.	('KEAP1', 'Gene', (26, 31))	('deregulation', 'Var', (42, 54))	('RBX1', 'Gene', '9978', (142, 146))	('CUL3', 'Gene', '8452', (137, 141))	('CUL3', 'Gene', (137, 141))	('KEAP1', 'Gene', '9817', (131, 136))	('CUL3', 'Gene', '8452', (81, 85))	('CUL3', 'Gene', (81, 85))	('KEAP1', 'Gene', (131, 136))	('KEAP1', 'Gene', '9817', (26, 31))	('RBX1', 'Gene', (142, 146))
265260	29643973	Mutations in CUL3, together with those in NFE2L2, are frequent in hereditary type 2 papillary renal cell carcinoma (PRCC2).	('hereditary type 2 papillary renal cell carcinoma', 'Disease', 'MESH:C538614', (66, 114))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (94, 114))	('hereditary type 2 papillary renal cell carcinoma', 'Disease', (66, 114))	('frequent', 'Reg', (54, 62))	('NFE2L2', 'Gene', '4780', (42, 48))	('CUL3', 'Gene', '8452', (13, 17))	('CUL3', 'Gene', (13, 17))	('type 2 papillary renal cell carcinoma', 'Phenotype', 'HP:0006732', (77, 114))	('NFE2L2', 'Gene', (42, 48))	('Mutations', 'Var', (0, 9))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('papillary renal cell carcinoma', 'Phenotype', 'HP:0006766', (84, 114))
265262	29643973	Dysfunction of the KEAP1/NRF2 axis by genetic mutations is gradually becoming a milestone to understand cancer development, progression, and resistance to conventional and biological treatments.	('KEAP1', 'Gene', (19, 24))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('KEAP1', 'Gene', '9817', (19, 24))	('genetic mutations', 'Var', (38, 55))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))
265263	29643973	It is now well known that loss-of-function mutations of the KEAP1 gene or gain-of-function mutations in NFE2L2 enhance the resistance of cancer cells to anticancer drugs, such as etoposide and carboplatin, and it is associated with poor outcome of platinum-based advanced NSCLC patients.	('KEAP1', 'Gene', (60, 65))	('resistance', 'CPA', (123, 133))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('cancer', 'Disease', (137, 143))	('enhance', 'PosReg', (111, 118))	('carboplatin', 'Chemical', 'MESH:D016190', (193, 204))	('loss-of-function', 'NegReg', (26, 42))	('platinum', 'Chemical', 'MESH:D010984', (248, 256))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('etoposide', 'Chemical', 'MESH:D005047', (179, 188))	('gain-of-function', 'PosReg', (74, 90))	('NSCLC', 'Disease', 'MESH:D002289', (272, 277))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('NFE2L2', 'Gene', '4780', (104, 110))	('cancer', 'Disease', (157, 163))	('NFE2L2', 'Gene', (104, 110))	('NSCLC', 'Disease', (272, 277))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('mutations', 'Var', (43, 52))	('mutations', 'Var', (91, 100))	('patients', 'Species', '9606', (278, 286))	('KEAP1', 'Gene', '9817', (60, 65))
265266	29643973	Jeong and coworkers suggested a new role for KEAP1 and NFE2L2 mutations in radiotherapy resistance of NSCLC patients and in identifying patients who might benefit from radiation dose escalation.	('NSCLC', 'Disease', 'MESH:D002289', (102, 107))	('KEAP1', 'Gene', '9817', (45, 50))	('NFE2L2', 'Gene', '4780', (55, 61))	('patients', 'Species', '9606', (136, 144))	('KEAP1', 'Gene', (45, 50))	('patients', 'Species', '9606', (108, 116))	('NSCLC', 'Disease', (102, 107))	('NFE2L2', 'Gene', (55, 61))	('mutations', 'Var', (62, 71))	('radiotherapy resistance', 'MPA', (75, 98))
265271	29643973	Moreover, cells expressing oncogenic allele of KRAS are able to activate NRF2 via the MAPK pathway in mouse embryonic fibroblasts.	('MAPK pathway', 'Pathway', (86, 98))	('NRF2', 'Gene', (73, 77))	('KRAS', 'Var', (47, 51))	('mouse', 'Species', '10090', (102, 107))	('activate', 'PosReg', (64, 72))
265272	29643973	In the same way, the loss of KEAP1 by the CRISPR-Cas9 system cooperates with the tumor mutational landscape in modulating the response to BRAF, MEK, EGFR, and ALK inhibition and in allowing cancer cells to increase their ability to resist to treatments and proliferate.	('MEK', 'Gene', (144, 147))	('ability', 'CPA', (221, 228))	('allowing', 'Reg', (181, 189))	('loss', 'Var', (21, 25))	('cancer', 'Disease', (190, 196))	('EGFR', 'Gene', '1956', (149, 153))	('modulating', 'Reg', (111, 121))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('tumor', 'Disease', (81, 86))	('ALK', 'Gene', '238', (159, 162))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('ALK', 'Gene', (159, 162))	('KEAP1', 'Gene', '9817', (29, 34))	('response', 'MPA', (126, 134))	('BRAF', 'Gene', (138, 142))	('BRAF', 'Gene', '673', (138, 142))	('rat', 'Species', '10116', (66, 69))	('KEAP1', 'Gene', (29, 34))	('cancer', 'Disease', 'MESH:D009369', (190, 196))	('proliferate', 'CPA', (257, 268))	('MEK', 'Gene', '5609', (144, 147))	('EGFR', 'Gene', (149, 153))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('rat', 'Species', '10116', (264, 267))	('increase', 'PosReg', (206, 214))
265274	29643973	In the same context of resistance to target therapy, it is possible that NFE2L2 mutations can contribute to survival under crizotinib treatment and can allow the cells to acquire additional resistance mutations over time.	('NFE2L2', 'Gene', (73, 79))	('mutations', 'Var', (80, 89))	('crizotinib', 'Chemical', 'MESH:D000077547', (123, 133))	('allow', 'Reg', (152, 157))	('NFE2L2', 'Gene', '4780', (73, 79))	('resistance mutations', 'MPA', (190, 210))	('contribute', 'Reg', (94, 104))
265275	29643973	recently identified a hotspot mutation in NFE2L2 in a patient with acquired resistance to ALK inhibitors that could exert a synergic effect with a secondary ALK mutation in the resistance to second-generation ALK inhibitors.	('patient', 'Species', '9606', (54, 61))	('hotspot', 'Reg', (22, 29))	('NFE2L2', 'Gene', '4780', (42, 48))	('ALK', 'Gene', '238', (90, 93))	('mutation', 'Var', (161, 169))	('mutation', 'Var', (30, 38))	('ALK', 'Gene', (209, 212))	('ALK', 'Gene', (157, 160))	('NFE2L2', 'Gene', (42, 48))	('ALK', 'Gene', (90, 93))	('ALK', 'Gene', '238', (209, 212))	('rat', 'Species', '10116', (202, 205))	('ALK', 'Gene', '238', (157, 160))
265276	29643973	Recent additional studies in this field gave the first hint of the prognostic role of single-nucleotide polymorphisms (SNPs) of the KEAP1 gene in breast cancer without inducing any evident and detectable variations of the protein structure or conformation.	('breast cancer', 'Disease', 'MESH:D001943', (146, 159))	('KEAP1', 'Gene', '9817', (132, 137))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('breast cancer', 'Disease', (146, 159))	('breast cancer', 'Phenotype', 'HP:0003002', (146, 159))	('KEAP1', 'Gene', (132, 137))	('single-nucleotide polymorphisms', 'Var', (86, 117))
265277	29643973	More specifically, five tagging SNPs (rs34197572, rs9676881, rs1048290, rs11085735, and rs8113472) located in the KEAP1 were genotyped and appeared to be in allelic linkage disequilibrium (LD) with each other.	('rs8113472', 'Mutation', 'rs8113472', (88, 97))	('rs11085735', 'Mutation', 'rs11085735', (72, 82))	('KEAP1', 'Gene', '9817', (114, 119))	('rs1048290', 'Var', (61, 70))	('rs1048290', 'Mutation', 'rs1048290', (61, 70))	('rs34197572', 'Var', (38, 48))	('rs34197572', 'Mutation', 'rs34197572', (38, 48))	('KEAP1', 'Gene', (114, 119))	('rs9676881', 'Var', (50, 59))	('rs11085735', 'Var', (72, 82))	('rs9676881', 'Mutation', 'rs9676881', (50, 59))	('rs8113472', 'Var', (88, 97))
265279	29643973	The two SNPs rs9676881 and rs1048290 resulted to be significantly associated with a shorter PFS survival in invasive breast cancer patients.	('patients', 'Species', '9606', (131, 139))	('rs1048290', 'Var', (27, 36))	('rs1048290', 'Mutation', 'rs1048290', (27, 36))	('PFS survival', 'MPA', (92, 104))	('rs9676881', 'Var', (13, 22))	('rs9676881', 'Mutation', 'rs9676881', (13, 22))	('invasive breast cancer', 'Disease', (108, 130))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('breast cancer', 'Phenotype', 'HP:0003002', (117, 130))	('shorter', 'NegReg', (84, 91))	('invasive breast cancer', 'Disease', 'MESH:D001943', (108, 130))
265281	29643973	The SNP rs1048290 is located in the DGR domain, so it may affect the maintenance of physiological levels of NRF2.	('SNP', 'Var', (4, 7))	('maintenance of physiological levels', 'MPA', (69, 104))	('rs1048290', 'Mutation', 'rs1048290', (8, 17))	('NRF2', 'Protein', (108, 112))	('affect', 'Reg', (58, 64))
265282	29643973	The SNP rs1048290 was found in LD with the SNP rs9676881, which is located in a putative enhancer region, few bases downstream of the 3'-untraslated region (3'-UTR) of the KEAP1 gene and 410 bp from the miR-200a binding site.	('rs9676881', 'Mutation', 'rs9676881', (47, 56))	('rs9676881', 'Var', (47, 56))	('KEAP1', 'Gene', '9817', (172, 177))	('rs1048290', 'Mutation', 'rs1048290', (8, 17))	('miR-200a', 'Gene', '406983', (203, 211))	('miR-200a', 'Gene', (203, 211))	('rs1048290', 'Var', (8, 17))	('KEAP1', 'Gene', (172, 177))
265284	29643973	The two SNPs rs9676881 and rs1048290 appeared to be the most interesting ones and resulted to be significantly associated with a shorter PFS survival in both invasive and ER-positive tamoxifen-treated invasive breast cancer patients.	('invasive breast cancer', 'Disease', 'MESH:D001943', (201, 223))	('rs1048290', 'Var', (27, 36))	('rs1048290', 'Mutation', 'rs1048290', (27, 36))	('PFS survival', 'MPA', (137, 149))	('rs9676881', 'Var', (13, 22))	('rs9676881', 'Mutation', 'rs9676881', (13, 22))	('invasive breast cancer', 'Disease', (201, 223))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))	('patients', 'Species', '9606', (224, 232))	('breast cancer', 'Phenotype', 'HP:0003002', (210, 223))	('tamoxifen', 'Chemical', 'MESH:D013629', (183, 192))	('shorter', 'NegReg', (129, 136))
265285	29643973	Epigenetic mechanisms are clearly implicated in the complex regulation of the KEAP1/NRF2 axis and are actually considered the most frequent mechanisms of KEAP1 silencing in solid tumors.	('KEAP1', 'Gene', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('silencing', 'NegReg', (160, 169))	('KEAP1', 'Gene', (154, 159))	('solid tumors', 'Disease', 'MESH:D009369', (173, 185))	('tumors', 'Phenotype', 'HP:0002664', (179, 185))	('implicated', 'Reg', (34, 44))	('KEAP1', 'Gene', '9817', (78, 83))	('KEAP1', 'Gene', '9817', (154, 159))	('solid tumors', 'Disease', (173, 185))	('Epigenetic mechanisms', 'Var', (0, 21))
265287	29643973	All the scientific findings on the hypermethylation of the KEAP1 promoter and its effects on the KEAP1/NRF2 pathway are summarized in Table 3.	('hypermethylation', 'Var', (35, 51))	('KEAP1', 'Gene', '9817', (97, 102))	('KEAP1', 'Gene', (59, 64))	('KEAP1', 'Gene', (97, 102))	('effects', 'Reg', (82, 89))	('KEAP1', 'Gene', '9817', (59, 64))
265291	29643973	In lung cancer, the presence of epigenetic abnormalities in the KEAP1 gene plus its point mutations/LOH matched with the prevalence of NRF2 nuclear accumulation in NSCLC tissues and was associated with an increased risk of lung cancer progression in surgically resected patients.	('NSCLC', 'Disease', (164, 169))	('epigenetic abnormalities', 'Var', (32, 56))	('patients', 'Species', '9606', (270, 278))	('lung cancer', 'Disease', (223, 234))	('KEAP1', 'Gene', (64, 69))	('lung cancer', 'Disease', (3, 14))	('NSCLC', 'Disease', 'MESH:D002289', (164, 169))	('lung cancer', 'Phenotype', 'HP:0100526', (3, 14))	('lung cancer', 'Phenotype', 'HP:0100526', (223, 234))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('NRF2', 'Gene', (135, 139))	('associated with', 'Reg', (186, 201))	('lung cancer', 'Disease', 'MESH:D008175', (3, 14))	('nuclear accumulation', 'MPA', (140, 160))	('KEAP1', 'Gene', '9817', (64, 69))	('lung cancer', 'Disease', 'MESH:D008175', (223, 234))
265292	29643973	In clear renal cell carcinoma (ccRCC), the epigenetic modulation of KEAP1 was shown to be the leading mechanism of KEAP1 deregulation (48.6%), thus supporting a driver role of the KEAP1/NRF2 axis in renal cancer.	('renal cancer', 'Disease', (199, 211))	('KEAP1', 'Gene', '9817', (180, 185))	('KEAP1', 'Gene', (68, 73))	('KEAP1', 'Gene', '9817', (115, 120))	('clear renal cell carcinoma', 'Disease', 'MESH:C538614', (3, 29))	('renal cancer', 'Phenotype', 'HP:0009726', (199, 211))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (9, 29))	('epigenetic modulation', 'Var', (43, 64))	('KEAP1', 'Gene', (180, 185))	('renal cancer', 'Disease', 'MESH:D007680', (199, 211))	('KEAP1', 'Gene', (115, 120))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('carcinoma', 'Phenotype', 'HP:0030731', (20, 29))	('clear renal cell carcinoma', 'Phenotype', 'HP:0006770', (3, 29))	('clear renal cell carcinoma', 'Disease', (3, 29))	('KEAP1', 'Gene', '9817', (68, 73))
265293	29643973	TCGA (The Cancer Genome Atlas) concomitant data analysis suggested that KEAP1 hypermethylation is able to strongly predict patient survival.	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (10, 29))	('patient', 'Species', '9606', (123, 130))	('KEAP1', 'Gene', '9817', (72, 77))	('predict', 'Reg', (115, 122))	('KEAP1', 'Gene', (72, 77))	('Cancer', 'Phenotype', 'HP:0002664', (10, 16))	('hypermethylation', 'Var', (78, 94))	('Cancer Genome Atlas', 'Disease', (10, 29))	('patient survival', 'CPA', (123, 139))
265294	29643973	In primary breast cancers and preinvasive lesions, an aberrant KEAP1 promoter methylation was seen to be more recurrent in ER-positive, HER2-negative than in triple-negative breast cancers and was hypothesized to be a prognostic marker since a higher mortality risk in triple-negative patients was predicted.	('KEAP1', 'Gene', '9817', (63, 68))	('breast cancers', 'Phenotype', 'HP:0003002', (174, 188))	('cancers', 'Phenotype', 'HP:0002664', (18, 25))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('breast cancers', 'Disease', 'MESH:D001943', (174, 188))	('breast cancers', 'Phenotype', 'HP:0003002', (11, 25))	('breast cancers', 'Disease', (174, 188))	('breast cancer', 'Phenotype', 'HP:0003002', (174, 187))	('KEAP1', 'Gene', (63, 68))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('breast cancers', 'Disease', 'MESH:D001943', (11, 25))	('breast cancers', 'Disease', (11, 25))	('HER2', 'Gene', (136, 140))	('breast cancer', 'Phenotype', 'HP:0003002', (11, 24))	('patients', 'Species', '9606', (285, 293))	('cancers', 'Phenotype', 'HP:0002664', (181, 188))	('HER2', 'Gene', '2064', (136, 140))	('aberrant', 'Var', (54, 62))
265295	29643973	Moreover, KEAP1 promoter silencing by methylation was also predictive of a lower risk of tumor relapse in patients treated with sequential therapy of anthracyclines and cyclophosphamide followed by taxanes.	('KEAP1', 'Gene', '9817', (10, 15))	('lower', 'NegReg', (75, 80))	('anthracyclines', 'Chemical', 'MESH:D018943', (150, 164))	('cyclophosphamide', 'Chemical', 'MESH:D003520', (169, 185))	('methylation', 'Var', (38, 49))	('KEAP1', 'Gene', (10, 15))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('taxanes', 'Chemical', 'MESH:D043823', (198, 205))	('patients', 'Species', '9606', (106, 114))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
265296	29643973	Gliomas are the second tumor described by our group to have a promoter hypermethylation.	('promoter hypermethylation', 'Var', (62, 87))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('Gliomas', 'Disease', 'MESH:D005910', (0, 7))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('Gliomas', 'Phenotype', 'HP:0009733', (0, 7))	('Gliomas', 'Disease', (0, 7))	('tumor', 'Disease', (23, 28))
265299	29643973	The pharmacological demethylation of the KEAP1 CpG promoter islands was demonstrated to induce an increase in transcript levels and a consequent overexpression of NRF2, GSS, and HO-1.	('HO-1', 'Gene', '3162', (178, 182))	('KEAP1', 'Gene', '9817', (41, 46))	('transcript levels', 'MPA', (110, 127))	('demethylation', 'Var', (20, 33))	('increase', 'PosReg', (98, 106))	('KEAP1', 'Gene', (41, 46))	('NRF2', 'Gene', (163, 167))	('rat', 'Species', '10116', (79, 82))	('overexpression', 'PosReg', (145, 159))	('HO-1', 'Gene', (178, 182))
265300	29643973	Aberrant KEAP1 methylation was also reported in 53% of colorectal cancer and head and neck cancer tissues (29.3%) and was also linked to the worse prognosis of these tumors.	('head and neck cancer', 'Phenotype', 'HP:0012288', (77, 97))	('linked', 'Reg', (127, 133))	('tumors', 'Disease', 'MESH:D009369', (166, 172))	('Aberrant', 'Var', (0, 8))	('colorectal cancer', 'Disease', 'MESH:D015179', (55, 72))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('KEAP1', 'Gene', '9817', (9, 14))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('colorectal cancer', 'Phenotype', 'HP:0003003', (55, 72))	('head and neck cancer', 'Disease', 'MESH:D006258', (77, 97))	('reported', 'Reg', (36, 44))	('KEAP1', 'Gene', (9, 14))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('colorectal cancer', 'Disease', (55, 72))	('tumors', 'Disease', (166, 172))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))
265305	29643973	They found that elevated reactive oxygen species (ROS) level induced by 5-FU activates TET (ten-eleven translocation) DNA demethylases and produces a hypomethylation of the NFE2L2 promoter with consequent activation of NRF2 translation.	('NFE2L2', 'Gene', (173, 179))	('hypomethylation', 'MPA', (150, 165))	('NRF2', 'Gene', (219, 223))	('activation', 'PosReg', (205, 215))	('elevated', 'PosReg', (16, 24))	('5-FU', 'Var', (72, 76))	('activates', 'PosReg', (77, 86))	('translation', 'MPA', (224, 235))	('TET', 'Chemical', '-', (87, 90))	('5-FU', 'Chemical', 'MESH:D005472', (72, 76))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (25, 48))	('ROS', 'Chemical', 'MESH:D017382', (50, 53))	('NFE2L2', 'Gene', '4780', (173, 179))	('elevated reactive oxygen species', 'Phenotype', 'HP:0025464', (16, 48))
265315	29643973	The increased expression of miR-155 correlates with radiation-induced severe fibrosis in a murine skin model, similar to miR-140, whose deficiency increased activation of TGF-beta1 signaling, inflammation, and myofibroblast differentiation in fibrotic lung tissue after radiation treatment.	('deficiency', 'Var', (136, 146))	('fibrosis', 'Disease', 'MESH:D005355', (77, 85))	('fibrosis', 'Disease', (77, 85))	('murine', 'Species', '10090', (91, 97))	('miR-140', 'Gene', '387158', (121, 128))	('expression', 'MPA', (14, 24))	('inflammation', 'Disease', 'MESH:D007249', (192, 204))	('inflammation', 'Disease', (192, 204))	('miR-155', 'Gene', (28, 35))	('myofibroblast differentiation', 'CPA', (210, 239))	('activation', 'PosReg', (157, 167))	('miR-140', 'Gene', (121, 128))	('TGF-beta1', 'Gene', '21803', (171, 180))	('fibrotic lung', 'Phenotype', 'HP:0002206', (243, 256))	('TGF-beta1', 'Gene', (171, 180))	('increased', 'PosReg', (4, 13))
265318	29643973	By contrast, inhibition of miR-144-3p in human leukemia HL-60 cells reduced cell viability and prompted apoptosis by interfering with NRF2 activity.	('leukemia', 'Phenotype', 'HP:0001909', (47, 55))	('leukemia', 'Disease', 'MESH:D007938', (47, 55))	('interfering', 'NegReg', (117, 128))	('leukemia', 'Disease', (47, 55))	('NRF2', 'Protein', (134, 138))	('inhibition', 'Var', (13, 23))	('human', 'Species', '9606', (41, 46))	('cell viability', 'CPA', (76, 90))	('miR-144', 'Gene', (27, 34))	('miR-144', 'Gene', '406936', (27, 34))	('activity', 'MPA', (139, 147))	('reduced', 'NegReg', (68, 75))	('apoptosis', 'CPA', (104, 113))	('HL-60', 'CellLine', 'CVCL:0002', (56, 61))
265323	29643973	In SH-SY5Y neuroblastoma cells, the 3'-UTR of NFE2L2 is targeted by miR-153, miR27a, and miR-142-5p, with a consequent decrease in Gclc glutamate-cysteine ligase (GCLC) and glutathione-disulfide reductase (GSR) expression levels.	('neuroblastoma', 'Phenotype', 'HP:0003006', (11, 24))	('glutathione-disulfide reductase', 'Gene', '2936', (173, 204))	('SH-SY5Y', 'CellLine', 'CVCL:0019', (3, 10))	('miR-153', 'Gene', (68, 75))	('neuroblastoma', 'Disease', 'MESH:D009447', (11, 24))	('Gclc', 'Gene', '25283', (131, 135))	('miR-142-5p', 'Var', (89, 99))	('miR27a', 'Gene', '407018', (77, 83))	('GCLC', 'Gene', (163, 167))	('GSR', 'Gene', (206, 209))	('miR-153', 'Gene', '100314038', (68, 75))	('GSR', 'Gene', '2936', (206, 209))	('NFE2L2', 'Gene', (46, 52))	('glutathione-disulfide reductase', 'Gene', (173, 204))	('miR27a', 'Gene', (77, 83))	('Gclc', 'Gene', (131, 135))	('GCLC', 'Gene', '2729', (163, 167))	('decrease', 'NegReg', (119, 127))	('cysteine', 'Chemical', 'MESH:D003545', (146, 154))	('NFE2L2', 'Gene', '4780', (46, 52))	('neuroblastoma', 'Disease', (11, 24))
265327	29643973	Finally, miR-507, miR-634, miR-450a, and miR-129-5p appeared to negatively modulate the NRF2 activity by targeting both the NFE2L2 and ME1 transcripts, a well-known target of NRF2.	('NFE2L2', 'Gene', (124, 130))	('NRF2', 'Enzyme', (88, 92))	('ME1', 'Gene', (135, 138))	('activity', 'MPA', (93, 101))	('miR-634', 'Gene', (18, 25))	('miR-507', 'Gene', (9, 16))	('targeting', 'Reg', (105, 114))	('miR-507', 'Gene', '574512', (9, 16))	('ME1', 'Gene', '4199', (135, 138))	('modulate', 'Reg', (75, 83))	('miR-129-5p', 'Gene', '100302178', (41, 51))	('NFE2L2', 'Gene', '4780', (124, 130))	('miR-450a', 'Var', (27, 35))	('miR-634', 'Gene', '693219', (18, 25))	('miR-129-5p', 'Gene', (41, 51))	('negatively', 'NegReg', (64, 74))
265333	29643973	In their work, SNP rs1048290 has been found in LD with SNP rs9676881, which is located in a putative enhancer region, few bases downstream of the 3'-untranslated region (3'-UTR) of the KEAP1 gene, the specific target region of miR-200a.	('KEAP1', 'Gene', (185, 190))	('SNP', 'Var', (55, 58))	('rs1048290', 'Mutation', 'rs1048290', (19, 28))	('rs9676881', 'Mutation', 'rs9676881', (59, 68))	('miR-200a', 'Gene', (227, 235))	('miR-200a', 'Gene', '406983', (227, 235))	('SNP', 'Var', (15, 18))	('KEAP1', 'Gene', '9817', (185, 190))
265343	29643973	The miRNAs let-7b and let-7c were firstly demonstrated to negatively modulate the expression of BACH1 in the liver, a transcription factor that works in association with the small MAF proteins in a dominant condition in respect of NRF2.	('BACH1', 'Gene', (96, 101))	('expression', 'MPA', (82, 92))	('let-7b', 'Gene', '406884', (11, 17))	('let-7c', 'Gene', (22, 28))	('MAF', 'Gene', '4094', (180, 183))	('BACH1', 'Gene', '571', (96, 101))	('let-7b', 'Gene', (11, 17))	('let-7c', 'Gene', '406885', (22, 28))	('modulate', 'Reg', (69, 77))	('rat', 'Species', '10116', (49, 52))	('miRNAs', 'Var', (4, 10))	('MAF', 'Gene', (180, 183))	('negatively', 'NegReg', (58, 68))
265344	29643973	By consequence, the repression of BACH1 induces an upregulation of HO-1 expression via NRF2 transcription.	('upregulation', 'PosReg', (51, 63))	('BACH1', 'Gene', (34, 39))	('NRF2', 'Gene', (87, 91))	('BACH1', 'Gene', '571', (34, 39))	('HO-1', 'Gene', (67, 71))	('expression', 'MPA', (72, 82))	('repression', 'Var', (20, 30))	('HO-1', 'Gene', '3162', (67, 71))
265348	29643973	Under stress induced by cigarette smoke, the SCAL1 expression increases in lung cancer cell lines and appears to be directly correlated with NFE2L2 mutations.	('lung cancer', 'Disease', (75, 86))	('lung cancer', 'Phenotype', 'HP:0100526', (75, 86))	('mutations', 'Var', (148, 157))	('correlated', 'Reg', (125, 135))	('increases', 'PosReg', (62, 71))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('NFE2L2', 'Gene', '4780', (141, 147))	('lung cancer', 'Disease', 'MESH:D008175', (75, 86))	('expression', 'MPA', (51, 61))	('SCAL1', 'Gene', (45, 50))	('NFE2L2', 'Gene', (141, 147))	('SCAL1', 'Gene', '100505994', (45, 50))
265351	29643973	NFE2L2 knockdown leads to the overexpression of lncRNA ROR in mammary embryonic stem cells.	('ROR', 'Gene', (55, 58))	('NFE2L2', 'Gene', '4780', (0, 6))	('overexpression', 'PosReg', (30, 44))	('ROR', 'Gene', '100885779', (55, 58))	('lncRNA', 'Protein', (48, 54))	('NFE2L2', 'Gene', (0, 6))	('knockdown', 'Var', (7, 16))
265353	29643973	However, although KEAP1/NRF2 dysfunction is now well known to confer resistance to chemo- and radiotherapy, the KEAP1-NFE2L2 mutational status assessment is not used to make treatment decisions in lung cancer yet.	('KEAP1', 'Gene', '9817', (18, 23))	('KEAP1', 'Gene', (112, 117))	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('lung cancer', 'Disease', 'MESH:D008175', (197, 208))	('KEAP1', 'Gene', (18, 23))	('dysfunction', 'Var', (29, 40))	('NFE2L2', 'Gene', '4780', (118, 124))	('KEAP1', 'Gene', '9817', (112, 117))	('lung cancer', 'Disease', (197, 208))	('lung cancer', 'Phenotype', 'HP:0100526', (197, 208))	('NFE2L2', 'Gene', (118, 124))
265354	29643973	Moreover, molecular profiling of these two proteins in pretreated and resistant tumor samples will help to elucidate if the loss of KEAP1 or the gain of NFE2L2 may be clinically relevant mechanisms of acquired and intrinsic resistance to therapies in lung cancer and other solid tumors or not.	('tumor', 'Phenotype', 'HP:0002664', (279, 284))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('acquired', 'CPA', (201, 209))	('cancer', 'Phenotype', 'HP:0002664', (256, 262))	('loss', 'Var', (124, 128))	('lung cancer', 'Disease', (251, 262))	('gain', 'PosReg', (145, 149))	('NFE2L2', 'Gene', '4780', (153, 159))	('solid tumors', 'Disease', (273, 285))	('tumor', 'Disease', (279, 284))	('tumor', 'Disease', (80, 85))	('lung cancer', 'Disease', 'MESH:D008175', (251, 262))	('tumor', 'Disease', 'MESH:D009369', (279, 284))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('NFE2L2', 'Gene', (153, 159))	('solid tumors', 'Disease', 'MESH:D009369', (273, 285))	('lung cancer', 'Phenotype', 'HP:0100526', (251, 262))	('KEAP1', 'Gene', '9817', (132, 137))	('tumors', 'Phenotype', 'HP:0002664', (279, 285))	('KEAP1', 'Gene', (132, 137))
265355	29643973	From an epigenetic point of view, the effects produced by KEAP1 hypermethylation on the KEAP1/NRF2 signaling in cancer remain partially understood.	('KEAP1', 'Gene', '9817', (58, 63))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('KEAP1', 'Gene', (58, 63))	('KEAP1', 'Gene', '9817', (88, 93))	('hypermethylation', 'Var', (64, 80))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('KEAP1', 'Gene', (88, 93))
265357	29643973	According to these observations, it would be of great interest to determine if in tumors with different origins there are similar or different methylation CpG density patterns at the P1 region and if demethylation of the KEAP1 promoter in neoplastic tissues could really suppress tumor progression and enhance resistance to therapies.	('tumors', 'Disease', (82, 88))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('enhance', 'PosReg', (302, 309))	('KEAP1', 'Gene', '9817', (221, 226))	('tumor', 'Disease', 'MESH:D009369', (280, 285))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('demethylation', 'Var', (200, 213))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (280, 285))	('tumor', 'Disease', (280, 285))	('tumor', 'Disease', (82, 87))	('KEAP1', 'Gene', (221, 226))	('resistance to therapies', 'CPA', (310, 333))	('suppress', 'NegReg', (271, 279))
265370	27871329	Moreover, silencing of EPB41L5 only marginally improved the drug resistance of SCC-9 cells, even when coupled with ionizing radiation.	('improved', 'PosReg', (47, 55))	('EPB41L5', 'Gene', '57669', (23, 30))	('drug resistance of SCC-9 cells', 'CPA', (60, 90))	('drug resistance', 'Phenotype', 'HP:0020174', (60, 75))	('SCC-9', 'CellLine', 'CVCL:1685', (79, 84))	('EPB41L5', 'Gene', (23, 30))	('silencing', 'Var', (10, 19))
265402	27871329	siRNA-mediated silencing of EPB41L5 significantly, but only partially, inhibited the Matrigel invasion of SCC-9 cells (Fig.	('inhibited', 'NegReg', (71, 80))	('Matrigel invasion of SCC-9 cells', 'CPA', (85, 117))	('SCC-9', 'CellLine', 'CVCL:1685', (106, 111))	('EPB41L5', 'Gene', (28, 35))	('silencing', 'Var', (15, 24))	('EPB41L5', 'Gene', '57669', (28, 35))
265403	27871329	Silencing of EPB41L5 did not notably affect cell morphology (data not shown).	('EPB41L5', 'Gene', '57669', (13, 20))	('Silencing', 'Var', (0, 9))	('EPB41L5', 'Gene', (13, 20))
265405	27871329	We have previously shown that silencing of EPB41L5 in other types of cancers, such as breast cancer and renal cancer, drastically improves their drug-resistance.	('cancers', 'Disease', 'MESH:D009369', (69, 76))	('EPB41L5', 'Gene', (43, 50))	('cancers', 'Phenotype', 'HP:0002664', (69, 76))	('drug-resistance', 'Phenotype', 'HP:0020174', (145, 160))	('drug-resistance', 'MPA', (145, 160))	('EPB41L5', 'Gene', '57669', (43, 50))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('renal cancer', 'Disease', (104, 116))	('improves', 'PosReg', (130, 138))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('renal cancer', 'Disease', 'MESH:D007680', (104, 116))	('breast cancer', 'Disease', 'MESH:D001943', (86, 99))	('renal cancer', 'Phenotype', 'HP:0009726', (104, 116))	('breast cancer', 'Phenotype', 'HP:0003002', (86, 99))	('breast cancer', 'Disease', (86, 99))	('silencing', 'Var', (30, 39))	('cancers', 'Disease', (69, 76))
265407	27871329	Contrary to our expectation, however, silencing of EPB41L5 did not at all improve sensitivity of SCC-9 cells towards cisplatin (50 nM for 72 h) (Fig.	('sensitivity', 'MPA', (82, 93))	('improve', 'PosReg', (74, 81))	('cisplatin', 'Chemical', 'MESH:D002945', (117, 126))	('EPB41L5', 'Gene', (51, 58))	('EPB41L5', 'Gene', '57669', (51, 58))	('silencing', 'Var', (38, 47))	('SCC-9', 'CellLine', 'CVCL:1685', (97, 102))
265455	27081085	We identified known and novel, significantly over- and under-expressed (p <= 0.01 and FDR<=0.1) miRNAs in lung adenocarcinoma compared to normal lung tissue: let-7a, miR-10a, miR-15b, miR-23b, miR-26a, miR-26b, miR-29a, miR-30e, miR-99a, miR-146b, miR-181b, miR-181c, miR-421, miR-181a, miR-574 and miR-1247.	('miR-421', 'Gene', '693122', (268, 275))	('miR-99a', 'Gene', (229, 236))	('miR-1247', 'Gene', (299, 307))	('miR-181c', 'Gene', '406957', (258, 266))	('miR-181b', 'Var', (248, 256))	('miR-30e', 'Gene', '407034', (220, 227))	('miR-10a', 'Gene', (166, 173))	('miR-23b', 'Gene', (184, 191))	('miR-574', 'Gene', (287, 294))	('miR-574', 'Gene', '693159', (287, 294))	('lung adenocarcinoma', 'Disease', (106, 125))	('miR-99a', 'Gene', '407055', (229, 236))	('over-', 'PosReg', (45, 50))	('miR-146b', 'Gene', (238, 246))	('miR-181c', 'Gene', (258, 266))	('under-expressed', 'NegReg', (55, 70))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('miR-26a', 'Gene', (193, 200))	('miR-26b', 'Gene', '407017', (202, 209))	('miR-1247', 'Gene', '100302145', (299, 307))	('miR-421', 'Gene', (268, 275))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (106, 125))	('miR-10a', 'Gene', '406902', (166, 173))	('miR-15b', 'Gene', '406949', (175, 182))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (106, 125))	('miR-181a', 'Var', (277, 285))	('miR-26a', 'Gene', '407015', (193, 200))	('miR-29a', 'Gene', '407021', (211, 218))	('let-7a', 'Var', (158, 164))	('miR-26b', 'Gene', (202, 209))	('miR-23b', 'Gene', '407011', (184, 191))	('miR-146b', 'Gene', '574447', (238, 246))	('miR-15b', 'Gene', (175, 182))	('miR-29a', 'Gene', (211, 218))	('miR-30e', 'Gene', (220, 227))
265465	27081085	Advances in the treatment of patients with lung adenocarcinoma were made with the introduction of molecularly targeted approaches, such as the use of tyrosine-kinase inhibitors for patients with tumors containing activating, sensitizing EGFR mutations and Crizotinib for ALK rearrangements.	('ALK', 'Gene', '238', (271, 274))	('tumors', 'Disease', (195, 201))	('EGFR', 'Gene', '1956', (237, 241))	('sensitizing', 'PosReg', (225, 236))	('tumors', 'Disease', 'MESH:D009369', (195, 201))	('patients', 'Species', '9606', (29, 37))	('activating', 'PosReg', (213, 223))	('tumors', 'Phenotype', 'HP:0002664', (195, 201))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (43, 62))	('EGFR', 'Gene', (237, 241))	('ALK', 'Gene', (271, 274))	('mutations', 'Var', (242, 251))	('carcinoma', 'Phenotype', 'HP:0030731', (53, 62))	('patients', 'Species', '9606', (181, 189))	('lung adenocarcinoma', 'Disease', (43, 62))	('Crizotinib', 'Chemical', 'MESH:D000077547', (256, 266))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (43, 62))
265467	27081085	LCMC data showed that actionable mutations in genes such as EGFR, K-RAS, N-RAS, ALK, ERBB2, BRAF, PIK3CA, AKT, MEK1 and MET amplification, were found in >60% of lung adenocarcinomas and patients who received treatment guided by tumor genotyping lived longer compared to patients who did not receive targeted treatment.	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (161, 181))	('tumor', 'Disease', 'MESH:D009369', (228, 233))	('mutations', 'Var', (33, 42))	('PIK3CA', 'Gene', '5290', (98, 104))	('K-RAS', 'Gene', (66, 71))	('lung adenocarcinomas', 'Disease', (161, 181))	('AKT', 'Gene', '207', (106, 109))	('N-RAS', 'Gene', (73, 78))	('MEK1', 'Gene', (111, 115))	('K-RAS', 'Gene', '3845', (66, 71))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('found', 'Reg', (144, 149))	('EGFR', 'Gene', '1956', (60, 64))	('patients', 'Species', '9606', (186, 194))	('BRAF', 'Gene', '673', (92, 96))	('ERBB2', 'Gene', (85, 90))	('PIK3CA', 'Gene', (98, 104))	('BRAF', 'Gene', (92, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (171, 180))	('MEK1', 'Gene', '5604', (111, 115))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (161, 181))	('AKT', 'Gene', (106, 109))	('patients', 'Species', '9606', (270, 278))	('N-RAS', 'Gene', '4893', (73, 78))	('ERBB2', 'Gene', '2064', (85, 90))	('MET amplification', 'Gene', (120, 137))	('ALK', 'Gene', '238', (80, 83))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (161, 180))	('tumor', 'Disease', (228, 233))	('EGFR', 'Gene', (60, 64))	('ALK', 'Gene', (80, 83))
265468	27081085	Moreover, candidate driver mutations were found in TP53, KEAP1, NF1 and RIT1 in tumors lacking oncogene mutations.	('mutations', 'Var', (27, 36))	('KEAP1', 'Gene', (57, 62))	('TP53', 'Gene', (51, 55))	('RIT1', 'Gene', '6016', (72, 76))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('NF1', 'Gene', (64, 67))	('tumors', 'Disease', (80, 86))	('NF1', 'Gene', '4763', (64, 67))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('KEAP1', 'Gene', '9817', (57, 62))	('TP53', 'Gene', '7157', (51, 55))	('RIT1', 'Gene', (72, 76))
265470	27081085	Although several studies have identified driver mutations with a therapeutic role in lung adenocarcinoma, ~40% of such changes are yet unidentified.	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (85, 104))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('lung adenocarcinoma', 'Disease', (85, 104))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (85, 104))	('mutations', 'Var', (48, 57))
265473	27081085	Deregulated miRNA expression has been associated with lung tumorigenesis.	('tumor', 'Disease', (59, 64))	('Deregulated', 'Var', (0, 11))	('associated', 'Reg', (38, 48))	('miRNA expression', 'Protein', (12, 28))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
265481	27081085	The remaining deregulated miRNAs we identified have not been previously reported in lung adenocarcinoma compared to normal lung tissue (we refer to these as "novel"): 13 over-expressed: let-7a, miR-10a, miR-15b, miR-23b, miR-26a, miR-26b, miR-29a, miR-30e, miR-99a, miR-146b, miR-181b, miR-181c, miR-421 and 3 under-expressed: miR-181a, miR-574 and miR-1247.	('miR-574', 'Gene', '693159', (337, 344))	('miR-146b', 'Gene', (266, 274))	('over-expressed', 'PosReg', (170, 184))	('lung adenocarcinoma', 'Disease', (84, 103))	('miR-181c', 'Gene', (286, 294))	('miR-421 and 3', 'Gene', '693122', (296, 309))	('miR-26a', 'Gene', (221, 228))	('miR-26b', 'Gene', '407017', (230, 237))	('let-7a', 'Var', (186, 192))	('miR-23b', 'Gene', '407011', (212, 219))	('miR-1247', 'Gene', '100302145', (349, 357))	('miR-26a', 'Gene', '407015', (221, 228))	('miR-10a', 'Gene', '406902', (194, 201))	('miR-15b', 'Gene', '406949', (203, 210))	('miR-26b', 'Gene', (230, 237))	('miR-99a', 'Gene', (257, 264))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (84, 103))	('miR-146b', 'Gene', '574447', (266, 274))	('miR-181b', 'Var', (276, 284))	('miR-29a', 'Gene', '407021', (239, 246))	('miR-15b', 'Gene', (203, 210))	('miR-29a', 'Gene', (239, 246))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (84, 103))	('miR-181a', 'Var', (327, 335))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('miR-30e', 'Gene', (248, 255))	('miR-23b', 'Gene', (212, 219))	('miR-574', 'Gene', (337, 344))	('miR-181c', 'Gene', '406957', (286, 294))	('miR-1247', 'Gene', (349, 357))	('miR-30e', 'Gene', '407034', (248, 255))	('miR-10a', 'Gene', (194, 201))	('miR-99a', 'Gene', '407055', (257, 264))
265484	27081085	We identified 11 miRNAs whose n2down is significantly enriched (p < 0.05) by deregulated genes; deregulation of these miRNAs may play an important role in lung adenocarcinoma, leading to gene expression changes.	('lung adenocarcinoma', 'Disease', (155, 174))	('deregulation', 'Var', (96, 108))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (155, 174))	('deregulated', 'MPA', (77, 88))	('gene expression changes', 'MPA', (187, 210))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (155, 174))	('carcinoma', 'Phenotype', 'HP:0030731', (165, 174))
265496	27081085	We identified deregulated miRNAs that have not been previously reported in lung adenocarcinoma.	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (75, 94))	('lung adenocarcinoma', 'Disease', (75, 94))	('miRNAs', 'MPA', (26, 32))	('deregulated', 'Var', (14, 25))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (75, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))
265511	27081085	miR-15b over-expression was detected in the blood of patients with NSCLC and deregulated expression of miR-15b and miR-27b, combined, was able to distinguish patients with NSCLC from healthy individuals.	('deregulated', 'Var', (77, 88))	('expression', 'MPA', (89, 99))	('miR-15b', 'Gene', (103, 110))	('patients', 'Species', '9606', (53, 61))	('NSCLC', 'Disease', (172, 177))	('miR-27b', 'Gene', (115, 122))	('over-expression', 'PosReg', (8, 23))	('miR-15b', 'Gene', '406949', (0, 7))	('NSCLC', 'Disease', 'MESH:D002289', (172, 177))	('miR-15b', 'Gene', '406949', (103, 110))	('NSCLC', 'Disease', (67, 72))	('miR-15b', 'Gene', (0, 7))	('patients', 'Species', '9606', (158, 166))	('NSCLC', 'Disease', 'MESH:D002289', (67, 72))	('miR-27b', 'Gene', '407019', (115, 122))
265514	27081085	PPM1D encodes a serine/threonine phosphatase that plays a role in dephosphorylation of several DNA damage-response proteins such as ATM, ATR, p38MAPK, CHK1 and CHK2.	('CHK2', 'Gene', (160, 164))	('ATM', 'Gene', (132, 135))	('CHK2', 'Gene', '11200', (160, 164))	('CHK1', 'Gene', (151, 155))	('dephosphorylation', 'MPA', (66, 83))	('PPM1D', 'Gene', (0, 5))	('ATM', 'Gene', '472', (132, 135))	('p38MAPK', 'Var', (142, 149))	('CHK1', 'Gene', '1111', (151, 155))	('PPM1D', 'Gene', '8493', (0, 5))
265515	27081085	MAPK and PI3K pathways activation was associated with known mutations in a small fraction of lung adenocarcinomas, suggesting other mechanisms of pathway activation during tumorigenesis, which could include post-transcriptional regulation by miRNAs.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('lung adenocarcinomas', 'Disease', (93, 113))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('tumor', 'Disease', (172, 177))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (93, 113))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (93, 113))	('activation', 'PosReg', (23, 33))	('PI3K pathways', 'Pathway', (9, 22))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('mutations', 'Var', (60, 69))	('MAPK', 'Pathway', (0, 4))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (93, 112))
265528	27081085	We showed a complex miRNA-transcription factor regulatory network composed, in part, of novel, differentially expressed miRNAs (miR-15b, miR-23b, miR-29a, miR-30e, miR-146b, miR-181b, and miR-181c).	('miR-23b', 'Gene', '407011', (137, 144))	('miR-30e', 'Gene', (155, 162))	('miR-146b', 'Gene', (164, 172))	('miR-15b', 'Gene', (128, 135))	('miR-181c', 'Gene', '406957', (188, 196))	('miR-181b', 'Var', (174, 182))	('miR-23b', 'Gene', (137, 144))	('miR-146b', 'Gene', '574447', (164, 172))	('miR-29a', 'Gene', (146, 153))	('miR-29a', 'Gene', '407021', (146, 153))	('miR-30e', 'Gene', '407034', (155, 162))	('miR-15b', 'Gene', '406949', (128, 135))	('miR-181c', 'Gene', (188, 196))
265560	27081085	Statistical analyses were performed to correlate deregulated miRNA expression with clinical and histopathological data of patients.	('patients', 'Species', '9606', (122, 130))	('miRNA', 'Protein', (61, 66))	('deregulated', 'Var', (49, 60))
265561	32468587	Molecular characterisation of TP53 mutated squamous cell carcinomas of the lung to identify putative targets for therapy Personalised cancer treatment depends on identification of therapeutically relevant biological subgroups of patients for assessing effect of treatment and to discover new therapeutic options.	('squamous cell carcinomas of the lung', 'Phenotype', 'HP:0030359', (43, 79))	('mutated', 'Var', (35, 42))	('patients', 'Species', '9606', (229, 237))	('TP53', 'Gene', (30, 34))	('squamous cell carcinomas', 'Disease', (43, 67))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (43, 67))	('carcinomas of the lung', 'Phenotype', 'HP:0100526', (57, 79))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (43, 67))	('carcinoma', 'Phenotype', 'HP:0030731', (57, 66))	('carcinomas', 'Phenotype', 'HP:0030731', (57, 67))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (43, 66))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('TP53', 'Gene', '7157', (30, 34))
265566	32468587	The tumours were analysed for copy number alterations (n = 152) and gene expression from tumour (n = 188) and normal lung (n = 21), with both data levels present in 140 patients.	('patients', 'Species', '9606', (169, 177))	('tumour', 'Phenotype', 'HP:0002664', (89, 95))	('tumour', 'Phenotype', 'HP:0002664', (4, 10))	('tumour', 'Disease', 'MESH:D009369', (89, 95))	('gene expression', 'MPA', (68, 83))	('tumour', 'Disease', (89, 95))	('tumour', 'Disease', 'MESH:D009369', (4, 10))	('tumours', 'Phenotype', 'HP:0002664', (4, 11))	('tumours', 'Disease', 'MESH:D009369', (4, 11))	('tumour', 'Disease', (4, 10))	('copy number alterations', 'Var', (30, 53))	('tumours', 'Disease', (4, 11))
265567	32468587	We studied alterations in tumours harbouring mutations in TP53 and in previously published gene expression subtypes.	('mutations', 'Var', (45, 54))	('TP53', 'Gene', '7157', (58, 62))	('TP53', 'Gene', (58, 62))	('tumours', 'Disease', 'MESH:D009369', (26, 33))	('tumours', 'Disease', (26, 33))	('tumour', 'Phenotype', 'HP:0002664', (26, 32))	('tumours', 'Phenotype', 'HP:0002664', (26, 33))
265568	32468587	The most convincing biomarker in TP53 mutated squamous cell carcinomas of the lung was BIRC5 with amplification in 36% of mutated samples, 5% in wild-type samples and a 17%-fold change of expression between TP53 mutated tumours and normal lung tissue.	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (46, 70))	('TP53', 'Gene', '7157', (207, 211))	('tumour', 'Phenotype', 'HP:0002664', (220, 226))	('TP53', 'Gene', '7157', (33, 37))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (46, 70))	('mutated', 'Var', (212, 219))	('mutated', 'Var', (38, 45))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (46, 69))	('carcinomas of the lung', 'Phenotype', 'HP:0100526', (60, 82))	('amplification', 'Var', (98, 111))	('squamous cell carcinomas', 'Disease', (46, 70))	('change', 'Reg', (178, 184))	('squamous cell carcinomas of the lung', 'Phenotype', 'HP:0030359', (46, 82))	('TP53', 'Gene', (207, 211))	('TP53', 'Gene', (33, 37))	('BIRC5', 'Gene', '332', (87, 92))	('tumours', 'Disease', (220, 227))	('BIRC5', 'Gene', (87, 92))	('expression', 'MPA', (188, 198))	('tumours', 'Phenotype', 'HP:0002664', (220, 227))	('carcinoma', 'Phenotype', 'HP:0030731', (60, 69))	('carcinomas', 'Phenotype', 'HP:0030731', (60, 70))	('tumours', 'Disease', 'MESH:D009369', (220, 227))
265570	32468587	We suggest BIRC5 as a putative predictive biomarker and putative druggable target in squamous cell lung carcinomas harbouring TP53 mutation or classified as classical and primitive subtypes.	('squamous cell lung carcinomas', 'Disease', (85, 114))	('TP53', 'Gene', (126, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('carcinomas', 'Phenotype', 'HP:0030731', (104, 114))	('squamous cell lung carcinomas', 'Phenotype', 'HP:0030359', (85, 114))	('squamous cell lung carcinomas', 'Disease', 'MESH:D002294', (85, 114))	('BIRC5', 'Gene', '332', (11, 16))	('BIRC5', 'Gene', (11, 16))	('TP53', 'Gene', '7157', (126, 130))	('mutation', 'Var', (131, 139))
265571	32468587	This study presents a target gene search combining copy number alteration and gene expression to identify putative genes for therapeutic and predictive approaches in TP53 mutated lung squamous cell carcinoma (SCC) and published gene expression subtypes with high percentages of TP53 mutations.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (184, 207))	('TP53', 'Gene', '7157', (278, 282))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (179, 207))	('TP53', 'Gene', (278, 282))	('carcinoma', 'Phenotype', 'HP:0030731', (198, 207))	('TP53', 'Gene', '7157', (166, 170))	('lung squamous cell carcinoma', 'Disease', (179, 207))	('TP53', 'Gene', (166, 170))	('mutated', 'Var', (171, 178))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (179, 207))
265572	32468587	The results suggest that BIRC5 is one of the most appealing targets in TP53 mutated cancers and in the classical and primitive subtypes and should be tested clinically in these subgroups.	('BIRC5', 'Gene', (25, 30))	('cancers', 'Disease', 'MESH:D009369', (84, 91))	('cancers', 'Phenotype', 'HP:0002664', (84, 91))	('mutated', 'Var', (76, 83))	('cancers', 'Disease', (84, 91))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('TP53', 'Gene', '7157', (71, 75))	('TP53', 'Gene', (71, 75))	('BIRC5', 'Gene', '332', (25, 30))
265582	32468587	5 ,  6    TP53 is a well-known tumour suppressor gene and inactivation, primarily through genetic mutations or loss of heterozygosity, is frequent as an early step in carcinogenesis.	('genetic mutations', 'Var', (90, 107))	('TP53', 'Gene', (10, 14))	('tumour', 'Phenotype', 'HP:0002664', (31, 37))	('carcinogenesis', 'Disease', (167, 181))	('tumour', 'Disease', 'MESH:D009369', (31, 37))	('loss of heterozygosity', 'Var', (111, 133))	('tumour', 'Disease', (31, 37))	('carcinogenesis', 'Disease', 'MESH:D063646', (167, 181))	('TP53', 'Gene', '7157', (10, 14))
265583	32468587	8  As mutations in TP53 are common in many cancer types, treatments linked to this genotype could potentially be effective in similar subgroups of various cancer diseases.	('common', 'Reg', (28, 34))	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('cancer', 'Disease', (43, 49))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('TP53', 'Gene', '7157', (19, 23))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('TP53', 'Gene', (19, 23))	('cancer diseases', 'Disease', (155, 170))	('cancer diseases', 'Disease', 'MESH:D009369', (155, 170))	('cancer', 'Disease', (155, 161))	('cancer', 'Disease', 'MESH:D009369', (155, 161))	('mutations', 'Var', (6, 15))
265584	32468587	Mutations in TP53 have been linked to exposure of various carcinogens, including tobacco and the incidence of TP53 mutations is particularly high in smoking-associated cancers, such as SCC of the lung.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('TP53', 'Gene', (13, 17))	('mutations', 'Var', (115, 124))	('high', 'Reg', (141, 145))	('linked', 'Reg', (28, 34))	('TP53', 'Gene', (110, 114))	('tobacco', 'Species', '4097', (81, 88))	('TP53', 'Gene', '7157', (110, 114))	('cancers', 'Phenotype', 'HP:0002664', (168, 175))	('Mutations', 'Var', (0, 9))	('SCC of the lung', 'Disease', (185, 200))	('cancers', 'Disease', (168, 175))	('cancers', 'Disease', 'MESH:D009369', (168, 175))	('TP53', 'Gene', '7157', (13, 17))
265585	32468587	7  Although TP53 mutations have been widely studied in cancer, therapies targeting the gene alterations have not been introduced to the clinic and alternative approaches are needed to improve the predictive power and response to therapy in patients with TP53 mutated lung cancers.	('lung cancer', 'Phenotype', 'HP:0100526', (267, 278))	('TP53', 'Gene', '7157', (254, 258))	('cancer', 'Phenotype', 'HP:0002664', (272, 278))	('TP53', 'Gene', (254, 258))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('lung cancers', 'Disease', 'MESH:D008175', (267, 279))	('lung cancers', 'Phenotype', 'HP:0100526', (267, 279))	('cancers', 'Phenotype', 'HP:0002664', (272, 279))	('mutated', 'Var', (259, 266))	('TP53', 'Gene', '7157', (12, 16))	('cancer', 'Disease', 'MESH:D009369', (272, 278))	('patients', 'Species', '9606', (240, 248))	('cancer', 'Disease', (272, 278))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('TP53', 'Gene', (12, 16))	('lung cancers', 'Disease', (267, 279))	('cancer', 'Disease', (55, 61))
265592	32468587	We have studied early-stage lung carcinomas integrating information at the genetic and transcriptomic levels to identify alterations that could be predictive biomarkers in the presence of TP53 mutations and in the published subtypes of SCC.	('lung carcinomas', 'Disease', (28, 43))	('carcinoma', 'Phenotype', 'HP:0030731', (33, 42))	('mutations', 'Var', (193, 202))	('carcinomas', 'Phenotype', 'HP:0030731', (33, 43))	('presence', 'Reg', (176, 184))	('lung carcinomas', 'Disease', 'MESH:D008175', (28, 43))	('TP53', 'Gene', '7157', (188, 192))	('TP53', 'Gene', (188, 192))
265602	32468587	Consecutive samples (n = 111) were tested for TP53 mutations by the Sanger Sequencing method as previously described.	('TP53', 'Gene', '7157', (46, 50))	('TP53', 'Gene', (46, 50))	('mutations', 'Var', (51, 60))
265604	32468587	Allele-specific copy number analysis of tumours (ASCAT) was applied to estimate copy number gains (amplifications) and losses (deletions).	('tumours', 'Disease', 'MESH:D009369', (40, 47))	('tumours', 'Disease', (40, 47))	('gains', 'PosReg', (92, 97))	('losses', 'NegReg', (119, 125))	('copy number', 'Var', (80, 91))	('tumour', 'Phenotype', 'HP:0002664', (40, 46))	('tumours', 'Phenotype', 'HP:0002664', (40, 47))
265606	32468587	In the OUH cohort, flat profiles of 46 samples indicated insufficient percentage of tumour cells and these samples were excluded from further analysis, leaving available information about copy number alterations for 152 patients.	('copy number alterations', 'Var', (188, 211))	('tumour', 'Disease', (84, 90))	('flat profiles', 'Phenotype', 'HP:0012368', (19, 32))	('OUH', 'Chemical', '-', (7, 10))	('tumour', 'Phenotype', 'HP:0002664', (84, 90))	('patients', 'Species', '9606', (220, 228))	('tumour', 'Disease', 'MESH:D009369', (84, 90))
265609	32468587	Regions with significant differences in gain or loss at given position in two groups were determined using two-proportions z-test implemented in prop.test function in R. The Spearman correlation coefficient was calculated using the R (v3.5.0) to estimate the correlation between copy number alteration and mRNA expression in 140 OUH samples and 443 samples in TCGA cohort.	('copy number alteration', 'Var', (279, 301))	('alteration', 'Var', (291, 301))	('mRNA expression', 'MPA', (306, 321))	('OUH', 'Chemical', '-', (329, 332))
265612	32468587	Subgroups of lung SCC were identified by the presence of TP53 mutations and by the previously published lung SCC subtypes.	('presence', 'Reg', (45, 53))	('lung SCC', 'Disease', (13, 21))	('TP53', 'Gene', '7157', (57, 61))	('TP53', 'Gene', (57, 61))	('mutations', 'Var', (62, 71))
265613	32468587	11   The candidate genes were tested for survival in patients with TP53 mutated tumours receiving adjuvant platinum-based chemotherapy.	('platinum', 'Chemical', 'MESH:D010984', (107, 115))	('mutated', 'Var', (72, 79))	('tumours', 'Disease', 'MESH:D009369', (80, 87))	('patients', 'Species', '9606', (53, 61))	('tumours', 'Disease', (80, 87))	('tumour', 'Phenotype', 'HP:0002664', (80, 86))	('TP53', 'Gene', '7157', (67, 71))	('TP53', 'Gene', (67, 71))	('tumours', 'Phenotype', 'HP:0002664', (80, 87))
265619	32468587	Of the 18 wild-type samples, 10 (56%) had deletions in the region harbouring the TP53 gene, 8 (44%) had no genomic alteration in the gene and there were no amplifications in this specific region.	('deletions', 'Var', (42, 51))	('TP53', 'Gene', '7157', (81, 85))	('TP53', 'Gene', (81, 85))
265620	32468587	Of the samples with a mutation in TP53, four samples (6%) also had a genomic amplification in the same region.	('mutation', 'Var', (22, 30))	('TP53', 'Gene', (34, 38))	('TP53', 'Gene', '7157', (34, 38))
265622	32468587	Frequency plots of TP53 wild-type (n = 18 OUH, n = TCGA) and TP53 mutant (n = 72 OUH, n = TCGA) tumours were generated separately (File S2, Figure S1).	('mutant', 'Var', (66, 72))	('OUH', 'Chemical', '-', (81, 84))	('tumours', 'Phenotype', 'HP:0002664', (96, 103))	('tumour', 'Phenotype', 'HP:0002664', (96, 102))	('OUH', 'Chemical', '-', (42, 45))	('TP53', 'Gene', '7157', (19, 23))	('TP53', 'Gene', (19, 23))	('tumours', 'Disease', 'MESH:D009369', (96, 103))	('tumours', 'Disease', (96, 103))	('TP53', 'Gene', '7157', (61, 65))	('TP53', 'Gene', (61, 65))
265623	32468587	The highest percentage of significant amplifications in TP53 mutated vs wild-type samples was found on chromosomes 2 (10.7%), 12 (19.9%) and 17 (13.3%), respectively.	('TP53', 'Gene', '7157', (56, 60))	('TP53', 'Gene', (56, 60))	('mutated', 'Var', (61, 68))
265624	32468587	TP53 mutant tumours demonstrate a higher level of aberrations than wild-type tumours.	('tumours', 'Phenotype', 'HP:0002664', (77, 84))	('TP53', 'Gene', '7157', (0, 4))	('tumours', 'Disease', 'MESH:D009369', (12, 19))	('TP53', 'Gene', (0, 4))	('tumours', 'Disease', 'MESH:D009369', (77, 84))	('tumours', 'Disease', (12, 19))	('tumours', 'Disease', (77, 84))	('mutant', 'Var', (5, 11))	('tumours', 'Phenotype', 'HP:0002664', (12, 19))	('tumour', 'Phenotype', 'HP:0002664', (12, 18))	('tumour', 'Phenotype', 'HP:0002664', (77, 83))
265625	32468587	To identify putative target genes in TP53 mutated tumours, we followed an approach specified in Figure 1.	('tumours', 'Phenotype', 'HP:0002664', (50, 57))	('mutated', 'Var', (42, 49))	('tumours', 'Disease', 'MESH:D009369', (50, 57))	('tumours', 'Disease', (50, 57))	('TP53', 'Gene', '7157', (37, 41))	('TP53', 'Gene', (37, 41))	('tumour', 'Phenotype', 'HP:0002664', (50, 56))
265626	32468587	For TP53 mutated samples, putative genes were those with amplification in more than 25%, correlation between copy number alterations and gene expression and, compared to wild-type tumours both overexpression of the transcript and more than the double frequency of amplifications.	('overexpression', 'PosReg', (193, 207))	('tumours', 'Disease', 'MESH:D009369', (180, 187))	('tumours', 'Disease', (180, 187))	('TP53', 'Gene', (4, 8))	('mutated', 'Var', (9, 16))	('tumour', 'Phenotype', 'HP:0002664', (180, 186))	('tumours', 'Phenotype', 'HP:0002664', (180, 187))	('TP53', 'Gene', '7157', (4, 8))	('copy number alterations', 'Var', (109, 132))
265628	32468587	Of these 148 genes, 70 have differential expression between TP53 mutated tumours and normal lung tissue in the OUH cohort, of which 67 are upregulated in tumours and constitute our candidate biomarkers (File S3 and Figure 1).	('tumour', 'Phenotype', 'HP:0002664', (154, 160))	('OUH', 'Chemical', '-', (111, 114))	('upregulated', 'PosReg', (139, 150))	('tumours', 'Disease', (73, 80))	('tumours', 'Phenotype', 'HP:0002664', (154, 161))	('expression', 'MPA', (41, 51))	('tumours', 'Disease', 'MESH:D009369', (73, 80))	('differential', 'Reg', (28, 40))	('tumours', 'Disease', 'MESH:D009369', (154, 161))	('tumours', 'Disease', (154, 161))	('TP53', 'Gene', '7157', (60, 64))	('tumour', 'Phenotype', 'HP:0002664', (73, 79))	('tumours', 'Phenotype', 'HP:0002664', (73, 80))	('TP53', 'Gene', (60, 64))	('mutated', 'Var', (65, 72))
265631	32468587	TKI1 has the highest gene expression in TP53 mutated samples compared to all genes, but due to the relatively high expression in normal samples, the fold change is higher for BIRC5.	('TKI1', 'Gene', (0, 4))	('gene expression', 'MPA', (21, 36))	('BIRC5', 'Gene', '332', (175, 180))	('higher', 'PosReg', (164, 170))	('TP53', 'Gene', '7157', (40, 44))	('TP53', 'Gene', (40, 44))	('expression', 'MPA', (115, 125))	('BIRC5', 'Gene', (175, 180))	('fold', 'MPA', (149, 153))	('mutated', 'Var', (45, 52))
265633	32468587	Looking for association to relapse (local or systemic) in the OUH cohort, log-rank tests were performed using gene expression from samples with TP53 mutations (n = 105) and the list of 70 validated genes with differential expression in normal and tumour tissue.	('TP53', 'Gene', '7157', (144, 148))	('TP53', 'Gene', (144, 148))	('tumour', 'Phenotype', 'HP:0002664', (247, 253))	('mutations', 'Var', (149, 158))	('tumour', 'Disease', 'MESH:D009369', (247, 253))	('OUH', 'Chemical', '-', (62, 65))	('tumour', 'Disease', (247, 253))
265644	32468587	Performing the same analysis in patients with TP53 mutated tumours all receiving adjuvant chemotherapy (n = 19), there is a borderline significance toward better prognosis for patients with higher expression of the gene.	('patients', 'Species', '9606', (176, 184))	('patients', 'Species', '9606', (32, 40))	('TP53', 'Gene', '7157', (46, 50))	('tumour', 'Phenotype', 'HP:0002664', (59, 65))	('tumours', 'Phenotype', 'HP:0002664', (59, 66))	('better', 'PosReg', (155, 161))	('TP53', 'Gene', (46, 50))	('tumours', 'Disease', 'MESH:D009369', (59, 66))	('expression', 'MPA', (197, 207))	('tumours', 'Disease', (59, 66))	('mutated', 'Var', (51, 58))
265645	32468587	The presence of TP53 mutations is one possible way of identifying subgroups for target gene search.	('TP53', 'Gene', '7157', (16, 20))	('TP53', 'Gene', (16, 20))	('mutations', 'Var', (21, 30))
265648	32468587	Testing the occurrence of TP53 mutations in the gene expression subtypes, we found an uneven distribution of mutations with the highest frequencies in the classical and primitive subtypes (Fisher exact P value = .04; Table 5).	('TP53', 'Gene', (26, 30))	('mutations', 'Var', (109, 118))	('TP53', 'Gene', '7157', (26, 30))
265650	32468587	As an effort to meet the challenges of heterogeneity of squamous cell lung cancer and the lack of useful biomarkers, we have performed a focused target gene search in surgically removed samples harbouring TP53 mutations, using a TCGA cohort for validation.	('mutations', 'Var', (210, 219))	('TP53', 'Gene', '7157', (205, 209))	('squamous cell lung cancer', 'Disease', (56, 81))	('TP53', 'Gene', (205, 209))	('lung cancer', 'Phenotype', 'HP:0100526', (70, 81))	('squamous cell lung cancer', 'Disease', 'MESH:D002294', (56, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('squamous cell lung cancer', 'Phenotype', 'HP:0030359', (56, 81))
265651	32468587	We have identified several putative target genes, focusing particularly on BIRC5 which is amplified and overexpressed in TP53 mutated squamous cell lung carcinomas as well as in the two gene expression subtypes with highest percentage of TP53 mutations; Classical and Primitive.	('squamous cell lung carcinomas', 'Phenotype', 'HP:0030359', (134, 163))	('BIRC5', 'Gene', '332', (75, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (153, 162))	('TP53', 'Gene', '7157', (121, 125))	('carcinomas', 'Phenotype', 'HP:0030731', (153, 163))	('BIRC5', 'Gene', (75, 80))	('TP53', 'Gene', (121, 125))	('overexpressed', 'PosReg', (104, 117))	('squamous cell lung carcinomas', 'Disease', 'MESH:D002294', (134, 163))	('mutations', 'Var', (243, 252))	('TP53', 'Gene', '7157', (238, 242))	('TP53', 'Gene', (238, 242))	('squamous cell lung carcinomas', 'Disease', (134, 163))	('mutated', 'Var', (126, 133))
265658	32468587	Downregulation of BIRC5 by various micro-RNAs have increased chemo-sensitivity in cancer cell lines.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('increased', 'PosReg', (51, 60))	('Downregulation', 'NegReg', (0, 14))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('micro-RNAs', 'Var', (35, 45))	('BIRC5', 'Gene', '332', (18, 23))	('BIRC5', 'Gene', (18, 23))
265659	32468587	26 ,  27  Similarly, one study found that inhibition of NF-kappaB reduced expression of BIRC5 in lung cancer stem cells and hence induced apoptosis.	('expression', 'MPA', (74, 84))	('reduced', 'NegReg', (66, 73))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('induced', 'Reg', (130, 137))	('BIRC5', 'Gene', '332', (88, 93))	('BIRC5', 'Gene', (88, 93))	('lung cancer', 'Disease', 'MESH:D008175', (97, 108))	('NF-kappaB', 'Gene', '4790', (56, 65))	('NF-kappaB', 'Gene', (56, 65))	('inhibition', 'Var', (42, 52))	('apoptosis', 'CPA', (138, 147))	('lung cancer', 'Disease', (97, 108))	('lung cancer', 'Phenotype', 'HP:0100526', (97, 108))
265662	32468587	One possible approach in the future studies of BIRC5-targeting therapies could be to improve patient selection to include patients with tumours harbouring TP53 mutations or displaying the classical or primitive gene expression subtypes only, or to stratify the survival analyses on these features.	('tumours', 'Phenotype', 'HP:0002664', (136, 143))	('mutations', 'Var', (160, 169))	('TP53', 'Gene', '7157', (155, 159))	('patient', 'Species', '9606', (122, 129))	('BIRC5', 'Gene', '332', (47, 52))	('tumours', 'Disease', 'MESH:D009369', (136, 143))	('BIRC5', 'Gene', (47, 52))	('TP53', 'Gene', (155, 159))	('tumours', 'Disease', (136, 143))	('patients', 'Species', '9606', (122, 130))	('patient', 'Species', '9606', (93, 100))	('tumour', 'Phenotype', 'HP:0002664', (136, 142))
265665	32468587	If high gene expression is actually associated with favourable prognosis after adjuvant chemotherapy, BIRC5-inhibition to increase chemo-sensitivity does not seem like a good idea.	('BIRC5', 'Gene', '332', (102, 107))	('BIRC5', 'Gene', (102, 107))	('high gene', 'Var', (3, 12))
265667	32468587	35   Other genes present themselves as candidate genes combining overexpression and amplification in TP53 mutated lung squamous cell carcinomas (Table 2).	('lung squamous cell carcinomas', 'Disease', (114, 143))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (119, 143))	('TP53', 'Gene', '7157', (101, 105))	('amplification', 'Var', (84, 97))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (114, 142))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('TP53', 'Gene', (101, 105))	('lung squamous cell carcinomas', 'Disease', 'MESH:D002294', (114, 143))	('carcinomas', 'Phenotype', 'HP:0030731', (133, 143))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (119, 142))	('mutated', 'Var', (106, 113))
265675	32468587	Although there are no drugs targeting CBX2 directly, there are inhibitors of histone deacetylase that indirectly modulate the targets of CBX2.	('CBX2', 'Gene', '84733', (137, 141))	('modulate', 'Reg', (113, 121))	('CBX2', 'Gene', (137, 141))	('CBX2', 'Gene', '84733', (38, 42))	('CBX2', 'Gene', (38, 42))	('inhibitors', 'Var', (63, 73))
265678	32468587	Searching for targets across datasets with several cancer types is reasonable, since similar genetic alterations may occur in different cancer diseases leading to a target-driven treatment rather than diagnosis-driven treatment.	('leading to', 'Reg', (152, 162))	('cancer diseases', 'Disease', (136, 151))	('genetic alterations', 'Var', (93, 112))	('occur', 'Reg', (117, 122))	('cancer diseases', 'Disease', 'MESH:D009369', (136, 151))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('cancer', 'Disease', (136, 142))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
265682	32468587	Indeed, we do observe a high level of genomic aberrations in the TP53 mutated cancers.	('TP53', 'Gene', '7157', (65, 69))	('TP53', 'Gene', (65, 69))	('cancers', 'Disease', 'MESH:D009369', (78, 85))	('cancers', 'Phenotype', 'HP:0002664', (78, 85))	('cancers', 'Disease', (78, 85))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('mutated', 'Var', (70, 77))
265683	32468587	Since therapies targeting TP53 have not found their way into the clinic, alternative strategies for developing new therapies in TP53 mutated tumours are needed.	('tumours', 'Disease', (141, 148))	('TP53', 'Gene', (26, 30))	('TP53', 'Gene', '7157', (128, 132))	('tumour', 'Phenotype', 'HP:0002664', (141, 147))	('TP53', 'Gene', (128, 132))	('tumours', 'Disease', 'MESH:D009369', (141, 148))	('tumours', 'Phenotype', 'HP:0002664', (141, 148))	('mutated', 'Var', (133, 140))	('TP53', 'Gene', '7157', (26, 30))
265690	32309852	Three up-regulated circRNAs (hsa_circ_0014235, hsa_circ_0025580 and hsa_circ_0026403) were implied to participate in cancer-related pathways.	('hsa_circ_0014235', 'Var', (29, 45))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('hsa_circ_0025580', 'Var', (47, 63))	('participate', 'Reg', (102, 113))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('cancer', 'Disease', (117, 123))	('hsa_circ_0026403', 'Var', (68, 84))	('up-regulated', 'PosReg', (6, 18))
265709	32309852	As shown in Figure 3A, the up-regulation of hsa_circ_0014235 and hsa_circ_0025580 was detected in LUSC patients compared with controls (fold change: 2.78 and 2.25, respectively; P < 0.05), consistent with previous sequencing data (fold change: 6.86 and 8.03, respectively).	('LUSC', 'Disease', (98, 102))	('up-regulation', 'PosReg', (27, 40))	('hsa_circ_0014235', 'Var', (44, 60))	('LUSC', 'Phenotype', 'HP:0030359', (98, 102))	('hsa_circ_0025580', 'Var', (65, 81))	('patients', 'Species', '9606', (103, 111))
265711	32309852	As shown in Table 2, increased expression of hsa_circ_0014235 and hsa_circ_0025580 was strongly correlated with higher TNM stage (P-value: 0.028 and 0.019, respectively) and larger tumor size (P-value: 0.026 and 0.022, respectively).	('increased', 'PosReg', (21, 30))	('tumor', 'Disease', (181, 186))	('higher', 'PosReg', (112, 118))	('TNM', 'Gene', (119, 122))	('hsa_circ_0014235', 'Var', (45, 61))	('expression', 'MPA', (31, 41))	('hsa_circ_0025580', 'Var', (66, 82))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('TNM', 'Gene', '10178', (119, 122))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))
265716	32309852	For these mRNAs that indirectly targeted by circRNAs, we performed KEGG pathway enrichment analyses and found that three circRNAs (hsa_circ_0014235, hsa_circ_0025580 and hsa_circ_0026403) may involve in cancer-related pathway.	('hsa_circ_0025580', 'Var', (149, 165))	('involve', 'Reg', (192, 199))	('hsa_circ_0026403', 'Var', (170, 186))	('cancer', 'Disease', (203, 209))	('cancer', 'Disease', 'MESH:D009369', (203, 209))	('hsa_circ_0014235', 'Var', (131, 147))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))
265736	32059076	In this study, four microarray datasets (GSE18842,5 GSE33532,6 GSE62113,7 and GSE747068) were downloaded from the GEO database, and key genes identified by combining bioinformatics analyses in NSCLC.	('GSE747068', 'Var', (78, 87))	('NSCLC', 'Phenotype', 'HP:0030358', (193, 198))	('GSE18842,5', 'Var', (41, 51))	('NSCLC', 'Disease', (193, 198))	('NSCLC', 'Disease', 'MESH:D002289', (193, 198))
265741	32059076	GSE33532 consisted of four different sites (A, B, C, D) of individual primary tumors and matched distant normal lung tissue from 20 patients.	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('tumors', 'Disease', (78, 84))	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('GSE33532', 'Var', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('patients', 'Species', '9606', (132, 140))
265742	32059076	GSE62113 was total RNAs from xenografts, primary tumor, and normal adjacent tissues.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('GSE62113', 'Var', (0, 8))	('tumor', 'Disease', (49, 54))
265786	32059076	We found hub gene mutation frequencies were highest in LUAD.	('highest', 'Reg', (44, 51))	('hub', 'Gene', (9, 12))	('LUAD', 'Disease', (55, 59))	('mutation', 'Var', (18, 26))	('hub', 'Gene', '1993', (9, 12))
265799	32059076	Cell cycle dysregulation underlies the aberrant cell proliferation which characterizes cancer, and the loss of cell cycle checkpoint control promotes genetic instability.	('cancer', 'Disease', (87, 93))	('loss', 'Var', (103, 107))	('aberrant cell proliferation', 'Phenotype', 'HP:0031377', (39, 66))	('Cell cycle dysregulation', 'CPA', (0, 24))	('cell proliferation', 'CPA', (48, 66))	('Cell cycle dysregulation', 'Phenotype', 'HP:0011018', (0, 24))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('genetic', 'MPA', (150, 157))
265808	32059076	reported that HJURP was found to be overexpressed in lung cancer65 and promoted NSCLC cell proliferation and metastasis by inactivating the Wnt/beta-catenin pathway in the report by Wei et al.66 Our observations suggest that HJURP abnormalities may contribute to the risk of developing lung cancer.	('HJURP', 'Gene', '55355', (14, 19))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('NSCLC', 'Disease', (80, 85))	('overexpressed', 'PosReg', (36, 49))	('lung cancer', 'Disease', (286, 297))	('lung cancer', 'Disease', (53, 64))	('beta-catenin', 'Gene', (144, 156))	('NSCLC', 'Phenotype', 'HP:0030358', (80, 85))	('beta-catenin', 'Gene', '1499', (144, 156))	('promoted', 'PosReg', (71, 79))	('HJURP', 'Gene', (14, 19))	('HJURP', 'Gene', '55355', (225, 230))	('metastasis', 'CPA', (109, 119))	('contribute', 'Reg', (249, 259))	('lung cancer', 'Disease', 'MESH:D008175', (286, 297))	('lung cancer', 'Disease', 'MESH:D008175', (53, 64))	('abnormalities', 'Var', (231, 244))	('HJURP', 'Gene', (225, 230))	('inactivating', 'NegReg', (123, 135))	('lung cancer', 'Phenotype', 'HP:0100526', (286, 297))	('lung cancer', 'Phenotype', 'HP:0100526', (53, 64))	('cancer', 'Phenotype', 'HP:0002664', (291, 297))	('NSCLC', 'Disease', 'MESH:D002289', (80, 85))
265821	30828525	Cancer is a complex genetic disease associated with aberrant genomic alterations in germline or somatic genomes.	('genetic disease', 'Disease', (20, 35))	('genetic disease', 'Disease', 'MESH:D030342', (20, 35))	('aberrant genomic alterations', 'Var', (52, 80))	('Cancer', 'Disease', (0, 6))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('associated', 'Reg', (36, 46))
265824	30828525	Clearly, these methods can be limited by the currently incomplete known pathways and interaction networks in databases.12, 13  De novo computational methods have been developed to discover driver pathways based on two observations: 1) a large number of cancer samples have mutated genes in each driver pathway or module, referred to as high coverage property, where the coverage of a gene or a module is defined as the number of samples in which the gene or genes in the module are mutated; and 2) genes in a single driver pathway are altered exclusively in a cancer sample, referred to as high exclusivity,14, 15, 16, 17 i.e., at most one driver gene in a driver pathway is mutated in most samples.	('cancer', 'Phenotype', 'HP:0002664', (560, 566))	('cancer', 'Disease', 'MESH:D009369', (253, 259))	('cancer', 'Disease', (253, 259))	('altered', 'Reg', (535, 542))	('mutated', 'Var', (273, 280))	('cancer', 'Disease', (560, 566))	('cancer', 'Disease', 'MESH:D009369', (560, 566))	('cancer', 'Phenotype', 'HP:0002664', (253, 259))
265825	30828525	The phenomenon has led to the hypothesis that mutation in a single driver gene is usually sufficient to disturb the pathway and drive the cancer.	('cancer', 'Disease', (138, 144))	('drive', 'Reg', (128, 133))	('pathway', 'Pathway', (116, 123))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('mutation', 'Var', (46, 54))	('disturb', 'Reg', (104, 111))	('cancer', 'Disease', 'MESH:D009369', (138, 144))
265858	30828525	Enrichment analysis against the KEGG pathway database44 using DAVID42, 43 revealed that these genes were significantly enriched for chronic myeloid leukemia (hsa05220, p = 1.11E-06), LAML (hsa05221, p = 1.37E-05), central carbon metabolism in cancer (hsa05230, p = 2.34E-05), microRNAs in cancer (hsa05206, p = 8.04E-05), Ras signaling pathway (hsa04014, p = 2.86E-04), cell cycle (hsa04110, p = 3.11E-04) and pathways in cancer (hsa05200, p = 4.69E-04).	('central carbon metabolism', 'MPA', (214, 239))	('cancer', 'Phenotype', 'HP:0002664', (289, 295))	('cancer', 'Disease', (422, 428))	('cancer', 'Phenotype', 'HP:0002664', (422, 428))	('Ras signaling pathway', 'Pathway', (322, 343))	('cancer', 'Disease', 'MESH:D009369', (243, 249))	('leukemia', 'Phenotype', 'HP:0001909', (148, 156))	('chronic myeloid leukemia', 'Phenotype', 'HP:0005506', (132, 156))	('cancer', 'Disease', 'MESH:D009369', (289, 295))	('chronic myeloid leukemia', 'Disease', 'MESH:D015464', (132, 156))	('pathways', 'Pathway', (410, 418))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (140, 156))	('cancer', 'Disease', 'MESH:D009369', (422, 428))	('hsa04110', 'Var', (382, 390))	('cell', 'Pathway', (370, 374))	('cancer', 'Disease', (243, 249))	('hsa04014', 'Var', (345, 353))	('chronic myeloid leukemia', 'Disease', (132, 156))	('cancer', 'Phenotype', 'HP:0002664', (243, 249))	('cancer', 'Disease', (289, 295))
265866	30828525	The genes were also enriched for KEGG pathways such as pancreatic cancer (hsa05212, p = 2.33E-06), bladder cancer (hsa05219, p = 1.04E-05), pathways in cancer (hsa05200, p = 3.35E-05), and non-small cell lung cancer (hsa05223, p = 3.64E-05).	('bladder cancer', 'Phenotype', 'HP:0009725', (99, 113))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (189, 215))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('pancreatic cancer', 'Disease', 'MESH:D010190', (55, 72))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('KEGG pathways', 'Pathway', (33, 46))	('cancer', 'Disease', (152, 158))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (193, 215))	('cancer', 'Disease', 'MESH:D009369', (209, 215))	('pancreatic cancer', 'Disease', (55, 72))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (189, 215))	('hsa05200', 'Var', (160, 168))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('pathways', 'Pathway', (140, 148))	('lung cancer', 'Phenotype', 'HP:0100526', (204, 215))	('non-small cell lung cancer', 'Disease', (189, 215))	('cancer', 'Disease', (107, 113))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (55, 72))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('bladder cancer', 'Disease', 'MESH:D001749', (99, 113))	('cancer', 'Disease', (209, 215))	('bladder cancer', 'Disease', (99, 113))	('cancer', 'Disease', (66, 72))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
265868	30828525	Of the 12 genes (CFH, CHD8, CR1, EP400, F13A1, HCFC1, ITGAM, ITGAX, LILRB2, NAV1, and NAV2) that are not NCG cancer genes, several genes have been reported to be related to lung cancer.	('HCFC1', 'Gene', (47, 52))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('lung cancer', 'Disease', 'MESH:D008175', (173, 184))	('CR1', 'Gene', (28, 31))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('CFH', 'Disease', 'MESH:C562875', (17, 20))	('cancer', 'Disease', (109, 115))	('cancer', 'Disease', (178, 184))	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('F13A1', 'Gene', (40, 45))	('CFH', 'Disease', (17, 20))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('EP400', 'Var', (33, 38))	('lung cancer', 'Disease', (173, 184))	('lung cancer', 'Phenotype', 'HP:0100526', (173, 184))	('related', 'Reg', (162, 169))
265900	30055580	The predictive factors for worse OS on multivariate analysis were preoperative VA < 20/400 (adjusted hazard ratio [aHR] 4.67, P = 0.003), tumor size larger than 20 mm (aHR 3.14, P = 0.022,) and positive distant metastasis at diagnosis (aHR 15.31, P <  0.001).	('tumor', 'Disease', (138, 143))	('OS', 'Chemical', '-', (33, 35))	('VA < 20/400', 'Var', (79, 90))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
265963	30055580	Interestingly, we revealed that tumor-related survival was significantly better for patients with a preoperative VA >=20/400 than for patients with a VA < 20/400.	('patients', 'Species', '9606', (84, 92))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('patients', 'Species', '9606', (134, 142))	('>=20/400', 'Var', (116, 124))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('better', 'PosReg', (73, 79))	('tumor', 'Disease', (32, 37))
266005	28607579	We also discuss new mutations in NSCLC where ongoing clinical trials are establishing targeted therapies.	('NSCLC', 'Disease', (33, 38))	('NSCLC', 'Phenotype', 'HP:0030358', (33, 38))	('NSCLC', 'Disease', 'MESH:D002289', (33, 38))	('mutations', 'Var', (20, 29))
266007	28607579	In the last decade, the introduction of molecularly targeted therapies in a wide range of cancers has led to increasing demands on health care resources.	('molecularly', 'Var', (40, 51))	('cancers', 'Disease', (90, 97))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('cancers', 'Disease', 'MESH:D009369', (90, 97))
266012	28607579	For example, if a patient is being investigated for metastatic NSCLC, the pretest probability of having an epidermal growth factor receptor (EGFR) mutation would be 5-15% in an unselected population.	('NSCLC', 'Disease', (63, 68))	('EGFR', 'Gene', '1956', (141, 145))	('NSCLC', 'Disease', 'MESH:D002289', (63, 68))	('mutation', 'Var', (147, 155))	('epidermal growth factor receptor', 'Gene', (107, 139))	('EGFR', 'Gene', (141, 145))	('NSCLC', 'Phenotype', 'HP:0030358', (63, 68))	('patient', 'Species', '9606', (18, 25))	('epidermal growth factor receptor', 'Gene', '1956', (107, 139))
266013	28607579	However, if following pathological confirmation a diagnosis of metastatic pulmonary adenocarcinoma is made and the patient is Asian, the pretest probability of having an EGFR mutation will increase to 36-60%.	('pulmonary adenocarcinoma', 'Phenotype', 'HP:0030078', (74, 98))	('EGFR', 'Gene', '1956', (170, 174))	('mutation', 'Var', (175, 183))	('EGFR', 'Gene', (170, 174))	('patient', 'Species', '9606', (115, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('pulmonary adenocarcinoma', 'Disease', (74, 98))	('pulmonary adenocarcinoma', 'Disease', 'MESH:D008175', (74, 98))
266015	28607579	For example, advanced NSCLC patients with a high pretest probability of having a tumoral EGFR mutation (such as never-smoking Asians with pulmonary adenocarcinoma), but that in fact have EGFR wild-type tumours, have inferior progression-free survival and quality of life if treated with initial EGFR-tyrosine kinase inhibitor (EGFR-TKI) instead of platinum-based chemotherapy.	('carcinoma', 'Phenotype', 'HP:0030731', (153, 162))	('tumours', 'Phenotype', 'HP:0002664', (202, 209))	('inferior', 'NegReg', (216, 224))	('tumours', 'Disease', 'MESH:D009369', (202, 209))	('NSCLC', 'Disease', 'MESH:D002289', (22, 27))	('tumour', 'Phenotype', 'HP:0002664', (202, 208))	('EGFR', 'Gene', '1956', (187, 191))	('EGFR', 'Gene', (327, 331))	('progression-free survival', 'CPA', (225, 250))	('NSCLC', 'Disease', (22, 27))	('pulmonary adenocarcinoma', 'Phenotype', 'HP:0030078', (138, 162))	('patients', 'Species', '9606', (28, 36))	('EGFR', 'Gene', (295, 299))	('EGFR', 'Gene', (89, 93))	('platinum', 'Chemical', 'MESH:D010984', (348, 356))	('NSCLC', 'Phenotype', 'HP:0030358', (22, 27))	('pulmonary adenocarcinoma', 'Disease', (138, 162))	('pulmonary adenocarcinoma', 'Disease', 'MESH:D008175', (138, 162))	('tumoral', 'Disease', (81, 88))	('tumoral', 'Disease', 'MESH:D009369', (81, 88))	('EGFR', 'Gene', '1956', (89, 93))	('EGFR', 'Gene', '1956', (327, 331))	('EGFR', 'Gene', (187, 191))	('tumours', 'Disease', (202, 209))	('EGFR', 'Gene', '1956', (295, 299))	('mutation', 'Var', (94, 102))
266022	28607579	Prior to proceeding with EGFR mutation testing, physicians consider several variables, including histology, sex, smoking history and ethnicity.	('mutation', 'Var', (30, 38))	('EGFR', 'Gene', '1956', (25, 29))	('EGFR', 'Gene', (25, 29))
266023	28607579	These factors when taken together can affect the pretest probability of having an EGFR mutation.	('EGFR', 'Gene', (82, 86))	('EGFR', 'Gene', '1956', (82, 86))	('mutation', 'Var', (87, 95))	('affect', 'Reg', (38, 44))
266024	28607579	However, no pretest probability model currently exists which comprises all possible variables that may impact EGFR mutation prevalence.	('EGFR', 'Gene', (110, 114))	('mutation', 'Var', (115, 123))	('impact', 'Reg', (103, 109))	('EGFR', 'Gene', '1956', (110, 114))
266025	28607579	For example, EGFR mutation prevalence is approximately 5% in squamous cell histology, and the guidelines do not recommend testing for EGFR mutation unless certain clinical and histological features are present.	('EGFR', 'Gene', (134, 138))	('mutation', 'Var', (18, 26))	('EGFR', 'Gene', '1956', (13, 17))	('EGFR', 'Gene', (13, 17))	('EGFR', 'Gene', '1956', (134, 138))
266028	28607579	While the examples presented here focus on EGFR mutations, there is an increasing number of actionable mutations being identified and therefore patient selection will become even more important.	('EGFR', 'Gene', '1956', (43, 47))	('EGFR', 'Gene', (43, 47))	('mutations', 'Var', (48, 57))	('patient', 'Species', '9606', (144, 151))
266031	28607579	For example, in metastatic adenocarcinoma, the pretest probability of a patient having an EGFR mutation is approximately 25%.	('EGFR', 'Gene', '1956', (90, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (32, 41))	('patient', 'Species', '9606', (72, 79))	('adenocarcinoma', 'Disease', (27, 41))	('EGFR', 'Gene', (90, 94))	('adenocarcinoma', 'Disease', 'MESH:D000230', (27, 41))	('mutation', 'Var', (95, 103))
266035	28607579	For example, consider the pretest probability of having an EGFR mutation in three new patients presenting to a thoracic oncology clinic: Patient A, a 40-year-old never-smoking Asian female with a diagnosis of stage IV adenocarcinoma; Patient B, a 68-year-old Caucasian male with a 50 pack per year smoking history diagnosed with metastatic NSCLC, squamous cell histology; and Patient C, a 40-year-old never-smoking Asian female with a diagnosis of stage IV lung squamous cell carcinoma (large tissue sample).	('NSCLC', 'Disease', 'MESH:D002289', (340, 345))	('EGFR', 'Gene', (59, 63))	('IV adenocarcinoma', 'Disease', 'MESH:D000230', (215, 232))	('NSCLC', 'Disease', (340, 345))	('carcinoma', 'Phenotype', 'HP:0030731', (223, 232))	('patients', 'Species', '9606', (86, 94))	('NSCLC', 'Phenotype', 'HP:0030358', (340, 345))	('carcinoma', 'Phenotype', 'HP:0030731', (476, 485))	('EGFR', 'Gene', '1956', (59, 63))	('Patient', 'Species', '9606', (234, 241))	('squamous cell', 'Disease', (347, 360))	('Patient', 'Species', '9606', (376, 383))	('mutation', 'Var', (64, 72))	('stage IV lung squamous cell carcinoma', 'Disease', (448, 485))	('stage IV lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (448, 485))	('oncology', 'Phenotype', 'HP:0002664', (120, 128))	('IV adenocarcinoma', 'Disease', (215, 232))	('Patient', 'Species', '9606', (137, 144))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (457, 485))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (462, 485))
266036	28607579	The additive effect of each variable in Patient A's case - histological subtype, Asian, female, never-smoker - increases the pretest probability of having an EGFR mutation.	('EGFR', 'Gene', '1956', (158, 162))	('mutation', 'Var', (163, 171))	('Patient', 'Species', '9606', (40, 47))	('EGFR', 'Gene', (158, 162))
266038	28607579	EGFR mutation testing is performed by direct sequencing or real-time quantitative PCR-based approach.	('mutation', 'Var', (5, 13))	('EGFR', 'Gene', '1956', (0, 4))	('EGFR', 'Gene', (0, 4))
266039	28607579	For Patient B, when we consider the additional variables along with squamous histology - male, Caucasian, heavy smoking history - the probability of having an EGFR mutation is further reduced.	('Patient', 'Species', '9606', (4, 11))	('EGFR', 'Gene', '1956', (159, 163))	('reduced', 'NegReg', (184, 191))	('mutation', 'Var', (164, 172))	('EGFR', 'Gene', (159, 163))
266042	28607579	In this situation, most clinicians would consider testing for an EGFR mutation.	('mutation', 'Var', (70, 78))	('testing', 'Reg', (50, 57))	('EGFR', 'Gene', '1956', (65, 69))	('EGFR', 'Gene', (65, 69))
266047	28607579	Identification of an EGFR mutation in this subgroup will not change therapeutic management, but may have value at a later stage in the event of relapsed disease (common in NSCLC).	('EGFR', 'Gene', '1956', (21, 25))	('EGFR', 'Gene', (21, 25))	('mutation', 'Var', (26, 34))	('NSCLC', 'Disease', (172, 177))	('NSCLC', 'Disease', 'MESH:D002289', (172, 177))	('NSCLC', 'Phenotype', 'HP:0030358', (172, 177))
266048	28607579	In addition, although double mutations in ALK, EGFR and KRAS have been described, these are rare and more commonly are mutually exclusive.	('ALK', 'Gene', '238', (42, 45))	('KRAS', 'Gene', (56, 60))	('KRAS', 'Gene', '3845', (56, 60))	('ALK', 'Gene', (42, 45))	('EGFR', 'Gene', '1956', (47, 51))	('double mutations', 'Var', (22, 38))	('EGFR', 'Gene', (47, 51))
266052	28607579	ALK translocations have been described in 2-7% of NSCLC patients and is more commonly seen in adenocarcinoma histology and never- or light smokers.	('translocations', 'Var', (4, 18))	('patients', 'Species', '9606', (56, 64))	('NSCLC', 'Phenotype', 'HP:0030358', (50, 55))	('ALK', 'Gene', (0, 3))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('NSCLC', 'Disease', (50, 55))	('adenocarcinoma', 'Disease', (94, 108))	('NSCLC', 'Disease', 'MESH:D002289', (50, 55))	('adenocarcinoma', 'Disease', 'MESH:D000230', (94, 108))	('ALK', 'Gene', '238', (0, 3))
266055	28607579	Resistance to crizotinib eventually develops, with secondary ALK mutations being one of the main mechanisms of resistance.	('ALK', 'Gene', '238', (61, 64))	('ALK', 'Gene', (61, 64))	('crizotinib', 'Chemical', 'MESH:D000077547', (14, 24))	('mutations', 'Var', (65, 74))
266065	28607579	KRAS mutations are the most common mutation in lung cancer and are more frequently seen in adenocarcinoma (25%) versus squamous histology (5%), non-Asian ethnic origin and in current or ex-smokers.	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('seen', 'Reg', (83, 87))	('lung cancer', 'Disease', (47, 58))	('lung cancer', 'Phenotype', 'HP:0100526', (47, 58))	('adenocarcinoma', 'Disease', 'MESH:D000230', (91, 105))	('mutations', 'Var', (5, 14))	('lung cancer', 'Disease', 'MESH:D008175', (47, 58))	('KRAS', 'Gene', (0, 4))	('adenocarcinoma', 'Disease', (91, 105))	('KRAS', 'Gene', '3845', (0, 4))
266066	28607579	Studies to date have not conclusively identified KRAS as a prognostic or predictive marker, with the exception of negative predictive value of KRAS mutations and response to EGFR-TKI.	('EGFR', 'Gene', (174, 178))	('mutations', 'Var', (148, 157))	('KRAS', 'Gene', '3845', (49, 53))	('KRAS', 'Gene', (49, 53))	('KRAS', 'Gene', (143, 147))	('KRAS', 'Gene', '3845', (143, 147))	('EGFR', 'Gene', '1956', (174, 178))
266067	28607579	The majority of KRAS mutations in NSCLC are single amino acid substitutions in codon 12 and to a lesser extent in codon 13 and 61.	('NSCLC', 'Disease', (34, 39))	('NSCLC', 'Disease', 'MESH:D002289', (34, 39))	('NSCLC', 'Phenotype', 'HP:0030358', (34, 39))	('KRAS', 'Gene', (16, 20))	('KRAS', 'Gene', '3845', (16, 20))	('mutations', 'Var', (21, 30))
266069	28607579	KRAS mutations can be associated with other genetic alterations and these different genetic profile combinations may require alternative therapeutics.	('associated', 'Reg', (22, 32))	('KRAS', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))	('KRAS', 'Gene', '3845', (0, 4))
266075	28607579	MET amplification occurs in approximately 2-4% of lung cancer cases, and in addition might contribute to progression after treatment with EGFR inhibitors in 5-20% of patients (www.mycancergenome.org/content/disease/lung-cancer/met/59).	('MET amplification', 'Var', (0, 17))	('lung cancer', 'Disease', 'MESH:D008175', (50, 61))	('EGFR', 'Gene', (138, 142))	('cancer', 'Disease', 'MESH:D009369', (220, 226))	('lung cancer', 'Phenotype', 'HP:0100526', (50, 61))	('contribute', 'Reg', (91, 101))	('cancer', 'Disease', (182, 188))	('cancer', 'Disease', (55, 61))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('EGFR', 'Gene', '1956', (138, 142))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('lung-cancer', 'Disease', 'MESH:D008175', (215, 226))	('cancer', 'Disease', (220, 226))	('lung-cancer', 'Disease', (215, 226))	('lung cancer', 'Disease', (50, 61))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('patients', 'Species', '9606', (166, 174))
266076	28607579	Exon 14 MET splice mutations occur in 3% of patients with lung cancer.	('patients', 'Species', '9606', (44, 52))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('lung cancer', 'Disease', (58, 69))	('lung cancer', 'Phenotype', 'HP:0100526', (58, 69))	('MET splice mutations', 'Var', (8, 28))	('occur', 'Reg', (29, 34))	('lung cancer', 'Disease', 'MESH:D008175', (58, 69))
266083	28607579	MET exon 14 skipping mutations occur in 3% of patients with NSCLC.	('patients', 'Species', '9606', (46, 54))	('NSCLC', 'Phenotype', 'HP:0030358', (60, 65))	('skipping mutations', 'Var', (12, 30))	('NSCLC', 'Disease', (60, 65))	('MET exon', 'Var', (0, 8))	('NSCLC', 'Disease', 'MESH:D002289', (60, 65))
266087	28607579	A phase Ib/II trial investigated the safety and efficacy of capamatinib plus gefitinib in EGFR mutant, cMET positive NSCLC who progressed on gefitinib, erlotinib, or afatinib.	('NSCLC', 'Disease', (117, 122))	('cMET', 'Gene', (103, 107))	('erlotinib', 'Chemical', 'MESH:D000069347', (152, 161))	('capamatinib', 'Chemical', '-', (60, 71))	('gefitinib', 'Chemical', 'MESH:D000077156', (141, 150))	('EGFR', 'Gene', '1956', (90, 94))	('progressed', 'PosReg', (127, 137))	('NSCLC', 'Disease', 'MESH:D002289', (117, 122))	('afatinib', 'Chemical', 'MESH:D000077716', (166, 174))	('EGFR', 'Gene', (90, 94))	('NSCLC', 'Phenotype', 'HP:0030358', (117, 122))	('mutant', 'Var', (95, 101))	('gefitinib', 'Chemical', 'MESH:D000077156', (77, 86))	('cMET', 'Gene', '4233', (103, 107))
266092	28607579	ROS-1 rearrangements have been reported to be mutually exclusive with other oncogenic driver alterations (EGFR, KRAS, ALK, HER2, RET).	('RET', 'Gene', (129, 132))	('rearrangements', 'Var', (6, 20))	('HER2', 'Gene', (123, 127))	('ALK', 'Gene', '238', (118, 121))	('ROS-1', 'Gene', (0, 5))	('HER2', 'Gene', '2064', (123, 127))	('KRAS', 'Gene', (112, 116))	('RET', 'Gene', '5979', (129, 132))	('EGFR', 'Gene', '1956', (106, 110))	('KRAS', 'Gene', '3845', (112, 116))	('ALK', 'Gene', (118, 121))	('ROS-1', 'Gene', '6098', (0, 5))	('EGFR', 'Gene', (106, 110))
266093	28607579	Nine fusion protein variants have been described in NSCLC; fluorescence in-situ hybridization (FISH) assay is currently considered the gold standard for ROS-1 fusion detection.	('variants', 'Var', (20, 28))	('NSCLC', 'Disease', (52, 57))	('ROS-1', 'Gene', (153, 158))	('ROS-1', 'Gene', '6098', (153, 158))	('NSCLC', 'Disease', 'MESH:D002289', (52, 57))	('NSCLC', 'Phenotype', 'HP:0030358', (52, 57))
266095	28607579	A retrospective European study of 31 patients with ROS-1 rearrangement treated with crizotinib demonstrated a median PFS of 9.1 months.	('ROS-1', 'Gene', (51, 56))	('crizotinib', 'Chemical', 'MESH:D000077547', (84, 94))	('patients', 'Species', '9606', (37, 45))	('ROS-1', 'Gene', '6098', (51, 56))	('rearrangement', 'Var', (57, 70))
266121	27123052	In various tumors, abnormal claudin expression alters TJ structure and function, causing a disruption in cell polarity and a decrease in cell adhesion, thus enhancing the invasive and metastatic potential of tumor cells.	('function', 'MPA', (71, 79))	('enhancing', 'PosReg', (157, 166))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('alters', 'Reg', (47, 53))	('tumor', 'Disease', 'MESH:D009369', (208, 213))	('tumors', 'Phenotype', 'HP:0002664', (11, 17))	('tumor', 'Disease', (11, 16))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('tumors', 'Disease', (11, 17))	('tumors', 'Disease', 'MESH:D009369', (11, 17))	('decrease', 'NegReg', (125, 133))	('abnormal', 'Var', (19, 27))	('tumor', 'Disease', (208, 213))	('cell polarity', 'CPA', (105, 118))	('claudin', 'Gene', (28, 35))	('disruption', 'Reg', (91, 101))	('tumor', 'Disease', 'MESH:D009369', (11, 16))	('cell adhesion', 'CPA', (137, 150))
266159	27123052	Log-rank test of 97 HSCC patients who were followed-up for 3-5 years demonstrated that the patient survival rate was significantly lower in patients with high expression levels of claudin-1, compared with patients with low expression levels of claudin-1 (51.71+-4.02% vs. 31.78+-2.09%; P=0.003; Fig.	('claudin-1', 'Gene', (180, 189))	('HSCC', 'Phenotype', 'HP:0012182', (20, 24))	('patient survival rate', 'CPA', (91, 112))	('patients', 'Species', '9606', (205, 213))	('claudin-1', 'Gene', '9076', (244, 253))	('high', 'Var', (154, 158))	('patient', 'Species', '9606', (140, 147))	('patient', 'Species', '9606', (25, 32))	('patient', 'Species', '9606', (91, 98))	('patients', 'Species', '9606', (25, 33))	('claudin-1', 'Gene', '9076', (180, 189))	('patients', 'Species', '9606', (140, 148))	('lower', 'NegReg', (131, 136))	('claudin-1', 'Gene', (244, 253))	('patient', 'Species', '9606', (205, 212))
266160	27123052	Furthermore, patients with high expression levels of cyclin B1 exhibited a lower survival rate, compared with patients with those exhibiting low expression levels of cyclin B1 (43.06+-4.25% vs. 38.06+-3.11%; P=0.305), although this was not statistically significant (Fig.	('lower', 'NegReg', (75, 80))	('patients', 'Species', '9606', (13, 21))	('cyclin B1', 'Gene', '891', (166, 175))	('cyclin B1', 'Gene', (166, 175))	('high expression levels', 'Var', (27, 49))	('cyclin B1', 'Gene', '891', (53, 62))	('cyclin B1', 'Gene', (53, 62))	('survival rate', 'CPA', (81, 94))	('patients', 'Species', '9606', (110, 118))
266179	27123052	Abnormalities in claudins expression or localization result in abnormal intercellular signaling and promote tumor formation and metastasis.	('expression', 'MPA', (26, 36))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('claudins', 'Protein', (17, 25))	('Abnormalities', 'Var', (0, 13))	('result in abnormal', 'Reg', (53, 71))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('tumor', 'Disease', (108, 113))	('promote', 'PosReg', (100, 107))	('intercellular signaling', 'MPA', (72, 95))
266180	27123052	Altered claudin-1 expression leads to the destruction of epithelial permeability and barrier function, loss of cell polarity, decrease in intercellular adhesion force and tumor development.	('epithelial permeability', 'MPA', (57, 80))	('claudin-1', 'Gene', (8, 17))	('cell polarity', 'CPA', (111, 124))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('intercellular adhesion force', 'MPA', (138, 166))	('decrease', 'NegReg', (126, 134))	('Altered', 'Var', (0, 7))	('barrier function', 'CPA', (85, 101))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', (171, 176))	('claudin-1', 'Gene', '9076', (8, 17))	('destruction', 'NegReg', (42, 53))	('loss', 'NegReg', (103, 107))
266182	27123052	Changes in claudin-1 localization within the cell membrane, alongside a decrease in E-cadherin expression and an increase in the expression of the components of the E-cadherin/TCF signaling pathway, may promote tumor development.	('E-cadherin', 'Gene', (84, 94))	('E-cadherin', 'Gene', '999', (84, 94))	('expression', 'MPA', (129, 139))	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('E-cadherin', 'Gene', '999', (165, 175))	('claudin-1', 'Gene', '9076', (11, 20))	('TCF', 'Gene', (176, 179))	('promote', 'PosReg', (203, 210))	('TCF', 'Gene', '3172', (176, 179))	('Changes', 'Var', (0, 7))	('tumor', 'Disease', (211, 216))	('E-cadherin', 'Gene', (165, 175))	('increase', 'PosReg', (113, 121))	('decrease', 'NegReg', (72, 80))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('claudin-1', 'Gene', (11, 20))	('expression', 'MPA', (95, 105))	('localization', 'MPA', (21, 33))
266214	32884946	In CSCC patients, the disease-free and disease-specific survival rates with diffuse PD-L1 expression were largely lower than those with marginal PD-L1 expression on the tumor and stroma interface.	('PD-L1', 'Gene', (84, 89))	('SCC', 'Phenotype', 'HP:0002860', (4, 7))	('-free', 'Disease', 'MESH:D008569', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('-free', 'Disease', (29, 34))	('CSCC', 'Disease', (3, 7))	('lower', 'NegReg', (114, 119))	('diffuse', 'Var', (76, 83))
266215	32884946	Similarly, one study revealed that cervical adenocarcinoma patients with tumor-related macrophages of PD-L1 positive expression represented lower disease-specific survival ratio, relative to those with adenocarcinoma with PD-L1 negative tumor-associated macrophages.	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('disease-specific survival ratio', 'CPA', (146, 177))	('lower', 'NegReg', (140, 145))	('PD-L1 negative tumor', 'Disease', 'MESH:D010300', (222, 242))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('carcinoma', 'Phenotype', 'HP:0030731', (207, 216))	('PD-L1', 'Gene', (102, 107))	('cervical adenocarcinoma', 'Disease', (35, 58))	('positive expression', 'Var', (108, 127))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))	('PD-L1 negative tumor', 'Disease', (222, 242))
266224	32884946	CD8+ TILS situating inside of tumor nests indicated intraepithelial neoplasm infiltration, while CD8+ TILS staying in the adjacent stroma represented peripheral neoplasm infiltration.	('neoplasm', 'Phenotype', 'HP:0002664', (161, 169))	('intraepithelial neoplasm', 'Phenotype', 'HP:0032187', (52, 76))	('neoplasm infiltration', 'Disease', (68, 89))	('CD8+', 'Var', (97, 101))	('neoplasm infiltration', 'Disease', 'MESH:D017254', (68, 89))	('neoplasm infiltration', 'Disease', (161, 182))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('neoplasm infiltration', 'Disease', 'MESH:D017254', (161, 182))	('neoplasm', 'Phenotype', 'HP:0002664', (68, 76))	('CD8+', 'Var', (0, 4))
266225	32884946	Three rich areas of CD8+ TILS in tumor cells were chosen under a low-magnification microscope to avoid bleeding and/or necrotic lesions.	('bleeding', 'Disease', (103, 111))	('CD8+ TILS', 'Var', (20, 29))	('necrotic lesions', 'Disease', (119, 135))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('necrotic lesions', 'Disease', 'MESH:D009336', (119, 135))	('bleeding', 'Disease', 'MESH:D006470', (103, 111))
266231	32884946	's report that PD-L1 expression was linked to CD8+ TILS density in pancreatic cancer tissues.	('PD-L1', 'Gene', (15, 20))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (67, 84))	('CD8+', 'Var', (46, 50))	('pancreatic cancer', 'Disease', (67, 84))	('pancreatic cancer', 'Disease', 'MESH:D010190', (67, 84))	('linked', 'Reg', (36, 42))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))
266233	32884946	Previous studies have shown that the density of CD8+ TILS is related to the long-term survival rate of patients with various cancers.	('cancers', 'Disease', 'MESH:D009369', (125, 132))	('cancers', 'Phenotype', 'HP:0002664', (125, 132))	('cancers', 'Disease', (125, 132))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('CD8+ TILS', 'Var', (48, 57))	('related', 'Reg', (61, 68))
266234	32884946	Regarding the correlation between PD-L1 and CD8+ TILS, the evident association between the CD8+ TILS expression density and PD-L1 expression on tumor cells resulted from the mechanism of PD-L1/PD-1, which inhibited T cell activation by repressing transduction of the TCR signal and costimulation of CD28-CD80.	('PD-L1', 'Gene', (124, 129))	('inhibited T cell activation', 'Phenotype', 'HP:0005419', (205, 232))	('CD80', 'Gene', '397161', (304, 308))	('PD-L1/PD-1', 'Var', (187, 197))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('CD80', 'Gene', (304, 308))
266235	32884946	Combination of PD-L1 and CD8+ TILS in gastric cancer specimens is of great significance to evaluate the immune status and prognosis of gastric cancer, showing to be related to the low survival rate of esophageal cancer, gastric cancer, colorectal cancer, and lung cancer.	('gastric cancer', 'Disease', (135, 149))	('lung cancer', 'Phenotype', 'HP:0100526', (259, 270))	('gastric cancer', 'Phenotype', 'HP:0012126', (220, 234))	('gastric cancer', 'Disease', (38, 52))	('colorectal cancer', 'Phenotype', 'HP:0003003', (236, 253))	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('gastric cancer', 'Disease', 'MESH:D013274', (135, 149))	('esophageal cancer', 'Disease', (201, 218))	('gastric cancer', 'Disease', 'MESH:D013274', (38, 52))	('CD8+', 'Var', (25, 29))	('gastric cancer', 'Disease', (220, 234))	('lung cancer', 'Disease', (259, 270))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('gastric cancer', 'Phenotype', 'HP:0012126', (135, 149))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('colorectal cancer', 'Disease', 'MESH:D015179', (236, 253))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('low', 'NegReg', (180, 183))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))	('gastric cancer', 'Disease', 'MESH:D013274', (220, 234))	('gastric cancer', 'Phenotype', 'HP:0012126', (38, 52))	('colorectal cancer', 'Disease', (236, 253))	('lung cancer', 'Disease', 'MESH:D008175', (259, 270))
266236	32884946	In our study, multivariate analysis indicated that the high density of CD8+ TILS in highly differentiated pericarcinoma was correlated with better survival.	('pericarcinoma', 'Disease', (106, 119))	('better', 'PosReg', (140, 146))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('pericarcinoma', 'Disease', 'None', (106, 119))	('CD8+ TILS', 'Var', (71, 80))
266250	27894333	AHR foreign ligands include chemicals such as PAHs; polyhalogenated dibenzo-p-dioxins, dibenzofurans and biphenyls; and benzoflavones found especially in cruciferous plants.	('polyhalogenated', 'Var', (52, 67))	('biphenyls', 'Chemical', 'MESH:C010574', (105, 114))	('polyhalogenated dibenzo-p-dioxins', 'Chemical', '-', (52, 85))	('AHR', 'Gene', '196', (0, 3))	('PAHs', 'Chemical', 'MESH:D011084', (46, 50))	('AHR', 'Gene', (0, 3))	('dibenzofurans', 'Chemical', 'MESH:D000072318', (87, 100))	('benzoflavones', 'Chemical', 'MESH:D001571', (120, 133))
266279	27894333	At all times, we followed the clinical protocol:titled "Human Cancer and AHR/CYP1A1/1A2/1B1 Gene Polymorphisms" (#03-08-07-01):annually approved for the entire study, without any HIPAA issues or concerns, by the University of Cincinnati Medical Center Institutional Review Board (IRB).	('AHR', 'Gene', '196', (73, 76))	('AHR', 'Gene', (73, 76))	('Human', 'Species', '9606', (56, 61))	('Cancer', 'Phenotype', 'HP:0002664', (62, 68))	('Polymorphisms', 'Var', (97, 110))	('CYP1A1', 'Gene', (77, 83))	('CYP1A1', 'Gene', '1543', (77, 83))	('clinical', 'Species', '191496', (30, 38))
266287	27894333	Bioinformatics software HaploView (v. 4.2, Mark Daly's lab; MIT/Harvard Broad Institute) was used to determine associations between the markers:variation in SNPs:and phenotype in HS vs. HR samples.	('variation', 'Var', (144, 153))	('SNPs', 'Gene', (157, 161))	('Mark', 'Gene', (43, 47))	('associations', 'Interaction', (111, 123))	('Mark', 'Gene', '4139', (43, 47))
266292	27894333	Compared with malignancies in nonsmokers, smokers exhibit more tumors of the larynx, hypopharynx, and floor of the mouth; a much greater TP53 mutation rate; a substantially higher percent of loss of heterozygosity at Chr 3p, 4q, and 11q13; and a greater overall average number of chromosomal losses.	('floor of the mouth', 'Phenotype', 'HP:0410012', (102, 120))	('malignancies', 'Disease', 'MESH:D009369', (14, 26))	('loss', 'NegReg', (191, 195))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('tumors', 'Disease', (63, 69))	('malignancies', 'Disease', (14, 26))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('TP53', 'Gene', '7157', (137, 141))	('mutation', 'Var', (142, 150))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('greater', 'PosReg', (129, 136))	('TP53', 'Gene', (137, 141))
266299	27894333	We used Genome Assembly GRCh38.p2 (Annotation Release 107) for this analysis; data were calculated from the genomic sequences of Ensembl transcripts AHR-002 (ENST00000242057), CYP1A1-001 (ENST00000379727), CYP1A2-001 (ENST00000343932), and CYP1B1-001 (ENST00000610745).	('AHR', 'Gene', (149, 152))	('CYP1A2', 'Gene', '1544', (206, 212))	('CYP1A2', 'Gene', (206, 212))	('CYP1A1', 'Gene', (176, 182))	('ENST00000343932', 'Var', (218, 233))	('ENST00000379727', 'Var', (188, 203))	('CYP1B1', 'Gene', '1545', (240, 246))	('CYP1A1', 'Gene', '1543', (176, 182))	('CYP1B1', 'Gene', (240, 246))	('ENST00000610745', 'Var', (252, 267))	('AHR', 'Gene', '196', (149, 152))	('ENST00000242057', 'Var', (158, 173))
266300	27894333	From chi-square analysis, there is only one SNP that appears to show a significant P value in the AHR gene: rs4719497 (P = 0.0134).	('rs4719497', 'Mutation', 'rs4719497', (108, 117))	('AHR', 'Gene', (98, 101))	('AHR', 'Gene', '196', (98, 101))	('rs4719497', 'Var', (108, 117))
266315	27894333	We found no studies in the literature concerning AHR polymorphisms associated with HNSCC.	('AHR', 'Gene', (49, 52))	('HNSCC', 'Disease', (83, 88))	('HNSCC', 'Phenotype', 'HP:0012288', (83, 88))	('associated', 'Reg', (67, 77))	('AHR', 'Gene', '196', (49, 52))	('polymorphisms', 'Var', (53, 66))
266316	27894333	(a) The Leu-432 allele of CYP1B1 has been associated with a greater frequency [odds-ratio (O.R.)	('CYP1B1', 'Gene', '1545', (26, 32))	('Leu-432', 'Var', (8, 15))	('Leu', 'Chemical', 'MESH:D007930', (8, 11))	('CYP1B1', 'Gene', (26, 32))
266317	27894333	>4] of TP53 gene mutations and HNSCC in cigarette smokers; however, this "greater risk" is difficult to reconcile experimentally:given the fact that the Leu-432 mutant was shown in an E. coli expression assay in vitro to metabolize PAHs only 1.2- to 1.5-fold better than the Val-432 variant.	('PAHs', 'Chemical', 'MESH:D011084', (232, 236))	('Val', 'Chemical', 'MESH:D014633', (275, 278))	('metabolize', 'MPA', (221, 231))	('TP53', 'Gene', '7157', (7, 11))	('TP53', 'Gene', (7, 11))	('E. coli', 'Species', '562', (184, 191))	('HNSCC', 'Phenotype', 'HP:0012288', (31, 36))	('Leu', 'Chemical', 'MESH:D007930', (153, 156))	('Leu-432', 'Var', (153, 160))
266318	27894333	(b) Four nonsynonymous coding SNPs (p.R48G, p.A119S, p.L432V, and p.N453S) were studied in 150 cases of HNSCC and 150 controls; when the four SNPs were analyzed as a haplotype, amino acid changes p.A48G and p.A119S exhibited complete LD in all cases and controls, and significant differences (P < 0.05) were reported in the two haplotypes:GTCA and GTGA:as being associated with increased risk of HNSCC.	('HNSCC', 'Disease', (396, 401))	('p.A48G', 'Mutation', 'rs1215102009', (196, 202))	('p.L432V', 'Mutation', 'rs1056836', (53, 60))	('p.A119S', 'Mutation', 'rs1056827', (207, 214))	('p.N453S', 'Mutation', 'rs1800440', (66, 73))	('HNSCC', 'Phenotype', 'HP:0012288', (396, 401))	('HNSCC', 'Phenotype', 'HP:0012288', (104, 109))	('p.A119S', 'Var', (207, 214))	('associated', 'Reg', (362, 372))	('p.R48G', 'Mutation', 'rs10012', (36, 42))	('p.A48G', 'Var', (196, 202))	('p.A119S', 'Mutation', 'rs1056827', (44, 51))
266319	27894333	(c) Another study, comparing 312 HNSCC cases and 300 noncancer controls, looked at the impact of 22 sequence variations in CYP1A1, CYP1B1, CYP2E1, GSTM1, and six other genes encoding either xenobiotic-metabolizing or DNA repair enzymes; using logit regression and a Bayesian version of logit regression, authors found significant (P < 0.05) associations of CYP1B1 p.L432V and CYP2E1 -70G > T (O.R.	('CYP2E1', 'Gene', '1571', (139, 145))	('CYP1A1', 'Gene', '1543', (123, 129))	('CYP1B1', 'Gene', '1545', (357, 363))	('CYP1B1', 'Gene', (357, 363))	('-70G > T', 'Mutation', 'rs1408446209', (383, 391))	('cancer', 'Disease', (56, 62))	('p.L432V', 'Mutation', 'rs1056836', (364, 371))	('p.L432V', 'Var', (364, 371))	('CYP2E1', 'Gene', '1571', (376, 382))	('HNSCC', 'Phenotype', 'HP:0012288', (33, 38))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('CYP2E1', 'Gene', (139, 145))	('CYP1B1', 'Gene', '1545', (131, 137))	('CYP1B1', 'Gene', (131, 137))	('GSTM1', 'Gene', (147, 152))	('xenobiotic-', 'Phenotype', 'HP:0031838', (190, 201))	('associations', 'Interaction', (341, 353))	('CYP2E1', 'Gene', (376, 382))	('CYP1A1', 'Gene', (123, 129))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('GSTM1', 'Gene', '2944', (147, 152))
266320	27894333	10.84; 95% CI, 1.64-71.53), as well as CYP1B1 p.L432V and GSTM1(0/0) null/null (OR 11.79; 95% CI, 2.18-63.77) with HNSCC risk.	('HNSCC', 'Disease', (115, 120))	('HNSCC', 'Phenotype', 'HP:0012288', (115, 120))	('p.L432V', 'Var', (46, 53))	('p.L432V', 'Mutation', 'rs1056836', (46, 53))	('GSTM1', 'Gene', '2944', (58, 63))	('CYP1B1', 'Gene', '1545', (39, 45))	('GSTM1', 'Gene', (58, 63))	('CYP1B1', 'Gene', (39, 45))
266321	27894333	(d) In another study of 153 HNSCC cases and 145 controls with no current or previous diagnosis of cancer, authors examined CYP1A1, CYP1A2, CYP2E1, GSTM1, and GSTT1 SNPs as risk factors in HNSCC; a significant difference (P < 0.001) was detected for tobacco and alcohol consumption between cases and controls; moreover, the CYP1A2*1D (OR 16.24) variant and GSTM1(0/0) null alleles (OR 0.02) conferred increased risk of HNSCC, and alcohol consumption in HNSCC patients was associated with the CYP2E1*5B variant allele (P < 0.0001, OR 190.6).	('CYP2E1', 'Gene', '1571', (139, 145))	('CYP1A1', 'Gene', '1543', (123, 129))	('CYP1A2', 'Gene', '1544', (131, 137))	('HNSCC', 'Phenotype', 'HP:0012288', (28, 33))	('CYP2E1', 'Gene', (491, 497))	('CYP1A2', 'Gene', '1544', (323, 329))	('alcohol', 'Chemical', 'MESH:D000438', (261, 268))	('alcohol', 'Chemical', 'MESH:D000438', (429, 436))	('cancer', 'Disease', (98, 104))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('patients', 'Species', '9606', (458, 466))	('GSTM1', 'Gene', '2944', (356, 361))	('CYP2E1', 'Gene', (139, 145))	('associated', 'Interaction', (471, 481))	('GSTM1', 'Gene', (147, 152))	('tobacco', 'Species', '4097', (249, 256))	('CYP1A2', 'Gene', (131, 137))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('CYP1A2', 'Gene', (323, 329))	('HNSCC', 'Phenotype', 'HP:0012288', (452, 457))	('CYP1A1', 'Gene', (123, 129))	('CYP2E1', 'Gene', '1571', (491, 497))	('HNSCC', 'Disease', (418, 423))	('GSTM1', 'Gene', (356, 361))	('GSTM1', 'Gene', '2944', (147, 152))	('HNSCC', 'Phenotype', 'HP:0012288', (418, 423))	('HNSCC', 'Phenotype', 'HP:0012288', (188, 193))	('variant', 'Var', (344, 351))
266322	27894333	(e) Performing meta-analysis of six published case-control studies of HNSCC:which included some studies that had concluded no significant risk:authors found that the CYP1B1 p.L432V polymorphism was significantly related with HNSCC risk (OR = 1.13, 95% CI = 1.03-1.25, P = 0.014), whereas no significant association between CYP1B1 p.N453S polymorphism and HNSCC risk was found.	('p.L432V', 'Var', (173, 180))	('p.L432V', 'Mutation', 'rs1056836', (173, 180))	('HNSCC', 'Phenotype', 'HP:0012288', (70, 75))	('HNSCC', 'Disease', (225, 230))	('HNSCC', 'Phenotype', 'HP:0012288', (355, 360))	('HNSCC', 'Phenotype', 'HP:0012288', (225, 230))	('p.N453S', 'Mutation', 'rs1800440', (330, 337))	('CYP1B1', 'Gene', '1545', (323, 329))	('related', 'Reg', (212, 219))	('CYP1B1', 'Gene', '1545', (166, 172))	('CYP1B1', 'Gene', (323, 329))	('CYP1B1', 'Gene', (166, 172))
266339	27894333	Such evidence for an etiologic role of HPV includes (a) observations of higher rate of anti-HPV antibody sero-positivity:even after adjustment for smoking:among patients with HNSCC, compared with that among cancer-free individuals; (b) preferential occurrence of HPV-positive tumors in the oropharynx; (c) unique demographic features, including an increased number of lifetime sexual partners and less exposure to tobacco and alcohol; (d) lower rates of TP53 gene mutations, in HPV-positive than HPV-negative oropharyngeal tumors; and (e) improved survival among HPV-positive oropharynx cancers, compared to HPV-negative oropharynx carcinomas in both retrospective and prospective analyses of clinical trial data.	('TP53', 'Gene', '7157', (454, 458))	('survival', 'CPA', (548, 556))	('tumor', 'Phenotype', 'HP:0002664', (276, 281))	('HPV', 'Species', '10566', (496, 499))	('HPV-positive oropharynx cancers', 'Disease', (563, 594))	('tumors', 'Phenotype', 'HP:0002664', (523, 529))	('HPV', 'Species', '10566', (92, 95))	('tumors', 'Phenotype', 'HP:0002664', (276, 282))	('lower', 'NegReg', (439, 444))	('HPV', 'Species', '10566', (608, 611))	('carcinomas', 'Disease', (632, 642))	('cancer', 'Disease', (207, 213))	('tumor', 'Phenotype', 'HP:0002664', (523, 528))	('negative oropharynx', 'Phenotype', 'HP:0009555', (612, 631))	('alcohol', 'Chemical', 'MESH:D000438', (426, 433))	('cancers', 'Phenotype', 'HP:0002664', (587, 594))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('cancer', 'Disease', (587, 593))	('HNSCC', 'Phenotype', 'HP:0012288', (175, 180))	('improved', 'PosReg', (539, 547))	('TP53', 'Gene', (454, 458))	('cancer', 'Phenotype', 'HP:0002664', (587, 593))	('HPV', 'Species', '10566', (478, 481))	('HPV-positive tumors', 'Disease', (263, 282))	('patients', 'Species', '9606', (161, 169))	('HPV', 'Species', '10566', (263, 266))	('HPV', 'Species', '10566', (563, 566))	('mutations', 'Var', (464, 473))	('tobacco', 'Species', '4097', (414, 421))	('carcinoma', 'Phenotype', 'HP:0030731', (632, 641))	('carcinomas', 'Phenotype', 'HP:0030731', (632, 642))	('cancer', 'Disease', 'MESH:D009369', (207, 213))	('carcinomas', 'Disease', 'MESH:D002277', (632, 642))	('HPV-positive tumors', 'Disease', 'MESH:D030361', (263, 282))	('oropharyngeal tumors', 'Disease', (509, 529))	('HPV-positive oropharynx cancers', 'Disease', 'MESH:D009959', (563, 594))	('clinical', 'Species', '191496', (693, 701))	('oropharyngeal tumors', 'Phenotype', 'HP:0100638', (509, 529))	('cancer', 'Disease', 'MESH:D009369', (587, 593))	('oropharyngeal tumors', 'Disease', 'MESH:D009959', (509, 529))	('HPV', 'Species', '10566', (39, 42))	('rates', 'MPA', (445, 450))
266350	27894333	With regard to our EDP method of rigorously selecting cohorts of N = 112 highly-sensitive (HS) light smokers with HNSCC and N = 99 highly resistant (HR) heavy smokers with no cancer, we conclude that the carefully chosen single-nucleotide variants located in and near four genes:AHR, CYP1A1, CYP1A2, CYP1B1, alone, or in combination:are not statistically significantly associated with risk of cigarette-smoking-induced HNSCC.	('CYP1A2', 'Gene', (292, 298))	('HNSCC', 'Phenotype', 'HP:0012288', (419, 424))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('CYP1B1', 'Gene', '1545', (300, 306))	('EDP', 'Chemical', '-', (19, 22))	('cancer', 'Disease', (175, 181))	('cigarette-smoking-induced HNSCC', 'Disease', (393, 424))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('CYP1B1', 'Gene', (300, 306))	('HNSCC', 'Phenotype', 'HP:0012288', (114, 119))	('CYP1A1', 'Gene', (284, 290))	('CYP1A1', 'Gene', '1543', (284, 290))	('associated', 'Reg', (369, 379))	('CYP1A2', 'Gene', '1544', (292, 298))	('AHR', 'Gene', '196', (279, 282))	('single-nucleotide variants', 'Var', (221, 247))	('AHR', 'Gene', (279, 282))
266355	26910889	RGMB was downregulated in NSCLC (P <= 0.001), possibly through promoter hypermethylation.	('NSCLC', 'Phenotype', 'HP:0030358', (26, 31))	('hypermethylation', 'Var', (72, 88))	('RGMB', 'Gene', (0, 4))	('NSCLC', 'Disease', (26, 31))	('downregulated', 'NegReg', (9, 22))	('NSCLC', 'Disease', 'MESH:D002289', (26, 31))
266357	26910889	RGMB knockdown promoted cell adhesion, invasion and migration, in both NSCLC cell lines and an in vivo mouse model, which enhanced metastatic potential.	('promoted', 'PosReg', (15, 23))	('enhanced', 'PosReg', (122, 130))	('migration', 'CPA', (52, 61))	('NSCLC', 'Phenotype', 'HP:0030358', (71, 76))	('cell adhesion', 'CPA', (24, 37))	('invasion', 'CPA', (39, 47))	('knockdown', 'Var', (5, 14))	('mouse', 'Species', '10090', (103, 108))	('metastatic potential', 'CPA', (131, 151))	('RGMB', 'Gene', (0, 4))	('NSCLC', 'Disease', (71, 76))	('NSCLC', 'Disease', 'MESH:D002289', (71, 76))
266376	26910889	Suppression of RGMB promoted metastasis, thereby providing mechanistic insight into the role of RGMB in lung cancer development.	('lung cancer', 'Disease', 'MESH:D008175', (104, 115))	('RGMB', 'Gene', (15, 19))	('metastasis', 'CPA', (29, 39))	('Suppression', 'Var', (0, 11))	('lung cancer', 'Disease', (104, 115))	('lung cancer', 'Phenotype', 'HP:0100526', (104, 115))	('promoted', 'PosReg', (20, 28))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))
266396	26910889	Therefore, RGMB was knocked down or overexpressed in both A-549 and H1299 cells (Figure 2B, Figure S1).	('knocked', 'Var', (20, 27))	('A-549', 'CellLine', 'CVCL:0023', (58, 63))	('H1299', 'CellLine', 'CVCL:0060', (68, 73))	('overexpressed', 'PosReg', (36, 49))	('RGMB', 'Gene', (11, 15))
266397	26910889	Although alteration of RGMB expression did not impact the proliferation of NSCLC cells (Figure S2A, S2B and S2C), cell adhesion and invasion were significantly enhanced or suppressed by RGMB knockdown or overexpression, respectively (Figure S3, Figure 2C and 2D).	('expression', 'Species', '29278', (28, 38))	('NSCLC', 'Phenotype', 'HP:0030358', (75, 80))	('RGMB', 'Protein', (186, 190))	('enhanced', 'PosReg', (160, 168))	('suppressed', 'NegReg', (172, 182))	('knockdown', 'Var', (191, 200))	('expression', 'Species', '29278', (208, 218))	('NSCLC', 'Disease', (75, 80))	('cell adhesion', 'CPA', (114, 127))	('NSCLC', 'Disease', 'MESH:D002289', (75, 80))	('overexpression', 'PosReg', (204, 218))	('invasion', 'CPA', (132, 140))
266398	26910889	Electric cell substrate impedance sensing (ECIS) and wounding assays showed that the ability of the lung cancer cells to attach (Figure 2E) and migrate (Figure 2F, 2G and Figure S3) was enhanced by RGMB knockdown.	('migrate', 'CPA', (144, 151))	('RGMB', 'Protein', (198, 202))	('attach', 'CPA', (121, 127))	('lung cancer', 'Phenotype', 'HP:0100526', (100, 111))	('lung cancer', 'Disease', (100, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('enhanced', 'PosReg', (186, 194))	('knockdown', 'Var', (203, 212))	('lung cancer', 'Disease', 'MESH:D008175', (100, 111))
266404	26910889	However, an increased number of GFP-labeled RGMB-knockdown cells migrated to the lung compared to the A-549 empty vector controls (Figure.	('A-549', 'CellLine', 'CVCL:0023', (102, 107))	('RGMB-knockdown', 'Gene', (44, 58))	('RGMB-knockdown', 'Var', (44, 58))
266406	26910889	More cancer cells were present in the circulation and at distant metastatic sites such as the liver, bone marrow, and spleen following RGMB knockdown as detected via fluorescence activated cell sorting (FACS) (Figure 3C and 3D; Table 4).	('cancer', 'Disease', 'MESH:D009369', (5, 11))	('cancer', 'Disease', (5, 11))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))	('knockdown', 'Var', (140, 149))	('RGMB', 'Gene', (135, 139))
266409	26910889	The Smad-independent (MAPK) pathway consists of a chain of activation in which MAPK (as JNK, ERK1/2) is activated following sequential activation of MAP4K/MAP3K/MAP2K.	('JNK', 'Gene', (88, 91))	('MAPK', 'Gene', (79, 83))	('JNK', 'Gene', '5599', (88, 91))	('MAP4K/MAP3K/MAP2K', 'Var', (149, 166))
266411	26910889	An increase in phosphorylated Smad-1/5/8 levels was observed in RGMB knockdown cells (Figure 5A).	('Smad-1/5/8', 'Gene', (30, 40))	('RGMB', 'Gene', (64, 68))	('Smad-1/5/8', 'Gene', '4086;4090;4093', (30, 40))	('knockdown', 'Var', (69, 78))	('increase', 'PosReg', (3, 11))
266412	26910889	In addition, knockdown of Smad1 eliminated RGMB knockdown-enhanced cell migration (Figure.	('knockdown-enhanced', 'Var', (48, 66))	('Smad1', 'Gene', (26, 31))	('RGMB', 'Protein', (43, 47))	('Smad1', 'Gene', '4086', (26, 31))	('cell migration', 'CPA', (67, 81))
266419	26910889	These results suggest that the methylation of CpG units in the RGMB promoter region is only one of the mechanisms by which RGMB is downregulated in some lung cancer tumors.	('lung cancer tumors', 'Disease', (153, 171))	('RGMB', 'Gene', (123, 127))	('tumors', 'Phenotype', 'HP:0002664', (165, 171))	('lung cancer tumors', 'Disease', 'MESH:D008175', (153, 171))	('methylation', 'Var', (31, 42))	('lung cancer', 'Phenotype', 'HP:0100526', (153, 164))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('downregulated', 'NegReg', (131, 144))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
266421	26910889	Our results also suggest that hypermethylation of the RGMB promoter is one mechanism underlying the downregulation of RGMB in lung cancer.	('RGMB', 'Gene', (54, 58))	('RGMB', 'Gene', (118, 122))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('lung cancer', 'Disease', (126, 137))	('lung cancer', 'Phenotype', 'HP:0100526', (126, 137))	('downregulation', 'NegReg', (100, 114))	('lung cancer', 'Disease', 'MESH:D008175', (126, 137))	('hypermethylation', 'Var', (30, 46))
266424	26910889	These results indicate that RGMB expression is downregulated as a result of the degree of methylation, which is in line with our observations.	('downregulated', 'NegReg', (47, 60))	('expression', 'Species', '29278', (33, 43))	('methylation', 'Var', (90, 101))	('RGMB', 'Gene', (28, 32))	('expression', 'MPA', (33, 43))
266427	26910889	In line with the observations from the NSCLC tumors, our in vitro and in vivo data have shown that RGMB can inhibit NSCLC cell metastasis.	('NSCLC', 'Disease', 'MESH:D002289', (116, 121))	('NSCLC', 'Phenotype', 'HP:0030358', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('NSCLC', 'Disease', 'MESH:D002289', (39, 44))	('RGMB', 'Var', (99, 103))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('NSCLC tumors', 'Disease', 'MESH:D009369', (39, 51))	('NSCLC', 'Phenotype', 'HP:0030358', (116, 121))	('NSCLC tumors', 'Disease', (39, 51))	('NSCLC', 'Disease', (39, 44))	('NSCLC', 'Disease', (116, 121))	('inhibit', 'NegReg', (108, 115))
266430	26910889	Blocking Smad1 in RGMB-knockdown A-549 cells diminishes the RGMB knockdown-enhanced migration of these cells suggesting that RGMB can inhibit the metastatic potential of lung cancer cells through suppression of the Smad-1/5/8 pathway.	('Smad-1/5/8', 'Gene', (215, 225))	('lung cancer', 'Phenotype', 'HP:0100526', (170, 181))	('Smad1', 'Gene', '4086', (9, 14))	('RGMB', 'Gene', (60, 64))	('metastatic potential of', 'CPA', (146, 169))	('Blocking', 'Var', (0, 8))	('inhibit', 'NegReg', (134, 141))	('diminishes', 'NegReg', (45, 55))	('lung cancer', 'Disease', 'MESH:D008175', (170, 181))	('Smad-1/5/8', 'Gene', '4086;4090;4093', (215, 225))	('A-549', 'CellLine', 'CVCL:0023', (33, 38))	('Smad1', 'Gene', (9, 14))	('lung cancer', 'Disease', (170, 181))	('suppression', 'NegReg', (196, 207))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
266461	26910889	To knock down RGMB expression, a shRNA that specifically targeted human RGMB (sequence: 5'-UUAUUAUCUAUGAGUGGCCAGGCCC-3') was purchased from Life Technologies (validation information for this shRNA target sequence can also be obtained from Sigma-Aldrich: product number: TRCN0000365323).	('knock down', 'Var', (3, 13))	('RGMB expression', 'Gene', (14, 29))	('expression', 'Species', '29278', (19, 29))	('human', 'Species', '9606', (66, 71))
266469	26910889	Briefly, female 8-10-week-old NSI mice were injected subcutaneously with 100 muL of a suspension of RGMB knockdown cells or vector control A-549 cells (approximately 1 x 106 cells).	('A-549', 'CellLine', 'CVCL:0023', (139, 144))	('mice', 'Species', '10090', (34, 38))	('RGMB', 'Gene', (100, 104))	('knockdown', 'Var', (105, 114))
266493	32961983	Phosphorylation of ACC inhibits catabolic functions such as lipid storage and causes cellular metabolism to switch to fatty acid oxidation (FAO).	('FAO', 'Chemical', '-', (140, 143))	('lipid', 'Chemical', 'MESH:D008055', (60, 65))	('age', 'Gene', '5973', (70, 73))	('causes', 'Reg', (78, 84))	('fatty acid oxidation', 'MPA', (118, 138))	('Phosphorylation', 'Var', (0, 15))	('fatty acid', 'Chemical', 'MESH:D005227', (118, 128))	('catabolic functions', 'MPA', (32, 51))	('age', 'Gene', (70, 73))	('switch', 'Reg', (108, 114))	('inhibits', 'NegReg', (23, 31))	('ACC', 'Gene', (19, 22))	('cellular metabolism', 'MPA', (85, 104))
266513	32961983	Regarding clinical T status (Table 4), patients with a higher T stage (T3/T4) were more likely to have a moderate to high FAS expression (2+ to 3+ score) and high MCAD expression (3+ score) than patients with a lower T stage (T1/T2) (FAS: 12 of 58 patients with T3/T4 stage (20.69%) vs. 2 of 44 patients with T1/T2 stage (4.55%), p = 0.04, Fisher's exact test; MCAD: 27 of 58 patients with T3/T4 stage (46.55%) vs. 8 of 44 patients with T1/T2 stage (18.18%), p = 0.01, chi2 test).	('patients', 'Species', '9606', (39, 47))	('age', 'Gene', '5973', (445, 448))	('age', 'Gene', '5973', (270, 273))	('FAS', 'Gene', '2194', (234, 237))	('age', 'Gene', '5973', (317, 320))	('age', 'Gene', '5973', (221, 224))	('age', 'Gene', (66, 69))	('patients', 'Species', '9606', (195, 203))	('FAS', 'Gene', '2194', (122, 125))	('FAS', 'Gene', (234, 237))	('patients', 'Species', '9606', (376, 384))	('age', 'Gene', (398, 401))	('MCAD', 'Gene', '34', (163, 167))	('MCAD', 'Gene', '34', (361, 365))	('patients', 'Species', '9606', (423, 431))	('age', 'Gene', (445, 448))	('FAS', 'Gene', (122, 125))	('patients', 'Species', '9606', (248, 256))	('age', 'Gene', '5973', (66, 69))	('MCAD', 'Gene', (163, 167))	('MCAD', 'Gene', (361, 365))	('age', 'Gene', (270, 273))	('patients', 'Species', '9606', (295, 303))	('T3/T4', 'Var', (390, 395))	('age', 'Gene', (317, 320))	('age', 'Gene', '5973', (398, 401))	('age', 'Gene', (221, 224))
266537	32961983	A low expression or methylation of LCAD has been associated with poor survival outcomes in several cancers such as HCC and breast cancer.	('low', 'NegReg', (2, 5))	('HCC', 'Disease', (115, 118))	('breast cancer', 'Disease', 'MESH:D001943', (123, 136))	('HCC', 'Phenotype', 'HP:0001402', (115, 118))	('expression', 'MPA', (6, 16))	('breast cancer', 'Disease', (123, 136))	('cancers', 'Disease', 'MESH:D009369', (99, 106))	('LCAD', 'Gene', '33', (35, 39))	('breast cancer', 'Phenotype', 'HP:0003002', (123, 136))	('LCAD', 'Gene', (35, 39))	('cancers', 'Disease', (99, 106))	('cancers', 'Phenotype', 'HP:0002664', (99, 106))	('methylation', 'Var', (20, 31))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
266539	32961983	In HCC cells, loss of LCAD has been shown to promote tumor progression as a consequence of the activation of Yap or reduction of phosphatase and tensin homolog, while overexpression of LCAD has been shown to inhibit tumor growth, indicating that LCAD has tumor-suppressive functions.	('LCAD', 'Gene', (185, 189))	('tumor', 'Phenotype', 'HP:0002664', (255, 260))	('inhibit', 'NegReg', (208, 215))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('Yap', 'Gene', '10413', (109, 112))	('reduction', 'NegReg', (116, 125))	('tumor', 'Disease', (216, 221))	('loss', 'Var', (14, 18))	('LCAD', 'Gene', '33', (185, 189))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Disease', 'MESH:D009369', (216, 221))	('LCAD', 'Gene', (246, 250))	('Yap', 'Gene', (109, 112))	('tumor', 'Disease', (255, 260))	('activation', 'PosReg', (95, 105))	('promote', 'PosReg', (45, 52))	('LCAD', 'Gene', '33', (246, 250))	('LCAD', 'Gene', (22, 26))	('tumor', 'Disease', 'MESH:D009369', (255, 260))	('HCC', 'Phenotype', 'HP:0001402', (3, 6))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('phosphatase', 'Protein', (129, 140))	('tumor', 'Disease', (53, 58))	('LCAD', 'Gene', '33', (22, 26))
266548	32961983	Although the correlation between MCAD expression and cancer-related death was not observed in our multivariate analysis, a previous study has shown that a high expression of MCAD was associated with a better overall survival (OS) in neuroblastoma patients.	('MCAD', 'Gene', (33, 37))	('neuroblastoma', 'Phenotype', 'HP:0003006', (233, 246))	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('death', 'Disease', 'MESH:D003643', (68, 73))	('death', 'Disease', (68, 73))	('overall survival', 'MPA', (208, 224))	('MCAD', 'Gene', '34', (33, 37))	('patients', 'Species', '9606', (247, 255))	('high expression', 'Var', (155, 170))	('MCAD', 'Gene', (174, 178))	('neuroblastoma', 'Disease', 'MESH:D009447', (233, 246))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('better', 'PosReg', (201, 207))	('MCAD', 'Gene', '34', (174, 178))	('neuroblastoma', 'Disease', (233, 246))
266585	31341405	Mutation and copy number alteration of histone methylation related genes both exist in NSCLC.	('copy number alteration', 'Var', (13, 35))	('NSCLC', 'Disease', (87, 92))	('exist', 'Reg', (78, 83))	('NSCLC', 'Disease', 'MESH:D002289', (87, 92))	('NSCLC', 'Phenotype', 'HP:0030358', (87, 92))
266586	31341405	Conclusions: Our result suggests that alteration of histone methylation is strongly involved in NSCLC.	('NSCLC', 'Disease', (96, 101))	('NSCLC', 'Disease', 'MESH:D002289', (96, 101))	('alteration', 'Var', (38, 48))	('NSCLC', 'Phenotype', 'HP:0030358', (96, 101))	('involved', 'Reg', (84, 92))	('histone', 'Protein', (52, 59))
266592	31341405	DNA methylation participates in carcinogenesis both at the transcriptional and post-transcriptional levels.	('carcinogenesis', 'Disease', (32, 46))	('carcinogenesis', 'Disease', 'MESH:D063646', (32, 46))	('methylation', 'Var', (4, 15))	('participates', 'Reg', (16, 28))
266595	31341405	There are five lysines in histone H3 (K4, K9, K27, K36, K79) that have been shown to be modulated by methylation.	('K27', 'Gene', (46, 49))	('K79', 'Gene', (56, 59))	('K79', 'Gene', '338785', (56, 59))	('K4', 'Var', (38, 40))	('histone H3', 'Protein', (26, 36))	('modulated', 'Reg', (88, 97))	('lysines', 'Chemical', 'MESH:D008239', (15, 22))	('K36', 'Gene', '8689', (51, 54))	('K36', 'Gene', (51, 54))	('K27', 'Gene', '342574', (46, 49))
266596	31341405	In addition, a lysine in histone H4 (K20) could be methylated by the specific histone lysine methyltransferase.	('K20', 'Gene', '54474', (37, 40))	('K20', 'Gene', (37, 40))	('lysine', 'Chemical', 'MESH:D008239', (86, 92))	('lysine', 'Chemical', 'MESH:D008239', (15, 21))	('lysine', 'Var', (15, 21))
266597	31341405	The methylation of H3K4 and H3K36 can active gene transcription while the methyltion at H3K9, H3K27, H3K79 and H4K20 can repress gene transcription.	('H3K4', 'Var', (19, 23))	('K20', 'Gene', '54474', (113, 116))	('K36', 'Gene', '8689', (30, 33))	('K20', 'Gene', (113, 116))	('K79', 'Gene', '338785', (103, 106))	('K36', 'Gene', (30, 33))	('methylation', 'Var', (4, 15))	('repress', 'NegReg', (121, 128))	('K27', 'Gene', '342574', (96, 99))	('K27', 'Gene', (96, 99))	('methyltion', 'Var', (74, 84))	('active gene transcription', 'MPA', (38, 63))	('K79', 'Gene', (103, 106))	('gene transcription', 'MPA', (129, 147))
266610	31341405	The Copy number variation (Amplification and Deep deletion) and somatic mutation data (Truncating mutation and Missense mutation) of lung cancer was downloaded from TCGA through cBioPortal and GISTIC.	('lung cancer', 'Disease', (133, 144))	('lung cancer', 'Phenotype', 'HP:0100526', (133, 144))	('Missense', 'Var', (111, 119))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('lung cancer', 'Disease', 'MESH:D008175', (133, 144))
266619	31341405	An oncoprint image of histone methyltransferases and demethylases gene alteration in lung adenocarcinoma and squamous cell carcinoma was generated in cBioportal based on TCGA data (Fig.	('demethylase', 'Gene', (53, 64))	('demethylase', 'Gene', '8932', (53, 64))	('alteration', 'Var', (71, 81))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (85, 104))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (109, 132))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('lung adenocarcinoma', 'Disease', (85, 104))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (85, 104))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('squamous cell carcinoma', 'Disease', (109, 132))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (109, 132))
266620	31341405	Gene amplification, deep deletion and missense mutation were frequently found in different histone methyltransferases and demethylases gene.	('missense mutation', 'Var', (38, 55))	('histone methyltransferases', 'Enzyme', (91, 117))	('demethylase', 'Gene', (122, 133))	('demethylase', 'Gene', '8932', (122, 133))	('deep deletion', 'Var', (20, 33))
266621	31341405	Among H3K4 methyltransferases and demethylases, PRDM9 had the highest frequency of copy number amplification and missense mutation.	('copy', 'MPA', (83, 87))	('PRDM9', 'Gene', '56979', (48, 53))	('demethylase', 'Gene', (34, 45))	('demethylase', 'Gene', '8932', (34, 45))	('missense mutation', 'Var', (113, 130))	('PRDM9', 'Gene', (48, 53))
266627	31341405	A variety of mutation points were found across the protein for SETD2, DOT1L, PRDM9 and KDM5A/B.	('DOT1L', 'Gene', '84444', (70, 75))	('KDM5A/B', 'Gene', (87, 94))	('KDM5A/B', 'Gene', '5927;10765', (87, 94))	('mutation points', 'Var', (13, 28))	('SETD2', 'Gene', '29072', (63, 68))	('PRDM9', 'Gene', (77, 82))	('SETD2', 'Gene', (63, 68))	('DOT1L', 'Gene', (70, 75))	('PRDM9', 'Gene', '56979', (77, 82))
266628	31341405	Moreover, mutations were found in the catalytic SET domain for methyltransferases SETD2, SMYD2, SMYD3, KMT5A, SETDB2 and PRDM9 and Jmjc domain for demethylases KDM5A/B.	('SETD2', 'Gene', '29072', (82, 87))	('PRDM9', 'Gene', (121, 126))	('SETD2', 'Gene', (82, 87))	('SMYD2', 'Gene', (89, 94))	('SETDB2', 'Gene', (110, 116))	('SMYD3', 'Gene', (96, 101))	('demethylase', 'Gene', (147, 158))	('KMT5A', 'Gene', (103, 108))	('methyltransferases', 'Enzyme', (63, 81))	('SETDB2', 'Gene', '83852', (110, 116))	('PRDM9', 'Gene', '56979', (121, 126))	('SMYD3', 'Gene', '64754', (96, 101))	('KMT5A', 'Gene', '387893', (103, 108))	('demethylase', 'Gene', '8932', (147, 158))	('KDM5A/B', 'Gene', '5927;10765', (160, 167))	('KDM5A/B', 'Gene', (160, 167))	('mutations', 'Var', (10, 19))	('SMYD2', 'Gene', '56950', (89, 94))
266652	31341405	A growing body of evidence indicates that amplification, translocation or mutation of histone methyltransferases and demethylases is linked to the development of many human cancers.	('mutation', 'Var', (74, 82))	('cancers', 'Disease', 'MESH:D009369', (173, 180))	('cancers', 'Disease', (173, 180))	('cancers', 'Phenotype', 'HP:0002664', (173, 180))	('men', 'Species', '9606', (154, 157))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('demethylase', 'Gene', (117, 128))	('translocation', 'Var', (57, 70))	('amplification', 'Var', (42, 55))	('demethylase', 'Gene', '8932', (117, 128))	('human', 'Species', '9606', (167, 172))	('histone methyltransferases', 'Enzyme', (86, 112))	('linked', 'Reg', (133, 139))
266656	31341405	PRDM9 has also been regarded as a meiosis-specific protein that methylates H3K4 and variation strongly influences recombination hot-spot activity and meiotic instability in human.	('H3K4', 'Protein', (75, 79))	('influences', 'Reg', (103, 113))	('human', 'Species', '9606', (173, 178))	('meiotic instability', 'CPA', (150, 169))	('recombination hot-spot activity', 'MPA', (114, 145))	('PRDM9', 'Gene', (0, 5))	('PRDM9', 'Gene', '56979', (0, 5))	('variation', 'Var', (84, 93))
266657	31341405	Recently, PRDM9 variability has been implicated in genome instability and having a potential role in the risk of acquiring genome rearrangements associated with childhood leukemogenesis.	('PRDM9', 'Gene', '56979', (10, 15))	('implicated', 'Reg', (37, 47))	('genome instability', 'MPA', (51, 69))	('men', 'Species', '9606', (139, 142))	('childhood leukemogenesis', 'Disease', (161, 185))	('variability', 'Var', (16, 27))	('PRDM9', 'Gene', (10, 15))
266668	31341405	KDM6A (UTX) and KDM6B (JMJD3), antagonists to EZH2, were both tumor suppressors and the high expression of them was associated with better patient survival.	('high', 'Var', (88, 92))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('UTX', 'Gene', '7403', (7, 10))	('JMJD3', 'Gene', (23, 28))	('KDM6B', 'Gene', (16, 21))	('tumor', 'Disease', (62, 67))	('KDM6A', 'Gene', '7403', (0, 5))	('JMJD3', 'Gene', '23135', (23, 28))	('patient survival', 'CPA', (139, 155))	('KDM6B', 'Gene', '23135', (16, 21))	('EZH2', 'Gene', '2146', (46, 50))	('UTX', 'Gene', (7, 10))	('better', 'PosReg', (132, 138))	('EZH2', 'Gene', (46, 50))	('patient', 'Species', '9606', (139, 146))	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('KDM6A', 'Gene', (0, 5))
266674	31341405	Consistent with its oncogenic function, high expression of KMT5A predicts poor survival from our result.	('high', 'Var', (40, 44))	('KMT5A', 'Gene', (59, 64))	('poor', 'NegReg', (74, 78))	('KMT5A', 'Gene', '387893', (59, 64))	('expression', 'MPA', (45, 55))
266700	31221127	Comparison of larynx SCC high TrkB-T1 RNA expressers to low expressers (n = 96) revealed gene expression differences consistent with the high TrkB-T1 tumors being more neural-like.	('tumors', 'Disease', (150, 156))	('SCC', 'Gene', (21, 24))	('tumors', 'Disease', 'MESH:D009369', (150, 156))	('TrkB', 'Gene', (142, 146))	('tumors', 'Phenotype', 'HP:0002664', (150, 156))	('SCC', 'Phenotype', 'HP:0002860', (21, 24))	('SCC', 'Gene', '6317', (21, 24))	('high', 'Var', (137, 141))	('TrkB', 'Gene', '4915', (30, 34))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('TrkB', 'Gene', (30, 34))	('TrkB', 'Gene', '4915', (142, 146))
266733	31221127	The ease of reproducible measurement of TrkB-T1 mRNA, via detection of the terminal exon using DNA microarrays or RNASeq, was used to determine if tumors highly enriched for TrkB-T1 mRNA make up a separate subtype of head and neck SCC and to discern pathways that are enriched in this subset of SCCs.	('TrkB', 'Gene', '4915', (40, 44))	('SCC', 'Gene', '6317', (231, 234))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('SCCs', 'Phenotype', 'HP:0002860', (295, 299))	('SCC', 'Phenotype', 'HP:0002860', (295, 298))	('tumors', 'Disease', (147, 153))	('SCC', 'Gene', '6317', (295, 298))	('tumors', 'Phenotype', 'HP:0002664', (147, 153))	('TrkB', 'Gene', (40, 44))	('tumors', 'Disease', 'MESH:D009369', (147, 153))	('TrkB', 'Gene', '4915', (174, 178))	('SCC', 'Gene', (231, 234))	('SCC', 'Phenotype', 'HP:0002860', (231, 234))	('TrkB', 'Gene', (174, 178))	('mRNA', 'Var', (182, 186))	('SCC', 'Gene', (295, 298))
266744	31221127	All genes were considered in determining gene sets differentially represented in the high and low TrkB-T1 mRNA groups for Larynx + Oral, ESSC, LUSC, and LUAD.	('Larynx + Oral', 'Disease', (122, 135))	('TrkB', 'Gene', '4915', (98, 102))	('high', 'Var', (85, 89))	('LUAD', 'Disease', (153, 157))	('TrkB', 'Gene', (98, 102))	('LUAD', 'Phenotype', 'HP:0030078', (153, 157))	('low', 'NegReg', (94, 97))	('ESSC', 'Disease', (137, 141))	('LUSC', 'Disease', (143, 147))
266749	31221127	Logistic regression was used to determine the relation between the presence of CASP8, PIK3CA mutations and NTRK2 expression (Statistical Analysis Software, Cary, NC, USA).	('expression', 'MPA', (113, 123))	('NTRK2', 'Gene', '4915', (107, 112))	('mutations', 'Var', (93, 102))	('CASP8', 'Gene', '841', (79, 84))	('CASP8', 'Gene', (79, 84))	('PIK3CA', 'Gene', (86, 92))	('NTRK2', 'Gene', (107, 112))	('PIK3CA', 'Gene', '5290', (86, 92))
266758	31221127	High TrkB-T1 expressers comprised 30% of tumors for LASC (vs. 0% of normal controls), 20% of tumors for OSCC (vs 21% of normal controls), 35% for LUSC (vs. 0% of normal controls), and 36% for ESSC (vs. 0% for normal controls).	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('TrkB', 'Gene', '4915', (5, 9))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('High', 'Var', (0, 4))	('LASC', 'Disease', (52, 56))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('LASC', 'Chemical', '-', (52, 56))	('tumors', 'Disease', 'MESH:D009369', (93, 99))	('tumors', 'Disease', (41, 47))	('tumors', 'Disease', 'MESH:D009369', (41, 47))	('TrkB', 'Gene', (5, 9))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('SCC', 'Gene', (105, 108))	('SCC', 'Phenotype', 'HP:0002860', (105, 108))	('tumors', 'Disease', (93, 99))	('SCC', 'Gene', '6317', (105, 108))
266759	31221127	For adenocarcinomas, the fractions of tumors with TrkB-T1 expression over the average were 13% for LUAD (vs. 24% of normal controls) and 10% for ESAD (vs. 54% of normal controls) (Additional file 2: Table S1).	('ESAD', 'Disease', (145, 149))	('LUAD', 'Disease', (99, 103))	('over', 'PosReg', (69, 73))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('TrkB', 'Gene', '4915', (50, 54))	('adenocarcinomas', 'Disease', 'MESH:D000230', (4, 19))	('tumors', 'Disease', (38, 44))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('ESAD', 'Phenotype', 'HP:0011459', (145, 149))	('carcinoma', 'Phenotype', 'HP:0030731', (9, 18))	('TrkB', 'Gene', (50, 54))	('carcinomas', 'Phenotype', 'HP:0030731', (9, 19))	('tumors', 'Disease', 'MESH:D009369', (38, 44))	('adenocarcinomas', 'Disease', (4, 19))	('expression', 'Var', (58, 68))	('LUAD', 'Phenotype', 'HP:0030078', (99, 103))
266765	31221127	When this analysis was done for high TrkB-T1 RNA expresser LUSCs, the similarity to brain tissue was seen, and for ESSC the top nine out of ten matches were brain tissue samples.	('high', 'Var', (32, 36))	('TrkB', 'Gene', (37, 41))	('TrkB', 'Gene', '4915', (37, 41))
266771	31221127	The next step was to determine if transcriptome patterns associated with high TrkB expression indicated similar pathways were enriched in tumor sites distinct from the head and neck.	('TrkB', 'Gene', '4915', (78, 82))	('tumor', 'Disease', (138, 143))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('TrkB', 'Gene', (78, 82))	('expression', 'MPA', (83, 93))	('high', 'Var', (73, 77))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
266772	31221127	Again, the same pathways were seen to be enriched in high TrkB-T1 expressers versus low expresser ESSCs and LUSCs (Fig.	('TrkB', 'Gene', (58, 62))	('high', 'Var', (53, 57))	('TrkB', 'Gene', '4915', (58, 62))	('expressers', 'Var', (66, 76))
266773	31221127	A second gene set analysis tool was used to verify common differences in biological pathways seen in high versus low TrkB-T1 expressers in SCCs.	('SCC', 'Gene', '6317', (139, 142))	('TrkB', 'Gene', (117, 121))	('low', 'NegReg', (113, 116))	('SCC', 'Gene', (139, 142))	('SCCs', 'Phenotype', 'HP:0002860', (139, 143))	('TrkB', 'Gene', '4915', (117, 121))	('SCC', 'Phenotype', 'HP:0002860', (139, 142))	('high', 'Var', (101, 105))
266778	31221127	That and the retinol metabolism pathway were included among pathways enriched in TrkB-T1 SCC high expressers, though the statistical significance of the enrichment was much weaker.	('SCC', 'Gene', '6317', (89, 92))	('TrkB', 'Gene', '4915', (81, 85))	('retinol', 'Chemical', 'MESH:D014801', (13, 20))	('TrkB', 'Gene', (81, 85))	('high expressers', 'Var', (93, 108))	('retinol metabolism pathway', 'Pathway', (13, 39))	('SCC', 'Gene', (89, 92))	('SCC', 'Phenotype', 'HP:0002860', (89, 92))
266789	31221127	cBioPortal was used to examine genes whose mutation, amplification and mRNA level are associated with head and neck SCC and are suspect drivers of SCC at that site.	('SCC', 'Gene', (116, 119))	('SCC', 'Gene', (147, 150))	('SCC', 'Phenotype', 'HP:0002860', (147, 150))	('SCC', 'Phenotype', 'HP:0002860', (116, 119))	('mutation', 'Var', (43, 51))	('amplification', 'Var', (53, 66))	('SCC', 'Gene', '6317', (116, 119))	('associated', 'Reg', (86, 96))	('SCC', 'Gene', '6317', (147, 150))	('mRNA level', 'MPA', (71, 81))
266797	31221127	An examination of patient outcomes revealed that high expressers of TrkB-T1 had reduced overall survival (p < 0.04, Fig.	('TrkB', 'Gene', '4915', (68, 72))	('overall survival', 'MPA', (88, 104))	('reduced', 'NegReg', (80, 87))	('TrkB', 'Gene', (68, 72))	('patient', 'Species', '9606', (18, 25))	('high expressers', 'Var', (49, 64))
266799	31221127	In the first 1000 days, high levels of TrkB-T1 mRNA trended toward predicting better outcomes in that time period but not after that.	('TrkB', 'Gene', (39, 43))	('better', 'PosReg', (78, 84))	('TrkB', 'Gene', '4915', (39, 43))	('high levels', 'Var', (24, 35))
266800	31221127	In the TCGA data set more of the high TrkB-T1 expresser tumors were advanced stage tumors (Additional file 2: Table S1).	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('high', 'Var', (33, 37))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('stage tumors', 'Disease', (77, 89))	('tumors', 'Disease', (83, 89))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('tumors', 'Disease', (56, 62))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('tumors', 'Disease', 'MESH:D009369', (83, 89))	('TrkB', 'Gene', '4915', (38, 42))	('stage tumors', 'Disease', 'MESH:D062706', (77, 89))	('TrkB', 'Gene', (38, 42))
266803	31221127	An examination of two additional LUSC datasets revealed, in one, a similar pattern with TrkB high expressers showing better outcomes (GSE457) while the other, with only 56 patients, showed no difference (GSE17710).	('TrkB', 'Gene', '4915', (88, 92))	('GSE457', 'Chemical', '-', (134, 140))	('TrkB', 'Gene', (88, 92))	('better', 'PosReg', (117, 123))	('patients', 'Species', '9606', (172, 180))	('high expressers', 'Var', (93, 108))
266809	31221127	LUSC tumors that were enriched for PIK3CA gene copy number trended toward showing favorable outcomes (Fig.	('tumors', 'Disease', (5, 11))	('tumors', 'Disease', 'MESH:D009369', (5, 11))	('copy number', 'Var', (47, 58))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('PIK3CA', 'Gene', (35, 41))	('PIK3CA', 'Gene', '5290', (35, 41))	('tumors', 'Phenotype', 'HP:0002664', (5, 11))
266820	31221127	These high TrkB-T1 SCCs would likely be a subset of the neuroendocrine-like tumors or C4 classification of Chen et al.	('SCC', 'Gene', '6317', (19, 22))	('TrkB', 'Gene', (11, 15))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('neuroendocrine-like tumors', 'Disease', (56, 82))	('high', 'Var', (6, 10))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('SCC', 'Gene', (19, 22))	('TrkB', 'Gene', '4915', (11, 15))	('SCCs', 'Phenotype', 'HP:0002860', (19, 23))	('SCC', 'Phenotype', 'HP:0002860', (19, 22))	('neuroendocrine-like tumors', 'Disease', 'MESH:D018358', (56, 82))
266825	31221127	The Tcfap2a transcription factor binding site sequence was overrepresented in the promoters of DE genes in high TrkB-T1 mRNA expressers versus low expressers in all 4 SCCs studied.	('Tcfap2a', 'Gene', (4, 11))	('SCCs', 'Phenotype', 'HP:0002860', (167, 171))	('SCC', 'Phenotype', 'HP:0002860', (167, 170))	('SCC', 'Gene', '6317', (167, 170))	('TrkB', 'Gene', '4915', (112, 116))	('overrepresented', 'PosReg', (59, 74))	('TrkB', 'Gene', (112, 116))	('high', 'Var', (107, 111))	('SCC', 'Gene', (167, 170))
266839	31221127	These include glutathione metabolism and xenobiotic/drug metabolism by cyp450, two KEGG pathways associated with high TrkB-T1 mRNA levels in SCC.	('xenobiotic/drug metabolism', 'Enzyme', (41, 67))	('high', 'Var', (113, 117))	('TrkB', 'Gene', '4915', (118, 122))	('KEGG pathways', 'Pathway', (83, 96))	('SCC', 'Gene', (141, 144))	('TrkB', 'Gene', (118, 122))	('glutathione', 'Chemical', 'MESH:D005978', (14, 25))	('SCC', 'Phenotype', 'HP:0002860', (141, 144))	('cyp450', 'Enzyme', (71, 77))	('SCC', 'Gene', '6317', (141, 144))	('mRNA levels', 'MPA', (126, 137))	('glutathione metabolism', 'Enzyme', (14, 36))
266840	31221127	In non-SCC breast cancer, TrkB kinase activity has been shown to reduce levels of the Keap inhibitor, which increases Nfe2l2 directed transcription.	('SCC', 'Gene', (7, 10))	('levels of the', 'MPA', (72, 85))	('increases', 'PosReg', (108, 117))	('SCC', 'Phenotype', 'HP:0002860', (7, 10))	('SCC', 'Gene', '6317', (7, 10))	('breast cancer', 'Disease', 'MESH:D001943', (11, 24))	('TrkB', 'Gene', '4915', (26, 30))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('breast cancer', 'Disease', (11, 24))	('TrkB', 'Gene', (26, 30))	('breast cancer', 'Phenotype', 'HP:0003002', (11, 24))	('reduce', 'NegReg', (65, 71))	('kinase activity', 'Var', (31, 46))	('Nfe2l2', 'Gene', (118, 124))	('Nfe2l2', 'Gene', '4780', (118, 124))
266845	31221127	While the correlation between TrkB-T1 mRNA level and PIK3CA copy number was marginal in the SCCs (Additional file 8: Table S4), the functional interaction of these genes in these tumors was further supported by the increase in mutagenic PIK3CA activation in high TrkB expressers in LASC for example (Fig.	('SCC', 'Gene', '6317', (92, 95))	('tumors', 'Disease', 'MESH:D009369', (179, 185))	('LASC', 'Chemical', '-', (282, 286))	('TrkB', 'Gene', (30, 34))	('SCC', 'Gene', (92, 95))	('TrkB', 'Gene', '4915', (263, 267))	('PIK3CA', 'Gene', '5290', (237, 243))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('SCCs', 'Phenotype', 'HP:0002860', (92, 96))	('PIK3CA', 'Gene', '5290', (53, 59))	('tumors', 'Phenotype', 'HP:0002664', (179, 185))	('TrkB', 'Gene', (263, 267))	('SCC', 'Phenotype', 'HP:0002860', (92, 95))	('mutagenic', 'Var', (227, 236))	('tumors', 'Disease', (179, 185))	('increase', 'PosReg', (215, 223))	('PIK3CA', 'Gene', (237, 243))	('TrkB', 'Gene', '4915', (30, 34))	('PIK3CA', 'Gene', (53, 59))	('activation', 'PosReg', (244, 254))
266848	31221127	These and other findings allow speculation that PI3K activation and increased transcription of TrkB-FL and TrkB-T1 are mutually stimulatory.	('TrkB', 'Gene', (107, 111))	('PI3K', 'Var', (48, 52))	('TrkB', 'Gene', '4915', (95, 99))	('TrkB', 'Gene', (95, 99))	('TrkB', 'Gene', '4915', (107, 111))	('increased', 'PosReg', (68, 77))	('transcription', 'MPA', (78, 91))
266855	31221127	Pik3ca enrichment in head and neck SCC predicts poorer outcomes while amplified PIKC3A in LUSC may have the opposite effect (Fig.	('SCC', 'Gene', (35, 38))	('SCC', 'Phenotype', 'HP:0002860', (35, 38))	('PIKC3A', 'Gene', (80, 86))	('amplified', 'Var', (70, 79))	('poorer', 'NegReg', (48, 54))	('SCC', 'Gene', '6317', (35, 38))	('Pik3ca', 'Gene', (0, 6))	('Pik3ca', 'Gene', '5290', (0, 6))
266856	31221127	Likewise, enrichment of factors linked to activated Nfe2l2 are associated with poor survival of head and neck SCC and LUAD, but that is not the case for LUSC and other cancers.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('activated', 'Var', (42, 51))	('SCC', 'Gene', (110, 113))	('SCC', 'Phenotype', 'HP:0002860', (110, 113))	('cancers', 'Phenotype', 'HP:0002664', (168, 175))	('LUAD', 'Disease', (118, 122))	('Nfe2l2', 'Gene', (52, 58))	('Nfe2l2', 'Gene', '4780', (52, 58))	('cancers', 'Disease', (168, 175))	('LUAD', 'Phenotype', 'HP:0030078', (118, 122))	('cancers', 'Disease', 'MESH:D009369', (168, 175))	('SCC', 'Gene', '6317', (110, 113))	('poor', 'NegReg', (79, 83))
266877	30458852	A deeper knowledge of the mechanisms underlying BCC development and progression has allowed the discovery of mutations in the sonic hedgehog homolog (SHH) pathway as the most common oncogenic alterations.	('sonic hedgehog homolog', 'Gene', (126, 148))	('SHH', 'Gene', '6469', (150, 153))	('SHH', 'Gene', (150, 153))	('mutations', 'Var', (109, 118))	('sonic hedgehog homolog', 'Gene', '6469', (126, 148))	('BCC', 'Phenotype', 'HP:0002671', (48, 51))
266899	30458852	No targetable oncogenic alterations (EGFR mutations, ALK/ROS-1 rearrangements and BRAF mutations) were detected.	('ALK', 'Gene', (53, 56))	('BRAF', 'Gene', '673', (82, 86))	('BRAF', 'Gene', (82, 86))	('ROS-1', 'Gene', (57, 62))	('rearrangements', 'Var', (63, 77))	('EGFR', 'Gene', '1956', (37, 41))	('ALK', 'Gene', '238', (53, 56))	('ROS-1', 'Gene', '6098', (57, 62))	('EGFR', 'Gene', (37, 41))	('mutations', 'Var', (42, 51))	('mutations', 'Var', (87, 96))
266940	30458852	Mutations cause an increased expression of neoantigens in the context of HLA class I antigens enhancing the recognition of cancer cells by cognate T cells.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('HLA class I antigen', 'Gene', (73, 92))	('neoantigens', 'Protein', (43, 54))	('HLA class I antigen', 'Gene', '100507436', (73, 92))	('recognition', 'MPA', (108, 119))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('increased', 'PosReg', (19, 28))	('Mutations', 'Var', (0, 9))	('cancer', 'Disease', (123, 129))	('enhancing', 'PosReg', (94, 103))	('expression', 'MPA', (29, 39))
266958	30458852	Therefore a lack of beta2-m expression might reflect mutations in beta2-m genes.	('beta2', 'Gene', '10383', (20, 25))	('expression', 'MPA', (28, 38))	('beta2', 'Gene', (20, 25))	('mutations', 'Var', (53, 62))	('beta2', 'Gene', '10383', (66, 71))	('beta2', 'Gene', (66, 71))	('lack', 'NegReg', (12, 16))
266960	30458852	However we did not perform a genetic analysis of beta2-m and additional studies are needed to define beta2-m mutations in BCCs.	('BCCs', 'Disease', (122, 126))	('beta2', 'Gene', '10383', (101, 106))	('BCC', 'Phenotype', 'HP:0002671', (122, 125))	('mutations', 'Var', (109, 118))	('beta2', 'Gene', (49, 54))	('beta2', 'Gene', '10383', (49, 54))	('beta2', 'Gene', (101, 106))
266963	30458852	Alterations in the IFNgamma pathway genes can be responsible of ICI resistance, but to the best of our knowledge no information about IFNgamma pathway genes is at present available for BCCs.	('Alterations', 'Var', (0, 11))	('IFNgamma', 'Gene', (19, 27))	('ICI', 'Chemical', '-', (64, 67))	('IFNgamma', 'Gene', '3458', (19, 27))	('IFNgamma', 'Gene', (134, 142))	('IFNgamma', 'Gene', '3458', (134, 142))	('BCC', 'Phenotype', 'HP:0002671', (185, 188))	('responsible', 'Reg', (49, 60))	('ICI resistance', 'Disease', (64, 78))
266964	30458852	In the patient we have described we hypothesize that HLA class I down-regulation cannot be restored by IFNgamma because of the association between lack of beta2-m expression and irreversible mutations of beta2-m gene.	('lack', 'NegReg', (147, 151))	('IFNgamma', 'Gene', '3458', (103, 111))	('patient', 'Species', '9606', (7, 14))	('beta2', 'Gene', (204, 209))	('mutations', 'Var', (191, 200))	('expression', 'MPA', (163, 173))	('beta2', 'Gene', '10383', (155, 160))	('beta2', 'Gene', (155, 160))	('beta2', 'Gene', '10383', (204, 209))	('down-regulation', 'NegReg', (65, 80))	('IFNgamma', 'Gene', (103, 111))
266970	30458852	Immunotherapy with ICIs is completely revolutionizing the clinical approach to patients with different types of malignancies such as melanoma, NSCLC, renal cell carcinoma, head and neck squamous cell carcinoma, and microsatellite instability-high and mismatch repair-deficient cancers.	('carcinoma', 'Phenotype', 'HP:0030731', (200, 209))	('NSCLC', 'Disease', 'MESH:D002289', (143, 148))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (150, 170))	('malignancies', 'Disease', 'MESH:D009369', (112, 124))	('deficient cancers', 'Disease', (267, 284))	('deficient cancers', 'Disease', 'MESH:D009369', (267, 284))	('NSCLC', 'Disease', (143, 148))	('malignancies', 'Disease', (112, 124))	('melanoma', 'Phenotype', 'HP:0002861', (133, 141))	('melanoma', 'Disease', (133, 141))	('cancer', 'Phenotype', 'HP:0002664', (277, 283))	('neck squamous cell carcinoma', 'Disease', (181, 209))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (186, 209))	('cancers', 'Phenotype', 'HP:0002664', (277, 284))	('renal cell carcinoma', 'Disease', (150, 170))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (181, 209))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (150, 170))	('microsatellite instability-high', 'Var', (215, 246))	('melanoma', 'Disease', 'MESH:D008545', (133, 141))	('patients', 'Species', '9606', (79, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (161, 170))	('ICIs', 'Chemical', '-', (19, 23))
266985	33931086	BBOX1-AS1 deficiency resulted in an inhibition of cell proliferation, migration, invasion and EMT in vitro.	('migration', 'CPA', (70, 79))	('invasion', 'CPA', (81, 89))	('inhibition', 'NegReg', (36, 46))	('EMT in vitro', 'CPA', (94, 106))	('deficiency', 'Var', (10, 20))	('BBOX1-AS1', 'Gene', '103695435;8424;5729', (0, 9))	('BBOX1-AS1', 'Gene', (0, 9))	('cell proliferation', 'CPA', (50, 68))
266986	33931086	Also, knockdown of BBOX1-AS1 suppressed NSCLC xenograft tumor growth in mice in vivo.	('SCLC', 'Phenotype', 'HP:0030357', (41, 45))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('BBOX1-AS1', 'Gene', '103695435;8424;5729', (19, 28))	('NSCLC', 'Phenotype', 'HP:0030358', (40, 45))	('BBOX1-AS1', 'Gene', (19, 28))	('NSCLC xenograft tumor', 'Disease', 'MESH:D009369', (40, 61))	('NSCLC xenograft tumor', 'Disease', (40, 61))	('mice', 'Species', '10090', (72, 76))	('knockdown', 'Var', (6, 15))	('suppressed', 'NegReg', (29, 39))
266988	33931086	miR-27a-5p was confirmed as a tumor suppressor in NSCLC.	('SCLC', 'Phenotype', 'HP:0030357', (51, 55))	('miR-27a-5p', 'Var', (0, 10))	('NSCLC', 'Phenotype', 'HP:0030358', (50, 55))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('miR-27a-5p', 'Chemical', '-', (0, 10))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('NSCLC', 'Disease', (50, 55))	('NSCLC', 'Disease', 'MESH:D002289', (50, 55))	('tumor', 'Disease', (30, 35))
266989	33931086	Moreover, BBOX1-AS1-induced increase of cell proliferation, migration, invasion and EMT was greatly reversed due to the overexpression of miR-27a-5p.	('overexpression', 'PosReg', (120, 134))	('invasion', 'CPA', (71, 79))	('miR-27a-5p', 'Var', (138, 148))	('miR-27a-5p', 'Chemical', '-', (138, 148))	('EMT', 'CPA', (84, 87))	('migration', 'CPA', (60, 69))	('cell proliferation', 'CPA', (40, 58))	('BBOX1-AS1', 'Gene', '103695435;8424;5729', (10, 19))	('increase', 'PosReg', (28, 36))	('BBOX1-AS1', 'Gene', (10, 19))
266992	33931086	KLF5-induced BBOX1-AS1 exerts tumor-promotive roles in NSCLC via sponging miR-27a-5p to activate MELK/FAK signaling, providing the possibility of employing BBOX1-AS1 as a therapeutic target for NSCLC patients.	('FAK', 'Gene', '5747', (102, 105))	('NSCLC', 'Disease', 'MESH:D002289', (55, 60))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('MELK', 'Gene', (97, 101))	('SCLC', 'Phenotype', 'HP:0030357', (195, 199))	('NSCLC', 'Disease', (55, 60))	('NSCLC', 'Disease', 'MESH:D002289', (194, 199))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('NSCLC', 'Phenotype', 'HP:0030358', (55, 60))	('miR-27a-5p', 'Chemical', '-', (74, 84))	('sponging', 'Var', (65, 73))	('KLF5', 'Gene', '688', (0, 4))	('NSCLC', 'Disease', (194, 199))	('BBOX1-AS1', 'Gene', (156, 165))	('activate', 'PosReg', (88, 96))	('MELK', 'Gene', '9833', (97, 101))	('BBOX1-AS1', 'Gene', (13, 22))	('NSCLC', 'Phenotype', 'HP:0030358', (194, 199))	('KLF5', 'Gene', (0, 4))	('patients', 'Species', '9606', (200, 208))	('BBOX1-AS1', 'Gene', '103695435;8424;5729', (156, 165))	('FAK', 'Gene', (102, 105))	('SCLC', 'Phenotype', 'HP:0030357', (56, 60))	('tumor', 'Disease', (30, 35))	('BBOX1-AS1', 'Gene', '103695435;8424;5729', (13, 22))
267001	33931086	A growing list of lncRNAs are reported as tumor suppressors or drivers in NSCLC via impacting fundamental cellular processes, such as proliferation, survival, apoptosis, migration, invasion and epithelial to mesenchymal transition (EMT).	('lncRNAs', 'Var', (18, 25))	('impacting', 'Reg', (84, 93))	('tumor', 'Disease', (42, 47))	('migration', 'CPA', (170, 179))	('NSCLC', 'Phenotype', 'HP:0030358', (74, 79))	('epithelial to mesenchymal transition', 'CPA', (194, 230))	('SCLC', 'Phenotype', 'HP:0030357', (75, 79))	('NSCLC', 'Disease', (74, 79))	('invasion', 'CPA', (181, 189))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('survival', 'CPA', (149, 157))	('proliferation', 'CPA', (134, 147))	('NSCLC', 'Disease', 'MESH:D002289', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('apoptosis', 'CPA', (159, 168))
267002	33931086	For instance, lncRNA LINC01234 conferred an aggressive phenotype to NSCLC by sponging miR-340-5p/miR-27b-3p in the cytoplasm and inhibiting BTG2 expression in the nucleus.	('inhibiting', 'NegReg', (129, 139))	('lncRNA', 'Var', (14, 20))	('NSCLC', 'Disease', 'MESH:D002289', (68, 73))	('SCLC', 'Phenotype', 'HP:0030357', (69, 73))	('LINC01234', 'Gene', '100506465', (21, 30))	('miR-340-5p/miR-27b-3p', 'MPA', (86, 107))	('expression', 'MPA', (145, 155))	('NSCLC', 'Phenotype', 'HP:0030358', (68, 73))	('LINC01234', 'Gene', (21, 30))	('sponging', 'NegReg', (77, 85))	('BTG2', 'Gene', (140, 144))	('BTG2', 'Gene', '7832', (140, 144))	('NSCLC', 'Disease', (68, 73))
267003	33931086	Hypoxia-induced lncRNA AC020978 facilitates cell proliferation, migration and glycolytic metabolism in NSCLC through controlling PKM2/HIF-1alpha axis.	('Hypoxia', 'Disease', 'MESH:D000860', (0, 7))	('PKM2', 'Gene', '5315', (129, 133))	('SCLC', 'Phenotype', 'HP:0030357', (104, 108))	('cell proliferation', 'CPA', (44, 62))	('Hypoxia', 'Disease', (0, 7))	('glycolytic metabolism', 'MPA', (78, 99))	('NSCLC', 'Disease', (103, 108))	('HIF-1alpha', 'Gene', '3091', (134, 144))	('AC020978', 'Var', (23, 31))	('NSCLC', 'Disease', 'MESH:D002289', (103, 108))	('facilitates', 'PosReg', (32, 43))	('NSCLC', 'Phenotype', 'HP:0030358', (103, 108))	('PKM2', 'Gene', (129, 133))	('migration', 'CPA', (64, 73))	('HIF-1alpha', 'Gene', (134, 144))
267005	33931086	Through mining the microarray data of GEO database including GSE18842 and GSE19188, BBOX1-AS1 expression was found to be higher in NSCLC tumor tissues than that in adjacent non-cancerous tissues.	('NSCLC tumor', 'Disease', 'MESH:D009369', (131, 142))	('SCLC', 'Phenotype', 'HP:0030357', (132, 136))	('BBOX1-AS1', 'Gene', '103695435;8424;5729', (84, 93))	('GSE19188', 'Var', (74, 82))	('cancerous', 'Disease', (177, 186))	('BBOX1-AS1', 'Gene', (84, 93))	('NSCLC tumor', 'Disease', (131, 142))	('expression', 'MPA', (94, 104))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('cancerous', 'Disease', 'MESH:D009369', (177, 186))	('higher', 'PosReg', (121, 127))	('NSCLC', 'Phenotype', 'HP:0030358', (131, 136))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
267008	33931086	In this study, we demonstrated that KLF5-induced BBOX1-AS1 could serve as a molecular sponge for miR-27a-5p to up-regulate MELK expression and activate FAK signaling, thereby facilitating NSCLC cell proliferation and metastasis in vitro and in vivo.	('SCLC', 'Phenotype', 'HP:0030357', (189, 193))	('KLF5', 'Gene', (36, 40))	('NSCLC', 'Disease', 'MESH:D002289', (188, 193))	('BBOX1-AS1', 'Gene', (49, 58))	('MELK', 'Gene', '9833', (123, 127))	('expression', 'MPA', (128, 138))	('NSCLC', 'Disease', (188, 193))	('FAK', 'Gene', (152, 155))	('BBOX1-AS1', 'Gene', '103695435;8424;5729', (49, 58))	('up-regulate', 'PosReg', (111, 122))	('facilitating', 'PosReg', (175, 187))	('miR-27a-5p', 'Var', (97, 107))	('NSCLC', 'Phenotype', 'HP:0030358', (188, 193))	('FAK', 'Gene', '5747', (152, 155))	('miR-27a-5p', 'Chemical', '-', (97, 107))	('metastasis', 'CPA', (217, 227))	('activate', 'PosReg', (143, 151))	('MELK', 'Gene', (123, 127))	('KLF5', 'Gene', '688', (36, 40))
267024	33931086	For miR-27a-5p, cDNAs were generated from total RNA with TaqMan MicroRNA reverse transcription kit (Applied Biosystems, Foster City, CA, USA).	('kit', 'Gene', '3815', (95, 98))	('kit', 'Gene', (95, 98))	('miR-27a-5p', 'Var', (4, 14))	('miR-27a-5p', 'Chemical', '-', (4, 14))
267058	33931086	Mice were subcutaneously injected with A549 cells (6 x 106) with lentivirus vectors carrying sh-BBOX1-AS1 or sh-NC at the left armpit.	('BBOX1-AS1', 'Gene', '103695435;8424;5729', (96, 105))	('BBOX1-AS1', 'Gene', (96, 105))	('sh-NC', 'Var', (109, 114))	('Mice', 'Species', '10090', (0, 4))	('A549', 'CellLine', 'CVCL:0023', (39, 43))
267077	33931086	Together, abnormally up-regulated BBOX1-AS1 might be associated with NSCLC progression and prognosis.	('NSCLC', 'Disease', (69, 74))	('abnormally', 'Var', (10, 20))	('SCLC', 'Phenotype', 'HP:0030357', (70, 74))	('NSCLC', 'Disease', 'MESH:D002289', (69, 74))	('associated', 'Reg', (53, 63))	('BBOX1-AS1', 'Gene', '103695435;8424;5729', (34, 43))	('NSCLC', 'Phenotype', 'HP:0030358', (69, 74))	('BBOX1-AS1', 'Gene', (34, 43))	('up-regulated', 'PosReg', (21, 33))
267083	33931086	The results showed that BBOX1-AS1 expression was inhibited upon KLF5 knockdown, but was promoted due to KLF5 up-regulation in both A549 and SK-MES-1 cells (Fig.	('promoted', 'PosReg', (88, 96))	('KLF5', 'Gene', (104, 108))	('expression', 'MPA', (34, 44))	('inhibited', 'NegReg', (49, 58))	('KLF5', 'Gene', '688', (104, 108))	('SK-MES-1', 'CellLine', 'CVCL:0630', (140, 148))	('A549', 'CellLine', 'CVCL:0023', (131, 135))	('KLF5', 'Gene', (64, 68))	('up-regulation', 'PosReg', (109, 122))	('KLF5', 'Gene', '688', (64, 68))	('knockdown', 'Var', (69, 78))	('BBOX1-AS1', 'Gene', '103695435;8424;5729', (24, 33))	('BBOX1-AS1', 'Gene', (24, 33))
267085	33931086	ChIP assay results revealed that there was an occupancy for KLF5 at the P2 site (- 57 ~ - 48) on BBOX1-AS1 promoter (Fig.	('BBOX1-AS1', 'Gene', '103695435;8424;5729', (97, 106))	('BBOX1-AS1', 'Gene', (97, 106))	('KLF5', 'Gene', (60, 64))	('- 57', 'Var', (81, 85))	('KLF5', 'Gene', '688', (60, 64))
267086	33931086	Afterwards, luciferase reporter vectors were constructed by inserting the wild type or mutant P2 sequence of BBOX1-AS1 promoter into pmirGLO, named as wt-P2 and mut-P2 (Fig.	('mutant', 'Var', (87, 93))	('BBOX1-AS1', 'Gene', '103695435;8424;5729', (109, 118))	('BBOX1-AS1', 'Gene', (109, 118))
267088	33931086	On the contrary, the luciferase activity of wt-P2 but not that of mut-P2 was decreased in SK-MES-1 cells with KLF5 knockdown (Fig.	('SK-MES-1', 'CellLine', 'CVCL:0630', (90, 98))	('KLF5', 'Gene', (110, 114))	('KLF5', 'Gene', '688', (110, 114))	('activity', 'MPA', (32, 40))	('luciferase', 'Enzyme', (21, 31))	('decreased', 'NegReg', (77, 86))	('knockdown', 'Var', (115, 124))
267096	33931086	Transwell invasion assays revealed that the number of invasive cells was reduced due to BBOX1-AS1 knockdown (Fig.	('BBOX1-AS1', 'Gene', '103695435;8424;5729', (88, 97))	('knockdown', 'Var', (98, 107))	('BBOX1-AS1', 'Gene', (88, 97))	('reduced', 'NegReg', (73, 80))
267110	33931086	By performing the luciferase reporter assays, miR-27a-5p suppressed the luciferase activity of wild-type BBOX1-AS1 reporter in HEK293T cells rather than miR-3664-3p or miR-4778-3p.	('miR-27a-5p', 'Chemical', '-', (46, 56))	('activity', 'MPA', (83, 91))	('HEK293T', 'CellLine', 'CVCL:0063', (127, 134))	('BBOX1-AS1', 'Gene', '103695435;8424;5729', (105, 114))	('miR-27a-5p', 'Var', (46, 56))	('BBOX1-AS1', 'Gene', (105, 114))	('luciferase', 'Enzyme', (72, 82))	('suppressed', 'NegReg', (57, 67))
267113	33931086	Dual-luciferase reporter assays were conducted in A549 and SK-MES-1 cells co-transfected with miR-NC or miR-27a-5p and BBOX1-AS1-wt or BBOX1-AS1-mut reporter.	('BBOX1-AS1', 'Gene', (119, 128))	('BBOX1-AS1', 'Gene', '103695435;8424;5729', (119, 128))	('BBOX1-AS1', 'Gene', '103695435;8424;5729', (135, 144))	('BBOX1-AS1', 'Gene', (135, 144))	('miR-27a-5p', 'Var', (104, 114))	('miR-27a-5p', 'Chemical', '-', (104, 114))	('miR-NC', 'Disease', (94, 100))	('A549', 'CellLine', 'CVCL:0023', (50, 54))	('miR-NC', 'Disease', 'OMIM:617025', (94, 100))	('SK-MES-1', 'CellLine', 'CVCL:0630', (59, 67))
267114	33931086	The results showed that the luciferase activity of BBOX1-AS1-wt reporter but not that of BBOX1-AS1-mut was inhibited by miR-27a-5p overexpression in NSCLC cells (Fig.	('SCLC', 'Phenotype', 'HP:0030357', (150, 154))	('BBOX1-AS1', 'Gene', (89, 98))	('miR-27a-5p', 'Chemical', '-', (120, 130))	('BBOX1-AS1', 'Gene', '103695435;8424;5729', (51, 60))	('BBOX1-AS1', 'Gene', (51, 60))	('NSCLC', 'Disease', 'MESH:D002289', (149, 154))	('NSCLC', 'Disease', (149, 154))	('activity', 'MPA', (39, 47))	('luciferase', 'Enzyme', (28, 38))	('inhibited', 'NegReg', (107, 116))	('BBOX1-AS1', 'Gene', '103695435;8424;5729', (89, 98))	('overexpression', 'PosReg', (131, 145))	('miR-27a-5p', 'Var', (120, 130))	('NSCLC', 'Phenotype', 'HP:0030358', (149, 154))
267115	33931086	RNA pull-down assay disclosed that much more BBOX1-AS1 was captured by Biotin-miR-27a-5p rather than by Biotin-NC (Fig.	('more', 'PosReg', (40, 44))	('BBOX1-AS1', 'Gene', '103695435;8424;5729', (45, 54))	('Biotin-miR-27a-5p', 'Var', (71, 88))	('miR-27a-5p', 'Chemical', '-', (78, 88))	('Biotin', 'Chemical', 'MESH:D001710', (71, 77))	('BBOX1-AS1', 'Gene', (45, 54))	('Biotin', 'Chemical', 'MESH:D001710', (104, 110))
267117	33931086	Furthermore, qRT-PCR assays found that miR-27a-5p was down-regulated in NSCLC tumor tissues and inversely associated with BBOX1-AS1 expression (Fig.	('NSCLC tumor', 'Disease', 'MESH:D009369', (72, 83))	('NSCLC tumor', 'Disease', (72, 83))	('SCLC', 'Phenotype', 'HP:0030357', (73, 77))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('miR-27a-5p', 'Var', (39, 49))	('BBOX1-AS1', 'Gene', '103695435;8424;5729', (122, 131))	('BBOX1-AS1', 'Gene', (122, 131))	('NSCLC', 'Phenotype', 'HP:0030358', (72, 77))	('miR-27a-5p', 'Chemical', '-', (39, 49))	('down-regulated', 'NegReg', (54, 68))
267123	33931086	Then, we further unearthed the role of miR-27a-5p in NSCLC, and whether miR-27a-5p was implicated in the regulation of BBOX1-AS1 in cell malignant behaviors.	('BBOX1-AS1', 'Gene', (119, 128))	('NSCLC', 'Phenotype', 'HP:0030358', (53, 58))	('miR-27a-5p', 'Chemical', '-', (72, 82))	('miR-27a-5p', 'Var', (39, 49))	('NSCLC', 'Disease', (53, 58))	('SCLC', 'Phenotype', 'HP:0030357', (54, 58))	('NSCLC', 'Disease', 'MESH:D002289', (53, 58))	('miR-27a-5p', 'Chemical', '-', (39, 49))	('BBOX1-AS1', 'Gene', '103695435;8424;5729', (119, 128))
267124	33931086	As a result, enforced expression of miR-27a-5p led to a significant repression of cell growth and colony forming capability (Fig.	('miR-27a-5p', 'Chemical', '-', (36, 46))	('colony forming capability', 'CPA', (98, 123))	('repression', 'NegReg', (68, 78))	('cell growth', 'CPA', (82, 93))	('miR-27a-5p', 'Var', (36, 46))
267125	33931086	Moreover, cell migration and invasion potential was effectively attenuated in response to miR-27a-5p overexpression (Fig.	('overexpression', 'PosReg', (101, 115))	('cell migration', 'CPA', (10, 24))	('miR-27a-5p', 'Var', (90, 100))	('invasion potential', 'CPA', (29, 47))	('miR-27a-5p', 'Chemical', '-', (90, 100))	('attenuated', 'NegReg', (64, 74))
267126	33931086	Similarly, increased E-cadherin expression as well as decreased N-cadherin and Vimentin expression were found in NSCLC cells with miR-27a-5p up-regulation (Fig.	('miR-27a-5p', 'Var', (130, 140))	('Vimentin', 'Gene', (79, 87))	('miR-27a-5p', 'Chemical', '-', (130, 140))	('N-cadherin', 'Gene', (64, 74))	('increased', 'PosReg', (11, 20))	('up-regulation', 'PosReg', (141, 154))	('E-cadherin', 'Gene', '999', (21, 31))	('Vimentin', 'Gene', '7431', (79, 87))	('N-cadherin', 'Gene', '1000', (64, 74))	('NSCLC', 'Phenotype', 'HP:0030358', (113, 118))	('decreased', 'NegReg', (54, 63))	('SCLC', 'Phenotype', 'HP:0030357', (114, 118))	('E-cadherin', 'Gene', (21, 31))	('NSCLC', 'Disease', (113, 118))	('expression', 'MPA', (32, 42))	('expression', 'MPA', (88, 98))	('NSCLC', 'Disease', 'MESH:D002289', (113, 118))
267127	33931086	5e), suggesting the inhibitory effect of miR-27a-5p on EMT.	('miR-27a-5p', 'Chemical', '-', (41, 51))	('EMT', 'CPA', (55, 58))	('miR-27a-5p', 'Var', (41, 51))
267128	33931086	As noted above, miR-27a-5p was a tumor-suppressive factor in NSCLC.	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('NSCLC', 'Phenotype', 'HP:0030358', (61, 66))	('SCLC', 'Phenotype', 'HP:0030357', (62, 66))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('NSCLC', 'Disease', (61, 66))	('tumor', 'Disease', (33, 38))	('NSCLC', 'Disease', 'MESH:D002289', (61, 66))	('miR-27a-5p', 'Var', (16, 26))	('miR-27a-5p', 'Chemical', '-', (16, 26))
267129	33931086	Importantly, BBOX1-AS1-induced cell proliferation was greatly abrogated due to the overexpression of miR-27a-5p (Fig.	('abrogated', 'NegReg', (62, 71))	('overexpression', 'PosReg', (83, 97))	('miR-27a-5p', 'Chemical', '-', (101, 111))	('miR-27a-5p', 'Var', (101, 111))	('BBOX1-AS1', 'Gene', '103695435;8424;5729', (13, 22))	('BBOX1-AS1', 'Gene', (13, 22))
267130	33931086	Consistently, exogenous expression of miR-27a-5p also eliminated the promotive effects of BBOX1-AS1 on cell migration, invasion and EMT (Fig.	('eliminated', 'NegReg', (54, 64))	('miR-27a-5p', 'Var', (38, 48))	('promotive effects', 'MPA', (69, 86))	('invasion', 'CPA', (119, 127))	('EMT', 'CPA', (132, 135))	('BBOX1-AS1', 'Gene', (90, 99))	('cell migration', 'CPA', (103, 117))	('BBOX1-AS1', 'Gene', '103695435;8424;5729', (90, 99))	('miR-27a-5p', 'Chemical', '-', (38, 48))
267132	33931086	In order to make an investigation into the possible mechanism behind the inhibitory influence of miR-27a-5p on NSCLC, we collected the expression profile from 4 lung cancer microarrays (GSE19188, GSE18842, GSE29250 and GSE33532) to identify the differentially expressed genes in lung cancer.	('lung cancer', 'Disease', 'MESH:D008175', (279, 290))	('NSCLC', 'Disease', (111, 116))	('GSE19188', 'Var', (186, 194))	('GSE29250', 'Var', (206, 214))	('lung cancer', 'Disease', (161, 172))	('GSE18842', 'Var', (196, 204))	('lung cancer', 'Disease', (279, 290))	('NSCLC', 'Disease', 'MESH:D002289', (111, 116))	('GSE33532', 'Var', (219, 227))	('lung cancer', 'Phenotype', 'HP:0100526', (279, 290))	('lung cancer', 'Phenotype', 'HP:0100526', (161, 172))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('cancer', 'Phenotype', 'HP:0002664', (284, 290))	('NSCLC', 'Phenotype', 'HP:0030358', (111, 116))	('miR-27a-5p', 'Chemical', '-', (97, 107))	('SCLC', 'Phenotype', 'HP:0030357', (112, 116))	('lung cancer', 'Disease', 'MESH:D008175', (161, 172))
267137	33931086	Moreover, patients with high MELK expression showed a significantly decreased overall survival compared to that with low MELK expression in lung cancer by Kaplan-Meier Plotter (Fig.	('lung cancer', 'Disease', (140, 151))	('decreased', 'NegReg', (68, 77))	('MELK', 'Gene', (29, 33))	('lung cancer', 'Phenotype', 'HP:0100526', (140, 151))	('MELK', 'Gene', '9833', (29, 33))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('lung cancer', 'Disease', 'MESH:D008175', (140, 151))	('high', 'Var', (24, 28))	('patients', 'Species', '9606', (10, 18))	('MELK', 'Gene', '9833', (121, 125))	('MELK', 'Gene', (121, 125))
267138	33931086	The wild-type or mutant binding sites of MELK-3'UTR on miR-27a-5p were delineated in Fig.	('MELK', 'Gene', (41, 45))	('mutant', 'Var', (17, 23))	('miR-27a-5p', 'Chemical', '-', (55, 65))	('MELK', 'Gene', '9833', (41, 45))
267140	33931086	The results revealed that the luciferase activity of MELK-wt reporter was greatly suppressed due to miR-27a-5p overexpression, while no change was observed for the luciferase activity of MELK-mut reporter between miR-NC and miR-27a-5p (Fig.	('miR-NC', 'Disease', (213, 219))	('miR-27a-5p', 'Var', (100, 110))	('MELK', 'Gene', (53, 57))	('luciferase', 'Enzyme', (30, 40))	('MELK', 'Gene', '9833', (53, 57))	('suppressed', 'NegReg', (82, 92))	('miR-NC', 'Disease', 'OMIM:617025', (213, 219))	('miR-27a-5p', 'Chemical', '-', (100, 110))	('miR-27a-5p', 'Chemical', '-', (224, 234))	('overexpression', 'PosReg', (111, 125))	('MELK', 'Gene', (187, 191))	('activity', 'MPA', (41, 49))	('MELK', 'Gene', '9833', (187, 191))
267141	33931086	In contrast with Biotin-NC group, MELK was significantly enriched in RNA complex pulled down by Biotin-miR-27a-5p (Fig.	('miR-27a-5p', 'Chemical', '-', (103, 113))	('RNA complex', 'MPA', (69, 80))	('MELK', 'Gene', '9833', (34, 38))	('pulled down', 'NegReg', (81, 92))	('Biotin-miR-27a-5p', 'Var', (96, 113))	('MELK', 'Gene', (34, 38))	('Biotin', 'Chemical', 'MESH:D001710', (17, 23))	('Biotin', 'Chemical', 'MESH:D001710', (96, 102))
267142	33931086	Western blot assays manifested that overexpression of miR-27a-5p inhibited MELK protein level, while miR-27a-5p knockdown led to an increase of MELK protein expression in A549 and SK-MES-1 cells (Fig.	('A549', 'CellLine', 'CVCL:0023', (171, 175))	('increase', 'PosReg', (132, 140))	('SK-MES-1', 'CellLine', 'CVCL:0630', (180, 188))	('MELK', 'Gene', '9833', (75, 79))	('MELK', 'Gene', (75, 79))	('MELK', 'Gene', (144, 148))	('inhibited', 'NegReg', (65, 74))	('miR-27a-5p', 'Chemical', '-', (54, 64))	('MELK', 'Gene', '9833', (144, 148))	('miR-27a-5p', 'Var', (101, 111))	('miR-27a-5p', 'Var', (54, 64))	('miR-27a-5p', 'Chemical', '-', (101, 111))
267143	33931086	It is thus apparent that MELK was a downstream target of miR-27a-5p in NSCLC cells.	('miR-27a-5p', 'Chemical', '-', (57, 67))	('NSCLC', 'Phenotype', 'HP:0030358', (71, 76))	('SCLC', 'Phenotype', 'HP:0030357', (72, 76))	('MELK', 'Gene', '9833', (25, 29))	('MELK', 'Gene', (25, 29))	('miR-27a-5p', 'Var', (57, 67))	('NSCLC', 'Disease', (71, 76))	('NSCLC', 'Disease', 'MESH:D002289', (71, 76))
267148	33931086	What's more, MELK protein level was increased in response to BBOX1-AS1 up-regulation in A549 cells, but this effect was impaired by miR-27a-5p overexpression or MELK knockdown (Fig.	('knockdown', 'Var', (166, 175))	('MELK', 'Gene', (13, 17))	('MELK', 'Gene', (161, 165))	('MELK', 'Gene', '9833', (13, 17))	('MELK', 'Gene', '9833', (161, 165))	('increased', 'PosReg', (36, 45))	('up-regulation', 'PosReg', (71, 84))	('BBOX1-AS1', 'Gene', (61, 70))	('A549', 'CellLine', 'CVCL:0023', (88, 92))	('BBOX1-AS1', 'Gene', '103695435;8424;5729', (61, 70))	('miR-27a-5p', 'Chemical', '-', (132, 142))
267154	33931086	In line with a previous document, knockdown of MELK was found to exert an inhibitory effect on NSCLC cell proliferation, migration and invasion (Additional file 1: Fig.	('inhibitory', 'NegReg', (74, 84))	('migration', 'CPA', (121, 130))	('NSCLC', 'Disease', 'MESH:D002289', (95, 100))	('SCLC', 'Phenotype', 'HP:0030357', (96, 100))	('MELK', 'Gene', (47, 51))	('MELK', 'Gene', '9833', (47, 51))	('NSCLC', 'Phenotype', 'HP:0030358', (95, 100))	('knockdown', 'Var', (34, 43))	('NSCLC', 'Disease', (95, 100))	('invasion', 'CPA', (135, 143))
267156	33931086	It turned out that the proliferation inhibition triggered by BBOX1-AS depletion was restored upon MELK up-regulation (Fig.	('up-regulation', 'PosReg', (103, 116))	('MELK', 'Gene', (98, 102))	('MELK', 'Gene', '9833', (98, 102))	('BBOX1-AS depletion', 'Var', (61, 79))	('proliferation', 'CPA', (23, 36))
267163	33931086	The results showed that silencing of BBOX1-AS1 significantly suppressed tumor growth when compared with sh-NC group (Fig.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('suppressed', 'NegReg', (61, 71))	('tumor', 'Disease', (72, 77))	('BBOX1-AS1', 'Gene', '103695435;8424;5729', (37, 46))	('BBOX1-AS1', 'Gene', (37, 46))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('silencing', 'Var', (24, 33))
267168	33931086	Moreover, inhibition of BBOX1-AS1 led to an increase of E-cadherin protein level, but a decrease of N-cadherin protein expression in the excised tumors (Fig.	('decrease', 'NegReg', (88, 96))	('E-cadherin', 'Gene', '999', (56, 66))	('N-cadherin', 'Gene', '1000', (100, 110))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumors', 'Disease', (145, 151))	('increase', 'PosReg', (44, 52))	('N-cadherin', 'Gene', (100, 110))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('tumors', 'Disease', 'MESH:D009369', (145, 151))	('inhibition', 'Var', (10, 20))	('E-cadherin', 'Gene', (56, 66))	('BBOX1-AS1', 'Gene', '103695435;8424;5729', (24, 33))	('BBOX1-AS1', 'Gene', (24, 33))
267173	33931086	Aberrantly up-regulated BBOX1-AS1 was selected as the object for function and mechanism investigation.	('up-regulated', 'PosReg', (11, 23))	('Aberrantly', 'Var', (0, 10))	('BBOX1-AS1', 'Gene', '103695435;8424;5729', (24, 33))	('BBOX1-AS1', 'Gene', (24, 33))
267175	33931086	Moreover, high BBOX1-AS1 expression was positively related to tumor size, TNM stage and lymph node metastasis.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('TNM', 'Gene', (74, 77))	('expression', 'MPA', (25, 35))	('lymph node metastasis', 'CPA', (88, 109))	('tumor', 'Disease', (62, 67))	('BBOX1-AS1', 'Gene', '103695435;8424;5729', (15, 24))	('BBOX1-AS1', 'Gene', (15, 24))	('high', 'Var', (10, 14))	('related', 'Reg', (51, 58))	('TNM', 'Gene', '10178', (74, 77))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
267191	33931086	Moreover, knockdown of BBOX1-AS1 slowed xenograft growth in vivo.	('xenograft growth in vivo', 'CPA', (40, 64))	('BBOX1-AS1', 'Gene', '103695435;8424;5729', (23, 32))	('BBOX1-AS1', 'Gene', (23, 32))	('knockdown', 'Var', (10, 19))	('slowed', 'NegReg', (33, 39))
267196	33931086	A previous document confirmed the downregulation of miR-27a-5p in small cell lung cancer (SCLC) clinical specimens, and ectopic expression of miR-27a-5p suppressed cancer cell aggressiveness.	('small cell lung cancer', 'Disease', 'MESH:D055752', (66, 88))	('SCLC', 'Disease', 'MESH:D018288', (90, 94))	('lung cancer', 'Phenotype', 'HP:0100526', (77, 88))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (66, 88))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('cancer cell aggressiveness', 'Disease', (164, 190))	('SCLC', 'Phenotype', 'HP:0030357', (90, 94))	('miR-27a-5p', 'Gene', (52, 62))	('downregulation', 'NegReg', (34, 48))	('miR-27a-5p', 'Chemical', '-', (52, 62))	('small cell lung cancer', 'Disease', (66, 88))	('cancer cell aggressiveness', 'Disease', 'MESH:D009369', (164, 190))	('miR-27a-5p', 'Var', (142, 152))	('aggressiveness', 'Phenotype', 'HP:0000718', (176, 190))	('suppressed', 'NegReg', (153, 163))	('miR-27a-5p', 'Chemical', '-', (142, 152))	('SCLC', 'Disease', (90, 94))
267197	33931086	What's more, a recent document revealed that miR-27a-5p was down-regulated in lung adenocarcinoma and exerted an tumor-suppressive activity via inhibiting cell colony forming ability.	('tumor', 'Disease', (113, 118))	('exerted', 'NegReg', (102, 109))	('down-regulated', 'NegReg', (60, 74))	('inhibiting', 'NegReg', (144, 154))	('miR-27a-5p', 'Var', (45, 55))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (78, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('miR-27a-5p', 'Chemical', '-', (45, 55))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('lung adenocarcinoma', 'Disease', (78, 97))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (78, 97))	('cell colony forming ability', 'CPA', (155, 182))
267198	33931086	Nonetheless, there is still an insufficient understanding of role miR-27a-5p's role in NSCLC development.	('NSCLC', 'Disease', (87, 92))	('NSCLC', 'Disease', 'MESH:D002289', (87, 92))	('miR-27a-5p', 'Var', (66, 76))	('miR-27a-5p', 'Chemical', '-', (66, 76))	('SCLC', 'Phenotype', 'HP:0030357', (88, 92))	('NSCLC', 'Phenotype', 'HP:0030358', (87, 92))
267199	33931086	In this current study, we found that miR-27a-5p overexpression significantly suppressed proliferation, migration, invasion and EMT of both A549 and SK-MES-1 cells.	('suppressed', 'NegReg', (77, 87))	('SK-MES-1', 'CellLine', 'CVCL:0630', (148, 156))	('miR-27a-5p', 'Var', (37, 47))	('miR-27a-5p', 'Chemical', '-', (37, 47))	('A549', 'CellLine', 'CVCL:0023', (139, 143))	('proliferation', 'CPA', (88, 101))	('invasion', 'CPA', (114, 122))	('EMT', 'CPA', (127, 130))	('migration', 'CPA', (103, 112))
267200	33931086	More importantly, miR-27a-5p could partly countervail the promotive effects of BBOX1-AS1 on NSCLC cell malignant phenotypes.	('BBOX1-AS1', 'Gene', '103695435;8424;5729', (79, 88))	('BBOX1-AS1', 'Gene', (79, 88))	('NSCLC', 'Phenotype', 'HP:0030358', (92, 97))	('miR-27a-5p', 'Var', (18, 28))	('SCLC', 'Phenotype', 'HP:0030357', (93, 97))	('miR-27a-5p', 'Chemical', '-', (18, 28))	('NSCLC', 'Disease', (92, 97))	('NSCLC', 'Disease', 'MESH:D002289', (92, 97))
267204	33931086	Through a series of bioinformatic prediction and experiment validation, MELK was identified as a direct target of miR-27a-5p.	('miR-27a-5p', 'Chemical', '-', (114, 124))	('MELK', 'Gene', (72, 76))	('MELK', 'Gene', '9833', (72, 76))	('miR-27a-5p', 'Var', (114, 124))
267205	33931086	Functionally, silencing of MELK resulted in a significant repression of cell proliferation, migration and invasion in NSCLC.	('silencing', 'Var', (14, 23))	('NSCLC', 'Phenotype', 'HP:0030358', (118, 123))	('NSCLC', 'Disease', (118, 123))	('cell proliferation', 'CPA', (72, 90))	('repression', 'NegReg', (58, 68))	('MELK', 'Gene', (27, 31))	('migration', 'CPA', (92, 101))	('MELK', 'Gene', '9833', (27, 31))	('NSCLC', 'Disease', 'MESH:D002289', (118, 123))	('invasion in', 'CPA', (106, 117))	('SCLC', 'Phenotype', 'HP:0030357', (119, 123))
267207	33931086	Mechanistically, BBOX1-AS1 served as a molecular sponge for miR-27a-5p to attenuate its suppressive effects on MELK expression.	('BBOX1-AS1', 'Gene', '103695435;8424;5729', (17, 26))	('miR-27a-5p', 'Chemical', '-', (60, 70))	('BBOX1-AS1', 'Gene', (17, 26))	('attenuate', 'NegReg', (74, 83))	('MELK', 'Gene', (111, 115))	('MELK', 'Gene', '9833', (111, 115))	('miR-27a-5p', 'Var', (60, 70))
267208	33931086	Furthermore, the tumor-suppressive activity owing to BBOX1-AS1 knockdown was partly reversed by MELK overexpression.	('tumor', 'Disease', (17, 22))	('MELK', 'Gene', (96, 100))	('BBOX1-AS1', 'Gene', '103695435;8424;5729', (53, 62))	('MELK', 'Gene', '9833', (96, 100))	('BBOX1-AS1', 'Gene', (53, 62))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('knockdown', 'Var', (63, 72))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
267211	33931086	Thus, we concluded that BBOX1-AS exerted oncogenic effects in NSCLC at least in part by positively regulating MELK/FAK pathway via sponging miR-27a-5p.	('FAK', 'Gene', (115, 118))	('FAK', 'Gene', '5747', (115, 118))	('NSCLC', 'Disease', (62, 67))	('miR-27a-5p', 'Chemical', '-', (140, 150))	('SCLC', 'Phenotype', 'HP:0030357', (63, 67))	('NSCLC', 'Disease', 'MESH:D002289', (62, 67))	('positively regulating', 'PosReg', (88, 109))	('BBOX1-AS', 'Var', (24, 32))	('NSCLC', 'Phenotype', 'HP:0030358', (62, 67))	('MELK', 'Gene', (110, 114))	('MELK', 'Gene', '9833', (110, 114))
267218	33931086	Functionally, knockdown of BBOX1-AS1 inhibited cell proliferation, migration, invasion and EMT in vitro and slowered tumor growth in vivo.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('BBOX1-AS1', 'Gene', '103695435;8424;5729', (27, 36))	('BBOX1-AS1', 'Gene', (27, 36))	('inhibited', 'NegReg', (37, 46))	('invasion', 'CPA', (78, 86))	('tumor', 'Disease', (117, 122))	('EMT in vitro', 'CPA', (91, 103))	('migration', 'CPA', (67, 76))	('knockdown', 'Var', (14, 23))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('slowered', 'NegReg', (108, 116))	('cell proliferation', 'CPA', (47, 65))
267229	33469547	Genomic studies of head and neck tumors have shown that although beta-catenin is not frequently mutated in HNSCC, its activity is not inhibited by mutations in upstream gene encoding beta-catenin, NOTCH1, FAT1, and AJUBA.	('mutations', 'Var', (147, 156))	('HNSCC', 'Phenotype', 'HP:0012288', (107, 112))	('beta-catenin', 'Gene', (183, 195))	('head and neck tumor', 'Phenotype', 'HP:0012288', (19, 38))	('beta-catenin', 'Gene', '1499', (65, 77))	('beta-catenin', 'Gene', '1499', (183, 195))	('FAT1', 'Gene', '2195', (205, 209))	('head and neck tumors', 'Phenotype', 'HP:0012288', (19, 39))	('activity', 'MPA', (118, 126))	('NOTCH1', 'Gene', (197, 203))	('AJUBA', 'Gene', '84962', (215, 220))	('neck tumors', 'Disease', (28, 39))	('NOTCH1', 'Gene', '4851', (197, 203))	('AJUBA', 'Gene', (215, 220))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('FAT1', 'Gene', (205, 209))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('beta-catenin', 'Gene', (65, 77))	('neck tumors', 'Disease', 'MESH:D006258', (28, 39))
267230	33469547	Genetic defects affect the components of the Wnt pathway in oral squamous cell carcinoma (OSCC) and the epigenetic mechanisms that regulate inhibitors of the Wnt pathway.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (65, 88))	('Wnt', 'Gene', '35975', (158, 161))	('Genetic defects', 'Var', (0, 15))	('oral squamous cell carcinoma', 'Disease', (60, 88))	('Wnt', 'Gene', (158, 161))	('Wnt', 'Gene', '35975', (45, 48))	('affect', 'Reg', (16, 22))	('Wnt', 'Gene', (45, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (60, 88))
267239	33469547	Previous studies have shown that dysfunction of the Wnt signaling pathway can promote the development of oral cancer and that abnormalities in this pathway affect the prognosis of patients with HNSCC.	('oral cancer', 'Disease', (105, 116))	('promote', 'PosReg', (78, 85))	('prognosis', 'CPA', (167, 176))	('HNSCC', 'Phenotype', 'HP:0012288', (194, 199))	('affect', 'Reg', (156, 162))	('patients', 'Species', '9606', (180, 188))	('HNSCC', 'Disease', (194, 199))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('development', 'CPA', (90, 101))	('Wnt', 'Gene', '35975', (52, 55))	('oral cancer', 'Disease', 'MESH:D009369', (105, 116))	('dysfunction', 'Var', (33, 44))	('Wnt', 'Gene', (52, 55))	('abnormalities', 'Var', (126, 139))
267253	33469547	The first phosphorylation is at Ser45 by CK1alpha, and subsequently at Thr41, Ser37, and Ser33 by GSK3beta.	('Ser37', 'Var', (78, 83))	('CK1', 'Species', '2498238', (41, 44))	('Thr41', 'Chemical', '-', (71, 76))	('Ser33', 'Chemical', '-', (89, 94))	('Ser45', 'Chemical', '-', (32, 37))	('Ser37', 'Chemical', '-', (78, 83))	('Ser45', 'Var', (32, 37))
267283	33469547	For example, Wnt1-induced signaling pathway protein 1 (WISP-1) is involved in the progression of OSCC, and high expression of WISP-1 is significantly associated with treatment failure.	('associated', 'Reg', (150, 160))	('Wnt1', 'Gene', (13, 17))	('WISP-1', 'Gene', '8840', (55, 61))	('WISP-1', 'Gene', (126, 132))	('high expression', 'Var', (107, 122))	('Wnt1', 'Gene', '7471', (13, 17))	('WISP-1', 'Gene', '8840', (126, 132))	('WISP-1', 'Gene', (55, 61))	('OSCC', 'Disease', (97, 101))
267288	33469547	Wnt5b gene silencing can significantly inhibit the formation of filopodia-like protrusive structures and migration, whereas stimulation with Wnt5b can significantly increase the formation of filopodia-like protrusions in SAS-LM8 cells.	('increase', 'PosReg', (165, 173))	('Wnt5b', 'Gene', (141, 146))	('Wnt5b', 'Gene', '81029', (0, 5))	('inhibit', 'NegReg', (39, 46))	('gene silencing', 'Var', (6, 20))	('migration', 'CPA', (105, 114))	('formation of filopodia-like protrusive structures', 'CPA', (51, 100))	('Wnt5b', 'Gene', (0, 5))	('Wnt5b', 'Gene', '81029', (141, 146))	('SAS-LM8', 'CellLine', 'CVCL:1675', (221, 228))
267298	33469547	According to reports, E6/E7 may also suppress E3 ubiquitin ligase protein to induce nuclear translocation of beta-catenin.	('induce', 'PosReg', (77, 83))	('suppress', 'NegReg', (37, 45))	('beta-catenin', 'Gene', (109, 121))	('nuclear translocation', 'MPA', (84, 105))	('beta-catenin', 'Gene', '1499', (109, 121))	('E6/E7', 'Var', (22, 27))	('E3 ubiquitin ligase protein', 'Protein', (46, 73))
267303	33469547	Components of the Wnt signaling pathway, such as Wnt ligand proteins, Wnt antagonists, membrane receptors, and intracellular conduction medium, are often disrupted by genetic or epigenetic inheritance in human tumors.	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('tumors', 'Disease', (210, 216))	('disrupted', 'NegReg', (154, 163))	('tumors', 'Phenotype', 'HP:0002664', (210, 216))	('Wnt', 'Gene', '35975', (18, 21))	('Wnt', 'Gene', '35975', (49, 52))	('tumors', 'Disease', 'MESH:D009369', (210, 216))	('Wnt', 'Gene', (49, 52))	('human', 'Species', '9606', (204, 209))	('Wnt', 'Gene', '35975', (70, 73))	('epigenetic inheritance', 'Var', (178, 200))	('Wnt', 'Gene', (18, 21))	('Wnt', 'Gene', (70, 73))
267304	33469547	It is reported that the activation of the Wnt1 and Wnt pathways occurs due to epigenetic changes in secreted frizzled-related protein (SFRP), Wnt inhibitory factor (WIF), and the Wnt signaling pathway inhibitor Dickkopf 3 (DKK3).	('Wnt1', 'Gene', '7471', (42, 46))	('epigenetic changes', 'Var', (78, 96))	('DKK3', 'Gene', '27122', (223, 227))	('Wnt', 'Gene', '35975', (179, 182))	('Dickkopf 3', 'Gene', (211, 221))	('DKK3', 'Gene', (223, 227))	('SFRP', 'Gene', (135, 139))	('Wnt', 'Gene', (42, 45))	('Wnt', 'Gene', '35975', (42, 45))	('Wnt', 'Gene', '35975', (51, 54))	('Wnt', 'Gene', (179, 182))	('Wnt', 'Gene', '35975', (142, 145))	('Wnt1', 'Gene', (42, 46))	('Wnt', 'Gene', (142, 145))	('activation', 'PosReg', (24, 34))	('Wnt', 'Gene', (51, 54))	('Dickkopf 3', 'Gene', '27122', (211, 221))
267306	33469547	Therefore, epigenetic changes of DKK3 may be closely related to the occurrence and development of HNSCC.	('related', 'Reg', (53, 60))	('HNSCC', 'Disease', (98, 103))	('epigenetic changes', 'Var', (11, 29))	('DKK3', 'Gene', '27122', (33, 37))	('HNSCC', 'Phenotype', 'HP:0012288', (98, 103))	('DKK3', 'Gene', (33, 37))
267307	33469547	Epigenetic alterations of SFRP, WIF-1, and DKK-3 genes can active Wnt pathways, resulting in delocalization of catenin in HNSCC.	('Epigenetic alterations', 'Var', (0, 22))	('active', 'PosReg', (59, 65))	('WIF-1', 'Gene', '11197', (32, 37))	('catenin', 'MPA', (111, 118))	('Wnt', 'Gene', '35975', (66, 69))	('SFRP', 'Gene', (26, 30))	('DKK-3', 'Gene', '27122', (43, 48))	('WIF-1', 'Gene', (32, 37))	('Wnt', 'Gene', (66, 69))	('delocalization', 'MPA', (93, 107))	('HNSCC', 'Disease', (122, 127))	('HNSCC', 'Phenotype', 'HP:0012288', (122, 127))	('DKK-3', 'Gene', (43, 48))
267310	33469547	Previous studies have suggested that mutations in APC, Axin, and beta-catenin are widespread in colon cancer, esophageal cancer, and gastric cancer.	('gastric cancer', 'Phenotype', 'HP:0012126', (133, 147))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('beta-catenin', 'Gene', '1499', (65, 77))	('colon cancer', 'Phenotype', 'HP:0003003', (96, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('Axin', 'Gene', '8312', (55, 59))	('Axin', 'Gene', (55, 59))	('colon cancer', 'Disease', 'MESH:D015179', (96, 108))	('gastric cancer', 'Disease', (133, 147))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('cancer', 'Disease', (141, 147))	('APC', 'Gene', '324', (50, 53))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('cancer', 'Disease', (102, 108))	('mutations', 'Var', (37, 46))	('gastric cancer', 'Disease', 'MESH:D013274', (133, 147))	('widespread', 'Reg', (82, 92))	('colon cancer', 'Disease', (96, 108))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('APC', 'Gene', (50, 53))	('cancer', 'Disease', (121, 127))	('beta-catenin', 'Gene', (65, 77))
267311	33469547	The Axin1 mutation was first identified in hepatocellular carcinoma.	('Axin1', 'Gene', (4, 9))	('mutation', 'Var', (10, 18))	('Axin1', 'Gene', '8312', (4, 9))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (43, 67))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (43, 67))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))	('hepatocellular carcinoma', 'Disease', (43, 67))
267312	33469547	In a small, diverse group of colon cancer cases, activation of point mutations in beta-catenin removed the regulated N-terminal Ser/Thr residue.	('colon cancer', 'Phenotype', 'HP:0003003', (29, 41))	('colon cancer', 'Disease', 'MESH:D015179', (29, 41))	('Thr', 'Chemical', 'MESH:D013912', (132, 135))	('regulated N-terminal Ser/Thr residue', 'MPA', (107, 143))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('colon cancer', 'Disease', (29, 41))	('Ser', 'Chemical', 'MESH:D012694', (128, 131))	('removed', 'NegReg', (95, 102))	('point mutations', 'Var', (63, 78))	('beta-catenin', 'Gene', (82, 94))	('beta-catenin', 'Gene', '1499', (82, 94))
267313	33469547	Similar beta-catenin mutations have also been reported in melanoma and other tumors.	('tumors', 'Disease', (77, 83))	('tumors', 'Disease', 'MESH:D009369', (77, 83))	('melanoma', 'Disease', 'MESH:D008545', (58, 66))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('beta-catenin', 'Gene', (8, 20))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('reported', 'Reg', (46, 54))	('beta-catenin', 'Gene', '1499', (8, 20))	('melanoma', 'Phenotype', 'HP:0002861', (58, 66))	('melanoma', 'Disease', (58, 66))	('mutations', 'Var', (21, 30))
267314	33469547	Mutations in these genes stabilize beta-catenin, allowing it to accumulate in the nucleus, and subsequently activate the Wnt signaling pathway.	('beta-catenin', 'Gene', (35, 47))	('stabilize', 'PosReg', (25, 34))	('beta-catenin', 'Gene', '1499', (35, 47))	('activate', 'PosReg', (108, 116))	('Mutations', 'Var', (0, 9))	('Wnt', 'Gene', '35975', (121, 124))	('Wnt', 'Gene', (121, 124))	('accumulate', 'PosReg', (64, 74))
267315	33469547	However, mutants of APC, Axin, or beta-catenin still ultimately depend on exogenous Wnts.	('depend', 'Reg', (64, 70))	('Wnt', 'Gene', (84, 87))	('APC', 'Gene', (20, 23))	('Axin', 'Gene', (25, 29))	('beta-catenin', 'Gene', '1499', (34, 46))	('mutants', 'Var', (9, 16))	('APC', 'Gene', '324', (20, 23))	('Wnt', 'Gene', '35975', (84, 87))	('Axin', 'Gene', '8312', (25, 29))	('beta-catenin', 'Gene', (34, 46))
267317	33469547	Although Wnt/beta-catenin mutations are not common in HNSCC, other signal pathways, such as FAT1 and AJUBA, can crosstalk with Wnt/beta-catenin, resulting in changes in the activity of Wnt signaling pathway.	('changes', 'Reg', (158, 165))	('FAT1', 'Gene', (92, 96))	('mutations', 'Var', (26, 35))	('beta-catenin', 'Gene', (13, 25))	('crosstalk', 'Reg', (112, 121))	('beta-catenin', 'Gene', '1499', (13, 25))	('Wnt', 'Gene', '35975', (185, 188))	('FAT1', 'Gene', '2195', (92, 96))	('activity', 'MPA', (173, 181))	('Wnt', 'Gene', (185, 188))	('AJUBA', 'Gene', '84962', (101, 106))	('Wnt', 'Gene', '35975', (9, 12))	('Wnt', 'Gene', (9, 12))	('AJUBA', 'Gene', (101, 106))	('Wnt', 'Gene', '35975', (127, 130))	('beta-catenin', 'Gene', (131, 143))	('Wnt', 'Gene', (127, 130))	('beta-catenin', 'Gene', '1499', (131, 143))	('HNSCC', 'Phenotype', 'HP:0012288', (54, 59))
267318	33469547	Mutations in these signaling cascades are almost entirely related to HPV-negative tumors and to the absence of epithelial differentiation programs.	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('HPV-negative tumors', 'Disease', 'MESH:D030361', (69, 88))	('related', 'Reg', (58, 65))	('Mutations', 'Var', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('HPV-negative tumors', 'Disease', (69, 88))	('epithelial differentiation programs', 'CPA', (111, 146))
267321	33469547	Epigenetic regulation may contribute to the silencing of Wnt related genes.	('Epigenetic regulation', 'Var', (0, 21))	('silencing', 'MPA', (44, 53))	('Wnt', 'Gene', '35975', (57, 60))	('Wnt', 'Gene', (57, 60))
267322	33469547	Because there is no changes of methylation levels in the CpG island of APC, Axin, and beta-catenin genes in OSCC, downregulation of Wnt signaling in OSCC and HNSCC is usually due to methylation of different Wnt pathway inhibitors, such as SFRP-2, WIF-1, DKK-1, Dachshund family transcription factor 1 (DACH1), and RUNT-related transcription factor 3 (RUNX3).	('SFRP-2', 'Gene', (239, 245))	('methylation', 'Var', (182, 193))	('APC', 'Gene', (71, 74))	('Wnt', 'Gene', '35975', (132, 135))	('DACH1', 'Gene', '1602', (302, 307))	('RUNT-related transcription factor 3', 'Gene', '864', (314, 349))	('Wnt', 'Gene', (132, 135))	('RUNX3', 'Gene', '864', (351, 356))	('RUNT-related transcription factor 3', 'Gene', (314, 349))	('Dachshund family transcription factor 1', 'Gene', (261, 300))	('beta-catenin', 'Gene', (86, 98))	('beta-catenin', 'Gene', '1499', (86, 98))	('DKK-1', 'Gene', (254, 259))	('WIF-1', 'Gene', '11197', (247, 252))	('DKK-1', 'Gene', '22943', (254, 259))	('Wnt', 'Gene', '35975', (207, 210))	('downregulation', 'NegReg', (114, 128))	('HNSCC', 'Phenotype', 'HP:0012288', (158, 163))	('Wnt', 'Gene', (207, 210))	('APC', 'Gene', '324', (71, 74))	('WIF-1', 'Gene', (247, 252))	('SFRP-2', 'Gene', '6423', (239, 245))	('RUNX3', 'Gene', (351, 356))	('Axin', 'Gene', '8312', (76, 80))	('Axin', 'Gene', (76, 80))	('Dachshund family transcription factor 1', 'Gene', '1602', (261, 300))	('DACH1', 'Gene', (302, 307))
267325	33469547	For example, in OSCC cell, the WIF-1 and SFRP2 genes are frequently methylated, whereas the DACH1 and Dkk1 genes are less frequently methylated.	('DACH1', 'Gene', (92, 97))	('methylated', 'Var', (68, 78))	('DACH1', 'Gene', '1602', (92, 97))	('Dkk1', 'Gene', (102, 106))	('WIF-1', 'Gene', (31, 36))	('SFRP2', 'Gene', '6423', (41, 46))	('SFRP2', 'Gene', (41, 46))	('WIF-1', 'Gene', '11197', (31, 36))	('Dkk1', 'Gene', '22943', (102, 106))
267326	33469547	In the same way, the WIF-1 gene is often methylated in primary oropharyngeal cancer tissue and associated with poorer survival.	('survival', 'MPA', (118, 126))	('WIF-1', 'Gene', (21, 26))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('methylated', 'Var', (41, 51))	('poorer', 'NegReg', (111, 117))	('WIF-1', 'Gene', '11197', (21, 26))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('associated', 'Reg', (95, 105))
267327	33469547	In addition, methylation of the E-cadherin promoter is the main reason for the loss of membrane beta-catenin expression, which leads to the release of beta-catenin from the E-cadherin/beta-catenin complex into the cytoplasm.	('loss', 'NegReg', (79, 83))	('E-cadherin', 'Gene', (173, 183))	('E-cadherin', 'Gene', '999', (173, 183))	('E-cadherin', 'Gene', (32, 42))	('beta-catenin', 'Gene', '1499', (96, 108))	('methylation', 'Var', (13, 24))	('beta-catenin', 'Gene', '1499', (151, 163))	('E-cadherin', 'Gene', '999', (32, 42))	('beta-catenin', 'Gene', (184, 196))	('release', 'MPA', (140, 147))	('beta-catenin', 'Gene', '1499', (184, 196))	('beta-catenin', 'Gene', (151, 163))	('beta-catenin', 'Gene', (96, 108))
267328	33469547	By performing chromatin immunoprecipitation promoter array and gene expression analyses in hepatocellular carcinoma, found that enhancer of zeste homolog 2 (EZH2) occupancy of the promoter decreased the expression of several Wnt antagonists including Axin2, NKD1, PPP2R2B, DKK1, and SFRP5.	('Axin2', 'Gene', '8313', (251, 256))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (91, 115))	('NKD1', 'Gene', (258, 262))	('enhancer of zeste homolog 2', 'Gene', '2146', (128, 155))	('PPP2R2B', 'Gene', '5521', (264, 271))	('PPP2R2B', 'Gene', (264, 271))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (91, 115))	('Wnt', 'Gene', '35975', (225, 228))	('EZH2', 'Gene', '2146', (157, 161))	('DKK1', 'Gene', (273, 277))	('Wnt', 'Gene', (225, 228))	('decreased', 'NegReg', (189, 198))	('EZH2', 'Gene', (157, 161))	('DKK1', 'Gene', '22943', (273, 277))	('SFRP5', 'Gene', '6425', (283, 288))	('hepatocellular carcinoma', 'Disease', (91, 115))	('occupancy', 'Var', (163, 172))	('enhancer of zeste homolog 2', 'Gene', (128, 155))	('SFRP5', 'Gene', (283, 288))	('NKD1', 'Gene', '85407', (258, 262))	('Axin2', 'Gene', (251, 256))	('expression', 'MPA', (203, 213))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))
267332	33469547	These findings show that inhibiting the activity of Wnt antagonists through DNA methylation and histone modification enables to the constitutive activation of Wnt/beta-catenin signaling.	('activation', 'PosReg', (145, 155))	('DNA methylation', 'Var', (76, 91))	('beta-catenin', 'Gene', (163, 175))	('Wnt', 'Gene', '35975', (159, 162))	('inhibiting', 'NegReg', (25, 35))	('beta-catenin', 'Gene', '1499', (163, 175))	('Wnt', 'Gene', '35975', (52, 55))	('activity', 'MPA', (40, 48))	('histone', 'Protein', (96, 103))	('Wnt', 'Gene', (159, 162))	('Wnt', 'Gene', (52, 55))
267336	33469547	According to reports, aberrant Wnt signaling has a promoting effect on different forms of cancer (such as colon cancer, liver cancer, and lung cancer), and plays a key role in guarding CSCs.	('lung cancer', 'Disease', 'MESH:D008175', (138, 149))	('cancer', 'Disease', (112, 118))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('colon cancer', 'Phenotype', 'HP:0003003', (106, 118))	('lung cancer', 'Phenotype', 'HP:0100526', (138, 149))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('promoting effect', 'PosReg', (51, 67))	('cancer', 'Disease', (126, 132))	('colon cancer', 'Disease', 'MESH:D015179', (106, 118))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('liver cancer', 'Disease', 'MESH:D006528', (120, 132))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('lung cancer', 'Disease', (138, 149))	('colon cancer', 'Disease', (106, 118))	('aberrant', 'Var', (22, 30))	('liver cancer', 'Phenotype', 'HP:0002896', (120, 132))	('liver cancer', 'Disease', (120, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('Wnt', 'Gene', '35975', (31, 34))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('Wnt', 'Gene', (31, 34))	('cancer', 'Disease', (90, 96))
267363	33469547	The ability of spheroid cells to exhibit CSC-induced chemotherapy resistance was eliminated after knocking out the genes for beta-catenin synthesis.	('beta-catenin', 'Gene', (125, 137))	('beta-catenin', 'Gene', '1499', (125, 137))	('knocking out', 'Var', (98, 110))
267368	33469547	Using small inhibitors of PORCN, such as IWP, C59, and LGK974 caused rapid decreases in the expression of Wnt signaling.	('PORCN', 'Gene', (26, 31))	('LGK974', 'Gene', (55, 61))	('Wnt', 'Gene', '35975', (106, 109))	('PORCN', 'Gene', '64840', (26, 31))	('Wnt', 'Gene', (106, 109))	('C59', 'Var', (46, 49))	('decreases', 'NegReg', (75, 84))
267369	33469547	In vitro, C59 inhibited the activity of PORCN, and then inhibited the Wnt palmitoylation, Wnt interaction with carrier protein Wntless/WLS, Wnt secretion, and Wnt activation of beta-catenin reporter protein.	('C59', 'Var', (10, 13))	('PORCN', 'Gene', '64840', (40, 45))	('interaction', 'Interaction', (94, 105))	('beta-catenin', 'Gene', (177, 189))	('Wnt', 'Gene', '35975', (70, 73))	('beta-catenin', 'Gene', '1499', (177, 189))	('Wnt', 'Gene', (70, 73))	('PORCN', 'Gene', (40, 45))	('Wnt', 'Gene', '35975', (140, 143))	('Wnt', 'Gene', '35975', (90, 93))	('Wnt', 'Gene', (140, 143))	('Wnt', 'Gene', (90, 93))	('Wnt', 'Gene', '35975', (159, 162))	('Wnt', 'Gene', (159, 162))	('inhibited', 'NegReg', (56, 65))	('Wnt', 'Gene', '35975', (127, 130))	('activity', 'MPA', (28, 36))	('Wnt', 'Gene', (127, 130))	('inhibited', 'NegReg', (14, 23))
267370	33469547	The chick chorioallantoic membrane (CAM) experiment proved that LGK974 can inhibit the growth and metastasis of HNSCC.	('inhibit', 'NegReg', (75, 82))	('HNSCC', 'Disease', (112, 117))	('chick', 'Species', '9031', (4, 9))	('LGK974', 'Var', (64, 70))	('HNSCC', 'Phenotype', 'HP:0012288', (112, 117))
267373	33469547	Additionally, inhibitors of tankyrase stabilize axin and antagonize Wnt signaling including XAV939, IWR, G007-LK, and G244-LM, though they have not yet entered clinical trials.	('axin', 'Gene', '8312', (48, 52))	('Wnt', 'Gene', '35975', (68, 71))	('stabilize', 'PosReg', (38, 47))	('axin', 'Gene', (48, 52))	('G244-LM', 'Var', (118, 125))	('antagonize', 'NegReg', (57, 67))	('tankyrase', 'Gene', '8658', (28, 37))	('Wnt', 'Gene', (68, 71))	('tankyrase', 'Gene', (28, 37))	('XAV939', 'Var', (92, 98))	('inhibitors', 'Var', (14, 24))	('IWR', 'Disease', (100, 103))	('G007-LK', 'Var', (105, 112))
267382	33469547	As outlined above, aberrant activation of the Wnt signaling pathway may impact on HNSCC.	('Wnt', 'Gene', (46, 49))	('HNSCC', 'Phenotype', 'HP:0012288', (82, 87))	('HNSCC', 'Disease', (82, 87))	('activation', 'PosReg', (28, 38))	('Wnt', 'Gene', '35975', (46, 49))	('impact', 'Reg', (72, 78))	('aberrant', 'Var', (19, 27))
267384	33469547	Because the epigenetic alterations of Wnt antagonists are the cause of Wnt signal activation, it may become a potential biomarker for predicting OSCC recurrence in plasma.	('Wnt', 'Gene', (71, 74))	('OSCC', 'Disease', (145, 149))	('epigenetic alterations', 'Var', (12, 34))	('cause', 'Reg', (62, 67))	('activation', 'PosReg', (82, 92))	('Wnt', 'Gene', '35975', (38, 41))	('Wnt', 'Gene', (38, 41))	('Wnt', 'Gene', '35975', (71, 74))
267385	33469547	Appropriate methods are required to deal with CSC generated by aberrant Wnt signaling.	('Wnt', 'Gene', '35975', (72, 75))	('aberrant', 'Var', (63, 71))	('CSC', 'Disease', (46, 49))	('Wnt', 'Gene', (72, 75))
267411	32951460	We extracted TSCC patients from the SEER database by selecting the primary sites of TSCC using the terms "C09.0 Tonsillar fossa," "C09.1 Tonsillar pillar," "C09.8 Overlapping lesion of tonsil," and "C09.9 Tonsil, NOS."	('C09.8', 'Var', (157, 162))	('SCC', 'Phenotype', 'HP:0002860', (14, 17))	('Tonsillar pillar', 'Disease', 'MESH:D014067', (137, 153))	('Tonsillar pillar', 'Disease', (137, 153))	('lesion of tonsil', 'Phenotype', 'HP:0011110', (175, 191))	('patients', 'Species', '9606', (18, 26))	('SCC', 'Phenotype', 'HP:0002860', (85, 88))
267412	32951460	Additionally, the following ICD-O-3 (third revision of the International Classification of Diseases for Oncology) histology/behavior codes for TSCC were selected: "8070/3: Squamous cell carcinoma, NOS," "8071/3: Squamous cell carcinoma, keratinizing, NOS," "8072/3: Squamous cell carcinoma, large cell, nonkeratinizing, NOS," and "8083/3: Basaloid squamous cell carcinoma."	('8072/3', 'Var', (258, 264))	('Classification of Diseases', 'Disease', 'MESH:D008310', (73, 99))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (348, 371))	('Squamous cell carcinoma', 'Phenotype', 'HP:0002860', (172, 195))	('Squamous cell carcinoma', 'Phenotype', 'HP:0002860', (212, 235))	('SCC', 'Phenotype', 'HP:0002860', (144, 147))	('Squamous cell carcinoma', 'Disease', (212, 235))	('ICD', 'Gene', '79158', (28, 31))	('Squamous cell carcinoma', 'Disease', (172, 195))	('Classification of Diseases', 'Disease', (73, 99))	('Squamous cell carcinoma', 'Disease', 'MESH:D002294', (172, 195))	('Squamous cell carcinoma', 'Disease', 'MESH:D002294', (212, 235))	('Squamous cell carcinoma', 'Phenotype', 'HP:0002860', (266, 289))	('nonkeratinizing', 'Disease', (303, 318))	('keratinizing', 'Disease', (237, 249))	('Squamous cell carcinoma', 'Disease', (266, 289))	('Basaloid squamous cell carcinoma', 'Phenotype', 'HP:0002671', (339, 371))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (348, 371))	('carcinoma', 'Phenotype', 'HP:0030731', (226, 235))	('Squamous cell carcinoma', 'Disease', 'MESH:D002294', (266, 289))	('large cell', 'Disease', (291, 301))	('carcinoma', 'Phenotype', 'HP:0030731', (280, 289))	('carcinoma', 'Phenotype', 'HP:0030731', (186, 195))	('carcinoma', 'Phenotype', 'HP:0030731', (362, 371))	('ICD', 'Gene', (28, 31))	('squamous cell carcinoma', 'Disease', (348, 371))	('Oncology', 'Phenotype', 'HP:0002664', (104, 112))
267429	32951460	The primary tumor site in most patients was C09.9, and the predominant histological type was 8070/3.	('C09.9', 'Var', (44, 49))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('8070/3', 'Var', (93, 99))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('patients', 'Species', '9606', (31, 39))	('tumor', 'Disease', (12, 17))
267456	30999697	Clinical Implications of Noncoding Indels in the Surfactant-Encoding Genes in Lung Cancer Lung cancer arises from the accumulation of genetic mutations, usually in exons.	('mutations', 'Var', (142, 151))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('cancer', 'Disease', (95, 101))	('Lung cancer', 'Phenotype', 'HP:0100526', (90, 101))	('Noncoding Indels', 'Var', (25, 41))	('Lung Cancer', 'Phenotype', 'HP:0100526', (78, 89))	('Cancer', 'Phenotype', 'HP:0002664', (83, 89))	('Cancer', 'Disease', (83, 89))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('Cancer', 'Disease', 'MESH:D009369', (83, 89))	('Surfactant-Encoding Genes', 'Gene', (49, 74))
267457	30999697	A recent study identified indel mutations in the noncoding region of surfactant-encoding genes in lung adenocarcinoma cases.	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (98, 117))	('surfactant-encoding genes', 'Gene', (69, 94))	('lung adenocarcinoma', 'Disease', (98, 117))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (98, 117))	('indel mutations', 'Var', (26, 41))
267460	30999697	Indels in the noncoding region of surfactant-encoding genes were identified in 29/113 (25.7%) cases and represent the precise cell of origin for the lung cancer, irrespective of histological type and/or disease stage.	('lung cancer', 'Disease', 'MESH:D008175', (149, 160))	('Indels in', 'Var', (0, 9))	('surfactant-encoding genes', 'Gene', (34, 59))	('lung cancer', 'Phenotype', 'HP:0100526', (149, 160))	('lung cancer', 'Disease', (149, 160))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))
267464	30999697	reported the presence of noncoding insertions/deletions (indels) in certain cancer types, which is reportedly a prevalent and hitherto unrecognized mutational process linking cellular lineage and cancer.	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('noncoding insertions/deletions', 'Var', (25, 55))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (196, 202))	('cancer', 'Disease', (196, 202))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))
267465	30999697	analyzed whole-genome sequences of lung adenocarcinoma using a somatic burden test based on Gamma-Poisson regression for the analysis of both indel and single nucleotide variant somatic mutations.	('lung adenocarcinoma', 'Disease', (35, 54))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (35, 54))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (35, 54))	('single nucleotide variant', 'Var', (152, 177))	('carcinoma', 'Phenotype', 'HP:0030731', (45, 54))
267466	30999697	Using statistical analysis of whole-genome sequences across a diverse collection of cancers, they determined that other tumor types harbor similarly prevalent hotspots of noncoding somatic indel mutations, targeting lineage-defining genes (i.e., ALB, TG, and LIPF).	('indel mutations', 'Var', (189, 204))	('cancers', 'Disease', 'MESH:D009369', (84, 91))	('cancers', 'Phenotype', 'HP:0002664', (84, 91))	('ALB', 'Gene', '213', (246, 249))	('LIPF', 'Gene', '8513', (259, 263))	('cancers', 'Disease', (84, 91))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('ALB', 'Gene', (246, 249))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('LIPF', 'Gene', (259, 263))	('tumor', 'Disease', (120, 125))
267469	30999697	Furthermore, it remains to be determined at which stage of tumor phylogeny these noncoding indel mutations occur, how they are involved in oncogenesis, what effects they have on biological behavior, and what their clinical implications are.	('mutations', 'Var', (97, 106))	('tumor', 'Disease', (59, 64))	('involved', 'Reg', (127, 135))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('noncoding indel mutations', 'Var', (81, 106))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
267480	30999697	The detection rate of the indels in the three-surfactant protein (SFTP) genes was 6/113 (5.3%) in SFTPA1, 23/113 (20.4%) in SFTPB, and 2/113 (1.8%) in SFTPC.	('SFTPA1', 'Gene', (98, 104))	('SFTPC', 'Gene', '6440', (151, 156))	('indels', 'Var', (26, 32))	('SFTP) genes', 'Gene', (66, 77))	('rat', 'Species', '10116', (14, 17))	('SFTPA1', 'Gene', '653509', (98, 104))	('SFTPB', 'Gene', (124, 129))	('SFTPB', 'Gene', '6439', (124, 129))	('SFTPC', 'Gene', (151, 156))
267481	30999697	The co-occurrence of noncoding indels in SFTPA and SFTPB was found in 2 patients (Case 1 and 25 in Table S1).	('noncoding indels', 'Var', (21, 37))	('SFTPA', 'Gene', (41, 46))	('found', 'Reg', (61, 66))	('SFTPB', 'Gene', (51, 56))	('SFTPB', 'Gene', '6439', (51, 56))	('patients', 'Species', '9606', (72, 80))
267483	30999697	Allele fraction of detected noncoding indels was on average 34.4 +- 17.6%, relatively higher than that of the frequent mutations detected in the coding regions in lung cancer.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('lung cancer', 'Disease', 'MESH:D008175', (163, 174))	('noncoding indels', 'Var', (28, 44))	('lung cancer', 'Phenotype', 'HP:0100526', (163, 174))	('lung cancer', 'Disease', (163, 174))
267488	30999697	There was no significant difference in either postoperative disease-free survival or overall survival between patients with lung cancers harboring noncoding indels and those not harboring noncoding indels (Figure 1).	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('lung cancers', 'Disease', (124, 136))	('noncoding indels', 'Var', (147, 163))	('patients', 'Species', '9606', (110, 118))	('postoperative disease-free', 'Disease', (46, 72))	('cancers', 'Phenotype', 'HP:0002664', (129, 136))	('lung cancers', 'Phenotype', 'HP:0100526', (124, 136))	('lung cancers', 'Disease', 'MESH:D008175', (124, 136))	('lung cancer', 'Phenotype', 'HP:0100526', (124, 135))	('postoperative disease-free', 'Disease', 'MESH:D019106', (46, 72))
267492	30999697	Based on the histological classification, 23 (26.1%) of 88 adenocarcinomas, four (25.0%) of 16 squamous cell carcinomas, one (25.0%) of four pleomorphic carcinomas, and one (25.0%) of four small-cell carcinomas harbored noncoding indel mutations (Figure 3).	('carcinomas', 'Disease', (64, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (200, 209))	('small-cell carcinoma', 'Disease', (189, 209))	('pleomorphic carcinomas', 'Disease', (141, 163))	('carcinoma', 'Phenotype', 'HP:0030731', (153, 162))	('carcinomas', 'Phenotype', 'HP:0030731', (153, 163))	('carcinomas', 'Disease', 'MESH:D002277', (200, 210))	('carcinomas', 'Disease', 'MESH:D002277', (153, 163))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (95, 118))	('carcinomas', 'Phenotype', 'HP:0030731', (200, 210))	('carcinomas', 'Disease', (109, 119))	('squamous cell carcinomas', 'Disease', (95, 119))	('adenocarcinomas', 'Disease', 'MESH:D000230', (59, 74))	('adenocarcinomas', 'Disease', (59, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))	('carcinomas', 'Phenotype', 'HP:0030731', (64, 74))	('carcinomas', 'Disease', 'MESH:D002277', (64, 74))	('pleomorphic carcinomas', 'Disease', 'MESH:D008228', (141, 163))	('small-cell carcinoma', 'Phenotype', 'HP:0030357', (189, 209))	('carcinomas', 'Disease', (200, 210))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('carcinomas', 'Disease', (153, 163))	('carcinomas', 'Phenotype', 'HP:0030731', (109, 119))	('carcinomas', 'Disease', 'MESH:D002277', (109, 119))	('noncoding indel mutations', 'Var', (220, 245))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (95, 119))	('small-cell carcinoma', 'Disease', 'MESH:D018288', (189, 209))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (95, 119))
267493	30999697	Interestingly, noncoding indel mutations were detected in poorly differentiated carcinomas such as squamous cell and pleomorphic carcinomas at frequencies similar to those in adenocarcinomas.	('pleomorphic carcinomas', 'Disease', (117, 139))	('carcinomas', 'Disease', (180, 190))	('carcinomas', 'Phenotype', 'HP:0030731', (129, 139))	('carcinomas', 'Disease', 'MESH:D002277', (129, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('carcinomas', 'Phenotype', 'HP:0030731', (80, 90))	('carcinomas', 'Disease', 'MESH:D002277', (80, 90))	('pleomorphic carcinomas', 'Disease', 'MESH:D008228', (117, 139))	('carcinomas', 'Disease', 'MESH:D002277', (180, 190))	('carcinoma', 'Phenotype', 'HP:0030731', (180, 189))	('carcinomas', 'Phenotype', 'HP:0030731', (180, 190))	('noncoding indel mutations', 'Var', (15, 40))	('carcinomas', 'Disease', (129, 139))	('adenocarcinomas', 'Disease', 'MESH:D000230', (175, 190))	('adenocarcinomas', 'Disease', (175, 190))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('carcinomas', 'Disease', (80, 90))	('detected', 'Reg', (46, 54))	('squamous cell', 'Disease', (99, 112))
267502	30999697	Thus, noncoding indels were detected in lesions ranging from early-stage lung cancer, as in case I, to massive and poorly differentiated cancer, as in this case.	('lung cancer', 'Disease', 'MESH:D008175', (73, 84))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('noncoding indels', 'Var', (6, 22))	('detected', 'Reg', (28, 36))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('cancer', 'Disease', (137, 143))	('lung cancer', 'Disease', (73, 84))	('lung cancer', 'Phenotype', 'HP:0100526', (73, 84))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('massive', 'Disease', (103, 110))
267505	30999697	Whole-exome sequencing analysis of each component was performed, and phylogenetic analysis showed that the separate components shared several common mutations and that the sarcomatous component ramified from the carcinomatous component in the early phase of the evolutionary process and accumulated several mutations that were different from those of the carcinomatous component (Figure 5D).	('carcinoma', 'Phenotype', 'HP:0030731', (355, 364))	('rat', 'Species', '10116', (111, 114))	('mutations', 'Var', (307, 316))	('mutations', 'Var', (149, 158))	('sarcomatous component', 'Disease', 'MESH:D018316', (172, 193))	('sarcoma', 'Phenotype', 'HP:0100242', (172, 179))	('sarcomatous component', 'Disease', (172, 193))	('accumulated', 'PosReg', (287, 298))	('carcinoma', 'Phenotype', 'HP:0030731', (212, 221))	('carcinomatous component', 'Disease', 'MESH:D055756', (212, 235))	('carcinomatous component', 'Disease', 'MESH:D055756', (355, 378))	('carcinomatous component', 'Disease', (212, 235))	('carcinomatous component', 'Disease', (355, 378))
267509	30999697	Importantly, detection of noncoding indels in the SFTP gene was helpful in determining whether either of the tumors were primary or metastatic in nature, as shown in Cases IV-XIV.	('tumors', 'Disease', 'MESH:D009369', (109, 115))	('tumors', 'Disease', (109, 115))	('SFTP', 'Gene', (50, 54))	('noncoding indels', 'Var', (26, 42))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))
267510	30999697	In cases IV-X, one of the two tumors harbored noncoding indels, whereas the other did not (Figure 6A-G).	('harbored', 'Reg', (37, 45))	('tumors', 'Disease', (30, 36))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('noncoding indels', 'Var', (46, 62))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))
267511	30999697	In cases XI and XII, SFTPB mutations were identified in both tumors, but they differed in nucleotide position and variance (Figure 6H,I).	('mutations', 'Var', (27, 36))	('tumors', 'Disease', (61, 67))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('SFTPB', 'Gene', (21, 26))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('SFTPB', 'Gene', '6439', (21, 26))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))
267515	30999697	Targeted deep sequencing revealed that the noncoding indel mutation in 2 tumors in each patient involved SFTP (Figure 6J,K).	('patient', 'Species', '9606', (88, 95))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('involved', 'Reg', (96, 104))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('tumors', 'Disease', (73, 79))	('tumors', 'Disease', 'MESH:D009369', (73, 79))	('SFTP', 'Disease', (105, 109))	('noncoding indel mutation', 'Var', (43, 67))
267517	30999697	Noncoding indels in the SFTP gene may indicate the precise cell of origin in lung cancer.	('lung cancer', 'Phenotype', 'HP:0100526', (77, 88))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('Noncoding indels', 'Var', (0, 16))	('lung cancer', 'Disease', 'MESH:D008175', (77, 88))	('lung cancer', 'Disease', (77, 88))	('SFTP', 'Gene', (24, 28))
267520	30999697	Among five mediastinal lymph node cancers, noncoding indels were detected in two cases (Cases XV and XVI, Figure 7).	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('detected', 'Reg', (65, 73))	('lymph node cancers', 'Disease', (23, 41))	('lymph node cancer', 'Phenotype', 'HP:0002665', (23, 40))	('lymph node cancers', 'Disease', 'MESH:D000072717', (23, 41))	('mediastinal lymph node cancer', 'Phenotype', 'HP:0100721', (11, 40))	('cancers', 'Phenotype', 'HP:0002664', (34, 41))	('mediastinal lymph node cancer', 'Disease', (11, 40))	('noncoding indels', 'Var', (43, 59))	('mediastinal lymph node cancer', 'Disease', 'MESH:D008479', (11, 40))
267523	30999697	Targeted sequencing was performed using a surgical specimen and it showed that the cancer harbored noncoding indels in the SFTPA1 and SFTPB genes (Table 2).	('SFTPB', 'Gene', (134, 139))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('men', 'Species', '9606', (56, 59))	('SFTPB', 'Gene', '6439', (134, 139))	('SFTPA1', 'Gene', '653509', (123, 129))	('noncoding indels', 'Var', (99, 115))	('SFTPA1', 'Gene', (123, 129))	('cancer', 'Disease', (83, 89))
267525	30999697	Using the EBUS specimen, targeted sequencing was performed and revealed that the cancer harbored noncoding indels in the SFTPB gene, leading to a diagnosis of mediastinal lung cancer (Table 2).	('mediastinal lung cancer', 'Disease', (159, 182))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('noncoding indels', 'Var', (97, 113))	('mediastinal lung cancer', 'Disease', 'MESH:D008479', (159, 182))	('lung cancer', 'Phenotype', 'HP:0100526', (171, 182))	('cancer', 'Disease', (81, 87))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('SFTPB', 'Gene', (121, 126))	('leading to', 'Reg', (133, 143))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('cancer', 'Disease', (176, 182))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('SFTPB', 'Gene', '6439', (121, 126))	('men', 'Species', '9606', (20, 23))
267526	30999697	In summary, SFTP noncoding indels were detected in two (Cases XV and XVI) of five cases of mediastinal lymph node cancer, and it was validated genomically that these mediastinal cancers originated from the lung (lung cancer).	('mediastinal lymph node cancer', 'Disease', (91, 120))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('lung cancer', 'Disease', (212, 223))	('lung cancer', 'Phenotype', 'HP:0100526', (212, 223))	('SFTP noncoding indels', 'Var', (12, 33))	('mediastinal lymph node cancer', 'Disease', 'MESH:D008479', (91, 120))	('cancers', 'Disease', 'MESH:D009369', (178, 185))	('cancers', 'Phenotype', 'HP:0002664', (178, 185))	('cancers', 'Disease', (178, 185))	('originated', 'Reg', (186, 196))	('detected', 'Reg', (39, 47))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('lymph node cancer', 'Phenotype', 'HP:0002665', (103, 120))	('lung cancer', 'Disease', 'MESH:D008175', (212, 223))	('mediastinal lymph node cancer', 'Phenotype', 'HP:0100721', (91, 120))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))
267531	30999697	In our study, we intensively and efficiently searched for and analyzed the previously reported noncoding indels in our cases of surgically treated lung cancer, using a cancer panel designed in-house.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('lung cancer', 'Disease', (147, 158))	('lung cancer', 'Phenotype', 'HP:0100526', (147, 158))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('noncoding indels', 'Var', (95, 111))	('cancer', 'Disease', (168, 174))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('lung cancer', 'Disease', 'MESH:D008175', (147, 158))
267535	30999697	Imielinski et al demonstrated that noncoding indels in the SFTP gene were detected exclusively in lung adenocarcinoma.	('noncoding indels', 'Var', (35, 51))	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (98, 117))	('detected', 'Reg', (74, 82))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (98, 117))	('lung adenocarcinoma', 'Disease', (98, 117))	('rat', 'Species', '10116', (24, 27))	('SFTP', 'Gene', (59, 63))
267536	30999697	However, our study revealed that not only adenocarcinoma but also other types of poorly differentiated carcinomas such as squamous cell carcinoma and pleomorphic carcinoma in the lung, harbored noncoding indels.	('carcinomas', 'Phenotype', 'HP:0030731', (103, 113))	('carcinomas', 'Disease', (103, 113))	('carcinomas', 'Disease', 'MESH:D002277', (103, 113))	('adenocarcinoma', 'Disease', (42, 56))	('carcinoma', 'Phenotype', 'HP:0030731', (47, 56))	('adenocarcinoma', 'Disease', 'MESH:D000230', (42, 56))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (122, 145))	('pleomorphic carcinoma', 'Disease', 'MESH:D008228', (150, 171))	('noncoding indels', 'Var', (194, 210))	('squamous cell carcinoma', 'Disease', (122, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (122, 145))	('pleomorphic carcinoma', 'Disease', (150, 171))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (162, 171))
267537	30999697	The frequency of noncoding indels in lung cancer had no association with the clinical findings such as stage and histology; indels therefore appear to be a general phenomenon that can occur at random in all lung cancers.	('lung cancers', 'Disease', 'MESH:D008175', (207, 219))	('lung cancer', 'Disease', (37, 48))	('lung cancers', 'Phenotype', 'HP:0100526', (207, 219))	('lung cancer', 'Phenotype', 'HP:0100526', (37, 48))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('lung cancer', 'Disease', 'MESH:D008175', (207, 218))	('men', 'Species', '9606', (169, 172))	('cancers', 'Phenotype', 'HP:0002664', (212, 219))	('lung cancers', 'Disease', (207, 219))	('lung cancer', 'Disease', 'MESH:D008175', (37, 48))	('indels', 'Var', (124, 130))	('lung cancer', 'Phenotype', 'HP:0100526', (207, 218))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))
267541	30999697	The phylogenetic analysis also showed that the sarcomatous component had ramified from the carcinomatous component in the early phase of the evolutionary process and accumulated several mutations that were different from those of the carcinomatous component.	('carcinomatous component', 'Disease', (234, 257))	('mutations', 'Var', (186, 195))	('carcinomatous component', 'Disease', 'MESH:D055756', (91, 114))	('carcinomatous component', 'Disease', (91, 114))	('carcinomatous component', 'Disease', 'MESH:D055756', (234, 257))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (234, 243))	('sarcomatous component', 'Disease', 'MESH:D018316', (47, 68))	('sarcomatous component', 'Disease', (47, 68))	('sarcoma', 'Phenotype', 'HP:0100242', (47, 54))
267542	30999697	In this study, noncoding indels were detected in both the carcinomatous and sarcomatous components in the pleomorphic carcinoma in case III.	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('sarcomatous component', 'Disease', 'MESH:D018316', (76, 97))	('pleomorphic carcinoma', 'Disease', 'MESH:D008228', (106, 127))	('sarcomatous component', 'Disease', (76, 97))	('carcinomatous and sarcomatous', 'Disease', 'MESH:D055756', (58, 87))	('detected', 'Reg', (37, 45))	('noncoding indels', 'Var', (15, 31))	('sarcoma', 'Phenotype', 'HP:0100242', (76, 83))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))	('pleomorphic carcinoma', 'Disease', (106, 127))
267544	30999697	This is also supported by the detection of noncoding indels in the early cancer lesion in case I with AIS.	('cancer lesion', 'Disease', (73, 86))	('noncoding indels', 'Var', (43, 59))	('cancer lesion', 'Disease', 'MESH:D009062', (73, 86))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))
267546	30999697	Thus, we previously conducted lung cancer mutation analysis by targeted deep sequencing and found that mutations in individual lung cancers can serve as clonal markers, allowing identification of the clonality of individual tumors.	('lung cancers', 'Disease', (127, 139))	('lung cancer', 'Phenotype', 'HP:0100526', (30, 41))	('mutations', 'Var', (103, 112))	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('lung cancer', 'Disease', (30, 41))	('lung cancer', 'Phenotype', 'HP:0100526', (127, 138))	('lung cancers', 'Disease', 'MESH:D008175', (127, 139))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('tumors', 'Disease', (224, 230))	('tumors', 'Disease', 'MESH:D009369', (224, 230))	('tumors', 'Phenotype', 'HP:0002664', (224, 230))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('lung cancer', 'Disease', 'MESH:D008175', (30, 41))	('mutation', 'Var', (42, 50))	('lung cancers', 'Phenotype', 'HP:0100526', (127, 139))	('lung cancer', 'Disease', 'MESH:D008175', (127, 138))	('cancers', 'Phenotype', 'HP:0002664', (132, 139))
267547	30999697	In this study, on the assumption that mutations in the noncoding region would also serve as clonal markers, we compared different tumors regarding the mutation pattern and found that noncoding indels in the SFTP gene can serve as clonal markers.	('tumors', 'Disease', (130, 136))	('tumors', 'Disease', 'MESH:D009369', (130, 136))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('SFTP', 'Gene', (207, 211))	('noncoding indels', 'Var', (183, 199))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('mutations', 'Var', (38, 47))
267552	30999697	In contrast, a pivotal driver mutation serves as the trigger of clonal expansion and is estimated to be retained homogenously within tumors of the same clone.	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('tumors', 'Disease', 'MESH:D009369', (133, 139))	('tumors', 'Disease', (133, 139))	('mutation', 'Var', (30, 38))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))
267571	30999697	Thus, it is assumed that noncoding indel may be a more accurate marker than TTF-1 immunostaining.	('rat', 'Species', '10116', (59, 62))	('noncoding indel', 'Var', (25, 40))	('TTF-1', 'Gene', '7080', (76, 81))	('TTF-1', 'Gene', (76, 81))
267573	30999697	One limitation in terms of clinical application is that there is still a significant number of CUP of unknown origin owing to the low detection rate of SFTP noncoding indels in lung cancer.	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('lung cancer', 'Disease', 'MESH:D008175', (177, 188))	('lung cancer', 'Disease', (177, 188))	('lung cancer', 'Phenotype', 'HP:0100526', (177, 188))	('rat', 'Species', '10116', (144, 147))	('SFTP noncoding indels', 'Var', (152, 173))
267574	30999697	One possibility is that these mutations are not causally tied to the associated genetic lesions, but rather tag a particular evolutionary trajectory in tumorigenesis that is reflected in the transcriptional signature.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('tag', 'Reg', (108, 111))	('rat', 'Species', '10116', (101, 104))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('tumor', 'Disease', (152, 157))	('mutations', 'Var', (30, 39))
267589	30999697	A previous report showed that indel mutations are frequently identified in surfactant protein genes (SFTPA1, SFTPB, and SFTPC) in lung adenocarcinoma, the albumin gene in liver cancer, gastric lipase gene in stomach carcinoma, and thyroglobulin gene in thyroid carcinoma.	('stomach carcinoma', 'Disease', 'MESH:D013274', (208, 225))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (253, 270))	('SFTPC', 'Gene', (120, 125))	('lung adenocarcinoma', 'Disease', (130, 149))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('liver cancer', 'Phenotype', 'HP:0002896', (171, 183))	('thyroglobulin', 'Gene', (231, 244))	('SFTPB', 'Gene', (109, 114))	('stomach carcinoma', 'Phenotype', 'HP:0012126', (208, 225))	('SFTPA1', 'Gene', '653509', (101, 107))	('liver cancer', 'Disease', (171, 183))	('indel mutations', 'Var', (30, 45))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (130, 149))	('SFTPC', 'Gene', '6440', (120, 125))	('carcinoma', 'Phenotype', 'HP:0030731', (261, 270))	('stomach carcinoma', 'Disease', (208, 225))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (130, 149))	('SFTPA1', 'Gene', (101, 107))	('SFTPB', 'Gene', '6439', (109, 114))	('identified', 'Reg', (61, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))	('gastric lipase', 'Gene', (185, 199))	('thyroglobulin', 'Gene', '7038', (231, 244))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (253, 270))	('gastric lipase', 'Gene', '8513', (185, 199))	('carcinoma', 'Phenotype', 'HP:0030731', (216, 225))	('thyroid carcinoma', 'Disease', (253, 270))	('liver cancer', 'Disease', 'MESH:D006528', (171, 183))
267593	30999697	Following data analysis, annotation of single nucleotide variants, insertions and deletions was performed using an Ion Reporter Server System (Thermo Fisher Scientific), and lymphocyte DNA from peripheral blood was used as a control to detect variants (tumor-normal pair analysis), as described previously.	('deletions', 'Var', (82, 91))	('tumor', 'Disease', 'MESH:D009369', (253, 258))	('tumor', 'Phenotype', 'HP:0002664', (253, 258))	('tumor', 'Disease', (253, 258))	('variants', 'Var', (243, 251))
267601	30999697	We identified indels in the noncoding region of surfactant-encoding genes in approximately 25% of lung adenocarcinoma, squamous cell carcinoma, pleomorphic carcinoma, and small-cell carcinoma cases.	('indels', 'Var', (14, 20))	('pleomorphic carcinoma', 'Disease', (144, 165))	('small-cell carcinoma', 'Disease', (171, 191))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (119, 142))	('carcinoma', 'Phenotype', 'HP:0030731', (156, 165))	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('carcinoma', 'Phenotype', 'HP:0030731', (182, 191))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (98, 117))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('small-cell carcinoma', 'Disease', 'MESH:D018288', (171, 191))	('surfactant-encoding genes', 'Gene', (48, 73))	('lung adenocarcinoma', 'Disease', (98, 117))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (119, 142))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (98, 117))	('small-cell carcinoma', 'Phenotype', 'HP:0030357', (171, 191))	('squamous cell carcinoma', 'Disease', (119, 142))	('pleomorphic carcinoma', 'Disease', 'MESH:D008228', (144, 165))
267604	30999697	Furthermore, in patients with cancers of unknown primary sites, the lung can be identified as the primary site based on the presence of these indels.	('presence', 'Var', (124, 132))	('cancers', 'Phenotype', 'HP:0002664', (30, 37))	('cancers', 'Disease', (30, 37))	('patients', 'Species', '9606', (16, 24))	('cancers', 'Disease', 'MESH:D009369', (30, 37))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('indels', 'Var', (142, 148))
267606	30999697	The following are available online at , Figure S1: Validation of noncoding indels by Sanger sequencing, Figure S2: Lung cancer mutation profiles in association with the functional pathways.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('association', 'Reg', (148, 159))	('mutation', 'Var', (127, 135))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('Lung cancer', 'Phenotype', 'HP:0100526', (115, 126))
267611	29088807	Three miRNome profiling datasets (GSE19945, GSE25508 and GSE51853) containing lung squamous cell carcinoma (SCC), lung adenocarcinoma (ADC) and large cell lung cancer (LCLC) samples were obtained for bioinformatics and survival analysis.	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('LCLC', 'Phenotype', 'HP:0030360', (168, 172))	('SCC', 'Gene', (108, 111))	('GSE', 'Chemical', '-', (34, 37))	('lung adenocarcinoma', 'Disease', (114, 133))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (78, 106))	('GSE', 'Chemical', '-', (57, 60))	('cell lung cancer', 'Disease', 'MESH:D008175', (150, 166))	('GSE25508', 'Var', (44, 52))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (114, 133))	('SCC', 'Phenotype', 'HP:0002860', (108, 111))	('GSE19945', 'Var', (34, 42))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (114, 133))	('cell lung cancer', 'Disease', (150, 166))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (78, 106))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (83, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('lung squamous cell carcinoma', 'Disease', (78, 106))	('large cell lung cancer', 'Phenotype', 'HP:0030360', (144, 166))	('SCC', 'Gene', '6317', (108, 111))	('lung cancer', 'Phenotype', 'HP:0100526', (155, 166))	('GSE', 'Chemical', '-', (44, 47))	('GSE51853', 'Var', (57, 65))
267628	29088807	Firstly, we compared the miRNA expression profiles in three miRNA datasets (GSE19945, GSE25508 and GSE51852).	('GSE19945', 'Var', (76, 84))	('GSE', 'Chemical', '-', (86, 89))	('GSE', 'Chemical', '-', (76, 79))	('GSE', 'Chemical', '-', (99, 102))	('GSE25508', 'Var', (86, 94))	('GSE51852', 'Var', (99, 107))
267649	29088807	"Pathway in cancer (KEGG_05200)", "Focal adhesion (KEGG_04510)" and "Adherens junction (KEGG_04520)" were commonly top pathways by function prediction of three miRNAs.	('KEGG_04520', 'Var', (88, 98))	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('Focal adhesion', 'CPA', (35, 49))	('cancer', 'Disease', (12, 18))	('Adherens', 'CPA', (69, 77))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('KEGG_05200', 'Var', (20, 30))	('KEGG_04510', 'Var', (51, 61))
267663	29088807	Here, we employed three miRNA expression profiles (GSE19945, GSE25508 and GSE51853) to search for the key miRNAs as candidate clinical biomarkers in different histological subtypes of NSCLC.	('GSE51853', 'Var', (74, 82))	('NSCLC', 'Phenotype', 'HP:0030358', (184, 189))	('GSE', 'Chemical', '-', (51, 54))	('GSE25508', 'Var', (61, 69))	('NSCLC', 'Disease', (184, 189))	('GSE', 'Chemical', '-', (74, 77))	('GSE', 'Chemical', '-', (61, 64))	('NSCLC', 'Disease', 'MESH:D002289', (184, 189))	('GSE19945', 'Var', (51, 59))
267673	29088807	From ADC vs. normal, there were two miRNAs significantly up-regulated (miR-210 and miR-130b) and none down-regulated.	('miR-130b', 'Gene', (83, 91))	('miR-210', 'Gene', (71, 78))	('ADC', 'Var', (5, 8))	('miR-210', 'Gene', '406992', (71, 78))	('up-regulated', 'PosReg', (57, 69))	('miR-130b', 'Gene', '406920', (83, 91))
267686	29088807	TP63 (tumor protein p63), a member of p53 family, was considered as one of "squamous markers", and its copy number variation was reported to be associated with SCC.	('tumor protein p63', 'Gene', (6, 23))	('p53', 'Gene', (38, 41))	('tumor protein p63', 'Gene', '8626', (6, 23))	('associated', 'Reg', (144, 154))	('p53', 'Gene', '7157', (38, 41))	('copy number variation', 'Var', (103, 124))	('SCC', 'Gene', (160, 163))	('TP63', 'Gene', '8626', (0, 4))	('TP63', 'Gene', (0, 4))	('SCC', 'Phenotype', 'HP:0002860', (160, 163))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('SCC', 'Gene', '6317', (160, 163))
267696	29088807	Finally, three datasets (GSE19945, GSE25508 and GSE51853) were selected for further analysis.	('GSE', 'Chemical', '-', (35, 38))	('GSE', 'Chemical', '-', (48, 51))	('GSE51853', 'Var', (48, 56))	('GSE19945', 'Var', (25, 33))	('GSE25508', 'Var', (35, 43))	('GSE', 'Chemical', '-', (25, 28))
267699	29088807	Meanwhile, GSE51853, based on GPL6480 platform (Agilent-014850 Whole Human Genome Microarray 4x44K G4112F), consisted of 76 ADC, 29 SCC, 17 LCLC and 5 normal lung tissue samples.	('G4112F', 'Mutation', 'p.G4112F', (99, 105))	('Human', 'Species', '9606', (69, 74))	('SCC', 'Gene', (132, 135))	('GSE51853', 'Var', (11, 19))	('SCC', 'Phenotype', 'HP:0002860', (132, 135))	('SCC', 'Gene', '6317', (132, 135))	('GSE', 'Chemical', '-', (11, 14))	('LCLC', 'Phenotype', 'HP:0030360', (140, 144))
267719	32195008	PD-L1 positivity, high tumor mutational burden and infiltration of NK cells, CD8, CD26 and Tim3 positive lymphocytes at time of surgery have been correlated with pathologic responses.	('CD8', 'Gene', (77, 80))	('CD8', 'Gene', '925', (77, 80))	('correlated', 'Reg', (146, 156))	('Tim3', 'Gene', (91, 95))	('CD26', 'Gene', '1803', (82, 86))	('positivity', 'Var', (6, 16))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('CD26', 'Gene', (82, 86))	('PD-L1', 'Gene', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('tumor', 'Disease', (23, 28))	('PD-L1', 'Gene', '29126', (0, 5))	('Tim3', 'Gene', '84868', (91, 95))
267748	32195008	A study of patients with stage T2-T4, N0-N2 previously untreated SCC of the oral cavity (OSCC) failed to show a significant difference in locoregional relapse or survival with the addition of neoadjuvant PF.	('locoregional relapse', 'CPA', (138, 158))	('PF', 'Chemical', 'MESH:C002997', (204, 206))	('N0-N2', 'Var', (38, 43))	('OS', 'Chemical', '-', (89, 91))	('patients', 'Species', '9606', (11, 19))
267767	32195008	Patients with a resectable T2-T4,N0-N3,M0 SCC of the oral cavity and oropharynx were assigned randomly to receive surgery and radiotherapy or to receive IL-2, surgery, and radiotherapy.	('IL-2', 'Gene', '3558', (153, 157))	('Patients', 'Species', '9606', (0, 8))	('N0-N3', 'Var', (33, 38))	('IL-2', 'Gene', (153, 157))
267797	32195008	Pathological response was associated with robust immune cell infiltration, particularly CD8 positive T cells at time of surgery and PD-L1 and PD-L2 positivity at both pre-treatment biopsy and time of surgery.	('CD8', 'Gene', '925', (88, 91))	('PD-L1', 'Gene', (132, 137))	('PD-L1', 'Gene', '29126', (132, 137))	('immune cell infiltration', 'CPA', (49, 73))	('positivity', 'Var', (148, 158))	('PD-L2', 'Gene', (142, 147))	('PD-L2', 'Gene', '80380', (142, 147))	('CD8', 'Gene', (88, 91))
267854	32195008	Results from the phase 1b portion of immunomodulation by the combination of ipilimumab and nivolumab neoadjuvant to (salvage) surgery in advanced or recurrent head and neck carcinoma, IMCISION (NCT03003637) were also presented at ASCO 2019.	('ipilimumab', 'Chemical', 'MESH:D000074324', (76, 86))	('carcinoma', 'Phenotype', 'HP:0030731', (173, 182))	('nivolumab neoadjuvant', 'Chemical', '-', (91, 112))	('neck carcinoma', 'Disease', (168, 182))	('neck carcinoma', 'Disease', 'MESH:D006258', (168, 182))	('head and neck carcinoma', 'Phenotype', 'HP:0012288', (159, 182))	('NCT03003637', 'Var', (194, 205))
267905	24525231	Recent therapies targeting pathways active in NSCLC sub-types have resulted in encouraging new treatments for LAC driven by EGFR or EML4-ALK mutations.	('mutations', 'Var', (141, 150))	('EGFR', 'Gene', '1956', (124, 128))	('NSCLC', 'Disease', (46, 51))	('ALK', 'Gene', (137, 140))	('EGFR', 'Gene', (124, 128))	('EML4', 'Gene', (132, 136))	('NSCLC', 'Disease', 'MESH:D002289', (46, 51))	('LAC', 'Disease', (110, 113))	('ALK', 'Gene', '238', (137, 140))	('EML4', 'Gene', '27436', (132, 136))	('NSCLC', 'Phenotype', 'HP:0030358', (46, 51))
267909	24525231	These highly tumorigenic cells exhibit self-renewal by activating developmental pathways including Wnt, Hedgehog and Notch, and by aberrant expression of stem-related genes such as BMI1, OCT3/4 , SOX2, and NANOG which participate in their maintenance.	('developmental', 'CPA', (66, 79))	('tumor', 'Disease', (13, 18))	('self-renewal', 'CPA', (39, 51))	('BMI1', 'Gene', '648', (181, 185))	('expression', 'MPA', (140, 150))	('Notch', 'Gene', (117, 122))	('OCT3/4', 'Gene', '5460', (187, 193))	('BMI1', 'Gene', (181, 185))	('activating', 'PosReg', (55, 65))	('Hedgehog', 'Gene', (104, 112))	('NANOG', 'Gene', '79923', (206, 211))	('NANOG', 'Gene', (206, 211))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('aberrant', 'Var', (131, 139))	('OCT3/4', 'Gene', (187, 193))	('Wnt', 'Pathway', (99, 102))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
267912	24525231	PRKCI is overexpressed in LSCC cells and primary tumors due to tumor specific amplification of a chromosome 3q26 amplicon.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Disease', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('amplification', 'Var', (78, 91))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('LSCC', 'Phenotype', 'HP:0030359', (26, 30))	('tumor', 'Disease', (49, 54))	('PRKCI', 'Gene', (0, 5))	('tumors', 'Disease', (49, 55))	('overexpressed', 'PosReg', (9, 22))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumors', 'Disease', 'MESH:D009369', (49, 55))	('PRKCI', 'Gene', '5584', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
267915	24525231	Here, we demonstrate that PRKCI maintains a highly tumorigenic phenotype in lung cancer cells harboring PRKCI amplification, and in LSCC tumors.	('tumors', 'Disease', (137, 143))	('amplification', 'Var', (110, 123))	('PRKCI', 'Gene', '5584', (26, 31))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('PRKCI', 'Gene', '5584', (104, 109))	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('tumor', 'Disease', (51, 56))	('lung cancer', 'Disease', (76, 87))	('LSCC', 'Phenotype', 'HP:0030359', (132, 136))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('tumor', 'Disease', (137, 142))	('PRKCI', 'Gene', (26, 31))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('PRKCI', 'Gene', (104, 109))	('lung cancer', 'Disease', 'MESH:D008175', (76, 87))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('lung cancer', 'Phenotype', 'HP:0100526', (76, 87))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
267919	24525231	We isolated stem-like cells from five human lung cancer cell lines harboring 3q26 copy number gains (H1299, H1703, ChagoK1, H520 and H1869) using established protocols.	('3q26', 'Gene', (77, 81))	('H1703', 'Var', (108, 113))	('lung cancer', 'Phenotype', 'HP:0100526', (44, 55))	('human', 'Species', '9606', (38, 43))	('H1869', 'Var', (133, 138))	('H1299', 'CellLine', 'CVCL:0060', (101, 106))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('lung cancer', 'Disease', 'MESH:D008175', (44, 55))	('H1703', 'CellLine', 'CVCL:1490', (108, 113))	('H1299', 'Var', (101, 106))	('H520', 'Var', (124, 128))	('lung cancer', 'Disease', (44, 55))
267927	24525231	A similar increase in tumor take was observed in H520 oncospheres when compared to parental H520 cells (Fig.	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('tumor', 'Disease', (22, 27))	('increase', 'PosReg', (10, 18))	('H520', 'Var', (49, 53))
267931	24525231	Finally, H1299 oncosphere cells efficiently generate tumors of similar morphology through three serial passages in mice (data not shown).	('mice', 'Species', '10090', (115, 119))	('H1299', 'CellLine', 'CVCL:0060', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('H1299', 'Var', (9, 14))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('tumors', 'Disease', (53, 59))
267962	24525231	As expected, H1299 NT RNAi oncospheres exhibited an increased tumor take rate (10/10 vs. 2/10 mice for NT parental cells) and developed significantly larger tumors than NT RNAi parental cells (Fig.	('tumor', 'Disease', (157, 162))	('increased', 'PosReg', (52, 61))	('tumors', 'Phenotype', 'HP:0002664', (157, 163))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('H1299 NT', 'Var', (13, 21))	('tumor', 'Disease', (62, 67))	('tumors', 'Disease', (157, 163))	('tumors', 'Disease', 'MESH:D009369', (157, 163))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('larger', 'PosReg', (150, 156))	('mice', 'Species', '10090', (94, 98))	('H1299', 'CellLine', 'CVCL:0060', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
267981	24525231	Analysis also revealed a strong positive correlation between PKCiota and SOX2 expression with HHAT and GLI1, two key Hh pathway components regulated by PKCiota in oncospheres harboring PRKCI copy number gains (Fig.	('SOX2', 'Gene', (73, 77))	('GLI1', 'Gene', (103, 107))	('PKC', 'Gene', (61, 64))	('PKC', 'Gene', '5584;18759', (152, 155))	('PRKCI', 'Gene', '5584', (185, 190))	('copy number gains', 'Var', (191, 208))	('PKC', 'Gene', (152, 155))	('PRKCI', 'Gene', (185, 190))	('HHAT', 'Gene', (94, 98))	('PKC', 'Gene', '5584;18759', (61, 64))
267983	24525231	We next assessed whether co-ordinate PRKCI and SOX2 amplification may drive a "stem-like" genotype in primary LSCC tumors.	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('PRKCI', 'Gene', (37, 42))	('PRKCI', 'Gene', '5584', (37, 42))	('tumors', 'Disease', (115, 121))	('drive', 'PosReg', (70, 75))	('tumors', 'Disease', 'MESH:D009369', (115, 121))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('LSCC', 'Phenotype', 'HP:0030359', (110, 114))	('SOX2', 'Gene', (47, 51))	('amplification', 'Var', (52, 65))
267998	24525231	To assess the importance of T118 phosphorylation we first introduced a silent mutation into a FLAG-tagged SOX2 cDNA to render it resistant to SOX2 RNAi #2 and then mutagenized T118 to either alanine (T118A) or aspartic acid (T118D) to eliminate or mimic T118 phosphorylation.	('T118D', 'Var', (225, 230))	('T118 phosphorylation', 'MPA', (254, 274))	('T118', 'Chemical', '-', (176, 180))	('mutation', 'Var', (78, 86))	('T118', 'Chemical', '-', (200, 204))	('mutagenized', 'Var', (164, 175))	('T118', 'Chemical', '-', (225, 229))	('T118A', 'Mutation', 'rs1352479562', (200, 205))	('resistant', 'MPA', (129, 138))	('alanine', 'Chemical', 'MESH:D000409', (191, 198))	('T118D', 'Mutation', 'p.T118D', (225, 230))	('aspartic acid', 'Chemical', 'MESH:D001224', (210, 223))	('T118', 'Chemical', '-', (254, 258))	('T118', 'Gene', (176, 180))	('T118', 'Chemical', '-', (28, 32))
267999	24525231	Immunoblot analysis of H1299 oncospheres stably transfected with WT-SOX2, T118A-SOX2, T118D-SOX2 or empty control vector, followed by SOX2 RNAi revealed efficient loss of endogenous SOX2 and expression of similar levels of WT and T118 SOX2 mutants (Fig.	('T118', 'Chemical', '-', (230, 234))	('T118', 'Chemical', '-', (86, 90))	('-SOX2', 'Gene', '6657', (67, 72))	('loss', 'NegReg', (163, 167))	('T118', 'Var', (230, 234))	('-SOX2', 'Gene', '6657', (91, 96))	('T118', 'Chemical', '-', (74, 78))	('-SOX2', 'Gene', '6657', (79, 84))	('H1299', 'CellLine', 'CVCL:0060', (23, 28))	('-SOX2', 'Gene', (91, 96))	('T118D', 'SUBSTITUTION', 'None', (86, 91))	('T118A', 'SUBSTITUTION', 'None', (74, 79))	('-SOX2', 'Gene', (67, 72))	('T118A', 'Var', (74, 79))	('endogenous SOX2', 'MPA', (171, 186))	('expression', 'MPA', (191, 201))	('T118D', 'Var', (86, 91))	('-SOX2', 'Gene', (79, 84))
268000	24525231	In contrast, expression of exogenous WT- or T118D-SOX2 significantly restored HHAT and GLI1 expression in SOX2 RNAi cells, whereas T118A-SOX2 did not (Fig.	('T118D', 'SUBSTITUTION', 'None', (44, 49))	('GLI1', 'Gene', (87, 91))	('HHAT', 'Protein', (78, 82))	('T118D', 'Var', (44, 49))	('restored', 'PosReg', (69, 77))	('T118A', 'SUBSTITUTION', 'None', (131, 136))	('T118A', 'Var', (131, 136))
268002	24525231	Expression of WT- or T118D-SOX2 significantly reconstituted clonal expansion and soft agar growth in SOX2 RNAi oncospheres whereas T118A SOX2 did not (Fig.	('clonal expansion', 'CPA', (60, 76))	('T118A', 'Mutation', 'rs1352479562', (131, 136))	('soft agar growth', 'CPA', (81, 97))	('T118D', 'SUBSTITUTION', 'None', (21, 26))	('agar', 'Chemical', 'MESH:D000362', (86, 90))	('reconstituted', 'Reg', (46, 59))	('T118D', 'Var', (21, 26))
268003	24525231	SOX2 ChIP assays revealed reduced SOX2 occupancy of the HHAT promoter in SOX2 RNAi oncospheres expressing empty control vector that is significantly restored by expression of either WT or T118D SOX2, but not T118A SOX2 (Fig.	('T118D', 'Mutation', 'p.T118D', (188, 193))	('SOX2', 'Gene', (73, 77))	('T118A', 'Mutation', 'rs1352479562', (208, 213))	('T118D', 'Var', (188, 193))	('reduced', 'NegReg', (26, 33))	('SOX2 occupancy', 'MPA', (34, 48))	('HHAT', 'Gene', (56, 60))
268004	24525231	T118 resides between the HMG domain and a consensus nuclear localization sequence (NLS) in SOX2, suggesting that T118 phosphorylation could affect SOX2 DNA binding and/or nuclear localization.	('T118', 'Var', (113, 117))	('T118', 'Chemical', '-', (113, 117))	('affect', 'Reg', (140, 146))	('DNA binding', 'Interaction', (152, 163))	('SOX2', 'Protein', (147, 151))	('T118', 'Chemical', '-', (0, 4))	('nuclear localization', 'MPA', (171, 191))
268005	24525231	Immunoblot analysis revealed that WT, T118A and T118D SOX2 are predominantly nuclear (Fig.	('T118D', 'Mutation', 'p.T118D', (48, 53))	('T118A', 'Var', (38, 43))	('SOX2', 'Gene', (54, 58))	('T118D', 'Var', (48, 53))	('T118A', 'Mutation', 'rs1352479562', (38, 43))
268006	24525231	Next, SOX2 RNAi oncospheres expressing either wild-type, T118A or T118D SOX2, or control empty pCMV vector were transfected with a HHAT promoter luciferase reporter (pGL4-HHAT-luc) and assessed for HHAT promoter activity (Fig.	('SOX2', 'Gene', (72, 76))	('T118D', 'Mutation', 'p.T118D', (66, 71))	('T118A', 'Mutation', 'rs1352479562', (57, 62))	('pGL4', 'Gene', (166, 170))	('T118D', 'Var', (66, 71))	('pGL4', 'Gene', '6390', (166, 170))	('T118A', 'Var', (57, 62))
268007	24525231	In all four cell lines tested, wild-type and T118D SOX2 stimulated HHAT promoter activity whereas T118A did not.	('HHAT', 'Protein', (67, 71))	('T118D', 'Mutation', 'p.T118D', (45, 50))	('T118A', 'Mutation', 'rs1352479562', (98, 103))	('T118D', 'Var', (45, 50))	('stimulated', 'PosReg', (56, 66))	('SOX2', 'Gene', (51, 55))
268015	24525231	Here we show that PKCiota plays a vital and previously unrecognized role in maintenance of stem-like cells isolated from human lung cancer cells harboring PRKCI copy number gains, and primary LSCC tumors.	('PRKCI', 'Gene', (155, 160))	('copy number gains', 'Var', (161, 178))	('tumors', 'Disease', 'MESH:D009369', (197, 203))	('lung cancer', 'Disease', (127, 138))	('PKC', 'Gene', '5584;18759', (18, 21))	('lung cancer', 'Phenotype', 'HP:0100526', (127, 138))	('PKC', 'Gene', (18, 21))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('tumors', 'Phenotype', 'HP:0002664', (197, 203))	('LSCC', 'Phenotype', 'HP:0030359', (192, 196))	('human', 'Species', '9606', (121, 126))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('lung cancer', 'Disease', 'MESH:D008175', (127, 138))	('tumors', 'Disease', (197, 203))	('PRKCI', 'Gene', '5584', (155, 160))
268017	24525231	Aberrant Hh signaling has been implicated in the initiation and progression of various cancer subtypes including lung.	('cancer', 'Disease', (87, 93))	('implicated', 'Reg', (31, 41))	('Aberrant', 'Var', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('lung', 'Disease', (113, 117))	('cancer', 'Disease', 'MESH:D009369', (87, 93))
268018	24525231	In basal cell carcinomas and medulloblastomas, Hh signaling is activated by tumor-specific mutations in the Hh pathway components Patched, Smoothened or Suppressor of Fused.	('medulloblastomas', 'Disease', (29, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (14, 23))	('carcinomas', 'Phenotype', 'HP:0030731', (14, 24))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('basal cell carcinomas', 'Phenotype', 'HP:0002671', (3, 24))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (3, 23))	('Hh signaling', 'MPA', (47, 59))	('mutations', 'Var', (91, 100))	('Hh pathway', 'Gene', (108, 118))	('activated', 'PosReg', (63, 72))	('medulloblastomas', 'Disease', 'MESH:D008527', (29, 45))	('basal cell carcinomas', 'Disease', (3, 24))	('basal cell carcinomas', 'Disease', 'MESH:D002280', (3, 24))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
268022	24525231	We find that PKCiota regulates autocrine Hh signaling in oncospheres harboring PRKCI copy number gains, and define a signaling cascade in which PKCiota regulates HHAT, which catalyzes the rate-limiting step in Hh ligand processing.	('PKC', 'Gene', '5584;18759', (144, 147))	('PKC', 'Gene', (144, 147))	('copy number gains', 'Var', (85, 102))	('autocrine Hh signaling', 'MPA', (31, 53))	('PKC', 'Gene', (13, 16))	('HHAT', 'MPA', (162, 166))	('regulates', 'Reg', (21, 30))	('PRKCI', 'Gene', '5584', (79, 84))	('gains', 'Var', (97, 102))	('regulates', 'Reg', (152, 161))	('PRKCI', 'Gene', (79, 84))	('PKC', 'Gene', '5584;18759', (13, 16))
268026	24525231	Sox2 overexpression in mouse lung leads to increased lung epithelial cell proliferation and hyperplasia, whereas Sox2 deletion in mouse bronchiolar Clara cells, a potential lung regional stem cell, results in reduced cell proliferation and loss of airway differentiation markers.	('loss', 'NegReg', (240, 244))	('cell proliferation', 'CPA', (217, 235))	('lung epithelial cell proliferation', 'CPA', (53, 87))	('airway differentiation markers', 'CPA', (248, 278))	('mouse', 'Species', '10090', (23, 28))	('hyperplasia', 'Disease', (92, 103))	('hyperplasia', 'Disease', 'MESH:D006965', (92, 103))	('reduced', 'NegReg', (209, 216))	('increased', 'PosReg', (43, 52))	('Sox2', 'Gene', (113, 117))	('deletion', 'Var', (118, 126))	('mouse', 'Species', '10090', (130, 135))
268027	24525231	SOX2 is required for LSCC cell growth in vitro, and SOX2 overexpression in lung epithelial cells induces migration, transformed growth and tumor formation in vivo.	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('SOX2', 'Gene', (52, 56))	('LSCC', 'Phenotype', 'HP:0030359', (21, 25))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('transformed growth', 'CPA', (116, 134))	('tumor', 'Disease', (139, 144))	('induces', 'PosReg', (97, 104))	('migration', 'CPA', (105, 114))	('overexpression', 'Var', (57, 71))
268031	24525231	Phosphorylation can regulate Sox2 function in mouse embryonic stem cells and phosphoproteome analysis has identified Ser249, Ser250, and Ser251 as potential SOX2 phosphorylation sites.	('Ser251', 'Var', (137, 143))	('function', 'MPA', (34, 42))	('mouse', 'Species', '10090', (46, 51))	('Sox2', 'Enzyme', (29, 33))	('Ser249', 'Chemical', '-', (117, 123))	('regulate', 'Reg', (20, 28))	('Ser250', 'Chemical', '-', (125, 131))	('Ser250', 'Var', (125, 131))	('Ser251', 'Chemical', '-', (137, 143))	('Ser249', 'Var', (117, 123))
268034	24525231	T118 phosphorylation regulates SOX2 binding to, and activity of the HHAT promoter.	('HHAT', 'Gene', (68, 72))	('activity', 'MPA', (52, 60))	('T118', 'Var', (0, 4))	('regulates', 'Reg', (21, 30))	('T118', 'Chemical', '-', (0, 4))	('SOX2', 'Protein', (31, 35))	('binding to', 'Interaction', (36, 46))
268035	24525231	Our MS analysis, which interrogated all known SOX2 phosphorylation sites, detected pT118 but no other sites in LSCC oncospheres (data not shown).	('pT118', 'Var', (83, 88))	('pT118', 'Chemical', '-', (83, 88))	('LSCC', 'Phenotype', 'HP:0030359', (111, 115))	('detected', 'Reg', (74, 82))
268037	24525231	Regardless, our functional data demonstrate the importance of T118 phosphorylation in SOX2 function and stem-like behavior.	('stem-like behavior', 'CPA', (104, 122))	('SOX2', 'Gene', (86, 90))	('T118 phosphorylation', 'Var', (62, 82))	('T118', 'Chemical', '-', (62, 66))
268038	24525231	Chromosome 3q26 amplification is one of the most frequent chromosomal alterations in human cancer and is found in a majority of LSCC, serous ovarian, cervical, head and neck , oral and esophageal tumors.	('oral', 'Disease', (176, 180))	('cervical', 'Disease', (150, 158))	('tumors', 'Phenotype', 'HP:0002664', (196, 202))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('found', 'Reg', (105, 110))	('esophageal tumors', 'Disease', 'MESH:D004938', (185, 202))	('Chromosome', 'Var', (0, 10))	('esophageal tumors', 'Disease', (185, 202))	('LSCC', 'Disease', (128, 132))	('human', 'Species', '9606', (85, 90))	('esophageal tumors', 'Phenotype', 'HP:0100751', (185, 202))	('serous ovarian', 'Disease', 'MESH:D010051', (134, 148))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('LSCC', 'Phenotype', 'HP:0030359', (128, 132))	('serous ovarian', 'Disease', (134, 148))
268043	24525231	Interestingly, whereas each of the cell lines analyzed here harbor PRKCI gene copy number gain and exhibit PKCiota-dependent Hh signaling, not all of these cell lines are classified as LSCC.	('PKC', 'Gene', '5584;18759', (107, 110))	('PRKCI', 'Gene', '5584', (67, 72))	('PKC', 'Gene', (107, 110))	('PRKCI', 'Gene', (67, 72))	('gain', 'PosReg', (90, 94))	('gene copy number', 'Var', (73, 89))	('LSCC', 'Phenotype', 'HP:0030359', (185, 189))
268044	24525231	Three cell lines are classified histologically as LSCC (H1703, H520 and H1869), whereas ChagoK1 and H1299 cells are classified as bronchiogenic carcinoma and LCLC, respectively, suggesting that PKCiota-SOX2-HHAT signaling may be operative in lung tumor types other than LSCC that harbor PRKCI gene copy number gain.	('tumor', 'Phenotype', 'HP:0002664', (247, 252))	('bronchiogenic carcinoma', 'Disease', (130, 153))	('LCLC', 'Phenotype', 'HP:0030360', (158, 162))	('LSCC', 'Phenotype', 'HP:0030359', (270, 274))	('LSCC', 'Phenotype', 'HP:0030359', (50, 54))	('lung tumor', 'Disease', 'MESH:D008175', (242, 252))	('gene copy number gain', 'Var', (293, 314))	('PRKCI', 'Gene', '5584', (287, 292))	('PKCiota-SOX2-HHAT', 'Disease', (194, 211))	('PRKCI', 'Gene', (287, 292))	('lung tumor', 'Disease', (242, 252))	('bronchiogenic carcinoma', 'Disease', 'MESH:D002277', (130, 153))	('Thr', 'Chemical', 'MESH:D013912', (0, 3))	('H1703', 'CellLine', 'CVCL:1490', (56, 61))	('PKCiota-SOX2-HHAT', 'Disease', 'MESH:C565948', (194, 211))	('lung tumor', 'Phenotype', 'HP:0100526', (242, 252))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('H1299', 'CellLine', 'CVCL:0060', (100, 105))
268045	24525231	Given the prevalence of chromosome 3q26 amplification in human tumors, further studies are warranted to determine whether the PKCiota-SOX2-Hh signaling axis elucidated here maintains a stem-like phenotype in other major tumor types harboring these genetic alteration.	('tumor', 'Disease', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('PKC', 'Gene', (126, 129))	('-SOX2', 'Gene', '6657', (133, 138))	('human', 'Species', '9606', (57, 62))	('tumor', 'Disease', (220, 225))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('tumors', 'Disease', (63, 69))	('amplification', 'Var', (40, 53))	('-SOX2', 'Gene', (133, 138))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('tumor', 'Disease', 'MESH:D009369', (220, 225))	('PKC', 'Gene', '5584;18759', (126, 129))
268046	24525231	SMO inhibitors are in clinical development, but their utility is limited in tumors that acquire Hh mutations that confer resistance.	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumors', 'Disease', (76, 82))	('mutations', 'Var', (99, 108))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('SMO', 'Gene', '6608', (0, 3))	('SMO', 'Gene', (0, 3))
268047	24525231	PKCiota, which regulates the Hh pathway both upstream and downstream of SMO, may serve as an alternative therapeutic strategy for modulating Hh signaling in tumors harboring such mutations.	('PKC', 'Gene', (0, 3))	('tumors', 'Phenotype', 'HP:0002664', (157, 163))	('SMO', 'Gene', '6608', (72, 75))	('SMO', 'Gene', (72, 75))	('tumors', 'Disease', (157, 163))	('tumors', 'Disease', 'MESH:D009369', (157, 163))	('mutations', 'Var', (179, 188))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('modulating', 'Reg', (130, 140))	('Hh pathway', 'Pathway', (29, 39))	('PKC', 'Gene', '5584;18759', (0, 3))	('regulates', 'Reg', (15, 24))
268049	24525231	Such inhibitors may exhibit particular potency in tumors harboring chromosome 3q26 amplification and commensurate activation of the autocrine PKCiota-SOX2-HHAT signaling axis described here.	('activation', 'PosReg', (114, 124))	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('chromosome 3q26 amplification', 'Var', (67, 96))	('PKCiota-SOX2-HHAT', 'Disease', 'MESH:C565948', (142, 159))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('tumors', 'Disease', (50, 56))	('amplification', 'Var', (83, 96))	('PKCiota-SOX2-HHAT', 'Disease', (142, 159))
268074	24525231	Our data indicate that chromosome 3q26 copy number gains serve to genetically activate PRKCI and SOX2 which together establish a PKCiota-SOX2-HHAT signaling axis that drives a stem-like phenotype.	('SOX2', 'Gene', (97, 101))	('PKCiota-SOX2-HHAT', 'Disease', (129, 146))	('stem-like phenotype', 'CPA', (176, 195))	('PKCiota-SOX2-HHAT', 'Disease', 'MESH:C565948', (129, 146))	('drives', 'PosReg', (167, 173))	('PRKCI', 'Gene', '5584', (87, 92))	('copy number gains', 'Var', (39, 56))	('activate', 'PosReg', (78, 86))	('PRKCI', 'Gene', (87, 92))
268076	32243837	KMT2D deficiency impairs super-enhancers to confer a glycolytic vulnerability in lung cancer Epigenetic modifiers frequently harbor loss-of-function mutations in lung cancer, but their tumor-suppressive roles are poorly characterized.	('tumor', 'Disease', (185, 190))	('lung cancer', 'Disease', (81, 92))	('deficiency impairs', 'Disease', 'MESH:D060825', (6, 24))	('lung cancer', 'Phenotype', 'HP:0100526', (81, 92))	('mutations', 'Var', (149, 158))	('lung cancer', 'Disease', 'MESH:D008175', (162, 173))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('deficiency impairs', 'Disease', (6, 24))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('KMT2D', 'Gene', (0, 5))	('lung cancer', 'Disease', (162, 173))	('loss-of-function', 'NegReg', (132, 148))	('lung cancer', 'Disease', 'MESH:D008175', (81, 92))	('KMT2D', 'Gene', '8085', (0, 5))	('lung cancer', 'Phenotype', 'HP:0100526', (162, 173))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('glycolytic vulnerability', 'MPA', (53, 77))
268078	32243837	Here we show that lung-specific loss of Kmt2d promotes lung tumorigenesis in mice and upregulates pro-tumorigenic programs, including glycolysis.	('mice', 'Species', '10090', (77, 81))	('tumor', 'Disease', (102, 107))	('Kmt2d', 'Gene', (40, 45))	('lung tumor', 'Phenotype', 'HP:0100526', (55, 65))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('glycolysis', 'MPA', (134, 144))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('loss', 'Var', (32, 36))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('promotes', 'PosReg', (46, 54))	('tumor', 'Disease', (60, 65))	('lung tumor', 'Disease', (55, 65))	('upregulates', 'PosReg', (86, 97))	('lung tumor', 'Disease', 'MESH:D008175', (55, 65))
268080	32243837	These findings indicate that KMT2D is a lung tumor suppressor and KMT2D deficiency confers a therapeutic vulnerability to glycolytic inhibitors.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('lung tumor', 'Disease', (40, 50))	('lung tumor', 'Disease', 'MESH:D008175', (40, 50))	('deficiency', 'Var', (72, 82))	('glycolytic inhibitors', 'MPA', (122, 143))	('lung tumor', 'Phenotype', 'HP:0100526', (40, 50))	('KMT2D', 'Gene', (66, 71))
268084	32243837	Epigenetic modifiers are frequently lost in lung cancer, but how this provokes lung tumorigenesis remains unclear.	('lung cancer', 'Phenotype', 'HP:0100526', (44, 55))	('lung tumor', 'Phenotype', 'HP:0100526', (79, 89))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('lung cancer', 'Disease', 'MESH:D008175', (44, 55))	('Epigenetic modifiers', 'Var', (0, 20))	('provokes', 'Reg', (70, 78))	('lung tumor', 'Disease', (79, 89))	('lung tumor', 'Disease', 'MESH:D008175', (79, 89))	('lost', 'NegReg', (36, 40))	('lung cancer', 'Disease', (44, 55))
268090	32243837	KMT2D deficiency induces aberrant metabolic reprogramming via super-enhancer impairment, conferring sensitivity to glycolytic inhibitors in lung cancer with KMT2D-inactivating mutations.	('sensitivity to glycolytic inhibitors', 'MPA', (100, 136))	('lung cancer', 'Disease', (140, 151))	('lung cancer', 'Phenotype', 'HP:0100526', (140, 151))	('induces', 'Reg', (17, 24))	('men', 'Species', '9606', (83, 86))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('deficiency', 'Var', (6, 16))	('metabolic reprogramming', 'CPA', (34, 57))	('impairment', 'NegReg', (77, 87))	('KMT2D', 'Gene', (0, 5))	('lung cancer', 'Disease', 'MESH:D008175', (140, 151))	('KMT2D-inactivating', 'Gene', (157, 175))
268093	32243837	Lung cancer is often characterized by gain-of-function mutations and amplification of oncogenic kinase genes (e.g., KRAS and EGFR) as well as loss-of-function alterations in tumor suppressor genes (e.g., TP53 and LKB1).	('tumor', 'Disease', (174, 179))	('LKB1', 'Gene', (213, 217))	('mutations', 'Var', (55, 64))	('EGFR', 'Gene', '1956', (125, 129))	('LKB1', 'Gene', '6794', (213, 217))	('Lung cancer', 'Phenotype', 'HP:0100526', (0, 11))	('TP53', 'Gene', '7157', (204, 208))	('gain-of-function', 'PosReg', (38, 54))	('EGFR', 'Gene', (125, 129))	('loss-of-function', 'NegReg', (142, 158))	('Lung cancer', 'Disease', (0, 11))	('KRAS', 'Gene', (116, 120))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('TP53', 'Gene', (204, 208))	('Lung cancer', 'Disease', 'MESH:D008175', (0, 11))	('amplification', 'Var', (69, 82))
268094	32243837	Much research for lung cancer has focused on kinase signaling pathways, leading to the development of the kinase-targeted therapies, such as the EGFR mutant inhibitors and the ALK inhibitors.	('lung cancer', 'Disease', 'MESH:D008175', (18, 29))	('EGFR', 'Gene', '1956', (145, 149))	('men', 'Species', '9606', (94, 97))	('ALK', 'Gene', '238', (176, 179))	('EGFR', 'Gene', (145, 149))	('lung cancer', 'Phenotype', 'HP:0100526', (18, 29))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('lung cancer', 'Disease', (18, 29))	('ALK', 'Gene', (176, 179))	('mutant inhibitors', 'Var', (150, 167))
268100	32243837	Epigenetic alterations, which represent heritable aberrations in gene expression or cellular phenotype without alterations of DNA sequences, have emerged as a major type of cancer-driving events.	('Epigenetic alterations', 'Var', (0, 22))	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('cancer', 'Disease', (173, 179))
268101	32243837	Interestingly, histone methylation, which can occur at lysine and arginine residues in histones, is linked to either gene activation or silencing, depending on the methylation residues within the histones.	('lysine', 'Chemical', 'MESH:D008239', (55, 61))	('histone methylation', 'MPA', (15, 34))	('linked', 'Reg', (100, 106))	('lysine', 'Var', (55, 61))	('silencing', 'NegReg', (136, 145))	('activation', 'PosReg', (122, 132))	('arginine', 'Chemical', 'MESH:D001120', (66, 74))
268102	32243837	Notably, histone methylation modifiers and other epigenetic modifiers are often mutated in lung tumors, including lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC), which comprise 40% to 50% and 25% to 30% of lung cancer, respectively.	('histone', 'Protein', (9, 16))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('lung tumors', 'Disease', (91, 102))	('lung cancer', 'Phenotype', 'HP:0100526', (226, 237))	('mutated', 'Var', (80, 87))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (150, 173))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (145, 173))	('lung squamous cell carcinoma', 'Disease', (145, 173))	('lung adenocarcinoma', 'Disease', (114, 133))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('lung cancer', 'Disease', (226, 237))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (114, 133))	('lung tumors', 'Disease', 'MESH:D008175', (91, 102))	('carcinoma', 'Phenotype', 'HP:0030731', (164, 173))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (114, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('lung tumors', 'Phenotype', 'HP:0100526', (91, 102))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (145, 173))	('lung tumor', 'Phenotype', 'HP:0100526', (91, 101))	('lung cancer', 'Disease', 'MESH:D008175', (226, 237))
268103	32243837	In fact, a substantial percentage of such mutations results in loss of function, suggesting that epigenetic modifiers can have tumor-suppressive functions.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('epigenetic modifiers', 'Var', (97, 117))	('loss', 'NegReg', (63, 67))	('tumor', 'Disease', (127, 132))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('mutations', 'Var', (42, 51))
268105	32243837	In the present study, we sought to identify an epigenetic modifier with tumor-suppressive function in lung cancer.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('lung cancer', 'Phenotype', 'HP:0100526', (102, 113))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('tumor', 'Disease', (72, 77))	('lung cancer', 'Disease', (102, 113))	('lung cancer', 'Disease', 'MESH:D008175', (102, 113))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('epigenetic modifier', 'Var', (47, 66))
268106	32243837	To identify an epigenetic modifier with tumor-suppressive function in lung cancer, we examined which epigenetic modifiers most frequently undergo genomic alterations (i.e., truncations, missense mutations, and insertions/deletions) that are related to loss-of-function mutations in lung tumors.	('lung cancer', 'Disease', (70, 81))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('lung tumors', 'Disease', (282, 293))	('insertions/deletions', 'Var', (210, 230))	('tumor', 'Disease', (287, 292))	('truncations', 'MPA', (173, 184))	('lung cancer', 'Disease', 'MESH:D008175', (70, 81))	('tumor', 'Disease', 'MESH:D009369', (287, 292))	('lung cancer', 'Phenotype', 'HP:0100526', (70, 81))	('tumors', 'Phenotype', 'HP:0002664', (287, 293))	('missense mutations', 'Var', (186, 204))	('tumor', 'Disease', (40, 45))	('loss-of-function', 'NegReg', (252, 268))	('lung tumor', 'Phenotype', 'HP:0100526', (282, 292))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('lung tumors', 'Disease', 'MESH:D008175', (282, 293))	('undergo', 'Reg', (138, 145))	('tumor', 'Phenotype', 'HP:0002664', (287, 292))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('lung tumors', 'Phenotype', 'HP:0100526', (282, 293))
268108	32243837	Of note, it has been reported that a majority of KMT2D missense mutations in lymphoma significantly reduce KMT2D enzymatic activity, indicating a negative effect for KMT2D missense mutations in KMT2D activity.	('lymphoma', 'Disease', (77, 85))	('lymphoma', 'Disease', 'MESH:D008223', (77, 85))	('KMT2D enzymatic activity', 'MPA', (107, 131))	('lymphoma', 'Phenotype', 'HP:0002665', (77, 85))	('missense mutations', 'Var', (55, 73))	('reduce', 'NegReg', (100, 106))	('KMT2D', 'Gene', (49, 54))
268110	32243837	We analyzed whether KMT2D alterations frequently co-occur with alterations in the two most frequently mutated genes TP53 and KRAS in human lung cancer.	('lung cancer', 'Disease', (139, 150))	('TP53', 'Gene', (116, 120))	('lung cancer', 'Disease', 'MESH:D008175', (139, 150))	('alterations', 'Var', (26, 37))	('KMT2D', 'Gene', (20, 25))	('TP53', 'Gene', '7157', (116, 120))	('human', 'Species', '9606', (133, 138))	('lung cancer', 'Phenotype', 'HP:0100526', (139, 150))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
268111	32243837	About 71% of KMT2D alterations co-occur with TP53 alterations in lung tumors, and about 22% of KMT2D alterations coincide with KRAS alterations in LUAD (Figure S1D).	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('TP53', 'Gene', (45, 49))	('alterations', 'Var', (101, 112))	('lung tumor', 'Phenotype', 'HP:0100526', (65, 75))	('alterations', 'Var', (50, 61))	('KMT2D', 'Gene', (95, 100))	('lung tumors', 'Disease', 'MESH:D008175', (65, 76))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('alterations', 'Var', (19, 30))	('lung tumors', 'Disease', (65, 76))	('TP53', 'Gene', '7157', (45, 49))	('lung tumors', 'Phenotype', 'HP:0100526', (65, 76))
268112	32243837	Therefore, we sought to determine whether lung-specific loss of Kmt2d cooperates with Trp53 inactivation or Kras activation for lung tumorigenesis in mice.	('lung tumor', 'Disease', 'MESH:D008175', (128, 138))	('mice', 'Species', '10090', (150, 154))	('lung tumor', 'Disease', (128, 138))	('loss', 'Var', (56, 60))	('Kmt2d', 'Gene', (64, 69))	('lung tumor', 'Phenotype', 'HP:0100526', (128, 138))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('Trp53', 'Protein', (86, 91))
268113	32243837	We first generated several genetically engineered mouse models (GEMMs), including Trp53fl/fl;Kmt2dfl/fl and KrasLSL-G12D;Kmt2dfl/fl (Figures S2A-S2C).	('Trp53fl/fl', 'Var', (82, 92))	('KrasLSL', 'Gene', '16653', (108, 115))	('mouse', 'Species', '10090', (50, 55))	('KrasLSL', 'Gene', (108, 115))	('Kmt2dfl/fl', 'Var', (121, 131))	('G12D', 'Mutation', 'rs121913529', (116, 120))
268115	32243837	Lung-specific single loss or co-loss of Kmt2d and Trp53 by Adeno-Cre-mediated deletion neither induced any detectable tumor in mouse lungs for up to 16 months post-infection nor changed mouse survival times (Figures 1B-1D and S2D).	('mouse', 'Species', '10090', (127, 132))	('infection', 'Disease', (164, 173))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('co-loss', 'Var', (29, 36))	('infection', 'Disease', 'MESH:D007239', (164, 173))	('Kmt2d', 'Gene', (40, 45))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('deletion', 'Var', (78, 86))	('mouse', 'Species', '10090', (186, 191))	('tumor', 'Disease', (118, 123))	('changed', 'Reg', (178, 185))	('Trp53', 'Gene', (50, 55))	('loss', 'NegReg', (21, 25))
268116	32243837	This may be partly because Trp53 loss alone rarely induces lung tumors in mice although Trp53 loss promotes oncogene-driven lung tumorigenesis.	('lung tumor', 'Disease', (124, 134))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('lung tumor', 'Disease', 'MESH:D008175', (124, 134))	('lung tumors', 'Disease', 'MESH:D008175', (59, 70))	('lung tumor', 'Phenotype', 'HP:0100526', (59, 69))	('loss', 'NegReg', (94, 98))	('promotes', 'PosReg', (99, 107))	('induces', 'Reg', (51, 58))	('lung tumor', 'Phenotype', 'HP:0100526', (124, 134))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('loss', 'Var', (33, 37))	('Trp53', 'Gene', (88, 93))	('lung tumors', 'Disease', (59, 70))	('lung tumors', 'Phenotype', 'HP:0100526', (59, 70))	('mice', 'Species', '10090', (74, 78))	('lung tumor', 'Disease', 'MESH:D008175', (59, 69))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
268117	32243837	In addition, because KMT2D and p53 in a multi-protein complex may activate a similar set of the DNA damage response pathway genes, their co-loss may not cooperate for tumorigenesis.	('p53', 'Gene', (31, 34))	('p53', 'Gene', '7157', (31, 34))	('activate', 'PosReg', (66, 74))	('DNA damage response pathway', 'Pathway', (96, 123))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('KMT2D', 'Var', (21, 26))	('tumor', 'Disease', (167, 172))
268119	32243837	Kras activation was induced by lung-specific deletion of the LSL (loxP-STOP-loxP) cassette via Adeno-Cre virus infection, as previously described.	('virus infection', 'Disease', 'MESH:D001102', (105, 120))	('virus infection', 'Disease', (105, 120))	('deletion', 'Var', (45, 53))	('activation', 'PosReg', (5, 15))	('Kras', 'CPA', (0, 4))
268121	32243837	Data from micro-CT scans and hematoxylin and eosin (H&E)-stained tumor sections showed that lung-specific loss of Kmt2d promoted KRAS-induced lung tumorigenesis (Figures 1B and 1C).	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('lung tumor', 'Disease', (142, 152))	('eosin', 'Chemical', 'MESH:D004801', (45, 50))	('Kmt2d', 'PosReg', (114, 119))	('lung-specific', 'Var', (92, 105))	('tumor', 'Disease', (65, 70))	('lung tumor', 'Disease', 'MESH:D008175', (142, 152))	('lung tumor', 'Phenotype', 'HP:0100526', (142, 152))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('H&E', 'Chemical', '-', (52, 55))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('hematoxylin', 'Chemical', 'MESH:D006416', (29, 40))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
268122	32243837	Specifically, our H&E data demonstrated that a higher percentage of the pulmonary parenchyma was effaced by tumors in the Kras;Kmt2d-/- group of mice than in the Kras group of mice (Figures 1B, 1C, S2E, and S2F).	('S2E', 'Mutation', 'p.S2E', (198, 201))	('the', 'Var', (118, 121))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('H&E', 'Chemical', '-', (18, 21))	('the pulmonary', 'CPA', (68, 81))	('mice', 'Species', '10090', (176, 180))	('tumors', 'Disease', (108, 114))	('tumors', 'Disease', 'MESH:D009369', (108, 114))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('mice', 'Species', '10090', (145, 149))
268127	32243837	To understand how lung-specific loss of Kmt2d promotes LUAD, we isolated tumor lesions from Kras and Kras;Kmt2d-/- lungs and compared their gene expression profiles using RNA-seq.	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('Kmt2d', 'Gene', (40, 45))	('LUAD', 'Disease', (55, 59))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Disease', (73, 78))	('loss', 'Var', (32, 36))	('promotes', 'PosReg', (46, 54))
268129	32243837	In contrast, these two analyses did not share a pathway downregulated by Kmt2d loss, as GSEA analysis did not show any pathway that was significantly downregulated by Kmt2d loss (Figure 2E).	('GSEA', 'Chemical', '-', (88, 92))	('Kmt2d', 'Gene', (73, 78))	('loss', 'NegReg', (173, 177))	('loss', 'Var', (79, 83))
268130	32243837	In line with our RNA-seq results, analysis of the TCGA lung cancer database showed that glycolytic and OXPHOS genes were enriched in human KMT2D-low/mutant LUAD samples as compared with human KMT2D-high LUAD samples (Figures 2F-2H and Table S2).	('glycolytic', 'Gene', (88, 98))	('lung cancer', 'Disease', 'MESH:D008175', (55, 66))	('KMT2D-low/mutant', 'Var', (139, 155))	('lung cancer', 'Disease', (55, 66))	('human', 'Species', '9606', (186, 191))	('lung cancer', 'Phenotype', 'HP:0100526', (55, 66))	('OXPHOS genes', 'Gene', (103, 115))	('human', 'Species', '9606', (133, 138))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
268137	32243837	Moreover, high mRNA levels of ENO1, PGK1, PGAM1, LDHA, and GAPDH were associated with poor survival in LUAD patients (Figure 3E).	('PGAM1', 'Gene', '5223', (42, 47))	('GAPDH', 'Gene', (59, 64))	('LDHA', 'Gene', (49, 53))	('PGK1', 'Gene', '5230', (36, 40))	('PGK1', 'Gene', (36, 40))	('mRNA levels', 'MPA', (15, 26))	('associated', 'Reg', (70, 80))	('LDHA', 'Gene', '3939', (49, 53))	('ENO1', 'Gene', (30, 34))	('high', 'Var', (10, 14))	('ENO1', 'Gene', '2023', (30, 34))	('patients', 'Species', '9606', (108, 116))	('PGAM1', 'Gene', (42, 47))	('GAPDH', 'Gene', '2597', (59, 64))	('poor', 'NegReg', (86, 90))
268142	32243837	In the ChIP-seq experiment, we also included H3K79me2 and H3K9me3, because H3K79me2 is associated with transcriptional elongation and H3K9me3 is a marker for heterochromatin repression.	('H3K9me3', 'Var', (134, 141))	('H3K79me2', 'Var', (75, 83))	('associated', 'Reg', (87, 97))	('transcriptional elongation', 'CPA', (103, 129))	('men', 'Species', '9606', (22, 25))
268144	32243837	In agreement with these, IF analyses showed that global levels of H3K4me1 and H3K27ac but not H3K4me3 were downregulated by Kmt2d loss (Figure S3H).	('men', 'Species', '9606', (8, 11))	('H3K27ac', 'Protein', (78, 85))	('downregulated', 'NegReg', (107, 120))	('loss', 'NegReg', (130, 134))	('Kmt2d', 'Gene', (124, 129))	('H3K4me1', 'Var', (66, 73))
268146	32243837	This led us to test whether the inhibition of glycolytic pathways or H3K27 deacetylation would impede the growth of human lung cancer cell lines bearing loss-of-function mutations in KMT2D.	('growth', 'CPA', (106, 112))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('KMT2D', 'Gene', (183, 188))	('lung cancer', 'Disease', (122, 133))	('lung cancer', 'Phenotype', 'HP:0100526', (122, 133))	('inhibition', 'NegReg', (32, 42))	('mutations', 'Var', (170, 179))	('glycolytic pathways', 'Pathway', (46, 65))	('impede', 'NegReg', (95, 101))	('test', 'Reg', (15, 19))	('human', 'Species', '9606', (116, 121))	('lung cancer', 'Disease', 'MESH:D008175', (122, 133))	('loss-of-function', 'NegReg', (153, 169))	('deacetylation', 'MPA', (75, 88))	('H3K27', 'Protein', (69, 74))
268149	32243837	We compared the inhibitory effects of these agents on cell confluency of human LUAD cell lines with wild-type (WT) KMT2D (A549, H1792, H1437, H23, and H358) and human LUAD cell lines bearing KMT2D-truncating mutations (i.e., H1568, with nonsense at E758; DV-90, with the truncating mutation P2118fs; and CORL-105, with the truncating mutation R2188fs) (Table S3).	('human', 'Species', '9606', (161, 166))	('H1437', 'CellLine', 'CVCL:1472', (135, 140))	('R2188fs', 'Mutation', 'p.R2188fsX', (343, 350))	('DV-90', 'CellLine', 'CVCL:1184', (255, 260))	('H358', 'CellLine', 'CVCL:1559', (151, 155))	('H1792', 'CellLine', 'CVCL:1495', (128, 133))	('human', 'Species', '9606', (73, 78))	('H1568', 'CellLine', 'CVCL:1476', (225, 230))	('R2188fs', 'Var', (343, 350))	('P2118fs', 'Var', (291, 298))	('A549', 'CellLine', 'CVCL:0023', (122, 126))	('P2118fs', 'Mutation', 'p.P2118fsX', (291, 298))
268150	32243837	Of note, glucose uptake, lactate excretion, and glycolysis metabolites (e.g., glucose-6-phosphate, fructose-6-phosphate, glucose-1,6-bisphosphate, and fructose-1,6-bisphosphate) tended to be higher in the KMT2D-mutant cell lines than in the KMT2D-WT cell lines (Figures S5A-S5C).	('higher', 'PosReg', (191, 197))	('glucose uptake', 'MPA', (9, 23))	('fructose-1,6-bisphosphate', 'Chemical', 'MESH:C029063', (151, 176))	('glucose', 'Chemical', 'MESH:D005947', (121, 128))	('fructose-6-phosphate', 'MPA', (99, 119))	('KMT2D-mutant', 'Var', (205, 217))	('glucose', 'Chemical', 'MESH:D005947', (9, 16))	('fructose-6-phosphate', 'Chemical', 'MESH:C027618', (99, 119))	('glucose-6-phosphate', 'MPA', (78, 97))	('glucose', 'Chemical', 'MESH:D005947', (78, 85))	('lactate excretion', 'MPA', (25, 42))	('lactate', 'Chemical', 'MESH:D019344', (25, 32))	('glycolysis metabolites', 'MPA', (48, 70))
268151	32243837	2-DG (and to a lesser extent POMHEX, KA, and Vorinostat) inhibited the confluency of the KMT2D-mutant cell lines to a greater extent than that of the KMT2D-WT cell lines (Figures 5A and 5B).	('POMHEX', 'Chemical', '-', (29, 35))	('inhibited', 'NegReg', (57, 66))	('2-DG', 'Chemical', 'MESH:D003847', (0, 4))	('Vorinostat', 'Chemical', 'MESH:D000077337', (45, 55))	('confluency', 'CPA', (71, 81))	('KMT2D-mutant', 'Var', (89, 101))
268155	32243837	Consistent with the notion that 2-DG can induce cell death in a cell-type- and dose-dependent manner, 2-DG induced more cell death in the three KMT2D-mutant cell lines than in two KMT2D-WT cell lines tested (Figure S5H).	('death', 'Disease', 'MESH:D003643', (53, 58))	('2-DG', 'Chemical', 'MESH:D003847', (32, 36))	('death', 'Disease', (53, 58))	('2-DG', 'Var', (102, 106))	('2-DG', 'Chemical', 'MESH:D003847', (102, 106))	('death', 'Disease', 'MESH:D003643', (125, 130))	('death', 'Disease', (125, 130))	('KMT2D-mutant', 'Var', (144, 156))
268156	32243837	In addition, 2-DG tended to inhibit the extracellular acidification rates (ECARs; an indicator for glycolysis) of the KMT2D-mutant cell lines to a greater extent than those of the KMT2D-WT cell lines (Figures S5I and S5J).	('extracellular acidification rates', 'MPA', (40, 73))	('KMT2D-mutant', 'Var', (118, 130))	('2-DG', 'Chemical', 'MESH:D003847', (13, 17))	('inhibit', 'NegReg', (28, 35))
268158	32243837	A three-dimensional (3D) cell culture system was used, because 1) it better mimics an in vivo situation than a 2D culture system does and 2) KMT2D knockdown increased the sizes of the spheroids formed from LKR10 cells in the 3D culture (Figure S6A) : In contrast, KMT2D knockdown decreased the proliferation of several LUAD cell lines in the 2D culture system (data not shown).	('men', 'Species', '9606', (10, 13))	('knockdown', 'Var', (270, 279))	('decreased', 'NegReg', (280, 289))	('proliferation', 'CPA', (294, 307))	('KMT2D', 'Gene', (264, 269))
268159	32243837	In line with its inhibitory effect on confluency of human LUAD cells, 2-DG inhibited spheroid growth of KMT2D-depleted LKR-10 cells to a greater extent than that of shLuciferase (shLuc)-treated LKR-10 cells (a control) in the 3D culture system (Figures S6A and S6B).	('LKR-10', 'CellLine', 'CVCL:8804', (119, 125))	('inhibited', 'NegReg', (75, 84))	('human', 'Species', '9606', (52, 57))	('2-DG', 'Chemical', 'MESH:D003847', (70, 74))	('LKR-10', 'CellLine', 'CVCL:8804', (194, 200))	('spheroid growth', 'CPA', (85, 100))	('2-DG', 'Var', (70, 74))
268160	32243837	To examine whether 2-DG selectively inhibits tumorigenic growth of KMT2D-mutant LUAD cells over KMT2D-WT LUAD cells, we used H1568 cells harboring a KMT2D's truncation mutation and H358 cells harboring WT KMT2D.	('KMT2D-mutant', 'Gene', (67, 79))	('2-DG', 'Chemical', 'MESH:D003847', (19, 23))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('KMT2D', 'Var', (149, 154))	('H358', 'CellLine', 'CVCL:1559', (181, 185))	('tumor', 'Disease', (45, 50))	('inhibits', 'NegReg', (36, 44))	('H1568', 'CellLine', 'CVCL:1476', (125, 130))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
268162	32243837	Notably, 2-DG preferentially inhibited the tumorigenicity of KMT2D-mutant H1568 cells as compared with KMT2D-WT H358 cells in a mouse subcutaneous xenograft model (Figures 5C-5E).	('inhibited', 'NegReg', (29, 38))	('H1568', 'Var', (74, 79))	('H358', 'CellLine', 'CVCL:1559', (112, 116))	('2-DG', 'Chemical', 'MESH:D003847', (9, 13))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('mouse', 'Species', '10090', (128, 133))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('H1568', 'CellLine', 'CVCL:1476', (74, 79))	('KMT2D-mutant H1568', 'Var', (61, 79))	('tumor', 'Disease', (43, 48))
268163	32243837	However, KA, which less selectively inhibited KMT2D-mutant cell lines than did 2-DG, weakly and insignificantly impeded the tumorigenicity of H1568 cells as compared with H358 cells (Figures S6D and S6E).	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('S6E', 'Mutation', 'p.S6E', (199, 202))	('KMT2D-mutant', 'Var', (46, 58))	('impeded', 'NegReg', (112, 119))	('H358', 'CellLine', 'CVCL:1559', (171, 175))	('tumor', 'Disease', (124, 129))	('H1568', 'CellLine', 'CVCL:1476', (142, 147))	('2-DG', 'Chemical', 'MESH:D003847', (79, 83))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
268165	32243837	H1792 cells grew faster than DV-90 cells did in a 2D culture (Figure S6C), but DV-90 cells formed tumors faster than H1792 cells did in a mouse xenograft model (Figure 5F).	('DV-90', 'CellLine', 'CVCL:1184', (79, 84))	('tumors', 'Disease', (98, 104))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('mouse', 'Species', '10090', (138, 143))	('tumors', 'Disease', 'MESH:D009369', (98, 104))	('DV-90', 'Var', (79, 84))	('DV-90', 'CellLine', 'CVCL:1184', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('H1792', 'CellLine', 'CVCL:1495', (0, 5))	('H1792', 'CellLine', 'CVCL:1495', (117, 122))
268166	32243837	In agreement with the above results, 2-DG selectively inhibited tumorigenic growth of KMT2D-mutant DV-90 cells over KMT2D-WT H1792 cells (Figure 5F).	('inhibited', 'NegReg', (54, 63))	('tumor', 'Disease', (64, 69))	('2-DG', 'Chemical', 'MESH:D003847', (37, 41))	('KMT2D-mutant', 'Var', (86, 98))	('H1792', 'CellLine', 'CVCL:1495', (125, 130))	('men', 'Species', '9606', (8, 11))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('DV-90', 'CellLine', 'CVCL:1184', (99, 104))
268167	32243837	Finally, to test the effect of 2-DG on the tumorigenicity of KMT2D-WT and KMT2D-mutant LUAD cells in an isogenic cell state, we generated KMT2D-mutant H1568 cells harboring doxycycline (Dox)-inducible WT KMT2D (Figure S6F) and then compared the inhibitory effect of 2-DG on tumorigenic growth of these cells between Dox treatment and Dox untreatment.	('2-DG', 'Chemical', 'MESH:D003847', (266, 270))	('KMT2D-mutant', 'Var', (138, 150))	('Dox', 'Chemical', 'MESH:D004318', (316, 319))	('doxycycline', 'Chemical', 'MESH:D004318', (173, 184))	('Dox', 'Chemical', 'MESH:D004318', (334, 337))	('tumor', 'Disease', 'MESH:D009369', (274, 279))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('H1568', 'CellLine', 'CVCL:1476', (151, 156))	('men', 'Species', '9606', (325, 328))	('men', 'Species', '9606', (345, 348))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('Dox', 'Chemical', 'MESH:D004318', (186, 189))	('2-DG', 'Chemical', 'MESH:D003847', (31, 35))	('tumor', 'Phenotype', 'HP:0002664', (274, 279))	('tumor', 'Disease', (274, 279))	('tumor', 'Disease', (43, 48))
268168	32243837	In line with the above results, 2-DG tended to preferentially impede tumorigenic growth of KMT2D-inducible H1568 cells in Dox-untreated mice as compared with Dox-treated mice (Figure S6G).	('2-DG', 'Var', (32, 36))	('2-DG', 'Chemical', 'MESH:D003847', (32, 36))	('Dox', 'Chemical', 'MESH:D004318', (122, 125))	('mice', 'Species', '10090', (136, 140))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('Dox', 'Chemical', 'MESH:D004318', (158, 161))	('tumor', 'Disease', (69, 74))	('H1568', 'CellLine', 'CVCL:1476', (107, 112))	('mice', 'Species', '10090', (170, 174))	('impede', 'NegReg', (62, 68))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
268174	32243837	Of note, Kmt2d loss in KRAS-driven lung tumors did not affect expression of Dnmt3a (a transcriptional co-repressor gene) and DNMT3A-regulated Ras activator genes (Rasgrp1, Rasgrf1, Rasgrf2, Rapgef5, and Rgl1) (Figure S7B), although expression of Dnmt3a was downregulated by Kmt2d loss in other types of tumors (e.g., medulloblastoma).	('tumor', 'Phenotype', 'HP:0002664', (303, 308))	('lung tumor', 'Phenotype', 'HP:0100526', (35, 45))	('medulloblastoma', 'Disease', 'MESH:D008527', (317, 332))	('loss', 'Var', (15, 19))	('tumors', 'Disease', (303, 309))	('downregulated', 'NegReg', (257, 270))	('medulloblastoma', 'Phenotype', 'HP:0002885', (317, 332))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('lung tumors', 'Disease', (35, 46))	('tumors', 'Disease', (40, 46))	('medulloblastoma', 'Disease', (317, 332))	('loss', 'NegReg', (280, 284))	('tumors', 'Disease', 'MESH:D009369', (303, 309))	('tumors', 'Disease', 'MESH:D009369', (40, 46))	('Kmt2d', 'Gene', (274, 279))	('Kmt2d', 'Gene', (9, 14))	('lung tumors', 'Disease', 'MESH:D008175', (35, 46))	('Rgl1', 'Gene', (203, 207))	('tumors', 'Phenotype', 'HP:0002664', (303, 309))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('lung tumors', 'Phenotype', 'HP:0100526', (35, 46))
268176	32243837	Of these five genes, the circadian rhythm repressor gene Per2 was particularly interesting for the following reasons: 1) Per2 loss in mouse lung promoted lung tumorigenesis; 2) Per2 loss increased glucose metabolism, implicating PER2 in regulation of glycolysis; and 3) disruption of circadian rhythm increased the tumorigenicity.	('disruption', 'Var', (270, 280))	('increased glucose', 'Phenotype', 'HP:0003074', (187, 204))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('tumor', 'Disease', 'MESH:D009369', (315, 320))	('Per2', 'Gene', (121, 125))	('mouse', 'Species', '10090', (134, 139))	('Per2', 'Gene', (177, 181))	('promoted', 'PosReg', (145, 153))	('lung tumor', 'Disease', 'MESH:D008175', (154, 164))	('tumor', 'Phenotype', 'HP:0002664', (315, 320))	('tumor', 'Disease', (159, 164))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('lung tumor', 'Disease', (154, 164))	('increased', 'PosReg', (301, 310))	('loss increased glucose metabolism', 'Disease', 'MESH:D044882', (182, 215))	('loss', 'NegReg', (126, 130))	('lung tumor', 'Phenotype', 'HP:0100526', (154, 164))	('loss increased glucose metabolism', 'Disease', (182, 215))	('tumor', 'Disease', (315, 320))
268179	32243837	ChIP results also showed that PER2 occupied several glycolytic genes (e.g., Eno1, Pgk1, Pgam1, Ldha, Gapdh, and Cdk1) and that KMT2D knockdown reduced PER2 occupancy in these genes (Figures 7H and S7H).	('PER2 occupancy', 'MPA', (151, 165))	('Pgam1', 'Gene', '5223', (88, 93))	('Eno1', 'Gene', '2023', (76, 80))	('Ldha', 'Gene', '3939', (95, 99))	('Cdk1', 'Gene', '983', (112, 116))	('Pgk1', 'Gene', (82, 86))	('Eno1', 'Gene', (76, 80))	('Ldha', 'Gene', (95, 99))	('knockdown', 'Var', (133, 142))	('Gapdh', 'Gene', (101, 106))	('Cdk1', 'Gene', (112, 116))	('Pgam1', 'Gene', (88, 93))	('PER2', 'Gene', (30, 34))	('Gapdh', 'Gene', '2597', (101, 106))	('Pgk1', 'Gene', '5230', (82, 86))	('reduced', 'NegReg', (143, 150))
268180	32243837	Similar to the effect of Kmt2d loss on glycolytic genes in Kras tumors, our RNA-seq and RT-PCR data showed that KMT2D knockdown in LKR10 cells robustly upregulated expression levels of the glycolytic genes while downregulating Per2 expression (Figures 8A and S8A).	('upregulated', 'PosReg', (152, 163))	('downregulating', 'NegReg', (212, 226))	('expression levels', 'MPA', (164, 181))	('Kras tumors', 'Disease', 'MESH:D009369', (59, 70))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('knockdown', 'Var', (118, 127))	('glycolytic genes', 'Gene', (189, 205))	('Kras tumors', 'Disease', (59, 70))	('KMT2D', 'Gene', (112, 117))	('Per2', 'Gene', (227, 231))	('expression', 'MPA', (232, 242))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
268181	32243837	In line with this, KMT2D knockdown increased glucose uptake, lactate excretion, several glycolysis metabolites (e.g., glucose-6-phosphate, fructose-6-phosphate, glucose-1,6-bisphosphate and fructose-1,6-bisphosphate), and ECAR in LKR10 cells (Figures 8B, S8B, and S8C).	('increased', 'PosReg', (35, 44))	('lactate excretion', 'MPA', (61, 78))	('KMT2D', 'Gene', (19, 24))	('glucose-6-phosphate', 'MPA', (118, 137))	('glucose', 'Chemical', 'MESH:D005947', (118, 125))	('increased glucose', 'Phenotype', 'HP:0003074', (35, 52))	('ECAR', 'MPA', (222, 226))	('lactate', 'Chemical', 'MESH:D019344', (61, 68))	('glucose', 'Chemical', 'MESH:D005947', (45, 52))	('fructose-1,6-bisphosphate', 'Chemical', 'MESH:C029063', (190, 215))	('glucose uptake', 'MPA', (45, 59))	('glucose', 'Chemical', 'MESH:D005947', (161, 168))	('knockdown', 'Var', (25, 34))	('S8C', 'Mutation', 'p.S8C', (264, 267))	('fructose-6-phosphate', 'Chemical', 'MESH:C027618', (139, 159))
268182	32243837	Of note, KMT2D knockdown increased expression of OXPHOS genes and oxygen consumption rate to a lesser extent than expression of glycolytic genes and ECARs (Figures S8C and S8D).	('KMT2D', 'Gene', (9, 14))	('increased', 'PosReg', (25, 34))	('knockdown', 'Var', (15, 24))	('OXPHOS genes', 'Gene', (49, 61))	('expression', 'MPA', (35, 45))	('oxygen', 'Chemical', 'MESH:D010100', (66, 72))	('oxygen consumption rate', 'MPA', (66, 89))	('S8C', 'Mutation', 'p.S8C', (164, 167))
268186	32243837	To convincingly confirm the regulation of glycolytic genes by PER2, we examined the effect of PER2 overexpression and PER2 knockdown on expression of glycolytic genes (e.g., Eno1, Pgk1, Pgam1, Ldha, Gapdh, and Cdk1) in LKR10 cells.	('Eno1', 'Gene', (174, 178))	('Gapdh', 'Gene', (199, 204))	('PER2', 'Gene', (94, 98))	('Pgam1', 'Gene', '5223', (186, 191))	('PER2', 'Gene', (118, 122))	('Cdk1', 'Gene', (210, 214))	('Cdk1', 'Gene', '983', (210, 214))	('Pgk1', 'Gene', '5230', (180, 184))	('Gapdh', 'Gene', '2597', (199, 204))	('Pgam1', 'Gene', (186, 191))	('Ldha', 'Gene', '3939', (193, 197))	('knockdown', 'Var', (123, 132))	('Eno1', 'Gene', '2023', (174, 178))	('Ldha', 'Gene', (193, 197))	('Pgk1', 'Gene', (180, 184))
268187	32243837	PER2 knockdown increased their expression levels and ECAR while slightly increasing expression of several OXPHOS genes (Figures 8H, S8F, and S8G).	('knockdown', 'Var', (5, 14))	('OXPHOS genes', 'Gene', (106, 118))	('expression levels', 'MPA', (31, 48))	('ECAR', 'MPA', (53, 57))	('increased', 'PosReg', (15, 24))	('S8G', 'Mutation', 'p.S8G', (141, 144))	('expression', 'MPA', (84, 94))	('increasing', 'PosReg', (73, 83))	('PER2', 'Gene', (0, 4))	('S8F', 'Mutation', 'p.S8F', (132, 135))
268188	32243837	In agreement with gene expression data, enzyme assays showed that KMT2D or PER2 knockdown increased ENO1 and GAPDH activities whereas KMT2D or PER2 overexpression decreased their activities (Figure S8H).	('GAPDH', 'Gene', (109, 114))	('knockdown', 'Var', (80, 89))	('increased', 'PosReg', (90, 99))	('men', 'Species', '9606', (8, 11))	('activities', 'MPA', (179, 189))	('PER2', 'Gene', (75, 79))	('ENO1', 'Gene', '2023', (100, 104))	('ENO1', 'Gene', (100, 104))	('GAPDH', 'Gene', '2597', (109, 114))
268190	32243837	These results indicate that tumor-suppressive function of KMT2D is dependent, at least in part, on the downregulation of glycolytic genes by PER2.	('tumor', 'Disease', (28, 33))	('PER2', 'Gene', (141, 145))	('glycolytic genes', 'Gene', (121, 137))	('downregulation', 'NegReg', (103, 117))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('KMT2D', 'Var', (58, 63))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
268191	32243837	In the present study, our results indicate that KMT2D acts as an epigenetic LUAD suppressor by positively regulating super-enhancers (e.g., Per2 super-enhancer) and thereby increasing expression of the tumor suppressor gene Per2.	('increasing', 'PosReg', (173, 183))	('KMT2D', 'Var', (48, 53))	('tumor', 'Disease', (202, 207))	('regulating', 'PosReg', (106, 116))	('Per2', 'Gene', (224, 228))	('expression', 'MPA', (184, 194))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('super-enhancers', 'MPA', (117, 132))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))
268194	32243837	Interestingly, glycolysis pathway is enriched not only in our Kras;Kmt2d-/- tumor model over Kras model but also in human LUAD tumors with low/mutant KMT2D over those with high WT KMT2D.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('tumor', 'Disease', (127, 132))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('glycolysis pathway', 'Pathway', (15, 33))	('KMT2D', 'Var', (150, 155))	('low/mutant KMT2D', 'Var', (139, 155))	('LUAD tumors', 'Disease', (122, 133))	('LUAD tumors', 'Disease', 'MESH:D009369', (122, 133))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('human', 'Species', '9606', (116, 121))
268197	32243837	In contrast, results reported here showed that lung-specific deletion of Kmt2d significantly promoted KRAS-driven lung tumorigenesis in mice and shortened the survival of mice bearing KRAS-driven tumors, suggesting that Kmt2d loss cooperates with other oncogenic aberrations (e.g., Kras activation) to increase LUAD tumorigenicity.	('lung tumor', 'Disease', (114, 124))	('tumor', 'Disease', (196, 201))	('lung tumor', 'Phenotype', 'HP:0100526', (114, 124))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('loss', 'NegReg', (226, 230))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('tumors', 'Phenotype', 'HP:0002664', (196, 202))	('tumor', 'Phenotype', 'HP:0002664', (316, 321))	('mice', 'Species', '10090', (171, 175))	('promoted', 'PosReg', (93, 101))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('lung tumor', 'Disease', 'MESH:D008175', (114, 124))	('tumors', 'Disease', (196, 202))	('deletion', 'Var', (61, 69))	('shortened', 'NegReg', (145, 154))	('tumor', 'Disease', (119, 124))	('mice', 'Species', '10090', (136, 140))	('tumors', 'Disease', 'MESH:D009369', (196, 202))	('tumor', 'Disease', (316, 321))	('survival', 'CPA', (159, 167))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('Kmt2d', 'Gene', (73, 78))	('tumor', 'Disease', 'MESH:D009369', (316, 321))
268198	32243837	The lung tumor-suppressive function of KMT2D is further supported by our following additional results: 1) Kmt2d loss upregulated expression of tumor-promoting glycolytic genes, such as Eno1, Pgk1, Pgam1, Ldha and Gapdh; 2) Kmt2d loss downregulated tumor-suppressive genes, such as Per2; and 3) KMT2D depletion increased sizes of spheroids formed by lung cancer cells in the 3D culture system.	('Eno1', 'Gene', '2023', (185, 189))	('lung cancer', 'Disease', (349, 360))	('Pgam1', 'Gene', '5223', (197, 202))	('Per2', 'Gene', (281, 285))	('lung tumor', 'Phenotype', 'HP:0100526', (4, 14))	('Pgk1', 'Gene', '5230', (191, 195))	('Ldha', 'Gene', '3939', (204, 208))	('Pgk1', 'Gene', (191, 195))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('tumor', 'Disease', (248, 253))	('expression', 'MPA', (129, 139))	('loss downregulated', 'NegReg', (229, 247))	('sizes of spheroids formed', 'CPA', (320, 345))	('tumor', 'Disease', (9, 14))	('lung cancer', 'Disease', 'MESH:D008175', (349, 360))	('tumor', 'Disease', 'MESH:D009369', (248, 253))	('Pgam1', 'Gene', (197, 202))	('lung tumor', 'Disease', 'MESH:D008175', (4, 14))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('lung cancer', 'Phenotype', 'HP:0100526', (349, 360))	('Gapdh; 2', 'Gene', (213, 221))	('Kmt2d', 'Gene', (106, 111))	('loss', 'NegReg', (112, 116))	('tumor', 'Phenotype', 'HP:0002664', (248, 253))	('Eno1', 'Gene', (185, 189))	('Ldha', 'Gene', (204, 208))	('tumor', 'Disease', (143, 148))	('increased', 'PosReg', (310, 319))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('cancer', 'Phenotype', 'HP:0002664', (354, 360))	('Gapdh; 2', 'Gene', '26330', (213, 221))	('upregulated', 'PosReg', (117, 128))	('Kmt2d', 'Gene', (223, 228))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('lung tumor', 'Disease', (4, 14))	('depletion', 'Var', (300, 309))
268200	32243837	Our and other recent studies indicate that KMT2D acts as a tumor suppressor in melanoma and pancreatic cancer cells.	('tumor', 'Disease', (59, 64))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (92, 109))	('melanoma and pancreatic cancer', 'Disease', 'MESH:C563985', (79, 109))	('KMT2D', 'Var', (43, 48))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('melanoma', 'Phenotype', 'HP:0002861', (79, 87))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
268201	32243837	Furthermore, other studies have demonstrated that genetic ablation of Kmt2d in B cells enhanced B cell lymphoma genesis, also indicating KMT2D's tumor-suppressive function.	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('lymphoma genesis', 'Disease', (103, 119))	('tumor', 'Disease', (145, 150))	('B cell lymphoma', 'Phenotype', 'HP:0012191', (96, 111))	('Kmt2d', 'Gene', (70, 75))	('enhanced', 'PosReg', (87, 95))	('lymphoma', 'Phenotype', 'HP:0002665', (103, 111))	('lymphoma genesis', 'Disease', 'MESH:D008223', (103, 119))	('genetic ablation', 'Var', (50, 66))
268202	32243837	Thus, the anti- or pro-tumorigenicity of KMT2D may be cell-type-dependent, although many studies suggest that KMT2D has a tumor-suppressive function in a majority of tissues.	('KMT2D', 'Var', (110, 115))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumor', 'Disease', (23, 28))	('tumor', 'Disease', (122, 127))
268210	32243837	Results reported here indicate that KMT2D upregulates Per2 expression and indirectly represses tumor-promoting glycolysis via Per2 activation.	('activation', 'PosReg', (131, 141))	('tumor', 'Disease', (95, 100))	('Per2', 'Gene', (126, 130))	('KMT2D', 'Var', (36, 41))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('expression', 'MPA', (59, 69))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('represses', 'NegReg', (85, 94))	('Per2', 'Gene', (54, 58))	('upregulates', 'PosReg', (42, 53))
268212	32243837	Therefore, KMT2D-mediated Per2 activation represents a previously unknown tumor-suppressive mechanism that links an epigenetic tumor suppressor to a circadian rhythm regulator.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('Per2', 'Gene', (26, 30))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Disease', (127, 132))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('epigenetic', 'Var', (116, 126))	('tumor', 'Disease', (74, 79))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('activation', 'PosReg', (31, 41))
268215	32243837	Taken together, our findings reveal a tumor-suppressive mechanism in which KMT2D indirectly downregulates glycolytic genes by enhancing Per2 expression via super-enhancer activation and thereby suppresses LUAD.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('suppresses', 'NegReg', (194, 204))	('Per2', 'Gene', (136, 140))	('downregulates', 'NegReg', (92, 105))	('enhancing', 'PosReg', (126, 135))	('KMT2D', 'Var', (75, 80))	('LUAD', 'MPA', (205, 209))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('expression', 'MPA', (141, 151))	('glycolytic genes', 'Gene', (106, 122))
268265	32243837	Publicly available PER2 ChIP-seq data for mouse (GSE3997) were reanalyzed by using six samples (GSM982733, GSM982734, GSM982735, GSM982736, GSM982737 and GSM982738).	('GSM982735', 'Var', (118, 127))	('mouse', 'Species', '10090', (42, 47))	('GSM982737', 'Var', (140, 149))	('GSM982736', 'Var', (129, 138))	('GSE3997', 'Chemical', '-', (49, 56))	('GSM982738', 'Var', (154, 163))	('GSM982734', 'Var', (107, 116))	('GSM982733', 'Var', (96, 105))
268303	32243837	Of note, the mini-KMT2D construct was previously described as MLL4fusion construct (1358-1572aa/4507-5537aa).	('1358-1572aa/4507-5537aa', 'Var', (84, 107))	('MLL4', 'Gene', (62, 66))	('MLL4', 'Gene', '8085', (62, 66))	('mini-KMT2D', 'Gene', (13, 23))	('mini-KMT2D', 'Gene', '8085', (13, 23))
268313	30799957	They generate comprehensive lists of genomic and epigenomic alterations present in diverse tumor samples.	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor', 'Disease', (91, 96))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('epigenomic alterations', 'Var', (49, 71))
268316	30799957	These include frequent mutations of several genes (TP53, PIK3CA, CDKN2A, NOTCH1, and MET) as well as copy number gain in EGFR, CCND1, and PIK3CA.	('copy number', 'Var', (101, 112))	('CDKN2A', 'Gene', '1029', (65, 71))	('CCND1', 'Gene', '595', (127, 132))	('MET', 'Gene', (85, 88))	('PIK3CA', 'Gene', '5290', (57, 63))	('EGFR', 'Gene', '1956', (121, 125))	('TP53', 'Gene', (51, 55))	('PIK3CA', 'Gene', '5290', (138, 144))	('EGFR', 'Gene', (121, 125))	('PIK3CA', 'Gene', (57, 63))	('PIK3CA', 'Gene', (138, 144))	('mutations', 'Var', (23, 32))	('gain', 'PosReg', (113, 117))	('CCND1', 'Gene', (127, 132))	('CDKN2A', 'Gene', (65, 71))	('TP53', 'Gene', '7157', (51, 55))	('NOTCH1', 'Gene', '4851', (73, 79))	('NOTCH1', 'Gene', (73, 79))
268317	30799957	Based on the recently identified mutations in HNSCCs, the major pathologic pathways implicated in the tumorigenesis of HNSCC include dysregulation of four processes: 1) cellular survival and proliferation (eg, TP53, EGFR, MET, and PIK3CA); 2) cell-cycle control (eg, CDKN2A and CCND1); 3) cellular differentiation (eg, NOTCH1); and 4) adhesion and invasion signaling (eg, FAT1).	('CDKN2A', 'Gene', '1029', (267, 273))	('NOTCH1', 'Gene', '4851', (319, 325))	('mutations', 'Var', (33, 42))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('FAT1', 'Gene', '2195', (372, 376))	('EGFR', 'Gene', (216, 220))	('PIK3CA', 'Gene', '5290', (231, 237))	('TP53', 'Gene', (210, 214))	('CCND1', 'Gene', '595', (278, 283))	('invasion signaling', 'CPA', (348, 366))	('CCND1', 'Gene', (278, 283))	('EGFR', 'Gene', '1956', (216, 220))	('tumor', 'Disease', (102, 107))	('TP53', 'Gene', '7157', (210, 214))	('FAT1', 'Gene', (372, 376))	('PIK3CA', 'Gene', (231, 237))	('CDKN2A', 'Gene', (267, 273))	('HNSCCs', 'Gene', (46, 52))	('cellular differentiation', 'CPA', (289, 313))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('NOTCH1', 'Gene', (319, 325))	('cellular survival', 'CPA', (169, 186))	('cell-cycle control', 'CPA', (243, 261))
268319	30799957	Alterations of these genes are most frequently seen in alcohol and tobacco-related HNSCC.	('seen', 'Reg', (47, 51))	('Alterations', 'Var', (0, 11))	('alcohol', 'Chemical', 'MESH:D000438', (55, 62))	('tobacco', 'Species', '4097', (67, 74))
268321	30799957	Mutations in the tumor suppressor P53(TP53) gene are present in about 70% of HNSCC.	('tumor', 'Disease', (17, 22))	('P53', 'Gene', (39, 42))	('TP53', 'Gene', (38, 42))	('P53', 'Gene', '7157', (39, 42))	('P53', 'Gene', (34, 37))	('Mutations', 'Var', (0, 9))	('HNSCC', 'Disease', (77, 82))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('P53', 'Gene', '7157', (34, 37))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('TP53', 'Gene', '7157', (38, 42))
268322	30799957	Missense mutations in TP53, including those at codons R248, R273, G245, R175, R282, and H179, are the most frequent hotspot mutations in HNSCC.	('R273', 'Var', (60, 64))	('R175', 'Var', (72, 76))	('R282', 'Var', (78, 82))	('G245', 'Var', (66, 70))	('TP53', 'Gene', '7157', (22, 26))	('H179', 'Var', (88, 92))	('TP53', 'Gene', (22, 26))	('Missense mutations', 'Var', (0, 18))
268323	30799957	Two thousand four hundred ninety-eight samples in seven studies (Head and Neck Squamous Cell Carcinoma [Broad, Science 2011]; Head and Neck Squamous Cell Carcinoma [Johns Hopkins, Science 2011]; Head and Neck Squamous Cell Carcinoma [TCGA, Nature 2015]; Head and Neck Squamous Cell Carcinoma [TCGA, PanCancer Atlas]; Head and Neck Squamous Cell Carcinoma [TCGA, Provisional]; Oral Squamous Cell Carcinoma [MD Anderson, Cancer Discov 2013]) showed 62.7% of somatic mutation and 45.2% of missense mutations (http://www.cbioportal.org/).	('Head and Neck Squamous Cell Carcinoma', 'Phenotype', 'HP:0012288', (65, 102))	('Head and Neck Squamous Cell Carcinoma', 'Disease', 'MESH:D000077195', (195, 232))	('missense mutations', 'Var', (486, 504))	('Carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('Head and Neck Squamous Cell Carcinoma', 'Phenotype', 'HP:0012288', (254, 291))	('Head and Neck Squamous Cell Carcinoma', 'Phenotype', 'HP:0012288', (317, 354))	('Head and Neck Squamous Cell Carcinoma', 'Disease', 'MESH:D000077195', (65, 102))	('Carcinoma', 'Phenotype', 'HP:0030731', (282, 291))	('Carcinoma', 'Phenotype', 'HP:0030731', (345, 354))	('Cancer', 'Phenotype', 'HP:0002664', (302, 308))	('Head and Neck Squamous Cell Carcinoma', 'Phenotype', 'HP:0012288', (126, 163))	('Head and Neck Squamous Cell Carcinoma', 'Disease', 'MESH:D000077195', (254, 291))	('Carcinoma', 'Phenotype', 'HP:0030731', (154, 163))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (79, 102))	('Head and Neck Squamous Cell Carcinoma', 'Disease', 'MESH:D000077195', (317, 354))	('Head and Neck Squamous Cell Carcinoma', 'Phenotype', 'HP:0012288', (195, 232))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (140, 163))	('Oral Squamous Cell Carcinoma', 'Disease', 'MESH:D002294', (376, 404))	('Head and Neck Squamous Cell Carcinoma', 'Disease', 'MESH:D000077195', (126, 163))	('Carcinoma', 'Phenotype', 'HP:0030731', (223, 232))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (268, 291))	('Oral Squamous Cell Carcinoma', 'Disease', (376, 404))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (331, 354))	('Cancer', 'Phenotype', 'HP:0002664', (419, 425))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (209, 232))
268324	30799957	TP53 mutation was markedly higher in metastatic HNSCC.	('higher', 'Reg', (27, 33))	('TP53', 'Gene', '7157', (0, 4))	('metastatic HNSCC', 'Disease', (37, 53))	('TP53', 'Gene', (0, 4))	('mutation', 'Var', (5, 13))
268325	30799957	TP53 mutation involves varieties of proteins that contribute to tumorigenesis and tumor progression.	('TP53', 'Gene', '7157', (0, 4))	('involves', 'Reg', (14, 22))	('tumor', 'Disease', (64, 69))	('contribute', 'Reg', (50, 60))	('TP53', 'Gene', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('proteins', 'Protein', (36, 44))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Disease', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('mutation', 'Var', (5, 13))
268328	30799957	Moreover, tumors of the larynx and hypopharynx have the highest TP53 mutation rate (83.5%).	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('tumors', 'Disease', 'MESH:D009369', (10, 16))	('tumors', 'Disease', (10, 16))	('tumors', 'Phenotype', 'HP:0002664', (10, 16))	('tumors of the larynx and hypopharynx', 'Phenotype', 'HP:0100638', (10, 46))	('mutation', 'Var', (69, 77))	('TP53', 'Gene', '7157', (64, 68))	('TP53', 'Gene', (64, 68))
268329	30799957	Tumors of the tongue and oral cavity have a TP53 mutation rate of 75.6%, and those of the oropharynx (including the tonsils), and base of the tongue have the lowest TP53 mutation rate (28.6%).	('TP53', 'Gene', (165, 169))	('Tumors of the tongue', 'Phenotype', 'HP:0100648', (0, 20))	('Tumors of the tongue and oral cavity', 'Phenotype', 'HP:0100649', (0, 36))	('mutation', 'Var', (49, 57))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('TP53', 'Gene', '7157', (165, 169))	('TP53', 'Gene', '7157', (44, 48))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('TP53', 'Gene', (44, 48))
268330	30799957	Previous studies have shown that TP53 mutation correlated with resistance to chemotherapy drugs such as cisplatin, doxorubicin, and paclitaxel.	('cisplatin', 'Chemical', 'MESH:D002945', (104, 113))	('paclitaxel', 'Chemical', 'MESH:D017239', (132, 142))	('TP53', 'Gene', '7157', (33, 37))	('resistance to chemotherapy drugs', 'MPA', (63, 95))	('doxorubicin', 'MPA', (115, 126))	('correlated', 'Reg', (47, 57))	('TP53', 'Gene', (33, 37))	('mutation', 'Var', (38, 46))	('doxorubicin', 'Chemical', 'MESH:D004317', (115, 126))
268331	30799957	It has been recently further demonstrated that cisplatin resistance was associated with aneuploidy of chromosome 17, increased TP53 copy numbers, and overexpression of mutant variant R248L.	('R248L', 'Var', (183, 188))	('increased', 'PosReg', (117, 126))	('aneuploidy', 'Disease', (88, 98))	('cisplatin', 'MPA', (47, 56))	('overexpression', 'PosReg', (150, 164))	('R248L', 'Mutation', 'rs11540652', (183, 188))	('cisplatin', 'Chemical', 'MESH:D002945', (47, 56))	('TP53', 'Gene', '7157', (127, 131))	('TP53', 'Gene', (127, 131))
268332	30799957	TP53 mutation has also been indicated for assessment of postoperative radiotherapy.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('mutation', 'Var', (5, 13))
268335	30799957	The value of TP53 mutation in diagnosis is different between subtypes.	('TP53', 'Gene', '7157', (13, 17))	('TP53', 'Gene', (13, 17))	('mutation', 'Var', (18, 26))
268337	30799957	Perrone et al categorized TP53 mutation significance based on the transactivation activity as functional, partially functional, or nonfunctional.	('TP53', 'Gene', (26, 30))	('mutation', 'Var', (31, 39))	('transactivation activity', 'MPA', (66, 90))	('TP53', 'Gene', '7157', (26, 30))
268339	30799957	Accumulating evidence suggests that gain of function (GOF) of TP53 mutants as well mediates drug resistance.	('gain of function', 'PosReg', (36, 52))	('TP53', 'Gene', '7157', (62, 66))	('mediates', 'Reg', (83, 91))	('TP53', 'Gene', (62, 66))	('mutants', 'Var', (67, 74))	('drug resistance', 'CPA', (92, 107))	('drug resistance', 'Phenotype', 'HP:0020174', (92, 107))
268340	30799957	Another large study classified TP53 mutation as disruptive and nondisruptive, based on alteration of DNA binding.	('alteration', 'Reg', (87, 97))	('TP53', 'Gene', '7157', (31, 35))	('TP53', 'Gene', (31, 35))	('DNA binding', 'Interaction', (101, 112))	('mutation', 'Var', (36, 44))
268341	30799957	Disruptive TP53 mutation strongly predicted locoregional recurrence driven by tumor cell radioresistance.	('locoregional', 'Disease', (44, 56))	('predicted', 'Reg', (34, 43))	('mutation', 'Var', (16, 24))	('TP53', 'Gene', '7157', (11, 15))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('TP53', 'Gene', (11, 15))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Disease', (78, 83))
268343	30799957	Evolutionary action (EATP53), a novel computational approach, has been applied to stratify tumor patients with TP53 mutation as high- or low risk.	('TP53', 'Gene', '7157', (111, 115))	('mutation', 'Var', (116, 124))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('TP53', 'Gene', (111, 115))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('TP53', 'Gene', '7157', (23, 27))	('TP53', 'Gene', (23, 27))	('tumor', 'Disease', (91, 96))	('patients', 'Species', '9606', (97, 105))
268345	30799957	High-risk mutations promote invasion, metastasis, as well as cisplatin resistance in head and neck cancer cell lines, as they acquired oncogenic GOF properties, while low-risk mutations retained wild-type (WT) TP53 activity.	('head and neck cancer', 'Phenotype', 'HP:0012288', (85, 105))	('cisplatin resistance', 'MPA', (61, 81))	('TP53', 'Gene', (210, 214))	('cisplatin', 'Chemical', 'MESH:D002945', (61, 70))	('promote', 'PosReg', (20, 27))	('invasion', 'CPA', (28, 36))	('mutations', 'Var', (10, 19))	('neck cancer', 'Disease', 'MESH:D006258', (94, 105))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('metastasis', 'CPA', (38, 48))	('TP53', 'Gene', '7157', (210, 214))	('neck cancer', 'Disease', (94, 105))
268346	30799957	Different effect of TP53 mutation on cisplatin response has been observed in vitro and in vivo.	('TP53', 'Gene', (20, 24))	('cisplatin response', 'MPA', (37, 55))	('mutation', 'Var', (25, 33))	('cisplatin', 'Chemical', 'MESH:D002945', (37, 46))	('TP53', 'Gene', '7157', (20, 24))
268347	30799957	Mice with HNSCC harboring WT or low-risk mutations responded well to cisplatin treatment.	('mutations', 'Var', (41, 50))	('cisplatin', 'Chemical', 'MESH:D002945', (69, 78))	('Mice', 'Species', '10090', (0, 4))	('responded', 'Reg', (51, 60))
268348	30799957	Quite the opposite, TP53 null type or high-risk TP53 mutations failed to show any growth inhibition with cisplatin therapy.	('TP53', 'Gene', '7157', (48, 52))	('TP53', 'Gene', (20, 24))	('TP53', 'Gene', (48, 52))	('mutations', 'Var', (53, 62))	('cisplatin', 'Chemical', 'MESH:D002945', (105, 114))	('TP53', 'Gene', '7157', (20, 24))
268350	30799957	The high-risk TP53 mutations were associated with decreased OS.	('decreased', 'NegReg', (50, 59))	('TP53', 'Gene', (14, 18))	('TP53', 'Gene', '7157', (14, 18))	('mutations', 'Var', (19, 28))
268351	30799957	Researchers have explored introduction of exogenous WT TP53 into HNSCC cells, or reactivation of some level of WT function in mutant p53-bearing cells, otherwise promotion of mutant TP53 degradation.	('promotion', 'PosReg', (162, 171))	('TP53', 'Gene', '7157', (182, 186))	('TP53', 'Gene', (182, 186))	('degradation', 'MPA', (187, 198))	('TP53', 'Gene', '7157', (55, 59))	('TP53', 'Gene', (55, 59))	('p53', 'Gene', '7157', (133, 136))	('p53', 'Gene', (133, 136))	('mutant', 'Var', (175, 181))	('mutant', 'Var', (126, 132))
268352	30799957	Of all the compounds that restore WT activity, the only drug directly targeting mutant TP53 that has reached the clinical stage is PRIMA-1(met)/APR-246.	('TP53', 'Gene', '7157', (87, 91))	('PRIMA-1', 'Gene', (131, 138))	('mutant', 'Var', (80, 86))	('APR', 'Gene', '5366', (144, 147))	('TP53', 'Gene', (87, 91))	('APR', 'Gene', (144, 147))	('PRIMA-1', 'Gene', '145270', (131, 138))
268354	30799957	In addition to targeting mutant p53 directly, investigators have used strategies targeting mutant TP53-regulated downstream targets and signaling pathways.	('p53', 'Gene', (32, 35))	('p53', 'Gene', '7157', (32, 35))	('TP53', 'Gene', '7157', (98, 102))	('mutant', 'Var', (91, 97))	('TP53', 'Gene', (98, 102))
268355	30799957	Mutant TP53 proteins are believed to achieve GOF activity by interacting with other molecular alterations that coexist in HNSCC.	('activity', 'MPA', (49, 57))	('TP53', 'Gene', '7157', (7, 11))	('TP53', 'Gene', (7, 11))	('proteins', 'Protein', (12, 20))	('interacting', 'Reg', (61, 72))	('Mutant', 'Var', (0, 6))
268358	30799957	A genomic analysis of human HNSCCs detected that CDKN2A suppresses the oncogenic function of TP53 mutation that promotes malignant progression, and the prognostic value of mutant p53 needs to be considered in the context of CDKN2A.	('mutant', 'Var', (172, 178))	('p53', 'Gene', (179, 182))	('CDKN2A', 'Gene', '1029', (49, 55))	('promotes', 'PosReg', (112, 120))	('human', 'Species', '9606', (22, 27))	('mutation', 'Var', (98, 106))	('oncogenic function', 'CPA', (71, 89))	('p53', 'Gene', '7157', (179, 182))	('CDKN2A', 'Gene', '1029', (224, 230))	('TP53', 'Gene', '7157', (93, 97))	('TP53', 'Gene', (93, 97))	('suppresses', 'NegReg', (56, 66))	('CDKN2A', 'Gene', (224, 230))	('CDKN2A', 'Gene', (49, 55))	('malignant progression', 'CPA', (121, 142))
268359	30799957	The survival of patients with HNSCCs bearing co-occurring high-risk TP53 mutation and CDKN2A homozygous deletions was extremely lower than that of patients with tumors in which high-risk TP53 mutation did not contain CDKN2A homozygous deletions, or that of patients with tumors in which homozygous CDKN2A deletions coexisted with either low-risk TP53 mutation or potential loss-of-function mutations in TP53 (high- and low risk according to the EATP53 classification system).	('tumor', 'Phenotype', 'HP:0002664', (271, 276))	('tumors', 'Disease', (161, 167))	('mutations', 'Var', (390, 399))	('tumors', 'Disease', (271, 277))	('patients', 'Species', '9606', (16, 24))	('CDKN2A', 'Gene', (217, 223))	('CDKN2A', 'Gene', (298, 304))	('TP53', 'Gene', (187, 191))	('TP53', 'Gene', (68, 72))	('TP53', 'Gene', (403, 407))	('TP53', 'Gene', (346, 350))	('deletions', 'Var', (305, 314))	('tumors', 'Disease', 'MESH:D009369', (271, 277))	('tumors', 'Disease', 'MESH:D009369', (161, 167))	('patients', 'Species', '9606', (147, 155))	('patients', 'Species', '9606', (257, 265))	('CDKN2A', 'Gene', '1029', (217, 223))	('CDKN2A', 'Gene', '1029', (298, 304))	('mutation', 'Var', (73, 81))	('loss-of-function', 'NegReg', (373, 389))	('TP53', 'Gene', (447, 451))	('TP53', 'Gene', '7157', (187, 191))	('TP53', 'Gene', '7157', (403, 407))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('lower', 'NegReg', (128, 133))	('TP53', 'Gene', '7157', (346, 350))	('TP53', 'Gene', '7157', (68, 72))	('CDKN2A', 'Gene', (86, 92))	('tumors', 'Phenotype', 'HP:0002664', (161, 167))	('tumors', 'Phenotype', 'HP:0002664', (271, 277))	('CDKN2A', 'Gene', '1029', (86, 92))	('TP53', 'Gene', '7157', (447, 451))
268360	30799957	Preliminary findings from TCGA Head and Neck Cancer have detected amplifications or putative activating mutations in PIK3CA in 30% of 279 HNSCC tumors, which overlap with WT and mutant TP53 subsets.	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('mutations', 'Var', (104, 113))	('Head and Neck Cancer', 'Disease', 'MESH:D006258', (31, 51))	('TP53', 'Gene', (185, 189))	('amplifications', 'Var', (66, 80))	('PIK3CA', 'Gene', (117, 123))	('Cancer', 'Phenotype', 'HP:0002664', (45, 51))	('Head and Neck Cancer', 'Phenotype', 'HP:0012288', (31, 51))	('activating', 'PosReg', (93, 103))	('PIK3CA', 'Gene', '5290', (117, 123))	('HNSCC tumors', 'Disease', (138, 150))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('HNSCC tumors', 'Disease', 'MESH:D000077195', (138, 150))	('TP53', 'Gene', '7157', (185, 189))
268361	30799957	The aforementioned studies indicate that increase in phosphoinositide 3-kinase (PI3K)/Akt activation has been linked to frequent alterations in TP53 via multiple mechanisms.	('TP53', 'Gene', '7157', (144, 148))	('Akt', 'Gene', (86, 89))	('phosphoinositide 3-kinase', 'Gene', (53, 78))	('activation', 'PosReg', (90, 100))	('TP53', 'Gene', (144, 148))	('Akt', 'Gene', '207', (86, 89))	('alterations', 'Var', (129, 140))	('phosphoinositide 3-kinase', 'Gene', '5290', (53, 78))	('increase', 'PosReg', (41, 49))
268364	30799957	The dual PI3K/PLK inhibitor rigosertib has such potent antiproliferative effects on patient tumor xenografts, which carried combination of a PIK3CA-activating event driven by amplification or mutation and a TP53-inactivating event driven by either human papillomavirus (HPV)-negative or nonsense TP53 mutation.	('PLK', 'Gene', '5347', (14, 17))	('rigosertib', 'Gene', (28, 38))	('TP53', 'Gene', '7157', (296, 300))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('TP53', 'Gene', '7157', (207, 211))	('mutation', 'Var', (192, 200))	('antiproliferative effects', 'MPA', (55, 80))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('PLK', 'Gene', (14, 17))	('PIK3CA', 'Gene', '5290', (141, 147))	('TP53', 'Gene', (296, 300))	('amplification', 'Var', (175, 188))	('human papillomavirus', 'Species', '10566', (248, 268))	('TP53', 'Gene', (207, 211))	('HPV', 'Species', '10566', (270, 273))	('patient', 'Species', '9606', (84, 91))	('rigosertib', 'Chemical', 'MESH:C507134', (28, 38))	('PIK3CA', 'Gene', (141, 147))	('tumor', 'Disease', (92, 97))
268367	30799957	CDKN2A mutation is considered as "noncoding mutations", "inactivation", or "loss of function".	('loss of function', 'NegReg', (76, 92))	('mutation', 'Var', (7, 15))	('CDKN2A', 'Gene', (0, 6))	('inactivation', 'Var', (57, 69))	('CDKN2A', 'Gene', '1029', (0, 6))
268369	30799957	Most of the mutations in CDKN2A were found in exon 2 of the gene.	('mutations', 'Var', (12, 21))	('CDKN2A', 'Gene', '1029', (25, 31))	('CDKN2A', 'Gene', (25, 31))
268370	30799957	However, these are likely insufficient to drive tumorigenesis by CDKN2A mutations themselves.	('CDKN2A', 'Gene', '1029', (65, 71))	('mutations', 'Var', (72, 81))	('tumor', 'Disease', (48, 53))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('CDKN2A', 'Gene', (65, 71))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
268371	30799957	For example, CDKN2A mutations in benign epithelial lesions have low potential to transform into malignancy.	('malignancy', 'Disease', 'MESH:D009369', (96, 106))	('malignancy', 'Disease', (96, 106))	('CDKN2A', 'Gene', (13, 19))	('transform', 'Reg', (81, 90))	('CDKN2A', 'Gene', '1029', (13, 19))	('mutations', 'Var', (20, 29))
268376	30799957	HPV-positive HNSCC rarely has CDKN2A mutation and thus has the p16INK4a function; those patients are significantly less likely to develop a locoregional recurrence.	('less', 'NegReg', (115, 119))	('HPV', 'Species', '10566', (0, 3))	('mutation', 'Var', (37, 45))	('locoregional recurrence', 'CPA', (140, 163))	('CDKN2A', 'Gene', (30, 36))	('patients', 'Species', '9606', (88, 96))	('CDKN2A', 'Gene', '1029', (30, 36))	('p16INK4a', 'Gene', (63, 71))	('p16INK4a', 'Gene', '1029', (63, 71))
268377	30799957	On the other hand, up to 90% of HPV-negative HNSCCs have loss of p16INK4a function as a result of CDKN2A mutation, promoter methylation, or gene/chromosome 9p21 deletion.	('p21', 'Gene', (157, 160))	('mutation', 'Var', (105, 113))	('p21', 'Gene', '644914', (157, 160))	('CDKN2A', 'Gene', (98, 104))	('promoter', 'MPA', (115, 123))	('p16INK4a', 'Gene', (65, 73))	('loss', 'NegReg', (57, 61))	('HPV', 'Species', '10566', (32, 35))	('CDKN2A', 'Gene', '1029', (98, 104))	('function', 'MPA', (74, 82))	('p16INK4a', 'Gene', '1029', (65, 73))
268378	30799957	But the recent study found that CDKN2A mutation still reflects the p16INK4a expression in HPV-negative HNSCC.	('p16INK4a', 'Gene', (67, 75))	('mutation', 'Var', (39, 47))	('HPV', 'Species', '10566', (90, 93))	('CDKN2A', 'Gene', (32, 38))	('CDKN2A', 'Gene', '1029', (32, 38))	('p16INK4a', 'Gene', '1029', (67, 75))	('reflects', 'Reg', (54, 62))
268379	30799957	Loss of CDKN2A function as a result of CDKN2A mutation induced p16INK4a mRNA transcription strongly.	('CDKN2A', 'Gene', (8, 14))	('CDKN2A', 'Gene', (39, 45))	('CDKN2A', 'Gene', '1029', (8, 14))	('CDKN2A', 'Gene', '1029', (39, 45))	('induced', 'PosReg', (55, 62))	('p16INK4a', 'Gene', (63, 71))	('mutation', 'Var', (46, 54))	('p16INK4a', 'Gene', '1029', (63, 71))
268380	30799957	Hence, p16INK4a overexpression is associated with CDKN2A mutation in a subset of cases.	('mutation', 'Var', (57, 65))	('associated', 'Reg', (34, 44))	('CDKN2A', 'Gene', (50, 56))	('p16INK4a', 'Gene', '1029', (7, 15))	('overexpression', 'PosReg', (16, 30))	('CDKN2A', 'Gene', '1029', (50, 56))	('p16INK4a', 'Gene', (7, 15))
268383	30799957	Mutations, amplification, and overexpression of this gene, which alters cell-cycle progression, are observed frequently in a variety of tumors and may contribute to tumorigenesis.	('tumors', 'Disease', (136, 142))	('tumors', 'Disease', 'MESH:D009369', (136, 142))	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('overexpression', 'PosReg', (30, 44))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('Mutations', 'Var', (0, 9))	('contribute', 'Reg', (151, 161))	('cell-cycle progression', 'CPA', (72, 94))	('alters', 'Reg', (65, 71))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('tumor', 'Disease', (136, 141))	('amplification', 'Var', (11, 24))	('tumor', 'Disease', (165, 170))
268386	30799957	CCND1 amplification had a statistically significant association with recurrence, distant metastasis, platinum and cisplatin resistance, and EGFR-inhibitor resistance.	('EGFR', 'Gene', (140, 144))	('platinum', 'Chemical', 'MESH:D010984', (101, 109))	('significant association', 'Reg', (40, 63))	('cisplatin', 'Chemical', 'MESH:D002945', (114, 123))	('distant metastasis', 'CPA', (81, 99))	('CCND1', 'Gene', '595', (0, 5))	('CCND1', 'Gene', (0, 5))	('amplification', 'Var', (6, 19))	('EGFR', 'Gene', '1956', (140, 144))	('recurrence', 'CPA', (69, 79))	('platinum', 'CPA', (101, 109))
268387	30799957	Allele A may be a risk factor for upper aerodigestive tract cancer, especially in nonalcoholics.	('Allele A', 'Var', (0, 8))	('risk factor', 'Reg', (18, 29))	('alcohol', 'Chemical', 'MESH:D000438', (85, 92))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('cancer', 'Disease', (60, 66))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
268388	30799957	Patients of recurrent and metastatic head and neck cancer with CCND1 alterations have poor OS rate (Figure 4).	('head and neck cancer', 'Phenotype', 'HP:0012288', (37, 57))	('CCND1', 'Gene', '595', (63, 68))	('alterations', 'Var', (69, 80))	('neck cancer', 'Disease', 'MESH:D006258', (46, 57))	('neck cancer', 'Disease', (46, 57))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('Patients', 'Species', '9606', (0, 8))	('metastatic', 'CPA', (26, 36))	('CCND1', 'Gene', (63, 68))
268397	30799957	A study in vitro explored the relationship between deregulated cyclin D1 expression and sensitivity to gefitinib to determine whether this frequently occurring oncogenic change affected the cellular response to gefitinib.	('affected', 'Reg', (177, 185))	('gefitinib', 'Chemical', 'MESH:D000077156', (103, 112))	('cyclin D1', 'Gene', '595', (63, 72))	('gefitinib', 'Chemical', 'MESH:D000077156', (211, 220))	('deregulated', 'Var', (51, 62))	('cyclin D1', 'Gene', (63, 72))	('cellular response to gefitinib', 'MPA', (190, 220))
268402	30799957	Upon ligand binding, functions of NOTCH1 in oral SCC are considered tumor-suppressive.	('tumor', 'Disease', (68, 73))	('ligand', 'Reg', (5, 11))	('NOTCH1', 'Gene', '4851', (34, 40))	('oral SCC', 'Disease', (44, 52))	('NOTCH1', 'Gene', (34, 40))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('binding', 'Interaction', (12, 19))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('functions', 'Var', (21, 30))
268403	30799957	In tongue cancer xenografts, the presence of NOTCH1 caused a dramatic tumor reduction compared to tumors in which this gene was absent.	('tumors', 'Disease', (98, 104))	('reduction', 'NegReg', (76, 85))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('NOTCH1', 'Gene', (45, 51))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('tumors', 'Disease', 'MESH:D009369', (98, 104))	('tumor', 'Disease', (70, 75))	('tongue cancer', 'Disease', (3, 16))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('presence', 'Var', (33, 41))	('tongue cancer', 'Disease', 'MESH:D014062', (3, 16))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('NOTCH1', 'Gene', '4851', (45, 51))	('tumor', 'Disease', (98, 103))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
268405	30799957	Point mutations affecting this gene occurred in 11% of the HNSCC tumors.	('HNSCC tumors', 'Disease', 'MESH:D000077195', (59, 71))	('occurred', 'Reg', (36, 44))	('HNSCC tumors', 'Disease', (59, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('Point mutations', 'Var', (0, 15))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
268406	30799957	Missense mutations in NOTCH1 are considered tumor-suppressive in OSCC.	('NOTCH1', 'Gene', '4851', (22, 28))	('NOTCH1', 'Gene', (22, 28))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('OSCC', 'Disease', (65, 69))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumor', 'Disease', (44, 49))	('Missense mutations', 'Var', (0, 18))
268407	30799957	Notably, OSCC patients with NOTCH pathway mutations (AR, ARNT, EP300, CREBBP, JAK2, JAK, NOTCH1, NOTCH2, NOTCH3, and PARP1) were 3.3 times more likely to die with recurrent disease compared to those who did not have these alterations.	('CREBBP', 'Gene', '1387', (70, 76))	('OSCC', 'Disease', (9, 13))	('NOTCH1', 'Gene', '4851', (89, 95))	('patients', 'Species', '9606', (14, 22))	('PARP1', 'Gene', '142', (117, 122))	('JAK2', 'Gene', '3717', (78, 82))	('NOTCH2', 'Gene', '4853', (97, 103))	('NOTCH3', 'Gene', '4854', (105, 111))	('EP300', 'Gene', '2033', (63, 68))	('JAK2', 'Gene', (78, 82))	('CREBBP', 'Gene', (70, 76))	('recurrent disease', 'Disease', (163, 180))	('JAK', 'Var', (84, 87))	('PARP1', 'Gene', (117, 122))	('NOTCH3', 'Gene', (105, 111))	('EP300', 'Gene', (63, 68))	('NOTCH2', 'Gene', (97, 103))	('NOTCH1', 'Gene', (89, 95))	('ARNT', 'Gene', '405', (57, 61))	('NOTCH pathway', 'Gene', (28, 41))	('ARNT', 'Gene', (57, 61))
268408	30799957	The NOTCH1 mutation status recently served as biomarker for the identification of HNSCC with higher sensitivity to radio- and chemotherapy, as significant association of NOTCH1 mutations with improved localregional control and increased overall survival was observed after chemora-diotherapy.	('improved', 'PosReg', (192, 200))	('localregional control', 'CPA', (201, 222))	('increased', 'PosReg', (227, 236))	('NOTCH1', 'Gene', (170, 176))	('NOTCH1', 'Gene', '4851', (170, 176))	('mutations', 'Var', (177, 186))	('NOTCH1', 'Gene', '4851', (4, 10))	('overall survival', 'CPA', (237, 253))	('NOTCH1', 'Gene', (4, 10))
268410	30799957	For HNSCC it is should be carefully evaluated given evidence of an increased frequency of squamous cell carcinoma in vivo with genetic reductional gamma-secretase activity.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (90, 113))	('genetic', 'Var', (127, 134))	('reductional', 'NegReg', (135, 146))	('squamous cell carcinoma', 'Disease', (90, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (90, 113))	('activity', 'MPA', (163, 171))	('gamma-secretase', 'Protein', (147, 162))
268411	30799957	Analysis of recurrent and metastatic head and neck cancer suggests a similar trend toward better 5-year (60 months) OS in patients with alterations in NOTCH1, but after 5 years the OS in patients with alterations was worse; however, this was not statistically significant (Figure 4).	('patients', 'Species', '9606', (187, 195))	('neck cancer', 'Disease', 'MESH:D006258', (46, 57))	('neck cancer', 'Disease', (46, 57))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('NOTCH1', 'Gene', '4851', (151, 157))	('alterations', 'Var', (136, 147))	('patients', 'Species', '9606', (122, 130))	('head and neck cancer', 'Phenotype', 'HP:0012288', (37, 57))	('NOTCH1', 'Gene', (151, 157))
268414	30799957	Furthermore, in NOTCH1 mutant breast cells that lack the extracellular domain, BEZ-235 sensitivity could also be restored by inhibiting gamma-secretase, indicating that naturally cleaved NOTCH1 also confers resistance to PI3K inhibition.	('BEZ-235', 'Chemical', 'MESH:C531198', (79, 86))	('NOTCH1', 'Gene', '4851', (16, 22))	('NOTCH1', 'Gene', (187, 193))	('NOTCH1', 'Gene', (16, 22))	('resistance', 'MPA', (207, 217))	('inhibiting', 'NegReg', (125, 135))	('NOTCH1', 'Gene', '4851', (187, 193))	('mutant', 'Var', (23, 29))
268418	30799957	PIK3CA alterations encoding the key catalytic subunit of PI3K pathway were subsequently found to be prevalent.	('PIK3CA', 'Gene', '5290', (0, 6))	('alterations', 'Var', (7, 18))	('PIK3CA', 'Gene', (0, 6))
268419	30799957	Data from the querying 2,498 samples showed PIK3CA alterations around 29%, including copy number gain (high polysomy or amplification) or mutations (Figure 3).	('PIK3CA', 'Gene', (44, 50))	('alterations', 'Reg', (51, 62))	('PIK3CA', 'Gene', '5290', (44, 50))	('copy', 'MPA', (85, 89))	('mutations', 'Var', (138, 147))
268421	30799957	PIK3CA mutations seem to favor advanced HNSCC, which harbor multiple PI3K-pathway mutations.	('favor', 'PosReg', (25, 30))	('PIK3CA', 'Gene', (0, 6))	('PIK3CA', 'Gene', '5290', (0, 6))	('advanced HNSCC', 'Disease', (31, 45))	('mutations', 'Var', (7, 16))
268422	30799957	PIK3CA copy number gain (high polysomy or amplification) but not PIK3CA mutation was detected to be associated with significantly lower disease-free survival, resulting from an NGS.	('lower', 'NegReg', (130, 135))	('disease-free survival', 'CPA', (136, 157))	('PIK3CA', 'Gene', (0, 6))	('PIK3CA', 'Gene', (65, 71))	('PIK3CA', 'Gene', '5290', (0, 6))	('copy number', 'Var', (7, 18))	('gain', 'PosReg', (19, 23))	('PIK3CA', 'Gene', '5290', (65, 71))
268423	30799957	The most frequent mutations occur in exons 9 and 20, with hotspots at H1047R (eight mutations total), E542K (three mutations), and E545K/G (four mutations).	('E542K', 'Mutation', 'rs121913273', (102, 107))	('E545K', 'SUBSTITUTION', 'None', (131, 136))	('H1047R', 'Chemical', '-', (70, 76))	('E542K', 'Var', (102, 107))	('E545K', 'Var', (131, 136))	('H1047R', 'Var', (70, 76))
268424	30799957	H1047R was more potent than E545K at inducing resistance in PI3K pathway activation.	('H1047R', 'Chemical', '-', (0, 6))	('PI3K pathway activation', 'Pathway', (60, 83))	('E545K', 'Mutation', 'rs104886003', (28, 33))	('inducing', 'Reg', (37, 45))	('H1047R', 'Var', (0, 6))
268425	30799957	PIK3CA canonical and novel mutations increase survival.	('mutations', 'Var', (27, 36))	('PIK3CA', 'Gene', (0, 6))	('increase', 'PosReg', (37, 45))	('PIK3CA', 'Gene', '5290', (0, 6))	('survival', 'CPA', (46, 54))
268426	30799957	These canonical hotspot mutations showed significantly enhanced HNSCC growth compared to overexpression of WT PIK3CA.	('enhanced', 'PosReg', (55, 63))	('HNSCC growth', 'CPA', (64, 76))	('mutations', 'Var', (24, 33))	('PIK3CA', 'Gene', (110, 116))	('PIK3CA', 'Gene', '5290', (110, 116))
268429	30799957	PIK3CA activation either caused by mutation or copy number gain is oncogenic and is thus a commonly activating point mutation with targeted agents.	('PIK3CA', 'Gene', (0, 6))	('copy number gain', 'Var', (47, 63))	('PIK3CA', 'Gene', '5290', (0, 6))	('mutation', 'Var', (35, 43))	('activation', 'PosReg', (7, 17))
268432	30799957	HNSCC cell lines containing hotspots endogenous PIK3CA (H1047R) mutations demonstrated increased sensitivity to PI3K pathway inhibition by the mTOR/PI3K inhibitor BEZ-235 compared to the representative HNSCC cells with WT PIK3CA.	('increased', 'PosReg', (87, 96))	('PIK3CA', 'Gene', (222, 228))	('BEZ-235', 'Chemical', 'MESH:C531198', (163, 170))	('PIK3CA', 'Gene', '5290', (222, 228))	('H1047R', 'Chemical', '-', (56, 62))	('PIK3CA', 'Gene', (48, 54))	('PI3K pathway', 'Pathway', (112, 124))	('sensitivity', 'MPA', (97, 108))	('mutations', 'Var', (64, 73))	('mTOR', 'Gene', '2475', (143, 147))	('PIK3CA', 'Gene', '5290', (48, 54))	('mTOR', 'Gene', (143, 147))
268433	30799957	Furthermore, they were more sensitive to the combination of BEZ-235 plus cetuximab compared to cetuximab alone.	('cetuximab', 'Chemical', 'MESH:D000068818', (73, 82))	('BEZ-235', 'Chemical', 'MESH:C531198', (60, 67))	('sensitive', 'MPA', (28, 37))	('cetuximab', 'Chemical', 'MESH:D000068818', (95, 104))	('combination', 'Interaction', (45, 56))	('BEZ-235', 'Var', (60, 67))
268434	30799957	PIK3CA mutations are more common in HPV-positive HNSCC and are associated with activation of mTOR.	('mTOR', 'Gene', (93, 97))	('HNSCC', 'Disease', (49, 54))	('mTOR', 'Gene', '2475', (93, 97))	('associated', 'Reg', (63, 73))	('PIK3CA', 'Gene', (0, 6))	('common', 'Reg', (26, 32))	('HPV', 'Species', '10566', (36, 39))	('PIK3CA', 'Gene', '5290', (0, 6))	('mutations', 'Var', (7, 16))
268435	30799957	Patient-derived HPV-positive OPSCC tumor-grafts in vivo with PIK3CA (E542K) mutation were also sensitive to a dual mTOR/PI3K inhibitor (BEZ-235), in contrast to PIK3CA WT tumorgrafts.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('PIK3CA', 'Gene', (61, 67))	('PIK3CA', 'Gene', '5290', (61, 67))	('E542K', 'Mutation', 'rs121913273', (69, 74))	('mTOR', 'Gene', '2475', (115, 119))	('BEZ-235', 'Chemical', 'MESH:C531198', (136, 143))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('mTOR', 'Gene', (115, 119))	('PIK3CA', 'Gene', (161, 167))	('tumor', 'Disease', (35, 40))	('sensitive', 'MPA', (95, 104))	('HPV', 'Species', '10566', (16, 19))	('PIK3CA', 'Gene', '5290', (161, 167))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', (171, 176))	('E542K', 'Var', (69, 74))	('Patient', 'Species', '9606', (0, 7))
268436	30799957	These results suggest that mTOR/PI3K inhibitors may have activity against PIK3CA mutant HNSCC, particularly in HPV-positive HNSCC.	('PIK3CA', 'Gene', '5290', (74, 80))	('HNSCC', 'Disease', (88, 93))	('HPV', 'Species', '10566', (111, 114))	('activity', 'MPA', (57, 65))	('mutant', 'Var', (81, 87))	('mTOR', 'Gene', '2475', (27, 31))	('mTOR', 'Gene', (27, 31))	('HPV-positive', 'Disease', (111, 123))	('PIK3CA', 'Gene', (74, 80))
268440	30799957	PIK3CA activating mutations are common in several tumor types and can potentially confer resistance to anti-receptor tyrosine kinase therapy.	('activating', 'PosReg', (7, 17))	('receptor tyrosine kinase', 'Gene', (108, 132))	('receptor tyrosine kinase', 'Gene', '5979', (108, 132))	('PIK3CA', 'Gene', (0, 6))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('PIK3CA', 'Gene', '5290', (0, 6))	('resistance', 'MPA', (89, 99))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Disease', (50, 55))	('mutations', 'Var', (18, 27))
268441	30799957	Hotspots E545K and H1047R confer resistance to MET inhibition in MET-driven models.	('H1047R', 'Var', (19, 25))	('MET', 'MPA', (47, 50))	('E545K', 'Mutation', 'rs104886003', (9, 14))	('E545K', 'Var', (9, 14))	('H1047R', 'Chemical', '-', (19, 25))
268442	30799957	Combined MET/PI3K inhibition leads to enhanced antitumor activity in MET-expressing HNSCC harboring endogenous PIK3CA (H1047R).	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('enhanced', 'PosReg', (38, 46))	('tumor', 'Disease', (51, 56))	('PIK3CA', 'Gene', (111, 117))	('H1047R', 'Var', (119, 125))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('PIK3CA', 'Gene', '5290', (111, 117))	('H1047R', 'Chemical', '-', (119, 125))
268443	30799957	PIK3CA mutations can lead to resistance to MET inhibition, supporting future clinical evaluation of combinations of PI3K and MET inhibitors in common scenarios of malignant neoplasms featuring aberrant MET expression and PIK3CA mutations.	('PIK3CA', 'Gene', '5290', (221, 227))	('neoplasms', 'Phenotype', 'HP:0002664', (173, 182))	('PIK3CA', 'Gene', (0, 6))	('PIK3CA', 'Gene', '5290', (0, 6))	('resistance to MET inhibition', 'MPA', (29, 57))	('PIK3CA', 'Gene', (221, 227))	('malignant neoplasms', 'Disease', 'MESH:D009369', (163, 182))	('malignant neoplasms', 'Disease', (163, 182))	('mutations', 'Var', (7, 16))
268446	30799957	Preclinical studies suggest that PIK3CA and RAS mutations may predict intrinsic resistance to cetuximab, which may be prevented by combination of cetuximab and PI3K and/or mTOR inhibitors in HNSCC patients.	('intrinsic resistance to', 'MPA', (70, 93))	('mTOR', 'Gene', (172, 176))	('patients', 'Species', '9606', (197, 205))	('PIK3CA', 'Gene', '5290', (33, 39))	('cetuximab', 'Chemical', 'MESH:D000068818', (146, 155))	('predict', 'Reg', (62, 69))	('cetuximab', 'Chemical', 'MESH:D000068818', (94, 103))	('HNSCC', 'Disease', (191, 196))	('RAS', 'Gene', (44, 47))	('PIK3CA', 'Gene', (33, 39))	('mutations', 'Var', (48, 57))	('mTOR', 'Gene', '2475', (172, 176))
268449	30799957	TCGA data have detected EGFR alteration in 14.34% cases including 65.0% with EGFR amplification.	('EGFR', 'Gene', '1956', (24, 28))	('EGFR', 'Gene', (24, 28))	('EGFR', 'Gene', '1956', (77, 81))	('EGFR', 'Gene', (77, 81))	('alteration', 'Var', (29, 39))
268450	30799957	High-level EGFR amplifications in ~10% of HNSCC, and polysomy are present in even more.	('EGFR', 'Gene', (11, 15))	('EGFR', 'Gene', '1956', (11, 15))	('amplifications', 'Var', (16, 30))	('HNSCC', 'Disease', (42, 47))
268453	30799957	However, EGFR alteration also has no significant prognoses value in metastatic head and neck cancer analyzed in cBioPortal (Figure 4).	('head and neck cancer', 'Phenotype', 'HP:0012288', (79, 99))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('neck cancer', 'Disease', 'MESH:D006258', (88, 99))	('neck cancer', 'Disease', (88, 99))	('EGFR', 'Gene', '1956', (9, 13))	('EGFR', 'Gene', (9, 13))	('alteration', 'Var', (14, 24))
268455	30799957	EGFR amplification is highly associated with resistance to chemotherapy and radiation in HNSCC.	('EGFR', 'Gene', (0, 4))	('amplification', 'Var', (5, 18))	('HNSCC', 'Disease', (89, 94))	('associated', 'Reg', (29, 39))	('resistance to chemotherapy', 'CPA', (45, 71))	('EGFR', 'Gene', '1956', (0, 4))
268461	30799957	EGFR inhibitors have been used to treat both lung and head and neck cancers with squamous cell histology.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('lung', 'Disease', (45, 49))	('neck cancers', 'Disease', (63, 75))	('EGFR', 'Gene', (0, 4))	('cancers', 'Phenotype', 'HP:0002664', (68, 75))	('inhibitors', 'Var', (5, 15))	('neck cancers', 'Disease', 'MESH:D006258', (63, 75))	('head and neck cancer', 'Phenotype', 'HP:0012288', (54, 74))	('EGFR', 'Gene', '1956', (0, 4))	('head and neck cancers', 'Phenotype', 'HP:0012288', (54, 75))
268468	30799957	Several studies explored the biology, genomics, and patterns of response to EGFR inhibitors to inform identification of potential biomarkers that have shown promise in preclinical studies and clinical trials.	('EGFR', 'Gene', '1956', (76, 80))	('EGFR', 'Gene', (76, 80))	('inhibitors', 'Var', (81, 91))
268470	30799957	Genomic studies suggest that EGFR alteration is more common in HPV-negative tumors compared to HPV-positive tumors.	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('alteration', 'Var', (34, 44))	('HPV', 'Species', '10566', (63, 66))	('HPV-positive tumors', 'Disease', 'MESH:D030361', (95, 114))	('HPV-positive tumors', 'Disease', (95, 114))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('common', 'Reg', (53, 59))	('tumors', 'Disease', (76, 82))	('EGFR', 'Gene', '1956', (29, 33))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('EGFR', 'Gene', (29, 33))	('tumors', 'Disease', (108, 114))	('HPV-negative', 'Disease', (63, 75))	('tumors', 'Disease', 'MESH:D009369', (108, 114))	('HPV', 'Species', '10566', (95, 98))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('HPV-negative', 'NegReg', (63, 75))
268473	30799957	Hepatocyte growth factor (HGF) receptor (MET) is functionally novel in HNSCC with prominent overexpression, and increased copy number and mutations.	('copy', 'MPA', (122, 126))	('overexpression', 'PosReg', (92, 106))	('MET', 'Gene', (41, 44))	('Hepatocyte growth factor (HGF) receptor', 'Gene', '4233', (0, 39))	('increased', 'PosReg', (112, 121))	('HNSCC', 'Disease', (71, 76))	('mutations', 'Var', (138, 147))
268483	30799957	For example, MET mutations are present in up to 20% of patients with resistance to EGFR inhibitors, like cetuximab.	('EGFR', 'Gene', '1956', (83, 87))	('EGFR', 'Gene', (83, 87))	('cetuximab', 'Chemical', 'MESH:D000068818', (105, 114))	('patients', 'Species', '9606', (55, 63))	('MET', 'Var', (13, 16))
268486	30799957	Therefore, patients treated with EGFR inhibitors have a worse prognosis.	('patients', 'Species', '9606', (11, 19))	('inhibitors', 'Var', (38, 48))	('EGFR', 'Gene', '1956', (33, 37))	('EGFR', 'Gene', (33, 37))
268487	30799957	Experimental studies in vitro and in vivo of R/M HNSCC documented a synthetic lethal effect of dual blockade using c-MET (SU11274, PF2341066, and PF04217903) and EGFR TKIs (cetuximab, erlotinib, and gefitinib).	('gefitinib', 'Chemical', 'MESH:D000077156', (199, 208))	('erlotinib', 'Chemical', 'MESH:D000069347', (184, 193))	('c-MET', 'Gene', (115, 120))	('EGFR', 'Gene', '1956', (162, 166))	('synthetic lethal effect', 'MPA', (68, 91))	('EGFR', 'Gene', (162, 166))	('SU11274', 'Var', (122, 129))	('SU11274', 'Chemical', 'MESH:C478479', (122, 129))	('cetuximab', 'Chemical', 'MESH:D000068818', (173, 182))	('c-MET', 'Gene', '4233', (115, 120))	('PF2341066', 'Var', (131, 140))	('PF04217903', 'Var', (146, 156))
268489	30799957	Multiple gene mutations, along with the corresponding protein dysfunction or molecular pathway dysregulations, are causative in the process of carcinogenesis or drug resistance.	('protein dysfunction', 'Disease', (54, 73))	('drug resistance', 'Phenotype', 'HP:0020174', (161, 176))	('carcinogenesis', 'Disease', 'MESH:D063646', (143, 157))	('causative', 'Reg', (115, 124))	('carcinogenesis', 'Disease', (143, 157))	('protein dysfunction', 'Disease', 'MESH:D011488', (54, 73))	('mutations', 'Var', (14, 23))	('molecular pathway', 'Pathway', (77, 94))
268493	30799957	HPV-negative HNSCC featured novel focal deletions in tumor suppressor genes (eg, NOTCH1 and CDKN2A).	('CDKN2A', 'Gene', (92, 98))	('HPV', 'Species', '10566', (0, 3))	('deletions', 'Var', (40, 49))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('NOTCH1', 'Gene', '4851', (81, 87))	('NOTCH1', 'Gene', (81, 87))	('CDKN2A', 'Gene', '1029', (92, 98))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Disease', (53, 58))
268494	30799957	Also, mutations of TP53, CDKN2A, PIK3CA, and NOTCH genes are enriched.	('NOTCH genes', 'Gene', (45, 56))	('PIK3CA', 'Gene', '5290', (33, 39))	('TP53', 'Gene', '7157', (19, 23))	('TP53', 'Gene', (19, 23))	('CDKN2A', 'Gene', (25, 31))	('PIK3CA', 'Gene', (33, 39))	('mutations', 'Var', (6, 15))	('CDKN2A', 'Gene', '1029', (25, 31))
268507	29240723	The molecular pathogenesis of carcinogenesis may be a combination of somatic mutations, and epigenetic and transcriptional alterations.	('epigenetic', 'Var', (92, 102))	('carcinogenesis', 'Disease', (30, 44))	('carcinogenesis', 'Disease', 'MESH:D063646', (30, 44))
268508	29240723	With advances of sequencing and high-throughput DNA microarray analyses, numerous gene alterations manifesting differentially expressed genes (DEGs) have been demonstrated to be correlated with the genesis and progression of tumors.	('tumors', 'Disease', (225, 231))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('alterations', 'Var', (87, 98))	('tumors', 'Disease', 'MESH:D009369', (225, 231))	('correlated', 'Reg', (178, 188))	('tumors', 'Phenotype', 'HP:0002664', (225, 231))
268509	29240723	found a significant association between methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms and p16 and O6-methylguanine-DNA methyltransferase (MGMT) gene promoter methylation in oral squamous cell cancer (OSCC) patients, which suggests that hypermethylation of cancer-related genes may be affected by MTHFR polymorphisms.	('p16', 'Gene', (107, 110))	('oral squamous cell cancer', 'Disease', 'MESH:D002294', (190, 215))	('MTHFR', 'Gene', '4524', (77, 82))	('oral squamous cell cancer', 'Disease', (190, 215))	('MTHFR', 'Gene', '4524', (313, 318))	('cancer', 'Disease', 'MESH:D009369', (273, 279))	('p16', 'Gene', '1029', (107, 110))	('MGMT', 'Gene', (155, 159))	('polymorphisms', 'Var', (89, 102))	('cancer', 'Disease', 'MESH:D009369', (209, 215))	('O6-methylguanine-DNA methyltransferase', 'Gene', (115, 153))	('MTHFR', 'Gene', (77, 82))	('MTHFR', 'Gene', (313, 318))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (195, 215))	('methylenetetrahydrofolate reductase', 'Gene', '4524', (40, 75))	('cancer', 'Disease', (273, 279))	('MGMT', 'Gene', '4255', (155, 159))	('cancer', 'Phenotype', 'HP:0002664', (273, 279))	('cancer', 'Disease', (209, 215))	('patients', 'Species', '9606', (223, 231))	('O6-methylguanine-DNA methyltransferase', 'Gene', '4255', (115, 153))	('methylenetetrahydrofolate reductase', 'Gene', (40, 75))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
268511	29240723	Obvious genetic genes changes, including loss of TRAF3 and amplification of E2F1 (a cell cycle gene), have been found in head and neck squamous carcinoma.	('neck squamous carcinoma', 'Disease', 'MESH:D000077195', (130, 153))	('neck squamous carcinoma', 'Disease', (130, 153))	('E2F1', 'Gene', '100036852', (76, 80))	('E2F1', 'Gene', (76, 80))	('found', 'Reg', (112, 117))	('head and neck squamous carcinoma', 'Phenotype', 'HP:0012288', (121, 153))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('amplification', 'Var', (59, 72))	('TRAF3', 'Gene', (49, 54))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (135, 153))	('loss', 'NegReg', (41, 45))
268539	29240723	The genesis of tumor is an extremely complicated process during which lots of genetic and epigenetic modifications of driving genes occur.	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('epigenetic modifications', 'Var', (90, 114))	('tumor', 'Disease', (15, 20))	('occur', 'Reg', (132, 137))
268547	29240723	Loss-of-function studies, either by APP knockdown or blockage of APP function by antibody application, have demonstrated regression of carcinoma growth in vitro and in vivo .	('Loss-of-function', 'NegReg', (0, 16))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('blockage', 'NegReg', (53, 61))	('knockdown', 'Var', (40, 49))	('carcinoma growth', 'Disease', 'MESH:D006130', (135, 151))	('carcinoma growth', 'Disease', (135, 151))
268554	29240723	EGFR copy number alteration, rather than overexpression, was a better prognostic indicator in TSCC.	('EGFR', 'Gene', (0, 4))	('TSCC', 'Phenotype', 'HP:0030413', (94, 98))	('TSCC', 'Disease', (94, 98))	('copy number alteration', 'Var', (5, 27))	('EGFR', 'Gene', '1956', (0, 4))
268563	29240723	HRAS belongs to the Ras oncogene family; obvious mutations of the HRAS gene were found in oral cancer, suggesting that RAS may affect the tumorigenesis process.	('HRAS', 'Gene', (0, 4))	('mutations', 'Var', (49, 58))	('tumor', 'Disease', (138, 143))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('oral cancer', 'Disease', 'MESH:D009062', (90, 101))	('HRAS', 'Gene', (66, 70))	('found', 'Reg', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('oral cancer', 'Disease', (90, 101))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('HRAS', 'Gene', '3265', (0, 4))	('affect', 'Reg', (127, 133))	('HRAS', 'Gene', '3265', (66, 70))
268564	29240723	There was another interesting finding: activated HRAS mutations could overcome the resistance to erlotinib in an HNSCC cell line with HRAS mutation.	('HRAS', 'Gene', (134, 138))	('HRAS', 'Gene', '3265', (49, 53))	('erlotinib', 'Chemical', 'MESH:D000069347', (97, 106))	('HRAS', 'Gene', (49, 53))	('overcome', 'PosReg', (70, 78))	('mutations', 'Var', (54, 63))	('HRAS', 'Gene', '3265', (134, 138))	('resistance to erlotinib', 'MPA', (83, 106))
268570	29240723	Abnormal function of chemokines in cancer promotes cell survival, facilitated proliferation, angiogenesis, and metastasis in multiple types of tumors.	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('metastasis', 'CPA', (111, 121))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('tumors', 'Disease', (143, 149))	('tumors', 'Disease', 'MESH:D009369', (143, 149))	('cell survival', 'CPA', (51, 64))	('promotes', 'PosReg', (42, 50))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('chemokines', 'Gene', (21, 31))	('facilitated', 'PosReg', (66, 77))	('cancer', 'Disease', (35, 41))	('Abnormal function', 'Var', (0, 17))	('angiogenesis', 'CPA', (93, 105))
268659	28205554	Mutual exclusivity analysis with genomic alteration data showed that STK11 alterations in cancer patients rarely co-occur with CDK4, CDKN2A, CDKN2B or RB1, supporting a role for STK11 in an oncogenic pathway that is intimately associated with cell cycle function (Fig.	('CDKN2B', 'Gene', '1030', (141, 147))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('RB1', 'Gene', '5925', (151, 154))	('STK11', 'Gene', (178, 183))	('CDK4', 'Gene', (127, 131))	('CDKN2A', 'Gene', (133, 139))	('STK11', 'Gene', (69, 74))	('CDK4', 'Gene', '1019', (127, 131))	('alterations', 'Var', (75, 86))	('STK11', 'Gene', '6794', (178, 183))	('CDKN2A', 'Gene', '1029', (133, 139))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('CDKN2B', 'Gene', (141, 147))	('STK11', 'Gene', '6794', (69, 74))	('cancer', 'Disease', (90, 96))	('RB1', 'Gene', (151, 154))	('patients', 'Species', '9606', (97, 105))
268663	28205554	Indeed, using STK11 copy number and mRNA expression data in the Cancer Cell Line Encyclopedia to define cell lines with high (STK11 High, 41 cell lines) and low (STK11 Low, 22 cell lines) STK11 expression, we observed significantly greater palbociclib sensitivity (P=0.002, two-sided T-test) for the STK11 Low group (Supplementary Fig.	('palbociclib sensitivity', 'MPA', (240, 263))	('STK11', 'Gene', (188, 193))	('Cancer', 'Disease', 'MESH:D009369', (64, 70))	('STK11', 'Gene', '6794', (126, 131))	('STK11', 'Gene', (162, 167))	('STK11', 'Gene', '6794', (14, 19))	('STK11', 'Gene', '6794', (300, 305))	('expression', 'Species', '29278', (194, 204))	('STK11', 'Gene', '6794', (188, 193))	('STK11', 'Gene', '6794', (162, 167))	('palbociclib', 'Chemical', 'MESH:C500026', (240, 251))	('Cancer', 'Phenotype', 'HP:0002664', (64, 70))	('greater', 'PosReg', (232, 239))	('expression', 'Species', '29278', (41, 51))	('Cancer', 'Disease', (64, 70))	('STK11', 'Gene', (126, 131))	('STK11', 'Gene', (14, 19))	('STK11', 'Gene', (300, 305))	('low', 'Var', (157, 160))
268668	28205554	Further, knockdown of STK11 was correlated with enhanced CDK4 kinase activity as shown by increased phosphorylation of RB (pRB), a physiological CDK4 substrate (Fig.	('CDK4', 'Gene', (145, 149))	('activity', 'MPA', (69, 77))	('knockdown', 'Var', (9, 18))	('pRB', 'Gene', (123, 126))	('STK11', 'Gene', '6794', (22, 27))	('increased', 'PosReg', (90, 99))	('CDK4', 'Gene', '1019', (145, 149))	('CDK4', 'Gene', (57, 61))	('enhanced', 'PosReg', (48, 56))	('phosphorylation', 'MPA', (100, 115))	('CDK4', 'Gene', '1019', (57, 61))	('pRB', 'Gene', '5925', (123, 126))	('STK11', 'Gene', (22, 27))
268679	28205554	Lung cancer A549 cells with defective STK11 (Q37*) (data not shown) or cell lines with STK11 knockdown showed undetectable effect on pAMPK when treated with palbociclib (Fig.	('knockdown', 'Var', (93, 102))	('palbociclib', 'Chemical', 'MESH:C500026', (157, 168))	('cancer', 'Disease', 'MESH:D009369', (5, 11))	('pAMPK', 'Chemical', '-', (133, 138))	('pAMPK', 'MPA', (133, 138))	('STK11', 'Gene', (38, 43))	('cancer', 'Disease', (5, 11))	('STK11', 'Gene', (87, 92))	('Lung cancer', 'Phenotype', 'HP:0100526', (0, 11))	('STK11', 'Gene', '6794', (38, 43))	('A549', 'CellLine', 'CVCL:0023', (12, 16))	('Q37*', 'Var', (45, 49))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))	('Q37*', 'SUBSTITUTION', 'None', (45, 49))	('STK11', 'Gene', '6794', (87, 92))
268683	28205554	Similarly, when treated with palbociclib, STK11 silenced cells showed increased sensitivity over the parental H1792 cells (Fig.	('increased', 'PosReg', (70, 79))	('H1792', 'CellLine', 'CVCL:1495', (110, 115))	('STK11', 'Gene', (42, 47))	('sensitivity', 'MPA', (80, 91))	('silenced', 'Var', (48, 56))	('STK11', 'Gene', '6794', (42, 47))	('palbociclib', 'Chemical', 'MESH:C500026', (29, 40))
268685	28205554	Thus, loss of STK11 in lung cancer cells may lead to enhanced sensitivity to palbociclib, demonstrating an STK11-loss evoked enhanced-dependency of cells on CDK4.	('lung cancer', 'Disease', (23, 34))	('loss', 'Var', (6, 10))	('lung cancer', 'Phenotype', 'HP:0100526', (23, 34))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('STK11', 'Gene', (14, 19))	('STK11', 'Gene', (107, 112))	('enhanced-dependency', 'PosReg', (125, 144))	('sensitivity to palbociclib', 'MPA', (62, 88))	('CDK4', 'Gene', (157, 161))	('lung cancer', 'Disease', 'MESH:D008175', (23, 34))	('STK11', 'Gene', '6794', (14, 19))	('STK11', 'Gene', '6794', (107, 112))	('palbociclib', 'Chemical', 'MESH:C500026', (77, 88))	('CDK4', 'Gene', '1019', (157, 161))	('enhanced', 'PosReg', (53, 61))
268688	28205554	The observed positive correlation supports future testing of this hypothesis to examine a potential therapeutic strategy for treating lung cancer patients harbouring STK11 alterations with a CDK4 inhibitor such as palbociclib.	('lung cancer', 'Disease', (134, 145))	('lung cancer', 'Phenotype', 'HP:0100526', (134, 145))	('CDK4', 'Gene', '1019', (191, 195))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('alterations', 'Var', (172, 183))	('lung cancer', 'Disease', 'MESH:D008175', (134, 145))	('STK11', 'Gene', (166, 171))	('palbociclib', 'Chemical', 'MESH:C500026', (214, 225))	('STK11', 'Gene', '6794', (166, 171))	('patients', 'Species', '9606', (146, 154))	('CDK4', 'Gene', (191, 195))
268709	28205554	Connectivity of STK11 with CDK4 suggests a potential application of CDK4 inhibitors for the treatment of patients with defective STK11.	('STK11', 'Gene', (129, 134))	('patients', 'Species', '9606', (105, 113))	('defective', 'Var', (119, 128))	('STK11', 'Gene', '6794', (16, 21))	('STK11', 'Gene', '6794', (129, 134))	('CDK4', 'Gene', (68, 72))	('CDK4', 'Gene', '1019', (68, 72))	('CDK4', 'Gene', (27, 31))	('CDK4', 'Gene', '1019', (27, 31))	('STK11', 'Gene', (16, 21))
268712	28205554	Thus, it is hypothesized that loss of STK11 in lung cancer may lead to enhanced dependency on upregulated CDK4.	('enhanced', 'PosReg', (71, 79))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('lung cancer', 'Disease', (47, 58))	('STK11', 'Gene', (38, 43))	('lung cancer', 'Phenotype', 'HP:0100526', (47, 58))	('dependency', 'MPA', (80, 90))	('CDK4', 'Gene', (106, 110))	('STK11', 'Gene', '6794', (38, 43))	('upregulated', 'PosReg', (94, 105))	('CDK4', 'Gene', '1019', (106, 110))	('lung cancer', 'Disease', 'MESH:D008175', (47, 58))	('loss', 'Var', (30, 34))
268715	28205554	In addition, although heterogeneous mutational status of STK11 may be masked in large-scale genomics datasets, using Cancer Cell Line Encyclopedia datasets we observed increased palbociclib sensitivity for cell lines with low STK11 copy number and mRNA expression (Supplementary Fig.	('copy number', 'Var', (232, 243))	('STK11', 'Gene', (57, 62))	('increased', 'PosReg', (168, 177))	('STK11', 'Gene', (226, 231))	('low', 'NegReg', (222, 225))	('STK11', 'Gene', '6794', (57, 62))	('STK11', 'Gene', '6794', (226, 231))	('Cancer', 'Disease', (117, 123))	('Cancer', 'Disease', 'MESH:D009369', (117, 123))	('mRNA expression', 'MPA', (248, 263))	('expression', 'Species', '29278', (253, 263))	('Cancer', 'Phenotype', 'HP:0002664', (117, 123))	('palbociclib sensitivity', 'MPA', (178, 201))	('palbociclib', 'Chemical', 'MESH:C500026', (178, 189))
268726	28205554	PDONR223-EGFR, pDONR223-MET were gifts from William Hahn and David Root (Addgene plasmids #23935, #23889).	('EGFR', 'Gene', '1956', (9, 13))	('EGFR', 'Gene', (9, 13))	('pDONR223-MET', 'Var', (15, 27))
268762	28205554	HEK293T cells were grown in six-well plates and transfected using Xtreme-Gene (Roche 6366546001) with Venus-FLAG-NSD3s or Venus vector along with Myc-Ebox-containing luciferase reporter plasmids, with either wild-type (GCCACGTGGCCACGTGGCCACGTGGC) or mutant (GCCTCGAGGCCTCGAGGCCTCGAGGC) E-boxes driving expression of firefly luciferase.	('NSD3', 'Gene', (113, 117))	('expression', 'Species', '29278', (302, 312))	('Myc', 'Gene', '4609', (146, 149))	('mutant', 'Var', (250, 256))	('HEK293T', 'CellLine', 'CVCL:0063', (0, 7))	('NSD3', 'Gene', '54904', (113, 117))	('Myc', 'Gene', (146, 149))
268774	24565585	Targeted Therapies in NSCLC: Emerging oncogene targets following the success of EGFR The diagnostic testing, treatment and prognosis of non-small cell lung cancer (NSCLC) has undergone a paradigm shift since the discovery of sensitizing mutations in the epidermal growth factor receptor (EGFR) gene in a subset of NSCLC patients.	('epidermal growth factor receptor', 'Gene', (254, 286))	('men', 'Species', '9606', (114, 117))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (136, 162))	('EGFR', 'Gene', '1956', (80, 84))	('epidermal growth factor receptor', 'Gene', '1956', (254, 286))	('NSCLC', 'Disease', 'MESH:D002289', (22, 27))	('EGFR', 'Gene', (288, 292))	('sensitizing', 'PosReg', (225, 236))	('NSCLC', 'Disease', 'MESH:D002289', (164, 169))	('non-small cell lung cancer', 'Disease', (136, 162))	('NSCLC', 'Disease', 'MESH:D002289', (314, 319))	('NSCLC', 'Disease', (22, 27))	('mutations', 'Var', (237, 246))	('NSCLC', 'Disease', (164, 169))	('lung cancer', 'Phenotype', 'HP:0100526', (151, 162))	('NSCLC', 'Disease', (314, 319))	('EGFR', 'Gene', (80, 84))	('EGFR', 'Gene', '1956', (288, 292))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (136, 162))	('patients', 'Species', '9606', (320, 328))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (140, 162))
268779	24565585	During this interval, preclinical and clinical investigators identified and characterized several key 'oncogenic mutations' - where mutations is inclusive of genetic alterations resulting in amino acid substitutions, in-frame insertions or deletions, gene fusions resulting from chromosomal rearrangements, or gene amplification.	('gene fusions', 'Var', (251, 263))	('amino acid substitutions', 'Var', (191, 215))	('men', 'Species', '9606', (300, 303))	('rat', 'Species', '10116', (170, 173))	('deletions', 'Var', (240, 249))	('gene amplification', 'Var', (310, 328))	('in-frame insertions', 'Var', (217, 236))
268780	24565585	These oncogenic mutations result in activation of key intracellular signal transduction pathways that allow unregulated tumor growth.	('key intracellular signal transduction pathways', 'Pathway', (50, 96))	('mutations', 'Var', (16, 25))	('activation', 'PosReg', (36, 46))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('tumor', 'Disease', (120, 125))
268781	24565585	Characteristic mutations had been well described in different NSCLC subtypes, such as Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations in adenocarcinoma.	('rat', 'Species', '10116', (94, 97))	('adenocarcinoma', 'Disease', 'MESH:D000230', (149, 163))	('NSCLC', 'Disease', (62, 67))	('NSCLC', 'Disease', 'MESH:D002289', (62, 67))	('sarcoma', 'Disease', 'MESH:D012509', (98, 105))	('KRAS', 'Gene', (130, 134))	('mutations', 'Var', (136, 145))	('sarcoma', 'Disease', (98, 105))	('adenocarcinoma', 'Disease', (149, 163))	('carcinoma', 'Phenotype', 'HP:0030731', (154, 163))	('sarcoma', 'Phenotype', 'HP:0100242', (98, 105))
268783	24565585	Initial success with targeted therapy in NSCLC occurred with discovery of a subset of lung adenocarcinomas harboring epidermal growth factor receptor (EGFR) gene mutations and correlation to response to the EGFR tyrosine kinase inhibitor (TKI) gefitinib.	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (86, 106))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (86, 106))	('mutations', 'Var', (162, 171))	('epidermal growth factor receptor', 'Gene', (117, 149))	('gefitinib', 'Chemical', 'MESH:D000077156', (244, 253))	('NSCLC', 'Disease', (41, 46))	('EGFR', 'Gene', (151, 155))	('EGFR', 'Gene', '1956', (207, 211))	('NSCLC', 'Disease', 'MESH:D002289', (41, 46))	('epidermal growth factor receptor', 'Gene', '1956', (117, 149))	('EGFR', 'Gene', (207, 211))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (86, 105))	('tyrosine', 'Chemical', 'MESH:D014443', (212, 220))	('lung adenocarcinomas', 'Disease', (86, 106))	('EGFR', 'Gene', '1956', (151, 155))
268788	24565585	This review will focus on the rapid progress in this field of NSCLC since the discovery of EGFR mutations, the growing body of literature supporting each oncogene, and how they can serve as predictive biomarkers for therapy.	('rat', 'Species', '10116', (131, 134))	('EGFR', 'Gene', (91, 95))	('NSCLC', 'Disease', (62, 67))	('NSCLC', 'Disease', 'MESH:D002289', (62, 67))	('EGFR', 'Gene', '1956', (91, 95))	('mutations', 'Var', (96, 105))
268794	24565585	Several other fusion EML4-ALK fusion variants and other fusion partners, most notably kinesin factor 5B (KIF5B), have been described.	('ALK', 'Gene', (26, 29))	('EML4', 'Gene', (21, 25))	('KIF5B', 'Gene', '3799', (105, 110))	('kinesin factor 5B', 'Gene', (86, 103))	('EML4', 'Gene', '27436', (21, 25))	('variants', 'Var', (37, 45))	('kinesin factor 5B', 'Gene', '3799', (86, 103))	('ALK', 'Gene', '238', (26, 29))	('fusion variants', 'Var', (30, 45))	('KIF5B', 'Gene', (105, 110))
268795	24565585	Fluorescence in situ hybridization (FISH) remains the gold standard for clinical detection of ALK gene rearrangements and is the only commercially available ALK screening modality, although evaluation of immunohistochemistry (IHC) and reverse transcription polymerase chain reaction (RT-PCR) based platforms have yielded similar sensitivity (100% RT-PCR and IHC) and specificity (100% and 75%-87.5%, RT-PCR and IHC, respectively) when compared to FISH.	('ALK', 'Gene', '238', (94, 97))	('rearrangements', 'Var', (103, 117))	('ALK', 'Gene', (157, 160))	('ALK', 'Gene', (94, 97))	('men', 'Species', '9606', (112, 115))	('ALK', 'Gene', '238', (157, 160))
268797	24565585	Different histological patterns such as signet-ring histology have been reported in association with ALK rearrangements, but these features are not exclusively associated with ALK positivity.	('ALK', 'Gene', (101, 104))	('signet-ring histology', 'Disease', (40, 61))	('men', 'Species', '9606', (114, 117))	('ALK', 'Gene', '238', (176, 179))	('ALK', 'Gene', '238', (101, 104))	('ALK', 'Gene', (176, 179))	('rearrangements', 'Var', (105, 119))
268798	24565585	While the majority of ALK gene rearrangements commonly occur independently of KRAS and EGFR driver mutations, these mutations are not mutually exclusive, as multiple cases of dual oncogenic mutations have been reported.	('EGFR', 'Gene', '1956', (87, 91))	('occur', 'Reg', (55, 60))	('KRAS', 'Gene', (78, 82))	('EGFR', 'Gene', (87, 91))	('rearrangements', 'Var', (31, 45))	('ALK', 'Gene', '238', (22, 25))	('men', 'Species', '9606', (40, 43))	('ALK', 'Gene', (22, 25))
268805	24565585	Median PFS was superior for the crizotinib group compared to chemotherapy (7.7 vs. 3.0 mos; HR 0.49; 95% CI 0.37-0.64; p<0.001) with a significant difference in ORR (65% vs. 20%; p<0.001) per independent radiologic review.	('crizotinib', 'Chemical', 'MESH:D000077547', (32, 42))	('crizotinib', 'Var', (32, 42))	('PFS', 'MPA', (7, 10))
268815	24565585	In aggregate, the incidence of treatment related adverse events was similar in the crizotinib and chemotherapy arms (33% vs. 32%, respectively) with only 6% of patients discontinuing crizotinib due to treatment related toxicity compared to 10% of patients in the chemotherapy arm.	('crizotinib', 'Chemical', 'MESH:D000077547', (183, 193))	('discontinuing', 'NegReg', (169, 182))	('crizotinib', 'Chemical', 'MESH:D000077547', (83, 93))	('patients', 'Species', '9606', (160, 168))	('toxicity', 'Disease', 'MESH:D064420', (219, 227))	('toxicity', 'Disease', (219, 227))	('crizotinib', 'Var', (183, 193))	('patients', 'Species', '9606', (247, 255))	('men', 'Species', '9606', (36, 39))	('men', 'Species', '9606', (206, 209))
268822	24565585	The most described mutation, L1196M occurs within the ATP binding site of the kinase, decreasing binding of crizotinib in the ATP domain and restoring downstream signal transduction despite the presence of crizotinib.	('crizotinib', 'Chemical', 'MESH:D000077547', (108, 118))	('ATP', 'Chemical', 'MESH:D000255', (54, 57))	('restoring', 'PosReg', (141, 150))	('ATP', 'Chemical', 'MESH:D000255', (126, 129))	('binding', 'Interaction', (97, 104))	('L1196M', 'Var', (29, 35))	('crizotinib', 'Chemical', 'MESH:D000077547', (206, 216))	('decreasing', 'NegReg', (86, 96))	('L1196M', 'Mutation', 'rs1057519784', (29, 35))	('downstream signal transduction', 'MPA', (151, 181))
268824	24565585	Unlike the T790M mutation in EGFR+ NSCLC, there does not appear to be one dominant ALK-dependent mechanism of resistance, with ALK copy number gain and multiple point mutations - both within and outside of the ALK kinase domain - described in the literature.	('point mutations -', 'Var', (161, 178))	('ALK', 'Gene', '238', (210, 213))	('ALK', 'Gene', '238', (83, 86))	('NSCLC', 'Disease', (35, 40))	('ALK copy number gain', 'Disease', 'MESH:D015430', (127, 147))	('ALK', 'Gene', (210, 213))	('ALK', 'Gene', (127, 130))	('EGFR', 'Gene', '1956', (29, 33))	('NSCLC', 'Disease', 'MESH:D002289', (35, 40))	('EGFR', 'Gene', (29, 33))	('T790M', 'Mutation', 'rs121434569', (11, 16))	('rat', 'Species', '10116', (251, 254))	('ALK', 'Gene', (83, 86))	('T790M', 'Var', (11, 16))	('ALK copy number gain', 'Disease', (127, 147))	('ALK', 'Gene', '238', (127, 130))
268839	24565585	Co-existent EGFR mutations with ROS1 fusions have been observed.	('fusions', 'Var', (37, 44))	('EGFR', 'Gene', '1956', (12, 16))	('ROS1', 'Gene', (32, 36))	('EGFR', 'Gene', (12, 16))	('mutations', 'Var', (17, 26))
268842	24565585	Patients treated with the TKI crizotinib have demonstrated marked clinical response similar to those seen in ALK+ NSCLC.	('TKI', 'Var', (26, 29))	('ALK', 'Gene', (109, 112))	('crizotinib', 'Chemical', 'MESH:D000077547', (30, 40))	('NSCLC', 'Disease', (114, 119))	('rat', 'Species', '10116', (53, 56))	('Patients', 'Species', '9606', (0, 8))	('ALK', 'Gene', '238', (109, 112))	('NSCLC', 'Disease', 'MESH:D002289', (114, 119))
268845	24565585	A kinase domain mutation, G2032R, which interferes with crizotinib inhibition of the ROS1 kinase has been described in a ROS1+ NSCLC patient progressing on crizotinib.	('NSCLC', 'Disease', (127, 132))	('G2032R', 'Mutation', 'rs1057519788', (26, 32))	('crizotinib', 'Chemical', 'MESH:D000077547', (156, 166))	('G2032R', 'Var', (26, 32))	('NSCLC', 'Disease', 'MESH:D002289', (127, 132))	('patient', 'Species', '9606', (133, 140))	('ROS1 kinase', 'Enzyme', (85, 96))	('crizotinib', 'Chemical', 'MESH:D000077547', (56, 66))
268848	24565585	Foretinib (GSK1363089/XL880) also has shown activity in preclinical studies of ROS1+ NSCLC and retains activity against the G2032R resistance mutation and is currently under study in NSCLC.	('NSCLC', 'Disease', (85, 90))	('activity', 'MPA', (103, 111))	('NSCLC', 'Disease', 'MESH:D002289', (85, 90))	('GSK1363089', 'Chemical', 'MESH:C544831', (11, 21))	('NSCLC', 'Disease', (183, 188))	('activity', 'MPA', (44, 52))	('Foretinib', 'Chemical', 'MESH:C544831', (0, 9))	('NSCLC', 'Disease', 'MESH:D002289', (183, 188))	('G2032R', 'Mutation', 'rs1057519788', (124, 130))	('G2032R', 'Var', (124, 130))
268851	24565585	Unlike ALK gene fusions and EGFR mutations, KRAS mutations appear at a lower frequency in never smokers when compared to current/light smokers and are relatively rare in East Asian patient cohorts.	('EGFR', 'Gene', '1956', (28, 32))	('mutations', 'Var', (49, 58))	('patient', 'Species', '9606', (181, 188))	('EGFR', 'Gene', (28, 32))	('ALK', 'Gene', (7, 10))	('KRAS', 'Gene', (44, 48))	('ALK', 'Gene', '238', (7, 10))
268853	24565585	In a meta-analysis of NSCLC patients, those with an activating KRAS mutation had a worse overall prognosis when compared to wild type patients,.	('mutation', 'Var', (68, 76))	('patients', 'Species', '9606', (134, 142))	('activating', 'PosReg', (52, 62))	('NSCLC', 'Disease', (22, 27))	('patients', 'Species', '9606', (28, 36))	('NSCLC', 'Disease', 'MESH:D002289', (22, 27))	('KRAS', 'Gene', (63, 67))
268854	24565585	However, a recent large retrospective study found no difference in prognosis by KRAS exon 12 mutation in patients with early stage NSCLC, calling into question the role of KRAS mutations a prognostic biomarkers.	('patients', 'Species', '9606', (105, 113))	('NSCLC', 'Disease', (131, 136))	('NSCLC', 'Disease', 'MESH:D002289', (131, 136))	('mutation', 'Var', (93, 101))	('KRAS exon 12', 'Gene', (80, 92))
268857	24565585	Promising phase II results have been reported for the MEK1/2 inhibitor selumetinib (formerly AZD6244), where 87 KRAS-mutant NSCLC that progressed on first line therapy were randomized to docetaxel plus selumetinib or placebo.	('AZD6244', 'Chemical', 'MESH:C517975', (93, 100))	('NSCLC', 'Disease', (124, 129))	('selumetinib', 'Chemical', 'MESH:C517975', (71, 82))	('docetaxel', 'Chemical', 'MESH:D000077143', (187, 196))	('NSCLC', 'Disease', 'MESH:D002289', (124, 129))	('MEK1/2', 'Gene', '5604;5605', (54, 60))	('KRAS-mutant', 'Var', (112, 123))	('MEK1/2', 'Gene', (54, 60))	('selumetinib', 'Chemical', 'MESH:C517975', (202, 213))
268860	24565585	Toxicity of the docetaxel + selumetinib combination is a concern, as there was a greater frequency of grade 3/4 adverse events with selumetinib (45%) compared to placebo (4%), including febrile neutropenia (14% vs. 0%) and pneumonia (9% vs. 0%).	('neutropenia', 'Phenotype', 'HP:0001875', (194, 205))	('selumetinib', 'Chemical', 'MESH:C517975', (28, 39))	('selumetinib', 'Chemical', 'MESH:C517975', (132, 143))	('Toxicity', 'Disease', (0, 8))	('Toxicity', 'Disease', 'MESH:D064420', (0, 8))	('selumetinib', 'Var', (132, 143))	('docetaxel', 'Chemical', 'MESH:D000077143', (16, 25))	('pneumonia', 'Phenotype', 'HP:0002090', (223, 232))	('febrile neutropenia', 'Disease', (186, 205))	('febrile neutropenia', 'Disease', 'MESH:D009503', (186, 205))	('pneumonia', 'Disease', (223, 232))	('pneumonia', 'Disease', 'MESH:D011014', (223, 232))
268866	24565585	The predictive and prognostic factors of HER2 amplification in breast and esophageal adenocarcinoma are well known, with established US FDA approved HER2 monoclonal antibodies directed against the extracellular domain (trastuzumab, ado-trastuzumab emtansine, pertuzumab) and aTKI that targets the intracellular ATP binding domain (lapatinib).	('breast and esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (63, 99))	('trastuzumab', 'Chemical', 'MESH:D000068878', (219, 230))	('HER2', 'Gene', (149, 153))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('amplification', 'Var', (46, 59))	('pertuzumab', 'Chemical', 'MESH:C485206', (259, 269))	('ado-trastuzumab emtansine', 'Chemical', 'MESH:C550911', (232, 257))	('HER2', 'Gene', '2064', (149, 153))	('lapatinib', 'Chemical', 'MESH:D000077341', (331, 340))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (74, 99))	('HER2', 'Gene', (41, 45))	('trastuzumab', 'Chemical', 'MESH:D000068878', (236, 247))	('ATP', 'Chemical', 'MESH:D000255', (311, 314))	('HER2', 'Gene', '2064', (41, 45))
268870	24565585	Two different NSCLC patient cohorts have been evaluated for HER2 mutations with an approximate prevalence of 2-4% in adenocarcinoma and 1.2% in an overall NSCLC cohort, with mutations more prevalent within never-smokers.	('NSCLC', 'Disease', (14, 19))	('NSCLC', 'Disease', 'MESH:D002289', (14, 19))	('HER2', 'Gene', (60, 64))	('adenocarcinoma', 'Disease', (117, 131))	('NSCLC', 'Disease', (155, 160))	('HER2', 'Gene', '2064', (60, 64))	('patient', 'Species', '9606', (20, 27))	('NSCLC', 'Disease', 'MESH:D002289', (155, 160))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('adenocarcinoma', 'Disease', 'MESH:D000230', (117, 131))	('mutations', 'Var', (65, 74))
268871	24565585	HER2 amplification was established as a poor prognostic factor in a recent meta-analysis, with HR for OS of 1.48 (95% CI 1.22-1.80) for NSCLC and a HR of 1.95 (95% CI 1.56-2.43) for lung adenocarcinoma specifically.	('lung adenocarcinoma', 'Disease', (182, 201))	('NSCLC', 'Disease', 'MESH:D002289', (136, 141))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (182, 201))	('amplification', 'Var', (5, 18))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (182, 201))	('HER2', 'Gene', (0, 4))	('HER2', 'Gene', '2064', (0, 4))	('NSCLC', 'Disease', (136, 141))	('carcinoma', 'Phenotype', 'HP:0030731', (192, 201))
268873	24565585	The prognostic value of HER2 insertions in NSCLC is yet to be determined.	('HER2', 'Gene', (24, 28))	('NSCLC', 'Disease', (43, 48))	('insertions', 'Var', (29, 39))	('HER2', 'Gene', '2064', (24, 28))	('NSCLC', 'Disease', 'MESH:D002289', (43, 48))
268874	24565585	Response to HER2 targeted therapy for HER2 amplification, overexpression and exon 20 insertions have been evaluated in several preclinical models.	('insertions', 'Var', (85, 95))	('HER2', 'Gene', (12, 16))	('amplification', 'Var', (43, 56))	('HER2', 'Gene', '2064', (12, 16))	('HER2', 'Gene', (38, 42))	('HER2', 'Gene', '2064', (38, 42))	('exon', 'Var', (77, 81))
268877	24565585	The clinical benefit of HER2 targeted therapies in HER2 overexpressing or HER2 mutant NSCLC remains under investigation.	('overexpressing', 'PosReg', (56, 70))	('NSCLC', 'Disease', (86, 91))	('mutant', 'Var', (79, 85))	('HER2', 'Gene', (74, 78))	('NSCLC', 'Disease', 'MESH:D002289', (86, 91))	('HER2', 'Gene', '2064', (74, 78))	('HER2', 'Gene', (51, 55))	('HER2', 'Gene', (24, 28))	('HER2', 'Gene', '2064', (51, 55))	('HER2', 'Gene', '2064', (24, 28))
268882	24565585	Currently, there are multiple trials investigating the utility of nextgeneration irreversible pan-HER or HER2 TKI's, including dacomitinib, afatinib, and neratinib (Table 1).	('pan-HER', 'Protein', (94, 101))	('rat', 'Species', '10116', (156, 159))	('afatinib', 'Chemical', 'MESH:D000077716', (140, 148))	('HER2', 'Gene', (105, 109))	('dacomitinib', 'Chemical', 'MESH:C525726', (127, 138))	('HER2', 'Gene', '2064', (105, 109))	('rat', 'Species', '10116', (74, 77))	('nextgeneration', 'Var', (66, 80))	('neratinib', 'Chemical', 'MESH:C487932', (154, 163))
268883	24565585	A randomized phase II trial is currently enrolling HER2 mutation positive NSCLC patients to HER2 TKI neratinib with or without mTOR inhibitor temsirolimus (NCT01827267, Table 1) with other TKI's being evaluated in an unselected NSCLC population (Table 2).	('mTOR', 'Gene', '2475', (127, 131))	('patients', 'Species', '9606', (80, 88))	('HER2', 'Gene', '2064', (51, 55))	('HER2', 'Gene', '2064', (92, 96))	('HER2', 'Gene', (92, 96))	('NSCLC', 'Disease', 'MESH:D002289', (228, 233))	('NSCLC', 'Disease', (74, 79))	('NSCLC', 'Disease', (228, 233))	('mTOR', 'Gene', (127, 131))	('HER2', 'Gene', (51, 55))	('mutation', 'Var', (56, 64))	('NSCLC', 'Disease', 'MESH:D002289', (74, 79))	('neratinib', 'Chemical', 'MESH:C487932', (101, 110))
268885	24565585	BRAF mutations were initially described in malignant melanoma with subsequent reports in colorectal adenocarcinoma and papillary thyroid cancer, amongst others.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('malignant melanoma', 'Disease', 'MESH:D008545', (43, 61))	('colorectal adenocarcinoma and papillary thyroid cancer', 'Disease', 'MESH:D000077273', (89, 143))	('melanoma', 'Phenotype', 'HP:0002861', (53, 61))	('mutations', 'Var', (5, 14))	('papillary thyroid cancer', 'Phenotype', 'HP:0002895', (119, 143))	('malignant melanoma', 'Phenotype', 'HP:0002861', (43, 61))	('BRAF', 'Gene', '673', (0, 4))	('thyroid cancer', 'Phenotype', 'HP:0002890', (129, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('BRAF', 'Gene', (0, 4))	('described', 'Reg', (30, 39))	('malignant melanoma', 'Disease', (43, 61))
268886	24565585	BRAF targeted therapies have gained recent notoriety in melanoma, as the BRAF-specific TKI vemurafenib gained FDA approval as the first targeted therapy for BRAF mutant metastatic melanoma.	('BRAF', 'Gene', '673', (73, 77))	('melanoma', 'Phenotype', 'HP:0002861', (180, 188))	('melanoma', 'Disease', (180, 188))	('melanoma', 'Disease', 'MESH:D008545', (56, 64))	('melanoma', 'Phenotype', 'HP:0002861', (56, 64))	('melanoma', 'Disease', (56, 64))	('melanoma', 'Disease', 'MESH:D008545', (180, 188))	('BRAF', 'Gene', '673', (157, 161))	('mutant', 'Var', (162, 168))	('BRAF', 'Gene', '673', (0, 4))	('BRAF', 'Gene', (157, 161))	('BRAF', 'Gene', (0, 4))	('BRAF', 'Gene', (73, 77))	('vemurafenib', 'Chemical', 'MESH:D000077484', (91, 102))
268887	24565585	BRAF mutations are found in approximately 1-5% of NSCLC, almost exclusively in adenocarcinomas.	('adenocarcinomas', 'Disease', 'MESH:D000230', (79, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('adenocarcinomas', 'Disease', (79, 94))	('mutations', 'Var', (5, 14))	('BRAF', 'Gene', '673', (0, 4))	('NSCLC', 'Disease', (50, 55))	('BRAF', 'Gene', (0, 4))	('NSCLC', 'Disease', 'MESH:D002289', (50, 55))
268888	24565585	BRAF V600E mutations that induce constitutive kinase activity occur in NSCLC, but there also multiple 'non-V600E' mutations that in aggregate constitute nearly 50% of the known BRAF mutations in NSCLC and occur within exons 11 and 15.	('mutations', 'Var', (11, 20))	('NSCLC', 'Disease', 'MESH:D002289', (195, 200))	('V600E mutations', 'Var', (5, 20))	('V600E', 'Mutation', 'rs113488022', (5, 10))	('BRAF', 'Gene', (177, 181))	('mutations', 'Var', (114, 123))	('BRAF', 'Gene', '673', (177, 181))	('V600E', 'Mutation', 'rs113488022', (107, 112))	('BRAF', 'Gene', '673', (0, 4))	('BRAF', 'Gene', (0, 4))	('NSCLC', 'Disease', (71, 76))	('NSCLC', 'Disease', (195, 200))	('mutations', 'Var', (182, 191))	('NSCLC', 'Disease', 'MESH:D002289', (71, 76))
268889	24565585	When compared to the non-V600E population, V600E BRAF mutations occur predominantly in light/never smokers, are more common amongst women and are associated with micropapillary histology.	('micropapillary histology', 'Disease', (162, 186))	('women', 'Species', '9606', (132, 137))	('V600E', 'Mutation', 'rs113488022', (43, 48))	('BRAF', 'Gene', '673', (49, 53))	('associated with', 'Reg', (146, 161))	('V600E', 'Mutation', 'rs113488022', (25, 30))	('V600E', 'Var', (43, 48))	('BRAF', 'Gene', (49, 53))
268890	24565585	In addition, a non-V600E BRAF mutant cohort was associated with lower overall survival when adjusted for age, gender, and smoking status (HR 2.18; p=0.014) when compared to a BRAF wild-type cohort.	('overall survival', 'MPA', (70, 86))	('V600E', 'Mutation', 'rs113488022', (19, 24))	('lower', 'NegReg', (64, 69))	('non-V600E', 'Var', (15, 24))	('BRAF', 'Gene', (175, 179))	('BRAF', 'Gene', '673', (175, 179))	('BRAF', 'Gene', '673', (25, 29))	('BRAF', 'Gene', (25, 29))
268893	24565585	Preclinical data suggest a differential response to the BRAF TKI vemurafenib with respect to the type of BRAF mutation with sensitivity in V600E BRAF mutant cell lines and resistance in non-V600E BRAF mutant melanoma cell lines.	('V600E', 'Mutation', 'rs113488022', (190, 195))	('BRAF', 'Gene', '673', (105, 109))	('BRAF', 'Gene', (145, 149))	('V600E', 'Mutation', 'rs113488022', (139, 144))	('BRAF', 'Gene', '673', (56, 60))	('BRAF', 'Gene', (105, 109))	('melanoma', 'Disease', (208, 216))	('melanoma', 'Phenotype', 'HP:0002861', (208, 216))	('vemurafenib', 'Chemical', 'MESH:D000077484', (65, 76))	('BRAF', 'Gene', '673', (196, 200))	('melanoma', 'Disease', 'MESH:D008545', (208, 216))	('V600E', 'Var', (139, 144))	('BRAF', 'Gene', (196, 200))	('mutant', 'Var', (150, 156))	('BRAF', 'Gene', '673', (145, 149))	('BRAF', 'Gene', (56, 60))
268894	24565585	Additional preclinical data suggests that BRAF activating mutations may predict sensitivity to downstream MEK TKI's, which is supported by clinical benefit seen with MEK inhibition in BRAF mutated melanoma.	('BRAF', 'Gene', '673', (42, 46))	('mutations', 'Var', (58, 67))	('mutated', 'Var', (189, 196))	('BRAF', 'Gene', (184, 188))	('melanoma', 'Disease', 'MESH:D008545', (197, 205))	('MEK', 'Gene', (106, 109))	('melanoma', 'Phenotype', 'HP:0002861', (197, 205))	('melanoma', 'Disease', (197, 205))	('sensitivity', 'MPA', (80, 91))	('MEK', 'Gene', '5609', (106, 109))	('MEK', 'Gene', (166, 169))	('MEK', 'Gene', '5609', (166, 169))	('BRAF', 'Gene', (42, 46))	('BRAF', 'Gene', '673', (184, 188))
268895	24565585	BRAF-specific trials in NSCLC are utilizing different BRAF molecular cohorts in their trial designs, including V600E-specific trials, as seen in the phase II trial utilizing BRAF inhibitor GSK2118436 (NCT01336634) and trials evaluating downstream MEK and AKT inhibition in BRAF mutant NSCLC regardless of the specific BRAF mutation (Table 1).	('NSCLC', 'Disease', (24, 29))	('BRAF', 'Gene', '673', (318, 322))	('BRAF', 'Gene', (318, 322))	('NSCLC', 'Disease', 'MESH:D002289', (285, 290))	('AKT', 'Gene', '207', (255, 258))	('BRAF', 'Gene', '673', (0, 4))	('BRAF', 'Gene', (0, 4))	('mutant', 'Var', (278, 284))	('inhibition', 'NegReg', (259, 269))	('BRAF', 'Gene', (54, 58))	('BRAF', 'Gene', '673', (54, 58))	('NSCLC', 'Disease', (285, 290))	('BRAF', 'Gene', '673', (174, 178))	('BRAF', 'Gene', (174, 178))	('MEK', 'Gene', '5609', (247, 250))	('V600E', 'Mutation', 'rs113488022', (111, 116))	('AKT', 'Gene', (255, 258))	('BRAF', 'Gene', '673', (273, 277))	('MEK', 'Gene', (247, 250))	('NSCLC', 'Disease', 'MESH:D002289', (24, 29))	('BRAF', 'Gene', (273, 277))
268897	24565585	Activating amino acid substitutions encoded by germline mutations have been described in multiple endocrine neoplasia (MEN) 2A and 2B, sporadic missense mutations in non-MEN related medullary thyroid cancer, and gene fusions discovered in a subset of papillary thyroid cancers.	('Activating', 'PosReg', (0, 10))	('missense mutations', 'Var', (144, 162))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('endocrine neoplasia (MEN) 2A and 2B', 'Gene', '5979', (98, 133))	('neoplasia', 'Phenotype', 'HP:0002664', (108, 117))	('thyroid cancer', 'Disease', 'MESH:D013964', (261, 275))	('thyroid cancer', 'Phenotype', 'HP:0002890', (261, 275))	('MEN', 'Species', '9606', (119, 122))	('papillary thyroid cancers', 'Disease', 'MESH:D000077273', (251, 276))	('endocrine neoplasia', 'Phenotype', 'HP:0100568', (98, 117))	('papillary thyroid cancers', 'Disease', (251, 276))	('cancers', 'Phenotype', 'HP:0002664', (269, 276))	('thyroid cancer', 'Disease', (192, 206))	('cancer', 'Phenotype', 'HP:0002664', (269, 275))	('thyroid cancer', 'Disease', 'MESH:D013964', (192, 206))	('medullary thyroid cancer', 'Phenotype', 'HP:0002865', (182, 206))	('papillary thyroid cancer', 'Phenotype', 'HP:0002895', (251, 275))	('papillary thyroid cancers', 'Phenotype', 'HP:0002895', (251, 276))	('MEN', 'Species', '9606', (170, 173))	('thyroid cancer', 'Phenotype', 'HP:0002890', (192, 206))
268898	24565585	Oncogenic properties in NSCLC were discovered via transcriptome analysis of banked tumor samples and next generation sequencing, revealing oncogenic KIF5B-RET gene fusions that occur through a paracentric inversion on chromosome 10.	('NSCLC', 'Disease', (24, 29))	('rat', 'Species', '10116', (110, 113))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('RET', 'Gene', '5979', (155, 158))	('NSCLC', 'Disease', 'MESH:D002289', (24, 29))	('tumor', 'Disease', (83, 88))	('RET', 'Gene', (155, 158))	('fusions', 'Var', (164, 171))	('KIF5B', 'Gene', (149, 154))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('KIF5B', 'Gene', '3799', (149, 154))
268907	24565585	In addition to being a primary oncogenic event, MET amplification acts as a mechanism of resistance to EGFR TKI's in EGFR+ NSCLC via 'oncogene switch' in approximately 5-20% of patients.	('EGFR', 'Gene', '1956', (103, 107))	('NSCLC', 'Disease', (123, 128))	('EGFR', 'Gene', '1956', (117, 121))	('NSCLC', 'Disease', 'MESH:D002289', (123, 128))	('EGFR', 'Gene', (103, 107))	('EGFR', 'Gene', (117, 121))	('patients', 'Species', '9606', (177, 185))	('MET amplification', 'Var', (48, 65))
268908	24565585	MET mutations occur at a lower frequency and are clustered around the sema and juxtamembrane domains of HGFR.	('sema', 'Disease', (70, 74))	('sema', 'Disease', 'None', (70, 74))	('HGFR', 'Gene', '4233', (104, 108))	('HGFR', 'Gene', (104, 108))	('mutations', 'Var', (4, 13))
268909	24565585	The oncogenic potential of these mutations in NSCLC are unknown.	('NSCLC', 'Disease', 'MESH:D002289', (46, 51))	('NSCLC', 'Disease', (46, 51))	('mutations', 'Var', (33, 42))
268910	24565585	Transcriptome sequencing also recently identified exon 14 deletions in MET from NSCLC tumor samples that have been previously demonstrated as oncogenic alterations in lung cancer.	('NSCLC tumor', 'Disease', 'MESH:D009369', (80, 91))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('rat', 'Species', '10116', (156, 159))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('lung cancer', 'Disease', (167, 178))	('lung cancer', 'Phenotype', 'HP:0100526', (167, 178))	('exon 14 deletions', 'Var', (50, 67))	('NSCLC tumor', 'Disease', (80, 91))	('rat', 'Species', '10116', (133, 136))	('lung cancer', 'Disease', 'MESH:D008175', (167, 178))	('MET', 'Gene', (71, 74))
268927	24565585	While by no means complete, this group of potential driver mutations includes PIC3CA mutations, fibroblast growth factor receptor 1 (FGFR1), insulin-like growth factor receptor 1 (IGF1R), discoidin domain receptor 2 (DDR2) and neurotrophic tyrosine kinase, receptor, type 1 (NTRK1).	('IGF1R', 'Gene', '3480', (180, 185))	('FGFR1', 'Gene', (133, 138))	('discoidin domain receptor 2', 'Gene', '4921', (188, 215))	('FGFR1', 'Gene', '2260', (133, 138))	('fibroblast growth factor receptor 1', 'Gene', '2260', (96, 131))	('NTRK1', 'Gene', (275, 280))	('IGF1R', 'Gene', (180, 185))	('mutations', 'Var', (85, 94))	('PIC3CA', 'Gene', (78, 84))	('DDR2', 'Gene', '4921', (217, 221))	('mutations', 'Var', (59, 68))	('fibroblast growth factor receptor 1', 'Gene', (96, 131))	('DDR2', 'Gene', (217, 221))	('discoidin domain receptor 2', 'Gene', (188, 215))	('neurotrophic tyrosine kinase, receptor, type 1', 'Gene', '4914', (227, 273))
268928	24565585	As a signal mediator between several different transmembrane growth factor receptors and downstream pathways, PIK3CA deregulation in NSCLC occurs via kinase mutations or gene amplification.	('deregulation', 'PosReg', (117, 129))	('gene amplification', 'Var', (170, 188))	('NSCLC', 'Disease', (133, 138))	('kinase mutations', 'Var', (150, 166))	('PIK3CA', 'Gene', (110, 116))	('NSCLC', 'Disease', 'MESH:D002289', (133, 138))	('PIK3CA', 'Gene', '5290', (110, 116))
268929	24565585	PIK3CA mutations occur at a rate of ~2% of NSCLC with suggestion of increased frequency (~11%) in a recently published squamous cell cohort.	('mutations', 'Var', (7, 16))	('PIK3CA', 'Gene', (0, 6))	('PIK3CA', 'Gene', '5290', (0, 6))	('NSCLC', 'Disease', (43, 48))	('rat', 'Species', '10116', (28, 31))	('NSCLC', 'Disease', 'MESH:D002289', (43, 48))
268933	24565585	In contrast to ALK, EGFR, ROS1 and other aforementioned oncogenes, mutations in the DDR2 gene occur more frequently in patients with squamous cell histology at a rate of ~4%.	('ALK', 'Gene', (15, 18))	('DDR2', 'Gene', '4921', (84, 88))	('rat', 'Species', '10116', (162, 165))	('EGFR', 'Gene', (20, 24))	('patients', 'Species', '9606', (119, 127))	('DDR2', 'Gene', (84, 88))	('mutations', 'Var', (67, 76))	('ALK', 'Gene', '238', (15, 18))	('men', 'Species', '9606', (46, 49))	('squamous cell histology', 'Disease', (133, 156))	('EGFR', 'Gene', '1956', (20, 24))
268935	24565585	DDR2 kinase mutations are susceptible to preclinical and clinical inhibition with the ABL kinase family of drugs and most notably with dasatinib.	('DDR2', 'Gene', (0, 4))	('mutations', 'Var', (12, 21))	('DDR2', 'Gene', '4921', (0, 4))	('dasatinib', 'Chemical', 'MESH:D000069439', (135, 144))
268936	24565585	However, kinase mutations in DDR2 only represent ~50% of the total known mutations, and there does not appear to be a dominant set of point mutations within the exons that encode DDR2 kinase domain.	('DDR2', 'Gene', (29, 33))	('DDR2', 'Gene', '4921', (179, 183))	('kinase mutations', 'Var', (9, 25))	('DDR2', 'Gene', (179, 183))	('DDR2', 'Gene', '4921', (29, 33))
268937	24565585	While DDR2 mutation specific trials with dasatinib are ongoing, phase II results with dasatinib in unselected NSCLC cohorts are disappointing.	('NSCLC', 'Disease', (110, 115))	('DDR2', 'Gene', '4921', (6, 10))	('dasatinib', 'Chemical', 'MESH:D000069439', (41, 50))	('NSCLC', 'Disease', 'MESH:D002289', (110, 115))	('dasatinib', 'Chemical', 'MESH:D000069439', (86, 95))	('mutation', 'Var', (11, 19))	('DDR2', 'Gene', (6, 10))
268941	24565585	While preclinical studies validate that IGF1R plays a role in NSCLC oncogenesis, the frequency of these IGF1R deregulations in NSCLC patient cohorts has not been fully defined.	('NSCLC', 'Disease', (127, 132))	('NSCLC', 'Disease', (62, 67))	('NSCLC', 'Disease', 'MESH:D002289', (127, 132))	('IGF1R', 'Gene', '3480', (104, 109))	('NSCLC', 'Disease', 'MESH:D002289', (62, 67))	('IGF1R', 'Gene', (40, 45))	('patient', 'Species', '9606', (133, 140))	('deregulations', 'Var', (110, 123))	('oncogenesis', 'Disease', (68, 79))	('IGF1R', 'Gene', '3480', (40, 45))	('IGF1R', 'Gene', (104, 109))
268943	24565585	Currently, there are several clinical trials utilizing IGF1R inhibitors in unselected NSCLC patients, most notably with the dual IGF1R linsitinib (formerly OSI-906), which is being investigated as a single agent and in combination with erlotinib.	('linsitinib', 'Chemical', 'MESH:C551528', (135, 145))	('IGF1R', 'Gene', (129, 134))	('IGF1R', 'Gene', '3480', (55, 60))	('inhibitors', 'Var', (61, 71))	('NSCLC', 'Disease', (86, 91))	('patients', 'Species', '9606', (92, 100))	('NSCLC', 'Disease', 'MESH:D002289', (86, 91))	('IGF1R', 'Gene', '3480', (129, 134))	('erlotinib', 'Chemical', 'MESH:D000069347', (236, 245))	('OSI-906', 'Chemical', 'MESH:C551528', (156, 163))	('IGF1R', 'Gene', (55, 60))
268945	24565585	FGFR1 amplification occurs at a frequency to ~20% in squamous cell carcinoma.	('FGFR1', 'Gene', (0, 5))	('FGFR1', 'Gene', '2260', (0, 5))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (53, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('squamous cell carcinoma', 'Disease', (53, 76))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (53, 76))	('amplification', 'Var', (6, 19))
268946	24565585	FGFR1 amplification is a relatively rare occurrence in adenocarcinoma, occurring at a rate of ~1-3%.	('FGFR1', 'Gene', (0, 5))	('FGFR1', 'Gene', '2260', (0, 5))	('amplification', 'Var', (6, 19))	('carcinoma', 'Phenotype', 'HP:0030731', (60, 69))	('adenocarcinoma', 'Disease', (55, 69))	('rat', 'Species', '10116', (86, 89))	('adenocarcinoma', 'Disease', 'MESH:D000230', (55, 69))
268950	24565585	Activating mutations in the FGFR2/3 genes that are oncogenic and drug sensitive have recently been described in lung squamous cell cancers.	('FGFR2', 'Gene', (28, 33))	('FGFR2', 'Gene', '2263', (28, 33))	('cancers', 'Phenotype', 'HP:0002664', (131, 138))	('squamous cell cancers', 'Phenotype', 'HP:0002860', (117, 138))	('Activating mutations', 'Var', (0, 20))	('lung squamous cell cancers', 'Disease', 'MESH:D002294', (112, 138))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('lung squamous cell cancers', 'Disease', (112, 138))
268951	24565585	Oncogenic gene fusions involving the FGFR1/2/3 genes have recently been discovered in tumor samples from lung squamous cell cancers and may provide an additional predictive biomarker for FGFR-directed therapy.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('lung squamous cell cancers', 'Disease', 'MESH:D002294', (105, 131))	('tumor', 'Disease', (86, 91))	('fusions', 'Var', (15, 22))	('FGFR1/2/3', 'Gene', (37, 46))	('FGFR1/2/3', 'Gene', '2260;2263;2261', (37, 46))	('squamous cell cancers', 'Phenotype', 'HP:0002860', (110, 131))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('discovered', 'Reg', (72, 82))	('lung squamous cell cancers', 'Disease', (105, 131))	('cancers', 'Phenotype', 'HP:0002664', (124, 131))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
268953	24565585	Germline mutations in NTRK1 have been noted in patients with congenital insensitivity to pain, and sporadic chimeric gene fusions have been observed in papillary thyroid cancer and colon cancer.	('Germline mutations', 'Var', (0, 18))	('papillary thyroid cancer', 'Phenotype', 'HP:0002895', (152, 176))	('thyroid cancer', 'Phenotype', 'HP:0002890', (162, 176))	('pain', 'Disease', (89, 93))	('patients', 'Species', '9606', (47, 55))	('colon cancer', 'Phenotype', 'HP:0003003', (181, 193))	('papillary thyroid cancer', 'Disease', 'MESH:D000077273', (152, 176))	('observed', 'Reg', (140, 148))	('insensitivity to pain', 'Phenotype', 'HP:0007021', (72, 93))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('colon cancer', 'Disease', 'MESH:D015179', (181, 193))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('pain', 'Phenotype', 'HP:0012531', (89, 93))	('pain', 'Disease', 'MESH:D010146', (89, 93))	('NTRK1', 'Gene', (22, 27))	('papillary thyroid cancer', 'Disease', (152, 176))	('noted', 'Reg', (38, 43))	('colon cancer', 'Disease', (181, 193))
268954	24565585	Recent reports describe novel gene fusions of NTRK1 in 3/91 (3.3%) of NSCLC that were negative for other known oncogenic alterations via FISH and next generation sequencing.	('rat', 'Species', '10116', (125, 128))	('NTRK1', 'Gene', (46, 51))	('NSCLC', 'Disease', (70, 75))	('NSCLC', 'Disease', 'MESH:D002289', (70, 75))	('rat', 'Species', '10116', (155, 158))	('gene fusions', 'Var', (30, 42))
268957	24565585	The concept of 'personalized medicine' and 'targeted therapy' continue to evolve since the discovery of EGFR driver mutations and utilization of EGFR-specific TKI's in NSCLC.	('EGFR', 'Gene', '1956', (104, 108))	('EGFR', 'Gene', (104, 108))	('EGFR', 'Gene', '1956', (145, 149))	('NSCLC', 'Disease', 'MESH:D002289', (168, 173))	('EGFR', 'Gene', (145, 149))	('mutations', 'Var', (116, 125))	('NSCLC', 'Disease', (168, 173))
268958	24565585	Molecular techniques such as multiplex PCR, FISH, and next generation sequencing have improved in quality and cost to where multiple platforms now exist to identify clinically significant driver mutations, gene amplifications, or chimeric fusions from tumor tissue at the time of diagnosis or progression.	('rat', 'Species', '10116', (63, 66))	('tumor', 'Disease', 'MESH:D009369', (252, 257))	('tumor', 'Phenotype', 'HP:0002664', (252, 257))	('chimeric', 'Var', (230, 238))	('mutations', 'Var', (195, 204))	('tumor', 'Disease', (252, 257))
268963	24565585	While the majority of patients experience an initial clinical benefit, crizotinib-treated ALK+ NSCLC and erlotinib/gefitinib-treated EGFR+ NSCLC patients eventually develop resistance, doing so by additional point mutations, gene amplifications, or by switching to different driver oncogenes entirely.	('patients', 'Species', '9606', (145, 153))	('NSCLC', 'Disease', 'MESH:D002289', (95, 100))	('develop', 'PosReg', (165, 172))	('crizotinib', 'Chemical', 'MESH:D000077547', (71, 81))	('gene amplifications', 'Var', (225, 244))	('resistance', 'MPA', (173, 183))	('gefitinib', 'Chemical', 'MESH:D000077156', (115, 124))	('ALK', 'Gene', '238', (90, 93))	('patients', 'Species', '9606', (22, 30))	('NSCLC', 'Disease', (95, 100))	('NSCLC', 'Disease', (139, 144))	('erlotinib', 'Chemical', 'MESH:D000069347', (105, 114))	('ALK', 'Gene', (90, 93))	('EGFR', 'Gene', '1956', (133, 137))	('NSCLC', 'Disease', 'MESH:D002289', (139, 144))	('point mutations', 'Var', (208, 223))	('EGFR', 'Gene', (133, 137))
268967	24565585	Techniques that allow for a 'liquid biopsy' and molecular diagnosis of ALK and EGFR mutations via circulating tumor cells are being evaluated with promising initial results, but await prospective validation before they replace current companion diagnostic tests.	('ALK', 'Gene', (71, 74))	('EGFR', 'Gene', '1956', (79, 83))	('EGFR', 'Gene', (79, 83))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('ALK', 'Gene', '238', (71, 74))	('mutations', 'Var', (84, 93))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
268968	24565585	Lastly, there is significant heterogeneity in mutation prevalence amongst different NSCLC histologies, and while progress has been made in defining molecular subtypes in squamous cell carcinoma, the molecular landscape for this and rarer NSCLC histologic subtypes is not well characterized.	('carcinoma', 'Phenotype', 'HP:0030731', (184, 193))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (170, 193))	('NSCLC', 'Disease', (84, 89))	('squamous cell carcinoma', 'Disease', (170, 193))	('NSCLC', 'Disease', (238, 243))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (170, 193))	('NSCLC', 'Disease', 'MESH:D002289', (84, 89))	('NSCLC', 'Disease', 'MESH:D002289', (238, 243))	('mutation', 'Var', (46, 54))
268981	32674491	Approximately 3-7% of nonsmall cell lung cancer (NSCLC) patients have neoplasms with constitutive anaplastic large-cell lymphoma kinase (ALK) activity due to ALK abnormalities, most frequently in the form of intrachromosomal inversion and consequent ALK rearrangement with the partner echinoderm microtubule associated protein-like 4 (EML4) forming EML4-ALK fusion.	('patients', 'Species', '9606', (56, 64))	('NSCLC', 'Disease', (49, 54))	('ALK', 'Gene', '238', (354, 357))	('echinoderm microtubule associated protein-like 4', 'Gene', (285, 333))	('ALK', 'Gene', '238', (250, 253))	('ALK', 'Gene', (354, 357))	('NSCLC', 'Phenotype', 'HP:0030358', (49, 54))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('ALK', 'Gene', (250, 253))	('activity', 'MPA', (142, 150))	('neoplasms', 'Disease', 'MESH:D009369', (70, 79))	('cell lymphoma', 'Phenotype', 'HP:0012191', (115, 128))	('lymphoma', 'Phenotype', 'HP:0002665', (120, 128))	('ALK abnormalities', 'Disease', (158, 175))	('men', 'Species', '9606', (263, 266))	('nonsmall cell lung cancer', 'Disease', 'MESH:D002289', (22, 47))	('ALK', 'Gene', '238', (137, 140))	('rearrangement', 'Var', (254, 267))	('ALK', 'Gene', (137, 140))	('neoplasms', 'Disease', (70, 79))	('intrachromosomal inversion', 'Var', (208, 234))	('ALK abnormalities', 'Disease', 'MESH:D018376', (158, 175))	('ALK', 'Gene', '238', (158, 161))	('anaplastic large-cell lymphoma', 'Phenotype', 'HP:0012193', (98, 128))	('EML4', 'Gene', (349, 353))	('lymphoma', 'Disease', (120, 128))	('lymphoma', 'Disease', 'MESH:D008223', (120, 128))	('ALK', 'Gene', (158, 161))	('EML4', 'Gene', (335, 339))	('echinoderm microtubule associated protein-like 4', 'Gene', '27436', (285, 333))	('NSCLC', 'Disease', 'MESH:D002289', (49, 54))	('EML4', 'Gene', '27436', (349, 353))	('EML4', 'Gene', '27436', (335, 339))	('nonsmall cell lung cancer', 'Disease', (22, 47))	('nonsmall cell lung cancer', 'Phenotype', 'HP:0030358', (22, 47))	('lung cancer', 'Phenotype', 'HP:0100526', (36, 47))	('neoplasms', 'Phenotype', 'HP:0002664', (70, 79))
269016	32674491	A total of 21 (50%) samples were positive for ALK rearrangement, with positive result rates ranging from 18 to 88% (median, 50%) of nuclei.	('men', 'Species', '9606', (59, 62))	('ALK', 'Gene', (46, 49))	('ALK', 'Gene', '238', (46, 49))	('rearrangement', 'Var', (50, 63))
269023	32674491	The first specimen of case #12 was tested twice with ALK FISH, but only 9-10% of tumor cells were identified as positive for ALK rearrangement, which is below the established cutoff value (>=15%) for a positive result.	('rearrangement', 'Var', (129, 142))	('ALK', 'Gene', (53, 56))	('men', 'Species', '9606', (138, 141))	('ALK', 'Gene', '238', (125, 128))	('men', 'Species', '9606', (15, 18))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('ALK', 'Gene', '238', (53, 56))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('ALK', 'Gene', (125, 128))	('tumor', 'Disease', (81, 86))
269025	32674491	The discrepancy can likely be explained by sensitivity; the number of ALK rearrangement positive cells in this specimen was below the limit of detection by FISH, but not by RNA-seq.	('ALK', 'Gene', '238', (70, 73))	('men', 'Species', '9606', (83, 86))	('ALK', 'Gene', (70, 73))	('rearrangement', 'Var', (74, 87))	('men', 'Species', '9606', (116, 119))	('positive', 'Reg', (88, 96))
269040	32674491	The high frequency of negative results was expected, as we test all new patients with lung cancer by FISH for ALK status, and the frequency of ALK rearrangement in lung cancer ranges from 3 to 7% in various studies.	('rearrangement', 'Var', (147, 160))	('test', 'Reg', (59, 63))	('lung cancer', 'Disease', (164, 175))	('lung cancer', 'Phenotype', 'HP:0100526', (164, 175))	('ALK', 'Gene', '238', (110, 113))	('men', 'Species', '9606', (156, 159))	('ALK', 'Gene', (143, 146))	('lung cancer', 'Phenotype', 'HP:0100526', (86, 97))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('lung cancer', 'Disease', (86, 97))	('ALK', 'Gene', (110, 113))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('lung cancer', 'Disease', 'MESH:D008175', (164, 175))	('ALK', 'Gene', '238', (143, 146))	('lung cancer', 'Disease', 'MESH:D008175', (86, 97))	('patients', 'Species', '9606', (72, 80))
269058	32674491	The subsequent ALK rearrangement negative tumor cells may be related to clonal evolution under selective pressure by ALK TKIs.	('ALK', 'Gene', (15, 18))	('tumor', 'Disease', (42, 47))	('men', 'Species', '9606', (28, 31))	('ALK', 'Gene', '238', (117, 120))	('ALK', 'Gene', '238', (15, 18))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('ALK', 'Gene', (117, 120))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('rearrangement', 'Var', (19, 32))
269094	32674491	However, genes such as ALK, BRAF, EGFR, KRAS, RET and many other mutations that are considered to be hotspots for lung cancer are included in both 50-gene and 134-gene panels.	('BRAF', 'Gene', '673', (28, 32))	('lung cancer', 'Disease', 'MESH:D008175', (114, 125))	('EGFR', 'Gene', (34, 38))	('ALK', 'Gene', (23, 26))	('KRAS', 'Gene', (40, 44))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('RET', 'Gene', '5979', (46, 49))	('lung cancer', 'Disease', (114, 125))	('ALK', 'Gene', '238', (23, 26))	('KRAS', 'Gene', '3845', (40, 44))	('lung cancer', 'Phenotype', 'HP:0100526', (114, 125))	('BRAF', 'Gene', (28, 32))	('EGFR', 'Gene', '1956', (34, 38))	('mutations', 'Var', (65, 74))	('RET', 'Gene', (46, 49))
269099	32674491	This RNA-seq assay is amplicon-based and specific for EML4-ALK fusions.	('ALK', 'Gene', '238', (59, 62))	('EML4', 'Gene', '27436', (54, 58))	('ALK', 'Gene', (59, 62))	('fusions', 'Var', (63, 70))	('EML4', 'Gene', (54, 58))
269114	30405797	Outcomes indicated that combined treatment of lenvatinib and rAd-p53 markedly inhibited tumor growth compared to lenvatinib and rAd-p53 alone for NSCLC patients.	('lenvatinib', 'Var', (46, 56))	('rAd', 'Gene', '6236', (128, 131))	('p53', 'Gene', '7157', (65, 68))	('rAd', 'Gene', (61, 64))	('p53', 'Gene', (65, 68))	('lenvatinib', 'Chemical', 'MESH:C531958', (113, 123))	('NSCLC', 'Disease', 'MESH:D002289', (146, 151))	('tumor', 'Disease', (88, 93))	('rAd', 'Gene', (128, 131))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('p53', 'Gene', '7157', (132, 135))	('NSCLC', 'Disease', (146, 151))	('rAd', 'Gene', '6236', (61, 64))	('NSCLC', 'Phenotype', 'HP:0030358', (146, 151))	('patients', 'Species', '9606', (152, 160))	('men', 'Species', '9606', (38, 41))	('lenvatinib', 'Chemical', 'MESH:C531958', (46, 56))	('inhibited', 'NegReg', (78, 87))	('p53', 'Gene', (132, 135))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))
269186	30405797	Blood vessel density was lower in combined treatment of Lenvatinib and rAd-p53group than rAd-p53 and Lenvatinib groups (Fig.	('Lenvatinib', 'Chemical', 'MESH:C531958', (101, 111))	('Blood vessel density', 'CPA', (0, 20))	('men', 'Species', '9606', (48, 51))	('rAd', 'Gene', (71, 74))	('p53', 'Gene', (93, 96))	('p53', 'Gene', '7157', (93, 96))	('rAd', 'Gene', '6236', (71, 74))	('Lenvatinib', 'Var', (56, 66))	('lower', 'NegReg', (25, 30))	('p53', 'Gene', (75, 78))	('rAd', 'Gene', (89, 92))	('p53', 'Gene', '7157', (75, 78))	('rAd', 'Gene', '6236', (89, 92))	('Lenvatinib', 'Chemical', 'MESH:C531958', (56, 66))
269192	30405797	Notably, outcomes found that combined treatment of Lenvatinib and rAd-p53 improved survival rate of and progression-free survival (PFS) compared to either Lenvatinib or rAd-p53 for NSCLC patients (Fig.	('NSCLC', 'Disease', 'MESH:D002289', (181, 186))	('men', 'Species', '9606', (43, 46))	('Lenvatinib', 'Chemical', 'MESH:C531958', (155, 165))	('NSCLC', 'Disease', (181, 186))	('rAd', 'Gene', (66, 69))	('patients', 'Species', '9606', (187, 195))	('rAd', 'Gene', (169, 172))	('survival rate', 'CPA', (83, 96))	('p53', 'Gene', '7157', (173, 176))	('NSCLC', 'Phenotype', 'HP:0030358', (181, 186))	('Lenvatinib', 'Chemical', 'MESH:C531958', (51, 61))	('p53', 'Gene', (173, 176))	('progression-free survival', 'CPA', (104, 129))	('p53', 'Gene', '7157', (70, 73))	('Lenvatinib', 'Var', (51, 61))	('rAd', 'Gene', '6236', (66, 69))	('p53', 'Gene', (70, 73))	('rAd', 'Gene', '6236', (169, 172))	('improved', 'PosReg', (74, 82))
269210	30405797	Study has found that surgery combined with adenoviral p53 gene therapy showed efficacious effects in preventing recurrence or metastasis and improving progression free survival and overall survival after a radical surgery in patients with NSCLC in a phase II study.	('patients', 'Species', '9606', (225, 233))	('recurrence', 'CPA', (112, 122))	('progression free survival', 'CPA', (151, 176))	('NSCLC', 'Phenotype', 'HP:0030358', (239, 244))	('p53', 'Gene', (54, 57))	('metastasis', 'CPA', (126, 136))	('NSCLC', 'Disease', (239, 244))	('adenoviral', 'Var', (43, 53))	('p53', 'Gene', '7157', (54, 57))	('NSCLC', 'Disease', 'MESH:D002289', (239, 244))	('improving', 'PosReg', (141, 150))	('overall survival', 'CPA', (181, 197))
269213	30405797	Outcomes found that the most common treatment-related treatment-emergent adverse events were hypertension, diarrhea, nausea, proteinuria and body weight less in NSCLC patients after treatment with Lenvatinib and/or rAd-p53, which could metabolize after 48 h drug taken.	('Lenvatinib', 'Chemical', 'MESH:C531958', (197, 207))	('rAd', 'Gene', '6236', (215, 218))	('proteinuria', 'Phenotype', 'HP:0000093', (125, 136))	('diarrhea', 'Phenotype', 'HP:0002014', (107, 115))	('men', 'Species', '9606', (41, 44))	('Lenvatinib', 'Var', (197, 207))	('hypertension', 'Phenotype', 'HP:0000822', (93, 105))	('less', 'NegReg', (153, 157))	('nausea', 'Phenotype', 'HP:0002018', (117, 123))	('diarrhea', 'Disease', (107, 115))	('NSCLC', 'Disease', 'MESH:D002289', (161, 166))	('rAd', 'Gene', (215, 218))	('hypertension', 'Disease', (93, 105))	('nausea', 'Disease', (117, 123))	('body weight', 'CPA', (141, 152))	('diarrhea', 'Disease', 'MESH:D003967', (107, 115))	('NSCLC', 'Disease', (161, 166))	('p53', 'Gene', '7157', (219, 222))	('proteinuria', 'Disease', (125, 136))	('men', 'Species', '9606', (187, 190))	('patients', 'Species', '9606', (167, 175))	('nausea', 'Disease', 'MESH:D009325', (117, 123))	('hypertension', 'Disease', 'MESH:D006973', (93, 105))	('NSCLC', 'Phenotype', 'HP:0030358', (161, 166))	('proteinuria', 'Disease', 'MESH:D011507', (125, 136))	('p53', 'Gene', (219, 222))	('men', 'Species', '9606', (59, 62))
269214	30405797	Notably, combined treatment of Lenvatinib and rAd-p53 improved survival rate of and progression-free survival (PFS) compared to either Lenvatinib or rAd-p53 for NSCLC patients.	('Lenvatinib', 'Var', (31, 41))	('p53', 'Gene', (50, 53))	('p53', 'Gene', '7157', (153, 156))	('progression-free survival', 'CPA', (84, 109))	('rAd', 'Gene', '6236', (149, 152))	('rAd', 'Gene', '6236', (46, 49))	('p53', 'Gene', (153, 156))	('improved', 'PosReg', (54, 62))	('NSCLC', 'Disease', 'MESH:D002289', (161, 166))	('men', 'Species', '9606', (23, 26))	('NSCLC', 'Disease', (161, 166))	('rAd', 'Gene', (149, 152))	('Lenvatinib', 'Chemical', 'MESH:C531958', (135, 145))	('survival rate', 'CPA', (63, 76))	('rAd', 'Gene', (46, 49))	('patients', 'Species', '9606', (167, 175))	('NSCLC', 'Phenotype', 'HP:0030358', (161, 166))	('p53', 'Gene', '7157', (50, 53))	('Lenvatinib', 'Chemical', 'MESH:C531958', (31, 41))
269223	28558758	Amplification of fibroblast growth factor receptor 1 (FGFR1) is one of the most frequent targets in lung squamous cell carcinoma (SQCC).	('fibroblast growth factor receptor 1', 'Gene', '2260', (17, 52))	('SQCC', 'Phenotype', 'HP:0002860', (130, 134))	('Amplification', 'Var', (0, 13))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (100, 128))	('FGFR1', 'Gene', (54, 59))	('FGFR1', 'Gene', '2260', (54, 59))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (100, 128))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (105, 128))	('lung squamous cell carcinoma', 'Disease', (100, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('fibroblast growth factor receptor 1', 'Gene', (17, 52))
269227	28558758	Pharmacological or genetic inhibition of FGFR1 by AZD4547 or FGFR1 short hairpin RNA (shRNA) induced autophagy in FGFR1-amplified non-small cell lung cancer (NSCLC) cells, H1581 and H520 cells.	('NSCLC', 'Disease', 'MESH:D002289', (158, 163))	('FGFR1', 'Gene', '2260', (61, 66))	('cell lung cancer', 'Disease', 'MESH:D008175', (140, 156))	('inhibition', 'Var', (27, 37))	('lung cancer', 'Phenotype', 'HP:0100526', (145, 156))	('FGFR1', 'Gene', (41, 46))	('NSCLC', 'Disease', (158, 163))	('autophagy', 'CPA', (101, 110))	('cell lung cancer', 'Disease', (140, 156))	('NSCLC', 'Phenotype', 'HP:0030358', (158, 163))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (130, 156))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('FGFR1', 'Gene', '2260', (114, 119))	('FGFR1', 'Gene', (61, 66))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (134, 156))	('FGFR1', 'Gene', '2260', (41, 46))	('H1581', 'CellLine', 'CVCL:1479', (172, 177))	('induced', 'Reg', (93, 100))	('H520', 'CellLine', 'CVCL:1566', (182, 186))	('AZD4547', 'Chemical', 'MESH:C572463', (50, 57))	('FGFR1', 'Gene', (114, 119))
269229	28558758	Furthermore, activation of ERK/MAPK by transfection with a constitutively active MEK1 (caMEK1) construct or knockdown of beclin-1 by RNAi could attenuate autophagy induced by FGFR1 inhibition.	('knockdown', 'Var', (108, 117))	('RNAi', 'Gene', (133, 137))	('attenuate', 'NegReg', (144, 153))	('beclin-1', 'Gene', (121, 129))	('MEK1', 'Gene', '5604', (81, 85))	('FGFR1', 'Gene', (175, 180))	('MEK1', 'Gene', '5604', (89, 93))	('MEK1', 'Gene', (81, 85))	('activation', 'PosReg', (13, 23))	('MAPK', 'Gene', (31, 35))	('beclin-1', 'Gene', '8678', (121, 129))	('MAPK', 'Gene', '5595;5594;5595', (31, 35))	('ERK', 'Gene', '5594', (27, 30))	('MEK1', 'Gene', (89, 93))	('FGFR1', 'Gene', '2260', (175, 180))	('autophagy', 'CPA', (154, 163))	('ERK', 'Gene', (27, 30))
269231	28558758	Inhibition of autophagy by beclin-1 silencing could enhance apoptosis after AZD4547 treatment in H1581 and H520 cells.	('autophagy', 'CPA', (14, 23))	('H1581', 'CellLine', 'CVCL:1479', (97, 102))	('beclin-1', 'Gene', '8678', (27, 35))	('H520', 'CellLine', 'CVCL:1566', (107, 111))	('apoptosis', 'CPA', (60, 69))	('enhance', 'PosReg', (52, 59))	('silencing', 'Var', (36, 45))	('AZD4547', 'Chemical', 'MESH:C572463', (76, 83))	('beclin-1', 'Gene', (27, 35))
269232	28558758	High levels of LC3B mRNA was a marker of poor prognosis in NSCLC patients.	('NSCLC', 'Disease', 'MESH:D002289', (59, 64))	('High', 'Var', (0, 4))	('LC3B', 'Gene', '81631', (15, 19))	('NSCLC', 'Phenotype', 'HP:0030358', (59, 64))	('patients', 'Species', '9606', (65, 73))	('LC3B', 'Gene', (15, 19))	('NSCLC', 'Disease', (59, 64))
269240	28558758	Aberrant FGFR signaling due to FGFR amplification, autocrine stimulation, gene fusion, or activating mutation is associated with many cancers.	('gene fusion', 'Var', (74, 85))	('Aberrant', 'Var', (0, 8))	('cancers', 'Disease', 'MESH:D009369', (134, 141))	('cancers', 'Phenotype', 'HP:0002664', (134, 141))	('cancers', 'Disease', (134, 141))	('amplification', 'Var', (36, 49))	('activating', 'MPA', (90, 100))	('FGFR', 'Gene', (31, 35))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('FGFR signaling', 'MPA', (9, 23))	('associated', 'Reg', (113, 123))
269241	28558758	The frequency of FGFR1 amplification is 21-22% in lung SQCC samples.	('SQCC', 'Phenotype', 'HP:0002860', (55, 59))	('amplification', 'Var', (23, 36))	('FGFR1', 'Gene', (17, 22))	('FGFR1', 'Gene', '2260', (17, 22))	('lung SQCC', 'Disease', (50, 59))
269250	28558758	have revealed that activation of FGFR3 inhibited autophagic activity through decreasing the level of ATG12-ATG5 conjugation in chondrocytes.	('activation', 'Var', (19, 29))	('ATG5', 'Gene', '9474', (107, 111))	('inhibited', 'NegReg', (39, 48))	('decreasing', 'NegReg', (77, 87))	('ATG12', 'Gene', '9140', (101, 106))	('FGFR3', 'Gene', '2261', (33, 38))	('ATG5', 'Gene', (107, 111))	('autophagic activity', 'CPA', (49, 68))	('ATG12', 'Gene', (101, 106))	('FGFR3', 'Gene', (33, 38))
269255	28558758	Suppression of FGFR1 increases the protein level of beclin-1 and induces autophagy through inhibiting the ERK/MAPK pathway.	('inhibiting', 'NegReg', (91, 101))	('increases', 'PosReg', (21, 30))	('autophagy', 'CPA', (73, 82))	('FGFR1', 'Gene', '2260', (15, 20))	('Suppression', 'Var', (0, 11))	('MAPK', 'Gene', (110, 114))	('induces', 'Reg', (65, 72))	('protein level', 'MPA', (35, 48))	('beclin-1', 'Gene', (52, 60))	('beclin-1', 'Gene', '8678', (52, 60))	('ERK', 'Gene', '5594', (106, 109))	('MAPK', 'Gene', '5595;5594;5595', (110, 114))	('ERK', 'Gene', (106, 109))	('FGFR1', 'Gene', (15, 20))
269259	28558758	A selective inhibitor of FGFR1, 2 and 3, AZD4547 (a gift from AstraZeneca) was dissolved in dimethyl sulfoxide (DMSO) for storage.	('AZD4547', 'Chemical', 'MESH:C572463', (41, 48))	('DMSO', 'Chemical', 'MESH:D004121', (112, 116))	('dimethyl sulfoxide', 'Chemical', 'MESH:D004121', (92, 110))	('FGFR1', 'Gene', (25, 30))	('FGFR1', 'Gene', '2260', (25, 30))	('AZD4547', 'Var', (41, 48))
269261	28558758	The antibodies for western blotting and their relevant sources are as follows: Anti-LC3B (Sigma-Aldrich); GAPDH (Abmart); Tubulin (Abcam); total and Tyr653/654-phosphorylated FGFR, total and T202/Y204-phosphorylated extracellular signal-activated kinase (ERK), total and Tyr705-phosphorylated Stat3, PARP and Caspase-9 (Cell Signaling Technology, Inc.); total and S473-phosphorylated AKT1 (Epitomics); beclin-1 (Proteintech).	('Caspase-9', 'Gene', '842', (309, 318))	('PARP', 'Gene', '142', (300, 304))	('LC3B', 'Gene', '81631', (84, 88))	('beclin-1', 'Gene', (402, 410))	('Caspase-9', 'Gene', (309, 318))	('PARP', 'Gene', (300, 304))	('S473-phosphorylated', 'Var', (364, 383))	('ERK', 'Gene', '5594', (255, 258))	('GAPDH', 'Gene', (106, 111))	('ERK', 'Gene', (255, 258))	('AKT1', 'Gene', '207', (384, 388))	('Stat3', 'Gene', (293, 298))	('Stat3', 'Gene', '6774', (293, 298))	('AKT1', 'Gene', (384, 388))	('beclin-1', 'Gene', '8678', (402, 410))	('extracellular signal-activated kinase', 'Gene', '5594', (216, 253))	('extracellular signal-activated kinase', 'Gene', (216, 253))	('LC3B', 'Gene', (84, 88))	('GAPDH', 'Gene', '2597', (106, 111))
269288	28558758	Constitutively active MEK (S218D/S222D), and FGFR1 construct were ordered from Addgene.	('S218D', 'Var', (27, 32))	('S218D', 'SUBSTITUTION', 'None', (27, 32))	('S222D', 'SUBSTITUTION', 'None', (33, 38))	('S222D', 'Var', (33, 38))	('FGFR1', 'Gene', (45, 50))	('MEK', 'Gene', (22, 25))	('FGFR1', 'Gene', '2260', (45, 50))	('MEK', 'Gene', '5609', (22, 25))
269303	28558758	2a-d, AZD4547 resulted in a minor increase in the level of LC3-II.	('AZD4547', 'Var', (6, 13))	('AZD4547', 'Chemical', 'MESH:C572463', (6, 13))	('LC3', 'Gene', '84557', (59, 62))	('LC3', 'Gene', (59, 62))	('increase', 'PosReg', (34, 42))	('level', 'MPA', (50, 55))
269306	28558758	Thus AZD4547 induced a more pronounced accumulation of LC3-II in the presence of lysosomal protease inhibitors (Fig.	('LC3', 'Gene', '84557', (55, 58))	('LC3', 'Gene', (55, 58))	('AZD4547', 'Var', (5, 12))	('AZD4547', 'Chemical', 'MESH:C572463', (5, 12))	('accumulation', 'PosReg', (39, 51))
269308	28558758	Using two well established markers of this cellular process, we demonstrated that knockdown of FGFR1 induced autophagy by the increase in the level of LC3-II in H1581 and H520 cells (Fig.	('LC3', 'Gene', '84557', (151, 154))	('LC3', 'Gene', (151, 154))	('FGFR1', 'Gene', (95, 100))	('knockdown', 'Var', (82, 91))	('H1581', 'CellLine', 'CVCL:1479', (161, 166))	('FGFR1', 'Gene', '2260', (95, 100))	('level', 'MPA', (142, 147))	('increase', 'PosReg', (126, 134))	('autophagy', 'CPA', (109, 118))	('H520', 'CellLine', 'CVCL:1566', (171, 175))
269309	28558758	FGFR1 silencing increased GFP-LC3 puncta in H1581 cells stably transfected with GFP-LC3 (Fig.	('increased GFP', 'Phenotype', 'HP:0012214', (16, 29))	('FGFR1', 'Gene', (0, 5))	('H1581', 'CellLine', 'CVCL:1479', (44, 49))	('FGFR1', 'Gene', '2260', (0, 5))	('increased', 'PosReg', (16, 25))	('LC3', 'Gene', '84557', (84, 87))	('LC3', 'Gene', '84557', (30, 33))	('silencing', 'Var', (6, 15))	('LC3', 'Gene', (30, 33))	('LC3', 'Gene', (84, 87))
269311	28558758	In addition to utilization of LC3-II accumulation and GFP-LC3 puncta formation as markers of autophagy, we further explored MDC staining to confirm induction of autophagy by AZD4547.	('AZD4547', 'Chemical', 'MESH:C572463', (174, 181))	('LC3', 'Gene', (58, 61))	('MDC', 'Chemical', 'MESH:C008542', (124, 127))	('AZD4547', 'Var', (174, 181))	('LC3', 'Gene', '84557', (30, 33))	('LC3', 'Gene', (30, 33))	('LC3', 'Gene', '84557', (58, 61))
269312	28558758	As shown in Additional file 5: Figure S3, treatment with AZD4547 induced the accumulation of MDC in the cytoplasmic vacuoles in both cell lines.	('AZD4547', 'Chemical', 'MESH:C572463', (57, 64))	('accumulation', 'PosReg', (77, 89))	('MDC', 'Chemical', 'MESH:C008542', (93, 96))	('MDC in', 'MPA', (93, 99))	('AZD4547', 'Var', (57, 64))
269314	28558758	All these suggest that pharmacological or genetic inhibition of FGFR1 induces autophagic activity in FGFR1-amplified NSCLC cells.	('NSCLC', 'Disease', (117, 122))	('inhibition', 'Var', (50, 60))	('induces', 'Reg', (70, 77))	('autophagic activity', 'CPA', (78, 97))	('FGFR1', 'Gene', (64, 69))	('NSCLC', 'Disease', 'MESH:D002289', (117, 122))	('FGFR1', 'Gene', '2260', (64, 69))	('NSCLC', 'Phenotype', 'HP:0030358', (117, 122))	('FGFR1', 'Gene', (101, 106))	('FGFR1', 'Gene', '2260', (101, 106))
269321	28558758	Downregulation of FGFR1 by transduction of FGFR1-specific shRNAs inhibited ERK1/2 phosphorylation, but no effect on phosphorylation of AKT in H1581 and H520 cells (Fig.	('FGFR1', 'Gene', (43, 48))	('transduction', 'Var', (27, 39))	('Downregulation', 'NegReg', (0, 14))	('H520', 'CellLine', 'CVCL:1566', (152, 156))	('FGFR1', 'Gene', '2260', (43, 48))	('FGFR1', 'Gene', (18, 23))	('ERK1/2', 'Gene', '5595;5594', (75, 81))	('inhibited', 'NegReg', (65, 74))	('FGFR1', 'Gene', '2260', (18, 23))	('ERK1/2', 'Gene', (75, 81))	('H1581', 'CellLine', 'CVCL:1479', (142, 147))
269323	28558758	These data partially indicated that inhibition of the ERK/MAPK signaling pathway was required for the induction of autophagy after AZD4547 treatment.	('ERK', 'Gene', '5594', (54, 57))	('autophagy', 'CPA', (115, 124))	('AZD4547', 'Var', (131, 138))	('MAPK', 'Gene', (58, 62))	('ERK', 'Gene', (54, 57))	('MAPK', 'Gene', '5595;5594;5595', (58, 62))	('AZD4547', 'Chemical', 'MESH:C572463', (131, 138))
269326	28558758	These results indicate that the induction of autophagy after FGFR1 inhibition is mediated through suppressing the ERK/MAPK pathway, but not the PI3K/AKT pathway.	('inhibition', 'Var', (67, 77))	('FGFR1', 'Gene', (61, 66))	('autophagy', 'CPA', (45, 54))	('ERK', 'Gene', (114, 117))	('suppressing', 'NegReg', (98, 109))	('FGFR1', 'Gene', '2260', (61, 66))	('MAPK', 'Gene', (118, 122))	('MAPK', 'Gene', '5595;5594;5595', (118, 122))	('ERK', 'Gene', '5594', (114, 117))
269327	28558758	4a and b, AZD4547 treatment upregulated the expression of beclin-1 in H1581 and H520 cells.	('expression', 'MPA', (44, 54))	('AZD4547', 'Var', (10, 17))	('beclin-1', 'Gene', (58, 66))	('AZD4547', 'Chemical', 'MESH:C572463', (10, 17))	('H520', 'CellLine', 'CVCL:1566', (80, 84))	('beclin-1', 'Gene', '8678', (58, 66))	('upregulated', 'PosReg', (28, 39))	('H1581', 'CellLine', 'CVCL:1479', (70, 75))
269328	28558758	Similarly, knockdown of FGFR1 increased the level of beclin-1 in stably transduced H1581 and H520 cells (Fig.	('H1581', 'CellLine', 'CVCL:1479', (83, 88))	('H520', 'CellLine', 'CVCL:1566', (93, 97))	('beclin-1', 'Gene', '8678', (53, 61))	('FGFR1', 'Gene', (24, 29))	('FGFR1', 'Gene', '2260', (24, 29))	('increased', 'PosReg', (30, 39))	('FGFR1 increased', 'Phenotype', 'HP:0030269', (24, 39))	('beclin-1', 'Gene', (53, 61))	('knockdown', 'Var', (11, 20))
269330	28558758	AZD4547-induced autophagy was inhibited by beclin-1 silencing in H1581 cells (Fig.	('H1581', 'CellLine', 'CVCL:1479', (65, 70))	('silencing', 'Var', (52, 61))	('AZD4547', 'Chemical', 'MESH:C572463', (0, 7))	('inhibited', 'NegReg', (30, 39))	('beclin-1', 'Gene', (43, 51))	('autophagy', 'CPA', (16, 25))	('beclin-1', 'Gene', '8678', (43, 51))
269331	28558758	Furthermore, inhibition of beclin-1 prevented LC3-II accumulation induced by shFGFR1 (Fig.	('beclin-1', 'Gene', '8678', (27, 35))	('inhibition', 'Var', (13, 23))	('FGFR1', 'Gene', (79, 84))	('LC3', 'Gene', '84557', (46, 49))	('LC3', 'Gene', (46, 49))	('FGFR1', 'Gene', '2260', (79, 84))	('beclin-1', 'Gene', (27, 35))
269335	28558758	5b) blocked upregulation of beclin-1 by FGFR1 inhibition.	('inhibition', 'Var', (46, 56))	('upregulation', 'PosReg', (12, 24))	('beclin-1', 'Gene', (28, 36))	('FGFR1', 'Gene', (40, 45))	('beclin-1', 'Gene', '8678', (28, 36))	('FGFR1', 'Gene', '2260', (40, 45))
269336	28558758	Activation of ERK/MAPK pathway prevented LC3-II accumulation induced by FGFR1 inhibition (Fig.	('ERK', 'Gene', (14, 17))	('LC3', 'Gene', '84557', (41, 44))	('LC3', 'Gene', (41, 44))	('MAPK', 'Gene', (18, 22))	('prevented', 'NegReg', (31, 40))	('inhibition', 'Var', (78, 88))	('MAPK', 'Gene', '5595;5594;5595', (18, 22))	('ERK', 'Gene', '5594', (14, 17))	('FGFR1', 'Gene', (72, 77))	('FGFR1', 'Gene', '2260', (72, 77))
269337	28558758	These indicate that pharmacological or genetic inhibition of FGFR1 increased level of beclin-1, which is mediated at least in part through inhibiting ERK/MAPK pathway.	('FGFR1 increased level', 'Phenotype', 'HP:0030269', (61, 82))	('MAPK', 'Gene', (154, 158))	('FGFR1', 'Gene', (61, 66))	('MAPK', 'Gene', '5595;5594;5595', (154, 158))	('ERK', 'Gene', '5594', (150, 153))	('FGFR1 increased', 'Phenotype', 'HP:0030269', (61, 76))	('beclin-1', 'Gene', (86, 94))	('beclin-1', 'Gene', '8678', (86, 94))	('FGFR1', 'Gene', '2260', (61, 66))	('ERK', 'Gene', (150, 153))	('increased', 'PosReg', (67, 76))	('genetic inhibition', 'Var', (39, 57))	('inhibiting', 'NegReg', (139, 149))
269338	28558758	Downregulation of beclin-1 suppressed the induction of autophagy by FGFR1 inhibition (Fig.	('inhibition', 'Var', (74, 84))	('FGFR1', 'Gene', (68, 73))	('Downregulation', 'NegReg', (0, 14))	('autophagy', 'CPA', (55, 64))	('beclin-1', 'Gene', (18, 26))	('beclin-1', 'Gene', '8678', (18, 26))	('FGFR1', 'Gene', '2260', (68, 73))
269339	28558758	4e and g) but did not affect inhibition of ERK phosphorylation by AZD4547 or shFGFR1 (Fig.	('AZD4547', 'Chemical', 'MESH:C572463', (66, 73))	('ERK', 'Gene', '5594', (43, 46))	('FGFR1', 'Gene', (79, 84))	('ERK', 'Gene', (43, 46))	('FGFR1', 'Gene', '2260', (79, 84))	('AZD4547', 'Var', (66, 73))
269342	28558758	A statistically negative correlation between beclin-1 and p-MEK1 (S217/S221, Pearson's r = -0.2152) was observed in a cohort of lung SQCC samples (Fig.	('negative', 'NegReg', (16, 24))	('MEK1', 'Gene', '5604', (60, 64))	('beclin-1', 'Gene', (45, 53))	('S217/S221', 'Var', (66, 75))	('beclin-1', 'Gene', '8678', (45, 53))	('MEK1', 'Gene', (60, 64))	('SQCC', 'Phenotype', 'HP:0002860', (133, 137))	('lung SQCC', 'Disease', (128, 137))
269343	28558758	Inverse correlation of beclin-1 expression and MEK1 phosphorylation (S217/S221, Pearson's r = -0.2273) was also observed in lung adenocarcinoma patients (Fig.	('MEK1', 'Gene', '5604', (47, 51))	('lung adenocarcinoma', 'Disease', (124, 143))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (124, 143))	('S217/S221', 'Var', (69, 78))	('MEK1', 'Gene', (47, 51))	('patients', 'Species', '9606', (144, 152))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('beclin-1', 'Gene', (23, 31))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (124, 143))	('expression', 'MPA', (32, 42))	('phosphorylation', 'MPA', (52, 67))	('beclin-1', 'Gene', '8678', (23, 31))
269346	28558758	In the presence of AZD4547, substantial decrease in cell viability was obtained (Fig.	('cell viability', 'CPA', (52, 66))	('AZD4547', 'Var', (19, 26))	('decrease', 'NegReg', (40, 48))	('AZD4547', 'Chemical', 'MESH:C572463', (19, 26))
269347	28558758	These indicate that inhibition of autophagy enhances cell death after AZD4547 treatment.	('AZD4547', 'Var', (70, 77))	('autophagy', 'CPA', (34, 43))	('AZD4547', 'Chemical', 'MESH:C572463', (70, 77))	('enhances', 'PosReg', (44, 52))	('inhibition', 'NegReg', (20, 30))	('cell death', 'CPA', (53, 63))
269349	28558758	Western blot assays showed that the combination of AZD4547 with beclin-1 silencing noticeably increased the cleavage of poly (ADP-ribose) polymerase (PARP) and caspase-9 in H1581 and H520 cells (Fig.	('AZD4547', 'Var', (51, 58))	('combination', 'Interaction', (36, 47))	('H520', 'CellLine', 'CVCL:1566', (183, 187))	('H1581', 'CellLine', 'CVCL:1479', (173, 178))	('PARP', 'Gene', (150, 154))	('caspase-9', 'Gene', (160, 169))	('AZD4547', 'Chemical', 'MESH:C572463', (51, 58))	('increased', 'PosReg', (94, 103))	('caspase-9', 'Gene', '842', (160, 169))	('cleavage', 'MPA', (108, 116))	('PARP', 'Gene', '142', (150, 154))	('poly (ADP-ribose) polymerase', 'Gene', (120, 148))	('beclin-1', 'Gene', '8678', (64, 72))	('poly (ADP-ribose) polymerase', 'Gene', '142', (120, 148))	('beclin-1', 'Gene', (64, 72))	('silencing', 'NegReg', (73, 82))
269351	28558758	Flow cytometry analysis showed that the proportions of early apoptotic cells (FITC Annexin V positive and PI negative) and late apoptotic cells (FITC Annexin V positive and PI positive) increased when NSCLC cells were cotreated with AZD4547 and beclin-1 siRNA (Fig.	('Annexin V', 'Gene', (150, 159))	('AZD4547', 'Chemical', 'MESH:C572463', (233, 240))	('NSCLC', 'Phenotype', 'HP:0030358', (201, 206))	('Annexin V', 'Gene', '308', (83, 92))	('Annexin V', 'Gene', (83, 92))	('FITC', 'Chemical', 'MESH:D016650', (145, 149))	('FITC', 'Chemical', 'MESH:D016650', (78, 82))	('NSCLC', 'Disease', (201, 206))	('beclin-1', 'Gene', (245, 253))	('beclin-1', 'Gene', '8678', (245, 253))	('Annexin V', 'Gene', '308', (150, 159))	('NSCLC', 'Disease', 'MESH:D002289', (201, 206))	('AZD4547', 'Var', (233, 240))
269352	28558758	These data indicated that the type of cell death induced by combination of AZD4547 and beclin-1 silencing was partially caspase-dependent apoptosis.	('caspase-dependent', 'CPA', (120, 137))	('beclin-1', 'Gene', (87, 95))	('AZD4547', 'Var', (75, 82))	('beclin-1', 'Gene', '8678', (87, 95))	('AZD4547', 'Chemical', 'MESH:C572463', (75, 82))	('silencing', 'NegReg', (96, 105))
269354	28558758	High LC3B expression was a marker of poor prognosis in both lung SQCC (Fig.	('LC3B', 'Gene', '81631', (5, 9))	('High', 'Var', (0, 4))	('lung SQCC', 'Disease', (60, 69))	('expression', 'MPA', (10, 20))	('SQCC', 'Phenotype', 'HP:0002860', (65, 69))	('LC3B', 'Gene', (5, 9))
269357	28558758	Lung cancer patients with alterations in LC3B exhibited lower overall survival (OS) than those without alterations in LC3B (Additional file 8: Figure S6).	('patients', 'Species', '9606', (12, 20))	('LC3B', 'Gene', (41, 45))	('LC3B', 'Gene', '81631', (118, 122))	('Lung cancer', 'Phenotype', 'HP:0100526', (0, 11))	('alterations', 'Var', (26, 37))	('lower', 'NegReg', (56, 61))	('Lung cancer', 'Disease', (0, 11))	('LC3B', 'Gene', (118, 122))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))	('LC3B', 'Gene', '81631', (41, 45))	('Lung cancer', 'Disease', 'MESH:D008175', (0, 11))	('overall survival', 'MPA', (62, 78))
269359	28558758	In low FGFR1-expressing lung SQCC, high LC3B expression had significantly poorer OS compared with low LC3B expression (Fig.	('poorer', 'NegReg', (74, 80))	('low LC3B expression', 'Phenotype', 'HP:0032431', (98, 117))	('LC3B', 'Gene', '81631', (40, 44))	('FGFR1', 'Gene', (7, 12))	('LC3B', 'Gene', '81631', (102, 106))	('expression', 'MPA', (45, 55))	('LC3B', 'Gene', (40, 44))	('FGFR1', 'Gene', '2260', (7, 12))	('SQCC', 'Phenotype', 'HP:0002860', (29, 33))	('high', 'Var', (35, 39))	('LC3B', 'Gene', (102, 106))
269360	28558758	In high FGFR1-expressing lung SQCC, high LC3B expression conferred worse OS in comparison to low LC3B expression (Fig.	('FGFR1', 'Gene', (8, 13))	('SQCC', 'Phenotype', 'HP:0002860', (30, 34))	('LC3B', 'Gene', (41, 45))	('FGFR1', 'Gene', '2260', (8, 13))	('LC3B', 'Gene', (97, 101))	('low LC3B expression', 'Phenotype', 'HP:0032431', (93, 112))	('LC3B', 'Gene', '81631', (41, 45))	('high', 'Var', (36, 40))	('LC3B', 'Gene', '81631', (97, 101))
269363	28558758	Clinical application of FGF/FGFR-targeted therapy is under development for the treatment of cancers caused by aberrant FGF signaling.	('cancers', 'Phenotype', 'HP:0002664', (92, 99))	('cancers', 'Disease', 'MESH:D009369', (92, 99))	('FGF', 'Protein', (119, 122))	('aberrant', 'Var', (110, 118))	('cancers', 'Disease', (92, 99))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
269364	28558758	Patients with FGFR genetic alterations are predicted to be appropriate candidates for FGFR inhibitors-based therapy.	('genetic alterations', 'Var', (19, 38))	('Patients', 'Species', '9606', (0, 8))	('FGFR', 'Gene', (14, 18))
269368	28558758	On one hand, autophagy appears to function as a tumor suppressor mechanism as defective autophagy is associated with malignant transformation and carcinogenesis.	('carcinogenesis', 'Disease', (146, 160))	('tumor', 'Disease', (48, 53))	('malignant transformation', 'CPA', (117, 141))	('autophagy', 'CPA', (88, 97))	('associated', 'Reg', (101, 111))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('defective', 'Var', (78, 87))	('carcinogenesis', 'Disease', 'MESH:D063646', (146, 160))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
269369	28558758	Studies have demonstrated that heterozygous disruption of beclin-1 promotes tumorigenesis while the overexpression inhibits tumorigenesis.	('promotes', 'PosReg', (67, 75))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('beclin-1', 'Gene', (58, 66))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('tumor', 'Disease', (124, 129))	('beclin-1', 'Gene', '8678', (58, 66))	('heterozygous disruption', 'Var', (31, 54))	('inhibits', 'NegReg', (115, 123))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
269371	28558758	Our study indicated that suppression of autophagy promoted apoptosis after AZD4547 treatment.	('suppression', 'NegReg', (25, 36))	('promoted', 'PosReg', (50, 58))	('AZD4547', 'Var', (75, 82))	('apoptosis', 'CPA', (59, 68))	('autophagy', 'CPA', (40, 49))	('AZD4547', 'Chemical', 'MESH:C572463', (75, 82))
269372	28558758	This study is designed to test the hypothesis that FGFR inhibitor AZD4547 induced autophagy in FGFR1-amplified NSCLC cells.	('FGFR1', 'Gene', (95, 100))	('NSCLC', 'Disease', (111, 116))	('AZD4547', 'Chemical', 'MESH:C572463', (66, 73))	('induced', 'Reg', (74, 81))	('NSCLC', 'Disease', 'MESH:D002289', (111, 116))	('FGFR1', 'Gene', '2260', (95, 100))	('autophagy', 'CPA', (82, 91))	('NSCLC', 'Phenotype', 'HP:0030358', (111, 116))	('AZD4547', 'Var', (66, 73))
269374	28558758	AZD4547 induced protective autophagy in FGFR1-amplified NSCLC cells.	('autophagy', 'CPA', (27, 36))	('AZD4547', 'Chemical', 'MESH:C572463', (0, 7))	('FGFR1', 'Gene', (40, 45))	('NSCLC', 'Disease', (56, 61))	('FGFR1', 'Gene', '2260', (40, 45))	('NSCLC', 'Disease', 'MESH:D002289', (56, 61))	('AZD4547', 'Var', (0, 7))	('NSCLC', 'Phenotype', 'HP:0030358', (56, 61))
269379	28558758	A high-throughput image-based screening and analysis approach indicate that knockdown of FGFR1 increases autophagy flux.	('knockdown', 'Var', (76, 85))	('autophagy flux', 'CPA', (105, 119))	('FGFR1', 'Gene', (89, 94))	('FGFR1', 'Gene', '2260', (89, 94))	('increases', 'PosReg', (95, 104))
269380	28558758	FGFR1 TKI induces protective autophagy through suppressing AKT/mTOR signaling pathway in FGFR1-amplified breast cancer cell lines.	('AKT/mTOR signaling pathway', 'Pathway', (59, 85))	('suppressing', 'NegReg', (47, 58))	('induces', 'PosReg', (10, 17))	('FGFR1', 'Gene', (89, 94))	('FGFR1', 'Gene', (0, 5))	('TKI', 'Var', (6, 9))	('FGFR1', 'Gene', '2260', (0, 5))	('FGFR1', 'Gene', '2260', (89, 94))	('protective autophagy', 'CPA', (18, 38))	('breast cancer', 'Disease', 'MESH:D001943', (105, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('breast cancer', 'Disease', (105, 118))	('breast cancer', 'Phenotype', 'HP:0003002', (105, 118))
269381	28558758	Similarly, our studies demonstrate that FGFR1 inhibition promotes induction of autophagy.	('FGFR1', 'Gene', (40, 45))	('autophagy', 'CPA', (79, 88))	('inhibition', 'Var', (46, 56))	('FGFR1', 'Gene', '2260', (40, 45))
269383	28558758	In our study, AZD4547 treatment induced autophagic activity in both of the cells, suggesting that synergy with autophagy inhibition is a sequence of the drug itself inducing autophagy.	('AZD4547', 'Var', (14, 21))	('autophagic activity', 'CPA', (40, 59))	('AZD4547', 'Chemical', 'MESH:C572463', (14, 21))
269385	28558758	This is in contrast to a recent study, which has shown that autophagy induction contributes to EGFR TKI responses in NSCLC with active EGFR mutations, and the use of autophagy inhibitors in patients receiving EGFR TKI may adversely (rather than favorably) affect their clinical course.	('NSCLC', 'Disease', (117, 122))	('EGFR', 'Gene', (209, 213))	('patients', 'Species', '9606', (190, 198))	('responses', 'MPA', (104, 113))	('EGFR', 'Gene', '1956', (135, 139))	('NSCLC', 'Disease', 'MESH:D002289', (117, 122))	('affect', 'Reg', (256, 262))	('EGFR', 'Gene', (135, 139))	('EGFR', 'Gene', '1956', (95, 99))	('mutations', 'Var', (140, 149))	('NSCLC', 'Phenotype', 'HP:0030358', (117, 122))	('EGFR', 'Gene', '1956', (209, 213))	('autophagy', 'CPA', (60, 69))	('EGFR', 'Gene', (95, 99))
269393	28558758	In a summary, we found that pharmacological or genetic inhibition of FGFR1 induced autophagy; the response was elicited through complex mechanisms involving both inhibition of the ERK/MAPK pathway and upregulation of beclin-1.	('inhibition', 'NegReg', (162, 172))	('genetic inhibition', 'Var', (47, 65))	('induced', 'Reg', (75, 82))	('ERK', 'Gene', '5594', (180, 183))	('upregulation', 'PosReg', (201, 213))	('autophagy', 'CPA', (83, 92))	('beclin-1', 'Gene', (217, 225))	('beclin-1', 'Gene', '8678', (217, 225))	('ERK', 'Gene', (180, 183))	('FGFR1', 'Gene', (69, 74))	('pharmacological', 'Var', (28, 43))	('MAPK', 'Gene', (184, 188))	('MAPK', 'Gene', '5595;5594;5595', (184, 188))	('FGFR1', 'Gene', '2260', (69, 74))
269401	28558758	PBS Phosphate buffered saline PFA Paraformaldehyde RPPA Reverse-phase protein array RTK Receptor tyrosine kinase shRNA Short hairpin RNA siRNA Small interfering RNA SQCC Squamous cell carcinoma	('Squamous cell carcinoma', 'Disease', (170, 193))	('Paraformaldehyde', 'Chemical', 'MESH:C003043', (34, 50))	('carcinoma', 'Phenotype', 'HP:0030731', (184, 193))	('SQCC', 'Phenotype', 'HP:0002860', (165, 169))	('RTK', 'Gene', (84, 87))	('PFA', 'Chemical', 'MESH:C003043', (30, 33))	('Squamous cell carcinoma', 'Disease', 'MESH:D002294', (170, 193))	('Small', 'Var', (143, 148))	('PBS', 'Chemical', '-', (0, 3))	('Phosphate buffered saline', 'Chemical', '-', (4, 29))	('RTK', 'Gene', '5979', (84, 87))	('Squamous cell carcinoma', 'Phenotype', 'HP:0002860', (170, 193))
269408	25379706	Cases with moderate nuclear Wig-1 staining and positive cytoplasmic Wig-1 staining showed longer survival than patients with strong nuclear and negative cytoplasmic staining (p = 0.042).	('Wig-1', 'Gene', (68, 73))	('Wig-1', 'Gene', (28, 33))	('Wig-1', 'Gene', '64393', (28, 33))	('longer', 'PosReg', (90, 96))	('survival', 'CPA', (97, 105))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('staining', 'Var', (34, 42))	('Wig-1', 'Gene', '64393', (68, 73))	('patients', 'Species', '9606', (111, 119))
269413	25379706	Persistent infection with high risk (HR) human papillomavirus (HPV) is a major risk factor for the development of cervical cancer and the two predominant types are HPV18 and HPV16, followed by HPV45, 31, 33, 58, 52, 35, 59, 56, 6, 51, 68, 39, 82, 73, 66 and 70 in order of prevalence.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('HPV', 'Species', '10566', (164, 167))	('Persistent infection', 'Phenotype', 'HP:0031035', (0, 20))	('HPV', 'Species', '10566', (63, 66))	('infection', 'Disease', (11, 20))	('HPV16', 'Species', '333760', (174, 179))	('HPV', 'Species', '10566', (193, 196))	('human papillomavirus', 'Species', '10566', (41, 61))	('HPV45', 'Var', (193, 198))	('HPV18', 'Var', (164, 169))	('HPV16', 'Var', (174, 179))	('infection', 'Disease', 'MESH:D007239', (11, 20))	('HPV', 'Species', '10566', (174, 177))	('cervical cancer', 'Disease', (114, 129))	('cervical cancer', 'Disease', 'MESH:D002583', (114, 129))
269418	25379706	Genomic alterations such as gene amplifications are important features of cervical carcinogenesis.	('carcinogenesis', 'Disease', (83, 97))	('carcinogenesis', 'Disease', 'MESH:D063646', (83, 97))	('gene amplifications', 'Var', (28, 47))
269419	25379706	Copy number gain in the long arm of chromosome 3 has been shown to be a biomarker of progression from carcinoma in situ to invasive cancer.	('Copy number gain', 'Var', (0, 16))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('carcinoma in situ to invasive cancer', 'Disease', (102, 138))	('carcinoma in situ to invasive cancer', 'Disease', 'MESH:D002278', (102, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (102, 119))
269430	25379706	Our results indicate that high nuclear Wig-1 expression is a marker for poor prognosis in cervical carcinoma.	('high', 'Var', (26, 30))	('Wig-1', 'Gene', (39, 44))	('Wig-1', 'Gene', '64393', (39, 44))	('expression', 'MPA', (45, 55))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('cervical carcinoma', 'Disease', 'MESH:D002575', (90, 108))	('cervical carcinoma', 'Disease', (90, 108))
269469	25379706	All nine lines studied by CGH exhibited copy number alterations of chromosome 3 (Figure 1A; Table 1).	('copy number alterations', 'Var', (40, 63))	('exhibited', 'Reg', (30, 39))	('C', 'Chemical', 'MESH:D002244', (26, 27))
269470	25379706	Amplifications were found in Ca Ski, ME-180 and SiHa that involved 3q23-26, 3q27-ter and 3q23-24, respectively.	('3q27-ter', 'Var', (76, 84))	('SiHa', 'CellLine', 'CVCL:0032', (48, 52))	('Ca Ski', 'CellLine', 'CVCL:1100', (29, 35))	('3q23-24', 'Var', (89, 96))	('3q23-26', 'Var', (67, 74))
269483	25379706	However, no associations were found between WIG-1 expression levels and copy number alterations at the DNA level.	('copy number alterations', 'Var', (72, 95))	('WIG-1', 'Gene', '64393', (44, 49))	('WIG-1', 'Gene', (44, 49))	('expression', 'MPA', (50, 60))
269501	25379706	Interestingly, we found that moderate nuclear Wig-1 expression was associated with better overall survival (Figure 3A).	('moderate', 'Var', (29, 37))	('Wig-1', 'Gene', '64393', (46, 51))	('Wig-1', 'Gene', (46, 51))	('expression', 'MPA', (52, 62))	('better', 'PosReg', (83, 89))	('overall survival', 'MPA', (90, 106))
269508	25379706	The value of detection of genomic amplification of 3q as a biomarker for progression during uterine cervix tumorigenesis was evaluated in several studies.	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('uterine cervix', 'Phenotype', 'HP:0030160', (92, 106))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('genomic amplification', 'Var', (26, 47))
269512	25379706	It is clear from our SKY, CGH and Southern blotting analyses of chromosome 3q amplifications in cervical cancer cell lines, that WIG-1 is not a main target for the frequent gains.	('amplifications', 'Var', (78, 92))	('WIG-1', 'Gene', '64393', (129, 134))	('cervical cancer', 'Disease', 'MESH:D002583', (96, 111))	('C', 'Chemical', 'MESH:D002244', (26, 27))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('WIG-1', 'Gene', (129, 134))	('cervical cancer', 'Disease', (96, 111))
269516	25379706	Moreover, our analysis of WIG-1 mRNA and protein levels in the cervical carcinoma cell lines did not reveal any significant correlation between WIG-1 expression and copy number alterations at the DNA level.	('WIG-1', 'Gene', (144, 149))	('cervical carcinoma', 'Disease', 'MESH:D002575', (63, 81))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('copy number alterations', 'Var', (165, 188))	('WIG-1', 'Gene', '64393', (144, 149))	('carcinoma cell', 'Disease', 'MESH:C538614', (72, 86))	('carcinoma cell', 'Disease', (72, 86))	('cervical carcinoma', 'Disease', (63, 81))	('WIG-1', 'Gene', (26, 31))	('WIG-1', 'Gene', '64393', (26, 31))
269525	25379706	This is consistent with the observation that the cervical carcinoma cell lines carrying high risk HPV had lower Wig-1 mRNA levels compared to the HPV-negative lines.	('lower', 'NegReg', (106, 111))	('HPV', 'Var', (98, 101))	('cervical carcinoma', 'Disease', 'MESH:D002575', (49, 67))	('carcinoma cell', 'Disease', 'MESH:C538614', (58, 72))	('carcinoma cell', 'Disease', (58, 72))	('HPV', 'Species', '10566', (146, 149))	('Wig-1', 'Gene', '64393', (112, 117))	('cervical carcinoma', 'Disease', (49, 67))	('Wig-1', 'Gene', (112, 117))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))	('HPV', 'Species', '10566', (98, 101))
269534	25379706	Among 8 of the cervical cancer cell lines studied here, the only two HPV-negative lines, C-33A and HT-3, both carry TP53 mutation (Table 2).	('TP53', 'Gene', (116, 120))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('cervical cancer', 'Disease', (15, 30))	('cervical cancer', 'Disease', 'MESH:D002583', (15, 30))	('HT-3', 'CellLine', 'CVCL:1293', (99, 103))	('HPV', 'Species', '10566', (69, 72))	('carry', 'Reg', (110, 115))	('mutation', 'Var', (121, 129))	('TP53', 'Gene', '7157', (116, 120))	('C-33A', 'Mutation', 'c.-33C>A', (89, 94))
269566	31632145	Many previous studies have demonstrated a significant association between high miR-22 expression and good prognosis in cancer patients, such as epithelial ovarian cancer (EOC), hepatocellular carcinoma (HCC), and breast cancer (BC); but some studies did not reveal significant association, and still others showed a negative correlation.	('breast cancer', 'Phenotype', 'HP:0003002', (213, 226))	('EOC', 'Disease', (171, 174))	('cancer', 'Disease', 'MESH:D009369', (220, 226))	('epithelial ovarian cancer', 'Disease', (144, 169))	('patients', 'Species', '9606', (126, 134))	('HCC', 'Disease', 'MESH:D006528', (203, 206))	('cancer', 'Disease', 'MESH:D009369', (163, 169))	('carcinoma', 'Phenotype', 'HP:0030731', (192, 201))	('breast cancer', 'Disease', 'MESH:D001943', (213, 226))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (177, 201))	('breast cancer', 'Disease', (213, 226))	('ovarian cancer', 'Phenotype', 'HP:0100615', (155, 169))	('cancer', 'Disease', (119, 125))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('BC', 'Disease', 'MESH:D001943', (228, 230))	('EOC', 'Disease', 'MESH:D010051', (171, 174))	('expression', 'MPA', (86, 96))	('HCC', 'Disease', (203, 206))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (177, 201))	('cancer', 'Disease', (220, 226))	('cancer', 'Disease', (163, 169))	('epithelial ovarian cancer', 'Disease', 'MESH:D010051', (144, 169))	('miR-22', 'Gene', '407004', (79, 85))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('high', 'Var', (74, 78))	('miR-22', 'Gene', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('hepatocellular carcinoma', 'Disease', (177, 201))	('epithelial ovarian cancer', 'Phenotype', 'HP:0025318', (144, 169))
269582	31632145	As revealed in Figure 2, high expression of miR-22 represents a good OS of cancer patients (HR =0.76, 95% CI: 0.62-0.92), indicating that patients with high miR-22 expression may have longer survival time.	('miR-22', 'Gene', (157, 163))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('patients', 'Species', '9606', (82, 90))	('miR-22', 'Gene', '407004', (157, 163))	('cancer', 'Disease', (75, 81))	('high expression', 'Var', (25, 40))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('miR-22', 'Gene', '407004', (44, 50))	('longer', 'PosReg', (184, 190))	('miR-22', 'Gene', (44, 50))	('patients', 'Species', '9606', (138, 146))	('survival time', 'CPA', (191, 204))
269617	31632145	Therefore, we conduct this meta-analysis to evaluate the association between high expression of miR-22 and the OS as well as clinicopathological significance of cancer patients.	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('high expression', 'Var', (77, 92))	('miR-22', 'Gene', '407004', (96, 102))	('miR-22', 'Gene', (96, 102))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('association', 'Interaction', (57, 68))	('patients', 'Species', '9606', (168, 176))	('cancer', 'Disease', (161, 167))
269619	31632145	In our study, high expression of miR-22 predicted a good OS (HR =0.76, 95% CI: 0.62-0.92) (Figure 2, Table 2) and PFS/RFS/DFS (HR =0.57, 95% CI: 0.37-0.87) (Figure 4A, Table 3) for cancer patients, while no significant correlation was found between the expression of miR-22 and MFS/DMFS (Figure 4A, Table 3).	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('miR-22', 'Gene', '407004', (267, 273))	('patients', 'Species', '9606', (188, 196))	('miR-22', 'Gene', '407004', (33, 39))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('miR-22', 'Gene', (267, 273))	('high expression', 'Var', (14, 29))	('PFS/RFS/DFS', 'Gene', (114, 125))	('miR-22', 'Gene', (33, 39))	('cancer', 'Disease', (181, 187))	('PFS/RFS/DFS', 'Gene', '65211', (114, 125))
269627	31632145	In the subgroup analysis of PRS/RFS/DFS, high expression of miR-22 might predict a good DFS (Figure 4B), which suggested that the miR-22 high expression prolongs the DFS time of cancer patients, while no significant association was found in RFS and PFS subgroup (Figure 4B).	('miR-22', 'Gene', (60, 66))	('RFS', 'Gene', (241, 244))	('RFS', 'Gene', '65211', (32, 35))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('miR-22', 'Gene', '407004', (60, 66))	('high expression', 'Var', (137, 152))	('DFS time', 'MPA', (166, 174))	('prolongs', 'PosReg', (153, 161))	('RFS', 'Gene', (32, 35))	('cancer', 'Disease', (178, 184))	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('miR-22', 'Gene', '407004', (130, 136))	('patients', 'Species', '9606', (185, 193))	('RFS', 'Gene', '65211', (241, 244))	('miR-22', 'Gene', (130, 136))
269638	31632145	In addition, there was no significant association between high expression of microRNA-22 and T stage (RR =0.87, 95% CI: 0.71-1.07), tumor differentiation (HR =0.99, 95% CI: 0.85-1.15) and lymphatic invasion (RR =0.86, 95% CI: 0.70-1.05) (Figure S3).	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('high expression', 'Var', (58, 73))	('tumor', 'Disease', (132, 137))	('T stage', 'CPA', (93, 100))	('lymphatic invasion', 'CPA', (188, 206))	('microRNA-22', 'Gene', '407004', (77, 88))	('microRNA-22', 'Gene', (77, 88))
269697	31227017	When lymph node status determined by SUVmax was more than 2.6 with iso-attenuation or low attenuation on noncontrast CT images, the accuracy was improved in detecting individual lymph node metastasis in patients with oesophageal SCC (Fig.	('iso-attenuation', 'Var', (67, 82))	('patients', 'Species', '9606', (203, 211))	('improved', 'PosReg', (145, 153))	('oesophageal SCC', 'Disease', 'MESH:D005764', (217, 232))	('oesophageal SCC', 'Disease', (217, 232))
269710	31227017	A recent meta-analysis study indicated the 18F-FDG PET/CT for detecting regional lymph node metastasis had a sensitivity and specificity with 95% CI of 62% (40-79) and 96% (93-98).	('18F-FDG', 'Var', (43, 50))	('regional lymph node metastasis', 'CPA', (72, 102))	('18F-FDG', 'Chemical', 'MESH:D019788', (43, 50))
269714	31227017	These nodes showed follicular hyperplasia in the cortex and anthracitic pigmentation and macrophage infiltration in the medulla, and these inflammatory changes can provoke high false-positive rates and low specificity with 18F-FDG PET/CT.	('macrophage infiltration', 'CPA', (89, 112))	('follicular hyperplasia', 'Phenotype', 'HP:0002729', (19, 41))	('follicular hyperplasia', 'Disease', (19, 41))	('pigmentation', 'Disease', 'MESH:D010859', (72, 84))	('follicular hyperplasia', 'Disease', 'MESH:D006965', (19, 41))	('pigmentation', 'Disease', (72, 84))	('18F-FDG', 'Chemical', 'MESH:D019788', (223, 230))	('18F-FDG PET/CT', 'Var', (223, 237))
269737	31186635	Interestingly, survival analysis based on NEAT1 expression in several cancer tissues revealed that the p53 wild-type group with high NEAT1 expression had a good prognosis, while poor prognosis or no correlation between NEAT1 expression and survival was observed in the p53-mutated group.	('p53', 'Gene', (269, 272))	('p53', 'Gene', '7157', (269, 272))	('p53', 'Gene', (103, 106))	('NEAT1', 'Gene', '283131', (42, 47))	('p53', 'Gene', '7157', (103, 106))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('NEAT1', 'Gene', '283131', (219, 224))	('NEAT1', 'Gene', (42, 47))	('NEAT1', 'Gene', '283131', (133, 138))	('NEAT1', 'Gene', (219, 224))	('high', 'Var', (128, 132))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('expression', 'MPA', (139, 149))	('NEAT1', 'Gene', (133, 138))
269742	31186635	Furthermore, abnormality of p53 such as mutation or deletion causes poor prognosis and resistance to various cancer therapies.	('p53', 'Gene', (28, 31))	('mutation', 'Var', (40, 48))	('p53', 'Gene', '7157', (28, 31))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('cancer', 'Disease', (109, 115))	('resistance', 'CPA', (87, 97))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('deletion', 'Var', (52, 60))
269749	31186635	NEAT1 knockdown had an effect on p53-induced transactivation and enhanced cancer cell growth.	('transactivation', 'MPA', (45, 60))	('NEAT1', 'Gene', (0, 5))	('NEAT1', 'Gene', '283131', (0, 5))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('enhanced', 'PosReg', (65, 73))	('cancer', 'Disease', (74, 80))	('p53', 'Gene', (33, 36))	('p53', 'Gene', '7157', (33, 36))	('knockdown', 'Var', (6, 15))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
269758	31186635	Total 11,095 RNA-seq files were analyzed using a series of cufflinks software programs, cuffquant and cuffnorm to quantify and normalize the expression of NEAT1, NEAT1_2 (NR_131012), CDKN1A, and MDM2 genes.	('CDKN1A', 'Gene', '1026', (183, 189))	('MDM2', 'Gene', '4193', (195, 199))	('MDM2', 'Gene', (195, 199))	('NEAT1', 'Gene', '283131', (162, 167))	('NEAT1', 'Gene', '283131', (155, 160))	('NEAT1', 'Gene', (162, 167))	('NR_131012', 'Var', (171, 180))	('NEAT1', 'Gene', (155, 160))	('CDKN1A', 'Gene', (183, 189))
269766	31186635	RNA-seq data of tumors were divided into two groups, wild-type p53 or mutated p53 (including homologous deletion) groups, and then, the expression of NEAT1 and two major p53 transcriptional targets, CDKN1A (encoding p21) and MDM2, was analyzed and compared among the groups (Figure 2 and Supplementary Figure 1).	('p21', 'Gene', (216, 219))	('p53', 'Gene', (170, 173))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('tumors', 'Disease', (16, 22))	('MDM2', 'Gene', (225, 229))	('p53', 'Gene', '7157', (63, 66))	('CDKN1A', 'Gene', (199, 205))	('CDKN1A', 'Gene', '1026', (199, 205))	('tumors', 'Disease', 'MESH:D009369', (16, 22))	('p53', 'Gene', '7157', (78, 81))	('MDM2', 'Gene', '4193', (225, 229))	('p21', 'Gene', '1026', (216, 219))	('p53', 'Gene', (63, 66))	('NEAT1', 'Gene', (150, 155))	('p53', 'Gene', (78, 81))	('p53', 'Gene', '7157', (170, 173))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('mutated', 'Var', (70, 77))	('NEAT1', 'Gene', '283131', (150, 155))
269780	31186635	Among 32 cancer tissues, in 11 cancer types (BLCA, BRCA, head and neck squamous cell carcinoma (HNSC), LIHC, LUAD, MESO, OV, rectal adenocarcinoma (READ), SARC, skin cutaneous melanoma (SKCM), and STAD), the rate of survival was significantly higher among patients whose tumors had high levels of NEAT1 expression compared with those with low NEAT1-expressing tumors ("Good" in "Total" column of Table 1).	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (161, 184))	('cancer', 'Disease', (9, 15))	('tumors', 'Disease', 'MESH:D009369', (360, 366))	('NEAT1', 'Gene', (297, 302))	('melanoma', 'Phenotype', 'HP:0002861', (176, 184))	('tumor', 'Phenotype', 'HP:0002664', (271, 276))	('tumors', 'Disease', (271, 277))	('SARC', 'Disease', (155, 159))	('skin cutaneous melanoma', 'Disease', (161, 184))	('rectal adenocarcinoma', 'Disease', 'MESH:D012004', (125, 146))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (71, 94))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (166, 184))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('READ', 'Disease', 'None', (148, 152))	('survival', 'MPA', (216, 224))	('BRCA', 'Gene', '672', (51, 55))	('NEAT1', 'Gene', (343, 348))	('tumors', 'Disease', 'MESH:D009369', (271, 277))	('LUAD', 'Phenotype', 'HP:0030078', (109, 113))	('expression', 'MPA', (303, 313))	('cancer', 'Disease', (31, 37))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('LIHC', 'Disease', (103, 107))	('NEAT1', 'Gene', '283131', (297, 302))	('SARC', 'Phenotype', 'HP:0100242', (155, 159))	('tumors', 'Phenotype', 'HP:0002664', (360, 366))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('BRCA', 'Gene', (51, 55))	('rectal adenocarcinoma', 'Disease', (125, 146))	('higher', 'PosReg', (243, 249))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (57, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('high', 'Var', (282, 286))	('tumor', 'Phenotype', 'HP:0002664', (360, 365))	('NEAT1', 'Gene', '283131', (343, 348))	('LIHC', 'Disease', 'None', (103, 107))	('READ', 'Disease', (148, 152))	('tumors', 'Disease', (360, 366))	('neck squamous cell carcinoma', 'Disease', (66, 94))	('tumors', 'Phenotype', 'HP:0002664', (271, 277))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (66, 94))	('patients', 'Species', '9606', (256, 264))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('BRCA', 'Phenotype', 'HP:0003002', (51, 55))
269781	31186635	On the other hand, in 7 cancer types, the survival rate was significantly lower among patients whose tumors had high levels of NEAT1 expression than among those with low NEAT1 expression in tumors (colon adenocarcinoma (COAD), glioblastoma multiforme (GBM), KIRC, lower grade glioma (LGG), THYM, uterine corpus endometrial carcinoma (UCEC), and uveal melanoma (UVM)) ("Poor" in "Total" column of Table 1).	('uveal melanoma', 'Disease', 'MESH:C536494', (345, 359))	('THYM', 'Phenotype', 'HP:0100522', (290, 294))	('uveal melanoma', 'Disease', (345, 359))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('NEAT1', 'Gene', '283131', (127, 132))	('high', 'Var', (112, 116))	('cancer', 'Disease', (24, 30))	('COAD', 'Disease', 'MESH:D029424', (220, 224))	('tumors', 'Disease', (190, 196))	('lower', 'NegReg', (74, 79))	('glioma', 'Phenotype', 'HP:0009733', (276, 282))	('patients', 'Species', '9606', (86, 94))	('uveal melanoma', 'Phenotype', 'HP:0007716', (345, 359))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('colon adenocarcinoma', 'Disease', (198, 218))	('NEAT1', 'Gene', '283131', (170, 175))	('glioblastoma multiforme', 'Disease', (227, 250))	('tumors', 'Disease', 'MESH:D009369', (190, 196))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('tumors', 'Phenotype', 'HP:0002664', (190, 196))	('glioblastoma', 'Phenotype', 'HP:0012174', (227, 239))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (227, 250))	('carcinoma', 'Phenotype', 'HP:0030731', (209, 218))	('endometrial carcinoma', 'Disease', (311, 332))	('carcinoma', 'Phenotype', 'HP:0030731', (323, 332))	('COAD', 'Disease', (220, 224))	('cancer', 'Disease', 'MESH:D009369', (24, 30))	('NEAT1', 'Gene', (127, 132))	('tumors', 'Disease', (101, 107))	('expression', 'MPA', (133, 143))	('glioma', 'Disease', (276, 282))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (311, 332))	('survival', 'CPA', (42, 50))	('colon adenocarcinoma', 'Disease', 'MESH:D003110', (198, 218))	('glioma', 'Disease', 'MESH:D005910', (276, 282))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (311, 332))	('NEAT1', 'Gene', (170, 175))	('melanoma', 'Phenotype', 'HP:0002861', (351, 359))	('tumors', 'Disease', 'MESH:D009369', (101, 107))
269784	31186635	To clarify the p53 dependency of the prognostic effect of NEAT1, tumors were divided into two groups, wild-type p53 and mutated p53 (including homologous deletion) groups, and then, prognosis was analyzed in 18 cancer tissues that had sufficient sample numbers of both wild-type and mutated p53 tumor tissues.	('p53', 'Gene', '7157', (128, 131))	('NEAT1', 'Gene', (58, 63))	('mutated', 'Var', (283, 290))	('tumors', 'Disease', (65, 71))	('p53', 'Gene', '7157', (112, 115))	('cancer', 'Disease', 'MESH:D009369', (211, 217))	('tumor', 'Disease', (65, 70))	('p53', 'Gene', (128, 131))	('p53', 'Gene', '7157', (15, 18))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('p53', 'Gene', (112, 115))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumor', 'Disease', (295, 300))	('NEAT1', 'Gene', '283131', (58, 63))	('p53', 'Gene', (15, 18))	('tumor', 'Disease', 'MESH:D009369', (295, 300))	('p53', 'Gene', '7157', (291, 294))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('cancer', 'Disease', (211, 217))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('tumor', 'Phenotype', 'HP:0002664', (295, 300))	('p53', 'Gene', (291, 294))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))
269785	31186635	Interestingly, in BRCA and OV, the p53 wild-type group with high NEAT1 expression had a good prognosis compared with those with low NEAT1 expression, while poor prognosis was indicated in the p53-mutated group with high NEAT1 expression compared with low NEAT1 expression (Figure 3 and Table 1).	('BRCA', 'Phenotype', 'HP:0003002', (18, 22))	('p53', 'Gene', (35, 38))	('p53', 'Gene', '7157', (35, 38))	('high', 'Var', (60, 64))	('NEAT1', 'Gene', '283131', (65, 70))	('BRCA', 'Gene', '672', (18, 22))	('NEAT1', 'Gene', '283131', (220, 225))	('p53', 'Gene', '7157', (192, 195))	('BRCA', 'Gene', (18, 22))	('NEAT1', 'Gene', (65, 70))	('NEAT1', 'Gene', '283131', (255, 260))	('NEAT1', 'Gene', (220, 225))	('NEAT1', 'Gene', '283131', (132, 137))	('NEAT1', 'Gene', (255, 260))	('p53', 'Gene', (192, 195))	('NEAT1', 'Gene', (132, 137))
269787	31186635	Furthermore, in BLCA, lung squamous cell carcinoma (LUSC), and SKCM, the p53 wild-type group with high NEAT1 expression had a good prognosis compared with the group with low NEAT1 expression, while the p53-mutated groups did not exhibit a significant prognosis difference based on NEAT1 expression (Supplementary Figure 4).	('NEAT1', 'Gene', '283131', (281, 286))	('lung squamous cell carcinoma', 'Disease', (22, 50))	('carcinoma', 'Phenotype', 'HP:0030731', (41, 50))	('LUSC', 'Phenotype', 'HP:0030359', (52, 56))	('NEAT1', 'Gene', (281, 286))	('p53', 'Gene', (73, 76))	('p53', 'Gene', '7157', (73, 76))	('NEAT1', 'Gene', (174, 179))	('NEAT1', 'Gene', '283131', (174, 179))	('high', 'Var', (98, 102))	('NEAT1', 'Gene', '283131', (103, 108))	('expression', 'Var', (109, 119))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (22, 50))	('NEAT1', 'Gene', (103, 108))	('p53', 'Gene', '7157', (202, 205))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (22, 50))	('p53', 'Gene', (202, 205))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (27, 50))
269806	31186635	In 11 of 32 cancer types (BLCA, BRCA, HNSC, LIHC, LUAD, MESO, OV, READ, SARC, SKCM, and STAD), high NEAT1 expression suggested a good prognosis but suggested a poor prognosis in seven other cancer types (COAD, GBM, KIRC, LGG, THYM, UCEC, and UVM) (Table 1, Supplementary Figure 3).	('GBM', 'Disease', (210, 213))	('SARC', 'Phenotype', 'HP:0100242', (72, 76))	('THYM', 'Phenotype', 'HP:0100522', (226, 230))	('LIHC', 'Disease', 'None', (44, 48))	('READ', 'Disease', (66, 70))	('cancer', 'Disease', (190, 196))	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('COAD', 'Disease', 'MESH:D029424', (204, 208))	('high', 'Var', (95, 99))	('NEAT1', 'Gene', '283131', (100, 105))	('BRCA', 'Phenotype', 'HP:0003002', (32, 36))	('LGG', 'Disease', (221, 224))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('THYM', 'Disease', (226, 230))	('KIRC', 'Disease', (215, 219))	('READ', 'Disease', 'None', (66, 70))	('BRCA', 'Gene', '672', (32, 36))	('COAD', 'Disease', (204, 208))	('cancer', 'Disease', 'MESH:D009369', (190, 196))	('cancer', 'Disease', (12, 18))	('LIHC', 'Disease', (44, 48))	('UCEC', 'Disease', (232, 236))	('LUAD', 'Phenotype', 'HP:0030078', (50, 54))	('NEAT1', 'Gene', (100, 105))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('BRCA', 'Gene', (32, 36))
269808	31186635	Therefore, considering p53 mutational status, we divided tumors into two groups, wild-type p53 and mutated p53 groups, and then, prognosis was analyzed.	('p53', 'Gene', (107, 110))	('p53', 'Gene', '7157', (107, 110))	('p53', 'Gene', (91, 94))	('p53', 'Gene', '7157', (91, 94))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('mutated', 'Var', (99, 106))	('p53', 'Gene', (23, 26))	('p53', 'Gene', '7157', (23, 26))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('tumors', 'Disease', (57, 63))	('tumors', 'Disease', 'MESH:D009369', (57, 63))
269809	31186635	Surprisingly, in seven cancer types (BLCA, BRCA, LUSC, OV, SARC, SKCM and STAD), the p53 wild-type group with high NEAT1 expression had a good prognosis, while the opposite result or no correlation between NEAT1 expression and survival was observed in the p53-mutated group (Figure 3, Table 1, Supplementary Figure 4).	('SARC', 'Disease', (59, 63))	('LUSC', 'Phenotype', 'HP:0030359', (49, 53))	('NEAT1', 'Gene', '283131', (206, 211))	('cancer', 'Disease', 'MESH:D009369', (23, 29))	('BRCA', 'Phenotype', 'HP:0003002', (43, 47))	('p53', 'Gene', (256, 259))	('high', 'Var', (110, 114))	('BRCA', 'Gene', '672', (43, 47))	('NEAT1', 'Gene', '283131', (115, 120))	('p53', 'Gene', '7157', (85, 88))	('SARC', 'Phenotype', 'HP:0100242', (59, 63))	('cancer', 'Disease', (23, 29))	('NEAT1', 'Gene', (206, 211))	('p53', 'Gene', (85, 88))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('BRCA', 'Gene', (43, 47))	('LUSC', 'Disease', (49, 53))	('p53', 'Gene', '7157', (256, 259))	('NEAT1', 'Gene', (115, 120))	('SKCM', 'Disease', (65, 69))
269815	29928883	Suppression of Cleavage Factor Im 25 Promotes the Proliferation of Lung Cancer Cells through Alternative Polyadenylation Non-small cell lung cancer (NSCLC) is a life-threatening disease that has a poor prognosis and low survival rate.	('lung cancer', 'Phenotype', 'HP:0100526', (136, 147))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (125, 147))	('Non-small cell lung cancer', 'Phenotype', 'HP:0030358', (121, 147))	('Lung Cancer', 'Phenotype', 'HP:0100526', (67, 78))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('Non-small cell lung cancer', 'Disease', (121, 147))	('NSCLC', 'Disease', (149, 154))	('Suppression', 'Var', (0, 11))	('Cancer', 'Phenotype', 'HP:0002664', (72, 78))	('NSCLC', 'Disease', 'MESH:D002289', (149, 154))	('Promotes', 'PosReg', (37, 45))	('Non-small cell lung cancer', 'Disease', 'MESH:D002289', (121, 147))	('NSCLC', 'Phenotype', 'HP:0030358', (149, 154))
269823	29928883	The transcript levels of CCND1 and GSK3beta were significantly increased and the dPAS usage of several oncogenes (IGF1R, CCND1 and GSK3beta) were decreased after CFIm25 knockdown.	('CFIm25', 'Gene', (162, 168))	('CCND1', 'Gene', (25, 30))	('dPAS', 'Gene', '249157', (81, 85))	('increased', 'PosReg', (63, 72))	('IGF1R', 'Gene', '3480', (114, 119))	('GSK3beta', 'Gene', (131, 139))	('knockdown', 'Var', (169, 178))	('GSK3beta', 'Gene', '2932', (35, 43))	('CCND1', 'Gene', '595', (25, 30))	('CCND1', 'Gene', '595', (121, 126))	('decreased', 'NegReg', (146, 155))	('CFIm25', 'Gene', '11051', (162, 168))	('GSK3beta', 'Gene', '2932', (131, 139))	('transcript levels', 'MPA', (4, 21))	('IGF1R', 'Gene', (114, 119))	('dPAS', 'Gene', (81, 85))	('CCND1', 'Gene', (121, 126))	('GSK3beta', 'Gene', (35, 43))
269832	29928883	However, the underlying molecular mechanisms that account for altered oncogene expression and promote the abnormal proliferation of lung cancer cells are extremely complex and remain unknown.	('altered', 'Var', (62, 69))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('lung cancer', 'Disease', 'MESH:D008175', (132, 143))	('abnormal proliferation', 'CPA', (106, 128))	('lung cancer', 'Disease', (132, 143))	('promote', 'PosReg', (94, 101))	('lung cancer', 'Phenotype', 'HP:0100526', (132, 143))	('oncogene', 'Protein', (70, 78))
269833	29928883	More than half of mammalian mRNA have more than one polyadenylation sites (PAS), thus usage of different PAS can result in transcripts with different sizes of 3'-untranslated regions (3'UTRs) or different transcripts, a process called alternative polyadenylation (APA).	('usage', 'Var', (86, 91))	('mammalian', 'Species', '9606', (18, 27))	('transcripts', 'MPA', (205, 216))	('result in', 'Reg', (113, 122))	('PAS', 'Gene', '249157', (105, 108))	('PAS', 'Gene', '249157', (75, 78))	('PAS', 'Gene', (75, 78))	('transcripts', 'MPA', (123, 134))	('PAS', 'Gene', (105, 108))
269838	29928883	To understand the role of CFIm25 and APA in lung cancer cell proliferation, we used siRNA to knockdown CFIm25 expression in A549 cells, a well characterized lung adenocarcinoma cell line, and analyzed the expression of several proteins involved in cell proliferation and apoptosis.	('knockdown', 'Var', (93, 102))	('lung cancer', 'Phenotype', 'HP:0100526', (44, 55))	('CFIm25', 'Gene', '11051', (103, 109))	('A549', 'CellLine', 'CVCL:0023', (124, 128))	('CFIm25', 'Gene', (26, 32))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (157, 176))	('lung cancer', 'Disease', 'MESH:D008175', (44, 55))	('carcinoma', 'Phenotype', 'HP:0030731', (167, 176))	('CFIm25', 'Gene', '11051', (26, 32))	('lung adenocarcinoma', 'Disease', (157, 176))	('CFIm25', 'Gene', (103, 109))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (157, 176))	('lung cancer', 'Disease', (44, 55))
269839	29928883	We observed increased A549 proliferation upon CFIm25 knockdown, possibly due to enhanced expression of IGF1R and CCND1.	('IGF1R', 'Gene', '3480', (103, 108))	('CFIm25', 'Gene', (46, 52))	('expression', 'MPA', (89, 99))	('knockdown', 'Var', (53, 62))	('increased', 'PosReg', (12, 21))	('A549 proliferation', 'CPA', (22, 40))	('CCND1', 'Gene', (113, 118))	('CFIm25', 'Gene', '11051', (46, 52))	('IGF1R', 'Gene', (103, 108))	('enhanced expression of IGF1R', 'Phenotype', 'HP:0030269', (80, 108))	('enhanced', 'PosReg', (80, 88))	('CCND1', 'Gene', '595', (113, 118))	('A549', 'CellLine', 'CVCL:0023', (22, 26))
269871	29928883	Overexpression of IGF1R in cancer cells can promote abnormal cell proliferation .	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('promote', 'PosReg', (44, 51))	('abnormal cell proliferation', 'CPA', (52, 79))	('IGF1R', 'Gene', (18, 23))	('abnormal cell proliferation', 'Phenotype', 'HP:0031377', (52, 79))	('Overexpression', 'Var', (0, 14))	('cancer', 'Disease', (27, 33))	('cancer', 'Disease', 'MESH:D009369', (27, 33))	('IGF1R', 'Gene', '3480', (18, 23))
269882	29928883	In summary, our studies indicate that CFIm25 depletion promotes lung cancer cell proliferation and CCND1 expression, and subsequently increases cell proliferation and suppresses apoptosis.	('lung cancer', 'Disease', (64, 75))	('CFIm25', 'Gene', '11051', (38, 44))	('lung cancer', 'Phenotype', 'HP:0100526', (64, 75))	('cell proliferation', 'CPA', (144, 162))	('suppresses', 'NegReg', (167, 177))	('CCND1', 'Gene', '595', (99, 104))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('depletion', 'Var', (45, 54))	('promotes', 'PosReg', (55, 63))	('apoptosis', 'CPA', (178, 187))	('CCND1', 'Gene', (99, 104))	('CFIm25', 'Gene', (38, 44))	('lung cancer', 'Disease', 'MESH:D008175', (64, 75))	('increases', 'PosReg', (134, 143))	('expression', 'MPA', (105, 115))
269894	29928883	We have shown that CFIm25 depletion can promote the 3'UTR shortening of IGF1R, which is sufficient to increase its protein expression in A549 cells, suggesting that 3'UTR shortening of IGF1R is a potential mechanism to promote its protein expression in lung cancers.	('protein expression', 'MPA', (115, 133))	('IGF1R', 'Gene', (185, 190))	('increase', 'PosReg', (102, 110))	('CFIm25', 'Gene', '11051', (19, 25))	('IGF1R', 'Gene', '3480', (72, 77))	('promote', 'PosReg', (40, 47))	('CFIm25', 'Gene', (19, 25))	('IGF1R', 'Gene', (72, 77))	('lung cancers', 'Disease', 'MESH:D008175', (253, 265))	('depletion', 'Var', (26, 35))	('promote', 'PosReg', (219, 226))	('lung cancers', 'Disease', (253, 265))	('protein expression', 'MPA', (231, 249))	('lung cancer', 'Phenotype', 'HP:0100526', (253, 264))	('cancer', 'Phenotype', 'HP:0002664', (258, 264))	('lung cancers', 'Phenotype', 'HP:0100526', (253, 265))	("3'UTR shortening", 'MPA', (52, 68))	('IGF1R', 'Gene', '3480', (185, 190))	('cancers', 'Phenotype', 'HP:0002664', (258, 265))	('A549', 'CellLine', 'CVCL:0023', (137, 141))
269905	29928883	It has been reported that global 3'UTR shortening has been found in highly proliferating cells, suggesting that CFIm25 depletion may lead to cancer cell proliferation.	('lead to', 'Reg', (133, 140))	('CFIm25', 'Gene', (112, 118))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('depletion', 'Var', (119, 128))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('CFIm25', 'Gene', '11051', (112, 118))	('cancer', 'Disease', (141, 147))
269906	29928883	Indeed, CFIm25 depletion has significantly enhanced cancer proliferation and increased glioblastoma tumor growth.	('depletion', 'Var', (15, 24))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('enhanced', 'PosReg', (43, 51))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('glioblastoma tumor', 'Disease', (87, 105))	('CFIm25', 'Gene', '11051', (8, 14))	('increased', 'PosReg', (77, 86))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('glioblastoma', 'Phenotype', 'HP:0012174', (87, 99))	('glioblastoma tumor', 'Disease', 'MESH:D005909', (87, 105))	('cancer', 'Disease', (52, 58))	('CFIm25', 'Gene', (8, 14))
269915	29928883	The shortened transcripts were sufficient to increase its protein turnover without increasing its transcript level, suggesting that 3'UTR shortening of IGF1R could be a mechanisms that promotes its protein expression in NSCLC.	('NSCLC', 'Disease', (220, 225))	('IGF1R', 'Gene', '3480', (152, 157))	('protein turnover', 'MPA', (58, 74))	('shortening', 'Var', (138, 148))	('promotes', 'PosReg', (185, 193))	('NSCLC', 'Disease', 'MESH:D002289', (220, 225))	('protein expression', 'MPA', (198, 216))	('NSCLC', 'Phenotype', 'HP:0030358', (220, 225))	('IGF1R', 'Gene', (152, 157))	('increase', 'PosReg', (45, 53))
269921	29928883	Abrogated expression or mutation of proteins controlling the cell cycle process, including CCND1, is one of the major reasons by which cancer cells evade cell cycle checkpoints, thus accelerating their cell division rate.	('cell division rate', 'CPA', (202, 220))	('cancer', 'Disease', (135, 141))	('Abrogated', 'Var', (0, 9))	('evade', 'NegReg', (148, 153))	('CCND1', 'Gene', (91, 96))	('cell cycle checkpoints', 'CPA', (154, 176))	('expression', 'MPA', (10, 20))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('mutation', 'Var', (24, 32))	('accelerating', 'PosReg', (183, 195))	('CCND1', 'Gene', '595', (91, 96))	('cancer', 'Disease', 'MESH:D009369', (135, 141))
269922	29928883	Overexpression of CCND1 has been linked to the development of various cancers .	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('linked to', 'Reg', (33, 42))	('CCND1', 'Gene', '595', (18, 23))	('Overexpression', 'Var', (0, 14))	('cancers', 'Disease', 'MESH:D009369', (70, 77))	('CCND1', 'Gene', (18, 23))	('cancers', 'Phenotype', 'HP:0002664', (70, 77))	('cancers', 'Disease', (70, 77))
269923	29928883	In addition, mutation or suppression of key genes that induce programmed cell death, including P53, is another cause of cancer development.	('suppression', 'NegReg', (25, 36))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('mutation', 'Var', (13, 21))	('P53', 'Gene', '7157', (95, 98))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('cause', 'Reg', (111, 116))	('P53', 'Gene', (95, 98))
269939	30006565	Here the authors show that CD39 and CD103 mark a subset of tumor-infiltrating CD8 T cells that are tumor-reactive and exhibit characteristics of exhausted or tissue-resident memory T cells.	('tumor', 'Disease', (99, 104))	('CD8', 'Gene', (78, 81))	('tumor', 'Disease', (59, 64))	('CD103', 'Gene', (36, 41))	('CD8', 'Gene', '925', (78, 81))	('CD39', 'Var', (27, 31))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('CD103', 'Gene', '3682', (36, 41))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
269943	30006565	A percentage of tumor-infiltrating CD8 T cells (CD8 TIL) recognize tumor-associated antigens, which include overexpressed self-antigens, as well as tumor-specific neoantigens, which arise as a consequence of tumor-specific mutations.	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('tumor', 'Disease', 'MESH:D009369', (208, 213))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Disease', (148, 153))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('CD8', 'Gene', (48, 51))	('CD8', 'Gene', (35, 38))	('tumor', 'Disease', (16, 21))	('tumor', 'Disease', (208, 213))	('tumor', 'Disease', (67, 72))	('CD8', 'Gene', '925', (35, 38))	('CD8', 'Gene', '925', (48, 51))	('mutations', 'Var', (223, 232))	('tumor', 'Disease', 'MESH:D009369', (148, 153))
270054	30006565	Therefore, using CD39 and CD103 to enrich for tumor-reactive CD8 T cells prior to TIL expansion may be a way to increase the clinical success of adoptive immunotherapy.	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('CD39', 'Var', (17, 21))	('CD8', 'Gene', (61, 64))	('CD103', 'Gene', (26, 31))	('CD8', 'Gene', '925', (61, 64))	('tumor', 'Disease', (46, 51))	('CD103', 'Gene', '3682', (26, 31))	('increase', 'PosReg', (112, 120))	('clinical success', 'CPA', (125, 141))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
270146	26862848	Interestingly, inhibition of ELOVL6 drastically reduced colony formation of multiple SCC cell lines in vitro and significantly attenuated their growth as xenografts in vivo in mouse models.	('attenuated', 'NegReg', (127, 137))	('SCC', 'Gene', '6317', (85, 88))	('colony formation', 'CPA', (56, 72))	('reduced', 'NegReg', (48, 55))	('mouse', 'Species', '10090', (176, 181))	('ELOVL6', 'Gene', (29, 35))	('SCC', 'Gene', (85, 88))	('SCC', 'Phenotype', 'HP:0002860', (85, 88))	('inhibition', 'Var', (15, 25))	('growth', 'CPA', (144, 150))
270166	26862848	To corroborate these findings and to unequivocally demonstrate that phospholipids with longer acyl chains are more prominent in cancer tissue compared to normal tissue, we performed 2D-imaging mass spectrometry (MS) of a representative series of phospholipids differing in combined acyl chain length (PC32:3, PC34:3, PC36:3, PC38:3 and PC40:3) in tissue sections containing both cancer and adjacent non-malignant tissue.	('PC36:3', 'Var', (317, 323))	('phospholipids', 'Chemical', 'MESH:D010743', (68, 81))	('cancer', 'Disease', (128, 134))	('PC32:3', 'Var', (301, 307))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('PC', 'Chemical', 'MESH:D010713', (336, 338))	('PC32', 'CellLine', 'CVCL:E445', (301, 305))	('cancer', 'Disease', (379, 385))	('cancer', 'Phenotype', 'HP:0002664', (379, 385))	('PC', 'Chemical', 'MESH:D010713', (301, 303))	('phospholipids', 'Chemical', 'MESH:D010743', (246, 259))	('PC', 'Chemical', 'MESH:D010713', (325, 327))	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('PC38', 'CellLine', 'CVCL:7271', (325, 329))	('PC40:3', 'Var', (336, 342))	('PC', 'Chemical', 'MESH:D010713', (309, 311))	('PC', 'Chemical', 'MESH:D010713', (317, 319))	('PC34:3', 'Var', (309, 315))	('PC34', 'CellLine', 'CVCL:J663', (309, 313))	('cancer', 'Disease', 'MESH:D009369', (379, 385))	('PC38:3', 'Var', (325, 331))
270167	26862848	This analysis revealed that the shorter species (PC32:3 and PC34:3) were predominant in normal tissue, whereas the longer species (PC36:3, PC38:3 and PC40:3) were mainly found in cancer regions of the tissue sections (Figure 2).	('PC32:3', 'Var', (49, 55))	('PC', 'Chemical', 'MESH:D010713', (131, 133))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('PC', 'Chemical', 'MESH:D010713', (49, 51))	('PC', 'Chemical', 'MESH:D010713', (139, 141))	('PC', 'Chemical', 'MESH:D010713', (60, 62))	('PC32', 'CellLine', 'CVCL:E445', (49, 53))	('PC38', 'CellLine', 'CVCL:7271', (139, 143))	('PC', 'Chemical', 'MESH:D010713', (150, 152))	('PC38:3', 'Var', (139, 145))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('PC40:3', 'Var', (150, 156))	('PC36:3', 'Var', (131, 137))	('cancer', 'Disease', (179, 185))	('PC34', 'CellLine', 'CVCL:J663', (60, 64))	('PC34:3', 'Var', (60, 66))
270168	26862848	High signals of PC36:3 and PC38:3 were found in both tumor nests and associated stroma.	('PC', 'Chemical', 'MESH:D010713', (27, 29))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('PC38', 'CellLine', 'CVCL:7271', (27, 31))	('PC38:3', 'Var', (27, 33))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('PC', 'Chemical', 'MESH:D010713', (16, 18))	('PC36:3', 'Protein', (16, 22))	('tumor', 'Disease', (53, 58))
270171	26862848	To demonstrate that changes in acyl chain length of phospholipids are more universally linked to lung SCC development, we sought to confirm these findings in a lung SCC mouse model.	('phospholipids', 'Chemical', 'MESH:D010743', (52, 65))	('SCC', 'Phenotype', 'HP:0002860', (102, 105))	('SCC', 'Gene', '6317', (102, 105))	('SCC', 'Gene', (165, 168))	('SCC', 'Phenotype', 'HP:0002860', (165, 168))	('linked', 'Reg', (87, 93))	('lung', 'Disease', (97, 101))	('acyl chain length', 'MPA', (31, 48))	('SCC', 'Gene', '6317', (165, 168))	('men', 'Species', '9606', (113, 116))	('mouse', 'Species', '10090', (169, 174))	('changes', 'Var', (20, 27))	('SCC', 'Gene', (102, 105))
270183	26862848	Interestingly, only ELOVL6 knockdown completely reversed the elongation profile observed in SCC (shown for PC in Figure 5 (siRNA 1) and Supplementary Figure S2 (siRNA 2)).	('ELOVL6', 'Gene', (20, 26))	('knockdown', 'Var', (27, 36))	('men', 'Species', '9606', (142, 145))	('SCC', 'Gene', '6317', (92, 95))	('PC', 'Chemical', 'MESH:D010713', (107, 109))	('elongation', 'CPA', (61, 71))	('SCC', 'Gene', (92, 95))	('SCC', 'Phenotype', 'HP:0002860', (92, 95))
270184	26862848	Silencing of ELOVL6 using siRNA showed identical effects in another established human SCC cell line H2170 (Supplementary Figure S3).	('SCC', 'Gene', (86, 89))	('ELOVL6', 'Gene', (13, 19))	('SCC', 'Phenotype', 'HP:0002860', (86, 89))	('SCC', 'Gene', '6317', (86, 89))	('human', 'Species', '9606', (80, 85))	('men', 'Species', '9606', (113, 116))	('Silencing', 'Var', (0, 9))
270213	26862848	ELOVL4 has been shown to be methylated in pancreatic cancer, whereas there is loss of copy number in hepatocellular carcinoma.	('pancreatic cancer', 'Disease', (42, 59))	('methylated', 'Var', (28, 38))	('pancreatic cancer', 'Disease', 'MESH:D010190', (42, 59))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (101, 125))	('hepatocellular carcinoma', 'Disease', (101, 125))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (101, 125))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (42, 59))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('ELOVL4', 'Gene', (0, 6))	('ELOVL4', 'Gene', '6785', (0, 6))
270231	26862848	Knockdown or inhibition of ELOVL6 in several lung SCC cell line models completely reversed the elongation phenotype.	('SCC', 'Gene', '6317', (50, 53))	('inhibition', 'Var', (13, 23))	('ELOVL6', 'Gene', (27, 33))	('SCC', 'Gene', (50, 53))	('SCC', 'Phenotype', 'HP:0002860', (50, 53))	('elongation', 'CPA', (95, 105))
270233	26862848	Importantly, our findings indicate that reversal of the elongation phenotype by inhibition of ELOVL6 affects cancer biology and may have potential for antineoplastic intervention.	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('cancer', 'Disease', (109, 115))	('ELOVL6', 'Gene', (94, 100))	('inhibition', 'Var', (80, 90))	('affects', 'Reg', (101, 108))
270234	26862848	In earlier reports it has been shown that silencing of ELOVL1 reduced cell viability of breast cancer cells significantly and that inhibition of ELOVL7 resulted in drastic attenuation of prostate cancer cell growth.	('silencing', 'Var', (42, 51))	('ELOVL7', 'Gene', (145, 151))	('breast cancer', 'Phenotype', 'HP:0003002', (88, 101))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('cell viability', 'CPA', (70, 84))	('drastic attenuation of prostate cancer', 'Disease', (164, 202))	('ELOVL7', 'Gene', '79993', (145, 151))	('reduced', 'NegReg', (62, 69))	('drastic attenuation of prostate cancer', 'Disease', 'MESH:D011471', (164, 202))	('prostate cancer', 'Phenotype', 'HP:0012125', (187, 202))	('ELOVL1', 'Gene', '64834', (55, 61))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('breast cancer', 'Disease', (88, 101))	('breast cancer', 'Disease', 'MESH:D001943', (88, 101))	('ELOVL1', 'Gene', (55, 61))	('inhibition', 'NegReg', (131, 141))
270235	26862848	Here we show that inhibition of ELOVL6 affects colony formation in soft agar, and tumor growth in vivo but not in monolayer, suggesting that mechanisms of anchorage-independent growth are affected by ELOVL6-mediated acyl chain elongation.	('affected', 'Reg', (188, 196))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('inhibition', 'Var', (18, 28))	('agar', 'Chemical', 'MESH:D000362', (72, 76))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('ELOVL6', 'Gene', (32, 38))	('colony formation in soft agar', 'CPA', (47, 76))	('tumor', 'Disease', (82, 87))
270241	26862848	These findings suggest that inhibition of acyl chain elongation may represent a novel therapeutic approach to target a broad range of lung SCC patients.	('SCC', 'Gene', '6317', (139, 142))	('inhibition', 'Var', (28, 38))	('patients', 'Species', '9606', (143, 151))	('acyl chain', 'Protein', (42, 52))	('SCC', 'Gene', (139, 142))	('SCC', 'Phenotype', 'HP:0002860', (139, 142))
270249	26862848	Mice were euthanized, tumor and matched normal lung tissues were dissected and washed in PBS prior to snap-freezing in liquid nitrogen and storage at -80 C. H2170 human and KLN205 mouse SCC cells were obtained from the American Type Culture Collection (ATCC; Manassas, Virginia, USA; December 2012) and from The European Collection of Cell Cultures (ECACC; Public Health England, Salisbury, UK; January 2014), respectively, and were cultured in RPMI1640 (Life Technologies, Carlsbad, California, USA).	('KLN205', 'Chemical', '-', (173, 179))	('PBS', 'Chemical', 'MESH:D007854', (89, 92))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('nitrogen', 'Chemical', 'MESH:D009584', (126, 134))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('human', 'Species', '9606', (163, 168))	('mouse SCC', 'CellLine', 'CVCL:0594', (180, 189))	('tumor', 'Disease', (22, 27))	('KLN205', 'Var', (173, 179))	('Mice', 'Species', '10090', (0, 4))	('SCC', 'Phenotype', 'HP:0002860', (186, 189))
270271	26862848	Commercially available primers (TaqMan Gene Expression Assay; Life Technologies) for ELOVL1-7 (Hs00249277_m1, Hs00214936_m1, Hs00537016_m1, Hs00224122_m1, Hs01094704_m1, Hs00907564_m1, Hs00405150_m1), and the housekeeping genes ESD (Hs00382667_m1), HMBS (Hs00609297_m1), POLR2A (Hs00172187_m1), PSMB4 (Hs00160598_m1), TBP (Hs00427621_m1) and UBC (Hs00824723_m1) were used.	('POLR2A', 'Gene', (271, 277))	('Hs00427621_m1', 'Var', (323, 336))	('HMBS', 'Gene', '3145', (249, 253))	('Hs00537016_m1', 'Var', (125, 138))	('Hs00382667_m1', 'Var', (233, 246))	('PSMB4', 'Gene', (295, 300))	('Hs00824723_m1', 'Var', (347, 360))	('Hs00172187_m1', 'Var', (279, 292))	('POLR2A', 'Gene', '5430', (271, 277))	('ELOVL1-7', 'Gene', '64834;54898;83401;6785;60481;79071;79993', (85, 93))	('Hs00609297_m1', 'Var', (255, 268))	('ELOVL1-7', 'Gene', (85, 93))	('PSMB4', 'Gene', '5692', (295, 300))	('Hs00160598_m1', 'Var', (302, 315))	('HMBS', 'Gene', (249, 253))	('TBP', 'Gene', (318, 321))	('TBP', 'Gene', '6908', (318, 321))
270292	24887580	In A431-SCC-co-culture the concentration of 17 proteins was significantly increased compared to the ADSCs mono-culture (2.8- to 357-fold), and 15 proteins were expressed more highly (2.8- to 1,527-fold) compared to the A431-SCCs mono-culture.	('expressed', 'MPA', (160, 169))	('A431-SCC-co-culture', 'Var', (3, 22))	('A431-SCC', 'CellLine', 'CVCL:0037', (219, 227))	('A431-SCC', 'CellLine', 'CVCL:0037', (3, 11))	('concentration of 17', 'MPA', (27, 46))	('proteins', 'Protein', (146, 154))	('increased', 'PosReg', (74, 83))	('highly', 'PosReg', (175, 181))	('proteins', 'Protein', (47, 55))
270315	24887580	The following monoclonal antibodies conjugated to fluorochromes were used: anti-CD13-APC, anti-CD29-PE, anti-CD31-FITC, anti-CD34-FITC, anti-CD44-APC, anti-CD45-FITC, anti-CD49a-PE, anti-CD63-FITC,-anti-CD73-PE, anti-CD90-APC, anti-CD105-FITC, anti-CD106-APC and anti-CD-166-PE (all from Becton Dickinson, Heidelberg, Germany).	('CD63', 'Gene', '967', (187, 191))	('CD13', 'Gene', (80, 84))	('CD29', 'Gene', '3688', (95, 99))	('CD31', 'Gene', '5175', (109, 113))	('CD106', 'Gene', (249, 254))	('CD34', 'Gene', '947', (125, 129))	('anti-CD-166-PE', 'Var', (263, 277))	('CD29', 'Gene', (95, 99))	('CD13', 'Gene', '290', (80, 84))	('CD90', 'Gene', (217, 221))	('CD73', 'Gene', '4907', (203, 207))	('CD31', 'Gene', (109, 113))	('CD49a', 'Gene', '3672', (172, 177))	('CD73', 'Gene', (203, 207))	('CD63', 'Gene', (187, 191))	('CD44', 'Gene', '960', (141, 145))	('CD34', 'Gene', (125, 129))	('CD90', 'Gene', '7070', (217, 221))	('CD49a', 'Gene', (172, 177))	('anti-CD105-FITC', 'Var', (227, 242))	('CD44', 'Gene', (141, 145))	('CD106', 'Gene', '7412', (249, 254))	('CD45', 'Gene', (156, 160))	('CD45', 'Gene', '5788', (156, 160))
270337	24887580	In order to further investigate a potential epithelial to mesenchymal transition (EMT) of the cells during co-culture the gene expression of E- and N-cadherin was analyzed using specific TaqMan gene expression assays (Hs01023894 for E-cadherin, Hs00983056 for N-cadherin) with 10 ng of cDNA per sample.	('N-cadherin', 'Gene', '1000', (148, 158))	('N-cadherin', 'Gene', (260, 270))	('N-cadherin', 'Gene', '1000', (260, 270))	('Hs01023894', 'Var', (218, 228))	('E-cadherin', 'Gene', (233, 243))	('Hs00983056', 'Var', (245, 255))	('N-cadherin', 'Gene', (148, 158))	('E-cadherin', 'Gene', '999', (233, 243))
270344	24887580	ADSCs were positive for CD13, CD29, CD44, CD49a, CD63, CD73, CD90, CD105 and CD166.	('CD63', 'Gene', (49, 53))	('CD44', 'Gene', (36, 40))	('CD166', 'Gene', (77, 82))	('CD29', 'Gene', '3688', (30, 34))	('CD73', 'Gene', '4907', (55, 59))	('CD13', 'Gene', '290', (24, 28))	('CD49a', 'Gene', '3672', (42, 47))	('CD63', 'Gene', '967', (49, 53))	('CD29', 'Gene', (30, 34))	('CD73', 'Gene', (55, 59))	('CD13', 'Gene', (24, 28))	('CD49a', 'Gene', (42, 47))	('CD105', 'Var', (67, 72))	('CD166', 'Gene', '214', (77, 82))	('CD90', 'Gene', '7070', (61, 65))	('CD90', 'Gene', (61, 65))	('CD44', 'Gene', '960', (36, 40))
270346	24887580	In all donors adipogenically induced cells showed a significantly higher oil red staining than non-induced control cells (Figure 2a).	('adipogenically', 'Var', (14, 28))	('oil red', 'Chemical', 'MESH:C009213', (73, 80))	('higher', 'PosReg', (66, 72))	('oil red staining', 'MPA', (73, 89))
270388	24887580	ADSCs and A431-SCCs showed invasive behavior by actively digesting the extracellular matrix blocking the transwell pores and migrating to the lower surface of the transwell inserts' floor.	('A431-SCC', 'CellLine', 'CVCL:0037', (10, 18))	('migrating', 'CPA', (125, 134))	('transwell pores', 'CPA', (105, 120))	('blocking', 'NegReg', (92, 100))	('digesting', 'Var', (57, 66))
270468	24887580	High expression of CCND2 in vitro has been strongly associated with a more invasive SCC cell type in vivo and malignant progression.	('SCC', 'Gene', '6317', (84, 87))	('CCND2', 'Gene', (19, 24))	('associated with', 'Reg', (52, 67))	('High', 'Var', (0, 4))	('CCND2', 'Gene', '894', (19, 24))	('SCC', 'Gene', (84, 87))	('malignant progression', 'CPA', (110, 131))
270478	24887580	Thereby ADSCs may strongly increase the risk of squamous cell carcinoma tumor growth and metastasis in vivo.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('ADSCs', 'Var', (8, 13))	('squamous cell carcinoma tumor', 'Disease', (48, 77))	('squamous cell carcinoma tumor', 'Disease', 'MESH:D002294', (48, 77))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (48, 71))	('metastasis', 'CPA', (89, 99))	('increase', 'PosReg', (27, 35))	('carcinoma', 'Phenotype', 'HP:0030731', (62, 71))
270486	32580248	Comprehensive analysis of multicomponent data across reformed and current smokers identified a total of 85 differential expressed genes (DEGs) affected by different modes of genetic and epigenetic regulation, potentially representing cancer drivers in smokers.	('epigenetic', 'Var', (186, 196))	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('affected', 'Reg', (143, 151))	('cancer', 'Disease', 'MESH:D009369', (234, 240))	('cancer', 'Disease', (234, 240))	('differential expressed genes', 'MPA', (107, 135))
270494	32580248	In addition to causing frequent gene mutations, tobacco smoking also appears to break the immune homeostasis, which may contribute to tumorigenesis [6].	('contribute', 'Reg', (120, 130))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('mutations', 'Var', (37, 46))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('immune homeostasis', 'MPA', (90, 108))	('tobacco', 'Species', '4097', (48, 55))	('break', 'NegReg', (80, 85))	('tumor', 'Disease', (134, 139))
270511	32580248	In age-adjusted models, quitting smoking was significantly associated with longer survival time in CESC, HNSC, LUSC, and PAAD.	('longer', 'PosReg', (75, 81))	('HNSC', 'Phenotype', 'HP:0012288', (105, 109))	('LUSC', 'Disease', (111, 115))	('LUSC', 'Phenotype', 'HP:0030359', (111, 115))	('CESC', 'Disease', (99, 103))	('quitting', 'Var', (24, 32))	('HNSC', 'Disease', (105, 109))	('PAAD', 'Phenotype', 'HP:0006725', (121, 125))	('LUSC', 'Chemical', '-', (111, 115))	('PAAD', 'Disease', (121, 125))
270543	32580248	Many studies confirmed that variants in LIG1 may predispose to smoking-related lung cancer [31, 32].	('lung cancer', 'Disease', 'MESH:D008175', (79, 90))	('predispose', 'Reg', (49, 59))	('variants', 'Var', (28, 36))	('lung cancer', 'Disease', (79, 90))	('lung cancer', 'Phenotype', 'HP:0100526', (79, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('LIG1', 'Gene', (40, 44))	('LIG1', 'Gene', '3978', (40, 44))
270559	32580248	M0 macrophages were reported to be inversely associated with patients' outcomes in various, such as adrenal cortical carcinoma and lung cancer [46, 47].	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('adrenal cortical carcinoma', 'Phenotype', 'HP:0006744', (100, 126))	('M0 macrophages', 'Var', (0, 14))	('patients', 'Species', '9606', (61, 69))	('lung cancer', 'Disease', 'MESH:D008175', (131, 142))	('associated with', 'Reg', (45, 60))	('adrenal cortical carcinoma', 'Disease', 'MESH:D018268', (100, 126))	('lung cancer', 'Disease', (131, 142))	('lung cancer', 'Phenotype', 'HP:0100526', (131, 142))	('adrenal cortical carcinoma', 'Disease', (100, 126))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
270562	32580248	confirmed that patients with high mutational smoking signature had poorer overall survival in HNSC (HR = 1.50, 95% CI = 1.23-1.81, P < 0.01), but the mutational smoking signature was not prognostic in LUSC (HR = 1.02, 95% CI = 0.71-1.46, P = 0.92) [52] and LUAD (HR = 1.18, 95% CI = 0.46-3.04, P = 0.74).	('LUAD', 'Phenotype', 'HP:0030078', (257, 261))	('patients', 'Species', '9606', (15, 23))	('high mutational', 'Var', (29, 44))	('LUAD', 'Disease', (257, 261))	('LUSC', 'Phenotype', 'HP:0030359', (201, 205))	('LUSC', 'Disease', (201, 205))	('HNSC', 'Disease', (94, 98))	('mutational', 'Var', (34, 44))	('poorer', 'NegReg', (67, 73))	('overall', 'MPA', (74, 81))	('LUSC', 'Chemical', '-', (201, 205))	('HNSC', 'Phenotype', 'HP:0012288', (94, 98))
270598	32121422	However, with respect to the beneficial effects of butyrate on colitis, pathological bone loss, anti-microbial activity, and on a M1-to-M2 shift in macrophages it should not be ruled out that SCFA may also contribute to tissue homeostasis by modulation of ICAM-1.	('colitis', 'Disease', 'MESH:D003092', (63, 70))	('butyrate', 'Chemical', 'MESH:D002087', (51, 59))	('bone loss', 'Disease', 'MESH:D016301', (85, 94))	('colitis', 'Disease', (63, 70))	('modulation', 'Var', (242, 252))	('colitis', 'Phenotype', 'HP:0002583', (63, 70))	('contribute', 'Reg', (206, 216))	('SCFA', 'Chemical', 'MESH:D005232', (192, 196))	('ICAM-1', 'Gene', (256, 262))	('bone loss', 'Phenotype', 'HP:0002797', (85, 94))	('bone loss', 'Disease', (85, 94))	('tissue', 'MPA', (220, 226))
270628	32121422	Consistently, butyrate had no impact on HO-1 expression in HSC2 cells (data not shown) and the lack of Nrf2 had no impact on the suppression activity of butyrate on the LPS-induced ICAM-1 expression in primary macrophages (Figure S4).	('butyrate', 'Chemical', 'MESH:D002087', (14, 22))	('expression', 'MPA', (188, 198))	('LPS', 'Gene', '21898', (169, 172))	('ICAM-1', 'Gene', (181, 187))	('lack', 'Var', (95, 99))	('HO-1', 'Gene', (40, 44))	('LPS', 'Gene', (169, 172))	('butyrate', 'Chemical', 'MESH:D002087', (153, 161))	('Nrf2', 'Gene', (103, 107))	('HSC2', 'CellLine', 'CVCL:1287;0.0017906403992038328', (59, 63))
270658	32121422	Indeed, macrophages from Nrf2 knockout and wildtype mice showed similar inhibition of ICAM-1 expression.	('knockout', 'Var', (30, 38))	('mice', 'Species', '10090', (52, 56))	('ICAM-1', 'Gene', (86, 92))	('Nrf2', 'Gene', (25, 29))	('expression', 'MPA', (93, 103))	('inhibition', 'NegReg', (72, 82))
270664	32121422	ICAM-1 deficiency increases M2 macrophage polarization and suppress tumor metastasis, but others reported that downregulation of ICAM-1 in RAW264.7 macrophages resulted in inflammatory M1 polarization.	('tumor metastasis', 'Disease', 'MESH:D009362', (68, 84))	('tumor metastasis', 'Disease', (68, 84))	('RAW264.7', 'CellLine', 'CVCL:0493;0.03859164641166958', (139, 147))	('increases', 'PosReg', (18, 27))	('ICAM-1', 'Gene', (0, 6))	('M2 macrophage polarization', 'CPA', (28, 54))	('deficiency', 'Var', (7, 17))	('downregulation', 'NegReg', (111, 125))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('suppress', 'NegReg', (59, 67))	('inflammatory M1 polarization', 'CPA', (172, 200))	('ICAM-1', 'Gene', (129, 135))
270712	31564971	The KM plotter analysis suggested that ERRalpha is correlated with poor prognosis in LUAD (n=720) rather than in lung squamous cell carcinoma (LSCC) (n=524).	('LUAD', 'Disease', (85, 89))	('LUAD', 'Disease', 'MESH:C538231', (85, 89))	('ERRalpha', 'Var', (39, 47))	('LSCC', 'Disease', (143, 147))	('lung squamous cell carcinoma', 'Disease', (113, 141))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (118, 141))	('LSCC', 'Phenotype', 'HP:0030359', (143, 147))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (113, 141))	('LSCC', 'Disease', 'MESH:D002294', (143, 147))	('LUAD', 'Phenotype', 'HP:0030078', (85, 89))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (113, 141))
270716	31564971	The results indicate that the death risk of ERRalpha high expression is 1.597 times higher than ERRalpha low level in LUAD patients.	('patients', 'Species', '9606', (123, 131))	('LUAD', 'Disease', (118, 122))	('LUAD', 'Disease', 'MESH:C538231', (118, 122))	('LUAD', 'Phenotype', 'HP:0030078', (118, 122))	('ERRalpha high expression', 'Var', (44, 68))
270717	31564971	In summary, our findings suggest that ERRalpha is a potential aggressive factor of LUAD which implies poor prognosis.	('LUAD', 'Disease', (83, 87))	('LUAD', 'Disease', 'MESH:C538231', (83, 87))	('LUAD', 'Phenotype', 'HP:0030078', (83, 87))	('ERRalpha', 'Var', (38, 46))
270732	31564971	To further elucidate the function of ERRalpha, we established ERRalpha-knockdown LUAD cells (A549-ERRalpha-ko, H1975-ERRalpha-ko, H1395-ERRalpha-ko).	('LUAD', 'Phenotype', 'HP:0030078', (81, 85))	('H1395-ERRalpha-ko', 'Var', (130, 147))	('H1975-ERRalpha-ko', 'Var', (111, 128))	('LUAD', 'Disease', (81, 85))	('LUAD', 'Disease', 'MESH:C538231', (81, 85))
270762	31564971	The membrane was then incubated overnight at 4 C with the following primary antibody: ERRalpha (1:2000, abcam ab76228) and beta-actin (1:3000, Santa Cruz Biotechnology).	('1:2000', 'Var', (96, 102))	('beta-actin', 'Gene', (123, 133))	('beta-actin', 'Gene', '728378', (123, 133))
270767	31564971	Endogenous peroxidase activity was blocked by dropwise addition of 3% H2O2, followed by incubated for 10 mins at room temperature, and washed 3 times with PBS.	('H2O2', 'Var', (70, 74))	('H2O2', 'Chemical', 'MESH:D014867', (70, 74))	('Endogenous peroxidase', 'Enzyme', (0, 21))	('activity', 'MPA', (22, 30))	('blocked', 'NegReg', (35, 42))
270779	31564971	The results showed that patients with LUAD with high expression of ERRalpha had a worse prognosis (HR=1.68, P<0.001) (Figure 1A), while no significant correlation was found between the expression level of ERRalpha and the survival time of patients with LSCC (P=0.78) (Figure 1B).	('LUAD', 'Disease', (38, 42))	('LSCC', 'Disease', (253, 257))	('ERRalpha', 'Gene', (67, 75))	('LUAD', 'Disease', 'MESH:C538231', (38, 42))	('LUAD', 'Phenotype', 'HP:0030078', (38, 42))	('LSCC', 'Phenotype', 'HP:0030359', (253, 257))	('patients', 'Species', '9606', (239, 247))	('LSCC', 'Disease', 'MESH:D002294', (253, 257))	('high expression', 'Var', (48, 63))	('patients', 'Species', '9606', (24, 32))
270788	31564971	The results suggested that after knockdown of ERRalpha, the viability of LUAD cells was significantly suppressed (P<0.001, Figure 5A).	('LUAD', 'Phenotype', 'HP:0030078', (73, 77))	('knockdown', 'Var', (33, 42))	('LUAD', 'Disease', (73, 77))	('LUAD', 'Disease', 'MESH:C538231', (73, 77))	('suppressed', 'NegReg', (102, 112))	('ERRalpha', 'Gene', (46, 54))
270792	31564971	As shown in Figure 6, the accumulation of ERRalpha-knockdown cells in the G2/M phase was higher compared with control (P<0.05, Figure 6) suggesting that knockdown of ERRalpha could lead to LUAD cells arresting in the G2/M phase.	('knockdown', 'Var', (153, 162))	('LUAD', 'Phenotype', 'HP:0030078', (189, 193))	('LUAD', 'Disease', (189, 193))	('LUAD', 'Disease', 'MESH:C538231', (189, 193))	('lead to', 'Reg', (181, 188))	('ERRalpha', 'Gene', (166, 174))
270808	31564971	Functional studies demonstrated that knockdown of ERRalpha impairs cell proliferation, migration, and metastasis of LUAD cells.	('migration', 'CPA', (87, 96))	('knockdown', 'Var', (37, 46))	('ERRalpha', 'Gene', (50, 58))	('impairs', 'NegReg', (59, 66))	('cell proliferation', 'CPA', (67, 85))	('LUAD', 'Disease', (116, 120))	('LUAD', 'Disease', 'MESH:C538231', (116, 120))	('LUAD', 'Phenotype', 'HP:0030078', (116, 120))
270809	31564971	Moreover, evaluation of ERRalpha in LUAD tissues indicated that high expression of ERRalpha positively associates with poor prognosis in LUAD patients, suggesting that ERRalpha is an independent risk factor for poor prognosis.	('LUAD', 'Disease', 'MESH:C538231', (137, 141))	('high', 'Var', (64, 68))	('ERRalpha', 'Gene', (83, 91))	('LUAD', 'Disease', (36, 40))	('LUAD', 'Phenotype', 'HP:0030078', (36, 40))	('LUAD', 'Phenotype', 'HP:0030078', (137, 141))	('LUAD', 'Disease', 'MESH:C538231', (36, 40))	('patients', 'Species', '9606', (142, 150))	('poor', 'Disease', (119, 123))	('LUAD', 'Disease', (137, 141))
270825	31564971	Patients with high expression of ERRalpha had poor prognosis (P=0.041), and high expression of ERRalpha was a prognostic risk factor (P=0.013, HR=1.597).	('high', 'Var', (76, 80))	('ERRalpha', 'Protein', (33, 41))	('high expression', 'Var', (14, 29))	('Patients', 'Species', '9606', (0, 8))
270831	31564971	Further study suggested ERRalpha as an independent risk factor of poor prognosis in LUAD.	('LUAD', 'Disease', 'MESH:C538231', (84, 88))	('LUAD', 'Phenotype', 'HP:0030078', (84, 88))	('ERRalpha', 'Var', (24, 32))	('LUAD', 'Disease', (84, 88))
270840	27546810	Moreover, compared to patients with pulmonary fibrosis alone in the non-CPFE group (n = 31), patients with CPFE were predominantly male (P = 0.008) and smokers (P < 0.001), with LC-CPFE predominantly exhibiting SqCC histology (P = 0.010) and being contiguous with the tumor-associated fibrotic areas (P < 0.001).	('LC', 'Phenotype', 'HP:0100526', (178, 180))	('SqCC', 'Disease', (211, 215))	('tumor', 'Phenotype', 'HP:0002664', (268, 273))	('exhibiting', 'Reg', (200, 210))	('LC-CPFE', 'Chemical', '-', (178, 185))	('pulmonary fibrosis', 'Disease', 'MESH:D011658', (36, 54))	('LC-CPFE', 'Var', (178, 185))	('CPFE', 'Chemical', '-', (181, 185))	('tumor', 'Disease', (268, 273))	('patients', 'Species', '9606', (22, 30))	('pulmonary fibrosis', 'Phenotype', 'HP:0002206', (36, 54))	('pulmonary fibrosis', 'Disease', (36, 54))	('CPFE', 'Chemical', '-', (107, 111))	('CPFE', 'Chemical', '-', (72, 76))	('SqCC', 'Phenotype', 'HP:0002860', (211, 215))	('patients', 'Species', '9606', (93, 101))	('tumor', 'Disease', 'MESH:D009369', (268, 273))
270841	27546810	Multivariate analysis revealed that CPFE was an independent predictor of overall survival (hazard ratio: 1.734; 95% confidence interval: 1.060-2.791; P = 0.028).	('CPFE', 'Chemical', '-', (36, 40))	('CPFE', 'Var', (36, 40))	('overall survival', 'MPA', (73, 89))
270874	27546810	The tumor grade of the LC-CPFE group was significantly higher than those in the other groups (P < 0.001).	('tumor', 'Disease', (4, 9))	('LC-CPFE', 'Chemical', '-', (23, 30))	('LC-CPFE', 'Var', (23, 30))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('higher', 'PosReg', (55, 61))	('LC', 'Phenotype', 'HP:0100526', (23, 25))
270878	27546810	Similarly, the LC-CPFE group exhibited a poorer OS compared to the LC-PF group, although the difference was not statistically significant (P = 0.060).	('LC-CPFE', 'Var', (15, 22))	('LC-CPFE', 'Chemical', '-', (15, 22))	('LC-PF', 'Chemical', '-', (67, 72))	('poorer', 'NegReg', (41, 47))	('LC', 'Phenotype', 'HP:0100526', (67, 69))	('LC', 'Phenotype', 'HP:0100526', (15, 17))
270880	27546810	The univariate analysis revealed numerous significant risk factors for poor DFS and OS, and patients with CPFE exhibited a higher risk of recurrence (hazard ratio [HR]: 4.641; 95% confidence interval [CI]: 2.824-7.358; P < 0.001) and mortality (HR: 4.993; 95% CI: 3.195-7.595; P < 0.001) compared to the patients without CPFE.	('CPFE', 'Chemical', '-', (106, 110))	('CPFE', 'Chemical', '-', (321, 325))	('patients', 'Species', '9606', (304, 312))	('CPFE', 'Var', (106, 110))	('recurrence', 'MPA', (138, 148))	('patients', 'Species', '9606', (92, 100))	('mortality', 'CPA', (234, 243))
270893	27546810	Furthermore, LC-CPFE was associated with a significantly smaller tumor size (mean: 29.5 mm vs. 39.6 mm, P = 0.036).	('smaller', 'NegReg', (57, 64))	('tumor', 'Disease', (65, 70))	('LC-CPFE', 'Chemical', '-', (13, 20))	('LC-CPFE', 'Var', (13, 20))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('LC', 'Phenotype', 'HP:0100526', (13, 15))
270905	27546810	Moreover, dysplastic epithelium in the fibrotic area was frequently identified in these cases, which indicates that the development of lung cancer in patients with CPFE is distinct from the development of lung cancer in patients without CPFE.	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('lung cancer', 'Disease', 'MESH:D008175', (205, 216))	('CPFE', 'Chemical', '-', (164, 168))	('dysplastic', 'Disease', (10, 20))	('dysplastic', 'Disease', 'MESH:D004416', (10, 20))	('CPFE', 'Var', (164, 168))	('men', 'Species', '9606', (197, 200))	('patients', 'Species', '9606', (150, 158))	('patients', 'Species', '9606', (220, 228))	('CPFE', 'Chemical', '-', (237, 241))	('lung cancer', 'Disease', 'MESH:D008175', (135, 146))	('lung cancer', 'Disease', (205, 216))	('lung cancer', 'Phenotype', 'HP:0100526', (205, 216))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('men', 'Species', '9606', (127, 130))	('lung cancer', 'Disease', (135, 146))	('lung cancer', 'Phenotype', 'HP:0100526', (135, 146))
270916	27546810	Although most previous studies have highlighted a risk of developing lung cancer in patients with CPFE, and compared their overall prognosis to patients with emphysema or IPF 6, 7, 9, 10, only one study has compared the prognoses of LC-CPFE and LC-PF.	('emphysema', 'Phenotype', 'HP:0002097', (158, 167))	('CPFE', 'Chemical', '-', (236, 240))	('lung cancer', 'Disease', 'MESH:D008175', (69, 80))	('LC-PF', 'Chemical', '-', (245, 250))	('CPFE', 'Chemical', '-', (98, 102))	('patients', 'Species', '9606', (84, 92))	('LC-CPFE', 'Chemical', '-', (233, 240))	('CPFE', 'Var', (98, 102))	('emphysema', 'Disease', (158, 167))	('patients', 'Species', '9606', (144, 152))	('lung cancer', 'Disease', (69, 80))	('LC-CPFE', 'Disease', (233, 240))	('emphysema', 'Disease', 'MESH:D004646', (158, 167))	('lung cancer', 'Phenotype', 'HP:0100526', (69, 80))	('LC', 'Phenotype', 'HP:0100526', (245, 247))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('LC', 'Phenotype', 'HP:0100526', (233, 235))
270917	27546810	retrospectively analyzed the effect of CPFE on the prognosis of patients with NSCLC after complete tumor resection 11, and concluded that CPFE was a significant predictor of a poor prognosis for NSCLC.	('tumor', 'Disease', (99, 104))	('NSCLC', 'Disease', 'MESH:D002289', (195, 200))	('CPFE', 'Chemical', '-', (39, 43))	('NSCLC', 'Disease', 'MESH:D002289', (78, 83))	('patients', 'Species', '9606', (64, 72))	('LC', 'Phenotype', 'HP:0100526', (81, 83))	('LC', 'Phenotype', 'HP:0100526', (198, 200))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('CPFE', 'Chemical', '-', (138, 142))	('NSCLC', 'Disease', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('CPFE', 'Var', (138, 142))	('NSCLC', 'Disease', (195, 200))
270918	27546810	In this study, we found that patients with LC-CPFE exhibited poorer OS, compared to patients with LC-PF (although this difference was not statistically significant), despite both groups exhibiting similar DFS.	('patients', 'Species', '9606', (29, 37))	('LC-CPFE', 'Chemical', '-', (43, 50))	('LC-PF', 'Chemical', '-', (98, 103))	('patients', 'Species', '9606', (84, 92))	('LC-CPFE', 'Var', (43, 50))	('LC', 'Phenotype', 'HP:0100526', (43, 45))	('LC', 'Phenotype', 'HP:0100526', (98, 100))	('poorer', 'NegReg', (61, 67))
270924	27546810	These findings may indicate that lung adenocarcinomas in the CPFE group were different from those in the non-CPFE group.	('CPFE', 'Chemical', '-', (61, 65))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (33, 52))	('CPFE', 'Var', (61, 65))	('lung adenocarcinomas', 'Disease', (33, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (43, 52))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (33, 53))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (33, 53))	('CPFE', 'Chemical', '-', (109, 113))
270936	27633630	Aberrant microRNA (miRNA) expression has been shown to promote lung cancer development and aggressiveness.	('miR', 'Gene', '220972', (19, 22))	('aggressiveness', 'Disease', 'MESH:D001523', (91, 105))	('miR', 'Gene', (19, 22))	('lung cancer', 'Disease', 'MESH:D008175', (63, 74))	('aggressiveness', 'Disease', (91, 105))	('si', 'Chemical', 'MESH:D012825', (97, 99))	('Aberrant', 'Var', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('si', 'Chemical', 'MESH:D012825', (32, 34))	('aggressiveness', 'Phenotype', 'HP:0000718', (91, 105))	('lung cancer', 'Disease', (63, 74))	('lung cancer', 'Phenotype', 'HP:0100526', (63, 74))	('microRNA', 'Protein', (9, 17))	('promote', 'PosReg', (55, 62))
270943	27633630	Overexpression of TPD52 was observed in lung SCC clinical specimens, and knockdown of TPD52 significantly suppressed cancer cell migration and invasion in lung SCC cell lines.	('TPD52', 'Gene', (86, 91))	('SCC', 'Gene', (45, 48))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('invasion', 'CPA', (143, 151))	('SCC', 'Gene', '6317', (45, 48))	('suppressed', 'NegReg', (106, 116))	('si', 'Chemical', 'MESH:D012825', (92, 94))	('SCC', 'Gene', (160, 163))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('si', 'Chemical', 'MESH:D012825', (147, 149))	('cancer', 'Disease', (117, 123))	('si', 'Chemical', 'MESH:D012825', (10, 12))	('SCC', 'Gene', '6317', (160, 163))	('knockdown', 'Var', (73, 82))
270954	27633630	Therefore, aberrantly expressed miRNAs may upset tightly regulated cellular RNA networks.	('miR', 'Gene', (32, 35))	('upset', 'Reg', (43, 48))	('aberrantly expressed', 'Var', (11, 31))	('tightly regulated cellular RNA networks', 'CPA', (49, 88))	('miR', 'Gene', '220972', (32, 35))
270956	27633630	In fact, aberrantly expressed miRNAs have been reported in various types of human cancers, including lung SCC.	('miR', 'Gene', '220972', (30, 33))	('miR', 'Gene', (30, 33))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('aberrantly expressed', 'Var', (9, 29))	('SCC', 'Gene', '6317', (106, 109))	('cancers', 'Phenotype', 'HP:0002664', (82, 89))	('cancers', 'Disease', (82, 89))	('human', 'Species', '9606', (76, 81))	('cancers', 'Disease', 'MESH:D009369', (82, 89))	('reported', 'Reg', (47, 55))	('SCC', 'Gene', (106, 109))
270964	27633630	We found that restoration of miR-218 significantly suppressed cancer cell migration and invasion.	('restoration', 'Var', (14, 25))	('miR', 'Gene', '220972', (29, 32))	('invasion', 'CPA', (88, 96))	('miR', 'Gene', (29, 32))	('si', 'Chemical', 'MESH:D012825', (37, 39))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('suppressed', 'NegReg', (51, 61))	('si', 'Chemical', 'MESH:D012825', (92, 94))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))
270979	27633630	Pre-miR  miRNA precursors for miR-218 (hsa-miR-218-5p, P/N: AM1 7100; Applied Biosystems) and negative control miRNA (P/N: AM 17111; Applied Biosystems), Stealth Select RNAi siRNA, si-TPD52 (P/N: HSS120730 and HSS120731; Invitrogen, Carlsbad, CA, USA), and negative control siRNA (P/N: 4390843; Invitrogen) were used in this study.	('miR', 'Gene', '220972', (30, 33))	('miR', 'Gene', (30, 33))	('HSS120731', 'Var', (210, 219))	('miR', 'Gene', '220972', (43, 46))	('miR', 'Gene', (43, 46))	('miR', 'Gene', (4, 7))	('AM1', 'Species', '408139', (60, 63))	('si', 'Chemical', 'MESH:D012825', (174, 176))	('si', 'Chemical', 'MESH:D012825', (274, 276))	('miR', 'Gene', '220972', (4, 7))	('P/N', 'Var', (191, 194))	('miR', 'Gene', '220972', (9, 12))	('si', 'Chemical', 'MESH:D012825', (181, 183))	('miR', 'Gene', '220972', (111, 114))	('miR', 'Gene', (111, 114))	('miR', 'Gene', (9, 12))
271006	27633630	Cell proliferation assays showed that cancer cell growth was slightly inhibited in miR-218 transfectants compared with mock- or miR control-transfected EBC-1 and SK-MES-1 cells (Fig.	('transfectants', 'Var', (91, 104))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('SK-MES-1', 'CellLine', 'CVCL:0630', (162, 170))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('miR', 'Gene', '220972', (83, 86))	('miR', 'Gene', '220972', (128, 131))	('miR', 'Gene', (83, 86))	('miR', 'Gene', (128, 131))	('cancer', 'Disease', (38, 44))	('inhibited', 'NegReg', (70, 79))
271007	27633630	Cancer cell migration and invasion activities were significantly inhibited in miR-218 transfectants compared with mock- or miR-control-transfectants (P<0.0001; Fig.	('miR', 'Gene', '220972', (78, 81))	('miR', 'Gene', '220972', (123, 126))	('miR', 'Gene', (78, 81))	('miR', 'Gene', (123, 126))	('si', 'Chemical', 'MESH:D012825', (30, 32))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('inhibited', 'NegReg', (65, 74))	('invasion activities', 'CPA', (26, 45))	('transfectants', 'Var', (86, 99))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('si', 'Chemical', 'MESH:D012825', (51, 53))
271014	27633630	First, we measured the expression of TPD52/TPD52 using quantitative RT-PCR and western blotting to determine whether restoration of miR-218 in EBC-1 and SK-MES-1 cells suppressed the expression of TPD52/TPD52.	('si', 'Chemical', 'MESH:D012825', (29, 31))	('restoration', 'Var', (117, 128))	('si', 'Chemical', 'MESH:D012825', (189, 191))	('SK-MES-1', 'CellLine', 'CVCL:0630', (153, 161))	('suppressed', 'NegReg', (168, 178))	('si', 'Chemical', 'MESH:D012825', (50, 52))	('expression', 'MPA', (183, 193))	('miR', 'Gene', '220972', (132, 135))	('miR', 'Gene', (132, 135))	('TPD52/TPD52', 'Gene', (197, 208))
271015	27633630	3A and B, the expression levels of TPD52/TPD52 were markedly repressed by miR-218 transfection compared with mock- or miR-control-transfected cells.	('miR', 'Gene', (74, 77))	('expression levels', 'MPA', (14, 31))	('miR', 'Gene', '220972', (74, 77))	('transfection', 'Var', (82, 94))	('repressed', 'PosReg', (61, 70))	('miR', 'Gene', (118, 121))	('si', 'Chemical', 'MESH:D012825', (20, 22))	('miR', 'Gene', '220972', (118, 121))	('TPD52/TPD52', 'Var', (35, 46))
271017	27633630	We used vectors encoding either partial wild-type sequences of the 3'-UTR of TPD52 including the predicted miR-218 target sites (positions 52-58, 778-784, 940-946 of the TPD52 3'-UTR), or deletion vectors lacking these sites (Fig.	('si', 'Chemical', 'MESH:D012825', (131, 133))	('si', 'Chemical', 'MESH:D012825', (122, 124))	('TPD52', 'Gene', (77, 82))	('deletion', 'Var', (188, 196))	('si', 'Chemical', 'MESH:D012825', (219, 221))	('miR', 'Gene', '220972', (107, 110))	('miR', 'Gene', (107, 110))	('lacking', 'NegReg', (205, 212))
271020	27633630	We performed loss-of-function studies using si-TPD52 to investigate the oncogenic function of TPD52 in lung SCC cells.	('si', 'Chemical', 'MESH:D012825', (39, 41))	('SCC', 'Gene', (108, 111))	('si', 'Chemical', 'MESH:D012825', (44, 46))	('SCC', 'Gene', '6317', (108, 111))	('si-TPD52', 'Var', (44, 52))
271022	27633630	RT-PCR and western blotting showed that two siRNAs (si-TPD52-1 and si-TPD52-2) could effectively reduce the expression of TPD52/TPD52 in EBC-1 and SK-MES-1 cells (Fig.	('si-TPD52-2', 'Var', (67, 77))	('si', 'Chemical', 'MESH:D012825', (114, 116))	('si', 'Chemical', 'MESH:D012825', (67, 69))	('TPD52/TPD52', 'Gene', (122, 133))	('si', 'Chemical', 'MESH:D012825', (44, 46))	('SK-MES-1', 'CellLine', 'CVCL:0630', (147, 155))	('expression', 'MPA', (108, 118))	('si', 'Chemical', 'MESH:D012825', (52, 54))	('si-TPD52-1', 'Var', (52, 62))	('reduce', 'NegReg', (97, 103))
271024	27633630	XTT assays demonstrated that cell proliferation was inhibited by si-TPD52 transfection only in SK-MES-1 cells (Fig.	('transfection', 'Var', (74, 86))	('SK-MES-1', 'CellLine', 'CVCL:0630', (95, 103))	('cell proliferation', 'CPA', (29, 47))	('si-TPD52', 'Gene', (65, 73))	('inhibited', 'NegReg', (52, 61))	('si', 'Chemical', 'MESH:D012825', (65, 67))
271025	27633630	Cell migration and invasion activities were significantly inhibited by si-TPD52 transfection in both EBC-1 and SK-MES-1 cells in comparison with mock- or negative-control transfectants (Fig.	('SK-MES-1', 'CellLine', 'CVCL:0630', (111, 119))	('Cell migration', 'CPA', (0, 14))	('si', 'Chemical', 'MESH:D012825', (71, 73))	('si', 'Chemical', 'MESH:D012825', (23, 25))	('si-TPD52 transfection', 'Var', (71, 92))	('invasion activities', 'CPA', (19, 38))	('si', 'Chemical', 'MESH:D012825', (44, 46))	('inhibited', 'NegReg', (58, 67))	('transfection', 'Var', (80, 92))
271028	27633630	To identify the downstream genes regulated by TPD52, genome-wide gene expression analysis and in silico analysis were performed in lung SCC cells transfected with si-TPD52.	('si', 'Chemical', 'MESH:D012825', (76, 78))	('SCC', 'Gene', (136, 139))	('si', 'Chemical', 'MESH:D012825', (163, 165))	('si', 'Chemical', 'MESH:D012825', (97, 99))	('TPD52', 'Gene', (46, 51))	('SCC', 'Gene', '6317', (136, 139))	('si', 'Chemical', 'MESH:D012825', (109, 111))	('si-TPD52', 'Var', (163, 171))	('si', 'Chemical', 'MESH:D012825', (86, 88))
271029	27633630	A total of 2,278 genes were identified as downregulated in si-TPD52-transfected EBC-1 cells compared with the control (log2 ratio <-0.5).	('si', 'Chemical', 'MESH:D012825', (59, 61))	('downregulated', 'NegReg', (42, 55))	('si-TPD52-transfected', 'Var', (59, 79))
271034	27633630	Thus, aberrant expression of miRNAs disrupts the RNA network in cancer cells.	('miR', 'Gene', '220972', (29, 32))	('miR', 'Gene', (29, 32))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('aberrant expression', 'Var', (6, 25))	('RNA network', 'CPA', (49, 60))	('si', 'Chemical', 'MESH:D012825', (21, 23))	('disrupts', 'NegReg', (36, 44))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
271035	27633630	Identification of aberrantly expressed miRNAs and the novel cancer networks they regulate is a research trend of the post-genome-sequencing era.	('aberrantly expressed', 'Var', (18, 38))	('miR', 'Gene', '220972', (39, 42))	('miR', 'Gene', (39, 42))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('cancer', 'Disease', (60, 66))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
271036	27633630	Recent evidence shows that disruption of normally-regulated RNA networks by aberrantly expressed miRNAs triggers cancer cell development, progression and metastasis.	('si', 'Chemical', 'MESH:D012825', (145, 147))	('RNA', 'Protein', (60, 63))	('aberrantly expressed', 'Var', (76, 96))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('triggers', 'Reg', (104, 112))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('cancer', 'Disease', (113, 119))	('disruption', 'Var', (27, 37))	('metastasis', 'CPA', (154, 164))	('progression', 'CPA', (138, 149))	('si', 'Chemical', 'MESH:D012825', (161, 163))	('miR', 'Gene', '220972', (97, 100))	('miR', 'Gene', (97, 100))
271064	27633630	Ectopic expression of mouse TPD52 in 3T3 fibroblasts resulted in a transformed phenotype that progressed to metastasis.	('resulted in', 'Reg', (53, 64))	('si', 'Chemical', 'MESH:D012825', (14, 16))	('si', 'Chemical', 'MESH:D012825', (115, 117))	('Ectopic expression', 'Var', (0, 18))	('mouse', 'Species', '10090', (22, 27))	('progressed', 'PosReg', (94, 104))	('TPD52', 'Gene', (28, 33))
271066	27633630	Other studies showed that TPD52 knockdown increases apoptotic cell death in ERBB2-amplified breast cancer cell lines.	('death', 'Disease', 'MESH:D003643', (67, 72))	('breast cancer', 'Phenotype', 'HP:0003002', (92, 105))	('death', 'Disease', (67, 72))	('increases', 'PosReg', (42, 51))	('breast cancer', 'Disease', (92, 105))	('knockdown', 'Var', (32, 41))	('TPD52', 'Gene', (26, 31))	('ERBB2', 'Gene', (76, 81))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('ERBB2', 'Gene', '2064', (76, 81))	('breast cancer', 'Disease', 'MESH:D001943', (92, 105))
271069	27633630	Downregulation of TPD52 expression was observed by miR-107 and miR-185 transfection into non-small cell lung cancer cells and miR-34a transfection into colorectal cancer cells.	('colorectal cancer', 'Disease', 'MESH:D015179', (152, 169))	('Downregulation', 'NegReg', (0, 14))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (89, 115))	('miR-34a', 'Gene', '407040', (126, 133))	('colorectal cancer', 'Disease', (152, 169))	('TPD52', 'Gene', (18, 23))	('miR-107', 'Gene', (51, 58))	('transfection', 'Var', (71, 83))	('miR-185', 'Gene', '406961', (63, 70))	('expression', 'MPA', (24, 34))	('transfection', 'Var', (134, 146))	('lung cancer', 'Phenotype', 'HP:0100526', (104, 115))	('non-small cell lung cancer', 'Disease', (89, 115))	('miR-107', 'Gene', '406901', (51, 58))	('si', 'Chemical', 'MESH:D012825', (30, 32))	('colorectal cancer', 'Phenotype', 'HP:0003003', (152, 169))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (93, 115))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (89, 115))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('miR-185', 'Gene', (63, 70))	('miR-34a', 'Gene', (126, 133))
271070	27633630	Our previous data showed that the tumor-suppressive miR-224 directly regulates oncogenic TPD52 in prostate cancer cells, and silencing TPD52 results in significant reductions in cancer cell migration and invasion in prostate cancer cells.	('invasion', 'CPA', (204, 212))	('si', 'Chemical', 'MESH:D012825', (208, 210))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('cancer', 'Disease', (225, 231))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('reductions', 'NegReg', (164, 174))	('prostate cancer', 'Disease', 'MESH:D011471', (98, 113))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('prostate cancer', 'Disease', 'MESH:D011471', (216, 231))	('si', 'Chemical', 'MESH:D012825', (152, 154))	('prostate cancer', 'Phenotype', 'HP:0012125', (98, 113))	('tumor', 'Disease', (34, 39))	('silencing', 'Var', (125, 134))	('prostate cancer', 'Phenotype', 'HP:0012125', (216, 231))	('prostate cancer', 'Disease', (98, 113))	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('prostate cancer', 'Disease', (216, 231))	('TPD52', 'Gene', (89, 94))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('miR-224', 'Gene', (52, 59))	('si', 'Chemical', 'MESH:D012825', (125, 127))	('miR-224', 'Gene', '407009', (52, 59))	('cancer', 'Disease', 'MESH:D009369', (225, 231))	('TPD52', 'Gene', (135, 140))	('si', 'Chemical', 'MESH:D012825', (47, 49))	('cancer', 'Disease', (107, 113))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('cancer', 'Disease', (178, 184))	('regulates', 'Reg', (69, 78))
271074	27633630	In the present study, we identified TPD52-mediated cancer pathways using genome-wide gene expression analysis of si-TPD52-transfected lung SCC cells.	('SCC', 'Gene', '6317', (139, 142))	('TPD52-mediated', 'Gene', (36, 50))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('si', 'Chemical', 'MESH:D012825', (68, 70))	('si', 'Chemical', 'MESH:D012825', (113, 115))	('si', 'Chemical', 'MESH:D012825', (106, 108))	('si', 'Chemical', 'MESH:D012825', (96, 98))	('SCC', 'Gene', (139, 142))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('si-TPD52-transfected', 'Var', (113, 133))
271082	27633630	In bladder cancer, CCNB2 was overexpressed in cancer cells and knockdown of CCNB2 inhibited invasion and metastatic abilities.	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('CCNB2', 'Gene', '9133', (76, 81))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('bladder cancer', 'Phenotype', 'HP:0009725', (3, 17))	('inhibited', 'NegReg', (82, 91))	('cancer', 'Disease', (46, 52))	('CCNB2', 'Gene', '9133', (19, 24))	('CCNB2', 'Gene', (76, 81))	('cancer', 'Disease', 'MESH:D009369', (11, 17))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('bladder cancer', 'Disease', 'MESH:D001749', (3, 17))	('bladder cancer', 'Disease', (3, 17))	('cancer', 'Disease', (11, 17))	('knockdown', 'Var', (63, 72))	('si', 'Chemical', 'MESH:D012825', (96, 98))	('CCNB2', 'Gene', (19, 24))
271104	31641374	GSTM1 deficiency would significantly increase the risk of LSCC.	('increase', 'Reg', (37, 45))	('deficiency', 'Var', (6, 16))	('GSTM1', 'Gene', '2944', (0, 5))	('GSTM1', 'Gene', (0, 5))	('LSCC', 'Disease', (58, 62))	('LSCC', 'Phenotype', 'HP:0030359', (58, 62))	('LSCC', 'Disease', 'MESH:D002294', (58, 62))
271106	31641374	Epidemiology studies showed that there was an increasing risk of developing lung cancer in cigarette amount dependent manner on both GSTM1 and CYP1A1 gene mutate patients.	('patients', 'Species', '9606', (162, 170))	('CYP1A1', 'Gene', '1543', (143, 149))	('lung cancer', 'Disease', 'MESH:D008175', (76, 87))	('gene mutate', 'Var', (150, 161))	('GSTM1', 'Gene', '2944', (133, 138))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('GSTM1', 'Gene', (133, 138))	('lung cancer', 'Disease', (76, 87))	('lung cancer', 'Phenotype', 'HP:0100526', (76, 87))	('CYP1A1', 'Gene', (143, 149))
271107	31641374	Other genes with gain or loss of function mutations, such as FGFR1, TP53 and NOTCH1, might also play important roles in developing LSCC.	('FGFR1', 'Gene', (61, 66))	('NOTCH1', 'Gene', '4851', (77, 83))	('NOTCH1', 'Gene', (77, 83))	('LSCC', 'Disease', 'MESH:D002294', (131, 135))	('gain', 'Disease', (17, 21))	('FGFR1', 'Gene', '2260', (61, 66))	('TP53', 'Gene', '7157', (68, 72))	('mutations', 'Var', (42, 51))	('gain', 'Disease', 'MESH:D015430', (17, 21))	('loss', 'NegReg', (25, 29))	('TP53', 'Gene', (68, 72))	('LSCC', 'Disease', (131, 135))	('LSCC', 'Phenotype', 'HP:0030359', (131, 135))
271127	31641374	Integrative analysis of RNA-seq and DNA methylation data was performed and detected cis-related correlations of CpG methylation and RNA expression.	('N', 'Chemical', 'MESH:D009584', (37, 38))	('methylation', 'Var', (116, 127))	('N', 'Chemical', 'MESH:D009584', (133, 134))	('N', 'Chemical', 'MESH:D009584', (25, 26))	('CpG', 'Gene', (112, 115))
271145	31641374	These findings are critical for fully understanding the mechanism of high cigarette smoking caused LSCC and other type of lung cancers, and provides guidance for future lung cancer research focusing on RNA function targeted therapies and diagnosis biomarkers.	('type of lung cancers', 'Disease', (114, 134))	('lung cancer', 'Disease', 'MESH:D008175', (169, 180))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('LSCC', 'Disease', (99, 103))	('lung cancer', 'Phenotype', 'HP:0100526', (122, 133))	('LSCC', 'Phenotype', 'HP:0030359', (99, 103))	('type of lung cancers', 'Disease', 'MESH:D008175', (114, 134))	('N', 'Chemical', 'MESH:D009584', (203, 204))	('lung cancer', 'Phenotype', 'HP:0100526', (169, 180))	('cancers', 'Phenotype', 'HP:0002664', (127, 134))	('LSCC', 'Disease', 'MESH:D002294', (99, 103))	('lung cancer', 'Disease', 'MESH:D008175', (122, 133))	('lung cancer', 'Disease', (169, 180))	('lung cancers', 'Phenotype', 'HP:0100526', (122, 134))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('high cigarette', 'Var', (69, 83))
271147	31641374	Cigarette smoking is reported to impair the function of lysosome through dysfunction of NRF-2 antioxidant pathway and immune-response apoptotic pathways, which pathways are well organized as critical regulators in many human cancer carcinogenesis.	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('human', 'Species', '9606', (219, 224))	('immune-response apoptotic pathways', 'Pathway', (118, 152))	('NRF-2', 'Gene', '4780', (88, 93))	('NRF-2', 'Gene', (88, 93))	('cancer carcinogenesis', 'Disease', 'MESH:D009369', (225, 246))	('dysfunction', 'Var', (73, 84))	('lysosome', 'MPA', (56, 64))	('impair', 'NegReg', (33, 39))	('cancer carcinogenesis', 'Disease', (225, 246))	('function', 'MPA', (44, 52))
271163	31641374	The entire coMet Fig contains three layer: top layer shows chromosome position of gene, and CpG site methylation changes with -log (p-value) plot.	('coMet', 'Species', '302767', (11, 16))	('methylation', 'Var', (101, 112))	('changes', 'Reg', (113, 120))
271165	31641374	For AIRE gene, cg09510531 to cg00495713, and cg01351072 to cg18876487 show strong positive correlation.	('cg09510531', 'Var', (15, 25))	('AIRE', 'Gene', (4, 8))	('AIRE', 'Gene', '326', (4, 8))	('cg18876487', 'Var', (59, 69))	('cg00495713', 'Var', (29, 39))	('cg01351072', 'Var', (45, 55))
271166	31641374	For PENK gene, cg04612444 to cg06066137, and cg11060276 to cg27531336 show strong positive correlation.	('cg27531336', 'Var', (59, 69))	('PENK', 'Gene', '5179', (4, 8))	('cg11060276', 'Var', (45, 55))	('PENK', 'Gene', (4, 8))	('cg04612444', 'Var', (15, 25))	('cg06066137', 'Var', (29, 39))
271167	31641374	For SLC6A3, cg04073265 to cg15999077 and cg17306747 to cg27580375 show strong positive correlation.	('cg27580375', 'Var', (55, 65))	('SLC6A3', 'Gene', (4, 10))	('cg17306747', 'Var', (41, 51))	('SLC6A3', 'Gene', '6531', (4, 10))	('cg15999077', 'Var', (26, 36))	('cg04073265', 'Var', (12, 22))
271171	31641374	Mutation of AIRE genes caused the dysfunction of T cell development and the immune system self-tolerance breakdown.	('AIRE', 'Gene', (12, 16))	('AIRE', 'Gene', '326', (12, 16))	('T cell development', 'CPA', (49, 67))	('Mutation', 'Var', (0, 8))	('immune system self-tolerance breakdown', 'CPA', (76, 114))	('caused', 'Reg', (23, 29))
271175	31641374	AIRE deficiency finds to decrease the expression of Tyrosinase Related Protein 1 (TYRP1) in thymus, yet increases the T cell immune responses against melanoma development.	('deficiency', 'Var', (5, 15))	('expression', 'MPA', (38, 48))	('AIRE', 'Gene', (0, 4))	('decrease', 'NegReg', (25, 33))	('increases', 'PosReg', (104, 113))	('TYRP1', 'Gene', '7306', (82, 87))	('gain', 'Disease', (143, 147))	('Tyrosinase Related Protein 1', 'Gene', (52, 80))	('TYRP1', 'Gene', (82, 87))	('AIRE', 'Gene', '326', (0, 4))	('gain', 'Disease', 'MESH:D015430', (143, 147))	('melanoma', 'Disease', 'MESH:D008545', (150, 158))	('melanoma', 'Phenotype', 'HP:0002861', (150, 158))	('melanoma', 'Disease', (150, 158))	('Tyrosinase Related Protein 1', 'Gene', '7306', (52, 80))
271181	31641374	It has been identified that PENK was associated with has-miR126, which was found significantly down regulated in NSCLC.	('PENK', 'Gene', '5179', (28, 32))	('N', 'Chemical', 'MESH:D009584', (113, 114))	('N', 'Chemical', 'MESH:D009584', (30, 31))	('NSCLC', 'Phenotype', 'HP:0030358', (113, 118))	('has-miR126', 'Var', (53, 63))	('SCLC', 'Phenotype', 'HP:0030357', (114, 118))	('NSCLC', 'Disease', (113, 118))	('PENK', 'Gene', (28, 32))	('down regulated', 'NegReg', (95, 109))
271184	31641374	It was found that the polymorphisms of SLC6A3 was highly associated with body mass index, which the later one have been strongly suggested as risk factor of many types of cancer including lung.	('body mass index', 'Disease', (73, 88))	('polymorphisms', 'Var', (22, 35))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('cancer', 'Disease', (171, 177))	('SLC6A3', 'Gene', (39, 45))	('lung', 'Disease', (188, 192))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('SLC6A3', 'Gene', '6531', (39, 45))	('associated', 'Reg', (57, 67))
271186	31641374	Methylation status in promoter region of SLC6A3 gene shows significant strong correlation with overall survival, with significant probability difference over 40%.	('correlation', 'Interaction', (78, 89))	('SLC6A3', 'Gene', (41, 47))	('Methylation status', 'Var', (0, 18))	('SLC6A3', 'Gene', '6531', (41, 47))	('overall survival', 'CPA', (95, 111))
271188	31641374	Moreover, SLC6A3 c.-1476 T > G polymorphism may increase the risk of NSCLC, and the gain of 5p15.33 (which containing SLC6A3) is the most frequent genetic event in early stage NSCLC.	('SLC6A3', 'Gene', (10, 16))	('gain', 'Disease', (84, 88))	('NSCLC', 'Disease', (69, 74))	('gain', 'Disease', 'MESH:D015430', (84, 88))	('NSCLC', 'Phenotype', 'HP:0030358', (69, 74))	('SCLC', 'Phenotype', 'HP:0030357', (70, 74))	('SLC6A3', 'Gene', '6531', (10, 16))	('SLC6A3', 'Gene', '6531', (118, 124))	('SLC6A3', 'Gene', (118, 124))	('c.-1476 T > G', 'Var', (17, 30))	('c.-1476 T > G', 'Mutation', 'c.-1476T>G', (17, 30))	('N', 'Chemical', 'MESH:D009584', (69, 70))	('SCLC', 'Phenotype', 'HP:0030357', (177, 181))	('N', 'Chemical', 'MESH:D009584', (176, 177))	('NSCLC', 'Phenotype', 'HP:0030358', (176, 181))	('increase', 'PosReg', (48, 56))
271221	31324812	Recently, the development of targeted drugs for specific gene mutations has greatly improved the therapy of advanced LUAD patients.	('LUAD', 'Phenotype', 'HP:0030078', (117, 121))	('patients', 'Species', '9606', (122, 130))	('advanced LUAD', 'Disease', (108, 121))	('improved', 'PosReg', (84, 92))	('mutations', 'Var', (62, 71))
271239	31324812	circTP63 is correlated with larger tumor size and higher TNM stage in LUSC patients and promotes cell proliferation by functioning as a ceRNA to upregulate FOXM1.	('promotes', 'PosReg', (88, 96))	('TNM', 'Gene', '10178', (57, 60))	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('higher', 'PosReg', (50, 56))	('LUSC', 'Phenotype', 'HP:0030359', (70, 74))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('circTP63', 'Var', (0, 8))	('patients', 'Species', '9606', (75, 83))	('TNM', 'Gene', (57, 60))	('tumor', 'Disease', (35, 40))	('FOXM1', 'Gene', '2305', (156, 161))	('FOXM1', 'Gene', (156, 161))	('si', 'Chemical', 'MESH:D012825', (41, 43))	('cell proliferation', 'CPA', (97, 115))	('circTP63', 'Chemical', '-', (0, 8))	('upregulate', 'PosReg', (145, 155))
271256	31324812	The preliminary Kaplan-Meier analysis showed that patients with higher level of circTP63 were more likely to be poor overall survivals (OS), although p-value was not significant (p = 0.2930, Supplementary Fig.	('overall survivals', 'CPA', (117, 134))	('patients', 'Species', '9606', (50, 58))	('si', 'Chemical', 'MESH:D012825', (166, 168))	('circTP63', 'Chemical', '-', (80, 88))	('poor', 'NegReg', (112, 116))	('si', 'Chemical', 'MESH:D012825', (34, 36))	('circTP63', 'Var', (80, 88))
271275	31324812	Cell proliferation assay revealed that silencing of circTP63 significantly suppressed cell growth (Fig.	('circTP63', 'Gene', (52, 60))	('cell growth', 'CPA', (86, 97))	('suppressed', 'NegReg', (75, 85))	('circTP63', 'Chemical', '-', (52, 60))	('si', 'Chemical', 'MESH:D012825', (39, 41))	('si', 'Chemical', 'MESH:D012825', (61, 63))	('silencing', 'Var', (39, 48))
271277	31324812	In order to prove that circTP63 was responsible for the phenotypes, we mutated the si-circTP63 targeted back splice junction (Supplementary Fig.	('si-circTP63', 'Chemical', '-', (83, 94))	('circTP63', 'Chemical', '-', (86, 94))	('mutated', 'Var', (71, 78))	('si', 'Chemical', 'MESH:D012825', (83, 85))	('circTP63', 'Chemical', '-', (23, 31))	('si', 'Chemical', 'MESH:D012825', (42, 44))	('si-circTP63', 'Gene', (83, 94))
271278	31324812	The circTP63-si-mut plasmid was co-transfected with si-circTP63 into H1703 cells to determine whether it could affect the cell proliferation.	('affect', 'Reg', (111, 117))	('circTP63', 'Chemical', '-', (55, 63))	('si-circTP63', 'Var', (52, 63))	('si-circTP63', 'Chemical', '-', (52, 63))	('H1703', 'CellLine', 'CVCL:1490', (69, 74))	('si', 'Chemical', 'MESH:D012825', (13, 15))	('si', 'Chemical', 'MESH:D012825', (52, 54))	('circTP63', 'Chemical', '-', (4, 12))	('cell proliferation', 'CPA', (122, 140))
271279	31324812	Result showed that circTP63-si-mut could rescue the proliferation phenotype and promoted the cell growth (Supplementary Fig.	('rescue', 'PosReg', (41, 47))	('si', 'Chemical', 'MESH:D012825', (28, 30))	('cell growth', 'CPA', (93, 104))	('promoted', 'PosReg', (80, 88))	('circTP63', 'Chemical', '-', (19, 27))	('circTP63-si-mut', 'Var', (19, 34))	('proliferation phenotype', 'CPA', (52, 75))
271282	31324812	Cell cycle analysis illustrated that silencing of circTP63 decreased the number of cells in G2/M phase, but increased the number of cells in G1 phase as compared with the controls (Fig.	('decreased', 'NegReg', (59, 68))	('circTP63', 'Gene', (50, 58))	('si', 'Chemical', 'MESH:D012825', (37, 39))	('increased', 'PosReg', (108, 117))	('si', 'Chemical', 'MESH:D012825', (16, 18))	('silencing', 'Var', (37, 46))	('circTP63', 'Chemical', '-', (50, 58))	('G1 phase', 'CPA', (141, 149))
271286	31324812	To identify the effect of circTP63 on tumor growth in vivo, we established a nude mice xenograft model by implanting H2170 cells with vector or circTP63.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('circTP63', 'Var', (144, 152))	('nude mice', 'Species', '10090', (77, 86))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('H2170', 'CellLine', 'CVCL:1535', (117, 122))	('circTP63', 'Chemical', '-', (26, 34))	('circTP63', 'Chemical', '-', (144, 152))
271289	31324812	The tumor volumes and weights were significantly accelerated by circTP63 (Fig.	('tumor', 'Disease', (4, 9))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('circTP63', 'Chemical', '-', (64, 72))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('circTP63', 'Var', (64, 72))	('accelerated', 'PosReg', (49, 60))	('si', 'Chemical', 'MESH:D012825', (35, 37))
271291	31324812	A xenograft tumor model of H1703 cells was developed, then treated with intratumoral injection of cholesterol-conjugated si-circTP63 or si-NC.	('si-circTP63', 'Chemical', '-', (121, 132))	('cholesterol', 'Chemical', 'MESH:D002784', (98, 109))	('si', 'Chemical', 'MESH:D012825', (136, 138))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('H1703', 'CellLine', 'CVCL:1490', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Disease', (12, 17))	('tumor', 'Disease', (77, 82))	('si', 'Chemical', 'MESH:D012825', (121, 123))	('si-circTP63', 'Var', (121, 132))
271292	31324812	3h, treatment with si-circTP63 significantly inhibited growth of H1703 in vivo.	('3h', 'Chemical', 'MESH:D014316', (0, 2))	('si', 'Chemical', 'MESH:D012825', (19, 21))	('growth', 'CPA', (55, 61))	('si-circTP63', 'Var', (19, 30))	('H1703', 'CellLine', 'CVCL:1490', (65, 70))	('si-circTP63', 'Chemical', '-', (19, 30))	('inhibited', 'NegReg', (45, 54))	('si', 'Chemical', 'MESH:D012825', (31, 33))
271294	31324812	Results revealed that xenograft tumors derived from H1703 cells with circTP63 knockdown had lower expression of Ki67 and PCNA than the si-NC group (Supplementary Fig.	('xenograft tumors', 'Disease', (22, 38))	('si', 'Chemical', 'MESH:D012825', (135, 137))	('PCNA', 'Gene', '5111', (121, 125))	('knockdown', 'Var', (78, 87))	('Ki67', 'Gene', (112, 116))	('H1703', 'CellLine', 'CVCL:1490', (52, 57))	('circTP63', 'Chemical', '-', (69, 77))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('xenograft tumors', 'Disease', 'MESH:D009369', (22, 38))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('PCNA', 'Gene', (121, 125))	('circTP63', 'Gene', (69, 77))	('si', 'Chemical', 'MESH:D012825', (104, 106))	('lower', 'NegReg', (92, 97))	('expression', 'MPA', (98, 108))
271296	31324812	Taken together, these findings suggest that circTP63 may play an oncogenic role in LUSC in vitro and in vivo.	('circTP63', 'Var', (44, 52))	('LUSC', 'Disease', (83, 87))	('circTP63', 'Chemical', '-', (44, 52))	('LUSC', 'Phenotype', 'HP:0030359', (83, 87))
271309	31324812	qRT-PCR and western blots revealed that circTP63 knockdown significantly reduced the levels of FOXM1 mRNA and protein, and the opposite results were observed when circTP63 was overexpressed (Fig.	('si', 'Chemical', 'MESH:D012825', (131, 133))	('knockdown', 'Var', (49, 58))	('circTP63', 'Gene', (40, 48))	('circTP63', 'Chemical', '-', (163, 171))	('reduced', 'NegReg', (73, 80))	('circTP63', 'Chemical', '-', (40, 48))	('FOXM1', 'Gene', (95, 100))	('FOXM1', 'Gene', '2305', (95, 100))	('levels', 'MPA', (85, 91))	('si', 'Chemical', 'MESH:D012825', (59, 61))
271311	31324812	To explore the function of circTP63 on FOXM1, cell proliferation after knockdown of FOXM1 was examined.	('FOXM1', 'Gene', '2305', (84, 89))	('FOXM1', 'Gene', (39, 44))	('FOXM1', 'Gene', (84, 89))	('knockdown', 'Var', (71, 80))	('FOXM1', 'Gene', '2305', (39, 44))	('circTP63', 'Chemical', '-', (27, 35))
271314	31324812	In addition, knockdown of FOXM1 could abrogate the effects of circTP63 on promoting cell proliferation (Fig.	('circTP63', 'Chemical', '-', (62, 70))	('FOXM1', 'Gene', '2305', (26, 31))	('FOXM1', 'Gene', (26, 31))	('promoting', 'PosReg', (74, 83))	('abrogate', 'NegReg', (38, 46))	('cell proliferation', 'CPA', (84, 102))	('knockdown', 'Var', (13, 22))
271315	31324812	4g), while overexpression of FOXM1 could significantly rescue the proliferative inhibition of H1703 cells with circTP63 knockdown (Fig.	('circTP63', 'Chemical', '-', (111, 119))	('FOXM1', 'Gene', (29, 34))	('rescue', 'PosReg', (55, 61))	('FOXM1', 'Gene', '2305', (29, 34))	('knockdown', 'Var', (120, 129))	('proliferative inhibition', 'CPA', (66, 90))	('si', 'Chemical', 'MESH:D012825', (21, 23))	('si', 'Chemical', 'MESH:D012825', (41, 43))	('H1703', 'CellLine', 'CVCL:1490', (94, 99))
271330	31324812	To confirm circTP63 and FOXM1 could be regulated by miR-873-3p, we constructed luciferase reporters containing wild type and mutated putative binding sites of circTP63 or FOXM1 transcripts (Supplementary Fig.	('circTP63', 'Chemical', '-', (159, 167))	('circTP63', 'Chemical', '-', (11, 19))	('miR-873', 'Gene', '100126316', (52, 59))	('mutated', 'Var', (125, 132))	('si', 'Chemical', 'MESH:D012825', (150, 152))	('FOXM1', 'Gene', '2305', (171, 176))	('miR-873', 'Gene', (52, 59))	('FOXM1', 'Gene', (171, 176))	('FOXM1', 'Gene', '2305', (24, 29))	('FOXM1', 'Gene', (24, 29))
271332	31324812	In addition, we found that circTP63 overexpression or knockdown could further increase or reduce the luciferase activity of FOXM1 wild type reporter (Fig.	('FOXM1', 'Gene', '2305', (124, 129))	('circTP63', 'Var', (27, 35))	('overexpression', 'PosReg', (36, 50))	('luciferase', 'Enzyme', (101, 111))	('FOXM1', 'Gene', (124, 129))	('knockdown', 'Var', (54, 63))	('si', 'Chemical', 'MESH:D012825', (46, 48))	('increase', 'PosReg', (78, 86))	('reduce', 'NegReg', (90, 96))	('activity', 'MPA', (112, 120))	('circTP63', 'Chemical', '-', (27, 35))
271340	31324812	5f, upper panel), and overexpression of circTP63 in H2170 cells led to the decreased enrichment of FOXM1 on miR-873-3p (Fig.	('H2170', 'CellLine', 'CVCL:1535', (52, 57))	('overexpression', 'PosReg', (22, 36))	('enrichment', 'MPA', (85, 95))	('si', 'Chemical', 'MESH:D012825', (32, 34))	('miR-873', 'Gene', '100126316', (108, 115))	('circTP63', 'Chemical', '-', (40, 48))	('miR-873', 'Gene', (108, 115))	('FOXM1', 'Gene', (99, 104))	('FOXM1', 'Gene', '2305', (99, 104))	('circTP63', 'Var', (40, 48))	('decreased', 'NegReg', (75, 84))
271345	31324812	To futher confirm the cellular phenotype was caused by binding of circTP63 with miR-873-3p, we mutated miR-873-3p-binding site on circTP63 and transfected the circTP63-miR-mut into H226 and H2170 cells.	('miR', 'Gene', '220972', (80, 83))	('circTP63', 'Chemical', '-', (159, 167))	('miR', 'Gene', (80, 83))	('H2170', 'CellLine', 'CVCL:1535', (190, 195))	('circTP63', 'Chemical', '-', (66, 74))	('miR-873', 'Gene', '100126316', (103, 110))	('miR', 'Gene', '220972', (168, 171))	('si', 'Chemical', 'MESH:D012825', (122, 124))	('miR', 'Gene', (168, 171))	('H226', 'CellLine', 'CVCL:J621', (181, 185))	('miR-873', 'Gene', '100126316', (80, 87))	('mutated', 'Var', (95, 102))	('miR-873', 'Gene', (103, 110))	('miR', 'Gene', '220972', (103, 106))	('miR', 'Gene', (103, 106))	('circTP63', 'Chemical', '-', (130, 138))	('miR-873', 'Gene', (80, 87))	('caused by', 'Reg', (45, 54))
271351	31324812	Results showed that CENPA, CENPB, and CCNB1 were regulated by circTP63, while another 5-cell cycle-related genes had no significant change (Fig.	('CENPA', 'Gene', '1058', (20, 25))	('CCNB1', 'Gene', '891', (38, 43))	('regulated', 'Reg', (49, 58))	('circTP63', 'Chemical', '-', (62, 70))	('CENPA', 'Gene', (20, 25))	('si', 'Chemical', 'MESH:D012825', (120, 122))	('circTP63', 'Var', (62, 70))	('CENPB', 'Gene', (27, 32))	('CCNB1', 'Gene', (38, 43))	('CENPB', 'Gene', '1059', (27, 32))
271355	31324812	Cell proliferation analysis showed that knockdown of CENPA or CENPB alone could diminish the effect of circTP63 overexpression on proliferation (Supplementary Fig.	('diminish', 'NegReg', (80, 88))	('circTP63', 'Chemical', '-', (103, 111))	('si', 'Chemical', 'MESH:D012825', (122, 124))	('knockdown', 'Var', (40, 49))	('CENPA', 'Gene', (53, 58))	('CENPB', 'Gene', (62, 67))	('CENPB', 'Gene', '1059', (62, 67))	('proliferation', 'CPA', (130, 143))	('CENPA', 'Gene', '1058', (53, 58))	('circTP63 overexpression', 'MPA', (103, 126))	('si', 'Chemical', 'MESH:D012825', (24, 26))
271356	31324812	And when CENPA and CENPB were knocked down together, more remarkable suppression effect on cell proliferation was observed (Fig.	('CENPB', 'Gene', (19, 24))	('si', 'Chemical', 'MESH:D012825', (76, 78))	('suppression', 'NegReg', (69, 80))	('CENPB', 'Gene', '1059', (19, 24))	('knocked down', 'Var', (30, 42))	('CENPA', 'Gene', (9, 14))	('CENPA', 'Gene', '1058', (9, 14))	('cell proliferation', 'CPA', (91, 109))
271359	31324812	Results showed lower expression of FOXM1, CENPA, and CENPB in si-circTP63 group than in si-NC group (Supplementary Fig.	('FOXM1', 'Gene', (35, 40))	('CENPB', 'Gene', (53, 58))	('FOXM1', 'Gene', '2305', (35, 40))	('CENPA', 'Gene', '1058', (42, 47))	('CENPB', 'Gene', '1059', (53, 58))	('expression', 'MPA', (21, 31))	('si', 'Chemical', 'MESH:D012825', (88, 90))	('lower', 'NegReg', (15, 20))	('si', 'Chemical', 'MESH:D012825', (62, 64))	('si-circTP63', 'Var', (62, 73))	('CENPA', 'Gene', (42, 47))	('si', 'Chemical', 'MESH:D012825', (27, 29))	('si-circTP63', 'Chemical', '-', (62, 73))
271363	31324812	These data indicate that circTP63 promotes the cell proliferation through the FOXM1-CENPA/B pathway.	('circTP63', 'Var', (25, 33))	('CENPA', 'Gene', (84, 89))	('promotes', 'PosReg', (34, 42))	('FOXM1', 'Gene', '2305', (78, 83))	('FOXM1', 'Gene', (78, 83))	('CENPA', 'Gene', '1058', (84, 89))	('circTP63', 'Chemical', '-', (25, 33))	('cell proliferation', 'CPA', (47, 65))
271370	31324812	6d), revealing that circTP63 promotes LUSC cell growth via the ceRNA mechanism.	('circTP63', 'Var', (20, 28))	('LUSC cell growth', 'CPA', (38, 54))	('LUSC', 'Phenotype', 'HP:0030359', (38, 42))	('circTP63', 'Chemical', '-', (20, 28))	('promotes', 'PosReg', (29, 37))
271371	31324812	Genetic alterations in signaling networks frequently occur in cancer to sustain proliferation and maintain viability.	('Genetic alterations', 'Var', (0, 19))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('signaling networks', 'Pathway', (23, 41))	('sustain proliferation', 'CPA', (72, 93))	('si', 'Chemical', 'MESH:D012825', (23, 25))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('occur', 'Reg', (53, 58))
271378	31324812	In this study, we showed that FOXM1 was upregulated in LUSC tissues and knockdown of FOXM1 inhibited the cell proliferation.	('LUSC', 'Phenotype', 'HP:0030359', (55, 59))	('inhibited', 'NegReg', (91, 100))	('FOXM1', 'Gene', (30, 35))	('FOXM1', 'Gene', '2305', (30, 35))	('FOXM1', 'Gene', (85, 90))	('FOXM1', 'Gene', '2305', (85, 90))	('knockdown', 'Var', (72, 81))	('cell proliferation', 'CPA', (105, 123))	('upregulated', 'PosReg', (40, 51))
271379	31324812	Notably, circTP63 could upregulate FOXM1 expression and the effect of circTP63 on promoting cell proliferation could be blocked by silencing FOXM1 (Fig.	('si', 'Chemical', 'MESH:D012825', (131, 133))	('FOXM1', 'Gene', (141, 146))	('FOXM1', 'Gene', (35, 40))	('FOXM1', 'Gene', '2305', (35, 40))	('FOXM1', 'Gene', '2305', (141, 146))	('silencing', 'Var', (131, 140))	('expression', 'MPA', (41, 51))	('circTP63', 'Chemical', '-', (70, 78))	('circTP63', 'Chemical', '-', (9, 17))	('si', 'Chemical', 'MESH:D012825', (47, 49))	('upregulate', 'PosReg', (24, 34))	('promoting', 'PosReg', (82, 91))	('cell proliferation', 'CPA', (92, 110))
271410	31324812	All of human LUSC cells (NCI-H2170, NCI-H1703, NCI-H226, NCI-H520, SW900, SK-MES-1, BEAS-2B, and HFL-1) were purchased from the American Type Culture Collection (ATCC) and were tested negative for mycoplasma contamination.	('HFL-1', 'Gene', '3078', (97, 102))	('BEAS-2B', 'CellLine', 'CVCL:0168', (84, 91))	('NCI-H2170', 'Var', (25, 34))	('HFL-1', 'Gene', (97, 102))	('human', 'Species', '9606', (7, 12))	('SK-MES-1', 'CellLine', 'CVCL:0630', (74, 82))	('NCI-H2170', 'CellLine', 'CVCL:1535', (25, 34))	('SW900', 'CellLine', 'CVCL:1731', (67, 72))	('mycoplasma', 'Disease', 'MESH:D009175', (197, 207))	('NCI-H520', 'CellLine', 'CVCL:1566', (57, 65))	('LUSC', 'Phenotype', 'HP:0030359', (13, 17))	('NCI-H226', 'CellLine', 'CVCL:1544', (47, 55))	('NCI-H1703', 'CellLine', 'CVCL:1490', (36, 45))	('mycoplasma', 'Disease', (197, 207))
271433	31324812	For the mutant version of circTP63, the same method was performed except using different primers.	('si', 'Chemical', 'MESH:D012825', (18, 20))	('mutant', 'Var', (8, 14))	('si', 'Chemical', 'MESH:D012825', (74, 76))	('circTP63', 'Gene', (26, 34))	('circTP63', 'Chemical', '-', (26, 34))
271434	31324812	In mutant primer-F, GCCAACA (the sequence in the 5' end of TP63 mRNA that is targeted by si-circTP63) was replaced with ACAACCG.	('mutant', 'Var', (3, 9))	('si-circTP63', 'Chemical', '-', (89, 100))	('TP63', 'Gene', (59, 63))	('TP63', 'Gene', '8626', (59, 63))	('TP63', 'Gene', '8626', (96, 100))	('TP63', 'Gene', (96, 100))
271436	31324812	The linear TP63 or mutant linear TP63 is back spliced, and generated as circTP63 or circTP63-si-mut.	('TP63', 'Gene', (11, 15))	('TP63', 'Gene', (76, 80))	('si', 'Chemical', 'MESH:D012825', (93, 95))	('TP63', 'Gene', '8626', (76, 80))	('TP63', 'Gene', '8626', (33, 37))	('circTP63', 'Chemical', '-', (72, 80))	('TP63', 'Gene', (88, 92))	('TP63', 'Gene', '8626', (88, 92))	('TP63', 'Gene', (33, 37))	('circTP63', 'Chemical', '-', (84, 92))	('mutant', 'Var', (19, 25))	('TP63', 'Gene', '8626', (11, 15))
271438	31324812	Mutations of miRNA-binding sites in circTP63 and FOXM1 3'UTR sequence were generated using Mutagenesis Kit (Vazyme, Nanjing, China).	('FOXM1', 'Gene', (49, 54))	('FOXM1', 'Gene', '2305', (49, 54))	('miR', 'Gene', '220972', (13, 16))	('miR', 'Gene', (13, 16))	('circTP63', 'Chemical', '-', (36, 44))	('si', 'Chemical', 'MESH:D012825', (99, 101))	('Mutations', 'Var', (0, 9))	('si', 'Chemical', 'MESH:D012825', (27, 29))	('si', 'Chemical', 'MESH:D012825', (86, 88))
271448	31324812	Two weeks later, mice with palpable tumors (~62 mm3) were randomly divided into two groups (six mice per group), 50 nmol cholesterol-conjugated si-NC or si-circTP63 was intratumorally injected into the two groups three times per week for two weeks.	('tumor', 'Disease', (174, 179))	('si-circTP63', 'Chemical', '-', (153, 164))	('mice', 'Species', '10090', (17, 21))	('si', 'Chemical', 'MESH:D012825', (153, 155))	('si-circTP63', 'Var', (153, 164))	('si-NC', 'Var', (144, 149))	('mice', 'Species', '10090', (96, 100))	('tumors', 'Disease', 'MESH:D009369', (36, 42))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('si', 'Chemical', 'MESH:D012825', (144, 146))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('si', 'Chemical', 'MESH:D012825', (92, 94))	('cholesterol', 'Chemical', 'MESH:D002784', (121, 132))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('tumors', 'Disease', (36, 42))	('tumor', 'Disease', (36, 41))
271503	30587218	The parameters mu, mv are related to the tumor doubling times Tu and Tv by mu =  ln 2/Tu and mv =  ln 2/Tv, and the clearance rate of DCs is Upsilonw =  ln 2/Th, and ma =  ln 2/Ta where Th is the half time for the dead cell recycling and Ta is the half time for the programmed cell death.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('Upsilonw', 'Var', (141, 149))	('tumor', 'Disease', (41, 46))	('DCs', 'Chemical', '-', (134, 137))	('tumor', 'Disease', 'MESH:D009369', (41, 46))
271594	30518397	Recent studies demonstrated that inflammation could initiate and promote malignant transformation, whereas the genetic and epigenetic changes of malignant cells could generate the inflammatory microenvironment to further support the progression of the tumor.	('support', 'PosReg', (221, 228))	('malignant transformation', 'CPA', (73, 97))	('inflammation', 'Disease', 'MESH:D007249', (33, 45))	('tumor', 'Disease', 'MESH:D009369', (252, 257))	('epigenetic changes', 'Var', (123, 141))	('tumor', 'Disease', (252, 257))	('tumor', 'Phenotype', 'HP:0002664', (252, 257))	('inflammation', 'Disease', (33, 45))	('promote', 'PosReg', (65, 72))	('genetic', 'Var', (111, 118))
271620	30518397	The primary antibodies against phospho-STAT3 (Tyr705), STAT3, phospho-JAK2 (Tyr1007/1008), JAK2, PARP, MCL1, XIAP, Cox2 and iNOS were purchased from Cell Signaling Technology (Danvers, MA).	('JAK2', 'Gene', (70, 74))	('JAK2', 'Gene', '3717', (91, 95))	('Cox2', 'Gene', (115, 119))	('iNOS', 'Gene', '4843', (124, 128))	('Tyr705', 'Var', (46, 52))	('iNOS', 'Gene', (124, 128))	('XIAP', 'Gene', (109, 113))	('MCL1', 'Gene', '4170', (103, 107))	('JAK2', 'Gene', (91, 95))	('PARP', 'Gene', '1302', (97, 101))	('Tyr1007/1008', 'Var', (76, 88))	('PARP', 'Gene', (97, 101))	('Tyr705', 'Chemical', '-', (46, 52))	('MCL1', 'Gene', (103, 107))	('XIAP', 'Gene', '331', (109, 113))	('JAK2', 'Gene', '3717', (70, 74))	('Cox2', 'Gene', '4513', (115, 119))	('Tyr1007', 'Chemical', '-', (76, 83))
271645	30518397	After throughly washing with TBST, the slides were incubated overnight at 4  C with primary antibodies: p-STAT3, Cox-2 and Caspase-3 diluted in 5% BSA-TBST (1:50) respectively.	('Caspase-3', 'Gene', (123, 132))	('TBST', 'Chemical', '-', (29, 33))	('Caspase-3', 'Gene', '836', (123, 132))	('Cox-2', 'Gene', '4513', (113, 118))	('TBST', 'Chemical', '-', (151, 155))	('p-STAT3', 'Var', (104, 111))	('Cox-2', 'Gene', (113, 118))
271662	30518397	The curcumin-induced apoptosis was also significantly blocked by Z-VAD-FMK, a potent caspase inhibitor (Fig.	('blocked', 'NegReg', (54, 61))	('Z-VAD-FMK', 'Chemical', 'MESH:C096713', (65, 74))	('Z-VAD-FMK', 'Var', (65, 74))	('curcumin', 'Chemical', 'MESH:D003474', (4, 12))	('apoptosis', 'CPA', (21, 30))
271665	30518397	In contrast, the presence of AG490, a STAT3 inhibitor, markedly enhanced the effect of curcumin on inducing ESCC cell death (Fig.	('AG490', 'Var', (29, 34))	('AG490', 'Chemical', 'MESH:C095512', (29, 34))	('ESCC cell death', 'Disease', 'MESH:D004938', (108, 123))	('ESCC cell death', 'Disease', (108, 123))	('curcumin', 'Chemical', 'MESH:D003474', (87, 95))	('enhanced', 'PosReg', (64, 72))
271676	30518397	Glu898, Val911, Tyr931, Leu932, Ser936, Asp939 and Asp994 of JAK2 formed strong interactions with curcumin.	('Leu932', 'Chemical', '-', (24, 30))	('JAK2', 'Gene', '3717', (61, 65))	('Asp939', 'Var', (40, 46))	('Tyr931', 'Var', (16, 22))	('curcumin', 'Chemical', 'MESH:D003474', (98, 106))	('Asp994', 'Var', (51, 57))	('Asp939', 'Chemical', '-', (40, 46))	('Val911', 'Var', (8, 14))	('Leu932', 'Var', (24, 30))	('Ser936', 'Chemical', '-', (32, 38))	('JAK2', 'Gene', (61, 65))	('Glu898', 'Chemical', '-', (0, 6))	('Glu898', 'Var', (0, 6))	('interactions', 'Interaction', (80, 92))	('Val911', 'Chemical', '-', (8, 14))	('Tyr931', 'Chemical', '-', (16, 22))	('Asp994', 'Chemical', '-', (51, 57))	('Ser936', 'Var', (32, 38))
271677	30518397	Among them, Val911, Tyr931 and Ser936 may interact hydrophobically with curcumin, whereas Glu898, Leu932, Asp939 and Asp994 are able to form H-bonds with curcumin.	('Tyr931', 'Chemical', '-', (20, 26))	('hydrophobically', 'MPA', (51, 66))	('Asp939', 'Var', (106, 112))	('Asp994', 'Var', (117, 123))	('Tyr931', 'Var', (20, 26))	('Leu932', 'Var', (98, 104))	('Glu898', 'Var', (90, 96))	('Asp994', 'Chemical', '-', (117, 123))	('Val911', 'Chemical', '-', (12, 18))	('curcumin', 'Chemical', 'MESH:D003474', (154, 162))	('Asp939', 'Chemical', '-', (106, 112))	('Ser936', 'Chemical', '-', (31, 37))	('Glu898', 'Chemical', '-', (90, 96))	('Val911', 'Var', (12, 18))	('Leu932', 'Chemical', '-', (98, 104))	('H-bonds', 'Interaction', (141, 148))	('curcumin', 'Chemical', 'MESH:D003474', (72, 80))	('interact', 'Interaction', (42, 50))	('Ser936', 'Var', (31, 37))	('form', 'Reg', (136, 140))
271693	30518397	The representative photos of the excised tumors from EG60 and EG84 were shown in Fig.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('EG84', 'Var', (62, 66))	('tumors', 'Disease', 'MESH:D009369', (41, 47))	('tumors', 'Disease', (41, 47))	('EG60', 'Var', (53, 57))
271700	30518397	The IHC analysis with specific antibodies showed that the levels of phosphorylated STAT3 and its target protein Cox2 were markedly decreased in tumors treated with curcumin or curcumin prevention, whereas caspase 3 staining was significantly increased in these tumors (Fig.	('tumors', 'Disease', (144, 150))	('curcumin', 'Var', (176, 184))	('staining', 'MPA', (215, 223))	('tumors', 'Phenotype', 'HP:0002664', (261, 267))	('curcumin', 'Chemical', 'MESH:D003474', (164, 172))	('tumors', 'Disease', 'MESH:D009369', (144, 150))	('tumor', 'Phenotype', 'HP:0002664', (261, 266))	('tumors', 'Disease', (261, 267))	('increased', 'PosReg', (242, 251))	('curcumin', 'Chemical', 'MESH:D003474', (176, 184))	('tumors', 'Disease', 'MESH:D009369', (261, 267))	('caspase 3', 'Gene', (205, 214))	('caspase 3', 'Gene', '836', (205, 214))	('curcumin', 'Var', (164, 172))	('levels', 'MPA', (58, 64))	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('Cox2', 'Gene', '4513', (112, 116))	('decreased', 'NegReg', (131, 140))	('Cox2', 'Gene', (112, 116))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))
271717	30518397	Both constitutive and IL6-induced STAT3 activations were strongly inhibited by curcumin treatment in EC9706 and TE13 cells (Fig.	('TE13', 'CellLine', 'CVCL:4463', (112, 116))	('EC9706', 'Var', (101, 107))	('curcumin', 'Chemical', 'MESH:D003474', (79, 87))	('inhibited', 'NegReg', (66, 75))	('IL6', 'Gene', '3569', (22, 25))	('IL6', 'Gene', (22, 25))	('EC9706', 'CellLine', 'CVCL:E307', (101, 107))	('STAT3 activations', 'MPA', (34, 51))
271726	30518397	5a-c, preventive administration of curcumin was markedly more effective in inhibiting PDXs derived from EG2, EG37 and EG60 than giving curcumin only after innoculation of tumors.	('inhibiting', 'NegReg', (75, 85))	('curcumin', 'Chemical', 'MESH:D003474', (135, 143))	('tumors', 'Disease', 'MESH:D009369', (171, 177))	('EG60', 'Var', (118, 122))	('PDXs', 'MPA', (86, 90))	('EG37', 'Var', (109, 113))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('curcumin', 'Chemical', 'MESH:D003474', (35, 43))	('tumors', 'Disease', (171, 177))	('tumors', 'Phenotype', 'HP:0002664', (171, 177))
271733	29262625	Genomic variations in paired normal controls for lung adenocarcinomas Somatic genomic mutations in lung adenocarcinomas (LUADs) have been extensively dissected, but whether the counterpart normal lung tissues that are exposed to ambient air or tobacco smoke as the tumor tissues do, harbor genomic variations, remains unclear.	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (49, 69))	('mutations', 'Var', (86, 95))	('tumor', 'Phenotype', 'HP:0002664', (265, 270))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (49, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (59, 68))	('LUAD', 'Phenotype', 'HP:0030078', (121, 125))	('LUADs', 'Phenotype', 'HP:0030078', (121, 126))	('tumor', 'Disease', (265, 270))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (99, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('lung adenocarcinomas', 'Disease', (99, 119))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (99, 119))	('tobacco', 'Species', '4097', (244, 251))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (49, 68))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (99, 119))	('tumor', 'Disease', 'MESH:D009369', (265, 270))	('lung adenocarcinomas', 'Disease', (49, 69))
271739	29262625	Genomic alterations in cancers include point mutations, insertions and deletions (indels), structural variations, copy number alterations, epigenetic changes, and microbial infections.	('structural variations', 'Var', (91, 112))	('deletions', 'Var', (71, 80))	('point mutations', 'Var', (39, 54))	('microbial infections', 'Disease', 'MESH:D015163', (163, 183))	('cancers', 'Disease', 'MESH:D009369', (23, 30))	('cancers', 'Phenotype', 'HP:0002664', (23, 30))	('insertions', 'Var', (56, 66))	('cancers', 'Disease', (23, 30))	('copy number alterations', 'Var', (114, 137))	('microbial infections', 'Disease', (163, 183))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('epigenetic', 'Disease', (139, 149))
271740	29262625	Abnormalities in oncogenes and tumor suppressors act as driver mutations to initiate the onset and progression of cancers.	('cancers', 'Disease', 'MESH:D009369', (114, 121))	('cancers', 'Phenotype', 'HP:0002664', (114, 121))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('cancers', 'Disease', (114, 121))	('Abnormalities', 'Var', (0, 13))	('tumor', 'Disease', (31, 36))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('oncogenes', 'Protein', (17, 26))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
271741	29262625	Technically, these alterations are identified by comparing the cancer genome sequence with a reference human genome and excluding those also found in normal controls (counterpart normal tissues or peripheral blood) and single nucleotide polymorphisms (SNPs).	('single nucleotide polymorphisms', 'Var', (219, 250))	('human', 'Species', '9606', (103, 108))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('cancer', 'Disease', (63, 69))
271750	29262625	Accumulation of genetic alterations in the premalignant field results in proliferation of the cells and expansion of the field, gradually displacing the normal epithelium and developing into a malignant neoplasm.	('neoplasm', 'Phenotype', 'HP:0002664', (203, 211))	('expansion', 'CPA', (104, 113))	('developing', 'Reg', (175, 185))	('genetic alterations', 'Var', (16, 35))	('malignant neoplasm', 'Disease', (193, 211))	('displacing', 'NegReg', (138, 148))	('malignant neoplasm', 'Disease', 'MESH:D009369', (193, 211))	('results in', 'Reg', (62, 72))
271751	29262625	However, very few studies systematically dissect genomic mutations specifically occurred in "normal" lung tissues and their roles in carcinogenesis, and no study reports how the adjacent tissues escape from developing into malignant neoplasms.	('neoplasm', 'Phenotype', 'HP:0002664', (233, 241))	('carcinogenesis', 'Disease', 'MESH:D063646', (133, 147))	('occurred', 'Reg', (80, 88))	('malignant neoplasms', 'Disease', 'MESH:D009369', (223, 242))	('carcinogenesis', 'Disease', (133, 147))	('malignant neoplasms', 'Disease', (223, 242))	('mutations', 'Var', (57, 66))	('neoplasms', 'Phenotype', 'HP:0002664', (233, 242))
271756	29262625	This change might lead to P335L substitution in the encoded protein.	('lead to', 'Reg', (18, 25))	('P335L', 'Var', (26, 31))	('P335L', 'Mutation', 'rs770777399', (26, 31))
271758	29262625	Nucleotide T at this position of ZNF521 was not found in dbSNP138 common germline variants.	('ZNF521', 'Gene', (33, 39))	('dbSNP138', 'Chemical', '-', (57, 65))	('Nucleotide T', 'Var', (0, 12))	('ZNF521', 'Gene', '25925', (33, 39))	('dbSNP138', 'Gene', (57, 65))
271760	29262625	This change might lead to T105M substitution in the encoded protein.	('lead to', 'Reg', (18, 25))	('T105M', 'Mutation', 'rs369567020', (26, 31))	('T105M substitution', 'Var', (26, 44))
271763	29262625	Substitutions of GT by AC were seen in UNC93A in normal lung tissue of a patient with untreated LUAD (Figure 1F).	('LUAD', 'Phenotype', 'HP:0030078', (96, 100))	('AC', 'Chemical', 'MESH:D000186', (23, 25))	('UNC93A', 'Gene', '54346', (39, 45))	('patient', 'Species', '9606', (73, 80))	('Substitutions', 'Var', (0, 13))	('UNC93A', 'Gene', (39, 45))
271768	29262625	We also analyzed genomic mutations in tumor samples by comparing the cancer genome sequencing with reference and excluding those found in CNCs with the same calling criteria, and reported that tumor samples had much more mutations than CNCs (Table 2 and Supplementary Figure 2E-2H).	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('mutations', 'Var', (221, 230))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('tumor', 'Disease', (193, 198))	('cancer', 'Disease', (69, 75))
271770	29262625	In tumor samples, while the C:G A:T transversions were the most prevalent nucleotide substitutions, the C:G T:A transitions represented the second most prevalent nucleotide substitutions (Figure 2A).	('tumor', 'Disease', (3, 8))	('prevalent', 'Reg', (152, 161))	('C:G T:A transitions', 'Var', (104, 123))	('tumor', 'Disease', 'MESH:D009369', (3, 8))	('C:G A:T transversions', 'Var', (28, 49))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))
271771	29262625	In consistence with previous report, the C:G T:A transitions were the most prevalent nucleotide substitutions in tumor samples of nonsmokers (Figure 2C), whereas the C:G A:T transversions were the most prevalent nucleotide substitutions in tumor samples of smokers (Figure 2C).	('tumor', 'Disease', (113, 118))	('C:G A:T transversions', 'Var', (166, 187))	('tumor', 'Disease', (240, 245))	('C:G T:A transitions', 'Var', (41, 60))	('prevalent', 'Reg', (75, 84))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Disease', 'MESH:D009369', (240, 245))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (240, 245))
271772	29262625	MUC4 represented the most frequently altered gene, which was mutated in 46/513 (8.97%) of the CNC samples (Figure 2D).	('MUC4', 'Gene', (0, 4))	('MUC4', 'Gene', '4585', (0, 4))	('mutated', 'Var', (61, 68))
271773	29262625	FAM90A1, ARSD, MADCAM1, ZNF814, CDC27, and HDGFRP2 were mutated in 35 (6.82%), 32 (6.24%), 26 (5.07%), 22 (4.29%), 17 (3.31%), and 16 (3.12%) of the 513 CNC samples, respectively (Figure 2D).	('MADCAM1', 'Gene', (15, 22))	('FAM90A1', 'Gene', '55138', (0, 7))	('CDC27', 'Gene', '996', (32, 37))	('mutated', 'Var', (56, 63))	('ZNF814', 'Gene', '730051', (24, 30))	('ARSD', 'Gene', (9, 13))	('MADCAM1', 'Gene', '8174', (15, 22))	('CDC27', 'Gene', (32, 37))	('HDGFRP2', 'Gene', (43, 50))	('ZNF814', 'Gene', (24, 30))	('ARSD', 'Gene', '414', (9, 13))	('FAM90A1', 'Gene', (0, 7))	('HDGFRP2', 'Gene', '84717', (43, 50))
271774	29262625	TP53, KRAS and EGFR which were frequently mutated in LUADs, were mutated in only 2 (0.39%), 0, and 0 CNCs, respectively (Supplementary Table 5).	('KRAS', 'Gene', '3845', (6, 10))	('TP53', 'Gene', '7157', (0, 4))	('mutated', 'Var', (42, 49))	('TP53', 'Gene', (0, 4))	('LUADs', 'Phenotype', 'HP:0030078', (53, 58))	('EGFR', 'Gene', '1956', (15, 19))	('EGFR', 'Gene', (15, 19))	('LUAD', 'Phenotype', 'HP:0030078', (53, 57))	('KRAS', 'Gene', (6, 10))
271776	29262625	We found 35 types of variations distributed throughout the entire gene of MUC4, including 4 recurrent ones (Figure 3).	('MUC4', 'Gene', (74, 78))	('variations', 'Var', (21, 31))	('MUC4', 'Gene', '4585', (74, 78))
271777	29262625	Frequent variations were found in FAM90A1, in that in all 35 patients with variant FAM90A1, the nucleotide G of codon (ACG) for T344 was replaced by A and a codon for valine (GUC) was inserted in 12:8374781 position at Chr 8, leading to insertion of V right after T344 (Figure 3).	('FAM90A1', 'Gene', (83, 90))	('V right', 'MPA', (250, 257))	('T344', 'Chemical', '-', (264, 268))	('ACG', 'Chemical', 'MESH:C023716', (119, 122))	('T344', 'Chemical', '-', (128, 132))	('T344 was replaced by A', 'Mutation', 'c.344T>A', (128, 150))	('variant', 'Var', (75, 82))	('FAM90A1', 'Gene', '55138', (34, 41))	('patients', 'Species', '9606', (61, 69))	('FAM90A1', 'Gene', '55138', (83, 90))	('valine', 'Chemical', 'MESH:D014633', (167, 173))	('GUC', 'Chemical', '-', (175, 178))	('insertion', 'MPA', (237, 246))	('FAM90A1', 'Gene', (34, 41))
271778	29262625	There were 67 variations in Arylsulfatase D (ARSD) gene in 32 CNCs, with S157F, G175D, and S176K substitutions found in 9 (14.8%), 10 (16.4%), and 10 (16.4%) of the total variations.	('G175D', 'Var', (80, 85))	('S176K', 'Var', (91, 96))	('S157F', 'Var', (73, 78))	('ARSD', 'Gene', '414', (45, 49))	('Arylsulfatase D', 'Gene', (28, 43))	('Arylsulfatase D', 'Gene', '414', (28, 43))	('S157F', 'Mutation', 'rs73632978', (73, 78))	('S176K', 'Mutation', 'p.S176K', (91, 96))	('G175D', 'Mutation', 'rs73632976', (80, 85))	('ARSD', 'Gene', (45, 49))
271780	29262625	Variations in ZNF814, CDC27, HDGFRP2, RBMX, WDR66, and ANKRD36 in CNCs were also shown in Figure 3.	('ZNF814', 'Gene', (14, 20))	('ANKRD36', 'Gene', (55, 62))	('RBMX', 'Gene', '27316', (38, 42))	('ANKRD36', 'Gene', '375248', (55, 62))	('CDC27', 'Gene', '996', (22, 27))	('HDGFRP2', 'Gene', (29, 36))	('RBMX', 'Gene', (38, 42))	('Variations', 'Var', (0, 10))	('HDGFRP2', 'Gene', '84717', (29, 36))	('WDR66', 'Gene', '144406', (44, 49))	('CDC27', 'Gene', (22, 27))	('WDR66', 'Gene', (44, 49))	('ZNF814', 'Gene', '730051', (14, 20))
271782	29262625	We analyzed the potential association between the CNC variations and the prognosis of the patients using the Kaplan-Meier method, and found that variations in 8 genes were associated with the prognosis of 502 patients whose survival information was available (Figure 4).	('patients', 'Species', '9606', (209, 217))	('associated with', 'Reg', (172, 187))	('patients', 'Species', '9606', (90, 98))	('variations', 'Var', (145, 155))
271783	29262625	Sixteen variations were found in MUC5B in 12 (2.34%) of the 513 patients (Figure 4A).	('MUC5B', 'Gene', '727897', (33, 38))	('variations', 'Var', (8, 18))	('MUC5B', 'Gene', (33, 38))	('patients', 'Species', '9606', (64, 72))
271784	29262625	As compared with patients (n=490) harboring wild type MUC5B, those with mutant transcript had much shorter overall survival (P=0.013; Figure 4A).	('shorter', 'NegReg', (99, 106))	('mutant transcript', 'Var', (72, 89))	('MUC5B', 'Gene', '727897', (54, 59))	('overall survival', 'MPA', (107, 123))	('MUC5B', 'Gene', (54, 59))	('patients', 'Species', '9606', (17, 25))
271785	29262625	ZXDB variations were seen in 10 (1.95%) of the patients, whose overall survival time was shorter than those (n=492) with wild type ZXDB (Figure 4A).	('variations', 'Var', (5, 15))	('ZXDB', 'Gene', (131, 135))	('patients', 'Species', '9606', (47, 55))	('ZXDB', 'Gene', '158586', (0, 4))	('ZXDB', 'Gene', '158586', (131, 135))	('ZXDB', 'Gene', (0, 4))	('shorter', 'NegReg', (89, 96))
271786	29262625	Patients with variant PLIN4 , CCDC144NL, CNTNAP3B, or CCDC180 in CNCs also had shorter overall survival than patients with wild type transcripts (Figure 4A).	('CCDC144NL', 'Gene', '339184', (30, 39))	('PLIN4', 'Gene', (22, 27))	('patients', 'Species', '9606', (109, 117))	('CCDC180', 'Gene', (54, 61))	('shorter', 'NegReg', (79, 86))	('CNTNAP3B', 'Gene', '728577', (41, 49))	('CNTNAP3B', 'Gene', (41, 49))	('PLIN4', 'Gene', '729359', (22, 27))	('Patients', 'Species', '9606', (0, 8))	('CCDC144NL', 'Gene', (30, 39))	('CCDC180', 'Gene', '100499483', (54, 61))	('variant', 'Var', (14, 21))	('overall survival', 'MPA', (87, 103))
271788	29262625	These variations encoded proteins with P99Lsubstitution in 1 patient, I234L substitution in 8 patients, and S237P change in 5 patients (Figure 4B).	('I234L', 'Mutation', 'rs768618853', (70, 75))	('S237P', 'Mutation', 'rs761963029', (108, 113))	('S237P change', 'Var', (108, 120))	('I234L substitution', 'Var', (70, 88))	('patients', 'Species', '9606', (94, 102))	('patient', 'Species', '9606', (61, 68))	('patient', 'Species', '9606', (126, 133))	('patients', 'Species', '9606', (126, 134))	('P99Lsubstitution', 'Var', (39, 55))	('patient', 'Species', '9606', (94, 101))	('proteins', 'Protein', (25, 33))	('encoded', 'Reg', (17, 24))
271789	29262625	Interestingly, none of the variant CHD3-bearing patients died within a follow-up of up to 2261 days, whereas the median overall survival of patients with wild type CHD3 (n=490) was 1492 days (range, 0-7248 days) (p=0.047; Figure 4B).	('CHD3', 'Gene', (35, 39))	('CHD3', 'Gene', '1107', (164, 168))	('CHD3', 'Gene', '1107', (35, 39))	('patients', 'Species', '9606', (140, 148))	('CHD3', 'Gene', (164, 168))	('variant', 'Var', (27, 34))	('patients', 'Species', '9606', (48, 56))
271790	29262625	Deletion mutations, i.e., deletion of codons for G41 - G43 and G43 - A53 of the protein product encoded by KRTAP5-5 gene, were found in CNCs of 10 patients.	('G43 - A53', 'Var', (63, 72))	('deletion of', 'Var', (26, 37))	('G41', 'Gene', '55012', (49, 52))	('G41', 'Gene', (49, 52))	('patients', 'Species', '9606', (147, 155))	('KRTAP5-5', 'Gene', '439915', (107, 115))	('KRTAP5-5', 'Gene', (107, 115))
271791	29262625	Of note, patients with variant KRTAP5-5 had longer overall survival time than those with wild type transcript (p=0.048; Figure 4B).	('patients', 'Species', '9606', (9, 17))	('longer', 'PosReg', (44, 50))	('variant', 'Var', (23, 30))	('KRTAP5-5', 'Gene', '439915', (31, 39))	('KRTAP5-5', 'Gene', (31, 39))	('overall survival', 'MPA', (51, 67))
271792	29262625	In our work characterizing somatic mutations in air pollution-related lung cancer, we unexpectedly noted that compared to reference human genome and cancerous tissues, the normal control lung tissues also had single nucleotide variations.	('lung cancer', 'Disease', 'MESH:D008175', (70, 81))	('single nucleotide variations', 'Var', (209, 237))	('cancerous', 'Disease', (149, 158))	('lung cancer', 'Disease', (70, 81))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('lung cancer', 'Phenotype', 'HP:0100526', (70, 81))	('cancerous', 'Disease', 'MESH:D009369', (149, 158))	('human', 'Species', '9606', (132, 137))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))
271795	29262625	In CNC genomes of TCGA datasets, the variation rates were 0.2721 exonic variations/Mb and 5.2885 altered genes/sample, and the recurrent variants were of intermediate frequency (~ 8.97% of the patients), whereas variations in 8 genes were associated with poor or favorable prognosis of the patients.	('TCGA', 'Gene', (18, 22))	('patients', 'Species', '9606', (193, 201))	('patients', 'Species', '9606', (290, 298))	('variations', 'Var', (212, 222))	('variants', 'Var', (137, 145))
271799	29262625	For instance, PAHs which are the main carcinogens of tobacco smoke and air pollution, induce the C:G A:T substitutions in the genome.	('C:G A:T substitutions', 'Var', (97, 118))	('PAHs', 'Chemical', 'MESH:D011084', (14, 18))	('induce', 'Reg', (86, 92))	('tobacco', 'Species', '4097', (53, 60))
271801	29262625	In tumor samples of the patients, the C:G T:A substitutions were the predominant nucleotide changes in non-smokers, while C:G A:T transversions were the most frequently detected substitutions in smokers (Figure 2C).	('tumor', 'Disease', (3, 8))	('C:G A:T transversions', 'Var', (122, 143))	('tumor', 'Disease', 'MESH:D009369', (3, 8))	('patients', 'Species', '9606', (24, 32))	('C:G T:A', 'Var', (38, 45))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))
271803	29262625	The significance of these CNC variations in lung carcinogenesis remains unclear.	('variations', 'Var', (30, 40))	('lung carcinogenesis', 'Disease', (44, 63))	('lung carcinogenesis', 'Disease', 'MESH:D063646', (44, 63))
271804	29262625	One possibility was that some of the variant genes (e.g., MUC4) were pro-oncogenes, cells harboring these CNC variations were in a "precancerous" stage, and accumulation of other mutations would result in transformation and development of malignant neoplasms.	('accumulation', 'PosReg', (157, 169))	('MUC4', 'Gene', '4585', (58, 62))	('malignant neoplasms', 'Disease', (239, 258))	('malignant neoplasms', 'Disease', 'MESH:D009369', (239, 258))	('cancerous', 'Disease', (135, 144))	('neoplasms', 'Phenotype', 'HP:0002664', (249, 258))	('MUC4', 'Gene', (58, 62))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('variant', 'Var', (37, 44))	('transformation', 'CPA', (205, 219))	('cancerous', 'Disease', 'MESH:D009369', (135, 144))	('result in', 'Reg', (195, 204))	('mutations', 'Var', (179, 188))	('neoplasm', 'Phenotype', 'HP:0002664', (249, 257))	('CNC', 'Gene', (106, 109))
271809	29262625	Those CNC variations associated with poor outcome (MUC5B, ZXDB, PLIN4, CCDC144NL, CNTNAP3B, and CCDC180) may probably facilitate cancer initiation and progression, and may be a new clue to study cancer metastasis and evolution.	('cancer metastasis', 'Disease', (195, 212))	('ZXDB', 'Gene', (58, 62))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('CNTNAP3B', 'Gene', (82, 90))	('cancer metastasis', 'Disease', 'MESH:D009362', (195, 212))	('progression', 'CPA', (151, 162))	('PLIN4', 'Gene', (64, 69))	('cancer initiation', 'Disease', (129, 146))	('CCDC180', 'Gene', (96, 103))	('MUC5B', 'Gene', '727897', (51, 56))	('CCDC144NL', 'Gene', '339184', (71, 80))	('PLIN4', 'Gene', '729359', (64, 69))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('CNTNAP3B', 'Gene', '728577', (82, 90))	('cancer initiation', 'Disease', 'MESH:D009369', (129, 146))	('CCDC144NL', 'Gene', (71, 80))	('CCDC180', 'Gene', '100499483', (96, 103))	('CNC variations', 'Var', (6, 20))	('facilitate', 'PosReg', (118, 128))	('ZXDB', 'Gene', '158586', (58, 62))	('MUC5B', 'Gene', (51, 56))
271812	29262625	Whether variations in these two genes modulate transcription machinery or tumor microenvironment to constrain cancer and thus contribute to favorable prognosis, needs to be determined.	('cancer', 'Disease', (110, 116))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('variations', 'Var', (8, 18))	('tumor', 'Disease', (74, 79))	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('modulate', 'Reg', (38, 46))
271835	27457246	TP53 mutations are an early phenomenon already seen in 40 % of in situ cSCC.	('cSCC', 'Phenotype', 'HP:0006739', (71, 75))	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))
271837	27457246	MicroRNAs (miRNAs) are a class of small non-coding RNAs that can regulate gene expression of a very broad set of targets including loci in the protein-coding region of mRNAs, 5' UTRs, intronic and intergenic transcripts and other non-protein-coding RNAs.	('mRNAs', 'Gene', (168, 173))	('gene expression', 'MPA', (74, 89))	('miR', 'Gene', '220972', (11, 14))	('miR', 'Gene', (11, 14))	('regulate', 'Reg', (65, 73))	('loci', 'Var', (131, 135))
271840	27457246	Aberrant miRNA expression is linked to cancer development and progression and affects several processes including proliferation, apoptosis, differentiation and invasiveness.	('apoptosis', 'CPA', (129, 138))	('Aberrant', 'Var', (0, 8))	('cancer', 'Disease', (39, 45))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('affects', 'Reg', (78, 85))	('invasiveness', 'CPA', (160, 172))	('linked', 'Reg', (29, 35))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('differentiation', 'CPA', (140, 155))	('miR', 'Gene', '220972', (9, 12))	('miR', 'Gene', (9, 12))
271849	27457246	The microarray technology used was Agilent Human miRNA microarrays (V2, G4470B, Agilent Technologies, Sanger Database version 10.1).	('G4470B', 'Var', (72, 78))	('miR', 'Gene', '220972', (49, 52))	('G4470B', 'SUBSTITUTION', 'None', (72, 78))	('miR', 'Gene', (49, 52))	('Human', 'Species', '9606', (43, 48))
271908	27457246	According to the gene expression data, miR-204 antagomir transfected cells displayed lower PTPN11 mRNA levels than their control antagomir counterparts, whereas the expression of the miR-204 mimic enhanced PTPN11 levels (Additional file 1: Figure S3A).	('PTPN11', 'Gene', (91, 97))	('miR-204', 'Gene', (39, 46))	('lower', 'NegReg', (85, 90))	('antagomir', 'Var', (47, 56))	('PTPN11', 'Gene', '5781', (206, 212))	('enhanced', 'PosReg', (197, 205))	('miR-204', 'Gene', '406987', (183, 190))	('PTPN11', 'Gene', (206, 212))	('PTPN11', 'Gene', '5781', (91, 97))	('miR-204', 'Gene', (183, 190))	('miR-204', 'Gene', '406987', (39, 46))
271916	27457246	Cell cycle status assessed by BrdU staining to detect DNA synthesis revealed that miR-204 depletion in HaCaT cells impairs BrdU incorporation while cells transfected with miR-204 mimic displayed an enhancement in BrdU staining (Additional file 1: Figure S3B).	('BrdU', 'Chemical', 'MESH:D001973', (123, 127))	('BrdU incorporation', 'MPA', (123, 141))	('BrdU staining', 'MPA', (213, 226))	('BrdU', 'Chemical', 'MESH:D001973', (30, 34))	('miR-204', 'Gene', '406987', (171, 178))	('miR-204', 'Gene', (171, 178))	('miR-204', 'Gene', (82, 89))	('BrdU', 'Chemical', 'MESH:D001973', (213, 217))	('enhancement', 'PosReg', (198, 209))	('HaCaT', 'CellLine', 'CVCL:0038', (103, 108))	('depletion', 'Var', (90, 99))	('impairs', 'NegReg', (115, 122))	('miR-204', 'Gene', '406987', (82, 89))
271926	27457246	To this end, HaCaT cells transfected with control or miR-204 mimics were stimulated with EGF for 30 min or 24 h. MiR-204 mimic-transfected cells displayed higher basal and induced mRNA levels of the tested genes at short time points.	('miR-204', 'Gene', (53, 60))	('EGF', 'Gene', (89, 92))	('induced', 'PosReg', (172, 179))	('mRNA levels', 'MPA', (180, 191))	('MiR-204', 'Gene', (113, 120))	('HaCaT', 'CellLine', 'CVCL:0038', (13, 18))	('EGF', 'Gene', '1950', (89, 92))	('miR-204', 'Gene', '406987', (53, 60))	('mimic-transfected', 'Var', (121, 138))	('higher', 'PosReg', (155, 161))	('MiR-204', 'Gene', '406987', (113, 120))
271944	27457246	However, similar levels of S727 phosphorylation could be observed regardless miR-204 expression.	('miR-204', 'Gene', '406987', (77, 84))	('miR-204', 'Gene', (77, 84))	('S727', 'Var', (27, 31))
271945	27457246	PTPN11 levels were higher in untreated cells as well as upon FGF9 and IL6 treatments in control cells when compared to similar conditions in miR-204 overexpressing cells at this time point.	('PTPN11', 'Gene', '5781', (0, 6))	('FGF9', 'Gene', '2254', (61, 65))	('treatments', 'Var', (74, 84))	('higher', 'PosReg', (19, 25))	('miR-204', 'Gene', '406987', (141, 148))	('PTPN11', 'Gene', (0, 6))	('IL6', 'Gene', '3569', (70, 73))	('IL6', 'Gene', (70, 73))	('miR-204', 'Gene', (141, 148))	('FGF9', 'Gene', (61, 65))
271961	27457246	MiRNAs alterations are involved in the development of several skin cancers.	('cancers', 'Phenotype', 'HP:0002664', (67, 74))	('skin cancers', 'Disease', 'MESH:D012878', (62, 74))	('skin cancer', 'Phenotype', 'HP:0008069', (62, 73))	('involved', 'Reg', (23, 31))	('MiRNAs', 'Gene', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('skin cancers', 'Disease', (62, 74))	('skin cancers', 'Phenotype', 'HP:0008069', (62, 74))	('alterations', 'Var', (7, 18))
271964	27457246	We here report hypermethylation of the miR-204 promoter in AKs and in a high proportion of cSCCs.	('miR-204', 'Gene', (39, 46))	('AK', 'Phenotype', 'HP:0025127', (59, 61))	('cSCC', 'Phenotype', 'HP:0006739', (91, 95))	('hypermethylation', 'Var', (15, 31))	('miR-204', 'Gene', '406987', (39, 46))
271965	27457246	Since this genomic region also displays STAT3-binding sites, and phosphorylated STAT3 suppresses miR-204 expression in pulmonary arterial hypertension, STAT3 activation by alterations in proteins modulating this pathway could account as an alternative mechanism for miR-204 dowregulation in cSCC.	('pulmonary arterial hypertension', 'Disease', 'MESH:D000081029', (119, 150))	('STAT3', 'Gene', '6774', (152, 157))	('STAT3', 'Gene', (80, 85))	('STAT3', 'Gene', (40, 45))	('expression', 'MPA', (105, 115))	('STAT3', 'Gene', '6774', (80, 85))	('pulmonary arterial hypertension', 'Disease', (119, 150))	('STAT3', 'Gene', '6774', (40, 45))	('miR-204', 'Gene', '406987', (97, 104))	('alterations', 'Var', (172, 183))	('hypertension', 'Phenotype', 'HP:0000822', (138, 150))	('miR-204', 'Gene', (266, 273))	('suppresses', 'NegReg', (86, 96))	('pulmonary arterial hypertension', 'Phenotype', 'HP:0002092', (119, 150))	('cSCC', 'Disease', (291, 295))	('STAT3', 'Gene', (152, 157))	('cSCC', 'Phenotype', 'HP:0006739', (291, 295))	('miR-204', 'Gene', '406987', (266, 273))	('miR-204', 'Gene', (97, 104))
271968	27457246	Some in vitro studies with hepatic, renal, ovarian and breast cancer cell lines have shown that loss of miR-204 results in activation of an EMT, leading to cancer cell migration and invasion.	('leading to', 'Reg', (145, 155))	('loss', 'Var', (96, 100))	('cancer', 'Disease', (156, 162))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('miR-204', 'Gene', '406987', (104, 111))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('hepatic, renal, ovarian and breast cancer', 'Disease', 'MESH:D010051', (27, 68))	('cancer', 'Disease', (62, 68))	('activation', 'PosReg', (123, 133))	('miR-204', 'Gene', (104, 111))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('invasion', 'CPA', (182, 190))	('breast cancer', 'Phenotype', 'HP:0003002', (55, 68))	('EMT', 'CPA', (140, 143))
271982	27457246	MicroRNA-204 may act as a "rheostat" that controls the signaling towards the MAPK pathway or the STAT3 pathway.	('MAPK', 'Gene', (77, 81))	('MAPK', 'Gene', '5595;5594;5595', (77, 81))	('STAT3', 'Gene', (97, 102))	('signaling', 'MPA', (55, 64))	('MicroRNA-204', 'Var', (0, 12))	('STAT3', 'Gene', '6774', (97, 102))
272029	26745629	One contains 24 paired tumor and normal samples from GSE42743 with platform of Affymetrix U133 plus 2.0 array.	('tumor', 'Disease', (23, 28))	('GSE42743', 'Var', (53, 61))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('tumor', 'Disease', 'MESH:D009369', (23, 28))
272052	26745629	Recent studies have shown that PDIA3 regulates cell invasiveness in cervical cancer and that a high level of PDIA3 is associated with a low patient survival rate.	('regulates', 'Reg', (37, 46))	('PDIA3', 'Gene', '2923', (109, 114))	('cell invasiveness', 'CPA', (47, 64))	('patient survival rate', 'CPA', (140, 161))	('PDIA3', 'Gene', (109, 114))	('patient', 'Species', '9606', (140, 147))	('cervical cancer', 'Disease', (68, 83))	('cervical cancer', 'Disease', 'MESH:D002583', (68, 83))	('low', 'NegReg', (136, 139))	('PDIA3', 'Gene', '2923', (31, 36))	('high level', 'Var', (95, 105))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('PDIA3', 'Gene', (31, 36))
272061	26745629	There is strong clinical and experimental evidence of an association between elevated levels of matrix metalloproteinase MMP9 and cancer progression, metastasis and shortened patient survival, as it plays a key role in tumor cell migration by digesting the basement membrane and ECM components.	('patient survival', 'CPA', (175, 191))	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('tumor', 'Disease', (219, 224))	('shortened', 'NegReg', (165, 174))	('cancer', 'Disease', (130, 136))	('MMP9', 'Gene', (121, 125))	('patient', 'Species', '9606', (175, 182))	('MMP9', 'Gene', '4318', (121, 125))	('metastasis', 'CPA', (150, 160))	('elevated', 'PosReg', (77, 85))	('clinical', 'Species', '191496', (16, 24))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('tumor', 'Disease', 'MESH:D009369', (219, 224))	('digesting', 'Var', (243, 252))
272071	26745629	Some reports have shown that BGH3 inhibits tumor cell migration by interacting with other ECM components and regulating integrin expression and that high expression of BGH3I increases the sensitivity of tumors to chemotherapy.	('increases', 'PosReg', (174, 183))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('tumor', 'Disease', (203, 208))	('interacting', 'Interaction', (67, 78))	('inhibits', 'NegReg', (34, 42))	('regulating', 'Reg', (109, 119))	('BGH3I', 'Gene', (168, 173))	('tumors', 'Disease', (203, 209))	('integrin expression', 'MPA', (120, 139))	('tumors', 'Disease', 'MESH:D009369', (203, 209))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumors', 'Phenotype', 'HP:0002664', (203, 209))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('BGH3', 'Gene', (29, 33))	('high expression', 'Var', (149, 164))	('tumor', 'Disease', (43, 48))
272073	26745629	A recent study of myeloma showed that hypermethylation of the BGH3 gene was associated with tumor promotion.	('hypermethylation', 'Var', (38, 54))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('myeloma', 'Disease', 'MESH:D009101', (18, 25))	('BGH3', 'Gene', (62, 66))	('associated', 'Reg', (76, 86))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Disease', (92, 97))	('myeloma', 'Disease', (18, 25))
272076	26745629	found that BGH3 was cleaved by MMP-9, and its cleavage resulted in changes in its binding properties and cell adhesion, cell migration, FAK/Src signal, and chemoattractant effects.	('changes', 'Reg', (67, 74))	('MMP-9', 'Gene', '4318', (31, 36))	('Src', 'Gene', (140, 143))	('Src', 'Gene', '6714', (140, 143))	('MMP-9', 'Gene', (31, 36))	('BGH3', 'Gene', (11, 15))	('FAK', 'Gene', (136, 139))	('FAK', 'Gene', '5747', (136, 139))	('cell adhesion', 'CPA', (105, 118))	('cleavage', 'Var', (46, 54))	('binding', 'Interaction', (82, 89))	('cell migration', 'CPA', (120, 134))
272262	31496743	The original whole lung volume, GTV, PTVHigh, PTVLow, and dose-level volumes of the lung V10, V20, V27, V30, and V50% of the maximal prescribed dose, where dose volume Vx was defined as the total organ volume exceeding a radiation dose of "x", were generated as regions of interest (ROIs) at planning CT and were co-registered to the corresponding relative PET/CT.	('V27', 'Gene', '28803', (99, 102))	('V27', 'Gene', (99, 102))	('GTV', 'Chemical', '-', (32, 35))	('V30', 'Var', (104, 107))
272293	31496743	For chronic radiation pulmonary fibrosis, both simple and multivariate regression analyses demonstrated a significant correlation between %DeltaSUVR of V50%, V27, and V30.	('chronic radiation pulmonary fibrosis', 'Disease', (4, 40))	('pulmonary fibrosis', 'Phenotype', 'HP:0002206', (22, 40))	('V50%', 'Var', (152, 156))	('V27', 'Gene', '28803', (158, 161))	('chronic radiation pulmonary fibrosis', 'Disease', 'MESH:D011832', (4, 40))	('V30', 'Var', (167, 170))	('V27', 'Gene', (158, 161))
272297	31496743	The cutoff value at the 6.2% increment of V20 area DeltaSUVR and the 8.9% increment of V27 area DeltaSUVR were selected as the new bio-physic constraint.	('V27', 'Gene', (87, 90))	('V27', 'Gene', '28803', (87, 90))	('V20', 'Var', (42, 45))
272300	31496743	The cutoff values at the 6.2% increment of V20 area DeltaSUVR and the 8.9% increment of V27 area DeltaSUVR are powerful predictors of acute RP and chronic lung fibrosis, respectively, and could potentially represent a new bio-physic constraint model in treatment planning for NACCRT in patients with advanced thoracic esophageal squamous cell carcinoma.	('V20 area DeltaSUVR', 'Var', (43, 61))	('lung fibrosis', 'Disease', 'MESH:D005355', (155, 168))	('V27', 'Gene', '28803', (88, 91))	('patients', 'Species', '9606', (286, 294))	('lung fibrosis', 'Disease', (155, 168))	('acute RP', 'Disease', (134, 142))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (318, 352))	('NACCRT', 'Chemical', '-', (276, 282))	('carcinoma', 'Phenotype', 'HP:0030731', (343, 352))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (329, 352))	('V27', 'Gene', (88, 91))	('lung fibrosis', 'Phenotype', 'HP:0002206', (155, 168))	('esophageal squamous cell carcinoma', 'Disease', (318, 352))
272324	30079348	Therefore, we conducted a meta-analysis to determine whether PINX1 expression is associated with overall survival (OS), disease-specific survival (DSS), disease-free survival (DFS), recurrence-free survival (RFS), and clinicopathological characteristics in patients with malignant tumors.	('tumors', 'Disease', (281, 287))	('tumors', 'Disease', 'MESH:D009369', (281, 287))	('tumors', 'Phenotype', 'HP:0002664', (281, 287))	('expression', 'Var', (67, 77))	('OS', 'Chemical', '-', (115, 117))	('patient', 'Species', '9606', (257, 264))	('overall', 'MPA', (97, 104))	('malignant tumors', 'Disease', (271, 287))	('DSS', 'Gene', (147, 150))	('PINX1', 'Gene', (61, 66))	('recurrence-free', 'Disease', (182, 197))	('patients', 'Species', '9606', (257, 265))	('disease-free', 'Disease', (153, 165))	('malignant tumors', 'Disease', 'MESH:D018198', (271, 287))	('DSS', 'Gene', '5376', (147, 150))	('tumor', 'Phenotype', 'HP:0002664', (281, 286))	('associated', 'Reg', (81, 91))
272336	30079348	The association between PINX1 dysregulation and carcinogenesis has been described in several reports.	('carcinogenesis', 'Disease', (48, 62))	('carcinogenesis', 'Disease', 'MESH:D063646', (48, 62))	('PINX1', 'Gene', (24, 29))	('dysregulation', 'Var', (30, 43))
272339	33786615	Differential MUC22 expression by epigenetic alterations in human lung squamous cell carcinoma and adenocarcinoma Disruption in mucins (MUCs) is involved in cancer development and metastasis and is thus used as a biomarker.	('MUC22', 'Gene', '100507679', (13, 18))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (65, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (70, 93))	('expression', 'MPA', (19, 29))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('involved', 'Reg', (144, 152))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (65, 93))	('lung squamous cell carcinoma', 'Disease', (65, 93))	('adenocarcinoma', 'Disease', (98, 112))	('epigenetic alterations', 'Var', (33, 55))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('mucin', 'Gene', (127, 132))	('MUC22', 'Gene', (13, 18))	('human', 'Species', '9606', (59, 64))	('mucin', 'Gene', '100508689', (127, 132))	('cancer', 'Disease', (156, 162))	('adenocarcinoma', 'Disease', 'MESH:D000230', (98, 112))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))
272342	33786615	Here, we report distinct expression and epigenetic alterations in mucin 22 (MUC22), a new MUC family member, in LUSC vs. LUAD.	('MUC22', 'Gene', (76, 81))	('LUAD', 'Phenotype', 'HP:0030078', (121, 125))	('mucin 22', 'Gene', (66, 74))	('mucin 22', 'Gene', '100507679', (66, 74))	('MUC22', 'Gene', '100507679', (76, 81))	('epigenetic alterations', 'Var', (40, 62))
272344	33786615	The aberrant expression of MUC22 was inversely correlated with its promoter hypermethylation in LUSC and hypomethylation in LUAD cells and tissues, respectively.	('MUC22', 'Gene', (27, 32))	('promoter hypermethylation', 'MPA', (67, 92))	('hypomethylation', 'MPA', (105, 120))	('LUAD', 'Phenotype', 'HP:0030078', (124, 128))	('MUC22', 'Gene', '100507679', (27, 32))	('aberrant', 'Var', (4, 12))
272346	33786615	MUC22 knockdown increased the growth and motility of lung cancer cells and an immortalized human bronchial epithelial BEAS-2B cell line via NF-kappaB activation.	('motility of lung cancer', 'Disease', (41, 64))	('BEAS-2B', 'CellLine', 'CVCL:0168', (118, 125))	('MUC22', 'Gene', '100507679', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('NF-kappaB', 'Gene', '4790', (140, 149))	('activation', 'PosReg', (150, 160))	('NF-kappaB', 'Gene', (140, 149))	('increased', 'PosReg', (16, 25))	('motility of lung cancer', 'Disease', 'MESH:D008175', (41, 64))	('MUC22', 'Gene', (0, 5))	('knockdown', 'Var', (6, 15))	('lung cancer', 'Phenotype', 'HP:0100526', (53, 64))	('human', 'Species', '9606', (91, 96))
272348	33786615	Our study reveals that changes in MUC22 expression due to epigenetic alterations in NSCLC may have important biological significance and prognostic potential in LUSC when compared to LUAD.	('expression', 'MPA', (40, 50))	('NSCLC', 'Phenotype', 'HP:0030358', (84, 89))	('changes', 'Reg', (23, 30))	('MUC22', 'Gene', '100507679', (34, 39))	('LUAD', 'Phenotype', 'HP:0030078', (183, 187))	('NSCLC', 'Disease', (84, 89))	('NSCLC', 'Disease', 'MESH:D002289', (84, 89))	('epigenetic alterations', 'Var', (58, 80))	('LUSC', 'Disease', (161, 165))	('MUC22', 'Gene', (34, 39))
272349	33786615	Thus, MUC22 expression and epigenetic alterations may be used for molecular subtyping of NSCLC in precision medicine.	('MUC22', 'Gene', '100507679', (6, 11))	('NSCLC', 'Disease', 'MESH:D002289', (89, 94))	('NSCLC', 'Phenotype', 'HP:0030358', (89, 94))	('MUC22', 'Gene', (6, 11))	('epigenetic alterations', 'Var', (27, 49))	('NSCLC', 'Disease', (89, 94))
272359	33786615	Aberrant expression of MUCs is associated with the degree of lung cancer malignancy via multiple pathways.	('Aberrant expression', 'Var', (0, 19))	('lung cancer', 'Phenotype', 'HP:0100526', (61, 72))	('lung cancer malignancy', 'Disease', (61, 83))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('associated', 'Reg', (31, 41))	('MUCs', 'Protein', (23, 27))	('lung cancer malignancy', 'Disease', 'MESH:D008175', (61, 83))
272362	33786615	In the present study, we examined the differential expression and epigenetic alterations of MUCs in LUSC and LUAD as potential tumor biomarkers.	('epigenetic alterations', 'Var', (66, 88))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumor', 'Disease', (127, 132))	('LUAD', 'Phenotype', 'HP:0030078', (109, 113))	('tumor', 'Disease', 'MESH:D009369', (127, 132))
272363	33786615	We found that MUC22, a new MUC family member, was decreased in the cells and tissues of LUSC (MUC22Low) but increased in LUAD (MUC22High) due to diverse epigenetic alterations.	('MUC22', 'Gene', '100507679', (127, 132))	('MUC22', 'Gene', '100507679', (14, 19))	('epigenetic alterations', 'Var', (153, 175))	('MUC22', 'Gene', (94, 99))	('LUAD', 'Phenotype', 'HP:0030078', (121, 125))	('increased', 'PosReg', (108, 117))	('decreased', 'NegReg', (50, 59))	('MUC22', 'Gene', '100507679', (94, 99))	('MUC22', 'Gene', (127, 132))	('MUC22', 'Gene', (14, 19))
272365	33786615	Our results suggest the potential of MUC22 expression and its epigenetic alterations to distinguish NSCLC subtypes important for precision treatment.	('NSCLC', 'Disease', (100, 105))	('MUC22', 'Gene', (37, 42))	('NSCLC', 'Disease', 'MESH:D002289', (100, 105))	('MUC22', 'Gene', '100507679', (37, 42))	('epigenetic alterations', 'Var', (62, 84))	('NSCLC', 'Phenotype', 'HP:0030358', (100, 105))
272379	33786615	MSP-qPCR was performed by using primer pairs specifically for either methylated or unmethylated sequences of the MUC22 (Table SII).	('methylated', 'Var', (69, 79))	('MUC22', 'Gene', (113, 118))	('MUC22', 'Gene', '100507679', (113, 118))
272385	33786615	The membranes were blocked with PBS containing 5% milk and 0.1% Tween-20 at room temperature for 1 h. The primary antibodies were as follows: beta-actin (mouse monoclonal, dilution 1:10,000; A4551) was from Sigma-Aldrich; Merck KGaA.	('mouse', 'Species', '10090', (154, 159))	('A4551', 'Var', (191, 196))	('beta-actin', 'Protein', (142, 152))
272420	33786615	ChIP-qPCR analysis of genomic DNA immunoprecipitated with anti-H3K9ac antibody in SK-MES-1 cells showed that H3K9ac was significantly enriched in the MUC22 promoter region upon the treatment (Fig.	('IP', 'Chemical', 'MESH:C041508', (2, 4))	('H3K9ac', 'Var', (109, 115))	('SK-MES-1', 'CellLine', 'CVCL:0630', (82, 90))	('MUC22', 'Gene', (150, 155))	('MUC22', 'Gene', '100507679', (150, 155))
272421	33786615	These results demonstrate that coordinated epigenetic modifications regulate MUC22 expression in LUSC cells, in which epigenetic silent MUC22 differentially responded to 5-Aza or TSA, suggesting heterogeneity of NSCLC cells subject to epigenetic regulation.	('epigenetic silent', 'Var', (118, 135))	('NSCLC', 'Disease', 'MESH:D002289', (212, 217))	('TSA', 'Chemical', 'MESH:C012589', (179, 182))	('epigenetic', 'Var', (43, 53))	('NSCLC', 'Phenotype', 'HP:0030358', (212, 217))	('MUC22', 'Gene', (77, 82))	('MUC22', 'Gene', (136, 141))	('TSA', 'MPA', (179, 182))	('5-Aza', 'Chemical', 'MESH:D000077209', (170, 175))	('responded', 'Reg', (157, 166))	('NSCLC', 'Disease', (212, 217))	('MUC22', 'Gene', '100507679', (77, 82))	('MUC22', 'Gene', '100507679', (136, 141))
272423	33786615	3B, knockdown of MUC22 promoted the proliferation of both SK-MES-1 and NCI-H522 cell lines.	('promoted', 'PosReg', (23, 31))	('MUC22', 'Gene', '100507679', (17, 22))	('NCI-H522', 'CellLine', 'CVCL:1567', (71, 79))	('proliferation', 'CPA', (36, 49))	('knockdown', 'Var', (4, 13))	('SK-MES-1', 'CellLine', 'CVCL:0630', (58, 66))	('MUC22', 'Gene', (17, 22))
272424	33786615	Transwell migration assay showed significantly increased number of migrating SK-MES-1 and NCI-H522 cells after MUC22 knockdown (Fig.	('MUC22', 'Gene', (111, 116))	('MUC22', 'Gene', '100507679', (111, 116))	('increased', 'PosReg', (47, 56))	('SK-MES-1', 'CellLine', 'CVCL:0630', (77, 85))	('NCI-H522', 'CellLine', 'CVCL:1567', (90, 98))	('knockdown', 'Var', (117, 126))
272426	33786615	We further observed suppressive effect of MUC22 on lung cell malignancy in an immortalized bronchial epithelial cell line BEAS-2B, in which MUC22 knockdown promoted cell growth and motility (Fig.	('knockdown', 'Var', (146, 155))	('motility', 'CPA', (181, 189))	('MUC22', 'Gene', '100507679', (140, 145))	('MUC22', 'Gene', '100507679', (42, 47))	('BEAS-2B', 'CellLine', 'CVCL:0168', (122, 129))	('MUC22', 'Gene', (42, 47))	('lung cell malignancy', 'CPA', (51, 71))	('MUC22', 'Gene', (140, 145))	('cell growth', 'CPA', (165, 176))	('promoted', 'PosReg', (156, 164))
272433	33786615	These results suggest that epigenetic silencing of MUC22 facilitates lung cancer cell growth and motility via NF-kappaB activation.	('lung cancer', 'Disease', 'MESH:D008175', (69, 80))	('MUC22', 'Gene', (51, 56))	('epigenetic silencing', 'Var', (27, 47))	('motility', 'CPA', (97, 105))	('activation', 'PosReg', (120, 130))	('MUC22', 'Gene', '100507679', (51, 56))	('lung cancer', 'Disease', (69, 80))	('lung cancer', 'Phenotype', 'HP:0100526', (69, 80))	('NF-kappaB', 'Gene', '4790', (110, 119))	('facilitates', 'PosReg', (57, 68))	('NF-kappaB', 'Gene', (110, 119))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
272440	33786615	In the present study, we revealed the biological significance and prognostic values of distinct expression and epigenetic alterations of mucin 22 (MUC22) in lung adenocarcinoma (LUAD) vs. squamous cell carcinoma (LUSC).	('epigenetic alterations', 'Var', (111, 133))	('MUC22', 'Gene', '100507679', (147, 152))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (157, 176))	('LUAD', 'Phenotype', 'HP:0030078', (178, 182))	('squamous cell carcinoma', 'Disease', (188, 211))	('expression', 'MPA', (96, 106))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (157, 176))	('carcinoma', 'Phenotype', 'HP:0030731', (167, 176))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (188, 211))	('lung adenocarcinoma', 'Disease', (157, 176))	('carcinoma', 'Phenotype', 'HP:0030731', (202, 211))	('mucin 22', 'Gene', (137, 145))	('MUC22', 'Gene', (147, 152))	('mucin 22', 'Gene', '100507679', (137, 145))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (188, 211))
272443	33786615	Abnormal MUC expression has been reported in various cancer types including lung cancer.	('lung cancer', 'Disease', 'MESH:D008175', (76, 87))	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('cancer', 'Disease', (81, 87))	('lung cancer', 'Disease', (76, 87))	('lung cancer', 'Phenotype', 'HP:0100526', (76, 87))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('MUC', 'Protein', (9, 12))	('Abnormal', 'Var', (0, 8))	('reported', 'Reg', (33, 41))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))
272453	33786615	Since MUC22 was co-localized with MUC21 in a mucin gene cluster on chromosome 6p21.3, co-expression of MUC22 with MUC21 may indicate a link between MUC21 and MUC22 in lung cancer progression contributing to lung cancer heterogeneity.	('mucin', 'Gene', '100508689', (45, 50))	('lung cancer', 'Disease', (167, 178))	('co-expression', 'Var', (86, 99))	('MUC22', 'Gene', (103, 108))	('MUC21', 'Gene', (148, 153))	('lung cancer', 'Disease', 'MESH:D008175', (207, 218))	('MUC21', 'Gene', '394263', (34, 39))	('lung cancer', 'Disease', 'MESH:D008175', (167, 178))	('MUC22', 'Gene', (6, 11))	('MUC22', 'Gene', (158, 163))	('lung cancer', 'Phenotype', 'HP:0100526', (207, 218))	('MUC21', 'Gene', '394263', (114, 119))	('lung cancer', 'Phenotype', 'HP:0100526', (167, 178))	('MUC22', 'Gene', '100507679', (103, 108))	('MUC21', 'Gene', '394263', (148, 153))	('MUC21', 'Gene', (34, 39))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))	('link', 'Reg', (135, 139))	('MUC22', 'Gene', '100507679', (6, 11))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('MUC22', 'Gene', '100507679', (158, 163))	('MUC21', 'Gene', (114, 119))	('mucin', 'Gene', (45, 50))	('lung cancer', 'Disease', (207, 218))
272457	33786615	Promoter hypomethylation associated with mucin expression was also shown in several types of cancer cells and tissues, including lung cancer.	('cancer', 'Disease', (93, 99))	('lung cancer', 'Disease', (129, 140))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('lung cancer', 'Phenotype', 'HP:0100526', (129, 140))	('associated', 'Reg', (25, 35))	('mucin', 'Gene', '100508689', (41, 46))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('Promoter hypomethylation', 'Var', (0, 24))	('lung cancer', 'Disease', 'MESH:D008175', (129, 140))	('mucin', 'Gene', (41, 46))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('expression', 'MPA', (47, 57))
272464	33786615	We found that MUC22 knockdown promoted the growth and motility of lung cancer cells as well as an immortalized bronchial epithelial BEAS-2B cell line.	('motility of lung cancer', 'Disease', 'MESH:D008175', (54, 77))	('BEAS-2B', 'CellLine', 'CVCL:0168', (132, 139))	('MUC22', 'Gene', '100507679', (14, 19))	('lung cancer', 'Phenotype', 'HP:0100526', (66, 77))	('promoted', 'PosReg', (30, 38))	('motility of lung cancer', 'Disease', (54, 77))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('growth', 'CPA', (43, 49))	('knockdown', 'Var', (20, 29))	('MUC22', 'Gene', (14, 19))
272469	33786615	Therefore, it is important to delineate the precise molecular mechanisms underlying epigenetic regulation of MUC22 that contributes to phenotypic differences within NSCLC.	('MUC22', 'Gene', '100507679', (109, 114))	('NSCLC', 'Disease', 'MESH:D002289', (165, 170))	('contributes', 'Reg', (120, 131))	('epigenetic regulation', 'Var', (84, 105))	('NSCLC', 'Phenotype', 'HP:0030358', (165, 170))	('MUC22', 'Gene', (109, 114))	('NSCLC', 'Disease', (165, 170))
272471	33786615	Epigenetic silencing of MUC22 may provide a molecular model for dissecting mucin-associated lung cancer heterogeneity, thus having clinical implication in distinguishing NSCLC subtypes for precision treatment.	('lung cancer', 'Disease', (92, 103))	('lung cancer', 'Phenotype', 'HP:0100526', (92, 103))	('NSCLC', 'Phenotype', 'HP:0030358', (170, 175))	('MUC22', 'Gene', '100507679', (24, 29))	('mucin', 'Gene', (75, 80))	('NSCLC', 'Disease', (170, 175))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('lung cancer', 'Disease', 'MESH:D008175', (92, 103))	('Epigenetic silencing', 'Var', (0, 20))	('NSCLC', 'Disease', 'MESH:D002289', (170, 175))	('mucin', 'Gene', '100508689', (75, 80))	('MUC22', 'Gene', (24, 29))
272481	31160489	The results showed that GPC3 expression levels in lung SCC tissues and cells were significantly elevated, and the high expression of GPC3 significantly promoted cell growth and tumorigenesis and repressed cell apoptosis, as well as increased beta-catenin expression.	('cell apoptosis', 'CPA', (205, 219))	('tumorigenesis', 'CPA', (177, 190))	('GPC3', 'Gene', (133, 137))	('beta-catenin', 'Gene', (242, 254))	('SCC', 'Gene', (55, 58))	('SCC', 'Phenotype', 'HP:0002860', (55, 58))	('expression', 'MPA', (255, 265))	('SCC', 'Gene', '6317', (55, 58))	('high expression', 'Var', (114, 129))	('increased', 'PosReg', (232, 241))	('GPC3 expression levels', 'MPA', (24, 46))	('elevated', 'PosReg', (96, 104))	('beta-catenin', 'Gene', '1499', (242, 254))	('cell growth', 'CPA', (161, 172))	('promoted', 'PosReg', (152, 160))
272482	31160489	Moreover, knockdown of beta-catenin obviously weakened GPC3 role in the promotion of cell proliferation and tumorigenesis, as well as the inhibition of cell apoptosis.	('cell apoptosis', 'CPA', (152, 166))	('inhibition', 'NegReg', (138, 148))	('cell proliferation', 'CPA', (85, 103))	('promotion', 'PosReg', (72, 81))	('tumorigenesis', 'CPA', (108, 121))	('beta-catenin', 'Gene', (23, 35))	('knockdown', 'Var', (10, 19))	('GPC3', 'Protein', (55, 59))	('beta-catenin', 'Gene', '1499', (23, 35))	('weakened', 'NegReg', (46, 54))
272488	31160489	Increasing evidence has identified that low expression of tumour suppressor genes and/or hyper-activation of oncogenes obviously accelerates the occurrence and development of lung SCC.	('development', 'CPA', (160, 171))	('hyper-activation', 'Var', (89, 105))	('expression', 'MPA', (44, 54))	('low', 'NegReg', (40, 43))	('accelerates', 'PosReg', (129, 140))	('tumour', 'Phenotype', 'HP:0002664', (58, 64))	('oncogenes', 'Gene', (109, 118))	('SCC', 'Gene', (180, 183))	('tumour', 'Disease', 'MESH:D009369', (58, 64))	('tumour', 'Disease', (58, 64))	('SCC', 'Phenotype', 'HP:0002860', (180, 183))	('SCC', 'Gene', '6317', (180, 183))
272495	31160489	However, whether GPC3 induces beta-catenin signalling activation in lung SCC remains unknown.	('beta-catenin', 'Gene', '1499', (30, 42))	('GPC3', 'Var', (17, 21))	('SCC', 'Gene', (73, 76))	('SCC', 'Phenotype', 'HP:0002860', (73, 76))	('activation', 'PosReg', (54, 64))	('SCC', 'Gene', '6317', (73, 76))	('beta-catenin', 'Gene', (30, 42))
272531	31160489	To explore the function of GPC3/beta-catenin in the tumorigenesis of lung SCC cells, LTEP-s or SK-MES-1 cells (1 x 107 cells diluted in 200 mul of PBS) with stable expression of vector-NC+sh-NC, vector-GPC3+sh-NC, vector-NC+sh-beta-catenin or vector-GPC3 + sh-beta-catenin were subcutaneously injected into nude mice, with five mice in each group.	('mice', 'Species', '10090', (328, 332))	('beta-catenin', 'Gene', '1499', (260, 272))	('beta-catenin', 'Gene', (227, 239))	('vector-GPC3 +', 'Var', (243, 256))	('vector-GPC3+sh-NC', 'Var', (195, 212))	('beta-catenin', 'Gene', '1499', (227, 239))	('beta-catenin', 'Gene', (32, 44))	('SK-MES-1', 'CellLine', 'CVCL:0630', (95, 103))	('PBS', 'Chemical', 'MESH:D007854', (147, 150))	('nude mice', 'Species', '10090', (307, 316))	('beta-catenin', 'Gene', '1499', (32, 44))	('SCC', 'Gene', (74, 77))	('vector-NC+sh-NC', 'Var', (178, 193))	('beta-catenin', 'Gene', (260, 272))	('SCC', 'Phenotype', 'HP:0002860', (74, 77))	('mice', 'Species', '10090', (312, 316))	('SCC', 'Gene', '6317', (74, 77))
272536	31160489	As shown from the WB results, the expression of GPC3 protein in NCI-H520, NCI-H226 and SK-MES-1 cells was obviously higher than that in BEAS-2B cells (Figure 1D).	('BEAS-2B', 'CellLine', 'CVCL:0168', (136, 143))	('NCI-H520', 'Var', (64, 72))	('expression', 'MPA', (34, 44))	('higher', 'PosReg', (116, 122))	('NCI-H226', 'CellLine', 'CVCL:1544', (74, 82))	('GPC3 protein', 'Protein', (48, 60))	('NCI-H520', 'CellLine', 'CVCL:1566', (64, 72))	('SK-MES-1', 'CellLine', 'CVCL:0630', (87, 95))
272539	31160489	Infection of LTEP-s and SK-MES-1 cells with lentivirus vector-GPC3 significantly increased GPC3 expression compared with cells treated with vector-NC (Figure 2A).	('SK-MES-1', 'CellLine', 'CVCL:0630', (24, 32))	('increased', 'PosReg', (81, 90))	('vector-GPC3', 'Var', (55, 66))	('GPC3 expression', 'MPA', (91, 106))
272541	31160489	In addition, up-regulation of GPC3 with vector-GPC3 transfection significantly enhanced cell growth, and down-regulation of GPC3 with sh-2 treatment obviously decreased cell growth in LTEP-s and SK-MES-1 cells (Figure 2C,D).	('vector-GPC3', 'Var', (40, 51))	('cell growth', 'CPA', (169, 180))	('down-regulation', 'NegReg', (105, 120))	('GPC3', 'Gene', (30, 34))	('enhanced', 'PosReg', (79, 87))	('cell growth', 'CPA', (88, 99))	('decreased', 'NegReg', (159, 168))	('transfection', 'Var', (52, 64))	('up-regulation', 'PosReg', (13, 26))	('SK-MES-1', 'CellLine', 'CVCL:0630', (195, 203))
272543	31160489	All data indicate that GPC3 accelerates the progression of lung SCC.	('progression', 'CPA', (44, 55))	('SCC', 'Gene', '6317', (64, 67))	('accelerates', 'PosReg', (28, 39))	('GPC3', 'Var', (23, 27))	('SCC', 'Gene', (64, 67))	('SCC', 'Phenotype', 'HP:0002860', (64, 67))
272552	31160489	Consistently, knockdown of beta-catenin rescued GPC3 overexpression and caused cell apoptosis inhibition in both LTEP-s and SK-MES-1 cells (Figure 4F,G).	('SK-MES-1', 'CellLine', 'CVCL:0630', (124, 132))	('rescued', 'PosReg', (40, 47))	('beta-catenin', 'Gene', '1499', (27, 39))	('overexpression', 'PosReg', (53, 67))	('cell apoptosis', 'CPA', (79, 93))	('knockdown', 'Var', (14, 23))	('beta-catenin', 'Gene', (27, 39))	('GPC3', 'Protein', (48, 52))
272553	31160489	Moreover, up-regulation of GPC3 increased the tumorigenesis of SK-MES-1 cells, while down-regulation of beta-catenin reduced tumorigenesis, and knockdown of beta-catenin weakened the tumorigenesis induced by GPC3 overexpression in SK-MES-1 cells (Figure 5).	('SK-MES-1', 'CellLine', 'CVCL:0630', (63, 71))	('beta-catenin', 'Gene', '1499', (157, 169))	('beta-catenin', 'Gene', (104, 116))	('tumorigenesis', 'CPA', (183, 196))	('SK-MES-1', 'CellLine', 'CVCL:0630', (231, 239))	('beta-catenin', 'Gene', '1499', (104, 116))	('GPC3', 'Gene', (27, 31))	('overexpression', 'PosReg', (213, 227))	('knockdown', 'Var', (144, 153))	('increased', 'PosReg', (32, 41))	('beta-catenin', 'Gene', (157, 169))	('up-regulation', 'PosReg', (10, 23))	('weakened', 'NegReg', (170, 178))	('tumorigenesis', 'CPA', (46, 59))	('GPC3', 'Gene', (208, 212))
272568	31160489	In addition, we postulated that beta-catenin was closely involved in the process by which GPC3 obviously accelerated lung SCC progression.	('SCC', 'Gene', (122, 125))	('SCC', 'Phenotype', 'HP:0002860', (122, 125))	('accelerated', 'PosReg', (105, 116))	('lung', 'Disease', (117, 121))	('beta-catenin', 'Gene', (32, 44))	('SCC', 'Gene', '6317', (122, 125))	('GPC3', 'Var', (90, 94))	('beta-catenin', 'Gene', '1499', (32, 44))
272573	31160489	Furthermore, researchers have revealed that beta-catenin signalling could also be activated by hyper-activated GPC3, thereby modulating cell proliferation.	('hyper-activated', 'Var', (95, 110))	('activated', 'PosReg', (82, 91))	('modulating', 'Reg', (125, 135))	('beta-catenin', 'Gene', '1499', (44, 56))	('beta-catenin', 'Gene', (44, 56))	('GPC3', 'Gene', (111, 115))	('cell proliferation', 'CPA', (136, 154))
272574	31160489	Similarly, we demonstrated that GPC3 promoted the growth and tumorigenesis and inhibited the apoptosis of lung SCC cells through up-regulating beta-catenin with no obvious influence on the expression of Wnt, suggesting that there might be a direct effect of GPC3 on beta-catenin.	('SCC', 'Phenotype', 'HP:0002860', (111, 114))	('beta-catenin', 'Gene', '1499', (143, 155))	('promoted', 'PosReg', (37, 45))	('beta-catenin', 'Gene', '1499', (266, 278))	('up-regulating', 'PosReg', (129, 142))	('tumorigenesis', 'CPA', (61, 74))	('SCC', 'Gene', (111, 114))	('GPC3', 'Var', (32, 36))	('growth', 'CPA', (50, 56))	('inhibited', 'NegReg', (79, 88))	('beta-catenin', 'Gene', (266, 278))	('beta-catenin', 'Gene', (143, 155))	('apoptosis', 'CPA', (93, 102))	('SCC', 'Gene', '6317', (111, 114))
272575	31160489	In conclusion, the present study reveals, for the first time that GPC3 accelerates the progression of lung SCC in a beta-catenin-dependent manner.	('a beta', 'Gene', (114, 120))	('GPC3', 'Var', (66, 70))	('SCC', 'Gene', (107, 110))	('SCC', 'Phenotype', 'HP:0002860', (107, 110))	('a beta', 'Gene', '351', (114, 120))	('SCC', 'Gene', '6317', (107, 110))	('beta-catenin', 'Gene', (116, 128))	('progression', 'CPA', (87, 98))	('accelerates', 'PosReg', (71, 82))	('beta-catenin', 'Gene', '1499', (116, 128))
272591	30072739	Emerging biomarkers for anti-PD-1 response include the expression level of its ligand PD-L1 , mutation burden or mismatch-repair deficiency , and tumor-infiltrating lymphocytes .	('PD-1', 'Gene', '5133', (29, 33))	('deficiency', 'Disease', 'MESH:D007153', (129, 139))	('expression level', 'MPA', (55, 71))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('PD-L1', 'Gene', '29126', (86, 91))	('tumor', 'Disease', (146, 151))	('mismatch-repair', 'MPA', (113, 128))	('mutation burden', 'Var', (94, 109))	('deficiency', 'Disease', (129, 139))	('PD-L1', 'Gene', (86, 91))	('PD-1', 'Gene', (29, 33))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
272596	30072739	Several other types of non-coding RNAs, such as long-noncoding RNAs (lncRNAs) , enhancer RNAs  and circular RNAs  have also been implicated in various cancer types .	('circular RNAs', 'Var', (99, 112))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('enhancer', 'PosReg', (80, 88))	('implicated', 'Reg', (129, 139))	('long-noncoding', 'Var', (48, 62))	('cancer', 'Disease', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (151, 157))
272606	30072739	Here we performed a pan-cancer analysis of ~22 nt size-selected small RNA-seq (smRNA-seq) datasets from TCGA, exploring the expression of small RNAs mapping to annotated human snoRNAs in 10,262 patient samples across 32 cancer types.	('patient', 'Species', '9606', (194, 201))	('small', 'Var', (138, 143))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('snoRNA', 'Gene', '85390', (176, 182))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('cancer', 'Disease', (24, 30))	('cancer', 'Disease', 'MESH:D009369', (24, 30))	('cancer', 'Disease', 'MESH:D009369', (220, 226))	('human', 'Species', '9606', (170, 175))	('cancer', 'Disease', (220, 226))	('snoRNA', 'Gene', (176, 182))
272620	30072739	This pan-cancer sdRNA transcriptome is derived from several subtypes of snoRNAs with distinct structures and motifs, such as canonical C/D box snoRNAs, H/ACA box snoRNAs, C/D box small Cajal body RNAs (scaRNAs), H/ACA box scaRNAs, hybrid snoRNAs, and several other subtypes (Figure 1b, Table S1, Table S2).	('snoRNA', 'Gene', '85390', (143, 149))	('cancer', 'Disease', (9, 15))	('snoRNA', 'Gene', (162, 168))	('snoRNA', 'Gene', '85390', (72, 78))	('snoRNA', 'Gene', '85390', (162, 168))	('snoRNA', 'Gene', '85390', (238, 244))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('snoRNA', 'Gene', (143, 149))	('C/D box', 'Var', (171, 178))	('snoRNA', 'Gene', (72, 78))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('snoRNA', 'Gene', (238, 244))
272625	30072739	In the case of C/D snoRNAs, these analyses revealed three classes of read distributions, corresponding to 5' sdRNAs, 3' sdRNAs, or mixed sdRNAs (Figure 1c).	('D snoRNAs', 'Phenotype', 'HP:0025267', (17, 26))	('C/D', 'Var', (15, 18))	('snoRNA', 'Gene', (19, 25))	('mixed', 'Disease', (131, 136))	('snoRNA', 'Gene', '85390', (19, 25))	('D snoRNA', 'Phenotype', 'HP:0025267', (17, 25))
272635	30072739	The sdRNA transcriptome exhibited a wide dynamic range of expression across all cancers (Figure S5a), such that 300.13 +- 4.21 (mean +- s.e.m.)	('300.13 +- 4.21', 'Var', (112, 126))	('cancers', 'Disease', 'MESH:D009369', (80, 87))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancers', 'Disease', (80, 87))	('sdRNA', 'Gene', (4, 9))	('cancers', 'Phenotype', 'HP:0002664', (80, 87))
272717	30072739	For instance, high expression of sdRNAs derived from SNORA116, an H/ACA snoRNA, was connected to poorer survival in three independent cohorts: lower grade gliomas (LGG), liver hepatocellular carcinoma (LIHC), and uterine corpus endometrial carcinoma (UCEC) (Figure 7b).	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (228, 249))	('gliomas', 'Phenotype', 'HP:0009733', (155, 162))	('expression', 'MPA', (19, 29))	('snoRNA', 'Gene', '85390', (72, 78))	('corpus endometrial carcinoma', 'Disease', (221, 249))	('corpus endometrial carcinoma', 'Disease', 'MESH:D016889', (221, 249))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (176, 200))	('ACA snoRNA', 'Phenotype', 'HP:0025267', (68, 78))	('carcinoma', 'Phenotype', 'HP:0030731', (191, 200))	('liver hepatocellular carcinoma', 'Disease', 'MESH:D006528', (170, 200))	('liver hepatocellular carcinoma', 'Disease', (170, 200))	('glioma', 'Phenotype', 'HP:0009733', (155, 161))	('SNORA116', 'Var', (53, 61))	('poorer', 'NegReg', (97, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (240, 249))	('snoRNA', 'Gene', (72, 78))	('gliomas', 'Disease', (155, 162))	('gliomas', 'Disease', 'MESH:D005910', (155, 162))
272718	30072739	As another example, high levels of sdRNAs from SNORD145, a CD snoRNA, were associated with shorter survival times in kidney clear cell carcinoma (KIRC), sarcoma (SARC), and uterine corpus endometrial carcinoma (UCEC) (Figure 7c).	('sarcoma', 'Disease', 'MESH:D012509', (153, 160))	('corpus endometrial carcinoma', 'Disease', 'MESH:D016889', (181, 209))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (188, 209))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('sarcoma', 'Disease', (153, 160))	('corpus endometrial carcinoma', 'Disease', (181, 209))	('SARC', 'Phenotype', 'HP:0100242', (162, 166))	('carcinoma', 'Phenotype', 'HP:0030731', (200, 209))	('kidney clear cell carcinoma', 'Disease', 'MESH:C538614', (117, 144))	('SNORD145', 'Var', (47, 55))	('sarcoma', 'Phenotype', 'HP:0100242', (153, 160))	('D snoRNA', 'Phenotype', 'HP:0025267', (60, 68))	('snoRNA', 'Gene', (62, 68))	('survival times', 'CPA', (99, 113))	('shorter', 'NegReg', (91, 98))	('sdRNAs', 'MPA', (35, 41))	('snoRNA', 'Gene', '85390', (62, 68))	('kidney clear cell carcinoma', 'Disease', (117, 144))
272719	30072739	SdRNAs from SNORA116 and SNORD145 thus appear to be indicators of cancers with a more aggressive course.	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('SNORA116', 'Var', (12, 20))	('cancers', 'Phenotype', 'HP:0002664', (66, 73))	('SNORD145', 'Var', (25, 33))	('cancers', 'Disease', (66, 73))	('cancers', 'Disease', 'MESH:D009369', (66, 73))
272737	30072739	Because the ImmuneSurv score analyses were conducted in a cancer type-specific manner, we then sought a global assessment of sdRNAs and their relationships to cancer immunity regardless of cancer type (PANCAN32), by compiling all sdRNAs that were found to be significant in any of the 5 categories: PD-L1, CD8+ T cell abundance, GZMA, survival, or copy number variation (supplemental results, Figure S9) in any cancer type.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('cancer', 'Disease', 'MESH:D009369', (411, 417))	('cancer immunity regardless of cancer', 'Disease', 'MESH:D009369', (159, 195))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('CD8', 'Gene', (306, 309))	('GZMA', 'Gene', '3001', (329, 333))	('cancer', 'Disease', (159, 165))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('GZMA', 'Gene', (329, 333))	('PD-L1', 'Gene', (299, 304))	('PD-L1', 'Gene', '29126', (299, 304))	('cancer', 'Disease', (411, 417))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('CD8', 'Gene', '925', (306, 309))	('copy number variation', 'Var', (348, 369))	('cancer', 'Disease', (189, 195))	('cancer', 'Phenotype', 'HP:0002664', (411, 417))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('cancer immunity regardless of cancer', 'Disease', (159, 195))	('cancer', 'Disease', (58, 64))
272748	30072739	Of note, SNORD115 has been demonstrated to act as a regulator of alternative splicing , and its deletion is sufficient to cause Prader-Willi syndrome.	('SNORD115', 'Gene', '692218', (9, 17))	('cause', 'Reg', (122, 127))	('deletion', 'Var', (96, 104))	('Prader-Willi syndrome', 'Disease', 'MESH:D011218', (128, 149))	('Prader-Willi syndrome', 'Disease', (128, 149))	('alternative splicing', 'MPA', (65, 85))	('SNORD115', 'Gene', (9, 17))
272775	30072739	GISTIC 2.0 copy number variation calls were obtained from the GDAC Firehose (http://gdac.broadinstitute.org/) on September 2017.	('copy number variation', 'Var', (11, 32))	('DAC', 'Gene', (63, 66))	('DAC', 'Gene', '6468', (63, 66))
272777	30072739	Raw fastq files for independent smRNA-seq datasets (GSE33858, GSE46622, E-MTAB-3494) were accessed by NCBI GEO (https://www.ncbi.nlm.nih.gov/geo/) or EBI (https://www.ebi.ac.uk/).	('EBI', 'Gene', (150, 153))	('GSE46622', 'Var', (62, 70))	('EBI', 'Gene', '6907', (150, 153))	('GSE33858', 'Var', (52, 60))	('ebi', 'Gene', '6907', (167, 170))	('ebi', 'Gene', (167, 170))
272803	30072739	As these tables report the precise genomic coordinates in which the amplification or deletion was identified, we utilized a q < 0.05 threshold and subsequently intersected the coordinates with the snoRNA annotations .	('deletion', 'Var', (85, 93))	('snoRNA', 'Gene', (197, 203))	('snoRNA', 'Gene', '85390', (197, 203))
272804	30072739	Amplification and deletion calls for individual snoRNAs were then compiled into separate tables.	('deletion', 'Var', (18, 26))	('snoRNA', 'Gene', (48, 54))	('snoRNA', 'Gene', '85390', (48, 54))
272807	30072739	For pan-cancer analysis, we considered all sdRNAs that were found to be significant in at least one cancer type across the following 5 analyses: CD274 correlation, GMZA correlation, CD8+ T cell abundance, copy number variation, and survival.	('cancer', 'Disease', (8, 14))	('CD8', 'Gene', (182, 185))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('CD8', 'Gene', '925', (182, 185))	('CD274', 'Gene', '29126', (145, 150))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('copy number variation', 'Var', (205, 226))	('cancer', 'Disease', 'MESH:D009369', (8, 14))	('CD274', 'Gene', (145, 150))
272813	30072739	Thus, for the example above (NNSNSN), sdRNAs from snoRNA X were found to be significantly associated with survival and significant for CNV in cancer type Y.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('snoRNA', 'Gene', (50, 56))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('associated with', 'Reg', (90, 105))	('sdRNAs', 'Var', (38, 44))	('snoRNA', 'Gene', '85390', (50, 56))	('cancer', 'Disease', (142, 148))
272871	30526542	Gene set variation analysis (GSVA) was used to compare the expression of these macrophage signatures across the cancer datasets GSE31210 and GSE72194.	('GSE', 'Chemical', '-', (141, 144))	('GSE', 'Chemical', '-', (128, 131))	('GSVA', 'Chemical', '-', (29, 33))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('GSE72194', 'Var', (141, 149))	('GSE31210', 'Var', (128, 136))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))
272948	30526542	COPD Chronic obstructive pulmonary disease CT Computed tomography GSVA Gene set variation analysis NSCLC Non-small cell lung carcinoma SEM Standard error of mean FN conceived and carried out the experiments.	('Chronic obstructive pulmonary disease', 'Disease', 'MESH:D029424', (5, 42))	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('Non-small cell lung carcinoma', 'Disease', 'MESH:D002289', (105, 134))	('COPD', 'Phenotype', 'HP:0006510', (0, 4))	('obstructive pulmonary disease', 'Phenotype', 'HP:0006536', (13, 42))	('NSCLC', 'Phenotype', 'HP:0030358', (99, 104))	('COPD', 'Disease', 'MESH:D029424', (0, 4))	('COPD', 'Disease', (0, 4))	('GSVA', 'Chemical', '-', (66, 70))	('Chronic obstructive pulmonary disease', 'Phenotype', 'HP:0006510', (5, 42))	('variation', 'Var', (80, 89))	('Non-small cell lung carcinoma', 'Disease', (105, 134))	('Non-small cell lung carcinoma', 'Phenotype', 'HP:0030358', (105, 134))	('NSCLC', 'Disease', (99, 104))	('Chronic obstructive pulmonary disease', 'Disease', (5, 42))	('small cell lung carcinoma', 'Phenotype', 'HP:0030357', (109, 134))	('NSCLC', 'Disease', 'MESH:D002289', (99, 104))
272951	24999802	Here we generate pseudogene expression profiles in 2,808 patient samples of seven cancer types from The Cancer Genome Atlas RNA-seq data using a newly developed computational pipeline.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('patient', 'Species', '9606', (57, 64))	('pseudogene expression', 'Var', (17, 38))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('Cancer Genome Atlas', 'Disease', (104, 123))	('Cancer', 'Phenotype', 'HP:0002664', (104, 110))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (104, 123))
272953	24999802	Across cancer types, the tumor subtypes revealed by pseudogene expression show extensive and strong concordance with the subtypes defined by other molecular data.	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumor', 'Disease', (25, 30))	('pseudogene', 'Var', (52, 62))	('cancer', 'Disease', (7, 13))	('cancer', 'Disease', 'MESH:D009369', (7, 13))	('tumor', 'Disease', 'MESH:D009369', (25, 30))
272954	24999802	Strikingly, in kidney cancer, the pseudogene-expression subtypes not only significantly correlate with patient survival, but also help stratify patients in combination with clinical variables.	('correlate', 'Reg', (88, 97))	('patient', 'Species', '9606', (144, 151))	('patients', 'Species', '9606', (144, 152))	('kidney cancer', 'Phenotype', 'HP:0009726', (15, 28))	('kidney cancer', 'Disease', 'MESH:D007680', (15, 28))	('pseudogene-expression', 'Var', (34, 55))	('patient', 'Species', '9606', (103, 110))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('kidney cancer', 'Disease', (15, 28))
272955	24999802	Our study highlights the potential of pseudogene expression analysis as a new paradigm for investigating cancer mechanisms and discovering prognostic biomarkers.	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('pseudogene', 'Var', (38, 48))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))
272957	24999802	In recent years, a growing body of evidence has strongly suggested that individual pseudogenes play critical roles in human diseases such as cancer.	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('pseudogenes', 'Var', (83, 94))	('roles', 'Reg', (109, 114))	('human', 'Species', '9606', (118, 123))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('cancer', 'Disease', (141, 147))
272959	24999802	(2010) showed that the pseudogenes of key cancer genes (e.g., PTENP1 and KRASP1) can regulate the expression of their wild-type (WT) cognate genes by sequestering miRNAs.	('PTENP1', 'Gene', '11191', (62, 68))	('pseudogenes', 'Var', (23, 34))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('miRNAs', 'MPA', (163, 169))	('sequestering', 'NegReg', (150, 162))	('regulate', 'Reg', (85, 93))	('KRASP1', 'Gene', '3844', (73, 79))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('PTENP1', 'Gene', (62, 68))	('KRASP1', 'Gene', (73, 79))	('expression', 'MPA', (98, 108))
272960	24999802	More recently, Kalyana-Sundaram and colleagues (2012) performed the first genome-wide characterization of pseudogene expression in human cancers using the RNA-seq approach and revealed a considerable number of pseudogenes with a lineage- or cancer-specific expression pattern.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('pseudogenes', 'Var', (210, 221))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('cancers', 'Disease', 'MESH:D009369', (137, 144))	('human', 'Species', '9606', (131, 136))	('cancers', 'Phenotype', 'HP:0002664', (137, 144))	('cancer', 'Disease', (137, 143))	('cancers', 'Disease', (137, 144))	('cancer', 'Disease', (241, 247))	('cancer', 'Disease', 'MESH:D009369', (241, 247))
272963	24999802	In particular, it remains unclear whether pseudogene expression can effectively characterize the tumor heterogeneity within a specific cancer type and represent a meaningful dimension for patient stratification.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('cancer', 'Disease', (135, 141))	('patient', 'Species', '9606', (188, 195))	('pseudogene', 'Var', (42, 52))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('tumor', 'Disease', (97, 102))	('cancer', 'Disease', 'MESH:D009369', (135, 141))
272966	24999802	With this unprecedented dataset, we first identified differentially expressed pseudogenes among established tumor subtypes and demonstrated the predictive power in classifying clinical tumor subtypes of endometrial cancer.	('endometrial cancer', 'Disease', (203, 221))	('pseudogenes', 'Var', (78, 89))	('tumor', 'Disease', (185, 190))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('endometrial cancer', 'Phenotype', 'HP:0012114', (203, 221))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('endometrial cancer', 'Disease', 'MESH:D016889', (203, 221))	('tumor', 'Disease', (108, 113))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('differentially', 'Reg', (53, 67))
272967	24999802	Then we examined the biomedical relevance of the tumor subtypes revealed by pseudogene expression and assessed the potential clinical utility of pseudogene-expression subtypes in terms of predicting patient survival.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('patient', 'Species', '9606', (199, 206))	('tumor', 'Disease', (49, 54))	('pseudogene', 'Var', (76, 86))
272968	24999802	Taken together, our results indicate that expressed pseudogenes represent an exciting paradigm for investigating cancer-related molecular mechanisms and discovering effective prognostic biomarkers.	('cancer', 'Disease', (113, 119))	('pseudogenes', 'Var', (52, 63))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
272969	24999802	To comprehensively detect expressed pseudogenes and quantify their expression levels in human cancer, we developed a computational pipeline, as shown in Fig.	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('expression', 'MPA', (67, 77))	('human', 'Species', '9606', (88, 93))	('pseudogenes', 'Var', (36, 47))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
272974	24999802	For each cancer type, we observed generally weak correlations between the expression level of pseudogenes and their WT genes, which is consistent with the previous study (Supplementary Fig.	('expression', 'MPA', (74, 84))	('cancer', 'Disease', (9, 15))	('pseudogenes', 'Var', (94, 105))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('correlations', 'Interaction', (49, 61))	('cancer', 'Disease', 'MESH:D009369', (9, 15))
272976	24999802	(2012), we detected some tumor-lineage-specific pseudogenes (296 from the paired-end group and 41 from the single-end group, Supplementary Fig.	('tumor', 'Disease', (25, 30))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('pseudogenes', 'Var', (48, 59))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))
272977	24999802	In addition, for three cancer types with available RNA-seq data from nontumor tissue samples, we identified differentially expressed pseudogenes between tumor and nontumor samples (54 in BRCA, 110 in KIRC and 138 in LUSC, Supplementary Fig.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('tumor', 'Disease', (72, 77))	('BRCA', 'Gene', '672', (187, 191))	('tumor', 'Disease', (166, 171))	('cancer', 'Disease', (23, 29))	('tumor', 'Disease', (153, 158))	('cancer', 'Disease', 'MESH:D009369', (23, 29))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('BRCA', 'Gene', (187, 191))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('pseudogenes', 'Var', (133, 144))
272978	24999802	However, the tumor-lineage-specific or cancer-specific pseudogenes identified above may only reflect biological characteristics unique to distinct tissue types rather than key biological factors involved in tumorigenesis.	('tumor', 'Disease', (13, 18))	('cancer', 'Disease', (39, 45))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('pseudogenes', 'Var', (55, 66))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('tumor', 'Disease', (207, 212))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
272997	24999802	The pseudogene expression subtypes also correlate with the mutation status of key cancer genes: subtype 1 shows a depletion of GATA3 mutations; and subtype 2 has many samples of TP53 mutations.	('TP53', 'Gene', '7157', (178, 182))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('GATA3', 'Gene', '2625', (127, 132))	('mutations', 'Var', (183, 192))	('TP53', 'Gene', (178, 182))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('mutations', 'Var', (133, 142))	('GATA3', 'Gene', (127, 132))
273007	24999802	However, a crucial question remains unclear: does pseudogene expression, as a whole, represent a biologically meaningful dimension that can characterize tumor heterogeneity and provide clinical applications?	('tumor', 'Disease', (153, 158))	('pseudogene', 'Var', (50, 60))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))
273008	24999802	Here, we performed a pan-cancer analysis of pseudogene expression for what is, to our knowledge, the largest number of cancer patient samples (~3,000) in one such analysis.	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('patient', 'Species', '9606', (126, 133))	('cancer', 'Disease', (119, 125))	('cancer', 'Disease', 'MESH:D009369', (25, 31))	('cancer', 'Disease', (25, 31))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('pseudogene', 'Var', (44, 54))
273011	24999802	Because many tumor-lineage or cancer-specific pseudogenes could arise from tissue-related rather than tumorigenesis-related effects, they may or may not have the power to differentiate tumor subtypes.	('tumor', 'Disease', (185, 190))	('tumor', 'Disease', (13, 18))	('arise from', 'Reg', (64, 74))	('cancer', 'Disease', (30, 36))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('pseudogenes', 'Var', (46, 57))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
273012	24999802	Strikingly, our analysis reveals an unexpected prognostic power of pseudogene expression in kidney cancer: pseudogene-expression subtypes not only correlate with patient survival but also confer additional prognostic powers for a group of patients whose survival times cannot be well predicted based on conventional clinical variables.	('patient', 'Species', '9606', (239, 246))	('kidney cancer', 'Disease', (92, 105))	('patients', 'Species', '9606', (239, 247))	('prognostic', 'MPA', (206, 216))	('kidney cancer', 'Phenotype', 'HP:0009726', (92, 105))	('patient', 'Species', '9606', (162, 169))	('kidney cancer', 'Disease', 'MESH:D007680', (92, 105))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('pseudogene-expression', 'Var', (107, 128))
273013	24999802	This finding implies a novel prognostic strategy that incorporates both the risk scores defined by the clinical-variable model and the tumor subtypes revealed by pseudogene expression (subtype 1 and subtype 2): among medium-risk patients, patients of subtype 2 may benefit from earlier, more aggressive therapies.	('patients', 'Species', '9606', (229, 237))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('benefit', 'PosReg', (265, 272))	('patients', 'Species', '9606', (239, 247))	('tumor', 'Disease', (135, 140))	('subtype 2', 'Var', (251, 260))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
273018	24999802	Further efforts are required to elucidate how these pseudogenes functionally contribute to tumor initiation and development and how they are regulated through the complex gene regulatory network.	('contribute', 'Reg', (77, 87))	('development', 'CPA', (112, 123))	('pseudogenes', 'Var', (52, 63))	('tumor initiation', 'Disease', 'MESH:D009369', (91, 107))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor initiation', 'Disease', (91, 107))
273021	24999802	The pseudogenes with detectable expression were defined as those with an average RPKM >= 1 across all samples in each cancer type, as used in the literature.	('cancer', 'Disease', (118, 124))	('pseudogenes', 'Var', (4, 15))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('expression', 'MPA', (32, 42))	('cancer', 'Disease', 'MESH:D009369', (118, 124))
273022	24999802	To identify tumor-lineage-specific/cancer-specific pseudogenes, or those differentially expressed among established molecular or histological subtypes, we used analysis of variance (ANOVA) or student t-test to detect the statistical difference between two or more groups.	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('pseudogenes', 'Var', (51, 62))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('tumor', 'Disease', (12, 17))	('cancer', 'Disease', (35, 41))
273025	24999802	To perform an objective assessment, we obtained independently defined molecular subtypes by other genomic data from TCGA marker papers whenever possible; and if not, then from TCGA Pan-Cancer Analysis Working Group (through a similar NMF-based unsupervised analysis) (syn1688309 for microRNA expression, syn1701558 for DNA methylation, and syn1682511 for mRNA expression, copy number variation, and protein expression [Reverse phase protein array]).	('mRNA expression', 'MPA', (355, 370))	('microRNA expression', 'MPA', (283, 302))	('syn1701558', 'Var', (304, 314))	('Cancer', 'Phenotype', 'HP:0002664', (185, 191))	('Cancer', 'Disease', (185, 191))	('protein expression', 'MPA', (399, 417))	('Cancer', 'Disease', 'MESH:D009369', (185, 191))	('syn1688309', 'Var', (268, 278))	('syn1682511', 'Var', (340, 350))
273044	24874471	The average number of driver mutations per tumor sample was two to six, suggesting that a small number of mutated driver genes could induce carcinogenesis.	('carcinogenesis', 'Disease', 'MESH:D063646', (140, 154))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('carcinogenesis', 'Disease', (140, 154))	('mutated', 'Var', (106, 113))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Disease', (43, 48))	('induce', 'Reg', (133, 139))
273046	24874471	Further analysis revealed pathway-specific genetic driver mutations in breast cancer subtypes, such as BRCA1/2 alterations and PIK3CA alterations in basal-like and luminal breast cancers, respectively.	('mutations', 'Var', (58, 67))	('breast cancer', 'Phenotype', 'HP:0003002', (71, 84))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('breast cancer', 'Disease', 'MESH:D001943', (71, 84))	('breast cancer', 'Disease', (71, 84))	('breast cancers', 'Phenotype', 'HP:0003002', (172, 186))	('luminal breast cancers', 'Disease', 'MESH:D001943', (164, 186))	('PIK3CA', 'Gene', '5290', (127, 133))	('breast cancer', 'Phenotype', 'HP:0003002', (172, 185))	('BRCA1', 'Gene', '672', (103, 108))	('breast cancer', 'Disease', 'MESH:D001943', (172, 185))	('BRCA1', 'Gene', (103, 108))	('alterations', 'Var', (134, 145))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('basal-like', 'Disease', (149, 159))	('alterations', 'Var', (111, 122))	('PIK3CA', 'Gene', (127, 133))	('cancers', 'Phenotype', 'HP:0002664', (179, 186))	('luminal breast cancers', 'Disease', (164, 186))
273056	24874471	For example, single gene amplification of KIT on chromosome 4 can occur in testicular tumors, yet larger amplicons containing KIT, PDGFRA, and KDR are amplified in glioblastoma.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('single gene amplification', 'Var', (13, 38))	('PDGFRA', 'Gene', (131, 137))	('testicular tumors', 'Disease', 'MESH:D013736', (75, 92))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('glioblastoma', 'Disease', (164, 176))	('KDR', 'Gene', '3791', (143, 146))	('glioblastoma', 'Disease', 'MESH:D005909', (164, 176))	('PDGFRA', 'Gene', '5156', (131, 137))	('testicular tumors', 'Phenotype', 'HP:0010788', (75, 92))	('glioblastoma', 'Phenotype', 'HP:0012174', (164, 176))	('testicular tumors', 'Disease', (75, 92))	('KIT', 'Gene', (126, 129))	('KDR', 'Gene', (143, 146))
273079	24874471	For each cancer amplified gene, the cell lines used for validation studies and their corresponding gene copy numbers are as follows: (1) NSD3: H1581 (7 copies), H1703 (6 copies), SW48 (5 copies), SW837 (non-amplified); (2) DCUN1D1: KYSE (6 copies), T47D (4 copies), SW48 (non-amplified), HCT15 (non-amplified).	('cancer', 'Disease', (9, 15))	('H1703', 'CellLine', 'CVCL:1490', (161, 166))	('H1581', 'Var', (143, 148))	('SW837', 'Var', (196, 201))	('SW48', 'Var', (179, 183))	('H1703', 'Var', (161, 166))	('NSD3', 'Gene', (137, 141))	('HCT15', 'Gene', (288, 293))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('SW48', 'CellLine', 'CVCL:1724', (266, 270))	('HCT15', 'CellLine', 'CVCL:0292', (288, 293))	('H1581', 'CellLine', 'CVCL:1479', (143, 148))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('NSD3', 'Gene', '54904', (137, 141))	('SW48', 'CellLine', 'CVCL:1724', (179, 183))	('SW837', 'CellLine', 'CVCL:1729', (196, 201))
273130	24874471	Other genes with high level amplifications include PRKAB2 (6-10 copies in ovarian cancer), MDM4 (10-30 copies in glioblastoma), MDM2 (10-15 copies in lung adenocarcinoma), PIK3CA (5-20 copies in lung squamous cancer), DCUN1D1 (5-15 copies in lung squamous cancer), FADD and PPFIA1 (each with 5-10 copies in head and neck cancer), NDUFC2 (5-15 copies in ovarian cancer), and RAP1B (5-15 copies in lung adenocarcinoma).	('neck cancer', 'Disease', (316, 327))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (150, 169))	('carcinoma', 'Phenotype', 'HP:0030731', (160, 169))	('carcinoma', 'Phenotype', 'HP:0030731', (406, 415))	('head and neck cancer', 'Phenotype', 'HP:0012288', (307, 327))	('ovarian cancer', 'Disease', 'MESH:D010051', (353, 367))	('PIK3CA', 'Gene', (172, 178))	('cancer', 'Phenotype', 'HP:0002664', (321, 327))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (396, 415))	('10-15', 'Var', (134, 139))	('PPFIA1', 'Gene', (274, 280))	('cancer', 'Phenotype', 'HP:0002664', (256, 262))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (396, 415))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('DCUN1D1', 'Gene', (218, 225))	('glioblastoma', 'Disease', 'MESH:D005909', (113, 125))	('ovarian cancer', 'Disease', 'MESH:D010051', (74, 88))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))	('FADD', 'Gene', '8772', (265, 269))	('ovarian cancer', 'Disease', (353, 367))	('MDM2', 'Gene', (128, 132))	('glioblastoma', 'Disease', (113, 125))	('RAP1B', 'Gene', (374, 379))	('NDUFC2', 'Gene', '4718', (330, 336))	('MDM4', 'Gene', '4194', (91, 95))	('ovarian cancer', 'Phenotype', 'HP:0100615', (353, 367))	('PPFIA1', 'Gene', '8500', (274, 280))	('glioblastoma', 'Phenotype', 'HP:0012174', (113, 125))	('RAP1B', 'Gene', '5908', (374, 379))	('NDUFC2', 'Gene', (330, 336))	('lung squamous cancer', 'Disease', 'MESH:D008175', (242, 262))	('ovarian cancer', 'Disease', (74, 88))	('PIK3CA', 'Gene', '5290', (172, 178))	('lung adenocarcinoma', 'Disease', (150, 169))	('PRKAB2', 'Gene', '5565', (51, 57))	('squamous cancer', 'Phenotype', 'HP:0002860', (200, 215))	('lung squamous cancer', 'Disease', 'MESH:D008175', (195, 215))	('ovarian cancer', 'Phenotype', 'HP:0100615', (74, 88))	('10-30', 'Var', (97, 102))	('lung squamous cancer', 'Disease', (242, 262))	('lung adenocarcinoma', 'Disease', (396, 415))	('cancer', 'Phenotype', 'HP:0002664', (361, 367))	('PRKAB2', 'Gene', (51, 57))	('squamous cancer', 'Phenotype', 'HP:0002860', (247, 262))	('FADD', 'Gene', (265, 269))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (150, 169))	('lung squamous cancer', 'Disease', (195, 215))	('neck cancer', 'Disease', 'MESH:D006258', (316, 327))	('MDM4', 'Gene', (91, 95))
273134	24874471	In addition to copy number ranges, the frequency of gene amplification in patient tumors was calculated by using copy number 4 as a cutoff for amplification (Fig.	('patient', 'Species', '9606', (74, 81))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('tumors', 'Disease', (82, 88))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('copy number', 'Var', (113, 124))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))
273150	24874471	A single amino acid substitution in KRAS results in activating mutation and dependence of the cancer cells on the MAP kinase pathway.	('dependence', 'Reg', (76, 86))	('KRAS', 'Gene', (36, 40))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('MAP kinase pathway', 'Pathway', (114, 132))	('KRAS', 'Gene', '3845', (36, 40))	('single amino acid substitution', 'Var', (2, 32))	('cancer', 'Disease', (94, 100))	('results in', 'Reg', (41, 51))	('activating mutation', 'MPA', (52, 71))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
273151	24874471	Although mutation of KRAS is frequently used for cancer diagnosis and clinical management, KRAS amplification is typically not tested in patients.	('mutation', 'Var', (9, 17))	('KRAS', 'Gene', '3845', (21, 25))	('KRAS', 'Gene', '3845', (91, 95))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('patients', 'Species', '9606', (137, 145))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('KRAS', 'Gene', (21, 25))	('KRAS', 'Gene', (91, 95))	('cancer', 'Disease', (49, 55))
273153	24874471	KRAS mutations and amplifications are largely mutually exclusive in uterine, gastric, and lung cancers (Figure 5C).	('lung cancers', 'Disease', 'MESH:D008175', (90, 102))	('lung cancers', 'Phenotype', 'HP:0100526', (90, 102))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('cancers', 'Phenotype', 'HP:0002664', (95, 102))	('mutations', 'Var', (5, 14))	('lung cancers', 'Disease', (90, 102))	('uterine', 'Disease', (68, 75))	('lung cancer', 'Phenotype', 'HP:0100526', (90, 101))	('gastric', 'Disease', (77, 84))	('KRAS', 'Gene', (0, 4))	('KRAS', 'Gene', '3845', (0, 4))
273156	24874471	KRAS copy number was negatively correlated with shRNA score, suggesting that cancer cell lines with KRAS amplification are most sensitive to Kras shRNA-mediated cell death (Figure 5A, 5F).	('KRAS', 'Gene', (100, 104))	('Kras', 'Gene', '3845', (141, 145))	('KRAS', 'Gene', '3845', (100, 104))	('amplification', 'Var', (105, 118))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('sensitive', 'Reg', (128, 137))	('KRAS', 'Gene', (0, 4))	('Kras', 'Gene', (141, 145))	('KRAS', 'Gene', '3845', (0, 4))
273158	24874471	KRAS copy number was also positively correlated to KRAS protein levels in a panel of cancer cell lines (Figure 5D).	('KRAS', 'Gene', '3845', (51, 55))	('copy number', 'Var', (5, 16))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('correlated', 'Reg', (37, 47))	('cancer', 'Disease', (85, 91))	('KRAS', 'Gene', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('KRAS', 'Gene', (51, 55))	('KRAS', 'Gene', '3845', (0, 4))
273159	24874471	These data suggest that amplification of wild-type KRAS may be an independent cancer driver in several disease subtypes.	('KRAS', 'Gene', '3845', (51, 55))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('amplification', 'Var', (24, 37))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('KRAS', 'Gene', (51, 55))
273165	24874471	Since GRB7 is a molecular adaptor for EGFR receptor tyrosine kinases, including ERBB2, the amplification of GRB7 may have a functional consequence in Her-2 driven cancers.	('EGFR', 'Gene', '1956', (38, 42))	('GRB7', 'Gene', '2886', (6, 10))	('cancers', 'Phenotype', 'HP:0002664', (163, 170))	('cancers', 'Disease', (163, 170))	('GRB7', 'Gene', (6, 10))	('GRB7', 'Gene', '2886', (108, 112))	('GRB7', 'Gene', (108, 112))	('EGFR', 'Gene', (38, 42))	('cancers', 'Disease', 'MESH:D009369', (163, 170))	('amplification', 'Var', (91, 104))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('Her-2', 'Gene', '2064', (150, 155))	('ERBB2', 'Gene', '2064', (80, 85))	('Her-2', 'Gene', (150, 155))	('ERBB2', 'Gene', (80, 85))
273166	24874471	In Project Achilles, both the GRB7 and ERBB2 composite Achilles scores showed a statistically signification association with GRB7 amplification (p = 0.001 and 0.0009, respectively, data not shown), indicating that GRB7 may be necessary for cancer cells harboring this amplicon, as previously suggested.	('ERBB2', 'Gene', '2064', (39, 44))	('GRB7', 'Gene', '2886', (125, 129))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('GRB7', 'Gene', (125, 129))	('amplification', 'Var', (130, 143))	('GRB7', 'Gene', '2886', (214, 218))	('cancer', 'Disease', 'MESH:D009369', (240, 246))	('GRB7', 'Gene', (214, 218))	('GRB7', 'Gene', '2886', (30, 34))	('cancer', 'Disease', (240, 246))	('GRB7', 'Gene', (30, 34))	('ERBB2', 'Gene', (39, 44))
273167	24874471	Recent reports suggest that ERBB2/GRB7 co-amplification may be a necessary step for cancer progression in specific cancer types, such as Barrett's carcinoma.	("Barrett's carcinoma", 'Disease', (137, 156))	('cancer', 'Disease', (115, 121))	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('GRB7', 'Gene', (34, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (147, 156))	("Barrett's carcinoma", 'Disease', 'MESH:D001471', (137, 156))	('cancer', 'Disease', (84, 90))	('co-amplification', 'Var', (39, 55))	('ERBB2', 'Gene', '2064', (28, 33))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('ERBB2', 'Gene', (28, 33))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('GRB7', 'Gene', '2886', (34, 38))	('cancer', 'Disease', 'MESH:D009369', (115, 121))
273168	24874471	Further, GRB7 amplification may be a drug resistance mechanism during anti-Her-2 therapy, such as lapatinib treatment in breast cancers.	('cancers', 'Phenotype', 'HP:0002664', (128, 135))	('breast cancers', 'Phenotype', 'HP:0003002', (121, 135))	('Her-2', 'Gene', '2064', (75, 80))	('GRB7', 'Gene', '2886', (9, 13))	('GRB7', 'Gene', (9, 13))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('breast cancers', 'Disease', 'MESH:D001943', (121, 135))	('lapatinib', 'Chemical', 'MESH:D000077341', (98, 107))	('Her-2', 'Gene', (75, 80))	('breast cancers', 'Disease', (121, 135))	('breast cancer', 'Phenotype', 'HP:0003002', (121, 134))	('drug resistance', 'Phenotype', 'HP:0020174', (37, 52))	('amplification', 'Var', (14, 27))
273172	24874471	DCUN1D1 amplification in squamous cancers is associated with poor outcome and its knockdown in cells by shRNA leads to apoptosis.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('squamous cancers', 'Disease', (25, 41))	('amplification', 'Var', (8, 21))	('leads to', 'Reg', (110, 118))	('knockdown', 'Var', (82, 91))	('apoptosis', 'CPA', (119, 128))	('squamous cancers', 'Disease', 'MESH:D002294', (25, 41))	('DCUN1D1', 'Gene', (0, 7))	('squamous cancer', 'Phenotype', 'HP:0002860', (25, 40))	('cancers', 'Phenotype', 'HP:0002664', (34, 41))
273174	24874471	We further validated DCUN1D1 oncogenic activity through shRNA knockdown in the DCUN1D1-amplified cell lines KYSE and T47D and the wild-type cell lines HCT15 and SW48.	('SW48', 'CellLine', 'CVCL:1724', (161, 165))	('DCUN1D1-amplified', 'Gene', (79, 96))	('shRNA', 'Gene', (56, 61))	('oncogenic activity', 'MPA', (29, 47))	('DCUN1D1', 'Gene', (21, 28))	('HCT15', 'CellLine', 'CVCL:0292', (151, 156))	('knockdown', 'Var', (62, 71))
273186	24874471	Invasive breast cancers were divided into two largely mutually exclusive groups with amplifications in NSD3 (15%) and SETDB1 (15%).	('amplifications', 'Var', (85, 99))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('SETDB1', 'Gene', '9869', (118, 124))	('NSD3', 'Gene', '54904', (103, 107))	('breast cancers', 'Phenotype', 'HP:0003002', (9, 23))	('SETDB1', 'Gene', (118, 124))	('breast cancers', 'Disease', 'MESH:D001943', (9, 23))	('NSD3', 'Gene', (103, 107))	('breast cancers', 'Disease', (9, 23))	('breast cancer', 'Phenotype', 'HP:0003002', (9, 22))	('cancers', 'Phenotype', 'HP:0002664', (16, 23))
273187	24874471	These data suggest that distinct epigenetic regulators may control specific cancer disease subtypes.	('epigenetic', 'Var', (33, 43))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('cancer disease', 'Disease', (76, 90))	('control', 'Reg', (59, 66))	('cancer disease', 'Disease', 'MESH:D009369', (76, 90))
273189	24874471	We identified cancer cell lines with NSD3 amplification for further experimental validation, including the non small-cell lung cancer (NSCLC) cell lines H1581 (7 copies Nsd3) and H-1703 (6 copies Nsd3), as well as the colorectal cancer cell line SW837 (5 copies Nsd3).	('colorectal cancer', 'Disease', (218, 235))	('H1581', 'CellLine', 'CVCL:1479', (153, 158))	('H-1703', 'CellLine', 'CVCL:1490', (179, 185))	('Nsd3', 'Gene', '54904', (196, 200))	('cancer', 'Disease', 'MESH:D009369', (229, 235))	('NSCLC', 'Disease', (135, 140))	('Nsd3', 'Gene', (169, 173))	('NSD3', 'Gene', '54904', (37, 41))	('lung cancer', 'Disease', 'MESH:D008175', (122, 133))	('cancer', 'Disease', 'MESH:D009369', (14, 20))	('Nsd3', 'Gene', (262, 266))	('lung cancer', 'Phenotype', 'HP:0100526', (122, 133))	('cancer', 'Disease', (127, 133))	('amplification', 'Var', (42, 55))	('Nsd3', 'Gene', (196, 200))	('colorectal cancer', 'Phenotype', 'HP:0003003', (218, 235))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('cancer', 'Disease', (229, 235))	('Nsd3', 'Gene', '54904', (169, 173))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('cancer', 'Disease', (14, 20))	('lung cancer', 'Disease', (122, 133))	('NSD3', 'Gene', (37, 41))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('Nsd3', 'Gene', '54904', (262, 266))	('colorectal cancer', 'Disease', 'MESH:D015179', (218, 235))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('SW837', 'CellLine', 'CVCL:1729', (246, 251))	('NSCLC', 'Disease', 'MESH:D002289', (135, 140))
273191	24874471	NSD3 protein was detected by western blot in the four cancer cell lines, and the relative NSD3 protein levels positively correlated with NSD3 copy number (Figure 7D), suggesting that NSD3 amplification leads to higher NSD3 protein levels.	('NSD3', 'Gene', '54904', (0, 4))	('NSD3', 'Gene', (90, 94))	('NSD3', 'Gene', (218, 222))	('higher', 'PosReg', (211, 217))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('NSD3', 'Gene', '54904', (183, 187))	('amplification', 'Var', (188, 201))	('NSD3', 'Gene', (137, 141))	('cancer', 'Disease', (54, 60))	('NSD3', 'Gene', '54904', (90, 94))	('NSD3', 'Gene', (0, 4))	('NSD3', 'Gene', '54904', (218, 222))	('NSD3', 'Gene', (183, 187))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('NSD3', 'Gene', '54904', (137, 141))	('copy number', 'Var', (142, 153))
273193	24874471	Using the Cell Titer Glo cell proliferation assay, we found that NSD3 siRNA knockdown led to reduced cancer cell proliferation in all four cell lines, and the relative inhibition of proliferation correlated with NSD3 copy number (e.g., 80% inhibition in H1581 cells versus 40% inhibition in SW48 cells) (Figure 7E).	('inhibition', 'NegReg', (240, 250))	('proliferation', 'CPA', (182, 195))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('NSD3', 'Gene', '54904', (212, 216))	('knockdown', 'Var', (76, 85))	('cancer', 'Disease', (101, 107))	('NSD3', 'Gene', '54904', (65, 69))	('reduced', 'NegReg', (93, 100))	('NSD3', 'Gene', (212, 216))	('SW48', 'CellLine', 'CVCL:1724', (291, 295))	('copy number', 'Var', (217, 228))	('inhibition', 'NegReg', (168, 178))	('NSD3', 'Gene', (65, 69))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('H1581', 'CellLine', 'CVCL:1479', (254, 259))
273194	24874471	To determine if the effects of NSD3 knockdown were due to changes in proliferation or cell survival, we measured the levels of apoptosis in cancer cells after NSD3 siRNA transfection using the Caspase Glo assay.	('NSD3', 'Gene', (159, 163))	('NSD3', 'Gene', '54904', (31, 35))	('cancer', 'Disease', (140, 146))	('changes', 'Reg', (58, 65))	('NSD3', 'Gene', '54904', (159, 163))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('NSD3', 'Gene', (31, 35))	('transfection', 'Var', (170, 182))
273195	24874471	Interestingly, all four cancer cell lines exhibited apoptosis starting 24 hours after NSD3 siRNA transfection, and the relative apoptosis levels increased steadily after 48 and 72 hours post-transfection (Figure 7F).	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('exhibited', 'Reg', (42, 51))	('NSD3', 'Gene', '54904', (86, 90))	('cancer', 'Disease', (24, 30))	('cancer', 'Disease', 'MESH:D009369', (24, 30))	('transfection', 'Var', (97, 109))	('NSD3', 'Gene', (86, 90))
273196	24874471	This suggested that loss of NSD3 lead to apoptosis of cancer cells, suggesting that NSD3 may be a bona fide cancer driver gene.	('loss', 'Var', (20, 24))	('NSD3', 'Gene', (84, 88))	('NSD3', 'Gene', '54904', (28, 32))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('cancer', 'Disease', (54, 60))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('apoptosis', 'CPA', (41, 50))	('NSD3', 'Gene', '54904', (84, 88))	('NSD3', 'Gene', (28, 32))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
273197	24874471	A recent report also found that NSD3 knockdown led to reduced cell proliferation and increased apoptosis, which was attributed to G2/M cell cycle arrest.	('NSD3', 'Gene', (32, 36))	('apoptosis', 'CPA', (95, 104))	('knockdown', 'Var', (37, 46))	('cell proliferation', 'CPA', (62, 80))	('NSD3', 'Gene', '54904', (32, 36))	('reduced', 'NegReg', (54, 61))	('increased', 'PosReg', (85, 94))
273199	24874471	We measured the relative fraction of cancer cells in G1, S and G2 phases following NSD3 siRNA transfection.	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('NSD3', 'Gene', '54904', (83, 87))	('cancer', 'Disease', (37, 43))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('NSD3', 'Gene', (83, 87))	('transfection', 'Var', (94, 106))
273201	24874471	In fact, there were fewer cells in G2 phase and more cells in G1 phase after NSD3 knockdown (Figure 7H).	('NSD3', 'Gene', (77, 81))	('knockdown', 'Var', (82, 91))	('more', 'PosReg', (48, 52))	('G1 phase', 'CPA', (62, 70))	('NSD3', 'Gene', '54904', (77, 81))	('fewer', 'NegReg', (20, 25))	('G2 phase', 'CPA', (35, 43))
273208	24874471	Further, the Notch pathway is an important driver in oncogenesis, as activating mutations in Notch pathway components, such as NOTCH1 and NOTCH2, can drive specific cancer types.	('drive', 'Reg', (150, 155))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('NOTCH2', 'Gene', (138, 144))	('cancer', 'Disease', (165, 171))	('NOTCH1', 'Gene', (127, 133))	('NOTCH1', 'Gene', '4851', (127, 133))	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('NOTCH2', 'Gene', '4853', (138, 144))	('activating mutations', 'Var', (69, 89))
273214	24874471	Analysis of TCGA datasets was used to identify cancer subtypes containing gene amplifications of interest.	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('gene amplifications', 'Var', (74, 93))	('cancer', 'Disease', (47, 53))
273216	24874471	Additional experiments with candidate lead compounds and siRNA/shRNA knockdown reagents can be used to further validate the cancer driver activity of a gene amplification in a specific disease context.	('cancer', 'Disease', (124, 130))	('amplification', 'Var', (157, 170))	('cancer', 'Disease', 'MESH:D009369', (124, 130))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))
273222	24874471	Disruptions in complex I have been linked to cancer initiation/progression due to alterations in the NAD-/NADH ratio.	('complex I', 'Protein', (15, 24))	('NADH', 'Chemical', 'MESH:D009243', (106, 110))	('Disruptions', 'Var', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('linked', 'Reg', (35, 41))	('cancer initiation', 'Disease', 'MESH:D009369', (45, 62))	('NAD', 'Chemical', 'MESH:D009243', (101, 104))	('alterations', 'Reg', (82, 93))	('NAD-/NADH ratio', 'MPA', (101, 116))	('NAD', 'Chemical', 'MESH:D009243', (106, 109))	('cancer initiation', 'Disease', (45, 62))
273223	24874471	Mitochondrial complex I inhibitors can induce cell death and autophagy, possibly mediated through reactive oxygen species.	('cell death', 'CPA', (46, 56))	('Mitochondrial complex I', 'Enzyme', (0, 23))	('inhibitors', 'Var', (24, 34))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (98, 121))	('autophagy', 'CPA', (61, 70))	('induce', 'PosReg', (39, 45))
273231	24874471	These modifications can lead to abnormal alterations in gene transcription, replication or repair, which can lead to the induction and maintenance of many cancers.	('modifications', 'Var', (6, 19))	('lead to', 'Reg', (109, 116))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('gene transcription', 'MPA', (56, 74))	('lead', 'Reg', (24, 28))	('repair', 'MPA', (91, 97))	('replication', 'CPA', (76, 87))	('cancers', 'Phenotype', 'HP:0002664', (155, 162))	('cancers', 'Disease', 'MESH:D009369', (155, 162))	('cancers', 'Disease', (155, 162))	('alterations', 'Reg', (41, 52))
273232	24874471	A large number of DNA/chromatin modifying enzymes directly conjugate these modifications to target DNA/histones, including SETDB1 (a H3K9 methyltransferase), NSD3 (a H3K4/H3K27 methyltransferase) and YEATS4 (histone acetyltransferase).	('SETDB1', 'Gene', (123, 129))	('YEATS4', 'Gene', '8089', (200, 206))	('YEATS4', 'Gene', (200, 206))	('NSD3', 'Gene', (158, 162))	('SETDB1', 'Gene', '9869', (123, 129))	('modifications', 'Var', (75, 88))	('NSD3', 'Gene', '54904', (158, 162))
273234	24874471	Together these epigenetic regulatory genes play important roles in cancer initiation/progression, with a number of cancers being driven by mutations in the gene families.	('cancers', 'Disease', 'MESH:D009369', (115, 122))	('cancers', 'Phenotype', 'HP:0002664', (115, 122))	('cancer initiation', 'Disease', 'MESH:D009369', (67, 84))	('mutations', 'Var', (139, 148))	('cancers', 'Disease', (115, 122))	('cancer initiation', 'Disease', (67, 84))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('driven by', 'Reg', (129, 138))
273239	24874471	While the amplifications of SETDB1 and BRD4 have been previously identified and their roles in cancer have been well-studied, less is known about the functions of YEATS4 and NSD3 in cancer.	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('NSD3', 'Gene', '54904', (174, 178))	('YEATS4', 'Gene', '8089', (163, 169))	('BRD4', 'Gene', (39, 43))	('SETDB1', 'Gene', (28, 34))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('YEATS4', 'Gene', (163, 169))	('cancer', 'Disease', (95, 101))	('NSD3', 'Gene', (174, 178))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('amplifications', 'Var', (10, 24))	('cancer', 'Disease', (182, 188))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('BRD4', 'Gene', '23476', (39, 43))	('SETDB1', 'Gene', '9869', (28, 34))
273241	24874471	NSD1 has been linked to several cancers, including multiple myeloma and lung cancer, and translocations involving NSD1 and NUP98 have been identified in childhood acute myeloid leukemia.	('NSD1', 'Gene', '64324', (114, 118))	('NUP98', 'Gene', (123, 128))	('NSD1', 'Gene', '64324', (0, 4))	('translocations', 'Var', (89, 103))	('cancers', 'Phenotype', 'HP:0002664', (32, 39))	('multiple myeloma', 'Phenotype', 'HP:0006775', (51, 67))	('cancers', 'Disease', (32, 39))	('lung cancer', 'Phenotype', 'HP:0100526', (72, 83))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('acute myeloid leukemia', 'Disease', (163, 185))	('multiple myeloma', 'Disease', 'MESH:D009101', (51, 67))	('NSD1', 'Gene', (114, 118))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (169, 185))	('myeloma and lung cancer', 'Disease', 'MESH:D008175', (60, 83))	('NSD1', 'Gene', (0, 4))	('cancers', 'Disease', 'MESH:D009369', (32, 39))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (163, 185))	('multiple myeloma', 'Disease', (51, 67))	('linked', 'Reg', (14, 20))	('NUP98', 'Gene', '4928', (123, 128))	('identified', 'Reg', (139, 149))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (163, 185))	('leukemia', 'Phenotype', 'HP:0001909', (177, 185))
273244	24874471	NSD2 also has been linked to several cancers, such as prostate cancer and multiple myeloma, and it is also the target of translocations in multiple myeloma.	('NSD2', 'Gene', '7468', (0, 4))	('translocations', 'Var', (121, 135))	('prostate cancer', 'Disease', (54, 69))	('cancers', 'Phenotype', 'HP:0002664', (37, 44))	('NSD2', 'Gene', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('cancers', 'Disease', (37, 44))	('multiple myeloma', 'Phenotype', 'HP:0006775', (139, 155))	('multiple myeloma', 'Disease', 'MESH:D009101', (139, 155))	('cancers', 'Disease', 'MESH:D009369', (37, 44))	('multiple myeloma', 'Phenotype', 'HP:0006775', (74, 90))	('multiple myeloma', 'Disease', (139, 155))	('prostate cancer', 'Disease', 'MESH:D011471', (54, 69))	('multiple myeloma', 'Disease', 'MESH:D009101', (74, 90))	('linked', 'Reg', (19, 25))	('multiple myeloma', 'Disease', (74, 90))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('prostate cancer', 'Phenotype', 'HP:0012125', (54, 69))
273248	24874471	NSD3 knockdown by siRNA led to reduced cell proliferation and increased apoptosis in NSD3- amplified cell lines.	('increased', 'PosReg', (62, 71))	('NSD3', 'Gene', '54904', (0, 4))	('reduced', 'NegReg', (31, 38))	('knockdown', 'Var', (5, 14))	('NSD3', 'Gene', (85, 89))	('NSD3', 'Gene', (0, 4))	('apoptosis', 'CPA', (72, 81))	('cell proliferation', 'CPA', (39, 57))	('NSD3', 'Gene', '54904', (85, 89))
273251	24874471	Post-translational modifications of proteins by ubiquitin and ubiquitin-like proteins have emerged as important regulators of cancer cell signaling, survival, and homeostasis.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('Post-translational modifications', 'Var', (0, 32))	('ubiquitin', 'Protein', (48, 57))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('proteins', 'Protein', (36, 44))
273255	24874471	The ubiquitin ligases CBL and SKP2 were identified as candidate oncogenes, while the ubiquitin ligase FBXW7 is a bona fide tumor suppressor that is mutated frequently in breast and colorectal cancers.	('FBXW7', 'Gene', '55294', (102, 107))	('colorectal cancer', 'Phenotype', 'HP:0003003', (181, 198))	('tumor', 'Disease', (123, 128))	('SKP2', 'Gene', '6502', (30, 34))	('mutated', 'Var', (148, 155))	('FBXW7', 'Gene', (102, 107))	('cancers', 'Phenotype', 'HP:0002664', (192, 199))	('breast and colorectal cancers', 'Disease', 'MESH:D015179', (170, 199))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('SKP2', 'Gene', (30, 34))	('CBL', 'Gene', (22, 25))	('CBL', 'Gene', '867', (22, 25))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))
273263	24874471	A number of transcriptional cofactors and chromatin remodeling factors are targets of the small ubiquitin-like modifier (SUMO), and as a result a number of oncogenes and tumor suppressors are regulated by SUMOylation.	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('SUMOylation', 'Var', (205, 216))	('tumor', 'Disease', (170, 175))	('regulated', 'Reg', (192, 201))	('oncogenes', 'Gene', (156, 165))
273268	24874471	We found that DCUN1D1-amplified cancer cell lines exhibited decreased cell proliferation/survival in response to DCUN1D1 knockdown, consistent with earlier reports that DCUN1D1 knockdown leads to apoptosis in cells.	('knockdown', 'Var', (121, 130))	('decreased', 'NegReg', (60, 69))	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('DCUN1D1', 'Gene', (113, 120))	('cancer', 'Disease', (32, 38))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('cell proliferation/survival', 'CPA', (70, 97))
273277	24874471	Recent studies suggest that KRAS gene amplification predicts resistance to anti-EGFR therapy and anti-Met therapy, suggesting that KRAS amplification may be a resistance mechanism to MAP kinase inhibitors.	('predicts', 'Reg', (52, 60))	('KRAS', 'Gene', (28, 32))	('KRAS', 'Gene', '3845', (28, 32))	('KRAS', 'Gene', (131, 135))	('resistance', 'MPA', (61, 71))	('EGFR', 'Gene', '1956', (80, 84))	('EGFR', 'Gene', (80, 84))	('KRAS', 'Gene', '3845', (131, 135))	('amplification', 'Var', (38, 51))
273279	24874471	Further work will be necessary to define the role of KRAS amplification in cancer metastases and in drug resistant tumors, especially in tumors that have acquired resistance to receptor tyrosine kinase inhibitors.	('cancer metastases', 'Disease', (75, 92))	('tumors', 'Disease', (137, 143))	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumors', 'Disease', (115, 121))	('tumors', 'Disease', 'MESH:D009369', (115, 121))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('cancer metastases', 'Disease', 'MESH:D009362', (75, 92))	('KRAS', 'Gene', (53, 57))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('KRAS', 'Gene', '3845', (53, 57))	('amplification', 'Var', (58, 71))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
273284	24874471	The analysis was based on patient tumor-derived gene copy number and mRNA expression, siRNA/shRNA gene knockdown and association with clinical parameters.	('patient', 'Species', '9606', (26, 33))	('siRNA/shRNA', 'Gene', (86, 97))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('tumor', 'Disease', (34, 39))	('mRNA expression', 'MPA', (69, 84))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('knockdown', 'Var', (103, 112))
273324	33540736	Similarly, intestinal metaplasia within the stomach can lead to the development of intestinal-type gastric adenocarcinoma over time.	('intestinal-type gastric adenocarcinoma', 'Disease', (83, 121))	('men', 'Species', '9606', (75, 78))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('intestinal-type gastric adenocarcinoma', 'Disease', 'MESH:D013274', (83, 121))	('intestinal metaplasia', 'Var', (11, 32))	('lead to', 'Reg', (56, 63))
273328	33540736	Non-invasive approaches to screening for premalignant lesions of the esophagus include devices such as the "EsophaCap" and cytosponge -TFF3 that detect genetic and epigenetic alterations on samples gathered non-invasively and can be used by primary care physicians to screen for Barrett's esophagus.	('TFF3', 'Gene', '7033', (135, 139))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (279, 298))	('epigenetic alterations', 'Var', (164, 186))	("Barrett's esophagus", 'Disease', (279, 298))	('genetic', 'Var', (152, 159))	('TFF3', 'Gene', (135, 139))
273364	33540736	In terms of N staging, EUS has acceptable accuracy, with a pooled sensitivity for diagnosing esophageal cancer of 85% and EUS fine needle aspiration (FNA) increasing the sensitivity for diagnosing esophageal cancer to 97% (95% CI: 0.92-0.99).	('cancer', 'Disease', (208, 214))	('aspiration', 'Phenotype', 'HP:0002835', (138, 148))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('fine needle', 'Var', (126, 137))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (208, 214))
273367	33540736	Barrett's esophagus with low- or high-grade dysplasia (HGD) without visible lesions can be treated with radio-frequency ablation (RFA) or cryoablation therapies.	('low-', 'Var', (25, 29))	('dysplasia', 'Disease', 'MESH:C536170', (44, 53))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (0, 19))	("Barrett's esophagus", 'Disease', (0, 19))	('dysplasia', 'Disease', (44, 53))
273393	33540736	This approach is important as cardiac dose is increasingly seen as an independent risk factor for reduced survival and has been correlated with excess G3+ cardiac toxicity.	('cardiac toxicity', 'Disease', 'MESH:D066126', (155, 171))	('cardiac toxicity', 'Disease', (155, 171))	('reduced', 'NegReg', (98, 105))	('survival', 'MPA', (106, 114))	('G3+', 'Chemical', '-', (151, 154))	('cardiac', 'Var', (30, 37))
273402	33540736	Early studies on patients who received 4000 cGy followed by surgery 1-4 weeks after found no difference in resectability or survival compared to surgery alone.	('resectability', 'CPA', (107, 120))	('4000 cGy', 'Var', (39, 47))	('patients', 'Species', '9606', (17, 25))
273433	33540736	With a goal of improving on the near 50% local failure rate seen in previous studies as well as overcoming high rates of persistent disease, dose escalation in the modern era appears to be more tolerable but still carries an elevated risk of toxicity as well as minimal evidence of clinical benefit.	('dose', 'Var', (141, 145))	('toxicity', 'Disease', 'MESH:D064420', (242, 250))	('toxicity', 'Disease', (242, 250))
273454	33540736	It demonstrated that pembrolizumab plus chemotherapy improved overall survival in patients with squamous cell carcinoma of the esophagus with PD-L1 CPS >=10 tumors, all squamous cell carcinomas, all patients with CPS >=10, and the study population as a whole.	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (169, 192))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('PD-L1', 'Gene', (142, 147))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (96, 119))	('tumors', 'Phenotype', 'HP:0002664', (157, 163))	('PD-L1', 'Gene', '29126', (142, 147))	('CPS', 'Chemical', '-', (148, 151))	('carcinoma', 'Phenotype', 'HP:0030731', (183, 192))	('carcinomas', 'Phenotype', 'HP:0030731', (183, 193))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (169, 193))	('overall survival', 'MPA', (62, 78))	('squamous cell carcinoma', 'Disease', (96, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('patients', 'Species', '9606', (82, 90))	('tumors', 'Disease', (157, 163))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (169, 193))	('CPS >=10', 'Var', (148, 156))	('improved', 'PosReg', (53, 61))	('carcinoma of the esophagus', 'Phenotype', 'HP:0011459', (110, 136))	('pembrolizumab', 'Chemical', 'MESH:C582435', (21, 34))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (169, 192))	('tumors', 'Disease', 'MESH:D009369', (157, 163))	('squamous cell carcinomas', 'Disease', (169, 193))	('patients', 'Species', '9606', (199, 207))	('CPS', 'Chemical', '-', (213, 216))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (96, 119))
273484	33540736	Rarely, genetic mutations such as CDH-1 contribute to familial predisposition to gastric adenocarcinoma.	('CDH-1', 'Gene', (34, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('gastric adenocarcinoma', 'Disease', 'MESH:D013274', (81, 103))	('gastric adenocarcinoma', 'Disease', (81, 103))	('genetic mutations', 'Var', (8, 25))	('CDH-1', 'Gene', '999', (34, 39))
273509	33540736	These tumors may express mutations in tyrosine kinase (TK), KIT receptor, or platelet-derived growth factor (PDGF).	('PDGF', 'Gene', '5156', (109, 113))	('mutations', 'Var', (25, 34))	('express', 'Reg', (17, 24))	('KIT', 'Gene', '3815', (60, 63))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('tumors', 'Disease', (6, 12))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('KIT', 'Gene', (60, 63))	('tyrosine kinase', 'Gene', (38, 53))	('PDGF', 'Gene', (109, 113))	('tyrosine kinase', 'Gene', '7294', (38, 53))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('TK', 'Gene', '7294', (55, 57))
273514	33540736	Laparoscopic or minimally invasive resections have been associated with less blood loss, lower rates of complications, and shorter hospital stays without compromise of oncologic principles.	('Laparoscopic', 'Disease', (0, 12))	('minimally invasive', 'Var', (16, 34))	('blood loss', 'Disease', 'MESH:D006473', (77, 87))	('blood loss', 'Disease', (77, 87))	('less', 'NegReg', (72, 76))
273521	33540736	Imatinib is the treatment of choice in this setting; however, tumors that have a platelet-derived growth factor receptor-alpha (PDGFRA) D842V mutation, or a succinate dehydrogenase (SDH)-deficient or neurofibromatosis (NF)-related GIST, are considered resistant to imatinib and will not benefit from neoadjuvant treatment; in these cases, upfront surgery is recommended.	('D842V', 'Var', (136, 141))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('neurofibromatosis', 'Disease', 'MESH:C537392', (200, 217))	('SDH', 'Gene', '6390', (182, 185))	('neurofibromatosis', 'Disease', (200, 217))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('succinate dehydrogenase', 'Gene', '6390', (157, 180))	('Imatinib', 'Chemical', 'MESH:D000068877', (0, 8))	('tumors', 'Disease', (62, 68))	('NF', 'Phenotype', 'HP:0001067', (219, 221))	('platelet-derived growth factor receptor-alpha', 'Gene', '5156', (81, 126))	('imatinib', 'Chemical', 'MESH:D000068877', (265, 273))	('SDH', 'Gene', (182, 185))	('men', 'Species', '9606', (317, 320))	('tumors', 'Disease', 'MESH:D009369', (62, 68))	('platelet-derived growth factor receptor-alpha', 'Gene', (81, 126))	('men', 'Species', '9606', (363, 366))	('men', 'Species', '9606', (21, 24))	('succinate dehydrogenase', 'Gene', (157, 180))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (200, 217))	('PDGFRA', 'Gene', '5156', (128, 134))	('PDGFRA', 'Gene', (128, 134))	('D842V', 'Mutation', 'rs121908585', (136, 141))
273522	33540736	Tumors that harbor an exon 9 KIT mutation should be treated with an initial dose of 800 mg per day.	('mutation', 'Var', (33, 41))	('KIT', 'Gene', '3815', (29, 32))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('KIT', 'Gene', (29, 32))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))
273546	33540736	H. pylori is noted as a causative factor for MALT lymphoma and eradication of H. pylori can result in remission in 50-90% of cases.	('H. pylori', 'Species', '210', (78, 87))	('MALT lymphoma', 'Disease', 'MESH:D018442', (45, 58))	('lymphoma', 'Phenotype', 'HP:0002665', (50, 58))	('H. pylori', 'Species', '210', (0, 9))	('H. pylori', 'Disease', (0, 9))	('eradication', 'Var', (63, 74))	('MALT lymphoma', 'Disease', (45, 58))	('H. pylori', 'Gene', (78, 87))
273547	33540736	Therefore, eradication of H. pylori is regarded as a first-line treatment for gastric MALT lymphoma, with remission favorably associated with early lesions, lesions limited to the mucosa, and absence of the API2MALT1 mutation.	('H. pylori', 'Species', '210', (26, 35))	('men', 'Species', '9606', (69, 72))	('gastric MALT lymphoma', 'Disease', (78, 99))	('lymphoma', 'Phenotype', 'HP:0002665', (91, 99))	('absence', 'NegReg', (192, 199))	('gastric MALT lymphoma', 'Disease', 'MESH:C535648', (78, 99))	('gastric MALT lymphoma', 'Phenotype', 'HP:0045038', (78, 99))	('mutation', 'Var', (217, 225))	('API2MALT1', 'Gene', (207, 216))
273561	33540736	However, if pT2+ or pN+, adjuvant chemotherapy is given with consideration for radiotherapy based on risk factors of positive margins or inadequate nodal dissection (D1, or <15 total LN).	('nodal', 'Gene', '4838', (148, 153))	('nodal', 'Gene', (148, 153))	('pN', 'Gene', '79650', (20, 22))	('pT2+', 'Var', (12, 16))
273568	33540736	Elective node coverage can be omitted in patients with pT2-3N0 disease with D2 nodal dissection with >=15 LN removed.	('patients', 'Species', '9606', (41, 49))	('pT2-3N0', 'Var', (55, 62))	('nodal', 'Gene', '4838', (79, 84))	('nodal', 'Gene', (79, 84))
273635	29187727	In addition, patients with low miR-588-expressing carcinomas had much shorter overall survival.	('shorter', 'NegReg', (70, 77))	('patients', 'Species', '9606', (13, 21))	('carcinoma', 'Phenotype', 'HP:0030731', (50, 59))	('overall survival', 'MPA', (78, 94))	('miR-588', 'Gene', (31, 38))	('low', 'Var', (27, 30))	('carcinomas', 'Phenotype', 'HP:0030731', (50, 60))	('miR-588', 'Gene', '693173', (31, 38))	('carcinomas', 'Disease', 'MESH:D002277', (50, 60))	('carcinomas', 'Disease', (50, 60))
273637	29187727	miR-588 is downregulated in BC and its aberrant expression is closely associated with patients' poor prognosis and overall survival, thus suggesting a biomarker role.	('miR-588', 'Gene', (0, 7))	('downregulated', 'NegReg', (11, 24))	('miR-588', 'Gene', '693173', (0, 7))	('BC', 'Phenotype', 'HP:0003002', (28, 30))	('aberrant', 'Var', (39, 47))	('patients', 'Species', '9606', (86, 94))
273675	29187727	Breast cancer patient overall survival was assessed using the Kaplan-Meier model and compared between patients expressing low and high miR-588 using the log-rank test.	('miR-588', 'Gene', (135, 142))	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('miR-588', 'Gene', '693173', (135, 142))	('Breast cancer', 'Phenotype', 'HP:0003002', (0, 13))	('patient', 'Species', '9606', (102, 109))	('Breast cancer', 'Disease', 'MESH:D001943', (0, 13))	('patients', 'Species', '9606', (102, 110))	('patient', 'Species', '9606', (14, 21))	('low', 'Var', (122, 125))	('Breast cancer', 'Disease', (0, 13))
273692	29187727	QPCR showed that, in infected MCF-7 and MDA-MB-231 cells, miR-588 was significantly upregulated by Lenti-588 (Figure 3A, *P<0.05).	('upregulated', 'PosReg', (84, 95))	('Lenti-588', 'Var', (99, 108))	('miR-588', 'Gene', (58, 65))	('miR-588', 'Gene', '693173', (58, 65))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (40, 50))	('MCF-7', 'CellLine', 'CVCL:0031', (30, 35))
273740	27330805	Similar to VEGF, Ang2 can also affect tumor immunity by augmenting the expression of immunosuppressive cytokines (i.e, IL-10) in monocytes and macrophages, and promote the expansion of T-regs.	('affect', 'Reg', (31, 37))	('tumor', 'Disease', (38, 43))	('expression', 'MPA', (71, 81))	('expansion', 'CPA', (172, 181))	('promote', 'PosReg', (160, 167))	('augmenting', 'PosReg', (56, 66))	('VEGF', 'Gene', (11, 15))	('IL-10', 'Gene', '3586', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('VEGF', 'Gene', '7422', (11, 15))	('IL-10', 'Gene', (119, 124))	('Ang2', 'Var', (17, 21))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('T-regs', 'CPA', (185, 191))
273787	27330805	The association with changes in PLGF values was also no longer significant after adjusting for multiple testing.	('changes', 'Var', (21, 28))	('PLGF', 'Gene', (32, 36))	('PLGF', 'Gene', '5228', (32, 36))
273804	27330805	Moreover, high levels of serum VEGF in patients with advanced melanoma was associated with poorer overall survival when treated with ipilimumab (anti-CTLA4 antibody) and also predicted lack of response to high-dose IL-2 therapy.	('CTLA4', 'Gene', '1493', (150, 155))	('melanoma', 'Disease', (62, 70))	('VEGF', 'Gene', (31, 35))	('patients', 'Species', '9606', (39, 47))	('CTLA4', 'Gene', (150, 155))	('high levels', 'Var', (10, 21))	('VEGF', 'Gene', '7422', (31, 35))	('IL-2', 'Gene', '3558', (215, 219))	('overall survival', 'MPA', (98, 114))	('IL-2', 'Gene', (215, 219))	('ipilimumab', 'Chemical', 'MESH:D000074324', (133, 143))	('poorer', 'NegReg', (91, 97))	('melanoma', 'Disease', 'MESH:D008545', (62, 70))	('melanoma', 'Phenotype', 'HP:0002861', (62, 70))
273806	27330805	Systemic upregulation of circulating levels of PLGF have been observed after antiangiogenic therapy (i.e, bevacizumab) in several malignancies, suggesting that changes in PLGF could promote escape from treatments that inhibit angiogenesis.	('PLGF', 'Gene', (171, 175))	('PLGF', 'Gene', '5228', (171, 175))	('upregulation', 'PosReg', (9, 21))	('changes', 'Var', (160, 167))	('malignancies', 'Disease', (130, 142))	('promote', 'PosReg', (182, 189))	('bevacizumab', 'Chemical', 'MESH:D000068258', (106, 117))	('PLGF', 'Gene', (47, 51))	('escape', 'CPA', (190, 196))	('malignancies', 'Disease', 'MESH:D009369', (130, 142))	('PLGF', 'Gene', '5228', (47, 51))
273811	27330805	Serum levels of Ang2 were elevated at baseline in 143 breast cancer patients compared to 100 healthy controls, and the 5-year overall survival was significantly lower in the Ang2 high expression group compared to patients with low serum Ang2.	('breast cancer', 'Disease', (54, 67))	('lower', 'NegReg', (161, 166))	('Serum levels', 'MPA', (0, 12))	('high expression', 'Var', (179, 194))	('elevated', 'PosReg', (26, 34))	('patients', 'Species', '9606', (68, 76))	('patients', 'Species', '9606', (213, 221))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('breast cancer', 'Disease', 'MESH:D001943', (54, 67))	('Ang2', 'Gene', (174, 178))	('breast cancer', 'Phenotype', 'HP:0003002', (54, 67))
273814	27330805	Antibodies to multiple angiogenic cytokines including Ang2 were also found to be associated with improved survival following hematopoetic stem cell transplantation and GM-CSF based vaccine administered to treat leukemia.	('Antibodies', 'Var', (0, 10))	('survival', 'CPA', (106, 114))	('improved', 'PosReg', (97, 105))	('Ang2', 'Gene', (54, 58))	('GM-CSF', 'Gene', (168, 174))	('GM-CSF', 'Gene', '1437', (168, 174))	('leukemia', 'Phenotype', 'HP:0001909', (211, 219))	('leukemia', 'Disease', (211, 219))	('leukemia', 'Disease', 'MESH:D007938', (211, 219))
273820	27330805	The functional role of increased levels of PLGF is controversial, with some suggestion that systemic upregulation may promote resistance to anti-VEGF therapy as mentioned above, and others suggesting that increased PLGF may actually functionally impair angiogenesis and predict response to antiangiogenic therapy.	('increased', 'Var', (205, 214))	('upregulation', 'PosReg', (101, 113))	('angiogenesis', 'CPA', (253, 265))	('VEGF', 'Gene', (145, 149))	('predict', 'Reg', (270, 277))	('PLGF', 'Gene', (215, 219))	('PLGF', 'Gene', '5228', (215, 219))	('VEGF', 'Gene', '7422', (145, 149))	('PLGF', 'Gene', (43, 47))	('impair', 'NegReg', (246, 252))	('promote', 'PosReg', (118, 125))	('PLGF', 'Gene', '5228', (43, 47))
273842	27330805	Ongoing and planned studies continue to examine the role of VEGF inhibition in HNSCC (NCT00588770, NCT01639911), as well as study combining immunotherapy with anti-angiogenic therapy (NCT02210117, NCT02348008, NCT02141542).	('VEGF', 'Gene', '7422', (60, 64))	('inhibition', 'NegReg', (65, 75))	('SCC', 'Gene', '6317', (81, 84))	('NCT01639911', 'Var', (99, 110))	('VEGF', 'Gene', (60, 64))	('NCT02210117', 'Var', (184, 195))	('SCC', 'Gene', (81, 84))	('NCT02348008', 'Var', (197, 208))	('HNSCC', 'Phenotype', 'HP:0012288', (79, 84))	('NCT00588770', 'Var', (86, 97))
273911	33905431	VHL and PBRM1 are major genes that cause mutations in more than 40% of clear cell renal cell carcinoma, and SETD2 and PTEN, which are quite frequent, are genes that cause both copy number loss and mutation.	('mutations', 'Var', (41, 50))	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('SETD2', 'Gene', (108, 113))	('PBRM1', 'Gene', '55193', (8, 13))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (71, 102))	('clear cell renal cell carcinoma', 'Disease', (71, 102))	('PTEN', 'Gene', '5728', (118, 122))	('number loss', 'Disease', 'MESH:D007674', (181, 192))	('PTEN', 'Gene', (118, 122))	('VHL', 'Gene', (0, 3))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (82, 102))	('SETD2', 'Gene', '29072', (108, 113))	('VHL', 'Gene', '7428', (0, 3))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (71, 102))	('number loss', 'Disease', (181, 192))	('PBRM1', 'Gene', (8, 13))
273912	33905431	The BRAF gene of THCA is the most important gene with 60% missense mutation and more than 2% fusion, and includes a list of most oncogenes such as NRAS, TP53, PTEN, and RB1.	('THCA', 'Gene', (17, 21))	('missense mutation', 'Var', (58, 75))	('PTEN', 'Gene', (159, 163))	('PTEN', 'Gene', '5728', (159, 163))	('RB1', 'Gene', (169, 172))	('TP53', 'Gene', '7157', (153, 157))	('RB1', 'Gene', '5925', (169, 172))	('NRAS', 'Gene', (147, 151))	('BRAF', 'Gene', (4, 8))	('BRAF', 'Gene', '673', (4, 8))	('TP53', 'Gene', (153, 157))	('NRAS', 'Gene', '4893', (147, 151))
273990	33557271	The expression data of HLA-I and APM components were obtained from the TCGA of 103 HPV- OSCC lesions.	('lesions', 'Var', (93, 100))	('HPV', 'Species', '10566', (83, 86))	('APM', 'Gene', '290', (33, 36))	('APM', 'Gene', (33, 36))
274003	33557271	The reason for the impaired HLA-I/APM expression of phenotype II might be structural alterations or epigenetic silencing of both HLA-I and APM components, while in phenotype III, the APM component expression is functional, and only the HLA-I expression is reduced or discordant, which might be foremost caused by deregulation of HLA-I expression at the transcriptional and posttranscriptional level rather than structural alterations.	('silencing', 'NegReg', (111, 120))	('APM', 'Gene', (34, 37))	('APM', 'Gene', (183, 186))	('APM', 'Gene', '290', (139, 142))	('impaired', 'NegReg', (19, 27))	('APM', 'Gene', '290', (34, 37))	('APM', 'Gene', (139, 142))	('epigenetic', 'Var', (100, 110))	('APM', 'Gene', '290', (183, 186))
274072	32576270	Loss-of-function mutations in KEAP1 drive lung cancer progression via KEAP1/NRF2 pathway activation Targeted therapy and immunotherapy have led to dramatic change in the treatment of lung cancer, however, the overall 5-year survival rate of lung cancer patients is still suboptimal.	('NRF2', 'Gene', '4780', (76, 80))	('patients', 'Species', '9606', (253, 261))	('lung cancer', 'Phenotype', 'HP:0100526', (241, 252))	('mutations', 'Var', (17, 26))	('lung cancer', 'Disease', 'MESH:D008175', (42, 53))	('lung cancer', 'Disease', 'MESH:D008175', (183, 194))	('NRF2', 'Gene', (76, 80))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))	('lung cancer', 'Phenotype', 'HP:0100526', (42, 53))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('lung cancer', 'Phenotype', 'HP:0100526', (183, 194))	('lung cancer', 'Disease', (241, 252))	('KEAP1', 'Gene', '9817', (70, 75))	('KEAP1', 'Gene', (70, 75))	('KEAP1', 'Gene', '9817', (30, 35))	('Loss-of-function', 'NegReg', (0, 16))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('KEAP1', 'Gene', (30, 35))	('lung cancer', 'Disease', (42, 53))	('lung cancer', 'Disease', (183, 194))	('lung cancer', 'Disease', 'MESH:D008175', (241, 252))
274073	32576270	High-frequency somatic mutations in KEAP1/NRF2 (27.9%) have been identified in lung squamous cell carcinoma.	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (79, 107))	('identified', 'Reg', (65, 75))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (79, 107))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (84, 107))	('KEAP1/NRF2', 'Gene', (36, 46))	('lung squamous cell carcinoma', 'Disease', (79, 107))	('somatic mutations', 'Var', (15, 32))
274074	32576270	In this research, we explored the role of KEAP1 somatic mutations in the development of LSCC and whether a nuclear factor erythroid 2-related factor 2(NRF2) inhibitor be potential to target lung cancer carrying KEAP1/NRF2 mutations.	('LSCC', 'Phenotype', 'HP:0030359', (88, 92))	('nuclear factor erythroid 2-related factor 2', 'Gene', (107, 150))	('lung cancer', 'Disease', 'MESH:D008175', (190, 201))	('KEAP1/NRF2', 'Gene', (211, 221))	('mutations', 'Var', (222, 231))	('nuclear factor erythroid 2-related factor 2', 'Gene', '4780', (107, 150))	('lung cancer', 'Disease', (190, 201))	('lung cancer', 'Phenotype', 'HP:0100526', (190, 201))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('LSCC', 'Disease', (88, 92))
274075	32576270	Lung cancer cell lines A549 and H460 with loss-of-function mutations in KEAP1 stably transfected with wild-type (WT) KEAP1 or somatic mutations in KEAP1 were used to investigate the functions of somatic mutations in KEAP1.	('Lung cancer', 'Phenotype', 'HP:0100526', (0, 11))	('KEAP1', 'Gene', (72, 77))	('Lung cancer', 'Disease', (0, 11))	('loss-of-function', 'NegReg', (42, 58))	('mutations', 'Var', (59, 68))	('H460', 'CellLine', 'CVCL:0459', (32, 36))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))	('A549', 'CellLine', 'CVCL:0023', (23, 27))	('Lung cancer', 'Disease', 'MESH:D008175', (0, 11))
274077	32576270	The expression of NRF2 and its target genes increased, and tumor cell proliferation, migration, and tumor growth were accelerated in A549 and H460 cells stably transfected with KEAP1 mutants compared to control cells with a loss-of-function KEAP1 mutation and stably transfected with WT KEAP1 in both in vitro and in vivo studies.	('accelerated', 'PosReg', (118, 129))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Disease', (59, 64))	('NRF2', 'Gene', (18, 22))	('tumor', 'Disease', (100, 105))	('mutation', 'Var', (247, 255))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('expression', 'MPA', (4, 14))	('mutants', 'Var', (183, 190))	('loss-of-function', 'NegReg', (224, 240))	('KEAP1', 'Gene', (241, 246))	('H460', 'CellLine', 'CVCL:0459', (142, 146))	('migration', 'CPA', (85, 94))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('increased', 'PosReg', (44, 53))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('A549', 'CellLine', 'CVCL:0023', (133, 137))	('KEAP1', 'Gene', (177, 182))
274078	32576270	The proliferation of A549 cell line trasfected with the R320Q KEAP1 mutant was inhibited more apparent than that of the A549 cell line trasfected with WT KEAP1 after treatment with NRF2 inhibitor ML385.	('A549', 'CellLine', 'CVCL:0023', (21, 25))	('proliferation', 'CPA', (4, 17))	('R320Q', 'Var', (56, 61))	('KEAP1', 'Gene', (62, 67))	('R320Q', 'Mutation', 'p.R320Q', (56, 61))	('inhibited', 'NegReg', (79, 88))	('ML385', 'Chemical', '-', (196, 201))	('A549', 'CellLine', 'CVCL:0023', (120, 124))
274080	32576270	NRF2 inhibition with ML385 could inhibit the proliferation of tumor cells with KEAP1 mutation.	('NRF2', 'Gene', (0, 4))	('ML385', 'Var', (21, 26))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('KEAP1', 'Gene', (79, 84))	('inhibit', 'NegReg', (33, 40))	('tumor', 'Disease', (62, 67))	('mutation', 'Var', (85, 93))	('inhibition', 'NegReg', (5, 15))	('ML385', 'Chemical', '-', (21, 26))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
274085	32576270	Because most lung cancer patients are already in the advanced stage of disease at the time of diagnosis, they have lost the opportunity for surgical treatment, and the prognosis of LSCC has not obviously improved, although the finding of high-frequency mutations in epidermal growth factor receptor (EGFR) kinase has led to a dramatic change in the treatment of patients with lung adenocarcinoma, and recent data have indicated that targeting mutations in BRAF, AKT1, ERBB2, and PIK3CA as well as fusions that involve receptor tyrosine kinase genes ALK, ROS1, and RET may also be successful.	('RET', 'Gene', '5979', (564, 567))	('PIK3CA', 'Gene', '5290', (479, 485))	('ERBB2', 'Gene', (468, 473))	('AKT1', 'Gene', (462, 466))	('patients', 'Species', '9606', (362, 370))	('lung cancer', 'Disease', (13, 24))	('EGFR', 'Gene', '1956', (300, 304))	('lung adenocarcinoma', 'Disease', (376, 395))	('mutations', 'Var', (253, 262))	('ERBB2', 'Gene', '2064', (468, 473))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('LSCC', 'Phenotype', 'HP:0030359', (181, 185))	('RET', 'Gene', (564, 567))	('epidermal growth factor receptor', 'Gene', (266, 298))	('ALK', 'Gene', '238', (549, 552))	('ROS1', 'Gene', (554, 558))	('mutations', 'Var', (443, 452))	('PIK3CA', 'Gene', (479, 485))	('epidermal growth factor receptor', 'Gene', '1956', (266, 298))	('ALK', 'Gene', (549, 552))	('carcinoma', 'Phenotype', 'HP:0030731', (386, 395))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (376, 395))	('BRAF', 'Gene', '673', (456, 460))	('patients', 'Species', '9606', (25, 33))	('BRAF', 'Gene', (456, 460))	('lung cancer', 'Disease', 'MESH:D008175', (13, 24))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (376, 395))	('AKT1', 'Gene', '207', (462, 466))	('lung cancer', 'Phenotype', 'HP:0100526', (13, 24))	('EGFR', 'Gene', (300, 304))	('ROS1', 'Gene', '6098', (554, 558))
274086	32576270	Unfortunately, the activating mutations in EGFR and ALK fusions are limited in lung adenocarcinoma and are not present in LSCC, and targeted agents developed for these activating mutations are largely ineffective in LSCC.	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (79, 98))	('ALK', 'Gene', '238', (52, 55))	('LSCC', 'Phenotype', 'HP:0030359', (216, 220))	('LSCC', 'Phenotype', 'HP:0030359', (122, 126))	('EGFR', 'Gene', '1956', (43, 47))	('mutations', 'Var', (30, 39))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (79, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('EGFR', 'Gene', (43, 47))	('ALK', 'Gene', (52, 55))	('lung adenocarcinoma', 'Disease', (79, 98))
274087	32576270	Interestingly, a search of the TCGA database revealed that approximately 30% of LSCCs undergo recurrent mutations in KEAP1 and NFE2L2(also named as NRF2).	('mutations', 'Var', (104, 113))	('NFE2L2', 'Gene', '4780', (127, 133))	('KEAP1', 'Gene', (117, 122))	('NFE2L2', 'Gene', (127, 133))	('LSCCs', 'Disease', (80, 85))	('LSCC', 'Phenotype', 'HP:0030359', (80, 84))
274088	32576270	In our previous study, we identified that KEAP1 and NRF2 mutations are recurrent in Chinese patients with LSCC, with a 5.8% frequency for KEAP1 and a 27.9% frequency for KEAP1/NRF2 mutations.	('NRF2', 'Gene', (52, 56))	('LSCC', 'Disease', (106, 110))	('LSCC', 'Phenotype', 'HP:0030359', (106, 110))	('patients', 'Species', '9606', (92, 100))	('KEAP1', 'Gene', (42, 47))	('mutations', 'Var', (57, 66))
274089	32576270	However, mutations in KEAP1/NRF2 in Chinese patients with lung adenocarcinoma are rarely found, which is consistent with reports from Takahashi T. Interestingly, KEAP1 and NRF2 mutations show mutual exclusive in Chinese patients with LSCC.	('patients', 'Species', '9606', (44, 52))	('NRF2', 'Gene', (172, 176))	('mutations', 'Var', (9, 18))	('mutations', 'Var', (177, 186))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (58, 77))	('LSCC', 'Disease', (234, 238))	('LSCC', 'Phenotype', 'HP:0030359', (234, 238))	('patients', 'Species', '9606', (220, 228))	('carcinoma', 'Phenotype', 'HP:0030731', (68, 77))	('KEAP1', 'Gene', (162, 167))	('lung adenocarcinoma', 'Disease', (58, 77))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (58, 77))
274092	32576270	More recently, the data have also shown that loss of function of KEAP1 promotes KRAS-driven lung cancer and results in the dependence on glutaminolysis.	('lung cancer', 'Disease', (92, 103))	('results in', 'Reg', (108, 118))	('lung cancer', 'Phenotype', 'HP:0100526', (92, 103))	('promotes', 'PosReg', (71, 79))	('KRAS', 'Gene', (80, 84))	('KEAP1', 'Gene', (65, 70))	('loss of function', 'Var', (45, 61))	('KRAS', 'Gene', '3845', (80, 84))	('lung cancer', 'Disease', 'MESH:D008175', (92, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('dependence on glutaminolysis', 'MPA', (123, 151))
274093	32576270	Therefore, we aimed to test whether mutations in KEAP1, identified in our previous study, accelerate the development of lung cancer, and whether a NRF2 inhibitor can be used as a targeted therapeutic drug in patients with lung cancer carrying KEAP1/NRF2 mutations.	('development', 'CPA', (105, 116))	('patients', 'Species', '9606', (208, 216))	('lung cancer', 'Disease', (222, 233))	('lung cancer', 'Disease', (120, 131))	('lung cancer', 'Phenotype', 'HP:0100526', (222, 233))	('lung cancer', 'Phenotype', 'HP:0100526', (120, 131))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('mutations', 'Var', (36, 45))	('KEAP1', 'Gene', (49, 54))	('accelerate', 'PosReg', (90, 100))	('lung cancer', 'Disease', 'MESH:D008175', (222, 233))	('KEAP1/NRF2', 'Gene', (243, 253))	('lung cancer', 'Disease', 'MESH:D008175', (120, 131))	('mutations', 'Var', (254, 263))
274098	32576270	A retrovirus-mediated infection system was used to construct A549 and H460 cells stably over-expressing 3FLAG-tagged KEAP1(WT or mutant).	('3FLAG-tagged', 'Var', (104, 116))	('infection', 'Disease', 'MESH:D007239', (22, 31))	('over-expressing', 'PosReg', (88, 103))	('KEAP1', 'Gene', (117, 122))	('H460', 'CellLine', 'CVCL:0459', (70, 74))	('infection', 'Disease', (22, 31))	('A549', 'CellLine', 'CVCL:0023', (61, 65))
274103	32576270	The antibodies used in our study were as follows: anti-FLAG M2 monoclonal (Sigma, St. Louis, MO, USA), anti-NRF2 (Abcam, Cambridge, UnitedKingdom), anti-beta-actin (Cell Signaling,Danvers, MA, USA), anti-HO-1 (Cell Signaling), anti-LaminB1 (Cell Signaling), anti-Lamin A/C (Cell Signaling).	('beta-actin', 'Gene', '728378', (153, 163))	('beta-actin', 'Gene', (153, 163))	('LaminB1', 'Gene', '4001', (232, 239))	('Lamin A/C', 'Gene', (263, 272))	('HO-1', 'Gene', (204, 208))	('Lamin A/C', 'Gene', '4000', (263, 272))	('HO-1', 'Gene', '3162', (204, 208))	('LaminB1', 'Gene', (232, 239))	('anti-NRF2', 'Var', (103, 112))
274111	32576270	We infected A549-KEAP1-WT or A549-KEAP1-R320W cells (1 x 108) subcutaneously into the right flank of BALB/c nude mice and measured the tumor dimensions by calipers every 3-4 days.	('nude mice', 'Species', '10090', (108, 117))	('infected', 'Disease', 'MESH:D007239', (3, 11))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('tumor', 'Disease', (135, 140))	('A549-KEAP1-R320W', 'Var', (29, 45))	('infected', 'Disease', (3, 11))	('A549', 'CellLine', 'CVCL:0023', (29, 33))	('A549', 'CellLine', 'CVCL:0023', (12, 16))	('R320W', 'Mutation', 'p.R320W', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
274115	32576270	To explore the effect of KEAP1 loss on activation of the KEAP1/NRF2 pathway, we collected three NSCLC cell lines with KEAP1 mutations (A549, NCI-H460, and NCI-H838) and four NSCLC cell lines without KEAP1/NRF2 mutations (NCI-H1299, NCI-H292, 95D, and SPCA1).	('NCI-H1299', 'CellLine', 'CVCL:0060', (221, 230))	('NSCLC', 'Disease', (96, 101))	('mutations', 'Var', (124, 133))	('NSCLC', 'Disease', 'MESH:D002289', (174, 179))	('NSCLC', 'Phenotype', 'HP:0030358', (96, 101))	('NSCLC', 'Disease', 'MESH:D002289', (96, 101))	('NSCLC', 'Phenotype', 'HP:0030358', (174, 179))	('A549', 'CellLine', 'CVCL:0023', (135, 139))	('NCI-H460', 'CellLine', 'CVCL:0459', (141, 149))	('SPCA1', 'Gene', '27032', (251, 256))	('NCI-H292', 'CellLine', 'CVCL:0455', (232, 240))	('SPCA1', 'Gene', (251, 256))	('KEAP1', 'Gene', (118, 123))	('NSCLC', 'Disease', (174, 179))
274116	32576270	In the present study, we have found the frequency of KEAP1/NRF2 mutation was higher in human LSCC than that in LUAD patients, thus we hope find the LSCC cell lines with KEAP1 mutation to investigate the effect of KEAP1 mutation on the function of KEAP1/NRF2 pathaway.	('mutation', 'Var', (64, 72))	('human', 'Species', '9606', (87, 92))	('patients', 'Species', '9606', (116, 124))	('LUAD', 'Disease', 'None', (111, 115))	('LUAD', 'Disease', (111, 115))	('KEAP1/NRF2', 'Gene', (53, 63))	('LSCC', 'Disease', (93, 97))	('LSCC', 'Phenotype', 'HP:0030359', (93, 97))	('LSCC', 'Phenotype', 'HP:0030359', (148, 152))
274117	32576270	We further collected all available 7 lung cancer cell lines and found three of them carried the KEAP1 mutation (A549, NCI-H460, NCI-H838), thus, in the present study, all the seven lung cancer cell lines were used to study the influence of KEAP1 mutation on the function of KEAP1/NRF2 pathway.	('A549', 'CellLine', 'CVCL:0023', (112, 116))	('lung cancer', 'Disease', (37, 48))	('lung cancer', 'Phenotype', 'HP:0100526', (37, 48))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('mutation', 'Var', (102, 110))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('KEAP1/NRF2 pathway', 'Pathway', (274, 292))	('lung cancer', 'Disease', (181, 192))	('lung cancer', 'Phenotype', 'HP:0100526', (181, 192))	('lung cancer', 'Disease', 'MESH:D008175', (37, 48))	('NCI-H460', 'CellLine', 'CVCL:0459', (118, 126))	('lung cancer', 'Disease', 'MESH:D008175', (181, 192))
274118	32576270	As expected, Sanger sequencing revealed that the A549, H460, and H838 cell lines carried homozygous point mutations at D236H, G333C, and E444* in KEAP1, respectively; however, H1299, NCI-H292, 95D, and SPCA1 cell lines did not carry mutations in neither KEAP1 nor NRF2(Fig.	('H1299', 'CellLine', 'CVCL:0060', (176, 181))	('E444*', 'SUBSTITUTION', 'None', (137, 142))	('A549', 'CellLine', 'CVCL:0023', (49, 53))	('D236H', 'Mutation', 'p.D236H', (119, 124))	('SPCA1', 'Gene', '27032', (202, 207))	('H460', 'CellLine', 'CVCL:0459', (55, 59))	('E444*', 'Var', (137, 142))	('NCI-H292', 'CellLine', 'CVCL:0455', (183, 191))	('D236H', 'Var', (119, 124))	('G333C', 'Var', (126, 131))	('G333C', 'Mutation', 'c.333G>C', (126, 131))	('SPCA1', 'Gene', (202, 207))
274119	32576270	Next, we found that the mRNA expression of downstream target genes of the KEAP1/NRF2 pathway, such as GCLC, GCLM, TXN, TXNRD, HO1, NQO1, GSR, and G6PD, which encode detoxifying enzymes and antioxidant proteins, were significantly higher in KEAP1 mutant cell lines than in wild-type (WT) lung cancer cells by real-time polymerase chain reaction (PCR), but the mRNA expression of NRF2 showed no significant difference between lung cancer cell lines with and without KEAP1 mutation (Fig.	('GCLM', 'Gene', '2730', (108, 112))	('lung cancer', 'Disease', 'MESH:D008175', (287, 298))	('lung cancer', 'Disease', 'MESH:D008175', (424, 435))	('higher', 'PosReg', (230, 236))	('lung cancer', 'Phenotype', 'HP:0100526', (287, 298))	('cancer', 'Phenotype', 'HP:0002664', (429, 435))	('TXN', 'Gene', (119, 122))	('lung cancer', 'Phenotype', 'HP:0100526', (424, 435))	('HO1', 'Gene', (126, 129))	('NQO1', 'Gene', '1728', (131, 135))	('TXN', 'Gene', '7295', (119, 122))	('G6PD', 'Gene', '2539', (146, 150))	('mutant', 'Var', (246, 252))	('GCLC', 'Gene', '2729', (102, 106))	('NQO1', 'Gene', (131, 135))	('cancer', 'Phenotype', 'HP:0002664', (292, 298))	('G6PD', 'Gene', (146, 150))	('mRNA expression', 'MPA', (24, 39))	('GCLM', 'Gene', (108, 112))	('lung cancer', 'Disease', (287, 298))	('lung cancer', 'Disease', (424, 435))	('GCLC', 'Gene', (102, 106))	('TXN', 'Gene', (114, 117))	('HO1', 'Gene', '3162', (126, 129))	('TXN', 'Gene', '7295', (114, 117))
274121	32576270	As expected, function loss of KEAP1 significantly increased nuclear NRF2 levels and HO-1 levels incytoplasm (Fig.	('KEAP1', 'Gene', (30, 35))	('increased', 'PosReg', (50, 59))	('HO-1', 'Gene', (84, 88))	('nuclear NRF2 levels', 'MPA', (60, 79))	('HO-1', 'Gene', '3162', (84, 88))	('function loss', 'Var', (13, 26))
274123	32576270	Thus, we checked whether KEAP1 loss could decrease ROS production in lung cancer cell lines.	('lung cancer', 'Disease', 'MESH:D008175', (69, 80))	('ROS', 'Chemical', 'MESH:D017382', (51, 54))	('ROS production', 'MPA', (51, 65))	('lung cancer', 'Disease', (69, 80))	('decrease', 'NegReg', (42, 50))	('lung cancer', 'Phenotype', 'HP:0100526', (69, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('KEAP1 loss', 'Var', (25, 35))
274126	32576270	In our previous study, we identified five nonsynonymous mutations in KEAP1 from five patients with LSCC.	('patients', 'Species', '9606', (85, 93))	('KEAP1', 'Gene', (69, 74))	('LSCC', 'Phenotype', 'HP:0030359', (99, 103))	('nonsynonymous mutations', 'Var', (42, 65))
274127	32576270	However, the role of these KEAP1 mutations in tumorigenesis is unclear.	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Disease', (46, 51))	('mutations', 'Var', (33, 42))	('KEAP1', 'Gene', (27, 32))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
274129	32576270	To verify whether these five somatic mutations in KEAP1 influence the function of KEAP1, WT and five KEAP1 mutants were stably transfected with retroviral vectors into A549/H460 lung cancer cell lines that carry loss-of-function mutations in KEAP1.	('KEAP1', 'Gene', (242, 247))	('KEAP1', 'Gene', (50, 55))	('loss-of-function', 'NegReg', (212, 228))	('lung cancer', 'Disease', (178, 189))	('A549', 'CellLine', 'CVCL:0023', (168, 172))	('lung cancer', 'Phenotype', 'HP:0100526', (178, 189))	('mutations', 'Var', (229, 238))	('mutants', 'Var', (107, 114))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('mutations', 'Var', (37, 46))	('function', 'MPA', (70, 78))	('influence', 'Reg', (56, 65))	('lung cancer', 'Disease', 'MESH:D008175', (178, 189))	('H460', 'CellLine', 'CVCL:0459', (173, 177))
274132	32576270	These lung cancer cell lines that carry loss-of-function mutations in KEAP1, were losing the ability to mediate NRF2 degradation.	('lung cancer', 'Disease', 'MESH:D008175', (6, 17))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('lung cancer', 'Disease', (6, 17))	('losing', 'NegReg', (82, 88))	('lung cancer', 'Phenotype', 'HP:0100526', (6, 17))	('mutations', 'Var', (57, 66))	('mediate NRF2 degradation', 'MPA', (104, 128))	('KEAP1', 'Gene', (70, 75))	('ability', 'MPA', (93, 100))	('loss-of-function', 'NegReg', (40, 56))
274134	32576270	However, mRNA levels of NRF2 and its target genes HO-1, GCLC, and FTH1 were significantly increased in the A549 or H460 lung cancer cell lines stably transfected with these five KEAP1 mutants (Fig.	('FTH1', 'Gene', '2495', (66, 70))	('GCLC', 'Gene', '2729', (56, 60))	('NRF2', 'Gene', (24, 28))	('lung cancer', 'Disease', (120, 131))	('HO-1', 'Gene', (50, 54))	('increased', 'PosReg', (90, 99))	('lung cancer', 'Phenotype', 'HP:0100526', (120, 131))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('mRNA levels', 'MPA', (9, 20))	('A549', 'CellLine', 'CVCL:0023', (107, 111))	('mutants', 'Var', (184, 191))	('HO-1', 'Gene', '3162', (50, 54))	('H460', 'CellLine', 'CVCL:0459', (115, 119))	('FTH1', 'Gene', (66, 70))	('lung cancer', 'Disease', 'MESH:D008175', (120, 131))	('GCLC', 'Gene', (56, 60))
274137	32576270	In our present study, we found somatic mutations at R320Q, R413L, and D479H in the Kelch repeat domains of KEAP1, a somatic mutation at R234W in the IVR domain, and a somatic mutation at F174L in the BTB domain of KEAP1 (Fig.	('F174L', 'Mutation', 'p.F174L', (187, 192))	('at R234W', 'Var', (133, 141))	('R413L', 'Mutation', 'p.R413L', (59, 64))	('at R320Q', 'Var', (49, 57))	('R413L', 'Var', (59, 64))	('D479H', 'Mutation', 'p.D479H', (70, 75))	('D479H', 'Var', (70, 75))	('at F174L', 'Var', (184, 192))	('R320Q', 'Mutation', 'p.R320Q', (52, 57))	('R234W', 'Mutation', 'p.R234W', (136, 141))
274138	32576270	Interestingly, mutants at R413L and D479H in the Kelch repeat domain of KEAP1 did not bind to NRF2 (Fig.	('D479H', 'Mutation', 'p.D479H', (36, 41))	('D479H', 'Var', (36, 41))	('bind', 'Interaction', (86, 90))	('KEAP1', 'Gene', (72, 77))	('not', 'NegReg', (82, 85))	('R413L', 'Mutation', 'p.R413L', (26, 31))
274141	32576270	To uncover whether these five somatic mutations in KEAP1 influence the biological behavior of lung cancer cells, cell proliferation and migration were detected by colony-formation and scratch experiments.	('lung cancer', 'Disease', 'MESH:D008175', (94, 105))	('influence', 'Reg', (57, 66))	('lung cancer', 'Disease', (94, 105))	('lung cancer', 'Phenotype', 'HP:0100526', (94, 105))	('KEAP1', 'Gene', (51, 56))	('biological behavior', 'CPA', (71, 90))	('mutations', 'Var', (38, 47))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
274143	32576270	However, after being stably transfected with KEAP1 mutants, the colony formation and migration of A549/H460 lung cancer cell lines significantly increased (Fig.	('A549', 'CellLine', 'CVCL:0023', (98, 102))	('lung cancer', 'Disease', 'MESH:D008175', (108, 119))	('mutants', 'Var', (51, 58))	('colony formation', 'CPA', (64, 80))	('H460', 'CellLine', 'CVCL:0459', (103, 107))	('increased', 'PosReg', (145, 154))	('lung cancer', 'Disease', (108, 119))	('lung cancer', 'Phenotype', 'HP:0100526', (108, 119))	('migration', 'CPA', (85, 94))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
274145	32576270	1d, e), the reduced number of colonies and migration in cells knockouted with NRF2.These data suggest that the newly found somatic mutations in KEAP1 promote tumor cell activity through activating NRF2 antioxidant stress signaling pathways.	('tumor', 'Disease', (158, 163))	('mutations', 'Var', (131, 140))	('promote', 'PosReg', (150, 157))	('NRF2 antioxidant stress signaling pathways', 'Pathway', (197, 239))	('KEAP1', 'Gene', (144, 149))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('activating', 'PosReg', (186, 196))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))
274146	32576270	Due to we have considered that R320Q mutant has a considerable effection to KEAP1'S function, the ability of the antioxidative stress or proliferation and migration was significantly increased.	('antioxidative stress', 'MPA', (113, 133))	('effection', 'Reg', (63, 72))	('migration', 'CPA', (155, 164))	('R320Q', 'Var', (31, 36))	('increased', 'PosReg', (183, 192))	('antioxidative stress', 'Phenotype', 'HP:0025464', (113, 133))	('R320Q', 'Mutation', 'p.R320Q', (31, 36))	('oxidative stress', 'Phenotype', 'HP:0025464', (117, 133))	('proliferation', 'CPA', (137, 150))	('function', 'MPA', (84, 92))
274148	32576270	To further examine the effect of the somatic mutations in KEAP1 on the growth of lung cancer cell lines in vivo, the A549 cell lines stably transfected with WT KEAP1 or the R320Q mutant of KEAP1 were grafted subcutaneously into 4 to 5-week-old nude mice.	('lung cancer', 'Disease', (81, 92))	('lung cancer', 'Phenotype', 'HP:0100526', (81, 92))	('A549', 'CellLine', 'CVCL:0023', (117, 121))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('R320Q', 'Var', (173, 178))	('lung cancer', 'Disease', 'MESH:D008175', (81, 92))	('nude mice', 'Species', '10090', (244, 253))	('R320Q', 'Mutation', 'p.R320Q', (173, 178))
274151	32576270	The tumor sizes of the A549 cell line stably transfected with the R320Q KEAP1mutant were significantly larger than those of the A549 cell line stably transfected with WT KEAP1(Fig.	('tumor', 'Disease', (4, 9))	('A549', 'CellLine', 'CVCL:0023', (128, 132))	('R320Q', 'Mutation', 'p.R320Q', (66, 71))	('KEAP1mutant', 'Var', (72, 83))	('R320Q KEAP1mutant', 'Var', (66, 83))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('A549', 'CellLine', 'CVCL:0023', (23, 27))	('larger', 'PosReg', (103, 109))
274152	32576270	Additionally, the tumor growth of the A549 cell line stably transfected with the R320Q KEAP1 mutant was strongly accelerated compared with that of the A549 cell line stably transfected with WT KEAP1, as measured by the change in tumor volume (Fig.	('A549', 'CellLine', 'CVCL:0023', (151, 155))	('A549', 'CellLine', 'CVCL:0023', (38, 42))	('R320Q', 'Mutation', 'p.R320Q', (81, 86))	('tumor', 'Disease', 'MESH:D009369', (229, 234))	('tumor', 'Disease', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('accelerated', 'PosReg', (113, 124))	('KEAP1', 'Gene', (87, 92))	('tumor', 'Disease', (229, 234))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('R320Q', 'Var', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
274153	32576270	Consistent with the in vitro results, the KEAP1 mutant showed significantly accelerated tumor growth in vivo.	('KEAP1 mutant', 'Var', (42, 54))	('mutant', 'Var', (48, 54))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('accelerated', 'PosReg', (76, 87))	('tumor', 'Disease', (88, 93))
274156	32576270	Compared with the expression of NRF2 in the nucleus and its target protein HO-1 in the cytoplasm in tumor tissues from the A549 cell line transfected with WT KEAP1, the expression levels of NRF2 and its target protein HO-1 were significantly increased in the tumor tissues from the A549 cell line transfected with the R320Q KEAP1 mutant (Fig.	('HO-1', 'Gene', '3162', (75, 79))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Disease', (259, 264))	('tumor', 'Disease', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (259, 264))	('A549', 'CellLine', 'CVCL:0023', (282, 286))	('tumor', 'Phenotype', 'HP:0002664', (259, 264))	('NRF2', 'Gene', (190, 194))	('HO-1', 'Gene', (218, 222))	('increased', 'PosReg', (242, 251))	('expression levels', 'MPA', (169, 186))	('KEAP1', 'Gene', (324, 329))	('HO-1', 'Gene', (75, 79))	('R320Q', 'Var', (318, 323))	('A549', 'CellLine', 'CVCL:0023', (123, 127))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('HO-1', 'Gene', '3162', (218, 222))	('R320Q', 'Mutation', 'p.R320Q', (318, 323))
274157	32576270	The mRNA levels of NRF2 and its target genes HMOX1, HO-1, GCLC, and NQO1 in the grafted tumor tissues from the A549 cell line transfected with the R320Q KEAP1 mutant were remarkably increased compared with that in grafted tumor tissues from the A549 cell line transfected with WT KEAP1(Fig.	('HO-1', 'Gene', (52, 56))	('mRNA levels', 'MPA', (4, 15))	('increased', 'PosReg', (182, 191))	('NQO1', 'Gene', '1728', (68, 72))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('HMOX1', 'Gene', (45, 50))	('NQO1', 'Gene', (68, 72))	('A549', 'CellLine', 'CVCL:0023', (111, 115))	('A549', 'CellLine', 'CVCL:0023', (245, 249))	('NRF2', 'Gene', (19, 23))	('tumor', 'Disease', (88, 93))	('GCLC', 'Gene', (58, 62))	('R320Q', 'Var', (147, 152))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('R320Q', 'Mutation', 'p.R320Q', (147, 152))	('tumor', 'Disease', (222, 227))	('HMOX1', 'Gene', '3162', (45, 50))	('tumor', 'Disease', 'MESH:D009369', (222, 227))	('HO-1', 'Gene', '3162', (52, 56))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('GCLC', 'Gene', '2729', (58, 62))
274158	32576270	Increased cellular oxidative stress levels by small-molecule compounds to enhance cytotoxicity have been identified as a viable cancer treatment strategy.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('cellular oxidative stress levels', 'MPA', (10, 42))	('oxidative stress', 'Phenotype', 'HP:0025464', (19, 35))	('cancer', 'Disease', (128, 134))	('cytotoxicity', 'Disease', (82, 94))	('Increased', 'PosReg', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('cytotoxicity', 'Disease', 'MESH:D064420', (82, 94))	('small-molecule compounds', 'Var', (46, 70))	('enhance', 'PosReg', (74, 81))
274160	32576270	A subset of NRF2 inhibitors has been reported to inhibit the proliferation of cancer cells by down-regulating the expression of NRF2, resulting in elevated levels of intracellular ROS and increased cytotoxicity.	('down-regulating', 'NegReg', (94, 109))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('levels of intracellular ROS', 'MPA', (156, 183))	('cytotoxicity', 'Disease', (198, 210))	('NRF2', 'Gene', (128, 132))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('ROS', 'Chemical', 'MESH:D017382', (180, 183))	('elevated', 'PosReg', (147, 155))	('inhibitors', 'Var', (17, 27))	('cytotoxicity', 'Disease', 'MESH:D064420', (198, 210))	('expression', 'MPA', (114, 124))	('NRF2', 'Gene', (12, 16))	('proliferation', 'CPA', (61, 74))	('inhibit', 'NegReg', (49, 56))	('increased', 'PosReg', (188, 197))
274161	32576270	Thus, we selected an effective NRF2 inhibitor, ML385, which specifically and directly interacts with NRF2 protein, blocks NRF2 transcriptional activity, and enhances the efficacy of carboplatin and other chemotherapeutic drugs in lung cancer cells.	('efficacy', 'MPA', (170, 178))	('transcriptional activity', 'MPA', (127, 151))	('protein', 'Protein', (106, 113))	('ML385', 'Chemical', '-', (47, 52))	('lung cancer', 'Disease', (230, 241))	('NRF2', 'Gene', (101, 105))	('carboplatin', 'Chemical', 'MESH:D016190', (182, 193))	('lung cancer', 'Phenotype', 'HP:0100526', (230, 241))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))	('enhances', 'PosReg', (157, 165))	('blocks', 'NegReg', (115, 121))	('ML385', 'Var', (47, 52))	('NRF2', 'Gene', (122, 126))	('lung cancer', 'Disease', 'MESH:D008175', (230, 241))	('interacts', 'Interaction', (86, 95))
274162	32576270	The lung cancer cell line A549 transfected with the R320Q KEAP1 mutant (KEAP1-R320Q mutant) or with WT KEAP1 (KEAP1-WT) and H1299 lung cancer cells, which carry both WT KEAP1 and NRF2, were selected and treated with ML385.	('lung cancer', 'Phenotype', 'HP:0100526', (130, 141))	('H1299', 'CellLine', 'CVCL:0060', (124, 129))	('R320Q', 'Var', (52, 57))	('ML385', 'Chemical', '-', (216, 221))	('KEAP1', 'Gene', (58, 63))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('lung cancer', 'Disease', (4, 15))	('lung cancer', 'Disease', 'MESH:D008175', (130, 141))	('lung cancer', 'Phenotype', 'HP:0100526', (4, 15))	('R320Q', 'Mutation', 'p.R320Q', (52, 57))	('A549', 'CellLine', 'CVCL:0023', (26, 30))	('lung cancer', 'Disease', 'MESH:D008175', (4, 15))	('R320Q', 'Mutation', 'p.R320Q', (78, 83))	('lung cancer', 'Disease', (130, 141))
274164	32576270	Interestingly, when the lung cancer cell lines were treated with ML385 at a low dose, such as 0.25 or 0.5 muM/L, the proliferation of theA549 lung cancer cell line transfected with the R320Q KEAP1 mutant showed more significant inhibition than that of A549 cells transfected with WT KEAP1 or that of H1299 lung cancer cells (Fig.	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('lung cancer', 'Disease', (24, 35))	('lung cancer', 'Disease', (142, 153))	('cancer', 'Phenotype', 'HP:0002664', (311, 317))	('H1299', 'CellLine', 'CVCL:0060', (300, 305))	('proliferation', 'CPA', (117, 130))	('inhibition', 'NegReg', (228, 238))	('ML385', 'Chemical', '-', (65, 70))	('lung cancer', 'Disease', (306, 317))	('lung cancer', 'Disease', 'MESH:D008175', (24, 35))	('R320Q', 'Var', (185, 190))	('lung cancer', 'Disease', 'MESH:D008175', (142, 153))	('R320Q', 'Mutation', 'p.R320Q', (185, 190))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('lung cancer', 'Phenotype', 'HP:0100526', (24, 35))	('lung cancer', 'Phenotype', 'HP:0100526', (142, 153))	('A549', 'CellLine', 'CVCL:0023', (252, 256))	('lung cancer', 'Disease', 'MESH:D008175', (306, 317))	('lung cancer', 'Phenotype', 'HP:0100526', (306, 317))	('A549', 'CellLine', 'CVCL:0023', (137, 141))
274165	32576270	The proliferation of lung cancer cell lines showed no significant difference between A549 cells transfected with WT KEAP1 and H1299 lung cancer cells without KEAP1 and NFR2 mutation (Fig.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('A549', 'CellLine', 'CVCL:0023', (85, 89))	('lung cancer', 'Disease', 'MESH:D008175', (132, 143))	('lung cancer', 'Disease', (21, 32))	('lung cancer', 'Phenotype', 'HP:0100526', (21, 32))	('NFR2', 'Gene', (168, 172))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('H1299', 'CellLine', 'CVCL:0060', (126, 131))	('lung cancer', 'Disease', (132, 143))	('lung cancer', 'Phenotype', 'HP:0100526', (132, 143))	('lung cancer', 'Disease', 'MESH:D008175', (21, 32))	('mutation', 'Var', (173, 181))
274167	32576270	To further detect whether the effect of ML385 on lung cancer cell proliferation is mediated by inhibiting the KEAP1/NRF2 pathway, the expression of NRF2 and its target genes HO-1, GCLC and NQO1 in lung cancer cell lines treated with ML385 were investigated by western blot and real-time PCR.	('GCLC', 'Gene', (180, 184))	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('NRF2', 'Gene', (148, 152))	('lung cancer', 'Disease', (197, 208))	('NQO1', 'Gene', (189, 193))	('ML385', 'Var', (40, 45))	('lung cancer', 'Disease', 'MESH:D008175', (49, 60))	('ML385', 'Chemical', '-', (233, 238))	('lung cancer', 'Phenotype', 'HP:0100526', (49, 60))	('KEAP1/NRF2 pathway', 'Pathway', (110, 128))	('HO-1', 'Gene', '3162', (174, 178))	('GCLC', 'Gene', '2729', (180, 184))	('lung cancer', 'Disease', 'MESH:D008175', (197, 208))	('HO-1', 'Gene', (174, 178))	('lung cancer', 'Phenotype', 'HP:0100526', (197, 208))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('inhibiting', 'NegReg', (95, 105))	('ML385', 'Chemical', '-', (40, 45))	('lung cancer', 'Disease', (49, 60))	('NQO1', 'Gene', '1728', (189, 193))
274168	32576270	4c, the expression levels of HO-1 and NRF2 protein in A549 lung cancer cells transfected with F174L, R234W, R320Q, and R413L KEAP1 mutants were significantly inhibited by ML385.	('NRF2', 'Gene', (38, 42))	('lung cancer', 'Disease', 'MESH:D008175', (59, 70))	('R413L', 'Mutation', 'p.R413L', (119, 124))	('ML385', 'Chemical', '-', (171, 176))	('R234W', 'Mutation', 'p.R234W', (101, 106))	('lung cancer', 'Phenotype', 'HP:0100526', (59, 70))	('R234W', 'Var', (101, 106))	('expression levels', 'MPA', (8, 25))	('F174L', 'Mutation', 'p.F174L', (94, 99))	('R320Q', 'Var', (108, 113))	('A549', 'CellLine', 'CVCL:0023', (54, 58))	('R320Q', 'Mutation', 'p.R320Q', (108, 113))	('R413L KEAP1', 'Var', (119, 130))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('lung cancer', 'Disease', (59, 70))	('HO-1', 'Gene', '3162', (29, 33))	('F174L', 'Var', (94, 99))	('HO-1', 'Gene', (29, 33))	('inhibited', 'NegReg', (158, 167))	('protein', 'Protein', (43, 50))
274170	32576270	Although mRNA expression levels of NRF2 and its target gene NQO1 in A549 cells transfected with WT KEAP1 were significantly inhibited by ML385, the mRNA expression levels of the NRF2 target genes GCLC and HO-1 were not influenced by ML385 (Fig.	('ML385', 'Var', (137, 142))	('A549', 'CellLine', 'CVCL:0023', (68, 72))	('mRNA expression levels', 'MPA', (9, 31))	('HO-1', 'Gene', (205, 209))	('NQO1', 'Gene', (60, 64))	('GCLC', 'Gene', (196, 200))	('NRF2', 'Gene', (35, 39))	('NQO1', 'Gene', '1728', (60, 64))	('ML385', 'Chemical', '-', (137, 142))	('GCLC', 'Gene', '2729', (196, 200))	('HO-1', 'Gene', '3162', (205, 209))	('ML385', 'Chemical', '-', (233, 238))	('inhibited', 'NegReg', (124, 133))
274171	32576270	Notably, the mRNA expression levels of NRF2 and its target genes HO-1, GCLC, and NQO1 in A549 cells transfected with F174L, R234W, R320Q, and R413L KEAP1 mutants were dramatically decreased after treatment with ML385 (Fig.	('HO-1', 'Gene', '3162', (65, 69))	('F174L', 'Mutation', 'p.F174L', (117, 122))	('HO-1', 'Gene', (65, 69))	('A549', 'CellLine', 'CVCL:0023', (89, 93))	('ML385', 'Chemical', '-', (211, 216))	('GCLC', 'Gene', '2729', (71, 75))	('R234W', 'Mutation', 'p.R234W', (124, 129))	('R320Q', 'Var', (131, 136))	('R413L', 'Var', (142, 147))	('R234W', 'Var', (124, 129))	('R320Q', 'Mutation', 'p.R320Q', (131, 136))	('decreased', 'NegReg', (180, 189))	('mRNA expression levels', 'MPA', (13, 35))	('F174L', 'Var', (117, 122))	('NQO1', 'Gene', '1728', (81, 85))	('R413L', 'Mutation', 'p.R413L', (142, 147))	('GCLC', 'Gene', (71, 75))	('NQO1', 'Gene', (81, 85))	('NRF2', 'Gene', (39, 43))
274174	32576270	In addition, recent evidence suggests that in mouse models of lung cancers, activated Nrf2 inhibits the Fbxo22-dependent degradation of Bach1 via induction of Ho-1 expression, and high levels of Bach1 promoting metastasis.	('mouse', 'Species', '10090', (46, 51))	('activated', 'Var', (76, 85))	('Bach1', 'Gene', (195, 200))	('promoting', 'PosReg', (201, 210))	('Nrf2', 'Gene', '18024', (86, 90))	('Bach1', 'Gene', '12013', (195, 200))	('inhibits', 'NegReg', (91, 99))	('Fbxo22', 'Gene', '71999', (104, 110))	('lung cancer', 'Phenotype', 'HP:0100526', (62, 73))	('metastasis', 'CPA', (211, 221))	('Bach1', 'Gene', (136, 141))	('Ho-1', 'Gene', '15368', (159, 163))	('lung cancers', 'Disease', 'MESH:D008175', (62, 74))	('cancers', 'Phenotype', 'HP:0002664', (67, 74))	('Ho-1', 'Gene', (159, 163))	('lung cancers', 'Disease', (62, 74))	('induction', 'Reg', (146, 155))	('expression', 'MPA', (164, 174))	('Bach1', 'Gene', '12013', (136, 141))	('Fbxo22', 'Gene', (104, 110))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('lung cancers', 'Phenotype', 'HP:0100526', (62, 74))	('Nrf2', 'Gene', (86, 90))
274175	32576270	The loss-of-function mutation of KEAP1 promoted the tumorigenesis of Kras- and Pten-driven lung cancer cell lines in mice.	('lung cancer', 'Phenotype', 'HP:0100526', (91, 102))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('promoted', 'PosReg', (39, 47))	('tumor', 'Disease', (52, 57))	('loss-of-function', 'NegReg', (4, 20))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('mutation', 'Var', (21, 29))	('lung cancer', 'Disease', 'MESH:D008175', (91, 102))	('mice', 'Species', '10090', (117, 121))	('Kras', 'Gene', (69, 73))	('Pten', 'Gene', (79, 83))	('KEAP1', 'Gene', (33, 38))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('Pten', 'Gene', '19211', (79, 83))	('lung cancer', 'Disease', (91, 102))	('Kras', 'Gene', '16653', (69, 73))
274176	32576270	Moreover, the KEAP1/NRF2 pathway synergized with TP53 deletion mutation could induce LSCC and radiation resistance.	('induce', 'PosReg', (78, 84))	('LSCC', 'Disease', (85, 89))	('TP53', 'Gene', '7157', (49, 53))	('TP53', 'Gene', (49, 53))	('LSCC', 'Phenotype', 'HP:0030359', (85, 89))	('radiation resistance', 'CPA', (94, 114))	('deletion mutation', 'Var', (54, 71))	('KEAP1/NRF2 pathway', 'Pathway', (14, 32))
274177	32576270	However, no evidence that KEAP1 or NRF2 mutations identified in lung cancer patients are involved in tumorgenesis has been reported.	('lung cancer', 'Disease', (64, 75))	('patients', 'Species', '9606', (76, 84))	('lung cancer', 'Phenotype', 'HP:0100526', (64, 75))	('involved', 'Reg', (89, 97))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('NRF2', 'Gene', (35, 39))	('mutations', 'Var', (40, 49))	('lung cancer', 'Disease', 'MESH:D008175', (64, 75))	('tumorgenesis', 'Disease', (101, 113))	('tumorgenesis', 'Disease', 'None', (101, 113))
274178	32576270	In the present study, we found that the ability of the antioxidative stress response mediated by activation of the KEAP1/NRF2 pathway is higher in lung cancer cell lines with KEAP1 mutation (A549, NCI-H460, NCI-H838) than in lung cancer cell lines without KEAP1 mutation (NCI-H1299, NCI-H292, 95D, and SPCA1).	('lung cancer', 'Phenotype', 'HP:0100526', (147, 158))	('A549', 'CellLine', 'CVCL:0023', (191, 195))	('lung cancer', 'Disease', 'MESH:D008175', (225, 236))	('NCI-H292', 'CellLine', 'CVCL:0455', (283, 291))	('antioxidative stress', 'Phenotype', 'HP:0025464', (55, 75))	('lung cancer', 'Phenotype', 'HP:0100526', (225, 236))	('KEAP1', 'Gene', (175, 180))	('NCI-H1299', 'CellLine', 'CVCL:0060', (272, 281))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('activation', 'PosReg', (97, 107))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('lung cancer', 'Disease', (147, 158))	('oxidative stress', 'Phenotype', 'HP:0025464', (59, 75))	('KEAP1/NRF2 pathway', 'Pathway', (115, 133))	('lung cancer', 'Disease', (225, 236))	('NCI-H460', 'CellLine', 'CVCL:0459', (197, 205))	('SPCA1', 'Gene', (302, 307))	('higher', 'PosReg', (137, 143))	('mutation', 'Var', (181, 189))	('antioxidative stress response', 'MPA', (55, 84))	('SPCA1', 'Gene', '27032', (302, 307))	('lung cancer', 'Disease', 'MESH:D008175', (147, 158))
274179	32576270	Interestingly, compared with the lung cancer cell lines A549 and H460, which carry KEAP1 mutation, after stable transfection with WT KEAP1, the mRNA levels of NRF2 and its target genes are significantly increased in A549 and H460 lung cancer cell lines transfected with KEAP1 mutants.	('KEAP1', 'Gene', (270, 275))	('lung cancer', 'Phenotype', 'HP:0100526', (33, 44))	('A549', 'CellLine', 'CVCL:0023', (216, 220))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('lung cancer', 'Disease', (230, 241))	('A549', 'CellLine', 'CVCL:0023', (56, 60))	('H460', 'CellLine', 'CVCL:0459', (225, 229))	('H460', 'CellLine', 'CVCL:0459', (65, 69))	('lung cancer', 'Phenotype', 'HP:0100526', (230, 241))	('mutants', 'Var', (276, 283))	('NRF2', 'Gene', (159, 163))	('lung cancer', 'Disease', 'MESH:D008175', (33, 44))	('increased', 'PosReg', (203, 212))	('mRNA levels', 'MPA', (144, 155))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))	('lung cancer', 'Disease', 'MESH:D008175', (230, 241))	('lung cancer', 'Disease', (33, 44))
274180	32576270	Moreover, colony formation and migration were increased in A549 and H460 lung cancer cell lines transfected with KEAP1 mutants.	('lung cancer', 'Disease', 'MESH:D008175', (73, 84))	('KEAP1', 'Gene', (113, 118))	('A549', 'CellLine', 'CVCL:0023', (59, 63))	('migration', 'CPA', (31, 40))	('increased', 'PosReg', (46, 55))	('lung cancer', 'Disease', (73, 84))	('lung cancer', 'Phenotype', 'HP:0100526', (73, 84))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('mutants', 'Var', (119, 126))	('colony formation', 'CPA', (10, 26))	('H460', 'CellLine', 'CVCL:0459', (68, 72))
274181	32576270	Similarly, the grafted subcutaneous tumor sizes in nude mice were significantly larger in A549 cells transfected with the R320Q KEAP1 mutant than those inA549 cells transfected with WT KEAP1.	('A549', 'CellLine', 'CVCL:0023', (154, 158))	('larger', 'PosReg', (80, 86))	('R320Q', 'Mutation', 'p.R320Q', (122, 127))	('subcutaneous tumor', 'Phenotype', 'HP:0001482', (23, 41))	('A549', 'CellLine', 'CVCL:0023', (90, 94))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('R320Q', 'Var', (122, 127))	('KEAP1', 'Gene', (128, 133))	('tumor', 'Disease', (36, 41))	('nude mice', 'Species', '10090', (51, 60))
274182	32576270	These data suggest that the somatic mutations of KEAP1 identified in Chinese patients with LSCC likely promote the development of lung cancer through activation of the antioxidative stress response in the KEAP1/NRF2 pathway.	('lung cancer', 'Phenotype', 'HP:0100526', (130, 141))	('antioxidative stress', 'Phenotype', 'HP:0025464', (168, 188))	('activation', 'PosReg', (150, 160))	('mutations', 'Var', (36, 45))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('lung cancer', 'Disease', 'MESH:D008175', (130, 141))	('KEAP1', 'Gene', (49, 54))	('patients', 'Species', '9606', (77, 85))	('LSCC', 'Phenotype', 'HP:0030359', (91, 95))	('oxidative stress', 'Phenotype', 'HP:0025464', (172, 188))	('promote', 'PosReg', (103, 110))	('antioxidative stress response', 'MPA', (168, 197))	('lung cancer', 'Disease', (130, 141))
274183	32576270	Although genomic analysis identified some high-frequency gene mutations from LSCC, such as TP53, PI3KCA, and SOX2, no clear operationable targets for the treatment of LSCC have been found thus far.	('TP53', 'Gene', (91, 95))	('LSCC', 'Phenotype', 'HP:0030359', (77, 81))	('LSCC', 'Phenotype', 'HP:0030359', (167, 171))	('LSCC', 'Gene', (77, 81))	('SOX2', 'Gene', '6657', (109, 113))	('SOX2', 'Gene', (109, 113))	('TP53', 'Gene', '7157', (91, 95))	('PI3KCA', 'Disease', (97, 103))	('mutations', 'Var', (62, 71))
274188	32576270	Thus, it is tempting to presume that inhibitors of the KEAP1/NRF2 pathway will likely treat Lung cancer patients carrying KEAP1/NRF2 mutations.	('Lung cancer', 'Disease', (92, 103))	('Lung cancer', 'Disease', 'MESH:D008175', (92, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('mutations', 'Var', (133, 142))	('KEAP1/NRF2', 'Gene', (122, 132))	('treat', 'Reg', (86, 91))	('patients', 'Species', '9606', (104, 112))	('Lung cancer', 'Phenotype', 'HP:0100526', (92, 103))
274189	32576270	To date, some inhibitors of the KEAP1/NRF2 pathway have been identified, such as NRF2 inhibitors that inhibit this pathway: ML385, Brucea chinensis, clonazepa propionate, luteolin, all-trans retinoic acid, and flavonoid molecular compounds.	('flavonoid', 'Chemical', 'MESH:D005419', (210, 219))	('KEAP1/NRF2 pathway', 'Pathway', (32, 50))	('ML385', 'Chemical', '-', (124, 129))	('Brucea chinensis', 'Chemical', '-', (131, 147))	('inhibit', 'NegReg', (102, 109))	('clonazepa propionate', 'Chemical', '-', (149, 169))	('luteolin', 'Chemical', 'MESH:D047311', (171, 179))	('inhibitors', 'Var', (86, 96))	('NRF2', 'Gene', (81, 85))	('all-trans retinoic acid', 'Chemical', 'MESH:D014212', (181, 204))
274191	32576270	We further explored the effect of ML385 on the development of lung cancer cell lines with or without KEAP1 mutations.	('mutations', 'Var', (107, 116))	('lung cancer', 'Phenotype', 'HP:0100526', (62, 73))	('ML385', 'Chemical', '-', (34, 39))	('lung cancer', 'Disease', (62, 73))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('KEAP1', 'Gene', (101, 106))	('lung cancer', 'Disease', 'MESH:D008175', (62, 73))
274192	32576270	Compared with A549 lung cancer cell lines trasfected with WT KEAP1, proliferation of the A549 lung cancer cell line trasfected with the R320Q KEAP1 mutant was dramatically inhibited by ML385.	('lung cancer', 'Phenotype', 'HP:0100526', (19, 30))	('R320Q', 'Mutation', 'p.R320Q', (136, 141))	('proliferation', 'CPA', (68, 81))	('lung cancer', 'Disease', 'MESH:D008175', (94, 105))	('A549', 'CellLine', 'CVCL:0023', (89, 93))	('A549', 'CellLine', 'CVCL:0023', (14, 18))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('lung cancer', 'Disease', 'MESH:D008175', (19, 30))	('lung cancer', 'Disease', (94, 105))	('ML385', 'Chemical', '-', (185, 190))	('KEAP1', 'Gene', (142, 147))	('lung cancer', 'Phenotype', 'HP:0100526', (94, 105))	('inhibited', 'NegReg', (172, 181))	('R320Q', 'Var', (136, 141))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('lung cancer', 'Disease', (19, 30))
274193	32576270	These preliminary datas suggest that ML385 inhibits the proliferation of lung cancer cells with KEAP1 mutations by blocking the KEAP1/NRF2 antioxidant stress response pathway.	('lung cancer', 'Disease', 'MESH:D008175', (73, 84))	('ML385', 'Chemical', '-', (37, 42))	('blocking', 'NegReg', (115, 123))	('proliferation', 'CPA', (56, 69))	('KEAP1', 'Gene', (96, 101))	('mutations', 'Var', (102, 111))	('KEAP1/NRF2 antioxidant stress response pathway', 'Pathway', (128, 174))	('lung cancer', 'Disease', (73, 84))	('ML385', 'Var', (37, 42))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('inhibits', 'NegReg', (43, 51))	('lung cancer', 'Phenotype', 'HP:0100526', (73, 84))
274194	32576270	It will provide a new option for therapy targeted to the KEAP1/NRF2 pathway in patients with LSCC carrying the KEAP1 mutation.	('KEAP1', 'Gene', (111, 116))	('patients', 'Species', '9606', (79, 87))	('LSCC', 'Disease', (93, 97))	('LSCC', 'Phenotype', 'HP:0030359', (93, 97))	('mutation', 'Var', (117, 125))
274196	32576270	The somatic nonsynonymous mutations in KEAP1 derived from patients with lung cancer likely promote tumorigenesis via activation of the KEAP1/NRF2 antioxidant stress response pathway.	('tumor', 'Disease', (99, 104))	('KEAP1', 'Gene', (39, 44))	('promote', 'PosReg', (91, 98))	('nonsynonymous mutations', 'Var', (12, 35))	('lung cancer', 'Disease', (72, 83))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('lung cancer', 'Phenotype', 'HP:0100526', (72, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('patients', 'Species', '9606', (58, 66))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('activation', 'PosReg', (117, 127))	('lung cancer', 'Disease', 'MESH:D008175', (72, 83))	('KEAP1/NRF2 antioxidant stress response pathway', 'Pathway', (135, 181))
274197	32576270	Notably, NRF2 inhibitor ML385 may inhibit the proliferation of tumor cells with KEAP1 mutation by enhancing the oxidative stress level of lung cancer cells.	('tumor', 'Disease', (63, 68))	('enhancing', 'PosReg', (98, 107))	('lung cancer', 'Disease', 'MESH:D008175', (138, 149))	('oxidative stress level', 'MPA', (112, 134))	('ML385', 'Var', (24, 29))	('lung cancer', 'Phenotype', 'HP:0100526', (138, 149))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('oxidative stress', 'Phenotype', 'HP:0025464', (112, 128))	('proliferation', 'CPA', (46, 59))	('ML385', 'Chemical', '-', (24, 29))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('lung cancer', 'Disease', (138, 149))	('inhibit', 'NegReg', (34, 41))	('KEAP1', 'Gene', (80, 85))	('mutation', 'Var', (86, 94))
274202	29661164	The Helicase-like Transcription Factor (HLTF) is a tumor suppressor, altered in cancer either by gene hypermethylation or mRNA alternative splicing.	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('tumor', 'Disease', (51, 56))	('altered', 'Reg', (69, 76))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('Helicase', 'Gene', (4, 12))	('HLTF', 'Gene', (40, 44))	('mRNA alternative splicing', 'Var', (122, 147))	('Helicase', 'Gene', '164045', (4, 12))	('cancer', 'Disease', (80, 86))
274203	29661164	This study assessed the expression and the clinical relevance of wild-type (WT) and variant forms of HLTF RNAs in NSCLC.	('NSCLC', 'Phenotype', 'HP:0030358', (114, 119))	('variant', 'Var', (84, 91))	('NSCLC', 'Disease', (114, 119))	('HLTF RNAs', 'Gene', (101, 110))	('NSCLC', 'Disease', 'MESH:D002289', (114, 119))
274205	29661164	In silico analyses identified HLTF gene alterations more frequently in lung squamous cell carcinoma than in adenocarcinoma.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (76, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('HLTF gene', 'Gene', (30, 39))	('alterations', 'Var', (40, 51))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (71, 99))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (71, 99))	('adenocarcinoma', 'Disease', (108, 122))	('adenocarcinoma', 'Disease', 'MESH:D000230', (108, 122))	('lung squamous cell carcinoma', 'Disease', (71, 99))
274207	29661164	The subgroup of 25 patients presenting a combined low WT HLTF expression and a high I21R HLTF expression had a significantly worse disease-free survival than the other 146 patients in univariate (HR 1.96, CI 1.17-3.30; p = 0.011) and multivariate analyses (HR 1.98, CI 1.15-3.40; p = 0.014).	('low', 'NegReg', (50, 53))	('patients', 'Species', '9606', (19, 27))	('worse', 'NegReg', (125, 130))	('I21R', 'Var', (84, 88))	('patients', 'Species', '9606', (172, 180))	('disease-free survival', 'CPA', (131, 152))	('I21R', 'Mutation', 'p.I21R', (84, 88))
274208	29661164	A low WT HLTF expression with a high I21R HLTF expression is associated with a poor DFS.	('DFS', 'Disease', (84, 87))	('I21R', 'Var', (37, 41))	('I21R', 'Mutation', 'p.I21R', (37, 41))
274218	29661164	In cancer, two different alterations in HLTF expression were reported: (i) an epigenetic silencing by hypermethylation of its promoter and (ii) an alternative splicing of its mRNA, leading to the production of several shorter forms of the protein lacking DNA repair domains.	('epigenetic', 'MPA', (78, 88))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('production', 'MPA', (196, 206))	('cancer', 'Disease', (3, 9))	('HLTF', 'Gene', (40, 44))	('hypermethylation', 'Var', (102, 118))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
274219	29661164	The hypermethylation of HLTF promoter was first identified in colon cancer and was reported in other types of cancers, including gastric cancers.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('reported', 'Reg', (83, 91))	('cancers', 'Phenotype', 'HP:0002664', (137, 144))	('cancers', 'Disease', (137, 144))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('identified', 'Reg', (48, 58))	('gastric cancers', 'Disease', 'MESH:D013274', (129, 144))	('colon cancer', 'Disease', (62, 74))	('gastric cancers', 'Disease', (129, 144))	('gastric cancers', 'Phenotype', 'HP:0012126', (129, 144))	('cancers', 'Phenotype', 'HP:0002664', (110, 117))	('cancers', 'Disease', (110, 117))	('HLTF promoter', 'Gene', (24, 37))	('cancers', 'Disease', 'MESH:D009369', (137, 144))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('colon cancer', 'Phenotype', 'HP:0003003', (62, 74))	('hypermethylation', 'Var', (4, 20))	('colon cancer', 'Disease', 'MESH:D015179', (62, 74))	('cancers', 'Disease', 'MESH:D009369', (110, 117))
274224	29661164	Promoter hypermethylation was found in 21 patients (39.6%), including 9/20 squamous cell carcinoma (SCC) and 12/33 adenocarinoma (ADC).	('adenocarinoma', 'Disease', (115, 128))	('SCC', 'Gene', (100, 103))	('SCC', 'Phenotype', 'HP:0002860', (100, 103))	('found', 'Reg', (30, 35))	('SCC', 'Gene', '6317', (100, 103))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (75, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('squamous cell carcinoma', 'Disease', (75, 98))	('patients', 'Species', '9606', (42, 50))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (75, 98))	('adenocarinoma', 'Disease', 'None', (115, 128))	('Promoter hypermethylation', 'Var', (0, 25))
274225	29661164	Patients whose tumors harboured HLTF hypermethylation had shorter survival, in comparison with patients whose tumors had a hypomethylated HLTF promoter (log-rank, p = 0.035).	('shorter', 'NegReg', (58, 65))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('survival', 'MPA', (66, 74))	('patients', 'Species', '9606', (95, 103))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumors', 'Disease', 'MESH:D009369', (15, 21))	('Patients', 'Species', '9606', (0, 8))	('tumors', 'Disease', (110, 116))	('tumors', 'Disease', 'MESH:D009369', (110, 116))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('HLTF', 'Var', (32, 36))	('tumors', 'Disease', (15, 21))
274238	29661164	Among these, there were 33 of the adenocarcinoma (ADC) subtype (H1693, H2122, H2228, H2279, H1573, H1395, H522, H1792, H838, H1819, H4011, H2291, H2073, H1568, H920, H1993, H4006, HCC827, H3255, H23, H4019, H2126, H1437, H1944, H2009, H2405, H1373, H1355, H1975, HCC2935, A549, H650, H1650), two large cell carcinoma (H661, H4017), one mixed adenosquamous carcinoma (H647) and two of undefined histology (DFC1032, DFC1024).	('H4019', 'Var', (200, 205))	('adenosquamous carcinoma', 'Disease', 'MESH:D018196', (342, 365))	('H661', 'Var', (318, 322))	('H647', 'CellLine', 'CVCL:1574', (367, 371))	('A549', 'CellLine', 'CVCL:0023', (272, 276))	('H2126', 'CellLine', 'CVCL:1532', (207, 212))	('H1792', 'Var', (112, 117))	('H3255', 'Var', (188, 193))	('H1944', 'Var', (221, 226))	('H1373', 'Var', (242, 247))	('H2228', 'Var', (78, 83))	('H838', 'Var', (119, 123))	('H1355', 'CellLine', 'CVCL:1464', (249, 254))	('H1568', 'Var', (153, 158))	('H1437', 'Var', (214, 219))	('H1693', 'Var', (64, 69))	('H1437', 'CellLine', 'CVCL:1472', (214, 219))	('H2073', 'Var', (146, 151))	('H3255', 'CellLine', 'CVCL:6831', (188, 193))	('cell carcinoma', 'Disease', (302, 316))	('H2291', 'CellLine', 'CVCL:1546', (139, 144))	('H4017', 'Var', (324, 329))	('carcinoma', 'Phenotype', 'HP:0030731', (39, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (356, 365))	('H1944', 'CellLine', 'CVCL:1508', (221, 226))	('H1355', 'Var', (249, 254))	('H2009', 'Var', (228, 233))	('H1395', 'Var', (99, 104))	('H522', 'Var', (106, 110))	('H2009', 'CellLine', 'CVCL:1514', (228, 233))	('HCC827', 'Var', (180, 186))	('H1819', 'CellLine', 'CVCL:1497', (125, 130))	('H920', 'CellLine', 'CVCL:1599', (160, 164))	('carcinoma', 'Phenotype', 'HP:0030731', (307, 316))	('adenocarcinoma', 'Disease', (34, 48))	('H4006', 'CellLine', 'CVCL:1269', (173, 178))	('H2122', 'CellLine', 'CVCL:1531', (71, 76))	('H4019', 'CellLine', 'CVCL:1X16', (200, 205))	('H4011', 'Var', (132, 137))	('H2073', 'CellLine', 'CVCL:1521', (146, 151))	('H1573', 'CellLine', 'CVCL:1478', (92, 97))	('H2279', 'Var', (85, 90))	('A549', 'Var', (272, 276))	('HCC827', 'CellLine', 'CVCL:2063', (180, 186))	('H1819', 'Var', (125, 130))	('H1975', 'CellLine', 'CVCL:1511', (256, 261))	('H2291', 'Var', (139, 144))	('H2279', 'CellLine', 'CVCL:9642', (85, 90))	('H1975', 'Var', (256, 261))	('H1568', 'CellLine', 'CVCL:1476', (153, 158))	('HCC2935', 'CellLine', 'CVCL:1265', (263, 270))	('H920', 'Var', (160, 164))	('H1373', 'CellLine', 'CVCL:1465', (242, 247))	('H1693', 'CellLine', 'CVCL:1488', (64, 69))	('H4011', 'CellLine', 'CVCL:S700', (132, 137))	('H661', 'CellLine', 'CVCL:1577', (318, 322))	('cell carcinoma', 'Disease', 'MESH:C538614', (302, 316))	('HCC2935', 'Var', (263, 270))	('H23', 'Var', (195, 198))	('H2228', 'CellLine', 'CVCL:1543', (78, 83))	('adenosquamous carcinoma', 'Disease', (342, 365))	('H1993', 'CellLine', 'CVCL:1512', (166, 171))	('H2405', 'Var', (235, 240))	('large cell carcinoma', 'Phenotype', 'HP:0030360', (296, 316))	('H1573', 'Var', (92, 97))	('H1993', 'Var', (166, 171))	('H4006', 'Var', (173, 178))	('H1792', 'CellLine', 'CVCL:1495', (112, 117))	('adenocarcinoma', 'Disease', 'MESH:D000230', (34, 48))	('H2122', 'Var', (71, 76))	('H1650', 'Var', (284, 289))	('H2126', 'Var', (207, 212))	('H650', 'Var', (278, 282))
274244	29661164	This signal is then used in the calculation of HTLF copy number by a Poisson regression (QuantaSoft, Bio-Rad).	('Rad', 'Gene', '6236', (105, 108))	('HTLF', 'Gene', '3344', (47, 51))	('Rad', 'Gene', (105, 108))	('copy', 'Var', (52, 56))	('HTLF', 'Gene', (47, 51))
274250	29661164	The averages of the three replicates of WT and I21R HLTF expressions were tested for their associations with OS and DFS using the Cox proportional hazards regression.	('I21R', 'Mutation', 'p.I21R', (47, 51))	('Cox', 'Gene', '1351', (130, 133))	('Cox', 'Gene', (130, 133))	('HLTF', 'Gene', (52, 56))	('DFS', 'Disease', (116, 119))	('I21R', 'Var', (47, 51))	('associations', 'Interaction', (91, 103))	('OS', 'Chemical', '-', (109, 111))
274255	29661164	We collected available online data for HLTF alterations in NSCLC from TCGA (Lung ADC and SCC, TCGA Provisional 2015/02/04) and COSMIC, focusing on mutations, copy number alterations (CNAs), and methylation data.	('NSCLC', 'Disease', 'MESH:D002289', (59, 64))	('SCC', 'Gene', '6317', (89, 92))	('OS', 'Chemical', '-', (128, 130))	('NSCLC', 'Phenotype', 'HP:0030358', (59, 64))	('alterations', 'Var', (44, 55))	('HLTF', 'Gene', (39, 43))	('NSCLC', 'Disease', (59, 64))	('SCC', 'Gene', (89, 92))	('SCC', 'Phenotype', 'HP:0002860', (89, 92))
274259	29661164	HLTF copy number gain was more frequent in SCC (57% vs 23.3%, p < 0.0001) as well as high amplifications (26.1% s 2.1%, p < 0.0001).	('SCC', 'Gene', '6317', (43, 46))	('HLTF', 'Gene', (0, 4))	('copy number gain', 'Var', (5, 21))	('SCC', 'Gene', (43, 46))	('SCC', 'Phenotype', 'HP:0002860', (43, 46))
274261	29661164	HLTF mutation is a rare event both in ADC and SCC, 2.2 and 1.5%, respectively (Table 1).	('HLTF', 'Gene', (0, 4))	('ADC', 'Disease', (38, 41))	('SCC', 'Gene', (46, 49))	('SCC', 'Phenotype', 'HP:0002860', (46, 49))	('mutation', 'Var', (5, 13))	('SCC', 'Gene', '6317', (46, 49))
274262	29661164	The majority of the 13 mutations (12 missense and 1 splice site mutation) reported in ADC and 8 mutations (6 missense, 1 splice site and 1 nonsense mutations) in SCC are found in regions encoding functional domains involved in DNA binding (HIRAN domain), Sp1/Sp3 interaction (carboxyl-terminal domain), and DNA repair (SNF2_N/helicase-ATPase and RING finger domains) (Fig.	('ADC', 'Gene', (86, 89))	('Sp3', 'Gene', '6670', (259, 262))	('helicase', 'Gene', '164045', (326, 334))	('Sp3', 'Gene', (259, 262))	('mutations', 'Var', (23, 32))	('SCC', 'Gene', (162, 165))	('SCC', 'Phenotype', 'HP:0002860', (162, 165))	('helicase', 'Gene', (326, 334))	('SCC', 'Gene', '6317', (162, 165))
274271	29661164	There was no difference between SCC and ADC for WT and I21R HLTF expressions (p = 0.09 and 0.17, respectively).	('I21R', 'Var', (55, 59))	('I21R', 'Mutation', 'p.I21R', (55, 59))	('SCC', 'Gene', (32, 35))	('SCC', 'Phenotype', 'HP:0002860', (32, 35))	('HLTF', 'Gene', (60, 64))	('SCC', 'Gene', '6317', (32, 35))
274272	29661164	Overall, the level of HLTF expression was lower in tumours from patients than in cell lines (WT HLTF: 20.6 vs. 71.5, p = 9.3 x 10- 11 and I21R HLTF: 2.2 vs. 18.3, p = 2.8 x 10- 12, Wilcoxon rank-sum test; Fig.	('I21R', 'Var', (138, 142))	('patients', 'Species', '9606', (64, 72))	('lower', 'NegReg', (42, 47))	('tumour', 'Phenotype', 'HP:0002664', (51, 57))	('expression', 'MPA', (27, 37))	('tumours', 'Phenotype', 'HP:0002664', (51, 58))	('I21R', 'Mutation', 'p.I21R', (138, 142))	('tumours', 'Disease', 'MESH:D009369', (51, 58))	('HLTF', 'Protein', (22, 26))	('tumours', 'Disease', (51, 58))
274273	29661164	WT and I21R HLTF expressions were first tested for their association with patient clinical characteristics (age, sex, histology, and stage).	('patient', 'Species', '9606', (74, 81))	('I21R', 'Var', (7, 11))	('HLTF', 'Gene', (12, 16))	('I21R', 'Mutation', 'p.I21R', (7, 11))
274274	29661164	Second, we considered a composite covariate combining WT and I21R HLTF expressions dichotomized at their median levels.	('I21R', 'Var', (61, 65))	('I21R', 'Mutation', 'p.I21R', (61, 65))	('HLTF', 'Gene', (66, 70))
274276	29661164	A univariate analysis (Cox proportional hazard regression model and log-rank test) was first performed to assess the association between WT and I21R HLTF expression levels, and OS and DFS.	('Cox', 'Gene', (23, 26))	('I21R', 'Mutation', 'p.I21R', (144, 148))	('OS', 'Chemical', '-', (177, 179))	('HLTF', 'Protein', (149, 153))	('Cox', 'Gene', '1351', (23, 26))	('I21R', 'Var', (144, 148))	('expression levels', 'MPA', (154, 171))
274278	29661164	The association of the combined covariates of WT and I21R HLTF expression with OS and DFS were analyzed by the log-rank test.	('OS', 'Chemical', '-', (79, 81))	('HLTF', 'Gene', (58, 62))	('I21R', 'Var', (53, 57))	('DFS', 'Disease', (86, 89))	('I21R', 'Mutation', 'p.I21R', (53, 57))
274284	29661164	The expressions of WT (model 1) and I21R HLTF (model 2) were not associated with DFS.	('DFS', 'Disease', (81, 84))	('I21R', 'Mutation', 'p.I21R', (36, 40))	('I21R', 'Var', (36, 40))	('HLTF', 'Gene', (41, 45))
274286	29661164	The purpose of this study was to assess the expression of WT and variant forms of HLTF mRNAs in NSCLC and evaluate their clinical relevance.	('NSCLC', 'Disease', (96, 101))	('NSCLC', 'Disease', 'MESH:D002289', (96, 101))	('HLTF mRNAs', 'Gene', (82, 92))	('variant', 'Var', (65, 72))	('NSCLC', 'Phenotype', 'HP:0030358', (96, 101))
274287	29661164	Our hypothesis was that the expression of HLTF mRNA variant I21R has a poor prognosis on patients with NSCLC.	('I21R', 'Mutation', 'p.I21R', (60, 64))	('NSCLC', 'Disease', (103, 108))	('HLTF mRNA', 'Gene', (42, 51))	('NSCLC', 'Disease', 'MESH:D002289', (103, 108))	('I21R', 'Var', (60, 64))	('patients', 'Species', '9606', (89, 97))	('NSCLC', 'Phenotype', 'HP:0030358', (103, 108))
274289	29661164	The present study showed that in a cohort of 171 patients, the combination of low expression of WT HLTF transcript and high expression of I21R HLTF transcript was associated with poor prognosis in early stage NSCLC.	('NSCLC', 'Disease', 'MESH:D002289', (209, 214))	('I21R', 'Var', (138, 142))	('HLTF', 'Gene', (143, 147))	('low', 'NegReg', (78, 81))	('high', 'PosReg', (119, 123))	('NSCLC', 'Phenotype', 'HP:0030358', (209, 214))	('I21R', 'Mutation', 'p.I21R', (138, 142))	('patients', 'Species', '9606', (49, 57))	('NSCLC', 'Disease', (209, 214))
274290	29661164	Overall, in silico analysis showed that HLTF alterations, including gene amplifications, high expression, and methylation occurred more frequently in SCC than in ADC.	('SCC', 'Gene', '6317', (150, 153))	('alterations', 'Var', (45, 56))	('methylation', 'MPA', (110, 121))	('high expression', 'MPA', (89, 104))	('SCC', 'Gene', (150, 153))	('HLTF', 'Gene', (40, 44))	('SCC', 'Phenotype', 'HP:0002860', (150, 153))
274291	29661164	Mutations in HLTF were rare in both ADC and SCC; however, the mutations observed in ADC were different from those found in SCC.	('SCC', 'Gene', '6317', (44, 47))	('SCC', 'Phenotype', 'HP:0002860', (44, 47))	('SCC', 'Phenotype', 'HP:0002860', (123, 126))	('SCC', 'Gene', '6317', (123, 126))	('Mutations', 'Var', (0, 9))	('SCC', 'Gene', (44, 47))	('ADC', 'Disease', (84, 87))	('HLTF', 'Gene', (13, 17))	('SCC', 'Gene', (123, 126))
274292	29661164	Conversely, in SCC, mutations did not occur in functional domains but there are 2 nonsense mutations leading to the expression of a shorter protein containing only the DBD.	('expression', 'MPA', (116, 126))	('leading to', 'Reg', (101, 111))	('SCC', 'Gene', (15, 18))	('mutations', 'Var', (91, 100))	('SCC', 'Phenotype', 'HP:0002860', (15, 18))	('SCC', 'Gene', '6317', (15, 18))
274301	29661164	Spliced variants I21R lead to the expression of shorter protein forms, which are thought to disturb WT HLTF function and act as oncogene proteins.	('I21R', 'Mutation', 'p.I21R', (17, 21))	('variants I21R', 'Var', (8, 21))	('expression', 'MPA', (34, 44))	('disturb', 'Reg', (92, 99))	('I21R', 'Var', (17, 21))
274304	29661164	It was reported that the I21R transcripts have a lower abundance than the WT HLTF transcript in mouse heart and brain transcriptomes.	('mouse', 'Species', '10090', (96, 101))	('I21R', 'Mutation', 'p.I21R', (25, 29))	('abundance', 'MPA', (55, 64))	('lower', 'NegReg', (49, 54))	('I21R', 'Var', (25, 29))
274307	29661164	studied the methylation for several genes including HLTF in NSCLC and reported that patients with HLTF methylation have shorter survival; this study represents the only study of HLTF in lung cancer.	('survival', 'MPA', (128, 136))	('shorter', 'NegReg', (120, 127))	('patients', 'Species', '9606', (84, 92))	('lung cancer', 'Disease', 'MESH:D008175', (186, 197))	('NSCLC', 'Phenotype', 'HP:0030358', (60, 65))	('lung cancer', 'Disease', (186, 197))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('methylation', 'Var', (103, 114))	('NSCLC', 'Disease', (60, 65))	('lung cancer', 'Phenotype', 'HP:0100526', (186, 197))	('NSCLC', 'Disease', 'MESH:D002289', (60, 65))
274310	29661164	So far to our knowledge, our study is the first to assess the clinical impact of WT and variant forms of HLTF expression in patients with NSCLC.	('NSCLC', 'Disease', (138, 143))	('variant', 'Var', (88, 95))	('NSCLC', 'Disease', 'MESH:D002289', (138, 143))	('HLTF', 'Gene', (105, 109))	('NSCLC', 'Phenotype', 'HP:0030358', (138, 143))	('patients', 'Species', '9606', (124, 132))
274311	29661164	TCGA in silico analysis of HLTF alterations including mutations, amplification, and mRNA expression modifications were more frequent in SCC than in ADC.	('SCC', 'Gene', (136, 139))	('SCC', 'Phenotype', 'HP:0002860', (136, 139))	('HLTF', 'Gene', (27, 31))	('mutations', 'Var', (54, 63))	('SCC', 'Gene', '6317', (136, 139))	('mRNA expression modifications', 'MPA', (84, 113))	('amplification', 'MPA', (65, 78))	('alterations', 'Var', (32, 43))	('frequent', 'Reg', (124, 132))
274313	29661164	In a cohort of 171 patients with resected stage I-II NSCLC, the combination of a low WT HLTF expression with a high I21R HLTF expression was associated with shorter DFS both in univariate and multivariate analyses.	('I21R', 'Mutation', 'p.I21R', (116, 120))	('HLTF', 'Gene', (88, 92))	('NSCLC', 'Phenotype', 'HP:0030358', (53, 58))	('shorter', 'NegReg', (157, 164))	('patients', 'Species', '9606', (19, 27))	('DFS', 'MPA', (165, 168))	('NSCLC', 'Disease', (53, 58))	('I21R', 'Var', (116, 120))	('NSCLC', 'Disease', 'MESH:D002289', (53, 58))
274316	29661164	If validated in independant cohorts, the combination of low WT and high I21R HLTF might belong to this biomarker panel for the prognostic of surgically resected NSCLC.	('NSCLC', 'Disease', 'MESH:D002289', (161, 166))	('NSCLC', 'Phenotype', 'HP:0030358', (161, 166))	('I21R', 'Mutation', 'p.I21R', (72, 76))	('HLTF', 'Protein', (77, 81))	('NSCLC', 'Disease', (161, 166))	('high I21R', 'Var', (67, 76))
274320	29661164	ADC Adenocarcinoma CNA Copy number alteration DFS Disease-free survival HLTF Helicase-like transcription factor HR Hazard ratio ICC Intraclass coefficient NSCLC Non-small cell lung cancer OS Overall survival RT-ddPCR Reverse transcription-droplet digital PCR SCC Squamous cell carcinoma WT Wild-type LD and CM designed the study and wrote the manuscript.	('SCC', 'Gene', '6317', (259, 262))	('carcinoma', 'Phenotype', 'HP:0030731', (9, 18))	('Adenocarcinoma', 'Disease', 'MESH:D000230', (4, 18))	('Non-small cell lung cancer', 'Disease', (161, 187))	('SCC', 'Gene', (259, 262))	('carcinoma', 'Phenotype', 'HP:0030731', (277, 286))	('Non-small cell lung cancer', 'Phenotype', 'HP:0030358', (161, 187))	('NSCLC', 'Disease', 'MESH:D002289', (155, 160))	('alteration', 'Var', (35, 45))	('lung cancer', 'Phenotype', 'HP:0100526', (176, 187))	('Adenocarcinoma', 'Disease', (4, 18))	('NSCLC', 'Disease', (155, 160))	('SCC', 'Phenotype', 'HP:0002860', (259, 262))	('NSCLC', 'Phenotype', 'HP:0030358', (155, 160))	('Squamous cell carcinoma', 'Phenotype', 'HP:0002860', (263, 286))	('OS', 'Chemical', '-', (188, 190))	('Squamous cell carcinoma', 'Disease', (263, 286))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('Helicase', 'Gene', (77, 85))	('Squamous cell carcinoma', 'Disease', 'MESH:D002294', (263, 286))	('Non-small cell lung cancer', 'Disease', 'MESH:D002289', (161, 187))	('Helicase', 'Gene', '164045', (77, 85))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (165, 187))
274335	29642758	Previous studies revealed that mutations of various genes like tumor protein p53 (TP53), PIK3CA,  phosphatase and tensin homolog (PTEN), as well as aberrant copy number alterations of many oncogenes and tumor suppressors may be involved in the development and progression of cervical carcinoma.	('tumor', 'Disease', (203, 208))	('PIK3CA', 'Gene', '5290', (89, 95))	('cervical carcinoma', 'Disease', (275, 293))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('aberrant copy number alterations', 'Var', (148, 180))	('carcinoma', 'Phenotype', 'HP:0030731', (284, 293))	('p53', 'Gene', '7157', (77, 80))	('cervical carcinoma', 'Disease', 'MESH:D002575', (275, 293))	('PTEN', 'Gene', (130, 134))	('tumor', 'Disease', (63, 68))	('TP53', 'Gene', (82, 86))	('mutations', 'Var', (31, 40))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('PIK3CA', 'Gene', (89, 95))	('p53', 'Gene', (77, 80))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('PTEN', 'Gene', '5728', (130, 134))	('involved', 'Reg', (228, 236))	('TP53', 'Gene', '7157', (82, 86))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
274343	29642758	Bioinformatic analysis is an effective and practical method to predict the possible oncogenes and gene set variation in tumorigenesis or other pathological process.	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('variation', 'Var', (107, 116))	('tumor', 'Disease', (120, 125))
274373	29642758	Survival rate of patients with high expression score of DNA replication was significantly superior to those patients with low expression score (P < .001).	('superior', 'PosReg', (90, 98))	('Survival', 'CPA', (0, 8))	('DNA replication', 'Protein', (56, 71))	('patients', 'Species', '9606', (17, 25))	('high expression score', 'Var', (31, 52))	('patients', 'Species', '9606', (108, 116))
274378	29642758	On the other hand, high expression of MCM2, MCM4, MCM5, PCNA, and RNASEH2A could bring high rate of survival, which was consistent with the result of gene set survival curves we presented before.	('PCNA', 'Gene', '5111', (56, 60))	('RNASEH2A', 'Gene', (66, 74))	('MCM5', 'Gene', '4174', (50, 54))	('survival', 'CPA', (100, 108))	('MCM2', 'Var', (38, 42))	('RNASEH2A', 'Gene', '10535', (66, 74))	('MCM4', 'Gene', (44, 48))	('PCNA', 'Gene', (56, 60))	('MCM5', 'Gene', (50, 54))
274379	29642758	Together, high level of these 5 genes may be the promising prognostic factors to predict the better survival of cervical cancer.	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('cervical cancer', 'Disease', (112, 127))	('cervical cancer', 'Disease', 'MESH:D002583', (112, 127))	('high', 'Var', (10, 14))
274404	29642758	The level of MCM4 and PCNA was reported to be upregulated by mutant p53, a primary determinant in variety cancers.	('variety cancers', 'Disease', (98, 113))	('variety cancers', 'Disease', 'MESH:D009369', (98, 113))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('PCNA', 'Gene', (22, 26))	('cancers', 'Phenotype', 'HP:0002664', (106, 113))	('PCNA', 'Gene', '5111', (22, 26))	('mutant', 'Var', (61, 67))	('p53', 'Gene', (68, 71))	('p53', 'Gene', '7157', (68, 71))	('upregulated', 'PosReg', (46, 57))
274405	29642758	Tatsumi and Ishim also reported the detection of an MCM4 mutation in HeLa cells, and those cells where the mutant MCM4 was expressed had abnormal nuclear morphology, suggesting that DNA replication was perturbed in the presence of the mutant MCM4.	('mutation', 'Var', (57, 65))	('perturbed', 'NegReg', (202, 211))	('mutant', 'Var', (107, 113))	('abnormal', 'Reg', (137, 145))	('MCM4', 'Gene', (52, 56))	('DNA', 'CPA', (182, 185))	('nuclear morphology', 'CPA', (146, 164))	('mutant', 'Var', (235, 241))	('HeLa', 'CellLine', 'CVCL:0030', (69, 73))
274406	29642758	Since the mutant MCM4 may affect human MCM4/6/7 complex formation, the complex containing the mutant MCM4 protein is unstable and tend to be degraded, which would affect the proliferation of cancer further.	('complex', 'Interaction', (71, 78))	('protein', 'Protein', (106, 113))	('cancer', 'Disease', (191, 197))	('cancer', 'Disease', 'MESH:D009369', (191, 197))	('mutant', 'Var', (10, 16))	('MCM4/6/7', 'Gene', '4173;4175;4176', (39, 47))	('affect', 'Reg', (163, 169))	('MCM4', 'Gene', (101, 105))	('MCM4/6/7', 'Gene', (39, 47))	('mutant', 'Var', (94, 100))	('affect', 'Reg', (26, 32))	('degraded', 'NegReg', (141, 149))	('human', 'Species', '9606', (33, 38))	('human', 'Protein', (33, 38))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('proliferation', 'CPA', (174, 187))
274409	29642758	After finding the slightly reduced amount of protein level of MCM4 in Mcm4Chaos3/Chaos3 MEFs, they observed the development of breast cancer in Mcm4Chaos3 homozygous females further and proved the disposition to breast cancer and worse survival latency in homozygous females compared to wild-type mice.	('reduced', 'NegReg', (27, 34))	('MEFs', 'CellLine', 'CVCL:9115', (88, 92))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('protein level', 'MPA', (45, 58))	('breast cancer', 'Disease', (212, 225))	('amount', 'MPA', (35, 41))	('breast cancer', 'Disease', 'MESH:D001943', (127, 140))	('breast cancer', 'Phenotype', 'HP:0003002', (212, 225))	('breast cancer', 'Disease', (127, 140))	('Mcm4Chaos3', 'Var', (144, 154))	('breast cancer', 'Phenotype', 'HP:0003002', (127, 140))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('mice', 'Species', '10090', (297, 301))	('breast cancer', 'Disease', 'MESH:D001943', (212, 225))
274410	29642758	These findings suggest that hypomorphic alleles of the genes encoding the subunits of the MCM2-7 complex may increase breast cancer risk.	('hypomorphic alleles', 'Var', (28, 47))	('MCM2-7', 'Gene', (90, 96))	('MCM2-7', 'Gene', '4171;4172;4173;4174;4175;4176', (90, 96))	('increase', 'PosReg', (109, 117))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('breast cancer', 'Disease', 'MESH:D001943', (118, 131))	('breast cancer', 'Disease', (118, 131))	('breast cancer', 'Phenotype', 'HP:0003002', (118, 131))
274420	29642758	RNASEH2A gene can encode an enzyme in humans named Ribonuclease H2 subunit A; mutations in this gene cause a rare genetic disorder, Aicardi-Goutieres syndrome, which affects the brain and the skin.	('RNASEH2A', 'Gene', '10535', (0, 8))	('Ribonuclease H2 subunit A', 'Gene', (51, 76))	('genetic disorder', 'Disease', 'MESH:D030342', (114, 130))	('Aicardi-Goutieres syndrome', 'Disease', (132, 158))	('mutations', 'Var', (78, 87))	('Ribonuclease H2 subunit A', 'Gene', '10535', (51, 76))	('cause', 'Reg', (101, 106))	('humans', 'Species', '9606', (38, 44))	('genetic disorder', 'Disease', (114, 130))	('Aicardi-Goutieres syndrome', 'Disease', 'MESH:C535607', (132, 158))	('RNASEH2A', 'Gene', (0, 8))
274455	28664179	The patient, six months after initial diagnosis of FIGO (International Federation of Gynecology and Obstetrics) stage 1b, T1b N0 M0, vulvar carcinoma, developed swelling of the labia and increased drainage around the genital area.	('swelling of the labia', 'Phenotype', 'HP:0000065', (161, 182))	('drainage around the genital area', 'CPA', (197, 229))	('patient', 'Species', '9606', (4, 11))	('swelling of the labia', 'Disease', (161, 182))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))	('swelling of the labia', 'Disease', 'MESH:D004487', (161, 182))	('vulvar carcinoma', 'Disease', (133, 149))	('vulvar carcinoma', 'Disease', 'MESH:D014846', (133, 149))	('increased', 'PosReg', (187, 196))	('T1b N0 M0', 'Var', (122, 131))
274516	26169172	Many aberrant STPs have been associated with various cancers.	('cancers', 'Phenotype', 'HP:0002664', (53, 60))	('cancers', 'Disease', (53, 60))	('cancers', 'Disease', 'MESH:D009369', (53, 60))	('aberrant STPs', 'Var', (5, 18))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('associated', 'Reg', (29, 39))
274544	26169172	provide evidence to support a role for aberrant Rap1 activation in prostate cancer progression.	('prostate cancer', 'Disease', (67, 82))	('activation', 'PosReg', (53, 63))	('Rap1', 'Gene', '5906', (48, 52))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('prostate cancer', 'Disease', 'MESH:D011471', (67, 82))	('Rap1', 'Gene', (48, 52))	('prostate cancer', 'Phenotype', 'HP:0012125', (67, 82))	('aberrant', 'Var', (39, 47))
274555	26169172	Furthermore, there is research substantiating that the BRAF mutation is prominent in melanoma and colorectal cancer.	('colorectal cancer', 'Disease', (98, 115))	('mutation', 'Var', (60, 68))	('colorectal cancer', 'Disease', 'MESH:D015179', (98, 115))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('melanoma', 'Disease', (85, 93))	('BRAF', 'Gene', '673', (55, 59))	('colorectal cancer', 'Phenotype', 'HP:0003003', (98, 115))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('melanoma', 'Disease', 'MESH:D008545', (85, 93))	('BRAF', 'Gene', (55, 59))
274601	26169172	This result indicates that there might be a common region of aberrant signaling in these two cancers, which does not overlap with regions of aberrant signaling in other cancers.	('aberrant', 'Var', (61, 69))	('cancers', 'Disease', (93, 100))	('cancers', 'Disease', (169, 176))	('cancers', 'Phenotype', 'HP:0002664', (93, 100))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('cancers', 'Phenotype', 'HP:0002664', (169, 176))	('cancers', 'Disease', 'MESH:D009369', (93, 100))	('cancers', 'Disease', 'MESH:D009369', (169, 176))
274663	32860673	LAMC2 overexpression in cancer cells appears to promote tumor progression.	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('overexpression', 'Var', (6, 20))	('tumor', 'Disease', (56, 61))	('cancer', 'Disease', (24, 30))	('cancer', 'Disease', 'MESH:D009369', (24, 30))	('LAMC2', 'Gene', (0, 5))	('promote', 'PosReg', (48, 55))	('LAMC2', 'Gene', '3918', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
274675	32860673	The genomic profiles were determined by mutations, putative copy number alterations from GISTIC (Genomic Identification of Significant Targets in Cancer), mRNA expression Z scores (RNA-seq v.2 RSEM), and protein expression Z scores (RPPA).	('copy number alterations', 'Var', (60, 83))	('mutations', 'Var', (40, 49))	('protein expression', 'MPA', (204, 222))	('Cancer', 'Phenotype', 'HP:0002664', (146, 152))	('Cancer', 'Disease', (146, 152))	('mRNA expression', 'MPA', (155, 170))	('Cancer', 'Disease', 'MESH:D009369', (146, 152))
274709	32860673	These results indicated that highly expressed LAMC2 is a prognostic factor for HNSC.	('LAMC2', 'Gene', (46, 51))	('highly expressed', 'Var', (29, 45))	('HNSC', 'Disease', (79, 83))	('LAMC2', 'Gene', '3918', (46, 51))
274721	32860673	GO enrichment analysis according to GSEA analysis documented that LAMC2 and its significantly correlated genes were mainly link to gene silencing, gene silencing by RNA, and mRNA binding (Figure 10A).	('gene', 'Var', (147, 151))	('LAMC2', 'Gene', (66, 71))	('gene', 'MPA', (131, 135))	('LAMC2', 'Gene', '3918', (66, 71))	('link', 'Reg', (123, 127))	('mRNA', 'MPA', (174, 178))
274750	32860673	Some studies have demonstrated that LAMC3 mutation is linked to changes in the structure and function of the visual attention network, which modulates astrocyte migration and angiogenesis by modulating the activation of retinal microglia.	('retinal microglia', 'CPA', (220, 237))	('astrocyte migration', 'CPA', (151, 170))	('changes', 'Reg', (64, 71))	('modulates', 'Reg', (141, 150))	('structure', 'MPA', (79, 88))	('LAMC3', 'Gene', '10319', (36, 41))	('LAMC3', 'Gene', (36, 41))	('mutation', 'Var', (42, 50))	('function', 'MPA', (93, 101))	('angiogenesis', 'CPA', (175, 187))	('modulating', 'Reg', (191, 201))
274753	32860673	reported that LAMC3 mutations result in malformations of occipital cortical development.	('malformations', 'Disease', (40, 53))	('result in', 'Reg', (30, 39))	('LAMC3', 'Gene', '10319', (14, 19))	('mutations', 'Var', (20, 29))	('malformations', 'Disease', 'MESH:D000014', (40, 53))	('LAMC3', 'Gene', (14, 19))
274793	30918060	In addition, both NOKs pWPI and NOKs HPV16 E6E7 maintained their epithelial morphology in culture (Fig.	('E6E7', 'Var', (43, 47))	('epithelial morphology', 'CPA', (65, 86))	('HPV16', 'Species', '333760', (37, 42))
274795	30918060	3a, when the same cutoff (q < 0.05) was applied to the results from all methods (with fold changes of at least +-0.5), the combination of Bowtie2 and DESeq2 (BtDe) generated the smallest number of DE genes (301 in total; 120 up- and 181 downregulated).	('BtDe', 'Chemical', '-', (158, 162))	('up-', 'PosReg', (225, 228))	('downregulated', 'NegReg', (237, 250))	('Bowtie2', 'Var', (138, 145))
274805	30918060	STAT1 (a well-documented factor in gamma interferon signaling that is decreased upon HPV oncogene expression) not only displays a self-regulatory loop but additionally is regulated by five upstream factors, including a transcription factor (CNOT7) shown to negatively affect STAT1 expression.	('STAT1', 'Gene', '6772', (0, 5))	('CNOT7', 'Gene', (241, 246))	('self-regulatory loop', 'MPA', (130, 150))	('HPV oncogene expression', 'Var', (85, 108))	('STAT1', 'Gene', (275, 280))	('decreased', 'NegReg', (70, 79))	('CNOT7', 'Gene', '29883', (241, 246))	('STAT1', 'Gene', '6772', (275, 280))	('HPV', 'Species', '10566', (85, 88))	('expression', 'MPA', (281, 291))	('STAT1', 'Gene', (0, 5))
274808	30918060	Notably, knockdown of SPDEF was previously shown to increase the expression of HIF1alpha.	('knockdown', 'Var', (9, 18))	('increase', 'PosReg', (52, 60))	('HIF1alpha', 'Gene', (79, 88))	('SPDEF', 'Gene', (22, 27))	('SPDEF', 'Gene', '25803', (22, 27))	('expression', 'MPA', (65, 75))	('HIF1alpha', 'Gene', '3091', (79, 88))
274818	30918060	As expected, in cells expressing HPV oncogenes, processes favoring viral replication and propagation as well as host cell cycle were activated, whereas functions associated with immune responses were inhibited.	('oncogenes', 'Var', (37, 46))	('HPV oncogenes', 'Var', (33, 46))	('activated', 'PosReg', (133, 142))	('host cell cycle', 'CPA', (112, 127))	('viral replication', 'CPA', (67, 84))	('HPV', 'Species', '10566', (33, 36))	('propagation', 'CPA', (89, 100))
274819	30918060	These ratios, ranging from 40% (migration of cells, epithelial-mesenchymal transition of tumor cell lines) to up to 83% (viral infection), suggest that these regulators play a paramount role in HPV16 E6E7-expressing cells.	('HPV16', 'Gene', (194, 199))	('HPV16', 'Species', '333760', (194, 199))	('viral infection', 'Disease', 'MESH:D001102', (121, 136))	('E6E7-expressing', 'Var', (200, 215))	('viral infection', 'Disease', (121, 136))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
274826	30918060	We also found a deregulation of several gene families, including HOX genes, which are master transcriptional regulators with diverse roles in carcinogenesis, frizzled genes, a family of G protein-coupled receptor proteins that serve as receptors in the Wnt signaling pathway, and FK506 binding proteins, which have been shown to affect a wide range of cellular processes, including protein folding, receptor signaling, and apoptosis.	('carcinogenesis', 'Disease', (142, 156))	('carcinogenesis', 'Disease', 'MESH:D063646', (142, 156))	('FK506', 'Var', (280, 285))	('FK506', 'Chemical', 'MESH:D016559', (280, 285))	('receptor signaling', 'MPA', (399, 417))	('protein', 'Protein', (382, 389))	('apoptosis', 'CPA', (423, 432))	('frizzled genes', 'Gene', (158, 172))	('deregulation', 'Reg', (16, 28))	('affect', 'Reg', (329, 335))
274842	30918060	For both MMP2 and COL5A, the mRNA levels in HPV-positive tumor samples were significantly reduced, whereas the levels of CLDN7 were increased.	('MMP2', 'Gene', '4313', (9, 13))	('reduced', 'NegReg', (90, 97))	('COL5A', 'Var', (18, 23))	('CLDN7', 'Gene', (121, 126))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('mRNA levels', 'MPA', (29, 40))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('CLDN7', 'Gene', '1366', (121, 126))	('HPV', 'Species', '10566', (44, 47))	('MMP2', 'Gene', (9, 13))	('tumor', 'Disease', (57, 62))
274853	30918060	Therefore, we used freshly established HPV16 E6- and E7-expressing immortalized human oral keratinocytes and combined quantitative proteome and transcriptome analyses (Fig.	('HPV16', 'Species', '333760', (39, 44))	('HPV16', 'Gene', (39, 44))	('E7-expressing', 'Var', (53, 66))	('human', 'Species', '9606', (80, 85))	('E6-', 'Var', (45, 48))
274856	30918060	This suggests a substantial role of transcriptional regulation in the cellular changes caused by HPV16 E6E7.	('E6E7', 'Var', (103, 107))	('HPV16', 'Gene', (97, 102))	('HPV16', 'Species', '333760', (97, 102))
274873	30918060	While it is known that HPV16 can modulate host tryptophan metabolism, a key metabolic event contributing to immune escape by upregulating the immunoregulatory molecule indoleamine 2,3-dioxygenase (IDO 1), much less is known about the role of kynureninase (KYNU), another key enzyme in the kynurenine pathway.	('HPV16', 'Species', '333760', (23, 28))	('HPV16', 'Var', (23, 28))	('KYNU', 'Gene', '8942', (256, 260))	('modulate', 'Reg', (33, 41))	('host tryptophan metabolism', 'MPA', (42, 68))	('KYNU', 'Gene', (256, 260))	('kynurenine', 'Chemical', 'MESH:D007737', (289, 299))	('upregulating', 'PosReg', (125, 137))	('tryptophan', 'Chemical', 'MESH:D014364', (47, 57))
274883	30918060	Furthermore, network interactions can also be affected by the amount of E6/E7 oncoproteins within the respective host cell and may explain why transcriptomes of infected cells with high copy numbers differ from host cells, harboring only a few copies of integrated HPV.	('network interactions', 'MPA', (13, 33))	('HPV', 'Species', '10566', (265, 268))	('E6/E7', 'Var', (72, 77))	('affected', 'Reg', (46, 54))	('oncoproteins', 'Protein', (78, 90))
274893	30918060	NOKs pWPI and NOKs HPV16 E6E7 were kept in keratinocyte serum-free medium (SFM) (Life Technologies) containing recombinant human epidermal growth factor (rhEGF) and bovine pituitary gland extract (Life Technologies) for daily cultivating and passaging.	('HPV16 E6E7', 'Var', (19, 29))	('HPV16', 'Species', '333760', (19, 24))	('human', 'Species', '9606', (123, 128))	('bovine', 'Species', '9913', (165, 171))	('epidermal growth factor', 'Gene', (129, 152))	('epidermal growth factor', 'Gene', '1950', (129, 152))
274915	30918060	The proteomic data were achieved in a larger and integrated experiment involving comparison of NOKs pWPI, NOKs HPV16 E6E7, and NOKs HPV16 E6E7 infected with Chlamydia trachomatis.	('Chlamydia trachomatis', 'Species', '813', (157, 178))	('E6E7', 'Var', (138, 142))	('E6E7', 'Var', (117, 121))	('HPV16', 'Species', '333760', (111, 116))	('HPV16', 'Species', '333760', (132, 137))
274916	30918060	For the purpose of this study, only the data comparing NOKs HPV16 E6E7 to NOKs pWPI were further analyzed.	('HPV16', 'Gene', (60, 65))	('HPV16', 'Species', '333760', (60, 65))	('E6E7', 'Var', (66, 70))
274932	30918060	Data were searched against a database constructed by merging the reference proteome sets of Homo sapiens (downloaded from UniProt, accession number UP000005640, November 2017), human papillomavirus types 16 and 18 (accession numbers UP000106302 and UP000009109, respectively, November 2017), and Chlamydia trachomatis (accession number UP000050023, March 2017).	('human papillomavirus types', 'Species', '173087', (177, 203))	('accession number UP000005640', 'Disease', (131, 159))	('accession number UP000005640', 'Disease', 'MESH:D007674', (131, 159))	('Chlamydia trachomatis', 'Species', '813', (296, 317))	('Homo sapiens', 'Species', '9606', (92, 104))	('UP000009109', 'Var', (249, 260))
274956	29629426	Chromosomal translocations involving TMPRSS2, an androgen-regulated gene encoding a transmembrane serine protease, and members of the ETS transcription factor family including ERG, are frequently observed in prostate cancer.	('TMPRSS2', 'Gene', (37, 44))	('ERG', 'Gene', '2078', (176, 179))	('prostate cancer', 'Disease', 'MESH:D011471', (208, 223))	('Chromosomal', 'Var', (0, 11))	('observed', 'Reg', (196, 204))	('prostate cancer', 'Phenotype', 'HP:0012125', (208, 223))	('ERG', 'Gene', (176, 179))	('TMPRSS2', 'Gene', '7113', (37, 44))	('prostate cancer', 'Disease', (208, 223))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))
274959	29629426	The prognostic and predictive value of TMPRSS2-ERG fusions is still under active investigation; however, some studies have suggested an association of the fusion gene with higher recurrence risk and possibly even increased risk of prostate cancer-related death.	('TMPRSS2', 'Gene', (39, 46))	('prostate cancer', 'Disease', (231, 246))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('ERG', 'Gene', '2078', (47, 50))	('recurrence', 'CPA', (179, 189))	('death', 'Disease', 'MESH:D003643', (255, 260))	('prostate cancer', 'Disease', 'MESH:D011471', (231, 246))	('prostate cancer', 'Phenotype', 'HP:0012125', (231, 246))	('TMPRSS2', 'Gene', '7113', (39, 46))	('death', 'Disease', (255, 260))	('ERG', 'Gene', (47, 50))	('association', 'Interaction', (136, 147))	('fusion gene', 'Var', (155, 166))
274967	29629426	Base substitutions, short insertions, deletions, copy number changes, gene fusions, and rearrangements were identified.	('men', 'Species', '9606', (97, 100))	('copy number changes', 'Var', (49, 68))	('Base substitutions', 'Var', (0, 18))	('deletions', 'Var', (38, 47))
274976	29629426	The prostate cancer histologic subtypes with the fusion gene included acinar adenocarcinoma (n=214; 29.9% of cases), neuroendocrine carcinoma (n=18; 35.3%), undifferentiated carcinoma (n=11; 27.5%) and ductal adenocarcinoma (n=7; 36.8%).	('ductal adenocarcinoma', 'Disease', (202, 223))	('prostate cancer', 'Disease', 'MESH:D011471', (4, 19))	('neuroendocrine carcinoma', 'Disease', 'MESH:D018278', (117, 141))	('undifferentiated carcinoma', 'Disease', 'MESH:D002277', (157, 183))	('neuroendocrine carcinoma', 'Disease', (117, 141))	('prostate cancer', 'Phenotype', 'HP:0012125', (4, 19))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('carcinoma', 'Phenotype', 'HP:0030731', (174, 183))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('carcinoma', 'Phenotype', 'HP:0030731', (214, 223))	('acinar adenocarcinoma', 'Disease', (70, 91))	('acinar adenocarcinoma', 'Disease', 'MESH:D018267', (70, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('neuroendocrine carcinoma', 'Phenotype', 'HP:0100634', (117, 141))	('prostate cancer', 'Disease', (4, 19))	('ductal adenocarcinoma', 'Disease', 'MESH:D044584', (202, 223))	('undifferentiated carcinoma', 'Disease', (157, 183))	('fusion gene', 'Var', (49, 60))
274993	29629426	All three carcinoma specimens shared the TMPRSS2-ERG fusion, loss of PTEN exons 5-9, the TP53 missense mutation V147G, and variants of unknown significance in the genes PDGFRB (R177C) and PRKDC (S1660Y).	('carcinoma', 'Disease', (10, 19))	('V147G', 'Var', (112, 117))	('S1660Y', 'Mutation', 'p.S1660Y', (195, 201))	('men', 'Species', '9606', (25, 28))	('PTEN', 'Gene', '5728', (69, 73))	('TP53', 'Gene', '7157', (89, 93))	('carcinoma', 'Disease', 'MESH:D002277', (10, 19))	('ERG', 'Gene', (49, 52))	('PDGFRB', 'Gene', '5159', (169, 175))	('PDGFRB', 'Gene', (169, 175))	('PRKDC', 'Gene', '5591', (188, 193))	('TMPRSS2', 'Gene', '7113', (41, 48))	('TP53', 'Gene', (89, 93))	('ERG', 'Gene', '2078', (49, 52))	('PRKDC', 'Gene', (188, 193))	('V147G', 'Mutation', 'rs1453167097', (112, 117))	('TMPRSS2', 'Gene', (41, 48))	('R177C', 'Mutation', 'rs142683442', (177, 182))	('carcinoma', 'Phenotype', 'HP:0030731', (10, 19))	('PTEN', 'Gene', (69, 73))
274995	29629426	The adenocarcinoma metastasis also harbored a subclonal NFE2L2 mutation (W8C), while the squamous cell carcinoma carried a distinct variant of unknown significance (CIC G133C).	('carcinoma', 'Phenotype', 'HP:0030731', (9, 18))	('G133C', 'Mutation', 'rs374210352', (169, 174))	('NFE2L2', 'Gene', '4780', (56, 62))	('adenocarcinoma metastasis', 'Disease', 'MESH:D009362', (4, 29))	('mutation', 'Var', (63, 71))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (89, 112))	('NFE2L2', 'Gene', (56, 62))	('adenocarcinoma metastasis', 'Disease', (4, 29))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (89, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('squamous cell carcinoma', 'Disease', (89, 112))
275002	29629426	We observed TMPRSS2-ERG fusions in approximately 30% of prostate cancers which were predominantly adenocarcinoma, but the frequency of fusion-positive cases held true across histologic prostate tumor types.	('adenocarcinoma', 'Disease', (98, 112))	('ERG', 'Gene', '2078', (20, 23))	('prostate tumor', 'Disease', 'MESH:D011471', (185, 199))	('adenocarcinoma', 'Disease', 'MESH:D000230', (98, 112))	('ERG', 'Gene', (20, 23))	('TMPRSS2', 'Gene', '7113', (12, 19))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('prostate cancer', 'Phenotype', 'HP:0012125', (56, 71))	('prostate tumor', 'Disease', (185, 199))	('prostate cancers', 'Disease', 'MESH:D011471', (56, 72))	('prostate tumor', 'Phenotype', 'HP:0100787', (185, 199))	('cancers', 'Phenotype', 'HP:0002664', (65, 72))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('prostate cancers', 'Phenotype', 'HP:0012125', (56, 72))	('TMPRSS2', 'Gene', (12, 19))	('prostate cancers', 'Disease', (56, 72))	('fusions', 'Var', (24, 31))
275007	29629426	Interestingly, in a study of ERG gene rearrangements in small cell carcinoma of the prostate - a tumor type in which platinum-based chemotherapy is commonly used - the rate of ERG rearrangements was reported to be similar to that of prostatic acinar carcinomas.	('prostatic acinar carcinomas', 'Disease', 'MESH:D018267', (233, 260))	('carcinoma of the prostate', 'Disease', (67, 92))	('prostatic acinar carcinomas', 'Disease', (233, 260))	('small cell carcinoma', 'Phenotype', 'HP:0030357', (56, 76))	('ERG', 'Gene', (29, 32))	('rearrangements', 'Var', (38, 52))	('rearrangements', 'Var', (180, 194))	('tumor', 'Disease', (97, 102))	('ERG', 'Gene', '2078', (29, 32))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('ERG', 'Gene', (176, 179))	('men', 'Species', '9606', (47, 50))	('carcinoma of the prostate', 'Disease', 'MESH:D011472', (67, 92))	('men', 'Species', '9606', (189, 192))	('platinum', 'Chemical', 'MESH:D010984', (117, 125))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('ERG', 'Gene', '2078', (176, 179))	('carcinoma', 'Phenotype', 'HP:0030731', (250, 259))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('carcinomas', 'Phenotype', 'HP:0030731', (250, 260))
275014	29629426	Although this event represents the vast majority of ETS rearrangements, TMPRSS2 can be rearranged with other biologically relevant partner genes that were not specifically studied here and that could be similarly pathognomonic for a prostatic origin of advanced cancer in men.	('cancer', 'Disease', (262, 268))	('men', 'Species', '9606', (272, 275))	('pathognomonic', 'Reg', (213, 226))	('men', 'Species', '9606', (65, 68))	('TMPRSS2', 'Gene', '7113', (72, 79))	('TMPRSS2', 'Gene', (72, 79))	('cancer', 'Phenotype', 'HP:0002664', (262, 268))	('prostatic origin of', 'Disease', (233, 252))	('cancer', 'Disease', 'MESH:D009369', (262, 268))	('rearranged', 'Var', (87, 97))
275043	25822850	The histology codes were grouped into five categories based largely on the International Agency for Research on Cancer (IARC) classifications: (1) small cell carcinoma (International Classification of Diseases for Oncology Third Edition [ICD-O-3] codes 8041-8045, 8246]) (2) squamous cell carcinoma (8050-8078, 8083,8084); (3) large cell carcinoma (8012-8031, 8035, 8310); (4) adenocarcinoma (8140, 8211, 8230,8231, 8255-8260, 8323, 8480-8490, 8550,8551, 8570-8574, 8576); and (5) BAC (8250-8254).	('small cell carcinoma', 'Disease', 'MESH:D018288', (147, 167))	('squamous cell carcinoma', 'Disease', (275, 298))	('carcinoma', 'Phenotype', 'HP:0030731', (382, 391))	('8323', 'Var', (427, 431))	('carcinoma', 'Phenotype', 'HP:0030731', (289, 298))	('cell carcinoma', 'Disease', 'MESH:C538614', (284, 298))	('IARC', 'Disease', (120, 124))	('8050-8078', 'Var', (300, 309))	('Oncology', 'Phenotype', 'HP:0002664', (214, 222))	('Cancer', 'Phenotype', 'HP:0002664', (112, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (158, 167))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (275, 298))	('Cancer', 'Disease', (112, 118))	('small cell carcinoma', 'Phenotype', 'HP:0030357', (147, 167))	('cell carcinoma', 'Disease', 'MESH:C538614', (153, 167))	('cell carcinoma', 'Disease', (333, 347))	('adenocarcinoma', 'Disease', (377, 391))	('8012-8031', 'Var', (349, 358))	('IARC', 'Disease', 'None', (120, 124))	('Cancer', 'Disease', 'MESH:D009369', (112, 118))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (275, 298))	('carcinoma', 'Phenotype', 'HP:0030731', (338, 347))	('8480-8490', 'Var', (433, 442))	('large cell carcinoma', 'Phenotype', 'HP:0030360', (327, 347))	('adenocarcinoma', 'Disease', 'MESH:D000230', (377, 391))	('small cell carcinoma', 'Disease', (147, 167))	('cell carcinoma', 'Disease', 'MESH:C538614', (333, 347))	('8140', 'Var', (393, 397))
275112	33540875	Methods: Herein, we report the design, synthesis, and anti-proliferative activity of new aminopyrimidine derivatives structurally related to RDS 3442 obtained by carrying out substitutions at position 6 of the pyrimidine core and/or on the 2-aniline ring of our hit.	('2-aniline', 'Chemical', '-', (240, 249))	('aminopyrimidine', 'Chemical', 'MESH:C012180', (89, 104))	('pyrimidine', 'Chemical', 'MESH:C030986', (210, 220))	('pyrimidine', 'Chemical', 'MESH:C030986', (94, 104))	('anti-proliferative activity', 'MPA', (54, 81))	('substitutions', 'Var', (175, 188))
275130	33540875	Thus, by keeping fixed the structure of the reference compound, we investigated the role of the chlorine atom in position 3 of the aniline ring by substitution with both electron-withdrawing and electron-donating groups (fluorine, methoxy or nitro group), proper of compounds 1b-d.	('chlorine', 'Chemical', 'MESH:D002713', (96, 104))	('fluorine', 'Chemical', 'MESH:D005461', (221, 229))	('substitution', 'Var', (147, 159))	('aniline', 'Chemical', 'MESH:C023650', (131, 138))	('nitro', 'Chemical', '-', (242, 247))	('investigated', 'Reg', (67, 79))
275150	33540875	In general, derivatives of series 2 caused significant negative regulation of cell proliferation for all five tumors, showing higher potencies than series 1, even with a slight cytotoxic activity for normal fibroblasts, anyway completely not significant when considered the concentrations required for antitumor activity.	('tumor', 'Disease', 'MESH:D009369', (306, 311))	('derivatives', 'Var', (12, 23))	('tumor', 'Disease', 'MESH:D009369', (110, 115))	('tumor', 'Phenotype', 'HP:0002664', (306, 311))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('negative', 'NegReg', (55, 63))	('tumor', 'Disease', (306, 311))	('tumors', 'Disease', (110, 116))	('tumors', 'Disease', 'MESH:D009369', (110, 116))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('cell proliferation', 'CPA', (78, 96))
275158	33540875	Among the compounds of series 1, propanediamine substituted derivatives were characterized by different substituents in meta position of the aniline portion whose activity decreases in the following order: F > NO2 > Cl   OCH3 (proper of derivatives 1b, 1d, 1a and 1c, respectively).	('NO2', 'Chemical', '-', (210, 213))	('C', 'Chemical', 'MESH:D002244', (216, 217))	('decreases', 'NegReg', (172, 181))	('F > NO2 >', 'Var', (206, 215))	('aniline', 'Chemical', 'MESH:C023650', (141, 148))	('activity', 'MPA', (163, 171))	('C', 'Chemical', 'MESH:D002244', (222, 223))	('F', 'Chemical', 'MESH:D005461', (206, 207))	('propanediamine', 'Chemical', '-', (33, 47))
275163	33540875	These results indicate that, for compounds bearing a m-Cl substituent on the aniline residue, the activity decreases in the following order with respect to the 6-amino group: dipropylamine > propanediamine > methylpiperazine (corresponding to derivatives 1e, 1a, and 1g, respectively).	('methylpiperazine', 'Chemical', '-', (208, 224))	('aniline', 'Chemical', 'MESH:C023650', (77, 84))	('C', 'Chemical', 'MESH:D002244', (55, 56))	('decreases', 'NegReg', (107, 116))	('m-Cl substituent', 'Var', (53, 69))	('activity', 'MPA', (98, 106))	('dipropylamine', 'MPA', (175, 188))	('dipropylamine', 'Chemical', '-', (175, 188))	('1e', 'Chemical', '-', (255, 257))	('propanediamine', 'Chemical', '-', (191, 205))
275169	33540875	Among this series, propanediamine substituted derivatives were characterized by different substituents in meta position of the aniline portion whose activity decreases in the following order: Cl > F > NO2   OCH3 (proper of derivatives 2a, 2b, 2d and 2c, respectively).	('aniline', 'Chemical', 'MESH:C023650', (127, 134))	('C', 'Chemical', 'MESH:D002244', (208, 209))	('NO2', 'Chemical', '-', (201, 204))	('activity', 'MPA', (149, 157))	('2d', 'Chemical', '-', (243, 245))	('2c', 'Chemical', '-', (250, 252))	('propanediamine', 'Chemical', '-', (19, 33))	('Cl > F >', 'Var', (192, 200))	('F', 'Chemical', 'MESH:D005461', (197, 198))	('C', 'Chemical', 'MESH:D002244', (192, 193))
275176	33540875	Overall, it can be stated that the introduction of the p-F benzyl ring on the nitrogen of the aniline residue led to a more significant decrease in cell viability for all the tested cell lines (N-benzyl substituted 2a proved to be from 4- to 13-fold more active than its analog 1a).	('N-benzyl', 'Chemical', '-', (194, 202))	('active', 'MPA', (255, 261))	('more', 'PosReg', (250, 254))	('nitrogen', 'Chemical', 'MESH:D009584', (78, 86))	('decrease', 'NegReg', (136, 144))	('p-F', 'Var', (55, 58))	('aniline', 'Chemical', 'MESH:C023650', (94, 101))	('cell viability', 'CPA', (148, 162))	('F', 'Chemical', 'MESH:D005461', (57, 58))
275321	33540875	Structure-activity relationship studies allowed us to conclude that it is possible to achieve an activity improvement when the aminopyrimidine core is endowed with: (i) a p-F benzyl ring on the nitrogen of the aniline residue in 2-position along with a primary aliphatic base as the propanediamine one in position 6; or (ii) a secondary aliphatic base as the dipropylamine in 6-position without the N-benzyl ring linked to the aniline substituent in position 2.	('nitrogen', 'Chemical', 'MESH:D009584', (194, 202))	('aminopyrimidine', 'Chemical', 'MESH:C012180', (127, 142))	('dipropylamine', 'Chemical', '-', (359, 372))	('activity', 'MPA', (97, 105))	('aniline', 'Chemical', 'MESH:C023650', (210, 217))	('N-benzyl', 'Chemical', '-', (399, 407))	('aniline', 'Chemical', 'MESH:C023650', (427, 434))	('F', 'Chemical', 'MESH:D005461', (173, 174))	('improvement', 'PosReg', (106, 117))	('p-F', 'Var', (171, 174))	('propanediamine', 'Chemical', '-', (283, 297))
275366	27835592	Epigenetic upregulation of ARL4C, due to DNA hypomethylation in the 3'-untranslated region, promotes tumorigenesis of lung squamous cell carcinoma ADP-ribosylation factor (ARF)-like 4c (ARL4C) expression, induced by a combination of Wnt/beta-catenin and EGF/Ras signaling, has been demonstrated to form epithelial morphogenesis.	('ARL4C', 'Gene', '10123', (27, 32))	('promotes', 'PosReg', (92, 100))	('tumorigenesis', 'CPA', (101, 114))	('beta-catenin and EGF', 'Gene', '1499;1950', (237, 257))	('ARL4C', 'Gene', '10123', (186, 191))	('hypomethylation', 'Var', (45, 60))	('ARL4C', 'Gene', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (118, 146))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('ARL4C', 'Gene', (186, 191))	('ARF', 'Disease', 'MESH:D058186', (172, 175))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (123, 146))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (118, 146))	('lung squamous cell carcinoma', 'Disease', (118, 146))	('ARF', 'Disease', (172, 175))	('upregulation', 'PosReg', (11, 23))
275368	27835592	It was also reported that ARL4C expression correlates with DNA hypomethylation in the 3'-untranslated region (UTR) of ARL4C gene during lymphogenesis.	('DNA hypomethylation', 'Var', (59, 78))	('ARL4C', 'Gene', '10123', (118, 123))	('ARL4C', 'Gene', '10123', (26, 31))	('ARL4C', 'Gene', (118, 123))	('expression', 'MPA', (32, 42))	('ARL4C', 'Gene', (26, 31))
275369	27835592	The current study was conducted to investigate the expression and functions of ARL4C due to DNA hypomethylation in lung and tongue cancers.	('cancers', 'Phenotype', 'HP:0002664', (131, 138))	('ARL4C', 'Gene', (79, 84))	('hypomethylation', 'Var', (96, 111))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('lung and tongue cancers', 'Disease', 'MESH:D014062', (115, 138))	('ARL4C', 'Gene', '10123', (79, 84))
275371	27835592	Although inhibition of Wnt/beta-catenin or Ras/MAP kinase signaling did not decrease ARL4C expression in NCI-H520 lung SCC cells, ARL4C DNA was clearly hypomethylated in the 3'-UTR.	('ARL4C', 'Gene', '10123', (85, 90))	('SCC', 'Gene', '6317', (119, 122))	('beta-catenin', 'Gene', '1499', (27, 39))	('hypomethylated', 'Var', (152, 166))	('NCI-H520', 'CellLine', 'CVCL:1566', (105, 113))	('ARL4C', 'Gene', '10123', (130, 135))	('beta-catenin', 'Gene', (27, 39))	('SCC', 'Gene', (119, 122))	('SCC', 'Phenotype', 'HP:0002860', (119, 122))	('ARL4C', 'Gene', (85, 90))	('ARL4C', 'Gene', (130, 135))
275375	27835592	These results suggest that ARL4C is expressed due to hypomethylation in the 3'-UTR for certain types of cancers and that ARL4C methylation status is involved in cancer cell function.	('cancer', 'Disease', (161, 167))	('ARL4C', 'Gene', '10123', (27, 32))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('ARL4C', 'Gene', '10123', (121, 126))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('ARL4C', 'Gene', (27, 32))	('ARL4C', 'Gene', (121, 126))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('cancers', 'Phenotype', 'HP:0002664', (104, 111))	('hypomethylation', 'Var', (53, 68))	('involved', 'Reg', (149, 157))	('cancer', 'Disease', (104, 110))	('cancers', 'Disease', (104, 111))	('cancers', 'Disease', 'MESH:D009369', (104, 111))
275381	27835592	Genetic alterations of Wnt/beta-catenin and EGF/Ras pathways are common in various types of cancer.	('Genetic alterations', 'Var', (0, 19))	('beta-catenin and EGF', 'Gene', '1499;1950', (27, 47))	('common', 'Reg', (65, 71))	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
275385	27835592	The underlying cause of genome-wide hypomethylation in cancers remains unknown, but the hypomethylation might cause genome instability and reactivation of transposons, resulting in the aberrant activation of oncogenes.	('cancers', 'Disease', 'MESH:D009369', (55, 62))	('activation', 'PosReg', (194, 204))	('transposons', 'Protein', (155, 166))	('oncogenes', 'Gene', (208, 217))	('reactivation', 'MPA', (139, 151))	('hypomethylation', 'Var', (88, 103))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('cause', 'Reg', (110, 115))	('cancers', 'Phenotype', 'HP:0002664', (55, 62))	('genome instability', 'MPA', (116, 134))	('cancers', 'Disease', (55, 62))
275386	27835592	Aberrant hypermethylation in cancer usually occurs at CpG islands, and the resulting changes effectively suppress transcription of tumor suppressor genes.	('cancer', 'Disease', (29, 35))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('Aberrant hypermethylation', 'Var', (0, 25))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('suppress', 'NegReg', (105, 113))	('changes', 'Var', (85, 92))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('hypermethylation', 'Var', (9, 25))	('tumor', 'Disease', (131, 136))	('transcription', 'MPA', (114, 127))	('cancer', 'Disease', 'MESH:D009369', (29, 35))
275387	27835592	In contrast, oncogene expression due to gene-specific hypomethylation also occurs in cancer.	('occurs', 'Reg', (75, 81))	('oncogene expression', 'MPA', (13, 32))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('cancer', 'Disease', (85, 91))	('hypomethylation', 'Var', (54, 69))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
275390	27835592	Thus, alterations in DNA methylation occur in cancer, including hypermethylation of tumor suppressor genes and hypomethylation of oncogenes.	('alterations', 'Var', (6, 17))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('DNA', 'Gene', (21, 24))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('cancer', 'Disease', (46, 52))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('hypermethylation', 'MPA', (64, 80))	('tumor', 'Disease', (84, 89))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('hypomethylation', 'MPA', (111, 126))
275392	27835592	For instance, DNA methylation was associated with aberrant gene expression, leading to tumorigenesis in NSCLC, such as squamous cell carcinoma (SCC).	('DNA methylation', 'Var', (14, 29))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (119, 142))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('SCC', 'Gene', (144, 147))	('SCC', 'Phenotype', 'HP:0002860', (144, 147))	('NSCLC', 'Disease', (104, 109))	('tumor', 'Disease', (87, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('NSCLC', 'Disease', 'MESH:D002289', (104, 109))	('SCC', 'Gene', '6317', (144, 147))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (119, 142))	('leading to', 'Reg', (76, 86))	('squamous cell carcinoma', 'Disease', (119, 142))	('NSCLC', 'Phenotype', 'HP:0030358', (104, 109))
275395	27835592	Hypermethylation of the promoter of tumor suppressor genes, such as FHIT, p16INK4a and RARbeta, was correlated with high expression of DNMT1 in NSCLC.	('NSCLC', 'Disease', (144, 149))	('p16INK4a', 'Gene', (74, 82))	('DNMT1', 'Gene', (135, 140))	('DNMT1', 'Gene', '1786', (135, 140))	('NSCLC', 'Disease', 'MESH:D002289', (144, 149))	('FHIT', 'Disease', 'None', (68, 72))	('Hypermethylation', 'Var', (0, 16))	('RARbeta', 'Gene', '5915', (87, 94))	('expression', 'MPA', (121, 131))	('high', 'PosReg', (116, 120))	('FHIT', 'Disease', (68, 72))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('p16INK4a', 'Gene', '1029', (74, 82))	('NSCLC', 'Phenotype', 'HP:0030358', (144, 149))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('RARbeta', 'Gene', (87, 94))	('correlated', 'Reg', (100, 110))	('tumor', 'Disease', (36, 41))
275416	27835592	Genomic deletion and the complete loss of ARL4C protein in the knockout cells were confirmed (Figure 3A and Supplementary Figure 2B).	('ARL4C', 'Gene', (42, 47))	('protein', 'Protein', (48, 55))	('loss', 'NegReg', (34, 38))	('ARL4C', 'Gene', '10123', (42, 47))	('deletion', 'Var', (8, 16))
275417	27835592	ARL4C knockout suppressed proliferation of NCI-H520 cells in 2D culture conditions (Figure 3B).	('ARL4C', 'Gene', (0, 5))	('NCI-H520', 'CellLine', 'CVCL:1566', (43, 51))	('knockout', 'Var', (6, 14))	('ARL4C', 'Gene', '10123', (0, 5))	('suppressed', 'NegReg', (15, 25))	('proliferation', 'CPA', (26, 39))
275418	27835592	When SAS cells were grown in 3D culture conditions with Matrigel, knockout of ARL4C reduced the spherical area of the tumor by half (Figure 3C).	('knockout', 'Var', (66, 74))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('reduced', 'NegReg', (84, 91))	('ARL4C', 'Gene', '10123', (78, 83))	('tumor', 'Disease', (118, 123))	('ARL4C', 'Gene', (78, 83))
275420	27835592	ARL4C knockout also decreased the migration activity of NCI-H520 and SAS cells (Figure 3D), while ARL4C expression rescued the ARL4C-knockout phenotype in NCI-H520 cells (Figure 3E), excluding off target effects of the ARL4C knockout by CRISPR/Cas9.	('ARL4C', 'Gene', (0, 5))	('ARL4C', 'Gene', '10123', (127, 132))	('ARL4C', 'Gene', '10123', (219, 224))	('NCI-H520', 'CellLine', 'CVCL:1566', (155, 163))	('ARL4C', 'Gene', (127, 132))	('ARL4C', 'Gene', (219, 224))	('decreased', 'NegReg', (20, 29))	('NCI-H520', 'CellLine', 'CVCL:1566', (56, 64))	('ARL4C', 'Gene', '10123', (98, 103))	('knockout', 'Var', (6, 14))	('ARL4C', 'Gene', '10123', (0, 5))	('migration activity', 'CPA', (34, 52))	('ARL4C', 'Gene', (98, 103))
275421	27835592	It was shown that ARL4C mRNA is efficiently transcribed by the simultaneous activation of Wnt/beta-catenin and EGF/Ras pathways and that inhibition of these pathways suppressed ARL4C mRNA expression.	('ARL4C', 'Gene', '10123', (18, 23))	('ARL4C', 'Gene', (18, 23))	('inhibition', 'Var', (137, 147))	('beta-catenin and EGF', 'Gene', '1499;1950', (94, 114))	('ARL4C', 'Gene', '10123', (177, 182))	('ARL4C', 'Gene', (177, 182))	('suppressed', 'NegReg', (166, 176))	('activation', 'PosReg', (76, 86))
275423	27835592	The inhibition of the MAPK pathway by PD184161, a MEK1/2 inhibitor, suppressed ARL4C mRNA expression in SAS cells but not in NCI-H520 cells (Figure 4A), suggesting that ARL4C mRNA expression was dependent upon Ras/MAPK signaling in SAS cells.	('MAPK', 'Gene', (22, 26))	('ARL4C', 'Gene', (79, 84))	('PD184161', 'Var', (38, 46))	('MAPK', 'Gene', '5595;5594;5595', (22, 26))	('NCI-H520', 'CellLine', 'CVCL:1566', (125, 133))	('suppressed', 'NegReg', (68, 78))	('inhibition', 'NegReg', (4, 14))	('ARL4C', 'Gene', '10123', (169, 174))	('MEK1/2', 'Gene', '5604;5605', (50, 56))	('ARL4C', 'Gene', (169, 174))	('MEK1/2', 'Gene', (50, 56))	('PD184161', 'Chemical', 'MESH:C488185', (38, 46))	('MAPK', 'Gene', (214, 218))	('MAPK', 'Gene', '5595;5594;5595', (214, 218))	('ARL4C', 'Gene', '10123', (79, 84))
275425	27835592	It was also reported that transcription of ARL4C mRNA is increased by demethylation in the T-DMRs, in which 3 (CpG No.6 to CpG No.8) of 8 CpGs were highly hypomethylated, of the ARL4C gene 3'-UTR during T-cell development.	('transcription', 'MPA', (26, 39))	('ARL4C', 'Gene', (178, 183))	('ARL4C', 'Gene', '10123', (43, 48))	('increased', 'PosReg', (57, 66))	('ARL4C', 'Gene', '10123', (178, 183))	('demethylation', 'Var', (70, 83))	('ARL4C', 'Gene', (43, 48))
275426	27835592	Since the 3'-UTR (+2988 to +3744) of the human ARL4C gene also contains 8 CpGs, the methylation levels of CpG No.	('+2988 to +3744', 'Var', (18, 32))	('human', 'Species', '9606', (41, 46))	('ARL4C', 'Gene', '10123', (47, 52))	('methylation', 'MPA', (84, 95))	('ARL4C', 'Gene', (47, 52))
275427	27835592	8 (+3744) were analyzed for the 3'-UTR of the ARL4C gene.	('ARL4C', 'Gene', (46, 51))	('+3744', 'Var', (3, 8))	('ARL4C', 'Gene', '10123', (46, 51))
275438	27835592	Although ARL4C mRNA levels were slightly, but significantly, decreased by a using a combination of siRNAs against the three TET proteins (Supplementary Figure S4A), the slight reduction of ARL4C mRNA by knockdown of the three TET proteins did not affect NCI-H520 cell migration (Supplementary Figure S4B).	('reduction', 'NegReg', (176, 185))	('TET', 'Chemical', '-', (124, 127))	('NCI-H520', 'CellLine', 'CVCL:1566', (254, 262))	('ARL4C', 'Gene', (189, 194))	('combination', 'Interaction', (84, 95))	('ARL4C', 'Gene', '10123', (9, 14))	('ARL4C', 'Gene', (9, 14))	('TET', 'Chemical', '-', (226, 229))	('decreased', 'NegReg', (61, 70))	('ARL4C', 'Gene', '10123', (189, 194))	('knockdown', 'Var', (203, 212))
275446	27835592	In addition, to examine whether the alternation in DNA methylation status at the 3'-UTR of the ARL4C gene affects transcription, chromatin immunoprecipitation assay using the antibody for trimethylated H3K4 (H3K4me3), which is preferentially detected in transcriptional active genes, was performed.	('alternation', 'Var', (36, 47))	('ARL4C', 'Gene', (95, 100))	('affects', 'Reg', (106, 113))	('transcription', 'MPA', (114, 127))	('ARL4C', 'Gene', '10123', (95, 100))
275448	27835592	The putative binding site (+3605 to +3612) of cAMP-responsive element-binding protein (CREB) transcription factor was found around the 3'-UTR methylation sites using ECR Browser software (http://ecrbrowser.dcode.org).	('cAMP-responsive element-binding protein', 'Gene', (46, 85))	('+3605 to +3612', 'Var', (27, 41))	('CREB', 'Gene', (87, 91))	('CREB', 'Gene', '1385', (87, 91))	('cAMP-responsive element-binding protein', 'Gene', '1385', (46, 85))
275450	27835592	Therefore, we do not know at present whether the 3'-UTR methylation variation affects the interaction of transcriptional factors with the 3'-UTR of the ARL4C gene, but the 3'-UTR methylation could suppress ARL4C gene transcription.	('ARL4C', 'Gene', '10123', (206, 211))	('variation', 'Var', (68, 77))	('ARL4C', 'Gene', '10123', (152, 157))	('affects', 'Reg', (78, 85))	('suppress', 'NegReg', (197, 205))	('interaction', 'Interaction', (90, 101))	('transcription', 'MPA', (217, 230))	('ARL4C', 'Gene', (206, 211))	('ARL4C', 'Gene', (152, 157))	("3'-UTR methylation", 'Var', (172, 190))
275461	27835592	In addition, a significant inverse correlation between the level of ARL4C DNA methylation and gene expression was observed in the 3'-UTR more dominantly than the promoter region (Figure 6E) and especially in cg24441922 sites of the 3'-UTR (Supplementary Figure S6B), indicating that ARL4C DNA hypomethylation of the 3'-UTR might be essential for induction of ARL4C gene expression.	('cg24441922', 'Var', (208, 218))	('ARL4C', 'Gene', (68, 73))	('ARL4C', 'Gene', '10123', (359, 364))	('ARL4C', 'Gene', (359, 364))	('ARL4C', 'Gene', '10123', (283, 288))	('ARL4C', 'Gene', (283, 288))	('ARL4C', 'Gene', '10123', (68, 73))
275474	27835592	Since ARL4C regulates cellular migration and invasion through the activation of Rac and the inactivation of Rho, its overexpression in the peripheral areas of tumor lesions could promote invasiveness of cancer cells.	('inactivation', 'Var', (92, 104))	('ARL4C', 'Gene', (6, 11))	('regulates', 'Reg', (12, 21))	('tumor lesions', 'Disease', 'MESH:D051437', (159, 172))	('ARL4C', 'Gene', '10123', (6, 11))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('Rac', 'Gene', '5879', (80, 83))	('invasiveness of cancer', 'Disease', 'MESH:D009362', (187, 209))	('promote', 'PosReg', (179, 186))	('invasiveness of cancer', 'Disease', (187, 209))	('Rac', 'Gene', (80, 83))	('cellular migration', 'CPA', (22, 40))	('overexpression', 'PosReg', (117, 131))	('invasion', 'CPA', (45, 53))	('tumor lesions', 'Disease', (159, 172))	('Rho', 'Gene', (108, 111))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('activation', 'PosReg', (66, 76))
275475	27835592	Knockdown and knockout of ARL4C suppressed migration and proliferation of NCI-H520 and SAS cells.	('ARL4C', 'Gene', '10123', (26, 31))	('NCI-H520', 'CellLine', 'CVCL:1566', (74, 82))	('migration', 'CPA', (43, 52))	('knockout', 'Var', (14, 22))	('ARL4C', 'Gene', (26, 31))	('suppressed', 'NegReg', (32, 42))
275477	27835592	During the lineage-specific differentiation of thymocyte progenitors from hematopoietic progenitors, ARL4C was found to be upregulated and its 3'-UTR was hypomethylated, indicating that ARL4C expression is regulated by DNA methylation in the T-DMRs.	('ARL4C', 'Gene', '10123', (101, 106))	('ARL4C', 'Gene', '10123', (186, 191))	('upregulated', 'PosReg', (123, 134))	('ARL4C', 'Gene', (101, 106))	('ARL4C', 'Gene', (186, 191))	('hypomethylated', 'Var', (154, 168))
275480	27835592	In addition, lung SCC patients obtained from the TCGA dataset showed that ARL4C mRNA is highly expressed when the DNA is hypomethylated in the 3'-UTR and promoter region.	('highly', 'PosReg', (88, 94))	('SCC', 'Gene', (18, 21))	('patients', 'Species', '9606', (22, 30))	('ARL4C', 'Gene', '10123', (74, 79))	('SCC', 'Phenotype', 'HP:0002860', (18, 21))	('expressed', 'MPA', (95, 104))	('SCC', 'Gene', '6317', (18, 21))	('ARL4C', 'Gene', (74, 79))	('hypomethylated', 'Var', (121, 135))
275482	27835592	Lung adenocarcinoma patients from the TCGA dataset also showed high expression of ARL4C mRNA in tumor lesions with DNA hypomethylation in the 3'-UTR and inverse correlation between the levels of ARL4C DNA methylation and ARL4C mRNA expression.	('ARL4C', 'Gene', (195, 200))	('hypomethylation', 'Var', (119, 134))	('adenocarcinoma', 'Disease', (5, 19))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('expression', 'MPA', (68, 78))	('adenocarcinoma', 'Disease', 'MESH:D000230', (5, 19))	('ARL4C', 'Gene', '10123', (221, 226))	('ARL4C', 'Gene', (221, 226))	('tumor lesions', 'Disease', (96, 109))	('patients', 'Species', '9606', (20, 28))	('ARL4C', 'Gene', '10123', (82, 87))	('Lung adenocarcinoma', 'Phenotype', 'HP:0030078', (0, 19))	('inverse', 'NegReg', (153, 160))	('carcinoma', 'Phenotype', 'HP:0030731', (10, 19))	('ARL4C', 'Gene', '10123', (195, 200))	('ARL4C', 'Gene', (82, 87))	('tumor lesions', 'Disease', 'MESH:D051437', (96, 109))
275483	27835592	These results suggest that ARL4C overexpression is involved in tumorigenesis through ARL4C DNA hypomethylation in the 3'-UTR in lung cancer, such as SCC and adenocarcinoma.	('ARL4C', 'Gene', '10123', (27, 32))	('ARL4C', 'Gene', (27, 32))	('lung cancer', 'Disease', 'MESH:D008175', (128, 139))	('adenocarcinoma', 'Disease', (157, 171))	('SCC', 'Phenotype', 'HP:0002860', (149, 152))	('lung cancer', 'Phenotype', 'HP:0100526', (128, 139))	('tumor', 'Disease', (63, 68))	('SCC', 'Gene', '6317', (149, 152))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('adenocarcinoma', 'Disease', 'MESH:D000230', (157, 171))	('hypomethylation', 'Var', (95, 110))	('ARL4C', 'Gene', '10123', (85, 90))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (162, 171))	('ARL4C', 'Gene', (85, 90))	('SCC', 'Gene', (149, 152))	('involved', 'Reg', (51, 59))	('lung cancer', 'Disease', (128, 139))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
275484	27835592	Importantly, CpG No.6, CpG No.7, and CpG No.8 in the 3'-UTR were hypomethylated in cancer cells and the corresponding regions were also hypomethylated in T cell progenitors during lymphogenesis.	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('hypomethylated', 'Var', (65, 79))	('cancer', 'Disease', (83, 89))
275488	27835592	We found that Ets constitutively binds to the 3'-UTR (+3060 to +3067) of the mouse Arl4c gene, which corresponds to the 3'-UTR (+2852 to +2859) of the human ARL4C gene, and that a combination of Wnt3a and EGF induces formation of a complex between Ets, beta-catenin, and Tcf4, enhancing Arl4c mRNA expression.	('enhancing', 'PosReg', (277, 286))	('Arl4c mRNA expression', 'MPA', (287, 308))	('human', 'Species', '9606', (151, 156))	('+3060 to +3067', 'Var', (54, 68))	('Tcf4', 'Gene', (271, 275))	('Arl4c', 'Gene', (83, 88))	('beta-catenin', 'Gene', (253, 265))	('Wnt3a and EGF', 'Gene', '89780;1950', (195, 208))	('Tcf4', 'Gene', '6925', (271, 275))	('ARL4C', 'Gene', '10123', (157, 162))	('beta-catenin', 'Gene', '1499', (253, 265))	('mouse', 'Species', '10090', (77, 82))	('ARL4C', 'Gene', (157, 162))	('complex', 'Interaction', (232, 239))
275489	27835592	Since we showed that the 3'-UTR (+3622 to +3744) of the human ARL4C gene is demethylated by TET proteins, the 3'-UTR might be an essential site for the regulation of ARL4C expression by both growth factor signaling and epigenetic modification.	('ARL4C', 'Gene', '10123', (62, 67))	('ARL4C', 'Gene', '10123', (166, 171))	('TET', 'Chemical', '-', (92, 95))	('ARL4C', 'Gene', (62, 67))	('epigenetic modification', 'Var', (219, 242))	('human', 'Species', '9606', (56, 61))	('ARL4C', 'Gene', (166, 171))	('+3622 to +3744', 'Var', (33, 47))
275490	27835592	Although we do not know which transcription factor(s) are controlled by methylation of CpG sites in the 3'-UTR, transcription of the ARL4C gene could be upregulated by hypomethylation of its CpG sites, because a ChIP assay revealed that the level of H3K4me3 is decreased in the 3'-UTR of TET-knockout NCI-H520 cells.	('TET', 'Chemical', '-', (288, 291))	('hypomethylation', 'Var', (168, 183))	('ARL4C', 'Gene', '10123', (133, 138))	('upregulated', 'PosReg', (153, 164))	('NCI-H520', 'CellLine', 'CVCL:1566', (301, 309))	('ARL4C', 'Gene', (133, 138))	('transcription', 'MPA', (112, 125))
275493	27835592	Recently, TET proteins were also reported to be involved in tumorigenesis through DNA demethylation by regulating tumor suppressor genes or oncogenes.	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Disease', (114, 119))	('involved', 'Reg', (48, 56))	('TET', 'Chemical', '-', (10, 13))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('regulating', 'Reg', (103, 113))	('oncogenes', 'Gene', (140, 149))	('DNA', 'Var', (82, 85))	('tumor', 'Disease', (60, 65))
275494	27835592	For example, TET2 gene mutation and its catalytic inactivation are closely related to acute myeloid leukemia.	('myeloid leukemia', 'Phenotype', 'HP:0012324', (92, 108))	('related', 'Reg', (75, 82))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (86, 108))	('mutation', 'Var', (23, 31))	('leukemia', 'Phenotype', 'HP:0001909', (100, 108))	('TET2', 'Gene', '54790', (13, 17))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (86, 108))	('TET2', 'Gene', (13, 17))	('catalytic', 'MPA', (40, 49))	('acute myeloid leukemia', 'Disease', (86, 108))
275495	27835592	Leukemia-associated TET2 mutations cause loss of function with respect to TET2-mediated hydroxymethylation, leading to increased cytosine methylation in patients with TET2 mutations.	('mutations', 'Var', (172, 181))	('mutations', 'Var', (25, 34))	('TET2', 'Gene', (20, 24))	('Leukemia', 'Disease', 'MESH:D007938', (0, 8))	('patients', 'Species', '9606', (153, 161))	('TET2', 'Gene', '54790', (74, 78))	('TET2', 'Gene', '54790', (167, 171))	('cytosine', 'Chemical', 'MESH:D003596', (129, 137))	('Leukemia', 'Disease', (0, 8))	('TET2', 'Gene', (74, 78))	('TET2', 'Gene', '54790', (20, 24))	('Leukemia', 'Phenotype', 'HP:0001909', (0, 8))	('TET2', 'Gene', (167, 171))	('cytosine methylation', 'MPA', (129, 149))	('increased', 'PosReg', (119, 128))
275501	27835592	Tet1-deficient mouse embryonic stem cells (mESCs) maintained pluripotency and were largely normal, whereas knockout of both Tet1 and Tet2 or three Tets in mESCs showed severe abnormalities in differentiation.	('Tet1', 'Gene', (124, 128))	('were', 'MPA', (78, 82))	('mouse', 'Species', '10090', (15, 20))	('pluripotency', 'Disease', (61, 73))	('knockout', 'Var', (107, 115))	('pluripotency', 'Disease', 'None', (61, 73))
275502	27835592	It was also reported that knockdown of Tet1 or Tet2 minimally affects pluripotency gene Nanog mRNA expression, but knockdown of both Tet1 and Tet2 reduces Nanog mRNA expression significantly in mESCs and that TET1, TET2, and TET3 are required for the expression of the tumor suppressor gene TCF21 mRNA in cancer cells.	('tumor', 'Disease', 'MESH:D009369', (269, 274))	('reduces', 'NegReg', (147, 154))	('pluripotency', 'Disease', (70, 82))	('TET2', 'Gene', '54790', (215, 219))	('TET1', 'Gene', (209, 213))	('TCF21', 'Gene', (291, 296))	('knockdown', 'Var', (115, 124))	('tumor', 'Phenotype', 'HP:0002664', (269, 274))	('TET3', 'Gene', '200424', (225, 229))	('cancer', 'Disease', 'MESH:D009369', (305, 311))	('pluripotency', 'Disease', 'None', (70, 82))	('Tet1', 'Gene', (133, 137))	('Nanog', 'Gene', '79923', (155, 160))	('TET3', 'Gene', (225, 229))	('Nanog', 'Gene', (155, 160))	('TET2', 'Gene', (215, 219))	('TCF21', 'Gene', '6943', (291, 296))	('cancer', 'Disease', (305, 311))	('Nanog', 'Gene', '79923', (88, 93))	('TET1', 'Gene', '80312', (209, 213))	('tumor', 'Disease', (269, 274))	('Nanog', 'Gene', (88, 93))	('cancer', 'Phenotype', 'HP:0002664', (305, 311))
275507	27835592	Since we already demonstrated that ARL4C is overexpressed in lung adenocarcinoma and colon cancer through aberrant activation of growth factor signaling and that ARL4C depletion suppressed cancer cell proliferation and migration.	('activation', 'PosReg', (115, 125))	('ARL4C', 'Gene', '10123', (35, 40))	('ARL4C', 'Gene', (35, 40))	('colon cancer', 'Disease', 'MESH:D015179', (85, 97))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (61, 80))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('overexpressed', 'PosReg', (44, 57))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (61, 80))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('growth factor signaling', 'MPA', (129, 152))	('colon cancer', 'Disease', (85, 97))	('depletion', 'Var', (168, 177))	('cancer', 'Disease', (189, 195))	('ARL4C', 'Gene', '10123', (162, 167))	('suppressed', 'NegReg', (178, 188))	('colon cancer', 'Phenotype', 'HP:0003003', (85, 97))	('cancer', 'Disease', (91, 97))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('ARL4C', 'Gene', (162, 167))	('lung adenocarcinoma', 'Disease', (61, 80))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))
275523	27835592	HeLaS3, A549 and X293T cells were grown in Dulbecco's modified Eagle's medium (DMEM) supplemented with 10% fetal bovine serum (FBS).	('bovine', 'Species', '9913', (113, 119))	('HeLaS3', 'CellLine', 'CVCL:0058', (0, 6))	('X293T', 'SUBSTITUTION', 'None', (17, 22))	('FBS', 'Disease', 'MESH:D005198', (127, 130))	('DMEM', 'Chemical', '-', (79, 83))	('X293T', 'Var', (17, 22))	('A549', 'CellLine', 'CVCL:0023', (8, 12))	("Dulbecco's modified Eagle's medium", 'Chemical', '-', (43, 77))	('FBS', 'Disease', (127, 130))
275526	27835592	Anti-ARL4C antibody and anti-double strand (ds) DNA antibody were from Abcam (Cambridge, UK).	('ARL4C', 'Gene', (5, 10))	('anti-double strand', 'Var', (24, 42))	('ARL4C', 'Gene', '10123', (5, 10))
275529	27835592	Anti-phospho-p44/42 (ERK1/2) (Thr202/Tyr204) and anti-p44/42 (ERK1/2) antibodies were from Cell Signaling Technology (Beverly, MA, USA).	('ERK1/2', 'Gene', (62, 68))	('ERK1/2', 'Gene', (21, 27))	('p44', 'Gene', (54, 57))	('ERK1/2', 'Gene', '5595;5594', (21, 27))	('ERK1/2', 'Gene', '5595;5594', (62, 68))	('p44', 'Gene', (13, 16))	('p44', 'Gene', '10561', (54, 57))	('Thr202/Tyr204', 'Var', (30, 43))	('p44', 'Gene', '10561', (13, 16))	('Tyr204', 'Chemical', '-', (37, 43))	('Thr202', 'Chemical', '-', (30, 36))
275533	27835592	We used Probe ID on the Infinium HumanMethylation 450 array, cg24441922, cg05204104, and cg15016771 for the 3'-UTR or cg13539030, cg09453076, cg05308656, cg15235893 and cg09935994 for the promoter region of ARL4C DNA, respectively.	('cg09453076', 'Var', (130, 140))	('cg09935994', 'Var', (169, 179))	('ARL4C', 'Gene', (207, 212))	('cg05308656', 'Var', (142, 152))	('cg24441922', 'Var', (61, 71))	('cg15235893', 'Var', (154, 164))	('cg15016771', 'Var', (89, 99))	('ARL4C', 'Gene', '10123', (207, 212))	('cg13539030', 'Var', (118, 128))	('Human', 'Species', '9606', (33, 38))	('cg05204104', 'Var', (73, 83))
275573	33842373	Among the identified targets, genetic alterations occurred most frequently in EGFR (7%), particularly in glioblastoma, esophageal squamous cell cancer, head and neck squamous cell cancer, and non-small-cell lung cancer, and were associated with poor prognoses and survival of patients, while other targets were less frequently altered.	('patients', 'Species', '9606', (276, 284))	('occurred', 'Reg', (50, 58))	('head and neck squamous cell cancer', 'Disease', 'MESH:D000077195', (152, 186))	('EGFR', 'Gene', '1956', (78, 82))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('non-small-cell lung cancer', 'Disease', (192, 218))	('head and neck squamous cell cancer', 'Phenotype', 'HP:0012288', (152, 186))	('non-small-cell lung cancer', 'Disease', 'MESH:D002289', (192, 218))	('glioblastoma', 'Disease', 'MESH:D005909', (105, 117))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (166, 186))	('esophageal squamous cell cancer', 'Disease', 'MESH:D002294', (119, 150))	('glioblastoma', 'Disease', (105, 117))	('associated', 'Reg', (229, 239))	('lung cancer', 'Phenotype', 'HP:0100526', (207, 218))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('glioblastoma', 'Phenotype', 'HP:0012174', (105, 117))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (196, 218))	('genetic alterations', 'Var', (30, 49))	('EGFR', 'Gene', (78, 82))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (192, 218))	('esophageal squamous cell cancer', 'Disease', (119, 150))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (130, 150))
275574	33842373	NSC765598 displayed selective antiproliferative and cytotoxic preferences for NSCLC (50% growth inhibition (GI50) = 1.12-3.95 microM; total growth inhibition (TGI) = 3.72-16.60 muM), leukemia (GI50 = 1.20-3.10 microM; TGI = 3.90-12.70 muM), melanoma (GI50 = 1.45-3.59 microM), and renal cancer (GI50 = 1.38-3.40 microM; TGI = 4.84-13.70 muM) cell lines, while panels of colon, breast, ovarian, prostate, and central nervous system (CNS) cancer cell lines were less sensitive to NSC765598.	('NSC765598', 'Chemical', '-', (0, 9))	('melanoma', 'Disease', 'MESH:D008545', (241, 249))	('renal cancer', 'Phenotype', 'HP:0009726', (281, 293))	('melanoma', 'Disease', (241, 249))	('melanoma', 'Phenotype', 'HP:0002861', (241, 249))	('renal cancer', 'Disease', 'MESH:D007680', (281, 293))	('NSC765598', 'Var', (0, 9))	('NSC765598', 'Chemical', '-', (478, 487))	('central nervous system (CNS) cancer', 'Disease', 'MESH:D002493', (408, 443))	('leukemia', 'Disease', (183, 191))	('leukemia', 'Phenotype', 'HP:0001909', (183, 191))	('leukemia', 'Disease', 'MESH:D007938', (183, 191))	('cancer', 'Phenotype', 'HP:0002664', (437, 443))	('cancer', 'Phenotype', 'HP:0002664', (287, 293))	('NSCLC', 'Disease', (78, 83))	('renal cancer', 'Disease', (281, 293))	('NSCLC', 'Disease', 'MESH:D002289', (78, 83))
275575	33842373	Interestingly, NSC765598 docked well into the binding cavity of the targets by conventional H-bonds, van der Waal forces, and a variety of pi-interactions, with higher preferences for EGFR (DeltaG = -11.0 kcal/mol), NOS2 (DeltaG = -11.0 kcal/mol), and mTOR (DeltaG = -8.8 kcal/mol).	('pi-interactions', 'Var', (139, 154))	('EGFR', 'Gene', '1956', (184, 188))	('NOS2', 'Gene', '4843', (216, 220))	('EGFR', 'Gene', (184, 188))	('docked', 'Reg', (25, 31))	('mTOR', 'Gene', (252, 256))	('NSC765598', 'Chemical', '-', (15, 24))	('NOS2', 'Gene', (216, 220))	('mTOR', 'Gene', '2475', (252, 256))	('NSC765598', 'Var', (15, 24))
275576	33842373	NSC765598 shares similar anti-cancer fingerprints with NCI standard agents displayed acceptable physicochemical values and met the criteria of drug-likeness.	('NSC765598', 'Chemical', '-', (0, 9))	('C', 'Chemical', 'MESH:D002244', (56, 57))	('NSC765598', 'Var', (0, 9))	('cancer', 'Disease', (30, 36))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('C', 'Chemical', 'MESH:D002244', (2, 3))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
275577	33842373	NSC765598 displayed significant anticancer and potential multi-target properties, thus serve as a novel candidate worthy of further preclinical studies.	('NSC765598', 'Chemical', '-', (0, 9))	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('NSC765598', 'Var', (0, 9))	('cancer', 'Disease', (36, 42))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))
275596	33842373	As a continuing effort to find and screen more active derivatives of NDMC101, in the present study, we reported a new derivative, NSC765598, for anticancer activities and identified mTOR/EGR receptor (EGFR)/iNOS/MAP2K/TGF-beta1 (TGFB1)/fibroblast growth factor receptor-1 (FGFR1) as its potential targets.	('mTOR', 'Gene', '2475', (182, 186))	('iNOS', 'Gene', '4843', (207, 211))	('NDMC101', 'Chemical', 'MESH:C577570', (69, 76))	('fibroblast growth factor receptor-1', 'Gene', (236, 271))	('TGF-beta1', 'Gene', '7040', (218, 227))	('EGFR', 'Gene', (201, 205))	('FGFR1', 'Gene', '2260', (273, 278))	('cancer', 'Disease', (149, 155))	('EGFR', 'Gene', '1956', (201, 205))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('mTOR', 'Gene', (182, 186))	('NSC765598', 'Var', (130, 139))	('FGFR1', 'Gene', (273, 278))	('iNOS', 'Gene', (207, 211))	('TGFB1', 'Gene', '7040', (229, 234))	('TGF-beta1', 'Gene', (218, 227))	('fibroblast growth factor receptor-1', 'Gene', '2260', (236, 271))	('TGFB1', 'Gene', (229, 234))	('cancer', 'Disease', 'MESH:D009369', (149, 155))	('NSC765598', 'Chemical', '-', (130, 139))
275606	33842373	The crystal structures of MAPK2K (PDB:3FXW), FGF (PDB: 1IJT), the mTORdeltaN-mLST8 complex (PDB: 4JSN), tumor growth factor beta1 (PDB:1KLC), EGFR kinase (T790M/L858R) apo (PDB: 5EDP), and iNOS (PDB:2BHJ) were obtained from the Protein Data Bank  in protein data bank (PDB) file format and subsequently converted into the Auto Dock Pdbqt format using AutoDock Vina (vers.	('iNOS', 'Gene', '4843', (189, 193))	('mTOR', 'Gene', (66, 70))	('C', 'Chemical', 'MESH:D002244', (138, 139))	('T790M', 'Var', (155, 160))	('mTOR', 'Gene', '2475', (66, 70))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('iNOS', 'Gene', (189, 193))	('EGFR', 'Gene', '1956', (142, 146))	('EGFR', 'Gene', (142, 146))	('tumor', 'Disease', (104, 109))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('mLST8', 'Gene', '56716', (77, 82))	('T790M', 'SUBSTITUTION', 'None', (155, 160))	('L858R', 'SUBSTITUTION', 'None', (161, 166))	('MAPK2', 'Gene', '5594', (26, 31))	('L858R', 'Var', (161, 166))	('MAPK2', 'Gene', (26, 31))	('mLST8', 'Gene', (77, 82))
275621	33842373	The activity patterns (fingerprints) of NSC765598 were correlated to NCI synthetic compounds and standard agents using the DTP-COMPARE algorithms.	('C', 'Chemical', 'MESH:D002244', (42, 43))	('NSC765598', 'Var', (40, 49))	('C', 'Chemical', 'MESH:D002244', (70, 71))	('activity', 'MPA', (4, 12))	('NSC765598', 'Chemical', '-', (40, 49))	('C', 'Chemical', 'MESH:D002244', (127, 128))
275625	33842373	The growth inhibition by NSC765598 in the single-dose assay was obtained by subtracting the positive value on the plot from 100, i.e., a value of 60 would indicate 40% growth inhibition.	('growth', 'MPA', (4, 10))	('NSC765598', 'Chemical', '-', (25, 34))	('NSC765598', 'Var', (25, 34))
275629	33842373	Interestingly, NSC765598 exhibited a high human intestinal absorption capability and was permeant to the blood-brain barrier (  Table 1  ).	('human', 'Species', '9606', (42, 47))	('permeant', 'MPA', (89, 97))	('NSC765598', 'Chemical', '-', (15, 24))	('human intestinal absorption', 'MPA', (42, 69))	('NSC765598', 'Var', (15, 24))
275630	33842373	Our PASS analysis of NSC765598 predicted among other activities, anti-inflammatory, antiangiogenic, and anti-proliferative activities, with Pa (probability of being active) values of 0.491, 0.443, and 0.205, respectively and low Pi (probability of being inactive) values of < 0.060, 0.029, and 0.092, respectively.	('NSC765598', 'Chemical', '-', (21, 30))	('NSC765598', 'Var', (21, 30))	('anti-proliferative', 'CPA', (104, 122))	('antiangiogenic', 'CPA', (84, 98))	('Pa', 'Chemical', 'MESH:D011478', (140, 142))	('anti-inflammatory', 'CPA', (65, 82))
275633	33842373	Coherent with the PASS target predictions, SwissTarget also identified EGFR, TGFB1, FGFR1, iNOS, VEGFR2, MAPK, and serine/threonine-protein kinase mTOR as top druggable targets of NSC765598 ( Supplementary Table 2 ).	('FGFR1', 'Gene', '2260', (84, 89))	('EGFR', 'Gene', '1956', (71, 75))	('TGFB1', 'Gene', '7040', (77, 82))	('serine', 'Chemical', 'MESH:D012694', (115, 121))	('mTOR', 'Gene', '2475', (147, 151))	('EGFR', 'Gene', (98, 102))	('TGFB1', 'Gene', (77, 82))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('NSC765598', 'Var', (180, 189))	('VEGFR2', 'Gene', (97, 103))	('FGFR1', 'Gene', (84, 89))	('VEGFR2', 'Gene', '3791', (97, 103))	('NSC765598', 'Chemical', '-', (180, 189))	('EGFR', 'Gene', '1956', (98, 102))	('men', 'Species', '9606', (198, 201))	('C', 'Chemical', 'MESH:D002244', (182, 183))	('EGFR', 'Gene', (71, 75))	('iNOS', 'Gene', (91, 95))	('iNOS', 'Gene', '4843', (91, 95))	('mTOR', 'Gene', (147, 151))
275634	33842373	Interestingly out of 1627 drug targets (459 of which were human protein targets) on PharmMapper, EGFR, TGF-betaR1, FGFR1 and -2, VEGFR2, iNOS, MAPK, HGFR, insulin-like growth factor 1 receptor (IGF1R), B-Raf proto-oncogene serine/threonine-protein kinase, serine/threonine-protein kinase Chk1, and cyclin-dependent kinase 5 (CDK5) activator 1 were predicted to be among the top 20 targets for NSC765598.	('IGF1R', 'Gene', (194, 199))	('FGFR1 and -2', 'Gene', '2260;2263', (115, 127))	('human', 'Species', '9606', (58, 63))	('insulin-like growth factor 1 receptor', 'Gene', (155, 192))	('EGFR', 'Gene', (130, 134))	('HGFR', 'Gene', (149, 153))	('VEGFR2', 'Gene', (129, 135))	('EGFR', 'Gene', (97, 101))	('VEGFR2', 'Gene', '3791', (129, 135))	('serine', 'Chemical', 'MESH:D012694', (256, 262))	('insulin-like growth factor 1 receptor', 'Gene', '3480', (155, 192))	('Chk1', 'Gene', (288, 292))	('CDK5) activator 1', 'Gene', '8851;1020', (325, 342))	('Chk1', 'Gene', '1111', (288, 292))	('serine', 'Chemical', 'MESH:D012694', (223, 229))	('HGFR', 'Gene', '4233', (149, 153))	('EGFR', 'Gene', '1956', (130, 134))	('cyclin-dependent kinase 5', 'Gene', '1020', (298, 323))	('NSC765598', 'Var', (393, 402))	('iNOS', 'Gene', (137, 141))	('EGFR', 'Gene', '1956', (97, 101))	('cyclin-dependent kinase 5', 'Gene', (298, 323))	('IGF1R', 'Gene', '3480', (194, 199))	('NSC765598', 'Chemical', '-', (393, 402))	('iNOS', 'Gene', '4843', (137, 141))
275638	33842373	Hub genes with the highest numbers of nodes were mTOR, MAP2K1, and EGFR with 23, 14, and 13 nodes, respectively, and connectivity scores that ranged 0.433 to 0.999 (mTOR), 0.433-0.999 (EGFR), and 0.402 to 0.999 (MAP2K1), while FGFR1 (0.433-0.836), TGFB1 (0.473-0.965), and NOS2 (0.473) had the fewest nodes with four, four, and one, respectively.	('0.402', 'Var', (196, 201))	('FGFR1', 'Gene', '2260', (227, 232))	('EGFR', 'Gene', (67, 71))	('MAP2K1', 'Gene', '5604', (55, 61))	('mTOR', 'Gene', (49, 53))	('MAP2K1', 'Gene', (55, 61))	('EGFR', 'Gene', (185, 189))	('MAP2K1', 'Gene', '5604', (212, 218))	('MAP2K1', 'Gene', (212, 218))	('TGFB1', 'Gene', '7040', (248, 253))	('mTOR', 'Gene', '2475', (49, 53))	('TGFB1', 'Gene', (248, 253))	('FGFR1', 'Gene', (227, 232))	('EGFR', 'Gene', '1956', (67, 71))	('mTOR', 'Gene', (165, 169))	('EGFR', 'Gene', '1956', (185, 189))	('NOS2', 'Gene', '4843', (273, 277))	('NOS2', 'Gene', (273, 277))	('0.433-0.999', 'Var', (172, 183))	('mTOR', 'Gene', '2475', (165, 169))
275655	33842373	We found that of the 10,967 cancer cohorts representing 33 cancer types, genetic alterations in EGFR occurred in 821 (7%) cohorts of 26 cancer types ( Figure 6A ).	('genetic alterations', 'Var', (73, 92))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('EGFR', 'Gene', (96, 100))	('occurred', 'Reg', (101, 109))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('cancer', 'Disease', (136, 142))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('cancer', 'Disease', (28, 34))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('EGFR', 'Gene', '1956', (96, 100))
275656	33842373	EGFR mutations occurred most frequently in glioblastomas (47.3%), esophageal squamous cell carcinoma (17.89%), head and neck squamous cell carcinoma (12.62%), NSCLC (12.16%), esophagogastric adenocarcinomas (10.7%), and diffuse gliomas (10.53%), while pleural mesothelioma, seminoma, well-differentiated thyroid cancer, thymic epithelial tumor, ocular melanoma, and mature B cell neoplasm cohorts were devoid of EGFR mutations ( Figure 6A ).	('neoplasm', 'Phenotype', 'HP:0002664', (380, 388))	('gliomas', 'Disease', 'MESH:D005910', (228, 235))	('NSCLC', 'Disease', (159, 164))	('melanoma', 'Phenotype', 'HP:0002861', (352, 360))	('ocular melanoma', 'Disease', (345, 360))	('esophageal squamous cell carcinoma', 'Disease', (66, 100))	('glioma', 'Phenotype', 'HP:0009733', (228, 234))	('glioblastomas', 'Phenotype', 'HP:0012174', (43, 56))	('pleural mesothelioma', 'Disease', 'MESH:D008654', (252, 272))	('cancer', 'Phenotype', 'HP:0002664', (312, 318))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (125, 148))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (252, 272))	('EGFR', 'Gene', '1956', (412, 416))	('seminoma', 'Disease', (274, 282))	('neck squamous cell carcinoma', 'Disease', (120, 148))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (120, 148))	('gliomas', 'Phenotype', 'HP:0009733', (228, 235))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (77, 100))	('thyroid cancer', 'Disease', (304, 318))	('seminoma', 'Disease', 'MESH:D018239', (274, 282))	('epithelial tumor', 'Disease', (327, 343))	('epithelial tumor', 'Phenotype', 'HP:0031492', (327, 343))	('ocular melanoma', 'Phenotype', 'HP:0007716', (345, 360))	('epithelial tumor', 'Disease', 'MESH:D002277', (327, 343))	('EGFR', 'Gene', (0, 4))	('neoplasm', 'Disease', 'MESH:D009369', (380, 388))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (66, 100))	('occurred', 'Reg', (15, 23))	('tumor', 'Phenotype', 'HP:0002664', (338, 343))	('glioblastomas', 'Disease', (43, 56))	('mutations', 'Var', (5, 14))	('glioblastoma', 'Phenotype', 'HP:0012174', (43, 55))	('ocular melanoma', 'Disease', 'MESH:D008545', (345, 360))	('carcinoma', 'Phenotype', 'HP:0030731', (196, 205))	('adenocarcinomas', 'Disease', 'MESH:D000230', (191, 206))	('thyroid cancer', 'Disease', 'MESH:D013964', (304, 318))	('adenocarcinomas', 'Disease', (191, 206))	('neoplasm', 'Disease', (380, 388))	('glioblastomas', 'Disease', 'MESH:D005909', (43, 56))	('pleural mesothelioma', 'Disease', (252, 272))	('gliomas', 'Disease', (228, 235))	('EGFR', 'Gene', (412, 416))	('carcinoma', 'Phenotype', 'HP:0030731', (139, 148))	('NSCLC', 'Disease', 'MESH:D002289', (159, 164))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('thyroid cancer', 'Phenotype', 'HP:0002890', (304, 318))	('EGFR', 'Gene', '1956', (0, 4))
275657	33842373	The most common alterations of EGFR gene were amplification and gene gain, while gene deletions were the least common alterations in EGFR genes ( Figures 6A, E  ).	('EGFR', 'Gene', '1956', (31, 35))	('amplification', 'Var', (46, 59))	('gain', 'PosReg', (69, 73))	('EGFR', 'Gene', (31, 35))	('gene', 'MPA', (64, 68))	('EGFR', 'Gene', '1956', (133, 137))	('EGFR', 'Gene', (133, 137))
275658	33842373	These alterations in EGFR genes were associated with low OS (p < 10-10), disease-specific survival (p < 10-10), and disease-progression survival (p < 10-10) in those cohorts ( Figures 6B   -D ).	('EGFR', 'Gene', '1956', (21, 25))	('alterations', 'Var', (6, 17))	('EGFR', 'Gene', (21, 25))	('low OS', 'Disease', (53, 59))	('disease-specific survival', 'CPA', (73, 98))	('associated', 'Reg', (37, 47))	('disease-progression survival', 'CPA', (116, 144))
275659	33842373	We also determine the gene alteration co-occurrence frequencies with respect to EGFR-altered and EGFR-unaltered cohorts and found a number of other gene mutations that co-occurred with alteration of EGFR ( Figures 6F, G  ).	('EGFR', 'Gene', (199, 203))	('mutations', 'Var', (153, 162))	('alteration', 'Var', (185, 195))	('EGFR', 'Gene', '1956', (97, 101))	('EGFR', 'Gene', '1956', (80, 84))	('EGFR', 'Gene', (80, 84))	('EGFR', 'Gene', (97, 101))	('EGFR', 'Gene', '1956', (199, 203))
275660	33842373	The top ten gene mutations that were significantly (p value= 1.07 x 10-23 to 4.79 x 10-21 and q value 2.07 x 10-19 to 9.32 x 10-18) enriched in EGFR-altered cohorts were RICTOR, UGGT1, ATRNL1, AHNAK2, RIMS2, DSP, STXBP5L, DUOX2, PKD1L1, and MYH3 ( Figure 6F ,  Table 2 ), while only two genes, viz., KRAS (p = 11.7 x 10-03 and q = 2.22 x 10-03) and IDH1 (p = 0.017 and q = 0.0194) were enriched in unaltered EGFR cohorts ( Figure 6G ,  Table 2 ).	('PKD1L1', 'Gene', (229, 235))	('KRAS', 'Gene', (300, 304))	('UGGT1', 'Gene', '56886', (178, 183))	('DUOX2', 'Gene', (222, 227))	('IDH1', 'Gene', (349, 353))	('RICTOR', 'Gene', '253260', (170, 176))	('PKD1L1', 'Gene', '168507', (229, 235))	('RIMS2', 'Gene', '9699', (201, 206))	('DSP', 'Gene', (208, 211))	('mutations', 'Var', (17, 26))	('STXBP5L', 'Gene', (213, 220))	('RIMS2', 'Gene', (201, 206))	('RICTOR', 'Gene', (170, 176))	('EGFR', 'Gene', (408, 412))	('AHNAK2', 'Gene', '113146', (193, 199))	('MYH3', 'Gene', (241, 245))	('EGFR', 'Gene', '1956', (144, 148))	('IDH1', 'Gene', '3417', (349, 353))	('UGGT1', 'Gene', (178, 183))	('AHNAK2', 'Gene', (193, 199))	('enriched', 'Reg', (132, 140))	('EGFR', 'Gene', (144, 148))	('MYH3', 'Gene', '4621', (241, 245))	('DUOX2', 'Gene', '50506', (222, 227))	('EGFR', 'Gene', '1956', (408, 412))	('DSP', 'Gene', '1832', (208, 211))	('KRAS', 'Gene', '3845', (300, 304))	('STXBP5L', 'Gene', '9515', (213, 220))	('ATRNL1', 'Gene', (185, 191))	('ATRNL1', 'Gene', '26033', (185, 191))
275662	33842373	However, only 6% (662/10953), 4% (478/10967), 3% (346/10967), 1% (141/10967), and 1% (133/10967) of cohorts had FGFR, mTOR, iNOS, TGFB1, and MAP2K1 gene alterations (  Supplementary Figure 2  ) and were not associated (p > 0.05) with poor survival or prognosis (  Supplementary Figures 3-7  ).	('FGFR', 'Gene', (112, 116))	('TGFB1', 'Gene', (130, 135))	('alterations', 'Var', (153, 164))	('MAP2K1', 'Gene', (141, 147))	('iNOS', 'Gene', '4843', (124, 128))	('mTOR', 'Gene', (118, 122))	('iNOS', 'Gene', (124, 128))	('mTOR', 'Gene', '2475', (118, 122))	('men', 'Species', '9606', (270, 273))	('TGFB1', 'Gene', '7040', (130, 135))	('MAP2K1', 'Gene', '5604', (141, 147))	('men', 'Species', '9606', (174, 177))
275663	33842373	In order to evaluate the strength and nature of interactions between NSC765598 and the selected mapped pharmacophores, NSC765598 was docked into the active sites of EGFR, mTOR, NOS2, TGFB1, MAP2K1, and FGFR1.	('EGFR', 'Gene', (165, 169))	('MAP2K1', 'Gene', '5604', (190, 196))	('NSC765598', 'Chemical', '-', (119, 128))	('MAP2K1', 'Gene', (190, 196))	('NSC765598', 'Chemical', '-', (69, 78))	('interactions', 'Interaction', (48, 60))	('NSC765598', 'Var', (119, 128))	('TGFB1', 'Gene', '7040', (183, 188))	('FGFR1', 'Gene', (202, 207))	('NOS2', 'Gene', (177, 181))	('TGFB1', 'Gene', (183, 188))	('FGFR1', 'Gene', '2260', (202, 207))	('mTOR', 'Gene', (171, 175))	('mTOR', 'Gene', '2475', (171, 175))	('NOS2', 'Gene', '4843', (177, 181))	('EGFR', 'Gene', '1956', (165, 169))
275665	33842373	The NSC765598- mTOR complex was bonded by conventional H-bonds with GLN1937, VAL2227, and ARG2224, C-H bonding with GLN2200, halogen bonding with GLN1937 and VAL2227, and multiple pi-interactions.	('GLN2200', 'Var', (116, 123))	('VAL2227', 'Chemical', '-', (158, 165))	('C', 'Chemical', 'MESH:D002244', (99, 100))	('VAL2227', 'Var', (158, 165))	('ARG2224', 'Chemical', '-', (90, 97))	('GLN2200', 'Chemical', '-', (116, 123))	('VAL2227', 'Chemical', '-', (77, 84))	('halogen bonding', 'MPA', (125, 140))	('VAL2227', 'Var', (77, 84))	('GLN1937', 'Chemical', '-', (68, 75))	('mTOR', 'Gene', (15, 19))	('C', 'Chemical', 'MESH:D002244', (6, 7))	('GLN1937', 'Chemical', '-', (146, 153))	('NSC765598', 'Chemical', '-', (4, 13))	('C-H', 'MPA', (99, 102))	('GLN1937', 'Var', (68, 75))	('mTOR', 'Gene', '2475', (15, 19))	('GLN1937', 'Var', (146, 153))	('ARG2224', 'Var', (90, 97))
275666	33842373	NSC765598 also forms 4 hydrophobic contacts with LEU1936, GLN1937, and GLN2200 residues of mTOR.	('NSC765598', 'Chemical', '-', (0, 9))	('GLN2200', 'Chemical', '-', (71, 78))	('LEU1936', 'Chemical', '-', (49, 56))	('LEU1936', 'Var', (49, 56))	('hydrophobic contacts', 'MPA', (23, 43))	('GLN1937', 'Var', (58, 65))	('NSC765598', 'Var', (0, 9))	('GLN1937', 'Chemical', '-', (58, 65))	('mTOR', 'Gene', (91, 95))	('mTOR', 'Gene', '2475', (91, 95))	('GLN2200 residues', 'Var', (71, 87))
275667	33842373	Stabilization of NSC765598- mTOR complex was also supported by the Van der Waal forces between the ligand and ASP1933, PRO21146, ALA2226, GLU2196, MET2199, PRO1940, GLY2203, LEU2204, LEU1900, and ASN1899 residues of the receptor binding pocket (  Figure 7A  ).	('MET2199', 'Chemical', '-', (147, 154))	('mTOR', 'Gene', (28, 32))	('PRO1940', 'Chemical', '-', (156, 163))	('LEU1900', 'Var', (183, 190))	('ASN1899', 'Var', (196, 203))	('GLU2196', 'Chemical', '-', (138, 145))	('GLY2203', 'Var', (165, 172))	('GLU2196', 'Var', (138, 145))	('mTOR', 'Gene', '2475', (28, 32))	('LEU2204', 'Chemical', '-', (174, 181))	('ASN1899', 'Chemical', '-', (196, 203))	('NSC765598', 'Chemical', '-', (17, 26))	('PRO1940', 'Var', (156, 163))	('LEU2204', 'Var', (174, 181))	('MET2199', 'Var', (147, 154))	('ALA2226', 'Var', (129, 136))	('PRO21146', 'Chemical', '-', (119, 127))	('ASP1933', 'Chemical', '-', (110, 117))	('LEU1900', 'Chemical', '-', (183, 190))	('ALA2226', 'Chemical', '-', (129, 136))	('GLY2203', 'Chemical', '-', (165, 172))	('ASP1933', 'Var', (110, 117))	('PRO21146', 'Var', (119, 127))
275669	33842373	Molecular docking studies revealed that NSC765598 docked well into the MAP2K binding cavity with more robust interactions, stronger binding affinity (-7.6 kcal/mol), and shorter interaction distances (2.85-3.96 A) than the interaction observed between MAP2K and a standard inhibitor, mirdamatinib (-6.5 kcal/mol, 2.78-4.59 A).	('interactions', 'Interaction', (109, 121))	('interaction', 'Interaction', (178, 189))	('stronger', 'PosReg', (123, 131))	('binding affinity', 'Interaction', (132, 148))	('NSC765598', 'Var', (40, 49))	('mirdamatinib', 'Chemical', '-', (284, 296))	('MAP2K', 'Gene', (71, 76))	('NSC765598', 'Chemical', '-', (40, 49))
275670	33842373	There NSC765598-MAP2K complex was bonded by conventional H-bonds with Arg129 and Tyr174, a carbon-hydrogen bond with Arg141, halogen bonding with Glu145, Glu142, and Asp149, and multiple pi-interactions, including pi-anion interaction with Asp149, pi-sigma interaction with Glu142, and pi-alkylation with Arg141.	('pi-alkylation', 'Var', (286, 299))	('Glu145', 'Chemical', '-', (146, 152))	('Tyr174', 'Chemical', '-', (81, 87))	('Arg141', 'Chemical', '-', (305, 311))	('Asp149', 'Var', (240, 246))	('bonded', 'Reg', (34, 40))	('Asp149', 'Chemical', '-', (240, 246))	('pi-sigma', 'Var', (248, 256))	('carbon', 'Chemical', 'MESH:D002244', (91, 97))	('Tyr174', 'Var', (81, 87))	('hydrogen', 'Chemical', 'MESH:D006859', (98, 106))	('NSC765598', 'Chemical', '-', (6, 15))	('Glu142', 'Chemical', '-', (274, 280))	('pi-anion', 'Var', (214, 222))	('halogen', 'MPA', (125, 132))	('Glu142', 'Chemical', '-', (154, 160))	('Arg141', 'Chemical', '-', (117, 123))	('Asp149', 'Chemical', '-', (166, 172))	('NSC765598-MAP2K', 'Var', (6, 21))	('Arg129', 'Chemical', '-', (70, 76))	('Arg129', 'Var', (70, 76))
275671	33842373	NSC765598 also forms 4 hydrophobic contacts with ARG141, GLU142 and GLU145 residue of MAP2K.	('ARG141', 'Chemical', '-', (49, 55))	('NSC765598', 'Chemical', '-', (0, 9))	('MAP2K', 'Gene', (86, 91))	('ARG141', 'Var', (49, 55))	('GLU145', 'Chemical', '-', (68, 74))	('NSC765598', 'Var', (0, 9))	('GLU145 residue', 'Var', (68, 82))	('hydrophobic contacts', 'MPA', (23, 43))	('GLU142', 'Var', (57, 63))	('GLU142', 'Chemical', '-', (57, 63))
275672	33842373	Stabilization of the NSC765598-MAP2K complex was also supported by Van der Waal forces between the ligand and the amino acid residues (Gen312, Lys179, Ile146, Leu183, Ala181, and His96) in the receptor binding pocket (  Figure 7B ,  Table 3  ).	('Ile146', 'Var', (151, 157))	('His96', 'Var', (179, 184))	('Gen312', 'Chemical', '-', (135, 141))	('Gen312', 'Var', (135, 141))	('Ile146', 'Chemical', '-', (151, 157))	('NSC765598', 'Chemical', '-', (21, 30))	('Leu183', 'Var', (159, 165))	('Lys179', 'Chemical', '-', (143, 149))	('Lys179', 'Var', (143, 149))	('Ala181', 'Chemical', '-', (167, 173))	('Leu183', 'Chemical', '-', (159, 165))	('His96', 'Chemical', '-', (179, 184))	('Ala181', 'Var', (167, 173))
275674	33842373	The NSC765598-EGFR complex was bonded by strong H-bond interactions with GLU762 and CYS797, halogen bond interactions with ASN842, ARG841, and ASP855, and multiple pi-interactions, including pi-pi interaction with PHE723, pi-alkyl interaction with LEU844, and pi-sulfur interactions with MET790 and CYS797 (  Figure 7C  ).	('sulfur', 'Chemical', 'MESH:D013455', (263, 269))	('ASN842', 'Var', (123, 129))	('C', 'Chemical', 'MESH:D002244', (299, 300))	('PHE723', 'Var', (214, 220))	('LEU844', 'Chemical', '-', (248, 254))	('pi-pi', 'Var', (191, 196))	('ASP855', 'Chemical', '-', (143, 149))	('EGFR', 'Gene', '1956', (14, 18))	('ASN842', 'Chemical', '-', (123, 129))	('PHE723', 'Chemical', '-', (214, 220))	('ASP855', 'Var', (143, 149))	('pi-sulfur', 'Var', (260, 269))	('GLU762', 'Var', (73, 79))	('ARG841', 'Chemical', '-', (131, 137))	('C', 'Chemical', 'MESH:D002244', (317, 318))	('CYS797', 'Var', (84, 90))	('ARG841', 'Var', (131, 137))	('LEU844', 'Var', (248, 254))	('CYS797', 'Chemical', '-', (84, 90))	('C', 'Chemical', 'MESH:D002244', (6, 7))	('MET790', 'Var', (288, 294))	('CYS797', 'Var', (299, 305))	('NSC765598', 'Chemical', '-', (4, 13))	('EGFR', 'Gene', (14, 18))	('GLU762', 'Chemical', '-', (73, 79))	('H-bond', 'Protein', (48, 54))	('CYS797', 'Chemical', '-', (299, 305))	('C', 'Chemical', 'MESH:D002244', (84, 85))	('pi-alkyl', 'Var', (222, 230))	('halogen bond interactions', 'MPA', (92, 117))
275675	33842373	In terms of interaction distances between the ligand atoms and receptor atoms, the hydrogen bond interactions of GLU762 (2.42 A) and CYS797 (2.29 A) were the shortest, while pi-interactions of LEU844 (5.49 A), CYS797 (3.63 A), and MET790 (5.43 A) had longer distance interactions within the NSC765598-EGFR complex.	('CYS797', 'Chemical', '-', (133, 139))	('LEU844', 'Chemical', '-', (193, 199))	('NSC765598', 'Chemical', '-', (291, 300))	('CYS797', 'Chemical', '-', (210, 216))	('GLU762', 'Chemical', '-', (113, 119))	('hydrogen', 'Chemical', 'MESH:D006859', (83, 91))	('EGFR', 'Gene', '1956', (301, 305))	('LEU844', 'Var', (193, 199))	('EGFR', 'Gene', (301, 305))	('shortest', 'NegReg', (158, 166))	('CYS797', 'Var', (210, 216))	('hydrogen bond interactions', 'MPA', (83, 109))	('interactions', 'Interaction', (267, 279))
275676	33842373	NSC765598 also forms 5 hydrophobic contacts with PHE723 and LEU844 residues of EGFR.	('NSC765598', 'Chemical', '-', (0, 9))	('PHE723', 'Var', (49, 55))	('LEU844 residues', 'Var', (60, 75))	('EGFR', 'Gene', (79, 83))	('PHE723', 'Chemical', '-', (49, 55))	('NSC765598', 'Var', (0, 9))	('hydrophobic contacts', 'MPA', (23, 43))	('EGFR', 'Gene', '1956', (79, 83))	('LEU844', 'Chemical', '-', (60, 66))
275677	33842373	Stabilization of the NSC765598-EGFR complex was also supported by Van der Waal forces between the ligand and ARG858, LYS745, LEU788, and THR854 in receptor binding pockets (  Figure 7C ,  Table 3  ).	('Van der Waal', 'MPA', (66, 78))	('EGFR', 'Gene', '1956', (31, 35))	('LEU788', 'Var', (125, 131))	('THR854', 'Chemical', '-', (137, 143))	('NSC765598', 'Chemical', '-', (21, 30))	('C', 'Chemical', 'MESH:D002244', (183, 184))	('EGFR', 'Gene', (31, 35))	('C', 'Chemical', 'MESH:D002244', (23, 24))	('LYS745', 'Var', (117, 123))	('THR854', 'Var', (137, 143))	('LYS745', 'Chemical', '-', (117, 123))	('ARG858', 'Var', (109, 115))	('ARG858', 'Chemical', '-', (109, 115))	('LEU788', 'Chemical', '-', (125, 131))
275678	33842373	NSC765598 docked well with the binding pocket of FGFR1 with a binding affinity of -7.3 kcal/mol stronger than the interactions between FGFR and Erdafitinib (-5.7 Kcal/mol).	('NSC765598', 'Chemical', '-', (0, 9))	('binding', 'Interaction', (62, 69))	('NSC765598', 'Var', (0, 9))	('stronger', 'PosReg', (96, 104))	('FGFR1', 'Gene', (49, 54))	('Erdafitinib', 'Chemical', 'MESH:C000604580', (144, 155))	('FGFR1', 'Gene', '2260', (49, 54))
275680	33842373	In addition, halogen interactions (PRO120, 2.54 A and PRO149, 3.05 A), pi-pi stacking with the aromatic ring of PHE129, and Amide-Pi stacking with SER119 were also observed between the NSC765598_FGFR1 complex.	('PRO120', 'Var', (35, 41))	('NSC765598', 'Chemical', '-', (185, 194))	('FGFR1', 'Gene', (195, 200))	('PRO149', 'Var', (54, 60))	('FGFR1', 'Gene', '2260', (195, 200))	('Amide-Pi', 'Var', (124, 132))	('pi-pi', 'Var', (71, 76))	('observed', 'Reg', (164, 172))	('halogen interactions', 'MPA', (13, 33))
275681	33842373	NSC765598-FGFR1 complex was also supported by several Van der Waal forces created around the backbone of the ligand with respective amino acid residues (LYS81, GLU117, ARG134, PHE136, PHE151, PHE150, and SER127) of the receptor binding pocket (  Figure 8A ,  Table 4  ).	('NSC765598', 'Chemical', '-', (0, 9))	('LYS81', 'Var', (153, 158))	('LYS81', 'Chemical', '-', (153, 158))	('GLU117', 'Var', (160, 166))	('PHE151', 'Chemical', '-', (184, 190))	('PHE151', 'Var', (184, 190))	('SER127', 'Var', (204, 210))	('PHE136', 'Chemical', '-', (176, 182))	('ARG134', 'Gene', (168, 174))	('ARG134', 'Gene', '27335', (168, 174))	('GLU117', 'Chemical', '-', (160, 166))	('FGFR1', 'Gene', (10, 15))	('PHE150', 'Var', (192, 198))	('SER127', 'Chemical', '-', (204, 210))	('FGFR1', 'Gene', '2260', (10, 15))	('PHE136', 'Var', (176, 182))	('PHE150', 'Chemical', '-', (192, 198))
275683	33842373	NSC765598 interacts with iNOS by three H-bonds with TYR483, GLY196, and GLY363, and halogen interactions with GLN257, PRO344, and THR184.	('NSC765598', 'Chemical', '-', (0, 9))	('GLY196', 'Var', (60, 66))	('PRO344', 'Chemical', '-', (118, 124))	('iNOS', 'Gene', (25, 29))	('iNOS', 'Gene', '4843', (25, 29))	('GLY363', 'Chemical', '-', (72, 78))	('GLN257', 'Var', (110, 116))	('H-bonds', 'Interaction', (39, 46))	('GLY363', 'Var', (72, 78))	('NSC765598', 'Var', (0, 9))	('GLN257', 'Chemical', '-', (110, 116))	('GLY196', 'Chemical', '-', (60, 66))	('THR184', 'Var', (130, 136))	('TYR483', 'Var', (52, 58))	('TYR483', 'Chemical', '-', (52, 58))	('interacts', 'Reg', (10, 19))	('PRO344', 'Var', (118, 124))
275684	33842373	Binding interaction proximities in the NSC765598-iNOS complex ranged 2.65-3.28 A; the shortest distance interactions were conventional H-bonds with TYR483 (2.65 A) and GLY196 (2.87 A).	('TYR483', 'Chemical', '-', (148, 154))	('iNOS', 'Gene', '4843', (49, 53))	('GLY196', 'Var', (168, 174))	('iNOS', 'Gene', (49, 53))	('TYR483', 'Var', (148, 154))	('GLY196', 'Chemical', '-', (168, 174))	('NSC765598', 'Chemical', '-', (39, 48))
275685	33842373	The NSC765598-iNOS complex was also supported by pi-interactions; pi-pi stacking with aromatic rings of TRP188 and PHE363, and pi-alkyl interactions with CYS194, LEU203, and PRO344.	('iNOS', 'Gene', '4843', (14, 18))	('TRP188', 'Chemical', '-', (104, 110))	('LEU203', 'Var', (162, 168))	('iNOS', 'Gene', (14, 18))	('NSC765598', 'Chemical', '-', (4, 13))	('PHE363', 'Chemical', '-', (115, 121))	('CYS194', 'Chemical', '-', (154, 160))	('PRO344', 'Var', (174, 180))	('PRO344', 'Chemical', '-', (174, 180))	('pi-pi', 'Var', (66, 71))	('TRP188', 'Gene', (104, 110))	('PHE363', 'Var', (115, 121))	('pi-alkyl', 'Var', (127, 135))	('CYS194', 'Var', (154, 160))	('LEU203', 'Chemical', '-', (162, 168))
275686	33842373	The interaction was also stabilized by Van der Waal forces created on the backbone with the following amino acids: ILE238, SER236, GLN199, TRP366, MET368, TYR367, ALA345, VAL346, and ASN364 (  Figure 8B ,  Table 4  ).	('TYR367', 'Var', (155, 161))	('TRP366', 'Chemical', '-', (139, 145))	('ASN364', 'Var', (183, 189))	('GLN199', 'Chemical', '-', (131, 137))	('MET368', 'Var', (147, 153))	('VAL346', 'Chemical', '-', (171, 177))	('ILE238', 'Var', (115, 121))	('MET368', 'Chemical', '-', (147, 153))	('SER236', 'Chemical', '-', (123, 129))	('ASN364', 'Chemical', '-', (183, 189))	('ILE238', 'Chemical', '-', (115, 121))	('VAL346', 'Var', (171, 177))	('TYR367', 'Chemical', '-', (155, 161))	('ALA345', 'Var', (163, 169))	('GLN199', 'Var', (131, 137))	('ALA345', 'Chemical', '-', (163, 169))	('SER236', 'Var', (123, 129))	('TRP366', 'Var', (139, 145))
275687	33842373	Furthermore, NSC765598 interaction with iNOS is more robust and with higher affinity than the interactions between iNOS and N-Iminoethyl-L-lysine dihydrochloride (-5.3 Kcal/mol), a standard iNOS inhibitor (  Table 4  ).	('NSC765598', 'Chemical', '-', (13, 22))	('N-Iminoethyl-L-lysine dihydrochloride', 'Chemical', '-', (124, 161))	('NSC765598', 'Var', (13, 22))	('iNOS', 'Gene', '4843', (190, 194))	('iNOS', 'Gene', '4843', (115, 119))	('iNOS', 'Gene', (190, 194))	('iNOS', 'Gene', (40, 44))	('iNOS', 'Gene', (115, 119))	('iNOS', 'Gene', '4843', (40, 44))	('interaction', 'Interaction', (23, 34))
275688	33842373	In addition, NSC765598 forms 4 hydrophobic contact with TRP188, PRO344, and PHE363 residue of iNOS as compared to 1 hydrophobic contact in the iNOS_N-Iminoethyl-L-lysine dihydrochloride complex NSC765598 docked well to the binding cavity of TGF-beta1 with an affinity of -7.2 kcal/mol comparable with the affinity that galunisertib (a standard TGF-beta1 inhibitor) has for TGF-beta1 (-7.1 kcal/mol).	('TGF-beta1', 'Gene', '7040', (373, 382))	('NSC765598', 'Chemical', '-', (13, 22))	('TGF-beta1', 'Gene', (373, 382))	('TGF-beta1', 'Gene', '7040', (241, 250))	('TRP188', 'Chemical', '-', (56, 62))	('TGF-beta1', 'Gene', (241, 250))	('PRO344', 'Chemical', '-', (64, 70))	('iNOS', 'Gene', '4843', (94, 98))	('NSC765598', 'Var', (13, 22))	('iNOS', 'Gene', (94, 98))	('TGF-beta1', 'Gene', (344, 353))	('N-Iminoethyl-L-lysine dihydrochloride', 'Chemical', '-', (148, 185))	('TGF-beta1', 'Gene', '7040', (344, 353))	('iNOS', 'Gene', '4843', (143, 147))	('NSC765598', 'Chemical', '-', (194, 203))	('galunisertib', 'Chemical', 'MESH:C557799', (319, 331))	('PHE363', 'Chemical', '-', (76, 82))	('iNOS', 'Gene', (143, 147))
275689	33842373	NSC765598 binds with TGF-beta1 by single H-bond (TRY32) as against three (3) H-bonds (CYS48, ASN66, SER73) between galunisertib_TGF-beta1 complex.	('NSC765598', 'Chemical', '-', (0, 9))	('TGF-beta1', 'Gene', (21, 30))	('C', 'Chemical', 'MESH:D002244', (86, 87))	('NSC765598', 'Var', (0, 9))	('CYS48', 'Var', (86, 91))	('galunisertib', 'Chemical', 'MESH:C557799', (115, 127))	('TGF-beta1', 'Gene', '7040', (128, 137))	('C', 'Chemical', 'MESH:D002244', (2, 3))	('TGF-beta1', 'Gene', (128, 137))	('TGF-beta1', 'Gene', '7040', (21, 30))	('binds', 'Interaction', (10, 15))
275690	33842373	In addition to the halogen interactions (GLY29 and LEU28), pi-stacking with the aromatic ring of TRP30, and pi-alkyl interaction with LEU64 residues of TGF-beta1, NSC765598-TGF-beta1 complex was also supported by Van der Waal forces created between the ligand backbone and amino acid residues (LEU101, GLN57, LYS31, and HIS68) of TGF-beta1 binding pocket (  Figure 8C ,  Table 4  ).	('GLN57', 'Var', (302, 307))	('TGF-beta1', 'Gene', (152, 161))	('TGF-beta1', 'Gene', '7040', (330, 339))	('GLN57', 'Chemical', '-', (302, 307))	('LEU28', 'Chemical', '-', (51, 56))	('HIS68', 'Var', (320, 325))	('TGF-beta1', 'Gene', '7040', (152, 161))	('LYS31', 'Chemical', '-', (309, 314))	('C', 'Chemical', 'MESH:D002244', (366, 367))	('HIS68', 'Chemical', '-', (320, 325))	('LEU64', 'Chemical', '-', (134, 139))	('LEU64', 'Var', (134, 139))	('GLY29', 'Var', (41, 46))	('TGF-beta1', 'Gene', (173, 182))	('C', 'Chemical', 'MESH:D002244', (165, 166))	('TRP30', 'Chemical', '-', (97, 102))	('TGF-beta1', 'Gene', (330, 339))	('LYS31', 'Var', (309, 314))	('TGF-beta1', 'Gene', '7040', (173, 182))	('LEU101', 'Var', (294, 300))	('NSC765598', 'Chemical', '-', (163, 172))	('LEU101', 'Chemical', '-', (294, 300))	('GLY29', 'Chemical', '-', (41, 46))
275691	33842373	In addition, NSC765598 forms 3 hydrophobic contact with TRP32 and LEU64 residues of TGFB as compared to 1 hydrophobic contact (PRO47) in the TGF-beta1_ galunisertib complex.	('TGF-beta1_', 'Gene', (141, 151))	('NSC765598', 'Chemical', '-', (13, 22))	('galunisertib', 'Chemical', 'MESH:C557799', (152, 164))	('TGFB', 'Gene', '7040', (84, 88))	('NSC765598', 'Var', (13, 22))	('TRP32', 'Gene', (56, 61))	('LEU64', 'Chemical', '-', (66, 71))	('LEU64', 'Var', (66, 71))	('TRP32', 'Gene', '9352', (56, 61))	('TGF-beta1_', 'Gene', '7040', (141, 151))	('TGFB', 'Gene', (84, 88))
275692	33842373	The percent growth inhibition (GI) caused by single-dose testing revealed that NSC765598 inhibited the growth of all of the NCI60 cell line panels of breast, prostate, renal, ovarian, colon, melanoma, CNS, leukemia, and non-small cell lung cancers.	('leukemia', 'Phenotype', 'HP:0001909', (206, 214))	('melanoma', 'Phenotype', 'HP:0002861', (191, 199))	('lung cancers', 'Phenotype', 'HP:0100526', (235, 247))	('NSC765598', 'Var', (79, 88))	('cancers', 'Phenotype', 'HP:0002664', (240, 247))	('CNS', 'Disease', (201, 204))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('non-small cell lung cancers', 'Phenotype', 'HP:0030358', (220, 247))	('leukemia', 'Disease', 'MESH:D007938', (206, 214))	('NSC765598', 'Chemical', '-', (79, 88))	('leukemia', 'Disease', (206, 214))	('C', 'Chemical', 'MESH:D002244', (201, 202))	('C', 'Chemical', 'MESH:D002244', (81, 82))	('prostate', 'Disease', (158, 166))	('renal, ovarian, colon, melanoma', 'Disease', 'MESH:D008545', (168, 199))	('inhibited', 'NegReg', (89, 98))	('small cell lung cancers', 'Phenotype', 'HP:0030357', (224, 247))	('growth', 'MPA', (103, 109))	('lung cancers', 'Disease', 'MESH:D008175', (235, 247))	('C', 'Chemical', 'MESH:D002244', (125, 126))	('lung cancers', 'Disease', (235, 247))	('breast', 'Disease', (150, 156))	('lung cancer', 'Phenotype', 'HP:0100526', (235, 246))
275693	33842373	Single-dose (10 muM) treatment with NSC765598 exhibited more than 50% growth inhibition of all the NCI60 cell line panels except for two colon cancer cell lines (HT29 and COLO 205) which were completely insensitive to NSC765598 treatment ( Figure 9 ).	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('NSC765598', 'Var', (36, 45))	('C', 'Chemical', 'MESH:D002244', (100, 101))	('C', 'Chemical', 'MESH:D002244', (220, 221))	('colon cancer', 'Phenotype', 'HP:0003003', (137, 149))	('NSC765598', 'Chemical', '-', (36, 45))	('colon cancer', 'Disease', 'MESH:D015179', (137, 149))	('COLO', 'Species', '307630', (171, 175))	('colon cancer', 'Disease', (137, 149))	('men', 'Species', '9606', (26, 29))	('NSC765598', 'Chemical', '-', (218, 227))	('C', 'Chemical', 'MESH:D002244', (171, 172))	('growth inhibition', 'CPA', (70, 87))	('men', 'Species', '9606', (233, 236))	('C', 'Chemical', 'MESH:D002244', (38, 39))	('HT29', 'CellLine', 'CVCL:0320', (162, 166))
275696	33842373	The primary single-dose results clearly indicated the anticancer activities of NSC765598 against different kinds of human cancer cell lines, and thus it is worthy of further evaluation for dose-dependent activities.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('NSC765598', 'Chemical', '-', (79, 88))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('NSC765598', 'Var', (79, 88))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('cancer', 'Disease', (58, 64))	('human', 'Species', '9606', (116, 121))
275697	33842373	In the five-dose assay screening, NSC765598 demonstrated selective dose-dependent cytotoxic effects against the panel of NCI60 human tumor cell lines (  Figure 10  ).	('NSC765598', 'Chemical', '-', (34, 43))	('human', 'Species', '9606', (127, 132))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('NSC765598', 'Var', (34, 43))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('C', 'Chemical', 'MESH:D002244', (36, 37))	('cytotoxic effects', 'CPA', (82, 99))	('tumor', 'Disease', (133, 138))	('C', 'Chemical', 'MESH:D002244', (122, 123))
275698	33842373	The GI50 values of NSC765598 (concentration of NSC765598 that causes 50% inhibition of cell growth) against individual cells of the NCI60 panels of human cell lines tested were lower than 5.0 microM, except for COLO 205, a colon cancer cell line with a GI50 of 16.0 microM ( Figure 11 ).	('NSC765598', 'Var', (19, 28))	('C', 'Chemical', 'MESH:D002244', (21, 22))	('C', 'Chemical', 'MESH:D002244', (49, 50))	('COLO', 'Species', '307630', (211, 215))	('human', 'Species', '9606', (148, 153))	('C', 'Chemical', 'MESH:D002244', (211, 212))	('NSC765598', 'Chemical', '-', (47, 56))	('cell', 'CPA', (87, 91))	('colon cancer', 'Phenotype', 'HP:0003003', (223, 235))	('C', 'Chemical', 'MESH:D002244', (133, 134))	('NSC765598', 'Chemical', '-', (19, 28))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('colon cancer', 'Disease', 'MESH:D015179', (223, 235))	('colon cancer', 'Disease', (223, 235))
275700	33842373	Furthermore, NSC765598, displayed the least TGI (concentration causing 100% growth inhibition of cancer cells) against six panels of NSCLC cell lines (TGI =3.72-16.60 muM), six panels of leukemia cell lines (TGI = 3.90-12.70 muM), and eight panels of renal cancer cell lines (TGI = 4.84-13.70 muM), while the highest TGI (11.80 to > 100 muM) and perhaps the lowest activity were recorded for the seven panels of colon cancer cell lines.	('least', 'NegReg', (38, 43))	('renal cancer', 'Disease', (251, 263))	('cancer', 'Phenotype', 'HP:0002664', (257, 263))	('renal cancer', 'Phenotype', 'HP:0009726', (251, 263))	('cancer', 'Disease', 'MESH:D009369', (418, 424))	('NSCLC', 'Disease', (133, 138))	('TGI', 'MPA', (44, 47))	('cancer', 'Disease', (97, 103))	('renal cancer', 'Disease', 'MESH:D007680', (251, 263))	('colon cancer', 'Phenotype', 'HP:0003003', (412, 424))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('leukemia', 'Phenotype', 'HP:0001909', (187, 195))	('cancer', 'Disease', 'MESH:D009369', (257, 263))	('NSC765598', 'Var', (13, 22))	('colon cancer', 'Disease', 'MESH:D015179', (412, 424))	('cancer', 'Disease', (418, 424))	('leukemia', 'Disease', (187, 195))	('leukemia', 'Disease', 'MESH:D007938', (187, 195))	('cancer', 'Disease', 'MESH:D009369', (97, 103))	('cancer', 'Phenotype', 'HP:0002664', (418, 424))	('NSC765598', 'Chemical', '-', (13, 22))	('colon cancer', 'Disease', (412, 424))	('NSCLC', 'Disease', 'MESH:D002289', (133, 138))	('cancer', 'Disease', (257, 263))
275701	33842373	Furthermore, as revealed by the LC50 (concentration causing 50% lethality of cancer cells), cytotoxic activities of NSC765598 were more pronounced against NSCLC cell lines of HOP-92 (LC50 = 18.90 muM) and HOP-62 (LC50 = 92.0 muM), leukemia cell lines of HL-60 (LC50 = 20.30 muM), RPMI-8226 (LC50 = 29.50 muM), and MOLT-4 (LC50 = 71.10 muM), melanoma cell lines of SK-MEL-5 (LC50 = 7.68 muM) and SK-MEL-2 (LC50 = 23.50 muM), brain cancer cell lines of U251 (LC50 = 40.0 muM) and SNB-75 (LC50 = 65.70 muM), and renal cancer cell lines of RXF 393 (LC50 = 41.60 muM), 786-0 (LC50 = 67.0 muM), A498 (LC50 = 78.70 muM), and TK-10 (LC50 = 84.20 muM), while the two panels of prostate cancer cell lines (PC-3 and DU-145) were less responsive to the cytotoxic effects of NSC765598 (LC50 > 100 muM).	('HL-60', 'CellLine', 'CVCL:0002', (254, 259))	('cancer', 'Phenotype', 'HP:0002664', (677, 683))	('HOP-92', 'CellLine', 'CVCL:1286', (175, 181))	('prostate cancer', 'Disease', 'MESH:D011471', (668, 683))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('C', 'Chemical', 'MESH:D002244', (774, 775))	('C', 'Chemical', 'MESH:D002244', (487, 488))	('prostate cancer', 'Phenotype', 'HP:0012125', (668, 683))	('leukemia', 'Disease', (231, 239))	('leukemia', 'Disease', 'MESH:D007938', (231, 239))	('cancer', 'Disease', (430, 436))	('prostate cancer', 'Disease', (668, 683))	('melanoma', 'Phenotype', 'HP:0002861', (341, 349))	('C', 'Chemical', 'MESH:D002244', (764, 765))	('melanoma', 'Disease', (341, 349))	('C', 'Chemical', 'MESH:D002244', (375, 376))	('C', 'Chemical', 'MESH:D002244', (406, 407))	('cancer', 'Phenotype', 'HP:0002664', (430, 436))	('NSC765598', 'Var', (762, 771))	('C', 'Chemical', 'MESH:D002244', (184, 185))	('brain cancer', 'Phenotype', 'HP:0030692', (424, 436))	('leukemia', 'Phenotype', 'HP:0001909', (231, 239))	('C', 'Chemical', 'MESH:D002244', (33, 34))	('SK-MEL-5', 'CellLine', 'CVCL:0527', (364, 372))	('cancer', 'Disease', 'MESH:D009369', (677, 683))	('C', 'Chemical', 'MESH:D002244', (572, 573))	('NSCLC', 'Disease', 'MESH:D002289', (155, 160))	('brain cancer', 'Disease', 'MESH:D001932', (424, 436))	('cancer', 'Disease', (515, 521))	('C', 'Chemical', 'MESH:D002244', (262, 263))	('C', 'Chemical', 'MESH:D002244', (626, 627))	('NSC765598', 'Chemical', '-', (762, 771))	('C', 'Chemical', 'MESH:D002244', (159, 160))	('renal cancer', 'Disease', (509, 521))	('cancer', 'Disease', (77, 83))	('C', 'Chemical', 'MESH:D002244', (214, 215))	('C', 'Chemical', 'MESH:D002244', (596, 597))	('NSCLC', 'Disease', (155, 160))	('U251', 'CellLine', 'CVCL:0021', (451, 455))	('renal cancer', 'Phenotype', 'HP:0009726', (509, 521))	('cancer', 'Phenotype', 'HP:0002664', (515, 521))	('C', 'Chemical', 'MESH:D002244', (157, 158))	('RPMI-8226', 'Chemical', '-', (280, 289))	('cancer', 'Disease', 'MESH:D009369', (430, 436))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('NSC765598', 'Chemical', '-', (116, 125))	('C', 'Chemical', 'MESH:D002244', (292, 293))	('C', 'Chemical', 'MESH:D002244', (697, 698))	('SK-MEL-2', 'CellLine', 'CVCL:0069', (395, 403))	('melanoma', 'Disease', 'MESH:D008545', (341, 349))	('C', 'Chemical', 'MESH:D002244', (323, 324))	('C', 'Chemical', 'MESH:D002244', (546, 547))	('C', 'Chemical', 'MESH:D002244', (118, 119))	('renal cancer', 'Disease', 'MESH:D007680', (509, 521))	('C', 'Chemical', 'MESH:D002244', (458, 459))	('brain cancer', 'Disease', (424, 436))	('PC-3', 'CellLine', 'CVCL:0035', (696, 700))	('cancer', 'Disease', (677, 683))	('DU-145', 'CellLine', 'CVCL:0105', (705, 711))	('cancer', 'Disease', 'MESH:D009369', (515, 521))
275702	33842373	However, contrary to the primary one-dose cell growth percent inhibition assay, the colon cancer cell line, COLO 205 was found to be the most sensitive to five-dose testing of NSC765598 than the other colon cancer cell lines, displaying total growth inhibition and 50% cytotoxic response at NSC765598 concentrations of 35.80 and 80.30 muM, respectively (  Figure 11 ,  Table 5  ).	('colon cancer', 'Phenotype', 'HP:0003003', (84, 96))	('colon cancer', 'Disease', 'MESH:D015179', (84, 96))	('colon cancer', 'Disease', 'MESH:D015179', (201, 213))	('colon cancer', 'Disease', (201, 213))	('growth inhibition', 'CPA', (243, 260))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('colon cancer', 'Disease', (84, 96))	('cytotoxic', 'CPA', (269, 278))	('NSC765598', 'Chemical', '-', (176, 185))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('colon cancer', 'Phenotype', 'HP:0003003', (201, 213))	('NSC765598', 'Var', (176, 185))	('COLO', 'Species', '307630', (108, 112))	('NSC765598', 'Chemical', '-', (291, 300))
275703	33842373	DTP-COMPARE analysis indicated that NSC765598 share similar antitumor fingerprints with a number of NCI standard agents.	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('NSC765598', 'Var', (36, 45))	('tumor', 'Disease', (64, 69))	('C', 'Chemical', 'MESH:D002244', (101, 102))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('NSC765598', 'Chemical', '-', (36, 45))	('C', 'Chemical', 'MESH:D002244', (4, 5))	('C', 'Chemical', 'MESH:D002244', (38, 39))
275705	33842373	All NCI synthetic compounds with NSC765598 similar antitumor fingerprints are small molecules (MW; 277.3-461.9 g/mol).	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('NSC765598', 'Var', (33, 42))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('C', 'Chemical', 'MESH:D002244', (35, 36))	('tumor', 'Disease', (55, 60))	('C', 'Chemical', 'MESH:D002244', (5, 6))	('NSC765598', 'Chemical', '-', (33, 42))
275721	33842373	We found that genetic alterations in EGFR occurred in 7% of cancer cohorts, most frequently in GBM, ESCC, HNSCC, and NSCLC, and were associated with poor prognoses and survival of patients.	('occurred', 'Reg', (42, 50))	('NSCLC', 'Disease', (117, 122))	('genetic alterations', 'Var', (14, 33))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('NSCLC', 'Disease', 'MESH:D002289', (117, 122))	('cancer', 'Disease', (60, 66))	('ESCC', 'Disease', (100, 104))	('EGFR', 'Gene', '1956', (37, 41))	('GBM', 'Disease', (95, 98))	('HNSCC', 'Disease', (106, 111))	('EGFR', 'Gene', (37, 41))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('patients', 'Species', '9606', (180, 188))	('associated', 'Reg', (133, 143))
275724	33842373	studied genetic alterations of 20 genes and found alteration frequencies ranging 0.8% to 3% for 19 individual genes, while only one gene (NBN) had an alteration frequency of 9%.	('NBN', 'Gene', '4683', (138, 141))	('genetic alterations', 'Var', (8, 27))	('alterations', 'Var', (16, 27))	('NBN', 'Gene', (138, 141))	('alteration', 'Reg', (50, 60))
275725	33842373	Therefore, percentages of patients with genetic alterations in EGFR (7%), FGFR (6%), mTOR (4%), and iNOS (3%) as reported in this study were on the high side and thus strengthen our earlier observations that these signatures are very important in cancer progression and can thus serve as attractive targets worthy of further exploration.	('iNOS', 'Gene', '4843', (100, 104))	('EGFR', 'Gene', '1956', (63, 67))	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('iNOS', 'Gene', (100, 104))	('EGFR', 'Gene', (63, 67))	('patients', 'Species', '9606', (26, 34))	('cancer', 'Disease', (247, 253))	('cancer', 'Disease', 'MESH:D009369', (247, 253))	('genetic alterations', 'Var', (40, 59))	('mTOR', 'Gene', '2475', (85, 89))	('mTOR', 'Gene', (85, 89))	('FGFR', 'Gene', (74, 78))
275728	33842373	Alterations in these genes were found to be positively enriched in patients with altered EGFR, while alterations in KRAS and IDH1 were only enriched in patients without genetically altered EGFR.	('EGFR', 'Gene', '1956', (189, 193))	('EGFR', 'Gene', (89, 93))	('patients', 'Species', '9606', (67, 75))	('Alterations', 'Var', (0, 11))	('EGFR', 'Gene', (189, 193))	('IDH1', 'Gene', '3417', (125, 129))	('KRAS', 'Gene', '3845', (116, 120))	('KRAS', 'Gene', (116, 120))	('patients', 'Species', '9606', (152, 160))	('altered', 'Var', (81, 88))	('EGFR', 'Gene', '1956', (89, 93))	('IDH1', 'Gene', (125, 129))
275729	33842373	Intriguingly, we also observed that the most common genetic alterations in the EGFR gene were amplifications and gene gains, supporting the role of EGFR as an oncoprotein.	('EGFR', 'Gene', '1956', (79, 83))	('EGFR', 'Gene', (79, 83))	('EGFR', 'Gene', '1956', (148, 152))	('EGFR', 'Gene', (148, 152))	('gene gains', 'Var', (113, 123))	('amplifications', 'Var', (94, 108))
275731	33842373	However, contrary to our earlier observations on the poor survival rates of cohorts with high mRNA expressions of EGFR, mTOR, FGFR iNOS, TGFB1, and MAP2K1, only genetic alterations of EGFR, but not those of mTOR, iNOS, TGFB1, or MAP2K1, were associated with poor prognoses and survival of patients.	('genetic alterations', 'Var', (161, 180))	('TGFB1', 'Gene', '7040', (219, 224))	('poor prognoses', 'CPA', (258, 272))	('iNOS', 'Gene', (213, 217))	('mTOR', 'Gene', (207, 211))	('MAP2K1', 'Gene', '5604', (229, 235))	('TGFB1', 'Gene', (219, 224))	('MAP2K1', 'Gene', (229, 235))	('EGFR', 'Gene', (184, 188))	('mTOR', 'Gene', (120, 124))	('EGFR', 'Gene', (114, 118))	('patients', 'Species', '9606', (289, 297))	('MAP2K1', 'Gene', '5604', (148, 154))	('iNOS', 'Gene', '4843', (213, 217))	('mTOR', 'Gene', '2475', (207, 211))	('MAP2K1', 'Gene', (148, 154))	('iNOS', 'Gene', (131, 135))	('mTOR', 'Gene', '2475', (120, 124))	('associated', 'Reg', (242, 252))	('TGFB1', 'Gene', '7040', (137, 142))	('TGFB1', 'Gene', (137, 142))	('EGFR', 'Gene', '1956', (184, 188))	('iNOS', 'Gene', '4843', (131, 135))	('EGFR', 'Gene', '1956', (114, 118))
275733	33842373	It is therefore plausible to say that genetic alterations in EGFR are a major contributor to this dilemma.	('genetic alterations', 'Var', (38, 57))	('EGFR', 'Gene', '1956', (61, 65))	('EGFR', 'Gene', (61, 65))
275735	33842373	identified that alterations in EGFR are major oncogenic drivers of acquired resistance and predict poor survival in NSCLC, while Saadeh et al.	('NSCLC', 'Disease', 'MESH:D002289', (116, 121))	('EGFR', 'Gene', '1956', (31, 35))	('alterations', 'Var', (16, 27))	('EGFR', 'Gene', (31, 35))	('acquired', 'MPA', (67, 75))	('poor', 'NegReg', (99, 103))	('NSCLC', 'Disease', (116, 121))
275736	33842373	reported high correlations of EGFR mutations with poor therapeutic responses and survival of glioblastoma patients.	('glioblastoma', 'Phenotype', 'HP:0012174', (93, 105))	('EGFR', 'Gene', (30, 34))	('glioblastoma', 'Disease', 'MESH:D005909', (93, 105))	('glioblastoma', 'Disease', (93, 105))	('patients', 'Species', '9606', (106, 114))	('EGFR', 'Gene', '1956', (30, 34))	('mutations', 'Var', (35, 44))
275737	33842373	Although, treatments with EGFR tyrosine kinase inhibitors (TKIs) showed initial therapeutic responses, acquired resistance to 1st-, 2nd-, and recently approved 3rd-generation TKIs (osimertinib) owing to EGFR mutations has been well reported.	('EGFR', 'Gene', (26, 30))	('EGFR', 'Gene', '1956', (203, 207))	('resistance', 'MPA', (112, 122))	('EGFR', 'Gene', (203, 207))	('men', 'Species', '9606', (15, 18))	('mutations', 'Var', (208, 217))	('EGFR', 'Gene', '1956', (26, 30))
275738	33842373	Taken together, patients with high EGFR mRNA expression are more likely to harbor genetically altered EGFR and experience worse prognoses.	('mRNA expression', 'MPA', (40, 55))	('harbor', 'Reg', (75, 81))	('patients', 'Species', '9606', (16, 24))	('EGFR', 'Gene', '1956', (35, 39))	('EGFR', 'Gene', (35, 39))	('high', 'Var', (30, 34))	('genetically altered', 'Var', (82, 101))	('EGFR', 'Gene', '1956', (102, 106))	('EGFR', 'Gene', (102, 106))
275741	33842373	Hence, we explored this avenue to evaluate the anticancer properties of NSC765598 against the NCI60 panel of cell lines.	('NSC765598', 'Chemical', '-', (72, 81))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('C', 'Chemical', 'MESH:D002244', (74, 75))	('C', 'Chemical', 'MESH:D002244', (95, 96))	('NSC765598', 'Var', (72, 81))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))
275742	33842373	Interestingly we found that NSC765598 exhibited antiproliferative effects on all panels of breast cancer, prostate cancer, renal cancer, ovarian cancer, melanoma, CNS cancer, leukemia, and NSCLC cells with GI50 values of < 5 microM, but it showed lower anti-proliferative activities against colon cancer cell lines.	('cancer', 'Disease', (145, 151))	('leukemia', 'Phenotype', 'HP:0001909', (175, 183))	('NSCLC', 'Disease', 'MESH:D002289', (189, 194))	('C', 'Chemical', 'MESH:D002244', (163, 164))	('colon cancer', 'Disease', 'MESH:D015179', (291, 303))	('melanoma', 'Phenotype', 'HP:0002861', (153, 161))	('cancer', 'Disease', (167, 173))	('melanoma', 'Disease', (153, 161))	('cancer', 'Disease', (129, 135))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('cancer', 'Disease', (98, 104))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('renal cancer', 'Disease', (123, 135))	('prostate cancer', 'Disease', 'MESH:D011471', (106, 121))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('NSCLC', 'Disease', (189, 194))	('renal cancer', 'Phenotype', 'HP:0009726', (123, 135))	('cancer', 'Disease', 'MESH:D009369', (297, 303))	('leukemia', 'Disease', (175, 183))	('prostate cancer', 'Phenotype', 'HP:0012125', (106, 121))	('leukemia', 'Disease', 'MESH:D007938', (175, 183))	('ovarian cancer', 'Disease', 'MESH:D010051', (137, 151))	('antiproliferative effects', 'MPA', (48, 73))	('C', 'Chemical', 'MESH:D002244', (193, 194))	('prostate cancer', 'Disease', (106, 121))	('colon cancer', 'Disease', (291, 303))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('CNS cancer', 'Phenotype', 'HP:0100006', (163, 173))	('breast cancer', 'Phenotype', 'HP:0003002', (91, 104))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('renal cancer', 'Disease', 'MESH:D007680', (123, 135))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('NSC765598', 'Var', (28, 37))	('melanoma', 'Disease', 'MESH:D008545', (153, 161))	('C', 'Chemical', 'MESH:D002244', (191, 192))	('ovarian cancer', 'Disease', (137, 151))	('breast cancer', 'Disease', 'MESH:D001943', (91, 104))	('breast cancer', 'Disease', (91, 104))	('cancer', 'Disease', (297, 303))	('cancer', 'Disease', (115, 121))	('ovarian cancer', 'Phenotype', 'HP:0100615', (137, 151))	('NSC765598', 'Chemical', '-', (28, 37))	('colon cancer', 'Phenotype', 'HP:0003003', (291, 303))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('C', 'Chemical', 'MESH:D002244', (30, 31))
275743	33842373	Among the nine types of cancer involved in this assay, NSC765598 had some cytotoxic preference for NSCLC, leukemia, melanoma, and renal cancer cell lines.	('leukemia', 'Disease', (106, 114))	('leukemia', 'Disease', 'MESH:D007938', (106, 114))	('cancer', 'Disease', (24, 30))	('cancer', 'Disease', (136, 142))	('melanoma', 'Disease', 'MESH:D008545', (116, 124))	('cytotoxic preference', 'CPA', (74, 94))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('NSC765598', 'Var', (55, 64))	('NSCLC', 'Disease', 'MESH:D002289', (99, 104))	('renal cancer', 'Disease', (130, 142))	('renal cancer', 'Phenotype', 'HP:0009726', (130, 142))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('melanoma', 'Phenotype', 'HP:0002861', (116, 124))	('melanoma', 'Disease', (116, 124))	('cancer', 'Disease', 'MESH:D009369', (24, 30))	('NSC765598', 'Chemical', '-', (55, 64))	('NSCLC', 'Disease', (99, 104))	('leukemia', 'Phenotype', 'HP:0001909', (106, 114))	('renal cancer', 'Disease', 'MESH:D007680', (130, 142))
275744	33842373	Interestingly, NSC765598 also exhibited activity against a drug-resistant cell line, NCI/ADR-RES (GI50 = 2.54 microM; TGI = 8.00 muM).	('C', 'Chemical', 'MESH:D002244', (17, 18))	('C', 'Chemical', 'MESH:D002244', (86, 87))	('activity', 'MPA', (40, 48))	('NSC765598', 'Chemical', '-', (15, 24))	('NSC765598', 'Var', (15, 24))
275745	33842373	However, the least amounts of cell lethality were found against panels of colon, breast, ovarian, prostate, and CNS cancer cell lines (TGI > 20 microM in most cases and LC50 >100 microM in almost all cases), suggesting that NSC765598 is not generally toxic to growing cell lines, but displays some degree of specificity to NSCLC, renal cancer, leukemia, and melanomas.	('melanoma', 'Phenotype', 'HP:0002861', (358, 366))	('NSC765598', 'Chemical', '-', (224, 233))	('renal cancer', 'Disease', (330, 342))	('C', 'Chemical', 'MESH:D002244', (170, 171))	('melanomas', 'Phenotype', 'HP:0002861', (358, 367))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('NSCLC', 'Disease', 'MESH:D002289', (323, 328))	('renal cancer', 'Phenotype', 'HP:0009726', (330, 342))	('cancer', 'Disease', (336, 342))	('C', 'Chemical', 'MESH:D002244', (327, 328))	('cancer', 'Phenotype', 'HP:0002664', (336, 342))	('NSCLC', 'Disease', (323, 328))	('renal cancer', 'Disease', 'MESH:D007680', (330, 342))	('C', 'Chemical', 'MESH:D002244', (112, 113))	('melanomas', 'Disease', 'MESH:D008545', (358, 367))	('cancer', 'Disease', (116, 122))	('leukemia', 'Phenotype', 'HP:0001909', (344, 352))	('cancer', 'Disease', 'MESH:D009369', (336, 342))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('C', 'Chemical', 'MESH:D002244', (325, 326))	('melanomas', 'Disease', (358, 367))	('CNS cancer', 'Phenotype', 'HP:0100006', (112, 122))	('NSC765598', 'Var', (224, 233))	('leukemia', 'Disease', (344, 352))	('leukemia', 'Disease', 'MESH:D007938', (344, 352))	('C', 'Chemical', 'MESH:D002244', (226, 227))
275746	33842373	The NCI60 cell lines used in this study have been well characterized for proteins, genes, microRNA expressions, mutations, and DNA methylation.	('mutations', 'Var', (112, 121))	('C', 'Chemical', 'MESH:D002244', (5, 6))	('proteins', 'Protein', (73, 81))
275747	33842373	Mutations in the EGFR TK domain have been reported in NSCLC and have been associated with response to gefitinib and erlotinib.	('reported', 'Reg', (42, 50))	('erlotinib', 'Chemical', 'MESH:D000069347', (116, 125))	('Mutations in', 'Var', (0, 12))	('EGFR', 'Gene', '1956', (17, 21))	('gefitinib', 'Chemical', 'MESH:D000077156', (102, 111))	('NSCLC', 'Disease', (54, 59))	('NSCLC', 'Disease', 'MESH:D002289', (54, 59))	('associated', 'Reg', (74, 84))	('EGFR', 'Gene', (17, 21))
275748	33842373	In addition, among the NCI60 cell lines, mutations in the EGFR gene have been identified in the leukemia cell line (RPMI-8226) and melanoma cell line (SK-MEL-28) and were found to be associated with the resistant of these cell lines to 12 tyrosine kinase inhibitors (TKI) including the erlotinib.	('resistant', 'MPA', (203, 212))	('mutations', 'Var', (41, 50))	('EGFR', 'Gene', '1956', (58, 62))	('SK-MEL-28', 'CellLine', 'CVCL:0526', (151, 160))	('erlotinib', 'Chemical', 'MESH:D000069347', (286, 295))	('melanoma', 'Phenotype', 'HP:0002861', (131, 139))	('melanoma', 'Disease', (131, 139))	('leukemia', 'Disease', (96, 104))	('EGFR', 'Gene', (58, 62))	('leukemia', 'Disease', 'MESH:D007938', (96, 104))	('melanoma', 'Disease', 'MESH:D008545', (131, 139))	('leukemia', 'Phenotype', 'HP:0001909', (96, 104))	('associated with', 'Reg', (183, 198))	('C', 'Chemical', 'MESH:D002244', (24, 25))	('RPMI-8226', 'Chemical', '-', (116, 125))
275749	33842373	It is, therefore, noteworthy that NSC765598 demonstrated high activity on these cells line ( Figure 11 ,  Table 5 ).	('NSC765598', 'Chemical', '-', (34, 43))	('NSC765598', 'Var', (34, 43))	('activity', 'MPA', (62, 70))
275750	33842373	COMPARE analysis indicated that NSC765598 shares a similar antitumor fingerprint with a number of NCI standard agents and a very strong correlation with NCI synthetic compounds (p-value 0.61~0.89).	('tumor', 'Disease', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('NSC765598', 'Var', (32, 41))	('C', 'Chemical', 'MESH:D002244', (99, 100))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('C', 'Chemical', 'MESH:D002244', (34, 35))	('C', 'Chemical', 'MESH:D002244', (154, 155))	('NSC765598', 'Chemical', '-', (32, 41))
275753	33842373	Hence, it is very likely that anticancer activities demonstrated by NSC765598 could be attributed to suppression of EGF, MAPK, and mTOR signaling pathways, which is in line with the in silico target prediction and molecular docking.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('NSC765598', 'Chemical', '-', (68, 77))	('MAPK', 'Pathway', (121, 125))	('mTOR', 'Gene', (131, 135))	('NSC765598', 'Var', (68, 77))	('mTOR', 'Gene', '2475', (131, 135))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('suppression', 'NegReg', (101, 112))	('EGF', 'Gene', (116, 119))	('cancer', 'Disease', (34, 40))	('EGF', 'Gene', '1950', (116, 119))
275754	33842373	Collectively, this study has provided in vitro and in silico evidence for anticancer activities of NSC765598 and inhibition of EGFR, mTOR, NOS2, TGFB1, MAP2K1, and FGFR1 as the most probable mechanism of action.	('MAP2K1', 'Gene', '5604', (152, 158))	('MAP2K1', 'Gene', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('FGFR1', 'Gene', '2260', (164, 169))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('EGFR', 'Gene', (127, 131))	('TGFB1', 'Gene', '7040', (145, 150))	('FGFR1', 'Gene', (164, 169))	('cancer', 'Disease', (78, 84))	('TGFB1', 'Gene', (145, 150))	('mTOR', 'Gene', (133, 137))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('NOS2', 'Gene', '4843', (139, 143))	('NSC765598', 'Var', (99, 108))	('C', 'Chemical', 'MESH:D002244', (101, 102))	('NOS2', 'Gene', (139, 143))	('inhibition', 'NegReg', (113, 123))	('mTOR', 'Gene', '2475', (133, 137))	('EGFR', 'Gene', '1956', (127, 131))	('NSC765598', 'Chemical', '-', (99, 108))
275756	33842373	We found that NSC765598 docked well into the binding cavity of EGFR, mTOR, NOS2, TGFB1, FGFR1, and MAP2K1 with binding affinities ranging -7.2 to -11.0 kcal/mol.	('EGFR', 'Gene', '1956', (63, 67))	('mTOR', 'Gene', (69, 73))	('FGFR1', 'Gene', (88, 93))	('FGFR1', 'Gene', '2260', (88, 93))	('NOS2', 'Gene', '4843', (75, 79))	('NSC765598', 'Chemical', '-', (14, 23))	('MAP2K1', 'Gene', '5604', (99, 105))	('docked', 'Reg', (24, 30))	('EGFR', 'Gene', (63, 67))	('NSC765598', 'Var', (14, 23))	('binding', 'Interaction', (111, 118))	('MAP2K1', 'Gene', (99, 105))	('TGFB1', 'Gene', '7040', (81, 86))	('NOS2', 'Gene', (75, 79))	('mTOR', 'Gene', '2475', (69, 73))	('TGFB1', 'Gene', (81, 86))
275758	33842373	Interestingly, interactions of all targets with NSC765598 predominantly involved conventional hydrogen bonds, fluorine bonds, hydrophobic contacts, van der Waal forces, and a variety of pi-interactions including pi-pi stacking, and pi-anion and pi-cation interactions, which consequently led to high binding affinities and strong ligand-NSC765598 complexes, and likely compromised the expression integrity of the proteins.	('conventional', 'CPA', (81, 93))	('pi-pi stacking', 'Var', (212, 226))	('pi-interactions', 'Var', (186, 201))	('NSC765598', 'Chemical', '-', (48, 57))	('binding', 'Interaction', (300, 307))	('NSC765598', 'Chemical', '-', (337, 346))	('hydrophobic contacts', 'CPA', (126, 146))	('van der Waal forces', 'CPA', (148, 167))	('NSC765598', 'Gene', (48, 57))	('pi-anion', 'Var', (232, 240))	('complexes', 'Interaction', (347, 356))	('involved', 'Reg', (72, 80))	('expression integrity', 'MPA', (385, 405))	('fluorine', 'Chemical', 'MESH:D005461', (110, 118))	('compromised', 'NegReg', (369, 380))	('fluorine bonds', 'MPA', (110, 124))	('interactions', 'Interaction', (15, 27))	('hydrogen', 'Chemical', 'MESH:D006859', (94, 102))
275759	33842373	Among the targets, EGFR and iNOS demonstrated unique interactions with a higher binding affinity of -11 kcal/mol compared to other targets, thereby suggesting higher promising inhibitory effects of NSC765598 against EGFR and iNOS.	('EGFR', 'Gene', (216, 220))	('iNOS', 'Gene', '4843', (28, 32))	('iNOS', 'Gene', (28, 32))	('EGFR', 'Gene', '1956', (19, 23))	('iNOS', 'Gene', '4843', (225, 229))	('NSC765598', 'Chemical', '-', (198, 207))	('iNOS', 'Gene', (225, 229))	('EGFR', 'Gene', (19, 23))	('binding', 'Interaction', (80, 87))	('EGFR', 'Gene', '1956', (216, 220))	('NSC765598', 'Var', (198, 207))	('inhibitory effects', 'MPA', (176, 194))	('higher', 'PosReg', (159, 165))	('interactions', 'Interaction', (53, 65))
275760	33842373	The high binding affinities and unique stability of NSC765598 in binding pockets of iNOS and EGFR were chiefly attributed to three conventional H-bonds with TYR483, GLY196, and GLY363 of iNOS and two conventional H-bonds with GLU762 and CYS797 of EGFR; halogen interactions with GLN257, PRO344, and THR184 of iNOS, and ASN842, ARG841, and ASP855 of EGFR; and multiple hydrophobic and Pi interactions (pi-stacking, pi-alkyl, and pi-sulfur).	('GLN257', 'Chemical', '-', (279, 285))	('ARG841', 'Chemical', '-', (327, 333))	('iNOS', 'Gene', (309, 313))	('sulfur', 'Chemical', 'MESH:D013455', (431, 437))	('GLY363', 'Var', (177, 183))	('THR184', 'Var', (299, 305))	('GLU762', 'Var', (226, 232))	('ARG841', 'Var', (327, 333))	('pi-sulfur', 'Var', (428, 437))	('EGFR', 'Gene', (247, 251))	('PRO344', 'Var', (287, 293))	('ASN842', 'Var', (319, 325))	('GLN257', 'Var', (279, 285))	('EGFR', 'Gene', '1956', (93, 97))	('iNOS', 'Gene', '4843', (309, 313))	('GLY196', 'Var', (165, 171))	('TYR483', 'Var', (157, 163))	('GLY363', 'Chemical', '-', (177, 183))	('iNOS', 'Gene', (187, 191))	('ASP855', 'Chemical', '-', (339, 345))	('iNOS', 'Gene', (84, 88))	('GLY196', 'Chemical', '-', (165, 171))	('CYS797', 'Var', (237, 243))	('EGFR', 'Gene', (349, 353))	('GLU762', 'Chemical', '-', (226, 232))	('PRO344', 'Chemical', '-', (287, 293))	('pi-alkyl', 'Var', (414, 422))	('ASN842', 'Chemical', '-', (319, 325))	('CYS797', 'Chemical', '-', (237, 243))	('iNOS', 'Gene', '4843', (187, 191))	('TYR483', 'Chemical', '-', (157, 163))	('NSC765598', 'Var', (52, 61))	('binding', 'Interaction', (9, 16))	('iNOS', 'Gene', '4843', (84, 88))	('ASP855', 'Var', (339, 345))	('EGFR', 'Gene', '1956', (247, 251))	('NSC765598', 'Chemical', '-', (52, 61))	('EGFR', 'Gene', (93, 97))	('EGFR', 'Gene', '1956', (349, 353))
275761	33842373	The large numbers of pi-interactions, which mostly involve charge transfer, helped NSC765598 intercalate in binding cavities of the receptors.	('intercalate', 'Reg', (93, 104))	('NSC765598', 'Chemical', '-', (83, 92))	('charge transfer', 'MPA', (59, 74))	('NSC765598', 'Var', (83, 92))	('pi-interactions', 'Var', (21, 36))
275762	33842373	Furthermore, higher Van der Waal forces created on the NSC765598 backbone with the respective amino acids of ILE238, SER236, GLN199, TRP366, MET368, TYR367, ALA345, VAL346, and ASN364 in the binding pocket of iNOS; and ARG858, LYS745, LEU788, and THR854 in the binding pocket of EGFR created strong cohesive environments, thereby stabilizing the complexes formed.	('TYR367', 'Var', (149, 155))	('ARG858', 'Chemical', '-', (219, 225))	('GLN199', 'Var', (125, 131))	('TRP366', 'Chemical', '-', (133, 139))	('TYR367', 'Chemical', '-', (149, 155))	('ASN364', 'Var', (177, 183))	('created', 'Reg', (284, 291))	('EGFR', 'Gene', (279, 283))	('Van der Waal forces', 'MPA', (20, 39))	('ALA345', 'Chemical', '-', (157, 163))	('ASN364', 'Chemical', '-', (177, 183))	('TRP366', 'Var', (133, 139))	('higher', 'PosReg', (13, 19))	('iNOS', 'Gene', '4843', (209, 213))	('SER236', 'Chemical', '-', (117, 123))	('NSC765598', 'Var', (55, 64))	('THR854', 'Chemical', '-', (247, 253))	('LYS745', 'Chemical', '-', (227, 233))	('NSC765598', 'Chemical', '-', (55, 64))	('ILE238', 'Var', (109, 115))	('THR854', 'Var', (247, 253))	('men', 'Species', '9606', (315, 318))	('GLN199', 'Chemical', '-', (125, 131))	('VAL346', 'Var', (165, 171))	('SER236', 'Var', (117, 123))	('MET368', 'Var', (141, 147))	('iNOS', 'Gene', (209, 213))	('ARG858', 'Var', (219, 225))	('complexes', 'Interaction', (346, 355))	('EGFR', 'Gene', '1956', (279, 283))	('VAL346', 'Chemical', '-', (165, 171))	('LYS745', 'Var', (227, 233))	('ALA345', 'Var', (157, 163))	('LEU788', 'Chemical', '-', (235, 241))	('stabilizing', 'PosReg', (330, 341))	('LEU788', 'Var', (235, 241))	('MET368', 'Chemical', '-', (141, 147))	('ILE238', 'Chemical', '-', (109, 115))	('cohesive environments', 'MPA', (299, 320))
275763	33842373	Therefore, the specific alkylation of the LEU844 residue of EGFR and alkylation of the three CYS194, LEU203, and PRO344 residues of iNOS by NSC765598 could mediate the modification of substrate binding sites and subsequently induce alkylation-dependent inhibition of target proteins.	('LEU203', 'Chemical', '-', (101, 107))	('NSC765598', 'Chemical', '-', (140, 149))	('LEU203', 'Var', (101, 107))	('substrate binding sites', 'Interaction', (184, 207))	('CYS194', 'Chemical', '-', (93, 99))	('LEU844', 'Var', (42, 48))	('iNOS', 'Gene', '4843', (132, 136))	('NSC765598', 'Var', (140, 149))	('iNOS', 'Gene', (132, 136))	('alkylation-dependent', 'MPA', (232, 252))	('PRO344', 'Chemical', '-', (113, 119))	('inhibition', 'NegReg', (253, 263))	('modification', 'Reg', (168, 180))	('EGFR', 'Gene', '1956', (60, 64))	('proteins', 'Protein', (274, 282))	('LEU844', 'Chemical', '-', (42, 48))	('induce', 'Reg', (225, 231))	('EGFR', 'Gene', (60, 64))
275764	33842373	Collectively, the strong interactions observed between NSC765598 and EGFR/iNOS may compromise their activity/expression abilities and consequently affect the survival of cells that depend on these proteins for their vital activities.	('EGFR', 'Gene', '1956', (69, 73))	('EGFR', 'Gene', (69, 73))	('interactions', 'Interaction', (25, 37))	('activity/expression', 'MPA', (100, 119))	('C', 'Chemical', 'MESH:D002244', (57, 58))	('iNOS', 'Gene', '4843', (74, 78))	('NSC765598', 'Chemical', '-', (55, 64))	('compromise', 'NegReg', (83, 93))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('iNOS', 'Gene', (74, 78))	('NSC765598', 'Var', (55, 64))	('survival of cells', 'CPA', (158, 175))	('affect', 'Reg', (147, 153))
275765	33842373	These findings, therefore, suggest that the anticancer activities demonstrated by NSC765598 could be attributed more to its dual inhibition of iNOS and EGFR.	('NSC765598', 'Var', (82, 91))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('EGFR', 'Gene', '1956', (152, 156))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('EGFR', 'Gene', (152, 156))	('iNOS', 'Gene', '4843', (143, 147))	('NSC765598', 'Chemical', '-', (82, 91))	('iNOS', 'Gene', (143, 147))
275766	33842373	Specifically, the docking results corroborated our observations of NSCLC cell lines, which were observed to demonstrate higher responses to NSC765598 (GI50 = 1.12-3.95 microM; TGI = 3.72-16.60 muM).	('NSC765598', 'Chemical', '-', (140, 149))	('NSC765598', 'Var', (140, 149))	('NSCLC', 'Disease', (67, 72))	('NSCLC', 'Disease', 'MESH:D002289', (67, 72))	('responses', 'MPA', (127, 136))
275768	33842373	Interestingly, NSC765598 demonstrated more robust interactions and higher binding affinities for MAP2K, EGFR, iNOS, and FGFR1 than does their respective standard drugs; mirdametinib, gefitinib, N-Iminoethyl-l-lysine dihydrochloride, and erdafitinib.	('MAP2K', 'Gene', (97, 102))	('higher', 'PosReg', (67, 73))	('iNOS', 'Gene', '4843', (110, 114))	('iNOS', 'Gene', (110, 114))	('FGFR1', 'Gene', (120, 125))	('EGFR', 'Gene', (104, 108))	('erdafitinib', 'Chemical', 'MESH:C000604580', (237, 248))	('mirdametinib', 'Chemical', 'MESH:C506614', (169, 181))	('FGFR1', 'Gene', '2260', (120, 125))	('gefitinib', 'Chemical', 'MESH:D000077156', (183, 192))	('N-Iminoethyl-l-lysine dihydrochloride', 'Chemical', '-', (194, 231))	('NSC765598', 'Chemical', '-', (15, 24))	('interactions', 'Interaction', (50, 62))	('binding', 'Interaction', (74, 81))	('EGFR', 'Gene', '1956', (104, 108))	('NSC765598', 'Var', (15, 24))
275771	33842373	Therefore, the results of the present study indicate that NSC765598 could serve as a novel iNOS inhibitor worthy of further preclinical and clinical developments.	('iNOS', 'Gene', (91, 95))	('men', 'Species', '9606', (156, 159))	('NSC765598', 'Chemical', '-', (58, 67))	('NSC765598', 'Var', (58, 67))	('iNOS', 'Gene', '4843', (91, 95))
275772	33842373	NSC765598 forms several hydrophobic contacts with amino acid residues of the mTOR/EGFR/MAP2K/iNOS/FGFR/TGFB1 (  Tables 3  and  4  ).	('NSC765598', 'Chemical', '-', (0, 9))	('EGFR', 'Gene', (82, 86))	('TGFB1', 'Gene', '7040', (103, 108))	('NSC765598', 'Var', (0, 9))	('iNOS', 'Gene', '4843', (93, 97))	('TGFB1', 'Gene', (103, 108))	('iNOS', 'Gene', (93, 97))	('mTOR', 'Gene', '2475', (77, 81))	('hydrophobic contacts', 'MPA', (24, 44))	('mTOR', 'Gene', (77, 81))	('EGFR', 'Gene', '1956', (82, 86))
275774	33842373	It's noteworthy that NSC765598 forms higher hydrophobic contacts with the receptors than do some of the standard inhibitors used for comparison in this study (  Table 4  ).	('higher', 'PosReg', (37, 43))	('hydrophobic contacts', 'MPA', (44, 64))	('NSC765598', 'Chemical', '-', (21, 30))	('NSC765598', 'Var', (21, 30))	('receptors', 'Protein', (74, 83))
275775	33842373	Collectively, this study suggested that NSC765598 has a potential for multi-target inhibition of EGFR/iNOS/mTOR/TGFB1/FGFR/MAP2K1 and could serve as a lead compound for developing new therapeutics for cancer treatment.	('cancer', 'Disease', (201, 207))	('mTOR', 'Gene', (107, 111))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('C', 'Chemical', 'MESH:D002244', (42, 43))	('iNOS', 'Gene', (102, 106))	('NSC765598', 'Var', (40, 49))	('mTOR', 'Gene', '2475', (107, 111))	('EGFR', 'Gene', (97, 101))	('iNOS', 'Gene', '4843', (102, 106))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('men', 'Species', '9606', (213, 216))	('NSC765598', 'Chemical', '-', (40, 49))	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('MAP2K1', 'Gene', '5604', (123, 129))	('TGFB1', 'Gene', '7040', (112, 117))	('MAP2K1', 'Gene', (123, 129))	('TGFB1', 'Gene', (112, 117))	('inhibition', 'NegReg', (83, 93))	('EGFR', 'Gene', '1956', (97, 101))
275777	33842373	Our computational study of toxicity indicated that NSC765598 displayed LD50 at high concentration and, thus may be safely used for acute administration, while the drug-likeness studies indicated that it met acceptable criteria of being used as a drug for therapeutic applications.	('toxicity', 'Disease', 'MESH:D064420', (27, 35))	('toxicity', 'Disease', (27, 35))	('LD50', 'MPA', (71, 75))	('NSC765598', 'Chemical', '-', (51, 60))	('NSC765598', 'Var', (51, 60))
275780	33842373	NSC765598 displayed anti-proliferative activities and selective cytotoxic preferences for NSCLC, leukemia, melanoma, and renal cancer cell lines.	('NSC765598', 'Chemical', '-', (0, 9))	('melanoma', 'Phenotype', 'HP:0002861', (107, 115))	('melanoma', 'Disease', (107, 115))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('cytotoxic preferences', 'CPA', (64, 85))	('melanoma', 'Disease', 'MESH:D008545', (107, 115))	('NSC765598', 'Var', (0, 9))	('renal cancer', 'Disease', (121, 133))	('NSCLC', 'Disease', (90, 95))	('anti-proliferative', 'CPA', (20, 38))	('NSCLC', 'Disease', 'MESH:D002289', (90, 95))	('leukemia', 'Disease', (97, 105))	('leukemia', 'Phenotype', 'HP:0001909', (97, 105))	('leukemia', 'Disease', 'MESH:D007938', (97, 105))	('renal cancer', 'Disease', 'MESH:D007680', (121, 133))	('renal cancer', 'Phenotype', 'HP:0009726', (121, 133))
275781	33842373	In addition, NSC765598 displayed favorable properties as a drug lead compound and thus could be considered a novel small molecule with potential for multi-target inhibition of EGFR/iNOS/mTOR/TGFB1/FGFR/MAP2K1 and could serve as a lead compound for developing new therapeutics for cancer treatment.	('iNOS', 'Gene', '4843', (181, 185))	('iNOS', 'Gene', (181, 185))	('men', 'Species', '9606', (292, 295))	('cancer', 'Disease', 'MESH:D009369', (280, 286))	('NSC765598', 'Chemical', '-', (13, 22))	('mTOR', 'Gene', (186, 190))	('cancer', 'Disease', (280, 286))	('EGFR', 'Gene', '1956', (176, 180))	('mTOR', 'Gene', '2475', (186, 190))	('NSC765598', 'Var', (13, 22))	('EGFR', 'Gene', (176, 180))	('TGFB1', 'Gene', '7040', (191, 196))	('MAP2K1', 'Gene', '5604', (202, 208))	('cancer', 'Phenotype', 'HP:0002664', (280, 286))	('TGFB1', 'Gene', (191, 196))	('MAP2K1', 'Gene', (202, 208))
275793	33363385	We identified mutations associated with sex, early ESCC, high TMB, and metastasis lymph nodes.	('early ESCC', 'Disease', (45, 55))	('TMB', 'Chemical', '-', (62, 65))	('associated', 'Reg', (24, 34))	('high TMB', 'Disease', (57, 65))	('metastasis lymph nodes', 'Disease', (71, 93))	('sex', 'Disease', (40, 43))	('mutations', 'Var', (14, 23))
275794	33363385	KMT2D mutations associated with sex (P = 0.035), tumor stage (P = 0.016), high TMB (P = 0.0072), and overall survival of patients (P = 0.0026).	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('TMB', 'Chemical', '-', (79, 82))	('tumor', 'Disease', (49, 54))	('sex', 'Disease', (32, 35))	('KMT2D', 'Gene', (0, 5))	('KMT2D', 'Gene', '8085', (0, 5))	('associated', 'Reg', (16, 26))	('high', 'Disease', (74, 78))	('patients', 'Species', '9606', (121, 129))	('mutations', 'Var', (6, 15))
275795	33363385	SPEN mutations associated with high TMB (P = 0.0016) and metastasis-positive lymph nodes (P = 0.027).	('metastasis-positive lymph nodes', 'CPA', (57, 88))	('high', 'Disease', (31, 35))	('SPEN', 'Gene', '23013', (0, 4))	('mutations', 'Var', (5, 14))	('associated', 'Reg', (15, 25))	('TMB', 'Chemical', '-', (36, 39))	('SPEN', 'Gene', (0, 4))
275805	33363385	The mutation of TP53 is considered an early event in ESCC carcinogenesis, and some studies have shown that patients with TP53 alterations respond better to angiogenesis inhibitors than those without the alterations.	('patients', 'Species', '9606', (107, 115))	('ESCC', 'Disease', (53, 57))	('respond', 'MPA', (138, 145))	('TP53', 'Gene', '7157', (121, 125))	('carcinogenesis', 'Disease', 'MESH:D063646', (58, 72))	('TP53', 'Gene', (121, 125))	('carcinogenesis', 'Disease', (58, 72))	('TP53', 'Gene', '7157', (16, 20))	('better', 'PosReg', (146, 152))	('alterations', 'Var', (126, 137))	('TP53', 'Gene', (16, 20))
275806	33363385	As both an oncogene and a tumor suppressor, NOTCH1 is closely related to human carcinogenesis, and NOTCH1 mutations have been observed in many cancers.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('NOTCH1', 'Gene', '4851', (99, 105))	('NOTCH1', 'Gene', '4851', (44, 50))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('NOTCH1', 'Gene', (99, 105))	('human', 'Species', '9606', (73, 78))	('NOTCH1', 'Gene', (44, 50))	('observed', 'Reg', (126, 134))	('cancers', 'Disease', 'MESH:D009369', (143, 150))	('carcinogenesis', 'Disease', 'MESH:D063646', (79, 93))	('cancers', 'Phenotype', 'HP:0002664', (143, 150))	('cancers', 'Disease', (143, 150))	('carcinogenesis', 'Disease', (79, 93))	('mutations', 'Var', (106, 115))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))
275813	33363385	Many studies have focused on the molecular mechanism of ESCC incidence and found that tobacco and alcohol use contribute to genome variations, such as TP53 gene mutations, in ESCC.	('ESCC', 'Disease', (56, 60))	('alcohol use', 'Phenotype', 'HP:0030955', (98, 109))	('TP53', 'Gene', (151, 155))	('alcohol', 'Chemical', 'MESH:D000438', (98, 105))	('tobacco', 'Species', '4097', (86, 93))	('ESCC', 'Disease', (175, 179))	('mutations', 'Var', (161, 170))	('TP53', 'Gene', '7157', (151, 155))
275819	33363385	Genomic alterations were identified according to a previous study: Briefly, single nucleotide variants were identified with MuTect (v1.17) and insertion-deletion polymorphisms were identified using PINDEL (v0.2.4); the functional impact of these mutations was annotated with SnpEff3.0.	('v1.17', 'Gene', '28822', (132, 137))	('MuTect', 'Gene', (124, 130))	('insertion-deletion polymorphisms', 'Var', (143, 175))	('mutations', 'Var', (246, 255))	('v1.17', 'Gene', (132, 137))
275820	33363385	We estimated the Tumor mutational burden (TMB) in each patient by counting the somatic mutations from the coding region, including single nucleotide variants and insertion-deletion polymorphisms, per megabase of sequence examined.	('insertion-deletion polymorphisms', 'Var', (162, 194))	('TMB', 'Chemical', '-', (42, 45))	('single nucleotide variants', 'Var', (131, 157))	('Tumor', 'Phenotype', 'HP:0002664', (17, 22))	('patient', 'Species', '9606', (55, 62))
275827	33363385	We detected 2,859 alterations in the 225 samples of Chinese patients with ESCC, including 1,109 substitution/insertion-deletion polymorphisms, 1,172 gene amplifications, 420 truncations, 90 homozygous gene deletions, and 66 fusions/rearrangements.	('ESCC', 'Disease', (74, 78))	('patients', 'Species', '9606', (60, 68))	('alterations', 'Var', (18, 29))	('substitution/insertion-deletion polymorphisms', 'Var', (96, 141))
275830	33363385	The amplification of FGF19, FGF3 and FGF4 were all located on chromosome 11q13 and occurred together in patients.	('FGF4', 'Gene', (37, 41))	('FGF3', 'Gene', '2248', (28, 32))	('FGF19', 'Gene', (21, 26))	('FGF19', 'Gene', '9965', (21, 26))	('FGF4', 'Gene', '2249', (37, 41))	('amplification', 'Var', (4, 17))	('FGF3', 'Gene', (28, 32))	('patients', 'Species', '9606', (104, 112))	('occurred', 'Reg', (83, 91))
275832	33363385	The most common fusion/rearrangement mutations occurred in CDKN2A.	('CDKN2A', 'Gene', (59, 65))	('fusion/rearrangement', 'Var', (16, 36))	('CDKN2A', 'Gene', '1029', (59, 65))
275833	33363385	We observed more mutations in the cell cycle, fibroblast growth factor, PI3K/MTOR, and histone modification pathways in ESCC than in the homologous recombination deficiency, DNA mismatch repair, and WNT pathways.	('histone modification pathways', 'Pathway', (87, 116))	('ESCC', 'Disease', (120, 124))	('MTOR', 'Gene', (77, 81))	('fibroblast growth factor', 'Pathway', (46, 70))	('MTOR', 'Gene', '2475', (77, 81))	('cell cycle', 'Pathway', (34, 44))	('mutations', 'Var', (17, 26))
275843	33363385	Interestingly, we found that mutations of LRP1, AXIN2, CFTR, CREB3L1, and TAF1 occurred exclusively in female patients.	('CFTR', 'Gene', '1080', (55, 59))	('TAF1', 'Gene', '6872', (74, 78))	('AXIN2', 'Gene', (48, 53))	('AXIN2', 'Gene', '8313', (48, 53))	('LRP1', 'Gene', (42, 46))	('mutations', 'Var', (29, 38))	('TAF1', 'Gene', (74, 78))	('CREB3L1', 'Gene', (61, 68))	('CFTR', 'Gene', (55, 59))	('LRP1', 'Gene', '4035', (42, 46))	('CREB3L1', 'Gene', '90993', (61, 68))	('occurred', 'Reg', (79, 87))	('patients', 'Species', '9606', (110, 118))
275844	33363385	The mutational frequencies of LRP1 (P=0.0049), JAK2 (P=0.0091), CDK12 (P=0.018), AXIN2 (P=0.029), CFTR (P=0.029), CREB3L1 (P=0.029), TAF1 (P=0.029), and KMT2D (P=0.035) were significantly higher in female than in male patients (Figure 3A).	('AXIN2', 'Gene', (81, 86))	('LRP1', 'Gene', (30, 34))	('KMT2D', 'Gene', (153, 158))	('LRP1', 'Gene', '4035', (30, 34))	('CDK12', 'Gene', (64, 69))	('mutational', 'Var', (4, 14))	('JAK2', 'Gene', '3717', (47, 51))	('CREB3L1', 'Gene', (114, 121))	('higher', 'PosReg', (188, 194))	('TAF1', 'Gene', '6872', (133, 137))	('CFTR', 'Gene', '1080', (98, 102))	('AXIN2', 'Gene', '8313', (81, 86))	('CDK12', 'Gene', '51755', (64, 69))	('KMT2D', 'Gene', '8085', (153, 158))	('CFTR', 'Gene', (98, 102))	('patients', 'Species', '9606', (218, 226))	('CREB3L1', 'Gene', '90993', (114, 121))	('JAK2', 'Gene', (47, 51))	('TAF1', 'Gene', (133, 137))
275847	33363385	We found that the mutational frequencies of NOTCH2 (11.93% vs 2.56%, P=0.027) and SPEN (9.17% vs 1.28%, P=0.027) were significantly higher in lymph node metastasis-positive patients than in negative patients, whereas the mutational frequencies of FOS (0.92% vs 8.97%, P=0.01), DOT1L (0.00% vs 6.41%, P=0.012), and VEGFA (0.00% vs 5.13%, P=0.029) were significantly lower in lymph node metastasis-positive patients than in negative patients (Figure 3B).	('FOS', 'Gene', (247, 250))	('NOTCH2', 'Gene', '4853', (44, 50))	('FOS', 'Gene', '2353', (247, 250))	('DOT1L', 'Gene', '84444', (277, 282))	('VEGFA', 'Gene', '7422', (314, 319))	('patients', 'Species', '9606', (173, 181))	('lymph node', 'Disease', (374, 384))	('NOTCH2', 'Gene', (44, 50))	('higher', 'PosReg', (132, 138))	('mutational', 'Var', (18, 28))	('SPEN', 'Gene', '23013', (82, 86))	('patients', 'Species', '9606', (431, 439))	('lower', 'NegReg', (365, 370))	('lymph', 'Disease', (142, 147))	('DOT1L', 'Gene', (277, 282))	('SPEN', 'Gene', (82, 86))	('VEGFA', 'Gene', (314, 319))	('patients', 'Species', '9606', (405, 413))	('patients', 'Species', '9606', (199, 207))
275848	33363385	We also analyzed the associations of gene alterations with tumors stage.	('alterations', 'Var', (42, 53))	('tumors', 'Disease', (59, 65))	('tumors', 'Disease', 'MESH:D009369', (59, 65))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('associations', 'Interaction', (21, 33))
275850	33363385	The mutational frequencies of DOT1L (P=0.009), BMPR1A (P=0.024) and KMT2D (P=0.016) were significantly higher in early-stage tumors than in advanced-stage tumors (Figure 3C).	('higher', 'Reg', (103, 109))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('BMPR1A', 'Gene', '657', (47, 53))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('DOT1L', 'Gene', (30, 35))	('tumors', 'Phenotype', 'HP:0002664', (155, 161))	('tumors', 'Disease', (125, 131))	('tumors', 'Disease', 'MESH:D009369', (125, 131))	('KMT2D', 'Gene', '8085', (68, 73))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('DOT1L', 'Gene', '84444', (30, 35))	('tumors', 'Disease', (155, 161))	('tumors', 'Disease', 'MESH:D009369', (155, 161))	('KMT2D', 'Gene', (68, 73))	('BMPR1A', 'Gene', (47, 53))	('mutational', 'Var', (4, 14))
275852	33363385	Statistical analysis revealed that mutations of KMT2D (P=0.0072) and SPEN (P=0.0016) were significantly associated with high TMB (Figure 3D and E).	('associated', 'Reg', (104, 114))	('SPEN', 'Gene', '23013', (69, 73))	('TMB', 'Chemical', '-', (125, 128))	('high TMB', 'Disease', (120, 128))	('KMT2D', 'Gene', '8085', (48, 53))	('KMT2D', 'Gene', (48, 53))	('SPEN', 'Gene', (69, 73))	('mutations', 'Var', (35, 44))
275855	33363385	We found that KMT2D mutation was significantly associated with overall survival (P=0.026), but did not correlate with disease-free survival (P=0.08) (Figure 4).	('overall survival', 'MPA', (63, 79))	('KMT2D', 'Gene', '8085', (14, 19))	('associated with', 'Reg', (47, 62))	('mutation', 'Var', (20, 28))	('KMT2D', 'Gene', (14, 19))
275856	33363385	We also analyzed the relationship between mutations in genes in related pathways and the prognosis of ESCC patients but did not detect a correlation.	('analyzed', 'Reg', (8, 16))	('ESCC', 'Disease', (102, 106))	('patients', 'Species', '9606', (107, 115))	('mutations', 'Var', (42, 51))
275858	33363385	We detected mutations in 24 genes:CCND1, CDKN2A, PIK3CA, CDKN2B, FBXW7, EGFR, FGFR1, PTEN, BRCA1, ERBB2, BRCA2, MET, STK11, CDK4, CDK6, ERBB3, KDR, VEGFRA, ARAF, CD274, FGFR3, PDCD1LG2, PDGFB, and TSC1:that are targeted by available drugs.	('ARAF', 'Gene', '369', (156, 160))	('ERBB2', 'Gene', '2064', (98, 103))	('ARAF', 'Gene', (156, 160))	('CCND1', 'Gene', '595', (34, 39))	('EGFR', 'Gene', '1956', (72, 76))	('CDK6', 'Gene', (130, 134))	('BRCA2', 'Gene', (105, 110))	('TSC1', 'Gene', (197, 201))	('KDR', 'Gene', '3791', (143, 146))	('CD274', 'Gene', '29126', (162, 167))	('CDKN2B', 'Gene', '1030', (57, 63))	('CCND1', 'Gene', (34, 39))	('PTEN', 'Gene', (85, 89))	('BRCA1', 'Gene', '672', (91, 96))	('PIK3CA', 'Gene', '5290', (49, 55))	('STK11', 'Gene', '6794', (117, 122))	('MET', 'Gene', (112, 115))	('FGFR1', 'Gene', (78, 83))	('BRCA1', 'Gene', (91, 96))	('ERBB3', 'Gene', (136, 141))	('FBXW7', 'Gene', '55294', (65, 70))	('CDK4', 'Gene', '1019', (124, 128))	('TSC1', 'Gene', '7248', (197, 201))	('PDCD1LG2', 'Gene', '80380', (176, 184))	('EGFR', 'Gene', '1956', (149, 153))	('CDKN2A', 'Gene', (41, 47))	('BRCA2', 'Gene', '675', (105, 110))	('PTEN', 'Gene', '5728', (85, 89))	('CD274', 'Gene', (162, 167))	('PDGFB', 'Gene', '5155', (186, 191))	('EGFR', 'Gene', (72, 76))	('PIK3CA', 'Gene', (49, 55))	('PDCD1LG2', 'Gene', (176, 184))	('ERBB3', 'Gene', '2065', (136, 141))	('FGFR3', 'Gene', (169, 174))	('MET', 'Gene', '79811', (112, 115))	('KDR', 'Gene', (143, 146))	('CDKN2A', 'Gene', '1029', (41, 47))	('ERBB2', 'Gene', (98, 103))	('CDK6', 'Gene', '1021', (130, 134))	('FGFR1', 'Gene', '2260', (78, 83))	('mutations', 'Var', (12, 21))	('CDKN2B', 'Gene', (57, 63))	('PDGFB', 'Gene', (186, 191))	('FBXW7', 'Gene', (65, 70))	('STK11', 'Gene', (117, 122))	('FGFR3', 'Gene', '2261', (169, 174))	('EGFR', 'Gene', (149, 153))	('CDK4', 'Gene', (124, 128))
275859	33363385	In this cohort, nearly 61% (137/225) of patients harbored at least 1 mutation of CCND1, CDKN2A, CDKN2B, CDK4, or CDK6, and nearly 37% (84/225) of patients harbored at least 1 mutation of PIK3CA, FBXW7, PTEN, STK11, or TSC1.	('FBXW7', 'Gene', '55294', (195, 200))	('CDK6', 'Gene', (113, 117))	('harbored', 'Reg', (49, 57))	('PIK3CA', 'Gene', (187, 193))	('PTEN', 'Gene', (202, 206))	('CCND1', 'Gene', '595', (81, 86))	('CDKN2A', 'Gene', (88, 94))	('CDKN2B', 'Gene', '1030', (96, 102))	('TSC1', 'Gene', (218, 222))	('CCND1', 'Gene', (81, 86))	('CDK4', 'Gene', (104, 108))	('PTEN', 'Gene', '5728', (202, 206))	('STK11', 'Gene', (208, 213))	('patients', 'Species', '9606', (146, 154))	('TSC1', 'Gene', '7248', (218, 222))	('CDKN2A', 'Gene', '1029', (88, 94))	('FBXW7', 'Gene', (195, 200))	('harbored', 'Reg', (155, 163))	('CDK4', 'Gene', '1019', (104, 108))	('PIK3CA', 'Gene', '5290', (187, 193))	('STK11', 'Gene', '6794', (208, 213))	('CDK6', 'Gene', '1021', (113, 117))	('patients', 'Species', '9606', (40, 48))	('mutation', 'Var', (69, 77))	('CDKN2B', 'Gene', (96, 102))
275860	33363385	Cancers with mutations in CCND1, CDKN2A, CDKN2B, CDK4, and CDK6 respond to drugs such as palbociclib, ribociclib, and abemaciclib.	('respond', 'Reg', (64, 71))	('CDK4', 'Gene', (49, 53))	('CDKN2A', 'Gene', (33, 39))	('CDKN2B', 'Gene', (41, 47))	('Cancers', 'Disease', (0, 7))	('CDKN2A', 'Gene', '1029', (33, 39))	('Cancers', 'Phenotype', 'HP:0002664', (0, 7))	('CDK6', 'Gene', (59, 63))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('CCND1', 'Gene', (26, 31))	('CDK6', 'Gene', '1021', (59, 63))	('Cancers', 'Disease', 'MESH:D009369', (0, 7))	('mutations', 'Var', (13, 22))	('CCND1', 'Gene', '595', (26, 31))	('CDKN2B', 'Gene', '1030', (41, 47))	('CDK4', 'Gene', '1019', (49, 53))
275861	33363385	Cancers with mutations in PIK3CA, FBXW7, PTEN, STK11, and TSC1 respond to drugs such as everolimus and temsirolimus (Figure 5).	('temsirolimus', 'Chemical', 'MESH:C401859', (103, 115))	('Cancers', 'Disease', (0, 7))	('PIK3CA', 'Gene', '5290', (26, 32))	('Cancers', 'Phenotype', 'HP:0002664', (0, 7))	('STK11', 'Gene', '6794', (47, 52))	('respond', 'Reg', (63, 70))	('FBXW7', 'Gene', '55294', (34, 39))	('everolimus', 'Chemical', 'MESH:D000068338', (88, 98))	('PTEN', 'Gene', (41, 45))	('TSC1', 'Gene', (58, 62))	('PIK3CA', 'Gene', (26, 32))	('temsirolimus', 'MPA', (103, 115))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancers', 'Disease', 'MESH:D009369', (0, 7))	('everolimus', 'MPA', (88, 98))	('TSC1', 'Gene', '7248', (58, 62))	('mutations', 'Var', (13, 22))	('PTEN', 'Gene', '5728', (41, 45))	('STK11', 'Gene', (47, 52))	('FBXW7', 'Gene', (34, 39))
275871	33363385	We detected frequent mutations in TP53, CCND1, FAT1, and CDKN2A, as in other studies, and further identified frequent mutations in FGF19, FGF3, FGF4, and KMT2D.	('FGF3', 'Gene', '2248', (138, 142))	('TP53', 'Gene', (34, 38))	('FGF4', 'Gene', '2249', (144, 148))	('CDKN2A', 'Gene', (57, 63))	('FGF4', 'Gene', (144, 148))	('FAT1', 'Gene', '2195', (47, 51))	('mutations', 'Var', (118, 127))	('KMT2D', 'Gene', (154, 159))	('CDKN2A', 'Gene', '1029', (57, 63))	('CCND1', 'Gene', (40, 45))	('FGF19', 'Gene', '9965', (131, 136))	('KMT2D', 'Gene', '8085', (154, 159))	('FAT1', 'Gene', (47, 51))	('FGF19', 'Gene', (131, 136))	('FGF3', 'Gene', (138, 142))	('CCND1', 'Gene', '595', (40, 45))	('TP53', 'Gene', '7157', (34, 38))	('mutations', 'Var', (21, 30))
275874	33363385	Similar to a previous study, we also observed frequent amplification of CCND1, FGF19, FGF3, and FGF4, which supports the occurrence of chromosome 11q13 instability in ESCC patients.	('CCND1', 'Gene', (72, 77))	('amplification', 'Var', (55, 68))	('FGF19', 'Gene', '9965', (79, 84))	('CCND1', 'Gene', '595', (72, 77))	('ESCC', 'Disease', (167, 171))	('FGF19', 'Gene', (79, 84))	('FGF3', 'Gene', '2248', (86, 90))	('FGF4', 'Gene', (96, 100))	('patients', 'Species', '9606', (172, 180))	('FGF3', 'Gene', (86, 90))	('FGF4', 'Gene', '2249', (96, 100))
275876	33363385	Mutation of KMT2D frequently occurs in follicular lymphoma and diffuse large B-cell lymphoma.	('lymphoma', 'Disease', 'MESH:D008223', (50, 58))	('lymphoma', 'Disease', 'MESH:D008223', (84, 92))	('lymphoma', 'Phenotype', 'HP:0002665', (50, 58))	('lymphoma', 'Phenotype', 'HP:0002665', (84, 92))	('KMT2D', 'Gene', (12, 17))	('KMT2D', 'Gene', '8085', (12, 17))	('Mutation', 'Var', (0, 8))	('B-cell lymphoma', 'Disease', (77, 92))	('B-cell lymphoma', 'Disease', 'MESH:D016393', (77, 92))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (77, 92))	('occurs', 'Reg', (29, 35))	('lymphoma', 'Disease', (50, 58))	('lymphoma', 'Disease', (84, 92))
275877	33363385	Mutation of KMT2D has also been reported as a tumor inhibitor, but few studies have reported a high frequency of KMT2D mutations in ESCC.	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('KMT2D', 'Gene', (12, 17))	('KMT2D', 'Gene', '8085', (12, 17))	('Mutation', 'Var', (0, 8))	('tumor', 'Disease', (46, 51))	('KMT2D', 'Gene', (113, 118))	('KMT2D', 'Gene', '8085', (113, 118))	('mutations', 'Var', (119, 128))	('ESCC', 'Disease', (132, 136))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
275878	33363385	Mutation of KMT2D is reportedly associated with poor prognosis in many cancers, such as non-small-cell lung carcinoma, breast cancer, and ovarian metastases of colorectal cancer.	('breast cancer', 'Phenotype', 'HP:0003002', (119, 132))	('associated', 'Reg', (32, 42))	('lung carcinoma', 'Disease', 'MESH:D008175', (103, 117))	('breast cancer', 'Disease', 'MESH:D001943', (119, 132))	('cancers', 'Phenotype', 'HP:0002664', (71, 78))	('KMT2D', 'Gene', '8085', (12, 17))	('cancers', 'Disease', (71, 78))	('breast cancer', 'Disease', (119, 132))	('ovarian metastases of colorectal cancer', 'Disease', (138, 177))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('colorectal cancer', 'Phenotype', 'HP:0003003', (160, 177))	('lung carcinoma', 'Disease', (103, 117))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('ovarian metastases of colorectal cancer', 'Disease', 'MESH:D009362', (138, 177))	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('cancers', 'Disease', 'MESH:D009369', (71, 78))	('small-cell lung carcinoma', 'Phenotype', 'HP:0030357', (92, 117))	('KMT2D', 'Gene', (12, 17))	('Mutation', 'Var', (0, 8))	('non-small-cell lung carcinoma', 'Phenotype', 'HP:0030358', (88, 117))
275879	33363385	On the contrary, mutation of KMT2D correlates with longer survival of small cell lung cancer patients.	('lung cancer', 'Disease', (81, 92))	('KMT2D', 'Gene', '8085', (29, 34))	('lung cancer', 'Phenotype', 'HP:0100526', (81, 92))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (70, 92))	('KMT2D', 'Gene', (29, 34))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('mutation', 'Var', (17, 25))	('longer', 'PosReg', (51, 57))	('lung cancer', 'Disease', 'MESH:D008175', (81, 92))	('patients', 'Species', '9606', (93, 101))
275881	33363385	In this study, we identified frequent mutation of KMT2D and found that these mutations were associated with sex, early tumor stage, and high TMB.	('tumor', 'Disease', (119, 124))	('sex', 'Disease', (108, 111))	('KMT2D', 'Gene', (50, 55))	('KMT2D', 'Gene', '8085', (50, 55))	('TMB', 'Chemical', '-', (141, 144))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('mutation', 'Var', (38, 46))	('high TMB', 'Disease', (136, 144))	('associated', 'Reg', (92, 102))
275883	33363385	In addition, we found that patients with a KMT2D mutation had better disease-free and overall survival than those without a KMT2D mutation, suggesting that KMT2D mutation is associated with a good ESCC prognosis.	('KMT2D', 'Gene', (124, 129))	('KMT2D', 'Gene', '8085', (124, 129))	('KMT2D', 'Gene', (43, 48))	('ESCC', 'Disease', (197, 201))	('better', 'PosReg', (62, 68))	('disease-free', 'CPA', (69, 81))	('KMT2D', 'Gene', (156, 161))	('KMT2D', 'Gene', '8085', (156, 161))	('mutation', 'Var', (49, 57))	('KMT2D', 'Gene', '8085', (43, 48))	('patients', 'Species', '9606', (27, 35))	('mutation', 'Var', (162, 170))
275887	33363385	The high expression of SPEN was associated with metastasis in breast cancer.	('SPEN', 'Gene', '23013', (23, 27))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('breast cancer', 'Disease', 'MESH:D001943', (62, 75))	('SPEN', 'Gene', (23, 27))	('breast cancer', 'Phenotype', 'HP:0003002', (62, 75))	('breast cancer', 'Disease', (62, 75))	('high', 'Var', (4, 8))	('associated with', 'Reg', (32, 47))	('metastasis', 'CPA', (48, 58))
275891	33363385	Interestingly, both NOTCH2 and SPEN mutations were associated with lymph node metastases in our cohort.	('SPEN', 'Gene', (31, 35))	('metastases', 'Disease', 'MESH:D009362', (78, 88))	('NOTCH2', 'Gene', '4853', (20, 26))	('mutations', 'Var', (36, 45))	('associated with', 'Reg', (51, 66))	('SPEN', 'Gene', '23013', (31, 35))	('metastases', 'Disease', (78, 88))	('NOTCH2', 'Gene', (20, 26))
275892	33363385	These results suggested that SPEN mutations may predict the poor prognosis of ESCC patients.	('ESCC', 'Disease', (78, 82))	('SPEN', 'Gene', (29, 33))	('patients', 'Species', '9606', (83, 91))	('SPEN', 'Gene', '23013', (29, 33))	('mutations', 'Var', (34, 43))
275893	33363385	Meanwhile, our results also showed the association between SPEN mutation and high TMB.	('mutation', 'Var', (64, 72))	('SPEN', 'Gene', '23013', (59, 63))	('high TMB', 'Disease', (77, 85))	('SPEN', 'Gene', (59, 63))	('TMB', 'Chemical', '-', (82, 85))	('association', 'Interaction', (39, 50))
275895	33363385	These results also suggested the potential association between SPEN mutations and a good prognosis.	('mutations', 'Var', (68, 77))	('SPEN', 'Gene', '23013', (63, 67))	('SPEN', 'Gene', (63, 67))
275898	33363385	Interestingly, we identified associations between mutation of FOS, DOT1L, and VEGFA and metastasis-negative lymph nodes in ESCC.	('DOT1L', 'Gene', (67, 72))	('FOS', 'Gene', (62, 65))	('VEGFA', 'Gene', '7422', (78, 83))	('ESCC', 'Disease', (123, 127))	('FOS', 'Gene', '2353', (62, 65))	('associations', 'Interaction', (29, 41))	('DOT1L', 'Gene', '84444', (67, 72))	('VEGFA', 'Gene', (78, 83))	('metastasis-negative lymph nodes', 'CPA', (88, 119))	('mutation', 'Var', (50, 58))
275899	33363385	The mutation of FOS is reportedly associated with poor prognosis in colorectal cancer, and high expression of DOT1L and VEGFA indicates poor prognosis in many cancers, such as lung cancer, gastric cancer, and clear cell renal cell carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (231, 240))	('mutation', 'Var', (4, 12))	('FOS', 'Gene', (16, 19))	('gastric cancer', 'Disease', (189, 203))	('VEGFA', 'Gene', (120, 125))	('colorectal cancer', 'Phenotype', 'HP:0003003', (68, 85))	('cancers', 'Phenotype', 'HP:0002664', (159, 166))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (209, 240))	('FOS', 'Gene', '2353', (16, 19))	('cancers', 'Disease', (159, 166))	('lung cancer', 'Disease', 'MESH:D008175', (176, 187))	('DOT1L', 'Gene', '84444', (110, 115))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('expression', 'MPA', (96, 106))	('gastric cancer', 'Disease', 'MESH:D013274', (189, 203))	('lung cancer', 'Phenotype', 'HP:0100526', (176, 187))	('lung cancer', 'Disease', (176, 187))	('VEGFA', 'Gene', '7422', (120, 125))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('colorectal cancer', 'Disease', 'MESH:D015179', (68, 85))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (209, 240))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('cancers', 'Disease', 'MESH:D009369', (159, 166))	('colorectal cancer', 'Disease', (68, 85))	('gastric cancer', 'Phenotype', 'HP:0012126', (189, 203))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('clear cell renal cell carcinoma', 'Disease', (209, 240))	('DOT1L', 'Gene', (110, 115))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (220, 240))
275907	33363385	This supported the reliability of correlations between high TMB-related gene mutations such as those in KMT2B and SPEN, and between high TMB and clinical characteristics such as drinking status.	('KMT2B', 'Gene', (104, 109))	('high', 'Gene', (55, 59))	('drinking status', 'Disease', (178, 193))	('TMB', 'Chemical', '-', (137, 140))	('SPEN', 'Gene', (114, 118))	('KMT2B', 'Gene', '9757', (104, 109))	('mutations', 'Var', (77, 86))	('TMB', 'Chemical', '-', (60, 63))	('SPEN', 'Gene', '23013', (114, 118))	('correlations', 'Interaction', (34, 46))
275909	33363385	High TMB was reported to associate with prolonged progression-free and overall survival after immunotherapy.	('prolonged', 'PosReg', (40, 49))	('High TMB', 'Var', (0, 8))	('overall survival', 'CPA', (71, 87))	('TMB', 'Chemical', '-', (5, 8))	('progression-free', 'CPA', (50, 66))
275913	33363385	Targeting these genes influences the occurrence and development of tumors by inhibiting cell proliferation, angiogenesis, invasion, and metastasis; promoting cell apoptosis; and regulating key molecules or signal transduction pathways of inflammation.	('inhibiting', 'NegReg', (77, 87))	('promoting', 'PosReg', (148, 157))	('cell proliferation', 'CPA', (88, 106))	('occurrence', 'CPA', (37, 47))	('invasion', 'CPA', (122, 130))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('influences', 'Reg', (22, 32))	('inflammation', 'Disease', 'MESH:D007249', (238, 250))	('regulating', 'Reg', (178, 188))	('Targeting', 'Var', (0, 9))	('cell apoptosis', 'CPA', (158, 172))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('signal transduction pathways', 'Pathway', (206, 234))	('angiogenesis', 'CPA', (108, 120))	('tumors', 'Disease', (67, 73))	('key molecules', 'Pathway', (189, 202))	('inflammation', 'Disease', (238, 250))	('metastasis', 'CPA', (136, 146))	('development', 'CPA', (52, 63))	('tumors', 'Disease', 'MESH:D009369', (67, 73))
275914	33363385	Recently, studies reported that targeted therapies for EGFR mutations showed only limited success in improving the overall survival of ESCC patients in clinical trials.	('EGFR', 'Gene', '1956', (55, 59))	('ESCC', 'Disease', (135, 139))	('EGFR', 'Gene', (55, 59))	('patients', 'Species', '9606', (140, 148))	('mutations', 'Var', (60, 69))
275918	33363385	We also analyzed the relationship between the number of metastatic lymph nodes and prognosis, and the potential prognostic role of SPEN and KMT2D mutations.	('mutations', 'Var', (146, 155))	('SPEN', 'Gene', (131, 135))	('KMT2D', 'Gene', (140, 145))	('KMT2D', 'Gene', '8085', (140, 145))	('SPEN', 'Gene', '23013', (131, 135))
275924	32984843	Through comprehensive analyses of sequence and structural alterations, we discovered a significant enrichment in activating mutations in receptor tyrosine kinase (RTK) genes in nonresponding tumors in three immunotherapy treated cohorts.	('nonresponding', 'Disease', (177, 190))	('receptor tyrosine kinase', 'Gene', (137, 161))	('activating', 'PosReg', (113, 123))	('tumors', 'Phenotype', 'HP:0002664', (191, 197))	('RTK', 'Gene', (163, 166))	('mutations', 'Var', (124, 133))	('receptor tyrosine kinase', 'Gene', '5979', (137, 161))	('tumors', 'Disease', 'MESH:D009369', (191, 197))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('tumors', 'Disease', (191, 197))
275925	32984843	An integrated multivariable model incorporating cTMB, RTK mutations, smoking-related mutational signature and human leukocyte antigen status provided an improved predictor of response to immunotherapy that was independently validated.	('mutations', 'Var', (58, 67))	('RTK', 'Gene', (54, 57))	('human', 'Species', '9606', (110, 115))	('cTMB', 'Chemical', '-', (48, 52))	('cTMB', 'Gene', (48, 52))
275927	32984843	Antitumor responses are integrally connected to tumor genomics as neoantigens stemming from somatic mutations seem to shape immune responses and drive clinical benefit from immunotherapy in several tumor types including non-small-cell lung cancer (NSCLC).	('tumor', 'Disease', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (224, 246))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('shape', 'Reg', (118, 123))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (220, 246))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('lung cancer', 'Disease', (235, 246))	('tumor', 'Disease', (48, 53))	('immune responses', 'CPA', (124, 140))	('NSCLC', 'Disease', 'MESH:D002289', (248, 253))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Disease', (198, 203))	('mutations', 'Var', (100, 109))	('NSCLC', 'Disease', (248, 253))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('lung cancer', 'Disease', 'MESH:D008175', (235, 246))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('lung cancer', 'Phenotype', 'HP:0100526', (235, 246))
275935	32984843	Genetic variation in the antigen presentation machinery, both at a germline as well as a somatic level may therefore modulate an effective antitumor immune response.	('modulate', 'Reg', (117, 125))	('Genetic variation', 'Var', (0, 17))	('tumor', 'Disease', (143, 148))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
275952	32984843	2), in the two immunotherapy treated NSCLC cohorts, the correlation between obsTMB and tumor purity was particularly pronounced for tumor purity less than 30% (P = 0.008 and P = 0.08 for overall comparisons of TMB across tumor purity tiers for cohort 1 and cohort 2, respectively; see Extended Data Fig.	('NSCLC', 'Disease', 'MESH:D002289', (37, 42))	('TMB across tumor', 'Disease', (210, 226))	('TMB', 'Chemical', '-', (210, 213))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('TMB', 'Chemical', '-', (79, 82))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('tumor', 'Disease', (87, 92))	('tumor', 'Disease', (221, 226))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('NSCLC', 'Disease', (37, 42))	('TMB across tumor', 'Disease', 'MESH:D009369', (210, 226))	('tumor', 'Disease', (132, 137))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('less', 'Var', (145, 149))	('tumor', 'Disease', 'MESH:D009369', (221, 226))
275970	32984843	An analysis of tumor samples with at least 20 mutations revealed an enrichment of the molecular smoking signature in patients with durable clinical benefit (Mann-Whitney U test P = 0.003, FDR-adjusted P = 0.027, Fig.	('mutations', 'Var', (46, 55))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumor', 'Disease', (15, 20))	('patients', 'Species', '9606', (117, 125))
275977	32984843	We found a significant enrichment in activating mutations in RTK genes in patients who did not derive durable clinical benefit from ICB (Fisher's exact P < 0.001, FDR-adjusted P = 0.002, Fig.	('ICB', 'Chemical', '-', (132, 135))	('RTK genes', 'Gene', (61, 70))	('patients', 'Species', '9606', (74, 82))	('activating', 'PosReg', (37, 47))	('mutations', 'Var', (48, 57))
275978	32984843	The RTK superfamily of cell-surface receptors serve as mediators of cell signaling by extra-cellular growth factors and these oncogenes are activated by point mutations, amplifications (FGFR1, IGF1R) or both (EGFR, ERBB2, MET).	('FGFR1', 'Gene', '2260', (186, 191))	('ERBB2', 'Gene', '2064', (215, 220))	('MET', 'Gene', (222, 225))	('EGFR', 'Gene', (209, 213))	('IGF1R', 'Gene', (193, 198))	('ERBB2', 'Gene', (215, 220))	('EGFR', 'Gene', '1956', (209, 213))	('IGF1R', 'Gene', '3480', (193, 198))	('activated', 'PosReg', (140, 149))	('amplifications', 'Var', (170, 184))	('MET', 'Gene', '79811', (222, 225))	('point mutations', 'Var', (153, 168))	('FGFR1', 'Gene', (186, 191))
275979	32984843	EGFR exon 19 in-frame deletions (745KELREA>T, E746_A750del, L747_T751del), exon 20 in-frame insertions (N771_H773dup) and exon 21 point mutations (L858R) as well as ERBB2 exon 19 (E770_ A771insAYVM) and exon 20 (776G>VC) in-frame insertions were exclusively found in nonresponding tumors in cohort 1 (Fig.	('tumors', 'Disease', 'MESH:D009369', (281, 287))	('H773dup', 'Mutation', 'p.773dupH', (109, 116))	('N771_H773dup', 'Var', (104, 116))	('nonresponding', 'Disease', (267, 280))	('L747_T751del', 'Var', (60, 72))	('745KELREA>T', 'Mutation', 'c.745KELREA>T', (33, 44))	('ERBB2', 'Gene', (165, 170))	('L858R', 'Mutation', 'rs121434568', (147, 152))	('776G>VC', 'Var', (212, 219))	('tumors', 'Phenotype', 'HP:0002664', (281, 287))	('EGFR', 'Gene', (0, 4))	('745KELREA>T', 'Var', (33, 44))	('E770_ A771insAYVM', 'Var', (180, 197))	('ERBB2', 'Gene', '2064', (165, 170))	('E770_ A771insAYVM', 'Mutation', 'p.770,771insA,AYVM', (180, 197))	('E746_A750del', 'Mutation', 'p.746,750delA', (46, 58))	('tumor', 'Phenotype', 'HP:0002664', (281, 286))	('L747_T751del', 'Mutation', 'p.747,751delT', (60, 72))	('tumors', 'Disease', (281, 287))	('L858R', 'Var', (147, 152))	('EGFR', 'Gene', '1956', (0, 4))	('E746_A750del', 'Var', (46, 58))
275981	32984843	The distribution of activating RTK mutations was independent of TMB (Mann-Whitney U test P = 0.33 for TMB differences between RTK+ and RTK- tumors) and remained significantly associated with clinical response to ICB after correction for TMB (logistic regression P = 0.006, Supplementary Table 7).	('RTK', 'Gene', (31, 34))	('TMB', 'Chemical', '-', (64, 67))	('tumors', 'Disease', (140, 146))	('activating', 'PosReg', (20, 30))	('associated with', 'Reg', (175, 190))	('tumors', 'Disease', 'MESH:D009369', (140, 146))	('TMB', 'Chemical', '-', (237, 240))	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('clinical response to', 'MPA', (191, 211))	('TMB', 'Chemical', '-', (102, 105))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('ICB', 'Chemical', '-', (212, 215))	('mutations', 'Var', (35, 44))
275983	32984843	Consistent with this notion, we found a significantly lower CD8+ T cell infiltration in tumors with activating RTK mutations (CD8+ T cell density of 7.36 +- 2.5 versus 15.16 +- 2.5 for tumors with and without activating RTK mutations, P = 0.036), indicating that RTK signaling may be linked to intratumoral T cell depletion.	('tumors', 'Disease', (185, 191))	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('tumor', 'Phenotype', 'HP:0002664', (299, 304))	('tumor', 'Disease', (185, 190))	('CD8', 'Gene', '925', (126, 129))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('tumors', 'Disease', 'MESH:D009369', (185, 191))	('tumor', 'Disease', (88, 93))	('RTK', 'Gene', (111, 114))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('CD8', 'Gene', '925', (60, 63))	('activating', 'PosReg', (100, 110))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('mutations', 'Var', (115, 124))	('tumor', 'Disease', (299, 304))	('CD8', 'Gene', (126, 129))	('tumors', 'Phenotype', 'HP:0002664', (185, 191))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor', 'Disease', 'MESH:D009369', (299, 304))	('tumors', 'Disease', (88, 94))	('lower', 'NegReg', (54, 59))	('CD8', 'Gene', (60, 63))
275984	32984843	5a) and we validated these observations in cohort 2, where an enrichment of activating mutations in RTK genes was found in nonresponding tumors and resulted in worse PFS (log-rank P = 0.009, Extended Data Fig.	('tumors', 'Disease', (137, 143))	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('activating', 'PosReg', (76, 86))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('PFS', 'MPA', (166, 169))	('RTK genes', 'Gene', (100, 109))	('mutations', 'Var', (87, 96))	('worse', 'NegReg', (160, 165))
275986	32984843	The data from this cohort confirmed our findings and revealed that RTK activating mutations in EGFR, ERBB2, MET, FGFR1 and IGF1R were enriched in nonresponding tumors (Fisher's exact P = 0.027) and that RTK alterations were associated with shorter PFS (log-rank P = 0.035, Extended Data Fig.	('FGFR1', 'Gene', (113, 118))	('MET', 'Gene', '79811', (108, 111))	('IGF1R', 'Gene', (123, 128))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('EGFR', 'Gene', '1956', (95, 99))	('tumors', 'Disease', (160, 166))	('activating', 'PosReg', (71, 81))	('ERBB2', 'Gene', (101, 106))	('tumors', 'Disease', 'MESH:D009369', (160, 166))	('shorter', 'NegReg', (240, 247))	('MET', 'Gene', (108, 111))	('FGFR1', 'Gene', '2260', (113, 118))	('ERBB2', 'Gene', '2064', (101, 106))	('EGFR', 'Gene', (95, 99))	('PFS', 'Disease', (248, 251))	('RTK', 'Gene', (67, 70))	('mutations', 'Var', (82, 91))	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('IGF1R', 'Gene', '3480', (123, 128))
275987	32984843	Recurrent alterations in ARID1A were found in patients from cohort 1 with durable clinical benefit (Mann-Whitney U test P = 0.005, FDR-adjusted P = 0.024), with a trend toward statistical significance after correction for TMB (P = 0.062, Fig.	('TMB', 'Chemical', '-', (222, 225))	('patients', 'Species', '9606', (46, 54))	('alterations', 'Var', (10, 21))	('ARID1A', 'Gene', '8289', (25, 31))	('ARID1A', 'Gene', (25, 31))	('benefit', 'PosReg', (91, 98))
275988	32984843	ARID1A deficiency has been shown to impair mismatch repair, which would in turn cause an increased mutation burden and drive responses to ICB.	('ICB', 'Chemical', '-', (138, 141))	('cause', 'Reg', (80, 85))	('responses to ICB', 'MPA', (125, 141))	('ARID1A', 'Gene', '8289', (0, 6))	('drive', 'PosReg', (119, 124))	('mismatch repair', 'MPA', (43, 58))	('deficiency', 'Var', (7, 17))	('mutation burden', 'MPA', (99, 114))	('ARID1A', 'Gene', (0, 6))	('increased', 'PosReg', (89, 98))	('impair', 'NegReg', (36, 42))
275989	32984843	KEAP1 mutations, in particular inactivating mutations with concurrent loss of the wild-type allele, were more commonly found in patients with nondurable clinical benefit, however, this observation did not reach statistical significance (P = 0.074, Fig.	('KEAP1', 'Gene', (0, 5))	('inactivating mutations', 'Var', (31, 53))	('found', 'Reg', (119, 124))	('patients', 'Species', '9606', (128, 136))	('KEAP1', 'Gene', '9817', (0, 5))	('mutations', 'Var', (6, 15))
275990	32984843	A homozygous deletion in PTEN was found in one patient with a short-lived response to ICB and MDM2/MDM4 amplifications were identified in three patients with nondurable clinical benefit (Fig.	('MDM2', 'Gene', (94, 98))	('ICB', 'Chemical', '-', (86, 89))	('patient', 'Species', '9606', (47, 54))	('MDM4', 'Gene', (99, 103))	('MDM4', 'Gene', '4194', (99, 103))	('patient', 'Species', '9606', (144, 151))	('deletion', 'Var', (13, 21))	('patients', 'Species', '9606', (144, 152))	('found', 'Reg', (34, 39))	('PTEN', 'Gene', (25, 29))	('PTEN', 'Gene', '5728', (25, 29))	('MDM2', 'Gene', '4193', (94, 98))
275991	32984843	We did not detect any loss-of-function mutations in JAK1 or JAK2 (ref. )	('JAK2', 'Gene', '3717', (60, 64))	('JAK1', 'Gene', '3716', (52, 56))	('JAK2', 'Gene', (60, 64))	('mutations', 'Var', (39, 48))	('JAK1', 'Gene', (52, 56))
275992	32984843	or an enrichment of cooccurring KRAS and inactivating STK11 mutations in nonresponding tumors (Fig.	('STK11', 'Gene', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('STK11', 'Gene', '6794', (54, 59))	('KRAS', 'Gene', (32, 36))	('KRAS', 'Gene', '3845', (32, 36))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('tumors', 'Disease', (87, 93))	('mutations', 'Var', (60, 69))	('inactivating', 'Var', (41, 53))	('tumors', 'Disease', 'MESH:D009369', (87, 93))
275994	32984843	CDKN2A and the group of IFN-gamma pathway genes are on chromosome 9p 917Kb apart, and therefore IFN-gamma deletions may be cooccurring passengers in the setting of a driver CDKN2A deletion.	('IFN-gamma', 'Gene', (24, 33))	('deletion', 'Var', (180, 188))	('IFN-gamma', 'Gene', '3458', (96, 105))	('CDKN2A', 'Gene', (173, 179))	('IFN-gamma', 'Gene', (96, 105))	('deletions', 'Var', (106, 115))	('CDKN2A', 'Gene', '1029', (173, 179))	('CDKN2A', 'Gene', (0, 6))	('CDKN2A', 'Gene', '1029', (0, 6))	('IFN-gamma', 'Gene', '3458', (24, 33))
275998	32984843	We identified one responding TMB-high tumor with biallellic inactivation of MLH1, but did not identify an overall enrichment in deleterious somatic DNA repair gene mutations in responding tumors (Extended Data Fig.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumors', 'Disease', (188, 194))	('tumors', 'Disease', 'MESH:D009369', (188, 194))	('tumors', 'Phenotype', 'HP:0002664', (188, 194))	('TMB-high tumor', 'Disease', (29, 43))	('TMB-high tumor', 'Disease', 'MESH:D009369', (29, 43))	('biallellic', 'Var', (49, 59))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('MLH1', 'Gene', '4292', (76, 80))	('MLH1', 'Gene', (76, 80))
275999	32984843	Similarly, we detected a gain-of-function CTNNB1 hotspot mutation in a nonresponding tumor but no additional differences in activating mutations in the WNT pathway between responders and nonresponders (Extended Data Fig.	('mutation', 'Var', (57, 65))	('tumor', 'Disease', (85, 90))	('gain-of-function', 'PosReg', (25, 41))	('CTNNB1', 'Gene', (42, 48))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('CTNNB1', 'Gene', '1499', (42, 48))
276004	32984843	Responding tumors showed a trend for a higher number of predicted MANAs derived from frameshift mutations (Mann-Whitney U test P = 0.08, Fig.	('MANA', 'Gene', (66, 70))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('tumors', 'Phenotype', 'HP:0002664', (11, 17))	('MANA', 'Gene', '4123', (66, 70))	('tumors', 'Disease', 'MESH:D009369', (11, 17))	('tumors', 'Disease', (11, 17))	('frameshift mutations', 'Var', (85, 105))
276005	32984843	We then studied the potential of hotspot mutations in driver and other genes to generate fit MANAs as such alterations may be less likely to be eliminated as a means of immune escape.	('mutations', 'Var', (41, 50))	('MANA', 'Gene', '4123', (93, 97))	('MANA', 'Gene', (93, 97))
276006	32984843	A subset of clonal hotspot frameshifts and in-frame indels generated fit MANAs (Extended Data Fig.	('MANA', 'Gene', '4123', (73, 77))	('MANA', 'Gene', (73, 77))	('frameshifts', 'Var', (27, 38))
276008	32984843	While these findings do not provide definitive evidence that clonal hotspot MANAs are indeed immunogenic, they provide the foundation for further exploration of hotspot peptide-specific T cell responses, especially when derived from frameshift mutations.	('frameshift mutations', 'Var', (233, 253))	('MANA', 'Gene', (76, 80))	('MANA', 'Gene', '4123', (76, 80))
276012	32984843	The beta2-microglobulin locus was frequently lost by LOH, however, we did not detect any concurrent inactivating mutations, rendering this an infrequent mechanism of immune evasion in cohort 1 (Fig.	('LOH', 'Var', (53, 56))	('lost', 'NegReg', (45, 49))	('beta2-microglobulin', 'Gene', '567', (4, 23))	('beta2-microglobulin', 'Gene', (4, 23))
276021	32984843	Furthermore, cases with maximal HLA class I heterozygosity were found to have a less clonal T cell receptor (TCR) repertoire (P = 0.01, Extended Data Fig.	('TCR', 'Gene', '6962', (109, 112))	('T cell receptor', 'Gene', (92, 107))	('less', 'NegReg', (80, 84))	('T cell receptor', 'Gene', '6962', (92, 107))	('heterozygosity', 'Var', (44, 58))	('TCR', 'Gene', (109, 112))
276022	32984843	We then assessed correlations among genomic and immune features and identified four clusters of inter-correlated features centered on RTK mutations, HLA genetic variation, tumor aneuploidy and cTMB (Extended Data Fig.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('tumor aneuploidy', 'Disease', (172, 188))	('cTMB', 'Chemical', '-', (193, 197))	('tumor aneuploidy', 'Disease', 'MESH:D000782', (172, 188))	('RTK', 'Gene', (134, 137))	('mutations', 'Var', (138, 147))
276031	32984843	While targeted NGS may alleviate the tumor purity effect given the higher coverage compared to whole-exome sequencing, our findings suggest that TMB values should only be interpreted after taking into consideration the tumor purity of the sample analyzed in both settings.	('NGS', 'Var', (15, 18))	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('alleviate', 'NegReg', (23, 32))	('tumor', 'Disease', (219, 224))	('TMB', 'Chemical', '-', (145, 148))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('tumor', 'Disease', 'MESH:D009369', (219, 224))
276034	32984843	We report here a significant enrichment in activating RTK genomic alterations in nonresponding tumors that identified patients with an inferior outcome from ICB in three independent NSCLC cohorts.	('genomic alterations', 'Var', (58, 77))	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('NSCLC', 'Disease', (182, 187))	('NSCLC', 'Disease', 'MESH:D002289', (182, 187))	('patients', 'Species', '9606', (118, 126))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('ICB', 'Chemical', '-', (157, 160))	('RTK', 'Gene', (54, 57))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('activating', 'PosReg', (43, 53))	('tumors', 'Disease', (95, 101))
276035	32984843	While activating EGFR and MET mutations have been described in patients that do not benefit from ICB, our study demonstrates that activating genomic alterations in RTK genes including EGFR, HER2, MET, FGFR1 and IGF1R are linked with primary resistance to ICB independent of mutation burden.	('FGFR1', 'Gene', (201, 206))	('MET', 'Gene', (26, 29))	('MET', 'Gene', '79811', (196, 199))	('IGF1R', 'Gene', (211, 216))	('RTK genes', 'Gene', (164, 173))	('EGFR', 'Gene', (17, 21))	('HER2', 'Gene', '2064', (190, 194))	('EGFR', 'Gene', (184, 188))	('MET', 'Gene', '79811', (26, 29))	('ICB', 'Chemical', '-', (255, 258))	('ICB', 'Chemical', '-', (97, 100))	('MET', 'Gene', (196, 199))	('FGFR1', 'Gene', '2260', (201, 206))	('primary', 'MPA', (233, 240))	('mutations', 'Var', (30, 39))	('EGFR', 'Gene', '1956', (17, 21))	('HER2', 'Gene', (190, 194))	('alterations', 'Var', (149, 160))	('activating', 'PosReg', (130, 140))	('EGFR', 'Gene', '1956', (184, 188))	('IGF1R', 'Gene', '3480', (211, 216))	('patients', 'Species', '9606', (63, 71))
276036	32984843	RTKs transduce signals through the mitogen-activated protein kinase and PI3K-AKT-mTOR pathways, which have been implicated in regulation of immune responses in the tumor microenvironment such that oncogenic signaling through mitogen-activated protein kinase and PI3K renders the microenvironment less permeable to cytotoxic T cells.	('AKT', 'Gene', (77, 80))	('tumor', 'Disease', (164, 169))	('AKT', 'Gene', '207', (77, 80))	('PI3K', 'Var', (262, 266))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('mTOR', 'Gene', (81, 85))	('mTOR', 'Gene', '2475', (81, 85))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))
276039	32984843	Our multivariable model incorporates an improved measure of TMB through correction of tumor purity, RTK mutations, molecular smoking signature and HLA genetic variation, highlighting the need for development of integrative platforms that capture the complexities of the cancer-immune system crosstalk.	('RTK', 'Gene', (100, 103))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('mutations', 'Var', (104, 113))	('tumor', 'Disease', (86, 91))	('cancer', 'Disease', (270, 276))	('cancer', 'Disease', 'MESH:D009369', (270, 276))	('cancer', 'Phenotype', 'HP:0002664', (270, 276))	('TMB', 'Chemical', '-', (60, 63))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
276050	32984843	A publicly available cohort of 240 NSCLC patients treated with ICB was obtained through CBioPortal for Cancer Genomics and used to validate the association of RTK mutations with outcome (cohort 3).	('RTK', 'Gene', (159, 162))	('association', 'Interaction', (144, 155))	('mutations', 'Var', (163, 172))	('NSCLC', 'Disease', (35, 40))	('Cancer', 'Disease', (103, 109))	('patients', 'Species', '9606', (41, 49))	('NSCLC', 'Disease', 'MESH:D002289', (35, 40))	('Cancer', 'Disease', 'MESH:D009369', (103, 109))	('Cancer', 'Phenotype', 'HP:0002664', (103, 109))	('ICB', 'Chemical', '-', (63, 66))
276052	32984843	Eighty patients were treated with anti-PD1 therapy, seven patients received combination anti-PD1 and anti-CTLA4 therapy and two patients were treated with chemotherapy and anti-PD1 therapy.	('CTLA4', 'Gene', (106, 111))	('anti-PD1', 'Var', (34, 42))	('patients', 'Species', '9606', (58, 66))	('patients', 'Species', '9606', (128, 136))	('CTLA4', 'Gene', '1493', (106, 111))	('patients', 'Species', '9606', (7, 15))
276062	32984843	The mean depth of total and distinct coverage for the pretreatment tumors were x231 and x144, respectively (Supplementary Tables 2, 3 and 6).	('tumors', 'Disease', 'MESH:D009369', (67, 73))	('x231', 'Var', (79, 83))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('x144', 'Var', (88, 92))	('tumors', 'Disease', (67, 73))
276063	32984843	Somatic mutations, consisting of point mutations, insertions, and deletions across the whole exome were identified using the VariantDx custom software for identifying mutations in matched tumor and normal samples as previously described.	('tumor', 'Disease', (188, 193))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('deletions', 'Var', (66, 75))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))
276064	32984843	Mutations were characterized as hotspots when the same amino acid change was reported in at least ten tumor samples in COSMIC v.84 database.	('Mutations', 'Var', (0, 9))	('tumor', 'Disease', (102, 107))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))
276065	32984843	Missense mutations were evaluated for their potential as cancer drivers by CHASMplus.	('CHASMplus', 'Disease', (75, 84))	('CHASMplus', 'Disease', 'None', (75, 84))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('cancer', 'Disease', (57, 63))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('Missense mutations', 'Var', (0, 18))
276066	32984843	We performed an unbiased enrichment analysis for sequence and focal copy number alterations across the exome in responding versus nonresponding tumors.	('tumors', 'Disease', (144, 150))	('copy number alterations', 'Var', (68, 91))	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('tumors', 'Disease', 'MESH:D009369', (144, 150))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))
276075	32984843	A single MANA per mutation was selected based on their MHC affinity and neoantigen candidates with an MHC affinity <500 nM were further selected to estimate the neoantigen tumor burden and used for downstream analyses.	('MHC', 'Gene', (55, 58))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('MHC', 'Gene', '3107', (55, 58))	('tumor', 'Disease', (172, 177))	('MANA', 'Gene', (9, 13))	('MHC', 'Gene', (102, 105))	('MANA', 'Gene', '4123', (9, 13))	('mutation', 'Var', (18, 26))	('MHC', 'Gene', '3107', (102, 105))	('tumor', 'Disease', 'MESH:D009369', (172, 177))
276076	32984843	We further characterized MANAs based on their immunogenic potential by selecting neopeptides with high MHC affinity for which their wild-type counterpart predicted not to bind MHC class I molecules (fit MANA: MHC affinity for mutant peptide <50 nM and for wild-type peptide >1,000 nM).	('MHC', 'Gene', (103, 106))	('MHC', 'Gene', (176, 179))	('mutant', 'Var', (226, 232))	('MANA', 'Gene', '4123', (25, 29))	('MHC', 'Gene', '3107', (103, 106))	('peptide', 'Protein', (233, 240))	('MANA', 'Gene', '4123', (203, 207))	('MHC', 'Gene', '3107', (176, 179))	('high MHC', 'Phenotype', 'HP:0025548', (98, 106))	('MANA', 'Gene', (25, 29))	('MHC', 'Gene', (209, 212))	('MANA', 'Gene', (203, 207))	('MHC', 'Gene', '3107', (209, 212))
276077	32984843	For MANAs stemming from frameshift mutations, we considered the length of the resulting protein until a stop codon was reached, as a longer amino acid sequence would have the potential to generate more immunogenic neoantigens.	('MANA', 'Gene', (4, 8))	('immunogenic neoantigens', 'MPA', (202, 225))	('MANA', 'Gene', '4123', (4, 8))	('frameshift mutations', 'Var', (24, 44))
276078	32984843	Frameshift MANAs were interrogated for similarity to microbial and viral antigens by matching the peptide sequence to peptides in the Immune Epitope Database (IEDB, www.iedb.org), requiring a match of >80% for identity and >75% for length.	('MANA', 'Gene', (11, 15))	('MANA', 'Gene', '4123', (11, 15))	('Frameshift', 'Var', (0, 10))
276081	32984843	A total of 76 tumors (64 lung adenocarcinomas (LUAD) and 12 lung squamous cell carcinomas (LUSC), with average patient pack years of 43.8 and 32.8, respectively) with mutational loads >250 (requiring a minimum 10% MAF and at least four variant supporting reads per mutation) and a detected smoking signature with >75% contribution were diluted in silico by subsampling to lower mutation counts from 5 up to 100.	('carcinomas', 'Phenotype', 'HP:0030731', (79, 89))	('carcinoma', 'Phenotype', 'HP:0030731', (35, 44))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (25, 45))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (65, 88))	('carcinomas', 'Phenotype', 'HP:0030731', (35, 45))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('tumors', 'Disease', (14, 20))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('lung squamous cell carcinomas', 'Disease', (60, 89))	('mutational', 'Var', (167, 177))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (25, 44))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (65, 89))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('patient', 'Species', '9606', (111, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('lung adenocarcinomas', 'Disease', (25, 45))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (25, 45))	('lung squamous cell carcinomas', 'Disease', 'MESH:D002294', (60, 89))
276090	32984843	For a segment with total copy number (n) and minor copy number (nB), the expected levels for log copy ratio (logR) and minor allele frequency (M) can be calculated as   where alpha represents tumor purity and phi denotes tumor ploidy.	('tumor', 'Disease', (192, 197))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('tumor', 'Disease', (221, 226))	('minor copy number', 'Var', (45, 62))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('tumor ploidy', 'Disease', 'MESH:D009369', (221, 233))	('tumor ploidy', 'Disease', (221, 233))	('tumor', 'Disease', 'MESH:D009369', (221, 226))
276098	32984843	We restricted our analysis to 3,788 TCGA samples from seven tumor types (BLCA, BRCA, COAD, HNSCC, KIRC, LUAD, LUSC and SKCM) that had both MC3 mutation calls and a consensus tumor purity estimate.	('COAD', 'Disease', (85, 89))	('tumor', 'Disease', (174, 179))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('COAD', 'Disease', 'MESH:D029424', (85, 89))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('MC3', 'Gene', (139, 142))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('MC3', 'Gene', '4159', (139, 142))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('tumor', 'Disease', (60, 65))	('mutation calls', 'Var', (143, 157))
276101	32984843	MAF, ploidy and purity were incorporated to estimate mutation cellular fraction that is the fraction of cancer cells that harbor a specific mutation (Supplementary Table 3).	('ploidy', 'Disease', 'None', (5, 11))	('ploidy', 'Disease', (5, 11))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('mutation', 'Var', (140, 148))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))
276102	32984843	Briefly, the expected MAF (Vexp) of a mutation with mutation cellular fraction (CF) present in m copies (mutation multiplicity), at a locus with total copy number in the tumor sample (nT) and total copy number in the matched normal sample (nN), with purity (alpha) can be calculated as  where m indicates multiplicity; that is, the number of mutant copies present in the cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (371, 377))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('tumor', 'Disease', (170, 175))	('cancer', 'Disease', (371, 377))	('cancer', 'Disease', 'MESH:D009369', (371, 377))	('mutation', 'Var', (38, 46))
276106	32984843	The first simulated tumor with TMB of 265 contained four mutation clusters at cellular fractions 1.00 (n = 100), 0.70 (n = 50), 0.40 (n = 40) and 0.2 (n = 75).	('TMB', 'Chemical', '-', (31, 34))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('TMB of 265', 'Gene', (31, 41))	('0.70', 'Var', (113, 117))	('tumor', 'Disease', (20, 25))
276110	32984843	Distinct mutant read count (m) were generated by assuming a draw from a binomial distribution with probability of success set to the expected mutation allele frequency (upsilonexp) given the purity of the tumor sample (alpha) and cellular fraction of the mutation (CF), assuming absence of somatic copy number alterations at the mutation loci as follows:  Mutations with simulated distinct coverage c >= 10, distinct mutant read count m >= 3 and observed allele frequency  were determined to be present, and were tallied up to derive the obsTMB.	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('Mutations', 'Var', (356, 365))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('mutant', 'Var', (417, 423))	('tumor', 'Disease', (205, 210))	('TMB', 'Chemical', '-', (541, 544))
276120	32984843	We derived an estimate for the clonal composition of each tumor defined as the frequency of observed mutations in cellular fraction bins of width 0.05 spanning the [0,1] interval, and used these estimates as a basis to model mutation cellular fraction values in the simulation experiment.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('mutations', 'Var', (101, 110))
276125	32984843	The cancer cell fraction of mutations in each tumor were determined by sampling from a multinomial distribution with p parameters set to match the tumor's clonal composition.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('tumor', 'Disease', 'MESH:D009369', (46, 51))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('tumor', 'Disease', (46, 51))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('cancer', 'Disease', 'MESH:D009369', (4, 10))	('cancer', 'Disease', (4, 10))	('mutations', 'Var', (28, 37))
276132	32984843	The higher depth of coverage in targeted sequencing allows detection of mutations at lower allelic fractions while avoiding false positives, which enables more sensitive detection of clonal mutations in low tumor purity samples and subclonal mutations in samples of moderate to high purity.	('low tumor', 'Disease', 'MESH:D009800', (203, 212))	('mutations', 'Var', (72, 81))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('low tumor', 'Disease', (203, 212))
276133	32984843	First, in determining the extent of intratumor heterogeneity, MC3 mutation calls from TCGA were not filtered based on MAF or distinct mutant read count.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Disease', (41, 46))	('mutation', 'Var', (66, 74))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('MC3', 'Gene', (62, 65))	('MC3', 'Gene', '4159', (62, 65))
276156	32984843	A multivariable Cox proportional hazards model was employed using cTMB, RTK mutations, smoking mutational signature and number of HLA germline alleles for cohort 1.	('mutations', 'Var', (76, 85))	('cTMB', 'Chemical', '-', (66, 70))	('cTMB', 'Gene', (66, 70))	('RTK', 'Gene', (72, 75))
276161	32984843	Missense mutations were evaluated for their potential as cancer drivers by CHASMplus (v.1.0.0) with consequence prediction using CRAVAT (v.4.3).	('CHASMplus', 'Disease', (75, 84))	('CHASMplus', 'Disease', 'None', (75, 84))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('cancer', 'Disease', (57, 63))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('Missense mutations', 'Var', (0, 18))
276163	31382962	Aberration of miRNA expressions could affect their targeting mRNAs involved in cancer-related signaling pathways.	('targeting mRNAs', 'MPA', (51, 66))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('miRNA expressions', 'Protein', (14, 31))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('affect', 'Reg', (38, 44))	('Aberration', 'Var', (0, 10))
276171	31382962	Cancer is a genetic disease caused by alterations of genes that control the cell behavior, like cell growth and division.	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('caused by', 'Reg', (28, 37))	('genetic disease', 'Disease', (12, 27))	('genetic disease', 'Disease', 'MESH:D030342', (12, 27))	('alterations', 'Var', (38, 49))
276175	31382962	TCGA data has been used to characterize key genomic changes, find novel mutations, define intrinsic tumor types, discover similarities and differences across cancer types, reveal therapy resistance mechanisms, and collect tumor evolution evidence.	('mutations', 'Var', (72, 81))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (222, 227))	('tumor', 'Disease', (100, 105))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('cancer', 'Disease', (158, 164))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('tumor', 'Disease', (222, 227))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
276178	31382962	The aberration of miRNA expression could affect a large number of mRNAs and cancer-related signaling pathways.	('aberration', 'Var', (4, 14))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('miRNA expression', 'Protein', (18, 34))	('mRNAs', 'Pathway', (66, 71))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('affect', 'Reg', (41, 47))
276208	31382962	Intuitively, the arithmetic mean of absolute values (ie., T_CC and N_CC) is an option to quantify the inversion of their expressional correlation coefficient, namely, inversion of N_CC to T_CC for a miRNA-mRNA pair as shown in Fig.	('inversion', 'Var', (167, 176))	('N_CC', 'Gene', (67, 71))	('N_CC', 'Gene', '6559', (180, 184))	('T_CC', 'Gene', (58, 62))	('T_CC', 'Gene', '94081', (58, 62))	('N_CC', 'Gene', '6559', (67, 71))	('T_CC', 'Gene', (188, 192))	('T_CC', 'Gene', '94081', (188, 192))	('N_CC', 'Gene', (180, 184))
276257	31382962	Biologically, the MWMM approach yields clusters that has relatively higher intra-cluster and relatively lower inter-cluster average GO term similarity distance scores compared to other six clustering algorithms in most of cancer types that are tested.	('cancer', 'Disease', 'MESH:D009369', (222, 228))	('GO term similarity distance scores', 'MPA', (132, 166))	('cancer', 'Disease', (222, 228))	('higher', 'PosReg', (68, 74))	('lower', 'NegReg', (104, 109))	('MWMM', 'Var', (18, 22))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))
276322	30348119	Inflammatory markers such as C-reactive protein in esophageal squamous cancer, Colony-stimulating factor-1 in mammary tumor, and inhibitors of metalloproteinases in NSCLC, all have been suggested as alternative markers for tumor progression.	('C-reactive protein', 'Gene', '1401', (29, 47))	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('tumor', 'Disease', (223, 228))	('NSCLC', 'Disease', 'MESH:D002289', (165, 170))	('C-reactive protein', 'Gene', (29, 47))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('inhibitors', 'Var', (129, 139))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('Colony-stimulating factor-1', 'Gene', (79, 106))	('tumor', 'Disease', (118, 123))	('Colony-stimulating factor-1', 'Gene', '1435', (79, 106))	('tumor', 'Disease', 'MESH:D009369', (223, 228))	('squamous cancer', 'Phenotype', 'HP:0002860', (62, 77))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('esophageal squamous cancer', 'Disease', 'MESH:D004938', (51, 77))	('NSCLC', 'Disease', (165, 170))	('esophageal squamous cancer', 'Disease', (51, 77))
276346	30348119	In addition, as shown in the subgroup analysis, the monocyte count was found to be significantly associated with poor prognosis when stratified by gender, age, smoking history, TNM stage, surgical procedure and histological type.	('TNM', 'Gene', (177, 180))	('monocyte count', 'Var', (52, 66))	('TNM', 'Gene', '10178', (177, 180))
276379	28460090	Pol II, H3k4me2, H3k4me3, H3k9ac and H3k27ac, H3K9me3, H3K27me3, H3k79me2 and H3K63me3 signals within the region +-2k bp around the predicted TSSs with the bin size of 200 bp were analyzed.	('H3K9me3', 'Var', (46, 53))	('27a', 'Species', '1412829', (40, 43))	('H3k79me2', 'Var', (65, 73))	('H3K27me3', 'Var', (55, 63))	('H3k27ac', 'Var', (37, 44))
276390	28460090	Additionally, we observed stronger activating methylation marks (H3K4me2 and H3K4me3) and acetylation marks (H3K9ac and H3K27ac) around TSSs by mirSTP (Figure 2).	('H3K27ac', 'Var', (120, 127))	('H3K9ac', 'Var', (109, 115))	('stronger', 'PosReg', (26, 34))	('27a', 'Species', '1412829', (123, 126))	('acetylation', 'MPA', (90, 101))	('H3K4me2', 'Var', (65, 72))	('activating methylation', 'MPA', (35, 57))	('H3K4me3', 'Var', (77, 84))
276412	28460090	For example, miRNA clusters, like miR192/194-2, miR221/222, miR23a/27a, miR29b-2/29c and miR30b/30d, were co-expressed in all 10 TCGA cancer types.	('miR23a/27a', 'Var', (60, 70))	('miR29b-2/29c', 'Var', (72, 84))	('27a', 'Species', '1412829', (67, 70))	('miR221', 'Gene', '407006', (48, 54))	('miR221', 'Gene', (48, 54))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('miR30b/30d', 'Var', (89, 99))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('miR192/194-2', 'Var', (34, 46))
276426	28460090	After JQ1 treatment, 10 pri-miRNAs showed a significant increase in pausing index (FDR < 0.01), while only two pri-miRNAs exhibited a decrease in pausing index (FDR < 0.01, Supplementary Table S5), which suggested that these 12 pri-miRNAs are direct targets of the BET family (Figure 5A).	('BET', 'Gene', (265, 268))	('increase', 'PosReg', (56, 64))	('pausing index', 'MPA', (68, 81))	('JQ1', 'Var', (6, 9))	('BET', 'Gene', '92737', (265, 268))
276437	28460090	After BET inhibitor treatment, pri-miRNAs with significant pausing index changes were highly likely to be BRD2/3/4 targets, and, in fact, each contains BRD4 binding in the predicted promoter regions.	('BET', 'Gene', (6, 9))	('binding', 'Interaction', (157, 164))	('BRD4', 'Gene', (152, 156))	('pausing index', 'MPA', (59, 72))	('BRD4', 'Gene', '23476', (152, 156))	('BET', 'Gene', '92737', (6, 9))	('contains', 'Reg', (143, 151))	('changes', 'Var', (73, 80))
276445	28460090	National Cancer Institute [5U01 CA163056-05 to YS, 5R01 CA178030-02 to SH, 2R01 CA064140-21A1 to S.H.	('Cancer', 'Phenotype', 'HP:0002664', (9, 15))	('CA064140-21A1', 'Var', (80, 93))	('U01', 'CellLine', 'CVCL:2220', (28, 31))	('Cancer', 'Disease', (9, 15))	('CA178030-02 to', 'Var', (56, 70))	('Cancer', 'Disease', 'MESH:D009369', (9, 15))
276520	24533532	The CCRT thus inevitably aggravates gastrointestinal adverse reactions, which makes it more difficult for patients to tolerate.	('aggravates', 'PosReg', (25, 35))	('CCRT', 'Var', (4, 8))	('gastrointestinal adverse reactions', 'Disease', (36, 70))	('gastrointestinal adverse reactions', 'Disease', 'MESH:D064420', (36, 70))	('CR', 'Chemical', '-', (5, 7))	('rat', 'Species', '10116', (122, 125))	('patients', 'Species', '9606', (106, 114))
276550	28694421	Human esophageal squamous cell carcinoma (ESCC) cell line CaEs-17, TE-1, EC109, KYSE510, KYSE140, KYSE70, and KYSE30 were selected to detect their sensitivity to cisplatin.	('Human', 'Species', '9606', (0, 5))	('carcinoma', 'Phenotype', 'HP:0030731', (31, 40))	('cisplatin', 'Chemical', 'MESH:D002945', (162, 171))	('esophageal squamous cell carcinoma', 'Disease', (6, 40))	('KYSE140', 'Chemical', '-', (89, 96))	('EC109', 'CellLine', 'CVCL:6898', (73, 78))	('KYSE70', 'Var', (98, 104))	('KYSE30', 'Var', (110, 116))	('KYSE510', 'Var', (80, 87))	('TE', 'Chemical', 'MESH:D013691', (67, 69))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (17, 40))	('KYSE140', 'Var', (89, 96))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (6, 40))
276570	28694421	In esophageal squamous cell carcinoma (ESCC), KLF4 is decreased; and KLF4 deletion in mice leads to squamous cell dysplasia.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (14, 37))	('carcinoma', 'Phenotype', 'HP:0030731', (28, 37))	('KLF4', 'MPA', (46, 50))	('deletion', 'Var', (74, 82))	('esophageal squamous cell carcinoma', 'Disease', (3, 37))	('mice', 'Species', '10090', (86, 90))	('squamous cell dysplasia', 'Disease', 'MESH:D002294', (100, 123))	('KLF4', 'Gene', (69, 73))	('decreased', 'NegReg', (54, 63))	('squamous cell dysplasia', 'Phenotype', 'HP:0002860', (100, 123))	('leads to', 'Reg', (91, 99))	('squamous cell dysplasia', 'Disease', (100, 123))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (3, 37))
276572	28694421	The KLF4 gene has been shown to be epigenetically inactivated in human cervical cancer and lung cancer.	('lung cancer', 'Phenotype', 'HP:0100526', (91, 102))	('human', 'Species', '9606', (65, 70))	('KLF4 gene', 'Gene', (4, 13))	('cervical cancer', 'Disease', (71, 86))	('cervical cancer', 'Disease', 'MESH:D002583', (71, 86))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('epigenetically inactivated', 'Var', (35, 61))	('lung cancer', 'Disease', 'MESH:D008175', (91, 102))	('lung cancer', 'Disease', (91, 102))
276573	28694421	Moreover, KLF4 enhances the sensitivity of cisplatin to lung cancer cells.	('KLF4', 'Var', (10, 14))	('enhances', 'PosReg', (15, 23))	('lung cancer', 'Disease', 'MESH:D008175', (56, 67))	('cisplatin', 'Chemical', 'MESH:D002945', (43, 52))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('lung cancer', 'Disease', (56, 67))	('lung cancer', 'Phenotype', 'HP:0100526', (56, 67))	('sensitivity of cisplatin', 'MPA', (28, 52))
276576	28694421	Two human ESCC cell lines (TE-1 and KYSE140) were selected from seven cell lines (CaEs-17, TE-1, EC109, KYSE510, KYSE140, KYSE70, and KYSE30) according to the cell line sensitivity of cisplatin.	('KYSE140', 'Chemical', '-', (36, 43))	('KYSE70', 'Var', (122, 128))	('human', 'Species', '9606', (4, 9))	('KYSE30', 'Var', (134, 140))	('KYSE140', 'Chemical', '-', (113, 120))	('TE', 'Chemical', 'MESH:D013691', (27, 29))	('EC109', 'CellLine', 'CVCL:6898', (97, 102))	('cisplatin', 'Chemical', 'MESH:D002945', (184, 193))	('KYSE510', 'Var', (104, 111))	('TE', 'Chemical', 'MESH:D013691', (91, 93))	('KYSE140', 'Var', (113, 120))
276578	28694421	Human ESCC cell line CaEs-17, TE-1, EC109, KYSE510, KYSE140, KYSE70, and KYSE30 were cultured in RPMI1640 (Gibco) supplemented with 10% (v/v) fetal calf serum (FBS, Gibco) at 37 C in a humidified 5% CO2 incubator.	('Human', 'Species', '9606', (0, 5))	('CO2', 'Chemical', '-', (199, 202))	('KYSE70', 'Var', (61, 67))	('FBS', 'Disease', (160, 163))	('KYSE140', 'Var', (52, 59))	('RPMI1640', 'Chemical', '-', (97, 105))	('calf', 'Species', '9913', (148, 152))	('TE', 'Chemical', 'MESH:D013691', (30, 32))	('EC109', 'CellLine', 'CVCL:6898', (36, 41))	('KYSE140', 'Chemical', '-', (52, 59))	('FBS', 'Disease', 'MESH:D005198', (160, 163))
276597	28694421	The sensitivity to cisplatin of KYSE140 was relatively high compared to the other five cell lines; whereas TE-1 was the relative less sensitive to cisplatin as compared with the other five.	('KYSE140', 'Chemical', '-', (32, 39))	('sensitivity to cisplatin', 'MPA', (4, 28))	('cisplatin', 'Chemical', 'MESH:D002945', (147, 156))	('TE', 'Chemical', 'MESH:D013691', (107, 109))	('cisplatin', 'Chemical', 'MESH:D002945', (19, 28))	('KYSE140', 'Var', (32, 39))
276600	28694421	Additionally, cisplatin sensitivity of KYSE140 was significantly higher than TE-1, KYSE510, and KYSE70 under 5 mg/L cisplatin; and significantly higher than TE-1, CaEs-17, KYSE510, KYSE70, and KYSE30 under 10 mg/L cisplatin (Figure 1).	('cisplatin', 'Chemical', 'MESH:D002945', (14, 23))	('TE', 'Chemical', 'MESH:D013691', (157, 159))	('KYSE140', 'Chemical', '-', (39, 46))	('cisplatin sensitivity', 'MPA', (14, 35))	('cisplatin', 'Chemical', 'MESH:D002945', (214, 223))	('TE', 'Chemical', 'MESH:D013691', (77, 79))	('cisplatin', 'Chemical', 'MESH:D002945', (116, 125))	('higher', 'PosReg', (65, 71))	('KYSE140', 'Var', (39, 46))	('higher', 'PosReg', (145, 151))
276601	28694421	Relative high levels of KLF4 were found in ESCC cell line CaEs-17, EC109, KYSE140, KYSE70, and KYSE30; while relative low levels of KLF4 were found in TE-1 and KYSE510 (Figure 2A).	('KYSE30', 'Var', (95, 101))	('KYSE140', 'Var', (74, 81))	('TE', 'Chemical', 'MESH:D013691', (151, 153))	('KYSE140', 'Chemical', '-', (74, 81))	('EC109', 'CellLine', 'CVCL:6898', (67, 72))	('KYSE70', 'Var', (83, 89))
276603	28694421	Moreover, combining our results of cisplatin sensitivity of the seven ESCC cell lines, we found that a high level of KLF4 was associated with high sensitivity to cisplatin.	('associated', 'Reg', (126, 136))	('cisplatin', 'Chemical', 'MESH:D002945', (162, 171))	('high sensitivity to cisplatin', 'MPA', (142, 171))	('cisplatin', 'Chemical', 'MESH:D002945', (35, 44))	('high', 'Var', (103, 107))
276633	28694421	However, it should be noted that besides the downregulation of KLF4 through the aforementioned mechanisms, splicing variants of KLF4 also play an important role in tumor formation and progression.	('progression', 'CPA', (184, 195))	('tumor', 'Disease', (164, 169))	('splicing variants', 'Var', (107, 124))	('KLF4', 'Protein', (63, 67))	('downregulation', 'NegReg', (45, 59))	('KLF4', 'Gene', (128, 132))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('play', 'Reg', (138, 142))
276639	28694421	In cervical cancer, methylation in the promoter region could inhibit expression of KLF4 and restoring KLF4 expression using demethylating agent 5-Azacytidine (5-Aza) could enhance the sensitivity to cisplatin of cervical cancer cells.	('5-Aza', 'Chemical', 'MESH:D001374', (159, 164))	('cisplatin', 'Chemical', 'MESH:D002945', (199, 208))	('enhance', 'PosReg', (172, 179))	('cervical cancer', 'Disease', 'MESH:D002583', (3, 18))	('KLF4', 'Protein', (83, 87))	('restoring', 'PosReg', (92, 101))	('expression', 'MPA', (107, 117))	('expression', 'MPA', (69, 79))	('cervical cancer', 'Disease', (3, 18))	('cervical cancer', 'Disease', (212, 227))	('methylation', 'Var', (20, 31))	('sensitivity to cisplatin', 'MPA', (184, 208))	('inhibit', 'NegReg', (61, 68))	('cervical cancer', 'Disease', 'MESH:D002583', (212, 227))	('5-Azacytidine', 'Chemical', 'MESH:D001374', (144, 157))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('5-Aza', 'Chemical', 'MESH:D001374', (144, 149))
276641	28694421	In the present study, under the final concentration of 0.5 mg/L, 0.1 mg/L, 2.5 mg/L, 5 mg/L, and 10 mg/L of cisplatin, cell viability was significantly decreased after treatment of demethylation reagents 5-Aza-CdR in TE-1 cells.	('TE', 'Chemical', 'MESH:D013691', (217, 219))	('cisplatin', 'Chemical', 'MESH:D002945', (108, 117))	('5-Aza', 'Chemical', 'MESH:D001374', (204, 209))	('decreased', 'NegReg', (152, 161))	('cell viability', 'CPA', (119, 133))	('0.1', 'Var', (65, 68))
276642	28694421	These results suggested that demethylation in the promoter region and the restored expression of KLF4 could inhibit cell proliferation and increase the sensitivity to cisplatin.	('cisplatin', 'Chemical', 'MESH:D002945', (167, 176))	('sensitivity to cisplatin', 'MPA', (152, 176))	('increase', 'PosReg', (139, 147))	('expression', 'MPA', (83, 93))	('restored', 'PosReg', (74, 82))	('KLF4', 'Gene', (97, 101))	('inhibit', 'NegReg', (108, 115))	('cell proliferation', 'CPA', (116, 134))	('demethylation', 'Var', (29, 42))
276643	28694421	In the meanwhile, the cell viability of KYSE140 was significantly decreased compared with TE-1 cells, which suggested that hypomethylation in promoter and high level of KLF4 could inhibit the proliferation of human ESCC cells.	('human', 'Species', '9606', (209, 214))	('proliferation', 'CPA', (192, 205))	('KYSE140', 'Chemical', '-', (40, 47))	('inhibit', 'NegReg', (180, 187))	('decreased', 'NegReg', (66, 75))	('TE', 'Chemical', 'MESH:D013691', (90, 92))	('cell viability', 'CPA', (22, 36))	('hypomethylation', 'Var', (123, 138))
276644	28694421	In oral squamous cell carcinoma, overexpression of KLF4 has been reported to promote cell cycle arrest in vitro and induce apoptosis in vivo.	('induce', 'PosReg', (116, 122))	('cell cycle arrest', 'CPA', (85, 102))	('promote', 'PosReg', (77, 84))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (3, 31))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (8, 31))	('KLF4', 'Gene', (51, 55))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('apoptosis', 'CPA', (123, 132))	('oral squamous cell carcinoma', 'Disease', (3, 31))	('overexpression', 'Var', (33, 47))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (85, 102))
276645	28694421	Consistent with these findings, the results of flow cytometry assay showed that the apoptosis rate was significantly increased in KYSE140 cells when cells were treated with 1 mg/L cisplatin, compared with TE-1 cells, suggesting that high levels of KLF4 with promoter hypomethylation could induce cell apoptosis in human ESCC cells.	('apoptosis rate', 'CPA', (84, 98))	('increased', 'PosReg', (117, 126))	('KYSE140', 'Chemical', '-', (130, 137))	('cisplatin', 'Chemical', 'MESH:D002945', (180, 189))	('promoter hypomethylation', 'Var', (258, 282))	('cell apoptosis', 'CPA', (296, 310))	('human', 'Species', '9606', (314, 319))	('induce', 'PosReg', (289, 295))	('TE', 'Chemical', 'MESH:D013691', (205, 207))
276646	28694421	Moreover, when TE-1 cells were treated with cisplatin at a final concentration of 5 mg/L and 10 mg/L, the apoptosis of TE-1 cells was significantly increased after 5-Aza-CdR treatment, suggesting enhanced sensitivity to cisplatin of human ESCC cells by high level of KLF4.	('cisplatin', 'Chemical', 'MESH:D002945', (220, 229))	('enhanced', 'PosReg', (196, 204))	('TE', 'Chemical', 'MESH:D013691', (119, 121))	('human', 'Species', '9606', (233, 238))	('increased', 'PosReg', (148, 157))	('apoptosis', 'CPA', (106, 115))	('5-Aza-CdR', 'Var', (164, 173))	('sensitivity', 'MPA', (205, 216))	('TE', 'Chemical', 'MESH:D013691', (15, 17))	('cisplatin', 'Chemical', 'MESH:D002945', (44, 53))	('5-Aza', 'Chemical', 'MESH:D001374', (164, 169))
276649	28694421	We found that in KYSE140 cell line with high levels of KLF4, the percentage of cells arrested at S phase was significantly higher than TE-1 cells.	('KLF4', 'Var', (55, 59))	('higher', 'PosReg', (123, 129))	('cells arrested at S phase', 'CPA', (79, 104))	('TE', 'Chemical', 'MESH:D013691', (135, 137))	('KYSE140', 'Chemical', '-', (17, 24))	('high levels', 'Var', (40, 51))
276652	28694421	Our findings showed that KLF4, acting as a tumor suppressor in human ESCC cells, was downregulated in human ESCC cells by hypermethylation in the promoter region.	('downregulated', 'NegReg', (85, 98))	('human', 'Species', '9606', (63, 68))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('KLF4', 'Gene', (25, 29))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Disease', (43, 48))	('hypermethylation', 'Var', (122, 138))	('human', 'Species', '9606', (102, 107))
276658	26876213	Inhibition of autophagy sensitizes HNSCC cells to EGFR blockade.	('EGFR', 'Gene', (50, 54))	('Inhibition', 'Var', (0, 10))	('autophagy', 'CPA', (14, 23))	('EGFR', 'Gene', '1956', (50, 54))
276663	26876213	These findings expand our understanding of the components involved in HNSCC autophagy machinery that responds to EGFR inhibitors, and suggest potential combinatorial approaches to enhance its therapeutic efficacy.	('enhance', 'PosReg', (180, 187))	('inhibitors', 'Var', (118, 128))	('EGFR', 'Gene', (113, 117))	('EGFR', 'Gene', '1956', (113, 117))
276680	26876213	A defect in SQSTM1/p62 expression was shown to impair tumor growth in vivo , and overexpression of p62 resulted in an increase in xenograft tumor mass .	('p62', 'Gene', (99, 102))	('SQSTM1', 'Gene', (12, 18))	('increase', 'PosReg', (118, 126))	('tumor', 'Disease', (140, 145))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('defect', 'Var', (2, 8))	('SQSTM1', 'Gene', '8878', (12, 18))	('overexpression', 'PosReg', (81, 95))	('p62', 'Gene', '8878', (99, 102))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('p62', 'Gene', '8878', (19, 22))	('tumor', 'Disease', (54, 59))	('p62', 'Gene', (19, 22))	('impair', 'NegReg', (47, 53))	('expression', 'MPA', (23, 33))
276696	26876213	In PCI-13 cells, cetuximab and gefitinib both induced puncta formation, similar to everolimus-treated (positive control) cells (Fig.	('puncta formation', 'MPA', (54, 70))	('induced', 'Reg', (46, 53))	('gefitinib', 'Chemical', 'MESH:D000077156', (31, 40))	('everolimus', 'Chemical', 'MESH:D000068338', (83, 93))	('cetuximab', 'Var', (17, 26))	('PCI-13', 'Chemical', '-', (3, 9))	('cetuximab', 'Chemical', 'MESH:D000068818', (17, 26))
276709	26876213	In order to understand how EGFR signaling blockade promotes autophagy in HNSCC cells, we employed a loss-of-function approach to examine the role of a unique mitochondrial protein complex.	('EGFR', 'Gene', '1956', (27, 31))	('EGFR', 'Gene', (27, 31))	('blockade', 'Var', (42, 50))	('promotes', 'PosReg', (51, 59))	('autophagy', 'CPA', (60, 69))
276723	26876213	Notably, when we knocked down NLRX1 in PCI-13 cells, cetuximab-induced phosphorylation of eIF2alpha was abrogated, lending support to the critical role of NLRX1 in ER stress signaling, which serves as an underpinning mechanism for autophagy induction.	('abrogated', 'NegReg', (104, 113))	('knocked down', 'Var', (17, 29))	('NLRX1', 'Gene', (155, 160))	('eIF2alpha', 'Gene', (90, 99))	('PCI-13', 'Chemical', '-', (39, 45))	('NLRX1', 'Gene', '79671', (30, 35))	('cetuximab', 'Chemical', 'MESH:D000068818', (53, 62))	('NLRX1', 'Gene', (30, 35))	('cetuximab-induced', 'MPA', (53, 70))	('eIF2alpha', 'Gene', '83939', (90, 99))	('phosphorylation', 'CPA', (71, 86))	('NLRX1', 'Gene', '79671', (155, 160))
276742	26876213	A defect in TUFM severely compromised autophagy induction by cetuximab or gefitinib, as evidenced by a failure of LC3B-II production (Fig.	('failure', 'NegReg', (103, 110))	('TUFM', 'Gene', '7284', (12, 16))	('LC3B', 'Gene', '81631', (114, 118))	('defect', 'Var', (2, 8))	('LC3B', 'Gene', (114, 118))	('cetuximab', 'Chemical', 'MESH:D000068818', (61, 70))	('gefitinib', 'Chemical', 'MESH:D000077156', (74, 83))	('TUFM', 'Gene', (12, 16))	('autophagy induction', 'CPA', (38, 57))	('compromised', 'NegReg', (26, 37))
276754	26876213	Consistent with previous report , knocking down Beclin-1 potentiated cetuximab-induced, NK cells-mediated cytotoxicity (Figure S4A).	('cetuximab', 'Chemical', 'MESH:D000068818', (69, 78))	('potentiated', 'PosReg', (57, 68))	('cytotoxicity', 'Disease', (106, 118))	('Beclin-1', 'Gene', (48, 56))	('Beclin-1', 'Gene', '8678', (48, 56))	('cytotoxicity', 'Disease', 'MESH:D064420', (106, 118))	('knocking down', 'Var', (34, 47))
276757	26876213	High p62 level was also associated with a worse prognosis .	('p62', 'Gene', '8878', (5, 8))	('p62', 'Gene', (5, 8))	('High', 'Var', (0, 4))
276770	26876213	A defect in NLRX1-TUFM protein complex compromised the autophagy induction in cancer cells.	('compromised', 'NegReg', (39, 50))	('NLRX1', 'Gene', '79671', (12, 17))	('TUFM', 'Gene', (18, 22))	('NLRX1', 'Gene', (12, 17))	('cancer', 'Disease', (78, 84))	('defect', 'Var', (2, 8))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('TUFM', 'Gene', '7284', (18, 22))
276795	26876213	Another critical target of PERK is eIF2alpha; and a non-phosphorylatable mutant (S51A) of eIF2alpha loses its capacity in inducing autophagy .	('PERK', 'Gene', (27, 31))	('inducing', 'Reg', (122, 130))	('PERK', 'Gene', '9451', (27, 31))	('loses', 'NegReg', (100, 105))	('eIF2alpha', 'Gene', (35, 44))	('autophagy', 'CPA', (131, 140))	('eIF2alpha', 'Gene', (90, 99))	('S51A', 'Mutation', 'p.S51A', (81, 85))	('S51A', 'Var', (81, 85))	('eIF2alpha', 'Gene', '83939', (90, 99))	('eIF2alpha', 'Gene', '83939', (35, 44))
276840	26876213	P35GCol-1.5-14-C, MatTek) 24hrs prior to transfection with pEGFP-LC3.	('LC3', 'Gene', '84557', (65, 68))	('LC3', 'Gene', (65, 68))	('P35GCol-1.5-14-C', 'Var', (0, 16))
276855	31659278	Copy number variations were detected in 52% (14/27) of the patients, with a majority having advanced-stage disease (10/14).	('Copy number variations', 'Var', (0, 22))	('patients', 'Species', '9606', (59, 67))	('detected', 'Reg', (28, 36))
276856	31659278	Except for the detection of ERBB2 amplification and KRAS mutation in two patients, no other classic lung cancer driver mutations were detected.	('KRAS', 'Gene', (52, 56))	('KRAS', 'Gene', '3845', (52, 56))	('ERBB2', 'Gene', '2064', (28, 33))	('lung cancer', 'Phenotype', 'HP:0100526', (100, 111))	('ERBB2', 'Gene', (28, 33))	('lung cancer', 'Disease', (100, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('amplification', 'Var', (34, 47))	('patients', 'Species', '9606', (73, 81))	('lung cancer', 'Disease', 'MESH:D008175', (100, 111))
276857	31659278	Interestingly, 78% (21/27) of the patients had mutations in epigenetic regulators.	('epigenetic regulators', 'Protein', (60, 81))	('patients', 'Species', '9606', (34, 42))	('mutations', 'Var', (47, 56))
276859	31659278	In conclusion, we elucidated a distinct genomic landscape associated with pulmonary lymphoepithelioma-like carcinoma with no classic lung cancer driver mutation but an enrichment of mutations in epigenetic regulators.	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('lung cancer', 'Disease', (133, 144))	('associated', 'Reg', (58, 68))	('lung cancer', 'Phenotype', 'HP:0100526', (133, 144))	('pulmonary lymphoepithelioma-like carcinoma', 'Disease', (74, 116))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('lung cancer', 'Disease', 'MESH:D008175', (133, 144))	('pulmonary lymphoepithelioma-like carcinoma', 'Disease', 'MESH:D008175', (74, 116))	('mutations', 'Var', (182, 191))
276906	31659278	Collectively, 184 genomic alterations in 109 genes were detected from 26 patients, including 107 single nucleotide variations, 12 insertions or deletions, and 65 copy number amplifications (Table S2).	('copy number amplifications', 'Var', (162, 188))	('insertions', 'Var', (130, 140))	('single nucleotide variations', 'Var', (97, 125))	('patients', 'Species', '9606', (73, 81))
276911	31659278	Interestingly, half of the cohort (51%, 14/27) had at least one copy number variation detected, with a majority detected among patients with advanced-stage disease (72%, 47/65 copy number variations in 10 advanced-stage patients vs. 28%, 18/65 in 4 early-stage patients; P = 0.057; Fig.	('copy number variations', 'Var', (176, 198))	('patients', 'Species', '9606', (127, 135))	('detected', 'Reg', (112, 120))	('patients', 'Species', '9606', (220, 228))	('patients', 'Species', '9606', (261, 269))
276912	31659278	The copy number variations detected in the cohort included 7 CCND1, 5 DAXX, 4 GRM3, 3 FGF19, 3 FGF3, 3 FGF4, 3 MDM4, 3 STAT3, and 3 RPS6KB2.	('FGF19', 'Gene', (86, 91))	('FGF19', 'Gene', '9965', (86, 91))	('DAXX', 'Gene', (70, 74))	('STAT3', 'Gene', (119, 124))	('copy number variations', 'Var', (4, 26))	('FGF4', 'Gene', '2249', (103, 107))	('DAXX', 'Gene', '1616', (70, 74))	('MDM4', 'Gene', '4194', (111, 115))	('STAT3', 'Gene', '6774', (119, 124))	('MDM4', 'Gene', (111, 115))	('GRM3', 'Gene', '2913', (78, 82))	('RPS6KB2', 'Gene', (132, 139))	('FGF3', 'Gene', (95, 99))	('CCND1', 'Gene', '595', (61, 66))	('FGF3', 'Gene', '2248', (95, 99))	('GRM3', 'Gene', (78, 82))	('RPS6KB2', 'Gene', '6199', (132, 139))	('CCND1', 'Gene', (61, 66))	('FGF4', 'Gene', (103, 107))
276914	31659278	In addition, STAT3 amplifications were only detected among advanced-stage patients, with two of the STAT3 concurrent with CCND1 gene amplifications (P7 and P16, Fig.	('P16', 'Gene', '1029', (156, 159))	('P7', 'Var', (149, 151))	('STAT3', 'Gene', (100, 105))	('CCND1', 'Gene', '595', (122, 127))	('patients', 'Species', '9606', (74, 82))	('CCND1', 'Gene', (122, 127))	('STAT3', 'Gene', '6774', (13, 18))	('P16', 'Gene', (156, 159))	('STAT3', 'Gene', '6774', (100, 105))	('STAT3', 'Gene', (13, 18))
276916	31659278	Furthermore, our data revealed that 78% (21/27) of the patients had mutations in epigenetic regulators.	('mutations', 'Var', (68, 77))	('epigenetic regulators', 'Protein', (81, 102))	('patients', 'Species', '9606', (55, 63))
276920	31659278	Three advanced-stage patients with only copy number variations had zero tumor mutation burden (Fig.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Disease', (72, 77))	('patients', 'Species', '9606', (21, 29))	('copy number variations', 'Var', (40, 62))	('tumor', 'Disease', 'MESH:D009369', (72, 77))
276926	31659278	With frequent mutations in epigenetic regulators observed in our cohort, we first examined whether this is a pulmonary lymphoepithelioma-like carcinoma-specific event or it is common among other EBV+ cancers.	('cancers', 'Disease', 'MESH:D009369', (200, 207))	('cancers', 'Phenotype', 'HP:0002664', (200, 207))	('pulmonary lymphoepithelioma-like carcinoma', 'Disease', (109, 151))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('cancers', 'Disease', (200, 207))	('pulmonary lymphoepithelioma-like carcinoma', 'Disease', 'MESH:D008175', (109, 151))	('mutations', 'Var', (14, 23))	('carcinoma', 'Phenotype', 'HP:0030731', (142, 151))
276927	31659278	Comparing to EBV+ nasopharyngeal carcinoma (77.8 vs. 46.4%; P = 0.009) and EBV+ gastric cancer (77.8 vs. 50%; P = 0.053), pulmonary lymphoepithelioma-like carcinoma tumors had significantly more mutations in epigenetic-related genes (Fig.	('carcinoma', 'Phenotype', 'HP:0030731', (155, 164))	('gastric cancer', 'Disease', (80, 94))	('epigenetic-related genes', 'Gene', (208, 232))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('gastric cancer', 'Disease', 'MESH:D013274', (80, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (33, 42))	('tumors', 'Phenotype', 'HP:0002664', (165, 171))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (18, 42))	('pulmonary lymphoepithelioma-like carcinoma tumors', 'Disease', (122, 171))	('carcinoma', 'Disease', (155, 164))	('gastric cancer', 'Phenotype', 'HP:0012126', (80, 94))	('mutations', 'Var', (195, 204))	('carcinoma', 'Disease', 'MESH:D009369', (155, 164))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('carcinoma', 'Disease', (33, 42))	('carcinoma', 'Disease', 'MESH:D009369', (33, 42))	('pulmonary lymphoepithelioma-like carcinoma tumors', 'Disease', 'MESH:D008175', (122, 171))
276928	31659278	In contrast, our analysis revealed significantly fewer mutations in epigenetics-related genes in pulmonary lymphoepithelioma-like carcinoma tumors as compared with other non-small cell lung cancer tumors (77.8% vs. LUAD = 93%; P = 0.012; LUSC = 97.1%; P < 0.001; Fig.	('pulmonary lymphoepithelioma-like carcinoma tumors', 'Disease', (97, 146))	('non-small cell lung cancer', 'Disease', (170, 196))	('LUAD', 'Phenotype', 'HP:0030078', (215, 219))	('tumors', 'Phenotype', 'HP:0002664', (197, 203))	('lung cancer tumors', 'Disease', (185, 203))	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('lung cancer', 'Phenotype', 'HP:0100526', (185, 196))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (170, 196))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('lung cancer tumors', 'Disease', 'MESH:D008175', (185, 203))	('mutations', 'Var', (55, 64))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (174, 196))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (170, 196))	('epigenetics-related genes', 'Gene', (68, 93))	('fewer', 'NegReg', (49, 54))	('pulmonary lymphoepithelioma-like carcinoma tumors', 'Disease', 'MESH:D008175', (97, 146))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))
276931	31659278	Furthermore, our analysis revealed that pulmonary lymphoepithelioma-like carcinoma had a significantly lower mutation frequencies in TP53 (54.1 vs. 25.9%, P = 0.005), KRAS (32.4 vs. 3.7%, P < 0.001), and LRP1B (35.0 vs. 7.4%, P = 0.003) than lung adenocarcinoma.	('pulmonary lymphoepithelioma-like carcinoma', 'Disease', 'MESH:D008175', (40, 82))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (242, 261))	('lung adenocarcinoma', 'Disease', (242, 261))	('LRP1B', 'Gene', '53353', (204, 209))	('carcinoma', 'Phenotype', 'HP:0030731', (252, 261))	('lower', 'NegReg', (103, 108))	('pulmonary lymphoepithelioma-like carcinoma', 'Disease', (40, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (242, 261))	('KRAS', 'Gene', (167, 171))	('LRP1B', 'Gene', (204, 209))	('KRAS', 'Gene', '3845', (167, 171))	('TP53', 'Gene', '7157', (133, 137))	('TP53', 'Gene', (133, 137))	('mutation', 'Var', (109, 117))
276932	31659278	It also had a significant lower mutation frequencies in TP53, (86.4 vs. 25.9%, P < 0.001) and LRP1B (35.3 vs. 7.4%, P = 0.002) than lung squamous cell carcinoma.	('LRP1B', 'Gene', '53353', (94, 99))	('TP53', 'Gene', '7157', (56, 60))	('TP53', 'Gene', (56, 60))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (137, 160))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (132, 160))	('lung squamous cell carcinoma', 'Disease', (132, 160))	('LRP1B', 'Gene', (94, 99))	('mutation', 'Var', (32, 40))	('lower', 'NegReg', (26, 31))	('carcinoma', 'Phenotype', 'HP:0030731', (151, 160))
276934	31659278	Interestingly, mutations in NFkappaB1A were found to be significantly higher in pulmonary lymphoepithelioma-like carcinoma than all tumor types analyzed (PLELC = 14.8%; LUAD = 1.1%, P < 0.001; LUSC = 0.8%, P < 0.001; EBV+ NPC = 1.8%, P = 0.033; EBV+ GC = 0%, P < 0.001).	('higher', 'Reg', (70, 76))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('pulmonary lymphoepithelioma-like carcinoma', 'Disease', (80, 122))	('mutations', 'Var', (15, 24))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('LUAD', 'Phenotype', 'HP:0030078', (169, 173))	('NFkappaB1A', 'Gene', (28, 38))	('tumor', 'Disease', (132, 137))	('NPC', 'Phenotype', 'HP:0100630', (222, 225))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('pulmonary lymphoepithelioma-like carcinoma', 'Disease', 'MESH:D008175', (80, 122))	('GC', 'Phenotype', 'HP:0012126', (250, 252))
276935	31659278	Collectively, we elucidated a distinct genomic landscape associated with pulmonary lymphoepithelioma-like carcinoma with no classic non-small-cell lung cancer driver mutation but an enrichment of mutations in epigenetic regulators.	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (136, 158))	('pulmonary lymphoepithelioma-like carcinoma', 'Disease', 'MESH:D008175', (73, 115))	('lung cancer', 'Phenotype', 'HP:0100526', (147, 158))	('mutations', 'Var', (196, 205))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('non-small-cell lung cancer', 'Disease', 'MESH:D002289', (132, 158))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('non-small-cell lung cancer', 'Disease', (132, 158))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (132, 158))	('pulmonary lymphoepithelioma-like carcinoma', 'Disease', (73, 115))	('associated', 'Reg', (57, 67))
276957	31659278	Despite the EGFR mutation rate of 12.1% (8/66) reported by Chang et al., only one patient was detected with a sensitizing EGFR mutation:an EGFR exon 19 deletion; all the other 11 EGFR mutations detected in 7 pulmonary lymphoepithelioma-like carcinoma patients located in exons 18-21 are uncommon mutations with no evidence of therapeutic response to EGFR inhibitors.	('EGFR', 'Gene', (179, 183))	('carcinoma', 'Phenotype', 'HP:0030731', (241, 250))	('EGFR', 'Gene', '1956', (350, 354))	('EGFR', 'Gene', (350, 354))	('deletion', 'Var', (152, 160))	('patient', 'Species', '9606', (82, 89))	('mutations', 'Var', (184, 193))	('patient', 'Species', '9606', (251, 258))	('pulmonary lymphoepithelioma-like carcinoma', 'Disease', (208, 250))	('EGFR', 'Gene', '1956', (139, 143))	('EGFR', 'Gene', '1956', (12, 16))	('patients', 'Species', '9606', (251, 259))	('EGFR', 'Gene', (139, 143))	('EGFR', 'Gene', (12, 16))	('EGFR', 'Gene', '1956', (122, 126))	('pulmonary lymphoepithelioma-like carcinoma', 'Disease', 'MESH:D008175', (208, 250))	('EGFR', 'Gene', (122, 126))	('EGFR', 'Gene', '1956', (179, 183))
276959	31659278	In addition to oncogenic drivers, TP53 mutations E298X, R273C, and G279R were also detected in three patients, resulting in a TP53 mutation rate of 6.5% (3/46).	('patients', 'Species', '9606', (101, 109))	('TP53', 'Gene', (34, 38))	('TP53', 'Gene', (126, 130))	('E298X', 'Mutation', 'rs201744589', (49, 54))	('G279R', 'Mutation', 'p.G279R', (67, 72))	('E298X', 'Var', (49, 54))	('TP53', 'Gene', '7157', (126, 130))	('R273C', 'Mutation', 'rs121913343', (56, 61))	('G279R', 'Var', (67, 72))	('TP53', 'Gene', '7157', (34, 38))	('R273C', 'Var', (56, 61))	('mutation', 'Var', (131, 139))
276964	31659278	Instead, we revealed an enrichment of mutations in epigenetic regulators, occurring in 78% (21/27) of the patients, indicating that chromatin remodeling and modification might be involved in the development of pulmonary lymphoepithelioma-like carcinoma tumors.	('tumors', 'Phenotype', 'HP:0002664', (253, 259))	('pulmonary lymphoepithelioma-like carcinoma tumors', 'Disease', 'MESH:D008175', (210, 259))	('involved', 'Reg', (179, 187))	('carcinoma', 'Phenotype', 'HP:0030731', (243, 252))	('tumor', 'Phenotype', 'HP:0002664', (253, 258))	('patients', 'Species', '9606', (106, 114))	('pulmonary lymphoepithelioma-like carcinoma tumors', 'Disease', (210, 259))	('mutations', 'Var', (38, 47))
276965	31659278	In addition to genetic factors, alterations in epigenetic regulation contribute significantly to the initiation and progression of cancer.	('cancer', 'Disease', (131, 137))	('epigenetic regulation', 'MPA', (47, 68))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('alterations', 'Var', (32, 43))	('contribute', 'Reg', (69, 79))	('cancer', 'Disease', 'MESH:D009369', (131, 137))
276974	31659278	Pulmonary lymphoepithelioma-like carcinoma tumors harbored significantly more mutations in epigenetic regulators than EBV+ nasopharyngeal carcinoma (77.8 vs. 46.4%; P = 0.009) and have a trend of having more mutations in epigenetic regulators in EBV+ gastric cancer tumors (77.8 vs. 50%; P = 0.053).	('gastric cancer', 'Phenotype', 'HP:0012126', (251, 265))	('carcinoma', 'Phenotype', 'HP:0030731', (33, 42))	('mutations', 'Var', (208, 217))	('carcinoma', 'Disease', 'MESH:D009369', (138, 147))	('carcinoma', 'Disease', (33, 42))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (123, 147))	('mutations', 'Var', (78, 87))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('tumors', 'Phenotype', 'HP:0002664', (266, 272))	('carcinoma', 'Disease', 'MESH:D009369', (33, 42))	('gastric cancer tumors', 'Disease', 'MESH:D013274', (251, 272))	('cancer', 'Phenotype', 'HP:0002664', (259, 265))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (266, 271))	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('epigenetic', 'MPA', (91, 101))	('carcinoma', 'Disease', (138, 147))	('gastric cancer tumors', 'Disease', (251, 272))	('Pulmonary lymphoepithelioma-like carcinoma tumors harbored', 'Disease', 'MESH:D008175', (0, 58))
276977	31659278	Of which, CCND1 amplifications were the most predominant, with a mutation rate of 30% (8/27).	('CCND1', 'Gene', (10, 15))	('CCND1', 'Gene', '595', (10, 15))	('amplifications', 'Var', (16, 30))
276978	31659278	Copy number variations are associated with various human cancers.	('Copy number variations', 'Var', (0, 22))	('cancers', 'Phenotype', 'HP:0002664', (57, 64))	('associated', 'Reg', (27, 37))	('cancers', 'Disease', (57, 64))	('human', 'Species', '9606', (51, 56))	('cancers', 'Disease', 'MESH:D009369', (57, 64))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))
276979	31659278	In particular, gene amplification in CCDN1 is considered as one of the key drivers in lung carcinogenesis by regulating cell cycle progression.	('regulating', 'Reg', (109, 119))	('lung carcinogenesis', 'Disease', (86, 105))	('lung carcinogenesis', 'Disease', 'MESH:D063646', (86, 105))	('gene amplification', 'Var', (15, 33))	('cell cycle progression', 'CPA', (120, 142))	('CCDN1', 'Gene', (37, 42))
276984	31659278	Numerous studies have consistently demonstrated long-term tumor responses from PD-1/PD-L1 inhibitors as compared with conventional chemotherapy in patients with PD-L1-positive tumors or in some cancer types regardless of PD-L1 status.	('PD-L1-positive tumors', 'Disease', (161, 182))	('cancer', 'Disease', 'MESH:D009369', (194, 200))	('PD-L1', 'Gene', (221, 226))	('tumor', 'Disease', (58, 63))	('PD-L1', 'Gene', '29126', (221, 226))	('tumor', 'Disease', (176, 181))	('patients', 'Species', '9606', (147, 155))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('tumor', 'Disease', 'MESH:D009369', (176, 181))	('PD-L1-positive tumors', 'Disease', 'MESH:D010300', (161, 182))	('PD-L1', 'Gene', (84, 89))	('PD-L1', 'Gene', '29126', (84, 89))	('PD-1', 'Gene', (79, 83))	('tumors', 'Phenotype', 'HP:0002664', (176, 182))	('PD-1', 'Gene', '5133', (79, 83))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('cancer', 'Disease', (194, 200))	('PD-L1', 'Gene', (161, 166))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('PD-L1', 'Gene', '29126', (161, 166))	('inhibitors', 'Var', (90, 100))
276985	31659278	PD-L1 positivity, defined as the presence of moderate to strong membrane staining in at least 5% of the tumor cells, is considered to be a predictive biomarker for checkpoint immunotherapy response in various cancer types.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('positivity', 'Var', (6, 16))	('tumor', 'Disease', (104, 109))	('cancer', 'Disease', 'MESH:D009369', (209, 215))	('PD-L1', 'Gene', (0, 5))	('cancer', 'Disease', (209, 215))	('PD-L1', 'Gene', '29126', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
276992	31659278	Moreover, they have observed that the patients with PD-L1 expression contained abundant lymphocytes in the stroma, despite the lack of EBV positivity.	('expression', 'Var', (58, 68))	('PD-L1', 'Gene', (52, 57))	('PD-L1', 'Gene', '29126', (52, 57))	('patients', 'Species', '9606', (38, 46))
277020	31071530	Further experiments have confirmed that SBF2-AS1 could promote LUAD tumorigenesis by sponging miR-338/miR-362 and subsequent increased expression of E2F1.	('tumor', 'Disease', (68, 73))	('LUAD', 'Phenotype', 'HP:0030078', (63, 67))	('increased', 'PosReg', (125, 134))	('E2F1', 'Gene', '100036852', (149, 153))	('E2F1', 'Gene', (149, 153))	('miR-362', 'Gene', '723851', (102, 109))	('expression', 'Species', '29278', (135, 145))	('SBF2-AS1', 'Gene', (40, 48))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('expression', 'MPA', (135, 145))	('promote', 'PosReg', (55, 62))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('sponging', 'Var', (85, 93))	('miR-362', 'Gene', (102, 109))
277025	31071530	SBF2-AS1 expression was then analyzed online (kmplot.com/analysis/), using microarray data from 673 LUAD and 271 lung squamous cell carcinoma (LUSC) patients, and the results in Figure 2C show that high SBF2-AS1 expression is associated with poor overall survival in LUAD (hazard ratio [HR] = 1.38; 95% confidence interval [CI]: 1.07-1.73; log rank p = 0.012) but not with LUSC (HR = 0.78; log rank p = 0.11).	('patients', 'Species', '9606', (149, 157))	('lung squamous cell carcinoma', 'Disease', (113, 141))	('poor', 'NegReg', (242, 246))	('high', 'Var', (198, 202))	('expression', 'Species', '29278', (212, 222))	('LUAD', 'Phenotype', 'HP:0030078', (100, 104))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (118, 141))	('expression', 'MPA', (212, 222))	('expression', 'Species', '29278', (9, 19))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('LUSC', 'Phenotype', 'HP:0030359', (143, 147))	('overall survival', 'MPA', (247, 263))	('LUAD', 'Disease', (267, 271))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (113, 141))	('LUSC', 'Phenotype', 'HP:0030359', (373, 377))	('LUAD', 'Phenotype', 'HP:0030078', (267, 271))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (113, 141))	('SBF2-AS1', 'Gene', (203, 211))
277026	31071530	Notably, given that SBF2-AS1 is an early-stage-specific lncRNA, when limited to stage T1 LUAD, we observed that patients with high SBF2-AS1 expression had significantly poorer survival than those with low SBF2-AS1 expression (HR = 2.58; 95% CI: 1.26-5.31; log rank p = 0.0037; Figure 2C).	('expression', 'Species', '29278', (140, 150))	('SBF2-AS1', 'Gene', (131, 139))	('survival', 'MPA', (176, 184))	('patients', 'Species', '9606', (112, 120))	('high', 'Var', (126, 130))	('poorer', 'NegReg', (169, 175))	('expression', 'Species', '29278', (214, 224))	('LUAD', 'Phenotype', 'HP:0030078', (89, 93))
277027	31071530	In addition, TCGA data (Figure 2D) also confirm that high SBF2-AS1 expression indicated shorter survival time in LUAD but not in LUSC (log rank p = 0.04 for LUAD, and log rank p = 0.213 for LUSC; data are from https://ibl.mdanderson.org/tanric/_design/basic/index.html).	('shorter', 'NegReg', (88, 95))	('LUAD', 'Phenotype', 'HP:0030078', (157, 161))	('high', 'Var', (53, 57))	('LUSC', 'Phenotype', 'HP:0030359', (190, 194))	('survival time', 'CPA', (96, 109))	('expression', 'Species', '29278', (67, 77))	('LUSC', 'Phenotype', 'HP:0030359', (129, 133))	('LUAD', 'Phenotype', 'HP:0030078', (113, 117))	('expression', 'MPA', (67, 77))	('SBF2-AS1', 'Gene', (58, 66))
277028	31071530	Small interfering RNA (siRNA) and expression vector were utilized to knock down and overexpress SBF2-AS1, respectively.	('overexpress', 'PosReg', (84, 95))	('SBF2-AS1', 'Gene', (96, 104))	('knock down', 'Var', (69, 79))	('expression', 'Species', '29278', (34, 44))
277029	31071530	RNA sequencing was first performed to identify a gene expression profile after silence of SBF2-AS1 in A549 cells, and the results revealed that the expression of numerous genes was altered (Table S2).	('altered', 'Reg', (181, 188))	('SBF2-AS1', 'Gene', (90, 98))	('silence', 'Var', (79, 86))	('expression', 'Species', '29278', (148, 158))	('expression', 'MPA', (148, 158))	('expression', 'Species', '29278', (54, 64))	('A549', 'CellLine', 'CVCL:0023', (102, 106))
277030	31071530	GSEAs suggested that these deregulated genes are mostly involved in biological processes of cell cycle and proliferation (Figure 3A; Table S3), indicating that SBF2-AS1 might mainly impact cell cycle and proliferation.	('SBF2-AS1', 'Var', (160, 168))	('cell cycle', 'CPA', (189, 199))	('GSEAs', 'Chemical', '-', (0, 5))	('impact', 'Reg', (182, 188))
277031	31071530	As shown, knockdown of SBF2-AS1 led to G1 phase cell-cycle arrest both in A549 (Figures 3B and 3C) and H1299 cells (Figure S2A).	('H1299', 'CellLine', 'CVCL:0060', (103, 108))	('G1 phase cell-cycle arrest', 'CPA', (39, 65))	('SBF2-AS1', 'Gene', (23, 31))	('A549', 'CellLine', 'CVCL:0023', (74, 78))	('knockdown', 'Var', (10, 19))
277035	31071530	Together with the photoactivatable ribonucleoside-enhanced crosslinking and immunoprecipitation (PAR-CLIP) sequencing data, we identified 4 miRNAs that could potentially bind with SBF2-AS1: miR-338-3p, miR-362-3p (Figure 4B), miR-329, and miR-140.	('SBF2-AS1', 'Gene', (180, 188))	('miR-338-3p', 'Var', (190, 200))	('miR-362', 'Gene', (202, 209))	('miR-329', 'Var', (226, 233))	('bind', 'Interaction', (170, 174))	('miR-140', 'Var', (239, 246))	('miR-362', 'Gene', '723851', (202, 209))	('ribonucleoside', 'Chemical', 'MESH:D012263', (35, 49))
277038	31071530	Results suggested that miR-338-3p and miR-362-3p could significantly enrich SBF2-AS1 (Figure 4D), while miR-329 and miR-140 did not.	('miR-362', 'Gene', (38, 45))	('SBF2-AS1', 'Gene', (76, 84))	('miR-338-3p', 'Var', (23, 33))	('miR-362', 'Gene', '723851', (38, 45))	('enrich', 'PosReg', (69, 75))
277040	31071530	These experiments prove that SBF2-AS1 could bind with miR-338-3p and miR-362-3p.	('SBF2-AS1', 'Gene', (29, 37))	('miR-338-3p', 'Var', (54, 64))	('miR-362', 'Gene', (69, 76))	('bind', 'Interaction', (44, 48))	('miR-362', 'Gene', '723851', (69, 76))
277041	31071530	Given that many cell-cycle-related genes were downregulated upon SBF2-AS1 knockdown (Table S2) and that SBF2-AS1 could bind with miRNA miR-338-3p and miR-362-3p, we therefore hypothesized that SBF2-AS1 may regulate cell-cycle-related genes through miR-338-3p and miR-362-3p.	('miR-362', 'Gene', '723851', (263, 270))	('miR-338-3p', 'Var', (248, 258))	('miR-362', 'Gene', '723851', (150, 157))	('knockdown', 'Var', (74, 83))	('regulate', 'Reg', (206, 214))	('bind', 'Interaction', (119, 123))	('miR-362', 'Gene', (263, 270))	('downregulated', 'NegReg', (46, 59))	('cell-cycle-related genes', 'Gene', (16, 40))	('cell-cycle-related genes', 'Gene', (215, 239))	('SBF2-AS1', 'Gene', (65, 73))	('miR-362', 'Gene', (150, 157))
277042	31071530	A Venn plot was performed to identify ceRNA targets of SBF2-AS1 using the target genes of miR-338-3p and miR-362-3p and the 19 genes.	('miR-362', 'Gene', '723851', (105, 112))	('miR-362', 'Gene', (105, 112))	('miR-338-3p', 'Var', (90, 100))	('SBF2-AS1', 'Gene', (55, 63))
277043	31071530	As shown, 2 genes (CDC7 and CDC25A) were targets of miR-338-3p, 2 genes (PTTG1 and MAD2L1) were targets of miR-362-3p, and 4 genes (E2F1, CHEK1, CDC6, and CDK1) were targets of both miR-338-3p and miR-362-3p (Figure 4G).	('miR-362', 'Gene', '723851', (197, 204))	('E2F1', 'Gene', '100036852', (132, 136))	('E2F1', 'Gene', (132, 136))	('CHEK1', 'CellLine', 'CVCL:B526', (138, 143))	('CDC7', 'Gene', (19, 23))	('miR-362', 'Gene', (107, 114))	('miR-362', 'Gene', (197, 204))	('CDC25A', 'Gene', (28, 34))	('miR-338-3p', 'Var', (52, 62))	('CDK1', 'Gene', (155, 159))	('miR-362', 'Gene', '723851', (107, 114))
277044	31071530	All 8 genes decreased after SBF2-AS1 knockdown, while E2F1 was most downregulated (Figure 4H); therefore, we selected E2F1 for further validation.	('SBF2-AS1', 'Gene', (28, 36))	('knockdown', 'Var', (37, 46))	('E2F1', 'Gene', '100036852', (54, 58))	('E2F1', 'Gene', '100036852', (118, 122))	('E2F1', 'Gene', (54, 58))	('E2F1', 'Gene', (118, 122))	('decreased', 'NegReg', (12, 21))
277045	31071530	Biotin-labeled miRNA pull-down assay showed that miR-338-3p and miR-362-3p could bind with E2F1 (Figure 4I).	('miR-362', 'Gene', '723851', (64, 71))	('miR-362', 'Gene', (64, 71))	('E2F1', 'Gene', '100036852', (91, 95))	('bind', 'Interaction', (81, 85))	('E2F1', 'Gene', (91, 95))	('Biotin', 'Chemical', 'MESH:D001710', (0, 6))	('miR-338-3p', 'Var', (49, 59))
277046	31071530	A dual-luciferase reporter gene assay confirmed that miR-338-3p and miR-362-3p could bind to the 3' UTR of E2F1 and significantly inhibit luciferase activity, whereas when the binding sites of miR-338-3p and miR-362-3p were deletion-mutated, the inhibition was reversed (Figures 4J and 4K).	('E2F1', 'Gene', '100036852', (107, 111))	('E2F1', 'Gene', (107, 111))	('miR-362', 'Gene', '723851', (208, 215))	('miR-362', 'Gene', (208, 215))	('miR-338-3p', 'Var', (53, 63))	('inhibit', 'NegReg', (130, 137))	('miR-362', 'Gene', '723851', (68, 75))	('activity', 'MPA', (149, 157))	('bind', 'Interaction', (85, 89))	('luciferase', 'Enzyme', (138, 148))	('miR-362', 'Gene', (68, 75))
277047	31071530	In addition, ectopic expression of both miR-338-3p and miR-362-3p could inhibit expression of E2F1 (Figures 4L and 4M).	('E2F1', 'Gene', '100036852', (94, 98))	('E2F1', 'Gene', (94, 98))	('expression', 'Species', '29278', (21, 31))	('miR-338-3p', 'Var', (40, 50))	('miR-362', 'Gene', (55, 62))	('expression', 'Species', '29278', (80, 90))	('expression', 'MPA', (80, 90))	('inhibit', 'NegReg', (72, 79))	('miR-362', 'Gene', '723851', (55, 62))
277048	31071530	Together, these results revealed that E2F1 is target of miR-338-3p and miR-362-3p.	('miR-362', 'Gene', (71, 78))	('E2F1', 'Gene', '100036852', (38, 42))	('miR-338-3p', 'Var', (56, 66))	('E2F1', 'Gene', (38, 42))	('miR-362', 'Gene', '723851', (71, 78))
277049	31071530	As shown, E2F1 protein decreased when SBF2-AS1 was knocked down and increased when SBF2-AS1 was overexpressed (Figure 5A).	('SBF2-AS1', 'Gene', (38, 46))	('E2F1', 'Gene', '100036852', (10, 14))	('knocked down', 'Var', (51, 63))	('protein', 'Protein', (15, 22))	('decreased', 'NegReg', (23, 32))	('increased', 'PosReg', (68, 77))	('E2F1', 'Gene', (10, 14))
277052	31071530	To this end, we constructed 2 deletion-mutated SBF2-AS1 expression vectors, of which the binding sites of miR-338-3p (SBF2-AS1-MUT1) and miR-362-3p (SBF2-AS1-MUT2) were deletion-mutated, respectively (plasmid sequence is provided in Data S1).	('SBF2-AS1-MUT', 'Disease', (149, 161))	('SBF2-AS1-MUT', 'Disease', 'OMIM:607277', (149, 161))	('SBF2-AS1-MUT', 'Disease', 'OMIM:607277', (118, 130))	('miR-362', 'Gene', '723851', (137, 144))	('SBF2-AS1', 'Gene', (47, 55))	('miR-338-3p', 'Var', (106, 116))	('expression vectors', 'Species', '29278', (56, 74))	('SBF2-AS1-MUT', 'Disease', (118, 130))	('miR-362', 'Gene', (137, 144))
277053	31071530	As shown, E2F1 expression was decreased by miR-338-3p, while ectopic expression of SBF2-AS1 restored E2F1 expression.	('miR-338-3p', 'Var', (43, 53))	('expression', 'Species', '29278', (106, 116))	('E2F1', 'Gene', '100036852', (101, 105))	('E2F1', 'Gene', (101, 105))	('expression', 'Species', '29278', (69, 79))	('expression', 'MPA', (106, 116))	('expression', 'Species', '29278', (15, 25))	('expression', 'MPA', (15, 25))	('E2F1', 'Gene', '100036852', (10, 14))	('E2F1', 'Gene', (10, 14))	('decreased', 'NegReg', (30, 39))	('SBF2-AS1', 'Gene', (83, 91))
277054	31071530	However, when miR-338-3p binding sites were mutated, the mutated SBF2-AS1 failed to restore E2F1 expression (Figure 5C).	('E2F1', 'Gene', '100036852', (92, 96))	('failed', 'NegReg', (74, 80))	('E2F1', 'Gene', (92, 96))	('expression', 'Species', '29278', (97, 107))	('mutated', 'Var', (57, 64))	('SBF2-AS1', 'Gene', (65, 73))	('expression', 'MPA', (97, 107))
277060	31071530	An in vivo xenograft model showed that SBF2-AS1 overexpression promoted lung cancer growth; however, when the binding sites of miR-338-3p and miR-362-3p were both mutated (SBF2-AS1-MUT), SBF2-AS1 failed to promote growth of lung cancer (Figure 6A).	('lung cancer', 'Disease', 'MESH:D008175', (224, 235))	('SBF2-AS1-MUT', 'Disease', 'OMIM:607277', (172, 184))	('growth of lung cancer', 'Disease', 'MESH:D008175', (214, 235))	('mutated', 'Var', (163, 170))	('expression', 'Species', '29278', (52, 62))	('miR-362', 'Gene', (142, 149))	('lung cancer', 'Phenotype', 'HP:0100526', (224, 235))	('lung cancer', 'Disease', (72, 83))	('lung cancer', 'Phenotype', 'HP:0100526', (72, 83))	('SBF2-AS1-MUT', 'Disease', (172, 184))	('growth of lung cancer', 'Disease', (214, 235))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('miR-362', 'Gene', '723851', (142, 149))	('lung cancer', 'Disease', 'MESH:D008175', (72, 83))
277061	31071530	Further analyses of the tumor samples with immunohistochemical (IHC) suggested that E2F1 staining intensity decreased when miR-338-3p and miR-362-3p binding sites were both mutated, in comparison with wild-type SBF2-AS1 (Figure 6B).	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumor', 'Disease', (24, 29))	('mutated', 'Var', (173, 180))	('miR-362', 'Gene', (138, 145))	('E2F1', 'Gene', (84, 88))	('miR-338-3p', 'Gene', (123, 133))	('E2F1', 'Gene', '100036852', (84, 88))	('binding', 'Interaction', (149, 156))	('decreased', 'NegReg', (108, 117))	('miR-362', 'Gene', '723851', (138, 145))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('staining intensity', 'MPA', (89, 107))
277073	31071530	Considering that these genes are also potential targets of miR-338-3p and miR-362-3p, it is reasonable to infer that SBF2-AS1 might increase expression of the 8 genes with a ceRNA mechanism.	('miR-362', 'Gene', '723851', (74, 81))	('SBF2-AS1', 'Var', (117, 125))	('increase', 'PosReg', (132, 140))	('expression', 'Species', '29278', (141, 151))	('expression', 'MPA', (141, 151))	('miR-362', 'Gene', (74, 81))	('miR-338-3p', 'Var', (59, 69))
277074	31071530	A Venn plot shows that more than half of the 144 cell-cycle-related genes (84 of 144) are potential targets of miR-338-3p and miR-362-3p (Figure S4A).	('miR-338-3p', 'Var', (111, 121))	('cell-cycle-related genes', 'Gene', (49, 73))	('miR-362', 'Gene', (126, 133))	('miR-362', 'Gene', '723851', (126, 133))
277075	31071530	Among the 84 genes, we filtered 25 genes that can bind with miR-338-3p and miR-362-3p according to PAR-CLIP and high-throughput sequencing (PAR-CLIP-seq) and draw the potential ceRNA network driven by SBF2-AS1 (Figure S4B).	('miR-362', 'Gene', '723851', (75, 82))	('miR-338-3p', 'Var', (60, 70))	('miR-362', 'Gene', (75, 82))	('SBF2-AS1', 'Gene', (201, 209))
277090	31071530	Authentication of A549, H1299, H1975, and SPC-A1 was verified by short tandem repeat DNA profiling within 6 months of use for the present study.	('H1975', 'Var', (31, 36))	('A549', 'CellLine', 'CVCL:0023', (18, 22))	('H1975', 'CellLine', 'CVCL:1511', (31, 36))	('H1299', 'Var', (24, 29))	('SPC-A1', 'Gene', '27032', (42, 48))	('SPC-A1', 'Gene', (42, 48))	('H1299', 'CellLine', 'CVCL:0060', (24, 29))
277105	31071530	Anti-p21, anti-Cyclin E1, anti-E2F1, and anti-Cyclin D1 were from Cell Signaling Technology (Boston, MA, USA).	('E2F1', 'Gene', (31, 35))	('Cyclin E1', 'Gene', (15, 24))	('anti-Cyclin', 'Var', (41, 52))	('Anti-p21', 'Var', (0, 8))	('Cyclin E1', 'Gene', '397840', (15, 24))	('E2F1', 'Gene', '100036852', (31, 35))
277109	31053176	DNA methylation at an enhancer of the three prime repair exonuclease 2 gene (TREX2) is linked to gene expression and survival in laryngeal cancer Genetic aberrations in DNA repair genes are linked to cancer, but less is reported about epigenetic regulation of DNA repair and functional consequences.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('expression', 'Species', '29278', (102, 112))	('three prime repair exonuclease 2', 'Gene', (38, 70))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('linked', 'Reg', (190, 196))	('TREX2', 'Gene', '11219', (77, 82))	('three prime repair exonuclease 2', 'Gene', '11219', (38, 70))	('DNA repair', 'Gene', (169, 179))	('aberrations', 'Var', (154, 165))	('cancer', 'Disease', 'MESH:D009369', (200, 206))	('TREX2', 'Gene', (77, 82))	('laryngeal cancer', 'Phenotype', 'HP:0012118', (129, 145))	('cancer', 'Disease', (200, 206))	('cancer', 'Disease', (139, 145))
277110	31053176	We investigated the intragenic methylation loss at the three prime repair exonuclease 2 (TREX2) locus in laryngeal (n = 256) and colorectal cancer cases (n = 95) and in pan-cancer data from The Cancer Genome Atlas (TCGA).	('colorectal cancer', 'Disease', (129, 146))	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('Cancer', 'Phenotype', 'HP:0002664', (194, 200))	('Cancer Genome Atlas', 'Disease', (194, 213))	('cancer', 'Disease', (173, 179))	('three prime repair exonuclease 2', 'Gene', (55, 87))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (194, 213))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('colorectal cancer', 'Disease', 'MESH:D015179', (129, 146))	('three prime repair exonuclease 2', 'Gene', '11219', (55, 87))	('methylation', 'Var', (31, 42))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('loss', 'NegReg', (43, 47))	('laryngeal', 'Disease', (105, 114))	('colorectal cancer', 'Phenotype', 'HP:0003003', (129, 146))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('TREX2', 'Gene', (89, 94))
277112	31053176	Methylation loss correlated with immunohistochemically staining for TREX2 (p < 0.0001) in laryngeal tumors and improved overall survival of laryngeal cancer patients (p = 0.045).	('laryngeal cancer', 'Phenotype', 'HP:0012118', (140, 156))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('Methylation', 'Var', (0, 11))	('laryngeal tumors', 'Disease', (90, 106))	('improved', 'PosReg', (111, 119))	('loss', 'NegReg', (12, 16))	('patients', 'Species', '9606', (157, 165))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('laryngeal cancer', 'Disease', 'MESH:D007822', (140, 156))	('laryngeal tumors', 'Disease', 'MESH:D007822', (90, 106))	('laryngeal tumors', 'Phenotype', 'HP:0012118', (90, 106))	('overall survival', 'CPA', (120, 136))	('laryngeal cancer', 'Disease', (140, 156))	('TREX2', 'Gene', (68, 73))
277118	31053176	Recent research has highlighted the importance of genetic variation in DNA repair and tumor suppressor genes for the response to genotoxic exposure and cancer risk, but genetic variants alone cannot fully explain the heterogeneous treatment and survival outcomes observed.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('tumor', 'Disease', (86, 91))	('genetic variation', 'Var', (50, 67))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('DNA repair', 'Gene', (71, 81))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
277120	31053176	Recently, we identified DNA methylation changes at promoter regions of DNA repair genes in HNSCC and other tumors using quantitative methylation analysis.	('DNA repair genes', 'Gene', (71, 87))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumors', 'Disease', (107, 113))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('methylation changes', 'Var', (28, 47))	('tumors', 'Disease', 'MESH:D009369', (107, 113))	('HNSCC', 'Disease', (91, 96))	('HNSCC', 'Phenotype', 'HP:0012288', (91, 96))
277121	31053176	We here quantified DNA methylation at the DNA repair gene three prime repair exonuclease 2 (TREX2) in tumor tissue compared to adjacent normal tissue in an independent, population-based case-control study of laryngeal cancer patients from Germany.	('three prime repair exonuclease 2', 'Gene', (58, 90))	('patients', 'Species', '9606', (225, 233))	('methylation', 'Var', (23, 34))	('laryngeal cancer', 'Disease', 'MESH:D007822', (208, 224))	('three prime repair exonuclease 2', 'Gene', '11219', (58, 90))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('laryngeal cancer', 'Disease', (208, 224))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('TREX2', 'Gene', (92, 97))	('laryngeal cancer', 'Phenotype', 'HP:0012118', (208, 224))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))
277125	31053176	Low TREX2 methylation correlated with prolonged overall survival in laryngeal and colorectal cancer.	('colorectal cancer', 'Disease', (82, 99))	('overall survival', 'MPA', (48, 64))	('prolonged', 'PosReg', (38, 47))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('colorectal cancer', 'Disease', 'MESH:D015179', (82, 99))	('methylation', 'Var', (10, 21))	('colorectal cancer', 'Phenotype', 'HP:0003003', (82, 99))	('laryngeal', 'Disease', (68, 77))	('Low', 'NegReg', (0, 3))	('TREX2', 'Gene', (4, 9))
277126	31053176	In summary, epigenetic deregulation of TREX2 expression was observed in multiple cancers.	('epigenetic deregulation', 'Var', (12, 35))	('cancers', 'Phenotype', 'HP:0002664', (81, 88))	('expression', 'Species', '29278', (45, 55))	('observed', 'Reg', (60, 68))	('cancers', 'Disease', (81, 88))	('cancers', 'Disease', 'MESH:D009369', (81, 88))	('TREX2', 'Gene', (39, 44))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))
277138	31053176	In the HNSCC patient cohort (n = 528) from TCGA, DNA methylation loss was found strongest for probes cg09364317 and cg18879010 and to a minor extent for cg12869875 and cg07206019 while nearby regions largely retained their high degree of methylation.	('loss', 'NegReg', (65, 69))	('cg18879010', 'Var', (116, 126))	('HNSCC', 'Phenotype', 'HP:0012288', (7, 12))	('cg09364317', 'Var', (101, 111))	('patient', 'Species', '9606', (13, 20))	('cg07206019', 'Var', (168, 178))	('methylation', 'MPA', (238, 249))	('methylation', 'MPA', (53, 64))	('cg12869875', 'Var', (153, 163))
277139	31053176	The differentially methylated region (DMR) covered by probes cg09364317 and cg18879010 was scrutinized in the further TCGA cancer studies (Fig.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('DMR', 'Chemical', '-', (38, 41))	('cg09364317', 'Var', (61, 71))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('cg18879010', 'Var', (76, 86))	('cancer', 'Disease', (123, 129))
277144	31053176	Overall, this pan-cancer analysis suggests methylation loss at the TREX2 locus as a frequent event in cancer.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('TREX2', 'Gene', (67, 72))	('cancer', 'Disease', (18, 24))	('cancer', 'Disease', 'MESH:D009369', (18, 24))	('methylation loss', 'Var', (43, 59))
277145	31053176	Methylation decrease at the TREX2 DMR in tumor tissue should be associated with an increase in gene expression.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('DMR', 'Chemical', '-', (34, 37))	('increase', 'PosReg', (83, 91))	('gene expression', 'MPA', (95, 110))	('tumor', 'Disease', (41, 46))	('Methylation', 'MPA', (0, 11))	('expression', 'Species', '29278', (100, 110))	('DMR', 'Var', (34, 37))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('decrease', 'NegReg', (12, 20))
277147	31053176	A significant inverse correlation between TREX2 DMR methylation and TREX2 mRNA expression was found, mainly for the cg09364317 probe and TREX2 mRNA expression (R = - 0.143, p = 0.001; Additional file 1: Figure S2).	('expression', 'Species', '29278', (79, 89))	('cg09364317', 'Var', (116, 126))	('DMR', 'Chemical', '-', (48, 51))	('TREX2', 'MPA', (137, 142))	('expression', 'Species', '29278', (148, 158))	('inverse', 'NegReg', (14, 21))
277153	31053176	3d), and tumor samples with high H-scores showed significantly (p = 0.02) lower methylation of the TREX2 DMR (Fig.	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('methylation', 'MPA', (80, 91))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumor', 'Disease', (9, 14))	('DMR', 'Chemical', '-', (105, 108))	('high', 'Var', (28, 32))	('lower', 'NegReg', (74, 79))	('TREX2', 'Gene', (99, 104))
277157	31053176	Next, we validated the association of TREX2 methylation status and survival in TCGA patient cohorts.	('TCGA', 'Disease', (79, 83))	('association', 'Interaction', (23, 34))	('methylation', 'Var', (44, 55))	('patient', 'Species', '9606', (84, 91))
277158	31053176	In the TCGA laryngeal cancer cases, an adjusted HR value of 0.106 (95% Cl = 0.017-0.686) was found for the probe cg09364317, supporting the results of the German laryngeal cancer study (Table 2).	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('laryngeal cancer', 'Disease', (162, 178))	('laryngeal cancer', 'Disease', (12, 28))	('laryngeal cancer', 'Phenotype', 'HP:0012118', (162, 178))	('laryngeal cancer', 'Phenotype', 'HP:0012118', (12, 28))	('cg09364317', 'Var', (113, 123))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('laryngeal cancer', 'Disease', 'MESH:D007822', (162, 178))	('laryngeal cancer', 'Disease', 'MESH:D007822', (12, 28))
277161	31053176	In summary, survival benefits in laryngeal and colon cancer patients linked to TREX2 DMR methylation loss imply a functional role of this region in tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('colon cancer', 'Phenotype', 'HP:0003003', (47, 59))	('loss', 'NegReg', (101, 105))	('laryngeal', 'Disease', (33, 42))	('patients', 'Species', '9606', (60, 68))	('tumor', 'Disease', (148, 153))	('methylation', 'Var', (89, 100))	('colon cancer', 'Disease', 'MESH:D015179', (47, 59))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('DMR methylation', 'Var', (85, 100))	('DMR', 'Chemical', '-', (85, 88))	('benefits', 'PosReg', (21, 29))	('colon cancer', 'Disease', (47, 59))	('TREX2', 'Gene', (79, 84))
277172	31053176	Further luciferase reporter assays combined the TREX2 DMR with a minimal promoter or the endogenous TREX2 promoter sequences TREX2_PROM1 and 2.	('DMR', 'Chemical', '-', (54, 57))	('DMR', 'Var', (54, 57))	('PROM1', 'Gene', '8842', (131, 136))	('PROM1', 'Gene', (131, 136))
277174	31053176	In addition, the TREX2 DMR acted in an orientation-independent manner, a feature of gene enhancers (Fig.	('DMR', 'Var', (23, 26))	('TREX2', 'Gene', (17, 22))	('DMR', 'Chemical', '-', (23, 26))
277175	31053176	In vitro CpG methylation of the luciferase reporters blocked the TREX2 DMR activity (Fig.	('blocked', 'NegReg', (53, 60))	('luciferase', 'Enzyme', (32, 42))	('methylation', 'Var', (13, 24))	('DMR', 'Chemical', '-', (71, 74))	('TREX2', 'Enzyme', (65, 70))
277178	31053176	Taken together, these data suggest enhancer function for the TREX2 DMR.	('DMR', 'Var', (67, 70))	('DMR', 'Chemical', '-', (67, 70))	('TREX2', 'Gene', (61, 66))	('enhancer', 'PosReg', (35, 43))
277185	31053176	The TREX2 promoter, which also contains two conserved CEBPA binding sites, was also induced, and its activity was enhanced further by the addition of the TREX2 DMR in several of the tested cell lines.	('DMR', 'Var', (160, 163))	('CEBPA', 'Gene', (54, 59))	('activity', 'MPA', (101, 109))	('CEBPA', 'Gene', '1050', (54, 59))	('DMR', 'Chemical', '-', (160, 163))	('enhanced', 'PosReg', (114, 122))	('induced', 'PosReg', (84, 91))	('TREX2 promoter', 'Gene', (4, 18))	('TREX2', 'Gene', (154, 159))
277186	31053176	Mutating the predicted consensus CEBPA recognition sites reduced the CEBPA-induced TREX2 enhancer (Fig.	('Mutating', 'Var', (0, 8))	('CEBPA', 'Gene', (33, 38))	('CEBPA', 'Gene', '1050', (33, 38))	('reduced', 'NegReg', (57, 64))	('CEBPA', 'Gene', (69, 74))	('CEBPA', 'Gene', '1050', (69, 74))
277192	31053176	Using tumors and adjacent normal tissues from laryngeal cancer patients, we found DNA methylation loss at the TREX2 locus for a substantial number of tumors which confirms the recently reported aberrant methylation in HNSCC.	('tumors', 'Disease', (150, 156))	('tumors', 'Disease', 'MESH:D009369', (150, 156))	('tumors', 'Phenotype', 'HP:0002664', (150, 156))	('laryngeal cancer', 'Disease', 'MESH:D007822', (46, 62))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('TREX2', 'Gene', (110, 115))	('laryngeal cancer', 'Disease', (46, 62))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('HNSCC', 'Phenotype', 'HP:0012288', (218, 223))	('tumors', 'Disease', (6, 12))	('methylation', 'Var', (86, 97))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('loss', 'NegReg', (98, 102))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('laryngeal cancer', 'Phenotype', 'HP:0012118', (46, 62))	('patients', 'Species', '9606', (63, 71))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))
277194	31053176	TREX2 DMR methylation was associated with altered protein and mRNA expression and improved survival in patients with laryngeal cancer from Germany and TCGA, suggesting a role of TREX2 methylation in cancer etiology.	('protein', 'MPA', (50, 57))	('altered', 'Reg', (42, 49))	('laryngeal cancer', 'Disease', (117, 133))	('laryngeal cancer', 'Phenotype', 'HP:0012118', (117, 133))	('cancer', 'Disease', (199, 205))	('TREX2', 'Gene', (0, 5))	('DMR', 'Chemical', '-', (6, 9))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('expression', 'Species', '29278', (67, 77))	('cancer', 'Disease', (127, 133))	('DMR methylation', 'Var', (6, 21))	('survival', 'CPA', (91, 99))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('mRNA expression', 'MPA', (62, 77))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('patients', 'Species', '9606', (103, 111))	('laryngeal cancer', 'Disease', 'MESH:D007822', (117, 133))	('improved', 'PosReg', (82, 90))
277196	31053176	In cancers, recent data have indicated heterogeneous TREX2 levels caused by aberrant regulation.	('heterogeneous', 'MPA', (39, 52))	('caused', 'Reg', (66, 72))	('TREX2 levels', 'MPA', (53, 65))	('aberrant regulation', 'Var', (76, 95))	('cancers', 'Phenotype', 'HP:0002664', (3, 10))	('cancers', 'Disease', (3, 10))	('cancers', 'Disease', 'MESH:D009369', (3, 10))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
277197	31053176	Rare genetic inactivation of TREX2 has been reported in CRC, suggesting that TREX2 has a tumor suppressive function.	('genetic inactivation', 'Var', (5, 25))	('CRC', 'Disease', (56, 59))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('TREX2', 'Gene', (29, 34))	('CRC', 'Phenotype', 'HP:0003003', (56, 59))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
277198	31053176	In HNSCC and UV-exposed skin, TREX2 levels were shown to vary considerably, with high TREX2 being associated with enhanced UV protection and lower skin cancer risk.	('HNSCC', 'Phenotype', 'HP:0012288', (3, 8))	('skin cancer', 'Phenotype', 'HP:0008069', (147, 158))	('TREX2', 'Var', (86, 91))	('high TREX2', 'Var', (81, 91))	('skin cancer', 'Disease', (147, 158))	('UV protection', 'CPA', (123, 136))	('enhanced', 'PosReg', (114, 122))	('lower', 'NegReg', (141, 146))	('skin cancer', 'Disease', 'MESH:D012878', (147, 158))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))
277199	31053176	Our data support literature data on the role of TREX2 in carcinogenesis as tumor patients with high TREX2 expression show improved overall survival in our analysis.	('carcinogenesis', 'Disease', 'MESH:D063646', (57, 71))	('expression', 'Species', '29278', (106, 116))	('TREX2', 'Gene', (100, 105))	('carcinogenesis', 'Disease', (57, 71))	('high', 'Var', (95, 99))	('patients', 'Species', '9606', (81, 89))	('overall', 'MPA', (131, 138))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', (75, 80))	('improved', 'PosReg', (122, 130))
277201	31053176	There is additional evidence for the beneficial role of high TREX2 expression in tumors.	('tumors', 'Disease', (81, 87))	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('beneficial', 'PosReg', (37, 47))	('expression', 'Species', '29278', (67, 77))	('TREX2', 'Gene', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('expression', 'MPA', (67, 77))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('high', 'Var', (56, 60))
277212	31053176	We suggest that the association which we see between methylation loss and increased TREX2 expression could be responsible for beneficial downstream events like improved immune response and the survival benefit observed in a subgroup of laryngeal cancer patients.	('loss', 'NegReg', (65, 69))	('survival benefit', 'CPA', (193, 209))	('patients', 'Species', '9606', (253, 261))	('expression', 'Species', '29278', (90, 100))	('laryngeal cancer', 'Disease', 'MESH:D007822', (236, 252))	('TREX2', 'Gene', (84, 89))	('increased', 'PosReg', (74, 83))	('expression', 'MPA', (90, 100))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))	('laryngeal cancer', 'Phenotype', 'HP:0012118', (236, 252))	('improved', 'PosReg', (160, 168))	('laryngeal cancer', 'Disease', (236, 252))	('immune response', 'CPA', (169, 184))	('methylation', 'Var', (53, 64))
277216	31053176	High TREX2 expression might render cells uniquely dependent on canonical end joining, especially in the absence of ATM, and thus might open new possibilities for treatments based on synthetic lethality effects.	('ATM', 'Gene', (115, 118))	('expression', 'Species', '29278', (11, 21))	('High', 'Var', (0, 4))	('open', 'Reg', (135, 139))	('ATM', 'Gene', '472', (115, 118))	('canonical end joining', 'MPA', (63, 84))	('TREX2', 'Gene', (5, 10))	('dependent', 'Reg', (50, 59))
277217	31053176	This is supported by our molecular analysis which revealed that the TREX2 locus affected by methylation loss has gene enhancer activity and likely drives gene expression of TREX2 in cis by serving as a transcription factor binding site for CEBPA and possibly other factors.	('loss', 'NegReg', (104, 108))	('methylation', 'Var', (92, 103))	('enhancer', 'PosReg', (118, 126))	('expression', 'Species', '29278', (159, 169))	('drives', 'PosReg', (147, 153))	('expression', 'MPA', (159, 169))	('CEBPA', 'Gene', (240, 245))	('CEBPA', 'Gene', '1050', (240, 245))	('TREX2', 'Gene', (68, 73))
277223	31053176	Thus, we conclude that TREX2 DNA methylation might be useful as a biomarker to understand carcinogenesis in stratified epithelia and as a possible predictor of treatment response.	('methylation', 'Var', (33, 44))	('TREX2', 'Gene', (23, 28))	('epithelia', 'Disease', 'None', (119, 128))	('epithelia', 'Disease', (119, 128))	('carcinogenesis', 'Disease', 'MESH:D063646', (90, 104))	('carcinogenesis', 'Disease', (90, 104))
277224	31053176	In particular, tumors with high TREX2 expression might be less aggressive or respond better to specific therapies exploiting DNA damage response pathways.	('tumors', 'Disease', (15, 21))	('expression', 'Species', '29278', (38, 48))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('expression', 'MPA', (38, 48))	('aggressive', 'CPA', (63, 73))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumors', 'Disease', 'MESH:D009369', (15, 21))	('high', 'Var', (27, 31))	('TREX2', 'Gene', (32, 37))	('less', 'NegReg', (58, 62))
277281	27216194	Genomic Landscape Established by Allelic Imbalance in the Cancerization Field of a Normal Appearing Airway Visually normal cells adjacent to, and extending from, tumors of the lung may carry molecular alterations characteristics of the tumor itself, an effect referred to as airway field of cancerization.	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('Imbalance', 'Phenotype', 'HP:0002172', (41, 50))	('Allelic', 'Var', (33, 40))	('tumors of the lung', 'Disease', 'MESH:D008175', (162, 180))	('cancer', 'Phenotype', 'HP:0002664', (291, 297))	('cancer', 'Disease', (291, 297))	('cancer', 'Disease', 'MESH:D009369', (291, 297))	('tumor', 'Disease', (162, 167))	('tumor', 'Disease', 'MESH:D009369', (236, 241))	('tumors of the lung', 'Disease', (162, 180))	('Cancer', 'Phenotype', 'HP:0002664', (58, 64))	('tumor', 'Phenotype', 'HP:0002664', (236, 241))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))	('tumors of the lung', 'Phenotype', 'HP:0100526', (162, 180))	('tumor', 'Disease', (236, 241))	('tumor', 'Disease', 'MESH:D009369', (162, 167))
277298	27216194	Previously described airway field changes include loss-of-heterozygosity (LOH) at chromosomal regions 3p and 9p, promoter methylation of CDKN2A, mutations in the EGFR, and KRAS oncogenes as well as gene expression profiles that are common between tumors and adjacent normal airway cells.	('KRAS', 'Gene', (172, 176))	('tumor', 'Phenotype', 'HP:0002664', (247, 252))	('KRAS', 'Gene', '3845', (172, 176))	('gene expression profiles', 'MPA', (198, 222))	('tumors', 'Disease', (247, 253))	('tumors', 'Disease', 'MESH:D009369', (247, 253))	('mutations', 'Var', (145, 154))	('EGFR', 'Gene', '1956', (162, 166))	('tumors', 'Phenotype', 'HP:0002664', (247, 253))	('airway field changes', 'CPA', (21, 41))	('EGFR', 'Gene', (162, 166))	('CDKN2A', 'Gene', (137, 143))	('promoter methylation', 'MPA', (113, 133))	('CDKN2A', 'Gene', '1029', (137, 143))	('loss-of-heterozygosity', 'NegReg', (50, 72))
277318	27216194	This method is based on identifying subtle B-allele frequency (BAF) shifts among heterozygous markers that are congruent with one of the parental haplotypes and thus consistent with an AI event such as deletion, duplication, orcn-LOH (Supplementary Fig.	('B-allele', 'MPA', (43, 51))	('BAF', 'Gene', '8815', (63, 66))	('men', 'Species', '9606', (241, 244))	('BAF', 'Gene', (63, 66))	('duplication', 'Var', (212, 223))	('deletion', 'Var', (202, 210))
277338	27216194	Our findings suggest that somatic events are distributed along a spatial gradient in the normal-appearing airway field, particularly in LUAD patients, in which samples in closer proximity to the primary tumor are more likely to exhibit somatic chromosomal alterations (Fig.	('chromosomal alterations', 'Var', (244, 267))	('tumor', 'Disease', (203, 208))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('exhibit', 'Reg', (228, 235))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('patients', 'Species', '9606', (141, 149))	('LUAD', 'Phenotype', 'HP:0030078', (136, 140))
277349	27216194	For 4 of these 13, the event designations (e.g., deletion, duplication) differed between airway and tumor.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Disease', (100, 105))	('duplication', 'Var', (59, 70))	('deletion', 'Var', (49, 57))	('differed', 'Reg', (72, 80))	('tumor', 'Disease', 'MESH:D009369', (100, 105))
277351	27216194	These observations imply regions of genomic instability and recurrent independent AI (independent mutations in the airway and tumor).	('mutations', 'Var', (98, 107))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumor', 'Disease', (126, 131))
277355	27216194	To understand the effects of these AI field events on the pathobiology of NSCLC, we annotated the identified field alterations as bona fide drivers in cancer and with genes previously reported to be aberrant in NSCLCs (e.g., lineage-restricted oncogenes).	('drivers', 'Reg', (140, 147))	('NSCLC', 'Phenotype', 'HP:0030358', (74, 79))	('NSCLC', 'Phenotype', 'HP:0030358', (211, 216))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('alterations', 'Var', (115, 126))	('NSCLC', 'Disease', (74, 79))	('cancer', 'Disease', (151, 157))	('NSCLC', 'Disease', (211, 216))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('NSCLC', 'Disease', 'MESH:D002289', (74, 79))	('NSCLC', 'Disease', 'MESH:D002289', (211, 216))
277356	27216194	Losses or cn-LOH in 9q, spanning KLF4 (9q31), PTCH1 (9q22), GNAQ (9q21), TSC1 (9q34), ABL1 (9q34), and NOTCH1 (9q34), were the most frequent CNAs in the airway field of both LUADs and LUSCs (Fig.	('KLF4', 'Gene', (33, 37))	('Losses', 'NegReg', (0, 6))	('cn-LOH', 'Var', (10, 16))	('GNAQ', 'Gene', (60, 64))	('LUAD', 'Phenotype', 'HP:0030078', (174, 178))	('PTCH1', 'Gene', '5727', (46, 51))	('ABL1', 'Gene', '25', (86, 90))	('ABL1', 'Gene', (86, 90))	('NOTCH1', 'Gene', (103, 109))	('GNAQ', 'Gene', '2776', (60, 64))	('TSC1', 'Gene', '7248', (73, 77))	('PTCH1', 'Gene', (46, 51))	('NOTCH1', 'Gene', '4851', (103, 109))	('KLF4', 'Gene', '9314', (33, 37))	('TSC1', 'Gene', (73, 77))
277368	27216194	LOH in 9q (TSC1) and 17p13 (TP53) as well as reduced protein expression of STK11 were reported in atypical adenomatous hyperplasias, precursor lesions in the histopathologic sequence of LUAD development.	('TP53', 'Gene', '7157', (28, 32))	('reduced', 'NegReg', (45, 52))	('LOH', 'Var', (0, 3))	('adenomatous hyperplasias', 'Phenotype', 'HP:0040261', (107, 131))	('TP53', 'Gene', (28, 32))	('STK11', 'Gene', '6794', (75, 80))	('LUAD', 'Phenotype', 'HP:0030078', (186, 190))	('TSC1', 'Gene', '7248', (11, 15))	('adenomatous hyperplasias', 'Disease', 'MESH:D011125', (107, 131))	('protein expression', 'MPA', (53, 71))	('men', 'Species', '9606', (198, 201))	('TSC1', 'Gene', (11, 15))	('STK11', 'Gene', (75, 80))	('adenomatous hyperplasias', 'Disease', (107, 131))
277369	27216194	Also, AI events in 8p22 (MTUS1), 13q14 (RB1), and 17p13 (TP53) were detected in squamous preinvasive lesions.	('MTUS1', 'Gene', (25, 30))	('17p13', 'Var', (50, 55))	('RB1', 'Gene', (40, 43))	('squamous preinvasive lesions', 'Disease', (80, 108))	('TP53', 'Gene', '7157', (57, 61))	('TP53', 'Gene', (57, 61))	('MTUS1', 'Gene', '57509', (25, 30))	('RB1', 'Gene', '5925', (40, 43))
277376	27216194	It is worthwhile to mention that previous work demonstrated that LUSC tumors harbor more frequent copy number alterations compared with ever-smoker LUADs.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('copy number alterations', 'Var', (98, 121))	('LUAD', 'Phenotype', 'HP:0030078', (148, 152))	('tumors', 'Disease', (70, 76))	('tumors', 'Disease', 'MESH:D009369', (70, 76))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('men', 'Species', '9606', (20, 23))
277384	27216194	Earlier work pointed to common gene expression profiles between normal large airways and nasal epithelia of phenotypically healthy smokers, suggesting that intrathoracic gene expression changes may extend to extrathoracic (e.g., nasal) cavities.	('changes', 'Var', (186, 193))	('nasal epithelia', 'Disease', (89, 104))	('nasal epithelia', 'Disease', 'MESH:D009668', (89, 104))
277387	27216194	It is important to note that the previously reported airway field profiling studies in smokers with cancer centered on the bronchial compartment demonstrating that gene expression changes in bronchial epithelia can improve diagnostic performance of bronchoscopy.	('changes', 'Var', (180, 187))	('diagnostic performance', 'MPA', (223, 245))	('men', 'Species', '9606', (140, 143))	('cancer', 'Disease', (100, 106))	('gene expression changes', 'Var', (164, 187))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('bronchoscopy', 'Disease', (249, 261))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('improve', 'PosReg', (215, 222))
277388	27216194	It is likely that the nasal epithelial field may harbor different types of alterations (e.g., epigenetic) and that warrant future studies.	('epigenetic', 'Var', (94, 104))	('nasal epithelia', 'Disease', (22, 37))	('nasal epithelia', 'Disease', 'MESH:D009668', (22, 37))
277391	27216194	We also shed light on driver gene copy number alterations that are present in the normal-appearing airway field of cancerization and, thus, may embody early events in the pathogenesis of NSCLC.	('cancer', 'Disease', (115, 121))	('NSCLC', 'Phenotype', 'HP:0030358', (187, 192))	('copy number alterations', 'Var', (34, 57))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('NSCLC', 'Disease', (187, 192))	('alterations', 'Var', (46, 57))	('embody', 'Reg', (144, 150))	('NSCLC', 'Disease', 'MESH:D002289', (187, 192))	('cancer', 'Disease', 'MESH:D009369', (115, 121))
277458	33608558	As presented in Table 1, the whole-slide training method with GAP layers achieved AUC scores of 0.6506 (0.6213-0.6798) for adenocarcinoma and 0.5597 (0.5176-0.6018) for squamous cell carcinoma classification, indicating the model only captures limited information from inputs.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (169, 192))	('0.5597', 'Var', (142, 148))	('adenocarcinoma', 'Disease', (123, 137))	('carcinoma', 'Phenotype', 'HP:0030731', (183, 192))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (169, 192))	('squamous cell carcinoma', 'Disease', (169, 192))	('adenocarcinoma', 'Disease', 'MESH:D000230', (123, 137))
277460	33608558	By contrast, the whole-slide training method with GMP layers achieved AUC scores of 0.9594 (0.9500-0.9689) for adenocarcinoma and 0.9414 (0.9234-0.9593) for squamous cell carcinoma, which were significantly superior to those achieved by the other approaches, including CNN-MaxFeat-based RF (P = 3.565e-7 and 3.189e-4 for classifying adenocarcinoma and squamous cell carcinoma, respectively) and MIL-RNN (P = 2.279e-9 and 0.02498 for classifying adenocarcinoma and squamous cell carcinoma, respectively).	('squamous cell carcinoma', 'Disease', (157, 180))	('adenocarcinoma', 'Disease', (445, 459))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (464, 487))	('adenocarcinoma', 'Disease', (333, 347))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (352, 375))	('carcinoma', 'Phenotype', 'HP:0030731', (366, 375))	('adenocarcinoma and squamous cell carcinoma', 'Disease', 'MESH:D002294', (445, 487))	('adenocarcinoma', 'Disease', 'MESH:D000230', (111, 125))	('0.9414', 'Var', (130, 136))	('squamous cell carcinoma', 'Disease', (464, 487))	('MIL-RNN', 'Chemical', '-', (395, 402))	('adenocarcinoma', 'Disease', 'MESH:D000230', (445, 459))	('adenocarcinoma', 'Disease', 'MESH:D000230', (333, 347))	('squamous cell carcinoma', 'Disease', (352, 375))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (157, 180))	('carcinoma', 'Phenotype', 'HP:0030731', (450, 459))	('adenocarcinoma and squamous cell carcinoma', 'Disease', 'MESH:D002294', (333, 375))	('carcinoma', 'Phenotype', 'HP:0030731', (171, 180))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (157, 180))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (464, 487))	('GMP', 'Chemical', '-', (50, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (338, 347))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (352, 375))	('adenocarcinoma', 'Disease', (111, 125))
277479	33608558	Notably, even though the reduction in resolution affected model performance, the AUCs of the whole-slide training method on downsampled slides were still high, and those using x1 magnification were higher than 0.9 (0.9252 for adenocarcinoma and 0.9061 for squamous cell carcinoma).	('0.9061', 'Var', (245, 251))	('adenocarcinoma', 'Disease', (226, 240))	('carcinoma', 'Phenotype', 'HP:0030731', (231, 240))	('adenocarcinoma', 'Disease', 'MESH:D000230', (226, 240))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (256, 279))	('carcinoma', 'Phenotype', 'HP:0030731', (270, 279))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (256, 279))	('squamous cell carcinoma', 'Disease', (256, 279))
277484	33608558	The AUC scores were 0.9548 (0.9450-0.9646) for adenocarcinoma and 0.9414 (0.9239-0.9588) for squamous cell carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('carcinoma', 'Phenotype', 'HP:0030731', (52, 61))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (93, 116))	('adenocarcinoma', 'Disease', 'MESH:D000230', (47, 61))	('squamous cell carcinoma', 'Disease', (93, 116))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (93, 116))	('0.9414', 'Var', (66, 72))	('adenocarcinoma', 'Disease', (47, 61))
277528	31997506	 Fusobacterium nucleatum promotes epithelial-mesenchymal transiton through regulation of the lncRNA MIR4435-2HG/miR-296-5p/Akt2/SNAI1 signaling pathway Fusobacterium nucleatum, an anaerobic oral opportunistic pathogen associated with periodontitis, has been considered to be associated with the development of oral squamous cell carcinoma (OSCC).	('Fusobacterium nucleatum', 'Species', '851', (152, 175))	('Fusobacterium nucleatum', 'Species', '851', (1, 24))	('periodontitis', 'Disease', 'MESH:D010518', (234, 247))	('Akt2', 'Gene', (123, 127))	('Akt2', 'Gene', '208', (123, 127))	('periodontitis', 'Phenotype', 'HP:0000704', (234, 247))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (310, 338))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (315, 338))	('oral squamous cell carcinoma', 'Disease', (310, 338))	('SNAI1', 'Gene', '6615', (128, 133))	('SNAI1', 'Gene', (128, 133))	('miR', 'Gene', '220972', (112, 115))	('associated', 'Reg', (275, 285))	('MIR4435-2HG', 'Gene', '541471', (100, 111))	('epithelial-mesenchymal transiton', 'CPA', (34, 66))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (315, 338))	('miR-296', 'Gene', (112, 119))	('miR', 'Gene', (112, 115))	('miR-296', 'Gene', '407022', (112, 119))	('periodontitis', 'Disease', (234, 247))	('Fusobacterium', 'Var', (152, 165))	('carcinoma', 'Phenotype', 'HP:0030731', (329, 338))	('MIR4435-2HG', 'Gene', (100, 111))
277530	31997506	In the present study, we monitored the ability of F. nucleatum to induce EMT-associated features, and our results showed that F. nucleatum infection promoted cell migration in either noncancerous human immortalized oral epithelial cells (HIOECs) or the two OSCC cell lines SCC-9 and HSC-4, but did not accelerate cell proliferation or cell cycle progression.	('promoted', 'PosReg', (149, 157))	('cell migration', 'CPA', (158, 172))	('infection', 'Var', (139, 148))	('HSC-4', 'CellLine', 'CVCL:1289', (283, 288))	('cancerous', 'Disease', (186, 195))	('human', 'Species', '9606', (196, 201))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('SCC-9', 'CellLine', 'CVCL:1685', (273, 278))	('cancerous', 'Disease', 'MESH:D009369', (186, 195))	('F. nucleatum infection', 'Var', (126, 148))	('cancer', 'Disease', (186, 192))	('cancer', 'Disease', 'MESH:D009369', (186, 192))
277532	31997506	The upregulated lncRNA MIR4435-2HG identified by the high-throughput sequencing was demonstrated to negatively regulate the expression of miR-296-5p, which was downregulated in F. nucleatum-infected HIOECs and SCC-9 cells.	('infected', 'Disease', (190, 198))	('negatively', 'NegReg', (100, 110))	('upregulated', 'PosReg', (4, 15))	('expression', 'MPA', (124, 134))	('infected', 'Disease', 'MESH:D007239', (190, 198))	('miR-296-5p', 'Var', (138, 148))	('MIR4435-2HG', 'Var', (23, 34))
277539	31997506	HOX transcript antisense RNA (HOTAIR) is frequently overexpressed in a wide variety of malignancies and has been demonstrated to enhance EMT by sponging miR-23b-3p from ZEB1 in hepatocellular carcinoma 17.	('carcinoma', 'Phenotype', 'HP:0030731', (192, 201))	('antisense', 'Var', (15, 24))	('EMT', 'CPA', (137, 140))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (177, 201))	('malignancies', 'Disease', 'MESH:D009369', (87, 99))	('hepatocellular carcinoma', 'Disease', (177, 201))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (177, 201))	('miR-23b-3p', 'Var', (153, 163))	('malignancies', 'Disease', (87, 99))	('enhance', 'PosReg', (129, 136))
277540	31997506	MIR4435-2HG, also known as LINC00978, is a novel lncRNA located in 2q13 and has been reported to promote cell growth and tumorigenesis in lung and gastric cancers 19.	('MIR4435-2HG', 'Var', (0, 11))	('LINC00978', 'Gene', (27, 36))	('gastric cancer', 'Phenotype', 'HP:0012126', (147, 161))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('cell growth', 'CPA', (105, 116))	('LINC00978', 'Gene', '541471', (27, 36))	('tumor', 'Disease', (121, 126))	('lung', 'Disease', (138, 142))	('gastric cancers', 'Phenotype', 'HP:0012126', (147, 162))	('gastric cancers 19', 'Disease', 'MESH:C000657245', (147, 165))	('gastric cancers 19', 'Disease', (147, 165))	('cancers', 'Phenotype', 'HP:0002664', (155, 162))	('gastric cancer', 'Disease', 'MESH:D013274', (147, 161))	('promote', 'PosReg', (97, 104))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
277545	31997506	An increase in the amount of SNAIL1 protein was also observed at 24 h following F. nucleatum infection, whereas S. gordonii did not cause elevated SNAIL1 protein expression (Fig.	('SNAIL1', 'Gene', '6615', (29, 35))	('SNAIL1', 'Gene', (147, 153))	('SNAIL1', 'Gene', '6615', (147, 153))	('amount', 'MPA', (19, 25))	('infection', 'Var', (93, 102))	('SNAIL1', 'Gene', (29, 35))	('increase', 'PosReg', (3, 11))
277547	31997506	The expression levels of MIR4435-2HG and SNAI1 were found to be positively correlated in various carcinomas, including head and neck squamous cell carcinoma (HNSCC) in the online database TCGA-Pan-Cancer (ChIPBase v2.0) (Fig.	('expression levels', 'MPA', (4, 21))	('Cancer', 'Phenotype', 'HP:0002664', (197, 203))	('Cancer', 'Disease', (197, 203))	('MIR4435-2HG', 'Var', (25, 36))	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('Cancer', 'Disease', 'MESH:D009369', (197, 203))	('correlated', 'Reg', (75, 85))	('carcinomas', 'Phenotype', 'HP:0030731', (97, 107))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (119, 156))	('carcinomas', 'Disease', (97, 107))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (133, 156))	('carcinoma', 'Phenotype', 'HP:0030731', (147, 156))	('SNAI1', 'Gene', (41, 46))
277548	31997506	As is reported, Helicobacter pylori induces EMT in a cytotoxin-associated gene A (CagA)-dependent manner, which induces an increase in EMT markers and stabilizing SNAIL1 protein by reducing GSK-3 activity in gastric epithelial cancer cells 21, 22, 23.	('SNAIL1 protein', 'Protein', (163, 177))	('CagA', 'Gene', (82, 86))	('reducing', 'NegReg', (181, 189))	('CagA', 'Gene', '6279', (82, 86))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('Helicobacter pylori', 'Var', (16, 35))	('activity', 'MPA', (196, 204))	('EMT markers', 'MPA', (135, 146))	('increase', 'PosReg', (123, 131))	('induces', 'PosReg', (36, 43))	('EMT', 'CPA', (44, 47))	('gastric epithelial cancer', 'Disease', 'MESH:D013274', (208, 233))	('Helicobacter pylori', 'Species', '210', (16, 35))	('epithelial cancer', 'Phenotype', 'HP:0031492', (216, 233))	('GSK-3', 'Enzyme', (190, 195))	('gastric epithelial cancer', 'Disease', (208, 233))	('stabilizing', 'MPA', (151, 162))
277549	31997506	Moreover, researchers have verified that FimA-positive P. gingivalis was capable of initiating a mesenchymal-like transition through ZEB1 in gingival epithelial cells 24.	('P. gingivalis', 'Species', '837', (55, 68))	('P. gingivalis', 'Var', (55, 68))	('initiating', 'Reg', (84, 94))	('mesenchymal-like transition', 'CPA', (97, 124))
277553	31997506	However, F. nucleatum can also impair the proliferation of human gingival fibroblasts (GFs), HUVECs, or promote the proliferation of colorectal cancer cell lines LoVo and SW480 cells 31, 32, 33, 34.	('SW480', 'CellLine', 'CVCL:0546', (171, 176))	('LoVo', 'CellLine', 'CVCL:0399', (162, 166))	('colorectal cancer', 'Disease', (133, 150))	('proliferation', 'CPA', (42, 55))	('impair', 'NegReg', (31, 37))	('promote', 'PosReg', (104, 111))	('proliferation', 'CPA', (116, 129))	('F. nucleatum', 'Var', (9, 21))	('colorectal cancer', 'Phenotype', 'HP:0003003', (133, 150))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
277554	31997506	Higher expression of MIR4435-2HG was observed in colorectal and gastric epithelial cancer tissues, and knockdown of MIR4435-2HG inhibited the migration and invasion of gastric cancer cells 19, 40, 41.	('MIR4435-2HG', 'Var', (116, 127))	('epithelial cancer', 'Phenotype', 'HP:0031492', (72, 89))	('MIR4435-2HG', 'Var', (21, 32))	('gastric cancer', 'Phenotype', 'HP:0012126', (168, 182))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('expression', 'MPA', (7, 17))	('Higher', 'PosReg', (0, 6))	('inhibited', 'NegReg', (128, 137))	('colorectal and gastric epithelial cancer', 'Disease', 'MESH:D013274', (49, 89))
277555	31997506	Studies have revealed that increased MIR4435-2HG expression might be a potential biomarker for the diagnosis and prognosis of colorectal cancer, correlated with lymphatic metastasis, and predict poor survival in patients with gastric cancer or breast cancer 19, 41, 42.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('lymphatic metastasis', 'CPA', (161, 181))	('correlated', 'Reg', (145, 155))	('increased', 'PosReg', (27, 36))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('colorectal cancer', 'Disease', (126, 143))	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('gastric cancer', 'Disease', (226, 240))	('breast cancer', 'Phenotype', 'HP:0003002', (244, 257))	('poor', 'NegReg', (195, 199))	('cancer 19', 'Disease', 'MESH:C000657245', (251, 260))	('gastric cancer', 'Phenotype', 'HP:0012126', (226, 240))	('colorectal cancer', 'Phenotype', 'HP:0003003', (126, 143))	('cancer 19', 'Disease', (251, 260))	('MIR4435-2HG', 'Var', (37, 48))
277556	31997506	However, a specific role for MIR4435-2HG in bacterial infection or EMT in oral epithelial cells has not been identified.	('bacterial infection', 'Disease', (44, 63))	('MIR4435-2HG', 'Var', (29, 40))	('bacterial infection', 'Phenotype', 'HP:0002718', (44, 63))	('bacterial infection', 'Disease', 'MESH:D001424', (44, 63))
277583	26508273	Aberrant miR expression contributes to initiation and cell progression of cancers.	('Aberrant', 'Var', (0, 8))	('cancers', 'Disease', 'MESH:D009369', (74, 81))	('cancers', 'Phenotype', 'HP:0002664', (74, 81))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('cancers', 'Disease', (74, 81))	('cell progression', 'CPA', (54, 70))	('contributes', 'Reg', (24, 35))	('miR', 'Gene', '220972', (9, 12))	('miR', 'Gene', (9, 12))
277585	26508273	Deregulations of miRs may contribute to cSCC carcinogenesis is through acting as oncogenic or tumour suppressive miRs.	('tumour', 'Disease', (94, 100))	('SCC', 'Gene', (41, 44))	('cSCC', 'Phenotype', 'HP:0006739', (40, 44))	('miR', 'Gene', '220972', (113, 116))	('Deregulations', 'Var', (0, 13))	('miR', 'Gene', (113, 116))	('contribute', 'Reg', (26, 36))	('miR', 'Gene', '220972', (17, 20))	('miR', 'Gene', (17, 20))	('SCC', 'Gene', '6317', (41, 44))	('tumour', 'Phenotype', 'HP:0002664', (94, 100))	('carcinogenesis', 'Disease', 'MESH:D063646', (45, 59))	('carcinogenesis', 'Disease', (45, 59))	('tumour', 'Disease', 'MESH:D009369', (94, 100))
277595	26508273	In addition, deregulation of miR expression has been shown to play significant roles in a variety of cancers, in which miRs can act as tumour suppressors or oncogenes by regulating the multiple target genes 8, 12.	('regulating', 'Reg', (170, 180))	('cancers', 'Disease', 'MESH:D009369', (101, 108))	('miR', 'Gene', '220972', (29, 32))	('cancers', 'Phenotype', 'HP:0002664', (101, 108))	('miR', 'Gene', (29, 32))	('miR', 'Gene', '220972', (119, 122))	('miR', 'Gene', (119, 122))	('cancers', 'Disease', (101, 108))	('tumour', 'Phenotype', 'HP:0002664', (135, 141))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('tumour', 'Disease', 'MESH:D009369', (135, 141))	('deregulation', 'Var', (13, 25))	('tumour', 'Disease', (135, 141))
277596	26508273	Recently, miR deregulation has been proved to be involved in the development of cSCC (Table 1).	('SCC', 'Gene', '6317', (81, 84))	('deregulation', 'Var', (14, 26))	('involved', 'Reg', (49, 57))	('miR', 'Gene', '220972', (10, 13))	('miR', 'Gene', (10, 13))	('SCC', 'Gene', (81, 84))	('cSCC', 'Phenotype', 'HP:0006739', (80, 84))
277618	26508273	Deregulated miR-124 is described to play important roles in different types of cancer.	('roles', 'Reg', (51, 56))	('Deregulated', 'Var', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('miR-1', 'Gene', (12, 17))	('miR-1', 'Gene', '83856', (12, 17))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))
277626	26508273	Supplement expression of miR-124 and miR-21 inhibited the cell proliferation via normalizing ERK1/2 (extracellular regulated protein kinases) levels in the cSCC cell in vitro.	('SCC', 'Gene', (157, 160))	('cSCC', 'Phenotype', 'HP:0006739', (156, 160))	('miR-1', 'Gene', (25, 30))	('rat', 'Species', '10116', (70, 73))	('miR-1', 'Gene', '83856', (25, 30))	('inhibited', 'NegReg', (44, 53))	('cell proliferation', 'CPA', (58, 76))	('SCC', 'Gene', '6317', (157, 160))	('ERK1/2', 'Gene', (93, 99))	('ERK1/2', 'Gene', '5595;5594', (93, 99))	('normalizing', 'NegReg', (81, 92))	('miR-21', 'Var', (37, 43))
277650	26508273	found that miR-193b-3p and miR-365-3p are highly expressed in epidermis.	('miR-365-3p', 'Gene', (27, 37))	('miR-193b-3p', 'Var', (11, 22))	('miR-365-3p', 'Gene', '100500833', (27, 37))
277654	26508273	The expression levels of KRAS and MAX were significantly decreased by miR-193b-3p and miR-365-3p 54.	('miR-193b-3p', 'Var', (70, 81))	('miR-365-3p', 'Gene', (86, 96))	('expression levels', 'MPA', (4, 21))	('miR-365-3p', 'Gene', '100500833', (86, 96))	('KRAS', 'MPA', (25, 29))	('decreased', 'NegReg', (57, 66))	('MAX', 'MPA', (34, 37))
277695	26508273	Therefore, antagomir to miR-205 may provide a novel treatment of cSCC.	('SCC', 'Gene', (66, 69))	('miR-205', 'Gene', '406988', (24, 31))	('SCC', 'Gene', '6317', (66, 69))	('cSCC', 'Phenotype', 'HP:0006739', (65, 69))	('miR-205', 'Gene', (24, 31))	('antagomir', 'Var', (11, 20))
277699	26508273	showed that miR-365 was up-regulated in both cells and clinical specimens of cSCC and it promoted the development of cSCCs through targeting nuclear factor I/B 85, 86.	('cSCC', 'Phenotype', 'HP:0006739', (117, 121))	('up-regulated', 'PosReg', (24, 36))	('SCC', 'Gene', '6317', (78, 81))	('I/B 85', 'Var', (156, 162))	('cSCC', 'Phenotype', 'HP:0006739', (77, 81))	('SCC', 'Gene', (118, 121))	('development', 'CPA', (102, 113))	('I/B 85', 'SUBSTITUTION', 'None', (156, 162))	('promoted', 'PosReg', (89, 97))	('targeting', 'Reg', (131, 140))	('SCC', 'Gene', '6317', (118, 121))	('miR', 'Gene', '220972', (12, 15))	('SCC', 'Gene', (78, 81))	('miR', 'Gene', (12, 15))
277700	26508273	HaCaTpre-miR-365-2 cell line, which overexpressed miR-365, induced subcutaneous tumours while antagomir-365, an anti-miR-365 oligonucleotide, inhibited cutaneous tumour formation in vivo.	('cutaneous tumour', 'Disease', 'OMIM:614564', (70, 86))	('cutaneous tumour', 'Disease', (152, 168))	('subcutaneous tumours', 'Disease', 'MESH:D012871', (67, 87))	('miR', 'Gene', (117, 120))	('cutaneous tumour', 'Phenotype', 'HP:0008069', (152, 168))	('miR', 'Gene', '220972', (50, 53))	('antagomir-365', 'Var', (94, 107))	('tumour', 'Phenotype', 'HP:0002664', (162, 168))	('miR', 'Gene', '220972', (9, 12))	('miR', 'Gene', (50, 53))	('cutaneous tumour', 'Disease', 'OMIM:614564', (152, 168))	('subcutaneous tumours', 'Disease', (67, 87))	('oligonucleotide', 'Chemical', 'MESH:D009841', (125, 140))	('tumour', 'Phenotype', 'HP:0002664', (80, 86))	('cutaneous tumour', 'Phenotype', 'HP:0008069', (70, 86))	('inhibited', 'NegReg', (142, 151))	('tumours', 'Phenotype', 'HP:0002664', (80, 87))	('miR', 'Gene', (9, 12))	('induced', 'PosReg', (59, 66))	('HaCa', 'CellLine', 'CVCL:4970', (0, 4))	('miR', 'Gene', '220972', (117, 120))
277701	26508273	MicroRNA-365 could also induce G1 phase arrest and apoptosis of cancer cells.	('induce', 'PosReg', (24, 30))	('G1 phase arrest', 'CPA', (31, 46))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('apoptosis', 'CPA', (51, 60))	('MicroRNA-365', 'Var', (0, 12))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
277706	26508273	Increasing evidence has observed that deregulated miRs in cSCC, providing potential diagnostic and therapeutic targets.	('miR', 'Gene', '220972', (50, 53))	('miR', 'Gene', (50, 53))	('SCC', 'Gene', (59, 62))	('deregulated', 'Var', (38, 49))	('SCC', 'Gene', '6317', (59, 62))	('cSCC', 'Phenotype', 'HP:0006739', (58, 62))
277709	26508273	For example, inhibitory medicines against miR-21s can be used in treatment of cSCC patients in future.	('SCC', 'Gene', (79, 82))	('miR-21s', 'Gene', (42, 49))	('cSCC', 'Phenotype', 'HP:0006739', (78, 82))	('inhibitory', 'Var', (13, 23))	('SCC', 'Gene', '6317', (79, 82))	('patients', 'Species', '9606', (83, 91))
277711	26097874	Epigenetic silencing of S100A2 in bladder and head and neck cancers S100A2, a member of the S100 protein family, is known to be downregulated in a number of human cancers, leading to its designation as a potential tumor suppressor gene.	('S100', 'Gene', (92, 96))	('S100', 'Gene', (68, 72))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('cancers', 'Disease', 'MESH:D009369', (163, 170))	('cancers', 'Disease', 'MESH:D009369', (60, 67))	('S100A2', 'Gene', '6273', (68, 74))	('S100A2', 'Gene', (68, 74))	('downregulated', 'NegReg', (128, 141))	('human', 'Species', '9606', (157, 162))	('head and neck cancers', 'Phenotype', 'HP:0012288', (46, 67))	('S100', 'Gene', '6285', (24, 28))	('S100A2', 'Gene', '6273', (24, 30))	('S100', 'Gene', (24, 28))	('S100A2', 'Gene', (24, 30))	('Epigenetic silencing', 'Var', (0, 20))	('tumor', 'Disease', (214, 219))	('bladder', 'Disease', (34, 41))	('cancers', 'Phenotype', 'HP:0002664', (163, 170))	('cancers', 'Disease', (163, 170))	('cancers', 'Phenotype', 'HP:0002664', (60, 67))	('neck cancers', 'Disease', (55, 67))	('tumor', 'Disease', 'MESH:D009369', (214, 219))	('cancers', 'Disease', (60, 67))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('neck cancers', 'Disease', 'MESH:D006258', (55, 67))	('head and neck cancer', 'Phenotype', 'HP:0012288', (46, 66))	('S100', 'Gene', '6285', (68, 72))	('S100', 'Gene', '6285', (92, 96))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
277715	26097874	We found S100A2 is silenced in association with aberrant promoter-region methylation and its expression is restored with 5-aza-2'-deoxycytidine treatment.	('aberrant', 'Var', (48, 56))	('silenced', 'NegReg', (19, 27))	('expression', 'MPA', (93, 103))	('promoter-region methylation', 'MPA', (57, 84))	('S100A2', 'Gene', '6273', (9, 15))	('S100A2', 'Gene', (9, 15))	("5-aza-2'-deoxycytidine", 'Chemical', 'MESH:D000077209', (121, 143))
277719	26097874	Together, this data shows that methylation-associated inactivation of S100A2 is frequent and may be an important event in the tumorigenesis of head&neck and bladder cancer.	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('bladder cancer', 'Phenotype', 'HP:0009725', (157, 171))	('tumorigenesis of head&neck', 'Phenotype', 'HP:0012288', (126, 152))	('head&', 'Disease', (143, 148))	('methylation-associated', 'Var', (31, 53))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('inactivation', 'NegReg', (54, 66))	('bladder cancer', 'Disease', 'MESH:D001749', (157, 171))	('S100A2', 'Gene', '6273', (70, 76))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('bladder cancer', 'Disease', (157, 171))	('S100A2', 'Gene', (70, 76))	('tumor', 'Disease', (126, 131))
277730	26097874	Among proteins which expression is effected by promoter methylation are S100A4, S100A6, S100A10, S100P which were shown to aberrantly hyper- or hypomethylated in breast cancer, colon, pancreas, prostate, gastric and endometrial cancer, among others.	('endometrial cancer', 'Disease', (216, 234))	('pancreas', 'Disease', 'MESH:D010190', (184, 192))	('hyper-', 'PosReg', (134, 140))	('endometrial cancer', 'Disease', 'MESH:D016889', (216, 234))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('gastric', 'Disease', 'MESH:D013274', (204, 211))	('S100', 'Gene', '6285', (97, 101))	('colon', 'Disease', 'MESH:D015179', (177, 182))	('breast cancer', 'Phenotype', 'HP:0003002', (162, 175))	('S100A6', 'Gene', (80, 86))	('S100', 'Gene', '6285', (88, 92))	('S100A4', 'Gene', '6275', (72, 78))	('S100', 'Gene', (97, 101))	('S100', 'Gene', (88, 92))	('S100P', 'SUBSTITUTION', 'None', (97, 102))	('colon', 'Disease', (177, 182))	('S100A6', 'Gene', '6277', (80, 86))	('S100', 'Gene', '6285', (72, 76))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('S100', 'Gene', '6285', (80, 84))	('breast cancer', 'Disease', 'MESH:D001943', (162, 175))	('breast cancer', 'Disease', (162, 175))	('S100', 'Gene', (80, 84))	('S100', 'Gene', (72, 76))	('pancreas', 'Disease', (184, 192))	('prostate', 'Disease', (194, 202))	('endometrial cancer', 'Phenotype', 'HP:0012114', (216, 234))	('S100P', 'Var', (97, 102))	('gastric', 'Disease', (204, 211))	('hypomethylated', 'Var', (144, 158))	('S100A4', 'Gene', (72, 78))
277731	26097874	S100A2 appears to be gene particularly targeted by hypermetylation.	('hypermetylation', 'Var', (51, 66))	('S100A2', 'Gene', '6273', (0, 6))	('S100A2', 'Gene', (0, 6))
277738	26097874	Furthermore, we demonstrate high frequency of aberrant methylation of S100A2 in primary head&neck and bladder tumor samples.	('head&', 'Disease', (88, 93))	('aberrant methylation', 'Var', (46, 66))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('bladder tumor', 'Disease', 'MESH:D001749', (102, 115))	('S100A2', 'Gene', '6273', (70, 76))	('bladder tumor', 'Phenotype', 'HP:0009725', (102, 115))	('S100A2', 'Gene', (70, 76))	('bladder tumor', 'Disease', (102, 115))
277749	26097874	The QMSP results were consistent with our bisulfite sequencing results; higher methylation values were detected in 8 cell lines (011, 012, 022, 028, 5637, HT1376, J82, and SCaBER), all of which had no S100A2 expression in RT-PCR or Western blotting analysis, whereas the head&neck cancer cell lines 013, 019, Fadu, KYSE30, KYSE410, and KYSE520, which express S100A2, were unmethylated in this promoter region.	('S100A2', 'Gene', '6273', (201, 207))	('S100A2', 'Gene', (201, 207))	('cancer', 'Phenotype', 'HP:0002664', (281, 287))	('methylation', 'MPA', (79, 90))	('neck cancer', 'Disease', 'MESH:D006258', (276, 287))	('neck cancer', 'Disease', (276, 287))	('head&neck cancer', 'Phenotype', 'HP:0012288', (271, 287))	('bisulfite', 'Chemical', 'MESH:C042345', (42, 51))	('S100A2', 'Gene', '6273', (359, 365))	('S100A2', 'Gene', (359, 365))	('express', 'Var', (351, 358))	('HT1376', 'CellLine', 'CVCL:1292', (155, 161))
277754	26097874	In the bladder, 80% (25 of 31) of the primary tumor samples showed methylation while 33% (2 of 6) of the normal bladder tissues were methylated (p=0.017).	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('primary tumor', 'Disease', 'MESH:D009369', (38, 51))	('primary tumor', 'Disease', (38, 51))	('methylation', 'Var', (67, 78))
277759	26097874	Aberrant S100A2 methylation in primary head&neck and bladder tumors had no correlation with patient demographic data, including age and gender, histological subtype, and staging of the tumor (data not shown).	('tumor', 'Disease', (185, 190))	('patient', 'Species', '9606', (92, 99))	('Aberrant', 'Var', (0, 8))	('bladder tumors', 'Disease', 'MESH:D001749', (53, 67))	('bladder tumors', 'Phenotype', 'HP:0009725', (53, 67))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('bladder tumor', 'Phenotype', 'HP:0009725', (53, 66))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('bladder tumors', 'Disease', (53, 67))	('methylation', 'Var', (16, 27))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('S100A2', 'Gene', '6273', (9, 15))	('S100A2', 'Gene', (9, 15))	('tumor', 'Disease', (61, 66))
277762	26097874	In cancer cell lines, DNA promoter hypermethylation correlated with loss of gene expression and could be efficiently restored with the de-methylation agent, 5-aza-2'-deoxycytidine.	('hypermethylation', 'Var', (35, 51))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('gene expression', 'MPA', (76, 91))	('cancer', 'Disease', (3, 9))	('loss', 'NegReg', (68, 72))	("5-aza-2'-deoxycytidine", 'Chemical', 'MESH:D000077209', (157, 179))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
277763	26097874	In addition, our findings of significantly high frequency of S100A2 methylation in primary head&neck and bladder cancer support the fact that epigenetic silencing of this gene may be a tumor-specific event.	('tumor', 'Disease', (185, 190))	('bladder cancer', 'Phenotype', 'HP:0009725', (105, 119))	('S100A2', 'Gene', '6273', (61, 67))	('S100A2', 'Gene', (61, 67))	('methylation', 'Var', (68, 79))	('that epigenetic', 'Var', (137, 152))	('bladder cancer', 'Disease', (105, 119))	('primary head&', 'Disease', (83, 96))	('bladder cancer', 'Disease', 'MESH:D001749', (105, 119))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
277765	26097874	We also found S100A2 methylatation cases in normal head&neck and bladder tissue in 1 of 9 head&neck and 2 of 6 normal bladder tissues.	('S100A2', 'Gene', '6273', (14, 20))	('S100A2', 'Gene', (14, 20))	('methylatation', 'Var', (21, 34))
277769	26097874	The role of S100A2 as a tumor suppressor is supported by study of BRCA1 mutant and basal-like breast cancer cell lines, in which S100A2 exogenous expression resulted in growth inhibition, while siRNA knockdown enhanced proliferation.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('S100A2', 'Gene', '6273', (12, 18))	('S100A2', 'Gene', (12, 18))	('growth inhibition', 'CPA', (169, 186))	('proliferation', 'CPA', (219, 232))	('BRCA1', 'Gene', '672', (66, 71))	('S100A2', 'Gene', '6273', (129, 135))	('tumor', 'Disease', (24, 29))	('enhanced', 'PosReg', (210, 218))	('mutant', 'Var', (72, 78))	('BRCA1', 'Gene', (66, 71))	('S100A2', 'Gene', (129, 135))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('breast cancer', 'Disease', 'MESH:D001943', (94, 107))	('breast cancer', 'Phenotype', 'HP:0003002', (94, 107))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('breast cancer', 'Disease', (94, 107))
277771	26097874	Additionally, aberrant S100A2 expression in cancer has been demonstrated in many studies.	('expression', 'MPA', (30, 40))	('S100A2', 'Gene', '6273', (23, 29))	('S100A2', 'Gene', (23, 29))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('aberrant', 'Var', (14, 22))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
277779	26097874	In support of this, S100A2 transcription repression in breast, lung, and prostate cancer cells and cell lines was shown to be mediated at least in part by site-specific methylation in the promoter region, similarly to a number of known and putative tumor suppressor genes.	('prostate cancer', 'Disease', (73, 88))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('tumor', 'Disease', 'MESH:D009369', (249, 254))	('tumor', 'Phenotype', 'HP:0002664', (249, 254))	('prostate cancer', 'Disease', 'MESH:D011471', (73, 88))	('S100A2', 'Gene', '6273', (20, 26))	('S100A2', 'Gene', (20, 26))	('transcription', 'MPA', (27, 40))	('prostate cancer', 'Phenotype', 'HP:0012125', (73, 88))	('repression', 'NegReg', (41, 51))	('tumor', 'Disease', (249, 254))	('methylation', 'Var', (169, 180))
277780	26097874	This report furthers these previous studies by demonstrating promoter region hypermethylation in head and neck and bladder cancer cell lines and primary cancer tissues.	('bladder cancer', 'Disease', (115, 129))	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('cancer', 'Disease', (153, 159))	('head and', 'Disease', (97, 105))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('cancer', 'Disease', (123, 129))	('bladder cancer', 'Phenotype', 'HP:0009725', (115, 129))	('hypermethylation', 'Var', (77, 93))	('bladder cancer', 'Disease', 'MESH:D001749', (115, 129))
277782	26097874	Interestingly, in prostate cancer the frequency of methylation was significantly higher in grade III tumors as compared to grade I and II tumors.	('II tumors', 'Disease', (135, 144))	('II tumors', 'Disease', 'MESH:D009369', (135, 144))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('II tumors', 'Disease', (98, 107))	('prostate cancer', 'Disease', 'MESH:D011471', (18, 33))	('II tumors', 'Disease', 'MESH:D009369', (98, 107))	('higher', 'PosReg', (81, 87))	('prostate cancer', 'Phenotype', 'HP:0012125', (18, 33))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('methylation', 'Var', (51, 62))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('prostate cancer', 'Disease', (18, 33))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
277795	26097874	Therefore, it seems that loss of S100A2 might be an important event in tumor progression towards more malignant cell phenotype in head and neck cancer, but the decrease in its level may be also attributed to loss of epithelial phenotype.	('decrease', 'NegReg', (160, 168))	('loss', 'Var', (25, 29))	('head and neck cancer', 'Phenotype', 'HP:0012288', (130, 150))	('neck cancer', 'Disease', 'MESH:D006258', (139, 150))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('neck cancer', 'Disease', (139, 150))	('level', 'MPA', (176, 181))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Disease', (71, 76))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('S100A2', 'Gene', '6273', (33, 39))	('S100A2', 'Gene', (33, 39))
277796	26097874	As it was shown by many, tumor derived genetic disturbances can be detected in body fluids and used as cancer markers.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('tumor', 'Disease', (25, 30))	('genetic disturbances', 'Var', (39, 59))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('tumor', 'Disease', 'MESH:D009369', (25, 30))
277798	26097874	Results presented here showed that frequency of hypermethylation of S100A2 is significantly higher in urine samples from bladder tumor cases than in healthy subjects (96% vs 48% respectively).	('higher', 'PosReg', (92, 98))	('bladder tumor', 'Phenotype', 'HP:0009725', (121, 134))	('hypermethylation', 'Var', (48, 64))	('S100A2', 'Gene', '6273', (68, 74))	('S100A2', 'Gene', (68, 74))	('bladder tumor', 'Disease', (121, 134))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('bladder tumor', 'Disease', 'MESH:D001749', (121, 134))
277801	26097874	In a recent study, while noting presence of S100A2 methylation in head and neck squamous cell cancer tissue, very limited hypermethylation of S100A2 was detected in saliva and serum in this malignancy.	('S100A2', 'Gene', (142, 148))	('head and neck squamous cell cancer', 'Phenotype', 'HP:0012288', (66, 100))	('S100A2', 'Gene', '6273', (44, 50))	('S100A2', 'Gene', (44, 50))	('malignancy', 'Disease', 'MESH:D009369', (190, 200))	('S100A2', 'Gene', '6273', (142, 148))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (80, 100))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('neck squamous cell cancer', 'Disease', (75, 100))	('methylation', 'Var', (51, 62))	('neck squamous cell cancer', 'Disease', 'MESH:D002294', (75, 100))	('malignancy', 'Disease', (190, 200))
277803	26097874	In summary, we have demonstrated aberrant S100A2 gene methylation in human head&neck and bladder cancer and most importantly promoter methylation of S100A2 is inversely associated with gene expression.	('head&', 'Disease', (75, 80))	('bladder cancer', 'Phenotype', 'HP:0009725', (89, 103))	('methylation', 'Var', (54, 65))	('human', 'Species', '9606', (69, 74))	('bladder cancer', 'Disease', 'MESH:D001749', (89, 103))	('bladder cancer', 'Disease', (89, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('S100A2', 'Gene', '6273', (42, 48))	('S100A2', 'Gene', (42, 48))	('aberrant', 'Var', (33, 41))	('S100A2', 'Gene', '6273', (149, 155))	('S100A2', 'Gene', (149, 155))
277804	26097874	Because S100A2 gene methylation is significantly more frequent in higher grade tumors, it may have a use as a marker of tumor progression.	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('frequent', 'Reg', (54, 62))	('tumor', 'Disease', (79, 84))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('tumors', 'Disease', (79, 85))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('methylation', 'Var', (20, 31))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('S100A2', 'Gene', '6273', (8, 14))	('tumor', 'Disease', (120, 125))	('S100A2', 'Gene', (8, 14))
277844	33181667	Thus, high expression of TGF-beta2 not only facilitates the prognosis in CRC patients, but also may provide a new target for the treatment of CRC.	('CRC', 'Disease', (73, 76))	('TGF-beta2', 'Gene', '7042', (25, 34))	('patients', 'Species', '9606', (77, 85))	('high', 'Var', (6, 10))	('prognosis', 'CPA', (60, 69))	('facilitates', 'PosReg', (44, 55))	('TGF-beta2', 'Gene', (25, 34))	('CRC', 'Disease', (142, 145))
277847	33181667	Immunotherapy has provided antitumor effects in malignant melanoma and non-small cell lung cancer by targeting cytotoxic T lymphocyte-associated antigen 4 (CTLA4), and inhibitors of programmed death 1 (PD-1) receptor, and programmed death ligand 1 (PD-L1).	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (71, 97))	('PD-1', 'Gene', (202, 206))	('PD-1', 'Gene', '5133', (202, 206))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (75, 97))	('inhibitors', 'Var', (168, 178))	('lung cancer', 'Disease', (86, 97))	('malignant melanoma', 'Phenotype', 'HP:0002861', (48, 66))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('programmed death 1', 'Gene', '5133', (182, 200))	('programmed death ligand 1', 'Gene', (222, 247))	('malignant melanoma', 'Disease', 'MESH:D008545', (48, 66))	('programmed death 1', 'Gene', (182, 200))	('CTLA4', 'Gene', '1493', (156, 161))	('cytotoxic T lymphocyte-associated antigen 4', 'Gene', (111, 154))	('lung cancer', 'Disease', 'MESH:D008175', (86, 97))	('cytotoxic T lymphocyte-associated antigen 4', 'Gene', '1493', (111, 154))	('lung cancer', 'Phenotype', 'HP:0100526', (86, 97))	('CTLA4', 'Gene', (156, 161))	('PD-L1', 'Gene', (249, 254))	('programmed death ligand 1', 'Gene', '29126', (222, 247))	('tumor', 'Disease', (31, 36))	('malignant melanoma', 'Disease', (48, 66))	('PD-L1', 'Gene', '29126', (249, 254))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('melanoma', 'Phenotype', 'HP:0002861', (58, 66))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
277859	33181667	Inhibition of TGF-beta signaling prevents metastasis or further development of certain advanced tumors such as CRC and gastric cancer, while TGF-beta1 can impair immune cell responsiveness and promote angiogenesis.	('promote', 'PosReg', (193, 200))	('angiogenesis', 'CPA', (201, 213))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('TGF-beta', 'Gene', (14, 22))	('tumors', 'Disease', (96, 102))	('gastric cancer', 'Disease', (119, 133))	('TGF-beta', 'Gene', (141, 149))	('impair', 'NegReg', (155, 161))	('gastric cancer', 'Disease', 'MESH:D013274', (119, 133))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('TGF-beta1', 'Gene', (141, 150))	('immune cell responsiveness', 'CPA', (162, 188))	('Inhibition', 'Var', (0, 10))	('metastasis', 'CPA', (42, 52))	('gastric cancer', 'Phenotype', 'HP:0012126', (119, 133))	('prevents', 'NegReg', (33, 41))	('CRC', 'Disease', (111, 114))	('TGF-beta1', 'Gene', '7040', (141, 150))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('TGF-beta', 'Gene', '7039', (14, 22))	('TGF-beta', 'Gene', '7039', (141, 149))	('further development', 'CPA', (56, 75))
277894	33181667	This analysis documented that upregulation of TGF- beta2 was strongly related to the poor prognosis of patients with gastric cancer (OS HR = 1.88 (95%CI: 1.57-2.24), P < .0001; PPS HR = 2.51 (95%CI: 2.01-3.15), P < .0001; 209908_s_at), breast cancer (OS HR = 0.77 (95%CI: 0.61-0.99), P = .039; no-distance survival HR = 0.78 (95%CI: 0.62-0.99), P = .043; 209908_s_at) (2K-L), lung cancer (OS HR = 1.23 (1.08-1.4), P = .0013, 220407_s_at; PPS HR = 1.34 (1.04-1.73), P = .025, 220406_at), and Ovarian cancer (OS HR = 1.18 (1.04-1.34), P = .013, 209909_s_at; progression-free survival, progression-free survival, HR = 1.22 (1.07-1.39), P = .0036, 220407_s_at;) (Fig.	('lung cancer', 'Disease', 'MESH:D008175', (376, 387))	('TGF- beta2', 'Gene', '7042', (46, 56))	('patients', 'Species', '9606', (103, 111))	('gastric cancer', 'Disease', (117, 131))	('lung cancer', 'Phenotype', 'HP:0100526', (376, 387))	('220407_s_at', 'Var', (644, 655))	('breast cancer', 'Phenotype', 'HP:0003002', (236, 249))	('209909_s_at', 'Var', (543, 554))	('cancer', 'Disease', 'MESH:D009369', (243, 249))	('Ovarian cancer', 'Phenotype', 'HP:0100615', (491, 505))	('TGF- beta2', 'Gene', (46, 56))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', (381, 387))	('gastric cancer', 'Disease', 'MESH:D013274', (117, 131))	('breast cancer', 'Disease', 'MESH:D001943', (236, 249))	('cancer', 'Disease', (499, 505))	('breast cancer', 'Disease', (236, 249))	('cancer', 'Phenotype', 'HP:0002664', (381, 387))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('cancer', 'Phenotype', 'HP:0002664', (499, 505))	('upregulation', 'PosReg', (30, 42))	('lung cancer', 'Disease', (376, 387))	('gastric cancer', 'Phenotype', 'HP:0012126', (117, 131))	('cancer', 'Disease', (243, 249))	('cancer', 'Disease', 'MESH:D009369', (381, 387))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('cancer', 'Phenotype', 'HP:0002664', (243, 249))	('cancer', 'Disease', 'MESH:D009369', (499, 505))
277895	33181667	Conversely, the expression of TGF-beta2 appeared as a protective factor in the prostate, breast cancer, colorectal, blood cancer, brain, gastric, lung, and ovarian cancers.	('ovarian cancers', 'Phenotype', 'HP:0100615', (156, 171))	('breast cancer', 'Disease', 'MESH:D001943', (89, 102))	('breast cancer', 'Disease', (89, 102))	('TGF-beta2', 'Gene', (30, 39))	('prostate', 'Disease', (79, 87))	('gastric', 'Disease', (137, 144))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('TGF-beta2', 'Gene', '7042', (30, 39))	('blood cancer', 'Phenotype', 'HP:0001909', (116, 128))	('ovarian cancers', 'Disease', (156, 171))	('ovarian cancers', 'Disease', 'MESH:D010051', (156, 171))	('cancers', 'Phenotype', 'HP:0002664', (164, 171))	('expression', 'Var', (16, 26))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('lung', 'Disease', (146, 150))	('brain', 'Disease', (130, 135))	('colorectal, blood cancer', 'Disease', 'MESH:D015179', (104, 128))	('breast cancer', 'Phenotype', 'HP:0003002', (89, 102))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))
277913	33181667	Data on the expression of markers of DCs (CD1C, NRP1, and ITGAX) indicate that high TGF-beta2 expression increases DC infiltration in COAD.	('CD1C', 'Gene', '911', (42, 46))	('DC infiltration', 'MPA', (115, 130))	('TGF-beta2', 'Gene', '7042', (84, 93))	('TGF-beta2', 'Gene', (84, 93))	('ITGAX', 'Gene', (58, 63))	('NRP1', 'Gene', '8829', (48, 52))	('high', 'Var', (79, 83))	('NRP1', 'Gene', (48, 52))	('ITGAX', 'Gene', '3687', (58, 63))	('CD1C', 'Gene', (42, 46))	('increases', 'PosReg', (105, 114))
277918	33181667	The present work demonstrated that TGF-beta2 expression correlates with the prognosis of patients with multiple types of cancer, and particularly strong correlation is present between high TGF-beta2 expression and the prognosis of CRC patients.	('TGF-beta2', 'Gene', '7042', (35, 44))	('TGF-beta2', 'Gene', (35, 44))	('expression', 'MPA', (199, 209))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('patients', 'Species', '9606', (235, 243))	('CRC', 'Disease', (231, 234))	('patients', 'Species', '9606', (89, 97))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('TGF-beta2', 'Gene', '7042', (189, 198))	('cancer', 'Disease', (121, 127))	('TGF-beta2', 'Gene', (189, 198))	('high', 'Var', (184, 188))
277926	33181667	Variations in TGF-beta2 expression in a range of different cancers may be related to discrepancies in data collection methods between individual studies or differences in underlying biological mechanisms.	('related', 'Reg', (74, 81))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('Variations', 'Var', (0, 10))	('cancers', 'Disease', 'MESH:D009369', (59, 66))	('cancers', 'Phenotype', 'HP:0002664', (59, 66))	('TGF-beta2', 'Gene', (14, 23))	('cancers', 'Disease', (59, 66))	('TGF-beta2', 'Gene', '7042', (14, 23))
277927	33181667	In the database used in the current work, a correlation between high TGF-beta2 expression and poor prognosis of CRC was observed.	('high', 'Var', (64, 68))	('expression', 'MPA', (79, 89))	('CRC', 'Disease', (112, 115))	('TGF-beta2', 'Gene', '7042', (69, 78))	('TGF-beta2', 'Gene', (69, 78))
277952	31579414	Since the discovery of epidermal growth factor receptor (EGFR)-activating mutations and mutations of anaplastic lymphoma kinase (ALK), the potential avenues for novel or repurposed therapeutics have increased.	('epidermal growth factor receptor', 'Gene', (23, 55))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (101, 120))	('-activating', 'PosReg', (62, 73))	('ALK', 'Gene', (129, 132))	('epidermal growth factor receptor', 'Gene', '1956', (23, 55))	('mutations', 'Var', (88, 97))	('mutations', 'Var', (74, 83))	('lymphoma', 'Phenotype', 'HP:0002665', (112, 120))	('anaplastic lymphoma kinase', 'Gene', '238', (101, 127))	('EGFR', 'Gene', '1956', (57, 61))	('ALK', 'Gene', '238', (129, 132))	('EGFR', 'Gene', (57, 61))	('anaplastic lymphoma kinase', 'Gene', (101, 127))
277955	31579414	EGFR mutations and ALK fusion genes are two well-studied and common oncogenic drivers in patients with lung cancer, and small molecule inhibitors of these target genes have been utilized in the clinic to selectively inhibit the growth of gene-positive non-small cell lung cancer.	('lung cancer', 'Phenotype', 'HP:0100526', (267, 278))	('cancer', 'Phenotype', 'HP:0002664', (272, 278))	('lung cancer', 'Disease', (103, 114))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (252, 278))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (256, 278))	('ALK', 'Gene', '238', (19, 22))	('ALK', 'Gene', (19, 22))	('EGFR', 'Gene', (0, 4))	('lung cancer', 'Disease', 'MESH:D008175', (103, 114))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (252, 278))	('mutations', 'Var', (5, 14))	('lung cancer', 'Phenotype', 'HP:0100526', (103, 114))	('non-small cell lung cancer', 'Disease', (252, 278))	('lung cancer', 'Disease', 'MESH:D008175', (267, 278))	('patients', 'Species', '9606', (89, 97))	('inhibit', 'NegReg', (216, 223))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('EGFR', 'Gene', '1956', (0, 4))	('growth', 'MPA', (228, 234))
277956	31579414	Furthermore, expression of the mutant genes in cancer may additionally serve as identifying markers for lung cancer and cancer typing.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('lung cancer', 'Disease', 'MESH:D008175', (104, 115))	('mutant', 'Var', (31, 37))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('expression', 'MPA', (13, 23))	('cancer', 'Disease', (47, 53))	('cancer', 'Disease', (109, 115))	('cancer', 'Disease', (120, 126))	('lung cancer', 'Disease', (104, 115))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('lung cancer', 'Phenotype', 'HP:0100526', (104, 115))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))
277966	31579414	In addition, a previous study suggested that chromosomal rearrangements of the RSPO2 and RSPO3 genes may initiate hyperplasia and tumor development in vivo.	('RSPO2', 'Gene', (79, 84))	('chromosomal rearrangements', 'Var', (45, 71))	('hyperplasia', 'Disease', (114, 125))	('initiate', 'PosReg', (105, 113))	('RSPO3', 'Gene', '84870', (89, 94))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('hyperplasia', 'Disease', 'MESH:D006965', (114, 125))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumor', 'Disease', (130, 135))	('RSPO3', 'Gene', (89, 94))
277996	31579414	High mRNA expression levels of RSPO2 and RSPO3 were associated with improved OS in all patients with lung cancer [RSPO2, hazard ratio (HR)=0.72, P=0.00015; RSPO3, HR=0.79, P=0.0053; Fig.	('RSPO3', 'Gene', '84870', (41, 46))	('RSPO3', 'Gene', (41, 46))	('lung cancer', 'Disease', 'MESH:D008175', (101, 112))	('mRNA expression levels', 'MPA', (5, 27))	('RSPO2', 'Var', (31, 36))	('RSPO3', 'Gene', '84870', (156, 161))	('RSPO3', 'Gene', (156, 161))	('lung cancer', 'Phenotype', 'HP:0100526', (101, 112))	('patients', 'Species', '9606', (87, 95))	('lung cancer', 'Disease', (101, 112))	('improved', 'PosReg', (68, 76))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
278005	31579414	Recently, research showed that the RSPO family fusion gene was found in superficially serrated adenoma, which is a recently proposed subtype of colorectal serrated lesion, suggesting that the deletion of RSPO protein family is closely related to the development of colorectal cancer.	('colorectal cancer', 'Disease', 'MESH:D015179', (265, 282))	('RSPO', 'Gene', (35, 39))	('related', 'Reg', (235, 242))	('adenoma', 'Disease', (95, 102))	('RSPO', 'Gene', (204, 208))	('colorectal cancer', 'Phenotype', 'HP:0003003', (265, 282))	('colorectal serrated lesion', 'Disease', 'MESH:D015179', (144, 170))	('colorectal serrated lesion', 'Disease', (144, 170))	('colorectal serrated', 'Phenotype', 'HP:0032222', (144, 163))	('deletion', 'Var', (192, 200))	('colorectal cancer', 'Disease', (265, 282))	('RSPO', 'Gene', '284654', (35, 39))	('cancer', 'Phenotype', 'HP:0002664', (276, 282))	('adenoma', 'Disease', 'MESH:D000236', (95, 102))	('serrated adenoma', 'Phenotype', 'HP:0032222', (86, 102))	('RSPO', 'Gene', '284654', (204, 208))
278016	31579414	Survival analysis of RSPO1 in the present study demonstrated similar results, high expression of RSPO1 was associated with improved OS in patients with lung cancer, particularly in lung adenocarcinoma, suggesting RSPO1 tumor-suppressive role.	('RSPO1', 'Gene', (21, 26))	('tumor', 'Disease', (219, 224))	('RSPO1', 'Gene', '284654', (21, 26))	('tumor', 'Disease', 'MESH:D009369', (219, 224))	('lung cancer', 'Disease', 'MESH:D008175', (152, 163))	('carcinoma', 'Phenotype', 'HP:0030731', (191, 200))	('RSPO1', 'Gene', (97, 102))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (181, 200))	('RSPO1', 'Gene', '284654', (97, 102))	('lung cancer', 'Phenotype', 'HP:0100526', (152, 163))	('patients', 'Species', '9606', (138, 146))	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('improved', 'PosReg', (123, 131))	('RSPO1', 'Gene', (213, 218))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('high expression', 'Var', (78, 93))	('RSPO1', 'Gene', '284654', (213, 218))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (181, 200))	('lung adenocarcinoma', 'Disease', (181, 200))	('lung cancer', 'Disease', (152, 163))
278018	31579414	A previous study has also indicated that induced mucosal RSPO2 expression in susceptible mice lead to the generation of a poorly differentiated epithelium and to fatal colitis, and implicated RSPO2-mediated Wnt signaling activation in intestinal morphogenesis, proliferation and carcinogenesis.	('colitis', 'Disease', (168, 175))	('RSPO2', 'Gene', (57, 62))	('mice', 'Species', '10090', (89, 93))	('colitis', 'Phenotype', 'HP:0002583', (168, 175))	('poorly differentiated', 'CPA', (122, 143))	('carcinogenesis', 'Disease', 'MESH:D063646', (279, 293))	('lead to', 'Reg', (94, 101))	('colitis', 'Disease', 'MESH:D003092', (168, 175))	('carcinogenesis', 'Disease', (279, 293))	('expression', 'Var', (63, 73))
278021	31579414	To the best of our knowledge, the present study is the first to demonstrate that high RSPO2 expression predicted better survival in patients with lung cancer, particularly in lung adenocarcinoma, although there was no significant effect on survival in patients with squamous cell carcinoma.	('lung cancer', 'Disease', 'MESH:D008175', (146, 157))	('high', 'Var', (81, 85))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (175, 194))	('squamous cell carcinoma', 'Disease', (266, 289))	('lung cancer', 'Phenotype', 'HP:0100526', (146, 157))	('patients', 'Species', '9606', (132, 140))	('patients', 'Species', '9606', (252, 260))	('survival', 'MPA', (120, 128))	('better', 'PosReg', (113, 119))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (266, 289))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (175, 194))	('lung cancer', 'Disease', (146, 157))	('lung adenocarcinoma', 'Disease', (175, 194))	('expression', 'MPA', (92, 102))	('carcinoma', 'Phenotype', 'HP:0030731', (280, 289))	('RSPO2', 'Gene', (86, 91))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (266, 289))	('carcinoma', 'Phenotype', 'HP:0030731', (185, 194))
278023	31579414	Vidal et al suggested that deletion of RSPO3 resulted in a loss of Sonic-hedgehog signaling and therefore impaired organ growth.	('organ growth', 'CPA', (115, 127))	('deletion', 'Var', (27, 35))	('impaired', 'NegReg', (106, 114))	('RSPO3', 'Gene', '84870', (39, 44))	('RSPO3', 'Gene', (39, 44))	('loss', 'NegReg', (59, 63))	('Sonic-hedgehog signaling', 'Pathway', (67, 91))
278026	31579414	Furthermore, high levels of RSPO3 predicted improved OS in patients with lung cancer, particularly in lung adenocarcinoma.	('lung cancer', 'Disease', 'MESH:D008175', (73, 84))	('RSPO3', 'Gene', '84870', (28, 33))	('RSPO3', 'Gene', (28, 33))	('high', 'Var', (13, 17))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (102, 121))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (102, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('patients', 'Species', '9606', (59, 67))	('lung cancer', 'Disease', (73, 84))	('lung cancer', 'Phenotype', 'HP:0100526', (73, 84))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('improved', 'PosReg', (44, 52))	('lung adenocarcinoma', 'Disease', (102, 121))
278087	30147334	Meanwhile, Shu et al have found two mutations, ie, epidermal growth factor receptor (EGFR) mutations and six harboring kirsten rat sarcoma 2 viral oncogene homolog (KRAS) mutations, respectively, in 19 ASC specimens, with mutations present in both components.	('EGFR', 'Gene', (85, 89))	('sarcoma', 'Disease', 'MESH:D012509', (131, 138))	('epidermal growth factor receptor', 'Gene', '24329', (51, 83))	('epidermal growth factor receptor', 'Gene', (51, 83))	('sarcoma', 'Disease', (131, 138))	('men', 'Species', '9606', (211, 214))	('mutations', 'Var', (91, 100))	('rat', 'Species', '10116', (127, 130))	('sarcoma', 'Phenotype', 'HP:0100242', (131, 138))
278093	30147334	The results revealed a higher prevalence of EGFR and PI3K pathway-concerned mutations (31.25% and 25%, respectively) in contrast with classic Caucasian ADC and SCC, and the same EGFR mutations were contained in both components, while no KRAS mutations were observed.	('PI3K', 'Gene', (53, 57))	('mutations', 'Var', (76, 85))	('SCC', 'Gene', (160, 163))	('EGFR', 'Gene', (44, 48))	('SCC', 'Phenotype', 'HP:0002860', (160, 163))	('SCC', 'Gene', '6317', (160, 163))
278094	30147334	Moreover, this study showed centralization of drive mutations in the trunk and a high incidence of branch mutations in ASC, suggesting that ASC arose from a common precursor cell, which was in line with findings obtained in other studies, while the separation of ADC and SCC components may have taken place very early during the proceeding of ASC.	('mutations', 'Var', (52, 61))	('SCC', 'Phenotype', 'HP:0002860', (271, 274))	('SCC', 'Gene', '6317', (271, 274))	('rat', 'Species', '10116', (253, 256))	('mutations', 'Var', (106, 115))	('ASC', 'Gene', (119, 122))	('SCC', 'Gene', (271, 274))
278133	30147334	Wang et al have determined mutational status of EGFR in postoperative specimens of ASC using PCR.	('men', 'Species', '9606', (75, 78))	('rat', 'Species', '10116', (63, 66))	('EGFR', 'Gene', (48, 52))	('mutational', 'Var', (27, 37))
278134	30147334	Of 76 ASCs, the frequency of EGFR mutations is 31.6% (24/76), which is lower than that in ADC but higher than that in SCC, and it is consistent with some other studies.	('SCC', 'Gene', (118, 121))	('EGFR', 'Gene', (29, 33))	('SCC', 'Phenotype', 'HP:0002860', (118, 121))	('SCC', 'Gene', '6317', (118, 121))	('mutations', 'Var', (34, 43))
278135	30147334	A significantly higher rate of EGFR mutations occurred in nonsmokers (51.5% vs 16.3%; P=0.001) and in tumors lager than 3 cm (41.3% vs 16.7%; P=0.024).	('tumors', 'Disease', 'MESH:D009369', (102, 108))	('tumors', 'Disease', (102, 108))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('rat', 'Species', '10116', (23, 26))	('EGFR', 'Gene', (31, 35))	('mutations', 'Var', (36, 45))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))
278145	30147334	Detection for EGFR mutation in advanced patients with ASC should be a routine testing, and EGFR-TKI therapy for EGFR-positive ASC patients is recommended.	('mutation', 'Var', (19, 27))	('EGFR', 'Gene', (14, 18))	('patients', 'Species', '9606', (40, 48))	('patients', 'Species', '9606', (130, 138))	('men', 'Species', '9606', (147, 150))
278146	30147334	NSCLC patients with anaplastic lymphoma kinase (ALK) rearrangements are sensitive to ALK inhibitors.	('men', 'Species', '9606', (62, 65))	('NSCLC', 'Disease', 'MESH:D002289', (0, 5))	('ALK', 'Gene', '238', (48, 51))	('anaplastic lymphoma kinase', 'Gene', '238', (20, 46))	('ALK', 'Gene', (85, 88))	('NSCLC', 'Phenotype', 'HP:0030358', (0, 5))	('anaplastic lymphoma kinase', 'Gene', (20, 46))	('ALK', 'Gene', (48, 51))	('patients', 'Species', '9606', (6, 14))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (20, 39))	('ALK', 'Gene', '238', (85, 88))	('lymphoma', 'Phenotype', 'HP:0002665', (31, 39))	('rearrangements', 'Var', (53, 67))	('NSCLC', 'Disease', (0, 5))
278150	30147334	Mesenchymal-epithelial transition factor (MET) is a potential therapeutic target in NSCLC, while the significant efficacy of crizotinib for NSCLC patients with ROS proto-oncogene 1 (ROS1) rearrangements has been confirmed.	('rearrangements', 'Var', (188, 202))	('NSCLC', 'Phenotype', 'HP:0030358', (84, 89))	('NSCLC', 'Disease', 'MESH:D002289', (140, 145))	('ROS proto-oncogene 1', 'Gene', '6098', (160, 180))	('ROS proto-oncogene 1', 'Gene', (160, 180))	('NSCLC', 'Disease', (84, 89))	('ROS1', 'Gene', (182, 186))	('men', 'Species', '9606', (197, 200))	('NSCLC', 'Phenotype', 'HP:0030358', (140, 145))	('ROS1', 'Gene', '6098', (182, 186))	('NSCLC', 'Disease', 'MESH:D002289', (84, 89))	('crizotinib', 'Chemical', 'MESH:D000077547', (125, 135))	('patients', 'Species', '9606', (146, 154))	('NSCLC', 'Disease', (140, 145))
278152	30147334	Further studies are needed to determine whether ALK inhibitors may be effective for MET-mutant or ROS1 rearrangements in patients with ASC.	('ROS1', 'Gene', (98, 102))	('rearrangements', 'Var', (103, 117))	('ROS1', 'Gene', '6098', (98, 102))	('ALK', 'Gene', '238', (48, 51))	('ALK', 'Gene', (48, 51))	('men', 'Species', '9606', (112, 115))	('MET-mutant', 'Var', (84, 94))	('patients', 'Species', '9606', (121, 129))	('ASC', 'Disease', (135, 138))
278162	30147334	Detection of EGFR mutation in advanced patients with ASC should be a routine testing, and EGFR-TKIs can be an effective treatment for EGFR-positive patients with ASC.	('patients', 'Species', '9606', (148, 156))	('patients', 'Species', '9606', (39, 47))	('men', 'Species', '9606', (125, 128))	('mutation', 'Var', (18, 26))	('EGFR', 'Gene', (13, 17))
278185	28674712	Silencing SOX2 can induce the transcription of p21Cip1 and p27Kip1, leading to cell cycle arrest and cell growth inhibition.	('SOX2', 'Gene', (10, 14))	('induce', 'PosReg', (19, 25))	('transcription', 'MPA', (30, 43))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (79, 96))	('cell cycle arrest', 'CPA', (79, 96))	('p21Cip1', 'Gene', '1026', (47, 54))	('p27Kip1', 'Gene', '1027', (59, 66))	('p27Kip1', 'Gene', (59, 66))	('cell growth inhibition', 'CPA', (101, 123))	('p21Cip1', 'Gene', (47, 54))	('Silencing', 'Var', (0, 9))
278186	28674712	Silencing the expression of SOX2 in lung squamous cell carcinoma results in cell suppression by up regulating the tumor suppressor BMP4.	('lung squamous cell carcinoma', 'Disease', (36, 64))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('SOX2', 'Gene', (28, 32))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (55, 64))	('BMP4', 'Gene', '652', (131, 135))	('tumor', 'Disease', (114, 119))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (36, 64))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (36, 64))	('cell suppression', 'CPA', (76, 92))	('Silencing', 'Var', (0, 9))	('BMP4', 'Gene', (131, 135))	('up regulating', 'PosReg', (96, 109))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (41, 64))
278238	28674712	Schaefer et al found that Ser/Thr-kinase AKT is an upstream regulator of SOX2 protein, and ectopic expression of SOX2 enhances the ability of clones of tumor cells and restores the cellular tumorigenicity of cells that were inhibited by AKT inhibitors in vivo.	('enhances', 'PosReg', (118, 126))	('AKT', 'Gene', (237, 240))	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('ectopic expression', 'Var', (91, 109))	('tumor', 'Disease', (152, 157))	('tumor', 'Disease', (190, 195))	('AKT', 'Gene', '207', (41, 44))	('restores', 'PosReg', (168, 176))	('SOX2', 'Gene', (113, 117))	('AKT', 'Gene', '207', (237, 240))	('ability', 'CPA', (131, 138))	('AKT', 'Gene', (41, 44))
278239	28674712	AKT inhibitors can effectively inhibit the growth of tumor stem cells with SOX2 expression on which conventional chemotherapeutic agents usually act.	('AKT', 'Gene', (0, 3))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('AKT', 'Gene', '207', (0, 3))	('SOX2', 'Gene', (75, 79))	('tumor', 'Disease', (53, 58))	('inhibit', 'NegReg', (31, 38))	('expression', 'Var', (80, 90))
278252	28674712	The tumor stem/progenitor cell population decreases and sensitivity to tamoxifen is restored if the expression of SOX2 gene is knocked out.	('tumor', 'Disease', (4, 9))	('tamoxifen', 'Chemical', 'MESH:D013629', (71, 80))	('decreases', 'NegReg', (42, 51))	('expression', 'MPA', (100, 110))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('SOX2 gene', 'Gene', (114, 123))	('knocked out', 'Var', (127, 138))	('sensitivity', 'MPA', (56, 67))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))
278287	26684028	We observed that the Bcl-xL protein level was higher in CARgpc3 T cells than in control T cells (including MOCK- or 2D3-28BBZ-transduced T cells) in the presence of LSCC cells with GPC3 over-expression (Supplementary Figure 2).	('higher', 'PosReg', (46, 52))	('Bcl-xL', 'Gene', '598', (21, 27))	('GPC3', 'Gene', (181, 185))	('Bcl-xL', 'Gene', (21, 27))	('LSCC', 'Phenotype', 'HP:0030359', (165, 169))	('over-expression', 'PosReg', (186, 201))	('CARgpc3', 'Var', (56, 63))
278291	26684028	As shown in Figure 3A-3B, when they were co-cultured with NCI-H520-GPC3 or SK-MES-1-GPC3 cells but not with NCI-H520 or SK-MES-1 cells, CARgpc3 T cells released a significantly increased amount of IFN-gamma, IL-2, TNF-alpha, IL-4 and IL-10, indicating the T cell activation.	('IL-4', 'Gene', '3565', (225, 229))	('IL-4', 'Gene', (225, 229))	('IL-10', 'Gene', '3586', (234, 239))	('SK-MES-1-GPC3', 'CellLine', 'CVCL:0630', (75, 88))	('TNF-alpha', 'Gene', '7124', (214, 223))	('SK-MES-1', 'CellLine', 'CVCL:0630', (75, 83))	('increased', 'PosReg', (177, 186))	('SK-MES-1', 'CellLine', 'CVCL:0630', (120, 128))	('IFN-gamma', 'Gene', '3458', (197, 206))	('IFN-gamma', 'Gene', (197, 206))	('IL-10', 'Gene', (234, 239))	('released', 'MPA', (152, 160))	('IL-2', 'Gene', '3558', (208, 212))	('TNF-alpha', 'Gene', (214, 223))	('IL-2', 'Gene', (208, 212))	('CARgpc3', 'Var', (136, 143))
278298	26684028	Both NCI-H520-GPC3 or SK-MES-1-GPC3 tumors in mice treated with CARgpc3 T cells grew significantly more slowly than those in mice treated with Mock, 2D3-28BBZ CAR T cells or saline alone (p < 0.001) (Figure 5A, 5C).	('CARgpc3', 'Var', (64, 71))	('saline', 'Chemical', 'MESH:D012965', (174, 180))	('NCI-H520-GPC3 or SK-MES-1-GPC3 tumors', 'Disease', (5, 42))	('grew', 'CPA', (80, 84))	('mice', 'Species', '10090', (125, 129))	('NCI-H520-GPC3 or SK-MES-1-GPC3 tumors', 'Disease', 'MESH:C536133', (5, 42))	('mice', 'Species', '10090', (46, 50))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('slowly', 'NegReg', (104, 110))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))
278301	26684028	The IHC results showed that there were very few GPC3-positive tumor cells in the group of CARgpc3 T cells compared with the control groups (treatment with Mock, 2D3-28BBZ CAR T cells or saline alone).	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', (62, 67))	('saline', 'Chemical', 'MESH:D012965', (186, 192))	('few', 'NegReg', (44, 47))	('GPC3-positive', 'Protein', (48, 61))	('CARgpc3 T cells', 'Var', (90, 105))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
278302	26684028	Only a very weak band at the expected molecular mass (66 kDa) of GPC3 protein was detected in tumors from of anti-GPC3 CAR-T cells group while strong bind of GPC3 protein was observed in tumors from the other control groups (Figure 7B, 7D).	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('anti-GPC3', 'Var', (109, 118))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('CAR-T', 'Gene', (119, 124))	('tumors', 'Disease', (94, 100))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('tumors', 'Disease', (187, 193))	('GPC3', 'Gene', (65, 69))	('CAR-T', 'Gene', '9607', (119, 124))	('tumors', 'Disease', 'MESH:D009369', (187, 193))	('tumors', 'Phenotype', 'HP:0002664', (187, 193))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))
278306	26684028	The results indicated that the numbers of CAR T cells were significantly higher in mice treated with CARgpc3 T cells compared with mice treated with other T cells (p < 0.01) (Figure 6A-6B).	('CARgpc3 T cells', 'Var', (101, 116))	('mice', 'Species', '10090', (83, 87))	('mice', 'Species', '10090', (131, 135))	('CAR T cells', 'CPA', (42, 53))	('higher', 'PosReg', (73, 79))
278315	26684028	A genomic analysis of squamous cell carcinomas found that many samples exhibited inactivating mutations in the human leukocyte antigen-A class I major histocompatibility gene.	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (22, 46))	('human', 'Species', '9606', (111, 116))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (22, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (36, 45))	('carcinomas', 'Phenotype', 'HP:0030731', (36, 46))	('inactivating mutations', 'Var', (81, 103))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (22, 46))	('squamous cell carcinomas', 'Disease', (22, 46))
278324	26684028	Additionally, a much higher number of CAR-GPC3 T cells might persist in the peripheral blood and infiltrate the tumor tissues compared with other control T cells, which suggests that GPC3-targeting is important for the activation and expansion of CAR T cells.	('tumor', 'Disease', (112, 117))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('CAR-GPC3', 'Var', (38, 46))
278376	26581505	Knocking down of Fra-2 responsible for aggressive tongue tumorigenesis led to significant reduction in c-Fos, c-Jun, MMP-9 and HPVE6/E7 expression but Fra-1 and p53 were upregulated.	('tongue tumor', 'Disease', 'MESH:D014062', (50, 62))	('MMP-9', 'Gene', '4318', (117, 122))	('MMP-9', 'Gene', (117, 122))	('p53', 'Gene', (161, 164))	('expression', 'MPA', (136, 146))	('tongue tumor', 'Disease', (50, 62))	('Fra-2', 'Gene', (17, 22))	('Fra-2', 'Gene', '2355', (17, 22))	('c-Jun', 'Gene', '3725', (110, 115))	('reduction', 'NegReg', (90, 99))	('c-Fos', 'MPA', (103, 108))	('Fra-1', 'Gene', '8061', (151, 156))	('c-Jun', 'Gene', (110, 115))	('Fra-1', 'Gene', (151, 156))	('HPVE6/E7', 'Gene', (127, 135))	('HPV', 'Species', '10566', (127, 130))	('Knocking down', 'Var', (0, 13))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tongue tumor', 'Phenotype', 'HP:0100648', (50, 62))	('p53', 'Gene', '7157', (161, 164))
278409	26581505	Both tongue cancer cell lines also showed similar functional AP-1 complex formation mainly by c-Fos and Fra-2 along with JunB and JunD though they differ in their extent of involvement (Fig.	('tongue cancer', 'Disease', 'MESH:D014062', (5, 18))	('AP-1', 'Gene', (61, 65))	('Fra-2', 'Gene', '2355', (104, 109))	('JunD', 'Gene', (130, 134))	('c-Fos', 'Var', (94, 99))	('JunD', 'Gene', '3727', (130, 134))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('tongue cancer', 'Disease', (5, 18))	('Fra-2', 'Gene', (104, 109))	('AP-1', 'Gene', '2353', (61, 65))
278434	26581505	4a,b, transfection of these cells by increasing concentration (20 nM to 80 nM) of Fra-2 siRNA resulted in a dose-dependent decline in the expression of Fra-2, while, it remained unchanged in scrambled siRNA treated cells even at the highest concentration (80 nM) used.	('Fra-2', 'Gene', '2355', (152, 157))	('Fra-2', 'Gene', (82, 87))	('transfection', 'Var', (6, 18))	('Fra-2', 'Gene', '2355', (82, 87))	('expression', 'MPA', (138, 148))	('Fra-2', 'Gene', (152, 157))	('rat', 'Species', '10116', (55, 58))	('decline', 'NegReg', (123, 130))	('rat', 'Species', '10116', (248, 251))
278438	26581505	Most interestingly, silencing of Fra-2 led to a significant (~95%) downregulation of viral oncogenes E6/E7 expression at 80 nM concentration and a dose-dependent accumulation of p53 level in HPV+ve cells (Fig.	('Fra-2', 'Gene', (33, 38))	('downregulation', 'NegReg', (67, 81))	('Fra-2', 'Gene', '2355', (33, 38))	('expression', 'MPA', (107, 117))	('HPV', 'Species', '10566', (191, 194))	('accumulation', 'PosReg', (162, 174))	('rat', 'Species', '10116', (134, 137))	('p53', 'Gene', (178, 181))	('silencing', 'Var', (20, 29))	('p53', 'Gene', '7157', (178, 181))	('E6/E7', 'Gene', (101, 106))
278445	26581505	The cancer cells transfected with Fra-2-siRNA (20-80 nM) at 48 hr or prior to harvesting, resulted in only about 30% reduction in cell proliferation (Supplementary Fig.	('reduction', 'NegReg', (117, 126))	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('rat', 'Species', '10116', (142, 145))	('20-80 nM', 'Var', (47, 55))	('Fra-2', 'Gene', (34, 39))	('cancer', 'Disease', 'MESH:D009369', (4, 10))	('Fra-2', 'Gene', '2355', (34, 39))	('cancer', 'Disease', (4, 10))	('cell proliferation', 'CPA', (130, 148))
278449	26581505	Interestingly, Fra-2 silencing was more effective in HPV+ve cells to prevent cell invasion through the Matrigel as compared with HPV-ve cells.	('cell invasion through the Matrigel', 'CPA', (77, 111))	('Fra-2', 'Gene', (15, 20))	('Fra-2', 'Gene', '2355', (15, 20))	('prevent', 'NegReg', (69, 76))	('HPV', 'Species', '10566', (53, 56))	('HPV', 'Species', '10566', (129, 132))	('silencing', 'Var', (21, 30))
278453	26581505	Fra-2 knockdown in AW13516 (HPV-ve) cells for 18 hours showed an ~63% migration rate while untreated or scrambled treated control cells showed ~100% migration (Fig.	('migration rate', 'CPA', (70, 84))	('HPV', 'Species', '10566', (28, 31))	('rat', 'Species', '10116', (152, 155))	('rat', 'Species', '10116', (80, 83))	('Fra-2', 'Gene', (0, 5))	('Fra-2', 'Gene', '2355', (0, 5))	('knockdown', 'Var', (6, 15))	('rat', 'Species', '10116', (73, 76))
278455	26581505	These results together correlate well with the significant decrease in proinvasive factor MMP-9 expression and the reduction in cell invasion and migration after knocking down Fra-2 in both HPV+ve and HPV-ve tongue cancer cells.	('rat', 'Species', '10116', (149, 152))	('reduction', 'NegReg', (115, 124))	('MMP-9', 'Gene', '4318', (90, 95))	('HPV-ve tongue cancer', 'Disease', (201, 221))	('HPV', 'Species', '10566', (201, 204))	('knocking down', 'Var', (162, 175))	('expression', 'MPA', (96, 106))	('MMP-9', 'Gene', (90, 95))	('HPV', 'Species', '10566', (190, 193))	('decrease', 'NegReg', (59, 67))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('HPV-ve tongue cancer', 'Disease', 'MESH:D014062', (201, 221))	('Fra-2', 'Gene', '2355', (176, 181))	('Fra-2', 'Gene', (176, 181))
278474	26581505	It suggests that female patients who are generally non-smokers or mild smokers in India and are more likely to contract HPV infection leading to well differentiated tumors which would show better prognosis while males, in contrast, are often heavy smokers and are likely to have HPV-ve poorly differentiated tumors with worst prognosis.	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('HPV', 'Species', '10566', (279, 282))	('tumors', 'Disease', 'MESH:D009369', (308, 314))	('contract', 'Var', (111, 119))	('tumors', 'Disease', (165, 171))	('tumors', 'Disease', 'MESH:D009369', (165, 171))	('HPV infection', 'Disease', (120, 133))	('tumors', 'Phenotype', 'HP:0002664', (165, 171))	('leading to', 'Reg', (134, 144))	('tumors', 'Phenotype', 'HP:0002664', (308, 314))	('tumor', 'Phenotype', 'HP:0002664', (308, 313))	('well', 'Disease', (145, 149))	('patients', 'Species', '9606', (24, 32))	('HPV infection', 'Disease', 'MESH:D030361', (120, 133))	('HPV', 'Species', '10566', (120, 123))	('tumors', 'Disease', (308, 314))
278482	26581505	Furthermore, Fra-2 silencing also downregulates c-Jun.	('c-Jun', 'Gene', (48, 53))	('silencing', 'Var', (19, 28))	('downregulates', 'NegReg', (34, 47))	('Fra-2', 'Gene', (13, 18))	('Fra-2', 'Gene', '2355', (13, 18))	('c-Jun', 'Gene', '3725', (48, 53))
278487	26581505	On the other hand, participation of JunD observed specifically in HPV16+ve cases appears to induce tumor differentiation as majority of the HPV+ve cases were found to have well differentiated tumors (WDSCCs) that show better prognosis.	('JunD', 'Gene', (36, 40))	('tumor', 'Disease', (99, 104))	('HPV', 'Species', '10566', (66, 69))	('tumor', 'Disease', (192, 197))	('JunD', 'Gene', '3727', (36, 40))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('tumors', 'Disease', (192, 198))	('tumors', 'Disease', 'MESH:D009369', (192, 198))	('tumors', 'Phenotype', 'HP:0002664', (192, 198))	('HPV16+ve', 'Var', (66, 74))	('HPV16', 'Species', '333760', (66, 71))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('HPV+ve', 'Var', (140, 146))	('HPV', 'Species', '10566', (140, 143))
278491	26581505	It has been also suggested that the functional change of JunD from growth suppressor to a growth promoter could be possibly due to presence of mutant form of JunD.	('JunD', 'Gene', (57, 61))	('mutant', 'Var', (143, 149))	('JunD', 'Gene', '3727', (57, 61))	('JunD', 'Gene', (158, 162))	('JunD', 'Gene', '3727', (158, 162))	('functional', 'MPA', (36, 46))
278496	26581505	Overexpression of Fra-2 has been shown to induce aggressive progression and metastasis particularly in triple negative breast cancer.	('metastasis', 'CPA', (76, 86))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('breast cancer', 'Disease', 'MESH:D001943', (119, 132))	('breast cancer', 'Disease', (119, 132))	('aggressive progression', 'CPA', (49, 71))	('breast cancer', 'Phenotype', 'HP:0003002', (119, 132))	('Fra-2', 'Gene', (18, 23))	('Overexpression', 'Var', (0, 14))	('Fra-2', 'Gene', '2355', (18, 23))
278503	26581505	This gains strong support from our present findings that knocking down of Fra-2 (responsible for aggressive tumorigenesis and drug resistance) led to upregulation of p53 (Fig.	('Fra-2', 'Gene', (74, 79))	('Fra-2', 'Gene', '2355', (74, 79))	('drug resistance', 'Phenotype', 'HP:0020174', (126, 141))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('p53', 'Gene', (166, 169))	('p53', 'Gene', '7157', (166, 169))	('aggressive tumor', 'Disease', 'MESH:D001523', (97, 113))	('knocking down', 'Var', (57, 70))	('upregulation', 'PosReg', (150, 162))	('aggressive tumor', 'Disease', (97, 113))
278515	26581505	Also, HPV E6/E7 showed significant down regulation.	('HPV', 'Gene', (6, 9))	('down regulation', 'NegReg', (35, 50))	('E6/E7', 'Var', (10, 15))	('HPV', 'Species', '10566', (6, 9))
278519	26581505	Our functional in vitro cell invasion and migration assays demonstrated Fra-2 knockdown can significantly reduce TSCC cell invasion and migration capability of both HPV+ve and HPV-ve tongue cancer cells in vitro.	('HPV-ve tongue cancer', 'Disease', 'MESH:D014062', (176, 196))	('HPV', 'Species', '10566', (165, 168))	('rat', 'Species', '10116', (139, 142))	('HPV-ve tongue cancer', 'Disease', (176, 196))	('knockdown', 'Var', (78, 87))	('HPV', 'Species', '10566', (176, 179))	('reduce', 'NegReg', (106, 112))	('TSCC cell invasion', 'CPA', (113, 131))	('Fra-2', 'Gene', '2355', (72, 77))	('rat', 'Species', '10116', (66, 69))	('TSCC', 'Phenotype', 'HP:0030413', (113, 117))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('Fra-2', 'Gene', (72, 77))	('migration capability', 'CPA', (136, 156))	('rat', 'Species', '10116', (45, 48))
278520	26581505	It has previously been reported that Fra-2 silencing significantly decreased cell migration and invasion in breast cancer cells.	('Fra-2', 'Gene', (37, 42))	('Fra-2', 'Gene', '2355', (37, 42))	('rat', 'Species', '10116', (85, 88))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('silencing', 'Var', (43, 52))	('invasion', 'CPA', (96, 104))	('breast cancer', 'Disease', 'MESH:D001943', (108, 121))	('decreased', 'NegReg', (67, 76))	('cell migration', 'CPA', (77, 91))	('breast cancer', 'Disease', (108, 121))	('breast cancer', 'Phenotype', 'HP:0003002', (108, 121))
278521	26581505	These results together suggest potential effects of Fra-2 silencing on inhibiting invasion, migration and chemo-radio sensitization of TSCC cells.	('inhibiting', 'NegReg', (71, 81))	('chemo-radio sensitization', 'CPA', (106, 131))	('rat', 'Species', '10116', (95, 98))	('invasion', 'CPA', (82, 90))	('TSCC', 'Phenotype', 'HP:0030413', (135, 139))	('TSCC', 'Disease', (135, 139))	('migration', 'CPA', (92, 101))	('Fra-2', 'Gene', '2355', (52, 57))	('Fra-2', 'Gene', (52, 57))	('silencing', 'Var', (58, 67))
278542	26581505	After 5 min, 10,000 cpm of the [gamma32P] ATP 5'-end labelled double-stranded AP-1 oligonucleotide probe was added and the incubation was continued for additional 25 min at room temperature and the DNA-protein complex was resolved in a 4.5% non-denaturing polyacrylamide gel.	('rat', 'Species', '10116', (183, 186))	('AP-1', 'Gene', (78, 82))	('[gamma32P] ATP', 'Chemical', '-', (31, 45))	('oligonucleotide', 'Chemical', 'MESH:D009841', (83, 98))	('polyacrylamide', 'Chemical', 'MESH:C016679', (256, 270))	('AP-1', 'Gene', '2353', (78, 82))	('[gamma32P]', 'Var', (31, 41))
278571	32434476	An integrative investigation on significant mutations and their down-stream pathways in lung squamous cell carcinoma reveals CUL3/KEAP1/NRF2 relevant subtypes Molecular mechanism of lung squamous cell carcinoma (LUSC) remains poorly understood, hampering effective targeted therapies or precision diagnosis about LUSC.	('KEAP1', 'Gene', (130, 135))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (88, 116))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (182, 210))	('NRF2', 'Gene', '4780', (136, 140))	('CUL3', 'Gene', '8452', (125, 129))	('LUSC', 'Phenotype', 'HP:0030359', (212, 216))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (88, 116))	('CUL3', 'Gene', (125, 129))	('lung squamous cell carcinoma', 'Disease', (88, 116))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (187, 210))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (182, 210))	('lung squamous cell carcinoma', 'Disease', (182, 210))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (93, 116))	('NRF2', 'Gene', (136, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('LUSC', 'Phenotype', 'HP:0030359', (313, 317))	('carcinoma', 'Phenotype', 'HP:0030731', (201, 210))	('mutations', 'Var', (44, 53))	('KEAP1', 'Gene', '9817', (130, 135))
278575	32434476	Interestingly, the good prognosis subtype was enriched with mutations in CUL3/KEAP1/NRF2 pathway and with markedly suppressed expressions of multiple down-stream pathways like epithelial mesenchymal transition.	('KEAP1', 'Gene', (78, 83))	('epithelial mesenchymal transition', 'CPA', (176, 209))	('expressions', 'MPA', (126, 137))	('NRF2', 'Gene', '4780', (84, 88))	('CUL3', 'Gene', '8452', (73, 77))	('down-stream pathways', 'Pathway', (150, 170))	('NRF2', 'Gene', (84, 88))	('suppressed', 'NegReg', (115, 125))	('mutations', 'Var', (60, 69))	('CUL3', 'Gene', (73, 77))	('KEAP1', 'Gene', '9817', (78, 83))
278577	32434476	NFE2L2, KEAP1 and RASA1 mutations showed remarkable effects on the subtype-determinant gene expressions, especially for the inflammatory relevant genes.	('KEAP1', 'Gene', (8, 13))	('subtype-determinant gene expressions', 'MPA', (67, 103))	('effects', 'Reg', (52, 59))	('NFE2L2', 'Gene', '4780', (0, 6))	('KEAP1', 'Gene', '9817', (8, 13))	('NFE2L2', 'Gene', (0, 6))	('RASA1', 'Gene', '5921', (18, 23))	('mutations', 'Var', (24, 33))	('RASA1', 'Gene', (18, 23))
278581	32434476	Several targeted drugs have been developed to treat LUAD patients which have mutations on specific genes like EGFR (Paez et al.)	('EGFR', 'Gene', '1956', (110, 114))	('LUAD', 'Disease', (52, 56))	('EGFR', 'Gene', (110, 114))	('patients', 'Species', '9606', (57, 65))	('LUAD', 'Phenotype', 'HP:0030078', (52, 56))	('mutations', 'Var', (77, 86))
278584	32434476	Some genomic studies have revealed significant mutations in a collection of genes, such as TP53, PIK3CA, NFE2L2, KEAP1, FBXW7, etc., and some of the mutations showed significant associations with LUSC prognostic outcomes (Choi et al.	('TP53', 'Gene', (91, 95))	('FBXW7', 'Gene', '55294', (120, 125))	('KEAP1', 'Gene', (113, 118))	('mutations', 'Var', (149, 158))	('NFE2L2', 'Gene', (105, 111))	('FBXW7', 'Gene', (120, 125))	('TP53', 'Gene', '7157', (91, 95))	('mutations', 'Var', (47, 56))	('LUSC prognostic outcomes', 'Disease', (196, 220))	('PIK3CA', 'Gene', '5290', (97, 103))	('KEAP1', 'Gene', '9817', (113, 118))	('LUSC', 'Phenotype', 'HP:0030359', (196, 200))	('PIK3CA', 'Gene', (97, 103))	('NFE2L2', 'Gene', '4780', (105, 111))	('associations', 'Reg', (178, 190))
278590	32434476	As results, we identified two LUSC-specific subtypes which showed significant differences in mutational, expressional as well as clinical patterns, and the better prognosis subtype was enriched by mutations in CUL3/KEAP1/NRF2 pathway and displayed suppressed expressions of genes involved in epithelial mesenchymal transition (EMT), inflammatory responses and other potential down-stream pathways.	('KEAP1', 'Gene', '9817', (215, 220))	('KEAP1', 'Gene', (215, 220))	('epithelial mesenchymal transition', 'CPA', (292, 325))	('NRF2', 'Gene', '4780', (221, 225))	('LUSC', 'Phenotype', 'HP:0030359', (30, 34))	('NRF2', 'Gene', (221, 225))	('mutations', 'Var', (197, 206))	('CUL3', 'Gene', '8452', (210, 214))	('CUL3', 'Gene', (210, 214))	('inflammatory responses', 'CPA', (333, 355))	('suppressed', 'NegReg', (248, 258))	('expressions', 'MPA', (259, 270))
278608	32434476	The mRNA expression matrix and the corresponding clinical information for two lung cancer cohorts (GSE30219 and GSE37745) were downloaded from Gene Expression Omnibus (GEO) database by the R package 'GEOquery' (Sean and Meltzer).	('lung cancer', 'Disease', (78, 89))	('lung cancer', 'Phenotype', 'HP:0100526', (78, 89))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('GSE37745', 'Var', (112, 120))	('lung cancer', 'Disease', 'MESH:D008175', (78, 89))
278616	32434476	To evaluate the most direct mutational effects, we compared the expressions of these SMGs in the mutated and wild type samples.	('compared', 'Reg', (51, 59))	('mutated', 'Var', (97, 104))	('SMGs', 'Chemical', '-', (85, 89))
278618	32434476	For instance, the mutations of RB1 were related with significantly reduced expressions of RB1 while mutations of CDKN2A, NFE2L2 might improve the expression levels (Figure S1A).	('mutations', 'Var', (100, 109))	('RB1', 'Gene', (31, 34))	('improve', 'PosReg', (134, 141))	('RB1', 'Gene', (90, 93))	('expression levels', 'MPA', (146, 163))	('CDKN2A', 'Gene', (113, 119))	('NFE2L2', 'Gene', '4780', (121, 127))	('reduced', 'NegReg', (67, 74))	('RB1', 'Gene', '5925', (31, 34))	('RB1', 'Gene', '5925', (90, 93))	('CDKN2A', 'Gene', '1029', (113, 119))	('NFE2L2', 'Gene', (121, 127))	('expressions', 'MPA', (75, 86))	('mutations', 'Var', (18, 27))
278620	32434476	Here, we found its mutation may be related with a higher level of expression in this gene, then the inactivation of CDKN2A may be caused by some other effects like silencing methylation or homozygous deletion (Cancer Genome Atlas Research N; Wikman and Kettunen).	('level', 'MPA', (57, 62))	('inactivation', 'NegReg', (100, 112))	('higher', 'PosReg', (50, 56))	('mutation', 'Var', (19, 27))	('silencing methylation', 'Var', (164, 185))	('CDKN2A', 'Gene', (116, 122))	('expression', 'MPA', (66, 76))	('CDKN2A', 'Gene', '1029', (116, 122))	('Cancer', 'Phenotype', 'HP:0002664', (210, 216))	('Cancer', 'Disease', (210, 216))	('Cancer', 'Disease', 'MESH:D009369', (210, 216))
278622	32434476	Among the significant SMGs for LUSC, the mutations of certain pairs of SMGs, like NFE2L2 and KEAP1, RB1 and CDKN2A, PTEN and CDKN2A were mutual exclusive (Fig.	('mutations', 'Var', (41, 50))	('RB1', 'Gene', (100, 103))	('NFE2L2', 'Gene', '4780', (82, 88))	('CDKN2A', 'Gene', '1029', (108, 114))	('SMGs', 'Chemical', '-', (71, 75))	('KEAP1', 'Gene', '9817', (93, 98))	('LUSC', 'Phenotype', 'HP:0030359', (31, 35))	('SMGs', 'Chemical', '-', (22, 26))	('NFE2L2', 'Gene', (82, 88))	('RB1', 'Gene', '5925', (100, 103))	('KEAP1', 'Gene', (93, 98))	('CDKN2A', 'Gene', (125, 131))	('PTEN', 'Gene', (116, 120))	('PTEN', 'Gene', '5728', (116, 120))	('CDKN2A', 'Gene', (108, 114))	('CDKN2A', 'Gene', '1029', (125, 131))
278624	32434476	For instance, KEAP1 encodes the adapter protein of an E3 ligase complex which can ubiquitinate NRF2, and previous studies have proven that mutations in KEAP1 and NFE2L2 may lead to NRF2 activation which may further contribute to spontaneous cancer development (Leinonen et al.	('NRF2', 'Gene', (181, 185))	('NFE2L2', 'Gene', (162, 168))	('KEAP1', 'Gene', '9817', (14, 19))	('activation', 'PosReg', (186, 196))	('contribute', 'Reg', (215, 225))	('mutations', 'Var', (139, 148))	('NRF2', 'Gene', '4780', (181, 185))	('KEAP1', 'Gene', '9817', (152, 157))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('KEAP1', 'Gene', (14, 19))	('NRF2', 'Gene', '4780', (95, 99))	('cancer', 'Disease', (241, 247))	('cancer', 'Disease', 'MESH:D009369', (241, 247))	('KEAP1', 'Gene', (152, 157))	('NFE2L2', 'Gene', '4780', (162, 168))	('NRF2', 'Gene', (95, 99))	('lead to', 'Reg', (173, 180))
278628	32434476	The mutations of these SMGs might lead to significant expressional alterations of the other genes.	('mutations', 'Var', (4, 13))	('lead to', 'Reg', (34, 41))	('SMGs', 'Chemical', '-', (23, 27))	('expressional alterations', 'MPA', (54, 78))
278631	32434476	This is just coherent with the above notion that co-exclusive SMGs may produce convergent down-steam effects.	('SMGs', 'Var', (62, 66))	('down-steam effects', 'MPA', (90, 108))	('SMGs', 'Chemical', '-', (62, 66))
278632	32434476	Meanwhile, some SMGs may lead to remarkable expressional alterations of well-known oncogenes or tumor suppressor genes, e.g., the mutations in RB1 may regulate the up-regulation of the oncogene DEK, and the mutations in TP53 may be related with up-regulation of both oncogene SOX2 and tumor suppressor gene WNK2 (Figure S2, role of the downstream genes were annotated based on the COSMIC database (Forbes et al.	('TP53', 'Gene', (220, 224))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('RB1', 'Gene', '5925', (143, 146))	('tumor', 'Phenotype', 'HP:0002664', (285, 290))	('up-regulation', 'PosReg', (245, 258))	('WNK2', 'Gene', (307, 311))	('mutations', 'Var', (207, 216))	('expressional', 'MPA', (44, 56))	('TP53', 'Gene', '7157', (220, 224))	('SOX2', 'Gene', (276, 280))	('tumor', 'Disease', (96, 101))	('DEK', 'Gene', (194, 197))	('SOX2', 'Gene', '6657', (276, 280))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('up-regulation', 'PosReg', (164, 177))	('SMGs', 'Chemical', '-', (16, 20))	('DEK', 'Gene', '7913', (194, 197))	('tumor', 'Disease', (285, 290))	('mutations', 'Var', (130, 139))	('WNK2', 'Gene', '65268', (307, 311))	('RB1', 'Gene', (143, 146))	('tumor', 'Disease', 'MESH:D009369', (285, 290))
278640	32434476	The first group included ARID1A, TP53, CDKN2A, FBXW7, NFE2L2, CUL3, KEAP1 and COL11A1, their mutation may lead to the up-regulations of mTOR signaling pathway, MYC targets and the down-regulations of inflammatory response.	('NFE2L2', 'Gene', '4780', (54, 60))	('down-regulations', 'NegReg', (180, 196))	('KEAP1', 'Gene', (68, 73))	('TP53', 'Gene', '7157', (33, 37))	('COL11A1', 'Gene', '1301', (78, 85))	('FBXW7', 'Gene', (47, 52))	('up-regulations', 'PosReg', (118, 132))	('inflammatory response', 'CPA', (200, 221))	('ARID1A', 'Gene', (25, 31))	('NFE2L2', 'Gene', (54, 60))	('MYC', 'Gene', (160, 163))	('CUL3', 'Gene', '8452', (62, 66))	('mTOR', 'Gene', (136, 140))	('COL11A1', 'Gene', (78, 85))	('CDKN2A', 'Gene', (39, 45))	('ARID1A', 'Gene', '8289', (25, 31))	('TP53', 'Gene', (33, 37))	('mTOR', 'Gene', '2475', (136, 140))	('FBXW7', 'Gene', '55294', (47, 52))	('MYC', 'Gene', '4609', (160, 163))	('CDKN2A', 'Gene', '1029', (39, 45))	('CUL3', 'Gene', (62, 66))	('mutation', 'Var', (93, 101))	('KEAP1', 'Gene', '9817', (68, 73))
278641	32434476	The second one included FAT1, RASA1, NF1, ZNF716, RB1, et al., and their mutations may generate somewhat reversed pathway impacts compared to the first group, for instance, their mutations may largely lead to up-regulations in inflammatory response and rarely lead to significant alterations in the mTOR signaling pathway.	('mTOR', 'Gene', (299, 303))	('mTOR', 'Gene', '2475', (299, 303))	('inflammatory response', 'CPA', (227, 248))	('ZNF716', 'Gene', '441234', (42, 48))	('NF1', 'Gene', (37, 40))	('RASA1', 'Gene', (30, 35))	('ZNF716', 'Gene', (42, 48))	('NF1', 'Gene', '4763', (37, 40))	('RB1', 'Gene', '5925', (50, 53))	('RB1', 'Gene', (50, 53))	('FAT1', 'Gene', '2195', (24, 28))	('RASA1', 'Gene', '5921', (30, 35))	('mutations', 'Var', (179, 188))	('up-regulations', 'PosReg', (209, 223))	('FAT1', 'Gene', (24, 28))	('mutations', 'Var', (73, 82))
278652	32434476	The significantly differential expression patterns were probably associated with the mutations of NFE2L2, CUL3, KEAP1, COL11A1 and RASA1, where mutations of NFE2L2, CUL3, KEAP1 and COL11A1 were significantly enriched in C2 (p < 0.05, hypergeometric distribution), while RASA1 mutations were enriched in C1 (p = 6.22e-3, hypergeometric distribution).	('NFE2L2', 'Gene', '4780', (157, 163))	('RASA1', 'Gene', '5921', (270, 275))	('differential', 'Reg', (18, 30))	('KEAP1', 'Gene', '9817', (112, 117))	('mutations', 'Var', (144, 153))	('COL11A1', 'Gene', '1301', (181, 188))	('COL11A1', 'Gene', (119, 126))	('KEAP1', 'Gene', (112, 117))	('CUL3', 'Gene', (106, 110))	('CUL3', 'Gene', '8452', (165, 169))	('NFE2L2', 'Gene', (157, 163))	('RASA1', 'Gene', (270, 275))	('RASA1', 'Gene', '5921', (131, 136))	('COL11A1', 'Gene', (181, 188))	('NFE2L2', 'Gene', '4780', (98, 104))	('mutations', 'Var', (85, 94))	('KEAP1', 'Gene', '9817', (171, 176))	('expression patterns', 'MPA', (31, 50))	('KEAP1', 'Gene', (171, 176))	('CUL3', 'Gene', '8452', (106, 110))	('RASA1', 'Gene', (131, 136))	('COL11A1', 'Gene', '1301', (119, 126))	('CUL3', 'Gene', (165, 169))	('NFE2L2', 'Gene', (98, 104))
278653	32434476	The mutations of these five SMGs together with their significant influences on the down-stream pathways may contribute to the LUSC molecular heterogeneity.	('down-stream pathways', 'Pathway', (83, 103))	('influences', 'Reg', (65, 75))	('SMGs', 'Chemical', '-', (28, 32))	('mutations', 'Var', (4, 13))	('LUSC', 'Phenotype', 'HP:0030359', (126, 130))	('contribute', 'Reg', (108, 118))
278655	32434476	Interestingly, although previous studies have revealed that KEAP1/NEF2L2 mutations may contribute to LUSC or poor prognosis (Tian et al.	('contribute', 'Reg', (87, 97))	('KEAP1', 'Gene', (60, 65))	('LUSC', 'Phenotype', 'HP:0030359', (101, 105))	('LUSC', 'Disease', (101, 105))	('poor prognosis', 'CPA', (109, 123))	('KEAP1', 'Gene', '9817', (60, 65))	('mutations', 'Var', (73, 82))
278656	32434476	), here, we found that both KEAP1 and NFE2L2 mutations were enriched in the better prognosis subtype (C2, Fig.	('mutations', 'Var', (45, 54))	('KEAP1', 'Gene', '9817', (28, 33))	('NFE2L2', 'Gene', '4780', (38, 44))	('KEAP1', 'Gene', (28, 33))	('NFE2L2', 'Gene', (38, 44))
278667	32434476	To further understand the relationships between mutational patterns and down-stream expressional profiles which all contributed to the two identified subtypes, we further examined whether the mutations of the five SMGs were associated with significant expressional alterations of the top-50 important genes in separating two subtypes.	('SMGs', 'Gene', (214, 218))	('mutations', 'Var', (192, 201))	('expressional alterations', 'MPA', (252, 276))	('SMGs', 'Chemical', '-', (214, 218))
278669	32434476	6) describing which genes involved in the down-stream pathways were more likely to be directly regulated by the SMGs.	('SMGs', 'Chemical', '-', (112, 116))	('regulated', 'Reg', (95, 104))	('SMGs', 'Var', (112, 116))
278670	32434476	As results, NFE2L2 mutations showed significant influences on the largest number of subtype-determinant down-stream genes, especially the genes in inflammatory response pathway, e.g., ICAM1 (van Buul et al.	('ICAM1', 'Gene', (184, 189))	('influences', 'Reg', (48, 58))	('NFE2L2', 'Gene', (12, 18))	('mutations', 'Var', (19, 28))	('ICAM1', 'Gene', '3383', (184, 189))	('NFE2L2', 'Gene', '4780', (12, 18))
278682	32434476	According to our analysis, we identified 18 SMGs with significant mutations in LUSC.	('mutations', 'Var', (66, 75))	('LUSC', 'Gene', (79, 83))	('LUSC', 'Phenotype', 'HP:0030359', (79, 83))	('SMGs', 'Chemical', '-', (44, 48))
278685	32434476	Here, we observed that mutations of NFE2L2 and KEAP1 were highly co-exclusive, suggesting the convergent down-stream effects.	('KEAP1', 'Gene', (47, 52))	('NFE2L2', 'Gene', (36, 42))	('mutations', 'Var', (23, 32))	('KEAP1', 'Gene', '9817', (47, 52))	('NFE2L2', 'Gene', '4780', (36, 42))
278690	32434476	The two subtypes showed distinctively mutational patterns in NFE2L2, KEAP1, RASA1, CUL3 and COL11A1, and remarkably differential expressions of genes involved in multiple pathways like EMT, inflammatory response, and IL6-JAK-STAT3 signaling pathways.	('IL6', 'Gene', '3569', (217, 220))	('inflammatory', 'CPA', (190, 202))	('CUL3', 'Gene', (83, 87))	('NFE2L2', 'Gene', (61, 67))	('COL11A1', 'Gene', '1301', (92, 99))	('IL6', 'Gene', (217, 220))	('RASA1', 'Gene', '5921', (76, 81))	('KEAP1', 'Gene', '9817', (69, 74))	('STAT3', 'Gene', (225, 230))	('CUL3', 'Gene', '8452', (83, 87))	('KEAP1', 'Gene', (69, 74))	('mutational', 'Var', (38, 48))	('COL11A1', 'Gene', (92, 99))	('EMT', 'CPA', (185, 188))	('STAT3', 'Gene', '6774', (225, 230))	('differential', 'Reg', (116, 128))	('expressions', 'MPA', (129, 140))	('RASA1', 'Gene', (76, 81))	('NFE2L2', 'Gene', '4780', (61, 67))
278691	32434476	Interestingly, the better survival subtype (C2) was observed to be with higher mutation frequencies considering NFE2L2, KEAP1 and CUL3 which may be onco-driver of LUSC (Polonen and Levonen; Kandoth et al.).	('mutation frequencies', 'Var', (79, 99))	('NFE2L2', 'Gene', (112, 118))	('KEAP1', 'Gene', (120, 125))	('CUL3', 'Gene', '8452', (130, 134))	('CUL3', 'Gene', (130, 134))	('LUSC', 'Phenotype', 'HP:0030359', (163, 167))	('higher', 'PosReg', (72, 78))	('NFE2L2', 'Gene', '4780', (112, 118))	('KEAP1', 'Gene', '9817', (120, 125))
278692	32434476	This indicates although mutations of certain genes may contribute to the development of cancer, their mutations are not indicators of poor prognosis.	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('contribute', 'Reg', (55, 65))	('mutations', 'Var', (24, 33))
278700	32434476	These potential down-stream pathways for KEAP1/NFE2L2/CUL3 mutations can also provide alternative way for LUSC treatment where therapeutic interventions for governing NRF2 activity have proven largely intractable.	('CUL3', 'Gene', '8452', (54, 58))	('CUL3', 'Gene', (54, 58))	('down-stream', 'NegReg', (16, 27))	('KEAP1', 'Gene', '9817', (41, 46))	('NFE2L2', 'Gene', (47, 53))	('LUSC', 'Phenotype', 'HP:0030359', (106, 110))	('NRF2', 'Gene', '4780', (167, 171))	('KEAP1', 'Gene', (41, 46))	('mutations', 'Var', (59, 68))	('LUSC', 'Disease', (106, 110))	('NRF2', 'Gene', (167, 171))	('NFE2L2', 'Gene', '4780', (47, 53))
278702	32434476	Although large-scale genomic studies have identified the frequent mutations in KEAP1/NRF2/ CUL3 pathway and their prominent roles in LUSC and other cancers, less attention is paid on their complicated down-stream effects.	('mutations', 'Var', (66, 75))	('NRF2', 'Gene', (85, 89))	('cancers', 'Disease', 'MESH:D009369', (148, 155))	('cancers', 'Phenotype', 'HP:0002664', (148, 155))	('cancers', 'Disease', (148, 155))	('KEAP1', 'Gene', (79, 84))	('CUL3', 'Gene', '8452', (91, 95))	('CUL3', 'Gene', (91, 95))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('NRF2', 'Gene', '4780', (85, 89))	('LUSC', 'Disease', (133, 137))	('LUSC', 'Phenotype', 'HP:0030359', (133, 137))	('roles', 'Reg', (124, 129))	('KEAP1', 'Gene', '9817', (79, 84))
278703	32434476	Also, an integrative study of both SMG and the down-stream expression profiles of LUSC help recognized two robust subtypes where one subtype with markedly suppressed expressions in EMT and inflammatory response pathways showed significant better survivals and higher mutation frequencies in the KEAP1/NRF2/ CUL3 pathway.	('survivals', 'CPA', (246, 255))	('better', 'PosReg', (239, 245))	('SMG', 'Gene', '23034', (35, 38))	('mutation', 'Var', (267, 275))	('EMT', 'Gene', (181, 184))	('KEAP1', 'Gene', (295, 300))	('NRF2', 'Gene', '4780', (301, 305))	('higher', 'PosReg', (260, 266))	('suppressed', 'NegReg', (155, 165))	('LUSC', 'Phenotype', 'HP:0030359', (82, 86))	('NRF2', 'Gene', (301, 305))	('SMG', 'Gene', (35, 38))	('CUL3', 'Gene', '8452', (307, 311))	('expressions', 'MPA', (166, 177))	('KEAP1', 'Gene', '9817', (295, 300))	('CUL3', 'Gene', (307, 311))
278706	27213344	The Clinical Significance of the Insulin-Like Growth Factor-1 Receptor Polymorphism in Non-Small-Cell Lung Cancer with Epidermal Growth Factor Receptor Mutation The insulin-like growth factor 1 (IGF1) signaling pathway mediates multiple cancer cell biological processes.	('Polymorphism', 'Var', (71, 83))	('IGF1', 'Gene', '3479', (195, 199))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('Insulin-Like Growth Factor-1 Receptor', 'Gene', '3480', (33, 70))	('insulin-like growth factor 1', 'Gene', (165, 193))	('insulin-like growth factor 1', 'Gene', '3479', (165, 193))	('IGF1', 'Gene', (195, 199))	('Non-Small-Cell Lung Cancer', 'Phenotype', 'HP:0030358', (87, 113))	('Epidermal Growth Factor Receptor', 'Gene', '1956', (119, 151))	('Lung Cancer', 'Phenotype', 'HP:0100526', (102, 113))	('Insulin-Like Growth Factor-1 Receptor', 'Gene', (33, 70))	('Cancer', 'Phenotype', 'HP:0002664', (107, 113))	('cancer', 'Disease', 'MESH:D009369', (237, 243))	('Non-Small-Cell Lung Cancer', 'Disease', (87, 113))	('Small-Cell Lung Cancer', 'Phenotype', 'HP:0030357', (91, 113))	('cancer', 'Disease', (237, 243))	('Non-Small-Cell Lung Cancer', 'Disease', 'MESH:D002289', (87, 113))	('Epidermal Growth Factor Receptor', 'Gene', (119, 151))
278708	27213344	However, the association between IGF1R genetic variants and the clinical utility of NSCLC positive for epidermal growth factor receptor (EGFR) mutation is not clear.	('EGFR', 'Gene', (137, 141))	('IGF1R', 'Gene', (33, 38))	('variants', 'Var', (47, 55))	('NSCLC', 'Phenotype', 'HP:0030358', (84, 89))	('IGF1R', 'Gene', '3480', (33, 38))	('mutation', 'Var', (143, 151))	('NSCLC', 'Disease', (84, 89))	('epidermal growth factor receptor', 'Gene', (103, 135))	('NSCLC', 'Disease', 'MESH:D002289', (84, 89))	('EGFR', 'Gene', '1956', (137, 141))	('epidermal growth factor receptor', 'Gene', '1956', (103, 135))	('SCLC', 'Phenotype', 'HP:0030357', (85, 89))
278709	27213344	The current study investigated the association between the IGF1R genetic variants, the occurrence of EGFR mutations, and clinicopathological characteristics in NSCLC patients.	('SCLC', 'Phenotype', 'HP:0030357', (161, 165))	('variants', 'Var', (73, 81))	('EGFR', 'Gene', '1956', (101, 105))	('EGFR', 'Gene', (101, 105))	('NSCLC', 'Phenotype', 'HP:0030358', (160, 165))	('IGF1R', 'Gene', (59, 64))	('association', 'Interaction', (35, 46))	('mutations', 'Var', (106, 115))	('NSCLC', 'Disease', (160, 165))	('IGF1R', 'Gene', '3480', (59, 64))	('patients', 'Species', '9606', (166, 174))	('NSCLC', 'Disease', 'MESH:D002289', (160, 165))
278710	27213344	A total of 452 participants, including 362 adenocarcinoma lung cancer and 90 squamous cell carcinoma lung cancer patients, were selected for analysis of IGF1R genetic variants (rs7166348, rs2229765, and rs8038415) using real-time polymerase chain reaction (PCR)genotyping.	('squamous cell carcinoma lung cancer', 'Disease', (77, 112))	('adenocarcinoma lung cancer', 'Disease', 'MESH:D008175', (43, 69))	('IGF1R', 'Gene', '3480', (153, 158))	('lung cancer', 'Phenotype', 'HP:0100526', (58, 69))	('rs7166348', 'Mutation', 'rs7166348', (177, 186))	('adenocarcinoma lung cancer', 'Phenotype', 'HP:0030078', (43, 69))	('rs8038415', 'Mutation', 'rs8038415', (203, 212))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (48, 57))	('IGF1R', 'Gene', (153, 158))	('squamous cell carcinoma lung cancer', 'Disease', 'MESH:D002294', (77, 112))	('rs7166348', 'Var', (177, 186))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (77, 100))	('adenocarcinoma lung cancer', 'Disease', (43, 69))	('rs2229765', 'Var', (188, 197))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('patients', 'Species', '9606', (113, 121))	('rs2229765', 'Mutation', 'rs2229765', (188, 197))	('rs8038415', 'Var', (203, 212))	('participants', 'Species', '9606', (15, 27))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('lung cancer', 'Phenotype', 'HP:0100526', (101, 112))	('squamous cell carcinoma lung cancer', 'Phenotype', 'HP:0030359', (77, 112))
278711	27213344	The results indicated that GA + AA genotypes of IGF1R rs2229765 were significantly associated with EGFR mutation in female lung adenocarcinoma patients (odds ratio (OR) = 0.39, 95% confidence interval (CI) = 0.17-0.87).	('EGFR', 'Gene', (99, 103))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (123, 142))	('patients', 'Species', '9606', (143, 151))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (123, 142))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('associated', 'Reg', (83, 93))	('mutation', 'Var', (104, 112))	('rs2229765', 'Var', (54, 63))	('IGF1R', 'Gene', (48, 53))	('lung adenocarcinoma', 'Disease', (123, 142))	('EGFR', 'Gene', '1956', (99, 103))	('IGF1R', 'Gene', '3480', (48, 53))	('rs2229765', 'Mutation', 'rs2229765', (54, 63))
278712	27213344	Moreover, The GA + AA genotype IGF1R rs2229765 was significantly associated with EGFR L858R mutation (p = 0.02) but not with the exon 19 in-frame deletion.	('IGF1R', 'Gene', '3480', (31, 36))	('rs2229765', 'Mutation', 'rs2229765', (37, 46))	('EGFR', 'Gene', '1956', (81, 85))	('L858R', 'Var', (86, 91))	('L858R', 'Mutation', 'rs121434568', (86, 91))	('rs2229765', 'Var', (37, 46))	('IGF1R', 'Gene', (31, 36))	('EGFR', 'Gene', (81, 85))
278713	27213344	Furthermore, among patients without EGFR mutation, those who have at least one polymorphic A allele of IGF1R rs7166348 have an increased incidence of lymph node metastasis when compared with those patients homozygous for GG (OR, 2.75; 95% CI, 1.20-2.31).	('IGF1R', 'Gene', '3480', (103, 108))	('increased incidence of lymph node', 'Phenotype', 'HP:0032536', (127, 160))	('patients', 'Species', '9606', (197, 205))	('patients', 'Species', '9606', (19, 27))	('rs7166348', 'Var', (109, 118))	('EGFR', 'Gene', '1956', (36, 40))	('lymph node metastasis', 'CPA', (150, 171))	('IGF1R', 'Gene', (103, 108))	('EGFR', 'Gene', (36, 40))	('rs7166348', 'Mutation', 'rs7166348', (109, 118))
278714	27213344	Our results showed that IGF1R genetic variants are related to EGFR mutation in female lung adenocarcinoma patients and may be a predictive factor for tumor lymph node metastasis in Taiwanese patients with NSCLC.	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (86, 105))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (86, 105))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('NSCLC', 'Disease', 'MESH:D002289', (205, 210))	('IGF1R', 'Gene', '3480', (24, 29))	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('EGFR', 'Gene', '1956', (62, 66))	('mutation', 'Var', (67, 75))	('NSCLC', 'Disease', (205, 210))	('IGF1R', 'Gene', (24, 29))	('related', 'Reg', (51, 58))	('NSCLC', 'Phenotype', 'HP:0030358', (205, 210))	('patients', 'Species', '9606', (106, 114))	('tumor', 'Disease', (150, 155))	('SCLC', 'Phenotype', 'HP:0030357', (206, 210))	('lung adenocarcinoma', 'Disease', (86, 105))	('patients', 'Species', '9606', (191, 199))	('variants', 'Var', (38, 46))	('EGFR', 'Gene', (62, 66))	('tumor', 'Disease', 'MESH:D009369', (150, 155))
278722	27213344	It has been reported that mutation in the TK domain of EGFR gene is associated with NSCLC.	('EGFR', 'Gene', '1956', (55, 59))	('NSCLC', 'Phenotype', 'HP:0030358', (84, 89))	('associated', 'Reg', (68, 78))	('EGFR', 'Gene', (55, 59))	('NSCLC', 'Disease', (84, 89))	('NSCLC', 'Disease', 'MESH:D002289', (84, 89))	('SCLC', 'Phenotype', 'HP:0030357', (85, 89))	('mutation in the', 'Var', (26, 41))
278723	27213344	The most common mutations in the TK domain of EGFR are the in-frame deletion mutation in exon 19 and the substitution mutation (L858R) in exon 21.	('EGFR', 'Gene', '1956', (46, 50))	('EGFR', 'Gene', (46, 50))	('L858R', 'Var', (128, 133))	('deletion mutation', 'Var', (68, 85))	('L858R', 'Mutation', 'rs121434568', (128, 133))
278724	27213344	Mutation in the TK domain of EGFR causes the conformational change in protein structure.	('EGFR', 'Gene', (29, 33))	('EGFR', 'Gene', '1956', (29, 33))	('conformational change in protein structure', 'MPA', (45, 87))	('Mutation', 'Var', (0, 8))
278726	27213344	It has been reported that gefitinib and erlotinib are EGFR tyrosine kinase inhibitors (TKIs) for in-frame deletion in exon 19 and the substitution mutation (L858R) in exon 21.	('L858R', 'Var', (157, 162))	('L858R', 'Mutation', 'rs121434568', (157, 162))	('erlotinib', 'Chemical', 'MESH:D000069347', (40, 49))	('EGFR', 'Gene', '1956', (54, 58))	('EGFR', 'Gene', (54, 58))	('gefitinib', 'Chemical', 'MESH:D000077156', (26, 35))
278730	27213344	Numerous studies have demonstrated that dysfunction of the IGF1 signaling pathway results in various diseases, including cancer, metabolic disease, as well as neurodegenerative diseases.	('IGF1', 'Gene', '3479', (59, 63))	('metabolic disease', 'Disease', 'MESH:D008659', (129, 146))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('IGF1', 'Gene', (59, 63))	('neurodegenerative diseases', 'Disease', (159, 185))	('neurodegenerative diseases', 'Phenotype', 'HP:0002180', (159, 185))	('results in', 'Reg', (82, 92))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('neurodegenerative diseases', 'Disease', 'MESH:D019636', (159, 185))	('dysfunction', 'Var', (40, 51))	('cancer', 'Disease', (121, 127))	('metabolic disease', 'Disease', (129, 146))
278731	27213344	In addition, IGF1 system dysregulation has been reported in cancers such as NSCLC and in other tumors.	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('cancers', 'Phenotype', 'HP:0002664', (60, 67))	('IGF1', 'Gene', (13, 17))	('cancers', 'Disease', (60, 67))	('NSCLC', 'Disease', (76, 81))	('reported', 'Reg', (48, 56))	('cancers', 'Disease', 'MESH:D009369', (60, 67))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('NSCLC', 'Disease', 'MESH:D002289', (76, 81))	('dysregulation', 'Var', (25, 38))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('IGF1', 'Gene', '3479', (13, 17))	('SCLC', 'Phenotype', 'HP:0030357', (77, 81))	('tumors', 'Disease', (95, 101))	('NSCLC', 'Phenotype', 'HP:0030358', (76, 81))
278733	27213344	The results showed that high membranous IGF1R expression was predictive of poor progression-free survival (PFS) in adenocarcinoma, but had better PFS in squamous cell carcinoma.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (153, 176))	('squamous cell carcinoma', 'Disease', (153, 176))	('IGF1R', 'Gene', (40, 45))	('poor', 'NegReg', (75, 79))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (153, 176))	('carcinoma', 'Phenotype', 'HP:0030731', (167, 176))	('progression-free survival', 'CPA', (80, 105))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('high', 'Var', (24, 28))	('adenocarcinoma', 'Disease', (115, 129))	('IGF1R', 'Gene', '3480', (40, 45))	('adenocarcinoma', 'Disease', 'MESH:D000230', (115, 129))
278734	27213344	also characterized the IGF1R mutations, single nucleotide polymorphisms (SNPs), and protein expression in resected NSCLC and found that patients with adenocarcinomas and homozygous for the rs8038415 T-allele had significantly better survival, but found no different in disease free survival.	('carcinoma', 'Phenotype', 'HP:0030731', (155, 164))	('rs8038415', 'Var', (189, 198))	('IGF1R', 'Gene', (23, 28))	('adenocarcinomas', 'Disease', (150, 165))	('better', 'PosReg', (226, 232))	('NSCLC', 'Disease', (115, 120))	('mutations', 'Var', (29, 38))	('survival', 'CPA', (233, 241))	('IGF1R', 'Gene', '3480', (23, 28))	('NSCLC', 'Disease', 'MESH:D002289', (115, 120))	('patients', 'Species', '9606', (136, 144))	('rs8038415', 'Mutation', 'rs8038415', (189, 198))	('SCLC', 'Phenotype', 'HP:0030357', (116, 120))	('adenocarcinomas', 'Disease', 'MESH:D000230', (150, 165))	('NSCLC', 'Phenotype', 'HP:0030358', (115, 120))
278737	27213344	However, the correlation between IGF1R gene polymorphisms and the hotspot mutations of EGFR (in-frame deletion mutation in exon 19 and L858R mutation) of NSCLC have not been clarified.	('IGF1R', 'Gene', (33, 38))	('EGFR', 'Gene', '1956', (87, 91))	('NSCLC', 'Disease', 'MESH:D002289', (154, 159))	('NSCLC', 'Phenotype', 'HP:0030358', (154, 159))	('IGF1R', 'Gene', '3480', (33, 38))	('EGFR', 'Gene', (87, 91))	('SCLC', 'Phenotype', 'HP:0030357', (155, 159))	('L858R mutation', 'Var', (135, 149))	('in-frame deletion mutation in', 'Var', (93, 122))	('L858R', 'Mutation', 'rs121434568', (135, 140))	('NSCLC', 'Disease', (154, 159))
278738	27213344	In the present study, the selection of two common polymorphisms (rs7166348 and rs8038415) from the IGF1R gene is based on their wide associations with the development of cancer.	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('rs7166348', 'Mutation', 'rs7166348', (65, 74))	('cancer', 'Disease', (170, 176))	('rs8038415', 'Var', (79, 88))	('IGF1R', 'Gene', (99, 104))	('IGF1R', 'Gene', '3480', (99, 104))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('associations', 'Reg', (133, 145))	('rs8038415', 'Mutation', 'rs8038415', (79, 88))	('rs7166348', 'Var', (65, 74))
278739	27213344	Moreover, synonymous with the SNP, rs2229765 (E598E in exon 16) was selected in this study since it was found to be associated with levels of free IGF-1.	('E598E', 'Mutation', 'rs2229765', (46, 51))	('rs2229765', 'Var', (35, 44))	('IGF-1', 'Gene', '3479', (147, 152))	('IGF-1', 'Gene', (147, 152))	('rs2229765', 'Mutation', 'rs2229765', (35, 44))	('associated', 'Reg', (116, 126))
278740	27213344	Thus, in this study we aimed to explore the association between the genetic SNPs of IGF1R (rs7166348, rs2229765, and rs8038415) and the TK-domain mutations of EGFR in NSCLC.	('NSCLC', 'Disease', 'MESH:D002289', (167, 172))	('IGF1R', 'Gene', (84, 89))	('SCLC', 'Phenotype', 'HP:0030357', (168, 172))	('IGF1R', 'Gene', '3480', (84, 89))	('NSCLC', 'Phenotype', 'HP:0030358', (167, 172))	('EGFR', 'Gene', '1956', (159, 163))	('rs8038415', 'Var', (117, 126))	('rs2229765', 'Mutation', 'rs2229765', (102, 111))	('rs7166348', 'Var', (91, 100))	('EGFR', 'Gene', (159, 163))	('rs7166348', 'Mutation', 'rs7166348', (91, 100))	('NSCLC', 'Disease', (167, 172))	('rs2229765', 'Var', (102, 111))	('association', 'Interaction', (44, 55))	('rs8038415', 'Mutation', 'rs8038415', (117, 126))
278750	27213344	The distribution frequency of rs7166348, rs2229765, and rs8038415 of IGF1R genotypes in the lung adenocarcinoma and squamous cell carcinoma are shown in Table 2.	('rs8038415', 'Mutation', 'rs8038415', (56, 65))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (92, 111))	('rs2229765', 'Var', (41, 50))	('rs8038415', 'Var', (56, 65))	('adenocarcinoma and squamous cell carcinoma', 'Disease', 'MESH:D002294', (97, 139))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (116, 139))	('rs7166348', 'Var', (30, 39))	('IGF1R', 'Gene', (69, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('lung adenocarcinoma', 'Disease', (92, 111))	('rs2229765', 'Mutation', 'rs2229765', (41, 50))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (92, 111))	('rs7166348', 'Mutation', 'rs7166348', (30, 39))	('IGF1R', 'Gene', '3480', (69, 74))
278751	27213344	The alleles with the highest distribution frequency for rs7166348, rs2229765, and rs8038415 of IGF1R in recruited patients with NSCLC were heterozygous G/A, homozygous G/G, and heterozygous T/C, respectively.	('rs2229765', 'Mutation', 'rs2229765', (67, 76))	('NSCLC', 'Phenotype', 'HP:0030358', (128, 133))	('rs7166348', 'Mutation', 'rs7166348', (56, 65))	('IGF1R', 'Gene', (95, 100))	('NSCLC', 'Disease', (128, 133))	('rs8038415', 'Mutation', 'rs8038415', (82, 91))	('IGF1R', 'Gene', '3480', (95, 100))	('NSCLC', 'Disease', 'MESH:D002289', (128, 133))	('SCLC', 'Phenotype', 'HP:0030357', (129, 133))	('rs2229765', 'Var', (67, 76))	('rs8038415', 'Var', (82, 91))	('rs7166348', 'Var', (56, 65))	('patients', 'Species', '9606', (114, 122))
278752	27213344	After adjusting for variance, there was no significant difference between the lung adenocarcinoma and squamous cell carcinoma with polymorphisms of the IGF1R gene in rs7166348, rs2229765, and rs8038415 when compared with wild-type individuals.	('rs8038415', 'Var', (192, 201))	('IGF1R', 'Gene', '3480', (152, 157))	('rs7166348', 'Var', (166, 175))	('rs2229765', 'Mutation', 'rs2229765', (177, 186))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (78, 97))	('rs7166348', 'Mutation', 'rs7166348', (166, 175))	('adenocarcinoma and squamous cell carcinoma', 'Disease', 'MESH:D002294', (83, 125))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('rs2229765', 'Var', (177, 186))	('lung adenocarcinoma', 'Disease', (78, 97))	('rs8038415', 'Mutation', 'rs8038415', (192, 201))	('IGF1R', 'Gene', (152, 157))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (78, 97))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (102, 125))
278753	27213344	We further investigated the associations between EGFR mutations and patient characteristics.	('EGFR', 'Gene', '1956', (49, 53))	('patient', 'Species', '9606', (68, 75))	('investigated', 'Reg', (11, 23))	('EGFR', 'Gene', (49, 53))	('mutations', 'Var', (54, 63))
278754	27213344	As shown in Table 3, both substitution mutation (L858R) and exon 19 in-frame deletion mutations had higher percentages in female patients (male vs. female = 22.8% vs. 77.2% and 46.9% vs. 53.1%, respectively) and in never-smoker patients (never-smokers vs. ever-smokers = 88.6% vs. 11.4% and 69.1% vs. 30.9%, respectively).	('substitution mutation (L858R', 'Var', (26, 54))	('patients', 'Species', '9606', (129, 137))	('patients', 'Species', '9606', (228, 236))	('L858R', 'Var', (49, 54))	('deletion mutations', 'Var', (77, 95))	('L858R', 'Mutation', 'rs121434568', (49, 54))
278755	27213344	The distributions were shown to be significantly different between the control (wild-type) and EGFR mutations for gender (p < 0.05) and cigarette smoking status (p < 0.05).	('mutations', 'Var', (100, 109))	('different', 'Reg', (49, 58))	('EGFR', 'Gene', '1956', (95, 99))	('EGFR', 'Gene', (95, 99))
278756	27213344	These results indicate that EGFR mutations are associated with gender and cigarette smoking status.	('associated', 'Reg', (47, 57))	('EGFR', 'Gene', '1956', (28, 32))	('EGFR', 'Gene', (28, 32))	('mutations', 'Var', (33, 42))
278757	27213344	To clarify the association between the polymorphism of IFG1R gene and EGFR mutation in different gender groups, the distribution frequency of IGF1R gene (rs7166348, rs2229765, and rs8038415) genotypes of wild-type and EGFR mutation type in lung adenocarcinoma patients was estimated.	('IGF1R', 'Gene', '3480', (142, 147))	('rs2229765', 'Var', (165, 174))	('rs8038415', 'Mutation', 'rs8038415', (180, 189))	('lung adenocarcinoma', 'Disease', (240, 259))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (240, 259))	('EGFR', 'Gene', '1956', (70, 74))	('rs8038415', 'Var', (180, 189))	('patients', 'Species', '9606', (260, 268))	('carcinoma', 'Phenotype', 'HP:0030731', (250, 259))	('rs2229765', 'Mutation', 'rs2229765', (165, 174))	('EGFR', 'Gene', '1956', (218, 222))	('EGFR', 'Gene', (70, 74))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (240, 259))	('rs7166348', 'Var', (154, 163))	('rs7166348', 'Mutation', 'rs7166348', (154, 163))	('EGFR', 'Gene', (218, 222))	('IGF1R', 'Gene', (142, 147))
278758	27213344	As shown in Table 4, GA and GA + AA genotypes of IGF1R rs2229765 had significant association with EGFR mutation in female lung adenocarcinoma patients (OR = 0.35, 95% CI = 0.15-0.82 and OR = 0.39, 95% CI = 0.17-0.87, respectively).	('association', 'Interaction', (81, 92))	('EGFR', 'Gene', (98, 102))	('IGF1R', 'Gene', '3480', (49, 54))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (122, 141))	('rs2229765', 'Var', (55, 64))	('EGFR', 'Gene', '1956', (98, 102))	('mutation', 'Var', (103, 111))	('IGF1R', 'Gene', (49, 54))	('rs2229765', 'Mutation', 'rs2229765', (55, 64))	('patients', 'Species', '9606', (142, 150))	('lung adenocarcinoma', 'Disease', (122, 141))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (122, 141))
278759	27213344	Additionally from Table 4, the polymorphism of IGF1R rs2229765 was associated with EGFR mutation only in female lung adenocarcinoma patients.	('EGFR', 'Gene', '1956', (83, 87))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (112, 131))	('polymorphism', 'Var', (31, 43))	('IGF1R', 'Gene', (47, 52))	('rs2229765', 'Mutation', 'rs2229765', (53, 62))	('EGFR', 'Gene', (83, 87))	('lung adenocarcinoma', 'Disease', (112, 131))	('IGF1R', 'Gene', '3480', (47, 52))	('associated', 'Reg', (67, 77))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (112, 131))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('rs2229765', 'Var', (53, 62))	('patients', 'Species', '9606', (132, 140))
278760	27213344	Therefore, further analyses were focused on the association between the polymorphism of IFG1R gene and EGFR hotspot mutations in female lung adenocarcinoma patients.	('patients', 'Species', '9606', (156, 164))	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('EGFR', 'Gene', '1956', (103, 107))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (136, 155))	('EGFR', 'Gene', (103, 107))	('IFG1R', 'Gene', (88, 93))	('association', 'Interaction', (48, 59))	('polymorphism', 'Var', (72, 84))	('mutations', 'Var', (116, 125))	('lung adenocarcinoma', 'Disease', (136, 155))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (136, 155))
278761	27213344	Table 5 shows that the GA and GA + AA genotypes of IGF1R rs2229765 demonstrated significant association with L858R mutation in female lung adenocarcinoma patients (OR = 0.35, 95% CI = 0.14-0.88 and OR = 0.34, 95% CI = 0.14-0.84, respectively).	('IGF1R', 'Gene', '3480', (51, 56))	('association', 'Interaction', (92, 103))	('rs2229765', 'Mutation', 'rs2229765', (57, 66))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (134, 153))	('L858R', 'Mutation', 'rs121434568', (109, 114))	('patients', 'Species', '9606', (154, 162))	('lung adenocarcinoma', 'Disease', (134, 153))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('IGF1R', 'Gene', (51, 56))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (134, 153))	('rs2229765', 'Var', (57, 66))	('L858R', 'Var', (109, 114))
278762	27213344	These results indicate that the polymorphisms of IGF1R rs2229765 gene are associated with L858R mutation in female adenocarcinoma patients.	('polymorphisms', 'Var', (32, 45))	('IGF1R', 'Gene', '3480', (49, 54))	('L858R mutation', 'Disease', (90, 104))	('rs2229765', 'Mutation', 'rs2229765', (55, 64))	('rs2229765', 'Var', (55, 64))	('patients', 'Species', '9606', (130, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('adenocarcinoma', 'Disease', (115, 129))	('L858R', 'Mutation', 'rs121434568', (90, 95))	('IGF1R', 'Gene', (49, 54))	('adenocarcinoma', 'Disease', 'MESH:D000230', (115, 129))	('associated', 'Reg', (74, 84))
278765	27213344	We further reveal the association between polymorphisms of IGF1R gene and different clinical N stage of lung cancer in different types of patients.	('lung cancer', 'Disease', 'MESH:D008175', (104, 115))	('lung cancer', 'Disease', (104, 115))	('IGF1R', 'Gene', (59, 64))	('lung cancer', 'Phenotype', 'HP:0100526', (104, 115))	('polymorphisms', 'Var', (42, 55))	('association', 'Interaction', (22, 33))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('IGF1R', 'Gene', '3480', (59, 64))	('patients', 'Species', '9606', (138, 146))
278766	27213344	As shown in Table 6, GA + AA genotype of IGF1R rs7166348 was shown to be significantly associated with the clinical N stage in lung adenocarcinoma (OR = 1.66, 95% CI = 1.07-2.95; p = 0.024).	('IGF1R', 'Gene', '3480', (41, 46))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (127, 146))	('rs7166348', 'Var', (47, 56))	('associated', 'Reg', (87, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('rs7166348', 'Mutation', 'rs7166348', (47, 56))	('IGF1R', 'Gene', (41, 46))	('lung adenocarcinoma', 'Disease', (127, 146))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (127, 146))
278768	27213344	These findings indicate that the polymorphisms of IGF1R rs7166348 may be associated with the clinical N stage of lung cancer.	('polymorphisms', 'Var', (33, 46))	('lung cancer', 'Disease', (113, 124))	('rs7166348', 'Mutation', 'rs7166348', (56, 65))	('lung cancer', 'Phenotype', 'HP:0100526', (113, 124))	('IGF1R', 'Gene', (50, 55))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('associated', 'Reg', (73, 83))	('IGF1R', 'Gene', '3480', (50, 55))	('lung cancer', 'Disease', 'MESH:D008175', (113, 124))	('rs7166348', 'Var', (56, 65))
278769	27213344	Mutations in the TK domain of the EGFR gene were associated with NSCLC.	('EGFR', 'Gene', (34, 38))	('SCLC', 'Phenotype', 'HP:0030357', (66, 70))	('associated', 'Reg', (49, 59))	('NSCLC', 'Disease', 'MESH:D002289', (65, 70))	('NSCLC', 'Phenotype', 'HP:0030358', (65, 70))	('Mutations in', 'Var', (0, 12))	('EGFR', 'Gene', '1956', (34, 38))	('NSCLC', 'Disease', (65, 70))
278770	27213344	Previous studies have reported that EGFR mutations had higher frequency in adenocarcinoma than other types of NSCLCs, in never-smoker as opposed to ever-smokers, and in females rather than males.	('mutations', 'Var', (41, 50))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('adenocarcinoma', 'Disease', 'MESH:D000230', (75, 89))	('NSCLC', 'Disease', (110, 115))	('SCLC', 'Phenotype', 'HP:0030357', (111, 115))	('EGFR', 'Gene', '1956', (36, 40))	('NSCLC', 'Phenotype', 'HP:0030358', (110, 115))	('NSCLC', 'Disease', 'MESH:D002289', (110, 115))	('EGFR', 'Gene', (36, 40))	('adenocarcinoma', 'Disease', (75, 89))
278771	27213344	Indeed, as shown in Table 3, both substitution mutation (L858R) and in-frame deletion mutation were shown to have a higher frequency in female patients (male vs. female = 22.8% vs. 77.2% and 46.9% vs. 53.1%, respectively) and in never-smoker patients (never-smokers vs. ever-smokers = 88.6% vs. 11.4% and 69.1% vs. 30.9%, respectively).	('L858R', 'Mutation', 'rs121434568', (57, 62))	('patients', 'Species', '9606', (143, 151))	('substitution mutation (L858R', 'Var', (34, 62))	('L858R', 'Var', (57, 62))	('patients', 'Species', '9606', (242, 250))
278772	27213344	These results were consistent with previous studies indicating that the mutation of EGFR was associated with adenocarcinoma, smoking status, and gender.	('adenocarcinoma', 'Disease', (109, 123))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('adenocarcinoma', 'Disease', 'MESH:D000230', (109, 123))	('associated', 'Reg', (93, 103))	('EGFR', 'Gene', '1956', (84, 88))	('mutation', 'Var', (72, 80))	('EGFR', 'Gene', (84, 88))	('smoking status', 'Disease', (125, 139))
278774	27213344	In previous studies, polymorphism of the IGF1R rs2229765 gene was associated with levels of free IGF1 and human longevity.	('human', 'Species', '9606', (106, 111))	('human longevity', 'CPA', (106, 121))	('IGF1R', 'Gene', '3480', (41, 46))	('rs2229765', 'Mutation', 'rs2229765', (47, 56))	('associated', 'Reg', (66, 76))	('IGF1', 'Gene', '3479', (97, 101))	('IGF1', 'Gene', (41, 45))	('IGF1', 'Gene', (97, 101))	('polymorphism', 'Var', (21, 33))	('IGF1R', 'Gene', (41, 46))	('levels', 'MPA', (82, 88))	('IGF1', 'Gene', '3479', (41, 45))	('rs2229765', 'Var', (47, 56))
278775	27213344	In addition, it has been reported that IGF1R rs7166348 gene and IGF1 levels are associated with colorectal neoplasia.	('IGF1R', 'Gene', (39, 44))	('IGF1', 'Gene', (39, 43))	('IGF1', 'Gene', (64, 68))	('colorectal neoplasia', 'Disease', 'MESH:D009369', (96, 116))	('rs7166348', 'Mutation', 'rs7166348', (45, 54))	('neoplasia', 'Phenotype', 'HP:0002664', (107, 116))	('IGF1R', 'Gene', '3480', (39, 44))	('associated', 'Reg', (80, 90))	('IGF1', 'Gene', '3479', (39, 43))	('IGF1', 'Gene', '3479', (64, 68))	('rs7166348 gene', 'Var', (45, 59))	('colorectal neoplasia', 'Disease', (96, 116))
278776	27213344	However, fewer studies were reported for association between IGF1R gene polymorphisms and lung cancer.	('lung cancer', 'Disease', 'MESH:D008175', (90, 101))	('IGF1R', 'Gene', (61, 66))	('association', 'Interaction', (41, 52))	('lung cancer', 'Disease', (90, 101))	('lung cancer', 'Phenotype', 'HP:0100526', (90, 101))	('IGF1R', 'Gene', '3480', (61, 66))	('polymorphisms', 'Var', (72, 85))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))
278777	27213344	have reported the clinical significance of IGF1R single nucleotide polymorphisms (SNPs) in resected NSCLC.	('IGF1R', 'Gene', (43, 48))	('NSCLC', 'Disease', (100, 105))	('single nucleotide polymorphisms', 'Var', (49, 80))	('SCLC', 'Phenotype', 'HP:0030357', (101, 105))	('NSCLC', 'Disease', 'MESH:D002289', (100, 105))	('IGF1R', 'Gene', '3480', (43, 48))	('NSCLC', 'Phenotype', 'HP:0030358', (100, 105))
278779	27213344	In this study, we have reported the relationship between the polymorphism of the IGFIR gene and EGFR mutation in NSCLC.	('IGFIR', 'Gene', (81, 86))	('EGFR', 'Gene', (96, 100))	('NSCLC', 'Disease', 'MESH:D002289', (113, 118))	('NSCLC', 'Phenotype', 'HP:0030358', (113, 118))	('IGFIR', 'Gene', '3480', (81, 86))	('SCLC', 'Phenotype', 'HP:0030357', (114, 118))	('NSCLC', 'Disease', (113, 118))	('mutation', 'Var', (101, 109))	('polymorphism', 'Var', (61, 73))	('EGFR', 'Gene', '1956', (96, 100))
278780	27213344	In our studies, three SNPs (rs7166348, rs2229765, and rs8038415) of IGF1R were used.	('rs8038415', 'Mutation', 'rs8038415', (54, 63))	('rs2229765', 'Mutation', 'rs2229765', (39, 48))	('IGF1R', 'Gene', (68, 73))	('rs8038415', 'Var', (54, 63))	('IGF1R', 'Gene', '3480', (68, 73))	('rs2229765', 'Var', (39, 48))	('rs7166348', 'Var', (28, 37))	('rs7166348', 'Mutation', 'rs7166348', (28, 37))
278781	27213344	The results shown in Table 4 and Table 5 indicated that GA and GA + AA genotypes of the IGF1R rs2229765 gene are associated with the L858R mutation of the EGFR in the female lung adenocarcinoma patients.	('L858R', 'Mutation', 'rs121434568', (133, 138))	('patients', 'Species', '9606', (194, 202))	('carcinoma', 'Phenotype', 'HP:0030731', (184, 193))	('IGF1R', 'Gene', (88, 93))	('EGFR', 'Gene', '1956', (155, 159))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (174, 193))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (174, 193))	('rs2229765', 'Mutation', 'rs2229765', (94, 103))	('EGFR', 'Gene', (155, 159))	('rs2229765', 'Var', (94, 103))	('IGF1R', 'Gene', '3480', (88, 93))	('lung adenocarcinoma', 'Disease', (174, 193))	('L858R', 'Var', (133, 138))	('associated', 'Reg', (113, 123))
278784	27213344	As shown in Table 6, GA + AA genotype of IGF1R rs7166348 shows significant association with the clinical stage in lung adenocarcinoma (OR = 1.66, 95% CI = 1.07-2.59).	('lung adenocarcinoma', 'Disease', (114, 133))	('IGF1R', 'Gene', '3480', (41, 46))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('rs7166348', 'Var', (47, 56))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (114, 133))	('rs7166348', 'Mutation', 'rs7166348', (47, 56))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (114, 133))	('IGF1R', 'Gene', (41, 46))	('association', 'Interaction', (75, 86))
278785	27213344	Furthermore, GA + AA genotype of IGF1R rs7166348 was also shown to be significantly associated with clinical N stage in wild-type lung adenocarcinoma patients (OR = 2.75, 95% CI = 1.20-6.31).	('IGF1R', 'Gene', (33, 38))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (130, 149))	('IGF1R', 'Gene', '3480', (33, 38))	('rs7166348', 'Var', (39, 48))	('rs7166348', 'Mutation', 'rs7166348', (39, 48))	('patients', 'Species', '9606', (150, 158))	('lung adenocarcinoma', 'Disease', (130, 149))	('associated', 'Reg', (84, 94))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (130, 149))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))
278786	27213344	These findings implied a relationship linking the polymorphism of the IGFIR gene to the clinical N stage of lung cancer.	('IGFIR', 'Gene', '3480', (70, 75))	('lung cancer', 'Disease', 'MESH:D008175', (108, 119))	('IGFIR', 'Gene', (70, 75))	('lung cancer', 'Disease', (108, 119))	('lung cancer', 'Phenotype', 'HP:0100526', (108, 119))	('polymorphism', 'Var', (50, 62))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
278787	27213344	In addition, previous reports have indicated that rs7166348 in IGF1R was more strongly associated with IGF1 levels in colorectal neoplasia patients.	('IGF1', 'Gene', '3479', (63, 67))	('IGF1', 'Gene', '3479', (103, 107))	('rs7166348', 'Var', (50, 59))	('patients', 'Species', '9606', (139, 147))	('colorectal neoplasia', 'Disease', 'MESH:D009369', (118, 138))	('rs7166348', 'Mutation', 'rs7166348', (50, 59))	('IGF1', 'Gene', (63, 67))	('associated', 'Reg', (87, 97))	('IGF1', 'Gene', (103, 107))	('IGF1R', 'Gene', (63, 68))	('neoplasia', 'Phenotype', 'HP:0002664', (129, 138))	('IGF1R', 'Gene', '3480', (63, 68))	('colorectal neoplasia', 'Disease', (118, 138))
278788	27213344	It is suggested that rs7166348 SNP may increase the activity or expression of IGF1 at the NSCLC progressive stage.	('rs7166348', 'Mutation', 'rs7166348', (21, 30))	('rs7166348 SNP', 'Var', (21, 34))	('IGF1', 'Gene', (78, 82))	('expression', 'MPA', (64, 74))	('activity', 'MPA', (52, 60))	('NSCLC', 'Disease', (90, 95))	('increase', 'PosReg', (39, 47))	('NSCLC', 'Disease', 'MESH:D002289', (90, 95))	('IGF1', 'Gene', '3479', (78, 82))	('SCLC', 'Phenotype', 'HP:0030357', (91, 95))	('NSCLC', 'Phenotype', 'HP:0030358', (90, 95))
278792	27213344	Allelic discrimination of IGF1R rs7166348, rs2229765, and rs8038415 gene polymorphism was assessed with the ABI StepOne  Real-Time PCR System (Applied Biosystems, Foster City, CA, USA) and analyzed using SDS vers.	('SDS', 'Chemical', 'MESH:D012967', (204, 207))	('rs2229765', 'Mutation', 'rs2229765', (43, 52))	('rs8038415', 'Var', (58, 67))	('IGF1R', 'Gene', (26, 31))	('rs7166348', 'Var', (32, 41))	('rs7166348', 'Mutation', 'rs7166348', (32, 41))	('IGF1R', 'Gene', '3480', (26, 31))	('rs2229765', 'Var', (43, 52))	('rs8038415', 'Mutation', 'rs8038415', (58, 67))
278794	27213344	The odds ratio and 95% CIs of the association between the genotype frequencies and EGFR mutation risk and the clinical pathological characteristics were estimated using multiple logistic regression models after controlling for other covariates.	('EGFR', 'Gene', '1956', (83, 87))	('mutation', 'Var', (88, 96))	('EGFR', 'Gene', (83, 87))
278795	27213344	In conclusion, the mutation of EGFR was associated with adenocarcinoma, smoking status, and gender and the polymorphisms of the IGF1R rs2229765 gene were associated with the L858R mutation of EGFR in female lung adenocarcinoma patients who had never smoked.	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (207, 226))	('adenocarcinoma', 'Disease', 'MESH:D000230', (56, 70))	('associated', 'Reg', (40, 50))	('EGFR', 'Gene', (192, 196))	('rs2229765', 'Var', (134, 143))	('EGFR', 'Gene', '1956', (31, 35))	('mutation', 'Var', (19, 27))	('L858R', 'Var', (174, 179))	('rs2229765', 'Mutation', 'rs2229765', (134, 143))	('adenocarcinoma', 'Disease', (212, 226))	('IGF1R', 'Gene', '3480', (128, 133))	('patients', 'Species', '9606', (227, 235))	('IGF1R', 'Gene', (128, 133))	('lung adenocarcinoma', 'Disease', (207, 226))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('adenocarcinoma', 'Disease', 'MESH:D000230', (212, 226))	('EGFR', 'Gene', '1956', (192, 196))	('associated', 'Reg', (154, 164))	('EGFR', 'Gene', (31, 35))	('L858R', 'Mutation', 'rs121434568', (174, 179))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (207, 226))	('polymorphisms', 'Var', (107, 120))	('adenocarcinoma', 'Disease', (56, 70))	('carcinoma', 'Phenotype', 'HP:0030731', (217, 226))
278796	27213344	Furthermore, the polymorphism of IGFIR rs7166348 gene was associated with the clinical N stage of lung cancer.	('associated with', 'Reg', (58, 73))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('lung cancer', 'Disease', (98, 109))	('lung cancer', 'Phenotype', 'HP:0100526', (98, 109))	('IGFIR', 'Gene', '3480', (33, 38))	('rs7166348', 'Var', (39, 48))	('rs7166348', 'Mutation', 'rs7166348', (39, 48))	('IGFIR', 'Gene', (33, 38))	('lung cancer', 'Disease', 'MESH:D008175', (98, 109))	('polymorphism', 'Var', (17, 29))
278829	25364189	The cells within the strands in these regions showed prominent pleomorphism, hyperchromasia, mitosis about 5-6/HPF, individual cell keratinization and keratin pearl formation [Figures 5-8].	('pleomorphism', 'Var', (63, 75))	('hyperchromasia, mitosis', 'Disease', 'None', (77, 100))	('keratin pearl formation', 'CPA', (151, 174))	('individual cell keratinization', 'CPA', (116, 146))
278863	25364189	reported that the rate of allelic loss in a study involving chromosomes 1p, 3p, 9p, 10q and 17p in ameloblastic carcinomas are similar to those in benign tumors indicating that different genetic mechanisms may be responsible in malignant behavior.	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('allelic loss', 'Var', (26, 38))	('ameloblastic carcinomas', 'Disease', 'MESH:D009810', (99, 122))	('benign tumors', 'Disease', 'MESH:D009369', (147, 160))	('ameloblastic carcinomas', 'Disease', (99, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('carcinomas', 'Phenotype', 'HP:0030731', (112, 122))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('benign tumors', 'Disease', (147, 160))
278867	25364189	Changes in the BH3-only proteins, which are responsible for apoptosis in odontogenic tissues can lead to formation of tumors.	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('BH3-only proteins', 'Protein', (15, 32))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('Changes', 'Var', (0, 7))	('tumors', 'Disease', (118, 124))	('lead to', 'Reg', (97, 104))	('tumors', 'Disease', 'MESH:D009369', (118, 124))
278869	25364189	concluded that hyper methylation of p16 gene was involved in the malignant transformation of pre-existing benign ameloblastoma to an ameloblastic carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('benign ameloblastoma', 'Disease', 'MESH:D000564', (106, 126))	('ameloblastic carcinoma', 'Disease', (133, 155))	('involved', 'Reg', (49, 57))	('p16', 'Gene', '1029', (36, 39))	('ameloblastic carcinoma', 'Disease', 'MESH:D009810', (133, 155))	('hyper methylation', 'Var', (15, 32))	('benign ameloblastoma', 'Disease', (106, 126))	('p16', 'Gene', (36, 39))
278903	33501784	In addition, silencing of SPRR1B could inhibit the cell proliferation, invasion, and migration of lung adenocarcinoma cells, but induced cell apoptosis and G2/M phase arrest in vitro.	('SPRR1B', 'Gene', (26, 32))	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (98, 117))	('inhibit', 'NegReg', (39, 46))	('induced', 'Reg', (129, 136))	('invasion', 'CPA', (71, 79))	('cell apoptosis', 'CPA', (137, 151))	('arrest', 'Disease', 'MESH:D006323', (167, 173))	('cell proliferation', 'CPA', (51, 69))	('migration', 'CPA', (85, 94))	('lung adenocarcinoma', 'Disease', (98, 117))	('arrest', 'Disease', (167, 173))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (98, 117))	('silencing', 'Var', (13, 22))
278904	33501784	The result of GSEA and immunoblotting revealed that SPRR1B activated the MAPK signaling pathway involved in the proliferation and metastasis of lung cancer.	('metastasis of lung cancer', 'Disease', 'MESH:D008175', (130, 155))	('lung cancer', 'Phenotype', 'HP:0100526', (144, 155))	('MAPK signaling pathway', 'Pathway', (73, 95))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('SPRR1B', 'Var', (52, 58))	('activated', 'PosReg', (59, 68))	('metastasis of lung cancer', 'Disease', (130, 155))	('GSEA', 'Chemical', '-', (14, 18))
278959	33501784	To investigate the effect of SPRR1B on the proliferative capability of lung adenocarcinoma cells, the cell proliferative capability was examined using the colony formation assay and EdU assay after transfection with SPRR1B siRNA for 48 h. The result (Figure 5(a)) showed that the proliferation of both cell lines was obviously inhibited after SPRR1B knockdown in H1650 and H1975 cells (p < 0.001 and p < 0.0001, respectively).	('H1975', 'CellLine', 'CVCL:1511', (373, 378))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (71, 90))	('SPRR1B', 'Gene', (343, 349))	('lung adenocarcinoma', 'Disease', (71, 90))	('knockdown', 'Var', (350, 359))	('EdU', 'Chemical', 'MESH:C031086', (182, 185))	('proliferation', 'CPA', (280, 293))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (71, 90))	('inhibited', 'NegReg', (327, 336))	('H1650', 'CellLine', 'CVCL:1483', (363, 368))
278960	33501784	EdU proliferation assay also revealed that silencing SPRR1B decreased the number of EdU-positive cells (p < 0.0001 and p < 0.0001, respectively (Figure 5(b)).	('decreased', 'NegReg', (60, 69))	('EdU', 'Chemical', 'MESH:C031086', (84, 87))	('silencing', 'Var', (43, 52))	('EdU', 'Chemical', 'MESH:C031086', (0, 3))	('SPRR1B', 'Gene', (53, 59))
278961	33501784	These data demonstrated that silencing SPRR1B inhibited cell proliferation of lung adenocarcinoma cells.	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (78, 97))	('silencing', 'Var', (29, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('cell proliferation of', 'CPA', (56, 77))	('lung adenocarcinoma', 'Disease', (78, 97))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (78, 97))	('inhibited', 'NegReg', (46, 55))	('SPRR1B', 'Gene', (39, 45))
278964	33501784	These results demonstrate that SPRR1B inhibition can enhance cell apoptosis in lung adenocarcinoma cells.	('cell apoptosis', 'CPA', (61, 75))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (79, 98))	('SPRR1B', 'Gene', (31, 37))	('inhibition', 'Var', (38, 48))	('enhance', 'PosReg', (53, 60))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (79, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('lung adenocarcinoma', 'Disease', (79, 98))
278966	33501784	Results revealed that SPRR1B knockdown significantly inhibited cell migration (901.0 to 204.0, p < 0.01 and 469.7 to 83.0, p = 0.01, Figure 7(a)) and invasiveness (1423.0 to 182.3, p < 0.01 and 909.3 to 29.7, p < 0.01) in H1650 and H1975.	('H1650', 'CellLine', 'CVCL:1483', (222, 227))	('inhibited', 'NegReg', (53, 62))	('knockdown', 'Var', (29, 38))	('cell migration', 'CPA', (63, 77))	('H1975', 'CellLine', 'CVCL:1511', (232, 237))	('invasiveness', 'CPA', (150, 162))	('SPRR1B', 'Gene', (22, 28))
278971	33501784	The western blot results showed that the expression level of phosphorylated MAP kinase in SPRR1B knockdown cells were significantly downregulated (Figure 8(c)), which implies that SPRR1B may affect the phenotype of lung adenocarcinoma cells by regulating the MAP kinase signaling pathway.	('MAP kinase signaling pathway', 'Pathway', (259, 287))	('affect', 'Reg', (191, 197))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (215, 234))	('MAP', 'Enzyme', (76, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (225, 234))	('lung adenocarcinoma', 'Disease', (215, 234))	('SPRR1B', 'Gene', (90, 96))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (215, 234))	('SPRR1B', 'Var', (180, 186))	('regulating', 'Reg', (244, 254))	('downregulated', 'NegReg', (132, 145))	('expression level', 'MPA', (41, 57))
278979	33501784	SPRR1B knockdown can inhibit lung adenocarcinoma cell proliferation, migration, and invasion, and it induced the G2/M phase arrest in vitro.	('invasion', 'CPA', (84, 92))	('arrest', 'Disease', 'MESH:D006323', (124, 130))	('lung adenocarcinoma', 'Disease', (29, 48))	('arrest', 'Disease', (124, 130))	('SPRR1B', 'Gene', (0, 6))	('induced', 'Reg', (101, 108))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (29, 48))	('inhibit', 'NegReg', (21, 28))	('carcinoma', 'Phenotype', 'HP:0030731', (39, 48))	('knockdown', 'Var', (7, 16))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (29, 48))	('migration', 'CPA', (69, 78))
278991	33501784	Oncomine also showed, in our analysis, that SPRR1B and SPRR2D are overexpressed in lung cancer.	('lung cancer', 'Disease', 'MESH:D008175', (83, 94))	('SPRR1B', 'Var', (44, 50))	('overexpressed', 'PosReg', (66, 79))	('SPRR2D', 'Gene', (55, 61))	('lung cancer', 'Disease', (83, 94))	('lung cancer', 'Phenotype', 'HP:0100526', (83, 94))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('Oncomine', 'Chemical', '-', (0, 8))	('SPRR2D', 'Gene', '6703', (55, 61))
278994	33501784	According to the results of the EdU proliferation assay and the colony formation assay, decreased expression of SPRR1B inhibited lung adenocarcinoma proliferation, induced G2/M-phase arrest, and promoted apoptosis, which differs from the reported enhanced entry of cells into the G0 phase discussed by Tesfaigzi et al.	('EdU', 'Chemical', 'MESH:C031086', (32, 35))	('expression', 'Var', (98, 108))	('arrest', 'Disease', 'MESH:D006323', (183, 189))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (129, 148))	('carcinoma', 'Phenotype', 'HP:0030731', (139, 148))	('SPRR1B', 'Gene', (112, 118))	('induced', 'Reg', (164, 171))	('inhibited', 'NegReg', (119, 128))	('promoted', 'PosReg', (195, 203))	('decreased', 'NegReg', (88, 97))	('arrest', 'Disease', (183, 189))	('lung adenocarcinoma proliferation', 'Disease', (129, 162))	('lung adenocarcinoma proliferation', 'Disease', 'MESH:D000077192', (129, 162))	('apoptosis', 'CPA', (204, 213))
278995	33501784	31  Simultaneously, SPRR1B knockdown inhibited lung cancer cell migration and invasion, which indicates the potential role of SPRR1B in tumor invasion and metastasis, although further study is also needed.	('knockdown', 'Var', (27, 36))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('SPRR1B', 'Gene', (20, 26))	('lung cancer', 'Disease', (47, 58))	('inhibited', 'NegReg', (37, 46))	('lung cancer', 'Phenotype', 'HP:0100526', (47, 58))	('invasion', 'CPA', (78, 86))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('lung cancer', 'Disease', 'MESH:D008175', (47, 58))	('tumor', 'Disease', (136, 141))
279016	32300359	Recent Studies indicated that the occurrence of IPF and NSCLC share the same genetic mutations and abnormal activation of signal pathways, suggesting potential molecular mechanisms between IPF and NSCLC, and there is speculation IPF could lead to cancer.	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('NSCLC', 'Phenotype', 'HP:0030358', (197, 202))	('lead to', 'Reg', (239, 246))	('NSCLC', 'Disease', (56, 61))	('cancer', 'Disease', (247, 253))	('cancer', 'Disease', 'MESH:D009369', (247, 253))	('mutations', 'Var', (85, 94))	('NSCLC', 'Disease', 'MESH:D002289', (56, 61))	('NSCLC', 'Disease', (197, 202))	('signal pathways', 'Pathway', (122, 137))	('NSCLC', 'Disease', 'MESH:D002289', (197, 202))	('NSCLC', 'Phenotype', 'HP:0030358', (56, 61))
279024	32300359	Selection criteria on the Gene Expression Omnibus (GEO) database1 are: (1) The datasets contain miRNA expression profiles and gene expression profiles; (2) there are normal group (normal tissue samples) and IPF group (IPF tissue samples) in the datasets; and (3) the number of samples in each group is more than 10. miRNA expression profiles (GSE32538 and GSE27430) and gene expression profiles (GSE32537, GSE10667, and GSE70866) related to IPF were downloaded from GEO database.	('GSE70866', 'Var', (420, 428))	('GSE32538', 'Var', (343, 351))	('GSE32537', 'Var', (396, 404))	('GSE10667', 'Var', (406, 414))	('GSE27430', 'Var', (356, 364))	('miR', 'Gene', '220972', (96, 99))	('miR', 'Gene', '220972', (316, 319))	('miR', 'Gene', (96, 99))	('miR', 'Gene', (316, 319))
279025	32300359	Among them, GSE32537 and GSE32538 were used to identify hub genes and hub miRNAs by WGCNA separately.	('hub', 'Gene', (56, 59))	('miR', 'Gene', (74, 77))	('hub', 'Gene', (70, 73))	('miR', 'Gene', '220972', (74, 77))	('GSE32538', 'Var', (25, 33))	('hub', 'Gene', '1993', (70, 73))	('hub', 'Gene', '1993', (56, 59))
279026	32300359	After doing analysis of variance for GSE32537, we chose the top 25% most variant genes (2987 genes) for constructing networks, while we did not to do pretreatment for GSE32538 due to the small number of miRNAs (1801 miRNAs).	('miR', 'Gene', '220972', (216, 219))	('miR', 'Gene', '220972', (203, 206))	('miR', 'Gene', (216, 219))	('miR', 'Gene', (203, 206))	('variant', 'Var', (73, 80))
279038	32300359	To verify our results, GSE10667 (including 15 normal lung tissues and 31 IPF tissues) and GSE70866 (including 20 normal lung tissues and 110 IPF tissues), were used to validate the different expression levels of hub genes between normal tissue and IPF tissues with two-tailed student's t-tests, separately.	('GSE70866', 'Var', (90, 98))	('hub', 'Gene', (212, 215))	('expression', 'MPA', (191, 201))	('hub', 'Gene', '1993', (212, 215))
279047	32300359	To further understand the role of hub genes and hub miRNAs in clinical practice, we selected two data sets (GSE70866 and GSE27430) with clearer clinical information to do clinicopathological correlation analysis separately.	('hub', 'Gene', (48, 51))	('miR', 'Gene', '220972', (52, 55))	('hub', 'Gene', '1993', (34, 37))	('hub', 'Gene', '1993', (48, 51))	('GSE70866', 'Var', (108, 116))	('GSE27430', 'Var', (121, 129))	('hub', 'Gene', (34, 37))	('miR', 'Gene', (52, 55))
279056	32300359	The clustering dendrograms of the genes of GSE32537 are generated in Figure 2A, while miRNAs of GSE32538 are shown in Figure 2B.	('GSE32537', 'Var', (43, 51))	('miR', 'Gene', '220972', (86, 89))	('miR', 'Gene', (86, 89))
279071	32300359	From the results of two-tailed student's t-tests for GSE10667 and GSE70866, the expression levels of all hub genes (COL3A1, COL1A2, OGN, COL15A1, ASPN, and MXRA5) were significantly higher in IPF tissues (Figure 5).	('MXRA5', 'Gene', (156, 161))	('OGN', 'Gene', (132, 135))	('COL1A2', 'Gene', '1278', (124, 130))	('expression levels', 'MPA', (80, 97))	('higher', 'PosReg', (182, 188))	('GSE10667', 'Var', (53, 61))	('COL1A2', 'Gene', (124, 130))	('COL15A1', 'Gene', (137, 144))	('COL3A1', 'Gene', '1281', (116, 122))	('ASPN', 'Gene', (146, 150))	('IPF', 'Disease', (192, 195))	('COL15A1', 'Gene', '1306', (137, 144))	('GSE70866', 'Var', (66, 74))	('ASPN', 'Gene', '54829', (146, 150))	('COL3A1', 'Gene', (116, 122))	('hub', 'Gene', (105, 108))	('OGN', 'Gene', '4969', (132, 135))	('MXRA5', 'Gene', '25878', (156, 161))	('hub', 'Gene', '1993', (105, 108))
279094	32300359	More importantly, it was the first time to explore the common mechanisms and molecular targets between IPF and NSCLC in bioinformatics, which would provide more information about that IPF causing NSCLC and poor NSCLC prognosis, and this more attention is to be called on IPF-NSCLC patients.	('NSCLC', 'Disease', (196, 201))	('NSCLC', 'Phenotype', 'HP:0030358', (275, 280))	('NSCLC', 'Disease', (275, 280))	('NSCLC', 'Disease', (111, 116))	('NSCLC', 'Phenotype', 'HP:0030358', (211, 216))	('NSCLC', 'Disease', 'MESH:D002289', (196, 201))	('patients', 'Species', '9606', (281, 289))	('NSCLC', 'Disease', 'MESH:D002289', (275, 280))	('NSCLC', 'Disease', 'MESH:D002289', (111, 116))	('IPF', 'Var', (184, 187))	('IPF-NSCLC', 'Disease', 'MESH:D054990', (271, 280))	('NSCLC', 'Disease', (211, 216))	('IPF-NSCLC', 'Disease', (271, 280))	('NSCLC', 'Phenotype', 'HP:0030358', (196, 201))	('causing', 'Reg', (188, 195))	('NSCLC', 'Disease', 'MESH:D002289', (211, 216))	('NSCLC', 'Phenotype', 'HP:0030358', (111, 116))
279126	31844042	Hsa_circ_0002483 inhibited the progression and enhanced the Taxol sensitivity of non-small cell lung cancer by targeting miR-182-5p In this study, we identified a novel circRNA, circ_0002483, and further investigated its functions in the progression and Taxol resistance of NSCLC.	('miR-182', 'Gene', '406958', (121, 128))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('Taxol', 'Chemical', 'MESH:D017239', (60, 65))	('circ_0002483', 'Var', (178, 190))	('investigated', 'Reg', (204, 216))	('lung cancer', 'Phenotype', 'HP:0100526', (96, 107))	('NSCLC', 'Disease', 'MESH:D002289', (274, 279))	('enhanced', 'PosReg', (47, 55))	('inhibited', 'NegReg', (17, 26))	('Taxol', 'Chemical', 'MESH:D017239', (254, 259))	('NSCLC', 'Disease', (274, 279))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (81, 107))	('cancer', 'Disease', (101, 107))	('NSCLC', 'Phenotype', 'HP:0030358', (274, 279))	('Taxol sensitivity', 'MPA', (60, 77))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (85, 107))	('circ_0002483', 'Chemical', '-', (178, 190))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('progression', 'MPA', (31, 42))	('miR-182', 'Gene', (121, 128))	('circ_0002483', 'Chemical', '-', (4, 16))
279127	31844042	We found that circ_0002483 was expressed at low levels in NSCLC tissues and cell lines.	('NSCLC', 'Disease', (58, 63))	('circ_0002483', 'Chemical', '-', (14, 26))	('NSCLC', 'Disease', 'MESH:D002289', (58, 63))	('circ_0002483', 'Var', (14, 26))	('NSCLC', 'Phenotype', 'HP:0030358', (58, 63))
279129	31844042	Mechanistically, circ_0002483 was identified to sponge multiple miRNAs including miR-182-5p (also named miR-182), miR-520q-3p, miR-582-3p, miR-587, and miR-655.	('miR-182', 'Gene', '406958', (104, 111))	('miR-182', 'Gene', (81, 88))	('miR-582-3p', 'Var', (127, 137))	('miR-182-5p', 'Gene', '100302183', (81, 91))	('miR-587', 'Gene', (139, 146))	('circ_0002483', 'Var', (17, 29))	('miR-182', 'Gene', '406958', (81, 88))	('miR-655', 'Gene', '724025', (152, 159))	('circ_0002483', 'Chemical', '-', (17, 29))	('miR-587', 'Gene', '693172', (139, 146))	('miR-182', 'Gene', (104, 111))	('miR-520q-3p', 'Var', (114, 125))	('miR-182-5p', 'Gene', (81, 91))	('miR-655', 'Gene', (152, 159))
279130	31844042	In addition, circ_0002483 was also demonstrated to regulate the expression of GRB2, FOXO1, and FOXO3, three target genes of miR-182-5p, by sponging miR-182-5p.	('expression', 'MPA', (64, 74))	('FOXO3', 'Gene', (95, 100))	('FOXO1', 'Gene', '2308', (84, 89))	('GRB2', 'Gene', (78, 82))	('miR-182-5p', 'Gene', '100302183', (124, 134))	('miR-182-5p', 'Gene', (124, 134))	('regulate', 'Reg', (51, 59))	('sponging', 'Var', (139, 147))	('FOXO3', 'Gene', '2309', (95, 100))	('miR-182-5p', 'Gene', (148, 158))	('GRB2', 'Gene', '2885', (78, 82))	('miR-182-5p', 'Gene', '100302183', (148, 158))	('circ_0002483', 'Chemical', '-', (13, 25))	('FOXO1', 'Gene', (84, 89))
279131	31844042	Circ_0002483 was demonstrated to inhibit NSCLC progression in vitro and in vivo and enhanced the sensitivity of NSCLC cells to Taxol by sponging miR-182-5p to release the inhibition on GRB2, FOXO1, and FOXO3 mRNAs.	('Circ_0002483', 'Var', (0, 12))	('GRB2', 'Gene', '2885', (185, 189))	('NSCLC', 'Disease', (41, 46))	('inhibit', 'NegReg', (33, 40))	('NSCLC', 'Phenotype', 'HP:0030358', (112, 117))	('GRB2', 'Gene', (185, 189))	('NSCLC', 'Phenotype', 'HP:0030358', (41, 46))	('FOXO3', 'Gene', '2309', (202, 207))	('FOXO1', 'Gene', (191, 196))	('miR-182-5p', 'Gene', (145, 155))	('sensitivity', 'MPA', (97, 108))	('enhanced', 'PosReg', (84, 92))	('NSCLC', 'Disease', 'MESH:D002289', (112, 117))	('NSCLC', 'Disease', 'MESH:D002289', (41, 46))	('miR-182-5p', 'Gene', '100302183', (145, 155))	('Taxol', 'Chemical', 'MESH:D017239', (127, 132))	('FOXO3', 'Gene', (202, 207))	('NSCLC', 'Disease', (112, 117))	('FOXO1', 'Gene', '2308', (191, 196))
279144	31844042	Previous studies have shown that the dysregulation of miRNAs, lncRNAs, and circRNAs is involved in the tumorigenesis of multiple human cancers by regulating corresponding oncogenes or tumor suppressor genes.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('dysregulation', 'Var', (37, 50))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('cancers', 'Phenotype', 'HP:0002664', (135, 142))	('cancers', 'Disease', (135, 142))	('tumor', 'Disease', (103, 108))	('cancers', 'Disease', 'MESH:D009369', (135, 142))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('oncogenes', 'Gene', (171, 180))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('involved', 'Reg', (87, 95))	('tumor', 'Disease', (184, 189))	('human', 'Species', '9606', (129, 134))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('regulating', 'Reg', (146, 156))
279147	31844042	reported the profiles of differentially expressed circRNAs in Taxol-resistant NSCLC, showing 2909 significantly increased and 8372 decreased circRNAs in Taxol-resistant NSCLC cells compared with normal NSCLC cells.	('NSCLC', 'Phenotype', 'HP:0030358', (169, 174))	('NSCLC', 'Disease', (202, 207))	('NSCLC', 'Phenotype', 'HP:0030358', (78, 83))	('decreased', 'NegReg', (131, 140))	('NSCLC', 'Disease', (169, 174))	('NSCLC', 'Disease', 'MESH:D002289', (202, 207))	('NSCLC', 'Disease', 'MESH:D002289', (169, 174))	('increased', 'PosReg', (112, 121))	('circRNAs', 'MPA', (141, 149))	('NSCLC', 'Disease', (78, 83))	('NSCLC', 'Phenotype', 'HP:0030358', (202, 207))	('8372', 'Var', (126, 130))	('Taxol', 'Chemical', 'MESH:D017239', (62, 67))	('NSCLC', 'Disease', 'MESH:D002289', (78, 83))	('Taxol', 'Chemical', 'MESH:D017239', (153, 158))
279180	31844042	To confirm the interaction between circ_0002483 and miR-182-5p, the wild-type (WT) and mutant (Mut) fragments of circ_0002483 containing putative miR-182-5p binding sites were amplified and subcloned into the pGL3 (Promega, USA) vector to form circ_0002483-WT and circ_0002483-Mut recombinant plasmids.	('pGL3', 'Gene', '6391', (209, 213))	('miR-182-5p', 'Gene', '100302183', (52, 62))	('miR-182-5p', 'Gene', (52, 62))	('mutant', 'Var', (87, 93))	('circ_0002483', 'Chemical', '-', (113, 125))	('circ_0002483', 'Chemical', '-', (244, 256))	('miR-182-5p', 'Gene', '100302183', (146, 156))	('miR-182-5p', 'Gene', (146, 156))	('pGL3', 'Gene', (209, 213))	('circ_0002483', 'Chemical', '-', (35, 47))	('circ_0002483', 'Chemical', '-', (264, 276))
279184	31844042	The interaction between circ_0002483 and miR-520q-3p, miR-582-3p, miR-587 or miR-655 was also verified to be the same as that between miR-182-5p and circ_0002483.	('miR-582-3p', 'Var', (54, 64))	('miR-182-5p', 'Gene', '100302183', (134, 144))	('interaction', 'Interaction', (4, 15))	('circ_0002483', 'Chemical', '-', (149, 161))	('miR-520q-3p', 'Var', (41, 52))	('circ_0002483', 'Var', (24, 36))	('miR-655', 'Gene', '724025', (77, 84))	('miR-587', 'Gene', (66, 73))	('miR-587', 'Gene', '693172', (66, 73))	('miR-182-5p', 'Gene', (134, 144))	('miR-655', 'Gene', (77, 84))	('circ_0002483', 'Chemical', '-', (24, 36))
279191	31844042	Moreover, we analyzed the top 20 downregulated circRNAs in 8 pairs of NSCLC and adjacent normal tissue samples, and circ_0002483 also showed the most obvious change (Fig.	('circ_0002483', 'Var', (116, 128))	('NSCLC', 'Disease', (70, 75))	('NSCLC', 'Disease', 'MESH:D002289', (70, 75))	('circ_0002483', 'Chemical', '-', (116, 128))	('NSCLC', 'Phenotype', 'HP:0030358', (70, 75))	('downregulated', 'NegReg', (33, 46))
279193	31844042	Next, we found that circ_0002483 was significantly downregulated in NSCLC tissue samples compared with normal tissue samples (n = 46, Fig.	('NSCLC', 'Disease', 'MESH:D002289', (68, 73))	('circ_0002483', 'Var', (20, 32))	('NSCLC', 'Phenotype', 'HP:0030358', (68, 73))	('downregulated', 'NegReg', (51, 64))	('circ_0002483', 'Chemical', '-', (20, 32))	('NSCLC', 'Disease', (68, 73))
279195	31844042	1g) and was downregulated in A549/Taxol and H1299/Taxol compared with the parental cell lines A549 and H1299 cells (Fig.	('H1299', 'CellLine', 'CVCL:0060', (103, 108))	('downregulated', 'NegReg', (12, 25))	('H1299/Taxol', 'Var', (44, 55))	('Taxol', 'Chemical', 'MESH:D017239', (50, 55))	('A549', 'CellLine', 'CVCL:0023', (94, 98))	('H1299', 'CellLine', 'CVCL:0060', (44, 49))	('Taxol', 'Chemical', 'MESH:D017239', (34, 39))	('A549', 'CellLine', 'CVCL:0023', (29, 33))
279196	31844042	In addition, NSCLC patients with low circ_0002483 expression exhibited a worse prognosis than those with high circ_0002483 expression (Fig.	('NSCLC', 'Disease', (13, 18))	('circ_0002483', 'Chemical', '-', (110, 122))	('patients', 'Species', '9606', (19, 27))	('NSCLC', 'Disease', 'MESH:D002289', (13, 18))	('circ_0002483', 'Chemical', '-', (37, 49))	('low circ_0002483 expression', 'Var', (33, 60))	('NSCLC', 'Phenotype', 'HP:0030358', (13, 18))
279197	31844042	To investigate the biological functions of circ_0002483 in NSCLC, we overexpressed circ_0002483 by transfecting A549 and H1299 cells with Circ_0002483 (Circ OE) (Fig.	('A549', 'CellLine', 'CVCL:0023', (112, 116))	('NSCLC', 'Disease', 'MESH:D002289', (59, 64))	('H1299', 'CellLine', 'CVCL:0060', (121, 126))	('circ_0002483', 'Chemical', '-', (83, 95))	('Circ_0002483', 'Var', (138, 150))	('NSCLC', 'Phenotype', 'HP:0030358', (59, 64))	('circ_0002483', 'Chemical', '-', (43, 55))	('NSCLC', 'Disease', (59, 64))
279198	31844042	The CCK-8 assay and colony formation assay showed that circ_0002483 overexpression significantly suppressed cell viability in both A549 and H1299 cells compared with the vector group (Fig.	('CCK-8', 'Chemical', '-', (4, 9))	('cell viability', 'CPA', (108, 122))	('overexpression', 'PosReg', (68, 82))	('circ_0002483', 'Var', (55, 67))	('A549', 'CellLine', 'CVCL:0023', (131, 135))	('H1299', 'CellLine', 'CVCL:0060', (140, 145))	('suppressed', 'NegReg', (97, 107))	('circ_0002483', 'Chemical', '-', (55, 67))
279202	31844042	Our previous data showed that circ_0002483 was significantly downregulated in Taxol-resistant NSCLC cells, implying that targeting circ_0002483 would overcome Taxol resistance.	('NSCLC', 'Phenotype', 'HP:0030358', (94, 99))	('overcome', 'PosReg', (150, 158))	('downregulated', 'NegReg', (61, 74))	('Taxol', 'Chemical', 'MESH:D017239', (78, 83))	('circ_0002483', 'Chemical', '-', (131, 143))	('Taxol resistance', 'MPA', (159, 175))	('NSCLC', 'Disease', (94, 99))	('NSCLC', 'Disease', 'MESH:D002289', (94, 99))	('circ_0002483', 'Gene', (30, 42))	('Taxol', 'Chemical', 'MESH:D017239', (159, 164))	('circ_0002483', 'Chemical', '-', (30, 42))	('circ_0002483', 'Var', (131, 143))
279205	31844042	The CCK-8 assay showed that circ_0002483 overexpression significantly enhanced the sensitivity of A549/Taxol and H1299/Taxol cells to Taxol (Fig.	('A549', 'CellLine', 'CVCL:0023', (98, 102))	('circ_0002483', 'Chemical', '-', (28, 40))	('sensitivity', 'MPA', (83, 94))	('Taxol', 'Chemical', 'MESH:D017239', (134, 139))	('Taxol', 'Chemical', 'MESH:D017239', (119, 124))	('circ_0002483', 'Var', (28, 40))	('enhanced', 'PosReg', (70, 78))	('H1299', 'CellLine', 'CVCL:0060', (113, 118))	('Taxol', 'Chemical', 'MESH:D017239', (103, 108))	('overexpression', 'PosReg', (41, 55))	('CCK-8', 'Chemical', '-', (4, 9))
279206	31844042	3b, c), while circ_0002483 knockdown remarkably attenuated the sensitivity of A549/Taxol and H1299/Taxol cells to Taxol (Fig.	('circ_0002483', 'Chemical', '-', (14, 26))	('knockdown', 'Var', (27, 36))	('H1299', 'CellLine', 'CVCL:0060', (93, 98))	('attenuated', 'NegReg', (48, 58))	('sensitivity', 'MPA', (63, 74))	('Taxol', 'Chemical', 'MESH:D017239', (83, 88))	('Taxol', 'Chemical', 'MESH:D017239', (99, 104))	('circ_0002483 knockdown', 'Var', (14, 36))	('A549', 'CellLine', 'CVCL:0023', (78, 82))	('Taxol', 'Chemical', 'MESH:D017239', (114, 119))
279207	31844042	Moreover, we found that Circ OE treatment resulted in a significant downregulation of the IC50 value of A549/Taxol and H1299/Taxol cells (Fig.	('A549', 'CellLine', 'CVCL:0023', (104, 108))	('H1299/Taxol', 'Var', (119, 130))	('Taxol', 'Chemical', 'MESH:D017239', (109, 114))	('downregulation', 'NegReg', (68, 82))	('H1299', 'CellLine', 'CVCL:0060', (119, 124))	('IC50 value', 'MPA', (90, 100))	('Taxol', 'Chemical', 'MESH:D017239', (125, 130))
279211	31844042	Among the 24 predicted miRNAs, only five miRNAs (miR-182-5p, miR-520q-3p, miR-582-3p, miR-587, and miR-655) significantly attenuated the luciferase activity of A549 cells (Fig.	('miR-520q-3p', 'Var', (61, 72))	('miR-582-3p', 'Var', (74, 84))	('miR-655', 'Gene', (99, 106))	('miR-182-5p', 'Gene', (49, 59))	('activity', 'MPA', (148, 156))	('miR-182-5p', 'Gene', '100302183', (49, 59))	('luciferase', 'Enzyme', (137, 147))	('miR-655', 'Gene', '724025', (99, 106))	('A549', 'CellLine', 'CVCL:0023', (160, 164))	('miR-587', 'Gene', (86, 93))	('miR-587', 'Gene', '693172', (86, 93))	('attenuated', 'NegReg', (122, 132))
279212	31844042	We subsequently predicted the target genes of miR-182-5p, miR-520q-3p, miR-582-3p, miR-587, and miR-655 by using TargetScan 7.2 and analyzed the identified target genes in a KEGG pathway analysis (Fig.	('miR-582-3p', 'Var', (71, 81))	('miR-520q-3p', 'Var', (58, 69))	('miR-587', 'Gene', '693172', (83, 90))	('miR-655', 'Gene', (96, 103))	('miR-182-5p', 'Gene', '100302183', (46, 56))	('miR-182-5p', 'Gene', (46, 56))	('miR-587', 'Gene', (83, 90))	('miR-655', 'Gene', '724025', (96, 103))
279213	31844042	Based on this analysis, the top 30 target genes of the five miRNAs were found to be involved in the following four common, critical pathways: pathways in cancer, proteoglycans in cancer, Ras signaling pathway and FoxO signaling pathway (Fig.	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('Ras signaling pathway', 'Pathway', (187, 208))	('cancer', 'Disease', (154, 160))	('miRNAs', 'Var', (60, 66))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('cancer', 'Disease', (179, 185))	('involved', 'Reg', (84, 92))	('FoxO signaling pathway', 'Pathway', (213, 235))
279217	31844042	The RIP assay showed a specific enrichment of circ_0002483 and miR-182-5p in the miR-182-5p probe group compared with the scramble group in both A549 and H1299 cells (Fig.	('circ_0002483', 'Chemical', '-', (46, 58))	('miR-182-5p', 'Gene', (63, 73))	('miR-182-5p', 'Gene', '100302183', (63, 73))	('A549', 'CellLine', 'CVCL:0023', (145, 149))	('H1299', 'CellLine', 'CVCL:0060', (154, 159))	('miR-182-5p', 'Gene', '100302183', (81, 91))	('miR-182-5p', 'Gene', (81, 91))	('circ_0002483', 'Var', (46, 58))
279220	31844042	Furthermore, the expression of miR-182-5p and circ_0002483 were negatively correlated in NSCLC (r = -0.1401) but the difference was not statistically significant (P = 0.3531) (Fig.	('NSCLC', 'Disease', 'MESH:D002289', (89, 94))	('correlated', 'Interaction', (75, 85))	('expression', 'MPA', (17, 27))	('circ_0002483', 'Chemical', '-', (46, 58))	('miR-182-5p', 'Gene', '100302183', (31, 41))	('miR-182-5p', 'Gene', (31, 41))	('NSCLC', 'Phenotype', 'HP:0030358', (89, 94))	('circ_0002483', 'Var', (46, 58))	('NSCLC', 'Disease', (89, 94))	('negatively', 'NegReg', (64, 74))
279224	31844042	In addition, we found that miR-182-5p was significantly higher in A549/Taxol and H1299/Taxol cells than in A549 and H1299 cells (Fig.	('H1299/Taxol', 'Var', (81, 92))	('miR-182-5p', 'Gene', (27, 37))	('Taxol', 'Chemical', 'MESH:D017239', (71, 76))	('A549', 'CellLine', 'CVCL:0023', (66, 70))	('miR-182-5p', 'Gene', '100302183', (27, 37))	('A549', 'CellLine', 'CVCL:0023', (107, 111))	('H1299', 'CellLine', 'CVCL:0060', (116, 121))	('Taxol', 'Chemical', 'MESH:D017239', (87, 92))	('H1299', 'CellLine', 'CVCL:0060', (81, 86))	('higher', 'PosReg', (56, 62))	('A549/Taxol', 'Var', (66, 76))
279230	31844042	In addition, we found that overexpression of circ_0002483 in A549 and H1299 cells led to remarkably upregulated expression of GRB2, FOXO1 and FOXO3, while overexpression of miR-182-5p in A549 and H1299 cells resulted in the opposite effect on GRB2, FOXO1 and FOXO3 expression (Fig.	('expression', 'MPA', (265, 275))	('FOXO3', 'Gene', (142, 147))	('circ_0002483', 'Var', (45, 57))	('upregulated', 'PosReg', (100, 111))	('expression', 'MPA', (112, 122))	('H1299', 'CellLine', 'CVCL:0060', (70, 75))	('miR-182-5p', 'Gene', '100302183', (173, 183))	('overexpression', 'PosReg', (27, 41))	('H1299', 'CellLine', 'CVCL:0060', (196, 201))	('FOXO1', 'Gene', '2308', (132, 137))	('FOXO1', 'Gene', '2308', (249, 254))	('FOXO3', 'Gene', (259, 264))	('FOXO3', 'Gene', '2309', (142, 147))	('GRB2', 'Gene', '2885', (126, 130))	('A549', 'CellLine', 'CVCL:0023', (187, 191))	('GRB2', 'Gene', (126, 130))	('GRB2', 'Gene', '2885', (243, 247))	('circ_0002483', 'Chemical', '-', (45, 57))	('FOXO1', 'Gene', (249, 254))	('A549', 'CellLine', 'CVCL:0023', (61, 65))	('FOXO1', 'Gene', (132, 137))	('FOXO3', 'Gene', '2309', (259, 264))	('GRB2', 'Gene', (243, 247))	('miR-182-5p', 'Gene', (173, 183))
279231	31844042	Moreover, our findings suggested that A549 and H1299 cells cotransfected with miR-182-5p and circ_0002483 could restore the expression of GRB2, FOXO1 and FOXO3 back to normal levels (Fig.	('miR-182-5p', 'Gene', '100302183', (78, 88))	('miR-182-5p', 'Gene', (78, 88))	('restore', 'PosReg', (112, 119))	('circ_0002483', 'Chemical', '-', (93, 105))	('A549', 'CellLine', 'CVCL:0023', (38, 42))	('FOXO3', 'Gene', (154, 159))	('GRB2', 'Gene', '2885', (138, 142))	('FOXO1', 'Gene', (144, 149))	('FOXO1', 'Gene', '2308', (144, 149))	('FOXO3', 'Gene', '2309', (154, 159))	('expression', 'MPA', (124, 134))	('circ_0002483', 'Var', (93, 105))	('H1299', 'CellLine', 'CVCL:0060', (47, 52))	('GRB2', 'Gene', (138, 142))
279232	31844042	Furthermore, co-overexpressing miR-182-5p and circ_0002483 rescues the resistance to Taxol in lung cancer cells, indicated circ_0002483 enhances the sensitivity of NSCLC cells to Taxol by sponging miR-182-5p (Fig.	('Taxol', 'Chemical', 'MESH:D017239', (179, 184))	('Taxol', 'Chemical', 'MESH:D017239', (85, 90))	('lung cancer', 'Disease', (94, 105))	('resistance to Taxol', 'MPA', (71, 90))	('NSCLC', 'Disease', 'MESH:D002289', (164, 169))	('circ_0002483', 'Var', (123, 135))	('miR-182-5p', 'Gene', '100302183', (31, 41))	('enhances', 'PosReg', (136, 144))	('miR-182-5p', 'Gene', '100302183', (197, 207))	('cat', 'Gene', (117, 120))	('NSCLC', 'Disease', (164, 169))	('lung cancer', 'Disease', 'MESH:D008175', (94, 105))	('rescues', 'PosReg', (59, 66))	('circ_0002483', 'Chemical', '-', (46, 58))	('sensitivity', 'MPA', (149, 160))	('lung cancer', 'Phenotype', 'HP:0100526', (94, 105))	('NSCLC', 'Phenotype', 'HP:0030358', (164, 169))	('cat', 'Gene', '847', (117, 120))	('miR-182-5p', 'Gene', (31, 41))	('circ_0002483', 'Chemical', '-', (123, 135))	('miR-182-5p', 'Gene', (197, 207))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
279233	31844042	These results suggested that circ_0002483 inhibited the progression and enhanced the Taxol sensitivity of NSCLC through the miR-182-5p/GRB2/FOXO1/FOXO3 signaling pathway (Fig.	('circ_0002483', 'Var', (29, 41))	('GRB2', 'Gene', (135, 139))	('NSCLC', 'Disease', 'MESH:D002289', (106, 111))	('FOXO3', 'Gene', '2309', (146, 151))	('FOXO1', 'Gene', (140, 145))	('FOXO1', 'Gene', '2308', (140, 145))	('progression', 'MPA', (56, 67))	('Taxol', 'Chemical', 'MESH:D017239', (85, 90))	('miR-182-5p', 'Gene', '100302183', (124, 134))	('enhanced', 'PosReg', (72, 80))	('inhibited', 'NegReg', (42, 51))	('miR-182-5p', 'Gene', (124, 134))	('Taxol sensitivity', 'MPA', (85, 102))	('GRB2', 'Gene', '2885', (135, 139))	('FOXO3', 'Gene', (146, 151))	('circ_0002483', 'Chemical', '-', (29, 41))	('NSCLC', 'Phenotype', 'HP:0030358', (106, 111))	('NSCLC', 'Disease', (106, 111))
279245	31844042	We demonstrated that circ_0002483 inhibited the progression and enhanced the Taxol sensitivity of NSCLC.	('circ_0002483', 'Chemical', '-', (21, 33))	('Taxol', 'Chemical', 'MESH:D017239', (77, 82))	('NSCLC', 'Disease', (98, 103))	('NSCLC', 'Phenotype', 'HP:0030358', (98, 103))	('inhibited', 'NegReg', (34, 43))	('circ_0002483', 'Var', (21, 33))	('progression', 'MPA', (48, 59))	('NSCLC', 'Disease', 'MESH:D002289', (98, 103))	('enhanced', 'PosReg', (64, 72))
279246	31844042	Mechanistically, five miRNAs (miR-182-5p, miR-520q-3p, miR-582-3p, miR-587, and miR-655) were identified as target miRNAs of circ_0002483, and GRB2, FOXO1 and FOXO3 were verified as target genes of miR-182-5p.	('miR-182-5p', 'Gene', (30, 40))	('miR-587', 'Gene', (67, 74))	('circ_0002483', 'Chemical', '-', (125, 137))	('miR-587', 'Gene', '693172', (67, 74))	('miR-182-5p', 'Gene', '100302183', (30, 40))	('GRB2', 'Gene', '2885', (143, 147))	('GRB2', 'Gene', (143, 147))	('miR-655', 'Gene', '724025', (80, 87))	('miR-520q-3p', 'Var', (42, 53))	('miR-182-5p', 'Gene', (198, 208))	('miR-582-3p', 'Var', (55, 65))	('FOXO1', 'Gene', '2308', (149, 154))	('FOXO3', 'Gene', (159, 164))	('miR-182-5p', 'Gene', '100302183', (198, 208))	('miR-655', 'Gene', (80, 87))	('FOXO3', 'Gene', '2309', (159, 164))	('FOXO1', 'Gene', (149, 154))
279247	31844042	Moreover, increased miR-182-5p was demonstrated to act as an oncogene in NSCLC, and circ_0002483 could regulate its target genes (GRB2, FOXO1, and FOXO3) through sponging miR-182-5p.	('miR-182-5p', 'Gene', '100302183', (20, 30))	('miR-182-5p', 'Gene', (20, 30))	('FOXO1', 'Gene', (136, 141))	('FOXO1', 'Gene', '2308', (136, 141))	('circ_0002483', 'Chemical', '-', (84, 96))	('GRB2', 'Gene', (130, 134))	('NSCLC', 'Disease', (73, 78))	('FOXO3', 'Gene', (147, 152))	('regulate', 'Reg', (103, 111))	('FOXO3', 'Gene', '2309', (147, 152))	('NSCLC', 'Phenotype', 'HP:0030358', (73, 78))	('GRB2', 'Gene', '2885', (130, 134))	('miR-182-5p', 'Gene', '100302183', (171, 181))	('miR-182-5p', 'Gene', (171, 181))	('NSCLC', 'Disease', 'MESH:D002289', (73, 78))	('circ_0002483', 'Var', (84, 96))
279248	31844042	In conclusion, our findings suggested that circ_0002483 inhibited the progression and enhanced the Taxol sensitivity of NSCLC through the miR-182-5p/GRB2/FOXO1/FOXO3 signaling pathway, providing several potential therapeutic targets to overcome the Taxol resistance of NSCLC.	('NSCLC', 'Phenotype', 'HP:0030358', (120, 125))	('NSCLC', 'Disease', 'MESH:D002289', (269, 274))	('Taxol sensitivity', 'MPA', (99, 116))	('circ_0002483', 'Chemical', '-', (43, 55))	('Taxol', 'Chemical', 'MESH:D017239', (249, 254))	('FOXO3', 'Gene', (160, 165))	('NSCLC', 'Disease', (269, 274))	('Taxol', 'Chemical', 'MESH:D017239', (99, 104))	('miR-182-5p', 'Gene', (138, 148))	('NSCLC', 'Phenotype', 'HP:0030358', (269, 274))	('FOXO1', 'Gene', '2308', (154, 159))	('circ_0002483', 'Var', (43, 55))	('FOXO3', 'Gene', '2309', (160, 165))	('enhanced', 'PosReg', (86, 94))	('GRB2', 'Gene', '2885', (149, 153))	('inhibited', 'NegReg', (56, 65))	('GRB2', 'Gene', (149, 153))	('NSCLC', 'Disease', 'MESH:D002289', (120, 125))	('FOXO1', 'Gene', (154, 159))	('miR-182-5p', 'Gene', '100302183', (138, 148))	('progression', 'MPA', (70, 81))	('NSCLC', 'Disease', (120, 125))
279266	31783879	In NSCLC, DHA not only inhibits cancer cell proliferation and migration, but also suppresses angiogenesis.	('NSCLC', 'Disease', (3, 8))	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('DHA', 'Var', (10, 13))	('cancer', 'Disease', (32, 38))	('NSCLC', 'Disease', 'MESH:D002289', (3, 8))	('DHA', 'Chemical', 'MESH:D004281', (10, 13))	('suppresses', 'NegReg', (82, 92))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('NSCLC', 'Phenotype', 'HP:0030358', (3, 8))	('inhibits', 'NegReg', (23, 31))	('angiogenesis', 'CPA', (93, 105))
279271	31783879	Aberrant expression of some miRNAs has been reported to be associated with malignant phenotypes in various cancers, participating in not only cell proliferation, but also invasion and metastasis.	('cancers', 'Disease', (107, 114))	('Aberrant expression', 'Var', (0, 19))	('cancers', 'Disease', 'MESH:D009369', (107, 114))	('participating', 'Reg', (116, 129))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('invasion', 'CPA', (171, 179))	('associated', 'Reg', (59, 69))	('cell proliferation', 'CPA', (142, 160))	('miRNAs', 'Gene', (28, 34))	('cancers', 'Phenotype', 'HP:0002664', (107, 114))
279273	31783879	Among them, miR-138-5p is postulated as a tumor suppressor.	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor', 'Disease', (42, 47))	('miR-138-5p', 'Var', (12, 22))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
279274	31783879	Accordingly, the expression of miR-138-5p is decreased in many cancer tissues, compared with adjacent noncancerous tissues; and reduced expression of miR-138-5p is significantly correlated with patients' clinicopathological factors and poor survival.	('expression', 'MPA', (136, 146))	('patients', 'Species', '9606', (194, 202))	('reduced', 'NegReg', (128, 135))	('cancer', 'Disease', (105, 111))	('expression', 'MPA', (17, 27))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('decreased', 'NegReg', (45, 54))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('miR-138-5p', 'Var', (150, 160))	('cancer', 'Disease', (63, 69))
279275	31783879	Among NSCLC cases, miR-138-5p is involved in the elevation of GADD45A and inhibits cell growth.	('NSCLC', 'Disease', 'MESH:D002289', (6, 11))	('GADD45A', 'Gene', '13197', (62, 69))	('NSCLC', 'Phenotype', 'HP:0030358', (6, 11))	('GADD45A', 'Gene', (62, 69))	('inhibits', 'NegReg', (74, 82))	('miR-138-5p', 'Var', (19, 29))	('elevation', 'PosReg', (49, 58))	('NSCLC', 'Disease', (6, 11))	('cell growth', 'CPA', (83, 94))
279282	31783879	Further, miR-138-5p was upregulated in RvD1-treated lung cancer cells.	('lung cancer', 'Disease', 'MESH:D008175', (52, 63))	('miR-138-5p', 'Var', (9, 19))	('lung cancer', 'Disease', (52, 63))	('upregulated', 'PosReg', (24, 35))	('lung cancer', 'Phenotype', 'HP:0100526', (52, 63))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))
279289	31783879	The following were commercially obtained antibodies: the anti-Akt (#9272), anti-phospho-Akt (Ser473, #4060), the anti-Erk1/2 (#4696), and anti-phospho-Erk1/2 (Thr202/Tyr204, #8544) antibodies were obtained from Cell Signaling Technology (Danvers, MA, USA); the anti-FOXC1 antibody (#115201) was obtained from Abcam plc (Cambridge, UK); the anti-GAPDH antibody was obtained from Bioworld Technology (Atlanta, Georgia30,305, USA).	('Tyr204', 'Chemical', 'MESH:C003808', (166, 172))	('Akt', 'Gene', '11651', (88, 91))	('GAPDH', 'Gene', '14433', (345, 350))	('#115201', 'Var', (282, 289))	('#9272', 'Var', (67, 72))	('Erk1/2', 'Gene', '26417;26413', (118, 124))	('Bi', 'Chemical', 'MESH:D001729', (378, 380))	('Erk1/2', 'Gene', (151, 157))	('Akt', 'Gene', '11651', (62, 65))	('Ser', 'Chemical', 'MESH:C530429', (93, 96))	('Akt', 'Gene', (88, 91))	('GAPDH', 'Gene', (345, 350))	('Erk1/2', 'Gene', (118, 124))	('Erk1/2', 'Gene', '26417;26413', (151, 157))	('Akt', 'Gene', (62, 65))
279290	31783879	EnVision+single reagents (Mouse, Rabbit) were from DAKO (K4000, K4002, Glostrup, Denmark).	('K4000', 'Var', (57, 62))	('Rabbit', 'Species', '9986', (33, 39))	('K4002', 'Var', (64, 69))	('Mouse', 'Species', '10090', (26, 31))	('K4002', 'Chemical', 'MESH:D011188', (64, 69))
279332	31783879	The cells were then co-transfected with either wild-type (WT1 and WT2) or mutant-type (mut1 and mut2) luciferase reporter plasmids, and equal amounts of miR-138-5p using Lipofectamine2000 according the manufacturer's instruction.	('WT1', 'Gene', (58, 61))	('mut2', 'Gene', '17852', (96, 100))	('WT1', 'Gene', '22431', (58, 61))	('miR-138-5p', 'Var', (153, 163))	('luciferase', 'Enzyme', (102, 112))	('mutant-type', 'Var', (74, 85))	('mut1', 'Gene', (87, 91))	('mut1', 'Gene', '17851', (87, 91))	('mut2', 'Gene', (96, 100))
279342	31783879	The expression of mfat-1 allowed more than 50% increase in endogenous DHA level (from 1.61 to 2.46%, P < 0.05) (Fig.	('increase', 'PosReg', (47, 55))	('mfat-1', 'Gene', '100035507', (18, 24))	('mfat-1', 'Gene', (18, 24))	('DHA', 'Chemical', 'MESH:D004281', (70, 73))	('endogenous DHA level', 'MPA', (59, 79))	('expression', 'Var', (4, 14))
279343	31783879	The inhibition of lung cancer growth by endogenously elevated DHA was further shown in the cancer model grafts derived from subcutaneously implanted LLC cells in both the wild-type (WT) and mfat-1 transgenic mice.	('lung cancer', 'Disease', 'MESH:D008175', (18, 29))	('transgenic mice', 'Species', '10090', (197, 212))	('cancer', 'Disease', (91, 97))	('DHA', 'Gene', (62, 65))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('DHA', 'Chemical', 'MESH:D004281', (62, 65))	('cancer', 'Disease', (23, 29))	('cancer', 'Disease', 'MESH:D009369', (23, 29))	('endogenously elevated', 'Var', (40, 61))	('mfat-1', 'Gene', (190, 196))	('mfat-1', 'Gene', '100035507', (190, 196))	('lung cancer', 'Phenotype', 'HP:0100526', (18, 29))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('lung cancer', 'Disease', (18, 29))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('inhibition', 'NegReg', (4, 14))
279347	31783879	After euthanasia, we found endogenous DHA caused lower lungs weight and partial tumor regression (Fig.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('DHA', 'Chemical', 'MESH:D004281', (38, 41))	('tumor', 'Disease', (80, 85))	('lungs weight', 'CPA', (55, 67))	('lower lungs weight', 'Phenotype', 'HP:0002089', (49, 67))	('lower', 'NegReg', (49, 54))	('endogenous DHA', 'Var', (27, 41))
279354	31783879	RvD1 decreased cell viability in A549, H1299 and LLC cells in a dose-dependent manner (Fig.	('RvD1', 'Var', (0, 4))	('H1299', 'CellLine', 'CVCL:0060', (39, 44))	('cell viability', 'CPA', (15, 29))	('A549', 'CellLine', 'CVCL:0023', (33, 37))	('decreased', 'NegReg', (5, 14))
279359	31783879	Using a human miRNA microarray, we found that the expression levels of many miRNA species were affected by the addition of RvD1 in A549 cells.	('addition', 'Var', (111, 119))	('expression levels', 'MPA', (50, 67))	('A549', 'CellLine', 'CVCL:0023', (131, 135))	('miRNA species', 'MPA', (76, 89))	('human', 'Species', '9606', (8, 13))	('RvD1', 'Gene', (123, 127))	('affected', 'Reg', (95, 103))
279361	31783879	In LUSC patients, miR-138 expression was significantly reduced in cases with distant metastasis, and high expression of miR-138 showed longer survival tendency than those with low miR-138 expression (Fig.	('expression', 'MPA', (26, 36))	('miR-138', 'Gene', (120, 127))	('reduced', 'NegReg', (55, 62))	('distant metastasis', 'CPA', (77, 95))	('survival', 'CPA', (142, 150))	('miR-138', 'Gene', (18, 25))	('longer', 'PosReg', (135, 141))	('high expression', 'Var', (101, 116))	('patients', 'Species', '9606', (8, 16))
279364	31783879	We found that the mimics of miR-138-5p, after applied to the cultured cells, could decrease cell viability and invasion in A549 cells (Fig.	('miR-138-5p', 'Var', (28, 38))	('decrease', 'NegReg', (83, 91))	('cell viability', 'CPA', (92, 106))	('A549', 'CellLine', 'CVCL:0023', (123, 127))	('invasion', 'CPA', (111, 119))
279365	31783879	These data indicated that induction of miR-138-5p expression was an important contributing mechanism for the suppressive effect of RvD1 on lung cancer cell growth and invasion.	('lung cancer', 'Disease', (139, 150))	('miR-138-5p expression', 'Var', (39, 60))	('suppressive', 'NegReg', (109, 120))	('lung cancer', 'Disease', 'MESH:D008175', (139, 150))	('invasion', 'CPA', (167, 175))	('RvD1', 'Gene', (131, 135))	('lung cancer', 'Phenotype', 'HP:0100526', (139, 150))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
279367	31783879	Bioinformatics analysis suggests that Forkhead Box C1 (FOXC1) is potentially a target of miR-138-5p (www.targetscan.org/).	('FOXC1', 'Gene', (55, 60))	('Forkhead Box C1', 'Gene', (38, 53))	('Bi', 'Chemical', 'MESH:D001729', (0, 2))	('Forkhead Box C1', 'Gene', '17300', (38, 53))	('miR-138-5p', 'Var', (89, 99))
279370	31783879	Transfection of miR-138-5p inhibited the expression of the reporter gene containing the WT, but not the mut1 or mut2, of the 3'-UTR region of FOXC1 (Fig.	('FOXC1', 'Gene', (142, 147))	('expression', 'MPA', (41, 51))	('mut1', 'Gene', (104, 108))	('miR-138-5p', 'Var', (16, 26))	('inhibited', 'NegReg', (27, 36))	('mut2', 'Gene', (112, 116))	('mut1', 'Gene', '17851', (104, 108))	('mut2', 'Gene', '17852', (112, 116))
279374	31783879	In 60 lung cancer cases (30 LUSC and 30 LUAD), in situ hybridization assays were used to detect miR-138-5p expression, and immunohistochemistry assays were used to detect FOXC1 expression.	('lung cancer', 'Disease', 'MESH:D008175', (6, 17))	('miR-138-5p', 'Var', (96, 106))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('lung cancer', 'Disease', (6, 17))	('lung cancer', 'Phenotype', 'HP:0100526', (6, 17))	('FOXC1', 'Gene', (171, 176))	('expression', 'MPA', (177, 187))
279375	31783879	To establish the cross regulation of FOXC1 activity by miR-138-5p, A549 cells were transfected with miR-138-5p mimics with or without co-transfection of a CMV promoter-driven FOXC1 construct.	('A549', 'CellLine', 'CVCL:0023', (67, 71))	('activity', 'MPA', (43, 51))	('miR-138-5p', 'Var', (100, 110))	('FOXC1', 'Gene', (37, 42))
279378	31783879	In cell invasion assay, although RvD1 treatment led to 42% reduction in lung cancer cell invasion, overexpression of FOXC1 significantly attenuated the effect to a 23% loss of cell invasive ability.	('FOXC1', 'Gene', (117, 122))	('loss', 'NegReg', (168, 172))	('overexpression', 'Var', (99, 113))	('lung cancer', 'Disease', (72, 83))	('cell invasive ability', 'CPA', (176, 197))	('reduction', 'NegReg', (59, 68))	('lung cancer', 'Phenotype', 'HP:0100526', (72, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('lung cancer', 'Disease', 'MESH:D008175', (72, 83))	('attenuated', 'NegReg', (137, 147))
279379	31783879	Taken together, these data indicated that miR-138-5p directly targeted FOXC1 to reduce cancer cell growth and invasion.	('miR-138-5p', 'Var', (42, 52))	('cancer', 'Disease', (87, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('FOXC1', 'Gene', (71, 76))	('reduce', 'NegReg', (80, 86))	('invasion', 'CPA', (110, 118))	('cancer', 'Disease', 'MESH:D009369', (87, 93))
279389	31783879	The current study addressed this issue by revealing that RvD1, one of DHA-initiated eicosanoid metabolites, played a critical role in mediating the effects of DHA by decreasing lung cancer cell growth and invasion.	('invasion', 'CPA', (205, 213))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('eicosanoid', 'Chemical', 'MESH:D015777', (84, 94))	('decreasing', 'NegReg', (166, 176))	('lung cancer', 'Disease', 'MESH:D008175', (177, 188))	('DHA', 'Var', (159, 162))	('DHA', 'Chemical', 'MESH:D004281', (159, 162))	('DHA', 'Chemical', 'MESH:D004281', (70, 73))	('lung cancer', 'Disease', (177, 188))	('RvD1', 'Gene', (57, 61))	('decreasing lung', 'Phenotype', 'HP:0002089', (166, 181))	('lung cancer', 'Phenotype', 'HP:0100526', (177, 188))
279393	31783879	MiR-138-5p has been reported as a tumor suppressor in several types of cancer such as multiple myeloma and ovarian cancer by targeting EZH2 and survivin.	('multiple myeloma', 'Disease', 'MESH:D009101', (86, 102))	('EZH2', 'Gene', '14056', (135, 139))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('ovarian cancer', 'Disease', (107, 121))	('survivin', 'Gene', (144, 152))	('tumor', 'Disease', (34, 39))	('multiple myeloma', 'Disease', (86, 102))	('cancer', 'Disease', (71, 77))	('ovarian cancer', 'Phenotype', 'HP:0100615', (107, 121))	('survivin', 'Gene', '11799', (144, 152))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('EZH2', 'Gene', (135, 139))	('MiR-138-5p', 'Var', (0, 10))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('multiple myeloma', 'Phenotype', 'HP:0006775', (86, 102))	('cancer', 'Disease', (115, 121))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('targeting', 'Reg', (125, 134))	('ovarian cancer', 'Disease', 'MESH:D010051', (107, 121))
279394	31783879	Overexpression of miR-138-5p inhibited cancer cell proliferation and invasion while enhancing drug sensitivity.	('inhibited', 'NegReg', (29, 38))	('drug sensitivity', 'Phenotype', 'HP:0020174', (94, 110))	('cancer', 'Disease', (39, 45))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('miR-138-5p', 'Var', (18, 28))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('invasion', 'CPA', (69, 77))	('enhancing', 'PosReg', (84, 93))	('drug sensitivity', 'CPA', (94, 110))
279398	31783879	FOXC1 has been highlighted as an important transcriptional regulator involved in diverse tumorigenic processes, such as proliferation, invasion, and angiogenesis with high FOXC1 expression associated with poor prognosis in cancer patients.	('FOXC1', 'Gene', (172, 177))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('high', 'Var', (167, 171))	('associated', 'Reg', (189, 199))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('patients', 'Species', '9606', (230, 238))	('cancer', 'Disease', 'MESH:D009369', (223, 229))	('cancer', 'Disease', (223, 229))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
279408	28683775	ALK-rearranged lung squamous cell carcinoma responding to alectinib: a case report and review of the literature Although anaplastic lymphoma kinase (ALK) fusion genes are generally identified in lung adenocarcinoma patients, they are relatively rare in patients with squamous cell carcinoma (SqCC).	('alectinib', 'Chemical', 'MESH:C582670', (58, 67))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (20, 43))	('patients', 'Species', '9606', (253, 261))	('anaplastic lymphoma', 'Disease', 'MESH:D017728', (121, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (281, 290))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (121, 140))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (195, 214))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (195, 214))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (267, 290))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (15, 43))	('anaplastic lymphoma', 'Disease', (121, 140))	('identified', 'Reg', (181, 191))	('fusion genes', 'Var', (154, 166))	('SqCC', 'Phenotype', 'HP:0002860', (292, 296))	('carcinoma', 'Phenotype', 'HP:0030731', (205, 214))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (267, 290))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (15, 43))	('ALK', 'Gene', '238', (0, 3))	('patients', 'Species', '9606', (215, 223))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (20, 43))	('lymphoma', 'Phenotype', 'HP:0002665', (132, 140))	('lung squamous cell carcinoma', 'Disease', (15, 43))	('ALK', 'Gene', '238', (149, 152))	('squamous cell carcinoma', 'Disease', (267, 290))	('ALK', 'Gene', (0, 3))	('ALK', 'Gene', (149, 152))	('lung adenocarcinoma', 'Disease', (195, 214))	('carcinoma', 'Phenotype', 'HP:0030731', (34, 43))
279409	28683775	Metastatic ALK-rearranged lung adenocarcinoma patients treated with ALK inhibitors demonstrate higher response rates, improved progression-free survival, and reduced toxicity relative to those treated with conventional chemotherapy regimens.	('response rates', 'CPA', (102, 116))	('progression-free survival', 'CPA', (127, 152))	('patients', 'Species', '9606', (46, 54))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (26, 45))	('ALK', 'Gene', (68, 71))	('improved', 'PosReg', (118, 126))	('higher', 'PosReg', (95, 101))	('carcinoma', 'Phenotype', 'HP:0030731', (36, 45))	('ALK', 'Gene', (11, 14))	('lung adenocarcinoma', 'Disease', (26, 45))	('toxicity', 'Disease', 'MESH:D064420', (166, 174))	('toxicity', 'Disease', (166, 174))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (26, 45))	('ALK', 'Gene', '238', (68, 71))	('inhibitors', 'Var', (72, 82))	('ALK', 'Gene', '238', (11, 14))
279414	28683775	ALK testing was subsequently performed, revealing positive ALK expression and gene rearrangement.	('ALK', 'Gene', '238', (59, 62))	('gene rearrangement', 'Var', (78, 96))	('expression', 'MPA', (63, 73))	('ALK', 'Gene', (0, 3))	('ALK', 'Gene', (59, 62))	('positive', 'Reg', (50, 58))	('ALK', 'Gene', '238', (0, 3))
279418	28683775	Numerous oncogenic driver mutations have been identified in patients with non-small cell lung cancer.	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (74, 100))	('lung cancer', 'Phenotype', 'HP:0100526', (89, 100))	('patients', 'Species', '9606', (60, 68))	('non-small cell lung cancer', 'Disease', (74, 100))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (78, 100))	('mutations', 'Var', (26, 35))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (74, 100))
279473	24936140	Hypermethylation of CpG islands is an important mechanism to inactivate tumor suppressor genes.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('inactivate', 'NegReg', (61, 71))	('tumor', 'Disease', (72, 77))	('Hypermethylation', 'Var', (0, 16))	('tumor', 'Disease', 'MESH:D009369', (72, 77))
279474	24936140	In addition, DNA methylation is frequently not restricted to a single CpG island but affects multiple independent loci, which is reflective of a widespread deregulation of DNA methylation pattern in different types of tumors.	('affects', 'Reg', (85, 92))	('methylation', 'Var', (17, 28))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('tumors', 'Phenotype', 'HP:0002664', (218, 224))	('tumors', 'Disease', (218, 224))	('tumors', 'Disease', 'MESH:D009369', (218, 224))
279514	24936140	Finally, we obtained nine DNA methylation probes which were significantly associated with poor prognosis of patients (Figure 1B).	('patients', 'Species', '9606', (108, 116))	('methylation', 'Var', (30, 41))	('associated', 'Reg', (74, 84))
279520	24936140	CpG hypermethylation of all eight genes showed an association with poor survival outcome, suggesting that these eight genes may function as tumor suppressor-like genes in ESCC tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('association', 'Reg', (50, 61))	('tumor', 'Disease', (176, 181))	('ESCC', 'Disease', (171, 175))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('hypermethylation', 'Var', (4, 20))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('tumor', 'Disease', 'MESH:D009369', (176, 181))	('tumor', 'Disease', (140, 145))
279531	24936140	The Table 2 shows that the methylation level of eight-gene panel was an independent prognosis factor in ESCC patients even after adjusting for other variables including tumor stage, age and cancer recurrence status by the multivariate analysis (hazard ratio, HR, 1.996; 95% confidence interval, CI, 1.153-3.456; P=0.014).	('cancer', 'Disease', (190, 196))	('cancer', 'Disease', 'MESH:D009369', (190, 196))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('patients', 'Species', '9606', (109, 117))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('methylation', 'Var', (27, 38))	('ESCC', 'Disease', (104, 108))	('tumor', 'Disease', (169, 174))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))
279533	24936140	Given that aberrant methylation can result in transcriptional silencing of the target gene, we further examined the mRNA expression level of SOX17 in 61 ESCC patients.	('transcriptional', 'MPA', (46, 61))	('result in', 'Reg', (36, 45))	('SOX17', 'Gene', (141, 146))	('aberrant methylation', 'Var', (11, 31))	('methylation', 'Var', (20, 31))	('patients', 'Species', '9606', (158, 166))	('SOX17', 'Gene', '64321', (141, 146))	('ESCC', 'Disease', (153, 157))
279534	24936140	The qRT-PCR results indicated that mRNA level of SOX17 was significantly lower in the high methylation group than the low methylation group of tumor tissues from ESCC patients (P=0.018, Figure 4A).	('tumor', 'Disease', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('patients', 'Species', '9606', (167, 175))	('mRNA level', 'MPA', (35, 45))	('SOX17', 'Gene', (49, 54))	('high methylation', 'Var', (86, 102))	('lower', 'NegReg', (73, 78))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('ESCC', 'Disease', (162, 166))	('SOX17', 'Gene', '64321', (49, 54))
279535	24936140	Importantly, an inverse correlation between SOX17 DNA methylation and mRNA expression was observed (r= -0.418, P<0.01, Figure 4B), suggesting that DNA hypermethylation of SOX17 resulted in low mRNA expression in ESCC patients.	('DNA hypermethylation', 'Var', (147, 167))	('SOX17', 'Gene', '64321', (171, 176))	('ESCC', 'Disease', (212, 216))	('SOX17', 'Gene', '64321', (44, 49))	('low', 'NegReg', (189, 192))	('patients', 'Species', '9606', (217, 225))	('SOX17', 'Gene', (171, 176))	('SOX17', 'Gene', (44, 49))	('mRNA expression', 'MPA', (193, 208))
279545	24936140	They further compared the methylation patterns of ESCC patients with esophageal mucosa from four healthy individuals and the TFF1 promoter methylation was speculated to represent an early event in the development of ESCC.	('ESCC', 'Disease', (50, 54))	('ESCC', 'Disease', (216, 220))	('TFF1', 'Gene', '7031', (125, 129))	('patients', 'Species', '9606', (55, 63))	('TFF1', 'Gene', (125, 129))	('methylation', 'Var', (139, 150))
279552	24936140	These results suggested that DNA hypermethylation is a predominant mechanism for SOX17 gene silencing, which is in agreement with previous reports of esophageal cancer patients determined by methylation-specific PCR method.	('DNA hypermethylation', 'Var', (29, 49))	('esophageal cancer', 'Disease', (150, 167))	('esophageal cancer', 'Disease', 'MESH:D004938', (150, 167))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('silencing', 'NegReg', (92, 101))	('SOX17', 'Gene', '64321', (81, 86))	('patients', 'Species', '9606', (168, 176))	('SOX17', 'Gene', (81, 86))
279573	27810391	Cancer location is not important for adenocarcinoma staging, but in conjunction with grade it is necessary to subgroup pT3N0M0 squamous cell carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (127, 150))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('adenocarcinoma staging', 'Disease', 'MESH:D000230', (37, 59))	('pT3N0M0', 'Var', (119, 126))	('adenocarcinoma staging', 'Disease', (37, 59))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('squamous cell carcinoma', 'Disease', (127, 150))	('carcinoma', 'Phenotype', 'HP:0030731', (42, 51))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (127, 150))
279579	27810391	Subcategorization of T1 combined with grade requires three pStage I subgroups: pStage IA (pT1aN0M0G1), pStage IB (pT1aN0M0G2 and pT1bN0M0G1-2), and pStage IC (pT1N0M0G3 and pT2N0M0G1-2).	('pT1', 'Gene', '58492', (114, 117))	('pT2N0M0G1-2', 'Var', (173, 184))	('pT1', 'Gene', (159, 162))	('pT1', 'Gene', (90, 93))	('pStage IB', 'Disease', (103, 112))	('pT1', 'Gene', (114, 117))	('pStage IA', 'Disease', (79, 88))	('pT1', 'Gene', '58492', (129, 132))	('pT1', 'Gene', '58492', (159, 162))	('pT1', 'Gene', '58492', (90, 93))	('pT1', 'Gene', (129, 132))
279580	27810391	pT2N0M0G3 remains the sole cancer in pStage IIA.	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('pStage IIA', 'Disease', (37, 47))	('pT2N0M0G3', 'Var', (0, 9))	('cancer', 'Disease', (27, 33))	('cancer', 'Disease', 'MESH:D009369', (27, 33))
279583	27810391	pT2N1M0 and pT1N2M0 form pStage IIIA, whereas pT2N2M0, pT3N1-2M0, and pT4aN0-1M0 form pStage IIIB.	('pStage IIIA', 'Disease', (25, 36))	('pT2N2M0', 'Var', (46, 53))	('pT1', 'Gene', '58492', (12, 15))	('pT2N1M0', 'Var', (0, 7))	('pT3N1-2M0', 'Var', (55, 64))	('pT1', 'Gene', (12, 15))	('pT4aN0-1M0', 'Var', (70, 80))
279585	27810391	pT4aN2M0, pT4bN0-2M0, and pTanyN3M0 are pStage IVA.	('IVA', 'Disease', (47, 50))	('IVA', 'Disease', 'MESH:C538167', (47, 50))	('pTanyN3M0', 'Var', (26, 35))	('pT4aN2M0', 'Var', (0, 8))	('pT4bN0-2M0', 'Var', (10, 20))
279587	27810391	Subcategorization of T1 combined with grade requires two pStage I subgroups: pStage IA (pT1aN0M0G1) and pStage IB (pT1aN0M0G2-3, pT1bN0M0, and pT2N0M0G1).	('pT1', 'Gene', '58492', (115, 118))	('pStage IA', 'Disease', (77, 86))	('pT2N0M0G1', 'Var', (143, 152))	('pT1', 'Gene', '58492', (88, 91))	('pT1', 'Gene', '58492', (129, 132))	('pT1', 'Gene', (115, 118))	('pT1', 'Gene', (88, 91))	('pT1', 'Gene', (129, 132))
279588	27810391	pStage IIA comprises pT2N0M0G2-3 cancers, pT3N0M0 cancers of the lower thoracic esophagus, and pT3N0M0G1 cancers of the upper middle thoracic esophagus.	('cancers of the upper middle thoracic esophagus', 'Disease', 'MESH:D004938', (105, 151))	('cancers of the upper middle thoracic esophagus', 'Disease', (105, 151))	('cancers', 'Phenotype', 'HP:0002664', (105, 112))	('pT2N0M0G2-3', 'Var', (21, 32))	('pT3N0M0', 'Var', (42, 49))	('cancers', 'Phenotype', 'HP:0002664', (33, 40))	('cancers', 'Disease', 'MESH:D009369', (50, 57))	('cancers', 'Phenotype', 'HP:0002664', (50, 57))	('pT3N0M0G1', 'Var', (95, 104))	('cancers', 'Disease', (105, 112))	('cancers', 'Disease', (33, 40))	('cancers', 'Disease', (50, 57))	('cancers', 'Disease', 'MESH:D009369', (105, 112))	('cancers', 'Disease', 'MESH:D009369', (33, 40))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))
279589	27810391	pStage IIB comprises T3N0M0G2-3 cancers of the upper middle thoracic esophagus and pT1N1M0 cancers.	('cancers of the upper middle thoracic esophagus', 'Disease', (32, 78))	('pT1', 'Gene', '58492', (83, 86))	('cancers', 'Disease', 'MESH:D009369', (32, 39))	('cancers', 'Disease', 'MESH:D009369', (91, 98))	('cancers', 'Phenotype', 'HP:0002664', (32, 39))	('cancers', 'Phenotype', 'HP:0002664', (91, 98))	('cancers', 'Disease', (32, 39))	('cancers', 'Disease', (91, 98))	('pT1', 'Gene', (83, 86))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('cancers of the upper middle thoracic esophagus', 'Disease', 'MESH:D004938', (32, 78))	('T3N0M0G2-3', 'Var', (21, 31))
279592	27810391	Drivers of this addition include absence of equivalent pathologic (pTNM) categories for the peculiar postneoadjuvant pathologic categories (ypT0N0-3M0 and ypTisN0-3M0), dissimilar stage group compositions, and markedly different survival profiles.	('TNM', 'Gene', '10178', (68, 71))	('ypTisN0-3M0', 'Var', (155, 166))	('TNM', 'Gene', (68, 71))	('ypT0N0-3M0', 'Var', (140, 150))	('postneoadjuvant pathologic', 'Disease', (101, 127))
279595	27810391	ypStage IIIB comprises ypT1-3N2M0, ypT3N1M0, and ypT4aN0M0 cancers.	('cancers', 'Disease', (59, 66))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('ypT1', 'Gene', (23, 27))	('ypT1', 'Gene', '5861', (23, 27))	('cancers', 'Disease', 'MESH:D009369', (59, 66))	('cancers', 'Phenotype', 'HP:0002664', (59, 66))	('ypT4aN0M0', 'Var', (49, 58))	('ypT3N1M0', 'Var', (35, 43))
279596	27810391	ypStage IVA includes ypT4aN1-2M0, ypT4bN0-2M0, and yp TanyN3M0.	('yp TanyN3M0', 'Var', (51, 62))	('ypT4aN1-2M0', 'Var', (21, 32))	('IVA', 'Disease', (8, 11))	('ypT4bN0-2M0', 'Var', (34, 45))	('IVA', 'Disease', 'MESH:C538167', (8, 11))
279601	27810391	cStage IVA consists of T4bN0-1M0 and all cN2-N3M0 cancers.	('cN2', 'Gene', '55748', (41, 44))	('cancers', 'Disease', 'MESH:D009369', (50, 57))	('IVA', 'Disease', (7, 10))	('cancers', 'Phenotype', 'HP:0002664', (50, 57))	('T4bN0-1M0', 'Var', (23, 32))	('cancers', 'Disease', (50, 57))	('IVA', 'Disease', 'MESH:C538167', (7, 10))	('cN2', 'Gene', (41, 44))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))
279603	27810391	cStage II comprises cT2N0-1M0 and cT3N0M0 cancers.	('cancers', 'Disease', (42, 49))	('cT3N0M0', 'Var', (34, 41))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('cancers', 'Phenotype', 'HP:0002664', (42, 49))	('cancers', 'Disease', 'MESH:D009369', (42, 49))
279604	27810391	cStage III comprises cT3N1M0 and cT1-3N2M0 cancers.	('cancers', 'Phenotype', 'HP:0002664', (43, 50))	('cancers', 'Disease', (43, 50))	('cancers', 'Disease', 'MESH:D009369', (43, 50))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('cT1-3N2M0', 'Var', (33, 42))
279605	27810391	cT4N0-2M0 and all cN3M0 cancers are placed in cStage IVA.	('IVA', 'Disease', (53, 56))	('IVA', 'Disease', 'MESH:C538167', (53, 56))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('cN3M0', 'Var', (18, 23))	('cancers', 'Phenotype', 'HP:0002664', (24, 31))	('cancers', 'Disease', 'MESH:D009369', (24, 31))	('cancers', 'Disease', (24, 31))
279617	29928402	LNalpha3 and LNgamma2 positivity was significantly associated with differentiation, depth of invasion and advanced stage (P<0.05).	('gamma2', 'Gene', (15, 21))	('differentiation', 'CPA', (67, 82))	('associated', 'Reg', (51, 61))	('advanced stage', 'CPA', (106, 120))	('depth of invasion', 'CPA', (84, 101))	('gamma2', 'Gene', '7453', (15, 21))	('LNalpha3', 'Protein', (0, 8))	('positivity', 'Var', (22, 32))
279620	29928402	Patients with B-type LNgamma2 demonstrated significantly better outcomes than patients with the C or M type (P=0.012 and P=0.003, respectively).	('outcomes', 'MPA', (64, 72))	('gamma2', 'Gene', (23, 29))	('patients', 'Species', '9606', (78, 86))	('B-type', 'Var', (14, 20))	('Patients', 'Species', '9606', (0, 8))	('better', 'PosReg', (57, 63))	('gamma2', 'Gene', '7453', (23, 29))
279687	29928402	LNalpha3 positivity was significantly associated with tumor differentiation, depth of invasion, and advanced stage (P<0.05).	('associated', 'Reg', (38, 48))	('advanced stage', 'CPA', (100, 114))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('positivity', 'Var', (9, 19))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumor', 'Disease', (54, 59))	('LNalpha3', 'Protein', (0, 8))	('depth of invasion', 'CPA', (77, 94))
279688	29928402	LNgamma2 positivity was significantly correlated with differentiation, invasion into the serosa, depth of invasion, and TNM stage (P<0.05).	('TNM', 'Gene', '10178', (120, 123))	('gamma2', 'Gene', (2, 8))	('invasion into the serosa', 'CPA', (71, 95))	('TNM', 'Gene', (120, 123))	('positivity', 'Var', (9, 19))	('depth of invasion', 'CPA', (97, 114))	('gamma2', 'Gene', '7453', (2, 8))	('differentiation', 'CPA', (54, 69))	('correlated', 'Reg', (38, 48))
279693	29928402	Patient outcomes for those with high expression were significantly worse than for those with low expression using the Kaplan-Meier method with log-rank analysis (P=0.008; Fig.	('worse', 'NegReg', (67, 72))	('Patient', 'Species', '9606', (0, 7))	('high expression', 'Var', (32, 47))
279694	29928402	In our previous study, Patient outcomes for those with high expression were significantly worse than for those with low expression using the Kaplan-Meier method with log-rank analysis.	('worse', 'NegReg', (90, 95))	('Patient', 'Species', '9606', (23, 30))	('high expression', 'Var', (55, 70))
279697	29928402	Patient outcomes for those with high expression were significantly worse than for those with low expression using the Kaplan-Meier method with log-rank analysis (P<0.001; Fig.	('worse', 'NegReg', (67, 72))	('Patient', 'Species', '9606', (0, 7))	('high expression', 'Var', (32, 47))
279698	29928402	Patient outcomes for those with high expression of all three subunits were significantly worse than for those with other expression patterns using the Kaplan-Meier method with log-rank analysis (P<0.001; Fig.	('worse', 'NegReg', (89, 94))	('Patient', 'Species', '9606', (0, 7))	('high expression', 'Var', (32, 47))
279718	29928402	In biliary cancer, the high positivity of LNgamma2 was significantly associated with worse differentiation, deeper depth of invasion (into the serosa), and more advanced stage, while an LNbeta3 invasive front-dominant pattern is significantly associated with worse differentiation and more advanced stage.	('high positivity', 'Var', (23, 38))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('associated', 'Reg', (69, 79))	('biliary cancer', 'Disease', (3, 17))	('gamma2', 'Gene', (44, 50))	('biliary cancer', 'Disease', 'MESH:D001661', (3, 17))	('worse differentiation', 'CPA', (85, 106))	('gamma2', 'Gene', '7453', (44, 50))	('beta3', 'Gene', '1934', (188, 193))	('beta3', 'Gene', (188, 193))
279721	29928402	We previously reported of staining for LNbeta3 in all patients with PDA and found that it was related to worse differentiation, more advanced stage, and shorter survival time.	('beta3', 'Gene', '1934', (41, 46))	('beta3', 'Gene', (41, 46))	('patients', 'Species', '9606', (54, 62))	('PDA', 'Disease', (68, 71))	('shorter', 'NegReg', (153, 160))	('PDA', 'Chemical', '-', (68, 71))	('worse', 'NegReg', (105, 110))	('staining', 'Var', (26, 34))
279722	29928402	In current study, the positivity LNalpha3 and LNgamma2 were significantly associated with worse differentiation, deeper depth of invasion, more advanced stage, and shorter survival time.	('worse differentiation', 'CPA', (90, 111))	('LNalpha3', 'Gene', (33, 41))	('shorter', 'NegReg', (164, 171))	('gamma2', 'Gene', '7453', (48, 54))	('survival time', 'CPA', (172, 185))	('gamma2', 'Gene', (48, 54))	('positivity', 'Var', (22, 32))
279725	29928402	Survival outcomes were significantly worse for patients with high expression of all three subunits than for those with other expression patterns.	('high expression', 'Var', (61, 76))	('Survival outcomes', 'CPA', (0, 17))	('patients', 'Species', '9606', (47, 55))	('worse', 'NegReg', (37, 42))
279731	29928402	In present study, not only in squamous carcinomas but also in adenocarcinomas, the high expression of three subunits was associated with worse cancer differentiation, not only in squamous carcinomas but also in adenocarcinomas.	('high expression', 'Var', (83, 98))	('adenocarcinomas', 'Disease', 'MESH:D000230', (211, 226))	('adenocarcinomas', 'Disease', (211, 226))	('squamous carcinomas', 'Disease', (179, 198))	('carcinomas', 'Phenotype', 'HP:0030731', (216, 226))	('carcinoma', 'Phenotype', 'HP:0030731', (39, 48))	('squamous carcinomas', 'Disease', 'MESH:D002294', (30, 49))	('carcinomas', 'Phenotype', 'HP:0030731', (39, 49))	('cancer', 'Disease', (143, 149))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('carcinoma', 'Phenotype', 'HP:0030731', (188, 197))	('carcinomas', 'Phenotype', 'HP:0030731', (188, 198))	('squamous carcinomas', 'Disease', 'MESH:D002294', (179, 198))	('adenocarcinomas', 'Disease', 'MESH:D000230', (62, 77))	('associated', 'Reg', (121, 131))	('adenocarcinomas', 'Disease', (62, 77))	('squamous carcinomas', 'Disease', (30, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('carcinomas', 'Phenotype', 'HP:0030731', (67, 77))	('carcinoma', 'Phenotype', 'HP:0030731', (216, 225))	('cancer', 'Disease', 'MESH:D009369', (143, 149))
279733	29928402	In adenomas, the staining expression of LM332 subunits is continuous and even enhanced.	('adenomas', 'Disease', 'MESH:D000236', (3, 11))	('LM332', 'Var', (40, 45))	('adenomas', 'Disease', (3, 11))	('staining expression', 'MPA', (17, 36))	('enhanced', 'PosReg', (78, 86))
279774	28303973	In this study, by silencing of E6/E7 in high-risk HPV16 or HPV18 infected cervical cancer, we identified multiple microenvironment genes which were altered after E6/E7 silencing.	('silencing', 'Var', (168, 177))	('silencing', 'Var', (18, 27))	('HPV18 infected cervical cancer', 'Disease', 'MESH:D002583', (59, 89))	('infected cervical cancer', 'Phenotype', 'HP:0030159', (65, 89))	('HPV18 infected cervical cancer', 'Disease', (59, 89))	('HPV16', 'Gene', (50, 55))	('HPV16', 'Species', '333760', (50, 55))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('altered', 'Reg', (148, 155))	('E6/E7', 'Gene', '1489078', (31, 36))	('E6/E7', 'Gene', (31, 36))	('E6/E7', 'Gene', '1489078', (162, 167))	('E6/E7', 'Gene', (162, 167))
279779	28303973	The qPCR result confirmed that the expression of CTHRC1 was greatly reduced in Caski cells and Ms751 cells after silencing of E6/E7 (Fig.	('CTHRC1', 'Gene', (49, 55))	('E6/E7', 'Gene', (126, 131))	('E6/E7', 'Gene', '1489078', (126, 131))	('expression', 'MPA', (35, 45))	('silencing', 'Var', (113, 122))	('reduced', 'NegReg', (68, 75))
279801	28303973	Moreover, silencing of CTHRC1 also suppressed cervical cancer cell invasion in vitro by transwell invasion assay (Fig.	('cervical cancer', 'Disease', 'MESH:D002583', (46, 61))	('cervical cancer', 'Disease', (46, 61))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('suppressed', 'NegReg', (35, 45))	('CTHRC1', 'Gene', (23, 29))	('silencing', 'Var', (10, 19))
279807	28303973	To examine the role of CTHRC1 in cervical cancer cells metastasis in vivo, using a microsyringe, the pulmonary of nude mice were orthotopically inoculated with Lenti-CTHRC1/Siha or Lenti-Crtl/Siha cells.	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('cervical cancer', 'Disease', (33, 48))	('cervical cancer', 'Disease', 'MESH:D002583', (33, 48))	('nude mice', 'Species', '10090', (114, 123))	('Lenti-CTHRC1/Siha', 'Var', (160, 177))
279810	28303973	The number of pulmonary metastatic nodules was lower in the mice inoculated with the Lenti-Crtl/Siha cells than in the mice inoculated with the Lenti- CTHRC1/Siha cells (Fig.	('mice', 'Species', '10090', (119, 123))	('lower', 'NegReg', (47, 52))	('pulmonary metastatic nodules', 'CPA', (14, 42))	('Lenti-Crtl/Siha', 'Var', (85, 100))	('mice', 'Species', '10090', (60, 64))
279814	28303973	To find which specific transcription factor directly regulates CTHRC1 expression by silencing of E6/E7, the transcription profiling microarray of Caski and Ms751 after silencing of E6/E7 was further analyzed.	('regulates', 'Reg', (53, 62))	('CTHRC1', 'Gene', (63, 69))	('E6/E7', 'Gene', (181, 186))	('silencing', 'Var', (84, 93))	('E6/E7', 'Gene', '1489078', (181, 186))	('expression', 'MPA', (70, 80))	('E6/E7', 'Gene', (97, 102))	('E6/E7', 'Gene', '1489078', (97, 102))
279824	28303973	Then we examined the effect of CTHRC1 on the JNK activation after knockdown the Wnt/PCP pathway-specific coreceptors ROR2 and VANGL2.	('JNK', 'Gene', '5599', (45, 48))	('VANGL2', 'Gene', '57216', (126, 132))	('ROR2', 'Gene', '4920', (117, 121))	('ROR2', 'Gene', (117, 121))	('JNK', 'Gene', (45, 48))	('knockdown', 'Var', (66, 75))	('VANGL2', 'Gene', (126, 132))
279826	28303973	Moreover, phosphorylation levels of JNK were decreased after knockdown of ROR2, VANGL2 or ROR2 + VANGL2, respectively, compared to that of the control group (Fig.	('JNK', 'Gene', (36, 39))	('VANGL2', 'Gene', '57216', (97, 103))	('VANGL2', 'Gene', (80, 86))	('decreased', 'NegReg', (45, 54))	('VANGL2', 'Gene', (97, 103))	('knockdown', 'Var', (61, 70))	('JNK', 'Gene', '5599', (36, 39))	('phosphorylation levels', 'MPA', (10, 32))	('ROR2', 'Gene', '4920', (90, 94))	('ROR2', 'Gene', (90, 94))	('ROR2', 'Gene', '4920', (74, 78))	('ROR2', 'Gene', (74, 78))	('VANGL2', 'Gene', '57216', (80, 86))
279846	28303973	HPV16 and HPV18 are two of the most important high-risk types of HPV associated with cervical cancer, and about 70% of cervical cancer cases are associated with HPV16 and HPV 18.	('HPV16', 'Species', '333760', (161, 166))	('HPV16', 'Species', '333760', (0, 5))	('cervical cancer', 'Disease', 'MESH:D002583', (85, 100))	('cervical cancer', 'Disease', 'MESH:D002583', (119, 134))	('associated', 'Reg', (69, 79))	('cervical cancer', 'Disease', (85, 100))	('associated', 'Reg', (145, 155))	('HPV16', 'Var', (161, 166))	('cervical cancer', 'Disease', (119, 134))	('HPV 18', 'Var', (171, 177))	('HPV18', 'Gene', (10, 15))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))
279848	28303973	It has been reported that HPV E6-induced promoter hypermethylation of the XRCC3 and XRCC5 DNA repair genes contributes to lung tumorigenesis in nonsmokers.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('XRCC5', 'Gene', (84, 89))	('XRCC3', 'Gene', (74, 79))	('XRCC3', 'Gene', '7517', (74, 79))	('tumor', 'Disease', (127, 132))	('XRCC5', 'Gene', '7520', (84, 89))	('contributes', 'Reg', (107, 118))	('promoter hypermethylation', 'Var', (41, 66))	('tumor', 'Disease', 'MESH:D009369', (127, 132))
279862	28303973	In this study, by silencing E6/E7 in HPV16 and HPV18 infected cervical cancer cells, we found that E6/E7 can regulate many microenvironment factors, like CTHRC1.	('HPV18 infected cervical cancer', 'Disease', (47, 77))	('CTHRC1', 'Disease', (154, 160))	('regulate', 'Reg', (109, 117))	('silencing', 'Var', (18, 27))	('microenvironment factors', 'MPA', (123, 147))	('HPV16', 'Species', '333760', (37, 42))	('E6/E7', 'Gene', (99, 104))	('E6/E7', 'Gene', '1489078', (99, 104))	('E6/E7', 'Gene', '1489078', (28, 33))	('infected cervical cancer', 'Phenotype', 'HP:0030159', (53, 77))	('E6/E7', 'Gene', (28, 33))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('HPV18 infected cervical cancer', 'Disease', 'MESH:D002583', (47, 77))
279865	28303973	Many microenvironmental factors are significantly altered by silencing of E6/E7, but we only studied the function of CTHRC1 in cervical cancer.	('E6/E7', 'Gene', '1489078', (74, 79))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('cervical cancer', 'Disease', 'MESH:D002583', (127, 142))	('silencing', 'Var', (61, 70))	('altered', 'Reg', (50, 57))	('cervical cancer', 'Disease', (127, 142))	('E6/E7', 'Gene', (74, 79))
279909	27293274	The general condition of the patient became worse, with low intelligence poor appetite, weight loss, decreased strength, right limb tremor, and intermittent convulsions.	('patient', 'Species', '9606', (29, 36))	('weight loss', 'Disease', (88, 99))	('convulsions', 'Disease', (157, 168))	('weight loss', 'Phenotype', 'HP:0001824', (88, 99))	('limb tremor', 'Phenotype', 'HP:0200085', (127, 138))	('tremor', 'Phenotype', 'HP:0001337', (132, 138))	('right limb tremor', 'Disease', 'MESH:D014202', (121, 138))	('decreased', 'NegReg', (101, 110))	('strength', 'CPA', (111, 119))	('low intelligence', 'Var', (56, 72))	('convulsions', 'Disease', 'MESH:D012640', (157, 168))	('low intelligence', 'Phenotype', 'HP:0001249', (56, 72))	('intermittent', 'Disease', (144, 156))	('weight loss', 'Disease', 'MESH:D015431', (88, 99))	('right limb tremor', 'Phenotype', 'HP:0007351', (121, 138))	('poor', 'NegReg', (73, 77))	('right limb tremor', 'Disease', (121, 138))	('poor appetite', 'Phenotype', 'HP:0004396', (73, 86))
279931	27293274	MFT has been associated with mutations in the CYLD gene on a chromosome.	('associated', 'Reg', (13, 23))	('mutations', 'Var', (29, 38))	('MFT', 'Disease', (0, 3))	('CYLD', 'Gene', (46, 50))	('CYLD', 'Gene', '1540', (46, 50))
279932	27293274	Mutations in this gene have also been linked to familial cylindromatosis and Brooke-Spiegler syndrome, in which the patients develop trichoepitheliomas and cylindromas.	('linked', 'Reg', (38, 44))	('trichoepithelioma', 'Phenotype', 'HP:0025367', (133, 150))	('Brooke-Spiegler syndrome', 'Disease', (77, 101))	('patients', 'Species', '9606', (116, 124))	('familial cylindromatosis', 'Disease', (48, 72))	('develop', 'PosReg', (125, 132))	('trichoepitheliomas and cylindromas', 'Disease', 'MESH:D003528', (133, 167))	('familial cylindromatosis', 'Disease', 'MESH:C536611', (48, 72))	('Mutations', 'Var', (0, 9))	('Brooke-Spiegler syndrome', 'Disease', 'MESH:C536611', (77, 101))
279945	27293274	In addition, squamous cell carcinoma can directly develop from the skin follicle cells by mutation must be taken into account.	('carcinoma', 'Phenotype', 'HP:0030731', (27, 36))	('squamous cell carcinoma', 'Disease', (13, 36))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (13, 36))	('mutation', 'Var', (90, 98))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (13, 36))
279951	32978168	Using an integrated screening approach, we found that miR-671-5p reduces LUSC metastasis by inhibiting a circular RNA (circRNA), CDR1as.	('LUSC metastasis', 'CPA', (73, 88))	('reduces', 'NegReg', (65, 72))	('miR-671-5p', 'Var', (54, 64))	('CDR1as', 'Gene', (129, 135))	('LUSC', 'Chemical', '-', (73, 77))	('CDR1as', 'Gene', '103611090', (129, 135))	('inhibiting', 'NegReg', (92, 102))
279953	32978168	Silencing of CDR1as or CDR1 significantly inhibited LUSC metastases and CDR1 was sufficient to promote migration and metastases.	('CDR1', 'Gene', (23, 27))	('promote', 'PosReg', (95, 102))	('metastases', 'Disease', 'MESH:D009362', (117, 127))	('metastases', 'Disease', (57, 67))	('LUSC', 'Chemical', '-', (52, 56))	('CDR1as', 'Gene', (13, 19))	('inhibited', 'NegReg', (42, 51))	('metastases', 'Disease', 'MESH:D009362', (57, 67))	('CDR1as', 'Gene', '103611090', (13, 19))	('Silencing', 'Var', (0, 9))	('metastases', 'Disease', (117, 127))
279955	32978168	Therapeutic inhibition of the CDR1as/CDR1 axis with miR-671-5p mimics reduced metastasis in vivo.	('reduced', 'NegReg', (70, 77))	('inhibition', 'NegReg', (12, 22))	('CDR1as', 'Gene', (30, 36))	('CDR1as', 'Gene', '103611090', (30, 36))	('metastasis', 'CPA', (78, 88))	('miR-671-5p', 'Var', (52, 62))
279961	32978168	Extensive molecular profiling through The Cancer Genome Atlas (TCGA) has revealed LUSC tumors have non-recurrent somatic mutations and are largely driven by copy number alterations and distinct transcriptional programs.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('copy number alterations', 'Var', (157, 180))	('driven by', 'Reg', (147, 156))	('Cancer', 'Disease', 'MESH:D009369', (42, 48))	('Cancer', 'Disease', (42, 48))	('LUSC tumors', 'Disease', 'MESH:D009369', (82, 93))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('Cancer', 'Phenotype', 'HP:0002664', (42, 48))	('LUSC tumors', 'Disease', (82, 93))
279965	32978168	Gene expression programs within cancer cells facilitate egress from the tumor through blood or lymphatic vessels, extravasation, and colonization of distant organs.	('colonization', 'CPA', (133, 145))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('Gene expression programs', 'Var', (0, 24))	('tumor', 'Disease', (72, 77))	('cancer', 'Disease', (32, 38))	('facilitate', 'PosReg', (45, 55))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('extravasation', 'CPA', (114, 127))	('egress', 'CPA', (56, 62))	('tumor', 'Disease', 'MESH:D009369', (72, 77))
279976	32978168	Using a targeted lipid nanoparticle to deliver miR-671-5p to target the CDR1as/CDR1 axis we inhibited metastatic spread in vivo.	('inhibited', 'NegReg', (92, 101))	('lipid', 'Chemical', 'MESH:D008055', (17, 22))	('CDR1as', 'Gene', '103611090', (72, 78))	('miR-671-5p', 'Var', (47, 57))	('metastatic spread', 'CPA', (102, 119))	('CDR1as', 'Gene', (72, 78))
279985	32978168	Cells were expanded and FACS was performed using FITC-conjugated anti-human HLA-A,B,C antibody (32294x, Pharmingen) to remove any contaminating mouse cells.	('mouse', 'Species', '10090', (144, 149))	('32294x', 'Var', (96, 102))	('human', 'Species', '9606', (70, 75))	('HLA-A', 'Gene', '3105', (76, 81))	('FITC', 'Chemical', 'MESH:D016650', (49, 53))	('HLA-A', 'Gene', (76, 81))
280010	32978168	While mice injected with SK-MES-1 lived >120 days, LN1-injected mice had substantially reduced survival (median 41 days, p<0.0001) (Supplementary Fig.	('SK-MES-1', 'Var', (25, 33))	('mice', 'Species', '10090', (6, 10))	('reduced', 'NegReg', (87, 94))	('mice', 'Species', '10090', (64, 68))	('SK-MES-1', 'CellLine', 'CVCL:0630', (25, 33))	('survival', 'CPA', (95, 103))
280011	32978168	Similarly, H520 and H520-LN3 (LN3), which was generated from 3 in vivo passages, had LN metastasis rates of 20% and 100%, respectively (Supplementary Fig.	('H520-LN3', 'Gene', '104189', (20, 28))	('LN3', 'Gene', (25, 28))	('LN3', 'Gene', '104189', (30, 33))	('LN3', 'Gene', (30, 33))	('LN3', 'Gene', '104189', (25, 28))	('H520-LN3', 'Gene', (20, 28))	('H520', 'Var', (11, 15))	('LN metastasis', 'CPA', (85, 98))
280012	32978168	In vivo passaging of H520 significantly reduced survival of orthotopically injected mice from >60 days to 39.5 days mean survival (p<0.0001) (Supplementary Fig.	('survival', 'CPA', (48, 56))	('reduced', 'NegReg', (40, 47))	('H520', 'Var', (21, 25))	('mice', 'Species', '10090', (84, 88))
280027	32978168	All miR candidates were decreased based on qPCR in both metastatic LN1 and LN3 sub-clones relative to their respective parental lines (Fig.	('LN3', 'Gene', (75, 78))	('decreased', 'NegReg', (24, 33))	('LN3', 'Gene', '104189', (75, 78))	('miR', 'Gene', (4, 7))	('miR', 'Gene', '220972', (4, 7))	('qPCR', 'Var', (43, 47))
280028	32978168	Of these candidates, miR-671-5p was the most consistently reduced (<20% of parental expression) in both LN1 and LN3.	('LN3', 'Gene', (112, 115))	('miR-671-5p', 'Var', (21, 31))	('reduced', 'NegReg', (58, 65))	('LN3', 'Gene', '104189', (112, 115))
280031	32978168	Survival analysis based on the expression of the miR-671 gene and miR-671-5p and -3p isoforms in TCGA revealed that miR-671-5p (HR=0.56, 95% CI 0.39 to 0.80, p=0.002), but not -3p (HR=0.92, 95% CI 0.64 to 1.33, p=0.7), was strongly associated with LUSC survival (Fig.	('miR-671-5p', 'Var', (116, 126))	('LUSC', 'Chemical', '-', (248, 252))	('miR-671', 'Gene', (49, 56))	('associated with', 'Reg', (232, 247))	('LUSC survival', 'CPA', (248, 261))
280040	32978168	Effects of miR-671 manipulation on CDR1as were notably stronger than on IL-16 in most experiments.	('CDR1as', 'Gene', '103611090', (35, 41))	('manipulation', 'Var', (19, 31))	('IL-16', 'Gene', (72, 77))	('stronger', 'PosReg', (55, 63))	('IL-16', 'Gene', '3603', (72, 77))	('miR-671', 'Gene', (11, 18))	('CDR1as', 'Gene', (35, 41))
280043	32978168	We confirmed that miR-671-5p potently decreased CDR1as expression in both of our metastatic sub-clones (Fig.	('decreased', 'NegReg', (38, 47))	('expression', 'MPA', (55, 65))	('CDR1as', 'Gene', (48, 54))	('CDR1as', 'Gene', '103611090', (48, 54))	('miR-671-5p', 'Var', (18, 28))
280044	32978168	These data show that miR-671-5p strongly targets the non-coding RNA CDR1as.	('targets', 'Reg', (41, 48))	('CDR1as', 'Gene', (68, 74))	('miR-671-5p', 'Var', (21, 31))	('CDR1as', 'Gene', '103611090', (68, 74))
280046	32978168	CDR1as (also known as ciRS-7), is a direct target of miR-671-5p as confirmed by luciferase assay and Argonaut cross-linking and immunoprecipitation (AGO-CLIP) in mouse and human.	('CDR1as', 'Gene', '103611090', (0, 6))	('miR-671-5p', 'Var', (53, 63))	('mouse', 'Species', '10090', (162, 167))	('human', 'Species', '9606', (172, 177))	('CDR1as', 'Gene', (0, 6))
280051	32978168	Interestingly, we found no significant changes in miR-7 targets in LN1 or LN3 cells overexpressing miR-671.	('miR-7', 'Gene', '10859', (50, 55))	('LN3', 'Gene', (74, 77))	('LN3', 'Gene', '104189', (74, 77))	('miR-7', 'Gene', (50, 55))	('miR-671', 'Var', (99, 106))
280052	32978168	These findings suggest miR-671-5p's role in LUSC metastasis may occur through CDR1as, although in a miR-7-independent manner.	('miR-7', 'Gene', (100, 105))	('miR-671-5p', 'Var', (23, 33))	('miR-7', 'Gene', '10859', (100, 105))	('CDR1as', 'Gene', (78, 84))	('LUSC metastasis', 'CPA', (44, 59))	('CDR1as', 'Gene', '103611090', (78, 84))	('LUSC', 'Chemical', '-', (44, 48))
280056	32978168	To confirm that miR-671-5p also reduced CDR1 expression in LUSC cells, we measured CDR1 by strand-specific reverse transcription followed by qPCR in cells transfected with miR-671-5p mimics.	('miR-671-5p', 'Var', (16, 26))	('reduced', 'NegReg', (32, 39))	('LUSC', 'Chemical', '-', (59, 63))	('expression', 'MPA', (45, 55))	('CDR1', 'Gene', (40, 44))
280057	32978168	miR-671-5p strongly decreased CDR1 expression in both LN1 and LN3 sub-clones (Fig.	('decreased', 'NegReg', (20, 29))	('CDR1', 'Gene', (30, 34))	('LN3', 'Gene', (62, 65))	('expression', 'MPA', (35, 45))	('LN3', 'Gene', '104189', (62, 65))	('miR-671-5p', 'Var', (0, 10))
280061	32978168	High CDR1as expression was associated with worse survival in non-small cell lung cancer (NSCLC) (HR=1.39, 95% CI 1.01 to 1.94, p=0.048) (Fig.	('lung cancer', 'Disease', 'MESH:D008175', (76, 87))	('NSCLC', 'Disease', 'MESH:D002289', (89, 94))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (65, 87))	('High', 'Var', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('CDR1as', 'Gene', (5, 11))	('lung cancer', 'Disease', (76, 87))	('lung cancer', 'Phenotype', 'HP:0100526', (76, 87))	('CDR1as', 'Gene', '103611090', (5, 11))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (61, 87))	('expression', 'MPA', (12, 22))	('NSCLC', 'Disease', (89, 94))	('worse', 'NegReg', (43, 48))
280065	32978168	High CDR1 expression was associated with worse survival in NSCLC (HR=1.43, 95% CI 1.02 to 2.01, p=0.0429).	('CDR1', 'Gene', (5, 9))	('NSCLC', 'Disease', 'MESH:D002289', (59, 64))	('High', 'Var', (0, 4))	('expression', 'MPA', (10, 20))	('NSCLC', 'Disease', (59, 64))
280066	32978168	Similarly, in TCGA, high expression of CDR1 in LUSC patients was associated with significantly worse survival (HR=1.57, 95% CI 1.10 to 2.24, p=0.019) (Fig.	('worse', 'NegReg', (95, 100))	('CDR1', 'Gene', (39, 43))	('LUSC', 'Chemical', '-', (47, 51))	('survival', 'MPA', (101, 109))	('high', 'Var', (20, 24))	('patients', 'Species', '9606', (52, 60))
280067	32978168	To address the importance of the miR-671-5p/CDR1as/CDR1 axis in LUSC, we performed a dual survival analysis of miR-671-5p and CDR1 and found that Low miR-671-5p/High CDR1 expression in tumors was associated with worse survival than High miR-671-5p/Low CDR1 expression (HR=2.094, 95% CI 1.311 to 3.344, p=0.002) (Fig.	('worse', 'NegReg', (212, 217))	('tumors', 'Disease', (185, 191))	('tumors', 'Phenotype', 'HP:0002664', (185, 191))	('CDR1as', 'Gene', (44, 50))	('survival', 'MPA', (218, 226))	('Low miR-671-5p/High CDR1', 'Var', (146, 170))	('CDR1as', 'Gene', '103611090', (44, 50))	('tumors', 'Disease', 'MESH:D009369', (185, 191))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('LUSC', 'Chemical', '-', (64, 68))
280068	32978168	Using TCGA to cluster LUSC tumors based on High CDR1/Low miR-671-5p and Low CDR1/High miR-671-5p expression, we identified 2,123 differentially expressed genes (Supplementary Fig.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('High CDR1/Low', 'Var', (43, 56))	('LUSC tumors', 'Disease', 'MESH:D009369', (22, 33))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('LUSC tumors', 'Disease', (22, 33))	('Low CDR1/High miR-671-5p', 'Var', (72, 96))
280075	32978168	Inhibition of CDR1/CDR1as with several independent shRs (Supplementary Fig.	('CDR1as', 'Gene', '103611090', (19, 25))	('CDR1as', 'Gene', (19, 25))	('Inhibition', 'Var', (0, 10))
280077	32978168	In addition, inhibition of CDR1 or CDR1as markedly reduced LN metastases (Fig.	('reduced', 'NegReg', (51, 58))	('CDR1as', 'Gene', '103611090', (35, 41))	('metastases', 'Disease', 'MESH:D009362', (62, 72))	('inhibition', 'Var', (13, 23))	('CDR1', 'Gene', (27, 31))	('metastases', 'Disease', (62, 72))	('CDR1as', 'Gene', (35, 41))
280082	32978168	CDH1 was decreased in tumors over-expressing CDR1, supporting a role for CDR1 in EMT (Supplementary Fig.	('tumors', 'Phenotype', 'HP:0002664', (22, 28))	('over-expressing', 'Var', (29, 44))	('CDH1', 'Gene', '999', (0, 4))	('CDR1', 'Gene', (45, 49))	('tumors', 'Disease', 'MESH:D009369', (22, 28))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('decreased', 'NegReg', (9, 18))	('tumors', 'Disease', (22, 28))	('CDH1', 'Gene', (0, 4))
280084	32978168	Importantly, overexpression of CDR1 was able to partially rescue the metastatic phenotype of CDR1as knockdown, showing that the biological function of CDR1as is at least in part dependent on its regulation of CDR1 (Fig.	('knockdown', 'Var', (100, 109))	('CDR1as', 'Gene', (93, 99))	('CDR1', 'Gene', (209, 213))	('CDR1as', 'Gene', '103611090', (93, 99))	('CDR1as', 'Gene', (151, 157))	('CDR1as', 'Gene', '103611090', (151, 157))	('metastatic phenotype', 'CPA', (69, 89))
280094	32978168	Time-kinetic experiments revealed that miR-671-5p LPH-NPs decreased CDR1as expression by 60% relative to control LPH-NPs at 24h, and CDR1 positive cells by 70% at 48h (Supplementary Fig.	('miR-671-5p', 'Var', (39, 49))	('decreased', 'NegReg', (58, 67))	('LPH', 'Chemical', '-', (50, 53))	('CDR1as', 'Gene', (68, 74))	('LPH', 'Chemical', '-', (113, 116))	('CDR1as', 'Gene', '103611090', (68, 74))	('expression', 'MPA', (75, 85))
280095	32978168	Treatment with miR-671-5p NPs 3x per week for three weeks significantly decreased the number of LN metastases in H520-LN3 mice (Fig.	('mice', 'Species', '10090', (122, 126))	('decreased', 'NegReg', (72, 81))	('H520-LN3', 'Gene', (113, 121))	('metastases', 'Disease', (99, 109))	('metastases', 'Disease', 'MESH:D009362', (99, 109))	('H520-LN3', 'Gene', '104189', (113, 121))	('miR-671-5p', 'Var', (15, 25))
280097	32978168	In tumors collected 24h after the final NP injection, the number of CDR1 positive cells was significantly decreased in LN metastases of mice treated with miR-671-5p NPs compared to controls (Fig.	('decreased', 'NegReg', (106, 115))	('mice', 'Species', '10090', (136, 140))	('tumors', 'Phenotype', 'HP:0002664', (3, 9))	('CDR1', 'Gene', (68, 72))	('tumors', 'Disease', (3, 9))	('tumors', 'Disease', 'MESH:D009369', (3, 9))	('metastases', 'Disease', (122, 132))	('miR-671-5p NPs', 'Var', (154, 168))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))	('metastases', 'Disease', 'MESH:D009362', (122, 132))
280102	32978168	Similarly, SK-MES-1-CDR1 cells moved with greater velocity (p<0.01) and traveled a greater distance (p<0.05) compared to SK-MES-1-GFP in a random migration assay on type 1 collagen (Fig.	('SK-MES-1-CDR1', 'CellLine', 'CVCL:9168', (11, 24))	('SK-MES-1', 'CellLine', 'CVCL:0630', (11, 19))	('random migration', 'CPA', (139, 155))	('greater', 'PosReg', (42, 49))	('SK-MES-1-CDR1', 'Var', (11, 24))	('moved', 'CPA', (31, 36))	('SK-MES-1', 'CellLine', 'CVCL:0630', (121, 129))
280103	32978168	These experimental outcomes are aligned with the GO analysis of the genes upregulated in High CDR1/Low miR-671-5p, which shows that one of the most significant biological process of these patients is 'positive regulation of cell migration' (Supplementary Fig.	('patients', 'Species', '9606', (188, 196))	('CDR1/Low', 'Gene', (94, 102))	('upregulated', 'PosReg', (74, 85))	('High', 'Var', (89, 93))
280104	32978168	A total of 34 proteins were associated with CDR1 in both 293T and LN1 cells stably expressing CDR1-Flag (Fig.	('CDR1', 'Gene', (44, 48))	('CDR1-Flag', 'Var', (94, 103))	('proteins', 'Protein', (14, 22))	('associated', 'Interaction', (28, 38))	('293T', 'CellLine', 'CVCL:0063', (57, 61))
280113	32978168	Consistent with a pro-migratory phenotype, SK-MES-1-CDR1 cells invaded the scratch in significantly greater numbers than SK-MES-1-EV cells (Fig 7A and B).	('greater', 'PosReg', (100, 107))	('SK-MES-1', 'CellLine', 'CVCL:0630', (43, 51))	('SK-MES-1-CDR1', 'CellLine', 'CVCL:9168', (43, 56))	('invaded the scratch', 'CPA', (63, 82))	('SK-MES-1-CDR1', 'Var', (43, 56))	('SK-MES-1', 'CellLine', 'CVCL:0630', (121, 129))
280121	32978168	There was a significantly higher proportion of "fast" trafficking cells in CDR1 (4/11 cells) compared to EV cells (0/11 cells) (p<0.05) (Fig.	('fast', 'Gene', '10922', (48, 52))	('CDR1', 'Var', (75, 79))	('fast', 'Gene', (48, 52))
280126	32978168	Expression of miR-671-5p was strongly associated with patient survival and genetic overexpression or therapeutic delivery of miR-671-5p was capable of inhibiting metastasis.	('metastasis', 'CPA', (162, 172))	('patient', 'Species', '9606', (54, 61))	('associated', 'Reg', (38, 48))	('inhibiting', 'NegReg', (151, 161))	('overexpression', 'PosReg', (83, 97))	('miR-671-5p', 'Var', (125, 135))	('miR-671-5p', 'Var', (14, 24))
280127	32978168	The circRNA, CDR1as, was strongly inhibited by miR-671-5p as was its antisense transcript CDR1.	('miR-671-5p', 'Var', (47, 57))	('CDR1as', 'Gene', '103611090', (13, 19))	('CDR1as', 'Gene', (13, 19))	('inhibited', 'NegReg', (34, 43))
280128	32978168	This CDR1as/CDR1 axis was associated with worse survival in LUSC patients and inhibition of CDR1as or CDR1 decreased tumor burden and metastases.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('LUSC', 'Chemical', '-', (60, 64))	('CDR1', 'Gene', (102, 106))	('CDR1as', 'Gene', (92, 98))	('worse', 'NegReg', (42, 47))	('decreased tumor', 'Disease', (107, 122))	('CDR1as', 'Gene', (5, 11))	('inhibition', 'Var', (78, 88))	('metastases', 'Disease', (134, 144))	('CDR1as', 'Gene', '103611090', (92, 98))	('decreased tumor', 'Disease', 'MESH:D002303', (107, 122))	('CDR1as', 'Gene', '103611090', (5, 11))	('patients', 'Species', '9606', (65, 73))	('metastases', 'Disease', 'MESH:D009362', (134, 144))
280131	32978168	In agreement with previous studies, we found that miR-671-5p targeted the circular RNA CDR1as.	('miR-671-5p', 'Var', (50, 60))	('CDR1as', 'Gene', '103611090', (87, 93))	('CDR1as', 'Gene', (87, 93))	('targeted', 'Reg', (61, 69))
280136	32978168	Using non-transformed human bronchial cells, we found that CDR1 expression increased mucin secretion.	('mucin', 'Gene', (85, 90))	('CDR1', 'Gene', (59, 63))	('expression', 'Var', (64, 74))	('increased', 'PosReg', (75, 84))	('human', 'Species', '9606', (22, 27))	('mucin', 'Gene', '100508689', (85, 90))
280142	32978168	In neurons, excess miR-7 can also enhance the silencing of CDR1as by miR-671-5p.	('CDR1as', 'Gene', '103611090', (59, 65))	('enhance', 'PosReg', (34, 41))	('miR-7', 'Gene', (19, 24))	('silencing', 'MPA', (46, 55))	('miR-7', 'Gene', '10859', (19, 24))	('miR-671-5p', 'Var', (69, 79))	('CDR1as', 'Gene', (59, 65))
280143	32978168	Importantly, no adverse effects of CDR1as deletion were found outside the CNS, making CDR1as a highly appealing therapeutic target for cancer.	('CDR1as', 'Gene', '103611090', (86, 92))	('cancer', 'Disease', (135, 141))	('CDR1as', 'Gene', '103611090', (35, 41))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('deletion', 'Var', (42, 50))	('CDR1as', 'Gene', (86, 92))	('cancer', 'Disease', 'MESH:D009369', (135, 141))	('CDR1as', 'Gene', (35, 41))
280155	32978168	We found miR-671-5p's role in suppressing metastasis occurred through a CDR1as/CDR1 axis and that CDR1 alone was sufficient to promote metastasis.	('metastasis', 'CPA', (135, 145))	('CDR1as', 'Gene', '103611090', (72, 78))	('suppressing', 'NegReg', (30, 41))	('promote', 'PosReg', (127, 134))	('CDR1as', 'Gene', (72, 78))	('miR-671-5p', 'Var', (9, 19))
280158	32978168	In conclusion, we have found that miR-671-5p inhibits LUSC metastases by targeting the poorly understood CDR1as/CDR1 axis.	('LUSC', 'Chemical', '-', (54, 58))	('inhibits', 'NegReg', (45, 53))	('metastases', 'Disease', 'MESH:D009362', (59, 69))	('CDR1as', 'Gene', (105, 111))	('miR-671-5p', 'Var', (34, 44))	('targeting', 'Reg', (73, 82))	('CDR1as', 'Gene', '103611090', (105, 111))	('metastases', 'Disease', (59, 69))
280164	31900418	Interpreting pathways to discover cancer driver genes with Moonlight Cancer driver gene alterations influence cancer development, occurring in oncogenes, tumor suppressors, and dual role genes.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('cancer', 'Disease', (110, 116))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('alterations', 'Var', (88, 99))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('cancer', 'Disease', (34, 40))	('Cancer', 'Phenotype', 'HP:0002664', (69, 75))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('influence', 'Reg', (100, 109))	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('tumor', 'Disease', (154, 159))
280171	31900418	We discover inactivation of tumor suppressors in intron regions and that tissue type and subtype indicate dual role status.	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('tumor', 'Disease', (28, 33))	('inactivation', 'Var', (12, 24))
280178	31900418	Cancer progression is accelerated by the accumulation of genomic abnormalities in two different categories of cancer driver genes: oncogenes or tumor suppressors.	('genomic abnormalities', 'Var', (57, 78))	('tumor', 'Disease', (144, 149))	('cancer', 'Disease', (110, 116))	('accelerated', 'PosReg', (22, 33))	('accumulation', 'PosReg', (41, 53))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('Cancer progression', 'CPA', (0, 18))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('cancer', 'Disease', 'MESH:D009369', (110, 116))
280183	31900418	In addition, it has been shown that concomitant Notch activation and p53 deletion trigger epithelial-to-mesenchymal transition and metastasis.	('p53', 'Gene', (69, 72))	('epithelial-to-mesenchymal transition', 'CPA', (90, 126))	('Notch', 'MPA', (48, 53))	('p53', 'Gene', '7157', (69, 72))	('activation', 'PosReg', (54, 64))	('deletion', 'Var', (73, 81))	('trigger', 'PosReg', (82, 89))
280232	31900418	Moonlight detected 233 genes associated with hypermethylation (tumor-suppressor critical) and 404 with hypomethylation (oncogene critical).	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('tumor-suppressor', 'Gene', '7248', (63, 79))	('tumor-suppressor', 'Gene', (63, 79))	('hypermethylation', 'Var', (45, 61))
280236	31900418	These findings were confirmed by data on lung cancer, and associated with copy-number changes in head-and-neck cancer cell lines, but it has not been validated yet as oncogene for head-and-neck tumors, suggesting an interesting target for future studies.	('head-and-neck cancer', 'Disease', 'MESH:D006258', (97, 117))	('head-and-neck cancer', 'Disease', (97, 117))	('neck cancer', 'Phenotype', 'HP:0012288', (106, 117))	('lung cancer', 'Disease', (41, 52))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('lung cancer', 'Phenotype', 'HP:0100526', (41, 52))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('tumors', 'Disease', 'MESH:D009369', (194, 200))	('tumors', 'Phenotype', 'HP:0002664', (194, 200))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('copy-number changes', 'Var', (74, 93))	('tumors', 'Disease', (194, 200))	('lung cancer', 'Disease', 'MESH:D008175', (41, 52))
280237	31900418	For breast cancer, we found that 231 (30%) of the predicted oncogenic mediators experienced epigenetic changes.	('epigenetic changes', 'Var', (92, 110))	('experienced', 'Reg', (80, 91))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('breast cancer', 'Disease', 'MESH:D001943', (4, 17))	('breast cancer', 'Phenotype', 'HP:0003002', (4, 17))	('breast cancer', 'Disease', (4, 17))
280238	31900418	Of these genes, 54 tumor suppressors showed hypermethylation while 80 oncogenes showed hypomethylation.	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('hypermethylation', 'Var', (44, 60))	('tumor', 'Disease', (19, 24))
280246	31900418	Recently, it was shown that knockdown of RRM2 led to intrinsic apoptosis in head-and-neck squamous cell carcinoma and non-small cell lung cancer cell lines, confirming our findings.	('intrinsic apoptosis', 'CPA', (53, 72))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (118, 144))	('RRM2', 'Gene', (41, 45))	('RRM2', 'Gene', '6241', (41, 45))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (90, 113))	('squamous cell carcinoma', 'Disease', (90, 113))	('lung cancer', 'Phenotype', 'HP:0100526', (133, 144))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('non-small cell lung cancer', 'Disease', (118, 144))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (90, 113))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (122, 144))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (118, 144))	('knockdown', 'Var', (28, 37))
280248	31900418	We also found hypermethylation of colon adenocarcinoma and lung adenocarcinoma, specifically in two CpG loci associated with FLI1: cg11017065 (colon cancer) and cg04691908 (lung adenocarcinoma).	('colon adenocarcinoma and lung adenocarcinoma', 'Disease', 'MESH:C538231', (34, 78))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (59, 78))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (173, 192))	('lung adenocarcinoma', 'Disease', (59, 78))	('colon cancer', 'Phenotype', 'HP:0003003', (143, 155))	('carcinoma', 'Phenotype', 'HP:0030731', (183, 192))	('FLI1', 'Gene', (125, 129))	('cg11017065', 'Var', (131, 141))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))	('hypermethylation', 'Var', (14, 30))	('FLI1', 'Gene', '2313', (125, 129))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('colon cancer', 'Disease', 'MESH:D015179', (143, 155))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (59, 78))	('carcinoma', 'Phenotype', 'HP:0030731', (45, 54))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (173, 192))	('cg04691908', 'Var', (161, 171))	('lung adenocarcinoma', 'Disease', (173, 192))	('colon cancer', 'Disease', (143, 155))
280249	31900418	We hypothesize that differentially methylated CpG islands, or hypermethylation of the FLI1 promoter, may also lead to inactivation of FLI1's tumor-suppressor ability.	('FLI1', 'Gene', (134, 138))	('hypermethylation', 'Var', (62, 78))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumor-suppressor', 'Gene', (141, 157))	('inactivation', 'NegReg', (118, 130))	('FLI1', 'Gene', (86, 90))	('FLI1', 'Gene', '2313', (86, 90))	('tumor-suppressor', 'Gene', '7248', (141, 157))	('FLI1', 'Gene', '2313', (134, 138))
280251	31900418	Hypermethylation, especially in tumor suppressors, is a well-known epigenetic control mechanism that is important for gene inactivation in cancer cells.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('Hypermethylation', 'Var', (0, 16))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumor', 'Disease', (32, 37))	('cancer', 'Disease', (139, 145))
280252	31900418	Furthermore, DNA hypomethylation can be found early in carcinogenesis, and is often associated with tumor progression and oncogenes.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Disease', (100, 105))	('associated', 'Reg', (84, 94))	('carcinogenesis', 'Disease', 'MESH:D063646', (55, 69))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('DNA hypomethylation', 'Var', (13, 32))	('carcinogenesis', 'Disease', (55, 69))
280253	31900418	Therefore, Moonlight's highlighted mechanisms on CpG-island promoter regions can be summarized as follows: (i) oncogene activation is associated with DNA hypomethylation at the promoter sites, and (ii) tumor-suppressor inactivation is associated with DNA hypermethylation at the promoter sites.	('oncogene', 'Gene', (111, 119))	('tumor-suppressor', 'Gene', '7248', (202, 218))	('activation', 'PosReg', (120, 130))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('tumor-suppressor', 'Gene', (202, 218))	('hypomethylation', 'Var', (154, 169))
280261	31900418	We also reported overall higher chromatin peaks signal for oncogenes when compared with tumor suppressors (Fig.	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('oncogenes', 'Var', (59, 68))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor', 'Disease', (88, 93))	('higher', 'PosReg', (25, 31))	('chromatin peaks signal', 'MPA', (32, 54))
280267	31900418	In particular, among 151 dual-role genes detected by Moonlight one interesting gene, ANGPTL4, was predicted to be an oncogene in kidney cancers with associated promoter peaks as well as a tumor suppressor in prostate adenocarcinoma with hypermethylation in the promoter region (Supplementary Data 7, 8; Methods).	('tumor', 'Disease', (188, 193))	('kidney cancers', 'Disease', (129, 143))	('ANGPTL4', 'Gene', '51129', (85, 92))	('ANGPTL4', 'Gene', (85, 92))	('kidney cancers', 'Phenotype', 'HP:0009726', (129, 143))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('cancers', 'Phenotype', 'HP:0002664', (136, 143))	('prostate adenocarcinoma', 'Disease', (208, 231))	('carcinoma', 'Phenotype', 'HP:0030731', (222, 231))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('promoter', 'MPA', (160, 168))	('prostate adenocarcinoma', 'Disease', 'MESH:D011471', (208, 231))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('hypermethylation', 'Var', (237, 253))	('kidney cancers', 'Disease', 'MESH:D007680', (129, 143))
280270	31900418	The relationship between DNA hypomethylation of oncogenes, hypermethylation of tumor suppressors, and copy-number amplification or deletion is another well-known mechanism to modulate cancer driver genes.	('cancer', 'Disease', (184, 190))	('tumor', 'Disease', (79, 84))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('copy-number amplification', 'Var', (102, 127))	('modulate', 'Reg', (175, 183))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('deletion', 'Var', (131, 139))
280272	31900418	For the 3123 mediators predicted by Moonlight within 18 cancer types, 848 showed copy-number changes and 358 showed critical copy-number cancer driver genes (eg.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('copy-number changes', 'Var', (81, 100))	('cancer', 'Disease', (137, 143))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))
280273	31900418	observed amplification of oncogenes and deletion of tumor suppressors) (Supplementary Data 9).	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('deletion', 'Var', (40, 48))	('tumor', 'Disease', (52, 57))	('oncogenes', 'Gene', (26, 35))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('amplification', 'MPA', (9, 22))
280274	31900418	For example, we observed amplification of the oncogenes CCND1 (supported by study) and CCNE1 in breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('CCND1', 'Gene', '595', (56, 61))	('breast cancer', 'Disease', 'MESH:D001943', (96, 109))	('breast cancer', 'Disease', (96, 109))	('CCNE1', 'Gene', (87, 92))	('CCNE1', 'Gene', '898', (87, 92))	('breast cancer', 'Phenotype', 'HP:0003002', (96, 109))	('CCND1', 'Gene', (56, 61))	('amplification', 'Var', (25, 38))
280275	31900418	Moreover, we identified deletions in tumor suppressors, such as DACT2 and TGFBR3 (Fig.	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('DACT2', 'Gene', '168002', (64, 69))	('TGFBR3', 'Gene', '7049', (74, 80))	('deletions', 'Var', (24, 33))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('DACT2', 'Gene', (64, 69))	('TGFBR3', 'Gene', (74, 80))
280276	31900418	In addition, Moonlight predicted FOXM1 as an oncogene with associated amplification in colon adenocarcinoma and lung squamous cell carcinoma.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (117, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('FOXM1', 'Gene', (33, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('FOXM1', 'Gene', '2305', (33, 38))	('colon adenocarcinoma and lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (87, 140))	('amplification', 'Var', (70, 83))
280277	31900418	Among the 151 predicted dual-role genes, 19 were identified with associated copy-number changes, while 12 genes were critical copy-number cancer driver genes, including ADAM6, BCL2, CACNA2D2, CDKN2B, CLEC1A, DIXDC1, FAM129A, GPSM2, IQGAP2, MAP1B, PALM, and TSPAN4.	('cancer', 'Disease', (138, 144))	('ADAM6', 'Gene', '8755', (169, 174))	('CACNA2D2', 'Gene', (182, 190))	('FAM129A', 'Gene', (216, 223))	('CACNA2D2', 'Gene', '9254', (182, 190))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('GPSM2', 'Gene', (225, 230))	('CDKN2B', 'Gene', '1030', (192, 198))	('MAP1B', 'Gene', '4131', (240, 245))	('CLEC1A', 'Gene', '51267', (200, 206))	('IQGAP2', 'Gene', (232, 238))	('BCL2', 'Gene', '596', (176, 180))	('GPSM2', 'Gene', '29899', (225, 230))	('cancer', 'Disease', 'MESH:D009369', (138, 144))	('copy-number', 'Var', (76, 87))	('BCL2', 'Gene', (176, 180))	('MAP1B', 'Gene', (240, 245))	('DIXDC1', 'Gene', '85458', (208, 214))	('TSPAN4', 'Gene', (257, 263))	('TSPAN4', 'Gene', '7106', (257, 263))	('DIXDC1', 'Gene', (208, 214))	('ADAM6', 'Gene', (169, 174))	('changes', 'Var', (88, 95))	('FAM129A', 'Gene', '116496', (216, 223))	('IQGAP2', 'Gene', '10788', (232, 238))	('CDKN2B', 'Gene', (192, 198))	('CLEC1A', 'Gene', (200, 206))
280281	31900418	Moonlight also identified BCL2 as a tumor suppressor in prostate adenocarcinoma with promoter hypermethylation, deletion, and associated with increased apoptosis (Supplementary Data 7, 9).	('BCL2', 'Gene', (26, 30))	('prostate adenocarcinoma', 'Disease', (56, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('increased', 'PosReg', (142, 151))	('deletion', 'Var', (112, 120))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('prostate adenocarcinoma', 'Disease', 'MESH:D011471', (56, 79))	('BCL2', 'Gene', '596', (26, 30))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('apoptosis', 'CPA', (152, 161))	('tumor', 'Disease', (36, 41))
280283	31900418	While it has been shown that highly mutated genes promote cancer progression, it is yet unknown if methylation and copy-number changes to cancer driver genes directly imply that these genes have been mutated.	('cancer', 'Disease', (138, 144))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('promote', 'PosReg', (50, 57))	('genes', 'Var', (44, 49))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('highly mutated genes', 'Var', (29, 49))	('cancer', 'Disease', (58, 64))	('cancer', 'Disease', 'MESH:D009369', (138, 144))
280285	31900418	Moonlight applied to pan-cancer data revealed mutations in intron region (Fig.	('intron region', 'Gene', (59, 72))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('mutations', 'Var', (46, 55))	('cancer', 'Disease', 'MESH:D009369', (25, 31))	('cancer', 'Disease', (25, 31))
280286	31900418	4b) for tumor suppressors and mutations in promoter regions for oncogenes.	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('oncogenes', 'Gene', (64, 73))	('mutations', 'Var', (30, 39))	('tumor', 'Disease', (8, 13))
280288	31900418	Moonlight identified three oncogenes, CMYA5, ASPM, and ERBB2, showing 34, 30, and 29 samples with missense mutations, respectively (Methods; Supplementary Data 10).	('missense mutations', 'Var', (98, 116))	('ASPM', 'Gene', '259266', (45, 49))	('CMYA5', 'Gene', (38, 43))	('CMYA5', 'Gene', '202333', (38, 43))	('ERBB2', 'Gene', (55, 60))	('ASPM', 'Gene', (45, 49))	('ERBB2', 'Gene', '2064', (55, 60))
280292	31900418	Interestingly, Moonlight detected GATA3 as an oncogene in breast cancer with several mutated samples: frameshift insertion, deletion, and splice site.	('GATA3', 'Gene', '2625', (34, 39))	('frameshift insertion', 'Var', (102, 122))	('breast cancer', 'Disease', 'MESH:D001943', (58, 71))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('splice site', 'Var', (138, 149))	('breast cancer', 'Disease', (58, 71))	('breast cancer', 'Phenotype', 'HP:0003002', (58, 71))	('GATA3', 'Gene', (34, 39))	('deletion', 'Var', (124, 132))
280293	31900418	In particular, we observed that GATA3 showed the highest mutation rate in breast-cancer samples in splice-site and frameshift insertions.	('mutation', 'Var', (57, 65))	('breast-cancer', 'Disease', 'MESH:D001943', (74, 87))	('frameshift insertions', 'Var', (115, 136))	('GATA3', 'Gene', (32, 37))	('highest', 'Reg', (49, 56))	('breast-cancer', 'Disease', (74, 87))	('GATA3', 'Gene', '2625', (32, 37))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('splice-site', 'Var', (99, 110))
280294	31900418	Therefore, we show the mutation site (x308, D335, p408) for the GATA3 gene (Supplementary Fig.	('GATA3', 'Gene', '2625', (64, 69))	('p408', 'Var', (50, 54))	('GATA3', 'Gene', (64, 69))	('x308', 'Var', (38, 42))
280297	31900418	In a recent study, we applied Moonlight to discover several pathways that are differentially expressed between wild-type GATA3 and GATA3 with frameshift/nonsense or missense mutations in breast-cancer samples.	('breast-cancer', 'Disease', 'MESH:D001943', (187, 200))	('GATA3', 'Gene', (131, 136))	('GATA3', 'Gene', '2625', (121, 126))	('GATA3', 'Gene', '2625', (131, 136))	('frameshift/nonsense', 'Var', (142, 161))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('breast-cancer', 'Disease', (187, 200))	('GATA3', 'Gene', (121, 126))
280300	31900418	It is well known that highly expressed oncogenes in cancer patients are associated with a worse prognosis, negatively impacting survival outcomes, whereas tumor suppressors present better outcomes.	('survival', 'MPA', (128, 136))	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('negatively', 'NegReg', (107, 117))	('tumor', 'Disease', (155, 160))	('highly expressed', 'Var', (22, 38))	('patients', 'Species', '9606', (59, 67))	('oncogenes', 'Protein', (39, 48))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('impacting', 'Reg', (118, 127))
280340	31900418	To aid in effective cancer treatments which concurrently activate tumor suppressors and inactivate oncogenes, novel drug-combination therapies are required.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Disease', (66, 71))	('cancer', 'Disease', 'MESH:D009369', (20, 26))	('oncogenes', 'Gene', (99, 108))	('cancer', 'Disease', (20, 26))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('inactivate', 'Var', (88, 98))	('activate', 'PosReg', (57, 65))
280354	31900418	For instance, Moonlight extracted mutation-context differences in samples with and without mutations (somatic or germline) of BRCA1 and/or BRCA2, as well as in known cancer driver-gene mutations (e.g., missense or frameshift/nonsense).	('cancer', 'Disease', (166, 172))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('BRCA1', 'Gene', (126, 131))	('missense', 'Var', (202, 210))	('BRCA2', 'Gene', (139, 144))	('BRCA', 'Phenotype', 'HP:0003002', (139, 143))	('BRCA2', 'Gene', '675', (139, 144))	('frameshift/nonsense', 'Var', (214, 233))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('BRCA1', 'Gene', '672', (126, 131))	('BRCA', 'Phenotype', 'HP:0003002', (126, 130))
280364	31900418	Moonlight identified hypermethylated tumor suppressors and hypomethylated oncogenes.	('hypomethylated', 'Var', (59, 73))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('oncogenes', 'Gene', (74, 83))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('hypermethylated', 'Var', (21, 36))
280366	31900418	Also, Moonlight identified more mutations in intron regions than in promoter regions for tumor-suppressor genes.	('tumor-suppressor', 'Gene', (89, 105))	('mutations', 'Var', (32, 41))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor-suppressor', 'Gene', '7248', (89, 105))
280367	31900418	It is known that intron retention is a widespread mechanism of tumor-suppressor inactivation, which was consistent with our observation.	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('tumor-suppressor', 'Gene', (63, 79))	('tumor-suppressor', 'Gene', '7248', (63, 79))	('intron retention', 'Var', (17, 33))
280385	31900418	Among the state-of-the-art methods to identify cancer driver genes (CDGs), three of them have predicted the role of a CDG, such as TSG or OCG including 20/20, 20/20+, and OncodriveRole.	('TSG', 'Disease', (131, 134))	('OncodriveRole', 'Disease', (171, 184))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('20/20+', 'Var', (159, 165))	('cancer', 'Disease', (47, 53))	('20/20', 'Var', (152, 157))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))
280405	31900418	Genes were identified as significantly differentially expressed if  logFC  >= 1 and FDR < 0.01 in at least one tumor type of the 18 different tumor types, which yielded 13,182 unique genes in total.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumor', 'Disease', (142, 147))	('tumor', 'Disease', (111, 116))	('FDR < 0.01', 'Var', (84, 94))	('logFC  >= 1', 'Var', (68, 79))	('tumor', 'Disease', 'MESH:D009369', (142, 147))
280412	31900418	This function carries out two differential phenotypes analysis: if dataType is selected as "Gene Expression", it detects DEGs wrapping the function TCGAanalyze_DEA from TCGAbiolinks.	('DEGs', 'Var', (121, 125))	('DEGs', 'Chemical', 'MESH:C062694', (121, 125))	('TCG', 'Chemical', 'MESH:C068682', (169, 172))	('TCG', 'Chemical', 'MESH:C068682', (148, 151))	('TCGAanalyze_DEA', 'Gene', (148, 163))
280438	31900418	The MC3 effort provided consensus calls of variants from seven software packages: MuTect, MuSE, VarScan2, Radia, Pindel, Somatic Sniper, and Indelocator.	('variants', 'Var', (43, 51))	('MuSE', 'Gene', '399806', (90, 94))	('MuSE', 'Gene', (90, 94))
280455	31258780	Dysregulation of MiR-519d Affects Oral Squamous Cell Carcinoma Invasion and Metastasis by Targeting MMP3 MicroRNA-519d (miR-519d) has been reported to play important roles in tumor development and progression in multiple cancers, either as tumor suppressor or tumor promotor.	('tumor', 'Disease', (260, 265))	('Dysregulation', 'Var', (0, 13))	('MMP', 'Gene', (100, 103))	('tumor', 'Disease', 'MESH:D009369', (260, 265))	('MicroRNA-519d', 'Gene', (105, 118))	('play', 'Reg', (151, 155))	('Carcinoma', 'Phenotype', 'HP:0030731', (53, 62))	('Squamous Cell Carcinoma', 'Disease', 'MESH:D002294', (39, 62))	('tumor', 'Disease', (240, 245))	('miR-519d', 'Gene', '574480', (120, 128))	('miR-519d', 'Gene', (120, 128))	('tumor', 'Disease', 'MESH:D009369', (240, 245))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (39, 62))	('tumor', 'Phenotype', 'HP:0002664', (260, 265))	('multiple cancers', 'Disease', 'MESH:D009369', (212, 228))	('tumor', 'Disease', (175, 180))	('MiR-519d', 'Gene', (17, 25))	('cancers', 'Phenotype', 'HP:0002664', (221, 228))	('MMP', 'Gene', '4313;4314;17392', (100, 103))	('MiR-519d', 'Gene', '574480', (17, 25))	('Squamous Cell Carcinoma', 'Disease', (39, 62))	('Invasion', 'CPA', (63, 71))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('Affects', 'Reg', (26, 33))	('tumor', 'Phenotype', 'HP:0002664', (240, 245))	('Metastasis', 'Disease', 'MESH:D009362', (76, 86))	('Metastasis', 'Disease', (76, 86))	('multiple cancers', 'Disease', (212, 228))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('MicroRNA-519d', 'Gene', '574480', (105, 118))
280518	31258780	To further illustrate whether MMP3 is the direct target of miR-519d, 293T, HN4 and HN30 cells growing in 6-well plates were co-transfected with the 1 mug MMP3 3' UTR wild-type or mutant plasmid, 100 nM miR-519d mimics or miR-519d inhibitor and 100 ng Renilla luciferase vector (pRL-CMV; Genomeditech, China).	('mutant', 'Var', (179, 185))	('miR-519d', 'Gene', (221, 229))	('293T', 'CellLine', 'CVCL:0063', (69, 73))	('miR-519d', 'Gene', '574480', (202, 210))	('miR-519d', 'Gene', '574480', (59, 67))	('HN4', 'Gene', '100463285', (75, 78))	('miR-519d', 'Gene', (202, 210))	('miR-519d', 'Gene', (59, 67))	('HN4', 'Gene', (75, 78))	('miR-519d', 'Gene', '574480', (221, 229))
280540	31258780	More importantly, a previous study has demonstrated that the aberrant methylation of the DNA region located upstream of C19MC contributes greatly to the dysregulation of miR-519d in hepatocellular carcinoma.	('aberrant', 'Var', (61, 69))	('dysregulation', 'MPA', (153, 166))	('hepatocellular carcinoma', 'Disease', (182, 206))	('miR-519d', 'Gene', (170, 178))	('C19MC', 'Gene', (120, 125))	('methylation', 'MPA', (70, 81))	('carcinoma', 'Phenotype', 'HP:0030731', (197, 206))	('C19MC', 'Chemical', '-', (120, 125))	('miR-519d', 'Gene', '574480', (170, 178))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (182, 206))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (182, 206))
280543	31258780	Moreover, in 19 of 24 (79.2%) cases the hypermethylation was associated with an downregulation of miR-519d in OSCC tissue.	('hypermethylation', 'Var', (40, 56))	('miR-519d', 'Gene', '574480', (98, 106))	('downregulation', 'NegReg', (80, 94))	('miR-519d', 'Gene', (98, 106))
280551	31258780	According to the proliferation curves by Figure 2B, 2D, the growth rates of HN4 and HN30 cells were not obviously changed after the overexpression or silencing of miR-519d.	('miR-519d', 'Gene', (163, 171))	('overexpression', 'PosReg', (132, 146))	('HN4', 'Gene', '100463285', (76, 79))	('silencing', 'Var', (150, 159))	('HN4', 'Gene', (76, 79))	('miR-519d', 'Gene', '574480', (163, 171))
280563	31258780	On the contrary, silencing of miR-519d in OSCC cells led to approximately two-fold increase of MMP3 mRNA levels (Figure 3C).	('increase', 'PosReg', (83, 91))	('miR-519d', 'Gene', '574480', (30, 38))	('miR-519d', 'Gene', (30, 38))	('silencing', 'Var', (17, 26))	('MMP3 mRNA levels', 'MPA', (95, 111))
280566	31258780	As illustrated by Figure 3F, overexpression of miR-519d in 293T cells expressing the wild type MMP3 3' UTR reporters resulted in approximately half reduction in luciferase activities, whereas mutations in the miR-519d-binding seed region of the MMP3 3' UTR abrogated the repressive effect of miR-519d.	('reduction', 'NegReg', (148, 157))	('abrogated', 'NegReg', (257, 266))	('293T', 'CellLine', 'CVCL:0063', (59, 63))	('activities', 'MPA', (172, 182))	('miR-519d', 'Gene', (209, 217))	('miR-519d', 'Gene', '574480', (47, 55))	('miR-519d', 'Gene', '574480', (209, 217))	('miR-519d', 'Gene', (47, 55))	('repressive', 'MPA', (271, 281))	('miR-519d', 'Gene', '574480', (292, 300))	('luciferase', 'Enzyme', (161, 171))	('mutations', 'Var', (192, 201))	('miR-519d', 'Gene', (292, 300))
280583	31258780	Importantly, the Kaplan-Meier survival curves show that patients with high expression levels of MMP3 had poorer overall survival than patients with low MMP3 expression (Figure 6D).	('patients', 'Species', '9606', (56, 64))	('patients', 'Species', '9606', (134, 142))	('MMP3', 'Gene', (96, 100))	('high expression levels', 'Var', (70, 92))	('overall survival', 'MPA', (112, 128))	('poorer', 'NegReg', (105, 111))
280608	31258780	Previous studies concluded that the possible causes of miRNA dysregulation include DNA copy number aberrations, mutations, epigenetic aberrations, dysregulation of transcription factors targeting miRNAs and alterations in the miRNA biogenesis pathway.	('dysregulation', 'Var', (147, 160))	('alterations', 'Reg', (207, 218))	('DNA', 'Gene', (83, 86))	('causes', 'Reg', (45, 51))	('miR', 'Gene', (196, 199))	('mutations', 'Var', (112, 121))	('epigenetic aberrations', 'Var', (123, 145))	('miR', 'Gene', (226, 229))	('miR', 'Gene', (55, 58))	('miR', 'Gene', '22877', (226, 229))	('miR', 'Gene', '22877', (196, 199))	('miR', 'Gene', '22877', (55, 58))
280612	31258780	In addition, a great number of studies have identified that aberrant DNA methylation of miRNA genes could serve as an essential mechanism of miRNA dysregulation in cancers.	('miR', 'Gene', (88, 91))	('miR', 'Gene', '22877', (141, 144))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('cancers', 'Phenotype', 'HP:0002664', (164, 171))	('miR', 'Gene', '22877', (88, 91))	('cancers', 'Disease', (164, 171))	('miR', 'Gene', (141, 144))	('cancers', 'Disease', 'MESH:D009369', (164, 171))	('DNA', 'MPA', (69, 72))	('aberrant', 'Var', (60, 68))
280613	31258780	Epigenetic gene silencing due to promoter hypermethylation is one of the most common mechanisms by which tumor suppressor genes are inactivated during tumorigenesis, including miRNAs as well.	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('miR', 'Gene', '22877', (176, 179))	('promoter hypermethylation', 'Var', (33, 58))	('tumor', 'Disease', (151, 156))	('Epigenetic gene', 'Var', (0, 15))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('tumor', 'Disease', 'MESH:D009369', (151, 156))	('inactivated', 'NegReg', (132, 143))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumor', 'Disease', (105, 110))	('miR', 'Gene', (176, 179))
280615	31258780	Fortunately, we found that hypermethylation of the DNA region located upstream of C19MC was associated with the downregulation of miR-519d in OSCC.	('OSCC', 'Disease', (142, 146))	('hypermethylation', 'Var', (27, 43))	('downregulation', 'NegReg', (112, 126))	('miR-519d', 'Gene', '574480', (130, 138))	('miR-519d', 'Gene', (130, 138))	('C19MC', 'Chemical', '-', (82, 87))
280620	31258780	Meanwhile, previous studies described that dysregulation of MMP3 could be an important factor for mammary tumor cell progression to an invasive phenotype.	('MMP3', 'Gene', (60, 64))	('dysregulation', 'Var', (43, 56))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Disease', (106, 111))
280622	31258780	Furthermore, it was reported that MMP3 was closely associated with EMT characteristics, the acquisition of which facilitated tumor invasion and metastasis.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('acquisition', 'Var', (92, 103))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumor', 'Disease', (125, 130))	('facilitated', 'PosReg', (113, 124))	('metastasis', 'CPA', (144, 154))
280628	31258780	Another study stated that MMP3-induced EMT conversion is accompanied by E-cadherin cleavage and a redistribution of B-catenin, where it can form a transcriptional complex and induces the transcription of some genes involved in EMT process.	('E-cadherin', 'Protein', (72, 82))	('induces', 'PosReg', (175, 182))	('B-catenin', 'Gene', '1499', (116, 125))	('B-catenin', 'Gene', (116, 125))	('EMT conversion', 'CPA', (39, 53))	('redistribution', 'MPA', (98, 112))	('transcription', 'MPA', (187, 200))	('MMP3-induced', 'Var', (26, 38))
280637	31043585	So we compared FSCN1 expression between TSCC and normal cell lines and knocked down FSCN1 in TSCC cells to observe its influence on the viability and trans-migration in vitro and tumor growth in vivo.	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('knocked', 'Var', (71, 78))	('TSCC', 'Phenotype', 'HP:0030413', (93, 97))	('influence', 'Reg', (119, 128))	('TSCC', 'Phenotype', 'HP:0030413', (40, 44))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('trans-migration', 'CPA', (150, 165))	('FSCN1', 'Gene', (84, 89))	('FSCN1', 'Gene', (15, 20))	('tumor', 'Disease', (179, 184))
280646	31043585	Aberrant expression of Fascin actin-bundling protein 1 (FSCN1) encodes a member of the Fascin family of actin-binding proteins.	('Fascin', 'Gene', (23, 29))	('Aberrant', 'Var', (0, 8))	('FSCN1', 'Gene', (56, 61))	('Fascin', 'Gene', (87, 93))	('Fascin', 'Gene', '6624', (87, 93))	('Fascin', 'Gene', '6624', (23, 29))	('Fascin actin-bundling protein 1', 'Gene', '6624', (23, 54))	('Fascin actin-bundling protein 1', 'Gene', (23, 54))
280693	31043585	On the 32nd day, we observed that the tumor proliferation of nude mice injected with FSCN1-knockdown cells was slower than the control cells both in CAL-27 and SCC-25 cell lines (Fig.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('FSCN1-knockdown', 'Var', (85, 100))	('FSCN1-knockdown', 'Gene', (85, 100))	('nude mice', 'Species', '10090', (61, 70))	('slower', 'NegReg', (111, 117))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('SCC-25', 'CellLine', 'CVCL:1682', (160, 166))
280704	31043585	The potential prognoses of FSCN1 for DFS and OS in TSCC patients was evaluated by comparing the survival time and disease-free survival time of patients with high FSCN1 expression to patients with low FSCN1 expression.	('patients', 'Species', '9606', (56, 64))	('TSCC', 'Phenotype', 'HP:0030413', (51, 55))	('high', 'Var', (158, 162))	('patients', 'Species', '9606', (144, 152))	('FSCN1', 'Gene', (163, 168))	('patients', 'Species', '9606', (183, 191))
280705	31043585	The data identified from TCGA database demonstrated that high expression of FSCN1 suggested poor OS (p = 0.006) in 496 TSCC patients (Fig.	('high', 'Var', (57, 61))	('expression', 'MPA', (62, 72))	('FSCN1', 'Gene', (76, 81))	('TSCC', 'Phenotype', 'HP:0030413', (119, 123))	('TSCC', 'Disease', (119, 123))	('patients', 'Species', '9606', (124, 132))
280716	31043585	In order to observe more obvious changes of FSCN1 expression after knocking down, we selected the CAL-27 and SCC-25 cell lines for the following experiment as for their higher expression of FSCN1.	('FSCN1', 'Gene', (190, 195))	('knocking', 'Var', (67, 75))	('FSCN1', 'Gene', (44, 49))	('SCC-25', 'CellLine', 'CVCL:1682', (109, 115))
280721	31043585	showed that the knockdown of Fascin did not impair the viability or proliferation of oral cancer cells.	('oral cancer', 'Disease', (85, 96))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('knockdown', 'Var', (16, 25))	('Fascin', 'Gene', (29, 35))	('Fascin', 'Gene', '6624', (29, 35))	('oral cancer', 'Disease', 'MESH:D009062', (85, 96))
280731	31043585	Furthermore, we discovered the relationship between high levels of FSCN1 and clinical pathological characteristics of TSCC patients.	('patients', 'Species', '9606', (123, 131))	('TSCC', 'Phenotype', 'HP:0030413', (118, 122))	('TSCC', 'Disease', (118, 122))	('high', 'Var', (52, 56))	('FSCN1', 'Gene', (67, 72))
280732	31043585	In addition, the TSCC patients with high FSCN1 expression were more likely to relapse.	('patients', 'Species', '9606', (22, 30))	('FSCN1', 'Gene', (41, 46))	('expression', 'MPA', (47, 57))	('relapse', 'CPA', (78, 85))	('TSCC', 'Phenotype', 'HP:0030413', (17, 21))	('TSCC', 'Disease', (17, 21))	('high', 'Var', (36, 40))
280735	31043585	The above results suggested that tumors with high FSCN1 levels might be more aggressive and may forecast poor prognosis in TSCC patients.	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('high', 'Var', (45, 49))	('tumors', 'Disease', 'MESH:D009369', (33, 39))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('aggressive', 'CPA', (77, 87))	('more', 'PosReg', (72, 76))	('patients', 'Species', '9606', (128, 136))	('tumors', 'Disease', (33, 39))	('TSCC', 'Phenotype', 'HP:0030413', (123, 127))	('TSCC', 'Disease', (123, 127))
280736	31043585	Our Kaplan-Meier survival analysis confirmed this hypothesis that TSCC patients with high FSCN1 expression had a higher risk of recurrence and shorter DFS.	('shorter', 'NegReg', (143, 150))	('TSCC', 'Disease', (66, 70))	('TSCC', 'Phenotype', 'HP:0030413', (66, 70))	('patients', 'Species', '9606', (71, 79))	('expression', 'MPA', (96, 106))	('high', 'Var', (85, 89))	('FSCN1', 'Gene', (90, 95))
280743	31043585	Some recent studies have found that some microRNAs (miRNAs/miRs) could inhibit proliferation, migration or invasion via targeting FSCN1 in different cancers, such as miR-200b and microRNA-133b in non-small cell lung cancer, microRNA-663 in colorectal cancer, miR-539 in hepatocellular carcinoma and miR-145-5p in laryngeal squamous cell carcinoma.	('lung cancer', 'Phenotype', 'HP:0100526', (211, 222))	('proliferation', 'CPA', (79, 92))	('inhibit', 'NegReg', (71, 78))	('microRNA-133b', 'Gene', (179, 192))	('colorectal cancer', 'Disease', (240, 257))	('squamous cell carcinoma', 'Disease', (323, 346))	('hepatocellular carcinoma', 'Disease', (270, 294))	('invasion', 'CPA', (107, 115))	('miR-539', 'Gene', (259, 266))	('miR-200b', 'Gene', (166, 174))	('miR-145', 'Gene', '406937', (299, 306))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (200, 222))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (196, 222))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('targeting', 'Var', (120, 129))	('migration', 'CPA', (94, 103))	('miR-539', 'Gene', '664612', (259, 266))	('microRNA-133b', 'Gene', '442890', (179, 192))	('cancers', 'Phenotype', 'HP:0002664', (149, 156))	('miR-145', 'Gene', (299, 306))	('FSCN1', 'Gene', (130, 135))	('cancers', 'Disease', (149, 156))	('colorectal cancer', 'Phenotype', 'HP:0003003', (240, 257))	('carcinoma', 'Phenotype', 'HP:0030731', (285, 294))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (323, 346))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (196, 222))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (270, 294))	('miR-200b', 'Gene', '406984', (166, 174))	('microRNA-663', 'Var', (224, 236))	('carcinoma', 'Phenotype', 'HP:0030731', (337, 346))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (323, 346))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (270, 294))	('colorectal cancer', 'Disease', 'MESH:D015179', (240, 257))	('non-small cell lung cancer', 'Disease', (196, 222))	('cancers', 'Disease', 'MESH:D009369', (149, 156))
280744	31043585	reported the development of Fascin-specific small molecules (NP-G2-011 and NP-G2-044) that inhibit the interaction between Fascin and actin.	('Fascin', 'Gene', '6624', (28, 34))	('Fascin', 'Gene', (123, 129))	('inhibit', 'NegReg', (91, 98))	('Fascin', 'Gene', (28, 34))	('interaction', 'Interaction', (103, 114))	('NP-G2-044', 'Var', (75, 84))	('actin', 'Protein', (134, 139))	('Fascin', 'Gene', '6624', (123, 129))
280748	31043585	explored the Correlation between Fascin and miR-138 and miR-145 expression in oral squamous cell carcinoma and finally found that forced expression of miR-138 in oral squamous cell carcinoma cells significantly decreased the expression of Fascin.	('oral squamous cell carcinoma', 'Disease', (162, 190))	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('miR-138', 'Chemical', '-', (44, 51))	('miR-145', 'Gene', '406937', (56, 63))	('miR-138', 'Var', (151, 158))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (167, 190))	('Fascin', 'Gene', (33, 39))	('Fascin', 'Gene', '6624', (239, 245))	('expression', 'MPA', (225, 235))	('miR-145', 'Gene', (56, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (181, 190))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (78, 106))	('Fascin', 'Gene', (239, 245))	('oral squamous cell carcinoma', 'Disease', (78, 106))	('miR-138', 'Chemical', '-', (151, 158))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (83, 106))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (162, 190))	('Fascin', 'Gene', '6624', (33, 39))	('decreased', 'NegReg', (211, 220))
280764	31242703	Kenting Water Mint Suppresses Two-Stage Skin Carcinogenesis Accelerated by BRAF Inhibitor Vemurafenib The v-raf murine sarcoma viral homolog B1 (BRAF) inhibitor drug vemurafenib (PLX4032) is used to treat melanoma; however, epidemiological evidence reveals that it could cause cutaneous keratoacanthomas and squamous cell carcinoma in cancer patients with the most prevalent HRASQ61L mutation.	('HRASQ61L', 'Gene', (375, 383))	('BRAF', 'Gene', (145, 149))	('PLX4032', 'Chemical', 'MESH:D000077484', (179, 186))	('cancer', 'Disease', (335, 341))	('raf', 'Gene', (170, 173))	('cause', 'Reg', (271, 276))	('sarcoma', 'Phenotype', 'HP:0100242', (119, 126))	('Vemurafenib', 'Chemical', 'MESH:D000077484', (90, 101))	('cancer', 'Phenotype', 'HP:0002664', (335, 341))	('raf', 'Gene', '387609', (170, 173))	('cutaneous keratoacanthomas and squamous cell carcinoma', 'Disease', 'MESH:D002294', (277, 331))	('melanoma', 'Phenotype', 'HP:0002861', (205, 213))	('mutation', 'Var', (384, 392))	('melanoma', 'Disease', (205, 213))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (308, 331))	('BRAF', 'Gene', '109880', (75, 79))	('Water Mint', 'Species', '190902', (8, 18))	('raf', 'Gene', (94, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (322, 331))	('cancer', 'Disease', 'MESH:D009369', (335, 341))	('vemurafenib', 'Chemical', 'MESH:D000077484', (166, 177))	('raf', 'Gene', '387609', (94, 97))	('BRAF', 'Gene', '109880', (145, 149))	('sarcoma viral', 'Disease', 'MESH:D001102', (119, 132))	('melanoma', 'Disease', 'MESH:D008545', (205, 213))	('sarcoma viral', 'Disease', (119, 132))	('murine', 'Species', '10090', (112, 118))	('keratoacanthomas', 'Phenotype', 'HP:0031525', (287, 303))	('patients', 'Species', '9606', (342, 350))	('raf', 'Gene', (108, 111))	('keratoacanthoma', 'Phenotype', 'HP:0031525', (287, 302))	('BRAF', 'Gene', (75, 79))	('raf', 'Gene', '387609', (108, 111))
280767	31242703	Kenting Water Mint essential oil (KWM-EO) against PDV cells, mouse keratinocytes bearing HRASQ61L mutation, and its effect on inhibiting papilloma formation in a two-stage skin carcinogenesis mouse model with or without PLX4032 co-treatment.	('Kenting', 'Chemical', '-', (0, 7))	('essential oil', 'Chemical', 'MESH:D009822', (19, 32))	('mouse', 'Species', '10090', (192, 197))	('inhibiting', 'NegReg', (126, 136))	('mutation', 'Var', (98, 106))	('Water Mint', 'Species', '190902', (8, 18))	('papilloma', 'Phenotype', 'HP:0012740', (137, 146))	('KWM-EO', 'Chemical', '-', (34, 40))	('mouse', 'Species', '10090', (61, 66))	('PLX4032', 'Chemical', 'MESH:D000077484', (220, 227))	('papilloma', 'Disease', (137, 146))	('HRASQ61L', 'Gene', (89, 97))	('papilloma', 'Disease', 'MESH:D010212', (137, 146))
280768	31242703	Our results revealed that KWM-EO effectively attenuated cell viability, colony formation, and the invasive and migratory abilities of PDV cells.	('colony formation', 'CPA', (72, 88))	('KWM-EO', 'Chemical', '-', (26, 32))	('KWM-EO', 'Var', (26, 32))	('attenuated', 'NegReg', (45, 55))	('cell viability', 'CPA', (56, 70))
280771	31242703	Immunohistochemistry analyses showed overexpression of keratin14 and COX-2 in DT and DTP skin were profoundly suppressed by KWM-EO treatment.	('overexpression', 'PosReg', (37, 51))	('DT', 'Chemical', 'MESH:D013936', (85, 87))	('keratin14', 'Gene', (55, 64))	('DT', 'Chemical', 'MESH:D013936', (78, 80))	('KWM-EO treatment', 'Var', (124, 140))	('keratin14', 'Gene', '16664', (55, 64))	('COX-2', 'Gene', '17709', (69, 74))	('suppressed', 'NegReg', (110, 120))	('COX-2', 'Gene', (69, 74))	('KWM-EO', 'Chemical', '-', (124, 130))
280772	31242703	This study demonstrates that KWM-EO has chemopreventive effects against PLX4032-induced cutaneous side-effects in a DMBA/TPA-induced two-stage carcinogenesis model and will be worth further exploration for possible application in melanoma patients.	('KWM-EO', 'Chemical', '-', (29, 35))	('KWM-EO', 'Var', (29, 35))	('patients', 'Species', '9606', (239, 247))	('PLX4032-induced', 'Gene', (72, 87))	('PLX4032', 'Chemical', 'MESH:D000077484', (72, 79))	('DMBA/TPA', 'Chemical', '-', (116, 124))	('melanoma', 'Phenotype', 'HP:0002861', (230, 238))	('melanoma', 'Disease', (230, 238))	('melanoma', 'Disease', 'MESH:D008545', (230, 238))	('chemopreventive effects', 'CPA', (40, 63))
280774	31242703	Functional studies have demonstrated that these serious side-effects caused during the treatment of PLX4032 are through paradoxical activation of the MAPK signaling pathway of wild-type BRAF cell lines bearing either oncogenic RAS mutations or upstream receptor tyrosine kinase activity.	('PLX4032', 'Gene', (100, 107))	('activation', 'PosReg', (132, 142))	('mutations', 'Var', (231, 240))	('PLX4032', 'Chemical', 'MESH:D000077484', (100, 107))	('MAPK signaling pathway', 'Pathway', (150, 172))
280777	31242703	Topical exposure of carcinogens, 7,12-dimethyl[a]anthracene (DMBA), as a tumor initiator results in HRASQ61L mutation in mouse skin.	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('DMBA', 'Chemical', 'MESH:D015127', (61, 65))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('mouse', 'Species', '10090', (121, 126))	('results in', 'Reg', (89, 99))	('tumor', 'Disease', (73, 78))	('HRASQ61L', 'Gene', (100, 108))	('7,12-dimethyl[a]anthracene', 'Chemical', '-', (33, 59))	('mutation', 'Var', (109, 117))
280782	31242703	The extrinsic pathways are related to a continued inflammatory condition, while the intrinsic pathways are stimulated by genetic transformations, which result in the activation of oncogenes or inactivation of tumor suppressor genes.	('activation', 'PosReg', (166, 176))	('tumor', 'Disease', (209, 214))	('oncogenes', 'Protein', (180, 189))	('inactivation', 'Var', (193, 205))	('tumor', 'Disease', 'MESH:D009369', (209, 214))	('extrinsic pathways', 'Pathway', (4, 22))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))
280795	31242703	The PDV cell line is a mouse keratinocyte bearing HRASQ61L mutation, which is the most relevant mutation in BRAF inhibitor-induced cutaneous squamous cell carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (155, 164))	('cutaneous squamous cell carcinoma', 'Disease', (131, 164))	('HRASQ61L', 'Var', (50, 58))	('mouse', 'Species', '10090', (23, 28))	('cutaneous squamous cell carcinoma', 'Disease', 'MESH:D002294', (131, 164))	('cutaneous squamous cell carcinoma', 'Phenotype', 'HP:0006739', (131, 164))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (141, 164))
280809	31242703	According to cell-cycle analysis, an elevated percentage of the sub-G1 population was also observed with KWM-EO and PLX4032+KWM-EO treatment.	('sub-G1 population', 'CPA', (64, 81))	('PLX4032', 'Chemical', 'MESH:D000077484', (116, 123))	('KWM-EO', 'Chemical', '-', (105, 111))	('KWM-EO', 'Var', (105, 111))	('PLX4032+KWM-EO', 'Var', (116, 130))	('KWM-EO', 'Chemical', '-', (124, 130))
280814	31242703	Phosphorylation of Thr161 in cdc2 is required for activation of MPF and brings on the onset of mitosis.	('cdc2', 'Gene', (29, 33))	('MPF', 'Gene', (64, 67))	('Phosphorylation', 'Var', (0, 15))	('mitosis', 'Disease', (95, 102))	('mitosis', 'Disease', 'None', (95, 102))	('brings on', 'Reg', (72, 81))	('cdc2', 'Gene', '12534', (29, 33))	('Thr161', 'Chemical', '-', (19, 25))
280819	31242703	Paradoxical MAPK activation is known to be the main reason for cutaneous squamous cell carcinoma induced by BRAF inhibitor in RAS mutant cells.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (73, 96))	('cutaneous squamous cell carcinoma', 'Disease', 'MESH:D002294', (63, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))	('cutaneous squamous cell carcinoma', 'Phenotype', 'HP:0006739', (63, 96))	('BRAF inhibitor', 'Gene', (108, 122))	('activation', 'PosReg', (17, 27))	('mutant', 'Var', (130, 136))	('MAPK', 'Gene', (12, 16))	('cutaneous squamous cell carcinoma', 'Disease', (63, 96))
280829	31242703	The papilloma number was significantly decreased by KWM-EO treatment in DTP mice.	('papilloma', 'Disease', 'MESH:D010212', (4, 13))	('KWM-EO', 'Chemical', '-', (52, 58))	('DT', 'Chemical', 'MESH:D013936', (72, 74))	('mice', 'Species', '10090', (76, 80))	('papilloma', 'Phenotype', 'HP:0012740', (4, 13))	('decreased', 'NegReg', (39, 48))	('KWM-EO', 'Var', (52, 58))	('papilloma', 'Disease', (4, 13))
280832	31242703	The mouse organ index was unchanged for the heart, lung, and kidney within the groups; however, the index of the liver organ was lower in the KWM-EO-treated mice, and the index of the spleen organ was increased in PLX4032-treated mice.	('mouse', 'Species', '10090', (4, 9))	('KWM-EO-treated', 'Var', (142, 156))	('KWM-EO', 'Chemical', '-', (142, 148))	('PLX4032', 'Chemical', 'MESH:D000077484', (214, 221))	('mice', 'Species', '10090', (157, 161))	('mice', 'Species', '10090', (230, 234))	('index', 'MPA', (100, 105))	('lower', 'NegReg', (129, 134))	('liver organ', 'MPA', (113, 124))
280836	31242703	With DMBA and TPA treatment in the presence or absence of PLX4032, the thickness of the epidermis was elevated compared to the sham group (Figure 4A), while the epidermal hyperplasia was attenuated by repeated treatment with KWM-EO for 12 weeks.	('DMBA', 'Chemical', 'MESH:D015127', (5, 9))	('hyperplasia', 'Disease', 'MESH:D006965', (171, 182))	('KWM-EO', 'Chemical', '-', (225, 231))	('PLX4032', 'Chemical', 'MESH:D000077484', (58, 65))	('elevated', 'PosReg', (102, 110))	('TPA', 'Chemical', 'MESH:D013755', (14, 17))	('absence', 'Var', (47, 54))	('PLX4032', 'Var', (58, 65))	('thickness of the epidermis', 'CPA', (71, 97))	('hyperplasia', 'Disease', (171, 182))
280841	31242703	The IHC staining result revealed considerable p-ERK protein between the dermis and papilloma, especially in the group with PLX4032 stimulation; and this activation was significantly diminished by KWM-EO treatment (Figure 4C).	('p-ERK', 'Gene', (46, 51))	('papilloma', 'Disease', 'MESH:D010212', (83, 92))	('p-ERK', 'Gene', '13666', (46, 51))	('PLX4032', 'Chemical', 'MESH:D000077484', (123, 130))	('diminished', 'NegReg', (182, 192))	('PLX4032', 'Var', (123, 130))	('papilloma', 'Phenotype', 'HP:0012740', (83, 92))	('KWM-EO', 'Chemical', '-', (196, 202))	('stimulation', 'PosReg', (131, 142))	('papilloma', 'Disease', (83, 92))
280845	31242703	Upon treatment with KWM-EO, the neutrophil and macrophage infiltration and upregulation of COX-2 were alleviated (Figure 5A,B).	('COX-2', 'Gene', '17709', (91, 96))	('KWM-EO', 'Chemical', '-', (20, 26))	('KWM-EO', 'Var', (20, 26))	('upregulation', 'PosReg', (75, 87))	('COX-2', 'Gene', (91, 96))	('alleviated', 'NegReg', (102, 112))
280857	31242703	According to the histopathological analysis of skin tissue sections, KWM-EO not only attenuated the abnormal proliferation and hyperplasia of the epidermis but also decreased the inflammatory neutrophil and macrophage infiltration and COX-2 overexpression in neutrophils.	('hyperplasia', 'Disease', 'MESH:D006965', (127, 138))	('decreased', 'NegReg', (165, 174))	('KWM-EO', 'Var', (69, 75))	('KWM-EO', 'Chemical', '-', (69, 75))	('COX-2', 'Gene', (235, 240))	('hyperplasia', 'Disease', (127, 138))	('overexpression', 'PosReg', (241, 255))	('attenuated', 'NegReg', (85, 95))	('COX-2', 'Gene', '17709', (235, 240))
280865	31242703	PDV keratinocytes harboring HRAS mutation are commonly found in DT-induced mouse SCC.	('SCC', 'Gene', '6317', (81, 84))	('mutation', 'Var', (33, 41))	('DT', 'Chemical', 'MESH:D013936', (64, 66))	('HRAS', 'Gene', (28, 32))	('mouse', 'Species', '10090', (75, 80))	('SCC', 'Gene', (81, 84))
280868	31242703	The PDV cell invasive and migratory abilities were promoted by PLX4032, which were suppressed by KWM-EO treatment.	('KWM-EO', 'Chemical', '-', (97, 103))	('PLX4032', 'Var', (63, 70))	('PLX4032', 'Chemical', 'MESH:D000077484', (63, 70))	('promoted', 'PosReg', (51, 59))
280869	31242703	KWM-EO also induced G2/M arrest in PDV cells through deregulating p-cdc2, p-cdc25C, and cyclin B1 proteins.	('cdc2', 'Gene', (68, 72))	('cyclin B1', 'Gene', '268697', (88, 97))	('arrest', 'Disease', (25, 31))	('cdc25C', 'Gene', (76, 82))	('cdc25C', 'Gene', '12532', (76, 82))	('cyclin B1', 'Gene', (88, 97))	('cdc2', 'Gene', '12534', (76, 80))	('deregulating', 'NegReg', (53, 65))	('cdc2', 'Gene', (76, 80))	('KWM-EO', 'Chemical', '-', (0, 6))	('KWM-EO', 'Var', (0, 6))	('cdc2', 'Gene', '12534', (68, 72))	('arrest', 'Disease', 'MESH:D006323', (25, 31))
280870	31242703	The cell apoptosis induced by KWM-EO was through activation of caspase 3 and PARP-1 after cells were treated for 6 h. These in vitro data support in part the inhibitory activity of KWM-EO in the DT and DTP mouse skin on keratinocyte proliferation and papilloma formation.	('papilloma', 'Disease', (251, 260))	('caspase 3', 'Gene', (63, 72))	('keratinocyte proliferation', 'CPA', (220, 246))	('DT', 'Chemical', 'MESH:D013936', (195, 197))	('DT', 'Chemical', 'MESH:D013936', (202, 204))	('mouse', 'Species', '10090', (206, 211))	('papilloma', 'Disease', 'MESH:D010212', (251, 260))	('KWM-EO', 'Chemical', '-', (30, 36))	('caspase 3', 'Gene', '12367', (63, 72))	('PARP-1', 'Gene', (77, 83))	('PARP-1', 'Gene', '11545', (77, 83))	('KWM-EO', 'Chemical', '-', (181, 187))	('KWM-EO', 'Var', (181, 187))	('papilloma', 'Phenotype', 'HP:0012740', (251, 260))
280873	31242703	Our current data show that topical application of KWM-EO attenuated the formation of cutaneous papilloma in mice induced by DMBA/TPA or by DMBA/TPA/PLX4032.	('cutaneous papilloma', 'Disease', (85, 104))	('DMBA/TPA', 'Var', (124, 132))	('DMBA/TPA', 'Chemical', '-', (139, 147))	('KWM-EO', 'Chemical', '-', (50, 56))	('cutaneous papilloma', 'Disease', 'MESH:D010212', (85, 104))	('formation', 'CPA', (72, 81))	('mice', 'Species', '10090', (108, 112))	('papilloma', 'Phenotype', 'HP:0012740', (95, 104))	('PLX4032', 'Chemical', 'MESH:D000077484', (148, 155))	('attenuated', 'NegReg', (57, 67))	('DMBA/TPA', 'Chemical', '-', (124, 132))
280874	31242703	The paradoxical MAPK activation induced by PLX4032 in vitro in PDV keratinocytes and in skin of DT and DTP mice was suppressed by KWM-EO.	('suppressed', 'NegReg', (116, 126))	('PLX4032', 'Chemical', 'MESH:D000077484', (43, 50))	('KWM-EO', 'Chemical', '-', (130, 136))	('PLX4032', 'Var', (43, 50))	('DT', 'Chemical', 'MESH:D013936', (103, 105))	('DT', 'Chemical', 'MESH:D013936', (96, 98))	('mice', 'Species', '10090', (107, 111))	('MAPK', 'Enzyme', (16, 20))	('activation', 'PosReg', (21, 31))
280922	31242703	This study is the first to prove that KWM-EO has potential for prevention of chemically induced two-stage skin carcinogenesis.	('KWM-EO', 'Chemical', '-', (38, 44))	('KWM-EO', 'Var', (38, 44))	('chemically induced two-stage skin carcinogenesis', 'Disease', (77, 125))
280923	31242703	Topical application of KWM-EO significantly attenuated the number of papillomas in DMBA-initiated and TPA-promoted mouse skin, with or without co-stimulation with PLX4032.	('TPA', 'Chemical', 'MESH:D013755', (102, 105))	('papillomas', 'Disease', (69, 79))	('mouse', 'Species', '10090', (115, 120))	('DMBA', 'Chemical', 'MESH:D015127', (83, 87))	('KWM-EO', 'Chemical', '-', (23, 29))	('KWM-EO', 'Var', (23, 29))	('papillomas', 'Phenotype', 'HP:0012740', (69, 79))	('papilloma', 'Phenotype', 'HP:0012740', (69, 78))	('PLX4032', 'Chemical', 'MESH:D000077484', (163, 170))	('attenuated', 'NegReg', (44, 54))	('papillomas', 'Disease', 'MESH:D010212', (69, 79))
280930	29896273	Aberrant DNA methylation of the p16, APC, MGMT, TIMP3 and CDH1 gene promoters in tumours and the surgical margins of patients with oral cavity cancer Oral cavity cancer is a type of head and neck squamous cell carcinoma (HNSCC) and contributes to significant morbidity and mortality each year.	('carcinoma', 'Phenotype', 'HP:0030731', (210, 219))	('MGMT', 'Gene', '4255', (42, 46))	('cancer', 'Disease', (162, 168))	('tumours', 'Disease', (81, 88))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('neck squamous cell carcinoma', 'Disease', (191, 219))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (191, 219))	('patients', 'Species', '9606', (117, 125))	('tumours', 'Phenotype', 'HP:0002664', (81, 88))	('APC', 'Gene', '324', (37, 40))	('Aberrant DNA methylation', 'Var', (0, 24))	('cancer Oral cavity', 'Phenotype', 'HP:0100649', (143, 161))	('tumours', 'Disease', 'MESH:D009369', (81, 88))	('cancer', 'Disease', (143, 149))	('TIMP3', 'Gene', (48, 53))	('p16', 'Gene', (32, 35))	('APC', 'Phenotype', 'HP:0005227', (37, 40))	('TIMP3', 'Gene', '7078', (48, 53))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (196, 219))	('tumour', 'Phenotype', 'HP:0002664', (81, 87))	('MGMT', 'Gene', (42, 46))	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('p16', 'Gene', '1029', (32, 35))	('HNSCC', 'Phenotype', 'HP:0012288', (221, 226))	('CDH1', 'Gene', '999', (58, 62))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (182, 219))	('APC', 'Gene', (37, 40))	('CDH1', 'Gene', (58, 62))	('cancer', 'Disease', 'MESH:D009369', (143, 149))
280932	29896273	For our study, we selected genes for which silencing caused by hypermethylation can promote cancer development.	('cancer', 'Disease', (92, 98))	('promote', 'PosReg', (84, 91))	('hypermethylation', 'Var', (63, 79))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('silencing', 'MPA', (43, 52))	('men', 'Species', '9606', (106, 109))
280935	29896273	Our observations confirm the presence of epigenetic changes not only in the cancer cells, but also in the surrounding mucosa and represent a basis for further analysis to unravel these complicated issues.	('epigenetic changes', 'Var', (41, 59))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))
280936	29896273	Appropriate cancer risk assessment based on epigenetic alterations in surgical margins may influence a patient's diagnosis and cure.	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('cure', 'CPA', (127, 131))	('diagnosis', 'CPA', (113, 122))	('cancer', 'Disease', (12, 18))	('influence', 'Reg', (91, 100))	('men', 'Species', '9606', (30, 33))	('epigenetic alterations', 'Var', (44, 66))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('patient', 'Species', '9606', (103, 110))
280939	29896273	As well as genetic abnormalities, epigenetic alterations have also been implicated in cancer.	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('genetic abnormalities', 'Disease', 'MESH:D030342', (11, 32))	('epigenetic alterations', 'Var', (34, 56))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('genetic abnormalities', 'Disease', (11, 32))	('cancer', 'Disease', (86, 92))	('implicated', 'Reg', (72, 82))
280940	29896273	DNA methylation is an encouraging marker for past exposure to carcinogens and future risk of cancer development.	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('men', 'Species', '9606', (107, 110))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('methylation', 'Var', (4, 15))
280942	29896273	Other publications address epigenetic changes in HNSCC cancers, but few have compared the methylation level of tumours vs surgical margins.	('HNSCC', 'Phenotype', 'HP:0012288', (49, 54))	('HNSCC cancers', 'Disease', 'MESH:D000077195', (49, 62))	('tumours', 'Disease', (111, 118))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('tumour', 'Phenotype', 'HP:0002664', (111, 117))	('epigenetic changes', 'Var', (27, 45))	('HNSCC cancers', 'Disease', (49, 62))	('cancers', 'Phenotype', 'HP:0002664', (55, 62))	('tumours', 'Phenotype', 'HP:0002664', (111, 118))	('tumours', 'Disease', 'MESH:D009369', (111, 118))
280976	29896273	Methylation of the p16, APC, MGMT, TIMP3 and CDH1 gene promoters was detected in tumours and surgical margins.	('TIMP3', 'Gene', (35, 40))	('p16', 'Gene', (19, 22))	('detected', 'Reg', (69, 77))	('tumours', 'Phenotype', 'HP:0002664', (81, 88))	('Methylation', 'Var', (0, 11))	('CDH1', 'Gene', '999', (45, 49))	('APC', 'Gene', (24, 27))	('MGMT', 'Gene', '4255', (29, 33))	('APC', 'Phenotype', 'HP:0005227', (24, 27))	('tumours', 'Disease', 'MESH:D009369', (81, 88))	('MGMT', 'Gene', (29, 33))	('tumours', 'Disease', (81, 88))	('tumour', 'Phenotype', 'HP:0002664', (81, 87))	('p16', 'Gene', '1029', (19, 22))	('APC', 'Gene', '324', (24, 27))	('TIMP3', 'Gene', '7078', (35, 40))	('CDH1', 'Gene', (45, 49))
280982	29896273	Patients with a family history of cancer showed more frequently methylated MGMT genes in tumour samples (OR=3.04; 95% CI: 1.08-8.55; p<0.05).	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('tumour', 'Phenotype', 'HP:0002664', (89, 95))	('methylated', 'Var', (64, 74))	('tumour', 'Disease', 'MESH:D009369', (89, 95))	('tumour', 'Disease', (89, 95))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('Patients', 'Species', '9606', (0, 8))	('cancer', 'Disease', (34, 40))	('MGMT', 'Gene', '4255', (75, 79))	('MGMT', 'Gene', (75, 79))
280983	29896273	We noted that advanced tumour stage was associated with a higher frequency of methylation of this gene in matched surgical margin samples (OR=1.78; 95% CI: 0.98-3.24; p<0.1).	('tumour', 'Disease', (23, 29))	('tumour', 'Phenotype', 'HP:0002664', (23, 29))	('tumour', 'Disease', 'MESH:D009369', (23, 29))	('methylation', 'Var', (78, 89))
280988	29896273	Moreover, aberrant promoter hypermethylation of all five genes (CpG Island Methylator Phenotype, CIMP-positive) was found in tumour samples in four cases (5.3%).	('promoter hypermethylation', 'MPA', (19, 44))	('CIMP', 'Chemical', '-', (97, 101))	('tumour', 'Phenotype', 'HP:0002664', (125, 131))	('aberrant', 'Var', (10, 18))	('found', 'Reg', (116, 121))	('tumour', 'Disease', 'MESH:D009369', (125, 131))	('tumour', 'Disease', (125, 131))
280990	29896273	Hypermethylation of p16 has been observed in many tumour types e.g., colon, breast, brain, kidney, pancreas, liver and also in HNSCC in several studies, not only in tumour tissues but also in adjacent healthy mucosa.	('tumour', 'Disease', 'MESH:D009369', (50, 56))	('brain', 'Disease', (84, 89))	('pancreas', 'Disease', 'MESH:D010190', (99, 107))	('tumour', 'Disease', (50, 56))	('observed', 'Reg', (33, 41))	('pancreas', 'Disease', (99, 107))	('Hypermethylation', 'Var', (0, 16))	('breast', 'Disease', (76, 82))	('p16', 'Gene', (20, 23))	('tumour', 'Phenotype', 'HP:0002664', (165, 171))	('colon', 'Disease', (69, 74))	('tumour', 'Disease', 'MESH:D009369', (165, 171))	('tumour', 'Disease', (165, 171))	('tumour', 'Phenotype', 'HP:0002664', (50, 56))	('p16', 'Gene', '1029', (20, 23))	('HNSCC', 'Phenotype', 'HP:0012288', (127, 132))
280992	29896273	Moreover, 42.6% of patients showed hyper-methylation of this gene both in the tumour and matched surgical margin.	('hyper-methylation', 'Var', (35, 52))	('patients', 'Species', '9606', (19, 27))	('tumour', 'Disease', 'MESH:D009369', (78, 84))	('tumour', 'Disease', (78, 84))	('tumour', 'Phenotype', 'HP:0002664', (78, 84))
280993	29896273	According to our collected literature, the frequencies of hypermethylation in HNSCC tumours vary from 86.8% to 82%, 49%, 36%, and 27% to 20%.	('hypermethylation', 'Var', (58, 74))	('HNSCC tumours', 'Disease', 'MESH:D000077195', (78, 91))	('HNSCC tumours', 'Disease', (78, 91))	('tumour', 'Phenotype', 'HP:0002664', (84, 90))	('HNSCC', 'Phenotype', 'HP:0012288', (78, 83))	('tumours', 'Phenotype', 'HP:0002664', (84, 91))
280997	29896273	p16 hypermethylation showed no association with clinical and demographic features in our study population, as confirmed in other studies.	('p16', 'Gene', '1029', (0, 3))	('p16', 'Gene', (0, 3))	('hypermethylation', 'Var', (4, 20))
280999	29896273	Moreover, based on other findings, hypermethylation of p16 was associated with younger age, nodal involvement, distant metastasis, increased recurrence rate and shortened disease-free survival, suggesting it as a candidate prognostic and predictive biomarker in oropharyngeal squamous cell carcinoma.	('hypermethylation', 'Var', (35, 51))	('disease-free survival', 'CPA', (171, 192))	('shortened', 'NegReg', (161, 170))	('increased', 'PosReg', (131, 140))	('oropharyngeal squamous cell carcinoma', 'Disease', (262, 299))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (276, 299))	('p16', 'Gene', (55, 58))	('nodal', 'Gene', (92, 97))	('men', 'Species', '9606', (105, 108))	('nodal', 'Gene', '4838', (92, 97))	('oropharyngeal squamous cell carcinoma', 'Phenotype', 'HP:0012182', (262, 299))	('recurrence rate', 'CPA', (141, 156))	('carcinoma', 'Phenotype', 'HP:0030731', (290, 299))	('oropharyngeal squamous cell carcinoma', 'Disease', 'MESH:D002294', (262, 299))	('p16', 'Gene', '1029', (55, 58))	('distant metastasis', 'CPA', (111, 129))
281002	29896273	Independent studies also reported hypermethylation of APC in OSCC samples, but Esteller et al.	('APC', 'Gene', '324', (54, 57))	('APC', 'Phenotype', 'HP:0005227', (54, 57))	('hypermethylation', 'Var', (34, 50))	('APC', 'Gene', (54, 57))
281005	29896273	reported that APC was methylated in 7% of DNA samples extracted from the plasma of a cancer-free population, and promoter methylation of this gene was not associated with several potential risk factors e.g., age, smoking and alcohol status, family cancer history, diet, and nutrition.	('cancer', 'Disease', (248, 254))	('cancer', 'Disease', 'MESH:D009369', (248, 254))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('cancer', 'Phenotype', 'HP:0002664', (248, 254))	('APC', 'Phenotype', 'HP:0005227', (14, 17))	('APC', 'Gene', (14, 17))	('cancer', 'Disease', (85, 91))	('APC', 'Gene', '324', (14, 17))	('methylated', 'Var', (22, 32))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('alcohol', 'Chemical', 'MESH:D000438', (225, 232))
281008	29896273	Aberrant promoter hypermethylation of this gene is often observed in cancers including HNSCC.	('cancers', 'Disease', 'MESH:D009369', (69, 76))	('HNSCC', 'Phenotype', 'HP:0012288', (87, 92))	('Aberrant', 'Var', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('observed', 'Reg', (57, 65))	('promoter', 'MPA', (9, 17))	('cancers', 'Phenotype', 'HP:0002664', (69, 76))	('cancers', 'Disease', (69, 76))	('HNSCC', 'Disease', (87, 92))
281010	29896273	Aberrant promoter hypermethylation of the MGMT gene was detected in 73.7% of oral cavity cancers, with a significant difference between cases and controls, by Kordi-Tamandani et al.. Martone et al.	('MGMT', 'Gene', (42, 46))	('MGMT', 'Gene', '4255', (42, 46))	('Aberrant', 'Var', (0, 8))	('detected', 'Reg', (56, 64))	('cancers', 'Phenotype', 'HP:0002664', (89, 96))	('cancers', 'Disease', 'MESH:D009369', (89, 96))	('promoter', 'MPA', (9, 17))	('cancers', 'Disease', (89, 96))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
281011	29896273	observed that MGMT was hypermethylated in 50% and 56% of primary HNSCC tumours, and the results showed association of gene-specific hypermethylation status in tumours and paired surgical margins.	('MGMT', 'Gene', (14, 18))	('tumours', 'Disease', (159, 166))	('tumours', 'Disease', 'MESH:D009369', (71, 78))	('tumours', 'Disease', (71, 78))	('association', 'Interaction', (103, 114))	('tumour', 'Phenotype', 'HP:0002664', (159, 165))	('tumour', 'Phenotype', 'HP:0002664', (71, 77))	('tumours', 'Phenotype', 'HP:0002664', (159, 166))	('HNSCC tumours', 'Disease', 'MESH:D000077195', (65, 78))	('hypermethylation status', 'Var', (132, 155))	('tumours', 'Disease', 'MESH:D009369', (159, 166))	('HNSCC', 'Phenotype', 'HP:0012288', (65, 70))	('MGMT', 'Gene', '4255', (14, 18))	('HNSCC tumours', 'Disease', (65, 78))	('tumours', 'Phenotype', 'HP:0002664', (71, 78))
281013	29896273	showed an association between methylation in tumour cells and lymph node involvement, and in turn Taioli et.	('methylation', 'Var', (30, 41))	('lymph node involvement', 'CPA', (62, 84))	('tumour', 'Phenotype', 'HP:0002664', (45, 51))	('men', 'Species', '9606', (80, 83))	('tumour', 'Disease', 'MESH:D009369', (45, 51))	('tumour', 'Disease', (45, 51))
281014	29896273	al observed that reduced disease-free survival and reduced overall survival are associated with hypermethylation of this gene in HNSCC patients.	('patients', 'Species', '9606', (135, 143))	('reduced', 'NegReg', (51, 58))	('HNSCC', 'Phenotype', 'HP:0012288', (129, 134))	('disease-free survival', 'CPA', (25, 46))	('HNSCC', 'Disease', (129, 134))	('overall survival', 'CPA', (59, 75))	('reduced', 'NegReg', (17, 24))	('hypermethylation', 'Var', (96, 112))
281015	29896273	Moreover, hypermethylation of MGMT is postulated as a potential prognostic biomarker.	('hypermethylation', 'Var', (10, 26))	('MGMT', 'Gene', (30, 34))	('MGMT', 'Gene', '4255', (30, 34))
281020	29896273	Furthermore, this gene was hypermethylated in exfoliated tumour cells in HNSCC patients compared to the healthy control group.	('tumour', 'Disease', (57, 63))	('HNSCC', 'Phenotype', 'HP:0012288', (73, 78))	('HNSCC', 'Disease', (73, 78))	('hypermethylated', 'Var', (27, 42))	('patients', 'Species', '9606', (79, 87))	('tumour', 'Phenotype', 'HP:0002664', (57, 63))	('tumour', 'Disease', 'MESH:D009369', (57, 63))
281026	29896273	showed hypermethylated promoters of E-cadherin in 64% of oral carcinoma cases, and downregulation of its expression was found to be related to promoter hypermethylation.	('carcinoma', 'Phenotype', 'HP:0030731', (62, 71))	('oral carcinoma', 'Disease', (57, 71))	('E-cadherin', 'Gene', (36, 46))	('E-cadherin', 'Gene', '999', (36, 46))	('downregulation', 'NegReg', (83, 97))	('hypermethylated', 'Var', (7, 22))	('promoter hypermethylation', 'Var', (143, 168))	('expression', 'MPA', (105, 115))	('oral carcinoma', 'Disease', 'MESH:D020820', (57, 71))
281027	29896273	The influence of CDH1 promoter methylation in the invasive progression of HNSCC was observed based on an increased frequency of gene methylation at stages beyond the early tumour stage.	('gene', 'MPA', (128, 132))	('CDH1', 'Gene', '999', (17, 21))	('tumour', 'Phenotype', 'HP:0002664', (172, 178))	('HNSCC', 'Disease', (74, 79))	('tumour', 'Disease', 'MESH:D009369', (172, 178))	('HNSCC', 'Phenotype', 'HP:0012288', (74, 79))	('tumour', 'Disease', (172, 178))	('methylation', 'Var', (31, 42))	('CDH1', 'Gene', (17, 21))
281029	29896273	showed that patients with advanced oral squamous cell carcinoma with E-cad promoter methylation had significantly worse overall survival, and this factor can be proposed as a potential molecular marker for poor survival.	('overall', 'MPA', (120, 127))	('patients', 'Species', '9606', (12, 20))	('carcinoma', 'Phenotype', 'HP:0030731', (54, 63))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (35, 63))	('promoter methylation', 'Var', (75, 95))	('E-cad', 'Gene', '999', (69, 74))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (40, 63))	('worse', 'NegReg', (114, 119))	('oral squamous cell carcinoma', 'Disease', (35, 63))	('E-cad', 'Gene', (69, 74))
281032	29896273	investigated silencing of E-cadherin and postulated hypermethylation as a mechanism of inactivation.	('E-cadherin', 'Gene', (26, 36))	('hypermethylation', 'Var', (52, 68))	('E-cadherin', 'Gene', '999', (26, 36))	('silencing', 'MPA', (13, 22))
281036	29896273	In our study, aberrant promoter hypermethylation was found in all five genes (CIMP-positive) in four cases (5.3%) of tumour samples.	('found', 'Reg', (53, 58))	('CIMP', 'Chemical', '-', (78, 82))	('tumour', 'Phenotype', 'HP:0002664', (117, 123))	('aberrant', 'Var', (14, 22))	('tumour', 'Disease', 'MESH:D009369', (117, 123))	('promoter', 'MPA', (23, 31))	('tumour', 'Disease', (117, 123))
281039	29896273	There is increasing evidence that methylation of specific genes is related with tumour biology, such as prognosis and drug response, and is linked with particular tumour histological features.	('tumour', 'Disease', (80, 86))	('related', 'Reg', (67, 74))	('methylation', 'Var', (34, 45))	('particular tumour', 'Disease', (152, 169))	('particular tumour', 'Disease', 'MESH:D009369', (152, 169))	('tumour', 'Disease', 'MESH:D009369', (163, 169))	('tumour', 'Phenotype', 'HP:0002664', (163, 169))	('tumour', 'Phenotype', 'HP:0002664', (80, 86))	('tumour', 'Disease', 'MESH:D009369', (80, 86))	('linked', 'Reg', (140, 146))	('tumour', 'Disease', (163, 169))
281043	29896273	Furthermore, in our cohort of patients those with a family history of cancer showed more frequently methylated MGMT genes.	('MGMT', 'Gene', (111, 115))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('MGMT', 'Gene', '4255', (111, 115))	('methylated', 'Var', (100, 110))	('patients', 'Species', '9606', (30, 38))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))
281045	29896273	A connection between the presence of methylation and a family history of cancer was also shown previously, indicating a shared aetiology such as genetic predisposition.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('methylation', 'Var', (37, 48))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('presence', 'Var', (25, 33))
281053	29896273	There is also evidence that epigenetic mechanisms such as DNA methylation play a crucial role in the pathophysiology of alcoholism.	('DNA methylation', 'Var', (58, 73))	('alcoholism', 'Disease', 'MESH:D000437', (120, 130))	('alcoholism', 'Disease', (120, 130))	('alcoholism', 'Phenotype', 'HP:0030955', (120, 130))
281059	29896273	Moreover, methylation of MGMT not only led to sensitivity to alkylating drugs used in chemotherapy, but also exposed a mutator phenotype.	('mutator phenotype', 'MPA', (119, 136))	('led to', 'Reg', (39, 45))	('sensitivity to alkylating drugs', 'MPA', (46, 77))	('methylation', 'Var', (10, 21))	('MGMT', 'Gene', (25, 29))	('MGMT', 'Gene', '4255', (25, 29))	('exposed', 'Reg', (109, 116))
281060	29896273	Polymorphisms of genes vulnerable to environmental carcinogens were especially common in those coding for enzymes involved in carcinogen metabolism, such as MGMT, as a mechanism for differential cancer susceptibility.	('common', 'Reg', (79, 85))	('Polymorphisms', 'Var', (0, 13))	('cancer', 'Disease', (195, 201))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('men', 'Species', '9606', (44, 47))	('MGMT', 'Gene', '4255', (157, 161))	('MGMT', 'Gene', (157, 161))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
281062	29896273	An MGMT Ile143Val polymorphism may play a role in modulating the risk of cancer in the presence of alcohol.	('MGMT', 'Gene', (3, 7))	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('MGMT', 'Gene', '4255', (3, 7))	('Ile143Val', 'Var', (8, 17))	('alcohol', 'Chemical', 'MESH:D000438', (99, 106))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('Ile143Val', 'Chemical', '-', (8, 17))	('modulating', 'Reg', (50, 60))
281064	29896273	Aberrant methylation profiles could be caused by various factors including the above-mentioned tobacco and alcohol consumption and also Human Papilloma Virus (HPV) infection.	('alcohol consumption and also Human Papilloma Virus (HPV) infection', 'Disease', 'MESH:D030361', (107, 173))	('methylation profiles', 'MPA', (9, 29))	('tobacco', 'Species', '4097', (95, 102))	('Aberrant', 'Var', (0, 8))	('Papilloma', 'Phenotype', 'HP:0012740', (142, 151))	('men', 'Species', '9606', (85, 88))	('caused', 'Reg', (39, 45))
281069	29896273	Our results showed aberrant DNA methylation both in tumour and surgical margins, which might be due to the existence of a heterogeneous preneoplastic field that is not detectable by basic histologic analysis and ipso facto revealing the impact of DNA aberrant methylation in tumorigenesis.	('methylation', 'Var', (32, 43))	('tumour', 'Phenotype', 'HP:0002664', (52, 58))	('tumour', 'Disease', 'MESH:D009369', (52, 58))	('DNA', 'Gene', (28, 31))	('tumour', 'Disease', (52, 58))	('aberrant', 'Var', (19, 27))	('tumorigenesis', 'CPA', (275, 288))
281071	29896273	The genetically altered mucosa that remains after therapy can cause local recurrences and second primary tumours after surgery to remove the primary carcinoma.	('tumours', 'Phenotype', 'HP:0002664', (105, 112))	('carcinoma', 'Disease', 'MESH:D002277', (149, 158))	('carcinoma', 'Phenotype', 'HP:0030731', (149, 158))	('local recurrences', 'CPA', (68, 85))	('cause', 'Reg', (62, 67))	('primary tumours', 'Disease', 'MESH:D009369', (97, 112))	('genetically altered', 'Var', (4, 23))	('carcinoma', 'Disease', (149, 158))	('primary tumours', 'Disease', (97, 112))	('tumour', 'Phenotype', 'HP:0002664', (105, 111))
281076	29896273	Moreover, in surgical practice, particularly regarding the head and neck, the problem is to completely remove collateral areas because any remaining cells with molecular abnormalities increase the risk of developing a second primary tumour.	('tumour', 'Disease', (233, 239))	('tumour', 'Phenotype', 'HP:0002664', (233, 239))	('molecular abnormalities', 'Var', (160, 183))	('tumour', 'Disease', 'MESH:D009369', (233, 239))
281079	29896273	Based on our observations, aberrant methylation is an important epigenetic event in HNSCC cancer.	('HNSCC cancer', 'Disease', 'MESH:D000077195', (84, 96))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('HNSCC', 'Phenotype', 'HP:0012288', (84, 89))	('HNSCC cancer', 'Disease', (84, 96))	('aberrant methylation', 'Var', (27, 47))
281080	29896273	The hypermethylation of the promoter region of the MGMT and CDH1 genes could be a potential biomarker in HNSCC cancer.	('HNSCC cancer', 'Disease', 'MESH:D000077195', (105, 117))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('HNSCC', 'Phenotype', 'HP:0012288', (105, 110))	('HNSCC cancer', 'Disease', (105, 117))	('CDH1', 'Gene', (60, 64))	('hypermethylation', 'Var', (4, 20))	('CDH1', 'Gene', '999', (60, 64))	('MGMT', 'Gene', (51, 55))	('MGMT', 'Gene', '4255', (51, 55))
281081	29896273	Our observations confirm the presence of epigenetic changes not only in the cancer cells but also in the surrounding mucosa, and represent a basis for the suggestion that appropriate cancer risk assessment based on epigenetic alterations in surgical margins may influence a patient's diagnosis and cure.	('patient', 'Species', '9606', (274, 281))	('cancer', 'Disease', (183, 189))	('cure', 'CPA', (298, 302))	('men', 'Species', '9606', (201, 204))	('cancer', 'Disease', 'MESH:D009369', (183, 189))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('epigenetic alterations', 'Var', (215, 237))	('epigenetic changes', 'Var', (41, 59))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('influence', 'Reg', (262, 271))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('diagnosis', 'CPA', (284, 293))
281088	29535832	Phylogenetic analysis showed that the sarcomatous component had ramified from the carcinomatous component in the early phase of the evolution process and accumulated a number of mutations that were different from those of the carcinomatous component.	('sarcomatous component', 'Disease', 'MESH:D018316', (38, 59))	('sarcomatous component', 'Disease', (38, 59))	('carcinomatous component', 'Disease', (226, 249))	('sarcoma', 'Phenotype', 'HP:0100242', (38, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (226, 235))	('carcinomatous component', 'Disease', 'MESH:D055756', (82, 105))	('carcinomatous component', 'Disease', 'MESH:D055756', (226, 249))	('carcinomatous component', 'Disease', (82, 105))	('mutations', 'Var', (178, 187))
281089	29535832	Moreover, microsatellite instability was detected in a case of sarcomatoid cancer and PD-L1 was strongly positive (>= 50%) in all sarcomatoid cancers.	('sarcomatoid cancer', 'Disease', 'MESH:C538614', (63, 81))	('PD-L1', 'Gene', '29126', (86, 91))	('sarcoma', 'Phenotype', 'HP:0100242', (63, 70))	('sarcomatoid cancers', 'Disease', 'MESH:C538614', (130, 149))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('sarcomatoid cancer', 'Phenotype', 'HP:0100242', (63, 81))	('sarcomatoid cancer', 'Disease', 'MESH:C538614', (130, 148))	('sarcomatoid cancer', 'Disease', (63, 81))	('cancers', 'Phenotype', 'HP:0002664', (142, 149))	('sarcoma', 'Phenotype', 'HP:0100242', (130, 137))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('sarcomatoid cancers', 'Disease', (130, 149))	('sarcomatoid cancer', 'Phenotype', 'HP:0100242', (130, 148))	('PD-L1', 'Gene', (86, 91))	('detected', 'Reg', (41, 49))	('positive', 'Reg', (105, 113))	('microsatellite instability', 'Var', (10, 36))
281113	29535832	In contrast, the sarcomatous component had many mutations that were different from those of the carcinomatous component, and the number of mutations identified was greater in the sarcomatous component (Figure 2).	('sarcomatous component', 'Disease', 'MESH:D018316', (17, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('sarcomatous component', 'Disease', 'MESH:D018316', (179, 200))	('sarcoma', 'Phenotype', 'HP:0100242', (17, 24))	('sarcoma', 'Phenotype', 'HP:0100242', (179, 186))	('sarcomatous component', 'Disease', (179, 200))	('sarcomatous component', 'Disease', (17, 38))	('carcinomatous component', 'Disease', (96, 119))	('carcinomatous component', 'Disease', 'MESH:D055756', (96, 119))	('mutations', 'Var', (48, 57))
281114	29535832	The analysis showed that the cellular prevalence of the common mutations between the carcinomatous and sarcomatous components was relatively high in all cases (Figure 4).	('mutations', 'Var', (63, 72))	('sarcoma', 'Phenotype', 'HP:0100242', (103, 110))	('sarcomatous components', 'Disease', 'MESH:D018316', (103, 125))	('carcinomatous and sarcomatous', 'Disease', 'MESH:D055756', (85, 114))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('sarcomatous components', 'Disease', (103, 125))
281117	29535832	In addition, in each of these tumors, homologous mutations were highly prevalent in two sites of the same tumor (Supplementary Figure 1).	('tumors', 'Disease', (30, 36))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('prevalent', 'Reg', (71, 80))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('homologous', 'Var', (38, 48))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Disease', (30, 35))	('tumor', 'Disease', (106, 111))
281120	29535832	This finding reflects the fact that many mutations different from those in the epithelial component accumulated in the sarcomatous component.	('mutations', 'Var', (41, 50))	('accumulated', 'Reg', (100, 111))	('sarcoma', 'Phenotype', 'HP:0100242', (119, 126))	('sarcomatous component', 'Disease', 'MESH:D018316', (119, 140))	('sarcomatous component', 'Disease', (119, 140))
281122	29535832	The sarcomatous component accumulated a large number of unique mutations, indicating that this component was substantially different from the epithelial component in terms of genetic status (Figure 6).	('mutations', 'Var', (63, 72))	('sarcoma', 'Phenotype', 'HP:0100242', (4, 11))	('sarcomatous component', 'Disease', 'MESH:D018316', (4, 25))	('sarcomatous component', 'Disease', (4, 25))
281123	29535832	Whole exome sequencing revealed somatic mutations in the MutL homolog 1 (MLH1) gene in Case 1 (Table 2, Supplementary Table 1).	('MutL homolog 1', 'Gene', '4292', (57, 71))	('revealed', 'Reg', (23, 31))	('MutL homolog 1', 'Gene', (57, 71))	('mutations', 'Var', (40, 49))	('MLH1', 'Gene', '4292', (73, 77))	('MLH1', 'Gene', (73, 77))
281139	29535832	In addition, comparison of the mutation profile in each component showed that the genomic distance between carcinomatous and sarcomatous components increased following the accumulation of additional mutations.	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('mutations', 'Var', (199, 208))	('sarcomatous components', 'Disease', (125, 147))	('increased', 'PosReg', (148, 157))	('sarcoma', 'Phenotype', 'HP:0100242', (125, 132))	('sarcomatous components', 'Disease', 'MESH:D018316', (125, 147))	('carcinomatous and sarcomatous', 'Disease', 'MESH:D055756', (107, 136))	('genomic distance', 'CPA', (82, 98))
281140	29535832	Furthermore, the sarcomatous component showed a greater accumulation of mutations and a larger genetic distance to the common-origin than the epithelial component.	('sarcomatous component', 'Disease', 'MESH:D018316', (17, 38))	('mutations', 'Var', (72, 81))	('sarcoma', 'Phenotype', 'HP:0100242', (17, 24))	('sarcomatous component', 'Disease', (17, 38))	('accumulation', 'PosReg', (56, 68))	('genetic distance to the common-origin', 'CPA', (95, 132))
281142	29535832	The neighbor-joining method was applied to analyze complex models of nucleotide substitutions for the purpose of estimating evolutionary distance and to infer the phylogeny of the sarcomatoid cancer.	('sarcomatoid cancer', 'Disease', 'MESH:C538614', (180, 198))	('nucleotide substitutions', 'Var', (69, 93))	('sarcomatoid cancer', 'Phenotype', 'HP:0100242', (180, 198))	('sarcomatoid cancer', 'Disease', (180, 198))	('sarcoma', 'Phenotype', 'HP:0100242', (180, 187))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))
281146	29535832	The mutation burden in sarcomatoid carcinoma was significantly higher than that in adenocarcinoma and squamous cell carcinoma (Supplementary Figure 2).	('sarcomatoid carcinoma', 'Phenotype', 'HP:0100242', (23, 44))	('sarcomatoid carcinoma', 'Disease', 'MESH:C538614', (23, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (35, 44))	('sarcoma', 'Phenotype', 'HP:0100242', (23, 30))	('sarcomatoid carcinoma', 'Disease', (23, 44))	('adenocarcinoma and squamous cell carcinoma', 'Disease', 'MESH:D002294', (83, 125))	('mutation', 'Var', (4, 12))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (102, 125))	('higher', 'PosReg', (63, 69))
281147	29535832	In several cohort studies, higher nonsynonymous mutation burden in tumors was associated with improved objective response, durable clinical benefit and progression-free survival in anti-PD-1/PD-L1 therapies.	('nonsynonymous mutation burden', 'Var', (34, 63))	('PD-L1', 'Gene', (191, 196))	('tumors', 'Disease', 'MESH:D009369', (67, 73))	('objective response', 'CPA', (103, 121))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('improved', 'PosReg', (94, 102))	('PD-L1', 'Gene', '29126', (191, 196))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('PD-1', 'Gene', '5133', (186, 190))	('PD-1', 'Gene', (186, 190))	('tumors', 'Disease', (67, 73))
281150	29535832	The MMR genes (MLH1, MSH2, MSH6 and PMS2), which are key components of the MMR system, recognize and excise single-base mismatches and insertion/deletion loops that occur during DNA replication or DNA damage.	('insertion/deletion loops', 'Var', (135, 159))	('MSH6', 'Gene', '2956', (27, 31))	('MSH2', 'Gene', (21, 25))	('single-base mismatches', 'Var', (108, 130))	('MSH2', 'Gene', '4436', (21, 25))	('PMS2', 'Gene', (36, 40))	('MSH6', 'Gene', (27, 31))	('PMS2', 'Gene', '5395', (36, 40))	('MLH1', 'Gene', '4292', (15, 19))	('MLH1', 'Gene', (15, 19))
281152	29535832	MMR-deficient colorectal cancers have 10-100 times as many somatic mutations as MMR-proficient colorectal cancers.	('MMR-deficient colorectal cancers', 'Disease', (0, 32))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('colorectal cancers', 'Disease', (95, 113))	('colorectal cancer', 'Phenotype', 'HP:0003003', (14, 31))	('MMR-deficient colorectal cancers', 'Disease', 'MESH:D015179', (0, 32))	('cancers', 'Phenotype', 'HP:0002664', (106, 113))	('mutations', 'Var', (67, 76))	('colorectal cancers', 'Disease', 'MESH:D015179', (14, 32))	('cancers', 'Phenotype', 'HP:0002664', (25, 32))	('colorectal cancer', 'Phenotype', 'HP:0003003', (95, 112))	('colorectal cancers', 'Disease', 'MESH:D015179', (95, 113))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
281154	29535832	MMR deficiency occurs in several types of cancers, including those of the colorectum, uterus, stomach, biliary tract, pancreas, ovary, prostate and small intestine.	('prostate', 'Disease', (135, 143))	('cancers', 'Disease', (42, 49))	('occurs', 'Reg', (15, 21))	('stomach', 'Disease', (94, 101))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('biliary tract', 'Disease', (103, 116))	('deficiency', 'Var', (4, 14))	('uterus', 'Disease', (86, 92))	('pancreas', 'Disease', (118, 126))	('cancers', 'Phenotype', 'HP:0002664', (42, 49))	('ovary', 'Disease', (128, 133))	('MMR', 'Gene', (0, 3))	('small intestine', 'Disease', (148, 163))	('cancers', 'Disease', 'MESH:D009369', (42, 49))	('pancreas', 'Disease', 'MESH:D010190', (118, 126))
281156	29535832	Data on the prevalence of microsatellite instability among non-small cell lung cancers are conflicting, with estimates ranging between 0% and 0.8%, and the clinical relevance of microsatellite instability is largely unknown.	('lung cancer', 'Phenotype', 'HP:0100526', (74, 85))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (59, 85))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('non-small cell lung cancers', 'Phenotype', 'HP:0030358', (59, 86))	('lung cancers', 'Phenotype', 'HP:0100526', (74, 86))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (59, 85))	('small cell lung cancers', 'Disease', (63, 86))	('small cell lung cancers', 'Disease', 'MESH:D055752', (63, 86))	('non-small cell lung cancer', 'Disease', (59, 85))	('small cell lung cancers', 'Phenotype', 'HP:0030357', (63, 86))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('microsatellite instability', 'Var', (26, 52))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (63, 85))
281157	29535832	Hereditary nonpolyposis colorectal cancer (also known as Lynch syndrome) results from an inherited germline defect in one of four MMR genes (MLH1, MSH2, MSH6 and PMS2) followed by a second inactivating somatic change in the remaining wild-type allele.	('Hereditary nonpolyposis colorectal cancer', 'Disease', (0, 41))	('defect', 'Var', (108, 114))	('MSH2', 'Gene', (147, 151))	('colorectal cancer', 'Phenotype', 'HP:0003003', (24, 41))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('PMS2', 'Gene', (162, 166))	('MSH2', 'Gene', '4436', (147, 151))	('Hereditary nonpolyposis colorectal cancer', 'Phenotype', 'HP:0006716', (0, 41))	('MSH6', 'Gene', (153, 157))	('Lynch syndrome', 'Disease', 'MESH:D003123', (57, 71))	('Lynch syndrome', 'Disease', (57, 71))	('MLH1', 'Gene', '4292', (141, 145))	('results from', 'Reg', (73, 85))	('PMS2', 'Gene', '5395', (162, 166))	('MMR', 'Gene', (130, 133))	('Hereditary nonpolyposis colorectal cancer', 'Disease', 'MESH:D003123', (0, 41))	('MLH1', 'Gene', (141, 145))	('MSH6', 'Gene', '2956', (153, 157))
281179	29535832	To estimate the fraction of cancer cells harboring a mutation, PyClone analysis was performed.	('cancer', 'Disease', (28, 34))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('mutation', 'Var', (53, 61))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))
281180	29535832	For MSI analysis, five microsatellite markers (BAT25, BAT26, D5S346, D2S123 and D17S250) were used to classify the tumor as MSI-high (the presence of at least two markers showing novel alleles compared with normal control), MSI-low (defined as one marker with a novel allele), or microsatellite stable (MSS, no marker with novel alleles).	('MSI-low', 'Disease', (224, 231))	('D17S250', 'Var', (80, 87))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('D5S346', 'Var', (61, 67))	('tumor', 'Disease', (115, 120))	('MSI-low', 'Disease', 'MESH:D009800', (224, 231))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('D2S123', 'Var', (69, 75))
281183	29535832	Immunohistochemistry analysis was performed on tumor samples using commercially available detection kits, automated staining techniques (Ventana Benchmark ULTRA system; Roche, Tucson, AZ), and antibodies against MLH1 (M1; Ventana), MSH2 (G219-1129; Ventana), MSH6 (44; Ventana), PMS2 (EPR3947; Ventana) and PD-L1 (ab205921;Abcam, at 1/250 dilution).	('MSH2', 'Gene', (232, 236))	('MSH2', 'Gene', '4436', (232, 236))	('MLH1', 'Gene', '4292', (212, 216))	('PD-L1', 'Gene', '29126', (307, 312))	('MLH1', 'Gene', (212, 216))	('PMS2', 'Gene', (279, 283))	('EPR3947;', 'Var', (285, 293))	('MSH6', 'Gene', (259, 263))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('PMS2', 'Gene', '5395', (279, 283))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('MSH6', 'Gene', '2956', (259, 263))	('tumor', 'Disease', (47, 52))	('PD-L1', 'Gene', (307, 312))
281274	28584268	Results revealed that patients with higher PE Grade and forced vital capacity (FVC) <2.8 L had a higher risk to the development of Grade >=2RP (P = 0.012 and P = 0.022, respectively).	('<2.8', 'Var', (84, 88))	('patients', 'Species', '9606', (22, 30))	('PE', 'Phenotype', 'HP:0002097', (43, 45))	('Grade', 'MPA', (131, 136))
281278	28584268	The results showed that higher PE Grade (P = 0.006) and older age (P = 0.009) were significantly associated with the development of Grade >=3 RP in NSCLC.	('NSCLC', 'Disease', (148, 153))	('NSCLC', 'Disease', 'MESH:D002289', (148, 153))	('PE Grade', 'CPA', (31, 39))	('Grade >=3 RP', 'Var', (132, 144))	('NSCLC', 'Phenotype', 'HP:0030358', (148, 153))	('PE', 'Phenotype', 'HP:0002097', (31, 33))
281280	28584268	The results of unconditional logistic analysis showed that PE was the major factor with the association of Grade >=2 RP (OR = 1.985, P = 0.01) and Grade >=3 RP (OR = 2.275, P = 0.02) in NSCLC.	('NSCLC', 'Phenotype', 'HP:0030358', (186, 191))	('Grade >=3 RP', 'Var', (147, 159))	('NSCLC', 'Disease', (186, 191))	('Grade >=2 RP', 'Var', (107, 119))	('NSCLC', 'Disease', 'MESH:D002289', (186, 191))	('PE', 'Phenotype', 'HP:0002097', (59, 61))
281281	28584268	Subgroup analysis showed that PE was the independent factor with the development of Grade >=2 RP (OR = 3.304, P = 0.002) and Grade >=3 RP (OR = 2.718, P = 0.031) in patients with SCC (Table 4).	('SCC', 'Gene', (179, 182))	('SCC', 'Phenotype', 'HP:0002860', (179, 182))	('SCC', 'Gene', '6317', (179, 182))	('PE', 'Phenotype', 'HP:0002097', (30, 32))	('patients', 'Species', '9606', (165, 173))	('Grade >=2 RP', 'Var', (84, 96))	('Grade >=3 RP', 'Var', (125, 137))
281283	28584268	In addition, the ROC curve revealed that the area under the curve (AUC) of PE in NSCLC was 0.647 (P = 0.01) in Grade >=2 RP and 0.715 (P < 0.001) in Grade >=3 RP; and with the combination of the five factors (PE, age, FVC, PO2 and MLD), the AUC was up to 0.729 (P < 0.001) in Grade >=2 RP and 0.797 (P < 0.001) in Grade >=3 RP (P < 0.001).	('PO2', 'Chemical', 'MESH:C093415', (223, 226))	('MLD', 'Disease', 'MESH:D007966', (231, 234))	('MLD', 'Disease', (231, 234))	('NSCLC', 'Phenotype', 'HP:0030358', (81, 86))	('PE', 'Phenotype', 'HP:0002097', (75, 77))	('PE', 'Phenotype', 'HP:0002097', (209, 211))	('NSCLC', 'Disease', (81, 86))	('0.715', 'Var', (128, 133))	('NSCLC', 'Disease', 'MESH:D002289', (81, 86))
281285	28584268	The events of Grade >=2 RP in NSCLC patients with PE Grade 0, PE Grade 1 and PE Grade >=2 were 12 (14.1%), 11 (24.4%) and 10 (43.5%), respectively, while the events of Grade >=3 RP in NSCLC patients with PE Grade 0, PE Grade 1 and PE Grade >=2 were 3 (3.5%), 8 (17.8%) and 5 (21.7%), respectively.	('NSCLC', 'Disease', 'MESH:D002289', (30, 35))	('PE', 'Phenotype', 'HP:0002097', (216, 218))	('NSCLC', 'Phenotype', 'HP:0030358', (184, 189))	('patients', 'Species', '9606', (36, 44))	('patients', 'Species', '9606', (190, 198))	('PE', 'Phenotype', 'HP:0002097', (77, 79))	('PE', 'Phenotype', 'HP:0002097', (50, 52))	('NSCLC', 'Phenotype', 'HP:0030358', (30, 35))	('NSCLC', 'Disease', (184, 189))	('NSCLC', 'Disease', 'MESH:D002289', (184, 189))	('Grade >=2', 'Var', (80, 89))	('NSCLC', 'Disease', (30, 35))	('PE', 'Phenotype', 'HP:0002097', (62, 64))	('PE', 'Phenotype', 'HP:0002097', (204, 206))
281290	28584268	Some investigations have implied that V20 >= 25% or MLD >=14 Gy would be a risk factor to increase the incidence of severe RP.	('V20 >= 25%', 'Var', (38, 48))	('MLD', 'Disease', 'MESH:D007966', (52, 55))	('MLD', 'Disease', (52, 55))	('severe RP', 'Disease', (116, 125))
281328	27308463	Whole-genome sequencing analysis of 17 NSCLC samples identified biclonal tumors, some of which had potentially targetable mutations in one subclone next to a clonal targetable mutation.	('NSCLC', 'Phenotype', 'HP:0030358', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('biclonal tumors', 'Disease', (64, 79))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('biclonal tumors', 'Disease', 'MESH:D009369', (64, 79))	('mutations', 'Var', (122, 131))	('NSCLC', 'Disease', (39, 44))	('NSCLC', 'Disease', 'MESH:D002289', (39, 44))
281334	27308463	On average, two-thirds of all mutations identified in a tumor were present in all regions of that tumor, whereas one-third of the mutations were present in only one or a few regions.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Disease', (56, 61))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('mutations', 'Var', (30, 39))	('tumor', 'Disease', (98, 103))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
281336	27308463	Nevertheless, all tumors revealed candidate driver mutations and/or copy number aberrations present in only one or two regions.	('mutations', 'Var', (51, 60))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('tumors', 'Disease', (18, 24))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
281337	27308463	To investigate the temporal heterogeneity in mutations, we separated 'early' mutations (present in all tumor regions) from 'late' mutations (present in at least one, but not all regions) and explored the mutational spectra over time.	('tumor', 'Disease', (103, 108))	('mutations', 'Var', (77, 86))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))
281338	27308463	We found that all tumors from former and current smokers showed a decrease in smoking-associated C>A mutations over time, accompanied by an increase in C>T and C>G mutations at TpC sites in the majority of tumors, indicative of apolipoprotein-B mRNA editing catalytic polypeptide-like (APOBEC) cytidine deaminase-mediated mutagenesis.	('apolipoprotein-B', 'Gene', (228, 244))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('cytidine deaminase', 'Gene', (294, 312))	('mutations', 'Var', (101, 110))	('tumors', 'Phenotype', 'HP:0002664', (206, 212))	('apolipoprotein-B', 'Gene', '338', (228, 244))	('cytidine deaminase', 'Gene', '978', (294, 312))	('tumors', 'Disease', (206, 212))	('tumors', 'Disease', 'MESH:D009369', (206, 212))	('tumors', 'Disease', (18, 24))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('C>T', 'Var', (152, 155))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('decrease', 'NegReg', (66, 74))	('C>G mutations', 'Var', (160, 173))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
281339	27308463	On average, 31% of the 'late' non-silent mutations occurred in an APOBEC context compared to 11% of the 'early' non-silent mutations, indicating a functional impact of APOBEC activity later in NSCLC evolution.	('mutations', 'Var', (41, 50))	('NSCLC', 'Phenotype', 'HP:0030358', (193, 198))	('NSCLC', 'Disease', (193, 198))	('occurred', 'Reg', (51, 59))	('NSCLC', 'Disease', 'MESH:D002289', (193, 198))
281343	27308463	Multiregion sequencing of 10 renal cancer samples revealed that many known driver mutations were always subclonally present.	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('mutations', 'Var', (82, 91))	('renal cancer', 'Disease', (29, 41))	('renal cancer', 'Disease', 'MESH:D007680', (29, 41))	('renal cancer', 'Phenotype', 'HP:0009726', (29, 41))
281346	27308463	In these cases, all 'early' driver mutations had occurred more than 2 decades prior to surgery, indicating a long period during which these tumors have been shaped, most likely involving many processes prior to clinical presentation.	('tumors', 'Disease', 'MESH:D009369', (140, 146))	('tumors', 'Disease', (140, 146))	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('mutations', 'Var', (35, 44))
281348	27308463	Importantly, we found that the mutations present in metastasized tumor cells of patients with lymph node involvement closely correlated with one particular region within the primary tumor, indicating that a minor subclones present in a distinct region in the primary tumor can determine clinical outcome.	('mutations', 'Var', (31, 40))	('patients', 'Species', '9606', (80, 88))	('tumor', 'Disease', (65, 70))	('tumor', 'Disease', (182, 187))	('tumor', 'Disease', 'MESH:D009369', (267, 272))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (267, 272))	('tumor', 'Disease', (267, 272))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('determine', 'Reg', (277, 286))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
281361	26919318	CAP may be a promising cancer treatment method by inducing EGFR dysfunction in EGFR-overexpressing oral squamous cell carcinoma via nitric oxide radicals.	('nitric oxide', 'Chemical', 'MESH:D009569', (132, 144))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (104, 127))	('EGFR', 'Gene', '1956', (79, 83))	('EGFR', 'Gene', (59, 63))	('EGFR', 'Gene', (79, 83))	('oral squamous cell carcinoma', 'Disease', (99, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('cancer', 'Disease', (23, 29))	('cancer', 'Disease', 'MESH:D009369', (23, 29))	('inducing', 'Reg', (50, 58))	('CAP', 'Chemical', '-', (0, 3))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (99, 127))	('dysfunction', 'Var', (64, 75))	('EGFR', 'Gene', '1956', (59, 63))
281385	26919318	The aim of this study was to investigate the selective killing effect of cold atmospheric pressure plasma with dysfunction of the EGFR in oral squamous cell carcinoma.	('oral squamous cell carcinoma', 'Disease', (138, 166))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (138, 166))	('carcinoma', 'Phenotype', 'HP:0030731', (157, 166))	('dysfunction', 'Var', (111, 122))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (143, 166))	('EGFR', 'Gene', '1956', (130, 134))	('EGFR', 'Gene', (130, 134))
281424	26919318	The following primary antibodies were used: EGFR (#2232), phospho-EGFR (#6963), and beta-actin (#4970).	('#4970', 'Var', (96, 101))	('beta-actin', 'Gene', '728378', (84, 94))	('beta-actin', 'Gene', (84, 94))	('EGFR', 'Gene', '1956', (66, 70))	('EGFR', 'Gene', (66, 70))	('#2232', 'Var', (50, 55))	('#6963', 'Var', (72, 77))	('EGFR', 'Gene', '1956', (44, 48))	('EGFR', 'Gene', (44, 48))
281450	26919318	According to the results, pretreatment with C-PTIO, scavenger of NO, diminished oxidation capacity of 1500 sccm CAP-treated media compared to N-acetyl-L-cysteine and Trolox (P<0.05).	('C-PTIO', 'Var', (44, 50))	('C-PTIO', 'Chemical', 'MESH:C079393', (44, 50))	('Trolox', 'Chemical', 'MESH:C010643', (166, 172))	('CAP', 'Chemical', '-', (112, 115))	('oxidation capacity', 'MPA', (80, 98))	('diminished', 'NegReg', (69, 79))	('N-acetyl-L-cysteine', 'Chemical', 'MESH:D000111', (142, 161))
281455	26919318	Only C-PTIO, scavenger of NO, significantly reduced the rate of nitrite and nitrate formation (P<0.05).	('C-PTIO', 'Chemical', 'MESH:C079393', (5, 11))	('reduced', 'NegReg', (44, 51))	('nitrite', 'Chemical', 'MESH:D009573', (64, 71))	('nitrate', 'Chemical', 'MESH:D009566', (76, 83))	('C-PTIO', 'Var', (5, 11))
281483	26919318	EGFR dysfunction leads to cell apoptosis as seen with treatments like ROS and ultraviolet light for cancer or psoriasis.	('EGFR', 'Gene', (0, 4))	('psoriasis', 'Disease', (110, 119))	('cell apoptosis', 'CPA', (26, 40))	('psoriasis', 'Disease', 'MESH:D011565', (110, 119))	('psoriasis', 'Phenotype', 'HP:0003765', (110, 119))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('ROS', 'Chemical', 'MESH:D017382', (70, 73))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('dysfunction', 'Var', (5, 16))	('EGFR', 'Gene', '1956', (0, 4))
281486	26919318	However, H2O2 leads to the sustained activation of EGFR pathway.	('EGFR', 'Gene', (51, 55))	('activation', 'PosReg', (37, 47))	('H2O2', 'Var', (9, 13))	('H2O2', 'Chemical', 'MESH:D006861', (9, 13))	('EGFR', 'Gene', '1956', (51, 55))
281527	26919318	In summary, treatment with CAP may be a promising cancer treatment by targeting EGFR dysfunction in EGFR-overexpressing oral squamous cell carcinoma cells via generation of NO radicals in the applied solution.	('dysfunction', 'Var', (85, 96))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (125, 148))	('EGFR', 'Gene', '1956', (100, 104))	('cancer', 'Disease', (50, 56))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (120, 148))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('carcinoma', 'Phenotype', 'HP:0030731', (139, 148))	('EGFR', 'Gene', (100, 104))	('oral squamous cell carcinoma', 'Disease', (120, 148))	('EGFR', 'Gene', '1956', (80, 84))	('EGFR', 'Gene', (80, 84))	('CAP', 'Chemical', '-', (27, 30))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('NO radicals', 'Chemical', '-', (173, 184))
281528	26919318	Future in vivo study using EGFR-null mutants will be needed to observe selective killing effects of CAP depending on the expression of EGFR.	('EGFR', 'Gene', '1956', (27, 31))	('EGFR', 'Gene', (27, 31))	('EGFR', 'Gene', '1956', (135, 139))	('EGFR', 'Gene', (135, 139))	('mutants', 'Var', (37, 44))	('CAP', 'Chemical', '-', (100, 103))
281532	26759717	Recurrent somatic amplifications at 8q were found to be enriched in stage I tumors and the deletions of 4p-q and 5q were particularly identified in stage III tumors.	('I tumors', 'Disease', (74, 82))	('tumors', 'Phenotype', 'HP:0002664', (158, 164))	('III tumors', 'Disease', (154, 164))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('deletions', 'Var', (91, 100))	('I tumors', 'Disease', 'MESH:D009369', (74, 82))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('III tumors', 'Disease', 'MESH:D009369', (154, 164))	('identified', 'Reg', (134, 144))	('I tumors', 'Disease', 'MESH:D009369', (156, 164))	('4p-q', 'Gene', (104, 108))
281535	26759717	Although the cancer-associated genes TP53, PIK3CA, CDKN2A and their pathways showed no significant difference between stage I and stage III tumors, we identified and validated a prevalence of mutations in NOTCH1 and in the NOTCH pathway that indicate that they are involved in the preclinical and early stages of ESCC.	('NOTCH pathway', 'Pathway', (223, 236))	('cancer', 'Disease', 'MESH:D009369', (13, 19))	('ESCC', 'Disease', (313, 317))	('III tumors', 'Disease', 'MESH:D009369', (136, 146))	('TP53', 'Gene', (37, 41))	('CDKN2A', 'Gene', (51, 57))	('mutations', 'Var', (192, 201))	('PIK3CA', 'Gene', (43, 49))	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('NOTCH1', 'Gene', (205, 211))	('clinical', 'Species', '191496', (284, 292))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('CDKN2A', 'Gene', '1029', (51, 57))	('NOTCH1', 'Gene', '4851', (205, 211))	('cancer', 'Disease', (13, 19))	('TP53', 'Gene', '7157', (37, 41))	('PIK3CA', 'Gene', '5290', (43, 49))	('III tumors', 'Disease', (136, 146))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))
281545	26759717	Analyses of somatic copy number alterations (SCNAs) using array-based technologies have identified frequently altered regions such as 3q26, 11q13.3 and 8q24.3, and exome-wide investigations have revealed point mutations in the well-known cancer-associated genes TP53, PIK3CA, CDKN2A and novel genes ZNF750, FAT1, FAT2 and FAM135B.	('FAT1', 'Gene', '2195', (307, 311))	('cancer', 'Disease', (238, 244))	('TP53', 'Gene', '7157', (262, 266))	('CDKN2A', 'Gene', (276, 282))	('FAM135B', 'Gene', (322, 329))	('FAT1', 'Gene', (307, 311))	('cancer', 'Disease', 'MESH:D009369', (238, 244))	('TP53', 'Gene', (262, 266))	('CDKN2A', 'Gene', '1029', (276, 282))	('ZNF750', 'Gene', (299, 305))	('FAT2', 'Gene', '2196', (313, 317))	('FAM135B', 'Gene', '51059', (322, 329))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('FAT2', 'Gene', (313, 317))	('PIK3CA', 'Gene', (268, 274))	('point mutations', 'Var', (204, 219))	('PIK3CA', 'Gene', '5290', (268, 274))
281556	26759717	Candidate non-silent mutations identified from 48 stage I and 48 stage III tumors were selected for TCS (at least 365x; Additional file 3: Table S2C).	('III tumors', 'Disease', (71, 81))	('TCS', 'Chemical', '-', (100, 103))	('non-silent mutations', 'Var', (10, 30))	('III tumors', 'Disease', 'MESH:D009369', (71, 81))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))
281557	26759717	We found 73 (range 24-189) non-silent mutations per tumor in this cohort, and this rate is in line with published rates (Additional file 5: Figure S2C), underscoring the representative nature of our analysis.	('tumor', 'Disease', (52, 57))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('non-silent mutations', 'Var', (27, 47))
281561	26759717	Genomic identification of significant targets in cancer (GISTIC) analysis in the WGS set yielded universal deletions affecting 4p, 11p, 16p, 19p and 19q, and frequent gains of 3q, 5p, 7p, 7q, 8p, 8q, 12p, 14q, 18p, 20q, 21q, Xp and Xq (Additional file 6: Figure S3C).	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('gains', 'PosReg', (167, 172))	('deletions', 'Var', (107, 116))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('cancer', 'Disease', (49, 55))
281562	26759717	In particular, recurrent somatic amplifications at 8q (containing MYC and FAM84B) were found to be enriched in stage I tumors; the deletions of 4p-q (containing VEGFC, FBXW7 and FAT1) and 5q (containing PTTG and MAML1) were particularly identified in stage III tumors (p < 0.05, Fisher's exact test, Fig.	('III tumors', 'Disease', 'MESH:D009369', (257, 267))	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('MYC', 'Gene', (66, 69))	('tumors', 'Phenotype', 'HP:0002664', (261, 267))	('FBXW7', 'Gene', (168, 173))	('I tumors', 'Disease', (117, 125))	('PTTG', 'Gene', (203, 207))	('VEGFC', 'Gene', '7424', (161, 166))	('deletions', 'Var', (131, 140))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (261, 266))	('MYC', 'Gene', '4609', (66, 69))	('4p-q', 'Gene', (144, 148))	('FAT1', 'Gene', (178, 182))	('identified', 'Reg', (237, 247))	('FBXW7', 'Gene', '55294', (168, 173))	('III tumors', 'Disease', (257, 267))	('MAML1', 'Gene', (212, 217))	('FAM84B', 'Gene', (74, 80))	('FAM84B', 'Gene', '157638', (74, 80))	('PTTG', 'Gene', '9232', (203, 207))	('I tumors', 'Disease', 'MESH:D009369', (117, 125))	('FAT1', 'Gene', '2195', (178, 182))	('MAML1', 'Gene', '9794', (212, 217))	('I tumors', 'Disease', 'MESH:D009369', (259, 267))	('VEGFC', 'Gene', (161, 166))
281564	26759717	Thus, although stage I and stage III tumors of ESCC are genomically similar, our results reveal that the copy-number variations exhibit a pattern that is associated with the clinical stage of the tumor.	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('tumor', 'Disease', (196, 201))	('copy-number variations', 'Var', (105, 127))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('III tumors', 'Disease', 'MESH:D009369', (33, 43))	('tumor', 'Disease', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('clinical', 'Species', '191496', (174, 182))	('associated', 'Reg', (154, 164))	('III tumors', 'Disease', (33, 43))
281565	26759717	We also applied a modified GISTIC method to profile genome segments with copy number variations in the 14 tumors analyzed by WGS, which revealed 126 significantly altered regions (Additional file 7: Figure S4).	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('copy number variations', 'Var', (73, 95))	('14 tumors', 'Disease', 'MESH:C567448', (103, 112))	('altered', 'Reg', (163, 170))	('14 tumors', 'Disease', (103, 112))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))
281573	26759717	In addition, we knocked down FAM84B in KYSE150 and TE-1 cells that have high levels of endogenous FAM84B and observed that FAM84B depletion attenuated cell growth, migration and invasion (Fig.	('FAM84B', 'Gene', (123, 129))	('FAM84B', 'Gene', '157638', (98, 104))	('FAM84B', 'Gene', '157638', (123, 129))	('depletion', 'Var', (130, 139))	('FAM84B', 'Gene', (29, 35))	('invasion', 'CPA', (178, 186))	('FAM84B', 'Gene', '157638', (29, 35))	('attenuated', 'NegReg', (140, 150))	('cell growth', 'CPA', (151, 162))	('knocked down', 'Var', (16, 28))	('FAM84B', 'Gene', (98, 104))
281578	26759717	This analysis led to the identification of eight SMGs with q < 0.2 (Additional file 12: Table S6A).	('SMG', 'Gene', '23034', (49, 52))	('q < 0.2', 'Var', (59, 66))	('SMG', 'Gene', (49, 52))
281580	26759717	Of the 104 tumors that we comprehensively characterized, 50 % (52 out of 104 cases) displayed mutations in two or more SMGs, 44 % (46 out of 104 cases) of cases harbored alterations in one SMG, and six cases did not have mutations in any of the SMGs.	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('SMG', 'Gene', (245, 248))	('mutations', 'Var', (94, 103))	('tumors', 'Phenotype', 'HP:0002664', (11, 17))	('SMG', 'Gene', '23034', (245, 248))	('SMG', 'Gene', (119, 122))	('alterations', 'Reg', (170, 181))	('tumors', 'Disease', (11, 17))	('tumors', 'Disease', 'MESH:D009369', (11, 17))	('SMG', 'Gene', '23034', (119, 122))	('SMG', 'Gene', (189, 192))	('SMG', 'Gene', '23034', (189, 192))
281583	26759717	The other four SMGs, each contributing relatively infrequently, were responsible for the remaining 14 % (26 of 184) of the non-silent mutations (Fig.	('non-silent mutations', 'Var', (123, 143))	('SMG', 'Gene', (15, 18))	('SMG', 'Gene', '23034', (15, 18))
281585	26759717	Interestingly, a pronounced diversity of NOTCH1 mutations was observed in 35 % of stage I tumors but in only 8 % of stage III tumors (p < 0.0006, Fisher's test).	('III tumors', 'Disease', (122, 132))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('I tumors', 'Disease', 'MESH:D009369', (124, 132))	('NOTCH1', 'Gene', '4851', (41, 47))	('NOTCH1', 'Gene', (41, 47))	('III tumors', 'Disease', 'MESH:D009369', (122, 132))	('I tumors', 'Disease', (88, 96))	('mutations', 'Var', (48, 57))	('I tumors', 'Disease', 'MESH:D009369', (88, 96))
281587	26759717	NOTCH1 mutations are relatively common in head and neck squamous cell carcinoma (HNSCC), lung SCC and breast cancer, with 5 % to 15 % of tumors harboring protein-coding changes.	('breast cancer', 'Disease', (102, 115))	('tumors', 'Disease', (137, 143))	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('neck squamous cell carcinoma', 'Disease', (51, 79))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (56, 79))	('breast cancer', 'Phenotype', 'HP:0003002', (102, 115))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (51, 79))	('common', 'Reg', (32, 38))	('lung SCC', 'Disease', (89, 97))	('NOTCH1', 'Gene', '4851', (0, 6))	('NOTCH1', 'Gene', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('breast cancer', 'Disease', 'MESH:D001943', (102, 115))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('mutations', 'Var', (7, 16))
281588	26759717	In our cohort, 22 somatic mutations were identified in NOTCH1 with a mutation frequency of 21 % (Additional file 12: Table S6B).	('mutations', 'Var', (26, 35))	('NOTCH1', 'Gene', '4851', (55, 61))	('NOTCH1', 'Gene', (55, 61))
281589	26759717	Notably, we found another six non-silent mutations including four missense and two frameshift indels, with a mutation frequency of 16.7 % in the 36 atypical hyperplasia tissues (Additional file 13: Table S7).	('hyperplasia', 'Disease', 'MESH:D006965', (157, 168))	('missense', 'Var', (66, 74))	('hyperplasia', 'Disease', (157, 168))	('frameshift indels', 'Var', (83, 100))
281590	26759717	Moreover, the nonsense mutations observed in NOTCH1 generate a premature stop codon, resulting in a C-terminally truncated NOTCH1 protein lacking a PEST sequence (a sequence rich in proline, glutamic acid, serine and threonine) that is important for transcription activation.	('threonine', 'Chemical', 'MESH:D013912', (217, 226))	('proline', 'Chemical', 'MESH:D011392', (182, 189))	('NOTCH1', 'Gene', '4851', (123, 129))	('lacking', 'NegReg', (138, 145))	('glutamic acid', 'Chemical', 'MESH:D018698', (191, 204))	('serine', 'Chemical', 'MESH:D012694', (206, 212))	('mutations', 'Var', (23, 32))	('NOTCH1', 'Gene', (123, 129))	('C-terminally truncated', 'MPA', (100, 122))	('NOTCH1', 'Gene', '4851', (45, 51))	('NOTCH1', 'Gene', (45, 51))	('protein', 'Protein', (130, 137))
281591	26759717	In addition, five out of nine mutations identified in NOTCH2/3 were truncating, and two stopgains were identified in RBPJ, one of the target genes of NOTCH.	('RBPJ', 'Gene', (117, 121))	('NOTCH2', 'Gene', '4853', (54, 60))	('RBPJ', 'Gene', '3516', (117, 121))	('truncating', 'MPA', (68, 78))	('mutations', 'Var', (30, 39))	('NOTCH2', 'Gene', (54, 60))
281592	26759717	Thus, in contrast to T-cell acute lymphoblastic leukemia, chronic lymphoblastic leukemia and breast cancer, in which NOTCH1 serves as an oncogene, this pattern of mutations suggest that the NOTCH pathway has a tumor suppressing role in ESCC.	('ESCC', 'Disease', (236, 240))	('NOTCH pathway', 'Pathway', (190, 203))	('leukemia', 'Phenotype', 'HP:0001909', (48, 56))	('breast cancer', 'Phenotype', 'HP:0003002', (93, 106))	('NOTCH1', 'Gene', (117, 123))	('leukemia', 'Phenotype', 'HP:0001909', (80, 88))	('tumor', 'Disease', (210, 215))	('breast cancer', 'Disease', 'MESH:D001943', (93, 106))	('breast cancer', 'Disease', (93, 106))	('NOTCH1', 'Gene', '4851', (117, 123))	('chronic lymphoblastic leukemia', 'Disease', 'MESH:D015451', (58, 88))	('T-cell acute lymphoblastic leukemia', 'Phenotype', 'HP:0006727', (21, 56))	('tumor', 'Disease', 'MESH:D009369', (210, 215))	('chronic lymphoblastic leukemia', 'Phenotype', 'HP:0005550', (58, 88))	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (28, 56))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (34, 56))	('T-cell acute lymphoblastic leukemia', 'Disease', 'MESH:D054218', (21, 56))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (66, 88))	('T-cell acute lymphoblastic leukemia', 'Disease', (21, 56))	('chronic lymphoblastic leukemia', 'Disease', (58, 88))	('mutations', 'Var', (163, 172))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))
281593	26759717	Of related interest, 8 % of ESCC tumors (12 % of stage I tumors and 4 % of stage III tumors) harbored mutations in the F-box protein FBXW7 (Fig.	('FBXW7', 'Gene', (133, 138))	('III tumors', 'Disease', (81, 91))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('I tumors', 'Disease', (55, 63))	('ESCC tumors', 'Disease', (28, 39))	('mutations', 'Var', (102, 111))	('harbored', 'Reg', (93, 101))	('I tumors', 'Disease', 'MESH:D009369', (83, 91))	('I tumors', 'Disease', 'MESH:D009369', (55, 63))	('ESCC tumors', 'Disease', 'MESH:D004938', (28, 39))	('III tumors', 'Disease', 'MESH:D009369', (81, 91))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('FBXW7', 'Gene', '55294', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))
281596	26759717	Moreover, most of the mutations occur within the WD40 domain involved in substrate recognition; mutation of this site prevents the recognition of targets such as NOTCH1 for degradation.	('NOTCH1', 'Gene', '4851', (162, 168))	('NOTCH1', 'Gene', (162, 168))	('mutation', 'Var', (96, 104))	('recognition', 'MPA', (131, 142))	('mutations', 'Var', (22, 31))	('prevents', 'NegReg', (118, 126))
281597	26759717	In particular, mutations occurred in genes associated with pyrimidine metabolism (31 % of stage I tumors versus 13 % of stage III), glycine/serine/threonine metabolism (16 % versus 2 %) and fructose and mannose metabolism (16 % versus 2 %).	('threonine', 'Chemical', 'MESH:D013912', (147, 156))	('serine', 'Chemical', 'MESH:D012694', (140, 146))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('I tumors', 'Disease', (96, 104))	('mutations', 'Var', (15, 24))	('I tumors', 'Disease', 'MESH:D009369', (96, 104))	('glycine', 'Chemical', 'MESH:D005998', (132, 139))	('glycine/serine/threonine metabolism', 'MPA', (132, 167))	('fructose', 'Chemical', 'MESH:D005632', (190, 198))	('pyrimidine', 'Chemical', 'MESH:C030986', (59, 69))	('mannose', 'Chemical', 'MESH:D008358', (203, 210))	('pyrimidine metabolism', 'MPA', (59, 80))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))
281609	26759717	Moreover, genomic characterization of different stages of ESCC tumors led us to identify dysregulated NOTCH1 and NOTCH signaling predominantly in stage I tumors, indicating the involvement of this gene and its pathway in the early development of ESCC.	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('involvement', 'Reg', (177, 188))	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('NOTCH signaling', 'MPA', (113, 128))	('ESCC tumors', 'Disease', (58, 69))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('NOTCH1', 'Gene', '4851', (102, 108))	('ESCC tumors', 'Disease', 'MESH:D004938', (58, 69))	('I tumors', 'Disease', (152, 160))	('NOTCH1', 'Gene', (102, 108))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('I tumors', 'Disease', 'MESH:D009369', (152, 160))	('dysregulated', 'Var', (89, 101))
281610	26759717	Thus, the prevalence of NOTCH1 provides a potential biomarker to detect ESCC in its early stages.	('ESCC', 'Disease', (72, 76))	('prevalence', 'Var', (10, 20))	('NOTCH1', 'Gene', '4851', (24, 30))	('NOTCH1', 'Gene', (24, 30))
281612	26759717	The spectrum of mutations involving the NOTCH pathway in our cohort is consistent with it having a tumor suppressor role in ESCC rather than an oncogenic function.	('tumor', 'Disease', (99, 104))	('mutations', 'Var', (16, 25))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('NOTCH pathway', 'Pathway', (40, 53))	('ESCC', 'Disease', (124, 128))
281623	26759717	At least 65x target depth and 30-fold haploid coverage for tumors and normal samples were achieved in all samples.	('tumors', 'Disease', (59, 65))	('tumors', 'Disease', 'MESH:D009369', (59, 65))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('haploid', 'Var', (38, 45))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
281634	26759717	distance between adjacent somatic SNV distance should be over 10 bp; v. mapping qualities of reads supporting mutant alleles in the tumor should be significantly higher than 30 (Wilcoxon rank sum test, p < 0.2); vi.base qualities of reads supporting mutant alleles in the tumor should be significantly higher than 20 (Wilcoxon rank sum test, p < 0.05); vii.mutations should not be enriched within 5 bp 5' or 3' of read end (Wilcoxon rank sum test, p < 0.1); viii.	('tumor', 'Phenotype', 'HP:0002664', (272, 277))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('tumor', 'Disease', (272, 277))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumor', 'Disease', (132, 137))	('mutant', 'Var', (250, 256))	('tumor', 'Disease', 'MESH:D009369', (272, 277))
281653	26759717	Prevalidated primers for the relevant genes were obtained from Applied Biosystems (accession numbers Hs02758348_Cn for MYC, Hs00655850_Cn for FAM84B, Hs01654625_Cn for VEGFC, Hs05965356_Cn for FBXW7 and Hs00703603_Cn for FAT1).	('FAT1', 'Gene', '2195', (221, 225))	('Hs00703603_Cn', 'Var', (203, 216))	('FBXW7', 'Gene', (193, 198))	('FAT1', 'Gene', (221, 225))	('Hs02758348_Cn', 'Var', (101, 114))	('VEGFC', 'Gene', (168, 173))	('FAM84B', 'Gene', (142, 148))	('Hs05965356_Cn', 'Var', (175, 188))	('Hs00655850_Cn', 'Var', (124, 137))	('MYC', 'Gene', '4609', (119, 122))	('Hs01654625_Cn', 'Var', (150, 163))	('FBXW7', 'Gene', '55294', (193, 198))	('FAM84B', 'Gene', '157638', (142, 148))	('MYC', 'Gene', (119, 122))	('VEGFC', 'Gene', '7424', (168, 173))
281670	26759717	BWA Burrows-Wheeler Aligner ESCC Esophageal squamous cell carcinoma FAM84B Family with sequence similarity 84, member B GISTIC Genomic identification of significant targets in cancer HNSCC Head and neck squamous cell carcinoma IGV Integrative genomics viewer SCNA Somatic copy number alterations SMG Significantly mutated gene SNV Single nucleotide variation TCS Target capture sequencing WES Whole-exome sequencing WGS Whole-genome sequencing	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (203, 226))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (198, 226))	('FAM84B', 'Gene', '157638', (68, 74))	('Single nucleotide variation', 'Var', (331, 358))	('carcinoma', 'Phenotype', 'HP:0030731', (217, 226))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (44, 67))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))	('SMG', 'Gene', (296, 299))	('Esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (33, 67))	('neck squamous cell carcinoma', 'Disease', (198, 226))	('SMG', 'Gene', '23034', (296, 299))	('FAM84B', 'Gene', (68, 74))	('cancer', 'Disease', (176, 182))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('Esophageal squamous cell carcinoma', 'Disease', (33, 67))	('TCS', 'Chemical', '-', (359, 362))
281679	34011067	Kaplan-Meier survival analysis suggested that ESCC patients with high PDGFA expression were associated with poorer overall survival compared to those with low PDGFA expression (P < .05), especially in advanced T stage (P < .05).	('ESCC', 'Disease', (46, 50))	('PDGFA', 'Gene', '5154', (159, 164))	('overall survival', 'MPA', (115, 131))	('poorer', 'NegReg', (108, 114))	('high', 'Var', (65, 69))	('PDGFA', 'Gene', (70, 75))	('expression', 'MPA', (76, 86))	('patients', 'Species', '9606', (51, 59))	('PDGFA', 'Gene', (159, 164))	('PDGFA', 'Gene', '5154', (70, 75))
281680	34011067	Cox analyses showed that high expression of PDGFA was an independent predictor for poor prognosis in ESCC patients.	('PDGFA', 'Gene', (44, 49))	('PDGFA', 'Gene', '5154', (44, 49))	('high', 'Var', (25, 29))	('patients', 'Species', '9606', (106, 114))	('ESCC', 'Disease', (101, 105))
281681	34011067	Gene set enrichment analysis identified 3 signaling pathways (extracellular matrix receptor interaction, focal adhesion, and glycosaminoglycan biosynthesis chondroitin sulfate) that were enriched in PDGFA high expression phenotype (all P < .01).	('glycosaminoglycan', 'Chemical', 'MESH:D006025', (125, 142))	('signaling pathways', 'Pathway', (42, 60))	('PDGFA', 'Gene', (199, 204))	('PDGFA', 'Gene', '5154', (199, 204))	('focal adhesion', 'MPA', (105, 119))	('chondroitin sulfate', 'Chemical', 'MESH:D002809', (156, 175))	('high expression', 'Var', (205, 220))
281694	34011067	In addition, numerous clinical studies indicated that high expression of PDGFs was positively associated with clinicopathological parameters including TNM stage, lymph node metastasis, and depth of invasion.	('lymph node metastasis', 'CPA', (162, 183))	('depth of invasion', 'CPA', (189, 206))	('high', 'Var', (54, 58))	('PDGF', 'Gene', '5154;5155;56034;80310', (73, 77))	('PDGF', 'Gene', (73, 77))	('expression', 'MPA', (59, 69))	('associated', 'Reg', (94, 104))	('TNM stage', 'CPA', (151, 160))
281702	34011067	The difference in PDGFA expression between tumoral and nontumoral tissues was analyzed using GSE53625, GSE23400, and GSE67269.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumoral', 'Disease', (43, 50))	('tumoral', 'Disease', 'MESH:D009369', (43, 50))	('tumoral', 'Disease', (58, 65))	('tumoral', 'Disease', 'MESH:D009369', (58, 65))	('PDGFA', 'Gene', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('GSE23400', 'Var', (103, 111))	('PDGFA', 'Gene', '5154', (18, 23))	('GSE53625', 'Var', (93, 101))
281714	34011067	GSEA was carried out to explore the signaling pathway associated with PDGFA expression in tumoral tissues of GSE53625, GSE23400, and GSE67269 using GSEA 4.1.0.	('GSE53625', 'Var', (109, 117))	('GSEA', 'Chemical', '-', (148, 152))	('GSE23400', 'Var', (119, 127))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('PDGFA', 'Gene', (70, 75))	('tumoral', 'Disease', (90, 97))	('tumoral', 'Disease', 'MESH:D009369', (90, 97))	('GSEA', 'Chemical', '-', (0, 4))	('PDGFA', 'Gene', '5154', (70, 75))
281718	34011067	ESCC patients in GSE53625 were divided into high-PDGFA (n = 89) and low-PDGFA expression (n = 90) groups according to the median expression value of PDGFA, and Kaplan-Meier analysis and log-rank test were used to compare the OS between the 2 groups.	('PDGFA', 'Gene', '5154', (49, 54))	('patients', 'Species', '9606', (5, 13))	('PDGFA', 'Gene', '5154', (149, 154))	('GSE53625', 'Var', (17, 25))	('ESCC', 'Disease', (0, 4))	('PDGFA', 'Gene', (49, 54))	('PDGFA', 'Gene', (72, 77))	('PDGFA', 'Gene', '5154', (72, 77))	('PDGFA', 'Gene', (149, 154))
281722	34011067	In datasets of GSE53625, GSE23400, and GSE67269, it was indicated that PDGFA expression was significantly higher in ESCC samples than in adjacent normal tissues (Fig.	('expression', 'MPA', (77, 87))	('PDGFA', 'Gene', (71, 76))	('GSE53625', 'Var', (15, 23))	('ESCC', 'Disease', (116, 120))	('GSE67269', 'Var', (39, 47))	('PDGFA', 'Gene', '5154', (71, 76))	('higher', 'PosReg', (106, 112))	('GSE23400', 'Var', (25, 33))
281725	34011067	ESCC patients in GSE53625 were divided into high and low groups based on the median expression value of PDGFA in tumoral tissues and the relationship between PDGFA expression and clinicopathological parameters were investigated using chi-square test.	('patients', 'Species', '9606', (5, 13))	('tumoral', 'Disease', (113, 120))	('tumoral', 'Disease', 'MESH:D009369', (113, 120))	('GSE53625', 'Var', (17, 25))	('PDGFA', 'Gene', (158, 163))	('PDGFA', 'Gene', '5154', (158, 163))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('PDGFA', 'Gene', (104, 109))	('PDGFA', 'Gene', '5154', (104, 109))
281729	34011067	The results revealed that ESCC patients with high PDGFA mRNA expression had a poorer OS compared with those with low PDGFA mRNA expression (Fig.	('PDGFA', 'Gene', (50, 55))	('ESCC', 'Disease', (26, 30))	('PDGFA', 'Gene', '5154', (50, 55))	('high', 'Var', (45, 49))	('PDGFA', 'Gene', (117, 122))	('patients', 'Species', '9606', (31, 39))	('PDGFA', 'Gene', '5154', (117, 122))
281731	34011067	Subgroup analysis results suggested that high PDGFA expression was associated with unfavorable OS in patients with advanced T stage (T3 + T4) (Fig.	('patients', 'Species', '9606', (101, 109))	('high', 'Var', (41, 45))	('unfavorable', 'Disease', (83, 94))	('expression', 'MPA', (52, 62))	('associated', 'Reg', (67, 77))	('PDGFA', 'Gene', (46, 51))	('PDGFA', 'Gene', '5154', (46, 51))
281738	34011067	To investigate the signaling pathways associated with PDGFA, GSEA was performed between high and low PDGFA expression datasets based on GSE53625, GSE23400, and GSE67269.	('PDGFA', 'Gene', '5154', (101, 106))	('GSE67269', 'Var', (160, 168))	('PDGFA', 'Gene', (54, 59))	('PDGFA', 'Gene', '5154', (54, 59))	('GSE53625', 'Var', (136, 144))	('GSEA', 'Chemical', '-', (61, 65))	('GSE23400', 'Var', (146, 154))	('PDGFA', 'Gene', (101, 106))
281739	34011067	The results demonstrated that 3 signaling pathways were significantly enriched in PDGFA high expression phenotype, including extracellular matrix (ECM) receptor interaction, focal adhesion, and glycosaminoglycan biosynthesis chondroitin sulfate, which were shared by GSE53625, GSE23400, and GSE67269 (Fig.	('PDGFA', 'Gene', (82, 87))	('GSE53625', 'Var', (267, 275))	('PDGFA', 'Gene', '5154', (82, 87))	('glycosaminoglycan', 'Chemical', 'MESH:D006025', (194, 211))	('GSE67269', 'Var', (291, 299))	('GSE23400', 'Var', (277, 285))	('chondroitin sulfate', 'Chemical', 'MESH:D002809', (225, 244))	('signaling pathways', 'Pathway', (32, 50))	('focal adhesion', 'MPA', (174, 188))	('glycosaminoglycan', 'MPA', (194, 211))
281763	34011067	Additionally, Kaplan-Meier analysis showed that high PDGFA expression was associated with unfavorable prognosis ESCC patients, especially in advanced T stage.	('PDGFA', 'Gene', (53, 58))	('PDGFA', 'Gene', '5154', (53, 58))	('ESCC', 'Disease', (112, 116))	('expression', 'MPA', (59, 69))	('patients', 'Species', '9606', (117, 125))	('high', 'Var', (48, 52))
281764	34011067	Subsequent Cox regression analysis indicated that high PDGFA expression was an independent factor to predict unfavorable prognosis, which coincided with the results from a few clinical studies about other kinds of tumors, such as osteosarcoma, nephroblastoma, cholangiocarcinoma, gastric cancer, oral squamous cell carcinoma, and neuroblastoma.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (260, 278))	('gastric cancer', 'Disease', 'MESH:D013274', (280, 294))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (301, 324))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('tumors', 'Disease', (214, 220))	('nephroblastoma', 'Phenotype', 'HP:0002667', (244, 258))	('cancer', 'Phenotype', 'HP:0002664', (288, 294))	('osteosarcoma', 'Phenotype', 'HP:0002669', (230, 242))	('gastric cancer', 'Phenotype', 'HP:0012126', (280, 294))	('tumors', 'Disease', 'MESH:D009369', (214, 220))	('PDGFA', 'Gene', '5154', (55, 60))	('carcinoma', 'Phenotype', 'HP:0030731', (269, 278))	('carcinoma', 'Phenotype', 'HP:0030731', (315, 324))	('high', 'Var', (50, 54))	('neuroblastoma', 'Disease', (330, 343))	('nephroblastoma', 'Disease', 'MESH:D009396', (244, 258))	('osteosarcoma', 'Disease', (230, 242))	('osteosarcoma', 'Disease', 'MESH:D012516', (230, 242))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (296, 324))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (260, 278))	('neuroblastoma', 'Phenotype', 'HP:0003006', (330, 343))	('gastric cancer', 'Disease', (280, 294))	('nephroblastoma', 'Disease', (244, 258))	('oral squamous cell carcinoma', 'Disease', (296, 324))	('tumors', 'Phenotype', 'HP:0002664', (214, 220))	('PDGFA', 'Gene', (55, 60))	('neuroblastoma', 'Disease', 'MESH:D009447', (330, 343))	('cholangiocarcinoma', 'Disease', (260, 278))
281770	34011067	The results of GSEA showed that "ECM receptor interaction," "focal adhesion," and "glycosaminoglycan biosynthesis chondroitin sulfate" were significantly enriched in PDGFA high expression phenotype.	('PDGFA', 'Gene', '5154', (166, 171))	('glycosaminoglycan', 'Chemical', 'MESH:D006025', (83, 100))	('glycosaminoglycan biosynthesis chondroitin sulfate', 'MPA', (83, 133))	('GSEA', 'Chemical', '-', (15, 19))	('chondroitin sulfate', 'Chemical', 'MESH:D002809', (114, 133))	('high expression', 'Var', (172, 187))	('PDGFA', 'Gene', (166, 171))	('focal adhesion', 'CPA', (61, 75))
281796	31440059	Previous studies have identified the correlation between aberrant expressed genes and human cancers, and revealed promise of these genes as biomarkers in predicting patients' survival.	('cancers', 'Phenotype', 'HP:0002664', (92, 99))	('human', 'Species', '9606', (86, 91))	('cancers', 'Disease', 'MESH:D009369', (92, 99))	('aberrant expressed genes', 'Var', (57, 81))	('cancers', 'Disease', (92, 99))	('patients', 'Species', '9606', (165, 173))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
281797	31440059	Overexpressed HUWE1 was found to be associated with poor patient outcome.	('HUWE1', 'Gene', '10075', (14, 19))	('Overexpressed', 'Var', (0, 13))	('patient', 'Species', '9606', (57, 64))	('HUWE1', 'Gene', (14, 19))
281799	31440059	These studies demonstrate that changes in single gene expression and in RNA expression are meaningful for predicting the prognosis of lung cancer.	('lung cancer', 'Disease', (134, 145))	('lung cancer', 'Phenotype', 'HP:0100526', (134, 145))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('lung cancer', 'Disease', 'MESH:D008175', (134, 145))	('RNA expression', 'MPA', (72, 86))	('changes', 'Var', (31, 38))
281826	31440059	Many studies have found that changes in gene expression affect prognosis, and there are reports that combine this analysis to predict prognosis of lung adenocarcinoma, kidney cancer, and pancreatic cancer.	('affect', 'Reg', (56, 62))	('changes', 'Var', (29, 36))	('prognosis', 'MPA', (63, 72))	('kidney cancer', 'Disease', 'MESH:D007680', (168, 181))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (187, 204))	('kidney cancer', 'Phenotype', 'HP:0009726', (168, 181))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (147, 166))	('kidney cancer', 'Disease', (168, 181))	('pancreatic cancer', 'Disease', (187, 204))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('carcinoma', 'Phenotype', 'HP:0030731', (157, 166))	('pancreatic cancer', 'Disease', 'MESH:D010190', (187, 204))	('lung adenocarcinoma', 'Disease', (147, 166))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (147, 166))
281832	31440059	A meta-analysis reported that the rs13275170 locus of DEFA6 increased 1.3-fold in gastric cancer, suggesting that DEFA6 is associated with tumorgenesis.	('DEFA6', 'Gene', '1671', (54, 59))	('associated', 'Reg', (123, 133))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('gastric cancer', 'Phenotype', 'HP:0012126', (82, 96))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('gastric cancer', 'Disease', 'MESH:D013274', (82, 96))	('gastric cancer', 'Disease', (82, 96))	('DEFA6', 'Gene', (114, 119))	('rs13275170', 'Var', (34, 44))	('rs13275170', 'Mutation', 'rs13275170', (34, 44))	('DEFA6', 'Gene', '1671', (114, 119))	('DEFA6', 'Gene', (54, 59))	('increased', 'PosReg', (60, 69))
281838	31440059	The high expression of CLEC18B can activate the activity of Wnt/beta-catenin signaling pathway.	('CLEC18B', 'Gene', (23, 30))	('activity', 'MPA', (48, 56))	('activate', 'PosReg', (35, 43))	('high expression', 'Var', (4, 19))	('beta-catenin', 'Gene', (64, 76))	('CLEC18B', 'Gene', '497190', (23, 30))	('beta-catenin', 'Gene', '1499', (64, 76))
281853	28202209	Low body mass index, ever smoker, more advanced stage, squamous cell or small cell carcinoma and high serum carcinoembryonic antigen level at study entry were crudely associated with an increased risk of all-cause mortality after adjustment for age.	('small cell carcinoma', 'Disease', (72, 92))	('Low', 'Var', (0, 3))	('high serum carcinoembryonic antigen level', 'Phenotype', 'HP:0031029', (97, 138))	('small cell carcinoma', 'Disease', 'MESH:D018288', (72, 92))	('Low body mass index', 'Phenotype', 'HP:0045082', (0, 19))	('small cell carcinoma', 'Phenotype', 'HP:0030357', (72, 92))	('high serum carcinoembryonic antigen level', 'MPA', (97, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))	('associated', 'Reg', (167, 177))	('Low body mass', 'Phenotype', 'HP:0004325', (0, 13))	('squamous cell', 'Disease', (55, 68))
281946	28202209	In addition to cancer stage and histological type, we observed that ever smoker, low body mass index, and elevated serum CEA level were also crudely associated with poorer prognosis after adjustment for age and study entry year.	('CEA', 'Gene', (121, 124))	('low', 'Var', (81, 84))	('cancer', 'Disease', (15, 21))	('CEA', 'Gene', '1084', (121, 124))	('cancer', 'Disease', 'MESH:D009369', (15, 21))	('elevated serum CEA', 'Phenotype', 'HP:0031029', (106, 124))	('low body mass', 'Phenotype', 'HP:0004325', (81, 94))	('elevated', 'PosReg', (106, 114))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))
281973	31796020	Our paper contributes to these diagnostic investigations by studying the classification capabilities of protein coding and non-coding RNAs from lung cancer.	('lung cancer', 'Disease', (144, 155))	('lung cancer', 'Phenotype', 'HP:0100526', (144, 155))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('lung cancer', 'Disease', 'MESH:D008175', (144, 155))	('non-coding', 'Var', (123, 133))
282013	31796020	The differences are not large but sufficient to demonstrate that the predictive abilities of non-coding RNAs are at least as good as for coding RNAs for the diagnostics of lung adenocarcinoma.	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (172, 191))	('non-coding', 'Var', (93, 103))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (172, 191))	('carcinoma', 'Phenotype', 'HP:0030731', (182, 191))	('lung adenocarcinoma', 'Disease', (172, 191))
282015	31796020	From analyzing the classification of lung adenocarcinoma patients by using a number of different state-of-the-art classification methods, we found that data from non-coding RNAs have a comparable classification performance as data from coding RNAs, whereas for DBN we found an even better performance.	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (37, 56))	('non-coding RNAs', 'Var', (162, 177))	('patients', 'Species', '9606', (57, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (47, 56))	('lung adenocarcinoma', 'Disease', (37, 56))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (37, 56))
282053	30314454	It has further been demonstrated that that high expression of vimentin and FN is associated with advanced stage and poor prognosis in ESCC.	('FN', 'Gene', '2335', (75, 77))	('high', 'Var', (43, 47))	('vimentin', 'Gene', (62, 70))	('ESCC', 'Disease', (134, 138))	('associated', 'Reg', (81, 91))	('vimentin', 'Gene', '7431', (62, 70))
282130	27869826	Pan-cancer analysis of somatic copy number alterations implicates IRS4 and IGF2 in enhancer hijacking Extensive prior research has focused on somatic copy-number alterations (SCNAs) affecting cancer genes, yet the extent to which recurrent SCNAs exert their influence through rearranging cis-regulatory elements remains unclear.	('Pan-cancer', 'Disease', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('IGF2', 'Gene', '3481', (75, 79))	('IRS4', 'Gene', '8471', (66, 70))	('Pan-cancer', 'Disease', 'MESH:C537931', (0, 10))	('IRS4', 'Gene', (66, 70))	('cancer', 'Disease', (192, 198))	('cancer', 'Disease', 'MESH:D009369', (192, 198))	('alterations', 'Var', (43, 54))	('cancer', 'Disease', 'MESH:D009369', (4, 10))	('recurrent SCNAs', 'Phenotype', 'HP:0100776', (230, 245))	('IGF2', 'Gene', (75, 79))	('cancer', 'Disease', (4, 10))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))
282133	27869826	We demonstrate that IRS4 overexpression in lung cancer associates with recurrent deletions in cis, and present evidence supporting a tumor-promoting role.	('lung cancer', 'Disease', (43, 54))	('cis', 'Gene', (94, 97))	('deletions', 'Var', (81, 90))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('IRS4', 'Gene', (20, 24))	('lung cancer', 'Phenotype', 'HP:0100526', (43, 54))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumor', 'Disease', (133, 138))	('lung cancer', 'Disease', 'MESH:D008175', (43, 54))	('overexpression', 'PosReg', (25, 39))
282135	27869826	IGF2-containing tandem duplications result in the de novo formation of a 3D contact domain comprising IGF2 and a lineage-specific super-enhancer, which mediates high-level gene activation.	('tandem duplications', 'Var', (16, 35))	('IGF2', 'Gene', '3481', (102, 106))	('result in', 'Reg', (36, 45))	('IGF2', 'Gene', '3481', (0, 4))	('IGF2', 'Gene', (102, 106))	('IGF2', 'Gene', (0, 4))
282137	27869826	Several recent studies have uncovered somatic point mutations modulating gene regulation in cancer cells, including those affecting CREs near TERT, PAX5 and TAL1.	('TAL1', 'Gene', (157, 161))	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('TERT', 'Gene', '7015', (142, 146))	('TAL1', 'Gene', '6886', (157, 161))	('modulating', 'Reg', (62, 72))	('gene regulation', 'MPA', (73, 88))	('TERT', 'Gene', (142, 146))	('PAX5', 'Gene', (148, 152))	('PAX5', 'Gene', '5079', (148, 152))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('point mutations', 'Var', (46, 61))
282154	27869826	A relatively high expression fold change when measured at the pan-cancer level (>25-fold) was observed for clustered deletions associated with upregulation of the insulin receptor substrate 4 (IRS4) gene.	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('upregulation', 'PosReg', (143, 155))	('expression', 'MPA', (18, 28))	('insulin receptor substrate 4', 'Gene', '8471', (163, 191))	('IRS4', 'Gene', (193, 197))	('deletions', 'Var', (117, 126))	('cancer', 'Disease', (66, 72))	('insulin receptor substrate 4', 'Gene', (163, 191))
282162	27869826	Both losses and gains contributed to overexpression, with deletions in cis occasionally resulting in even higher fold-changes than high-level (copy-number >=4) TERT amplicons (Fig.	('fold-changes', 'MPA', (113, 125))	('TERT', 'Gene', '7015', (160, 164))	('resulting', 'Reg', (88, 97))	('overexpression', 'MPA', (37, 51))	('gains', 'PosReg', (16, 21))	('cis', 'Gene', (71, 74))	('higher', 'PosReg', (106, 112))	('deletions', 'Var', (58, 67))	('TERT', 'Gene', (160, 164))
282168	27869826	IRS4 overexpression has been shown to enhance insulin-like growth factor-1 (IGF1) induced cell proliferation in the 3T3 cell line48 and to mediate proliferation and cell migration in hepatoblastoma cells.	('cell migration', 'CPA', (165, 179))	('hepatoblastoma', 'Disease', 'MESH:D018197', (183, 197))	('IRS4', 'Gene', (0, 4))	('3T3', 'CellLine', 'CVCL:0594', (116, 119))	('enhance', 'PosReg', (38, 45))	('hepatoblastoma', 'Phenotype', 'HP:0002884', (183, 197))	('cell proliferation', 'CPA', (90, 108))	('hepatoblastoma', 'Disease', (183, 197))	('IGF1', 'Gene', '16000', (76, 80))	('insulin-like growth factor-1', 'Gene', '16000', (46, 74))	('insulin-like growth factor-1', 'Gene', (46, 74))	('overexpression', 'Var', (5, 19))	('proliferation', 'CPA', (147, 160))	('IGF1', 'Gene', (76, 80))	('mediate', 'Reg', (139, 146))
282171	27869826	We focused our analysis on LUSC, where CESAM identified a set of recurrent deletions (N=20) clustering 103kb downstream of IRS4 within a region demarcated by chrX: 107,549,609-107,872,288 (hg19) (Fig.	('IRS4', 'Gene', (123, 127))	('deletions', 'Var', (75, 84))	('CESAM', 'Chemical', '-', (39, 44))
282172	27869826	IRS4 expression was increased by on average 400-fold when comparing LUSC deletion carriers to non-carrier control LUSC samples, and 25-fold when specifically comparing pan-cancer deletion carriers to pan-cancer non-carrier controls, whereas other genes in cis, by comparison, exhibited only modest expression alteration (Fig.	('increased', 'PosReg', (20, 29))	('cancer', 'Disease', (204, 210))	('expression', 'MPA', (5, 15))	('cancer', 'Disease', 'MESH:D009369', (204, 210))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('IRS4', 'Gene', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('deletion', 'Var', (179, 187))	('cancer', 'Disease', (172, 178))	('deletion', 'Var', (73, 81))
282175	27869826	In sarcomas, and to a lesser extent cervical squamous carcinoma, CESAM identified recurrent deletions at the exact same genomic interval in association with IRS4 overexpression (Supplementary Figs.	('sarcomas', 'Disease', 'MESH:D012509', (3, 11))	('sarcoma', 'Phenotype', 'HP:0100242', (3, 10))	('sarcomas', 'Phenotype', 'HP:0100242', (3, 11))	('carcinoma', 'Phenotype', 'HP:0030731', (54, 63))	('cervical squamous carcinoma', 'Disease', (36, 63))	('sarcomas', 'Disease', (3, 11))	('association', 'Reg', (140, 151))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (45, 63))	('cervical squamous carcinoma', 'Disease', 'MESH:D002294', (36, 63))	('overexpression', 'PosReg', (162, 176))	('CESAM', 'Chemical', '-', (65, 70))	('deletions', 'Var', (92, 101))
282181	27869826	Additionally, we observed a significant co-occurrence of deletions in cis of IRS4 and amplifications of the FGFR1 cancer census gene on chromosome 8 (Pearson's chi-square test, X2=7.6; P=0.006, Supplementary Fig.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('deletions', 'Var', (57, 66))	('FGFR1', 'Gene', '2260', (108, 113))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('FGFR1', 'Gene', (108, 113))	('IRS4', 'Gene', (77, 81))	('cancer', 'Disease', (114, 120))
282185	27869826	We observed palpable tumor formation in mice receiving transgenic IRS4 overexpression plasmids as well as the empty control, albeit with a significantly increased tumor growth in tumors harboring the IRS4 overexpression plasmids in both experimental replicates (P=0.046 and P=0.03, respectively; two-tailed t-test; Supplementary Fig.	('transgenic', 'Var', (55, 65))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('tumor', 'Disease', (21, 26))	('tumors', 'Disease', (179, 185))	('tumors', 'Phenotype', 'HP:0002664', (179, 185))	('increased', 'PosReg', (153, 162))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('IRS4', 'Gene', (66, 70))	('tumors', 'Disease', 'MESH:D009369', (179, 185))	('tumor', 'Disease', (163, 168))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('mice', 'Species', '10090', (40, 44))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('plasmids', 'Var', (86, 94))	('tumor', 'Disease', (179, 184))
282188	27869826	In addition, an H3K27ac peak at the bidirectional promoter of two nearby genes, COL4A5 and COL4A6 encoding collagen type IV subunits, showed significant loss of signal consistent with deletion of these genes' promoter.	('deletion', 'Var', (184, 192))	('loss', 'NegReg', (153, 157))	('COL4A5', 'Gene', '1287', (80, 86))	('signal', 'MPA', (161, 167))	('COL4A6', 'Gene', '1288', (91, 97))	('H3K27ac', 'Var', (16, 23))	('COL4A6', 'Gene', (91, 97))	('COL4A5', 'Gene', (80, 86))
282200	27869826	Amongst the CRC samples exhibiting IGF2 dysregulation, 20 harbored gains and two harbored focal deletions in cis (Fig.	('dysregulation', 'Var', (40, 53))	('IGF2', 'Gene', (35, 39))	('gains', 'PosReg', (67, 72))	('deletions', 'Var', (96, 105))	('IGF2', 'Gene', '3481', (35, 39))
282204	27869826	These data indicate that the recurrent gain at the IGF2 locus results from single-copy tandem duplications.	('gain', 'PosReg', (39, 43))	('single-copy tandem duplications', 'Var', (75, 106))	('IGF2', 'Gene', '3481', (51, 55))	('IGF2', 'Gene', (51, 55))
282208	27869826	Interestingly, the IGF2 locus tandem duplications extend over the intervening TAD boundary and also encompass this super-enhancer (Fig.	('IGF2', 'Gene', '3481', (19, 23))	('tandem duplications', 'Var', (30, 49))	('IGF2', 'Gene', (19, 23))
282209	27869826	We hence used 4C-Seq to investigate whether IGF2 dysregulation could be driven by topological or contact domain reorganization.	('dysregulation', 'Var', (49, 62))	('IGF2', 'Gene', (44, 48))	('IGF2', 'Gene', '3481', (44, 48))
282213	27869826	Indeed, the tandem duplications are inferred to result in copies of IGF2 and the super-enhancer being positioned in a head-to-tail orientation, with both now being able to contact each other via chromatin looping (see our model in Fig.	('tandem duplications', 'Var', (12, 31))	('IGF2', 'Gene', '3481', (68, 72))	('contact', 'Interaction', (172, 179))	('result', 'Reg', (48, 54))	('IGF2', 'Gene', (68, 72))
282215	27869826	Lastly, we also identified three larger somatic duplications of IGF2 in the TCGA data, which based on their size and location with respect to TAD boundaries are inferred to not lead to the formation of a 3D contact domain comprising IGF2 and this super-enhancer (Supplementary Fig.	('lead to', 'Reg', (177, 184))	('3D contact domain', 'MPA', (204, 221))	('IGF2', 'Gene', '3481', (64, 68))	('IGF2', 'Gene', (64, 68))	('IGF2', 'Gene', '3481', (233, 237))	('duplications', 'Var', (48, 60))	('IGF2', 'Gene', (233, 237))
282216	27869826	Notably, none of these three IGF2 duplication carriers exhibited appreciable levels of IGF2 overexpression (exhibiting significantly lower IGF2 expression compared to tandem duplications with the potential to lead to 3D contact domain formation; P=0.01; Wilcoxon rank-sum test), lending additional support to our new model.	('IGF2', 'Gene', '3481', (29, 33))	('IGF2', 'Gene', (87, 91))	('3D contact domain formation', 'MPA', (217, 244))	('expression', 'MPA', (144, 154))	('duplication', 'Var', (34, 45))	('IGF2', 'Gene', (139, 143))	('IGF2', 'Gene', (29, 33))	('IGF2', 'Gene', '3481', (87, 91))	('lower', 'NegReg', (133, 138))	('IGF2', 'Gene', '3481', (139, 143))
282221	27869826	Our data collectively suggest that activation of cancer genes by juxtaposition of CREs is a fairly common process, which may be comparable to the number of recurrent in-frame gene fusions leading to 3' target overexpression in cancer (e.g.	('juxtaposition', 'Var', (65, 78))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('overexpression', 'PosReg', (209, 223))	('cancer', 'Disease', 'MESH:D009369', (227, 233))	('cancer', 'Disease', (227, 233))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('cancer', 'Disease', (49, 55))	('activation', 'PosReg', (35, 45))
282225	27869826	Our data are compatible with disruptions of CTCF insulators at TAD boundaries through recurring deletions, the consequence of which appears to be the spreading of active chromatin marks in the context of IRS4 (see our model depicted in Supplementary Fig.	('CTCF', 'Gene', '10664', (44, 48))	('CTCF', 'Gene', (44, 48))	('deletions', 'Var', (96, 105))	('active', 'MPA', (163, 169))
282226	27869826	Consistent with our findings, CRISPR-mediated deletion of a CTCF insulator region at the Hox gene cluster has recently been shown to lead to spreading of active chromatin to neighbouring gene regions in embryonic stem cells.	('deletion', 'Var', (46, 54))	('CTCF', 'Gene', '10664', (60, 64))	('lead to', 'Reg', (133, 140))	('CTCF', 'Gene', (60, 64))	('spreading of active chromatin', 'MPA', (141, 170))
282228	27869826	This involves a previously undescribed mechanism, whereby tandem duplication-mediated de novo formation of a contact domain accompanying a super-enhancer normally inaccessible to IGF2 results in >250-fold gene upregulation.	('gene', 'MPA', (205, 209))	('IGF2', 'Gene', '3481', (179, 183))	('tandem duplication-mediated', 'Var', (58, 85))	('upregulation', 'PosReg', (210, 222))	('IGF2', 'Gene', (179, 183))
282291	27869826	The third most significant differential peak, which again exhibited more H3K27ac in SCNA carriers, localized ~20kb upstream of VSIG1.	('more', 'PosReg', (68, 72))	('VSIG1', 'Gene', (127, 132))	('VSIG1', 'Gene', '340547', (127, 132))	('H3K27ac', 'Var', (73, 80))
282292	27869826	However, as opposed to IRS4, VSIG1 is barely expressed and its expression showed only slight increases in deletion-carriers (2.7-fold for VSIG1, vs. 400-fold for IRS4; see Fig.	('VSIG1', 'Gene', '340547', (138, 143))	('VSIG1', 'Gene', (138, 143))	('expression', 'MPA', (63, 73))	('increases', 'PosReg', (93, 102))	('VSIG1', 'Gene', '340547', (29, 34))	('VSIG1', 'Gene', (29, 34))	('deletion-carriers', 'Var', (106, 123))
282294	27869826	The fourth peak localizing at the bidirectional promoter of the COL4A5/COL4A6 showed significantly less H3K27ac signal in deletion-carriers in line with promoter deletion in SCNA carriers and with the lower expression of COL4A5 and COL4A6 in LUSC deletion-carriers (Fig.	('COL4A5', 'Gene', (221, 227))	('COL4A6', 'Gene', '1288', (232, 238))	('COL4A6', 'Gene', '1288', (71, 77))	('COL4A6', 'Gene', (232, 238))	('COL4A6', 'Gene', (71, 77))	('COL4A5', 'Gene', '1287', (221, 227))	('less', 'NegReg', (99, 103))	('COL4A5', 'Gene', (64, 70))	('deletion-carriers', 'Var', (122, 139))	('H3K27ac', 'Protein', (104, 111))	('COL4A5', 'Gene', '1287', (64, 70))
282295	27869826	Differential H3K27ac occupancy analysis for CRC samples showing IGF2 tandem duplication versus non-carrier controls did not reveal a single peak with differential H3K27ac signal on chromosome 11 when controlling the FDR at 5%.	('tandem duplication', 'Var', (69, 87))	('H3K27ac', 'Var', (163, 170))	('IGF2', 'Gene', (64, 68))	('IGF2', 'Gene', '3481', (64, 68))
282297	27869826	5a) as differentially marked with H3K27ac on chromosome 11 (which is consistent with the massive activation of IGF2 as a consequence of recurrent locus rearrangements).	('H3K27ac', 'Var', (34, 41))	('IGF2', 'Gene', '3481', (111, 115))	('IGF2', 'Gene', (111, 115))
282401	30996564	SCC and CYFRA21-1 are generally considered to be highly specific for lung squamous cell carcinoma.	('SCC', 'Gene', (0, 3))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (69, 97))	('SCC', 'Gene', '6317', (0, 3))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (74, 97))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (69, 97))	('lung squamous cell carcinoma', 'Disease', (69, 97))	('CYFRA21-1', 'Var', (8, 17))
282564	30996564	It is recommended that epidermal growth factor receptor (EGFR) mutation should be examined for II-IIIa non-squmous-cell lung cancer with positive N1/N2 and small specimen squamous-cell lung cancer patients.	('epidermal growth factor receptor', 'Gene', (23, 55))	('lung cancer', 'Disease', 'MESH:D008175', (185, 196))	('patients', 'Species', '9606', (197, 205))	('lung cancer', 'Disease', (120, 131))	('epidermal growth factor receptor', 'Gene', '1956', (23, 55))	('lung cancer', 'Phenotype', 'HP:0100526', (120, 131))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('squamous-cell lung cancer', 'Disease', (171, 196))	('mutation', 'Var', (63, 71))	('EGFR', 'Gene', '1956', (57, 61))	('lung cancer', 'Phenotype', 'HP:0100526', (185, 196))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('squamous-cell lung cancer', 'Disease', 'MESH:D002294', (171, 196))	('lung cancer', 'Disease', 'MESH:D008175', (120, 131))	('EGFR', 'Gene', (57, 61))
282567	30996564	The detection of EGFR mutation can adopt ARMS method.	('mutation', 'Var', (22, 30))	('EGFR', 'Gene', '1956', (17, 21))	('EGFR', 'Gene', (17, 21))
282572	30996564	Detection of EGFR T790M was recommended in patients with EGFR TKIs resistance.	('patients', 'Species', '9606', (43, 51))	('T790M', 'Mutation', 'rs121434569', (18, 23))	('EGFR', 'Gene', '1956', (57, 61))	('EGFR', 'Gene', '1956', (13, 17))	('EGFR', 'Gene', (57, 61))	('EGFR', 'Gene', (13, 17))	('T790M', 'Var', (18, 23))
282573	30996564	Histological examination was the gold standard, if tissues cannot be offered, detection of ctDNA, EGFR, T790M of blood can be the effective supplement.	('EGFR', 'Gene', (98, 102))	('T790M', 'Var', (104, 109))	('T790M', 'Mutation', 'rs121434569', (104, 109))	('EGFR', 'Gene', '1956', (98, 102))
282677	30996564	The key to lobectomy is to dissect the fissures between the lobes, ligate the branches of pulmonary arteries and pulmonary veins of the lobe, and cut off all these blood vessels and the bronchus of the lobe, so as to removed the lobe.	('cut off', 'NegReg', (146, 153))	('ligate', 'Var', (67, 73))	('removed', 'Reg', (217, 224))	('pulmonary veins of the lobe', 'Disease', (113, 140))	('pulmonary veins of the lobe', 'Disease', 'MESH:D000071078', (113, 140))
282692	30996564	By the postoperative adhesions on the surface of the lung, the volume of air leakage reduced gradually in most of the patients.	('adhesions', 'Var', (21, 30))	('reduced', 'NegReg', (85, 92))	('patients', 'Species', '9606', (118, 126))	('volume of air leakage', 'MPA', (63, 84))
282738	30996564	PCI can also reduce the risk of brain metastasis in extensive stage SCLC when chemotherapy is effective.	('PCI', 'Var', (0, 3))	('extensive', 'Disease', (52, 61))	('reduce', 'NegReg', (13, 19))	('brain metastasis', 'CPA', (32, 48))	('SCLC', 'Gene', (68, 72))	('SCLC', 'Gene', '7864', (68, 72))
282750	30996564	Patients with EGFR mutation (including exon 19 deletion, exon 21L858R and L861Q, exon 18 G719X, and exon 20 S768I) can receive epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), including gefitinib, erlotinib, icotinib or alfatinib.	('L861Q', 'Mutation', 'rs121913444', (74, 79))	('epidermal growth factor receptor', 'Gene', (127, 159))	('EGFR', 'Gene', '1956', (14, 18))	('EGFR', 'Gene', (14, 18))	('S768I', 'Mutation', 'rs121913465', (108, 113))	('EGFR', 'Gene', '1956', (187, 191))	('G719X', 'Mutation', 'p.G719X', (89, 94))	('icotinib', 'Chemical', 'MESH:C531470', (230, 238))	('G719X', 'Var', (89, 94))	('alfatinib', 'Chemical', '-', (242, 251))	('EGFR', 'Gene', (187, 191))	('epidermal growth factor receptor', 'Gene', '1956', (127, 159))	('L861Q', 'Var', (74, 79))	('gefitinib', 'Chemical', 'MESH:D000077156', (208, 217))	('exon 21L858R', 'Var', (57, 69))	('Patients', 'Species', '9606', (0, 8))	('erlotinib', 'Chemical', 'MESH:D000069347', (219, 228))	('S768I', 'Var', (108, 113))
282751	30996564	Patients with ALK or ROS1 fusion genes positive can receive crizotinib.	('positive', 'Reg', (39, 47))	('fusion genes', 'Var', (26, 38))	('ALK', 'Gene', '238', (14, 17))	('ROS1', 'Gene', (21, 25))	('crizotinib', 'Chemical', 'MESH:D000077547', (60, 70))	('ROS1', 'Gene', '6098', (21, 25))	('Patients', 'Species', '9606', (0, 8))	('ALK', 'Gene', (14, 17))
282754	30996564	EGFR-TKI can be selected for maintenance therapy in patients with sensitive EGFR gene mutation.	('EGFR', 'Gene', (0, 4))	('EGFR', 'Gene', '1956', (76, 80))	('EGFR', 'Gene', (76, 80))	('mutation', 'Var', (86, 94))	('EGFR', 'Gene', '1956', (0, 4))	('patients', 'Species', '9606', (52, 60))
282756	30996564	In patients with positive mutations in lung cancer-driving genes, if no corresponding molecular targeting drugs are used for first-line and maintenance therapy, molecular targeting drugs should be given priority in second-line treatment.	('lung cancer', 'Phenotype', 'HP:0100526', (39, 50))	('lung cancer', 'Disease', (39, 50))	('mutations', 'Var', (26, 35))	('lung cancer', 'Disease', 'MESH:D008175', (39, 50))	('patients', 'Species', '9606', (3, 11))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
282757	30996564	In patients with first-line EGFR-TKIs resistance and haboring EGFR T790M mutation, Osimertinib should be given priority in second-line treatment.	('EGFR', 'Gene', '1956', (28, 32))	('EGFR', 'Gene', '1956', (62, 66))	('T790M', 'Mutation', 'rs121434569', (67, 72))	('EGFR', 'Gene', (28, 32))	('T790M', 'Var', (67, 72))	('EGFR', 'Gene', (62, 66))	('patients', 'Species', '9606', (3, 11))	('Osimertinib', 'Chemical', 'MESH:C000603933', (83, 94))
282758	30996564	For AlK mutation patients who develop drug resistance after first-line crizotinib, seretinib can be used sequentially during second-line treatment.	('drug resistance', 'Phenotype', 'HP:0020174', (38, 53))	('crizotinib', 'Chemical', 'MESH:D000077547', (71, 81))	('AlK', 'Gene', (4, 7))	('drug resistance', 'MPA', (38, 53))	('patients', 'Species', '9606', (17, 25))	('mutation', 'Var', (8, 16))	('AlK', 'Gene', '238', (4, 7))	('seretinib', 'Chemical', '-', (83, 92))	('develop', 'Reg', (30, 37))
282783	30996564	(1) Lung cancer patients with KPS <60 or ECOG >2 are not suitable for chemotherapy.	('EC', 'Chemical', '-', (41, 43))	('patients', 'Species', '9606', (16, 24))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('Lung cancer', 'Phenotype', 'HP:0100526', (4, 15))	('Lung cancer', 'Disease', (4, 15))	('KPS <60', 'Var', (30, 37))	('Lung cancer', 'Disease', 'MESH:D008175', (4, 15))	('ECOG', 'Var', (41, 45))
282784	30996564	(2) Lung cancer patients with leukocytes less than 3.0x109/L, neutrophils less than 1.5x109/L, platelets less than 6x1010/L, red blood cells less than 2x1012/L, and hemoglobin lower than 80 g/L should not be treated with chemotherapy in principle.	('patients', 'Species', '9606', (16, 24))	('less', 'Var', (41, 45))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('Lung cancer', 'Phenotype', 'HP:0100526', (4, 15))	('Lung cancer', 'Disease', (4, 15))	('less than', 'Var', (74, 83))	('hemoglobin lower', 'Phenotype', 'HP:0001903', (165, 181))	('Lung cancer', 'Disease', 'MESH:D008175', (4, 15))	('less', 'Var', (141, 145))	('less than', 'Var', (105, 114))
282814	30996564	(1) Surgical treatment + adjuvant chemotherapy or radical chemotherapy are recommended in T3-4N1 or T4N0 patients, and neoadjuvant treatment is worth considering.	('T3-4N1', 'Var', (90, 96))	('patients', 'Species', '9606', (105, 113))	('T4N0', 'Var', (100, 104))
282816	30996564	For patients with EGFR mutation, surgery + adjuvant EGFR-TKI treatment +/- postoperative radiotherapy.	('EGFR', 'Gene', '1956', (18, 22))	('mutation', 'Var', (23, 31))	('EGFR', 'Gene', '1956', (52, 56))	('EGFR', 'Gene', (52, 56))	('EGFR', 'Gene', (18, 22))	('patients', 'Species', '9606', (4, 12))
282818	30996564	Some patients have the lung cancer with EGFR mutation, the treatment of surgery + combined adjuvant EGFR-TKI treatment +/- postoperative radiotherapy should also be recommended.	('lung cancer', 'Disease', (23, 34))	('EGFR', 'Gene', '1956', (100, 104))	('lung cancer', 'Phenotype', 'HP:0100526', (23, 34))	('patients', 'Species', '9606', (5, 13))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('EGFR', 'Gene', (100, 104))	('EGFR', 'Gene', '1956', (40, 44))	('mutation', 'Var', (45, 53))	('lung cancer', 'Disease', 'MESH:D008175', (23, 34))	('EGFR', 'Gene', (40, 44))
282828	30996564	(1) First-line EGFR-TKI treatment is recommended for stage IV NSCLC patients with EGFR-sensitive mutation.	('EGFR', 'Gene', (82, 86))	('NSCLC', 'Disease', (62, 67))	('NSCLC', 'Disease', 'MESH:D002289', (62, 67))	('patients', 'Species', '9606', (68, 76))	('EGFR', 'Gene', '1956', (15, 19))	('EGFR', 'Gene', (15, 19))	('mutation', 'Var', (97, 105))	('EGFR', 'Gene', '1956', (82, 86))
282830	30996564	Patients with positive ROS1 fusion gene are recommend first-line treatment with Crizotinib.	('ROS1', 'Gene', (23, 27))	('ROS1', 'Gene', '6098', (23, 27))	('fusion', 'Var', (28, 34))	('Patients', 'Species', '9606', (0, 8))	('Crizotinib', 'Chemical', 'MESH:D000077547', (80, 90))
282833	30996564	(3) Patients with advanced NSCLC with ECOG PS score of 2 should be given single-drug chemotherapy, but those with ECOG PS score >2 are not recommended to use cytotoxic drugs.	('ECOG', 'Var', (38, 42))	('NSCLC', 'Disease', (27, 32))	('EC', 'Chemical', '-', (114, 116))	('NSCLC', 'Disease', 'MESH:D002289', (27, 32))	('Patients', 'Species', '9606', (4, 12))	('EC', 'Chemical', '-', (38, 40))
282839	30996564	EGFR-TKI should be given priority in second-line treatment if EGFR-TKI is not used in first-line and maintenance therapy in patients with EGFR-sensitive mutations.	('EGFR', 'Gene', '1956', (62, 66))	('EGFR', 'Gene', (0, 4))	('EGFR', 'Gene', '1956', (138, 142))	('mutations', 'Var', (153, 162))	('EGFR', 'Gene', (62, 66))	('EGFR', 'Gene', (138, 142))	('EGFR', 'Gene', '1956', (0, 4))	('patients', 'Species', '9606', (124, 132))
282840	30996564	It is recommended to treat NSCLC patients with EGFR-TKI resistance and positive EGFR T790M mutation with oxitinib monotherapy.	('patients', 'Species', '9606', (33, 41))	('NSCLC', 'Disease', (27, 32))	('T790M', 'Mutation', 'rs121434569', (85, 90))	('NSCLC', 'Disease', 'MESH:D002289', (27, 32))	('EGFR', 'Gene', '1956', (80, 84))	('EGFR', 'Gene', (80, 84))	('T790M', 'Var', (85, 90))	('oxitinib', 'Chemical', '-', (105, 113))	('EGFR', 'Gene', '1956', (47, 51))	('EGFR', 'Gene', (47, 51))
282841	30996564	For patients with EGFR mutation negative/ALK fusion negative (including non-squamous cell carcinoma and squamous cell carcinoma), based on the fact that PD-1 inhibitor nabolizumab is significantly superior to chemotherapy in efficacy and safety, the use of nabolizumab for second-line treatment should be given priority.	('non-squamous cell carcinoma', 'Disease', 'MESH:D002294', (72, 99))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (76, 99))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (104, 127))	('EGFR', 'Gene', '1956', (18, 22))	('mutation', 'Var', (23, 31))	('squamous cell carcinoma', 'Disease', (104, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (104, 127))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (76, 99))	('nabolizumab', 'Chemical', '-', (168, 179))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('EGFR', 'Gene', (18, 22))	('ALK', 'Gene', (41, 44))	('nabolizumab', 'Chemical', '-', (257, 268))	('negative', 'NegReg', (52, 60))	('non-squamous cell carcinoma', 'Disease', (72, 99))	('patients', 'Species', '9606', (4, 12))	('ALK', 'Gene', '238', (41, 44))
282895	30453881	Gene characteristics predicting missense, nonsense and frameshift mutations in tumor samples Because driver mutations provide selective advantage to the mutant clone, they tend to occur at a higher frequency in tumor samples compared to selectively neutral (passenger) mutations.	('frameshift mutations', 'Var', (55, 75))	('mutations', 'Var', (108, 117))	('tumor', 'Disease', (79, 84))	('advantage', 'PosReg', (136, 145))	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('mutant', 'Var', (153, 159))	('missense', 'Var', (32, 40))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('tumor', 'Disease', (211, 216))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('nonsense', 'Var', (42, 50))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
282899	30453881	By comparing the observed and predicted number of mutations in a gene, we have identified known cancer-associated genes as well as 111 novel cancer associated genes.	('mutations', 'Var', (50, 59))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('cancer', 'Disease', (96, 102))	('cancer', 'Disease', (141, 147))
282904	30453881	Mutations providing a proliferative or survival advantage to the mutant clone (drivers) occur more frequently in tumor samples compared to selectively neutral (passenger) mutations.	('tumor', 'Disease', (113, 118))	('mutant', 'Var', (65, 71))	('proliferative', 'CPA', (22, 35))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('survival advantage', 'CPA', (39, 57))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))
282909	30453881	The authors noted that about half of the identified driver mutations "occur in yet-to-be-discovered cancer genes".	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('mutations', 'Var', (59, 68))
282913	30453881	The excess of mutations unexplained by gene characteristics is due to the gene involvement in cancer development and can be used to identify cancer-associated genes.	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('involvement', 'Reg', (79, 90))	('mutations', 'Var', (14, 23))	('cancer', 'Disease', (141, 147))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
282917	30453881	In total there were 2,233,115 missense, 163,823 nonsense, and 85,272 frameshift (FS) mutations, including those resulted from nucleotide insertions as well as nucleotide deletions.	('missense', 'Var', (30, 38))	('nucleotide insertions', 'Var', (126, 147))	('frameshift', 'Reg', (69, 79))	('mutations', 'Var', (85, 94))	('FS', 'Disease', 'MESH:D018223', (81, 83))	('nonsense', 'Var', (48, 56))
282925	30453881	The mean chromatin accessibility across 10 lymphoblastic cell lines was computed for each gene and used as a predictor for density of missense, nonsense and FS mutations separately.	('chromatin accessibility', 'MPA', (9, 32))	('missense', 'Var', (134, 142))	('FS', 'Disease', 'MESH:D018223', (157, 159))	('nonsense', 'Var', (144, 152))
282930	30453881	Residual analysis was used to detect outliers - genes with a higher than expected number of missense, nonsense, or FS mutations.	('nonsense', 'Var', (102, 110))	('mutations', 'Var', (118, 127))	('missense', 'Var', (92, 100))	('FS', 'Disease', 'MESH:D018223', (115, 117))
282931	30453881	For each gene, residual Z-scores were computed separately for missense, nonsense and FS mutations.	('missense', 'Var', (62, 70))	('FS', 'Disease', 'MESH:D018223', (85, 87))	('nonsense', 'Var', (72, 80))
282934	30453881	For nonsense mutations, there was a linear relationship between the percentage of each nucleotide and the mutation density, as expected from the nucleotide composition of stop codons (TAA, TAG, and TGA).	('TGA', 'Gene', '6899', (198, 201))	('TGA', 'Gene', (198, 201))	('nonsense mutations', 'Var', (4, 22))
282936	30453881	For missense mutations, the peaks are driven by TP53 and KRAS.	('TP53', 'Gene', '7157', (48, 52))	('TP53', 'Gene', (48, 52))	('missense mutations', 'Var', (4, 22))	('KRAS', 'Gene', (57, 61))	('KRAS', 'Gene', '3845', (57, 61))
282937	30453881	We found that the density of missense mutations in olfactory receptors is twice that of other genes in the human genome: 107.5 +- 2.9 versus 49.4 +- 0.4 mutations per 1 kb.	('olfactory receptors', 'Gene', (51, 70))	('human', 'Species', '9606', (107, 112))	('missense mutations', 'Var', (29, 47))
282938	30453881	Densities of nonsense and FS mutations in olfactory genes are not elevated.	('nonsense', 'Var', (13, 21))	('FS', 'Disease', 'MESH:D018223', (26, 28))	('olfactory genes', 'Gene', (42, 57))
282940	30453881	Figure 3c shows the relationship between the mutation densities of missense, nonsense and FS mutations and the relative replication time.	('nonsense', 'Var', (77, 85))	('missense', 'Var', (67, 75))	('FS', 'Disease', 'MESH:D018223', (90, 92))
282948	30453881	Gene size was the most significant predictor followed by the nucleotide diversity (negative association) and the percentages of "A" and "C" nucleotides that were positively associated with the number of FS mutations in the gene.	('mutations', 'Var', (206, 215))	('FS', 'Disease', 'MESH:D018223', (203, 205))	('associated', 'Reg', (173, 183))
282951	30453881	We tested how well the pan-mutation model works for predicting missense, nonsense and FS mutations separately.	('nonsense', 'Var', (73, 81))	('FS', 'Disease', 'MESH:D018223', (86, 88))	('missense', 'Var', (63, 71))
282960	30453881	Five genes, ATM, LRP1B, CSMD3, FBXW, and SMAD4 have an excess of missense and nonsense mutations.	('ATM', 'Gene', (12, 15))	('CSMD3', 'Gene', (24, 29))	('CSMD3', 'Gene', '114788', (24, 29))	('missense', 'Var', (65, 73))	('LRP1B', 'Gene', '53353', (17, 22))	('LRP1B', 'Gene', (17, 22))	('ATM', 'Gene', '472', (12, 15))	('SMAD4', 'Gene', '4089', (41, 46))	('SMAD4', 'Gene', (41, 46))	('nonsense mutations', 'Var', (78, 96))
282961	30453881	Three genes, COL11A1, SLC25A5, and PCLO show a significant excess of frameshift and missense mutations.	('frameshift', 'Var', (69, 79))	('COL11A1', 'Gene', (13, 20))	('PCLO', 'Gene', (35, 39))	('PCLO', 'Gene', '27445', (35, 39))	('COL11A1', 'Gene', '1301', (13, 20))	('SLC25A5', 'Gene', '292', (22, 29))	('SLC25A5', 'Gene', (22, 29))	('missense mutations', 'Var', (84, 102))
282962	30453881	Twelve genes: APC, AXIN1, TET2, ASXL1, ARID2, RB1, NF1, VHL, PBRM1, KMT2D, KMT2C, and ARID1A, show an excess of frameshift and nonsense mutations.	('VHL', 'Gene', (56, 59))	('KMT2C', 'Gene', (75, 80))	('RB1', 'Gene', (46, 49))	('ASXL1', 'Gene', (32, 37))	('TET2', 'Gene', '54790', (26, 30))	('AXIN1', 'Gene', '8312', (19, 24))	('KMT2C', 'Gene', '58508', (75, 80))	('VHL', 'Gene', '7428', (56, 59))	('ARID2', 'Gene', '196528', (39, 44))	('KMT2D', 'Gene', '8085', (68, 73))	('frameshift', 'Var', (112, 122))	('APC', 'Disease', 'MESH:D011125', (14, 17))	('RB1', 'Gene', '5925', (46, 49))	('APC', 'Disease', (14, 17))	('NF1', 'Gene', '4763', (51, 54))	('PBRM1', 'Gene', '55193', (61, 66))	('ARID1A', 'Gene', (86, 92))	('ARID2', 'Gene', (39, 44))	('TET2', 'Gene', (26, 30))	('AXIN1', 'Gene', (19, 24))	('NF1', 'Gene', (51, 54))	('nonsense mutations', 'Var', (127, 145))	('PBRM1', 'Gene', (61, 66))	('ASXL1', 'Gene', '171023', (32, 37))	('ARID1A', 'Gene', '8289', (86, 92))	('KMT2D', 'Gene', (68, 73))
282964	30453881	The mean Z-score for known TSs was significantly higher for FS, missense, and nonsense mutations compared to Z-scores for all other genes.	('nonsense mutations', 'Var', (78, 96))	('Z-score', 'MPA', (9, 16))	('FS', 'Disease', 'MESH:D018223', (60, 62))	('higher', 'PosReg', (49, 55))	('missense', 'Var', (64, 72))
282965	30453881	A higher Z-score for missense mutations is expected because typically activating missense mutations in oncogenes drive tumorigenesis.. We found that gene characteristics can explain considerable proportion of inter genic variation in the number of somatic mutations: 88% for missense, 40% for nonsense, and 23% for frameshift mutations.	('nonsense', 'Var', (293, 301))	('tumor', 'Disease', (119, 124))	('frameshift mutations', 'Var', (315, 335))	('missense', 'Var', (275, 283))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))
282968	30453881	If we assume that the unexplained variation in the number of mutations is due to an involvement of the gene in cancer development, the results show that FS most frequently associated with tumorigenesis followed by nonsense and missense mutations.	('tumor', 'Disease', (188, 193))	('FS', 'Disease', 'MESH:D018223', (153, 155))	('nonsense', 'Var', (214, 222))	('associated with', 'Reg', (172, 187))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('missense mutations', 'Var', (227, 245))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))
282969	30453881	Each gene in the human genome acquires mutations on background level based on intrinsic mutability of the gene which depends on gene characteristics.	('human', 'Species', '9606', (17, 22))	('hic', 'Gene', '29969', (112, 115))	('hic', 'Gene', (112, 115))	('mutations', 'Var', (39, 48))
282975	30453881	We have identified 18 novel cancer-associated genes with an excess of missense mutations: MUC4, CSMD3, FLG, USH2A, DNAH8, FAT4, MUC17, MUC16, SYNE1, COL11A1, RP1, SI, SACS, SLC25A5, DMD, DST, XIRP2, and PKHD1L1.	('COL11A1', 'Gene', '1301', (149, 156))	('CSMD3', 'Gene', (96, 101))	('SYNE1', 'Gene', (142, 147))	('SI', 'Disease', 'None', (163, 165))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('FLG', 'Gene', '2312', (103, 106))	('USH2A', 'Gene', '7399', (108, 113))	('FAT4', 'Gene', '79633', (122, 126))	('SLC25A5', 'Gene', (173, 180))	('SACS', 'Gene', '26278', (167, 171))	('SYNE1', 'Gene', '23345', (142, 147))	('COL11A1', 'Gene', (149, 156))	('missense mutations', 'Var', (70, 88))	('MUC16', 'Gene', '94025', (135, 140))	('DNAH8', 'Gene', (115, 120))	('XIRP2', 'Gene', '129446', (192, 197))	('SACS', 'Gene', (167, 171))	('MUC4', 'Gene', '4585', (90, 94))	('MUC17', 'Gene', (128, 133))	('MUC4', 'Gene', (90, 94))	('PKHD1L1', 'Gene', '93035', (203, 210))	('PKHD1L1', 'Gene', (203, 210))	('FAT4', 'Gene', (122, 126))	('MUC17', 'Gene', '140453', (128, 133))	('cancer', 'Disease', (28, 34))	('RP1', 'Gene', (158, 161))	('USH2A', 'Gene', (108, 113))	('CSMD3', 'Gene', '114788', (96, 101))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('MUC16', 'Gene', (135, 140))	('DMD', 'Disease', 'MESH:D020388', (182, 185))	('DMD', 'Disease', (182, 185))	('XIRP2', 'Gene', (192, 197))	('SLC25A5', 'Gene', '292', (173, 180))	('FLG', 'Gene', (103, 106))	('RP1', 'Gene', '6101', (158, 161))	('DNAH8', 'Gene', '1769', (115, 120))
282977	30453881	A larger number of novel cancer-associated genes identified through the analyses of FS and nonsense mutilations compared to the analysis of missense mutations can be due to the fact that a large proportion of variation in number of mutation is due to gene involvement in cancer development.	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('mutation', 'Var', (232, 240))	('cancer', 'Phenotype', 'HP:0002664', (271, 277))	('involvement', 'Reg', (256, 267))	('FS', 'Disease', 'MESH:D018223', (84, 86))	('cancer', 'Disease', 'MESH:D009369', (25, 31))	('nonsense mutilations', 'Phenotype', 'HP:0000742', (91, 111))	('cancer', 'Disease', 'MESH:D009369', (271, 277))	('cancer', 'Disease', (25, 31))	('cancer', 'Disease', (271, 277))
282979	30453881	For example, the observed number of missense mutations in AKT1 oncogene is 113.	('AKT1', 'Gene', (58, 62))	('missense mutations', 'Var', (36, 54))	('AKT1', 'Gene', '207', (58, 62))
282981	30453881	If we exclude p.E17K, in the reminder of the AKT1 gene the observed number of mutations is lower than expected: 27 observed versus 70 expected.	('p.E17K', 'Var', (14, 20))	('AKT1', 'Gene', '207', (45, 49))	('p.E17K', 'Mutation', 'rs121434592', (14, 20))	('AKT1', 'Gene', (45, 49))
282982	30453881	Missense mutations in functional domains may be loss-of-function mutations and as a result are negatively selected in tumors.	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('Missense mutations', 'Var', (0, 18))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('loss-of-function', 'NegReg', (48, 64))	('tumors', 'Disease', (118, 124))	('tumors', 'Disease', 'MESH:D009369', (118, 124))
282983	30453881	Because our modeling does not take into account the distribution of mutations within the coding region, it may miss cancer genes with a clustering of functional mutations but a similar number of observed and expected mutations.	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('miss', 'NegReg', (111, 115))	('mutations', 'Var', (161, 170))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))
282984	30453881	Interestingly, many novel cancer-associated genes identified by the excess of missense mutations are large genes with repetitive functional domains: LRP1B, CSMD3, FLG, USH2A and others.	('missense mutations', 'Var', (78, 96))	('USH2A', 'Gene', '7399', (168, 173))	('cancer', 'Disease', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('LRP1B', 'Gene', '53353', (149, 154))	('FLG', 'Gene', (163, 166))	('FLG', 'Gene', '2312', (163, 166))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('CSMD3', 'Gene', (156, 161))	('CSMD3', 'Gene', '114788', (156, 161))	('USH2A', 'Gene', (168, 173))	('LRP1B', 'Gene', (149, 154))
282985	30453881	For example, one of the frequent mutations in CSMD3 gene is G > A substitution.	('G > A substitution', 'Var', (60, 78))	('CSMD3', 'Gene', (46, 51))	('CSMD3', 'Gene', '114788', (46, 51))
282986	30453881	It leads to arginine (R) to glutamine (Q) substitution.	('leads to', 'Reg', (3, 11))	('arginine', 'Chemical', 'MESH:D001120', (12, 20))	('glutamine', 'Chemical', 'MESH:D005973', (28, 37))	('arginine', 'Var', (12, 20))
282987	30453881	We found that the number of silent mutations reported by COSMIC genome wide screens across all cancer types is the most significant predictor of missense mutations.	('missense mutations', 'Var', (145, 163))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('cancer', 'Disease', (95, 101))	('cancer', 'Disease', 'MESH:D009369', (95, 101))
282995	30453881	Therefore, the total number of silent mutations per gene generated by whole genome (exome) mutational screens across different cancer types is a key predictor of somatic mutations and needs to be included in cancer gene prediction models including MutsigCV to increase the specificity of the results.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('cancer', 'Disease', (208, 214))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('mutational', 'Var', (91, 101))	('cancer', 'Disease', (127, 133))	('cancer', 'Disease', 'MESH:D009369', (208, 214))
282996	30453881	We found that top predictors for missense, nonsense and FS mutations are different.	('nonsense and', 'Var', (43, 55))	('missense', 'Var', (33, 41))	('FS', 'Disease', 'MESH:D018223', (56, 58))
282998	30453881	We applied stepwise best subset multivariate model to predict missense, nonsense, and FS mutations using gene characteristics, and by comparison of the observed and expected number of mutations identified novel cancer-associated genes.	('cancer', 'Disease', 'MESH:D009369', (211, 217))	('FS', 'Disease', 'MESH:D018223', (86, 88))	('missense', 'Var', (62, 70))	('cancer', 'Disease', (211, 217))	('mutations', 'Var', (89, 98))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('nonsense', 'Var', (72, 80))
283001	30453881	CCLE Cancer Cell Line Encyclopedia COSMIC Catalog of Somatic Mutations in Cancer FS Frameshift mutations LUAD Lung adenocarcinoma LUSC Lung squamous cell carcinoma ND Nucleotide diversity OG Oncogene SKCM Skin cutaneous melanoma SNS Single nucleotide substitution TS Tumor suppressors Conception and design: IG, CA, OG.	('Skin cutaneous melanoma', 'Disease', (205, 228))	('Cancer Cell Line Encyclopedia', 'Disease', (5, 34))	('Cancer', 'Phenotype', 'HP:0002664', (5, 11))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('Skin cutaneous melanoma', 'Disease', 'MESH:C562393', (205, 228))	('Lung adenocarcinoma', 'Phenotype', 'HP:0030078', (110, 129))	('Cancer', 'Disease', (5, 11))	('Single nucleotide substitution', 'Var', (233, 263))	('Lung adenocarcinoma', 'Disease', 'MESH:D000077192', (110, 129))	('Cancer', 'Phenotype', 'HP:0002664', (74, 80))	('CCLE', 'Chemical', '-', (0, 4))	('Tumor', 'Phenotype', 'HP:0002664', (267, 272))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (140, 163))	('melanoma', 'Phenotype', 'HP:0002861', (220, 228))	('Cancer', 'Disease', (74, 80))	('Cancer', 'Disease', 'MESH:D009369', (5, 11))	('Cancer Cell Line Encyclopedia', 'Disease', 'MESH:C538614', (5, 34))	('FS', 'Disease', 'MESH:D018223', (81, 83))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (140, 163))	('Lung adenocarcinoma', 'Disease', (110, 129))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (210, 228))	('Cancer', 'Disease', 'MESH:D009369', (74, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (154, 163))	('squamous cell carcinoma', 'Disease', (140, 163))
283033	29599927	However, high-expression of CXCR2 in digestive tract cancer (HR = 1.26, 95% CI = 0.68-2.35, p = 0.46; I2 = 73%, p = 0.005) has no effect on OS statistically.	('high-expression', 'Var', (9, 24))	('CXCR2', 'Gene', '3579', (28, 33))	('CXCR2', 'Gene', (28, 33))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('digestive tract cancer', 'Phenotype', 'HP:0007378', (37, 59))	('tract cancer', 'Disease', 'MESH:D014571', (47, 59))	('tract cancer', 'Disease', (47, 59))
283034	29599927	As shown in Figure 4, significant difference was detected between high- and low-expression of CXCR2 without heterogeneity in group with multivariate models (HR = 1.78, 95% CI = 1.52-2.08, p < 0.01; I2 = 0%, p = 0.76).	('CXCR2', 'Gene', '3579', (94, 99))	('high-', 'Var', (66, 71))	('low-expression', 'NegReg', (76, 90))	('CXCR2', 'Gene', (94, 99))
283036	29599927	As shown in Figure 5, there was significant difference between high- and low-expression of CXCR2 without heterogeneity in Asian group (HR = 1.93, 95% CI = 1.58-2.34, p < 0.01; I2 = 0%, p = 0.76).	('low-expression', 'NegReg', (73, 87))	('CXCR2', 'Gene', (91, 96))	('CXCR2', 'Gene', '3579', (91, 96))	('high-', 'Var', (63, 68))
283038	29599927	As what was shown in Figure 6, there was significant difference between high- and low-expression of CXCR2 without heterogeneity in small sample size group (HR = 1.81, 95% CI = 1.46-2.24, p < 0.01; I2 = 0%, p = 0.68).	('CXCR2', 'Gene', (100, 105))	('CXCR2', 'Gene', '3579', (100, 105))	('high-', 'Var', (72, 77))	('low-expression', 'NegReg', (82, 96))
283045	29599927	In our meta-analysis, it was presented that high expression of CXCR2 was significantly related to shorten OS and was a risk factor of OS.	('CXCR2', 'Gene', '3579', (63, 68))	('high expression', 'Var', (44, 59))	('CXCR2', 'Gene', (63, 68))	('shorten OS', 'Disease', (98, 108))	('related', 'Reg', (87, 94))	('risk factor', 'Reg', (119, 130))
283046	29599927	Among the studies included in quantitative synthesis, the synthetic analysis of 4 eligible studies reported that high CXCR2 expression was correlated with shorten recurrence-free survival (RFS).	('high', 'Var', (113, 117))	('shorten', 'NegReg', (155, 162))	('CXCR2', 'Gene', '3579', (118, 123))	('recurrence-free survival', 'CPA', (163, 187))	('CXCR2', 'Gene', (118, 123))
283091	29073199	variation and mutations in specific cancers, for IQGAP2 and IQGAP3.	('variation', 'Var', (0, 9))	('cancers', 'Disease', 'MESH:D009369', (36, 43))	('cancers', 'Phenotype', 'HP:0002664', (36, 43))	('cancers', 'Disease', (36, 43))	('IQGAP3', 'Gene', (60, 66))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('IQGAP2', 'Disease', (49, 55))	('IQGAP3', 'Gene', '128239', (60, 66))	('mutations', 'Var', (14, 23))
283117	29073199	The parameters used for survival analysis was as follows; cancer type-specific cancer name, dataset- TCGA, duplicate gene-max gene probe expression and max high risk.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('cancer', 'Disease', (58, 64))	('duplicate gene-max', 'Var', (107, 125))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))
283154	29073199	The data from the respective probes (probe IDs listed in S1 Table) showed reduced OS and FP, for patients with low IQGAP2 expression (Fig 2E).	('low', 'Var', (111, 114))	('expression', 'MPA', (122, 132))	('IQGAP2', 'Gene', (115, 121))	('OS', 'Chemical', '-', (82, 84))	('reduced', 'NegReg', (74, 81))	('patients', 'Species', '9606', (97, 105))
283189	29073199	First dataset (229538_s_at) showed a poor OS and reduced probability of FP of the patient with low IQGAP3 expression (S1 Table) whereas; second one (dataset 1569061_at) showed better OS and enhanced probability of FP with low IQGAP3 expression (Fig 4E).	('OS', 'Chemical', '-', (42, 44))	('reduced', 'NegReg', (49, 56))	('low', 'Var', (95, 98))	('patient', 'Species', '9606', (82, 89))	('OS', 'Chemical', '-', (183, 185))	('IQGAP3', 'Gene', (99, 105))	('IQGAP3', 'Gene', '128239', (99, 105))	('enhanced', 'PosReg', (190, 198))	('IQGAP3', 'Gene', '128239', (226, 232))	('IQGAP3', 'Gene', (226, 232))
283246	29073199	The percentage of each type of IQGAP2 and IQGAP3 genetic alteration with cancer type has been summarised in S5 Table.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('IQGAP3', 'Gene', '128239', (42, 48))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('genetic alteration', 'Var', (49, 67))	('IQGAP3', 'Gene', (42, 48))	('IQGAP2', 'Gene', (31, 37))
283249	29073199	Mutation analysis of IQGAP3 showed high frequency of mutations in colorectal (5.2%), lung squamous cell carcinoma (7.3%) and stomach cancer (5.2%), where the frequency of copy number change was very low.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (90, 113))	('stomach cancer', 'Disease', 'MESH:D013274', (125, 139))	('lung squamous cell carcinoma', 'Disease', (85, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('stomach cancer', 'Phenotype', 'HP:0012126', (125, 139))	('stomach cancer', 'Disease', (125, 139))	('mutations', 'Var', (53, 62))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (85, 113))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (85, 113))	('colorectal', 'Disease', (66, 76))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('IQGAP3', 'Gene', (21, 27))	('IQGAP3', 'Gene', '128239', (21, 27))
283250	29073199	Here it is noteworthy that one frequent mutation (V293I/X293_splice) was present in four stomach cancer cases, at the splice site of IQGAP3.	('stomach cancer', 'Disease', (89, 103))	('V293I', 'SUBSTITUTION', 'None', (50, 55))	('V293I', 'Var', (50, 55))	('IQGAP3', 'Gene', (133, 139))	('stomach cancer', 'Disease', 'MESH:D013274', (89, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('stomach cancer', 'Phenotype', 'HP:0012126', (89, 103))	('IQGAP3', 'Gene', '128239', (133, 139))
283252	29073199	Besides copy number change, the overall frequency of mutation was high in lung adenocarcinoma, lung squamous cell carcinoma and colorectal cancer, but in depth analysis did not show high frequency of any single mutation (S5 Fig).	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (100, 123))	('colorectal cancer', 'Disease', 'MESH:D015179', (128, 145))	('lung squamous cell carcinoma', 'Disease', (95, 123))	('copy', 'Var', (8, 12))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (95, 123))	('mutation', 'Var', (53, 61))	('colorectal cancer', 'Phenotype', 'HP:0003003', (128, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (74, 93))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('colorectal cancer', 'Disease', (128, 145))	('lung adenocarcinoma', 'Disease', (74, 93))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (74, 93))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (95, 123))
283299	29073199	Likewise for IQGAP2 previous studies have identified its role as a tumor suppressor in ovarian cancer wherein reduced levels of IQGAP2 correlated with poor overall survival of patients and IQGAP2 inhibited EMT, migration and invasion.	('patients', 'Species', '9606', (176, 184))	('IQGAP2', 'Gene', (128, 134))	('IQGAP2', 'Var', (189, 195))	('EMT', 'Gene', (206, 209))	('reduced', 'NegReg', (110, 117))	('levels', 'MPA', (118, 124))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('EMT', 'Gene', '3702', (206, 209))	('ovarian cancer', 'Phenotype', 'HP:0100615', (87, 101))	('ovarian cancer', 'Disease', 'MESH:D010051', (87, 101))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('inhibited', 'NegReg', (196, 205))	('poor', 'NegReg', (151, 155))	('tumor', 'Disease', (67, 72))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('ovarian cancer', 'Disease', (87, 101))
283311	29073199	We observed that high frequency of mutations were present in IQGAP3 promoter but not in IQGAP2 promoter in different cancers.	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('IQGAP3', 'Gene', (61, 67))	('mutations', 'Var', (35, 44))	('IQGAP3', 'Gene', '128239', (61, 67))	('cancers', 'Phenotype', 'HP:0002664', (117, 124))	('cancers', 'Disease', 'MESH:D009369', (117, 124))	('cancers', 'Disease', (117, 124))
283312	29073199	Interestingly, one frequent mutation (V293I/X293_splice) was present in four stomach cancer cases, at the splice site of IQGAP3.	('stomach cancer', 'Disease', (77, 91))	('IQGAP3', 'Gene', '128239', (121, 127))	('V293I', 'SUBSTITUTION', 'None', (38, 43))	('stomach cancer', 'Disease', 'MESH:D013274', (77, 91))	('stomach cancer', 'Phenotype', 'HP:0012126', (77, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('V293I', 'Var', (38, 43))	('IQGAP3', 'Gene', (121, 127))
283319	29073199	The observed mutations in IQGAP3 promoter could well provide additional means via which IQGAP3 expression is regulated.	('IQGAP3', 'Gene', (88, 94))	('IQGAP3', 'Gene', (26, 32))	('IQGAP3', 'Gene', '128239', (88, 94))	('IQGAP3', 'Gene', '128239', (26, 32))	('mutations', 'Var', (13, 22))	('expression', 'MPA', (95, 105))
283321	29073199	IQGAP2 methylation is significantly associated with loss of the IQGAP2 expression in the primary gastric cancer tissues as well as gastric cancer cell lines, thereby leading to tumor invasion and a poor prognosis.	('expression', 'MPA', (71, 81))	('gastric cancer', 'Disease', (97, 111))	('loss', 'NegReg', (52, 56))	('leading to', 'Reg', (166, 176))	('gastric cancer', 'Disease', 'MESH:D013274', (131, 145))	('gastric cancer', 'Disease', 'MESH:D013274', (97, 111))	('gastric cancer', 'Phenotype', 'HP:0012126', (131, 145))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('methylation', 'Var', (7, 18))	('gastric cancer', 'Phenotype', 'HP:0012126', (97, 111))	('IQGAP2', 'Gene', (64, 70))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('tumor', 'Disease', (177, 182))	('gastric cancer', 'Disease', (131, 145))	('IQGAP2', 'Gene', (0, 6))
283324	29073199	To our knowledge, no association between epigenetic activation of IQGAP3 gene has been investigated in previous studies.	('epigenetic', 'Var', (41, 51))	('IQGAP3', 'Gene', '128239', (66, 72))	('IQGAP3', 'Gene', (66, 72))
283330	29073199	This will pave the way for using IQGAP2 and IQGAP3 as promising therapeutic targets and novel prognostic biomarkers for human carcinomas in the near future.	('human', 'Species', '9606', (120, 125))	('IQGAP2', 'Var', (33, 39))	('IQGAP3', 'Gene', (44, 50))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('IQGAP3', 'Gene', '128239', (44, 50))	('carcinomas', 'Phenotype', 'HP:0030731', (126, 136))	('carcinomas', 'Disease', (126, 136))	('carcinomas', 'Disease', 'MESH:D002277', (126, 136))
283334	26646588	MiRNAs alterations in human cancers may act as a rheostat of the oncogenic RAS signal that is often amplified as cancers progress.	('cancers', 'Disease', (28, 35))	('MiR', 'Gene', (0, 3))	('MiR', 'Gene', '220972', (0, 3))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('cancers', 'Disease', 'MESH:D009369', (113, 120))	('cancers', 'Phenotype', 'HP:0002664', (113, 120))	('cancers', 'Disease', (113, 120))	('cancers', 'Phenotype', 'HP:0002664', (28, 35))	('rat', 'Species', '10116', (11, 14))	('human', 'Species', '9606', (22, 27))	('cancers', 'Disease', 'MESH:D009369', (28, 35))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('alterations', 'Var', (7, 18))
283335	26646588	However, specific mechanisms leading to miRNAs deregulation and their functional consequences in cancer are far from being fully elucidated.	('cancer', 'Disease', (97, 103))	('miRNAs', 'Protein', (40, 46))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('deregulation', 'Var', (47, 59))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
283339	26646588	Aberrant activation of this pathway is a major and highly prevalent oncogenic event in many human cancers.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('activation', 'PosReg', (9, 19))	('Aberrant', 'Var', (0, 8))	('cancers', 'Phenotype', 'HP:0002664', (98, 105))	('cancers', 'Disease', 'MESH:D009369', (98, 105))	('cancers', 'Disease', (98, 105))	('human', 'Species', '9606', (92, 97))
283340	26646588	Oncogenic RAS mutations occur in approximately 30% of all tumor types; however, mutations in upstream regulators and downstream effectors are also prevalent.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('mutations', 'Var', (80, 89))	('RAS', 'Gene', (10, 13))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('mutations', 'Var', (14, 23))
283341	26646588	As an example, KRAS (V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog) somatic mutations were identified in more than 90% of pancreatic ductal adenocarcinoma (PDAC); BRAF and NRAS mutations occur with mutual exclusion in melanoma and account altogether for 83% of the cases; RAS-MAPK signaling pathway is altered in 67% of the T-cell precursor acute lymphoblastic leukemia including mutations in NRAS, KRAS, BRAF, NF1, and PTPN11; 55% of colon and rectal cancer have alterations in KRAS, NRAS, or BRAF; KRAS, EGFR, NF1, and BRAF mutations occur in 27%, 17%, 11%, and 3% in lung adenocarcinomas, respectively.	('carcinoma', 'Phenotype', 'HP:0030731', (152, 161))	('lymphoblastic leukemia', 'Disease', 'MESH:D054198', (354, 376))	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (348, 376))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (129, 161))	('lymphoblastic leukemia', 'Disease', (354, 376))	('rat', 'Species', '10116', (475, 478))	('BRAF; KRAS', 'Gene', (501, 511))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (577, 597))	('rectal cancer', 'Phenotype', 'HP:0100743', (452, 465))	('melanoma', 'Disease', 'MESH:D008545', (225, 233))	('pancreatic ductal adenocarcinoma', 'Disease', (129, 161))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (577, 596))	('rat', 'Species', '10116', (39, 42))	('T-cell precursor acute lymphoblastic leukemia', 'Phenotype', 'HP:0006727', (331, 376))	('PDAC', 'Chemical', '-', (163, 167))	('colon and rectal cancer', 'Disease', 'MESH:D012004', (442, 465))	('alterations', 'Reg', (471, 482))	('carcinoma', 'Phenotype', 'HP:0030731', (587, 596))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (577, 597))	('carcinomas', 'Phenotype', 'HP:0030731', (587, 597))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (354, 376))	('NRAS', 'Gene', (492, 496))	('PDAC', 'Phenotype', 'HP:0006725', (163, 167))	('sarcoma', 'Disease', 'MESH:D012509', (43, 50))	('leukemia', 'Phenotype', 'HP:0001909', (368, 376))	('BRAF', 'Gene', (528, 532))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (129, 161))	('KRAS', 'Gene', (486, 490))	('lung adenocarcinomas', 'Disease', (577, 597))	('cancer', 'Phenotype', 'HP:0002664', (459, 465))	('sarcoma', 'Disease', (43, 50))	('NF1', 'Gene', (519, 522))	('melanoma', 'Phenotype', 'HP:0002861', (225, 233))	('melanoma', 'Disease', (225, 233))	('EGFR', 'Gene', (513, 517))	('KRAS', 'Gene', (507, 511))	('sarcoma', 'Phenotype', 'HP:0100242', (43, 50))	('mutations', 'Var', (533, 542))
283343	26646588	Recently, epigenetic alterations were described to potentiate this activation in human tumors.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('tumors', 'Disease', (87, 93))	('epigenetic alterations', 'Var', (10, 32))	('potentiate', 'PosReg', (51, 61))	('rat', 'Species', '10116', (25, 28))	('tumors', 'Disease', 'MESH:D009369', (87, 93))	('human', 'Species', '9606', (81, 86))
283344	26646588	Epigenetic modifications refer to heritable genomic changes in the absence of alterations in the DNA sequence through covalent histone-tail modifications, DNA methylation, chromatin remodeling, and regulation of non-coding RNA expression.	('methylation', 'Var', (159, 170))	('DNA', 'Gene', (155, 158))	('rat', 'Species', '10116', (82, 85))	('Epigenetic modifications', 'Var', (0, 24))
283345	26646588	In addition, epigenetic factors can be responsible for the dysregulation of the miRNome (defined as the full spectrum of miRNAs expression) observed in cancer.	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('responsible', 'Reg', (39, 50))	('epigenetic factors', 'Var', (13, 31))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('dysregulation', 'MPA', (59, 72))
283347	26646588	MiRNAs are small (~ 22 nucleotides long) highly conserved noncoding RNAs that epigenetically target mRNAs and subsequently repress protein expression.	('MiR', 'Gene', (0, 3))	('repress', 'NegReg', (123, 130))	('MiR', 'Gene', '220972', (0, 3))	('epigenetically', 'Var', (78, 92))	('protein expression', 'MPA', (131, 149))	('mRNAs', 'Protein', (100, 105))
283354	26646588	In 2009, germline inactivating DICER1 mutations have been associated with familial pleuropulmonary blastoma, a rare malignant lung tumor mainly affecting children.	('DICER1', 'Gene', (31, 37))	('DICER1', 'Gene', '23405', (31, 37))	('associated', 'Reg', (58, 68))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('familial pleuropulmonary blastoma', 'Disease', 'MESH:C537516', (74, 107))	('mutations', 'Var', (38, 47))	('malignant lung tumor', 'Disease', 'MESH:D018198', (116, 136))	('familial pleuropulmonary blastoma', 'Disease', (74, 107))	('pleuropulmonary blastoma', 'Phenotype', 'HP:0100528', (83, 107))	('malignant lung tumor', 'Disease', (116, 136))	('lung tumor', 'Phenotype', 'HP:0100526', (126, 136))	('children', 'Species', '9606', (154, 162))	('germline inactivating', 'Var', (9, 30))
283356	26646588	In addition to pleuropulmonary blastoma, germline DICER1 mutations also predispose to a large variety of different rare tumors.	('pleuropulmonary blastoma', 'Phenotype', 'HP:0100528', (15, 39))	('tumors', 'Disease', (120, 126))	('predispose', 'Reg', (72, 82))	('tumors', 'Disease', 'MESH:D009369', (120, 126))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('pleuropulmonary blastoma', 'Disease', 'MESH:C537516', (15, 39))	('pleuropulmonary blastoma', 'Disease', (15, 39))	('mutations', 'Var', (57, 66))	('DICER1', 'Gene', (50, 56))	('DICER1', 'Gene', '23405', (50, 56))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))
283359	26646588	Although it is likely that alterations in DICER1 and DROSHA genes globally disturb miRNA processing, the precise effect on miRNome is not well known.	('miRNA processing', 'MPA', (83, 99))	('DICER1', 'Gene', '23405', (42, 48))	('disturb', 'NegReg', (75, 82))	('rat', 'Species', '10116', (31, 34))	('DROSHA', 'Gene', '29102', (53, 59))	('DICER1', 'Gene', (42, 48))	('alterations', 'Var', (27, 38))	('DROSHA', 'Gene', (53, 59))
283364	26646588	Hence, deregulation of such miRNAs in cancer cells most likely contributes to tumorigenesis by leading to an aberrant activation of the RAS-MAPK pathway.	('activation', 'PosReg', (118, 128))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('RAS-MAPK pathway', 'Pathway', (136, 152))	('deregulation', 'Var', (7, 19))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Disease', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('contributes', 'Reg', (63, 74))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('cancer', 'Disease', (38, 44))
283372	26646588	In the era of molecular and personalized therapeutics, the discovery of mutations in EGFR in 15-20% of lung adenocarcinomas and the associated response to EGFR-targeting tyrosine kinase inhibitors have provided a successful avenue of treatment in high-stage lung adenocarcinomas.	('lung adenocarcinomas', 'Disease', (103, 123))	('EGFR', 'Gene', (85, 89))	('mutations', 'Var', (72, 81))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (258, 278))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (258, 278))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (103, 123))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (103, 123))	('carcinomas', 'Phenotype', 'HP:0030731', (268, 278))	('tyrosine', 'Chemical', 'MESH:D014443', (170, 178))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (268, 277))	('carcinomas', 'Phenotype', 'HP:0030731', (113, 123))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (258, 277))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (103, 122))	('lung adenocarcinomas', 'Disease', (258, 278))
283379	26646588	Interestingly, miR-145 transfection in lung adenocarcinoma cells inhibited proliferation.	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('transfection', 'Var', (23, 35))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (39, 58))	('miR-145', 'Gene', (15, 22))	('miR-145', 'Gene', '406937', (15, 22))	('rat', 'Species', '10116', (82, 85))	('inhibited', 'NegReg', (65, 74))	('lung adenocarcinoma', 'Disease', (39, 58))	('proliferation', 'CPA', (75, 88))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (39, 58))
283383	26646588	Interestingly, phosphorylation of ERK1/2 and AKT downstream effectors were inhibited by restoration of miR-206 in cancer cells, indicating that tumor-suppressive miR-206 inhibited dual signaling networks activated by MET and EGFR.	('ERK1/2', 'Gene', '5595;5594', (34, 40))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('miR-206', 'Gene', (103, 110))	('miR-206', 'Gene', '406989', (103, 110))	('inhibited', 'NegReg', (170, 179))	('AKT', 'Gene', (45, 48))	('inhibited', 'NegReg', (75, 84))	('rat', 'Species', '10116', (93, 96))	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('phosphorylation', 'MPA', (15, 30))	('tumor', 'Disease', (144, 149))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('restoration', 'Var', (88, 99))	('miR-206', 'Gene', (162, 169))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('AKT', 'Gene', '207', (45, 48))	('dual signaling networks', 'Pathway', (180, 203))	('miR-206', 'Gene', '406989', (162, 169))	('ERK1/2', 'Gene', (34, 40))	('cancer', 'Disease', (114, 120))
283396	26646588	Mean survival time was significantly shortened for patients whose GBM had both EGFR amplification and miR-34a deletion with significantly lower miR-34a expression.	('miR-34a', 'Gene', (144, 151))	('EGFR', 'Gene', (79, 83))	('amplification', 'Var', (84, 97))	('lower', 'NegReg', (138, 143))	('miR-34a', 'Gene', '407040', (102, 109))	('expression', 'MPA', (152, 162))	('GBM', 'Phenotype', 'HP:0012174', (66, 69))	('patients', 'Species', '9606', (51, 59))	('miR-34a', 'Gene', '407040', (144, 151))	('miR-34a', 'Gene', (102, 109))	('shortened', 'NegReg', (37, 46))	('deletion', 'Var', (110, 118))
283413	26646588	Ectopic expression of miR-133 inhibited cell proliferation, migration and invasion in these cells by targeting EGFR.	('rat', 'Species', '10116', (52, 55))	('miR-1', 'Gene', '79187', (22, 27))	('inhibited', 'NegReg', (30, 39))	('Ectopic expression', 'Var', (0, 18))	('miR-1', 'Gene', (22, 27))	('EGFR', 'Gene', (111, 115))	('invasion in these cells', 'CPA', (74, 97))	('migration', 'CPA', (60, 69))	('targeting', 'Reg', (101, 110))	('rat', 'Species', '10116', (63, 66))	('cell proliferation', 'CPA', (40, 58))
283453	26646588	Polymorphisms in KRAS 3'-UTR have been described to alter let-7 binding, resulting in KRAS overexpression and subsequent aberrant activation of the RAS-MAPK pathway.	('binding', 'Interaction', (64, 71))	('overexpression', 'PosReg', (91, 105))	('KRAS', 'Gene', (86, 90))	('Polymorphisms', 'Var', (0, 13))	('activation', 'PosReg', (130, 140))	('let-7', 'Gene', '266952', (58, 63))	('alter', 'Reg', (52, 57))	('let-7', 'Gene', (58, 63))	('RAS-MAPK pathway', 'Pathway', (148, 164))	('KRAS', 'Gene', (17, 21))
283454	26646588	The LCS6 (Let-7 Complementary Sites 6) SNP (rs61764370) has been associated with an increased risk of lung cancer among people with a moderate smoking history.	('rat', 'Species', '10116', (138, 141))	('lung cancer', 'Phenotype', 'HP:0100526', (102, 113))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('rs61764370', 'Mutation', 'rs61764370', (44, 54))	('lung cancer', 'Disease', (102, 113))	('associated', 'Reg', (65, 75))	('lung cancer', 'Disease', 'MESH:D008175', (102, 113))	('Let-7', 'Gene', '266952', (10, 15))	('rs61764370', 'Var', (44, 54))	('people', 'Species', '9606', (120, 126))	('Let-7', 'Gene', (10, 15))
283455	26646588	This LCS6 SNP was also described as a biomarker of cancer treatment response in oral cancer and colorectal cancer.	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('colorectal cancer', 'Phenotype', 'HP:0003003', (96, 113))	('oral cancer', 'Disease', 'MESH:D009062', (80, 91))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('cancer', 'Disease', (85, 91))	('LCS6', 'Var', (5, 9))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('colorectal cancer', 'Disease', (96, 113))	('oral cancer', 'Disease', (80, 91))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('rectal cancer', 'Phenotype', 'HP:0100743', (100, 113))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', (107, 113))	('colorectal cancer', 'Disease', 'MESH:D015179', (96, 113))
283456	26646588	Finally, LCS6 SNP predicted improved response to anti-EGFR monoclonal antibody monotherapy in patients with metastatic colorectal cancer.	('colorectal cancer', 'Phenotype', 'HP:0003003', (119, 136))	('patients', 'Species', '9606', (94, 102))	('improved', 'PosReg', (28, 36))	('response', 'MPA', (37, 45))	('colorectal cancer', 'Disease', (119, 136))	('rectal cancer', 'Phenotype', 'HP:0100743', (123, 136))	('LCS6 SNP', 'Var', (9, 17))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('colorectal cancer', 'Disease', 'MESH:D015179', (119, 136))
283459	26646588	A genome-wide analysis has revealed HRAS mutations in ~12% of OSCC.	('mutations', 'Var', (41, 50))	('SCC', 'Phenotype', 'HP:0002860', (63, 66))	('HRAS', 'Gene', '3265', (36, 40))	('revealed', 'Reg', (27, 35))	('HRAS', 'Gene', (36, 40))	('OSCC', 'Disease', (62, 66))
283486	26646588	This result indicates that, as for miR-181c, miR-433 down-regulation is mediated through methylation epigenetic silencing.	('miR-433', 'Gene', '574034', (45, 52))	('down-regulation', 'NegReg', (53, 68))	('miR-433', 'Gene', (45, 52))	('miR-181c', 'Gene', (35, 43))	('miR-181c', 'Gene', '406957', (35, 43))	('methylation epigenetic silencing', 'Var', (89, 121))
283494	26646588	Both miR-193b and miR-365a could acted as a tumor suppressor in the epidermis by directly targeting KRAS oncogene.	('miR-365a', 'Gene', '100126355', (18, 26))	('miR-365a', 'Gene', (18, 26))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('miR-193b', 'Var', (5, 13))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('targeting', 'Reg', (90, 99))	('KRAS oncogene', 'Gene', (100, 113))	('tumor', 'Disease', (44, 49))
283497	26646588	Re-expression of miR-206 in PDAC cells was sufficient to inhibit tumor blood and lymphatic vessel formation, thus leading to a significant delay of tumor growth and progression.	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('tumor', 'Disease', (65, 70))	('miR-206', 'Gene', (17, 24))	('PDAC', 'Chemical', '-', (28, 32))	('tumor', 'Disease', (148, 153))	('inhibit', 'NegReg', (57, 64))	('Re-expression', 'Var', (0, 13))	('miR-206', 'Gene', '406989', (17, 24))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('PDAC', 'Phenotype', 'HP:0006725', (28, 32))	('delay', 'NegReg', (139, 144))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
283499	26646588	MiR-21 production was up-regulated by oncogenic KRAS in thyroid carcinomas, non-small-cell lung cancers, laryngeal squamous cell carcinoma, and PDAC.	('lung cancer', 'Phenotype', 'HP:0100526', (91, 102))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (56, 73))	('lung cancers', 'Phenotype', 'HP:0100526', (91, 103))	('laryngeal squamous cell carcinoma', 'Disease', 'MESH:D002294', (105, 138))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (80, 102))	('cancers', 'Phenotype', 'HP:0002664', (96, 103))	('thyroid carcinomas', 'Phenotype', 'HP:0002890', (56, 74))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (76, 102))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))	('carcinomas', 'Phenotype', 'HP:0030731', (64, 74))	('up-regulated', 'PosReg', (22, 34))	('MiR-21', 'Gene', (0, 6))	('MiR-21', 'Gene', '406991', (0, 6))	('laryngeal squamous cell carcinoma', 'Disease', (105, 138))	('PDAC', 'Chemical', '-', (144, 148))	('lung cancers', 'Disease', 'MESH:D008175', (91, 103))	('KRAS', 'Var', (48, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('thyroid carcinomas', 'Disease', 'MESH:D013964', (56, 74))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (115, 138))	('PDAC', 'Phenotype', 'HP:0006725', (144, 148))	('lung cancers', 'Disease', (91, 103))	('thyroid carcinomas', 'Disease', (56, 74))
283510	26646588	Somatic loss-of-function mutations in the tumor suppressor NF1, leading to RAS-MAPK pathway activation, have been described in ~25 % of GBM.	('mutations', 'Var', (25, 34))	('tumor', 'Disease', (42, 47))	('activation', 'PosReg', (92, 102))	('RAS-MAPK pathway', 'Pathway', (75, 91))	('GBM', 'Phenotype', 'HP:0012174', (136, 139))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('NF1', 'Gene', (59, 62))	('loss-of-function', 'NegReg', (8, 24))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('GBM', 'Disease', (136, 139))
283515	26646588	MiR-146a was shown to be highly up-regulated by oncogenic BRAF and NRAS mutants frequently observed in melanomas.	('mutants', 'Var', (72, 79))	('melanomas', 'Disease', 'MESH:D008545', (103, 112))	('melanoma', 'Phenotype', 'HP:0002861', (103, 111))	('up-regulated', 'PosReg', (32, 44))	('NRAS', 'Gene', (67, 71))	('melanomas', 'Disease', (103, 112))	('MiR-146a', 'Gene', '406938', (0, 8))	('MiR-146a', 'Gene', (0, 8))	('BRAF', 'Gene', (58, 62))	('melanomas', 'Phenotype', 'HP:0002861', (103, 112))
283525	26646588	Although there have been few evidences of miRNA directly targeting BRAF mRNA, it has been demonstrated that BRAF oncogenic mutations were associated with miRNAs deregulation in many cancer types.	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('rat', 'Species', '10116', (97, 100))	('BRAF', 'Gene', (108, 112))	('deregulation', 'NegReg', (161, 173))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('associated', 'Reg', (138, 148))	('cancer', 'Disease', (182, 188))	('miRNAs', 'MPA', (154, 160))	('mutations', 'Var', (123, 132))
283527	26646588	MiR-146b expression level was significantly higher in papillary thyroid carcinoma with BRAF mutation and significantly associated with invasive behavior.	('invasive behavior', 'CPA', (135, 152))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('mutation', 'Var', (92, 100))	('associated with', 'Reg', (119, 134))	('higher', 'PosReg', (44, 50))	('expression level', 'MPA', (9, 25))	('papillary thyroid carcinoma', 'Disease', (54, 81))	('MiR-146b', 'Gene', '574447', (0, 8))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (64, 81))	('papillary thyroid carcinoma', 'Disease', 'MESH:D000077273', (54, 81))	('MiR-146b', 'Gene', (0, 8))	('papillary thyroid carcinoma', 'Phenotype', 'HP:0002895', (54, 81))	('BRAF', 'Gene', (87, 91))
283528	26646588	MiR-146a (another miR-146 family member) was highly up-regulated by oncogenic BRAF and NRAS mutations in melanomas.	('melanomas', 'Disease', (105, 114))	('up-regulated', 'PosReg', (52, 64))	('melanoma', 'Phenotype', 'HP:0002861', (105, 113))	('BRAF', 'Gene', (78, 82))	('mutations', 'Var', (92, 101))	('melanomas', 'Phenotype', 'HP:0002861', (105, 114))	('MiR-146a', 'Gene', '406938', (0, 8))	('melanomas', 'Disease', 'MESH:D008545', (105, 114))	('miR-1', 'Gene', '79187', (18, 23))	('MiR-146a', 'Gene', (0, 8))	('NRAS', 'Gene', (87, 91))	('miR-1', 'Gene', (18, 23))
283529	26646588	MiR-193a, miR-338, and miR-565 were down-regulated in melanomas with BRAF mutations.	('MiR-193a', 'Gene', (0, 8))	('miR-338', 'Gene', '442906', (10, 17))	('miR-338', 'Gene', (10, 17))	('melanomas', 'Phenotype', 'HP:0002861', (54, 63))	('mutations', 'Var', (74, 83))	('melanomas', 'Disease', 'MESH:D008545', (54, 63))	('melanoma', 'Phenotype', 'HP:0002861', (54, 62))	('melanomas', 'Disease', (54, 63))	('MiR-193a', 'Gene', '406968', (0, 8))	('miR-565', 'Gene', (23, 30))	('down-regulated', 'NegReg', (36, 50))	('BRAF', 'Gene', (69, 73))
283531	26646588	MiR-31-5p was one the most up-regulated miRNA in colorectal cancers with BRAF p.V600E oncogenic mutation, compared with wild-type BRAF and play a role in cell invasion and proliferation in this tumor type.	('up-regulated', 'PosReg', (27, 39))	('cell invasion', 'CPA', (154, 167))	('rectal cancer', 'Phenotype', 'HP:0100743', (53, 66))	('proliferation', 'CPA', (172, 185))	('cancers', 'Phenotype', 'HP:0002664', (60, 67))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('MiR-31', 'Gene', (0, 6))	('colorectal cancer', 'Phenotype', 'HP:0003003', (49, 66))	('MiR-31', 'Gene', '407035', (0, 6))	('p.V600E', 'Var', (78, 85))	('colorectal cancers', 'Disease', 'MESH:D015179', (49, 67))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('p.V600E', 'SUBSTITUTION', 'None', (78, 85))	('tumor', 'Disease', (194, 199))	('rat', 'Species', '10116', (179, 182))	('BRAF', 'Gene', (73, 77))	('colorectal cancers', 'Disease', (49, 67))
283536	26646588	MiR-34a expression was down-regulated in many tumor types by promoter methylation.	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Disease', (46, 51))	('MiR-34a', 'Gene', (0, 7))	('MiR-34a', 'Gene', '407040', (0, 7))	('promoter methylation', 'Var', (61, 81))	('expression', 'MPA', (8, 18))	('down-regulated', 'NegReg', (23, 37))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
283562	26646588	Since induction of angiogenesis is a hallmark of cancer, initiation of neovascularization mediated by miRNAs deregulation emphasizes the importance of miRNAs in tumor formation by a mechanism different from merely enhancing proliferation.	('angiogenesis', 'CPA', (19, 31))	('rat', 'Species', '10116', (231, 234))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('hallmark of cancer', 'Disease', (37, 55))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('miRNAs', 'Gene', (102, 108))	('hallmark of cancer', 'Disease', 'MESH:D009369', (37, 55))	('neovascularization', 'CPA', (71, 89))	('deregulation', 'Var', (109, 121))	('tumor', 'Disease', (161, 166))
283569	26646588	Interestingly, NF1 gene deletions and mutations are frequent oncogenic events in acute myeloid leukemia and MPNST.	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (81, 103))	('NF1', 'Gene', (15, 18))	('acute myeloid leukemia', 'Disease', (81, 103))	('deletions', 'Var', (24, 33))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (81, 103))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (87, 103))	('mutations', 'Var', (38, 47))	('leukemia', 'Phenotype', 'HP:0001909', (95, 103))	('MPNST', 'Disease', (108, 113))
283576	26646588	Oncogenic RAS mutations occur in approximately 30% of tumors; however, mutations in upstream regulators and downstream effectors are also highly prevalent in many tumor types.	('tumors', 'Disease', 'MESH:D009369', (54, 60))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('prevalent', 'Reg', (145, 154))	('RAS', 'Gene', (10, 13))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('mutations', 'Var', (71, 80))	('tumor', 'Disease', (163, 168))	('tumor', 'Disease', (54, 59))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('mutations', 'Var', (14, 23))	('tumors', 'Disease', (54, 60))
283577	26646588	Irrespective of the etiology, the oncogenic RAS signal is frequently potentiated as cancers progress through amplification of mutant RAS genes or suppression of negative feedback pathways.	('negative feedback pathways', 'Pathway', (161, 187))	('cancers', 'Disease', 'MESH:D009369', (84, 91))	('suppression', 'NegReg', (146, 157))	('RAS genes', 'Gene', (133, 142))	('cancers', 'Phenotype', 'HP:0002664', (84, 91))	('cancers', 'Disease', (84, 91))	('amplification', 'Var', (109, 122))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('potentiated', 'PosReg', (69, 80))	('mutant', 'Var', (126, 132))	('progress', 'PosReg', (92, 100))
283578	26646588	Epigenetic is likely to contribute to this emerging aspect of tumor evolution.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', (62, 67))	('contribute', 'Reg', (24, 34))	('Epigenetic', 'Var', (0, 10))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
283580	26646588	Specific mechanisms leading to miRNAs deregulation and their functional consequences in cancer are far from being fully elucidated.	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('deregulation', 'Var', (38, 50))	('miRNAs', 'Protein', (31, 37))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))
283581	26646588	Integration of the different single miRNAs variations and targets of the RAS-MAPK pathway in human cancers is also challenging.	('human', 'Species', '9606', (93, 98))	('cancers', 'Disease', 'MESH:D009369', (99, 106))	('cancers', 'Phenotype', 'HP:0002664', (99, 106))	('rat', 'Species', '10116', (5, 8))	('cancers', 'Disease', (99, 106))	('variations', 'Var', (43, 53))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
283584	26646588	Dysregulation of miRNAs that target the RAS-MAPK pathway can represent an oncogenic event leading to sustained proliferation.	('Dysregulation', 'Var', (0, 13))	('rat', 'Species', '10116', (118, 121))	('sustained proliferation', 'CPA', (101, 124))	('RAS-MAPK pathway', 'Pathway', (40, 56))
283590	26646588	In colorectal cancer patients, LSC6 polymorphism in the let-7 binding site of the KRAS gene, has been proposed to predict the tumor responsiveness in EGFR-directed (cetuximab) treated patients.	('patients', 'Species', '9606', (184, 192))	('predict', 'Reg', (114, 121))	('colorectal cancer', 'Phenotype', 'HP:0003003', (3, 20))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('patients', 'Species', '9606', (21, 29))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('colorectal cancer', 'Disease', (3, 20))	('rectal cancer', 'Phenotype', 'HP:0100743', (7, 20))	('polymorphism', 'Var', (36, 48))	('LSC6', 'Gene', (31, 35))	('cetuximab', 'Chemical', 'MESH:D000068818', (165, 174))	('let-7', 'Gene', '266952', (56, 61))	('colorectal cancer', 'Disease', 'MESH:D015179', (3, 20))	('let-7', 'Gene', (56, 61))	('tumor', 'Disease', (126, 131))
283591	26646588	Finally, the function of miRNAs can be efficiently and specifically inhibited by chemically modified antisense oligonucleotides, supporting their potential as targets for the development of novel therapies.	('function', 'MPA', (13, 21))	('antisense oligonucleotides', 'Var', (101, 127))	('inhibited', 'NegReg', (68, 77))	('oligonucleotides', 'Chemical', 'MESH:D009841', (111, 127))
283593	26646588	For example, in vivo treatment with miR-34a prevented tumor formation and progression in a pre-clinical transgenic therapeutically resistant KrasLSL-G12D/+;Trp53LSL-R172H/+ mouse lung cancer model.	('Trp53', 'Gene', '22059', (156, 161))	('R172H', 'SUBSTITUTION', 'None', (165, 170))	('progression', 'CPA', (74, 85))	('prevented', 'NegReg', (44, 53))	('lung cancer', 'Disease', (179, 190))	('G12D', 'Mutation', 'rs121913529', (149, 153))	('lung cancer', 'Phenotype', 'HP:0100526', (179, 190))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('miR-34a', 'Gene', '407040', (36, 43))	('tumor', 'Disease', (54, 59))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('miR-34a', 'Gene', (36, 43))	('R172H', 'Var', (165, 170))	('Trp53', 'Gene', (156, 161))	('lung cancer', 'Disease', 'MESH:D008175', (179, 190))
283594	26646588	Another study suggested that the delivery of let-7 miRNA into tumors may have therapeutic benefit in patients with cancer and mimic are currently developed.	('cancer', 'Disease', (115, 121))	('patients', 'Species', '9606', (101, 109))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumors', 'Disease', (62, 68))	('miRNA', 'Var', (51, 56))	('tumors', 'Disease', 'MESH:D009369', (62, 68))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('let-7', 'Gene', '266952', (45, 50))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('let-7', 'Gene', (45, 50))
283644	24167666	In the univariate analysis, FIGO stage (p=0.041), pretreatment hemoglobin levels <10.5 g/dL (p=0.001), tumor size >=40 mm (p=0.001), pelvic lymph node metastasis (p=0.001) and CCRT (p=0.016) were shown to be associated with OS (Table 3).	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('hemoglobin levels', 'MPA', (63, 80))	('pelvic lymph node metastasis', 'CPA', (133, 161))	('tumor', 'Disease', (103, 108))	('>=40', 'Var', (114, 118))	('CCRT', 'CPA', (176, 180))	('CR', 'Chemical', '-', (177, 179))	('associated', 'Reg', (208, 218))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
283646	24167666	The three-year OS rates for patients with serum SCC-Ag levels <1.15 ng/mL and >=1.15 ng/mL were 90.7% and 36.6%, respectively (p<0.001) (Fig.	('patients', 'Species', '9606', (28, 36))	('>=1.15', 'Var', (78, 84))	('SCC', 'Gene', (48, 51))	('SCC', 'Gene', '6317', (48, 51))
283647	24167666	The three-year PFS rates for patients with serum SCC-Ag levels <1.15 ng/mL and >=1.15 ng/mL were 74.7% and 19.5%, respectively (p<0.001) (Fig.	('SCC', 'Gene', (49, 52))	('SCC', 'Gene', '6317', (49, 52))	('>=1.15', 'Var', (79, 85))	('patients', 'Species', '9606', (29, 37))
283730	32907876	Melanoma and ovarian cancer patients with high levels of TIPB showed significantly longer overall survival (likelihood ratio test p < 0.01 for both, hazard ratio 0.56 melanoma, 0.69 ovarian cancer, Fig.	('ovarian cancer', 'Phenotype', 'HP:0100615', (182, 196))	('overall', 'MPA', (90, 97))	('high levels', 'Var', (42, 53))	('melanoma', 'Phenotype', 'HP:0002861', (167, 175))	('melanoma', 'Disease', (167, 175))	('ovarian cancer', 'Disease', (13, 27))	('TIPB', 'Gene', (57, 61))	('Melanoma and ovarian cancer', 'Disease', 'MESH:D008545', (0, 27))	('ovarian cancer', 'Phenotype', 'HP:0100615', (13, 27))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('longer', 'PosReg', (83, 89))	('patients', 'Species', '9606', (28, 36))	('Melanoma', 'Phenotype', 'HP:0002861', (0, 8))	('ovarian cancer', 'Disease', 'MESH:D010051', (182, 196))	('melanoma', 'Disease', 'MESH:D008545', (167, 175))	('TIPB', 'Chemical', '-', (57, 61))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('ovarian cancer', 'Disease', 'MESH:D010051', (13, 27))	('ovarian cancer', 'Disease', (182, 196))
283733	32907876	We subsequently assessed pathway-level differences between patients with high- and low-levels of TIPB in the five cohorts.	('TIPB', 'Gene', (97, 101))	('TIPB', 'Chemical', '-', (97, 101))	('high-', 'Var', (73, 78))	('patients', 'Species', '9606', (59, 67))	('low-levels', 'NegReg', (83, 93))
283763	32231310	Here, we show that this comes at a significant cost for cancer cells with high SLC7A11 expression.	('high', 'Var', (74, 78))	('expression', 'Species', '29278', (87, 97))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('expression', 'MPA', (87, 97))	('SLC7A11', 'Gene', (79, 86))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))
283778	32231310	In this study, we reveal a metabolic vulnerability associated with high SLC7A11 expression in cancer cells and propose corresponding therapeutic strategies to target SLC7A11-high cancers.	('high', 'Var', (67, 71))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('cancer', 'Disease', 'MESH:D009369', (94, 100))	('SLC7A11', 'Gene', (72, 79))	('expression', 'Species', '29278', (80, 90))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('expression', 'MPA', (80, 90))	('cancers', 'Disease', 'MESH:D009369', (179, 186))	('cancers', 'Phenotype', 'HP:0002664', (179, 186))	('cancers', 'Disease', (179, 186))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', (179, 185))
283792	32231310	An analysis of the expression levels of SLC7A11 and PPP enzymes in a panel of cancer cell lines revealed that SLC7A11-high cell lines generally exhibited higher expression of PPP enzymes than SLC7A11-low cell lines (Fig.	('expression', 'Species', '29278', (161, 171))	('expression', 'MPA', (161, 171))	('cancer', 'Disease', (78, 84))	('SLC7A11-high', 'Var', (110, 122))	('higher', 'PosReg', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('PPP enzymes', 'Enzyme', (175, 186))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('expression', 'Species', '29278', (19, 29))
283793	32231310	Knockdown of G6PD, the rate-limiting enzyme in the PPP, promoted cell death under glucose-limiting conditions in G6PD-high/SLC7A11-high cells (UMRC6 and A498 cells) (Extended Data Fig.	('UMRC6', 'CellLine', 'CVCL:2741', (143, 148))	('A498', 'CellLine', 'CVCL:1056', (153, 157))	('G6PD', 'Var', (13, 17))	('G6PD-high/SLC7A11-high', 'Var', (113, 135))	('glucose', 'Chemical', 'MESH:D005947', (82, 89))	('cell death', 'CPA', (65, 75))	('promoted', 'PosReg', (56, 64))
283794	32231310	Consistent with previous reports by us and others , SLC7A11 overexpression promoted cell death under glucose-limiting conditions (Fig.	('promoted', 'PosReg', (75, 83))	('glucose', 'Chemical', 'MESH:D005947', (101, 108))	('SLC7A11', 'Gene', (52, 59))	('cell death', 'CPA', (84, 94))	('expression', 'Species', '29278', (64, 74))	('overexpression', 'Var', (60, 74))
283795	32231310	We found that G6PD knockdown promoted, whereas its overexpression attenuated, glucose-limitation-induced cell death in SLC7A11-overexpressing cells (Fig.	('promoted', 'PosReg', (29, 37))	('glucose-limitation-induced', 'MPA', (78, 104))	('G6PD knockdown', 'Var', (14, 28))	('knockdown', 'Var', (19, 28))	('attenuated', 'NegReg', (66, 76))	('expression', 'Species', '29278', (55, 65))	('glucose', 'Chemical', 'MESH:D005947', (78, 85))
283804	32231310	Finally, we showed that, in certain cancers such as kidney papillary cell carcinoma (KIRP), combining high SLC7A11 with high G6PD, PGD, or GLUT1 expression predicted a far worse clinical outcome than either parameter alone (Fig.	('cancers', 'Disease', 'MESH:D009369', (36, 43))	('high', 'Var', (102, 106))	('cancers', 'Phenotype', 'HP:0002664', (36, 43))	('PGD', 'Protein', (131, 134))	('cancers', 'Disease', (36, 43))	('expression', 'Species', '29278', (145, 155))	('kidney papillary cell carcinoma', 'Disease', 'MESH:C538614', (52, 83))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('kidney papillary cell carcinoma', 'Disease', (52, 83))	('G6PD', 'Var', (125, 129))	('SLC7A11', 'Gene', (107, 114))	('GLUT1', 'Gene', (139, 144))
283817	32231310	We further confirmed our findings in SLC7A11-high UMRC6 cells with SLC7A11 deletion (Fig.	('UMRC6', 'CellLine', 'CVCL:2741', (50, 55))	('deletion', 'Var', (75, 83))	('SLC7A11', 'Gene', (67, 74))
283818	32231310	In addition, treatment with sulfasalazine (SAS), an inhibitor of SLC7A11 transporter activity, blocked cystine uptake and exerted similar rescuing effects to SLC7A11 deletion in these cells under glucose starvation (Extended Data Fig.	('SAS', 'Chemical', 'MESH:D012460', (43, 46))	('deletion', 'Var', (166, 174))	('SLC7A11', 'Gene', (158, 165))	('blocked', 'NegReg', (95, 102))	('cystine', 'Chemical', 'MESH:D003553', (103, 110))	('cystine uptake', 'MPA', (103, 117))	('sulfasalazine', 'Chemical', 'MESH:D012460', (28, 41))	('glucose', 'Chemical', 'MESH:D005947', (196, 203))
283824	32231310	This observation may seem odd, because cystine in culture medium is required for cell survival and it is well established that cystine deprivation induces ferroptosis .	('cystine deprivation', 'Var', (127, 146))	('induces', 'Reg', (147, 154))	('ferroptosis', 'Disease', (155, 166))	('cystine', 'Chemical', 'MESH:D003553', (39, 46))	('cystine', 'Chemical', 'MESH:D003553', (127, 134))
283834	32231310	2-deoxy-D-[1-2H] glucose (2H-2DG) tracing experiments confirmed that 2DG indeed contributed to NADPH generation under glucose starvation (Fig.	('2DG', 'Var', (69, 72))	('contributed', 'Reg', (80, 91))	('NADPH generation', 'MPA', (95, 111))	('2H', 'Chemical', 'MESH:D003903', (26, 28))	('glucose', 'Chemical', 'MESH:D005947', (118, 125))	('2DG', 'Chemical', '-', (69, 72))	('2H', 'Chemical', 'MESH:D003903', (13, 15))	('2H-2DG', 'Chemical', '-', (26, 32))	('glucose', 'Chemical', 'MESH:D005947', (17, 24))	('2DG', 'Chemical', '-', (29, 32))
283843	32231310	In addition, NAC (but not Trolox or Tempol) presumably can prevent cystine or other disulfide accumulation under glucose starvation through disulfide exchange (e.g., Cys-Cys + NAC   Cys + NAC-Cys).	('disulfide', 'Chemical', 'MESH:D004220', (140, 149))	('cystine', 'MPA', (67, 74))	('Cys', 'Chemical', 'MESH:D003545', (166, 169))	('Cys', 'Chemical', 'MESH:D003545', (170, 173))	('Trolox', 'Chemical', 'MESH:C010643', (26, 32))	('NAC', 'Chemical', 'MESH:D000111', (188, 191))	('NAC', 'Chemical', 'MESH:D000111', (13, 16))	('Cys-Cys', 'Chemical', 'MESH:C046557', (166, 173))	('Tempol', 'Chemical', 'MESH:C001803', (36, 42))	('prevent', 'NegReg', (59, 66))	('Cys', 'Chemical', 'MESH:D003545', (182, 185))	('disulfide', 'Chemical', 'MESH:D004220', (84, 93))	('glucose', 'Chemical', 'MESH:D005947', (113, 120))	('cystine', 'Chemical', 'MESH:D003553', (67, 74))	('Cys', 'Chemical', 'MESH:D003545', (192, 195))	('disulfide exchange', 'MPA', (140, 158))	('NAC', 'Chemical', 'MESH:D000111', (176, 179))	('Cys-Cys + NAC   Cys + NAC-Cys', 'Var', (166, 195))
283848	32231310	Importantly, reducing cystine to cysteine can improve its solubility by more than 2,000-fold (Extended Data Fig.	('solubility', 'MPA', (58, 68))	('cysteine', 'Chemical', 'MESH:D003545', (33, 41))	('cystine', 'Var', (22, 29))	('cystine', 'Chemical', 'MESH:D003553', (22, 29))	('improve', 'PosReg', (46, 53))
283861	32231310	We confirmed that KL-11743 or BAY-876 potently inhibited glucose uptake (Fig.	('KL-11743', 'Chemical', '-', (18, 26))	('inhibited', 'NegReg', (47, 56))	('KL-11743', 'Var', (18, 26))	('glucose', 'Chemical', 'MESH:D005947', (57, 64))	('BAY-876', 'Chemical', 'MESH:C000620175', (30, 37))	('BAY-876', 'Gene', (30, 37))	('glucose uptake', 'CPA', (57, 71))
283864	32231310	5c), and that SLC7A11 deletion (or its overexpression) in SLC7A11-high (or -low) cancer cells switched their sensitivity to GLUT inhibition (Fig.	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('deletion', 'Var', (22, 30))	('cancer', 'Disease', (81, 87))	('switched', 'Reg', (94, 102))	('SLC7A11', 'Gene', (14, 21))	('expression', 'Species', '29278', (43, 53))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('sensitivity to GLUT inhibition', 'MPA', (109, 139))
283866	32231310	Finally, we showed that G6PD overexpression in SLC7A11-overexpressing cells partially reversed the increased sensitivity to GLUT inhibition upon SLC7A11 overexpression (Fig.	('expression', 'Species', '29278', (157, 167))	('overexpression', 'PosReg', (153, 167))	('G6PD', 'Var', (24, 28))	('SLC7A11', 'Gene', (145, 152))	('SLC7A11-overexpressing', 'Gene', (47, 69))	('expression', 'Species', '29278', (33, 43))	('increased', 'PosReg', (99, 108))	('sensitivity to GLUT inhibition', 'MPA', (109, 139))
283867	32231310	Together, our data strongly suggest that SLC7A11 overexpression sensitizes cancer cells to GLUT inhibition.	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('GLUT inhibition', 'MPA', (91, 106))	('cancer', 'Disease', (75, 81))	('overexpression', 'Var', (49, 63))	('SLC7A11', 'Gene', (41, 48))	('expression', 'Species', '29278', (53, 63))	('sensitizes', 'Reg', (64, 74))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))
283871	32231310	Treatment with KL-11743 dramatically decreased the growth of SLC7A11-high NCI-H226 xenograft tumors; importantly, SLC7A11 deletion abolished the increased sensitivity of these tumors to GLUT inhibition (Fig.	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('sensitivity', 'MPA', (155, 166))	('abolished', 'NegReg', (131, 140))	('tumors', 'Disease', 'MESH:D009369', (93, 99))	('NCI-H226', 'CellLine', 'CVCL:1544', (74, 82))	('KL-11743', 'Chemical', '-', (15, 23))	('tumors', 'Disease', (176, 182))	('deletion', 'Var', (122, 130))	('tumors', 'Disease', 'MESH:D009369', (176, 182))	('tumors', 'Phenotype', 'HP:0002664', (176, 182))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('SLC7A11', 'Gene', (114, 121))	('tumors', 'Disease', (93, 99))
283873	32231310	Metabolite measurement in tumors confirmed that KL-11743 treatment decreased PPP intermediate 6-phosphogluconate levels and specifically increased NADP+/NADPH ratio in SLC7A11-high tumors (Fig.	('KL-11743', 'Chemical', '-', (48, 56))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('KL-11743', 'Var', (48, 56))	('tumors', 'Disease', (181, 187))	('NADP+', 'Chemical', 'MESH:D009249', (147, 152))	('tumors', 'Disease', 'MESH:D009369', (181, 187))	('tumors', 'Phenotype', 'HP:0002664', (181, 187))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('6-phosphogluconate', 'Chemical', 'MESH:C008884', (94, 112))	('increased', 'PosReg', (137, 146))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('PPP intermediate 6-phosphogluconate levels', 'MPA', (77, 119))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('decreased', 'NegReg', (67, 76))	('NADP+/NADPH ratio', 'MPA', (147, 164))	('tumors', 'Disease', (26, 32))
283874	32231310	Of note, GLUT inhibition decreased the levels of the metabolites in the upper glycolysis pathway (glucose-6-phosphate and fructose-1, 6- bisphosphate) but did not affect the levels of the glycolytic end-product lactate (Fig.	('lactate', 'Chemical', 'MESH:D019344', (211, 218))	('levels of', 'MPA', (39, 48))	('decreased', 'NegReg', (25, 34))	('GLUT', 'Protein', (9, 13))	('glucose', 'Chemical', 'MESH:D005947', (98, 105))	('upper glycolysis pathway', 'Pathway', (72, 96))	('metabolites', 'MPA', (53, 64))	('inhibition', 'Var', (14, 24))
283876	32231310	Conversely, SLC7A11 overexpression significantly sensitized xenograft tumors established from ACHN cells (a SLC7A11-low cell line) to GLUT inhibition (Fig.	('expression', 'Species', '29278', (24, 34))	('overexpression', 'Var', (20, 34))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('GLUT inhibition', 'MPA', (134, 149))	('sensitized', 'Reg', (49, 59))	('tumors', 'Disease', (70, 76))	('tumors', 'Disease', 'MESH:D009369', (70, 76))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('SLC7A11', 'Gene', (12, 19))
283883	32231310	Our data suggest that, in cancer cells with high SLC7A11 expression and cystine uptake, cystine reduction to cysteine is also an important NADPH consumer, a concept which is underappreciated in the current literature.	('expression', 'MPA', (57, 67))	('high', 'Var', (44, 48))	('cystine', 'Chemical', 'MESH:D003553', (72, 79))	('cystine reduction', 'Phenotype', 'HP:0500152', (88, 105))	('cancer', 'Disease', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('cysteine', 'Chemical', 'MESH:D003545', (109, 117))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('SLC7A11', 'Gene', (49, 56))	('cystine', 'MPA', (72, 79))	('cystine reduction to cysteine', 'MPA', (88, 117))	('cystine', 'Chemical', 'MESH:D003553', (88, 95))	('expression', 'Species', '29278', (57, 67))
283884	32231310	We propose that, in cancer cells with high SLC7A11 expression, the increased cystine uptake, while beneficial for cancer cells in antioxidant responses, also come at a significant cost.	('antioxidant responses', 'MPA', (130, 151))	('cystine uptake', 'MPA', (77, 91))	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('SLC7A11', 'Gene', (43, 50))	('expression', 'Species', '29278', (51, 61))	('high', 'Var', (38, 42))	('cancer', 'Disease', 'MESH:D009369', (20, 26))	('increased cystine', 'Phenotype', 'HP:0500151', (67, 84))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('increased', 'PosReg', (67, 76))	('cancer', 'Disease', (20, 26))	('cystine', 'Chemical', 'MESH:D003553', (77, 84))	('beneficial', 'PosReg', (99, 109))	('expression', 'Var', (51, 61))	('cancer', 'Disease', (114, 120))
283889	32231310	Limiting NADPH production from the PPP by glucose starvation (or GLUT inhibition) in the context of high SLC7A11 expression leads to a massive accumulation of small molecule disulfides (including cystine), a series of redox defects, and rapid cell death (Extended Data Fig.	('accumulation', 'PosReg', (143, 155))	('SLC7A11', 'Gene', (105, 112))	('cystine', 'Chemical', 'MESH:D003553', (196, 203))	('cell death', 'CPA', (243, 253))	('redox defects', 'MPA', (218, 231))	('high', 'Var', (100, 104))	('disulfides', 'Chemical', 'MESH:D004220', (174, 184))	('expression', 'Species', '29278', (113, 123))	('glucose', 'Chemical', 'MESH:D005947', (42, 49))
283898	32231310	However, despite potent blockade of glucose uptake, GLUT inhibition by KL-11743 does not have obvious single-agent cytotoxic or tumor-suppressive effects across a broad range of cancer cell lines or preclinical models, but appears to exert significant therapeutic effects only in certain cellular contexts, underscoring the need to identify the specific genetic or tumor backgrounds for therapeutic targeting of GLUTs.	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('tumor', 'Disease', 'MESH:D009369', (365, 370))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('blockade', 'NegReg', (24, 32))	('tumor', 'Phenotype', 'HP:0002664', (365, 370))	('GLUT', 'Protein', (52, 56))	('glucose uptake', 'MPA', (36, 50))	('inhibition', 'NegReg', (57, 67))	('glucose', 'Chemical', 'MESH:D005947', (36, 43))	('tumor', 'Disease', (365, 370))	('cancer', 'Disease', (178, 184))	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('KL-11743', 'Chemical', '-', (71, 79))	('tumor', 'Disease', (128, 133))	('KL-11743', 'Var', (71, 79))
283901	32231310	Our study therefore calls for further testing these GLUT inhibitors in treating SLC7A11-overexpressing tumors in future preclinical and clinical studies, and proposes that BAP1 or KEAP1 mutations may serve as potential biomarkers in selecting cancer patients with high SLC7A11 expression for GLUT inhibition.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('mutations', 'Var', (186, 195))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('BAP1', 'Gene', (172, 176))	('SLC7A11-overexpressing', 'Gene', (80, 102))	('patients', 'Species', '9606', (250, 258))	('cancer', 'Disease', (243, 249))	('tumors', 'Disease', (103, 109))	('tumors', 'Disease', 'MESH:D009369', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (243, 249))	('SLC7A11', 'Gene', (269, 276))	('cancer', 'Phenotype', 'HP:0002664', (243, 249))	('expression', 'Species', '29278', (277, 287))
283910	32231310	G6PD shRNA constructs in GIPZ vector and G6PD cDNA were obtained from the Functional Genomics Core Facility of The University of Texas MD Anderson Cancer Center.	('G6PD', 'Var', (41, 45))	('Cancer', 'Disease', 'MESH:D009369', (147, 153))	('Cancer', 'Phenotype', 'HP:0002664', (147, 153))	('Cancer', 'Disease', (147, 153))
283915	32231310	Following reagents were obtained from Sigma: BAY-876 (#SML1774-25MG), L-Glutamine-13C5 (#605166-100MG), N-Acetyl-L-Cysteine (NAC) (#A9165), 2-Deoxy-D-glucose (#D8375-1G), Sulfasalazine (#S0883-10G), D-Penicillamine (#P4875), L-Penicillamine (#196312), Trolox (#238813), 4-Hydroxy-TEMPO (#176141), Tris(2-carboxyethyl)phosphine hydrochloride(TCEP) (#C4706), 2-Mercaptoethanol (2ME) (#M6250), Deferoxamine mesylate salt (DFO) (#D9533), Ferrostatin-1 (#SML0583), 6-Aminonicotinamide (#A68203-1G), Methyl cellulose (#M0512-100G), TWEEN 80 (# P1754-500ML).	('NAC', 'Chemical', 'MESH:D000111', (125, 128))	('nicotinamide', 'Chemical', 'MESH:D009536', (467, 479))	('# P1754-500ML', 'Var', (536, 549))	('DFO', 'Chemical', 'MESH:D003676', (419, 422))	('Trolox', 'Chemical', 'MESH:C010643', (252, 258))	('C4706', 'CellLine', 'CVCL:S361', (349, 354))	('glucose', 'Chemical', 'MESH:D005947', (150, 157))	('TCEP', 'Chemical', 'MESH:C080938', (341, 345))	('#M0512-100G', 'Var', (512, 523))	('Tris', 'Chemical', '-', (297, 301))	('BAY-876', 'Chemical', 'MESH:C000620175', (45, 52))	('#A68203-1G', 'Var', (481, 491))	('#D9533', 'Var', (425, 431))	('Cysteine', 'Chemical', 'MESH:D003545', (115, 123))
283972	32231310	To measure the pharmacokinetic data of GLUT inhibitor KL-11743, CD1 mice were intraperitoneally injected with dosage of 100 mg/kg KL-11743 in vehicle (0.5% methylcellulose/ 0.25% Tween-80 in water).	('mice', 'Species', '10090', (68, 72))	('water', 'Chemical', 'MESH:D014867', (191, 196))	('methylcellulose', 'Chemical', 'MESH:D008747', (156, 171))	('CD1', 'Gene', (64, 67))	('KL-11743', 'Chemical', '-', (54, 62))	('Tween-80', 'Chemical', 'MESH:D011136', (179, 187))	('CD1', 'Gene', '111334', (64, 67))	('KL-11743', 'Chemical', '-', (130, 138))	('KL-11743', 'Var', (130, 138))
284003	30833271	In particular, immune checkpoint blockade (ICB) such as anti-PD1 antibodies have demonstrated durable response and unprecedented clinical benefit in a subset of patients across multiple types of solid tumors.	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('patients', 'Species', '9606', (161, 169))	('antibodies', 'Var', (65, 75))	('tumors', 'Disease', 'MESH:D009369', (201, 207))	('tumors', 'Disease', (201, 207))	('tumors', 'Phenotype', 'HP:0002664', (201, 207))	('PD1', 'Gene', (61, 64))	('PD1', 'Gene', '5133', (61, 64))
284009	30833271	These studies were primarily focused on tumor cell-intrinsic characteristics such as somatic mutations, copy number alternations, and dysregulated pathways.	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('copy number alternations', 'Var', (104, 128))
284040	30833271	In TCGA LUSC dataset, IS6 and IS4 had a marginally better OS compared with others (P = 0.071) (Supplementary Fig.	('better', 'PosReg', (51, 57))	('IS4', 'Gene', (30, 33))	('IS4', 'Gene', '100190785', (30, 33))	('IS6', 'Var', (22, 25))
284041	30833271	Of note, among HPV+ patients, there was significant difference in OS between two major subtypes (IS6 vs IS4: HR = 2.04, 95% CI: 1.06 - 3.95, P = 0.034, Supplementary Fig.	('IS4', 'Gene', (104, 107))	('HPV', 'Species', '10566', (15, 18))	('patients', 'Species', '9606', (20, 28))	('IS4', 'Gene', '100190785', (104, 107))	('IS6', 'Var', (97, 100))
284044	30833271	Consistent with an immune-cold phenotype, tumors in IS3 had the least leukocyte and stromal fraction (Supplementary Fig.	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('tumors', 'Disease', (42, 48))	('tumors', 'Disease', 'MESH:D009369', (42, 48))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('IS3', 'Var', (52, 55))	('least', 'NegReg', (64, 69))
284045	30833271	Interestingly, IS3 was also associated with the highest degree of somatic copy number variation such as a high aneuploidy score (Fig.	('IS3', 'Var', (15, 18))	('aneuploidy', 'Disease', (111, 121))	('aneuploidy', 'Disease', 'MESH:D000782', (111, 121))
284143	30510209	Based on these promising data, modulation of miRNA levels might possibly open a new era of targeted molecular based therapy in cancer treatment.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('modulation', 'Var', (31, 41))	('miR', 'Gene', '220972', (45, 48))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('miR', 'Gene', (45, 48))	('cancer', 'Disease', (127, 133))
284144	30510209	In support of this, multiple studies in recent years have shown that modulation of miRNAs impacts on cellular behaviour and response to chemotherapy in different tumor types.	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('modulation', 'Var', (69, 79))	('tumor', 'Disease', (162, 167))	('cellular behaviour', 'CPA', (101, 119))	('miR', 'Gene', '220972', (83, 86))	('miR', 'Gene', (83, 86))	('impacts', 'Reg', (90, 97))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('response to chemotherapy', 'CPA', (124, 148))
284196	30510209	Recently, we introduced the concept that modified miRNA expression in both directions can interfere with the available degree of regulatory freedom of cellular functional complexes and thus change their functional readout.	('miR', 'Gene', '220972', (50, 53))	('miR', 'Gene', (50, 53))	('functional readout', 'MPA', (203, 221))	('modified', 'Var', (41, 49))	('change', 'Reg', (190, 196))	('available degree of regulatory freedom', 'MPA', (109, 147))	('interfere', 'NegReg', (90, 99))
284201	30510209	Taken together, our data showed that manipulating the expression levels of miR-130a-3p and miR-148a-3p in both directions led to similar effects on chemotherapy response, and modulation of miR-148a-3p levels in both directions affected the metastatic potential of cell lines in the same way.	('metastatic potential of cell lines', 'CPA', (240, 274))	('manipulating', 'Var', (37, 49))	('miR-130a', 'Gene', '406919', (75, 83))	('miR-148a', 'Gene', '406940', (189, 197))	('miR-148a', 'Gene', (189, 197))	('miR-148a', 'Gene', '406940', (91, 99))	('modulation', 'Var', (175, 185))	('chemotherapy response', 'CPA', (148, 169))	('affected', 'Reg', (227, 235))	('miR-148a', 'Gene', (91, 99))	('effects', 'Reg', (137, 144))	('miR-130a', 'Gene', (75, 83))
284219	30510209	Consequently, modulation of miR-130a levels by upregulation can either sensitise cells to chemotherapeutic agents or contribute to drug resistance.	('modulation', 'Var', (14, 24))	('miR-130a', 'Gene', (28, 36))	('drug resistance', 'CPA', (131, 146))	('drug resistance', 'Phenotype', 'HP:0020174', (131, 146))	('upregulation', 'PosReg', (47, 59))	('miR-130a', 'Gene', '406919', (28, 36))	('sensitise', 'Reg', (71, 80))	('contribute to', 'Reg', (117, 130))
284224	30510209	increase in apoptosis or chemosensitivity following modulation of the miRNA of interest in one direction, and decrease in apoptosis or chemosensitivity when expression of the miRNA was modified in the other direction.	('chemosensitivity', 'CPA', (25, 41))	('modulation', 'Var', (52, 62))	('apoptosis', 'MPA', (122, 131))	('miR', 'Gene', '220972', (175, 178))	('miR', 'Gene', (175, 178))	('chemosensitivity', 'CPA', (135, 151))	('miR', 'Gene', '220972', (70, 73))	('decrease', 'NegReg', (110, 118))	('miR', 'Gene', (70, 73))	('increase', 'PosReg', (0, 8))	('apoptosis', 'CPA', (12, 21))
284245	30510209	For example, knockdown as well as enhanced miR-31 expression in AsPC-1 cells decreased the ability to migrate (miR-31 inhibition: -33%, miR-31 upregulation: -61%) or invade (miR-31 inhibition: -27%, miR-31 upregulation: -74%).	('miR-31', 'Gene', (199, 205))	('miR-31', 'Gene', '407035', (43, 49))	('enhanced', 'PosReg', (34, 42))	('AsPC-1', 'CellLine', 'CVCL:0152', (64, 70))	('miR-31', 'Gene', (111, 117))	('decreased', 'NegReg', (77, 86))	('miR-31', 'Gene', '407035', (136, 142))	('miR-31', 'Gene', '407035', (174, 180))	('miR-31', 'Gene', '407035', (199, 205))	('upregulation', 'PosReg', (143, 155))	('knockdown', 'Var', (13, 22))	('miR-31', 'Gene', (43, 49))	('invade', 'CPA', (166, 172))	('miR-31', 'Gene', '407035', (111, 117))	('miR-31', 'Gene', (174, 180))	('expression', 'MPA', (50, 60))	('miR-31', 'Gene', (136, 142))
284260	30510209	For example, ectopic expression of miR-148a induced apoptosis by suppression of Bcl-2 and activation of a caspase cascade in colorectal cancer cells.	('activation', 'PosReg', (90, 100))	('ectopic expression', 'Var', (13, 31))	('colorectal cancer', 'Disease', 'MESH:D015179', (125, 142))	('suppression', 'NegReg', (65, 76))	('Bcl-2', 'Gene', (80, 85))	('Bcl-2', 'Gene', '596', (80, 85))	('caspase cascade', 'Pathway', (106, 121))	('miR-148a', 'Gene', '406940', (35, 43))	('miR-148a', 'Gene', (35, 43))	('colorectal cancer', 'Phenotype', 'HP:0003003', (125, 142))	('colorectal cancer', 'Disease', (125, 142))	('apoptosis', 'Disease', (52, 61))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
284280	30510209	The four ESCC cell lines KYSE-70, KYSE-140, KYSE-270 and KYSE-410 were grown to 60-80% confluence, followed by a transfection with either mimics or inhibitors of miR-130a-3p or miR-148a-3p (Qiagen, #MSY0000243, #MSY0000425, #MIN0000243, #MIN0000425), or the negative scramble-control (Qiagen, #SI03650318) using Lipofectamine 2000 transfection agent (Life Technologies, #11668027).	('#MIN0000425', 'Var', (237, 248))	('miR-148a', 'Gene', (177, 185))	('#MSY0000425', 'Var', (211, 222))	('#MIN0000243', 'Var', (224, 235))	('miR-130a', 'Gene', (162, 170))	('miR-148a', 'Gene', '406940', (177, 185))	('miR-130a', 'Gene', '406919', (162, 170))
284282	30510209	Transfected cells were treated 24 h post-transfection with Cisplatin (Teva GmbH) or 5-FU (Medac GmbH), which represent the standard chemotherapy treatment for esophageal cancer.	('esophageal cancer', 'Disease', (159, 176))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('Medac', 'Chemical', '-', (90, 95))	('Teva', 'Chemical', '-', (70, 74))	('Cisplatin', 'Chemical', 'MESH:D002945', (59, 68))	('5-FU', 'Var', (84, 88))	('esophageal cancer', 'Disease', 'MESH:D004938', (159, 176))	('5-FU', 'Chemical', 'MESH:D005472', (84, 88))
284297	30510209	The effect that modulating miRNA expression had on the response to chemotherapy was analysed as described previously.	('miR', 'Gene', '220972', (27, 30))	('miR', 'Gene', (27, 30))	('modulating', 'Var', (16, 26))
284315	25864709	Additionally, we identified altered lncRNAs that may be up- or down-regulated due to an amplification or deletion, respectively, and associated lncRNA expression with the mutational status of commonly mutated genes in cancer which could suggest an acquired functional role in tumors.	('tumors', 'Phenotype', 'HP:0002664', (276, 282))	('cancer', 'Disease', 'MESH:D009369', (218, 224))	('deletion', 'Var', (105, 113))	('amplification', 'Var', (88, 101))	('cancer', 'Disease', (218, 224))	('tumor', 'Phenotype', 'HP:0002664', (276, 281))	('tumors', 'Disease', 'MESH:D009369', (276, 282))	('lncRNA expression', 'MPA', (144, 161))	('down-regulated', 'NegReg', (63, 77))	('up-', 'PosReg', (56, 59))	('mutational', 'Var', (171, 181))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('tumors', 'Disease', (276, 282))	('associated', 'Reg', (133, 143))
284360	25864709	As copy number variation plays an important role in cancer, we next investigated how amplifications and deletions might affect the expression level of lncRNAs.	('amplifications', 'Var', (85, 99))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('expression level', 'MPA', (131, 147))	('affect', 'Reg', (120, 126))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('deletions', 'Var', (104, 113))
284368	25864709	For example, onco-lncRNA-1, which is upregulated in 5 cancer types, has a significant association with TP53 mutation status in BRCA, LUAD, and UCEC (Fig.	('TP53', 'Gene', '7157', (103, 107))	('BRCA', 'Gene', '672', (127, 131))	('mutation status', 'Var', (108, 123))	('TP53', 'Gene', (103, 107))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('UCEC', 'Disease', (143, 147))	('cancer', 'Disease', (54, 60))	('onco-lncRNA-1', 'Disease', (13, 26))	('BRCA', 'Phenotype', 'HP:0003002', (127, 131))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('LUAD', 'Phenotype', 'HP:0030078', (133, 137))	('LUAD', 'Disease', (133, 137))	('BRCA', 'Gene', (127, 131))
284370	25864709	Similarly, MEG3 (onco-lncRNA-83) expression was associated with TP53 mutational status and may be regulated via a TP53 binding site within the MEG3 promoter (Table S10).	('mutational status', 'Var', (69, 86))	('associated', 'Reg', (48, 58))	('TP53', 'Gene', (114, 118))	('MEG3', 'Gene', '55384', (11, 15))	('TP53', 'Gene', '7157', (114, 118))	('MEG3', 'Gene', (143, 147))	('TP53', 'Gene', '7157', (64, 68))	('expression', 'MPA', (33, 43))	('TP53', 'Gene', (64, 68))	('MEG3', 'Gene', '55384', (143, 147))	('MEG3', 'Gene', (11, 15))
284378	25864709	As the CRNDE promoter resides in the same CpG island as that of the adjacent IRX5 gene, methylation of the promoter region results in coordinated expression.	('IRX5', 'Gene', (77, 81))	('coordinated expression', 'MPA', (134, 156))	('methylation', 'Var', (88, 99))	('results in', 'Reg', (123, 133))	('IRX5', 'Gene', '10265', (77, 81))	('CRNDE', 'Gene', '643911', (7, 12))	('CRNDE', 'Gene', (7, 12))
284390	25864709	Greater than 50% knockdown of CCAT1 in NCI-H322M and NCI-H522 cells using 2 different small interfering RNAs (siRNAs) resulted in decreased cell growth of ~20% and ~40%, respectively, as measured by cell counting for 6 d (Fig.	('NCI-H522', 'CellLine', 'CVCL:1567', (53, 61))	('cell growth', 'CPA', (140, 151))	('CCAT1', 'Gene', '100507056', (30, 35))	('NCI-H322M', 'CellLine', 'CVCL:1557', (39, 48))	('knockdown', 'Var', (17, 26))	('CCAT1', 'Gene', (30, 35))	('decreased', 'NegReg', (130, 139))
284404	25864709	Greater than 50% knockdown of onco-lncRNA-3 in NCI-H322M lung cells with 2 different siRNAs resulted in approximately 15% (p = 0.04) or 12% (p = 0.02), respectively, of EdU incorporation compared to 18% incorporation in scrambled control (Fig.	('rat', 'Species', '10116', (180, 183))	('EdU incorporation', 'MPA', (169, 186))	('onco-lncRNA-3', 'Gene', (30, 43))	('NCI-H322M', 'CellLine', 'CVCL:1557', (47, 56))	('knockdown', 'Var', (17, 26))	('rat', 'Species', '10116', (210, 213))	('onco-lncRNA-3', 'Gene', '100128338', (30, 43))
284420	25864709	Despite the lower sequence read coverage in a few of the cancer types, we are still able to detect a subset of altered lncRNAs, suggesting they are more highly expressed and markedly altered.	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('lncRNAs', 'Protein', (119, 126))	('cancer', 'Disease', (57, 63))	('altered', 'Reg', (183, 190))	('altered', 'Var', (111, 118))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))
284436	25864709	This is exemplified by the expression of MEG3 (onco-lncRNA-83), which has a TP53 binding site within its promoter, being associated with TP53 mutational status.	('MEG3', 'Gene', '55384', (41, 45))	('mutational status', 'Var', (142, 159))	('associated', 'Reg', (121, 131))	('TP53', 'Gene', '7157', (76, 80))	('MEG3', 'Gene', (41, 45))	('TP53', 'Gene', (76, 80))	('TP53', 'Gene', '7157', (137, 141))	('TP53', 'Gene', (137, 141))
284438	25864709	Similarly we also observed an NRF2 motif upstream of onco-lncRNA-3, which was found to have elevated expression in KEAP1 mutant patients in LUAD.	('LUAD', 'Phenotype', 'HP:0030078', (140, 144))	('NRF2', 'Gene', (30, 34))	('mutant', 'Var', (121, 127))	('KEAP1', 'Gene', '9817', (115, 120))	('elevated', 'PosReg', (92, 100))	('onco-lncRNA-3', 'Gene', (53, 66))	('onco-lncRNA-3', 'Gene', '100128338', (53, 66))	('KEAP1', 'Gene', (115, 120))	('NRF2', 'Gene', '4780', (30, 34))	('expression', 'MPA', (101, 111))	('patients', 'Species', '9606', (128, 136))
284441	25864709	Recent work has shown that KEAP1 mutant cells protect NRF2 from ubiquitination and degradation, constitutively activating the expression of NRF2 target genes.	('ubiquitination', 'MPA', (64, 78))	('KEAP1', 'Gene', '9817', (27, 32))	('degradation', 'MPA', (83, 94))	('expression', 'MPA', (126, 136))	('NRF2', 'Gene', '4780', (54, 58))	('activating', 'PosReg', (111, 121))	('KEAP1', 'Gene', (27, 32))	('mutant', 'Var', (33, 39))	('NRF2', 'Gene', (54, 58))	('NRF2', 'Gene', '4780', (140, 144))	('NRF2', 'Gene', (140, 144))
284442	25864709	Therefore, it is plausible that there is some interplay between KEAP1 mutant patients and elevated onco-lncRNA-3 expression via NRF2.	('KEAP1', 'Gene', '9817', (64, 69))	('expression', 'MPA', (113, 123))	('elevated', 'PosReg', (90, 98))	('KEAP1', 'Gene', (64, 69))	('NRF2', 'Gene', (128, 132))	('mutant', 'Var', (70, 76))	('patients', 'Species', '9606', (77, 85))	('onco-lncRNA-3', 'Gene', '100128338', (99, 112))	('onco-lncRNA-3', 'Gene', (99, 112))	('NRF2', 'Gene', '4780', (128, 132))
284456	25864709	For instance, antisense lncRNAs typically regulate protein-coding genes in close proximity whereas cytoplasmic competing endogenous RNAs (ceRNAs) will compete with cancer genes harboring similar microRNA binding sites to modulate expression.	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('expression', 'MPA', (230, 240))	('cancer', 'Disease', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('protein-coding', 'Protein', (51, 65))	('antisense', 'Var', (14, 23))	('regulate', 'Reg', (42, 50))
284477	25864709	The remaining transcripts were TMM normalized, then edgeR version 3.0.8 was used to test for differential expression between the tumor and normal pairs using a matched pair design with cutoffs of FDR <= 10-5 and absolute fold change >=2.	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('tumor', 'Disease', (129, 134))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('FDR <=', 'Var', (196, 202))
284490	25864709	2) and mutated in > 5% of tumors with RNA-Seq data.	('tumors', 'Disease', (26, 32))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('mutated', 'Var', (7, 14))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))
284508	25864709	The following siRNA sequences were used for knockdown of CCAT1: CCAT1 siRNA 1 (5'-UGUGGUAGGAAAGAGAAAUGAAUGG-3'), CCAT1 siRNA 2 (5'-GACCACUGCUUUAAAGCCUUUGCAU-3') or a control (a scrambled-matched %GC oligonucleotide synthesized by Invitrogen).	('GC', 'Chemical', 'MESH:C057580', (146, 148))	('GC', 'Chemical', 'MESH:C057580', (138, 140))	('GC', 'Chemical', 'MESH:C057580', (152, 154))	('oligonucleotide', 'Chemical', 'MESH:D009841', (199, 214))	('CCAT1', 'Gene', '100507056', (57, 62))	('CCAT1', 'Gene', (57, 62))	('CCAT1', 'Gene', '100507056', (64, 69))	('knockdown', 'Var', (44, 53))	('GC', 'Chemical', 'MESH:C057580', (196, 198))	('CCAT1', 'Gene', (113, 118))	('CCAT1', 'Gene', '100507056', (113, 118))	('CCAT1', 'Gene', (64, 69))
284514	33365308	Integrative Analysis of DNA Methylation and Gene Expression to Determine Specific Diagnostic Biomarkers and Prognostic Biomarkers of Breast Cancer Background: DNA methylation is a common event in the early development of various tumors, including breast cancer (BRCA), which has been studies as potential tumor biomarkers.	('breast cancer', 'Disease', 'MESH:D001943', (247, 260))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('BRCA', 'Gene', (262, 266))	('breast cancer', 'Disease', (247, 260))	('tumor', 'Disease', (305, 310))	('tumors', 'Phenotype', 'HP:0002664', (229, 235))	('cancer', 'Phenotype', 'HP:0002664', (254, 260))	('tumor', 'Disease', 'MESH:D009369', (305, 310))	('DNA', 'Gene', (159, 162))	('methylation', 'Var', (163, 174))	('tumors', 'Disease', (229, 235))	('BRCA', 'Phenotype', 'HP:0003002', (262, 266))	('Breast Cancer', 'Disease', 'MESH:D001943', (133, 146))	('tumor', 'Disease', (229, 234))	('tumor', 'Phenotype', 'HP:0002664', (305, 310))	('tumors', 'Disease', 'MESH:D009369', (229, 235))	('tumor', 'Disease', 'MESH:D009369', (229, 234))	('Breast Cancer', 'Disease', (133, 146))	('BRCA', 'Gene', '672', (262, 266))	('Cancer', 'Phenotype', 'HP:0002664', (140, 146))	('breast cancer', 'Phenotype', 'HP:0003002', (247, 260))	('Breast Cancer', 'Phenotype', 'HP:0003002', (133, 146))
284525	33365308	We also identified 6 methylation sites that are highly correlated with the OS of BRCA patients and can be used to accurately predict the survival of BRCA patients (training cohort: likelihood ratio = 70.25, p = 3.633 x 10-13, area under the curve (AUC) = 0.784; validation cohort: AUC = 0.734).	('BRCA', 'Gene', (81, 85))	('correlated', 'Reg', (55, 65))	('BRCA', 'Phenotype', 'HP:0003002', (149, 153))	('patients', 'Species', '9606', (154, 162))	('methylation', 'Var', (21, 32))	('BRCA', 'Gene', '672', (149, 153))	('BRCA', 'Gene', (149, 153))	('BRCA', 'Phenotype', 'HP:0003002', (81, 85))	('BRCA', 'Gene', '672', (81, 85))	('patients', 'Species', '9606', (86, 94))
284539	33365308	Studies have shown that DNA methylation abnormality, an epigenetic modification, is closely related to the occurrence and development of cancer (Hahn and Weinberg,; Gu et al.,; Shen et al.,; Guo et al.,).	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('related', 'Reg', (92, 99))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('methylation abnormality', 'Var', (28, 51))	('cancer', 'Disease', (137, 143))	('DNA', 'MPA', (24, 27))
284541	33365308	There are two patterns of cancer gene methylation which are related to cancer occurrence: genome-wide hypomethylation and promoter domain CpG island hypermethylation (Cheng et al.,).	('hypomethylation', 'Var', (102, 117))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('cancer', 'Disease', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('cancer', 'Disease', (71, 77))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))
284568	33365308	The univariate Cox proportional hazard analysis was performed in the training cohort to find the methylation sites significantly related to the survival of patients.	('patients', 'Species', '9606', (156, 164))	('related to', 'Reg', (129, 139))	('methylation', 'Var', (97, 108))
284570	33365308	The critical criterion was p-value < 0.05 and q-value < 0.25 Four DNA methylation datasets were collected from the Gene Expression Omnibus (GEO) database: GSE66695 (80 breast cancer, 40 normal), GSE78754 (Mathe et al.,) (80 breast cancer), GSE60185 (Fleischer et al.,) (239 breast cancer, 46 normal), and GSE69270 (Kananen et al.,) (normal blood).	('breast cancer', 'Disease', 'MESH:D001943', (274, 287))	('GSE66695', 'Var', (155, 163))	('GSE60185', 'Var', (240, 248))	('breast cancer', 'Disease', (274, 287))	('GSE78754', 'Var', (195, 203))	('breast cancer', 'Disease', 'MESH:D001943', (168, 181))	('breast cancer', 'Disease', 'MESH:D001943', (224, 237))	('breast cancer', 'Phenotype', 'HP:0003002', (274, 287))	('breast cancer', 'Phenotype', 'HP:0003002', (224, 237))	('breast cancer', 'Disease', (168, 181))	('breast cancer', 'Disease', (224, 237))	('breast cancer', 'Phenotype', 'HP:0003002', (168, 181))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('cancer', 'Phenotype', 'HP:0002664', (281, 287))	('GSE69270', 'Var', (305, 313))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
284576	33365308	There were 2,362 hypermethylated and 2,322 Hypomethylated DMSs in BRCA (Figure 1A), which correspond to 1,157 hypermethylation and 989 hypomethylated genes.	('Hypomethylated DMSs', 'Disease', (43, 62))	('BRCA', 'Phenotype', 'HP:0003002', (66, 70))	('hypermethylation', 'Var', (110, 126))	('BRCA', 'Gene', (66, 70))	('BRCA', 'Gene', '672', (66, 70))	('hypermethylated', 'Var', (17, 32))	('Hypomethylated DMSs', 'Disease', 'None', (43, 62))
284582	33365308	Two thousand six hundred and forty three DMSs that were differentially methylated between BRCA ( Deltabeta  > 0.2, FDR < 0.05) and healthy individuals' blood were left.	('BRCA', 'Phenotype', 'HP:0003002', (90, 94))	('DMSs', 'Chemical', '-', (41, 45))	('BRCA', 'Gene', '672', (90, 94))	('BRCA', 'Gene', (90, 94))	('methylated', 'Var', (71, 81))
284584	33365308	There were still 17 DMSs with methylation differences in BRCA and other cancers and adjacent tissues.	('methylation', 'Var', (30, 41))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('DMSs', 'Chemical', '-', (20, 24))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('BRCA', 'Phenotype', 'HP:0003002', (57, 61))	('BRCA', 'Gene', '672', (57, 61))	('cancers', 'Disease', (72, 79))	('differences', 'Reg', (42, 53))	('cancers', 'Disease', 'MESH:D009369', (72, 79))	('BRCA', 'Gene', (57, 61))
284585	33365308	Finally, we used the WrapperSubsetEval evaluator, which used cross-validation to evaluate the accuracy of each subset's learning scheme to assess the predictive power of each DMS and select the most representative of the 7 DMSs (cg20383521, cg09804858, cg06741896, cg01668352, cg10708955, cg06998282, cg04658021) (Table 2).	('DMS', 'Chemical', '-', (223, 226))	('cg06741896', 'Var', (253, 263))	('cg09804858', 'Var', (241, 251))	('DMSs', 'Chemical', '-', (223, 227))	('cg01668352', 'Var', (265, 275))	('cg10708955', 'Var', (277, 287))	('cg10708955', 'Chemical', '-', (277, 287))	('cg06998282', 'Var', (289, 299))	('cg04658021', 'Chemical', '-', (301, 311))	('DMS', 'Chemical', '-', (175, 178))	('cg04658021', 'Var', (301, 311))	('cg20383521', 'Var', (229, 239))
284587	33365308	These 7 DMSs were significantly correlated with each other (p < 0.05), Among them, cg10708955 and cg04658021 had the strongest correlation (r = 0.803), indicating that the 7 DMSs might jointly mediate the occurrence of BRCA (Figure 1E).	('BRCA', 'Phenotype', 'HP:0003002', (219, 223))	('cg10708955', 'Var', (83, 93))	('BRCA', 'Gene', '672', (219, 223))	('cg10708955', 'Chemical', '-', (83, 93))	('DMSs', 'Chemical', '-', (174, 178))	('BRCA', 'Gene', (219, 223))	('cg04658021', 'Chemical', '-', (98, 108))	('cg04658021', 'Var', (98, 108))	('DMSs', 'Chemical', '-', (8, 12))
284592	33365308	Three independent methylation data sets (GSE66695, GSE60185, and GSE78754) of BRCA were used as external test sets.	('GSE60185', 'Var', (51, 59))	('GSE78754', 'Var', (65, 73))	('BRCA', 'Phenotype', 'HP:0003002', (78, 82))	('BRCA', 'Gene', '672', (78, 82))	('BRCA', 'Gene', (78, 82))	('GSE66695', 'Var', (41, 49))
284607	33365308	KEGG pathway analysis indicated these pathways were significantly correlated with these genes: Cell cycle, p53 signaling pathway, Pathways in cancer, Breast cancer, PI3K-Akt signaling pathway, Proteoglycans in cancer, Transcriptional misregulation in cancer (p < 0.05) with the most significant related pathway was "Cell cycle" (p = 9.79 x 10-09) (Figure 3D).	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('p53', 'Gene', (107, 110))	('Breast cancer', 'Disease', 'MESH:D001943', (150, 163))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('cancer', 'Disease', 'MESH:D009369', (251, 257))	('Breast cancer', 'Disease', (150, 163))	('Breast cancer', 'Phenotype', 'HP:0003002', (150, 163))	('misregulation', 'Var', (234, 247))	('Cell', 'Pathway', (95, 99))	('cancer', 'Disease', 'MESH:D009369', (210, 216))	('cancer', 'Disease', (142, 148))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('Akt', 'Gene', (170, 173))	('cancer', 'Disease', (157, 163))	('cancer', 'Disease', (251, 257))	('Akt', 'Gene', '207', (170, 173))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('p53', 'Gene', '7157', (107, 110))	('cancer', 'Disease', (210, 216))
284610	33365308	By performing a univariate Cox proportional hazards regression analysis in the training cohort, a total of 611 DNA methylation sites were significantly associated with OS in BRCA patients (p < 1 x 10-3), and they were used as candidate markers (Supplementary Table 7).	('BRCA', 'Gene', (174, 178))	('methylation sites', 'Var', (115, 132))	('BRCA', 'Gene', '672', (174, 178))	('sites', 'Var', (127, 132))	('DNA', 'Gene', (111, 114))	('patients', 'Species', '9606', (179, 187))	('associated', 'Reg', (152, 162))	('BRCA', 'Phenotype', 'HP:0003002', (174, 178))
284611	33365308	Finally, the 6 methylation sites (cg04747226, cg04544154, cg16814416, cg03951219, cg17080504, cg19458602) was selected as the best prognosis model to predict OS (Figure 4B).	('cg19458602', 'Var', (94, 104))	('cg04544154', 'Chemical', '-', (46, 56))	('cg04544154', 'Var', (46, 56))	('cg04747226', 'Var', (34, 44))	('cg19458602', 'Chemical', '-', (94, 104))	('cg04747226', 'Chemical', '-', (34, 44))	('cg16814416', 'Var', (58, 68))	('cg03951219', 'Chemical', '-', (70, 80))	('cg17080504', 'Chemical', '-', (82, 92))	('cg03951219', 'Var', (70, 80))	('cg17080504', 'Var', (82, 92))	('cg16814416', 'Chemical', '-', (58, 68))
284612	33365308	The risk scoring formula was as follows: RiskScore = 1.78920 x cg04747226-1.97075 x cg04544154-2.92310 x cg16814416 + 1.69264 x cg03951219 + 1.84526 x cg17080504-2.33118 x cg19458602.	('cg04747226-1.97075', 'Var', (63, 81))	('cg04747226', 'Chemical', '-', (63, 73))	('cg04544154-2.92310', 'Var', (84, 102))	('cg19458602', 'Chemical', '-', (172, 182))	('cg16814416 +', 'Var', (105, 117))	('cg16814416', 'Chemical', '-', (105, 115))	('cg17080504-2.33118', 'Var', (151, 169))	('cg04544154', 'Chemical', '-', (84, 94))	('cg03951219 +', 'Var', (128, 140))	('cg19458602', 'Var', (172, 182))	('cg03951219', 'Chemical', '-', (128, 138))	('cg17080504', 'Chemical', '-', (151, 161))
284613	33365308	Among the 6 methylation sites, cg04747226, cg03951219, and cg17080504 had positive correlation coefficients, indicating that their high DNA methylation level may be related to the short OS.	('cg03951219', 'Chemical', '-', (43, 53))	('cg03951219', 'Var', (43, 53))	('cg17080504', 'Chemical', '-', (59, 69))	('cg17080504', 'Var', (59, 69))	('short OS', 'Disease', (180, 188))	('high DNA methylation level', 'MPA', (131, 157))	('related', 'Reg', (165, 172))	('cg04747226', 'Var', (31, 41))	('cg04747226', 'Chemical', '-', (31, 41))
284614	33365308	cg04544154, cg16814416, and cg19458602 had negative correlation coefficients, indicating that their high DNA methylation level might be related to the longer OS.	('cg19458602', 'Chemical', '-', (28, 38))	('cg16814416', 'Var', (12, 22))	('cg16814416', 'Chemical', '-', (12, 22))	('high DNA methylation level', 'MPA', (100, 126))	('cg04544154', 'Chemical', '-', (0, 10))	('cg04544154', 'Var', (0, 10))	('cg19458602', 'Var', (28, 38))
284616	33365308	cg04747226, cg03951219and cg17080504 shown long-term survival in patients who tended to have lower methylation levels, while cg04544154, cg16814416and cg19458602 shown long-term survival in patients who tend to have higher methylation levels (p < 0.05, Figure 4C).	('methylation levels', 'MPA', (99, 117))	('patients', 'Species', '9606', (190, 198))	('methylation levels', 'MPA', (223, 241))	('cg19458602', 'Chemical', '-', (151, 161))	('cg04747226', 'Var', (0, 10))	('cg04747226', 'Chemical', '-', (0, 10))	('lower', 'NegReg', (93, 98))	('cg17080504', 'Chemical', '-', (26, 36))	('cg16814416and', 'Chemical', '-', (137, 150))	('patients', 'Species', '9606', (65, 73))	('cg03951219and', 'Chemical', '-', (12, 25))	('cg19458602', 'Var', (151, 161))	('cg04544154', 'Chemical', '-', (125, 135))	('cg16814416and', 'Var', (137, 150))	('cg04544154', 'Var', (125, 135))	('cg17080504', 'Var', (26, 36))	('cg03951219and', 'Var', (12, 25))
284635	33365308	Previous studies have suggested that mutations in genes leading to changes in DNA sequences, activation of oncogenes, and inactivation of tumor suppressor genes are major mechanisms of tumorigenesis (Gough et al.,; Hahn and Weinberg,; Domchek et al.,; Ablain et al.,; Poillet-Perez et al.,).	('tumor', 'Disease', (185, 190))	('inactivation', 'NegReg', (122, 134))	('changes', 'Var', (67, 74))	('tumor', 'Disease', (138, 143))	('DNA', 'MPA', (78, 81))	('mutations', 'Var', (37, 46))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
284636	33365308	With the deepening of research on cancer, researchers have found that abnormal regulation mechanisms other than DNA sequences, that is, epigenetic changes also play a key role in tumorigenesis and development (Berdasco and Esteller,).	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('development', 'CPA', (197, 208))	('epigenetic changes', 'Var', (136, 154))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('cancer', 'Disease', (34, 40))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('tumor', 'Disease', (179, 184))
284637	33365308	The occurrence and development of breast cancer is a multi-step, multi-stage process, which is considered to be the result of accumulation of genetic and epigenetic variations (Widschwendter et al.,).	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('breast cancer', 'Disease', 'MESH:D001943', (34, 47))	('breast cancer', 'Disease', (34, 47))	('breast cancer', 'Phenotype', 'HP:0003002', (34, 47))	('epigenetic variations', 'Var', (154, 175))
284640	33365308	By comparing BRCA, normal tissue and non-BRCA cancer, we identified seven methylation sites as BRCA specific diagnostic biomarkers.	('BRCA', 'Gene', (95, 99))	('methylation', 'Var', (74, 85))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('BRCA', 'Gene', (41, 45))	('BRCA', 'Gene', '672', (41, 45))	('cancer', 'Disease', (46, 52))	('BRCA', 'Phenotype', 'HP:0003002', (13, 17))	('BRCA', 'Gene', '672', (13, 17))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('BRCA', 'Phenotype', 'HP:0003002', (95, 99))	('BRCA', 'Gene', '672', (95, 99))	('BRCA', 'Phenotype', 'HP:0003002', (41, 45))	('BRCA', 'Gene', (13, 17))
284644	33365308	Here, we found 7 BRCA specific differentially methylated sites, which are superior to the widely used serum biomarker CA125 in sensitivity and specificity.	('BRCA', 'Gene', (17, 21))	('CA125', 'Gene', (118, 123))	('differentially methylated sites', 'Var', (31, 62))	('BRCA', 'Phenotype', 'HP:0003002', (17, 21))	('BRCA', 'Gene', '672', (17, 21))	('CA125', 'Gene', '94025', (118, 123))
284647	33365308	Studies have shown that triple-negative breast cancer tends to have higher tumor grades, higher risk of lymph node metastasis or distant metastasis, and relatively lack of effective treatments, resulting in lower tumor-free survival rate (Liedtke et al.,).	('tumor', 'Disease', (213, 218))	('breast cancer', 'Disease', 'MESH:D001943', (40, 53))	('breast cancer', 'Disease', (40, 53))	('breast cancer', 'Phenotype', 'HP:0003002', (40, 53))	('higher', 'PosReg', (68, 74))	('lymph node metastasis', 'Disease', 'MESH:D009362', (104, 125))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Disease', 'MESH:D009369', (213, 218))	('triple-negative', 'Var', (24, 39))	('distant metastasis', 'CPA', (129, 147))	('lymph node metastasis', 'Disease', (104, 125))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', (75, 80))	('lower', 'NegReg', (207, 212))
284669	32781500	ICIs, specifically PD-1, PDL-1 and CTLA-4 inhibitors have been approved for the treatment of a variety of solid tumors, initially beginning with melanoma in 2011.	('melanoma', 'Phenotype', 'HP:0002861', (145, 153))	('melanoma', 'Disease', (145, 153))	('solid tumors', 'Disease', (106, 118))	('CTLA-4', 'Gene', (35, 41))	('melanoma', 'Disease', 'MESH:D008545', (145, 153))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('PDL-1', 'Gene', '29126', (25, 30))	('inhibitors', 'Var', (42, 52))	('men', 'Species', '9606', (85, 88))	('CTLA-4', 'Gene', '1493', (35, 41))	('solid tumors', 'Disease', 'MESH:D009369', (106, 118))	('PDL-1', 'Gene', (25, 30))	('PD-1', 'Gene', (19, 23))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))
284696	32781500	Patient who had received pembrolizumab had median overall survival of 10.6 months compared with 11.1 months for those who received chemotherapy only.	('pembrolizumab', 'Chemical', 'MESH:C582435', (25, 38))	('overall survival', 'MPA', (50, 66))	('pembrolizumab', 'Var', (25, 38))	('Patient', 'Species', '9606', (0, 7))
284713	32781500	However, a subgroup analysis demonstrated a significant benefit for use of pembrolizumab over a taxane in patients with a deficient mismatch repair (dMMR) GEJ or gastric cancer.	('dMMR', 'Chemical', '-', (149, 153))	('gastric cancer', 'Disease', 'MESH:D013274', (162, 176))	('deficient mismatch', 'Var', (122, 140))	('gastric cancer', 'Phenotype', 'HP:0012126', (162, 176))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('pembrolizumab', 'Chemical', 'MESH:C582435', (75, 88))	('mismatch', 'Var', (132, 140))	('patients', 'Species', '9606', (106, 114))	('gastric cancer', 'Disease', (162, 176))	('taxane', 'Chemical', 'MESH:C080625', (96, 102))
284806	32781500	There are currently ongoing ICI combination studies including ICIs with TGF-beta inhibitors, with indoleamine dioxygenase inhibitors, with intra-arterial therapies, with radiation and with angiogenesis inhibitors.	('TGF-beta', 'Gene', '7039', (72, 80))	('indoleamine dioxygenase', 'MPA', (98, 121))	('TGF-beta', 'Gene', (72, 80))	('inhibitors', 'Var', (81, 91))
284807	32781500	Some ongoing Phase III ICIs combination studies include: Nivolumab plus ipilimumab in advanced HCC as first line therapy (NCT03510871, NCT03222076, NCT03203304, NCT01658878, NCT04039607) and durvalumab plus tremelimumab in advanced HCC as second line therapy (NCT03298451).	('Nivolumab', 'Chemical', 'MESH:D000077594', (57, 66))	('durvalumab plus tremelimumab', 'Disease', 'MESH:D007625', (191, 219))	('advanced', 'Disease', (86, 94))	('ipilimumab', 'Chemical', 'MESH:D000074324', (72, 82))	('NCT03510871', 'Var', (122, 133))	('durvalumab plus tremelimumab', 'Disease', (191, 219))	('NCT03203304', 'Var', (148, 159))	('NCT03222076', 'Var', (135, 146))
284808	32781500	Phase III studies involving ICI and angiogenesis inhibitors include: nivolumab plus sorafenib in advanced HCC as first line therapy (NCT02576509, NCT01658878, NCT03439891), pembrolizumab plus lenvatinib in patients with advanced HCC as first line therapy (NCT03713593), atezolizumab plus cabozantinib in advanced HCC as first line therapy (NCT03755791), atezolizumab plus bevacizumab in advanced HCC as first line therapy (NCT03434379), durvalumab plus bevacizumab in localized and locally advanced HCC (NCT03847428, NCT03778957), camrelizumab plus apatinib in advanced HCC as first line therapy (NCT02942329, NCT03764293), tislelizumab plus sorafenib for advanced HCC as first line therapy (NCT03412773) and sintilimab plus IBI305 in advanced HCC as first line therapy (NCT03794440).	('bevacizumab', 'Chemical', 'MESH:D000068258', (372, 383))	('sorafenib', 'Chemical', 'MESH:D000077157', (642, 651))	('tislelizumab plus sorafenib', 'Disease', (624, 651))	('sorafenib', 'Chemical', 'MESH:D000077157', (84, 93))	('atezolizumab', 'Chemical', 'MESH:C000594389', (270, 282))	('NCT03412773', 'Var', (692, 703))	('tislelizumab plus sorafenib', 'Disease', 'MESH:D007625', (624, 651))	('lenvatinib', 'Chemical', 'MESH:C531958', (192, 202))	('atezolizumab plus bevacizumab', 'Disease', (354, 383))	('nivolumab', 'Chemical', 'MESH:D000077594', (69, 78))	('atezolizumab plus bevacizumab', 'Disease', 'MESH:D007625', (354, 383))	('cabozantinib', 'Chemical', 'MESH:C558660', (288, 300))	('pembrolizumab', 'Chemical', 'MESH:C582435', (173, 186))	('atezolizumab', 'Chemical', 'MESH:C000594389', (354, 366))	('bevacizumab', 'Chemical', 'MESH:D000068258', (453, 464))	('durvalumab', 'Chemical', 'MESH:C000613593', (437, 447))	('NCT02942329', 'Var', (597, 608))	('patients', 'Species', '9606', (206, 214))	('NCT03764293', 'CellLine', 'None', (610, 621))
284826	32781500	KEYNOTE-158, was a nonrandomized, open label, multisite phase II study that enrolled patients with histologically or cytologically confirmed MSI-H/dMMR advanced non-colorectal cancer, including biliary adenocarcinoma, who experienced failure with prior therapy received pembrolizumab 200 mg once every 3 weeks for 2 years until disease progression, unacceptable toxicity or patient withdrawal.	('patient', 'Species', '9606', (85, 92))	('colorectal cancer', 'Phenotype', 'HP:0003003', (165, 182))	('pembrolizumab', 'Chemical', 'MESH:C582435', (270, 283))	('patient', 'Species', '9606', (374, 381))	('non-colorectal cancer', 'Disease', 'MESH:D015179', (161, 182))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('dMMR', 'Chemical', '-', (147, 151))	('patients', 'Species', '9606', (85, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (207, 216))	('toxicity', 'Disease', 'MESH:D064420', (362, 370))	('toxicity', 'Disease', (362, 370))	('biliary adenocarcinoma', 'Disease', 'MESH:D000230', (194, 216))	('MSI-H/dMMR', 'Var', (141, 151))	('non-colorectal cancer', 'Disease', (161, 182))	('biliary adenocarcinoma', 'Disease', (194, 216))
284827	32781500	There are ongoing phase II trials with first line combination nivolumab plus ipilimumab in advanced cholangiocarcinoma (NCT03101566, NCT02834013), second line pembrolizumab monotherapy in advanced cholangiocarcinoma (NCT03110328, NCT02628067), second line nivolumab in advanced cholangiocarcinoma (NCT02829918), first line durvalumab and tremelimumab with chemotherapy in advanced cholangiocarcinoma (NCT03473574, NCT03046862, NCT03704480), first line toripalimab with chemotherapy in advanced cholangiocarcinoma (NCT03796429, NCT03982680, NCT04027764).	('carcinoma', 'Phenotype', 'HP:0030731', (390, 399))	('nivolumab', 'Chemical', 'MESH:D000077594', (256, 265))	('cholangiocarcinoma', 'Disease', (100, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (287, 296))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (100, 118))	('durvalumab', 'Chemical', 'MESH:C000613593', (323, 333))	('pembrolizumab', 'Chemical', 'MESH:C582435', (159, 172))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (494, 512))	('NCT02829918', 'Var', (298, 309))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (278, 296))	('NCT04027764', 'Var', (540, 551))	('nivolumab', 'Chemical', 'MESH:D000077594', (62, 71))	('tremelimumab', 'Chemical', 'MESH:C520704', (338, 350))	('NCT03110328', 'Var', (217, 228))	('cholangiocarcinoma', 'Disease', (494, 512))	('NCT03704480', 'Var', (427, 438))	('carcinoma', 'Phenotype', 'HP:0030731', (206, 215))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (494, 512))	('cholangiocarcinoma', 'Disease', (278, 296))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (278, 296))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (381, 399))	('ipilimumab', 'Chemical', 'MESH:D000074324', (77, 87))	('NCT03982680', 'Var', (527, 538))	('NCT03473574', 'Var', (401, 412))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (197, 215))	('cholangiocarcinoma', 'Disease', (381, 399))	('carcinoma', 'Phenotype', 'HP:0030731', (503, 512))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (381, 399))	('cholangiocarcinoma', 'Disease', (197, 215))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (100, 118))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (197, 215))	('NCT03796429', 'Var', (514, 525))
284828	32781500	There are ongoing phase III trials of first line durvalumab with chemotherapy for advanced cholangiocarcinoma (NCT03875235) and first line pembrolizumab with chemotherapy in advanced cholangiocarcinoma (NCT03260712, NCT03111732, NCT04003636).	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (91, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('NCT03875235', 'Var', (111, 122))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (183, 201))	('NCT03260712', 'Var', (203, 214))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (91, 109))	('pembrolizumab', 'Chemical', 'MESH:C582435', (139, 152))	('NCT03111732', 'Var', (216, 227))	('cholangiocarcinoma', 'Disease', (183, 201))	('NCT04003636', 'Var', (229, 240))	('cholangiocarcinoma', 'Disease', (91, 109))	('durvalumab', 'Chemical', 'MESH:C000613593', (49, 59))	('carcinoma', 'Phenotype', 'HP:0030731', (192, 201))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (183, 201))
284862	32781500	Another option is encorafenib along with cetuximab for BRAF mutation positive tumors.	('cetuximab', 'Chemical', 'MESH:D000068818', (41, 50))	('tumors', 'Disease', (78, 84))	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('mutation positive', 'Var', (60, 77))	('BRAF', 'Gene', '673', (55, 59))	('encorafenib', 'Chemical', 'MESH:C000601108', (18, 29))	('BRAF', 'Gene', (55, 59))
285112	30174440	To explore the biological function of MCM2 in LUSC cells, we induced downregulation of MCM2 in SK-MES-1 and H2170 cells by transfecting siRNA-MCM2, and the results were confirmed by qRT-PCR and Western blot (Figure 3A and B).	('H2170', 'CellLine', 'CVCL:1535', (108, 113))	('SK-MES-1', 'CellLine', 'CVCL:0630', (95, 103))	('LUSC', 'Phenotype', 'HP:0030359', (46, 50))	('MCM2', 'Gene', (87, 91))	('downregulation', 'NegReg', (69, 83))	('transfecting', 'Var', (123, 135))
285128	30174440	On the whole, high expression of MCM2 is associated with aggressive progression in most types of human cancers.	('cancers', 'Disease', 'MESH:D009369', (103, 110))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('associated with', 'Reg', (41, 56))	('MCM2', 'Gene', (33, 37))	('human', 'Species', '9606', (97, 102))	('high expression', 'Var', (14, 29))	('aggressive progression', 'CPA', (57, 79))	('cancers', 'Phenotype', 'HP:0002664', (103, 110))	('cancers', 'Disease', (103, 110))
285130	30174440	Generally, high expression of MCM2 predicts a poor prognosis in most types of human cancers such as gastric cancer, osteosarcoma, oral cavity squamocellular carcinoma, bladder cancer, prostate cancer, breast cancer, renal cell cancer and penile cancer.	('gastric cancer', 'Phenotype', 'HP:0012126', (100, 114))	('renal cell cancer', 'Phenotype', 'HP:0005584', (216, 233))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('high expression', 'Var', (11, 26))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('bladder cancer', 'Disease', 'MESH:D001749', (168, 182))	('bladder cancer', 'Disease', (168, 182))	('osteosarcoma', 'Disease', (116, 128))	('squamocellular carcinoma', 'Phenotype', 'HP:0002860', (142, 166))	('osteosarcoma', 'Disease', 'MESH:D012516', (116, 128))	('cancers', 'Disease', 'MESH:D009369', (84, 91))	('bladder cancer', 'Phenotype', 'HP:0009725', (168, 182))	('prostate cancer', 'Disease', 'MESH:D011471', (184, 199))	('carcinoma', 'Phenotype', 'HP:0030731', (157, 166))	('breast cancer', 'Phenotype', 'HP:0003002', (201, 214))	('prostate cancer', 'Phenotype', 'HP:0012125', (184, 199))	('human', 'Species', '9606', (78, 83))	('carcinoma', 'Disease', (157, 166))	('gastric cancer', 'Disease', (100, 114))	('prostate cancer', 'Disease', (184, 199))	('penile cancer', 'Disease', (238, 251))	('MCM2', 'Gene', (30, 34))	('breast cancer', 'Disease', 'MESH:D001943', (201, 214))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('breast cancer', 'Disease', (201, 214))	('penile cancer', 'Disease', 'MESH:D004414', (238, 251))	('gastric cancer', 'Disease', 'MESH:D013274', (100, 114))	('osteosarcoma', 'Phenotype', 'HP:0002669', (116, 128))	('cancers', 'Phenotype', 'HP:0002664', (84, 91))	('cancers', 'Disease', (84, 91))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('carcinoma', 'Disease', 'MESH:D002277', (157, 166))	('renal cell cancer', 'Disease', 'MESH:C538614', (216, 233))	('renal cell cancer', 'Disease', (216, 233))
285133	30174440	In our study, we presented more evidence suggesting that MCM2 expression was significantly associated with poor overall survival of LUSC patients, and MCM2 overexpression was an independent unfavorable prognostic factor for LUSC patients.	('patients', 'Species', '9606', (229, 237))	('LUSC', 'Phenotype', 'HP:0030359', (224, 228))	('LUSC', 'Phenotype', 'HP:0030359', (132, 136))	('patients', 'Species', '9606', (137, 145))	('MCM2', 'Gene', (57, 61))	('poor', 'NegReg', (107, 111))	('overall survival', 'MPA', (112, 128))	('expression', 'Var', (62, 72))	('associated', 'Reg', (91, 101))
285136	30174440	Similarly, Cheung et al showed MCM2 promoted lung cancer cell proliferation via the regulation of HMGA1 phosphorylation.	('lung cancer', 'Disease', 'MESH:D008175', (45, 56))	('HMGA1', 'Gene', (98, 103))	('HMGA1', 'Gene', '3159', (98, 103))	('lung cancer', 'Disease', (45, 56))	('lung cancer', 'Phenotype', 'HP:0100526', (45, 56))	('phosphorylation', 'MPA', (104, 119))	('MCM2', 'Var', (31, 35))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('promoted', 'PosReg', (36, 44))
285138	30174440	Meanwhile, Zhang et al found that downregulation of MCM2 expression increased Rb, cyclin D1 and CDK4 expression, and decreased p53 and p21 expression, which suggested that MCM2 triggered the arrest of G1/S or G2/M through the induction of cyclin-dependent kinase inhibitor p21cip14 and cyclin D/CDK4 cyclin D/CDK4.	('CDK4', 'Gene', '1019', (309, 313))	('cyclin D1', 'Gene', '595', (82, 91))	('G1/S', 'CPA', (201, 205))	('p53', 'Gene', '7157', (127, 130))	('p21', 'Gene', (135, 138))	('p21', 'Gene', '1026', (273, 276))	('CDK4', 'Gene', (96, 100))	('increased', 'PosReg', (68, 77))	('p53', 'Gene', (127, 130))	('G2/M', 'CPA', (209, 213))	('downregulation', 'NegReg', (34, 48))	('decreased', 'NegReg', (117, 126))	('CDK4', 'Gene', (295, 299))	('CDK4', 'Gene', (309, 313))	('MCM2', 'Gene', (52, 56))	('CDK4', 'Gene', '1019', (96, 100))	('p21', 'Gene', '1026', (135, 138))	('cyclin D1', 'Gene', (82, 91))	('MCM2', 'Var', (172, 176))	('CDK4', 'Gene', '1019', (295, 299))	('p21', 'Gene', (273, 276))	('expression', 'MPA', (101, 111))
285162	33204107	Antibodies against VEGF or VEGFR, bevacizumab and ramucirumab were suggested for addition to chemotherapy for advanced non-small-cell lung cancer (NSCLC) without driver mutation.	('lung cancer', 'Disease', (134, 145))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (119, 145))	('ramucirumab', 'Gene', (50, 61))	('Antibodies', 'Var', (0, 10))	('VEGF', 'Gene', '7422', (27, 31))	('VEGF', 'Gene', (27, 31))	('VEGF', 'Gene', '7422', (19, 23))	('VEGF', 'Gene', (19, 23))	('bevacizumab', 'Chemical', 'MESH:D000068258', (34, 45))	('lung cancer', 'Disease', 'MESH:D008175', (134, 145))	('lung cancer', 'Phenotype', 'HP:0100526', (134, 145))	('NSCLC', 'Disease', 'MESH:D002289', (147, 152))	('VEGFR', 'Gene', '3791', (27, 32))	('VEGFR', 'Gene', (27, 32))	('ramucirumab', 'Chemical', 'MESH:C543333', (50, 61))	('NSCLC', 'Disease', (147, 152))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (123, 145))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('NSCLC', 'Phenotype', 'HP:0030358', (147, 152))
285207	33204107	Of note, half of the patients in the present examination had PS >= 2, which might have an influence on the efficacy of apatinib.	('influence', 'Reg', (90, 99))	('PS >= 2', 'Var', (61, 68))	('apatinib', 'Chemical', 'MESH:C553458', (119, 127))	('patients', 'Species', '9606', (21, 29))
285221	33204107	Zeng et al reported the efficacy of apatinib (250-425 mg/d) in SCC patients with a median PFS of 3.1 months, which was significantly less than PFS of our patients.	('patients', 'Species', '9606', (67, 75))	('apatinib', 'Chemical', 'MESH:C553458', (36, 44))	('patients', 'Species', '9606', (154, 162))	('SCC', 'Disease', (63, 66))	('250-425 mg/d', 'Var', (46, 58))
285249	33217893	Conclusions: The co-expression of CAR/DSG2 predicted a worse overall survival in LUAD.	('LUAD', 'Phenotype', 'HP:0030078', (81, 85))	('DSG2', 'Gene', (38, 42))	('worse', 'NegReg', (55, 60))	('co-expression', 'Var', (17, 30))	('overall survival', 'MPA', (61, 77))	('DSG2', 'Gene', '1829', (38, 42))	('LUAD', 'Disease', (81, 85))
285260	33217893	Overexpression of CAR is considered to promote carcinogenesis when it occurs in breast cancer precursor cell lines.	('promote', 'PosReg', (39, 46))	('carcinogenesis', 'Disease', (47, 61))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('breast cancer', 'Disease', 'MESH:D001943', (80, 93))	('Overexpression', 'Var', (0, 14))	('breast cancer', 'Disease', (80, 93))	('breast cancer', 'Phenotype', 'HP:0003002', (80, 93))	('carcinogenesis', 'Disease', 'MESH:D063646', (47, 61))
285263	33217893	In short, high CAR expression might be a treatment failure predictor in NSCLC, indicating a poor survival outcome in lung cancer.	('NSCLC', 'Disease', (72, 77))	('lung cancer', 'Disease', (117, 128))	('NSCLC', 'Disease', 'MESH:D002289', (72, 77))	('lung cancer', 'Phenotype', 'HP:0100526', (117, 128))	('high', 'Var', (10, 14))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('lung cancer', 'Disease', 'MESH:D008175', (117, 128))
285276	33217893	Datasets GSE102511 and GSE52248 were gene expression data for normal lung parenchyma (NL) tissue that progressed to cancer, while GSE32683 and GSE68571 were gene expression data that compared NL tissue with cancerous tissue.	('cancer', 'Disease', 'MESH:D009369', (207, 213))	('cancer', 'Disease', (207, 213))	('cancer', 'Disease', (116, 122))	('GSE52248', 'Var', (23, 31))	('cancerous', 'Disease', (207, 216))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('GSE102511', 'Var', (9, 18))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cancerous', 'Disease', 'MESH:D009369', (207, 216))
285277	33217893	CAR was upregulated in the normal samples that progressed to cancer in GSE102511 and GSE52248.	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('cancer', 'Disease', (61, 67))	('GSE52248', 'Var', (85, 93))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('upregulated', 'PosReg', (8, 19))	('GSE102511', 'Var', (71, 80))
285300	33217893	CAR and DSG2 gene co-expression was higher in early stage lung adenocarcinoma and was shown to have a significantly poorer survival outcome, when compared with lower CAR and DSG2 gene expression (p = 0.0046) (Figure 4).	('DSG2', 'Gene', (174, 178))	('higher', 'PosReg', (36, 42))	('DSG2', 'Gene', '1829', (8, 12))	('CAR', 'Gene', (0, 3))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (58, 77))	('co-expression', 'Var', (18, 31))	('carcinoma', 'Phenotype', 'HP:0030731', (68, 77))	('DSG2', 'Gene', '1829', (174, 178))	('DSG2', 'Gene', (8, 12))	('poorer', 'NegReg', (116, 122))	('lung adenocarcinoma', 'Disease', (58, 77))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (58, 77))
285307	33217893	Since the hub expression of Ki-67, caspase 3, CD31, and EMT is commonly associated with tumor cell growth, proliferation, migration, and invasion ability (Ki-67 stands for proliferation, caspase 3 stands for apoptosis, CD31 stands for angiogenesis, and EMT ration stands for migration and invasion ability), correlations among these markers were evaluated.	('invasion ability', 'CPA', (137, 153))	('Ki-67', 'Gene', (28, 33))	('CD31', 'Gene', (46, 50))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('associated', 'Reg', (72, 82))	('CD31', 'Var', (219, 223))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('caspase', 'Gene', (35, 42))	('migration', 'CPA', (122, 131))	('tumor', 'Disease', (88, 93))
285313	33217893	As shown in Figure 7, high expression of either CAR or DSG2 was associated with significantly poorer overall survival (CAR, cutoff H-score = 50.5, p = 0.045); (DSG2, cutoff H-score = 120, p = 0.001) (Figure 7A,B).	('high expression', 'Var', (22, 37))	('DSG2', 'Gene', '1829', (160, 164))	('overall survival', 'MPA', (101, 117))	('DSG2', 'Gene', (55, 59))	('DSG2', 'Gene', (160, 164))	('poorer', 'NegReg', (94, 100))	('DSG2', 'Gene', '1829', (55, 59))
285316	33217893	Furthermore, when the Kaplan-Meier survival analysis was performed to explore the co-expression of CAR/DSG2 and survival, a high CAR/DSG2 expression was associated with a significantly worse overall survival time (Figure 7C, p = 0.011; Figure 7D, p = 0.015).	('DSG2', 'Gene', (103, 107))	('worse', 'NegReg', (185, 190))	('DSG2', 'Gene', '1829', (133, 137))	('overall', 'MPA', (191, 198))	('DSG2', 'Gene', '1829', (103, 107))	('high', 'Var', (124, 128))	('DSG2', 'Gene', (133, 137))
285321	33217893	The findings of co-expressed high CAR and DSG2 gene expression with poor survival from the TCGA database were consistent with the IHC staining prediction model in the 108 TMA LUAD patients.	('high', 'Var', (29, 33))	('DSG2', 'Gene', (42, 46))	('CAR', 'Gene', (34, 37))	('LUAD', 'Phenotype', 'HP:0030078', (175, 179))	('TMA LUAD', 'Disease', (171, 179))	('DSG2', 'Gene', '1829', (42, 46))	('patients', 'Species', '9606', (180, 188))	('TMA LUAD', 'Disease', 'MESH:D000783', (171, 179))
285326	33217893	In addition, silencing CAR in lung cancer cells reduced tumor engraftment efficiency as CAR exerted a potential role in EMT.	('lung cancer', 'Phenotype', 'HP:0100526', (30, 41))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('CAR', 'Gene', (23, 26))	('lung cancer', 'Disease', (30, 41))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('reduced', 'NegReg', (48, 55))	('tumor', 'Disease', (56, 61))	('lung cancer', 'Disease', 'MESH:D008175', (30, 41))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('silencing', 'Var', (13, 22))
285349	33217893	When the two markers were taken into consideration and divided into high or low expression levels according to cutoff values, high CAR/DSG2 co-expression could predict worsening outcomes both in the long term (250 months) and the short term (60 months).	('co-expression', 'Var', (140, 153))	('high', 'Var', (126, 130))	('DSG2', 'Gene', (135, 139))	('DSG2', 'Gene', '1829', (135, 139))
285350	33217893	Other than early stage disease (stage I and IIA), CAR/DSG2 co-expression could hamper survival outcomes when disease staging was relatively advanced.	('survival outcomes', 'CPA', (86, 103))	('hamper', 'NegReg', (79, 85))	('DSG2', 'Gene', '1829', (54, 58))	('co-expression', 'Var', (59, 72))	('DSG2', 'Gene', (54, 58))
285355	33217893	The current study showed that CAR, DSG2, or a co-expression of CAR and DSG2 in LUAD is a predictor of overall survival.	('DSG2', 'Gene', '1829', (35, 39))	('LUAD', 'Phenotype', 'HP:0030078', (79, 83))	('DSG2', 'Gene', '1829', (71, 75))	('CAR', 'Gene', (63, 66))	('DSG2', 'Gene', (35, 39))	('co-expression', 'Var', (46, 59))	('DSG2', 'Gene', (71, 75))	('overall survival', 'CPA', (102, 118))
285357	33217893	LUAD patients with high CAR or DSG2, and especially CAR and DSG2, had significantly reduced overall survival rates.	('DSG2', 'Gene', '1829', (31, 35))	('patients', 'Species', '9606', (5, 13))	('DSG2', 'Gene', '1829', (60, 64))	('DSG2', 'Gene', (31, 35))	('reduced', 'NegReg', (84, 91))	('high CAR', 'Var', (19, 27))	('DSG2', 'Gene', (60, 64))	('overall survival rates', 'CPA', (92, 114))	('LUAD', 'Phenotype', 'HP:0030078', (0, 4))
285366	32038103	Epigenome-wide analysis of common warts reveals aberrant promoter methylation Epigenetic alteration of host DNA is a common occurrence in both low- and high-risk human papillomavirus (HPV) infection.	('human', 'Species', '9606', (162, 167))	('aberrant', 'Var', (48, 56))	('wart', 'Phenotype', 'HP:0200043', (34, 38))	('promoter methylation', 'MPA', (57, 77))	('Epigenetic alteration', 'Var', (78, 99))	('warts', 'Phenotype', 'HP:0200043', (34, 39))	('papillomavirus (HPV) infection', 'Disease', 'MESH:D030361', (168, 198))
285376	32038103	In contrast to the hypermethylated CpG sites scattered throughout the human genome, CpG islands are not methylated, and the methylation of CpG islands initiates remodeling mechanisms that ultimately result in gene silencing.	('methyl', 'Chemical', 'MESH:C031105', (104, 110))	('methyl', 'Chemical', 'MESH:C031105', (124, 130))	('human', 'Species', '9606', (70, 75))	('methyl', 'Chemical', 'MESH:C031105', (24, 30))	('result in', 'Reg', (199, 208))	('gene', 'MPA', (209, 213))	('methylation', 'Var', (124, 135))
285378	32038103	In fact, promoter hypermethylation is a key part of cancer development and progression, as it results in the silencing of tumor suppressor gene expression.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('promoter hypermethylation', 'Var', (9, 34))	('expression', 'MPA', (144, 154))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('silencing', 'NegReg', (109, 118))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('methyl', 'Chemical', 'MESH:C031105', (23, 29))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('tumor', 'Disease', (122, 127))
285391	32038103	Using this scoring method, a total of 576 and 424 promoters were found to be hypomethylated and hypermethylated, respectively, in warts (W) compared to normal skin (NS), with a mean beta difference =>0.064 and =< -0.064 and p-value =< 0.001 (adjusted p-value =<0.007) (Figure 6).	('wart', 'Phenotype', 'HP:0200043', (130, 134))	('warts', 'Disease', (130, 135))	('methyl', 'Chemical', 'MESH:C031105', (101, 107))	('methyl', 'Chemical', 'MESH:C031105', (81, 87))	('warts', 'Phenotype', 'HP:0200043', (130, 135))	('hypermethylated', 'Var', (96, 111))
285401	32038103	Variation in the CYSLTR1 gene modulates asthma risk as well as adenoid hypertrophy progression, and it has been implicated in the disease outcome of colorectal, prostate, and squamous cell carcinoma.	('colorectal', 'Disease', (149, 159))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (175, 198))	('modulates', 'Reg', (30, 39))	('squamous cell carcinoma', 'Disease', (175, 198))	('asthma', 'Phenotype', 'HP:0002099', (40, 46))	('adenoid hypertrophy', 'Disease', 'MESH:D006984', (63, 82))	('implicated in', 'Reg', (112, 125))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (175, 198))	('CYSLTR1', 'Gene', (17, 24))	('prostate', 'Disease', (161, 169))	('CYSLTR1', 'Gene', '10800', (17, 24))	('colorectal', 'Disease', 'MESH:D015179', (149, 159))	('asthma', 'Disease', 'MESH:D001249', (40, 46))	('Variation', 'Var', (0, 9))	('adenoid hypertrophy', 'Disease', (63, 82))	('asthma', 'Disease', (40, 46))	('carcinoma', 'Phenotype', 'HP:0030731', (189, 198))	('adenoid hypertrophy', 'Phenotype', 'HP:0040261', (63, 82))
285408	32038103	Mutations in the KRT6B gene result in an autosomal dominant skin disorder known as pachyonychia congenita, which involves plantar keratoderma and pain alongside thickened toenails.	('pain', 'Phenotype', 'HP:0012531', (146, 150))	('pain', 'Disease', 'MESH:D010146', (146, 150))	('pain', 'Disease', (146, 150))	('pachyonychia congenita', 'Disease', (83, 105))	('skin disorder', 'Phenotype', 'HP:0000951', (60, 73))	('plantar keratoderma', 'Disease', 'MESH:D007645', (122, 141))	('KRT6B', 'Gene', '3854', (17, 22))	('autosomal dominant skin disorder', 'Disease', 'MESH:D012871', (41, 73))	('Mutations', 'Var', (0, 9))	('plantar keratoderma', 'Disease', (122, 141))	('result in', 'Reg', (28, 37))	('KRT6B', 'Gene', (17, 22))	('autosomal dominant skin disorder', 'Disease', (41, 73))	('pachyonychia congenita', 'Disease', 'MESH:D053549', (83, 105))
285413	32038103	Moreover, atypical HF3B expression was reported to be associated with colorectal cancer and chondroblastoma.	('colorectal cancer', 'Disease', 'MESH:D015179', (70, 87))	('chondroblastoma', 'Disease', 'MESH:D002804', (92, 107))	('expression', 'MPA', (24, 34))	('colorectal cancer', 'Phenotype', 'HP:0003003', (70, 87))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('colorectal cancer', 'Disease', (70, 87))	('atypical', 'Var', (10, 18))	('HF3B', 'Protein', (19, 23))	('chondroblastoma', 'Disease', (92, 107))	('associated', 'Reg', (54, 64))	('chondroblastoma', 'Phenotype', 'HP:0030432', (92, 107))
285414	32038103	On a similar note, epigenetic modifications have been linked to changes in metabolism in a number of different non-communicable diseases, including cancer and diabetes.	('cancer', 'Disease', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('epigenetic modifications', 'Var', (19, 43))	('diabetes', 'Disease', (159, 167))	('changes', 'Reg', (64, 71))	('diabetes', 'Disease', 'MESH:D003920', (159, 167))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('metabolism', 'MPA', (75, 85))	('linked', 'Reg', (54, 60))
285416	32038103	Like the CYSLTR1 gene, LTC4S polymorphisms were associated with asthma risk and drug responsiveness in different ethnic populations.	('CYSLTR1', 'Gene', (9, 16))	('CYSLTR1', 'Gene', '10800', (9, 16))	('asthma', 'Phenotype', 'HP:0002099', (64, 70))	('associated', 'Reg', (48, 58))	('LTC4S', 'Gene', '4056', (23, 28))	('LTC4S', 'Gene', (23, 28))	('asthma', 'Disease', (64, 70))	('polymorphisms', 'Var', (29, 42))	('asthma', 'Disease', 'MESH:D001249', (64, 70))
285419	32038103	Aberrant H3F3A expression has been associated with the promotion of pediatric and adolescent cancers as well as lung cancer cell migration.	('cancers', 'Disease', (93, 100))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('Aberrant', 'Var', (0, 8))	('lung cancer', 'Disease', (112, 123))	('promotion', 'PosReg', (55, 64))	('lung cancer', 'Phenotype', 'HP:0100526', (112, 123))	('associated', 'Reg', (35, 45))	('cancers', 'Phenotype', 'HP:0002664', (93, 100))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('H3F3A', 'Gene', '3020', (9, 14))	('expression', 'MPA', (15, 25))	('lung cancer', 'Disease', 'MESH:D008175', (112, 123))	('cancers', 'Disease', 'MESH:D009369', (93, 100))	('H3F3A', 'Gene', (9, 14))
285424	32038103	Analysis of genome-wide promoter methylation revealed that MAPK13 was hypermethylated in the majority of primary and metastatic melanomas.	('MAPK13', 'Gene', (59, 65))	('melanomas', 'Phenotype', 'HP:0002861', (128, 137))	('melanomas', 'Disease', 'MESH:D008545', (128, 137))	('methyl', 'Chemical', 'MESH:C031105', (33, 39))	('methyl', 'Chemical', 'MESH:C031105', (75, 81))	('hypermethylated', 'Var', (70, 85))	('primary and', 'Disease', (105, 116))	('melanomas', 'Disease', (128, 137))	('MAPK13', 'Gene', '5603', (59, 65))
285425	32038103	MAPK13 was also found to be hypermethylated in esophageal squamous cell carcinoma.	('MAPK13', 'Gene', (0, 6))	('esophageal squamous cell carcinoma', 'Disease', (47, 81))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:C562729', (47, 81))	('methyl', 'Chemical', 'MESH:C031105', (33, 39))	('MAPK13', 'Gene', '5603', (0, 6))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (58, 81))	('hypermethylated', 'Var', (28, 43))
285429	31525663	Comprehensive Characterization of Somatic Mutations Impacting lncRNA Expression for Pan-Cancer Somatic mutations have long been recognized as an important feature of cancer.	('Cancer', 'Disease', 'MESH:D009369', (88, 94))	('Cancer', 'Phenotype', 'HP:0002664', (88, 94))	('cancer', 'Disease', (166, 172))	('Impacting', 'Reg', (52, 61))	('lncRNA Expression', 'MPA', (62, 79))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('Pan', 'Gene', (84, 87))	('Pan', 'Gene', '51816', (84, 87))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('Mutations', 'Var', (42, 51))	('Cancer', 'Disease', (88, 94))
285431	31525663	In this study, we characterized some lncRNAs whose expression was affected by somatic mutations (defined as MutLncs) and constructed global MutLnc landscapes across 17 cancer types by systematically integrating multiple levels of data.	('mutations', 'Var', (86, 95))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('expression', 'MPA', (51, 61))	('cancer', 'Disease', (168, 174))	('affected', 'Reg', (66, 74))
285434	31525663	Several conserved and cancer-specific functions of MutLncs were determined.	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('MutLncs', 'Var', (51, 58))	('cancer', 'Disease', (22, 28))	('cancer', 'Disease', 'MESH:D009369', (22, 28))
285435	31525663	We further explored the somatic mutations affecting lncRNA expression via mixed and unmixed effects, which led to specific functions in pan-cancer.	('pan-cancer', 'Disease', (136, 146))	('lncRNA', 'Gene', (52, 58))	('mutations', 'Var', (32, 41))	('pan-cancer', 'Disease', 'MESH:C537931', (136, 146))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))
285440	31525663	Despite significant advancements in understanding lncRNA expression patterns and functions, knowledge of their involvement in the molecular mechanisms underlying cancer remains limited:in particular, the potential pathogenic mechanisms triggered by lncRNA-related somatic mutations.	('mutations', 'Var', (272, 281))	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('cancer', 'Disease', (162, 168))	('lncRNA-related', 'Gene', (249, 263))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))
285441	31525663	Previous studies have reported that somatic mutations affect cancer-related protein coding genes through diverse molecular mechanisms and ultimately contribute to cancer progression.	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('cancer', 'Disease', (61, 67))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('mutations', 'Var', (44, 53))	('affect', 'Reg', (54, 60))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('contribute', 'Reg', (149, 159))	('cancer', 'Disease', 'MESH:D009369', (163, 169))	('cancer', 'Disease', (163, 169))
285442	31525663	However, little is known about the roles of lncRNAs affected by somatic mutations (designated MutLncs) in cancer.	('mutations', 'Var', (72, 81))	('cancer', 'Disease', (106, 112))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
285443	31525663	MutLncs may represent a novel type of functional molecule with potential utility as biomarkers for cancer diagnostics and treatment.	('cancer', 'Disease', (99, 105))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('MutLncs', 'Var', (0, 7))
285444	31525663	Recent studies have revealed a comprehensive landscape of somatic mutations that affect the expression patterns of various genes to trigger different human cancers (pan-cancer).	('mutations', 'Var', (66, 75))	('trigger', 'Reg', (132, 139))	('human', 'Species', '9606', (150, 155))	('cancers', 'Phenotype', 'HP:0002664', (156, 163))	('pan-cancer', 'Disease', 'MESH:C537931', (165, 175))	('cancers', 'Disease', (156, 163))	('cancers', 'Disease', 'MESH:D009369', (156, 163))	('pan-cancer', 'Disease', (165, 175))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('expression patterns', 'MPA', (92, 111))	('affect', 'Reg', (81, 87))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))
285452	31525663	Mutational co-occurrence analyses disclosed a combination effect of mutations in pan-cancer.	('mutations', 'Var', (68, 77))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('pan-cancer', 'Disease', 'MESH:C537931', (81, 91))	('pan-cancer', 'Disease', (81, 91))
285454	31525663	We further explored the means by which somatic mutations affect lncRNA expression (i.e., via mixed and unmixed effect processes) in pan-cancer by integrating TCGA gene expression, microRNA (miRNA) expression, methylation, transcription factor (TF)-lncRNA interaction, and miRNA-lncRNA interaction data.	('lncRNA expression', 'MPA', (64, 81))	('pan-cancer', 'Disease', 'MESH:C537931', (132, 142))	('mutations', 'Var', (47, 56))	('affect', 'Reg', (57, 63))	('TCGA', 'Gene', (158, 162))	('pan-cancer', 'Disease', (132, 142))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
285461	31525663	Notably, the majority of MutLncs were categorized as unmixed (82%) in most of the cancer types examined.	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('MutLncs', 'Var', (25, 32))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('cancer', 'Disease', (82, 88))
285463	31525663	For example, methylation-related MutLncs constituted a high proportion of MutLncs in glioblastoma multiforme (GBM) and TF-related MutLncs in uterine corpus endometrial carcinoma (UCEC) (Figure S1B).	('carcinoma', 'Phenotype', 'HP:0030731', (168, 177))	('corpus endometrial carcinoma', 'Disease', (149, 177))	('corpus endometrial carcinoma', 'Disease', 'MESH:D016889', (149, 177))	('glioblastoma multiforme', 'Disease', (85, 108))	('glioblastoma', 'Phenotype', 'HP:0012174', (85, 97))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (85, 108))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (156, 177))	('methylation-related', 'Var', (13, 32))
285470	31525663	For instance, the MutLnc FLG-AS1 (Ensembl: ENSG00000237975) was mutated in 42% samples in stomach adenocarcinoma (STAD) and 18% samples in GBM, but no samples for some other cancer types.	('stomach adenocarcinoma', 'Disease', (90, 112))	('FLG-AS1', 'Gene', '339400', (25, 32))	('cancer', 'Disease', (174, 180))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('FLG-AS1', 'Gene', (25, 32))	('mutated', 'Var', (64, 71))	('stomach adenocarcinoma', 'Disease', 'MESH:D013274', (90, 112))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))
285471	31525663	Another example, TTN-AS1 (Ensembl: ENSG00000237298), displayed 44% mutational frequency in head-neck squamous cell carcinoma (HNSC), which was the highest for all MutLncs across all the cancer types examined.	('TTN-AS1', 'Gene', '100506866', (17, 24))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (101, 124))	('head-neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (91, 124))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('mutational', 'Var', (67, 77))	('head-neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (91, 124))	('TTN-AS1', 'Gene', (17, 24))	('HNSC', 'Phenotype', 'HP:0012288', (126, 130))	('head-neck squamous cell carcinoma', 'Disease', (91, 124))	('cancer', 'Disease', (186, 192))	('cancer', 'Disease', 'MESH:D009369', (186, 192))
285473	31525663	A previous study reported dysregulation of TTN-AS1 in nasopharyngeal nonkeratinizing carcinoma but did not discuss the underlying reasons.	('carcinoma', 'Disease', (85, 94))	('dysregulation', 'Var', (26, 39))	('TTN-AS1', 'Gene', (43, 50))	('carcinoma', 'Disease', 'MESH:D002277', (85, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('TTN-AS1', 'Gene', '100506866', (43, 50))
285476	31525663	Characterization of MutLnc TTN-AS1 may therefore provide novel insights into the specific roles of TTN in cancer.	('TTN', 'Gene', (99, 102))	('TTN', 'Gene', '7273', (99, 102))	('TTN-AS1', 'Gene', '100506866', (27, 34))	('TTN', 'Gene', (27, 30))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('cancer', 'Disease', (106, 112))	('TTN', 'Gene', '7273', (27, 30))	('TTN-AS1', 'Gene', (27, 34))	('MutLnc', 'Var', (20, 26))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
285478	31525663	For example, >75% and 73% MutLncs were downregulated in liver hepatocellular carcinoma (LIHC) and HNSC, while >94% MutLncs were upregulated in GBM.	('liver hepatocellular carcinoma', 'Disease', (56, 86))	('LIHC', 'Disease', (88, 92))	('LIHC', 'Disease', 'None', (88, 92))	('MutLncs', 'Var', (26, 33))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('HNSC', 'Phenotype', 'HP:0012288', (98, 102))	('liver hepatocellular carcinoma', 'Disease', 'MESH:D006528', (56, 86))	('HNSC', 'Disease', (98, 102))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (62, 86))	('downregulated', 'NegReg', (39, 52))
285480	31525663	The numbers of non-silent mutations were greater than silent mutations for each cancer type, with around 76% MutLncs being non-silent (Figure 2C).	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('non-silent mutations', 'Var', (15, 35))	('cancer', 'Disease', (80, 86))
285482	31525663	MYHAS (Ensembl: ENSG00000272975.1) was mutated in 15.3% samples and VCAN-AS1 only in 5.1% samples.	('VCAN-AS1', 'Gene', '105379054', (68, 76))	('mutated', 'Var', (39, 46))	('MYHAS', 'Gene', (0, 5))	('VCAN-AS1', 'Gene', (68, 76))	('MYHAS', 'Gene', '100128560', (0, 5))
285484	31525663	Previous studies have reported a correlation between chromosome 17 and cancer.	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('chromosome', 'Var', (53, 63))	('cancer', 'Disease', (71, 77))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('correlation', 'Interaction', (33, 44))
285486	31525663	Mutations in the chromosome 17 centromere region have been linked to cancer.	('linked', 'Reg', (59, 65))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('Mutations', 'Var', (0, 9))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Disease', (69, 75))
285489	31525663	We hypothesize that the somatic mutation affects FAM27L expression, in turn, leading to functional changes that trigger cancer development.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('trigger', 'Reg', (112, 119))	('leading to', 'Reg', (77, 87))	('cancer', 'Disease', (120, 126))	('FAM27L', 'Gene', '284123', (49, 55))	('FAM27L', 'Gene', (49, 55))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('expression', 'MPA', (56, 66))	('functional changes', 'MPA', (88, 106))	('mutation', 'Var', (32, 40))
285494	31525663	Overall, 95.9% and 4.1% common co-occurrence MutLnc pairs appeared in two and three cancer types, respectively (Figure 3B).	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('cancer', 'Disease', (84, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('appeared', 'Reg', (58, 66))	('MutLnc pairs', 'Var', (45, 57))
285507	31525663	For example, MutLnc AC108025.2 (Ensembl: ENSG00000230090.1) displayed co-occurrence with AC005550.5 (Ensembl: ENSG00000225974.1) in kidney renal clear cell carcinoma (KIRC), but occurred alone in CESC.	('MutLnc AC108025.2', 'Var', (13, 30))	('carcinoma', 'Phenotype', 'HP:0030731', (156, 165))	('kidney renal clear cell carcinoma', 'Disease', 'MESH:C538614', (132, 165))	('kidney renal clear cell carcinoma', 'Disease', (132, 165))	('AC108025.2', 'Var', (20, 30))
285520	31525663	For example, MutLncs in LUAD were enriched in the ERK1 and ERK2 cascades, which may show different mechanisms between cancer subtypes (Figure 4D).	('cancer', 'Disease', (118, 124))	('LUAD', 'Phenotype', 'HP:0030078', (24, 28))	('ERK1', 'Gene', (50, 54))	('MutLncs', 'Var', (13, 20))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('LUAD', 'Disease', (24, 28))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('ERK2', 'Gene', (59, 63))	('ERK1', 'Gene', '5595', (50, 54))	('ERK2', 'Gene', '5594', (59, 63))
285525	31525663	For example, MutLncs in STAD were enriched in specific pathways and GO terms related to stomach function, such as "taste transduction" and "maturity onset diabetes of the young" pathways.	('diabetes', 'Disease', 'MESH:D003920', (155, 163))	('diabetes', 'Disease', (155, 163))	('MutLncs', 'Var', (13, 20))	('maturity onset diabetes of the young', 'Phenotype', 'HP:0004904', (140, 176))
285526	31525663	We additionally detected common functions of MutLncs in different cancer types, such as synaptic transmission, shown to be related to cancer-associated pain and metastasis (Figure S4C).	('synaptic transmission', 'MPA', (88, 109))	('MutLncs', 'Var', (45, 52))	('pain', 'Phenotype', 'HP:0012531', (152, 156))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('cancer', 'Disease', (134, 140))	('pain', 'Disease', 'MESH:D010146', (152, 156))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('pain', 'Disease', (152, 156))	('related', 'Reg', (123, 130))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('cancer', 'Disease', (66, 72))
285532	31525663	Moreover, some MutLncs were associated with two mixed effects and showed more complex effect mechanisms in three cancer types.	('cancer', 'Disease', (113, 119))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('MutLncs', 'Var', (15, 22))
285534	31525663	In some cancers, such as STAD, most methylation-related MutLncs were associated with embryonic development and miRNA-related MutLncs with the ribosome, as reported in previous studies (Figure 5B).	('STAD', 'Disease', (25, 29))	('cancers', 'Disease', 'MESH:D009369', (8, 15))	('cancers', 'Phenotype', 'HP:0002664', (8, 15))	('cancers', 'Disease', (8, 15))	('associated', 'Reg', (69, 79))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('methylation-related', 'Var', (36, 55))	('embryonic development', 'CPA', (85, 106))
285536	31525663	MutLnc RP11-672L10.2 (Ensembl: ENSG00000265179) was linked to one gene, ADCYAP1B, and one methylation event, cg14489474 (Figure 5C).	('linked', 'Reg', (52, 58))	('RP11', 'Gene', '26121', (7, 11))	('ADCYAP1B', 'Gene', (72, 80))	('cg14489474', 'Var', (109, 119))	('RP11', 'Gene', (7, 11))
285539	31525663	These findings support the importance of MutLnc combined events in tumorigenesis and their prognostic value in clinical practice (Figure 6A).	('MutLnc', 'Var', (41, 47))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Disease', (67, 72))
285540	31525663	Moreover, 29 MutLncs were correlated with survival, and mutated samples were significantly associated with decreased survival in 14 types of cancer (Figure 6B).	('survival', 'MPA', (117, 125))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('mutated', 'Var', (56, 63))	('decreased', 'NegReg', (107, 116))	('correlated', 'Reg', (26, 36))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('cancer', 'Disease', (141, 147))
285541	31525663	For example, the MutLnc CACNA1C-AS3 (Ensembl: ENSG00000256769.1), with 7 mutated samples, was significantly related to survival (p = 0.00796), with shorter survival in mutated samples in STAD (Figure 6B).	('mutated', 'Var', (168, 175))	('survival', 'MPA', (156, 164))	('shorter', 'NegReg', (148, 155))	('CACNA1C-AS3', 'Gene', '106478964', (24, 35))	('survival', 'MPA', (119, 127))	('CACNA1C-AS3', 'Gene', (24, 35))	('related', 'Reg', (108, 115))
285544	31525663	First, the MutLnc CACNA1C-AS3 co-occurred with 12 MutLncs, such as HOTAIRM1 (Ensembl: ENSG00000233429), which is located between HOXA1 and HOXA2 genes (Figure 6C).	('HOTAIRM1', 'Gene', '100506311', (67, 75))	('CACNA1C-AS3', 'Gene', (18, 29))	('MutLnc', 'Var', (11, 17))	('HOTAIRM1', 'Gene', (67, 75))	('HOXA1', 'Gene', (129, 134))	('HOXA2', 'Gene', (139, 144))	('CACNA1C-AS3', 'Gene', '106478964', (18, 29))	('HOXA1', 'Gene', '3198', (129, 134))	('HOXA2', 'Gene', '3199', (139, 144))
285545	31525663	Second, prediction of the minimum free energy (MFE) changes caused by mutations in MutLnc CACNA1C-AS3 revealed significant effects on predicted lncRNA secondary structures, which, in turn, impacted lncRNA expression (Figures 6D and 6E).	('lncRNA secondary structures', 'MPA', (144, 171))	('mutations', 'Var', (70, 79))	('lncRNA expression', 'MPA', (198, 215))	('MutLnc', 'Var', (83, 89))	('impacted', 'Reg', (189, 197))	('minimum free energy', 'MPA', (26, 45))	('CACNA1C-AS3', 'Gene', '106478964', (90, 101))	('CACNA1C-AS3', 'Gene', (90, 101))	('changes', 'Reg', (52, 59))	('effects', 'Reg', (123, 130))
285546	31525663	Third, the mutations located on the TF FOXA1, GATA3, and EP300 binding sites may affect the binding of TF to alter lncRNA expression (Figure 6F).	('binding', 'Interaction', (92, 99))	('mutations', 'Var', (11, 20))	('GATA3', 'Gene', (46, 51))	('FOXA1', 'Gene', '3169', (39, 44))	('alter', 'Reg', (109, 114))	('GATA3', 'Gene', '2625', (46, 51))	('affect', 'Reg', (81, 87))	('FOXA1', 'Gene', (39, 44))	('lncRNA expression', 'MPA', (115, 132))
285549	31525663	Co-occurrence analysis highlights particular MutLnc combined patterns in pan-cancer.	('pan-cancer', 'Disease', 'MESH:C537931', (73, 83))	('pan-cancer', 'Disease', (73, 83))	('MutLnc', 'Var', (45, 51))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))
285554	31525663	The strong correlations between MutLncs and survival support their potential as specific cancer biomarkers.	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('cancer', 'Disease', (89, 95))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('MutLncs', 'Var', (32, 39))
285555	31525663	Moreover, MutLnc co-occurrence pairs might be effectively applied as new possible prognostic biomarkers for particular cancers.	('cancers', 'Phenotype', 'HP:0002664', (119, 126))	('MutLnc co-occurrence', 'Var', (10, 30))	('particular cancers', 'Disease', (108, 126))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('particular cancers', 'Disease', 'MESH:D009369', (108, 126))
285556	31525663	Cancers are clonal proliferation disorders that arise owing to mutations that confer a selective growth advantage to cells.	('mutations', 'Var', (63, 72))	('Cancers', 'Disease', (0, 7))	('Cancers', 'Phenotype', 'HP:0002664', (0, 7))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancers', 'Disease', 'MESH:D009369', (0, 7))
285564	31525663	Thus, investigation and interpretation of lncRNA mutations should provide novel and useful insights into the mechanisms underlying the functions of these molecules in cancer.	('lncRNA', 'Gene', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('mutations', 'Var', (49, 58))	('cancer', 'Disease', (167, 173))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))
285567	31525663	We found that numerous somatic mutations were located on lncRNA TF binding site (TFBS) regions in multiple cancer types (Figure S7A).	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('multiple cancer', 'Disease', 'MESH:D009369', (98, 113))	('mutations', 'Var', (31, 40))	('multiple cancer', 'Disease', (98, 113))
285570	31525663	For example, we found that some somatic mutations were located on lncRNA SNHG16, and these mutations caused the function loss of TFBSs for TF ESR1 in breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('ESR1', 'Gene', '2099', (142, 146))	('breast cancer', 'Disease', 'MESH:D001943', (150, 163))	('breast cancer', 'Phenotype', 'HP:0003002', (150, 163))	('loss', 'NegReg', (121, 125))	('breast cancer', 'Disease', (150, 163))	('ESR1', 'Gene', (142, 146))	('mutations', 'Var', (40, 49))	('SNHG16', 'Gene', (73, 79))	('mutations', 'Var', (91, 100))	('SNHG16', 'Gene', '100507246', (73, 79))	('TFBSs', 'Gene', (129, 134))
285576	31525663	In summary, the MutLnc profiles provide a global overview of the dysregulated lncRNAs affected by somatic mutations across different cancer types.	('cancer', 'Disease', (133, 139))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('mutations', 'Var', (106, 115))
285578	31525663	Integrating mutational and lncRNA expression data from tumor samples enhances the interpretation capacity of the mutations identified, which may facilitate optimal selectivity of targets for functional studies and the development of novel cancer therapeutics.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('cancer', 'Disease', 'MESH:D009369', (239, 245))	('tumor', 'Disease', (55, 60))	('interpretation', 'MPA', (82, 96))	('cancer', 'Disease', (239, 245))	('mutations', 'Var', (113, 122))	('enhances', 'PosReg', (69, 77))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))
285586	31525663	As reported widely, cancer samples frequently acquire genetic and epigenetic alterations that influence lncRNA expression through diverse mechanisms.	('epigenetic alterations', 'Var', (66, 88))	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('cancer', 'Disease', 'MESH:D009369', (20, 26))	('lncRNA', 'Protein', (104, 110))	('cancer', 'Disease', (20, 26))	('influence', 'Reg', (94, 103))	('genetic', 'Var', (54, 61))
285590	31525663	For each cancer pair, we quantified the number of MutLncs (1) in both, (2) only dysregulated in the first cancer, (3) only dysregulated in the second cancer, and (4) dysregulated in other cancers.	('cancer', 'Disease', (9, 15))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('cancers', 'Phenotype', 'HP:0002664', (188, 195))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('cancers', 'Disease', (188, 195))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('cancers', 'Disease', 'MESH:D009369', (188, 195))	('cancer', 'Disease', (150, 156))	('cancer', 'Disease', (106, 112))	('cancer', 'Disease', (188, 194))	('dysregulated', 'Var', (123, 135))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
285598	29057919	Inhibition of PD-L1 and PD-1 binding can restore host immunity towards tumor killing, and many new drugs have been developed to target this interaction.	('PD-L1', 'Protein', (14, 19))	('PD-1', 'Gene', (24, 28))	('restore', 'PosReg', (41, 48))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('PD-1', 'Gene', '5133', (24, 28))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('Inhibition', 'Var', (0, 10))	('tumor', 'Disease', (71, 76))	('binding', 'Interaction', (29, 36))
285634	29057919	All experimental protocols under Evaluation of Molecular Mutations in Lung Cancer, IRB #2004603, were approved by the University of Missouri Institutional Review Board.	('Cancer', 'Phenotype', 'HP:0002664', (75, 81))	('Mutations', 'Var', (57, 66))	('Lung Cancer', 'Disease', 'MESH:D008175', (70, 81))	('Lung Cancer', 'Disease', (70, 81))	('Lung Cancer', 'Phenotype', 'HP:0100526', (70, 81))
285666	29057919	The study resulted in identification of a high affinity peptide, RK-10-Cy5 for targeting PD-L1.	('PD-L1', 'Gene', (89, 94))	('10-Cy5', 'Chemical', '-', (68, 74))	('RK-10-Cy5', 'Var', (65, 74))	('peptide', 'Chemical', 'MESH:D010455', (56, 63))
285674	29057919	Y79 and MCF7 both have a much lower PD-L1 expression than MDA-MB-231, which correlates with expression seen using Cy5 conjugated peptide and comparing the cell lines with flow cytometry.	('lower', 'NegReg', (30, 35))	('Cy5', 'Chemical', 'MESH:C085321', (114, 117))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (58, 68))	('PD-L1', 'Gene', (36, 41))	('expression', 'MPA', (42, 52))	('MCF7', 'CellLine', 'CVCL:0031', (8, 12))	('peptide', 'Chemical', 'MESH:D010455', (129, 136))	('Y79', 'Var', (0, 3))
285675	29057919	Y79 and MCF7 MFI is close to tenfold lower than that seen in MDA-MB-231 in all lower concentrations.	('MCF7', 'CellLine', 'CVCL:0031', (8, 12))	('MCF7', 'Var', (8, 12))	('lower', 'NegReg', (37, 42))	('Y79', 'Var', (0, 3))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (61, 71))
285697	29057919	The SP263 antibody featured heavy edge staining but also showed membranous staining of the trophoblast cells, while the RK-10-Biotin peptide showed heavy membrane staining of the trophoblast cells without the intense edge artifacts seen when using the Ventana antibody.	('edge', 'MPA', (34, 38))	('membranous staining', 'CPA', (64, 83))	('-10-Biotin peptide', 'Chemical', '-', (122, 140))	('RK-10-Biotin', 'Chemical', '-', (120, 132))	('SP263', 'Var', (4, 9))	('SP263', 'Chemical', '-', (4, 9))
285709	29057919	The Cy5 signal in these tissues was consistent with the HRP staining, where RK-10-Cy5 peptide stained many areas of tumor that the SP263 antibody did not.	('10-Cy5', 'Chemical', '-', (79, 85))	('SP263', 'Chemical', '-', (131, 136))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('Cy5', 'Chemical', 'MESH:C085321', (82, 85))	('RK-10-Cy5', 'Var', (76, 85))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('peptide', 'Chemical', 'MESH:D010455', (86, 93))	('Cy5', 'Chemical', 'MESH:C085321', (4, 7))	('tumor', 'Disease', (116, 121))
285718	29057919	Interestingly, in the majority of cases, the SP263 antibody showed no tumor staining, while the RK-10-Cy5 peptide showed consistent, specific staining in tumor cells and immune infiltrate (Fig.	('SP263', 'Chemical', '-', (45, 50))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('SP263', 'Var', (45, 50))	('tumor', 'Disease', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('peptide', 'Chemical', 'MESH:D010455', (106, 113))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('10-Cy5', 'Chemical', '-', (99, 105))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('tumor', 'Disease', (154, 159))
285728	29057919	When using the RK-10-Cy5 peptide, RS cells were easily identified by the pathologist due to the heavy Cy5 fluorescent signal.	('RK-10-Cy5 peptide', 'Var', (15, 32))	('10-Cy5', 'Chemical', '-', (18, 24))	('Cy5', 'Chemical', 'MESH:C085321', (21, 24))	('heavy Cy5 fluorescent signal', 'MPA', (96, 124))	('Cy5', 'Chemical', 'MESH:C085321', (102, 105))	('peptide', 'Chemical', 'MESH:D010455', (25, 32))
285740	29057919	The PD-L1 targeting peptide RK-10-Cy5 was identified through structural analysis of PD-1:PD-L1 binding pocket structure.	('10-Cy5', 'Chemical', '-', (31, 37))	('RK-10-Cy5', 'Var', (28, 37))	('peptide', 'Chemical', 'MESH:D010455', (20, 27))	('PD-1', 'Gene', (84, 88))	('PD-1', 'Gene', '5133', (84, 88))
285744	29057919	While there were some cases that were negative using both SP263 and RK-10-Cy5, there were a large number of cases where RK-10-Cy5 showed very specific tumor staining that were not stained by the SP263 antibody.	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('SP263', 'Chemical', '-', (58, 63))	('tumor', 'Disease', (151, 156))	('10-Cy5', 'Chemical', '-', (71, 77))	('RK-10-Cy5', 'Var', (120, 129))	('SP263', 'Chemical', '-', (195, 200))	('10-Cy5', 'Chemical', '-', (123, 129))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
285760	26465158	We found 10 significantly recurrent copy number alterations accompanying gene expression changes, including loci 11q13.2, 7p11.2, 3q26.33, and 17q12, which harbored CCND1, EGFR, SOX2, and ERBB2, respectively.	('CCND1', 'Gene', '595', (165, 170))	('EGFR', 'Gene', '1956', (172, 176))	('SOX2', 'Gene', (178, 182))	('changes', 'Reg', (89, 96))	('EGFR', 'Gene', (172, 176))	('CCND1', 'Gene', (165, 170))	('copy number alterations', 'Var', (36, 59))	('gene expression', 'MPA', (73, 88))	('SOX2', 'Gene', '6657', (178, 182))
285764	26465158	Copy number aberrations (CNAs) and accompanying dysregulation of gene expression are known to play a critical role in the pathogenesis of human cancers.	('human', 'Species', '9606', (138, 143))	('dysregulation of gene expression', 'MPA', (48, 80))	('cancers', 'Phenotype', 'HP:0002664', (144, 151))	('cancers', 'Disease', (144, 151))	('cancers', 'Disease', 'MESH:D009369', (144, 151))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('Copy number aberrations', 'Var', (0, 23))
285767	26465158	This series of analyses suggest that GRB7, located on 17q12, was overexpressed due to copy number gains and play a critical role in tumor growth and invasion.	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('overexpressed', 'PosReg', (65, 78))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('copy number gains', 'Var', (86, 103))	('tumor', 'Disease', (132, 137))	('GRB7', 'Gene', (37, 41))	('invasion', 'CPA', (149, 157))
285790	26465158	ERBB2 and GRB7 proteins were detected using an anti-ERBB2 rabbit monoclonal antibody (Epitomics, Inc) at a 1:5000 dilution and an anti-GRB7 rabbit monoclonal antibody (Gene Tex International Corporation) at a 1:1000 dilution.	('ERBB2', 'Gene', (0, 5))	('detected', 'Reg', (29, 37))	('rabbit', 'Species', '9986', (140, 146))	('GRB7 proteins', 'Protein', (10, 23))	('rabbit', 'Species', '9986', (58, 64))	('anti-ERBB2', 'Var', (47, 57))
285802	26465158	The most significant deletion peak was observed at chromosome segment 9p21.3, containing CDKN2A (Fig 1b).	('CDKN2A', 'Gene', '1029', (89, 95))	('CDKN2A', 'Gene', (89, 95))	('deletion', 'Var', (21, 29))
285805	26465158	Moreover, deletion peaks of CDKN2A on 9p21.3 and FHIT on 3p14.2 were also observed in the GEO data set.	('FHIT', 'Gene', '2272', (49, 53))	('CDKN2A', 'Gene', (28, 34))	('deletion', 'Var', (10, 18))	('FHIT', 'Gene', (49, 53))	('CDKN2A', 'Gene', '1029', (28, 34))
285815	26465158	The combination of trastuzumab (0.1 mug/mL) plus transfection of siRNA targeting GRB7 had a stronger inhibitory effect on cell growth than administration of trastuzumab or siRNA targeting GRB7 alone (Fig 2d).	('trastuzumab', 'Chemical', 'MESH:D000068878', (157, 168))	('transfection', 'Var', (49, 61))	('siRNA', 'Var', (65, 70))	('inhibitory effect', 'NegReg', (101, 118))	('cell growth', 'CPA', (122, 133))	('GRB7', 'Gene', (81, 85))	('trastuzumab', 'Chemical', 'MESH:D000068878', (19, 30))
285816	26465158	This was observed under a high concentration of trastuzumab (1.0 mug/mL), which indicated that knockdown of GRB7 expression had a synergistic inhibitory effect on ESCC cell lines with amplification of 17q12.	('ESCC', 'Disease', (163, 167))	('synergistic inhibitory effect', 'MPA', (130, 159))	('GRB7', 'Gene', (108, 112))	('trastuzumab', 'Chemical', 'MESH:D000068878', (48, 59))	('knockdown', 'Var', (95, 104))
285819	26465158	With regard to overall survival, patients with high GRB7 expression had a significantly poorer prognosis than those with low GRB7 expression (P = 0.006; Fig 3b).	('GRB7', 'Protein', (52, 56))	('high', 'Var', (47, 51))	('poorer', 'NegReg', (88, 94))	('patients', 'Species', '9606', (33, 41))
285822	26465158	Similar to other cancers, recurrent amplification of 7p11.2, 8q24.21, and 11q13.2, harboring EGFR, MYC, and CCND1, has previously been reported in ESCC.	('EGFR', 'Gene', '1956', (93, 97))	('CCND1', 'Gene', (108, 113))	('MYC', 'Gene', '4609', (99, 102))	('EGFR', 'Gene', (93, 97))	('cancers', 'Phenotype', 'HP:0002664', (17, 24))	('amplification', 'Var', (36, 49))	('ESCC', 'Disease', (147, 151))	('CCND1', 'Gene', '595', (108, 113))	('cancers', 'Disease', (17, 24))	('reported', 'Reg', (135, 143))	('cancers', 'Disease', 'MESH:D009369', (17, 24))	('MYC', 'Gene', (99, 102))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
285824	26465158	Compared with esophageal adenocarcinoma, the estimated frequency of SOX2 amplification was reported to be significantly higher in ESCC.	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (14, 39))	('ESCC', 'Disease', (130, 134))	('higher', 'PosReg', (120, 126))	('SOX2', 'Gene', (68, 72))	('SOX2', 'Gene', '6657', (68, 72))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (14, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (30, 39))	('esophageal adenocarcinoma', 'Disease', (14, 39))	('amplification', 'Var', (73, 86))
285826	26465158	Additionally, we found additional genes previously not reported in any genome-wide studies in ESCC, such as FOXP1 and NFATC1, which were downregulated due to deletion.	('FOXP1', 'Gene', (108, 113))	('downregulated', 'NegReg', (137, 150))	('NFATC1', 'Gene', (118, 124))	('deletion', 'Var', (158, 166))	('FOXP1', 'Gene', '27086', (108, 113))	('NFATC1', 'Gene', '4772', (118, 124))	('ESCC', 'Gene', (94, 98))
285828	26465158	The significance of HER2 amplification at 17q12 in ESCC has been highlighted in previous studies.	('HER2', 'Gene', '2064', (20, 24))	('HER2', 'Gene', (20, 24))	('ESCC', 'Disease', (51, 55))	('amplification', 'Var', (25, 38))
285829	26465158	The frequency of amplification of HER2 in ESCC ranges from 3.9% to 41.4%.	('HER2', 'Gene', '2064', (34, 38))	('HER2', 'Gene', (34, 38))	('amplification', 'Var', (17, 30))
285837	26465158	Therefore, in addition to its applications in breast and gastric cancers, trastuzumab may be an effective drug for the treatment of patients with ESCC harboring amplification of 17q12.	('gastric cancers', 'Phenotype', 'HP:0012126', (57, 72))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('trastuzumab', 'Chemical', 'MESH:D000068878', (74, 85))	('amplification', 'Var', (161, 174))	('cancers', 'Phenotype', 'HP:0002664', (65, 72))	('ESCC', 'Disease', (146, 150))	('patients', 'Species', '9606', (132, 140))	('gastric cancers', 'Disease', (57, 72))	('gastric cancers', 'Disease', 'MESH:D013274', (57, 72))
285838	26465158	Moreover, when combined with trastuzumab, knockdown of GRB7 had a synergistic inhibitory effect on cell proliferation.	('GRB7', 'Gene', (55, 59))	('trastuzumab', 'Chemical', 'MESH:D000068878', (29, 40))	('cell proliferation', 'CPA', (99, 117))	('knockdown', 'Var', (42, 51))
285840	26465158	Collectively, we propose GRB7 as a novel therapeutic target in ESCC patients having 17q12 amplification.	('patients', 'Species', '9606', (68, 76))	('17q12 amplification', 'Var', (84, 103))	('ESCC', 'Disease', (63, 67))
285841	26465158	Moreover, since GRB7 reportedly acts with other tyrosine kinase receptors as well as ERBB2, we expect that inhibition of GRB7 would be a novel therapeutic strategy effective for ESCC patients with resistance to trastuzumab.	('GRB7', 'Gene', (121, 125))	('patients', 'Species', '9606', (183, 191))	('inhibition', 'Var', (107, 117))	('ESCC', 'Disease', (178, 182))	('trastuzumab', 'Chemical', 'MESH:D000068878', (211, 222))
285848	25491772	Intranasal application of anti-IL-6R antibodies in a murine model of lung adenocarcinoma, induced T regulatory cell markers such as Foxp3, Ctla4, Icos, Il10, Il21, Folr4 and Lag3 and inhibited Rorc in lung adenocarcinoma.	('lung adenocarcinoma', 'Disease', (69, 88))	('Lag3', 'Gene', '16768', (174, 178))	('Foxp3', 'Gene', (132, 137))	('anti-IL-6R antibodies', 'Var', (26, 47))	('Folr4', 'Gene', (164, 169))	('Rorc', 'Gene', '19885', (193, 197))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('Icos', 'Gene', (146, 150))	('Lag3', 'Gene', (174, 178))	('Il10', 'Gene', '16153', (152, 156))	('murine', 'Species', '10090', (53, 59))	('T regulatory', 'MPA', (98, 110))	('lung adenocarcinoma', 'Disease', (201, 220))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (69, 88))	('Ctla4', 'Gene', '12477', (139, 144))	('Il10', 'Gene', (152, 156))	('Folr4', 'Gene', '64931', (164, 169))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (69, 88))	('Ctla4', 'Gene', (139, 144))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (201, 220))	('Foxp3', 'Gene', '20371', (132, 137))	('inhibited', 'NegReg', (183, 192))	('antibodies', 'Var', (37, 47))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (201, 220))	('Il21', 'Gene', (158, 162))	('induced', 'PosReg', (90, 97))	('Rorc', 'Gene', (193, 197))	('carcinoma', 'Phenotype', 'HP:0030731', (211, 220))	('Il21', 'Gene', '60505', (158, 162))	('Icos', 'Gene', '54167', (146, 150))
285852	25491772	Most of lung cancer cell lines including those with Epidermal-growth factor receptor (EGFR) mutations harbour auto-phosphorylated STAT3 that cannot be inhibited by EGFR inhibitors.	('Epidermal-growth factor receptor', 'Gene', (52, 84))	('auto-phosphorylated', 'MPA', (110, 129))	('EGFR', 'Gene', (164, 168))	('EGFR', 'Gene', '13649', (164, 168))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('Epidermal-growth factor receptor', 'Gene', '13649', (52, 84))	('lung cancer', 'Disease', 'MESH:D008175', (8, 19))	('mutations', 'Var', (92, 101))	('EGFR', 'Gene', (86, 90))	('EGFR', 'Gene', '13649', (86, 90))	('lung cancer', 'Disease', (8, 19))	('lung cancer', 'Phenotype', 'HP:0100526', (8, 19))
285861	25491772	More than ninety percent of mice overexpressing human BATF in T cells by 1 year of age develop a lymphoproliferative disorder (LPD).	('human', 'Species', '9606', (48, 53))	('mice', 'Species', '10090', (28, 32))	('LPD', 'Disease', 'None', (127, 130))	('LPD', 'Phenotype', 'HP:0005523', (127, 130))	('BATF', 'Var', (54, 58))	('lymphoproliferative disorder', 'Phenotype', 'HP:0005523', (97, 125))	('lymphoproliferative disorder', 'Disease', (97, 125))	('lymphoproliferative disorder', 'Disease', 'MESH:D008232', (97, 125))	('LPD', 'Disease', (127, 130))
285863	25491772	We thus thought to clarify the role of IL-6 signaling on the Th17 pathway in lung cancer tumour-infiltrating lymphocytes (TIL) as well as in lung cancer cells in different subtypes of NSCLC, considering that STAT3 is also an oncogene whose activation has been linked to EGFR mutation, which are present in lung cancer.	('IL-6', 'Gene', (39, 43))	('lung cancer', 'Disease', (141, 152))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('cancer', 'Phenotype', 'HP:0002664', (311, 317))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('IL-6', 'Gene', '16193', (39, 43))	('lung cancer tumour', 'Disease', 'MESH:D008175', (77, 95))	('EGFR', 'Gene', '13649', (270, 274))	('lung cancer', 'Disease', (306, 317))	('Th1', 'Gene', '57314', (61, 64))	('EGFR', 'Gene', (270, 274))	('activation', 'PosReg', (240, 250))	('lung cancer', 'Disease', 'MESH:D008175', (141, 152))	('Th1', 'Gene', (61, 64))	('tumour', 'Phenotype', 'HP:0002664', (89, 95))	('lung cancer', 'Disease', 'MESH:D008175', (77, 88))	('lung cancer', 'Phenotype', 'HP:0100526', (141, 152))	('NSCLC', 'Disease', 'MESH:D002289', (184, 189))	('lung cancer', 'Disease', 'MESH:D008175', (306, 317))	('lung cancer tumour', 'Disease', (77, 95))	('lung cancer', 'Phenotype', 'HP:0100526', (77, 88))	('NSCLC', 'Disease', (184, 189))	('mutation', 'Var', (275, 283))	('lung cancer', 'Phenotype', 'HP:0100526', (306, 317))
285878	25491772	We have previously demonstrated that IL-6R alpha chain is expressed on lung CD4+CD25+Foxp-3+ T regulatory cells and that blockade of IL-6R induces T regulatory cells.	('T regulatory cells', 'CPA', (147, 165))	('CD25', 'Gene', (80, 84))	('CD25', 'Gene', '16184', (80, 84))	('IL-6R alpha', 'Gene', '16194', (37, 48))	('CD4', 'Gene', (76, 79))	('Foxp-3', 'Gene', (85, 91))	('Foxp-3', 'Gene', '20371', (85, 91))	('CD4', 'Gene', '12504', (76, 79))	('IL-6R', 'Gene', (133, 138))	('blockade', 'Var', (121, 129))	('IL-6R alpha', 'Gene', (37, 48))	('induces', 'Reg', (139, 146))
285940	25491772	STAT3 and BATF have been described to bind to the IL-17A promoter, thus reinforcing the role of RORgammaT in this pathway In a murine model of adenocarcinoma we could demonstrate by using affimetix array that intranasal delivery of anti-IL-6R antibody but not IgG induced T regulatory immunosuppressive genes, such as Il2ra, Ctla4, Icos, Folr4, Lag3, Il10, Il21 and Foxp3.	('Ctla4', 'Gene', '12477', (325, 330))	('Ctla4', 'Gene', (325, 330))	('adenocarcinoma', 'Disease', (143, 157))	('anti-IL-6R antibody', 'Var', (232, 251))	('murine', 'Species', '10090', (127, 133))	('Folr4', 'Gene', (338, 343))	('Il10', 'Gene', '16153', (351, 355))	('IL-17A', 'Gene', '16171', (50, 56))	('Il10', 'Gene', (351, 355))	('adenocarcinoma', 'Disease', 'MESH:D000230', (143, 157))	('Il2ra', 'Gene', '16184', (318, 323))	('Il21', 'Gene', (357, 361))	('carcinoma', 'Phenotype', 'HP:0030731', (148, 157))	('Icos', 'Gene', '54167', (332, 336))	('Lag3', 'Gene', '16768', (345, 349))	('Foxp3', 'Gene', (366, 371))	('Folr4', 'Gene', '64931', (338, 343))	('Il21', 'Gene', '60505', (357, 361))	('Lag3', 'Gene', (345, 349))	('Il2ra', 'Gene', (318, 323))	('Icos', 'Gene', (332, 336))	('IL-17A', 'Gene', (50, 56))	('Foxp3', 'Gene', '20371', (366, 371))
285945	25491772	Autophosphorylation of pSTAT3 favours mutations in this tumour.	('Autophosphorylation', 'MPA', (0, 19))	('tumour', 'Phenotype', 'HP:0002664', (56, 62))	('pSTAT3', 'Gene', (23, 29))	('tumour', 'Disease', 'MESH:D009369', (56, 62))	('mutations', 'Var', (38, 47))	('tumour', 'Disease', (56, 62))
285952	25491772	Moreover, we have described recently that BATF deficient mice have reduced STAT5 and FOXP-3+ T regulatory cells.	('mice', 'Species', '10090', (57, 61))	('FOXP-3', 'Gene', (85, 91))	('deficient', 'Var', (47, 56))	('FOXP-3', 'Gene', '20371', (85, 91))	('STAT5', 'Gene', '20850', (75, 80))	('reduced', 'NegReg', (67, 74))	('STAT5', 'Gene', (75, 80))
285956	25491772	It further highlights a possible negative effect of targeting IL-6R in adenocarcinoma tumour because it would induce immunosuppression.	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('IL-6R', 'Gene', (62, 67))	('tumour', 'Phenotype', 'HP:0002664', (86, 92))	('targeting', 'Var', (52, 61))	('immunosuppression', 'MPA', (117, 134))	('negative', 'NegReg', (33, 41))	('adenocarcinoma tumour', 'Disease', (71, 92))	('adenocarcinoma tumour', 'Disease', 'MESH:D000230', (71, 92))
286021	33772655	observed met exon 14 in lung cancer which could contribute to protein regions' deletion that restricts its kinase catalytic activity.	('kinase catalytic activity', 'MPA', (107, 132))	('met', 'Gene', '79811', (9, 12))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('lung cancer', 'Disease', (24, 35))	('restricts', 'NegReg', (93, 102))	('lung cancer', 'Phenotype', 'HP:0100526', (24, 35))	('met', 'Gene', (9, 12))	('deletion', 'Var', (79, 87))	('lung cancer', 'Disease', 'MESH:D008175', (24, 35))
286025	33772655	Moreover, several studies have shown that alteration in splicing factors might facilitate to activate oncogenes and tumor pathways or alternatively destruct the effect of tumor suppressors.	('oncogenes', 'Pathway', (102, 111))	('splicing factors', 'Protein', (56, 72))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('alteration', 'Var', (42, 52))	('destruct', 'NegReg', (148, 156))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('activate', 'PosReg', (93, 101))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', (171, 176))	('tumor', 'Disease', (116, 121))
286043	33772655	ES of NADSYN1 and AP of TMEM25 were adverse factors, whereas AT of TNFRSF1A and AT of FBXL12 were related to favorable prognosis.	('NADSYN1', 'Gene', (6, 13))	('FBXL12', 'Gene', '54850', (86, 92))	('FBXL12', 'Gene', (86, 92))	('NADSYN1', 'Gene', '55191', (6, 13))	('TNFRSF1A', 'Gene', '7132', (67, 75))	('TMEM25', 'Gene', (24, 30))	('TMEM25', 'Gene', '84866', (24, 30))	('AP of', 'Var', (18, 23))	('TNFRSF1A', 'Gene', (67, 75))
286048	33772655	revealed that the aberrant splicing expression of GSN gene had an obviously higher expression in tumor tissues than in adjacent tissues and regulated the HNSCC's cell proliferation process.	('GSN', 'Gene', (50, 53))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('GSN', 'Gene', '2934', (50, 53))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumor', 'Disease', (97, 102))	('aberrant splicing expression', 'Var', (18, 46))	('regulated', 'Reg', (140, 149))	('expression', 'MPA', (83, 93))	("HNSCC's cell proliferation process", 'CPA', (154, 188))	('higher', 'PosReg', (76, 82))
286049	33772655	Recently, a report suggested that KRAS-4A and KRAS-4B (KRAS isoforms) had significantly related to poor survival of CRC patients, especially microsatellite stable primary CRC.	('KRAS', 'Gene', (55, 59))	('KRAS-4A', 'Gene', (34, 41))	('KRAS', 'Gene', '3845', (34, 38))	('microsatellite', 'Var', (141, 155))	('KRAS-4A', 'Gene', '3845', (34, 41))	('related', 'Reg', (88, 95))	('KRAS-4B', 'Gene', (46, 53))	('KRAS', 'Gene', (46, 50))	('KRAS', 'Gene', '3845', (55, 59))	('KRAS-4B', 'Gene', '3845', (46, 53))	('KRAS', 'Gene', '3845', (46, 50))	('patients', 'Species', '9606', (120, 128))	('CRC', 'Disease', (116, 119))	('KRAS', 'Gene', (34, 38))
286053	33772655	In addition, AS variants were also related to drug sensitivity of lung cancer.	('drug sensitivity', 'Phenotype', 'HP:0020174', (46, 62))	('lung cancer', 'Disease', (66, 77))	('lung cancer', 'Phenotype', 'HP:0100526', (66, 77))	('related', 'Reg', (35, 42))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('variants', 'Var', (16, 24))	('lung cancer', 'Disease', 'MESH:D008175', (66, 77))
286054	33772655	It is previously reported that patients with lung adenocarcinoma with carcinogenic mutations at MET exon 14 RNA splice acceptor and donor sites could benefit from treatment with MET inhibitors crizotinib and cabozantinib, identifying a novel therapeutic target for lung adenocarcinoma.	('MET', 'Gene', (96, 99))	('carcinogenic', 'Disease', 'MESH:D063646', (70, 82))	('MET', 'Gene', '79811', (178, 181))	('lung adenocarcinoma', 'Disease', (265, 284))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (45, 64))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (45, 64))	('benefit', 'PosReg', (150, 157))	('crizotinib', 'Chemical', 'MESH:D000077547', (193, 203))	('MET', 'Gene', '79811', (96, 99))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (265, 284))	('carcinoma', 'Phenotype', 'HP:0030731', (55, 64))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (265, 284))	('cabozantinib', 'Chemical', 'MESH:C558660', (208, 220))	('mutations', 'Var', (83, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (275, 284))	('MET', 'Gene', (178, 181))	('patients', 'Species', '9606', (31, 39))	('carcinogenic', 'Disease', (70, 82))	('lung adenocarcinoma', 'Disease', (45, 64))
286055	33772655	Although some researchers have identified several prognostic alternative splicing events in LUAD and LUSC, with the development of high-throughput sequencing technique, novel prognosis-related AS events and potentially therapeutic targets needed to be explored further.	('AD', 'Disease', (94, 96))	('LUAD', 'Phenotype', 'HP:0030078', (92, 96))	('LUSC', 'Phenotype', 'HP:0030359', (101, 105))	('alternative splicing', 'Var', (61, 81))	('AD', 'Disease', 'MESH:D000544', (94, 96))
286070	30642944	The tumor suppressor FBW7 is commonly mutated or down-regulated in human LSCC, and oncogenic KRasG12D activation combined with Fbxw7 inactivation in mice (KF model) caused both LSCC and LADC.	('tumor', 'Disease', (4, 9))	('LADC', 'Disease', (186, 190))	('caused', 'Reg', (165, 171))	('LSCC', 'Phenotype', 'HP:0030359', (177, 181))	('Fbxw7', 'Gene', (127, 132))	('down-regulated', 'NegReg', (49, 63))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('mice', 'Species', '10090', (149, 153))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('LSCC', 'Disease', (177, 181))	('LADC', 'Phenotype', 'HP:0030078', (186, 190))	('LSCC', 'Phenotype', 'HP:0030359', (73, 77))	('KRasG12D', 'Gene', (93, 101))	('human', 'Species', '9606', (67, 72))	('inactivation', 'Var', (133, 145))
286071	30642944	Lineage-tracing experiments showed that CC10+, but not basal, cells are the cells of origin of LSCC in KF mice.	('LSCC', 'Disease', (95, 99))	('LSCC', 'Phenotype', 'HP:0030359', (95, 99))	('mice', 'Species', '10090', (106, 110))	('CC10+', 'Var', (40, 45))
286083	30642944	Lysine-63 (K63)- and methionine-1 (M1)-linked ubiquitin chains mediate the key upstream events of recruiting TAK1 and the IKK complex, respectively, resulting in the activation of the NF-kappaB pathway.	('TAK1', 'Protein', (109, 113))	('activation', 'PosReg', (166, 176))	('NF-kappaB pathway', 'Pathway', (184, 201))	('Lysine-63', 'Var', (0, 9))	('IKK', 'Protein', (122, 125))	('Lysine', 'Chemical', 'MESH:D008239', (0, 6))
286087	30642944	Here, we describe a novel genetic mouse model in which the loss of Fbxw7 concomitant with KRasG12D activation (KF mice) promoted the formation of two NSCLC cancers, LSCC as well as LADC.	('cancers', 'Phenotype', 'HP:0002664', (156, 163))	('SCLC', 'Phenotype', 'HP:0030357', (151, 155))	('mouse', 'Species', '10090', (34, 39))	('LSCC', 'Disease', (165, 169))	('promoted', 'PosReg', (120, 128))	('LADC', 'Phenotype', 'HP:0030078', (181, 185))	('NSCLC', 'Phenotype', 'HP:0030358', (150, 155))	('NSCLC cancers', 'Disease', 'MESH:D009369', (150, 163))	('LADC', 'Disease', (181, 185))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('LSCC', 'Phenotype', 'HP:0030359', (165, 169))	('NSCLC cancers', 'Disease', (150, 163))	('mice', 'Species', '10090', (114, 118))	('Fbxw7', 'Gene', (67, 72))	('loss', 'Var', (59, 63))
286090	30642944	Inhibition of LUBAC or NF-kappaB signaling resulted in sensitization of LSCC tumors to cisplatin, suggesting a future avenue for LSCC patient treatment.	('tumors', 'Disease', (77, 83))	('cisplatin', 'Chemical', 'MESH:D002945', (87, 96))	('tumors', 'Disease', 'MESH:D009369', (77, 83))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('LSCC', 'Phenotype', 'HP:0030359', (129, 133))	('sensitization', 'MPA', (55, 68))	('NF-kappaB', 'Protein', (23, 32))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('LSCC', 'Disease', (72, 76))	('Inhibition', 'Var', (0, 10))	('LSCC', 'Phenotype', 'HP:0030359', (72, 76))	('patient', 'Species', '9606', (134, 141))
286091	30642944	Genomic studies of human LSCC have reported recurrent mutations in the FBXW7 tumor suppressor gene.	('FBXW7', 'Gene', (71, 76))	('LSCC', 'Disease', (25, 29))	('mutations', 'Var', (54, 63))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('LSCC', 'Phenotype', 'HP:0030359', (25, 29))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('human', 'Species', '9606', (19, 24))	('tumor', 'Disease', (77, 82))
286092	30642944	Data from The Cancer Genome Atlas (TCGA) show 6.4% of human LSCC cases with mutations in FBXW7, the majority associated with loss of function (Fig.	('mutations', 'Var', (76, 85))	('LSCC', 'Phenotype', 'HP:0030359', (60, 64))	('FBXW7', 'Gene', (89, 94))	('loss of function', 'NegReg', (125, 141))	('Cancer Genome Atlas', 'Disease', (14, 33))	('Cancer', 'Phenotype', 'HP:0002664', (14, 20))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (14, 33))	('human', 'Species', '9606', (54, 59))	('LSCC', 'Disease', (60, 64))
286095	30642944	These data suggest that FBW7 is lost or down-regulated frequently in human LSCC, and hence that FBW7 inactivation could be a driver of human LSCC.	('LSCC', 'Disease', (75, 79))	('lost', 'NegReg', (32, 36))	('LSCC', 'Phenotype', 'HP:0030359', (75, 79))	('human', 'Species', '9606', (69, 74))	('human', 'Species', '9606', (135, 140))	('inactivation', 'Var', (101, 113))	('FBW7', 'Gene', (96, 100))	('FBW7', 'Gene', (24, 28))	('LSCC', 'Phenotype', 'HP:0030359', (141, 145))	('down-regulated', 'NegReg', (40, 54))
286097	30642944	KRAS mutations are very frequently observed in human LADC, but the RAS tumor driver pathway is also activated in up to half of human LSCC tumors, most commonly due to transcriptional up-regulation and amplification of KRAS and the upstream receptor tyrosine kinases EGFR and FGFR1 (Fig.	('tumor', 'Disease', (138, 143))	('tumors', 'Disease', 'MESH:D009369', (138, 144))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('KRAS', 'Gene', '3845', (218, 222))	('FGFR1', 'Gene', '2260', (275, 280))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('amplification', 'Var', (201, 214))	('activated', 'PosReg', (100, 109))	('LSCC', 'Phenotype', 'HP:0030359', (133, 137))	('up-regulation', 'PosReg', (183, 196))	('KRAS', 'Gene', (218, 222))	('human', 'Species', '9606', (47, 52))	('KRAS', 'Gene', '3845', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('human', 'Species', '9606', (127, 132))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('FGFR1', 'Gene', (275, 280))	('tumor', 'Disease', (71, 76))	('KRAS', 'Gene', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('tumors', 'Disease', (138, 144))	('EGFR', 'Gene', (266, 270))	('LADC', 'Phenotype', 'HP:0030078', (53, 57))
286107	30642944	LSCC occurred mainly in bronchi (occasionally manifesting as small foci in alveolar lung tissue), showed largely solid growth patterns, with occasional intracellular bridges and rare keratinization, and were negative for TTF1 but expressed CK5 and DeltaNp63 (Fig.	('alveolar lung', 'Disease', (75, 88))	('CK5', 'Var', (240, 243))	('TTF1', 'Gene', '22130', (221, 225))	('LSCC', 'Phenotype', 'HP:0030359', (0, 4))	('alveolar lung', 'Disease', 'MESH:D008171', (75, 88))	('DeltaNp63', 'Var', (248, 257))	('TTF1', 'Gene', (221, 225))	('expressed', 'Reg', (230, 239))	('solid growth patterns', 'CPA', (113, 134))
286109	30642944	As has been described for the Lkb1f/f, Ptenf/f LSCC model, the immune evasion markers PD-1 and PD-L1 were expressed in KF LSCC tumors, and they were positive for NGFR and Sox2, two other markers shown to be characteristic of human and mouse LSCC (Fig.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('LSCC', 'Disease', (47, 51))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('LSCC', 'Phenotype', 'HP:0030359', (47, 51))	('KF LSCC tumors', 'Disease', (119, 133))	('KF LSCC tumors', 'Disease', 'MESH:D009369', (119, 133))	('PD-L1', 'Gene', (95, 100))	('LSCC', 'Disease', (241, 245))	('NGFR', 'Gene', (162, 166))	('Lkb1f/f', 'Var', (30, 37))	('Sox2', 'Gene', '6657', (171, 175))	('human', 'Species', '9606', (225, 230))	('mouse', 'Species', '10090', (235, 240))	('LSCC', 'Phenotype', 'HP:0030359', (122, 126))	('NGFR', 'Gene', '4804', (162, 166))	('LSCC', 'Phenotype', 'HP:0030359', (241, 245))	('PD-L1', 'Gene', '29126', (95, 100))	('Sox2', 'Gene', (171, 175))
286116	30642944	Both CK5-CreERT; KF and CK14-CreERT; KF mice developed skin and life-limiting oral tumors after 3-4 wk.	('CK14', 'Gene', '16664', (24, 28))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('oral tumors', 'Phenotype', 'HP:0100649', (78, 89))	('developed', 'PosReg', (45, 54))	('oral tumors', 'Disease', 'MESH:D020820', (78, 89))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('CK5-CreERT', 'Var', (5, 15))	('oral tumors', 'Disease', (78, 89))	('mice', 'Species', '10090', (40, 44))	('CK14', 'Gene', (24, 28))
286120	30642944	However, KF animals treated with naphthalene and Ad5-CK5-Cre did not develop lung tumors even after a long latency (30 wk; Fig.	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('lung tumors', 'Disease', (77, 88))	('lung tumors', 'Phenotype', 'HP:0100526', (77, 88))	('naphthalene', 'Chemical', 'MESH:C031721', (33, 44))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('lung tumor', 'Phenotype', 'HP:0100526', (77, 87))	('lung tumors', 'Disease', 'MESH:D008175', (77, 88))	('Ad5-CK5-Cre', 'Var', (49, 60))
286125	30642944	LSCC tumors were located in and adjacent to the airways and expressed CK5 and DeltaNp63, whereas LADCs were located in the alveoli and positive for TTF1 and Sftpc (Fig.	('tumors', 'Disease', (5, 11))	('tumors', 'Disease', 'MESH:D009369', (5, 11))	('Sftpc', 'Gene', '20389', (157, 162))	('Sftpc', 'Gene', (157, 162))	('CK5', 'Var', (70, 73))	('TTF1', 'Gene', '22130', (148, 152))	('LSCC', 'Disease', (0, 4))	('LSCC', 'Phenotype', 'HP:0030359', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('TTF1', 'Gene', (148, 152))	('LADC', 'Phenotype', 'HP:0030078', (97, 101))	('DeltaNp63', 'Gene', (78, 87))	('tumors', 'Phenotype', 'HP:0002664', (5, 11))	('expressed', 'Reg', (60, 69))
286132	30642944	KF mice infected intratracheally with Lenti-FoxJ1-Cre virus did not develop LSCC tumors even after a long latency (30 wk; Fig.	('tumors', 'Disease', (81, 87))	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('mice', 'Species', '10090', (3, 7))	('Lenti-FoxJ1-Cre', 'Var', (38, 53))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('LSCC', 'Phenotype', 'HP:0030359', (76, 80))
286134	30642944	In contrast, KF mice infected with Ad5-CC10-Cre virus developed tumor lesions with histological characteristics of LSCC and were mainly located in and adjacent to the airways.	('tumor', 'Disease', (64, 69))	('Ad5-CC10-Cre virus', 'Var', (35, 53))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('LSCC', 'Disease', (115, 119))	('mice', 'Species', '10090', (16, 20))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('LSCC', 'Phenotype', 'HP:0030359', (115, 119))
286135	30642944	Markers characteristic of human LSCC, CK5 and DeltaNp63, were detected in these tumors (Fig.	('detected', 'Reg', (62, 70))	('LSCC', 'Phenotype', 'HP:0030359', (32, 36))	('DeltaNp63', 'Var', (46, 55))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('tumors', 'Disease', (80, 86))	('human', 'Species', '9606', (26, 31))
286137	30642944	Ad5-CC10-Cre infection also resulted in LADC tumors, which were found exclusively in the alveolar space and displayed high expression of TTF1 and Sftpc as expected (Fig.	('TTF1', 'Gene', (137, 141))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('LADC tumors', 'Disease', (40, 51))	('LADC tumors', 'Disease', 'MESH:D009369', (40, 51))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('infection', 'Var', (13, 22))	('Sftpc', 'Gene', '20389', (146, 151))	('Ad5-CC10-Cre infection', 'Var', (0, 22))	('Sftpc', 'Gene', (146, 151))	('LADC', 'Phenotype', 'HP:0030078', (40, 44))	('resulted in', 'Reg', (28, 39))	('TTF1', 'Gene', '22130', (137, 141))
286138	30642944	CC10+ cells originated predominantly LSCC (80%), with the remainder of the lesions being LADC tumors (Fig.	('LSCC', 'Disease', (37, 41))	('LSCC', 'Phenotype', 'HP:0030359', (37, 41))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('LADC', 'Phenotype', 'HP:0030078', (89, 93))	('CC10+', 'Var', (0, 5))	('LADC tumors', 'Disease', 'MESH:D009369', (89, 100))	('LADC tumors', 'Disease', (89, 100))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('originated', 'Reg', (12, 22))
286161	30642944	In vivo imaging showed reduced lung tumor mass in mice treated with cisplatin compared with vehicle control (Fig.	('lung tumor', 'Phenotype', 'HP:0100526', (31, 41))	('cisplatin', 'Var', (68, 77))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('mice', 'Species', '10090', (50, 54))	('reduced', 'NegReg', (23, 30))	('lung tumor', 'Disease', 'MESH:D008175', (31, 41))	('cisplatin', 'Chemical', 'MESH:D002945', (68, 77))	('lung tumor', 'Disease', (31, 41))
286166	30642944	In agreement with these findings, analysis of TCGA data showed that amplification or mRNA up-regulation of the genes encoding LUBAC components was more common in human LSCC compared with LADC (Fig.	('up-regulation', 'PosReg', (90, 103))	('human', 'Species', '9606', (162, 167))	('LSCC', 'Disease', (168, 172))	('mRNA', 'MPA', (85, 89))	('LADC', 'Phenotype', 'HP:0030078', (187, 191))	('LSCC', 'Phenotype', 'HP:0030359', (168, 172))	('amplification', 'Var', (68, 81))
286182	30642944	In support of this idea, knockdown of the LUBAC components HOIL-1 or HOIP also sensitized LSCC cells to cisplatin (Fig.	('knockdown', 'Var', (25, 34))	('sensitized', 'Reg', (79, 89))	('cisplatin', 'Chemical', 'MESH:D002945', (104, 113))	('LSCC', 'Phenotype', 'HP:0030359', (90, 94))
286185	30642944	Cisplatin did not have an additional effect on inhibition of P-p65 by 5Z-7 (Fig.	('P-p65', 'Gene', '18826', (61, 66))	('P-p65', 'Gene', (61, 66))	('5Z-7', 'Chemical', '-', (70, 74))	('Cisplatin', 'Chemical', 'MESH:D002945', (0, 9))	('5Z-7', 'Var', (70, 74))
286189	30642944	Inhibition of the TAK1 target and NF-kappaB upstream regulator IKK also sensitized LSCC cells to cisplatin (Fig.	('cisplatin', 'Chemical', 'MESH:D002945', (97, 106))	('IKK', 'Gene', (63, 66))	('LSCC', 'Disease', (83, 87))	('sensitized', 'Reg', (72, 82))	('Inhibition', 'Var', (0, 10))	('LSCC', 'Phenotype', 'HP:0030359', (83, 87))
286198	30642944	However, combination treatment with 5Z-7 sensitized LSCC tumors to cisplatin and induced a significant reduction in LSCC tumor number (Fig.	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('sensitized', 'Reg', (41, 51))	('5Z-7', 'Chemical', '-', (36, 40))	('LSCC', 'Phenotype', 'HP:0030359', (116, 120))	('reduction in LSCC tumor', 'Disease', (103, 126))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('LSCC', 'Disease', (52, 56))	('cisplatin', 'Chemical', 'MESH:D002945', (67, 76))	('reduction in LSCC tumor', 'Disease', 'MESH:D009369', (103, 126))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('tumors', 'Disease', (57, 63))	('5Z-7', 'Var', (36, 40))	('LSCC', 'Phenotype', 'HP:0030359', (52, 56))	('tumors', 'Disease', 'MESH:D009369', (57, 63))
286199	30642944	IHC analysis of Ki67 and active caspase-3 in tumors treated with cisplatin plus 5Z-7 showed decreased cell proliferation and increased cell death compared with vehicle-treated tumors (Fig.	('5Z-7', 'Chemical', '-', (80, 84))	('cisplatin', 'Chemical', 'MESH:D002945', (65, 74))	('caspase-3', 'Gene', '12367', (32, 41))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('Ki67', 'Gene', '17345', (16, 20))	('tumors', 'Disease', (45, 51))	('Ki67', 'Gene', (16, 20))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('caspase-3', 'Gene', (32, 41))	('tumors', 'Disease', (176, 182))	('tumors', 'Disease', 'MESH:D009369', (45, 51))	('5Z-7', 'Var', (80, 84))	('tumors', 'Disease', 'MESH:D009369', (176, 182))	('tumors', 'Phenotype', 'HP:0002664', (176, 182))	('cell death', 'CPA', (135, 145))	('decreased', 'NegReg', (92, 101))	('cell proliferation', 'CPA', (102, 120))
286200	30642944	TAK1 inhibition also increased cisplatin efficacy toward LADC tumors (Fig.	('LADC', 'Phenotype', 'HP:0030078', (57, 61))	('increased', 'PosReg', (21, 30))	('LADC tumors', 'Disease', 'MESH:D009369', (57, 68))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('TAK1', 'Gene', (0, 4))	('inhibition', 'Var', (5, 15))	('cisplatin', 'Chemical', 'MESH:D002945', (31, 40))	('LADC tumors', 'Disease', (57, 68))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('cisplatin efficacy', 'MPA', (31, 49))
286211	30642944	The combination of cisplatin and 5Z-7 treatment resulted in a significant increase in survival, with five of six animals surviving for >7 wk (Fig.	('5Z-7', 'Chemical', '-', (33, 37))	('increase', 'PosReg', (74, 82))	('cisplatin', 'Chemical', 'MESH:D002945', (19, 28))	('survival', 'CPA', (86, 94))	('5Z-7', 'Var', (33, 37))
286216	30642944	Here, we show that inactivation of Fbxw7 concomitant with KRasG12D expression in the adult mouse lung (KF model) leads to both LSCC and LADC formation.	('LADC', 'Phenotype', 'HP:0030078', (136, 140))	('LSCC', 'Disease', (127, 131))	('LSCC', 'Phenotype', 'HP:0030359', (127, 131))	('KRasG12D', 'Gene', (58, 66))	('LADC formation', 'CPA', (136, 150))	('Fbxw7', 'Gene', (35, 40))	('inactivation', 'Var', (19, 31))	('mouse', 'Species', '10090', (91, 96))	('leads to', 'Reg', (113, 121))
286217	30642944	Using lung cell type-restricted Cre viruses, we showed that KF LADC tumors originate mainly from alveolar Sftpc+ cells, but that targeted inactivation of Fbxw7 and activation of KRasG12D in club CC10+ cells generated predominantly LSCC lesions.	('LSCC', 'Phenotype', 'HP:0030359', (231, 235))	('Fbxw7', 'Gene', (154, 159))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('Sftpc', 'Gene', '20389', (106, 111))	('Sftpc', 'Gene', (106, 111))	('inactivation', 'Var', (138, 150))	('KRasG12D', 'Var', (178, 186))	('LADC', 'Phenotype', 'HP:0030078', (63, 67))	('LSCC lesions', 'Disease', (231, 243))	('club', 'Disease', 'MESH:D010004', (190, 194))	('club', 'Disease', (190, 194))	('club', 'Phenotype', 'HP:0001217', (190, 194))	('LADC tumors', 'Disease', 'MESH:D009369', (63, 74))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('LADC tumors', 'Disease', (63, 74))
286220	30642944	Given FBW7's role in regulating cell differentiation, it is possible that Fbxw7 inactivation (in our KF model) or loss of FBW7 protein (in human LSCC) causes some CC10+ cells to lose their identity and acquire a squamous phenotype.	('squamous phenotype', 'CPA', (212, 230))	('CC10+', 'Var', (163, 168))	('Fbxw7', 'Gene', (74, 79))	('acquire', 'Reg', (202, 209))	('loss', 'Var', (114, 118))	('FBW7', 'Gene', (122, 126))	('identity', 'CPA', (189, 197))	('human', 'Species', '9606', (139, 144))	('lose', 'NegReg', (178, 182))	('inactivation', 'Var', (80, 92))	('LSCC', 'Phenotype', 'HP:0030359', (145, 149))	('protein', 'Protein', (127, 134))
286221	30642944	Activation of KRasG12D, with or without concomitant p53 inactivation (KP model), induces LADC in both CC10+ and Sftpc+ populations, with the tumors being located predominantly in the alveolar space.	('Sftpc', 'Gene', '20389', (112, 117))	('Sftpc', 'Gene', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('LADC', 'Phenotype', 'HP:0030078', (89, 93))	('p53', 'Gene', (52, 55))	('tumors', 'Disease', (141, 147))	('p53', 'Gene', '22059', (52, 55))	('tumors', 'Disease', 'MESH:D009369', (141, 147))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('KRasG12D', 'Var', (14, 22))	('LADC', 'MPA', (89, 93))	('induces', 'Reg', (81, 88))
286222	30642944	Sftpc+ cells and CC10+ cells generated LADC lesions; however, in addition CC10+ cells efficiently originated LSCC.	('CC10+', 'Var', (74, 79))	('LSCC', 'Phenotype', 'HP:0030359', (109, 113))	('Sftpc', 'Gene', '20389', (0, 5))	('Sftpc', 'Gene', (0, 5))	('LSCC', 'Disease', (109, 113))	('LADC', 'Phenotype', 'HP:0030078', (39, 43))
286225	30642944	Depending on the nature of the driver mutations, either basal, club, or alveolar type II cells had the capability to give rise to LSCC.	('alveolar type II cells', 'CPA', (72, 94))	('LSCC', 'Disease', (130, 134))	('club', 'Disease', 'MESH:D010004', (63, 67))	('club', 'Disease', (63, 67))	('club', 'Phenotype', 'HP:0001217', (63, 67))	('LSCC', 'Phenotype', 'HP:0030359', (130, 134))	('basal', 'CPA', (56, 61))	('mutations', 'Var', (38, 47))	('give rise', 'Reg', (117, 126))
286229	30642944	Moreover, the same KF driver oncogene combination which resulted in cisplatin-resistant LSCC failed to induce cisplatin resistance in LADC cells.	('resulted in', 'Reg', (56, 67))	('LSCC', 'Phenotype', 'HP:0030359', (88, 92))	('cisplatin', 'Chemical', 'MESH:D002945', (110, 119))	('LADC', 'Phenotype', 'HP:0030078', (134, 138))	('cisplatin-resistant LSCC', 'Disease', (68, 92))	('cisplatin', 'Chemical', 'MESH:D002945', (68, 77))	('combination', 'Var', (38, 49))
286230	30642944	Therefore, high NF-kappaB activity, and consequently cisplatin resistance, is unlikely to be a direct molecular consequence of the absence of FBW7, but rather a general property of LSCC tumor cells.	('cisplatin resistance', 'MPA', (53, 73))	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('FBW7', 'Gene', (142, 146))	('absence', 'Var', (131, 138))	('NF-kappaB activity', 'MPA', (16, 34))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('tumor', 'Disease', (186, 191))	('LSCC', 'Phenotype', 'HP:0030359', (181, 185))	('cisplatin', 'Chemical', 'MESH:D002945', (53, 62))
286244	30642944	Ad5-CC10-Cre, Ad5-CMV-Cre, and Ad5-SPC-Cre have been previously described.	('SPC', 'Gene', (35, 38))	('SPC', 'Gene', '20693', (35, 38))	('Ad5-CC10-Cre', 'Var', (0, 12))
286245	30642944	6-8-wk-old mice were intratracheally intubated with 50 microl of purified Cre viruses: Ad5-CMV-Cre, Ad5-SPC-Cre, Ad5-CC10-Cre, and Ad5-CK5-Cre were used at 2.5 x 107 PFU; Lenti-FoxJ1-Cre was used at 1.4 x 108 PFU.	('SPC', 'Gene', (104, 107))	('Ad5-CMV-Cre', 'Var', (87, 98))	('mice', 'Species', '10090', (11, 15))	('SPC', 'Gene', '20693', (104, 107))	('Ad5-CC10-Cre', 'Var', (113, 125))
286277	30594912	DeltaNp63 promotes IGF1 signalling through IRS1 in squamous cell carcinoma Accumulating evidence has proved that deregulation of DeltaNp63 expression plays an oncogenic role in head and neck squamous cell carcinomas (HNSCCs).	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (51, 74))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (191, 214))	('DeltaNp63', 'Gene', (129, 138))	('SCC', 'Gene', '6317', (219, 222))	('HNSCC', 'Phenotype', 'HP:0012288', (217, 222))	('squamous cell carcinoma', 'Disease', (51, 74))	('SCC', 'Gene', (219, 222))	('expression', 'Species', '29278', (139, 149))	('neck squamous cell carcinomas', 'Disease', (186, 215))	('IRS1', 'Gene', '3667', (43, 47))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (191, 214))	('head and neck squamous cell carcinomas', 'Phenotype', 'HP:0012288', (177, 215))	('IRS1', 'Gene', (43, 47))	('neck squamous cell carcinomas', 'Disease', 'MESH:D000077195', (186, 215))	('carcinoma', 'Phenotype', 'HP:0030731', (205, 214))	('carcinomas', 'Phenotype', 'HP:0030731', (205, 215))	('IGF1', 'Gene', '3479', (19, 23))	('deregulation', 'Var', (113, 125))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (51, 74))	('HNSCCs', 'Phenotype', 'HP:0012288', (217, 223))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (191, 215))	('IGF1', 'Gene', (19, 23))
286280	30594912	Here we report that p63 directly controls IRS1 transcription and cellular abundance and fosters the PI3K/AKT and MAPK downstream signalling pathways.	('MAPK', 'Gene', '3354888', (113, 117))	('AKT', 'Gene', '41957', (105, 108))	('transcription', 'MPA', (47, 60))	('IRS1', 'Gene', '3667', (42, 46))	('IRS1', 'Gene', (42, 46))	('cellular abundance', 'MPA', (65, 83))	('AKT', 'Gene', (105, 108))	('MAPK', 'Gene', (113, 117))	('p63', 'Var', (20, 23))	('fosters', 'PosReg', (88, 95))
286281	30594912	Inactivation of DeltaNp63 expression indeed reduces tumour cell responsiveness to IGF1 stimulation, and inhibits the growth potential of HNSCC cells.	('SCC', 'Gene', '6317', (139, 142))	('HNSCC', 'Phenotype', 'HP:0012288', (137, 142))	('IGF1', 'Gene', (82, 86))	('inhibits', 'NegReg', (104, 112))	('tumour', 'Phenotype', 'HP:0002664', (52, 58))	('tumour', 'Disease', 'MESH:D009369', (52, 58))	('IGF1', 'Gene', '3479', (82, 86))	('SCC', 'Gene', (139, 142))	('tumour', 'Disease', (52, 58))	('expression', 'Species', '29278', (26, 36))	('reduces', 'NegReg', (44, 51))	('DeltaNp63', 'Gene', (16, 25))	('Inactivation', 'Var', (0, 12))
286283	30594912	Our findings indicate that aberrant expression of DeltaNp63 in HNSSC may act as an oncogenic stimulus by altering the IGF signalling pathway.	('IGF signalling pathway', 'Pathway', (118, 140))	('aberrant', 'Var', (27, 35))	('HNSSC', 'Disease', (63, 68))	('DeltaNp63', 'Gene', (50, 59))	('expression', 'Species', '29278', (36, 46))	('altering', 'Reg', (105, 113))
286287	30594912	The p53 family of transcription factors includes p53, p63 and p73, which are all involved in tumorigenesis as well as in fertility, metabolism, and aging regulation.	('p53', 'Gene', (49, 52))	('p73', 'Gene', '22062', (62, 65))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('involved', 'Reg', (81, 89))	('p53', 'Gene', '22060', (4, 7))	('tumor', 'Disease', (93, 98))	('p63', 'Var', (54, 57))	('p53', 'Gene', '22060', (49, 52))	('p53', 'Gene', (4, 7))	('p73', 'Gene', (62, 65))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
286290	30594912	Genomic amplification and overexpression of TP63, as a result of decreased methylation of CpGs at the DeltaNp63 promoter, is frequent in HNSCCs, in which DeltaNp63 promotes cancer cell survival, proliferation and chemoresistance.	('proliferation', 'CPA', (195, 208))	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('SCC', 'Gene', '6317', (139, 142))	('HNSCCs', 'Phenotype', 'HP:0012288', (137, 143))	('cancer', 'Disease', (173, 179))	('decreased', 'NegReg', (65, 74))	('overexpression', 'PosReg', (26, 40))	('TP63', 'Gene', (44, 48))	('promotes', 'PosReg', (164, 172))	('chemoresistance', 'CPA', (213, 228))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('methylation', 'MPA', (75, 86))	('SCC', 'Gene', (139, 142))	('DeltaNp63', 'Var', (154, 163))	('HNSCC', 'Phenotype', 'HP:0012288', (137, 142))	('expression', 'Species', '29278', (30, 40))
286299	30594912	Deregulation of the IGF axis has been implicated in the development and progression of several human cancers.	('human', 'Species', '9606', (95, 100))	('cancers', 'Disease', 'MESH:D009369', (101, 108))	('cancers', 'Phenotype', 'HP:0002664', (101, 108))	('Deregulation', 'Var', (0, 12))	('cancers', 'Disease', (101, 108))	('IGF axis', 'Pathway', (20, 28))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('implicated', 'Reg', (38, 48))
286313	30594912	Validation of RNA-seq data showed that, following p63 knockdown, IRS1 transcript and protein levels were reduced in NHEK and in a panel of HNSCC cell lines (Fig.	('knockdown', 'Var', (54, 63))	('IRS1', 'Gene', (65, 69))	('SCC', 'Gene', (141, 144))	('HNSCC', 'Phenotype', 'HP:0012288', (139, 144))	('SCC', 'Gene', '6317', (141, 144))	('reduced', 'NegReg', (105, 112))	('p63 knockdown', 'Var', (50, 63))	('IRS1', 'Gene', '3667', (65, 69))
286315	30594912	By ChIP experiments in HNSCC cells, we found binding of p63 to a regulatory region located downstream the Irs1 locus (+148 kbps from the TSS) (Fig.	('SCC', 'Gene', (25, 28))	('binding', 'Interaction', (45, 52))	('p63', 'Var', (56, 59))	('Irs1', 'Gene', (106, 110))	('Irs1', 'Gene', '3667', (106, 110))	('+148', 'Var', (118, 122))	('SCC', 'Gene', '6317', (25, 28))	('HNSCC', 'Phenotype', 'HP:0012288', (23, 28))
286318	30594912	We next tested whether knockdown of DeltaNp63 affects the level of activated IRS1.	('tested', 'Reg', (8, 14))	('knockdown', 'Var', (23, 32))	('IRS1', 'Gene', '3667', (77, 81))	('DeltaNp63', 'Gene', (36, 45))	('IRS1', 'Gene', (77, 81))
286321	30594912	To examine whether alteration of IRS1 and phospho-IRS1 levels induced by p63 silencing may affect downstream IGF signal transduction, we measured the activation of PI3K/AKT and MAPK downstream signalling pathways in p63-depleted cells.	('MAPK', 'Gene', (177, 181))	('MAPK', 'Gene', '3354888', (177, 181))	('AKT', 'Gene', (169, 172))	('activation', 'PosReg', (150, 160))	('IRS1', 'Gene', '3667', (33, 37))	('p63', 'Gene', (73, 76))	('affect', 'Reg', (91, 97))	('silencing', 'Var', (77, 86))	('IRS1', 'Gene', (50, 54))	('IRS1', 'Gene', '3667', (50, 54))	('IRS1', 'Gene', (33, 37))	('AKT', 'Gene', '41957', (169, 172))
286322	30594912	Upon p63 knock-down, we observed desensitization of HNSCC cells to IGF1 stimulation, as assessed by decreased amounts of phospho-AKT (Ser473) and phospho-S6 (Ser235/236) (Fig.	('phospho-S6 (Ser235/236', 'Var', (146, 168))	('IGF1', 'Gene', (67, 71))	('SCC', 'Gene', '6317', (54, 57))	('desensitization', 'NegReg', (33, 48))	('AKT', 'Gene', '41957', (129, 132))	('HNSCC', 'Phenotype', 'HP:0012288', (52, 57))	('Ser235', 'Chemical', '-', (158, 164))	('Ser473', 'Var', (134, 140))	('stimulation', 'PosReg', (72, 83))	('decreased', 'NegReg', (100, 109))	('p63', 'Var', (5, 8))	('IGF1', 'Gene', '3479', (67, 71))	('knock-down', 'Var', (9, 19))	('Ser473', 'Chemical', '-', (134, 140))	('SCC', 'Gene', (54, 57))	('AKT', 'Gene', (129, 132))
286324	30594912	3B), further proving that p63 affects cellular sensitivity to IGF1/insulin stimulation through the regulation of IRS1 cellular abundance.	('insulin', 'Gene', (67, 74))	('insulin', 'Gene', '3630', (67, 74))	('IGF1', 'Gene', '3479', (62, 66))	('affects', 'Reg', (30, 37))	('p63', 'Var', (26, 29))	('IGF1', 'Gene', (62, 66))	('IRS1', 'Gene', '3667', (113, 117))	('IRS1', 'Gene', (113, 117))
286325	30594912	Notably, knockdown of IRS1 hampered the proliferation of HNSCC cells, mimicking the effect of p63 inactivation (Fig.	('knockdown', 'Var', (9, 18))	('hampered', 'NegReg', (27, 35))	('SCC', 'Gene', (59, 62))	('SCC', 'Gene', '6317', (59, 62))	('IRS1', 'Gene', '3667', (22, 26))	('HNSCC', 'Phenotype', 'HP:0012288', (57, 62))	('IRS1', 'Gene', (22, 26))
286327	30594912	To examine possible correlations between the expression levels of DeltaNp63 and IRS1 in NHSCC primary tumours, clinical NHSCC tumour specimens samples and related benign controls were examined for p63 and IRS1 staining on tissue microarray slides.	('tumour', 'Phenotype', 'HP:0002664', (102, 108))	('tumour', 'Disease', 'MESH:D009369', (102, 108))	('tumour', 'Disease', (102, 108))	('SCC', 'Gene', '6317', (90, 93))	('expression', 'Species', '29278', (45, 55))	('SCC', 'Gene', (90, 93))	('SCC', 'Gene', '6317', (122, 125))	('primary tumours', 'Disease', (94, 109))	('primary tumours', 'Disease', 'MESH:D009369', (94, 109))	('DeltaNp63', 'Var', (66, 75))	('SCC', 'Gene', (122, 125))	('tumour', 'Phenotype', 'HP:0002664', (126, 132))	('IRS1', 'Gene', '3667', (205, 209))	('IRS1', 'Gene', '3667', (80, 84))	('tumour', 'Disease', 'MESH:D009369', (126, 132))	('tumours', 'Phenotype', 'HP:0002664', (102, 109))	('IRS1', 'Gene', (205, 209))	('IRS1', 'Gene', (80, 84))	('tumour', 'Disease', (126, 132))
286334	30594912	Notably, we found that 66.2% of tumour samples with p63 up-regulation also exhibited high levels of IRS1 expression A similar correlation was observed in samples with p63 down-regulation, in which 58% of the patients concomitantly displayed low levels of IRS1 transcripts (Fig.	('IRS1', 'Gene', (255, 259))	('IRS1', 'Gene', '3667', (100, 104))	('up-regulation', 'PosReg', (56, 69))	('IRS1', 'Gene', (100, 104))	('p63', 'Var', (52, 55))	('patients', 'Species', '9606', (208, 216))	('tumour', 'Disease', (32, 38))	('expression', 'Species', '29278', (105, 115))	('IRS1', 'Gene', '3667', (255, 259))	('tumour', 'Phenotype', 'HP:0002664', (32, 38))	('tumour', 'Disease', 'MESH:D009369', (32, 38))
286335	30594912	Overall, these findings demonstrate that a statistical significant positive association exists between p63 and IRS1 expression in HNSCC patients.	('expression', 'MPA', (116, 126))	('positive', 'PosReg', (67, 75))	('p63', 'Var', (103, 106))	('IRS1', 'Gene', '3667', (111, 115))	('SCC', 'Gene', (132, 135))	('IRS1', 'Gene', (111, 115))	('patients', 'Species', '9606', (136, 144))	('SCC', 'Gene', '6317', (132, 135))	('HNSCC', 'Phenotype', 'HP:0012288', (130, 135))	('expression', 'Species', '29278', (116, 126))
286336	30594912	It has been originally hypothesized that, DeltaNp63 mainly exerts its oncogenic functions by acting as a dominant negative repressor of the tumour suppressive members of the p53 family, including TAp63.	('tumour', 'Phenotype', 'HP:0002664', (140, 146))	('p53', 'Gene', '22060', (174, 177))	('tumour', 'Disease', 'MESH:D009369', (140, 146))	('tumour', 'Disease', (140, 146))	('oncogenic functions', 'CPA', (70, 89))	('p53', 'Gene', (174, 177))	('negative repressor', 'NegReg', (114, 132))	('exerts', 'Reg', (59, 65))	('DeltaNp63', 'Var', (42, 51))
286338	30594912	For instance, by acting in concert with the chromatin remodelling factor ACTL6A, p63 controls chromatin accessibility and functions as a direct transcriptional repressor of the Hippo/YAP regulator WWC1 in SCC.	('controls', 'Reg', (85, 93))	('p63', 'Var', (81, 84))	('chromatin accessibility', 'MPA', (94, 117))	('SCC', 'Gene', (205, 208))	('SCC', 'Gene', '6317', (205, 208))
286347	30594912	Notably, high expression of IRS1 in breast cancer cells was positively correlated with aberrant phosphorylation of AKT, which was significantly associated with lymph node metastasis.	('breast cancer', 'Phenotype', 'HP:0003002', (36, 49))	('AKT', 'Gene', '41957', (115, 118))	('high expression', 'Var', (9, 24))	('breast cancer', 'Disease', (36, 49))	('IRS1', 'Gene', '3667', (28, 32))	('associated', 'Reg', (144, 154))	('lymph node metastasis', 'CPA', (160, 181))	('expression', 'Species', '29278', (14, 24))	('IRS1', 'Gene', (28, 32))	('correlated', 'Reg', (71, 81))	('AKT', 'Gene', (115, 118))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('breast cancer', 'Disease', 'MESH:D001943', (36, 49))	('aberrant phosphorylation', 'MPA', (87, 111))
286361	30594912	For p63 siRNA-mediated knockdown, NHEK and HNSCC cells were transfected with the following siRNAs: sip63#1 (SASI_Hs02_00326864) and sip63#2 (SASI_Hs02_00326867) oligos were purchased from Sigma-Aldrich; the sense strand of the siDeltaNp63 is: 5'- GAAGAAAGGACAGCAGCATTG -3'.	('SASI_Hs02_00326864', 'Var', (108, 126))	('HNSCC', 'Phenotype', 'HP:0012288', (43, 48))	('SCC', 'Gene', (45, 48))	('SCC', 'Gene', '6317', (45, 48))
286366	30594912	qRT-PCR was performed using the Platinum SYBR Green qPCR SuperMix UDG (Invitrogen), using the following primer pairs: Irs1 5'- CTCAACTGGACATCACAGCAG -3' (sense) and 5'- AGGTCCTAGTTGTGAATCATG -3' (antisense); TAp63 5'- TCAGAAGATGGTGCGACAAAC -3' (sense) and 5'- GTTCAGGAGCCCCAGGTTCG-3' (antisense); DeltaNp63 5'- GAAGAAAGGACAGCAGCATTG -3' (sense) and 5'- GGGACTGGTGGACGAGGAG -3' (antisense).	("DeltaNp63 5'- GAAGAAAGGACAGCAGCATTG", 'Var', (297, 332))	('Irs1', 'Gene', (118, 122))	('Irs1', 'Gene', '3667', (118, 122))
286469	29699056	Many studies have been reported that cancer is not only affected by intrinsic but also by exogenous genetic alterations of cells and miRs act as a regulator of gene expression has been seen to be involved in tumor progression (Hutvagner et al., 2002).	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('genetic alterations', 'Var', (100, 119))	('involved', 'Reg', (196, 204))	('miR', 'Gene', '220972', (133, 136))	('tumor', 'Disease', 'MESH:D009369', (208, 213))	('miR', 'Gene', (133, 136))	('cancer', 'Disease', (37, 43))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('tumor', 'Disease', (208, 213))
286477	29699056	Hence abnormal expression pattern of miRs are more likely to yield valuable information as important biomarkers for the diagnosis, treatment and prognosis.	('miR', 'Gene', '220972', (37, 40))	('expression', 'MPA', (15, 25))	('abnormal', 'Var', (6, 14))	('miR', 'Gene', (37, 40))
286508	24115092	In vivo, intratumoral administration of VSV-rat-IFN-beta or VSV-human-IFN-beta in FAT-7 bearing or non-tumor bearing immunocompetent rats did not result in acute organ toxicity or death.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('toxicity', 'Disease', 'MESH:D064420', (168, 176))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('VSV-rat-IFN-beta', 'Var', (40, 56))	('VSV', 'Species', '11276', (40, 43))	('toxicity', 'Disease', (168, 176))	('rat', 'Species', '10116', (133, 136))	('rat', 'Species', '10116', (30, 33))	('death', 'Disease', (180, 185))	('VSV-human-IFN-beta', 'Var', (60, 78))	('human', 'Species', '9606', (64, 69))	('rat', 'Species', '10116', (12, 15))	('tumor', 'Disease', (103, 108))	('rat', 'Species', '10116', (44, 47))	('non-tumor', 'Disease', (99, 108))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('rats', 'Species', '10116', (133, 137))	('tumor', 'Disease', (14, 19))	('non-tumor', 'Disease', 'MESH:D009369', (99, 108))	('VSV', 'Species', '11276', (60, 63))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('death', 'Disease', 'MESH:D003643', (180, 185))
286510	24115092	Intratumoral or intravenous administration of VSV-IFN-beta resulted in growth delay and improved survival compared to controls.	('VSV', 'Species', '11276', (46, 49))	('growth delay', 'Phenotype', 'HP:0001510', (71, 83))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('rat', 'Species', '10116', (36, 39))	('rat', 'Species', '10116', (3, 6))	('growth delay', 'CPA', (71, 83))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('survival', 'CPA', (97, 105))	('VSV-IFN-beta', 'Var', (46, 58))	('improved', 'PosReg', (88, 96))	('tumor', 'Disease', (5, 10))
286518	24115092	Many oncolytic viral vectors can be genetically modified to carry genes that improve safety or antitumor effects.	('improve', 'PosReg', (77, 84))	('tumor', 'Disease', (99, 104))	('safety', 'CPA', (85, 91))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('genes', 'Var', (66, 71))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))
286529	24115092	Mouse (SCC-VII) and rat (FAT-7) SCC cell lines were obtained from ATCC (Manassas, VA) and maintained in DMEM medium with 10% fetal bovine serum (FBS) and 1% penicillin & streptomycin (1% P/S), and Ham's F12K medium with 0.01 mg/ml insulin, 250 ng/ml hydrocortisone and 0.0025 mg/ml transferrin, 10% FBS, respectively.	('S', 'Chemical', 'MESH:D013455', (7, 8))	('FBS', 'Disease', (145, 148))	('DMEM medium', 'Chemical', '-', (104, 115))	('transferrin', 'Gene', '24825', (282, 293))	('hydrocortisone', 'Chemical', 'MESH:D006854', (250, 264))	('FBS', 'Disease', 'MESH:D005198', (145, 148))	('P', 'Chemical', 'MESH:D010758', (187, 188))	('streptomycin', 'Chemical', 'MESH:D013307', (170, 182))	('F12K', 'Var', (203, 207))	('SCC', 'Gene', '6317', (32, 35))	('S', 'Chemical', 'MESH:D013455', (147, 148))	('SCC', 'Gene', '6317', (7, 10))	('penicillin', 'Chemical', 'MESH:D010406', (157, 167))	('SCC', 'Gene', (32, 35))	('rat', 'Species', '10116', (20, 23))	('SCC', 'Gene', (7, 10))	('FBS', 'Disease', (299, 302))	('F12K', 'SUBSTITUTION', 'None', (203, 207))	('transferrin', 'Gene', (282, 293))	('FBS', 'Disease', 'MESH:D005198', (299, 302))	('S', 'Chemical', 'MESH:D013455', (301, 302))	('bovine', 'Species', '9913', (131, 137))	('S', 'Chemical', 'MESH:D013455', (32, 33))	('Mouse', 'Species', '10090', (0, 5))	('and 0.0025', 'Var', (265, 275))	('S', 'Chemical', 'MESH:D013455', (189, 190))
286547	24115092	Studies were performed in tumor and non-tumor bearing rats, to assess the toxicity of VSV-r-IFN-beta or VSV-h-IFN-beta at different dose levels, after intratumoral or subcutaneous administration of the test agent.	('toxicity', 'Disease', (74, 82))	('tumor', 'Disease', (156, 161))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('VSV', 'Species', '11276', (104, 107))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('rat', 'Species', '10116', (54, 57))	('VSV-h-IFN-beta', 'Var', (104, 118))	('rat', 'Species', '10116', (188, 191))	('VSV', 'Species', '11276', (86, 89))	('tumor', 'Disease', (26, 31))	('rat', 'Species', '10116', (154, 157))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('non-tumor', 'Disease', (36, 45))	('S', 'Chemical', 'MESH:D013455', (105, 106))	('tumor', 'Disease', (40, 45))	('toxicity', 'Disease', 'MESH:D064420', (74, 82))	('rats', 'Species', '10116', (54, 58))	('S', 'Chemical', 'MESH:D013455', (0, 1))	('non-tumor', 'Disease', 'MESH:D009369', (36, 45))	('S', 'Chemical', 'MESH:D013455', (87, 88))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))
286548	24115092	Studies in non-tumor bearing rats assessed the safety of escalating doses of VSV-h-IFN-beta (n=9), and the safety of VSV-h-IFN-beta or VSV-r-IFN-beta at a fixed dose, compared to saline administration (n=8).	('VSV-r-IFN-beta', 'Var', (135, 149))	('rat', 'Species', '10116', (194, 197))	('non-tumor', 'Disease', (11, 20))	('VSV', 'Species', '11276', (135, 138))	('VSV-h-IFN-beta', 'Var', (117, 131))	('VSV', 'Species', '11276', (77, 80))	('rat', 'Species', '10116', (29, 32))	('non-tumor', 'Disease', 'MESH:D009369', (11, 20))	('saline', 'Chemical', 'MESH:D012965', (179, 185))	('S', 'Chemical', 'MESH:D013455', (118, 119))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('S', 'Chemical', 'MESH:D013455', (78, 79))	('S', 'Chemical', 'MESH:D013455', (136, 137))	('VSV-h-IFN-beta', 'Var', (77, 91))	('rats', 'Species', '10116', (29, 33))	('S', 'Chemical', 'MESH:D013455', (0, 1))	('VSV', 'Species', '11276', (117, 120))
286550	24115092	Studies in tumor bearing rats assessed the safety, biodistribution, and antibody formation of escalating doses of VSV-r-IFN-beta (n=38) or VSV-h-IFN-beta (n=24).	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('rats', 'Species', '10116', (25, 29))	('VSV-r-IFN-beta', 'Var', (114, 128))	('S', 'Chemical', 'MESH:D013455', (115, 116))	('tumor', 'Disease', (11, 16))	('VSV', 'Species', '11276', (139, 142))	('VSV-h-IFN-beta', 'Var', (139, 153))	('S', 'Chemical', 'MESH:D013455', (140, 141))	('tumor', 'Disease', 'MESH:D009369', (11, 16))	('S', 'Chemical', 'MESH:D013455', (0, 1))	('VSV', 'Species', '11276', (114, 117))
286590	24115092	VSV-r/m-IFN-beta significantly inhibited viability and induced cytotoxicity in a dose and time dependent manner in FAT-7 (Fig 1 A, B) and SCC-VII cells (Fig 2 A, B).	('man', 'Species', '9606', (105, 108))	('SCC', 'Gene', (138, 141))	('inhibited', 'NegReg', (31, 40))	('viability', 'CPA', (41, 50))	('cytotoxicity', 'Disease', (63, 75))	('SCC', 'Gene', '6317', (138, 141))	('VSV-r/m-IFN-beta', 'Var', (0, 16))	('induced', 'Reg', (55, 62))	('cytotoxicity', 'Disease', 'MESH:D064420', (63, 75))	('VSV', 'Species', '11276', (0, 3))
286591	24115092	VSV-r-IFN-beta (MOI=1) inhibited FAT-7 viability by 80% (p< 0.0001) and induced cytotoxicity (70% vs. 6% in controls, p< 0.0001) at an MOI of 1, at 48 hours (Fig.	('FAT-7 viability', 'CPA', (33, 48))	('inhibited', 'NegReg', (23, 32))	('cytotoxicity', 'Disease', 'MESH:D064420', (80, 92))	('VSV-r-IFN-beta', 'Var', (0, 14))	('induced', 'Reg', (72, 79))	('VSV', 'Species', '11276', (0, 3))	('cytotoxicity', 'Disease', (80, 92))
286592	24115092	Similar results were observed in SCC-VII cells, where VSV-m-IFN-beta (MOI=1) resulted in a 79.5% reduction in viability at 48 hours and significant cytotoxic effects (56.7% vs. 5.2%), compared to controls (p<0.0001 for both, Fig.	('reduction', 'NegReg', (97, 106))	('SCC', 'Gene', '6317', (33, 36))	('viability at 48 hours', 'CPA', (110, 131))	('VSV-m-IFN-beta', 'Var', (54, 68))	('cytotoxic effects', 'CPA', (148, 165))	('VSV', 'Species', '11276', (54, 57))	('S', 'Chemical', 'MESH:D013455', (55, 56))	('S', 'Chemical', 'MESH:D013455', (33, 34))	('SCC', 'Gene', (33, 36))	('S', 'Chemical', 'MESH:D013455', (0, 1))
286593	24115092	Statistically significant increased cytotoxicity was observed at MOIs of 0.01 and higher, both in FAT-7 (p=0.0019) and in SCC VII cells (p=0.013).	('MOIs of 0.01', 'Var', (65, 77))	('SCC', 'Gene', (122, 125))	('cytotoxicity', 'Disease', 'MESH:D064420', (36, 48))	('SCC', 'Gene', '6317', (122, 125))	('increased', 'PosReg', (26, 35))	('S', 'Chemical', 'MESH:D013455', (122, 123))	('S', 'Chemical', 'MESH:D013455', (0, 1))	('cytotoxicity', 'Disease', (36, 48))
286604	24115092	Similarly, FAT-7 cells were permissive to viral replication of both the human and rat variants of the virus, but titers of VSV-h-IFN-beta were higher than VSV-r-IFN-beta (Fig.	('VSV-h-IFN-beta', 'Var', (123, 137))	('S', 'Chemical', 'MESH:D013455', (124, 125))	('titers', 'MPA', (113, 119))	('human', 'Species', '9606', (72, 77))	('VSV', 'Species', '11276', (123, 126))	('S', 'Chemical', 'MESH:D013455', (156, 157))	('higher', 'PosReg', (143, 149))	('rat', 'Species', '10116', (82, 85))	('VSV', 'Species', '11276', (155, 158))	('S', 'Chemical', 'MESH:D013455', (0, 1))
286610	24115092	We observed that following s.c injection of 1010 VSV-r-IFN-beta in non-tumor bearing rats, a small focal subcutaneous cellulitis was observed which resolved spontaneously.	('non-tumor', 'Disease', 'MESH:D009369', (67, 76))	('rats', 'Species', '10116', (85, 89))	('1010 VSV-r-IFN-beta', 'Var', (44, 63))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('non-tumor', 'Disease', (67, 76))	('cellulitis', 'Phenotype', 'HP:0100658', (118, 128))	('cellulitis', 'Disease', 'MESH:D002481', (118, 128))	('cellulitis', 'Disease', (118, 128))	('VSV', 'Species', '11276', (49, 52))
286619	24115092	Infectious virus was detected in 5 of 6 tumor samples, and in none of the brain or spleen tissues at day2 in rats treated with 1x109 TCID50 VSV-h-IFN-beta (Fig.	('TCID50 VSV-h-IFN-beta', 'Var', (133, 154))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('VSV', 'Species', '11276', (140, 143))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('rats', 'Species', '10116', (109, 113))
286621	24115092	Additional studies were performed in non-tumor bearing rats, which were treated with a single subcutaneous (below the jaw line) injection of escalating doses (1x107, 1x108, 1x109 TCID50) of VSV-h-IFN-beta, or one dose (1x109 TCID50) of VSV-h-IFN-beta or VSV-r-IFN-beta (n=3 per group).	('escalating', 'PosReg', (141, 151))	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('VSV', 'Species', '11276', (236, 239))	('VSV', 'Species', '11276', (190, 193))	('1x108', 'Var', (166, 171))	('rats', 'Species', '10116', (55, 59))	('non-tumor', 'Disease', 'MESH:D009369', (37, 46))	('non-tumor', 'Disease', (37, 46))	('1x109 TCID50', 'Var', (173, 185))	('VSV', 'Species', '11276', (254, 257))	('1x107', 'Var', (159, 164))
286632	24115092	Rats treated with a dose of 5x108 PFUs had a significant delay in tumor growth (p<0.0001 at day 43; Fig.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('Rats', 'Species', '10116', (0, 4))	('P', 'Chemical', 'MESH:D010758', (34, 35))	('tumor', 'Disease', (66, 71))	('5x108 PFUs', 'Var', (28, 38))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('delay', 'NegReg', (57, 62))
286634	24115092	Next, we determined the effects of single vs. two intratumoral injections of VSV-r-IFN-beta (at a dose of 5x108 PFU) as well as the effects of intravenous administration of the virus (one dose of 5x108 PFU) in tumor bearing rats.	('rat', 'Species', '10116', (163, 166))	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('P', 'Chemical', 'MESH:D010758', (112, 113))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('rats', 'Species', '10116', (224, 228))	('VSV', 'Species', '11276', (77, 80))	('VSV-r-IFN-beta', 'Var', (77, 91))	('tumor', 'Disease', (210, 215))	('tumor', 'Disease', (55, 60))	('rat', 'Species', '10116', (53, 56))	('P', 'Chemical', 'MESH:D010758', (202, 203))	('rat', 'Species', '10116', (224, 227))	('tumor', 'Disease', 'MESH:D009369', (210, 215))
286635	24115092	Treatment with 1 or 2 IT doses or 1 IV dose of VSV-r-IFN-beta was associated with significant delay in tumor growth (p< 0.0001 at day 43; Fig.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor', 'Disease', (103, 108))	('VSV-r-IFN-beta', 'Var', (47, 61))	('VSV', 'Species', '11276', (47, 50))	('delay', 'NegReg', (94, 99))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
286643	24115092	In this report, we provided preclinical evidence of the safety and activity of VSV-IFN-beta in an immunocompetent, syngeneic rat model of head and neck squamous cell carcinoma.	('rat', 'Species', '10116', (125, 128))	('neck squamous cell carcinoma', 'Disease', (147, 175))	('VSV-IFN-beta', 'Var', (79, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (166, 175))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (152, 175))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (147, 175))	('activity', 'MPA', (67, 75))	('VSV', 'Species', '11276', (79, 82))
286646	24115092	Administration of both intratumoral or intravenous VSV-h-IFN-beta or VSV-r-IFN-beta was found to be safe.	('rat', 'Species', '10116', (8, 11))	('tumor', 'Disease', (28, 33))	('VSV-h-IFN-beta', 'Var', (51, 65))	('rat', 'Species', '10116', (26, 29))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('VSV', 'Species', '11276', (51, 54))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('VSV', 'Species', '11276', (69, 72))	('VSV-r-IFN-beta', 'Var', (69, 83))
286654	24115092	In vivo, both VSV-r-IFN-beta and VSV-h-IFN-beta were associated with significant delays in progression in rats bearing aggressive FAT-7 tumors.	('VSV', 'Species', '11276', (14, 17))	('VSV-r-IFN-beta', 'Var', (14, 28))	('tumors', 'Disease', (136, 142))	('tumors', 'Disease', 'MESH:D009369', (136, 142))	('rats', 'Species', '10116', (106, 110))	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('progression', 'MPA', (91, 102))	('VSV', 'Species', '11276', (33, 36))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('VSV-h-IFN-beta', 'Var', (33, 47))	('delays', 'NegReg', (81, 87))
286658	24115092	In conclusion, intratumoral administration of VSV-r-IFN-beta or VSV-h-IFN-beta in immunocompetent rats bearing syngeneic squamous cell tumors was feasible and safe at the doses tested.	('rat', 'Species', '10116', (18, 21))	('rats', 'Species', '10116', (98, 102))	('VSV', 'Species', '11276', (46, 49))	('VSV-h-IFN-beta', 'Var', (64, 78))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('rat', 'Species', '10116', (36, 39))	('VSV-r-IFN-beta', 'Var', (46, 60))	('syngeneic squamous cell tumors', 'Disease', (111, 141))	('tumor', 'Disease', (135, 140))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('rat', 'Species', '10116', (98, 101))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))	('VSV', 'Species', '11276', (64, 67))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('syngeneic squamous cell tumors', 'Disease', 'MESH:D002294', (111, 141))	('tumor', 'Disease', (20, 25))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
286669	32627026	Patients with NSCLC exhibiting high OSER1-AS1 expression had shorter overall survival than those exhibiting low OSER1-AS1 expression.	('overall survival', 'MPA', (69, 85))	('NSCLC', 'Disease', (14, 19))	('expression', 'Var', (46, 56))	('shorter', 'NegReg', (61, 68))	('NSCLC', 'Disease', 'MESH:D002289', (14, 19))	('OSER1-AS1', 'Gene', (36, 45))	('Patients', 'Species', '9606', (0, 8))	('NSCLC', 'Phenotype', 'HP:0030358', (14, 19))	('high', 'Var', (31, 35))
286671	32627026	OSER1-AS1 knockdown suppressed the tumorigenic ability of NSCLC cells in vivo.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('NSCLC', 'Disease', (58, 63))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('NSCLC', 'Disease', 'MESH:D002289', (58, 63))	('suppressed', 'NegReg', (20, 30))	('OSER1-AS1', 'Gene', (0, 9))	('tumor', 'Disease', (35, 40))	('NSCLC', 'Phenotype', 'HP:0030358', (58, 63))	('knockdown', 'Var', (10, 19))
286672	32627026	Mechanistically, OSER1-AS1 acts as a competing endogenous RNA (ceRNA) in NSCLC cells by sponging miR-433-3p and thereby increasing the expression of mothers against decapentaplegic homolog 2 (Smad2).	('miR-433-3p', 'MPA', (97, 107))	('mothers against decapentaplegic homolog 2', 'Gene', (149, 190))	('increasing', 'PosReg', (120, 130))	('miR-433-3p', 'Chemical', '-', (97, 107))	('NSCLC', 'Disease', (73, 78))	('expression', 'MPA', (135, 145))	('Smad2', 'Gene', (192, 197))	('sponging', 'Var', (88, 96))	('mothers against decapentaplegic homolog 2', 'Gene', '4087', (149, 190))	('NSCLC', 'Phenotype', 'HP:0030358', (73, 78))	('NSCLC', 'Disease', 'MESH:D002289', (73, 78))
286673	32627026	Finally, restoration experiments revealed that the suppression of miR-433-3p and restoration of Smad2 both counteracted the suppressive effects of OSER1-AS1 depletion in NSCLC cells.	('miR-433-3p', 'Chemical', '-', (66, 76))	('NSCLC', 'Phenotype', 'HP:0030358', (170, 175))	('miR-433-3p', 'Protein', (66, 76))	('suppression', 'NegReg', (51, 62))	('NSCLC', 'Disease', (170, 175))	('NSCLC', 'Disease', 'MESH:D002289', (170, 175))	('restoration', 'Var', (81, 92))	('Smad2', 'Gene', (96, 101))
286678	32627026	NSCLC is classified into three categories, one with actionable oncogene mutations including epidermal growth factor receptor (EGFR), Anaplastic lymphoma kinase (ALK) and ROS proto-oncogene 1, receptor tyrosine kinase (ROS1), one which responds to immune checkpoint inhibitors, and others.	('mutations', 'Var', (72, 81))	('receptor tyrosine kinase', 'Gene', '5979', (192, 216))	('NSCLC', 'Disease', 'MESH:D002289', (0, 5))	('ROS1', 'Gene', '6098', (218, 222))	('EGFR', 'Gene', (126, 130))	('ALK', 'Gene', (161, 164))	('epidermal growth factor receptor', 'Gene', (92, 124))	('epidermal growth factor receptor', 'Gene', '1956', (92, 124))	('ROS1', 'Gene', (218, 222))	('Anaplastic lymphoma kinase', 'Gene', '238', (133, 159))	('NSCLC', 'Phenotype', 'HP:0030358', (0, 5))	('EGFR', 'Gene', '1956', (126, 130))	('lymphoma', 'Phenotype', 'HP:0002665', (144, 152))	('Anaplastic lymphoma kinase', 'Gene', (133, 159))	('Anaplastic lymphoma', 'Phenotype', 'HP:0012193', (133, 152))	('NSCLC', 'Disease', (0, 5))	('ALK', 'Gene', '238', (161, 164))	('receptor tyrosine kinase', 'Gene', (192, 216))
286736	32627026	The OSER1-AS1 fragments carrying predicted wild-type miR-433-3p-binding sequences or mutant OSER1-AS1 fragments were amplified and inserted into the psiCHECK-2 plasmid (Promega Corp.).	('OSER1-AS1', 'Gene', (92, 101))	('psiCHECK', 'Disease', 'None', (149, 157))	('miR-433-3p', 'Chemical', '-', (53, 63))	('psiCHECK', 'Disease', (149, 157))	('mutant', 'Var', (85, 91))
286737	32627026	Cells were seeded in 24-well plates at a density of 1.5x105 cells per well and transfected with OSER1-AS1-wt or OSER1-AS1-mut in combination with miR-433-3p mimic or miR-NC using the Lipofectamine 2000  reagent.	('Lipofectamine 2000  reagent', 'Chemical', '-', (183, 210))	('miR-433-3p', 'Chemical', '-', (146, 156))	('OSER1-AS1-mut', 'Var', (112, 125))	('miR', 'Gene', '220972', (146, 149))	('miR', 'Gene', '220972', (166, 169))	('miR', 'Gene', (146, 149))	('miR', 'Gene', (166, 169))
286756	32627026	Using the CCK-8 assay, we demonstrated that OSER1-AS1 knockdown significantly decreased the proliferative abilities of H522 and A549 cells (Fig.	('CCK-8', 'Chemical', '-', (10, 15))	('proliferative abilities', 'CPA', (92, 115))	('knockdown', 'Var', (54, 63))	('A549', 'CellLine', 'CVCL:0023', (128, 132))	('OSER1-AS1', 'Gene', (44, 53))	('decreased', 'NegReg', (78, 87))
286757	32627026	2E) H522 and A549 cells were significantly reduced after si-OSER1-AS1 transfection, thus confirming that OSER1-AS1 silencing suppressed the migratory and invasion abilities of these cells.	('silencing', 'Var', (115, 124))	('si-OSER1-AS1 transfection', 'Var', (57, 82))	('suppressed', 'NegReg', (125, 135))	('transfection', 'Var', (70, 82))	('reduced', 'NegReg', (43, 50))	('A549', 'CellLine', 'CVCL:0023', (13, 17))
286767	32627026	In addition, RIP assay demonstrated notable abundance of OSER1-AS1 and miR-433-3p in Ago2-containing beads compared with that in the IgG controls, suggesting that miR-433-3p can directly bind to OSER1-AS1 in NSCLC cells (Fig.	('Ago2', 'Gene', (85, 89))	('NSCLC', 'Phenotype', 'HP:0030358', (208, 213))	('bind', 'Interaction', (187, 191))	('miR-433-3p', 'Chemical', '-', (163, 173))	('NSCLC', 'Disease', (208, 213))	('miR-433-3p', 'Chemical', '-', (71, 81))	('Ago2', 'Gene', '27161', (85, 89))	('NSCLC', 'Disease', 'MESH:D002289', (208, 213))	('miR-433-3p', 'Var', (163, 173))
286769	32627026	miR-433-3p expression was significantly increased in the H522 and A549 cells upon OSER1-AS1 knockdown (Fig.	('A549', 'CellLine', 'CVCL:0023', (66, 70))	('knockdown', 'Var', (92, 101))	('increased', 'PosReg', (40, 49))	('miR-433-3p', 'Chemical', '-', (0, 10))	('miR-433-3p', 'Gene', (0, 10))
286770	32627026	Furthermore, RT-qPCR data revealed that miR-433-3p was weakly expressed in the NSCLC tissues compared with that noted in the adjacent normal tissues (Fig.	('NSCLC', 'Disease', 'MESH:D002289', (79, 84))	('weakly', 'NegReg', (55, 61))	('miR-433-3p', 'Var', (40, 50))	('NSCLC', 'Phenotype', 'HP:0030358', (79, 84))	('miR-433-3p', 'Chemical', '-', (40, 50))	('NSCLC', 'Disease', (79, 84))
286772	32627026	In general, these results suggest that OSER1-AS1 acts as a ceRNA and molecular sponge for miR-433-3p in NSCLC cells.	('miR-433-3p', 'Chemical', '-', (90, 100))	('NSCLC', 'Disease', (104, 109))	('NSCLC', 'Disease', 'MESH:D002289', (104, 109))	('miR-433-3p', 'Var', (90, 100))	('NSCLC', 'Phenotype', 'HP:0030358', (104, 109))
286773	32627026	Given that OSER1-AS1 functions as a ceRNA in NSCLC, we hypothesized that it modulates the expression of mRNAs targeted by miR-433-3p.	('NSCLC', 'Disease', (45, 50))	('miR-433-3p', 'Var', (122, 132))	('NSCLC', 'Disease', 'MESH:D002289', (45, 50))	('expression', 'MPA', (90, 100))	('modulates', 'Reg', (76, 85))	('miR-433-3p', 'Chemical', '-', (122, 132))	('NSCLC', 'Phenotype', 'HP:0030358', (45, 50))
286774	32627026	Because a previous study identified Smad2 as a direct target of miR-433-3p in NSCLC cells, we next evaluated Smad2 mRNA and protein expression in OSER1-AS1-depleted H522 and A549 cells.	('A549', 'CellLine', 'CVCL:0023', (174, 178))	('NSCLC', 'Phenotype', 'HP:0030358', (78, 83))	('miR-433-3p', 'Var', (64, 74))	('Smad2', 'Gene', (109, 114))	('NSCLC', 'Disease', (78, 83))	('miR-433-3p', 'Chemical', '-', (64, 74))	('NSCLC', 'Disease', 'MESH:D002289', (78, 83))	('evaluated', 'Reg', (99, 108))
286775	32627026	RT-qPCR and western blotting revealed that silencing of OSER1-AS1 expression decreased Smad2 expression in the H522 and A549 cells at both the mRNA (Fig.	('silencing', 'Var', (43, 52))	('expression', 'MPA', (93, 103))	('Smad2', 'Gene', (87, 92))	('OSER1-AS1', 'Gene', (56, 65))	('decreased', 'NegReg', (77, 86))	('A549', 'CellLine', 'CVCL:0023', (120, 124))
286788	32627026	Furthermore, the reintroduction of anti-miR-433-3p abolished the effects of OSER1-AS1 knockdown on the migration (Fig.	('knockdown', 'Var', (86, 95))	('abolished', 'NegReg', (51, 60))	('miR-433-3p', 'Chemical', '-', (40, 50))	('OSER1-AS1', 'Gene', (76, 85))	('migration', 'CPA', (103, 112))
286803	32627026	These results suggest that OSER1-AS1 knockdown impedes the growth of NSCLC cells in vivo by upregulating miR-433-3p and downregulating Smad2 expression.	('Smad2', 'Gene', (135, 140))	('growth of', 'CPA', (59, 68))	('impedes', 'NegReg', (47, 54))	('miR-433-3p', 'MPA', (105, 115))	('NSCLC', 'Disease', (69, 74))	('knockdown', 'Var', (37, 46))	('NSCLC', 'Disease', 'MESH:D002289', (69, 74))	('expression', 'MPA', (141, 151))	('OSER1-AS1', 'Gene', (27, 36))	('miR-433-3p', 'Chemical', '-', (105, 115))	('NSCLC', 'Phenotype', 'HP:0030358', (69, 74))	('downregulating', 'NegReg', (120, 134))	('upregulating', 'PosReg', (92, 104))
286808	32627026	In this study, we evaluated OSER1 antisense RNA 1 (OSER1-AS1) expression in NSCLC tissues and cell lines and explored the clinical value of aberrantly high OSER1-AS1 expression in NSCLC.	('NSCLC', 'Disease', (180, 185))	('OSER1 antisense RNA 1', 'Gene', (28, 49))	('NSCLC', 'Disease', (76, 81))	('aberrantly', 'Var', (140, 150))	('NSCLC', 'Disease', 'MESH:D002289', (76, 81))	('NSCLC', 'Disease', 'MESH:D002289', (180, 185))	('OSER1 antisense RNA 1', 'Gene', '51526', (28, 49))	('NSCLC', 'Phenotype', 'HP:0030358', (180, 185))	('OSER1-AS1', 'Gene', (51, 60))	('NSCLC', 'Phenotype', 'HP:0030358', (76, 81))	('OSER1-AS1', 'Gene', (156, 165))
286812	32627026	Functionally, interference with OSER1-AS1 expression in hepatocellular carcinoma cells suppressed their proliferation, migration, and invasion and promoted their apoptosis.	('OSER1-AS1', 'Gene', (32, 41))	('proliferation', 'CPA', (104, 117))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (56, 80))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (56, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('hepatocellular carcinoma', 'Disease', (56, 80))	('invasion', 'CPA', (134, 142))	('promoted', 'PosReg', (147, 155))	('suppressed', 'NegReg', (87, 97))	('apoptosis', 'CPA', (162, 171))	('interference', 'Var', (14, 26))	('migration', 'CPA', (119, 128))
286818	32627026	Functional research affirmed that OSER1-AS1 knockdown restricted NSCLC cell proliferation, migration, and invasion in vitro; promoted cell apoptosis; and restrained tumor growth in vivo.	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('NSCLC', 'Disease', 'MESH:D002289', (65, 70))	('cell apoptosis', 'CPA', (134, 148))	('invasion', 'CPA', (106, 114))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('restricted', 'NegReg', (54, 64))	('NSCLC', 'Phenotype', 'HP:0030358', (65, 70))	('knockdown', 'Var', (44, 53))	('migration', 'CPA', (91, 100))	('restrained', 'NegReg', (154, 164))	('promoted', 'PosReg', (125, 133))	('NSCLC', 'Disease', (65, 70))	('tumor', 'Disease', (165, 170))
286827	32627026	Moreover, OSER1-AS1 knockdown led to increased miR-433-3p expression and decreased Smad2 (a direct target gene of miR-433-3p) expression in NSCLC cells, whereas miR-433-3p inhibition counteracted the regulatory effect of OSER1-AS1 knockdown on Smad2 expression.	('NSCLC', 'Disease', 'MESH:D002289', (140, 145))	('expression', 'MPA', (126, 136))	('decreased', 'NegReg', (73, 82))	('expression', 'MPA', (58, 68))	('miR-433-3p', 'Chemical', '-', (114, 124))	('miR-433-3p', 'Chemical', '-', (161, 171))	('NSCLC', 'Phenotype', 'HP:0030358', (140, 145))	('miR-433-3p', 'Gene', (47, 57))	('increased', 'PosReg', (37, 46))	('OSER1-AS1', 'Gene', (10, 19))	('miR-433-3p', 'Chemical', '-', (47, 57))	('knockdown', 'Var', (20, 29))	('Smad2', 'Gene', (83, 88))	('NSCLC', 'Disease', (140, 145))
286830	32627026	miR-372-3p is upregulated in NSCLC and exerts tumor-suppressive actions on cell growth and metastasis.	('miR-372-3p', 'Var', (0, 10))	('NSCLC', 'Phenotype', 'HP:0030358', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('cell growth', 'CPA', (75, 86))	('tumor', 'Disease', (46, 51))	('NSCLC', 'Disease', (29, 34))	('upregulated', 'PosReg', (14, 25))	('NSCLC', 'Disease', 'MESH:D002289', (29, 34))	('miR-372-3p', 'Chemical', '-', (0, 10))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
286832	32627026	Aberrant expression of miR-433-3p has been observed in multiple human cancer types including NSCLC.	('human', 'Species', '9606', (64, 69))	('NSCLC', 'Disease', (93, 98))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('miR-433-3p', 'Var', (23, 33))	('NSCLC', 'Disease', 'MESH:D002289', (93, 98))	('observed', 'Reg', (43, 51))	('expression', 'MPA', (9, 19))	('NSCLC', 'Phenotype', 'HP:0030358', (93, 98))	('miR-433-3p', 'Chemical', '-', (23, 33))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))
286833	32627026	In our study, miR-433-3p overexpression led to obvious decreases in NSCLC cell proliferation, migration, and invasion in vitro and hindered tumor growth in vivo.	('invasion', 'CPA', (109, 117))	('miR-433-3p', 'Chemical', '-', (14, 24))	('NSCLC', 'Disease', 'MESH:D002289', (68, 73))	('tumor', 'Disease', (140, 145))	('migration', 'CPA', (94, 103))	('decreases', 'NegReg', (55, 64))	('hindered', 'NegReg', (131, 139))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('NSCLC', 'Phenotype', 'HP:0030358', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('miR-433-3p', 'Var', (14, 24))	('overexpression', 'PosReg', (25, 39))	('NSCLC', 'Disease', (68, 73))
286834	32627026	Mechanistically, Smad2 has been verified as a direct downstream target of miR-433-3p in NSCLC cells.	('NSCLC', 'Phenotype', 'HP:0030358', (88, 93))	('miR-433-3p', 'Var', (74, 84))	('NSCLC', 'Disease', (88, 93))	('miR-433-3p', 'Chemical', '-', (74, 84))	('Smad2', 'Gene', (17, 22))	('NSCLC', 'Disease', 'MESH:D002289', (88, 93))
286838	32627026	Our restoration experiments revealed that enhanced activity of the miR-433-3p/Smad2 axis alleviated the inhibitory effects of OSER1-AS1 knockdown on NSCLC cell proliferation, migration, and invasion and reversed its apoptosis-enhancing effect.	('activity', 'MPA', (51, 59))	('invasion', 'CPA', (190, 198))	('NSCLC', 'Disease', (149, 154))	('enhanced', 'PosReg', (42, 50))	('knockdown', 'Var', (136, 145))	('miR-433-3p', 'Chemical', '-', (67, 77))	('apoptosis-enhancing', 'CPA', (216, 235))	('OSER1-AS1', 'Gene', (126, 135))	('alleviated', 'NegReg', (89, 99))	('migration', 'CPA', (175, 184))	('NSCLC', 'Disease', 'MESH:D002289', (149, 154))	('inhibitory effects', 'MPA', (104, 122))	('NSCLC', 'Phenotype', 'HP:0030358', (149, 154))
286839	32627026	These results collectively imply that the tumor-promoting actions of OSER1-AS1 in NSCLC cells may be attributable to the miR-433-3p-induced upregulation of Smad2 expression.	('miR-433-3p', 'Chemical', '-', (121, 131))	('tumor', 'Disease', (42, 47))	('upregulation', 'PosReg', (140, 152))	('NSCLC', 'Phenotype', 'HP:0030358', (82, 87))	('Smad2', 'Gene', (156, 161))	('miR-433-3p-induced', 'Var', (121, 139))	('expression', 'MPA', (162, 172))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('OSER1-AS1', 'Gene', (69, 78))	('NSCLC', 'Disease', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('NSCLC', 'Disease', 'MESH:D002289', (82, 87))
286848	31483286	We abolished type I IFN signaling in cancer cells by genetic elimination of its receptor, IFNAR1.	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('IFNAR1', 'Gene', '15975', (90, 96))	('genetic elimination', 'Var', (53, 72))	('abolished', 'NegReg', (3, 12))	('cancer', 'Disease', (37, 43))	('IFN', 'Gene', '3439', (20, 23))	('IFN', 'Gene', '3439', (90, 93))	('IFN', 'Gene', (20, 23))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('IFN', 'Gene', (90, 93))	('IFNAR1', 'Gene', (90, 96))
286849	31483286	Pronounced immune responses were provoked after ionizing radiation of tumors from 4 mouse cancer cell lines with Ifnar1 knockout.	('provoked', 'Reg', (33, 41))	('Ifnar1', 'Gene', (113, 119))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('immune responses', 'MPA', (11, 27))	('knockout', 'Var', (120, 128))	('tumors', 'Disease', (70, 76))	('tumors', 'Disease', 'MESH:D009369', (70, 76))	('mouse', 'Species', '10090', (84, 89))	('Ifnar1', 'Gene', '15975', (113, 119))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))
286858	31483286	In some studies abrogation of IFN signaling in the host or in cancer cells was shown to diminish localized or systemic immune responses after radiation therapy with or without immune checkpoint blockade.	('localized or systemic immune responses', 'CPA', (97, 135))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('abrogation', 'Var', (16, 26))	('IFN', 'Gene', (30, 33))	('diminish', 'NegReg', (88, 96))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('IFN', 'Gene', '3439', (30, 33))
286874	31483286	Finally IFN can mediate resistance in the face of immune checkpoint inhibition with anti-CTLA-4 or anti-PD-L1 combined with radiation.	('CTLA-4', 'Gene', '12477', (89, 95))	('anti-PD-L1', 'Var', (99, 109))	('IFN', 'Gene', '3439', (8, 11))	('mediate', 'Reg', (16, 23))	('CTLA-4', 'Gene', (89, 95))	('IFN', 'Gene', (8, 11))
286880	31483286	Accordingly, we investigated the effects of type I IFN signaling in cancer cells by genetic elimination of Ifnar1.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('genetic elimination', 'Var', (84, 103))	('IFN', 'Gene', '3439', (51, 54))	('Ifnar1', 'Gene', (107, 113))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('investigated', 'Reg', (16, 28))	('cancer', 'Disease', (68, 74))	('IFN', 'Gene', (51, 54))	('Ifnar1', 'Gene', '15975', (107, 113))
286887	31483286	To genetically abrogate its signaling, we used CRISPR/Cas9 methodology to inactivate Ifnar1.	('signaling', 'MPA', (28, 37))	('abrogate', 'NegReg', (15, 23))	('Ifnar1', 'Gene', '15975', (85, 91))	('Ifnar1', 'Gene', (85, 91))	('inactivate', 'Var', (74, 84))
286898	31483286	Overall, genetic abrogation of type I IFN signaling in cancer cells enhanced the tumor response to IR.	('enhanced', 'PosReg', (68, 76))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('IFN', 'Gene', '3439', (38, 41))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('genetic abrogation', 'Var', (9, 27))	('IFN', 'Gene', (38, 41))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('cancer', 'Disease', (55, 61))	('tumor', 'Disease', (81, 86))
286906	31483286	With CD8+ T cell depletion the growth delay in response to IR was significantly reduced in WT MC38 tumors, and it was almost completely abolished in Ifnar1-KO tumors (Figure 2, C and D; depletion validated in Supplemental Figure 3).	('tumors', 'Phenotype', 'HP:0002664', (99, 105))	('tumors', 'Disease', 'MESH:D009369', (99, 105))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('reduced', 'NegReg', (80, 87))	('tumors', 'Disease', (159, 165))	('WT MC38 tumors', 'Disease', (91, 105))	('Ifnar1', 'Gene', (149, 155))	('WT MC38 tumors', 'Disease', 'MESH:C536751', (91, 105))	('tumors', 'Phenotype', 'HP:0002664', (159, 165))	('CD8+ T cell depletion', 'Var', (5, 26))	('growth delay', 'Phenotype', 'HP:0001510', (31, 43))	('tumors', 'Disease', 'MESH:D009369', (159, 165))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('growth delay', 'MPA', (31, 43))	('abolished', 'NegReg', (136, 145))	('Ifnar1', 'Gene', '15975', (149, 155))	('tumors', 'Disease', (99, 105))
286915	31483286	To understand how abrogation of type I IFN signaling in cancer cells led to better tumor control, we characterized CD8+ T cells in tumors from WT or Ifnar1-KO MC38 tumors after IR.	('tumor', 'Disease', (164, 169))	('tumor', 'Disease', (83, 88))	('tumor', 'Disease', (131, 136))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('cancer', 'Disease', (56, 62))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('Ifnar1', 'Gene', '15975', (149, 155))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('tumors', 'Phenotype', 'HP:0002664', (164, 170))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('IFN', 'Gene', '3439', (39, 42))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumors', 'Disease', (164, 170))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumors', 'Disease', (131, 137))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('abrogation', 'Var', (18, 28))	('tumors', 'Disease', 'MESH:D009369', (164, 170))	('IFN', 'Gene', (39, 42))	('Ifnar1', 'Gene', (149, 155))	('tumors', 'Disease', 'MESH:D009369', (131, 137))
286927	31483286	In B16F10 and LLC tumors, there were many fewer cells expressing PD-1 than in MC38 tumors, but still no significant differences in the percentage of CD8+ T cells expressing PD-1 or TIM-3 between WT and Ifnar1-KO tumors were found.	('LLC tumors', 'Disease', (14, 24))	('TIM-3', 'Gene', '171285', (181, 186))	('tumors', 'Disease', (18, 24))	('tumors', 'Disease', 'MESH:D009369', (83, 89))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('TIM-3', 'Gene', (181, 186))	('Ifnar1', 'Gene', (202, 208))	('tumors', 'Phenotype', 'HP:0002664', (212, 218))	('PD-1', 'Gene', (65, 69))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('fewer', 'NegReg', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumors', 'Disease', (212, 218))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('B16F10', 'Var', (3, 9))	('Ifnar1', 'Gene', '15975', (202, 208))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('tumors', 'Disease', 'MESH:D009369', (212, 218))	('tumors', 'Disease', (83, 89))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('LLC tumors', 'Disease', 'MESH:D009369', (14, 24))
286954	31483286	Inhibition of JAK1 also abrogated the induction of Serpinb9 by type I IFN in WT cells.	('IFN', 'Gene', (70, 73))	('Serpinb9', 'Gene', (51, 59))	('induction', 'MPA', (38, 47))	('JAK1', 'Gene', (14, 18))	('Inhibition', 'Var', (0, 10))	('IFN', 'Gene', '3439', (70, 73))	('abrogated', 'NegReg', (24, 33))	('Serpinb9', 'Gene', '20723', (51, 59))	('JAK1', 'Gene', '16451', (14, 18))
286955	31483286	Inhibition of JAK1 also reduced the induction of Serpinb9 by IR in WT, but not in Ifnar1-KO, cells (Figure 6, E and F).	('Serpinb9', 'Gene', (49, 57))	('Ifnar1', 'Gene', (82, 88))	('induction', 'MPA', (36, 45))	('reduced', 'NegReg', (24, 31))	('Serpinb9', 'Gene', '20723', (49, 57))	('Ifnar1', 'Gene', '15975', (82, 88))	('Inhibition', 'Var', (0, 10))	('JAK1', 'Gene', (14, 18))	('JAK1', 'Gene', '16451', (14, 18))
286958	31483286	Both IRF1 and IRF3 were induced by IR in MC38 cells, and both IRF1 knockdown and IRF3 KO diminished Serpinb9 induction after IR, but only IRF3 KO affected Ifnb1 induction (Supplemental Figure 10 and Figure 6, G and H).	('IRF3', 'Gene', (14, 18))	('Serpinb9', 'Gene', (100, 108))	('Ifnb1', 'Gene', (155, 160))	('IRF3', 'Gene', '54131', (81, 85))	('diminished', 'NegReg', (89, 99))	('knockdown', 'Var', (67, 76))	('induction', 'MPA', (109, 118))	('IRF3', 'Gene', (138, 142))	('IRF3', 'Gene', '54131', (14, 18))	('IRF3', 'Gene', '54131', (138, 142))	('IRF1', 'Gene', (62, 66))	('Ifnb1', 'Gene', '15977', (155, 160))	('Serpinb9', 'Gene', '20723', (100, 108))	('IRF3', 'Gene', (81, 85))
286964	31483286	Ifnar1-KO cells with Serpinb9 overexpression showed a significant reduction in killing compared with cells with control vector (Figure 7B).	('Serpinb9', 'Gene', (21, 29))	('Ifnar1', 'Gene', (0, 6))	('killing', 'MPA', (79, 86))	('Serpinb9', 'Gene', '20723', (21, 29))	('overexpression', 'Var', (30, 44))	('Ifnar1', 'Gene', '15975', (0, 6))	('reduction', 'NegReg', (66, 75))
286974	31483286	Most importantly, reintroduction of Serpinb9 expression in Ifnar1-KO cancer cells abrogated their enhanced response to IR.	('enhanced', 'PosReg', (98, 106))	('Serpinb9', 'Gene', '20723', (36, 44))	('reintroduction', 'Var', (18, 32))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('Ifnar1', 'Gene', (59, 65))	('response to IR', 'MPA', (107, 121))	('Serpinb9', 'Gene', (36, 44))	('abrogated', 'NegReg', (82, 91))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('Ifnar1', 'Gene', '15975', (59, 65))	('cancer', 'Disease', (69, 75))
286980	31483286	Despite high percentages of cancer cells in the MC38 model expressing PD-L1, anti-PD-L1 only had a minor, not statistically significant, additional effect in WT MC38 tumors with or without IR (Figure 9, A and B).	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('WT MC38 tumors', 'Disease', (158, 172))	('anti-PD-L1', 'Var', (77, 87))	('WT MC38 tumors', 'Disease', 'MESH:C536751', (158, 172))	('cancer', 'Disease', (28, 34))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))	('PD-L1', 'Var', (70, 75))
286981	31483286	In contrast, anti-PD-L1 substantially extended the survival of mice bearing Ifnar1-KO tumors and further improved their outcomes when combined with IR (Figure 9, C and D).	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('outcomes', 'MPA', (120, 128))	('Ifnar1', 'Gene', (76, 82))	('tumors', 'Disease', (86, 92))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('survival', 'CPA', (51, 59))	('mice', 'Species', '10090', (63, 67))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('extended', 'PosReg', (38, 46))	('improved', 'PosReg', (105, 113))	('anti-PD-L1', 'Var', (13, 23))	('Ifnar1', 'Gene', '15975', (76, 82))
286983	31483286	Anti-PD-L1 similarly delayed tumor growth in the B16F10 model, but not in the KPC model (Figure 9, E-J, and Supplemental Figure 12).	('delayed', 'NegReg', (21, 28))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('Anti-PD-L1', 'Var', (0, 10))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumor', 'Disease', (29, 34))
286988	31483286	Abrogation of Ifnar1 in murine cancer cells resulted in an enhanced antitumor response after IR dependent on CD8+ T cells, which generally did not lead to increased numbers, augmented cytotoxic markers, or reduced exhaustion of tumor-infiltrating CD8+ T cells.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('Ifnar1', 'Gene', '15975', (14, 20))	('reduced', 'NegReg', (206, 213))	('Abrogation', 'Var', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('tumor', 'Disease', 'MESH:D009369', (228, 233))	('tumor', 'Disease', (72, 77))	('enhanced', 'PosReg', (59, 67))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('murine', 'Species', '10090', (24, 30))	('Ifnar1', 'Gene', (14, 20))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('tumor', 'Disease', (228, 233))	('cancer', 'Disease', (31, 37))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('rat', 'Species', '10116', (240, 243))
287014	31483286	In our experiments, abrogation of type I IFN signaling in cancer cells did not affect PD-L1 expression in vivo under most of our experimental conditions, perhaps because type II IFN signaling pathways remained intact.	('IFN', 'Gene', '3439', (178, 181))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('IFN', 'Gene', '3439', (41, 44))	('IFN', 'Gene', (41, 44))	('IFN', 'Gene', (178, 181))	('abrogation', 'Var', (20, 30))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('cancer', 'Disease', (58, 64))	('PD-L1', 'Gene', (86, 91))	('expression', 'MPA', (92, 102))
287090	29085461	Particular gene upregulation and p53 heterogeneous expression in TP53-mutated maxillary carcinoma It has been demonstrated that tumor protein p53 (TP53) mutation in maxillary squamous cell carcinoma, is more treatment-resistant compared with the carcinoma without TP53 mutation.	('TP53', 'Gene', '7157', (65, 69))	('TP53', 'Gene', '7157', (264, 268))	('upregulation', 'PosReg', (16, 28))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('p53', 'Gene', '7157', (33, 36))	('carcinoma', 'Disease', (88, 97))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (175, 198))	('TP53', 'Gene', (147, 151))	('p53', 'Gene', '7157', (142, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (246, 255))	('p53', 'Gene', (33, 36))	('carcinoma', 'Disease', (246, 255))	('carcinoma', 'Phenotype', 'HP:0030731', (189, 198))	('mutation', 'Var', (153, 161))	('carcinoma', 'Disease', (189, 198))	('p53', 'Gene', (142, 145))	('TP53', 'Gene', (65, 69))	('maxillary carcinoma', 'Disease', 'MESH:D008441', (78, 97))	('TP53', 'Gene', (264, 268))	('maxillary squamous cell carcinoma', 'Disease', 'MESH:D002294', (165, 198))	('carcinoma', 'Disease', 'MESH:D002277', (88, 97))	('tumor', 'Disease', (128, 133))	('TP53', 'Gene', '7157', (147, 151))	('maxillary carcinoma', 'Disease', (78, 97))	('maxillary squamous cell carcinoma', 'Disease', (165, 198))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('carcinoma', 'Disease', 'MESH:D002277', (246, 255))	('carcinoma', 'Disease', 'MESH:D002277', (189, 198))
287092	29085461	As a first step in understanding the biological differences between tumors with and without TP53 mutation, a comprehensive gene expression analysis of maxillary squamous cell carcinoma with or without TP53 mutation was performed.	('maxillary squamous cell carcinoma', 'Disease', (151, 184))	('tumors', 'Disease', (68, 74))	('tumors', 'Disease', 'MESH:D009369', (68, 74))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('TP53', 'Gene', '7157', (201, 205))	('maxillary squamous cell carcinoma', 'Disease', 'MESH:D002294', (151, 184))	('mutation', 'Var', (206, 214))	('TP53', 'Gene', (201, 205))	('TP53', 'Gene', '7157', (92, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (175, 184))	('TP53', 'Gene', (92, 96))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (161, 184))
287093	29085461	Quantification of their mRNA using quantitative polymerase chain reaction indicated 18 genes with high expression and three genes with low expression in TP53 mutated tumors vs. TP53 wild-type tumors.	('tumors', 'Disease', 'MESH:D009369', (166, 172))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('tumors', 'Disease', (192, 198))	('tumors', 'Disease', 'MESH:D009369', (192, 198))	('expression', 'MPA', (103, 113))	('tumors', 'Phenotype', 'HP:0002664', (192, 198))	('type tumors', 'Disease', (187, 198))	('TP53', 'Gene', '7157', (153, 157))	('high', 'PosReg', (98, 102))	('TP53', 'Gene', '7157', (177, 181))	('type tumors', 'Disease', 'MESH:D009369', (187, 198))	('mutated', 'Var', (158, 165))	('TP53', 'Gene', (153, 157))	('tumors', 'Disease', (166, 172))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))	('TP53', 'Gene', (177, 181))
287095	29085461	Among these genes, DSC3, SFN, and CSTA, whose expression was markedly increased, also demonstrated high protein expression in immunohistochemical staining of TP53 mutated tumors.	('TP53', 'Gene', '7157', (158, 162))	('tumors', 'Phenotype', 'HP:0002664', (171, 177))	('TP53', 'Gene', (158, 162))	('tumors', 'Disease', 'MESH:D009369', (171, 177))	('mutated', 'Var', (163, 170))	('increased', 'PosReg', (70, 79))	('SFN', 'Gene', (25, 28))	('CSTA', 'Gene', '1475', (34, 38))	('protein expression', 'MPA', (104, 122))	('DSC3', 'Gene', '1825', (19, 23))	('DSC3', 'Gene', (19, 23))	('CSTA', 'Gene', (34, 38))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('expression', 'MPA', (46, 56))	('tumors', 'Disease', (171, 177))	('SFN', 'Gene', '2810', (25, 28))
287096	29085461	The TP53 mutated tumors demonstrated high nuclear staining of the TP53 protein only in tumor cells at the tumor margins adjacent to the stroma, whereas the tumor interior was negative for TP53.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('TP53', 'Gene', '7157', (66, 70))	('tumors', 'Disease', (17, 23))	('protein', 'Protein', (71, 78))	('tumor', 'Disease', (156, 161))	('tumor', 'Disease', (106, 111))	('TP53', 'Gene', (4, 8))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('nuclear staining', 'MPA', (42, 58))	('TP53', 'Gene', '7157', (188, 192))	('tumor', 'Disease', (17, 22))	('TP53', 'Gene', (66, 70))	('tumor', 'Disease', (87, 92))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('TP53', 'Gene', '7157', (4, 8))	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('mutated', 'Var', (9, 16))	('TP53', 'Gene', (188, 192))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
287098	29085461	The combined findings suggest that TP53 mutated tumors possess a phenotype opposite to that associated with cancer progression and malignant transformation, and exhibit tumor cell heterogeneity between the tumor interior and margins.	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('tumor', 'Disease', (48, 53))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('tumors', 'Disease', (48, 54))	('tumor', 'Disease', (206, 211))	('tumors', 'Disease', 'MESH:D009369', (48, 54))	('TP53', 'Gene', '7157', (35, 39))	('TP53', 'Gene', (35, 39))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('mutated', 'Var', (40, 47))	('tumor', 'Disease', (169, 174))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Disease', 'MESH:D009369', (206, 211))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
287104	29085461	TP53 mutations are associated with treatment resistance not only in head and neck cancers, but also in breast cancer, lung cancer, hepatic cancer, and chronic lymphocytic leukemia.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('cancers', 'Phenotype', 'HP:0002664', (82, 89))	('breast cancer', 'Disease', 'MESH:D001943', (103, 116))	('breast cancer', 'Disease', (103, 116))	('lung cancer', 'Disease', (118, 129))	('neck cancers', 'Disease', (77, 89))	('associated with', 'Reg', (19, 34))	('TP53', 'Gene', '7157', (0, 4))	('neck cancers', 'Disease', 'MESH:D006258', (77, 89))	('hepatic cancer', 'Disease', 'MESH:D008113', (131, 145))	('chronic lymphocytic leukemia', 'Disease', 'MESH:D015451', (151, 179))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('hepatic cancer', 'Phenotype', 'HP:0002896', (131, 145))	('chronic lymphocytic leukemia', 'Disease', (151, 179))	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (151, 179))	('leukemia', 'Phenotype', 'HP:0001909', (171, 179))	('lung cancer', 'Disease', 'MESH:D008175', (118, 129))	('mutations', 'Var', (5, 14))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('lung cancer', 'Phenotype', 'HP:0100526', (118, 129))	('TP53', 'Gene', (0, 4))	('head and neck cancers', 'Phenotype', 'HP:0012288', (68, 89))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('breast cancer', 'Phenotype', 'HP:0003002', (103, 116))	('treatment resistance', 'CPA', (35, 55))	('hepatic cancer', 'Disease', (131, 145))
287108	29085461	In addition to the previously identified TP53, cyclin dependent kinase inhibitor 2A, Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha, and histidyl-tRNA synthetase genes, mutations in major genes that regulate squamous differentiation, including notch1, interferon regulatory factor 6, and tumor protein p63 (TP63), have been newly identified as drivers.	('TP53', 'Gene', '7157', (41, 45))	('TP63', 'Gene', '8626', (331, 335))	('TP53', 'Gene', (41, 45))	('TP63', 'Gene', (331, 335))	('cyclin dependent kinase inhibitor 2A', 'Gene', (47, 83))	('interferon regulatory factor 6', 'Gene', (276, 306))	('notch1', 'Gene', '4851', (268, 274))	('interferon regulatory factor 6', 'Gene', '3664', (276, 306))	('Phosphatidylinositol-4,5', 'Chemical', '-', (85, 109))	('notch1', 'Gene', (268, 274))	('tumor', 'Phenotype', 'HP:0002664', (312, 317))	('mutations', 'Var', (193, 202))	('tumor protein p63', 'Gene', (312, 329))	('tumor protein p63', 'Gene', '8626', (312, 329))	('cyclin dependent kinase inhibitor 2A', 'Gene', '1029', (47, 83))
287109	29085461	In particular, TP53 mutations occur at a high frequency in HNSCC, but many non-TP53 mutated tumors are human papillomavirus-positive.	('tumors', 'Disease', 'MESH:D009369', (92, 98))	('TP53', 'Gene', '7157', (79, 83))	('TP53', 'Gene', (79, 83))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('TP53', 'Gene', '7157', (15, 19))	('TP53', 'Gene', (15, 19))	('human papillomavirus', 'Species', '10566', (103, 123))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('HNSCC', 'Phenotype', 'HP:0012288', (59, 64))	('tumors', 'Disease', (92, 98))	('mutations', 'Var', (20, 29))	('HNSCC', 'Disease', (59, 64))
287111	29085461	As a first step in understanding the biological differences observed between tumors with and without TP53 mutation, this study aimed to clarify differences at the gene expression level between maxillary cancers with and without TP53 mutation.	('tumors', 'Disease', (77, 83))	('tumors', 'Disease', 'MESH:D009369', (77, 83))	('maxillary cancers', 'Disease', 'MESH:D008444', (193, 210))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('maxillary cancers', 'Disease', (193, 210))	('TP53', 'Gene', '7157', (101, 105))	('mutation', 'Var', (106, 114))	('TP53', 'Gene', (101, 105))	('TP53', 'Gene', '7157', (228, 232))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('TP53', 'Gene', (228, 232))	('cancers', 'Phenotype', 'HP:0002664', (203, 210))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))
287115	29085461	The synthesized cDNA was used to perform polymerase chain reaction (PCR) analysis of a high mutation region (aa115-aa342) of the TP53 gene as described previously.	('TP53', 'Gene', '7157', (129, 133))	('aa115-aa342', 'Var', (109, 120))	('TP53', 'Gene', (129, 133))
287116	29085461	Comprehensive gene expression analysis was performed in 5 patients each with and without TP53 mutations (Table I).	('patients', 'Species', '9606', (58, 66))	('TP53', 'Gene', '7157', (89, 93))	('TP53', 'Gene', (89, 93))	('mutations', 'Var', (94, 103))
287120	29085461	Genes with >3-fold differential expression between TP53 mutation (+) and (-), that were commonly identified using two parametric tests (Student's t-test and Welch's t-test), were used as gene candidates with differential expression (Fig.	('mutation', 'Var', (56, 64))	('TP53', 'Gene', '7157', (51, 55))	('TP53', 'Gene', (51, 55))
287127	29085461	Age, stage, grade, and mRNA expression levels were compared between the two groups with and without TP53 mutation using the Mann-Whitney U test.	('mRNA expression levels', 'MPA', (23, 45))	('TP53', 'Gene', '7157', (100, 104))	('TP53', 'Gene', (100, 104))	('mutation', 'Var', (105, 113))
287129	29085461	Table III compares the clinicopathological features of patients with and without TP53 mutations.	('patients', 'Species', '9606', (55, 63))	('mutations', 'Var', (86, 95))	('TP53', 'Gene', '7157', (81, 85))	('TP53', 'Gene', (81, 85))
287131	29085461	However, there was a correlation between TP53 mutations and age; thus, TP53 mutation-positive patients were significantly older than those without TP53 mutation (P=0.0273).	('TP53', 'Gene', '7157', (41, 45))	('TP53', 'Gene', (41, 45))	('TP53', 'Gene', (147, 151))	('patients', 'Species', '9606', (94, 102))	('TP53', 'Gene', '7157', (147, 151))	('TP53', 'Gene', '7157', (71, 75))	('mutation-positive', 'Var', (76, 93))	('TP53', 'Gene', (71, 75))
287134	29085461	The results showed 92 genes in TP53 mutated tumors with >=3-fold increased expression and 30 genes whose expression was decreased to approximately 1/3 compared to non-TP53 mutated tumors (Fig.	('tumors', 'Disease', (44, 50))	('increased', 'PosReg', (65, 74))	('tumors', 'Disease', 'MESH:D009369', (44, 50))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('expression', 'MPA', (75, 85))	('TP53', 'Gene', '7157', (31, 35))	('TP53', 'Gene', (31, 35))	('tumors', 'Phenotype', 'HP:0002664', (180, 186))	('mutated', 'Var', (36, 43))	('tumors', 'Disease', (180, 186))	('TP53', 'Gene', '7157', (167, 171))	('tumors', 'Disease', 'MESH:D009369', (180, 186))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('TP53', 'Gene', (167, 171))
287137	29085461	Table IV lists 18 genes with high expression and 3 genes with low expression in TP53 mutated tumors compared to non-TP53 mutated tumors.	('TP53', 'Gene', (116, 120))	('tumors', 'Disease', (129, 135))	('expression', 'MPA', (34, 44))	('high', 'PosReg', (29, 33))	('tumors', 'Disease', 'MESH:D009369', (129, 135))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumors', 'Disease', 'MESH:D009369', (93, 99))	('TP53', 'Gene', '7157', (80, 84))	('TP53', 'Gene', (80, 84))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('mutated', 'Var', (85, 92))	('tumors', 'Disease', (93, 99))	('TP53', 'Gene', '7157', (116, 120))
287139	29085461	Thus, in TP53 mutated tumors, the expression of genes that inhibited proliferation, invasion, and metastases was unexpectedly increased, compared to wild-type tumors.	('expression of genes', 'MPA', (34, 53))	('invasion', 'CPA', (84, 92))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('inhibited', 'NegReg', (59, 68))	('tumors', 'Disease', (159, 165))	('metastases', 'Disease', (98, 108))	('TP53', 'Gene', '7157', (9, 13))	('tumors', 'Phenotype', 'HP:0002664', (22, 28))	('mutated', 'Var', (14, 21))	('proliferation', 'CPA', (69, 82))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('tumors', 'Disease', 'MESH:D009369', (159, 165))	('tumors', 'Disease', (22, 28))	('type tumors', 'Disease', (154, 165))	('TP53', 'Gene', (9, 13))	('tumors', 'Disease', 'MESH:D009369', (22, 28))	('tumors', 'Phenotype', 'HP:0002664', (159, 165))	('metastases', 'Disease', 'MESH:D009362', (98, 108))	('type tumors', 'Disease', 'MESH:D009369', (154, 165))	('increased', 'PosReg', (126, 135))
287140	29085461	IHC analysis of the 3 genes with the highest differential expression between TP53 mutated and non-mutated tumors was performed.	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('tumors', 'Disease', (106, 112))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('mutated', 'Var', (82, 89))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('TP53', 'Gene', '7157', (77, 81))	('TP53', 'Gene', (77, 81))
287142	29085461	In TP53 mutated tumors, CSTA was strongly expressed throughout the entire tumor.	('TP53', 'Gene', '7157', (3, 7))	('TP53', 'Gene', (3, 7))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('mutated', 'Var', (8, 15))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('tumors', 'Disease', 'MESH:D009369', (16, 22))	('CSTA', 'Gene', (24, 28))	('CSTA', 'Gene', '1475', (24, 28))	('tumor', 'Disease', (74, 79))	('tumor', 'Disease', (16, 21))	('tumors', 'Disease', (16, 22))
287144	29085461	Staining of SFN was stronger in mutated tumors than in the wild-type tumors, and was localized more in the cell membrane than in the cytoplasm.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('tumors', 'Disease', 'MESH:D009369', (40, 46))	('mutated', 'Var', (32, 39))	('SFN', 'Gene', '2810', (12, 15))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('stronger', 'PosReg', (20, 28))	('tumors', 'Disease', (69, 75))	('tumors', 'Disease', 'MESH:D009369', (69, 75))	('type tumors', 'Disease', 'MESH:D009369', (64, 75))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('type tumors', 'Disease', (64, 75))	('SFN', 'Gene', (12, 15))	('tumors', 'Disease', (40, 46))
287146	29085461	Staining in tumors was stronger in cell membranes, with stronger staining in mutated tumors compared to wild-type tumors.	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('tumors', 'Disease', 'MESH:D009369', (85, 91))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('type tumors', 'Disease', 'MESH:D009369', (109, 120))	('mutated', 'Var', (77, 84))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('tumors', 'Disease', (114, 120))	('stronger', 'PosReg', (56, 64))	('tumors', 'Disease', (12, 18))	('staining', 'MPA', (65, 73))	('tumors', 'Disease', 'MESH:D009369', (114, 120))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('type tumors', 'Disease', (109, 120))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('tumors', 'Disease', 'MESH:D009369', (12, 18))	('tumors', 'Disease', (85, 91))
287150	29085461	Immunostaining of TP53 mutated tumors did not show p53 staining throughout the tumor; instead, strong nuclear p53 staining was only observed in tumor cells in the margins adjacent to the stroma.	('p53', 'Gene', (51, 54))	('TP53', 'Gene', '7157', (18, 22))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('mutated', 'Var', (23, 30))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumors', 'Disease', (31, 37))	('p53', 'Gene', '7157', (110, 113))	('tumor', 'Disease', (144, 149))	('p53', 'Gene', (110, 113))	('tumor', 'Disease', (79, 84))	('TP53', 'Gene', (18, 22))	('tumors', 'Disease', 'MESH:D009369', (31, 37))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('p53', 'Gene', '7157', (51, 54))	('tumor', 'Disease', (31, 36))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
287153	29085461	p53 IHC staining was negative in case M13 (R156AfsX14) because of the frameshift mutation.	('p53', 'Gene', (0, 3))	('frameshift mutation', 'Var', (70, 89))	('p53', 'Gene', '7157', (0, 3))	('R156AfsX14', 'Mutation', 'p.R156AfsX14', (43, 53))
287154	29085461	This study found clear differences in gene expression between TP53 mutated and TP53 wild-type maxillary squamous cell carcinoma tumors.	('TP53', 'Gene', '7157', (62, 66))	('TP53', 'Gene', '7157', (79, 83))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (104, 127))	('TP53', 'Gene', (79, 83))	('differences', 'Reg', (23, 34))	('TP53', 'Gene', (62, 66))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('mutated', 'Var', (67, 74))	('maxillary squamous cell carcinoma tumors', 'Disease', 'MESH:D002294', (94, 134))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('maxillary squamous cell carcinoma tumors', 'Disease', (94, 134))
287155	29085461	A characteristic finding was increased expression of cell growth inhibition genes and increased expression of cell adhesion genes such as DSC3 in the TP53 mutated tumors.	('mutated', 'Var', (155, 162))	('TP53', 'Gene', (150, 154))	('increased', 'PosReg', (86, 95))	('DSC3', 'Gene', (138, 142))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('expression', 'MPA', (96, 106))	('increased', 'PosReg', (29, 38))	('DSC3', 'Gene', '1825', (138, 142))	('tumors', 'Disease', (163, 169))	('tumors', 'Disease', 'MESH:D009369', (163, 169))	('tumors', 'Phenotype', 'HP:0002664', (163, 169))	('expression', 'MPA', (39, 49))	('TP53', 'Gene', '7157', (150, 154))	('cell', 'CPA', (53, 57))
287156	29085461	Takahashi et al compared gene expression using microarrays in breast cancer with and without TP53 mutations.	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('TP53', 'Gene', '7157', (93, 97))	('breast cancer', 'Disease', 'MESH:D001943', (62, 75))	('TP53', 'Gene', (93, 97))	('breast cancer', 'Phenotype', 'HP:0003002', (62, 75))	('mutations', 'Var', (98, 107))	('breast cancer', 'Disease', (62, 75))
287157	29085461	They found that the expression of genes that stimulate the cell cycle and cell division was increased in TP53 mutated tumors, thus suggesting that TP53 mutation was a poor prognostic factor in breast cancer.	('breast cancer', 'Disease', (193, 206))	('TP53', 'Gene', (147, 151))	('breast cancer', 'Phenotype', 'HP:0003002', (193, 206))	('cell division', 'CPA', (74, 87))	('mutated', 'Var', (110, 117))	('expression of genes', 'MPA', (20, 39))	('TP53', 'Gene', '7157', (147, 151))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('cell cycle', 'CPA', (59, 69))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('increased', 'PosReg', (92, 101))	('stimulate', 'PosReg', (45, 54))	('TP53', 'Gene', (105, 109))	('TP53', 'Gene', '7157', (105, 109))	('tumors', 'Disease', (118, 124))	('breast cancer', 'Disease', 'MESH:D001943', (193, 206))	('tumors', 'Disease', 'MESH:D009369', (118, 124))
287158	29085461	However, our results were the opposite; i.e., we found increased expression of 8 tumor suppressor genes including SFN in TP53 mutated tumors compared to wild type tumors.	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('increased', 'PosReg', (55, 64))	('TP53', 'Gene', '7157', (121, 125))	('SFN', 'Gene', (114, 117))	('tumor', 'Disease', (163, 168))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('mutated', 'Var', (126, 133))	('tumors', 'Disease', (134, 140))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('SFN', 'Gene', '2810', (114, 117))	('tumors', 'Phenotype', 'HP:0002664', (163, 169))	('expression', 'MPA', (65, 75))	('type tumors', 'Disease', 'MESH:D009369', (158, 169))	('tumor', 'Disease', (81, 86))	('tumors', 'Disease', 'MESH:D009369', (134, 140))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('TP53', 'Gene', (121, 125))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumors', 'Disease', (163, 169))	('tumor', 'Disease', (134, 139))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('tumors', 'Disease', 'MESH:D009369', (163, 169))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('type tumors', 'Disease', (158, 169))
287159	29085461	In particular, there was >=100-fold differential expression of CSTA and SFN based on TP53 mutation status (Table IV).	('TP53', 'Gene', (85, 89))	('SFN', 'Gene', '2810', (72, 75))	('expression', 'MPA', (49, 59))	('CSTA', 'Gene', '1475', (63, 67))	('TP53', 'Gene', '7157', (85, 89))	('SFN', 'Gene', (72, 75))	('CSTA', 'Gene', (63, 67))	('mutation', 'Var', (90, 98))
287161	29085461	Our study showed markedly increased expression of CSTA in TP53 mutated tumors, with strong expression in the cytoplasm.	('CSTA', 'Gene', (50, 54))	('mutated', 'Var', (63, 70))	('CSTA', 'Gene', '1475', (50, 54))	('TP53', 'Gene', '7157', (58, 62))	('TP53', 'Gene', (58, 62))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('increased', 'PosReg', (26, 35))	('tumors', 'Disease', (71, 77))	('expression', 'MPA', (36, 46))	('tumors', 'Disease', 'MESH:D009369', (71, 77))
287173	29085461	Cancers with high SFN expression have increased proliferation and anti-cancer drug resistance and thus SFN can be regarded as a tumor progressive protein.	('expression', 'Var', (22, 32))	('Cancers', 'Disease', (0, 7))	('proliferation', 'CPA', (48, 61))	('Cancers', 'Phenotype', 'HP:0002664', (0, 7))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('high', 'Var', (13, 17))	('cancer', 'Disease', (71, 77))	('SFN', 'Gene', (18, 21))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('SFN', 'Gene', '2810', (18, 21))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancers', 'Disease', 'MESH:D009369', (0, 7))	('SFN', 'Gene', (103, 106))	('tumor', 'Disease', (128, 133))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('SFN', 'Gene', '2810', (103, 106))	('increased', 'PosReg', (38, 47))	('drug resistance', 'Phenotype', 'HP:0020174', (78, 93))
287175	29085461	However, in our study, TP53 mutated tumors were associated with increased expression of DSC3, DSP, and JUP, which are three genes that encode desmosomal structural proteins, suggesting increased cell adhesion.	('expression', 'MPA', (74, 84))	('DSP', 'Gene', '1832', (94, 97))	('mutated', 'Var', (28, 35))	('increased', 'PosReg', (64, 73))	('tumors', 'Disease', 'MESH:D009369', (36, 42))	('DSP', 'Gene', (94, 97))	('DSC3', 'Gene', '1825', (88, 92))	('JUP', 'Gene', (103, 106))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('DSC3', 'Gene', (88, 92))	('TP53', 'Gene', '7157', (23, 27))	('TP53', 'Gene', (23, 27))	('JUP', 'Gene', '3728', (103, 106))	('tumors', 'Disease', (36, 42))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))
287181	29085461	HPV-related carcinogenesis is associated with TP53 inactivation, and thus many non-TP53 mutated tumors are HPV positive.	('TP53', 'Gene', '7157', (83, 87))	('HPV', 'Species', '10566', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('inactivation', 'Var', (51, 63))	('TP53', 'Gene', (83, 87))	('tumors', 'Disease', (96, 102))	('TP53', 'Gene', '7157', (46, 50))	('HPV', 'Species', '10566', (107, 110))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('TP53', 'Gene', (46, 50))	('HPV-related carcinogenesis', 'Disease', (0, 26))
287184	29085461	Staining was unevenly distributed in TP53 mutated tumors, with negative staining in the tumor center, but strongly positive staining in the tumor margins.	('TP53', 'Gene', (37, 41))	('mutated', 'Var', (42, 49))	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('TP53', 'Gene', '7157', (37, 41))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('positive', 'Reg', (115, 123))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumors', 'Disease', (50, 56))	('staining', 'MPA', (124, 132))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('tumor', 'Disease', (88, 93))	('tumor', 'Disease', (50, 55))	('tumor', 'Disease', (140, 145))
287186	29085461	In mutated tumors, TP53 degradation may be more likely, or synthesis may be inhibited, in the tumor center.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('synthesis', 'MPA', (59, 68))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumors', 'Phenotype', 'HP:0002664', (11, 17))	('tumor', 'Disease', (11, 16))	('tumor', 'Disease', (94, 99))	('tumors', 'Disease', (11, 17))	('tumors', 'Disease', 'MESH:D009369', (11, 17))	('TP53', 'Gene', '7157', (19, 23))	('TP53', 'Gene', (19, 23))	('inhibited', 'NegReg', (76, 85))	('tumor', 'Disease', 'MESH:D009369', (11, 16))	('degradation', 'MPA', (24, 35))	('mutated', 'Var', (3, 10))
287190	29085461	However, unlike complete regression of wild-type tumors, mutated tumors have some residual treatment-resistant tumor.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumor', 'Disease', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('tumor', 'Disease', (49, 54))	('tumor', 'Disease', (111, 116))	('tumors', 'Disease', (65, 71))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('tumors', 'Disease', (49, 55))	('tumors', 'Disease', 'MESH:D009369', (49, 55))	('type tumors', 'Disease', 'MESH:D009369', (44, 55))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('type tumors', 'Disease', (44, 55))	('mutated', 'Var', (57, 64))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
287191	29085461	This may be due to the heterogeneity of TP53 mutated tumors.	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('TP53', 'Gene', '7157', (40, 44))	('TP53', 'Gene', (40, 44))	('mutated', 'Var', (45, 52))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('tumors', 'Disease', (53, 59))
287192	29085461	Gain-of-function TP53 mutants have recently been shown to have upregulated chromatin regulatory genes that result in genome-wide increases in histone methylation and acetylation.	('acetylation', 'MPA', (166, 177))	('chromatin regulatory genes', 'Gene', (75, 101))	('Gain-of-function', 'PosReg', (0, 16))	('increases', 'PosReg', (129, 138))	('upregulated', 'PosReg', (63, 74))	('mutants', 'Var', (22, 29))	('histone methylation', 'MPA', (142, 161))	('TP53', 'Gene', '7157', (17, 21))	('TP53', 'Gene', (17, 21))
287194	29085461	Mutated TP53 can become a new transcription factor leading to transcription activation that does not occur with wild-type TP53.	('TP53', 'Gene', (122, 126))	('Mutated', 'Var', (0, 7))	('TP53', 'Gene', '7157', (8, 12))	('TP53', 'Gene', (8, 12))	('TP53', 'Gene', '7157', (122, 126))	('transcription activation', 'MPA', (62, 86))
287195	29085461	Thus this result suggested that TP53 mutation in tumors results in a tumor phenotype that is opposite to that of cancer progression and malignant transformation.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('mutation', 'Var', (37, 45))	('tumor', 'Disease', (69, 74))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('TP53', 'Gene', '7157', (32, 36))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('tumor', 'Disease', (49, 54))	('cancer', 'Disease', (113, 119))	('tumors', 'Disease', (49, 55))	('TP53', 'Gene', (32, 36))	('tumors', 'Disease', 'MESH:D009369', (49, 55))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('results in', 'Reg', (56, 66))
287214	32992741	miR105 from exosome is shown to downregulate ZO1, a tight junction protein that increases vascular permeability and helps in metastasis.	('downregulate', 'NegReg', (32, 44))	('helps', 'PosReg', (116, 121))	('miR105', 'Var', (0, 6))	('metastasis', 'CPA', (125, 135))	('increases', 'PosReg', (80, 89))	('miR105', 'Chemical', '-', (0, 6))	('ZO1', 'Gene', '7082', (45, 48))	('ZO1', 'Gene', (45, 48))	('vascular permeability', 'MPA', (90, 111))
287226	32992741	Thus, the overproduction of ROS increases stress in cells, which influences the exosomal release and autophagic activity.	('autophagic activity', 'CPA', (101, 120))	('ROS', 'Chemical', '-', (28, 31))	('influences', 'Reg', (65, 75))	('stress in', 'MPA', (42, 51))	('increases', 'PosReg', (32, 41))	('ROS', 'Gene', (28, 31))	('exosomal release', 'MPA', (80, 96))	('overproduction', 'Var', (10, 24))
287229	32992741	Any imbalance in stimuli or inflammation in the cornea may lead to neovascularization, causing opacity and vision loss.	('vision loss', 'Disease', 'MESH:D014786', (107, 118))	('inflammation', 'Disease', (28, 40))	('vision loss', 'Disease', (107, 118))	('causing', 'Reg', (87, 94))	('lead to', 'Reg', (59, 66))	('imbalance', 'Var', (4, 13))	('neovascularization', 'CPA', (67, 85))	('opacity', 'Disease', (95, 102))	('inflammation', 'Disease', 'MESH:D007249', (28, 40))	('vision loss', 'Phenotype', 'HP:0000572', (107, 118))	('imbalance', 'Phenotype', 'HP:0002172', (4, 13))
287245	32992741	The pathogenesis for UM involves genetic and molecular changes that include disruption in the Rb (retinoblastoma) tumor suppressor pathway, where cyclin D overexpression directly and the methylation and inactivation of the INK4A gene indirectly inactivate Rb by hyperphosphorylation.	('inactivate', 'NegReg', (245, 255))	('Rb (retinoblastoma) tumor', 'Disease', 'MESH:D012175', (94, 119))	('disruption', 'Reg', (76, 86))	('Rb', 'Gene', '5925', (256, 258))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('hyperphosphorylation', 'MPA', (262, 282))	('inactivation', 'Var', (203, 215))	('INK4A', 'Gene', '1029', (223, 228))	('retinoblastoma', 'Phenotype', 'HP:0009919', (98, 112))	('overexpression', 'PosReg', (155, 169))	('methylation', 'Var', (187, 198))	('UM', 'Phenotype', 'HP:0007716', (21, 23))	('INK4A', 'Gene', (223, 228))	('Rb', 'Gene', '5925', (94, 96))
287265	32992741	It occurs in two types: (1) Bilateral/multifocal (in both eyes), which is heritable, occurs because of germline mutation of the RB1 tumor suppressor gene in a developing retinal cell, and includes 25% of the total cases, and (2) Unilateral/unifocal (in one eye), which is non-heritable and includes 75% of all cases.	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('RB1', 'Gene', (128, 131))	('eyes', 'Disease', 'MESH:D000853', (58, 62))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('eyes', 'Disease', (58, 62))	('tumor', 'Disease', (132, 137))	('RB1', 'Gene', '5925', (128, 131))	('germline mutation', 'Var', (103, 120))	('RB', 'Phenotype', 'HP:0009919', (128, 130))
287266	32992741	Tumor formation is because of the loss of function mutation in both the alleles of the RB1 gene present in chromosome 13q.	('Tumor formation', 'CPA', (0, 15))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('RB1', 'Gene', (87, 90))	('loss of function', 'NegReg', (34, 50))	('RB1', 'Gene', '5925', (87, 90))	('mutation', 'Var', (51, 59))	('RB', 'Phenotype', 'HP:0009919', (87, 89))
287299	32992741	miR-182 alteration is related to cervical cancer pathogenesis and plays an oncogenic role involving apoptosis and cell cycle pathways.	('alteration', 'Var', (8, 18))	('cell cycle pathways', 'CPA', (114, 133))	('related', 'Reg', (22, 29))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('miR-182', 'Gene', (0, 7))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('miR-182', 'Gene', '406958', (0, 7))	('apoptosis', 'CPA', (100, 109))
287305	32992741	miR-30b-5p plays a role in the suppression of the tumor in esophageal squamous cell carcinoma.	('suppression', 'NegReg', (31, 42))	('miR-30b-5p', 'Chemical', '-', (0, 10))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (70, 93))	('esophageal squamous cell carcinoma', 'Disease', (59, 93))	('miR-30b-5p', 'Var', (0, 10))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Disease', (50, 55))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (59, 93))
287316	32992741	Another study has revealed the role of miR-582-5p as a tumor-suppressor in gastric cancer cell growth via targeting AKT3, suggesting it as a target for treatment as well as diagnosis of gastric cancer.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('gastric cancer', 'Disease', (186, 200))	('miR-582-5p', 'Var', (39, 49))	('gastric cancer', 'Disease', 'MESH:D013274', (186, 200))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('gastric cancer', 'Disease', (75, 89))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('targeting', 'Reg', (106, 115))	('miR-582-5p', 'Chemical', '-', (39, 49))	('gastric cancer', 'Disease', 'MESH:D013274', (75, 89))	('tumor', 'Disease', (55, 60))	('gastric cancer', 'Phenotype', 'HP:0012126', (186, 200))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('AKT3', 'Gene', (116, 120))	('gastric cancer', 'Phenotype', 'HP:0012126', (75, 89))	('AKT3', 'Gene', '10000', (116, 120))
287321	32992741	miR-483-5p, in coordination with miR-125-3p, is identified as a promoter of adipogenesis via the suppression of the RhoA/ROCK1/ERK1/2 pathway, and their studies may prove as a strategy to treat obesity or multiple symmetric lipomatosis (MSL).	('lipomatosis', 'Disease', 'MESH:D008068', (224, 235))	('miR-483-5p', 'Var', (0, 10))	('lipomatosis', 'Disease', (224, 235))	('suppression', 'NegReg', (97, 108))	('miR-125-3p', 'Gene', (33, 43))	('obesity', 'Disease', (194, 201))	('lipomatosis', 'Phenotype', 'HP:0001012', (224, 235))	('RhoA', 'Gene', (116, 120))	('ERK1/2', 'Gene', (127, 133))	('ROCK1', 'Gene', (121, 126))	('promoter', 'PosReg', (64, 72))	('ERK1/2', 'Gene', '5595;5594', (127, 133))	('obesity', 'Disease', 'MESH:D009765', (194, 201))	('miR-483-5p', 'Chemical', '-', (0, 10))	('adipogenesis', 'MPA', (76, 88))	('RhoA', 'Gene', '387', (116, 120))	('miR-125-3p', 'Gene', '100302208', (33, 43))	('ROCK1', 'Gene', '6093', (121, 126))	('obesity', 'Phenotype', 'HP:0001513', (194, 201))
287336	32992741	ATP6V1C1 controls tumor growth and bone metastasis, and the silencing of the gene suggests treatment and prevention strategies against cancer.	('cancer', 'Disease', (135, 141))	('tumor', 'Disease', (18, 23))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('ATP6V1C1', 'Gene', (0, 8))	('ATP6V1C1', 'Gene', '528', (0, 8))	('silencing', 'Var', (60, 69))	('bone metastasis', 'CPA', (35, 50))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('cancer', 'Disease', 'MESH:D009369', (135, 141))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
287339	32992741	Spectrin-associated protein 1 (Camsap1) is shown to be modulated by miR 26; this modulation alters the tumor microenvironment and inhibits metastasis.	('alters', 'Reg', (92, 98))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('miR', 'Gene', '220972', (68, 71))	('miR', 'Gene', (68, 71))	('tumor', 'Disease', (103, 108))	('metastasis', 'CPA', (139, 149))	('iron', 'Chemical', 'MESH:D007501', (117, 121))	('Camsap1', 'Gene', '157922', (31, 38))	('modulation', 'Var', (81, 91))	('Camsap1', 'Gene', (31, 38))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('inhibits', 'NegReg', (130, 138))
287346	32992741	KDM1B (flavin-dependent histone demethylases) knockdown shows to inhibit cellular proliferation and induce apoptotic activity in pancreatic cancer and suggests a role in prevention.	('cellular proliferation', 'CPA', (73, 95))	('pancreatic cancer', 'Disease', (129, 146))	('knockdown', 'Var', (46, 55))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (129, 146))	('KDM1B', 'Gene', (0, 5))	('KDM1B', 'Gene', '221656', (0, 5))	('induce', 'PosReg', (100, 106))	('flavin', 'Chemical', 'MESH:C024132', (7, 13))	('pancreatic cancer', 'Disease', 'MESH:D010190', (129, 146))	('inhibit', 'NegReg', (65, 72))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('apoptotic activity', 'CPA', (107, 125))
287384	32273729	Emerging evidence also suggests that abnormal expression of DPP9 may play a key role in the development and progression of cancer.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('si', 'Chemical', 'MESH:D012825', (115, 117))	('DPP9', 'Gene', (60, 64))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('cancer', 'Disease', (123, 129))	('si', 'Chemical', 'MESH:D012825', (52, 54))	('abnormal', 'Var', (37, 45))	('play', 'Reg', (69, 73))	('expression', 'MPA', (46, 56))
287397	32273729	To delete 624-704 (mFAP), we overlapped primers D and E. After using primers A and D, and primers B and C, respectively, to excise fragments F1 and F2, both fragments were added together as templates and used to clone out mFAP with primer A and primer E. These three fragments (wFAP, tFAP, mFAP) were cloned into plasmid pcDNA3.1(+) using restriction enzymes, BamHIand EcoRI.	('FAP', 'Gene', '2191', (20, 23))	('FAP', 'Gene', '2191', (279, 282))	('FAP', 'Gene', (291, 294))	('FAP', 'Gene', '2191', (285, 288))	('FAP', 'Gene', '2191', (223, 226))	('FAP', 'Gene', (285, 288))	('si', 'Chemical', 'MESH:D012825', (64, 66))	('FAP', 'Gene', (20, 23))	('FAP', 'Gene', (279, 282))	('delete', 'Var', (3, 9))	('FAP', 'Gene', (223, 226))	('FAP', 'Gene', '2191', (291, 294))	('si', 'Chemical', 'MESH:D012825', (334, 336))
287434	32273729	In SCC15 cell line transiently silence FAP showed higher DPP9 expression.	('higher', 'PosReg', (50, 56))	('FAP', 'Gene', (39, 42))	('silence', 'Var', (31, 38))	('DPP9', 'Gene', (57, 61))	('expression', 'MPA', (62, 72))	('si', 'Chemical', 'MESH:D012825', (23, 25))	('si', 'Chemical', 'MESH:D012825', (68, 70))	('si', 'Chemical', 'MESH:D012825', (31, 33))	('FAP', 'Gene', '2191', (39, 42))
287458	32273729	Taken together, these results suggested that DPP9 significantly attenuated cell growth in vitro.	('cell growth in vitro', 'CPA', (75, 95))	('si', 'Chemical', 'MESH:D012825', (50, 52))	('attenuated', 'NegReg', (64, 74))	('DPP9', 'Var', (45, 49))
287461	32273729	Immunoblotting showed DPP9-depletion can reduce E-cadherin, P53, phosphorylated-ERK 1/2, with increasing N-cadherin, MMP2, SAIL1 and SLUG, compared with no change of Vimentin and pan-ERK1/2 (Figure 4B).	('Vimentin', 'Gene', '7431', (166, 174))	('SAIL1', 'CPA', (123, 128))	('MMP2', 'Gene', '4313', (117, 121))	('ERK 1/2', 'Gene', '5595;5594', (80, 87))	('increasing', 'PosReg', (94, 104))	('SLUG', 'Gene', '6591', (133, 137))	('SLUG', 'Gene', (133, 137))	('Vimentin', 'Gene', (166, 174))	('ERK1/2', 'Gene', (183, 189))	('ERK1/2', 'Gene', '5595;5594', (183, 189))	('N-cadherin', 'Gene', (105, 115))	('P53', 'Gene', (60, 63))	('N-cadherin', 'Gene', '1000', (105, 115))	('E-cadherin', 'Gene', (48, 58))	('E-cadherin', 'Gene', '999', (48, 58))	('si', 'Chemical', 'MESH:D012825', (100, 102))	('DPP9-depletion', 'Var', (22, 36))	('ERK 1/2', 'Gene', (80, 87))	('P53', 'Gene', '7157', (60, 63))	('MMP2', 'Gene', (117, 121))	('reduce', 'NegReg', (41, 47))
287463	32273729	Tumor generation speed of si-DPP9 cells was significantly faster than in control cells, and final volume/weight (20 days) of si-DPP9 group is significantly larger (Figure 5A).	('faster', 'PosReg', (58, 64))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('si', 'Chemical', 'MESH:D012825', (142, 144))	('larger', 'PosReg', (156, 162))	('si-DPP9', 'Var', (125, 132))	('si', 'Chemical', 'MESH:D012825', (26, 28))	('si', 'Chemical', 'MESH:D012825', (44, 46))	('Tumor generation speed', 'CPA', (0, 22))	('si-DPP9', 'Var', (26, 33))	('si', 'Chemical', 'MESH:D012825', (125, 127))
287464	32273729	The EMT-associated protein in si-DPP9 group change similarly with treated cells in vitro compared with the untreated group by WB (Figure 5B).	('EMT-associated protein', 'Protein', (4, 26))	('si', 'Chemical', 'MESH:D012825', (30, 32))	('si-DPP9', 'Var', (30, 37))	('si', 'Chemical', 'MESH:D012825', (51, 53))
287467	32273729	CCK8 assay and colony formation assay demonstrated that the DPP9 plasmid decreased the cell proliferation and tumorigenesis (Figure 6B and D).	('decreased', 'NegReg', (73, 82))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('si', 'Chemical', 'MESH:D012825', (120, 122))	('cell proliferation', 'CPA', (87, 105))	('tumor', 'Disease', (110, 115))	('DPP9', 'Var', (60, 64))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
287468	32273729	Consistently, cells numbers of DPP9 plasmid treated cells of migration and invasion was reduced (Figure 6C).	('reduced', 'NegReg', (88, 95))	('si', 'Chemical', 'MESH:D012825', (3, 5))	('DPP9 plasmid treated', 'Var', (31, 51))	('si', 'Chemical', 'MESH:D012825', (79, 81))
287470	32273729	And Adhesion assay showed DPP9 transfection can furtherly reduce the adhesion ability of cells.	('adhesion ability of cells', 'CPA', (69, 94))	('si', 'Chemical', 'MESH:D012825', (73, 75))	('si', 'Chemical', 'MESH:D012825', (8, 10))	('DPP9 transfection', 'Var', (26, 43))	('reduce', 'NegReg', (58, 64))
287476	32273729	Overexpression of FAP and expression of mutant FAP, both displayed enhanced cancer phenotypes with no significant differences between the groups.	('FAP', 'Gene', '2191', (47, 50))	('si', 'Chemical', 'MESH:D012825', (32, 34))	('FAP', 'Gene', '2191', (18, 21))	('FAP', 'Gene', (47, 50))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('mutant', 'Var', (40, 46))	('si', 'Chemical', 'MESH:D012825', (102, 104))	('FAP', 'Gene', (18, 21))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('si', 'Chemical', 'MESH:D012825', (10, 12))	('enhanced', 'PosReg', (67, 75))
287488	32273729	On the one hand, Lu et al found DPP9 may act as a survival factor for cells from the Ewing's sarcoma family of tumors cells.	("Ewing's sarcoma", 'Disease', (85, 100))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumors', 'Disease', 'MESH:D009369', (111, 117))	('tumors', 'Disease', (111, 117))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('sarcoma', 'Phenotype', 'HP:0100242', (93, 100))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (85, 100))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (85, 100))	('DPP9', 'Var', (32, 36))
287501	32273729	It can be observed that enforcing DPP9 expression in SCC9-FAP+ cells can reverse tumor growth, migration, invasion and EMT-biomarkers.	('FAP', 'Gene', '2191', (58, 61))	('enforcing', 'Var', (24, 33))	('reverse', 'PosReg', (73, 80))	('si', 'Chemical', 'MESH:D012825', (110, 112))	('SCC9', 'CellLine', 'CVCL:1685', (53, 57))	('expression', 'Var', (39, 49))	('invasion', 'CPA', (106, 114))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('FAP', 'Gene', (58, 61))	('DPP9', 'Gene', (34, 38))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('migration', 'CPA', (95, 104))	('EMT-biomarkers', 'CPA', (119, 133))	('si', 'Chemical', 'MESH:D012825', (45, 47))	('tumor', 'Disease', (81, 86))
287509	31551362	Forced expression of p63 downregulated Brn2 in the 'neural' LUSC cells and invoked the classical LUSC lineage with more squamous/epithelial features, which were accompanied by increased activities of ErbB/Akt and MAPK-ERK pathways suggesting differential dependency.	('ErbB', 'Gene', '1956', (200, 204))	('MAPK-ERK pathways', 'Pathway', (213, 230))	('ErbB', 'Gene', (200, 204))	('increased', 'PosReg', (176, 185))	('LUSC', 'Phenotype', 'HP:0030359', (97, 101))	('activities', 'MPA', (186, 196))	('LUSC', 'Phenotype', 'HP:0030359', (60, 64))	('downregulated', 'NegReg', (25, 38))	('squamous/epithelial features', 'CPA', (120, 148))	('p63', 'Var', (21, 24))	('Brn2', 'Gene', (39, 43))	('classical LUSC lineage', 'CPA', (87, 109))	('invoked', 'PosReg', (75, 82))
287527	31551362	Fragmented chromatin was diluted in IP buffer (20 mM Tris-HCl pH 8.1, 150 mM NaCl, 2 mM EDTA, 1% Triton X-100) and incubated overnight at 4 C with Protein G magnetic beads (Dynabeads: ThemoFisher) that had been pre-incubated with anti-H3K27ac (Abcam, ab4729) or anti-Sox2 (R&D, AF2018) or anti-p63 (Santa Cruz, sc-8431) antibodies.	('anti-H3K27ac', 'Var', (230, 242))	('NaCl', 'Chemical', 'MESH:D012965', (77, 81))	('anti-Sox2', 'Protein', (262, 271))	('EDTA', 'Chemical', 'MESH:D004492', (88, 92))	('Triton X-100', 'Chemical', 'MESH:D017830', (97, 109))	('Tris', 'Chemical', '-', (53, 57))	('HCl', 'Chemical', 'MESH:D006851', (58, 61))
287535	31551362	ChIP signals for each sample were visualized on integrative genome viewer (IGV) genome browser using wiggle files with a 10 bp resolution for H3K27ac modification generated by MACS with tag shift that was rescaled to normalize to a total number of uniquely alignable sequences by WigMath function of Java-Genomic Toolkit.	('kit', 'Gene', (317, 320))	('H3K27ac', 'Var', (142, 149))	('kit', 'Gene', '3815', (317, 320))
287550	31551362	Hierarchical clustering of the LUSC tumors (n=416) was performed using the differentially expressed genes between POU3F2-high/ TP63-low and POU3F2-low/ TP63-high tumors with complete-linkage clustering (Fig.	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('LUSC', 'Phenotype', 'HP:0030359', (31, 35))	('tumors', 'Disease', 'MESH:D009369', (36, 42))	('POU3F2-high/ TP63-low', 'Var', (114, 135))	('LUSC tumors', 'Disease', 'MESH:D009369', (31, 42))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))	('tumors', 'Disease', (162, 168))	('tumors', 'Disease', 'MESH:D009369', (162, 168))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('POU3F2-low/ TP63-high', 'Var', (140, 161))	('tumors', 'Disease', (36, 42))	('LUSC tumors', 'Disease', (31, 42))
287585	31551362	T-test was performed to identify differentially expressed genes between POU3F2-high/ TP63-low and POU3F2-low/ TP63-high tumors based on cutoffs of fold change>2 and FDR<0.01.	('POU3F2-high/ TP63-low', 'Var', (72, 93))	('tumors', 'Disease', 'MESH:D009369', (120, 126))	('tumors', 'Disease', (120, 126))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('POU3F2-low/ TP63-high', 'Var', (98, 119))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))
287602	31551362	To investigate the difference in gene signatures between POU3F2-expressing LUSC tumors and TP63-expressing LUSC tumors, we next performed differential expression analysis in the TCGA-LUSC dataset comparing POU3F2-high/ TP63-low tumors vs. TP63-high/ POU3F2-low tumors (Fig.	('LUSC', 'Phenotype', 'HP:0030359', (183, 187))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumors', 'Phenotype', 'HP:0002664', (261, 267))	('tumors', 'Disease', (80, 86))	('tumors', 'Phenotype', 'HP:0002664', (228, 234))	('tumors', 'Disease', 'MESH:D009369', (112, 118))	('LUSC tumors', 'Disease', 'MESH:D009369', (75, 86))	('tumor', 'Phenotype', 'HP:0002664', (261, 266))	('tumors', 'Disease', (261, 267))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('tumors', 'Disease', (228, 234))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('LUSC tumors', 'Disease', 'MESH:D009369', (107, 118))	('POU3F2-high/ TP63-low', 'Var', (206, 227))	('tumors', 'Disease', 'MESH:D009369', (261, 267))	('LUSC tumors', 'Disease', (75, 86))	('tumors', 'Disease', 'MESH:D009369', (228, 234))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('LUSC tumors', 'Disease', (107, 118))	('LUSC', 'Phenotype', 'HP:0030359', (107, 111))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('LUSC', 'Phenotype', 'HP:0030359', (75, 79))	('tumors', 'Disease', (112, 118))
287603	31551362	A functional enrichment analysis of differentially expressed genes identified genes which play roles in neural cell differentiation significantly enriched in POU3F2-high/ TP63-low tumors while those involved in epithelial/ epidermal cell differentiation were significantly enriched in TP63-high/ POU3F2-low tumors (Fig.	('tumors', 'Phenotype', 'HP:0002664', (307, 313))	('neural cell differentiation', 'CPA', (104, 131))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('tumor', 'Phenotype', 'HP:0002664', (307, 312))	('tumors', 'Phenotype', 'HP:0002664', (180, 186))	('tumors', 'Disease', (180, 186))	('tumors', 'Disease', 'MESH:D009369', (180, 186))	('tumors', 'Disease', 'MESH:D009369', (307, 313))	('POU3F2-high/ TP63-low', 'Var', (158, 179))	('tumors', 'Disease', (307, 313))
287604	31551362	Further, we evaluated the prognostic significance of TP63/ POU3F2 expression status in the TCGA-LUSC dataset and found that patients with POU3F2-high/ TP63-low tumors showed significantly shorter survival compared to those with TP63-high/ POU3F2-low tumors, suggesting clinically distinct, aggressive features of this 'neural' subtype (Fig.	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('tumors', 'Disease', 'MESH:D009369', (160, 166))	('LUSC', 'Phenotype', 'HP:0030359', (96, 100))	('POU3F2-high/ TP63-low', 'Var', (138, 159))	('tumors', 'Phenotype', 'HP:0002664', (250, 256))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('tumor', 'Phenotype', 'HP:0002664', (250, 255))	('survival', 'MPA', (196, 204))	('tumors', 'Disease', (160, 166))	('tumors', 'Disease', 'MESH:D009369', (250, 256))	('tumors', 'Disease', (250, 256))	('patients', 'Species', '9606', (124, 132))	('shorter', 'NegReg', (188, 195))
287605	31551362	When we examined the relationship between these POU3F2-high/ TP63-low tumors and the LUSC expression subtypes, consistent with the report in which the 'neural' LK2 and NCI-H520 cells were predicted as primitive , all of the POU3F2-high/ TP63-low tumors were classified as the primitive subtype (Supplementary Fig.	('POU3F2-high/ TP63-low', 'Var', (224, 245))	('tumors', 'Phenotype', 'HP:0002664', (246, 252))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('NCI-H520', 'CellLine', 'CVCL:1566', (168, 176))	('tumors', 'Disease', (70, 76))	('tumors', 'Disease', 'MESH:D009369', (70, 76))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('tumors', 'Disease', (246, 252))	('LUSC', 'Phenotype', 'HP:0030359', (85, 89))	('tumors', 'Disease', 'MESH:D009369', (246, 252))
287609	31551362	Therefore, to determine whether p63 has any effects on Brn2 or vice versa, we first overexpressed deltaNp63-alpha (DNp63), the predominant isoform in squamous lineages including the normal squamous basal layers and squamous cell cancers (Supplementary Fig.	('cancers', 'Phenotype', 'HP:0002664', (229, 236))	('deltaNp63-alpha', 'Var', (98, 113))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('effects', 'Reg', (44, 51))	('squamous cell cancers', 'Disease', (215, 236))	('DNp63', 'Chemical', '-', (115, 120))	('squamous cell cancers', 'Phenotype', 'HP:0002860', (215, 236))	('squamous cell cancers', 'Disease', 'MESH:D002294', (215, 236))
287610	31551362	Introduction of DNp63 substantially suppressed Brn2 expression, while it also suppressed expression of Sox2 to a lesser extent in these cells (Fig.	('suppressed', 'NegReg', (36, 46))	('expression', 'MPA', (89, 99))	('suppressed', 'NegReg', (78, 88))	('expression', 'MPA', (52, 62))	('DNp63', 'Var', (16, 21))	('Brn2', 'Gene', (47, 51))	('DNp63', 'Chemical', '-', (16, 21))
287616	31551362	Notably, patches of p63-negative tumor cells in DNp63-overexpressed xenograft tumor shows reduced expression of Brn2 and Sox2 (Supplementary Fig.	('reduced', 'NegReg', (90, 97))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('Sox2', 'Gene', (121, 125))	('Brn2', 'Gene', (112, 116))	('DNp63', 'Chemical', '-', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumor', 'Disease', (33, 38))	('tumor', 'Disease', (78, 83))	('DNp63-overexpressed', 'Var', (48, 67))	('expression', 'MPA', (98, 108))
287617	31551362	S4F and S4G), likely due to imperfect selection or heterogeneous ectopic expression of DNp63, exhibiting a clear effect of DNp63 on suppressing Brn2.	('DNp63', 'Chemical', '-', (123, 128))	('DNp63', 'Chemical', '-', (87, 92))	('DNp63', 'Gene', (87, 92))	('Brn2', 'MPA', (144, 148))	('suppressing', 'NegReg', (132, 143))	('S4G', 'Var', (8, 11))
287618	31551362	Morphologically, p63-positive tumor cells showed open chromatin, larger nucleoli, and on average, had a polygonal shape and more cytoplasm indicative of more classical squamous cell carcinoma histology while p63-negative/ Brn2-positive cells have a slightly oval shape, less cytoplasm, denser chromatin and less frequent/smaller nucleoli (Fig.	('squamous cell carcinoma', 'Disease', (168, 191))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (168, 191))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('p63-positive', 'Var', (17, 29))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('carcinoma', 'Phenotype', 'HP:0030731', (182, 191))	('tumor', 'Disease', (30, 35))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (168, 191))
287619	31551362	These results suggest that DNp63 counteracts with Brn2 and induces a different tumor state characterized by more squamous/epithelial features of the cells.	('squamous/epithelial features of the cells', 'CPA', (113, 154))	('DNp63', 'Var', (27, 32))	('tumor', 'Disease', (79, 84))	('DNp63', 'Chemical', '-', (27, 32))	('induces', 'Reg', (59, 66))	('more', 'PosReg', (108, 112))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
287620	31551362	1E) and DNp63 induction suppressed SOX2 expression in the same subset (Fig.	('SOX2', 'Protein', (35, 39))	('DNp63', 'Var', (8, 13))	('DNp63', 'Chemical', '-', (8, 13))	('suppressed', 'NegReg', (24, 34))
287623	31551362	S6A) showed that DNp63-overexpressed LK2 cells were indeed closer to the classical LUSC cells compared to the control LK2 cells, or located between the control LK2 cells and the classical LUSC cells.	('LUSC', 'Phenotype', 'HP:0030359', (83, 87))	('LK2', 'Gene', (37, 40))	('DNp63', 'Chemical', '-', (17, 22))	('closer', 'PosReg', (59, 65))	('LUSC', 'Phenotype', 'HP:0030359', (188, 192))	('DNp63-overexpressed', 'Var', (17, 36))
287628	31551362	When we examined whether DNp63 introduction resulted in reduced super-enhancer activities specific to the 'neural' LUSC cells, we found H3K27ac signals indeed decreased in 5 out of 7 common super-enhancers exclusive to the 'neural' LUSC lines including POU3F2 and SOX2 super-enhancers (Supplementary Fig.	('activities', 'MPA', (79, 89))	('DNp63', 'Var', (25, 30))	('reduced', 'NegReg', (56, 63))	('H3K27ac signals', 'MPA', (136, 151))	('LUSC', 'Phenotype', 'HP:0030359', (115, 119))	('decreased', 'NegReg', (159, 168))	('DNp63', 'Chemical', '-', (25, 30))	('LUSC', 'Phenotype', 'HP:0030359', (232, 236))
287629	31551362	S7B), suggesting DNp63 contributes to suppress the original lineage program of the 'neural' LUSC cells.	('LUSC', 'Phenotype', 'HP:0030359', (92, 96))	('DNp63', 'Chemical', '-', (17, 22))	('suppress', 'NegReg', (38, 46))	('DNp63', 'Var', (17, 22))
287631	31551362	We found that while average ChIP-seq signals of all the Sox2 peaks decreased in the DNp63-overexpressed cells compared to the control LK2 cells, the DNp63-overexpressed cells showed increased signals near the Sox2 peaks exclusive to the 'classical' LUSC lines (Fig.	('Sox2 peaks', 'MPA', (209, 219))	('increased', 'PosReg', (182, 191))	('signals', 'MPA', (192, 199))	('DNp63-overexpressed', 'Var', (84, 103))	('LUSC', 'Phenotype', 'HP:0030359', (249, 253))	('DNp63', 'Chemical', '-', (149, 154))	('decreased', 'NegReg', (67, 76))	('DNp63', 'Chemical', '-', (84, 89))
287632	31551362	6C), suggesting that presence of DNp63 re-engages Sox2 cistrome in the 'classical' LUSC cells specific Sox2-binding regions (Fig.	('LUSC', 'Phenotype', 'HP:0030359', (83, 87))	('DNp63', 'Var', (33, 38))	('Sox2 cistrome', 'Enzyme', (50, 63))	('re-engages', 'PosReg', (39, 49))	('DNp63', 'Chemical', '-', (33, 38))	('presence', 'Var', (21, 29))
287634	31551362	These findings suggest that DNp63 overrides Sox2's transcriptional programs in the 'neural' state to redefine it into 'classical' squamous-cell state via superseding Brn2 as a Sox2 partner.	('overrides', 'PosReg', (34, 43))	('DNp63', 'Chemical', '-', (28, 33))	('transcriptional programs', 'MPA', (51, 75))	('Sox2', 'Gene', (44, 48))	('DNp63', 'Var', (28, 33))
287638	31551362	In contrast, ErbB4 phosphorylation was diminished and instead higher signals of ErbB3 phosphorylation emerged in the DNp63-overexpressed cells.	('ErbB3', 'Gene', '2065', (80, 85))	('diminished', 'NegReg', (39, 49))	('ErbB4', 'Gene', (13, 18))	('ErbB4', 'Gene', '2066', (13, 18))	('DNp63', 'Chemical', '-', (117, 122))	('phosphorylation', 'MPA', (86, 101))	('higher', 'PosReg', (62, 68))	('ErbB3', 'Gene', (80, 85))	('DNp63-overexpressed', 'Var', (117, 136))
287640	31551362	This line of experiments revealed that diminished phosphorylation of ErbB4 upon DNp63 overexpression was a consequence of suppressed ErbB4 protein level.	('diminished', 'NegReg', (39, 49))	('phosphorylation', 'MPA', (50, 65))	('suppressed', 'NegReg', (122, 132))	('ErbB4', 'Gene', (69, 74))	('overexpression', 'Var', (86, 100))	('ErbB4', 'Gene', '2066', (69, 74))	('protein level', 'MPA', (139, 152))	('ErbB4', 'Gene', '2066', (133, 138))	('ErbB4', 'Gene', (133, 138))	('DNp63', 'Chemical', '-', (80, 85))	('DNp63', 'Gene', (80, 85))
287641	31551362	In contrast, expression levels of ErbB3 are similar between DNp63 overexpressed and control cell lines while its activity was significantly increased upon DNp63 overexpression under the same growth condition (10% FBS) (Supplementary Fig.	('DNp63', 'Chemical', '-', (60, 65))	('overexpression', 'Var', (161, 175))	('ErbB3', 'Gene', (34, 39))	('ErbB3', 'Gene', '2065', (34, 39))	('DNp63', 'Chemical', '-', (155, 160))	('DNp63', 'Var', (60, 65))	('activity', 'MPA', (113, 121))	('DNp63', 'Gene', (155, 160))	('increased', 'PosReg', (140, 149))
287643	31551362	Indeed, we observed increased protein level of EGFR upon DNp63 overexpression, and in response to NRG1 stimulation, phosphorylation of ErbB3 and EGFR increased to even higher level in the DNp63-overexpressed cells (Fig.	('increased', 'PosReg', (20, 29))	('DNp63', 'Chemical', '-', (57, 62))	('DNp63 overexpression', 'Var', (57, 77))	('phosphorylation', 'MPA', (116, 131))	('DNp63', 'Chemical', '-', (188, 193))	('overexpression', 'Var', (63, 77))	('increased', 'PosReg', (150, 159))	('ErbB3', 'Gene', (135, 140))	('ErbB3', 'Gene', '2065', (135, 140))	('EGFR', 'Protein', (47, 51))	('protein level', 'MPA', (30, 43))
287648	31551362	In contrast, Erk1/2 phosphorylation levels were higher in the DNp63-overexpressed cells, but did not change after NRG1 stimulation, suggesting that the activation of MAPK-ERK pathway by DNp63 overexpression was independent from the phosphorylation of ErbB3 and EGFR.	('Erk1/2', 'Gene', (13, 19))	('ErbB3', 'Gene', (251, 256))	('ErbB3', 'Gene', '2065', (251, 256))	('DNp63', 'Chemical', '-', (62, 67))	('phosphorylation levels', 'MPA', (20, 42))	('higher', 'PosReg', (48, 54))	('DNp63', 'Chemical', '-', (186, 191))	('DNp63-overexpressed', 'Var', (62, 81))	('DNp63', 'Gene', (186, 191))	('MAPK-ERK pathway', 'Pathway', (166, 182))	('Erk1/2', 'Gene', '5595;5594', (13, 19))
287656	31551362	Sox2 has been described to have a role in determining cell differentiation states by cooperating with other lineage factors such as Oct4 in embryonic stem cells, Pax6 in eye lens development , p63 in squamous lineages and Brn2 in neural progenitor cells.	('Sox2', 'Gene', (0, 4))	('p63', 'Var', (193, 196))	('eye lens development', 'CPA', (170, 190))	('Pax6', 'Gene', (162, 166))	('Pax6', 'Gene', '25509', (162, 166))	('cooperating', 'Reg', (85, 96))	('Brn2', 'Gene', (222, 226))
287657	31551362	It suggests that rather than playing a role as a general oncogene, p63 defines more squamous differentiation states and the lineage program of this Brn2-positive 'neural' LUSC could lead to more aggressive phenotypes as cancer cells compared to that of the classical LUSC defined by p63.	('more', 'PosReg', (190, 194))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('p63', 'Var', (67, 70))	('aggressive phenotypes', 'CPA', (195, 216))	('lead to', 'Reg', (182, 189))	('Brn2-positive', 'Gene', (148, 161))	('LUSC', 'Phenotype', 'HP:0030359', (267, 271))	('cancer', 'Disease', 'MESH:D009369', (220, 226))	('squamous differentiation states', 'CPA', (84, 115))	('cancer', 'Disease', (220, 226))	('LUSC', 'Phenotype', 'HP:0030359', (171, 175))
287658	31551362	We also observed a change of RTK signaling activity profile through a shift in cell differentiation states induced by p63.	('change', 'Reg', (19, 25))	('p63', 'Var', (118, 121))	('RTK', 'Gene', (29, 32))	('cell differentiation states', 'CPA', (79, 106))	('shift', 'Reg', (70, 75))	('RTK', 'Gene', '5979', (29, 32))
287659	31551362	It has been reported that p63 regulates a various signaling pathway molecules depending on cell contexts such as beta-catenin, EGFR and Jagged1 in human airway epithelial basal cells, FGFR2 in murine squamous cell carcinoma model and NRG1 in mammary basal cells .	('Jagged1', 'Gene', '182', (136, 143))	('murine', 'Species', '10090', (193, 199))	('human', 'Species', '9606', (147, 152))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (200, 223))	('carcinoma', 'Phenotype', 'HP:0030731', (214, 223))	('squamous cell carcinoma', 'Disease', (200, 223))	('regulates', 'Reg', (30, 39))	('FGFR2', 'Gene', (184, 189))	('Jagged1', 'Gene', (136, 143))	('NRG1', 'Gene', (234, 238))	('signaling pathway', 'Pathway', (50, 67))	('p63', 'Var', (26, 29))	('beta-catenin', 'Gene', (113, 125))	('FGFR2', 'Gene', '2263', (184, 189))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (200, 223))	('EGFR', 'Gene', (127, 131))	('beta-catenin', 'Gene', '1499', (113, 125))
287674	30912749	Upon comparison with The Cancer Genome Atlas data, a clinically actionable mutation, p.Leu858Arg, in the EGFR gene was 6.64 times more frequent in the Ajou University School of Medicine database, while the p.Gly12Xaa mutation in the KRAS gene was 2.02 times more frequent in The Cancer Genome Atlas dataset.	('p.Leu858Arg', 'Mutation', 'rs121434568', (85, 96))	('KRAS', 'Gene', '3845', (233, 237))	('p.Gly12Xaa', 'Mutation', 'p.G12X', (206, 216))	('p.Gly12Xaa', 'Var', (206, 216))	('EGFR', 'Gene', '1956', (105, 109))	('p.Leu858Arg', 'Var', (85, 96))	('Cancer', 'Phenotype', 'HP:0002664', (25, 31))	('Cancer Genome Atlas', 'Disease', (25, 44))	('Cancer Genome Atlas', 'Disease', (279, 298))	('EGFR', 'Gene', (105, 109))	('Cancer', 'Phenotype', 'HP:0002664', (279, 285))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (25, 44))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (279, 298))	('KRAS', 'Gene', (233, 237))
287692	30912749	There are various types (>50) of public cancer databases describing variants, including comprehensive cancer projects, resources, and cancer type-specific databases .	('variants', 'Var', (68, 76))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('public cancer', 'Disease', 'MESH:D009369', (33, 46))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('cancer', 'Disease', (40, 46))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('public cancer', 'Disease', (33, 46))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))
287694	30912749	The database TCGA provides large-scale datasets of genomic alterations, including insertions/deletions (INDELs) or single nucleotide polymorphisms (SNPs), discovered in over 30 human tumor types to generate comprehensive profiles of cancer genomics.	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('single nucleotide polymorphisms', 'Var', (115, 146))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('cancer', 'Disease', (233, 239))	('cancer', 'Disease', 'MESH:D009369', (233, 239))	('INDEL', 'Chemical', '-', (104, 109))	('tumor', 'Disease', (183, 188))	('human', 'Species', '9606', (177, 182))	('insertions/deletions', 'Var', (82, 102))
287695	30912749	The database Catalogue of Somatic Mutations in Cancer provides somatic mutations across 1,391,372 tumor samples encompassing 5,977,977 coding mutations as of August 2018, while the database International Cancer Genome Consortium provides the datasets of oncogenic mutations of 50 different cancer types to support large-scale studies.	('cancer', 'Disease', 'MESH:D009369', (290, 296))	('Cancer', 'Phenotype', 'HP:0002664', (47, 53))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('cancer', 'Disease', (290, 296))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('mutations', 'Var', (71, 80))	('Mutations', 'Var', (34, 43))	('tumor', 'Disease', (98, 103))	('cancer', 'Phenotype', 'HP:0002664', (290, 296))	('Cancer', 'Phenotype', 'HP:0002664', (204, 210))
287720	30912749	Therefore, the proportions of actionable mutations in these five genes were compared between the two databases and between the subtypes of lung cancer.	('lung cancer', 'Disease', (139, 150))	('mutations', 'Var', (41, 50))	('lung cancer', 'Disease', 'MESH:D008175', (139, 150))	('lung cancer', 'Phenotype', 'HP:0100526', (139, 150))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
287723	30912749	Users can also freely explore the proportion of patients with mutations in specific genes or specific variants and can download the results as a plot or table to conduct distributed research.	('variants', 'Var', (102, 110))	('patients', 'Species', '9606', (48, 56))	('mutations', 'Var', (62, 71))
287725	30912749	In the AUSOM database, the top 10 genes had a variant frequency > 75% among patients with lung cancer, whereas only one gene, TP53, had a variant frequency > 25% in the TCGA database.	('lung cancer', 'Disease', 'MESH:D008175', (90, 101))	('patients', 'Species', '9606', (76, 84))	('variant', 'Var', (46, 53))	('TP53', 'Gene', (126, 130))	('lung cancer', 'Disease', (90, 101))	('lung cancer', 'Phenotype', 'HP:0100526', (90, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('TP53', 'Gene', '7157', (126, 130))
287726	30912749	In particular, EGFR variants showed very different frequencies in the AUSOM and TCGA databases (89.5% and 11.5%, respectively).	('EGFR', 'Gene', '1956', (15, 19))	('EGFR', 'Gene', (15, 19))	('variants', 'Var', (20, 28))
287727	30912749	In contrast, comparison of the waterfall plot of all 49 genes targeted in the cancer panel of the AUSOM database to that of the same gene set of the TCGA database showed a higher frequency of frameshift and nonsense type variants than splice type variants in the TCGA data, although the ranking of genes with more variants still differed between the two databases (Multimedia Appendix 8).	('nonsense type variants', 'Var', (207, 229))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('frameshift', 'Var', (192, 202))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))
287729	30912749	An actionable mutation is a specific genomic event that potentially affects a patient's response to a targeted therapy.	('patient', 'Species', '9606', (78, 85))	('response', 'MPA', (88, 96))	('affects', 'Reg', (68, 75))	('mutation', 'Var', (14, 22))	('actionable', 'Reg', (3, 13))
287730	30912749	Of the five representative actionable mutations for NSCLC examined (EGFR, KRAS, PIK3CA, BRAF, and NRAS), EGFR showed the greatest frequency of variants in the AUSOM database (21.9%), while KRAS showed the greatest frequency of variants in the TCGA database (20.2%; Figure 4a).	('KRAS', 'Gene', (189, 193))	('BRAF', 'Gene', (88, 92))	('BRAF', 'Gene', '673', (88, 92))	('NRAS', 'Gene', (98, 102))	('EGFR', 'Gene', (105, 109))	('KRAS', 'Gene', '3845', (74, 78))	('PIK3CA', 'Gene', '5290', (80, 86))	('NSCLC', 'Disease', 'MESH:D002289', (52, 57))	('KRAS', 'Gene', (74, 78))	('EGFR', 'Gene', '1956', (68, 72))	('variants', 'Var', (143, 151))	('AUSOM database', 'Gene', (159, 173))	('NSCLC', 'Disease', (52, 57))	('EGFR', 'Gene', '1956', (105, 109))	('PIK3CA', 'Gene', (80, 86))	('NRAS', 'Gene', '4893', (98, 102))	('NSCLC', 'Phenotype', 'HP:0030358', (52, 57))	('KRAS', 'Gene', '3845', (189, 193))	('EGFR', 'Gene', (68, 72))
287731	30912749	In particular, the point mutation p.Leu858Arg in EGFR was found in 17.5% of the patients, followed by p.Thr790Met (1.8%) in the AUSOM database (Figure 4b).	('EGFR', 'Gene', '1956', (49, 53))	('patients', 'Species', '9606', (80, 88))	('p.Thr790Met', 'Var', (102, 113))	('p.Leu858Arg', 'Mutation', 'rs121434568', (34, 45))	('EGFR', 'Gene', (49, 53))	('p.Thr790Met', 'Mutation', 'rs121434569', (102, 113))	('p.Leu858Arg', 'Var', (34, 45))
287732	30912749	Point mutations in the KRAS gene, such as p.Gly12Xaa and p.Gly13Xaa, were more frequent in the TCGA database (20.2%) than in the AUSOM database (9.7%; Figure 4a,c).	('p.Gly12Xaa', 'Mutation', 'p.G12X', (42, 52))	('p.Gly12Xaa', 'Var', (42, 52))	('KRAS', 'Gene', (23, 27))	('p.Gly13Xaa', 'Mutation', 'p.G13X', (57, 67))	('KRAS', 'Gene', '3845', (23, 27))	('p.Gly13Xaa', 'Var', (57, 67))
287737	30912749	Indeed, the total number of variants per patient was much higher for the AUSOM database than for the TCGA database, whereas the frequency of variants differed according to the variant type considered.	('patient', 'Species', '9606', (41, 48))	('higher', 'Reg', (58, 64))	('AUSOM', 'Disease', (73, 78))	('variants', 'Var', (28, 36))
287738	30912749	Comparison of actionable mutations in five genes of NSCLC showed a much higher mutation frequency of EGFR in the AUSOM database (a cohort of Asian patients) than in the TCGA database (a cohort of American patients).	('patients', 'Species', '9606', (205, 213))	('NSCLC', 'Disease', (52, 57))	('EGFR', 'Gene', '1956', (101, 105))	('EGFR', 'Gene', (101, 105))	('NSCLC', 'Disease', 'MESH:D002289', (52, 57))	('patients', 'Species', '9606', (147, 155))	('mutation', 'Var', (79, 87))	('higher', 'PosReg', (72, 78))	('NSCLC', 'Phenotype', 'HP:0030358', (52, 57))
287739	30912749	This finding is in line with previous knowledge that Asian patients with NSCLC have a higher prevalence of EGFR mutations than Americans.	('EGFR', 'Gene', '1956', (107, 111))	('EGFR', 'Gene', (107, 111))	('mutations', 'Var', (112, 121))	('NSCLC', 'Disease', (73, 78))	('patients', 'Species', '9606', (59, 67))	('NSCLC', 'Disease', 'MESH:D002289', (73, 78))	('NSCLC', 'Phenotype', 'HP:0030358', (73, 78))
287740	30912749	In contrast, actionable mutations in the KRAS gene were less prevalent in patients in the AUSOM database than in those in the TCGA database, which is also consistent with previous knowledge that Asian populations have a much lower rate of mutations in KRAS than non-Asian populations with NSCLC.	('less', 'NegReg', (56, 60))	('NSCLC', 'Phenotype', 'HP:0030358', (289, 294))	('KRAS', 'Gene', '3845', (41, 45))	('AUSOM', 'Disease', (90, 95))	('patients', 'Species', '9606', (74, 82))	('NSCLC', 'Disease', (289, 294))	('mutations', 'Var', (239, 248))	('KRAS', 'Gene', (252, 256))	('lower', 'NegReg', (225, 230))	('NSCLC', 'Disease', 'MESH:D002289', (289, 294))	('mutations', 'Var', (24, 33))	('KRAS', 'Gene', (41, 45))	('KRAS', 'Gene', '3845', (252, 256))
287758	30912749	Overall mutation profile of lung cancer patients for (a-b) total targeted genes in the Ajou University School of Medicine (AUSOM) and The Cancer Genome Atlas (TCGA) databases and (c) copy number variations in AUSOM.	('copy number variations', 'Var', (183, 205))	('lung cancer', 'Disease', 'MESH:D008175', (28, 39))	('patients', 'Species', '9606', (40, 48))	('mutation', 'Reg', (8, 16))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('lung cancer', 'Disease', (28, 39))	('lung cancer', 'Phenotype', 'HP:0100526', (28, 39))	('Cancer Genome Atlas', 'Disease', (138, 157))	('Cancer', 'Phenotype', 'HP:0002664', (138, 144))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (138, 157))
287759	30912749	AUSOM Ajou University School of Medicine CDM common data model CNV copy number variant G-CDM genomic common data model INDEL insertion/deletion NGS next-generation sequencing OHDSI Observational Health Data Sciences and Informatics OMOP Observational Medical Outcomes Partnership SNP single nucleotide polymorphism SQL structured query language TCGA The Cancer Genome Atlas	('single nucleotide polymorphism', 'Var', (284, 314))	('CDM', 'Chemical', '-', (41, 44))	('OHDSI', 'Chemical', '-', (175, 180))	('INDEL', 'Chemical', '-', (119, 124))	('OMOP', 'Chemical', '-', (232, 236))	('Cancer Genome Atlas', 'Disease', (354, 373))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (354, 373))	('Cancer', 'Phenotype', 'HP:0002664', (354, 360))	('CDM', 'Chemical', '-', (89, 92))	('G-CDM', 'Chemical', '-', (87, 92))
287816	29565465	We previously identified FAT1 as one of the significant mutant genes in esophageal squamous cell carcinoma (ESCC).	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (83, 106))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (72, 106))	('mutant', 'Var', (56, 62))	('FAT1', 'Gene', '2195', (25, 29))	('esophageal squamous cell carcinoma', 'Disease', (72, 106))	('FAT1', 'Gene', (25, 29))
287817	29565465	In the present study, the knockdown of FAT1 expression in YSE2 and Colo680N cell lines was carried out by lentivirus, and we found that knockdown of FAT1 led to acceleration of cell migration and invasion.	('FAT1', 'Gene', '2195', (149, 153))	('invasion', 'CPA', (196, 204))	('FAT1', 'Gene', '2195', (39, 43))	('FAT1', 'Gene', (149, 153))	('knockdown', 'Var', (136, 145))	('FAT1', 'Gene', (39, 43))	('cell migration', 'CPA', (177, 191))	('acceleration', 'PosReg', (161, 173))
287818	29565465	Furthermore, we detected the cell adhesive force and cell elasticity force by atomic force microscopy (AFM) and found that the suppression of endogenous expression of FAT1 led to a decrease in the cell adhesive force and increase in the cell elasticity force compared with the control groups.	('cell adhesive force', 'CPA', (197, 216))	('FAT1', 'Gene', '2195', (167, 171))	('decrease', 'NegReg', (181, 189))	('increase', 'PosReg', (221, 229))	('suppression', 'Var', (127, 138))	('FAT1', 'Gene', (167, 171))	('cell elasticity force', 'CPA', (237, 258))
287826	29565465	Among these SMGs, FAT1 was mutated in 15% of ESCC tumors.	('FAT1', 'Gene', (18, 22))	('mutated', 'Var', (27, 34))	('ESCC tumors', 'Disease', (45, 56))	('ESCC tumors', 'Disease', 'MESH:D004938', (45, 56))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('FAT1', 'Gene', '2195', (18, 22))
287840	29565465	Moreover, the cell adhesive force and cell elasticity force after FAT1 knockdown were detected by AFM.	('FAT1', 'Gene', (66, 70))	('detected', 'Reg', (86, 94))	('knockdown', 'Var', (71, 80))	('cell elasticity force', 'CPA', (38, 59))	('FAT1', 'Gene', '2195', (66, 70))	('cell adhesive force', 'CPA', (14, 33))
287868	29565465	We found that FAT1 was mutated frequently in ESCC.	('FAT1', 'Gene', '2195', (14, 18))	('mutated', 'Var', (23, 30))	('ESCC', 'Disease', (45, 49))	('FAT1', 'Gene', (14, 18))
287869	29565465	In addition, we analyzed several types of squamous cell carcinomas in a TCGA database using cBioPortal, and found that FAT1 was mutated frequently in squamous cell carcinomas (Fig.	('squamous cell carcinomas', 'Disease', (150, 174))	('carcinomas', 'Phenotype', 'HP:0030731', (56, 66))	('mutated', 'Var', (128, 135))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (150, 174))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (42, 66))	('squamous cell carcinomas', 'Disease', (42, 66))	('FAT1', 'Gene', '2195', (119, 123))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (150, 173))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (42, 66))	('FAT1', 'Gene', (119, 123))	('carcinoma', 'Phenotype', 'HP:0030731', (164, 173))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (150, 174))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (42, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (56, 65))	('carcinomas', 'Phenotype', 'HP:0030731', (164, 174))
287870	29565465	In ESCC, the frequency of FAT1 mutations was 11.7%, in head and neck squamous cell carcinoma (HNSCC), the frequency of FAT1 mutations was 21.7%, in lung squamous cell carcinoma (LSCC), the frequency of FAT1 mutations was 14.6%, and in oral squamous cell carcinoma (OSCC), the frequency of FAT1 mutations was 30%.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (240, 263))	('FAT1', 'Gene', '2195', (26, 30))	('FAT1', 'Gene', '2195', (119, 123))	('carcinoma', 'Phenotype', 'HP:0030731', (167, 176))	('carcinoma', 'Phenotype', 'HP:0030731', (254, 263))	('FAT1', 'Gene', (202, 206))	('neck squamous cell carcinoma', 'Disease', (64, 92))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (64, 92))	('FAT1', 'Gene', (289, 293))	('ESCC', 'Disease', (3, 7))	('mutations', 'Var', (31, 40))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (69, 92))	('FAT1', 'Gene', '2195', (202, 206))	('FAT1', 'Gene', (26, 30))	('FAT1', 'Gene', (119, 123))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (235, 263))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))	('FAT1', 'Gene', '2195', (289, 293))	('mutations', 'Var', (124, 133))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (153, 176))	('oral squamous cell carcinoma', 'Disease', (235, 263))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (148, 176))	('lung squamous cell carcinoma', 'Disease', (148, 176))
287879	29565465	The results showed that FAT1 depletion led to a significant increase in cell migration and invasion abilities in the YSE2 and Colo680N cell lines (Fig.	('depletion', 'Var', (29, 38))	('cell migration', 'CPA', (72, 86))	('increase', 'PosReg', (60, 68))	('FAT1', 'Gene', '2195', (24, 28))	('invasion abilities', 'CPA', (91, 109))	('FAT1', 'Gene', (24, 28))
287880	29565465	In the present study, AFM was used to visualize the morphology of YSE2 and Colo680N FAT1-knockdown cells in comparison to the corresponding control groups, respectively.	('Colo680N', 'Var', (75, 83))	('FAT1', 'Gene', '2195', (84, 88))	('FAT1', 'Gene', (84, 88))
287881	29565465	The results demonstrated that the cells became relatively thinner following FAT1 knockdown.	('FAT1', 'Gene', '2195', (76, 80))	('knockdown', 'Var', (81, 90))	('FAT1', 'Gene', (76, 80))	('thinner', 'NegReg', (58, 65))
287883	29565465	The results indicate that the cell surface may be smoother after knockdown of FAT1 (Fig.	('FAT1', 'Gene', (78, 82))	('knockdown', 'Var', (65, 74))	('FAT1', 'Gene', '2195', (78, 82))
287890	29565465	In glioblastoma multiforme, colorectal cancer and head and neck cancer, FAT1 was identified as a tumor suppressor, for which somatic mutations lead to aberrant Wnt signaling pathway activation.	('tumor suppressor', 'Gene', (97, 113))	('FAT1', 'Gene', '2195', (72, 76))	('colorectal cancer', 'Phenotype', 'HP:0003003', (28, 45))	('tumor suppressor', 'Gene', '7248', (97, 113))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('mutations', 'Var', (133, 142))	('head and neck cancer', 'Phenotype', 'HP:0012288', (50, 70))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('glioblastoma multiforme', 'Disease', (3, 26))	('activation', 'PosReg', (182, 192))	('glioblastoma', 'Phenotype', 'HP:0012174', (3, 15))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (3, 26))	('colorectal cancer', 'Disease', 'MESH:D015179', (28, 45))	('Wnt signaling pathway', 'Pathway', (160, 181))	('head and neck cancer', 'Disease', 'MESH:D006258', (50, 70))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('FAT1', 'Gene', (72, 76))	('colorectal cancer', 'Disease', (28, 45))	('lead to', 'Reg', (143, 150))
287899	29565465	Lian et al reported that artesunate attenuates cellular migration and invasion by affecting cellular mechanical properties in glioma.	('affecting', 'Reg', (82, 91))	('glioma', 'Disease', 'MESH:D005910', (126, 132))	('glioma', 'Phenotype', 'HP:0009733', (126, 132))	('artesunate', 'Var', (25, 35))	('artesunate', 'Chemical', 'MESH:D000077332', (25, 35))	('glioma', 'Disease', (126, 132))	('cellular mechanical properties', 'CPA', (92, 122))	('Lian', 'Species', '155640', (0, 4))	('cellular migration', 'CPA', (47, 65))	('attenuates', 'NegReg', (36, 46))	('invasion', 'CPA', (70, 78))
287904	29565465	In the present study, we verified that FAT1 knockdown effectively accelerated cell migration and invasion.	('FAT1', 'Gene', '2195', (39, 43))	('FAT1', 'Gene', (39, 43))	('knockdown', 'Var', (44, 53))	('accelerated', 'PosReg', (66, 77))	('invasion', 'CPA', (97, 105))	('cell migration', 'CPA', (78, 92))
287912	29565465	The datasets of FAT1 mutation in squamous cell carcinomas were obtained from the TCGA database.	('squamous cell carcinomas', 'Disease', (33, 57))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (33, 56))	('FAT1', 'Gene', '2195', (16, 20))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (33, 57))	('mutation', 'Var', (21, 29))	('carcinoma', 'Phenotype', 'HP:0030731', (47, 56))	('carcinomas', 'Phenotype', 'HP:0030731', (47, 57))	('FAT1', 'Gene', (16, 20))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (33, 57))
287959	29116177	Patients having a MCT+ mast cell density <=18%-quantile had a significantly lower body weight (mean 63.9 kg+/-12.3 kg SD) than those with a MCT+ mast cell density >18%-quantile (mean 70.32 kg+/- 14.22 kg SD).	('body weight', 'CPA', (82, 93))	('MCT', 'Gene', '6566', (140, 143))	('lower body weight', 'Phenotype', 'HP:0004325', (76, 93))	('<=18%-quantile', 'Var', (41, 55))	('lower', 'NegReg', (76, 81))	('MCT', 'Gene', (140, 143))	('Patients', 'Species', '9606', (0, 8))	('MCT', 'Gene', '6566', (18, 21))	('MCT', 'Gene', (18, 21))
287990	28489584	Cancer is typically a genetic disease derived from genome aberrances such as somatic mutations, copy-number alterations, DNA methylations, and gene fusions.	('genetic disease', 'Disease', (22, 37))	('copy-number alterations', 'Var', (96, 119))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('gene fusions', 'Var', (143, 155))	('genetic disease', 'Disease', 'MESH:D030342', (22, 37))
287992	28489584	For example, PAM50, a widely used breast cancer classifier based on gene expression profile, can divide patients into five subtypes corresponding to different clinical outcomes.	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('breast cancer', 'Phenotype', 'HP:0003002', (34, 47))	('breast cancer', 'Gene', '672', (34, 47))	('PAM50', 'Var', (13, 18))	('patients', 'Species', '9606', (104, 112))	('breast cancer', 'Gene', (34, 47))
288003	28489584	Studies on mutations, structural variations, or DNA copy number alterations have demonstrated the value of normal tissues in identifying cancer-associated genome variations accurately.	('variations', 'Var', (162, 172))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('cancer', 'Disease', (137, 143))	('cancer', 'Disease', 'MESH:D009369', (137, 143))
288035	28489584	Among tumor samples, immune scores were significantly higher in both C6-KIRC/KIRP and C8-LUAD/LUSC than those in the other clusters (C6 posthoc Maximum p value = 3.3E-06, C8 posthoc Maximum p value = 2.1E-05).	('higher', 'PosReg', (54, 60))	('immune scores', 'MPA', (21, 34))	('C8-LUAD', 'Disease', 'OMIM:613790', (86, 93))	('C8-LUAD', 'Disease', (86, 93))	('tumor', 'Disease', 'MESH:D009369', (6, 11))	('C6-KIRC/KIRP', 'Var', (69, 81))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('tumor', 'Disease', (6, 11))
288040	28489584	We found that apoptosis and cell cycle regulator TP53 harbored a high number of mutations in both two subtypes (Supplementary Figure 6A).	('TP53', 'Gene', (49, 53))	('apoptosis', 'Gene', (14, 23))	('TP53', 'Gene', '7157', (49, 53))	('mutations', 'Var', (80, 89))
288063	28489584	Short hairpin RNAs (shRNA) were designed to knock down the expression levels of FAM64A and TROAP in MDA-MB-231 cells.	('FAM64A', 'Gene', (80, 86))	('FAM64A', 'Gene', '54478', (80, 86))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (100, 110))	('knock', 'Var', (44, 49))	('expression', 'MPA', (59, 69))	('TROAP', 'Gene', (91, 96))	('TROAP', 'Gene', '10024', (91, 96))
288065	28489584	Compared with the control group, the groups with knockdown of FAM64A and TROAP exhibited significantly slower proliferation (1.76- and 1.41-fold, respectively) (Figure 6).	('knockdown', 'Var', (49, 58))	('TROAP', 'Gene', (73, 78))	('slower', 'NegReg', (103, 109))	('TROAP', 'Gene', '10024', (73, 78))	('FAM64A', 'Gene', (62, 68))	('FAM64A', 'Gene', '54478', (62, 68))
288066	28489584	These results suggest that inhibiting either FAM64A or TROAP can suppress the growth of breast cancer cells.	('inhibiting', 'Var', (27, 37))	('TROAP', 'Gene', (55, 60))	('breast cancer', 'Gene', '672', (88, 101))	('TROAP', 'Gene', '10024', (55, 60))	('growth of', 'CPA', (78, 87))	('breast cancer', 'Gene', (88, 101))	('FAM64A', 'Gene', (45, 51))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('suppress', 'NegReg', (65, 73))	('breast cancer', 'Phenotype', 'HP:0003002', (88, 101))	('FAM64A', 'Gene', '54478', (45, 51))
288117	28489584	The average and standard deviation of cell numbers of the three wells for FAM64A and TROAP knockdown groups and control group were calculated during five days.	('TROAP', 'Gene', '10024', (85, 90))	('FAM64A', 'Gene', (74, 80))	('FAM64A', 'Gene', '54478', (74, 80))	('knockdown', 'Var', (91, 100))	('TROAP', 'Gene', (85, 90))
288132	34030694	In recent years, the promising responses of immunotherapy based on inhibitors targeting cytotoxic T lymphocyte antigen 4 (CTLA-4), programmed death receptor 1 (PD-1), or its ligand (PD-L1) have brought revolutionary changes to the treatment of a variety of cancers.	('inhibitors', 'Var', (67, 77))	('cytotoxic T lymphocyte antigen 4', 'Gene', (88, 120))	('PD-L1', 'Gene', '29126', (182, 187))	('cancer', 'Phenotype', 'HP:0002664', (257, 263))	('PD-1', 'Gene', (160, 164))	('CTLA-4', 'Gene', '1493', (122, 128))	('cytotoxic T lymphocyte antigen 4', 'Gene', '1493', (88, 120))	('cancers', 'Disease', 'MESH:D009369', (257, 264))	('CTLA-4', 'Gene', (122, 128))	('cancers', 'Phenotype', 'HP:0002664', (257, 264))	('PD-L1', 'Gene', (182, 187))	('cancers', 'Disease', (257, 264))
288154	34030694	This mRNA microarray dataset was based on the Platform GPL14951 (Illumina HumanHT-12 WG-DASL V4.0 R2 expression beadchip) and included 300 patients with early cervical cancer (FIGO stage I-II).	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('patients', 'Species', '9606', (139, 147))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('cancer', 'Disease', (168, 174))	('GPL14951', 'Var', (55, 63))
288179	34030694	These available patients were from the metastatic melanoma cohort and treated with anti-CTLA-4 or anti-PD-1 antibodies at the University of Texas (UT) MD Anderson Cancer Center.	('CTLA-4', 'Gene', '1493', (88, 94))	('melanoma', 'Phenotype', 'HP:0002861', (50, 58))	('melanoma cohort', 'Disease', 'MESH:D008545', (50, 65))	('patients', 'Species', '9606', (16, 24))	('Cancer', 'Phenotype', 'HP:0002664', (163, 169))	('CTLA-4', 'Gene', (88, 94))	('melanoma cohort', 'Disease', (50, 65))	('Cancer', 'Disease', 'MESH:D009369', (163, 169))	('Cancer', 'Disease', (163, 169))	('anti-PD-1', 'Var', (98, 107))
288220	34030694	In the SCCH cohort, the top 20 mutation genes in sub1 were shown in the upper left panel of Fig.	('SCC', 'Gene', (7, 10))	('SCC', 'Gene', '6317', (7, 10))	('sub1', 'Gene', '10923', (49, 53))	('sub1', 'Gene', (49, 53))	('mutation genes', 'Var', (31, 45))
288222	34030694	SNVs analysis showed that transition mutations, specifically C to T, were prominent in both subtypes; C to G ranks second in sub1 and third in sub2 (Fig.	('sub1', 'Gene', '10923', (125, 129))	('sub1', 'Gene', (125, 129))	('C to G', 'Var', (102, 108))
288264	34030694	Our results suggested that the prognosis and the prediction of response to ICIs of patients with high TMB were better than those of patients with low TMB, which is also consistent with the existing clinical results of cervical cancer.	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('TMB', 'Chemical', '-', (102, 105))	('high TMB', 'Var', (97, 105))	('better', 'PosReg', (111, 117))	('cancer', 'Disease', (227, 233))	('cancer', 'Disease', 'MESH:D009369', (227, 233))	('patients', 'Species', '9606', (83, 91))	('TMB', 'Chemical', '-', (150, 153))	('patients', 'Species', '9606', (132, 140))	('prognosis', 'CPA', (31, 40))
288265	34030694	This could be due to the more mutations accumulated in the tumor, the more neoantigens are produced.	('tumor', 'Disease', (59, 64))	('neoantigens', 'MPA', (75, 86))	('mutations', 'Var', (30, 39))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('more', 'PosReg', (70, 74))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
288285	34030694	Cervical cancer with a high expression of CA9 has a higher rate of local recurrence and distant metastasis and is closely related to the poor prognosis of early cervical cancer.	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('cancer', 'Disease', (9, 15))	('high expression', 'Var', (23, 38))	('cancer', 'Disease', (170, 176))	('CA9', 'Gene', (42, 45))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('CA9', 'Gene', '768', (42, 45))	('related', 'Reg', (122, 129))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('higher', 'PosReg', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (9, 15))
288287	34030694	Although the relationship between TCHHL1 and cervical cancer remains unclear, the high expression of TCHHL1 plays an important role in promoting the proliferation of squamous cells.	('TCHHL1', 'Gene', (101, 107))	('high', 'Var', (82, 86))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('TCHHL1', 'Gene', (34, 40))	('promoting', 'PosReg', (135, 144))	('proliferation', 'CPA', (149, 162))	('cancer', 'Disease', (54, 60))	('TCHHL1', 'Gene', '126637', (101, 107))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('TCHHL1', 'Gene', '126637', (34, 40))
288324	33300026	It is estimated that ~70 000 lesions occur in genomic DNA in each human cell per day, most of which (75%) originate from oxidation reactions with endogenous byproducts of metabolism and base hydrolysis.	('human', 'Species', '9606', (66, 71))	('lesions', 'Var', (29, 36))	('originate from', 'Reg', (106, 120))
288325	33300026	To counteract the continuous threat these lesions pose to genome stability, cells have evolved a wide-ranging arsenal of repair programs, including DNA base excision repair (BER), mismatch repair (MMR), nucleotide excision repair (NER), translesion synthesis (TLS) and strand break repair (homologous recombination and various non-homologous end joining pathways), which together act upon particular types of lesion or at specific phases of the cell cycle to prevent mutations in DNA and cell death.	('mutations', 'Var', (467, 476))	('death', 'Disease', 'MESH:D003643', (493, 498))	('death', 'Disease', (493, 498))	('DNA', 'Gene', (480, 483))
288329	33300026	Indeed, despite the fact that replication-associated mutations have been linked to high frequencies of single base-pair substitutions (SBSs) in human cancers, mutational landscapes in cancer genomes are highly heterogeneous.	('cancer', 'Disease', (184, 190))	('human', 'Species', '9606', (144, 149))	('single base-pair substitutions', 'Var', (103, 133))	('cancers', 'Phenotype', 'HP:0002664', (150, 157))	('cancers', 'Disease', (150, 157))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('cancers', 'Disease', 'MESH:D009369', (150, 157))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('replication-associated', 'Disease', (30, 52))	('mutations', 'Var', (53, 62))	('cancer', 'Disease', (150, 156))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
288333	33300026	We showed that NEIL1 becomes stabilized on chromatin after site-specific (Lys296-298) acetylation, and accumulates almost exclusively at highly transcribed genomic regions as well as the transcription start sites (TSS) of weakly expressed genes, some of which are associated with poor prognosis when overexpressed in cancer.	('acetylation', 'Var', (86, 97))	('accumulates', 'PosReg', (103, 114))	('NEIL1', 'Gene', (15, 20))	('cancer', 'Phenotype', 'HP:0002664', (317, 323))	('Lys296-298) acetylation', 'Var', (74, 97))	('Lys296', 'Chemical', '-', (74, 80))	('acetyl', 'Chemical', '-', (86, 92))	('cancer', 'Disease', (317, 323))	('cancer', 'Disease', 'MESH:D009369', (317, 323))
288334	33300026	Bioinformatic analyses using cancer genome datasets and human germline population mutation datasets provide, with unprecedented resolution, information on the relationship between local variations in single base substitution (SBS) rates and ChIP-seq AcNEIL1 occupancy, both in cancer genomes and the germline.	('cancer', 'Disease', (29, 35))	('cancer', 'Disease', (277, 283))	('cancer', 'Disease', 'MESH:D009369', (277, 283))	('cancer', 'Phenotype', 'HP:0002664', (277, 283))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('human', 'Species', '9606', (56, 61))	('variations', 'Var', (186, 196))	('cancer', 'Disease', 'MESH:D009369', (29, 35))
288398	33300026	For XRCC1, we downloaded the original fastq file from the GEO (https://www.ncbi.nlm.nih.gov/geo/) repository (GSE95302, file SRR5282040) and processed it according to the pipeline we used here.	('GSE95302', 'Var', (110, 118))	('XRCC1', 'Gene', (4, 9))	('XRCC1', 'Gene', '7515', (4, 9))
288400	33300026	The file for OGG1 was GSM2357433_CP-Sample_Flag-OGG1-Con-2.tdf from the GEO record GSM2357433; the file was first converted to a bedGraph format using the 'igvtools tdftobedgraph'and then to bigWig.	('OGG1', 'Gene', '4968', (48, 52))	('GSM2357433', 'Var', (83, 93))	('OGG1', 'Gene', (13, 17))	('OGG1', 'Gene', '4968', (13, 17))	('OGG1', 'Gene', (48, 52))
288407	33300026	To this end we divided patients with each tumor type into two groups: group 1, with expression of gene x above the mean; and group 2, with expression of gene x below or at the mean value.	('tumor', 'Disease', (42, 47))	('patients', 'Species', '9606', (23, 31))	('gene x', 'Var', (98, 104))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('expression', 'MPA', (84, 94))	('below', 'NegReg', (160, 165))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
288420	33300026	We recently showed that p300 acetylates NEIL1 (herein referred to as AcNEIL1) at residues Lys296, Lys297 and Lys298, which serves to increase DG activity and stabilize the enzyme on chromatin-bound complexes.	('Lys298', 'Var', (109, 115))	('Lys297', 'Chemical', '-', (98, 104))	('Lys296', 'Var', (90, 96))	('p300', 'Gene', (24, 28))	('Lys296', 'Chemical', '-', (90, 96))	('NEIL1', 'Gene', (40, 45))	('DG activity', 'MPA', (142, 153))	('Lys297', 'Var', (98, 104))	('p300', 'Gene', '2033', (24, 28))	('increase', 'PosReg', (133, 141))	('Lys298', 'Chemical', '-', (109, 115))	('acetyl', 'Chemical', '-', (29, 35))	('stabilize', 'MPA', (158, 167))
288423	33300026	STED of human colorectal adenocarcinoma HCT116 cells labeled with anti-AcNEIL1 or anti-total-NEIL1 antibodies showed strong AcNEIL1 nuclear localization, as opposed to diffuse staining in nuclei and cytoplasm for non-acetylated NEIL1.	('anti-total-NEIL1', 'Var', (82, 98))	('HCT116', 'CellLine', 'CVCL:0291', (40, 46))	('AcNEIL1', 'Gene', (124, 131))	('colorectal adenocarcinoma', 'Disease', (14, 39))	('nuclear localization', 'MPA', (132, 152))	('acetyl', 'Chemical', '-', (217, 223))	('anti-AcNEIL1', 'Var', (66, 78))	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (14, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (30, 39))	('human', 'Species', '9606', (8, 13))	('TE', 'Chemical', 'MESH:D013691', (1, 3))
288433	33300026	H3K27Ac (Figure 1Dii) colocalized with AcNEIL1 on condensed chromosomes to a greater extent than total histone H3 (Figure 1Diii) and, likewise, AcNEIL1 yielded stronger fluorescent signal than total NEIL1 in nuclei (Supplementary Figure S2A, green trace).	('H3K27Ac', 'Protein', (0, 7))	('H3K27Ac', 'Chemical', '-', (0, 7))	('AcNEIL1', 'Var', (144, 151))	('fluorescent signal', 'MPA', (169, 187))	('stronger', 'PosReg', (160, 168))
288482	33300026	We therefore analyzed ~25.4 million SBSs specific to tumor samples, including 5.6 million coding region mutations and 19.8 million non-coding variants.	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('mutations', 'Var', (104, 113))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Disease', (53, 58))
288483	33300026	We conclude that transcription is an intrinsically mutagenic process, and that chromatin-bound AcNEIL1 is the active DG form of NElL1 in the context of BERosomes, which is responsible for the repair of oxidative DNA damage and the prevention of base-pair change accumulations, particularly transversion mutations at A:T base pairs.	('transversion mutations', 'Var', (290, 312))	('NElL1', 'Gene', (128, 133))	('NElL1', 'Gene', '4745', (128, 133))
288484	33300026	After establishing that the local variations in mutation rates observed in cancer genomes coincide with segmental AcNEIL1 occupancy, we next addressed whether similar patterns exist for genetic variations between populations.	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('mutation', 'Var', (48, 56))	('cancer', 'Disease', (75, 81))	('cancer', 'Disease', 'MESH:D009369', (75, 81))
288485	33300026	We selected SweGen, a database of single nucleotide polymorphisms (SNPs) in the Swedish population, which is comparable in size (~23 million SNPs) to the cancer dataset.	('single nucleotide polymorphisms', 'Var', (34, 65))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('cancer', 'Disease', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (154, 160))
288486	33300026	No qualitative differences were observed in the genome-wide distribution of SNPs as a function of AcNEIL1 ICS compared with those observed for cancer.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('SNPs', 'Disease', (76, 80))	('AcNEIL1 ICS', 'Var', (98, 109))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))
288487	33300026	Quantitatively, the frequency of incurring base changes at low AcNEIL1 (<500 000 ICS) was greater in cancer than in the germline, particularly for A>T and A>C transversions (Supplementary Figure S9C).	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('A>C transversions', 'Var', (155, 172))	('A>T', 'Var', (147, 150))	('cancer', 'Disease', (101, 107))	('base changes', 'MPA', (43, 55))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))
288488	33300026	We surveyed the Human Gene Mutation Database (HGMD) to assess the frequency of variants at G4 DNA motifs in 5'-UTRs known to cause or predispose toward inherited disease.	('Human', 'Species', '9606', (16, 21))	('variants', 'Var', (79, 87))	('inherited disease', 'Disease', (152, 169))	('cause', 'Reg', (125, 130))	('G4 DNA', 'Gene', (91, 97))	('inherited disease', 'Disease', 'MESH:D030342', (152, 169))
288493	33300026	The AcNEIL1 acetyl acceptors, Lys296, Lys297 and Lys298, are embedded within an intrinsically unstructured carboxyl-terminal (C-ter) domain (Supplementary Figure S10B), whose disordered nature has been well-conserved (Supplementary Figure S10B-D) despite the high degree of ordered protein folds expected among thermophilic lifeforms.	('acetyl', 'Chemical', '-', (12, 18))	('Lys297', 'Chemical', '-', (38, 44))	('Lys298', 'Chemical', '-', (49, 55))	('S10B', 'SUBSTITUTION', 'None', (162, 166))	('S10B', 'Var', (239, 243))	('Lys298', 'Var', (49, 55))	('Lys297', 'Var', (38, 44))	('Lys296', 'Var', (30, 36))	('S10B', 'SUBSTITUTION', 'None', (239, 243))	('Lys296', 'Chemical', '-', (30, 36))	('S10B', 'Var', (162, 166))
288499	33300026	The observed loading and stabilization of AcNEIL1 on chromatin is critically dependent upon PTM at three consecutive lysine residues (Lys297-299), an acetylation center that appears to be the result of consolidation among variable amino acids in protostomes, probably occurring during the Cambrian explosion, ~540 million years ago, during a transition from sulfur to oxygen as an energy source.	('AcNEIL1', 'Gene', (42, 49))	('sulfur', 'Chemical', 'MESH:D013455', (358, 364))	('acetyl', 'Chemical', '-', (150, 156))	('oxygen', 'Chemical', 'MESH:D010100', (368, 374))	('Lys297-299', 'Var', (134, 144))	('Lys297', 'Chemical', '-', (134, 140))	('lysine', 'Chemical', 'MESH:D008239', (117, 123))
288501	33300026	C>T (G>A) substitutions occur frequently at methylated CpG dinucleotides, particularly in single-stranded DNA where deamination of 5-methylcytosine to thymine, which produces G:T mismatches resulting in mutations (i.e.	('C>T (G>A', 'Gene', (0, 8))	('G:T mismatches', 'Var', (175, 189))	('5-methylcytosine', 'Chemical', 'MESH:D044503', (131, 147))	('thymine', 'Chemical', 'MESH:D013941', (151, 158))	('mismatches', 'Var', (179, 189))	('CpG dinucleotides', 'Chemical', 'MESH:C015772', (55, 72))	('mutations', 'Var', (203, 212))	('substitutions', 'Var', (10, 23))
288503	33300026	C>T transitions also arise from stable cytosine oxidation products, such as 5-hydroxycytosine.	('5-hydroxycytosine', 'Chemical', 'MESH:C017400', (76, 93))	('cytosine oxidation', 'MPA', (39, 57))	('5-hydroxycytosine', 'MPA', (76, 93))	('C>T', 'Var', (0, 3))	('cytosine', 'Chemical', 'MESH:D003596', (39, 47))	('cytosine', 'Chemical', 'MESH:D003596', (85, 93))	('arise', 'Reg', (21, 26))
288509	33300026	Regarding transcription-associated mutagenesis, the tumor suppressor TP53, the most commonly mutated gene associated with cancer, strikingly resides within the most highly transcribed 1-Mb domain in the human genome, raising the intriguing possibility that susceptibility to human cancer may stem, in part, from intrinsic genome architecture.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('mutagenesis', 'Var', (35, 46))	('cancer', 'Disease', 'MESH:D009369', (281, 287))	('human', 'Species', '9606', (203, 208))	('tumor', 'Disease', (52, 57))	('TP53', 'Gene', (69, 73))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', (281, 287))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('human', 'Species', '9606', (275, 280))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('cancer', 'Phenotype', 'HP:0002664', (281, 287))	('tumor', 'Disease', 'MESH:D009369', (52, 57))
288511	33300026	Studies on the mutagenic potential of formamidopyrimidines have suggested that direct base misincorporation can generate both transition and transversion mutations.	('transversion mutations', 'CPA', (141, 163))	('misincorporation', 'Var', (91, 107))	('formamidopyrimidines', 'Chemical', '-', (38, 58))	('transition', 'MPA', (126, 136))
288512	33300026	TG blocks DNA replication and its bypass, aided by translesion synthesis polymerases, can yield mutations when Poltheta is utilized.	('yield', 'Reg', (90, 95))	('TG', 'Chemical', 'MESH:C029389', (0, 2))	('DNA replication', 'CPA', (10, 25))	('mutations', 'Var', (96, 105))
288517	33300026	Our analysis that Hox overexpression, and especially AcNEIL1-containing Hox gene reactivation in low grade glioma, contributes to poor survival strengthens the growing support for their key role in tumorigenesis.	('Hox', 'Gene', '42536', (72, 75))	('overexpression', 'PosReg', (22, 36))	('Hox', 'Gene', (72, 75))	('survival', 'MPA', (135, 143))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('glioma', 'Disease', 'MESH:D005910', (107, 113))	('glioma', 'Phenotype', 'HP:0009733', (107, 113))	('poor', 'NegReg', (130, 134))	('reactivation', 'Var', (81, 93))	('glioma', 'Disease', (107, 113))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('tumor', 'Disease', (198, 203))	('Hox', 'Gene', (18, 21))	('Hox', 'Gene', '42536', (18, 21))
288518	33300026	Neil1-/- (or Neil2-/-) mouse embryoid bodies display neural defects, the downregulation of key developmental genes, including Hox genes, elevated levels of reactive oxygen species (ROS) and a pro-apoptotic TP53-associated DNA damage response.	('neural defects', 'CPA', (53, 67))	('pro-apoptotic', 'PosReg', (192, 205))	('Neil2', 'Gene', (13, 18))	('Neil1-/-', 'Var', (0, 8))	('ROS', 'Chemical', 'MESH:D017382', (181, 184))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (156, 179))	('elevated', 'PosReg', (137, 145))	('TP53-associated', 'CPA', (206, 221))	('mouse', 'Species', '10090', (23, 28))	('levels of reactive oxygen species', 'MPA', (146, 179))	('elevated levels of reactive oxygen species', 'Phenotype', 'HP:0025464', (137, 179))	('Hox', 'Gene', '42536', (126, 129))	('downregulation', 'NegReg', (73, 87))	('Neil2', 'Gene', '382913', (13, 18))	('Hox', 'Gene', (126, 129))
288521	33300026	The altered expression and mutations associated with polycomb complexes have also been linked to cancer, and it will be of interest to determine the extent to which escape from NEIL1 damage repair beyond the early developmental stages may contribute to tumorigenesis.	('mutations', 'Var', (27, 36))	('NEIL1', 'Gene', (177, 182))	('cancer', 'Disease', (97, 103))	('tumor', 'Disease', 'MESH:D009369', (253, 258))	('contribute', 'Reg', (239, 249))	('linked', 'Reg', (87, 93))	('tumor', 'Phenotype', 'HP:0002664', (253, 258))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('tumor', 'Disease', (253, 258))	('expression', 'MPA', (12, 22))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
288574	32856861	A previous study by Vlokova et al., (2012), involved the determination of markers of oxidative stress in leukoplakia, erythroplakia and lichen planus and they concluded that deficiency of anti-oxidant status and increase in lipo-peroxidation was established etiology in PMODs.	('leukoplakia, erythroplakia', 'Disease', 'MESH:D007971', (105, 131))	('deficiency', 'Var', (174, 184))	('lipo-peroxidation', 'MPA', (224, 241))	('oxidative stress', 'Phenotype', 'HP:0025464', (85, 101))	('increase', 'PosReg', (212, 220))	('PMODs', 'Disease', (270, 275))
288602	32856861	Accumulation of 8-OHdG is associated with a variety of disorders including cancers and neurodegenerative disorders.	('8-OHdG', 'Chemical', 'MESH:C067134', (16, 22))	('cancers', 'Disease', 'MESH:D009369', (75, 82))	('cancers', 'Phenotype', 'HP:0002664', (75, 82))	('cancers', 'Disease', (75, 82))	('8-OHdG', 'Var', (16, 22))	('neurodegenerative disorders', 'Disease', (87, 114))	('neurodegenerative disorders', 'Disease', 'MESH:D019636', (87, 114))	('neurodegenerative disorders', 'Phenotype', 'HP:0002180', (87, 114))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('associated', 'Reg', (26, 36))
288627	32796631	Three Delta-like ligands (DLL1, DLL3 and DLL4) and two Jagged ligands (JAG1 and JAG2) participate in the initiation of the Notch signaling pathway in mammals and are crucial controllers of the pathway activation.	('JAG2', 'Gene', (80, 84))	('JAG1', 'Gene', (71, 75))	('DLL3', 'Gene', (32, 36))	('JAG2', 'Gene', '3714', (80, 84))	('Notch', 'Gene', (123, 128))	('DLL3', 'Gene', '10683', (32, 36))	('Notch', 'Gene', '31293', (123, 128))	('JAG1', 'Gene', '182', (71, 75))	('participate', 'Reg', (86, 97))	('DLL1', 'Var', (26, 30))	('DLL4', 'Var', (41, 45))
288628	32796631	Both hypoactivation and hyperactivation of the Notch pathway can lead to a tumorigenic condition, depending on the type of tissue, the genetic alteration and the type of receptor-ligand interactions.	('hyperactivation', 'Var', (24, 39))	('Notch', 'Gene', '31293', (47, 52))	('hypoactivation', 'Var', (5, 19))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('Notch', 'Gene', (47, 52))	('lead to', 'Reg', (65, 72))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', (75, 80))
288629	32796631	Mutations of Notch1, for instance, have been identified in squamous cell carcinoma of the head and neck, esophagus and skin and have been linked with a hypoactivation of the pathway.	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (59, 82))	('carcinoma of the head and neck', 'Phenotype', 'HP:0012288', (73, 103))	('squamous cell carcinoma', 'Disease', (59, 82))	('identified', 'Reg', (45, 55))	('skin', 'Disease', (119, 123))	('linked', 'Reg', (138, 144))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))	('Mutations', 'Var', (0, 9))	('esophagus', 'Disease', (105, 114))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (59, 82))	('Notch1', 'Gene', (13, 19))
288630	32796631	On the other hand, Notch1 hyperactivation has been linked to the etiology of T-cell acute lymphoblastic leukemia (T-ALL) and chronic lymphocytic leukemia (CLL), breast cancer, adenoid cystic carcinoma and mantle cell lymphoma.	('cell lymphoma', 'Phenotype', 'HP:0012191', (212, 225))	('CLL', 'Phenotype', 'HP:0005550', (155, 158))	('linked', 'Reg', (51, 57))	('hyperactivation', 'Var', (26, 41))	('lymphoma', 'Phenotype', 'HP:0002665', (217, 225))	('Notch1', 'Gene', (19, 25))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('adenoid cystic carcinoma', 'Disease', 'MESH:D003528', (176, 200))	('T-cell acute lymphoblastic leukemia', 'Phenotype', 'HP:0006727', (77, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (191, 200))	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (84, 112))	('breast cancer', 'Phenotype', 'HP:0003002', (161, 174))	('mantle cell lymphoma', 'Disease', 'MESH:D020522', (205, 225))	('mantle cell lymphoma', 'Disease', (205, 225))	('adenoid cystic carcinoma', 'Disease', (176, 200))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (90, 112))	('breast cancer', 'Disease', 'MESH:D001943', (161, 174))	('breast cancer', 'Disease', (161, 174))	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (125, 153))	('leukemia', 'Phenotype', 'HP:0001909', (104, 112))	('leukemia', 'Phenotype', 'HP:0001909', (145, 153))	('T-ALL', 'Phenotype', 'HP:0006727', (114, 119))	('T-cell acute lymphoblastic leukemia (T-ALL) and chronic lymphocytic leukemia', 'Disease', 'MESH:D054218', (77, 153))
288631	32796631	Chromosomal aberrations involving the Notch pathway are often involved in the initiation of a cancerogenic progression.	('Chromosomal aberrations', 'Var', (0, 23))	('Notch', 'Gene', (38, 43))	('Chromosomal aberrations', 'Phenotype', 'HP:0040012', (0, 23))	('involved', 'Reg', (62, 70))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('Notch', 'Gene', '31293', (38, 43))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
288632	32796631	The very first link of the role of Notch in cancer was derived from the identification of an activating mutation in T-ALL patients, and it was linked to a chromosomal translocation of the Notch1 gene.	('T-ALL', 'Phenotype', 'HP:0006727', (116, 121))	('Notch', 'Gene', (188, 193))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('Notch', 'Gene', (35, 40))	('patients', 'Species', '9606', (122, 130))	('activating', 'PosReg', (93, 103))	('mutation', 'Var', (104, 112))	('Notch', 'Gene', '31293', (188, 193))	('linked to', 'Reg', (143, 152))	('Notch', 'Gene', '31293', (35, 40))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
288634	32796631	Further studies on leukemia and solid tumors revealed that chromosomal translocation was not the only way the Notch signaling pathway can drive cancer.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('Notch', 'Gene', '31293', (110, 115))	('solid tumors', 'Disease', 'MESH:D009369', (32, 44))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('chromosomal translocation', 'Var', (59, 84))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('cancer', 'Disease', (144, 150))	('leukemia', 'Phenotype', 'HP:0001909', (19, 27))	('Notch', 'Gene', (110, 115))	('solid tumors', 'Disease', (32, 44))	('leukemia', 'Disease', 'MESH:D007938', (19, 27))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('leukemia', 'Disease', (19, 27))
288635	32796631	Hyperactivation of its signal can be achieved by either activating mutations, increased expression or stabilization of the active cleaved portion of NOTCH, as well as ligand-independent activation of the pathway.	('NOTCH', 'Gene', '31293', (149, 154))	('activating mutations', 'Var', (56, 76))	('stabilization', 'MPA', (102, 115))	('NOTCH', 'Gene', (149, 154))	('active cleaved', 'MPA', (123, 137))	('increased', 'PosReg', (78, 87))	('expression', 'MPA', (88, 98))
288636	32796631	For instance, T-ALL is generated by the ligand-independent activation of the pathway upon point mutations or chromosomal rearrangement that leads to proteolysis of the receptor, resulting in high levels of the active form of NOTCH1 intracellular domain (N1ICD).	('leads to', 'Reg', (140, 148))	('proteolysis', 'MPA', (149, 160))	('active', 'MPA', (210, 216))	('NOTCH1', 'Gene', (225, 231))	('NOTCH1', 'Gene', '4851', (225, 231))	('T-ALL', 'Phenotype', 'HP:0006727', (14, 19))	('point mutations', 'Var', (90, 105))	('T-ALL', 'Disease', (14, 19))
288637	32796631	Adenoid cystic carcinoma and breast cancer also contain point mutations or deletions in the Notch1 gene, resulting in the constitutive production of the cleaved, active intracellular form.	('deletions', 'Var', (75, 84))	('Adenoid cystic carcinoma and breast cancer', 'Disease', 'MESH:D001943', (0, 42))	('carcinoma', 'Phenotype', 'HP:0030731', (15, 24))	('breast cancer', 'Phenotype', 'HP:0003002', (29, 42))	('Notch1', 'Gene', (92, 98))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('point mutations', 'Var', (56, 71))
288638	32796631	In non-small lung cancer, mutations on the regulatory portion of the receptor (PEST, NRR or the TAD region) result in aberrant activation of Notch in cancer cells.	('lung cancer', 'Disease', (13, 24))	('lung cancer', 'Phenotype', 'HP:0100526', (13, 24))	('non-small lung cancer', 'Phenotype', 'HP:0030358', (3, 24))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('mutations', 'Var', (26, 35))	('cancer', 'Disease', (150, 156))	('Notch', 'Gene', (141, 146))	('lung cancer', 'Disease', 'MESH:D008175', (13, 24))	('activation', 'PosReg', (127, 137))	('small lung', 'Phenotype', 'HP:0002089', (7, 17))	('Notch', 'Gene', '31293', (141, 146))	('cancer', 'Disease', (18, 24))	('cancer', 'Disease', 'MESH:D009369', (18, 24))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
288648	32796631	Deletion of Lnfg induces accumulation of the intracellular domain of NOTCH, which in turn stimulates tumor growth.	('NOTCH', 'Gene', (69, 74))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('accumulation', 'PosReg', (25, 37))	('Lnfg', 'Gene', (12, 16))	('stimulates', 'PosReg', (90, 100))	('NOTCH', 'Gene', '31293', (69, 74))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('Deletion', 'Var', (0, 8))
288650	32796631	In murine models of pancreatic cancer, the deletion of Lnfg causes an increased expression of Notch1, Notch3 and Hes1, resulting in an accumulation of aldehyde dehydrogenase 1 (ALDH1)-positive undifferentiated progenitor cells.	('aldehyde dehydrogenase 1', 'Gene', (151, 175))	('pancreatic cancer', 'Disease', 'MESH:D010190', (20, 37))	('aldehyde dehydrogenase 1', 'Gene', '11668', (151, 175))	('Hes1', 'Gene', (113, 117))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('Notch3', 'Gene', (102, 108))	('deletion', 'Var', (43, 51))	('increased', 'PosReg', (70, 79))	('Notch1', 'Gene', (94, 100))	('murine', 'Species', '10090', (3, 9))	('accumulation', 'PosReg', (135, 147))	('expression', 'MPA', (80, 90))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (20, 37))	('pancreatic cancer', 'Disease', (20, 37))	('Lnfg', 'Gene', (55, 59))
288671	32796631	Ablation of CSL in the mesenchyme activates matrix-remodeling enzymes and dysregulates p53, causing an uncontrolled proliferation of keratinocytes.	('uncontrolled', 'MPA', (103, 115))	('p53', 'Gene', (87, 90))	('p53', 'Gene', '7157', (87, 90))	('Ablation', 'Var', (0, 8))	('CSL', 'Gene', (12, 15))	('matrix-remodeling enzymes', 'Enzyme', (44, 69))	('dysregulates', 'Var', (74, 86))	('CSL', 'Gene', '3516', (12, 15))	('activates', 'PosReg', (34, 43))	('causing', 'Reg', (92, 99))
288685	32796631	Cancerogenic conditions have been associated with the accumulation of mutations, which involve more than one cellular element in driving tumor progression.	('mutations', 'Var', (70, 79))	('tumor', 'Disease', (137, 142))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
288705	32796631	NOTCH1 and NOTCH2 receptors are expressed in satellite stem cells and their ablation results in an exit from quiescence and a rapid exhaustion of the stem cell pool.	('NOTCH2', 'Gene', (11, 17))	('exit from quiescence', 'MPA', (99, 119))	('NOTCH2', 'Gene', '4853', (11, 17))	('NOTCH1', 'Gene', '4851', (0, 6))	('NOTCH1', 'Gene', (0, 6))	('ablation', 'Var', (76, 84))
288710	32796631	Ablation of Rbpj or Notch1 induces the acquisition of a neuronal fate, while overexpressing Hes1, Hes5 or the active form of Notch favors proliferation of undifferentiated progenitors.	('favors', 'PosReg', (131, 137))	('Notch', 'Gene', (20, 25))	('Rbpj', 'Gene', (12, 16))	('Hes5', 'Gene', (98, 102))	('Ablation', 'Var', (0, 8))	('neuronal fate', 'CPA', (56, 69))	('induces', 'Reg', (27, 34))	('Notch', 'Gene', (125, 130))	('Notch', 'Gene', '31293', (20, 25))	('Rbpj', 'Gene', '3516', (12, 16))	('Hes5', 'Gene', '388585', (98, 102))	('acquisition', 'CPA', (39, 50))	('Notch', 'Gene', '31293', (125, 130))
288720	32796631	In line with the role of Notch in preserving undifferentiation, Hes1 was shown to positively increase the stem cell marker cluster of differentiation 133 (CD133), as well as leading to the overexpression of stemness-related genes such as CD133, ATP-binding cassette super family G member 2 (ABCG2), ALDH1 and Nanog.	('CD133', 'Gene', (155, 160))	('stemness-related', 'CPA', (207, 223))	('increase', 'PosReg', (93, 101))	('CD133', 'Gene', (238, 243))	('ALDH1', 'Gene', (299, 304))	('Notch', 'Gene', (25, 30))	('Nanog', 'Gene', '79923', (309, 314))	('ABCG2', 'Gene', (291, 296))	('overexpression', 'PosReg', (189, 203))	('ABCG2', 'Gene', '9429', (291, 296))	('Hes1', 'Var', (64, 68))	('Notch', 'Gene', '31293', (25, 30))	('leading to', 'Reg', (174, 184))	('Nanog', 'Gene', (309, 314))
288745	32796631	Notch1 mutations were mostly detectable at the DN4 (CD25-CD44-) preleukemic stage.	('CD44', 'Gene', '960', (57, 61))	('CD25', 'Gene', '3559', (52, 56))	('mutations', 'Var', (7, 16))	('Notch1', 'Gene', (0, 6))	('CD44', 'Gene', (57, 61))	('detectable', 'Reg', (29, 39))	('CD25', 'Gene', (52, 56))	('DN4', 'Gene', '28488', (47, 50))	('DN4', 'Gene', (47, 50))
288746	32796631	These observations suggest that pre-TCR and TCR signaling play an important role in the acquisition of Notch1 activating mutations, which in turn play a role in clonal dominance during leukemia development.	('TCR', 'Gene', '6962', (44, 47))	('mutations', 'Var', (121, 130))	('Notch1', 'Gene', (103, 109))	('leukemia', 'Disease', (185, 193))	('leukemia', 'Phenotype', 'HP:0001909', (185, 193))	('leukemia', 'Disease', 'MESH:D007938', (185, 193))	('TCR', 'Gene', (36, 39))	('TCR', 'Gene', (44, 47))	('activating', 'PosReg', (110, 120))	('TCR', 'Gene', '6962', (36, 39))	('play', 'Reg', (146, 150))
288760	32796631	Cancerogenesis might be initiated by the accumulation of mutations to conserve the undifferentiated character of epithelial stem cells or revert committed progenitors to a more immature state.	('revert', 'NegReg', (138, 144))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('mutations', 'Var', (57, 66))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('undifferentiated', 'MPA', (83, 99))
288765	32796631	It was suggested that alterations in Notch signaling are involved in tumor formation (Figure 1).	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('Notch', 'Gene', '31293', (37, 42))	('tumor', 'Disease', (69, 74))	('alterations', 'Var', (22, 33))	('Notch', 'Gene', (37, 42))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('involved', 'Reg', (57, 65))
288770	32796631	In a genome-wide association study, a single nucleotide polymorphism (rs11249433) in the 1p11.2 region was identified as a genetic risk factor for breast cancer.	('breast cancer', 'Disease', 'MESH:D001943', (147, 160))	('single nucleotide polymorphism', 'Var', (38, 68))	('rs11249433', 'Var', (70, 80))	('breast cancer', 'Phenotype', 'HP:0003002', (147, 160))	('breast cancer', 'Disease', (147, 160))	('risk factor', 'Reg', (131, 142))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('rs11249433', 'Mutation', 'rs11249433', (70, 80))
288771	32796631	Notch pathway functions in stem cell differentiation of estrogen receptor positive (ER+) luminal cells, therefore increased Notch2 expression in carriers of rs11249433 may promote development of ER+ luminal tumors.	('Notch2', 'Gene', '4853', (124, 130))	('Notch', 'Gene', '31293', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('Notch', 'Gene', (124, 129))	('rs11249433', 'Mutation', 'rs11249433', (157, 167))	('luminal tumors', 'Disease', (199, 213))	('estrogen receptor', 'Gene', '2099', (56, 73))	('luminal', 'Chemical', 'MESH:D010634', (89, 96))	('ER', 'Gene', '2069', (84, 86))	('Notch', 'Gene', (0, 5))	('increased', 'PosReg', (114, 123))	('ER', 'Gene', '2069', (195, 197))	('promote', 'PosReg', (172, 179))	('Notch2', 'Gene', (124, 130))	('rs11249433', 'Var', (157, 167))	('luminal', 'Chemical', 'MESH:D010634', (199, 206))	('Notch', 'Gene', '31293', (124, 129))	('estrogen receptor', 'Gene', (56, 73))	('expression', 'MPA', (131, 141))	('tumors', 'Phenotype', 'HP:0002664', (207, 213))	('luminal tumors', 'Disease', 'MESH:D009369', (199, 213))
288772	32796631	Notch3 was reported to repress Notch1-mediated activation via Hes1 and Hes5.	('Hes5', 'Gene', (71, 75))	('Hes5', 'Gene', '388585', (71, 75))	('Notch3', 'Var', (0, 6))	('repress', 'NegReg', (23, 30))	('Notch1-mediated', 'Gene', (31, 46))
288778	32796631	In a mammary stem cell population, characterized by CD24+CD29high, N1ICD impairs mammary stem cell self-renewal and leads to their transformation via a cyclin D1-dependent pathway.	('cyclin D1', 'Gene', (152, 161))	('CD29', 'Gene', '3688', (57, 61))	('transformation', 'CPA', (131, 145))	('mammary stem cell self-renewal', 'CPA', (81, 111))	('CD29', 'Gene', (57, 61))	('impairs', 'NegReg', (73, 80))	('N1ICD', 'Var', (67, 72))	('CD24', 'Gene', '100133941', (52, 56))	('cyclin D1', 'Gene', '595', (152, 161))	('CD24', 'Gene', (52, 56))	('leads to', 'Reg', (116, 124))
288787	32796631	Cancer initiation is linked to genetic and chromosomal instability, where several mutations accumulated to drive progression from benign malignancies (polyps) to invasive cancer.	('malignancies', 'Disease', 'MESH:D009369', (137, 149))	('chromosomal instability', 'Phenotype', 'HP:0040012', (43, 66))	('invasive cancer', 'Disease', 'MESH:D009362', (162, 177))	('polyps', 'Disease', (151, 157))	('malignancies', 'Disease', (137, 149))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('mutations', 'Var', (82, 91))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('polyps', 'Disease', 'MESH:D011127', (151, 157))	('invasive cancer', 'Disease', (162, 177))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))
288788	32796631	One of the major targets of cancerogenic mutations is the adenomatous polyposis coli (Apc) gene, which regulates stem cell self-renewal in a variety of systems.	('mutations', 'Var', (41, 50))	('adenomatous polyposis coli', 'Gene', '324', (58, 84))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('Apc', 'Phenotype', 'HP:0005227', (86, 89))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('cancer', 'Disease', (28, 34))	('adenomatous polyposis coli', 'Gene', (58, 84))	('adenomatous polyposis coli', 'Phenotype', 'HP:0005227', (58, 84))
288790	32796631	Genetic knockout of the tumor suppressor Apc induces intestinal tumor formation in a mouse model of adenoma.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('mouse', 'Species', '10090', (85, 90))	('tumor', 'Disease', (64, 69))	('tumor', 'Disease', (24, 29))	('intestinal tumor', 'Disease', (53, 69))	('induces', 'Reg', (45, 52))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('intestinal tumor', 'Disease', 'MESH:D007414', (53, 69))	('adenoma', 'Disease', 'MESH:D000236', (100, 107))	('Apc', 'Phenotype', 'HP:0005227', (41, 44))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('adenoma', 'Disease', (100, 107))	('knockout', 'Var', (8, 16))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
288797	32796631	Mouse genetic models also showed that NICD-induced polyps, aberrant stem cell and progenitor cell proliferation and support the growth of a gastric tumor.	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('gastric tumor', 'Disease', (140, 153))	('growth', 'CPA', (128, 134))	('polyps', 'Disease', (51, 57))	('support', 'PosReg', (116, 123))	('Mouse', 'Species', '10090', (0, 5))	('gastric tumor', 'Disease', 'MESH:D013274', (140, 153))	('NICD-induced', 'Var', (38, 50))	('gastric tumor', 'Phenotype', 'HP:0006753', (140, 153))	('polyps', 'Disease', 'MESH:D011127', (51, 57))
288800	32796631	Though conflicting results exist, an increase of JAG1, JAG2, DLL1, DLL3, DLL4 and NOTCH1-4 expressions are reported to be present in 75% of the colorectal cancer tissues and specifically, tumor cell-autonomous signaling can occur by a copy number gain of the NOTCH1 receptor, which can be found in 22% of colorectal cancers (Figure 1).	('tumor', 'Disease', (188, 193))	('colorectal cancers', 'Disease', 'MESH:D015179', (305, 323))	('JAG2', 'Gene', '3714', (55, 59))	('NOTCH1', 'Gene', '4851', (82, 88))	('DLL3', 'Gene', (67, 71))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('colorectal cancer', 'Disease', 'MESH:D015179', (144, 161))	('gain', 'PosReg', (247, 251))	('NOTCH1', 'Gene', (259, 265))	('JAG1', 'Gene', '182', (49, 53))	('colorectal cancer', 'Disease', (144, 161))	('increase', 'PosReg', (37, 45))	('cancers', 'Phenotype', 'HP:0002664', (316, 323))	('colorectal cancer', 'Phenotype', 'HP:0003003', (305, 322))	('DLL3', 'Gene', '10683', (67, 71))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('NOTCH1', 'Gene', '4851', (259, 265))	('DLL1', 'Gene', (61, 65))	('colorectal cancers', 'Disease', (305, 323))	('cancer', 'Phenotype', 'HP:0002664', (316, 322))	('DLL4', 'Gene', (73, 77))	('JAG2', 'Gene', (55, 59))	('colorectal cancer', 'Phenotype', 'HP:0003003', (144, 161))	('copy number', 'Var', (235, 246))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('JAG1', 'Gene', (49, 53))	('colorectal cancer', 'Disease', 'MESH:D015179', (305, 322))	('NOTCH1', 'Gene', (82, 88))
288804	32796631	These mutations contribute to an increased CSCs self-renewal and metastasis formation, while a combination of Notch1 activation and p53 deletion caused metastatic disease in colon cancer.	('metastatic disease', 'Disease', (152, 170))	('caused', 'Reg', (145, 151))	('p53', 'Gene', (132, 135))	('p53', 'Gene', '7157', (132, 135))	('Notch1', 'Gene', (110, 116))	('CSCs self-renewal', 'CPA', (43, 60))	('colon cancer', 'Disease', 'MESH:D015179', (174, 186))	('colon cancer', 'Phenotype', 'HP:0003003', (174, 186))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('deletion', 'Var', (136, 144))	('increased', 'PosReg', (33, 42))	('colon cancer', 'Disease', (174, 186))	('metastasis formation', 'CPA', (65, 85))	('activation', 'PosReg', (117, 127))
288816	32796631	reported that Notch2 affects cell growth and apoptosis as well as a knockdown in vitro lead to decreased migration and invasion.	('decreased', 'NegReg', (95, 104))	('Notch2', 'Gene', '4853', (14, 20))	('cell growth', 'CPA', (29, 40))	('affects', 'Reg', (21, 28))	('knockdown', 'Var', (68, 77))	('Notch2', 'Gene', (14, 20))	('apoptosis', 'CPA', (45, 54))
288817	32796631	In HNSCC cells, inhibition of NOTCH3 decreases cell proliferation as well as the sphere forming ability, which is related to cancer stem cells.	('sphere forming ability', 'CPA', (81, 103))	('NOTCH3', 'Gene', (30, 36))	('cancer', 'Disease', (125, 131))	('NOTCH3', 'Gene', '4854', (30, 36))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('inhibition', 'Var', (16, 26))	('decreases', 'NegReg', (37, 46))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('cell proliferation', 'CPA', (47, 65))
288826	32796631	In oral squamous cell carcinoma (OSCC), Notch1 has an orchestrating role in the maintenance of undifferentiation, and blockage of the NOTCH1-Hes1 axis inhibits the CSC phenotype.	('inhibits', 'NegReg', (151, 159))	('orchestrating', 'MPA', (54, 67))	('blockage', 'Var', (118, 126))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (3, 31))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (8, 31))	('NOTCH1', 'Gene', '4851', (134, 140))	('NOTCH1', 'Gene', (134, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('oral squamous cell carcinoma', 'Disease', (3, 31))	('CSC', 'MPA', (164, 167))	('undifferentiation', 'MPA', (95, 112))
288828	32796631	Additionally, in TNFalpha-induced oral cancer, a knock-down of Hes1 leads to a decrease in self-renewal capacity of treated OSCC.	('TNFalpha', 'Gene', (17, 25))	('self-renewal capacity of treated OSCC', 'CPA', (91, 128))	('oral cancer', 'Disease', (34, 45))	('TNFalpha', 'Gene', '7124', (17, 25))	('decrease', 'NegReg', (79, 87))	('knock-down', 'Var', (49, 59))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('oral cancer', 'Disease', 'MESH:D009369', (34, 45))	('Hes1', 'Gene', (63, 67))
288836	32796631	The invasive pancreatic ductal carcinoma is thought to originate from an accumulation of immature cells, which in turn acquires mutations leading to the most advanced stages of the tumor.	('tumor', 'Disease', (181, 186))	('carcinoma', 'Phenotype', 'HP:0030731', (31, 40))	('mutations', 'Var', (128, 137))	('invasive pancreatic ductal carcinoma', 'Disease', (4, 40))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (24, 40))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('leading to', 'Reg', (138, 148))	('invasive pancreatic ductal carcinoma', 'Disease', 'MESH:D021441', (4, 40))
288838	32796631	Interestingly, this subpopulation expresses high levels of Notch1 and Notch2 compared to other pancreatic cancer cells.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (95, 112))	('Notch2', 'Gene', (70, 76))	('pancreatic cancer', 'Disease', (95, 112))	('pancreatic cancer', 'Disease', 'MESH:D010190', (95, 112))	('Notch1', 'Var', (59, 65))	('Notch2', 'Gene', '4853', (70, 76))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
288839	32796631	This finding correlates with the fact that pancreatic CSCs have low levels of miRNA-34 and miR-200, which were found to directly inhibit Notch expression.	('pancreatic CSCs', 'Disease', 'MESH:D010195', (43, 58))	('Notch', 'Gene', (137, 142))	('pancreatic CSCs', 'Disease', (43, 58))	('inhibit', 'NegReg', (129, 136))	('Notch', 'Gene', '31293', (137, 142))	('miRNA-34', 'Var', (78, 86))	('miR-200', 'Var', (91, 98))
288842	32796631	Blockage of NOTCH suppresses the TGFalpha-induced change of fate, suggesting that the Notch pathway is active since early tumorigenic stages.	('Blockage', 'Var', (0, 8))	('TGFalpha', 'Gene', (33, 41))	('NOTCH', 'Gene', (12, 17))	('NOTCH', 'Gene', '31293', (12, 17))	('fate', 'MPA', (60, 64))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('Notch', 'Gene', (86, 91))	('TGFalpha', 'Gene', '7039', (33, 41))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('suppresses', 'NegReg', (18, 28))	('tumor', 'Disease', (122, 127))	('Notch', 'Gene', '31293', (86, 91))
288854	32796631	Aberrant activation of Shh is known to be implicated in brain cancers.	('activation', 'PosReg', (9, 19))	('Aberrant', 'Var', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('Shh', 'Gene', (23, 26))	('brain cancers', 'Disease', 'MESH:D001932', (56, 69))	('brain cancers', 'Disease', (56, 69))	('cancers', 'Phenotype', 'HP:0002664', (62, 69))	('Shh', 'Gene', '6469', (23, 26))	('implicated', 'Reg', (42, 52))
288858	32796631	Blockage of Notch in medulloblastoma dramatically decreases the amount of CD133+-stem cells, consistently with the finding that upon Notch inhibition, Nestin+ undifferentiated cells are more likely to enter apoptosis than other cancer cells in the same tissue.	('Nestin', 'Gene', (151, 157))	('Blockage', 'Var', (0, 8))	('cancer', 'Disease', (228, 234))	('apoptosis', 'CPA', (207, 216))	('Notch', 'Gene', '31293', (12, 17))	('enter', 'PosReg', (201, 206))	('medulloblastoma', 'Disease', 'MESH:D008527', (21, 36))	('Notch', 'Gene', '31293', (133, 138))	('medulloblastoma', 'Phenotype', 'HP:0002885', (21, 36))	('decreases', 'NegReg', (50, 59))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('Nestin', 'Gene', '10763', (151, 157))	('amount', 'MPA', (64, 70))	('Notch', 'Gene', (12, 17))	('medulloblastoma', 'Disease', (21, 36))	('Notch', 'Gene', (133, 138))	('cancer', 'Disease', 'MESH:D009369', (228, 234))
288861	32796631	Notch1 loss-of-function mutations correlate with low-grade gliomas and have the best prognosis, in line with other studies where high expression of CSL, Notch1 or Notch2 sustains the tumor growth.	('Notch2', 'Gene', '4853', (163, 169))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('Notch1', 'Gene', (0, 6))	('CSL', 'Gene', (148, 151))	('loss-of-function', 'NegReg', (7, 23))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('glioma', 'Phenotype', 'HP:0009733', (59, 65))	('tumor', 'Disease', (183, 188))	('CSL', 'Gene', '3516', (148, 151))	('Notch2', 'Gene', (163, 169))	('gliomas', 'Disease', (59, 66))	('mutations', 'Var', (24, 33))	('gliomas', 'Disease', 'MESH:D005910', (59, 66))	('gliomas', 'Phenotype', 'HP:0009733', (59, 66))
288866	32796631	Importantly, regulation of Notch can result in augmented sensitivity to radiotherapy, as shown by GSI-treated samples exhibiting an increase in cell death following exposure to radiation.	('GSI', 'Chemical', '-', (98, 101))	('regulation', 'Var', (13, 23))	('Notch', 'Gene', (27, 32))	('Notch', 'Gene', '31293', (27, 32))	('sensitivity', 'MPA', (57, 68))	('death', 'Disease', 'MESH:D003643', (149, 154))	('augmented', 'PosReg', (47, 56))	('death', 'Disease', (149, 154))
288867	32796631	Consistently, external expression of the active intracellular portion of NOTCH1 and NOTCH2 has a protective effect on glioma CSCs, while knock-out of these receptors increase radioresistance.	('increase', 'PosReg', (166, 174))	('NOTCH2', 'Gene', '4853', (84, 90))	('glioma CSCs', 'Disease', 'MESH:D005910', (118, 129))	('protective effect', 'CPA', (97, 114))	('knock-out', 'Var', (137, 146))	('radioresistance', 'CPA', (175, 190))	('NOTCH2', 'Gene', (84, 90))	('glioma CSCs', 'Disease', (118, 129))	('glioma', 'Phenotype', 'HP:0009733', (118, 124))	('NOTCH1', 'Gene', '4851', (73, 79))	('NOTCH1', 'Gene', (73, 79))
288872	32796631	As a consequence of a chromosomal translocation in 19p, overexpression of Notch3 has been found in 40% of NSCLC patients.	('Notch3', 'Gene', (74, 80))	('chromosomal translocation in', 'Var', (22, 50))	('NSCLC', 'Disease', 'MESH:D002289', (106, 111))	('patients', 'Species', '9606', (112, 120))	('NSCLC', 'Phenotype', 'HP:0030358', (106, 111))	('overexpression', 'PosReg', (56, 70))	('NSCLC', 'Disease', (106, 111))
288873	32796631	Similarly, increased activity of Notch1 upon either gain-of-function mutations or downregulation of inhibitors (such as Numb) are linked to NSCLC development (Figure 1).	('mutations', 'Var', (69, 78))	('NSCLC', 'Disease', 'MESH:D002289', (140, 145))	('increased', 'PosReg', (11, 20))	('Numb', 'Gene', (120, 124))	('downregulation', 'NegReg', (82, 96))	('Numb', 'Gene', '8650', (120, 124))	('NSCLC', 'Phenotype', 'HP:0030358', (140, 145))	('Notch1', 'Gene', (33, 39))	('gain-of-function', 'PosReg', (52, 68))	('activity', 'MPA', (21, 29))	('NSCLC', 'Disease', (140, 145))
288877	32796631	The cancer subpopulation of the ALDH+ cells is also characterized by a high Notch expression, and inhibition of the pathway results in a decreased number of ALDH+ cells.	('Notch', 'Gene', '31293', (76, 81))	('inhibition', 'Var', (98, 108))	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('Notch', 'Gene', (76, 81))	('cancer', 'Disease', 'MESH:D009369', (4, 10))	('decreased', 'NegReg', (137, 146))	('cancer', 'Disease', (4, 10))
288882	32796631	Using a microarray high-throughput assay it was shown that mRNA of the receptor Notch2 is overexpressed in melanoma cells compared to healthy melanocytes (Figure 1).	('melanoma', 'Phenotype', 'HP:0002861', (107, 115))	('Notch2', 'Gene', '4853', (80, 86))	('melanoma', 'Disease', (107, 115))	('melanoma', 'Disease', 'MESH:D008545', (107, 115))	('overexpressed', 'PosReg', (90, 103))	('Notch2', 'Gene', (80, 86))	('mRNA', 'Var', (59, 63))
288896	32796631	In a mouse model where mice were treated with the carcinogen 7,12-dimethylbenz[a]anthracene (DMBA), deletion of Notch1 driven by the Keratin14 promoter lead to papilloma development.	('DMBA', 'Chemical', 'MESH:D015127', (93, 97))	('papilloma', 'Disease', (160, 169))	('Keratin14', 'Gene', (133, 142))	('papilloma', 'Phenotype', 'HP:0012740', (160, 169))	('papilloma', 'Disease', 'MESH:D010212', (160, 169))	('7,12-dimethylbenz[a]anthracene', 'Chemical', 'MESH:D015127', (61, 91))	('Notch1', 'Gene', (112, 118))	('mouse', 'Species', '10090', (5, 10))	('deletion', 'Var', (100, 108))	('lead to', 'Reg', (152, 159))	('Keratin14', 'Gene', '16664', (133, 142))	('mice', 'Species', '10090', (23, 27))
288900	32796631	A chimeric mouse model carrying Notch1 deletion via Msx2-Cre produces a mosaic pattern resulting in patches of Notch1 deficient and Notch1 expressing keratinocytes within the same microenvironment.	('Msx2', 'Gene', (52, 56))	('mouse', 'Species', '10090', (11, 16))	('Notch1', 'Gene', (32, 38))	('Notch1', 'Gene', (111, 117))	('deletion', 'Var', (39, 47))	('Msx2', 'Gene', '17702', (52, 56))	('deficient', 'NegReg', (118, 127))
288902	32796631	Interestingly, it could be demonstrated that tumors containing Notch1-expressing cells were as frequent as tumors predominantly containing Notch1-deficient cells in the same microenvironment.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumors', 'Disease', (45, 51))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('tumors', 'Disease', (107, 113))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('tumors', 'Disease', 'MESH:D009369', (45, 51))	('Notch1-expressing', 'Var', (63, 80))	('tumors', 'Disease', 'MESH:D009369', (107, 113))
288904	32796631	In a murine model of NMSC, the development of spontaneous BCC was observed over time upon Notch1 ablation.	('NMSC', 'Disease', (21, 25))	('Notch1', 'Gene', (90, 96))	('murine', 'Species', '10090', (5, 11))	('BCC', 'Phenotype', 'HP:0002671', (58, 61))	('ablation', 'Var', (97, 105))
288907	32796631	A crosstalk between the Notch and the Wnt signaling might exist in skin cancer, as ablation of Notch1 leads to increased beta-catenin, ultimately resulting in hyperplasia and BCC.	('skin cancer', 'Disease', (67, 78))	('hyperplasia', 'Disease', (159, 170))	('skin cancer', 'Disease', 'MESH:D012878', (67, 78))	('increased', 'PosReg', (111, 120))	('Notch', 'Gene', (95, 100))	('Notch', 'Gene', (24, 29))	('Notch', 'Gene', '31293', (95, 100))	('beta-catenin', 'Gene', (121, 133))	('BCC', 'CPA', (175, 178))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('resulting in', 'Reg', (146, 158))	('beta-catenin', 'Gene', '1499', (121, 133))	('hyperplasia', 'Disease', 'MESH:D006965', (159, 170))	('BCC', 'Phenotype', 'HP:0002671', (175, 178))	('Notch', 'Gene', '31293', (24, 29))	('skin cancer', 'Phenotype', 'HP:0008069', (67, 78))	('ablation', 'Var', (83, 91))
288908	32796631	Inhibition or deletion of Notch1 expression can lead to the development of squamous cell carcinomas of the skin.	('squamous cell carcinomas of the skin', 'Phenotype', 'HP:0006739', (75, 111))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (75, 99))	('carcinomas', 'Phenotype', 'HP:0030731', (89, 99))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (75, 99))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (75, 98))	('Inhibition', 'Var', (0, 10))	('Notch1', 'Gene', (26, 32))	('lead to', 'Reg', (48, 55))	('deletion', 'Var', (14, 22))	('squamous cell carcinomas', 'Disease', (75, 99))
288912	32796631	As p53 plays a major role in UV/DNA damage response, it is possible that sun-exposed downregulation of Notch1 is a consequence of UV induced mutations of p53, as evidence suggests that Notch1 is a downstream target of p53.	('p53', 'Gene', '7157', (3, 6))	('mutations', 'Var', (141, 150))	('downregulation', 'NegReg', (85, 99))	('Notch1', 'Gene', (103, 109))	('p53', 'Gene', (218, 221))	('p53', 'Gene', (154, 157))	('p53', 'Gene', '7157', (218, 221))	('p53', 'Gene', '7157', (154, 157))	('p53', 'Gene', (3, 6))
288931	32796631	However, self-renewal of breast CSCs is regulated by Notch signaling and knockdown of Notch4 showed a stronger effect than a Notch1 knockdown, underlining the importance of precise targeting.	('Notch', 'Gene', '31293', (53, 58))	('Notch', 'Gene', '31293', (125, 130))	('Notch', 'Gene', (125, 130))	('Notch', 'Gene', (86, 91))	('Notch', 'Gene', '31293', (86, 91))	('Notch', 'Gene', (53, 58))	('Notch4', 'Gene', (86, 92))	('Notch4', 'Gene', '4855', (86, 92))	('self-renewal', 'CPA', (9, 21))	('knockdown', 'Var', (73, 82))
288933	32796631	For instance, PF03084014 targeting advanced solid tumors has completed Phase-I with 72 patients in 2019.	('PF03084014', 'Var', (14, 24))	('solid tumors', 'Disease', 'MESH:D009369', (44, 56))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('PF03084014', 'Chemical', 'MESH:C550722', (14, 24))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('patients', 'Species', '9606', (87, 95))	('solid tumors', 'Disease', (44, 56))
288940	32796631	In the case of PF03084014, side effects included diarrhea, nausea, alopecia, leukopenia, anemia, vomiting, decreased appetite and fatigue.	('nausea', 'Disease', (59, 65))	('anemia', 'Disease', (89, 95))	('decreased appetite', 'Disease', 'MESH:D001068', (107, 125))	('alopecia', 'Disease', (67, 75))	('decreased appetite', 'Disease', (107, 125))	('decreased appetite', 'Phenotype', 'HP:0004396', (107, 125))	('diarrhea', 'Phenotype', 'HP:0002014', (49, 57))	('nausea', 'Disease', 'MESH:D009325', (59, 65))	('fatigue', 'Disease', (130, 137))	('fatigue', 'Phenotype', 'HP:0012378', (130, 137))	('diarrhea', 'Disease', (49, 57))	('anemia', 'Disease', 'MESH:D000740', (89, 95))	('leukopenia', 'Disease', 'MESH:D007970', (77, 87))	('alopecia', 'Phenotype', 'HP:0001596', (67, 75))	('vomiting', 'Disease', 'MESH:D014839', (97, 105))	('PF03084014', 'Chemical', 'MESH:C550722', (15, 25))	('leukopenia', 'Phenotype', 'HP:0001882', (77, 87))	('nausea', 'Phenotype', 'HP:0002018', (59, 65))	('diarrhea', 'Disease', 'MESH:D003967', (49, 57))	('PF03084014', 'Var', (15, 25))	('leukopenia', 'Disease', (77, 87))	('fatigue', 'Disease', 'MESH:D005221', (130, 137))	('vomiting', 'Phenotype', 'HP:0002013', (97, 105))	('anemia', 'Phenotype', 'HP:0001903', (89, 95))	('vomiting', 'Disease', (97, 105))
288946	32796631	In-vivo studies demonstrated that treatment with MEDI0639 led to non-functional vessel formation, therefore a Phase-1 trial had been conducted until 2017, in order to determine the effects in patients of solid tumors (; NCT01577745).	('non-functional', 'MPA', (65, 79))	('MEDI0639', 'Var', (49, 57))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('solid tumors', 'Disease', 'MESH:D009369', (204, 216))	('patients', 'Species', '9606', (192, 200))	('tumors', 'Phenotype', 'HP:0002664', (210, 216))	('MEDI0639', 'Chemical', '-', (49, 57))	('solid tumors', 'Disease', (204, 216))
288947	32796631	The antibody OMP21M18, a humanized IgG2 antibody, blocking the interaction of DLL4 with NOTCH1 and NOTCH4 and had been tested as a cancer stem cell agent in a Phase-I trial in patients with previously treated solid tumors (Figure 3).	('cancer', 'Disease', (131, 137))	('NOTCH1', 'Gene', (88, 94))	('NOTCH1', 'Gene', '4851', (88, 94))	('patients', 'Species', '9606', (176, 184))	('solid tumors', 'Disease', (209, 221))	('DLL4', 'Protein', (78, 82))	('interaction', 'Interaction', (63, 74))	('human', 'Species', '9606', (25, 30))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('blocking', 'NegReg', (50, 58))	('NOTCH4', 'Gene', (99, 105))	('NOTCH4', 'Gene', '4855', (99, 105))	('solid tumors', 'Disease', 'MESH:D009369', (209, 221))	('OMP21M18', 'Var', (13, 21))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('tumors', 'Phenotype', 'HP:0002664', (215, 221))
288951	32796631	Additionally, the redundancy of the Notch pathway might induce compensatory effects and bypass antibody-induce blockage.	('compensatory', 'MPA', (63, 75))	('Notch', 'Gene', '31293', (36, 41))	('redundancy', 'Var', (18, 28))	('induce', 'Reg', (56, 62))	('Notch', 'Gene', (36, 41))
288953	32796631	Additionally, a prolonged administration of OMP21M18 was associated with increased risk of congestive heart failure and hypertension in patients.	('congestive heart failure', 'Disease', 'MESH:D006333', (91, 115))	('hypertension', 'Disease', 'MESH:D006973', (120, 132))	('congestive heart failure', 'Disease', (91, 115))	('hypertension', 'Disease', (120, 132))	('hypertension', 'Phenotype', 'HP:0000822', (120, 132))	('patients', 'Species', '9606', (136, 144))	('OMP21M18', 'Var', (44, 52))	('congestive heart failure', 'Phenotype', 'HP:0001635', (91, 115))
288960	32796631	However, the choice of the target appears to be highly sensitive in regard to the outcome, as a genetic removal of CSL showed accelerated growth of xenografted tumors.	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('CSL', 'Gene', (115, 118))	('genetic removal', 'Var', (96, 111))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('accelerated', 'PosReg', (126, 137))	('CSL', 'Gene', '3516', (115, 118))	('tumors', 'Disease', (160, 166))	('growth', 'MPA', (138, 144))	('tumors', 'Disease', 'MESH:D009369', (160, 166))
288963	32796631	The use of a Notch1 decoy (N110-24) blocked JAG1/JAG2-mediated Notch1 signaling (Figure 3).	('JAG2', 'Gene', '3714', (49, 53))	('blocked', 'NegReg', (36, 43))	('JAG1', 'Gene', '182', (44, 48))	('N110-24', 'Var', (27, 34))	('JAG2', 'Gene', (49, 53))	('JAG1', 'Gene', (44, 48))
288965	32796631	Additionally, decoy N11-13 was able to interfere with DLL1-DLL4-mediated NOTCH1 signaling and led to hyper-sprouting.	('decoy N11-13', 'Var', (14, 26))	('interfere', 'NegReg', (39, 48))	('led to', 'Reg', (94, 100))	('hyper-sprouting', 'CPA', (101, 116))	('decoy N11-13', 'Chemical', '-', (14, 26))	('NOTCH1', 'Gene', '4851', (73, 79))	('NOTCH1', 'Gene', (73, 79))
288974	31695493	Clinical And Imageological Features Of Lung Squamous Cell Carcinoma With EGFR Mutations To analyze the distribution of epidermal growth factor receptor (EGFR) mutations; characterize the clinical and imageological features of lung squamous cell carcinoma (LSCC) in a large population of patients; and assess correlations between clinical and imageological characteristics and clinical outcomes of LSCC patients harboring EGFR mutations.	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (226, 254))	('lung squamous cell carcinoma', 'Disease', (226, 254))	('LSCC', 'Phenotype', 'HP:0030359', (256, 260))	('epidermal growth factor receptor', 'Gene', '1956', (119, 151))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (231, 254))	('Squamous Cell Carcinoma', 'Disease', (44, 67))	('LSCC', 'Phenotype', 'HP:0030359', (397, 401))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (44, 67))	('carcinoma', 'Phenotype', 'HP:0030731', (245, 254))	('EGFR', 'Gene', (73, 77))	('LSCC', 'Disease', 'MESH:D002294', (256, 260))	('EGFR', 'Gene', (421, 425))	('Lung Squamous Cell Carcinoma', 'Phenotype', 'HP:0030359', (39, 67))	('EGFR', 'Gene', (153, 157))	('patients', 'Species', '9606', (402, 410))	('LSCC', 'Disease', (256, 260))	('Mutations', 'Var', (78, 87))	('LSCC', 'Disease', 'MESH:D002294', (397, 401))	('Carcinoma', 'Phenotype', 'HP:0030731', (58, 67))	('mutations', 'Var', (426, 435))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (226, 254))	('LSCC', 'Disease', (397, 401))	('EGFR', 'Gene', '1956', (73, 77))	('Squamous Cell Carcinoma', 'Disease', 'MESH:D002294', (44, 67))	('EGFR', 'Gene', '1956', (421, 425))	('patients', 'Species', '9606', (287, 295))	('EGFR', 'Gene', '1956', (153, 157))	('epidermal growth factor receptor', 'Gene', (119, 151))
288976	31695493	Data on the distribution of EGFR mutations and the clinical and imageological characteristics of the patients were retrospectively collected.	('patients', 'Species', '9606', (101, 109))	('EGFR', 'Gene', '1956', (28, 32))	('EGFR', 'Gene', (28, 32))	('mutations', 'Var', (33, 42))
288977	31695493	Correlations between the EGFR mutation status and clinical outcomes were evaluated using univariate and multivariate analyses.	('mutation', 'Var', (30, 38))	('EGFR', 'Gene', '1956', (25, 29))	('EGFR', 'Gene', (25, 29))
288978	31695493	EGFR mutations were found in 3.4% of patients with LSCC and predominantly in female and non-smoking patients.	('EGFR', 'Gene', (0, 4))	('patients', 'Species', '9606', (37, 45))	('LSCC', 'Disease', (51, 55))	('mutations', 'Var', (5, 14))	('patients', 'Species', '9606', (100, 108))	('LSCC', 'Phenotype', 'HP:0030359', (51, 55))	('found', 'Reg', (20, 25))	('LSCC', 'Disease', 'MESH:D002294', (51, 55))	('EGFR', 'Gene', '1956', (0, 4))
288979	31695493	Tumor lesions in patients with EGFR-positive mutations were more irregularly shaped than those in patients with EGFR-negative mutations (P = 0.045).	('EGFR', 'Gene', (112, 116))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('Tumor lesions', 'Disease', (0, 13))	('mutations', 'Var', (45, 54))	('EGFR', 'Gene', '1956', (31, 35))	('EGFR', 'Gene', (31, 35))	('patients', 'Species', '9606', (98, 106))	('Tumor lesions', 'Disease', 'MESH:D001932', (0, 13))	('patients', 'Species', '9606', (17, 25))	('EGFR', 'Gene', '1956', (112, 116))
288983	31695493	Female gender, non-smoking habit, irregularly shaped tumor, and marked spiculation might predict the presence of EGFR mutations in LSCC.	('LSCC', 'Disease', 'MESH:D002294', (131, 135))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('mutations', 'Var', (118, 127))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('EGFR', 'Gene', '1956', (113, 117))	('EGFR', 'Gene', (113, 117))	('tumor', 'Disease', (53, 58))	('LSCC', 'Disease', (131, 135))	('LSCC', 'Phenotype', 'HP:0030359', (131, 135))
288984	31695493	The administration of tyrosine kinase inhibitors to patients with LSCC after screening for EGFR mutations based on their clinical and imageological features would likely result in a population with a greater sensitivity to afatinib.	('EGFR', 'Gene', (91, 95))	('LSCC', 'Disease', 'MESH:D002294', (66, 70))	('tyrosine', 'Chemical', 'None', (22, 30))	('afatinib', 'Chemical', 'MESH:C522924', (223, 231))	('LSCC', 'Disease', (66, 70))	('patients', 'Species', '9606', (52, 60))	('sensitivity', 'MPA', (208, 219))	('EGFR', 'Gene', '1956', (91, 95))	('LSCC', 'Phenotype', 'HP:0030359', (66, 70))	('mutations', 'Var', (96, 105))
288990	31695493	Targeting EGFR with tyrosine kinase inhibitors (TKIs) has become the cornerstone for the management of advanced non-squamous NSCLCs harboring activating mutations of the EGFR gene.	('EGFR', 'Gene', '1956', (10, 14))	('mutations', 'Var', (153, 162))	('EGFR', 'Gene', (10, 14))	('NSCLC', 'Disease', (125, 130))	('EGFR', 'Gene', '1956', (170, 174))	('NSCLC', 'Disease', 'MESH:D002289', (125, 130))	('tyrosine', 'Chemical', 'None', (20, 28))	('EGFR', 'Gene', (170, 174))	('men', 'Species', '9606', (95, 98))	('activating', 'PosReg', (142, 152))	('NSCLC', 'Phenotype', 'HP:0030358', (125, 130))
288992	31695493	The most frequent somatic mutations and alterations in LSCC have been identified in TP53, PIK3CA, FGFR1, MET, and DDR2, and none of these biomarkers have been validated as predictive for the particular targeted therapies.	('DDR2', 'Gene', '4921', (114, 118))	('FGFR1', 'Gene', (98, 103))	('DDR2', 'Gene', (114, 118))	('FGFR1', 'Gene', '2260', (98, 103))	('alterations', 'Var', (40, 51))	('TP53', 'Gene', '7157', (84, 88))	('PIK3CA', 'Gene', (90, 96))	('mutations', 'Var', (26, 35))	('LSCC', 'Disease', (55, 59))	('LSCC', 'Phenotype', 'HP:0030359', (55, 59))	('TP53', 'Gene', (84, 88))	('PIK3CA', 'Gene', '5290', (90, 96))	('MET', 'Gene', (105, 108))	('LSCC', 'Disease', 'MESH:D002294', (55, 59))
288994	31695493	Although activating mutations of EGFR are uncommon in LSCC, patients with the genetic mutations of this subtype might benefit from EGFR-TKI-targeted therapies with lower side effects and toxicities than those of chemotherapy, thus highlighting the benefit of EGFR mutation status identification in patients with LSCC.	('mutations', 'Var', (86, 95))	('LSCC', 'Disease', (312, 316))	('LSCC', 'Phenotype', 'HP:0030359', (54, 58))	('patients', 'Species', '9606', (60, 68))	('toxicities', 'Disease', (187, 197))	('LSCC', 'Phenotype', 'HP:0030359', (312, 316))	('patients', 'Species', '9606', (298, 306))	('EGFR', 'Gene', '1956', (33, 37))	('EGFR', 'Gene', '1956', (259, 263))	('EGFR', 'Gene', '1956', (131, 135))	('LSCC', 'Disease', 'MESH:D002294', (54, 58))	('EGFR', 'Gene', (131, 135))	('LSCC', 'Disease', 'MESH:D002294', (312, 316))	('EGFR', 'Gene', (33, 37))	('EGFR', 'Gene', (259, 263))	('toxicities', 'Disease', 'MESH:D064420', (187, 197))	('LSCC', 'Disease', (54, 58))
288995	31695493	Cumulative epidemiologic studies have identified several clinicopathological factors such as gender, smoking habits, histology of adenocarcinoma (ADC), and ethnicity that may be associated with a high prevalence of EGFR mutations.	('adenocarcinoma', 'Disease', (130, 144))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('adenocarcinoma', 'Disease', 'MESH:D000230', (130, 144))	('ADC', 'Disease', 'MESH:D000230', (146, 149))	('EGFR', 'Gene', '1956', (215, 219))	('ADC', 'Disease', (146, 149))	('EGFR', 'Gene', (215, 219))	('mutations', 'Var', (220, 229))
288996	31695493	In addition, other tumor imageological characteristics and biological parameters may have a predictive effect on the EGFR mutation status in lung ADC.	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('EGFR', 'Gene', '1956', (117, 121))	('mutation', 'Var', (122, 130))	('EGFR', 'Gene', (117, 121))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('lung ADC', 'Disease', 'MESH:C538231', (141, 149))	('tumor', 'Disease', (19, 24))	('lung ADC', 'Disease', (141, 149))
288997	31695493	Unfortunately, the distribution of EGFR mutations in LSCC is poorly investigated, and the imageological features related to EGFR mutations in LSCC remain unclear.	('LSCC', 'Disease', (53, 57))	('EGFR', 'Gene', '1956', (124, 128))	('LSCC', 'Phenotype', 'HP:0030359', (53, 57))	('EGFR', 'Gene', '1956', (35, 39))	('EGFR', 'Gene', (35, 39))	('EGFR', 'Gene', (124, 128))	('mutations', 'Var', (40, 49))	('LSCC', 'Disease', 'MESH:D002294', (53, 57))	('LSCC', 'Disease', (142, 146))	('LSCC', 'Phenotype', 'HP:0030359', (142, 146))	('LSCC', 'Disease', 'MESH:D002294', (142, 146))
288998	31695493	Therefore, in this study, we aimed to analyze the distribution of EGFR mutations and the clinical and morphological features of a large population of LSCC patients who underwent therapeutic resection and adjuvant chemotherapy post-surgery.	('LSCC', 'Disease', (150, 154))	('EGFR', 'Gene', '1956', (66, 70))	('EGFR', 'Gene', (66, 70))	('LSCC', 'Phenotype', 'HP:0030359', (150, 154))	('mutations', 'Var', (71, 80))	('patients', 'Species', '9606', (155, 163))	('LSCC', 'Disease', 'MESH:D002294', (150, 154))
288999	31695493	Additionally, we assessed the correlations between clinical and imageological characteristics and the clinical outcome of LSCC patients with EGFR mutations.	('mutations', 'Var', (146, 155))	('EGFR', 'Gene', '1956', (141, 145))	('LSCC', 'Disease', (122, 126))	('EGFR', 'Gene', (141, 145))	('LSCC', 'Phenotype', 'HP:0030359', (122, 126))	('patients', 'Species', '9606', (127, 135))	('LSCC', 'Disease', 'MESH:D002294', (122, 126))
289012	31695493	Mutations in the EGFR gene were detected using the Amoy Diagnostics Kit (AmoyDx, Xiamen, China) according to the manufacturer's instructions.	('Kit', 'Gene', '3815', (68, 71))	('Mutations', 'Var', (0, 9))	('men', 'Species', '9606', (84, 87))	('EGFR', 'Gene', '1956', (17, 21))	('Kit', 'Gene', (68, 71))	('EGFR', 'Gene', (17, 21))
289014	31695493	EGFR mutations were detected using the ACCB Diagnostics Kit (ACCB, Beijing, China) according to the manufacturer's protocol The test could detect mutations at a sensitivity of 1% in no less than 5 ng/muL of the DNA sample.	('EGFR', 'Gene', (0, 4))	('mutations', 'Var', (146, 155))	('Kit', 'Gene', (56, 59))	('ACCB', 'Gene', (39, 43))	('mutations', 'Var', (5, 14))	('detect', 'Reg', (139, 145))	('ACCB', 'Gene', (61, 65))	('Kit', 'Gene', '3815', (56, 59))	('N', 'Chemical', 'MESH:D009584', (212, 213))	('ACCB', 'Gene', '32', (39, 43))	('ACCB', 'Gene', '32', (61, 65))	('EGFR', 'Gene', '1956', (0, 4))
289027	31695493	EGFR gene mutations were detected in 80 of the 2,322 samples (mutation rate, 3.4%).	('mutations', 'Var', (10, 19))	('EGFR', 'Gene', '1956', (0, 4))	('EGFR', 'Gene', (0, 4))
289028	31695493	Exon 19 deletions (19-del) and the L858R mutations in exon 21 comprised 48.75% and 32.5% of all EGFR mutations, respectively, in LSCC patients.	('L858R', 'Mutation', 'p.L858R', (35, 40))	('mutations', 'Var', (101, 110))	('LSCC', 'Phenotype', 'HP:0030359', (129, 133))	('EGFR', 'Gene', (96, 100))	('patients', 'Species', '9606', (134, 142))	('LSCC', 'Disease', 'MESH:D002294', (129, 133))	('L858R', 'Var', (35, 40))	('LSCC', 'Disease', (129, 133))	('deletions', 'Var', (8, 17))	('EGFR', 'Gene', '1956', (96, 100))
289029	31695493	The uncommon EGFR mutations observed in the cohort included 5 (6.25%) cases of 20-ins mutations, 3 (3.75%) of T790M mutations, 3 (3.75%) of G719X mutations, and 1 (1.25%) of L861Q mutation.	('L861Q', 'Var', (174, 179))	('G719X', 'Mutation', 'p.G719X', (140, 145))	('T790M', 'Mutation', 'p.T790M', (110, 115))	('T790M mutations', 'Var', (110, 125))	('G719X', 'Var', (140, 145))	('L861Q', 'Mutation', 'p.L861Q', (174, 179))	('20-ins', 'Disease', (79, 85))	('EGFR', 'Gene', '1956', (13, 17))	('EGFR', 'Gene', (13, 17))	('mutations', 'Var', (18, 27))
289030	31695493	The dual T790M and L858R mutations were observed in 2 (2.5%) patients and dual G719X and L861Q mutations were found in 1 (1.25%) patient (Figure 1).	('patient', 'Species', '9606', (61, 68))	('T790M', 'Mutation', 'p.T790M', (9, 14))	('L861Q', 'Mutation', 'p.L861Q', (89, 94))	('L858R', 'Mutation', 'p.L858R', (19, 24))	('G719X', 'Mutation', 'p.G719X', (79, 84))	('patients', 'Species', '9606', (61, 69))	('L858R', 'Var', (19, 24))	('L861Q', 'Var', (89, 94))	('patient', 'Species', '9606', (129, 136))
289048	31695493	The incidence of EGFR mutations, imageological features, and clinical outcomes were evaluated in a large cohort of postoperative patients with LSCC in the present study.	('LSCC', 'Disease', (143, 147))	('patients', 'Species', '9606', (129, 137))	('LSCC', 'Phenotype', 'HP:0030359', (143, 147))	('mutations', 'Var', (22, 31))	('EGFR', 'Gene', '1956', (17, 21))	('LSCC', 'Disease', 'MESH:D002294', (143, 147))	('EGFR', 'Gene', (17, 21))
289049	31695493	EGFR mutations were detected with increased frequency in females and non-smokers.	('EGFR', 'Gene', '1956', (0, 4))	('EGFR', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))
289050	31695493	Moreover, the tumors in patients with EGFR-positive mutations were more irregularly shaped and demonstrated marked spiculation compared with those with EGFR-negative mutations.	('mutations', 'Var', (52, 61))	('EGFR', 'Gene', '1956', (38, 42))	('spiculation', 'CPA', (115, 126))	('EGFR', 'Gene', (38, 42))	('EGFR', 'Gene', '1956', (152, 156))	('tumors', 'Disease', (14, 20))	('patients', 'Species', '9606', (24, 32))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('EGFR', 'Gene', (152, 156))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
289051	31695493	Thus, patients with active EGFR mutations might benefit from second-generation EGFR-TKIs treatments.	('EGFR', 'Gene', '1956', (27, 31))	('EGFR', 'Gene', (27, 31))	('EGFR', 'Gene', '1956', (79, 83))	('EGFR', 'Gene', (79, 83))	('men', 'Species', '9606', (94, 97))	('mutations', 'Var', (32, 41))	('patients', 'Species', '9606', (6, 14))
289052	31695493	Consistent with the findings of previous studies, the EGFR mutation rate in patients with LSCC in the current study was 3.4%; however, this value was much lower than that reported in patients with ADC.	('patients', 'Species', '9606', (76, 84))	('LSCC', 'Disease', 'MESH:D002294', (90, 94))	('ADC', 'Disease', 'MESH:D000230', (197, 200))	('EGFR', 'Gene', '1956', (54, 58))	('mutation', 'Var', (59, 67))	('ADC', 'Disease', (197, 200))	('LSCC', 'Disease', (90, 94))	('EGFR', 'Gene', (54, 58))	('patients', 'Species', '9606', (183, 191))	('LSCC', 'Phenotype', 'HP:0030359', (90, 94))
289053	31695493	Exon 19-del and L858R mutations in exon 21 of the EGFR gene are the two commonest mutations that predict the favorable efficacy of EGFR-TKIs.	('L858R', 'Mutation', 'p.L858R', (16, 21))	('EGFR', 'Gene', '1956', (50, 54))	('EGFR', 'Gene', '1956', (131, 135))	('EGFR', 'Gene', (131, 135))	('EGFR', 'Gene', (50, 54))	('L858R', 'Var', (16, 21))
289054	31695493	The L858R mutation is reportedly the commonest type of mutation in patients with ADC, whereas exon 19-del is dominant in LSCC.	('L858R', 'Var', (4, 9))	('LSCC', 'Disease', 'MESH:D002294', (121, 125))	('patients', 'Species', '9606', (67, 75))	('ADC', 'Disease', 'MESH:D000230', (81, 84))	('L858R', 'Mutation', 'p.L858R', (4, 9))	('LSCC', 'Disease', (121, 125))	('LSCC', 'Phenotype', 'HP:0030359', (121, 125))	('ADC', 'Disease', (81, 84))
289055	31695493	In the present study, exon 19-del and EGFR L858R mutations accounted for 48.75% and 32.5% of all EGFR mutations, respectively, in patients with LSCC.	('EGFR', 'Gene', '1956', (38, 42))	('exon 19-del', 'Var', (22, 33))	('EGFR', 'Gene', '1956', (97, 101))	('EGFR', 'Gene', (38, 42))	('LSCC', 'Disease', (144, 148))	('LSCC', 'Phenotype', 'HP:0030359', (144, 148))	('L858R', 'Mutation', 'p.L858R', (43, 48))	('EGFR', 'Gene', (97, 101))	('patients', 'Species', '9606', (130, 138))	('mutations', 'Var', (102, 111))	('LSCC', 'Disease', 'MESH:D002294', (144, 148))	('L858R', 'Var', (43, 48))
289056	31695493	The mutation rate of the EGFR L858R mutation in patients with LSCC was lower than that reported in patients with non-squamous NSCLC.	('LSCC', 'Disease', 'MESH:D002294', (62, 66))	('NSCLC', 'Disease', 'MESH:D002289', (126, 131))	('EGFR', 'Gene', (25, 29))	('LSCC', 'Disease', (62, 66))	('patients', 'Species', '9606', (99, 107))	('L858R', 'Mutation', 'p.L858R', (30, 35))	('NSCLC', 'Phenotype', 'HP:0030358', (126, 131))	('LSCC', 'Phenotype', 'HP:0030359', (62, 66))	('mutation rate', 'MPA', (4, 17))	('patients', 'Species', '9606', (48, 56))	('EGFR', 'Gene', '1956', (25, 29))	('L858R', 'Var', (30, 35))	('NSCLC', 'Disease', (126, 131))	('lower', 'NegReg', (71, 76))
289057	31695493	In contrast, the uncommon EGFR mutations observed in the cohort included 5 (6.25%) cases of 20-ins mutations and 3 (3.75%) of T790M mutations.	('EGFR', 'Gene', (26, 30))	('20-ins mutations', 'Var', (92, 108))	('EGFR', 'Gene', '1956', (26, 30))	('T790M', 'Mutation', 'p.T790M', (126, 131))	('T790M mutations', 'Var', (126, 141))
289058	31695493	The frequency of uncommon mutations (20-ins and T790M) in LSCC was higher than that in NSCLC, which might partly explain the poor response to EGFR-TKIs.	('20-ins', 'Var', (37, 43))	('LSCC', 'Disease', 'MESH:D002294', (58, 62))	('NSCLC', 'Disease', (87, 92))	('EGFR', 'Gene', '1956', (142, 146))	('NSCLC', 'Disease', 'MESH:D002289', (87, 92))	('EGFR', 'Gene', (142, 146))	('LSCC', 'Disease', (58, 62))	('LSCC', 'Phenotype', 'HP:0030359', (58, 62))	('NSCLC', 'Phenotype', 'HP:0030358', (87, 92))	('T790M', 'Var', (48, 53))	('T790M', 'Mutation', 'p.T790M', (48, 53))
289059	31695493	Evaluation of the clinicopathological characteristics of the patients revealed the absence of any association between EGFR mutation and the majority of clinicopathological characteristics.	('patients', 'Species', '9606', (61, 69))	('EGFR', 'Gene', '1956', (118, 122))	('EGFR', 'Gene', (118, 122))	('mutation', 'Var', (123, 131))
289061	31695493	In addition, EGFR mutations were more frequent in non-smokers than in previous smokers or current smokers (P = 0.006).	('frequent', 'Reg', (38, 46))	('EGFR', 'Gene', '1956', (13, 17))	('EGFR', 'Gene', (13, 17))	('mutations', 'Var', (18, 27))
289062	31695493	Moreover, based on the logistic regression analysis, smoking was negatively correlated (odds ratio [OR], 0.68; 95% confidence interval [CI], 0.476-0.973; P = 0.035) with EGFR mutations (data not shown).	('EGFR', 'Gene', '1956', (170, 174))	('EGFR', 'Gene', (170, 174))	('mutations', 'Var', (175, 184))	('negatively', 'NegReg', (65, 75))
289063	31695493	This is consistent with the clinical characteristics of EGFR mutations in ADC and LSCC.	('LSCC', 'Disease', (82, 86))	('EGFR', 'Gene', '1956', (56, 60))	('LSCC', 'Phenotype', 'HP:0030359', (82, 86))	('mutations', 'Var', (61, 70))	('EGFR', 'Gene', (56, 60))	('ADC', 'Disease', 'MESH:D000230', (74, 77))	('LSCC', 'Disease', 'MESH:D002294', (82, 86))	('ADC', 'Disease', (74, 77))
289067	31695493	Nonetheless, the logistic regression analysis did not show any correlations between the imageological features and EGFR mutations.	('EGFR', 'Gene', '1956', (115, 119))	('EGFR', 'Gene', (115, 119))	('N', 'Chemical', 'MESH:D009584', (0, 1))	('mutations', 'Var', (120, 129))
289068	31695493	Targeting EGFR with TKIs has become the cornerstone for the management of advanced non-squamous NSCLC harboring activating EGFR mutations; however, the relevance of EGFR inhibitors in LSCC is poorly defined.	('EGFR', 'Gene', (123, 127))	('EGFR', 'Gene', (165, 169))	('EGFR', 'Gene', '1956', (10, 14))	('men', 'Species', '9606', (66, 69))	('NSCLC', 'Disease', (96, 101))	('LSCC', 'Disease', 'MESH:D002294', (184, 188))	('mutations', 'Var', (128, 137))	('EGFR', 'Gene', (10, 14))	('NSCLC', 'Disease', 'MESH:D002289', (96, 101))	('EGFR', 'Gene', '1956', (123, 127))	('NSCLC', 'Phenotype', 'HP:0030358', (96, 101))	('LSCC', 'Disease', (184, 188))	('LSCC', 'Phenotype', 'HP:0030359', (184, 188))	('EGFR', 'Gene', '1956', (165, 169))	('activating', 'PosReg', (112, 122))
289069	31695493	The role of erlotinib in the treatment of LSCC, irrespective of the EGFR mutation status, has been evaluated in several clinical trials, including the observational PEPiTA study, the BR.21 trial, the SATURN study, the TRUST study, the TITAN, and the DELTA trial.	('LSCC', 'Disease', 'MESH:D002294', (42, 46))	('N', 'Chemical', 'MESH:D009584', (205, 206))	('N', 'Chemical', 'MESH:D009584', (239, 240))	('LSCC', 'Disease', (42, 46))	('erlotinib', 'Chemical', 'MESH:C400278', (12, 21))	('DELTA', 'Mutation', 'c.del', (250, 255))	('EGFR', 'Gene', '1956', (68, 72))	('LSCC', 'Phenotype', 'HP:0030359', (42, 46))	('mutation', 'Var', (73, 81))	('EGFR', 'Gene', (68, 72))	('men', 'Species', '9606', (34, 37))
289074	31695493	Yuri Taniguchi and his colleagues showed that the administration of afatinib to LSCC patients who were selected using the EGFR mutation test based on the underlying pulmonary disease and smoking status would likely result in a population with a greater sensitivity to afatinib.	('LSCC', 'Disease', 'MESH:D002294', (80, 84))	('afatinib', 'Chemical', 'MESH:C522924', (68, 76))	('LSCC', 'Phenotype', 'HP:0030359', (80, 84))	('mutation', 'Var', (127, 135))	('pulmonary disease', 'Disease', 'MESH:D008171', (165, 182))	('patients', 'Species', '9606', (85, 93))	('afatinib', 'Chemical', 'MESH:C522924', (268, 276))	('sensitivity to afatinib', 'MPA', (253, 276))	('LSCC', 'Disease', (80, 84))	('EGFR', 'Gene', '1956', (122, 126))	('greater', 'PosReg', (245, 252))	('EGFR', 'Gene', (122, 126))	('pulmonary disease', 'Disease', (165, 182))
289076	31695493	Second, this was a retrospective study, and we could not collect any data related to targeted therapy (although afatinib has been shown to be effective for LSCC patients harboring activating EGFR mutations); therefore, the efficacy of EGFR-TKIs was not evaluated in this study.	('afatinib', 'Chemical', 'MESH:C522924', (112, 120))	('LSCC', 'Disease', 'MESH:D002294', (156, 160))	('EGFR', 'Gene', '1956', (191, 195))	('activating', 'PosReg', (180, 190))	('EGFR', 'Gene', (191, 195))	('patients', 'Species', '9606', (161, 169))	('EGFR', 'Gene', '1956', (235, 239))	('EGFR', 'Gene', (235, 239))	('LSCC', 'Disease', (156, 160))	('LSCC', 'Phenotype', 'HP:0030359', (156, 160))	('mutations', 'Var', (196, 205))
289078	31695493	The most important predictors of the presence of EGFR mutations in LSCC were female gender, non-smoking habit, irregularly-shaped lesions, and marked spiculation (imageological finding).	('EGFR', 'Gene', '1956', (49, 53))	('LSCC', 'Disease', (67, 71))	('EGFR', 'Gene', (49, 53))	('LSCC', 'Phenotype', 'HP:0030359', (67, 71))	('mutations', 'Var', (54, 63))	('LSCC', 'Disease', 'MESH:D002294', (67, 71))
289079	31695493	The administration of EGFR-TKIs to patients with LSCC after screening for EGFR mutations on the basis of their clinical and imageological features would likely result in a population with a greater sensitivity to afatinib.	('mutations', 'Var', (79, 88))	('afatinib', 'Chemical', 'MESH:C522924', (213, 221))	('LSCC', 'Disease', (49, 53))	('EGFR', 'Gene', '1956', (74, 78))	('EGFR', 'Gene', '1956', (22, 26))	('LSCC', 'Phenotype', 'HP:0030359', (49, 53))	('patients', 'Species', '9606', (35, 43))	('sensitivity', 'MPA', (198, 209))	('EGFR', 'Gene', (74, 78))	('LSCC', 'Disease', 'MESH:D002294', (49, 53))	('EGFR', 'Gene', (22, 26))
289082	30380420	We identify somatic drivers among Hippo genes and the related microRNA (miRNA) regulators, and using functional genomic approaches, we experimentally characterize YAP and TAZ mutation effects and miR-590 and miR-200a regulation for TAZ.	('TAZ', 'Gene', (171, 174))	('mutation', 'Var', (175, 183))	('miR-590', 'Gene', '693175', (196, 203))	('YAP', 'Gene', (163, 166))	('effects', 'Reg', (184, 191))	('miR-200a', 'Gene', (208, 216))	('miR-590', 'Gene', (196, 203))	('miR-200a', 'Gene', '406983', (208, 216))
289085	30380420	Our results highlight the importance of Hippo signaling in squamous cell cancers, characterized by frequent amplification of YAP/TAZ, high expression heterogeneity, and significant prognostic patterns.	('squamous cell cancer', 'Phenotype', 'HP:0002860', (59, 79))	('squamous cell cancers', 'Phenotype', 'HP:0002860', (59, 80))	('amplification', 'Var', (108, 121))	('YAP/TAZ', 'Gene', (125, 132))	('squamous cell cancers', 'Disease', 'MESH:D002294', (59, 80))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('expression', 'MPA', (139, 149))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('squamous cell cancers', 'Disease', (59, 80))
289091	30380420	Dysregulated signaling by the Hippo pathway has been reported in several cancer types such as breast, liver, lung, prostate, gastric, and colorectal tumors.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('colorectal tumors', 'Disease', (138, 155))	('liver', 'Disease', (102, 107))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('breast', 'Disease', (94, 100))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('Hippo pathway', 'Pathway', (30, 43))	('tumors', 'Phenotype', 'HP:0002664', (149, 155))	('Dysregulated', 'Var', (0, 12))	('gastric', 'Disease', (125, 132))	('lung', 'Disease', (109, 113))	('colorectal tumors', 'Disease', 'MESH:D015179', (138, 155))	('reported', 'Reg', (53, 61))	('prostate', 'Disease', (115, 123))
289101	30380420	Deep deletions occurred mostly in LATS1/2, consistent with their tumor suppressor role in cancer development.	('LATS1/2', 'Gene', '9113;26524', (34, 41))	('tumor', 'Disease', (65, 70))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('LATS1/2', 'Gene', (34, 41))	('Deep deletions', 'Var', (0, 14))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
289103	30380420	For oncogenes, the most significant amplification peak was an amplicon of 11q22.1 in cervical squamous cell carcinoma (CESC), driven by the amplification of YAP1 (Figure S1A).	('YAP1', 'Gene', '10413', (157, 161))	('YAP1', 'Gene', (157, 161))	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (94, 117))	('11q22.1', 'Gene', (74, 81))	('amplification', 'Var', (140, 153))	('cervical squamous cell carcinoma', 'Disease', 'MESH:D002294', (85, 117))	('cervical squamous cell carcinoma', 'Disease', (85, 117))
289105	30380420	Regarding the mutational profile, NF2 (23.2%) and LATS2 (9.8%) showed the highest mutation frequencies in mesothelioma (MESO).	('NF2', 'Gene', (34, 37))	('mesothelioma', 'Disease', (106, 118))	('mutation', 'Var', (82, 90))	('LATS2', 'Gene', (50, 55))	('LATS2', 'Gene', '26524', (50, 55))	('NF2', 'Gene', '4771', (34, 37))	('mesothelioma', 'Disease', 'MESH:D008654', (106, 118))
289106	30380420	NF2 showed a striking pattern in MESO: all of the mutations were truncating mutations and led to reduced protein expression, indicating its loss-of-function effects (Figure S1C).	('NF2', 'Gene', (0, 3))	('loss-of-function', 'NegReg', (140, 156))	('mutations', 'Var', (50, 59))	('NF2', 'Gene', '4771', (0, 3))	('reduced', 'NegReg', (97, 104))	('protein expression', 'MPA', (105, 123))
289109	30380420	To assess the cancer types in which Hippo pathway alterations are more (or less) prevalent than background expectation, we employed a random sampling approach (STAR Methods).	('cancer', 'Disease', (14, 20))	('Hippo pathway', 'Pathway', (36, 49))	('alterations', 'Var', (50, 61))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('cancer', 'Disease', 'MESH:D009369', (14, 20))
289111	30380420	Among the hyper-altered cancer types, MESO, kidney renal papillary cell carcinoma (KIRP), and CESC were the most significant, which was probably due to the high frequency of NF2, LATS2, and SAV1 mutations and YAP1 amplification.	('hyper-altered cancer', 'Disease', 'MESH:D009369', (10, 30))	('kidney renal papillary cell carcinoma', 'Disease', 'MESH:D007681', (44, 81))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('CESC', 'Disease', (94, 98))	('SAV1', 'Gene', (190, 194))	('YAP1', 'Gene', '10413', (209, 213))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('LATS2', 'Gene', (179, 184))	('NF2', 'Gene', '4771', (174, 177))	('LATS2', 'Gene', '26524', (179, 184))	('renal papillary cell carcinoma', 'Phenotype', 'HP:0006766', (51, 81))	('kidney renal papillary cell carcinoma', 'Disease', (44, 81))	('hyper-altered cancer', 'Disease', (10, 30))	('mutations', 'Var', (195, 204))	('MESO', 'Disease', (38, 42))	('NF2', 'Gene', (174, 177))	('SAV1', 'Gene', '60485', (190, 194))	('YAP1', 'Gene', (209, 213))
289117	30380420	Interestingly, the high-level amplifications of these two genes occurred in a mutually exclusive pattern in two squamous cell cancers (HNSC and CESC), collectively contributing to 14% and 19% of the tumor samples (Figure 2B).	('tumor', 'Disease', (199, 204))	('squamous cell cancers', 'Disease', 'MESH:D002294', (112, 133))	('amplifications', 'Var', (30, 44))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('squamous cell cancers', 'Phenotype', 'HP:0002860', (112, 133))	('contributing', 'Reg', (164, 176))	('cancers', 'Phenotype', 'HP:0002664', (126, 133))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('squamous cell cancers', 'Disease', (112, 133))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (112, 132))
289120	30380420	To understand the impact of YAP1/TAZ somatic mutations, we experimentally assessed the effect of each of 22 YAP1 and 19 TAZ non-silent mutations observed in the pan-cancer cohort using moderate-throughput, sensitive cell viability assays (Figures 2C and 2D; STAR Methods).	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('YAP1', 'Gene', '10413', (108, 112))	('YAP1', 'Gene', (108, 112))	('YAP1', 'Gene', (28, 32))	('mutations', 'Var', (135, 144))	('YAP1', 'Gene', '10413', (28, 32))	('cancer', 'Disease', (165, 171))	('cancer', 'Disease', 'MESH:D009369', (165, 171))
289123	30380420	These results provide large-scale experimental evidence of YAP1/TAZ mutation effects, highlighting an underappreciated functional diversity of somatic mutations observed in human cancers.	('YAP1', 'Gene', '10413', (59, 63))	('mutation', 'Var', (68, 76))	('YAP1', 'Gene', (59, 63))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('effects', 'Reg', (77, 84))	('human', 'Species', '9606', (173, 178))	('cancers', 'Disease', 'MESH:D009369', (179, 186))	('cancers', 'Phenotype', 'HP:0002664', (179, 186))	('cancers', 'Disease', (179, 186))
289142	30380420	To assess the clinical impact of a dysregulated Hippo pathway in cancer, we sought to examine the correlation of its activity with patients' overall survival times.	('patients', 'Species', '9606', (131, 139))	('dysregulated', 'Var', (35, 47))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('Hippo pathway', 'Pathway', (48, 61))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))
289165	30380420	Decreased NF2 expression level caused by NF2 truncating mutation was a dominant regulator of YAP/TAZ activity in MESO.	('NF2', 'Gene', (10, 13))	('NF2', 'Gene', (41, 44))	('Decreased', 'NegReg', (0, 9))	('NF2', 'Gene', '4771', (41, 44))	('NF2', 'Gene', '4771', (10, 13))	('truncating mutation', 'Var', (45, 64))	('expression level', 'MPA', (14, 30))
289166	30380420	Hyper-methylation of STK3, WWC1, and TAOK2 was predicted to strongly promote YAP/TAZ amplification in colorectal cancer, MESO, and BLCA, respectively.	('TAOK2', 'Gene', (37, 42))	('MESO', 'Disease', (121, 125))	('colorectal cancer', 'Disease', (102, 119))	('BLCA', 'Disease', (131, 135))	('YAP/TAZ amplification', 'MPA', (77, 98))	('STK3', 'Gene', (21, 25))	('Hyper-methylation', 'Var', (0, 17))	('colorectal cancer', 'Disease', 'MESH:D015179', (102, 119))	('TAOK2', 'Gene', '9344', (37, 42))	('promote', 'PosReg', (69, 76))	('colorectal cancer', 'Phenotype', 'HP:0003003', (102, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('WWC1', 'Gene', '23286', (27, 31))	('WWC1', 'Gene', (27, 31))
289167	30380420	Furthermore, copy number loss for the TAOK family was a major cause of elevated YAP/TAZ activity in KIRP and LUSC.	('YAP/TAZ activity', 'MPA', (80, 96))	('TAOK', 'Gene', '57551;9344', (38, 42))	('TAOK', 'Gene', (38, 42))	('elevated', 'PosReg', (71, 79))	('copy number loss', 'Var', (13, 29))
289170	30380420	Other recurrently identified somatic driver events included ERBB2, RB1, and SOX2 copy number changes.	('ERBB2', 'Gene', '2064', (60, 65))	('SOX2', 'Gene', '6657', (76, 80))	('ERBB2', 'Gene', (60, 65))	('copy number changes', 'Var', (81, 100))	('SOX2', 'Gene', (76, 80))	('RB1', 'Gene', (67, 70))	('RB1', 'Gene', '5925', (67, 70))
289171	30380420	Besides SCNAs, IDH1 and FGFR3 mutations were predicted to be associated with YAP/TAZ activity in LGG and BLCA, respectively.	('associated with', 'Reg', (61, 76))	('FGFR3', 'Gene', '2261', (24, 29))	('IDH1', 'Gene', (15, 19))	('IDH1', 'Gene', '3417', (15, 19))	('FGFR3', 'Gene', (24, 29))	('YAP/TAZ activity', 'MPA', (77, 93))	('mutations', 'Var', (30, 39))
289172	30380420	Other identified associated somatic driver events included EGFR, KRAS, and PDGFR copy number changes, consistent with the reported functional coupling of these pathways with Hippo pathway signaling.	('EGFR', 'Gene', (59, 63))	('KRAS', 'Gene', '3845', (65, 69))	('copy number changes', 'Var', (81, 100))	('PDGFR', 'Gene', (75, 80))	('PDGFR', 'Gene', '5159', (75, 80))	('EGFR', 'Gene', '1956', (59, 63))	('KRAS', 'Gene', (65, 69))
289174	30380420	Importantly, we found that Hippo pathway activity was associated with aberrations in a few clinically actionable genes with Food and Drug Administration (FDA)-approved drugs or compelling clinical evidence, which provides insights into clinical applications targeting the Hippo pathway in cancer therapy.	('aberrations', 'Var', (70, 81))	('cancer', 'Phenotype', 'HP:0002664', (289, 295))	('Hippo', 'Gene', (27, 32))	('associated', 'Reg', (54, 64))	('cancer', 'Disease', 'MESH:D009369', (289, 295))	('activity', 'MPA', (41, 49))	('cancer', 'Disease', (289, 295))
289177	30380420	In total, we identified 11 non-silent mutations that affect cell viability and proliferation, filling a critical knowledge gap about YAP1/TAZ somatic mutations.	('proliferation', 'CPA', (79, 92))	('cell viability', 'CPA', (60, 74))	('affect', 'Reg', (53, 59))	('mutations', 'Var', (38, 47))	('YAP1', 'Gene', (133, 137))	('YAP1', 'Gene', '10413', (133, 137))
289180	30380420	Our analysis reveals that diverse mechanisms drive pathway dysregulation in tumor contexts.	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('pathway dysregulation', 'Var', (51, 72))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
289182	30380420	Through our integrated analyses of BLCA, CESC, ESCA, LUSC, and HNSC, we reveal frequent YAP1/TAZ amplifications, high expression heterogeneity, and significant prognostic correlations.	('expression', 'MPA', (118, 128))	('amplifications', 'Var', (97, 111))	('YAP1', 'Gene', (88, 92))	('YAP1', 'Gene', '10413', (88, 92))
289184	30380420	Another cancer of particular interest is LGG, for which Hippo pathway activity shows the strongest correlation with patient survival times and the most extensive associations with known drivers such as IDH1 mutations.	('Hippo pathway', 'Pathway', (56, 69))	('LGG', 'Disease', (41, 44))	('cancer', 'Disease', (8, 14))	('activity', 'MPA', (70, 78))	('patient', 'Species', '9606', (116, 123))	('associations', 'Interaction', (162, 174))	('mutations', 'Var', (207, 216))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('IDH1', 'Gene', (202, 206))	('IDH1', 'Gene', '3417', (202, 206))	('cancer', 'Disease', 'MESH:D009369', (8, 14))
289196	30380420	Cell lines were confirmed using Short Tandem Repeat (STR) analysis and were tested and negative for mycoplasma contamination.	('mycoplasma', 'Disease', 'MESH:D009175', (100, 110))	('Short Tandem', 'Var', (32, 44))	('mycoplasma', 'Disease', (100, 110))
289204	30380420	i) Only mutations with "PASS" in the "FILTER" column were retained for all cancer types except OV and LAML, and we allowed "wga" for these two cancer types.	('LAML', 'Disease', (102, 106))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('cancer', 'Disease', (75, 81))	('mutations', 'Var', (8, 17))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))
289207	30380420	Functions of YAP1 and TAZ mutations were assayed in MCF10A cells, human non-tumorigenic mammary epithelial cells.	('MCF10A', 'CellLine', 'CVCL:0598', (52, 58))	('TAZ', 'Gene', (22, 25))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('human', 'Species', '9606', (66, 71))	('mutations', 'Var', (26, 35))	('YAP1', 'Gene', '10413', (13, 17))	('YAP1', 'Gene', (13, 17))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
289208	30380420	The mutations, wild-types and silent controls of YAP1 (YAP) and TAZ (WWTR1) genes were cloned into pHAGE-PURO lentivirus vector by HiTMMoB technique as described previously.	('WWTR1', 'Gene', '25937', (69, 74))	('YAP1', 'Gene', (49, 53))	('YAP1', 'Gene', '10413', (49, 53))	('mutations', 'Var', (4, 13))	('WWTR1', 'Gene', (69, 74))
289286	26699225	Besides these highly confident structure-based DDIs, transcript interactions constructed from 2989 predicted high-confidence DDIs and 2537 predicted medium-confidence DDIs in DOMINE were also included if the transcript interaction agrees with protein-protein interactions (PPI) in HPRD.	('ran', 'Gene', '5901', (209, 212))	('DDIs', 'Var', (125, 129))	('protein-protein', 'MPA', (243, 258))	('DOMINE', 'Species', '1262608', (175, 181))	('HPRD', 'Disease', (281, 285))	('HPRD', 'Disease', 'None', (281, 285))	('ran', 'Gene', (54, 57))	('ran', 'Gene', '5901', (54, 57))	('ran', 'Gene', (209, 212))
289295	26699225	In CD79A transcript NM_001783 contains an extra domain pfam07686 while transcript NM_021601 only contains a shorter hit pfam02189.	('NM_001783', 'Var', (20, 29))	('ran', 'Gene', (10, 13))	('ran', 'Gene', '5901', (10, 13))	('ran', 'Gene', (72, 75))	('ran', 'Gene', '5901', (72, 75))	('pfam07686', 'Var', (55, 64))	('CD79A', 'Gene', '973', (3, 8))	('CD79A', 'Gene', (3, 8))
289296	26699225	In CD79B transcripts NM_001039933 and NM_000626 contain a domain pfam07686, which is removed in alternative splicing of NM_021602.	('CD79B', 'Gene', '974', (3, 8))	('ran', 'Gene', (10, 13))	('ran', 'Gene', '5901', (10, 13))	('NM_001039933', 'Var', (21, 33))	('CD79B', 'Gene', (3, 8))
289298	26699225	In the transcripts in CD79A, the expression of NM_021601 will correlate with the transcripts in LCK and SYK, and NM_001783 will correlate with two transcripts in CD79B.	('ran', 'Gene', (82, 85))	('ran', 'Gene', '5901', (82, 85))	('LCK', 'Gene', (96, 99))	('CD79B', 'Gene', '974', (162, 167))	('NM_021601', 'Var', (47, 56))	('LCK', 'Gene', '3932', (96, 99))	('CD79A', 'Gene', '973', (22, 27))	('CD79A', 'Gene', (22, 27))	('ran', 'Gene', (8, 11))	('ran', 'Gene', (148, 151))	('ran', 'Gene', '5901', (8, 11))	('CD79B', 'Gene', (162, 167))	('ran', 'Gene', '5901', (148, 151))	('SYK', 'Gene', (104, 107))	('SYK', 'Gene', '6850', (104, 107))	('NM_001783', 'Var', (113, 122))	('correlate', 'Reg', (128, 137))
289370	26699225	Isoform NM_017778 interacts with 12 transcripts with average correlation coefficients 0.22 and the other isoform NM_023034 interacts with 13 more transcripts with average correlation coefficients 0.30 compared with the average correlation coefficient 0.188 against the other unconnected isoforms across the samples in the OV dataset.	('interacts', 'Reg', (18, 27))	('ran', 'Gene', (37, 40))	('ran', 'Gene', '5901', (37, 40))	('ran', 'Gene', (147, 150))	('ran', 'Gene', '5901', (147, 150))	('NM_017778', 'Var', (8, 17))	('interacts', 'Reg', (123, 132))	('NM_023034', 'Var', (113, 122))
289402	26699225	Net-RSTQ correctly predicted the overall enrichment of isoforms of HNRNPA2B1 and NSD1 (NM_031243 > NM_002137 in HNRNPA2B1 and NM_022455 > NM_172349 in NSD1).	('NM_031243 > NM_002137', 'Var', (87, 108))	('NSD1', 'Gene', (81, 85))	('NSD1', 'Gene', (151, 155))	('NM_022455 > NM_172349', 'Var', (126, 147))	('HNRNPA2B1', 'Gene', '3181', (67, 76))	('HNRNPA2B1', 'Gene', (67, 76))	('NSD1', 'Gene', '64324', (81, 85))	('NSD1', 'Gene', '64324', (151, 155))	('HNRNPA2B1', 'Gene', '3181', (112, 121))	('HNRNPA2B1', 'Gene', (112, 121))
289403	26699225	It is possible that the expressions of NM_002137 transcript in gene HNRNPA2B1 and NM_172349 in gene NSD1 were slightly over-smoothed by network information in Net-RSTQ with the fixed lambda parameter.	('ran', 'Gene', '5901', (50, 53))	('NSD1', 'Gene', (100, 104))	('HNRNPA2B1', 'Gene', '3181', (68, 77))	('over-smoothed', 'PosReg', (119, 132))	('NM_172349', 'Var', (82, 91))	('NSD1', 'Gene', '64324', (100, 104))	('HNRNPA2B1', 'Gene', (68, 77))	('ran', 'Gene', (50, 53))
289408	26699225	In summary, Net-RSTQ improved the overall isoform quantification significantly in the H9 stem cell data and predicted more consistent cases in OVCAR8 and MCF7 cancer cell lines data.	('H9', 'CellLine', 'CVCL:1240', (86, 88))	('isoform quantification', 'MPA', (42, 64))	('improved', 'PosReg', (21, 29))	('MCF7 cancer', 'Disease', (154, 165))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('MCF7 cancer', 'Disease', 'MESH:D009369', (154, 165))	('Net-RSTQ', 'Var', (12, 20))
289415	26699225	Net-RSTQ also outperformed Cufflinks and RSEM (transcript or gene) in five cases except the experiment on BRCA (relapse) dataset in Table 4.	('BRCA', 'Gene', (106, 110))	('RSEM', 'Chemical', '-', (41, 45))	('ran', 'Gene', (48, 51))	('Net-RSTQ', 'Var', (0, 8))	('ran', 'Gene', '5901', (48, 51))	('BRCA', 'Gene', '672', (106, 110))
289425	26699225	To measure the scalability of Net-RSTQ, we tested the Net-RSTQ algorithm on the data of the MCF7 breast cancer cell line with three different networks, the small network (898 transcripts), the large network (5599 transcripts) and an artificial huge network (10000 transcripts).	('ran', 'Gene', '5901', (214, 217))	('tested', 'Reg', (43, 49))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('ran', 'Gene', (265, 268))	('MCF7 breast cancer', 'Disease', (92, 110))	('898', 'Var', (171, 174))	('ran', 'Gene', '5901', (265, 268))	('ran', 'Gene', (176, 179))	('breast cancer', 'Phenotype', 'HP:0003002', (97, 110))	('ran', 'Gene', '5901', (176, 179))	('MCF7 breast cancer', 'Disease', 'MESH:D001943', (92, 110))	('ran', 'Gene', (214, 217))
289442	26193368	In addition, CD11b+ LIN- HLA-DR-CD33+ MDSCs were a critical cell population that mediates inflammation response and immune suppression in HPV-positive OPSCC.	('inflammation', 'Disease', 'MESH:D007249', (90, 102))	('OPSCC', 'Phenotype', 'HP:0012182', (151, 156))	('HPV', 'Species', '10566', (138, 141))	('inflammation', 'Disease', (90, 102))	('CD33', 'Gene', '945', (32, 36))	('CD33', 'Gene', (32, 36))	('mediates', 'Reg', (81, 89))	('immune suppression', 'CPA', (116, 134))	('CD11b+', 'Var', (13, 19))
289446	26193368	High-risk human papilloma virus (HPV) has been recognized as an important risk factor in a subset of oropharyngeal squamous cell carcinomas (OPSCC) and HPV-positive OPSCC has a more favorable prognosis compared to HPV-negative OPSCC.	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (115, 139))	('oropharyngeal squamous cell carcinomas', 'Disease', 'MESH:D002294', (101, 139))	('OPSCC', 'Phenotype', 'HP:0012182', (141, 146))	('papilloma', 'Phenotype', 'HP:0012740', (16, 25))	('HPV-positive', 'Var', (152, 164))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('HPV', 'Species', '10566', (152, 155))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (115, 138))	('human papilloma virus', 'Species', '10566', (10, 31))	('oropharyngeal squamous cell carcinomas', 'Disease', (101, 139))	('oropharyngeal squamous cell carcinomas', 'Phenotype', 'HP:0012182', (101, 139))	('HPV', 'Species', '10566', (33, 36))	('HPV', 'Species', '10566', (214, 217))	('carcinomas', 'Phenotype', 'HP:0030731', (129, 139))	('OPSCC', 'Phenotype', 'HP:0012182', (165, 170))	('OPSCC', 'Phenotype', 'HP:0012182', (227, 232))
289504	26193368	Flow cytometry results showed that CD11b+ LIN- HLA-DR- CD33+ MDSCs was obviously up-regulated in the specimens of HPV 16 infection with dysplasia, caner in situ and oropharyngeal cancer in comparsion with normal oral mucous(Fig 3B).	('caner', 'Disease', (147, 152))	('HPV 16', 'Species', '333760', (114, 120))	('CD33', 'Gene', '945', (55, 59))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('CD33', 'Gene', (55, 59))	('CD11b+', 'Var', (35, 41))	('oropharyngeal cancer', 'Disease', (165, 185))	('infection', 'Disease', (121, 130))	('infection', 'Disease', 'MESH:D007239', (121, 130))	('up-regulated', 'PosReg', (81, 93))	('dysplasia', 'Disease', (136, 145))	('HPV 16', 'Gene', (114, 120))	('dysplasia', 'Disease', 'MESH:D004476', (136, 145))	('oropharyngeal cancer', 'Disease', 'MESH:D009959', (165, 185))
289512	26193368	However, HPV-positive OPSCC has better prognosis than HPV-negative OPSCC, which pushed us to search the possible clues of tumorigenesis and malignant progression in OPSCC patients.	('HPV-positive', 'Var', (9, 21))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('patients', 'Species', '9606', (171, 179))	('HPV', 'Species', '10566', (9, 12))	('HPV', 'Species', '10566', (54, 57))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('OPSCC', 'Phenotype', 'HP:0012182', (22, 27))	('OPSCC', 'Phenotype', 'HP:0012182', (67, 72))	('tumor', 'Disease', (122, 127))	('OPSCC', 'Phenotype', 'HP:0012182', (165, 170))
289522	26193368	Singh et al showed that TNF-alpha (-238) G/A polymorphism was significantly associated with oral squamous cell carcinoma, however, TNF-alpha (-308) G/A polymorphism was not associated with oral squamous cell carcinoma.	('polymorphism', 'Var', (45, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('TNF-alpha', 'Gene', (24, 33))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (97, 120))	('TNF-alpha', 'Gene', '7124', (131, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (208, 217))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (189, 217))	('oral squamous cell carcinoma', 'Disease', (92, 120))	('TNF-alpha', 'Gene', (131, 140))	('associated', 'Reg', (76, 86))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (194, 217))	('oral squamous cell carcinoma', 'Disease', (189, 217))	('(-308) G/A', 'Mutation', 'rs1800629', (141, 151))	('TNF-alpha', 'Gene', '7124', (24, 33))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (92, 120))	('(-238) G/A', 'Mutation', 'c.(-238G>A', (34, 44))
289535	26193368	In addition, we also detected that there was the higher level of MDSCs in tissues with different degrees of dysplasia compared to normal mucous, as well as the higher level of MDSCs in HPV-positive OPSCC compared to normal mucous, suggesting that the aggregation of MDSCs facilitated HPV-positive oropharyngeal carcinogenesis.	('dysplasia', 'Disease', (108, 117))	('HPV', 'Species', '10566', (185, 188))	('dysplasia', 'Disease', 'MESH:D004476', (108, 117))	('OPSCC', 'Phenotype', 'HP:0012182', (198, 203))	('HPV-positive oropharyngeal carcinogenesis', 'Disease', 'MESH:D030361', (284, 325))	('HPV', 'Species', '10566', (284, 287))	('aggregation', 'Var', (251, 262))	('facilitated', 'PosReg', (272, 283))	('HPV-positive oropharyngeal carcinogenesis', 'Disease', (284, 325))
289536	26193368	MDSCs are known to inhibit the process that cell-mediated immunity protects from tumor occurrence and progression.	('MDSCs', 'Var', (0, 5))	('inhibit', 'NegReg', (19, 26))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Disease', (81, 86))
289543	26193368	Samoff et al have shown that concurrent infection with Chlamydia trachomatis could enhance the persistence of cervical HPV infection and the risk of cervical cancer.	('infection', 'Disease', (40, 49))	('infection', 'Disease', 'MESH:D007239', (40, 49))	('persistence', 'MPA', (95, 106))	('infection', 'Disease', (123, 132))	('cervical HPV infection', 'Disease', 'MESH:D030361', (110, 132))	('infection', 'Disease', 'MESH:D007239', (123, 132))	('Chlamydia trachomatis', 'Var', (55, 76))	('enhance', 'PosReg', (83, 90))	('cervical cancer', 'Disease', (149, 164))	('cervical cancer', 'Disease', 'MESH:D002583', (149, 164))	('cervical HPV infection', 'Disease', (110, 132))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('Chlamydia trachomatis', 'Species', '813', (55, 76))
289546	26193368	However, Abd Warif et al reported that the expression of HPV 16 E7 in epidermis of the K14E7 mouse could lead to hyperplasia and chronic inflammation.	('hyperplasia', 'Disease', 'MESH:D006965', (113, 124))	('mouse', 'Species', '10090', (93, 98))	('lead to', 'Reg', (105, 112))	('chronic inflammation', 'Disease', 'MESH:D007249', (129, 149))	('expression', 'Var', (43, 53))	('chronic inflammation', 'Disease', (129, 149))	('HPV 16', 'Species', '333760', (57, 63))	('hyperplasia', 'Disease', (113, 124))	('HPV 16', 'Gene', (57, 63))
289569	31788070	Each tumor harbors unique mutations, presents variable clinical outcomes and is associated with specific risk factors.	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('mutations', 'Var', (26, 35))	('tumor', 'Disease', (5, 10))	('harbors', 'Reg', (11, 18))
289584	31788070	GSE9844 included 26 OTSCC and 12 normal tissues, GSE13601 included 31 OTSCC and 26 normal tissues, GSE31056 included 22 OTSCC and 24 normal tissues, and GSE75538 included 14 OTSCC and 14 normal tissues.	('OTSCC', 'Disease', 'MESH:D002294', (20, 25))	('OTSCC', 'Disease', 'MESH:D002294', (120, 125))	('OTSCC', 'Disease', 'MESH:D002294', (174, 179))	('GSE75538', 'Var', (153, 161))	('OTSCC', 'Disease', (20, 25))	('OTSCC', 'Disease', (120, 125))	('OTSCC', 'Disease', (174, 179))	('GSE9844', 'Var', (0, 7))	('OTSCC', 'Disease', 'MESH:D002294', (70, 75))	('OTSCC', 'Disease', (70, 75))	('GSE13601', 'Var', (49, 57))	('GSE31056', 'Var', (99, 107))
289623	31788070	These genes serve important functions in numerous physiological and pathological processes involved in tumor progression and can promote tumor-induced angiogenesis and extracellular matrix disassembly, enhancing therefore tumor invasion and metastasis.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor', 'Disease', (137, 142))	('extracellular matrix disassembly', 'CPA', (168, 200))	('promote', 'PosReg', (129, 136))	('tumor', 'Disease', 'MESH:D009369', (222, 227))	('tumor', 'Disease', (103, 108))	('genes', 'Var', (6, 11))	('enhancing', 'PosReg', (202, 211))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('tumor', 'Disease', (222, 227))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
289831	29276394	Furthermore, Kaplan-Meier survival curves demonstrated that high CIP2A expression indicated poor prognosis in the subgroup of patients with squamous cell carcinoma (p=0.008).	('expression', 'MPA', (71, 81))	('CIP2A', 'Gene', (65, 70))	('high', 'Var', (60, 64))	('CIP2A', 'Gene', '57650', (65, 70))	('patients', 'Species', '9606', (126, 134))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (140, 163))	('carcinoma', 'Phenotype', 'HP:0030731', (154, 163))	('squamous cell carcinoma', 'Disease', (140, 163))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (140, 163))
289877	29276394	Kaplan-Meier survival curves demonstrated that high CIP2A expression was a predictor of poor prognosis in NSCLC patients (p=0.005, Figure 3A).	('NSCLC', 'Disease', 'MESH:D002289', (106, 111))	('expression', 'MPA', (58, 68))	('high', 'Var', (47, 51))	('CIP2A', 'Gene', (52, 57))	('patients', 'Species', '9606', (112, 120))	('NSCLC', 'Phenotype', 'HP:0030358', (106, 111))	('CIP2A', 'Gene', '57650', (52, 57))	('NSCLC', 'Disease', (106, 111))
289878	29276394	The median OS of patients with high CIP2A expression and low CIP2A expression were 31.0 months (95% CI, 23.79-38.21 months) and 68.0 months (95% CI, 48.20-87.80 months), respectively.	('CIP2A', 'Gene', '57650', (36, 41))	('CIP2A', 'Gene', '57650', (61, 66))	('expression', 'MPA', (42, 52))	('low CIP2A', 'Phenotype', 'HP:0032421', (57, 66))	('low', 'NegReg', (57, 60))	('patients', 'Species', '9606', (17, 25))	('expression', 'MPA', (67, 77))	('high', 'Var', (31, 35))	('CIP2A', 'Gene', (61, 66))	('CIP2A', 'Gene', (36, 41))
289879	29276394	In addition, multivariate Cox proportional hazard analysis demonstrated that high CIP2A expression (p=0.007) was an independent prognostic factor along with T stage (p=0.001), N stage (p=0.003), histological type (p<0.001), and chemotherapy (p<0.001) (Table 2).	('CIP2A', 'Gene', '57650', (82, 87))	('high', 'Var', (77, 81))	('Cox', 'Gene', '1351', (26, 29))	('expression', 'MPA', (88, 98))	('CIP2A', 'Gene', (82, 87))	('Cox', 'Gene', (26, 29))
289880	29276394	Overall, high CIP2A expression is a poor and independent prognostic factor for postoperative stage I-III NSCLC patients.	('NSCLC', 'Disease', 'MESH:D002289', (105, 110))	('expression', 'MPA', (20, 30))	('NSCLC', 'Phenotype', 'HP:0030358', (105, 110))	('CIP2A', 'Gene', (14, 19))	('CIP2A', 'Gene', '57650', (14, 19))	('high', 'Var', (9, 13))	('NSCLC', 'Disease', (105, 110))	('patients', 'Species', '9606', (111, 119))
289884	29276394	The median OS of patients who received postoperative chemotherapy with high (n=67) and low (n=84) expressions of CIP2A were 35.0 months (95% CI, 21.97-48.03 months) and 80.0 months (95% CI, 54.85-105.15 months), respectively (p=0.005, Figure 3D).	('CIP2A', 'Gene', '57650', (113, 118))	('expressions', 'Var', (98, 109))	('patients', 'Species', '9606', (17, 25))	('low', 'NegReg', (87, 90))	('CIP2A', 'Gene', (113, 118))
289886	29276394	Overall, high CIP2A expression was a poor and independent prognostic factor for stage I-III NSCLC patients who received postoperative chemotherapy.	('expression', 'MPA', (20, 30))	('CIP2A', 'Gene', (14, 19))	('NSCLC', 'Phenotype', 'HP:0030358', (92, 97))	('CIP2A', 'Gene', '57650', (14, 19))	('patients', 'Species', '9606', (98, 106))	('NSCLC', 'Disease', (92, 97))	('NSCLC', 'Disease', 'MESH:D002289', (92, 97))	('high', 'Var', (9, 13))
289887	29276394	In the subgroup of patients who received postoperative radiotherapy, a log-rank test demonstrated that high CIP2A expression correlated with poor OS (p=0.165).	('patients', 'Species', '9606', (19, 27))	('poor OS', 'Disease', (141, 148))	('high', 'Var', (103, 107))	('CIP2A', 'Gene', (108, 113))	('CIP2A', 'Gene', '57650', (108, 113))	('expression', 'MPA', (114, 124))
289903	29276394	Furthermore, we found that high CIP2A expression is associated with late pathologic stage and metastatic lymph node status in NSCLC.	('CIP2A', 'Gene', '57650', (32, 37))	('NSCLC', 'Disease', 'MESH:D002289', (126, 131))	('expression', 'MPA', (38, 48))	('metastatic lymph node status', 'CPA', (94, 122))	('associated', 'Reg', (52, 62))	('high', 'Var', (27, 31))	('NSCLC', 'Phenotype', 'HP:0030358', (126, 131))	('CIP2A', 'Gene', (32, 37))	('NSCLC', 'Disease', (126, 131))
289916	29276394	We also performed survival analyses on CIP2A expression in patients with different histological types and found that high CIP2A expression is a prognosis factor in squamous cell carcinoma (p=0.008, Figure 3B).	('CIP2A', 'Gene', (122, 127))	('high', 'Var', (117, 121))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (164, 187))	('CIP2A', 'Gene', '57650', (122, 127))	('patients', 'Species', '9606', (59, 67))	('carcinoma', 'Phenotype', 'HP:0030731', (178, 187))	('expression', 'MPA', (128, 138))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (164, 187))	('CIP2A', 'Gene', (39, 44))	('squamous cell carcinoma', 'Disease', (164, 187))	('CIP2A', 'Gene', '57650', (39, 44))
289917	29276394	High expression of CIP2A might be a prognostic factor even in adenocarcinoma; however, the result did not achieve statistical significance (p=0.084, Figure 3C).	('High', 'Var', (0, 4))	('adenocarcinoma', 'Disease', 'MESH:D000230', (62, 76))	('adenocarcinoma', 'Disease', (62, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('CIP2A', 'Gene', (19, 24))	('CIP2A', 'Gene', '57650', (19, 24))
289918	29276394	High CIP2A expression indicated poor prognosis in other squamous cell cancers, such as tongue cancer and nasopharyngeal cancer.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('squamous cell cancers', 'Disease', (56, 77))	('High', 'Var', (0, 4))	('squamous cell cancers', 'Phenotype', 'HP:0002860', (56, 77))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('nasopharyngeal cancer', 'Disease', 'MESH:D009303', (105, 126))	('expression', 'MPA', (11, 21))	('squamous cell cancers', 'Disease', 'MESH:D002294', (56, 77))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (56, 76))	('nasopharyngeal cancer', 'Disease', (105, 126))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('tongue cancer', 'Disease', (87, 100))	('cancers', 'Phenotype', 'HP:0002664', (70, 77))	('tongue cancer', 'Disease', 'MESH:D014062', (87, 100))	('nasopharyngeal cancer', 'Phenotype', 'HP:0100630', (105, 126))	('CIP2A', 'Gene', (5, 10))	('CIP2A', 'Gene', '57650', (5, 10))
289933	29276394	In summary, our research demonstrates that high CIP2A expression is associated with cancer aggressiveness and poor prognosis in NSCLC, especially in squamous cell carcinoma and in patients who received postoperative chemotherapy.	('expression', 'MPA', (54, 64))	('NSCLC', 'Phenotype', 'HP:0030358', (128, 133))	('associated', 'Reg', (68, 78))	('cancer aggressiveness', 'Disease', 'MESH:D009369', (84, 105))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (149, 172))	('high', 'Var', (43, 47))	('carcinoma', 'Phenotype', 'HP:0030731', (163, 172))	('CIP2A', 'Gene', (48, 53))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (149, 172))	('aggressiveness', 'Phenotype', 'HP:0000718', (91, 105))	('CIP2A', 'Gene', '57650', (48, 53))	('squamous cell carcinoma', 'Disease', (149, 172))	('NSCLC', 'Disease', (128, 133))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('NSCLC', 'Disease', 'MESH:D002289', (128, 133))	('cancer aggressiveness', 'Disease', (84, 105))	('patients', 'Species', '9606', (180, 188))
289946	29042600	For examples, through the crosslinking, ligation, and sequencing of hybrids (CLASH) analysis, 18,514 miRNA-mRNA interactions were detected and only ~22% were associated with seed region, via either contiguous or gapped complementary RNA base pairing.	('gapped complementary RNA base pairing', 'Var', (212, 249))	('miR', 'Gene', '220972', (101, 104))	('miR', 'Gene', (101, 104))
289949	29042600	Other factors, including genetic mutations, the competition with other RNA binding proteins and the conditional expression of miRNA and mRNA can also affect the status of miRNA-mRNA interactions.	('status', 'MPA', (161, 167))	('miR', 'Gene', '220972', (126, 129))	('miR', 'Gene', (126, 129))	('miR', 'Gene', (171, 174))	('miR', 'Gene', '220972', (171, 174))	('mutations', 'Var', (33, 42))	('affect', 'Reg', (150, 156))
289998	29042600	For example, Neurogenic Locus Notch Homolog Protein 2 gene (NOTCH2) was regulated by miR-744-5p, -25-3p, -92a-3p, and -27b-3p in KIRC and by miR-744-5p, -106a-5p, -130b-5p, and let-7c-5p in KIRP.	('miR', 'Gene', '220972', (85, 88))	('Neurogenic Locus Notch Homolog Protein 2', 'Gene', '4853', (13, 53))	('miR', 'Gene', (85, 88))	('NOTCH2', 'Gene', '4853', (60, 66))	('Neurogenic Locus Notch Homolog Protein 2', 'Gene', (13, 53))	('miR', 'Gene', '220972', (141, 144))	('miR', 'Gene', (141, 144))	('let-7c-5p', 'Var', (177, 186))	('NOTCH2', 'Gene', (60, 66))	('regulated', 'Reg', (72, 81))
290074	29042600	Then, raw RS of each miRNA-mRNA pair was calculated by the aggregation of the binding probability and the binding affinity, e.g., represented by the MFE of the corresponding interactions, as follows:where MFE k represents the minimum free energy of the binding site k and K is the total number of different binding sites between miRNA i and mRNA j.	('miR', 'Gene', '220972', (329, 332))	('miR', 'Gene', (329, 332))	('miR', 'Gene', '220972', (21, 24))	('miR', 'Gene', (21, 24))	('MFE k', 'Var', (205, 210))
290104	25421419	In addition, increased fiber intake appears to be associated with lower risk of all histological types of esophageal cancer.	('esophageal cancer', 'Disease', 'MESH:D004938', (106, 123))	('fiber', 'Chemical', 'MESH:D004043', (23, 28))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('fiber intake', 'Var', (23, 35))	('lower', 'NegReg', (66, 71))	('esophageal cancer', 'Disease', (106, 123))	('increased', 'PosReg', (13, 22))
290113	25421419	Further, a high-GI diet may increase cancer risk by modulating the insulin-like-growth factor (IGF) axis.	('insulin', 'Gene', (67, 74))	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('high-GI', 'Var', (11, 18))	('insulin', 'Gene', '3630', (67, 74))	('cancer', 'Disease', (37, 43))	('modulating', 'Reg', (52, 62))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('increase', 'PosReg', (28, 36))
290132	25421419	The cases consisted of 299 (M/F 271/28) EAC cases, 337 (M/F 289/48) EGJAC cases, and 245 (M/F147/98) ESCC cases for analysis.	('M/F 289', 'Var', (56, 63))	('EAC', 'Disease', (40, 43))	('M/F 289', 'SUBSTITUTION', 'None', (56, 63))	('M/F147', 'Var', (90, 96))	('M/F 271', 'SUBSTITUTION', 'None', (28, 35))	('M/F 271', 'Var', (28, 35))	('M/F147', 'SUBSTITUTION', 'None', (90, 96))
290191	25421419	It has been suggested that the direction and magnitude of glycemic indicators-cancer associations may be explained by the way in which high GI or high GL track with other dietary and lifestyle factors related to cancer development.	('cancer', 'Phenotype', 'HP:0002664', (212, 218))	('high GI', 'Var', (135, 142))	('high GL', 'Var', (146, 153))	('men', 'Species', '9606', (226, 229))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('cancer', 'Disease', (212, 218))	('cancer', 'Disease', 'MESH:D009369', (212, 218))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('associations', 'Interaction', (85, 97))
290218	24738062	Additionally, expression of BRF2 was found to be an independent prognostic factor in NSCLC patients.	('NSCLC', 'Disease', (85, 90))	('expression', 'Var', (14, 24))	('patients', 'Species', '9606', (91, 99))	('NSCLC', 'Disease', 'MESH:D002289', (85, 90))	('BRF2', 'Gene', '55290', (28, 32))	('NSCLC', 'Phenotype', 'HP:0030358', (85, 90))	('BRF2', 'Gene', (28, 32))
290219	24738062	Furthermore, we showed that targeted knockdown of BRF2 expression could inhibit the migratory and invasive abilities of NSCLC cells and induced loss of the epithelial-mesenchymal transition of NSCLC cells.	('NSCLC', 'Disease', 'MESH:D002289', (120, 125))	('BRF2', 'Gene', (50, 54))	('NSCLC', 'Phenotype', 'HP:0030358', (193, 198))	('knockdown', 'Var', (37, 46))	('BRF2', 'Gene', '55290', (50, 54))	('NSCLC', 'Phenotype', 'HP:0030358', (120, 125))	('NSCLC', 'Disease', (120, 125))	('inhibit', 'NegReg', (72, 79))	('NSCLC', 'Disease', (193, 198))	('loss', 'NegReg', (144, 148))	('NSCLC', 'Disease', 'MESH:D002289', (193, 198))
290237	24738062	Here, we evaluated the prognostic value of BRF2 expression in patients with resectable NSCLC and found that high expression of BRF2 in NSCLC predicted decreased overall 5-year survival and a higher risk of recurrence.	('BRF2', 'Gene', '55290', (43, 47))	('BRF2', 'Gene', '55290', (127, 131))	('NSCLC', 'Disease', (87, 92))	('NSCLC', 'Disease', 'MESH:D002289', (87, 92))	('NSCLC', 'Disease', (135, 140))	('decreased', 'NegReg', (151, 160))	('BRF2', 'Gene', (127, 131))	('BRF2', 'Gene', (43, 47))	('NSCLC', 'Disease', 'MESH:D002289', (135, 140))	('NSCLC', 'Phenotype', 'HP:0030358', (87, 92))	('high expression', 'Var', (108, 123))	('patients', 'Species', '9606', (62, 70))	('NSCLC', 'Phenotype', 'HP:0030358', (135, 140))
290238	24738062	Furthermore, disruption of BRF2 transcripts through small interfering RNA in NSCLC cells results in a reduced capacity of migration and invasion in vitro, inhibiting EMT related invasion in association with increased E-cadherin expression.	('NSCLC', 'Disease', 'MESH:D002289', (77, 82))	('EMT related invasion', 'CPA', (166, 186))	('BRF2', 'Gene', '55290', (27, 31))	('disruption', 'Var', (13, 23))	('NSCLC', 'Phenotype', 'HP:0030358', (77, 82))	('increased', 'PosReg', (207, 216))	('small interfering RNA', 'Var', (52, 73))	('E-cadherin', 'Gene', (217, 227))	('inhibiting', 'NegReg', (155, 165))	('BRF2', 'Gene', (27, 31))	('E-cadherin', 'Gene', '999', (217, 227))	('NSCLC', 'Disease', (77, 82))	('reduced', 'NegReg', (102, 109))
290256	24738062	BRF2 siRNA1: sense 5-GCACUUACAUGCAGAUAGUTT-3; antisense 5-ACUAUCUGCAUGUAAGUGCTT-3; BRF2 siRNA2: sense 5-GGUGGGAAAUAAUUCCUUATT-3;  antisense 5-UAAGGAAUUAUUUCCCACCTT-3; BRF2 siRNA3: sense 5-GCCACCAACAUUUGAGGAUTT-3; antisense 5-AUCCUCAAAUGUUGGUGGCTT-3; negative control: sense 5-UUCUCCGAACGUGUCACGUTT-3; antisense 5-ACGUGACACGUUCGGAGAATT-3.	('BRF2', 'Gene', '55290', (0, 4))	('antisense', 'Var', (301, 310))	('BRF2', 'Gene', (167, 171))	('5-UAAGGAAUUAUUUCCCACCTT-3', 'Chemical', '-', (140, 165))	('BRF2', 'Gene', '55290', (83, 87))	('BRF2', 'Gene', (83, 87))	('BRF2', 'Gene', (0, 4))	('BRF2', 'Gene', '55290', (167, 171))
290265	24738062	Membranes were blocked with 5% fat-free milk in Tris-buffered saline containing 0.1% Tween-20 (TBST) for 1.5 h at room temperature; the membranes were then incubated overnight at 4 C with anti-BRF2 (1 : 1000, Abcam, Cambridge, MA, USA), anti-E-Cadherin (1 : 1000, Cell Signaling, Danvers, MA, USA), anti-N-Cadherin (1 : 1000, Cell Signaling, Danvers, MA, USA), anti-snail (1 : 1000, Cell Signaling, Danvers, MA, USA), or anti-GADPH (1 : 1000, Abcam, Cambridge, MA, USA) antibodies.	('N-Cadherin', 'Gene', (304, 314))	('E-Cadherin', 'Gene', (242, 252))	('BRF2', 'Gene', (193, 197))	('N-Cadherin', 'Gene', '1000', (304, 314))	('snail', 'Gene', '6615', (366, 371))	('E-Cadherin', 'Gene', '999', (242, 252))	('snail', 'Gene', (366, 371))	('anti-GADPH', 'Var', (421, 431))	('BRF2', 'Gene', '55290', (193, 197))
290289	24738062	Univariate analysis demonstrated that the overall 5-year survival rate of patients with BRF2 protein high expression was significantly lower than that of the remaining patients among N1, T1-2, and adenocarcinoma (P = 0.008, P = 0.002, and P = 0.015, resp.	('BRF2', 'Gene', (88, 92))	('protein', 'Protein', (93, 100))	('patients', 'Species', '9606', (74, 82))	('T1-2', 'Gene', (187, 191))	('adenocarcinoma', 'Disease', 'MESH:D000230', (197, 211))	('lower', 'NegReg', (135, 140))	('patients', 'Species', '9606', (168, 176))	('T1-2', 'Gene', '923;9173;292', (187, 191))	('carcinoma', 'Phenotype', 'HP:0030731', (202, 211))	('BRF2', 'Gene', '55290', (88, 92))	('high expression', 'Var', (101, 116))	('adenocarcinoma', 'Disease', (197, 211))
290294	24738062	To find out whether BRF2 mediates prognosis in lung cancer through promoting metastasis, we applied small interfering RNA technology to knock down the BRF2 expression on the migratory and invasive ability of A549 and SK-MES-1 cells (Figure 5(a)).	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('lung cancer', 'Disease', (47, 58))	('BRF2', 'Gene', '55290', (151, 155))	('BRF2', 'Gene', '55290', (20, 24))	('lung cancer', 'Phenotype', 'HP:0100526', (47, 58))	('knock', 'Var', (136, 141))	('metastasis', 'CPA', (77, 87))	('invasive ability', 'CPA', (188, 204))	('migratory', 'CPA', (174, 183))	('BRF2', 'Gene', (151, 155))	('A549', 'CellLine', 'CVCL:0023', (208, 212))	('lung cancer', 'Disease', 'MESH:D008175', (47, 58))	('BRF2', 'Gene', (20, 24))	('SK-MES-1', 'CellLine', 'CVCL:0630', (217, 225))
290295	24738062	The results suggested that the disruption of BRF2 expression could significantly inhibit the migratory and invasive abilities of NSCLC cells by wound healing assay and transwell migration assay (Figures 5(b) and 5(c)).	('NSCLC', 'Phenotype', 'HP:0030358', (129, 134))	('BRF2', 'Gene', '55290', (45, 49))	('inhibit', 'NegReg', (81, 88))	('NSCLC', 'Disease', (129, 134))	('wound healing assay', 'CPA', (144, 163))	('BRF2', 'Gene', (45, 49))	('disruption', 'Var', (31, 41))	('NSCLC', 'Disease', 'MESH:D002289', (129, 134))	('transwell migration assay', 'CPA', (168, 193))
290297	24738062	To investigate whether BRF2 regulates the EMT transition in lung cancer cells, we examined the expression of the key EMT markers E cadherin and N-cadherin in BRF2 knocked down lung cancer cells by western blotting analysis.	('knocked', 'Var', (163, 170))	('BRF2', 'Gene', '55290', (23, 27))	('lung cancer', 'Disease', (60, 71))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('lung cancer', 'Disease', 'MESH:D008175', (176, 187))	('lung cancer', 'Phenotype', 'HP:0100526', (60, 71))	('N-cadherin', 'Gene', (144, 154))	('BRF2', 'Gene', '55290', (158, 162))	('BRF2', 'Gene', (23, 27))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('lung cancer', 'Disease', 'MESH:D008175', (60, 71))	('N-cadherin', 'Gene', '1000', (144, 154))	('BRF2', 'Gene', (158, 162))	('lung cancer', 'Disease', (176, 187))	('lung cancer', 'Phenotype', 'HP:0100526', (176, 187))
290298	24738062	We found that knockdown of BRF2 led to decreased expression of N-cadherin.	('BRF2', 'Gene', '55290', (27, 31))	('expression', 'MPA', (49, 59))	('N-cadherin', 'Gene', (63, 73))	('BRF2', 'Gene', (27, 31))	('knockdown', 'Var', (14, 23))	('N-cadherin', 'Gene', '1000', (63, 73))	('decreased', 'NegReg', (39, 48))
290299	24738062	Meanwhile, the expression of epithelial markers such as E-cadherin was elicited in response to BRF2 silencing.	('silencing', 'Var', (100, 109))	('BRF2', 'Gene', '55290', (95, 99))	('BRF2', 'Gene', (95, 99))	('expression', 'MPA', (15, 25))	('E-cadherin', 'Gene', (56, 66))	('E-cadherin', 'Gene', '999', (56, 66))	('elicited', 'Reg', (71, 79))
290302	24738062	Interestingly, the protein expression levels of snail were markedly suppressed in BRF2 downregulated expression cells compared to control cells (P < 0.05; Figure 6).	('BRF2', 'Gene', '55290', (82, 86))	('protein expression levels', 'MPA', (19, 44))	('expression', 'Var', (101, 111))	('snail', 'Gene', '6615', (48, 53))	('suppressed', 'NegReg', (68, 78))	('BRF2', 'Gene', (82, 86))	('downregulated', 'NegReg', (87, 100))	('snail', 'Gene', (48, 53))
290316	24738062	In our study, however, we found that BRF2 plays critical role in prognosis in 37 patients with AC; however, the log-rank test showed a trend towards better overall survival in the high BRF2 group in 40 patients with SCC but this did not reach statistical significance (P > 0.05).	('BRF2', 'Gene', '55290', (37, 41))	('BRF2', 'Gene', '55290', (185, 189))	('overall survival', 'MPA', (156, 172))	('BRF2', 'Gene', (37, 41))	('SCC', 'Disease', (216, 219))	('patients', 'Species', '9606', (81, 89))	('patients', 'Species', '9606', (202, 210))	('better', 'PosReg', (149, 155))	('BRF2', 'Gene', (185, 189))	('AC', 'Disease', (95, 97))	('high', 'Var', (180, 184))
290320	24738062	Our data revealed that inhibition of BRF2 could suppress the metastatic ability, while knocking down of BRF2 expression by siRNA inhibited the activity of tumor cell migratory and invasive properties in vitro and is companied by upregulated expression level of E-cadherin and downregulated expression level of N-cadherin.	('BRF2', 'Gene', '55290', (37, 41))	('E-cadherin', 'Gene', '999', (261, 271))	('upregulated', 'PosReg', (229, 240))	('expression level', 'MPA', (241, 257))	('BRF2', 'Gene', (37, 41))	('tumor', 'Disease', (155, 160))	('inhibited', 'NegReg', (129, 138))	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('metastatic ability', 'CPA', (61, 79))	('BRF2', 'Gene', '55290', (104, 108))	('downregulated', 'NegReg', (276, 289))	('BRF2', 'Gene', (104, 108))	('suppress', 'NegReg', (48, 56))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('knocking', 'Var', (87, 95))	('expression level', 'MPA', (290, 306))	('N-cadherin', 'Gene', (310, 320))	('N-cadherin', 'Gene', '1000', (310, 320))	('expression', 'MPA', (109, 119))	('inhibition', 'Var', (23, 33))	('E-cadherin', 'Gene', (261, 271))
290324	24738062	We provide evidence that downregulating BRF2 suppressed EMT associated with the expression transcription factors snail in vitro.	('snail', 'Gene', '6615', (113, 118))	('BRF2', 'Gene', (40, 44))	('EMT', 'CPA', (56, 59))	('suppressed', 'NegReg', (45, 55))	('snail', 'Gene', (113, 118))	('BRF2', 'Gene', '55290', (40, 44))	('downregulating', 'Var', (25, 39))
290333	33672117	We aimed to analyze genomic and transcriptomic variations including simple nucleotide variations (SNVs), copy number variations (CNVs) and differential expressed genes (DEGs) in order to find key genes and pathways for diagnostic and prognostic prediction for lung adenocarcinoma and lung squamous cell carcinoma.	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (284, 312))	('lung squamous cell carcinoma', 'Disease', (284, 312))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (260, 279))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (289, 312))	('copy number variations', 'Var', (105, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (270, 279))	('lung adenocarcinoma', 'Disease', (260, 279))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (260, 279))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (284, 312))	('carcinoma', 'Phenotype', 'HP:0030731', (303, 312))
290339	33672117	Both LUAD and LUSC have important gene alterations such as CDKN2A and CDKN2B deletions with different frequencies.	('deletions', 'Var', (77, 86))	('CDKN2B', 'Gene', '1030', (70, 76))	('LUAD', 'Phenotype', 'HP:0030078', (5, 9))	('CDKN2A', 'Gene', (59, 65))	('CDKN2B', 'Gene', (70, 76))	('LUSC', 'Phenotype', 'HP:0030359', (14, 18))	('CDKN2A', 'Gene', '1029', (59, 65))
290342	33672117	EGFR, MGA, SMARCA4, ATM, RBM10, and KDM5C genes are mutated only in LUAD but not in LUSC.	('RBM10', 'Gene', '8241', (25, 30))	('EGFR', 'Gene', (0, 4))	('MGA', 'Gene', (6, 9))	('mutated', 'Var', (52, 59))	('SMARCA4', 'Gene', (11, 18))	('KDM5C', 'Gene', (36, 41))	('RBM10', 'Gene', (25, 30))	('SMARCA4', 'Gene', '6597', (11, 18))	('KDM5C', 'Gene', '8242', (36, 41))	('ATM', 'Gene', (20, 23))	('LUSC', 'Phenotype', 'HP:0030359', (84, 88))	('LUAD', 'Phenotype', 'HP:0030078', (68, 72))	('EGFR', 'Gene', '1956', (0, 4))	('MGA', 'Gene', '23269', (6, 9))	('ATM', 'Gene', '472', (20, 23))
290346	33672117	The clinical treatment decisions are made based on tumor stage, histology, genetic alterations of a few driver oncogenes for targeted therapies, and patient's condition.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor', 'Disease', (51, 56))	('genetic alterations', 'Var', (75, 94))	('patient', 'Species', '9606', (149, 156))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
290356	33672117	They identified 18 significantly mutated genes, including TP53, KRAS which is mutually exclusive with EGFR, BRAF, PIK3CA, MET, STK11, KEAP1, NF1, RB1, CDKN2A, GTPase gene RIT1, including activating mutations and MGA including loss-of-function mutations.	('PIK3CA', 'Gene', '5290', (114, 120))	('loss-of-function', 'NegReg', (226, 242))	('TP53', 'Gene', '7157', (58, 62))	('MET', 'Gene', (122, 125))	('RIT1', 'Gene', (171, 175))	('STK11', 'Gene', '6794', (127, 132))	('NF1', 'Gene', (141, 144))	('EGFR', 'Gene', '1956', (102, 106))	('PIK3CA', 'Gene', (114, 120))	('BRAF', 'Gene', '673', (108, 112))	('KEAP1', 'Gene', '9817', (134, 139))	('KRAS', 'Gene', '3845', (64, 68))	('BRAF', 'Gene', (108, 112))	('MET', 'Gene', '79811', (122, 125))	('MGA', 'Gene', (212, 215))	('KEAP1', 'Gene', (134, 139))	('TP53', 'Gene', (58, 62))	('RB1', 'Gene', (146, 149))	('RIT1', 'Gene', '6016', (171, 175))	('KRAS', 'Gene', (64, 68))	('mutations', 'Var', (243, 252))	('CDKN2A', 'Gene', (151, 157))	('EGFR', 'Gene', (102, 106))	('STK11', 'Gene', (127, 132))	('RB1', 'Gene', '5925', (146, 149))	('CDKN2A', 'Gene', '1029', (151, 157))	('MGA', 'Gene', '23269', (212, 215))	('NF1', 'Gene', '4763', (141, 144))
290359	33672117	The Cancer Genome Atlas Research Network also profiled 178 lung squamous cell carcinomas and detected mutations in 11 genes, including mutations in TP53 (81%), CDKN2A, PTEN, PIK3CA, KEAP1, MLL2, HLA-A, NFE2L2, RB1, NOTCH1 including truncating mutations and loss-of-function mutations in the HLA-A class I major histocompatibility gene.	('PTEN', 'Gene', '5728', (168, 172))	('loss-of-function', 'NegReg', (257, 273))	('HLA-A', 'Gene', (291, 296))	('truncating', 'MPA', (232, 242))	('NOTCH1', 'Gene', (215, 221))	('TP53', 'Gene', (148, 152))	('Cancer', 'Phenotype', 'HP:0002664', (4, 10))	('HLA-A', 'Gene', (195, 200))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (64, 87))	('NOTCH1', 'Gene', '4851', (215, 221))	('lung squamous cell carcinomas', 'Disease', 'MESH:D002294', (59, 88))	('NFE2L2', 'Gene', '4780', (202, 208))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('mutations', 'Var', (135, 144))	('MLL2', 'Gene', '8085', (189, 193))	('PIK3CA', 'Gene', '5290', (174, 180))	('Cancer', 'Disease', (4, 10))	('mutations', 'Var', (102, 111))	('RB1', 'Gene', (210, 213))	('HLA-A', 'Gene', '3105', (291, 296))	('MLL2', 'Gene', (189, 193))	('KEAP1', 'Gene', '9817', (182, 187))	('CDKN2A', 'Gene', (160, 166))	('HLA-A', 'Gene', '3105', (195, 200))	('TP53', 'Gene', '7157', (148, 152))	('KEAP1', 'Gene', (182, 187))	('NFE2L2', 'Gene', (202, 208))	('Cancer', 'Disease', 'MESH:D009369', (4, 10))	('carcinomas', 'Phenotype', 'HP:0030731', (78, 88))	('lung squamous cell carcinomas', 'Disease', (59, 88))	('PTEN', 'Gene', (168, 172))	('PIK3CA', 'Gene', (174, 180))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (59, 87))	('RB1', 'Gene', '5925', (210, 213))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (64, 88))	('CDKN2A', 'Gene', '1029', (160, 166))	('mutations', 'Var', (274, 283))
290361	33672117	CNV analysis revealed the amplification of NFE2L2, MYC, CDK6, MDM2, BCL2L1 and EYS, and deletions of FOXP1, PTEN and NF1 genes with previously identified CNV genes, SOX2, PDGFRA, KIT, EGFR, FGFR1, WHSC1L1, CCND1, and CDKN2A.	('EYS', 'Gene', '346007', (79, 82))	('PTEN', 'Gene', (108, 112))	('MYC', 'Gene', (51, 54))	('CDKN2A', 'Gene', (217, 223))	('MDM2', 'Gene', '4193', (62, 66))	('PDGFRA', 'Gene', (171, 177))	('FGFR1', 'Gene', (190, 195))	('NFE2L2', 'Gene', '4780', (43, 49))	('KIT', 'Gene', (179, 182))	('CDK6', 'Gene', '1021', (56, 60))	('PDGFRA', 'Gene', '5156', (171, 177))	('NF1', 'Gene', '4763', (117, 120))	('PTEN', 'Gene', '5728', (108, 112))	('EGFR', 'Gene', (184, 188))	('FOXP1', 'Gene', '27086', (101, 106))	('BCL2L1', 'Gene', '598', (68, 74))	('CDKN2A', 'Gene', '1029', (217, 223))	('MYC', 'Gene', '4609', (51, 54))	('CDK6', 'Gene', (56, 60))	('NF1', 'Gene', (117, 120))	('deletions', 'Var', (88, 97))	('NFE2L2', 'Gene', (43, 49))	('CCND1', 'Gene', '595', (206, 211))	('KIT', 'Gene', '3815', (179, 182))	('CCND1', 'Gene', (206, 211))	('SOX2', 'Gene', '6657', (165, 169))	('FOXP1', 'Gene', (101, 106))	('SOX2', 'Gene', (165, 169))	('EYS', 'Gene', (79, 82))	('WHSC1L1', 'Gene', '54904', (197, 204))	('FGFR1', 'Gene', '2260', (190, 195))	('EGFR', 'Gene', '1956', (184, 188))	('BCL2L1', 'Gene', (68, 74))	('MDM2', 'Gene', (62, 66))	('WHSC1L1', 'Gene', (197, 204))
290362	33672117	They identified overexpression and amplification of SOX2 and TP63, loss-of-function mutations in NOTCH1, NOTCH2 and ASCL4 and focal deletions in FOXP1 which have known roles in squamous cell differentiation.	('ASCL4', 'Gene', '121549', (116, 121))	('NOTCH1', 'Gene', '4851', (97, 103))	('NOTCH1', 'Gene', (97, 103))	('SOX2', 'Gene', '6657', (52, 56))	('squamous cell differentiation', 'Disease', (177, 206))	('SOX2', 'Gene', (52, 56))	('NOTCH2', 'Gene', '4853', (105, 111))	('TP63', 'Gene', '8626', (61, 65))	('mutations', 'Var', (84, 93))	('FOXP1', 'Gene', '27086', (145, 150))	('TP63', 'Gene', (61, 65))	('ASCL4', 'Gene', (116, 121))	('NOTCH2', 'Gene', (105, 111))	('loss-of-function', 'NegReg', (67, 83))	('deletions', 'Var', (132, 141))	('FOXP1', 'Gene', (145, 150))
290363	33672117	CDKN2A is downregulated in over 70% of samples through epigenetic silencing by methylation (21%), inactivating mutation (18%), exon 1beta skipping (4%), or homozygous deletion (29%).	('inactivating mutation', 'Var', (98, 119))	('downregulated', 'NegReg', (10, 23))	('exon 1beta skipping', 'Var', (127, 146))	('methylation', 'Var', (79, 90))	('epigenetic', 'MPA', (55, 65))	('CDKN2A', 'Gene', (0, 6))	('CDKN2A', 'Gene', '1029', (0, 6))	('homozygous deletion', 'Var', (156, 175))
290366	33672117	developed TCGA RNAseq data-based prognostic signature including four protein-coding genes RHOV, CD109, FRRS1, and the lncRNA gene LINC00941, which showed high hazard ratios for stage I, EGFR wild-type, and EGFR mutant groups.	('stage I', 'Disease', (177, 184))	('EGFR', 'Gene', (206, 210))	('LINC00941', 'Gene', '100287314', (130, 139))	('LINC00941', 'Gene', (130, 139))	('FRRS1', 'Gene', '391059', (103, 108))	('EGFR', 'Gene', '1956', (186, 190))	('FRRS1', 'Gene', (103, 108))	('EGFR', 'Gene', (186, 190))	('CD109', 'Gene', (96, 101))	('mutant', 'Var', (211, 217))	('RHOV', 'Gene', (90, 94))	('RHOV', 'Gene', '171177', (90, 94))	('EGFR', 'Gene', '1956', (206, 210))	('CD109', 'Gene', '135228', (96, 101))
290398	33672117	SomInaClust computes a background mutation value to identify the hot spots using the known set of somatic mutations in "COSMIC" and the "Cancer Gene Census" (v92) datasets of COSMIC database for GRCh38.	('Cancer', 'Disease', 'MESH:D009369', (137, 143))	('Cancer', 'Phenotype', 'HP:0002664', (137, 143))	('Cancer', 'Disease', (137, 143))	('mutations', 'Var', (106, 115))
290405	33672117	Twenty-seven of them are protein-coding genes while two of them are long intergenic non-protein coding RNA (LINC00539, LINC00578), one is antisense RNA (ZNF571-AS1), three of them are pseudogenes (AC005077.4, AC113404.3, OGFRP1) and two of them are novel transcripts (AL365181.2, U91328.1) (Table S1).	('ZNF571-AS1', 'Gene', (153, 163))	('AC005077.4', 'Var', (197, 207))	('OGFRP1', 'Gene', (221, 227))	('ZNF571-AS1', 'Gene', '100507433', (153, 163))	('LINC00539', 'Gene', '100652865', (108, 117))	('LINC00578', 'Gene', '100505566', (119, 128))	('LINC00539', 'Gene', (108, 117))	('AL365181.2', 'Var', (268, 278))	('OGFRP1', 'Gene', '388906', (221, 227))	('LINC00578', 'Gene', (119, 128))
290416	33672117	Twenty-three of them are protein coding genes while two of them are long intergenic non-protein coding RNA (LINC01748, LINC01426), one is antisense RNA (SRP14-AS1), three of them are pseudo-genes (LPAL2, RPL37P6, WASH8P), three of them are novel transcripts (AC106786.1, AC096677.1, AC078883.1) and one is Y RNA (Table S3).	('AS1', 'Gene', '5729', (159, 162))	('AS1', 'Gene', (159, 162))	('AC106786.1', 'Var', (259, 269))	('LPAL2', 'Gene', '80350', (197, 202))	('LPAL2', 'Gene', (197, 202))	('LINC01748', 'Var', (108, 117))	('LINC01426', 'Gene', '100506385', (119, 128))	('SRP14', 'Gene', (153, 158))	('LINC01426', 'Gene', (119, 128))	('SRP14', 'Gene', '6727', (153, 158))	('RPL37P6', 'Gene', '346950', (204, 211))	('RPL37P6', 'Gene', (204, 211))
290458	33672117	The low-risk group patients have immune system pathways with amplified genes whereas high-risk group patients have immune system pathways with deleted genes.	('immune system pathways', 'Pathway', (33, 55))	('patients', 'Species', '9606', (101, 109))	('patients', 'Species', '9606', (19, 27))	('amplified genes', 'Var', (61, 76))	('immune system pathways', 'Pathway', (115, 137))
290459	33672117	On the other hand, high-risk group has amplified genes in metabolic pathways such as Gastric acid secretion and Insulin secretion (Figure S20).	('metabolic pathways', 'Pathway', (58, 76))	('Insulin', 'Gene', '3630', (112, 119))	('Insulin', 'Gene', (112, 119))	('Gastric acid secretion', 'MPA', (85, 107))	('amplified', 'PosReg', (39, 48))	('genes', 'Var', (49, 54))	('S20', 'Gene', '6224', (138, 141))	('S20', 'Gene', (138, 141))
290480	33672117	CSMD3 has more multi-hits (multiple mutations in one patient) in the low-risk group than the high-risk group.	('patient', 'Species', '9606', (53, 60))	('CSMD3', 'Gene', (0, 5))	('CSMD3', 'Gene', '114788', (0, 5))	('multi-hits', 'Var', (15, 25))
290495	33672117	When venn diagram is drawn by using all driver genes, all cancer and risk groups have TP53, CSMD3, KEAP1, NF1, RB1 and PIK3CA mutations.	('KEAP1', 'Gene', (99, 104))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('PIK3CA', 'Gene', (119, 125))	('TP53', 'Gene', '7157', (86, 90))	('PIK3CA', 'Gene', '5290', (119, 125))	('RB1', 'Gene', (111, 114))	('NF1', 'Gene', (106, 109))	('TP53', 'Gene', (86, 90))	('CSMD3', 'Gene', '114788', (92, 97))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('RB1', 'Gene', '5925', (111, 114))	('NF1', 'Gene', '4763', (106, 109))	('CSMD3', 'Gene', (92, 97))	('mutations', 'Var', (126, 135))	('cancer', 'Disease', (58, 64))	('KEAP1', 'Gene', '9817', (99, 104))
290500	33672117	TP53, STK11, KEAP1, SMARCA4 and MGA genes have deletions while CSMD3 and PIK3CA genes have amplification beside SNVs in both LUAD risk group.	('CSMD3', 'Gene', (63, 68))	('KEAP1', 'Gene', '9817', (13, 18))	('PIK3CA', 'Gene', '5290', (73, 79))	('TP53', 'Gene', '7157', (0, 4))	('deletions', 'Var', (47, 56))	('STK11', 'Gene', (6, 11))	('TP53', 'Gene', (0, 4))	('CSMD3', 'Gene', '114788', (63, 68))	('SMARCA4', 'Gene', (20, 27))	('KEAP1', 'Gene', (13, 18))	('MGA', 'Gene', '23269', (32, 35))	('SMARCA4', 'Gene', '6597', (20, 27))	('LUAD', 'Phenotype', 'HP:0030078', (125, 129))	('STK11', 'Gene', '6794', (6, 11))	('MGA', 'Gene', (32, 35))	('PIK3CA', 'Gene', (73, 79))
290502	33672117	Oncogenes tend to have amplifications while tumor suppressor genes tend to have deletions in both risk groups with exceptions (CSMD3, CDH10, HMCN1, AKAP6 and CTNNB1) (Figure 12).	('CSMD3', 'Gene', (127, 132))	('CSMD3', 'Gene', '114788', (127, 132))	('CTNNB1', 'Gene', (158, 164))	('CDH10', 'Gene', (134, 139))	('AKAP6', 'Gene', (148, 153))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('HMCN1', 'Gene', '83872', (141, 146))	('AKAP6', 'Gene', '9472', (148, 153))	('HMCN1', 'Gene', (141, 146))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('deletions', 'Var', (80, 89))	('CTNNB1', 'Gene', '1499', (158, 164))	('amplifications', 'Var', (23, 37))	('tumor', 'Disease', (44, 49))	('CDH10', 'Gene', '1008', (134, 139))	('Oncogenes', 'Gene', (0, 9))
290503	33672117	OncoPrints in Figure 13 show that TP53, CDKN2A, FAT1, RASA1, ARID1A and HRAS genes have deletions while only PIK3CA gene has amplification beside SNVs in both LUSC risk groups.	('deletions', 'Var', (88, 97))	('PIK3CA', 'Gene', (109, 115))	('ARID1A', 'Gene', (61, 67))	('TP53', 'Gene', (34, 38))	('PIK3CA', 'Gene', '5290', (109, 115))	('HRAS', 'Gene', '3265', (72, 76))	('LUSC', 'Phenotype', 'HP:0030359', (159, 163))	('CDKN2A', 'Gene', (40, 46))	('HRAS', 'Gene', (72, 76))	('RASA1', 'Gene', '5921', (54, 59))	('CDKN2A', 'Gene', '1029', (40, 46))	('RASA1', 'Gene', (54, 59))	('FAT1', 'Gene', '2195', (48, 52))	('ARID1A', 'Gene', '8289', (61, 67))	('TP53', 'Gene', '7157', (34, 38))	('FAT1', 'Gene', (48, 52))
290504	33672117	PIK3R1, KEAP1 and STK11 genes have deletions only in the high-risk group while SI, CSMD3, ZNF750, KRAS genes have amplification and NSD1, FGFR3, PTEN, SLC16A1, NRAS and CUL3 have deletion only in the low-risk group.	('NSD1', 'Gene', (132, 136))	('KRAS', 'Gene', '3845', (98, 102))	('CSMD3', 'Gene', '114788', (83, 88))	('NRAS', 'Gene', (160, 164))	('PIK3R1', 'Gene', '5295', (0, 6))	('FGFR3', 'Gene', (138, 143))	('STK11', 'Gene', (18, 23))	('deletions', 'Var', (35, 44))	('KRAS', 'Gene', (98, 102))	('KEAP1', 'Gene', '9817', (8, 13))	('NSD1', 'Gene', '64324', (132, 136))	('KEAP1', 'Gene', (8, 13))	('CSMD3', 'Gene', (83, 88))	('CUL3', 'Gene', (169, 173))	('ZNF750', 'Gene', '79755', (90, 96))	('FGFR3', 'Gene', '2261', (138, 143))	('PTEN', 'Gene', (145, 149))	('ZNF750', 'Gene', (90, 96))	('STK11', 'Gene', '6794', (18, 23))	('PTEN', 'Gene', '5728', (145, 149))	('NRAS', 'Gene', '4893', (160, 164))	('PIK3R1', 'Gene', (0, 6))	('SLC16A1', 'Gene', (151, 158))	('SLC16A1', 'Gene', '6566', (151, 158))	('CUL3', 'Gene', '8452', (169, 173))
290505	33672117	Oncogenes tend to have amplifications while tumor suppressor genes tend to have deletions in both risk groups with exceptions (CSMD3, FGFR3, ZNF750, NRAS, HRAS, KEAP1) (Figure 13).	('CSMD3', 'Gene', (127, 132))	('ZNF750', 'Gene', '79755', (141, 147))	('CSMD3', 'Gene', '114788', (127, 132))	('NRAS', 'Gene', (149, 153))	('KEAP1', 'Gene', (161, 166))	('FGFR3', 'Gene', (134, 139))	('HRAS', 'Gene', '3265', (155, 159))	('NRAS', 'Gene', '4893', (149, 153))	('HRAS', 'Gene', (155, 159))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('ZNF750', 'Gene', (141, 147))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('deletions', 'Var', (80, 89))	('amplifications', 'Var', (23, 37))	('FGFR3', 'Gene', '2261', (134, 139))	('KEAP1', 'Gene', '9817', (161, 166))	('tumor', 'Disease', (44, 49))	('Oncogenes', 'Gene', (0, 9))
290510	33672117	The remaining signature genes, CPXM2, ENPP5, SAMD13, SLC52A1, ZNF682, ZNF835, ZNF571-AS1 and U91328.1, have not been related to carcinoma, yet.	('ZNF682', 'Gene', (62, 68))	('ENPP5', 'Gene', '59084', (38, 43))	('SLC52A1', 'Gene', '55065', (53, 60))	('SAMD13', 'Gene', '148418', (45, 51))	('SLC52A1', 'Gene', (53, 60))	('ZNF682', 'Gene', '91120', (62, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('CPXM2', 'Gene', (31, 36))	('carcinoma', 'Disease', (128, 137))	('CPXM2', 'Gene', '119587', (31, 36))	('ENPP5', 'Gene', (38, 43))	('carcinoma', 'Disease', 'MESH:D009369', (128, 137))	('U91328.1', 'Var', (93, 101))	('ZNF835', 'Gene', '90485', (70, 76))	('ZNF835', 'Gene', (70, 76))	('ZNF571-AS1', 'Gene', (78, 88))	('ZNF571-AS1', 'Gene', '100507433', (78, 88))	('SAMD13', 'Gene', (45, 51))
290520	33672117	At CNV level both risk groups and cancer subtypes have huge number of genes with amplifications or deletions which can cause genomic instability and uncontrolled regulation.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('amplifications', 'Var', (81, 95))	('deletions', 'Var', (99, 108))	('cause', 'Reg', (119, 124))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('cancer', 'Disease', (34, 40))	('genomic instability', 'MPA', (125, 144))	('genes', 'Gene', (70, 75))
290521	33672117	Both LUAD and LUSC risk groups have important gene alterations such as CDKN2A and CDKN2B deletions which are associated with NSCLC and promotes KRAS and EGFR mutant tumorigenesis while SOX2 oncogene amplification in LUSC which is a common event in squamous cell carcinomas and amplification of PSMD4 in LUAD, with oncogenic roles in breast, hepatocellular, colorectal and prostate cancer cells.	('breast', 'Disease', (333, 339))	('LUAD', 'Phenotype', 'HP:0030078', (303, 307))	('SCLC', 'Phenotype', 'HP:0030357', (126, 130))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (248, 271))	('squamous cell carcinomas', 'Disease', (248, 272))	('NSCLC', 'Disease', 'MESH:D002289', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('CDKN2B', 'Gene', '1030', (82, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (262, 271))	('SOX2', 'Gene', (185, 189))	('carcinomas', 'Phenotype', 'HP:0030731', (262, 272))	('alterations', 'Var', (51, 62))	('SOX2', 'Gene', '6657', (185, 189))	('NSCLC', 'Disease', (125, 130))	('EGFR', 'Gene', (153, 157))	('mutant', 'Var', (158, 164))	('LUSC', 'Phenotype', 'HP:0030359', (14, 18))	('associated', 'Reg', (109, 119))	('KRAS', 'Gene', '3845', (144, 148))	('cancer', 'Phenotype', 'HP:0002664', (381, 387))	('CDKN2A', 'Gene', (71, 77))	('colorectal and prostate cancer', 'Disease', 'MESH:D011471', (357, 387))	('deletions', 'Var', (89, 98))	('LUAD', 'Phenotype', 'HP:0030078', (5, 9))	('prostate cancer', 'Phenotype', 'HP:0012125', (372, 387))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (248, 272))	('KRAS', 'Gene', (144, 148))	('tumor', 'Disease', (165, 170))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (248, 272))	('CDKN2A', 'Gene', '1029', (71, 77))	('EGFR', 'Gene', '1956', (153, 157))	('CDKN2B', 'Gene', (82, 88))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('PSMD4', 'Gene', '5710', (294, 299))	('promotes', 'PosReg', (135, 143))	('LUSC', 'Phenotype', 'HP:0030359', (216, 220))	('PSMD4', 'Gene', (294, 299))
290524	33672117	Additionally, EGFR, MGA, SMARCA4, ATM, RBM10 and KDM5C which are lung cancer related genes are mutated only in LUAD but not in LUSC.	('SMARCA4', 'Gene', (25, 32))	('ATM', 'Gene', (34, 37))	('LUSC', 'Phenotype', 'HP:0030359', (127, 131))	('MGA', 'Gene', '23269', (20, 23))	('lung cancer', 'Disease', 'MESH:D008175', (65, 76))	('EGFR', 'Gene', '1956', (14, 18))	('LUAD', 'Phenotype', 'HP:0030078', (111, 115))	('lung cancer', 'Phenotype', 'HP:0100526', (65, 76))	('KDM5C', 'Gene', '8242', (49, 54))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('SMARCA4', 'Gene', '6597', (25, 32))	('LUAD', 'Disease', (111, 115))	('RBM10', 'Gene', (39, 44))	('ATM', 'Gene', '472', (34, 37))	('EGFR', 'Gene', (14, 18))	('MGA', 'Gene', (20, 23))	('lung cancer', 'Disease', (65, 76))	('RBM10', 'Gene', '8241', (39, 44))	('mutated', 'Var', (95, 102))	('KDM5C', 'Gene', (49, 54))
290525	33672117	On the other hand, CDKN2A, PTEN and HRAS genes are mutated only in LUSC.	('CDKN2A', 'Gene', (19, 25))	('HRAS', 'Gene', '3265', (36, 40))	('CDKN2A', 'Gene', '1029', (19, 25))	('LUSC', 'Phenotype', 'HP:0030359', (67, 71))	('HRAS', 'Gene', (36, 40))	('PTEN', 'Gene', (27, 31))	('PTEN', 'Gene', '5728', (27, 31))	('mutated', 'Var', (51, 58))
290526	33672117	When SNV and CNV genes are plotted together, it can be seen that LUAD high-risk group has obvious oncogene amplifications and tumor suppressor deletions, while LUAD low-risk group has both tumor suppressor deletions and tumor suppressor amplifications with a few oncogene amplifications.	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('tumor', 'Disease', (189, 194))	('LUAD', 'Phenotype', 'HP:0030078', (65, 69))	('tumor', 'Disease', (220, 225))	('deletions', 'Var', (143, 152))	('LUAD', 'Phenotype', 'HP:0030078', (160, 164))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('amplifications', 'Var', (107, 121))	('oncogene', 'Gene', (98, 106))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('tumor', 'Disease', 'MESH:D009369', (220, 225))	('tumor', 'Disease', (126, 131))
290528	33672117	LUSC patients have mostly deletions on driver genes with only PIK3CA and KRAS oncogene amplifications.	('KRAS', 'Gene', (73, 77))	('patients', 'Species', '9606', (5, 13))	('KRAS', 'Gene', '3845', (73, 77))	('deletions', 'Var', (26, 35))	('PIK3CA', 'Gene', (62, 68))	('LUSC', 'Phenotype', 'HP:0030359', (0, 4))	('PIK3CA', 'Gene', '5290', (62, 68))	('LUSC', 'Disease', (0, 4))
290529	33672117	Both LUSC risk groups have obvious TP53 and CDKN2A tumor suppressor gene deletions, but amplification of CSMD3, which has differential roles in lung cancer, does not occur in LUSC high-risk group.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('lung cancer', 'Disease', (144, 155))	('lung cancer', 'Phenotype', 'HP:0100526', (144, 155))	('CDKN2A', 'Gene', (44, 50))	('tumor', 'Disease', (51, 56))	('TP53', 'Gene', '7157', (35, 39))	('TP53', 'Gene', (35, 39))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('CDKN2A', 'Gene', '1029', (44, 50))	('LUSC', 'Phenotype', 'HP:0030359', (5, 9))	('CSMD3', 'Gene', (105, 110))	('deletions', 'Var', (73, 82))	('CSMD3', 'Gene', '114788', (105, 110))	('LUSC', 'Phenotype', 'HP:0030359', (175, 179))	('lung cancer', 'Disease', 'MESH:D008175', (144, 155))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
290553	33482718	3c, d, compared with PCCL1000 with a value of 0.0006-0.9875, thePCCD1000value range is 0.4764-0.9905, and the paired t-test shows that PCCD1000is significantly higher thanPCCL1000 (p < 0.01).	('PCC', 'Chemical', '-', (64, 67))	('PCC', 'Chemical', '-', (171, 174))	('PCC', 'Chemical', '-', (21, 24))	('higher', 'PosReg', (160, 166))	('PCCD1000is', 'Var', (135, 145))	('PCC', 'Chemical', '-', (135, 138))
290559	33482718	This dataset contains 237 gene expression profiles from the GSE4573 and GSE10072 microarray datasets, including 49 normal samples, 58 lung adenocarcinoma (ADC) samples and 130 lung squamous cell carcinoma (SCC) samples.	('SCC', 'Gene', (206, 209))	('SCC', 'Phenotype', 'HP:0002860', (206, 209))	('GSE10072', 'Gene', (72, 80))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (134, 153))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (176, 204))	('SCC', 'Gene', '6317', (206, 209))	('GSE4573', 'Var', (60, 67))	('lung adenocarcinoma', 'Disease', (134, 153))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (176, 204))	('lung squamous cell carcinoma', 'Disease', (176, 204))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('carcinoma', 'Phenotype', 'HP:0030731', (195, 204))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (181, 204))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (134, 153))
290629	31133018	It is worth mentioning that five of the six patients with a cT4 in the first time cohort had a SCC despite exclusion of patients with invasion in the aorta or trachea.	('SCC', 'Gene', '6317', (95, 98))	('patients', 'Species', '9606', (44, 52))	('cT4', 'Var', (60, 63))	('patients', 'Species', '9606', (120, 128))	('SCC', 'Gene', (95, 98))	('SCC', 'Phenotype', 'HP:0002860', (95, 98))
290661	31945090	Pan-cancer analysis of somatic mutations and epigenetic alterations in insulated neighbourhood boundaries Recent evidence shows that the disruption of constitutive insulated neighbourhoods might lead to oncogene dysregulation.	('mutations', 'Var', (31, 40))	('epigenetic alterations', 'Var', (45, 67))	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('lead to', 'Reg', (195, 202))	('cancer', 'Disease', 'MESH:D009369', (4, 10))	('cancer', 'Disease', (4, 10))	('oncogene dysregulation', 'MPA', (203, 225))
290662	31945090	We present here a systematic pan-cancer characterisation of the associations between constitutive boundaries and genome alterations in cancer.	('cancer', 'Disease', (135, 141))	('cancer', 'Disease', (33, 39))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('genome alterations', 'Var', (113, 131))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('associations', 'Interaction', (64, 76))	('cancer', 'Disease', 'MESH:D009369', (135, 141))
290663	31945090	Specifically, we investigate the enrichment of somatic mutation, abnormal methylation, and copy number alteration events in the proximity of CTCF bindings overlapping with topological boundaries (junctions) in 26 cancer types.	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('abnormal', 'Var', (65, 73))	('bindings', 'Interaction', (146, 154))	('CTCF', 'Gene', (141, 145))	('copy number', 'CPA', (91, 102))	('cancer', 'Disease', 'MESH:D009369', (213, 219))	('cancer', 'Disease', (213, 219))	('methylation', 'MPA', (74, 85))
290664	31945090	Focusing on CTCF motifs that are both in-boundary (overlapping with junctions) and active (overlapping with peaks of CTCF expression), we find a significant enrichment of somatic mutations in several cancer types.	('cancer', 'Disease', 'MESH:D009369', (200, 206))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('cancer', 'Disease', (200, 206))	('mutations', 'Var', (179, 188))
290665	31945090	Furthermore, mutated junctions are significantly conserved across cancer types, and we also observe a positive selection of transversions rather than transitions in many cancer types.	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('cancer', 'Disease', (170, 176))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('transversions', 'Var', (124, 137))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('mutated', 'Var', (13, 20))	('cancer', 'Disease', (66, 72))
290667	31945090	Finally, in several cancer types we observe that copy number alterations tend to overlap with active junctions more often than in matched normal samples.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('cancer', 'Disease', 'MESH:D009369', (20, 26))	('copy number alterations', 'Var', (49, 72))	('cancer', 'Disease', (20, 26))	('active junctions', 'MPA', (94, 110))
290668	31945090	While several articles have recently reported a mutational enrichment at CTCF binding sites for specific cancer types, our analysis is pan-cancer and investigates abnormal methylation and copy number alterations in addition to somatic mutations.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('mutational', 'Var', (48, 58))	('cancer', 'Disease', (139, 145))
290673	31945090	Hypermethylation of CTCF binding sites has been observed to lead to loss of insulation between topological domains and consequent aberrant gene activation in gliomas.	('insulation between topological domains', 'MPA', (76, 114))	('glioma', 'Phenotype', 'HP:0009733', (158, 164))	('Hypermethylation', 'Var', (0, 16))	('gene', 'MPA', (139, 143))	('activation', 'PosReg', (144, 154))	('gliomas', 'Disease', 'MESH:D005910', (158, 165))	('loss', 'NegReg', (68, 72))	('gliomas', 'Disease', (158, 165))	('gliomas', 'Phenotype', 'HP:0009733', (158, 165))
290674	31945090	Microdeletions that eliminate the boundary sites of insulated neighborhoods containing prominent acute lymphoblastic leukemia proto-oncogenes have also been reported.	('lymphoblastic leukemia', 'Disease', 'MESH:D054198', (103, 125))	('leukemia', 'Phenotype', 'HP:0001909', (117, 125))	('lymphoblastic leukemia', 'Disease', (103, 125))	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (97, 125))	('boundary sites', 'MPA', (34, 48))	('Microdeletions', 'Var', (0, 14))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (103, 125))
290675	31945090	The same study also identified an enrichment in boundary CTCF site mutations in the genomes of esophageal and liver carcinoma.	('esophageal', 'Disease', (95, 105))	('liver carcinoma', 'Disease', (110, 125))	('liver carcinoma', 'Disease', 'MESH:D006528', (110, 125))	('mutations', 'Var', (67, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('liver carcinoma', 'Phenotype', 'HP:0001402', (110, 125))
290676	31945090	Furthermore, genomic rearrangements with breakpoints within TADs can lead to breakage or fusion of TADs that might result in oncogene activation, as observed in prostate cancer, where chromosomal deletions lead to the establishment of new domain boundaries and the rearrangement of gene interactions.	('chromosomal deletions', 'Var', (184, 205))	('gene', 'Protein', (282, 286))	('prostate cancer', 'Phenotype', 'HP:0012125', (161, 176))	('rearrangements', 'Var', (21, 35))	('breakage', 'Var', (77, 85))	('activation', 'PosReg', (134, 144))	('oncogene', 'MPA', (125, 133))	('prostate cancer', 'Disease', (161, 176))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('rearrangement', 'Reg', (265, 278))	('lead', 'Reg', (69, 73))	('breakpoints', 'Var', (41, 52))	('prostate cancer', 'Disease', 'MESH:D011471', (161, 176))	('interactions', 'Interaction', (287, 299))
290677	31945090	Hotspots of mutations within CTCF motifs have been independently observed in melanoma related to UV exposure, and in gastrointestinal cancers.	('CTCF motifs', 'Gene', (29, 40))	('gastrointestinal cancers', 'Disease', 'MESH:D005770', (117, 141))	('cancers', 'Phenotype', 'HP:0002664', (134, 141))	('mutations', 'Var', (12, 21))	('melanoma', 'Phenotype', 'HP:0002861', (77, 85))	('melanoma', 'Disease', (77, 85))	('melanoma', 'Disease', 'MESH:D008545', (77, 85))	('observed', 'Reg', (65, 73))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (117, 140))	('gastrointestinal cancers', 'Disease', (117, 141))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
290686	31945090	While mutations in CTCF binding sites have been reported to occur frequently in several cancers, the significance of these findings across the broad spectrum of cancer types has not yet been evaluated.	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('binding', 'Interaction', (24, 31))	('cancers', 'Disease', 'MESH:D009369', (88, 95))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('cancers', 'Disease', (88, 95))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('CTCF', 'Gene', (19, 23))	('cancer', 'Disease', (161, 167))	('mutations', 'Var', (6, 15))	('occur', 'Reg', (60, 65))
290687	31945090	Specifically, we selected 14 cancer types for which at least 200,000 mutations across all patients were reported:this threshold was imposed in order to ensure adequate statistics.	('mutations', 'Var', (69, 78))	('cancer', 'Disease', (29, 35))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('patients', 'Species', '9606', (90, 98))	('cancer', 'Disease', 'MESH:D009369', (29, 35))
290689	31945090	Fig 2, left subplot, shows the accumulation of mutations in esophageal adenocarcinoma (ESAD), one of the tumour types for which this phenomenon was more evident.	('tumour', 'Disease', 'MESH:D009369', (105, 111))	('ESAD', 'Phenotype', 'HP:0011459', (87, 91))	('ESAD', 'Disease', 'MESH:D004941', (87, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004941', (60, 85))	('esophageal adenocarcinoma', 'Disease', (60, 85))	('tumour', 'Disease', (105, 111))	('mutations', 'Var', (47, 56))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (60, 85))	('ESAD', 'Disease', (87, 91))	('tumour', 'Phenotype', 'HP:0002664', (105, 111))
290697	31945090	Hence, it could be argued that the enrichment of mutations in active in-boundary motifs is due to the proximity of these motifs to promoters, rather than to a cancer specific mechanism.	('cancer', 'Disease', (159, 165))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('mutations', 'Var', (49, 58))
290700	31945090	In no cancer type did we observe an enrichment of mutations in promoters, supporting the hypothesis that the accumulation of mutations in active CTCF motifs is not due to the overlap of promoters, and hence, not due to the open state of the chromatin.	('mutations', 'Var', (125, 134))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('mutations', 'Var', (50, 59))	('CTCF motifs', 'Gene', (145, 156))	('cancer', 'Disease', 'MESH:D009369', (6, 12))	('cancer', 'Disease', (6, 12))
290702	31945090	We also tried to test if mutations tend to cluster on active enhancers, defined as the intersection of H3K4me1 and H3K27Ac histone modifications, but for such regions we found a very small intersection with active in-boundary CTCF motifs and it was not possible to perform a significative statistical test.	('H3K27Ac', 'Var', (115, 122))	('H3K4me1', 'Chemical', 'MESH:C024755', (103, 110))	('mutations', 'Var', (25, 34))
290704	31945090	Notably, in the list of oncogenes we find TGFB1, whose up-regulation has been recently associated with disruption of CTCF binding motif due to somatic mutations in the melanoma A375 cell line.	('up-regulation', 'PosReg', (55, 68))	('TGFB1', 'Gene', (42, 47))	('melanoma', 'Disease', (168, 176))	('melanoma', 'Phenotype', 'HP:0002861', (168, 176))	('A375', 'CellLine', 'CVCL:0132', (177, 181))	('mutations', 'Var', (151, 160))	('melanoma', 'Disease', 'MESH:D008545', (168, 176))
290708	31945090	Next, we investigated whether the somatic mutations in active in-boundary motifs preferentially belong to a certain class of mutations, which could point to a specific tumourigenic mechanism.	('tumour', 'Phenotype', 'HP:0002664', (168, 174))	('tumour', 'Disease', 'MESH:D009369', (168, 174))	('tumour', 'Disease', (168, 174))	('point', 'Reg', (148, 153))	('mutations', 'Var', (42, 51))	('belong', 'Reg', (96, 102))
290710	31945090	Table 3 reports the counts of transition and transversion mutations for active in-boundary and active off-boundary motifs for all considered cancers.	('transversion mutations', 'Var', (45, 67))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('cancers', 'Phenotype', 'HP:0002664', (141, 148))	('cancers', 'Disease', 'MESH:D009369', (141, 148))	('cancers', 'Disease', (141, 148))
290714	31945090	Assuming that similar results can be generalised to somatic alterations, this finding suggests that transversions on CTCF motifs might have a stronger effect than transitions, which could hint towards a positive selection of transversions rather than transitions in insulated neighborhood boundaries in tumour cells, as these alterations are more likely to disrupt boundaries than transitions.	('neighborhood boundaries in tumour', 'Disease', (276, 309))	('neighborhood boundaries in tumour', 'Disease', 'MESH:D009369', (276, 309))	('tumour', 'Phenotype', 'HP:0002664', (303, 309))	('CTCF motifs', 'Gene', (117, 128))	('transversions', 'Var', (100, 113))
290716	31945090	We considered the five tumour types for which we have the highest number of mutations (see Table B in S1 File):and studied their mutation patterns.	('tumour', 'Disease', (23, 29))	('tumour', 'Disease', 'MESH:D009369', (23, 29))	('mutations', 'Var', (76, 85))	('tumour', 'Phenotype', 'HP:0002664', (23, 29))
290717	31945090	Esophageal Adenocarcinoma (ESAD), Liver Cancer (LIRI) and Breast Cancer (BRCA) were associated with the largest enrichment of in-boundary mutations in all 3 considered ChIA-PET experiments (see Table 2).	('Liver Cancer', 'Disease', 'MESH:D006528', (34, 46))	('Breast Cancer', 'Disease', 'MESH:D001943', (58, 71))	('Liver Cancer', 'Phenotype', 'HP:0002896', (34, 46))	('BRCA', 'Phenotype', 'HP:0003002', (73, 77))	('carcinoma', 'Phenotype', 'HP:0030731', (16, 25))	('Breast Cancer', 'Disease', (58, 71))	('Esophageal Adenocarcinoma', 'Disease', 'MESH:D004941', (0, 25))	('Cancer', 'Phenotype', 'HP:0002664', (65, 71))	('Breast Cancer', 'Phenotype', 'HP:0003002', (58, 71))	('Cancer', 'Phenotype', 'HP:0002664', (40, 46))	('ESAD', 'Disease', (27, 31))	('BRCA', 'Disease', (73, 77))	('Liver Cancer', 'Disease', (34, 46))	('mutations', 'Var', (138, 147))	('ESAD', 'Disease', 'MESH:D004941', (27, 31))	('Esophageal Adenocarcinoma', 'Phenotype', 'HP:0011459', (0, 25))	('BRCA', 'Disease', 'MESH:D001943', (73, 77))	('Esophageal Adenocarcinoma', 'Disease', (0, 25))	('ESAD', 'Phenotype', 'HP:0011459', (27, 31))
290721	31945090	Point mutations in skin cancer (MELA) and skin adenocarcinoma (SKCA) are shown in Fig 5D and 5E.	('carcinoma', 'Phenotype', 'HP:0030731', (52, 61))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('skin cancer', 'Phenotype', 'HP:0008069', (19, 30))	('skin cancer', 'Disease', (19, 30))	('SKCA', 'Disease', 'MESH:D000230', (63, 67))	('skin cancer', 'Disease', 'MESH:D012878', (19, 30))	('MELA', 'Phenotype', 'HP:0002861', (32, 36))	('MELA', 'Disease', 'MESH:D008545', (32, 36))	('skin adenocarcinoma', 'Disease', 'MESH:D000230', (42, 61))	('skin adenocarcinoma', 'Disease', (42, 61))	('Point mutations', 'Var', (0, 15))	('MELA', 'Disease', (32, 36))	('SKCA', 'Disease', (63, 67))
290722	31945090	These mutations are consistent with the observed enrichment of C T and CC TT mutations in ultraviolet exposure-driven melanoma tumours.	('melanoma', 'Phenotype', 'HP:0002861', (118, 126))	('CC TT', 'Gene', (71, 76))	('tumours', 'Phenotype', 'HP:0002664', (127, 134))	('melanoma tumours', 'Disease', 'MESH:D008545', (118, 134))	('tumour', 'Phenotype', 'HP:0002664', (127, 133))	('melanoma tumours', 'Disease', (118, 134))	('mutations', 'Var', (77, 86))
290725	31945090	In our analysis we found that signature SBS26, which is associated with defective DNA mismatch repair, is particularly prominent in the active in-boundary motifs in Esophageal Adenocarcinoma (ESAD Fig 6), Liver Cancer (LIRI, Fig I in S1 File) and Breast Cancer (BRCA, Fig H in S1 File), although the exposure of the same signature is not relevant in the whole genome of the same tumors.	('Cancer', 'Phenotype', 'HP:0002664', (211, 217))	('BRCA', 'Disease', 'MESH:D001943', (262, 266))	('Liver Cancer', 'Disease', (205, 217))	('tumors', 'Phenotype', 'HP:0002664', (379, 385))	('Esophageal Adenocarcinoma', 'Disease', (165, 190))	('ESAD', 'Phenotype', 'HP:0011459', (192, 196))	('tumor', 'Phenotype', 'HP:0002664', (379, 384))	('Cancer', 'Phenotype', 'HP:0002664', (254, 260))	('tumors', 'Disease', (379, 385))	('carcinoma', 'Phenotype', 'HP:0030731', (181, 190))	('Liver Cancer', 'Disease', 'MESH:D006528', (205, 217))	('Breast Cancer', 'Disease', 'MESH:D001943', (247, 260))	('BRCA', 'Phenotype', 'HP:0003002', (262, 266))	('Liver Cancer', 'Phenotype', 'HP:0002896', (205, 217))	('Breast Cancer', 'Disease', (247, 260))	('tumors', 'Disease', 'MESH:D009369', (379, 385))	('Esophageal Adenocarcinoma', 'Disease', 'MESH:D004941', (165, 190))	('Breast Cancer', 'Phenotype', 'HP:0003002', (247, 260))	('defective', 'Var', (72, 81))	('ESAD', 'Disease', (192, 196))	('SBS26', 'Var', (40, 45))	('BRCA', 'Disease', (262, 266))	('ESAD', 'Disease', 'MESH:D004941', (192, 196))	('Esophageal Adenocarcinoma', 'Phenotype', 'HP:0011459', (165, 190))
290726	31945090	For what it concerns Skin Sancer (MELA) and Skin Adenocarcinoma (SKCA) we found that within in-boundary motifs the signature SBS7b has the highest exposure and not signature SBS7a as in the whole genome (Figs J and K in S1 File).	('SKCA', 'Disease', 'MESH:D000230', (65, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (54, 63))	('SBS7b', 'Var', (125, 130))	('Skin Adenocarcinoma', 'Disease', (44, 63))	('MELA', 'Disease', (34, 38))	('exposure', 'MPA', (147, 155))	('MELA', 'Phenotype', 'HP:0002861', (34, 38))	('Skin Adenocarcinoma', 'Disease', 'MESH:D000230', (44, 63))	('SKCA', 'Disease', (65, 69))	('MELA', 'Disease', 'MESH:D008545', (34, 38))
290727	31945090	We also found a significant overlap of frequently mutated boundaries across tumour types in the same five tumour types (Melanoma, Esophageal Adenocarcinoma, Skin Adenocarcinoma, Liver Cancer and Breast Cancer) associated with the highest number of mutations, see Fig F in S1 File.	('mutations', 'Var', (248, 257))	('Melanoma', 'Disease', 'MESH:D008545', (120, 128))	('Cancer', 'Phenotype', 'HP:0002664', (202, 208))	('Breast Cancer', 'Disease', (195, 208))	('tumour', 'Phenotype', 'HP:0002664', (76, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (167, 176))	('Esophageal Adenocarcinoma', 'Disease', 'MESH:D004941', (130, 155))	('Cancer', 'Phenotype', 'HP:0002664', (184, 190))	('tumour', 'Disease', 'MESH:D009369', (76, 82))	('tumour', 'Disease', (76, 82))	('Breast Cancer', 'Phenotype', 'HP:0003002', (195, 208))	('Melanoma', 'Disease', (120, 128))	('Skin Adenocarcinoma, Liver Cancer', 'Disease', 'MESH:D006528', (157, 190))	('Esophageal Adenocarcinoma', 'Phenotype', 'HP:0011459', (130, 155))	('Melanoma', 'Phenotype', 'HP:0002861', (120, 128))	('tumour', 'Phenotype', 'HP:0002664', (106, 112))	('tumour', 'Disease', 'MESH:D009369', (106, 112))	('Esophageal Adenocarcinoma', 'Disease', (130, 155))	('tumour', 'Disease', (106, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('associated', 'Reg', (210, 220))	('Liver Cancer', 'Phenotype', 'HP:0002896', (178, 190))	('Breast Cancer', 'Disease', 'MESH:D001943', (195, 208))
290729	31945090	All pair-wise comparisons resulted in very significant p-values, confirming that mutations in boundaries do not happen by random chance, hinting to a concerted oncogenic mechanism to dysregulate key cancer driver genes.	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('mutations', 'Var', (81, 90))	('cancer', 'Disease', (199, 205))
290731	31945090	Increased methylation leading to disruption of CTCF binding patterns has also been observed in immortalized cell lines, suggesting that abnormal methylation of CTFC motifs might be a mechanism of cancer gene dysregulation.	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('abnormal', 'Var', (136, 144))	('methylation', 'MPA', (145, 156))	('mechanism', 'Reg', (183, 192))	('cancer', 'Disease', 'MESH:D009369', (196, 202))	('cancer', 'Disease', (196, 202))
290736	31945090	In several cancer types we observed hypermethylation on in-boundary motifs.	('cancer', 'Disease', (11, 17))	('cancer', 'Disease', 'MESH:D009369', (11, 17))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('hypermethylation', 'Var', (36, 52))
290746	31945090	Copy number alterations (CNA) are a main tumorigenic driver in many cancer types.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('tumor', 'Disease', (41, 46))	('Copy number alterations', 'Var', (0, 23))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('cancer', 'Disease', (68, 74))	('tumor', 'Disease', 'MESH:D009369', (41, 46))
290747	31945090	In the context of neighbourhood dysregulation, recent work has reported tandem duplications intersecting with a TAD that led to de novo 3D contact domain formation.	('neighbourhood dysregulation', 'Disease', (18, 45))	('neighbourhood dysregulation', 'Disease', 'MESH:D021081', (18, 45))	('3D contact domain formation', 'MPA', (136, 163))	('tandem duplications', 'Var', (72, 91))	('led to', 'Reg', (121, 127))
290748	31945090	The same work revealed that TAD boundary intersecting deletions are associated with IRS4 dysregulation (a gene often over-expressed in different cancer types) in sarcoma and squamous cancers.	('cancer', 'Disease', (145, 151))	('cancers', 'Phenotype', 'HP:0002664', (183, 190))	('associated', 'Reg', (68, 78))	('cancer', 'Disease', (183, 189))	('squamous cancers', 'Disease', 'MESH:D018307', (174, 190))	('sarcoma', 'Disease', 'MESH:D012509', (162, 169))	('sarcoma', 'Disease', (162, 169))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('sarcoma', 'Phenotype', 'HP:0100242', (162, 169))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('deletions', 'Var', (54, 63))	('IRS4', 'Gene', (84, 88))	('cancer', 'Disease', 'MESH:D009369', (183, 189))	('squamous cancers', 'Disease', (174, 190))
290749	31945090	Motivated by these findings, we investigate here whether copy number alterations may contribute to cancer phenotypes by disrupting topologically associated domain boundaries.	('disrupting', 'NegReg', (120, 130))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('cancer', 'Disease', (99, 105))	('contribute', 'Reg', (85, 95))	('topologically associated domain boundaries', 'MPA', (131, 173))	('copy number alterations', 'Var', (57, 80))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
290759	31945090	In recent work, principal component analysis (PCA) on CNA data was performed on various cancer types, and Ovarian, Lung and Breast (basal subtype) cancers were found to have a similar signature characterised by a higher degree of copy number alterations compared to other types of cancer.	('cancer', 'Phenotype', 'HP:0002664', (281, 287))	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('cancer', 'Disease', 'MESH:D009369', (281, 287))	('copy number alterations', 'Var', (230, 253))	('Ovarian', 'Disease', (106, 113))	('cancer', 'Disease', (281, 287))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('cancers', 'Phenotype', 'HP:0002664', (147, 154))	('Breast (basal subtype) cancers', 'Disease', 'MESH:D001943', (124, 154))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('cancer', 'Disease', (147, 153))	('Lung', 'Disease', (115, 119))
290764	31945090	In for instance, the loss of one boundary enables a constitutive enhancer to interact aberrantly with PDGFRA, a prominent oncogene in glioma.	('loss', 'Var', (21, 25))	('glioma', 'Phenotype', 'HP:0009733', (134, 140))	('PDGFRA', 'Gene', (102, 108))	('enhancer', 'PosReg', (65, 73))	('glioma', 'Disease', (134, 140))	('interact', 'Interaction', (77, 85))	('glioma', 'Disease', 'MESH:D005910', (134, 140))
290766	31945090	In, mutations of one insulator region identified as a melanoma driver are associated with the upregulation of TGFB1, although another study on melanoma could not find evidence of gene expression enrichment.	('upregulation', 'PosReg', (94, 106))	('melanoma', 'Disease', 'MESH:D008545', (54, 62))	('melanoma', 'Phenotype', 'HP:0002861', (54, 62))	('melanoma', 'Disease', (54, 62))	('melanoma', 'Phenotype', 'HP:0002861', (143, 151))	('melanoma', 'Disease', (143, 151))	('TGFB1', 'Gene', (110, 115))	('mutations', 'Var', (4, 13))	('melanoma', 'Disease', 'MESH:D008545', (143, 151))
290767	31945090	Other studies have described gene expression changes in the proximity of mutation hotspots at CTCF binding sites in gastrointestinal cancer.	('gastrointestinal cancer', 'Disease', 'MESH:D005770', (116, 139))	('gastrointestinal cancer', 'Disease', (116, 139))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (116, 139))	('CTCF', 'Gene', (94, 98))	('changes', 'Reg', (45, 52))	('mutation', 'Var', (73, 81))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('gene expression', 'MPA', (29, 44))
290768	31945090	While each of these results individually suggests an important role for the dysregulation of some constitutive neighbourhoods in specific tumors, a conclusive pan-cancer analysis is not yet available.	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('tumors', 'Disease', (138, 144))	('tumors', 'Disease', 'MESH:D009369', (138, 144))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('dysregulation', 'Var', (76, 89))	('cancer', 'Disease', (163, 169))	('cancer', 'Disease', 'MESH:D009369', (163, 169))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
290770	31945090	Table 5 summarises our analysis: we find that somatic mutations, methylation, and copy number variations are significantly enriched in the neighbourhood boundaries in some specific cancer types.	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('methylation', 'Var', (65, 76))	('copy number variations', 'Var', (82, 104))	('cancer', 'Disease', (181, 187))
290773	31945090	We also observe a very significant overlap of frequently mutated active boundaries on these five cancers (Table G in S1 File), confirming that mutations in boundary do not happen at random.	('cancers', 'Disease', 'MESH:D009369', (97, 104))	('cancers', 'Phenotype', 'HP:0002664', (97, 104))	('cancers', 'Disease', (97, 104))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('mutated', 'Var', (57, 64))
290774	31945090	A positive selection of transversions versus transitions seems to be prevalent in most cancer types.	('cancer', 'Disease', (87, 93))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('transversions', 'Var', (24, 37))
290777	31945090	Finally, we observe that copy number alterations significantly overlap with active junctions in four cancer types, namely in Breast Cancer (BRCA), Lung Adenocarcinoma (LUAD), Lung Squamous Carcinoma (LUSC) and Ovarian Cancer (OV), all of them cancers where important oncogenic CNA signatures have been identified.	('Squamous Carcinoma', 'Disease', 'MESH:D002294', (180, 198))	('Cancer', 'Phenotype', 'HP:0002664', (218, 224))	('LUSC', 'Phenotype', 'HP:0030359', (200, 204))	('Breast Cancer', 'Phenotype', 'HP:0003002', (125, 138))	('Squamous Carcinoma', 'Disease', (180, 198))	('Lung Adenocarcinoma', 'Phenotype', 'HP:0030078', (147, 166))	('Ovarian Cancer', 'Disease', (210, 224))	('Carcinoma', 'Phenotype', 'HP:0030731', (189, 198))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('LUAD', 'Phenotype', 'HP:0030078', (168, 172))	('Ovarian Cancer', 'Disease', 'MESH:D010051', (210, 224))	('copy number alterations', 'Var', (25, 48))	('overlap', 'Reg', (63, 70))	('Cancer', 'Phenotype', 'HP:0002664', (132, 138))	('BRCA', 'Disease', (140, 144))	('cancer', 'Disease', 'MESH:D009369', (243, 249))	('cancers', 'Disease', 'MESH:D009369', (243, 250))	('OV', 'Disease', 'MESH:D010051', (226, 228))	('carcinoma', 'Phenotype', 'HP:0030731', (157, 166))	('BRCA', 'Disease', 'MESH:D001943', (140, 144))	('Lung Adenocarcinoma', 'Disease', (147, 166))	('Lung Adenocarcinoma', 'Disease', 'MESH:C538231', (147, 166))	('LUAD', 'Disease', (168, 172))	('Squamous Carcinoma', 'Phenotype', 'HP:0002860', (180, 198))	('Ovarian Cancer', 'Phenotype', 'HP:0100615', (210, 224))	('Breast Cancer', 'Disease', 'MESH:D001943', (125, 138))	('LUAD', 'Disease', 'MESH:C538231', (168, 172))	('cancer', 'Disease', (101, 107))	('OV', 'Phenotype', 'HP:0100615', (226, 228))	('cancers', 'Phenotype', 'HP:0002664', (243, 250))	('cancer', 'Disease', (243, 249))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('cancers', 'Disease', (243, 250))	('Lung Squamous Carcinoma', 'Phenotype', 'HP:0030359', (175, 198))	('BRCA', 'Phenotype', 'HP:0003002', (140, 144))	('Breast Cancer', 'Disease', (125, 138))	('cancer', 'Phenotype', 'HP:0002664', (243, 249))
290859	31921651	This molecular array allows for the identification of the most important mutations of the KRAS, NRAS, BRAF, EGFR, PIK3CA, and ERBB2 genes.	('PIK3CA', 'Gene', '5290', (114, 120))	('EGFR', 'Gene', '1956', (108, 112))	('ERBB2', 'Gene', '2064', (126, 131))	('KRAS', 'Gene', (90, 94))	('EGFR', 'Gene', (108, 112))	('BRAF', 'Gene', '673', (102, 106))	('ERBB2', 'Gene', (126, 131))	('BRAF', 'Gene', (102, 106))	('KRAS', 'Gene', '3845', (90, 94))	('PIK3CA', 'Gene', (114, 120))	('NRAS', 'Gene', (96, 100))	('mutations', 'Var', (73, 82))	('NRAS', 'Gene', '4893', (96, 100))
290887	31921651	Two of them had a KRAS mutation, one had an EGFR mutation and one patient was wild type for the analyzed mutations.	('KRAS', 'Gene', (18, 22))	('mutation', 'Var', (23, 31))	('KRAS', 'Gene', '3845', (18, 22))	('patient', 'Species', '9606', (66, 73))	('EGFR', 'Gene', '1956', (44, 48))	('EGFR', 'Gene', (44, 48))
290933	31488816	Standard molecular-targeted therapies have been developed according to genetic alterations, such as EGFR mutations and ALK fusions, and expression of biomarkers, such as programmed death-ligand 1 (PD-L1).	('EGFR', 'Gene', '1956', (100, 104))	('PD-L1', 'Gene', (197, 202))	('ALK', 'Gene', (119, 122))	('EGFR', 'Gene', (100, 104))	('programmed death-ligand 1', 'Gene', (170, 195))	('programmed death-ligand 1', 'Gene', '29126', (170, 195))	('mutations', 'Var', (105, 114))	('PD-L1', 'Gene', '29126', (197, 202))	('fusions', 'Var', (123, 130))	('ALK', 'Gene', '238', (119, 122))
290987	31488816	The variant allele fraction (VAF) distribution in these organoids generally maintained the VAF distribution in original cancer tissues (Fig.	('maintained', 'Reg', (76, 86))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('VAF', 'MPA', (91, 94))	('variant', 'Var', (4, 11))	('original cancer', 'Disease', (111, 126))	('original cancer', 'Disease', 'MESH:D009369', (111, 126))
290989	31488816	This suggests that the organoid-specific mutations were likely present in the originating tumours at low frequencies, rather than being genuinely novel because primary tumour tissue contains normal cells, which lower its VAF (Fig.	('mutations', 'Var', (41, 50))	('VAF', 'MPA', (221, 224))	('tumour', 'Phenotype', 'HP:0002664', (168, 174))	('tumour', 'Disease', 'MESH:D009369', (168, 174))	('tumour', 'Phenotype', 'HP:0002664', (90, 96))	('tumours', 'Phenotype', 'HP:0002664', (90, 97))	('tumour', 'Disease', (168, 174))	('tumour', 'Disease', 'MESH:D009369', (90, 96))	('lower', 'NegReg', (211, 216))	('tumours', 'Disease', 'MESH:D009369', (90, 97))	('tumour', 'Disease', (90, 96))	('tumours', 'Disease', (90, 97))
290995	31488816	Therefore, if a mutation is common in all cancer cells, it will be represented in all sequencing data and thereby reaching to the highest score (=1).	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('mutation', 'Var', (16, 24))
291029	31488816	The PARP inhibitor olaparib targets tumours with homologous recombination repair deficiencies, including those with mutations in the DNA repair encoding gene BRCA2.	('olaparib', 'Chemical', 'MESH:C531550', (19, 27))	('PARP', 'Gene', '1302', (4, 8))	('tumours', 'Phenotype', 'HP:0002664', (36, 43))	('tumours', 'Disease', 'MESH:D009369', (36, 43))	('PARP', 'Gene', (4, 8))	('tumours', 'Disease', (36, 43))	('homologous', 'MPA', (49, 59))	('mutations', 'Var', (116, 125))	('tumour', 'Phenotype', 'HP:0002664', (36, 42))	('BRCA2', 'Gene', (158, 163))	('deficiencies', 'Var', (81, 93))	('BRCA2', 'Gene', '675', (158, 163))
291031	31488816	LCO-55 had a BRCA2 p.W2619C mutation and a lower olaparib IC50 than LCO-28, which had a BRCA2 p.M965I mutation (Fig.	('p.W2619C', 'Var', (19, 27))	('p.M965I', 'Mutation', 'p.M965I', (94, 101))	('LCO', 'Chemical', '-', (68, 71))	('olaparib', 'Chemical', 'MESH:C531550', (49, 57))	('BRCA2', 'Gene', (88, 93))	('p.M965I', 'Var', (94, 101))	('LCO', 'Chemical', '-', (0, 3))	('p.W2619C', 'SUBSTITUTION', 'None', (19, 27))	('BRCA2', 'Gene', '675', (88, 93))	('BRCA2', 'Gene', (13, 18))	('olaparib IC50', 'MPA', (49, 62))	('BRCA2', 'Gene', '675', (13, 18))	('lower', 'NegReg', (43, 48))
291033	31488816	The tumour growth of PDX from LCO-55 was also inhibited after olaparib treatment (Supplementary Fig.	('tumour growth', 'Disease', (4, 17))	('LCO', 'Chemical', '-', (30, 33))	('tumour', 'Phenotype', 'HP:0002664', (4, 10))	('tumour growth', 'Disease', 'MESH:D006130', (4, 17))	('olaparib', 'Chemical', 'MESH:C531550', (62, 70))	('LCO-55', 'Var', (30, 36))	('inhibited', 'NegReg', (46, 55))
291034	31488816	Protein function prediction using PolyPhen-2 suggested that p.W2619C is predicted to be detrimental to BRCA2 function, while p.M965I is non-pathogenic to BRCA2 function.	('BRCA2', 'Gene', '675', (103, 108))	('p.M965I', 'Mutation', 'p.M965I', (125, 132))	('p.M965I', 'Var', (125, 132))	('BRCA2', 'Gene', (154, 159))	('function', 'MPA', (109, 117))	('p.W2619C', 'SUBSTITUTION', 'None', (60, 68))	('BRCA2', 'Gene', (103, 108))	('BRCA2', 'Gene', '675', (154, 159))	('p.W2619C', 'Var', (60, 68))
291035	31488816	Our drug response results agree with the hypothesis that BRCA2 p.W2619C is a pathogenic alteration that exerts synthetic lethality with PARP inhibition.	('p.W2619C', 'SUBSTITUTION', 'None', (63, 71))	('PARP', 'Gene', (136, 140))	('BRCA2', 'Gene', (57, 62))	('p.W2619C', 'Var', (63, 71))	('BRCA2', 'Gene', '675', (57, 62))	('PARP', 'Gene', '1302', (136, 140))
291037	31488816	Two LCOs, LCO-43 and LCO-51, had EGFR p.L858R mutations but showed different responses to erlotinib.	('erlotinib', 'Chemical', 'MESH:D000069347', (90, 99))	('p.L858R', 'Mutation', 'rs121434568', (38, 45))	('EGFR', 'Gene', '1956', (33, 37))	('LCO', 'Chemical', '-', (4, 7))	('LCO', 'Chemical', '-', (21, 24))	('LCO', 'Chemical', '-', (10, 13))	('p.L858R', 'Var', (38, 45))	('LCO-51', 'Chemical', '-', (21, 27))	('EGFR', 'Gene', (33, 37))	('LCO-43', 'Chemical', '-', (10, 16))
291038	31488816	Whereas LCO-43 displayed high sensitivity to erlotinib, LCO-51 was resistant to erlotinib, with a similar IC50 value to an organoid without EGFR mutations (Fig.	('LCO-43', 'Chemical', '-', (8, 14))	('erlotinib', 'Chemical', 'MESH:D000069347', (80, 89))	('EGFR', 'Gene', (140, 144))	('mutations', 'Var', (145, 154))	('LCO-51', 'Chemical', '-', (56, 62))	('EGFR', 'Gene', '1956', (140, 144))	('erlotinib', 'Chemical', 'MESH:D000069347', (45, 54))
291059	31488816	Genomic analysis confirmed that the LCOs maintained up to 77% concordance of the mutations that were present in the original cancer tissues.	('original cancer', 'Disease', (116, 131))	('original cancer', 'Disease', 'MESH:D009369', (116, 131))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('mutations', 'Var', (81, 90))	('LCO', 'Chemical', '-', (36, 39))
291082	31488816	For example, the efficacy of olaparib, which targets cancers with deficiency in homologous recombination repair, differed in LCOs harbouring different BRCA2 alterations of unknown significance.	('cancers', 'Phenotype', 'HP:0002664', (53, 60))	('deficiency', 'Disease', (66, 76))	('cancers', 'Disease', (53, 60))	('cancers', 'Disease', 'MESH:D009369', (53, 60))	('BRCA2', 'Gene', '675', (151, 156))	('deficiency', 'Disease', 'MESH:D007153', (66, 76))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('olaparib', 'Chemical', 'MESH:C531550', (29, 37))	('alterations', 'Var', (157, 168))	('BRCA2', 'Gene', (151, 156))	('LCO', 'Chemical', '-', (125, 128))
291084	31488816	Although LCO-43 and LCO-51 had the same EGFR mutation, they responded differently to erlotinib and crizotinib due to different secondary alterations.	('responded', 'Reg', (60, 69))	('crizotinib', 'MPA', (99, 109))	('crizotinib', 'Chemical', 'MESH:D000077547', (99, 109))	('EGFR', 'Gene', '1956', (40, 44))	('LCO-51', 'Chemical', '-', (20, 26))	('EGFR', 'Gene', (40, 44))	('mutation', 'Var', (45, 53))	('erlotinib', 'Chemical', 'MESH:D000069347', (85, 94))	('LCO-43', 'Chemical', '-', (9, 15))
291142	31488816	After the nude mice had reached a volume of 80-120 mm3, animals were randomised (four mice with tumours on the flank per group) and administered drugs by intraperitoneal injection: Erlotinib (50MPK, seven times per a week), Crizotinib (50MPK, seven times per a week) and Olaparib (50MPK, seven times per a week).	('Erlotinib', 'Chemical', 'MESH:D000069347', (181, 190))	('50MPK', 'Var', (236, 241))	('Crizotinib', 'Chemical', 'MESH:D000077547', (224, 234))	('tumours', 'Phenotype', 'HP:0002664', (96, 103))	('Olaparib', 'Chemical', 'MESH:C531550', (271, 279))	('mice', 'Species', '10090', (86, 90))	('tumour', 'Phenotype', 'HP:0002664', (96, 102))	('50MPK', 'Var', (192, 197))	('tumours', 'Disease', 'MESH:D009369', (96, 103))	('tumours', 'Disease', (96, 103))	('mice', 'Species', '10090', (15, 19))	('nude mice', 'Species', '10090', (10, 19))
291164	29455652	EAC arises from metaplastic Barrett's esophagus (BE) and related to gastro-esophageal reflux (GER) and obesity.	('GER', 'Gene', '59330', (94, 97))	('esophageal reflux', 'Phenotype', 'HP:0002020', (75, 92))	('obesity', 'Phenotype', 'HP:0001513', (103, 110))	('gastro-esophageal reflux', 'Disease', (68, 92))	('related', 'Reg', (57, 64))	('GER', 'Gene', (94, 97))	('BE', 'Phenotype', 'HP:0100580', (49, 51))	("Barrett's esophagus", 'Disease', 'MESH:D001471', (28, 47))	('metaplastic', 'Var', (16, 27))	("Barrett's esophagus", 'Disease', (28, 47))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (28, 47))	('obesity', 'Disease', 'MESH:D009765', (103, 110))	('EAC', 'Disease', (0, 3))	('obesity', 'Disease', (103, 110))
291183	29455652	EGFR overexpression and amplification was frequently observed in ESCC and correlated with advanced tumor stage and poor prognosis.	('tumor', 'Disease', (99, 104))	('EGFR', 'Gene', (0, 4))	('overexpression', 'PosReg', (5, 19))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('amplification', 'Var', (24, 37))	('ESCC', 'Disease', (65, 69))	('correlated', 'Reg', (74, 84))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('EGFR', 'Gene', '1956', (0, 4))
291186	29455652	Overexpression of EGFR was correlated with poor prognosis.	('Overexpression', 'Var', (0, 14))	('EGFR', 'Gene', '1956', (18, 22))	('EGFR', 'Gene', (18, 22))
291192	29455652	The EGFR amplification has been associated with diseases outcome in ESCC.	('amplification', 'Var', (9, 22))	('EGFR', 'Gene', (4, 8))	('ESCC', 'Disease', (68, 72))	('associated with', 'Reg', (32, 47))	('EGFR', 'Gene', '1956', (4, 8))
291193	29455652	ESCC patients with low copy number observed to have longer survival as compared with patients with high copy number of EGFR gene.	('low copy number', 'Var', (19, 34))	('patients', 'Species', '9606', (5, 13))	('longer', 'PosReg', (52, 58))	('patients', 'Species', '9606', (85, 93))	('ESCC', 'Disease', (0, 4))	('EGFR', 'Gene', '1956', (119, 123))	('EGFR', 'Gene', (119, 123))
291194	29455652	EGFR amplification has been associated with advanced pathological stage and tumor lymph node metastasis.	('EGFR', 'Gene', (0, 4))	('tumor lymph node metastasis', 'Disease', 'MESH:D009362', (76, 103))	('associated', 'Reg', (28, 38))	('amplification', 'Var', (5, 18))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('advanced pathological stage', 'CPA', (44, 71))	('EGFR', 'Gene', '1956', (0, 4))	('tumor lymph node metastasis', 'Disease', (76, 103))
291206	29455652	EGFR has been studied extensively in relation to lung adenocarcinoma to target the mutant EGFR using erlotinib.	('erlotinib', 'Chemical', 'MESH:D000069347', (101, 110))	('lung adenocarcinoma', 'Disease', (49, 68))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (49, 68))	('EGFR', 'Gene', (0, 4))	('mutant', 'Var', (83, 89))	('carcinoma', 'Phenotype', 'HP:0030731', (59, 68))	('EGFR', 'Gene', '1956', (90, 94))	('EGFR', 'Gene', (90, 94))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (49, 68))	('EGFR', 'Gene', '1956', (0, 4))
291217	29455652	In an in vitro study on ESCC cell lines (TE8, T.T and T.Tn), Gefitinib inhibited cellular proliferation in a dose-dependent manner, induced cell cycle arrest, inhibited ligand induced autophosphorylation of EGFR, downstream signaling pathways including Ras/Raf/MAPK and PI3K/Akt, and cell death.	('T.Tn', 'Var', (54, 58))	('arrest', 'Disease', (151, 157))	('ligand', 'Interaction', (169, 175))	('PI3', 'Gene', '5266', (270, 273))	('Akt', 'Gene', (275, 278))	('Raf', 'Gene', '22882', (257, 260))	('EGFR', 'Gene', (207, 211))	('Akt', 'Gene', '207', (275, 278))	('arrest', 'Disease', 'MESH:D006323', (151, 157))	('autophosphorylation', 'MPA', (184, 203))	('Gefitinib', 'Var', (61, 70))	('PI3', 'Gene', (270, 273))	('inhibited', 'NegReg', (159, 168))	('induced', 'Reg', (132, 139))	('cell death', 'CPA', (284, 294))	('Gefitinib', 'Chemical', 'MESH:D000077156', (61, 70))	('inhibited', 'NegReg', (71, 80))	('EGFR', 'Gene', '1956', (207, 211))	('cellular proliferation', 'CPA', (81, 103))	('Raf', 'Gene', (257, 260))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (140, 157))
291230	29455652	Icotinib was clinically evaluated for the treatment of previously treated advanced ESCC patients who either had overexpression or amplification of EGFR in a single arm, multi-centric phase-II clinical trial.	('EGFR', 'Gene', (147, 151))	('overexpression', 'PosReg', (112, 126))	('patients', 'Species', '9606', (88, 96))	('amplification', 'Var', (130, 143))	('Icotinib', 'Chemical', 'MESH:C531470', (0, 8))	('ESCC', 'Disease', (83, 87))	('EGFR', 'Gene', '1956', (147, 151))
291252	29455652	Furthermore, treatment of these cell lines with anti-VEGFR1/2 antibodies inhibits proliferation of ESCC cells denotes validity of VEGFRs as the genuine targets in ESCC.	('VEGFR1/2', 'Gene', (53, 61))	('VEGFR', 'Gene', (53, 58))	('VEGFR1/2', 'Gene', '2321;3791', (53, 61))	('inhibits', 'NegReg', (73, 81))	('ESCC', 'Disease', (99, 103))	('VEGFR', 'Gene', (130, 135))	('antibodies', 'Var', (62, 72))	('proliferation', 'CPA', (82, 95))	('VEGFR', 'Gene', '3791', (53, 58))	('VEGFR', 'Gene', '3791', (130, 135))
291273	29455652	Amplification of MET oncogene was found in 4-10% of gastric cancer cases.	('Amplification', 'Var', (0, 13))	('gastric cancer', 'Phenotype', 'HP:0012126', (52, 66))	('found', 'Reg', (34, 39))	('MET oncogene', 'Gene', (17, 29))	('gastric cancer', 'Disease', (52, 66))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('gastric cancer', 'Disease', 'MESH:D013274', (52, 66))
291283	29455652	In ESCC cell lines (KYSE70 and KYSE180), AXL was playing an important as it exerted resistance towards PI3Kalpha via EGFR/PKC/mTOR pathway.	('resistance', 'MPA', (84, 94))	('PI3Kalpha', 'Gene', '5290', (103, 112))	('EGFR', 'Gene', '1956', (117, 121))	('PI3Kalpha', 'Gene', (103, 112))	('EGFR', 'Gene', (117, 121))	('PKC', 'Disease', (122, 125))	('AXL', 'Gene', '558', (41, 44))	('AXL', 'Gene', (41, 44))	('PKC', 'Disease', 'MESH:C537180', (122, 125))	('mTOR', 'Gene', (126, 130))	('mTOR', 'Gene', '2475', (126, 130))	('KYSE180', 'Var', (31, 38))
291293	29455652	Overexpression of PTK7 has been reported in a number of different malignancies including oral tongue squamous cell carcinoma (OTSCC), colorectal, and intrahepatic cholangiocarcinoma.	('intrahepatic cholangiocarcinoma', 'Disease', (150, 181))	('colorectal', 'Disease', 'MESH:D015179', (134, 144))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (101, 124))	('PTK7', 'Gene', '5754', (18, 22))	('oral tongue squamous cell carcinoma', 'Disease', (89, 124))	('colorectal', 'Disease', (134, 144))	('PTK7', 'Gene', (18, 22))	('malignancies', 'Disease', 'MESH:D009369', (66, 78))	('reported', 'Reg', (32, 40))	('Overexpression', 'Var', (0, 14))	('malignancies', 'Disease', (66, 78))	('oral tongue squamous cell carcinoma', 'Disease', 'MESH:D002294', (89, 124))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (150, 181))	('carcinoma', 'Phenotype', 'HP:0030731', (172, 181))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (163, 181))
291302	29455652	An improved sensitivity to radiation was found upon silencing IGF1R at in vitro and in vivo levels in ESCC cell lines.	('IGF1R', 'Gene', '3480', (62, 67))	('silencing', 'Var', (52, 61))	('improved', 'PosReg', (3, 11))	('sensitivity to radiation', 'Phenotype', 'HP:0011133', (12, 36))	('sensitivity', 'MPA', (12, 23))	('IGF1R', 'Gene', (62, 67))
291307	29455652	There are  established clinical development programs for IGF1R inhibitors among patients with gastric or gastro-intestinal adenocarcinoma, but little has been done (from the clinical perspective) in the indication of ESCC.	('gastro-intestinal adenocarcinoma', 'Disease', 'MESH:D007414', (105, 137))	('patients', 'Species', '9606', (80, 88))	('IGF1R', 'Gene', (57, 62))	('gastro-intestinal adenocarcinoma', 'Disease', (105, 137))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('gastric', 'Disease', (94, 101))	('IGF1R', 'Gene', '3480', (57, 62))	('inhibitors', 'Var', (63, 73))
291311	29455652	Expression of PDGFRalpha was studied in cancer-associated fibroblast derived from ESCC patients and observed as an essential factor in ESCC progression; and expression of PDGFRbeta was found to be associated with poorly differentiated tumors but not with prognosis.	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('PDGFRalpha', 'Gene', '5156', (14, 24))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('PDGFRbeta', 'Gene', '5159', (171, 180))	('PDGFRalpha', 'Gene', (14, 24))	('cancer', 'Disease', (40, 46))	('tumors', 'Phenotype', 'HP:0002664', (235, 241))	('PDGFRbeta', 'Gene', (171, 180))	('expression', 'Var', (157, 167))	('associated', 'Reg', (197, 207))	('tumors', 'Disease', 'MESH:D009369', (235, 241))	('patients', 'Species', '9606', (87, 95))	('tumors', 'Disease', (235, 241))
291334	27638861	Conversely, upregulation of NRF2, through KEAP1 depletion or NRF2-myc overexpression, or increasing GSH levels with N-acetylcysteine (NAC) or glutathione-ethyl-ester (GSH-E), decreased ER stress and abrogated alkylating agents-induced cell death.	('KEAP1', 'Gene', '9817', (42, 47))	('GSH-E', 'Chemical', '-', (167, 172))	('KEAP1', 'Gene', (42, 47))	('NAC', 'Chemical', 'MESH:D000111', (134, 137))	('ER stress', 'MPA', (185, 194))	('myc', 'Gene', '4609', (66, 69))	('alkylating', 'CPA', (209, 219))	('decreased', 'NegReg', (175, 184))	('myc', 'Gene', (66, 69))	('GSH', 'Chemical', '-', (100, 103))	('GSH levels', 'MPA', (100, 110))	('NRF2', 'Gene', (28, 32))	('N-acetylcysteine', 'Chemical', 'MESH:D000111', (116, 132))	('upregulation', 'PosReg', (12, 24))	('glutathione-ethyl-ester', 'Chemical', 'MESH:C042431', (142, 165))	('depletion', 'Var', (48, 57))	('increasing', 'PosReg', (89, 99))	('overexpression', 'PosReg', (70, 84))	('GSH', 'Chemical', '-', (167, 170))	('abrogated', 'NegReg', (199, 208))
291335	27638861	Based on these results, we identified a subset of lung and head-and-neck carcinomas with mutations in either KEAP1 or NRF2/NFE2L2 genes that correlate with NRF2 targets overexpression and poor survival.	('head-and-neck carcinomas', 'Disease', 'MESH:D006258', (59, 83))	('NFE2L2', 'Gene', '4780', (123, 129))	('KEAP1', 'Gene', (109, 114))	('carcinomas', 'Phenotype', 'HP:0030731', (73, 83))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))	('head-and-neck carcinomas', 'Disease', (59, 83))	('NFE2L2', 'Gene', (123, 129))	('head-and-neck carcinomas', 'Phenotype', 'HP:0012288', (59, 83))	('mutations', 'Var', (89, 98))	('lung', 'Disease', (50, 54))	('KEAP1', 'Gene', '9817', (109, 114))	('overexpression', 'PosReg', (169, 183))
291336	27638861	In KEAP1 mutant cancer cells, NRF2 knockdown and GSH depletion increased cell sensitivity via ER stress induction in a mechanism specific to alkylating drugs.	('knockdown', 'Var', (35, 44))	('NRF2', 'Gene', (30, 34))	('KEAP1', 'Gene', '9817', (3, 8))	('depletion', 'Var', (53, 62))	('increased', 'PosReg', (63, 72))	('GSH', 'Chemical', '-', (49, 52))	('cancer', 'Disease', 'MESH:D009369', (16, 22))	('cell sensitivity', 'CPA', (73, 89))	('mutant', 'Var', (9, 15))	('cancer', 'Disease', (16, 22))	('KEAP1', 'Gene', (3, 8))	('ER stress induction', 'MPA', (94, 113))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))
291337	27638861	Overall, we show that the NRF2-GSH influence on ER homeostasis implicates defects in NRF2-GSH or ER stress machineries as affecting alkylating therapy toxicity.	('toxicity', 'Disease', 'MESH:D064420', (151, 159))	('GSH', 'Chemical', '-', (31, 34))	('toxicity', 'Disease', (151, 159))	('ER homeostasis', 'MPA', (48, 62))	('GSH', 'Chemical', '-', (90, 93))	('affecting', 'Reg', (122, 131))	('defects', 'Var', (74, 81))	('implicates', 'Reg', (63, 73))	('influence', 'Reg', (35, 44))	('NRF2-GSH', 'Gene', (85, 93))
291347	27638861	Because the folding of nascent proteins within the ER lumen requires a more pro-oxidant environment compared to other cellular compartments, the ER is highly sensitive to variations in redox homeostasis, especially imbalances in protein thiol (protein-SH) and GSH pools.	('imbalances', 'Phenotype', 'HP:0002172', (215, 225))	('sensitive', 'Reg', (158, 167))	('variations', 'Reg', (171, 181))	('folding', 'MPA', (12, 19))	('imbalances', 'Var', (215, 225))	('redox homeostasis', 'MPA', (185, 202))	('thiol', 'Chemical', 'MESH:D013438', (237, 242))	('GSH pools', 'MPA', (260, 269))	('GSH', 'Chemical', '-', (260, 263))	('protein', 'Protein', (229, 236))
291385	27638861	Primary antibodies included NRF2 (D1Z9C), BiP/GRP78 (C50B12), IRE1alpha (14C10), CHOP (L63F7), Calnexin (C5C9) and PERK (D11A8) from Cell Signaling Technologies; p-IRE1alpha (Ser724; NB100-2323) from Novus Biologicals; GCLC (Ab41463), beta-actin (Ab8227), TBP (ab818) and ATF6 (Ab37149) from Abcam; p-PERK (Thr 981, sc-32577), NQO1 (C-19), and ATF3 (C19) from Santa Cruz.	('ATF3', 'Gene', '467', (344, 348))	('NQO1', 'Gene', '1728', (327, 331))	('ATF6', 'Gene', (272, 276))	('Ab41463', 'Var', (225, 232))	('beta-actin', 'Gene', '728378', (235, 245))	('ATF3', 'Gene', (344, 348))	('beta-actin', 'Gene', (235, 245))	('GCLC', 'Gene', (219, 223))	('GCLC', 'Gene', '2729', (219, 223))	('ATF6', 'Gene', '22926', (272, 276))	('TBP', 'Gene', (256, 259))	('NQO1', 'Gene', (327, 331))	('TBP', 'Gene', '6908', (256, 259))
291387	27638861	The siRNA duplexes (20 to 40 nM final concentrations) targeting human NRF2 (siRNA#1: sc-37030A and siRNA#2: sc-37030B), IRE1alpha (sc-40705), PERK (sc-36213), KEAP1 (sc-43878) and scrambled siRNA-A (sc-37007) were from Santa Cruz Biotechnology; ATF6 siRNAs (ID22926 trilencer-27) were from Origene.	('human', 'Species', '9606', (64, 69))	('sc-36213', 'Var', (148, 156))	('ATF6', 'Gene', '22926', (245, 249))	('KEAP1', 'Gene', '9817', (159, 164))	('NRF2', 'Gene', (70, 74))	('sc-40705', 'Var', (131, 139))	('KEAP1', 'Gene', (159, 164))	('ATF6', 'Gene', (245, 249))
291402	27638861	For NRF2 pathway signature expression in TCGA datasets, average Z-scores of each NRF2 target (same gene list as described in "Pathway Signature Expression" subsection) in wild-type and mutant KEAP1 groups were plotted with equal weights, and pathway signature expressions were analyzed by Kruskal-Wallis/Dunn's test (for multiple groups) or Mann-Whitney test (for 2-group comparison) at a p<0.05.	('KEAP1', 'Gene', '9817', (192, 197))	('mutant', 'Var', (185, 191))	('KEAP1', 'Gene', (192, 197))
291403	27638861	For heatmap representation, the samples were grouped based on their KEAP1 and NFE2L2/NRF2 mutational status and hierarchical clustering was performed using Euclidean Distance and Ward's linkage as dissimilarity measures and a clustering method, respectively.	('mutational', 'Var', (90, 100))	('KEAP1', 'Gene', (68, 73))	('NFE2L2', 'Gene', (78, 84))	('NFE2L2', 'Gene', '4780', (78, 84))	('KEAP1', 'Gene', '9817', (68, 73))
291404	27638861	We used the "Enrichment" tool available with the cBioportal for Cancer Genomics (http://cbioportal.org/) to detect mutations associated with upregulated expression of NRF2 targets in the lung and head and neck cancer datasets described above.	('Cancer', 'Disease', (64, 70))	('mutations', 'Var', (115, 124))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('Cancer', 'Disease', 'MESH:D009369', (64, 70))	('neck cancer', 'Disease', 'MESH:D006258', (205, 216))	('neck cancer', 'Disease', (205, 216))	('Cancer', 'Phenotype', 'HP:0002664', (64, 70))	('lung', 'Disease', (187, 191))	('upregulated', 'PosReg', (141, 152))	('expression', 'MPA', (153, 163))	('NRF2', 'Gene', (167, 171))	('head and neck cancer', 'Phenotype', 'HP:0012288', (196, 216))
291406	27638861	Thus, all TCGA cancer cohorts with DNA sequencing information were evaluated, and a ranked list of cancer datasets showing NFE2L2/KEAP1 alterations is provided.	('KEAP1', 'Gene', (130, 135))	('NFE2L2', 'Gene', '4780', (123, 129))	('cancer', 'Disease', (15, 21))	('cancer', 'Disease', 'MESH:D009369', (15, 21))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('cancer', 'Disease', (99, 105))	('NFE2L2', 'Gene', (123, 129))	('alterations', 'Var', (136, 147))	('KEAP1', 'Gene', '9817', (130, 135))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
291409	27638861	We first confirmed that MMS promoted total protein accumulation and nuclear translocation of NRF2 (Fig.	('total protein accumulation', 'MPA', (37, 63))	('MMS', 'Chemical', 'MESH:D008741', (24, 27))	('nuclear translocation', 'CPA', (68, 89))	('NRF2', 'Gene', (93, 97))	('MMS', 'Var', (24, 27))	('promoted', 'PosReg', (28, 36))
291414	27638861	By modulating NRF2 activity through NRF2-myc overexpression, NRF2 knockdown, or knockdown of its negative regulator KEAP1 (Fig.	('knockdown', 'Var', (80, 89))	('myc', 'Gene', (41, 44))	('KEAP1', 'Gene', (116, 121))	('modulating', 'Reg', (3, 13))	('myc', 'Gene', '4609', (41, 44))	('NRF2', 'Gene', (61, 65))	('activity', 'MPA', (19, 27))	('KEAP1', 'Gene', '9817', (116, 121))	('knockdown', 'Var', (66, 75))	('overexpression', 'PosReg', (45, 59))
291416	27638861	NRF2 silencing potentiated, whereas NRF2-myc overexpression or KEAP1 knockdown suppressed MMS, CDDP and 4-HC toxicity in cell growth assays (Fig.	('HC toxicity', 'Disease', (106, 117))	('KEAP1', 'Gene', '9817', (63, 68))	('NRF2', 'Gene', (0, 4))	('myc', 'Gene', (41, 44))	('HC toxicity', 'Disease', 'MESH:D064420', (106, 117))	('MMS', 'MPA', (90, 93))	('KEAP1', 'Gene', (63, 68))	('suppressed', 'NegReg', (79, 89))	('potentiated', 'PosReg', (15, 26))	('silencing', 'Var', (5, 14))	('myc', 'Gene', '4609', (41, 44))	('MMS', 'Chemical', 'MESH:D008741', (90, 93))	('CDDP', 'MPA', (95, 99))	('4-HC', 'Chemical', 'MESH:C011272', (104, 108))	('CDDP', 'Chemical', '-', (95, 99))
291426	27638861	We previously reported that glutathione pools are depleted in MMS-treated D. melanogaster and primary mouse fibroblasts due to non-enzymatic or/and GST-mediated conjugation of MMS reactive methyl group to GSH thus producing methyl-glutathione.	('depleted', 'NegReg', (50, 58))	('producing', 'Reg', (214, 223))	('glutathione pools', 'MPA', (28, 45))	('MMS', 'Chemical', 'MESH:D008741', (62, 65))	('glutathione', 'Chemical', 'MESH:D005978', (28, 39))	('methyl-glutathione', 'MPA', (224, 242))	('GSH', 'Chemical', '-', (205, 208))	('MMS', 'Chemical', 'MESH:D008741', (176, 179))	('mouse', 'Species', '10090', (102, 107))	('MMS', 'Var', (176, 179))	('methyl-glutathione', 'Chemical', 'MESH:C017514', (224, 242))	('glutathione', 'Chemical', 'MESH:D005978', (231, 242))	('D. melanogaster', 'Species', '7227', (74, 89))
291428	27638861	We also determined that NRF2 is a key regulator of glutathione synthesis in response to alkylating drugs exposure since NRF2 knockdown decreased both GCLC protein induction (Fig.	('knockdown', 'Var', (125, 134))	('glutathione', 'Chemical', 'MESH:D005978', (51, 62))	('GCLC', 'Gene', (150, 154))	('GCLC', 'Gene', '2729', (150, 154))	('decreased', 'NegReg', (135, 144))	('NRF2', 'Gene', (120, 124))
291430	27638861	Conversely, induction of NRF2 via KEAP1 knockdown enhanced glutathione pools (Fig.	('NRF2', 'Gene', (25, 29))	('glutathione pools', 'MPA', (59, 76))	('glutathione', 'Chemical', 'MESH:D005978', (59, 70))	('KEAP1', 'Gene', (34, 39))	('knockdown', 'Var', (40, 49))	('enhanced', 'PosReg', (50, 58))	('KEAP1', 'Gene', '9817', (34, 39))
291443	27638861	Alkylating agents-induced BiP/GRP78 and CHOP levels were decreased by knockdown of ATF6 and/or PERK, indicating activation of canonical ER stress machinery (Fig.	('knockdown', 'Var', (70, 79))	('activation', 'PosReg', (112, 122))	('ATF6', 'Gene', (83, 87))	('Alkylating agents-induced', 'MPA', (0, 25))	('ATF6', 'Gene', '22926', (83, 87))	('decreased', 'NegReg', (57, 66))	('CHOP levels', 'MPA', (40, 51))	('BiP/GRP78', 'Protein', (26, 35))
291445	27638861	In our model, depletion of IRE1alpha or ATF6 potentiated, while PERK silencing (the classical pro-apoptotic arm in the ER) partially reversed, cell growth inhibition (Fig.	('ATF6', 'Gene', '22926', (40, 44))	('cell growth inhibition', 'CPA', (143, 165))	('ATF6', 'Gene', (40, 44))	('potentiated', 'PosReg', (45, 56))	('IRE1alpha', 'Protein', (27, 36))	('depletion', 'MPA', (14, 23))	('silencing', 'Var', (69, 78))
291456	27638861	With regard to alkylating agent decreased protein-SH levels, depleting intracellular GSH with BSO led to an enhanced impact, while NAC or GSH-E, but not Trolox, protected protein-SH (Fig.	('NAC', 'Chemical', 'MESH:D000111', (131, 134))	('GSH', 'Chemical', '-', (138, 141))	('protein-SH levels', 'MPA', (42, 59))	('Trolox', 'Chemical', 'MESH:C010643', (153, 159))	('GSH', 'Chemical', '-', (85, 88))	('GSH-E', 'Chemical', '-', (138, 143))	('depleting', 'Var', (61, 70))	('BSO', 'Chemical', 'MESH:D019328', (94, 97))
291457	27638861	Corroborating these results, NRF2 knockdown emulated BSO, accentuating the impact of exposure to alkylating agents on protein-SH, while KEAP1 silencing and NRF2-myc overexpression were protective in both whole-cell (Fig.	('myc', 'Gene', (161, 164))	('KEAP1', 'Gene', (136, 141))	('BSO', 'Chemical', 'MESH:D019328', (53, 56))	('myc', 'Gene', '4609', (161, 164))	('NRF2', 'Gene', (29, 33))	('BSO', 'Disease', (53, 56))	('knockdown', 'Var', (34, 43))	('KEAP1', 'Gene', '9817', (136, 141))
291466	27638861	Further, modulating the GSH levels by inhibition (BSO) or augmentation (NAC supplementation) had no impact in the cytotoxicity caused by these agents (Fig.	('GSH', 'Chemical', '-', (24, 27))	('BSO', 'Chemical', 'MESH:D019328', (50, 53))	('NAC', 'Chemical', 'MESH:D000111', (72, 75))	('modulating', 'Var', (9, 19))	('cytotoxicity', 'Disease', 'MESH:D064420', (114, 126))	('inhibition', 'NegReg', (38, 48))	('cytotoxicity', 'Disease', (114, 126))
291467	27638861	Despite not inducing any obvious NRF2 activation, we noted that NRF2 depletion increase doxorubicin toxicity to MDA-MB231 cells, indicating that a NRF2 target other than the GSH synthesis enzymes may play a role in doxorubicin survival.	('increase', 'PosReg', (79, 87))	('doxorubicin', 'Chemical', 'MESH:D004317', (215, 226))	('doxorubicin', 'Chemical', 'MESH:D004317', (88, 99))	('toxicity', 'Disease', 'MESH:D064420', (100, 108))	('toxicity', 'Disease', (100, 108))	('MDA-MB231', 'CellLine', 'CVCL:0062', (112, 121))	('depletion', 'Var', (69, 78))	('NRF2', 'Gene', (64, 68))	('GSH', 'Chemical', '-', (174, 177))
291472	27638861	Comparative analysis of all TCGA cancer datasets indicated that lung adenocarcinoma, squamous cell carcinoma, and head-neck carcinoma, showed the highest frequency of genetic alterations in KEAP1 (mutation and/or deep-deletions) and/or NFE2L2/NRF2 (mutations and/or amplifications) (Fig.	('cancer', 'Disease', (33, 39))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (64, 83))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('head-neck carcinoma', 'Disease', (114, 133))	('NFE2L2', 'Gene', (236, 242))	('KEAP1', 'Gene', '9817', (190, 195))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (85, 108))	('genetic alterations', 'Var', (167, 186))	('KEAP1', 'Gene', (190, 195))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('deep-deletions', 'Var', (213, 227))	('lung adenocarcinoma', 'Disease', (64, 83))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (85, 108))	('mutation', 'Var', (197, 205))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('head-neck carcinoma', 'Disease', 'MESH:D006258', (114, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (64, 83))	('squamous cell carcinoma', 'Disease', (85, 108))	('NFE2L2', 'Gene', '4780', (236, 242))
291474	27638861	Mutation Enrichment Analysis (MEA) indicated that mutant KEAP1 is most associated with upregulation of NRF2 targets in lung adenocarcinomas (Fig.	('KEAP1', 'Gene', (57, 62))	('NRF2', 'Gene', (103, 107))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (119, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('lung adenocarcinomas', 'Disease', (119, 139))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (119, 139))	('mutant', 'Var', (50, 56))	('KEAP1', 'Gene', '9817', (57, 62))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (119, 139))	('carcinomas', 'Phenotype', 'HP:0030731', (129, 139))	('upregulation', 'PosReg', (87, 99))
291475	27638861	6D), whereas both NFE2L2 and KEAP1 mutations are related to NRF2 pathway signature enrichment in lung squamous cells (Fig.	('NFE2L2', 'Gene', '4780', (18, 24))	('KEAP1', 'Gene', '9817', (29, 34))	('related', 'Reg', (49, 56))	('NRF2 pathway', 'Pathway', (60, 72))	('NFE2L2', 'Gene', (18, 24))	('KEAP1', 'Gene', (29, 34))	('lung squamous cells', 'Disease', (97, 116))	('mutations', 'Var', (35, 44))
291476	27638861	6E); and only NFE2L2 mutation in head and neck carcinomas (Fig.	('neck carcinomas', 'Disease', 'MESH:D006258', (42, 57))	('mutation', 'Var', (21, 29))	('carcinoma', 'Phenotype', 'HP:0030731', (47, 56))	('carcinomas', 'Phenotype', 'HP:0030731', (47, 57))	('NFE2L2', 'Gene', '4780', (14, 20))	('neck carcinomas', 'Disease', (42, 57))	('NFE2L2', 'Gene', (14, 20))
291477	27638861	The majority of KEAP1 gene alterations are missense mutations that occur in the Kelch (hotspots: R470*, G333*, G480*) or BTB domains of KEAP1 (Fig.	('G480*', 'Var', (111, 116))	('Kelch', 'Gene', '11275', (80, 85))	('R470*', 'Var', (97, 102))	('G333*', 'SUBSTITUTION', 'None', (104, 109))	('KEAP1', 'Gene', (136, 141))	('G480*', 'SUBSTITUTION', 'None', (111, 116))	('Kelch', 'Gene', (80, 85))	('KEAP1', 'Gene', '9817', (16, 21))	('missense', 'Var', (43, 51))	('G333*', 'Var', (104, 109))	('KEAP1', 'Gene', '9817', (136, 141))	('R470*', 'SUBSTITUTION', 'None', (97, 102))	('alterations', 'Var', (27, 38))	('KEAP1', 'Gene', (16, 21))
291479	27638861	NFE2L2 mutations are mostly missense and occur within the first 100 amino acids (D29*, R34*, E79 and G81*) that contains the Neh2 domain which includes the two degrons that are specifically bound by KEAP1 and thus likely impede KEAP1-mediated NRF2 degradation.	('KEAP1', 'Gene', (228, 233))	('R34*', 'SUBSTITUTION', 'None', (87, 91))	('impede', 'NegReg', (221, 227))	('degradation', 'MPA', (248, 259))	('G81*', 'SUBSTITUTION', 'None', (101, 105))	('D29*', 'Var', (81, 85))	('KEAP1', 'Gene', (199, 204))	('KEAP1', 'Gene', '9817', (199, 204))	('NFE2L2', 'Gene', '4780', (0, 6))	('D29*', 'SUBSTITUTION', 'None', (81, 85))	('R34*', 'Var', (87, 91))	('bound', 'Interaction', (190, 195))	('NFE2L2', 'Gene', (0, 6))	('KEAP1', 'Gene', '9817', (228, 233))	('G81*', 'Var', (101, 105))	('E79', 'Var', (93, 96))	('mutations', 'Var', (7, 16))
291480	27638861	In addition to lung tumor datasets, the NRF2 signature was examined by gene expression profiling of a panel of 77 lung cancer cell lines (E-MTAB-2706 RNA sequencing dataset) with known KEAP1/NFE2L2 mutational status (derived from Cosmic).	('NFE2L2', 'Gene', (191, 197))	('lung tumor', 'Disease', 'MESH:D008175', (15, 25))	('E-MTAB-2706', 'CellLine', 'CVCL:9K64', (138, 149))	('lung cancer', 'Disease', 'MESH:D008175', (114, 125))	('KEAP1', 'Gene', (185, 190))	('mutational', 'Var', (198, 208))	('KEAP1', 'Gene', '9817', (185, 190))	('lung tumor', 'Phenotype', 'HP:0100526', (15, 25))	('lung cancer', 'Disease', (114, 125))	('lung cancer', 'Phenotype', 'HP:0100526', (114, 125))	('NFE2L2', 'Gene', '4780', (191, 197))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('lung tumor', 'Disease', (15, 25))
291481	27638861	The result confirmed an increase in NRF2 pathway signature in the KEAP1/NFE2L2 mutant cells (16 KEAP1 mutant; and 1 NFE2L2 mutant, the NCI-H2228 cell line) (Figs.	('increase', 'PosReg', (24, 32))	('KEAP1', 'Gene', '9817', (96, 101))	('NFE2L2', 'Gene', (116, 122))	('KEAP1', 'Gene', '9817', (66, 71))	('mutant', 'Var', (79, 85))	('NCI-H2228', 'CellLine', 'CVCL:1543', (135, 144))	('KEAP1', 'Gene', (96, 101))	('KEAP1', 'Gene', (66, 71))	('NFE2L2', 'Gene', '4780', (72, 78))	('NRF2 pathway', 'Pathway', (36, 48))	('NFE2L2', 'Gene', (72, 78))	('NFE2L2', 'Gene', '4780', (116, 122))
291482	27638861	7A and S4); no change in ER stress markers was associated with KEAP1/NFE2L2 mutations (data not shown).	('KEAP1', 'Gene', '9817', (63, 68))	('mutations', 'Var', (76, 85))	('KEAP1', 'Gene', (63, 68))	('NFE2L2', 'Gene', '4780', (69, 75))	('NFE2L2', 'Gene', (69, 75))
291483	27638861	Separate from mutation status in the Cosmic database, HCC15 was shown to carry a KEAP1 mutation.	('KEAP1', 'Gene', (81, 86))	('mutation', 'Var', (87, 95))	('HCC15', 'Gene', (54, 59))	('KEAP1', 'Gene', '9817', (81, 86))
291487	27638861	From our analysis we noted that the lung cancer cell line A549 carries a G333C KEAP1 hotspot mutation and could be used as a model to study the impact of NRF2 activating mutations on cell survival to different drug classes.	('lung cancer', 'Disease', (36, 47))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('KEAP1', 'Gene', (79, 84))	('A549', 'CellLine', 'CVCL:0023', (58, 62))	('G333C', 'Var', (73, 78))	('lung cancer', 'Disease', 'MESH:D008175', (36, 47))	('G333C', 'Mutation', 'c.333G>C', (73, 78))	('lung cancer', 'Phenotype', 'HP:0100526', (36, 47))	('NRF2', 'Gene', (154, 158))	('KEAP1', 'Gene', '9817', (79, 84))
291488	27638861	As a consequence of KEAP1 mutation, basal ARE-luciferase is increased by ~5-fold in A549 compared to MDA-MB231 (Fig.	('ARE-luciferase', 'Enzyme', (42, 56))	('MDA-MB231', 'CellLine', 'CVCL:0062', (101, 110))	('mutation', 'Var', (26, 34))	('KEAP1', 'Gene', (20, 25))	('KEAP1', 'Gene', '9817', (20, 25))	('A549', 'CellLine', 'CVCL:0023', (84, 88))	('increased', 'PosReg', (60, 69))
291489	27638861	Corroborating our aforementioned data, high NRF2 and glutathione/NAC protected while NRF2 knockdown and BSO sensitized A549 cells to MMS, 4-HC and CDDP but not doxorubicin, paclitaxel and etoposide (Fig.	('NRF2', 'Gene', (85, 89))	('knockdown', 'Var', (90, 99))	('paclitaxel', 'Chemical', 'MESH:D017239', (173, 183))	('sensitized', 'Reg', (108, 118))	('MMS', 'Chemical', 'MESH:D008741', (133, 136))	('4-HC', 'Chemical', 'MESH:C011272', (138, 142))	('etoposide', 'Chemical', 'MESH:D005047', (188, 197))	('BSO', 'Chemical', 'MESH:D019328', (104, 107))	('NAC', 'Chemical', 'MESH:D000111', (65, 68))	('glutathione', 'Chemical', 'MESH:D005978', (53, 64))	('CDDP', 'Chemical', '-', (147, 151))	('A549', 'CellLine', 'CVCL:0023', (119, 123))	('doxorubicin', 'Chemical', 'MESH:D004317', (160, 171))
291491	27638861	In addition, MMS induced ERSE-luciferase reporter activation while NRF2 knockdown or GSH depletion with BSO potentiated this MMS effect upon ERSE reporter gene (Fig.	('potentiated', 'PosReg', (108, 119))	('ERSE-luciferase', 'Enzyme', (25, 40))	('activation', 'PosReg', (50, 60))	('MMS', 'Chemical', 'MESH:D008741', (125, 128))	('GSH', 'Chemical', '-', (85, 88))	('NRF2', 'Gene', (67, 71))	('BSO', 'Chemical', 'MESH:D019328', (104, 107))	('MMS', 'Chemical', 'MESH:D008741', (13, 16))	('knockdown', 'Var', (72, 81))
291492	27638861	Interestingly, a concomitant overexpression of GRP78 attenuated the impact of NRF2 knockdown on ERSE reporter gene activation by MMS (Fig.	('activation', 'PosReg', (115, 125))	('overexpression', 'PosReg', (29, 43))	('ERSE reporter gene', 'MPA', (96, 114))	('attenuated', 'NegReg', (53, 63))	('NRF2', 'Gene', (78, 82))	('MMS', 'Chemical', 'MESH:D008741', (129, 132))	('knockdown', 'Var', (83, 92))
291500	27638861	GSH is essential for conjugation with MMS as we previously determined in fly and mouse cells, and GST enzymes (GstE5 and GstE3 fly orthologues) knockdown strongly sensitized Kc167 cells to MMS.	('MMS', 'Chemical', 'MESH:D008741', (38, 41))	('MMS', 'Chemical', 'MESH:D008741', (189, 192))	('sensitized', 'Reg', (163, 173))	('knockdown', 'Var', (144, 153))	('mouse', 'Species', '10090', (81, 86))	('GSH', 'Chemical', '-', (0, 3))
291513	27638861	It is also important to note that solely depleting GSH (with BSO or NRF2 knockdown) was not sufficient to affect cell survival (up to 72 h) or to cause ER stress; the presence of alkylating agent to trigger damage at the same time was required.	('ER stress', 'MPA', (152, 161))	('GSH', 'Chemical', '-', (51, 54))	('depleting', 'Var', (41, 50))	('BSO', 'Chemical', 'MESH:D019328', (61, 64))	('NRF2', 'Gene', (68, 72))	('cause', 'Reg', (146, 151))	('affect', 'Reg', (106, 112))	('cell survival', 'CPA', (113, 126))
291518	27638861	From various screened cancer types, we identified subsets of lung and head-neck carcinomas harboring KEAP1/NFE2L2 mutations, which showed upregulated expression of NRF2 targets and high-risk/poor survival.	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('expression', 'MPA', (150, 160))	('NFE2L2', 'Gene', (107, 113))	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('mutations', 'Var', (114, 123))	('KEAP1', 'Gene', '9817', (101, 106))	('cancer', 'Disease', (22, 28))	('carcinomas', 'Phenotype', 'HP:0030731', (80, 90))	('head-neck carcinomas', 'Disease', (70, 90))	('NFE2L2', 'Gene', '4780', (107, 113))	('head-neck carcinomas', 'Disease', 'MESH:D006258', (70, 90))	('KEAP1', 'Gene', (101, 106))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('upregulated', 'PosReg', (138, 149))	('lung', 'Disease', (61, 65))
291520	27638861	In keeping with our findings, CDDP has also been shown to cause ER stress in different models and GRP78 was found to reverse CDDP toxicity in melanoma and ovarian cancer cells.	('toxicity in melanoma and ovarian cancer', 'Disease', 'MESH:D010051', (130, 169))	('CDDP', 'Chemical', '-', (125, 129))	('cause', 'Reg', (58, 63))	('CDDP', 'Var', (30, 34))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('ER stress', 'MPA', (64, 73))	('ovarian cancer', 'Phenotype', 'HP:0100615', (155, 169))	('CDDP', 'Chemical', '-', (30, 34))	('melanoma', 'Phenotype', 'HP:0002861', (142, 150))
291522	27638861	TMZ also induces NRF2 and GRP78 upregulation in gliomas, supporting the concept of NRF2-GSH/ER stress as a general response to alkylating drugs.	('GRP78', 'Protein', (26, 31))	('gliomas', 'Disease', 'MESH:D005910', (48, 55))	('gliomas', 'Phenotype', 'HP:0009733', (48, 55))	('NRF2', 'Protein', (17, 21))	('upregulation', 'PosReg', (32, 44))	('TMZ', 'Var', (0, 3))	('GSH', 'Chemical', '-', (88, 91))	('TMZ', 'Chemical', 'MESH:D000077204', (0, 3))	('gliomas', 'Disease', (48, 55))
291526	27638861	For instance, NRF2 depletion sensitized gallbladder cancer cells to 5-FU, in contrast to the lack of effect of 5-FU treatment in A549.	('5-FU', 'Chemical', 'MESH:D005472', (68, 72))	('depletion', 'Var', (19, 28))	('NRF2', 'Gene', (14, 18))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('5-FU', 'Chemical', 'MESH:D005472', (111, 115))	('sensitized', 'Reg', (29, 39))	('gallbladder cancer', 'Disease', (40, 58))	('gallbladder cancer', 'Disease', 'MESH:D005706', (40, 58))	('A549', 'CellLine', 'CVCL:0023', (129, 133))
291534	27638861	Consequently, while NRF2 activating mutations could confer resistance and alkylating therapy failure, identifying an altered NRF2-GSH/ER stress status offers the opportunity to select alternative chemotherapeutics that may retain efficacy.	('NRF2-GSH/ER', 'Gene', (125, 136))	('NRF2', 'Gene', (20, 24))	('activating', 'PosReg', (25, 35))	('mutations', 'Var', (36, 45))	('GSH', 'Chemical', '-', (130, 133))
291828	33066437	Most of the 57 HPV-positive patients had tumors positive for HPV16 (48 patients), but other subtypes detected were HPV18 (3 patients), HPV33 (3 patients), HPV35, HPV58, and HPV73 (one patient each).	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('HPV33', 'Var', (135, 140))	('HPV', 'Species', '10566', (155, 158))	('HPV16', 'Species', '333760', (61, 66))	('patients', 'Species', '9606', (71, 79))	('HPV35', 'Var', (155, 160))	('HPV-positive', 'Gene', (15, 27))	('tumors', 'Disease', (41, 47))	('patient', 'Species', '9606', (71, 78))	('patients', 'Species', '9606', (124, 132))	('HPV', 'Species', '10566', (61, 64))	('patient', 'Species', '9606', (184, 191))	('HPV', 'Species', '10566', (162, 165))	('tumors', 'Disease', 'MESH:D009369', (41, 47))	('patient', 'Species', '9606', (144, 151))	('HPV', 'Species', '10566', (115, 118))	('patients', 'Species', '9606', (28, 36))	('HPV16', 'Gene', (61, 66))	('patient', 'Species', '9606', (124, 131))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('HPV', 'Species', '10566', (173, 176))	('patients', 'Species', '9606', (144, 152))	('patient', 'Species', '9606', (28, 35))	('HPV', 'Species', '10566', (15, 18))	('HPV', 'Species', '10566', (135, 138))
291894	33066437	Thus, again, we observed that single acute phase biomarkers are associated with prognosis rather than the cytokine profiles, and the high CRP/IL6 phenotype is associated with prognosis for this patient subset.	('CRP', 'Gene', (138, 141))	('associated', 'Reg', (64, 74))	('prognosis', 'Disease', (80, 89))	('CRP', 'Gene', '1401', (138, 141))	('patient', 'Species', '9606', (194, 201))	('high', 'Var', (133, 137))	('IL6', 'Gene', '3569', (142, 145))	('associated with', 'Reg', (159, 174))	('IL6', 'Gene', (142, 145))
291927	33066437	This conclusion is further supported by another immunohistochemical study that included 81 patients with SCC of the tongue; patients with high IL33 or IL33Ralpha expression then had significantly worse prognosis, and high IL33 expression was also associated with increased micro-vessel density, i.e., increased density of endothelial cells, which may also be a source of IL33.	('IL33', 'Gene', (143, 147))	('IL33', 'Gene', (222, 226))	('IL33', 'Gene', '90865', (143, 147))	('density', 'CPA', (311, 318))	('IL33', 'Gene', (371, 375))	('IL33', 'Gene', (151, 155))	('IL33', 'Gene', '90865', (222, 226))	('IL33', 'Gene', '90865', (151, 155))	('patients', 'Species', '9606', (91, 99))	('IL33', 'Gene', '90865', (371, 375))	('increased', 'PosReg', (263, 272))	('micro-vessel density', 'CPA', (273, 293))	('increased', 'PosReg', (301, 310))	('SCC', 'Gene', (105, 108))	('high', 'Var', (138, 142))	('patients', 'Species', '9606', (124, 132))	('SCC', 'Gene', '6317', (105, 108))
291940	33066437	When analyzing our overall data, we observed an association between good prognosis and HPV positivity, whereas adverse prognosis was associated with increasing both CRP levels and WBC counts.	('CRP', 'Gene', '1401', (165, 168))	('WBC counts', 'CPA', (180, 190))	('HPV', 'Species', '10566', (87, 90))	('HPV', 'Gene', (87, 90))	('CRP', 'Gene', (165, 168))	('positivity', 'Var', (91, 101))	('increasing', 'PosReg', (149, 159))
291946	33066437	This is to some extent surprising, in that the two cancer diseases have fundamentally different causes, i.e., HPV as a viral factor and patients with HPV-negative tumors in principle being due to DNA mutations most often caused by smoking in combination with alcohol consumption.	('DNA', 'Gene', (196, 199))	('HPV-negative tumors', 'Disease', (150, 169))	('alcohol', 'Chemical', 'MESH:D000438', (259, 266))	('mutations', 'Var', (200, 209))	('HPV', 'Species', '10566', (110, 113))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('men', 'Species', '9606', (77, 80))	('caused', 'Reg', (221, 227))	('patients', 'Species', '9606', (136, 144))	('tumors', 'Phenotype', 'HP:0002664', (163, 169))	('cancer diseases', 'Disease', (51, 66))	('due', 'Reg', (189, 192))	('HPV', 'Disease', (110, 113))	('HPV-negative tumors', 'Disease', 'MESH:D030361', (150, 169))	('HPV', 'Species', '10566', (150, 153))	('cancer diseases', 'Disease', 'MESH:D009369', (51, 66))
292046	30866469	Most of our characterised metabolite changes had already been linked to lung cancer, as also indicated by a joint-pathway analysis (Figure 4).	('changes', 'Var', (37, 44))	('lung cancer', 'Disease', (72, 83))	('lung cancer', 'Phenotype', 'HP:0100526', (72, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('linked', 'Reg', (62, 68))	('lung cancer', 'Disease', 'MESH:D008175', (72, 83))	('metabolite', 'MPA', (26, 36))
292109	30866469	The formation of S-lactoyl glutathione is catalysed by glyoxalase 1 (Glo1) and under-expression can promote tumour growth.	('glyoxalase 1', 'Gene', '2739', (55, 67))	('Glo1', 'Gene', (69, 73))	('under-expression', 'Var', (79, 95))	('Glo1', 'Gene', '2739', (69, 73))	('glyoxalase 1', 'Gene', (55, 67))	('tumour', 'Phenotype', 'HP:0002664', (108, 114))	('S-lactoyl glutathione', 'Chemical', 'MESH:C013585', (17, 38))	('tumour growth', 'Disease', (108, 121))	('tumour growth', 'Disease', 'MESH:D006130', (108, 121))	('promote', 'PosReg', (100, 107))
292113	30866469	Abnormalities in choline metabolism are emerging as a metabolic hallmark of oncogenesis and tumour progression.	('tumour', 'Disease', 'MESH:D009369', (92, 98))	('choline', 'Chemical', 'MESH:D002794', (17, 24))	('Abnormalities', 'Var', (0, 13))	('tumour', 'Disease', (92, 98))	('Abnormalities in choline metabolism', 'Phenotype', 'HP:0025047', (0, 35))	('tumour', 'Phenotype', 'HP:0002664', (92, 98))	('choline metabolism', 'MPA', (17, 35))
292124	30866469	Unlike other cofactors, deficiencies in PLP are seen in cancer tissues including lung cancer, and this may be linked to antioxidant and maintenance of genome integrity.	('lung cancer', 'Disease', (81, 92))	('PLP', 'Gene', '57026', (40, 43))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('lung cancer', 'Phenotype', 'HP:0100526', (81, 92))	('deficiencies', 'Var', (24, 36))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('linked', 'Reg', (110, 116))	('lung cancer', 'Disease', 'MESH:D008175', (81, 92))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('cancer', 'Disease', (56, 62))	('PLP', 'Gene', (40, 43))	('cancer', 'Disease', (86, 92))
292127	30866469	Perturbation of the inflammatory response is a cancer hallmark, but our study yielded equivocal results.	('cancer hallmark', 'Disease', (47, 62))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('cancer hallmark', 'Disease', 'MESH:D009369', (47, 62))	('Perturbation', 'Var', (0, 12))	('inflammatory response', 'CPA', (20, 41))
292182	26205654	The fold change in expression of TbetaRIII was calculated by using the 2-DeltaDeltaCt method, in which DeltaDeltaCT=DeltaCT (target-reference)-DeltaCT (target-reference).	('TbetaRII', 'Gene', '7048', (33, 41))	('expression', 'MPA', (19, 29))	('TbetaRII', 'Gene', (33, 41))	('DeltaDeltaCT=DeltaCT', 'Var', (103, 123))
292187	26205654	After blocking, the blots were incubated overnight with the appropriate primary antibodies against TbetaRIII, total or phospho-ERKs(1:500 dilution), phospho-JNKs(1:500 dilution), phospho-p38 MAPK(1:500 dilution) and CDKN2b (1:1,000 dilution), separately at 4 C overnight.	('MAPK', 'Gene', '5595;5594;26413;5595;26417', (191, 195))	('CDKN2b', 'Gene', (216, 222))	('p38', 'Gene', (187, 190))	('CDKN2b', 'Gene', '1030', (216, 222))	('phospho-JNKs', 'Var', (149, 161))	('ERKs', 'Gene', (127, 131))	('MAPK', 'Gene', (191, 195))	('TbetaRII', 'Gene', '7048', (99, 107))	('ERKs', 'Gene', '5595;5594;26413;5595;26417', (127, 131))	('TbetaRII', 'Gene', (99, 107))	('p38', 'Gene', '5594', (187, 190))
292207	26205654	However, the transfection of TbetaRIII markedly enhanced the decrease in TGF-beta1-induced cell viability by 38.8+-14.1 and 48.1+-12.1% respectively.	('TGF-beta1', 'Gene', '7040', (73, 82))	('decrease', 'NegReg', (61, 69))	('TGF-beta1', 'Gene', (73, 82))	('transfection', 'Var', (13, 25))	('TbetaRII', 'Gene', '7048', (29, 37))	('TbetaRII', 'Gene', (29, 37))	('enhanced', 'PosReg', (48, 56))	('cell viability', 'CPA', (91, 105))
292219	26205654	As illustrated in Figure 4, cells treated with 10 ng/ml TGF-beta1 for 1 h in the presence of TbetaRIII transfection resulted in a significant increase in total and phosphorylated p38 MAPK activities (Figure 4C), whereas the activity of ERK and JNK did not change (Figures 4A and 4B).	('phosphorylated', 'MPA', (164, 178))	('TGF-beta1', 'Gene', '7040', (56, 65))	('increase', 'PosReg', (142, 150))	('TbetaRII', 'Gene', (93, 101))	('TGF-beta1', 'Gene', (56, 65))	('ERK', 'Gene', (236, 239))	('MAPK', 'Gene', (183, 187))	('p38', 'Gene', '5594', (179, 182))	('transfection', 'Var', (103, 115))	('ERK', 'Gene', '5595;5594;26413;5595;26417', (236, 239))	('MAPK', 'Gene', '5595;5594;26413;5595;26417', (183, 187))	('TbetaRII', 'Gene', '7048', (93, 101))	('p38', 'Gene', (179, 182))	('activities', 'MPA', (188, 198))
292222	26205654	After the cells were treated with 10 ng/ml TGF-beta1 for 24 h, western blotting revealed that TbetaRIII transfection resulted in a significant increase in the protein levels of TGF-beta1-activated CDKN2b in a time-dependent manner.	('TbetaRII', 'Gene', '7048', (94, 102))	('protein levels', 'MPA', (159, 173))	('TbetaRII', 'Gene', (94, 102))	('CDKN2b', 'Gene', '1030', (197, 203))	('transfection', 'Var', (104, 116))	('TGF-beta1', 'Gene', '7040', (177, 186))	('CDKN2b', 'Gene', (197, 203))	('TGF-beta1', 'Gene', (177, 186))	('TGF-beta1', 'Gene', '7040', (43, 52))	('increase', 'PosReg', (143, 151))	('TGF-beta1', 'Gene', (43, 52))
292223	26205654	These results suggest that TbetaRIII transfection increases the kinase activity of CDKN2b to promote G0/G1 phase cell cycle arrest.	('CDKN2b', 'Gene', '1030', (83, 89))	('CDKN2b', 'Gene', (83, 89))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (113, 130))	('G0/G1 phase cell cycle arrest', 'CPA', (101, 130))	('increases', 'PosReg', (50, 59))	('kinase activity', 'MPA', (64, 79))	('TbetaRII', 'Gene', '7048', (27, 35))	('TbetaRII', 'Gene', (27, 35))	('promote', 'PosReg', (93, 100))	('transfection', 'Var', (37, 49))
292229	26205654	On the contrary, an expanding body of evidence indicates that a dysfunctional TbetaRIII mechanism due to loss of TbetaRIII receptors leads to the development and progression of several human malignancies, including breast cancer, prostate cancer and head and neck squamous carcinoma.	('breast cancer', 'Phenotype', 'HP:0003002', (215, 228))	('human', 'Species', '9606', (185, 190))	('dysfunctional TbetaRIII', 'Disease', (64, 87))	('TbetaRII', 'Gene', '7048', (113, 121))	('malignancies', 'Disease', 'MESH:D009369', (191, 203))	('TbetaRII', 'Gene', (78, 86))	('head and neck squamous carcinoma', 'Disease', 'MESH:D000077195', (250, 282))	('malignancies', 'Disease', (191, 203))	('breast cancer', 'Disease', 'MESH:D001943', (215, 228))	('breast cancer', 'Disease', (215, 228))	('dysfunctional TbetaRIII', 'Disease', 'MESH:D006331', (64, 87))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (264, 282))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))	('leads to', 'Reg', (133, 141))	('prostate cancer', 'Disease', 'MESH:D011471', (230, 245))	('prostate cancer', 'Phenotype', 'HP:0012125', (230, 245))	('TbetaRII', 'Gene', '7048', (78, 86))	('TbetaRII', 'Gene', (113, 121))	('loss', 'Var', (105, 109))	('prostate cancer', 'Disease', (230, 245))	('carcinoma', 'Phenotype', 'HP:0030731', (273, 282))
292244	26205654	For instance, in L6 myoblasts, the presence of TbetaRIII results in the activation of the p38 MAPK pathway in a TbetaRI receptor-dependent manner.	('activation', 'PosReg', (72, 82))	('presence', 'Var', (35, 43))	('MAPK', 'Gene', '5595;5594;26413;5595;26417', (94, 98))	('p38', 'Gene', (90, 93))	('TbetaRII', 'Gene', '7048', (47, 55))	('TbetaRII', 'Gene', (47, 55))	('MAPK', 'Gene', (94, 98))	('p38', 'Gene', '5594', (90, 93))
292260	33652578	Indeed, mutations, chromosomal alterations and the deregulation of teneurins expression have been associated with several tumor types and patient survival.	('teneurins', 'Protein', (67, 76))	('expression', 'MPA', (77, 87))	('deregulation', 'Var', (51, 63))	('teneurins', 'Chemical', '-', (67, 76))	('mutations', 'Var', (8, 17))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('patient', 'Species', '9606', (138, 145))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('chromosomal alterations', 'Var', (19, 42))	('rat', 'Species', '10116', (35, 38))	('associated', 'Reg', (98, 108))	('tumor', 'Disease', (122, 127))
292285	33652578	This trans-homodimerization of teneurins has been reported to allow the correct matching between axons and their targets to occur, thus contributing to correct circuit-wiring in the nervous system.	('circuit-wiring', 'CPA', (160, 174))	('contributing to', 'Reg', (136, 151))	('trans-homodimerization', 'Var', (5, 27))	('matching', 'MPA', (80, 88))	('teneurins', 'Chemical', '-', (31, 40))
292286	33652578	Upon homodimerization, teneurins' intracellular domains are cleaved close to the plasma membrane and translocate into the nucleus, where they regulate gene expression via direct and indirect interactions with transcription factors.	('gene expression', 'MPA', (151, 166))	('teneurins', 'Chemical', '-', (23, 32))	('regulate', 'Reg', (142, 150))	('interactions', 'Interaction', (191, 203))	('homodimerization', 'Var', (5, 21))
292291	33652578	The different teneurins' alternative variants interact with different ligands, mediating either teneurin homodimerization or heterodimerization with latrophilins, leading to the activation of different biological functions.	('biological functions', 'MPA', (202, 222))	('teneurin', 'Chemical', '-', (96, 104))	('teneurins', 'Gene', (14, 23))	('activation', 'PosReg', (178, 188))	('teneurin', 'Protein', (96, 104))	('mediating', 'Reg', (79, 88))	('teneurin', 'Chemical', '-', (14, 22))	('teneurins', 'Chemical', '-', (14, 23))	('variants', 'Var', (37, 45))	('heterodimerization', 'MPA', (125, 143))	('homodimerization', 'MPA', (105, 121))
292302	33652578	Recent data have demonstrated a role for TENM1 in the establishment of olfactory circuits; indeed, TENM1 deletion in mice affects their ability to detect odors and TENM1 mutations in humans are correlated with congenital anosmia.	('ability to detect odors', 'MPA', (136, 159))	('deletion', 'Var', (105, 113))	('TENM1', 'Gene', (99, 104))	('TENM1', 'Gene', (164, 169))	('congenital anosmia', 'Disease', (210, 228))	('humans', 'Species', '9606', (183, 189))	('mutations', 'Var', (170, 179))	('anosmia', 'Phenotype', 'HP:0000458', (221, 228))	('affects', 'Reg', (122, 129))	('mice', 'Species', '10090', (117, 121))	('rat', 'Species', '10116', (24, 27))	('correlated with', 'Reg', (194, 209))	('congenital anosmia', 'Disease', 'MESH:C535983', (210, 228))
292312	33652578	Indeed, in vivo studies in rodents have demonstrated that TCAP-1 administration impacts upon CRF-associated behavior, such as anxiety and depression, and increases glucose levels in rat brains.	('increases', 'PosReg', (154, 163))	('anxiety', 'Phenotype', 'HP:0000739', (126, 133))	('impacts', 'Reg', (80, 87))	('increases glucose levels', 'Phenotype', 'HP:0003074', (154, 178))	('depression', 'Disease', 'MESH:D000275', (138, 148))	('depression', 'Phenotype', 'HP:0000716', (138, 148))	('CRF-associated', 'Disease', (93, 107))	('rat', 'Species', '10116', (47, 50))	('depression', 'Disease', (138, 148))	('TCAP', 'Gene', (58, 62))	('rat', 'Species', '10116', (182, 185))	('glucose levels', 'MPA', (164, 178))	('TCAP', 'Gene', '8557', (58, 62))	('anxiety', 'Disease', 'MESH:D001007', (126, 133))	('glucose', 'Chemical', 'MESH:D005947', (164, 171))	('anxiety', 'Disease', (126, 133))	('administration', 'Var', (65, 79))	('rat', 'Species', '10116', (73, 76))
292313	33652578	Besides congenital general anosmia, TENM1 deregulation has also been associated with several tumors.	('TENM1', 'Gene', (36, 41))	('deregulation', 'Var', (42, 54))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('associated', 'Reg', (69, 79))	('tumors', 'Disease', 'MESH:D009369', (93, 99))	('congenital general anosmia', 'Disease', 'MESH:C535983', (8, 34))	('congenital general anosmia', 'Disease', (8, 34))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('tumors', 'Disease', (93, 99))	('anosmia', 'Phenotype', 'HP:0000458', (27, 34))
292317	33652578	However, data on the association between TENM1 deregulation and tumor progression are scarce and confined to a few tumor types, such as thyroid carcinoma, pituitary tumor and glioblastoma.	('tumor', 'Disease', (115, 120))	('pituitary tumor', 'Disease', (155, 170))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('deregulation', 'Var', (47, 59))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (136, 153))	('glioblastoma', 'Disease', 'MESH:D005909', (175, 187))	('thyroid carcinoma', 'Disease', (136, 153))	('tumor', 'Disease', (165, 170))	('tumor', 'Disease', (64, 69))	('TENM1', 'Gene', (41, 46))	('glioblastoma', 'Disease', (175, 187))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('glioblastoma', 'Phenotype', 'HP:0012174', (175, 187))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (136, 153))	('pituitary tumor', 'Disease', 'MESH:D010911', (155, 170))
292318	33652578	Further support for TENM1's functional contribution to carcinogenesis, TENM1 mutations and chromosomal alterations have occasionally been found in tumors of differing origins.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumors', 'Disease', (147, 153))	('tumors', 'Phenotype', 'HP:0002664', (147, 153))	('tumors', 'Disease', 'MESH:D009369', (147, 153))	('rat', 'Species', '10116', (107, 110))	('mutations', 'Var', (77, 86))	('carcinogenesis', 'Disease', 'MESH:D063646', (55, 69))	('TENM1', 'Gene', (71, 76))	('carcinogenesis', 'Disease', (55, 69))
292330	33652578	Moreover, miR-486 restoration in papillary thyroid carcinoma cells significantly inhibited tumor cell proliferation, migration and invasion in vitro, via ERK and protein kinase B (Akt) signaling pathways, as well as inhibiting epithelial-to-mesenchymal transition (EMT) regulation and tumor cell growth in vivo.	('papillary thyroid carcinoma', 'Disease', (33, 60))	('papillary thyroid carcinoma', 'Disease', 'MESH:D000077273', (33, 60))	('ERK', 'Gene', (154, 157))	('rat', 'Species', '10116', (120, 123))	('tumor', 'Disease', (91, 96))	('miR-486', 'Gene', '619554', (10, 17))	('invasion', 'CPA', (131, 139))	('tumor', 'Phenotype', 'HP:0002664', (285, 290))	('rat', 'Species', '10116', (23, 26))	('Akt', 'Gene', (180, 183))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('protein kinase B', 'Gene', '2185', (162, 178))	('rat', 'Species', '10116', (109, 112))	('Akt', 'Gene', '207', (180, 183))	('protein kinase B', 'Gene', (162, 178))	('restoration', 'Var', (18, 29))	('inhibited', 'NegReg', (81, 90))	('inhibiting', 'NegReg', (216, 226))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (43, 60))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor', 'Disease', (285, 290))	('ERK', 'Gene', '5594', (154, 157))	('miR-486', 'Gene', (10, 17))	('papillary thyroid carcinoma', 'Phenotype', 'HP:0002895', (33, 60))	('tumor', 'Disease', 'MESH:D009369', (285, 290))	('carcinoma', 'Phenotype', 'HP:0030731', (51, 60))
292331	33652578	Recent data show that TENM1 is also up-regulated in a follicular variant of papillary thyroid cancer, and it is significantly more highly expressed and mutated in thyroid malignant nodules than in benign ones.	('expressed', 'MPA', (138, 147))	('papillary thyroid cancer', 'Disease', (76, 100))	('thyroid cancer', 'Phenotype', 'HP:0002890', (86, 100))	('mutated', 'Var', (152, 159))	('up-regulated', 'PosReg', (36, 48))	('more highly', 'PosReg', (126, 137))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('TENM1', 'Gene', (22, 27))	('papillary thyroid cancer', 'Disease', 'MESH:D000077273', (76, 100))	('follicular', 'Disease', (54, 64))	('papillary thyroid cancer', 'Phenotype', 'HP:0002895', (76, 100))
292333	33652578	Another tumor in which TENM1 seems to play an oncogenic role is glioblastoma, where it promotes the cell proliferation, the cytoskeletal remodeling of tumor cells and the invasion of the surrounding environment, both in vitro and in vivo, via the Myc-dependent transcriptional up-regulation of ras homolog family member A (RhoA) and consequent rho-associated protein kinase (ROCK) activation.	('ras homolog family member A', 'Gene', '387', (294, 321))	('rho-associated', 'Enzyme', (344, 358))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('TENM1', 'Var', (23, 28))	('ras homolog family member A', 'Gene', (294, 321))	('rat', 'Species', '10116', (112, 115))	('RhoA', 'Gene', (323, 327))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('Myc', 'Gene', '4609', (247, 250))	('up-regulation', 'PosReg', (277, 290))	('glioblastoma', 'Disease', 'MESH:D005909', (64, 76))	('RhoA', 'Gene', '387', (323, 327))	('tumor', 'Disease', (8, 13))	('activation', 'PosReg', (381, 391))	('glioblastoma', 'Disease', (64, 76))	('Myc', 'Gene', (247, 250))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('tumor', 'Disease', (151, 156))	('glioblastoma', 'Phenotype', 'HP:0012174', (64, 76))	('cell proliferation', 'CPA', (100, 118))	('promotes', 'PosReg', (87, 95))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
292334	33652578	Indeed, the absence of TENM1, achieved via gene deletion or down-regulation by small interfering RNA (siRNA), drastically reduces the invasive capacity of glioblastoma cells.	('absence', 'NegReg', (12, 19))	('reduces', 'NegReg', (122, 129))	('glioblastoma', 'Disease', (155, 167))	('down-regulation', 'NegReg', (60, 75))	('TENM1', 'Gene', (23, 28))	('glioblastoma', 'Disease', 'MESH:D005909', (155, 167))	('gene deletion', 'Var', (43, 56))	('glioblastoma', 'Phenotype', 'HP:0012174', (155, 167))
292338	33652578	Moreover, TENM1 mRNA up-regulation in response to hypoxia increases cell migration capacity in glioblastoma cells, while the blockade of TENM1 expression results in reduces hypoxia-induced glioblastoma cell migration.	('hypoxia', 'Disease', (50, 57))	('glioblastoma', 'Disease', (189, 201))	('glioblastoma cell migration', 'Disease', 'MESH:D005909', (189, 216))	('glioblastoma', 'Phenotype', 'HP:0012174', (189, 201))	('hypoxia', 'Disease', 'MESH:D000860', (50, 57))	('increases', 'PosReg', (58, 67))	('glioblastoma cell migration', 'Disease', (189, 216))	('hypoxia', 'Disease', (173, 180))	('TENM1', 'Gene', (10, 15))	('glioblastoma', 'Disease', 'MESH:D005909', (95, 107))	('mRNA', 'MPA', (16, 20))	('rat', 'Species', '10116', (210, 213))	('hypoxia', 'Disease', 'MESH:D000860', (173, 180))	('up-regulation', 'PosReg', (21, 34))	('glioblastoma', 'Disease', (95, 107))	('reduces', 'NegReg', (165, 172))	('rat', 'Species', '10116', (76, 79))	('TENM1', 'Gene', (137, 142))	('glioblastoma', 'Phenotype', 'HP:0012174', (95, 107))	('glioblastoma', 'Disease', 'MESH:D005909', (189, 201))	('blockade', 'Var', (125, 133))
292345	33652578	Interestingly, a single-cell analysis of circulating tumor cells, performed on a lung cancer patient, highlighted the presence of an acquired TENM1 single nucleotide variation in circulating tumor cells, whose function has not been elucidated.	('lung cancer', 'Phenotype', 'HP:0100526', (81, 92))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('TENM1', 'Gene', (142, 147))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('single nucleotide variation', 'Var', (148, 175))	('patient', 'Species', '9606', (93, 100))	('tumor', 'Disease', (191, 196))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('tumor', 'Disease', (53, 58))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('cancer', 'Disease', (86, 92))
292355	33652578	It has been shown that the intracellular domain of TENM2, cleaved and released after TENM2 dimerization, translocate into the nucleus, where it represses Zic-1 mediated transcription, promoting cellular differentiation.	('represses', 'NegReg', (144, 153))	('TENM2', 'Gene', (85, 90))	('dimerization', 'Var', (91, 103))	('promoting', 'PosReg', (184, 193))	('TENM2', 'Gene', (51, 56))	('Zic-1', 'Gene', (154, 159))	('cellular differentiation', 'CPA', (194, 218))	('Zic-1', 'Gene', '7545', (154, 159))
292359	33652578	The possible tumor suppressor role of TENM2 is also suggested by the observation that hepatitis B virus-related insertional mutagenesis, leading to TENM2 gene disruption, is frequently associated with hepatocarcinogenesis.	('tumor', 'Disease', (13, 18))	('hepatitis B virus', 'Species', '10407', (86, 103))	('hepatocarcinogenesis', 'Disease', 'MESH:D063646', (201, 221))	('hepatitis', 'Phenotype', 'HP:0012115', (86, 95))	('TENM2', 'Gene', (148, 153))	('associated with', 'Reg', (185, 200))	('hepatocarcinogenesis', 'Disease', (201, 221))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('gene disruption', 'Var', (154, 169))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('hepatitis B virus-related', 'Disease', (86, 111))	('insertional mutagenesis', 'Var', (112, 135))
292370	33652578	A conflicting trend can be observed in urothelial, endometrial, head and neck, renal, stomach and thyroid cancers, as well as in glioma and melanoma, in which low levels of TENM2 expression are correlated with better patients' overall survival.	('endometrial', 'Disease', (51, 62))	('cancers', 'Phenotype', 'HP:0002664', (106, 113))	('low levels', 'Var', (159, 169))	('melanoma', 'Disease', 'MESH:D008545', (140, 148))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('renal', 'Disease', (79, 84))	('better', 'PosReg', (210, 216))	('glioma', 'Disease', (129, 135))	('glioma', 'Disease', 'MESH:D005910', (129, 135))	('thyroid cancers', 'Disease', 'MESH:D013964', (98, 113))	('overall survival', 'CPA', (227, 243))	('thyroid cancer', 'Phenotype', 'HP:0002890', (98, 112))	('melanoma', 'Phenotype', 'HP:0002861', (140, 148))	('melanoma', 'Disease', (140, 148))	('patients', 'Species', '9606', (217, 225))	('stomach', 'Disease', (86, 93))	('urothelial', 'Disease', (39, 49))	('glioma', 'Phenotype', 'HP:0009733', (129, 135))	('TENM2', 'Gene', (173, 178))	('thyroid cancers', 'Disease', (98, 113))
292373	33652578	Accordingly, an analysis of triple negative breast cancer (TNBC) patient samples has suggested that there is a significant correlation between high TENM2 expression and reduced patient metastatic-free survival time.	('breast cancer', 'Disease', 'MESH:D001943', (44, 57))	('breast cancer', 'Phenotype', 'HP:0003002', (44, 57))	('patient metastatic-free survival time', 'CPA', (177, 214))	('breast cancer', 'Disease', (44, 57))	('high', 'Var', (143, 147))	('TENM2', 'Gene', (148, 153))	('reduced', 'NegReg', (169, 176))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('patient', 'Species', '9606', (65, 72))	('patient', 'Species', '9606', (177, 184))	('expression', 'MPA', (154, 164))
292376	33652578	A possible link between TENM2 deregulation and the drug sensitivity of cancer cells has also been proposed, again with contradictory results.	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('TENM2', 'Gene', (24, 29))	('cancer', 'Disease', (71, 77))	('drug sensitivity', 'CPA', (51, 67))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('drug sensitivity', 'Phenotype', 'HP:0020174', (51, 67))	('deregulation', 'Var', (30, 42))
292384	33652578	Further evidence supporting a possible role for TENM2 deregulation in the tumor microenvironment comes from whole-genome single nucleotide polymorphism profiling, which compared the progressive passages of tumor-derived endothelial cells.	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('TENM2', 'Gene', (48, 53))	('tumor', 'Disease', (206, 211))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('deregulation', 'Var', (54, 66))	('tumor', 'Disease', (74, 79))	('tumor', 'Disease', 'MESH:D009369', (206, 211))
292389	33652578	Proof of the importance of TENM3 in visual system circuit connectivity has been found in behavioral studies that show that TENM3 KO mice lack binocular vision.	('vision', 'Disease', 'MESH:D015354', (152, 158))	('TENM3', 'Var', (123, 128))	('mice', 'Species', '10090', (132, 136))	('vision', 'Disease', (152, 158))	('lack', 'NegReg', (137, 141))
292404	33652578	Data from different tumor types has suggested that TENM3 may possibly contribute to cancer metastasization.	('cancer metastasization', 'Disease', (84, 106))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('TENM3', 'Var', (51, 56))	('contribute', 'Reg', (70, 80))	('tumor', 'Disease', (20, 25))	('cancer metastasization', 'Disease', 'MESH:D009362', (84, 106))
292407	33652578	Increased TENM3 copy numbers and expressions have also been found in glioblastoma patients with leptomeningeal dissemination, compared to patients who do not present this pattern of metastasization.	('TENM3', 'Gene', (10, 15))	('leptomeningeal dissemination', 'Disease', (96, 124))	('patients', 'Species', '9606', (82, 90))	('Increased', 'PosReg', (0, 9))	('glioblastoma', 'Disease', (69, 81))	('glioblastoma', 'Disease', 'MESH:D005909', (69, 81))	('expressions', 'MPA', (33, 44))	('patients', 'Species', '9606', (138, 146))	('glioblastoma', 'Phenotype', 'HP:0012174', (69, 81))	('copy numbers', 'Var', (16, 28))
292408	33652578	The possible pro-metastatic role of TENM3 can also be hypothesized in lung tumors in which patients' circulating tumor cells display TENM3 mutations that are also maintained in metastasis, suggesting that these mutations are important for the migration process.	('tumor', 'Disease', (113, 118))	('patients', 'Species', '9606', (91, 99))	('rat', 'Species', '10116', (246, 249))	('mutations', 'Var', (139, 148))	('lung tumors', 'Disease', 'MESH:D008175', (70, 81))	('TENM3', 'Gene', (133, 138))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('lung tumors', 'Disease', (70, 81))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('lung tumors', 'Phenotype', 'HP:0100526', (70, 81))	('tumor', 'Disease', (75, 80))
292409	33652578	Interestingly, a gene-based query at the Human Protein Atlas displayed a correlation between worst survival and high TENM3 expression in most of the tumors analyzed, including endometrial, lung, ovarian, stomach, thyroid, urothelial cancer and glioma.	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('expression', 'MPA', (123, 133))	('glioma', 'Disease', (244, 250))	('high', 'Var', (112, 116))	('stomach', 'Disease', (204, 211))	('Human', 'Species', '9606', (41, 46))	('glioma', 'Disease', 'MESH:D005910', (244, 250))	('tumors', 'Phenotype', 'HP:0002664', (149, 155))	('thyroid', 'Disease', (213, 220))	('ovarian', 'Disease', (195, 202))	('endometrial', 'Disease', (176, 187))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('glioma', 'Phenotype', 'HP:0009733', (244, 250))	('tumors', 'Disease', (149, 155))	('TENM3', 'Gene', (117, 122))	('lung', 'Disease', (189, 193))	('tumors', 'Disease', 'MESH:D009369', (149, 155))	('ovarian', 'Disease', 'MESH:D010049', (195, 202))	('urothelial cancer', 'Disease', 'MESH:D014523', (222, 239))	('urothelial cancer', 'Disease', (222, 239))
292416	33652578	Although no translocations have been reported for TENM3, a high frequency of TENM3 mutation has been found in skin cutaneous melanoma and pancreatic adenocarcinoma, suggesting that TENM3 may also play a role in carcinogenesis in these tumor types, and in others that have not yet been investigated.	('melanoma', 'Phenotype', 'HP:0002861', (125, 133))	('found', 'Reg', (101, 106))	('carcinogenesis', 'Disease', (211, 225))	('tumor', 'Disease', 'MESH:D009369', (235, 240))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (110, 133))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D000230', (138, 163))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('play', 'Reg', (196, 200))	('mutation', 'Var', (83, 91))	('pancreatic adenocarcinoma', 'Disease', (138, 163))	('tumor', 'Disease', (235, 240))	('TENM3', 'Gene', (77, 82))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (138, 163))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (115, 133))	('skin cutaneous melanoma', 'Disease', (110, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (154, 163))	('role', 'Reg', (203, 207))	('carcinogenesis', 'Disease', 'MESH:D063646', (211, 225))
292420	33652578	Interestingly, a specific TENM3-mutated epitope CD8+ T cell response was observed when peripheral blood mononuclear cells were re-stimulated.	('CD8', 'Gene', (48, 51))	('TENM3-mutated', 'Var', (26, 39))	('CD8', 'Gene', '925', (48, 51))
292428	33652578	The TENM4 protein bears a phenylalanine in the third residue of the fifth EGF repeat in the extracellular domain, and, in the intracellular domain, two SH3-binding domains and one nuclear localization sequence.	('phenylalanine in', 'Var', (26, 42))	('EGF', 'Gene', (74, 77))	('EGF', 'Gene', '1950', (74, 77))	('TENM4', 'Gene', (4, 9))	('phenylalanine', 'Chemical', 'MESH:D010649', (26, 39))	('SH3-binding', 'Protein', (152, 163))
292429	33652578	Lastly, TENM4 lacks the predicted furin cleavage sequence just outside the plasma membrane.	('lacks', 'NegReg', (14, 19))	('furin', 'Gene', '5045', (34, 39))	('TENM4', 'Var', (8, 13))	('furin', 'Gene', (34, 39))
292431	33652578	Indeed, TENM4 KO neuroblastoma cells of mouse origin display decreased neurite length and ability to generate filopodia-like protrusions through FAK, Cdc42 and Rac1, whereas TENM4 overexpression in neuroblastoma cells promotes protrusion formation.	('neuroblastoma', 'Disease', (17, 30))	('mouse', 'Species', '10090', (40, 45))	('neuroblastoma', 'Phenotype', 'HP:0003006', (17, 30))	('TENM4', 'Var', (174, 179))	('neuroblastoma', 'Disease', (198, 211))	('neuroblastoma', 'Disease', 'MESH:D009447', (17, 30))	('Cdc42', 'Gene', '12540', (150, 155))	('neuroblastoma', 'Phenotype', 'HP:0003006', (198, 211))	('neuroblastoma', 'Disease', 'MESH:D009447', (198, 211))	('promotes', 'PosReg', (218, 226))	('TENM4 KO', 'Var', (8, 16))	('protrusion formation', 'CPA', (227, 247))	('decreased', 'NegReg', (61, 70))	('Cdc42', 'Gene', (150, 155))	('FAK', 'Protein', (145, 148))	('Rac1', 'Gene', (160, 164))	('neurite length', 'CPA', (71, 85))	('rat', 'Species', '10116', (105, 108))	('Rac1', 'Gene', '19353', (160, 164))
292432	33652578	Here, its disruption limits the generation of normal oligodendrocyte processes, leading to lower axon myelination, which results in the essential tremor phenotype in mice.	('lower', 'NegReg', (91, 96))	('axon myelination', 'Disease', (97, 113))	('essential tremor', 'Phenotype', 'HP:0030186', (136, 152))	('disruption', 'Var', (10, 20))	('rat', 'Species', '10116', (36, 39))	('axon myelination', 'Disease', 'MESH:D003711', (97, 113))	('tremor', 'Phenotype', 'HP:0001337', (146, 152))	('tremor', 'Disease', 'MESH:D014202', (146, 152))	('mice', 'Species', '10090', (166, 170))	('results in', 'Reg', (121, 131))	('tremor', 'Disease', (146, 152))	('limits', 'NegReg', (21, 27))
292433	33652578	Moreover, a similar phenotype, which is related to TENM4 missense mutations, has been identified in humans, although contrasting results have been obtained in a study performed in the Canadian population.	('missense mutations', 'Var', (57, 75))	('TENM4', 'Gene', (51, 56))	('humans', 'Species', '9606', (100, 106))
292436	33652578	This suggests that TENM4 is down-regulated following the activation and proliferation of satellite cells, probably in response to NOTCH signaling, and that TENM4 has a pivotal role in suppressing myogenic differentiation.	('TENM4', 'Gene', (19, 24))	('down-regulated', 'NegReg', (28, 42))	('myogenic differentiation', 'CPA', (196, 220))	('rat', 'Species', '10116', (79, 82))	('TENM4', 'Var', (156, 161))	('suppressing', 'NegReg', (184, 195))
292441	33652578	Recently, a missense mutation of the gene has been found to co-segregate with schizophrenia, suggesting that TENM4 has a potential role in this pathology.	('schizophrenia', 'Phenotype', 'HP:0100753', (78, 91))	('schizophrenia', 'Disease', 'MESH:D012559', (78, 91))	('schizophrenia', 'Disease', (78, 91))	('missense mutation', 'Var', (12, 29))
292442	33652578	A TENM4 risk variant has also been associated with mood disorders, and with the early onset of bipolar disorders.	('bipolar disorders', 'Phenotype', 'HP:0007302', (95, 112))	('TENM4', 'Gene', (2, 7))	('associated', 'Reg', (35, 45))	('bipolar disorder', 'Phenotype', 'HP:0007302', (95, 111))	('mood disorders', 'Disease', (51, 65))	('bipolar disorders', 'Disease', (95, 112))	('variant', 'Var', (13, 20))	('bipolar disorders', 'Disease', 'MESH:D001714', (95, 112))	('mood disorders', 'Disease', 'MESH:D019964', (51, 65))
292450	33652578	Interestingly, in the breast cancer cell line MDA-MB-175, TENM4 is involved in a translocation that generates the TENM4-neureguilin-1 fusion gene, resulting in Upsilon-heregulin fusion protein production.	('TENM4-neureguilin-1', 'Var', (114, 133))	('breast cancer', 'Disease', (22, 35))	('breast cancer', 'Phenotype', 'HP:0003002', (22, 35))	('Upsilon-heregulin fusion protein production', 'MPA', (160, 203))	('MDA-MB-175', 'CellLine', 'CVCL:1400', (46, 56))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('TENM4', 'Gene', (58, 63))	('breast cancer', 'Disease', 'MESH:D001943', (22, 35))	('rat', 'Species', '10116', (104, 107))
292461	33652578	Significantly lower amounts of TENM4 mRNA transcripts, compared to normal tissues, can also be observed in ovarian serous cystadenocarcinoma, in skin cutaneous melanoma and in testicular germ cell tumors (Figure 5).	('tumors', 'Disease', 'MESH:D009369', (197, 203))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('melanoma', 'Phenotype', 'HP:0002861', (160, 168))	('lower', 'NegReg', (14, 19))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (145, 168))	('TENM4', 'Var', (31, 36))	('ovarian serous cystadenocarcinoma', 'Disease', 'MESH:D018284', (107, 140))	('tumors', 'Phenotype', 'HP:0002664', (197, 203))	('skin cutaneous melanoma', 'Disease', (145, 168))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('germ cell tumors', 'Phenotype', 'HP:0100728', (187, 203))	('ovarian serous cystadenocarcinoma', 'Disease', (107, 140))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (150, 168))	('tumors', 'Disease', (197, 203))	('ovarian serous cystadenocarcinoma', 'Phenotype', 'HP:0012887', (107, 140))
292465	33652578	Indeed, TENM4 peptides have been identified in a proteomic study using human urine, and TENM4 was detected as one of the most abundant proteins in the secretome and in the exosomes derived from a neuroblastoma cell line.	('neuroblastoma', 'Phenotype', 'HP:0003006', (196, 209))	('TENM4', 'Var', (88, 93))	('neuroblastoma', 'Disease', 'MESH:D009447', (196, 209))	('neuroblastoma', 'Disease', (196, 209))	('human', 'Species', '9606', (71, 76))
292468	33652578	Current findings suggest that teneurins deregulation is associated with cancer cells proliferation, migration and invasion.	('rat', 'Species', '10116', (103, 106))	('migration', 'CPA', (100, 109))	('teneurins', 'Protein', (30, 39))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('associated', 'Reg', (56, 66))	('teneurins', 'Chemical', '-', (30, 39))	('rat', 'Species', '10116', (92, 95))	('deregulation', 'Var', (40, 52))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('invasion', 'CPA', (114, 122))	('cancer', 'Disease', (72, 78))
292474	33652578	However, it has to be noted that an oncogenic role for TENM2 cannot be excluded, since in TNBC, a significant correlation between high TENM2 expression and reduced patient metastatic-free survival time has been demonstrated.	('TNBC', 'Disease', (90, 94))	('high', 'Var', (130, 134))	('patient', 'Species', '9606', (164, 171))	('reduced', 'NegReg', (156, 163))	('TENM2', 'Gene', (135, 140))	('rat', 'Species', '10116', (218, 221))	('expression', 'MPA', (141, 151))	('patient metastatic-free survival time', 'CPA', (164, 201))
292480	33652578	The data mining of publicly available data sets derived from large cohorts of oncologic patients provides interesting evidence about the presence of somatic mutations and chromosomal alterations (e.g., translocations, copy number variations, chromothripsis, and viral genome integration) leading to both teneurins' inactivation or overexpression in human tumors.	('viral genome integration', 'Var', (262, 286))	('inactivation', 'NegReg', (315, 327))	('rat', 'Species', '10116', (187, 190))	('human', 'Species', '9606', (349, 354))	('overexpression', 'PosReg', (331, 345))	('tumor', 'Phenotype', 'HP:0002664', (355, 360))	('copy number variations', 'Var', (218, 240))	('teneurins', 'Chemical', '-', (304, 313))	('patients', 'Species', '9606', (88, 96))	('rat', 'Species', '10116', (280, 283))	('chromothripsis', 'Disease', (242, 256))	('tumors', 'Disease', (355, 361))	('tumors', 'Disease', 'MESH:D009369', (355, 361))	('tumors', 'Phenotype', 'HP:0002664', (355, 361))	('chromothripsis', 'Disease', 'MESH:D000072837', (242, 256))	('teneurins', 'Protein', (304, 313))	('translocations', 'Var', (202, 216))
292487	33652578	; Writing:Original Draft Preparation: G.P., R.R., M.A., F.R., G.B.	('M.A.', 'Var', (50, 54))	('F.R.', 'Var', (56, 60))	('rat', 'Species', '10116', (30, 33))
292494	30894752	Sparsely infiltrated tumors exhibited evidence for historical immunoediting, with a waning of neoantigen-editing during tumor evolution, or copy number loss of historically clonal neoantigens.	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('tumor', 'Disease', (21, 26))	('tumors', 'Disease', (21, 27))	('tumors', 'Disease', 'MESH:D009369', (21, 27))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('neoantigen-editing', 'MPA', (94, 112))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('copy number loss', 'Var', (140, 156))	('tumor', 'Disease', (120, 125))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
292533	30894752	Alternatively, tumor subclones expressing neoantigens may be preferentially eliminated by the immune system resulting in purifying selection of subclones harboring them.	('tumor', 'Disease', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('neoantigens', 'Var', (42, 53))
292539	30894752	Among low infiltrate tumors, a decrease in immunoediting (increase in observed/expected neoantigens) was noted from clonal to subclonal mutations (p=8.8e-03, paired t-test) (Figure 2D), possibly reflecting an ancestral immune-active microenvironment which has subsequently become cold.	('immunoediting', 'MPA', (43, 56))	('increase', 'PosReg', (58, 66))	('tumors', 'Disease', (21, 27))	('decrease', 'NegReg', (31, 39))	('tumors', 'Disease', 'MESH:D009369', (21, 27))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('mutations', 'Var', (136, 145))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
292541	30894752	In tumor regions with low immune infiltration non-synonymous mutations predicted to be neoantigens, were more likely to occur on genomic segments subject to subclonal copy number loss as compared to their non-neoantigenic counterparts (p=1.2e-04) (Figure 2G).	('occur', 'Reg', (120, 125))	('tumor', 'Disease', (3, 8))	('non-synonymous mutations', 'Var', (46, 70))	('tumor', 'Disease', 'MESH:D009369', (3, 8))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))
292553	30894752	Defects in antigen presentation that interrupt tumor antigen recognition  may provide another immune evasion mechanism.	('antigen', 'Protein', (11, 18))	('Defects', 'Var', (0, 7))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor', 'Disease', (47, 52))
292554	30894752	Disruption to antigen presentation, through HLA LOH or through mutations affecting MHC stability, the HLA enhanceosome, and peptide generation were frequently observed in both lung histologies (56% of lung adenocarcinomas and 78% of lung squamous cell carcinomas).	('lung adenocarcinomas', 'Disease', (201, 221))	('MHC', 'Gene', '3107', (83, 86))	('Disruption', 'MPA', (0, 10))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (238, 261))	('lung adenocarcinomas', 'Disease', 'MESH:C538231', (201, 221))	('mutations', 'Var', (63, 72))	('peptide generation', 'MPA', (124, 142))	('lung squamous cell carcinomas', 'Disease', 'MESH:D002294', (233, 262))	('carcinoma', 'Phenotype', 'HP:0030731', (252, 261))	('carcinomas', 'Phenotype', 'HP:0030731', (252, 262))	('affecting', 'Reg', (73, 82))	('antigen presentation', 'MPA', (14, 34))	('MHC', 'Gene', (83, 86))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (201, 220))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (238, 262))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (201, 221))	('carcinoma', 'Phenotype', 'HP:0030731', (211, 220))	('carcinomas', 'Phenotype', 'HP:0030731', (211, 221))	('observed', 'Reg', (159, 167))	('lung squamous cell carcinomas', 'Disease', (233, 262))
292555	30894752	HLA LOH and alterations affecting other components of the antigen presentation machinery, including B2M mutations, had a tendency for mutually exclusivity (lung adeno.	('B2M', 'Gene', (100, 103))	('mutations', 'Var', (104, 113))	('B2M', 'Gene', '567', (100, 103))
292573	30894752	Our results show evidence of tumor evolution shaped through different immunoediting mechanisms, either affecting antigen presentation or neoantigenic mutations themselves at both the DNA and RNA-level.	('antigen presentation', 'MPA', (113, 133))	('neoantigenic', 'Var', (137, 149))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('affecting', 'Reg', (103, 112))	('tumor', 'Disease', (29, 34))
292574	30894752	Consistent with disruption to antigen presentation machinery being subject to strong positive selection , we found HLA LOH tended towards mutually exclusivity with other forms of antigen presentation disruption, such as mutations affecting MHC stability, the HLA enhanceosome, or peptide generation.	('MHC', 'Gene', '3107', (240, 243))	('mutations', 'Var', (220, 229))	('MHC', 'Gene', (240, 243))
292583	30894752	Epigenetic immune evasion supports the potential for epigenetic modulatory agents, in combination with immunotherapy, to restore or improve tumor immunogenicity .	('tumor', 'Disease', (140, 145))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('restore', 'PosReg', (121, 128))	('improve', 'PosReg', (132, 139))	('Epigenetic immune evasion', 'MPA', (0, 25))	('epigenetic modulatory agents', 'Var', (53, 81))
292584	30894752	One possibility is that epigenetic repression of a neoantigen in a lung cancer expressed gene may result at a fitness cost.	('fitness cost', 'CPA', (110, 122))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('lung cancer', 'Disease', 'MESH:D008175', (67, 78))	('result', 'Reg', (98, 104))	('epigenetic repression', 'Var', (24, 45))	('lung cancer', 'Disease', (67, 78))	('lung cancer', 'Phenotype', 'HP:0100526', (67, 78))
292631	30894752	All mutations present in any region from a tumor were turned into a binary matrix, where the rows were mutations and columns tumor regions.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Disease', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('mutations', 'Var', (4, 13))	('tumor', 'Disease', (43, 48))
292637	30894752	Of the 28,489 non-synonymous mutations in this cohort, 24,494 were predicted to encode peptides capable of binding to at least one of the patient's HLA class I alleles (binding affinity < 500nM or rank% < 2) and 13,884 were predicted to strongly bind (binding affinity < 50nM or rank% < 0.5) .	('bind', 'Interaction', (246, 250))	('mutations', 'Var', (29, 38))	('patient', 'Species', '9606', (138, 145))	('binding', 'Interaction', (107, 114))
292640	30894752	Neoantigens in genes that are consistently expressed across the TCGA NSCLC cohort were classified in two groups: expressed, where the mutant is detected in at least 30 reads, and non-expressed, where no mutant transcript is observed.	('NSCLC', 'Disease', (69, 74))	('mutant', 'Var', (134, 140))	('NSCLC', 'Disease', 'MESH:D002289', (69, 74))
292644	30894752	They included disruptive events (non-synonymous mutations or copy number loss defined relative to ploidy ) of the following genes: CIITA, IRF1, PSME1, PSME2, PSME3, ERAP1, ERAP2, HSPA, HSPC, TAP1, TAP2, TAPBP, CALR, CNX, PDIA3, B2M.	('TAP2', 'Gene', '6891', (197, 201))	('HSPC', 'Gene', '5688', (185, 189))	('HSPC', 'Gene', (185, 189))	('ERAP2', 'Gene', '64167', (172, 177))	('CALR', 'Gene', (210, 214))	('IRF1', 'Gene', '3659', (138, 142))	('ERAP1', 'Gene', (165, 170))	('CIITA', 'Gene', (131, 136))	('PDIA3', 'Gene', '2923', (221, 226))	('CALR', 'Gene', '811', (210, 214))	('HSPA', 'Gene', (179, 183))	('PSME3', 'Gene', '10197', (158, 163))	('B2M', 'Gene', (228, 231))	('CNX', 'Gene', '821', (216, 219))	('PSME1', 'Gene', (144, 149))	('loss', 'NegReg', (73, 77))	('copy number', 'Var', (61, 72))	('CNX', 'Gene', (216, 219))	('PSME2', 'Gene', (151, 156))	('B2M', 'Gene', '567', (228, 231))	('PSME1', 'Gene', '5720', (144, 149))	('ERAP1', 'Gene', '51752', (165, 170))	('TAP2', 'Gene', (197, 201))	('CIITA', 'Gene', '4261', (131, 136))	('TAPBP', 'Gene', (203, 208))	('TAPBP', 'Gene', '6892', (203, 208))	('ERAP2', 'Gene', (172, 177))	('IRF1', 'Gene', (138, 142))	('TAP1', 'Gene', (191, 195))	('PSME2', 'Gene', '5721', (151, 156))	('TAP1', 'Gene', '6890', (191, 195))	('PSME3', 'Gene', (158, 163))	('PDIA3', 'Gene', (221, 226))
292697	30653122	It was reported that abnormalities in blood flow as a result of surgical injury and the healing process may predispose the patient to development of metastases around surgical implants.	('metastases', 'Disease', (149, 159))	('patient', 'Species', '9606', (123, 130))	('predispose', 'Reg', (108, 118))	('metastases', 'Disease', 'MESH:D009362', (149, 159))	('blood flow', 'CPA', (38, 48))	('abnormalities', 'Var', (21, 34))
292705	29358619	Novel therapeutic strategy for cervical cancer harboring FGFR3-TACC3 fusions We previously found that therapeutic targetable fusions are detected across various cancers.	('FGFR3', 'Gene', (57, 62))	('cancer', 'Disease', (161, 167))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('TACC3', 'Gene', (63, 68))	('cancer', 'Disease', (40, 46))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('cancers', 'Disease', 'MESH:D009369', (161, 168))	('cancers', 'Phenotype', 'HP:0002664', (161, 168))	('FGFR3', 'Gene', '2261', (57, 62))	('cancers', 'Disease', (161, 168))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('TACC3', 'Gene', '10460', (63, 68))	('fusions', 'Var', (69, 76))
292712	29358619	Continuous expression of FGFR3-TACC3 fusion led to activation of the PI3K-AKT pathway only in the two cell lines that harbored PIK3CA mutations.	('FGFR3-TACC3', 'Gene', (25, 36))	('AKT', 'Gene', '207', (74, 77))	('PIK3CA', 'Gene', (127, 133))	('PIK3CA', 'Gene', '5290', (127, 133))	('mutations', 'Var', (134, 143))	('AKT', 'Gene', (74, 77))	('activation', 'PosReg', (51, 61))
292713	29358619	Sensitivity to the FGFR inhibitor, BGJ398, was found to depend on PIK3CA mutation status.	('BGJ398', 'Chemical', 'MESH:C568950', (35, 41))	('PIK3CA', 'Gene', (66, 72))	('BGJ398', 'Gene', (35, 41))	('depend', 'Reg', (56, 62))	('PIK3CA', 'Gene', '5290', (66, 72))	('mutation', 'Var', (73, 81))
292714	29358619	Dual inhibition of both FGFR and AKT showed an obvious synergistic effect in cell lines that harbor mutant PIK3CA.	('mutant', 'Var', (100, 106))	('FGFR', 'Gene', (24, 28))	('AKT', 'Gene', '207', (33, 36))	('inhibition', 'NegReg', (5, 15))	('PIK3CA', 'Gene', (107, 113))	('PIK3CA', 'Gene', '5290', (107, 113))	('AKT', 'Gene', (33, 36))
292724	29358619	Our pan-cancer fusion study showed that a number of cancers have targetable FGFR3-TACC3 fusion.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('cancers', 'Disease', (52, 59))	('cancer', 'Disease', (8, 14))	('cancers', 'Phenotype', 'HP:0002664', (52, 59))	('FGFR3-TACC3', 'Gene', (76, 87))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('fusion', 'Var', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (8, 14))	('cancers', 'Disease', 'MESH:D009369', (52, 59))
292725	29358619	Therefore, we planned to discover and validate the presence of therapeutically targetable events such as FGFR3-TACC3 fusion in cervical cancer using datasets from two large cervical cancer patient cohorts, and then to clarify the use of the fusion product as a therapeutic target, leading to the development of new therapeutic strategies for cervical cancer.	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('cervical cancer', 'Disease', (173, 188))	('cancer', 'Phenotype', 'HP:0002664', (351, 357))	('cervical cancer', 'Disease', 'MESH:D002583', (342, 357))	('cervical cancer', 'Disease', (342, 357))	('patient', 'Species', '9606', (189, 196))	('fusion', 'Var', (117, 123))	('cervical cancer', 'Disease', 'MESH:D002583', (127, 142))	('cervical cancer', 'Disease', (127, 142))	('FGFR3-TACC3', 'Gene', (105, 116))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('cervical cancer', 'Disease', 'MESH:D002583', (173, 188))
292729	29358619	The frequency of FGFR3-TACC3 fusion-positive cervical cancer is similar in the two large cervical cancer patient cohorts (1.3% and 1.9%, respectively).	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('FGFR3-TACC3', 'Gene', (17, 28))	('patient', 'Species', '9606', (105, 112))	('fusion-positive', 'Var', (29, 44))	('cervical cancer', 'Disease', 'MESH:D002583', (89, 104))	('cervical cancer', 'Disease', (89, 104))	('cervical cancer', 'Disease', (45, 60))	('cervical cancer', 'Disease', 'MESH:D002583', (45, 60))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
292730	29358619	All six FGFR3-TACC3 fusion-positive samples were histologically diagnosed as squamous cell carcinoma, which corresponds well to the finding that FGFR3-TACC3 fusions are detected in TCGA lung squamous cell carcinoma but not in TCGA lung adenocarcinoma (Fig.	('lung squamous cell carcinoma', 'Disease', (186, 214))	('carcinoma', 'Phenotype', 'HP:0030731', (241, 250))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (231, 250))	('diagnosed', 'Reg', (64, 73))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (191, 214))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (77, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (205, 214))	('detected', 'Reg', (169, 177))	('lung adenocarcinoma', 'Disease', (231, 250))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (77, 100))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (191, 214))	('FGFR3-TACC3', 'Gene', (8, 19))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('squamous cell carcinoma', 'Disease', (77, 100))	('fusions', 'Var', (157, 164))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (186, 214))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (231, 250))
292736	29358619	FGFR3-TACC3 fusion was therefore clearly associated with tumorigenesis of cervical squamous cell carcinoma.	('fusion', 'Var', (12, 18))	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (83, 106))	('FGFR3-TACC3', 'Gene', (0, 11))	('squamous cell carcinoma', 'Disease', (83, 106))	('associated with', 'Reg', (41, 56))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (83, 106))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Disease', (57, 62))
292739	29358619	A colony formation assay demonstrated that the number of colonies increased significantly in all cervical cancer cells transfected with FGFR3-TACC3 fusion, compared to those transfected with a control vector (Figs.	('cervical cancer', 'Disease', (97, 112))	('increased', 'PosReg', (66, 75))	('fusion', 'Var', (148, 154))	('FGFR3-TACC3', 'Gene', (136, 147))	('cervical cancer', 'Disease', 'MESH:D002583', (97, 112))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
292740	29358619	Increased phosphorylation of AKT was observed only in the two FGFR3-TACC3 fusion-transfected cell lines that harbored a PIK3CA-activating mutation (ME180 and Ca Ski) (Figs.	('Ca Ski', 'CellLine', 'CVCL:1100', (158, 164))	('PIK3CA', 'Gene', (120, 126))	('FGFR3-TACC3', 'Gene', (62, 73))	('AKT', 'Gene', '207', (29, 32))	('phosphorylation', 'MPA', (10, 25))	('PIK3CA', 'Gene', '5290', (120, 126))	('ME180', 'Var', (148, 153))	('AKT', 'Gene', (29, 32))
292741	29358619	ME180 and Ca Ski cell lines had no other common genetic alterations leading to activation of the PI3K-AKT pathway (Supplementary Table 2), suggesting that activation of the AKT pathway in these two FGFR3-TACC3 fusion-transfected cell lines might be associated with their mutated/activated PIK3CA status.	('AKT', 'Gene', '207', (173, 176))	('Ca Ski', 'CellLine', 'CVCL:1100', (10, 16))	('mutated/activated', 'Var', (271, 288))	('AKT', 'Gene', (173, 176))	('AKT', 'Gene', '207', (102, 105))	('PIK3CA', 'Gene', '5290', (289, 295))	('PIK3CA', 'Gene', (289, 295))	('activation', 'PosReg', (155, 165))	('AKT', 'Gene', (102, 105))
292745	29358619	We transfected a "kinase-dead mutant" FGFR3-TACC3 fusion transcript ("FGFR3-TACC3 KD fusion") into Ect1/E6E7, SiHa, and ME180 to investigate the significance of FGFR3 kinase activity in FGFR3-TACC3 fusion-positive cervical cancer.	('Ect1', 'Gene', (99, 103))	('cervical cancer', 'Disease', (214, 229))	('Ect1', 'Gene', '2263', (99, 103))	('FGFR3-TACC3', 'Gene', (38, 49))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('SiHa', 'CellLine', 'CVCL:0032', (110, 114))	('mutant', 'Var', (30, 36))	('cervical cancer', 'Disease', 'MESH:D002583', (214, 229))
292748	29358619	In addition, we performed RNA sequencing for Ect1/E6E7, SiHa, and ME180 to compare gene expression profiles between the FGFR3-TACC3 fusion, FGFR3-TACC3 KD fusion, and control transfection groups.	('FGFR3-TACC3', 'Gene', (120, 131))	('Ect1', 'Gene', (45, 49))	('Ect1', 'Gene', '2263', (45, 49))	('SiHa', 'CellLine', 'CVCL:0032', (56, 60))	('fusion', 'Var', (132, 138))
292753	29358619	Accordingly, IL-8 secretion was higher in the FGFR3-TACC3 fusion group compared to the other two groups, and suppression of the MAPK pathway via tramenitib reduced IL-8 secretion in the FGFR3-TACC3 fusion group (Supplementary Figure 3).	('tramenitib', 'Chemical', '-', (145, 155))	('IL-8', 'Gene', '3576', (13, 17))	('higher', 'PosReg', (32, 38))	('MAPK', 'Gene', '5594', (128, 132))	('IL-8', 'Gene', (13, 17))	('IL-8', 'Gene', '3576', (164, 168))	('MAPK', 'Gene', (128, 132))	('reduced', 'NegReg', (156, 163))	('FGFR3-TACC3', 'Var', (46, 57))	('IL-8', 'Gene', (164, 168))	('suppression', 'NegReg', (109, 120))	('secretion', 'MPA', (18, 27))
292758	29358619	However, sensitivity to FGFR inhibition for FGFR3-TACC3 fusion-transfected ME180 and Ca Ski cell lines that harbored PIK3CA-activating mutations was relatively lower than that for the fusion-transfected SiHa and HeLa cell lines that both carried a wild-type PIK3CA gene (Figs.	('mutations', 'Var', (135, 144))	('PIK3CA', 'Gene', (258, 264))	('Ca Ski', 'CellLine', 'CVCL:1100', (85, 91))	('PIK3CA', 'Gene', (117, 123))	('SiHa', 'CellLine', 'CVCL:0032', (203, 207))	('PIK3CA', 'Gene', '5290', (258, 264))	('HeLa', 'CellLine', 'CVCL:0030', (212, 216))	('PIK3CA', 'Gene', '5290', (117, 123))	('sensitivity', 'MPA', (9, 20))	('lower', 'NegReg', (160, 165))
292759	29358619	Corresponding to the differences in sensitivity, western blot analysis after treatment with the FGFR inhibitor showed that expression of phosphorylated ERK and AKT remained high in ME180 and Ca Ski cells that carried mutant PIK3CA (Fig.	('ERK', 'Gene', '5594', (152, 155))	('mutant', 'Var', (217, 223))	('AKT', 'Gene', '207', (160, 163))	('expression', 'MPA', (123, 133))	('high', 'PosReg', (173, 177))	('ERK', 'Gene', (152, 155))	('PIK3CA', 'Gene', (224, 230))	('Ca Ski', 'CellLine', 'CVCL:1100', (191, 197))	('PIK3CA', 'Gene', '5290', (224, 230))	('AKT', 'Gene', (160, 163))
292760	29358619	Although treatment with the MEK inhibitor trametinib alone induced decreases in phosphorylated ERK, leading to an antitumor effect (Supplementary Figures 5a and b), the combination treatment with the FGFR inhibitor and the MEK inhibitor showed an antitumor effect that was far less than expected, especially in FGFR3-TACC3 fusion-transfected cells that carried a PIK3CA mutation (Supplementary Figure 6).	('PIK3CA', 'Gene', (363, 369))	('tumor', 'Disease', (251, 256))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('ERK', 'Gene', '5594', (95, 98))	('mutation', 'Var', (370, 378))	('trametinib', 'Chemical', 'MESH:C560077', (42, 52))	('phosphorylated', 'MPA', (80, 94))	('ERK', 'Gene', (95, 98))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('MEK', 'Gene', (28, 31))	('MEK', 'Gene', (223, 226))	('MEK', 'Gene', '5609', (223, 226))	('PIK3CA', 'Gene', '5290', (363, 369))	('tumor', 'Disease', (118, 123))	('MEK', 'Gene', '5609', (28, 31))	('decreases', 'NegReg', (67, 76))	('tumor', 'Disease', 'MESH:D009369', (251, 256))	('tumor', 'Phenotype', 'HP:0002664', (251, 256))
292761	29358619	Meanwhile, there was no difference in sensitivity to the AKT inhibitor MK2206 between the FGFR3-TACC3 fusion-transfected and control-transfected cell lines (Supplementary Figures 5c and d).	('FGFR3-TACC3', 'Gene', (90, 101))	('AKT', 'Gene', '207', (57, 60))	('fusion-transfected', 'Var', (102, 120))	('MK2206', 'Chemical', 'MESH:C548887', (71, 77))	('AKT', 'Gene', (57, 60))
292762	29358619	Dual inhibition of both FGFR and AKT showed an obvious synergistic effect in the fusion-transfected ME180 and Ca Ski cell lines that harbored mutant PIK3CA, but little added effect in SiHa and HeLa cells that harbored wild-type PIK3CA (Fig.	('HeLa', 'CellLine', 'CVCL:0030', (193, 197))	('FGFR', 'Gene', (24, 28))	('AKT', 'Gene', '207', (33, 36))	('mutant', 'Var', (142, 148))	('inhibition', 'NegReg', (5, 15))	('PIK3CA', 'Gene', (149, 155))	('Ca Ski', 'CellLine', 'CVCL:1100', (110, 116))	('SiHa', 'CellLine', 'CVCL:0032', (184, 188))	('AKT', 'Gene', (33, 36))	('PIK3CA', 'Gene', (228, 234))	('PIK3CA', 'Gene', '5290', (149, 155))	('PIK3CA', 'Gene', '5290', (228, 234))
292763	29358619	Previous studies reported that the PI3K/AKT pathway is activated in about 30% of cervical cancers, and four of six FGFR3-TACC3 fusion-positive cervical cancer samples showed activation of the PI3K-AKT pathway due to copy number amplification or a somatic mutation of at least one gene in the PI3K-AKT pathway (Supplementary Figure 7 and Supplementary Table 5).	('copy number amplification', 'Var', (216, 241))	('AKT', 'Gene', '207', (297, 300))	('AKT', 'Gene', '207', (197, 200))	('cervical cancer', 'Disease', 'MESH:D002583', (81, 96))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('AKT', 'Gene', '207', (40, 43))	('cervical cancers', 'Disease', (81, 97))	('cervical cancers', 'Disease', 'MESH:D002583', (81, 97))	('AKT', 'Gene', (297, 300))	('AKT', 'Gene', (197, 200))	('cervical cancer', 'Disease', (143, 158))	('cervical cancer', 'Disease', 'MESH:D002583', (143, 158))	('AKT', 'Gene', (40, 43))	('activation', 'PosReg', (174, 184))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('activated', 'PosReg', (55, 64))
292765	29358619	Surprisingly, the TACC3 inhibitor KHS101 reduced not only wild-type TACC3 protein expression but also expression of the FGFR3-TACC3 fusion protein in FGFR3-TACC3 fusion-transfected cervical cancer cell lines, leading to suppression of phosphorylation of ERK and AKT (Fig.	('suppression', 'NegReg', (220, 231))	('ERK', 'Gene', (254, 257))	('reduced', 'NegReg', (41, 48))	('KHS101', 'Chemical', 'MESH:C553183', (34, 40))	('ERK', 'Gene', '5594', (254, 257))	('phosphorylation', 'MPA', (235, 250))	('expression', 'MPA', (82, 92))	('expression', 'MPA', (102, 112))	('AKT', 'Gene', (262, 265))	('TACC3', 'Gene', (68, 73))	('cervical cancer', 'Disease', 'MESH:D002583', (181, 196))	('KHS101', 'Var', (34, 40))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('cervical cancer', 'Disease', (181, 196))	('protein', 'Protein', (74, 81))	('AKT', 'Gene', '207', (262, 265))
292766	29358619	The FGFR3-TACC3 fusion-transfected cell line group was more sensitive to KHS101 compared to the control group (Fig.	('sensitive', 'MPA', (60, 69))	('FGFR3-TACC3', 'Gene', (4, 15))	('KHS101', 'Chemical', 'MESH:C553183', (73, 79))	('KHS101', 'Var', (73, 79))
292773	29358619	In line with this previous result, we detected FGFR3-TACC3 fusions only in uterine cervical squamous cell carcinoma but not adenocarcinoma (Fig.	('FGFR3-TACC3', 'Gene', (47, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('adenocarcinoma', 'Disease', 'MESH:D000230', (124, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (92, 115))	('adenocarcinoma', 'Disease', (124, 138))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (92, 115))	('squamous cell carcinoma', 'Disease', (92, 115))	('fusions', 'Var', (59, 66))
292774	29358619	1a and Supplementary Table 1) and demonstrated that transfection of FGFR3-TACC3 fusion transformed the cervical epithelial cell line established from the ectocervix (Ect1/E6E7) to squamous cell carcinoma.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (180, 203))	('carcinoma', 'Phenotype', 'HP:0030731', (194, 203))	('squamous cell carcinoma', 'Disease', (180, 203))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (180, 203))	('Ect1', 'Gene', '2263', (166, 170))	('fusion', 'Var', (80, 86))	('Ect1', 'Gene', (166, 170))	('transformed', 'PosReg', (87, 98))	('FGFR3-TACC3', 'Gene', (68, 79))
292776	29358619	Indeed, several FGFR inhibitors have been developed and are being assessed in cancers that harbor oncogenic FGFR alterations, including FGFR3-TACC3 fusion.	('cancers', 'Disease', 'MESH:D009369', (78, 85))	('cancers', 'Phenotype', 'HP:0002664', (78, 85))	('cancers', 'Disease', (78, 85))	('FGFR', 'Gene', (108, 112))	('alterations', 'Var', (113, 124))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))
292780	29358619	For instance, PI3K-AKT signaling is a key pathway to use in determining the efficacy of FGFR inhibitors for cancers that harbor FGFR alterations.	('cancers', 'Phenotype', 'HP:0002664', (108, 115))	('AKT', 'Gene', '207', (19, 22))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('cancers', 'Disease', 'MESH:D009369', (108, 115))	('FGFR', 'Gene', (128, 132))	('alterations', 'Var', (133, 144))	('AKT', 'Gene', (19, 22))	('cancers', 'Disease', (108, 115))	('FGFR', 'Gene', (88, 92))
292783	29358619	Similarly, proteomic analysis between FGFR inhibitor-resistant and inhibitor-sensitive cell lines that harbor FGFR3-TACC3 fusions demonstrates increased phosphorylation of Akt (T308 and S473) and its downstream target GSK3 (S9 and S21) in the inhibitor-resistant cell line compared to the inhibitor-sensitive cell line.	('increased', 'PosReg', (143, 152))	('S473', 'Var', (186, 190))	('T308', 'Var', (177, 181))	('GSK3', 'Gene', (218, 222))	('fusions', 'Var', (122, 129))	('FGFR3-TACC3', 'Gene', (110, 121))	('Akt', 'Gene', '11651', (172, 175))	('phosphorylation', 'MPA', (153, 168))	('Akt', 'Gene', (172, 175))	('GSK3', 'Gene', '56637', (218, 222))
292790	29358619	KHS101 has a potential to target coiled-coil domain of TACC3, Therefore, we estimated that KHS101 has suppressed FGFR3-TACC3 fusion protein that retains coiled-coil domain of TACC3.	('coiled-coil domain', 'MPA', (153, 171))	('KHS101', 'Var', (91, 97))	('fusion protein', 'Protein', (125, 139))	('suppressed', 'NegReg', (102, 112))	('KHS101', 'Chemical', 'MESH:C553183', (0, 6))	('KHS101', 'Chemical', 'MESH:C553183', (91, 97))	('FGFR3-TACC3', 'Gene', (113, 124))
292791	29358619	Indeed, our results show that KHS101 could suppress the FGFR3-TACC3 fusion protein and that dual inhibition of FGFR and TACC3 synergistically suppressed cell proliferation.	('FGFR3-TACC3 fusion protein', 'Protein', (56, 82))	('inhibition', 'NegReg', (97, 107))	('KHS101', 'Var', (30, 36))	('suppress', 'NegReg', (43, 51))	('cell proliferation', 'CPA', (153, 171))	('FGFR', 'Gene', (111, 115))	('suppressed', 'NegReg', (142, 152))	('KHS101', 'Chemical', 'MESH:C553183', (30, 36))
292794	29358619	In conclusion, our study suggested a novel fusion-specific treatment strategy against FGFR3-TACC3 fusion-positive cervical cancer.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('FGFR3-TACC3', 'Gene', (86, 97))	('fusion-positive', 'Var', (98, 113))	('cervical cancer', 'Disease', (114, 129))	('cervical cancer', 'Disease', 'MESH:D002583', (114, 129))
292795	29358619	Dual inhibition of FGFR and PI3K/AKT pathways may be a meaningful treatment strategy for other types of cancer that harbor both FGFR3-TACC3 fusion and genomic alteration of the PI3K/AKT pathway.	('fusion', 'Var', (140, 146))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('AKT', 'Gene', '207', (33, 36))	('AKT', 'Gene', '207', (182, 185))	('inhibition', 'NegReg', (5, 15))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('FGFR3-TACC3', 'Gene', (128, 139))	('genomic alteration', 'Var', (151, 169))	('AKT', 'Gene', (33, 36))	('FGFR', 'Gene', (19, 23))	('cancer', 'Disease', (104, 110))	('AKT', 'Gene', (182, 185))
292810	29358619	The kinase activity-deficient mutants were constructed by replacing tyrosine with phenylalanine at codons K508M in the FGFR3-TACC3 ("Fusion 1" and "Fusion 2") using a Prime STAR site-directed mutagenesis kit (Takara Bio).	('FGFR3-TACC3', 'Gene', (119, 130))	('tyrosine', 'MPA', (68, 76))	('kinase activity-deficient', 'MPA', (4, 29))	('phenylalanine', 'Chemical', 'MESH:D010649', (82, 95))	('tyrosine', 'Chemical', 'MESH:D014443', (68, 76))	('K508M', 'Mutation', 'p.K508M', (106, 111))	('replacing', 'Var', (58, 67))
292813	29358619	Antibodies were purchased from the indicated suppliers: FGFR3 (sc-13121, Santa Cruz; dilution ratio 1:200), TACC3 (sc-22773, Santa Cruz; dilution ratio 1:200), phosphorylated ERK (#4370, Cell Signaling Technology; dilution ratio 1:1000), ERK (#4695, Cell Signaling Technology; dilution ratio 1:1000), phosphorylated-AKT (#4060, Cell Signaling Technology; dilution ratio 1:1000), AKT (#4691, Cell Signaling Technology; dilution ratio 1:1000), phosphorylated-STAT3 (#9145, Cell Signaling Technology; dilution ratio, 1:1000), STAT3 (#9139, Cell Signaling Technology; dilution ratio 1:1000), and actin (MAB1501R, Merck Millipore Headquarters; dilution ratio 1:1000).	('STAT3', 'Gene', (457, 462))	('ERK', 'Gene', '5594', (238, 241))	('ERK', 'Gene', (238, 241))	('AKT', 'Gene', (316, 319))	('#9145', 'Var', (464, 469))	('AKT', 'Gene', '207', (379, 382))	('#9139', 'Var', (530, 535))	('STAT3', 'Gene', '6774', (523, 528))	('STAT3', 'Gene', (523, 528))	('AKT', 'Gene', (379, 382))	('ERK', 'Gene', '5594', (175, 178))	('AKT', 'Gene', '207', (316, 319))	('ERK', 'Gene', (175, 178))	('STAT3', 'Gene', '6774', (457, 462))
292814	29358619	Blots were then incubated with either anti-mouse or anti-rabbit horseradish peroxidase-conjugated secondary antibodies (#115-035-166 and #111-035-144, Jackson Immuno Research; dilution ratio 1:10,000), and visualized by chemiluminescence.	('rabbit', 'Species', '9986', (57, 63))	('horseradish', 'Species', '3704', (64, 75))	('#115-035-166', 'Var', (120, 132))	('#111-035-144', 'Var', (137, 149))	('mouse', 'Species', '10090', (43, 48))
292823	29358619	We performed RNA sequencing for Ect1/E6E7, SiHa, and ME180 cell lines in which FGFR3-TACC3 fusion, FGFR3 kinase-dead fusion, and the control vector were transfected, respectively.	('fusion', 'Var', (91, 97))	('SiHa', 'CellLine', 'CVCL:0032', (43, 47))	('FGFR3-TACC3', 'Gene', (79, 90))	('Ect1', 'Gene', (32, 36))	('Ect1', 'Gene', '2263', (32, 36))
292824	29358619	We used gene expression data to perform GSEA between the FGFR3-TACC3 fusion-transfected group and the control group or between the FGFR3-TACC3 fusion kinase-dead transfected group and the control group.	('FGFR3-TACC3', 'Gene', (57, 68))	('GSEA', 'Chemical', '-', (40, 44))	('fusion-transfected', 'Var', (69, 87))
292830	29358619	We used an analytical pipeline in which putative somatic single-nucleotide variants (SNVs) and short insertions and deletions (indels) were called based solely on whole-exome sequencing data from tumor samples without matched normal samples.	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('single-nucleotide variants', 'Var', (57, 83))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('tumor', 'Disease', (196, 201))
292870	33028767	Pirfenidone suppresses the production of inflammatory cytokines, enhances the release of anti-inflammatory interleukin-10, and inhibits TGF-beta-induced epithelial-mesenchymal transition, which might enhance the motility and invasiveness of carcinoma cells.	('carcinoma', 'Phenotype', 'HP:0030731', (241, 250))	('inhibits', 'NegReg', (127, 135))	('invasiveness of carcinoma', 'Disease', (225, 250))	('suppresses', 'NegReg', (12, 22))	('enhance', 'PosReg', (200, 207))	('TGF-beta', 'Gene', '7039', (136, 144))	('Pirfenidone', 'Chemical', 'MESH:C093844', (0, 11))	('production of inflammatory cytokines', 'MPA', (27, 63))	('invasiveness of carcinoma', 'Disease', 'MESH:D009361', (225, 250))	('interleukin-10', 'Gene', '3586', (107, 121))	('enhances', 'PosReg', (65, 73))	('motility', 'CPA', (212, 220))	('Pirfenidone', 'Var', (0, 11))	('TGF-beta', 'Gene', (136, 144))	('interleukin-10', 'Gene', (107, 121))
292872	33028767	It has been demonstrated that pirfenidone exerts in vivo anti-tumor activity synergistically with cisplatinum in a mouse transplanted with human lung or breast cancer cells.	('pirfenidone', 'Var', (30, 41))	('breast cancer', 'Phenotype', 'HP:0003002', (153, 166))	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('breast cancer', 'Disease', 'MESH:D001943', (153, 166))	('pirfenidone', 'Chemical', 'MESH:C093844', (30, 41))	('tumor', 'Disease', (62, 67))	('mouse', 'Species', '10090', (115, 120))	('human', 'Species', '9606', (139, 144))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('cisplatinum', 'Chemical', 'MESH:D002945', (98, 109))	('breast cancer', 'Disease', (153, 166))
292877	32896997	Correlation between CXCR4, CXCR5 and CCR7 expression and survival outcomes in patients with clinical T1N0M0 non-small cell lung cancer Lung cancer is the leading cause of cancer-related death.	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('lung cancer', 'Phenotype', 'HP:0100526', (123, 134))	('patients', 'Species', '9606', (78, 86))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('death', 'Disease', 'MESH:D003643', (186, 191))	('cancer', 'Disease', (128, 134))	('CXCR4', 'Gene', '7852', (20, 25))	('Lung cancer', 'Disease', 'MESH:D008175', (135, 146))	('CXCR5', 'Gene', '643', (27, 32))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (108, 134))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (112, 134))	('CXCR4', 'Gene', (20, 25))	('Lung cancer', 'Phenotype', 'HP:0100526', (135, 146))	('CCR7', 'Gene', (37, 41))	('Lung cancer', 'Disease', (135, 146))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', (171, 177))	('T1N0M0', 'Var', (101, 107))	('death', 'Disease', (186, 191))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('CCR7', 'Gene', '1236', (37, 41))	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('CXCR5', 'Gene', (27, 32))
292885	32896997	However, five-year DFS and five-year OS of patients with positive CCR7 expression were significantly higher (DFS: P < 0.001; OS: P < 0.001).	('positive', 'Var', (57, 65))	('DFS', 'MPA', (19, 22))	('higher', 'PosReg', (101, 107))	('patients', 'Species', '9606', (43, 51))	('CCR7', 'Gene', '1236', (66, 70))	('CCR7', 'Gene', (66, 70))
292888	32896997	Moreover, all three chemokines were correlated to the survival outcomes of patients with clinical T1N0M0 NSCLC, providing potential prognosticators and therapy targets for lung cancer treatment.	('NSCLC', 'Disease', 'MESH:D002289', (105, 110))	('NSCLC', 'Phenotype', 'HP:0030358', (105, 110))	('NSCLC', 'Disease', (105, 110))	('lung cancer', 'Disease', (172, 183))	('patients', 'Species', '9606', (75, 83))	('lung cancer', 'Phenotype', 'HP:0100526', (172, 183))	('correlated', 'Reg', (36, 46))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('T1N0M0', 'Var', (98, 104))	('SCLC', 'Phenotype', 'HP:0030357', (106, 110))	('lung cancer', 'Disease', 'MESH:D008175', (172, 183))
292907	32896997	33 ,  34 ,  35  Aberrant expression of CCR7 has been identified in several types of tumors, including breast cancer, head and neck squamous cell carcinoma, esophageal squamous cell carcinoma and melanoma.	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (117, 154))	('carcinoma', 'Phenotype', 'HP:0030731', (145, 154))	('breast cancer', 'Phenotype', 'HP:0003002', (102, 115))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (156, 190))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (167, 190))	('head and neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (117, 154))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('CCR7', 'Gene', (39, 43))	('breast cancer', 'Disease', 'MESH:D001943', (102, 115))	('melanoma', 'Disease', 'MESH:D008545', (195, 203))	('breast cancer', 'Disease', (102, 115))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('Aberrant expression', 'Var', (16, 35))	('tumors', 'Disease', (84, 90))	('carcinoma', 'Phenotype', 'HP:0030731', (181, 190))	('CCR7', 'Gene', '1236', (39, 43))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (131, 154))	('identified', 'Reg', (53, 63))	('tumors', 'Disease', 'MESH:D009369', (84, 90))	('melanoma', 'Phenotype', 'HP:0002861', (195, 203))	('esophageal squamous cell carcinoma', 'Disease', (156, 190))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('melanoma', 'Disease', (195, 203))
292910	32896997	From January 2011 to January 2012, clinicopathological data of patients with clinical T1N0M0 NSCLC who underwent curative lobectomy with systematic lymph node dissection at the Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China, was retrospectively collected.	('Cancer', 'Disease', (277, 283))	('Cancer', 'Disease', (270, 276))	('NSCLC', 'Disease', (93, 98))	('T1N0M0', 'Var', (86, 92))	('Cancer', 'Disease', 'MESH:D009369', (218, 224))	('Cancer', 'Disease', 'MESH:D009369', (277, 283))	('Cancer', 'Disease', 'MESH:D009369', (270, 276))	('Cancer', 'Phenotype', 'HP:0002664', (277, 283))	('NSCLC', 'Disease', 'MESH:D002289', (93, 98))	('Cancer', 'Phenotype', 'HP:0002664', (270, 276))	('SCLC', 'Phenotype', 'HP:0030357', (94, 98))	('Cancer', 'Phenotype', 'HP:0002664', (218, 224))	('patients', 'Species', '9606', (63, 71))	('NSCLC', 'Phenotype', 'HP:0030358', (93, 98))	('Cancer', 'Disease', (218, 224))
292921	32896997	After incubation in a nonspecific stain blocking agent, slides were incubated for two hours at 37 C with the following primary antibodies: anti-human CXCR4 antibody (GR262216-26; Abcam, Cambridge, UK; 1:100), anti-human CXCR5 antibody (GR297692-6; Abcam, Cambridge, UK; 1:100), and anti-human CCR7 antibody (GR314167-1; Abcam, Cambridge, UK; 1:100).	('GR297692-6', 'Var', (236, 246))	('human', 'Species', '9606', (144, 149))	('CXCR4', 'Gene', '7852', (150, 155))	('CCR7', 'Gene', (293, 297))	('CCR7', 'Gene', '1236', (293, 297))	('CXCR5', 'Gene', (220, 225))	('CXCR5', 'Gene', '643', (220, 225))	('GR314167-1;', 'Var', (308, 319))	('CXCR4', 'Gene', (150, 155))	('GR262216-26;', 'Var', (166, 178))	('human', 'Species', '9606', (214, 219))	('human', 'Species', '9606', (287, 292))
292930	32896997	A total of 244 qualified patients who were diagnosed with clinical T1N0M0 NSCLC were enrolled into this study, and their clinicopathological characteristics are shown in Table 1.	('NSCLC', 'Phenotype', 'HP:0030358', (74, 79))	('T1N0M0', 'Var', (67, 73))	('NSCLC', 'Disease', (74, 79))	('patients', 'Species', '9606', (25, 33))	('NSCLC', 'Disease', 'MESH:D002289', (74, 79))	('SCLC', 'Phenotype', 'HP:0030357', (75, 79))
292984	32896997	demonstrated that a splicing imbalance of CCR7 was associated with the clinical outcomes of patients.	('CCR7', 'Gene', '1236', (42, 46))	('imbalance', 'Phenotype', 'HP:0002172', (29, 38))	('patients', 'Species', '9606', (92, 100))	('splicing imbalance', 'Var', (20, 38))	('CCR7', 'Gene', (42, 46))	('associated', 'Reg', (51, 61))
293009	27036025	MicroRNAs (miRNAs), which are small endogenous non-coding regulatory RNAs have been found to be differentially expressed in cancers, and play important roles in regulating gene expression by base-pairing to the complementary sites on the target mRNAs, thus blocking the translation or triggering the degradation of the target mRNAs.	('blocking', 'NegReg', (257, 265))	('translation', 'MPA', (270, 281))	('gene expression', 'MPA', (172, 187))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('cancers', 'Disease', 'MESH:D009369', (124, 131))	('base-pairing', 'Var', (191, 203))	('triggering', 'Reg', (285, 295))	('cancers', 'Phenotype', 'HP:0002664', (124, 131))	('cancers', 'Disease', (124, 131))	('degradation', 'MPA', (300, 311))
293150	27414086	Strikingly, NDRG1 overexpression induces the epithelial mesenchymal transition (EMT) through activating the Wnt signaling pathway in ESCC cells, decreased the expression of E-cadherin and enhanced the expression of Snail.	('epithelial mesenchymal transition', 'CPA', (45, 78))	('Snail', 'Gene', (215, 220))	('enhanced', 'PosReg', (188, 196))	('E-cadherin', 'Gene', (173, 183))	('Snail', 'Gene', '6615', (215, 220))	('E-cadherin', 'Gene', '999', (173, 183))	('NDRG1', 'Gene', (12, 17))	('expression', 'MPA', (159, 169))	('overexpression', 'Var', (18, 32))	('activating', 'PosReg', (93, 103))	('decreased', 'NegReg', (145, 154))	('Wnt signaling pathway', 'Pathway', (108, 129))	('expression', 'MPA', (201, 211))	('induces', 'PosReg', (33, 40))
293173	27414086	For NDRG1 overexpression, the KYSE 30 cells were transfected with the pCMV6-entry-NDRG1 or pCMV6 empty vector (Origen, Rockville MD) by Lipofectamine 2000 (Invitrogen, USA).	('Lipofectamine 2000', 'Chemical', 'MESH:C086724', (136, 154))	('pCMV6-entry-NDRG1', 'Var', (70, 87))	('NDRG1', 'Gene', (4, 9))
293175	27414086	HEK293 cells were transiently transfected with pCMV6-entry-NDRG1, pCMV6-entry-TLE2, and pCMV6 empty vectors using the Lipofectamine 2000 reagent according to the manufacturer's protocol.	('Lipofectamine 2000', 'Chemical', 'MESH:C086724', (118, 136))	('TLE2', 'Gene', '7089', (78, 82))	('TLE2', 'Gene', (78, 82))	('HEK293', 'CellLine', 'CVCL:0045', (0, 6))	('pCMV6-entry-NDRG1', 'Var', (47, 64))
293198	27414086	The xenograft tumor volume was compared between the KYSE 30-NDRG1 and KYSE-vec control groups by Student's t tests in the mouse xenograft assay.	('tumor', 'Disease', (14, 19))	('KYSE 30-NDRG1', 'Var', (52, 65))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('mouse', 'Species', '10090', (122, 127))
293209	27414086	However, NDRG1 positivity did not have a significant association with other clinic pathological factors, including gender, age, pathological grade, tumor diameter, tumor position, lymphatic metastasis and AJCC stage (Table 1).	('tumor', 'Disease', (164, 169))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('lymphatic', 'Disease', (180, 189))	('NDRG1', 'Gene', (9, 14))	('tumor', 'Disease', (148, 153))	('positivity', 'Var', (15, 25))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('tumor', 'Disease', 'MESH:D009369', (148, 153))
293212	27414086	NDRG1 overexpression significantly enhanced motility in wound-healing assays in KYSE 30 cells and also elevated MMP2 activity, a surrogate marker of metastasis.	('overexpression', 'Var', (6, 20))	('MMP2', 'Gene', '4313', (112, 116))	('enhanced', 'PosReg', (35, 43))	('motility in wound-healing assays', 'CPA', (44, 76))	('elevated', 'PosReg', (103, 111))	('NDRG1', 'Gene', (0, 5))	('MMP2', 'Gene', (112, 116))
293214	27414086	Consistent with the phenotypic changes associated with NDRG1 overexpression, we also observed an increase in the expression of mesenchymal markers, including N-cadherin, Snail and MMP1, but we did not observe decreased expression of the epithelial marker E-cadherin at the protein level (Fig.	('expression', 'MPA', (113, 123))	('MMP1', 'Gene', (180, 184))	('increase', 'PosReg', (97, 105))	('N-cadherin', 'Gene', (158, 168))	('E-cadherin', 'Gene', '999', (255, 265))	('NDRG1', 'Gene', (55, 60))	('N-cadherin', 'Gene', '1000', (158, 168))	('MMP1', 'Gene', '4312', (180, 184))	('E-cadherin', 'Gene', (255, 265))	('Snail', 'Gene', '6615', (170, 175))	('Snail', 'Gene', (170, 175))	('overexpression', 'Var', (61, 75))
293216	27414086	2D and 2E the expression levels of the angiogenesis-related genes ANGPT1 and TGFB1, invasion and metastasis-related genes MMP1, MMP2, PLAUR and SERPINB5, adhesion-related genes MTSS1 and SYK, cell cycle-related gene CDC25A, and oncogenic transcription factor MYC were significantly enhanced after NDRG1 overexpression.	('MMP1', 'Gene', '4312', (122, 126))	('ANGPT1', 'Gene', '284', (66, 72))	('SERPINB5', 'Gene', (144, 152))	('MMP1', 'Gene', (122, 126))	('TGFB1', 'Gene', '7040', (77, 82))	('CDC25A', 'Gene', '993', (216, 222))	('SYK', 'Gene', '6850', (187, 190))	('TGFB1', 'Gene', (77, 82))	('expression levels', 'MPA', (14, 31))	('MTSS1', 'Gene', (177, 182))	('oncogenic', 'MPA', (228, 237))	('MYC', 'Gene', '4609', (259, 262))	('PLAUR', 'Gene', '5329', (134, 139))	('MMP2', 'Gene', (128, 132))	('NDRG1', 'Gene', (297, 302))	('ANGPT1', 'Gene', (66, 72))	('CDC25A', 'Gene', (216, 222))	('MTSS1', 'Gene', '9788', (177, 182))	('SERPINB5', 'Gene', '5268', (144, 152))	('overexpression', 'Var', (303, 317))	('MMP2', 'Gene', '4313', (128, 132))	('PLAUR', 'Gene', (134, 139))	('MYC', 'Gene', (259, 262))	('enhanced', 'PosReg', (282, 290))	('angiogenesis-related', 'CPA', (39, 59))	('SYK', 'Gene', (187, 190))
293223	27414086	Inversely, NDRG1 knock-down induced TLE2 upregulation at the transcript level in KYSE 30 cells.	('NDRG1', 'Gene', (11, 16))	('TLE2', 'Gene', '7089', (36, 40))	('TLE2', 'Gene', (36, 40))	('knock-down', 'Var', (17, 27))	('upregulation', 'PosReg', (41, 53))
293228	27414086	To determine whether NDRG1 overexpression or knock-down impacts TLE2 protein expression, we used western blot analysis to assess TLE2 expression.	('TLE2', 'Gene', '7089', (129, 133))	('TLE2', 'Gene', (129, 133))	('TLE2', 'Gene', '7089', (64, 68))	('protein', 'Protein', (69, 76))	('knock-down', 'Var', (45, 55))	('TLE2', 'Gene', (64, 68))	('NDRG1', 'Gene', (21, 26))	('impacts', 'Reg', (56, 63))
293229	27414086	4A, NDRG1 overexpression and knock-down altered TLE2 expression at the protein level in KYSE 30 cells.	('NDRG1', 'Gene', (4, 9))	('TLE2', 'Gene', '7089', (48, 52))	('altered', 'Reg', (40, 47))	('expression', 'MPA', (53, 63))	('knock-down', 'Var', (29, 39))	('TLE2', 'Gene', (48, 52))
293234	27414086	3F, we found that beta-catenin was enriched in both the cytosolic and nuclear fractions; in contrast, the inverse was found for TLE2, which was greatly decreased in the nuclear fraction after NDRG1 overexpression compared with the control group.	('TLE2', 'Gene', (128, 132))	('beta-catenin', 'Gene', (18, 30))	('beta-catenin', 'Gene', '1499', (18, 30))	('decreased', 'NegReg', (152, 161))	('overexpression', 'Var', (198, 212))	('NDRG1', 'Gene', (192, 197))	('TLE2', 'Gene', '7089', (128, 132))
293240	27414086	Together, these data indicate that NDRG1 overexpression promotes the activation of the Wnt signaling pathway, through increased beta-catenin and decreased TLE2.	('NDRG1', 'Gene', (35, 40))	('overexpression', 'Var', (41, 55))	('TLE2', 'Gene', (155, 159))	('beta-catenin', 'Gene', (128, 140))	('Wnt signaling pathway', 'Pathway', (87, 108))	('beta-catenin', 'Gene', '1499', (128, 140))	('increased', 'PosReg', (118, 127))	('decreased', 'NegReg', (145, 154))	('TLE2', 'Gene', '7089', (155, 159))
293241	27414086	To examine whether NDRG1 ectopic overexpression could affect tumor growth in vivo, we performed in vivo experiments via subcutaneous transplantation of transduced cells into nude mice, whereby we compared tumor growth rates induced by KYSE 30-Vec and KYSE 30-NDRG1 cells in a xenograft model.	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('NDRG1', 'Gene', (19, 24))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('nude mice', 'Species', '10090', (174, 183))	('ectopic', 'Var', (25, 32))	('tumor', 'Disease', (205, 210))	('affect', 'Reg', (54, 60))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumor', 'Disease', (61, 66))
293242	27414086	5A, the tumor growth rate of KYSE 30-NDRG1 cells was significantly faster than that of KYSE 30-Vec cells 20 d after inoculation by subcutaneous injection.	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('tumor', 'Disease', (8, 13))	('faster', 'PosReg', (67, 73))	('KYSE 30-NDRG1', 'Var', (29, 42))
293246	27414086	Our previous data showed that NDRG1 overexpression reduced TLE2 and affected the Wnt signaling pathway.	('reduced', 'NegReg', (51, 58))	('Wnt signaling pathway', 'Pathway', (81, 102))	('affected', 'Reg', (68, 76))	('NDRG1', 'Gene', (30, 35))	('TLE2', 'Gene', '7089', (59, 63))	('TLE2', 'Gene', (59, 63))	('overexpression', 'Var', (36, 50))
293247	27414086	To further investigate whether NDRG1 overexpression could impact the Wnt signaling pathway, we analyzed the expression of TLE2, beta-catenin and E-cadherin.	('NDRG1', 'Gene', (31, 36))	('E-cadherin', 'Gene', '999', (145, 155))	('beta-catenin', 'Gene', (128, 140))	('beta-catenin', 'Gene', '1499', (128, 140))	('Wnt signaling pathway', 'Pathway', (69, 90))	('impact', 'Reg', (58, 64))	('TLE2', 'Gene', '7089', (122, 126))	('TLE2', 'Gene', (122, 126))	('overexpression', 'Var', (37, 51))	('E-cadherin', 'Gene', (145, 155))
293269	27414086	TLE2 expression results in transcriptional repression of specific gene regulatory sequences, via the recruitment of Groucho.	('results in', 'Reg', (16, 26))	('expression', 'Var', (5, 15))	('TLE2', 'Gene', '7089', (0, 4))	('transcriptional repression', 'MPA', (27, 53))	('TLE2', 'Gene', (0, 4))
293271	27414086	Other reports have shown that the modification of TLE by XIAP-mediated ubiquitylation decreases its affinity with beta-catenin, thereby allowing the formation of the beta-catenin/TCF complex and thus the switch to an activated Wnt signaling pathway.	('beta-catenin', 'Gene', (114, 126))	('TCF', 'Gene', (179, 182))	('TCF', 'Gene', '3172', (179, 182))	('beta-catenin', 'Gene', (166, 178))	('XIAP', 'Gene', '331', (57, 61))	('formation', 'Interaction', (149, 158))	('TLE', 'Disease', 'MESH:D004833', (50, 53))	('beta-catenin', 'Gene', '1499', (114, 126))	('TLE', 'Disease', (50, 53))	('modification', 'Var', (34, 46))	('decreases', 'NegReg', (86, 95))	('beta-catenin', 'Gene', '1499', (166, 178))	('activated Wnt signaling pathway', 'Pathway', (217, 248))	('allowing', 'Reg', (136, 144))	('XIAP', 'Gene', (57, 61))	('switch', 'Reg', (204, 210))	('affinity', 'Interaction', (100, 108))
293290	34013188	All samples that were tested for EGFR mutation and ALK rearrangement were adequate for analysis.	('men', 'Species', '9606', (64, 67))	('mutation', 'Var', (38, 46))	('EGFR', 'Gene', (33, 37))
293300	34013188	The first druggable target identified in NSCLC was the EGFR mutation, with a higher prevalence reported in Asian population, females and never-smokers.	('mutation', 'Var', (60, 68))	('NSCLC', 'Disease', (41, 46))	('EGFR', 'Gene', (55, 59))	('NSCLC', 'Disease', 'MESH:D002289', (41, 46))	('NSCLC', 'Phenotype', 'HP:0030358', (41, 46))
293312	34013188	A recent study found an adequacy ratio of 88.6% and 93.8% for EGFR mutation, respectively ALK rearrangement.	('men', 'Species', '9606', (103, 106))	('EGFR', 'Gene', (62, 66))	('mutation', 'Var', (67, 75))
293330	34013188	For activating EGFR mutations analysis (exons 18-21) on small biopsies, 5-10 mum sections were prepared from the paraffin block, of which two of them were hematoxylin and eosin (H&E) stained, in order to evaluate the existence and quantity of tumor cells.	('H&E', 'Chemical', '-', (178, 181))	('activating', 'PosReg', (4, 14))	('tumor', 'Disease', 'MESH:D009369', (243, 248))	('hematoxylin', 'Chemical', 'MESH:D006416', (155, 166))	('EGFR', 'Gene', (15, 19))	('eosin', 'Chemical', 'MESH:D004801', (171, 176))	('paraffin', 'Chemical', 'MESH:D010232', (113, 121))	('mutations', 'Var', (20, 29))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))	('tumor', 'Disease', (243, 248))
293356	34013188	Two of the analyzed specimens harbored EGFR mutations (9.09%), namely L858R substitution in exon 21 and E746-A750del in exon 19.	('E746-A750del', 'Mutation', 'p.746,750delA', (104, 116))	('E746-A750del', 'Var', (104, 116))	('L858R substitution', 'Var', (70, 88))	('L858R', 'Mutation', 'rs121434568', (70, 75))	('men', 'Species', '9606', (25, 28))
293381	34013188	Two patients (9.09%) with adenocarcinoma harbored an EGFR mutation, namely L858R substitution and E746-A750del.	('L858R substitution', 'Var', (75, 93))	('L858R', 'Mutation', 'rs121434568', (75, 80))	('adenocarcinoma', 'Disease', (26, 40))	('E746-A750del', 'Var', (98, 110))	('adenocarcinoma', 'Disease', 'MESH:D000230', (26, 40))	('E746-A750del', 'Mutation', 'p.746,750delA', (98, 110))	('patients', 'Species', '9606', (4, 12))	('EGFR', 'Gene', (53, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (31, 40))
293386	34013188	As EGFR mutation and EML4-ALK rearrangement represent mutually exclusive alterations, FISH testing for ALK could be performed for lung adenocarcinomas with wild-type EGFR.	('EGFR', 'Gene', (3, 7))	('EML4', 'Gene', (21, 25))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (130, 149))	('EML4', 'Gene', '27436', (21, 25))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (130, 150))	('lung adenocarcinomas', 'Disease', (130, 150))	('mutation', 'Var', (8, 16))	('men', 'Species', '9606', (39, 42))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (130, 150))	('carcinomas', 'Phenotype', 'HP:0030731', (140, 150))
293407	34013188	This is the first report regarding the efficacy of mutational analysis on EBUS-TBNA small samples, obtained from patients with NSCLC, in Romania.	('NSCLC', 'Disease', (127, 132))	('NSCLC', 'Disease', 'MESH:D002289', (127, 132))	('patients', 'Species', '9606', (113, 121))	('EBUS-TBNA', 'Gene', (74, 83))	('mutational analysis', 'Var', (51, 70))	('Romania', 'Disease', (137, 144))	('NSCLC', 'Phenotype', 'HP:0030358', (127, 132))	('EBUS-TBNA', 'Chemical', '-', (74, 83))
293439	32280301	Moreover, 13 studies provided cut-off definitions for high or low GHET1 expression groups, including the median and median ratio.	('GHET1', 'Gene', (66, 71))	('high', 'Var', (54, 58))	('low', 'NegReg', (62, 65))	('expression', 'MPA', (72, 82))	('GHET1', 'Gene', '102723099', (66, 71))
293445	32280301	The pooled HR for the high GHET1 expression group versus the low group was 2.037 (95% CI 1.626-2.551, P < 0.001).	('high', 'Var', (22, 26))	('GHET1', 'Gene', '102723099', (27, 32))	('GHET1', 'Gene', (27, 32))
293446	32280301	This pooled result indicates a significant association between overexpressed GHET1 and poor OS.	('poor OS', 'Disease', (87, 94))	('GHET1', 'Gene', '102723099', (77, 82))	('GHET1', 'Gene', (77, 82))	('overexpressed', 'Var', (63, 76))
293453	32280301	Compared to low GHET1 expression, high GHET1 expression level was statistically correlated with larger tumor size (P < 0.001, fixed model), positive lymph node metastasis (P < 0.001, fixed model), positive distant metastasis (P < 0.001, fixed model), and advanced clinical stage (P < 0.001, fixed model).	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('GHET1', 'Gene', '102723099', (39, 44))	('tumor', 'Disease', (103, 108))	('GHET1', 'Gene', '102723099', (16, 21))	('GHET1', 'Gene', (39, 44))	('advanced clinical stage', 'CPA', (255, 278))	('high', 'Var', (34, 38))	('expression', 'MPA', (45, 55))	('GHET1', 'Gene', (16, 21))	('positive distant metastasis', 'CPA', (197, 224))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('positive lymph node metastasis', 'CPA', (140, 170))
293473	32280301	Many studies have tried to illustrate the correlation between high GHET1 expression and cancer prognosis; however, the molecular mechanism of GHET1 remained unclear.	('GHET1', 'Gene', '102723099', (142, 147))	('GHET1', 'Gene', (142, 147))	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('GHET1', 'Gene', '102723099', (67, 72))	('expression', 'MPA', (73, 83))	('GHET1', 'Gene', (67, 72))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('high', 'Var', (62, 66))
293477	32280301	Moreover, upregulation of GHET1 could be induced by hypoxia in gastric cancer cells, and the depletion of GHET1 c significantly enhanced the CpG island methylation of EGFR, which plays a crucial role in the metastasis of cancers.	('cancers', 'Disease', 'MESH:D009369', (221, 228))	('enhanced', 'PosReg', (128, 136))	('GHET1', 'Gene', '102723099', (106, 111))	('GHET1', 'Gene', (106, 111))	('hypoxia', 'Disease', 'MESH:D000860', (52, 59))	('gastric cancer', 'Disease', (63, 77))	('GHET1', 'Gene', '102723099', (26, 31))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('GHET1', 'Gene', (26, 31))	('EGFR', 'Gene', (167, 171))	('cancers', 'Phenotype', 'HP:0002664', (221, 228))	('gastric cancer', 'Disease', 'MESH:D013274', (63, 77))	('CpG island methylation', 'MPA', (141, 163))	('cancers', 'Disease', (221, 228))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('gastric cancer', 'Phenotype', 'HP:0012126', (63, 77))	('EGFR', 'Gene', '1956', (167, 171))	('hypoxia', 'Disease', (52, 59))	('depletion', 'Var', (93, 102))	('upregulation', 'PosReg', (10, 22))
293482	32280301	revealed that GHET1 depletion inhibited the proliferation, invasion, and epithelial-mesenchymal transition (EMT) of cancer cells by inhibiting the LATS1/YAP pathway.	('GHET1', 'Gene', (14, 19))	('YAP', 'Gene', '10413', (153, 156))	('GHET1', 'Gene', '102723099', (14, 19))	('cancer', 'Disease', (116, 122))	('inhibited', 'NegReg', (30, 39))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('LATS1', 'Gene', (147, 152))	('depletion', 'Var', (20, 29))	('YAP', 'Gene', (153, 156))	('invasion', 'CPA', (59, 67))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('inhibiting', 'NegReg', (132, 142))	('LATS1', 'Gene', '9113', (147, 152))
293497	28423489	In terms of prognostic features, a survival analysis revealed that the high GBE1 and HK2 expression group exhibited poorer survival in lung adenocarcinoma patients.	('GBE1', 'Gene', (76, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (145, 154))	('high', 'Var', (71, 75))	('lung adenocarcinoma', 'Disease', (135, 154))	('GBE1', 'Gene', '2632', (76, 80))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (135, 154))	('HK2', 'Gene', (85, 88))	('patients', 'Species', '9606', (155, 163))	('poorer', 'NegReg', (116, 122))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (135, 154))
293502	28423489	To clarify this possibility, we utilized a hospital-based database to examine whether the presence of OSAS increased lung cancer incidence and risk of progression or mortality from cancer.	('presence', 'Var', (90, 98))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('OSAS increased lung cancer', 'Disease', 'MESH:D008175', (102, 128))	('OSAS increased lung cancer', 'Disease', (102, 128))	('lung cancer', 'Phenotype', 'HP:0100526', (117, 128))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('cancer', 'Disease', (181, 187))
293506	28423489	In recent years, several cohort studies unravel potential associations between OSAS and cancers, suggesting that patients with OSAS increase risks for developing solid tumors and promoting adverse cancer outcomes.	('solid tumors', 'Disease', 'MESH:D009369', (162, 174))	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('OSAS', 'Var', (127, 131))	('patients', 'Species', '9606', (113, 121))	('cancers', 'Disease', 'MESH:D009369', (88, 95))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('adverse cancer', 'Disease', 'MESH:D064420', (189, 203))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('cancers', 'Disease', (88, 95))	('solid tumors', 'Disease', (162, 174))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('promoting', 'PosReg', (179, 188))	('adverse cancer', 'Disease', (189, 203))
293555	28423489	The survival analysis revealed that in lung adenocarcinoma patients, the ones with high expression of GBE1 and HK2 represented shorter overall survival than those with low expression of GBE1 (P=0.0332) and HK2 (P=0.0246), evidence supporting an association between these genes and cancer survival (Figure 4).	('shorter', 'NegReg', (127, 134))	('cancer', 'Phenotype', 'HP:0002664', (281, 287))	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('HK2', 'Gene', (111, 114))	('GBE1', 'Gene', (186, 190))	('cancer', 'Disease', 'MESH:D009369', (281, 287))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (39, 58))	('cancer', 'Disease', (281, 287))	('overall survival', 'MPA', (135, 151))	('GBE1', 'Gene', '2632', (186, 190))	('GBE1', 'Gene', (102, 106))	('high expression', 'Var', (83, 98))	('patients', 'Species', '9606', (59, 67))	('lung adenocarcinoma', 'Disease', (39, 58))	('GBE1', 'Gene', '2632', (102, 106))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (39, 58))
293590	28423489	Furthermore, a significant association emerged between expressions of GBE1/HK2 and the lung adenocarcinoma, but not lung squamous carcinoma in our analysis.	('GBE1', 'Gene', (70, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('lung squamous carcinoma', 'Phenotype', 'HP:0030359', (116, 139))	('lung adenocarcinoma', 'Disease', (87, 106))	('lung squamous carcinoma', 'Disease', 'MESH:D002294', (116, 139))	('GBE1', 'Gene', '2632', (70, 74))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (87, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('lung squamous carcinoma', 'Disease', (116, 139))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (121, 139))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (87, 106))	('expressions', 'Var', (55, 66))
293595	28423489	In lung cancer cell lines, HK2 was required for the human and mouse lung cancer cell growth; inhibition of HK2 inhibited human and mouse lung cancer cell growth through inducing cell apoptosis and autophagy.	('HK2', 'Gene', (107, 110))	('lung cancer', 'Phenotype', 'HP:0100526', (68, 79))	('lung cancer', 'Phenotype', 'HP:0100526', (3, 14))	('cell apoptosis', 'CPA', (178, 192))	('human', 'Species', '9606', (121, 126))	('lung cancer', 'Disease', 'MESH:D008175', (137, 148))	('mouse', 'Species', '10090', (62, 67))	('lung cancer', 'Phenotype', 'HP:0100526', (137, 148))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('autophagy', 'CPA', (197, 206))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('lung cancer', 'Disease', (68, 79))	('lung cancer', 'Disease', (3, 14))	('mouse', 'Species', '10090', (131, 136))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('inducing', 'NegReg', (169, 177))	('inhibited', 'NegReg', (111, 120))	('lung cancer', 'Disease', (137, 148))	('human', 'Species', '9606', (52, 57))	('lung cancer', 'Disease', 'MESH:D008175', (68, 79))	('lung cancer', 'Disease', 'MESH:D008175', (3, 14))	('inhibition', 'Var', (93, 103))
293597	28423489	Our work presents evidence that alteration of HIF1 in lung cancer cells is associated with HK2 and GBE1.	('lung cancer', 'Disease', (54, 65))	('alteration', 'Var', (32, 42))	('lung cancer', 'Phenotype', 'HP:0100526', (54, 65))	('HIF1', 'Gene', (46, 50))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('lung cancer', 'Disease', 'MESH:D008175', (54, 65))	('GBE1', 'Gene', (99, 103))	('HK2', 'Protein', (91, 94))	('HIF1', 'Gene', '3091', (46, 50))	('associated', 'Reg', (75, 85))	('GBE1', 'Gene', '2632', (99, 103))
293641	25374456	Such methods have revealed that despite the heterogeneity in mutations across tumor samples, many of these mutations are in genes that represent a common pathway or process.	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('mutations', 'Var', (107, 116))	('tumor', 'Disease', (78, 83))
293643	25374456	It was found that cancers can be grouped into those driven by copy number variations and those driven by somatic mutations.	('cancers', 'Disease', (18, 25))	('cancers', 'Disease', 'MESH:D009369', (18, 25))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('copy number variations', 'Var', (62, 84))	('cancers', 'Phenotype', 'HP:0002664', (18, 25))	('driven', 'Reg', (52, 58))
293685	25374456	MERLIN combines the strengths of two popular network inference strategies, "per-gene", which infers regulators for each gene individually, and "per-module", which infers a common set of regulators for an entire module.	('per-module', 'Var', (144, 154))	('MERLIN', 'Gene', '4771', (0, 6))	('MERLIN', 'Gene', (0, 6))
293745	25374456	In contrast to that example, a novel mutation in RFX-AP (another member of the RFX complex) has been connected to the loss of expression for MHC class II genes in diffuse large-B-cell lymphoma, which is also a known biomarker for decreased patient survival of that disease.	('RFX-AP', 'Gene', (49, 55))	('RFX', 'Gene', (79, 82))	('MHC class II', 'Gene', (141, 153))	('RFX', 'Gene', (49, 52))	('expression', 'MPA', (126, 136))	('mutation', 'Var', (37, 45))	('lymphoma', 'Phenotype', 'HP:0002665', (184, 192))	('loss of', 'NegReg', (118, 125))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (177, 192))	('patient', 'Species', '9606', (240, 247))	('RFX-AP', 'Gene', '5994', (49, 55))	('RFX', 'Gene', '5989', (79, 82))	('lymphoma', 'Disease', (184, 192))	('RFX', 'Gene', '5989', (49, 52))	('lymphoma', 'Disease', 'MESH:D008223', (184, 192))
293748	25374456	In fact, splice variants of the RFX4 gene that are specifically associated with glioma cancer cells have been identified, and RFX 1 has itself been identified as a tumor suppressor gene in glioblastoma.	('associated', 'Reg', (64, 74))	('tumor', 'Disease', (164, 169))	('glioma cancer', 'Disease', 'MESH:D005910', (80, 93))	('RFX4', 'Gene', '5992', (32, 36))	('RFX 1', 'Gene', (126, 131))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('glioblastoma', 'Disease', (189, 201))	('glioma', 'Phenotype', 'HP:0009733', (80, 86))	('glioblastoma', 'Disease', 'MESH:D005909', (189, 201))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('RFX4', 'Gene', (32, 36))	('splice variants', 'Var', (9, 24))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('glioma cancer', 'Disease', (80, 93))	('RFX 1', 'Gene', '5989', (126, 131))	('glioblastoma', 'Phenotype', 'HP:0012174', (189, 201))
293757	25374456	Mutations in the EP300 protein have been associated with several cancers, including colon and breast cancer.	('associated', 'Reg', (41, 51))	('EP300', 'Gene', '2033', (17, 22))	('EP300', 'Gene', (17, 22))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('colon and breast cancer', 'Disease', 'MESH:D001943', (84, 107))	('Mutations', 'Var', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('cancers', 'Disease', 'MESH:D009369', (65, 72))	('cancers', 'Phenotype', 'HP:0002664', (65, 72))	('breast cancer', 'Phenotype', 'HP:0003002', (94, 107))	('cancers', 'Disease', (65, 72))
293781	25374456	These genes might influence the cancerous state in different cancers through the same mechanisms.	('genes', 'Var', (6, 11))	('cancerous', 'Disease', (32, 41))	('cancers', 'Disease', 'MESH:D009369', (61, 68))	('cancers', 'Phenotype', 'HP:0002664', (61, 68))	('cancers', 'Disease', (61, 68))	('influence', 'Reg', (18, 27))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('cancerous', 'Disease', 'MESH:D009369', (32, 41))
293826	31707148	Additionally, Rab8 overexpression was also found to increase Klotho-mediated inhibition of NSCLC tumorigenesis in vivo.	('Rab8', 'Gene', '4218', (14, 18))	('NSCLC', 'Phenotype', 'HP:0030358', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('increase', 'PosReg', (52, 60))	('inhibition', 'NegReg', (77, 87))	('Klotho-mediated', 'MPA', (61, 76))	('overexpression', 'Var', (19, 33))	('NSCLC tumorigenesis', 'Disease', 'MESH:D063646', (91, 110))	('NSCLC tumorigenesis', 'Disease', (91, 110))	('Rab8', 'Gene', (14, 18))
293844	31707148	Specifically, Klotho inhibits activation of the Wnt-TCF/beta-catenin signaling pathway, leading to decreased expression of target genes such as c-Myc and Cyclin D1, thereby inhibiting cancer cell development and progression.	('cancer', 'Disease', (184, 190))	('decreased', 'NegReg', (99, 108))	('Klotho', 'Var', (14, 20))	('TCF', 'Gene', (52, 55))	('as c', 'Gene', (141, 145))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('inhibits', 'NegReg', (21, 29))	('c-Myc', 'Gene', (144, 149))	('beta-catenin', 'Gene', (56, 68))	('beta-catenin', 'Gene', '1499', (56, 68))	('c-Myc', 'Gene', '4609', (144, 149))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('TCF', 'Gene', '3172', (52, 55))	('progression', 'CPA', (212, 223))	('expression', 'MPA', (109, 119))	('Cyclin D1', 'Gene', '595', (154, 163))	('as c', 'Gene', '29108', (141, 145))	('inhibiting', 'NegReg', (173, 183))	('Cyclin D1', 'Gene', (154, 163))
293845	31707148	We have also previously first reported the role of Klotho in the pathogenesis of human lung cancer, showing that ectopic Klotho expression can inhibit lung cancer proliferation and motility, and trigger apoptosis by modulating IGF-1/insulin signaling and the Wnt signaling pathway.	('ectopic', 'Var', (113, 120))	('Klotho', 'Gene', (121, 127))	('inhibit', 'NegReg', (143, 150))	('lung cancer', 'Disease', (87, 98))	('Wnt signaling pathway', 'Pathway', (259, 280))	('IGF-1', 'Gene', (227, 232))	('human', 'Species', '9606', (81, 86))	('trigger', 'PosReg', (195, 202))	('modulating', 'Reg', (216, 226))	('apoptosis', 'CPA', (203, 212))	('insulin', 'Gene', (233, 240))	('lung cancer proliferation', 'Disease', 'MESH:D008175', (151, 176))	('IGF-1', 'Gene', '3479', (227, 232))	('lung cancer', 'Disease', 'MESH:D008175', (151, 162))	('lung cancer proliferation', 'Disease', (151, 176))	('lung cancer', 'Disease', 'MESH:D008175', (87, 98))	('lung cancer', 'Phenotype', 'HP:0100526', (151, 162))	('lung cancer', 'Phenotype', 'HP:0100526', (87, 98))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('insulin', 'Gene', '3630', (233, 240))
293897	31707148	In every experiment, including TrkB-FL and all the mutants, a consistent set of acquisition parameters was used for each set of images.	('TrkB', 'Gene', '4915', (31, 35))	('TrkB', 'Gene', (31, 35))	('mutants', 'Var', (51, 58))
293909	31707148	Then, cells were rewarmed with DMEM at 37  C for 30 min followed by three quick washes with cold PBS containing EDTA (1 mM) to dissociate the A488-M1 bound to un-internalized Klotho.	('A488-M1', 'Var', (142, 149))	('EDTA', 'Chemical', 'MESH:D004492', (112, 116))	('bound', 'Interaction', (150, 155))
293928	31707148	cBioPortal was used to examine multiple gene alterations, mutations and amplifications of klotho in the same NSCLC datasets.	('mutations', 'Var', (58, 67))	('NSCLC', 'Disease', 'MESH:D002289', (109, 114))	('klotho', 'Gene', '9365', (90, 96))	('amplifications', 'Var', (72, 86))	('NSCLC', 'Phenotype', 'HP:0030358', (109, 114))	('klotho', 'Gene', (90, 96))	('NSCLC', 'Disease', (109, 114))
293929	31707148	In NSCLC, 3% patients had mutations or deletions (Fig.	('NSCLC', 'Disease', (3, 8))	('deletions', 'Var', (39, 48))	('NSCLC', 'Disease', 'MESH:D002289', (3, 8))	('patients', 'Species', '9606', (13, 21))	('mutations', 'Var', (26, 35))	('NSCLC', 'Phenotype', 'HP:0030358', (3, 8))
293930	31707148	Interestingly, when browsing the common mutations of klotho in NSCLC genomic datasets, we found that klotho T968P or its near-neighbor is a mutational hotspot (Fig.	('NSCLC', 'Disease', (63, 68))	('klotho', 'Gene', (53, 59))	('klotho', 'Gene', (101, 107))	('NSCLC', 'Disease', 'MESH:D002289', (63, 68))	('T968P', 'Mutation', 'rs1260157369', (108, 113))	('klotho', 'Gene', '9365', (53, 59))	('T968P', 'Var', (108, 113))	('klotho', 'Gene', '9365', (101, 107))	('NSCLC', 'Phenotype', 'HP:0030358', (63, 68))
293932	31707148	The Kaplan-Meier survival curve for the overall lung cancer patients with low or high Klotho expression is shown in Supplementary Fig.	('low', 'NegReg', (74, 77))	('patients', 'Species', '9606', (60, 68))	('high', 'Var', (81, 85))	('overall lung cancer', 'Disease', (40, 59))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('Klotho', 'Protein', (86, 92))	('overall lung cancer', 'Disease', 'MESH:D008175', (40, 59))	('lung cancer', 'Phenotype', 'HP:0100526', (48, 59))
293955	31707148	We first constructed several small interfering RNAs (siRNAs) targeting Rab8 (siRab8) to knock down endogenous Rab8 (Fig.	('Rab8', 'Gene', (79, 83))	('Rab8', 'Gene', (110, 114))	('Rab8', 'Gene', '4218', (79, 83))	('Rab8', 'Gene', '4218', (110, 114))	('knock down', 'Var', (88, 98))	('Rab8', 'Gene', (71, 75))	('Rab8', 'Gene', '4218', (71, 75))
293956	31707148	As shown, the #1 and #3 Rab8 siRNA transfection reduced about 85% and 91% endogenous Rab8 protein, respectively, as detected by western blot analyses (n = 3, *p < 0.05, Student's t-test, Fig.	('protein', 'Protein', (90, 97))	('reduced', 'NegReg', (48, 55))	('transfection', 'Var', (35, 47))	('Rab8', 'Gene', (85, 89))	('Rab8', 'Gene', '4218', (85, 89))	('endogenous', 'MPA', (74, 84))	('Rab8', 'Gene', (24, 28))	('Rab8', 'Gene', '4218', (24, 28))
293957	31707148	Thus, we mainly used siRab8-3 to explore knockdown effects of Rab8 in this study (thus henceforth siRab8 is used to refer to siRab8-3).	('Rab8', 'Gene', '4218', (100, 104))	('Rab8', 'Gene', '4218', (62, 66))	('Rab8', 'Gene', (23, 27))	('Rab8', 'Gene', (127, 131))	('Rab8', 'Gene', '4218', (23, 27))	('Rab8', 'Gene', '4218', (127, 131))	('knockdown', 'Var', (41, 50))	('Rab8', 'Gene', (100, 104))	('Rab8', 'Gene', (62, 66))
293972	31707148	In order to address this question, we detected the medium Klotho (shedded from membrane) upon Rab8 overexpression or knocking down according to previous report.	('Rab8', 'Gene', (94, 98))	('overexpression', 'PosReg', (99, 113))	('knocking down', 'Var', (117, 130))	('Rab8', 'Gene', '4218', (94, 98))
293977	31707148	The results reveal that knockdown of Rab8 by siRNA significantly reduces cell surface levels of Klotho (Fig.	('cell surface levels of Klotho', 'MPA', (73, 102))	('reduces', 'NegReg', (65, 72))	('Rab8', 'Gene', (37, 41))	('Rab8', 'Gene', '4218', (37, 41))	('knockdown', 'Var', (24, 33))
293987	31707148	S3, we found Rab8 TN mutants could trap KL in Golgi.	('Rab8', 'Gene', '4218', (13, 17))	('KL in Golgi', 'MPA', (40, 51))	('TN mutants', 'Var', (18, 28))	('Rab8', 'Gene', (13, 17))
294009	31707148	5e and f, lung cancer cells with ectopic expression of Klotho displayed a significant decrease of invasion efficiency in NC group; whereas in the Rab8 overexpression group, Klotho overexpression inhibited the invasiveness ability of lung cancer cells more significantly.	('invasiveness ability of lung cancer', 'Disease', (209, 244))	('ectopic expression', 'Var', (33, 51))	('Rab8', 'Gene', (146, 150))	('invasion efficiency', 'CPA', (98, 117))	('lung cancer', 'Phenotype', 'HP:0100526', (233, 244))	('inhibited', 'NegReg', (195, 204))	('Rab8', 'Gene', '4218', (146, 150))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('lung cancer', 'Disease', (10, 21))	('Klotho', 'Gene', (55, 61))	('invasiveness ability of lung cancer', 'Disease', 'MESH:D008175', (209, 244))	('lung cancer', 'Phenotype', 'HP:0100526', (10, 21))	('lung cancer', 'Disease', 'MESH:D008175', (233, 244))	('decrease', 'NegReg', (86, 94))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('lung cancer', 'Disease', 'MESH:D008175', (10, 21))
294014	31707148	E-Cadherin was upregulated in both A549 and H1299 cells transfected with FLAG-KL compared to control cells, while co-transfection with siRab8 blocked this response.	('upregulated', 'PosReg', (15, 26))	('A549', 'CellLine', 'CVCL:0023', (35, 39))	('Rab8', 'Gene', (137, 141))	('FLAG-KL', 'Var', (73, 80))	('E-Cadherin', 'Gene', (0, 10))	('H1299', 'CellLine', 'CVCL:0060', (44, 49))	('Rab8', 'Gene', '4218', (137, 141))	('E-Cadherin', 'Gene', '999', (0, 10))
294020	31707148	Thus, we explored whether Rab8 knockdown affects Wnt signaling induced by Klotho overexpression in A549 and H1299 cells.	('A549', 'CellLine', 'CVCL:0023', (99, 103))	('Klotho', 'Gene', (74, 80))	('H1299', 'CellLine', 'CVCL:0060', (108, 113))	('overexpression', 'PosReg', (81, 95))	('Wnt signaling', 'MPA', (49, 62))	('Rab8', 'Gene', (26, 30))	('Rab8', 'Gene', '4218', (26, 30))	('knockdown', 'Var', (31, 40))
294021	31707148	6c and d, in the siNC group, Klotho could reduce the expression levels of active beta-catenin and Wnt3a; while in siRab8 group, we found that Rab8 knockdown by siRNA almost abolishes this effect.	('Wnt3a', 'Gene', (98, 103))	('beta-catenin', 'Gene', '1499', (81, 93))	('Rab8', 'Gene', (142, 146))	('Rab8', 'Gene', '4218', (142, 146))	('abolishes', 'NegReg', (173, 182))	('reduce', 'NegReg', (42, 48))	('Rab8', 'Gene', (116, 120))	('beta-catenin', 'Gene', (81, 93))	('expression levels', 'MPA', (53, 70))	('Rab8', 'Gene', '4218', (116, 120))	('knockdown', 'Var', (147, 156))	('Wnt3a', 'Gene', '89780', (98, 103))
294026	31707148	Alternatively, Rab8 knockdown did not affect IGF-1 signaling or p53 levels affected by Klotho overexpression in A549 cells (Supplementary Fig.	('A549', 'CellLine', 'CVCL:0023', (112, 116))	('Rab8', 'Gene', (15, 19))	('Rab8', 'Gene', '4218', (15, 19))	('knockdown', 'Var', (20, 29))	('p53', 'Gene', (64, 67))	('IGF-1', 'Gene', '3479', (45, 50))	('IGF-1', 'Gene', (45, 50))	('p53', 'Gene', '7157', (64, 67))
294035	31707148	7c, we found that, with Rab8 overexpression, Klotho was expressed to a greater extent on the surface when compared with KL-infected only group.	('overexpression', 'Var', (29, 43))	('Rab8', 'Gene', (24, 28))	('Rab8', 'Gene', '4218', (24, 28))
294040	31707148	Functional impairments of Rab proteins have been implicated in tumorigenesis, including Rab1, Rab2A, Rab3 D, Rab8 and others.	('Rab2A', 'Gene', '5862', (94, 99))	('Rab3 D', 'Gene', '9545', (101, 107))	('Rab3 D', 'Gene', (101, 107))	('Rab', 'Gene', (109, 112))	('Rab', 'Gene', '3267', (101, 104))	('Rab', 'Gene', (101, 104))	('Rab2A', 'Gene', (94, 99))	('impairments', 'Var', (11, 22))	('Rab8', 'Gene', (109, 113))	('Rab1', 'Gene', (88, 92))	('Rab', 'Gene', '3267', (26, 29))	('implicated', 'Reg', (49, 59))	('tumor', 'Disease', (63, 68))	('Rab', 'Gene', (26, 29))	('Rab', 'Gene', '3267', (109, 112))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('Rab', 'Gene', '3267', (88, 91))	('Rab1', 'Gene', '5861', (88, 92))	('Rab', 'Gene', (88, 91))	('Rab8', 'Gene', '4218', (109, 113))	('Rab', 'Gene', '3267', (94, 97))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('Rab', 'Gene', (94, 97))
294056	31707148	Additionally, our results also showed that, when treated with BFA, Rab8 failed to affect the surface expression of Klotho, while Rab8 TN mutants could trap KL in Golgi.	('BFA', 'Chemical', 'MESH:C524118', (62, 65))	('Rab8', 'Gene', (129, 133))	('trap KL in Golgi', 'MPA', (151, 167))	('Rab8', 'Gene', '4218', (129, 133))	('Rab8', 'Gene', (67, 71))	('TN mutants', 'Var', (134, 144))	('Rab8', 'Gene', '4218', (67, 71))
294072	30760860	The following numbers of cases were evaluated: 22C3 with tumor proportion score [n = 52585], 22C3 with combined positive score [n = 2631], 28-8 [n = 4191], SP142 [n = 850], and SP263 [n = 70].	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('SP263 [', 'Var', (177, 184))	('SP142 [', 'Var', (156, 163))	('tumor', 'Disease', (57, 62))
294073	30760860	In 22C3/tumor proportion score cases, the general results were as follows: negative 33.1% (n = 17,405), (low) expression 33.9% (n = 17,822), and high expression 29.5% (n = 15,486).	('negative', 'NegReg', (75, 83))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('tumor', 'Disease', (8, 13))	('high', 'Var', (145, 149))
294104	30760860	In 22C3/tumor proportion score scored cases, the general results were as follows: negative 33.1% (n = 17,405), (low) expression 33.9% (n = 17,822), and high expression 29.5% (n = 15,486) [Table 6].	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('high', 'Var', (152, 156))	('tumor', 'Disease', (8, 13))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))
294174	31423110	Knocking down the RASSF-1A gene in SCC9 cells promotes cell migration and proliferation, while reducing apoptosis and increasing CyclinD1 protein expression.	('increasing', 'PosReg', (118, 128))	('Knocking down', 'Var', (0, 13))	('SCC9', 'CellLine', 'CVCL:1685', (35, 39))	('promotes', 'PosReg', (46, 54))	('cell migration', 'CPA', (55, 69))	('RASSF-1A', 'Gene', (18, 26))	('proliferation', 'CPA', (74, 87))	('apoptosis', 'CPA', (104, 113))	('reducing', 'NegReg', (95, 103))	('CyclinD1 protein expression', 'MPA', (129, 156))
294183	31423110	Usually, cancer begins with a single cell mutation in a somatic cell that leads to further proliferation, which activates the protooncogene and becomes an oncogene.	('cancer', 'Disease', (9, 15))	('further proliferation', 'CPA', (83, 104))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('activates', 'PosReg', (112, 121))	('mutation', 'Var', (42, 50))	('leads to', 'Reg', (74, 82))	('protooncogene', 'MPA', (126, 139))	('cancer', 'Disease', 'MESH:D009369', (9, 15))
294186	31423110	If epigenetic modification abnormalities in somatic cells lead to abnormal expression of certain genes, such as oncogene activation and tumor suppressor gene inactivation, abnormal proliferation of somatic cells.	('abnormal proliferation', 'CPA', (172, 194))	('oncogene activation', 'Gene', (112, 131))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('epigenetic modification abnormalities', 'Var', (3, 40))	('lead to abnormal', 'Reg', (58, 74))	('tumor', 'Disease', (136, 141))	('expression', 'MPA', (75, 85))
294187	31423110	Recent studies have also shown that the occurrence of many malignant tumors is closely related to the epigenetic disorder of the cellular genome.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('malignant tumors', 'Disease', (59, 75))	('malignant tumors', 'Disease', 'MESH:D018198', (59, 75))	('related', 'Reg', (87, 94))	('epigenetic disorder', 'Var', (102, 121))
294191	31423110	If the epigenetic test is performed on the tissues, prediction or diagnosis can be made at an early stage or even before the cancer, and early prevention or treatment can improve the survival rate and improve the prognosis.	('improve', 'PosReg', (171, 178))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('epigenetic test', 'Var', (7, 22))	('survival rate', 'CPA', (183, 196))	('prognosis', 'CPA', (213, 222))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('improve', 'PosReg', (201, 208))
294196	31423110	Ectopic expression of c-Fos in HNSCC cells also displays increased sphere formation.	('c-Fos', 'Gene', (22, 27))	('sphere formation', 'CPA', (67, 83))	('HNSCC', 'Phenotype', 'HP:0012288', (31, 36))	('Ectopic expression', 'Var', (0, 18))	('c-Fos', 'Gene', '2353', (22, 27))	('increased', 'PosReg', (57, 66))	('HNSCC', 'CellLine', 'CVCL:5985', (31, 36))
294198	31423110	OSCC is a multi-factor participation, a common malignant tumor with multiple genes, and the inactivation and loss of tumor suppressor genes are closely related to its occurrence and development.	('inactivation', 'Var', (92, 104))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('malignant tumor', 'Disease', 'MESH:D018198', (47, 62))	('loss of tumor', 'Disease', 'MESH:D009369', (109, 122))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('loss of tumor', 'Disease', (109, 122))	('OSCC', 'Disease', (0, 4))	('malignant tumor', 'Disease', (47, 62))
294236	31423110	The results of CCK8 showed that the growth curve of SCC9 cells knocking down RASSF-1A gene was significantly higher than that of the control group at 72 and 96 h, with a significant difference (Fig.	('knocking down', 'Var', (63, 76))	('growth curve', 'CPA', (36, 48))	('RASSF-1A', 'Gene', (77, 85))	('higher', 'PosReg', (109, 115))	('SCC9', 'CellLine', 'CVCL:1685', (52, 56))
294237	31423110	Flow cytometry showed that the percentage of cells knocking down the RASSF-1A gene in the S phase was significantly higher than that in the control group, indicating that the proliferation of SCC9 cells was significantly increased after knocking down the gene (Fig.	('knocking down', 'Var', (237, 250))	('higher', 'PosReg', (116, 122))	('increased', 'PosReg', (221, 230))	('SCC9', 'CellLine', 'CVCL:1685', (192, 196))	('knocking down', 'Var', (51, 64))	('RASSF-1A', 'Gene', (69, 77))	('proliferation', 'CPA', (175, 188))
294239	31423110	It was found that knocking down RASSF1A protein increased the expression of CyclinD2 protein in cells (Fig.	('increased', 'PosReg', (48, 57))	('CyclinD2', 'Gene', '894', (76, 84))	('knocking down', 'Var', (18, 31))	('expression', 'MPA', (62, 72))	('RASSF1A', 'Gene', (32, 39))	('protein', 'Protein', (40, 47))	('protein', 'Protein', (85, 92))	('CyclinD2', 'Gene', (76, 84))
294242	31423110	The results showed that the expression of MMP2 protein in cells was significantly increased compared with the control group after knockdown of RASSF1A gene (Fig.	('protein', 'Protein', (47, 54))	('RASSF1A', 'Gene', (143, 150))	('MMP2', 'Gene', (42, 46))	('expression', 'MPA', (28, 38))	('knockdown', 'Var', (130, 139))	('increased', 'PosReg', (82, 91))	('MMP2', 'Gene', '4313', (42, 46))
294243	31423110	Usually cell proliferation and apoptosis are present at the same time, so we also detected SCC9 cells after knocking down the RASSF-1A gene.	('knocking down', 'Var', (108, 121))	('SCC9', 'CellLine', 'CVCL:1685', (91, 95))	('RASSF-1A', 'Gene', (126, 134))
294247	31423110	After knocking down RASSF-1A gene on SCC9 cells, CyclinD1 gene and protein levels were significantly increased, and the difference was statistically significant compared with the control group (Fig.	('RASSF-1A gene', 'Gene', (20, 33))	('SCC9', 'CellLine', 'CVCL:1685', (37, 41))	('increased', 'PosReg', (101, 110))	('knocking down', 'Var', (6, 19))
294252	31423110	The RASSF-1A gene was overexpressed in the mouse by adenovirus, and the expression of RASSF-1A protein in the tumor tissue of the virus group was found to be increased by western blot and the difference was statistically significant (Fig.	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('expression', 'MPA', (72, 82))	('virus', 'Var', (130, 135))	('RASSF-1A', 'Gene', (86, 94))	('mouse', 'Species', '10090', (43, 48))	('protein', 'Protein', (95, 102))	('increased', 'PosReg', (158, 167))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
294255	31423110	The weight and volume of the tumor tissue overexpressing the RASSF-1A gene were significantly lower than those of the control group, with a significant difference (Fig.	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('RASSF-1A', 'Gene', (61, 69))	('gene', 'Var', (70, 74))	('tumor', 'Disease', (29, 34))	('lower', 'NegReg', (94, 99))	('overexpressing', 'PosReg', (42, 56))
294266	31423110	Molecular epidemiological studies have shown that OSCC is a multi-gene multi-step malignant tumor involving the activation of proto-oncogenes and the inactivation of tumor suppressor genes.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('malignant tumor', 'Disease', 'MESH:D018198', (82, 97))	('OSCC', 'Disease', (50, 54))	('inactivation', 'Var', (150, 162))	('activation', 'PosReg', (112, 122))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('tumor', 'Disease', (166, 171))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Disease', (92, 97))	('malignant tumor', 'Disease', (82, 97))
294270	31423110	Current studies have demonstrated that cell cycle-dependent protein kinase 2A gene and RAS association domain family 1A (RASSF1A gene) promoter methylation play an important role in the early diagnosis and prognosis of non-small cell lung cancer.	('methylation', 'Var', (144, 155))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (219, 245))	('lung cancer', 'Phenotype', 'HP:0100526', (234, 245))	('RASSF1A gene', 'Gene', (121, 133))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (219, 245))	('non-small cell lung cancer', 'Disease', (219, 245))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (223, 245))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))
294271	31423110	The RASSF1A gene is a tumor suppressor gene, and its methylation impairs the cell regulation mechanism and causes cancer through multiple downstream transcription pathways.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('cancer', 'Disease', (114, 120))	('RASSF1A', 'Gene', (4, 11))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('causes', 'Reg', (107, 113))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('impairs', 'NegReg', (65, 72))	('tumor', 'Disease', (22, 27))	('cell regulation mechanism', 'CPA', (77, 102))	('methylation', 'Var', (53, 64))
294279	31423110	Kaplan-Meier single factor analysis showed that RASSF1A positive patients had higher survival time than negative patient.	('patient', 'Species', '9606', (113, 120))	('survival time', 'CPA', (85, 98))	('higher', 'PosReg', (78, 84))	('RASSF1A', 'Gene', (48, 55))	('positive', 'Var', (56, 64))	('patient', 'Species', '9606', (65, 72))	('patients', 'Species', '9606', (65, 73))
294282	31423110	At the same time, we detected tumor-associated proliferating proteins and found that high expression of CyclinD1 protein was observed in tumor cells that knocked down RASSF-1A.	('protein', 'Protein', (113, 120))	('tumor', 'Disease', (137, 142))	('knocked down', 'Var', (154, 166))	('RASSF-1A', 'Gene', (167, 175))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('expression', 'MPA', (90, 100))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('CyclinD1', 'Gene', (104, 112))	('tumor', 'Disease', (30, 35))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
294283	31423110	In vivo experiments also found that after overexpression of RASSF-1A gene in oral cancer model mice, tumor growth was slowed, tumor volume was decreased, and CyclinD1 protein expression in tumor tissues was decreased.	('oral cancer', 'Disease', (77, 88))	('mice', 'Species', '10090', (95, 99))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('overexpression', 'PosReg', (42, 56))	('decreased', 'NegReg', (207, 216))	('RASSF-1A', 'Gene', (60, 68))	('decreased', 'NegReg', (143, 152))	('slowed', 'NegReg', (118, 124))	('tumor', 'Disease', (126, 131))	('tumor', 'Disease', (189, 194))	('gene', 'Var', (69, 73))	('tumor', 'Disease', (101, 106))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('oral cancer', 'Disease', 'MESH:D009062', (77, 88))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('CyclinD1 protein expression', 'MPA', (158, 185))
294404	33907850	Following the depletion of P21 expression, lapiferin-mediated inhibition of cell proliferation and enhancement of cell apoptosis were significantly reduced.	('reduced', 'NegReg', (148, 155))	('P21', 'Gene', '1026', (27, 30))	('enhancement', 'PosReg', (99, 110))	('cell proliferation', 'CPA', (76, 94))	('lapiferin', 'Chemical', 'MESH:C549109', (43, 52))	('depletion', 'Var', (14, 23))	('inhibition', 'NegReg', (62, 72))	('P21', 'Gene', (27, 30))	('cell apoptosis', 'CPA', (114, 128))
294434	33907850	The sequences were as follows: siNC, sense 5'-ACUUACGAGUGACAGUAGA-3', antisense 5'-UCUACUGUCACUCGUAAGU-3'; and siP21, sense 5'-CCAACUCAUUCUCCAAGUA-3' and antisense 5'-UACUUGGAGAAUGAGUUGG-3'.	('P21', 'Gene', '1026', (113, 116))	('siNC', 'Disease', (31, 35))	('siNC', 'Disease', 'None', (31, 35))	('antisense', 'Var', (154, 163))	('P21', 'Gene', (113, 116))	('antisense', 'Var', (70, 79))
294474	33907850	Cell apoptotic rates peaked (3.5-fold) when cells were treated with lapiferin for 48 h. These results suggested that lapiferin increased cell apoptosis in a dose- and time-dependent manner in GSCC.	('lapiferin', 'Chemical', 'MESH:C549109', (117, 126))	('cell apoptosis', 'CPA', (137, 151))	('GSCC', 'Chemical', '-', (192, 196))	('lapiferin', 'Var', (117, 126))	('GSCC', 'Phenotype', 'HP:0030413', (192, 196))	('increased', 'PosReg', (127, 136))	('lapiferin', 'Chemical', 'MESH:C549109', (68, 77))
294505	33907850	Conversely, following knockdown of P21, lapiferin-mediated suppression of proliferation was markedly inhibited, indicating the P21-dependent mechanism of lapiferin-mediated antitumor activity.	('suppression', 'NegReg', (59, 70))	('P21', 'Gene', (35, 38))	('lapiferin', 'Chemical', 'MESH:C549109', (154, 163))	('P21', 'Gene', '1026', (127, 130))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('knockdown', 'Var', (22, 31))	('P21', 'Gene', '1026', (35, 38))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('lapiferin', 'Chemical', 'MESH:C549109', (40, 49))	('inhibited', 'NegReg', (101, 110))	('tumor', 'Disease', (177, 182))	('P21', 'Gene', (127, 130))
294549	32111002	These snoRNAs guide cleavage of rRNAs (i.e., SNORA73, SNORD3A (or U3), SNORD14, SNORD22 and SNORD118 (or U8)).	('SNORD22', 'Gene', (80, 87))	('snoRNA', 'Gene', '85389', (6, 12))	('snoRNA', 'Gene', (6, 12))	('SNORD3A', 'Gene', '780851', (54, 61))	('SNORD22', 'Gene', '9304', (80, 87))	('SNORD118', 'Var', (92, 100))	('SNORD3A', 'Gene', (54, 61))
294579	32111002	Hence, alterations of snoRNAs have a broad impact on human diseases reflecting the required roles of snoRNAs in diverse cellular processes.	('impact', 'Reg', (43, 49))	('snoRNA', 'Gene', (101, 107))	('snoRNA', 'Gene', (22, 28))	('snoRNA', 'Gene', '85389', (101, 107))	('snoRNA', 'Gene', '85389', (22, 28))	('human diseases', 'Disease', (53, 67))	('human', 'Species', '9606', (53, 58))	('alterations', 'Var', (7, 18))
294580	32111002	Alterations in the expression level of snoRNAs have also been associated with cancer.	('snoRNA', 'Gene', (39, 45))	('associated', 'Reg', (62, 72))	('Alterations', 'Var', (0, 11))	('snoRNA', 'Gene', '85389', (39, 45))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('expression level', 'MPA', (19, 35))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))
294581	32111002	Dysregulation of snoRNA expression has been reported in different types of cancers, from leukemia to carcinoma and even sarcoma.	('sarcoma', 'Phenotype', 'HP:0100242', (120, 127))	('leukemia', 'Phenotype', 'HP:0001909', (89, 97))	('cancers', 'Disease', 'MESH:D009369', (75, 82))	('expression', 'MPA', (24, 34))	('Dysregulation', 'Var', (0, 13))	('cancers', 'Phenotype', 'HP:0002664', (75, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('cancers', 'Disease', (75, 82))	('snoRNA', 'Gene', (17, 23))	('leukemia to carcinoma', 'Disease', (89, 110))	('sarcoma', 'Disease', 'MESH:D012509', (120, 127))	('leukemia to carcinoma', 'Disease', 'MESH:D009369', (89, 110))	('reported', 'Reg', (44, 52))	('snoRNA', 'Gene', '85389', (17, 23))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('sarcoma', 'Disease', (120, 127))
294607	32111002	Genomic alterations mainly correspond to activated mutations on genes encoding kinases, triggering the constitutive activation of signaling pathways to support tumorigenesis and aberrant cancer cell proliferation.	('cancer', 'Disease', 'MESH:D009369', (187, 193))	('support', 'PosReg', (152, 159))	('mutations', 'Var', (51, 60))	('cancer', 'Disease', (187, 193))	('alterations', 'Var', (8, 19))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('activation', 'PosReg', (116, 126))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('tumor', 'Disease', (160, 165))	('signaling pathways', 'Pathway', (130, 148))
294608	32111002	Intrinsic mutations on the Kristen Rat Sarcoma Viral Oncogene homolog (KRAS) are important alteration that occurs in 25% of lung adenocarcinoma.	('Sarcoma', 'Disease', (39, 46))	('lung adenocarcinoma', 'Disease', (124, 143))	('Sarcoma', 'Disease', 'MESH:D012509', (39, 46))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (124, 143))	('KRAS', 'Gene', (71, 75))	('Rat', 'Species', '10116', (35, 38))	('Sarcoma', 'Phenotype', 'HP:0100242', (39, 46))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (124, 143))	('mutations', 'Var', (10, 19))
294609	32111002	On other hand, alteration on the Epidermal Growth Factor Receptor (EGFR) gene is found in 15% of lung adenocarcinoma and translocations of the Anaplastic Lymphoma Kinase (ALK) gene occur in 3%-7% of lung adenocarcinoma.	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (97, 116))	('translocations', 'Var', (121, 135))	('Anaplastic Lymphoma', 'Phenotype', 'HP:0012193', (143, 162))	('EGFR', 'Gene', (67, 71))	('Lymphoma', 'Phenotype', 'HP:0002665', (154, 162))	('ALK', 'Gene', '238', (171, 174))	('Anaplastic Lymphoma Kinase', 'Gene', '238', (143, 169))	('ALK', 'Gene', (171, 174))	('found', 'Reg', (81, 86))	('lung adenocarcinoma', 'Disease', (199, 218))	('Epidermal Growth Factor Receptor', 'Gene', (33, 65))	('lung adenocarcinoma', 'Disease', (97, 116))	('Epidermal Growth Factor Receptor', 'Gene', '1956', (33, 65))	('EGFR', 'Gene', '1956', (67, 71))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (199, 218))	('alteration', 'Var', (15, 25))	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('Anaplastic Lymphoma Kinase', 'Gene', (143, 169))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (199, 218))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (97, 116))	('carcinoma', 'Phenotype', 'HP:0030731', (209, 218))
294622	32111002	Targeted therapies are small molecules successfully integrated into lung cancer patient management these past decades that mainly target the mutant tyrosine kinases, and are so called tyrosine kinase inhibitors (TKIs).	('lung cancer', 'Disease', (68, 79))	('lung cancer', 'Phenotype', 'HP:0100526', (68, 79))	('mutant', 'Var', (141, 147))	('men', 'Species', '9606', (94, 97))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('lung cancer', 'Disease', 'MESH:D008175', (68, 79))	('tyrosine kinases', 'Enzyme', (148, 164))	('patient', 'Species', '9606', (80, 87))
294624	32111002	For example, EGFR mutant-driven tumors that represent 15% of NSCLCs, can be treated by therapeutic molecules designed to specifically inhibit mutant and overactivated EGFR proteins, such as erlotinib, afatinib and gefitinib.	('proteins', 'Protein', (172, 180))	('overactivated', 'PosReg', (153, 166))	('mutant-driven', 'Var', (18, 31))	('erlotinib', 'Chemical', 'MESH:D000069347', (190, 199))	('inhibit', 'NegReg', (134, 141))	('afatinib', 'Chemical', 'MESH:D000077716', (201, 209))	('mutant', 'Var', (142, 148))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('NSCLCs', 'Disease', (61, 67))	('gefitinib', 'Chemical', 'MESH:D000077156', (214, 223))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('EGFR', 'Gene', '1956', (167, 171))	('NSCLCs', 'Disease', 'MESH:D002289', (61, 67))	('tumors', 'Disease', (32, 38))	('EGFR', 'Gene', '1956', (13, 17))	('EGFR', 'Gene', (13, 17))	('EGFR', 'Gene', (167, 171))	('tumors', 'Disease', 'MESH:D009369', (32, 38))
294629	32111002	For instance, in 50%-60% of cases, treating an EGFR-mutant primary tumor with targeted therapies induces a positive selection of resistant cancer cells within the tumor due to the acquisition of a secondary mutation, T790M in the EGFR protein that occurs outside of the ATP binding site.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('EGFR', 'Gene', '1956', (230, 234))	('EGFR', 'Gene', (230, 234))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Disease', (163, 168))	('T790M', 'Mutation', 'rs121434569', (217, 222))	('ATP', 'Chemical', 'MESH:D000255', (270, 273))	('tumor', 'Disease', (67, 72))	('EGFR', 'Gene', '1956', (47, 51))	('T790M', 'Var', (217, 222))	('EGFR', 'Gene', (47, 51))	('cancer', 'Disease', (139, 145))
294634	32111002	However, results of the KEYNOTE 042 clinical trial demonstrated that patients with locally advanced/metastatic lung cancer expressing low PD-L1 (1% tumor proportion score) benefit from first line pembrolizumab treatment.	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('tumor', 'Disease', (148, 153))	('lung cancer', 'Disease', 'MESH:D008175', (111, 122))	('men', 'Species', '9606', (215, 218))	('low', 'Var', (134, 137))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('patients', 'Species', '9606', (69, 77))	('lung cancer', 'Disease', (111, 122))	('PD-L1', 'Gene', (138, 143))	('lung cancer', 'Phenotype', 'HP:0100526', (111, 122))	('pembrolizumab', 'Chemical', 'MESH:C582435', (196, 209))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('PD-L1', 'Gene', '29126', (138, 143))
294693	32111002	Patients harboring lung tumors with high levels of each of these three snoRNAs displayed a poorer overall survival than patients carrying tumors with relatively lower levels.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('snoRNA', 'Gene', (71, 77))	('tumors', 'Disease', (24, 30))	('lung tumors', 'Phenotype', 'HP:0100526', (19, 30))	('snoRNA', 'Gene', '85389', (71, 77))	('tumors', 'Disease', 'MESH:D009369', (138, 144))	('lung tumor', 'Phenotype', 'HP:0100526', (19, 29))	('poorer', 'NegReg', (91, 97))	('tumors', 'Disease', 'MESH:D009369', (24, 30))	('lung tumors', 'Disease', (19, 30))	('Patients', 'Species', '9606', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('high levels', 'Var', (36, 47))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('tumors', 'Disease', (138, 144))	('patients', 'Species', '9606', (120, 128))	('lung tumors', 'Disease', 'MESH:D008175', (19, 30))	('overall survival', 'MPA', (98, 114))
294711	32111002	These severe effects observed in response to SNORA80E knockdown demonstrate its pivotal role in oncogenesis.	('SNORA80E', 'Gene', (45, 53))	('knockdown', 'Var', (54, 63))	('SNORA80E', 'Gene', '677823', (45, 53))
294714	32111002	In addition to the decreased cell proliferation, the proportion of apoptotic cells in response to siRNA-SNORA80E transfection was increased as well as the cleavage of caspase-3 and poly [ADP-ribose] polymerase 1 (PARP1), suggesting that SNORA80E promotes cell proliferation by inhibiting apoptosis.	('transfection', 'Var', (113, 125))	('inhibiting', 'NegReg', (277, 287))	('promotes', 'PosReg', (246, 254))	('SNORA80E', 'Gene', (237, 245))	('cell proliferation', 'CPA', (255, 273))	('SNORA80E', 'Gene', (104, 112))	('SNORA80E', 'Gene', '677823', (104, 112))	('SNORA80E', 'Gene', '677823', (237, 245))	('apoptosis', 'CPA', (288, 297))	('caspase-3 and poly [ADP-ribose] polymerase 1', 'Gene', '836;142', (167, 211))	('cleavage', 'MPA', (155, 163))	('cell proliferation', 'CPA', (29, 47))	('increased', 'PosReg', (130, 139))	('decreased', 'NegReg', (19, 28))	('PARP1', 'Gene', '142', (213, 218))	('PARP1', 'Gene', (213, 218))
294715	32111002	In vivo, SNORA80E knockdown inhibits tumorigenicity.	('knockdown', 'Var', (18, 27))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('inhibits', 'NegReg', (28, 36))	('SNORA80E', 'Gene', (9, 17))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('SNORA80E', 'Gene', '677823', (9, 17))
294716	32111002	Nude mice transplanted with H1944 NSCLC cells inoculated with siRNA-SNORA80E do not develop tumors, neither ectopically nor orthotopically after a latency of 14 or 28 days, respectively, in contrast to mice engrafted with cells transfected with the control siRNA.	('mice', 'Species', '10090', (5, 9))	('tumors', 'Disease', 'MESH:D009369', (92, 98))	('NSCLC', 'Disease', (34, 39))	('Nude mice', 'Species', '10090', (0, 9))	('mice', 'Species', '10090', (202, 206))	('H1944', 'Var', (28, 33))	('NSCLC', 'Disease', 'MESH:D002289', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('H1944', 'CellLine', 'CVCL:1508', (28, 33))	('develop', 'PosReg', (84, 91))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('tumors', 'Disease', (92, 98))	('SNORA80E', 'Gene', (68, 76))	('SNORA80E', 'Gene', '677823', (68, 76))
294718	32111002	Mei and colleagues reported that the SNORA80E knockdown is associated with an accumulation of the cellular tumor antigen p53 protein in a set of NSCLC cell lines (H460, H1944 and H292).	('H1944', 'CellLine', 'CVCL:1508', (169, 174))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('knockdown', 'Var', (46, 55))	('NSCLC', 'Disease', (145, 150))	('protein', 'Protein', (125, 132))	('NSCLC', 'Disease', 'MESH:D002289', (145, 150))	('H460', 'CellLine', 'CVCL:0459', (163, 167))	('SNORA80E', 'Gene', (37, 45))	('SNORA80E', 'Gene', '677823', (37, 45))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('H292', 'CellLine', 'CVCL:0455', (179, 183))	('accumulation', 'PosReg', (78, 90))
294721	32111002	Interestingly, apoptosis in p53-null (H299) or mutant p53 (A549) NSCLC cell lines was not affected by SNORA80E ectopic overexpression, suggesting that SNORA80E promotes cell proliferation through inhibition of apoptosis in a p53-dependent manner (Figure 2).	('promotes', 'PosReg', (160, 168))	('SNORA80E', 'Gene', '677823', (102, 110))	('SNORA80E', 'Gene', (151, 159))	('SNORA80E', 'Gene', '677823', (151, 159))	('A549', 'CellLine', 'CVCL:0023', (59, 63))	('NSCLC', 'Disease', 'MESH:D002289', (65, 70))	('H299', 'CellLine', 'CVCL:D765', (38, 42))	('p53', 'Gene', (54, 57))	('cell proliferation', 'CPA', (169, 187))	('apoptosis', 'CPA', (210, 219))	('inhibition', 'NegReg', (196, 206))	('mutant', 'Var', (47, 53))	('NSCLC', 'Disease', (65, 70))	('SNORA80E', 'Gene', (102, 110))
294735	32111002	In 56 NSCLC patients, the ones harboring lung tumors expressing high levels of SNORD78 displayed a poorer overall survival than patients with lung tumors expressing low SNORD78 levels.	('lung tumors', 'Disease', 'MESH:D008175', (41, 52))	('NSCLC', 'Disease', 'MESH:D002289', (6, 11))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('SNORD78', 'Gene', '692198', (169, 176))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('SNORD78', 'Gene', (169, 176))	('lung tumors', 'Phenotype', 'HP:0100526', (41, 52))	('high levels', 'Var', (64, 75))	('NSCLC', 'Disease', (6, 11))	('poorer', 'NegReg', (99, 105))	('overall', 'MPA', (106, 113))	('patients', 'Species', '9606', (12, 20))	('lung tumor', 'Phenotype', 'HP:0100526', (41, 51))	('lung tumors', 'Disease', 'MESH:D008175', (142, 153))	('lung tumors', 'Disease', (41, 52))	('lung tumors', 'Phenotype', 'HP:0100526', (142, 153))	('tumors', 'Phenotype', 'HP:0002664', (147, 153))	('SNORD78', 'Gene', '692198', (79, 86))	('lung tumor', 'Phenotype', 'HP:0100526', (142, 152))	('SNORD78', 'Gene', (79, 86))	('patients', 'Species', '9606', (128, 136))	('lung tumors', 'Disease', (142, 153))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))
294740	32111002	Thus, SNORD78 knockdown reduces cell proliferation by inducing cell cycle arrest and apoptosis.	('SNORD78', 'Gene', '692198', (6, 13))	('reduces', 'NegReg', (24, 31))	('inducing', 'PosReg', (54, 62))	('SNORD78', 'Gene', (6, 13))	('apoptosis', 'CPA', (85, 94))	('arrest', 'Disease', 'MESH:D006323', (74, 80))	('knockdown', 'Var', (14, 23))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (63, 80))	('cell proliferation', 'CPA', (32, 50))	('arrest', 'Disease', (74, 80))
294742	32111002	In vivo, nude mice engrafted with H1975 NSCLC cells expressing reduced levels of SNORD78 developed tumors although smaller than the ones developed by mice engrafted with scrambled shRNA infected cells.	('SNORD78', 'Gene', (81, 88))	('H1975', 'Var', (34, 39))	('mice', 'Species', '10090', (150, 154))	('nude mice', 'Species', '10090', (9, 18))	('tumors', 'Disease', 'MESH:D009369', (99, 105))	('SNORD78', 'Gene', '692198', (81, 88))	('mice', 'Species', '10090', (14, 18))	('H1975 NSCLC', 'CellLine', 'CVCL:1511', (34, 45))	('infected', 'Disease', 'MESH:D007239', (186, 194))	('smaller', 'NegReg', (115, 122))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))	('infected', 'Disease', (186, 194))	('tumors', 'Disease', (99, 105))
294762	32111002	The knockdown of SNORA71A in these two cell lines using an siRNA strategy induces a G0/G1 arrest, as shown by flow cytometric analyses and increases the expression of the inhibitor of G0/G1 checkpoint p27, the cyclin-dependent kinase inhibitor 1B.	('arrest', 'Disease', 'MESH:D006323', (90, 96))	('SNORA71A', 'Gene', (17, 25))	('cyclin-dependent kinase inhibitor 1B', 'Gene', (210, 246))	('induces', 'Reg', (74, 81))	('cyclin-dependent kinase inhibitor 1B', 'Gene', '1027', (210, 246))	('SNORA71A', 'Gene', '26777', (17, 25))	('arrest', 'Disease', (90, 96))	('increases', 'PosReg', (139, 148))	('p27', 'Gene', '3429', (201, 204))	('p27', 'Gene', (201, 204))	('expression', 'MPA', (153, 163))	('knockdown', 'Var', (4, 13))
294766	32111002	Remarkably, in vivo, xenografted mice derived from stable A549 cells with SNORA71A knockdown display a drastic reduction in tumor growth from 350 to 50 mm3 compared to mice xenografted with normal A549 cells, that corresponds to an 85% reduction in tumor volume.	('reduction', 'NegReg', (111, 120))	('tumor', 'Disease', 'MESH:D009369', (249, 254))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('A549', 'CellLine', 'CVCL:0023', (58, 62))	('tumor', 'Phenotype', 'HP:0002664', (249, 254))	('reduction', 'NegReg', (236, 245))	('tumor', 'Disease', (124, 129))	('mice', 'Species', '10090', (168, 172))	('tumor', 'Disease', (249, 254))	('mice', 'Species', '10090', (33, 37))	('A549', 'CellLine', 'CVCL:0023', (197, 201))	('SNORA71A', 'Gene', (74, 82))	('SNORA71A', 'Gene', '26777', (74, 82))	('knockdown', 'Var', (83, 92))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
294770	32111002	Interestingly, the authors identified a disruption in the MAPK pathway in response to SNORA71A knockdown in A549 and PC9 cells.	('A549', 'CellLine', 'CVCL:0023', (108, 112))	('knockdown', 'Var', (95, 104))	('disruption', 'Reg', (40, 50))	('SNORA71A', 'Gene', (86, 94))	('SNORA71A', 'Gene', '26777', (86, 94))	('PC9', 'CellLine', 'CVCL:B260', (117, 120))	('MAPK pathway', 'Pathway', (58, 70))
294772	32111002	It has to be noted that no rescue experiment was performed to demonstrate the involvement of MAPK pathway in the cellular processes affected by SNORA71A depletion, and that the molecular mechanisms from nucleolar snoRNA dysregulation to cytoplasmic MAPK pathway extinction have not been investigated.	('SNORA71A', 'Gene', (144, 152))	('SNORA71A', 'Gene', '26777', (144, 152))	('MAPK pathway', 'Pathway', (93, 105))	('involvement', 'Reg', (78, 89))	('snoRNA', 'Gene', (213, 219))	('men', 'Species', '9606', (40, 43))	('men', 'Species', '9606', (85, 88))	('snoRNA', 'Gene', '85389', (213, 219))	('depletion', 'Var', (153, 162))
294777	32111002	took an opposite stance by conducting a large-scale study to investigate whether snoRNA genes exhibiting frequent deletion could contribute to lung cancer tumorigenesis and/or progression.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('snoRNA', 'Gene', (81, 87))	('lung cancer', 'Disease', (143, 154))	('lung cancer', 'Phenotype', 'HP:0100526', (143, 154))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('tumor', 'Disease', (155, 160))	('contribute', 'Reg', (129, 139))	('snoRNA', 'Gene', '85389', (81, 87))	('lung cancer', 'Disease', 'MESH:D008175', (143, 154))	('deletion', 'Var', (114, 122))
294778	32111002	Using TCGA database, 5,473 pairs of tumoral/normal samples encompassing 21 types of cancers, which include two subtypes of lung cancer (297 LUAD and 278 LUSC), were analyzed to identify copy number alterations (CNAs) in genomic regions encoding snoRNAs.	('tumoral', 'Disease', (36, 43))	('tumoral', 'Disease', 'MESH:D009369', (36, 43))	('snoRNA', 'Gene', (245, 251))	('lung cancer', 'Disease', (123, 134))	('cancers', 'Disease', 'MESH:D009369', (84, 91))	('lung cancer', 'Phenotype', 'HP:0100526', (123, 134))	('cancers', 'Phenotype', 'HP:0002664', (84, 91))	('cancers', 'Disease', (84, 91))	('copy number alterations', 'Var', (186, 209))	('snoRNA', 'Gene', '85389', (245, 251))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('lung cancer', 'Disease', 'MESH:D008175', (123, 134))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))
294782	32111002	In agreement with observations in patients, nude mice xenografted with either A459 or NSCLC NCI-H23 lung cancer cell lines deleted in SNORD50A/B using the CRISPR method, developed larger tumors than mice injected with non-depleted cells.	('developed larger', 'PosReg', (170, 186))	('SNORD50A/B', 'Gene', '26799;692088', (134, 144))	('SNORD50A/B', 'Gene', (134, 144))	('mice', 'Species', '10090', (199, 203))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('men', 'Species', '9606', (8, 11))	('NSCLC NCI-H23 lung cancer', 'Disease', 'MESH:D008175', (86, 111))	('mice', 'Species', '10090', (49, 53))	('lung cancer', 'Phenotype', 'HP:0100526', (100, 111))	('NSCLC NCI-H23 lung cancer', 'Disease', (86, 111))	('patients', 'Species', '9606', (34, 42))	('nude mice', 'Species', '10090', (44, 53))	('tumors', 'Disease', (187, 193))	('tumors', 'Disease', 'MESH:D009369', (187, 193))	('tumors', 'Phenotype', 'HP:0002664', (187, 193))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('deleted', 'Var', (123, 130))
294784	32111002	identified molecular interactions between SNORD50A/B and cancer-related proteins to elucidate the molecular mechanisms by which SNORD50A/B deletion promotes lung tumorigenesis.	('interactions', 'Interaction', (21, 33))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('lung tumor', 'Phenotype', 'HP:0100526', (157, 167))	('deletion', 'Var', (139, 147))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('cancer', 'Disease', (57, 63))	('SNORD50A/B', 'Gene', '26799;692088', (42, 52))	('SNORD50A/B', 'Gene', (42, 52))	('lung tumor', 'Disease', (157, 167))	('SNORD50A/B', 'Gene', '26799;692088', (128, 138))	('lung tumor', 'Disease', 'MESH:D008175', (157, 167))	('promotes', 'PosReg', (148, 156))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('SNORD50A/B', 'Gene', (128, 138))
294791	32111002	SNORD50A/B overexpression in both wild-type and mutant KRas cells led to a decrease in ERK1/2 phosphorylation and limited cell growth and proliferation.	('mutant', 'Var', (48, 54))	('decrease', 'NegReg', (75, 83))	('limited', 'NegReg', (114, 121))	('ERK1/2', 'Gene', (87, 93))	('SNORD50A/B', 'Gene', '26799;692088', (0, 10))	('SNORD50A/B', 'Gene', (0, 10))	('ERK1/2', 'Gene', '5595;5594', (87, 93))	('phosphorylation', 'MPA', (94, 109))	('KRas', 'Gene', '3845', (55, 59))	('KRas', 'Gene', (55, 59))	('overexpression', 'PosReg', (11, 25))
294806	32111002	SNORD3A (U3) and SNORD118 (U8) belong to the small fraction of C/D box snoRNAs participating in the cleavage of the 47S pre-rRNA into the three main rRNA species (5.8S, 18S and 28S) prior to their assembly into ribosomal proteins in eukaryotic species.	('snoRNA', 'Gene', (71, 77))	('SNORD3A', 'Gene', '780851', (0, 7))	('SNORD118', 'Var', (17, 25))	('SNORD3A', 'Gene', (0, 7))	('snoRNA', 'Gene', '85389', (71, 77))
294811	32111002	In response to reduced SNORD3A or SNORD118 levels, p53 and p21 proteins accumulate (up to 25-fold after 24 h) as evidenced by Western blot, a regulation dependent on the presence of the ribosomal proteins RPL5 and RPL11.	('proteins', 'Protein', (63, 71))	('p21', 'Gene', (59, 62))	('SNORD118', 'Var', (34, 42))	('RPL5', 'Gene', (205, 209))	('p21', 'Gene', '644914', (59, 62))	('accumulate', 'PosReg', (72, 82))	('RPL5', 'Gene', '6125', (205, 209))	('reduced', 'NegReg', (15, 22))	('RPL11', 'Gene', '6135', (214, 219))	('RPL11', 'Gene', (214, 219))	('SNORD3A', 'Gene', '780851', (23, 30))	('p53', 'Protein', (51, 54))	('SNORD3A', 'Gene', (23, 30))
294812	32111002	It is associated first with a G1 blockade, around 80% of NSCLC H1944 cells being arrested only after 24 h of ASO treatment, and second with an increased proportion of apoptotic cells associated with progressive dislocation of the nucleolus.	('blockade', 'Var', (33, 41))	('men', 'Species', '9606', (118, 121))	('H1944', 'CellLine', 'CVCL:1508', (63, 68))	('arrest', 'Disease', 'MESH:D006323', (81, 87))	('ASO', 'Chemical', 'MESH:D016376', (109, 112))	('NSCLC', 'Disease', (57, 62))	('arrest', 'Disease', (81, 87))	('NSCLC', 'Disease', 'MESH:D002289', (57, 62))
294813	32111002	Thus, reduction of SNORD3A or SNORD118 levels promotes a p53 suppressive response in a ribosomal protein-dependent manner.	('SNORD3A', 'Gene', (19, 26))	('SNORD118', 'Var', (30, 38))	('suppressive response', 'MPA', (61, 81))	('p53', 'Gene', (57, 60))	('reduction', 'NegReg', (6, 15))	('promotes', 'PosReg', (46, 54))	('SNORD3A', 'Gene', '780851', (19, 26))
294814	32111002	Such response has been extensively studied and corresponds to a classical response termed ribosomal stress (or nucleolar stress), where defects in ribosome biogenesis, including defects in pre-rRNA cleavage, induce cell cycle arrest and apoptosis in a p53-dependent manner through disruption of the interaction between p53 and the human double minute 2 (Hdm2) protein by ribosomal proteins (for review see).	('cell cycle arrest', 'Phenotype', 'HP:0011018', (215, 232))	('stress', 'Disease', 'MESH:D000079225', (100, 106))	('Hdm2', 'Gene', '4193', (354, 358))	('arrest', 'Disease', (226, 232))	('stress', 'Disease', (121, 127))	('interaction', 'Interaction', (299, 310))	('stress', 'Disease', 'MESH:D000079225', (121, 127))	('stress', 'Disease', (100, 106))	('human', 'Species', '9606', (331, 336))	('Hdm2', 'Gene', (354, 358))	('pre-rRNA', 'Protein', (189, 197))	('apoptosis', 'CPA', (237, 246))	('disruption', 'NegReg', (281, 291))	('induce', 'PosReg', (208, 214))	('defects', 'Var', (136, 143))	('defects', 'Var', (178, 185))	('p53', 'Gene', (319, 322))	('arrest', 'Disease', 'MESH:D006323', (226, 232))
294816	32111002	While reduction of SNORD3A levels diminished colony formation by 75%, the effect of SNORD118 knockdown is even stronger since it completely prevents colony growth.	('knockdown', 'Var', (93, 102))	('SNORD3A', 'Gene', (19, 26))	('diminished', 'NegReg', (34, 44))	('colony growth', 'CPA', (149, 162))	('prevents', 'NegReg', (140, 148))	('reduction', 'NegReg', (6, 15))	('SNORD118', 'Gene', (84, 92))	('colony formation', 'CPA', (45, 61))	('SNORD3A', 'Gene', '780851', (19, 26))
294820	32111002	Polysome analysis of H1944 cells treated with specific ASO targeting either SNORD3A or SNORD118, revealed a reduction in 40S (i.e., small ribosome subunit) and 60S (i.e., large ribosome subunit) peaks, respectively.	('ASO', 'Chemical', 'MESH:D016376', (55, 58))	('SNORD118', 'Var', (87, 95))	('SNORD3A', 'Gene', '780851', (76, 83))	('H1944', 'CellLine', 'CVCL:1508', (21, 26))	('SNORD3A', 'Gene', (76, 83))	('reduction', 'NegReg', (108, 117))
294821	32111002	Indeed, some polysomes are still visible in response to SNORD3A knockdown, while they are largely absent in response to SNORD118 depletion.	('SNORD3A', 'Gene', '780851', (56, 63))	('SNORD3A', 'Gene', (56, 63))	('knockdown', 'Var', (64, 73))
294822	32111002	Such a difference may be due to the fact that knockdown expression of these snoRNAs alters different steps of the pre-rRNA cleavage as shown by Northern blot assays (SNORD3A: 5'-ETS and ITS1 leading to 18 rRNA; SNORD118: ITS2 and 3'-ETS involved in 28S rRNA), thus driving the accumulation of inappropriate rRNA intermediates.	('accumulation', 'PosReg', (277, 289))	('knockdown', 'Var', (46, 55))	('SNORD3A', 'Gene', (166, 173))	('snoRNA', 'Gene', (76, 82))	('SNORD3A', 'Gene', '780851', (166, 173))	('alters', 'Reg', (84, 90))	('inappropriate rRNA intermediates', 'MPA', (293, 325))	('snoRNA', 'Gene', '85389', (76, 82))
294824	32111002	Altogether, it appears that SNORD118 is more tumorigenic than SNORD3A.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('SNORD3A', 'Gene', '780851', (62, 69))	('SNORD3A', 'Gene', (62, 69))	('SNORD118', 'Var', (28, 36))	('tumor', 'Disease', (45, 50))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
294825	32111002	The difference observed in their individual impact on ribosome biogenesis might explained such a difference in tumorigenic activity, the 60S defects associated with SNORD118 depletion may have more impact on tumorigenesis than the 40S defects associated with SNORD3A although it remains to determine by which mechanism.	('impact', 'Reg', (198, 204))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('SNORD118', 'Gene', (165, 173))	('tumor', 'Disease', 'MESH:D009369', (208, 213))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('depletion', 'Var', (174, 183))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('tumor', 'Disease', (111, 116))	('tumor', 'Disease', (208, 213))	('SNORD3A', 'Gene', '780851', (259, 266))	('SNORD3A', 'Gene', (259, 266))
294826	32111002	Nevertheless, both SNORD3A and SNORD118 directly contribute to lung tumorigenesis by promoting ribosome production necessary to maintain cell growth and the high proliferative rate of cancer cells.	('ribosome production', 'MPA', (95, 114))	('SNORD3A', 'Gene', (19, 26))	('cancer', 'Disease', (184, 190))	('SNORD118', 'Var', (31, 39))	('lung tumor', 'Phenotype', 'HP:0100526', (63, 73))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('contribute', 'Reg', (49, 59))	('lung tumor', 'Disease', 'MESH:D008175', (63, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('lung tumor', 'Disease', (63, 73))	('promoting', 'PosReg', (85, 94))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('SNORD3A', 'Gene', '780851', (19, 26))
294833	32111002	Experimental inhibition of some individual snoRNAs abolished lung tumorigenesis in vitro and in vivo.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('snoRNA', 'Gene', (43, 49))	('lung tumor', 'Disease', (61, 71))	('inhibition', 'Var', (13, 23))	('abolished', 'NegReg', (51, 60))	('snoRNA', 'Gene', '85389', (43, 49))	('lung tumor', 'Disease', 'MESH:D008175', (61, 71))	('lung tumor', 'Phenotype', 'HP:0100526', (61, 71))	('men', 'Species', '9606', (6, 9))
294840	32111002	Indeed, alterations of rRNA 2'-O-ribose methylation directly affect translation of some mRNAs, which contain particular cis-regulator elements in their 5' UTR (i.e., Internal Ribosome Entry Sites or IRES), such as the Insulin-like Growth Factor 1 Receptor (IGF1R) or Myc proto-oncogene (MYC), in breast cancer and leukemia.	('translation', 'MPA', (68, 79))	('affect', 'Reg', (61, 67))	('IGF1R', 'Gene', (257, 262))	('men', 'Species', '9606', (137, 140))	('rRNA', 'MPA', (23, 27))	('cancer', 'Phenotype', 'HP:0002664', (303, 309))	('Insulin-like Growth Factor 1 Receptor', 'Gene', (218, 255))	('MYC', 'Gene', (287, 290))	('Myc', 'Gene', (267, 270))	('alterations', 'Var', (8, 19))	('breast cancer', 'Phenotype', 'HP:0003002', (296, 309))	('leukemia', 'Phenotype', 'HP:0001909', (314, 322))	('breast cancer', 'Disease', 'MESH:D001943', (296, 309))	('MYC', 'Gene', '4609', (287, 290))	('breast cancer', 'Disease', (296, 309))	('Insulin-like Growth Factor 1 Receptor', 'Gene', '3480', (218, 255))	('leukemia', 'Disease', (314, 322))	('Myc', 'Gene', '4609', (267, 270))	('leukemia', 'Disease', 'MESH:D007938', (314, 322))	('IGF1R', 'Gene', '3480', (257, 262))	("2'-O-ribose", 'Chemical', '-', (28, 39))
294853	32111002	Moreover, tools could be designed to repress snoRNAs in a specific manner, including antisense oligonucleotides or miRNAs.	('miRNAs', 'Var', (115, 121))	('oligonucleotides', 'Chemical', 'MESH:D009841', (95, 111))	('repress', 'NegReg', (37, 44))	('snoRNA', 'Gene', (45, 51))	('antisense oligonucleotides', 'Var', (85, 111))	('snoRNA', 'Gene', '85389', (45, 51))
294864	31620368	We further demonstrated the HGK induced the cell cycle arrest by flow cytometry and inhibited colony formation ability and cell movement.	('cell movement', 'CPA', (123, 136))	('HGK', 'Chemical', 'MESH:C051414', (28, 31))	('inhibited', 'NegReg', (84, 93))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (44, 61))	('cell cycle arrest', 'CPA', (44, 61))	('HGK', 'Var', (28, 31))
294865	31620368	The western blot showed that HGK induced cell cycle arrest through p21 activation and caused intrinsic cell apoptosis pathway.	('cell cycle arrest', 'CPA', (41, 58))	('caused', 'Reg', (86, 92))	('p21', 'Gene', '1026', (67, 70))	('activation', 'PosReg', (71, 81))	('HGK', 'Var', (29, 32))	('p21', 'Gene', (67, 70))	('HGK', 'Chemical', 'MESH:C051414', (29, 32))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (41, 58))	('intrinsic cell', 'Pathway', (93, 107))
294908	31620368	In a previous result, we confirmed that HGK increased the percentage of SAS cells but not OECM1 cells in G0/G1 phase.	('increased', 'PosReg', (44, 53))	('HGK', 'Chemical', 'MESH:C051414', (40, 43))	('SAS cells', 'CPA', (72, 81))	('HGK', 'Var', (40, 43))
294919	31620368	We demonstrated that HGK significantly dose-dependently inhibited the rate of cell growth in OECM1 and SAS cells.	('inhibited', 'NegReg', (56, 65))	('HGK', 'Chemical', 'MESH:C051414', (21, 24))	('HGK', 'Var', (21, 24))	('rate of cell growth in OECM1', 'CPA', (70, 98))
294930	31620368	HGK induced cell apoptosis through the intrinsic pathway by activation of cleave Caspase 9, and cleave PARP (Figure 7).	('cell apoptosis', 'CPA', (12, 26))	('PARP', 'Gene', '142', (103, 107))	('cleave', 'MPA', (74, 80))	('Caspase 9', 'Gene', '842', (81, 90))	('cleave', 'Var', (96, 102))	('PARP', 'Gene', (103, 107))	('activation', 'PosReg', (60, 70))	('Caspase 9', 'Gene', (81, 90))	('HGK', 'Chemical', 'MESH:C051414', (0, 3))	('intrinsic pathway', 'Pathway', (39, 56))
294942	31620368	The datasets generated in the study can be found in the SRA database (https://www.ncbi.nlm.nih.gov/sra) using the following accession numbers: STUDY: PRJNA559691, SAMPLE: OECM_HGK (SAMN12551609), EXPERIMENT: 7 (SRX6701569), RUN: OECM1-4_HHFT2DSXX_L4_R1.fastq.gz (SRR9953208), SAMPLE: OCEM_control (SAMN12551608), EXPERIMENT: 5 (SRX6701570), RUN: OECM1-3_HHFT2DSXX_L4_R1.fastq.gz (SRR9953207), SAMPLE: SAS_HGK (SAMN12551607), EXPERIMENT: 3 (SRX6701571), RUN: SAS-2_HHFT2DSXX_L4_R1.fastq.gz (SRR9953206), SAMPLE: SAS_control (SAMN12551606), EXPERIMENT: 1 (SRX6701572), RUN: SAS-1_HHFT2DSXX_L4_R1.fastq.gz (SRR9953205).	('SRX6701570', 'Chemical', 'MESH:C584649', (328, 338))	('SRX6701572', 'Var', (554, 564))	('SRR9953208', 'Chemical', 'MESH:C105415', (263, 273))	('HGK', 'Chemical', 'MESH:C051414', (176, 179))	('SAMN12551606', 'Var', (524, 536))	('SRX6701572', 'Chemical', 'MESH:C584649', (554, 564))	('PRJNA559691', 'Chemical', 'None', (150, 161))	('SAMN12551609', 'Chemical', 'None', (181, 193))	('SAMN12551607', 'Chemical', 'None', (410, 422))	('SRR9953207', 'Chemical', 'MESH:C105415', (380, 390))	('SRX6701569', 'Chemical', 'MESH:C584649', (211, 221))	('SRX6701571', 'Chemical', 'MESH:C584649', (440, 450))	('SAMN12551608', 'Chemical', 'None', (298, 310))	('HGK', 'Chemical', 'MESH:C051414', (405, 408))	('SAMN12551606', 'Chemical', 'None', (524, 536))
294947	30655874	Furthermore, depletion of USP10 in lung cancer cells causes decreased apoptosis and increased cell survival upon treatment with DNA-damaging agents.	('decreased', 'NegReg', (60, 69))	('lung cancer', 'Disease', 'MESH:D008175', (35, 46))	('USP10', 'Gene', (26, 31))	('depletion', 'Var', (13, 22))	('men', 'Species', '9606', (118, 121))	('lung cancer', 'Disease', (35, 46))	('cell survival', 'CPA', (94, 107))	('increased', 'PosReg', (84, 93))	('USP10', 'Gene', '9100', (26, 31))	('lung cancer', 'Phenotype', 'HP:0100526', (35, 46))	('apoptosis', 'CPA', (70, 79))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))
294964	30655874	It has been reported that knockdown of USP10 in lung cancer cells causes increased cell survival and decreased apoptosis upon treatment with a DNA-methylating and antimetabolite agent.	('increased', 'PosReg', (73, 82))	('USP10', 'Gene', (39, 44))	('cell survival', 'CPA', (83, 96))	('lung cancer', 'Disease', 'MESH:D008175', (48, 59))	('men', 'Species', '9606', (131, 134))	('decreased', 'NegReg', (101, 110))	('USP10', 'Gene', '9100', (39, 44))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('knockdown', 'Var', (26, 35))	('lung cancer', 'Disease', (48, 59))	('lung cancer', 'Phenotype', 'HP:0100526', (48, 59))	('apoptosis', 'CPA', (111, 120))
294965	30655874	Thereafter, the aforementioned phenotypes may be rescued by ectopic expression of MutS homolog 2 (MSH2).	('MSH2', 'Gene', (98, 102))	('MutS homolog 2', 'Gene', (82, 96))	('MSH2', 'Gene', '4436', (98, 102))	('MutS homolog 2', 'Gene', '4436', (82, 96))	('ectopic expression', 'Var', (60, 78))	('men', 'Species', '9606', (21, 24))
294970	30655874	The function of MSH2 is to recognize DNA mismatches and then assist in recruiting DNA repair proteins to the mismatched site.	('MSH2', 'Gene', (16, 20))	('recruiting', 'MPA', (71, 81))	('MSH2', 'Gene', '4436', (16, 20))	('DNA', 'Var', (37, 40))
294972	30655874	Inhibition of protein kinase B activity and MSH2 expression increased the tamoxifen-mediated cytotoxicity in lung cancer A549 and H1703 cells.	('activity', 'MPA', (31, 39))	('lung cancer', 'Disease', (109, 120))	('MSH2', 'Gene', (44, 48))	('cytotoxicity', 'Disease', 'MESH:D064420', (93, 105))	('MSH2', 'Gene', '4436', (44, 48))	('H1703', 'CellLine', 'CVCL:1490', (130, 135))	('tamoxifen', 'Chemical', 'MESH:D013629', (74, 83))	('lung cancer', 'Phenotype', 'HP:0100526', (109, 120))	('A549', 'CellLine', 'CVCL:0023', (121, 125))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('lung cancer', 'Disease', 'MESH:D008175', (109, 120))	('cytotoxicity', 'Disease', (93, 105))	('protein kinase B', 'Enzyme', (14, 30))	('Inhibition', 'Var', (0, 10))	('increased', 'PosReg', (60, 69))
295048	30655874	Lin et al identified that the protein expression levels of two interacting proteins (USP10 and SIRT6) were downregulated in human colon cancer, which also indicated that gene-dysregulated USP10 function promotes tumorigenesis through SIRT6 degradation.	('colon cancer', 'Phenotype', 'HP:0003003', (130, 142))	('USP10', 'Gene', (188, 193))	('USP10', 'Gene', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('colon cancer', 'Disease', 'MESH:D015179', (130, 142))	('promotes', 'PosReg', (203, 211))	('SIRT6', 'Gene', (95, 100))	('USP10', 'Gene', '9100', (85, 90))	('USP10', 'Gene', '9100', (188, 193))	('SIRT6', 'Gene', '51548', (95, 100))	('protein expression levels', 'MPA', (30, 55))	('colon cancer', 'Disease', (130, 142))	('SIRT6', 'Gene', (234, 239))	('tumor', 'Disease', (212, 217))	('gene-dysregulated', 'Var', (170, 187))	('SIRT6', 'Gene', '51548', (234, 239))	('tumor', 'Disease', 'MESH:D009369', (212, 217))	('human', 'Species', '9606', (124, 129))	('downregulated', 'NegReg', (107, 120))
295097	30655874	Furthermore, the two proteins were used together to predict the outcome, and only high BRCA1 and low MSH2 expression significantly predicted an improved overall survival time.	('overall survival time', 'CPA', (153, 174))	('improved', 'PosReg', (144, 152))	('high', 'Var', (82, 86))	('BRCA1', 'Gene', '672', (87, 92))	('expression', 'MPA', (106, 116))	('BRCA1', 'Gene', (87, 92))	('MSH2', 'Gene', (101, 105))	('MSH2', 'Gene', '4436', (101, 105))
295103	30655874	Thus, the detection of USP10 may be used as a biomarker to distinguish the tumorigenesis of NSCLC.	('USP10', 'Gene', (23, 28))	('NSCLC', 'Phenotype', 'HP:0030358', (92, 97))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('USP10', 'Gene', '9100', (23, 28))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('NSCLC', 'Disease', (92, 97))	('detection', 'Var', (10, 19))	('NSCLC', 'Disease', 'MESH:D002289', (92, 97))	('tumor', 'Disease', (75, 80))
295145	30258932	For example, in breast cancer, overexpression of NEAT1 promotes EMT and invasion in vitro as well as dissemination and metastasis in vivo.	('breast cancer', 'Disease', (16, 29))	('overexpression', 'Var', (31, 45))	('promotes', 'PosReg', (55, 63))	('NEAT1', 'Gene', '283131', (49, 54))	('NEAT1', 'Gene', (49, 54))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('dissemination', 'CPA', (101, 114))	('breast cancer', 'Disease', 'MESH:D001943', (16, 29))	('breast cancer', 'Phenotype', 'HP:0003002', (16, 29))
295146	30258932	Exogenous modulation of NEAT1 modulates gemcitabine sensitivity in cholangiocarcinoma.	('modulates', 'Reg', (30, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('modulation', 'Var', (10, 20))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (67, 85))	('gemcitabine sensitivity', 'MPA', (40, 63))	('NEAT1', 'Gene', '283131', (24, 29))	('NEAT1', 'Gene', (24, 29))	('cholangiocarcinoma', 'Disease', (67, 85))	('gemcitabine', 'Chemical', 'MESH:C056507', (40, 51))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (67, 85))
295148	30258932	Moreover, in breast cancer, hepatocellular carcinoma, and papillary kidney cancer, whole-genome analysis indicates NEAT1 carries specific mutations that affect their expression levels.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (28, 52))	('kidney cancer', 'Phenotype', 'HP:0009726', (68, 81))	('hepatocellular carcinoma', 'Disease', (28, 52))	('breast cancer', 'Disease', 'MESH:D001943', (13, 26))	('papillary kidney cancer', 'Disease', (58, 81))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (28, 52))	('affect', 'Reg', (153, 159))	('breast cancer', 'Phenotype', 'HP:0003002', (13, 26))	('expression levels', 'MPA', (166, 183))	('breast cancer', 'Disease', (13, 26))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('carcinoma', 'Phenotype', 'HP:0030731', (43, 52))	('papillary kidney cancer', 'Phenotype', 'HP:0006766', (58, 81))	('NEAT1', 'Gene', (115, 120))	('papillary kidney cancer', 'Disease', 'MESH:D007681', (58, 81))	('NEAT1', 'Gene', '283131', (115, 120))	('mutations', 'Var', (138, 147))
295149	30258932	rs512715 of NEAT1 is also associated with an increased risk of cervical cancer.	('rs512715', 'Mutation', 'rs512715', (0, 8))	('NEAT1', 'Gene', (12, 17))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('cervical cancer', 'Disease', 'MESH:D002583', (63, 78))	('rs512715', 'Var', (0, 8))	('cervical cancer', 'Disease', (63, 78))	('NEAT1', 'Gene', '283131', (12, 17))	('associated', 'Reg', (26, 36))
295172	30258932	However, a recent study indicated that in breast invasive cancer, from TCGA datasets, NEAT1 was focally deleted in ~8% of breast cancers and its promoters carried various mutations, and three out of the four mutations they validated reproducibly decreased NEAT1 expression compared with the wild type sequence.	('NEAT1', 'Gene', '283131', (256, 261))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('breast cancers', 'Disease', 'MESH:D001943', (122, 136))	('breast cancers', 'Disease', (122, 136))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('breast cancer', 'Phenotype', 'HP:0003002', (122, 135))	('NEAT1', 'Gene', (256, 261))	('deleted', 'NegReg', (104, 111))	('cancers', 'Phenotype', 'HP:0002664', (129, 136))	('expression', 'MPA', (262, 272))	('breast invasive cancer', 'Disease', (42, 64))	('mutations', 'Var', (208, 217))	('NEAT1', 'Gene', '283131', (86, 91))	('breast invasive cancer', 'Disease', 'MESH:D001943', (42, 64))	('NEAT1', 'Gene', (86, 91))	('breast cancers', 'Phenotype', 'HP:0003002', (122, 136))	('mutations', 'Var', (171, 180))	('decreased', 'NegReg', (246, 255))
295185	30258932	In lung cancer, NEAT1 is up-regulated by the direct binding of Oct4, since knockdown of NEAT1 abolishes Oct4-mediated lung cancer cell growth and motility.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('lung cancer', 'Phenotype', 'HP:0100526', (3, 14))	('Oct4', 'Gene', '5460', (63, 67))	('lung cancer', 'Disease', (118, 129))	('abolishes', 'NegReg', (94, 103))	('NEAT1', 'Gene', (88, 93))	('Oct4', 'Gene', (104, 108))	('knockdown', 'Var', (75, 84))	('binding', 'Interaction', (52, 59))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('NEAT1', 'Gene', (16, 21))	('lung cancer', 'Disease', (3, 14))	('Oct4', 'Gene', (63, 67))	('lung cancer', 'Disease', 'MESH:D008175', (118, 129))	('lung cancer', 'Phenotype', 'HP:0100526', (118, 129))	('NEAT1', 'Gene', '283131', (88, 93))	('up-regulated', 'PosReg', (25, 37))	('motility', 'CPA', (146, 154))	('NEAT1', 'Gene', '283131', (16, 21))	('lung cancer', 'Disease', 'MESH:D008175', (3, 14))	('Oct4', 'Gene', '5460', (104, 108))
295197	30258932	The aberrant expression of NEAT1 in certain types of cancer may be resulted from the cooperation and antagonism between different transcription factors.	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('expression', 'MPA', (13, 23))	('aberrant', 'Var', (4, 12))	('NEAT1', 'Gene', '283131', (27, 32))	('NEAT1', 'Gene', (27, 32))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('resulted from', 'Reg', (67, 80))
295204	30258932	In laryngeal squamous cell cancer, high expression of NEAT1 decreases miR-107 expression, thus regulating CDK6 level and exerting an oncogenic effect.	('decreases', 'NegReg', (60, 69))	('regulating', 'Reg', (95, 105))	('laryngeal squamous cell cancer', 'Disease', (3, 33))	('NEAT1', 'Gene', (54, 59))	('expression', 'MPA', (78, 88))	('NEAT1', 'Gene', '283131', (54, 59))	('laryngeal squamous cell cancer', 'Disease', 'MESH:D002294', (3, 33))	('CDK6', 'Gene', (106, 110))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('CDK6', 'Gene', '1021', (106, 110))	('oncogenic effect', 'CPA', (133, 149))	('high expression', 'Var', (35, 50))	('miR-107', 'Gene', '406901', (70, 77))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (13, 33))	('miR-107', 'Gene', (70, 77))
295223	30258932	Recently, several studies have revealed the mutations and polymorphisms of NEAT1 are also closely correlated with the prognosis of cancers, which has added complexity to NEAT1-associated signaling and function.	('NEAT1', 'Gene', '283131', (75, 80))	('cancers', 'Disease', 'MESH:D009369', (131, 138))	('cancers', 'Phenotype', 'HP:0002664', (131, 138))	('cancers', 'Disease', (131, 138))	('NEAT1', 'Gene', (75, 80))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('polymorphisms', 'Var', (58, 71))	('correlated', 'Reg', (98, 108))	('mutations', 'Var', (44, 53))	('NEAT1', 'Gene', '283131', (170, 175))	('NEAT1', 'Gene', (170, 175))
295224	30258932	Moreover, since the two major isoforms of NEAT1 produced from alternative transcription have been reported to have different cellular location and tumor regulation properties, it is necessary to distinguish the exact expression and function of these two isoforms.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('NEAT1', 'Gene', '283131', (42, 47))	('alternative transcription', 'Var', (62, 87))	('NEAT1', 'Gene', (42, 47))	('tumor', 'Disease', 'MESH:D009369', (147, 152))
295228	29617660	SCCs harbor 3q, 5p, and other recurrent chromosomal copy-number alterations (CNAs), DNA mutations, and/or aberrant methylation of genes and microRNAs, which are correlated with the expression of multi-gene programs linked to squamous cell stemness, epithelial-to-mesenchymal differentiation, growth, genomic integrity, oxidative damage, death, and inflammation.	('methylation', 'Var', (115, 126))	('SCC', 'Gene', (0, 3))	('inflammation', 'Disease', (348, 360))	('squamous cell stemness', 'Disease', (225, 247))	('mutations', 'Var', (88, 97))	('SCC', 'Gene', '6317', (0, 3))	('aberrant methylation', 'Var', (106, 126))	('squamous cell stemness', 'Disease', 'MESH:D002294', (225, 247))	('DNA', 'Gene', (84, 87))	('inflammation', 'Disease', 'MESH:D007249', (348, 360))
295229	29617660	Low-CNA SCCs tended to be HPV(+) and display hypermethylation with repression of TET1 demethylase and FANCF, previously linked to predisposition to SCC, or harbor mutations affecting CASP8, RAS-MAPK pathways, chromatin modifiers, and immunoregulatory molecules.	('RAS-MAPK pathways', 'Pathway', (190, 207))	('repression', 'NegReg', (67, 77))	('mutations', 'Var', (163, 172))	('TET1', 'Gene', '80312', (81, 85))	('FANCF', 'Gene', (102, 107))	('SCC', 'Gene', (8, 11))	('SCC', 'Gene', (148, 151))	('HPV', 'Species', '10566', (26, 29))	('hypermethylation', 'MPA', (45, 61))	('CASP8', 'Gene', '841', (183, 188))	('FANCF', 'Gene', '2188', (102, 107))	('TET1', 'Gene', (81, 85))	('SCC', 'Gene', '6317', (8, 11))	('CASP8', 'Gene', (183, 188))	('affecting', 'Reg', (173, 182))	('SCC', 'Gene', '6317', (148, 151))
295230	29617660	We uncovered hypomethylation of the alternative promoter that drives expression of the DeltaNp63 oncogene and embedded miR944.	('hypomethylation', 'Var', (13, 28))	('DeltaNp63', 'Chemical', '-', (87, 96))	('DeltaNp63', 'Gene', (87, 96))	('drives', 'PosReg', (62, 68))	('expression', 'MPA', (69, 79))	('miR944', 'Gene', (119, 125))	('miR944', 'Gene', '100126340', (119, 125))
295231	29617660	reveal that squamous cell cancers from different tissue sites may be distinguished from other cancers and subclassified molecularly by recurrent alterations in chromosomes, DNA methylation, messenger and microRNA expression, or by mutations.	('cancers', 'Disease', 'MESH:D009369', (94, 101))	('alterations', 'Reg', (145, 156))	('cancers', 'Phenotype', 'HP:0002664', (26, 33))	('mutations', 'Var', (231, 240))	('cancers', 'Disease', 'MESH:D009369', (26, 33))	('cancers', 'Phenotype', 'HP:0002664', (94, 101))	('cancers', 'Disease', (26, 33))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('squamous cell cancers', 'Disease', (12, 33))	('squamous cell cancers', 'Phenotype', 'HP:0002860', (12, 33))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('chromosomes', 'MPA', (160, 171))	('squamous cell cancers', 'Disease', 'MESH:D002294', (12, 33))	('cancers', 'Disease', (94, 101))	('DNA', 'MPA', (173, 176))
295241	29617660	Further, these tools uncovered broader and subtype-related genetic and epigenetic alterations that distinguish SCCs from other cancers and from one another.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('epigenetic alterations', 'Var', (71, 93))	('SCC', 'Gene', (111, 114))	('cancers', 'Disease', 'MESH:D009369', (127, 134))	('cancers', 'Phenotype', 'HP:0002664', (127, 134))	('cancers', 'Disease', (127, 134))	('SCC', 'Gene', '6317', (111, 114))
295243	29617660	These identified recurrent chromosomal alterations and CpG methylation strongly correlated with the expression of multiple genes that converge on pathways and functions relevant to SCC biology and therapeutics.	('correlated', 'Reg', (80, 90))	('chromosomal alterations', 'Var', (27, 50))	('SCC', 'Gene', (181, 184))	('SCC', 'Gene', '6317', (181, 184))	('expression', 'MPA', (100, 110))	('methylation', 'Var', (59, 70))
295248	29617660	To identify a molecular signature-based classification, we conducted an integrated TM and iC analysis of 9,759 tumor samples from PanCancer-33 cancers for which DNA copy-number alteration (CNA), methylation, mRNA, microRNA (miRNA), and a smaller set of protein expression profiles were available.	('copy-number alteration', 'Var', (165, 187))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('methylation', 'MPA', (195, 206))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('Cancer', 'Phenotype', 'HP:0002664', (133, 139))	('microRNA', 'MPA', (214, 222))	('mRNA', 'MPA', (208, 212))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumor', 'Disease', (111, 116))	('cancers', 'Disease', 'MESH:D009369', (143, 150))	('cancers', 'Phenotype', 'HP:0002664', (143, 150))	('cancers', 'Disease', (143, 150))
295252	29617660	All three major SCC-related clusters included significant chromosome 3q and 5p copy gains (Figures 1E and 1F; Table S1A).	('chromosome', 'Var', (58, 68))	('SCC', 'Gene', '6317', (16, 19))	('SCC', 'Gene', (16, 19))
295253	29617660	Many iC10/25 HPV(-) SCC tumors were associated with higher DNA CNA and broad hypomethylation, with corresponding patterns of increased mRNA and miRNA expression (Figures 1F-1I).	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('increased', 'PosReg', (125, 134))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('iC10/25 HPV(-', 'Var', (5, 18))	('higher', 'PosReg', (52, 58))	('SCC tumors', 'Disease', 'MESH:D009369', (20, 30))	('DNA CNA', 'MPA', (59, 66))	('SCC tumors', 'Disease', (20, 30))	('HPV', 'Species', '10566', (13, 16))	('broad hypomethylation', 'MPA', (71, 92))
295255	29617660	These observations suggest that most SCCs are driven by a combination of recurrent CN and other alterations, while HPV, epigenetic, or other alterations may have a greater role in subtypes with fewer CNAs.	('SCC', 'Gene', '6317', (37, 40))	('alterations', 'Var', (96, 107))	('SCC', 'Gene', (37, 40))	('HPV', 'Species', '10566', (115, 118))	('driven by', 'Reg', (46, 55))
295266	29617660	Unexpectedly, the CN/expression correlation for TP63 was lower than for other nearby genes, and it was associated with predominant expression of the DeltaNp63alpha isoform for all 5 sites (Figure 2H), consistent with epigenetic regulation of these alternatively transcribed isoforms discovered below.	('DeltaNp63alpha', 'Var', (149, 163))	('CN/expression correlation', 'MPA', (18, 43))	('DeltaNp63', 'Chemical', '-', (149, 158))	('TP63', 'Gene', (48, 52))	('TP63', 'Gene', '8626', (48, 52))	('lower', 'NegReg', (57, 62))
295269	29617660	These observations suggest that 3q26 or 11q22 CNAs could be alternative drivers orchestrating deregulation of ACTLA6/TP63 differentiation and Hippo growth pathway YAP1 gene expression in SCC subtypes.	('TP63', 'Gene', (117, 121))	('deregulation', 'MPA', (94, 106))	('SCC', 'Gene', (187, 190))	('3q26', 'Var', (32, 36))	('SCC', 'Gene', '6317', (187, 190))	('YAP1', 'Gene', (163, 167))	('YAP1', 'Gene', '10413', (163, 167))	('TP63', 'Gene', '8626', (117, 121))
295274	29617660	Together, alteration of 5p genes with these functions is consistent with the generation of increased CNAs found in most SCCs.	('5p genes', 'Gene', (24, 32))	('SCC', 'Gene', '6317', (120, 123))	('increased', 'PosReg', (91, 100))	('alteration', 'Var', (10, 20))	('CNAs', 'Gene', (101, 105))	('SCC', 'Gene', (120, 123))
295282	29617660	Copy loss of TNFR-associated factor TRAF3 has recently been implicated as a tumor suppressor of NF-kappaB gene expression and HPV infection, and it is a marker for HPV(+) HNSC tumors with better prognosis.	('TRAF3', 'Gene', (36, 41))	('tumor', 'Disease', (76, 81))	('NF-kappaB', 'Gene', (96, 105))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('tumor', 'Disease', (176, 181))	('TNFR', 'Gene', '7132', (13, 17))	('NF-kappaB', 'Gene', '4790', (96, 105))	('HPV infection', 'Disease', 'MESH:D030361', (126, 139))	('tumor', 'Disease', 'MESH:D009369', (176, 181))	('Copy loss', 'Var', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('HPV infection', 'Disease', (126, 139))	('TNFR', 'Gene', (13, 17))	('tumors', 'Phenotype', 'HP:0002664', (176, 182))	('HNSC tumors', 'Disease', 'MESH:D009369', (171, 182))	('TRAF3', 'Gene', '7187', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('HNSC tumors', 'Disease', (171, 182))	('HPV', 'Species', '10566', (164, 167))	('HPV', 'Species', '10566', (126, 129))
295286	29617660	Together, the significance of these CN alterations, distinguishing major subsets of SCC by iC (Figure 1B; Table S1A), and strongly correlated expression by MVisAGe (Figure 2), support their roles as important drivers of SCC.	('SCC', 'Gene', '6317', (84, 87))	('SCC', 'Gene', (220, 223))	('SCC', 'Gene', '6317', (220, 223))	('alterations', 'Var', (39, 50))	('SCC', 'Gene', (84, 87))
295287	29617660	Integration of unsupervised hierarchical clustering of significant CNAs, available for 1,386 samples of squamous histology, HPV status, and significant mutations, helped resolve different candidate drivers of high- and low-copy-number variation (CNV) subtypes (Figures 3A, 3B, and S2A-S2C).	('low-copy-number', 'NegReg', (219, 234))	('high-', 'Var', (209, 214))	('HPV', 'Species', '10566', (124, 127))
295289	29617660	C1-4 with higher CNAs displayed 5p amplification and the highest frequency of deleterious mutations of TP53, consistent with their function in maintaining genomic integrity.	('TP53', 'Gene', '7157', (103, 107))	('TP53', 'Gene', (103, 107))	('mutations', 'Var', (90, 99))	('5p amplification', 'MPA', (32, 48))
295290	29617660	Mutations in NFE2L2 and KEAP1, important in oxidative damage, were also enriched in C1-3.	('KEAP1', 'Gene', '9817', (24, 29))	('NFE2L2', 'Gene', '4780', (13, 19))	('KEAP1', 'Gene', (24, 29))	('NFE2L2', 'Gene', (13, 19))	('Mutations', 'Var', (0, 9))
295291	29617660	Low-CNA C5A and B tumors were enriched for mutations in (1) epigenetic modifiers EP300, MLL4, and CTCF; (2) mitogen pathway components EPHA2, HRAS, MAPK1, and RAC1; and (3) cell death mediator caspase CASP8 (Figures 1A, 1B, and S2B).	('CASP8', 'Gene', '841', (201, 206))	('tumors', 'Disease', (18, 24))	('caspase', 'Gene', (193, 200))	('CTCF', 'Gene', (98, 102))	('CASP8', 'Gene', (201, 206))	('C5A', 'Gene', (8, 11))	('EPHA2', 'Gene', '1969', (135, 140))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('EP300', 'Gene', '2033', (81, 86))	('MAPK1', 'Gene', '5594', (148, 153))	('RAC1', 'Gene', (159, 163))	('caspase', 'Gene', '841', (193, 200))	('MLL4', 'Gene', '8085', (88, 92))	('C5A', 'Gene', '728', (8, 11))	('MLL4', 'Gene', (88, 92))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('EP300', 'Gene', (81, 86))	('HRAS', 'Gene', '3265', (142, 146))	('RAC1', 'Gene', '5879', (159, 163))	('CTCF', 'Gene', '10664', (98, 102))	('HRAS', 'Gene', (142, 146))	('mutations', 'Var', (43, 52))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('EPHA2', 'Gene', (135, 140))	('MAPK1', 'Gene', (148, 153))
295293	29617660	Mutations in EPHA2, HRAS, MAPK1, and RAC1 cumulatively affected ~27% and 46% of C5 and C5A tumors, with EPHA2 and HRAS mutations tending toward mutual exclusivity across all C5 samples (Figure S2B; p = 0.037).	('tumors', 'Disease', 'MESH:D009369', (91, 97))	('RAC1', 'Gene', '5879', (37, 41))	('affected', 'Reg', (55, 63))	('MAPK1', 'Gene', '5594', (26, 31))	('HRAS', 'Gene', '3265', (20, 24))	('HRAS', 'Gene', (20, 24))	('EPHA2', 'Gene', '1969', (104, 109))	('EPHA2', 'Gene', (13, 18))	('Mutations', 'Var', (0, 9))	('C5A', 'Gene', (87, 90))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('MAPK1', 'Gene', (26, 31))	('HRAS', 'Gene', '3265', (114, 118))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('HRAS', 'Gene', (114, 118))	('EPHA2', 'Gene', '1969', (13, 18))	('tumors', 'Disease', (91, 97))	('RAC1', 'Gene', (37, 41))	('EPHA2', 'Gene', (104, 109))	('C5A', 'Gene', '728', (87, 90))
295294	29617660	EPHA2 mutations were enriched for truncating alterations, consistent with evidence that it serves as a negative regulator of RAS pathway signaling.	('truncating alterations', 'MPA', (34, 56))	('EPHA2', 'Gene', '1969', (0, 5))	('EPHA2', 'Gene', (0, 5))	('mutations', 'Var', (6, 15))
295295	29617660	Conversely, HRAS, MAPK1, and RAC1 showed missense hotspot mutations (Figure S2C), implicated in signal activation.	('MAPK1', 'Gene', '5594', (18, 23))	('RAC1', 'Gene', '5879', (29, 33))	('missense', 'Var', (41, 49))	('RAC1', 'Gene', (29, 33))	('MAPK1', 'Gene', (18, 23))	('HRAS', 'Gene', '3265', (12, 16))	('HRAS', 'Gene', (12, 16))
295297	29617660	C5A SCC displayed mutations of HLA-A and -B and deletions of B2M, implicated in immune escape (Figure 3B).	('SCC', 'Gene', (4, 7))	('B2M', 'Gene', (61, 64))	('B2M', 'Gene', '567', (61, 64))	('SCC', 'Gene', '6317', (4, 7))	('HLA-A and -B', 'Gene', '3105;3106', (31, 43))	('deletions', 'Var', (48, 57))	('C5A', 'Gene', '728', (0, 3))	('C5A', 'Gene', (0, 3))	('mutations', 'Var', (18, 27))
295300	29617660	CN and mutations inactivating FAT1 trended toward mutual exclusivity with amplification of YAP1 (p = 0.08), consistent with a role of FAT1 as a negative regulator of Hippo growth pathway.	('mutations inactivating', 'Var', (7, 29))	('FAT1', 'Gene', '2195', (30, 34))	('FAT1', 'Gene', '2195', (134, 138))	('YAP1', 'Gene', '10413', (91, 95))	('FAT1', 'Gene', (30, 34))	('FAT1', 'Gene', (134, 138))	('YAP1', 'Gene', (91, 95))
295301	29617660	Interestingly, these were exclusive of amplifications of 3q gene PIK3CA (p = 0.005) or mutations of PTEN (p = 0.002), which could potentially enhance AKT signaling implicated in YAP1 inactivation via cytoplasmic sequestration.	('PTEN', 'Gene', (100, 104))	('PTEN', 'Gene', '5728', (100, 104))	('YAP1', 'Gene', (178, 182))	('YAP1', 'Gene', '10413', (178, 182))	('AKT', 'Gene', '207', (150, 153))	('PIK3CA', 'Gene', (65, 71))	('enhance', 'PosReg', (142, 149))	('AKT', 'Gene', (150, 153))	('PIK3CA', 'Gene', '5290', (65, 71))	('mutations', 'Var', (87, 96))
295302	29617660	Inactivating deletions or mutations of TP63 and ZNF750 support possible alternative mechanisms for deregulation of the TP63-ZNF750 differentiation pathways (Figures 2D, 2E, S2D, and S2E).	('Inactivating deletions', 'Var', (0, 22))	('ZNF750', 'Gene', '79755', (124, 130))	('TP63', 'Gene', '8626', (119, 123))	('ZNF750', 'Gene', (48, 54))	('deregulation', 'MPA', (99, 111))	('TP63', 'Gene', (39, 43))	('TP63', 'Gene', '8626', (39, 43))	('mutations', 'Var', (26, 35))	('TP63', 'Gene', (119, 123))	('ZNF750', 'Gene', (124, 130))	('ZNF750', 'Gene', '79755', (48, 54))
295305	29617660	Notably, hypermethylated C2 enriched for HPV(+) CESC and HNSC (p < 2.2E-16) predominantly overlapped the low-CNA cluster C5A (Figures 4A, 4B, and S3A; Fisher's exact test for CNV-MethylMix Clusters, p = 1E-5).	('HPV', 'Species', '10566', (41, 44))	('hypermethylated', 'Var', (9, 24))	('S3A', 'Gene', (146, 149))	('S3A', 'Gene', '6189', (146, 149))	('C5A', 'Gene', '728', (121, 124))	('C5A', 'Gene', (121, 124))
295307	29617660	Among 28/51 genes significantly mutated and differentially distributed among the methylation clusters in SCC (Table S2L), hypermethylated HPV-enriched C2 also harbored fewer mutations in HRAS, CDKN2A(p16), CASP8, NFE2L2, NSD1, and TP53 than did clusters with predominantly HPV(-) SCC (Figures 4A and S3B).	('HRAS', 'Gene', '3265', (187, 191))	('NFE2L2', 'Gene', (213, 219))	('TP53', 'Gene', '7157', (231, 235))	('HRAS', 'Gene', (187, 191))	('SCC', 'Gene', '6317', (280, 283))	('SCC', 'Gene', '6317', (105, 108))	('NSD1', 'Gene', '64324', (221, 225))	('CDKN2A', 'Gene', (193, 199))	('HPV', 'Species', '10566', (138, 141))	('CASP8', 'Gene', '841', (206, 211))	('SCC', 'Gene', (280, 283))	('SCC', 'Gene', (105, 108))	('HPV', 'Species', '10566', (273, 276))	('mutations', 'Var', (174, 183))	('p16', 'Gene', (200, 203))	('p16', 'Gene', '1029', (200, 203))	('CDKN2A', 'Gene', '1029', (193, 199))	('CASP8', 'Gene', (206, 211))	('TP53', 'Gene', (231, 235))	('fewer', 'NegReg', (168, 173))	('NFE2L2', 'Gene', '4780', (213, 219))	('NSD1', 'Gene', (221, 225))
295308	29617660	Strikingly, hypomethylation in C5 was linked to inactivating mutations in the H3K36 histone methyltransferase NSD1, defining a distinct subtype across SCC tissue sites previously observed in HNSC.	('NSD1', 'Gene', '64324', (110, 114))	('linked', 'Reg', (38, 44))	('inactivating mutations', 'Var', (48, 70))	('SCC', 'Gene', '6317', (151, 154))	('NSD1', 'Gene', (110, 114))	('hypomethylation', 'MPA', (12, 27))	('H3K36', 'Gene', (78, 83))	('SCC', 'Gene', (151, 154))
295311	29617660	TET1 is a demethylase whose inactivation is implicated in sustaining CpG hypermethylation in cancer, consistent with hypermethylation found in C2 and C4.	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('hypermethylation', 'Var', (73, 89))	('TET1', 'Gene', '80312', (0, 4))	('inactivation', 'Var', (28, 40))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('CpG', 'Protein', (69, 72))	('TET1', 'Gene', (0, 4))
295313	29617660	A broader analysis of FANC and DNA damage repair pathway genes revealed an unexpectedly high frequency (~12%) of somatic methylation, CNAs, and mutations affecting FANC-BRCA genes in SCC (Figure 4E), suggesting that acquired as well as germline alterations in this pathway may contribute to the development of a subset of SCC.	('FANC', 'Gene', (164, 168))	('SCC', 'Gene', '6317', (322, 325))	('contribute', 'Reg', (277, 287))	('SCC', 'Gene', (183, 186))	('FANC-BRCA', 'Gene', '672', (164, 173))	('FANC-BRCA', 'Gene', (164, 173))	('FANC', 'Gene', '2188;5888;672', (22, 26))	('SCC', 'Gene', '6317', (183, 186))	('mutations', 'Var', (144, 153))	('SCC', 'Gene', (322, 325))	('FANC', 'Gene', (22, 26))	('FANC', 'Gene', '2188;5888;672', (164, 168))
295314	29617660	Of these, FANCF methylation is more often observed in Pan-SCC than other PanCan-33 tumors (Figures 4F and S3C; chi-square, p < 2.2E-16).	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('SCC', 'Gene', (58, 61))	('tumors', 'Disease', (83, 89))	('SCC', 'Gene', '6317', (58, 61))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('tumors', 'Disease', 'MESH:D009369', (83, 89))	('FANCF', 'Gene', (10, 15))	('methylation', 'Var', (16, 27))	('observed', 'Reg', (42, 50))	('FANCF', 'Gene', '2188', (10, 15))
295336	29617660	C1 was enriched for amplification of MAPK1 (p = 0.001) and deletion of NF-kappaB negative regulator TRAF3 (p = 3E-05), relative to other clusters.	('TRAF3', 'Gene', '7187', (100, 105))	('NF-kappaB', 'Gene', (71, 80))	('MAPK1', 'Gene', '5594', (37, 42))	('deletion', 'Var', (59, 67))	('MAPK1', 'Gene', (37, 42))	('NF-kappaB', 'Gene', '4790', (71, 80))	('TRAF3', 'Gene', (100, 105))
295337	29617660	In contrast, C2, with predominantly LUSC and ESCA, showed higher inferred activation of proliferation-related cell cycle components, with enrichment for CDK6 amplification (p = 1.3E-08), CDKN2A deletion (3.6E-07), a decreased immune signature, and a lower proportion of cases with amplification of immune checkpoint PDL1 (p = 0.0003).	('CDK6', 'Gene', (153, 157))	('deletion', 'Var', (194, 202))	('decreased', 'NegReg', (216, 225))	('CDKN2A', 'Gene', (187, 193))	('CDK6', 'Gene', '1021', (153, 157))	('CDKN2A', 'Gene', '1029', (187, 193))	('immune signature', 'MPA', (226, 242))	('PDL1', 'Gene', '29126', (316, 320))	('activation', 'PosReg', (74, 84))	('proliferation-related cell cycle components', 'CPA', (88, 131))	('PDL1', 'Gene', (316, 320))
295338	29617660	C3 with HNSC showed MAPK-JUN-FOS, TP53/63/73, and proliferation signatures and lower immune signatures, associated with amplifications of EGFR, IGF1R, and PDGFA (p <= 0.005).	('PDGFA', 'Gene', '5154', (155, 160))	('FOS', 'Gene', '2353', (29, 32))	('amplifications', 'Var', (120, 134))	('TP53', 'Gene', (34, 38))	('EGFR', 'Gene', '1956', (138, 142))	('lower', 'NegReg', (79, 84))	('EGFR', 'Gene', (138, 142))	('proliferation signatures', 'CPA', (50, 74))	('IGF1R', 'Gene', (144, 149))	('PDGFA', 'Gene', (155, 160))	('IGF1R', 'Gene', '3480', (144, 149))	('FOS', 'Gene', (29, 32))	('TP53', 'Gene', '7157', (34, 38))
295339	29617660	C4 and C5, with HPV+ CESC and some HPV(-) tumors, shared high proliferation-related features, but they had a lower proportion of cases with amplifications of MAPK1 (p <= 6.4E-0.05) and FGFR1 (p = 0.0006).	('lower', 'NegReg', (109, 114))	('amplifications', 'Var', (140, 154))	('HPV', 'Species', '10566', (35, 38))	('tumors', 'Disease', (42, 48))	('tumors', 'Disease', 'MESH:D009369', (42, 48))	('MAPK1', 'Gene', (158, 163))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('HPV', 'Species', '10566', (16, 19))	('FGFR1', 'Gene', (185, 190))	('MAPK1', 'Gene', '5594', (158, 163))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
295340	29617660	C4, which contains higher MYB/MYC negative regulator FBXW7 mutations (p = 0.04), displayed low inferred activation of immune features, while C5 was enriched for PDL1 (CD274) amplification (p = 0.0009), differentiating these HPV(+) SCC subsets.	('FBXW7', 'Gene', (53, 58))	('CD274', 'Gene', '29126', (167, 172))	('SCC', 'Gene', '6317', (231, 234))	('PDL1', 'Gene', '29126', (161, 165))	('HPV', 'Species', '10566', (224, 227))	('CD274', 'Gene', (167, 172))	('PDL1', 'Gene', (161, 165))	('mutations', 'Var', (59, 68))	('SCC', 'Gene', (231, 234))
295341	29617660	LUSC enriched cluster C6, which contained a higher proportion of cases with CDK6 amplifications (p = 1.9E-05) and exhibited higher proliferation-related signature but lower JUN/FOS and TP53/63/73 pathway activation.	('FOS', 'Gene', '2353', (177, 180))	('lower', 'NegReg', (167, 172))	('activation', 'PosReg', (204, 214))	('amplifications', 'Var', (81, 95))	('TP53', 'Gene', (185, 189))	('proliferation-related signature', 'MPA', (131, 162))	('FOS', 'Gene', (177, 180))	('higher', 'PosReg', (124, 130))	('CDK6', 'Gene', (76, 80))	('TP53', 'Gene', '7157', (185, 189))	('CDK6', 'Gene', '1021', (76, 80))
295347	29617660	Notably, a C2 arm and C3 with mostly HPV(+) CESC and C4 and C5 with LUSC, ESCA, CESC, and BLCA were enriched for growth factor and rapamycin-sensitive mTORC1 target P70S6KpT389 and RAD51 DNA damage factor.	('P70S6KpT389', 'Var', (165, 176))	('RAD51', 'Gene', '5888', (181, 186))	('mTORC1', 'Gene', '382056', (151, 157))	('HPV', 'Species', '10566', (37, 40))	('mTORC1', 'Gene', (151, 157))	('RAD51', 'Gene', (181, 186))
295351	29617660	AKTp473/T308 and GSK3p21S9 were enriched in C4 arm 1 and C6.	('AKT', 'Gene', (0, 3))	('C4 arm 1', 'Disease', (44, 52))	('GSK3p21S9', 'Var', (17, 26))	('AKT', 'Gene', '207', (0, 3))
295352	29617660	We found positive Pearson's correlations between upstream MAPKpT202Y204 and JUN phospho-proteins, between AKT and mTOR, and among GSK3alphabeta, GSK3p21S9, and NF-kappaBpS536 (Figure 6B).	('AKT', 'Gene', (106, 109))	('NF-kappaB', 'Gene', (160, 169))	('mTOR', 'Gene', '2475', (114, 118))	('JUN phospho-proteins', 'MPA', (76, 96))	('mTOR', 'Gene', (114, 118))	('AKT', 'Gene', '207', (106, 109))	('NF-kappaB', 'Gene', '4790', (160, 169))	('MAPKpT202Y204', 'Var', (58, 71))	('correlations', 'Interaction', (28, 40))
295361	29617660	Of these, we highlight the two with the largest positive fold changes in SCC, miR-205-5p and miR-944, and a set that included miRs-200a-c-5/3p, 141-5/3p, and 429, which we observed to exhibit decreased expression linked with an increased EMT score in miRNA C2 and C3 (Figures 7A and S7A, EMT score track).	('decreased', 'NegReg', (192, 201))	('miR-944', 'Gene', (93, 100))	('miR-205', 'Gene', (78, 85))	('SCC', 'Gene', (73, 76))	('miRs-200a-c-5/3p', 'Var', (126, 142))	('expression', 'MPA', (202, 212))	('EMT', 'Gene', (238, 241))	('miR-205', 'Gene', '406988', (78, 85))	('increased EMT', 'Phenotype', 'HP:0008151', (228, 241))	('increased', 'PosReg', (228, 237))	('EMT', 'Gene', '3702', (238, 241))	('EMT', 'Gene', (288, 291))	('SCC', 'Gene', '6317', (73, 76))	('EMT', 'Gene', '3702', (288, 291))	('miR-944', 'Gene', '100126340', (93, 100))
295362	29617660	Notably, miR-205-5p as well as miR-200/141 and 429 were anti-correlated (rho <= -0.4) to the EMT-related transcription factors ZEB1 and ZEB2 (Figures 7C and S7C).	('miR-205', 'Gene', (9, 16))	('ZEB2', 'Gene', '9839', (136, 140))	('miR-205', 'Gene', '406988', (9, 16))	('ZEB2', 'Gene', (136, 140))	('EMT', 'Gene', (93, 96))	('ZEB1', 'Gene', '6935', (127, 131))	('EMT', 'Gene', '3702', (93, 96))	('ZEB1', 'Gene', (127, 131))	('miR-200/141', 'Var', (31, 42))
295364	29617660	The EMT-related mRNAs ZEB2, CTGF, and CYR61 were observed to cluster together above in a branch of mRNA C1 with LUSC and C6 with HNSC that overlap miRNA C2 and C3 with decreased expression of these miRs (Figure S7A, mRNA track).	('miRNA', 'Var', (147, 152))	('CTGF', 'Gene', '1490', (28, 32))	('EMT', 'Gene', (4, 7))	('CYR61', 'Gene', '3491', (38, 43))	('CTGF', 'Gene', (28, 32))	('EMT', 'Gene', '3702', (4, 7))	('decreased', 'NegReg', (168, 177))	('expression', 'MPA', (178, 188))	('ZEB2', 'Gene', (22, 26))	('CYR61', 'Gene', (38, 43))	('ZEB2', 'Gene', '9839', (22, 26))
295373	29617660	The cg06520450 site with lowest methylation was most significantly correlated with overall expression of TP63 and miR-944 (Tables S5A and S5B).	('S5A', 'Gene', (130, 133))	('expression', 'MPA', (91, 101))	('miR-944', 'Gene', '100126340', (114, 121))	('cg06520450', 'Var', (4, 14))	('TP63', 'Gene', '8626', (105, 109))	('correlated', 'Reg', (67, 77))	('TP63', 'Gene', (105, 109))	('miR-944', 'Gene', (114, 121))	('S5B', 'Gene', '5711', (138, 141))	('methylation', 'MPA', (32, 43))	('lowest', 'NegReg', (25, 31))	('S5B', 'Gene', (138, 141))	('S5A', 'Gene', '5710', (130, 133))
295378	29617660	We uncovered a significant mutually exclusive relationship between gains in 3q or 11q22 affecting the majority of SCCs (Figure S1C; Table S2A).	('11q22', 'Gene', (82, 87))	('SCC', 'Gene', (114, 117))	('SCC', 'Gene', '6317', (114, 117))	('gains', 'Var', (67, 72))
295381	29617660	In that study, DeltaNp63 and AKT inhibition were shown to modulate YAP1.	('DeltaNp63', 'Var', (15, 24))	('AKT', 'Gene', '207', (29, 32))	('inhibition', 'NegReg', (33, 43))	('YAP1', 'Gene', (67, 71))	('DeltaNp63', 'Chemical', '-', (15, 24))	('AKT', 'Gene', (29, 32))	('modulate', 'Reg', (58, 66))	('YAP1', 'Gene', '10413', (67, 71))
295384	29617660	A correlation between overall TP63 expression and miR-944 due to hypomethylation of the same TSS CpG island is supported by a recent genome-wide analysis, but the link with the differential methylation of the alternative TSSs for TA/DeltaN isoforms was unrecognized.	('miR-944', 'Gene', '100126340', (50, 57))	('hypomethylation', 'Var', (65, 80))	('miR-944', 'Gene', (50, 57))	('TP63', 'Gene', (30, 34))	('TP63', 'Gene', '8626', (30, 34))
295387	29617660	These observations suggest that methylation and PI3K inhibitors could modulate TA/DeltaNp63 to inhibit SCC.	('modulate', 'Reg', (70, 78))	('methylation', 'Var', (32, 43))	('SCC', 'Gene', (103, 106))	('inhibit', 'NegReg', (95, 102))	('DeltaNp63', 'Chemical', '-', (82, 91))	('SCC', 'Gene', '6317', (103, 106))	('TA/DeltaNp63', 'Gene', (79, 91))
295388	29617660	Indeed, PI3K-AKT-mTOR-eIF signaling appears to be a common pathway in which recurrent 3q26 CNAs (69%; Table S2) and PIK3CA mutations (11%-27%; Figure S2A) are observed.	('PIK3CA', 'Gene', (116, 122))	('PIK3CA', 'Gene', '5290', (116, 122))	('AKT', 'Gene', '207', (13, 16))	('3q26', 'Gene', (86, 90))	('mTOR', 'Gene', (17, 21))	('mTOR', 'Gene', '2475', (17, 21))	('mutations', 'Var', (123, 132))	('AKT', 'Gene', (13, 16))
295391	29617660	SCCs are enriched for P70S6KpT389, RICTORpT1135, and RAD51 DNA damage proteins, which are associated with growth factor and rapamycin sensitivity.	('SCC', 'Gene', (0, 3))	('RICTOR', 'Gene', '253260', (35, 41))	('proteins', 'Protein', (70, 78))	('SCC', 'Gene', '6317', (0, 3))	('associated', 'Reg', (90, 100))	('RAD51', 'Gene', (53, 58))	('RAD51', 'Gene', '5888', (53, 58))	('P70S6KpT389', 'Var', (22, 33))	('RICTOR', 'Gene', (35, 41))
295393	29617660	CNAs or mutations that enhance expression and activation of receptors and kinases activating PI3K-AKT and MAPK signal axes were observed and supported by RPPA.	('activation', 'PosReg', (46, 56))	('mutations', 'Var', (8, 17))	('AKT', 'Gene', '207', (98, 101))	('expression', 'MPA', (31, 41))	('AKT', 'Gene', (98, 101))	('enhance', 'PosReg', (23, 30))
295398	29617660	FANC-BRCA defects are associated with increased sensitivity to standard DNA-damaging therapies, potentially helping explain the relative sensitivity of some HPV+ tumors to chemoradiotherapy and potential for their de-escalation.	('HPV', 'Species', '10566', (157, 160))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('FANC-BRCA', 'Gene', (0, 9))	('FANC-BRCA', 'Gene', '672', (0, 9))	('tumors', 'Disease', (162, 168))	('tumors', 'Disease', 'MESH:D009369', (162, 168))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))	('defects', 'Var', (10, 17))
295399	29617660	Targeted agents, such as WEE1 inhibitors that prevent G2 checkpoint arrest and DNA repair, may warrant investigation in SCCs with these defects or those with TP53 mutations.	('TP53', 'Gene', '7157', (158, 162))	('TP53', 'Gene', (158, 162))	('arrest', 'Disease', (68, 74))	('mutations', 'Var', (163, 172))	('SCC', 'Gene', '6317', (120, 123))	('DNA repair', 'MPA', (79, 89))	('WEE1', 'Gene', '7465', (25, 29))	('arrest', 'Disease', 'MESH:D006323', (68, 74))	('WEE1', 'Gene', (25, 29))	('SCC', 'Gene', (120, 123))
295401	29617660	Lastly, the prevalence of 11q13/22 with FADD/IAP alterations in >30% of HPV(-) HNSC, LUSC, and ESCA subtypes and their sensitivity to IAP inhibitors plus radiotherapy in recent preclinical studies support the investigation of IAP antagonists in those tumors.	('alterations', 'Var', (49, 60))	('IAP', 'Gene', (45, 48))	('clinical', 'Species', '191496', (180, 188))	('tumors', 'Disease', (251, 257))	('tumors', 'Disease', 'MESH:D009369', (251, 257))	('tumors', 'Phenotype', 'HP:0002664', (251, 257))	('tumor', 'Phenotype', 'HP:0002664', (251, 256))	('HPV', 'Species', '10566', (72, 75))	('IAP', 'Gene', '961', (134, 137))	('IAP', 'Gene', '961', (226, 229))	('11q13/22', 'Gene', (26, 34))	('IAP', 'Gene', (134, 137))	('IAP', 'Gene', (226, 229))	('IAP', 'Gene', '961', (45, 48))
295417	29617660	Significantly mutated genes were identified for each tumor type and for the combined PanSCC cohort using MutSig2CV, which combines p values from tests for high mutational frequency relative to the background mutation rate (pCV), clustering of mutations within the gene (pCL), and enrichment of mutations within evolutionarily conserved sites (pFN).	('pCL', 'Gene', (270, 273))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('mutations', 'Var', (243, 252))	('pCV', 'Species', '28355', (223, 226))	('SCC', 'Gene', (88, 91))	('tumor', 'Disease', (53, 58))	('mutations', 'Var', (294, 303))	('pCL', 'Gene', '2324', (270, 273))	('SCC', 'Gene', '6317', (88, 91))
295426	29617660	Therefore, the silencing status for p16 was called with probe cg13601799 on HM450 as previously described, with a beta value of 0.2 or above considered as epigenetic silencing.	('silencing', 'NegReg', (15, 24))	('cg13601799', 'Var', (62, 72))	('HM450', 'Chemical', '-', (76, 81))	('p16', 'Gene', '1029', (36, 39))	('HM450', 'Enzyme', (76, 81))	('p16', 'Gene', (36, 39))
295427	29617660	MethylMix was applied to CpG cluster data available for 1408 SCC tumors to identify CpG clusters (hereafter referred to as 'genes') that are abnormally methylated in all or a subset of cancers compared with adjacent normal tissue, where this abnormal methylation state is associated with decreased RNA expression of the same gene, as previously described.	('decreased', 'NegReg', (288, 297))	('CpG clusters', 'Gene', (84, 96))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('methylation', 'Var', (251, 262))	('SCC tumors', 'Disease', 'MESH:D009369', (61, 71))	('RNA expression', 'MPA', (298, 312))	('cancers', 'Phenotype', 'HP:0002664', (185, 192))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('cancers', 'Disease', 'MESH:D009369', (185, 192))	('SCC tumors', 'Disease', (61, 71))	('cancers', 'Disease', (185, 192))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
295429	29617660	We aimed to identify genes that were aberrantly methylated in cancer versus 125 normal adjacent tissue samples available across multiple SCC types, i.e., pan-cancer abnormally methylated genes.	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('abnormally methylated', 'Var', (165, 186))	('SCC', 'Gene', '6317', (137, 140))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('cancer', 'Disease', (158, 164))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('SCC', 'Gene', (137, 140))
295434	29617660	Overall, MethylMix identified 905 genes that were unimodal in normal tissue but abnormally methylated in cancer, and where methylation was inversely associated with RNA expression in cancer (Table S2K).	('cancer', 'Disease', (183, 189))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('methylation', 'Var', (123, 134))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('associated', 'Reg', (149, 159))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('RNA expression', 'MPA', (165, 179))	('cancer', 'Disease', 'MESH:D009369', (183, 189))
295441	29617660	For example, TET1 and FANCF are specifically hypermethylated in HPV+ subtype 2, while SYK is hypomethylated in HNSC, LUSC, and CESC within all subtypes.	('TET1', 'Gene', '80312', (13, 17))	('FANCF', 'Gene', (22, 27))	('HPV+', 'Gene', (64, 68))	('FANCF', 'Gene', '2188', (22, 27))	('SYK', 'Gene', (86, 89))	('TET1', 'Gene', (13, 17))	('hypermethylated', 'Var', (45, 60))	('SYK', 'Gene', '6850', (86, 89))	('HPV', 'Species', '10566', (64, 67))
295442	29617660	For each of the 905 abnormally methylated genes in SCC, MethylMix ascribed differential methylation (DM) values, a categorical variable indicating the methylation state for that gene (normal, hypomethylated or hypermethylated, relative to normal tissue) in each cancer.	('cancer', 'Disease', (262, 268))	('SCC', 'Gene', (51, 54))	('cancer', 'Phenotype', 'HP:0002664', (262, 268))	('SCC', 'Gene', '6317', (51, 54))	('hypermethylated', 'Var', (210, 225))	('methylation', 'MPA', (88, 99))	('hypomethylated', 'Var', (192, 206))	('DM', 'Disease', 'MESH:D009223', (101, 103))	('cancer', 'Disease', 'MESH:D009369', (262, 268))
295447	29617660	Review of this gene list confirms that it includes many of the most significant and novel cancer related genes and signatures associated with iC, CNAs, mutations, methylation, miRNAs, paradigm analysis, and RPPA analyses found in the present study.	('mutations', 'Var', (152, 161))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('CNAs', 'Disease', (146, 150))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))
295455	29617660	Gene alterations were called based on mutation, methylation, and deep copy number deletions from PanCan 33 dataset for 1409 Pan-SCC, and the top 10 are presented as an oncoprint, and compared with 8350 other cancers.	('cancers', 'Phenotype', 'HP:0002664', (208, 215))	('SCC', 'Gene', (128, 131))	('cancers', 'Disease', (208, 215))	('cancers', 'Disease', 'MESH:D009369', (208, 215))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('SCC', 'Gene', '6317', (128, 131))	('PanCan', 'Gene', (97, 103))	('deep copy number deletions', 'Var', (65, 91))
295467	29617660	SCCs show chromosome or methylation alterations affecting multiple related genes These regulate squamous stemness, differentiation, growth, survival, and inflammation Copy-quiet SCCs have hypermethylated (FANCF, TET1) or mutated (CASP8, MAPK-RAS) genes Potential targets include DeltaNp63, WEE1, IAPs, PI3K-mTOR/MAPK, and immune responses	('SCC', 'Gene', '6317', (178, 181))	('mTOR', 'Gene', '2475', (307, 311))	('DeltaNp63', 'Chemical', '-', (279, 288))	('CASP8', 'Gene', '841', (230, 235))	('alterations', 'Var', (36, 47))	('mutated', 'Var', (221, 228))	('WEE1', 'Gene', (290, 294))	('SCC', 'Gene', (178, 181))	('TET1', 'Gene', '80312', (212, 216))	('CASP8', 'Gene', (230, 235))	('FANCF', 'Gene', (205, 210))	('inflammation', 'Disease', 'MESH:D007249', (154, 166))	('hypermethylated', 'MPA', (188, 203))	('WEE1', 'Gene', '7465', (290, 294))	('SCC', 'Gene', '6317', (0, 3))	('TET1', 'Gene', (212, 216))	('inflammation', 'Disease', (154, 166))	('squamous stemness', 'Disease', (96, 113))	('SCC', 'Gene', (0, 3))	('mTOR', 'Gene', (307, 311))	('squamous stemness', 'Disease', 'MESH:D002294', (96, 113))	('FANCF', 'Gene', '2188', (205, 210))	('IAP', 'Gene', '961', (296, 299))	('IAP', 'Gene', (296, 299))
295483	26933457	Cavitary lung cancer can be encountered in as high as 16% of primary lung cancer on CT. Common radiological features of cavitary lesions suggestive of malignancy include spiculated or irregular inner and outer margins, as well as wall thickness.	('Cavitary lung cancer', 'Disease', 'MESH:D008175', (0, 20))	('primary lung cancer', 'Disease', (61, 80))	('Cavitary lung cancer', 'Disease', (0, 20))	('malignancy', 'Disease', 'MESH:D009369', (151, 161))	('spiculated', 'Var', (170, 180))	('malignancy', 'Disease', (151, 161))	('primary lung cancer', 'Disease', 'MESH:D008175', (61, 80))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('wall thickness', 'CPA', (230, 244))	('lung cancer', 'Phenotype', 'HP:0100526', (69, 80))	('cavitary', 'Disease', (120, 128))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('lung cancer', 'Phenotype', 'HP:0100526', (9, 20))
295562	25525410	In patients with normal performance status (ECOG = 0, n = 197), high Dicer expression entailed a significantly better prognosis than low Dicer expression (P = 0.024).	('Dicer', 'Gene', (69, 74))	('high', 'Var', (64, 68))	('better', 'PosReg', (111, 117))	('patients', 'Species', '9606', (3, 11))	('Dicer', 'Gene', '23405', (137, 142))	('Dicer', 'Gene', (137, 142))	('Dicer', 'Gene', '23405', (69, 74))
295565	25525410	Drosha/miR-126 co-expression had a significant negative impact on the disease-specific survival (DSS) rate (P < 0.001).	('negative', 'NegReg', (47, 55))	('DSS', 'Gene', '5376', (97, 100))	('Drosha', 'Gene', '29102', (0, 6))	('miR-126', 'Gene', '406913', (7, 14))	('miR-126', 'Gene', (7, 14))	('Drosha', 'Gene', (0, 6))	('disease-specific survival', 'CPA', (70, 95))	('co-expression', 'Var', (15, 28))	('DSS', 'Gene', (97, 100))
295578	25525410	An independent and tissue-specific prognostic impact of miR-126 has been demonstrated in NSCLC, where co-expression of miR-126 with vascular endothelial growth factor-A (VEGF-A) predicts poor survival .	('poor', 'NegReg', (187, 191))	('vascular endothelial growth factor-A', 'Gene', (132, 168))	('NSCLC', 'Disease', 'MESH:D002289', (89, 94))	('co-expression', 'Var', (102, 115))	('miR-126', 'Gene', (119, 126))	('NSCLC', 'Phenotype', 'HP:0030358', (89, 94))	('miR-126', 'Gene', '406913', (56, 63))	('vascular endothelial growth factor-A', 'Gene', '7422', (132, 168))	('miR-126', 'Gene', (56, 63))	('VEGF-A', 'Gene', '7422', (170, 176))	('VEGF-A', 'Gene', (170, 176))	('NSCLC', 'Disease', (89, 94))	('miR-126', 'Gene', '406913', (119, 126))
295609	25525410	Specific antibodies for Dicer (13D6-ChIP grade, ab14601) and Drosha (ab85027) (both Abcam, Cambridge, UK) have been validated in-house by the manufacturer for IHC analysis on paraffin-embedded material prior to use.	('Dicer', 'Gene', (24, 29))	('Drosha', 'Gene', (61, 67))	('ab85027', 'Var', (69, 76))	('Drosha', 'Gene', '29102', (61, 67))	('ab14601', 'Var', (48, 55))	('Dicer', 'Gene', '23405', (24, 29))	('paraffin', 'Chemical', 'MESH:D010232', (175, 183))
295649	25525410	However, in patients with normal performance status (ECOG = 0), high expression of Dicer was significantly correlated with longer DSS (P = 0.024,) (Figure  2D), but no differences in patients with reduced performance status (ECOG = 1-2) were observed (P = 0.518, Figure  2E).	('Dicer', 'Gene', (83, 88))	('patients', 'Species', '9606', (12, 20))	('high expression', 'Var', (64, 79))	('DSS', 'Gene', (130, 133))	('DSS', 'Gene', '5376', (130, 133))	('patients', 'Species', '9606', (183, 191))	('Dicer', 'Gene', '23405', (83, 88))
295650	25525410	In patients with both squamous cell carcinoma and normal performance status (ECOG = 0), high expression of Dicer was significantly correlated with long DSS (P = 0.013, Figure  2F).	('high', 'Var', (88, 92))	('correlated', 'Reg', (131, 141))	('Dicer', 'Gene', (107, 112))	('DSS', 'Gene', '5376', (152, 155))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (22, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (36, 45))	('patients', 'Species', '9606', (3, 11))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (22, 45))	('squamous cell carcinoma', 'Disease', (22, 45))	('Dicer', 'Gene', '23405', (107, 112))	('DSS', 'Gene', (152, 155))
295652	25525410	When combining expression of Drosha and miR-126, the subgroup of patients with both high Drosha and high miR-126 expression had significantly shorter DSS (P < 0.001) (Figure  4A) and overall survival (P = 0.001, Figure  4B).	('miR-126', 'Gene', (105, 112))	('overall survival', 'CPA', (183, 199))	('DSS', 'Gene', (150, 153))	('Drosha', 'Gene', (89, 95))	('shorter', 'NegReg', (142, 149))	('high', 'Var', (100, 104))	('DSS', 'Gene', '5376', (150, 153))	('miR-126', 'Gene', '406913', (40, 47))	('Drosha', 'Gene', '29102', (29, 35))	('patients', 'Species', '9606', (65, 73))	('Drosha', 'Gene', '29102', (89, 95))	('Drosha', 'Gene', (29, 35))	('miR-126', 'Gene', '406913', (105, 112))	('miR-126', 'Gene', (40, 47))
295678	25525410	However, in vitro experiments showed that silencing of Dicer and Drosha decreases angiogenesis .	('silencing', 'Var', (42, 51))	('Dicer', 'Gene', '23405', (55, 60))	('Dicer', 'Gene', (55, 60))	('decreases', 'NegReg', (72, 81))	('Drosha', 'Gene', '29102', (65, 71))	('angiogenesis', 'CPA', (82, 94))	('Drosha', 'Gene', (65, 71))
295680	25525410	Neuroblastoma and leukemia are two other examples where low levels of Dicer and Drosha are significant predictive factors for poor outcomes .	('Dicer', 'Gene', '23405', (70, 75))	('Dicer', 'Gene', (70, 75))	('Drosha', 'Gene', '29102', (80, 86))	('leukemia', 'Disease', 'MESH:D007938', (18, 26))	('Neuroblastoma', 'Phenotype', 'HP:0003006', (0, 13))	('Neuroblastoma', 'Disease', 'MESH:D009447', (0, 13))	('leukemia', 'Disease', (18, 26))	('low levels', 'Var', (56, 66))	('leukemia', 'Phenotype', 'HP:0001909', (18, 26))	('Neuroblastoma', 'Disease', (0, 13))	('Drosha', 'Gene', (80, 86))
295688	25525410	Interestingly, we found that the co-expression of Drosha and miR-126 also predicts poor survival, which is even more significant than the co-expression of miR-126 and VEGF-A reported previously .	('co-expression', 'Var', (33, 46))	('miR-126', 'Gene', '406913', (61, 68))	('Drosha', 'Gene', (50, 56))	('miR-126', 'Gene', (61, 68))	('miR-126', 'Gene', '406913', (155, 162))	('miR-126', 'Gene', (155, 162))	('Drosha', 'Gene', '29102', (50, 56))	('VEGF-A', 'Gene', '7422', (167, 173))	('poor', 'NegReg', (83, 87))	('VEGF-A', 'Gene', (167, 173))
295689	25525410	Although not significant (p = 0.06), the combination of high Drosha and low miR-126 was the most favorable in relation to DSS (see Table  1), suggesting that Drosha in itself is not a good prognostic marker for overall survival in NSCLC, which is consistent with our univariate analyses (see Figure  3A).	('low', 'Var', (72, 75))	('NSCLC', 'Phenotype', 'HP:0030358', (231, 236))	('Drosha', 'Gene', (61, 67))	('Drosha', 'Gene', (158, 164))	('NSCLC', 'Disease', (231, 236))	('DSS', 'Gene', (122, 125))	('miR-126', 'Gene', '406913', (76, 83))	('NSCLC', 'Disease', 'MESH:D002289', (231, 236))	('DSS', 'Gene', '5376', (122, 125))	('Drosha', 'Gene', '29102', (158, 164))	('Drosha', 'Gene', '29102', (61, 67))	('miR-126', 'Gene', (76, 83))	('high', 'Var', (56, 60))
295697	25525410	Several studies have also shown that knockdown of Dicer and Drosha only reduces a subset of miRNAs, implying alternative pathways for miRNA synthesis .	('reduces', 'NegReg', (72, 79))	('miR', 'Gene', '220972', (134, 137))	('miR', 'Gene', (92, 95))	('miR', 'Gene', (134, 137))	('Drosha', 'Gene', (60, 66))	('knockdown', 'Var', (37, 46))	('miR', 'Gene', '220972', (92, 95))	('Dicer', 'Gene', '23405', (50, 55))	('Dicer', 'Gene', (50, 55))	('Drosha', 'Gene', '29102', (60, 66))
295702	33368875	Personalized cancer vaccination in head and neck cancer Cancer is characterized by an accumulation of somatic mutations that represent a source of neoantigens for targeting by antigen-specific T cells.	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('mutations', 'Var', (110, 119))	('head and neck cancer', 'Phenotype', 'HP:0012288', (35, 55))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('Cancer', 'Phenotype', 'HP:0002664', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('cancer', 'Disease', (13, 19))	('Cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (13, 19))	('Cancer', 'Disease', 'MESH:D009369', (56, 62))	('head and neck cancer', 'Disease', 'MESH:D006258', (35, 55))	('cancer', 'Disease', (49, 55))
295720	33368875	Notably, in these immunotherapeutic treatment options, the revolution in cancer treatment has been through the application of CPIs, including anti-CTLA4, anti-PD-1, and anti-PD-L1.	('cancer', 'Disease', (73, 79))	('anti-PD-1', 'Var', (154, 163))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('CTLA4', 'Gene', '1493', (147, 152))	('CTLA4', 'Gene', (147, 152))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('PD-L1', 'Gene', (174, 179))	('CPIs', 'Chemical', '-', (126, 130))	('PD-L1', 'Gene', '29126', (174, 179))
295723	33368875	4  Despite the excitement surrounding this approach, only 15%-20% of HNSCC patients benefit from CPIs, thus highlighting the development of new immunotherapeutic methods or novel combinatorial strategies as an urgent task.	('HNSCC', 'Disease', (69, 74))	('HNSCC', 'Phenotype', 'HP:0012288', (69, 74))	('CPIs', 'Chemical', '-', (97, 101))	('patients', 'Species', '9606', (75, 83))	('CPIs', 'Var', (97, 101))
295760	33368875	Recent data have highlighted dynamic epigenetically driven CD8+ T cell differentiation using viral and antigen-specific murine tumor models.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('epigenetically', 'Var', (37, 51))	('tumor', 'Disease', (127, 132))	('murine', 'Species', '10090', (120, 126))	('CD8', 'Gene', (59, 62))	('CD8', 'Gene', '925', (59, 62))	('tumor', 'Disease', 'MESH:D009369', (127, 132))
295766	33368875	Patients with antigen spreading showed prolonged PFS, indicating that this phenomenon could be involved to induce robust anticancer effect using cancer vaccination therapy.	('cancer', 'Disease', (145, 151))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('PFS', 'MPA', (49, 52))	('antigen spreading', 'Var', (14, 31))	('Patients', 'Species', '9606', (0, 8))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (145, 151))
295777	33368875	34 ,  35  As a result, mutant and WT TP53 tetramer proteins tend to accumulate in most HNSCC cancer tissue harboring TP53 mutations.	('HNSCC', 'Phenotype', 'HP:0012288', (87, 92))	('TP53', 'Gene', '7157', (117, 121))	('HNSCC cancer', 'Disease', (87, 99))	('TP53', 'Gene', (117, 121))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('HNSCC cancer', 'Disease', 'MESH:D000077195', (87, 99))	('mutations', 'Var', (122, 131))	('tetramer proteins', 'Protein', (42, 59))	('TP53', 'Gene', '7157', (37, 41))	('TP53', 'Gene', (37, 41))	('accumulate', 'PosReg', (68, 78))	('mutant', 'Var', (23, 29))
295791	33368875	28 ,  42  Tumor-specific antigens are classified as foreign antigens associated with viral infection or neoantigens that arise from cancer-specific SNVs and indels.	('cancer', 'Disease', (132, 138))	('viral infection', 'Disease', (85, 100))	('Tumor', 'Phenotype', 'HP:0002664', (10, 15))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('indels', 'Var', (157, 163))	('viral infection', 'Disease', 'MESH:D001102', (85, 100))	('cancer', 'Disease', 'MESH:D009369', (132, 138))
295798	33368875	47  These promising data from combination therapy suggest that ISA101 long peptides might increase antigen-specific CD4+/CD8+ T cells and augment the efficacy of anti-PD-1 treatment.	('efficacy', 'CPA', (150, 158))	('anti-PD-1 treatment', 'CPA', (162, 181))	('increase', 'PosReg', (90, 98))	('CD4', 'Gene', '920', (116, 119))	('ISA101 long peptides', 'Var', (63, 83))	('antigen-specific', 'MPA', (99, 115))	('augment', 'NegReg', (138, 145))	('CD8', 'Gene', (121, 124))	('CD8', 'Gene', '925', (121, 124))	('CD4', 'Gene', (116, 119))
295801	33368875	50 ,  51   Cancer-specific somatic mutations can be classified as driver mutations that mainly contribute to cancer development and progression, and passenger mutations, which are bystander mutations that accumulate in the process of cancer development.	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('contribute', 'Reg', (95, 105))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('cancer', 'Disease', (109, 115))	('Cancer', 'Phenotype', 'HP:0002664', (11, 17))	('Cancer', 'Disease', (11, 17))	('cancer', 'Disease', 'MESH:D009369', (234, 240))	('Cancer', 'Disease', 'MESH:D009369', (11, 17))	('cancer', 'Disease', (234, 240))	('progression', 'CPA', (132, 143))	('mutations', 'Var', (35, 44))
295802	33368875	52  In addition, fusion-genes, which are sometimes present and expressed in the head and neck cancers, including adenoid cystic carcinoma, have been shown to stimulate cancer immunity.	('neck cancers', 'Disease', (89, 101))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('adenoid cystic carcinoma', 'Disease', (113, 137))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('stimulate', 'PosReg', (158, 167))	('fusion-genes', 'Var', (17, 29))	('neck cancers', 'Disease', 'MESH:D006258', (89, 101))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('cancer', 'Disease', (168, 174))	('adenoid cystic carcinoma', 'Disease', 'MESH:D003528', (113, 137))	('head and neck cancer', 'Phenotype', 'HP:0012288', (80, 100))	('cancers', 'Phenotype', 'HP:0002664', (94, 101))	('head and neck cancers', 'Phenotype', 'HP:0012288', (80, 101))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
295804	33368875	Considering the diversity of HLA types in each patient, although targeting driver mutations represents an attractive approach that can also target a cancer cell dependency, only limited patients might benefit.	('cancer', 'Disease', (149, 155))	('patient', 'Species', '9606', (47, 54))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('mutations', 'Var', (82, 91))	('patient', 'Species', '9606', (186, 193))	('cancer', 'Disease', 'MESH:D009369', (149, 155))	('patients', 'Species', '9606', (186, 194))
295811	33368875	60  A few reasons for this include: (i) less than accurate consideration of the numerous transcriptional and posttranscriptional events that regulate antigen processing and presentation; 61  (ii) the position of certain mutations within the epitope that could function as an anchor for MHC molecules; 62  and (iii) some mutations in neoepitopes alter TCR structural interaction.	('MHC', 'Gene', (286, 289))	('mutations', 'Var', (320, 329))	('TCR', 'Gene', (351, 354))	('MHC', 'Gene', '3107', (286, 289))	('neoepitopes', 'Gene', (333, 344))	('mutations', 'Var', (220, 229))	('TCR', 'Gene', '6962', (351, 354))	('alter', 'Reg', (345, 350))
295813	33368875	Ebrahimi-Nik et al 63  suggested that the combination of genomics, unbiased discovery MS immune-peptidomics, and targeted MS was useful to detect neoepitopes that elicit actual tumor rejection.	('actual tumor', 'Disease', (170, 182))	('Nik', 'Gene', (9, 12))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('actual tumor', 'Disease', 'MESH:D009369', (170, 182))	('elicit', 'Reg', (163, 169))	('neoepitopes', 'Var', (146, 157))	('Nik', 'Gene', '9020', (9, 12))
295832	33368875	Validation of candidates indicated prophylactic vaccination with mutant ICAM1 neoantigen-derived SLP induced significant T cell response and robust tumor suppression.	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('tumor', 'Disease', (148, 153))	('mutant', 'Var', (65, 71))	('ICAM1', 'Gene', '3383', (72, 77))	('T cell response', 'CPA', (121, 136))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('ICAM1', 'Gene', (72, 77))
295846	33368875	24 ,  47 ,  57  Notably, Zhou et al showed that the inhibitor of EZH2 promoted antigen presentation by epigenetically repressing H3K27me3, especially in the beta2-microglobulin promoter region in HNSCC.	('H3K27me3', 'Protein', (129, 137))	('HNSCC', 'Phenotype', 'HP:0012288', (196, 201))	('beta2-microglobulin', 'Gene', (157, 176))	('repressing', 'NegReg', (118, 128))	('antigen presentation', 'MPA', (79, 99))	('EZH2', 'Gene', (65, 69))	('epigenetically', 'Var', (103, 117))	('inhibitor', 'Var', (52, 61))	('EZH2', 'Gene', '2146', (65, 69))	('beta2-microglobulin', 'Gene', '567', (157, 176))	('promoted', 'PosReg', (70, 78))
295855	28832323	Prevalence of Epidermal Growth Factor Receptor Mutations in Patients with Non-Small Cell Lung Cancer in Turkish Population Epidermal growth factor receptor mutation analysis in non-small cell lung cancer is important for selecting patients who will receive treatment with tyrosine kinase inhibitors.	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (177, 203))	('men', 'Species', '9606', (262, 265))	('patients', 'Species', '9606', (231, 239))	('Patients', 'Species', '9606', (60, 68))	('Non-Small Cell Lung Cancer', 'Disease', 'MESH:D002289', (74, 100))	('lung cancer', 'Phenotype', 'HP:0100526', (192, 203))	('Mutations', 'Var', (47, 56))	('non-small cell lung cancer', 'Disease', (177, 203))	('Small Cell Lung Cancer', 'Phenotype', 'HP:0030357', (78, 100))	('Non-Small Cell Lung Cancer', 'Phenotype', 'HP:0030358', (74, 100))	('Lung Cancer', 'Phenotype', 'HP:0100526', (89, 100))	('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', 'Phenotype', 'HP:0002664', (94, 100))	('Non-Small Cell Lung Cancer', 'Disease', (74, 100))
295856	28832323	We retrospectively reviewed molecular pathology reports of 959 cases with lung cancer analysed for epidermal growth factor receptor mutations.	('lung cancer', 'Disease', (74, 85))	('lung cancer', 'Phenotype', 'HP:0100526', (74, 85))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('mutations', 'Var', (132, 141))	('lung cancer', 'Disease', 'MESH:D008175', (74, 85))
295857	28832323	The epidermal growth factor receptor mutation frequency was significantly higher in women (37.1%, n=96) than in men (9.1%, n=64) (p<0.001).	('women', 'Species', '9606', (84, 89))	('men', 'Species', '9606', (86, 89))	('higher', 'PosReg', (74, 80))	('epidermal growth factor receptor', 'Gene', (4, 36))	('mutation', 'Var', (37, 45))	('men', 'Species', '9606', (112, 115))
295865	28832323	Consequentially, abnormal expression of EGFR results in tumour cell proliferation, angiogenesis, invasion, metastasis and inhibition of apoptosis.	('expression', 'MPA', (26, 36))	('metastasis', 'CPA', (107, 117))	('apoptosis', 'CPA', (136, 145))	('tumour', 'Phenotype', 'HP:0002664', (56, 62))	('invasion', 'CPA', (97, 105))	('inhibition', 'NegReg', (122, 132))	('EGFR', 'Gene', (40, 44))	('tumour', 'Disease', 'MESH:D009369', (56, 62))	('abnormal', 'Var', (17, 25))	('angiogenesis', 'CPA', (83, 95))	('tumour', 'Disease', (56, 62))	('results in', 'Reg', (45, 55))
295867	28832323	In the 2004 studies, most of the lung cancer patients responding to EGFR TK inhibitors (TKIs), such as erlotinib and gefitinib, reportedly had EGFR mutations.	('EGFR', 'Gene', (143, 147))	('lung cancer', 'Phenotype', 'HP:0100526', (33, 44))	('mutations', 'Var', (148, 157))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('gefitinib', 'Chemical', 'MESH:D000077156', (117, 126))	('lung cancer', 'Disease', 'MESH:D008175', (33, 44))	('patients', 'Species', '9606', (45, 53))	('erlotinib', 'Chemical', 'MESH:D000069347', (103, 112))	('lung cancer', 'Disease', (33, 44))
295868	28832323	Some clinical characteristics (Asian origin, never smoked, female gender and histologic adenocarcinoma subtype) are associated with the presence of EGFR mutations in patients with non-small cell lung cancer (NSCLC).	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('adenocarcinoma subtype', 'Disease', (88, 110))	('adenocarcinoma subtype', 'Disease', 'MESH:D000230', (88, 110))	('non-small cell lung cancer', 'Disease', (180, 206))	('NSCLC', 'Phenotype', 'HP:0030358', (208, 213))	('mutations', 'Var', (153, 162))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (184, 206))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('EGFR', 'Gene', (148, 152))	('lung cancer', 'Phenotype', 'HP:0100526', (195, 206))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (180, 206))	('NSCLC', 'Disease', (208, 213))	('never', 'Disease', (45, 50))	('NSCLC', 'Disease', 'MESH:D002289', (208, 213))	('patients', 'Species', '9606', (166, 174))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (180, 206))	('associated', 'Reg', (116, 126))
295869	28832323	However, selection of the patients to be treated should be according to the EGFR mutation analysis results, rather than these clinicopathological characteristics.	('EGFR', 'Gene', (76, 80))	('mutation', 'Var', (81, 89))	('patients', 'Species', '9606', (26, 34))
295870	28832323	The purpose of this study was to identify EGFR mutation prevalence, mutation types and clinicopathological characteristics of these patients in the Turkish population.	('mutation', 'Var', (47, 55))	('EGFR', 'Gene', (42, 46))	('patients', 'Species', '9606', (132, 140))
295871	28832323	In this study, we retrospectively reviewed molecular pathology reports from 963 cases with NSCLC analysed for EGFR mutations at the Department of Pathology, Hacettepe University, from December 2011 through February 2015.	('NSCLC', 'Disease', 'MESH:D002289', (91, 96))	('mutations', 'Var', (115, 124))	('NSCLC', 'Phenotype', 'HP:0030358', (91, 96))	('EGFR', 'Gene', (110, 114))	('men', 'Species', '9606', (138, 141))	('NSCLC', 'Disease', (91, 96))
295873	28832323	The median age of the patients was 60 (range 22-87); 250 patients (26.1%) who were tested for EGFR mutations were diagnosed in our pathology department and 709 patients (73.9%) were diagnosed in other pathology laboratories from different regions of Turkey (Samsun, Erzurum, Trabzon, Gaziantep, etc.)	('patients', 'Species', '9606', (160, 168))	('patients', 'Species', '9606', (57, 65))	('patients', 'Species', '9606', (22, 30))	('EGFR', 'Gene', (94, 98))	('mutations', 'Var', (99, 108))	('Turkey', 'Species', '9103', (250, 256))	('men', 'Species', '9606', (147, 150))
295876	28832323	We used formalin-fixed paraffin-embedded (FFPE) tissues, cell blocks and stained cytology slides for EGFR mutation testing.	('paraffin', 'Chemical', 'MESH:D010232', (23, 31))	('formalin', 'Chemical', 'MESH:D005557', (8, 16))	('mutation', 'Var', (106, 114))	('EGFR', 'Gene', (101, 105))
295882	28832323	We found that patients with EGFR mutations were significantly older than those without EGFR mutations (p<0.001).	('patients', 'Species', '9606', (14, 22))	('EGFR', 'Gene', (28, 32))	('mutations', 'Var', (33, 42))
295884	28832323	We observed a statistically significantly higher EGFR mutation prevalence in adenocarcinomas (p<0.001).	('mutation', 'Var', (54, 62))	('EGFR', 'Gene', (49, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('higher', 'PosReg', (42, 48))	('adenocarcinomas', 'Disease', 'MESH:D000230', (77, 92))	('adenocarcinomas', 'Disease', (77, 92))
295885	28832323	Mutations were detected in 117/677 (17.3%) primary and 43/282 (15.2%) metastatic pulmonary tumour samples.	('pulmonary tumour', 'Phenotype', 'HP:0100526', (81, 97))	('pulmonary tumour', 'Disease', (81, 97))	('detected', 'Reg', (15, 23))	('pulmonary tumour', 'Disease', 'MESH:D008175', (81, 97))	('Mutations', 'Var', (0, 9))	('tumour', 'Phenotype', 'HP:0002664', (91, 97))
295887	28832323	Although the difference was not statistically significant, EGFR mutations were more frequent in non-smoking patients (10/25) than in smokers (2/10).	('patients', 'Species', '9606', (108, 116))	('mutations', 'Var', (64, 73))	('EGFR', 'Gene', (59, 63))
295888	28832323	Clinical characteristics of 959 patients with NSCLC who were subjected to EGFR mutation analysis and their association with EGFR mutations are summarized in Table 1.	('patients', 'Species', '9606', (32, 40))	('mutations', 'Var', (129, 138))	('NSCLC', 'Disease', (46, 51))	('NSCLC', 'Disease', 'MESH:D002289', (46, 51))	('mutation', 'Var', (79, 87))	('EGFR', 'Gene', (74, 78))	('NSCLC', 'Phenotype', 'HP:0030358', (46, 51))
295890	28832323	The other rarely seen drug-sensitive mutations were exon 18 G719X, observed in nine cases (5.6%), and an exon 21 L861Q mutation, seen in two patients (1.2%).	('G719X', 'Mutation', 'p.G719X', (60, 65))	('L861Q', 'Var', (113, 118))	('L861Q', 'Mutation', 'rs121913444', (113, 118))	('G719X', 'Var', (60, 65))	('exon 18 G719X', 'Var', (52, 65))	('patients', 'Species', '9606', (141, 149))
295891	28832323	In addition, an exon 20 mutation was found in nine cases (5.6%); eight were patients with exon 20 insertion mutations, and one case had an exon 20 T790M point mutation.	('T790M point', 'Var', (147, 158))	('patients', 'Species', '9606', (76, 84))	('insertion mutations', 'Var', (98, 117))	('T790M', 'Mutation', 'rs121434569', (147, 152))
295892	28832323	In two of these cases, the exon 19 deletion and exon 20 T790M point mutation were detected together, while an exon 21 L858R point mutation and exon 18 G718X point mutation was detected together in one patient.	('T790M', 'Var', (56, 61))	('detected', 'Reg', (82, 90))	('patient', 'Species', '9606', (201, 208))	('G718X', 'Mutation', 'p.G718X', (151, 156))	('L858R', 'Var', (118, 123))	('T790M', 'Mutation', 'rs121434569', (56, 61))	('L858R', 'Mutation', 'rs121434568', (118, 123))
295893	28832323	Determining the presence of EGFR mutations is crucial in terms of selecting patients with advanced or metastatic lung cancer who will receive treatments with TKIs, such as gefitinib or erlotinib, because activating mutations in the EGFR gene in lung tumours is associated with an effective and dramatic response to TKIs.	('tumours', 'Phenotype', 'HP:0002664', (250, 257))	('patients', 'Species', '9606', (76, 84))	('lung cancer', 'Disease', (113, 124))	('gefitinib', 'Chemical', 'MESH:D000077156', (172, 181))	('lung cancer', 'Phenotype', 'HP:0100526', (113, 124))	('activating mutations', 'Var', (204, 224))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('lung tumours', 'Disease', 'MESH:D008175', (245, 257))	('erlotinib', 'Chemical', 'MESH:D000069347', (185, 194))	('lung cancer', 'Disease', 'MESH:D008175', (113, 124))	('tumour', 'Phenotype', 'HP:0002664', (250, 256))	('EGFR', 'Gene', (232, 236))	('men', 'Species', '9606', (147, 150))	('lung tumours', 'Disease', (245, 257))
295894	28832323	In this study, we tried to determine the EGFR mutation frequency of 959 patients with NSCLC and found it to be 16.7% in the Turkish population.	('EGFR', 'Gene', (41, 45))	('NSCLC', 'Disease', (86, 91))	('NSCLC', 'Disease', 'MESH:D002289', (86, 91))	('NSCLC', 'Phenotype', 'HP:0030358', (86, 91))	('mutation', 'Var', (46, 54))	('patients', 'Species', '9606', (72, 80))
295895	28832323	We found a higher EGFR mutation frequency in women, the adenocarcinoma histological subtype and the elderly population.	('mutation', 'Var', (23, 31))	('EGFR', 'Gene', (18, 22))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('adenocarcinoma', 'Disease', (56, 70))	('higher', 'PosReg', (11, 17))	('adenocarcinoma', 'Disease', 'MESH:D000230', (56, 70))	('women', 'Species', '9606', (45, 50))
295899	28832323	Similar to our results, in a study conducted in 2009, the EGFR mutation rate of Caucasians (Spanish patients) was reported as 16.6%.	('EGFR', 'Gene', (58, 62))	('patients', 'Species', '9606', (100, 108))	('mutation', 'Var', (63, 71))
295900	28832323	The frequency of EGFR mutation depends not only on ethnicity but also on gender, NSCLC histological type and smoking status.	('mutation', 'Var', (22, 30))	('NSCLC', 'Phenotype', 'HP:0030358', (81, 86))	('NSCLC', 'Disease', (81, 86))	('NSCLC', 'Disease', 'MESH:D002289', (81, 86))	('EGFR', 'Gene', (17, 21))
295901	28832323	In many studies, EGFR mutation rates in women have been reported to be higher than those in men.	('higher', 'PosReg', (71, 77))	('mutation', 'Var', (22, 30))	('men', 'Species', '9606', (42, 45))	('women', 'Species', '9606', (40, 45))	('men', 'Species', '9606', (92, 95))	('EGFR', 'Gene', (17, 21))
295902	28832323	In parallel with these results in the literature, we found the frequency of EGFR mutation to be higher in female than in male patients (37.1% vs. 9.1%).	('EGFR', 'Gene', (76, 80))	('mutation', 'Var', (81, 89))	('patients', 'Species', '9606', (126, 134))
295903	28832323	We found the rate of EGFR mutation to be 20.3% in adenocarcinomas and 7.4% in NSCLC-NOS.	('NSCLC-NOS', 'Disease', 'MESH:D002289', (78, 87))	('EGFR', 'Gene', (21, 25))	('mutation', 'Var', (26, 34))	('NSCLC', 'Phenotype', 'HP:0030358', (78, 83))	('carcinoma', 'Phenotype', 'HP:0030731', (55, 64))	('NSCLC-NOS', 'Disease', (78, 87))	('adenocarcinomas', 'Disease', 'MESH:D000230', (50, 65))	('adenocarcinomas', 'Disease', (50, 65))
295904	28832323	In line with earlier studies, we found the mutation rate in the histological subtype of adenocarcinoma to be higher (p<0.001).	('mutation', 'Var', (43, 51))	('adenocarcinoma', 'Disease', 'MESH:D000230', (88, 102))	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('adenocarcinoma', 'Disease', (88, 102))
295905	28832323	However, we did not find EGFR mutations in any of the 18 cases diagnosed with squamous cell carcinoma.	('EGFR', 'Gene', (25, 29))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('mutations', 'Var', (30, 39))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (78, 101))	('squamous cell carcinoma', 'Disease', (78, 101))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (78, 101))
295906	28832323	In a few studies, the rate of EGFR mutation reported was very low in squamous cell carcinoma.	('EGFR', 'Gene', (30, 34))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (69, 92))	('squamous cell carcinoma', 'Disease', (69, 92))	('low', 'NegReg', (62, 65))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (69, 92))	('mutation', 'Var', (35, 43))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))
295907	28832323	However, consistent with our results, other studies could not detect any EGFR mutations in squamous cell carcinoma.	('EGFR', 'Gene', (73, 77))	('mutations', 'Var', (78, 87))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (91, 114))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('squamous cell carcinoma', 'Disease', (91, 114))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (91, 114))
295908	28832323	The most common mutations found in our study were an in-frame deletion (n=78, 48.8%) in exon 19 and a point mutation (L858R) in exon 21 (n=61, 38.1%).	('in-frame deletion', 'Var', (53, 70))	('L858R', 'Var', (118, 123))	('L858R', 'Mutation', 'rs121434568', (118, 123))
295910	28832323	Exon 18 G719X, exon 21 L861Q, exon 20 mutations and compound mutations that we have detected in three patients are rarely seen mutation types.	('G719X', 'Var', (8, 13))	('L861Q', 'Mutation', 'rs121913444', (23, 28))	('patients', 'Species', '9606', (102, 110))	('L861Q', 'Var', (23, 28))	('G719X', 'Mutation', 'p.G719X', (8, 13))
295911	28832323	Although exon 20 mutations are usually associated with resistance to EGFR TKIs, recent studies show that new covalent inhibitors have shown efficacy against relapsing disease during previous treatment with an existing EGFR inhibitor.	('men', 'Species', '9606', (196, 199))	('mutations', 'Var', (17, 26))	('relapsing disease', 'Disease', (157, 174))
295914	28832323	The most important reason of our inability to detect a correlation between the smoking status and the frequency of EGFR mutation is that we could only access the smoking history of very few patients.	('patients', 'Species', '9606', (190, 198))	('EGFR', 'Gene', (115, 119))	('mutation', 'Var', (120, 128))
295915	28832323	We found that patients with EGFR mutations were older than those without mutations.	('patients', 'Species', '9606', (14, 22))	('EGFR', 'Gene', (28, 32))	('mutations', 'Var', (33, 42))
295916	28832323	Discordances between primary tumours and corresponding metastatic tumours in terms of EGFR mutation status are extremely rare.	('mutation', 'Var', (91, 99))	('tumours', 'Disease', 'MESH:D009369', (29, 36))	('tumour', 'Phenotype', 'HP:0002664', (66, 72))	('tumours', 'Disease', (29, 36))	('tumours', 'Phenotype', 'HP:0002664', (66, 73))	('EGFR', 'Gene', (86, 90))	('tumour', 'Phenotype', 'HP:0002664', (29, 35))	('tumours', 'Disease', 'MESH:D009369', (66, 73))	('tumours', 'Disease', (66, 73))	('tumours', 'Phenotype', 'HP:0002664', (29, 36))
295918	28832323	In line with earlier studies in the literature, we found a higher mutation rate in the adenocarcinoma histological subtype, comparing to all other subtypes.	('higher', 'Reg', (59, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('adenocarcinoma', 'Disease', (87, 101))	('mutation', 'Var', (66, 74))	('adenocarcinoma', 'Disease', 'MESH:D000230', (87, 101))
295932	27042218	A few studies have reported promising results with anthracycline and cisplatin-based chemotherapies.5, 6, 7 However, as anthracyclines are associated with severe myelosuppression and cardiac toxicity, investigation of less toxic non-anthracycline regimens is needed.	('anthracyclines', 'Var', (120, 134))	('cisplatin', 'Chemical', 'MESH:D002945', (69, 78))	('anthracycline', 'Chemical', 'MESH:D018943', (51, 64))	('anthracyclines', 'Chemical', 'MESH:D018943', (120, 134))	('cardiac toxicity', 'Disease', 'MESH:D066126', (183, 199))	('cardiac toxicity', 'Disease', (183, 199))	('myelosuppression', 'Disease', 'MESH:D001855', (162, 178))	('anthracycline', 'Chemical', 'MESH:D018943', (120, 133))	('anthracycline', 'Chemical', 'MESH:D018943', (233, 246))	('myelosuppression', 'Disease', (162, 178))
295998	25989802	The Prognostic Significance of FGFR4 Gly388 Polymorphism in Esophageal Squamous Cell Carcinoma after Concurrent Chemoradiotherapy The purpose of this study is to investigate the role of fibroblast growth factor receptor 4 (FGFR4) polymorphism in esophageal cancer after chemoradiotherapy (CRT).	('FGFR4', 'Gene', (223, 228))	('fibroblast growth factor receptor 4', 'Gene', (186, 221))	('FGFR4', 'Gene', '2264', (31, 36))	('FGFR4', 'Gene', (31, 36))	('Gly388', 'Chemical', '-', (37, 43))	('cancer', 'Phenotype', 'HP:0002664', (257, 263))	('Carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('Esophageal Squamous Cell Carcinoma', 'Disease', (60, 94))	('Esophageal Squamous Cell Carcinoma', 'Disease', 'MESH:D000077277', (60, 94))	('esophageal cancer', 'Disease', 'MESH:D004938', (246, 263))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (71, 94))	('esophageal cancer', 'Disease', (246, 263))	('Gly388', 'Var', (37, 43))	('fibroblast growth factor receptor 4', 'Gene', '2264', (186, 221))	('FGFR4', 'Gene', '2264', (223, 228))	('polymorphism', 'Var', (230, 242))
296002	25989802	However, patients carrying the Gly388 allele showed a better overall response rate than Arg388 carriers (p=0.038).	('patients', 'Species', '9606', (9, 17))	('Gly388', 'Var', (31, 37))	('Arg388', 'Chemical', '-', (88, 94))	('response', 'MPA', (69, 77))	('Gly388', 'Chemical', '-', (31, 37))	('better', 'PosReg', (54, 60))
296003	25989802	In addition, Gly388 allele patients at an earlier stage showed better overall survival (OS) and progression-free survival than Arg388 carriers.	('Arg388', 'Chemical', '-', (127, 133))	('progression-free survival', 'CPA', (96, 121))	('overall survival', 'CPA', (70, 86))	('patients', 'Species', '9606', (27, 35))	('OS', 'Gene', '17451', (88, 90))	('better', 'PosReg', (63, 69))	('Gly388', 'Chemical', '-', (13, 19))	('Gly388 allele', 'Var', (13, 26))
296004	25989802	Among these, the Gly388 allele showed significantly improved OS compared to Arg388 carriers in the lymph node (LN) metastasis group (p=0.042) compared to the no LN metastasis group (p=0.125).	('Gly388', 'Var', (17, 23))	('Arg388', 'Var', (76, 82))	('lymph node', 'CPA', (99, 109))	('improved', 'PosReg', (52, 60))	('Arg388', 'Chemical', '-', (76, 82))	('OS', 'Gene', '17451', (61, 63))	('Gly388', 'Chemical', '-', (17, 23))
296005	25989802	This result suggests that the role of FGFR4 Gly388 in treatment outcomes differs according to esophageal cancer stage.	('FGFR4', 'Gene', '2264', (38, 43))	('Gly388', 'Var', (44, 50))	('esophageal cancer', 'Disease', (94, 111))	('Gly388', 'Chemical', '-', (44, 50))	('esophageal cancer', 'Disease', 'MESH:D004938', (94, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('FGFR4', 'Gene', (38, 43))
296006	25989802	It showed a predictive role in the response of esophageal cancer patients to CRT with a better trend for OS in Gly388 than Arg388 carriers in the early stages.	('esophageal cancer', 'Disease', 'MESH:D004938', (47, 64))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('Gly388', 'Var', (111, 117))	('OS', 'Gene', '17451', (105, 107))	('patients', 'Species', '9606', (65, 73))	('esophageal cancer', 'Disease', (47, 64))	('Arg388 carriers', 'Var', (123, 138))	('Gly388', 'Chemical', '-', (111, 117))	('Arg388', 'Chemical', '-', (123, 129))
296007	25989802	In particular, LN-positive early-stage patients carrying the Gly388 allele showed improved OS compared to those carrying Arg388.	('patients', 'Species', '9606', (39, 47))	('Arg388', 'Chemical', '-', (121, 127))	('Gly388', 'Chemical', '-', (61, 67))	('Gly388', 'Var', (61, 67))	('OS', 'Gene', '17451', (91, 93))	('improved', 'PosReg', (82, 90))
296017	25989802	Fibroblast growth factors (FGFs) are divided into four groups (FGF1-4), and dysregulation of their receptors (FGFRs) plays an important role in tumorigenesis.	('tumor', 'Disease', (144, 149))	('FGF1-4', 'Gene', '2259;2246;2247;2248;2249', (63, 69))	('FGF1-4', 'Gene', (63, 69))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('dysregulation', 'Var', (76, 89))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))
296020	25989802	An FGFR4 Gly388Arg polymorphism (rs351855), which causes the substitution of arginine for glycine (FGFR4 Arg388) in the transmembrane domain of the receptor, was reported to increase cancer risk, aggressiveness, metastasis, and drug resistance.	('aggressiveness', 'Disease', 'MESH:D001523', (196, 210))	('arginine', 'Chemical', 'MESH:D001120', (77, 85))	('glycine', 'Chemical', 'MESH:D005998', (90, 97))	('FGFR4', 'Gene', (99, 104))	('FGFR4', 'Gene', (3, 8))	('Gly388Arg', 'Var', (9, 18))	('cancer', 'Disease', (183, 189))	('Gly388Arg', 'SUBSTITUTION', 'None', (9, 18))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('drug resistance', 'CPA', (228, 243))	('metastasis', 'CPA', (212, 222))	('rs351855', 'Mutation', 'rs351855', (33, 41))	('cancer', 'Disease', 'MESH:D009369', (183, 189))	('aggressiveness', 'Disease', (196, 210))	('increase', 'PosReg', (174, 182))	('aggressiveness', 'Phenotype', 'HP:0000718', (196, 210))	('drug resistance', 'Phenotype', 'HP:0020174', (228, 243))	('FGFR4', 'Gene', '2264', (99, 104))	('Arg388', 'Chemical', '-', (105, 111))	('FGFR4', 'Gene', '2264', (3, 8))
296021	25989802	recently reported a significantly increased risk of head and neck squamous cell carcinoma (HNSCC) with the FGFR4 Gly388 allele, whereas Arg388 resulted in cisplatin sensitivity (p=0.141) in an in vitro assay.	('Gly388', 'Var', (113, 119))	('FGFR4', 'Gene', (107, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (61, 89))	('FGFR4', 'Gene', '2264', (107, 112))	('cisplatin', 'Chemical', 'MESH:D002945', (155, 164))	('Gly388', 'Chemical', '-', (113, 119))	('cisplatin sensitivity', 'MPA', (155, 176))	('Arg388', 'Var', (136, 142))	('neck squamous cell carcinoma', 'Disease', (61, 89))	('Arg388', 'Chemical', '-', (136, 142))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (66, 89))
296022	25989802	In addition, Arg388 carriers showed significantly poor survival outcome in head and neck or lung cancer patients.	('lung cancer', 'Disease', (92, 103))	('Arg388', 'Chemical', '-', (13, 19))	('lung cancer', 'Phenotype', 'HP:0100526', (92, 103))	('poor', 'NegReg', (50, 54))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('lung cancer', 'Disease', 'MESH:D008175', (92, 103))	('patients', 'Species', '9606', (104, 112))	('Arg388 carriers', 'Var', (13, 28))
296023	25989802	Considering the similar causal factors such as alcohol or smoking and treatment modality of head and neck, lung or esophageal cancer, FGFR4 polymorphism could be a targetable prognostic marker in esophageal cancer, for which there has been no reliable biomarker until now.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('lung', 'Disease', 'MESH:D008171', (107, 111))	('esophageal cancer', 'Disease', (196, 213))	('esophageal cancer', 'Disease', 'MESH:D004938', (196, 213))	('lung', 'Disease', (107, 111))	('alcohol', 'Chemical', 'MESH:D000438', (47, 54))	('esophageal cancer', 'Disease', (115, 132))	('esophageal cancer', 'Disease', 'MESH:D004938', (115, 132))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('FGFR4', 'Gene', '2264', (134, 139))	('FGFR4', 'Gene', (134, 139))	('polymorphism', 'Var', (140, 152))
296024	25989802	Thus, we investigated the role of FGFR4 polymorphisms in esophageal squamous cell carcinoma patients who were treated with CRT.	('esophageal squamous cell carcinoma', 'Disease', (57, 91))	('FGFR4', 'Gene', (34, 39))	('polymorphisms', 'Var', (40, 53))	('patients', 'Species', '9606', (92, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('investigated', 'Reg', (9, 21))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (57, 91))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (68, 91))	('FGFR4', 'Gene', '2264', (34, 39))
296030	25989802	FGFR4 Gly388Arg genotyping was performed using high-resolution melting (HRM) analysis with a Rotor Gene 6000 (Corbett Research, Sydney, Australia).	('FGFR4', 'Gene', (0, 5))	('Gly388Arg', 'SUBSTITUTION', 'None', (6, 15))	('Gly388Arg', 'Var', (6, 15))	('FGFR4', 'Gene', '2264', (0, 5))
296046	25989802	The frequencies of the FGFR4 Gly388Arg polymorphic genotypes were as follows: 94 patients (38.5%) had the Gly388 allele (G/G), 110 (45.4%) were heterozygous for G/A, and 40 (16.4%) had the Arg388 allele (A/A).	('Gly388', 'Chemical', '-', (29, 35))	('Gly388Arg', 'Var', (29, 38))	('Arg388', 'Var', (189, 195))	('Gly388', 'Var', (106, 112))	('Gly388Arg', 'SUBSTITUTION', 'None', (29, 38))	('Arg388', 'Chemical', '-', (189, 195))	('patients', 'Species', '9606', (81, 89))	('Gly388', 'Chemical', '-', (106, 112))	('FGFR4', 'Gene', '2264', (23, 28))	('FGFR4', 'Gene', (23, 28))
296047	25989802	Patients with the G/G allele (91.5%; 95% CI, 82.9 to 95.6) showed significantly better responses to CRT than Arg carriers (82.7%; 95% CI, 75.4 to 88.0; p=0.038) (Table 2).	('G/G', 'Var', (18, 21))	('Patients', 'Species', '9606', (0, 8))	('responses to CRT', 'MPA', (87, 103))	('Arg', 'Chemical', 'MESH:D001120', (109, 112))	('better', 'PosReg', (80, 86))
296048	25989802	However, no significant association was found between the FGFR4 genotype and any clinicopathological parameter examined, including tumor stage, differentiation, and tumor location (Table 1).	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('genotype', 'Var', (64, 72))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumor', 'Disease', (131, 136))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('FGFR4', 'Gene', '2264', (58, 63))	('FGFR4', 'Gene', (58, 63))	('tumor', 'Disease', (165, 170))
296052	25989802	In the early stages, patients with the Gly388 allele tended to have somewhat better PFS (unreached median OS [mOS] in G/G, 38 months in Arg388 carriers; 95% CI, 11.9 to 63.9; p=0.506) and OS rates (unreached mOS in G/G, 45 months; 95% CI, 26.1 to 63.5; p=0.773) (Fig.	('better', 'PosReg', (77, 83))	('PFS', 'CPA', (84, 87))	('mOS', 'Gene', (110, 113))	('Gly388', 'Chemical', '-', (39, 45))	('mOS', 'Gene', '17451', (110, 113))	('patients', 'Species', '9606', (21, 29))	('OS', 'Gene', '17451', (111, 113))	('mOS', 'Gene', (208, 211))	('OS', 'Gene', '17451', (106, 108))	('mOS', 'Gene', '17451', (208, 211))	('Arg388', 'Var', (136, 142))	('OS', 'Gene', '17451', (209, 211))	('OS', 'Gene', '17451', (188, 190))	('Arg388', 'Chemical', '-', (136, 142))	('Gly388', 'Var', (39, 45))
296054	25989802	However, patients with advanced stage disease showed similar patterns of PFS (9.6 months in G/G; 95% CI, 6.1 to 13 and 12.6 months in Arg388 carriers; 95% CI, 10.2 to 14.9; p=0.678) and OS (24.7 months in G/G; 95% CI, 19.5 to 29.90 and 22.4 months in Arg388 carriers, 95% CI, 15.3 to 29.5; p=0.668) (Fig.	('patients', 'Species', '9606', (9, 17))	('Arg388 carriers', 'Var', (251, 266))	('Arg388', 'Chemical', '-', (251, 257))	('OS', 'Gene', '17451', (186, 188))	('Arg388', 'Var', (134, 140))	('Arg388', 'Chemical', '-', (134, 140))
296055	25989802	In particular, patients with the Gly388 allele showed a significantly better OS rate than Arg388 carriers in the lymph node (LN) metastasis group (p=0.042) compared to the no LN metastasis group (p=0.125) (Fig.	('patients', 'Species', '9606', (15, 23))	('Arg388', 'Var', (90, 96))	('Gly388', 'Chemical', '-', (33, 39))	('Arg388', 'Chemical', '-', (90, 96))	('better', 'PosReg', (70, 76))	('OS', 'Gene', '17451', (77, 79))	('Gly388', 'Var', (33, 39))
296064	25989802	Studies of FGFR polymorphisms have reported association of Arg388 with increased cancer incidence, tumor size, and recurrence after adjuvant treatment.	('tumor', 'Disease', (99, 104))	('Arg388', 'Var', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('Arg388', 'Chemical', '-', (59, 65))	('cancer', 'Disease', (81, 87))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('FGFR', 'Gene', (11, 15))	('increased', 'PosReg', (71, 80))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('recurrence', 'CPA', (115, 125))	('association', 'Interaction', (44, 55))
296065	25989802	The current study was conducted in order to assess the role of FGFR4 Arg388 in patients treated with CRT for esophageal cancer, which is treated primarily by CRT in inoperable cases.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('Arg388', 'Var', (69, 75))	('Arg388', 'Chemical', '-', (69, 75))	('esophageal cancer', 'Disease', (109, 126))	('patients', 'Species', '9606', (79, 87))	('FGFR4', 'Gene', '2264', (63, 68))	('FGFR4', 'Gene', (63, 68))	('esophageal cancer', 'Disease', 'MESH:D004938', (109, 126))
296066	25989802	We found that patients with the Gly388 allele showed a significantly better response to CRT than Arg388 carriers, regardless of the cancer stage.	('response to CRT', 'MPA', (76, 91))	('patients', 'Species', '9606', (14, 22))	('Gly388', 'Chemical', '-', (32, 38))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('Arg388', 'Chemical', '-', (97, 103))	('better', 'PosReg', (69, 75))	('Gly388', 'Var', (32, 38))	('regardless of the cancer', 'Disease', 'MESH:D009369', (114, 138))	('regardless of the cancer', 'Disease', (114, 138))
296067	25989802	Interestingly, the PFS and OS rates in early esophageal cancer (stages I and II) showed improved survival trends with the Gly388 versus the Arg388 allele.	('Arg388', 'Chemical', '-', (140, 146))	('OS', 'Gene', '17451', (27, 29))	('esophageal cancer', 'Disease', (45, 62))	('esophageal cancer', 'Disease', 'MESH:D004938', (45, 62))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('Gly388', 'Chemical', '-', (122, 128))	('improved', 'PosReg', (88, 96))	('Gly388', 'Var', (122, 128))
296069	25989802	in breast cancer patients, disease-free survival with the Gly388 allele was prolonged significantly compared with the Arg388 allele when patients received adjuvant chemotherapy; however, no difference was observed among patients who underwent adjuvant endocrine therapy.	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('Gly388', 'Var', (58, 64))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('breast cancer', 'Disease', (3, 16))	('patients', 'Species', '9606', (137, 145))	('disease-free survival', 'CPA', (27, 48))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('patients', 'Species', '9606', (220, 228))	('prolonged', 'PosReg', (76, 85))	('Arg388', 'Chemical', '-', (118, 124))	('patients', 'Species', '9606', (17, 25))	('Gly388', 'Chemical', '-', (58, 64))
296074	25989802	Although the difference was not statistically significant, the pattern of survival differed according to stage, showing a tendency to be prolonged in Gly388 versus Arg388 carriers.	('prolonged', 'PosReg', (137, 146))	('Gly388', 'Var', (150, 156))	('Arg388', 'Chemical', '-', (164, 170))	('Gly388', 'Chemical', '-', (150, 156))	('Arg388', 'Var', (164, 170))
296075	25989802	In addition, in early esophageal cancer patients with LN invasion, significantly improved OS was observed in patients with the Gly388 allele compared to Arg388 carriers.	('improved', 'PosReg', (81, 89))	('OS', 'Gene', '17451', (90, 92))	('patients', 'Species', '9606', (109, 117))	('Gly388', 'Var', (127, 133))	('patients', 'Species', '9606', (40, 48))	('Arg388', 'Chemical', '-', (153, 159))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('Gly388', 'Chemical', '-', (127, 133))	('esophageal cancer', 'Disease', (22, 39))	('esophageal cancer', 'Disease', 'MESH:D004938', (22, 39))
296079	25989802	Taken together, the current data suggest that targeted therapy for FGFR4 could be more effective at earlier rather than more advanced stages of esophageal cancer, and that another treatment approach is needed for patients carrying Arg388 in order to improve the treatment outcome.	('Arg388', 'Chemical', '-', (231, 237))	('esophageal cancer', 'Disease', 'MESH:D004938', (144, 161))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('FGFR4', 'Gene', '2264', (67, 72))	('FGFR4', 'Gene', (67, 72))	('patients', 'Species', '9606', (213, 221))	('Arg388', 'Var', (231, 237))	('esophageal cancer', 'Disease', (144, 161))
296080	25989802	Unexpectedly, a better trend of OS was observed in Gly388 with LN invasion patients compared to Gly388 without LN invasion patients.	('Gly388', 'Chemical', '-', (51, 57))	('patients', 'Species', '9606', (75, 83))	('patients', 'Species', '9606', (123, 131))	('Gly388', 'Var', (51, 57))	('OS', 'Gene', '17451', (32, 34))	('LN invasion', 'Disease', (63, 74))	('Gly388', 'Chemical', '-', (96, 102))
296083	25989802	The molecular mechanism by which the FGFR4 Arg388 polymorphism leads to a more aggressive clinical phenotype is not yet fully understood.	('leads to', 'Reg', (63, 71))	('FGFR4', 'Gene', (37, 42))	('FGFR4', 'Gene', '2264', (37, 42))	('Arg388', 'Var', (43, 49))	('Arg388', 'Chemical', '-', (43, 49))
296085	25989802	showed that the FGFR4 Arg388 polymorphism induced overexpression of FGFR and that this could attenuate the response to chemotherapy.	('overexpression', 'PosReg', (50, 64))	('FGFR', 'Protein', (68, 72))	('FGFR4', 'Gene', '2264', (16, 21))	('Arg388', 'Var', (22, 28))	('FGFR4', 'Gene', (16, 21))	('attenuate', 'NegReg', (93, 102))	('Arg388', 'Chemical', '-', (22, 28))	('response to chemotherapy', 'CPA', (107, 131))
296086	25989802	A similar result was reported in a gastric cancer model showing that an FGFR4 inhibitor and 5-FU reduced proliferation and promoted apoptosis.	('apoptosis', 'CPA', (132, 141))	('FGFR4', 'Gene', '2264', (72, 77))	('FGFR4', 'Gene', (72, 77))	('gastric cancer', 'Phenotype', 'HP:0012126', (35, 49))	('gastric cancer', 'Disease', 'MESH:D013274', (35, 49))	('promoted', 'PosReg', (123, 131))	('reduced', 'NegReg', (97, 104))	('proliferation', 'CPA', (105, 118))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('gastric cancer', 'Disease', (35, 49))	('inhibitor', 'Var', (78, 87))	('5-FU', 'Chemical', 'MESH:D005472', (92, 96))
296087	25989802	For HNSCC, the association between CRT and FGFR4 was evaluated in vitro, showing increased sensitivity of cells containing the Arg388 allele to cisplatin, which differs from our observations.	('Arg388', 'Var', (127, 133))	('Arg388', 'Chemical', '-', (127, 133))	('FGFR4', 'Gene', '2264', (43, 48))	('FGFR4', 'Gene', (43, 48))	('increased', 'PosReg', (81, 90))	('cisplatin', 'Chemical', 'MESH:D002945', (144, 153))	('sensitivity', 'MPA', (91, 102))
296088	25989802	In contrast to various results primarily from in vitro studies, there is a lack of clear evidence for any relationship between the FGFR4 Arg388 genotype and protein expression or clinicopathological parameters in cancer patients However, the FGFR4 Gly388 allele has been reported as a prognostic marker for survival in breast and gastric cancer patients.	('gastric cancer', 'Disease', (330, 344))	('cancer', 'Disease', (338, 344))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('Gly388', 'Chemical', '-', (248, 254))	('FGFR4', 'Gene', '2264', (131, 136))	('FGFR4', 'Gene', (131, 136))	('patients', 'Species', '9606', (345, 353))	('gastric cancer', 'Phenotype', 'HP:0012126', (330, 344))	('cancer', 'Disease', 'MESH:D009369', (213, 219))	('Gly388', 'Var', (248, 254))	('FGFR4', 'Gene', (242, 247))	('patients', 'Species', '9606', (220, 228))	('FGFR4', 'Gene', '2264', (242, 247))	('cancer', 'Phenotype', 'HP:0002664', (338, 344))	('cancer', 'Disease', (213, 219))	('cancer', 'Disease', 'MESH:D009369', (338, 344))	('gastric cancer', 'Disease', 'MESH:D013274', (330, 344))	('Arg388', 'Chemical', '-', (137, 143))
296089	25989802	The lack of correlation between genotype and phenotype for FGFR4 may be explained in part by the lack of elevated tyrosine phosphorylation of FGFR4 Arg388 compared with FGFR4 Gly388, the use of different intracellular signal transduction pathway(s) or interactions with different cell surface protein(s), or linkage disequilibrium with other genetic changes that also contribute to a poor prognosis.	('FGFR4', 'Gene', (59, 64))	('interactions', 'Interaction', (252, 264))	('FGFR4', 'Gene', '2264', (142, 147))	('elevated', 'PosReg', (105, 113))	('FGFR4', 'Gene', (142, 147))	('tyrosine', 'Chemical', 'MESH:D014443', (114, 122))	('tyrosine phosphorylation', 'MPA', (114, 138))	('Arg388', 'Var', (148, 154))	('elevated tyrosine', 'Phenotype', 'HP:0003231', (105, 122))	('lack', 'NegReg', (97, 101))	('FGFR4', 'Gene', '2264', (169, 174))	('FGFR4', 'Gene', (169, 174))	('Gly388', 'Chemical', '-', (175, 181))	('Arg388', 'Chemical', '-', (148, 154))	('FGFR4', 'Gene', '2264', (59, 64))
296090	25989802	To the best of our knowledge, this is the first report describing a predictive role for FGFR4 Arg388 after CRT.	('FGFR4', 'Gene', (88, 93))	('Arg388', 'Var', (94, 100))	('FGFR4', 'Gene', '2264', (88, 93))	('Arg388', 'Chemical', '-', (94, 100))
296091	25989802	The biochemical effects of FGFR4 Arg388 with regard to chemotherapy should be evaluated in future studies including other biomarkers.	('Arg388', 'Var', (33, 39))	('FGFR4', 'Gene', '2264', (27, 32))	('FGFR4', 'Gene', (27, 32))	('Arg388', 'Chemical', '-', (33, 39))
296095	25989802	Although the FGFR4 polymorphism examined in this study is not a significant prognostic factor in esophageal cancer treated with CRT, esophageal cancer patients carrying FGFR4 Gly388 showed a good response after CRT.	('Gly388', 'Var', (175, 181))	('FGFR4', 'Gene', '2264', (13, 18))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('esophageal cancer', 'Disease', (97, 114))	('patients', 'Species', '9606', (151, 159))	('FGFR4', 'Gene', '2264', (169, 174))	('FGFR4', 'Gene', (169, 174))	('Gly388', 'Chemical', '-', (175, 181))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('esophageal cancer', 'Disease', 'MESH:D004938', (97, 114))	('esophageal cancer', 'Disease', (133, 150))	('esophageal cancer', 'Disease', 'MESH:D004938', (133, 150))	('FGFR4', 'Gene', (13, 18))
296096	25989802	Especially in early esophageal cancer, the Gly388 allele resulted in increased OS and PFS, and select patients showing LN invasion showed significant prolonged OS compared to Arg388 carriers.	('esophageal cancer', 'Disease', (20, 37))	('prolonged', 'PosReg', (150, 159))	('increased', 'PosReg', (69, 78))	('esophageal cancer', 'Disease', 'MESH:D004938', (20, 37))	('OS', 'Gene', '17451', (79, 81))	('Gly388', 'Chemical', '-', (43, 49))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('patients', 'Species', '9606', (102, 110))	('PFS', 'CPA', (86, 89))	('OS', 'Gene', '17451', (160, 162))	('Gly388', 'Var', (43, 49))	('Arg388', 'Chemical', '-', (175, 181))
296129	25873626	While DISTILLER achieved greater performance than the original cMonkey1 in these measures on our E. coli GRE detection benchmarks, primarily due to its greater precision, our analysis reveals that the algorithm modifications in cMonkey2 have enabled it to outperform all methods.	('outperform', 'PosReg', (256, 266))	('cMonkey2', 'Gene', (228, 236))	('modifications', 'Var', (211, 224))	('E. coli', 'Species', '562', (97, 104))
296135	25873626	Importantly, we first found that integration of MEME motifs in cMonkey2 optimization significantly increased the number of modules that were enriched for both ChIP-seq (350 vs. 187 significantly enriched modules, Student's t-test p-value = 5.0 x 10-12, Table 2) and TFOE (346 vs. 249 significantly enriched modules, p-value = 6.2 x 10-10, Table 2) TF targets, in comparison runs in which motifs were excluded from training (i.e.	('TFOE', 'Chemical', '-', (266, 270))	('cMonkey2', 'Gene', (63, 71))	('increased', 'PosReg', (99, 108))	('motifs', 'Var', (53, 59))
296238	24475740	Recent study suggested that aberrant expression of p53 and mdm-2 correlated with the high histological grade of the tumor and were associated with tumor behavior and local recurrence.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('p53', 'Gene', (51, 54))	('p53', 'Gene', '7157', (51, 54))	('mdm-2', 'Gene', (59, 64))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('aberrant', 'Var', (28, 36))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('associated with', 'Reg', (131, 146))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('mdm-2', 'Gene', '4193', (59, 64))	('local recurrence', 'CPA', (166, 182))	('expression', 'MPA', (37, 47))	('tumor', 'Disease', (116, 121))	('correlated', 'Reg', (65, 75))
296244	24475740	However, the overexpression or gene amplification of HER2 in intrahepatic mucoepidermoid carcinoma has not been clarified yet, although it could be detected in up to one-third of patients with mucoepidermoid carcinoma in the salivary glands.	('carcinoma', 'Phenotype', 'HP:0030731', (208, 217))	('carcinoma in the salivary', 'Phenotype', 'HP:0100684', (208, 233))	('gene amplification', 'Var', (31, 49))	('mucoepidermoid carcinoma', 'Disease', 'MESH:D018277', (193, 217))	('HER2', 'Gene', (53, 57))	('intrahepatic mucoepidermoid carcinoma', 'Disease', (61, 98))	('mucoepidermoid carcinoma', 'Disease', 'MESH:D018277', (74, 98))	('HER2', 'Gene', '2064', (53, 57))	('patients', 'Species', '9606', (179, 187))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('intrahepatic mucoepidermoid carcinoma', 'Disease', 'MESH:D018277', (61, 98))	('mucoepidermoid carcinoma', 'Disease', (193, 217))
296254	33033517	Impact of miR-424-5p on malignancy growth in vivo was further verified in a mouse xenograft model.	('mouse', 'Species', '10090', (76, 81))	('miR-424-5p', 'Chemical', '-', (10, 20))	('malignancy growth', 'Disease', 'MESH:D006130', (24, 41))	('malignancy growth', 'Disease', (24, 41))	('miR-424-5p', 'Var', (10, 20))
296256	33033517	Results: miR-424-5p expression was found upregulated in ESCC.	('ESCC', 'Disease', (56, 60))	('miR-424-5p', 'Var', (9, 19))	('miR-424-5p', 'Chemical', '-', (9, 19))	('upregulated', 'PosReg', (41, 52))
296257	33033517	miR-424-5p overexpression dramatically facilitated ESCC cells proliferation and migration capacity in vitro, while downregulation of miR-424-5p displayed the opposite trend.	('miR-424-5p', 'Chemical', '-', (0, 10))	('facilitated', 'PosReg', (39, 50))	('miR-424-5p', 'Chemical', '-', (133, 143))	('migration capacity', 'CPA', (80, 98))	('ESCC cells proliferation', 'CPA', (51, 75))	('miR-424-5p', 'Var', (0, 10))	('overexpression', 'PosReg', (11, 25))
296259	33033517	Moreover, SIRT4 was confirmed to be a specific target gene of miR-424-5p in ESCC and negatively modulated by miR-424-5p.	('miR-424-5p', 'Chemical', '-', (62, 72))	('SIRT4', 'Gene', '23409', (10, 15))	('miR-424-5p', 'Var', (109, 119))	('SIRT4', 'Gene', (10, 15))	('ESCC', 'Disease', (76, 80))	('miR-424-5p', 'Var', (62, 72))	('miR-424-5p', 'Chemical', '-', (109, 119))
296260	33033517	Finally, SIRT4 overexpression strongly rescued the promoting influence of miR-424-5p on the proliferative and migratory capacity of ESCC cells.	('rescued', 'PosReg', (39, 46))	('SIRT4', 'Gene', '23409', (9, 14))	('promoting', 'PosReg', (51, 60))	('miR-424-5p', 'Var', (74, 84))	('SIRT4', 'Gene', (9, 14))	('miR-424-5p', 'Chemical', '-', (74, 84))
296261	33033517	Conclusions: miR-424-5p had tumor promoting functions in proliferation and migration of ESCC by targeting SIRT4, suggesting that miR-424-5p may serve as a potential diagnostic biomarker and manipulation of miR-424-5p/SIRT4 axis could provide a novel therapeutic strategy for further ESCC treatment.	('promoting', 'PosReg', (34, 43))	('miR-424-5p', 'Chemical', '-', (13, 23))	('tumor', 'Disease', (28, 33))	('SIRT4', 'Gene', (106, 111))	('ESCC', 'Disease', (283, 287))	('miR-424-5p', 'Chemical', '-', (206, 216))	('SIRT4', 'Gene', (217, 222))	('miR-424-5p', 'Var', (129, 139))	('SIRT4', 'Gene', '23409', (106, 111))	('proliferation', 'CPA', (57, 70))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('migration', 'CPA', (75, 84))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('SIRT4', 'Gene', '23409', (217, 222))	('miR-424-5p', 'Chemical', '-', (129, 139))
296270	33033517	In thyroid cancer, miR-424-5p facilitates anoikis resistance and lung metastasis by inactivating Hippo signal transduction.	('inactivating', 'NegReg', (84, 96))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('thyroid cancer', 'Phenotype', 'HP:0002890', (3, 17))	('thyroid cancer', 'Disease', 'MESH:D013964', (3, 17))	('anoikis resistance', 'CPA', (42, 60))	('Hippo signal transduction', 'MPA', (97, 122))	('miR-424-5p', 'Var', (19, 29))	('miR-424-5p', 'Chemical', '-', (19, 29))	('thyroid cancer', 'Disease', (3, 17))	('facilitates', 'PosReg', (30, 41))	('lung metastasis', 'CPA', (65, 80))
296271	33033517	Additionally, miR-424-5p exhibits a pivotal impact in cervical, ovarian, hepatocellular, leukemia, breast cancer and so on.	('miR-424-5p', 'Var', (14, 24))	('breast cancer', 'Disease', 'MESH:D001943', (99, 112))	('leukemia', 'Phenotype', 'HP:0001909', (89, 97))	('breast cancer', 'Disease', (99, 112))	('leukemia', 'Disease', 'MESH:D007938', (89, 97))	('miR-424-5p', 'Chemical', '-', (14, 24))	('breast cancer', 'Phenotype', 'HP:0003002', (99, 112))	('impact', 'Reg', (44, 50))	('leukemia', 'Disease', (89, 97))	('hepatocellular', 'Disease', (73, 87))	('ovarian', 'Disease', (64, 71))	('cervical', 'Disease', (54, 62))	('ovarian', 'Disease', 'MESH:D010049', (64, 71))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
296276	33033517	Here, we observed that miR-424-5p could accelerate proliferation and migration of ESCC in our in vitro and in vivo experiments.	('accelerate', 'PosReg', (40, 50))	('ESCC', 'Protein', (82, 86))	('miR-424-5p', 'Var', (23, 33))	('proliferation', 'CPA', (51, 64))	('migration', 'CPA', (69, 78))	('miR-424-5p', 'Chemical', '-', (23, 33))
296277	33033517	In addition, we identified SIRT4 as a direct target of miR-424-5p.	('SIRT4', 'Gene', (27, 32))	('SIRT4', 'Gene', '23409', (27, 32))	('miR-424-5p', 'Var', (55, 65))	('miR-424-5p', 'Chemical', '-', (55, 65))
296278	33033517	Rescue assays further illustrated that miR-424-5p indeed manipulated proliferation and migration of ESCC cells through SIRT4.	('migration', 'CPA', (87, 96))	('proliferation', 'CPA', (69, 82))	('miR-424-5p', 'Var', (39, 49))	('SIRT4', 'Gene', (119, 124))	('SIRT4', 'Gene', '23409', (119, 124))	('miR-424-5p', 'Chemical', '-', (39, 49))	('manipulated', 'Reg', (57, 68))
296301	33033517	Co-transfection was performed based on four experimental groups (NC + SIRT4-WT, mimic + SIRT4-WT, NC + SIRT4-MT, and mimic + SIRT4-MT), and the Luciferase Reporter Assay Kit was used to detect luciferase activity as per the manufacturer's protocol.	('SIRT4', 'Gene', '23409', (125, 130))	('luciferase', 'Enzyme', (193, 203))	('activity', 'MPA', (204, 212))	('SIRT4', 'Gene', '23409', (88, 93))	('SIRT4', 'Gene', (103, 108))	('SIRT4', 'Gene', (70, 75))	('mimic', 'Var', (117, 122))	('SIRT4', 'Gene', (125, 130))	('SIRT4', 'Gene', (88, 93))	('SIRT4', 'Gene', '23409', (103, 108))	('SIRT4', 'Gene', '23409', (70, 75))
296308	33033517	1A, miR-424-5p was significantly elevated in 162 ESCC patients compared with 11 normal esophagus samples from starBase (P = 0.012).	('miR-424-5p', 'Chemical', '-', (4, 14))	('elevated', 'PosReg', (33, 41))	('patients', 'Species', '9606', (54, 62))	('ESCC', 'Disease', (49, 53))	('miR-424-5p', 'Var', (4, 14))
296309	33033517	Meanwhile, bioinformatics analysis from TCGA further confirmed similar conclusion that miR-424-5p expression was increased in ESCC specimens (Fig.	('miR-424-5p', 'Var', (87, 97))	('miR-424-5p', 'Chemical', '-', (87, 97))	('ESCC specimens', 'Disease', (126, 140))	('increased', 'PosReg', (113, 122))
296311	33033517	These data clearly demonstrate that miR-424-5p is upregulated in ESCC and is a potential oncogene.	('miR-424-5p', 'Chemical', '-', (36, 46))	('upregulated', 'PosReg', (50, 61))	('miR-424-5p', 'Var', (36, 46))	('ESCC', 'Disease', (65, 69))
296313	33033517	Compared with matched controls, miR-424-5p expression was conspicuously increased after miR-424-5p mimic transfection in EC-9706 while reduced after transfection with inhibitor in Eca-109 (Fig.	('transfection', 'Var', (105, 117))	('increased', 'PosReg', (72, 81))	('EC-9706', 'CellLine', 'CVCL:E307', (121, 128))	('miR-424-5p mimic transfection', 'Var', (88, 117))	('Eca', 'Chemical', '-', (180, 183))	('miR-424-5p expression', 'MPA', (32, 53))	('reduced', 'NegReg', (135, 142))	('miR-424-5p', 'Chemical', '-', (32, 42))	('miR-424-5p', 'Chemical', '-', (88, 98))	('EC', 'Phenotype', 'HP:0011459', (121, 123))
296314	33033517	To illustrate the potential biological functions of miR-424-5p in ESCC, we then performed various tumorigenic phenotyping experiments.	('miR-424-5p', 'Chemical', '-', (52, 62))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('ESCC', 'Disease', (66, 70))	('tumor', 'Disease', (98, 103))	('miR-424-5p', 'Var', (52, 62))
296315	33033517	The CCK8 assay revealed that increase in miR-424-5p expression typically expedited cell proliferation in EC-9706, while anti-miR-424-5p transfection attenuated growth of Eca-109 cells (Fig.	('anti-miR-424-5p', 'Var', (120, 135))	('EC', 'Phenotype', 'HP:0011459', (105, 107))	('miR-424-5p', 'Chemical', '-', (41, 51))	('miR-424-5p', 'Chemical', '-', (125, 135))	('cell proliferation', 'CPA', (83, 101))	('increase', 'PosReg', (29, 37))	('attenuated', 'NegReg', (149, 159))	('EC-9706', 'CellLine', 'CVCL:E307', (105, 112))	('expedited', 'PosReg', (73, 82))	('growth', 'CPA', (160, 166))	('miR-424-5p', 'Var', (41, 51))	('Eca', 'Chemical', '-', (170, 173))
296316	33033517	Similarly, the effects of miR-424-5p or anti-miR-424-5p were consistently observed in the colony-forming assay (Fig.	('miR-424-5p', 'Chemical', '-', (45, 55))	('observed', 'Reg', (74, 82))	('miR-424-5p', 'Var', (26, 36))	('colony-forming assay', 'CPA', (90, 110))	('miR-424-5p', 'Chemical', '-', (26, 36))	('anti-miR-424-5p', 'Var', (40, 55))
296318	33033517	Wound healing assay revealed that overexpression of miR-424-5p upregulated the migration quantity of EC-9706, and miR-424-5p knockdown significantly delayed the wound closure in Eca-109 (Fig.	('EC', 'Phenotype', 'HP:0011459', (101, 103))	('EC-9706', 'CellLine', 'CVCL:E307', (101, 108))	('miR-424-5p', 'Chemical', '-', (52, 62))	('wound closure', 'CPA', (161, 174))	('migration quantity', 'CPA', (79, 97))	('miR-424-5p', 'Chemical', '-', (114, 124))	('delayed', 'NegReg', (149, 156))	('upregulated', 'PosReg', (63, 74))	('miR-424-5p knockdown', 'Var', (114, 134))	('Eca', 'Chemical', '-', (178, 181))	('miR-424-5p', 'Var', (52, 62))
296319	33033517	2E, Transwell migration assay further demonstrated that miR-424-5p overexpression accelerated EC-9706 passing through the filter membranes.	('EC-9706', 'CellLine', 'CVCL:E307', (94, 101))	('miR-424-5p', 'Chemical', '-', (56, 66))	('accelerated', 'PosReg', (82, 93))	('EC', 'Phenotype', 'HP:0011459', (94, 96))	('EC-9706 passing through the', 'CPA', (94, 121))	('miR-424-5p', 'Var', (56, 66))
296320	33033517	On the contrary, silence of miR-424-5p restrained the migration capability of Eca-109.	('silence', 'Var', (17, 24))	('miR-424-5p', 'Chemical', '-', (28, 38))	('Eca-109', 'Gene', (78, 85))	('restrained', 'NegReg', (39, 49))	('migration capability', 'CPA', (54, 74))	('miR-424-5p', 'Protein', (28, 38))	('Eca', 'Chemical', '-', (78, 81))
296321	33033517	In short, these results indicate that miR-424-5p has a promoting role in ESCC cell proliferation and migration.	('miR-424-5p', 'Chemical', '-', (38, 48))	('migration', 'CPA', (101, 110))	('promoting', 'PosReg', (55, 64))	('miR-424-5p', 'Var', (38, 48))	('ESCC', 'Disease', (73, 77))
296322	33033517	We next explored whether miR-424-5p affects neoplasm formation in nude mice.	('miR-424-5p', 'Chemical', '-', (25, 35))	('neoplasm', 'Disease', (44, 52))	('neoplasm', 'Phenotype', 'HP:0002664', (44, 52))	('miR-424-5p', 'Var', (25, 35))	('nude mice', 'Species', '10090', (66, 75))	('neoplasm', 'Disease', 'MESH:D009369', (44, 52))
296323	33033517	Ten mice were randomly assigned into two groups receiving 5x106 Eca-109 cells stably expressing anti-miR-424-5p and anti-NC, respectively, in left underarm subcutaneously.	('anti-NC', 'Var', (116, 123))	('mice', 'Species', '10090', (4, 8))	('anti-miR-424-5p', 'Var', (96, 111))	('miR-424-5p', 'Chemical', '-', (101, 111))	('Eca', 'Chemical', '-', (64, 67))
296324	33033517	As compared control group, inhibition of miR-424-5p clearly slowed down the tumor growth (Fig.	('slowed down', 'NegReg', (60, 71))	('miR-424-5p', 'Chemical', '-', (41, 51))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('inhibition', 'Var', (27, 37))	('miR-424-5p', 'Var', (41, 51))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
296325	33033517	At the conclusion of the experiment, although all the mice developed xenograft tumors, the final sizes and weights of the tumors formed from anti-miR-424-5p expressing cells were more than 2-fold smaller than those formed from control cells (Fig.	('anti-miR-424-5p expressing', 'Var', (141, 167))	('tumors', 'Disease', (122, 128))	('tumors', 'Disease', 'MESH:D009369', (122, 128))	('smaller', 'NegReg', (196, 203))	('tumors', 'Disease', (79, 85))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('miR-424-5p', 'Chemical', '-', (146, 156))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('mice', 'Species', '10090', (54, 58))	('tumors', 'Phenotype', 'HP:0002664', (122, 128))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
296326	33033517	These findings further support the tumor suppressor role of miR-424-5p in ESCC as observed in our in vitro experiments.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('ESCC', 'Disease', (74, 78))	('tumor', 'Disease', (35, 40))	('miR-424-5p', 'Var', (60, 70))	('miR-424-5p', 'Chemical', '-', (60, 70))
296327	33033517	To gain further insight of miR-424-5p in ESCC, we employed four online bioinformatics databases including TargetScan, miRDB, mirDIP and miRWalk to identify potential target genes of miR-424-5p.	('ESCC', 'Disease', (41, 45))	('miR-424-5p', 'Chemical', '-', (27, 37))	('miR-424-5p', 'Var', (182, 192))	('miR-424-5p', 'Chemical', '-', (182, 192))
296332	33033517	Figure 4C showed predicted binding site of miR-424-5p on the 3'UTR of SIRT4 mRNA, based on which we constructed pmirGlo plasmids containing wild-type (WT) and mutant (MT) sequences for dual-luciferase reporter assay.	('mutant', 'Var', (159, 165))	('SIRT4', 'Gene', (70, 75))	('SIRT4', 'Gene', '23409', (70, 75))	('miR-424-5p', 'Chemical', '-', (43, 53))
296333	33033517	5D, miR-424-5p mimic refrained luciferase activity in EC-9706 cells transfected with SIRT4 3'-UTR-WT construct but did not affect that of SIRT4 3'-UTR-MT (Fig.	('EC', 'Phenotype', 'HP:0011459', (54, 56))	('activity', 'MPA', (42, 50))	('miR-424-5p', 'Chemical', '-', (4, 14))	('SIRT4', 'Gene', (85, 90))	('refrained', 'NegReg', (21, 30))	('EC-9706', 'CellLine', 'CVCL:E307', (54, 61))	('SIRT4', 'Gene', (138, 143))	('SIRT4', 'Gene', '23409', (85, 90))	('luciferase', 'Enzyme', (31, 41))	('SIRT4', 'Gene', '23409', (138, 143))	('miR-424-5p', 'Var', (4, 14))
296334	33033517	4D), suggesting that the WT binding site is responsible for miR-424-5p inhibition of luciferase activity.	('activity', 'MPA', (96, 104))	('luciferase', 'Enzyme', (85, 95))	('miR-424-5p', 'Var', (60, 70))	('inhibition', 'NegReg', (71, 81))	('miR-424-5p', 'Chemical', '-', (60, 70))
296336	33033517	As expected, transfection with miR-424-5p mimic significantly downregulated SIRT4 mRNA and protein expression in EC-9706 cells, and in contrast, anti-miR-424-5p transfection in Eca-109 cells displayed opposite effects (Fig.	('miR-424-5p', 'Var', (31, 41))	('SIRT4', 'Gene', '23409', (76, 81))	('miR-424-5p', 'Chemical', '-', (31, 41))	('EC', 'Phenotype', 'HP:0011459', (113, 115))	('downregulated', 'NegReg', (62, 75))	('EC-9706', 'CellLine', 'CVCL:E307', (113, 120))	('SIRT4', 'Gene', (76, 81))	('Eca', 'Chemical', '-', (177, 180))	('miR-424-5p', 'Chemical', '-', (150, 160))
296337	33033517	Taken together, these data indicate that SIRT4 is a direct target of miR-424-5p.	('SIRT4', 'Gene', (41, 46))	('SIRT4', 'Gene', '23409', (41, 46))	('miR-424-5p', 'Chemical', '-', (69, 79))	('miR-424-5p', 'Var', (69, 79))
296338	33033517	We have shown that miR-424-5p enhanced the proliferation and migration ability of ESCC in vitro and in vivo, and SIRT4 3'-UTR was a direct target of miR-424-5p.	('migration ability', 'CPA', (61, 78))	('enhanced', 'PosReg', (30, 38))	('SIRT4', 'Gene', (113, 118))	('miR-424-5p', 'Chemical', '-', (149, 159))	('ESCC', 'CPA', (82, 86))	('miR-424-5p', 'Var', (19, 29))	('SIRT4', 'Gene', '23409', (113, 118))	('proliferation', 'CPA', (43, 56))	('miR-424-5p', 'Chemical', '-', (19, 29))
296340	33033517	EC-9706 cells overexpressing miR-424-5p were transfected with SIRT4 plasmids or empty vectors as control.	('miR-424-5p', 'Var', (29, 39))	('miR-424-5p', 'Chemical', '-', (29, 39))	('SIRT4', 'Gene', (62, 67))	('EC', 'Phenotype', 'HP:0011459', (0, 2))	('EC-9706', 'CellLine', 'CVCL:E307', (0, 7))	('SIRT4', 'Gene', '23409', (62, 67))
296341	33033517	The expression level of SIRT4 protein was increased after EC-9706 cells were co-transfected with SIRT4 and miR-424-5p compared with cells transfected with miR-424-5p alone (Fig.	('expression level', 'MPA', (4, 20))	('increased', 'PosReg', (42, 51))	('SIRT4', 'Gene', '23409', (97, 102))	('miR-424-5p', 'Chemical', '-', (107, 117))	('SIRT4', 'Gene', (24, 29))	('miR-424-5p', 'Chemical', '-', (155, 165))	('EC', 'Phenotype', 'HP:0011459', (58, 60))	('EC-9706', 'CellLine', 'CVCL:E307', (58, 65))	('SIRT4', 'Gene', (97, 102))	('SIRT4', 'Gene', '23409', (24, 29))	('miR-424-5p', 'Var', (107, 117))
296343	33033517	5C) assays indicated, the promoting effect on cell proliferation by miR-424-5p in EC-9706 were significantly receded by ectopic expression of SIRT4.	('miR-424-5p', 'Chemical', '-', (68, 78))	('EC', 'Phenotype', 'HP:0011459', (82, 84))	('SIRT4', 'Gene', (142, 147))	('EC-9706', 'CellLine', 'CVCL:E307', (82, 89))	('miR-424-5p', 'Var', (68, 78))	('receded', 'NegReg', (109, 116))	('EC-9706', 'Gene', (82, 89))	('promoting', 'PosReg', (26, 35))	('cell proliferation', 'CPA', (46, 64))	('SIRT4', 'Gene', '23409', (142, 147))
296344	33033517	As anticipated, wound healing and Transwell migration analyses also showed that the augmented migratory capabilities by miR-424-5p in ESCC cells were weakened after SIRT4 overexpression (Fig.	('SIRT4', 'Gene', (165, 170))	('overexpression', 'PosReg', (171, 185))	('miR-424-5p', 'Var', (120, 130))	('weakened', 'NegReg', (150, 158))	('SIRT4', 'Gene', '23409', (165, 170))	('migratory capabilities', 'CPA', (94, 116))	('augmented', 'PosReg', (84, 93))	('miR-424-5p', 'Chemical', '-', (120, 130))
296345	33033517	Collectively, our data provides convincing evidence that SIRT4 is a functional target gene of miR-424-5p.	('SIRT4', 'Gene', (57, 62))	('miR-424-5p', 'Var', (94, 104))	('SIRT4', 'Gene', '23409', (57, 62))	('miR-424-5p', 'Chemical', '-', (94, 104))
296350	33033517	Recently, miR-424-5p has been recognized as an essential influencing factor in a variety of human cancers.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('cancers', 'Phenotype', 'HP:0002664', (98, 105))	('miR-424-5p', 'Chemical', '-', (10, 20))	('cancers', 'Disease', 'MESH:D009369', (98, 105))	('cancers', 'Disease', (98, 105))	('human', 'Species', '9606', (92, 97))	('miR-424-5p', 'Var', (10, 20))
296353	33033517	showed that miR-424-5p also reduced tumor growth in ovarian carcinoma through targeting KIF23, which was silenced by DNA methylation.	('KIF23', 'Gene', (88, 93))	('reduced', 'NegReg', (28, 35))	('miR-424-5p', 'Var', (12, 22))	('tumor growth in ovarian carcinoma', 'Disease', (36, 69))	('tumor growth in ovarian carcinoma', 'Disease', 'MESH:D010051', (36, 69))	('miR-424-5p', 'Chemical', '-', (12, 22))	('carcinoma', 'Phenotype', 'HP:0030731', (60, 69))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('KIF23', 'Gene', '9493', (88, 93))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (52, 69))
296354	33033517	In any case, plenty of studies considered miR-424-5p as an anti-tumor miRNA participating in tumorigenesis and progression of various tumors.	('tumors', 'Disease', (134, 140))	('tumor', 'Disease', (64, 69))	('miR-424-5p', 'Chemical', '-', (42, 52))	('tumors', 'Disease', 'MESH:D009369', (134, 140))	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Disease', (93, 98))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('miR-424-5p', 'Var', (42, 52))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('tumor', 'Disease', (134, 139))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
296356	33033517	suggested that miR-424-5p facilitated anorexia and lung metastasis by passivating Hippo signaling in thyroid cancer.	('miR-424-5p', 'Var', (15, 25))	('Hippo signaling', 'MPA', (82, 97))	('anorexia', 'Disease', (38, 46))	('facilitated', 'PosReg', (26, 37))	('anorexia', 'Phenotype', 'HP:0002039', (38, 46))	('thyroid cancer', 'Phenotype', 'HP:0002890', (101, 115))	('thyroid cancer', 'Disease', (101, 115))	('miR-424-5p', 'Chemical', '-', (15, 25))	('passivating', 'PosReg', (70, 81))	('thyroid cancer', 'Disease', 'MESH:D013964', (101, 115))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('lung metastasis', 'CPA', (51, 66))	('anorexia', 'Disease', 'MESH:D000855', (38, 46))
296357	33033517	Additionally, miR-424-5p enhanced the proliferation and metastasis of colorectal cancer through direct inhibition of SCN4B.	('miR-424-5p', 'Var', (14, 24))	('metastasis', 'CPA', (56, 66))	('colorectal cancer', 'Disease', 'MESH:D015179', (70, 87))	('proliferation', 'CPA', (38, 51))	('enhanced', 'PosReg', (25, 33))	('colorectal cancer', 'Phenotype', 'HP:0003003', (70, 87))	('miR-424-5p', 'Chemical', '-', (14, 24))	('colorectal cancer', 'Disease', (70, 87))	('SCN4B', 'Gene', (117, 122))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('SCN4B', 'Gene', '6330', (117, 122))	('inhibition', 'NegReg', (103, 113))
296358	33033517	Moreover, miR-424-5p has been identified as an oncogene affecting cell cycle process by directly targeting CADM1 in laryngeal squamous cell carcinoma.	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (126, 149))	('squamous cell carcinoma', 'Disease', (126, 149))	('cell cycle', 'CPA', (66, 76))	('CADM1', 'Gene', (107, 112))	('miR-424-5p', 'Chemical', '-', (10, 20))	('CADM1', 'Gene', '23705', (107, 112))	('targeting', 'Reg', (97, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (126, 149))	('miR-424-5p', 'Var', (10, 20))
296361	33033517	Moreover, functional tests (CCK8, colony-forming, wound healing and Transwell) elucidated that miR-424-5p knockdown restricted ESCC proliferation and migration compared with negative control.	('miR-424-5p knockdown', 'Var', (95, 115))	('ESCC proliferation', 'CPA', (127, 145))	('restricted', 'NegReg', (116, 126))	('miR-424-5p', 'Chemical', '-', (95, 105))	('migration', 'CPA', (150, 159))
296362	33033517	These results further confirmed the oncogenic role of miR-424-5p in ESCC.	('ESCC', 'Disease', (68, 72))	('miR-424-5p', 'Chemical', '-', (54, 64))	('miR-424-5p', 'Var', (54, 64))
296363	33033517	For the purpose of understanding how miR-424-5p promoted malignant phenotypes on ESCC, we utilized four bioinformatics databases (TargetScan, miRBD, mirDIP, and miRWalk) to screen for potential miR-424-5p target genes.	('miR-424-5p', 'Var', (37, 47))	('ESCC', 'Disease', (81, 85))	('malignant phenotypes', 'CPA', (57, 77))	('miR-424-5p', 'Chemical', '-', (194, 204))	('miR-424-5p', 'Chemical', '-', (37, 47))	('promoted', 'PosReg', (48, 56))
296365	33033517	Interestingly, miRNA-15b managed mitochondrial ROS production and the phenotype associated with aging about SIRT4.	('SIRT4', 'Gene', '23409', (108, 113))	('mitochondrial ROS production', 'MPA', (33, 61))	('SIRT4', 'Gene', (108, 113))	('miRNA-15b', 'Var', (15, 24))	('ROS', 'Chemical', '-', (47, 50))
296366	33033517	Meanwhile, miRNA-497 restrained cardiac hypertrophy through targeting SIRT4.	('restrained', 'NegReg', (21, 31))	('miRNA-497', 'Var', (11, 20))	('cardiac hypertrophy', 'Disease', (32, 51))	('cardiac hypertrophy', 'Disease', 'MESH:D006332', (32, 51))	('cardiac hypertrophy', 'Phenotype', 'HP:0001639', (32, 51))	('SIRT4', 'Gene', (70, 75))	('SIRT4', 'Gene', '23409', (70, 75))
296369	33033517	discovered that SIRT4 could inhibit tumorigenesis and advance in HCC through crippling glutamine metabolism and blocking mTOR signaling pathway which based on enhancing the ADP/AMP levels through phosphorylation of AMPK via LKB1.	('crippling', 'NegReg', (77, 86))	('SIRT4', 'Gene', '23409', (16, 21))	('LKB1', 'Gene', '6794', (224, 228))	('AMPK', 'Gene', '5563', (215, 219))	('enhancing', 'PosReg', (159, 168))	('tumor', 'Disease', (36, 41))	('advance', 'PosReg', (54, 61))	('mTOR', 'Gene', (121, 125))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('blocking', 'NegReg', (112, 120))	('glutamine', 'Chemical', 'MESH:D005973', (87, 96))	('SIRT4', 'Gene', (16, 21))	('mTOR', 'Gene', '2475', (121, 125))	('LKB1', 'Gene', (224, 228))	('AMPK', 'Gene', (215, 219))	('AMP', 'Chemical', 'MESH:D000249', (177, 180))	('ADP', 'Chemical', 'MESH:D000244', (173, 176))	('ADP/AMP levels', 'MPA', (173, 187))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('inhibit', 'NegReg', (28, 35))	('glutamine metabolism', 'MPA', (87, 107))	('AMP', 'Chemical', 'MESH:D000249', (215, 218))	('phosphorylation', 'Var', (196, 211))	('HCC', 'Disease', (65, 68))
296374	33033517	Markedly, the rescue experiments consolidated that SIRT4 is an important downstream target responsible for the oncogenic functions of miR-424-5p in ESCC.	('miR-424-5p', 'Var', (134, 144))	('SIRT4', 'Gene', (51, 56))	('ESCC', 'Disease', (148, 152))	('miR-424-5p', 'Chemical', '-', (134, 144))	('SIRT4', 'Gene', '23409', (51, 56))
296377	33033517	Since we have confirmed miR-424-5p has a tumor promoting function in proliferation and migration of ESCC by targeting SIRT4, we speculate that there may be a close association between miR-424-5p and metabolic reprogramming of ESCC.	('miR-424-5p', 'Var', (184, 194))	('migration', 'CPA', (87, 96))	('miR-424-5p', 'Chemical', '-', (24, 34))	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('proliferation', 'CPA', (69, 82))	('SIRT4', 'Gene', '23409', (118, 123))	('tumor', 'Disease', (41, 46))	('metabolic reprogramming', 'CPA', (199, 222))	('ESCC', 'Disease', (100, 104))	('miR-424-5p', 'Chemical', '-', (184, 194))	('miR-424-5p', 'Var', (24, 34))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('SIRT4', 'Gene', (118, 123))	('targeting', 'Reg', (108, 117))
296378	33033517	In summary, our study confirmed miR-424-5p as an oncogene for accelerating proliferation and migration of ESCC in vitro and in vivo, and for the first time we identified SIRT4 as a direct target of miR-424-5p in ESCC.	('SIRT4', 'Gene', '23409', (170, 175))	('SIRT4', 'Gene', (170, 175))	('miR-424-5p', 'Var', (198, 208))	('miR-424-5p', 'Var', (32, 42))	('migration', 'CPA', (93, 102))	('miR-424-5p', 'Chemical', '-', (32, 42))	('accelerating', 'PosReg', (62, 74))	('miR-424-5p', 'Chemical', '-', (198, 208))	('proliferation', 'CPA', (75, 88))
296380	26940869	Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade As tumors grow, they acquire mutations, some of which create neoantigens that influence the response of patients to immune checkpoint inhibitors.	('tumors', 'Phenotype', 'HP:0002664', (99, 105))	('mutations', 'Var', (125, 134))	('elicit', 'Reg', (19, 25))	('tumors', 'Disease', 'MESH:D009369', (99, 105))	('patients', 'Species', '9606', (200, 208))	('influence', 'Reg', (174, 183))	('response', 'MPA', (188, 196))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('create', 'Reg', (150, 156))	('tumors', 'Disease', (99, 105))
296393	26940869	In this setting, to determine clonality from sequencing of a single sample, the cancer cell fraction, which describes the proportion of cancer cells harboring a mutation, was determined for each neoantigen.	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('mutation', 'Var', (161, 169))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('cancer', 'Disease', (136, 142))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('cancer', 'Disease', (80, 86))
296408	26940869	CD8+ T cells reactive to mutant MTFR2D326Y (FAFQEYDSF) were identified in L011, whereas in L012, two distinct CD8+ T cell responses to mutant CHTF18L769V (LLDIVAPK) and MYADMR30W (SPMIVGSPW) were observed (Fig.	('MYADMR30W', 'Var', (169, 178))	('CHTF18', 'Gene', '63922', (142, 148))	('CHTF18', 'Gene', (142, 148))	('CD8', 'Gene', (0, 3))	('CD8', 'Gene', (110, 113))	('CD8', 'Gene', '925', (0, 3))	('MTFR2D326Y', 'Var', (32, 42))	('CD8', 'Gene', '925', (110, 113))	('mutant MTFR2D326Y', 'Var', (25, 42))
296409	26940869	MTFR2D326Y, CHTF18L769V, and MYADMR30W all represent clonal neoantigens, suggesting that immune-reactivity against clonal neoantigens can be detected in both homogeneous and heterogeneous NSCLC.	('NSCLC', 'Disease', 'MESH:D002289', (188, 193))	('MTFR2D326Y', 'Var', (0, 10))	('CHTF18', 'Gene', '63922', (12, 18))	('MYADMR30W', 'Var', (29, 38))	('CHTF18', 'Gene', (12, 18))	('NSCLC', 'Phenotype', 'HP:0030358', (188, 193))	('NSCLC', 'Disease', (188, 193))
296410	26940869	High HLA binding affinity was predicted for MTFR2D326Y and CHTF18L769V in both wild-type and mutant forms, but only the mutant peptide was found to elicit a T cell response.	('MTFR2D326Y', 'Var', (44, 54))	('CHTF18', 'Gene', '63922', (59, 65))	('CHTF18', 'Gene', (59, 65))	('HLA', 'Protein', (5, 8))
296411	26940869	Although the data suggest that T cells in this patient can recognize both mutant and wild-type peptides when stabilized within a MHC-multimer system, the very low predicted affinity of the wild-type peptide to HLA would be expected to prevent adequate presentation in vivo.	('mutant', 'Var', (74, 80))	('patient', 'Species', '9606', (47, 54))	('presentation', 'MPA', (252, 264))	('affinity', 'Interaction', (173, 181))
296412	26940869	MTFR2D326Y-reactive CD8+ T cells, identified in unexpanded L011, were analyzed by means of multicolor flow cytometry.	('CD8', 'Gene', (20, 23))	('CD8', 'Gene', '925', (20, 23))	('MTFR2D326Y-reactive', 'Var', (0, 19))
296418	26940869	Characterization of CHTF18L769V- and MYADMR30W-reactive CD8+ T cells mirrored findings in L011, with high expression of PD-1 observed in 97% and 99.6% of CHFT18L769V- and MYADMR30W-reactive CD8+ T cells, respectively (fig.	('CD8', 'Gene', '925', (190, 193))	('CHFT18L769V-', 'Var', (154, 166))	('CHTF18', 'Gene', '63922', (20, 26))	('MYADMR30W-reactive', 'Var', (37, 55))	('MYADMR30W-reactive', 'Var', (171, 189))	('CD8', 'Gene', (56, 59))	('CHTF18', 'Gene', (20, 26))	('CD8', 'Gene', (190, 193))	('CD8', 'Gene', '925', (56, 59))
296424	26940869	Almost every tumor (12 of 13) that exhibited a low neoantigen subclonal fraction (<5% subclonal) and high mutation burden (>=70, median clonal neoantigens of the cohort) demonstrated durable clinical benefit with anti-PD-1 therapy.	('tumor', 'Disease', (13, 18))	('anti-PD-1', 'Var', (213, 222))	('benefit', 'PosReg', (200, 207))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
296425	26940869	Conversely, only 2 out of 18 tumors with a high subclonal neoantigen fraction (>5%) or low clonal neoantigen burden benefited from pembrolizumab (Y2087 and SB10944).	('SB10944', 'Var', (156, 163))	('tumors', 'Disease', (29, 35))	('pembrolizumab', 'Chemical', 'MESH:C582435', (131, 144))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('tumors', 'Disease', 'MESH:D009369', (29, 35))	('Y2087', 'Var', (146, 151))
296426	26940869	For example, despite a large neoantigen burden, ZA6505 exhibited progressive disease, relapsing after 2 months.	('ZA6505', 'Chemical', '-', (48, 54))	('ZA6505', 'Var', (48, 54))	('neoantigen burden', 'MPA', (29, 46))
296427	26940869	ZA6505 was one of the most heterogeneous tumors within the cohort, with over 80% of mutations classified as subclonal.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('tumors', 'Disease', 'MESH:D009369', (41, 47))	('tumors', 'Disease', (41, 47))	('mutations', 'Var', (84, 93))	('ZA6505', 'Chemical', '-', (0, 6))
296436	26940869	Two of the most heterogeneous tumors (Pat58 and Pat151) with minimal or no benefit were among those treated with the alkylating agent dacarbazine (DTIC) before anti-CTLA therapy, and for both, >98% of subclonal mutations were attributable to mutational Signature 11, a signature associated with prior exposure to alkylating agents.	('tumors', 'Disease', (30, 36))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('dacarbazine', 'Chemical', 'MESH:D003606', (134, 145))	('mutational', 'Var', (242, 252))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('DTIC', 'Chemical', 'MESH:D003606', (147, 151))
296438	26940869	These data suggest that therapy may induce subclonal mutations that fail to drive an efficient antitumor response, although further data are needed to confirm this observation.	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumor', 'Disease', (99, 104))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('subclonal mutations', 'Var', (43, 62))
296442	26940869	Similarly, analysis of peripheral blood mononuclear cells (PBMCs) from the patients with CR9309 and CR0095:melanomas that responded to anti-CTLA-4 therapy, resulting in prolonged patient survival:identified CD8+ T cell populations, recognizing tumor-specific neoantigens.	('melanomas', 'Disease', 'MESH:D008545', (107, 116))	('CD8', 'Gene', '925', (207, 210))	('tumor', 'Phenotype', 'HP:0002664', (244, 249))	('patient survival', 'CPA', (179, 195))	('melanoma', 'Phenotype', 'HP:0002861', (107, 115))	('melanomas', 'Phenotype', 'HP:0002861', (107, 116))	('tumor', 'Disease', (244, 249))	('CR9309', 'Var', (89, 95))	('patient', 'Species', '9606', (179, 186))	('patients', 'Species', '9606', (75, 83))	('CTLA-4', 'Gene', '1493', (140, 146))	('tumor', 'Disease', 'MESH:D009369', (244, 249))	('melanomas', 'Disease', (107, 116))	('prolonged', 'PosReg', (169, 178))	('CTLA-4', 'Gene', (140, 146))	('patient', 'Species', '9606', (75, 82))	('CD8', 'Gene', (207, 210))
296448	26940869	The observation that certain anti-CTLA-4 refractory tumors were enriched for subclonal mutations caused by alkylating agents suggests that mutations induced by therapy may enhance total neoantigen burden but might not elicit an effective antitumor response, possibly because of the subclonal nature of the neoantigens that results from cytotoxic exposure.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('enhance', 'PosReg', (172, 179))	('tumor', 'Disease', (52, 57))	('mutations', 'Var', (139, 148))	('neoantigen burden', 'MPA', (186, 203))	('tumor', 'Disease', 'MESH:D009369', (242, 247))	('tumors', 'Disease', (52, 58))	('CTLA-4', 'Gene', '1493', (34, 40))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('tumor', 'Phenotype', 'HP:0002664', (242, 247))	('tumor', 'Disease', (242, 247))	('CTLA-4', 'Gene', (34, 40))	('tumor', 'Disease', 'MESH:D009369', (52, 57))
296449	26940869	These results highlight the need to consider both the antitumor effects of alkylating agents as well as the potential risk of inducing subclonal mutations.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('inducing', 'Reg', (126, 134))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('subclonal', 'Var', (135, 144))
296450	26940869	The identification of cytotoxic tumor-infiltrating T cells that recognize clonal mutations, shared by all tumor cells, might hold promise for adoptive therapy strategies to address the challenges of ITH.	('cytotoxic tumor', 'Disease', (22, 37))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('mutations', 'Var', (81, 90))	('cytotoxic tumor', 'Disease', 'MESH:D064420', (22, 37))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Disease', (32, 37))	('tumor', 'Disease', (106, 111))
296454	31907209	pVACtools supports identification of altered peptides from different mechanisms including point mutations, in-frame or frameshift insertions and deletions, and gene fusions.	('peptides', 'MPA', (45, 53))	('peptides', 'Chemical', 'MESH:D010455', (45, 53))	('frameshift insertions', 'Var', (119, 140))	('point mutations', 'Var', (90, 105))	('pVACtools', 'Chemical', '-', (0, 9))	('gene fusions', 'Var', (160, 172))	('deletions', 'Var', (145, 154))	('in-frame', 'Var', (107, 115))
296507	31907209	Variant coverageis assessed using bam-readcount (https://github.com/genome/bam-readcount) for both the tumor and normal DNA exome data, and this information is also annotated into the VCF output using VAtools (http://vatools.org).	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('cov', 'Species', '11118', (8, 11))	('tumor', 'Disease', (103, 108))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('Variant', 'Var', (0, 7))
296509	31907209	Additionally, coverage support for variants in RNAseq data is determined with bam-readcount.	('cov', 'Species', '11118', (14, 17))	('RNAseq', 'Gene', (47, 53))	('variants', 'Var', (35, 43))
296516	31907209	Since proximal variants can change the peptide sequence and affect neoantigen binding predictions, this is important for ensuring that the selected neoantigens correctly represent the individual's genome.	('change', 'Reg', (28, 34))	('neoantigen', 'Protein', (67, 77))	('peptide', 'Chemical', 'MESH:D010455', (39, 46))	('peptide sequence', 'MPA', (39, 55))	('affect', 'Reg', (60, 66))	('variants', 'Var', (15, 23))
296539	31907209	This is accomplished by using the core pVACseq module to predict the binding scores for each junctional peptide and by modifying junctions with spacer amino acid sequences, or by trimming the ends of the peptides in order to reduce reactivity.	('reduce', 'NegReg', (225, 231))	('peptide', 'Chemical', 'MESH:D010455', (204, 211))	('trimming', 'Var', (179, 187))	('reactivity', 'MPA', (232, 242))	('binding', 'Interaction', (69, 76))	('peptides', 'Chemical', 'MESH:D010455', (204, 212))	('modifying', 'Reg', (119, 128))	('peptide', 'Chemical', 'MESH:D010455', (104, 111))
296544	31907209	We used this annotated list of variants as input to the pVACseq component of pVACtools to predict neoantigenic peptides.	('pVACtools', 'Chemical', '-', (77, 86))	('variants', 'Var', (31, 39))	('peptides', 'Chemical', 'MESH:D010455', (111, 119))	('neoantigenic peptides', 'MPA', (98, 119))
296545	31907209	After applying our default median binding affinity cutoff of 500 nM across all eight MHC Class I prediction algorithms, there were 96,235 predicted strong binding neoantigens, derived from 34,552 somatic variants (32,788 missense SNVs, 1,603 frameshift variants, and 131 in-frame indels).	('missense SNVs', 'Var', (221, 234))	('MHC', 'Gene', '3107', (85, 88))	('MHC', 'Gene', (85, 88))	('frameshift variants', 'Var', (242, 261))
296547	31907209	This set was subsequently filtered by evaluation of exome sequencing data coverage and our recommended defaults as follows: by applying the default criteria of variant allele fraction (VAF) cutoff of > 25% in tumors and < 2% in normal samples, with at least 10X tumor coverage and at least 5X normal coverage, 10,730 neoantigens from 4,891 associated variants (4,826 SNVs, 56 frameshift, and 9 in-frame indels) were obtained, with an average of 36 neoantigens predicted per case.	('tumors', 'Disease', (209, 215))	('tumor', 'Phenotype', 'HP:0002664', (262, 267))	('tumor', 'Disease', (209, 214))	('tumors', 'Phenotype', 'HP:0002664', (209, 215))	('frameshift', 'Var', (376, 386))	('cov', 'Species', '11118', (268, 271))	('tumor', 'Disease', (262, 267))	('cov', 'Species', '11118', (300, 303))	('tumors', 'Disease', 'MESH:D009369', (209, 215))	('cov', 'Species', '11118', (74, 77))	('tumor', 'Disease', 'MESH:D009369', (209, 214))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))	('tumor', 'Disease', 'MESH:D009369', (262, 267))
296549	31907209	To condense the results even further, only the top ranked neoantigen was selected per variant ('top-score filter') across all alleles, lengths, and registers (position of amino acid mutation within peptide sequence), resulting in 4,891 total neoantigens with an average of 16 neoantigens per case.	('variant', 'Var', (86, 93))	('neoantigens', 'MPA', (242, 253))	('peptide', 'Chemical', 'MESH:D010455', (198, 205))	('neoantigens', 'MPA', (276, 287))
296561	31907209	a binding affinity mutant/wildtype ratio or differential agretopicity value indicating that the mutant version of the peptide is a stronger binder).	('peptide', 'Chemical', 'MESH:D010455', (118, 125))	('mutant/wildtype', 'Var', (19, 34))	('mutant', 'Var', (96, 102))	('binder', 'Interaction', (140, 146))	('binding', 'Interaction', (2, 9))	('stronger', 'PosReg', (131, 139))
296576	31907209	Analysis of a melanoma patient (pt3713) showed that pVACtools was able to recapitulate eight (80%) of the positively validated peptides in the filtered list of neoantigens using our suggested filtering methodology (median binding predicted IC50 < 500 nM, > 5x DNA & RNA coverage, > 10% DNA & RNA VAF, > 1 TPM gene expression).	('melanoma', 'Disease', (14, 22))	('IC50', 'Var', (240, 244))	('peptides', 'Chemical', 'MESH:D010455', (127, 135))	('cov', 'Species', '11118', (270, 273))	('pVACtools', 'Chemical', '-', (52, 61))	('melanoma', 'Disease', 'MESH:D008545', (14, 22))	('melanoma', 'Phenotype', 'HP:0002861', (14, 22))	('patient', 'Species', '9606', (23, 30))
296585	31907209	By supporting additional classes of variants as well as gene fusions, we predict an increased number of predicted neoantigens which may be critical for low mutational burden tumors.	('tumors', 'Disease', 'MESH:D009369', (174, 180))	('tumors', 'Disease', (174, 180))	('variants', 'Var', (36, 44))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('tumors', 'Phenotype', 'HP:0002664', (174, 180))
296586	31907209	To support a wider range of variant events not easily representable in VCF format such as alternatively spliced transcripts that may create tumor antigens, upcoming versions of pVACtools will add a new tool, pVACbind, which can be used to execute our prediction pipeline from sequences contained in a FASTA input file.	('pVACtools', 'Chemical', '-', (177, 186))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('variant', 'Var', (28, 35))	('tumor', 'Disease', (140, 145))
296723	28441176	One of the most commonly used recreational drugs is nitrite inhalants (amyl nitrite, butyl nitrite, isobutyl nitrite; commonly referred to as 'poppers').	('butyl nitrite', 'Chemical', 'MESH:C024225', (85, 98))	('butyl nitrite', 'MPA', (85, 98))	('nitrite', 'Chemical', 'MESH:D009573', (52, 59))	('isobutyl nitrite', 'Chemical', 'MESH:C018086', (100, 116))	('nitrite', 'Chemical', 'MESH:D009573', (76, 83))	('butyl nitrite', 'Chemical', 'MESH:C024225', (103, 116))	('amyl nitrite', 'Chemical', 'MESH:D000680', (71, 83))	('isobutyl', 'Var', (100, 108))	('nitrite', 'Chemical', 'MESH:D009573', (91, 98))	('nitrite', 'Chemical', 'MESH:D009573', (109, 116))
296756	28441176	Analyses restricted to HIV-infected study participants were adjusted for age, race, heavy popper use, calendar period, and time-varying CD4+ cell count (<200 vs. >=200 cells/mul) and plasma viral load (>400 vs. <= 400 HIV RNA copies/ml).	('HIV-infected', 'Disease', 'MESH:D015658', (23, 35))	('CD4', 'Gene', '920', (136, 139))	('participants', 'Species', '9606', (42, 54))	('>400', 'Var', (202, 206))	('HIV-infected', 'Disease', (23, 35))	('CD4', 'Gene', (136, 139))
296780	28441176	By contrast, low CD4+ cell count (<200 cells/mul) was associated with increased risk of Kaposi sarcoma (IRR, 2.83; 95% CI, 1.33-5.99), NHL (IRR, 5.31; 95% CI, 2.46-11.46), and anal cancer (IRR, 3.75; 95% CI, 1.36-10.36), whereas viral load (>400 copies/ml) was associated with increased risk of Kaposi sarcoma (IRR, 8.3; 95% CI, 3.54-9.46), NHL (IRR, 11.92; 95% CI, 4.46-31.88), and squamous cell carcinoma of the skin (IRR, 4.63; 95% CI, 1.9-11.27).	('sarcoma', 'Phenotype', 'HP:0100242', (302, 309))	('squamous cell carcinoma of the skin', 'Phenotype', 'HP:0006739', (383, 418))	('Kaposi sarcoma', 'Disease', 'MESH:D012514', (88, 102))	('anal cancer', 'Phenotype', 'HP:0032186', (176, 187))	('Kaposi sarcoma', 'Disease', 'MESH:D012514', (295, 309))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('sarcoma', 'Phenotype', 'HP:0100242', (95, 102))	('Kaposi sarcoma', 'Disease', (88, 102))	('Kaposi sarcoma', 'Disease', (295, 309))	('carcinoma', 'Phenotype', 'HP:0030731', (397, 406))	('squamous cell carcinoma of the skin', 'Disease', (383, 418))	('Kaposi sarcoma', 'Phenotype', 'HP:0100726', (88, 102))	('Kaposi sarcoma', 'Phenotype', 'HP:0100726', (295, 309))	('CD4', 'Gene', '920', (17, 20))	('squamous cell carcinoma of the skin', 'Disease', 'MESH:D002294', (383, 418))	('NHL', 'Disease', 'MESH:D008228', (341, 344))	('NHL', 'Disease', (341, 344))	('cancer', 'Disease', (181, 187))	('NHL', 'Disease', (135, 138))	('CD4', 'Gene', (17, 20))	('<200 cells/mul', 'Var', (34, 48))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (383, 406))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('NHL', 'Disease', 'MESH:D008228', (135, 138))
296806	28441176	Furthermore, HHV-8 and high-risk HPV seroprevalence is likely to be higher among HIV-infected compared with HIV-uninfected study participants, irrespective of popper use.	('participants', 'Species', '9606', (129, 141))	('HPV', 'Disease', (33, 36))	('HIV-infected', 'Disease', 'MESH:D015658', (81, 93))	('higher', 'PosReg', (68, 74))	('HHV-8', 'Gene', (13, 18))	('seroprevalence', 'Var', (37, 51))	('HIV-uninfected', 'Disease', (108, 122))	('HIV-uninfected', 'Disease', 'MESH:D015658', (108, 122))	('HPV', 'Disease', 'MESH:D030361', (33, 36))	('HHV-8', 'Species', '37296', (13, 18))	('HIV-infected', 'Disease', (81, 93))
296809	28441176	While low time-updated CD4+ cell count was associated with risk of anal cancer in HIV-infected individuals, consistent with, time-updated viral load (> 400 copies/ml) was associated with risk of squamous cell carcinoma of the skin.	('HIV-infected', 'Disease', (82, 94))	('HIV-infected', 'Disease', 'MESH:D015658', (82, 94))	('anal cancer', 'Phenotype', 'HP:0032186', (67, 78))	('> 400 copies/ml', 'Var', (150, 165))	('squamous cell carcinoma of the skin', 'Disease', (195, 230))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (195, 218))	('squamous cell carcinoma of the skin', 'Disease', 'MESH:D002294', (195, 230))	('CD4', 'Gene', '920', (23, 26))	('carcinoma', 'Phenotype', 'HP:0030731', (209, 218))	('squamous cell carcinoma of the skin', 'Phenotype', 'HP:0006739', (195, 230))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('CD4', 'Gene', (23, 26))	('associated', 'Reg', (171, 181))	('cancer', 'Disease', (72, 78))
296831	28441176	The MACS is funded by the National Institute of Allergy and Infectious Diseases (NIAID; U01-AI35039, U01-AI35040, U01-AI35041, U01-AI35042, and UM1-AI35043), with additional cofunding from the National Cancer Institute (NCI), National Institute on Drug Abuse (NIDA), and National Institute of Mental Health (NIMH) at the National Institutes of Health (NIH).	('U01', 'CellLine', 'CVCL:2220', (101, 104))	('U01', 'CellLine', 'CVCL:2220', (88, 91))	('U01', 'CellLine', 'CVCL:2220', (127, 130))	('U01-AI35039', 'Var', (88, 99))	('U01-AI35040', 'Var', (101, 112))	('UM1-AI35043', 'Var', (144, 155))	('Cancer', 'Disease', (202, 208))	('Cancer', 'Phenotype', 'HP:0002664', (202, 208))	('Cancer', 'Disease', 'MESH:D009369', (202, 208))	('U01-AI35041', 'Var', (114, 125))	('U01', 'CellLine', 'CVCL:2220', (114, 117))	('Allergy', 'Phenotype', 'HP:0012393', (48, 55))	('U01-AI35042', 'Var', (127, 138))
296837	33576304	More intriguingly, CD155 expression had a significant interaction with immune function in several tumors by analyzing Tumor mutational burden and microsatellite in stability, immune score and stromal score.	('tumors', 'Disease', (98, 104))	('CD155', 'Gene', '5817', (19, 24))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('microsatellite', 'Var', (146, 160))	('tumors', 'Disease', 'MESH:D009369', (98, 104))	('CD155', 'Gene', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('Tumor', 'Phenotype', 'HP:0002664', (118, 123))	('interaction', 'Reg', (54, 65))
296899	33576304	There is also evidence that CD155/CD226 interaction can attenuate the generation of CD8+ T cells by regulating NK T-cell differentiation.	('CD8', 'Gene', '925', (84, 87))	('attenuate', 'NegReg', (56, 65))	('CD226', 'Gene', '10666', (34, 39))	('CD155', 'Gene', '5817', (28, 33))	('interaction', 'Var', (40, 51))	('regulating', 'Reg', (100, 110))	('NK T-cell differentiation', 'CPA', (111, 136))	('CD155', 'Gene', (28, 33))	('CD8', 'Gene', (84, 87))	('CD226', 'Gene', (34, 39))
296910	33576304	ACC Adrenocortical carcinoma BLCA Bladder Urothelial Carcinoma BRCA Breast invasive carcinoma CESC Cervical squamous cell carcinoma and endocervical adenocarcinoma CHOL Cholangio carcinoma COAD Colon adenocarcinoma DLBC Lymphoid Neoplasm Diffuse Large B-cell Lymphoma ESCA Esophageal carcinoma GBM Glioblastoma multiforme HNSC Head and Neck squamous cell carcinoma KICH Kidney Chromophobe KIRC Kidney renal clear cell carcinoma KIRP Kidney renal papillary cell carcinoma LAML Acute Myeloid Leukemia LGG Brain Lower Grade Glioma LIHC Liver hepatocellular carcinoma LUAD Lung adenocarcinoma TME tumor microenvironment OS overall survival DSS Disease-specific survival LUSC Lung squamous cell carcinoma MESO Mesothelioma OV Ovarian serous cystadenocarcinoma PAAD Pancreatic adenocarcinoma PCPG Pheochromocytoma and Paraganglioma PRAD Prostate adenocarcinoma READ Rectum adenocarcinoma SARC Sarcoma SKCM Skin Cutaneous Melanoma STAD Stomach adenocarcinoma TGCT Testicular Germ Cell Tumors THCA Thyroid carcinoma THYM Thymoma UCEC Uterine Corpus Endometrial Carcinoma UCS Uterine Carcinosarcoma UVM Uveal Melanoma TMB Tumor mutational burden MSI microsatellite in stability DFI Disease-free interval PFI Progression-free interval	('Tumor', 'Phenotype', 'HP:0002664', (978, 983))	('carcinoma', 'Disease', 'MESH:D009369', (179, 188))	('carcinoma', 'Disease', (845, 854))	('Kidney renal clear cell carcinoma', 'Disease', 'MESH:C538614', (394, 427))	('Kidney renal papillary cell carcinoma', 'Disease', (433, 470))	('KICH', 'Disease', (365, 369))	('Thyroid carcinoma', 'Phenotype', 'HP:0002890', (990, 1007))	('tumor', 'Phenotype', 'HP:0002664', (593, 598))	('Adrenocortical carcinoma', 'Disease', (4, 28))	('Sarcoma', 'Disease', (887, 894))	('Kidney Chromophobe', 'Disease', (370, 388))	('serous cystadenocarcinoma', 'Disease', (729, 754))	('Corpus Endometrial Carcinoma', 'Disease', 'MESH:D016889', (1034, 1062))	('Breast invasive carcinoma', 'Disease', 'MESH:D001943', (68, 93))	('Paraganglioma', 'Phenotype', 'HP:0002668', (812, 825))	('carcinoma', 'Disease', (998, 1007))	('carcinoma', 'Disease', (776, 785))	('carcinoma', 'Disease', (579, 588))	('CHOL', 'Disease', 'None', (164, 168))	('Breast invasive carcinoma', 'Phenotype', 'HP:0003002', (68, 93))	('Urothelial Carcinoma', 'Disease', (42, 62))	('Neck squamous cell carcinoma', 'Disease', (336, 364))	('carcinoma', 'Disease', (554, 563))	('Acute Myeloid Leukemia', 'Disease', (476, 498))	('Melanoma', 'Disease', 'MESH:D008545', (915, 923))	('carcinoma', 'Disease', 'MESH:D009369', (461, 470))	('Pheochromocytoma and Paraganglioma', 'Disease', 'MESH:D010673', (791, 825))	('Melanoma', 'Disease', (1100, 1108))	('carcinoma', 'Disease', 'MESH:D009369', (284, 293))	('Pancreatic adenocarcinoma', 'Disease', 'MESH:D000230', (760, 785))	('carcinoma', 'Disease', (179, 188))	('Thyroid carcinoma', 'Disease', 'MESH:D013964', (990, 1007))	('Cholangio carcinoma', 'Phenotype', 'HP:0030153', (169, 188))	('Pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (760, 785))	('Pancreatic adenocarcinoma', 'Disease', (760, 785))	('Rectum adenocarcinoma', 'Disease', 'MESH:D012004', (860, 881))	('Colon adenocarcinoma', 'Disease', 'MESH:D003110', (194, 214))	('Prostate adenocarcinoma', 'Disease', 'MESH:D011471', (831, 854))	('CHOL', 'Disease', (164, 168))	('carcinoma', 'Disease', 'MESH:D009369', (872, 881))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('carcinoma', 'Disease', 'MESH:D009369', (418, 427))	('Melanoma', 'Phenotype', 'HP:0002861', (915, 923))	('Head and Neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (327, 364))	('squamous cell carcinoma', 'Disease', (108, 131))	('Cholangio carcinoma', 'Disease', (169, 188))	('Lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (671, 699))	('Carcinoma', 'Phenotype', 'HP:0030731', (53, 62))	('Breast invasive carcinoma', 'Disease', (68, 93))	('Kidney Chromophobe', 'Disease', 'MESH:D000238', (370, 388))	('carcinoma', 'Disease', (461, 470))	('endocervical adenocarcinoma', 'Disease', 'MESH:D000230', (136, 163))	('Lung adenocarcinoma', 'Phenotype', 'HP:0030078', (569, 588))	('Myeloid Leukemia', 'Phenotype', 'HP:0012324', (482, 498))	('carcinoma', 'Disease', (872, 881))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (108, 131))	('Mesothelioma', 'Disease', (705, 717))	('Kidney renal clear cell carcinoma', 'Disease', (394, 427))	('Thymoma', 'Disease', (1013, 1020))	('Corpus Endometrial Carcinoma', 'Disease', (1034, 1062))	('ACC', 'Gene', '31', (0, 3))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (539, 563))	('Liver hepatocellular carcinoma', 'Disease', (533, 563))	('Liver hepatocellular carcinoma', 'Disease', 'MESH:D006528', (533, 563))	('carcinoma', 'Phenotype', 'HP:0030731', (179, 188))	('Rectum adenocarcinoma', 'Disease', (860, 881))	('tumor', 'Disease', (593, 598))	('Neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (336, 364))	('carcinoma', 'Disease', (418, 427))	('KICH', 'Disease', 'None', (365, 369))	('TME', 'Chemical', '-', (589, 592))	('Stomach adenocarcinoma', 'Disease', (929, 951))	('DSS', 'Gene', '5376', (636, 639))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (108, 131))	('tumor', 'Disease', 'MESH:D009369', (593, 598))	('clear cell carcinoma KIRP Kidney', 'Phenotype', 'HP:0006770', (407, 439))	('Adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (4, 28))	('Prostate adenocarcinoma', 'Disease', (831, 854))	('Lymphoma', 'Phenotype', 'HP:0002665', (259, 267))	('Skin Cutaneous Melanoma', 'Disease', (900, 923))	('carcinoma', 'Disease', 'MESH:D009369', (942, 951))	('carcinoma', 'Disease', 'MESH:D009369', (355, 364))	('carcinoma', 'Disease', 'MESH:D009369', (690, 699))	('Thymoma', 'Disease', 'MESH:D013945', (1013, 1020))	('serous cystadenocarcinoma', 'Disease', 'MESH:D018284', (729, 754))	('Leukemia', 'Phenotype', 'HP:0001909', (490, 498))	('carcinoma', 'Disease', 'MESH:D009369', (745, 754))	('carcinoma', 'Disease', 'MESH:D009369', (84, 93))	('TMB', 'Chemical', '-', (1109, 1112))	('Pheochromocytoma', 'Phenotype', 'HP:0002666', (791, 807))	('Stomach adenocarcinoma', 'Disease', 'MESH:D000230', (929, 951))	('carcinoma', 'Disease', (19, 28))	('Carcinoma', 'Phenotype', 'HP:0030731', (1053, 1062))	('COAD', 'Disease', 'MESH:D029424', (189, 193))	('carcinoma', 'Disease', 'MESH:D009369', (19, 28))	('Glioma', 'Disease', (521, 527))	('MESO Mesothelioma', 'Phenotype', 'HP:0100001', (700, 717))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (341, 364))	('B-cell Lymphoma', 'Phenotype', 'HP:0012191', (252, 267))	('Tumors', 'Disease', 'MESH:D009369', (978, 984))	('carcinoma', 'Disease', 'MESH:D009369', (154, 163))	('Cholangio carcinoma', 'Disease', 'MESH:D009369', (169, 188))	('Glioblastoma', 'Phenotype', 'HP:0012174', (298, 310))	('Melanoma', 'Disease', 'MESH:D008545', (1100, 1108))	('Lung squamous cell carcinoma', 'Disease', (671, 699))	('carcinoma', 'Disease', (284, 293))	('Ovarian serous cystadenocarcinoma', 'Phenotype', 'HP:0012887', (721, 754))	('Acute Myeloid Leukemia', 'Disease', 'MESH:D015470', (476, 498))	('DSS', 'Gene', (636, 639))	('Skin Cutaneous Melanoma', 'Disease', 'MESH:C562393', (900, 923))	('carcinoma', 'Disease', (942, 951))	('Carcinosarcoma', 'Disease', 'MESH:D002296', (1075, 1089))	('carcinoma', 'Disease', (745, 754))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (341, 364))	('Colon adenocarcinoma', 'Disease', (194, 214))	('Uterine Carcinosarcoma', 'Phenotype', 'HP:0002891', (1067, 1089))	('Neoplasm', 'Phenotype', 'HP:0002664', (229, 237))	('Glioblastoma multiforme', 'Disease', 'MESH:D005909', (298, 321))	('carcinoma', 'Disease', 'MESH:D009369', (998, 1007))	('ACC', 'Gene', (0, 3))	('Tumors', 'Phenotype', 'HP:0002664', (978, 984))	('Thyroid carcinoma', 'Disease', (990, 1007))	('Melanoma', 'Phenotype', 'HP:0002861', (1100, 1108))	('Germ Cell Tumors', 'Phenotype', 'HP:0100728', (968, 984))	('carcinoma', 'Disease', 'MESH:D009369', (554, 563))	('THCA', 'Chemical', '-', (985, 989))	('Melanoma', 'Disease', (915, 923))	('endocervical adenocarcinoma', 'Disease', (136, 163))	('Lymphoid Neoplasm Diffuse Large B-cell Lymphoma', 'Disease', 'MESH:D016403', (220, 267))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (676, 699))	('carcinoma', 'Disease', (154, 163))	('Glioma', 'Phenotype', 'HP:0009733', (521, 527))	('carcinoma', 'Disease', 'MESH:D009369', (205, 214))	('Cutaneous Melanoma', 'Phenotype', 'HP:0012056', (905, 923))	('BRCA', 'Gene', (63, 67))	('Tumors', 'Disease', (978, 984))	('Endometrial Carcinoma', 'Phenotype', 'HP:0012114', (1041, 1062))	('Esophageal carcinoma', 'Phenotype', 'HP:0011459', (273, 293))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (676, 699))	('Thymoma', 'Phenotype', 'HP:0100522', (1013, 1020))	('carcinoma', 'Disease', 'MESH:D009369', (122, 131))	('Sarcoma', 'Phenotype', 'HP:0100242', (887, 894))	('Glioblastoma multiforme', 'Disease', (298, 321))	('Lung adenocarcinoma', 'Disease', 'MESH:D000077192', (569, 588))	('mutational', 'Var', (1119, 1129))	('Kidney renal papillary cell carcinoma', 'Disease', 'MESH:C538614', (433, 470))	('carcinoma', 'Disease', 'MESH:D009369', (845, 854))	('Urothelial Carcinoma', 'Disease', 'MESH:D014523', (42, 62))	('Uveal Melanoma', 'Phenotype', 'HP:0007716', (1094, 1108))	('Mesothelioma', 'Disease', 'MESH:D008654', (705, 717))	('COAD', 'Disease', (189, 193))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('Adrenocortical carcinoma', 'Disease', 'MESH:D018268', (4, 28))	('carcinoma', 'Disease', (355, 364))	('Acute Myeloid Leukemia', 'Phenotype', 'HP:0004808', (476, 498))	('carcinoma', 'Disease', (690, 699))	('carcinoma', 'Disease', (205, 214))	('carcinoma', 'Disease', (84, 93))	('Glioma', 'Disease', 'MESH:D005910', (521, 527))	('UCEC Uterine Corpus', 'Phenotype', 'HP:0000139', (1021, 1040))	('BRCA', 'Gene', '672', (63, 67))	('Lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (671, 699))	('Tumor', 'Phenotype', 'HP:0002664', (1113, 1118))	('Lymphoid Neoplasm Diffuse Large B-cell Lymphoma', 'Disease', (220, 267))	('carcinoma', 'Disease', 'MESH:D009369', (776, 785))	('carcinoma', 'Phenotype', 'HP:0030731', (19, 28))	('renal papillary cell carcinoma', 'Phenotype', 'HP:0006766', (440, 470))	('carcinoma', 'Disease', 'MESH:D009369', (579, 588))	('Lung adenocarcinoma', 'Disease', (569, 588))	('Carcinosarcoma', 'Disease', (1075, 1089))	('carcinoma', 'Phenotype', 'HP:0030731', (154, 163))	('carcinoma', 'Disease', (122, 131))	('Sarcoma', 'Disease', 'MESH:D012509', (887, 894))
297013	28967881	Emerging evidence indicates that somatic mutations in cancer genomes are non-randomly distributed, influenced by factors such as genomic context and DNA secondary structures, chromatin organization, transcriptional activity, and replication timing.	('mutations', 'Var', (41, 50))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('cancer', 'Disease', (54, 60))	('influenced', 'Reg', (99, 109))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
297017	28967881	For instance, the nuclear lamina-associated regions are refractory to homologous recombination-mediated repair and utilize an error-prone alternative end-joining mechanism to repair DNA double strand breaks.	('lamin', 'Gene', (26, 31))	('DNA', 'Var', (182, 185))	('lamin', 'Gene', '4000', (26, 31))
297026	28967881	Indeed, the AMR for chr18 was significantly higher compared to that for chr19 across all 6 cancer types analyzed (Figure 1B; Mann Whitney U test p-value < 1e-02 for all cohorts).	('higher', 'PosReg', (44, 50))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('AMR', 'MPA', (12, 15))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('chr18', 'Var', (20, 25))
297034	28967881	In the SKCA cohort UV-induced C>T substitutions, including those in the pi-pyrimidine context, were proportionally more common in the cLADs compared to the iLADs (Mann Whitney U test p-value < 1e-08) (Figure 2D; Supplementary Fig.	('pyrimidine', 'Chemical', 'MESH:C030986', (75, 85))	('common', 'Reg', (120, 126))	('C>T substitutions', 'Var', (30, 47))
297038	28967881	For instance, when we summarized the tri-nucleotide substitution patterns into mutational signatures using non-negative matrix factorization, mutation signatures 3 and 5 had a proportionally larger contribution in the iLAD and cLADs, respectively, in most cancer types as compared to the other signatures.	('cancer', 'Disease', 'MESH:D009369', (256, 262))	('cancer', 'Disease', (256, 262))	('larger', 'PosReg', (191, 197))	('mutation signatures', 'Var', (142, 161))	('iLAD', 'Disease', (218, 222))	('tri-nucleotide', 'Chemical', '-', (37, 51))	('cancer', 'Phenotype', 'HP:0002664', (256, 262))
297039	28967881	Translating the mutational signatures into substitution patterns, it became clear that a majority of the cancer types had a proportional increase in the contribution of mutations in the WNW context (W: A or T; N: A, G, C, or T) in the cLADs at the periphery compared to the iLADs in the core.	('mutations', 'Var', (169, 178))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('increase', 'PosReg', (137, 145))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))
297040	28967881	Different cancer types, however, showed subtle variation in the preference for specific sub-motifs; for instance, in the DLBCL and CLL cohorts, W[T>G]W and also W[T>C]W mutations were relatively more common in the cLADs than in the iLADs (Mann Whitney U test p-value < 1e-10).	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('cancer', 'Disease', 'MESH:D009369', (10, 16))	('W[T>C]', 'Var', (161, 167))	('W[T>G]', 'Var', (144, 150))	('cancer', 'Disease', (10, 16))
297047	28967881	The preference for C[C>T]N (where N: A, T, G, or C) in iLADs over cLADs was detectable in other cancer types including LUSC (signature SLUSC1).	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('C[C>T]N', 'Var', (19, 26))	('LUSC', 'Disease', (119, 123))	('cancer', 'Disease', (96, 102))
297049	28967881	In the DLBCL and CLL cohorts, we observed an increase in C>T transitions in iLADs and an increase in T>G transversions in the WTN tri-nucleotide context in cLADs (Mann Whitney U test p-value < 1e-05) (Supplementary Note).	('T>G transversions', 'Var', (101, 118))	('tri-nucleotide', 'Chemical', '-', (130, 144))	('C>T transitions', 'Var', (57, 72))
297070	28967881	Since the mutational landscape of cancer genomes is shaped by both the incidence of mutations as well as natural selection during clonal evolution acting on the variability thus generated, and since variant calling is technically challenging in some genomic regions (e.g.	('mutations', 'Var', (84, 93))	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('cancer', 'Disease', (34, 40))	('cancer', 'Disease', 'MESH:D009369', (34, 40))
297094	28900112	Notably, copy number alterations are prevalent in dysplasia and persist during the ESCC progression, which is distinct from the development of esophageal adenocarcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (159, 168))	('dysplasia', 'Disease', (50, 59))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (143, 168))	('prevalent', 'Reg', (37, 46))	('esophageal adenocarcinoma', 'Disease', (143, 168))	('dysplasia', 'Disease', 'MESH:D004476', (50, 59))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (143, 168))	('ESCC', 'Disease', (83, 87))	('copy number alterations', 'Var', (9, 32))
297100	28900112	The genomic landscape of ESCC has been characterized, revealing that the most common alteration is the mutation of TP53 through single-nucleotide variations and/or copy number losses.	('TP53', 'Gene', '7157', (115, 119))	('TP53', 'Gene', (115, 119))	('single-nucleotide variations', 'Var', (128, 156))	('copy number losses', 'Var', (164, 182))	('mutation', 'Var', (103, 111))
297104	28900112	Previous studies indicated that TP53 is altered in some of the patients with dysplasia, and some copy number alteration (CNA) events, such as amplifications in 3q and 5p and losses in 3p, are also identified in a small dysplasia cohort.	('dysplasia', 'Disease', 'MESH:D004476', (219, 228))	('copy number', 'MPA', (97, 108))	('TP53', 'Gene', '7157', (32, 36))	('dysplasia', 'Disease', (77, 86))	('dysplasia', 'Disease', 'MESH:D004476', (77, 86))	('losses', 'NegReg', (174, 180))	('patients', 'Species', '9606', (63, 71))	('TP53', 'Gene', (32, 36))	('altered', 'Reg', (40, 47))	('amplifications', 'Var', (142, 156))	('small dysplasia cohort', 'Disease', 'MESH:D018288', (213, 235))	('small dysplasia cohort', 'Disease', (213, 235))	('dysplasia', 'Disease', (219, 228))
297108	28900112	noted that there might be two paths for BE to transform to EAC: one way is through a gradual loss of tumor suppressor genes followed by genomic instability and amplification of oncogenes; the other way starts with the inactivation of TP53, followed by whole-genome doubling, which facilitates genomic instability and oncogene activation.	('TP53', 'Gene', '7157', (234, 238))	('facilitates', 'PosReg', (281, 292))	('TP53', 'Gene', (234, 238))	('oncogene', 'CPA', (317, 325))	('activation', 'PosReg', (326, 336))	('loss', 'NegReg', (93, 97))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('genomic instability', 'CPA', (293, 312))	('BE', 'Phenotype', 'HP:0100580', (40, 42))	('EAC', 'Phenotype', 'HP:0011459', (59, 62))	('inactivation', 'Var', (218, 230))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
297113	28900112	Moreover, the 'two-hit' events on TP53 are dominant in the dysplasia and carcinoma samples from the 45 ESCC patients, but rare in the dysplasia samples from the 13 tumor-free patients, suggesting that the full inactivation of TP53 is essential in promoting the development of ESCC.	('carcinoma', 'Disease', (73, 82))	('patients', 'Species', '9606', (108, 116))	('TP53', 'Gene', (226, 230))	('inactivation', 'Var', (210, 222))	('tumor-free', 'Disease', (164, 174))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('carcinoma', 'Disease', 'MESH:D002277', (73, 82))	('TP53', 'Gene', (34, 38))	('tumor-free', 'Disease', 'MESH:D000072662', (164, 174))	('dysplasia', 'Disease', (134, 143))	('TP53', 'Gene', '7157', (226, 230))	('dysplasia', 'Disease', 'MESH:D004476', (134, 143))	('ESCC', 'Disease', (276, 280))	('promoting', 'PosReg', (247, 256))	('patients', 'Species', '9606', (175, 183))	('dysplasia', 'Disease', (59, 68))	('TP53', 'Gene', '7157', (34, 38))	('dysplasia', 'Disease', 'MESH:D004476', (59, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
297124	28900112	Since these lesions were also categorized as low-grade dysplasia (Supplementary Data 3) on histopathology, the smaller number of mutations accumulated compared to LDs in the TD cohort is possibly due to a shorter period after the initiation of neoplasia.	('neoplasia', 'Disease', 'MESH:D009369', (244, 253))	('neoplasia', 'Phenotype', 'HP:0002664', (244, 253))	('dysplasia', 'Disease', (55, 64))	('mutations', 'Var', (129, 138))	('dysplasia', 'Disease', 'MESH:D004476', (55, 64))	('Dat', 'Gene', (80, 83))	('neoplasia', 'Disease', (244, 253))	('Dat', 'Gene', '6531', (80, 83))
297125	28900112	Regarding the mutational context, we observed a strong enrichment of C > T transitions in both squamous dysplasia and ESCC samples, especially at the CpG dinucleotides, which is denoted as signature 1 documented in the COSMIC Mutational Signature Framework (Fig.	('C > T transitions', 'Var', (69, 86))	('ESCC', 'Disease', (118, 122))	('esp', 'Gene', (132, 135))	('CpG dinucleotides', 'Chemical', 'MESH:C015772', (150, 167))	('squamous dysplasia', 'Disease', (95, 113))	('squamous dysplasia', 'Disease', 'MESH:D002294', (95, 113))	('esp', 'Gene', '148713', (132, 135))	('squamous dysplasia', 'Phenotype', 'HP:0002860', (95, 113))
297126	28900112	1c, d), suggesting that the spontaneous deamination of cytosine contributes most to the accumulation of mutations during tumorigenesis.	('mutations', 'Var', (104, 113))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumor', 'Disease', (121, 126))	('cytosine', 'Chemical', 'MESH:D003596', (55, 63))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
297130	28900112	Mutations in TP53 was the most recurrent event, present in dysplasia samples among 95.6% of patients and in ESCCs among 97.8% of patients.	('TP53', 'Gene', (13, 17))	('patients', 'Species', '9606', (129, 137))	('patients', 'Species', '9606', (92, 100))	('Mutations', 'Var', (0, 9))	('dysplasia', 'Disease', (59, 68))	('TP53', 'Gene', '7157', (13, 17))	('dysplasia', 'Disease', 'MESH:D004476', (59, 68))
297132	28900112	However, in ESCC we identified mutations in TP53 with a high frequency in dysplasia samples (95.6%), and some were found even in NTDs (30.8%; Fig.	('mutations', 'Var', (31, 40))	('found', 'Reg', (115, 120))	('NTD', 'Gene', '80199', (129, 132))	('dysplasia', 'Disease', (74, 83))	('dysplasia', 'Disease', 'MESH:D004476', (74, 83))	('TP53', 'Gene', '7157', (44, 48))	('NTD', 'Gene', (129, 132))	('TP53', 'Gene', (44, 48))
297133	28900112	2), suggesting that TP53 mutations may occur very early in ESCC progression.	('mutations', 'Var', (25, 34))	('ESCC', 'Disease', (59, 63))	('TP53', 'Gene', '7157', (20, 24))	('TP53', 'Gene', (20, 24))
297136	28900112	For patients with multiple samples (>=3) from the TD cohort, we portrayed the regional distribution of mutations of dysplasia samples and ESCCs (Fig.	('dysplasia', 'Disease', 'MESH:D004476', (116, 125))	('mutations', 'Var', (103, 112))	('dysplasia', 'Disease', (116, 125))	('patients', 'Species', '9606', (4, 12))
297137	28900112	Mutations were classified as 'trunk' if they were detected in all samples from one patient, 'shared' if they were detected in more than one but not all samples, and 'private' if they were specific to only one sample.	('detected', 'Reg', (50, 58))	('Mutations', 'Var', (0, 9))	('patient', 'Species', '9606', (83, 90))
297140	28900112	The mutational burdens of the 4 dysplasia samples and 4 ESCCs were comparable, with an average of 100 mutations (Fig.	('dysplasia', 'Disease', 'MESH:D004476', (32, 41))	('mutations', 'Var', (102, 111))	('dysplasia', 'Disease', (32, 41))
297142	28900112	By contrast, of the 4 dysplasia samples, LD1 shared 42 mutations with the 4 ESCCs, including the well-known ESCC related genes TP53, NFE2L2, and RB1, while the LD2, HD3, and HD4 had nearly no overlapping mutation with all 4 ESCCs.	('RB1', 'Gene', (145, 148))	('HD3', 'Gene', (165, 168))	('NFE2L2', 'Gene', '4780', (133, 139))	('mutations', 'Var', (55, 64))	('LD1', 'Gene', (41, 44))	('HD4', 'Gene', (174, 177))	('RB1', 'Gene', '5925', (145, 148))	('NFE2L2', 'Gene', (133, 139))	('HD3', 'Gene', '8841', (165, 168))	('dysplasia', 'Disease', (22, 31))	('ESCC', 'Disease', (108, 112))	('TP53', 'Gene', '7157', (127, 131))	('TP53', 'Gene', (127, 131))	('dysplasia', 'Disease', 'MESH:D004476', (22, 31))	('HD4', 'Gene', '9759', (174, 177))
297143	28900112	To further resolve the clonal relationship of LD1 and matched ESCCs, we calculated the cancer cell fraction (CCF) of mutations in LD1 and the 4 ESCCs.	('cancer', 'Disease', (87, 93))	('mutations', 'Var', (117, 126))	('LD1', 'Gene', (130, 133))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cancer', 'Disease', 'MESH:D009369', (87, 93))
297144	28900112	Of the ESCC private mutations, we found EGFR (p.F712L) in all 4 ESCCs and PIK3CA (p.E545K) in C3 and C4, implying they occurred late during the tumorigenesis progression.	('p.F712L', 'Var', (46, 53))	('tumor', 'Disease', (144, 149))	('p.F712L', 'Mutation', 'p.F712L', (46, 53))	('p.E545K', 'Mutation', 'rs104886003', (82, 89))	('PIK3CA', 'Gene', '5290', (74, 80))	('EGFR', 'Gene', '1956', (40, 44))	('EGFR', 'Gene', (40, 44))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('p.E545K', 'Var', (82, 89))	('PIK3CA', 'Gene', (74, 80))	('ESCC private', 'Gene', (7, 19))
297149	28900112	3d, f), each with one lymph node metastasis, we found that each patient's samples had a common ancestor, with 29 trunk mutations in P12 and 47 trunk mutations in P25.	('P12', 'Gene', (132, 135))	('patient', 'Species', '9606', (64, 71))	('P12', 'Gene', '56655', (132, 135))	('P25', 'Gene', '8851', (162, 165))	('P25', 'Gene', (162, 165))	('mutations', 'Var', (119, 128))
297152	28900112	In P25, metastasis had 91.4% of the mutations shared with one ESCC (C2), indicating that it was disseminated from C2 at a late stage.	('P25', 'Gene', '8851', (3, 6))	('mutations', 'Var', (36, 45))	('P25', 'Gene', (3, 6))
297153	28900112	Through analysis of the CCF values of the mutations in P25_C2 vs. P25_M, we identified a cluster of mutations that are clonal in P25_M but subclonal in P25_C2, which also proved the relationship between the metastasis and C2 (Supplementary Fig.	('mutations', 'Var', (100, 109))	('P25', 'Gene', '8851', (152, 155))	('P25', 'Gene', (55, 58))	('P25', 'Gene', (66, 69))	('P25', 'Gene', '8851', (129, 132))	('P25', 'Gene', (152, 155))	('P25', 'Gene', '8851', (55, 58))	('P25', 'Gene', (129, 132))	('mutations', 'Var', (42, 51))	('P25', 'Gene', '8851', (66, 69))
297161	28900112	Consistently, we found that the dysplasia samples had significantly more subclonal mutations (Fisher's exact test, P = 2.66e-5), strongly implying that the dysplasia samples were highly heterogeneous.	('dysplasia', 'Disease', (156, 165))	('more', 'PosReg', (68, 72))	('dysplasia', 'Disease', (32, 41))	('dysplasia', 'Disease', 'MESH:D004476', (156, 165))	('dysplasia', 'Disease', 'MESH:D004476', (32, 41))	('subclonal mutations', 'Var', (73, 92))
297168	28900112	We then examined the hot regions of CNAs previously reported in ESCC, identifying gains in 3q (especially 3q25.31-3q26.1 and 3q26.3), 5p15.33, 7p12.1-7p11.2, 8q, and 11q13.3-11q13.4, as well as losses in 3p21.31, 9p21.3, and 13q21.1 with high frequencies in both dysplasia samples and ESCCs, and these recurrent CNAs tended to be shared by all samples in each patient (Fig.	('esp', 'Gene', '148713', (95, 98))	('losses', 'NegReg', (194, 200))	('5p15.33', 'Var', (134, 141))	('esp', 'Gene', (95, 98))	('patient', 'Species', '9606', (360, 367))	('dysplasia', 'Disease', (263, 272))	('gains', 'PosReg', (82, 87))	('dysplasia', 'Disease', 'MESH:D004476', (263, 272))	('3p21.31', 'Gene', (204, 211))
297172	28900112	For those frequently altered regions in ESCC, we evaluated the proportion of the CNAs that were ubiquitous, and found that gains in 3q26.3 and 3q25.31-26.1 had significant bias towards being 'trunk' (Fisher's exact test, P = 0.009 and P = 0.05, respectively; Fig.	('esp', 'Gene', (246, 249))	('3q26.3', 'Var', (132, 138))	('gains', 'PosReg', (123, 128))	('3q25.31-26.1', 'Var', (143, 155))	('esp', 'Gene', '148713', (246, 249))
297175	28900112	Through the inspection of focal amplifications and deletions of driver genes, we observed a high occurrence of amplifications in SOX2, PIK3CA, MYC, CCND1, and FGFR1 in both dysplasia samples and ESCCs, but the copy number status did not show obvious progression (Fig.	('CCND1', 'Gene', (148, 153))	('dysplasia', 'Disease', (173, 182))	('CCND1', 'Gene', '595', (148, 153))	('SOX2', 'Gene', '6657', (129, 133))	('amplifications', 'Var', (111, 125))	('SOX2', 'Gene', (129, 133))	('deletions', 'Var', (51, 60))	('PIK3CA', 'Gene', (135, 141))	('MYC', 'Gene', '4609', (143, 146))	('PIK3CA', 'Gene', '5290', (135, 141))	('dysplasia', 'Disease', 'MESH:D004476', (173, 182))	('FGFR1', 'Gene', (159, 164))	('FGFR1', 'Gene', '2260', (159, 164))	('MYC', 'Gene', (143, 146))
297180	28900112	Nevertheless, in several cases from the TD cohort (P6, P8, and P25), while the mutational distributions of the samples in each patient were dissimilar, we observed a high consistency in the copy number patterns, implying that in these patients, the CNAs not only emerged early but also remained steady during the ESCC progression.	('patient', 'Species', '9606', (235, 242))	('patient', 'Species', '9606', (127, 134))	('patients', 'Species', '9606', (235, 243))	('P25', 'Gene', (63, 66))	('ESCC', 'Disease', (313, 317))	('CNAs', 'MPA', (249, 253))	('P25', 'Gene', '8851', (63, 66))	('P6', 'Var', (51, 53))
297184	28900112	In the other 6 cases, although each sample harbored one or more TP53 mutations, none was ubiquitous among all samples.	('harbored', 'Reg', (43, 51))	('mutations', 'Var', (69, 78))	('TP53', 'Gene', '7157', (64, 68))	('TP53', 'Gene', (64, 68))
297185	28900112	Moreover, the phylogenies of these 6 cases suggested that samples carrying independent TP53 mutations came from distantly related clones.	('TP53', 'Gene', '7157', (87, 91))	('TP53', 'Gene', (87, 91))	('mutations', 'Var', (92, 101))
297186	28900112	Nevertheless, according to the CCF, most of the mutations in TP53 were clonal.	('mutations', 'Var', (48, 57))	('TP53', 'Gene', '7157', (61, 65))	('TP53', 'Gene', (61, 65))
297187	28900112	In addition, 4 of the 13 NTDs possessed mutations in TP53 (Fig.	('mutations', 'Var', (40, 49))	('NTD', 'Gene', '80199', (25, 28))	('TP53', 'Gene', '7157', (53, 57))	('TP53', 'Gene', (53, 57))	('NTD', 'Gene', (25, 28))
297188	28900112	Thus, we inferred that mutations in TP53 arose early during ESCC development.	('TP53', 'Gene', (36, 40))	('ESCC', 'Disease', (60, 64))	('TP53', 'Gene', '7157', (36, 40))	('mutations', 'Var', (23, 32))
297189	28900112	Since most of the mutations occurred in the DNA binding domain of the p53 protein (Fig.	('occurred', 'Reg', (28, 36))	('p53', 'Gene', (70, 73))	('p53', 'Gene', '7157', (70, 73))	('protein', 'Protein', (74, 81))	('mutations', 'Var', (18, 27))
297191	28900112	In contrast to the truncating mutations, which would lead to the depletion of the protein, the missense mutations usually resulted in an enhanced expression of p53 protein (Supplementary Fig.	('enhanced', 'PosReg', (137, 145))	('missense mutations', 'Var', (95, 113))	('p53', 'Gene', (160, 163))	('p53', 'Gene', '7157', (160, 163))	('expression', 'MPA', (146, 156))
297192	28900112	Interestingly, the ESCC in case SP11 (SP11_C) had a shared protein truncating TP53 mutation and a private subclonal missense mutation.	('P11', 'Gene', (39, 42))	('protein truncating', 'MPA', (59, 77))	('mutation', 'Var', (83, 91))	('TP53', 'Gene', '7157', (78, 82))	('P11', 'Gene', (33, 36))	('TP53', 'Gene', (78, 82))	('P11', 'Gene', '6281', (33, 36))	('P11', 'Gene', '6281', (39, 42))
297194	28900112	In the TD cohort, 69 of the 71 dysplasia samples had a mutated TP53 in conjunction with LOH (two-hit), which is similar to the results of ESCCs, in which 51 of the 54 samples harbored the two-hit alterations in TP53.	('TP53', 'Gene', '7157', (63, 67))	('TP53', 'Gene', (63, 67))	('mutated', 'Var', (55, 62))	('dysplasia', 'Disease', 'MESH:D004476', (31, 40))	('TP53', 'Gene', '7157', (211, 215))	('TP53', 'Gene', (211, 215))	('dysplasia', 'Disease', (31, 40))
297196	28900112	In contrast, in the NTD cohort, even 3 NTDs showed LOH in TP53, none of the 10 NTDs harbored both the mutation and LOH in TP53 (samples with more than 1 mutation in TP53 but without LOH were excluded in the statistical analysis; Fig.	('NTD', 'Gene', (20, 23))	('TP53', 'Gene', (122, 126))	('TP53', 'Gene', (165, 169))	('TP53', 'Gene', '7157', (58, 62))	('NTD', 'Gene', (79, 82))	('TP53', 'Gene', (58, 62))	('NTD', 'Gene', '80199', (39, 42))	('LOH', 'Var', (51, 54))	('NTD', 'Gene', '80199', (20, 23))	('NTD', 'Gene', '80199', (79, 82))	('NTD', 'Gene', (39, 42))	('TP53', 'Gene', '7157', (122, 126))	('TP53', 'Gene', '7157', (165, 169))
297200	28900112	In conclusion, we inferred that LOH or mutations in TP53 could either occur early but the further development of ESCC requires the full inactivation of TP53.	('ESCC', 'Disease', (113, 117))	('TP53', 'Gene', '7157', (52, 56))	('TP53', 'Gene', '7157', (152, 156))	('TP53', 'Gene', (52, 56))	('mutations', 'Var', (39, 48))	('TP53', 'Gene', (152, 156))
297212	28900112	In summary, we postulate that the accumulation of CNAs and mutations may represent two distinct genetic timers during tumorigenesis of ESCC.	('ESCC', 'Disease', (135, 139))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumor', 'Disease', (118, 123))	('mutations', 'Var', (59, 68))	('CNAs', 'Gene', (50, 54))
297218	28900112	By analyzing the truncal events across cases in the TD cohort, we speculated that mutations in TP53 and gains in 3q are early alterations during the ESCC development.	('ESCC', 'Disease', (149, 153))	('gains', 'PosReg', (104, 109))	('mutations', 'Var', (82, 91))	('TP53', 'Gene', '7157', (95, 99))	('TP53', 'Gene', (95, 99))
297219	28900112	Moreover, we identified TP53 mutations in 4 NTDs, while gains in 3q were present in 8 NTDs and 2 normal tissues adjacent to tumors, reinforcing the idea that they play essential roles in initiating the tumorigenesis.	('NTD', 'Gene', (86, 89))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('tumor', 'Disease', (202, 207))	('TP53', 'Gene', (24, 28))	('NTD', 'Gene', '80199', (44, 47))	('mutations', 'Var', (29, 38))	('TP53', 'Gene', '7157', (24, 28))	('tumor', 'Disease', (124, 129))	('tumors', 'Disease', (124, 130))	('tumors', 'Disease', 'MESH:D009369', (124, 130))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('NTD', 'Gene', (44, 47))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('NTD', 'Gene', '80199', (86, 89))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
297225	28900112	As previously discussed by Stachler et al., one major path for BE to transform to EAC is through the inactivation of TP53, followed by whole-genome doubling.	('TP53', 'Gene', '7157', (117, 121))	('EAC', 'Phenotype', 'HP:0011459', (82, 85))	('TP53', 'Gene', (117, 121))	('inactivation', 'Var', (101, 113))	('BE', 'Phenotype', 'HP:0100580', (63, 65))
297241	28900112	To further confirm the fidelity of mutations that were called as described above, we validated a total of 96 non-silent mutations from 19 samples of 5 patients (SP6, SP14, P5, P11, and P14).	('P14', 'Gene', '1029', (167, 170))	('P14', 'Gene', '1029', (185, 188))	('P14', 'Gene', (167, 170))	('P14', 'Gene', (185, 188))	('patients', 'Species', '9606', (151, 159))	('SP6', 'Var', (161, 164))	('P11', 'Gene', (176, 179))	('P11', 'Gene', '6281', (176, 179))
297245	28900112	To identify potential driver mutations in dysplasia samples and ESCCs, we evaluated the non-synonymous mutations from the following three aspects: (1) Mutations in significantly mutated genes highlighted by recent large cohort sequencing studies of ESCC; (2) Mutations in genes that are documented by the COSMIC database (ESCC-associated or related to other types of cancer); (3) Mutations in genes that are present in the KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways in cancer.	('dysplasia', 'Disease', 'MESH:D004476', (42, 51))	('cancer', 'Disease', (482, 488))	('cancer', 'Disease', 'MESH:D009369', (482, 488))	('cancer', 'Disease', 'MESH:D009369', (367, 373))	('Mutations', 'Var', (380, 389))	('cancer', 'Disease', (367, 373))	('cancer', 'Phenotype', 'HP:0002664', (482, 488))	('cancer', 'Phenotype', 'HP:0002664', (367, 373))	('dysplasia', 'Disease', (42, 51))
297275	28900112	The Fisher's exact test was used to determine whether a potential driver alteration has bias towards being 'trunk', to compare the enrichment in the number of cases harboring mutations in ESCC-associated genes of different pathways, to compare the significant differences in the number of cases harboring the genome doubling event and the 'two-hit' event on TP53.	('mutations', 'Var', (175, 184))	('ESCC-associated', 'Gene', (188, 203))	('TP53', 'Gene', '7157', (358, 362))	('TP53', 'Gene', (358, 362))
297365	27580113	Cisplatin and HA-Pt both inhibited cell growth over 80% compared to PBS.	('HA-Pt', 'Var', (14, 19))	('PBS', 'Chemical', 'MESH:D007854', (68, 71))	('Cisplatin', 'Chemical', 'MESH:D002945', (0, 9))	('HA-Pt', 'Chemical', '-', (14, 19))	('inhibited', 'NegReg', (25, 34))	('cell growth', 'CPA', (35, 46))
297369	27580113	There were no significant differences in levels of liver enzymes (alanine transaminase (ALT), aspartate transaminase (AST), and alkaline phosphatase (ALP)) between any two of the three treatment groups (cisplatin vs. control, cisplatin vs. HA-Pt, and HA-Pt vs. control).	('ALP', 'Gene', '403548', (150, 153))	('alkaline phosphatase', 'Gene', '403548', (128, 148))	('ALP', 'Gene', (150, 153))	('cisplatin', 'Var', (226, 235))	('HA-Pt', 'Chemical', '-', (251, 256))	('HA-Pt', 'Chemical', '-', (240, 245))	('aspartate transaminase', 'MPA', (94, 116))	('alkaline phosphatase', 'Gene', (128, 148))	('cisplatin', 'Chemical', 'MESH:D002945', (226, 235))	('cisplatin', 'Chemical', 'MESH:D002945', (203, 212))
297482	27580113	Subsequently, the aquated platinum enters hepatic cells and causes DNA damage to the cells, resulting in elevated liver enzymes released by the necrotic cells.	('elevated liver enzymes', 'Phenotype', 'HP:0002910', (105, 127))	('causes', 'Reg', (60, 66))	('elevated', 'PosReg', (105, 113))	('necrotic', 'Disease', 'MESH:D009336', (144, 152))	('DNA damage', 'MPA', (67, 77))	('aquated', 'Var', (18, 25))	('platinum', 'Chemical', 'MESH:D010984', (26, 34))	('liver enzymes released', 'MPA', (114, 136))	('necrotic', 'Disease', (144, 152))
297501	25839409	PD0325901, a MAPK inhibitor, suppressed the MAPK pathway induced by iMDK and cooperatively inhibited cell viability and colony formation of NSCLC cells by inducing apoptosis in vitro.	('MDK', 'Gene', '4192', (69, 72))	('NSCLC', 'Disease', 'MESH:D002289', (140, 145))	('inducing', 'Reg', (155, 163))	('inhibited', 'NegReg', (91, 100))	('PD0325901', 'Var', (0, 9))	('MDK', 'Gene', (69, 72))	('apoptosis', 'CPA', (164, 173))	('MAPK pathway', 'Pathway', (44, 56))	('cell viability', 'CPA', (101, 115))	('colony formation', 'CPA', (120, 136))	('PD0325901', 'Chemical', 'MESH:C506614', (0, 9))	('NSCLC', 'Phenotype', 'HP:0030358', (140, 145))	('NSCLC', 'Disease', (140, 145))	('suppressed', 'NegReg', (29, 39))
297502	25839409	HUVEC tube formation, representing angiogenic processes in vitro, was also cooperatively inhibited by the combinatorial treatment of iMDK and PD0325901.	('HUVEC', 'CellLine', 'CVCL:2959', (0, 5))	('PD0325901', 'Chemical', 'MESH:C506614', (142, 151))	('MDK', 'Gene', (134, 137))	('HUVEC tube formation', 'CPA', (0, 20))	('inhibited', 'NegReg', (89, 98))	('PD0325901', 'Var', (142, 151))	('MDK', 'Gene', '4192', (134, 137))
297503	25839409	The combinatorial treatment of iMDK with PD0325901 cooperatively suppressed tumor growth and tumor-associated angiogenesis in a lung cancer xenograft model in vivo.	('lung cancer', 'Disease', 'MESH:D008175', (128, 139))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('tumor', 'Disease', (93, 98))	('MDK', 'Gene', '4192', (32, 35))	('suppressed', 'NegReg', (65, 75))	('lung cancer', 'Disease', (128, 139))	('PD0325901', 'Var', (41, 50))	('lung cancer', 'Phenotype', 'HP:0100526', (128, 139))	('PD0325901', 'Chemical', 'MESH:C506614', (41, 50))	('MDK', 'Gene', (32, 35))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
297504	25839409	Here, we demonstrate a novel treatment strategy using iMDK and PD0325901 to eradicate NSCLC.	('NSCLC', 'Disease', (86, 91))	('MDK', 'Gene', '4192', (55, 58))	('PD0325901', 'Var', (63, 72))	('NSCLC', 'Disease', 'MESH:D002289', (86, 91))	('MDK', 'Gene', (55, 58))	('PD0325901', 'Chemical', 'MESH:C506614', (63, 72))	('NSCLC', 'Phenotype', 'HP:0030358', (86, 91))
297509	25839409	For example, inhibition of MEK (a MAPKK; downstream of KRAS) by selumetinib, a MEK inhibitor, in addition to docetaxel (a chemotherapeutic drug) extended survival of KRAS-mutant NSCLC patients by 4 months compared to docetaxel alone.	('NSCLC', 'Disease', (178, 183))	('KRAS-mutant', 'Gene', (166, 177))	('docetaxel', 'Chemical', 'MESH:D000077143', (217, 226))	('KRAS-mutant', 'Var', (166, 177))	('MEK', 'Gene', (27, 30))	('extended', 'PosReg', (145, 153))	('NSCLC', 'Disease', 'MESH:D002289', (178, 183))	('patients', 'Species', '9606', (184, 192))	('MEK', 'Gene', (79, 82))	('survival', 'CPA', (154, 162))	('inhibition', 'Var', (13, 23))	('MEK', 'Gene', '5609', (79, 82))	('MEK', 'Gene', '5609', (27, 30))	('NSCLC', 'Phenotype', 'HP:0030358', (178, 183))	('docetaxel', 'Chemical', 'MESH:D000077143', (109, 118))	('selumetinib', 'Chemical', 'MESH:C517975', (64, 75))
297510	25839409	However, selumetinib plus docetaxel caused more adverse events than docetaxel alone, indicating that further improvements in this therapeutic strategy are needed to extend survival and reduce the adverse events associated with KRAS-mutant NSCLC.	('docetaxel', 'Chemical', 'MESH:D000077143', (68, 77))	('extend', 'PosReg', (165, 171))	('NSCLC', 'Phenotype', 'HP:0030358', (239, 244))	('survival', 'CPA', (172, 180))	('selumetinib', 'Chemical', 'MESH:C517975', (9, 20))	('NSCLC', 'Disease', (239, 244))	('KRAS-mutant', 'Var', (227, 238))	('docetaxel', 'Chemical', 'MESH:D000077143', (26, 35))	('NSCLC', 'Disease', 'MESH:D002289', (239, 244))
297512	25839409	For example, a PI3K inhibitor PI-103 inhibited the PI3K pathway while activating the MAPK pathway, suggesting a potential mechanism for tumor survival by the compensatory activation of an alternative tumorigenic pathway.	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('PI-103', 'Chemical', 'MESH:C522973', (30, 36))	('inhibited', 'NegReg', (37, 46))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('activating', 'PosReg', (70, 80))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('tumor', 'Disease', (200, 205))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('tumor', 'Disease', (136, 141))	('MAPK pathway', 'Pathway', (85, 97))	('PI3K pathway', 'Pathway', (51, 63))	('PI-103', 'Var', (30, 36))
297516	25839409	Since the combined inhibition of the PI3K and MAPK pathways by PI-103 and a MAPK inhibitor PD0325901 enhanced cell killing of NSCLC, in the present study, we tested whether the novel PI3K inhibitor iMDK further enhanced cell death of NSCLC in the presence of PD0325901.	('NSCLC', 'Disease', 'MESH:D002289', (126, 131))	('PD0325901', 'Chemical', 'MESH:C506614', (259, 268))	('PD0325901', 'Var', (91, 100))	('tested', 'Reg', (158, 164))	('cell', 'CPA', (220, 224))	('MDK', 'Gene', (199, 202))	('PI-103', 'Chemical', 'MESH:C522973', (63, 69))	('PI-103', 'Var', (63, 69))	('cell killing', 'CPA', (110, 122))	('NSCLC', 'Disease', (126, 131))	('NSCLC', 'Disease', 'MESH:D002289', (234, 239))	('NSCLC', 'Phenotype', 'HP:0030358', (126, 131))	('PD0325901', 'Chemical', 'MESH:C506614', (91, 100))	('MAPK pathways', 'Pathway', (46, 59))	('NSCLC', 'Disease', (234, 239))	('PI3K', 'Pathway', (37, 41))	('enhanced', 'PosReg', (101, 109))	('NSCLC', 'Phenotype', 'HP:0030358', (234, 239))	('enhanced', 'PosReg', (211, 219))	('MDK', 'Gene', '4192', (199, 202))	('inhibition', 'NegReg', (19, 29))
297517	25839409	Combined treatment of iMDK and PD0325901 significantly suppressed tumor growth of NSCLC, including KRAS-mutant NSCLC and squamous NSCLC.	('NSCLC', 'Disease', (111, 116))	('NSCLC', 'Phenotype', 'HP:0030358', (111, 116))	('MDK', 'Gene', (23, 26))	('squamous NSCLC', 'Disease', 'MESH:D002294', (121, 135))	('tumor', 'Disease', (66, 71))	('KRAS-mutant', 'Var', (99, 110))	('suppressed', 'NegReg', (55, 65))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('NSCLC', 'Disease', 'MESH:D002289', (82, 87))	('NSCLC', 'Disease', 'MESH:D002289', (130, 135))	('PD0325901', 'Var', (31, 40))	('squamous NSCLC', 'Disease', (121, 135))	('NSCLC', 'Disease', (82, 87))	('NSCLC', 'Disease', (130, 135))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('NSCLC', 'Phenotype', 'HP:0030358', (82, 87))	('NSCLC', 'Phenotype', 'HP:0030358', (130, 135))	('NSCLC', 'Disease', 'MESH:D002289', (111, 116))	('MDK', 'Gene', '4192', (23, 26))	('PD0325901', 'Chemical', 'MESH:C506614', (31, 40))
297519	25839409	Here, we demonstrate a novel strategy to treat NSCLC by simultaneously targeting both PI3K and MAPK pathways by iMDK and PD0325901.	('MAPK pathways', 'Pathway', (95, 108))	('targeting', 'Reg', (71, 80))	('MDK', 'Gene', (113, 116))	('NSCLC', 'Phenotype', 'HP:0030358', (47, 52))	('PD0325901', 'Var', (121, 130))	('MDK', 'Gene', '4192', (113, 116))	('NSCLC', 'Disease', (47, 52))	('NSCLC', 'Disease', 'MESH:D002289', (47, 52))	('PD0325901', 'Chemical', 'MESH:C506614', (121, 130))	('PI3K', 'Pathway', (86, 90))
297526	25839409	Antibody specific for AKT, phosphorylated-AKT (Ser473), ERK, and phosphorylated-ERK (Ser473) were obtained from Cell Signaling Technology (Beverly, MA).	('ERK', 'Gene', '5594', (80, 83))	('ERK', 'Gene', (56, 59))	('AKT', 'Gene', (42, 45))	('AKT', 'Gene', '207', (22, 25))	('Ser473', 'Var', (85, 91))	('ERK', 'Gene', (80, 83))	('Ser473', 'Var', (47, 53))	('Ser473', 'Chemical', '-', (47, 53))	('Ser473', 'Chemical', '-', (85, 91))	('AKT', 'Gene', (22, 25))	('AKT', 'Gene', '207', (42, 45))	('ERK', 'Gene', '5594', (56, 59))
297527	25839409	H441 cells and H2009 cells were plated in 96-well plates at a density of 1.5 x 103 cells and cultured at 37  C for 24 h. H441 and H2009 cells were treated with or without iMDK (2.5 muM) in the presence or absence of PD0325901 (0.5 muM).	('H2009', 'CellLine', 'CVCL:1514', (15, 20))	('MDK', 'Gene', '4192', (172, 175))	('H441', 'CellLine', 'CVCL:1561', (0, 4))	('PD0325901', 'Var', (216, 225))	('muM', 'Gene', '56925', (181, 184))	('H2009', 'CellLine', 'CVCL:1514', (130, 135))	('MDK', 'Gene', (172, 175))	('H441', 'CellLine', 'CVCL:1561', (121, 125))	('muM', 'Gene', (181, 184))	('muM', 'Gene', '56925', (231, 234))	('PD0325901', 'Chemical', 'MESH:C506614', (216, 225))	('muM', 'Gene', (231, 234))
297531	25839409	H441 cells were treated with iMDK at a concentration of 1 muM and/or PD0325901 at a concentration of 500 nM for 24 h and then released from the dish by incubation with trypsin/EDTA, counted, plated in triplicate at a density of 5 x 103 cells in six-well plates for 14 days.	('H441', 'CellLine', 'CVCL:1561', (0, 4))	('muM', 'Gene', (58, 61))	('EDTA', 'Chemical', 'MESH:D004492', (176, 180))	('PD0325901', 'Var', (69, 78))	('MDK', 'Gene', '4192', (30, 33))	('PD0325901', 'Chemical', 'MESH:C506614', (69, 78))	('MDK', 'Gene', (30, 33))	('muM', 'Gene', '56925', (58, 61))
297532	25839409	H2009 cells were treated with iMDK and/or PD0325901 at a concentration of 1 muM for 24 h and then released from the dish by incubation with trypsin/EDTA, counted, plated in triplicate at a density of 1 x 103 cells in six-well plates for 14 days.	('MDK', 'Gene', '4192', (31, 34))	('EDTA', 'Chemical', 'MESH:D004492', (148, 152))	('H2009', 'CellLine', 'CVCL:1514', (0, 5))	('MDK', 'Gene', (31, 34))	('muM', 'Gene', '56925', (76, 79))	('PD0325901', 'Var', (42, 51))	('muM', 'Gene', (76, 79))	('PD0325901', 'Chemical', 'MESH:C506614', (42, 51))
297536	25839409	Cells were treated with iMDK (10 nM) or PD0325901 (10 nM) alone, or iMDK (10 nM) in combination with PD0325901 (10 nM).	('MDK', 'Gene', '4192', (69, 72))	('PD0325901', 'Chemical', 'MESH:C506614', (101, 110))	('PD0325901', 'Var', (40, 49))	('MDK', 'Gene', (25, 28))	('MDK', 'Gene', (69, 72))	('PD0325901', 'Chemical', 'MESH:C506614', (40, 49))	('MDK', 'Gene', '4192', (25, 28))
297540	25839409	HUVECs were treated with iMDK (10 muM) and/or PD0325901 (10 muM) for 5 h and a tube formation assay was performed using an in vitro angiogenesis kit (Millipore Corp. Bedford, MA).	('HUVEC', 'CellLine', 'CVCL:2959', (0, 5))	('MDK', 'Gene', (26, 29))	('muM', 'Gene', (60, 63))	('muM', 'Gene', '56925', (34, 37))	('PD0325901', 'Chemical', 'MESH:C506614', (46, 55))	('muM', 'Gene', (34, 37))	('MDK', 'Gene', '4192', (26, 29))	('muM', 'Gene', '56925', (60, 63))	('PD0325901', 'Var', (46, 55))
297543	25839409	The mice were intraperitoneally injected with 100 mul solution containing iMDK (9 mg/kg) everyday and/or orally administered PD0325901 (5 mg/kg) in 0.5% [w/v] methylcellulose solution with 0.2% [v/v] polysorbate 80 [Tween 80] five times per week (on days 1, 2, 3, 4, 5, 7, 8, 9, 10, 11).	('PD0325901', 'Chemical', 'MESH:C506614', (125, 134))	('methylcellulose', 'Chemical', 'MESH:D008747', (159, 174))	('polysorbate 80', 'Chemical', 'MESH:D011136', (200, 214))	('mice', 'Species', '10090', (4, 8))	('MDK', 'Gene', '4192', (75, 78))	('Tween 80', 'Chemical', 'MESH:D011136', (216, 224))	('PD0325901', 'Var', (125, 134))	('MDK', 'Gene', (75, 78))
297554	25839409	In the previous study, we demonstrated that iMDK suppressed the PI3K-AKT pathway (12 h after treatment) while inducing the MAPK pathway (48 h after treatment), as detected by the phosphorylation of ERK (MAPK), in H441 lung adenocarcinoma cells that carry a KRAS mutation (KRASG12V).	('inducing', 'PosReg', (110, 118))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (218, 237))	('MDK', 'Gene', '4192', (45, 48))	('AKT', 'Gene', (69, 72))	('carcinoma', 'Phenotype', 'HP:0030731', (228, 237))	('phosphorylation', 'MPA', (179, 194))	('MDK', 'Gene', (45, 48))	('ERK', 'Gene', '5594', (198, 201))	('AKT', 'Gene', '207', (69, 72))	('H441 lung adenocarcinoma', 'Disease', 'MESH:D000077192', (213, 237))	('mutation', 'Var', (262, 270))	('suppressed', 'NegReg', (49, 59))	('ERK', 'Gene', (198, 201))	('H441 lung adenocarcinoma', 'Disease', (213, 237))	('MAPK pathway', 'Pathway', (123, 135))	('KRAS', 'Gene', (257, 261))
297562	25839409	In order to test this concept, we assessed whether the MAPK pathway activated by iMDK is suppressed by PD0325901, a MEK (MAPKK) inhibitor, in H441 cells.	('MDK', 'Gene', (82, 85))	('MEK', 'Gene', (116, 119))	('MEK', 'Gene', '5609', (116, 119))	('suppressed', 'NegReg', (89, 99))	('PD0325901', 'Var', (103, 112))	('H441', 'CellLine', 'CVCL:1561', (142, 146))	('MDK', 'Gene', '4192', (82, 85))	('PD0325901', 'Chemical', 'MESH:C506614', (103, 112))	('MAPK pathway', 'Pathway', (55, 67))
297563	25839409	1B, PD0325901 suppressed iMDK-induced phosphorylation of ERK in a dose-dependent fashion.	('MDK', 'Gene', (26, 29))	('PD0325901', 'Chemical', 'MESH:C506614', (4, 13))	('PD0325901', 'Var', (4, 13))	('ERK', 'Gene', '5594', (57, 60))	('MDK', 'Gene', '4192', (26, 29))	('ERK', 'Gene', (57, 60))	('suppressed', 'NegReg', (14, 24))
297564	25839409	These results indicate that the combinatorial treatment of iMDK with PD0325901 simultaneously inhibits two major KRAS tumorigenic pathways in H441 cells.	('MDK', 'Gene', (60, 63))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('PD0325901', 'Var', (69, 78))	('inhibits', 'NegReg', (94, 102))	('MDK', 'Gene', '4192', (60, 63))	('tumor', 'Disease', (118, 123))	('H441', 'CellLine', 'CVCL:1561', (142, 146))	('PD0325901', 'Chemical', 'MESH:C506614', (69, 78))
297565	25839409	Having demonstrated that the combinatorial treatment of iMDK and PD0325901 inhibited both the PI3K pathway and the iMDK-mediated activation of the MAPK pathway in H441 cells carrying KRASG12V (Fig.	('MDK', 'Gene', (57, 60))	('PI3K pathway', 'Pathway', (94, 106))	('MDK', 'Gene', (116, 119))	('inhibited', 'NegReg', (75, 84))	('KRASG12V', 'Var', (183, 191))	('PD0325901', 'Var', (65, 74))	('H441', 'CellLine', 'CVCL:1561', (163, 167))	('MAPK pathway', 'Pathway', (147, 159))	('MDK', 'Gene', '4192', (57, 60))	('MDK', 'Gene', '4192', (116, 119))	('PD0325901', 'Chemical', 'MESH:C506614', (65, 74))
297566	25839409	1), we assessed whether the combinatorial treatment would inhibit growth of H441 cells as well as other KRAS mutated NSCLC cells, including H2009 (non-small cell carcinoma; KRASG12A) and A549 (lung carcinoma; KRASG12S) cells, and KRAS wild type H520 (lung squamous cell carcinoma; KRASWT) cells.	('lung carcinoma', 'Disease', 'MESH:D008175', (193, 207))	('non-small cell carcinoma', 'Disease', 'MESH:D002289', (147, 171))	('small cell carcinoma', 'Phenotype', 'HP:0030357', (151, 171))	('NSCLC', 'Disease', 'MESH:D002289', (117, 122))	('mutated', 'Var', (109, 116))	('NSCLC', 'Disease', (117, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (198, 207))	('carcinoma', 'Phenotype', 'HP:0030731', (270, 279))	('NSCLC', 'Phenotype', 'HP:0030358', (117, 122))	('growth', 'MPA', (66, 72))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (251, 279))	('H2009', 'CellLine', 'CVCL:1514', (140, 145))	('lung carcinoma', 'Disease', (193, 207))	('non-small cell carcinoma', 'Disease', (147, 171))	('non-small cell carcinoma', 'Phenotype', 'HP:0030358', (147, 171))	('A549', 'CellLine', 'CVCL:0023', (187, 191))	('inhibit', 'NegReg', (58, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (162, 171))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (251, 279))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (256, 279))	('lung squamous cell carcinoma', 'Disease', (251, 279))	('H441', 'CellLine', 'CVCL:1561', (76, 80))	('KRASG12S', 'CellLine', 'CVCL:T291', (209, 217))
297569	25839409	Next, we treated the cells with iMDK and/or a MAPK inhibitor PD0325901.	('PD0325901', 'Var', (61, 70))	('MDK', 'Gene', '4192', (33, 36))	('MDK', 'Gene', (33, 36))	('PD0325901', 'Chemical', 'MESH:C506614', (61, 70))
297570	25839409	2A, PD0325901 further inhibited iMDK-mediated suppression of cell viability in KRAS mutated H441 and H2009 cells as well as KRAS wild type H520 cells.	('H441', 'CellLine', 'CVCL:1561', (92, 96))	('inhibited', 'NegReg', (22, 31))	('PD0325901', 'Chemical', 'MESH:C506614', (4, 13))	('PD0325901', 'Var', (4, 13))	('suppression', 'NegReg', (46, 57))	('mutated', 'Var', (84, 91))	('MDK', 'Gene', '4192', (33, 36))	('cell viability', 'CPA', (61, 75))	('H2009', 'CellLine', 'CVCL:1514', (101, 106))	('MDK', 'Gene', (33, 36))
297571	25839409	Though iMDK alone did not inhibit cell viability of A549 cells, the combinatorial treatment of iMDK with PD0325901 significantly inhibited that of A549 cells compared to the single treatment of PD0325901.	('inhibited', 'NegReg', (129, 138))	('A549', 'CellLine', 'CVCL:0023', (147, 151))	('PD0325901', 'Chemical', 'MESH:C506614', (194, 203))	('PD0325901', 'Var', (105, 114))	('MDK', 'Gene', '4192', (8, 11))	('A549', 'CellLine', 'CVCL:0023', (52, 56))	('MDK', 'Gene', (96, 99))	('PD0325901', 'Chemical', 'MESH:C506614', (105, 114))	('MDK', 'Gene', (8, 11))	('MDK', 'Gene', '4192', (96, 99))
297573	25839409	These results indicate that the combinatorial treatment inhibits cell viability of NSCLC cells independently of KRAS mutations or MDK expression.	('mutations', 'Var', (117, 126))	('NSCLC', 'Disease', (83, 88))	('MDK', 'Gene', (130, 133))	('inhibits', 'NegReg', (56, 64))	('cell viability', 'CPA', (65, 79))	('NSCLC', 'Disease', 'MESH:D002289', (83, 88))	('NSCLC', 'Phenotype', 'HP:0030358', (83, 88))	('KRAS', 'Gene', (112, 116))	('MDK', 'Gene', '4192', (130, 133))
297574	25839409	In addition to cell viability, colony formation of H441 and H2009 cells were also significantly reduced by the combinatorial treatment compared to either iMDK or PD0325901.	('MDK', 'Gene', '4192', (155, 158))	('H441', 'CellLine', 'CVCL:1561', (51, 55))	('H2009', 'CellLine', 'CVCL:1514', (60, 65))	('combinatorial treatment', 'Var', (111, 134))	('MDK', 'Gene', (155, 158))	('colony formation', 'CPA', (31, 47))	('PD0325901', 'Chemical', 'MESH:C506614', (162, 171))	('reduced', 'NegReg', (96, 103))
297575	25839409	In order to analyze the mechanism by which PD0325901 enhances iMDK-mediated cell growth inhibition in the NSCLC cells, we measured the degree of apoptosis after the combinatorial treatment in H441 cells by quantifying activated caspase-3 and TUNEL positive cells, which are markers of apoptosis.	('PD0325901', 'Var', (43, 52))	('MDK', 'Gene', '4192', (63, 66))	('NSCLC', 'Disease', 'MESH:D002289', (106, 111))	('H441', 'CellLine', 'CVCL:1561', (192, 196))	('caspase-3', 'Gene', (228, 237))	('enhances', 'PosReg', (53, 61))	('PD0325901', 'Chemical', 'MESH:C506614', (43, 52))	('MDK', 'Gene', (63, 66))	('NSCLC', 'Phenotype', 'HP:0030358', (106, 111))	('caspase-3', 'Gene', '836', (228, 237))	('NSCLC', 'Disease', (106, 111))
297576	25839409	3, flow cytometric analysis demonstrated that single use of iMDK or PD0325901 (10 nM) did not induce activation of caspase-3 (Fig.	('MDK', 'Gene', (61, 64))	('PD0325901', 'Var', (68, 77))	('caspase-3', 'Gene', '836', (115, 124))	('PD0325901', 'Chemical', 'MESH:C506614', (68, 77))	('MDK', 'Gene', '4192', (61, 64))	('caspase-3', 'Gene', (115, 124))
297577	25839409	Combinatorial treatment with iMDK and PD0325901 synergistically increased levels of activated caspapse-3.	('PD0325901', 'Var', (38, 47))	('levels of activated caspapse-3', 'MPA', (74, 104))	('MDK', 'Gene', '4192', (30, 33))	('PD0325901', 'Chemical', 'MESH:C506614', (38, 47))	('increased', 'PosReg', (64, 73))	('MDK', 'Gene', (30, 33))
297579	25839409	These results indicate that the inhibition of H441 cell growth by the combinatorial treatment of iMDK with PD0325901 is likely attributed to apoptosis.	('MDK', 'Gene', (98, 101))	('inhibition', 'NegReg', (32, 42))	('H441 cell growth', 'CPA', (46, 62))	('PD0325901', 'Var', (107, 116))	('H441', 'CellLine', 'CVCL:1561', (46, 50))	('MDK', 'Gene', '4192', (98, 101))	('PD0325901', 'Chemical', 'MESH:C506614', (107, 116))
297581	25839409	We sought to determine whether the combinatorial treatment with iMDK and PD0325901 influences not only NSCLC cells but also angiogenesis constituted from such endothelial cells.	('MDK', 'Gene', '4192', (65, 68))	('NSCLC', 'Disease', (103, 108))	('MDK', 'Gene', (65, 68))	('influences', 'Reg', (83, 93))	('NSCLC', 'Disease', 'MESH:D002289', (103, 108))	('PD0325901', 'Var', (73, 82))	('NSCLC', 'Phenotype', 'HP:0030358', (103, 108))	('angiogenesis', 'CPA', (124, 136))	('PD0325901', 'Chemical', 'MESH:C506614', (73, 82))
297582	25839409	First, using TUNEL staining, we assessed whether the treatment of iMDK, PD0325901 or both in combination would induce cell death in HUVEC (Human Umbilical Vein Endothelial Cells).	('PD0325901', 'Chemical', 'MESH:C506614', (72, 81))	('Umbilical Vein Endothelial', 'CellLine', 'CVCL:2G60', (145, 171))	('induce', 'Reg', (111, 117))	('MDK', 'Gene', '4192', (67, 70))	('HUVEC', 'CellLine', 'CVCL:2959', (132, 137))	('PD0325901', 'Var', (72, 81))	('MDK', 'Gene', (67, 70))	('Human', 'Species', '9606', (139, 144))	('cell death', 'CPA', (118, 128))
297583	25839409	iMDK, PD0325901 or a combination of the two did not induce cell death in HUVEC in vitro (Fig.	('PD0325901', 'Var', (6, 15))	('HUVEC', 'CellLine', 'CVCL:2959', (73, 78))	('MDK', 'Gene', '4192', (1, 4))	('PD0325901', 'Chemical', 'MESH:C506614', (6, 15))	('MDK', 'Gene', (1, 4))
297585	25839409	Next, we assessed whether treatment with iMDK, PD0325901 or both in combination influenced angiogenesis by assessing tube formation in HUVECs, which mimics angiogenesis in vitro.	('influenced', 'Reg', (80, 90))	('PD0325901', 'Var', (47, 56))	('MDK', 'Gene', '4192', (42, 45))	('tube formation', 'CPA', (117, 131))	('angiogenesis', 'CPA', (91, 103))	('PD0325901', 'Chemical', 'MESH:C506614', (47, 56))	('HUVEC', 'CellLine', 'CVCL:2959', (135, 140))	('MDK', 'Gene', (42, 45))
297586	25839409	Neither iMDK nor PD0325901, when used alone, inhibited angiogenesis as assessed by HUVEC tube formation.	('PD0325901', 'Chemical', 'MESH:C506614', (17, 26))	('HUVEC', 'CellLine', 'CVCL:2959', (83, 88))	('inhibited', 'NegReg', (45, 54))	('PD0325901', 'Var', (17, 26))	('MDK', 'Gene', '4192', (9, 12))	('MDK', 'Gene', (9, 12))	('angiogenesis', 'CPA', (55, 67))
297587	25839409	In contrast, combinatorial treatment with iMDK and PD0325901 significantly disrupted tube formation 5 h after treatment (Fig.	('MDK', 'Gene', (43, 46))	('disrupted', 'NegReg', (75, 84))	('PD0325901', 'Var', (51, 60))	('MDK', 'Gene', '4192', (43, 46))	('PD0325901', 'Chemical', 'MESH:C506614', (51, 60))	('tube formation', 'CPA', (85, 99))
297590	25839409	In order to determine whether combinatorial treatment of iMDK with PD0325901 cooperatively suppresses lung tumor growth in vivo, we treated nude mice carrying xenograft tumors derived from H441 cells with iMDK and/or PD0325901.	('PD0325901', 'Var', (67, 76))	('suppresses', 'NegReg', (91, 101))	('MDK', 'Gene', (206, 209))	('PD0325901', 'Var', (217, 226))	('lung tumor', 'Disease', 'MESH:D008175', (102, 112))	('tumors', 'Disease', 'MESH:D009369', (169, 175))	('MDK', 'Gene', '4192', (58, 61))	('PD0325901', 'Chemical', 'MESH:C506614', (67, 76))	('PD0325901', 'Chemical', 'MESH:C506614', (217, 226))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('MDK', 'Gene', (58, 61))	('H441', 'CellLine', 'CVCL:1561', (189, 193))	('nude mice', 'Species', '10090', (140, 149))	('tumors', 'Phenotype', 'HP:0002664', (169, 175))	('lung tumor', 'Disease', (102, 112))	('lung tumor', 'Phenotype', 'HP:0100526', (102, 112))	('MDK', 'Gene', '4192', (206, 209))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('tumors', 'Disease', (169, 175))
297591	25839409	5A, tumor growth was significantly suppressed after daily intraperitoneal injection of iMDK or oral administration of PD0325901 5 times a week.	('PD0325901', 'Var', (118, 127))	('tumor', 'Disease', (4, 9))	('PD0325901', 'Chemical', 'MESH:C506614', (118, 127))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('MDK', 'Gene', '4192', (88, 91))	('suppressed', 'NegReg', (35, 45))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('MDK', 'Gene', (88, 91))
297592	25839409	The combinatorial treatment of iMDK with PD0325901 further inhibited the tumor growth compared to either iMDK or PD0325901 alone.	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('MDK', 'Gene', (106, 109))	('inhibited', 'NegReg', (59, 68))	('MDK', 'Gene', '4192', (32, 35))	('PD0325901', 'Chemical', 'MESH:C506614', (113, 122))	('tumor', 'Disease', (73, 78))	('PD0325901', 'Var', (41, 50))	('MDK', 'Gene', (32, 35))	('MDK', 'Gene', '4192', (106, 109))	('PD0325901', 'Chemical', 'MESH:C506614', (41, 50))
297593	25839409	Angiogenesis in the xenografted tumor, which was assessed by the expression of CD31/PECAM-1, was also cooperatively inhibited by the combinatorial treatment of iMDK with PD0325901 compared to either iMDK or PD0325901 (Fig.	('CD31', 'Gene', '5175', (79, 83))	('PD0325901', 'Chemical', 'MESH:C506614', (170, 179))	('inhibited', 'NegReg', (116, 125))	('MDK', 'Gene', (161, 164))	('PECAM-1', 'Gene', (84, 91))	('CD31', 'Gene', (79, 83))	('PECAM-1', 'Gene', '5175', (84, 91))	('MDK', 'Gene', '4192', (200, 203))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('PD0325901', 'Chemical', 'MESH:C506614', (207, 216))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('expression', 'MPA', (65, 75))	('Angiogenesis in', 'CPA', (0, 15))	('PD0325901', 'Var', (170, 179))	('tumor', 'Disease', (32, 37))	('MDK', 'Gene', '4192', (161, 164))	('MDK', 'Gene', (200, 203))
297594	25839409	These results indicate that the combinatorial treatment of iMDK with PD0325901 significantly suppresses tumor growth and tumor-associated angiogenesis of NSCLC in vivo.	('suppresses', 'NegReg', (93, 103))	('MDK', 'Gene', (60, 63))	('NSCLC', 'Disease', 'MESH:D002289', (154, 159))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('NSCLC', 'Phenotype', 'HP:0030358', (154, 159))	('tumor', 'Disease', (104, 109))	('tumor', 'Disease', (121, 126))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('PD0325901', 'Var', (69, 78))	('MDK', 'Gene', '4192', (60, 63))	('PD0325901', 'Chemical', 'MESH:C506614', (69, 78))	('NSCLC', 'Disease', (154, 159))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
297596	25839409	A recent clinical trial using a MAPK inhibitor selumetinib, a molecularly targeted drug, in combination with docetaxel (chemotherapeutic [non-molecularly targeted] drug) extended survival by 4 months for patients whose lung adenocarcinomas carry KRAS mutations compared to those using docetaxel alone; however, the combinatorial treatment resulted in increased incidence of adverse effects compared to docetaxel only treatment.	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (219, 239))	('patients', 'Species', '9606', (204, 212))	('mutations', 'Var', (251, 260))	('docetaxel', 'Chemical', 'MESH:D000077143', (402, 411))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (219, 239))	('docetaxel', 'Chemical', 'MESH:D000077143', (285, 294))	('carcinoma', 'Phenotype', 'HP:0030731', (229, 238))	('KRAS', 'Gene', (246, 250))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (219, 238))	('selumetinib', 'Chemical', 'MESH:C517975', (47, 58))	('docetaxel', 'Chemical', 'MESH:D000077143', (109, 118))	('lung adenocarcinomas', 'Disease', (219, 239))	('extended', 'PosReg', (170, 178))
297602	25839409	iMDK did not reduce body weight or cause toxicity in mice, suggesting that the combinatorial use of iMDK with PD0325901 or other MAPK inhibitors, such as selumetinib, might be superior to the combinatorial use of docetaxel and selumetinib to prevent the adverse effects.	('docetaxel', 'Chemical', 'MESH:D000077143', (213, 222))	('selumetinib', 'Chemical', 'MESH:C517975', (227, 238))	('PD0325901', 'Chemical', 'MESH:C506614', (110, 119))	('toxicity', 'Disease', 'MESH:D064420', (41, 49))	('toxicity', 'Disease', (41, 49))	('MDK', 'Gene', '4192', (101, 104))	('MDK', 'Gene', (101, 104))	('MDK', 'Gene', '4192', (1, 4))	('MDK', 'Gene', (1, 4))	('selumetinib', 'Chemical', 'MESH:C517975', (154, 165))	('PD0325901', 'Var', (110, 119))	('reduce body weight', 'Phenotype', 'HP:0004325', (13, 31))	('mice', 'Species', '10090', (53, 57))	('MAPK', 'Gene', (129, 133))
297605	25839409	For example, the combinatorial use of NVP-BEZ235 (a PI3K inhibitor) and ARRY-142886 (a MAPK inhibitor) synergistically reduced Kras-mutant lung tumors in a transgenic mouse model.	('ARRY-142886', 'Var', (72, 83))	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('ARRY-142886', 'Chemical', 'MESH:C517975', (72, 83))	('lung tumors', 'Phenotype', 'HP:0100526', (139, 150))	('lung tumors', 'Disease', (139, 150))	('Kras', 'Gene', (127, 131))	('BEZ235', 'Chemical', 'MESH:C531198', (42, 48))	('Kras', 'Gene', '16653', (127, 131))	('lung tumor', 'Phenotype', 'HP:0100526', (139, 149))	('lung tumors', 'Disease', 'MESH:D008175', (139, 150))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('reduced', 'NegReg', (119, 126))	('NVP-BEZ235', 'Var', (38, 48))	('mouse', 'Species', '10090', (167, 172))
297614	25839409	The combinatorial treatment of iMDK with PD0325901 suppressed HUVEC tube formation but not HUVEC growth compared to either iMDK or PD0325901 (Fig.	('PD0325901', 'Chemical', 'MESH:C506614', (131, 140))	('MDK', 'Gene', '4192', (124, 127))	('HUVEC', 'CellLine', 'CVCL:2959', (62, 67))	('MDK', 'Gene', '4192', (32, 35))	('suppressed', 'NegReg', (51, 61))	('HUVEC tube formation', 'CPA', (62, 82))	('PD0325901', 'Var', (41, 50))	('MDK', 'Gene', (124, 127))	('HUVEC', 'CellLine', 'CVCL:2959', (91, 96))	('MDK', 'Gene', (32, 35))	('PD0325901', 'Chemical', 'MESH:C506614', (41, 50))
297621	25161999	Head and neck cancers can escape from anoikis and enter into the epithelial-mesenchymal transition stages via the modulation of E-cadherin expression with epigenetic mechanisms.	('modulation', 'Var', (114, 124))	('E-cadherin', 'Protein', (128, 138))	('Head and neck cancers', 'Phenotype', 'HP:0012288', (0, 21))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('enter', 'Reg', (50, 55))	('Head and neck cancer', 'Phenotype', 'HP:0012288', (0, 20))	('neck cancers', 'Disease', (9, 21))	('epithelial-mesenchymal transition stages', 'CPA', (65, 105))	('expression', 'MPA', (139, 149))	('neck cancers', 'Disease', 'MESH:D006258', (9, 21))	('cancers', 'Phenotype', 'HP:0002664', (14, 21))
297640	25161999	The gene encoding E-cadherin (CDH1) located at chromosome 16q22.1, a common hotspot of genetic abbreviations such as loss of heterozygosity (LOH) and mutations.	('CDH1', 'Gene', '999', (30, 34))	('loss of heterozygosity', 'Var', (117, 139))	('mutations', 'Var', (150, 159))	('CDH1', 'Gene', (30, 34))
297654	25161999	The most common form of epigenetic regulation includes changes in the CpG island methylation patterns in the promoter region via addition of an aberrant methyl group to the cytosine residue, remodeling of the chromatin structure via modifying the histone protein core, and control of the expression level with the negative transcription regulator, microRNA.	('expression', 'MPA', (288, 298))	('CpG island', 'Gene', (70, 80))	('histone protein core', 'Protein', (247, 267))	('cytosine', 'Chemical', 'MESH:D003596', (173, 181))	('aberrant methyl group', 'Var', (144, 165))	('methylation', 'MPA', (81, 92))	('changes', 'Reg', (55, 62))	('modifying', 'Reg', (233, 242))
297655	25161999	In terms of the epigenetic control of E-cadherin expression in the head and neck cancers, the most frequently reported mechanism includes promoter DNA hypermethylation and overexpression of the target microRNA.	('head and neck cancers', 'Phenotype', 'HP:0012288', (67, 88))	('cancers', 'Phenotype', 'HP:0002664', (81, 88))	('promoter DNA hypermethylation', 'Var', (138, 167))	('neck cancers', 'Disease', (76, 88))	('head and neck cancer', 'Phenotype', 'HP:0012288', (67, 87))	('overexpression', 'PosReg', (172, 186))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('neck cancers', 'Disease', 'MESH:D006258', (76, 88))
297658	25161999	In contrast, the most common form of E-cadherin alterations in head and neck cancer is DNA methylation.	('neck cancer', 'Disease', (72, 83))	('head and neck cancer', 'Phenotype', 'HP:0012288', (63, 83))	('alterations', 'Var', (48, 59))	('E-cadherin', 'Protein', (37, 47))	('common', 'Reg', (22, 28))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('neck cancer', 'Disease', 'MESH:D006258', (72, 83))
297661	25161999	In cancer, however, methyl CpG cluster (CpG islands) embedded in the regulatory regions of the tumor-related genes becomes methylated by the de novo DNA methyltransferases (DNMTs).	('methylated', 'Var', (123, 133))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('cancer', 'Disease', (3, 9))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Disease', (95, 100))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
297663	25161999	Promoter hypermethylation is a potential epigenetic mechanism to the E-cadherin gene due to the dense CpG dinucleotide density in the transcription regulatory region (Figure 1).	('E-cadherin', 'Gene', (69, 79))	('CpG dinucleotide', 'Chemical', 'MESH:C015772', (102, 118))	('Promoter hypermethylation', 'Var', (0, 25))
297666	25161999	Methylation of 5' promoter region of the E-cadherin is found to be an early event in oral cancer lesions.	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('oral cancer lesions', 'Disease', 'MESH:D009062', (85, 104))	('Methylation', 'Var', (0, 11))	('event', 'Reg', (76, 81))	('oral cancer lesions', 'Disease', (85, 104))	('E-cadherin', 'Protein', (41, 51))
297667	25161999	The presence of E-cadherin methylation is independent of the invasive and metastatic potential of the cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('E-cadherin', 'Protein', (16, 26))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('methylation', 'Var', (27, 38))
297668	25161999	At first, methylated DNA is thought as a specific cancer marker as the de novo methylated sequence is found largely in the cancerous tissue.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('cancerous', 'Disease', 'MESH:D009369', (123, 132))	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('methylated', 'Var', (10, 20))	('cancer', 'Disease', (123, 129))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('cancerous', 'Disease', (123, 132))
297671	25161999	However, before moving to the clinical use, it should be considered that methylated E-cadherin could possibly be deposited in the noncancerous epithelia in the head and neck region.	('noncancerous epithelia', 'Disease', 'None', (130, 152))	('E-cadherin', 'Protein', (84, 94))	('noncancerous epithelia', 'Disease', (130, 152))	('methylated', 'Var', (73, 83))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
297672	25161999	Using pyrosequencing, the existence of methylated E-cadherin DNA is demonstrated in both oral squamous cell carcinoma and normal tissues obtained from the resection margin of the same patients with no statistical difference.	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (94, 117))	('patients', 'Species', '9606', (184, 192))	('oral squamous cell carcinoma', 'Disease', (89, 117))	('E-cadherin', 'Protein', (50, 60))	('methylated', 'Var', (39, 49))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (89, 117))
297676	25161999	In the context of DNA methylation patterns, head and neck cancer infected with HPV has distinctive methylation imprints in comparison with the HPV negative counterparts.	('HPV', 'Species', '10566', (143, 146))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('neck cancer infected', 'Disease', 'MESH:D006258', (53, 73))	('HPV', 'Species', '10566', (79, 82))	('neck cancer infected', 'Disease', (53, 73))	('HPV', 'Var', (79, 82))	('methylation', 'MPA', (99, 110))	('head and neck cancer', 'Phenotype', 'HP:0012288', (44, 64))
297693	25161999	The migration inducing effects is demonstrated in the mouse bone marrow-derived mesenchymal stem cells with microRNA-10b.	('microRNA-10b', 'Var', (108, 120))	('mouse', 'Species', '10090', (54, 59))	('migration inducing', 'CPA', (4, 22))
297695	25161999	Compared with the normal oral mucosa, high microRNA-31 expression is found in the oral potential malignant disorder (OPMAD) tissues suggesting that microRNA-31 is a candidate oncogenic microRNA involved in the early development of oral tongue cancers.	('malignant disorder', 'Disease', 'MESH:D009369', (97, 115))	('microRNA-31', 'Gene', (43, 54))	('malignant disorder', 'Disease', (97, 115))	('microRNA-31', 'Var', (148, 159))	('cancers', 'Phenotype', 'HP:0002664', (243, 250))	('expression', 'MPA', (55, 65))	('oral tongue cancers', 'Disease', (231, 250))	('oral tongue cancers', 'Disease', 'MESH:D014062', (231, 250))	('cancer', 'Phenotype', 'HP:0002664', (243, 249))
297696	25161999	Ectopic expression of microRNA-31 could promote the growth and immortalization of the nontumorigenic oral keratinocytes.	('promote', 'PosReg', (40, 47))	('Ectopic expression', 'Var', (0, 18))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('microRNA-31', 'Gene', (22, 33))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
297712	25161999	Of the 5 miR-200 family members, microRNA-200b and microRNA-200c are suggested to be the regulators of E-cadherin through targeting p300 transcripts in the cancer cells.	('p300', 'Gene', '2033', (132, 136))	('microRNA-200c', 'Var', (51, 64))	('cancer', 'Disease', (156, 162))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('targeting', 'Reg', (122, 131))	('p300', 'Gene', (132, 136))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))
297724	25161999	The abnormality in the tumor microvasculature will increase the diffusion distances leading to the disturbance of gas exchange.	('increase', 'PosReg', (51, 59))	('disturbance of gas exchange', 'MPA', (99, 126))	('diffusion distances', 'MPA', (64, 83))	('abnormality', 'Var', (4, 15))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('tumor', 'Disease', (23, 28))
297755	33178577	Patients with an FNiT>=4.2% had a significantly higher risk for locoregional recurrence and cancer-caused death than those with an FNiT<4.2% (p=0.001 and p<0.001, respectively).	('locoregional recurrence', 'CPA', (64, 87))	('death', 'Disease', 'MESH:D003643', (106, 111))	('cancer', 'Disease', (92, 98))	('death', 'Disease', (106, 111))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('Patients', 'Species', '9606', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('>=4.2', 'Var', (21, 26))
297787	33178577	H157-L1 and H157-L2 were two subpopulations of poorly differentiated BMSCC cell lines, while H157-H1 and H157-H2 were two subpopulations of well-differentiated BMSCC cell lines.	('H157-L2', 'Var', (12, 19))	('H157-L1', 'Var', (0, 7))	('H157-H1', 'CellLine', 'CVCL:2458', (93, 100))
297831	33178577	We noted that H157-H1 and H157-H2 had higher ability to internalize more neutrophils than H157-L1 and H157-L2.	('internalize more neutrophils', 'MPA', (56, 84))	('H157-H1', 'Var', (14, 21))	('H157-H2', 'Var', (26, 33))	('H157-H1', 'CellLine', 'CVCL:2458', (14, 21))
297856	33178577	In our study, patients with high FNiT tended to have both a shorter RFS and DSS than those with low FNiT, which may be better explained by the role of neutrophils in the tumor microenvironment mentioned above.	('RFS', 'Disease', (68, 71))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('high FNiT', 'Var', (28, 37))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('RFS', 'Disease', 'MESH:D005198', (68, 71))	('tumor', 'Disease', (170, 175))	('DSS', 'MPA', (76, 79))	('DSS', 'Chemical', '-', (76, 79))	('shorter', 'NegReg', (60, 67))	('patients', 'Species', '9606', (14, 22))
297868	33178577	PMN-MDSCs, as well as other protumor neutrophils, can suppress CD8 T-cell function.	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumor', 'Disease', (31, 36))	('suppress', 'NegReg', (54, 62))	('CD8', 'Gene', (63, 66))	('CD8', 'Gene', '925', (63, 66))	('PMN-MDSCs', 'Var', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
297893	29657301	We performed guilt by association analysis to identify potential biological pathways regulated by differentially expressed LncRNA in LCLC patient samples.	('differentially expressed', 'Var', (98, 122))	('LncRNA', 'Gene', (123, 129))	('patient', 'Species', '9606', (138, 145))	('LCLC', 'Phenotype', 'HP:0030360', (133, 137))
297902	29657301	Genetic aberration associate with LCLCs have been described but still there are no markers available for proper diagnosis of these patients.	('patients', 'Species', '9606', (131, 139))	('LCLCs', 'Disease', (34, 39))	('LCLC', 'Phenotype', 'HP:0030360', (34, 38))	('Genetic aberration', 'Var', (0, 18))
297923	32160708	Pan-Cancer Analysis Reveals the Diverse Landscape of Novel Sense and Antisense Fusion Transcripts Gene fusions that contribute to oncogenicity can be explored for identifying cancer biomarkers and potential drug targets.	('cancer', 'Disease', (175, 181))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('Antisense Fusion Transcripts', 'Var', (69, 97))	('Cancer', 'Phenotype', 'HP:0002664', (4, 10))	('Sense', 'Var', (59, 64))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
297926	32160708	The majority of the recurrent non-canonical fusions found in our study are novel, unexplored, and exhibited highly variable profiles across cancers, with breast cancer and glioblastoma having the highest and lowest rates, respectively.	('breast cancer', 'Disease', 'MESH:D001943', (154, 167))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('breast cancer', 'Disease', (154, 167))	('breast cancer', 'Phenotype', 'HP:0003002', (154, 167))	('cancers', 'Phenotype', 'HP:0002664', (140, 147))	('cancers', 'Disease', (140, 147))	('glioblastoma', 'Disease', (172, 184))	('cancers', 'Disease', 'MESH:D009369', (140, 147))	('glioblastoma', 'Disease', 'MESH:D005909', (172, 184))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('non-canonical', 'Var', (30, 43))	('glioblastoma', 'Phenotype', 'HP:0012174', (172, 184))
297928	32160708	Genomic instability, a hallmark of cancer, leads to the accumulation of dynamic changes in the genome manifested as structural variants (SVs) that include quantitative (copy number variations [CNVs]), positional (translocations), or orientational (inversions) rearrangements.	('hallmark of cancer', 'Disease', 'MESH:D009369', (23, 41))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('hallmark of cancer', 'Disease', (23, 41))	('translocations', 'Var', (213, 227))
297930	32160708	Fusion transcripts that originate from fusion genes are likely unique to a cancer type, which can be exploited to understand the underlying mechanisms of malignancy and can serve as effective diagnostic or prognostic markers.	('cancer type', 'Disease', 'MESH:D009369', (75, 86))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('fusion genes', 'Var', (39, 51))	('malignancy', 'Disease', 'MESH:D009369', (154, 164))	('cancer type', 'Disease', (75, 86))	('malignancy', 'Disease', (154, 164))
297931	32160708	These chimeras could contribute to oncogenicity by altering the expression of tumor suppressor or proto-oncogenes, or by modifying the original function of a protein resulting in an abnormal chimeric protein that stimulates tumorigenesis.	('modifying', 'Reg', (121, 130))	('expression', 'MPA', (64, 74))	('abnormal', 'Var', (182, 190))	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('tumor suppressor', 'Gene', (78, 94))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('altering', 'Reg', (51, 59))	('stimulates', 'PosReg', (213, 223))	('tumor', 'Disease', (224, 229))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor suppressor', 'Gene', '7248', (78, 94))	('contribute', 'Reg', (21, 31))	('tumor', 'Disease', (78, 83))	('chimeric protein', 'MPA', (191, 207))	('tumor', 'Disease', 'MESH:D009369', (224, 229))
297932	32160708	Examples of established cancer-specific biomarkers include the nucleophosmin-anaplastic lymphoma tyrosine kinase (NPM-ALK) fusion transcript for the identification of NPM-ALK-positive anaplastic large cell lymphoma (ALCL), and BCR-ABL1 fusion in chronic myeloid leukemia.	('leukemia', 'Phenotype', 'HP:0001909', (262, 270))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (254, 270))	('cancer', 'Disease', (24, 30))	('NPM', 'Gene', (114, 117))	('NPM', 'Gene', '4869', (114, 117))	('ALK', 'Gene', '238', (171, 174))	('BCR-ABL1', 'Gene', (227, 235))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('lymphoma', 'Phenotype', 'HP:0002665', (88, 96))	('ALK', 'Gene', (171, 174))	('cell lymphoma', 'Phenotype', 'HP:0012191', (201, 214))	('lymphoma', 'Phenotype', 'HP:0002665', (206, 214))	('anaplastic large cell lymphoma', 'Phenotype', 'HP:0012193', (184, 214))	('anaplastic large cell lymphoma', 'Disease', (184, 214))	('chronic myeloid leukemia', 'Disease', (246, 270))	('NPM', 'Gene', (167, 170))	('NPM', 'Gene', '4869', (167, 170))	('cancer', 'Disease', 'MESH:D009369', (24, 30))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (77, 96))	('ALCL', 'Phenotype', 'HP:0012193', (216, 220))	('ALK', 'Gene', '238', (118, 121))	('chronic myeloid leukemia', 'Disease', 'MESH:D015464', (246, 270))	('ALK', 'Gene', (118, 121))	('fusion', 'Var', (236, 242))	('chronic myeloid leukemia', 'Phenotype', 'HP:0005506', (246, 270))
297937	32160708	Although fusions were initially found to be more prevalent in liquid cancers, later they were discovered to be prominent in solid tumors.	('cancers', 'Disease', 'MESH:D009369', (69, 76))	('solid tumors', 'Disease', 'MESH:D009369', (124, 136))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('prevalent', 'Reg', (49, 58))	('fusions', 'Var', (9, 16))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('solid tumors', 'Disease', (124, 136))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('cancers', 'Phenotype', 'HP:0002664', (69, 76))	('cancers', 'Disease', (69, 76))
297938	32160708	Furthermore, fusion transcripts were initially assumed to be exclusive to cancer cells, but several reports identified a large number of fusion transcripts in non-cancerous cells, suggesting that they are prevalent in normal cells as well.	('fusion', 'Var', (137, 143))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('cancer', 'Disease', (74, 80))	('cancer', 'Disease', (163, 169))	('cancer', 'Disease', 'MESH:D009369', (163, 169))
297943	32160708	ChimeRScope employs short k-mer-based unique transcript fingerprints to serve as a reference to match with k-mers from cancer transcriptome reads and identify fusion transcripts in cancer cells that harbor frequent chromosomal abnormalities and mutations.	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('mutations', 'Var', (245, 254))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('cancer', 'Disease', (119, 125))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('chromosomal abnormalities', 'Disease', (215, 240))	('mers', 'Species', '1335626', (109, 113))	('cancer', 'Disease', (181, 187))	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (215, 240))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
297947	32160708	We also screened for fusions that are recurrent in the common cancer cell lines (CCLE) as a means to corroborate fusions that are co-occurring in corresponding primary tumors.	('CCLE', 'Chemical', '-', (81, 85))	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('primary tumors', 'Disease', 'MESH:D001932', (160, 174))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('fusions', 'Var', (113, 120))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('primary tumors', 'Disease', (160, 174))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
297948	32160708	Fusions in CCLE that are also detected in TCGA patients serve as a valuable resource to carry out mechanistic studies aimed at exploring the functional significance of these events.	('Fusions', 'Var', (0, 7))	('CCLE', 'Gene', (11, 15))	('patients', 'Species', '9606', (47, 55))	('CCLE', 'Chemical', '-', (11, 15))
297950	32160708	In addition to fusion detection from 33 cancer types, we also experimentally validated some of the predicted fusions by Sanger sequencing of fusion transcripts identified from CCLE cell lines.	('cancer type', 'Disease', 'MESH:D009369', (40, 51))	('fusions', 'Var', (109, 116))	('CCLE', 'Chemical', '-', (176, 180))	('cancer type', 'Disease', (40, 51))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))
297970	32160708	In general, a very high percentage of CCLE samples contained recurrent fusions across all cancers compared to those of TCGA (Figure 1B).	('cancers', 'Disease', (90, 97))	('CCLE', 'Disease', (38, 42))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('fusions', 'Var', (71, 78))	('CCLE', 'Chemical', '-', (38, 42))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('cancers', 'Disease', 'MESH:D009369', (90, 97))
297972	32160708	MESO (mesothelioma) and PAAD (pancreatic adenocarcinoma) had more non-canonical fusions in CCLE than did corresponding primary tumors in TCGA.	('non-canonical fusions', 'Var', (66, 87))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D010195', (30, 55))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('mesothelioma', 'Disease', (6, 18))	('CCLE', 'Chemical', '-', (91, 95))	('pancreatic adenocarcinoma', 'Disease', (30, 55))	('primary tumors', 'Disease', 'MESH:D001932', (119, 133))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (46, 55))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (30, 55))	('mesothelioma', 'Disease', 'MESH:D008654', (6, 18))	('primary tumors', 'Disease', (119, 133))	('CCLE', 'Disease', (91, 95))
297981	32160708	FGFR3-TACC3 (fibroblast growth factor receptor 3 and transforming acidic coiled-coil containing protein 3) fusion associated with multiple cancers was also found to be recurrent in BLCA, ESCA (esophageal carcinoma), CESC (cervical squamous cell carcinoma and endocervical adenocarcinoma), HNSC, LIHC (liver hepatocellular carcinoma), and LUSC.	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (307, 331))	('HNSC', 'Disease', (289, 293))	('cancers', 'Phenotype', 'HP:0002664', (139, 146))	('fusion', 'Var', (107, 113))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (231, 254))	('BLCA', 'Disease', (181, 185))	('liver hepatocellular carcinoma', 'Disease', 'MESH:D006528', (301, 331))	('LUSC', 'Disease', (338, 342))	('carcinoma', 'Phenotype', 'HP:0030731', (245, 254))	('carcinoma', 'Phenotype', 'HP:0030731', (277, 286))	('endocervical adenocarcinoma', 'Disease', (259, 286))	('multiple cancers', 'Disease', (130, 146))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (193, 213))	('carcinoma', 'Phenotype', 'HP:0030731', (204, 213))	('carcinoma', 'Phenotype', 'HP:0030731', (322, 331))	('esophageal carcinoma', 'Disease', (193, 213))	('liver hepatocellular carcinoma', 'Disease', (301, 331))	('cervical squamous cell carcinoma', 'Disease', (222, 254))	('TACC3', 'Gene', '10460', (6, 11))	('endocervical adenocarcinoma', 'Disease', 'MESH:D000230', (259, 286))	('TACC3', 'Gene', (6, 11))	('FGFR3', 'Gene', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('associated', 'Reg', (114, 124))	('cervical squamous cell carcinoma', 'Disease', 'MESH:D002294', (222, 254))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (193, 213))	('multiple cancers', 'Disease', 'MESH:D009369', (130, 146))	('FGFR3', 'Gene', '2261', (0, 5))
297982	32160708	The occurrence of FGFR3-TACC3 fusion in CESC, ESCA, and LIHC has not been reported previously, signifying that this common fusion is prevalent in more tissue types than previously discovered.	('FGFR3', 'Gene', '2261', (18, 23))	('fusion', 'Var', (30, 36))	('TACC3', 'Gene', '10460', (24, 29))	('CESC', 'Disease', (40, 44))	('TACC3', 'Gene', (24, 29))	('FGFR3', 'Gene', (18, 23))	('ESCA', 'Disease', (46, 50))
297983	32160708	Other FGFR fusions partnering with BicC family RNA binding protein 1 (BICC1), shootin 1 (SHTN1), glyceraldehyde 3-phosphate dehydrogenase (GAPDH), and arginyltransferase 1 (ATE1) have also been detected in multiple cancers from our analysis.	('ATE1', 'Gene', (173, 177))	('GAPDH', 'Gene', (139, 144))	('FGF', 'Gene', '2247', (6, 9))	('shootin 1', 'Gene', (78, 87))	('SHTN1', 'Gene', (89, 94))	('multiple cancers', 'Disease', 'MESH:D009369', (206, 222))	('cancers', 'Phenotype', 'HP:0002664', (215, 222))	('detected', 'Reg', (194, 202))	('SHTN1', 'Gene', '57698', (89, 94))	('FGF', 'Gene', (6, 9))	('fusions', 'Var', (11, 18))	('arginyltransferase 1', 'Gene', (151, 171))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('ATE1', 'Gene', '11101', (173, 177))	('shootin 1', 'Gene', '57698', (78, 87))	('multiple cancers', 'Disease', (206, 222))	('BICC1', 'Gene', '80114', (70, 75))	('GAPDH', 'Gene', '2597', (139, 144))	('arginyltransferase 1', 'Gene', '11101', (151, 171))	('BICC1', 'Gene', (70, 75))	('glyceraldehyde 3-phosphate dehydrogenase', 'Gene', (97, 137))	('glyceraldehyde 3-phosphate dehydrogenase', 'Gene', '2597', (97, 137))
297984	32160708	Several of these FGFR fusions have been identified as activating fusions that have been linked to activation of downstream genes.	('FGF', 'Gene', (17, 20))	('FGF', 'Gene', '2247', (17, 20))	('fusions', 'Var', (22, 29))
297985	32160708	Following the same trend, ETV6-NTRK3 (ETS variant 6 and neurotrophic tyrosine kinase, receptor, type 3) fusions were also identified in multiple cancers including breast, colon, skin, and thyroid cancers.	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('multiple cancers', 'Disease', 'MESH:D009369', (136, 152))	('colon', 'Disease', (171, 176))	('thyroid cancers', 'Disease', 'MESH:D013964', (188, 203))	('fusions', 'Var', (104, 111))	('ETV6', 'Gene', '2120', (26, 30))	('breast', 'Disease', (163, 169))	('NTRK3', 'Gene', '4916', (31, 36))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('NTRK3', 'Gene', (31, 36))	('cancers', 'Phenotype', 'HP:0002664', (196, 203))	('thyroid cancer', 'Phenotype', 'HP:0002890', (188, 202))	('identified', 'Reg', (122, 132))	('multiple cancers', 'Disease', (136, 152))	('ETV6', 'Gene', (26, 30))	('cancers', 'Phenotype', 'HP:0002664', (145, 152))	('skin', 'Disease', (178, 182))	('thyroid cancers', 'Disease', (188, 203))
297986	32160708	This ETV6 fusion with NTRK3 has also been identified as oncogenic by the activation of the Ras-MAPK and phosphatidylinositol 3-kinase (PI3K)-AKT pathways.	('phosphatidylinositol 3-kinase', 'Gene', (104, 133))	('activation', 'PosReg', (73, 83))	('MAPK', 'Gene', (95, 99))	('phosphatidylinositol 3-kinase', 'Gene', '5295', (104, 133))	('NTRK3', 'Gene', '4916', (22, 27))	('AKT', 'Gene', (141, 144))	('fusion', 'Var', (10, 16))	('ETV6', 'Gene', (5, 9))	('AKT', 'Gene', '207', (141, 144))	('NTRK3', 'Gene', (22, 27))	('MAPK', 'Gene', '5594', (95, 99))	('ETV6', 'Gene', '2120', (5, 9))
297987	32160708	In contrast, most of the ESR1 (estrogen receptor 1) fusions except for ESR1-CCDC170 (coiled-coil domain containing 170) were found to be exclusively present in breast cancer.	('ESR1', 'Gene', (25, 29))	('coiled-coil domain containing 170', 'Gene', '80129', (85, 118))	('ESR1', 'Gene', '2099', (71, 75))	('estrogen receptor 1', 'Gene', '2099', (31, 50))	('CCDC170', 'Gene', '80129', (76, 83))	('present', 'Reg', (149, 156))	('estrogen receptor 1', 'Gene', (31, 50))	('ESR1', 'Gene', '2099', (25, 29))	('breast cancer', 'Disease', 'MESH:D001943', (160, 173))	('coiled-coil domain containing 170', 'Gene', (85, 118))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('ESR1', 'Gene', (71, 75))	('CCDC170', 'Gene', (76, 83))	('breast cancer', 'Disease', (160, 173))	('breast cancer', 'Phenotype', 'HP:0003002', (160, 173))	('fusions', 'Var', (52, 59))
297999	32160708	IL34 expression has been associated with the progression of tumor growth, metastasis, and poor prognosis in several cancers.	('associated', 'Reg', (25, 35))	('IL34', 'Gene', (0, 4))	('expression', 'Var', (5, 15))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('metastasis', 'CPA', (74, 84))	('cancers', 'Disease', 'MESH:D009369', (116, 123))	('cancers', 'Phenotype', 'HP:0002664', (116, 123))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cancers', 'Disease', (116, 123))	('tumor', 'Disease', (60, 65))	('IL34', 'Gene', '146433', (0, 4))
298007	32160708	An earlier report also identified a high percentage of recurrent kinase fusions in thyroid cancer, indicating that kinase fusions could be explored as biomarkers or therapeutic targets in this cancer.	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('thyroid cancer', 'Disease', 'MESH:D013964', (83, 97))	('cancer', 'Disease', (193, 199))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('thyroid cancer', 'Phenotype', 'HP:0002890', (83, 97))	('thyroid cancer', 'Disease', (83, 97))	('kinase fusions', 'Var', (65, 79))
298012	32160708	EML4 (echinoderm microtubule-associated protein-like 4) fusions with ALK (ALK receptor tyrosine kinase) that were previously associated with non-small-cell lung cancer (NSCLC) were identified in LUAD along with KIRP and THCA at low frequency.	('NSCLC', 'Phenotype', 'HP:0030358', (169, 174))	('fusions', 'Var', (56, 63))	('ALK', 'Gene', '238', (69, 72))	('echinoderm microtubule-associated protein-like 4', 'Gene', (6, 54))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (141, 167))	('ALK', 'Gene', (69, 72))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('associated', 'Reg', (125, 135))	('ALK', 'Gene', '238', (74, 77))	('ALK', 'Gene', (74, 77))	('non-small-cell lung cancer', 'Disease', (141, 167))	('non-small-cell lung cancer', 'Disease', 'MESH:D002289', (141, 167))	('NSCLC', 'Disease', 'MESH:D002289', (169, 174))	('KIRP', 'Chemical', '-', (211, 215))	('echinoderm microtubule-associated protein-like 4', 'Gene', '27436', (6, 54))	('EML4', 'Gene', (0, 4))	('NSCLC', 'Disease', (169, 174))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (145, 167))	('EML4', 'Gene', '27436', (0, 4))	('lung cancer', 'Phenotype', 'HP:0100526', (156, 167))
298017	32160708	Since alteration of oncogene or tumor suppressor functions can be key to the initiation and progression of cancer, we also screened for these fusions in our dataset.	('tumor suppressor', 'Gene', (32, 48))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('tumor suppressor', 'Gene', '7248', (32, 48))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('oncogene', 'Protein', (20, 28))	('alteration', 'Var', (6, 16))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('cancer', 'Disease', (107, 113))
298020	32160708	CCDC6-RET fusions in thyroid and CBFB-MYH11 (core-binding factor, beta subunit and myosin heavy chain 11) fusions in LAML (acute myeloid leukemia) were recurrent.	('leukemia', 'Phenotype', 'HP:0001909', (137, 145))	('RET', 'Gene', '5979', (6, 9))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (129, 145))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (123, 145))	('CBFB', 'Gene', '865', (33, 37))	('MYH11', 'Gene', (38, 43))	('acute myeloid leukemia', 'Disease', (123, 145))	('RET', 'Gene', (6, 9))	('CCDC6', 'Gene', '8030', (0, 5))	('CBFB', 'Gene', (33, 37))	('CCDC6', 'Gene', (0, 5))	('fusions', 'Var', (106, 113))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (123, 145))	('MYH11', 'Gene', '4629', (38, 43))	('fusions', 'Var', (10, 17))
298025	32160708	PRKAR1A fusions were recurrent across and within several cancer types.	('cancer type', 'Disease', 'MESH:D009369', (57, 68))	('fusions', 'Var', (8, 15))	('PRKAR1A', 'Gene', (0, 7))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('cancer type', 'Disease', (57, 68))	('PRKAR1A', 'Gene', '5573', (0, 7))
298027	32160708	The percentage of TSG/oncogene fusions among the recurrent non-canonical fusions predicted was similar to those in the canonical fusions, although the majority of these fusions were identified from BRCA (Table S11).	('S11', 'Gene', (210, 213))	('TSG', 'Gene', (18, 21))	('S11', 'Gene', '6267', (210, 213))	('TSG', 'Gene', '57045', (18, 21))	('BRCA', 'Gene', '672', (198, 202))	('BRCA', 'Gene', (198, 202))	('fusions', 'Var', (31, 38))
298030	32160708	Another interesting observation of breast cancer was the occurrence of ErbB2 fusions.	('ErbB2', 'Gene', (71, 76))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('fusions', 'Var', (77, 84))	('ErbB2', 'Gene', '2064', (71, 76))	('breast cancer', 'Disease', 'MESH:D001943', (35, 48))	('breast cancer', 'Disease', (35, 48))	('breast cancer', 'Phenotype', 'HP:0003002', (35, 48))
298031	32160708	BRCA samples that are HER2 positive or the HER2-E PAM50 subtype had statistically higher ErbB2 fusions (Fisher's exact test p = 0.004 and 0.002, respectively).	('BRCA', 'Gene', (0, 4))	('HER2', 'Gene', (43, 47))	('ErbB2', 'Gene', (89, 94))	('PAM50', 'Var', (50, 55))	('HER2', 'Gene', (22, 26))	('higher', 'PosReg', (82, 88))	('HER2', 'Gene', '2064', (43, 47))	('HER2', 'Gene', '2064', (22, 26))	('ErbB2', 'Gene', '2064', (89, 94))	('BRCA', 'Gene', '672', (0, 4))
298033	32160708	Overexpression of ErbB2, a receptor tyrosine kinase with intrinsic tyrosine kinase activity, is associated with breast cancer metastasis and lower survival rates.	('breast cancer', 'Phenotype', 'HP:0003002', (112, 125))	('breast cancer metastasis', 'Disease', (112, 136))	('associated', 'Reg', (96, 106))	('ErbB2', 'Gene', (18, 23))	('lower', 'NegReg', (141, 146))	('Overexpression', 'Var', (0, 14))	('breast cancer metastasis', 'Disease', 'MESH:D001943', (112, 136))	('ErbB2', 'Gene', '2064', (18, 23))	('survival rates', 'CPA', (147, 161))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
298034	32160708	These observations indicate the need to investigate ErbB2 fusions in breast cancer and their association with gene expression and patient survival.	('patient', 'Species', '9606', (130, 137))	('breast cancer', 'Disease', 'MESH:D001943', (69, 82))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('ErbB2', 'Gene', (52, 57))	('breast cancer', 'Disease', (69, 82))	('fusions', 'Var', (58, 65))	('breast cancer', 'Phenotype', 'HP:0003002', (69, 82))	('ErbB2', 'Gene', '2064', (52, 57))
298035	32160708	To investigate oncogenic pathways that are affected by fusions in each TCGA cancer type, we cataloged recurrent fusions identified across 10 important oncogenic pathways (selection based on a previous report).	('cancer type', 'Disease', (76, 87))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('fusions', 'Var', (112, 119))	('oncogenic pathways', 'Pathway', (151, 169))	('cancer type', 'Disease', 'MESH:D009369', (76, 87))
298036	32160708	RTKRAS, NOTCH, PI3K, and HIPPO signaling pathways were found to be the most affected oncogenic pathways by recurrent canonical fusions (Figure 3A; Table S12).	('HIPPO signaling pathways', 'Pathway', (25, 49))	('PI3K', 'Pathway', (15, 19))	('S12', 'Gene', (153, 156))	('oncogenic pathways', 'Pathway', (85, 103))	('S12', 'Gene', '6268', (153, 156))	('affected', 'Reg', (76, 84))	('canonical fusions', 'Var', (117, 134))	('NOTCH', 'Pathway', (8, 13))
298037	32160708	Thyroid cancer had more than 50% of the recurrent canonical fusions in the RTK (receptor tyrosine kinase)-RAS pathway, with a high frequency of CCDC-RET fusion.	('RET', 'Gene', '5979', (149, 152))	('Thyroid cancer', 'Disease', 'MESH:D013964', (0, 14))	('fusions', 'Var', (60, 67))	('Thyroid cancer', 'Phenotype', 'HP:0002890', (0, 14))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('Thyroid cancer', 'Disease', (0, 14))	('RET', 'Gene', (149, 152))
298040	32160708	OV, ESCA, and LAML mainly contributed to the pool of read-through fusions (>40%) while some cancers have none (Table S1).	('ESCA', 'Disease', (4, 8))	('cancers', 'Phenotype', 'HP:0002664', (92, 99))	('cancers', 'Disease', 'MESH:D009369', (92, 99))	('cancers', 'Disease', (92, 99))	('read-through fusions', 'Var', (53, 73))	('fusions', 'Var', (66, 73))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
298042	32160708	For example, ZCCHC8-RSRC2 fusion was detected in five cancers (BLCA, BRCA, CESC, HNSC, and PAAD) at very low frequency (Table S13).	('fusion', 'Var', (26, 32))	('ZCCHC8', 'Gene', (13, 19))	('BRCA', 'Gene', '672', (69, 73))	('cancers', 'Phenotype', 'HP:0002664', (54, 61))	('cancers', 'Disease', (54, 61))	('cancers', 'Disease', 'MESH:D009369', (54, 61))	('BRCA', 'Gene', (69, 73))	('RSRC2', 'Gene', (20, 25))	('RSRC2', 'Gene', '65117', (20, 25))	('detected', 'Reg', (37, 45))	('CESC', 'Disease', (75, 79))	('ZCCHC8', 'Gene', '55596', (13, 19))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('HNSC', 'Disease', (81, 85))
298054	32160708	LUSC and THYM shared 39 recurrent fusions, including RAB3IP (interactor of the Ras-like GTPase Rab3A) and CHRM3 as recurrent 5' fusion partners with other genes in both cancers.	('Rab3A', 'Gene', '5864', (95, 100))	('cancers', 'Disease', (169, 176))	('Ras-like GTPase', 'Gene', '282808', (79, 94))	('CHRM3', 'Gene', (106, 111))	('Rab3A', 'Gene', (95, 100))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('RAB3IP', 'Gene', (53, 59))	('CHRM3', 'Gene', '1131', (106, 111))	('RAB3IP', 'Gene', '117177', (53, 59))	('cancers', 'Phenotype', 'HP:0002664', (169, 176))	('Ras-like GTPase', 'Gene', (79, 94))	('fusions', 'Var', (34, 41))	('cancers', 'Disease', 'MESH:D009369', (169, 176))
298056	32160708	We also identified RAB3IP fusions in gastrointestinal (GI) cancers, including STAD, COAD, CHOL, and LIHC.	('gastrointestinal (GI) cancers', 'Disease', 'MESH:D005770', (37, 66))	('RAB3IP', 'Gene', '117177', (19, 25))	('fusions', 'Var', (26, 33))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('RAB3IP', 'Gene', (19, 25))	('CHOL', 'CellLine', 'None', (90, 94))	('cancers', 'Phenotype', 'HP:0002664', (59, 66))	('COAD', 'Disease', (84, 88))	('CHOL', 'Disease', (90, 94))	('STAD', 'Disease', (78, 82))	('LIHC', 'Disease', (100, 104))
298066	32160708	Fusions involving CHRM3 were expressed in several GI tract cancers studied.	('Fusions', 'Var', (0, 7))	('GI tract cancers', 'Disease', 'MESH:D005770', (50, 66))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('expressed', 'Reg', (29, 38))	('GI tract cancers', 'Disease', (50, 66))	('cancers', 'Phenotype', 'HP:0002664', (59, 66))	('CHRM3', 'Gene', (18, 23))	('CHRM3', 'Gene', '1131', (18, 23))
298070	32160708	RXR is a master regulator and plays a central role in nuclear signaling, and a truncated RXR has been associated with oncogenicity.	('associated', 'Reg', (102, 112))	('oncogenicity', 'CPA', (118, 130))	('truncated', 'Var', (79, 88))	('RXR', 'Gene', '6256', (89, 92))	('RXR', 'Gene', '6256', (0, 3))	('RXR', 'Gene', (89, 92))	('RXR', 'Gene', (0, 3))
298081	32160708	Among the recurrent non-canonical fusions, ErBB2 and ESR1 fusions were druggable and were only identified in breast cancer samples.	('breast cancer', 'Disease', (109, 122))	('breast cancer', 'Phenotype', 'HP:0003002', (109, 122))	('ErBB2', 'Gene', '2064', (43, 48))	('ESR1', 'Gene', '2099', (53, 57))	('fusions', 'Var', (58, 65))	('ErBB2', 'Gene', (43, 48))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('ESR1', 'Gene', (53, 57))	('breast cancer', 'Disease', 'MESH:D001943', (109, 122))
298090	32160708	We identified 2,524 unique recurrent fusions from these cell lines with approximately equal distribution of canonical and non-canonical fusions (Figure 1; Tables S16 and S17).	('S17', 'Gene', '6218', (170, 173))	('S16', 'Gene', (162, 165))	('S16', 'Gene', '6217', (162, 165))	('fusions', 'Var', (37, 44))	('S17', 'Gene', (170, 173))
298093	32160708	A large number of recurrent canonical fusions (91 fusions) were identified in more than 35% of the cancer cell lines analyzed across cancers, indicating that fusions present in cell lines are more pervasive across cancers than the ones identified in primary tumors.	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('cancers', 'Disease', 'MESH:D009369', (214, 221))	('cancers', 'Disease', 'MESH:D009369', (133, 140))	('cancer', 'Disease', (214, 220))	('tumors', 'Phenotype', 'HP:0002664', (258, 264))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('tumor', 'Phenotype', 'HP:0002664', (258, 263))	('primary tumors', 'Disease', 'MESH:D001932', (250, 264))	('cancers', 'Phenotype', 'HP:0002664', (214, 221))	('cancers', 'Disease', (214, 221))	('cancers', 'Phenotype', 'HP:0002664', (133, 140))	('cancer', 'Disease', (133, 139))	('cancers', 'Disease', (133, 140))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('cancer', 'Disease', 'MESH:D009369', (214, 220))	('cancer', 'Disease', (99, 105))	('fusions', 'Var', (158, 165))	('primary tumors', 'Disease', (250, 264))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
298099	32160708	We also identified a high frequency of chromosome Y genes in non-canonical fusions in lung squamous cell carcinoma.	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (86, 114))	('chromosome Y genes', 'Gene', (39, 57))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (86, 114))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (91, 114))	('lung squamous cell carcinoma', 'Disease', (86, 114))	('non-canonical fusions', 'Var', (61, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))
298102	32160708	Hierarchical clustering analysis of recurrent canonical or non-canonical fusions in CCLE revealed different patterns, except for some cancers of squamous origin (ESCA and HNSC), which clustered together in both groups (Figures S10A, S10B, S11A, and S11B).	('S10A', 'SUBSTITUTION', 'None', (227, 231))	('S10B', 'SUBSTITUTION', 'None', (233, 237))	('S11A', 'SUBSTITUTION', 'None', (239, 243))	('cancers', 'Disease', 'MESH:D009369', (134, 141))	('S10A', 'Var', (227, 231))	('S10B', 'Var', (233, 237))	('cancers', 'Phenotype', 'HP:0002664', (134, 141))	('cancers', 'Disease', (134, 141))	('S11A', 'Var', (239, 243))	('S11B', 'SUBSTITUTION', 'None', (249, 253))	('S11B', 'Var', (249, 253))	('CCLE', 'Chemical', '-', (84, 88))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
298104	32160708	The pool of recurrent fusions identified from CCLE samples was vastly different from those identified in TCGA tumors, with minimal overlap (Figures S12A and S12B).	('S12B', 'SUBSTITUTION', 'None', (157, 161))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('CCLE', 'Disease', (46, 50))	('tumors', 'Disease', (110, 116))	('tumors', 'Disease', 'MESH:D009369', (110, 116))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('CCLE', 'Chemical', '-', (46, 50))	('S12A', 'Var', (148, 152))	('S12B', 'Var', (157, 161))	('S12A', 'SUBSTITUTION', 'None', (148, 152))
298105	32160708	Of the common fusions identified between the two groups, canonical fusions were found to be more common (9%) than non-canonical fusions (2%) (Table S18).	('canonical', 'Var', (57, 66))	('S18', 'Gene', '6222', (148, 151))	('S18', 'Gene', (148, 151))
298106	32160708	Hierarchical clustering analysis of recurrent fusions identified in CCLE and TCGA also revealed separate clusters for primary tumor and cell lines for both canonical and non-canonical fusions, indicating that fusions in cell lines are vastly different from the primary tumors (Figures 5A-5D).	('tumor', 'Disease', 'MESH:D009369', (269, 274))	('tumor', 'Phenotype', 'HP:0002664', (269, 274))	('primary tumors', 'Disease', (261, 275))	('fusions', 'Var', (46, 53))	('tumors', 'Phenotype', 'HP:0002664', (269, 275))	('tumor', 'Disease', (269, 274))	('TCGA', 'Gene', (77, 81))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('CCLE', 'Gene', (68, 72))	('primary tumors', 'Disease', 'MESH:D001932', (261, 275))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('CCLE', 'Chemical', '-', (68, 72))	('tumor', 'Disease', (126, 131))
298110	32160708	In contrast to other cancers, breast cancer also had a high frequency of recurrent non-canonical fusions that were common between CCLE and TCGA samples.	('non-canonical fusions', 'Var', (83, 104))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('breast cancer', 'Disease', 'MESH:D001943', (30, 43))	('breast cancer', 'Phenotype', 'HP:0003002', (30, 43))	('breast cancer', 'Disease', (30, 43))	('cancers', 'Disease', 'MESH:D009369', (21, 28))	('cancers', 'Phenotype', 'HP:0002664', (21, 28))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('cancers', 'Disease', (21, 28))	('CCLE', 'Chemical', '-', (130, 134))
298112	32160708	Most of the reported fusions in TCGA that are also common between cell lines and TCGA primary tumors were non-recurrent canonical fusions.	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('primary tumors', 'Disease', (86, 100))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('primary tumors', 'Disease', 'MESH:D001932', (86, 100))	('fusions', 'Var', (21, 28))	('TCGA', 'Disease', (32, 36))
298117	32160708	Among the samples screened for structural variations using BreakDancer, inter-chromosomal translocations (CTXs) and insertions (INSs) were relatively rare compared to other structural variations within a cancer (Table S20).	('cancer', 'Disease', (204, 210))	('cancer', 'Disease', 'MESH:D009369', (204, 210))	('insertions', 'Var', (116, 126))	('S20', 'Gene', (218, 221))	('S20', 'Gene', '6224', (218, 221))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))
298118	32160708	Breast cancer displayed the highest percentage of both intra-chromosomal translocations (ITXs) and inversions (INVs), accounting for the majority of non-canonical fusions identified in these samples.	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('Breast cancer', 'Phenotype', 'HP:0003002', (0, 13))	('Breast cancer', 'Disease', 'MESH:D001943', (0, 13))	('intra-chromosomal', 'Var', (55, 72))	('inversions', 'Var', (99, 109))	('Breast cancer', 'Disease', (0, 13))
298124	32160708	We were also able to validate the existence of non-canonical fusions (at least one partner in antisense orientation: GBA-MTX1, DNHD1-RRP8, PRDM4-PWP1, RPL39L-ST6GAL1, BOP1-MROH1, SPDYE3-UPK3B) in CCLE cell lines, indicating that ChimeRScope can accurately predict fusions containing antisense genes along with canonical fusions (Figure S15).	('RRP8', 'Gene', '23378', (133, 137))	('BOP1', 'Gene', (167, 171))	('RRP8', 'Gene', (133, 137))	('RPL39L', 'Gene', '116832', (151, 157))	('ST6GAL1', 'Gene', '6480', (158, 165))	('MTX1', 'Gene', (121, 125))	('ST6GAL1', 'Gene', (158, 165))	('S15', 'Gene', '2202', (336, 339))	('UPK3B', 'Gene', (186, 191))	('UPK3B', 'Gene', '80761', (186, 191))	('PRDM4', 'Gene', '11108', (139, 144))	('BOP1', 'Gene', '23246', (167, 171))	('GBA', 'Gene', (117, 120))	('PRDM4', 'Gene', (139, 144))	('MROH1', 'Gene', '727957', (172, 177))	('MTX1', 'Gene', '4580', (121, 125))	('S15', 'Gene', (336, 339))	('CCLE', 'Chemical', '-', (196, 200))	('DNHD1', 'Gene', '144132', (127, 132))	('MROH1', 'Gene', (172, 177))	('GBA', 'Gene', '2629', (117, 120))	('SPDYE3', 'Gene', (179, 185))	('RPL39L', 'Gene', (151, 157))	('fusions', 'Var', (264, 271))	('SPDYE3', 'Gene', '441272', (179, 185))	('PWP1', 'Gene', (145, 149))	('PWP1', 'Gene', '11137', (145, 149))	('antisense genes', 'Var', (283, 298))	('DNHD1', 'Gene', (127, 132))
298126	32160708	Within these recurrent fusions, non-canonical fusions were more prevalent than canonical fusions in this cancer (Table S1).	('cancer', 'Disease', (105, 111))	('non-canonical fusions', 'Var', (32, 53))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('prevalent', 'Reg', (64, 73))
298131	32160708	Mutual exclusivity of mutations and fusions was recently identified as an important driver of genes in cancer.	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('mutations', 'Var', (22, 31))
298133	32160708	TP53 mutations were found to be significantly lower in the samples with high fusion category (23%) when compared to low fusion samples (51%, adjusted p = 0.01) (Figure 7).	('TP53', 'Gene', '7157', (0, 4))	('lower', 'NegReg', (46, 51))	('TP53', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))
298135	32160708	We limited our analysis only to fusion transcripts that were recurrent (n >= 2) either within or across cancers and generated a catalog of frequent high-confidence fusions across pan-cancer primary tumor and cell line samples.	('cancer', 'Disease', (183, 189))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('fusions', 'Var', (164, 171))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('cancers', 'Phenotype', 'HP:0002664', (104, 111))	('tumor', 'Disease', (198, 203))	('cancer', 'Disease', (104, 110))	('cancers', 'Disease', (104, 111))	('cancers', 'Disease', 'MESH:D009369', (104, 111))	('cancer', 'Disease', 'MESH:D009369', (183, 189))
298137	32160708	ChimeRScope also detected fusions in several of the normal samples, which is consistent with a recent report that fusions are also common in non-tumor cells.	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('fusions', 'Var', (26, 33))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumor', 'Disease', (145, 150))	('detected', 'Reg', (17, 25))
298142	32160708	This observation is consistent with earlier reports that suggest breast cancer harbors a large number of structural variations compared to other cancers, specifically intrachromosomal translocations and inversions being the most common types.	('cancers', 'Disease', (145, 152))	('cancers', 'Phenotype', 'HP:0002664', (145, 152))	('breast cancer', 'Disease', 'MESH:D001943', (65, 78))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('breast cancer', 'Disease', (65, 78))	('cancers', 'Disease', 'MESH:D009369', (145, 152))	('breast cancer', 'Phenotype', 'HP:0003002', (65, 78))	('intrachromosomal', 'Var', (167, 183))	('inversions', 'Var', (203, 213))
298143	32160708	We also detected a high incidence of inversions and intrachromosomal variations in the BRCA-WGS data, which supports a large number of non-canonical fusions identified in breast cancer compared to other cancers (Table S20).	('breast cancer', 'Disease', 'MESH:D001943', (171, 184))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('breast cancer', 'Disease', (171, 184))	('BRCA', 'Gene', '672', (87, 91))	('S20', 'Gene', (218, 221))	('inversions', 'Var', (37, 47))	('breast cancer', 'Phenotype', 'HP:0003002', (171, 184))	('S20', 'Gene', '6224', (218, 221))	('BRCA', 'Gene', (87, 91))	('cancers', 'Phenotype', 'HP:0002664', (203, 210))	('intrachromosomal variations', 'Var', (52, 79))	('cancers', 'Disease', 'MESH:D009369', (203, 210))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('cancers', 'Disease', (203, 210))
298144	32160708	A recent report on the transcriptional costs of structural variation in breast cancer identified the presence of genes in opposite transcriptional orientation resulting in stable antisense transcription.	('antisense transcription', 'MPA', (179, 202))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('structural variation', 'Var', (48, 68))	('breast cancer', 'Disease', 'MESH:D001943', (72, 85))	('breast cancer', 'Disease', (72, 85))	('breast cancer', 'Phenotype', 'HP:0003002', (72, 85))
298147	32160708	The pervasive expression of antisense transcripts has been reported in many cancers, which accounts for about 38% of the annotated transcripts.	('cancers', 'Disease', 'MESH:D009369', (76, 83))	('cancers', 'Phenotype', 'HP:0002664', (76, 83))	('reported', 'Reg', (59, 67))	('antisense transcripts', 'Var', (28, 49))	('cancers', 'Disease', (76, 83))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))
298151	32160708	Nevertheless, BreakDancer was selected as a structural variation detection tool for validation because this tool was able to detect more translocations, deletions, and inversions compared to other popular tools, such as SVDetect, DELLY, and Meerkat.	('translocations', 'Var', (137, 151))	('Meerkat', 'Species', '37032', (241, 248))	('deletions', 'Var', (153, 162))	('inversions', 'Var', (168, 178))
298156	32160708	We also identified several transcriptional read-through fusions that are recurrent in various cancers.	('cancers', 'Disease', 'MESH:D009369', (94, 101))	('fusions', 'Var', (56, 63))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('cancers', 'Phenotype', 'HP:0002664', (94, 101))	('cancers', 'Disease', (94, 101))
298162	32160708	Our data reconfirm the previous observation that thyroid cancer is one of the cancers that have the highest percentage of recurrent kinase fusions.	('thyroid cancer', 'Phenotype', 'HP:0002890', (49, 63))	('thyroid cancer', 'Disease', (49, 63))	('kinase fusions', 'Var', (132, 146))	('thyroid cancer', 'Disease', 'MESH:D013964', (49, 63))	('fusions', 'Var', (139, 146))	('cancers', 'Disease', 'MESH:D009369', (78, 85))	('cancers', 'Phenotype', 'HP:0002664', (78, 85))	('cancers', 'Disease', (78, 85))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))
298166	32160708	Understanding the possible involvement of SMG1 fusions in the accumulation of non-canonical fusions containing antisense transcripts requires further investigation.	('SMG1', 'Gene', '23049', (42, 46))	('fusions', 'Var', (47, 54))	('SMG1', 'Gene', (42, 46))
298169	32160708	It is also interesting that most of the recurrent fusions (78%) were recurrent only within breast cancer and are not found in other TCGA cancer samples (Table S2).	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('breast cancer', 'Disease', (91, 104))	('breast cancer', 'Phenotype', 'HP:0003002', (91, 104))	('fusions', 'Var', (50, 57))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('cancer', 'Disease', (137, 143))	('cancer', 'Disease', (98, 104))	('breast cancer', 'Disease', 'MESH:D001943', (91, 104))
298171	32160708	In addition, TP53 mutations were almost doubled in patients with low fusions, indicating that mutations on major oncogenes might be mutually exclusive with fusions.	('TP53', 'Gene', (13, 17))	('low fusions', 'Var', (65, 76))	('patients', 'Species', '9606', (51, 59))	('TP53', 'Gene', '7157', (13, 17))	('doubled', 'PosReg', (40, 47))	('mutations', 'Var', (18, 27))
298172	32160708	A recent study also found that fusions and mutations in driver genes are mutually exclusive across cancer types in TGCA.	('TGCA', 'Disease', (115, 119))	('cancer type', 'Disease', 'MESH:D009369', (99, 110))	('cancer type', 'Disease', (99, 110))	('fusions', 'Var', (31, 38))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
298173	32160708	Analysis of fusions in 802 tumor-derived cell lines from CCLE using ChimeRScope revealed a high frequency of recurrent fusions across several cell lines irrespective of the tissue of origin.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumor', 'Disease', (27, 32))	('fusions', 'Var', (119, 126))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('CCLE', 'Chemical', '-', (57, 61))
298174	32160708	Several reports, including a recent study on recurrent fusions across multiple cancer types, also identified fusions that were frequent across cell lines, but the mechanism behind this phenomenon is unexplored.	('cancer type', 'Disease', 'MESH:D009369', (79, 90))	('cancer type', 'Disease', (79, 90))	('fusions', 'Var', (109, 116))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))
298176	32160708	We were able to identify only 150 (including both canonical and non-canonical) recurrent fusions that were common between TCGA and CCLE.	('TCGA', 'Disease', (122, 126))	('fusions', 'Var', (89, 96))	('CCLE', 'Disease', (131, 135))	('CCLE', 'Chemical', '-', (131, 135))
298179	32160708	Most of these studies have compared gene expression profiles, copy number variations, and mutation profiles but have not investigated the differences in fusion profiles among the primary tumor and tumor-derived cell lines.	('gene expression', 'MPA', (36, 51))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('tumor', 'Disease', (187, 192))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('tumor', 'Disease', (197, 202))	('copy number variations', 'Var', (62, 84))
298182	32160708	Our analysis using ChimeRScope identified several recurrent fusion transcripts that are common across cancers, reemphasizing the need for identifying therapy focused on actionable targets.	('fusion', 'Var', (60, 66))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('cancers', 'Disease', 'MESH:D009369', (102, 109))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))	('cancers', 'Disease', (102, 109))
298221	32160708	Gene set enrichment analysis (GSEA) was used to identify enriched upregulated and downregulated pathways among the high and low fusion groups.	('high', 'Var', (115, 119))	('downregulated', 'NegReg', (82, 95))	('upregulated', 'PosReg', (66, 77))	('low', 'NegReg', (124, 127))	('GSEA', 'Chemical', '-', (30, 34))
298272	31170090	It was shown that proliferative rate of CAL27 and FADU cells treated with RHCG-shRNA was remarkably increased compared with negative control, while overexpression of RHCG in JHU011 cells showed the opposite effect (Figure 5D).	('RHCG-shRNA', 'Var', (74, 84))	('CAL27', 'CellLine', 'CVCL:1107', (40, 45))	('increased', 'PosReg', (100, 109))	('proliferative rate', 'CPA', (18, 36))
298273	31170090	Consistent with the results of CCK-8 assays and EdU assays, colony formation assay showed that knockdown of RHCG could promote HNSCC cell proliferation, whereas overexpression of RHCG promoted cell proliferation (Figure 5E).	('EdU', 'Chemical', '-', (48, 51))	('promote', 'PosReg', (119, 126))	('CCK-8', 'Chemical', '-', (31, 36))	('knockdown', 'Var', (95, 104))	('HNSCC cell proliferation', 'CPA', (127, 151))	('RHCG', 'Gene', (108, 112))	('HNSCC', 'Phenotype', 'HP:0012288', (127, 132))
298275	31170090	At 14 days post-injection, the volumes of tumors established in the RHCG-knockdown group (CAL27 and FADU) were dramatically bigger than those in the control group.	('RHCG-knockdown', 'Gene', (68, 82))	('CAL27', 'CellLine', 'CVCL:1107', (90, 95))	('tumors', 'Disease', 'MESH:D009369', (42, 48))	('tumors', 'Disease', (42, 48))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('RHCG-knockdown', 'Var', (68, 82))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('bigger', 'PosReg', (124, 130))
298277	31170090	Since DNA promoter hypermethylation is commonly implicated in inactivation of tumor suppressor genes in cancers, we then investigated whether the RHCG promoter hypermethylation may impair RHCG expression in HNSCC.	('RHCG', 'Gene', (188, 192))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('impair', 'NegReg', (181, 187))	('HNSCC', 'Phenotype', 'HP:0012288', (207, 212))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('HNSCC', 'Disease', (207, 212))	('hypermethylation', 'Var', (160, 176))	('cancers', 'Phenotype', 'HP:0002664', (104, 111))	('tumor', 'Disease', (78, 83))	('RHCG', 'Gene', (146, 150))	('expression', 'MPA', (193, 203))	('cancers', 'Disease', (104, 111))	('cancers', 'Disease', 'MESH:D009369', (104, 111))
298279	31170090	To determine the prognostic potential of RHCG methylation, the survival curve of 299 HNSCC patients stratified by RHCG methylation level was plotted, it was evident that patients with RHCG hypermethylation had a significantly shorter overall survival time compared with patients with RHCG hypomethylation (p=0.046) (Figure 7I).	('patients', 'Species', '9606', (170, 178))	('hypermethylation', 'Var', (189, 205))	('shorter', 'NegReg', (226, 233))	('patients', 'Species', '9606', (91, 99))	('patients', 'Species', '9606', (270, 278))	('RHCG hypermethylation', 'Var', (184, 205))	('HNSCC', 'Phenotype', 'HP:0012288', (85, 90))	('overall survival', 'MPA', (234, 250))
298280	31170090	Furthermore, patients with RHCG hypermethylation and RHCG low expression demonstrated a significantly shorter overall survival compared to those with RHCG hypomethylation and RHCG high expression (p = 0.012) (Figure 7J).	('overall survival', 'MPA', (110, 126))	('shorter', 'NegReg', (102, 109))	('RHCG', 'Gene', (53, 57))	('patients', 'Species', '9606', (13, 21))	('low', 'NegReg', (58, 61))	('hypermethylation', 'Var', (32, 48))
298281	31170090	By combining RHCG methylation level and RHCG expression level, it exhibited a much better prognostic capacity to distinguish patients with poor prognosis from those with good prognosis.	('expression', 'MPA', (45, 55))	('methylation', 'Var', (18, 29))	('patients', 'Species', '9606', (125, 133))
298292	31170090	RHCG silencing in HNSCC cell lines CAL27 and FADU could effectively promote cell viability, colony formation and cell migration and tumor formation in nude mice, while ectopic expression of RHCG in JHU011 cells could suppress these functions, which was in consistence with previous studies.	('CAL27', 'CellLine', 'CVCL:1107', (35, 40))	('HNSCC', 'Phenotype', 'HP:0012288', (18, 23))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('promote', 'PosReg', (68, 75))	('colony formation', 'CPA', (92, 108))	('silencing', 'Var', (5, 14))	('cell viability', 'CPA', (76, 90))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('RHCG', 'Gene', (0, 4))	('tumor', 'Disease', (132, 137))	('cell migration', 'CPA', (113, 127))	('nude mice', 'Species', '10090', (151, 160))
298294	31170090	Ming et al reported that RHCG could suppress the tumorigenicity and metastasis of esophageal squamous cell carcinoma via inhibiting NF-kappaB signaling and MMP1 expression; Wang et al discovered that RHCG might suppress cervical cancer progression through inducing apoptosis regulated by TGF-beta1.	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('TGF-beta1', 'Gene', (288, 297))	('NF-kappaB signaling', 'MPA', (132, 151))	('cervical cancer', 'Disease', 'MESH:D002583', (220, 235))	('inhibiting', 'NegReg', (121, 131))	('cervical cancer', 'Disease', (220, 235))	('metastasis of esophageal squamous cell carcinoma', 'Disease', (68, 116))	('TGF-beta1', 'Gene', '7040', (288, 297))	('inducing', 'PosReg', (256, 264))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (93, 116))	('tumor', 'Disease', (49, 54))	('RHCG', 'Var', (200, 204))	('MMP1', 'Gene', '4312', (156, 160))	('apoptosis', 'CPA', (265, 274))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('metastasis of esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (68, 116))	('MMP1', 'Gene', (156, 160))	('suppress', 'NegReg', (211, 219))	('suppress', 'NegReg', (36, 44))
298296	31170090	Downregulation of tumor suppressor genes is commonly observed in cancers, which is often caused by promoter hypermethylation, histone deacetylation, dysregulation by transcription factors and posttranscriptional silencing by microRNAs.	('promoter', 'MPA', (99, 107))	('dysregulation', 'MPA', (149, 162))	('tumor', 'Disease', (18, 23))	('Downregulation', 'NegReg', (0, 14))	('deacetylation', 'NegReg', (134, 147))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('cancers', 'Disease', 'MESH:D009369', (65, 72))	('cancers', 'Phenotype', 'HP:0002664', (65, 72))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('cancers', 'Disease', (65, 72))	('posttranscriptional silencing', 'Var', (192, 221))	('histone', 'MPA', (126, 133))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
298327	31170090	The following primary antibodies were used to detect proteins: rabbit anti-RHCG (1:1000; Proteintech, Wuhan, China) and anti-beta-actin (1:4000; Proteintech, Wuhan, China).	('beta-actin', 'Gene', '728378', (125, 135))	('1:4000', 'Var', (137, 143))	('beta-actin', 'Gene', (125, 135))	('rabbit', 'Species', '9986', (63, 69))
298361	30584540	Taken together, these findings show that altered expression of miRNAs could be used as biomarkers for HNSCC diagnosis in the high altitude mestizo Ecuadorian population.	('altered', 'Var', (41, 48))	('expression', 'MPA', (49, 59))	('miR', 'Gene', (63, 66))	('HNSCC', 'Disease', (102, 107))	('HNSCC', 'Phenotype', 'HP:0012288', (102, 107))	('miR', 'Gene', '29116', (63, 66))
298491	30584540	In addition, when miR-31 is deregulated in different types of cancer, including head and neck cancer, the hypoxia-inducible factor (HIF) is activated, promoting tumor angiogenesis.	('promoting', 'PosReg', (151, 160))	('hypoxia', 'Disease', (106, 113))	('miR-31', 'Gene', (18, 24))	('activated', 'PosReg', (140, 149))	('deregulated', 'Var', (28, 39))	('tumor', 'Disease', (161, 166))	('hypoxia', 'Disease', 'MESH:D000860', (106, 113))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('cancer', 'Disease', (62, 68))	('miR-31', 'Gene', '407035', (18, 24))	('cancer', 'Disease', (94, 100))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('neck cancer', 'Disease', 'MESH:D006258', (89, 100))	('neck cancer', 'Disease', (89, 100))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('head and neck cancer', 'Phenotype', 'HP:0012288', (80, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
298509	32764454	Thus, manipulation of key entry genes of this virus especially in lung cancer patients could be one of the best approaches to manage SARS-CoV-2 infection in this group of patients.	('SARS-CoV-2 infection', 'Disease', (133, 153))	('lung cancer', 'Disease', (66, 77))	('patients', 'Species', '9606', (78, 86))	('lung cancer', 'Phenotype', 'HP:0100526', (66, 77))	('patients', 'Species', '9606', (171, 179))	('SARS-CoV-2 infection', 'Disease', 'MESH:C000657245', (133, 153))	('manipulation', 'Var', (6, 18))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('lung cancer', 'Disease', 'MESH:D008175', (66, 77))
298558	32764454	Studies using the Xenopus oocyte expression system revealed that TMPRSS2 expression reduced both the epithelial sodium channel and protein levels.	('S', 'Gene', '43740568', (69, 70))	('Xenopus', 'Species', '8355', (18, 25))	('expression', 'Var', (73, 83))	('S', 'Gene', '43740568', (70, 71))	('sodium', 'Chemical', 'MESH:D012964', (112, 118))	('reduced', 'NegReg', (84, 91))	('S', 'Gene', '43740568', (0, 1))
298566	32764454	Collectively, these studies unequivocally establish the conceptual framework that ACE-2 is a central player in normal pulmonary function, and its imbalance leads to pulmonary diseases.	('imbalance', 'Var', (146, 155))	('imbalance', 'Phenotype', 'HP:0002172', (146, 155))	('pulmonary diseases', 'Disease', (165, 183))	('pulmonary diseases', 'Disease', 'MESH:D008171', (165, 183))	('leads to', 'Reg', (156, 164))
298569	32764454	In parallel, the expression of TMPRSS2 along with human airway trypsin-like protease (HAT) in the human lung is demonstrated to support spread of the human influenza virus.	('spread', 'MPA', (136, 142))	('human', 'Species', '9606', (150, 155))	('support', 'Reg', (128, 135))	('TMPRSS2', 'Gene', (31, 38))	('HAT', 'Gene', '9407', (86, 89))	('trypsin-like protease', 'Gene', (63, 84))	('expression', 'Var', (17, 27))	('trypsin-like protease', 'Gene', '11012', (63, 84))	('influenza virus', 'Species', '11308', (156, 171))	('human', 'Species', '9606', (50, 55))	('human', 'Species', '9606', (98, 103))	('HAT', 'Gene', (86, 89))
298574	32764454	Another study showed that TMPRSS2 depletion resulted in frailer, or delayed, inflammatory chemokine and cytokine responses mediated by Toll-like receptor 3 (TLR3).	('Toll-like receptor 3', 'Gene', (135, 155))	('delayed', 'NegReg', (68, 75))	('TMPRSS2', 'Gene', (26, 33))	('Toll-like receptor 3', 'Gene', '7098', (135, 155))	('depletion', 'Var', (34, 43))	('frailer', 'CPA', (56, 63))
298599	32764454	Another residue, R797 is also vital for S protein activation by TMPRSS2 and is often cleaved during viral entry.	('S', 'Gene', '43740568', (69, 70))	('R797', 'Var', (17, 21))	('activation', 'PosReg', (50, 60))	('S', 'Gene', '43740568', (40, 41))	('S', 'Gene', '43740568', (68, 69))
298622	32764454	ACE-2/Ang (1-7) axis overexpression has also been reported to inhibit cell proliferation in pancreatic cancer cell lines, BxPC3 and SW1990, reduce epithelial-mesenchymal transition (EMT) and inhibits the migration and invasion of non-small cell lung cancer (NSCLC) cells, A549.	('epithelial-mesenchymal transition', 'CPA', (147, 180))	('A549', 'CellLine', 'CVCL:0023', (272, 276))	('SCLC', 'Phenotype', 'HP:0030357', (259, 263))	('inhibit', 'NegReg', (62, 69))	('pancreatic cancer', 'Disease', 'MESH:D010190', (92, 109))	('lung cancer', 'Disease', (245, 256))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('NSCLC', 'Disease', 'MESH:D002289', (258, 263))	('migration', 'CPA', (204, 213))	('reduce', 'NegReg', (140, 146))	('invasion', 'CPA', (218, 226))	('pancreatic cancer', 'Disease', (92, 109))	('SW1990', 'CellLine', 'CVCL:1723', (132, 138))	('NSCLC', 'Disease', (258, 263))	('lung cancer', 'Disease', 'MESH:D008175', (245, 256))	('cell proliferation', 'CPA', (70, 88))	('NSCLC', 'Phenotype', 'HP:0030358', (258, 263))	('BxPC3', 'CellLine', 'CVCL:0186', (122, 127))	('lung cancer', 'Phenotype', 'HP:0100526', (245, 256))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (230, 256))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (92, 109))	('inhibits', 'NegReg', (191, 199))	('SW1990', 'Var', (132, 138))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (234, 256))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))
298623	32764454	A recent study reported that downregulation of the ACE-2 axis promotes breast cancer cell metastasis via increased calcium signaling.	('breast cancer', 'Disease', (71, 84))	('breast cancer', 'Phenotype', 'HP:0003002', (71, 84))	('calcium signaling', 'MPA', (115, 132))	('calcium', 'Chemical', 'MESH:D002118', (115, 122))	('promotes', 'PosReg', (62, 70))	('downregulation', 'Var', (29, 43))	('increased', 'PosReg', (105, 114))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('breast cancer', 'Disease', 'MESH:D001943', (71, 84))
298632	32764454	Gene fusion between TMPRSS2 and members of the E26 transformation specific (ETS) transcription factor family (ERG or ETV) is another mechanism by which TMPRSS2 plays a role in prostate cancer progression.	('ERG', 'Gene', '2078', (110, 113))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('prostate cancer', 'Disease', 'MESH:D011471', (176, 191))	('S', 'Gene', '43740568', (156, 157))	('ERG', 'Gene', (110, 113))	('S', 'Gene', '43740568', (78, 79))	('S', 'Gene', '43740568', (157, 158))	('plays', 'Reg', (160, 165))	('prostate cancer', 'Phenotype', 'HP:0012125', (176, 191))	('S', 'Gene', '43740568', (24, 25))	('S', 'Gene', '43740568', (25, 26))	('Gene fusion', 'Var', (0, 11))	('prostate cancer', 'Disease', (176, 191))
298635	32764454	Molecular research demonstrated dysregulated ERG expression to disrupt normal androgen receptor signaling and trigger epigenetic pathways, thus promoting tumorigenesis.	('androgen receptor', 'Gene', '367', (78, 95))	('ERG', 'Gene', '2078', (45, 48))	('ERG', 'Gene', (45, 48))	('disrupt', 'NegReg', (63, 70))	('dysregulated', 'Var', (32, 44))	('epigenetic pathways', 'Pathway', (118, 137))	('androgen receptor', 'Gene', (78, 95))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('trigger', 'Reg', (110, 117))	('promoting', 'PosReg', (144, 153))	('expression', 'Var', (49, 59))	('tumor', 'Disease', (154, 159))
298664	32764454	Nonetheless, modulation of ACE-2 in patients already infected by SARS-CoV-2 may be an effective therapeutic option in addressing the viral-mediated RAS imbalance and is currently under investigation in several clinical trials.	('SARS-CoV-2', 'Species', '2697049', (65, 75))	('S', 'Gene', '43740568', (65, 66))	('infected', 'Disease', (53, 61))	('patients', 'Species', '9606', (36, 44))	('imbalance', 'Phenotype', 'HP:0002172', (152, 161))	('N', 'Chemical', 'MESH:D009584', (0, 1))	('S', 'Gene', '43740568', (150, 151))	('infected', 'Disease', 'MESH:D007239', (53, 61))	('S', 'Gene', '43740568', (68, 69))	('ACE-2', 'Gene', (27, 32))	('modulation', 'Var', (13, 23))
298669	32764454	While, AT1R inactivation with antagonists has successfully reduced tumor growth of cancers including gastric, colorectal, prostate, renal, breast, and NSCLCs.	('reduced', 'NegReg', (59, 66))	('AT1R', 'Gene', (7, 11))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('inactivation', 'Var', (12, 24))	('tumor', 'Disease', (67, 72))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('colorectal', 'Disease', 'MESH:D015179', (110, 120))	('breast', 'Disease', (139, 145))	('NSCLC', 'Phenotype', 'HP:0030358', (151, 156))	('NSCLCs', 'Disease', (151, 157))	('colorectal', 'Disease', (110, 120))	('cancers', 'Disease', 'MESH:D009369', (83, 90))	('SCLC', 'Phenotype', 'HP:0030357', (152, 156))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('AT1R', 'Gene', '185', (7, 11))	('NSCLCs', 'Disease', 'MESH:D002289', (151, 157))	('prostate', 'Disease', (122, 130))	('renal', 'Disease', (132, 137))	('gastric', 'Disease', (101, 108))	('cancers', 'Phenotype', 'HP:0002664', (83, 90))	('cancers', 'Disease', (83, 90))
298678	32764454	It is known that if the RBD-Fc fusion attaches to human cells, the cytotoxicity of Fc domain will be eliminated by introducing mutations to disable Fc receptor binding.	('cytotoxicity', 'Disease', (67, 79))	('Fc receptor', 'Protein', (148, 159))	('cytotoxicity', 'Disease', 'MESH:D064420', (67, 79))	('binding', 'Interaction', (160, 167))	('mutations', 'Var', (127, 136))	('human', 'Species', '9606', (50, 55))	('disable', 'NegReg', (140, 147))
298688	32764454	Previous studies have shown that fusion of human IgG1 to an ACE-2 extracellular domain was successful in neutralizing SARS-coronavirus in-vitro.	('IgG1', 'Protein', (49, 53))	('human', 'Species', '9606', (43, 48))	('SARS-coronavirus', 'Protein', (118, 134))	('fusion', 'Var', (33, 39))	('neutralizing', 'MPA', (105, 117))	('SARS-coronavirus', 'Species', '694009', (118, 134))
298689	32764454	This study also offers proof that ACE-2-Fc could likewise inhibit SARS-CoV-2 in-vitro and possibly in patients.	('SARS-CoV-2', 'Species', '2697049', (66, 76))	('ACE-2-Fc', 'Var', (34, 42))	('patients', 'Species', '9606', (102, 110))	('SARS-CoV-2', 'Protein', (66, 76))	('inhibit', 'NegReg', (58, 65))
298714	32764454	On the other hand, developing in-vitro and in-vivo models including conditional double transgenic/knockout of ACE-2 and TMPRSS2 could be one of best models to understand to role of these genes in the infection process which also can help to develop new therapies based on the shutdown of one or both of these genes.	('ACE-2', 'Gene', (110, 115))	('TMPRSS2', 'Gene', (120, 127))	('transgenic/knockout', 'Var', (87, 106))	('infection', 'Disease', (200, 209))	('infection', 'Disease', 'MESH:D007239', (200, 209))
298722	30042205	Treatment with anti-TIM-3 concurrently with anti-PD-L1 and RT led to significant tumor growth delay, enhanced T-cell cytotoxicity, decreased Tregs, and improved survival in orthotopic models of HNSCC.	('T-cell cytotoxicity', 'Disease', (110, 129))	('tumor growth delay', 'Disease', 'MESH:D006130', (81, 99))	('survival', 'CPA', (161, 169))	('TIM-3', 'Gene', '171285', (20, 25))	('HNSCC', 'Phenotype', 'HP:0012288', (194, 199))	('decreased', 'NegReg', (131, 140))	('HNSCC', 'Disease', (194, 199))	('improved', 'PosReg', (152, 160))	('Tregs', 'CPA', (141, 146))	('enhanced', 'PosReg', (101, 109))	('tumor growth delay', 'Disease', (81, 99))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('anti-PD-L1', 'Var', (44, 54))	('growth delay', 'Phenotype', 'HP:0001510', (87, 99))	('T-cell cytotoxicity', 'Disease', 'MESH:D064420', (110, 129))	('TIM-3', 'Gene', (20, 25))
298737	30042205	Although the study showed a survival advantage in mice that received anti-PD-1 and anti-TIM-3 treatment, all mice died of increased tumor burden.	('survival advantage', 'CPA', (28, 46))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('anti-PD-1', 'Var', (69, 78))	('tumor', 'Disease', (132, 137))	('TIM-3', 'Gene', (88, 93))	('mice', 'Species', '10090', (50, 54))	('mice', 'Species', '10090', (109, 113))	('TIM-3', 'Gene', '171285', (88, 93))
298744	30042205	Treatment with anti-TIM-3 concurrently with anti-PD-L1 and RT led to a significant tumor growth delay, enhanced T-cell cytotoxicity, decreased Tregs, and improved survival.	('tumor growth delay', 'Disease', (83, 101))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('improved', 'PosReg', (154, 162))	('T-cell cytotoxicity', 'Disease', 'MESH:D064420', (112, 131))	('TIM-3', 'Gene', '171285', (20, 25))	('Tregs', 'CPA', (143, 148))	('T-cell cytotoxicity', 'Disease', (112, 131))	('tumor growth delay', 'Disease', 'MESH:D006130', (83, 101))	('growth delay', 'Phenotype', 'HP:0001510', (89, 101))	('enhanced', 'PosReg', (103, 111))	('anti-PD-L1', 'Var', (44, 54))	('survival', 'CPA', (163, 171))	('decreased', 'NegReg', (133, 142))	('TIM-3', 'Gene', (20, 25))
298756	30042205	Mice were randomized to receive IgG control (10 mg/kg; BioXcell), anti-PD-L1 (10 mg/kg; BioXcell,), anti-TIM-3 (10 mg/kg; BioX-Cell), anti-PD-L1+anti-TIM-3, RT+IgG, RT+anti-PD-L1, RT+anti-TIM-3, or RT+ anti-PD-L1+ anti-TIM-3.	('TIM-3', 'Gene', (188, 193))	('TIM-3', 'Gene', (219, 224))	('TIM-3', 'Gene', '171285', (105, 110))	('TIM-3', 'Gene', '171285', (150, 155))	('TIM-3', 'Gene', '171285', (188, 193))	('TIM-3', 'Gene', '171285', (219, 224))	('TIM-3', 'Gene', (105, 110))	('Mice', 'Species', '10090', (0, 4))	('RT+ anti-PD-L1+', 'Var', (198, 213))	('TIM-3', 'Gene', (150, 155))
298778	30042205	The following heavy-metal tagged antibodies were used: CD45-Y89, CD3e-Sm152, CD274-Eu153, CD152-Sm154, FoxP3-Gd158, CD366-Dy162, CD4-172Yb, CD8a-Nd146, CD11b-Nd148, CD278-Yb176, Intercalator Ir-191/Ir-193, and Cisplatin-Pt-195.	('Cisplatin-Pt-195', 'Chemical', 'MESH:D002945', (210, 226))	('CD4', 'Gene', (55, 58))	('CD3e', 'Gene', '12501', (65, 69))	('CD3', 'Gene', (116, 119))	('CD278-Yb176', 'Var', (165, 176))	('CD8', 'Gene', (140, 143))	('CD11b', 'Gene', (152, 157))	('CD152-Sm154', 'Var', (90, 101))	('CD45', 'Gene', '19264', (55, 59))	('CD3e', 'Gene', (65, 69))	('Nd148', 'Chemical', 'MESH:D009354', (158, 163))	('CD3', 'Gene', '12501', (116, 119))	('CD3', 'Gene', (65, 68))	('FoxP3', 'Gene', (103, 108))	('CD4', 'Gene', '12504', (55, 58))	('Nd146', 'Chemical', 'MESH:D009354', (145, 150))	('Ir', 'Chemical', 'MESH:D007495', (191, 193))	('CD45', 'Gene', (55, 59))	('CD274-Eu153', 'Var', (77, 88))	('CD8', 'Gene', '925', (140, 143))	('FoxP3', 'Gene', '20371', (103, 108))	('CD3', 'Gene', '12501', (65, 68))	('Eu153', 'Chemical', 'MESH:D005063', (83, 88))	('CD4', 'Gene', (129, 132))	('Ir', 'Chemical', 'MESH:D007495', (198, 200))	('CD11b', 'Gene', '16409', (152, 157))	('Ir-193', 'Chemical', 'MESH:D007495', (198, 204))	('CD4', 'Gene', '12504', (129, 132))
298779	30042205	Gating was performed on nucleated live cells (positive for Ir-191 and Ir-193 and negative for Pt-195).	('Ir-193', 'Var', (70, 76))	('Pt-195', 'Chemical', 'MESH:C499994', (94, 100))	('Ir', 'Chemical', 'MESH:D007495', (59, 61))	('Ir-191', 'Var', (59, 65))	('Ir', 'Chemical', 'MESH:D007495', (70, 72))	('Ir-193', 'Chemical', 'MESH:D007495', (70, 76))
298806	30042205	To elucidate mechanisms leading to tumor regrowth after RT + anti-PD-L1, we performed mass cytometry (CyTOF) on tumors harvested at early (1 week) and late (3 weeks) time points after treatment with appropriate controls at each time point (Fig.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('RT + anti-PD-L1', 'Var', (56, 71))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor', 'Disease', (35, 40))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumor', 'Disease', (112, 117))	('tumors', 'Disease', 'MESH:D009369', (112, 118))	('tumors', 'Disease', (112, 118))
298816	30042205	Of these Tregs, 50% were Ki67+ in control tumors, 80% were Ki67+ in early-phase RT+anti-PD-L1-treated tumors, and 99.9% were Ki67+ in late-phase RT anti-PD-L1-treated tumors (Fig.	('tumors', 'Disease', (102, 108))	('tumors', 'Disease', 'MESH:D009369', (102, 108))	('tumors', 'Disease', 'MESH:D009369', (167, 173))	('tumors', 'Disease', (42, 48))	('tumors', 'Disease', 'MESH:D009369', (42, 48))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('Ki67+', 'Var', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('Ki67+', 'Var', (25, 30))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumors', 'Disease', (167, 173))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('tumors', 'Phenotype', 'HP:0002664', (167, 173))	('Ki67+', 'Var', (125, 130))
298820	30042205	Taken together, our findings show transient activation of T cells in response to RT+anti-PD-L1 and rapid upregulation of the T-cell coinhibitory receptor, TIM-3.	('TIM-3', 'Gene', (155, 160))	('upregulation', 'PosReg', (105, 117))	('activation', 'PosReg', (44, 54))	('TIM-3', 'Gene', '171285', (155, 160))	('RT+anti-PD-L1', 'Var', (81, 94))
298834	30042205	We previously demonstrated that combination therapy with RT and anti-PD-L1 results in increased IFNgamma production by intratumoral CD4 and CD8 T cells compared with control tumors.	('increased', 'PosReg', (86, 95))	('CD8', 'Gene', (140, 143))	('tumor', 'Disease', (124, 129))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('tumor', 'Disease', 'MESH:D009369', (124, 129))	('tumors', 'Disease', (174, 180))	('CD4', 'Gene', (132, 135))	('rat', 'Species', '10116', (21, 24))	('IFNgamma', 'Gene', '15978', (96, 104))	('tumors', 'Disease', 'MESH:D009369', (174, 180))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('CD8', 'Gene', '925', (140, 143))	('CD4', 'Gene', '12504', (132, 135))	('IFNgamma', 'Gene', (96, 104))	('anti-PD-L1', 'Var', (64, 74))	('tumor', 'Disease', (174, 179))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('rat', 'Species', '10116', (122, 125))	('tumors', 'Phenotype', 'HP:0002664', (174, 180))
298835	30042205	Using flow cytometry, we analyzed T cells in LY2 tumors harvested 72 hours after administration of combined RT and anti-PD-L1 and anti-TIM-3 antibodies (Fig.	('LY2', 'Gene', (45, 48))	('anti-PD-L1', 'Var', (115, 125))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('TIM-3', 'Gene', (135, 140))	('rat', 'Species', '10116', (89, 92))	('tumors', 'Disease', (49, 55))	('tumors', 'Disease', 'MESH:D009369', (49, 55))	('LY2', 'Gene', '12525', (45, 48))	('TIM-3', 'Gene', '171285', (135, 140))
298837	30042205	Importantly, the addition of anti-TIM-3 to RT and anti-PD-L1 resulted in a significant increase in functional effector (CD44+IFNgamma+) CD8 and CD4 T cells compared with IgG and RT+IgG arms (Fig.	('CD4', 'Gene', (120, 123))	('CD4', 'Gene', (144, 147))	('IFNgamma', 'Gene', (125, 133))	('increase', 'PosReg', (87, 95))	('CD8', 'Gene', (136, 139))	('IFNgamma', 'Gene', '15978', (125, 133))	('CD4', 'Gene', '12504', (120, 123))	('CD44', 'Gene', '12505', (120, 124))	('CD4', 'Gene', '12504', (144, 147))	('CD44', 'Gene', (120, 124))	('TIM-3', 'Gene', '171285', (34, 39))	('anti-PD-L1', 'Var', (50, 60))	('CD8', 'Gene', '925', (136, 139))	('TIM-3', 'Gene', (34, 39))
298847	30042205	These findings showed that targeting TIM-3 in addition to PD-L1 can result in additional tumor growth delay and improved survival, but the response is not durable and alternative mechanisms of immune evasion are likely at play.	('growth delay', 'Phenotype', 'HP:0001510', (95, 107))	('tumor growth delay', 'Disease', 'MESH:D006130', (89, 107))	('survival', 'CPA', (121, 129))	('TIM-3', 'Gene', (37, 42))	('targeting', 'Var', (27, 36))	('tumor growth delay', 'Disease', (89, 107))	('improved', 'PosReg', (112, 120))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('TIM-3', 'Gene', '171285', (37, 42))
298852	30042205	Notably, the proportion of Ki67+ Tregs was >80% during early and late phases of response to RT+alphaPD-L1+alphaTIM3 (Fig.	('TIM3', 'Gene', '171285', (111, 115))	('TIM3', 'Gene', (111, 115))	('Ki67+', 'Var', (27, 32))
298856	30042205	In addition, an increase in the Treg chemokine, CCL20, was observed during the early phase of response to RT+anti-PD-L1 (3.52-fold increase) and which was further increased during the resistant phase of treatment (8.94-fold increase; Supplementary Fig.	('RT+anti-PD-L1', 'Var', (106, 119))	('CCL20', 'Gene', (48, 53))	('CCL20', 'Gene', '20297', (48, 53))	('increase', 'PosReg', (16, 24))
298865	30042205	To test this hypothesis, we treated mice with RT, anti-PD-L1, and anti-TIM-3 and used anti-CD25 treatment to deplete Treg populations, starting at the time point at which we found Tregs to be significantly decreased due to treatment (day 14).	('TIM-3', 'Gene', '171285', (71, 76))	('CD25', 'Gene', (91, 95))	('CD25', 'Gene', '16184', (91, 95))	('decreased', 'NegReg', (206, 215))	('Treg populations', 'CPA', (117, 133))	('anti-PD-L1', 'Var', (50, 60))	('Tregs', 'CPA', (180, 185))	('TIM-3', 'Gene', (71, 76))	('mice', 'Species', '10090', (36, 40))	('deplete', 'NegReg', (109, 116))
298886	30042205	This suggests that increased TIM-3 expression in the face of anti-PD-1/PD-L1 treatment could serve as a compensatory mechanism of T cell exhaustion.	('T cell exhaustion', 'Phenotype', 'HP:0005435', (130, 147))	('expression', 'MPA', (35, 45))	('increased', 'PosReg', (19, 28))	('TIM-3', 'Gene', (29, 34))	('anti-PD-1/PD-L1', 'Var', (61, 76))	('TIM-3', 'Gene', '171285', (29, 34))
298890	30042205	Thus, TIM-3 inhibition was not sufficient to eliminate Tregs, and their reemergence contributed to disease progression.	('reemergence', 'CPA', (72, 83))	('inhibition', 'Var', (12, 22))	('TIM-3', 'Gene', '171285', (6, 11))	('contributed to', 'Reg', (84, 98))	('Tregs', 'CPA', (55, 60))	('disease', 'Disease', (99, 106))	('TIM-3', 'Gene', (6, 11))
298891	30042205	Kim and colleagues demonstrated a durable response when TIM-3 inhibition was combined with stereotactic radiosurgery (SRS) and anti-PD-L1 in an orthotopic glioblastoma mouse model.	('mouse', 'Species', '10090', (168, 173))	('TIM-3', 'Gene', (56, 61))	('glioblastoma', 'Disease', (155, 167))	('rat', 'Species', '10116', (26, 29))	('glioblastoma', 'Disease', 'MESH:D005909', (155, 167))	('TIM-3', 'Gene', '171285', (56, 61))	('inhibition', 'NegReg', (62, 72))	('anti-PD-L1', 'Var', (127, 137))	('glioblastoma', 'Phenotype', 'HP:0012174', (155, 167))
298893	30042205	In our case, the combination of RT and dual checkpoint blockade reduced Tregs to 15%, but more than 80% of these Tregs were Ki67+, suggesting that local Tregs were undergoing extensive proliferation.	('reduced', 'NegReg', (64, 71))	('Ki67+', 'Var', (124, 129))	('Tregs', 'CPA', (72, 77))	('rat', 'Species', '10116', (192, 195))
298901	30042205	Ke and colleagues proposed a mechanism by which FoxP3 promoter demethylation leads to enhanced FoxP3 expression.	('FoxP3', 'Gene', (95, 100))	('FoxP3', 'Gene', '20371', (95, 100))	('FoxP3', 'Gene', (48, 53))	('FoxP3', 'Gene', '20371', (48, 53))	('enhanced', 'PosReg', (86, 94))	('demethylation', 'Var', (63, 76))	('expression', 'MPA', (101, 111))
298907	30042205	In addition to signaling mechanisms that promote Treg recruitment, we observed downregulation of several key IFNgamma signature-related genes including CXCL9, CXCL10, STAT1, and granzyme B. IFNgamma-related genes have been shown to negatively regulate the neogeneration of FoxP3+ Tregs through ROS-mediated apoptosis in the periphery, and their absence can promote Treg expansion.	('ROS-mediated apoptosis', 'CPA', (294, 316))	('absence', 'Var', (345, 352))	('FoxP3', 'Gene', (273, 278))	('IFNgamma', 'Gene', (109, 117))	('IFNgamma', 'Gene', (190, 198))	('rat', 'Species', '10116', (263, 266))	('CXCL10', 'Gene', '15945', (159, 165))	('granzyme B', 'Gene', '14939', (178, 188))	('STAT1', 'Gene', (167, 172))	('FoxP3', 'Gene', '20371', (273, 278))	('regulate', 'Reg', (243, 251))	('promote', 'PosReg', (357, 364))	('negatively', 'NegReg', (232, 242))	('CXCL9', 'Gene', '17329', (152, 157))	('neogeneration', 'CPA', (256, 269))	('Treg expansion', 'CPA', (365, 379))	('CXCL9', 'Gene', (152, 157))	('STAT1', 'Gene', '20846', (167, 172))	('CXCL10', 'Gene', (159, 165))	('IFNgamma', 'Gene', '15978', (109, 117))	('IFNgamma', 'Gene', '15978', (190, 198))	('granzyme B', 'Gene', (178, 188))
298911	30042205	TP53 mutations are present in 40% to 50% of HNSCCs tumors, and importantly, recent data suggest that TP53 loss-of-function mutations can lead to tumor immune evasion by inducing PD-L1 expression.	('HNSCCs tumors', 'Disease', 'MESH:C535575', (44, 57))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('loss-of-function', 'NegReg', (106, 122))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumor', 'Disease', (51, 56))	('inducing', 'PosReg', (169, 177))	('tumor', 'Disease', (145, 150))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('TP53', 'Gene', (101, 105))	('HNSCCs tumors', 'Disease', (44, 57))	('expression', 'MPA', (184, 194))	('PD-L1', 'Protein', (178, 183))	('HNSCC', 'Phenotype', 'HP:0012288', (44, 49))	('mutations', 'Var', (123, 132))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
298912	30042205	Interestingly, patients with TP53 mutations have been shown to have better response to immune therapies.	('patients', 'Species', '9606', (15, 23))	('TP53', 'Gene', (29, 33))	('mutations', 'Var', (34, 43))	('better', 'PosReg', (68, 74))
298980	30746793	LOC158602 is a gene with unknown function, but highly correlated with both PSMD10 and CMTX5.	('PSMD10', 'Gene', '5716', (75, 81))	('PSMD10', 'Gene', (75, 81))	('CMTX5', 'Gene', (86, 91))	('correlated', 'Reg', (54, 64))	('CMTX5', 'Gene', '5631', (86, 91))	('LOC158602', 'Var', (0, 9))
298983	30746793	Overexpression of DRG1 leads to chromosome missegregation and promotes tumor progression in NSCLC.	('NSCLC', 'Phenotype', 'HP:0030358', (92, 97))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('promotes', 'PosReg', (62, 70))	('DRG1', 'Gene', '4733', (18, 22))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('Overexpression', 'Var', (0, 14))	('NSCLC', 'Disease', (92, 97))	('DRG1', 'Gene', (18, 22))	('tumor', 'Disease', (71, 76))	('NSCLC', 'Disease', 'MESH:D002289', (92, 97))	('chromosome missegregation', 'CPA', (32, 57))	('leads to', 'Reg', (23, 31))
298988	30746793	Mutations in RIT1 may also induce resistance to EGFR inhibition, but in a MEK-dependent manner.	('MEK', 'Gene', '5609', (74, 77))	('EGFR', 'Gene', '1956', (48, 52))	('induce', 'Reg', (27, 33))	('EGFR', 'Gene', (48, 52))	('RIT1', 'Gene', '6016', (13, 17))	('RIT1', 'Gene', (13, 17))	('Mutations', 'Var', (0, 9))	('MEK', 'Gene', (74, 77))
298990	30746793	In recent decades, it has been recognized that network (or graph) based regularization methods are particularly effective in accommodating the correlation among genomic variants in a number of studies, nevertheless, their development and application in cancer survival studies are quite limited.	('cancer', 'Disease', (253, 259))	('variants', 'Var', (169, 177))	('cancer', 'Disease', 'MESH:D009369', (253, 259))	('cancer', 'Phenotype', 'HP:0002664', (253, 259))
299004	24880454	Importantly, whether the virus is biologically active in these tumors and involved in their pathogenesis, and second, what are the clinical implications with regard to patient management and outcome in the HPV-related variants.	('HPV', 'Species', '10566', (206, 209))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('patient', 'Species', '9606', (168, 175))	('tumors', 'Disease', (63, 69))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('variants', 'Var', (218, 226))
299007	24880454	Because of that, it is prudent at this stage, not to alter management protocols as a result of identification of HPV in these variants and to await additional information    Key words:Histopathologic risk-factors, oral cavity, oropharynx, squamous cell carcinoma variants, keratinizing squamous cell carcinoma, nonkeratinizing squamous cell carcinoma, HPV, basaloid squamous cell carcinoma, undifferentiated carcinoma, papillary squamous cell carcinoma, small cell carcinoma.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (327, 350))	('papillary squamous cell carcinoma', 'Disease', (419, 452))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (239, 262))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (366, 389))	('small cell carcinoma', 'Disease', (454, 474))	('carcinoma', 'Phenotype', 'HP:0030731', (341, 350))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (429, 452))	('small cell carcinoma', 'Disease', 'MESH:D018288', (454, 474))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (286, 309))	('basaloid squamous cell carcinoma', 'Disease', 'MESH:D002294', (357, 389))	('HPV', 'Species', '10566', (352, 355))	('carcinoma', 'Phenotype', 'HP:0030731', (253, 262))	('basaloid squamous cell carcinoma', 'Disease', (357, 389))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (327, 350))	('carcinoma', 'Phenotype', 'HP:0030731', (380, 389))	('variants', 'Var', (263, 271))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (239, 262))	('HPV', 'Species', '10566', (113, 116))	('HPV', 'Disease', (352, 355))	('carcinoma', 'Phenotype', 'HP:0030731', (300, 309))	('carcinoma', 'Phenotype', 'HP:0030731', (408, 417))	('squamous cell carcinoma', 'Disease', (286, 309))	('undifferentiated carcinoma', 'Disease', 'MESH:D002277', (391, 417))	('squamous cell carcinoma', 'Disease', (327, 350))	('squamous cell carcinoma', 'Disease', (239, 262))	('variants', 'Var', (126, 134))	('small cell carcinoma', 'Phenotype', 'HP:0030357', (454, 474))	('papillary squamous cell carcinoma', 'Disease', 'MESH:D002294', (419, 452))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (366, 389))	('basaloid squamous cell carcinoma', 'Phenotype', 'HP:0002671', (357, 389))	('undifferentiated carcinoma', 'Disease', (391, 417))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (429, 452))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (286, 309))
299012	24880454	The scores for all the variant are summed to provide a total malignancy score for a particular tumor.	('variant', 'Var', (23, 30))	('particular tumor', 'Disease', 'MESH:D009369', (84, 100))	('particular tumor', 'Disease', (84, 100))	('malignancy', 'Disease', 'MESH:D009369', (61, 71))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('malignancy', 'Disease', (61, 71))
299040	24880454	The paradoxical overexpression of an inhibitory protein in actively replicating neoplastic cells is thought to result from feed-back control secondary to pRb deregulation.	('pRb', 'Gene', (154, 157))	('deregulation', 'Var', (158, 170))	('overexpression', 'PosReg', (16, 30))	('pRb', 'Gene', '5925', (154, 157))
299042	24880454	The nonkeratinizing morphology is significantly more likely to be HPV and p16 positive than KSCC, and to have better overall survival (OS) and disease specific survival (DSS) with a p value of<0.001 and 0.01 respectively.	('p16', 'Gene', (74, 77))	('HPV', 'Species', '10566', (66, 69))	('overall survival', 'CPA', (117, 133))	('nonkeratinizing', 'Var', (4, 19))	('disease specific survival', 'CPA', (143, 168))	('p16', 'Gene', '1029', (74, 77))	('KSCC', 'Chemical', '-', (92, 96))	('SCC', 'Phenotype', 'HP:0002860', (93, 96))	('better', 'PosReg', (110, 116))	('DSS', 'Chemical', '-', (170, 173))	('HPV', 'Protein', (66, 69))
299058	24880454	Also, on rare occasion HPV+ OP SCC was reported to have multiple distant metastasis to unusual sites including the skin brain, gastrointestinal tract and intra-abdominal lymph nodes The interval from completion of therapy to onset of distant metastasis ranged from 4- 11 and 2-52 months with a median of onset 7 and 18 months respectively.	('SCC', 'Gene', (31, 34))	('HPV+ OP', 'Var', (23, 30))	('SCC', 'Phenotype', 'HP:0002860', (31, 34))	('SCC', 'Gene', '6317', (31, 34))	('gastrointestinal tract', 'Disease', (127, 149))	('HPV', 'Species', '10566', (23, 26))	('gastrointestinal tract', 'Disease', 'MESH:D004067', (127, 149))
299069	24880454	HPV+ oral SCC, unlike those in the OP, do not exhibit nonkeratinizing morphology.	('HPV', 'Species', '10566', (0, 3))	('oral', 'Disease', (5, 9))	('SCC', 'Gene', (10, 13))	('SCC', 'Phenotype', 'HP:0002860', (10, 13))	('HPV+', 'Var', (0, 4))	('SCC', 'Gene', '6317', (10, 13))
299072	24880454	However, more recently increasing numbers of variants of squamous cell carcinoma, that are HPV-positive, are reported in the oropharynx as well as in other head and neck sites.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (57, 80))	('variants', 'Var', (45, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (57, 80))	('HPV', 'Species', '10566', (91, 94))	('squamous cell carcinoma', 'Disease', (57, 80))
299073	24880454	Importantly, whether the virus is biologically active and involved in the pathogenesis of these tumors, and whether there are clinical implications with regard to patient outcome and treatment modality changes that may be needed in HPV related variants.	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('variants', 'Var', (244, 252))	('tumors', 'Disease', (96, 102))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('involved', 'Reg', (58, 66))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('HPV', 'Species', '10566', (232, 235))	('patient', 'Species', '9606', (163, 170))
299075	24880454	Some investigations have suggested favorable prognosis in some HPV positive variants, analogous to that of the nonkeratinizing carcinoma, while others showed poorer outcome.	('carcinoma', 'Disease', (127, 136))	('HPV', 'Species', '10566', (63, 66))	('variants', 'Var', (76, 84))	('carcinoma', 'Disease', 'MESH:D002277', (127, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('HPV positive', 'Gene', (63, 75))
299076	24880454	Because of this, it is prudent that at this stage, not to alter management protocols as a result of identification of HPV in these variants and to await additional studies.	('HPV', 'Gene', (118, 121))	('HPV', 'Species', '10566', (118, 121))	('variants', 'Var', (131, 139))
299087	24880454	Using PCR for HPV 16 DNA as well as p16 immunostaining, Begum and Westra documented HPV in 76% of oropharyngeal BSCC and in 6% of tumors in non-oropharyngeal sites.	('tumors', 'Disease', (130, 136))	('tumors', 'Disease', 'MESH:D009369', (130, 136))	('SCC', 'Phenotype', 'HP:0002860', (113, 116))	('HPV 16', 'Species', '333760', (14, 20))	('HPV', 'Species', '10566', (14, 17))	('SCC', 'Gene', '6317', (113, 116))	('BSCC', 'Phenotype', 'HP:0002671', (112, 116))	('p16', 'Gene', '1029', (36, 39))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('HPV', 'Species', '10566', (84, 87))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('SCC', 'Gene', (113, 116))	('HPV', 'Var', (84, 87))	('p16', 'Gene', (36, 39))
299110	24880454	An HPV relationship was identified by p16 immunoreactivity, HPV ISH and E6 and E7 mRNA ISH in a number of tumors (Fig.	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('tumors', 'Disease', (106, 112))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('p16', 'Gene', (38, 41))	('HPV', 'Species', '10566', (60, 63))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('E7 mRNA ISH', 'Var', (79, 90))	('p16', 'Gene', '1029', (38, 41))	('HPV', 'Species', '10566', (3, 6))
299143	24880454	As the numbers of reported HPV positive head and neck squamous cell carcinoma variants are increasing, particularly in the oropharynx, it is of importance to establish the status of the virus in the tumors cells and to distinguish between a causal agent "driver" and a bystander "passenger".	('HPV', 'Species', '10566', (27, 30))	('tumors', 'Disease', (199, 205))	('tumors', 'Disease', 'MESH:D009369', (199, 205))	('tumors', 'Phenotype', 'HP:0002664', (199, 205))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (40, 77))	('neck squamous cell carcinoma', 'Disease', (49, 77))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (54, 77))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (49, 77))	('carcinoma', 'Phenotype', 'HP:0030731', (68, 77))	('HPV positive', 'Gene', (27, 39))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('variants', 'Var', (78, 86))
299144	24880454	Currently, the number of cases of SCC variants with established HPV causal relationship is still limited.	('SCC', 'Gene', (34, 37))	('SCC', 'Phenotype', 'HP:0002860', (34, 37))	('variants', 'Var', (38, 46))	('SCC', 'Gene', '6317', (34, 37))	('HPV', 'Species', '10566', (64, 67))
299145	24880454	Based on these studies, there is some evidence to suggest that variants such as BSCC, undifferentiated carcinoma and PSCC may have favorable prognosis similar to that of conventional NKSCC and better than their HPV negative counterparts.	('SCC', 'Gene', '6317', (81, 84))	('undifferentiated carcinoma', 'Disease', (86, 112))	('SCC', 'Gene', (185, 188))	('variants', 'Var', (63, 71))	('BSCC', 'Phenotype', 'HP:0002671', (80, 84))	('KSCC', 'Chemical', '-', (184, 188))	('SCC', 'Phenotype', 'HP:0002860', (185, 188))	('SCC', 'Gene', (118, 121))	('HPV', 'Species', '10566', (211, 214))	('SCC', 'Gene', '6317', (185, 188))	('undifferentiated carcinoma', 'Disease', 'MESH:D002277', (86, 112))	('SCC', 'Phenotype', 'HP:0002860', (118, 121))	('SCC', 'Gene', '6317', (118, 121))	('SCC', 'Gene', (81, 84))	('SCC', 'Phenotype', 'HP:0002860', (81, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))
299151	29656435	We analysed BTG2 methylation data from 1230 early-stage NSCLC patients from five international cohorts, as well as gene expression data from 3038 lung cancer cases from multiple cohorts.	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('BTG2', 'Gene', (12, 16))	('lung cancer', 'Disease', 'MESH:D008175', (146, 157))	('NSCLC', 'Disease', (56, 61))	('BTG2', 'Gene', '7832', (12, 16))	('methylation', 'Var', (17, 28))	('NSCLC', 'Disease', 'MESH:D002289', (56, 61))	('lung cancer', 'Disease', (146, 157))	('lung cancer', 'Phenotype', 'HP:0100526', (146, 157))	('patients', 'Species', '9606', (62, 70))	('NSCLC', 'Phenotype', 'HP:0030358', (56, 61))
299152	29656435	Three CpG probes (cg01798157, cg06373167, cg23371584) that detected BTG2 hypermethylation in tumour tissues were associated with lower overall survival.	('tumour', 'Disease', (93, 99))	('hypermethylation', 'Var', (73, 89))	('cg01798157', 'Chemical', '-', (18, 28))	('BTG2', 'Gene', (68, 72))	('cg01798157', 'Var', (18, 28))	('BTG2', 'Gene', '7832', (68, 72))	('overall survival', 'MPA', (135, 151))	('cg06373167', 'Chemical', '-', (30, 40))	('cg23371584', 'Chemical', '-', (42, 52))	('cg23371584', 'Var', (42, 52))	('tumour', 'Phenotype', 'HP:0002664', (93, 99))	('tumour', 'Disease', 'MESH:D009369', (93, 99))	('cg06373167', 'Var', (30, 40))	('lower', 'NegReg', (129, 134))
299154	29656435	In the expression analysis, BTG2 expression was positively correlated with survival in each cohort (HR range, 0.28-0.68), which we confirmed with meta-analysis (HR = 0.61, 95% CI 0.54-0.68).	('expression', 'Var', (33, 43))	('survival', 'Disease', (75, 83))	('correlated with', 'Reg', (59, 74))	('BTG2', 'Gene', (28, 32))	('BTG2', 'Gene', '7832', (28, 32))
299156	29656435	Importantly, an integrative model of BTG2 methylation, expression and clinical information showed better predictive ability in the training set and validation set.	('BTG2', 'Gene', (37, 41))	('methylation', 'Var', (42, 53))	('BTG2', 'Gene', '7832', (37, 41))
299163	29656435	In addition to the traditional molecular biomarkers, DNA methylation has improved our understanding of tumour genomics by identifying key biomarkers for multiple cancers and has played an important role in the development of targeted therapy (Bock et al., 2016; Jones et al., 2016).	('methylation', 'Var', (57, 68))	('cancers', 'Phenotype', 'HP:0002664', (162, 169))	('tumour', 'Phenotype', 'HP:0002664', (103, 109))	('multiple cancers', 'Disease', (153, 169))	('tumour', 'Disease', 'MESH:D009369', (103, 109))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('multiple cancers', 'Disease', 'MESH:D009369', (153, 169))	('tumour', 'Disease', (103, 109))
299171	29656435	Further, BTG2 expression has also been found to be related to prognosis in bladder cancer (Wagener et al., 2013), breast cancer (Takahashi et al., 2011) and pancreatic cancer (Frampton et al., 2014).	('BTG2', 'Gene', (9, 13))	('expression', 'Var', (14, 24))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('bladder cancer', 'Disease', 'MESH:D001749', (75, 89))	('bladder cancer', 'Disease', (75, 89))	('BTG2', 'Gene', '7832', (9, 13))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('bladder cancer', 'Phenotype', 'HP:0009725', (75, 89))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (157, 174))	('breast cancer', 'Disease', 'MESH:D001943', (114, 127))	('pancreatic cancer', 'Disease', (157, 174))	('breast cancer', 'Phenotype', 'HP:0003002', (114, 127))	('related', 'Reg', (51, 58))	('pancreatic cancer', 'Disease', 'MESH:D010190', (157, 174))	('breast cancer', 'Disease', (114, 127))
299198	29656435	Three risk probes were significant with FDR-q < 0.05: cg01798157 (HR = 1.49, 95% CI 1.19-1.85, q = 0.002), cg06373167 (HR = 1.31, 95% CI 1.05-1.63, q = 0.043) and cg23371584 (HR = 1.58, 95% CI 1.27-1.97, q = 6.65 x 10-4) (Figs 2A and S1, Table S3).	('cg23371584', 'Chemical', '-', (163, 173))	('cg23371584', 'Var', (163, 173))	('cg06373167', 'Chemical', '-', (107, 117))	('FDR-q', 'Var', (40, 45))	('cg06373167', 'Var', (107, 117))	('cg01798157', 'Chemical', '-', (54, 64))	('cg01798157', 'Var', (54, 64))
299200	29656435	Using the training set to generate coefficients by Cox regression, the model is: prognostic scoremethylation = 0.0046  x cg01798157 + 0.0026 x cg06373167 + 0.0066 x cg23371584.	('cg06373167', 'Chemical', '-', (143, 153))	('cg01798157', 'Chemical', '-', (121, 131))	('Cox', 'Gene', '1351', (51, 54))	('Cox', 'Gene', (51, 54))	('cg23371584', 'Var', (165, 175))	('cg23371584', 'Chemical', '-', (165, 175))	('cg06373167 + 0.0066 x cg23371584', 'Var', (143, 175))
299212	29656435	We found that the three risk CpG probes were all negatively associated with BTG2 gene expression levels (cg01798157: beta = -22.9, 95% CI -26.0 to -19.8, q = 1.52 x 10-42; cg06373167: beta = -9.8, 95% CI -11.7 to -7.76, q = 5.41 x 10-20; cg23371584: beta = -4.18, 95% CI -6.19 to -2.18, q = 6.90 x 10-5) (Fig.	('BTG2', 'Gene', (76, 80))	('cg23371584', 'Var', (238, 248))	('BTG2', 'Gene', '7832', (76, 80))	('cg06373167', 'Var', (172, 182))	('negatively', 'NegReg', (49, 59))	('gene expression levels', 'MPA', (81, 103))	('cg06373167', 'Chemical', '-', (172, 182))	('to -7', 'Species', '1214577', (210, 215))	('cg01798157', 'Chemical', '-', (105, 115))	('cg23371584', 'Chemical', '-', (238, 248))
299225	29656435	First, over-expression of BTG2 is known to inhibit proliferation of cells and invasion in some tumours, including lung cancer cells (Wei et al., 2012), and acts as an anti-proliferation gene in cooperation with PRMT1 (Dolezal et al., 2017).	('PRMT1', 'Gene', (211, 216))	('proliferation of cells', 'CPA', (51, 73))	('tumours', 'Phenotype', 'HP:0002664', (95, 102))	('lung cancer', 'Disease', 'MESH:D008175', (114, 125))	('tumours', 'Disease', 'MESH:D009369', (95, 102))	('invasion', 'CPA', (78, 86))	('inhibit', 'NegReg', (43, 50))	('BTG2', 'Gene', (26, 30))	('tumours', 'Disease', (95, 102))	('over-expression', 'Var', (7, 22))	('lung cancer', 'Disease', (114, 125))	('BTG2', 'Gene', '7832', (26, 30))	('lung cancer', 'Phenotype', 'HP:0100526', (114, 125))	('PRMT1', 'Gene', '3276', (211, 216))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('tumour', 'Phenotype', 'HP:0002664', (95, 101))
299240	29656435	Further, previous reports suggest that BTG2 expression improved the radiosensitivity of NSCLC and breast cancer cells by affecting cell cycle distribution, enhancing radiation-induced apoptosis and inhibiting DNA repair-related protein expression (He et al., 2015; Hu et al., 2012), which suggests that BTG2 may be a novel target in radiotherapy for lung cancer.	('NSCLC', 'Phenotype', 'HP:0030358', (88, 93))	('lung cancer', 'Disease', (350, 361))	('BTG2', 'Gene', '7832', (39, 43))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('improved', 'PosReg', (55, 63))	('expression', 'Var', (44, 54))	('radiation-induced apoptosis', 'CPA', (166, 193))	('BTG2', 'Gene', (303, 307))	('enhancing', 'PosReg', (156, 165))	('lung cancer', 'Disease', 'MESH:D008175', (350, 361))	('breast cancer', 'Phenotype', 'HP:0003002', (98, 111))	('lung cancer', 'Phenotype', 'HP:0100526', (350, 361))	('cancer', 'Phenotype', 'HP:0002664', (355, 361))	('affecting', 'Reg', (121, 130))	('NSCLC', 'Disease', 'MESH:D002289', (88, 93))	('BTG2', 'Gene', '7832', (303, 307))	('radiosensitivity', 'CPA', (68, 84))	('inhibiting', 'NegReg', (198, 208))	('breast cancer', 'Disease', 'MESH:D001943', (98, 111))	('BTG2', 'Gene', (39, 43))	('breast cancer', 'Disease', (98, 111))	('DNA repair-related protein expression', 'MPA', (209, 246))	('NSCLC', 'Disease', (88, 93))	('cell', 'MPA', (131, 135))
299274	29390253	The most commonly recognized risk factors for OM include poor oral hygiene and periodontal disease, chronic alcohol consumption, cigarette smoking, hyposalivation, low body mass index (BMI < 18.5), as well as concurrent diseases such as diabetes mellitus.	('hyposalivation', 'Disease', (148, 162))	('diabetes mellitus', 'Disease', (237, 254))	('chronic alcohol consumption', 'Phenotype', 'HP:0030955', (100, 127))	('hyposalivation', 'Disease', 'MESH:D014987', (148, 162))	('diabetes mellitus', 'Disease', 'MESH:D003920', (237, 254))	('low body mass', 'Phenotype', 'HP:0004325', (164, 177))	('periodontal disease', 'Disease', (79, 98))	('poor oral', 'Phenotype', 'HP:0000160', (57, 66))	('periodontal disease', 'Disease', 'MESH:D010510', (79, 98))	('low body mass index', 'Phenotype', 'HP:0045082', (164, 183))	('low', 'Var', (164, 167))	('alcohol', 'Chemical', 'MESH:D000438', (108, 115))	('diabetes mellitus', 'Phenotype', 'HP:0000819', (237, 254))	('periodontal disease', 'Phenotype', 'HP:0000704', (79, 98))
299314	29390253	In addition, nicotine in tobacco causes vasoconstriction, and decrease inflammatory and immune response, thus enhancing infection risk.	('nicotine', 'Var', (13, 21))	('infection', 'Disease', 'MESH:D007239', (120, 129))	('infection', 'Disease', (120, 129))	('tobacco', 'Species', '4097', (25, 32))	('nicotine', 'Chemical', 'MESH:D009538', (13, 21))	('decrease', 'NegReg', (62, 70))	('enhancing', 'PosReg', (110, 119))	('decrease inflammatory and immune response', 'Phenotype', 'HP:0012648', (62, 103))	('vasoconstriction', 'MPA', (40, 56))
299330	29390253	Indirectly, chemotherapy may also cause injury through various mechanisms such as oral flora disturbance, bone marrow suppression, and inhibition of immune function leading to increased infection.	('oral flora disturbance', 'Disease', 'MESH:D020820', (82, 104))	('bone marrow suppression', 'Disease', (106, 129))	('bone marrow suppression', 'Disease', 'MESH:D001855', (106, 129))	('increased', 'PosReg', (176, 185))	('oral flora disturbance', 'Disease', (82, 104))	('cause', 'Reg', (34, 39))	('chemotherapy', 'Var', (12, 24))	('bone marrow suppression', 'Phenotype', 'HP:0005528', (106, 129))	('infection', 'Disease', (186, 195))	('infection', 'Disease', 'MESH:D007239', (186, 195))	('inhibition of immune function', 'Phenotype', 'HP:0002721', (135, 164))
299332	29390253	These effects may further damage the oral environment, leading to oral mucosal ulcers.	('oral mucosal ulcers', 'Phenotype', 'HP:0000155', (66, 85))	('oral environment', 'CPA', (37, 53))	('oral mucosal ulcers', 'Disease', (66, 85))	('effects', 'Var', (6, 13))	('damage', 'Reg', (26, 32))	('oral mucosal ulcers', 'Disease', 'MESH:D019226', (66, 85))	('leading to', 'Reg', (55, 65))
299342	28638796	Mean NGAL levels were highest in stage IV [1041.54 +- 222.15 ng/mL (stage IV) vs 1040 +- 0.00 ng/mL (stage I); 900 +- 0.00 ng/mL (stage II) and 1031.90 +- 202.55 ng/mL (stage III)] and chi2 test was highly significant (P < 0.001).	('1031.90 +- 202.55', 'Var', (144, 161))	('NGAL', 'Gene', '3934', (5, 9))	('NGAL', 'Gene', (5, 9))
299347	28638796	The molecular alterations observed in HNSCC are mainly due to oncogene activation and tumor suppressor gene inactivation, leading to dysregulation of cell proliferation.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('cell proliferation', 'CPA', (150, 168))	('tumor', 'Disease', (86, 91))	('activation', 'PosReg', (71, 81))	('inactivation', 'Var', (108, 120))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('oncogene', 'Protein', (62, 70))	('HNSCC', 'Disease', (38, 43))	('HNSCC', 'Phenotype', 'HP:0012288', (38, 43))
299348	28638796	These alterations include gene amplification and over expression of oncogenes such as ras, myc, epidermal growth factor receptor (EGFR) and cyclin D1 and mutations and deletions leading to p16 and TP53 tumor suppressor genes inactivation.	('inactivation', 'NegReg', (225, 237))	('myc', 'Gene', (91, 94))	('EGFR', 'Gene', (130, 134))	('TP53', 'Gene', (197, 201))	('ras', 'Gene', (86, 89))	('tumor', 'Disease', (202, 207))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('TP53', 'Gene', '7157', (197, 201))	('deletions', 'Var', (168, 177))	('EGFR', 'Gene', '1956', (130, 134))	('cyclin D1', 'Gene', (140, 149))	('p16', 'Gene', '1029', (189, 192))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('epidermal growth factor receptor', 'Gene', (96, 128))	('p16', 'Gene', (189, 192))	('over expression', 'PosReg', (49, 64))	('cyclin D1', 'Gene', '595', (140, 149))	('epidermal growth factor receptor', 'Gene', '1956', (96, 128))	('mutations', 'Var', (154, 163))	('myc', 'Gene', '4609', (91, 94))
299440	33992085	In addition, ectopic expressions of lncRNAs lead to the abnormality of ceRNA regulatory network, in which lncRNAs competitively interact with miRNAs to regulate expression patterns of target genes, thus inducing carcinogenesis and cancer growth.	('lead to', 'Reg', (44, 51))	('cancer', 'Disease', 'MESH:D009369', (231, 237))	('cancer', 'Disease', (231, 237))	('carcinogenesis', 'Disease', 'MESH:D063646', (212, 226))	('abnormality', 'MPA', (56, 67))	('ectopic expressions', 'Var', (13, 32))	('ceRNA', 'Gene', (71, 76))	('carcinogenesis', 'Disease', (212, 226))	('expression patterns', 'MPA', (161, 180))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('regulate', 'Reg', (152, 160))	('inducing', 'PosReg', (203, 211))
299441	33992085	For example, lncRNA ACTA2-AS1 promotes cervical cancer development through serving as a ceRNA for miR-143-3p to upregulate SMAD3 expression.	('expression', 'MPA', (129, 139))	('SMAD3', 'Gene', '4088', (123, 128))	('SMAD3', 'Gene', (123, 128))	('promotes', 'PosReg', (30, 38))	('upregulate', 'PosReg', (112, 122))	('AS1', 'Gene', (26, 29))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('AS1', 'Gene', '5729', (26, 29))	('miR-143-3p', 'Var', (98, 108))	('cancer', 'Disease', (48, 54))	('ACTA2', 'Gene', (20, 25))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('ACTA2', 'Gene', '59', (20, 25))
299477	33992085	Afterwards, the membrane was sealed with 5% non-fat milk for 10 min and incubated for 12 h at 4  C with primary antibodies of anti-GAPDH (1:2500, ab9485, Abcam) and anti-GATA6 (1:1000, ab175927, Abcam).	('1:2500', 'Var', (138, 144))	('1:1000', 'Var', (177, 183))	('GAPDH', 'Gene', (131, 136))	('GAPDH', 'Gene', '2597', (131, 136))
299480	33992085	Next, anti-Ago2 (ab186733, Abcam) or anti-IgG (ab205718, Abcam) was coincubated for 12 h with magnetic beads at 4  C for the purpose of acquiring immunoprecipitation complex.	('ab186733', 'Var', (17, 25))	('Ago2', 'Gene', '27161', (11, 15))	('Ago2', 'Gene', (11, 15))	('ab205718', 'Var', (47, 55))
299482	33992085	Partial sequences of GATA6-AS1 and GATA6 3' untranslated region (3'UTR) including wide type or mutant type miR-4530 binding sites were inserted into dual-luciferase reporter vector (pmirGLO; Promega, Madison, WI, USA) to produce GATA6-AS1-WT, GATA6-AS1-MUT and GATA6-WT, GATA6-MUT.	('GATA6-AS1', 'Gene', (21, 30))	('GATA6-AS1', 'Gene', (229, 238))	('GATA6-AS1', 'Gene', '100128893;2627;5729', (21, 30))	('miR-4530', 'Gene', '100616163', (107, 115))	('GATA6-AS1', 'Gene', (243, 252))	('mutant', 'Var', (95, 101))	('GATA6-AS1', 'Gene', '100128893;2627;5729', (229, 238))	('miR-4530', 'Gene', (107, 115))	('GATA6-AS1', 'Gene', '100128893;2627;5729', (243, 252))
299489	33992085	Later, the expression of GATA6-AS1 was significantly elevated in A549 and H1975 cells with transfection of pcDNA3.1-GATA6-AS1, as suggested by RT-qPCR (Fig.	('GATA6-AS1', 'Gene', '100128893;2627;5729', (116, 125))	('transfection', 'Var', (91, 103))	('GATA6-AS1', 'Gene', (25, 34))	('elevated', 'PosReg', (53, 61))	('A549', 'CellLine', 'CVCL:0023', (65, 69))	('expression', 'MPA', (11, 21))	('GATA6-AS1', 'Gene', '100128893;2627;5729', (25, 34))	('H1975', 'CellLine', 'CVCL:1511', (74, 79))	('GATA6-AS1', 'Gene', (116, 125))
299502	33992085	RT-qPCR analysis revealed that the expression of GATA6 was promoted in A549 and H1975 cells upon the transfection of pcDNA3.1-GATA6-AS1 (Fig.	('GATA6-AS1', 'Gene', '100128893;2627;5729', (126, 135))	('H1975', 'CellLine', 'CVCL:1511', (80, 85))	('expression', 'MPA', (35, 45))	('promoted', 'PosReg', (59, 67))	('transfection', 'Var', (101, 113))	('A549', 'CellLine', 'CVCL:0023', (71, 75))	('GATA6', 'Gene', (49, 54))	('GATA6-AS1', 'Gene', (126, 135))
299510	33992085	Next, two miRNAs (miR-4530 and miR-1520) sharing potential binding sites with GATA6-AS1 were screened out with the screening condition of miRDB and RegRNA2 databases (Fig.	('miR-1520', 'Var', (31, 39))	('miR-4530', 'Gene', '100616163', (18, 26))	('GATA6-AS1', 'Gene', (78, 87))	('miR-4530', 'Gene', (18, 26))	('GATA6-AS1', 'Gene', '100128893;2627;5729', (78, 87))
299512	33992085	Moreover, RT-qPCR analysis revealed that the expression of miR-4530 was elevated in A549 and H1975 cells with transfection of miR-4530-mimics (Fig.	('elevated', 'PosReg', (72, 80))	('H1975', 'CellLine', 'CVCL:1511', (93, 98))	('miR-4530', 'Gene', '100616163', (126, 134))	('miR-4530', 'Gene', '100616163', (59, 67))	('A549', 'CellLine', 'CVCL:0023', (84, 88))	('expression', 'MPA', (45, 55))	('miR-4530', 'Gene', (126, 134))	('transfection', 'Var', (110, 122))	('miR-4530', 'Gene', (59, 67))
299521	33992085	First, the expression of GATA6 was repressed significantly in A549 and H1975 cells after the knockdown of GATA6 (Fig.	('knockdown', 'Var', (93, 102))	('A549', 'CellLine', 'CVCL:0023', (62, 66))	('GATA6', 'Gene', (106, 111))	('H1975', 'CellLine', 'CVCL:1511', (71, 76))	('GATA6', 'Gene', (25, 30))
299522	33992085	Subsequently, an EdU assay revealed that the GATA6-AS1 upregulation-reduced apoptotic ability of A549 and H1975 cells was restored by silencing GATA6 (Fig.	('GATA6-AS1', 'Gene', (45, 54))	('GATA6', 'Gene', (144, 149))	('A549', 'CellLine', 'CVCL:0023', (97, 101))	('GATA6-AS1', 'Gene', '100128893;2627;5729', (45, 54))	('silencing', 'Var', (134, 143))	('apoptotic ability', 'CPA', (76, 93))	('H1975', 'CellLine', 'CVCL:1511', (106, 111))	('EdU', 'Chemical', '-', (17, 20))
299523	33992085	Additionally, the inhibited cell proliferation by GATA6-AS1 overexpression was countervailed after depleting GATA6, as suggested by a colony formation assay (Fig.	('cell proliferation', 'CPA', (28, 46))	('GATA6-AS1', 'Gene', (50, 59))	('GATA6-AS1', 'Gene', '100128893;2627;5729', (50, 59))	('inhibited', 'NegReg', (18, 27))	('overexpression', 'Var', (60, 74))
299524	33992085	Later, the TUNEL assay was performed to illustrate the inhibitory effect of GATA6 knockdown on cell apoptosis previously promoted by upregulated GATA6-AS1 (Fig.	('GATA6', 'Gene', (76, 81))	('upregulated', 'PosReg', (133, 144))	('GATA6-AS1', 'Gene', (145, 154))	('cell apoptosis', 'CPA', (95, 109))	('knockdown', 'Var', (82, 91))	('GATA6-AS1', 'Gene', '100128893;2627;5729', (145, 154))	('promoted', 'PosReg', (121, 129))
299543	33992085	GATA6 transcriptionally inactivates Shh to inhibit lung squamous cell carcinoma cell proliferation and migration.	('Shh', 'Gene', (36, 39))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (56, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('GATA6', 'Gene', (0, 5))	('inactivates', 'Var', (24, 35))	('inhibit', 'NegReg', (43, 50))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (51, 79))	('lung squamous cell carcinoma', 'Disease', (51, 79))	('Shh', 'Gene', '6469', (36, 39))
299555	33322692	Differential co-expression networks are useful tools to identify changes in response to an external perturbation, such as mutations predisposing to cancer development, and leading to changes in the activity of gene expression regulators or signalling.	('cancer', 'Disease', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('activity', 'MPA', (198, 206))	('mutations', 'Var', (122, 131))	('changes', 'Reg', (183, 190))	('gene', 'Protein', (210, 214))
299558	33322692	Via the comparison of normal and diseased conditions and of different tumour stages, studies based on these methods led to the definition of pathways involved in gene network reorganisation upon oncogenes' mutations and tumour progression, often converging on immune system signalling.	('mutations', 'Var', (206, 215))	('tumour', 'Phenotype', 'HP:0002664', (220, 226))	('tumour', 'Phenotype', 'HP:0002664', (70, 76))	('tumour', 'Disease', 'MESH:D009369', (220, 226))	('oncogenes', 'Gene', (195, 204))	('tumour', 'Disease', 'MESH:D009369', (70, 76))	('tumour', 'Disease', (220, 226))	('tumour', 'Disease', (70, 76))
299562	33322692	GRNs are the ideal reconstruction of interactions between genetic elements, comprising the activity of transcription factors (TFs) on their targets' expression, post-translational modifications influencing a protein's impact on other elements of the network, epigenetic modifications altering transcription and many additional levels of regulation.	('GRN', 'Gene', (0, 3))	('TF', 'Gene', '2152', (126, 128))	('GRN', 'Gene', '2896', (0, 3))	('impact', 'MPA', (218, 224))	('post-translational modifications', 'Var', (161, 193))	('influencing', 'Reg', (194, 205))	('transcription', 'MPA', (293, 306))	('interactions', 'Interaction', (37, 49))	('altering', 'Reg', (284, 292))	('epigenetic modifications', 'Var', (259, 283))
299570	33322692	In Mendelian disorders, for example, genes harbouring disease mutations with a dominant phenotype display significantly higher network connectivity than genes with a recessive phenotype, and cancer driver genes tend to be centrally located in protein-protein interaction networks.	('cancer', 'Disease', (191, 197))	('cancer', 'Disease', 'MESH:D009369', (191, 197))	('Mendelian disorders', 'Disease', 'MESH:D030342', (3, 22))	('higher', 'PosReg', (120, 126))	('network connectivity', 'MPA', (127, 147))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('Mendelian disorders', 'Disease', (3, 22))	('mutations', 'Var', (62, 71))
299582	33322692	Moreover, despite the most frequent comparisons being tumours at different stages, many kind of conditions have been contrasted (e.g., ER+ vs. ER- breast tumours, p53 mutated vs. p53 wild type).	('tumour', 'Phenotype', 'HP:0002664', (154, 160))	('p53', 'Gene', (179, 182))	('p53', 'Gene', '7157', (179, 182))	('tumours', 'Phenotype', 'HP:0002664', (154, 161))	('breast tumour', 'Phenotype', 'HP:0100013', (147, 160))	('tumours', 'Disease', 'MESH:D009369', (54, 61))	('p53', 'Gene', (163, 166))	('tumours', 'Disease', (54, 61))	('p53', 'Gene', '7157', (163, 166))	('breast tumours', 'Disease', (147, 161))	('tumours', 'Disease', 'MESH:D009369', (154, 161))	('ER', 'Gene', '2069', (143, 145))	('tumours', 'Disease', (154, 161))	('breast tumours', 'Disease', 'MESH:D001943', (147, 161))	('mutated', 'Var', (167, 174))	('tumour', 'Phenotype', 'HP:0002664', (54, 60))	('tumours', 'Phenotype', 'HP:0002664', (54, 61))	('ER', 'Gene', '2069', (135, 137))
299601	33322692	Interestingly, an independent report found an enrichment for targets of miRNAs related with cancer in two co-expression modules more strongly connected in lung cancer than in normal tissue.	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('cancer', 'Disease', (160, 166))	('lung cancer', 'Disease', (155, 166))	('lung cancer', 'Phenotype', 'HP:0100526', (155, 166))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('connected', 'Reg', (142, 151))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('lung cancer', 'Disease', 'MESH:D008175', (155, 166))	('miRNAs', 'Var', (72, 78))
299608	33322692	In the same vein, the differential co-expression module multivariate analysis method MultiDCox has been applied to breast cancer, revealing gene sets associated with mutant p53, ER status and grade.	('p53', 'Gene', (173, 176))	('ER', 'Gene', '2069', (178, 180))	('p53', 'Gene', '7157', (173, 176))	('mutant', 'Var', (166, 172))	('breast cancer', 'Disease', 'MESH:D001943', (115, 128))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('breast cancer', 'Disease', (115, 128))	('breast cancer', 'Phenotype', 'HP:0003002', (115, 128))
299641	33327871	Expression and Possible Molecular Mechanisms of microRNA-205-5p in Patients With Head and Neck Squamous Cell Carcinoma Head and neck squamous cell carcinoma (HNSCC) is the sixth most prevalent malignancy worldwide, with high incidence and poor survival rates.	('Carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (95, 118))	('Patients', 'Species', '9606', (67, 75))	('Head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (119, 156))	('Neck Squamous Cell Carcinoma', 'Disease', 'MESH:D000077195', (90, 118))	('neck squamous cell carcinoma', 'Disease', (128, 156))	('microRNA-205-5p', 'Var', (48, 63))	('Neck Squamous Cell Carcinoma', 'Disease', (90, 118))	('malignancy', 'Disease', 'MESH:D009369', (193, 203))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (128, 156))	('malignancy', 'Disease', (193, 203))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (133, 156))	('Head and Neck Squamous Cell Carcinoma', 'Phenotype', 'HP:0012288', (81, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (147, 156))
299642	33327871	Increased expression of microRNA-205-5p (miR-205-5p) may influence the outcomes of HNSCC, but the identities of miR-205-5p target genes and the potential signaling pathways related to HNSCC remain unclear.	('-205-5p', 'Chemical', '-', (44, 51))	('HNSCC', 'Disease', (83, 88))	('influence', 'Reg', (57, 66))	('miR-205-5p', 'Chemical', '-', (112, 122))	('outcomes', 'MPA', (71, 79))	('expression', 'MPA', (10, 20))	('Increased', 'PosReg', (0, 9))	('microRNA-205-5p', 'Var', (24, 39))	('miR-205-5p', 'Chemical', '-', (41, 51))	('-205-5p', 'Chemical', '-', (115, 122))	('-205-5p', 'Chemical', '-', (32, 39))
299643	33327871	RT-qPCR was used to detect the expression levels of miR-205-5p in the plasma of patients with HNSCC.	('patients', 'Species', '9606', (80, 88))	('HNSCC', 'Disease', (94, 99))	('expression', 'MPA', (31, 41))	('miR-205-5p', 'Chemical', '-', (52, 62))	('miR-205-5p', 'Var', (52, 62))
299644	33327871	We also performed a meta-analysis using data from relevant literature, and the Gene Expression Omnibus (GEO) and the Cancer Genome Atlas (TCGA) databases to evaluate the expression level of miR-205-5p in HNSCC.	('miR-205-5p', 'Var', (190, 200))	('Cancer', 'Disease', (117, 123))	('Cancer', 'Phenotype', 'HP:0002664', (117, 123))	('Cancer', 'Disease', 'MESH:D009369', (117, 123))	('miR-205-5p', 'Chemical', '-', (190, 200))
299646	33327871	We also used Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) for enrichment analyses adapted to investigate the dynamics and possible mechanisms of miR-205-5p in HNSCC.	('miR-205-5p', 'Chemical', '-', (170, 180))	('HNSCC', 'Disease', (184, 189))	('miR-205-5p', 'Var', (170, 180))
299649	33327871	Based on GO and KEGG analyses, we found that miR-205-5p was correlated with the progression of HNSCC through association with signaling pathways, including the drug metabolism-cytochrome P450 pathway.	('miR-205-5p', 'Var', (45, 55))	('cytochrome P450', 'Gene', (176, 191))	('signaling pathways', 'Pathway', (126, 144))	('miR-205-5p', 'Chemical', '-', (45, 55))	('HNSCC', 'Disease', (95, 100))	('association', 'Interaction', (109, 120))	('cytochrome P450', 'Gene', '4051', (176, 191))
299650	33327871	Analysis of the target genes revealed that flavin-containing monooxygenase isoform 2 (FMO2) and alcohol dehydrogenase 1B (ADH1B) may be important targets of miR-205-5p.	('flavin-containing monooxygenase isoform 2', 'Gene', '2327', (43, 84))	('alcohol dehydrogenase 1B', 'Gene', '125', (96, 120))	('ADH1B', 'Gene', (122, 127))	('miR-205-5p', 'Chemical', '-', (157, 167))	('flavin-containing monooxygenase isoform 2', 'Gene', (43, 84))	('FMO2', 'Gene', (86, 90))	('alcohol dehydrogenase 1B', 'Gene', (96, 120))	('ADH1B', 'Gene', '125', (122, 127))	('FMO2', 'Gene', '2327', (86, 90))	('miR-205-5p', 'Var', (157, 167))
299651	33327871	In summary, miR-205-5p may have a significant role in the prognosis of HNSCC and may serve as a potential biomarker in HNSCC.	('miR-205-5p', 'Var', (12, 22))	('miR-205-5p', 'Chemical', '-', (12, 22))	('HNSCC', 'Disease', (71, 76))
299657	33327871	Recently, miR-205-5p, located at 1q32.2, was found to be highly expressed in NPC patients.	('miR-205-5p', 'Chemical', '-', (10, 20))	('patients', 'Species', '9606', (81, 89))	('miR-205-5p', 'Var', (10, 20))	('NPC', 'Disease', (77, 80))
299658	33327871	Further, studies have demonstrated that miR-205-5p is highly expressed in HNSCC cell lines and plays an important role in hepatocellular, lung, and breast cancers.	('hepatocellular', 'Disease', (122, 136))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('role', 'Reg', (114, 118))	('miR-205-5p', 'Chemical', '-', (40, 50))	('lung', 'Disease', (138, 142))	('miR-205-5p', 'Var', (40, 50))	('breast cancers', 'Phenotype', 'HP:0003002', (148, 162))	('breast cancers', 'Disease', 'MESH:D001943', (148, 162))	('cancers', 'Phenotype', 'HP:0002664', (155, 162))	('breast cancers', 'Disease', (148, 162))	('plays', 'Reg', (95, 100))
299659	33327871	However, the precise role and mechanism of action of miR-205-5p in signaling pathways associated with HNSCC remain unclear.	('miR-205-5p', 'Chemical', '-', (53, 63))	('HNSCC', 'Disease', (102, 107))	('miR-205-5p', 'Var', (53, 63))
299660	33327871	The role of miR-205-5p as a potentially novel biomarker needs to be further examined to better understand its targets and molecular mechanisms, especially in relation to HNSCC.	('miR-205-5p', 'Var', (12, 22))	('miR-205-5p', 'Chemical', '-', (12, 22))	('HNSCC', 'Disease', (170, 175))
299662	33327871	We performed a meta-analysis to assess the expression level of miR-205-5p in HNSCC patients.	('HNSCC', 'Disease', (77, 82))	('patients', 'Species', '9606', (83, 91))	('miR-205-5p', 'Var', (63, 73))	('miR-205-5p', 'Chemical', '-', (63, 73))
299663	33327871	We also sought to examine and identify novel molecular mechanisms of miR-205-5p in HNSCC using the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analyses.	('miR-205-5p', 'Chemical', '-', (69, 79))	('HNSCC', 'Disease', (83, 88))	('miR-205-5p', 'Var', (69, 79))
299664	33327871	Our three major hypotheses were as follows: (1) Expression of miR-205-5p was significantly different in the HNSCC group compared to the control group; (2) miR-205-5p has predictive value in HNSCC, and (3) miR-205-5p plays a role in drug metabolism by inhibiting the specific target genes flavin-containing monooxygenase isoform 2 (FMO2), alcohol dehydrogenase 1B (ADH1B), and stimulating cytochrome P450 family 3 subfamily A member 5 (CYP3A5).	('miR-205-5p', 'Var', (155, 165))	('cytochrome P450 family 3 subfamily A member 5', 'Gene', '1577', (388, 433))	('inhibiting', 'NegReg', (251, 261))	('CYP3A5', 'Gene', (435, 441))	('miR-205-5p', 'Chemical', '-', (62, 72))	('cytochrome P450 family 3 subfamily A member 5', 'Gene', (388, 433))	('miR-205-5p', 'Chemical', '-', (205, 215))	('HNSCC', 'Disease', (190, 195))	('miR-205-5p', 'Chemical', '-', (155, 165))	('ADH1B', 'Gene', '125', (364, 369))	('different', 'Reg', (91, 100))	('flavin-containing monooxygenase isoform 2', 'Gene', '2327', (288, 329))	('alcohol dehydrogenase 1B', 'Gene', '125', (338, 362))	('ADH1B', 'Gene', (364, 369))	('FMO2', 'Gene', '2327', (331, 335))	('stimulating', 'PosReg', (376, 387))	('FMO2', 'Gene', (331, 335))	('drug metabolism', 'MPA', (232, 247))	('flavin-containing monooxygenase isoform 2', 'Gene', (288, 329))	('miR-205-5p', 'Var', (205, 215))	('alcohol dehydrogenase 1B', 'Gene', (338, 362))	('CYP3A5', 'Gene', '1577', (435, 441))
299685	33327871	RT-qPCR results revealed that miR-205-5p was significantly upregulated in HNSCC plasma samples compared with normal plasma samples (p < 0.05, Figure 1).	('upregulated', 'PosReg', (59, 70))	('miR-205-5p', 'Var', (30, 40))	('miR-205-5p', 'Chemical', '-', (30, 40))	('HNSCC', 'Disease', (74, 79))
299688	33327871	Scatter diagrams of the expression level of miR-205-5p in HNSCC and normal unafflicted tissues derived from TCGA and GEO databases are shown in Figure 3A-I.	('miR-205-5p', 'Var', (44, 54))	('HNSCC', 'Disease', (58, 63))	('miR-205-5p', 'Chemical', '-', (44, 54))
299690	33327871	In addition, Forest plots characterizing miR-205-5p expression level in HNSCC and normal unafflicted tissues from TCGA and GEO datasets using continuous variable meta-analysis are shown (Figure 4A-B).	('miR-205-5p', 'Chemical', '-', (41, 51))	('HNSCC', 'Disease', (72, 77))	('miR-205-5p', 'Var', (41, 51))
299691	33327871	Results of the Forest plots also revealed overexpression of miR-205-5p in HNSCC tissues compared to normal tissues (P < 0.05).	('miR-205-5p', 'Var', (60, 70))	('miR-205-5p', 'Chemical', '-', (60, 70))	('overexpression', 'PosReg', (42, 56))
299694	33327871	The expression level of miR-205-5p was significantly correlated with unpaired tissue type and age, but not with sex, lympho-vascular invasion, pathologic grade, clinical grade, histological grade, and alcohol concentration.	('expression level', 'MPA', (4, 20))	('alcohol', 'Chemical', 'MESH:D000438', (201, 208))	('correlated', 'Reg', (53, 63))	('miR-205-5p', 'Chemical', '-', (24, 34))	('miR-205-5p', 'Var', (24, 34))
299695	33327871	Enrichment analyses of GO and KEGG pathways were conducted to further study the mechanisms of miR-205-5p in HNSCC.	('miR-205-5p', 'Chemical', '-', (94, 104))	('HNSCC', 'Disease', (108, 113))	('miR-205-5p', 'Var', (94, 104))
299698	33327871	For KEGG pathway enrichment analyses, we found that the influence of miR-205-5p was important in the following crucial pathways: drug metabolism-cytochrome P450, retinol metabolism, and metabolism of xenobiotics by cytochrome P450 (Figure 10B; Table 5).	('retinol', 'Chemical', 'MESH:D014801', (162, 169))	('cytochrome P450', 'Gene', '4051', (215, 230))	('retinol metabolism', 'MPA', (162, 180))	('cytochrome P450', 'Gene', (145, 160))	('miR-205-5p', 'Var', (69, 79))	('metabolism of xenobiotics', 'MPA', (186, 211))	('cytochrome P450', 'Gene', (215, 230))	('cytochrome P450', 'Gene', '4051', (145, 160))	('miR-205-5p', 'Chemical', '-', (69, 79))
299701	33327871	In brief, the bioinformatics analyses indicated that miR-205-5p affects specific genes that are important in the dynamics and mechanistics of HNSCC.	('miR-205-5p', 'Chemical', '-', (53, 63))	('affects', 'Reg', (64, 71))	('miR-205-5p', 'Var', (53, 63))
299705	33327871	Recent studies have indicated that miR-205-5p plays a key role in facilitating biological processes, including proliferation, migration, invasiveness, apoptosis, and senescence of neoplastic pancreatic cancer, cervical cancer, and endothelial progenitor cells (EPCs).	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('miR-205-5p', 'Var', (35, 45))	('neoplastic pancreatic cancer', 'Disease', (180, 208))	('senescence', 'CPA', (166, 176))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (191, 208))	('proliferation', 'CPA', (111, 124))	('cancer', 'Disease', 'MESH:D009369', (202, 208))	('cancer', 'Disease', 'MESH:D009369', (219, 225))	('miR-205-5p', 'Chemical', '-', (35, 45))	('cancer', 'Disease', (202, 208))	('cancer', 'Disease', (219, 225))	('invasiveness', 'CPA', (137, 149))	('apoptosis', 'CPA', (151, 160))	('neoplastic pancreatic cancer', 'Disease', 'MESH:D010190', (180, 208))	('migration', 'CPA', (126, 135))
299706	33327871	Furthermore, recent research suggests that upregulation of miR-205-5p expression boosted vascular recanalization and stabilized angiogenesis in EPCs.	('boosted', 'PosReg', (81, 88))	('vascular recanalization', 'CPA', (89, 112))	('EPCs', 'Disease', (144, 148))	('upregulation', 'PosReg', (43, 55))	('miR-205-5p', 'Chemical', '-', (59, 69))	('miR-205-5p expression', 'Var', (59, 80))	('stabilized angiogenesis', 'CPA', (117, 140))
299707	33327871	Therefore, it has been postulated that miR-205-5p may be a novel diagnostic biomarker that can be used to predict and study cancer progression, and thus warrants further focused study.	('miR-205-5p', 'Chemical', '-', (39, 49))	('cancer', 'Disease', (124, 130))	('miR-205-5p', 'Var', (39, 49))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('cancer', 'Disease', 'MESH:D009369', (124, 130))
299708	33327871	Tian et al reported that miR-205-5p induces apoptosis of laryngeal squamous cell carcinoma by targeting and influencing the Bcl-2 pathway, which suggests that miR-205-5p may correlate with the onset and progression of HNSCC.	('miR-205-5p', 'Var', (25, 35))	('apoptosis', 'CPA', (44, 53))	('Bcl-2', 'Gene', (124, 129))	('Bcl-2', 'Gene', '596', (124, 129))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (67, 90))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('influencing', 'Reg', (108, 119))	('induces', 'PosReg', (36, 43))	('HNSCC', 'Disease', (218, 223))	('squamous cell carcinoma', 'Disease', (67, 90))	('miR-205-5p', 'Chemical', '-', (25, 35))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (67, 90))	('miR-205-5p', 'Chemical', '-', (159, 169))
299709	33327871	Therefore, we attempted to examine and validate the possible molecular mechanisms of miR-205-5p in HNSCC using GO and KEGG analyses.	('miR-205-5p', 'Var', (85, 95))	('miR-205-5p', 'Chemical', '-', (85, 95))	('HNSCC', 'Disease', (99, 104))
299713	33327871	Our results suggest that miR-205-5p may be a novel biomarker for the prediction and assessment of cancer incidence.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('miR-205-5p', 'Var', (25, 35))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('miR-205-5p', 'Chemical', '-', (25, 35))	('cancer', 'Disease', (98, 104))
299714	33327871	The diagnostic and prognostic roles of miR-205-5p were examined by Li and colleagues, and their results indicated that miR-205-5p could be used as a biomarker with relatively accurate results for the diagnosis of lung carcinoma.	('miR-205-5p', 'Chemical', '-', (39, 49))	('miR-205-5p', 'Chemical', '-', (119, 129))	('carcinoma', 'Phenotype', 'HP:0030731', (218, 227))	('lung carcinoma', 'Disease', 'MESH:D008175', (213, 227))	('lung carcinoma', 'Disease', (213, 227))	('miR-205-5p', 'Var', (119, 129))
299715	33327871	Lu and colleagues reported that miR-205-5p acts as a novel prognostic indicator for hepatocellular carcinoma.	('miR-205-5p', 'Chemical', '-', (32, 42))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (84, 108))	('miR-205-5p', 'Var', (32, 42))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('hepatocellular carcinoma', 'Disease', (84, 108))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (84, 108))
299716	33327871	We sought to evaluate the predicted value of miR-205-5p in HNSCC.	('miR-205-5p', 'Var', (45, 55))	('miR-205-5p', 'Chemical', '-', (45, 55))	('HNSCC', 'Disease', (59, 64))
299717	33327871	Therefore, we also sought to examine whether miR-205-5p represents a promising biomarker of tumorigenesis.	('miR-205-5p', 'Var', (45, 55))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('miR-205-5p', 'Chemical', '-', (45, 55))	('tumor', 'Disease', (92, 97))
299718	33327871	Recent accumulating evidence indicates that miR-205-5p plays an essential role in the occurrence of malignancies by regulating certain proteins and influencing signaling pathways.	('regulating', 'Reg', (116, 126))	('malignancies', 'Disease', 'MESH:D009369', (100, 112))	('influencing', 'Reg', (148, 159))	('proteins', 'Protein', (135, 143))	('miR-205-5p', 'Chemical', '-', (44, 54))	('malignancies', 'Disease', (100, 112))	('miR-205-5p', 'Var', (44, 54))	('signaling pathways', 'Pathway', (160, 178))
299719	33327871	Gulei and colleagues demonstrated that epithelial to mesenchymal transition (EMT) was suppressed following the upregulation of miR-205-5p in colon carcinoma cells that as found to be associated with E-cadherin expression.	('upregulation', 'PosReg', (111, 123))	('epithelial to mesenchymal transition', 'CPA', (39, 75))	('colon carcinoma', 'Disease', (141, 156))	('E-cadherin', 'Gene', (199, 209))	('miR-205-5p', 'Chemical', '-', (127, 137))	('E-cadherin', 'Gene', '999', (199, 209))	('suppressed', 'NegReg', (86, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (147, 156))	('colon carcinoma', 'Disease', 'MESH:D003110', (141, 156))	('miR-205-5p', 'Var', (127, 137))
299720	33327871	Moreover, miRNA-205-5p was shown to be an optimal biomarker for the assessment of renal carcinoma cells via its relationship to the PI3K/Akt/mTOR signaling pathway.	('mTOR', 'Gene', '2475', (141, 145))	('miRNA-205-5p', 'Var', (10, 22))	('renal carcinoma', 'Disease', 'MESH:C538614', (82, 97))	('mTOR', 'Gene', (141, 145))	('Akt', 'Gene', '207', (137, 140))	('renal carcinoma', 'Disease', (82, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('renal carcinoma', 'Phenotype', 'HP:0005584', (82, 97))	('Akt', 'Gene', (137, 140))	('-205-5p', 'Chemical', '-', (15, 22))
299721	33327871	The pathways associated with miR-205-5p and their influence on HNSCC are being increasingly analyzed.	('miR-205-5p', 'Var', (29, 39))	('HNSCC', 'Disease', (63, 68))	('miR-205-5p', 'Chemical', '-', (29, 39))
299722	33327871	For example, Zhang and colleagues reported that miR-205-5p functions to target PTEN via the PI3K/AKT signaling pathway during EMT in cisplatin-resistant NPC cells.	('AKT', 'Gene', '207', (97, 100))	('AKT', 'Gene', (97, 100))	('miR-205-5p', 'Chemical', '-', (48, 58))	('PTEN', 'Gene', (79, 83))	('cisplatin', 'Chemical', 'MESH:D002945', (133, 142))	('target', 'Reg', (72, 78))	('miR-205-5p', 'Var', (48, 58))	('PTEN', 'Gene', '5728', (79, 83))
299725	33327871	Polymorphisms of some of the drug-metabolizing enzymes of the cytochrome P450 system have been reported to increase susceptibility to HNSCC.	('susceptibility', 'Reg', (116, 130))	('increase', 'PosReg', (107, 115))	('Polymorphisms', 'Var', (0, 13))	('cytochrome P450', 'Gene', '4051', (62, 77))	('drug-metabolizing', 'Enzyme', (29, 46))	('HNSCC', 'Disease', (134, 139))	('cytochrome P450', 'Gene', (62, 77))
299727	33327871	Furthermore, the results suggest that both FMO2 and ADH1B were negatively correlated with miR-205-5p expression level, and that miR-205-5p may negatively regulate FMO2 and ADH1B.	('negatively', 'NegReg', (143, 153))	('FMO2', 'Gene', (163, 167))	('FMO2', 'Gene', '2327', (43, 47))	('miR-205-5p expression level', 'MPA', (90, 117))	('ADH1B', 'Gene', '125', (52, 57))	('miR-205-5p', 'Var', (128, 138))	('negatively', 'NegReg', (63, 73))	('regulate', 'Reg', (154, 162))	('FMO2', 'Gene', (43, 47))	('ADH1B', 'Gene', (172, 177))	('miR-205-5p', 'Chemical', '-', (128, 138))	('FMO2', 'Gene', '2327', (163, 167))	('correlated', 'Interaction', (74, 84))	('ADH1B', 'Gene', (52, 57))	('ADH1B', 'Gene', '125', (172, 177))	('miR-205-5p', 'Chemical', '-', (90, 100))
299729	33327871	Phillips and colleagues showed that genetic variations in FMO2 affect the metabolism of drug substrates, which is consistent with findings in the pathway we studied.	('affect', 'Reg', (63, 69))	('genetic variations', 'Var', (36, 54))	('FMO2', 'Gene', '2327', (58, 62))	('FMO2', 'Gene', (58, 62))	('metabolism of drug substrates', 'MPA', (74, 103))
299732	33327871	Thus, the results of our study are significant and may form the basis of further focused studies to examine the links between FMO2 and miR-205-5p in HNSCC patients.	('miR-205-5p', 'Var', (135, 145))	('links', 'Interaction', (112, 117))	('FMO2', 'Gene', '2327', (126, 130))	('HNSCC', 'Disease', (149, 154))	('FMO2', 'Gene', (126, 130))	('patients', 'Species', '9606', (155, 163))	('miR-205-5p', 'Chemical', '-', (135, 145))
299735	33327871	Polymorphisms of ADH1B affect the susceptibility to bladder carcinoma.	('bladder carcinoma', 'Phenotype', 'HP:0002862', (52, 69))	('Polymorphisms', 'Var', (0, 13))	('bladder carcinoma', 'Disease', (52, 69))	('bladder carcinoma', 'Disease', 'MESH:D001749', (52, 69))	('affect', 'Reg', (23, 29))	('carcinoma', 'Phenotype', 'HP:0030731', (60, 69))	('ADH1B', 'Gene', (17, 22))	('ADH1B', 'Gene', '125', (17, 22))	('susceptibility', 'MPA', (34, 48))
299736	33327871	Alcoholism is a major known risk factor for HNSCC; thus, polymorphism of ADH1B may increase the exposure to acetaldehyde converted by ADH1B during alcohol metabolism.	('increase', 'PosReg', (83, 91))	('ADH1B', 'Gene', '125', (73, 78))	('ADH1B', 'Gene', (134, 139))	('Alcoholism', 'Phenotype', 'HP:0030955', (0, 10))	('alcohol', 'Chemical', 'MESH:D000438', (147, 154))	('increase the exposure to acetaldehyde', 'Phenotype', 'HP:0003533', (83, 120))	('ADH1B', 'Gene', '125', (134, 139))	('acetaldehyde', 'Chemical', 'MESH:D000079', (108, 120))	('polymorphism', 'Var', (57, 69))	('exposure to acetaldehyde converted', 'MPA', (96, 130))	('ADH1B', 'Gene', (73, 78))
299738	33327871	Our results suggest that miR-205-5p is likely to target FMO2 and ADH1B, thereby altering the metabolic processes in HNSCC patients.	('miR-205-5p', 'Var', (25, 35))	('ADH1B', 'Gene', (65, 70))	('patients', 'Species', '9606', (122, 130))	('altering', 'Reg', (80, 88))	('HNSCC', 'Disease', (116, 121))	('miR-205-5p', 'Chemical', '-', (25, 35))	('target', 'Reg', (49, 55))	('ADH1B', 'Gene', '125', (65, 70))	('FMO2', 'Gene', '2327', (56, 60))	('metabolic processes', 'MPA', (93, 112))	('FMO2', 'Gene', (56, 60))
299739	33327871	Our study revealed that miR-205-5p is overexpressed in the HNSCC group compared to the normal control group, and has a predictive role in HNSCC.	('HNSCC', 'Disease', (138, 143))	('overexpressed', 'PosReg', (38, 51))	('miR-205-5p', 'Var', (24, 34))	('miR-205-5p', 'Chemical', '-', (24, 34))	('HNSCC', 'Disease', (59, 64))
299741	33327871	Overall, our findings suggest that miR-205-5p as a potential biomarker for prognosis of HNSCC patients, and will help to promote further research on the oncogenic roles of miR-205-5p in HNSCC.	('miR-205-5p', 'Var', (35, 45))	('patients', 'Species', '9606', (94, 102))	('HNSCC', 'Disease', (88, 93))	('miR-205-5p', 'Chemical', '-', (172, 182))	('miR-205-5p', 'Chemical', '-', (35, 45))
299769	29362353	Studies have demonstrated that defects in DNA damage repair lead to accumulated DNA damage, which confers a higher risk of cSCC cancer.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('DNA damage', 'MPA', (80, 90))	('defects', 'Var', (31, 38))	('cSCC', 'Phenotype', 'HP:0006739', (123, 127))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('cancer', 'Disease', (128, 134))
299772	29362353	Some reports revealed that genetic polymorphisms of XPD in the nucleotide excision repair pathway affected the capacity for DNA repair to influence susceptibility to many cancers, such as hepatocellular carcinoma, esophageal cancer, and squamous cell carcinoma.	('capacity for DNA repair', 'MPA', (111, 134))	('polymorphisms', 'Var', (35, 48))	('XPD', 'Gene', '2068', (52, 55))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (188, 212))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (237, 260))	('cancers', 'Disease', 'MESH:D009369', (171, 178))	('hepatocellular carcinoma', 'Disease', (188, 212))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (237, 260))	('susceptibility', 'MPA', (148, 162))	('XPD', 'Gene', (52, 55))	('influence', 'Reg', (138, 147))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('esophageal cancer', 'Disease', 'MESH:D004938', (214, 231))	('carcinoma', 'Phenotype', 'HP:0030731', (203, 212))	('carcinoma', 'Phenotype', 'HP:0030731', (251, 260))	('affected', 'Reg', (98, 106))	('squamous cell carcinoma', 'Disease', (237, 260))	('cancers', 'Phenotype', 'HP:0002664', (171, 178))	('esophageal cancer', 'Disease', (214, 231))	('cancers', 'Disease', (171, 178))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (188, 212))
299773	29362353	Also, ectopic expression of XPD was associated with the occurrence of angioderma pigmentosum and Cockayne's syndrome.	('XPD', 'Gene', (28, 31))	('associated', 'Reg', (36, 46))	('angioderma pigmentosum', 'Disease', 'MESH:D014983', (70, 92))	('angioderma pigmentosum', 'Disease', (70, 92))	('XPD', 'Gene', '2068', (28, 31))	('ectopic expression', 'Var', (6, 24))	("Cockayne's syndrome", 'Disease', 'MESH:D003057', (97, 116))	("Cockayne's syndrome", 'Disease', (97, 116))
299775	29362353	Furthermore, the studies of XPD were mainly focused on the association between XPD polymorphisms and various cancers.	('association', 'Interaction', (59, 70))	('XPD', 'Gene', (28, 31))	('cancers', 'Disease', 'MESH:D009369', (109, 116))	('XPD', 'Gene', (79, 82))	('cancers', 'Phenotype', 'HP:0002664', (109, 116))	('cancers', 'Disease', (109, 116))	('polymorphisms', 'Var', (83, 96))	('XPD', 'Gene', '2068', (28, 31))	('XPD', 'Gene', '2068', (79, 82))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))
299779	29362353	Furthermore, ectopic expression of XPD regulated the expression of cell proliferation-related, cell cycle-related, and cell apoptosis-related genes.	('cell', 'CPA', (119, 123))	('cell cycle-related', 'CPA', (95, 113))	('XPD', 'Gene', (35, 38))	('cell proliferation-related', 'CPA', (67, 93))	('regulated', 'Reg', (39, 48))	('XPD', 'Gene', '2068', (35, 38))	('expression', 'MPA', (53, 63))	('ectopic expression', 'Var', (13, 31))
299795	29362353	After being blocked with 5% non-fat milk in Tris-buffered saline containing 0.05% Tween-20 (TBST), the membrane was incubated with primary anti-c-myc mouse monoclonal antibody (D199941, 1: 5000 dilution), anti-cdc25A rabbit polyclonal antibody (D120394, 1: 1000 dilution), anti-cdk2 mouse monoclonal antibody (D199431, 1: 1000 dilution), anti-HIPK2 (D161742, 1: 1000 dilution), anti-p53 rabbit polyclonal antibody (D220082, 1: 1000 dilution), or anti-XPD mouse monoclonal antibody (D198536, 1: 5000 dilution) (Sangon, Beijing, China) at 4 C overnight.	('TBST', 'Chemical', '-', (92, 96))	('c-myc', 'Gene', (144, 149))	('HIPK2', 'Gene', (343, 348))	('p53', 'Gene', '7157', (383, 386))	('XPD', 'Gene', (451, 454))	('rabbit', 'Species', '9986', (217, 223))	('mouse', 'Species', '10090', (150, 155))	('cdk2', 'Gene', (278, 282))	('HIPK2', 'Gene', '28996', (343, 348))	('cdc25A', 'Gene', '993', (210, 216))	('p53', 'Gene', (383, 386))	('D120394', 'Var', (245, 252))	('mouse', 'Species', '10090', (283, 288))	('c-myc', 'Gene', '4609', (144, 149))	('mouse', 'Species', '10090', (455, 460))	('XPD', 'Gene', '2068', (451, 454))	('cdc25A', 'Gene', (210, 216))	('cdk2', 'Gene', '1017', (278, 282))	('rabbit', 'Species', '9986', (387, 393))	('D198536', 'Var', (482, 489))
299800	29362353	In Figure 1A, in pEGF-N2-transfected (EM+LF) or pEGF-N2-XPD-transfected (XPD+LF) groups, more than 70% of total cells were green.	('pEGF-N2', 'Chemical', '-', (48, 55))	('XPD', 'Gene', (56, 59))	('XPD', 'Gene', (73, 76))	('XPD', 'Gene', '2068', (73, 76))	('pEGF-N2-transfected', 'Var', (17, 36))	('XPD', 'Gene', '2068', (56, 59))	('pEGF-N2', 'Chemical', '-', (17, 24))
299822	29362353	Indeed, deficient DNA repair may lead to deregulation of cell growth, imbalance of cell cycle control, and development of many diseases, including cancers.	('lead to', 'Reg', (33, 40))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('DNA repair', 'Protein', (18, 28))	('imbalance', 'Phenotype', 'HP:0002172', (70, 79))	('cell growth', 'CPA', (57, 68))	('cancers', 'Disease', 'MESH:D009369', (147, 154))	('cancers', 'Phenotype', 'HP:0002664', (147, 154))	('imbalance', 'MPA', (70, 79))	('cancers', 'Disease', (147, 154))	('imbalance of cell cycle', 'Phenotype', 'HP:0011018', (70, 93))	('deregulation', 'MPA', (41, 53))	('deficient', 'Var', (8, 17))
299829	29362353	The mutation of XPD affected proper regulation of c-myc expression and is involved in the development of malignancy.	('c-myc', 'Gene', '4609', (50, 55))	('affected', 'Reg', (20, 28))	('regulation', 'MPA', (36, 46))	('mutation', 'Var', (4, 12))	('XPD', 'Gene', (16, 19))	('malignancy', 'Disease', 'MESH:D009369', (105, 115))	('malignancy', 'Disease', (105, 115))	('XPD', 'Gene', '2068', (16, 19))	('c-myc', 'Gene', (50, 55))	('involved', 'Reg', (74, 82))
299859	28954633	And also clusterin addition could increase SP-C mRNA expression in 4.05-fold, decreased p63 mRNA expression in 0.51-fold.	('SP-C', 'Gene', (43, 47))	('p63 mRNA expression', 'MPA', (88, 107))	('clusterin', 'Gene', '1191', (9, 18))	('clusterin', 'Gene', (9, 18))	('expression', 'Species', '29278', (97, 107))	('expression', 'Species', '29278', (53, 63))	('addition', 'Var', (19, 27))	('increase', 'PosReg', (34, 42))	('decreased', 'NegReg', (78, 87))	('SP-C', 'Gene', '50683', (43, 47))
299872	28954633	In human, there are two isoforms of CLU: secretory CLU protein (sCLU) (75-80 kDa) and nuclear CLU protein (nCLU) (55 kDa), they play different roles in process of cell growth apoptosis.	('play', 'Reg', (128, 132))	('CLU', 'Gene', (36, 39))	('cell growth apoptosis', 'CPA', (163, 184))	('CLU', 'Gene', '1191', (65, 68))	('CLU', 'Gene', '1191', (51, 54))	('human', 'Species', '9606', (3, 8))	('CLU', 'Gene', '1191', (108, 111))	('CLU', 'Gene', '1191', (94, 97))	('CLU', 'Gene', '1191', (36, 39))	('CLU', 'Gene', (51, 54))	('CLU', 'Gene', (94, 97))	('75-80', 'Var', (71, 76))	('CLU', 'Gene', (65, 68))	('CLU', 'Gene', (108, 111))
299874	28954633	It is reported that inhibition of CLU can increase the sensitivity of prostate cancer chemotherapy.	('prostate cancer', 'Disease', 'MESH:D011471', (70, 85))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('inhibition', 'Var', (20, 30))	('prostate cancer', 'Phenotype', 'HP:0012125', (70, 85))	('CLU', 'Gene', (34, 37))	('sensitivity', 'CPA', (55, 66))	('prostate cancer', 'Disease', (70, 85))	('CLU', 'Gene', '1191', (34, 37))	('increase', 'PosReg', (42, 50))
299927	28954633	The data showed that altered clusterin concentration could change these markers' expression.	('altered', 'Var', (21, 28))	('clusterin', 'Gene', '1191', (29, 38))	('clusterin', 'Gene', (29, 38))	('change', 'Reg', (59, 65))	('expression', 'Species', '29278', (81, 91))	('expression', 'MPA', (81, 91))
300091	27895703	Significantly different characteristics of HIV-unknown versus HIV-negative patients include that HIV-unknown patients were likely to be older, less likely to be diagnosed at an advanced stage of malignancy, and less likely to have been diagnosed with a subsequent type of cancer after their initial diagnosis.	('malignancy', 'Disease', (195, 205))	('less', 'NegReg', (211, 215))	('cancer', 'Phenotype', 'HP:0002664', (272, 278))	('HIV-unknown', 'Var', (97, 108))	('patients', 'Species', '9606', (109, 117))	('patients', 'Species', '9606', (75, 83))	('less', 'NegReg', (143, 147))	('cancer', 'Disease', 'MESH:D009369', (272, 278))	('cancer', 'Disease', (272, 278))	('malignancy', 'Disease', 'MESH:D009369', (195, 205))
300092	27895703	Additionally, HIV-unknown NADC patients had fewer comorbidities, were less likely to have tuberculosis, and less likely to have recorded mortality suggesting that this patient population may be healthier than the HIV-negative and -positive NADC patient groups.	('less', 'NegReg', (70, 74))	('patient', 'Species', '9606', (245, 252))	('NADC', 'Chemical', '-', (240, 244))	('tuberculosis', 'Disease', 'MESH:D014376', (90, 102))	('patient', 'Species', '9606', (168, 175))	('patient', 'Species', '9606', (31, 38))	('patients', 'Species', '9606', (31, 39))	('fewer', 'NegReg', (44, 49))	('HIV-unknown', 'Var', (14, 25))	('tuberculosis', 'Disease', (90, 102))	('NADC', 'Chemical', '-', (26, 30))
300161	29760583	Western blot was performed to detect the expression of TGF-beta1 after PVT1 siRNA silencing and overexpression.	('PVT1', 'Gene', (71, 75))	('TGF-beta1', 'Gene', '7040', (55, 64))	('PVT1', 'Gene', '5820', (71, 75))	('silencing', 'Var', (82, 91))	('TGF-beta1', 'Gene', (55, 64))	('overexpression', 'PosReg', (96, 110))
300166	29760583	PVT1 siRNA silencing inhibited the proliferation of cancer cells and reduced the expression of TGF-beta1, while PVT1 overexpression played an opposite role.	('silencing', 'Var', (11, 20))	('TGF-beta1', 'Gene', (95, 104))	('PVT1', 'Gene', (112, 116))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('reduced', 'NegReg', (69, 76))	('PVT1', 'Gene', '5820', (112, 116))	('PVT1', 'Gene', (0, 4))	('inhibited', 'NegReg', (21, 30))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('PVT1', 'Gene', '5820', (0, 4))	('TGF-beta1', 'Gene', '7040', (95, 104))	('expression', 'MPA', (81, 91))
300200	29760583	Blocking was performed with 5% skimmed milk at room temperature for 2 h. After that membranes were washed and incubated with primary antibodies including rabbit anti-TGF-beta1 antibody (1:2000, ab92486, Abcam) and anti-GAPDH antibody (1:1000, ab9485, Abcam) overnight at 4  C. The next day, membranes were washed and further incubated with anti-rabbit IgG-HRP secondary antibody (1:1000, MBS435036, MyBioSource) for 2 h at room temperature.	('GAPDH', 'Gene', '2597', (219, 224))	('rabbit', 'Species', '9986', (345, 351))	('GAPDH', 'Gene', (219, 224))	('TGF-beta1', 'Gene', '7040', (166, 175))	('TGF-beta1', 'Gene', (166, 175))	('rabbit', 'Species', '9986', (154, 160))	('1:1000', 'Var', (380, 386))
300212	29760583	3b, overall survival of cervical squamous cell carcinoma patient with high serum level of PVT1 was significantly shorter that that of patients with low serum level of PVT1 (p < 0.05).	('PVT1', 'Gene', (167, 171))	('cervical squamous cell carcinoma', 'Disease', 'MESH:D002294', (24, 56))	('PVT1', 'Gene', '5820', (90, 94))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (33, 56))	('patient', 'Species', '9606', (57, 64))	('cervical squamous cell carcinoma', 'Disease', (24, 56))	('patients', 'Species', '9606', (134, 142))	('carcinoma', 'Phenotype', 'HP:0030731', (47, 56))	('PVT1', 'Gene', '5820', (167, 171))	('PVT1', 'Gene', (90, 94))	('high', 'Var', (70, 74))	('shorter', 'NegReg', (113, 120))	('patient', 'Species', '9606', (134, 141))
300224	29760583	5a, PVT1 siRNA silencing significantly increased the expression level of TGF-beta1 in both cell lines (p < 0.05).	('TGF-beta1', 'Gene', '7040', (73, 82))	('TGF-beta1', 'Gene', (73, 82))	('PVT1', 'Gene', (4, 8))	('silencing', 'Var', (15, 24))	('expression level', 'MPA', (53, 69))	('increased', 'PosReg', (39, 48))	('PVT1', 'Gene', '5820', (4, 8))
300238	29760583	In another study, expression level of PVT1 was also found to be abnormally increased in gastric cancer patients, and abnormal expression of PVT1 showed promising diagnostic and prognostic values for this disease.	('gastric cancer', 'Disease', (88, 102))	('expression level', 'MPA', (18, 34))	('abnormal', 'Var', (117, 125))	('PVT1', 'Gene', (140, 144))	('gastric cancer', 'Disease', 'MESH:D013274', (88, 102))	('PVT1', 'Gene', (38, 42))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('PVT1', 'Gene', '5820', (140, 144))	('patients', 'Species', '9606', (103, 111))	('PVT1', 'Gene', '5820', (38, 42))	('gastric cancer', 'Phenotype', 'HP:0012126', (88, 102))	('increased', 'PosReg', (75, 84))
300249	29760583	PVT1 siRNA silencing inhibited the proliferation of two cervical squamous cell carcinoma cell lines, while PVT1 overexpression promoted the proliferation of cancer cells, indicating that PVT1 expression may promote the growth of cervical squamous cell carcinoma by promoting the proliferation of cancer cells.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (65, 88))	('cancer', 'Phenotype', 'HP:0002664', (296, 302))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (238, 261))	('proliferation', 'CPA', (279, 292))	('PVT1', 'Gene', (0, 4))	('promoted', 'PosReg', (127, 135))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('inhibited', 'NegReg', (21, 30))	('PVT1', 'Gene', '5820', (0, 4))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('promote', 'PosReg', (207, 214))	('cancer', 'Disease', 'MESH:D009369', (296, 302))	('PVT1', 'Gene', (187, 191))	('PVT1', 'Gene', '5820', (187, 191))	('proliferation', 'CPA', (140, 153))	('promoting', 'PosReg', (265, 274))	('carcinoma', 'Phenotype', 'HP:0030731', (252, 261))	('cancer', 'Disease', (157, 163))	('cervical squamous cell carcinoma', 'Disease', (56, 88))	('PVT1', 'Gene', (107, 111))	('cervical squamous cell carcinoma', 'Disease', (229, 261))	('growth', 'CPA', (219, 225))	('silencing', 'Var', (11, 20))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('PVT1', 'Gene', '5820', (107, 111))	('proliferation', 'CPA', (35, 48))	('cervical squamous cell carcinoma', 'Disease', 'MESH:D002294', (56, 88))	('cervical squamous cell carcinoma', 'Disease', 'MESH:D002294', (229, 261))	('cancer', 'Disease', (296, 302))
300361	28673362	reported better clinical outcomes for HNM in their intra-arterial chemotherapy study by combined CDDP and DOC than by CDDP alone.	('CDDP', 'Chemical', '-', (97, 101))	('HNM', 'Phenotype', 'HP:0012288', (38, 41))	('CDDP', 'Chemical', '-', (118, 122))	('DOC', 'Chemical', 'MESH:D000077143', (106, 109))	('better', 'PosReg', (9, 15))	('CDDP', 'Var', (97, 101))
300398	26504785	For almost three to four decades, changes in protein coding tumor suppressor genes and/or oncogenes have been thought to be the main drivers of tumor development.	('oncogenes', 'Gene', (90, 99))	('tumor', 'Disease', (144, 149))	('protein', 'Protein', (45, 52))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('changes', 'Var', (34, 41))	('tumor', 'Disease', (60, 65))
300413	26504785	Overexpression of miR-21 has also been observed in oral premalignant lesions (oral leukoplakia) compared to normal oral mucosa, indicating that alteration in miR-21 could be an earlier event in OSCC progression.	('oral leukoplakia', 'Disease', 'MESH:D007972', (78, 94))	('miR-21', 'Gene', '406991', (18, 24))	('OSCC', 'Disease', (194, 198))	('alteration', 'Var', (144, 154))	('miR-21', 'Gene', (18, 24))	('oral premalignant lesions', 'Disease', (51, 76))	('oral leukoplakia', 'Disease', (78, 94))	('miR-21', 'Gene', '406991', (158, 164))	('miR-21', 'Gene', (158, 164))	('oral leukoplakia', 'Phenotype', 'HP:0002745', (78, 94))
300425	26504785	miR-146a has been demonstrated to be overexpressed in OSCC and to enhance OSCC tumorigenesis both in the in vitro and in vivo mouse xenograft model.	('mouse', 'Species', '10090', (126, 131))	('miR-146a', 'Var', (0, 8))	('tumor', 'Disease', (79, 84))	('enhance', 'PosReg', (66, 73))	('OSCC', 'Disease', (74, 78))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('overexpressed', 'PosReg', (37, 50))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
300427	26504785	A previous study from the same group suggested an association between a higher OSCC miR-146a expression and nodal involvement in patients carrying C polymorphism (rs2910164).	('rs2910164', 'Var', (163, 172))	('rs2910164', 'Mutation', 'rs2910164', (163, 172))	('patients', 'Species', '9606', (129, 137))	('nodal involvement', 'CPA', (108, 125))	('expression', 'MPA', (93, 103))	('higher', 'PosReg', (72, 78))	('OSCC', 'Protein', (79, 83))
300428	26504785	indicated that the rs2910164 polymorphism is not associated with OSCC progression.	('rs2910164', 'Mutation', 'rs2910164', (19, 28))	('rs2910164', 'Var', (19, 28))	('OSCC', 'Disease', (65, 69))
300429	26504785	Further investigations are needed to clarify a possible role of the variant allele or rs2910164 in OSCC progression.	('OSCC', 'Disease', (99, 103))	('rs2910164', 'Mutation', 'rs2910164', (86, 95))	('rs2910164', 'Var', (86, 95))
300446	26504785	DNA hypermethylation has been suggested as one of the mechanisms for the downregulation of miR-9 in OSCC and oropharyngeal carcinoma.	('miR', 'Gene', (91, 94))	('miR', 'Gene', '220972', (91, 94))	('oropharyngeal carcinoma', 'Phenotype', 'HP:0012182', (109, 132))	('OSCC', 'Disease', (100, 104))	('oropharyngeal carcinoma', 'Disease', (109, 132))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('downregulation', 'NegReg', (73, 87))	('oropharyngeal carcinoma', 'Disease', 'MESH:D009959', (109, 132))	('hypermethylation', 'Var', (4, 20))
300479	26504785	Likewise, the elevated plasma levels of miR-21 and miR-146a were suggested to have a diagnostic value in OSCC.	('miR-146a', 'Var', (51, 59))	('OSCC', 'Disease', (105, 109))	('miR-21', 'Gene', (40, 46))	('plasma levels', 'MPA', (23, 36))	('miR-21', 'Gene', '406991', (40, 46))	('elevated', 'PosReg', (14, 22))
300499	26504785	Likewise, restoration of miR-99a level by miR mimic transfection markedly suppressed proliferation and induced apoptosis of TSCC cells.	('suppressed', 'NegReg', (74, 84))	('proliferation', 'CPA', (85, 98))	('miR-99a', 'Gene', '407055', (25, 32))	('miR', 'Gene', '220972', (25, 28))	('miR', 'Gene', (25, 28))	('miR-99a', 'Gene', (25, 32))	('transfection', 'Var', (52, 64))	('miR', 'Gene', '220972', (42, 45))	('miR', 'Gene', (42, 45))	('induced', 'Reg', (103, 110))	('apoptosis', 'CPA', (111, 120))
300510	26504785	Alteration in the expression pattern of miRNA is a common finding in OSCC tumorigenesis.	('miR', 'Gene', '220972', (40, 43))	('miR', 'Gene', (40, 43))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('Alteration', 'Var', (0, 10))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('expression pattern', 'MPA', (18, 36))	('tumor', 'Disease', (74, 79))	('OSCC', 'Disease', (69, 73))
300623	25402435	Among others, smoking directly damages the genetic integrity of cells, specifically by G C to T A transversions and hence smoking history can be traced by specific genetic signatures imprinted throughout the cancer cell genome.	('genetic integrity of cells', 'CPA', (43, 69))	('cancer', 'Disease', (208, 214))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('G C to T A transversions', 'Var', (87, 111))	('damages', 'NegReg', (31, 38))	('cancer', 'Disease', 'MESH:D009369', (208, 214))
300734	24465716	Taken together, high expression of ALDOA is associated with LSCC metastasis and poor prognosis.	('associated', 'Reg', (44, 54))	('SCC', 'Phenotype', 'HP:0002860', (61, 64))	('SCC', 'Gene', '6317', (61, 64))	('LSCC', 'Phenotype', 'HP:0030359', (60, 64))	('high', 'Var', (16, 20))	('SCC', 'Gene', (61, 64))	('ALDOA', 'Gene', '226', (35, 40))	('ALDOA', 'Gene', (35, 40))
300763	33665161	To conclude, additional study of CSCs in esophageal carcinoma could open promising therapeutic options in esophageal carcinomas by targeting hyper-activated signaling pathways, manipulating miRNA expression and hypoxia mechanisms in esophageal CSCs.	('carcinoma', 'Phenotype', 'HP:0030731', (52, 61))	('esophageal carcinomas', 'Phenotype', 'HP:0011459', (106, 127))	('miRNA expression', 'MPA', (190, 206))	('esophageal carcinoma', 'Disease', (41, 61))	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('manipulating', 'Var', (177, 189))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (41, 61))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (106, 126))	('carcinomas', 'Phenotype', 'HP:0030731', (117, 127))	('hypoxia', 'Disease', 'MESH:D000860', (211, 218))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (106, 126))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (41, 61))	('hyper-activated signaling pathways', 'Pathway', (141, 175))	('esophageal carcinomas', 'Disease', 'MESH:D004938', (106, 127))	('targeting', 'Reg', (131, 140))	('esophageal carcinomas', 'Disease', (106, 127))	('hypoxia', 'Disease', (211, 218))
300786	33665161	enhanced DNA repair efficiency, increased expression of detoxification enzymes (ALDH), increased expression of drug resistance proteins, up-regulation of anti-apoptotic proteins (Bcl-2, Bcl-xL, Mcl-l, Bcl-w), mutations in key signaling molecules, and overexpression of drug efflux pumps (P glycoprotein 1, ABCG2) etc.	('DNA repair efficiency', 'CPA', (9, 30))	('ABCG2', 'Gene', (306, 311))	('expression', 'MPA', (42, 52))	('ABCG2', 'Gene', '9429', (306, 311))	('drug resistance', 'Gene', (111, 126))	('Bcl-xL', 'Gene', '598', (186, 192))	('overexpression', 'PosReg', (251, 265))	('Bcl-w', 'Gene', '599', (201, 206))	('Bcl-2', 'Gene', (179, 184))	('enhanced', 'PosReg', (0, 8))	('drug efflux pumps', 'MPA', (269, 286))	('P glycoprotein 1', 'Gene', '5243', (288, 304))	('Bcl-2', 'Gene', '596', (179, 184))	('expression', 'MPA', (97, 107))	('Bcl-w', 'Gene', (201, 206))	('P glycoprotein 1', 'Gene', (288, 304))	('increased', 'PosReg', (87, 96))	('up-regulation', 'PosReg', (137, 150))	('mutations', 'Var', (209, 218))	('increased', 'PosReg', (32, 41))	('drug resistance', 'Phenotype', 'HP:0020174', (111, 126))	('Bcl-xL', 'Gene', (186, 192))
300801	33665161	Consistently cells with the expression of WNT10A showed enrichment for CD44+/CD24-, and these cells showed increased self-renewal, invasive and metastatic potential.	('increased', 'PosReg', (107, 116))	('WNT10A', 'Gene', '80326', (42, 48))	('expression', 'Var', (28, 38))	('self-renewal', 'CPA', (117, 129))	('CD44+/CD24-', 'Var', (71, 82))	('WNT10A', 'Gene', (42, 48))
300809	33665161	However, aberrant activation of this pathway is associated with many cancers including esophageal cancer.	('cancers', 'Disease', 'MESH:D009369', (69, 76))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('cancers', 'Disease', (69, 76))	('associated', 'Reg', (48, 58))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('cancer', 'Disease', (98, 104))	('aberrant', 'Var', (9, 17))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancers', 'Phenotype', 'HP:0002664', (69, 76))	('activation', 'PosReg', (18, 28))	('cancer', 'Disease', (69, 75))
300818	33665161	ABT263 reduces the expression of many oncogenes, including genes associated with stemness pathways such as Wnt and YAP/SOX9 axes.	('ABT263', 'Var', (0, 6))	('expression', 'MPA', (19, 29))	('YAP', 'Gene', '10413', (115, 118))	('reduces', 'NegReg', (7, 14))	('SOX9', 'Gene', '6662', (119, 123))	('YAP', 'Gene', (115, 118))	('oncogenes', 'Gene', (38, 47))	('ABT263', 'Chemical', 'MESH:C528561', (0, 6))	('SOX9', 'Gene', (119, 123))
300824	33665161	RARalpha knockdown suppresses the proliferation and metastasis of OSCC cells by minimizing the expression of proliferative markers (PCNA, Ki-67) and matrix metallo-proteinases (MMP7 and MMP9).	('MMP7', 'Gene', (177, 181))	('proliferation', 'CPA', (34, 47))	('RARalpha', 'Gene', (0, 8))	('knockdown', 'Var', (9, 18))	('PCNA', 'Gene', '5111', (132, 136))	('suppresses', 'NegReg', (19, 29))	('MMP7', 'Gene', '4316', (177, 181))	('MMP9', 'Gene', (186, 190))	('MMP9', 'Gene', '4318', (186, 190))	('Ki', 'Chemical', 'MESH:C066186', (138, 140))	('RARalpha', 'Gene', '5914', (0, 8))	('PCNA', 'Gene', (132, 136))	('minimizing', 'NegReg', (80, 90))	('expression', 'MPA', (95, 105))
300825	33665161	Not only that, RARalpha knockdown also enhances drug susceptibility of OSCC cells to 5-fluorouracil and cisplatin.	('RARalpha', 'Gene', '5914', (15, 23))	('drug susceptibility', 'MPA', (48, 67))	('cisplatin', 'Chemical', 'MESH:D002945', (104, 113))	('enhances', 'PosReg', (39, 47))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (85, 99))	('RARalpha', 'Gene', (15, 23))	('knockdown', 'Var', (24, 33))
300826	33665161	On top of that, RARalpha knockdown results in inhibition of Wnt/beta-catenin pathway by decreasing GSK3betaphosphorylation at Ser-9 and inducing phosphorylation at Tyr-216, which subsequently results in reduced expression of its downstream targets such as MMP7, MMP9, and P-glycoprotein.	('Ser', 'Chemical', 'MESH:D012694', (126, 129))	('MMP9', 'Gene', '4318', (262, 266))	('reduced', 'NegReg', (203, 210))	('MMP9', 'Gene', (262, 266))	('beta-catenin', 'Gene', (64, 76))	('GSK3beta', 'Gene', (99, 107))	('beta-catenin', 'Gene', '1499', (64, 76))	('inducing', 'Reg', (136, 144))	('MMP7', 'Gene', (256, 260))	('inhibition', 'NegReg', (46, 56))	('RARalpha', 'Gene', (16, 24))	('decreasing', 'NegReg', (88, 98))	('P-glycoprotein', 'Gene', (272, 286))	('RARalpha', 'Gene', '5914', (16, 24))	('GSK3beta', 'Gene', '2931', (99, 107))	('knockdown', 'Var', (25, 34))	('P-glycoprotein', 'Gene', '5243', (272, 286))	('MMP7', 'Gene', '4316', (256, 260))	('phosphorylation', 'MPA', (145, 160))	('Tyr', 'Chemical', 'MESH:D014443', (164, 167))	('expression', 'MPA', (211, 221))
300836	33665161	Furthermore, patient-derived xenograft models clearly demonstrated that inhibition of Notch signaling by gamma-secretase inhibitors is efficacious in downsizing tumor growth.	('patient', 'Species', '9606', (13, 20))	('inhibition', 'Var', (72, 82))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('Notch signaling', 'Pathway', (86, 101))	('downsizing tumor', 'Disease', 'MESH:D009369', (150, 166))	('downsizing tumor', 'Disease', (150, 166))
300837	33665161	Thus, inhibition of Notch signaling by DAPT could impair the stemness of OAC cells i.e.	('DAPT', 'Chemical', '-', (39, 43))	('stemness of OAC cells', 'CPA', (61, 82))	('DAPT', 'Gene', (39, 43))	('inhibition', 'Var', (6, 16))	('Notch signaling', 'Pathway', (20, 35))	('impair', 'NegReg', (50, 56))
300840	33665161	GASC1 epigenetically controls the stemness of OSCC by regulation of Notch1.	('stemness of OSCC', 'CPA', (34, 50))	('controls', 'Reg', (21, 29))	('regulation', 'Var', (54, 64))	('Notch1', 'Gene', '4851', (68, 74))	('epigenetically', 'Var', (6, 20))	('GASC1', 'Gene', (0, 5))	('GASC1', 'Gene', '23081', (0, 5))	('Notch1', 'Gene', (68, 74))
300844	33665161	Several stemness phenotypes of CSCs from OSCC were dramatically decreased after GASC1 blockade, which subsequently resulted in reduced Notch1 expression via demethylation of Notch1 promoters (H3K9me2 and H3K9me3).	('GASC1', 'Gene', (80, 85))	('Notch1', 'Gene', '4851', (174, 180))	('H3K9me2', 'Var', (192, 199))	('stemness phenotypes', 'CPA', (8, 27))	('demethylation', 'Var', (157, 170))	('Notch1', 'Gene', (135, 141))	('H3K9me3', 'Var', (204, 211))	('GASC1', 'Gene', '23081', (80, 85))	('Notch1', 'Gene', '4851', (135, 141))	('blockade', 'Var', (86, 94))	('expression', 'MPA', (142, 152))	('reduced', 'NegReg', (127, 134))	('Notch1', 'Gene', (174, 180))	('decreased', 'NegReg', (64, 73))
300846	33665161	This finding suggested that GASC1 promoted stemness in OSCC CSCs cells via Notch1 promoter demethylation.	('stemness', 'CPA', (43, 51))	('GASC1', 'Gene', '23081', (28, 33))	('demethylation', 'Var', (91, 104))	('promoted', 'PosReg', (34, 42))	('GASC1', 'Gene', (28, 33))	('Notch1', 'Gene', (75, 81))	('Notch1', 'Gene', '4851', (75, 81))
300860	33665161	In addition, activation of Hedgehog signaling could be inhibited by targeting transcription factor ATPase family AAA domain-containing protein 2 (ATAD2).	('ATPase family AAA domain-containing protein 2', 'Gene', (99, 144))	('Hedgehog signaling', 'Pathway', (27, 45))	('ATPase family AAA domain-containing protein 2', 'Gene', '29028', (99, 144))	('targeting', 'Var', (68, 77))	('ATAD2', 'Gene', (146, 151))	('inhibited', 'NegReg', (55, 64))
300864	33665161	Moreover, in vivo experiments in nude mice further validated the suppressive effect of siRNA mediated ATAD2 silencing on tumor growth.	('suppressive', 'NegReg', (65, 76))	('silencing', 'Var', (108, 117))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('nude mice', 'Species', '10090', (33, 42))	('tumor', 'Disease', (121, 126))	('ATAD2', 'Gene', (102, 107))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
300866	33665161	YAP1 plays a significant role in the maintenance of stemness of embryonic stem cells as well as contributing to the functions of CSCs.Therefore, deregulation of Hippo and activation of YAP1 in CSCs contributes many important properties of tumors, and thus, targeting YAP1 will be an effective strategy to target CSCs, thereby inhibiting tumor growth.	('tumors', 'Phenotype', 'HP:0002664', (239, 245))	('Hippo', 'Gene', (161, 166))	('YAP1', 'Gene', '10413', (0, 4))	('YAP1', 'Gene', (185, 189))	('tumor', 'Disease', (337, 342))	('tumor', 'Disease', 'MESH:D009369', (337, 342))	('tumors', 'Disease', (239, 245))	('YAP1', 'Gene', (0, 4))	('tumor', 'Disease', (239, 244))	('YAP1', 'Gene', '10413', (267, 271))	('inhibiting', 'NegReg', (326, 336))	('tumors', 'Disease', 'MESH:D009369', (239, 245))	('tumor', 'Phenotype', 'HP:0002664', (337, 342))	('tumor', 'Disease', 'MESH:D009369', (239, 244))	('YAP1', 'Gene', (267, 271))	('YAP1', 'Gene', '10413', (185, 189))	('tumor', 'Phenotype', 'HP:0002664', (239, 244))	('activation', 'PosReg', (171, 181))	('deregulation', 'Var', (145, 157))
300878	33665161	On the other hand, shRNA-mediated knockdown of YAP1 or SOX9 in transformed cells inhibited CSC phenotypes in vitro and tumorigenicity in vivo.	('tumor', 'Disease', (119, 124))	('SOX9', 'Gene', (55, 59))	('inhibited', 'NegReg', (81, 90))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('SOX9', 'Gene', '6662', (55, 59))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('knockdown', 'Var', (34, 43))	('CSC phenotypes', 'CPA', (91, 105))	('YAP1', 'Gene', '10413', (47, 51))	('YAP1', 'Gene', (47, 51))
300884	33665161	By blocking YAP1 and CDK6 with the YAP1 inhibitor CA3, and the CDK6 inhibitor LEE001 significantly suppressed esophageal cancer cell growth and CSC properties, particularly in radiation-resistant cells in both OAC and OSCC.	('suppressed', 'NegReg', (99, 109))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('CDK6', 'Gene', (21, 25))	('CDK6', 'Gene', '1021', (21, 25))	('YAP1', 'Gene', (35, 39))	('CDK6', 'Gene', (63, 67))	('YAP1', 'Gene', '10413', (35, 39))	('LEE001', 'Var', (78, 84))	('YAP1', 'Gene', (12, 16))	('CDK6', 'Gene', '1021', (63, 67))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('CSC properties', 'CPA', (144, 158))	('CA3', 'Gene', '761', (50, 53))	('YAP1', 'Gene', '10413', (12, 16))	('CA3', 'Gene', (50, 53))	('cancer', 'Disease', (121, 127))	('blocking', 'NegReg', (3, 11))
300885	33665161	The combination of LEE001 and CA3 exhibited the highest anti-tumor effects in radiation-resistant cells overexpressing YAP1 and CDK6 in both in vitro and in vivo by sensitizing resistant tumors to irradiation.	('YAP1', 'Gene', '10413', (119, 123))	('CA3', 'Gene', (30, 33))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('CDK6', 'Gene', '1021', (128, 132))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('sensitizing', 'PosReg', (165, 176))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Disease', (187, 192))	('LEE001', 'Var', (19, 25))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumors', 'Disease', (187, 193))	('tumors', 'Disease', 'MESH:D009369', (187, 193))	('tumors', 'Phenotype', 'HP:0002664', (187, 193))	('CDK6', 'Gene', (128, 132))	('tumor', 'Disease', (61, 66))	('YAP1', 'Gene', (119, 123))	('CA3', 'Gene', '761', (30, 33))
300886	33665161	Thus, it was implied that crosstalk between YAP1 and CDK6 seems to play a pivotal role in conferring radiation resistance and targeting both YAP1 and CDK6 could be a useful therapeutic strategy to treat both esophageal adenocarcinoma and squamous cell carcinoma.	('esophageal adenocarcinoma', 'Disease', (208, 233))	('CDK6', 'Gene', (53, 57))	('adenocarcinoma and squamous cell carcinoma', 'Disease', 'MESH:D002294', (219, 261))	('CDK6', 'Gene', '1021', (53, 57))	('targeting', 'Var', (126, 135))	('CDK6', 'Gene', (150, 154))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (238, 261))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (208, 233))	('CDK6', 'Gene', '1021', (150, 154))	('YAP1', 'Gene', (141, 145))	('YAP1', 'Gene', '10413', (141, 145))	('YAP1', 'Gene', '10413', (44, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (252, 261))	('esophageal adenocarcinoma', 'Disease', 'MESH:D000230', (208, 233))	('crosstalk', 'Var', (26, 35))	('YAP1', 'Gene', (44, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (224, 233))
300890	33665161	Thus, interrupting mTOR with novel therapeutic could induce a reduction of stemness of cancer cells and sensitize them to the therapies.	('stemness of cancer', 'Disease', 'MESH:D009369', (75, 93))	('sensitize', 'Reg', (104, 113))	('interrupting', 'Var', (6, 18))	('mTOR', 'Gene', '2475', (19, 23))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('mTOR', 'Gene', (19, 23))	('stemness of cancer', 'Disease', (75, 93))	('reduction', 'NegReg', (62, 71))
300893	33665161	Significant downregulation of mTOR pathway components including phospho-AKT, phospho-S6, phospho-70S6 was seen followed by metformin treatment, which are crucial to maintaining tumor cells' growth.	('downregulation', 'NegReg', (12, 26))	('AKT', 'Gene', '207', (72, 75))	('AKT', 'Gene', (72, 75))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('metformin', 'Chemical', 'MESH:D008687', (123, 132))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('phospho-70S6', 'Var', (89, 101))	('mTOR', 'Gene', '2475', (30, 34))	('tumor', 'Disease', (177, 182))	('mTOR', 'Gene', (30, 34))
300897	33665161	The JAK/STAT signaling pathway has been implicated in various physiological processes, and inhibition of this pathway could impede cancer cell growth and induce apoptosis in various cancers.	('cancer', 'Disease', (131, 137))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('inhibition', 'Var', (91, 101))	('induce', 'PosReg', (154, 160))	('impede', 'NegReg', (124, 130))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('apoptosis', 'CPA', (161, 170))	('cancers', 'Phenotype', 'HP:0002664', (182, 189))	('cancer', 'Disease', (182, 188))	('cancers', 'Disease', (182, 189))	('cancers', 'Disease', 'MESH:D009369', (182, 189))	('cancer', 'Disease', 'MESH:D009369', (131, 137))
300909	33665161	CSCs (CD44+/CD24-) were significantly enriched in EPC2T and OKF6T cells (transformed keratinocyte cell lines) overexpressing EGFR, which could induce EMT by TGF-beta1 in CSCs derived fromEPC2T and OKF6T cells.	('EPC2T', 'CellLine', 'CVCL:4361', (187, 192))	('OKF6T', 'CellLine', 'CVCL:L222', (197, 202))	('EPC2T', 'CellLine', 'CVCL:4361', (50, 55))	('CD44+/CD24-', 'Var', (6, 17))	('EGFR', 'Gene', '1956', (125, 129))	('OKF6T', 'CellLine', 'CVCL:L222', (60, 65))	('induce', 'PosReg', (143, 149))	('EGFR', 'Gene', (125, 129))	('EMT', 'CPA', (150, 153))	('TGF-beta1', 'Gene', '7040', (157, 166))	('TGF-beta1', 'Gene', (157, 166))	('overexpressing', 'Var', (110, 124))
300912	33665161	These results suggest that inhibition of EGFR may halt EMT by instigating differentiation in non-CSC populations, thereby suppressing enrichment of CSCs via inhibition of EMT.	('EGFR', 'Gene', (41, 45))	('EMT', 'CPA', (55, 58))	('instigating', 'Reg', (62, 73))	('enrichment of CSCs', 'CPA', (134, 152))	('suppressing', 'NegReg', (122, 133))	('inhibition', 'Var', (27, 37))	('inhibition', 'NegReg', (157, 167))	('halt', 'NegReg', (50, 54))	('EGFR', 'Gene', '1956', (41, 45))	('EMT', 'CPA', (171, 174))
300914	33665161	By contrast, some EGFR inhibitors suppress Zinc finger E-box binding proteins (ZEBs) and induce differentiation of CSCs in OSCC.	('induce', 'Reg', (89, 95))	('differentiation', 'CPA', (96, 111))	('EGFR', 'Gene', '1956', (18, 22))	('inhibitors', 'Var', (23, 33))	('EGFR', 'Gene', (18, 22))	('suppress', 'NegReg', (34, 42))	('Zinc', 'Protein', (43, 47))
300915	33665161	These findings suggested that EGFR inhibition might suppress the expression of ZEBs and induce differentiation in a wider variety of cancers, thereby blocking EMT-mediated enrichment of CSCs.	('suppress', 'NegReg', (52, 60))	('EGFR', 'Gene', (30, 34))	('cancers', 'Phenotype', 'HP:0002664', (133, 140))	('ZEBs', 'Gene', (79, 83))	('EMT-mediated enrichment of CSCs', 'CPA', (159, 190))	('cancers', 'Disease', (133, 140))	('expression', 'MPA', (65, 75))	('cancers', 'Disease', 'MESH:D009369', (133, 140))	('differentiation', 'CPA', (95, 110))	('induce', 'Reg', (88, 94))	('inhibition', 'Var', (35, 45))	('EGFR', 'Gene', '1956', (30, 34))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('blocking', 'NegReg', (150, 158))
300917	33665161	The key proteins in the NF-kappaB pathway (e.g., p50, p52, and Rel) were overexpressed in patients with OSCC.	('NF-kappaB pathway', 'Pathway', (24, 41))	('p52', 'Var', (54, 57))	('overexpressed', 'PosReg', (73, 86))	('p50', 'Var', (49, 52))	('Rel', 'MPA', (63, 66))	('patients', 'Species', '9606', (90, 98))	('OSCC', 'Disease', (104, 108))
300918	33665161	In addition, the aberrant activation of the NF-kappaB signaling pathway is a significant predictor for prognosis and recurrence of OSCC, which makes it a potential target in the treatment of patients with OSCC.	('aberrant', 'Var', (17, 25))	('patients', 'Species', '9606', (191, 199))	('OSCC', 'Disease', (131, 135))	('NF-kappaB signaling pathway', 'Pathway', (44, 71))	('activation', 'PosReg', (26, 36))
300920	33665161	Pristimerin demonstrated its anti-OSCC effects through the inhibition of NF-kappaB pathway by suppressing tumor necrosis factor alpha (TNFalpha)-induced Ikappa Balpha phosphorylation, p65 translocation, and the expression of NF-kappaB- dependent genes (e.g., p50, p52, and Rel).Furthermore, pristimerin inhibited cell proliferation, migration, invasion, induced apoptosis, and eliminated cancer stem-like cells (CSCs) derived from OSCC cells.	('Pristimerin', 'Chemical', 'MESH:C009043', (0, 11))	('invasion', 'CPA', (344, 352))	('pristimerin', 'Var', (291, 302))	('TNFalpha', 'Gene', (135, 143))	('eliminated', 'NegReg', (377, 387))	('tumor necrosis factor alpha', 'Gene', '7124', (106, 133))	('cancer', 'Disease', (388, 394))	('inhibited', 'NegReg', (303, 312))	('apoptosis', 'CPA', (362, 371))	('pristimerin', 'Chemical', 'MESH:C009043', (291, 302))	('p65', 'Gene', (184, 187))	('cancer', 'Phenotype', 'HP:0002664', (388, 394))	('induced', 'Reg', (354, 361))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('cell proliferation', 'CPA', (313, 331))	('p65', 'Gene', '5970', (184, 187))	('cancer', 'Disease', 'MESH:D009369', (388, 394))	('tumor necrosis factor alpha', 'Gene', (106, 133))	('TNFalpha', 'Gene', '7124', (135, 143))
300922	33665161	These results imply that pristimerin could increase chemo-sensitivity by suppressing the therapy-resistant CSC cell population in OSCCs.	('pristimerin', 'Var', (25, 36))	('pristimerin', 'Chemical', 'MESH:C009043', (25, 36))	('chemo-sensitivity', 'MPA', (52, 69))	('increase', 'PosReg', (43, 51))	('suppressing', 'NegReg', (73, 84))	('therapy-resistant CSC cell population', 'CPA', (89, 126))
300923	33665161	Depending on the roles of their target genes, miRNAs can act either as tumor suppressors or oncogenes.	('miRNAs', 'Var', (46, 52))	('tumor', 'Disease', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Disease', 'MESH:D009369', (71, 76))
300933	33665161	Since miR-203 and Bmi-1 were inversely expressed in SP cells, Bmi-1 might be a direct target of miR-203, thus therapeutics targeting miR-203 or Bmi-1could have the potential to eradicate CSCs in OSCC.	('SP', 'Chemical', '-', (52, 54))	('eradicate', 'NegReg', (177, 186))	('CSCs', 'Disease', (187, 191))	('OSCC', 'Disease', (195, 199))	('miR-203', 'Var', (96, 103))
300934	33665161	Another miRNA, miR-181b in association with STAT3, plays a significant role in stem cell properties of esophageal squamous cell carcinoma stem-like cells.	('stem cell properties of', 'CPA', (79, 102))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (103, 137))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (114, 137))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('esophageal squamous cell carcinoma', 'Disease', (103, 137))	('STAT3', 'Gene', '6774', (44, 49))	('STAT3', 'Gene', (44, 49))	('miR-181b', 'Var', (15, 23))
300936	33665161	The sphere-forming cells demonstrated cancer stem-like cell properties such as an enhanced population of CD44+/CD24- cells, increased stemness factors, mesenchymal marker expression, ATP-binding cassette (ABC) transporters and tumorigenicity in vivo when compared to that of parental cells.	('enhanced', 'PosReg', (82, 90))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('tumor', 'Disease', (227, 232))	('increased', 'PosReg', (124, 133))	('CD44+/CD24-', 'Var', (105, 116))	('stemness factors', 'CPA', (134, 150))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('mesenchymal marker expression', 'CPA', (152, 181))	('cancer', 'Disease', (38, 44))	('ATP-binding cassette', 'MPA', (183, 203))	('tumor', 'Disease', 'MESH:D009369', (227, 232))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))
300942	33665161	However, exogenous overexpression of miR-135a or silencing of SMO decreased the expression of Gli1, Gli2, and Shh, resulting in reduced proliferation migration, invasion and increased apoptosis of CSCs derived from esophageal cancer cells.	('miR-135a', 'Chemical', '-', (37, 45))	('SMO', 'Gene', (62, 65))	('silencing', 'Var', (49, 58))	('Gli1', 'Gene', (94, 98))	('decreased', 'NegReg', (66, 75))	('proliferation migration', 'CPA', (136, 159))	('overexpression', 'PosReg', (19, 33))	('Shh', 'Gene', (110, 113))	('reduced', 'NegReg', (128, 135))	('invasion', 'CPA', (161, 169))	('Gli2', 'Gene', (100, 104))	('cancer', 'Disease', 'MESH:D009369', (226, 232))	('expression', 'MPA', (80, 90))	('Shh', 'Gene', '6469', (110, 113))	('Gli1', 'Gene', '2735', (94, 98))	('apoptosis', 'CPA', (184, 193))	('SMO', 'Gene', '6608', (62, 65))	('Gli2', 'Gene', '2736', (100, 104))	('cancer', 'Disease', (226, 232))	('miR-135a', 'Var', (37, 45))	('increased', 'PosReg', (174, 183))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
300943	33665161	Interestingly, silencing of miR-135a was associated with increased carcinogenic capability of miR-135a in CSCs derived from OSCC.	('carcinogenic', 'Disease', 'MESH:D063646', (67, 79))	('carcinogenic', 'Disease', (67, 79))	('miR-135a', 'Gene', (28, 36))	('miR-135a', 'Chemical', '-', (28, 36))	('silencing', 'Var', (15, 24))	('increased', 'PosReg', (57, 66))	('miR-135a', 'Gene', (94, 102))	('miR-135a', 'Chemical', '-', (94, 102))
300952	33665161	Also, dysregulation of miR-455-3ppromoted chemoresistance and tumorigenesis of OSCC cells.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('miR-455-3p', 'Chemical', '-', (23, 33))	('tumor', 'Disease', (62, 67))	('dysregulation', 'Var', (6, 19))	('chemoresistance', 'CPA', (42, 57))	('miR-455-3ppromoted', 'Gene', (23, 41))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
300953	33665161	Interestingly, treatment with a miR-455-3p antagomir significantly chemo-sensitized OSCC cells and decreased CD90+ and CD271 + cell populations (a CSC phenotype) through inhibition of various stemness-associated pathways including Wnt/beta-catenin and TGF- beta signaling.	('miR-455-3p', 'Chemical', '-', (32, 42))	('decreased', 'NegReg', (99, 108))	('CD271', 'Gene', '4804', (119, 124))	('miR-455-3p', 'Var', (32, 42))	('TGF- beta', 'Gene', (252, 261))	('inhibition', 'NegReg', (170, 180))	('CD271', 'Gene', (119, 124))	('OSCC', 'Disease', (84, 88))	('TGF- beta', 'Gene', '7039', (252, 261))	('beta-catenin', 'Gene', (235, 247))	('stemness-associated', 'CPA', (192, 211))	('beta-catenin', 'Gene', '1499', (235, 247))
300965	33665161	Importantly, miR-221 knockdown in 5-FU resistant cells resulted in decreased cell proliferation, increased apoptosis, restored chemo-sensitivity, and led to inactivation of the stem cell pathway Wnt/beta-catenin by activation of DKK2 activity.	('activity', 'MPA', (234, 242))	('beta-catenin', 'Gene', '1499', (199, 211))	('increased', 'PosReg', (97, 106))	('chemo-sensitivity', 'MPA', (127, 144))	('activation', 'PosReg', (215, 225))	('5-FU', 'Chemical', 'MESH:D005472', (34, 38))	('miR-221', 'Gene', '407006', (13, 20))	('restored', 'PosReg', (118, 126))	('miR-221', 'Gene', (13, 20))	('DKK2', 'Gene', '27123', (229, 233))	('knockdown', 'Var', (21, 30))	('inactivation', 'NegReg', (157, 169))	('decreased', 'NegReg', (67, 76))	('apoptosis', 'CPA', (107, 116))	('DKK2', 'Gene', (229, 233))	('cell proliferation', 'CPA', (77, 95))	('beta-catenin', 'Gene', (199, 211))
300968	33665161	Furthermore, a substantial dysregulation of Wnt/beta-catenin signaling and chemoresistance target genes such as CDH1, CD44, MYC, and ABCG2 was reported as a result of miR-221 modulation in OAC.	('beta-catenin', 'Gene', (48, 60))	('CD44', 'Gene', (118, 122))	('MYC', 'Gene', '4609', (124, 127))	('MYC', 'Gene', (124, 127))	('miR-221', 'Gene', '407006', (167, 174))	('OAC', 'Disease', (189, 192))	('beta-catenin', 'Gene', '1499', (48, 60))	('modulation', 'Var', (175, 185))	('ABCG2', 'Gene', (133, 138))	('miR-221', 'Gene', (167, 174))	('CDH1', 'Gene', (112, 116))	('ABCG2', 'Gene', '9429', (133, 138))	('dysregulation', 'MPA', (27, 40))	('CDH1', 'Gene', '999', (112, 116))
300973	33665161	On the other hand, inhibition of HIF1alpha resulted in suppression of tumorigenicity of OSCC cells in both in vitro and in vivo.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('suppression', 'NegReg', (55, 66))	('inhibition', 'Var', (19, 29))	('HIF1alpha', 'Gene', '3091', (33, 42))	('tumor', 'Disease', (70, 75))	('HIF1alpha', 'Gene', (33, 42))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
300978	33665161	A significant reduction of cell proliferation, migration and tumor growth was occurred followed by HIF-1alpha knockdown in OSCC cells in vivo.	('knockdown', 'Var', (110, 119))	('cell proliferation', 'CPA', (27, 45))	('HIF-1alpha', 'Gene', '3091', (99, 109))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('migration', 'CPA', (47, 56))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('HIF-1alpha', 'Gene', (99, 109))	('reduction', 'NegReg', (14, 23))	('tumor', 'Disease', (61, 66))
300979	33665161	In addition, knockdown of HIF-1alpha also inhibited spheroid formation, inhibited expression of CSC-related genes and Wnt/beta-catenin target genes, thereby decreased Wnt/beta-catenin activity CSCs derived from OSCC.	('spheroid formation', 'CPA', (52, 70))	('beta-catenin', 'Gene', (122, 134))	('beta-catenin', 'Gene', '1499', (171, 183))	('HIF-1alpha', 'Gene', '3091', (26, 36))	('expression', 'MPA', (82, 92))	('beta-catenin', 'Gene', '1499', (122, 134))	('inhibited', 'NegReg', (42, 51))	('CSC-related genes', 'Gene', (96, 113))	('HIF-1alpha', 'Gene', (26, 36))	('decreased', 'NegReg', (157, 166))	('inhibited', 'NegReg', (72, 81))	('beta-catenin', 'Gene', (171, 183))	('knockdown', 'Var', (13, 22))
300980	33665161	Therefore, targeting hypoxia or its related factor and at the same time, inhibiting Wnt/beta-catenin might be an attractive option against patients with both OSCC and OAC.	('patients', 'Species', '9606', (139, 147))	('OAC', 'Disease', (167, 170))	('hypoxia', 'Disease', 'MESH:D000860', (21, 28))	('inhibiting', 'Var', (73, 83))	('hypoxia', 'Disease', (21, 28))	('beta-catenin', 'Gene', (88, 100))	('OSCC', 'Disease', (158, 162))	('beta-catenin', 'Gene', '1499', (88, 100))
301101	28587590	Some oncogenes showed low absolute fold-change between tumour and normal tissue as a consequence of being affected by mutations at DNA level rather than being differentially expressed.	('tumour', 'Disease', (55, 61))	('oncogenes', 'Gene', (5, 14))	('fold-change', 'MPA', (35, 46))	('mutations', 'Var', (118, 127))	('affected', 'Reg', (106, 114))	('tumour', 'Phenotype', 'HP:0002664', (55, 61))	('tumour', 'Disease', 'MESH:D009369', (55, 61))
301133	28587590	The final topic to be considered is the platform performance in identification of gene isoforms which may originate from alternative splicing in normal tissue and aberrant splicing in cancer.	('cancer', 'Disease', (184, 190))	('originate', 'Reg', (106, 115))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('aberrant splicing', 'Var', (163, 180))
301139	28587590	Both methods were able to identify splicing events in a small selected group of genes which were linked to cancer at isoform level in literature.	('splicing events', 'Var', (35, 50))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('linked', 'Reg', (97, 103))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('cancer', 'Disease', (107, 113))
301141	28587590	They originate from 207 genes which are strong candidates for further biological investigation, as they undergo alternative or aberrant splicing in lung squamous cell carcinoma.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (153, 176))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (148, 176))	('carcinoma', 'Phenotype', 'HP:0030731', (167, 176))	('undergo', 'Reg', (104, 111))	('aberrant splicing', 'Var', (127, 144))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (148, 176))	('lung squamous cell carcinoma', 'Disease', (148, 176))
301147	28587590	AUC Area under ROC curve CPM Counts per million DEA Differential expression analysis FDR False discovery rate FPKM Fragments per kilobase of transcript per million mapped reads GG-H GLUE Grant human transcriptome arrays GO Gene ontology HTA Affymetrix  Human Transcriptome Arrays 2.0 lncRNA Long non-coding RNA logFC Log2 fold change miRNA Micro RNA mRNA Messenger RNA PCA Principal component analysis PVCA Principal variance component analysis RIN RNA integrity number RLE Relative log expression RMA Robust multi-chip analysis RNA-seq RNA sequencing ROC Receiver operating characteristic rRNA Ribosomal RNA SCC Squamous cell carcinoma SI Splicing index SNP Single nucleotide polymorphism TCGA The Cancer Genome Atlas TMM Weighted trimmed mean method	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (699, 718))	('Human', 'Species', '9606', (253, 258))	('RMA', 'Chemical', '-', (498, 501))	('human', 'Species', '9606', (193, 198))	('DEA', 'Chemical', '-', (48, 51))	('GG-H', 'Gene', '8836', (177, 181))	('Cancer Genome Atlas', 'Disease', (699, 718))	('carcinoma', 'Phenotype', 'HP:0030731', (627, 636))	('SCC', 'Phenotype', 'HP:0002860', (609, 612))	('SI', 'Disease', 'None', (637, 639))	('Cancer', 'Phenotype', 'HP:0002664', (699, 705))	('HTA', 'Chemical', '-', (237, 240))	('Squamous cell carcinoma', 'Phenotype', 'HP:0002860', (613, 636))	('SCC', 'Gene', '6317', (609, 612))	('Squamous cell carcinoma', 'Disease', (613, 636))	('Single nucleotide polymorphism', 'Var', (659, 689))	('Squamous cell carcinoma', 'Disease', 'MESH:D002294', (613, 636))	('SCC', 'Gene', (609, 612))	('GG-H', 'Gene', (177, 181))
301229	26103446	In addition, the presence of anal hrHPV infection at baseline increased the risk of acquisition of any HPV type by 65% (95% CI 1%-170%), and the presence of anal low risk HPV infection increased the risk of acquisition of another HPV type by 80% (95% CI 8%-200%).	('HPV', 'Species', '10566', (171, 174))	('HPV', 'Species', '10566', (230, 233))	('HPV infection', 'Disease', (36, 49))	('HPV infection', 'Disease', 'MESH:D030361', (171, 184))	('HPV infection', 'Disease', (171, 184))	('presence', 'Var', (145, 153))	('HPV', 'Species', '10566', (103, 106))	('HPV', 'Species', '10566', (36, 39))	('HPV infection', 'Disease', 'MESH:D030361', (36, 49))	('presence', 'Var', (17, 25))	('acquisition', 'MPA', (84, 95))
301234	26103446	In addition, risk of anal infection was enhanced by the presence of multiple HPV types in the cervix.	('anal infection', 'Disease', (21, 35))	('enhanced', 'PosReg', (40, 48))	('presence', 'Var', (56, 64))	('HPV', 'Species', '10566', (77, 80))
301323	26103446	Risk increased with low CD4 nadir.	('CD4', 'Gene', (24, 27))	('CD4', 'Gene', '920', (24, 27))	('low', 'Var', (20, 23))
301410	26103446	Older regimens using cyclosporine and azathioprine were associated with the highest risk of anal cancer whereas newer regimens using tacrolimus and mycophenolate appeared to be protective against anal cancer.	('anal cancer', 'Disease', (196, 207))	('men', 'Species', '9606', (10, 13))	('anal cancer', 'Phenotype', 'HP:0032186', (196, 207))	('azathioprine', 'Chemical', 'MESH:D001379', (38, 50))	('tacrolimus', 'Chemical', 'MESH:D016559', (133, 143))	('anal cancer', 'Phenotype', 'HP:0032186', (92, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('anal cancer', 'Disease', (92, 103))	('anal cancer', 'Disease', 'MESH:D001005', (92, 103))	('mycophenolate', 'Chemical', 'MESH:D009173', (148, 161))	('cyclosporine', 'Var', (21, 33))	('cyclosporine', 'Chemical', 'MESH:D016572', (21, 33))	('anal cancer', 'Disease', 'MESH:D001005', (196, 207))	('men', 'Species', '9606', (122, 125))	('azathioprine', 'Var', (38, 50))
301417	26103446	Solid organ transplantation was associated with an anal cancer SIR of 14.4 (C.I.	('Solid', 'Var', (0, 5))	('anal cancer', 'Phenotype', 'HP:0032186', (51, 62))	('anal cancer', 'Disease', 'MESH:D001005', (51, 62))	('anal cancer', 'Disease', (51, 62))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))
301454	26103446	Cervical CIN3 was found to have an increased risk (SIR=1.8 (95% CI 1.2, 2.7):no risk was seen for invasive cervical cancer.	('CIN', 'Disease', 'MESH:D007674', (9, 12))	('Cervical', 'Var', (0, 8))	('invasive cervical cancer', 'Disease', (98, 122))	('invasive cervical cancer', 'Disease', 'MESH:D002583', (98, 122))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('CIN', 'Disease', (9, 12))
301545	26103446	In this study, the risk of AIN increased significantly in the presence of multicentric LGTN.	('LGTN', 'Chemical', '-', (87, 91))	('multicentric LGTN', 'Var', (74, 91))	('AIN', 'Disease', (27, 30))
301553	26103446	Biopsy proven AIN was higher in the women with LGTN [10.4%, (95%CI 5.6-17.3%)] than in women without LGTN (1.4% (95% CI 0.1-6.5%, p = 0.016).	('LGTN', 'Chemical', '-', (47, 51))	('LGTN', 'Chemical', '-', (101, 105))	('higher', 'PosReg', (22, 28))	('LGTN', 'Var', (47, 51))	('women', 'Species', '9606', (36, 41))	('women', 'Species', '9606', (87, 92))
301594	26103446	Attempts to enhance the suboptimal accuracy of the anal cytology have included the use of immunostaining for p16/Ki67 on the slide and detection of HPV16/18 DNA or HPV E6/E7 mRNA in the residual liquid-based specimen.	('detection', 'Reg', (135, 144))	('HPV16/18 DNA', 'Var', (148, 160))	('E6/E7', 'Gene', '25479186', (168, 173))	('HPV', 'Species', '10566', (148, 151))	('E6/E7', 'Gene', (168, 173))	('p16/Ki67', 'Var', (109, 117))	('HPV16', 'Species', '333760', (148, 153))	('men', 'Species', '9606', (213, 216))	('HPV', 'Species', '10566', (164, 167))
301642	26103446	For women with vulvar cancers or high-grade VIN, immediate screening is recommended.	('vulvar cancers', 'Disease', (15, 29))	('cancers', 'Phenotype', 'HP:0002664', (22, 29))	('VIN', 'Gene', '440900', (44, 47))	('men', 'Species', '9606', (77, 80))	('high-grade', 'Var', (33, 43))	('women', 'Species', '9606', (4, 9))	('VIN', 'Gene', (44, 47))	('vulvar cancer', 'Phenotype', 'HP:0030416', (15, 28))	('vulvar cancers', 'Disease', 'MESH:D014846', (15, 29))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('men', 'Species', '9606', (6, 9))
301643	26103446	For women with cervical or vaginal cancers or high-grade CIN or VaIN, screening with cytology or DARE and symptom review within 5 years of initial diagnosis is suggested.	('CIN', 'Disease', (57, 60))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('CIN', 'Disease', 'MESH:D007674', (57, 60))	('high-grade', 'Var', (46, 56))	('women', 'Species', '9606', (4, 9))	('vaginal cancer', 'Phenotype', 'HP:0100650', (27, 41))	('vaginal cancers', 'Disease', 'MESH:D014625', (27, 42))	('cancers', 'Phenotype', 'HP:0002664', (35, 42))	('cervical', 'Disease', (15, 23))	('vaginal cancers', 'Disease', (27, 42))
301664	33936178	For example, lung cancer patients with high ERCC1 expression have significantly longer overall survival than those with low ERCC1 expression.	('ERCC1', 'Gene', (44, 49))	('high', 'Var', (39, 43))	('lung cancer', 'Disease', (13, 24))	('lung cancer', 'Phenotype', 'HP:0100526', (13, 24))	('overall', 'MPA', (87, 94))	('expression', 'Var', (50, 60))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('ERCC1', 'Gene', '2067', (124, 129))	('ERCC1', 'Gene', (124, 129))	('patients', 'Species', '9606', (25, 33))	('longer', 'PosReg', (80, 86))	('lung cancer', 'Disease', 'MESH:D008175', (13, 24))	('ERCC1', 'Gene', '2067', (44, 49))
301665	33936178	BRCA1 is a prognostic biomarker in lung cancer, patients with high expression of BRCA1 have a poor outcome.	('BRCA1', 'Gene', (0, 5))	('BRCA1', 'Gene', (81, 86))	('lung cancer', 'Disease', 'MESH:D008175', (35, 46))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('BRCA1', 'Gene', '672', (0, 5))	('lung cancer', 'Disease', (35, 46))	('lung cancer', 'Phenotype', 'HP:0100526', (35, 46))	('high', 'Var', (62, 66))	('BRCA1', 'Gene', '672', (81, 86))	('patients', 'Species', '9606', (48, 56))
301668	33936178	Abnormal estrogen signal transduction can promote the occurrence of cancer and some metabolic diseases.	('metabolic diseases', 'Disease', 'MESH:D008659', (84, 102))	('Abnormal estrogen signal', 'Phenotype', 'HP:0025132', (0, 24))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('estrogen', 'Protein', (9, 17))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('promote', 'PosReg', (42, 49))	('metabolic diseases', 'Disease', (84, 102))	('Abnormal', 'Var', (0, 8))	('cancer', 'Disease', (68, 74))
301670	33936178	Abnormal ER signaling pathways may change the biological function of the tumor by affecting the proliferation and invasion of the tumor.	('affecting', 'Reg', (82, 91))	('biological function', 'MPA', (46, 65))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('proliferation', 'CPA', (96, 109))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('tumor', 'Disease', (73, 78))	('change', 'Reg', (35, 41))	('Abnormal', 'Var', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('ER', 'Gene', '2099', (9, 11))	('tumor', 'Disease', (130, 135))
301710	33936178	The GSE63459 had 31 lung tumor tissue and 31 paired adjacent lung normal tissues that were collected from 31 LUAD patients.	('lung tumor', 'Phenotype', 'HP:0100526', (20, 30))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('GSE63459', 'Var', (4, 12))	('lung tumor', 'Disease', (20, 30))	('LUAD', 'Phenotype', 'HP:0030078', (109, 113))	('lung tumor', 'Disease', 'MESH:D008175', (20, 30))	('patients', 'Species', '9606', (114, 122))
301728	33936178	The validation results showed that the FKBP4 and KRAS were the risk factors for the survival of LUAD patients and the high expressions of FKBP4 and KRAS reduced the survival time of LUAD patients.	('patients', 'Species', '9606', (187, 195))	('KRAS', 'Gene', (148, 152))	('KRAS', 'Gene', '3845', (49, 53))	('patients', 'Species', '9606', (101, 109))	('LUAD', 'Disease', (182, 186))	('FKBP4', 'Gene', '2288', (138, 143))	('LUAD', 'Phenotype', 'HP:0030078', (96, 100))	('high expressions', 'Var', (118, 134))	('FKBP4', 'Gene', (138, 143))	('survival time', 'CPA', (165, 178))	('reduced', 'NegReg', (153, 160))	('LUAD', 'Phenotype', 'HP:0030078', (182, 186))	('KRAS', 'Gene', '3845', (148, 152))	('FKBP4', 'Gene', '2288', (39, 44))	('FKBP4', 'Gene', (39, 44))	('KRAS', 'Gene', (49, 53))
301729	33936178	The ADCY9 was the protective factor for the survival of LUAD patients and the high expressions of ADCY9 prolonged the survival time of LUAD patients.	('ADCY9', 'Gene', (98, 103))	('ADCY9', 'Gene', (4, 9))	('ADCY9', 'Gene', '115', (98, 103))	('patients', 'Species', '9606', (61, 69))	('LUAD', 'Phenotype', 'HP:0030078', (56, 60))	('LUAD', 'Phenotype', 'HP:0030078', (135, 139))	('high expressions', 'Var', (78, 94))	('ADCY9', 'Gene', '115', (4, 9))	('prolonged', 'PosReg', (104, 113))	('patients', 'Species', '9606', (140, 148))	('survival time', 'CPA', (118, 131))
301735	33936178	Our study suggested that high-expression of FKBP4 and low-expression of ADCY9 were the risks of LUAD and reduced the overall survival time of LUAD patients.	('LUAD', 'Phenotype', 'HP:0030078', (96, 100))	('ADCY9', 'Gene', '115', (72, 77))	('LUAD', 'Disease', (96, 100))	('LUAD', 'Phenotype', 'HP:0030078', (142, 146))	('low-expression', 'NegReg', (54, 68))	('patients', 'Species', '9606', (147, 155))	('ADCY9', 'Gene', (72, 77))	('reduced', 'NegReg', (105, 112))	('high-expression', 'Var', (25, 40))	('FKBP4', 'Gene', '2288', (44, 49))	('risks', 'Reg', (87, 92))	('FKBP4', 'Gene', (44, 49))
301736	33936178	Overexpression of KRAS was a risk of LUAD and reduced the overall survival time of LUAD patients.	('overall', 'MPA', (58, 65))	('LUAD', 'Phenotype', 'HP:0030078', (83, 87))	('KRAS', 'Gene', (18, 22))	('KRAS', 'Gene', '3845', (18, 22))	('patients', 'Species', '9606', (88, 96))	('reduced', 'NegReg', (46, 53))	('LUAD', 'Phenotype', 'HP:0030078', (37, 41))	('Overexpression', 'Var', (0, 14))	('LUAD', 'Disease', (37, 41))
301749	33936178	The rs12582595 of FKBP4 was correlated with general health improvement in systemic lupus erythematosus patients.	('general health', 'Disease', (44, 58))	('men', 'Species', '9606', (66, 69))	('FKBP4', 'Gene', '2288', (18, 23))	('FKBP4', 'Gene', (18, 23))	('systemic lupus erythematosus', 'Disease', 'MESH:D008180', (74, 102))	('systemic lupus erythematosus', 'Disease', (74, 102))	('rs12582595', 'Mutation', 'rs12582595', (4, 14))	('patients', 'Species', '9606', (103, 111))	('systemic lupus erythematosus', 'Phenotype', 'HP:0002725', (74, 102))	('improvement', 'PosReg', (59, 70))	('rs12582595', 'Var', (4, 14))
301750	33936178	The FKBP4 SNP rs4409904 was associated with lower odds of polycystic ovary syndrome.	('rs4409904', 'Var', (14, 23))	('lower', 'NegReg', (44, 49))	('FKBP4', 'Gene', (4, 9))	('polycystic ovary syndrome', 'Disease', (58, 83))	('polycystic ovary syndrome', 'Disease', 'MESH:D011085', (58, 83))	('polycystic ovary', 'Phenotype', 'HP:0000147', (58, 74))	('ovary syndrome', 'Phenotype', 'HP:0000137', (69, 83))	('rs4409904', 'Mutation', 'rs4409904', (14, 23))	('FKBP4', 'Gene', '2288', (4, 9))
301754	33936178	In our study, the expression of FKBP4 was up-regulated in LUAD, and patients with high FKBP4 expression had a relatively poor prognosis, which was the first report in LUAD and was consistent with the expression changes in other cancers.	('cancers', 'Phenotype', 'HP:0002664', (228, 235))	('up-regulated', 'PosReg', (42, 54))	('LUAD', 'Phenotype', 'HP:0030078', (58, 62))	('cancers', 'Disease', (228, 235))	('high', 'Var', (82, 86))	('LUAD', 'Disease', (58, 62))	('FKBP4', 'Gene', (87, 92))	('cancers', 'Disease', 'MESH:D009369', (228, 235))	('FKBP4', 'Gene', '2288', (87, 92))	('patients', 'Species', '9606', (68, 76))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('expression', 'MPA', (93, 103))	('expression', 'MPA', (18, 28))	('FKBP4', 'Gene', (32, 37))	('FKBP4', 'Gene', '2288', (32, 37))	('LUAD', 'Phenotype', 'HP:0030078', (167, 171))
301758	33936178	reported that deletion of ADCY9 is the causation for the cardiac abnormalities.	('ADCY9', 'Gene', (26, 31))	('cardiac abnormalities', 'Phenotype', 'HP:0001627', (57, 78))	('ADCY9', 'Gene', '115', (26, 31))	('cardiac abnormalities', 'Disease', (57, 78))	('deletion', 'Var', (14, 22))	('cardiac abnormalities', 'Disease', 'MESH:D018376', (57, 78))
301759	33936178	SNP rs2238432 in the ADCY9 gene was linked with decreased stroke risk.	('decreased stroke', 'Disease', (48, 64))	('ADCY9', 'Gene', '115', (21, 26))	('rs2238432', 'Mutation', 'rs2238432', (4, 13))	('stroke', 'Phenotype', 'HP:0001297', (58, 64))	('SNP rs2238432', 'Var', (0, 13))	('ADCY9', 'Gene', (21, 26))	('decreased stroke', 'Disease', 'MESH:D020521', (48, 64))
301760	33936178	Proportional reductions in the risk of major vascular events with anacetrapib did not differ significantly by ADCY9 rs1967309 genotype.	('rs1967309', 'Mutation', 'rs1967309', (116, 125))	('rs1967309', 'Var', (116, 125))	('ADCY9', 'Gene', '115', (110, 115))	('anacetrapib', 'Chemical', 'MESH:C530884', (66, 77))	('reductions', 'NegReg', (13, 23))	('ADCY9', 'Gene', (110, 115))
301761	33936178	There was no significant association between the ADCY9 rs1967309 genotype and cardiovascular benefit or harm for the cholesteryl ester transfer protein inhibitor evacetrapib.	('ADCY9', 'Gene', '115', (49, 54))	('cholesteryl ester transfer protein', 'Gene', (117, 151))	('cardiovascular benefit', 'CPA', (78, 100))	('ADCY9', 'Gene', (49, 54))	('rs1967309', 'Mutation', 'rs1967309', (55, 64))	('rs1967309', 'Var', (55, 64))	('cholesteryl ester transfer protein', 'Gene', '1071', (117, 151))	('evacetrapib', 'Chemical', 'MESH:C568301', (162, 173))
301767	33936178	suggested that ADCY9 gene polymorphisms may alone, and in combination with ADRB2 gene polymorphisms, contribute to individual response to combination therapy in mild to moderate asthmatics.	('contribute', 'Reg', (101, 111))	('ADCY9', 'Gene', '115', (15, 20))	('polymorphisms', 'Var', (26, 39))	('ADRB2', 'Gene', '154', (75, 80))	('ADRB2', 'Gene', (75, 80))	('mild to moderate asthmatics', 'Disease', (161, 188))	('ADCY9', 'Gene', (15, 20))
301769	33936178	One study discovered the association of ADCY9 variants with glioma risk and prognosis and the other two studies suggested ADCY9 gene polymorphisms were associated with Hepatocellular Carcinoma and colorectal cancer risk in the Chinese Han population.	('ADCY9', 'Gene', (122, 127))	('Hepatocellular Carcinoma', 'Disease', 'MESH:D006528', (168, 192))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('glioma', 'Disease', (60, 66))	('associated', 'Reg', (152, 162))	('colorectal cancer', 'Phenotype', 'HP:0003003', (197, 214))	('glioma', 'Disease', 'MESH:D005910', (60, 66))	('ADCY9', 'Gene', '115', (40, 45))	('Hepatocellular Carcinoma', 'Phenotype', 'HP:0001402', (168, 192))	('glioma', 'Phenotype', 'HP:0009733', (60, 66))	('ADCY9', 'Gene', (40, 45))	('polymorphisms', 'Var', (133, 146))	('colorectal cancer', 'Disease', 'MESH:D015179', (197, 214))	('variants', 'Var', (46, 54))	('colorectal cancer', 'Disease', (197, 214))	('association', 'Interaction', (25, 36))	('Hepatocellular Carcinoma', 'Disease', (168, 192))	('ADCY9', 'Gene', '115', (122, 127))	('Carcinoma', 'Phenotype', 'HP:0030731', (183, 192))
301771	33936178	ADCY9 had hypermethylation and low-expression in bladder cancer.	('hypermethylation', 'Var', (10, 26))	('low-expression', 'NegReg', (31, 45))	('bladder cancer', 'Disease', (49, 63))	('ADCY9', 'Gene', (0, 5))	('bladder cancer', 'Phenotype', 'HP:0009725', (49, 63))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('ADCY9', 'Gene', '115', (0, 5))	('bladder cancer', 'Disease', 'MESH:D001749', (49, 63))
301773	33936178	ADCY9 had a different expression between EGFR/KRAS mutation groups in LUAD.	('EGFR', 'Gene', (41, 45))	('ADCY9', 'Gene', (0, 5))	('LUAD', 'Disease', (70, 74))	('KRAS', 'Gene', (46, 50))	('LUAD', 'Phenotype', 'HP:0030078', (70, 74))	('KRAS', 'Gene', '3845', (46, 50))	('mutation', 'Var', (51, 59))	('ADCY9', 'Gene', '115', (0, 5))	('EGFR', 'Gene', '1956', (41, 45))
301774	33936178	One study showed that ADCY9 immunoreactivity scores were significantly higher (P = 0.002) in tumor tissues than in adjacent normal samples in colon cancer, and ADCY9 high expression level was associated with poor disease-free survival (P = 0.001) but not overall survival (P = 0.055) in colon cancer.	('higher', 'PosReg', (71, 77))	('colon cancer', 'Disease', (142, 154))	('immunoreactivity scores', 'MPA', (28, 51))	('high', 'Var', (166, 170))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('colon cancer', 'Phenotype', 'HP:0003003', (287, 299))	('ADCY9', 'Gene', '115', (160, 165))	('disease-free survival', 'CPA', (213, 234))	('colon cancer', 'Phenotype', 'HP:0003003', (142, 154))	('ADCY9', 'Gene', (160, 165))	('poor', 'NegReg', (208, 212))	('ADCY9', 'Gene', '115', (22, 27))	('colon cancer', 'Disease', 'MESH:D015179', (287, 299))	('cancer', 'Phenotype', 'HP:0002664', (293, 299))	('colon cancer', 'Disease', 'MESH:D015179', (142, 154))	('ADCY9', 'Gene', (22, 27))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('tumor', 'Disease', (93, 98))	('colon cancer', 'Disease', (287, 299))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
301797	33936178	suggested that knockdown of ERbeta by short hairpin RNA constructs resulted in the loss of estrogen-dependent growth of lung cancer cells.	('knockdown', 'Var', (15, 24))	('estrogen-dependent growth', 'MPA', (91, 116))	('lung cancer', 'Disease', (120, 131))	('ERbeta', 'Gene', '2099', (28, 34))	('lung cancer', 'Phenotype', 'HP:0100526', (120, 131))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('lung cancer', 'Disease', 'MESH:D008175', (120, 131))	('ERbeta', 'Gene', (28, 34))	('loss', 'NegReg', (83, 87))
301810	33936178	POK3CA mutation may be related to the prognosis of lung squamous cell carcinoma.	('POK3CA', 'Gene', (0, 6))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (56, 79))	('related', 'Reg', (23, 30))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (51, 79))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (51, 79))	('lung squamous cell carcinoma', 'Disease', (51, 79))	('mutation', 'Var', (7, 15))
301811	33936178	NRF2 mutation is a risk factor for the prognosis of lung squamous cell carcinoma.	('NRF2', 'Gene', (0, 4))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (52, 80))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (57, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('mutation', 'Var', (5, 13))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (52, 80))	('NRF2', 'Gene', '4780', (0, 4))	('lung squamous cell carcinoma', 'Disease', (52, 80))	('risk', 'Reg', (19, 23))
301820	33936178	The FKBP4 is a risk factor of LUAD and the high expression of FKBP4 reduces the survival time of LUAD patients.	('LUAD', 'Disease', (30, 34))	('FKBP4', 'Gene', (4, 9))	('high expression', 'Var', (43, 58))	('FKBP4', 'Gene', (62, 67))	('FKBP4', 'Gene', '2288', (62, 67))	('patients', 'Species', '9606', (102, 110))	('LUAD', 'Phenotype', 'HP:0030078', (97, 101))	('LUAD', 'Disease', (97, 101))	('survival time', 'CPA', (80, 93))	('FKBP4', 'Gene', '2288', (4, 9))	('LUAD', 'Phenotype', 'HP:0030078', (30, 34))	('reduces', 'NegReg', (68, 75))
301821	33936178	The ADCY9 is a protective factor of LUAD and high expression of ADCY9 prolongs the survival time of LUAD patients.	('LUAD', 'Disease', (100, 104))	('ADCY9', 'Gene', (4, 9))	('patients', 'Species', '9606', (105, 113))	('prolongs', 'PosReg', (70, 78))	('LUAD', 'Phenotype', 'HP:0030078', (100, 104))	('ADCY9', 'Gene', (64, 69))	('survival time', 'CPA', (83, 96))	('LUAD', 'Disease', (36, 40))	('LUAD', 'Phenotype', 'HP:0030078', (36, 40))	('ADCY9', 'Gene', '115', (4, 9))	('high expression', 'Var', (45, 60))	('ADCY9', 'Gene', '115', (64, 69))
301849	32301286	Inclusion criteria were: (i) "Lung and Bronchus" restricted by site recode ICD-O-3/WHO2008; (ii) 8012 (large cell carcinoma), 8013 (large cell neuroendocrine carcinoma), 8070 (squamous cell carcinoma), 8083 (basaloid squamous cell carcinoma) and 8140 (adenocarcinoma) by histologic type ICD-O-3; (iii) "One primary only" by sequence number; and (iv) 2004-2015 by year at diagnosis, in which there was enough information to stage according to latest standard.	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (217, 240))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (176, 199))	('carcinoma', 'Phenotype', 'HP:0030731', (231, 240))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('large cell carcinoma', 'Phenotype', 'HP:0030360', (103, 123))	('carcinoma', 'Disease', (257, 266))	('carcinoma', 'Disease', (231, 240))	('carcinoma', 'Disease', (114, 123))	('neuroendocrine carcinoma', 'Disease', (143, 167))	('adenocarcinoma', 'Disease', (252, 266))	('basaloid squamous cell carcinoma', 'Disease', 'MESH:D002294', (208, 240))	('carcinoma', 'Phenotype', 'HP:0030731', (190, 199))	('basaloid squamous cell carcinoma', 'Disease', (208, 240))	('squamous cell carcinoma', 'Disease', (176, 199))	('carcinoma', 'Disease', (190, 199))	('8070', 'Var', (170, 174))	('carcinoma', 'Disease', 'MESH:D009369', (257, 266))	('carcinoma', 'Phenotype', 'HP:0030731', (158, 167))	('large cell neuroendocrine carcinoma', 'Phenotype', 'HP:0030360', (132, 167))	('carcinoma', 'Disease', 'MESH:D009369', (231, 240))	('carcinoma', 'Disease', 'MESH:D009369', (114, 123))	('carcinoma', 'Disease', (158, 167))	('adenocarcinoma', 'Disease', 'MESH:D000230', (252, 266))	('8013', 'Var', (126, 130))	('neuroendocrine carcinoma', 'Disease', 'MESH:D018278', (143, 167))	('carcinoma', 'Disease', 'MESH:D009369', (190, 199))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (217, 240))	('8083', 'Var', (202, 206))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (176, 199))	('neuroendocrine carcinoma', 'Phenotype', 'HP:0100634', (143, 167))	('8012', 'Var', (97, 101))	('basaloid squamous cell carcinoma', 'Phenotype', 'HP:0002671', (208, 240))	('carcinoma', 'Disease', 'MESH:D009369', (158, 167))	('carcinoma', 'Phenotype', 'HP:0030731', (257, 266))
301909	32301286	Advanced stage LCC was more common in younger patients, in males, high grade, and in the main bronchus or overlapping lesions of the lung.	('common', 'Reg', (28, 34))	('patients', 'Species', '9606', (46, 54))	('LCC', 'Phenotype', 'HP:0030360', (15, 18))	('LCC', 'Disease', (15, 18))	('high grade', 'Var', (66, 76))
301922	32301286	KRAS and EGFR mutations have been detected in the LCC-null and LCC-ADE.	('detected', 'Reg', (34, 42))	('ADE', 'Chemical', 'MESH:C060154', (67, 70))	('LCC-ADE', 'Disease', (63, 70))	('LCC', 'Phenotype', 'HP:0030360', (50, 53))	('LCC-null', 'Disease', (50, 58))	('EGFR', 'Gene', '1956', (9, 13))	('EGFR', 'Gene', (9, 13))	('LCC', 'Phenotype', 'HP:0030360', (63, 66))	('KRAS', 'Gene', (0, 4))	('mutations', 'Var', (14, 23))	('KRAS', 'Gene', '3845', (0, 4))
301923	32301286	Inversely, there were no EGFR and KRAS mutations in LCC-SCC, but there were low mutation rates in PIK3A, CDKN2A, and TP53.5, 27, 28 After reviewing several studies,10, 11, 12, 25, 26, 27, 29 the most common mutations in the LCC according to the new criteria were found to be KRAS and EGFR mutations.	('KRAS', 'Gene', '3845', (34, 38))	('KRAS', 'Gene', '3845', (275, 279))	('EGFR', 'Gene', (25, 29))	('CDKN2A', 'Gene', (105, 111))	('TP53', 'Gene', '7157', (117, 121))	('TP53', 'Gene', (117, 121))	('EGFR', 'Gene', '1956', (284, 288))	('CDKN2A', 'Gene', '1029', (105, 111))	('mutations', 'Var', (207, 216))	('EGFR', 'Gene', '1956', (25, 29))	('LCC', 'Phenotype', 'HP:0030360', (224, 227))	('EGFR', 'Gene', (284, 288))	('KRAS', 'Gene', (275, 279))	('KRAS', 'Gene', (34, 38))	('LCC', 'Phenotype', 'HP:0030360', (52, 55))	('LCC', 'Gene', (224, 227))
301924	32301286	The KRAS mutation rate was about 11.6%, and the most common were G12C and G12V mutations.	('G12C', 'Var', (65, 69))	('KRAS', 'Gene', '3845', (4, 8))	('G12C', 'Mutation', 'rs121913530', (65, 69))	('G12V', 'Mutation', 'rs121913529', (74, 78))	('common', 'Reg', (53, 59))	('G12V mutations', 'Var', (74, 88))	('KRAS', 'Gene', (4, 8))
301929	32301286	The EGFR mutation rate was around 6%, in which the rate of L858R mutation was highest.	('EGFR', 'Gene', (4, 8))	('L858R', 'Mutation', 'rs121434568', (59, 64))	('L858R', 'Var', (59, 64))	('EGFR', 'Gene', '1956', (4, 8))
301946	31579447	Luciferase activities in FOXO1 and DUSP1 wild type plasmid groups were compared to mutant groups.	('DUSP1', 'Gene', (35, 40))	('activities', 'MPA', (11, 21))	('mutant', 'Var', (83, 89))	('DUSP1', 'Gene', '1843', (35, 40))	('FOXO1', 'Gene', (25, 30))	('FOXO1', 'Gene', '2308', (25, 30))	('Luciferase', 'Enzyme', (0, 10))
301955	31579447	Targeting molecular mechanisms of lung cancer is currently the main therapeutic approaches, especially for targeting aberrant epidermal growth factor receptor (EGFR) activity.	('epidermal growth factor receptor', 'Gene', (126, 158))	('lung cancer', 'Disease', (34, 45))	('activity', 'MPA', (166, 174))	('lung cancer', 'Phenotype', 'HP:0100526', (34, 45))	('EGFR', 'Gene', '1956', (160, 164))	('aberrant', 'Var', (117, 125))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('lung cancer', 'Disease', 'MESH:D008175', (34, 45))	('EGFR', 'Gene', (160, 164))	('epidermal growth factor receptor', 'Gene', '1956', (126, 158))
302005	31579447	Inhibition of miR-96 led to downregulated migration, invasion and proliferation in NSCLC cell lines  A549 and PC-9 cells were treated with miR-96 inhibitor and corresponding negative control.	('migration', 'CPA', (42, 51))	('miR-96', 'Gene', '407053', (14, 20))	('miR-96', 'Gene', (139, 145))	('miR-96', 'Gene', (14, 20))	('PC-9', 'Gene', (110, 114))	('PC-9', 'Gene', '255738', (110, 114))	('NSCLC', 'Disease', (83, 88))	('invasion', 'CPA', (53, 61))	('proliferation', 'CPA', (66, 79))	('downregulated', 'NegReg', (28, 41))	('NSCLC', 'Disease', 'MESH:D002289', (83, 88))	('NSCLC', 'Phenotype', 'HP:0030358', (83, 88))	('Inhibition', 'Var', (0, 10))	('miR-96', 'Gene', '407053', (139, 145))
302006	31579447	MiR-96 inhibitor caused remarkably low cell growth rates in A549 and PC-9 cells compared to negative control group (Figure 2A).	('PC-9', 'Gene', (69, 73))	('PC-9', 'Gene', '255738', (69, 73))	('MiR-96', 'Gene', '407053', (0, 6))	('inhibitor', 'Var', (7, 16))	('MiR-96', 'Gene', (0, 6))	('low', 'NegReg', (35, 38))	('cell growth rates', 'CPA', (39, 56))
302008	31579447	Wound healing assay (Figure 2B) showed that miR-96 inhibitor suppressed migration of A549 and PC-9 significantly, and Transwell assay (Figure 2C) provided proofs that miR-96 inhibitor suppressed invasion.	('suppressed', 'NegReg', (61, 71))	('PC-9', 'Gene', (94, 98))	('PC-9', 'Gene', '255738', (94, 98))	('miR-96', 'Gene', '407053', (167, 173))	('miR-96', 'Gene', (44, 50))	('miR-96', 'Gene', (167, 173))	('invasion', 'CPA', (195, 203))	('inhibitor', 'Var', (51, 60))	('miR-96', 'Gene', '407053', (44, 50))	('suppressed', 'NegReg', (184, 194))
302010	31579447	Taken together, these results indicate that miR-96 exhibits a role of tumor induction and miR-96 inhibitor can reduce abilities of migration, invasion and proliferation of NSCLC cell lines.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('NSCLC', 'Disease', (172, 177))	('proliferation', 'CPA', (155, 168))	('tumor', 'Disease', (70, 75))	('NSCLC', 'Disease', 'MESH:D002289', (172, 177))	('miR-96', 'Gene', (44, 50))	('miR-96', 'Gene', '407053', (44, 50))	('inhibitor', 'Var', (97, 106))	('NSCLC', 'Phenotype', 'HP:0030358', (172, 177))	('reduce', 'NegReg', (111, 117))	('miR-96', 'Gene', '407053', (90, 96))	('invasion', 'CPA', (142, 150))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('miR-96', 'Gene', (90, 96))
302015	31579447	In Figure 3B, luciferase activity of FOXO1 and DUSP1 report plasmids were remarkably reduced by miR-96 mimics in HEK-293T cell when compared to miR-96 inhibitor and negative control.	('miR-96', 'Gene', (96, 102))	('FOXO1', 'Gene', (37, 42))	('mimics', 'Var', (103, 109))	('miR-96', 'Gene', '407053', (144, 150))	('DUSP1', 'Gene', (47, 52))	('miR-96', 'Gene', (144, 150))	('DUSP1', 'Gene', '1843', (47, 52))	('activity', 'MPA', (25, 33))	('reduced', 'NegReg', (85, 92))	('miR-96', 'Gene', '407053', (96, 102))	('FOXO1', 'Gene', '2308', (37, 42))	('luciferase', 'Enzyme', (14, 24))
302018	31579447	FOXO1 upregulated DUSP1 expression by sponging miR-96  Both FOXO1 and DUSP1 3'UTR have miR-96 targeted sites, thus we hypothesized that these three molecules can form a competitive endogenous RNA network that co-regulates NSCLC progression.	('miR-96', 'Gene', '407053', (87, 93))	('DUSP1', 'Gene', (70, 75))	('sponging', 'Var', (38, 46))	('FOXO1', 'Gene', (60, 65))	('miR-96', 'Gene', (87, 93))	('FOXO1', 'Gene', '2308', (60, 65))	('expression', 'MPA', (24, 34))	('FOXO1', 'Gene', (0, 5))	('FOXO1', 'Gene', '2308', (0, 5))	('DUSP1', 'Gene', '1843', (18, 23))	('miR-96', 'Gene', '407053', (47, 53))	('DUSP1', 'Gene', '1843', (70, 75))	('NSCLC', 'Phenotype', 'HP:0030358', (222, 227))	('miR-96', 'Gene', (47, 53))	('upregulated', 'PosReg', (6, 17))	('NSCLC', 'Disease', (222, 227))	('NSCLC', 'Disease', 'MESH:D002289', (222, 227))	('DUSP1', 'Gene', (18, 23))
302019	31579447	Fragments containing FOXO1 and DUSP1 targeted sites or mutant sites were transfected into A549 and PC-9 cells.	('DUSP1', 'Gene', (31, 36))	('FOXO1', 'Gene', '2308', (21, 26))	('DUSP1', 'Gene', '1843', (31, 36))	('mutant', 'Var', (55, 61))	('FOXO1', 'Gene', (21, 26))	('PC-9', 'Gene', (99, 103))	('PC-9', 'Gene', '255738', (99, 103))
302020	31579447	In Figure 4A, the level of miR-96 decreased remarkably in the groups transfected with FOXO1 and DUSP1 fragments, while their mutant sites could not change it, which suggests that both FOXO1 and DUSP1 function as sponges of miR-96.	('fragments', 'Var', (102, 111))	('DUSP1', 'Gene', (96, 101))	('decreased', 'NegReg', (34, 43))	('DUSP1', 'Gene', (194, 199))	('DUSP1', 'Gene', '1843', (96, 101))	('level', 'MPA', (18, 23))	('FOXO1', 'Gene', (86, 91))	('DUSP1', 'Gene', '1843', (194, 199))	('FOXO1', 'Gene', '2308', (86, 91))	('miR-96', 'Gene', '407053', (27, 33))	('miR-96', 'Gene', '407053', (223, 229))	('miR-96', 'Gene', (27, 33))	('FOXO1', 'Gene', (184, 189))	('miR-96', 'Gene', (223, 229))	('FOXO1', 'Gene', '2308', (184, 189))
302021	31579447	In addition, in Figure 4B, DUSP1 protein level was highly increased when treated with FOXO1 fragments in both cells, but DUSP1 could not affect FOXO1 protein level.	('fragments', 'Var', (92, 101))	('DUSP1', 'Gene', (121, 126))	('increased', 'PosReg', (58, 67))	('DUSP1', 'Gene', '1843', (27, 32))	('FOXO1', 'Gene', (144, 149))	('FOXO1', 'Gene', '2308', (144, 149))	('DUSP1', 'Gene', '1843', (121, 126))	('FOXO1', 'Gene', (86, 91))	('FOXO1', 'Gene', '2308', (86, 91))	('DUSP1', 'Gene', (27, 32))
302029	31579447	In Figure 5C, MMP2, and MMP11 were reduced by FOXO1, miR-96 inhibitor and AG1478, while miR-96 mimics can rescue their effect.	('AG1478', 'Chemical', 'MESH:C101044', (74, 80))	('miR-96', 'Gene', '407053', (88, 94))	('miR-96', 'Gene', '407053', (53, 59))	('miR-96', 'Gene', (88, 94))	('reduced', 'NegReg', (35, 42))	('MMP2', 'Gene', (14, 18))	('miR-96', 'Gene', (53, 59))	('MMP11', 'Gene', '4320', (24, 29))	('AG1478', 'Var', (74, 80))	('MMP2', 'Gene', '4313', (14, 18))	('FOXO1', 'Gene', '2308', (46, 51))	('FOXO1', 'Gene', (46, 51))	('MMP11', 'Gene', (24, 29))
302038	31579447	More importantly, inhibition of endogenous miR-96 in NSCLC cell lines reduced migration, invasion and proliferation of NSCLC cell lines.	('NSCLC', 'Disease', 'MESH:D002289', (119, 124))	('NSCLC', 'Phenotype', 'HP:0030358', (53, 58))	('endogenous', 'Protein', (32, 42))	('reduced', 'NegReg', (70, 77))	('miR-96', 'Gene', '407053', (43, 49))	('miR-96', 'Gene', (43, 49))	('NSCLC', 'Phenotype', 'HP:0030358', (119, 124))	('invasion', 'CPA', (89, 97))	('migration', 'CPA', (78, 87))	('proliferation', 'CPA', (102, 115))	('NSCLC', 'Disease', (53, 58))	('inhibition', 'Var', (18, 28))	('NSCLC', 'Disease', (119, 124))	('NSCLC', 'Disease', 'MESH:D002289', (53, 58))
302065	29361946	Multivariate analysis showed that high preoperative PNI was an independent prognostic factor for better OS (P = 0.000), PFS (P = 0.001), LRFS (P = 0.005) and DMFS (P = 0.016).	('PNI', 'Gene', (52, 55))	('DMFS', 'Chemical', '-', (158, 162))	('OS', 'Chemical', '-', (104, 106))	('DMFS', 'Disease', (158, 162))	('high', 'Var', (34, 38))	('better OS', 'Disease', (97, 106))	('LRFS', 'Disease', (137, 141))	('PFS', 'Disease', (120, 123))
302066	29361946	High PNI predicts superior survival in HPSCC patients treated with radical surgery.	('HPSCC', 'Disease', (39, 44))	('HPSCC', 'Phenotype', 'HP:0012182', (39, 44))	('patients', 'Species', '9606', (45, 53))	('survival', 'MPA', (27, 35))	('superior', 'PosReg', (18, 26))	('High PNI', 'Var', (0, 8))
302088	29361946	The prescribed dose was 66-70 Gy to the primary lesion of hypopharynx (GTVnx), 66-70 Gy to the gross tumor volume of metastatic neck lymph nodes (GTVnd), 60 Gy to the high-risk microinvasive areas (clinical target volume 1, CTV1) and 54 Gy to the low-risk areas (clinical target volume 2, CTV2).	('66-70 Gy', 'Var', (79, 87))	('lesion of hypopharynx', 'Disease', 'MESH:D051437', (48, 69))	('lesion of hypopharynx', 'Disease', (48, 69))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
302114	29361946	LRFS was significantly shortened in tumor from posterior wall/postcricoid (P = 0.000), advanced pT (P = 0.000), positive surgical margin (P = 0.011) and low PNI (P = 0.013).	('positive', 'Var', (112, 120))	('LRFS', 'MPA', (0, 4))	('shortened', 'NegReg', (23, 32))	('advanced pT', 'CPA', (87, 98))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumor', 'Disease', (36, 41))
302119	29361946	Advanced age (HR 2.510, 95% CI 1.376-4.580; P = 0.003), primary tumor at posterior wall/postcricoid (HR 2.914, 95% CI 1.296-6.553; P = 0.010), high LND (HR 2.430, 95% CI 1.206-4.896; P = 0.013) and low PNI (HR 2.133, 95% CI 1.154-3.943; P = 0.016) were still independently correlated with decreased DMFS.	('tumor', 'Disease', (64, 69))	('high LND', 'Var', (143, 151))	('DMFS', 'Chemical', '-', (299, 303))	('low', 'Var', (198, 201))	('decreased', 'NegReg', (289, 298))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('DMFS', 'MPA', (299, 303))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
302124	29361946	Of note, patients with high PNI had better locoregional and distant control.	('patients', 'Species', '9606', (9, 17))	('high PNI', 'Var', (23, 31))	('better', 'PosReg', (36, 42))
302143	29361946	Though Lo WC once reported that neutrophil to lymphocyte ratio (NLR) is a prognostic indicator of survival in HPSCC, several studies illustrated that PNI is more superior compared to other inflammatory and nutritional indexes in predicting survival, including NLR, platelet to lymphocyte ratio (PLR) and C reactive protein (CRP).	('CRP', 'Gene', (324, 327))	('CRP', 'Gene', '1401', (324, 327))	('HPSCC', 'Phenotype', 'HP:0012182', (110, 115))	('PNI', 'Var', (150, 153))	('HPSCC', 'Disease', (110, 115))	('NLR', 'Disease', (260, 263))	('C reactive protein', 'Gene', (304, 322))	('C reactive protein', 'Gene', '1401', (304, 322))	('platelet', 'MPA', (265, 273))
302146	29361946	There were 83.7% of 123 patients in our study had nodal metastasis in neck, it was similar to 79% of nodal metastasis reported by Zhejiang Cancer Hospital.	('Cancer', 'Phenotype', 'HP:0002664', (139, 145))	('nodal', 'Var', (50, 55))	('Cancer', 'Disease', (139, 145))	('patients', 'Species', '9606', (24, 32))	('Cancer', 'Disease', 'MESH:D009369', (139, 145))
302148	29361946	Our study revealed that LND > 0.06 was correlated with early distant metastasis (P = 0.013), tumor progression (P = 0.007) and a trend of worse OS (P = 0.070).	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Disease', (93, 98))	('early distant metastasis', 'CPA', (55, 79))	('OS', 'Chemical', '-', (144, 146))	('LND > 0.06', 'Var', (24, 34))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
302168	33567737	Activation of ErbB receptors family (e.g., epidermal growth factor receptors; EFGR) initiates a pathway of downstream signaling in cell proliferation, which has a role in glioma progression and germline polymorphism of EGFR.	('epidermal growth factor', 'Gene', '1950', (43, 66))	('glioma', 'Disease', 'MESH:D005910', (171, 177))	('EGFR', 'Gene', '1956', (219, 223))	('glioma', 'Phenotype', 'HP:0009733', (171, 177))	('role', 'Reg', (163, 167))	('EGFR', 'Gene', (219, 223))	('glioma', 'Disease', (171, 177))	('initiates', 'Reg', (84, 93))	('germline polymorphism', 'Var', (194, 215))	('cell proliferation', 'CPA', (131, 149))	('ErbB', 'Gene', '1956', (14, 18))	('ErbB', 'Gene', (14, 18))	('epidermal growth factor', 'Gene', (43, 66))
302169	33567737	Moreover, exons-mutations (exon 19 and 21) for the intracellular EGFR kinase domain render EFGR sensitive to the known EGFR tyrosine kinase inhibitors (TKI).	('EGFR', 'Gene', '1956', (65, 69))	('EGFR', 'Gene', (65, 69))	('exons-mutations', 'Var', (10, 25))	('EGFR', 'Gene', '1956', (119, 123))	('sensitive', 'MPA', (96, 105))	('EGFR', 'Gene', (119, 123))
302174	33567737	Interestingly, there is a meta-analysis for the afatinib impact on survival in advanced NSCLC (6 RCTs) and M/R HNSCC (1 RCT) based on the published trials before August 2018.	('afatinib', 'Gene', (48, 56))	('afatinib', 'Chemical', 'MESH:D000077716', (48, 56))	('M/R', 'Var', (107, 110))	('NSCLC', 'Disease', (88, 93))	('NSCLC', 'Disease', 'MESH:D002289', (88, 93))
302233	33567737	in terms of ethnicity settings through recruiting only Asian participants from the viewpoint that mutant EGFR is more common in Asians than non-Asians.	('participants', 'Species', '9606', (61, 73))	('common', 'Reg', (118, 124))	('EGFR', 'Gene', '1956', (105, 109))	('EGFR', 'Gene', (105, 109))	('mutant', 'Var', (98, 104))
302237	33567737	was statistically powered to recruit PFS as a primary endpoint assuming that among the 330 enrolled participants, it would be a minimum 217 PFS observed death events with an HR of 0.64 and an 11-months follow-up median with afatinib versus a 7-months with gemcitabine plus cisplatin chemotherapy.	('afatinib', 'Var', (224, 232))	('afatinib', 'Chemical', 'MESH:D000077716', (224, 232))	('participants', 'Species', '9606', (100, 112))	('cisplatin', 'Chemical', 'MESH:D002945', (273, 282))	('death', 'Disease', 'MESH:D003643', (153, 158))	('death', 'Disease', (153, 158))	('gemcitabine', 'Chemical', 'MESH:C056507', (256, 267))
302320	32977620	NME1 silencing is known to upregulate beta-catenin-dependent TCF/LEF-1 (T-cell factor/lymphoid enhancer-binding factor) transactivation through glycogen synthase kinase (GSK)-3beta-independent mechanisms by promoting nuclear translocation of beta-catenin.	('beta-catenin', 'Protein', (242, 254))	('nuclear translocation', 'MPA', (217, 238))	('silencing', 'Var', (5, 14))	('TCF/LEF-1', 'Gene', '3172;51176', (61, 70))	('glycogen synthase kinase (GSK)-3beta', 'Gene', '2931', (144, 180))	('upregulate', 'PosReg', (27, 37))	('promoting', 'PosReg', (207, 216))	('transactivation', 'MPA', (120, 135))	('NME1', 'Gene', (0, 4))	('TCF/LEF-1', 'Gene', (61, 70))
302382	32977620	Ki-67 proliferation was not significantly different according to abnormal expression of NME1 or beta-catenin irrespective of histology (Figure 4A) and cisplatin-based adjuvant chemotherapy (Figure 4B).	('cisplatin', 'Chemical', 'MESH:D002945', (151, 160))	('Ki-67', 'Gene', (0, 5))	('abnormal', 'Var', (65, 73))	('NME1', 'Gene', (88, 92))	('beta-catenin', 'Protein', (96, 108))
302385	32977620	Our data did not show an association of NME1 expression with tumor growth (Figure 4), consistent with a previous study showing that NME1 silencing does not provide epithelial cancer cells with a selective growth advantage.	('NME1', 'Gene', (132, 136))	('cancer', 'Disease', (175, 181))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('epithelial cancer', 'Phenotype', 'HP:0031492', (164, 181))	('silencing', 'Var', (137, 146))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Disease', (61, 66))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
302394	32977620	A splicing variant of NME1 inhibits the metastasis of lung cancer cells by interacting with Inhibitor of nuclear factor Kappa-B Kinase subunit beta (IKKbeta) in an isotype-specific fashion and regulating tumor necrosis factor alpha (TNFalpha)-stimulated Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) signaling negatively.	('TNFalpha', 'Gene', (233, 241))	('NF-kappaB', 'Gene', (318, 327))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('IKKbeta', 'Gene', (149, 156))	('NME1', 'Gene', (22, 26))	('NF-kappaB', 'Gene', '4790', (318, 327))	('lung cancer', 'Disease', (54, 65))	('tumor necrosis factor alpha', 'Gene', (204, 231))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('splicing variant', 'Var', (2, 18))	('inhibits', 'NegReg', (27, 35))	('lung cancer', 'Disease', 'MESH:D008175', (54, 65))	('TNFalpha', 'Gene', '7124', (233, 241))	('Inhibitor of nuclear factor Kappa-B Kinase subunit beta', 'Gene', '3551', (92, 147))	('tumor necrosis factor alpha', 'Gene', '7124', (204, 231))	('regulating', 'Reg', (193, 203))	('lung cancer', 'Phenotype', 'HP:0100526', (54, 65))	('interacting', 'Interaction', (75, 86))	('IKKbeta', 'Gene', '1147', (149, 156))	('negatively', 'NegReg', (339, 349))
302396	32977620	NME1 silencing induces the nuclear translocation of beta-catenin by disrupting adherence junction complexes mediated by E-cadherin and promotes extracellular matrix invasion by increasing invadopodia formation and pericellular matrix metalloproteinase (MMP) activity.	('beta-catenin', 'Protein', (52, 64))	('invadopodia formation', 'CPA', (188, 209))	('increasing', 'PosReg', (177, 187))	('activity', 'MPA', (258, 266))	('disrupting', 'NegReg', (68, 78))	('nuclear translocation', 'MPA', (27, 48))	('extracellular matrix invasion', 'CPA', (144, 173))	('silencing', 'Var', (5, 14))	('adherence junction complexes', 'Protein', (79, 107))	('E-cadherin', 'Gene', (120, 130))	('E-cadherin', 'Gene', '999', (120, 130))	('MMP', 'Gene', '4313', (253, 256))	('NME1', 'Gene', (0, 4))	('pericellular', 'CPA', (214, 226))	('promotes', 'PosReg', (135, 143))	('MMP', 'Gene', (253, 256))
302410	32977620	Therefore, restoring NME1 expression might be a therapeutic intervention strategy to surmount cisplatin resistance.	('expression', 'MPA', (26, 36))	('NME1', 'Gene', (21, 25))	('restoring', 'Var', (11, 20))	('cisplatin', 'Chemical', 'MESH:D002945', (94, 103))
302419	32977620	Fourth, EcoR1 (rs34214448-G/T) polymorphism in NME1 gene is associated with increased susceptibility to NSCLC and could potentially affect the results of the current analysis, which is based only on expression levels.	('affect', 'Reg', (132, 138))	('NSCLC', 'Disease', (104, 109))	('rs34214448-G/T', 'Var', (15, 29))	('NME1', 'Gene', (47, 51))	('NSCLC', 'Disease', 'MESH:D002289', (104, 109))	('susceptibility', 'Reg', (86, 100))	('EcoR1', 'Var', (8, 13))	('rs34214448', 'Mutation', 'rs34214448', (15, 25))	('NSCLC', 'Phenotype', 'HP:0030358', (104, 109))
302464	32578383	Lung SCC has more gene mutation sites, a higher tumor mutation burden, but there are no targeted drugs available.	('tumor', 'Disease', (48, 53))	('gene mutation sites', 'Var', (18, 37))	('Lung SCC', 'Disease', (0, 8))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('SCC', 'Phenotype', 'HP:0002860', (5, 8))
302467	32578383	It has previously been reported in the literature that in lung ADC and SCC, lung small cell carcinoma, head and neck squamous cell carcinoma, and liver cancer, C > A/G > T is associated with smoking.	('associated', 'Reg', (175, 185))	('liver cancer', 'Disease', 'MESH:D006528', (146, 158))	('SCC', 'Phenotype', 'HP:0002860', (71, 74))	('lung small', 'Phenotype', 'HP:0002089', (76, 86))	('neck squamous cell carcinoma', 'Disease', (112, 140))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (117, 140))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (112, 140))	('liver cancer', 'Phenotype', 'HP:0002896', (146, 158))	('lung ADC', 'Disease', (58, 66))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('liver cancer', 'Disease', (146, 158))	('lung small cell carcinoma', 'Disease', 'MESH:D055752', (76, 101))	('SCC', 'Disease', (71, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('C > A/G > T', 'Var', (160, 171))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (103, 140))	('lung small cell carcinoma', 'Disease', (76, 101))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('lung small cell carcinoma', 'Phenotype', 'HP:0030357', (76, 101))	('smoking', 'Disease', (191, 198))
302469	32578383	11 ,  12 ,  13  The mutation could be due to a combination of cancer-causing chemicals in cigarettes, which may interact with DNA and lead to the accumulation of somatic mutations.	('somatic mutations', 'MPA', (162, 179))	('lead to', 'Reg', (134, 141))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('mutation', 'Var', (20, 28))	('cancer', 'Disease', (62, 68))	('accumulation', 'PosReg', (146, 158))	('interact', 'Interaction', (112, 120))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('due', 'Reg', (38, 41))
302470	32578383	Second, C > T/G > A is positively correlated with age in most childhood and adult cancer types.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('C > T/G > A', 'Var', (8, 19))	('childhood and', 'Disease', (62, 75))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('correlated', 'Reg', (34, 44))
302473	32578383	This finding may be observed because most of the mutations of C > T occur continuously and stably throughout the life cycle of cancer patients, while other mutations show different degrees of mutation after exposure to different carcinogens.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('mutations', 'Var', (49, 58))	('patients', 'Species', '9606', (134, 142))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('cancer', 'Disease', (127, 133))	('C > T', 'Gene', (62, 67))
302526	29283433	For example, the gene DST is linked to SCC through some disease-related significant GO:BP terms:namely, extracellular structure organization (GO:0043062) (p-value = 0.006327), response to wounding (GO:0009611) (p-value = 0.005237), and some disease-related significant GO:CC terms such as extracellular matrix part (GO:0044420) (p-value = 0.001283).	('DST', 'Var', (22, 25))	('GO:0044420', 'Var', (316, 326))	('SCC', 'Disease', (39, 42))	('BP', 'Chemical', '-', (87, 89))	('linked', 'Reg', (29, 35))	('extracellular', 'MPA', (104, 117))	('extracellular matrix part', 'CPA', (289, 314))
302538	28111428	In all patients, the median PFS for treatment including afatinib was not correlated with the status of epidermal growth factor receptor (EGFR) mutation (p=0.122), EGFR fluorescence in situ hybridization (p=0.944), or EGFR immunohistochemistry (p=0.976).	('EGFR', 'Gene', (137, 141))	('EGFR', 'Gene', '1956', (217, 221))	('EGFR', 'Gene', (217, 221))	('EGFR', 'Gene', '1956', (163, 167))	('mutation', 'Var', (143, 151))	('afatinib', 'Chemical', 'MESH:D000077716', (56, 64))	('epidermal growth factor receptor', 'Gene', (103, 135))	('EGFR', 'Gene', (163, 167))	('EGFR', 'Gene', '1956', (137, 141))	('epidermal growth factor receptor', 'Gene', '1956', (103, 135))	('patients', 'Species', '9606', (7, 15))
302542	28111428	However, many preclinical and clinical studies have demonstrated that these drugs are only effective in a specific subset of NSCLC, in which the mutations are carried on the kinase domain of the EGFR gene.	('EGFR', 'Gene', (195, 199))	('NSCLC', 'Disease', (125, 130))	('mutations', 'Var', (145, 154))	('NSCLC', 'Disease', 'MESH:D002289', (125, 130))	('NSCLC', 'Phenotype', 'HP:0030358', (125, 130))	('EGFR', 'Gene', '1956', (195, 199))
302543	28111428	Thus, EGFR tyrosine kinase inhibitors (TKI) are a first-line therapy in patients with advanced NSCLC with EGFR mutations based on several randomized phase III studies showing a significantly improved response rate (RR) of about 70% and median progression-free survival (PFS) of about 10 months.	('mutations', 'Var', (111, 120))	('NSCLC', 'Disease', 'MESH:D002289', (95, 100))	('response', 'MPA', (200, 208))	('EGFR', 'Gene', (6, 10))	('patients', 'Species', '9606', (72, 80))	('NSCLC', 'Phenotype', 'HP:0030358', (95, 100))	('improved', 'PosReg', (191, 199))	('EGFR', 'Gene', '1956', (6, 10))	('EGFR', 'Gene', '1956', (106, 110))	('NSCLC', 'Disease', (95, 100))	('EGFR', 'Gene', (106, 110))
302544	28111428	However, only 10% of NSCLC patients in the United States and 35% in East Asia have tumors with EGFR mutations.	('mutations', 'Var', (100, 109))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('NSCLC', 'Disease', (21, 26))	('NSCLC', 'Disease', 'MESH:D002289', (21, 26))	('tumors', 'Disease', (83, 89))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('patients', 'Species', '9606', (27, 35))	('NSCLC', 'Phenotype', 'HP:0030358', (21, 26))	('tumors', 'Disease', 'MESH:D009369', (83, 89))	('EGFR', 'Gene', '1956', (95, 99))	('EGFR', 'Gene', (95, 99))
302559	28111428	Moreover, several preclinical studies demonstrated that combined gefitinib and lovastatin exerted significant synergic cytotoxic effects in vitro in squamous cell carcinomas, NSCLC, and colon carcinoma cell lines that do not possess the activating EGFR mutations.	('NSCLC', 'Disease', 'MESH:D002289', (175, 180))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (149, 173))	('EGFR', 'Gene', '1956', (248, 252))	('synergic', 'MPA', (110, 118))	('gefitinib', 'Chemical', 'MESH:D000077156', (65, 74))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (149, 172))	('carcinoma', 'Phenotype', 'HP:0030731', (163, 172))	('carcinomas', 'Phenotype', 'HP:0030731', (163, 173))	('EGFR', 'Gene', (248, 252))	('mutations', 'Var', (253, 262))	('NSCLC', 'Phenotype', 'HP:0030358', (175, 180))	('colon carcinoma', 'Disease', 'MESH:D015179', (186, 201))	('colon carcinoma', 'Disease', (186, 201))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (149, 173))	('NSCLC', 'Disease', (175, 180))	('carcinoma', 'Phenotype', 'HP:0030731', (192, 201))	('squamous cell carcinomas', 'Disease', (149, 173))	('lovastatin', 'Chemical', 'MESH:D008148', (79, 89))
302588	28111428	Tumors were considered to have an increased copy number (FISH-positive) if they showed gene amplification or chromosome 7 high polysomy based on previously described criteria.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('copy number', 'MPA', (44, 55))	('gene amplification', 'Var', (87, 105))	('high polysomy', 'Var', (122, 135))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('chromosome', 'Var', (109, 119))	('increased', 'PosReg', (34, 43))
302613	28111428	Among a total of 68 patients, the tumors of 64 patients were available for EGFR mutation analysis, 61 for the FISH test, and 56 for IHC staining analysis.	('tumors', 'Disease', (34, 40))	('tumors', 'Disease', 'MESH:D009369', (34, 40))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('patients', 'Species', '9606', (47, 55))	('patients', 'Species', '9606', (20, 28))	('EGFR', 'Gene', '1956', (75, 79))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('EGFR', 'Gene', (75, 79))	('mutation analysis', 'Var', (80, 97))
302614	28111428	EGFR mutations were detected in four of 64 cases (6.3%) (one exon 19 deletion, one exon 20 G810S, one exon 20 V786M, and one exon 21 G863S) (Table 4).	('detected', 'Reg', (20, 28))	('V786M', 'Mutation', 'rs762672864', (110, 115))	('EGFR', 'Gene', (0, 4))	('G863S', 'Var', (133, 138))	('G810S', 'Mutation', 'rs121913230', (91, 96))	('mutations', 'Var', (5, 14))	('G810S', 'Var', (91, 96))	('V786M', 'Var', (110, 115))	('G863S', 'Mutation', 'p.G863S', (133, 138))	('EGFR', 'Gene', '1956', (0, 4))
302615	28111428	Of the 61 tumors suitable for EGFR/FISH analysis, five (8.2%) were FISH-positive (two high polysomy, one gene amplification, and two both).	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('EGFR', 'Gene', (30, 34))	('tumors', 'Disease', 'MESH:D009369', (10, 16))	('tumors', 'Disease', (10, 16))	('tumors', 'Phenotype', 'HP:0002664', (10, 16))	('EGFR', 'Gene', '1956', (30, 34))	('high polysomy', 'Var', (86, 99))
302617	28111428	There was no difference in the rate of EGFR mutation (5.6% vs. 6.2%), FISH-positivity (8.3% vs. 6.2%), or IHC-positivity (47.2% vs. 46.9%) between arms.	('EGFR', 'Gene', (39, 43))	('mutation', 'Var', (44, 52))	('EGFR', 'Gene', '1956', (39, 43))
302619	28111428	There was no overlap between EGFR mutation and FISH positivity.	('EGFR', 'Gene', (29, 33))	('EGFR', 'Gene', '1956', (29, 33))	('mutation', 'Var', (34, 42))
302620	28111428	Upon analysis of all patients, EGFR mutation and EGFR/FISH status were significantly associated with the response to treatment, including afatinib, whereas EGFR IHC status was not.	('EGFR', 'Gene', '1956', (49, 53))	('response to treatment', 'MPA', (105, 126))	('EGFR', 'Gene', '1956', (31, 35))	('associated with', 'Reg', (85, 100))	('EGFR', 'Gene', (49, 53))	('EGFR', 'Gene', '1956', (156, 160))	('afatinib', 'Chemical', 'MESH:D000077716', (138, 146))	('EGFR', 'Gene', (31, 35))	('patients', 'Species', '9606', (21, 29))	('EGFR', 'Gene', (156, 160))	('mutation', 'Var', (36, 44))
302624	28111428	However, the EGFR mutation and EGFR/FISH status were not correlated with median PFS for treatment.	('EGFR', 'Gene', '1956', (31, 35))	('EGFR', 'Gene', (31, 35))	('mutation', 'Var', (18, 26))	('EGFR', 'Gene', '1956', (13, 17))	('EGFR', 'Gene', (13, 17))
302644	28111428	The median PFS was significantly longer for afatinib than for erlotinib, (2.4 months vs. 1.9 months; HR, 0.82; p=0.0427), as was the median OS (7.9 months vs. 6.8 months; HR, 0.81; p=0.0077).	('erlotinib', 'Chemical', 'MESH:D000069347', (62, 71))	('PFS', 'MPA', (11, 14))	('afatinib', 'Var', (44, 52))	('OS', 'Chemical', '-', (140, 142))	('afatinib', 'Chemical', 'MESH:D000077716', (44, 52))
302649	28111428	The EGFR mutation and EGFR/FISH status were significantly associated with RR, but not median PFS, whereas EGFR IHC status was not related to either RR or PFS.	('mutation', 'Var', (9, 17))	('EGFR', 'Gene', '1956', (4, 8))	('associated', 'Reg', (58, 68))	('PFS', 'Disease', (93, 96))	('EGFR', 'Gene', (4, 8))	('EGFR', 'Gene', '1956', (22, 26))	('EGFR', 'Gene', '1956', (106, 110))	('EGFR', 'Gene', (22, 26))	('EGFR', 'Gene', (106, 110))
302661	28111428	An EGFR exon 19 deletion mutation was detected in his resected lung tumor sample.	('EGFR', 'Gene', '1956', (3, 7))	('EGFR', 'Gene', (3, 7))	('lung tumor', 'Phenotype', 'HP:0100526', (63, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('lung tumor', 'Disease', (63, 73))	('deletion mutation', 'Var', (16, 33))	('lung tumor', 'Disease', 'MESH:D008175', (63, 73))
302662	28111428	Currently, the role of the EGFR mutation test in lung squamous cell carcinoma remains controversial; thus, the guidelines for this test are not consistent among oncology societies.	('EGFR', 'Gene', '1956', (27, 31))	('EGFR', 'Gene', (27, 31))	('oncology', 'Phenotype', 'HP:0002664', (161, 169))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (54, 77))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (49, 77))	('lung squamous cell carcinoma', 'Disease', (49, 77))	('carcinoma', 'Phenotype', 'HP:0030731', (68, 77))	('mutation', 'Var', (32, 40))
302663	28111428	Although activating mutations are rare in lung squamous cell carcinoma (< 5%), the treatment outcome with EGFR-TKI in squamous cell carcinoma with the EGFR mutation is not inferior to that in adenocarcinoma with the EGFR mutation, as shown in the CR case in our study.	('adenocarcinoma', 'Disease', 'MESH:D000230', (192, 206))	('CR', 'Chemical', '-', (247, 249))	('EGFR', 'Gene', (106, 110))	('EGFR', 'Gene', (216, 220))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (118, 141))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (42, 70))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (47, 70))	('lung squamous cell carcinoma', 'Disease', (42, 70))	('EGFR', 'Gene', (151, 155))	('carcinoma', 'Phenotype', 'HP:0030731', (197, 206))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (118, 141))	('EGFR', 'Gene', '1956', (106, 110))	('EGFR', 'Gene', '1956', (216, 220))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (47, 70))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('adenocarcinoma', 'Disease', (192, 206))	('squamous cell carcinoma', 'Disease', (118, 141))	('EGFR', 'Gene', '1956', (151, 155))	('mutation', 'Var', (156, 164))
302664	28111428	Thus, for personalized medicine with comprehensive genomic analysis, an EGFR mutation test also should be included to select the correct drugs for patients with lung squamous cell carcinoma.	('EGFR', 'Gene', '1956', (72, 76))	('mutation', 'Var', (77, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (180, 189))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (166, 189))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (161, 189))	('lung squamous cell carcinoma', 'Disease', (161, 189))	('EGFR', 'Gene', (72, 76))	('patients', 'Species', '9606', (147, 155))
302673	28111428	In another phase II study of patients with KRAS mutant refractory colorectal tumors, adding simvastatin to cetuximab and irinotecan produced highly favorable clinical outcomes with a disease control rate of 65.4%, a PFS of 7.6 months, and an OS of 12.8 months.	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('simvastatin', 'Chemical', 'MESH:D019821', (92, 103))	('patients', 'Species', '9606', (29, 37))	('mutant', 'Var', (48, 54))	('cetuximab', 'Chemical', 'MESH:D000068818', (107, 116))	('colorectal tumors', 'Disease', (66, 83))	('colorectal tumors', 'Disease', 'MESH:D015179', (66, 83))	('OS', 'Chemical', '-', (242, 244))	('KRAS', 'Gene', (43, 47))	('irinotecan', 'Chemical', 'MESH:D000077146', (121, 131))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('KRAS', 'Gene', '3845', (43, 47))
302677	28111428	EGFR mutation, EGFR FISH, and EGFR IHS status were not reliable as predictive markers for afatinib efficacy.	('EGFR', 'Gene', (30, 34))	('EGFR', 'Gene', (0, 4))	('afatinib', 'Chemical', 'MESH:D000077716', (90, 98))	('EGFR', 'Gene', '1956', (15, 19))	('EGFR', 'Gene', (15, 19))	('EGFR', 'Gene', '1956', (30, 34))	('EGFR', 'Gene', '1956', (0, 4))	('mutation', 'Var', (5, 13))
302708	28317894	As an example, microRNAs (miRNAs) are now universally recognized as key negative regulators in many intracellular processes as well as in cancer development and progression.	('microRNAs', 'Var', (15, 24))	('cancer', 'Disease', (138, 144))	('cancer', 'Disease', 'MESH:D009369', (138, 144))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))
302722	28317894	We investigated whether fight-club, date, and party hubs have distinct topological properties by evaluating the effects produced on the human cancer correlation networks upon their deletion (see Supplementary Fig.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('human', 'Species', '9606', (136, 141))	('hub', 'Gene', (52, 55))	('club', 'Phenotype', 'HP:0001217', (30, 34))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('hub', 'Gene', '1993', (52, 55))	('deletion', 'Var', (181, 189))	('cancer', 'Disease', (142, 148))
302726	28317894	Strikingly, the removal of fight-club hubs produces a drastic increase of the average shortest path that is in most cases very similar to the effect caused by the deletion of date hubs.	('club', 'Phenotype', 'HP:0001217', (33, 37))	('hub', 'Gene', (180, 183))	('shortest path', 'MPA', (86, 99))	('hub', 'Gene', '1993', (38, 41))	('removal', 'Var', (16, 23))	('hub', 'Gene', '1993', (180, 183))	('increase', 'PosReg', (62, 70))	('hub', 'Gene', (38, 41))	('fight-club', 'Gene', (27, 37))
302727	28317894	resilience to errors) of the network, we found that the drastic effect observed on the deletion of fight-club hubs, was largely due to their subset of switch genes rather than being a generic property of the entire set of fight-club hubs (see Supplementary Fig.	('hub', 'Gene', (110, 113))	('club', 'Phenotype', 'HP:0001217', (105, 109))	('hub', 'Gene', '1993', (233, 236))	('hub', 'Gene', '1993', (110, 113))	('hub', 'Gene', (233, 236))	('club', 'Phenotype', 'HP:0001217', (228, 232))	('deletion', 'Var', (87, 95))
302743	28317894	The clinical relevance of this gene is further supported by the evidence that mutations in BRIP1 confer an increased risk of breast cancer and transcription of BRIP1 has been found to be cell growth-related and controlled by the E2F/retinoblastoma (Rb) pathway through a conserved E2F-responsive site.	('Rb', 'Phenotype', 'HP:0009919', (249, 251))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('mutations', 'Var', (78, 87))	('BRIP1', 'Gene', (160, 165))	('BRIP1', 'Gene', (91, 96))	('breast cancer', 'Disease', 'MESH:D001943', (125, 138))	('retinoblastoma', 'Phenotype', 'HP:0009919', (233, 247))	('breast cancer', 'Disease', (125, 138))	('breast cancer', 'Phenotype', 'HP:0003002', (125, 138))	('BRIP1', 'Gene', '83990', (160, 165))	('BRIP1', 'Gene', '83990', (91, 96))	('retinoblastoma', 'Disease', 'MESH:D012175', (233, 247))	('retinoblastoma', 'Disease', (233, 247))
302765	28317894	We found that, among factors of the E2F family, E2F4 can be considered to be bound in vivo to virtually all the promoters, whereas NF-Y is bound to about 70-90% of the promoters according to the cell lines.	('E2F4', 'Var', (48, 52))	('NF-Y', 'Gene', '4801', (131, 135))	('NF-Y', 'Gene', (131, 135))
302771	28317894	Significant genome wide co-association with NF-Y was also reported in the same study for E2F4, SP1, and SP2.	('NF-Y', 'Gene', (44, 48))	('SP2', 'Gene', '6668', (104, 107))	('SP2', 'Gene', (104, 107))	('E2F4', 'Var', (89, 93))	('NF-Y', 'Gene', '4801', (44, 48))
302773	28317894	Moreover, a significant enrichment for E2F motifs could be found as well, situated outside the NF-Y bound regions (i.e.	('motifs', 'Var', (43, 49))	('NF-Y', 'Gene', '4801', (95, 99))	('NF-Y', 'Gene', (95, 99))	('E2F motifs', 'Var', (39, 49))
302790	28317894	Many studies that over the last years focused on the role of NF-Y in controlling cell proliferation converge on these main results: (i) NF-Y controls the expression of several key regulators of the cell cycle; (ii) NF-Y silencing impairs G2/M progression and induces apoptosis; (iii) widespread activation of G2/M and anti-apoptotic genes requires NF-Y; (iv) NF-Y and mutant p53 physically interact up-regulating the expression of many cell cycle related genes in response to DNA damage; (v) NF-Y over-expression increases the proliferation of cancer cells harboring endogenous mutant p53.	('NF-Y', 'Gene', '4801', (61, 65))	('p53', 'Gene', (375, 378))	('mutant', 'Var', (368, 374))	('cancer', 'Disease', 'MESH:D009369', (544, 550))	('NF-Y', 'Gene', (359, 363))	('NF-Y', 'Gene', (215, 219))	('NF-Y', 'Gene', (136, 140))	('up-regulating', 'PosReg', (399, 412))	('NF-Y', 'Gene', '4801', (359, 363))	('NF-Y', 'Gene', (492, 496))	('NF-Y', 'Gene', '4801', (215, 219))	('NF-Y', 'Gene', '4801', (136, 140))	('mutant', 'Var', (578, 584))	('NF-Y', 'Gene', '4801', (492, 496))	('p53', 'Gene', '7157', (585, 588))	('proliferation', 'CPA', (527, 540))	('cancer', 'Disease', (544, 550))	('NF-Y', 'Gene', (348, 352))	('p53', 'Gene', '7157', (375, 378))	('over-expression increases', 'PosReg', (497, 522))	('NF-Y', 'Gene', (61, 65))	('p53', 'Gene', (585, 588))	('cancer', 'Phenotype', 'HP:0002664', (544, 550))	('impairs', 'NegReg', (230, 237))	('NF-Y', 'Gene', '4801', (348, 352))	('expression', 'MPA', (417, 427))
302792	28317894	Regarding E2F4, even though it was previously known as a repressor of cell proliferation, some studies introduced the possibility that E2F4 may function as an activator of genes implicated in positive regulation of the cell cycle, among them MYBL2.	('activator', 'PosReg', (159, 168))	('E2F4', 'Var', (135, 139))	('MYBL2', 'Gene', (242, 247))	('MYBL2', 'Gene', '4605', (242, 247))
302793	28317894	In addition, E2F4 over-expression in transgenic mice leads to the development of tumors and mutated E2F4 has been reported in various human tumors, providing evidence for the oncogenic activity of E2F4.	('human', 'Species', '9606', (134, 139))	('tumors', 'Disease', (81, 87))	('tumors', 'Disease', (140, 146))	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('tumors', 'Disease', 'MESH:D009369', (140, 146))	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('reported', 'Reg', (114, 122))	('over-expression', 'PosReg', (18, 33))	('transgenic mice', 'Species', '10090', (37, 52))	('E2F4', 'Gene', (13, 17))	('mutated', 'Var', (92, 99))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('leads to', 'Reg', (53, 61))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('E2F4', 'Gene', (100, 104))
302871	33837652	Tang JY et al 20  indicated that ATG5 might be an indicator of overall survival and disease recurrence in OSCC and the high ATG5 expression of was related to high tumour grade, advanced clinical stage, large tumour size and lymph node metastasis of OSCC, indicating that autophagy play a crucial role in OSCC tumorigenesis and progression.	('ATG5', 'Gene', '9474', (124, 128))	('expression', 'MPA', (129, 139))	('tumour', 'Disease', (208, 214))	('high', 'Var', (119, 123))	('OSCC', 'Disease', (249, 253))	('ATG5', 'Gene', (124, 128))	('ATG5', 'Gene', '9474', (33, 37))	('OSCC', 'Disease', (304, 308))	('related', 'Reg', (147, 154))	('tumour', 'Phenotype', 'HP:0002664', (163, 169))	('OSCC', 'Disease', (106, 110))	('tumour', 'Phenotype', 'HP:0002664', (208, 214))	('tumour', 'Disease', 'MESH:D009369', (163, 169))	('tumour', 'Disease', 'MESH:D009369', (208, 214))	('ATG5', 'Gene', (33, 37))	('lymph node metastasis', 'CPA', (224, 245))	('tumour', 'Disease', (163, 169))
302877	33837652	In head and neck squamous cell carcinoma (HNSC), study showed that high expression level of ATG12 significantly increased the death risk after adjusting for age, gender, clinical stage, smoking and drinking status.	('high', 'Var', (67, 71))	('ATG12', 'Gene', (92, 97))	('death', 'Disease', 'MESH:D003643', (126, 131))	('death', 'Disease', (126, 131))	('neck squamous cell carcinoma', 'Disease', (12, 40))	('increased', 'PosReg', (112, 121))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (12, 40))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (3, 40))	('HNSC', 'Phenotype', 'HP:0012288', (42, 46))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (17, 40))	('carcinoma', 'Phenotype', 'HP:0030731', (31, 40))
302926	33371259	These results collectively indicate an oncogenic role of LOX in HCC, while demonstrating an anti-tumor effect of LOX-PP.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('LOX-PP', 'Chemical', '-', (113, 119))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('HCC', 'Disease', (64, 67))	('tumor', 'Disease', (97, 102))	('HCC', 'Phenotype', 'HP:0001402', (64, 67))	('LOX', 'Var', (57, 60))
302928	33371259	Adenovirus-delivered overexpression of LOX-PP in HCC cells enhances apoptosis and represses proliferation, migration, and invasion via the mitogen-activated protein kinase (MAPK) pathway.	('migration', 'CPA', (107, 116))	('LOX-PP', 'Var', (39, 45))	('Adenovirus', 'Species', '10508', (0, 10))	('apoptosis', 'CPA', (68, 77))	('invasion', 'CPA', (122, 130))	('HCC', 'Phenotype', 'HP:0001402', (49, 52))	('overexpression', 'PosReg', (21, 35))	('enhances', 'PosReg', (59, 67))	('represses', 'NegReg', (82, 91))	('LOX-PP', 'Chemical', '-', (39, 45))
302936	33371259	also observed a positive correlation between LOX and VEGF in HCC cells, demonstrating that the knockdown of LOX suppresses HCC proliferation, migration, and invasion.	('suppresses', 'NegReg', (112, 122))	('migration', 'CPA', (142, 151))	('invasion', 'CPA', (157, 165))	('LOX', 'Gene', (108, 111))	('VEGF', 'Gene', (53, 57))	('knockdown', 'Var', (95, 104))	('HCC', 'Phenotype', 'HP:0001402', (61, 64))	('HCC', 'Phenotype', 'HP:0001402', (123, 126))	('HCC proliferation', 'CPA', (123, 140))	('VEGF', 'Gene', '7422', (53, 57))
302939	33371259	showed that adenovirus-delivered LOX-PP overexpression in HCC cells hinders cell cycle progression cellular motility, as well as angiogenic activators MMP-2 and MMP-9.	('LOX-PP', 'Var', (33, 39))	('HCC', 'Phenotype', 'HP:0001402', (58, 61))	('cell cycle progression', 'CPA', (76, 98))	('adenovirus', 'Species', '10508', (12, 22))	('overexpression', 'PosReg', (40, 54))	('hinders', 'NegReg', (68, 75))	('MMP-9', 'Gene', '4318', (161, 166))	('LOX-PP', 'Chemical', '-', (33, 39))	('MMP-9', 'Gene', (161, 166))
302940	33371259	Nevertheless, the exact mechanism underlying LOX-PP perturbation of EC proliferation and vessel formation requires further study.	('LOX-PP', 'Chemical', '-', (45, 51))	('LOX-PP', 'Var', (45, 51))	('EC proliferation', 'CPA', (68, 84))	('vessel formation', 'CPA', (89, 105))
302947	33371259	found that the knockdown of LOXL1 suppresses proliferation and fibrogenesis induced by transforming growth factor-beta1-mothers against the decapentaplegic homolog 2/3 (TGF-beta1- Smad2/3) signaling pathway in an HSC line.	('transforming growth factor-beta1', 'Gene', (87, 119))	('knockdown', 'Var', (15, 24))	('fibrogenesis', 'CPA', (63, 75))	('proliferation', 'CPA', (45, 58))	('suppresses', 'NegReg', (34, 44))	('TGF-beta1', 'Gene', '7040', (169, 178))	('TGF-beta1', 'Gene', (169, 178))	('LOXL1', 'Gene', '4016', (28, 33))	('LOXL1', 'Gene', (28, 33))	('transforming growth factor-beta1', 'Gene', '7040', (87, 119))
302956	33371259	The knockdown of LOXL2 by siRNA has been shown to attenuate proliferation and cell colony formation, and to promote cycle arrest and apoptosis in HCC cells.	('cell colony formation', 'CPA', (78, 99))	('HCC', 'Phenotype', 'HP:0001402', (146, 149))	('proliferation', 'CPA', (60, 73))	('apoptosis', 'CPA', (133, 142))	('arrest', 'Disease', 'MESH:D006323', (122, 128))	('attenuate', 'NegReg', (50, 59))	('promote', 'PosReg', (108, 115))	('knockdown', 'Var', (4, 13))	('arrest', 'Disease', (122, 128))
302968	33371259	Furthermore, the expression of LOXL2 was respectively suppressed/augmented by knockdown/overexpression of the 67 laminin receptor (67LR).	('67 laminin receptor', 'Gene', '3921', (110, 129))	('expression', 'MPA', (17, 27))	('67LR', 'Gene', (131, 135))	('knockdown/overexpression', 'Var', (78, 102))	('67LR', 'Gene', '3921', (131, 135))	('knockdown/overexpression', 'PosReg', (78, 102))	('suppressed/augmented', 'PosReg', (54, 74))	('67 laminin receptor', 'Gene', (110, 129))
302974	33371259	In addition, silencing of LOXL2 can suppress cell invasion and EMT activity induced by the hepatitis C virus core protein (HCVc) in CCA.	('EMT activity', 'CPA', (63, 75))	('CCA', 'Disease', (132, 135))	('suppress', 'NegReg', (36, 44))	('cell invasion', 'CPA', (45, 58))	('hepatitis C virus', 'Species', '11103', (91, 108))	('CCA', 'Phenotype', 'HP:0030153', (132, 135))	('hepatitis', 'Phenotype', 'HP:0012115', (91, 100))	('silencing', 'Var', (13, 22))
302975	33371259	Table 3 outlines the mechanisms of LOXL2 in liver cancer and shaping of the hepatocarcinogenic microenvironment.	('liver cancer', 'Disease', (44, 56))	('LOXL2', 'Var', (35, 40))	('liver cancer', 'Phenotype', 'HP:0002896', (44, 56))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('liver cancer', 'Disease', 'MESH:D006528', (44, 56))
302976	33371259	revealed that the mRNA level and immunoreactivity of LOXL4 upregulates in HCC tissue, and that high LOXL4 protein expression predicts poor OS, DFS, and cumulative survival rate, and serves as an independent predictor for tumor size and TNM stage.	('cumulative survival rate', 'CPA', (152, 176))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('tumor', 'Disease', (221, 226))	('mRNA level', 'MPA', (18, 28))	('HCC', 'Phenotype', 'HP:0001402', (74, 77))	('tumor', 'Disease', 'MESH:D009369', (221, 226))	('high LOXL4', 'Var', (95, 105))	('upregulates', 'PosReg', (59, 70))	('poor OS', 'CPA', (134, 141))	('DFS', 'CPA', (143, 146))	('LOXL4', 'Gene', (53, 58))
302979	33371259	On the other hand, intercellular transfer of exosome-LOXL4 from HCC to human umbilical vein endothelial cells (HUVEC) promotes angiogenesis, as evidenced by increased HUVEC migration and tube formation.	('angiogenesis', 'CPA', (127, 139))	('HUVEC migration', 'CPA', (167, 182))	('promotes', 'PosReg', (118, 126))	('HCC', 'Phenotype', 'HP:0001402', (64, 67))	('tube formation', 'CPA', (187, 201))	('increased', 'PosReg', (157, 166))	('exosome-LOXL4', 'Var', (45, 58))	('human', 'Species', '9606', (71, 76))
302983	33371259	The mechanism underlying the immunosuppressive role of LOXL4 on shaping macrophage phenotype lies in an H2O2-dependent activation of the interferon alpha and beta receptor subunit-1-signal transducer and activator of transcription 1 and 3-programmed death-ligand 1 (IFNAR1-STAT1/3-PD-L1) pathway.	('PD-L1', 'Gene', (281, 286))	('IFNAR1', 'Gene', (266, 272))	('LOXL4', 'Var', (55, 60))	('activation', 'PosReg', (119, 129))	('PD-L1', 'Gene', '29126', (281, 286))	('IFNAR1', 'Gene', '3454', (266, 272))	('interferon alpha and beta receptor subunit-1', 'Gene', '3454', (137, 181))	('H2O2', 'Chemical', 'MESH:D006861', (104, 108))
302987	33371259	The mechanism accounting for the 5-azacytidine-induced LOXL4-p53 axis of HCC cells lies in the binding between D677/D679 in LOXL4 and K381/382 in p53, noted to occur in other cancer types, including lung, breast, and ovarian cancers, as well as melanoma.	('K381/382', 'Var', (134, 142))	('HCC', 'Phenotype', 'HP:0001402', (73, 76))	('p53', 'Gene', (146, 149))	('cancer', 'Disease', (225, 231))	('cancer', 'Disease', (175, 181))	('ovarian cancers', 'Phenotype', 'HP:0100615', (217, 232))	('breast', 'Disease', (205, 211))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('lung', 'Disease', (199, 203))	('melanoma', 'Phenotype', 'HP:0002861', (245, 253))	('melanoma', 'Disease', (245, 253))	('5-azacytidine', 'Chemical', 'MESH:D001374', (33, 46))	('ovarian cancer', 'Phenotype', 'HP:0100615', (217, 231))	('cancer', 'Disease', 'MESH:D009369', (225, 231))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('ovarian cancers', 'Disease', (217, 232))	('D677/D679', 'Var', (111, 120))	('ovarian cancers', 'Disease', 'MESH:D010051', (217, 232))	('p53', 'Gene', '7157', (61, 64))	('binding', 'Interaction', (95, 102))	('p53', 'Gene', '7157', (146, 149))	('melanoma', 'Disease', 'MESH:D008545', (245, 253))	('p53', 'Gene', (61, 64))	('cancers', 'Phenotype', 'HP:0002664', (225, 232))
302989	33371259	Given that the expression and intercellular crosstalk of LOX, LOXL2, and LOXL4 play critical roles in TME formation and the progression of HCC, elucidation of their regulatory pathways may identify promising therapeutic targets.	('TM', 'Chemical', 'MESH:C020809', (102, 104))	('HCC', 'Disease', (139, 142))	('HCC', 'Phenotype', 'HP:0001402', (139, 142))	('LOXL4', 'Var', (73, 78))	('TME', 'Disease', (102, 105))	('roles', 'Reg', (93, 98))
302991	33371259	demonstrated that siRNA-based knockdown of HIF-1 considerably reduces LOX expression HCC cells.	('LOX expression', 'MPA', (70, 84))	('reduces', 'NegReg', (62, 69))	('HIF-1', 'Gene', '3091', (43, 48))	('HCC', 'Phenotype', 'HP:0001402', (85, 88))	('knockdown', 'Var', (30, 39))	('HIF-1', 'Gene', (43, 48))
302995	33371259	showed that the TME-fostering effect of LOXL2 relies on the activation of the HIF-1alpha/TGF-B/SMAD4 pathway.	('TGF-B', 'Gene', (89, 94))	('HIF-1alpha', 'Gene', '3091', (78, 88))	('SMAD4', 'Gene', (95, 100))	('activation', 'PosReg', (60, 70))	('TGF-B', 'Gene', '7040', (89, 94))	('TM', 'Chemical', 'MESH:C020809', (16, 18))	('LOXL2', 'Var', (40, 45))	('HIF-1alpha', 'Gene', (78, 88))	('TME-fostering effect', 'CPA', (16, 36))	('SMAD4', 'Gene', '4089', (95, 100))
303007	33371259	In terms of the impact of genetic alteration, an Arg158Gln substitution in LOX-PP has been shown to be associated with susceptibility of breast, lung, colorectal, and ovarian cancer.	('Arg158Gln', 'SUBSTITUTION', 'None', (49, 58))	('LOX-PP', 'Chemical', '-', (75, 81))	('susceptibility', 'Reg', (119, 133))	('associated', 'Reg', (103, 113))	('lung', 'Disease', (145, 149))	('ovarian cancer', 'Phenotype', 'HP:0100615', (167, 181))	('colorectal, and ovarian cancer', 'Disease', 'MESH:D015179', (151, 181))	('Arg158Gln', 'Var', (49, 58))	('LOX-PP', 'Gene', (75, 81))	('breast', 'Disease', (137, 143))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
303008	33371259	showed that in knock-in strain LOX-PPGln mice that harbor an Arg152Gln substitution, corresponding to the human Arg158Gln polymorphism of LOX-PP, manifest increased susceptibility to carcinogen-induced breast cancer and hepatic inflammation compared to their wild type counterparts.	('Arg158Gln', 'Var', (112, 121))	('hepatic inflammation', 'Disease', 'MESH:D056486', (220, 240))	('Arg152Gln', 'Var', (61, 70))	('human', 'Species', '9606', (106, 111))	('breast cancer', 'Disease', 'MESH:D001943', (202, 215))	('Arg158Gln', 'SUBSTITUTION', 'None', (112, 121))	('increased', 'PosReg', (155, 164))	('mice', 'Species', '10090', (41, 45))	('breast cancer', 'Disease', (202, 215))	('susceptibility', 'Reg', (165, 179))	('LOX-PP', 'Chemical', '-', (31, 37))	('breast cancer', 'Phenotype', 'HP:0003002', (202, 215))	('hepatic inflammation', 'Phenotype', 'HP:0012115', (220, 240))	('Arg152Gln', 'SUBSTITUTION', 'None', (61, 70))	('LOX-PP', 'Chemical', '-', (138, 144))	('hepatic inflammation', 'Disease', (220, 240))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
303018	33371259	GW4869, a N-SMase inhibitor that blocks exosome generation, has been used to block intercellular exosome-LOXL4 transfer and reduce the cell migratory ability of HCC cells.	('intercellular exosome-LOXL4 transfer', 'MPA', (83, 119))	('GW4869', 'Chemical', 'MESH:C468773', (0, 6))	('N-SMase', 'Gene', (10, 17))	('GW4869', 'Var', (0, 6))	('HCC', 'Phenotype', 'HP:0001402', (161, 164))	('block', 'NegReg', (77, 82))	('cell migratory ability', 'CPA', (135, 157))	('N-SMase', 'Gene', '6610', (10, 17))	('reduce', 'NegReg', (124, 130))
303022	33371259	The LOXL2-neutrolazing monoclonal antibody AB0023 exerts the inhibitory effect of LOXL2 by targeting its SRCR domain; whereby, AB0023 has been shown to effectively alleviate liver fibrosis in mouse models induced by CCl4, by thioacetamide (TAA), and using Mdr2-/- plus 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC).	('AB0023', 'Var', (127, 133))	('thioacetamide', 'Chemical', 'MESH:D013853', (225, 238))	('TAA', 'Chemical', 'MESH:D013853', (240, 243))	('Mdr2', 'Gene', (256, 260))	('3,5-diethoxycarbonyl-1,4-dihydrocollidine', 'Chemical', 'MESH:C530773', (269, 310))	('mouse', 'Species', '10090', (192, 197))	('liver fibrosis', 'Phenotype', 'HP:0001395', (174, 188))	('liver fibrosis', 'Disease', (174, 188))	('DDC', 'Chemical', 'MESH:C530773', (312, 315))	('alleviate', 'NegReg', (164, 173))	('Mdr2', 'Gene', '18670', (256, 260))	('liver fibrosis', 'Disease', 'MESH:D008103', (174, 188))
303024	33371259	Furthermore, PXS-5153A, a dual LOXL2/LOXL3 inhibitor developed by Schilter et al., has been shown to ameliorate liver fibrosis in a CCl4 model and in a streptozotocin plus high fat diet-induced steatohepatitis model.	('ameliorate', 'PosReg', (101, 111))	('liver fibrosis', 'Disease', (112, 126))	('LOXL3', 'Gene', '84695', (37, 42))	('hepatitis', 'Phenotype', 'HP:0012115', (200, 209))	('liver fibrosis', 'Disease', 'MESH:D008103', (112, 126))	('PXS-5153A', 'Var', (13, 22))	('LOXL3', 'Gene', (37, 42))	('liver fibrosis', 'Phenotype', 'HP:0001395', (112, 126))	('streptozotocin', 'Chemical', 'MESH:D013311', (152, 166))	('steatohepatitis', 'Disease', (194, 209))	('steatohepatitis', 'Disease', 'MESH:D005234', (194, 209))
303025	33371259	The first selective inhibitor for LOXL2, LOXL2-IN-1 hydrochloride, has recently been identified to act to suppress Snail, HIF-1alpha, and VEGF, which are promotion factors in HCC invasion and angiogenesis.	('HCC invasion', 'CPA', (175, 187))	('HIF-1alpha', 'Gene', '3091', (122, 132))	('angiogenesis', 'CPA', (192, 204))	('LOXL2-IN-1', 'Var', (41, 51))	('VEGF', 'Gene', '7422', (138, 142))	('Snail', 'Gene', (115, 120))	('HCC', 'Phenotype', 'HP:0001402', (175, 178))	('HIF-1alpha', 'Gene', (122, 132))	('suppress', 'NegReg', (106, 114))	('Snail', 'Gene', '6615', (115, 120))	('VEGF', 'Gene', (138, 142))
303027	33371259	demonstrated that the LOX inhibitor CCT365623, bearing an aminomethylenethiophene (AMT) scaffold, has exhibited anti-metastasis efficacy in a LOX-driven spontaneous breast cancer model.	('breast cancer', 'Disease', 'MESH:D001943', (165, 178))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('breast cancer', 'Disease', (165, 178))	('CCT365623', 'Var', (36, 45))	('breast cancer', 'Phenotype', 'HP:0003002', (165, 178))	('aminomethylenethiophene', 'Chemical', '-', (58, 81))	('anti-metastasis efficacy', 'CPA', (112, 136))	('CCT365623', 'Chemical', '-', (36, 45))	('AMT', 'Chemical', '-', (83, 86))
303029	33371259	One of the AMTz-bearing inhibitors, AMTz-21b, effectively suppressed tumor growth in their spontaneous breast cancer mouse model.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor', 'Disease', (69, 74))	('mouse', 'Species', '10090', (117, 122))	('AMTz', 'Chemical', '-', (11, 15))	('breast cancer', 'Disease', 'MESH:D001943', (103, 116))	('suppressed', 'NegReg', (58, 68))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('breast cancer', 'Disease', (103, 116))	('AMTz', 'Chemical', '-', (36, 40))	('AMTz-21b', 'Var', (36, 44))	('breast cancer', 'Phenotype', 'HP:0003002', (103, 116))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
303037	33371259	MiRs are approximately 22 nucleotides in length, short non-coding RNAs, functioning in a pathway-centric manner by targeting multiple genes, and are potential therapeutic targets for liver cancer.	('targeting', 'Reg', (115, 124))	('MiRs', 'Var', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('liver cancer', 'Disease', 'MESH:D006528', (183, 195))	('liver cancer', 'Phenotype', 'HP:0002896', (183, 195))	('liver cancer', 'Disease', (183, 195))
303042	33371259	identified that miR-142-3p exerts an inhibitory role on LOX expression for overcoming chemoresistance in triple-negative breast cancer.	('overcoming', 'PosReg', (75, 85))	('breast cancer', 'Disease', 'MESH:D001943', (121, 134))	('miR-142-3p', 'Var', (16, 26))	('miR-142-3p', 'Chemical', '-', (16, 26))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('breast cancer', 'Disease', (121, 134))	('breast cancer', 'Phenotype', 'HP:0003002', (121, 134))	('chemoresistance', 'CPA', (86, 101))
303052	33371259	There is mounting clinical evidence indicating their significance in predicting prognosis and diagnosis, and their roles in promoting cancer cell proliferation, invasiveness, and shaping the TME of liver cancer (Figure 4), particularly LOX, LOXL2, and LOXL4.	('cancer', 'Disease', (204, 210))	('liver cancer', 'Disease', (198, 210))	('cancer', 'Disease', 'MESH:D009369', (204, 210))	('LOXL2', 'Var', (241, 246))	('promoting', 'PosReg', (124, 133))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('TM', 'Chemical', 'MESH:C020809', (191, 193))	('liver cancer', 'Phenotype', 'HP:0002896', (198, 210))	('LOXL4', 'Var', (252, 257))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('invasiveness', 'CPA', (161, 173))	('liver cancer', 'Disease', 'MESH:D006528', (198, 210))
303063	29262545	Moreover, Ad-ATF/SOX2 effectively inhibited tumor growth in a lung SCC xenograft mouse model.	('inhibited', 'NegReg', (34, 43))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('Ad-ATF/SOX2', 'Var', (10, 21))	('SCC', 'Gene', (67, 70))	('SCC', 'Phenotype', 'HP:0002860', (67, 70))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('mouse', 'Species', '10090', (81, 86))	('SCC', 'Gene', '6317', (67, 70))	('tumor', 'Disease', (44, 49))
303070	29262545	The identification of these mutations and amplifications can be used to predict sensitivity to clinical inhibitors of pulmonary adenocarcinoma.	('pulmonary adenocarcinoma', 'Disease', (118, 142))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('pulmonary adenocarcinoma', 'Disease', 'MESH:D008175', (118, 142))	('mutations', 'Var', (28, 37))	('pulmonary adenocarcinoma', 'Phenotype', 'HP:0030078', (118, 142))
303078	29262545	Amplification of chromosome 3q26 is the most common of the genetic alterations found in lung SCC.	('common', 'Reg', (45, 51))	('Amplification', 'Var', (0, 13))	('SCC', 'Gene', (93, 96))	('SCC', 'Phenotype', 'HP:0002860', (93, 96))	('SCC', 'Gene', '6317', (93, 96))
303079	29262545	SOX2 is a candidate oncogene present in this locus and amplification of SOX2 has been reported in lung and esophageal SCC.	('amplification', 'Var', (55, 68))	('SOX2', 'Gene', (72, 76))	('SCC', 'Gene', (118, 121))	('reported', 'Reg', (86, 94))	('SCC', 'Phenotype', 'HP:0002860', (118, 121))	('SCC', 'Gene', '6317', (118, 121))
303080	29262545	In a previous study, we demonstrated that silencing SOX2 by siRNA induced G1 cell cycle arrest mediated by upregulation of CDKN1A expression resulting in an anti tumor effect in SOX2-expressing lung SCC cells both in vitro and in vivo.	('upregulation', 'PosReg', (107, 119))	('silencing', 'Var', (42, 51))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('SCC', 'Gene', (199, 202))	('SCC', 'Phenotype', 'HP:0002860', (199, 202))	('tumor', 'Disease', (162, 167))	('CDKN1A', 'Gene', (123, 129))	('SCC', 'Gene', '6317', (199, 202))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (77, 94))	('G1 cell cycle arrest', 'CPA', (74, 94))
303082	29262545	In human lung SCC and esophageal SCC sections, SOX2 expression was detected in more than 87.5% of sections (Figure 1B and 1C) suggesting that molecular targeting of SOX2 might be useful for treating SCC.	('SCC', 'Gene', '6317', (33, 36))	('SCC', 'Gene', (199, 202))	('human', 'Species', '9606', (3, 8))	('SCC', 'Phenotype', 'HP:0002860', (199, 202))	('SCC', 'Gene', (14, 17))	('SCC', 'Phenotype', 'HP:0002860', (14, 17))	('SCC', 'Gene', '6317', (199, 202))	('SCC', 'Gene', '6317', (14, 17))	('SCC', 'Gene', (33, 36))	('SCC', 'Phenotype', 'HP:0002860', (33, 36))	('molecular targeting', 'Var', (142, 161))
303088	29262545	Furthermore, Ad-ATF/SOX2 induced an antitumor effect in SOX2-expressing SCC more effectively than did Ad-shSOX2 both in vitro and in vivo.	('Ad-ATF/SOX2', 'Var', (13, 24))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('SOX2-expressing', 'Gene', (56, 71))	('SCC', 'Gene', (72, 75))	('SCC', 'Phenotype', 'HP:0002860', (72, 75))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('SCC', 'Gene', '6317', (72, 75))
303094	29262545	On the other hand, in the presence of pcDNA3.1 ATF/SOX2, transcriptional activity of the SOX2 was significantly decreased in EBC2 cells (1.9-fold).	('ATF/SOX2', 'Gene', (47, 55))	('EBC', 'Chemical', '-', (125, 128))	('pcDNA3.1', 'Var', (38, 46))	('decreased', 'NegReg', (112, 121))	('transcriptional activity', 'MPA', (57, 81))
303095	29262545	In esophageal SCC cells, the region -1990/+436 exhibited significant transcriptional activity in TE1 cells (32 -fold) and in TE4 cells (65 -fold).	('SCC', 'Gene', (14, 17))	('SCC', 'Phenotype', 'HP:0002860', (14, 17))	('transcriptional activity', 'MPA', (69, 93))	('SCC', 'Gene', '6317', (14, 17))	('region -1990/+436', 'Var', (29, 46))
303099	29262545	We previously reported that CDKN1A is a SOX2 downstream gene and that silencing of SOX2 increases the expression of CDKN1A which induces cell cycle arrest in lung SCC cells.	('induces', 'Reg', (129, 136))	('SOX2', 'Gene', (83, 87))	('CDKN1A', 'Gene', (116, 122))	('expression', 'MPA', (102, 112))	('silencing', 'Var', (70, 79))	('SCC', 'Gene', (163, 166))	('SCC', 'Phenotype', 'HP:0002860', (163, 166))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (137, 154))	('increases', 'PosReg', (88, 97))	('SCC', 'Gene', '6317', (163, 166))	('cell cycle arrest', 'CPA', (137, 154))
303101	29262545	We then determined SOX2 and CDKN1A expression in lung and esophageal SCC cells after Ad-shSOX2 or Ad-ATF/SOX2 infection.	('Ad-shSOX2', 'Var', (85, 94))	('SCC', 'Gene', (69, 72))	('SCC', 'Phenotype', 'HP:0002860', (69, 72))	('CDKN1A', 'Gene', (28, 34))	('SCC', 'Gene', '6317', (69, 72))
303102	29262545	As shown in Figure 4, both Ad-shSOX2 and Ad-ATF/SOX2 effectively suppressed SOX2 expression in EBC2 lung SCC cells, TE1 and TE4 esophageal SCC cells 48 hours after adenoviral infections.	('adenoviral infections', 'Disease', (164, 185))	('SCC', 'Gene', '6317', (139, 142))	('adenoviral infections', 'Disease', 'MESH:D007239', (164, 185))	('SOX2', 'Gene', (76, 80))	('Ad-shSOX2', 'Var', (27, 36))	('suppressed', 'NegReg', (65, 75))	('SCC', 'Gene', (105, 108))	('EBC', 'Chemical', '-', (95, 98))	('SCC', 'Gene', (139, 142))	('SCC', 'Phenotype', 'HP:0002860', (139, 142))	('SCC', 'Phenotype', 'HP:0002860', (105, 108))	('SCC', 'Gene', '6317', (105, 108))
303103	29262545	Importantly, in EBC2 cells and TE4 cells, SOX2 protein expression was more robustly suppressed by Ad-shSOX2 than by Ad-ATF/SOX2, however, CDKN1A expression was greater in all kinds of cells in the Ad-ATF/SOX2 treated cells than in Ad-shSOX2 treated cells.	('SOX2', 'Gene', (42, 46))	('expression', 'MPA', (145, 155))	('EBC', 'Chemical', '-', (16, 19))	('greater', 'PosReg', (160, 167))	('CDKN1A', 'Gene', (138, 144))	('Ad-shSOX2', 'Var', (98, 107))	('suppressed', 'NegReg', (84, 94))
303104	29262545	Moreover, as shown in Supplementary Figure 2, G1 cell cycle arrest was induced in EBC2 cells and TE4 cells 36 hours after Ad-ATF/SOX2 infection, whereas the G0/G1 cell population was very weakly increased after Ad-shSOX2 infection.	('Ad-ATF/SOX2 infection', 'Var', (122, 143))	('induced', 'Reg', (71, 78))	('infection', 'Var', (134, 143))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (49, 66))	('G1 cell cycle arrest', 'CPA', (46, 66))	('EBC', 'Chemical', '-', (82, 85))
303105	29262545	In this study, EBC2 lung SCC cells, TE1 and TE4 esophageal SCC cells harbor mutant TP53.	('SCC', 'Gene', (25, 28))	('SCC', 'Gene', (59, 62))	('SCC', 'Phenotype', 'HP:0002860', (25, 28))	('TP53', 'Gene', (83, 87))	('mutant', 'Var', (76, 82))	('SCC', 'Phenotype', 'HP:0002860', (59, 62))	('SCC', 'Gene', '6317', (25, 28))	('SCC', 'Gene', '6317', (59, 62))	('EBC', 'Chemical', '-', (15, 18))
303109	29262545	Furthermore, as shown in Figure 5B and 5C, Ad-ATF/SOX2 significantly decreased colony formation more than Ad-null and Ad-shSOX2 in EBC2, TE1 and TE4 cells.	('Ad-ATF/SOX2', 'Var', (43, 54))	('colony formation', 'CPA', (79, 95))	('decreased', 'NegReg', (69, 78))	('EBC', 'Chemical', '-', (131, 134))
303111	29262545	In this experiment, Ad-shSOX2 inhibited colony formation of EBC2 cells but not of TE1 cells and TE4 cells.	('colony formation', 'CPA', (40, 56))	('Ad-shSOX2', 'Var', (20, 29))	('inhibited', 'NegReg', (30, 39))	('EBC2', 'Gene', (60, 64))	('EBC', 'Chemical', '-', (60, 63))
303112	29262545	On the other hand, CDKN1A expression was clearly different after Ad-null and Ad-shSOX2 infection in EBC2 cells.	('expression', 'MPA', (26, 36))	('CDKN1A', 'Gene', (19, 25))	('EBC', 'Chemical', '-', (100, 103))	('different', 'Reg', (49, 58))	('Ad-shSOX2', 'Var', (77, 86))
303113	29262545	It is possible that Ad-shSOX2 could not significantly inhibit cell viability in EBC2 lung SCC cells just 48 hours after infection but that it could show anti tumor effect in colony formation of EBC cells during a longer time incubation after treatment but not in TE1 and TE4 cells.	('tumor', 'Disease', (158, 163))	('Ad-shSOX2', 'Var', (20, 29))	('SCC', 'Gene', (90, 93))	('colony formation', 'CPA', (174, 190))	('SCC', 'Phenotype', 'HP:0002860', (90, 93))	('EBC', 'Chemical', '-', (194, 197))	('EBC', 'Chemical', '-', (80, 83))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('SCC', 'Gene', '6317', (90, 93))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))
303115	29262545	The tumor volume in the mice group treated with Ad-shSOX2 was approximately 37% of those in the mice group treated with Ad-null (p = 0.0026).	('tumor', 'Disease', (4, 9))	('mice', 'Species', '10090', (96, 100))	('mice', 'Species', '10090', (24, 28))	('Ad-shSOX2', 'Var', (48, 57))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))
303121	29262545	These results indicate that Ad-ATF/SOX2 could induce antitumor effect in SCC cells expressing SOX2 but not in normal cells.	('SOX2', 'Var', (94, 98))	('SCC', 'Gene', (73, 76))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('SCC', 'Phenotype', 'HP:0002860', (73, 76))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('expressing SOX2', 'Var', (83, 98))	('SCC', 'Gene', '6317', (73, 76))	('induce', 'PosReg', (46, 52))	('tumor', 'Disease', (57, 62))
303128	29262545	In this study, SOX2 expression was more robustly suppressed by Ad-shSOX2 than by Ad-ATF/SOX2 in EBC2 cells and TE4 cells.	('EBC', 'Chemical', '-', (96, 99))	('expression', 'MPA', (20, 30))	('Ad-shSOX2', 'Var', (63, 72))	('SOX2', 'Gene', (15, 19))	('suppressed', 'NegReg', (49, 59))
303154	29262545	We designed and constructed an artificial zinc finger protein (AZP) targeting -161 to -143 in the human SOX2 gene, where +1 is the transcription start site, by using our recognition code table as described.	('human', 'Species', '9606', (98, 103))	('targeting -161 to -143', 'Var', (68, 90))	('SOX2', 'Gene', (104, 108))
303176	29262545	The specific probe for CDKN1A (Hs00355782_m1), BMP2 (Hs00154192_m1), SNAI1 (Hs00195591_m1), VIM (Hs00958111_m1), ABL1 (Hs01104728_m1), RTN4 (Hs00199671_m1), KMT2B (Hs00207065_m1), MSH6 (Hs00943000_m1) and Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) (Hs03929097_g1) were derived from the commercially available TaqMan Gene Expression Assays (Applied Biosystems, Life Technologies, CA).	('Hs00943000_m1', 'Var', (186, 199))	('VIM', 'Gene', '7431', (92, 95))	('Hs00195591_m1', 'Var', (76, 89))	('ABL1', 'Gene', '25', (113, 117))	('Glyceraldehyde-3-phosphate dehydrogenase', 'Gene', '2597', (205, 245))	('VIM', 'Gene', (92, 95))	('Hs01104728_m1', 'Var', (119, 132))	('RTN4', 'Gene', '57142', (135, 139))	('KMT2B', 'Gene', '9757', (157, 162))	('Hs03929097_g1', 'Var', (255, 268))	('GAPDH', 'Gene', '2597', (247, 252))	('Hs00207065_m1', 'Var', (164, 177))	('MSH6', 'Gene', (180, 184))	('RTN4', 'Gene', (135, 139))	('MSH6', 'Gene', '2956', (180, 184))	('BMP2', 'Gene', '650', (47, 51))	('GAPDH', 'Gene', (247, 252))	('KMT2B', 'Gene', (157, 162))	('Hs00199671_m1', 'Var', (141, 154))	('SNAI1', 'Gene', '6615', (69, 74))	('SNAI1', 'Gene', (69, 74))	('Hs00154192_m1', 'Var', (53, 66))	('Glyceraldehyde-3-phosphate dehydrogenase', 'Gene', (205, 245))	('BMP2', 'Gene', (47, 51))	('Hs00958111_m1', 'Var', (97, 110))	('ABL1', 'Gene', (113, 117))	('Hs00355782_m1', 'Var', (31, 44))
303180	29262545	EBC2 lung SCC cells were plated in 15 cm dishes at a density of 4 x 106 per dish and cultured overnight at 37 C. The following day cells were infected with Ad-null, Ad-shSOX2 or Ad-ATF/SOX2 at a MOI of 250 for 24 hours.	('EBC', 'Chemical', '-', (0, 3))	('Ad-shSOX2', 'Var', (165, 174))	('SCC', 'Gene', (10, 13))	('Ad-null', 'Var', (156, 163))	('SCC', 'Phenotype', 'HP:0002860', (10, 13))	('Ad-ATF/SOX2', 'Var', (178, 189))	('SCC', 'Gene', '6317', (10, 13))
303297	33324671	Using multivariable Cox regression analysis, only CCI>=4, cancer site being NSCLC, FFMI<P10, HGS<P10, and GTVtotal remained statistically significant and were considered independent prognostic factors for OS.	('P10', 'Gene', (88, 91))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('CCI>=4', 'Var', (50, 56))	('Cox', 'Gene', (20, 23))	('NSCLC', 'Disease', (76, 81))	('Cox', 'Gene', '1351', (20, 23))	('FM', 'Gene', '2331', (84, 86))	('NSCLC', 'Disease', 'MESH:D002289', (76, 81))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('P10', 'Gene', (97, 100))	('cancer', 'Disease', (58, 64))	('P10', 'Gene', '6281', (97, 100))	('P10', 'Gene', '6281', (88, 91))
303315	33324671	HGS and FFMI <P10 at baseline as a surrogate marker for muscle wasting were both negative prognostic factors for OS, independent of cancer site (NSCLC or LAHNSCC) and GTV.	('muscle wasting', 'Disease', 'MESH:D009133', (56, 70))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('cancer', 'Disease', (132, 138))	('negative', 'NegReg', (81, 89))	('SCC', 'Gene', '6317', (158, 161))	('NSCLC', 'Disease', (145, 150))	('muscle wasting', 'Disease', (56, 70))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('NSCLC', 'Disease', 'MESH:D002289', (145, 150))	('FM', 'Gene', '2331', (9, 11))	('P10', 'Gene', (14, 17))	('P10', 'Gene', '6281', (14, 17))	('AH', 'Disease', 'MESH:D007039', (155, 157))	('muscle wasting', 'Phenotype', 'HP:0003202', (56, 70))	('SCC', 'Gene', (158, 161))	('HGS', 'Var', (0, 3))
303347	33324671	Etoposide has also shown to induce muscle wasting.	('Etoposide', 'Var', (0, 9))	('muscle wasting', 'Disease', 'MESH:D009133', (35, 49))	('muscle wasting', 'Disease', (35, 49))	('muscle wasting', 'Phenotype', 'HP:0003202', (35, 49))	('Etoposide', 'Chemical', 'MESH:D005047', (0, 9))
303448	32489474	Identification and validation of an alternative splicing-based prognostic signature for head and neck squamous cell carcinoma Increasing evidence has demonstrated that changes in alternative splicing (AS) events are closely associated with the initiation and progression of cancer.	('cancer', 'Phenotype', 'HP:0002664', (274, 280))	('cancer', 'Disease', 'MESH:D009369', (274, 280))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (88, 125))	('cancer', 'Disease', (274, 280))	('neck squamous cell carcinoma', 'Disease', (97, 125))	('associated', 'Reg', (224, 234))	('changes', 'Var', (168, 175))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (102, 125))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (97, 125))	('alternative splicing', 'MPA', (179, 199))
303455	32489474	For instance, the level of DOCK5 variant was notably increased in HNSCC.	('HNSCC', 'Disease', (66, 71))	('HNSCC', 'Phenotype', 'HP:0012288', (66, 71))	('variant', 'Var', (33, 40))	('DOCK5', 'Gene', '80005', (27, 32))	('increased', 'PosReg', (53, 62))	('DOCK5', 'Gene', (27, 32))
303456	32489474	Overexpression of DOCK5 variant promoted the malignant behaviors of cancer cells, and vice versa.	('malignant behaviors of cancer', 'Disease', 'MESH:D009369', (45, 74))	('promoted', 'PosReg', (32, 40))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('malignant behaviors of cancer', 'Disease', (45, 74))	('DOCK5', 'Gene', '80005', (18, 23))	('DOCK5', 'Gene', (18, 23))	('variant', 'Var', (24, 31))
303457	32489474	In addition, DOCK5 variant upregulation was closely associated with the unfavorable prognosis of HNSCC.	('HNSCC', 'Phenotype', 'HP:0012288', (97, 102))	('HNSCC', 'Disease', (97, 102))	('DOCK5', 'Gene', '80005', (13, 18))	('variant', 'Var', (19, 26))	('DOCK5', 'Gene', (13, 18))	('upregulation', 'PosReg', (27, 39))
303458	32489474	The CD44 variant 4 and variant 6 were exclusively abundant in HNSCC, while variant 1 and variant 2 were found in normal oral keratinocytes.	('HNSCC', 'Phenotype', 'HP:0012288', (62, 67))	('HNSCC', 'Disease', (62, 67))	('CD44', 'Gene', '960', (4, 8))	('CD44', 'Gene', (4, 8))	('variant 4', 'Var', (9, 18))
303459	32489474	In addition, higher levels of variant 4 and variant 6 were especially detected in HNSCC cases with advanced stage or the cells with aggressive potential, suggesting that CD44 variant 4 and variant 6 might be important for HNSCC progression and metastasis.	('CD44', 'Gene', (170, 174))	('HNSCC', 'Phenotype', 'HP:0012288', (222, 227))	('HNSCC', 'Disease', (82, 87))	('variant', 'Var', (175, 182))	('HNSCC', 'Phenotype', 'HP:0012288', (82, 87))	('CD44', 'Gene', '960', (170, 174))
303482	32489474	For instance, a total of 3691 and 2403 AS events were found to be significantly correlated with survival in lung adenocarcinoma and lung squamous cell carcinoma.	('correlated with', 'Reg', (80, 95))	('lung adenocarcinoma', 'Disease', (108, 127))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (108, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (132, 160))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (137, 160))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (132, 160))	('lung squamous cell carcinoma', 'Disease', (132, 160))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (108, 127))	('2403', 'Var', (34, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (151, 160))
303484	32489474	Abnormal splicing can generate protein isoforms that promote the formation and progression of tumor as well as resistance to therapy.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('Abnormal splicing', 'Var', (0, 17))	('formation', 'CPA', (65, 74))	('tumor', 'Disease', (94, 99))	('promote', 'PosReg', (53, 60))
303485	32489474	Therefore, it is common to observe that deregulation of SFs is closely involved in tumor development.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('involved', 'Reg', (71, 79))	('SFs', 'Gene', (56, 59))	('tumor', 'Disease', (83, 88))	('deregulation', 'Var', (40, 52))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
303494	32489474	AS alternative splicing HNSCC head and neck squamous cell carcinoma OS overall survival AA alternate acceptor site AD alternate donor site AP alternate promoter AT alternate terminator ES exon skip ME mutually exclusive exons RI retained intron TCGA The Cancer Genome Atlas PSI percent spliced in SF splicing factor LASSO least absolute shrinkage and selection operator TNM tumor, node, metastasis	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (39, 67))	('AD', 'Chemical', '-', (115, 117))	('tumor', 'Disease', (374, 379))	('skip', 'Var', (193, 197))	('HNSCC', 'Phenotype', 'HP:0012288', (24, 29))	('Cancer', 'Phenotype', 'HP:0002664', (254, 260))	('Cancer', 'Disease', (254, 260))	('ES', 'Chemical', '-', (185, 187))	('tumor', 'Disease', 'MESH:D009369', (374, 379))	('Cancer', 'Disease', 'MESH:D009369', (254, 260))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (44, 67))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (30, 67))	('LASSO', 'Chemical', '-', (316, 321))	('ME', 'Chemical', '-', (198, 200))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))	('neck squamous cell carcinoma', 'Disease', (39, 67))	('tumor', 'Phenotype', 'HP:0002664', (374, 379))
303495	32110052	ALK Rearrangement Adenocarcinoma with Histological Transformation to Squamous Cell Carcinoma Resistant to Alectinib and Ceritinib Specific tyrosine-kinase inhibitors (TKIs) are widely used for the treatment of non-small-cell lung cancers with anaplastic lymphoma kinase (ALK) translocations.	('Squamous Cell Carcinoma', 'Disease', (69, 92))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (243, 262))	('lung cancer', 'Phenotype', 'HP:0100526', (225, 236))	('anaplastic lymphoma kinase', 'Gene', '238', (243, 269))	('non-small-cell lung cancers', 'Disease', 'MESH:D002289', (210, 237))	('lung cancers', 'Phenotype', 'HP:0100526', (225, 237))	('carcinoma', 'Phenotype', 'HP:0030731', (23, 32))	('anaplastic lymphoma kinase', 'Gene', (243, 269))	('cancers', 'Phenotype', 'HP:0002664', (230, 237))	('Carcinoma', 'Phenotype', 'HP:0030731', (83, 92))	('lymphoma', 'Phenotype', 'HP:0002665', (254, 262))	('ALK', 'Gene', '238', (271, 274))	('Alectinib', 'Chemical', 'MESH:C582670', (106, 115))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('ALK', 'Gene', (271, 274))	('Squamous Cell Carcinoma', 'Disease', 'MESH:D002294', (69, 92))	('Ceritinib', 'Chemical', 'MESH:C586847', (120, 129))	('ALK', 'Gene', '238', (0, 3))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (69, 92))	('Adenocarcinoma', 'Disease', (18, 32))	('ALK', 'Gene', (0, 3))	('non-small-cell lung cancers', 'Disease', (210, 237))	('Rearrangement', 'Var', (4, 17))
303498	32110052	We, herein, report a case of ALK rearrangement-positive adenocarcinoma that transformed to squamous cell carcinoma after administration of alectinib, and was found to be resistant to ceritinib.	('ALK', 'Gene', (29, 32))	('ceritinib', 'Chemical', 'MESH:C586847', (183, 192))	('alectinib', 'Chemical', 'MESH:C582670', (139, 148))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (91, 114))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (91, 114))	('rearrangement-positive', 'Var', (33, 55))	('adenocarcinoma', 'Disease', (56, 70))	('ALK', 'Gene', '238', (29, 32))	('squamous cell carcinoma', 'Disease', (91, 114))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('adenocarcinoma', 'Disease', 'MESH:D000230', (56, 70))
303500	32110052	Immunohistochemistry revealed positivity for thyroid transcription factor-1 (TTF-1) (Figure 2B) and anaplastic lymphoma kinase (ALK) (Figure 2C).	('positivity', 'Var', (30, 40))	('ALK', 'Gene', '238', (128, 131))	('anaplastic lymphoma kinase', 'Gene', '238', (100, 126))	('thyroid transcription factor-1', 'Gene', '7080', (45, 75))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (100, 119))	('TTF-1', 'Gene', '7080', (77, 82))	('TTF-1', 'Gene', (77, 82))	('ALK', 'Gene', (128, 131))	('anaplastic lymphoma kinase', 'Gene', (100, 126))	('thyroid transcription factor-1', 'Gene', (45, 75))	('lymphoma', 'Phenotype', 'HP:0002665', (111, 119))
303502	32110052	Finally, the left lung adenocarcinoma was evaluated as c-T4N3M1c, c-stage IVB possessing ALK gene rearrangement, and the patient was administered alectinib.	('alectinib', 'Chemical', 'MESH:C582670', (146, 155))	('ALK', 'Gene', (89, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (28, 37))	('c-T4N3M1c', 'Var', (55, 64))	('left lung adenocarcinoma', 'Disease', 'MESH:C538231', (13, 37))	('left lung adenocarcinoma', 'Disease', (13, 37))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (18, 37))	('ALK', 'Gene', '238', (89, 92))	('patient', 'Species', '9606', (121, 128))
303508	32110052	Additional immunohistochemical analysis showed positivity for ALK (Figure 2H), and subsequent fluorescence in situ hybridization (FISH) using break-apart probes (Vysis ALK Break Apart FISH Probe Kit; Abbott, Abbott Park, IL, USA) confirmed ALK rearrangement, which was consistent with the findings from the primary LN biopsy.	('ALK', 'Gene', '238', (240, 243))	('ALK', 'Gene', (62, 65))	('ALK', 'Gene', (168, 171))	('rearrangement', 'Var', (244, 257))	('ALK', 'Gene', (240, 243))	('Break Apart', 'Phenotype', 'HP:0001061', (172, 183))	('ALK', 'Gene', '238', (62, 65))	('ALK', 'Gene', '238', (168, 171))
303525	32110052	We report a case of ALK rearrangement-positive adenocarcinoma that transformed to squamous cell carcinoma after administration of alectinib and was found to be resistant to ceritinib as well.	('ALK', 'Gene', '238', (20, 23))	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('squamous cell carcinoma', 'Disease', (82, 105))	('carcinoma', 'Phenotype', 'HP:0030731', (52, 61))	('rearrangement-positive', 'Var', (24, 46))	('adenocarcinoma', 'Disease', 'MESH:D000230', (47, 61))	('ceritinib', 'Chemical', 'MESH:C586847', (173, 182))	('ALK', 'Gene', (20, 23))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (82, 105))	('alectinib', 'Chemical', 'MESH:C582670', (130, 139))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (82, 105))	('adenocarcinoma', 'Disease', (47, 61))
303538	31324197	An ex vivo study showed that blockade of STAT3 attenuated the IL-6/IL-8-mediated impairment of NK cell function.	('blockade', 'Var', (29, 37))	('STAT3', 'Gene', (41, 46))	('NK cell function', 'CPA', (95, 111))	('attenuated', 'NegReg', (47, 57))	('STAT3', 'Gene', '6774', (41, 46))
303613	31324197	After co-culturing with NK cells, apart from NKp30 and NKG2D, there was no significant difference between the KYSE150 and EC9706 groups in terms of other activating receptors or inhibitory receptors, even though EC9706 is a well-recognized invasive oesophageal squamous cell carcinoma strain.	('activating', 'MPA', (154, 164))	('EC9706', 'CellLine', 'CVCL:E307', (122, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (275, 284))	('KYSE150', 'Var', (110, 117))	('NKp30', 'Gene', '259197', (45, 50))	('NKG2D', 'Gene', '22914', (55, 60))	('invasive oesophageal squamous cell carcinoma', 'Disease', (240, 284))	('EC9706', 'CellLine', 'CVCL:E307', (212, 218))	('invasive oesophageal squamous cell carcinoma', 'Disease', 'MESH:D002294', (240, 284))	('NKG2D', 'Gene', (55, 60))	('EC9706', 'Var', (122, 128))	('NKp30', 'Gene', (45, 50))	('EC9706', 'Var', (212, 218))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (261, 284))
303617	31324197	In addition, we noticed that the relative expression levels of IL-6 and IL-8 were both upregulated in the EC9706 group compared with those in the KYSE150 group.	('IL-8', 'Gene', (72, 76))	('expression levels', 'MPA', (42, 59))	('EC9706', 'CellLine', 'CVCL:E307', (106, 112))	('IL-6', 'Gene', (63, 67))	('upregulated', 'PosReg', (87, 98))	('EC9706', 'Var', (106, 112))
303623	31324197	For instance, STAT1 can enhance IFN-gamma production and the cytotoxicity of NK cells; phosphorylated STAT3 can impair tumour immune surveillance and promote tumour escape from immune control.	('impair', 'NegReg', (112, 118))	('tumour', 'Phenotype', 'HP:0002664', (158, 164))	('promote', 'PosReg', (150, 157))	('cytotoxicity', 'Disease', (61, 73))	('STAT1', 'Gene', (14, 19))	('tumour', 'Disease', 'MESH:D009369', (119, 125))	('tumour', 'Disease', 'MESH:D009369', (158, 164))	('STAT1', 'Gene', '6772', (14, 19))	('tumour', 'Phenotype', 'HP:0002664', (119, 125))	('enhance', 'PosReg', (24, 31))	('STAT3', 'Gene', '6774', (102, 107))	('phosphorylated', 'Var', (87, 101))	('IFN-gamma', 'Gene', (32, 41))	('tumour', 'Disease', (119, 125))	('tumour', 'Disease', (158, 164))	('IFN-gamma', 'Gene', '3458', (32, 41))	('cytotoxicity', 'Disease', 'MESH:D064420', (61, 73))	('STAT3', 'Gene', (102, 107))
303634	31324197	Moreover, the number of IL-6- and IL-8-positive tumour cells positively correlated with TNM stage, and high IL-6 and IL-8 expression was found to indicate poor overall survival of ESCC patients when the medium value of all IL-6 and IL-8 percentages was used as a comparison point.	('correlated', 'Reg', (72, 82))	('tumour', 'Phenotype', 'HP:0002664', (48, 54))	('TNM', 'Disease', (88, 91))	('overall survival', 'CPA', (160, 176))	('tumour', 'Disease', 'MESH:D009369', (48, 54))	('tumour', 'Disease', (48, 54))	('high', 'Var', (103, 107))	('IL-6- and IL-8', 'Gene', '3569;3576', (24, 38))	('patients', 'Species', '9606', (185, 193))	('ESCC', 'Disease', (180, 184))	('poor', 'NegReg', (155, 159))	('IL-6', 'Gene', (108, 112))
303654	31324197	Moreover, we validated that the proliferation potential of tumour-infiltrating NK cells was suppressed by detecting Ki67.	('Ki67', 'Var', (116, 120))	('suppressed', 'NegReg', (92, 102))	('proliferation potential', 'CPA', (32, 55))	('tumour', 'Phenotype', 'HP:0002664', (59, 65))	('tumour', 'Disease', 'MESH:D009369', (59, 65))	('tumour', 'Disease', (59, 65))
303667	31324197	For instance, STAT1 promotes the cytotoxicity of NK cells by increasing IFN-gamma expression; the activation of STAT6 has been reported to drive IL-5 and IL-13 production in cultured NK cells and to limit cytotoxic responses.	('STAT6', 'Gene', '6778', (112, 117))	('IL-13', 'Gene', '3596', (154, 159))	('cytotoxicity', 'Disease', (33, 45))	('STAT1', 'Gene', (14, 19))	('limit', 'NegReg', (199, 204))	('increasing', 'PosReg', (61, 71))	('IFN-gamma', 'Gene', (72, 81))	('STAT1', 'Gene', '6772', (14, 19))	('IFN-gamma', 'Gene', '3458', (72, 81))	('STAT6', 'Gene', (112, 117))	('cytotoxicity', 'Disease', 'MESH:D064420', (33, 45))	('cytotoxic responses', 'CPA', (205, 224))	('IL-5', 'Gene', '3567', (145, 149))	('IL-5', 'Gene', (145, 149))	('activation', 'Var', (98, 108))	('IL-13', 'Gene', (154, 159))	('drive', 'PosReg', (139, 144))
303686	31128216	COMPASS Ascending: Emerging clues regarding the roles of MLL3/KMT2C and MLL2/KMT2D proteins in cancer The KMT2 (lysine methyltransferase) family of histone modifying proteins play essential roles in regulating developmental pathways, and mutations in the genes encoding these proteins have been strongly linked to many blood and solid tumor cancers.	('MLL3', 'Gene', (57, 61))	('KMT2D', 'Gene', '8085', (77, 82))	('MLL2', 'Gene', '8085', (72, 76))	('cancer', 'Disease', (341, 347))	('MLL2', 'Gene', (72, 76))	('cancer', 'Phenotype', 'HP:0002664', (341, 347))	('linked to', 'Reg', (304, 313))	('mutations', 'Var', (238, 247))	('cancer', 'Disease', (95, 101))	('tumor cancers', 'Disease', 'MESH:D009369', (335, 348))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('cancers', 'Phenotype', 'HP:0002664', (341, 348))	('KMT2D', 'Gene', (77, 82))	('lysine', 'Chemical', 'MESH:D008239', (112, 118))	('MLL3', 'Gene', '58508', (57, 61))	('cancer', 'Disease', 'MESH:D009369', (341, 347))	('KMT2C', 'Gene', (62, 67))	('COMPASS', 'Gene', '37546', (0, 7))	('tumor cancers', 'Disease', (335, 348))	('COMPASS', 'Gene', (0, 7))	('KMT2C', 'Gene', '58508', (62, 67))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('tumor', 'Phenotype', 'HP:0002664', (335, 340))
303688	31128216	KMT2 mutations were initially associated with pediatric Mixed Lineage Leukemias (MLL) and found to be the result of rearrangements of the MLL1/KMT2A gene at 11q23.	('associated', 'Reg', (30, 40))	('MLL1', 'Gene', (138, 142))	('Leukemia', 'Phenotype', 'HP:0001909', (70, 78))	('Leukemias', 'Disease', 'MESH:D007938', (70, 79))	('Leukemias', 'Phenotype', 'HP:0001909', (70, 79))	('mutations', 'Var', (5, 14))	('KMT2', 'Gene', (0, 4))	('MLL1', 'Gene', '4297', (138, 142))	('MLL', 'Gene', (138, 141))	('KMT2A', 'Gene', (143, 148))	('MLL', 'Gene', '4297', (138, 141))	('Leukemias', 'Disease', (70, 79))	('KMT2A', 'Gene', '4297', (143, 148))	('MLL', 'Gene', (81, 84))	('rearrangements', 'Var', (116, 130))	('MLL', 'Gene', '4297', (81, 84))
303689	31128216	Over the past several years, large-scale tumor DNA sequencing studies have revealed the potential involvement of other KMT2 family genes, including heterozygous somatic mutations in the paralogous MLL3/KMT2C and MLL2(4)/KMT2D genes that are now among the most frequently associated with human cancer.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('cancer', 'Disease', (293, 299))	('MLL2', 'Gene', '8085', (212, 216))	('cancer', 'Disease', 'MESH:D009369', (293, 299))	('KMT2 family genes', 'Gene', (119, 136))	('mutations', 'Var', (169, 178))	('MLL3', 'Gene', (197, 201))	('tumor', 'Disease', (41, 46))	('associated', 'Reg', (271, 281))	('MLL2', 'Gene', (212, 216))	('involvement', 'Reg', (98, 109))	('MLL3', 'Gene', '58508', (197, 201))	('cancer', 'Phenotype', 'HP:0002664', (293, 299))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('human', 'Species', '9606', (287, 292))
303691	31128216	The methylation of lysine residues on N-terminal histone tails can provide both gene activation and repression signals and is one of the best-studied epigenetic modifications.	('methylation', 'Var', (4, 15))	('lysine', 'Protein', (19, 25))	('lysine', 'Chemical', 'MESH:D008239', (19, 25))	('gene activation', 'MPA', (80, 95))	('repression signals', 'MPA', (100, 118))
303692	31128216	Methylation of histone 3 lysine 4 (H3K4) is frequently associated with active transcription, with di- and trimethylated H3K4 associated with active gene promoters and monomethylation found at gene enhancers.	('active gene promoters', 'MPA', (141, 162))	('H3K4', 'Gene', (35, 39))	('associated', 'Reg', (55, 65))	('associated', 'Reg', (125, 135))	('H3K4', 'Gene', (120, 124))	('H3', 'Chemical', 'MESH:C012616', (35, 37))	('H3', 'Chemical', 'MESH:C012616', (120, 122))	('di-', 'Var', (98, 101))	('active transcription', 'MPA', (71, 91))	('lysine', 'Chemical', 'MESH:D008239', (25, 31))	('trimethylated', 'Var', (106, 119))
303693	31128216	The enzymes that place methyl modifications or marks on H3K4 are known as the KMT2 (lysine methyltransferase) family and are found embedded within enormous protein complexes, named COMPASS (COMplex of Proteins ASsociated with SET1).	('marks', 'Var', (47, 52))	('H3K4', 'Gene', (56, 60))	('methyl modifications', 'Var', (23, 43))	('H3', 'Chemical', 'MESH:C012616', (56, 58))	('SET1', 'Gene', (226, 230))	('lysine', 'Chemical', 'MESH:D008239', (84, 90))	('COMPASS', 'Gene', '37546', (181, 188))	('COMPASS', 'Gene', (181, 188))	('SET1', 'Gene', '9739', (226, 230))
303699	31128216	Genome duplication during mammalian evolution resulted in two paralogs in each KMT2 subgroup.	('resulted in', 'Reg', (46, 57))	('Genome duplication', 'Var', (0, 18))	('KMT2', 'Gene', (79, 83))	('mammalian', 'Species', '9606', (26, 35))	('paralogs', 'MPA', (62, 70))
303703	31128216	The COMPASS complexes are large, multi-subunit assemblies that carry out mono-, di- and trimethylation of histone 3 lysine 4 (H3K4).	('H3', 'Chemical', 'MESH:C012616', (126, 128))	('trimethylation', 'Var', (88, 102))	('lysine', 'Chemical', 'MESH:D008239', (116, 122))	('mono-', 'MPA', (73, 78))	('COMPASS', 'Gene', '37546', (4, 11))	('COMPASS', 'Gene', (4, 11))
303704	31128216	These modifications are placed on H3 N-terminal tails within nucleosomes at gene promoter and enhancer regions and are universally associated with transcription activation.	('modifications', 'Var', (6, 19))	('transcription', 'MPA', (147, 160))	('H3', 'Chemical', 'MESH:C012616', (34, 36))	('associated', 'Reg', (131, 141))
303705	31128216	The SET1A/B complexes perform the majority of di- and tri-methylation of H3K4 throughout the genome; whereas, the KMT2A/B (MLX) complexes are more limited in the targets of their enzymatic activities, primarily catalyzing di- and tri-methylation of H3K4 at gene promoters and nearby cis-regulatory sites where they maintain active transcription (Fig.	('H3', 'Chemical', 'MESH:C012616', (73, 75))	('H3K4', 'Protein', (249, 253))	('KMT2A/B', 'Gene', '4297;9757', (114, 121))	('di-', 'MPA', (46, 49))	('KMT2A/B', 'Gene', (114, 121))	('H3', 'Chemical', 'MESH:C012616', (249, 251))	('di-', 'MPA', (222, 225))	('active transcription', 'MPA', (324, 344))	('SET1A/B', 'Gene', (4, 11))	('SET1A/B', 'Gene', '9739', (4, 11))	('H3K4', 'Protein', (73, 77))	('tri-methylation', 'Var', (230, 245))
303709	31128216	The presence of multiple methyl groups on H3K27, catalyzed by the Polycomb repressor PRC2 complex, can block the addition of the activating acetyl mark.	('block', 'NegReg', (103, 108))	('addition of the activating acetyl mark', 'MPA', (113, 151))	('presence', 'Var', (4, 12))	('H3K27', 'Protein', (42, 47))	('H3', 'Chemical', 'MESH:C012616', (42, 44))
303711	31128216	KMT2A-D proteins are large (2715-5537aa) with multiple functional domains (see Fig.	('2715-5537aa', 'Var', (28, 39))	('KMT2A', 'Gene', (0, 5))	('KMT2A', 'Gene', '4297', (0, 5))
303716	31128216	A large number of cancer-associated missense mutations affecting the PHD finger clusters suggest these domains provide critical functions in controlling cellular growth and differentiation pathways through regulated binding to both modified histones and chromatin modifying complexes.	('histones', 'Protein', (241, 249))	('binding', 'Interaction', (216, 223))	('missense mutations', 'Var', (36, 54))	('modified histones', 'Protein', (232, 249))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('PHD', 'Disease', 'MESH:D011547', (69, 72))	('PHD', 'Disease', (69, 72))	('differentiation pathways', 'CPA', (173, 197))	('cellular growth', 'CPA', (153, 168))	('cancer', 'Disease', (18, 24))	('cancer', 'Disease', 'MESH:D009369', (18, 24))
303719	31128216	While the precise functional roles of methylated H3K4 in nucleosomes is uncertain, three key findings suggest that the H3K4me1 histone mark catalyzed by the MLR complexes is not essential for transcriptional regulation during development but is potentially important to control precise transcription levels or timing of gene transcription in vivo, perhaps critically in cancer.	('cancer', 'Disease', 'MESH:D009369', (370, 376))	('cancer', 'Phenotype', 'HP:0002664', (370, 376))	('cancer', 'Disease', (370, 376))	('H3', 'Chemical', 'MESH:C012616', (119, 121))	('H3K4me1', 'Var', (119, 126))	('H3', 'Chemical', 'MESH:C012616', (49, 51))
303722	31128216	Third, while the SET methyltransferase activity of MLR complexes may be primarily important in the marking of enhancers, the SET domains are frequently mutated in cancers suggesting that they are responsible for chromatin modifications that broadly impact gene regulation.	('cancers', 'Phenotype', 'HP:0002664', (163, 170))	('cancers', 'Disease', (163, 170))	('mutated', 'Var', (152, 159))	('impact', 'Reg', (249, 255))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('gene regulation', 'MPA', (256, 271))	('cancers', 'Disease', 'MESH:D009369', (163, 170))
303723	31128216	In support of this idea, there have been reported examples of SET domain cancer mutations in KMT2A and KMT2C that alter their enzymatic activity, in some cases increasing methylation activity while in other cases decreasing histone methylation, and truncations that specifically remove the SET domain in various tumors suggest that the methyltransferase activity may be important for cellular homeostasis.	('tumors', 'Disease', (312, 318))	('increasing', 'PosReg', (160, 170))	('SET domain', 'Gene', (62, 72))	('alter', 'Reg', (114, 119))	('KMT2A', 'Gene', '4297', (93, 98))	('cancer', 'Disease', (73, 79))	('mutations', 'Var', (80, 89))	('truncations', 'Var', (249, 260))	('tumors', 'Disease', 'MESH:D009369', (312, 318))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('KMT2C', 'Gene', (103, 108))	('tumor', 'Phenotype', 'HP:0002664', (312, 317))	('histone methylation', 'MPA', (224, 243))	('KMT2A', 'Gene', (93, 98))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('tumors', 'Phenotype', 'HP:0002664', (312, 318))	('methylation activity', 'MPA', (171, 191))	('decreasing', 'NegReg', (213, 223))	('enzymatic activity', 'MPA', (126, 144))
303724	31128216	The discovery of both gain and loss of SET domain activity in cancer implies that there is considerable complexity in the potential mechanisms of oncogenesis associated with altered methyltransferase function.	('loss', 'NegReg', (31, 35))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('SET domain activity', 'MPA', (39, 58))	('altered', 'Var', (174, 181))	('gain', 'PosReg', (22, 26))
303726	31128216	The AT-hooks bind to minor groove DNA and likely help to direct the KMT2 proteins to specific genomic regions and deletion of the AT hooks can impair leukemic fusion protein functions.	('AT hooks', 'Gene', (130, 138))	('KMT2', 'Gene', (68, 72))	('impair', 'NegReg', (143, 149))	('leukemic', 'Disease', (150, 158))	('leukemic', 'Disease', 'MESH:D007938', (150, 158))	('deletion', 'Var', (114, 122))
303730	31128216	The establishment of several disease-associated mutation databases (e.g., TCGA, OMIM, COSMIC) has revealed that cancer-associated truncating/inactivating mutations are widely dispersed along the KMT2A-D proteins, confirming their importance as tumor suppressors (Fig.	('tumor', 'Phenotype', 'HP:0002664', (244, 249))	('cancer', 'Disease', (112, 118))	('tumor', 'Disease', (244, 249))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('truncating/inactivating mutations', 'Var', (130, 163))	('KMT2A', 'Gene', (195, 200))	('KMT2A', 'Gene', '4297', (195, 200))	('tumor', 'Disease', 'MESH:D009369', (244, 249))
303732	31128216	Missense mutation 'hotspots' are associated with known functional domains, including the PHD fingers, SET methyltransferase and regions associated with protein interactions.	('PHD', 'Disease', 'MESH:D011547', (89, 92))	('Missense mutation', 'Var', (0, 17))	('PHD', 'Disease', (89, 92))	("'hotspots'", 'PosReg', (18, 28))
303734	31128216	The first PHD finger cluster of KMT2C is involved in protein interactions with the BAP1 histone deubiquitinating complex and cancer associated mutations in this PHD domain disrupted recruitment of KMT2C to enhancers.	('PHD', 'Disease', 'MESH:D011547', (161, 164))	('PHD', 'Disease', (161, 164))	('BAP1', 'Gene', (83, 87))	('PHD', 'Disease', 'MESH:D011547', (10, 13))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('PHD', 'Disease', (10, 13))	('disrupted', 'NegReg', (172, 181))	('recruitment', 'MPA', (182, 193))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('mutations', 'Var', (143, 152))	('BAP1', 'Gene', '8314', (83, 87))
303735	31128216	The epigenetic functions of the COMPASS complexes are vital for normal animal development and frequent mutations affecting these proteins or other components of the COMPASS complexes are associated with a large number of cancers.	('mutations', 'Var', (103, 112))	('cancers', 'Disease', 'MESH:D009369', (221, 228))	('COMPASS', 'Gene', (32, 39))	('cancers', 'Phenotype', 'HP:0002664', (221, 228))	('cancers', 'Disease', (221, 228))	('COMPASS', 'Gene', '37546', (32, 39))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('associated', 'Reg', (187, 197))	('COMPASS', 'Gene', '37546', (165, 172))	('COMPASS', 'Gene', (165, 172))
303736	31128216	Mutations involving KMT2 family genes are among the most commonly seen in many diverse cancer types and there is a statistically significant co-occurrence, raising the possibility that the simultaneous disabling of several KMT2 genes might be a critical step in some cancer types.	('cancer', 'Disease', (87, 93))	('KMT2 family', 'Gene', (20, 31))	('seen', 'Reg', (66, 70))	('cancer', 'Disease', (267, 273))	('cancer', 'Disease', 'MESH:D009369', (267, 273))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cancer', 'Phenotype', 'HP:0002664', (267, 273))	('Mutations', 'Var', (0, 9))	('KMT2', 'Gene', (223, 227))	('cancer', 'Disease', 'MESH:D009369', (87, 93))
303738	31128216	Similarly, murine knockout studies have shown that loss of Kmt2d can promote lymphomagenesis independent of additional mutations affecting other KMT2 family genes.	('lymphoma', 'Disease', (77, 85))	('loss', 'Var', (51, 55))	('lymphoma', 'Disease', 'MESH:D008223', (77, 85))	('Kmt2d', 'Gene', (59, 64))	('lymphoma', 'Phenotype', 'HP:0002665', (77, 85))	('promote', 'PosReg', (69, 76))	('murine', 'Species', '10090', (11, 17))
303739	31128216	Finally, a majority of cancers associated with KMT2 family genes are the result of somatic heterozygous loss-of-function mutations, suggesting that haploinsufficiency may underlie disease for these epigenetic regulators.	('mutations', 'Var', (121, 130))	('haploinsufficiency', 'Disease', (148, 166))	('cancers', 'Disease', 'MESH:D009369', (23, 30))	('cancers', 'Phenotype', 'HP:0002664', (23, 30))	('loss-of-function', 'NegReg', (104, 120))	('cancers', 'Disease', (23, 30))	('haploinsufficiency', 'Disease', 'MESH:D058495', (148, 166))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('KMT2 family', 'Gene', (47, 58))
303741	31128216	While the involvement of KMT2A/MLL1 translocation fusions in cancer have been extensively reviewed, recent cancer exome sequencing studies have revealed a large number of missense (78%) and nonsense (22%) mutations in the gene with an overall somatic mutation frequency of 2.9%, suggesting possible loss and gain of function alterations of KMT2A in oncogenesis.	('loss', 'NegReg', (299, 303))	('gain of function', 'PosReg', (308, 324))	('KMT2A', 'Gene', '4297', (25, 30))	('MLL1', 'Gene', (31, 35))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('KMT2A', 'Gene', (340, 345))	('mutations', 'Var', (205, 214))	('cancer', 'Disease', (61, 67))	('MLL1', 'Gene', '4297', (31, 35))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('KMT2A', 'Gene', (25, 30))	('KMT2A', 'Gene', '4297', (340, 345))	('cancer', 'Disease', (107, 113))	('missense', 'Var', (171, 179))
303742	31128216	KMT2B is also found mutated in a variety of cancer types, with the majority (71%) being missense mutations and an overall somatic mutation frequency in cancer of 1.6%.	('KMT2B', 'Gene', '9757', (0, 5))	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('KMT2B', 'Gene', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('missense mutations', 'Var', (88, 106))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
303746	31128216	More recently, the National Cancer Institute Genomic Data Commons (GDC) summary of over 33,000 cases revealed that KMT2D and KMT2C were the third and seventh most commonly mutated cancer genes (Fig.	('KMT2D', 'Gene', (115, 120))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('KMT2C', 'Gene', (125, 130))	('Cancer', 'Disease', 'MESH:D009369', (28, 34))	('Cancer', 'Disease', (28, 34))	('Cancer', 'Phenotype', 'HP:0002664', (28, 34))	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('mutated', 'Var', (172, 179))	('cancer', 'Disease', (180, 186))
303747	31128216	In addition, the cBio Portal database compendium of almost 47,000 cancer samples representing 175 studies reveals that KMT2D and KMT2C are mutated in approximately 14-16% of all cases, with the highest percentages in both melanoma (27%) and non-melanoma (~48%) skin cancers, urothelial carcinoma (40%), bladder cancer (33%), lung cancer (18-26%), head and neck and esophagogastric cancers (19%), as well as colorectal and small bowel cancers (13.5%).	('cancer', 'Disease', (311, 317))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('KMT2C', 'Gene', (129, 134))	('skin cancers', 'Phenotype', 'HP:0008069', (261, 273))	('colorectal and small bowel cancers', 'Disease', 'MESH:D015179', (407, 441))	('cancer', 'Disease', 'MESH:D009369', (330, 336))	('cancer', 'Phenotype', 'HP:0002664', (311, 317))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (275, 295))	('bladder cancer', 'Disease', 'MESH:D001749', (303, 317))	('bladder cancer', 'Disease', (303, 317))	('cancer', 'Disease', 'MESH:D009369', (266, 272))	('carcinoma', 'Phenotype', 'HP:0030731', (286, 295))	('cancer', 'Disease', (66, 72))	('cancers', 'Disease', 'MESH:D009369', (434, 441))	('melanoma', 'Phenotype', 'HP:0002861', (245, 253))	('cancers', 'Disease', 'MESH:D009369', (266, 273))	('melanoma', 'Disease', (245, 253))	('melanoma', 'Phenotype', 'HP:0002861', (222, 230))	('skin cancers', 'Disease', (261, 273))	('melanoma', 'Disease', (222, 230))	('KMT2D', 'Gene', (119, 124))	('lung cancer', 'Disease', 'MESH:D008175', (325, 336))	('cancers', 'Phenotype', 'HP:0002664', (381, 388))	('bladder cancer', 'Phenotype', 'HP:0009725', (303, 317))	('cancer', 'Disease', (381, 387))	('cancers', 'Disease', (381, 388))	('urothelial carcinoma', 'Disease', (275, 295))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('skin cancers', 'Disease', 'MESH:D012878', (261, 273))	('lung cancer', 'Phenotype', 'HP:0100526', (325, 336))	('cancer', 'Phenotype', 'HP:0002664', (381, 387))	('cancer', 'Disease', (434, 440))	('cancer', 'Disease', 'MESH:D009369', (311, 317))	('mutated', 'Var', (139, 146))	('cancer', 'Disease', (330, 336))	('cancers', 'Phenotype', 'HP:0002664', (266, 273))	('cancers', 'Phenotype', 'HP:0002664', (434, 441))	('cancer', 'Phenotype', 'HP:0002664', (330, 336))	('cancers', 'Disease', (266, 273))	('cancer', 'Disease', (266, 272))	('cancers', 'Disease', (434, 441))	('melanoma', 'Disease', 'MESH:D008545', (245, 253))	('cancer', 'Disease', 'MESH:D009369', (381, 387))	('melanoma', 'Disease', 'MESH:D008545', (222, 230))	('cancer', 'Phenotype', 'HP:0002664', (266, 272))	('cancers', 'Disease', 'MESH:D009369', (381, 388))	('lung cancer', 'Disease', (325, 336))	('cancer', 'Disease', 'MESH:D009369', (434, 440))
303749	31128216	However, there is no obvious strong correlation between changes in the RNA levels of these genes and cancer phenotype, suggesting that loss-of-function mutations rather than expression level changes are generally associated with oncogenesis.	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('mutations', 'Var', (152, 161))	('cancer', 'Disease', (101, 107))	('oncogenesis', 'Disease', (229, 240))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('loss-of-function', 'NegReg', (135, 151))
303750	31128216	Haploinsufficiency of the human 7q chromosome region in acute myeloid leukemia implicated KMT2C as a likely tumor suppressor, and recent tumor sequencing data (TCGA-BRCA study) has revealed a strong enrichment for KMT2C mutations in breast cancer, with approximately 8% across breast cancer types and over 10% within invasive breast cancers according to the cBio Portal database, with substantially greater frequency than any other H3K4 methyltransferase.	('breast cancer', 'Phenotype', 'HP:0003002', (277, 290))	('Haploinsufficiency', 'Disease', (0, 18))	('invasive breast cancers', 'Disease', (317, 340))	('tumor', 'Disease', (108, 113))	('H3', 'Chemical', 'MESH:C012616', (432, 434))	('human', 'Species', '9606', (26, 31))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('breast cancer', 'Disease', 'MESH:D001943', (277, 290))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (56, 78))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('breast cancer', 'Disease', (277, 290))	('cancers', 'Phenotype', 'HP:0002664', (333, 340))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (56, 78))	('leukemia', 'Phenotype', 'HP:0001909', (70, 78))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (62, 78))	('mutations', 'Var', (220, 229))	('cancer', 'Phenotype', 'HP:0002664', (333, 339))	('tumor', 'Disease', (137, 142))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('KMT2C', 'Gene', (214, 219))	('breast cancer', 'Phenotype', 'HP:0003002', (233, 246))	('Haploinsufficiency', 'Disease', 'MESH:D058495', (0, 18))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('cancer', 'Phenotype', 'HP:0002664', (284, 290))	('breast cancers', 'Phenotype', 'HP:0003002', (326, 340))	('breast cancer', 'Phenotype', 'HP:0003002', (326, 339))	('breast cancer', 'Disease', 'MESH:D001943', (233, 246))	('breast cancer', 'Disease', (233, 246))	('invasive breast cancers', 'Disease', 'MESH:D001943', (317, 340))	('acute myeloid leukemia', 'Disease', (56, 78))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('breast cancer', 'Disease', 'MESH:D001943', (326, 339))
303751	31128216	Importantly, KMT2C was recently shown to be important for driving hormone-stimulated cell proliferation in estrogen receptor alpha positive (ERalpha+) HER2- breast cancer cell lines but not ERalpha+ HER2+ cells, while knockdown of KMT2D more broadly suppressed proliferation in breast cancer cells.	('KMT2D', 'Gene', (231, 236))	('breast cancer', 'Disease', 'MESH:D001943', (278, 291))	('breast cancer', 'Phenotype', 'HP:0003002', (157, 170))	('breast cancer', 'Disease', (278, 291))	('HER2', 'Gene', '2064', (151, 155))	('HER2', 'Gene', '2064', (199, 203))	('breast cancer', 'Disease', 'MESH:D001943', (157, 170))	('breast cancer', 'Disease', (157, 170))	('estrogen receptor alpha', 'Gene', '2099', (107, 130))	('ERalpha', 'Gene', (141, 148))	('knockdown', 'Var', (218, 227))	('ERalpha', 'Gene', (190, 197))	('cancer', 'Phenotype', 'HP:0002664', (285, 291))	('ERalpha', 'Gene', '2099', (141, 148))	('HER2', 'Gene', (151, 155))	('HER2', 'Gene', (199, 203))	('ERalpha', 'Gene', '2099', (190, 197))	('estrogen receptor alpha', 'Gene', (107, 130))	('suppressed', 'NegReg', (250, 260))	('cell proliferation', 'CPA', (85, 103))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('breast cancer', 'Phenotype', 'HP:0003002', (278, 291))
303752	31128216	In this context, it appears that KMT2C is a critical co-factor in promoting ERalpha function and it appears to also have an important role in suppressing hormone-independent tumor expansion.	('tumor', 'Disease', (174, 179))	('promoting', 'PosReg', (66, 75))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('suppressing', 'NegReg', (142, 153))	('ERalpha', 'Gene', (76, 83))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('ERalpha', 'Gene', '2099', (76, 83))	('KMT2C', 'Var', (33, 38))
303755	31128216	They found that murine kmt2c inactivation in cells overexpressing Pik3ca blocked mammary gland differentiation and simultaneously increased cell stem cell self renewal activity through activation of the HIF pathway.	('Pik3ca', 'Gene', '5290', (66, 72))	('kmt2c', 'Gene', (23, 28))	('murine', 'Species', '10090', (16, 22))	('kmt2c', 'Gene', '58508', (23, 28))	('HIF pathway', 'Pathway', (203, 214))	('cell stem cell self renewal activity', 'CPA', (140, 176))	('mammary gland differentiation', 'CPA', (81, 110))	('increased', 'PosReg', (130, 139))	('Pik3ca', 'Gene', (66, 72))	('inactivation', 'Var', (29, 41))	('blocked', 'NegReg', (73, 80))
303759	31128216	Genetic ablation of murine Kmt2d in B cells promotes lymphoma development and impedes B cell differentiation, supporting its role as a tumor suppressor in germinal center B cells.	('lymphoma', 'Disease', (53, 61))	('promotes', 'PosReg', (44, 52))	('lymphoma', 'Disease', 'MESH:D008223', (53, 61))	('lymphoma', 'Phenotype', 'HP:0002665', (53, 61))	('B cell differentiation', 'CPA', (86, 108))	('murine', 'Var', (20, 26))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('impedes', 'NegReg', (78, 85))	('tumor', 'Disease', (135, 140))	('murine', 'Species', '10090', (20, 26))	('Kmt2d', 'Gene', (27, 32))	('ablation', 'Var', (8, 16))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
303764	31128216	SCLC is a highly aggressive neuroendocrine tumor with a very poor prognosis in which TP53 and RB1 are frequently mutated.	('TP53', 'Gene', (85, 89))	('neuroendocrine tumor', 'Phenotype', 'HP:0100634', (28, 48))	('RB1', 'Gene', (94, 97))	('aggressive neuroendocrine tumor', 'Disease', (17, 48))	('aggressive neuroendocrine tumor', 'Disease', 'MESH:D018358', (17, 48))	('RB1', 'Gene', '5925', (94, 97))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('mutated', 'Var', (113, 120))	('SCLC', 'Disease', (0, 4))	('TP53', 'Gene', '7157', (85, 89))	('SCLC', 'Disease', 'MESH:D018288', (0, 4))
303765	31128216	These studies revealed that KMT2D is not only among the most frequently mutated genes in SCLC, but there is a strong bias for the loss of KMT2D via truncating mutations in the pathogenesis of SCLC with potentially significant prognostic impact.	('SCLC', 'Disease', (192, 196))	('SCLC', 'Disease', 'MESH:D018288', (192, 196))	('loss', 'NegReg', (130, 134))	('KMT2D', 'Gene', (138, 143))	('SCLC', 'Disease', 'MESH:D018288', (89, 93))	('truncating mutations', 'Var', (148, 168))	('SCLC', 'Disease', (89, 93))
303769	31128216	identified deleterious KMT2D mutations in 12/105 NCSLC patients as well as reduced expression of KMT2D in tumors relative to paired adjacent non tumor tissues.	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('KMT2D', 'Gene', (23, 28))	('tumors', 'Disease', (106, 112))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('mutations', 'Var', (29, 38))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('reduced', 'NegReg', (75, 82))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Disease', (145, 150))	('expression', 'MPA', (83, 93))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('patients', 'Species', '9606', (55, 63))	('tumor', 'Disease', (106, 111))
303770	31128216	This study also included whole exome sequencing of nine non small cell lung cancers and found that KMT2D was the second most significantly mutated gene after TP53, showing three missense mutations and two nonsense mutations in three out of nine samples.	('TP53', 'Gene', '7157', (158, 162))	('TP53', 'Gene', (158, 162))	('cancers', 'Phenotype', 'HP:0002664', (76, 83))	('lung cancers', 'Disease', 'MESH:D008175', (71, 83))	('lung cancers', 'Phenotype', 'HP:0100526', (71, 83))	('missense mutations', 'Var', (178, 196))	('small cell lung cancers', 'Phenotype', 'HP:0030357', (60, 83))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('KMT2D', 'Gene', (99, 104))	('lung cancers', 'Disease', (71, 83))	('lung cancer', 'Phenotype', 'HP:0100526', (71, 82))
303771	31128216	While all tumor samples showed reduced expression of KMT2D independent of mutation status, only KMT2D mutations were significantly associated with lower recurrence free survival.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('reduced', 'NegReg', (31, 38))	('KMT2D', 'Gene', (53, 58))	('lower', 'NegReg', (147, 152))	('tumor', 'Disease', (10, 15))	('recurrence free survival', 'CPA', (153, 177))	('mutations', 'Var', (102, 111))	('expression', 'MPA', (39, 49))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('KMT2D', 'Gene', (96, 101))
303772	31128216	Interestingly, many of the mutations in KMT2D resulted in silenced or significantly reduced expression in all of the sequenced tumor tissues compared with adjacent non-tumorous lung tissue.	('mutations', 'Var', (27, 36))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumor', 'Disease', (168, 173))	('tumor', 'Disease', (127, 132))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('KMT2D', 'Gene', (40, 45))	('reduced', 'NegReg', (84, 91))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('silenced', 'NegReg', (58, 66))	('expression', 'MPA', (92, 102))
303773	31128216	A more recent analysis of 108 early stage (I-III) lung squamous cell carcinoma patients with matched normal tissue revealed KMT2D was mutated in 10.2% of lung tumors, consistent with TCGA data (178 patients) with a mutation frequency of 17.4%.	('lung squamous cell carcinoma', 'Disease', (50, 78))	('KMT2D', 'Gene', (124, 129))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (55, 78))	('patients', 'Species', '9606', (198, 206))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('lung tumors', 'Disease', (154, 165))	('tumors', 'Phenotype', 'HP:0002664', (159, 165))	('lung tumors', 'Disease', 'MESH:D008175', (154, 165))	('mutated', 'Var', (134, 141))	('lung tumors', 'Phenotype', 'HP:0100526', (154, 165))	('patients', 'Species', '9606', (79, 87))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (50, 78))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))
303774	31128216	In additon, it was found that patients with KMT2D mutations had a worse recurrence free survival, regardless of TP53 status.	('recurrence free survival', 'CPA', (72, 96))	('mutations', 'Var', (50, 59))	('KMT2D', 'Gene', (44, 49))	('worse', 'NegReg', (66, 71))	('patients', 'Species', '9606', (30, 38))	('TP53', 'Gene', '7157', (112, 116))	('TP53', 'Gene', (112, 116))
303775	31128216	As might be expected, many of the identified mutations in NSCLC affected genes involved with DNA damage checkpoint and cell cycle regulation.	('NSCLC', 'Disease', (58, 63))	('mutations', 'Var', (45, 54))	('affected', 'Reg', (64, 72))	('NSCLC', 'Disease', 'MESH:D002289', (58, 63))
303776	31128216	found that among LUSC patients with TP53 mutations, co-occurrence of KMT2D mutations was strongly correlated with poor recurrence free survival.	('mutations', 'Var', (41, 50))	('patients', 'Species', '9606', (22, 30))	('recurrence free survival', 'CPA', (119, 143))	('TP53', 'Gene', '7157', (36, 40))	('mutations', 'Var', (75, 84))	('TP53', 'Gene', (36, 40))	('KMT2D', 'Gene', (69, 74))
303777	31128216	An examination of the TCGA dataset for all NSCLC subtypes shows a significant co-occurrence between mutations in TP53 and both KMT2D (odds ratio 0.763) and KMT2C (odds ratio 0.908) with adjusted p-values <0.001 for both.	('mutations', 'Var', (100, 109))	('TP53', 'Gene', '7157', (113, 117))	('NSCLC', 'Disease', (43, 48))	('TP53', 'Gene', (113, 117))	('NSCLC', 'Disease', 'MESH:D002289', (43, 48))
303780	31128216	Significantly better survival rates are seen in adenocarcinoma of the lung with high expression levels of either KMT2C or KMT2D (Fig.	('expression levels', 'MPA', (85, 102))	('KMT2C', 'Var', (113, 118))	('adenocarcinoma', 'Disease', (48, 62))	('better', 'PosReg', (14, 20))	('carcinoma', 'Phenotype', 'HP:0030731', (53, 62))	('KMT2D', 'Var', (122, 127))	('adenocarcinoma', 'Disease', 'MESH:D000230', (48, 62))
303782	31128216	Regardless of this difference, survival rates in all lung cancers are 20% higher at 10 years with high expression of KMT2C and KMT2D compared to low expression of both.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('lung cancers', 'Disease', 'MESH:D008175', (53, 65))	('lung cancers', 'Phenotype', 'HP:0100526', (53, 65))	('higher', 'PosReg', (74, 80))	('high expression', 'Var', (98, 113))	('cancers', 'Phenotype', 'HP:0002664', (58, 65))	('KMT2C', 'Var', (117, 122))	('lung cancers', 'Disease', (53, 65))	('KMT2D', 'Var', (127, 132))	('survival', 'MPA', (31, 39))	('lung cancer', 'Phenotype', 'HP:0100526', (53, 64))
303783	31128216	The high rate of KMT2D mutations in these samples is suggestive that these alterations function as driver mutations, or mutations that are responsible for the development and progression of cancers.	('cancers', 'Phenotype', 'HP:0002664', (190, 197))	('cancers', 'Disease', (190, 197))	('cancers', 'Disease', 'MESH:D009369', (190, 197))	('mutations', 'Var', (23, 32))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('KMT2D', 'Gene', (17, 22))
303784	31128216	Data from the same meta analysis reveals that truncating mutations of KMT2C and KMT2D are present throughout all stages of the analyzed cancers, suggesting these mutations are present from early stages of cancer providing additional support for these alterations as driver mutations (Fig.	('alterations', 'Var', (251, 262))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('cancer', 'Disease', 'MESH:D009369', (205, 211))	('KMT2D', 'Gene', (80, 85))	('cancers', 'Phenotype', 'HP:0002664', (136, 143))	('cancer', 'Disease', (205, 211))	('cancers', 'Disease', (136, 143))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('cancers', 'Disease', 'MESH:D009369', (136, 143))	('cancer', 'Disease', (136, 142))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('KMT2C', 'Gene', (70, 75))
303788	31128216	These studies reveal several potential mechanisms through which KMT2C and KMT2D cooperate with TP53 in both transcription activation dependent and independent pathways to promote tumorigenesis.	('KMT2C', 'Var', (64, 69))	('KMT2D', 'Var', (74, 79))	('promote', 'PosReg', (171, 178))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('TP53', 'Gene', '7157', (95, 99))	('TP53', 'Gene', (95, 99))	('tumor', 'Disease', (179, 184))
303789	31128216	In human colon cancer cells harboring specific TP53 mutations, there is aberrant gene activation that is dependent on KMT2D deposition of H3K4me1 marks on enhancers providing a mechanistic explanation by which specific TP53 gain of function mutations contribute to tumor formation.	('mutations', 'Var', (52, 61))	('colon cancer', 'Disease', 'MESH:D015179', (9, 21))	('tumor', 'Phenotype', 'HP:0002664', (265, 270))	('H3', 'Chemical', 'MESH:C012616', (138, 140))	('TP53', 'Gene', (219, 223))	('human', 'Species', '9606', (3, 8))	('tumor', 'Disease', (265, 270))	('tumor', 'Disease', 'MESH:D009369', (265, 270))	('colon cancer', 'Disease', (9, 21))	('gain of function', 'PosReg', (224, 240))	('TP53', 'Gene', '7157', (219, 223))	('gene', 'MPA', (81, 85))	('TP53', 'Gene', '7157', (47, 51))	('activation', 'PosReg', (86, 96))	('colon cancer', 'Phenotype', 'HP:0003003', (9, 21))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('TP53', 'Gene', (47, 51))	('mutations', 'Var', (241, 250))
303791	31128216	Within early stage cancer cells, the KMT2C/D proteins help to maintain epithelial cell states, such that loss may contribute to a more stem-cell like state and progression to metastasis.	('cancer', 'Disease', 'MESH:D009369', (19, 25))	('more', 'PosReg', (130, 134))	('cancer', 'Disease', (19, 25))	('metastasis', 'CPA', (175, 185))	('loss', 'Var', (105, 109))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('contribute', 'Reg', (114, 124))
303794	31128216	Simultaneous removal of both KMT2C (-/-) and KMT2D (+/-) in MCF10a cells converted them from an epithelial to a more mesenchymal morphology with reduced sensitivity to NK killing, suggesting an important role for these epigenetic modifiers in anti-tumor immunity.	('KMT2D', 'Var', (45, 50))	('tumor', 'Disease', (248, 253))	('MCF10a', 'Gene', (60, 66))	('sensitivity', 'MPA', (153, 164))	('tumor', 'Disease', 'MESH:D009369', (248, 253))	('KMT2C', 'Var', (29, 34))	('MCF10a', 'CellLine', 'CVCL:0598', (60, 66))	('tumor', 'Phenotype', 'HP:0002664', (248, 253))
303795	31128216	The finding of KMT2C and KMT2D in essentially identical COMPASS complexes that catalyze mono-methylation of H3K4 at gene enhancers has raised the possibility that their functions were largely overlapping, such that loss of both might be important for oncogenesis.	('COMPASS', 'Gene', (56, 63))	('COMPASS', 'Gene', '37546', (56, 63))	('KMT2C', 'Var', (15, 20))	('H3K4', 'Protein', (108, 112))	('H3', 'Chemical', 'MESH:C012616', (108, 110))
303796	31128216	Support for this theory can be seen through meta analysis of >58,000 samples from the cBio Portal dataset that demonstrates significant tendency towards co-occurrence of KMT2C and KMT2D mutations with a log odds ratio of 1.65 (p-value <0.001), perhaps indicating that loss of both proteins' tumor suppressor functions are important to confer malignant characteristics.	('co-occurrence', 'Interaction', (153, 166))	('KMT2C', 'Gene', (170, 175))	('mutations', 'Var', (186, 195))	('tumor', 'Disease', 'MESH:D009369', (291, 296))	('tumor', 'Phenotype', 'HP:0002664', (291, 296))	('tumor', 'Disease', (291, 296))	('KMT2D', 'Gene', (180, 185))
303797	31128216	However, the preponderance of mutations affecting only one of the two genes in specific cancer types suggests that each may have a critical role in cell-type or tissue-specific cancer development.	('cancer', 'Disease', (177, 183))	('cancer', 'Disease', 'MESH:D009369', (177, 183))	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('mutations', 'Var', (30, 39))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))
303798	31128216	The high frequency of KMT2C and KMT2D mutations, together with significant co-occurrence (p < 0.001) with various driver mutations (e.g., TP53, PIK3CA, PTEN, APC) and the SWI/SNF complex component ARID1A (log odds ratio 1.73, p = <0.001) across multiple cancer types suggests that disruption of either KMT2C or KMT2D individually might serve as founder or gatekeeper mutations in early tumor cells, resulting in changes in the epigenomic landscape that are permissive for additional oncogenic changes.	('APC', 'Disease', 'MESH:D011125', (158, 161))	('KMT2D', 'Gene', (311, 316))	('APC', 'Disease', (158, 161))	('PIK3CA', 'Gene', '5290', (144, 150))	('changes', 'Reg', (412, 419))	('cancer', 'Disease', (254, 260))	('tumor', 'Disease', (386, 391))	('cancer', 'Phenotype', 'HP:0002664', (254, 260))	('epigenomic landscape', 'MPA', (427, 447))	('TP53', 'Gene', (138, 142))	('tumor', 'Disease', 'MESH:D009369', (386, 391))	('mutations', 'Var', (38, 47))	('KMT2C', 'Gene', (302, 307))	('disruption', 'Var', (281, 291))	('PIK3CA', 'Gene', (144, 150))	('cancer', 'Disease', 'MESH:D009369', (254, 260))	('tumor', 'Phenotype', 'HP:0002664', (386, 391))	('TP53', 'Gene', '7157', (138, 142))	('KMT2C', 'Gene', (22, 27))	('gatekeeper', 'Species', '111938', (356, 366))
303801	31128216	Analysis of cancer-associated mutations reveals that there is a large clustering of lung and breast cancer missense mutations in the first KMT2C domain that are not found similarly in KMT2D.	('breast cancer', 'Phenotype', 'HP:0003002', (93, 106))	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('cancer', 'Disease', (12, 18))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('breast cancer', 'Disease', 'MESH:D001943', (93, 106))	('breast cancer', 'Disease', (93, 106))	('missense mutations', 'Var', (107, 125))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('lung', 'Disease', (84, 88))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))
303805	31128216	Treatment of ER+ breast cancers with a PI3K inhibitor is effective clinically, but also results in increased ER-dependent transcription that can result in therapeutic resistance.	('result in', 'Reg', (145, 154))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('breast cancers', 'Disease', 'MESH:D001943', (17, 31))	('therapeutic resistance', 'MPA', (155, 177))	('breast cancers', 'Disease', (17, 31))	('breast cancer', 'Phenotype', 'HP:0003002', (17, 30))	('increased', 'PosReg', (99, 108))	('cancers', 'Phenotype', 'HP:0002664', (24, 31))	('ER', 'Gene', '2099', (109, 111))	('PI3K', 'Var', (39, 43))	('breast cancers', 'Phenotype', 'HP:0003002', (17, 31))	('ER', 'Gene', '2099', (13, 15))
303808	31128216	Subsequently, SGK1 can inactivate KMT2D through phosphorylation at S1331 near the second PHD finger cluster implicated in chromatin binding and result in downregulation of global H3K4me1 levels at ER-regulated loci, as part of a negative feedback loop.	('PHD', 'Disease', 'MESH:D011547', (89, 92))	('PHD', 'Disease', (89, 92))	('at S1331', 'Var', (64, 72))	('global H3K4me1 levels', 'MPA', (172, 193))	('inactivate', 'NegReg', (23, 33))	('downregulation', 'NegReg', (154, 168))	('SGK1', 'Gene', (14, 18))	('phosphorylation', 'MPA', (48, 63))	('ER', 'Gene', '2099', (197, 199))	('KMT2D', 'Gene', (34, 39))	('H3', 'Chemical', 'MESH:C012616', (179, 181))	('SGK1', 'Gene', '6446', (14, 18))
303809	31128216	Although the mechanism is unknown, targeted phosphorylation and inactivation of KMT2D by both SGK1 and/or AKT1 can lead to downregulation of enhancers controlled by KMT2D-associated transcription factors.	('inactivation', 'Var', (64, 76))	('KMT2D', 'Gene', (80, 85))	('AKT1', 'Gene', (106, 110))	('enhancers', 'MPA', (141, 150))	('SGK1', 'Gene', '6446', (94, 98))	('phosphorylation', 'Var', (44, 59))	('downregulation', 'NegReg', (123, 137))	('SGK1', 'Gene', (94, 98))	('AKT1', 'Gene', '207', (106, 110))
303811	31128216	The KMT2A-D genes are each essential for organismal viability, with strong depletion, homozygous loss of function mutations or deletions resulting in embryonic or perinatal lethality (KMT2A/MLL1:; KMT2B/MLL4(2):; KMT2C/MLL3 and KMT2D/MLL2(4):.	('MLL3', 'Gene', '58508', (219, 223))	('KMT2A', 'Gene', '4297', (184, 189))	('embryonic', 'CPA', (150, 159))	('MLL4', 'Gene', '8085', (203, 207))	('mutations', 'Var', (114, 123))	('MLL2', 'Gene', '8085', (234, 238))	('KMT2B', 'Gene', (197, 202))	('MLL4', 'Gene', (203, 207))	('MLL1', 'Gene', (190, 194))	('KMT2A', 'Gene', (4, 9))	('deletions', 'Var', (127, 136))	('KMT2B', 'Gene', '9757', (197, 202))	('MLL3', 'Gene', (219, 223))	('KMT2A', 'Gene', '4297', (4, 9))	('loss of function', 'NegReg', (97, 113))	('MLL2', 'Gene', (234, 238))	('MLL1', 'Gene', '4297', (190, 194))	('KMT2A', 'Gene', (184, 189))
303815	31128216	Inactivating mutations of KMT2B that include microdeletions and pathogenic variants have been linked to pediatric dystonia, a hyperkinetic movement disorder.	('microdeletions', 'Var', (45, 59))	('KMT2B', 'Gene', '9757', (26, 31))	('movement disorder', 'Phenotype', 'HP:0100022', (139, 156))	('linked', 'Reg', (94, 100))	('Inactivating mutations', 'Var', (0, 22))	('KMT2B', 'Gene', (26, 31))	('dystonia', 'Disease', 'MESH:D004421', (114, 122))	('hyperkinetic movement', 'Phenotype', 'HP:0002487', (126, 147))	('dystonia', 'Disease', (114, 122))	('dystonia', 'Phenotype', 'HP:0001332', (114, 122))	('variants', 'Var', (75, 83))
303816	31128216	Heterozygous mutations in human KMT2D are also frequently associated with developmental anomalies and malignancy.	('associated', 'Reg', (58, 68))	('developmental anomalies', 'Disease', (74, 97))	('malignancy', 'Disease', (102, 112))	('KMT2D', 'Gene', (32, 37))	('Heterozygous mutations', 'Var', (0, 22))	('human', 'Species', '9606', (26, 31))
303818	31128216	Although translocation fusions of KMT2A with a variety of partner proteins are directly linked to pediatric leukemias, there is no clear link between germline loss of KMT2A function and oncogenesis.	('leukemias', 'Phenotype', 'HP:0001909', (108, 117))	('leukemias', 'Disease', (108, 117))	('KMT2A', 'Gene', (167, 172))	('leukemia', 'Phenotype', 'HP:0001909', (108, 116))	('linked', 'Reg', (88, 94))	('KMT2A', 'Gene', '4297', (167, 172))	('KMT2A', 'Gene', (34, 39))	('leukemias', 'Disease', 'MESH:D007938', (108, 117))	('translocation fusions', 'Var', (9, 30))	('KMT2A', 'Gene', '4297', (34, 39))
303819	31128216	In contrast, heterozygous germline inactivating mutations in KMT2D have been linked to several cancers.	('germline inactivating mutations', 'Var', (26, 57))	('cancers', 'Phenotype', 'HP:0002664', (95, 102))	('KMT2D', 'Gene', (61, 66))	('cancers', 'Disease', (95, 102))	('cancers', 'Disease', 'MESH:D009369', (95, 102))	('linked', 'Reg', (77, 83))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))
303820	31128216	The de novo mutations are inherited in an autosomal dominant pattern and Kabuki syndrome patients have a modest predisposition to cancer, including lymphoma, Wilms tumor (kidney), hepatoblastoma (liver), synovial sarcoma (lung) and neuroblastoma.	('synovial sarcoma', 'Phenotype', 'HP:0012570', (204, 220))	('neuroblastoma', 'Disease', (232, 245))	('lymphoma', 'Disease', (148, 156))	('neuroblastoma', 'Phenotype', 'HP:0003006', (232, 245))	('lymphoma', 'Disease', 'MESH:D008223', (148, 156))	('sarcoma', 'Phenotype', 'HP:0100242', (213, 220))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('neuroblastoma', 'Disease', 'MESH:D009447', (232, 245))	('Wilms tumor', 'Disease', 'MESH:D009396', (158, 169))	('hepatoblastoma', 'Phenotype', 'HP:0002884', (180, 194))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('Wilms tumor', 'Phenotype', 'HP:0002667', (158, 169))	('autosomal dominant pattern and Kabuki syndrome', 'Disease', 'MESH:C537705', (42, 88))	('synovial sarcoma', 'Disease', (204, 220))	('lymphoma', 'Phenotype', 'HP:0002665', (148, 156))	('cancer', 'Disease', (130, 136))	('mutations', 'Var', (12, 21))	('hepatoblastoma', 'Disease', (180, 194))	('Wilms tumor', 'Disease', (158, 169))	('patients', 'Species', '9606', (89, 97))	('synovial sarcoma', 'Disease', 'MESH:D013584', (204, 220))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('hepatoblastoma', 'Disease', 'MESH:D018197', (180, 194))
303821	31128216	Brain-specific knockout of Kmt2d in mice is associated with spontaneous medulloblastoma, perhaps through hyperactivation of the Ras and Notch pathways and down-regulation of tumor suppressor genes.	('associated', 'Reg', (44, 54))	('tumor', 'Disease', (174, 179))	('down-regulation', 'NegReg', (155, 170))	('knockout', 'Var', (15, 23))	('Ras', 'Pathway', (128, 131))	('medulloblastoma', 'Disease', 'MESH:D008527', (72, 87))	('Kmt2d', 'Gene', (27, 32))	('medulloblastoma', 'Phenotype', 'HP:0002885', (72, 87))	('hyperactivation', 'PosReg', (105, 120))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('mice', 'Species', '10090', (36, 40))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('medulloblastoma', 'Disease', (72, 87))
303822	31128216	In light of the significant role of somatic loss of KMT2C/D in multiple cancer types, the relative lack of pediatric cancers associated with KMT2A/B/C suggest that heterozygous inactivation of these genes is insufficient to drive epigenetic changes associated with tumor formation and likely require additional cooperating mutations for cancer development.	('KMT2A/B', 'Gene', '4297;9757', (141, 148))	('loss', 'NegReg', (44, 48))	('cancer', 'Disease', 'MESH:D009369', (337, 343))	('cancers', 'Disease', 'MESH:D009369', (117, 124))	('cancer', 'Disease', (72, 78))	('tumor', 'Disease', (265, 270))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('cancer', 'Disease', (117, 123))	('tumor', 'Disease', 'MESH:D009369', (265, 270))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('KMT2A/B', 'Gene', (141, 148))	('KMT2C/D', 'Gene', (52, 59))	('epigenetic changes', 'MPA', (230, 248))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('cancer', 'Disease', (337, 343))	('cancers', 'Phenotype', 'HP:0002664', (117, 124))	('cancers', 'Disease', (117, 124))	('heterozygous inactivation', 'Var', (164, 189))	('tumor', 'Phenotype', 'HP:0002664', (265, 270))	('cancer', 'Phenotype', 'HP:0002664', (337, 343))	('cancer', 'Disease', 'MESH:D009369', (117, 123))
303827	31128216	These results reveal a critical role of KMT2C/D COMPASS complexes in establishing pluripotent cell identity during somatic reprogramming, thus suggesting a role for loss of KMT2C/D function in aberrant growth and differentiation.	('COMPASS', 'Gene', '37546', (48, 55))	('COMPASS', 'Gene', (48, 55))	('aberrant growth', 'Phenotype', 'HP:0001507', (193, 208))	('KMT2C/D', 'Gene', (173, 180))	('aberrant growth', 'CPA', (193, 208))	('establishing pluripotent cell identity', 'MPA', (69, 107))	('loss', 'Var', (165, 169))
303829	31128216	Most of these cancers are associated with mutations that alter the proteins through missense changes or truncations resulting in reduced functions, supporting their roles as tumor suppressors.	('cancers', 'Disease', (14, 21))	('tumor', 'Disease', (174, 179))	('missense changes', 'Var', (84, 100))	('cancers', 'Phenotype', 'HP:0002664', (14, 21))	('proteins', 'Protein', (67, 75))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('functions', 'MPA', (137, 146))	('truncations', 'MPA', (104, 115))	('reduced', 'NegReg', (129, 136))	('cancers', 'Disease', 'MESH:D009369', (14, 21))	('mutations', 'Var', (42, 51))
303832	31128216	Inhibitors that block the activities of EZH2, such as GSK126, result in the restoration of gene expression in KMT2C mutant cells.	('KMT2C', 'Gene', (110, 115))	('gene expression', 'MPA', (91, 106))	('EZH2', 'Gene', '2146', (40, 44))	('EZH2', 'Gene', (40, 44))	('mutant', 'Var', (116, 122))	('restoration', 'MPA', (76, 87))	('GSK126', 'Chemical', 'MESH:C577920', (54, 60))
303837	31128216	The loss of kmt2d in a zebrafish model of Kabuki syndrome results in hyperactivation of MEK within the RAS/MAPK pathway and treatment with the BRAF inhibitor desmethyl dabrafenib (dmDf) can rescue the Kabuki-like phenotypes.	('RAS/MAPK pathway', 'Pathway', (103, 119))	('Kabuki-like', 'Disease', (201, 212))	('hyperactivation', 'PosReg', (69, 84))	('Kabuki syndrome', 'Disease', 'MESH:C537705', (42, 57))	('MEK', 'Pathway', (88, 91))	('kmt2d', 'Gene', '100536523', (12, 17))	('BRAF', 'Gene', (143, 147))	('Kabuki syndrome', 'Disease', (42, 57))	('kmt2d', 'Gene', (12, 17))	('desmethyl dabrafenib', 'Chemical', '-', (158, 178))	('BRAF', 'Gene', '403065', (143, 147))	('zebrafish', 'Species', '7955', (23, 32))	('dmDf', 'Chemical', '-', (180, 184))	('loss', 'Var', (4, 8))
303839	31128216	KMT2C/D methyltransferases are frequently mutated in cancer KMT2C/D mutations frequently co-occur in lung cancer Somatic loss of KMT2C/D function as drivers of oncogenesis KMT2C/D function to maintain epithelial states MLR COMPASS complexes control gene transcriptional enhancer functions	('COMPASS', 'Gene', '37546', (223, 230))	('COMPASS', 'Gene', (223, 230))	('cancer', 'Disease', (53, 59))	('lung cancer', 'Disease', 'MESH:D008175', (101, 112))	('loss', 'NegReg', (121, 125))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('KMT2C/D', 'Gene', (129, 136))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('KMT2C/D', 'Gene', (60, 67))	('cancer', 'Disease', (106, 112))	('lung cancer', 'Phenotype', 'HP:0100526', (101, 112))	('mutations', 'Var', (68, 77))	('lung cancer', 'Disease', (101, 112))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
303844	30674868	In vitro, CASC9 knockdown in OSCC cells SCC15 and CAL27 significantly promotes autophagy and apoptosis, while inhibiting proliferation.	('autophagy', 'CPA', (79, 88))	('proliferation', 'CPA', (121, 134))	('CASC9', 'Gene', '101805492', (10, 15))	('knockdown', 'Var', (16, 25))	('CAL27', 'CellLine', 'CVCL:1107', (50, 55))	('CAL27', 'Gene', (50, 55))	('inhibiting', 'NegReg', (110, 120))	('promotes', 'PosReg', (70, 78))	('apoptosis', 'CPA', (93, 102))	('rat', 'Species', '10116', (128, 131))	('CASC9', 'Gene', (10, 15))
303848	30674868	In addition, CASC9 depletion suppressed tumor growth in vivo.	('depletion', 'Var', (19, 28))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('CASC9', 'Gene', '101805492', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('CASC9', 'Gene', (13, 18))	('suppressed', 'NegReg', (29, 39))
303854	30674868	Current studies have shown that variable abnormal expression of lncRNA is closely related to the occurrence of various diseases, including tumors.	('abnormal', 'Var', (41, 49))	('lncRNA', 'Protein', (64, 70))	('related', 'Reg', (82, 89))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumors', 'Disease', 'MESH:D009369', (139, 145))	('tumors', 'Disease', (139, 145))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))
303858	30674868	reported that high expression of CASC9 activates the PI3K/AKT signaling pathway, which promotes the invasion and metastasis of esophageal squamous carcinoma cells.	('carcinoma', 'Phenotype', 'HP:0030731', (147, 156))	('metastasis of esophageal squamous carcinoma', 'Disease', (113, 156))	('esophageal squamous carcinoma', 'Phenotype', 'HP:0011459', (127, 156))	('CASC9', 'Gene', (33, 38))	('CASC9', 'Gene', '101805492', (33, 38))	('activates', 'PosReg', (39, 48))	('metastasis of esophageal squamous carcinoma', 'Disease', 'MESH:D000077277', (113, 156))	('AKT', 'Gene', '207', (58, 61))	('invasion', 'CPA', (100, 108))	('high expression', 'Var', (14, 29))	('promotes', 'PosReg', (87, 95))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (138, 156))	('AKT', 'Gene', (58, 61))
303862	30674868	Moreover, silencing CASC9 inhibits OSCC growth in vivo.	('OSCC growth', 'CPA', (35, 46))	('inhibits', 'NegReg', (26, 34))	('CASC9', 'Gene', (20, 25))	('CASC9', 'Gene', '101805492', (20, 25))	('silencing', 'Var', (10, 19))
303880	30674868	We verified the knockdown efficiency of three siRNAs (si-1, si-2, si-3) targeting different sites of CASC9 in SCC15 and CAL27 cells, and the results showed that si-3 was the most effective siRNA for silencing CASC9 in both SCC15 and CAL27 cells (P < 0.0001) (Fig.	('si-3', 'Var', (161, 165))	('CASC9', 'Gene', (101, 106))	('CASC9', 'Gene', '101805492', (101, 106))	('CAL27', 'CellLine', 'CVCL:1107', (120, 125))	('CASC9', 'Gene', '101805492', (209, 214))	('silencing', 'NegReg', (199, 208))	('CASC9', 'Gene', (209, 214))	('CAL27', 'CellLine', 'CVCL:1107', (233, 238))
303888	30674868	Autophagic density was significantly increased in SCC15 and CAL27 cells after the knockdown of CASC9, according to the TEM analysis (P < 0.001) (Fig.	('Autophagic density', 'CPA', (0, 18))	('knockdown', 'Var', (82, 91))	('CAL27', 'CellLine', 'CVCL:1107', (60, 65))	('increased', 'PosReg', (37, 46))	('CASC9', 'Gene', '101805492', (95, 100))	('CASC9', 'Gene', (95, 100))
303897	30674868	These results demonstrate that CASC9 knockdown reduces the activation of the AKT/mTOR signaling pathway in OSCC cells.	('AKT', 'Gene', (77, 80))	('reduces', 'NegReg', (47, 54))	('AKT', 'Gene', '207', (77, 80))	('CASC9', 'Gene', (31, 36))	('CASC9', 'Gene', '101805492', (31, 36))	('knockdown', 'Var', (37, 46))	('rat', 'Species', '10116', (21, 24))	('mTOR', 'Gene', (81, 85))	('mTOR', 'Gene', '2475', (81, 85))
303903	30674868	To investigate the regulatory relationship between autophagy and apoptosis in OSCC, we detected apoptosis in SCC15 and CAL27 cells that were cotreated with si-CASC9 and the autophagy inhibitor (Autophinib) (HY-101920, MCE, New Jersey, USA).	('CASC9', 'Gene', '101805492', (159, 164))	('CASC9', 'Gene', (159, 164))	('CAL27', 'CellLine', 'CVCL:1107', (119, 124))	('Autophinib', 'Chemical', '-', (194, 204))	('HY-101920', 'Var', (207, 216))
303906	30674868	These results demonstrate that inhibition of autophagy in OSCC cells reversed the increased rate of apoptosis caused by the CASC9 knockdown, suggesting that the regulation of apoptosis by CASC9 in OSCC is dependent on the regulation of autophagy.	('CASC9', 'Gene', '101805492', (124, 129))	('CASC9', 'Gene', (124, 129))	('knockdown', 'Var', (130, 139))	('rat', 'Species', '10116', (92, 95))	('rat', 'Species', '10116', (21, 24))	('CASC9', 'Gene', '101805492', (188, 193))	('CASC9', 'Gene', (188, 193))
303910	30674868	These results indicate that silencing CASC9 significantly inhibits the growth of tumors in vivo.	('tumors', 'Disease', (81, 87))	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('inhibits', 'NegReg', (58, 66))	('CASC9', 'Gene', (38, 43))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('silencing', 'Var', (28, 37))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('CASC9', 'Gene', '101805492', (38, 43))
303912	30674868	However, in recent years, extensive research has demonstrated that abnormally expressed lncRNA is closely related to the occurrence and development of various cancers.	('cancers', 'Disease', (159, 166))	('rat', 'Species', '10116', (56, 59))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('related', 'Reg', (106, 113))	('cancers', 'Phenotype', 'HP:0002664', (159, 166))	('abnormally expressed', 'Var', (67, 87))	('cancers', 'Disease', 'MESH:D009369', (159, 166))	('lncRNA', 'Protein', (88, 94))
303922	30674868	Studies on esophageal squamous cell carcinoma and hepatocellular carcinoma have shown that high expression of CASC9 activates the PI3K/AKT signaling pathway, promoting the proliferation, invasion and metastasis of cancer cells.	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('high expression', 'Var', (91, 106))	('metastasis of cancer', 'Disease', 'MESH:D009362', (200, 220))	('esophageal squamous cell carcinoma', 'Disease', (11, 45))	('AKT', 'Gene', (135, 138))	('promoting', 'PosReg', (158, 167))	('CASC9', 'Gene', '101805492', (110, 115))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (22, 45))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (50, 74))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('activates', 'PosReg', (116, 125))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (11, 45))	('AKT', 'Gene', '207', (135, 138))	('proliferation', 'CPA', (172, 185))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (50, 74))	('rat', 'Species', '10116', (179, 182))	('metastasis of cancer', 'Disease', (200, 220))	('CASC9', 'Gene', (110, 115))	('carcinoma', 'Phenotype', 'HP:0030731', (36, 45))	('hepatocellular carcinoma', 'Disease', (50, 74))	('invasion', 'CPA', (187, 195))
303933	30674868	Our study found that autophagy and apoptosis were both increased in cells with silenced CASC9.	('autophagy', 'CPA', (21, 30))	('silenced', 'Var', (79, 87))	('increased', 'PosReg', (55, 64))	('CASC9', 'Gene', (88, 93))	('CASC9', 'Gene', '101805492', (88, 93))	('apoptosis', 'CPA', (35, 44))
303934	30674868	However, apoptosis was significantly reduced in the cells cotreated with si-CASC9 and the autophagy inhibitor, indicating that silencing CASC9 induced autophagy as a pro-death response.	('CASC9', 'Gene', '101805492', (137, 142))	('autophagy', 'CPA', (151, 160))	('CASC9', 'Gene', (76, 81))	('CASC9', 'Gene', '101805492', (76, 81))	('induced', 'Reg', (143, 150))	('reduced', 'NegReg', (37, 44))	('CASC9', 'Gene', (137, 142))	('silencing', 'Var', (127, 136))	('apoptosis', 'CPA', (9, 18))
303936	30674868	This study also found that CASC9 knockdown in OSCC cells increased the early apoptosis.	('early apoptosis', 'CPA', (71, 86))	('CASC9', 'Gene', (27, 32))	('CASC9', 'Gene', '101805492', (27, 32))	('knockdown', 'Var', (33, 42))	('increased', 'PosReg', (57, 66))
303940	30674868	Thus, we supposed that CASC9 depletion in OSCC cells might promote the binding of P62 to LC3, and then P62 is incorporated into autophagosomes, resulting in the degradation of P62; subsequently, reduction of P62 may increase the autophagy-mediated apoptosis.	('P62', 'Gene', (103, 106))	('depletion', 'Var', (29, 38))	('CASC9', 'Gene', '101805492', (23, 28))	('reduction', 'NegReg', (195, 204))	('autophagy-mediated apoptosis', 'CPA', (229, 257))	('LC3', 'Gene', '84557', (89, 92))	('P62', 'Gene', '23636', (82, 85))	('P62', 'Gene', '23636', (176, 179))	('P62', 'Gene', '23636', (208, 211))	('rat', 'Species', '10116', (117, 120))	('CASC9', 'Gene', (23, 28))	('P62', 'Gene', '23636', (103, 106))	('binding', 'Interaction', (71, 78))	('P62', 'Gene', (82, 85))	('increase', 'PosReg', (216, 224))	('LC3', 'Gene', (89, 92))	('degradation', 'MPA', (161, 172))	('P62', 'Gene', (176, 179))	('P62', 'Gene', (208, 211))	('promote', 'PosReg', (59, 66))
303944	30674868	We also demonstrated that CASC9 depletion increases autophagy by inhibiting the AKT/mTOR signaling pathway to promote autophagic apoptosis in OSCC cells (Fig.	('autophagy', 'CPA', (52, 61))	('increases', 'PosReg', (42, 51))	('rat', 'Species', '10116', (15, 18))	('depletion', 'Var', (32, 41))	('AKT', 'Gene', '207', (80, 83))	('mTOR', 'Gene', '2475', (84, 88))	('mTOR', 'Gene', (84, 88))	('AKT', 'Gene', (80, 83))	('autophagic apoptosis', 'CPA', (118, 138))	('promote', 'PosReg', (110, 117))	('CASC9', 'Gene', (26, 31))	('inhibiting', 'NegReg', (65, 75))	('CASC9', 'Gene', '101805492', (26, 31))
303956	30674868	The cells were cultured in Dulbecco's modified Eagle's medium (DMEM, Gibico, USA) containing 10% fetal bovine serum (FBS) and 1% penicillin-streptomycin in an incubator containing 5% CO2 at 37  C. In situ hybridization (ISH) was performed using a kit (MK10506-h, Boster, Wuhan, China) according to the manufacturer's protocol.	('MK10506-h', 'Var', (252, 261))	('DMEM', 'Chemical', '-', (63, 67))	("Dulbecco's modified Eagle's medium", 'Chemical', '-', (27, 61))	('bovine', 'Species', '9913', (103, 109))	('FBS', 'Disease', (117, 120))	('penicillin', 'Chemical', 'MESH:D010406', (129, 139))	('FBS', 'Disease', 'MESH:D005198', (117, 120))	('streptomycin', 'Chemical', 'MESH:D013307', (140, 152))	('CO2', 'Chemical', '-', (183, 186))
303977	30674868	The sh-RNAs were synthesized and packaged in lentiviral vectors by Shanghai GenePharma Co., Ltd. (Shanghai, China), designated sh-CASC9 and sh-NC.	('CASC9', 'Gene', (130, 135))	('Shanghai', 'Var', (98, 106))	('CASC9', 'Gene', '101805492', (130, 135))
303982	30674868	Next, the cells were incubated with 1% BSA for 30 min and then with antibodies against LC3B (ab192890, abcam, Cambridge, UK) and P62 (ab109012, abcam, Cambridge, UK) overnight at 4  C. Then, the cells were incubated with Cy3-labeled goat anti-rabbit IgG (H + L) (A0516, Biyuntian, China) for 1 h at room temperature in the dark.	('P62', 'Gene', '23636', (129, 132))	('Cy3', 'Chemical', '-', (221, 224))	('LC3B', 'Gene', (87, 91))	('ab192890', 'Var', (93, 101))	('P62', 'Gene', (129, 132))	('goat', 'Species', '9925', (233, 237))	('rabbit', 'Species', '9986', (243, 249))	('LC3B', 'Gene', '81631', (87, 91))	('rat', 'Species', '10116', (309, 312))	('ab109012', 'Var', (134, 142))
303995	30674868	Cell proliferation was measured using the Cell Proliferation Kit I (MTT) (11465007001, Roche, Switzerland) according to the manufacturer's instructions.	('rat', 'Species', '10116', (12, 15))	('MTT', 'Chemical', 'MESH:C070243', (68, 71))	('rat', 'Species', '10116', (54, 57))	('11465007001', 'Var', (74, 85))	('Cell proliferation', 'CPA', (0, 18))
304031	29984774	Immunohistochemical staining (IHC) revealed positivity for synaptophysin and CD56 and negativity for p40 (Fig.	('CD56', 'Gene', (77, 81))	('p40', 'Gene', '3578', (101, 104))	('synaptophysin', 'Gene', '6855', (59, 72))	('synaptophysin', 'Gene', (59, 72))	('p40', 'Gene', (101, 104))	('CD56', 'Gene', '4684', (77, 81))	('positivity', 'Var', (44, 54))	('negativity', 'NegReg', (86, 96))
304058	30405881	High expression level of CD44v8-10 in cancer stem-like cells is associated with poor prognosis in esophageal squamous cell carcinoma patients treated with chemoradiotherapy Strong reactive oxygen species (ROS) suppression in cancer stem-like cell components in various solid tumors is associated with therapeutic resistance.	('esophageal squamous cell carcinoma', 'Disease', (98, 132))	('cancer', 'Disease', (225, 231))	('patients', 'Species', '9606', (133, 141))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('solid tumors', 'Disease', 'MESH:D009369', (269, 281))	('tumors', 'Phenotype', 'HP:0002664', (275, 281))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (109, 132))	('ROS', 'Chemical', 'MESH:D017382', (205, 208))	('cancer', 'Disease', (38, 44))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (98, 132))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (180, 203))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('cancer', 'Disease', 'MESH:D009369', (225, 231))	('tumor', 'Phenotype', 'HP:0002664', (275, 280))	('expression level', 'MPA', (5, 21))	('CD44v8-10', 'Var', (25, 34))	('solid tumors', 'Disease', (269, 281))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))
304064	30405881	High CD44v8-10 expression was independently associated with poor prognosis in E-SCC patients treated with dCRT (hazard ratio = 2.906, 95% CI = 1.277-6.611, p = 0.011).	('SCC', 'Gene', '6317', (80, 83))	('dCRT', 'Gene', '45841', (106, 110))	('High', 'Var', (0, 4))	('CD44', 'Gene', (5, 9))	('patients', 'Species', '9606', (84, 92))	('dCRT', 'Gene', (106, 110))	('expression', 'MPA', (15, 25))	('SCC', 'Gene', (80, 83))	('CD44', 'Gene', '960', (5, 9))
304092	30405881	In these patients, univariate analysis showed that performance status (PS), tumor size, cStage and high CD44v8-10 expression (histo-score [H-score] >= 151) were associated with poor prognosis (hazard ratio [HR] = 2.975, 95% confidential interval [CI] 1.431-6.186, p = 0.004; HR = 3.755, 95% CI 1.784-7.903, p < 0.001; HR = 5.177, 95% CI 2.448-10.946, p < 0.001; HR = 3.438, 95% CI 1.549-7.631, p = 0.002, respectively) (Table 2).	('patients', 'Species', '9606', (9, 17))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('CD44', 'Gene', '960', (104, 108))	('high', 'Var', (99, 103))	('CD44', 'Gene', (104, 108))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
304093	30405881	Moreover, multivariate analysis showed that cStage and high CD44v8-10 expression were independent poor prognostic factors (HR = 3.536, 95% CI 1.176-10.626, p = 0.024; HR = 2.844, 95% CI 1.248-6.479, p = 0.013, respectively).	('expression', 'MPA', (70, 80))	('CD44', 'Gene', '960', (60, 64))	('CD44', 'Gene', (60, 64))	('high', 'Var', (55, 59))
304098	30405881	In contrast, overall survival of cStage II + III and cStage IVA + IVB (cM1-lym) subjects with high CD44v8-10 expression was significantly shorter than that of subjects of corresponding stages with low CD44v8-10 expression (p = 0.024, Figure 2C; p = 0.023, Figure 2D, respectively).	('CD44', 'Gene', (201, 205))	('CD44', 'Gene', '960', (201, 205))	('IVA', 'Disease', 'MESH:C538167', (60, 63))	('CD44', 'Gene', '960', (99, 103))	('shorter', 'NegReg', (138, 145))	('CD44', 'Gene', (99, 103))	('IVA', 'Disease', (60, 63))	('high', 'Var', (94, 98))
304105	30405881	As shown in Table 4, the 3-year cumulative lymphatic recurrence rate of subjects with high CD44v8-10 expression was higher than that of subjects with low CD44v8-10 expression (34.9%, 95% CI 13.4-57.5 vs 9.2%, 95% CI 1.5-25.9, p = 0.045).	('higher', 'PosReg', (116, 122))	('CD44', 'Gene', '960', (91, 95))	('CD44', 'Gene', '960', (154, 158))	('lymphatic recurrence', 'CPA', (43, 63))	('CD44', 'Gene', (91, 95))	('CD44', 'Gene', (154, 158))	('expression', 'MPA', (101, 111))	('high', 'Var', (86, 90))
304106	30405881	Our data suggest that patients with high CD44v8-10 expression are at high risk of lymphatic recurrence after dCRT.	('CD44', 'Gene', '960', (41, 45))	('patients', 'Species', '9606', (22, 30))	('CD44', 'Gene', (41, 45))	('lymphatic recurrence', 'CPA', (82, 102))	('dCRT', 'Gene', (109, 113))	('high', 'Var', (36, 40))	('dCRT', 'Gene', '45841', (109, 113))
304136	30405881	Second, H-score >= 151 was provisionally used as the definition for high CD44v8-10 expression, which has not been sufficiently verified.	('CD44', 'Gene', '960', (73, 77))	('H-score >= 151', 'Var', (8, 22))	('CD44', 'Gene', (73, 77))	('expression', 'MPA', (83, 93))
304191	27991568	Besides, the growth and metastasis of cancer often relate to combined effects of long non-coding RNAs (lncRNAs).	('metastasis of cancer', 'Disease', (24, 44))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('long non-coding RNAs', 'Var', (81, 101))	('relate', 'Reg', (51, 57))	('metastasis of cancer', 'Disease', 'MESH:D009362', (24, 44))	('growth', 'CPA', (13, 19))
304197	27991568	Cancers are the consequence of a process of somatic mutation and break the balance controlled by gene expression programs and cellular networks that typically maintain intracellular homeostasis and prevent unnecessary expansion.	('intracellular homeostasis', 'MPA', (168, 193))	('Cancers', 'Disease', (0, 7))	('Cancers', 'Phenotype', 'HP:0002664', (0, 7))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancers', 'Disease', 'MESH:D009369', (0, 7))	('mutation', 'Var', (52, 60))
304211	27991568	Lnc_bc060912 whose expression increased in human lung and other tumors and affected cell apoptosis via PARP1 and NPM1 which were two DNA damage repair protein.	('tumors', 'Disease', (64, 70))	('expression', 'MPA', (19, 29))	('NPM1', 'Gene', (113, 117))	('PARP1', 'Gene', (103, 108))	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('lung', 'Disease', (49, 53))	('PARP1', 'Gene', '142', (103, 108))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('affected', 'Reg', (75, 83))	('Lnc_bc060912', 'Var', (0, 12))	('NPM1', 'Gene', '4869', (113, 117))	('increased', 'PosReg', (30, 39))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('human', 'Species', '9606', (43, 48))	('cell apoptosis', 'CPA', (84, 98))
304216	27991568	For example, tumor suppressor response lncRNAs LOC572558 and MT1JP regulated the p53 signaling pathway in bladder cancer and other cancers, respectively.	('tumor', 'Disease', (13, 18))	('cancers', 'Disease', 'MESH:D009369', (131, 138))	('cancers', 'Phenotype', 'HP:0002664', (131, 138))	('cancers', 'Disease', (131, 138))	('regulated', 'Reg', (67, 76))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('MT1JP', 'Gene', (61, 66))	('bladder cancer', 'Disease', 'MESH:D001749', (106, 120))	('bladder cancer', 'Disease', (106, 120))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('p53', 'Gene', (81, 84))	('p53', 'Gene', '7157', (81, 84))	('LOC572558', 'Var', (47, 56))	('MT1JP', 'Gene', '4498', (61, 66))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('bladder cancer', 'Phenotype', 'HP:0009725', (106, 120))
304240	27991568	For example, Hassan M suggested that AC005076 might be a functional lncRNA to intervene apoptosis, and might be associated with cancer therapies clinically.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('AC005076', 'Var', (37, 45))	('associated', 'Reg', (112, 122))	('cancer', 'Disease', (128, 134))
304242	27991568	Particularly the lncRNA RP4-612B15 showed delicate changes of genome in mantle cell lymphomas (MCL), a subset of B-cell non-Hodgkin's lymphomas, and had been acknowledged as candidate neoplasia functional lncRNA, which suggested its potential as suppressor lncRNA.	('neoplasia', 'Disease', (184, 193))	('MCL', 'Disease', 'MESH:C535516', (95, 98))	('RP4-612B15', 'Var', (24, 34))	('neoplasia', 'Phenotype', 'HP:0002664', (184, 193))	('MCL', 'Disease', (95, 98))	('lymphomas', 'Phenotype', 'HP:0002665', (134, 143))	('mantle cell lymphomas', 'Disease', 'MESH:D020522', (72, 93))	('changes', 'Reg', (51, 58))	('mantle cell lymphomas', 'Disease', (72, 93))	('neoplasia', 'Disease', 'MESH:D009369', (184, 193))	('lymphomas', 'Phenotype', 'HP:0002665', (84, 93))	("Hodgkin's lymphomas", 'Phenotype', 'HP:0012189', (124, 143))	("Hodgkin's lymphomas", 'Disease', (124, 143))	('genome', 'MPA', (62, 68))	("Hodgkin's lymphomas", 'Disease', 'MESH:D006689', (124, 143))
304259	27991568	E2F transcription factors acts a functional role in cell proliferation, and is deregulated pRB pathway, which is a very recurrent occurrence in human cancer, suggesting these three risk pathways might be carcinogenesis traits of cancers.	('carcinogenesis traits of cancers', 'Disease', 'MESH:D063646', (204, 236))	('carcinogenesis traits of cancers', 'Disease', (204, 236))	('E2F', 'Var', (0, 3))	('deregulated', 'Reg', (79, 90))	('human', 'Species', '9606', (144, 149))	('cancer', 'Disease', (229, 235))	('cancer', 'Disease', 'MESH:D009369', (229, 235))	('cancers', 'Phenotype', 'HP:0002664', (229, 236))	('cell proliferation', 'CPA', (52, 70))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('pRB', 'Gene', '5925', (91, 94))	('cancer', 'Disease', (150, 156))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('pRB', 'Gene', (91, 94))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
304265	27991568	The average AUC values of 1000 permutation tests for 6 cancer datasets were calculated, which were 0.8194, 0.7843, 0.9712, 0.8339, 0.8618 and 0.8491, respectively, (Fig.	('0.9712', 'Var', (115, 121))	('0.8618', 'Var', (131, 137))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('0.8339', 'Var', (123, 129))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('0.7843', 'Var', (107, 113))	('cancer', 'Disease', (55, 61))	('0.8491', 'Var', (142, 148))
304278	27991568	The average AUC values of 1000 permutation tests for 6 cancer datasets were calculated, which were both 0.9527, 0.9873, 0.9894, 0.9682, 0.9691 and 0.8867, respectively, (Supplementary Figure 2), which indicated a high classification performance.	('0.9691', 'Var', (136, 142))	('0.9682', 'Var', (128, 134))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('0.9527', 'Var', (104, 110))	('0.9894', 'Var', (120, 126))	('0.9873', 'Var', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('0.8867', 'Var', (147, 153))	('cancer', 'Disease', (55, 61))
304304	27991568	RP4-612B15 showing subtle genomic alterations in mantle cell lymphomas had been found in BRCA and PRAD.	('PRAD', 'Disease', (98, 102))	('BRCA', 'Gene', (89, 93))	('RP4-612B15', 'Var', (0, 10))	('mantle cell lymphomas', 'Disease', 'MESH:D020522', (49, 70))	('mantle cell lymphomas', 'Disease', (49, 70))	('lymphomas', 'Phenotype', 'HP:0002665', (61, 70))	('BRCA', 'Gene', '672', (89, 93))
304308	27991568	The Cox regression p values and Log rank p values were not only significantly associated with OS in the six test datasets, but also in two validation datasets and eight additional independent validation datasets (Supplementary Table 2).	('associated', 'Reg', (78, 88))	('Cox', 'Gene', '1351', (4, 7))	('Cox', 'Gene', (4, 7))	('p values', 'Var', (19, 27))
304469	33061622	For example, miR-362 promotes the metastasis of NSCLC cells by down-regulating Sema3A; miR-330-5p overexpression suppresses the growth of NSCLC by inhibiting NOB1.	('NSCLC', 'Disease', (48, 53))	('Sema3A', 'Gene', (79, 85))	('promotes', 'PosReg', (21, 29))	('NSCLC', 'Phenotype', 'HP:0030358', (48, 53))	('NSCLC', 'Disease', 'MESH:D002289', (138, 143))	('suppresses', 'NegReg', (113, 123))	('inhibiting', 'NegReg', (147, 157))	('NOB1', 'Gene', '28987', (158, 162))	('NSCLC', 'Disease', (138, 143))	('metastasis', 'CPA', (34, 44))	('Sema3A', 'Gene', '10371', (79, 85))	('NSCLC', 'Phenotype', 'HP:0030358', (138, 143))	('miR-330-5p', 'Chemical', '-', (87, 97))	('growth', 'MPA', (128, 134))	('miR-362', 'Gene', (13, 20))	('down-regulating', 'NegReg', (63, 78))	('NSCLC', 'Disease', 'MESH:D002289', (48, 53))	('miR-330-5p', 'Var', (87, 97))	('miR-362', 'Gene', '574030', (13, 20))	('NOB1', 'Gene', (158, 162))
304512	33061622	Next, the 50 cases of NSCLC tissues were divided into GATA6-AS1 high expression group and low expression group according to the median expression of GATA6-AS1; then chi-square test suggested that the low expression level of GATA6-AS1 was significantly correlated with larger tumor size and positive lymph node metastasis (Table 1).	('GATA6-AS1', 'Gene', (224, 233))	('low', 'Var', (200, 203))	('tumor', 'Phenotype', 'HP:0002664', (275, 280))	('tumor', 'Disease', (275, 280))	('NSCLC', 'Phenotype', 'HP:0030358', (22, 27))	('GATA6-AS1', 'Gene', (54, 63))	('GATA6-AS1', 'Gene', (149, 158))	('correlated', 'Reg', (252, 262))	('GATA6-AS1', 'Gene', '100128893;2627;5729', (224, 233))	('NSCLC', 'Disease', (22, 27))	('GATA6-AS1', 'Gene', '100128893;2627;5729', (54, 63))	('GATA6-AS1', 'Gene', '100128893;2627;5729', (149, 158))	('tumor', 'Disease', 'MESH:D009369', (275, 280))	('NSCLC', 'Disease', 'MESH:D002289', (22, 27))	('positive lymph node metastasis', 'CPA', (290, 320))
304513	33061622	In order to explore the biological function of GATA6-AS1, GATA6-AS1 overexpression plasmid was transfected into H1299 cells, and shRNA against GATA6-AS1 was employed to knock down the expression of GATA6-AS1 in H460 cells (Figure 2A).	('GATA6-AS1', 'Gene', (58, 67))	('GATA6-AS1', 'Gene', '100128893;2627;5729', (47, 56))	('knock', 'Var', (169, 174))	('GATA6-AS1', 'Gene', '100128893;2627;5729', (143, 152))	('H1299', 'CellLine', 'CVCL:0060', (112, 117))	('GATA6-AS1', 'Gene', '100128893;2627;5729', (58, 67))	('GATA6-AS1', 'Gene', (198, 207))	('GATA6-AS1', 'Gene', (47, 56))	('H460', 'CellLine', 'CVCL:0459', (211, 215))	('GATA6-AS1', 'Gene', '100128893;2627;5729', (198, 207))	('GATA6-AS1', 'Gene', (143, 152))
304514	33061622	Subsequently, CCK-8 was adopted to detect cell proliferation, the results of which showed that in comparison with the control group, the up-regulation of GATA6-AS1 markedly inhibited the proliferation of H1299 cells, while knocking down GATA6-AS1 facilitated the proliferation of H460 cells (Figure 2B).	('CCK-8', 'Chemical', '-', (14, 19))	('GATA6-AS1', 'Gene', '100128893;2627;5729', (154, 163))	('knocking down', 'Var', (223, 236))	('inhibited', 'NegReg', (173, 182))	('H1299', 'CellLine', 'CVCL:0060', (204, 209))	('GATA6-AS1', 'Gene', '100128893;2627;5729', (237, 246))	('facilitated', 'PosReg', (247, 258))	('up-regulation', 'PosReg', (137, 150))	('proliferation', 'CPA', (187, 200))	('H460', 'CellLine', 'CVCL:0459', (280, 284))	('proliferation', 'CPA', (263, 276))	('GATA6-AS1', 'Gene', (154, 163))	('GATA6-AS1', 'Gene', (237, 246))
304515	33061622	In addition, Transwell assay was employed to detect cell migration and invasion, and the results suggested that GATA6-AS1 overexpression inhibited cell migration and invasion, and knocking down GATA6-AS1 effected oppositely (Figure 2C and D).	('invasion', 'CPA', (166, 174))	('cell migration', 'CPA', (147, 161))	('GATA6-AS1', 'Gene', '100128893;2627;5729', (112, 121))	('inhibited', 'NegReg', (137, 146))	('knocking down', 'Var', (180, 193))	('overexpression', 'PosReg', (122, 136))	('GATA6-AS1', 'Gene', (194, 203))	('GATA6-AS1', 'Gene', (112, 121))	('GATA6-AS1', 'Gene', '100128893;2627;5729', (194, 203))
304516	33061622	Western blot was employed to examine EMT indicators including E-cadherin and N-cadherin, and the results indicated that GATA6-AS1 overexpression remarkably increased E-cadherin expression and decreased N-cadherin, and the knockdown of GATA6-AS1 promoted the EMT process (Figure 2E).	('GATA6-AS1', 'Gene', '100128893;2627;5729', (120, 129))	('promoted', 'PosReg', (245, 253))	('decreased', 'NegReg', (192, 201))	('E-cadherin', 'Gene', (166, 176))	('E-cadherin', 'Gene', '999', (166, 176))	('N-cadherin', 'Gene', '1000', (77, 87))	('GATA6-AS1', 'Gene', (235, 244))	('increased', 'PosReg', (156, 165))	('N-cadherin', 'Gene', (202, 212))	('knockdown', 'Var', (222, 231))	('EMT process', 'CPA', (258, 269))	('E-cadherin', 'Gene', (62, 72))	('GATA6-AS1', 'Gene', (120, 129))	('GATA6-AS1', 'Gene', '100128893;2627;5729', (235, 244))	('N-cadherin', 'Gene', '1000', (202, 212))	('expression', 'MPA', (177, 187))	('N-cadherin', 'Gene', (77, 87))	('E-cadherin', 'Gene', '999', (62, 72))
304520	33061622	As shown, the number and size of tumor nodules in lung tissues in GATA6-AS1 overexpression group were decreased significantly compared with the control group (Supplementary Figure 3).	('GATA6-AS1', 'Gene', (66, 75))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('overexpression', 'Var', (76, 90))	('GATA6-AS1', 'Gene', '100128893;2627;5729', (66, 75))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumor nodules in lung', 'Phenotype', 'HP:0100526', (33, 54))	('tumor', 'Disease', (33, 38))	('decreased', 'NegReg', (102, 111))
304524	33061622	Furthermore, dual-luciferase reporter assay proved that miR-543 mimics could reduce the luciferase activity of GATA6-AS1-WT reporter, GATA6-AS1-MUT1 reporter and GATA6-AS1-MUT2 reporter, but had no significant effect on that of GATA6-AS1-MUT1&2 reporter (Figure 3C).	('luciferase', 'Enzyme', (88, 98))	('mimics', 'Var', (64, 70))	('reduce', 'NegReg', (77, 83))	('GATA6-AS1', 'Gene', (162, 171))	('miR-543', 'Gene', (56, 63))	('GATA6-AS1', 'Gene', '100128893;2627;5729', (134, 143))	('GATA6-AS1', 'Gene', (111, 120))	('miR-543', 'Gene', '100126335', (56, 63))	('GATA6-AS1', 'Gene', (228, 237))	('GATA6-AS1', 'Gene', '100128893;2627;5729', (162, 171))	('GATA6-AS1', 'Gene', '100128893;2627;5729', (111, 120))	('GATA6-AS1', 'Gene', (134, 143))	('GATA6-AS1', 'Gene', '100128893;2627;5729', (228, 237))	('activity', 'MPA', (99, 107))
304526	33061622	In addition, it was observed that GATA6-AS1 overexpression could down-regulate miR-543 expression in H1299 cells, while knocking down GATA6-AS1 could lead to opposite result in H460 cells (Figure 3F).	('miR-543', 'Gene', (79, 86))	('GATA6-AS1', 'Gene', '100128893;2627;5729', (134, 143))	('miR-543', 'Gene', '100126335', (79, 86))	('H1299', 'CellLine', 'CVCL:0060', (101, 106))	('GATA6-AS1', 'Gene', '100128893;2627;5729', (34, 43))	('down-regulate', 'NegReg', (65, 78))	('expression', 'MPA', (87, 97))	('GATA6-AS1', 'Gene', (134, 143))	('H460', 'CellLine', 'CVCL:0459', (177, 181))	('GATA6-AS1', 'Gene', (34, 43))	('knocking down', 'Var', (120, 133))
304532	33061622	Besides, miR-543 inhibitors partially reversed the effects of knocking down GATA6-AS1 on the proliferation, migration, invasion and EMT of H460 cells (Figure 5B-D).	('migration', 'CPA', (108, 117))	('knocking down', 'Var', (62, 75))	('invasion', 'CPA', (119, 127))	('EMT', 'CPA', (132, 135))	('GATA6-AS1', 'Gene', (76, 85))	('miR-543', 'Gene', (9, 16))	('miR-543', 'Gene', '100126335', (9, 16))	('GATA6-AS1', 'Gene', '100128893;2627;5729', (76, 85))	('H460', 'CellLine', 'CVCL:0459', (139, 143))
304537	33061622	As shown, GATA6-AS1 overexpression could significantly increase RKIP mRNA and protein levels, and knocking down GATA6-AS1 could inhibit RKIP mRNA and protein levels in NSCLC cells (Figure 5A and B).	('GATA6-AS1', 'Gene', (10, 19))	('increase', 'PosReg', (55, 63))	('inhibit', 'NegReg', (128, 135))	('GATA6-AS1', 'Gene', '100128893;2627;5729', (112, 121))	('NSCLC', 'Disease', 'MESH:D002289', (168, 173))	('GATA6-AS1', 'Gene', '100128893;2627;5729', (10, 19))	('RKIP', 'Gene', '5037', (64, 68))	('NSCLC', 'Phenotype', 'HP:0030358', (168, 173))	('RKIP', 'Gene', (64, 68))	('RKIP', 'Gene', '5037', (136, 140))	('GATA6-AS1', 'Gene', (112, 121))	('knocking down', 'Var', (98, 111))	('RKIP', 'Gene', (136, 140))	('NSCLC', 'Disease', (168, 173))
304542	33061622	The results suggested that knocking down the expression of RKIP weakened the inhibitory effect of overexpressing GATA6-AS1 on the proliferation, migration, invasion and EMT of NSCLC.	('invasion', 'CPA', (156, 164))	('GATA6-AS1', 'Gene', '100128893;2627;5729', (113, 122))	('knocking down', 'Var', (27, 40))	('weakened', 'NegReg', (64, 72))	('NSCLC', 'Disease', (176, 181))	('migration', 'CPA', (145, 154))	('overexpressing', 'PosReg', (98, 112))	('NSCLC', 'Disease', 'MESH:D002289', (176, 181))	('inhibitory effect', 'MPA', (77, 94))	('GATA6-AS1', 'Gene', (113, 122))	('RKIP', 'Gene', (59, 63))	('NSCLC', 'Phenotype', 'HP:0030358', (176, 181))	('RKIP', 'Gene', '5037', (59, 63))
304543	33061622	Conversely, the promotion of lung cancer cell proliferation, migration, invasion and EMT induced by knocking down GATA6-AS1 was partially reversed by RKIP overexpression of (Figure 6A-D).	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('RKIP', 'Gene', (150, 154))	('knocking down', 'Var', (100, 113))	('lung cancer', 'Disease', 'MESH:D008175', (29, 40))	('GATA6-AS1', 'Gene', (114, 123))	('migration', 'CPA', (61, 70))	('promotion', 'PosReg', (16, 25))	('GATA6-AS1', 'Gene', '100128893;2627;5729', (114, 123))	('EMT', 'CPA', (85, 88))	('invasion', 'CPA', (72, 80))	('lung cancer', 'Disease', (29, 40))	('RKIP', 'Gene', '5037', (150, 154))	('lung cancer', 'Phenotype', 'HP:0100526', (29, 40))
304545	33061622	In this work, Western blot showed that compared with the control group, overexpression of GATA6-AS1 significantly inhibited the expression level of phosphorylated STAT3 (p-STAT3), knockdown of GATA6-AS1 enhanced the p-STAT3 expression, and knockdown or overexpression of RKIP can reverse the effects of GATA6-AS1 on STAT3 activation (Supplementary Figure 4).	('knockdown', 'Var', (180, 189))	('GATA6-AS1', 'Gene', (303, 312))	('expression level', 'MPA', (128, 144))	('GATA6-AS1', 'Gene', (90, 99))	('GATA6-AS1', 'Gene', '100128893;2627;5729', (303, 312))	('GATA6-AS1', 'Gene', '100128893;2627;5729', (90, 99))	('GATA6-AS1', 'Gene', (193, 202))	('RKIP', 'Gene', '5037', (271, 275))	('GATA6-AS1', 'Gene', '100128893;2627;5729', (193, 202))	('STAT3', 'Gene', (316, 321))	('expression', 'MPA', (224, 234))	('STAT3', 'Gene', '6774', (316, 321))	('inhibited', 'NegReg', (114, 123))	('STAT3', 'Gene', (172, 177))	('STAT3', 'Gene', (163, 168))	('STAT3', 'Gene', (218, 223))	('STAT3', 'Gene', '6774', (172, 177))	('STAT3', 'Gene', '6774', (163, 168))	('STAT3', 'Gene', '6774', (218, 223))	('enhanced', 'PosReg', (203, 211))	('RKIP', 'Gene', (271, 275))
304548	33061622	For example, lncRNA MIR4435-2HG accelerates NSCLC progression by activating beta-catenin signaling; lncRNA GASL1 suppresses the growth of NSCLC cells by down-regulating TGF-beta1, and its low expression level indicates adverse prognosis of the patients; lncRNA NBAT-1 is down-regulated in NSCLC tissues, and overexpression of NBAT-1 impedes cancer cell and promotes apoptosis.	('NSCLC', 'Phenotype', 'HP:0030358', (289, 294))	('activating', 'PosReg', (65, 75))	('TGF-beta1', 'Gene', (169, 178))	('MIR4435-2HG', 'Gene', (20, 31))	('down-regulated', 'NegReg', (271, 285))	('patients', 'Species', '9606', (244, 252))	('cancer', 'Disease', (341, 347))	('accelerates', 'PosReg', (32, 43))	('down-regulating', 'NegReg', (153, 168))	('cancer', 'Phenotype', 'HP:0002664', (341, 347))	('NBAT-1', 'Gene', '729177', (326, 332))	('NSCLC', 'Disease', 'MESH:D002289', (138, 143))	('TGF-beta1', 'Gene', '7040', (169, 178))	('suppresses', 'NegReg', (113, 123))	('NBAT-1', 'Gene', '729177', (261, 267))	('NSCLC', 'Disease', 'MESH:D002289', (44, 49))	('impedes', 'NegReg', (333, 340))	('NSCLC', 'Disease', (138, 143))	('NSCLC', 'Disease', 'MESH:D002289', (289, 294))	('cancer', 'Disease', 'MESH:D009369', (341, 347))	('NBAT-1', 'Gene', (326, 332))	('NSCLC', 'Phenotype', 'HP:0030358', (138, 143))	('NSCLC', 'Disease', (44, 49))	('NBAT-1', 'Gene', (261, 267))	('promotes', 'PosReg', (357, 365))	('beta-catenin', 'Gene', (76, 88))	('apoptosis', 'CPA', (366, 375))	('NSCLC', 'Disease', (289, 294))	('MIR4435-2HG', 'Gene', '541471', (20, 31))	('NSCLC', 'Phenotype', 'HP:0030358', (44, 49))	('beta-catenin', 'Gene', '1499', (76, 88))	('overexpression', 'Var', (308, 322))
304550	33061622	The following functional experiments showed that overexpression of GATA6-AS1 significantly suppressed proliferation, migration, invasion and EMT of NSCLC cells, while knockdown of GATA6-AS1 promoted these malignant biological behaviors of NSCLC.	('suppressed', 'NegReg', (91, 101))	('migration', 'CPA', (117, 126))	('GATA6-AS1', 'Gene', (180, 189))	('NSCLC', 'Phenotype', 'HP:0030358', (239, 244))	('NSCLC', 'Disease', (148, 153))	('malignant biological behaviors of', 'CPA', (205, 238))	('GATA6-AS1', 'Gene', (67, 76))	('knockdown', 'Var', (167, 176))	('NSCLC', 'Disease', 'MESH:D002289', (148, 153))	('GATA6-AS1', 'Gene', '100128893;2627;5729', (180, 189))	('NSCLC', 'Disease', (239, 244))	('proliferation', 'CPA', (102, 115))	('GATA6-AS1', 'Gene', '100128893;2627;5729', (67, 76))	('NSCLC', 'Disease', 'MESH:D002289', (239, 244))	('invasion', 'CPA', (128, 136))	('NSCLC', 'Phenotype', 'HP:0030358', (148, 153))	('promoted', 'PosReg', (190, 198))
304554	33061622	Dysregulation of miRNAs may lead to malignant transformation of cells, and they also participate in regulating the malignancy of cancer cells.	('malignancy of cancer', 'Disease', (115, 135))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('malignant transformation of cells', 'CPA', (36, 69))	('Dysregulation', 'Var', (0, 13))	('miRNAs', 'Protein', (17, 23))	('participate', 'Reg', (85, 96))	('lead to', 'Reg', (28, 35))	('malignancy of cancer', 'Disease', 'MESH:D009369', (115, 135))
304571	33061622	In addition, the decrease in RKIP expression in NSCLC cells attenuated the inhibitory effects of GATA6-AS1 overexpression on cell proliferation, migration, invasion, and EMT, while the increase in RKIP expression partially reversed the cancer-promoting effect caused by knocking down GATA6-AS1.	('NSCLC', 'Disease', (48, 53))	('expression', 'MPA', (34, 44))	('cancer', 'Disease', 'MESH:D009369', (236, 242))	('GATA6-AS1', 'Gene', (97, 106))	('inhibitory effects', 'MPA', (75, 93))	('GATA6-AS1', 'Gene', '100128893;2627;5729', (97, 106))	('NSCLC', 'Phenotype', 'HP:0030358', (48, 53))	('GATA6-AS1', 'Gene', (284, 293))	('knocking', 'Var', (270, 278))	('GATA6-AS1', 'Gene', '100128893;2627;5729', (284, 293))	('cancer', 'Disease', (236, 242))	('decrease', 'NegReg', (17, 25))	('EMT', 'CPA', (170, 173))	('RKIP', 'Gene', (29, 33))	('cell proliferation', 'CPA', (125, 143))	('RKIP', 'Gene', (197, 201))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('NSCLC', 'Disease', 'MESH:D002289', (48, 53))	('migration', 'CPA', (145, 154))	('RKIP', 'Gene', '5037', (29, 33))	('RKIP', 'Gene', '5037', (197, 201))	('attenuated', 'NegReg', (60, 70))	('invasion', 'CPA', (156, 164))
304578	30880007	Here we employed a computational approach to uncover mechanisms underlying cancer mutational burden by focusing upon relationships between 1) translocation breakpoints and the thousands of G4 DNA-forming sequences within retrotransposons impacting transcription and exemplifying probable non-B DNA structures and 2) transcriptome profiling and cancer mutations.	('cancer', 'Disease', (344, 350))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('transcription', 'MPA', (248, 261))	('cancer', 'Disease', (75, 81))	('cancer', 'Disease', 'MESH:D009369', (344, 350))	('sequences', 'Var', (204, 213))	('cancer', 'Phenotype', 'HP:0002664', (344, 350))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('transposons', 'Species', '2387', (226, 237))	('impacting', 'Reg', (238, 247))
304580	30880007	By analyzing >97,000 unique translocation breakpoints from the Catalogue Of Somatic Mutations In Cancer (COSMIC), we found that breakpoints are overrepresented at G4 DNA-forming sequences within hominid-specific SVA retrotransposons, and generally occur in tumors with mutations in tumor suppressor genes, such as TP53.	('Cancer', 'Disease', 'MESH:D009369', (97, 103))	('tumor', 'Phenotype', 'HP:0002664', (282, 287))	('tumor', 'Disease', (257, 262))	('Mutations', 'Var', (84, 93))	('mutations', 'Var', (269, 278))	('occur', 'Reg', (248, 253))	('tumors', 'Disease', (257, 263))	('tumors', 'Disease', 'MESH:D009369', (257, 263))	('tumor', 'Disease', (282, 287))	('TP53', 'Gene', '7157', (314, 318))	('tumors', 'Phenotype', 'HP:0002664', (257, 263))	('transposons', 'Species', '2387', (221, 232))	('TP53', 'Gene', (314, 318))	('tumor', 'Disease', 'MESH:D009369', (257, 262))	('Cancer', 'Phenotype', 'HP:0002664', (97, 103))	('Cancer', 'Disease', (97, 103))	('tumor', 'Phenotype', 'HP:0002664', (257, 262))	('tumor', 'Disease', 'MESH:D009369', (282, 287))
304583	30880007	Thus, correlation analyses of DNA structure and gene expression with mutation loads complement and extend more traditional approaches to elucidate processes shaping genomic instability in cancer.	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('mutation loads', 'Var', (69, 83))	('cancer', 'Disease', (188, 194))
304585	30880007	Genomic instability, increased proliferation and escape from apoptosis are hallmarks of cancer.	('increased', 'PosReg', (21, 30))	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('proliferation', 'CPA', (31, 44))	('escape', 'CPA', (49, 55))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('Genomic', 'Var', (0, 7))
304586	30880007	A recent survey of >11000 tumor samples identified ~300 genes (cancer-driver genes) whose somatic mutations in terms of base substitutions are directly linked to malignancy.	('malignancy', 'Disease', 'MESH:D009369', (162, 172))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('linked', 'Reg', (152, 158))	('base substitutions', 'Var', (120, 138))	('malignancy', 'Disease', (162, 172))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('cancer', 'Disease', (63, 69))
304587	30880007	Another ~1100 genes may support tumorigenesis through alterations in their expression profiles as a consequence of copy-number alterations, gene fusions, and other types of genomic rearrangements.	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('expression profiles', 'MPA', (75, 94))	('alterations', 'Reg', (54, 65))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumor', 'Disease', (32, 37))	('copy-number alterations', 'Var', (115, 138))	('support', 'PosReg', (24, 31))
304591	30880007	Such genomic alterations are seen not only in adult but also in pediatric tumors, implicating DNA mutations and epigenetic changes in steering a normal cell into a malignant phenotype.	('epigenetic changes', 'Var', (112, 130))	('DNA', 'Gene', (94, 97))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('mutations', 'Var', (98, 107))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('tumors', 'Disease', 'MESH:D009369', (74, 80))	('steering', 'PosReg', (134, 142))	('tumors', 'Disease', (74, 80))
304592	30880007	Somatic mutations in driver genes are often instigated by predisposing germline variants, such as in BRCA1 and BRCA2, and impinge on 8 major cellular processes, with alterations in genes involved in maintaining genome integrity, such as the Fanconi anemia pathway, and in 10 signaling pathways (RTK/RAS, Nrf2, PI3K, TGFbeta, Wnt, Myc, TP53, cell cycle, Hippo, Notch) as being among the most commonly altered.	('alterations', 'Reg', (166, 177))	('TGFbeta', 'Gene', (316, 323))	('Fanconi anemia', 'Phenotype', 'HP:0001994', (241, 255))	('impinge', 'Reg', (122, 129))	('TP53', 'Gene', '7157', (335, 339))	('BRCA2', 'Gene', (111, 116))	('TGFbeta', 'Gene', '7039', (316, 323))	('Nrf2', 'Gene', (304, 308))	('Myc', 'Gene', (330, 333))	('mutations', 'Var', (8, 17))	('cell cycle', 'CPA', (341, 351))	('BRCA2', 'Gene', '675', (111, 116))	('signaling pathways', 'Pathway', (275, 293))	('variants', 'Var', (80, 88))	('Fanconi anemia', 'Disease', (241, 255))	('anemia', 'Phenotype', 'HP:0001903', (249, 255))	('TP53', 'Gene', (335, 339))	('BRCA1', 'Gene', '672', (101, 106))	('Fanconi anemia', 'Disease', 'MESH:D005199', (241, 255))	('Myc', 'Gene', '4609', (330, 333))	('altered', 'Reg', (400, 407))	('BRCA1', 'Gene', (101, 106))	('Nrf2', 'Gene', '4780', (304, 308))
304594	30880007	By extracting patterns of base changes in cancer genomes, ~30 distinct signatures have been catalogued, which inform on molecular processes likely to lead to mutations from either extrinsic (ultraviolet light, smoking, chemicals) or intrinsic (APOBEC misediting, DNA repair deficiencies, defective polymerase epsilon) sources.	('mutations', 'Var', (158, 167))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))
304595	30880007	Patterns of base substitutions have also been associated with direct damage to DNA bases by oxidants, such as reactive oxygen and nitrogen species (ROS and RNS respectively), which rise in tumor cells following glucose deprivation, deregulation of the mitochondrial electron transport chain and other organelles (endoplasmic reticulum, lysosomes and peroxisomes).	('rise', 'PosReg', (181, 185))	('tumor', 'Disease', (189, 194))	('base substitutions', 'Var', (12, 30))	('deregulation', 'Reg', (232, 244))	('glucose', 'Chemical', 'MESH:D005947', (211, 218))	('nitrogen', 'Chemical', 'MESH:D009584', (130, 138))	('RNS', 'Chemical', 'MESH:D011886', (156, 159))	('mitochondrial', 'Enzyme', (252, 265))	('ROS', 'Chemical', 'MESH:D017382', (148, 151))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))
304596	30880007	This sustained proliferation contributes to a condition referred to as "replication stress", a potent inducer of genomic instability triggered by a buildup of ssDNA from RPA depletion, the accumulation of secondary DNA structures, R-loops, collisions between replication and transcription, and other factors.	('RPA', 'Gene', '6117', (170, 173))	('collisions', 'Var', (240, 250))	('R-loops', 'Var', (231, 238))	('accumulation', 'PosReg', (189, 201))	('stress', 'Disease', 'MESH:D000079225', (84, 90))	('RPA', 'Gene', (170, 173))	('secondary DNA structures', 'Protein', (205, 229))	('stress', 'Disease', (84, 90))	('genomic', 'MPA', (113, 120))
304601	30880007	Tumor samples with translocation breakpoints at G4 DNA-forming sequences are also more likely to carry mutations in TP53 and less likely to harbor pathologic mutations in KRAS and CTNNB1, supporting a role for TP53 mutations in G4 DNA-induced instability.	('TP53', 'Gene', (116, 120))	('mutations', 'Var', (103, 112))	('CTNNB1', 'Gene', '1499', (180, 186))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('TP53', 'Gene', (210, 214))	('G4 DNA-forming', 'Var', (48, 62))	('CTNNB1', 'Gene', (180, 186))	('KRAS', 'Gene', (171, 175))	('TP53', 'Gene', '7157', (116, 120))	('KRAS', 'Gene', '3845', (171, 175))	('TP53', 'Gene', '7157', (210, 214))
304604	30880007	Thus, correlation analyses of G4 DNA structure and gene expression with mutation loads complement and extend more traditional approaches to elucidate sources of genomic instability in cancer.	('cancer', 'Disease', (184, 190))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('mutation loads', 'Var', (72, 86))
304621	30880007	single base substitutions and small insertion/deletions in exons genome-wide specific to the tumor but not the matched normal samples.	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Disease', (93, 98))	('insertion/deletions', 'Var', (36, 55))	('single base substitutions', 'Var', (0, 25))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
304635	30880007	In conclusion, our analysis shows that translocation breakpoints in cancer occur at G4 DNA-forming repeats more often than expected by chance alone.	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('translocation breakpoints', 'Var', (39, 64))	('cancer', 'Disease', (68, 74))
304637	30880007	First, we assessed the genome-wide load of translocations in each patient; we found that the group of patients with G4-associated breakpoints carried more translocations than the group of patients without G4-associated breakpoints (57.9 +- 59.7 vs. 17.3 +- 20.7; Fig.	('G4-associated', 'Var', (116, 129))	('breakpoints', 'Var', (130, 141))	('patient', 'Species', '9606', (188, 195))	('patient', 'Species', '9606', (102, 109))	('patients', 'Species', '9606', (102, 110))	('patient', 'Species', '9606', (66, 73))	('patients', 'Species', '9606', (188, 196))	('translocations', 'MPA', (155, 169))
304638	30880007	Second, even though tumor samples with and without G4-associated breakpoints carried pathologic mutations in cancer-related genes, such as TP53, KRAS, PIK3CA, etc.	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('pathologic', 'Reg', (85, 95))	('KRAS', 'Gene', (145, 149))	('PIK3CA', 'Gene', (151, 157))	('cancer', 'Disease', (109, 115))	('TP53', 'Gene', '7157', (139, 143))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('KRAS', 'Gene', '3845', (145, 149))	('PIK3CA', 'Gene', '5290', (151, 157))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('TP53', 'Gene', (139, 143))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('tumor', 'Disease', (20, 25))	('mutations', 'Var', (96, 105))
304639	30880007	(Figs 2C and D), samples with G4-containing breakpoints displayed a greater frequency of mutations at TP53, PTPRD and GATA3 than the alternate group.	('TP53', 'Gene', (102, 106))	('GATA3', 'Gene', (118, 123))	('PTPRD', 'Gene', '5789', (108, 113))	('PTPRD', 'Gene', (108, 113))	('mutations', 'Var', (89, 98))	('GATA3', 'Gene', '2625', (118, 123))	('TP53', 'Gene', '7157', (102, 106))	('G4-containing', 'Var', (30, 43))
304640	30880007	By contrast, the likelihood of harboring pathologic mutations at KRAS and CTNNB1 was significantly reduced (Fig.	('mutations', 'Var', (52, 61))	('CTNNB1', 'Gene', (74, 80))	('KRAS', 'Gene', '3845', (65, 69))	('CTNNB1', 'Gene', '1499', (74, 80))	('reduced', 'NegReg', (99, 106))	('KRAS', 'Gene', (65, 69))
304641	30880007	3E), in accordance with the expectation that mutations in the TP53, RTK/RAS and Wnt pathways are mutually exclusive.	('RTK/RAS', 'Pathway', (68, 75))	('mutations', 'Var', (45, 54))	('TP53', 'Gene', '7157', (62, 66))	('TP53', 'Gene', (62, 66))	('Wnt pathways', 'Pathway', (80, 92))
304642	30880007	We conclude that strand breaks at or near G4 DNA-forming sequences occur generally in tumors with high genetic instability, which is promoted in part by mutations in tumor suppressor genes, such as TP53.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('mutations', 'Var', (153, 162))	('tumor', 'Disease', (86, 91))	('strand', 'Var', (17, 23))	('tumors', 'Disease', (86, 92))	('tumor', 'Disease', (166, 171))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('TP53', 'Gene', '7157', (198, 202))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('TP53', 'Gene', (198, 202))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
304651	30880007	In conclusion, translocation breakpoints are more likely to be found at G4 DNA located in SVA elements than in L1 transposons; furthermore, it is possible that a subset of SVA elements in the human genome might be particularly unstable, yielding recurrent strand breaks in cancer.	('cancer', 'Disease', (273, 279))	('human', 'Species', '9606', (192, 197))	('transposons', 'Species', '2387', (114, 125))	('cancer', 'Disease', 'MESH:D009369', (273, 279))	('yielding', 'Reg', (237, 245))	('cancer', 'Phenotype', 'HP:0002664', (273, 279))	('SVA', 'Gene', (172, 175))	('elements', 'Var', (176, 184))	('strand breaks', 'MPA', (256, 269))	('recurrent strand breaks', 'Phenotype', 'HP:0040012', (246, 269))
304652	30880007	Recognizing that G4 DNA likely impacts transcription, we employed a separate set of analyses to assess the extent to which the cellular transcriptome and its regulation are associated with mutation loads in cancer genomes.	('cancer', 'Disease', 'MESH:D009369', (207, 213))	('cancer', 'Disease', (207, 213))	('G4 DNA', 'Var', (17, 23))	('mutation loads', 'Var', (189, 203))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('associated', 'Reg', (173, 183))	('impacts', 'Reg', (31, 38))	('transcription', 'MPA', (39, 52))
304654	30880007	Thus, an S-plot of all P-values allowed for a direct comparison across all tumors, which revealed a strong variability on tissue-dependent origin in the extent to which gene expression correlates with mutation loads.	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('gene expression', 'MPA', (169, 184))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('mutation', 'Var', (201, 209))	('tumors', 'Disease', (75, 81))
304662	30880007	Of the 10 top genes most negatively correlated with mutation loads, the strongest association was found for MLH1 in ESCA (Fig.	('ESCA', 'Disease', (116, 120))	('MLH1', 'Gene', '4292', (108, 112))	('MLH1', 'Gene', (108, 112))	('mutation', 'Var', (52, 60))
304663	30880007	Mutations in MLH1 or its low expression are known for their role in tumorigenesis, however none of the other 9 genes were listed in the COSMIC cancer gene census.	('tumor', 'Disease', (68, 73))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('MLH1', 'Gene', (13, 17))	('MLH1', 'Gene', '4292', (13, 17))	('Mutations', 'Var', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('expression', 'MPA', (29, 39))
304666	30880007	In summary, the top genes most strongly correlated with mutations loads reveal strong associations between deregulation of gene expression and poor survival in cancer.	('mutations', 'Var', (56, 65))	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('poor survival', 'CPA', (143, 156))	('cancer', 'Disease', (160, 166))	('deregulation', 'Var', (107, 119))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))
304667	30880007	To further explore the involvement of the top genes correlated with mutations in tumorigenesis, we focused on two genes: MYBL2 for the positive correlations and SDHAF3 for the negative correlations.	('MYBL2', 'Gene', '4605', (121, 126))	('SDHAF3', 'Gene', '57001', (161, 167))	('MYBL2', 'Gene', (121, 126))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('mutations', 'Var', (68, 77))	('SDHAF3', 'Gene', (161, 167))	('tumor', 'Disease', (81, 86))
304673	30880007	Poor prognosis was associated with high MYBL2 expression in 11/32 tumors (Fig.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumors', 'Disease', (66, 72))	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('MYBL2', 'Gene', '4605', (40, 45))	('expression', 'MPA', (46, 56))	('MYBL2', 'Gene', (40, 45))	('high', 'Var', (35, 39))
304681	30880007	In PRAD, where SDHAF3 displayed the strongest negative correlation between expression and mutation of all tumors, the gene was overexpressed relative to matched controls (not shown); however, SDHD was strongly downregulated.	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('SDHAF3', 'Gene', '57001', (15, 21))	('overexpressed', 'PosReg', (127, 140))	('tumors', 'Disease', (106, 112))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('PRAD', 'Disease', (3, 7))	('SDHAF3', 'Gene', (15, 21))	('SDHD', 'Gene', (192, 196))	('SDHD', 'Gene', '6392', (192, 196))	('downregulated', 'NegReg', (210, 223))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('negative', 'NegReg', (46, 54))	('mutation', 'Var', (90, 98))	('expression', 'MPA', (75, 85))
304685	30880007	Having established the validity of our analyses in uncovering genes whose deregulation seem to predict poor clinical outcome, we then conducted a systematic assessment of gene enrichment for a pool of genes with strong correlations in each tumor type.	('deregulation', 'Var', (74, 86))	('tumor', 'Disease', (240, 245))	('tumor', 'Phenotype', 'HP:0002664', (240, 245))	('tumor', 'Disease', 'MESH:D009369', (240, 245))
304692	30880007	We also conducted the gene enrichment analysis for the 270 genes (in each tumor type), whose expression was most negatively correlated with mutations, but did not find any enriched term.	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('expression', 'MPA', (93, 103))	('tumor', 'Disease', (74, 79))	('mutations', 'Var', (140, 149))	('negatively', 'NegReg', (113, 123))
304694	30880007	Therefore, our correlation analysis of gene expression versus mutation loads identified pathways that are commonly altered in different types of cancer.	('cancer', 'Disease', (145, 151))	('pathways', 'Pathway', (88, 96))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('mutation', 'Var', (62, 70))	('cancer', 'Disease', 'MESH:D009369', (145, 151))
304695	30880007	In LUAD, although not in KICH and PRAD, the main pathways for the repair of base mismatch and base lesions, i.e.	('KICH', 'Disease', 'None', (25, 29))	('base mismatch', 'Var', (76, 89))	('KICH', 'Disease', (25, 29))
304697	30880007	In addition, ALKBH3 (R = -0.22, P = 4.0x10-7) for alkylation damage reversal, RRM2B (R = -0.24, P = 2.7 x 10-8), which supplies dNTPs during DNA repair synthesis, POLK (R = -0.22, P = 3.9 x 10-7) for translesion DNA synthesis and UBE2B (R = -0.22, P = 4.9 x 10-7), involved in ubiquitination of PCNA also displayed negative correlations with mutational loads (Fig.	('RRM2B', 'Gene', (78, 83))	('ALKBH3', 'Gene', (13, 19))	('ALKBH3', 'Gene', '221120', (13, 19))	('PCNA', 'Gene', (295, 299))	('negative', 'NegReg', (315, 323))	('UBE2B', 'Gene', '7320', (230, 235))	('RRM2B', 'Gene', '50484', (78, 83))	('mutational', 'Var', (342, 352))	('PCNA', 'Gene', '5111', (295, 299))	('POLK', 'Gene', (163, 167))	('POLK', 'Gene', '51426', (163, 167))	('UBE2B', 'Gene', (230, 235))
304700	30880007	Translocation breakpoints were enriched at sequences with the potential to form G4 DNA structures in tumor samples that were characterized by elevated genetic instability and frequent mutations in tumor suppressor genes, such as TP53.	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('mutations', 'Var', (184, 193))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('TP53', 'Gene', '7157', (229, 233))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('TP53', 'Gene', (229, 233))	('tumor', 'Disease', (197, 202))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
304704	30880007	Genes whose expression is positively correlated with mutations were enriched in selected KEGG terms in more than one cancer type, which provides a platform for addressing the contribution of specific pathways to somatic mutation in cancer.	('cancer', 'Disease', 'MESH:D009369', (232, 238))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('cancer', 'Disease', (117, 123))	('cancer', 'Disease', (232, 238))	('mutations', 'Var', (53, 62))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('expression', 'MPA', (12, 22))
304707	30880007	Nevertheless, our estimates are in line with determinations of mutations at non-B DNA-forming motifs in cancer genomes and strengthens the concept, both from genome-wide and targeted studies, that non-B DNA structures contribute to mutagenesis, both in cancer and in genetic disease.	('mutations', 'Var', (63, 72))	('genetic disease', 'Disease', (267, 282))	('non-B DNA', 'Var', (197, 206))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('contribute', 'Reg', (218, 228))	('cancer', 'Phenotype', 'HP:0002664', (253, 259))	('cancer', 'Disease', 'MESH:D009369', (253, 259))	('cancer', 'Disease', (253, 259))	('mutagenesis', 'MPA', (232, 243))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('genetic disease', 'Disease', 'MESH:D030342', (267, 282))
304708	30880007	The prevalence of G4-associated translocation breakpoints with tumor samples carrying extensive genomic alterations is consistent with reports that TP53 mutant tumors are associated with high rates of genomic instability (reviewed in).	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('tumor', 'Disease', (63, 68))	('translocation breakpoints', 'Var', (32, 57))	('TP53', 'Gene', '7157', (148, 152))	('TP53', 'Gene', (148, 152))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('mutant', 'Var', (153, 159))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumors', 'Disease', (160, 166))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('G4-associated', 'Gene', (18, 31))	('tumor', 'Disease', (160, 165))	('genomic instability', 'MPA', (201, 220))	('tumors', 'Disease', 'MESH:D009369', (160, 166))
304709	30880007	TP53 mutants have been reported to sequester DNA repair factors, such as MRE11, away from double-strand breaks and at stalled replication forks, leading to an accumulation of translocations.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('MRE11', 'Gene', '4361', (73, 78))	('accumulation', 'PosReg', (159, 171))	('MRE11', 'Gene', (73, 78))	('translocations', 'MPA', (175, 189))	('mutants', 'Var', (5, 12))
304711	30880007	Changes in gene expression, which we show here are extensive and impact cancer mutagenesis, are also likely to influence G4 DNA structure-induced genetic instability.	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('Changes', 'Var', (0, 7))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('impact', 'Reg', (65, 71))	('influence', 'Reg', (111, 120))	('cancer', 'Disease', (72, 78))
304712	30880007	We are also learning how replication and repair proteins, such as FEN1, can act in trans to greatly impact mutations so molecular mechanisms are expected to be key to improve predictions.	('impact', 'Reg', (100, 106))	('FEN1', 'Gene', (66, 70))	('FEN1', 'Gene', '2237', (66, 70))	('mutations', 'Var', (107, 116))
304716	30880007	Hence, our findings expand the repertoire of genomic alterations attributed to SVA elements, which has included germline rearrangements and chromosomal breakages leading to chromothripsis.	('chromosomal break', 'Phenotype', 'HP:0040012', (140, 157))	('chromosomal breakages', 'Phenotype', 'HP:0040012', (140, 161))	('chromothripsis', 'Disease', (173, 187))	('chromothripsis', 'Disease', 'MESH:D000072837', (173, 187))	('chromosomal breakages', 'Var', (140, 161))	('leading to', 'Reg', (162, 172))
304719	30880007	MLH1 mediates protein-protein interactions during mismatch recognition, strand discrimination, and strand removal.	('protein-protein', 'Protein', (14, 29))	('MLH1', 'Gene', '4292', (0, 4))	('strand discrimination', 'Var', (72, 93))	('mediates', 'Reg', (5, 13))	('MLH1', 'Gene', (0, 4))	('mismatch recognition', 'Var', (50, 70))
304720	30880007	In colon and rectal cancers hypermutation has been linked in part to MLH1 hypermethylation, and in esophageal squamous cell carcinoma MLH1 promoter methylation correlates with weak expression and poor survival.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('expression', 'MPA', (181, 191))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (110, 133))	('linked', 'Reg', (51, 57))	('esophageal squamous cell carcinoma', 'Disease', (99, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('weak', 'NegReg', (176, 180))	('MLH1', 'Gene', '4292', (134, 138))	('MLH1', 'Gene', (134, 138))	('MLH1', 'Gene', '4292', (69, 73))	('hypermethylation', 'Var', (74, 90))	('MLH1', 'Gene', (69, 73))	('cancers', 'Phenotype', 'HP:0002664', (20, 27))	('hypermutation', 'Var', (28, 41))	('colon and rectal cancers', 'Disease', 'MESH:D015179', (3, 27))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (99, 133))
304725	30880007	The polymeric immunoglobulin receptor (the PIGR gene product) pIgR plays an important role in protecting small airways of the lung from airborne antigens and microorganisms; PIGR-/- mice develop chronic obstructive pulmonary disease (COMP)-like pathology with age and persistent activation of innate immune response to the lung microbiome.	('chronic obstructive pulmonary disease', 'Disease', (195, 232))	('pIgR', 'Gene', (62, 66))	('chronic obstructive pulmonary disease', 'Disease', 'MESH:D029424', (195, 232))	('mice', 'Species', '10090', (182, 186))	('PIGR-/-', 'Var', (174, 181))	('obstructive pulmonary disease', 'Phenotype', 'HP:0006536', (203, 232))	('pIgR', 'Gene', '18703', (62, 66))	('develop', 'Reg', (187, 194))	('chronic obstructive pulmonary disease', 'Phenotype', 'HP:0006510', (195, 232))
304726	30880007	Loss of PIGR is an early event in lung tumorigenesis, and it is plausible that the association of low PIGR with high mutation rates we observe reflects a role for the ensuing inflammation in mutagenesis, in part through the release of ROS and reactive nitrogen intermediates.	('nitrogen', 'Chemical', 'MESH:D009584', (252, 260))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('low', 'NegReg', (98, 101))	('PIGR', 'Gene', (8, 12))	('ROS', 'MPA', (235, 238))	('reactive nitrogen intermediates', 'MPA', (243, 274))	('PIGR', 'Gene', (102, 106))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumor', 'Disease', (39, 44))	('inflammation', 'Disease', 'MESH:D007249', (175, 187))	('inflammation', 'Disease', (175, 187))	('Loss', 'Var', (0, 4))	('release', 'MPA', (224, 231))	('ROS', 'Chemical', 'MESH:D017382', (235, 238))
304734	30880007	A causal association between MYBL2 expression and mutation loads has recently been reported, and involves transactivation of the APOBEC3B gene whose product (apolipoprotein B mRNA cytosine deaminase, A3B) generates ectopic C>U>T transitions and genomic hypermutation when overproduced.	('APOBEC3B', 'Gene', (129, 137))	('genomic hypermutation', 'CPA', (245, 266))	('apolipoprotein B', 'Gene', (158, 174))	('APOBEC3B', 'Gene', '9582', (129, 137))	('MYBL2', 'Gene', '4605', (29, 34))	('apolipoprotein B', 'Gene', '338', (158, 174))	('A3B', 'Gene', '9582', (200, 203))	('ectopic C', 'MPA', (215, 224))	('MYBL2', 'Gene', (29, 34))	('mutation', 'Var', (50, 58))	('A3B', 'Gene', (200, 203))
304735	30880007	The strong correlation of the SDH accessory factor SDHAF3 with mutations was of particular interest since a germline c.157T>C (p.Phe53Leu) substitution in this gene was recently associated with increased prevalence of familiar and sporadic pheochromocytoma and paraganglioma, which are characteristic of SDH-deficiency.	('SDHAF3', 'Gene', (51, 57))	('associated with', 'Reg', (178, 193))	('SDH', 'Gene', (51, 54))	('c.157T>C', 'Mutation', 'rs62624461', (117, 125))	('sporadic pheochromocytoma and paraganglioma', 'Disease', 'MESH:D010673', (231, 274))	('SDH', 'Gene', (304, 307))	('c.157T>C', 'Var', (117, 125))	('paraganglioma', 'Phenotype', 'HP:0002668', (261, 274))	('p.Phe53Leu', 'Mutation', 'rs62624461', (127, 137))	('familiar', 'Disease', (218, 226))	('glioma', 'Phenotype', 'HP:0009733', (268, 274))	('SDH', 'Gene', '6390', (30, 33))	('SDH-deficiency', 'Disease', 'MESH:D007153', (304, 318))	('SDH-deficiency', 'Disease', (304, 318))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (240, 256))	('SDH', 'Gene', '6390', (51, 54))	('SDH', 'Gene', (30, 33))	('SDH', 'Gene', '6390', (304, 307))	('SDHAF3', 'Gene', '57001', (51, 57))
304737	30880007	The fundamental importance of Fe-S clusters and control of superoxide support the observed connections of the SDHB subunit with mutational load.	('SDHB', 'Gene', (110, 114))	('superoxide', 'Chemical', 'MESH:D013481', (59, 69))	('Fe-S', 'Chemical', 'MESH:D007501', (30, 34))	('mutational load', 'Var', (128, 143))	('SDHB', 'Gene', '6390', (110, 114))	('connections', 'Interaction', (91, 102))
304740	30880007	Thus, anticorrelation between SDHAF3 expression and mutations may stem from SDH deficiency.	('stem from', 'Reg', (66, 75))	('mutations', 'Var', (52, 61))	('SDH deficiency', 'Disease', 'MESH:D007153', (76, 90))	('SDHAF3', 'Gene', '57001', (30, 36))	('SDHAF3', 'Gene', (30, 36))	('expression', 'MPA', (37, 47))	('SDH deficiency', 'Disease', (76, 90))
304742	30880007	The clustering encompassing KICH, LUAD, PRAD and LGG is centered on cell cycle, DNA replication and DNA repair genes, and the positive correlations with mutations likely arise from replication stress, excessive DNA damage (such as A3B activation) and its escape from repair.	('A3B', 'Gene', (231, 234))	('DNA', 'MPA', (211, 214))	('mutations', 'Var', (153, 162))	('KICH', 'Disease', (28, 32))	('stress', 'Disease', 'MESH:D000079225', (193, 199))	('A3B', 'Gene', '9582', (231, 234))	('stress', 'Disease', (193, 199))	('KICH', 'Disease', 'None', (28, 32))	('arise from', 'Reg', (170, 180))
304744	30880007	Thus, we propose that the association of mitochondrial gene expression with mutations likely stems from direct damage to DNA by increased ROS and other oxidants.	('ROS', 'MPA', (138, 141))	('mutations', 'Var', (76, 85))	('mitochondrial gene', 'Gene', (41, 59))	('increased', 'PosReg', (128, 137))	('ROS', 'Chemical', 'MESH:D017382', (138, 141))
304747	30880007	The ectopic expression and upregulation of olfactory receptors in melanoma (SKCM) is a potential source of malignant transformation, and it will be useful to assess their role in mutagenesis.	('melanoma', 'Disease', 'MESH:D008545', (66, 74))	('melanoma', 'Phenotype', 'HP:0002861', (66, 74))	('melanoma', 'Disease', (66, 74))	('olfactory receptors', 'Protein', (43, 62))	('upregulation', 'PosReg', (27, 39))	('ectopic expression', 'Var', (4, 22))
304751	30880007	We sought to computationally examine the impact of non-B DNA structure typified by G4 DNA sequences, which likely impact transcription and replication, and of transcription directly in genome instability and cancer.	('impact', 'Reg', (114, 120))	('cancer', 'Disease', (208, 214))	('transcription', 'MPA', (121, 134))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('cancer', 'Disease', 'MESH:D009369', (208, 214))	('DNA sequences', 'Var', (86, 99))	('replication', 'CPA', (139, 150))
304752	30880007	We found that G4 DNA-forming sequences are enriched twofold at translocation breakpoints, strengthening the view that G4 DNA structures contribute to genomic instability in cancer; many such structures are likely to originate from L1 and SVA retrotransposons and contribute to instability.	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('cancer', 'Disease', (173, 179))	('genomic instability', 'MPA', (150, 169))	('contribute', 'Reg', (136, 146))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('transposons', 'Species', '2387', (247, 258))	('G4 DNA', 'Var', (118, 124))
304753	30880007	Mutations in TP53 increase the chance of G4 DNA-induced translocations, possibly through defects in homologous recombination following replication fork stalling at G4 DNA.	('TP53', 'Gene', (13, 17))	('homologous', 'MPA', (100, 110))	('defects', 'NegReg', (89, 96))	('Mutations', 'Var', (0, 9))	('translocations', 'MPA', (56, 70))	('TP53', 'Gene', '7157', (13, 17))
304755	30880007	Transcriptome analyses identify two distinct branches though which alterations in gene expression may lead to an accumulation of single base substitutions in cancer: 1) activation of cell cycle/DNA repair; and 2) loss of homeostatic control of mitochondrial respiration.	('homeostatic control of mitochondrial respiration', 'MPA', (221, 269))	('cell cycle/DNA repair', 'CPA', (183, 204))	('activation', 'PosReg', (169, 179))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('alterations', 'Var', (67, 78))	('cancer', 'Disease', (158, 164))	('single base substitutions', 'Var', (129, 154))	('loss', 'NegReg', (213, 217))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
304758	30880007	Tumor-specific alterations in gene expression associated with mutation loads also include the ectopic expression of olfactory receptor genes in skin cancer, exacerbation of the ER unfolded protein response in breast cancer and altered HLA gene expression in cervical cancer.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('cancer', 'Disease', 'MESH:D009369', (267, 273))	('alterations', 'Reg', (15, 26))	('ER unfolded protein response', 'MPA', (177, 205))	('HLA', 'Protein', (235, 238))	('cancer', 'Disease', (216, 222))	('gene expression', 'MPA', (30, 45))	('skin cancer', 'Disease', (144, 155))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('mutation loads', 'Var', (62, 76))	('cancer', 'Disease', (149, 155))	('skin cancer', 'Phenotype', 'HP:0008069', (144, 155))	('cancer', 'Disease', (267, 273))	('breast cancer', 'Phenotype', 'HP:0003002', (209, 222))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('cancer', 'Phenotype', 'HP:0002664', (267, 273))	('cancer', 'Disease', 'MESH:D009369', (216, 222))	('ectopic expression', 'MPA', (94, 112))	('olfactory receptor genes', 'Gene', (116, 140))	('breast cancer', 'Disease', 'MESH:D001943', (209, 222))	('altered', 'Reg', (227, 234))	('breast cancer', 'Disease', (209, 222))	('skin cancer', 'Disease', 'MESH:D012878', (144, 155))	('exacerbation', 'PosReg', (157, 169))	('cancer', 'Disease', 'MESH:D009369', (149, 155))
304760	30880007	The second is to clarify how deregulation of the mitochondrial respiratory chain and its link to the TCA cycle through the SDH complex elicits mutations.	('SDH', 'Gene', (123, 126))	('deregulation', 'MPA', (29, 41))	('mitochondrial respiratory chain', 'Enzyme', (49, 80))	('elicits', 'Reg', (135, 142))	('TCA', 'Chemical', 'MESH:D014233', (101, 104))	('SDH', 'Gene', '6390', (123, 126))	('mutations', 'Var', (143, 152))
304769	31167586	LYM% and RDW were confirmed to be independent predictors of lung cancer risk.	('lung cancer', 'Disease', (60, 71))	('lung cancer', 'Phenotype', 'HP:0100526', (60, 71))	('RDW', 'Var', (9, 12))	('LYM%', 'Var', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('lung cancer', 'Disease', 'MESH:D008175', (60, 71))
304771	31167586	A high risk of lung cancer was closely correlated with low LYM% and high RDW.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('lung cancer', 'Disease', 'MESH:D008175', (15, 26))	('high RDW', 'Var', (68, 76))	('low LYM%', 'Var', (55, 63))	('lung cancer', 'Disease', (15, 26))	('lung cancer', 'Phenotype', 'HP:0100526', (15, 26))
304787	31167586	Elevated RDW was shown to contribute to cancer progression and prognosis in relation to breast, lung, esophageal, and gastrointestinal tract cancers.	('esophageal', 'Disease', (102, 112))	('lung', 'Disease', (96, 100))	('contribute', 'Reg', (26, 36))	('gastrointestinal tract cancers', 'Disease', (118, 148))	('Elevated', 'Var', (0, 8))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('cancer', 'Disease', (40, 46))	('breast', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('cancers', 'Phenotype', 'HP:0002664', (141, 148))	('RDW', 'MPA', (9, 12))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('cancer', 'Disease', (141, 147))	('gastrointestinal tract cancers', 'Disease', 'MESH:D004067', (118, 148))
304807	31167586	Albumin, RBC count, hemoglobin, and LYM were all significantly lower in the patients compared with the controls (all P < 0.05), while WBC, MON, CEA, CA12-5, CA15-3, and CA19-9 were all significantly higher in patients with lung cancer (all P < 0.001).	('CEA', 'Gene', '1084', (144, 147))	('CA15-3', 'Gene', (157, 163))	('hemoglobin', 'MPA', (20, 30))	('lung cancer', 'Disease', 'MESH:D008175', (223, 234))	('CA12-5', 'Gene', (149, 155))	('lung cancer', 'Phenotype', 'HP:0100526', (223, 234))	('patients', 'Species', '9606', (76, 84))	('lower', 'NegReg', (63, 68))	('LYM', 'MPA', (36, 39))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('patients', 'Species', '9606', (209, 217))	('CEA', 'Gene', (144, 147))	('CA12-5', 'Gene', '94025', (149, 155))	('CA19-9', 'Var', (169, 175))	('lung cancer', 'Disease', (223, 234))	('higher', 'PosReg', (199, 205))	('CA15-3', 'Gene', '4582', (157, 163))	('RBC count', 'MPA', (9, 18))	('Albumin', 'MPA', (0, 7))
304818	31167586	In addition, Spearman's correlation analysis showed a positive association between RDW and LYM, but no correlation between LYM% or RDW and any of the traditional tumor markers.	('RDW', 'Var', (83, 86))	('positive', 'PosReg', (54, 62))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('tumor', 'Disease', (162, 167))	('LYM', 'Disease', (91, 94))	('tumor', 'Disease', 'MESH:D009369', (162, 167))
304822	31167586	The current logistic regression analysis identified LYM% and RDW as independent predictors of lung cancer risk.	('lung cancer', 'Disease', 'MESH:D008175', (94, 105))	('lung cancer', 'Disease', (94, 105))	('lung cancer', 'Phenotype', 'HP:0100526', (94, 105))	('LYM%', 'Var', (52, 56))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
304848	28627030	Targeting relationship was verified by luciferase reporting assay, and miR-375 could effectively suppress SLC7A11 level in OSCC cells.	('miR-375', 'Var', (71, 78))	('suppress', 'NegReg', (97, 105))	('SLC7A11 level', 'MPA', (106, 119))	('OSCC', 'Chemical', '-', (123, 127))
304861	28627030	For instance, high miR-21 expression was confirmed to be associated with the proliferation and invasion of breast cancer 14.	('expression', 'MPA', (26, 36))	('invasion', 'CPA', (95, 103))	('proliferation', 'CPA', (77, 90))	('associated', 'Reg', (57, 67))	('si', 'Chemical', 'MESH:D012825', (32, 34))	('miR-21', 'Gene', '406991', (19, 25))	('breast cancer', 'Disease', 'MESH:D001943', (107, 120))	('si', 'Chemical', 'MESH:D012825', (99, 101))	('high', 'Var', (14, 18))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('breast cancer', 'Disease', (107, 120))	('breast cancer', 'Phenotype', 'HP:0003002', (107, 120))	('miR-21', 'Gene', (19, 25))
304865	28627030	Moreover, some exploratory researches with respect to the potential role of miR-375 in OSCC have been carried out and these studies revealed a preliminary conclusion that miR-375 may function as a tumor suppressor 1, 18.	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('OSCC', 'Chemical', '-', (87, 91))	('miR-375', 'Var', (171, 178))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('si', 'Chemical', 'MESH:D012825', (161, 163))	('OSCC', 'Disease', (87, 91))	('tumor', 'Disease', (197, 202))
304871	28627030	Apart from the potential relationship between SLC7A11 and ovarian cancer, another study discovered that the expression of SLC7A11 is able to regulate the resistance of cisplatin in patients with tongue squamous cell carcinoma which is another type of oral tumor 19, 28.	('si', 'Chemical', 'MESH:D012825', (114, 116))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('ovarian cancer', 'Disease', 'MESH:D010051', (58, 72))	('patients', 'Species', '9606', (181, 189))	('tongue squamous cell carcinoma', 'Disease', 'MESH:D002294', (195, 225))	('regulate', 'Reg', (141, 149))	('expression', 'Var', (108, 118))	('cisplatin', 'Chemical', 'MESH:D002945', (168, 177))	('ovarian cancer', 'Disease', (58, 72))	('tongue squamous cell carcinoma', 'Disease', (195, 225))	('tumor', 'Disease', (256, 261))	('ovarian cancer', 'Phenotype', 'HP:0100615', (58, 72))	('tumor', 'Disease', 'MESH:D009369', (256, 261))	('oral tumor', 'Phenotype', 'HP:0100649', (251, 261))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (202, 225))	('si', 'Chemical', 'MESH:D012825', (156, 158))	('SLC7A11', 'Gene', (122, 129))	('tongue squamous cell carcinoma', 'Phenotype', 'HP:0030413', (195, 225))	('carcinoma', 'Phenotype', 'HP:0030731', (216, 225))	('resistance of cisplatin', 'MPA', (154, 177))	('tumor', 'Phenotype', 'HP:0002664', (256, 261))
304873	28627030	This study was carried out in order to link both miR-375 and SLC7A11 with OSCC.	('link', 'Interaction', (39, 43))	('OSCC', 'Disease', (74, 78))	('SLC7A11', 'Gene', (61, 68))	('miR-375', 'Var', (49, 56))	('OSCC', 'Chemical', '-', (74, 78))
304892	28627030	PmiRGLO Dual Luciferase miRNA Target Expression Vector (E1330; Promega, Madison, WI) was used to construct the wild type and mutated type of SLC7A11 3'UTR.	('mutated', 'Var', (125, 132))	('si', 'Chemical', 'MESH:D012825', (43, 45))	('SLC7A11', 'Gene', (141, 148))
304893	28627030	MiR-375 mimics or miR-375 NC (50 nmol/L) and wild type or mutated type of SLC7A11 3'UTR vectors (500 ng) were co-transfected into HEK293T cells (ATCC, Manassas, VA) using LipotectamineTM 2000 (Invitrogen) following the manufacturer's instructions.	('HEK293T', 'CellLine', 'CVCL:0063', (130, 137))	('MiR-375', 'Gene', (0, 7))	('MiR-375', 'Gene', '494324', (0, 7))	('si', 'Chemical', 'MESH:D012825', (166, 168))	('miR-375', 'Var', (18, 25))
304923	28627030	MiR-375 increased in mimics group and mix group compared with negative control group while the expression of SLC7A11 increased in SLC7A11 group and decreased in mimics group and si-SLC7A11 group.	('SLC7A11', 'Gene', (109, 116))	('increased', 'PosReg', (117, 126))	('MiR-375', 'Gene', (0, 7))	('si', 'Chemical', 'MESH:D012825', (101, 103))	('MiR-375', 'Gene', '494324', (0, 7))	('decreased', 'NegReg', (148, 157))	('increased', 'PosReg', (8, 17))	('si', 'Chemical', 'MESH:D012825', (178, 180))	('SLC7A11', 'Var', (130, 137))	('expression', 'MPA', (95, 105))
304937	28627030	Collective data demonstrated that miR-375 suppressed OSCC cell proliferation and viability via downregulating SLC7A11 expression.	('si', 'Chemical', 'MESH:D012825', (124, 126))	('viability', 'CPA', (81, 90))	('OSCC', 'Chemical', '-', (53, 57))	('OSCC', 'Disease', (53, 57))	('suppressed', 'NegReg', (42, 52))	('SLC7A11', 'Gene', (110, 117))	('miR-375', 'Var', (34, 41))	('expression', 'MPA', (118, 128))	('downregulating', 'NegReg', (95, 109))
304938	28627030	Transwell assay demonstrated that the number of cells that invaded through matrigel matrix frequently decreased in cells (CAL-27 and Tca8113 cells) transfected with miR-375 mimics or SLC7A11 siRNA but increased in cells transfected with pcDNA3.1-SLC7A11 compared with the corresponding NC groups (P < 0.05; Fig.	('miR-375', 'Gene', (165, 172))	('increased', 'PosReg', (201, 210))	('si', 'Chemical', 'MESH:D012825', (191, 193))	('Tca8113', 'Chemical', '-', (133, 140))	('SLC7A11', 'Var', (183, 190))	('decreased', 'NegReg', (102, 111))
304940	28627030	Cells in the mimics or si-SLC7A11 group presented a smaller closure rate than those in NC1 and NC2 groups, whereas those in SLC7A11 group manifested bigger closure rate.	('smaller', 'NegReg', (52, 59))	('si-SLC7A11', 'Var', (23, 33))	('closure rate', 'CPA', (60, 72))	('si', 'Chemical', 'MESH:D012825', (23, 25))
304943	28627030	To further investigate the role of miR-375/SLC7A11 on OSCC cell mitosis and apoptosis, flow cytometry was used with PI and Annexin V-FITC staining.	('OSCC cell mitosis', 'Disease', 'MESH:C538614', (54, 71))	('Annexin V', 'Gene', (123, 132))	('OSCC cell mitosis', 'Disease', (54, 71))	('si', 'Chemical', 'MESH:D012825', (68, 70))	('Annexin V', 'Gene', '11747', (123, 132))	('si', 'Chemical', 'MESH:D012825', (82, 84))	('miR-375/SLC7A11', 'Var', (35, 50))
304946	28627030	Taken together, we demonstrated that miR-375 induced G1/G0 arrest and accelerated cell apoptosis via downregulating SLC7A11.	('si', 'Chemical', 'MESH:D012825', (93, 95))	('SLC7A11', 'Gene', (116, 123))	('G1/G0 arrest', 'CPA', (53, 65))	('cell apoptosis', 'CPA', (82, 96))	('downregulating', 'NegReg', (101, 115))	('miR-375', 'Var', (37, 44))	('accelerated', 'PosReg', (70, 81))
304950	28627030	Moreover, miR-375 can negatively regulate SLC7A11, suppressing the invasion and proliferation of OSCC cells.	('si', 'Chemical', 'MESH:D012825', (71, 73))	('OSCC', 'Chemical', '-', (97, 101))	('negatively', 'NegReg', (22, 32))	('SLC7A11', 'Gene', (42, 49))	('si', 'Chemical', 'MESH:D012825', (58, 60))	('suppressing', 'NegReg', (51, 62))	('miR-375', 'Var', (10, 17))
304952	28627030	As suggested by the majority of these studies mentioned above, miR-375 was classified as a significant tumor suppressor and increasing evidence supported the role of miR-375 in inflammation and cancers 1, 34, 35.	('si', 'Chemical', 'MESH:D012825', (79, 81))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('cancers', 'Phenotype', 'HP:0002664', (194, 201))	('inflammation and cancers', 'Disease', 'MESH:D007249', (177, 201))	('tumor', 'Disease', (103, 108))	('si', 'Chemical', 'MESH:D012825', (130, 132))	('si', 'Chemical', 'MESH:D012825', (91, 93))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('miR-375', 'Var', (63, 70))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('miR-375', 'Var', (166, 173))
304954	28627030	Though there is a few reports focusing on the relationship between miR-375 and OSCC, indicating that miR-375 may react as a suppressor, it is still essential to obtain further evidence 1, 36, 37, 38.	('miR-375', 'Var', (101, 108))	('si', 'Chemical', 'MESH:D012825', (34, 36))	('OSCC', 'Disease', (79, 83))	('OSCC', 'Chemical', '-', (79, 83))
304957	28627030	Moreover, replenishing of miR-375 decreased both mRNA expression and protein level of SLC7A11 in OSCC cells.	('protein level', 'MPA', (69, 82))	('decreased', 'NegReg', (34, 43))	('miR-375', 'Var', (26, 33))	('OSCC', 'Chemical', '-', (97, 101))	('SLC7A11', 'Gene', (86, 93))	('si', 'Chemical', 'MESH:D012825', (60, 62))	('mRNA expression', 'MPA', (49, 64))
304959	28627030	reported that SLC7A11 may modulate cisplatin (CDDP) resistance and they also concluded that CDDP can elevate the expression of SLC7A11 significantly in TSCC cells (tongue carcinoma cells) which is another type of head and neck tumor 28.	('CDDP', 'Var', (92, 96))	('SLC7A11', 'Gene', (127, 134))	('cisplatin', 'Chemical', 'MESH:D002945', (35, 44))	('CDDP', 'Chemical', 'MESH:D002945', (46, 50))	('TSCC', 'Disease', (152, 156))	('expression', 'MPA', (113, 123))	('si', 'Chemical', 'MESH:D012825', (135, 137))	('tongue carcinoma', 'Disease', (164, 180))	('si', 'Chemical', 'MESH:D012825', (119, 121))	('CDDP', 'Chemical', 'MESH:D002945', (92, 96))	('head and neck tumor', 'Phenotype', 'HP:0012288', (213, 232))	('elevate', 'PosReg', (101, 108))	('neck tumor', 'Disease', (222, 232))	('cisplatin', 'MPA', (35, 44))	('neck tumor', 'Disease', 'MESH:D006258', (222, 232))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))	('si', 'Chemical', 'MESH:D012825', (54, 56))	('modulate', 'Reg', (26, 34))	('carcinoma', 'Phenotype', 'HP:0030731', (171, 180))	('tongue carcinoma', 'Phenotype', 'HP:0030415', (164, 180))	('tongue carcinoma', 'Disease', 'MESH:D014062', (164, 180))
304961	28627030	Results of Western blot indicated that SLC7A11 was upregulated in OSCC cells and silencing of SLC7A11 resulted in an inhibition in the proliferation and invasion of OSCC cells as well as miR-375 mimics.	('invasion', 'CPA', (153, 161))	('SLC7A11', 'Gene', (39, 46))	('inhibition', 'NegReg', (117, 127))	('OSCC', 'Chemical', '-', (165, 169))	('OSCC', 'Chemical', '-', (66, 70))	('si', 'Chemical', 'MESH:D012825', (81, 83))	('proliferation', 'CPA', (135, 148))	('silencing', 'Var', (81, 90))	('si', 'Chemical', 'MESH:D012825', (157, 159))	('SLC7A11', 'Gene', (94, 101))	('upregulated', 'PosReg', (51, 62))
304962	28627030	Therefore, we assumed that miR-375 functions as a tumor-suppressing role in OSCC via downregulating SLC7A11 expression.	('OSCC', 'Disease', (76, 80))	('si', 'Chemical', 'MESH:D012825', (114, 116))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('OSCC', 'Chemical', '-', (76, 80))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('expression', 'MPA', (108, 118))	('SLC7A11', 'Gene', (100, 107))	('downregulating', 'NegReg', (85, 99))	('miR-375', 'Var', (27, 34))	('si', 'Chemical', 'MESH:D012825', (63, 65))	('tumor', 'Disease', (50, 55))
304969	28627030	Replenishing of miR-375 or silencing of SLC7A11 could be therapeutically valuable.	('SLC7A11', 'Gene', (40, 47))	('silencing', 'Var', (27, 36))	('si', 'Chemical', 'MESH:D012825', (27, 29))
305287	27602772	Among 90 tumor regulated genes 95% had consensus binding sites for c-Myc (represented by PWM EBOX_Q6_01) while the combined EBOX_Q6_01 and TFDP1 (represented by PWM E2F_Q4_01) PWMs fitted 58 gene specific promoters or 65% of regulated genes (see Supplementary Table S5).	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('binding', 'Interaction', (49, 56))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumor', 'Disease', (9, 14))	('c-Myc', 'Gene', '4609', (67, 72))	('TFDP1', 'Gene', (139, 144))	('TFDP1', 'Gene', '7027', (139, 144))	('c-Myc', 'Gene', (67, 72))	('EBOX_Q6_01', 'Var', (124, 134))
305297	27602772	Remarkably, the insertion of 2 Kb of the HK1 promoter resulted in high induction of luciferase expression, possibly due to the presence of 3 consecutive repeats of the canonical E-box motives (CACGTG) within this promoter.	('insertion', 'Var', (16, 25))	('luciferase', 'Enzyme', (84, 94))	('CACGTG', 'Gene', (193, 199))	('HK1', 'Gene', '3098', (41, 44))	('HK1', 'Gene', (41, 44))	('induction', 'PosReg', (71, 80))	('expression', 'MPA', (95, 105))
305327	27602772	As shown in panel A high expression of these genes was associated with poor outcome in lung adenocarcinoma (HR 3.11 p < 0.001) but not so in squamous cell carcinoma patients (HR 1.06 p = 0.71).	('carcinoma', 'Phenotype', 'HP:0030731', (155, 164))	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('lung adenocarcinoma', 'Disease', (87, 106))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (141, 164))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (87, 106))	('squamous cell carcinoma', 'Disease', (141, 164))	('expression', 'MPA', (25, 35))	('high', 'Var', (20, 24))	('patients', 'Species', '9606', (165, 173))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (87, 106))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (141, 164))
305332	27602772	Once again, high expression of these master regulators was associated with poor survival in lung adenocarcinoma but not squamous cell carcinoma patients (Figure 8C; HR 3.2 p < 0.001).	('high', 'Var', (12, 16))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (92, 111))	('survival', 'MPA', (80, 88))	('poor', 'NegReg', (75, 79))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (120, 143))	('patients', 'Species', '9606', (144, 152))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (120, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('lung adenocarcinoma', 'Disease', (92, 111))	('squamous cell carcinoma', 'Disease', (120, 143))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (92, 111))
305334	27602772	As shown in Figure 8D their high expression in lung adenocarcinoma patients was associated with better survival (HR 0.52 p < 0.001).	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (47, 66))	('patients', 'Species', '9606', (67, 75))	('better', 'PosReg', (96, 102))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (47, 66))	('carcinoma', 'Phenotype', 'HP:0030731', (57, 66))	('lung adenocarcinoma', 'Disease', (47, 66))	('survival', 'CPA', (103, 111))	('high', 'Var', (28, 32))
305347	27602772	Moreover, high Arg1 gene expression is associated with poor survival in human lung cancer patients (see Supplementary Table S9 and Figure 8).	('lung cancer', 'Disease', (78, 89))	('Arg1', 'Gene', (15, 19))	('lung cancer', 'Phenotype', 'HP:0100526', (78, 89))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('human', 'Species', '9606', (72, 77))	('lung cancer', 'Disease', 'MESH:D008175', (78, 89))	('high', 'Var', (10, 14))	('poor', 'NegReg', (55, 59))	('patients', 'Species', '9606', (90, 98))	('Arg1', 'Gene', '383', (15, 19))
305354	27602772	Furthermore, a recent study demonstrated HK2 to be essential for lung tumor initiation and maintenance; its systemic ablation conferred therapeutic efficacy in mouse models of lung cancer with Hk2 deletion, suppressing glucose-derived ribonucleotide synthesis in lung cancer cells.	('lung cancer', 'Disease', (263, 274))	('HK2', 'Gene', (41, 44))	('mouse', 'Species', '10090', (160, 165))	('glucose', 'Chemical', 'MESH:D005947', (219, 226))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('deletion', 'Var', (197, 205))	('Hk2', 'Gene', (193, 196))	('lung cancer', 'Disease', 'MESH:D008175', (176, 187))	('lung tumor', 'Phenotype', 'HP:0100526', (65, 75))	('ribo', 'Gene', '6173', (235, 239))	('lung cancer', 'Disease', 'MESH:D008175', (263, 274))	('lung tumor initiation', 'Disease', (65, 86))	('lung cancer', 'Phenotype', 'HP:0100526', (176, 187))	('lung cancer', 'Phenotype', 'HP:0100526', (263, 274))	('HK2', 'Gene', '15277', (41, 44))	('suppressing', 'NegReg', (207, 218))	('lung tumor initiation', 'Disease', 'MESH:D008175', (65, 86))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('cancer', 'Phenotype', 'HP:0002664', (268, 274))	('lung cancer', 'Disease', (176, 187))	('ribo', 'Gene', (235, 239))
305357	27602772	Note, a recent study evidenced Gapdh over-expression to be a prognostic factor for poor outcome in NSCLC patients and was shown to correlate with fluorodeoxyglucose uptake in diagnostic PET imaging.	('patients', 'Species', '9606', (105, 113))	('over-expression', 'Var', (37, 52))	('NSCLC', 'Phenotype', 'HP:0030358', (99, 104))	('Gapdh', 'Gene', (31, 36))	('fluorodeoxyglucose uptake', 'MPA', (146, 171))	('NSCLC', 'Disease', (99, 104))	('fluorodeoxyglucose', 'Chemical', 'MESH:D019788', (146, 164))	('NSCLC', 'Disease', 'MESH:D002289', (99, 104))
305365	27602772	Over-expression of FASN has been shown to result in changes of membrane composition and to modulate lipid rafts in tumor cells.	('FASN', 'Gene', '2194', (19, 23))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('lipid rafts', 'MPA', (100, 111))	('lipid', 'Chemical', 'MESH:D008055', (100, 105))	('tumor', 'Disease', (115, 120))	('modulate', 'Reg', (91, 99))	('membrane composition', 'MPA', (63, 83))	('Over-expression', 'Var', (0, 15))	('changes', 'Reg', (52, 59))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('FASN', 'Gene', (19, 23))
305376	27602772	A recent study reported the folate receptor alpha and Slc19a1 to be over-expressed in NSCLC with implications for antifolate chemotherapy, while an earlier investigation suggested genetic variants in folate metabolism genes to be associated with risk of lung cancer among Chinese patients.	('variants', 'Var', (188, 196))	('lung cancer', 'Disease', 'MESH:D008175', (254, 265))	('folate receptor alpha', 'Gene', '100689330', (28, 49))	('patients', 'Species', '9606', (280, 288))	('NSCLC', 'Disease', (86, 91))	('folate', 'Chemical', 'MESH:D005492', (28, 34))	('associated', 'Reg', (230, 240))	('lung cancer', 'Disease', (254, 265))	('Slc19a1', 'Gene', (54, 61))	('folate', 'Chemical', 'MESH:D005492', (200, 206))	('NSCLC', 'Disease', 'MESH:D002289', (86, 91))	('folate', 'Chemical', 'MESH:D005492', (118, 124))	('folate receptor alpha', 'Gene', (28, 49))	('lung cancer', 'Phenotype', 'HP:0100526', (254, 265))	('cancer', 'Phenotype', 'HP:0002664', (259, 265))	('Chinese', 'Species', '10029', (272, 279))	('NSCLC', 'Phenotype', 'HP:0030358', (86, 91))	('over-expressed', 'PosReg', (68, 82))
305379	27602772	A case-control study with 1,032 lung cancer patients and 1,145 matched cancer-free controls suggested variants of serine hydroxymethyl transferase 1 to play a role in the etiology of lung cancer and a recent study linked SNPs in folate metabolism genes to risk for lung cancer in never-smokers.	('lung cancer', 'Disease', 'MESH:D008175', (265, 276))	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('lung cancer', 'Phenotype', 'HP:0100526', (265, 276))	('patients', 'Species', '9606', (44, 52))	('cancer', 'Disease', (71, 77))	('lung cancer', 'Disease', 'MESH:D008175', (183, 194))	('cancer', 'Disease', (270, 276))	('lung cancer', 'Disease', 'MESH:D008175', (32, 43))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('cancer', 'Phenotype', 'HP:0002664', (270, 276))	('lung cancer', 'Phenotype', 'HP:0100526', (183, 194))	('lung cancer', 'Phenotype', 'HP:0100526', (32, 43))	('cancer', 'Disease', (37, 43))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('lung cancer', 'Disease', (265, 276))	('cancer', 'Disease', (188, 194))	('variants', 'Var', (102, 110))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('serine hydroxymethyl transferase 1', 'Gene', '6470', (114, 148))	('cancer', 'Disease', 'MESH:D009369', (270, 276))	('serine hydroxymethyl transferase 1', 'Gene', (114, 148))	('folate', 'Chemical', 'MESH:D005492', (229, 235))	('lung cancer', 'Disease', (183, 194))	('lung cancer', 'Disease', (32, 43))
305381	27602772	Moreover, serine hydroxymethyl transferase 1 knockdown induced apoptosis in lung cancer cells that was independent on serine or glycine starvation, but was the result of uracil disincorporation during DNA replication.	('lung cancer', 'Disease', 'MESH:D008175', (76, 87))	('serine hydroxymethyl transferase 1', 'Gene', (10, 44))	('lung cancer', 'Disease', (76, 87))	('serine', 'Chemical', 'MESH:D012694', (10, 16))	('glycine', 'Chemical', 'MESH:D005998', (128, 135))	('uracil', 'Chemical', 'MESH:D014498', (170, 176))	('serine hydroxymethyl transferase 1', 'Gene', '6470', (10, 44))	('apoptosis', 'CPA', (63, 72))	('serine', 'Chemical', 'MESH:D012694', (118, 124))	('lung cancer', 'Phenotype', 'HP:0100526', (76, 87))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('induced', 'Reg', (55, 62))	('knockdown', 'Var', (45, 54))
305386	27602772	Besides, polymorphisms of thymidylate synthase contribute to risk for lung cancer and its interactions with dietary factors in lung cancer development.	('lung cancer', 'Disease', 'MESH:D008175', (70, 81))	('lung cancer', 'Disease', (127, 138))	('thymidylate synthase', 'Gene', (26, 46))	('lung cancer', 'Phenotype', 'HP:0100526', (127, 138))	('risk', 'Reg', (61, 65))	('lung cancer', 'Disease', (70, 81))	('poly', 'Chemical', '-', (9, 13))	('thymidylate synthase', 'Gene', '7298', (26, 46))	('lung cancer', 'Phenotype', 'HP:0100526', (70, 81))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('interactions', 'Interaction', (90, 102))	('lung cancer', 'Disease', 'MESH:D008175', (127, 138))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('polymorphisms', 'Var', (9, 22))
305391	27602772	Silencing of Rrm1 and Rrm2 markedly enhanced the cytotoxicity of the topoisomerase I inhibitor camptothecin that might be exploited in chemotherapeutic strategies and RRM2 was shown to regulate Bcl-2 in lung cancers and considered to be a worthy target in cancer therapy.	('cancer', 'Disease', (208, 214))	('lung cancers', 'Disease', (203, 215))	('cancer', 'Disease', (256, 262))	('lung cancer', 'Phenotype', 'HP:0100526', (203, 214))	('cytotoxicity', 'Disease', (49, 61))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('Rrm2', 'Gene', (22, 26))	('Rrm2', 'Gene', '6241', (22, 26))	('Rrm1', 'Gene', (13, 17))	('RRM2', 'Gene', (167, 171))	('Silencing', 'Var', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (256, 262))	('lung cancers', 'Phenotype', 'HP:0100526', (203, 215))	('cytotoxicity', 'Disease', 'MESH:D064420', (49, 61))	('cancers', 'Phenotype', 'HP:0002664', (208, 215))	('Bcl-2', 'Gene', (194, 199))	('cancer', 'Disease', 'MESH:D009369', (208, 214))	('cancer', 'Disease', 'MESH:D009369', (256, 262))	('Bcl-2', 'Gene', '596', (194, 199))	('regulate', 'Reg', (185, 193))	('enhanced', 'PosReg', (36, 44))	('Rrm1', 'Gene', '6240', (13, 17))	('lung cancers', 'Disease', 'MESH:D008175', (203, 215))	('camptothecin', 'Chemical', 'MESH:D002166', (95, 107))	('RRM2', 'Gene', '6241', (167, 171))
305397	27602772	In a perspective article in clinical lung cancer the renaissance of polyamine metabolism inhibitors in cancer treatment was featured and original research found ODC (SCL25A21) mRNA expression in lung tumors to be a prognostic factor in NSLC.	('NSLC', 'Disease', (236, 240))	('lung cancer', 'Phenotype', 'HP:0100526', (37, 48))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('polyamine', 'Chemical', 'MESH:D011073', (68, 77))	('lung tumors', 'Disease', (195, 206))	('cancer', 'Disease', (103, 109))	('ODC', 'Gene', '4953', (161, 164))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('ODC', 'Gene', (161, 164))	('lung cancer', 'Disease', (37, 48))	('tumors', 'Phenotype', 'HP:0002664', (200, 206))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('lung tumor', 'Phenotype', 'HP:0100526', (195, 205))	('lung tumors', 'Disease', 'MESH:D008175', (195, 206))	('mRNA expression', 'Var', (176, 191))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('cancer', 'Disease', (42, 48))	('lung cancer', 'Disease', 'MESH:D008175', (37, 48))	('lung tumors', 'Phenotype', 'HP:0100526', (195, 206))
305400	27602772	Rpsa, Rpl10a, Rpl27a, Rpl36a, Mrpl12 and Mrps5, were significantly up-regulated in lung tumors of c-Myc transgenic mice.	('transgenic mice', 'Species', '10090', (104, 119))	('Rpl27a', 'Var', (14, 20))	('lung tumors', 'Disease', 'MESH:D008175', (83, 94))	('lung tumor', 'Phenotype', 'HP:0100526', (83, 93))	('Mrps5', 'Gene', (41, 46))	('Rpsa', 'Gene', (0, 4))	('Mrpl12', 'Gene', (30, 36))	('c-Myc', 'Gene', '4609', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('Rpl36a', 'Gene', (22, 28))	('up-regulated', 'PosReg', (67, 79))	('lung tumors', 'Phenotype', 'HP:0100526', (83, 94))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('lung tumors', 'Disease', (83, 94))	('c-Myc', 'Gene', (98, 103))	('Rpl10a', 'Gene', (6, 12))
305402	27602772	Likewise, the ribosomal proteins S2 and L10a have been explored as tumor antigens for the development of peptide-based cancer immunotherapies, and phage display of tumor antigens yielded a panel of antigens specific to squamous cell carcinomas with silencing of ribosomal protein L23 inhibiting proliferation, invasion and cell survival in a mouse disease model.	('tumor', 'Disease', (164, 169))	('inhibiting', 'NegReg', (284, 294))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('tumor', 'Disease', (67, 72))	('ribo', 'Gene', '6173', (14, 18))	('ribosomal protein L23', 'Gene', '65019', (262, 283))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('cancer', 'Disease', (119, 125))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (219, 243))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (219, 242))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('L10a', 'Gene', '4736', (40, 44))	('L10a', 'Gene', (40, 44))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (219, 243))	('ribo', 'Gene', (262, 266))	('silencing', 'Var', (249, 258))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('carcinomas', 'Phenotype', 'HP:0030731', (233, 243))	('invasion', 'CPA', (310, 318))	('cell survival in a mouse disease model', 'CPA', (323, 361))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('ribosomal protein L23', 'Gene', (262, 283))	('ribo', 'Gene', (14, 18))	('squamous cell carcinomas', 'Disease', (219, 243))	('mouse', 'Species', '10090', (342, 347))	('carcinoma', 'Phenotype', 'HP:0030731', (233, 242))	('ribo', 'Gene', '6173', (262, 266))
305411	27602772	A recent study also suggests snoRNAs to have multiple functions in carcinogenesis with snoRNA42 acting as an oncogene in lung tumors, while whole-exome sequencing of DNA from two early onset lung adenocarcinoma never-smoking patients revealed germline mutations in Nop58, therefore adding weight to the role of snoRNPs in lung cancer.	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('lung cancer', 'Phenotype', 'HP:0100526', (322, 333))	('lung tumor', 'Phenotype', 'HP:0100526', (121, 131))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('lung tumors', 'Disease', (121, 132))	('carcinogenesis', 'Disease', (67, 81))	('Nop58', 'Gene', '51602', (265, 270))	('cancer', 'Phenotype', 'HP:0002664', (327, 333))	('carcinogenesis', 'Disease', 'MESH:D063646', (67, 81))	('lung cancer', 'Disease', (322, 333))	('patients', 'Species', '9606', (225, 233))	('lung adenocarcinoma', 'Disease', (191, 210))	('germline mutations', 'Var', (243, 261))	('Nop58', 'Gene', (265, 270))	('carcinoma', 'Phenotype', 'HP:0030731', (201, 210))	('lung tumors', 'Disease', 'MESH:D008175', (121, 132))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (191, 210))	('lung cancer', 'Disease', 'MESH:D008175', (322, 333))	('lung tumors', 'Phenotype', 'HP:0100526', (121, 132))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (191, 210))
305426	27602772	Note, it was recently demonstrated that microRNA-21 targets ANP32A and their altered expression will effect chromatin remodeling to initiate undue expression of genes in response to c-Myc-hyperactivity.	('initiate', 'PosReg', (132, 140))	('expression', 'MPA', (85, 95))	('microRNA-21', 'Gene', '406991', (40, 51))	('ANP32A', 'Gene', (60, 66))	('c-Myc', 'Gene', (182, 187))	('chromatin remodeling', 'MPA', (108, 128))	('hyperactivity', 'Phenotype', 'HP:0000752', (188, 201))	('effect', 'Reg', (101, 107))	('microRNA-21', 'Gene', (40, 51))	('altered', 'Var', (77, 84))	('ANP32A', 'Gene', '8125', (60, 66))	('c-Myc', 'Gene', '4609', (182, 187))
305432	27602772	To the best of our knowledge, certain genes identified in the present study had not previously been associated with human lung carcinogenesis and translational research identified 47 PLAC up-regulated genes to be associated with poor outcome; conversely, high expression of the three repressed PLAC genes was associated with improved survival in lung adenocarcinoma but not squamous cell carcinoma patients (Figure 8, Supplementary Table S9).	('survival', 'MPA', (334, 342))	('lung carcinogenesis', 'Disease', (122, 141))	('lung carcinogenesis', 'Disease', 'MESH:D063646', (122, 141))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (346, 365))	('high', 'Var', (255, 259))	('lung adenocarcinoma', 'Disease', (346, 365))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (346, 365))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (374, 397))	('carcinoma', 'Phenotype', 'HP:0030731', (388, 397))	('improved', 'PosReg', (325, 333))	('patients', 'Species', '9606', (398, 406))	('squamous cell carcinoma', 'Disease', (374, 397))	('carcinoma', 'Phenotype', 'HP:0030731', (356, 365))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (374, 397))	('human', 'Species', '9606', (116, 121))
305472	27602772	Seventy-five or 100 mug of total protein extracts (50 mug in case of HEK293T transiently transfected with c-Myc vector) were separated on 12.0% SDS-polyacrylamide gel and blotted onto PVDF membranes in 25 mM Tris and 190 mM glycine at 4 C for 2 h at 350 mA or using the semi-dry iBlot transfer system (InVitrogen, Life Technologies).	('c-Myc', 'Gene', (106, 111))	('HEK293T', 'Var', (69, 76))	('polyacrylamide', 'Chemical', 'MESH:C016679', (148, 162))	('glycine', 'Chemical', 'MESH:D005998', (224, 231))	('PVDF', 'Chemical', 'MESH:C024865', (184, 188))	('c-Myc', 'Gene', '4609', (106, 111))	('Tris', 'Chemical', '-', (208, 212))	('HEK293T', 'CellLine', 'CVCL:0063', (69, 76))	('SDS', 'Chemical', 'MESH:D012967', (144, 147))
305481	25821560	Methylation of CHFR sensitizes esophageal squamous cell cancer to docetaxel and paclitaxel Esophageal squamous cell carcinoma (ESCC) is one of the most common malignancies worldwide.	('Esophageal squamous cell carcinoma', 'Disease', (91, 125))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (42, 62))	('malignancies', 'Disease', 'MESH:D009369', (159, 171))	('esophageal squamous cell cancer', 'Disease', 'MESH:D002294', (31, 62))	('Methylation', 'Var', (0, 11))	('paclitaxel', 'Chemical', 'MESH:D017239', (80, 90))	('docetaxel', 'Chemical', 'MESH:D000077143', (66, 75))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('CHFR', 'Gene', (15, 19))	('CHFR', 'Gene', '55743', (15, 19))	('malignancies', 'Disease', (159, 171))	('sensitizes', 'Reg', (20, 30))	('esophageal squamous cell cancer', 'Disease', (31, 62))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (102, 125))	('Esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (91, 125))
305482	25821560	Both genetic and epigenetic changes are involved in esophageal carcinogenesis.	('esophageal carcinogenesis', 'Disease', (52, 77))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (52, 77))	('epigenetic changes', 'Var', (17, 35))	('involved', 'Reg', (40, 48))
305483	25821560	CHFR methylation has been found frequently in different cancers and is regarded as a marker of taxane sensitivity.	('cancers', 'Disease', (56, 63))	('CHFR', 'Gene', (0, 4))	('cancers', 'Disease', 'MESH:D009369', (56, 63))	('methylation', 'Var', (5, 16))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('taxane', 'Chemical', 'MESH:C080625', (95, 101))	('found', 'Reg', (26, 31))	('cancers', 'Phenotype', 'HP:0002664', (56, 63))
305484	25821560	CHFR methylation was found in 0% (0/16) of normal mucosa, 2.9% (1/34) of grade I dysplasia, 0% (0/8) of grade II dysplasia, 12.5% (1/8) of grade III dysplasia and 45% (49/109) of invasive cancer.	('I dysplasia', 'Disease', 'MESH:C538215', (111, 122))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('methylation', 'Var', (5, 16))	('II dysplasia', 'Disease', 'MESH:D003784', (146, 158))	('II dysplasia', 'Disease', (110, 122))	('invasive cancer', 'Disease', (179, 194))	('II dysplasia', 'Disease', (146, 158))	('I dysplasia', 'Disease', 'MESH:C538215', (147, 158))	('I dysplasia', 'Disease', 'MESH:C538215', (79, 90))	('I dysplasia', 'Disease', (79, 90))	('invasive cancer', 'Disease', 'MESH:D009362', (179, 194))	('II dysplasia', 'Disease', 'MESH:D003784', (110, 122))
305485	25821560	When treated with docetaxel or paclitaxel, cell viability was lower in CHFR methylated esophageal cancer cells than in unmethylated cells (p<0.05).	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('paclitaxel', 'Chemical', 'MESH:D017239', (31, 41))	('docetaxel', 'Chemical', 'MESH:D000077143', (18, 27))	('esophageal cancer', 'Disease', (87, 104))	('CHFR methylated', 'Var', (71, 86))	('lower', 'NegReg', (62, 67))	('esophageal cancer', 'Disease', 'MESH:D004938', (87, 104))	('cell viability', 'CPA', (43, 57))
305489	25821560	Methylation of CHFR sensitized ESCC cells to taxanes.	('CHFR', 'Gene', (15, 19))	('Methylation', 'Var', (0, 11))	('sensitized', 'Reg', (20, 30))	('taxanes', 'Chemical', 'MESH:D043823', (45, 52))
305497	25821560	Accumulation of epigenetic changes in tumor suppressor genes is a well known event in human esophageal carcinogenesis.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('esophageal carcinogenesis', 'Disease', (92, 117))	('epigenetic changes', 'Var', (16, 34))	('human', 'Species', '9606', (86, 91))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (92, 117))
305498	25821560	DNA methylation may serve as marker for early cancer diagnosis, chemo-sensitivity as well as prognosis.	('cancer', 'Disease', (46, 52))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('methylation', 'Var', (4, 15))
305500	25821560	Loss of CHFR expression and promoter region hypermethylation were found frequently in different cancers.	('promoter', 'MPA', (28, 36))	('cancers', 'Phenotype', 'HP:0002664', (96, 103))	('expression', 'MPA', (13, 23))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('Loss', 'NegReg', (0, 4))	('CHFR', 'Gene', (8, 12))	('hypermethylation', 'Var', (44, 60))	('cancers', 'Disease', 'MESH:D009369', (96, 103))	('cancers', 'Disease', (96, 103))
305501	25821560	Methylation of CHFR was also regarded as a marker of taxane sensitivity in various cancers.	('cancers', 'Disease', 'MESH:D009369', (83, 90))	('Methylation', 'Var', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('CHFR', 'Gene', (15, 19))	('taxane', 'Chemical', 'MESH:C080625', (53, 59))	('cancers', 'Phenotype', 'HP:0002664', (83, 90))	('cancers', 'Disease', (83, 90))
305502	25821560	In 35 cases, no significant difference was found in the response of CHFR methylated and unmethylated esophageal cancer patients to the combined cisplatin and 5-fluorouracil therapy plus radiotherapy.	('patients', 'Species', '9606', (119, 127))	('esophageal cancer', 'Disease', (101, 118))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (158, 172))	('methylated', 'Var', (73, 83))	('esophageal cancer', 'Disease', 'MESH:D004938', (101, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('cisplatin', 'Chemical', 'MESH:D002945', (144, 153))
305505	25821560	Constant expression was found in KYSE30, KYSE140, KYSE180, KYSE450, KYSE520, TE7 and SEG1 cells while loss of expression was observed in KYSE70, KYSE150 and KYSE510 cells (Figure 1A).	('KYSE520', 'Var', (68, 75))	('SEG1', 'CellLine', 'CVCL:8113', (85, 89))	('KYSE140', 'Var', (41, 48))	('KYSE450', 'Var', (59, 66))	('KYSE180', 'Var', (50, 57))	('KYSE510', 'CellLine', 'CVCL:1354', (157, 164))	('KYSE30', 'Var', (33, 39))
305506	25821560	Complete methylation was found in KYSE70, KYSE150 and KYSE510 cells while KYSE30, KYSE140, KYSE180, KYSE450, KYSE520, TE7 and SEG1 cells were found to be without methylation (Figure 1B).	('KYSE140', 'Var', (82, 89))	('KYSE150', 'Var', (42, 49))	('KYSE30', 'Var', (74, 80))	('KYSE180', 'Var', (91, 98))	('KYSE510', 'CellLine', 'CVCL:1354', (54, 61))	('SEG1', 'CellLine', 'CVCL:8113', (126, 130))	('KYSE70', 'Var', (34, 40))	('methylation', 'MPA', (9, 20))	('KYSE510', 'Var', (54, 61))
305507	25821560	Restoration of CHFR expression was induced by 5-aza-2'-deoxycytidine (5-AZ) treatment in KYSE70, KYSE150 and KYSE510 cells (Figure 1A).	('KYSE510', 'Var', (109, 116))	('expression', 'MPA', (20, 30))	('KYSE150', 'Var', (97, 104))	('KYSE70', 'Var', (89, 95))	('KYSE510', 'CellLine', 'CVCL:1354', (109, 116))	('CHFR', 'Gene', (15, 19))	("5-aza-2'-deoxycytidine", 'Chemical', 'MESH:D000077209', (46, 68))	('5-AZ', 'Chemical', 'MESH:D000077209', (70, 74))
305508	25821560	These results suggest that the expression of CHFR was regulated by promoter region methylation in esophageal cancer cells.	('regulated', 'Reg', (54, 63))	('CHFR', 'Gene', (45, 49))	('expression', 'MPA', (31, 41))	('esophageal cancer', 'Disease', (98, 115))	('methylation', 'Var', (83, 94))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('esophageal cancer', 'Disease', 'MESH:D004938', (98, 115))
305509	25821560	Epigenetic alterations have been shown to progress in frequency during esophageal carcinogenesis.	('Epigenetic alterations', 'Var', (0, 22))	('progress', 'PosReg', (42, 50))	('esophageal carcinogenesis', 'Disease', (71, 96))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (71, 96))
305511	25821560	Promoter region hypermethylation was found in 0% (0/16) of normal mucosa, 2.9% (1/34) of grade I dysplasia, 0% (0/8) of grade II dysplasia, 12.5% (1/8) of grade III dysplasia and 44.95% (49/109) of invasive esophageal cancer (Figure 1C,1D,1E, Table1).	('II dysplasia', 'Disease', (126, 138))	('II dysplasia', 'Disease', 'MESH:D003784', (162, 174))	('I dysplasia', 'Disease', (95, 106))	('invasive esophageal cancer', 'Disease', (198, 224))	('I dysplasia', 'Disease', 'MESH:C538215', (95, 106))	('found', 'Reg', (37, 42))	('I dysplasia', 'Disease', 'MESH:C538215', (127, 138))	('II dysplasia', 'Disease', (162, 174))	('hypermethylation', 'Var', (16, 32))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('II dysplasia', 'Disease', 'MESH:D003784', (126, 138))	('I dysplasia', 'Disease', 'MESH:C538215', (163, 174))	('invasive esophageal cancer', 'Disease', 'MESH:D004938', (198, 224))
305512	25821560	CHFR was more infrequently methylated in esophageal dysplasia than in invasive esophageal cancer (p<0.01).	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('esophageal dysplasia', 'Disease', (41, 61))	('methylated', 'Var', (27, 37))	('invasive esophageal cancer', 'Disease', 'MESH:D004938', (70, 96))	('invasive esophageal cancer', 'Disease', (70, 96))	('esophageal dysplasia', 'Disease', 'MESH:D004941', (41, 61))
305513	25821560	This suggests that CHFR methylation was a late stage event of esophagus carcinogenesis.	('esophagus carcinogenesis', 'Disease', 'MESH:D063646', (62, 86))	('esophagus carcinogenesis', 'Disease', (62, 86))	('methylation', 'Var', (24, 35))
305514	25821560	No association was found between methylation and age, gender, TNM stage, tumor size, differentiation and lymph node metastasis (all p>0.05).	('methylation', 'Var', (33, 44))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Disease', (73, 78))	('TNM', 'Gene', (62, 65))	('lymph node metastasis', 'Disease', 'MESH:D009362', (105, 126))	('lymph node metastasis', 'Disease', (105, 126))	('TNM', 'Gene', '10178', (62, 65))
305515	25821560	Methylation of CHFR has been shown to sensitize different cancers to taxane treatment.	('taxane', 'Chemical', 'MESH:C080625', (69, 75))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('Methylation', 'Var', (0, 11))	('cancers', 'Phenotype', 'HP:0002664', (58, 65))	('CHFR', 'Gene', (15, 19))	('cancers', 'Disease', 'MESH:D009369', (58, 65))	('cancers', 'Disease', (58, 65))	('sensitize', 'Reg', (38, 47))
305516	25821560	In a small study, no association was found between CHFR methylation and the sensitivity of esophageal cancer to cisplatin and 5-fluorouracil.	('esophageal cancer', 'Disease', 'MESH:D004938', (91, 108))	('CHFR', 'Gene', (51, 55))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (126, 140))	('cisplatin', 'Chemical', 'MESH:D002945', (112, 121))	('esophageal cancer', 'Disease', (91, 108))	('methylation', 'Var', (56, 67))
305519	25821560	Methylated cells (KYSE70, KYSE150) were significantly more likely to undergo apoptosis than unmethylated cells (KYSE140, KYSE450) after paclitaxel or docetaxel treatment (Figure2, table 2, all p< 0.05).	('apoptosis', 'CPA', (77, 86))	('undergo', 'Reg', (69, 76))	('paclitaxel', 'Chemical', 'MESH:D017239', (136, 146))	('docetaxel', 'Chemical', 'MESH:D000077143', (150, 159))	('KYSE70', 'Var', (18, 24))
305522	25821560	While in the paclitaxel and docetaxel treated groups, no significant difference was found between the methylated (KYSE70, KYSE150) and unmethylated cells (KYSE140, KYSE450) when treated with 5-AZ (Figure2, table2, all p>0.05).	('KYSE70', 'Var', (114, 120))	('docetaxel', 'Chemical', 'MESH:D000077143', (28, 37))	('KYSE140', 'Var', (155, 162))	('KYSE150', 'Var', (122, 129))	('paclitaxel', 'Chemical', 'MESH:D017239', (13, 23))	('5-AZ', 'Chemical', 'MESH:D000077209', (191, 195))
305523	25821560	These results further suggest that the methylation of CHFR sensitizes esophageal cancer cells to paclitaxel and docetaxel, while the restoration of CHFR expression with 5-AZ induces resistance to these chemotherapeutic agents.	('sensitizes', 'Reg', (59, 69))	('5-AZ', 'Chemical', 'MESH:D000077209', (169, 173))	('methylation', 'Var', (39, 50))	('CHFR', 'Gene', (148, 152))	('esophageal cancer', 'Disease', (70, 87))	('CHFR', 'Gene', (54, 58))	('esophageal cancer', 'Disease', 'MESH:D004938', (70, 87))	('paclitaxel', 'Chemical', 'MESH:D017239', (97, 107))	('resistance', 'MPA', (182, 192))	('expression', 'MPA', (153, 163))	('docetaxel', 'Chemical', 'MESH:D000077143', (112, 121))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('induces', 'PosReg', (174, 181))
305524	25821560	CHFR methylation has been reported to sensitize cancer cells to taxanes.	('CHFR', 'Gene', (0, 4))	('methylation', 'Var', (5, 16))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('taxanes', 'Chemical', 'MESH:D043823', (64, 71))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('sensitize', 'Reg', (38, 47))
305525	25821560	In our study, promoter region methylation sensitized KYSE70 and KYSE150 cells to docetaxel and paclitaxel.	('paclitaxel', 'Chemical', 'MESH:D017239', (95, 105))	('sensitized', 'Reg', (42, 52))	('methylation', 'Var', (30, 41))	('docetaxel', 'Chemical', 'MESH:D000077143', (81, 90))
305537	25821560	Accumulation of genetic and epigenetic changes has been found in the development of various cancers, including esophageal cancer.	('cancers', 'Phenotype', 'HP:0002664', (92, 99))	('esophageal cancer', 'Disease', (111, 128))	('epigenetic changes', 'Var', (28, 46))	('cancers', 'Disease', 'MESH:D009369', (92, 99))	('cancers', 'Disease', (92, 99))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('esophageal cancer', 'Disease', 'MESH:D004938', (111, 128))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('genetic', 'Var', (16, 23))	('found', 'Reg', (56, 61))
305540	25821560	It suggests that CHFR methylation is a late stage marker of esophageal squamous cell carcinoma.	('esophageal squamous cell carcinoma', 'Disease', (60, 94))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (71, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (60, 94))	('CHFR', 'Gene', (17, 21))	('methylation', 'Var', (22, 33))
305541	25821560	Methylation of CHFR has been regarded as a chemo-sensitive marker in various cancers.	('cancers', 'Disease', 'MESH:D009369', (77, 84))	('cancers', 'Phenotype', 'HP:0002664', (77, 84))	('Methylation', 'Var', (0, 11))	('cancers', 'Disease', (77, 84))	('CHFR', 'Gene', (15, 19))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))
305542	25821560	We found CHFR methylation sensitizes esophageal cancer cells to docetaxel and paclitaxel, and 5-AZ induces chemoresistance of CHFR methylated cells to docetaxel and paclitaxel.	('induces', 'Reg', (99, 106))	('docetaxel', 'Chemical', 'MESH:D000077143', (151, 160))	('chemoresistance', 'CPA', (107, 122))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('sensitizes', 'Reg', (26, 36))	('5-AZ', 'Var', (94, 98))	('esophageal cancer', 'Disease', 'MESH:D004938', (37, 54))	('methylation', 'Var', (14, 25))	('esophageal cancer', 'Disease', (37, 54))	('paclitaxel', 'Chemical', 'MESH:D017239', (78, 88))	('5-AZ', 'Chemical', 'MESH:D000077209', (94, 98))	('docetaxel', 'Chemical', 'MESH:D000077143', (64, 73))	('paclitaxel', 'Chemical', 'MESH:D017239', (165, 175))
305543	25821560	These results suggest that CHFR methylation is a taxane sensitive marker in human esophageal squamous cancer.	('methylation', 'Var', (32, 43))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('squamous cancer', 'Phenotype', 'HP:0002860', (93, 108))	('taxane', 'Chemical', 'MESH:C080625', (49, 55))	('esophageal squamous cancer', 'Disease', 'MESH:D004938', (82, 108))	('esophageal squamous cancer', 'Disease', (82, 108))	('human', 'Species', '9606', (76, 81))
305544	25821560	There are a few reports about the ability of epigenetic therapy to undo chemoresistance and re-sensitize refractory tumors to specific chemotherapy agents.	('tumors', 'Disease', (116, 122))	('tumors', 'Disease', 'MESH:D009369', (116, 122))	('undo', 'Reg', (67, 71))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))	('chemoresistance', 'CPA', (72, 87))	('epigenetic therapy', 'Var', (45, 63))
305548	25821560	This result may be interpreted as a partial explanation for the mechanism by which epigenetic therapy re-sensitizes chemotherapy resistant, refractory tumors.	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumors', 'Disease', 'MESH:D009369', (151, 157))	('tumors', 'Disease', (151, 157))	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('epigenetic therapy', 'Var', (83, 101))
305551	25821560	In our study, silencing CHFR by promoter region hypermethylation sensitized esophageal cancer cells to docetaxel and paclitaxel.	('silencing', 'Var', (14, 23))	('docetaxel', 'Chemical', 'MESH:D000077143', (103, 112))	('paclitaxel', 'Chemical', 'MESH:D017239', (117, 127))	('esophageal cancer', 'Disease', (76, 93))	('sensitized', 'Reg', (65, 75))	('hypermethylation', 'Var', (48, 64))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('esophageal cancer', 'Disease', 'MESH:D004938', (76, 93))	('CHFR', 'Gene', (24, 28))
305556	25821560	Methylation of CHFR is a late stage event in esophageal cancer.	('esophageal cancer', 'Disease', (45, 62))	('Methylation', 'Var', (0, 11))	('esophageal cancer', 'Disease', 'MESH:D004938', (45, 62))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('CHFR', 'Gene', (15, 19))
305557	25821560	Methylation of CHFR sensitized esophageal cancer cells to docetaxel and paclitaxel.	('docetaxel', 'Chemical', 'MESH:D000077143', (58, 67))	('paclitaxel', 'Chemical', 'MESH:D017239', (72, 82))	('sensitized', 'Reg', (20, 30))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('esophageal cancer', 'Disease', (31, 48))	('Methylation', 'Var', (0, 11))	('CHFR', 'Gene', (15, 19))	('esophageal cancer', 'Disease', 'MESH:D004938', (31, 48))
305558	25821560	Finally, 5-AZ may re-sensitize chemotherapy resistant refractory tumors by inducing cell cycle phase re-distribution.	('chemotherapy', 'Disease', (31, 43))	('tumors', 'Disease', (65, 71))	('5-AZ', 'Var', (9, 13))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('cell cycle phase re-distribution', 'CPA', (84, 116))	('inducing', 'PosReg', (75, 83))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('5-AZ', 'Chemical', 'MESH:D000077209', (9, 13))
305559	25821560	Ten human esophageal cancer cell lines (KYSE30, KYSE140, KYSE180, KYSE450, KYSE520, TE7, SEG1, KYSE70, KYSE150 and KYSE510) were used in this study.	('KYSE510', 'CellLine', 'CVCL:1354', (115, 122))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('human', 'Species', '9606', (4, 9))	('esophageal cancer', 'Disease', (10, 27))	('KYSE70', 'Var', (95, 101))	('SEG1', 'CellLine', 'CVCL:8113', (89, 93))	('esophageal cancer', 'Disease', 'MESH:D004938', (10, 27))
305571	25821560	Group 2 was treated with 2mumol/L 5-AZ+10mug/ml paclitaxel, 5-AZ+18.4 mug/ml docetaxel (Doc), 5-AZ+ 25 mug/ml VP16, or 5-AZ+10 mug/ml cisplatin for 24 h, 48 h and 72 h respectively.	('5-AZ', 'Chemical', 'MESH:D000077209', (60, 64))	('5-AZ', 'Chemical', 'MESH:D000077209', (119, 123))	('VP16', 'Chemical', 'MESH:D005047', (110, 114))	('5-AZ', 'Chemical', 'MESH:D000077209', (94, 98))	('5-AZ', 'Chemical', 'MESH:D000077209', (34, 38))	('docetaxel', 'Chemical', 'MESH:D000077143', (77, 86))	('cisplatin', 'Chemical', 'MESH:D002945', (134, 143))	('5-AZ+ 25 mug/ml', 'Var', (94, 109))	('5-AZ+18.4', 'Var', (60, 69))	('Doc', 'Chemical', 'MESH:D000077143', (88, 91))	('paclitaxel', 'Chemical', 'MESH:D017239', (48, 58))
305579	32456271	Abnormally expressed miRNAs are strongly associated with cancer development, resistance to chemo-/radiotherapy, and metastatic potential through targeting a large variety of genes.	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('resistance to chemo-/radiotherapy', 'CPA', (77, 110))	('cancer', 'Disease', (57, 63))	('associated with', 'Reg', (41, 56))	('miRNAs', 'Protein', (21, 27))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('metastatic potential', 'CPA', (116, 136))	('Abnormally expressed', 'Var', (0, 20))	('targeting', 'Reg', (145, 154))
305597	32456271	Consequently, miRNAs may act either as onco-promotors or tumor suppressor genes, depending on their biological targets and the cellular context.	('tumor', 'Disease', (57, 62))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('miRNAs', 'Var', (14, 20))
305634	32456271	In addition, the study of miR-221 in LCa also showed to stimulate apoptosis resistance by affecting apoptotic protease activating factor-1 (Apaf-1).	('apoptotic protease activating factor-1', 'Gene', '317', (100, 138))	('apoptotic protease activating factor-1', 'Gene', (100, 138))	('affecting', 'Reg', (90, 99))	('stimulate', 'PosReg', (56, 65))	('apoptosis resistance', 'CPA', (66, 86))	('Apaf-1', 'Gene', '317', (140, 146))	('Apaf-1', 'Gene', (140, 146))	('LCa', 'Phenotype', 'HP:0012118', (37, 40))	('miR-221', 'Var', (26, 33))
305636	32456271	The authors identified that tumor repressor Smad4 is a direct downstream target of miR-302-3p.	('tumor', 'Disease', (28, 33))	('miR-302-3p', 'Var', (83, 93))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('Smad4', 'Gene', (44, 49))	('Smad4', 'Gene', '4089', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
305637	32456271	In silico prediction algorithms and further validation confirmed that adiponectin receptor 2 (AdipoR2) is directly regulated by miR-423-3p.	('regulated', 'Reg', (115, 124))	('AdipoR2', 'Gene', '79602', (94, 101))	('adiponectin receptor 2', 'Gene', (70, 92))	('adiponectin receptor 2', 'Gene', '79602', (70, 92))	('miR-423-3p', 'Var', (128, 138))	('AdipoR2', 'Gene', (94, 101))
305638	32456271	Several reports exhibited lower miRNA expression in LCa, and the miRNAs could suppress tumor development and metastasis through multiple direct/indirect target oncogenes.	('miRNAs', 'Var', (65, 71))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('miRNA expression', 'MPA', (32, 48))	('tumor', 'Disease', (87, 92))	('LCa', 'Phenotype', 'HP:0012118', (52, 55))	('suppress', 'NegReg', (78, 86))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('lower', 'NegReg', (26, 31))
305641	32456271	It was reported that miR-1 is significantly under-expressed in LCa tissues and ectopic miR-1 expression induces the suppression of cell growth and metastatic potential in Hep-2 cells.	('Hep-2', 'CellLine', 'CVCL:1906', (171, 176))	('miR-1', 'Gene', (87, 92))	('LCa', 'Phenotype', 'HP:0012118', (63, 66))	('miR-1', 'Gene', '79187', (21, 26))	('miR-1', 'Gene', '79187', (87, 92))	('ectopic', 'Var', (79, 86))	('suppression', 'NegReg', (116, 127))	('miR-1', 'Gene', (21, 26))
305651	32456271	Replacement of miR-34c expression in LCa cells induced both inhibition of growth and invasion by directly targeting c-Met.	('miR-34c', 'Gene', '407042', (15, 22))	('miR-34c', 'Gene', (15, 22))	('targeting', 'Reg', (106, 115))	('inhibition', 'NegReg', (60, 70))	('invasion', 'CPA', (85, 93))	('Replacement', 'Var', (0, 11))	('LCa', 'Phenotype', 'HP:0012118', (37, 40))	('growth', 'CPA', (74, 80))	('c-Met', 'Gene', (116, 121))	('c-Met', 'Gene', '4233', (116, 121))
305665	32456271	Inhibition of miR-155-5p promoted the epithelial marker E-cadherin, reduced signal transducer and activator of transcription 3 (STAT3), and activated suppressor of cytokine signaling 1 (SOCS1) in an OSCC cell line.	('epithelial marker', 'MPA', (38, 55))	('STAT3', 'Gene', '6774', (128, 133))	('SOCS1', 'Gene', '8651', (186, 191))	('signal transducer and activator of transcription 3', 'Gene', '6774', (76, 126))	('miR-155', 'Gene', '406947', (14, 21))	('STAT3', 'Gene', (128, 133))	('promoted', 'PosReg', (25, 33))	('SOCS1', 'Gene', (186, 191))	('miR-155', 'Gene', (14, 21))	('suppressor of cytokine signaling 1', 'Gene', (150, 184))	('activated', 'PosReg', (140, 149))	('Inhibition', 'Var', (0, 10))	('suppressor of cytokine signaling 1', 'Gene', '8651', (150, 184))	('reduced', 'NegReg', (68, 75))	('E-cadherin', 'Gene', (56, 66))	('E-cadherin', 'Gene', '999', (56, 66))
305673	32456271	Another group showed that miR-140-5p was decreased in hypopharyngeal squamous cell carcinoma (HSCC) tissues, and the downregulation was correlated with tumor size and lymph node metastases.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('hypopharyngeal squamous cell carcinoma', 'Disease', (54, 92))	('metastases', 'Disease', 'MESH:D009362', (178, 188))	('miR-140-5p', 'Var', (26, 36))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (69, 92))	('miR-140-5p', 'Chemical', '-', (26, 36))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('decreased', 'NegReg', (41, 50))	('HSCC', 'Phenotype', 'HP:0012182', (94, 98))	('hypopharyngeal squamous cell carcinoma', 'Phenotype', 'HP:0012182', (54, 92))	('tumor', 'Disease', (152, 157))	('hypopharyngeal squamous cell carcinoma', 'Disease', 'MESH:D002294', (54, 92))	('metastases', 'Disease', (178, 188))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))
305674	32456271	Moreover, functional analysis showed that miR-140-5p directly suppresses ADAM10.	('ADAM10', 'Gene', (73, 79))	('miR-140-5p', 'Var', (42, 52))	('miR-140-5p', 'Chemical', '-', (42, 52))	('ADAM10', 'Gene', '102', (73, 79))	('suppresses', 'NegReg', (62, 72))
305675	32456271	This study demonstrated that miR-140-5p suppressed cancer invasion and migration by inhibiting ADAM10-mediated Notch1 signaling pathway.	('miR-140-5p', 'Var', (29, 39))	('ADAM10', 'Gene', '102', (95, 101))	('miR-140-5p', 'Chemical', '-', (29, 39))	('ADAM10', 'Gene', (95, 101))	('suppressed', 'NegReg', (40, 50))	('Notch1', 'Gene', (111, 117))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('Notch1', 'Gene', '4851', (111, 117))	('inhibiting', 'NegReg', (84, 94))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))
305681	32456271	showed that miR-133b, miR-455-5p, and miR-196a were abnormally expressed in laryngeal tumors if compared to their matched non-oncological tissues.	('miR-1', 'Gene', (38, 43))	('miR-1', 'Gene', '79187', (12, 17))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumors', 'Disease', (86, 92))	('miR-133b', 'Gene', '442890', (12, 20))	('miR-455-5p', 'Var', (22, 32))	('miR-1', 'Gene', (12, 17))	('miR-1', 'Gene', '79187', (38, 43))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('miR-133b', 'Gene', (12, 20))	('laryngeal tumors', 'Phenotype', 'HP:0012118', (76, 92))
305693	32456271	The results showed eight up-regulations (miR-31, miR-33, miR-141, miR-149a, miR-182, LET-7a, miR-4853p and miR-122) and three down-regulations (miR-133a, miR-145 and miR-223) in LCa patients (n = 66) compared to healthy volunteers (n = 100).	('miR-31', 'Gene', (41, 47))	('miR-4853p', 'Var', (93, 102))	('miR-1', 'Gene', '79187', (154, 159))	('miR-122', 'Gene', '406906', (107, 114))	('patients', 'Species', '9606', (182, 190))	('miR-1', 'Gene', '79187', (66, 71))	('LCa', 'Phenotype', 'HP:0012118', (178, 181))	('miR-33', 'Gene', '407039', (49, 55))	('miR-1', 'Gene', '79187', (57, 62))	('miR-122', 'Gene', (107, 114))	('miR-1', 'Gene', '79187', (144, 149))	('miR-223', 'Gene', (166, 173))	('LCa', 'Disease', (178, 181))	('miR-31', 'Gene', '407035', (41, 47))	('miR-141', 'Gene', '406933', (57, 64))	('miR-1', 'Gene', (107, 112))	('miR-1', 'Gene', (76, 81))	('miR-141', 'Gene', (57, 64))	('miR-1', 'Gene', (154, 159))	('LET-7a', 'Var', (85, 91))	('miR-182', 'Gene', (76, 83))	('miR-1', 'Gene', (66, 71))	('miR-223', 'Gene', '407008', (166, 173))	('miR-182', 'Gene', '406958', (76, 83))	('miR-33', 'Gene', (49, 55))	('miR-1', 'Gene', (57, 62))	('down-regulations', 'NegReg', (126, 142))	('miR-1', 'Gene', '79187', (107, 112))	('miR-1', 'Gene', (144, 149))	('miR-1', 'Gene', '79187', (76, 81))	('up-regulations', 'PosReg', (25, 39))
305700	32456271	The deregulated miRNA expression patterns can also help clinicians to prognosticate cancer progression and outcome.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('cancer', 'Disease', (84, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('deregulated', 'Var', (4, 15))	('miRNA expression patterns', 'MPA', (16, 41))
305728	32456271	Likewise, miR-181a was found to inhibit Twist1 mediating EMT, enhancing metastatic potential, and inducing cisplatin chemo-resistance in TSCC cells.	('metastatic potential', 'CPA', (72, 92))	('inhibit', 'NegReg', (32, 39))	('cisplatin', 'Chemical', 'MESH:D002945', (107, 116))	('Twist1', 'Gene', '7291', (40, 46))	('enhancing', 'PosReg', (62, 71))	('miR-181a', 'Chemical', '-', (10, 18))	('TSCC', 'Phenotype', 'HP:0030413', (137, 141))	('miR-181a', 'Var', (10, 18))	('EMT', 'CPA', (57, 60))	('Twist1', 'Gene', (40, 46))	('cisplatin chemo-resistance', 'MPA', (107, 133))	('inducing', 'Reg', (98, 106))
305730	32456271	miR-222 downregulation by antisense transfection enhanced the sensitivity of OSCC to cisplatin through directly blocking PUMA (p53-upregulated modulator of apoptosis) gene expression, and thereby offering a combination of miR-222 antisense and cisplatin as a new powerful therapeutic approach.	('miR-222', 'Gene', '407007', (222, 229))	('PUMA', 'Gene', (121, 125))	('miR-222', 'Gene', '407007', (0, 7))	('cisplatin', 'Chemical', 'MESH:D002945', (85, 94))	('sensitivity', 'MPA', (62, 73))	('enhanced', 'PosReg', (49, 57))	('antisense', 'Var', (26, 35))	('blocking', 'NegReg', (112, 120))	('PUMA', 'Gene', '27113', (121, 125))	('expression', 'MPA', (172, 182))	('cisplatin', 'Chemical', 'MESH:D002945', (244, 253))	('miR-222', 'Gene', (222, 229))	('miR-222', 'Gene', (0, 7))	('p53', 'Gene', '7157', (127, 130))	('downregulation', 'NegReg', (8, 22))	('p53', 'Gene', (127, 130))
305731	32456271	miR-101-3p repressed cell proliferation and metastatic functions and induced apoptosis in a salivary gland adenoid cystic carcinoma cell (ACC) line.	('miR-101-3p', 'Var', (0, 10))	('apoptosis', 'CPA', (77, 86))	('cell proliferation', 'CPA', (21, 39))	('adenoid cystic carcinoma', 'Disease', 'MESH:D003528', (107, 131))	('miR-101-3p', 'Chemical', '-', (0, 10))	('metastatic functions', 'CPA', (44, 64))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('adenoid cystic carcinoma', 'Disease', (107, 131))	('induced', 'Reg', (69, 76))
305732	32456271	The authors also showed that miR-101-3p directly regulated Moloney murine leukemia virus 1 (Pim-1) oncogene and promoted the sensitivity to cisplatin in ACC cell lines.	('leukemia', 'Phenotype', 'HP:0001909', (74, 82))	('regulated', 'Reg', (49, 58))	('Moloney murine leukemia virus', 'Species', '11801', (59, 88))	('promoted', 'PosReg', (112, 120))	('miR-101-3p', 'Chemical', '-', (29, 39))	('sensitivity to cisplatin', 'MPA', (125, 149))	('miR-101-3p', 'Var', (29, 39))	('Pim-1', 'Gene', '5292', (92, 97))	('cisplatin', 'Chemical', 'MESH:D002945', (140, 149))	('Pim-1', 'Gene', (92, 97))
305738	32456271	Notably, reintroduction of miR-27a in resistant cells significantly accelerated hyperthermia-induced cell death and inhibited HSP90 and HSP110 expressions, implying that miR-27a was positively associated with thermal sensitivity through HSPs modulation.	('hyperthermia', 'Disease', 'MESH:D005334', (80, 92))	('miR-27a', 'Gene', (170, 177))	('expressions', 'MPA', (143, 154))	('reintroduction', 'Var', (9, 23))	('HSP90', 'Gene', (126, 131))	('death', 'Disease', (106, 111))	('inhibited', 'NegReg', (116, 125))	('death', 'Disease', 'MESH:D003643', (106, 111))	('hyperthermia', 'Disease', (80, 92))	('HSP90', 'Gene', '3320', (126, 131))	('accelerated', 'PosReg', (68, 79))	('miR-27a', 'Gene', (27, 34))	('HSP110', 'Protein', (136, 142))	('miR-27a', 'Gene', '407018', (27, 34))	('hyperthermia', 'Phenotype', 'HP:0001945', (80, 92))	('miR-27a', 'Gene', '407018', (170, 177))	('associated', 'Reg', (193, 203))
305750	32456271	demonstrated that the deregulation of 6 miRNAs was associated to cancer survival in oropharyngeal SCC patients.	('patients', 'Species', '9606', (102, 110))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('associated', 'Reg', (51, 61))	('oropharyngeal SCC', 'Disease', (84, 101))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('deregulation', 'Var', (22, 34))
305751	32456271	Three miRNAs (miR-142-3p, miR-146a, and miR-26b) were upregulated in surviving patients, while the remaining miRNAs (miR-31, miR-24, and miR-193b) were upregulated in patients who died.	('miR-146a', 'Gene', (26, 34))	('upregulated', 'PosReg', (54, 65))	('died', 'Disease', (180, 184))	('miR-26b', 'Gene', '407017', (40, 47))	('miR-193b', 'Gene', '574455', (137, 145))	('miR-146a', 'Gene', '406938', (26, 34))	('miR-24', 'Chemical', '-', (125, 131))	('miR-1', 'Gene', (14, 19))	('miR-31', 'Gene', (117, 123))	('miR-1', 'Gene', '79187', (26, 31))	('miR-26b', 'Gene', (40, 47))	('miR-1', 'Gene', '79187', (137, 142))	('died', 'Disease', 'MESH:D003643', (180, 184))	('miR-193b', 'Gene', (137, 145))	('miR-24', 'Var', (125, 131))	('miR-31', 'Gene', '407035', (117, 123))	('miR-1', 'Gene', '79187', (14, 19))	('upregulated', 'PosReg', (152, 163))	('patients', 'Species', '9606', (167, 175))	('patients', 'Species', '9606', (79, 87))	('miR-1', 'Gene', (26, 31))	('miR-1', 'Gene', (137, 142))
305753	32456271	More recently, a combination of 5 miRNAs (let-7g-3p, miR-6508-5p, miR-210-5p, miR-4306, and miR-7161-39) was also shown to correlate with the survival rate of HPV-negative HNSCC patients.	('let-7g-3p', 'Var', (42, 51))	('miR-6508', 'Gene', '102466972', (53, 61))	('HNSCC', 'Disease', (172, 177))	('HPV', 'Species', '10566', (159, 162))	('miR-4306', 'Gene', '100422861', (78, 86))	('HNSCC', 'Phenotype', 'HP:0012288', (172, 177))	('correlate with', 'Reg', (123, 137))	('miR-21', 'Gene', (66, 72))	('patients', 'Species', '9606', (178, 186))	('miR-7161-39', 'Var', (92, 103))	('miR-4306', 'Gene', (78, 86))	('survival', 'CPA', (142, 150))	('miR-6508', 'Gene', (53, 61))	('miR-21', 'Gene', '406991', (66, 72))
305754	32456271	Bersani et al., showed that overexpression of miR-155 in tonsillar and base of tongue cancer (TSCC/BOTSCC) was associated with HPV positivity and improved survival, while low miR-185 expression associated with HPV negativity and decreased survival for the disease.	('HPV', 'Species', '10566', (210, 213))	('miR-185', 'Gene', '406961', (175, 182))	('HPV', 'Gene', (127, 130))	('TSCC', 'Phenotype', 'HP:0030413', (101, 105))	('miR-185', 'Gene', (175, 182))	('low', 'NegReg', (171, 174))	('survival', 'CPA', (155, 163))	('TSCC', 'Phenotype', 'HP:0030413', (94, 98))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('improved', 'PosReg', (146, 154))	('positivity', 'Var', (131, 141))	('miR-155', 'Gene', '406947', (46, 53))	('decreased', 'NegReg', (229, 238))	('overexpression', 'PosReg', (28, 42))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('HPV', 'Species', '10566', (127, 130))	('miR-155', 'Gene', (46, 53))	('cancer', 'Disease', (86, 92))
305762	32456271	A previous report showed that miR-133a-3p was underexpressed in oropharyngeal squamous cell carcinoma tissues originated from HPV(+) smoker patients in comparison with that ones from HPV(+) non-smokers.	('oropharyngeal squamous cell carcinoma', 'Phenotype', 'HP:0012182', (64, 101))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('miR-1', 'Gene', '79187', (30, 35))	('HPV', 'Species', '10566', (183, 186))	('miR-1', 'Gene', (30, 35))	('patients', 'Species', '9606', (140, 148))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (78, 101))	('squamous cell carcinoma', 'Disease', (78, 101))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (78, 101))	('HPV(+', 'Var', (126, 131))	('HPV', 'Species', '10566', (126, 129))
305765	32456271	demonstrated that high expression of miR-499a was associated with lower overall survival and N stage in high tobacco exposed HNSCC patients.	('patients', 'Species', '9606', (131, 139))	('tobacco', 'Species', '4097', (109, 116))	('HNSCC', 'Phenotype', 'HP:0012288', (125, 130))	('N stage', 'CPA', (93, 100))	('overall survival', 'CPA', (72, 88))	('lower', 'NegReg', (66, 71))	('miR-499a', 'Var', (37, 45))
305772	32456271	A comprehensive study showed the deregulation of 4 miRNAs (miR-101, 181b, miR-486, and miR-1301) in epithelial cells (HaCaT and OKF4) exposed to cigarette treatment, indicating their involvement in smoking-related HNSCC development.	('HaCa', 'CellLine', 'CVCL:4970', (118, 122))	('involvement', 'Reg', (183, 194))	('miR-101', 'Var', (59, 66))	('miR-486', 'Gene', (74, 81))	('181b', 'Var', (68, 72))	('miR-1301', 'Gene', (87, 95))	('deregulation', 'MPA', (33, 45))	('miR-1301', 'Gene', '100302246', (87, 95))	('miR-486', 'Gene', '619554', (74, 81))	('HNSCC', 'Phenotype', 'HP:0012288', (214, 219))
305775	32456271	Single and combinatorial miRNA in silico analysis revealed that miRNAs dysregulated targeted genes and pathways that are involved in cancers.	('dysregulated', 'Reg', (71, 83))	('cancers', 'Phenotype', 'HP:0002664', (133, 140))	('pathways', 'Pathway', (103, 111))	('cancers', 'Disease', (133, 140))	('miRNAs', 'Var', (64, 70))	('cancers', 'Disease', 'MESH:D009369', (133, 140))	('genes', 'Gene', (93, 98))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
305789	32456271	Hemolysis and above-described both clinical and experimental variations also influence circulating miRNA profiles, eventually giving us conflicting findings.	('Hemolysis', 'Disease', 'MESH:D006461', (0, 9))	('influence', 'Reg', (77, 86))	('circulating miRNA profiles', 'MPA', (87, 113))	('Hemolysis', 'Disease', (0, 9))	('variations', 'Var', (61, 71))
305815	29163698	During the follow-up period, it is easy to harvest peripheral blood from OSCC patients, and our hypothesis is that CKs in the peripheral blood may predict recurrences and metastases.	('patients', 'Species', '9606', (78, 86))	('CKs', 'Var', (115, 118))	('metastases', 'Disease', (171, 181))	('recurrences', 'CPA', (155, 166))	('predict', 'Reg', (147, 154))	('metastases', 'Disease', 'MESH:D009362', (171, 181))
305827	29163698	Real-time RT-PCR analyses for CK17 mRNA, CK19 mRNA, CK20 mRNA and GAPDH mRNA (normalization) were performed using QuantiTect Primer Assay 200 (Hs KRT17 1 SG; QT00001680, QT00081137, QT00014784 and QT00079247, respectively; Qiagen GmbH).	('CK19', 'Gene', '3880', (41, 45))	('GAPDH', 'Gene', '2597', (66, 71))	('KRT17', 'Gene', (146, 151))	('CK20', 'Gene', (52, 56))	('GAPDH', 'Gene', (66, 71))	('CK17', 'Gene', (30, 34))	('CK17', 'Gene', '3872', (30, 34))	('QT00014784', 'Var', (182, 192))	('QT00001680', 'Var', (158, 168))	('QT00081137', 'Var', (170, 180))	('CK20', 'Gene', '54474', (52, 56))	('CK19', 'Gene', (41, 45))	('QT00079247', 'Var', (197, 207))	('KRT17', 'Gene', '3872', (146, 151))
305886	29163698	According to Frank Macfarlane Burnet, 3,000 cancer cells are made a day on healthy people due to gene transcription mistake etc.	('gene transcription mistake', 'Var', (97, 123))	('people', 'Species', '9606', (83, 89))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
305894	33291726	Global Autozygosity Is Associated with Cancer Risk, Mutational Signature and Prognosis Global autozygosity in the form of runs of homozygosity is associated with various diseases.	('Cancer', 'Disease', 'MESH:D009369', (39, 45))	('Cancer', 'Phenotype', 'HP:0002664', (39, 45))	('Global Autozygosity', 'Var', (0, 19))	('associated', 'Reg', (146, 156))	('Cancer', 'Disease', (39, 45))	('Associated', 'Reg', (23, 33))
305896	33291726	Our analysis shows strong and consistent associations between heterozygosity ratios and various cancer types.	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('heterozygosity ratios', 'Var', (62, 83))	('cancer', 'Disease', (96, 102))	('cancer', 'Disease', 'MESH:D009369', (96, 102))
305897	33291726	Further analysis reveals the heterozygosity ratio's potential connections to mutational signatures and cancer prognosis.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('connections', 'Reg', (62, 73))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('heterozygosity ratio', 'Var', (29, 49))
305899	33291726	From 4057 cancer subjects and 1668 healthy controls, we found strong associations between global autozygosity and risk in ten different cancer types.	('global autozygosity', 'Var', (90, 109))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('cancer', 'Disease', (136, 142))	('cancer', 'Disease', 'MESH:D009369', (10, 16))	('cancer', 'Disease', (10, 16))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
305900	33291726	For example, the heterozygosity ratio was found to be significantly associated with breast invasive carcinoma in Blacks and with male skin cutaneous melanoma in Caucasians.	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('associated', 'Reg', (68, 78))	('heterozygosity ratio', 'Var', (17, 37))	('melanoma', 'Phenotype', 'HP:0002861', (149, 157))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (139, 157))	('male skin cutaneous melanoma', 'Disease', 'MESH:D018567', (129, 157))	('breast invasive carcinoma', 'Disease', 'MESH:D001943', (84, 109))	('breast invasive carcinoma', 'Phenotype', 'HP:0003002', (84, 109))	('breast invasive carcinoma', 'Disease', (84, 109))	('male skin cutaneous melanoma', 'Disease', (129, 157))
305903	33291726	According to the GWAS catalog (May 2020), 4424 unique SNPs have been found to influence cancer risk with p < 10-5 significance.	('influence', 'Reg', (78, 87))	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('SNPs', 'Var', (54, 58))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))
305919	33291726	By comparing The Cancer Genome Atlas (TCGA) SNP data and reference allele in the GRCh38 genome, we estimated that around 8% of the variants in the human reference genome may not represent the major allele of the population.	('human', 'Species', '9606', (147, 152))	('Cancer', 'Disease', (17, 23))	('variants', 'Var', (131, 139))	('Cancer', 'Disease', 'MESH:D009369', (17, 23))	('Cancer', 'Phenotype', 'HP:0002664', (17, 23))
305960	33291726	Linear regression models were used to describe the association between mutational signatures and HRNonRef and ROH.	('ROH', 'Chemical', '-', (110, 113))	('HRNonRef', 'Disease', (97, 105))	('association', 'Interaction', (51, 62))	('mutational signatures', 'Var', (71, 92))	('ROH', 'Disease', (110, 113))
305962	33291726	Five of the seven significant HRNonRef associations were from the ovarian cancer dataset, and consisted of SBS9 , SBS18 , SBS5 , SBS7c , and SBS22 .	('HRNonRef', 'Gene', (30, 38))	('SBS5', 'Var', (122, 126))	('ovarian cancer', 'Phenotype', 'HP:0100615', (66, 80))	('ovarian cancer', 'Disease', (66, 80))	('SBS22', 'Var', (141, 146))	('SBS18', 'Var', (114, 119))	('SBS7c', 'Var', (129, 134))	('ovarian cancer', 'Disease', 'MESH:D010051', (66, 80))	('SBS9', 'Var', (107, 111))	('associations', 'Reg', (39, 51))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
305963	33291726	SBS18's etiology is proposed to be damaged by reactive oxygen species; SBS5's etiology is currently unknown; SBS7c is related to ultraviolet light damage and is possibly the consequence of translesion DNA synthesis by enzymes with a propensity to insert T, and SBS22 is related to aristolochic acid exposure.	('related', 'Reg', (118, 125))	('aristolochic acid', 'Chemical', 'MESH:C000228', (281, 298))	('SBS7c', 'Var', (109, 114))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (46, 69))
305964	33291726	The other two significant associations with HRNonRef were SBS44 (related to DNA mismatch repair,  in female skin cutaneous melanoma and SBS36 (related to defective base excision repair,  in prostate adenocarcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (204, 213))	('SBS44', 'Var', (58, 63))	('male skin cutaneous melanoma', 'Disease', (103, 131))	('prostate adenocarcinoma', 'Disease', (190, 213))	('melanoma', 'Phenotype', 'HP:0002861', (123, 131))	('SBS36', 'Var', (136, 141))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (113, 131))	('male skin cutaneous melanoma', 'Disease', 'MESH:D018567', (103, 131))
305966	33291726	The other three significant associations with ROH were SBS36 ( in prostate adenocarcinoma, SBS42 (related to haloalkanes exposure, ) in male lung squamous cell carcinoma, and SBS7b (related to ultraviolet light exposure,  in males in male lung squamous cell carcinoma.	('SBS36', 'Gene', (55, 60))	('prostate adenocarcinoma', 'Disease', (66, 89))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('SBS42', 'Gene', (91, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (160, 169))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (141, 169))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (146, 169))	('ROH', 'Chemical', '-', (46, 49))	('haloalkanes', 'Chemical', '-', (109, 120))	('ROH', 'Gene', (46, 49))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (239, 267))	('carcinoma', 'Phenotype', 'HP:0030731', (258, 267))	('SBS7b', 'Var', (175, 180))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (244, 267))
305971	33291726	Global autozygosity as a risk factor for diseases such as schizophrenia and Alzheimer's have been established.	('schizophrenia', 'Phenotype', 'HP:0100753', (58, 71))	('Alzheimer', 'Disease', 'MESH:D000544', (76, 85))	('Global autozygosity', 'Var', (0, 19))	('Alzheimer', 'Disease', (76, 85))	('schizophrenia', 'Disease', (58, 71))	('schizophrenia', 'Disease', 'MESH:D012559', (58, 71))
305978	33291726	The literature has shown that a single SNP can increase cancer risk.	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('increase', 'PosReg', (47, 55))	('SNP', 'Var', (39, 42))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('single SNP', 'Var', (32, 42))
305981	33291726	For example, germline variants in RBFOX1 increased the incidence of SF3B1 somatic mutation eight-fold via functional alterations in RNA splicing, and 19p13.3 variants were associated with a four-fold increased likelihood of somatic mutations in PTEN.	('alterations', 'Reg', (117, 128))	('RBFOX1', 'Gene', (34, 40))	('increased', 'PosReg', (41, 50))	('SF3B1', 'Gene', (68, 73))	('variants', 'Var', (158, 166))	('mutation', 'Var', (82, 90))	('RNA splicing', 'MPA', (132, 144))	('PTEN', 'Gene', (245, 249))	('PTEN', 'Gene', '5728', (245, 249))	('SF3B1', 'Gene', '23451', (68, 73))	('RBFOX1', 'Gene', '54715', (34, 40))
306000	33291726	The associations between mutational signatures and HRNonRef/ROH were found by linear regression (R glm function with family = Gaussian parameter).	('HRNonRef/ROH', 'Disease', (51, 63))	('mutational signatures', 'Var', (25, 46))	('ROH', 'Chemical', '-', (60, 63))	('associations', 'Interaction', (4, 16))
306005	33291726	More importantly, our study demonstrates the connections between global autozygosity and cancer risk.	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('connections', 'Interaction', (45, 56))	('cancer', 'Disease', (89, 95))	('global autozygosity', 'Var', (65, 84))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
306012	33291726	This research was supported by the Cancer Center Support Grant P30CA118100 and R01ES030993-01A1 from the National Cancer Institute of USA.	('R01ES030993-01A1', 'Var', (79, 95))	('P30CA118100', 'Var', (63, 74))	('Cancer', 'Phenotype', 'HP:0002664', (35, 41))	('R01ES030993-01A1', 'CellLine', 'CVCL:D092', (79, 95))	('Cancer', 'Disease', (35, 41))	('Cancer', 'Disease', (114, 120))	('Cancer', 'Phenotype', 'HP:0002664', (114, 120))	('Cancer', 'Disease', 'MESH:D009369', (35, 41))	('Cancer', 'Disease', 'MESH:D009369', (114, 120))
306017	32618129	Following this, we performed HPV DNA typing and the sensitive RNAscope in situ method to screen all the cases for HPV E6/E7 expression, which is a more reliable indicator of transcriptively active HPV in tumor cells.	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('HPV', 'Gene', (114, 117))	('tumor', 'Disease', (204, 209))	('E6/E7 expression', 'Var', (118, 134))
306026	32618129	Novel strategies based on molecular genetic fingerprinting such as microsatellite alterations and gene mutations have been introduced to clarify the distinction between a second primary tumor and lung metastasis.	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('mutations', 'Var', (103, 112))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('tumor', 'Disease', (186, 191))	('microsatellite alterations', 'Var', (67, 93))
306102	32618129	Conversely, the RNAscope, a new method is not limited by mRNA quality which can directly visualize E6/E7mRNA transcripts in tumor cells on FFPE histologic sections by ISH.	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('tumor', 'Disease', (124, 129))	('E6/E7mRNA', 'Var', (99, 108))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
306173	30732595	Superficial neoplastic cells from corneal epithelium were positive for CK5/6 but deeper acinar formations were negative for both CK5/6 and CK7.	('CK5/6', 'Var', (71, 76))	('CK7', 'Gene', (139, 142))	('positive', 'Reg', (58, 66))	('CK7', 'Gene', '477602', (139, 142))
306269	25491122	This assumption does not hold for biological situations where interactions between features are not necessarily preserved between classes, and this occurs frequently in biology when considering the possible effects of canalizing genes, nonlinear gene regulation, and mutations in the case of cancer.	('cancer', 'Disease', (292, 298))	('cancer', 'Disease', 'MESH:D009369', (292, 298))	('cancer', 'Phenotype', 'HP:0002664', (292, 298))	('mutations', 'Var', (267, 276))
306270	25491122	And finally, if one class represents normal gene expression and the other tumor-related expression, then a correlation might exist from a functioning pathway in the normal tissue, but a mutation could result in a lack of correlation effects in the tumor.	('tumor', 'Disease', (248, 253))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor', 'Disease', (74, 79))	('tumor', 'Disease', 'MESH:D009369', (248, 253))	('tumor', 'Phenotype', 'HP:0002664', (248, 253))	('mutation', 'Var', (186, 194))
306334	33247676	Only those curves are presented herein which showed significant differences in overall survival (p<0.05) of patients with high cut-off values compared to those with low cut-off values.	('patients', 'Species', '9606', (108, 116))	('high cut-off values', 'Var', (122, 141))	('differences', 'Reg', (64, 75))
306344	33247676	For mutation, it provides mutation ID, details of genetic change, protein change, type of mutation and its VEP impact across all available TCGA tumour data sets.	('tumour', 'Disease', 'MESH:D009369', (144, 150))	('tumour', 'Disease', (144, 150))	('tumour', 'Phenotype', 'HP:0002664', (144, 150))	('mutation', 'Var', (26, 34))
306380	33247676	TC2N mutation profile in pan-cancer  Our analyses show several frequent somatic mutations in TC2N gene in various cancers.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('cancers', 'Disease', 'MESH:D009369', (114, 121))	('cancer', 'Disease', (29, 35))	('cancers', 'Phenotype', 'HP:0002664', (114, 121))	('cancers', 'Disease', (114, 121))	('mutations', 'Var', (80, 89))	('TC2N', 'Gene', '123036', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('TC2N', 'Gene', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('TC2N', 'Gene', '123036', (93, 97))	('TC2N', 'Gene', (93, 97))	('cancer', 'Disease', 'MESH:D009369', (29, 35))	('cancer', 'Disease', (114, 120))
306381	33247676	A total of 142 mutations were identified across 145 cases in a total of 18 TCGA tumour types.	('tumour', 'Disease', (80, 86))	('mutations', 'Var', (15, 24))	('TCGA', 'Disease', (75, 79))	('tumour', 'Phenotype', 'HP:0002664', (80, 86))	('tumour', 'Disease', 'MESH:D009369', (80, 86))	('identified', 'Reg', (30, 40))
306382	33247676	Highest pathogenic mutation rates of TC2N were present in SKCM, UCEC, COAD, BLCA and BRCA (Table 3).	('BLCA', 'Disease', (76, 80))	('COAD', 'Disease', 'MESH:D029424', (70, 74))	('BRCA', 'Gene', (85, 89))	('mutation', 'Var', (19, 27))	('pathogenic', 'Reg', (8, 18))	('TC2N', 'Gene', (37, 41))	('BRCA', 'Gene', '672;675', (85, 89))	('UCEC', 'Disease', (64, 68))	('COAD', 'Disease', (70, 74))	('TC2N', 'Gene', '123036', (37, 41))	('SKCM', 'Disease', (58, 62))
306393	33247676	Promoter hypermethylation is a key feature for transcriptional silencing of several genes in cancer (Park, 2010).	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('Promoter hypermethylation', 'Var', (0, 25))
306394	33247676	In particular, tumour suppressor genes are silenced via hypermethylation in several caners (Nag and Yu, 2015).	('tumour', 'Disease', 'MESH:D009369', (15, 21))	('tumour', 'Disease', (15, 21))	('hypermethylation', 'Var', (56, 72))	('Nag', 'Gene', (92, 95))	('silenced', 'NegReg', (43, 51))	('Nag', 'Gene', '51594', (92, 95))	('tumour', 'Phenotype', 'HP:0002664', (15, 21))
306395	33247676	We also found TC2N promoter hypomethylation in HNSC and KIRC.	('TC2N', 'Gene', (14, 18))	('hypomethylation', 'Var', (28, 43))	('TC2N', 'Gene', '123036', (14, 18))
306396	33247676	There are evidence that hypomethylation may lead to increased genomic stability that may contribute towards carcinogenesis (Pfeifer, 2018).	('increased', 'PosReg', (52, 61))	('genomic stability', 'CPA', (62, 79))	('contribute', 'Reg', (89, 99))	('hypomethylation', 'Var', (24, 39))	('carcinogenesis', 'Disease', 'MESH:D063646', (108, 122))	('carcinogenesis', 'Disease', (108, 122))
306397	33247676	Moreover, DNA hypomethylation also leads to overexpression of proinvasive, antiapoptotic and angiogenic factors in prostate cancer (Vestergaar et al., 2010).	('prostate cancer', 'Disease', (115, 130))	('hypomethylation', 'Var', (14, 29))	('overexpression', 'PosReg', (44, 58))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('prostate cancer', 'Disease', 'MESH:D011471', (115, 130))	('prostate cancer', 'Phenotype', 'HP:0012125', (115, 130))	('DNA', 'Var', (10, 13))
306398	33247676	In summary, TC2N promoter hyper and hypo-methylation are important findings of this study demanding further exploration.	('TC2N', 'Gene', '123036', (12, 16))	('hyper', 'Var', (26, 31))	('hypo-methylation', 'Var', (36, 52))	('TC2N', 'Gene', (12, 16))
306407	33247676	In a recent study that recruited 28 highly-aggregated-extended-highrisk-familial-lung-cancer (HRFLC) families, highest cluster of genetic variants associated with lung cancer were identified within CATSPERB gene (14q32) (Musolf et al., 2019).	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('lung cancer', 'Disease', 'MESH:D008175', (163, 174))	('associated', 'Reg', (147, 157))	('familial-lung-cancer', 'Disease', (72, 92))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('CATSPERB', 'Gene', (198, 206))	('variants', 'Var', (138, 146))	('familial-lung-cancer', 'Disease', 'MESH:D008175', (72, 92))	('lung cancer', 'Phenotype', 'HP:0100526', (163, 174))	('lung cancer', 'Disease', (163, 174))	('CATSPERB', 'Gene', '79820', (198, 206))
306411	33247676	We identified a range of genetic alterations in the TC2N gene in several cancers.	('cancers', 'Disease', (73, 80))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('TC2N', 'Gene', '123036', (52, 56))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('TC2N', 'Gene', (52, 56))	('cancers', 'Disease', 'MESH:D009369', (73, 80))	('genetic alterations', 'Var', (25, 44))
306412	33247676	The highest pathogenic non-synonymous mutation rates were observed in SKCM, UCEC, COAD, BLCA and BRCA.	('COAD', 'Disease', (82, 86))	('UCEC', 'Disease', (76, 80))	('non-synonymous mutation', 'Var', (23, 46))	('SKCM', 'Disease', (70, 74))	('pathogenic', 'Reg', (12, 22))	('BLCA', 'Disease', (88, 92))	('COAD', 'Disease', 'MESH:D029424', (82, 86))	('BRCA', 'Gene', (97, 101))	('BRCA', 'Gene', '672;675', (97, 101))
306413	33247676	Whether these genetic mutations are causative or a sequel of cancer processes needs to be investigated.	('genetic mutations', 'Var', (14, 31))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('cancer', 'Disease', (61, 67))	('cancer', 'Disease', 'MESH:D009369', (61, 67))
306414	33247676	It is important to note that cancer cells are susceptible to accumulate several mutations for multiple reasons such as increased cellular turnover, inflammatory tumour microenvironment, altered metabolic wiring, increased reactive oxygen species, increased susceptibility to DNA damage and decreased capacity of DNA damage repair amongst others (Loeb and Loeb, 2000; Hanahan and Weinberg, 2011; Fouad and Anani, 2017).	('decreased', 'NegReg', (290, 299))	('oxygen', 'Chemical', 'MESH:D010100', (231, 237))	('cancer', 'Disease', (29, 35))	('susceptibility', 'MPA', (257, 271))	('mutations', 'Var', (80, 89))	('increased reactive oxygen species', 'Phenotype', 'HP:0025464', (212, 245))	('metabolic wiring', 'CPA', (194, 210))	('tumour', 'Phenotype', 'HP:0002664', (161, 167))	('tumour', 'Disease', 'MESH:D009369', (161, 167))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('altered', 'Reg', (186, 193))	('tumour', 'Disease', (161, 167))	('increased', 'PosReg', (212, 221))	('cancer', 'Disease', 'MESH:D009369', (29, 35))	('reactive oxygen species', 'MPA', (222, 245))	('increased', 'PosReg', (119, 128))	('cellular turnover', 'CPA', (129, 146))
306423	30998743	Prevalence of p53 dysregulations in feline oral squamous cell carcinoma and non-neoplastic oral mucosa Squamous cell carcinoma is the most common malignant oral tumor in cats.	('cats', 'Species', '9685', (170, 174))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (43, 71))	('dysregulations', 'Var', (18, 32))	('Squamous cell carcinoma', 'Disease', 'MESH:D002294', (103, 126))	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('p53', 'Gene', (14, 17))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('oral squamous cell carcinoma', 'Disease', (43, 71))	('neoplastic oral mucosa', 'Phenotype', 'HP:0100649', (80, 102))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (48, 71))	('Squamous cell carcinoma', 'Disease', (103, 126))	('Squamous cell carcinoma', 'Phenotype', 'HP:0002860', (103, 126))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('tumor', 'Disease', (161, 166))	('oral tumor in cats', 'Phenotype', 'HP:0100649', (156, 174))	('p53', 'Gene', '403869', (14, 17))	('carcinoma', 'Phenotype', 'HP:0030731', (62, 71))
306424	30998743	The immunohistochemical expression of the p53 tumor suppressor protein has been reported in 24% to 65% of feline oral squamous cell carcinomas, but no study has systematically evaluated in this tumor the presence of p53 encoding gene (TP53) mutations.	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (118, 142))	('tumor', 'Disease', 'MESH:D009369', (46, 51))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('oral squamous cell carcinomas', 'Disease', 'MESH:D002294', (113, 142))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (118, 141))	('tumor', 'Disease', (46, 51))	('oral squamous cell carcinomas', 'Disease', (113, 142))	('carcinomas', 'Phenotype', 'HP:0030731', (132, 142))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('tumor', 'Disease', (194, 199))	('TP53', 'Gene', (235, 239))	('mutations', 'Var', (241, 250))
306426	30998743	Additionally, the prevalence of p53 dysregulation in feline oral squamous cell carcinoma was compared with that of feline non-neoplastic oral mucosa, in order to investigate the relevance of these dysregulations in cancer development.	('dysregulation', 'Var', (36, 49))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (65, 88))	('neoplastic oral mucosa', 'Phenotype', 'HP:0100649', (126, 148))	('cancer', 'Disease', (215, 221))	('cancer', 'Disease', 'MESH:D009369', (215, 221))	('oral squamous cell carcinoma', 'Disease', (60, 88))	('p53', 'Gene', (32, 35))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (60, 88))
306429	30998743	Eighteen squamous cell carcinomas (69%) expressed p53 and 18 had mutations in exons 5-8 of TP53.	('TP53', 'Gene', (91, 95))	('mutations in exons', 'Var', (65, 83))	('p53', 'Var', (50, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (23, 32))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (9, 32))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (9, 33))	('expressed', 'Reg', (40, 49))	('carcinomas', 'Phenotype', 'HP:0030731', (23, 33))	('squamous cell carcinomas', 'Disease', (9, 33))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (9, 33))
306430	30998743	None of non-neoplastic oral mucosa samples had a positive immunohistochemical staining, while one case each of eosinophilic granuloma and chronic gingivostomatitis harbored TP53 mutations.	('granuloma', 'Phenotype', 'HP:0032252', (124, 133))	('chronic gingivostomatitis', 'Disease', 'MESH:D013283', (138, 163))	('chronic gingivostomatitis', 'Phenotype', 'HP:0009098', (138, 163))	('chronic gingivostomatitis', 'Disease', (138, 163))	('eosinophilic granuloma', 'Phenotype', 'HP:0032253', (111, 133))	('eosinophilic granuloma', 'Disease', (111, 133))	('eosinophilic granuloma', 'Disease', 'MESH:D004802', (111, 133))	('gingivostomatitis', 'Phenotype', 'HP:0010280', (146, 163))	('TP53', 'Gene', (173, 177))	('stomatitis', 'Phenotype', 'HP:0010280', (153, 163))	('mutations', 'Var', (178, 187))	('neoplastic oral mucosa', 'Phenotype', 'HP:0100649', (12, 34))
306441	30998743	Although an anecdotal report exists of a TP53 mutation in a FOSCC, no study has systematically evaluated the presence of TP53 mutations in these tumors, nor their association with IHC protein expression.	('TP53', 'Gene', (41, 45))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('association', 'Interaction', (163, 174))	('tumors', 'Disease', (145, 151))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('tumors', 'Disease', 'MESH:D009369', (145, 151))	('mutation', 'Var', (46, 54))
306444	30998743	Additionally, the prevalence of p53 expression and mutations in FOSCC was compared with feline normal oral mucosa and oral inflammatory lesions, in order to investigate the relevance of p53 dysregulation in cancer development.	('cancer', 'Disease', 'MESH:D009369', (207, 213))	('mutations', 'Var', (51, 60))	('FOSCC', 'Gene', (64, 69))	('cancer', 'Disease', (207, 213))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))
306469	30998743	Of the 18 tumors with mutated TP53, 3 were p53-negative; among these, case 10 showed a PolyPhen2 score of 0.756, indicating only a possible damage; case 13 showed two mutations both with a PolyPhen2 score of 1.00, indicating full protein damage, with a 60% and 27% VAF for p.Y155* and p.R206Q respectively.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('p.Y155*', 'Var', (273, 280))	('p.R206Q', 'Var', (285, 292))	('tumors', 'Disease', (10, 16))	('tumors', 'Disease', 'MESH:D009369', (10, 16))	('tumors', 'Phenotype', 'HP:0002664', (10, 16))	('VAF', 'Chemical', '-', (265, 268))	('p.R206Q', 'Mutation', 'p.R206Q', (285, 292))	('p.Y155*', 'Mutation', 'p.Y155*', (273, 280))
306477	30998743	TP53 missense mutations were detected in one eosinophilic granuloma (10%) and one chronic gingivostomatitis (10%); mutations were located in exons 5 (n = 1), 6 (n = 1) and 7 (n = 2; S2 Table).	('stomatitis', 'Phenotype', 'HP:0010280', (97, 107))	('missense mutations', 'Var', (5, 23))	('TP53', 'Gene', (0, 4))	('eosinophilic granuloma', 'Phenotype', 'HP:0032253', (45, 67))	('chronic gingivostomatitis', 'Disease', (82, 107))	('eosinophilic granuloma', 'Disease', (45, 67))	('detected', 'Reg', (29, 37))	('chronic gingivostomatitis', 'Disease', 'MESH:D013283', (82, 107))	('eosinophilic granuloma', 'Disease', 'MESH:D004802', (45, 67))	('chronic gingivostomatitis', 'Phenotype', 'HP:0009098', (82, 107))	('gingivostomatitis', 'Phenotype', 'HP:0010280', (90, 107))	('granuloma', 'Phenotype', 'HP:0032252', (58, 67))
306481	30998743	Both p53 IHC overexpression and TP53 mutations were significantly more frequent in FOSCC, and mutated cases had a significantly lower MC (Tables 2 and 3).	('FOSCC', 'Disease', (83, 88))	('MC', 'Chemical', '-', (134, 136))	('mutations', 'Var', (37, 46))	('p53', 'Gene', (5, 8))	('overexpression', 'PosReg', (13, 27))	('TP53', 'Gene', (32, 36))	('lower', 'NegReg', (128, 133))	('lower MC', 'Phenotype', 'HP:0025066', (128, 136))
306483	30998743	This is also the most frequent site of somatic genomic alterations in HNSCC, and the most important region for folding and stabilization of the tertiary structure of the protein, suggesting the importance of the loss of function of the p53 pathway in the development and progression of oral cancer in both species.	('alterations', 'Var', (55, 66))	('loss of function', 'NegReg', (212, 228))	('cancer', 'Phenotype', 'HP:0002664', (291, 297))	('p53 pathway', 'Pathway', (236, 247))	('oral cancer', 'Disease', 'MESH:D009062', (286, 297))	('oral cancer', 'Disease', (286, 297))
306486	30998743	In case 13 the simultaneous presence of two damaging mutations (p.Y155*; p.R206Q) with high VAF and high Polyphen2 score may justify the loss of p53 staining.	('VAF', 'Chemical', '-', (92, 95))	('p.R206Q', 'Var', (73, 80))	('p.Y155*; p.R206Q', 'Var', (64, 80))	('p.R206Q', 'Mutation', 'p.R206Q', (73, 80))	('p.Y155*', 'Mutation', 'p.Y155*', (64, 71))
306487	30998743	The same immunostaining behavior was detected for case 6, harboring a damaging mutation in p.H207P, very close to p.R206Q.	('p.H207P', 'Var', (91, 98))	('p.R206Q', 'Var', (114, 121))	('p.H207P', 'Mutation', 'p.H207P', (91, 98))	('p.R206Q', 'Mutation', 'p.R206Q', (114, 121))
306490	30998743	A study on different canine neoplasms obtained the highest percentage of positive cases with the polyclonal antibody CM-1; nevertheless, in this study the PAb 240 clone was preferred, because it has been reported to produce less background staining than CM-1 and to recognize more specifically the mutant epitopes of p53.	('neoplasms', 'Disease', (28, 37))	('p53', 'Gene', (317, 320))	('neoplasms', 'Disease', 'MESH:D009369', (28, 37))	('background staining', 'MPA', (229, 248))	('neoplasms', 'Phenotype', 'HP:0002664', (28, 37))	('mutant', 'Var', (298, 304))	('canine', 'Species', '9615', (21, 27))
306492	30998743	This study reports a significantly higher prevalence of p53 dysregulation in FOSCC compared with non-neoplastic oral lesions, further supporting a role of p53 in oral tumorigenesis.	('p53', 'Protein', (56, 59))	('non-neoplastic oral lesions', 'Disease', 'MESH:D009062', (97, 124))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('non-neoplastic oral lesions', 'Disease', (97, 124))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('neoplastic oral lesions', 'Phenotype', 'HP:0100649', (101, 124))	('oral lesions', 'Phenotype', 'HP:0100649', (112, 124))	('FOSCC', 'Disease', (77, 82))	('tumor', 'Disease', (167, 172))	('dysregulation', 'Var', (60, 73))
306493	30998743	In humans, p53 mutations are important determinants of the malignant potential of oral lesions and have been detected in the saliva and blood of HNSCC-bearing patients.	('p53', 'Gene', (11, 14))	('malignant potential of oral lesions', 'Phenotype', 'HP:0100649', (59, 94))	('oral lesions', 'Disease', (82, 94))	('mutations', 'Var', (15, 24))	('humans', 'Species', '9606', (3, 9))	('oral lesions', 'Disease', 'MESH:D020820', (82, 94))	('oral lesions', 'Phenotype', 'HP:0100649', (82, 94))	('patients', 'Species', '9606', (159, 167))
306505	30998743	It remains to be determined if the screening for p53 dysregulations, alone or in association with other markers, may contribute to the early detection of this detrimental disease, and eventually help to make it more curable.	('detrimental disease', 'Disease', 'MESH:D004194', (159, 178))	('dysregulations', 'Var', (53, 67))	('p53', 'Gene', (49, 52))	('detrimental disease', 'Disease', (159, 178))
306526	30882635	The validation datasets were downloaded from the GEO database: GSE74706 from Marwitz, Depner et al, GSE67061 from Tong, Feng et al, and GSE18842 from Sanchez-Palencia et al.	('Sanchez-Palencia', 'Disease', (150, 166))	('Sanchez-Palencia', 'Disease', 'MESH:C535577', (150, 166))	('GSE67061', 'Var', (100, 108))	('GSE18842', 'Var', (136, 144))	('GSE74706', 'Var', (63, 71))
306571	29976244	HPV may cause the evasion of those mechanisms, which leads to host cell transformation.	('cause', 'Reg', (8, 13))	('HPV', 'Species', '10566', (0, 3))	('evasion', 'MPA', (18, 25))	('HPV', 'Var', (0, 3))	('host cell transformation', 'CPA', (62, 86))	('leads to', 'Reg', (53, 61))
306680	29976244	It was also observed MDSCs induced angiogenesis, inflammation and immunosuppression by the reduction of CTLs activities and upregulation of Treg cells.	('upregulation', 'PosReg', (124, 136))	('MDSCs', 'Var', (21, 26))	('Treg', 'Chemical', '-', (140, 144))	('Treg cells', 'CPA', (140, 150))	('reduction', 'NegReg', (91, 100))	('induced', 'Reg', (27, 34))	('CTLs activities', 'CPA', (104, 119))	('inflammation', 'Disease', 'MESH:D007249', (49, 61))	('angiogenesis', 'CPA', (35, 47))	('inflammation', 'Disease', (49, 61))
306684	29976244	Other immune approaches, in order to suppress MDSC functions and/or recruitment, are also being tested in HNSCC treatment, such as the depletion of MDSC along with anti-CTLA-4 monoclonal antibody (in order to enhance anti-CTLA-4 antitumor effects), the use of STAT3 (AZD9150), and the recruitment of inhibitors (e.g.	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('depletion', 'Var', (135, 144))	('enhance', 'PosReg', (209, 216))	('CTLA-4', 'Gene', '1493', (222, 228))	('AZD9150', 'Chemical', 'MESH:C000610954', (267, 274))	('tumor', 'Disease', (233, 238))	('STAT3', 'Gene', '6774', (260, 265))	('CTLA-4', 'Gene', (222, 228))	('CTLA-4', 'Gene', (169, 175))	('STAT3', 'Gene', (260, 265))	('MDSC', 'Gene', (148, 152))	('tumor', 'Disease', 'MESH:D009369', (233, 238))	('CTLA-4', 'Gene', '1493', (169, 175))
306703	29976244	In HPV positive specimens NLR was lower than in HPV negative samples, and when the HPV status was taken into account the association between NLR and survival was not statistically significant.	('HPV', 'Species', '10566', (48, 51))	('NLR', 'MPA', (26, 29))	('HPV', 'Species', '10566', (83, 86))	('lower', 'NegReg', (34, 39))	('positive', 'Var', (7, 15))	('HPV positive', 'Var', (3, 15))	('HPV', 'Species', '10566', (3, 6))
306705	29976244	Mature dendritic cells are those positive for CD11c, CD40, CD80, CD83, CD86, CD209 and HLA-DR markers, and are essential in immune response against HPV.	('CD86', 'Gene', (71, 75))	('CD8', 'Gene', '925', (71, 74))	('CD209', 'Var', (77, 82))	('CD80', 'Gene', (59, 63))	('HPV', 'Species', '10566', (148, 151))	('CD40', 'Var', (53, 57))	('CD8', 'Gene', (59, 62))	('CD8', 'Gene', (65, 68))	('CD8', 'Gene', '925', (59, 62))	('CD11c', 'Gene', '3687', (46, 51))	('CD8', 'Gene', '925', (65, 68))	('CD80', 'Gene', '941', (59, 63))	('CD11c', 'Gene', (46, 51))	('CD86', 'Gene', '942', (71, 75))	('CD8', 'Gene', (71, 74))
306721	29976244	The anti-PD-L1 antibodies durvalumab (NCT02207530) and atezolizumab (NCT03073525), and the anti-PD-1 antibodies pembrolizumab (NCT02291055, NCT02255097 and NCT02252042) and nivolumab (NCT02054806, NCT02105636 and NCT02488759) have been tested in clinical trials (phases I and II) for both cervical and head and neck cancers.	('nivolumab', 'Chemical', 'MESH:D000077594', (173, 182))	('NCT03073525', 'Var', (69, 80))	('NCT02291055', 'Var', (127, 138))	('NCT02105636', 'Var', (197, 208))	('NCT02255097', 'Var', (140, 151))	('NCT02054806', 'Var', (184, 195))	('cancer', 'Phenotype', 'HP:0002664', (316, 322))	('PD-L1', 'Gene', '29126', (9, 14))	('neck cancers', 'Disease', 'MESH:D006258', (311, 323))	('NCT02252042', 'Var', (156, 167))	('cervical', 'Disease', (289, 297))	('NCT02488759', 'Var', (213, 224))	('cancers', 'Phenotype', 'HP:0002664', (316, 323))	('head and neck cancers', 'Phenotype', 'HP:0012288', (302, 323))	('PD-L1', 'Gene', (9, 14))	('neck cancers', 'Disease', (311, 323))	('NCT02207530', 'Var', (38, 49))
306728	29976244	A decrease in tumor growth and in Treg and CTLA-4 levels was observed following TIM-3 blockade, while M2 macrophage markers were not altered.	('CTLA-4', 'Gene', '1493', (43, 49))	('decrease', 'NegReg', (2, 10))	('tumor', 'Disease', (14, 19))	('CTLA-4', 'Gene', (43, 49))	('TIM-3', 'Gene', '84868', (80, 85))	('TIM-3', 'Gene', (80, 85))	('Treg', 'Chemical', '-', (34, 38))	('blockade', 'Var', (86, 94))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
306729	29976244	Also, TIM-3 blockade caused a significant increase in IFN-gamma synthesis, which highlights the importance of the use of this immune checkpoint protein in possible future immunotherapeutic approaches.	('TIM-3', 'Gene', '84868', (6, 11))	('IFN-gamma', 'Gene', '3458', (54, 63))	('IFN-gamma', 'Gene', (54, 63))	('blockade', 'Var', (12, 20))	('increase', 'PosReg', (42, 50))	('TIM-3', 'Gene', (6, 11))
306741	29976244	Both oncoproteins (E6 and E7) are the closest to ideal tumor associated antigens.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Disease', (55, 60))	('E7', 'Var', (26, 28))	('E6', 'Var', (19, 21))
306748	29976244	CD40 showed the best activity (together with LOX-1 and Dectin-1) among DC surface receptors inducing protection in mice with HPV16 E7-expressing tumor.	('LOX-1', 'Gene', (45, 50))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('Dectin-1', 'Gene', '56644', (55, 63))	('protection', 'MPA', (101, 111))	('Dectin-1', 'Gene', (55, 63))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('HPV16', 'Species', '333760', (125, 130))	('tumor', 'Disease', (145, 150))	('CD40', 'Var', (0, 4))	('LOX-1', 'Gene', '108078', (45, 50))	('mice', 'Species', '10090', (115, 119))	('activity', 'MPA', (21, 29))
306760	29976244	It was also found that the number of LCs was significantly lower in HPV-positive patients than in HPV-negative ones, what could be related to viral oncogenes activities on LCs.	('lower', 'NegReg', (59, 64))	('LCs', 'Disease', (37, 40))	('patients', 'Species', '9606', (81, 89))	('HPV-positive', 'Var', (68, 80))	('HPV', 'Species', '10566', (98, 101))	('HPV', 'Species', '10566', (68, 71))
306761	29976244	In laryngeal squamous cell carcinoma, LCs infiltration was related to longer disease-free survival, lower local recurrence and less lymph node metastasis.	('disease-free survival', 'CPA', (77, 98))	('lymph node metastasis', 'CPA', (132, 153))	('carcinoma', 'Phenotype', 'HP:0030731', (27, 36))	('local recurrence', 'CPA', (106, 122))	('laryngeal squamous cell carcinoma', 'Disease', (3, 36))	('lower', 'NegReg', (100, 105))	('less', 'NegReg', (127, 131))	('longer', 'PosReg', (70, 76))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (13, 36))	('laryngeal squamous cell carcinoma', 'Disease', 'MESH:D002294', (3, 36))	('LCs', 'Var', (38, 41))
306771	29976244	It was observed, for example, that HPV16 E6 and E7 prevented type I IFN signalling, the synthesis of IFN-gamma induced by IL-18 and the expression of MHC class I, and CXCL14 (the latter two by HPV16 E7) to create an adverse microenvironment to NK cell cytotoxic activity.	('HPV16', 'Species', '333760', (35, 40))	('IFN', 'Gene', (101, 104))	('CXCL1', 'Gene', '2919', (167, 172))	('expression', 'MPA', (136, 146))	('HPV16', 'Species', '333760', (193, 198))	('IFN', 'Gene', '3439', (68, 71))	('IFN-gamma', 'Gene', '3458', (101, 110))	('IFN-gamma', 'Gene', (101, 110))	('CXCL1', 'Gene', (167, 172))	('MHC', 'Gene', (150, 153))	('IFN', 'Gene', (68, 71))	('prevented', 'NegReg', (51, 60))	('IL-18', 'Gene', '3606', (122, 127))	('IL-18', 'Gene', (122, 127))	('IFN', 'Gene', '3439', (101, 104))	('HPV16 E6', 'Var', (35, 43))	('MHC', 'Gene', '3107', (150, 153))
306788	29976244	A study revealed an increased expression of HLA-E associated with the absence of NK cells at tumor milieu and other study reported the downregulation of HLA-E by HPV E7 induced-methylation in human keratinocytes.	('increased', 'PosReg', (20, 29))	('expression', 'MPA', (30, 40))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('induced-methylation', 'Var', (169, 188))	('human', 'Species', '9606', (192, 197))	('HPV', 'Species', '10566', (162, 165))	('tumor', 'Disease', (93, 98))	('downregulation', 'NegReg', (135, 149))	('HLA-E', 'Gene', '3133', (44, 49))	('HLA-E', 'Gene', (153, 158))	('HLA-E', 'Gene', '3133', (153, 158))	('HLA-E', 'Gene', (44, 49))	('HPV E7', 'Gene', (162, 168))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
306791	29976244	This ligand might play its activities indirectly by the presence of HLA-E and several haplotypes were correlated with high-grade lesions.	('HLA-E', 'Gene', (68, 73))	('presence', 'Var', (56, 64))	('high-grade lesions', 'Disease', (118, 136))	('correlated', 'Reg', (102, 112))	('HLA-E', 'Gene', '3133', (68, 73))
306792	29976244	HLA-Cw group 1, in its turn, was observed to be significantly overtransmitted in women with invasive cervical cancer, especially in the women infected by HPV16 or 18, while HLA-Cw group 2 was associated with a decreased risk of cervical cancer development .	('cervical cancer', 'Disease', 'MESH:D002583', (101, 116))	('cervical cancer', 'Disease', (228, 243))	('cervical cancer', 'Disease', 'MESH:D002583', (228, 243))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('women', 'Species', '9606', (81, 86))	('HPV16', 'Species', '333760', (154, 159))	('HPV16', 'Var', (154, 159))	('women', 'Species', '9606', (136, 141))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('invasive cervical cancer', 'Disease', (92, 116))	('invasive cervical cancer', 'Disease', 'MESH:D002583', (92, 116))	('overtransmitted', 'PosReg', (62, 77))
306798	29976244	Altogether, these studies reveal that modulation of NK cell receptors and ligands affect immune response against HPV.	('modulation', 'Var', (38, 48))	('NK cell receptors', 'Protein', (52, 69))	('immune response against', 'CPA', (89, 112))	('HPV', 'Species', '10566', (113, 116))	('affect', 'Reg', (82, 88))
306809	29976244	Furthermore, the KIR receptors and its HLA ligands variability can also affect treatment response in monoclonal antibody therapy, as observed for anti-EGFR therapy in solid tumors.	('treatment response', 'MPA', (79, 97))	('affect', 'Reg', (72, 78))	('solid tumors', 'Disease', (167, 179))	('EGFR', 'Gene', (151, 155))	('KIR', 'Gene', (17, 20))	('solid tumors', 'Disease', 'MESH:D009369', (167, 179))	('KIR', 'Gene', '3805', (17, 20))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('variability', 'Var', (51, 62))	('tumors', 'Phenotype', 'HP:0002664', (173, 179))	('EGFR', 'Gene', '1956', (151, 155))
306822	29976244	It was found that NKT cell induced a paradoxical local immunosuppression in spite of producing IFN-gamma and that NKT cells caused immunosuppression and cancer development.	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('local immunosuppression', 'MPA', (49, 72))	('cancer', 'Disease', (153, 159))	('NKT', 'Var', (114, 117))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('IFN-gamma', 'Gene', '3458', (95, 104))	('IFN-gamma', 'Gene', (95, 104))	('immunosuppression', 'CPA', (131, 148))
306833	29318605	Critically short telomeres can trigger programmed cell death while cells with longer telomeres may have increased likelihood of replicative errors, resulting in genetic mutations and chromosomal alterations, and ultimately promoting oncogenesis.	('promoting', 'PosReg', (223, 232))	('short telomeres', 'Phenotype', 'HP:0031413', (11, 26))	('oncogenesis', 'CPA', (233, 244))	('death', 'Disease', 'MESH:D003643', (55, 60))	('genetic mutations', 'Var', (161, 178))	('resulting in', 'Reg', (148, 160))	('trigger', 'Reg', (31, 38))	('replicative', 'MPA', (128, 139))	('death', 'Disease', (55, 60))	('chromosomal alterations', 'CPA', (183, 206))
306841	29318605	The agreement of results from this prospective cohort study with those of previous prospective studies and Mendelian randomization studies suggest a possible etiological role of telomere length in the development of lung adenocarcinoma.	('lung adenocarcinoma', 'Disease', (216, 235))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (216, 235))	('men', 'Species', '9606', (9, 12))	('etiological', 'Reg', (158, 169))	('telomere length', 'Var', (178, 193))	('men', 'Species', '9606', (208, 211))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (216, 235))	('carcinoma', 'Phenotype', 'HP:0030731', (226, 235))
306851	29318605	Our findings of a statistically significant, robust association between longer telomeres and increased risk of lung adenocarcinoma, along with previous prospective and Mendelian randomization studies, strongly support to a possible etiological role of telomere length in the development of lung adenocarcinoma.	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (111, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (300, 309))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (290, 309))	('lung adenocarcinoma', 'Disease', (111, 130))	('men', 'Species', '9606', (282, 285))	('longer telomeres', 'Var', (72, 88))	('lung adenocarcinoma', 'Disease', (290, 309))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (111, 130))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (290, 309))
306873	29318605	Other potential confounders included in the multivariate Cox proportional hazards models were age, sex, dialect group (Hokkiens or Cantonese), level of education (no formal education, primary school, secondary or higher education), body mass index (<20, 20-<24, 24-<28, or >=28 kg/m2), and alcohol consumption (Non-drinkers, <7, or >=7 drinks per week).	('<20', 'Var', (249, 252))	('Cox', 'Gene', '1351', (57, 60))	('Cox', 'Gene', (57, 60))	('alcohol', 'Chemical', 'MESH:D000438', (290, 297))
306889	29318605	Longer telomeres were significantly associated with higher risk of lung adenocarcinoma after adjustment for multiple confounders or age alone (Supplemental Table 1).	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (67, 86))	('men', 'Species', '9606', (149, 152))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('lung adenocarcinoma', 'Disease', (67, 86))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (67, 86))	('men', 'Species', '9606', (99, 102))	('Longer telomeres', 'Var', (0, 16))
306891	29318605	Telomere length was not associated with risk of lung squamous carcinoma or other/unknown histological type of lung cancer after adjustment for age alone or multiple confounders (Supplemental Table 1, Table 3).	('lung squamous carcinoma', 'Disease', (48, 71))	('Telomere length', 'Var', (0, 15))	('carcinoma', 'Phenotype', 'HP:0030731', (62, 71))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (53, 71))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('lung squamous carcinoma', 'Disease', 'MESH:D002294', (48, 71))	('type of lung cancer', 'Disease', (102, 121))	('men', 'Species', '9606', (184, 187))	('lung cancer', 'Phenotype', 'HP:0100526', (110, 121))	('lung squamous carcinoma', 'Phenotype', 'HP:0030359', (48, 71))	('type of lung cancer', 'Disease', 'MESH:D008175', (102, 121))	('men', 'Species', '9606', (134, 137))
306892	29318605	A statistically significant, positive association between telomere length and risk of lung adenocarcinoma was present in both never (HR 3.14, 95% CI 1.80-5.49 comparing the highest with the lowest quintile, Ptrend<0.0001) and ever smokers (HR 2.46, 95% CI 1.45-4.18, Ptrend=0.0010) (Table 4).	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('lung adenocarcinoma', 'Disease', (86, 105))	('telomere', 'Var', (58, 66))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (86, 105))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (86, 105))
306899	29318605	In this population-based prospective cohort study of 26,540 individuals with an average follow-up of 12 years, we showed that longer telomeres in peripheral blood leukocytes were associated with significantly increased risk of developing lung adenocarcinoma, but not with squamous cell carcinoma or other histological types of cancer.	('cancer', 'Disease', (327, 333))	('squamous cell carcinoma', 'Disease', (272, 295))	('cancer', 'Disease', 'MESH:D009369', (327, 333))	('carcinoma', 'Phenotype', 'HP:0030731', (286, 295))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (272, 295))	('lung adenocarcinoma', 'Disease', (238, 257))	('cancer', 'Phenotype', 'HP:0002664', (327, 333))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (238, 257))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (238, 257))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (272, 295))	('longer telomeres', 'Var', (126, 142))	('carcinoma', 'Phenotype', 'HP:0030731', (248, 257))
306922	29318605	Clinical studies have found a statistically significant association between telomere length and higher percentage of regulatory T cells (Treg) in the blood from patients with hepatocellular or renal cell carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (204, 213))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (193, 213))	('hepatocellular or renal cell carcinoma', 'Disease', (175, 213))	('hepatocellular or renal cell carcinoma', 'Disease', 'MESH:C538614', (175, 213))	('patients', 'Species', '9606', (161, 169))	('telomere length', 'Var', (76, 91))	('higher', 'PosReg', (96, 102))
306932	29318605	In summary, the present study demonstrates a dose-dependent association for telomere length in peripheral blood leukocytes at baseline with increased risk of lung adenocarcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (168, 177))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (158, 177))	('lung adenocarcinoma', 'Disease', (158, 177))	('telomere length', 'Var', (76, 91))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (158, 177))
306933	29318605	Our findings and those from previous prospective studies and Mendelian randomization studies support a potential etiological role of telomere length in the development of lung adenocarcinoma.	('men', 'Species', '9606', (163, 166))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (171, 190))	('telomere', 'Var', (133, 141))	('carcinoma', 'Phenotype', 'HP:0030731', (181, 190))	('lung adenocarcinoma', 'Disease', (171, 190))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (171, 190))
306937	29318605	Consistent with results of recent prospective and Mendelian randomization studies, the findings of the present study support a potential etiological role of telomere length in the development of lung adenocarcinoma.	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (195, 214))	('men', 'Species', '9606', (187, 190))	('carcinoma', 'Phenotype', 'HP:0030731', (205, 214))	('etiological', 'Reg', (137, 148))	('telomere length', 'Var', (157, 172))	('lung adenocarcinoma', 'Disease', (195, 214))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (195, 214))
306945	28036280	We thus assume that the destruction of a coordinated regulatory network might result in tumorigenesis and tumor progression.	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('result in', 'Reg', (78, 87))	('destruction', 'Var', (24, 35))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Disease', (88, 93))	('tumor', 'Disease', (106, 111))
306949	28036280	They proposed that perturbation of these conserved genes was associated with embryonic lethality and cancer.	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('cancer', 'Disease', (101, 107))	('perturbation', 'Var', (19, 31))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('associated', 'Reg', (61, 71))	('embryonic lethality', 'Disease', 'MESH:D020964', (77, 96))	('embryonic lethality', 'Disease', (77, 96))
306988	28036280	Meanwhile, gene ontology (GO) analysis of DEGs (244 genes) in at least 12 cancers revealed that they were mainly enriched in the cell cycle (FDR corrected P-value 1.6260E-40, 77 genes), organelle organization (FDR corrected P-value 5.6591E-18, 68 genes), mitosis (FDR corrected P-value 1.3085E-35, 45 genes), etc., which were all closely related to tumor characteristics (Figures 4B, , and 4D).	('mitosis', 'Disease', 'None', (255, 262))	('cell cycle', 'CPA', (129, 139))	('FDR', 'Var', (210, 213))	('cancers', 'Disease', 'MESH:D009369', (74, 81))	('cancers', 'Phenotype', 'HP:0002664', (74, 81))	('cancers', 'Disease', (74, 81))	('tumor', 'Disease', 'MESH:D009369', (349, 354))	('FDR', 'Var', (264, 267))	('organelle organization', 'CPA', (186, 208))	('mitosis', 'Disease', (255, 262))	('tumor', 'Phenotype', 'HP:0002664', (349, 354))	('related', 'Reg', (338, 345))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('tumor', 'Disease', (349, 354))
306992	28036280	Additionally, they can be significantly separated into two groups (Supplementary Figure 3, logrank test, P < 0.05) based on 3~25 survival-related DEGs in each cancer (Supplementary Table 3).	('cancer', 'Disease', (159, 165))	('DEGs', 'Var', (146, 150))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('cancer', 'Disease', 'MESH:D009369', (159, 165))
307006	28036280	Further identification of shared DEGs between normal and tumor tissues uncovers dysregulation of cell cycle processes, which is one of the hallmarks in cancer.	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('dysregulation of cell cycle', 'Phenotype', 'HP:0011018', (80, 107))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('cell cycle processes', 'CPA', (97, 117))	('dysregulation', 'Var', (80, 93))	('tumor', 'Disease', (57, 62))
307012	28036280	It encodes thyroid peroxidase enzyme, which is a thyroid-specific glycosylated hemoprotein, and aberrant regulation of TPO can result in thyroid dyshormonogenesis.	('TPO', 'Gene', (119, 122))	('aberrant regulation', 'Var', (96, 115))	('thyroid dyshormonogenesis', 'Disease', (137, 162))	('result in', 'Reg', (127, 136))	('thyroid dyshormonogenesis', 'Disease', 'MESH:C564766', (137, 162))	('TPO', 'Gene', '7173', (119, 122))
307061	26773058	CrossHub evaluates the hyper/hypo-methylation score for paired samples according to: (i) the mean Deltabeta-value between matched normal and tumor tissues; (ii) the frequency of cases with  Deltabeta  > 0.4; and (iii) the P-value for Wilcoxon signed ranked test.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumor', 'Disease', (141, 146))	('Deltabeta', 'Var', (190, 199))	('Deltabeta-value', 'MPA', (98, 113))
307076	26773058	Studies with CBX3-knockdown assays revealed that depletion of CBX3 resulted in downregulation of a subset of genes co-localized with CBX3; loss of CBX3 leads to a dramatic accumulation of unspliced nascent transcripts.	('CBX3', 'Gene', '11335', (133, 137))	('CBX3', 'Gene', '11335', (147, 151))	('unspliced nascent transcripts', 'MPA', (188, 217))	('loss', 'Var', (139, 143))	('CBX3', 'Gene', '11335', (62, 66))	('accumulation', 'PosReg', (172, 184))	('CBX3', 'Gene', (13, 17))	('CBX3', 'Gene', (133, 137))	('downregulation', 'NegReg', (79, 93))	('CBX3', 'Gene', (147, 151))	('CBX3', 'Gene', (62, 66))	('CBX3', 'Gene', '11335', (13, 17))
307078	26773058	CBX3 gene fusions and overexpression were found in cancer.	('CBX3', 'Gene', (0, 4))	('overexpression', 'PosReg', (22, 36))	('CBX3', 'Gene', '11335', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('found', 'Reg', (42, 47))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('fusions', 'Var', (10, 17))
307101	26773058	While ChIP-Seq data with wide tissue/cell coverage provided information regarding the global presence of TFBS in the genome, the gene expression profiling or correlation analysis performed for the current biological material revealed gene-TF associations with functional impacts prevailing for a particular type of tissue, tumor or cell type.	('tumor', 'Phenotype', 'HP:0002664', (323, 328))	('TFBS', 'Chemical', '-', (105, 109))	('tumor', 'Disease', (323, 328))	('tumor', 'Disease', 'MESH:D009369', (323, 328))	('gene-TF', 'Var', (234, 241))
307109	26773058	Methylation of a single CpG dinucleotide, and to a lesser extent its nearest neighbors, was found to play a crucial role in the expression regulation of protein kinase gene ZAP-70 involved in T-cell signaling and determining the prognosis of chronic lymphocytic leukemia.	('Methylation', 'Var', (0, 11))	('leukemia', 'Phenotype', 'HP:0001909', (262, 270))	('chronic lymphocytic leukemia', 'Disease', 'MESH:D015451', (242, 270))	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (242, 270))	('expression', 'MPA', (128, 138))	('chronic lymphocytic leukemia', 'Disease', (242, 270))	('CpG dinucleotide', 'Chemical', 'MESH:C015772', (24, 40))	('ZAP-70', 'Gene', '7535', (173, 179))	('ZAP-70', 'Gene', (173, 179))
307110	26773058	Similarly, methylation of a single intronic CpG was shown to dramatically affect the expression of peroxisomal membrane protein PMP24.	('expression', 'MPA', (85, 95))	('PMP24', 'Gene', (128, 133))	('methylation', 'Var', (11, 22))	('affect', 'Reg', (74, 80))	('PMP24', 'Gene', '11264', (128, 133))
307117	31964245	MicroRNA-425-5p Inhibits Lung Cancer Cell Growth in Vitro and in Vivo by Downregulating TFIIB-Related Factor 2 Lung cancer is the most common cancer type with increasingly high incidence.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('Lung cancer', 'Disease', 'MESH:D008175', (111, 122))	('Cancer', 'Phenotype', 'HP:0002664', (30, 36))	('cancer', 'Disease', (116, 122))	('Inhibits', 'NegReg', (16, 24))	('Downregulating', 'NegReg', (73, 87))	('TFIIB-Related Factor 2', 'Gene', (88, 110))	('MicroRNA-425-5p', 'Var', (0, 15))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('Lung cancer', 'Phenotype', 'HP:0100526', (111, 122))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('Lung Cancer', 'Disease', (25, 36))	('Lung cancer', 'Disease', (111, 122))	('Lung Cancer', 'Phenotype', 'HP:0100526', (25, 36))	('cancer', 'Disease', (142, 148))
307119	31964245	Thus, we aimed to investigate the function of microRNA-425-5p in lung cancer development and the underlying mechanisms.	('lung cancer', 'Disease', 'MESH:D008175', (65, 76))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('lung cancer', 'Disease', (65, 76))	('lung cancer', 'Phenotype', 'HP:0100526', (65, 76))	('microRNA-425-5p', 'Var', (46, 61))
307120	31964245	MicroRNA-425-5p overexpression inhibited A549 lung cancer cell proliferation in vitro and in vivo.	('A549', 'CellLine', 'CVCL:0023', (41, 45))	('overexpression', 'PosReg', (16, 30))	('MicroRNA-425-5p', 'Var', (0, 15))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('lung cancer', 'Disease', 'MESH:D008175', (46, 57))	('inhibited', 'NegReg', (31, 40))	('lung cancer', 'Disease', (46, 57))	('lung cancer', 'Phenotype', 'HP:0100526', (46, 57))
307121	31964245	On the other hand, microRNA-425-5p inhibition increased A549 proliferation.	('increased', 'PosReg', (46, 55))	('A549', 'CellLine', 'CVCL:0023', (56, 60))	('microRNA-425-5p inhibition', 'Var', (19, 45))
307122	31964245	Mechanistically, the underlying mechanism by which microRNA-425-5p inhibits lung cancer cell growth was mediated through its ability in targeting and downregulating the TFIIB-related factor 2.	('lung cancer', 'Disease', 'MESH:D008175', (76, 87))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('microRNA-425-5p', 'Var', (51, 66))	('lung cancer', 'Disease', (76, 87))	('lung cancer', 'Phenotype', 'HP:0100526', (76, 87))	('inhibits', 'NegReg', (67, 75))	('downregulating', 'NegReg', (150, 164))	('TFIIB-related', 'Protein', (169, 182))
307123	31964245	Our results for the first time identified microRNA-425-5p as a tumor suppressor in lung cancer.	('tumor', 'Disease', (63, 68))	('lung cancer', 'Disease', 'MESH:D008175', (83, 94))	('microRNA-425-5p', 'Var', (42, 57))	('lung cancer', 'Disease', (83, 94))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('lung cancer', 'Phenotype', 'HP:0100526', (83, 94))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
307124	31964245	Thus, microRNA-425-5p may serve as a potential therapeutic target for lung cancer.	('lung cancer', 'Disease', 'MESH:D008175', (70, 81))	('microRNA-425-5p', 'Var', (6, 21))	('lung cancer', 'Disease', (70, 81))	('lung cancer', 'Phenotype', 'HP:0100526', (70, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))
307134	31964245	However, the role of microRNA-425-5p in lung cancer metastasis and the underlying mechanisms remain to be elucidated.	('lung cancer metastasis', 'Disease', (40, 62))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('microRNA-425-5p', 'Var', (21, 36))	('lung cancer metastasis', 'Disease', 'MESH:D008175', (40, 62))	('lung cancer', 'Phenotype', 'HP:0100526', (40, 51))
307143	31964245	In summary, our work suggests that microRNA-425-5p may be a novel target for the clinical treatment of lung cancer.	('lung cancer', 'Disease', 'MESH:D008175', (103, 114))	('microRNA-425-5p', 'Var', (35, 50))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('lung cancer', 'Disease', (103, 114))	('lung cancer', 'Phenotype', 'HP:0100526', (103, 114))
307163	31964245	These results indicate that microRNA-425-5p inhibits lung cancer cell growth in vitro.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('microRNA-425-5p', 'Var', (28, 43))	('lung cancer', 'Disease', 'MESH:D008175', (53, 64))	('inhibits', 'NegReg', (44, 52))	('lung cancer', 'Disease', (53, 64))	('lung cancer', 'Phenotype', 'HP:0100526', (53, 64))
307179	31964245	On the other hand, miR-425-5p overexpression or inhibition failed to alter the luciferase intensity in A549 cells transfected with mutant BRF2 3'-UTR (Figure 3C), suggesting that BRF2 was a direct target of miR-425-5p.	('miR-425-5p', 'Gene', (19, 29))	('mutant', 'Var', (131, 137))	('miR-425-5p', 'Gene', '100422898', (207, 217))	('A549', 'CellLine', 'CVCL:0023', (103, 107))	('luciferase', 'Enzyme', (79, 89))	('miR-425-5p', 'Gene', '100422898', (19, 29))	('BRF2', 'Gene', (138, 142))	('miR-425-5p', 'Gene', (207, 217))
307195	31964245	To our knowledge, malignant tumors are often caused by the imbalance between oncogenes and tumor suppressor genes in normal cells and abnormal expression and dysfunction of automatic regulation of normal genes.	('dysfunction', 'Var', (158, 169))	('tumor', 'Disease', (28, 33))	('expression', 'MPA', (143, 153))	('imbalance', 'Phenotype', 'HP:0002172', (59, 68))	('oncogenes', 'Gene', (77, 86))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('malignant tumors', 'Disease', (18, 34))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('imbalance', 'Var', (59, 68))	('automatic regulation', 'MPA', (173, 193))	('malignant tumors', 'Disease', 'MESH:D009369', (18, 34))	('tumor', 'Disease', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('caused by', 'Reg', (45, 54))
307196	31964245	Until now, not only coding genes but also noncoding RNAs have been found to be involved in cancer metastasis.	('noncoding RNAs', 'Var', (42, 56))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('involved', 'Reg', (79, 87))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))
307198	31964245	So far, microRNAs have been extensively demonstrated to play regulatory roles in various cancer types, such as miR-9, miR-134, miR199, miR-425, and so on.	('miR-9', 'Disease', (111, 116))	('miR-134', 'Gene', '406924', (118, 125))	('miR-134', 'Gene', (118, 125))	('miR-425', 'Var', (135, 142))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('miR199', 'Var', (127, 133))	('cancer', 'Disease', (89, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
307233	31911802	Specifically, the high-risk genotype HPV-16 accounts for the vast majority (about 90% to 95%) of HPV-positive OP-SCC, while the HPV type is more variable in OC-SCC.	('HPV-16', 'Species', '333760', (37, 43))	('HPV-positive', 'Var', (97, 109))	('OP-SCC', 'Disease', (110, 116))	('OC-SCC', 'Disease', (157, 163))	('OC-SCC', 'Disease', 'MESH:D002294', (157, 163))	('OP-SCC', 'Phenotype', 'HP:0012182', (110, 116))	('HPV-16', 'Var', (37, 43))
307240	31911802	Further bioinformatic analyses revealed that the risk score exhibited excellent prognostic value for stratifying patients irrespective of mutation or copy number variation (CNV) patterns, and this risk score was highly associated with cell-cycle processes.	('patients', 'Species', '9606', (113, 121))	('copy number variation', 'Var', (150, 171))	('cell-cycle processes', 'CPA', (235, 255))	('associated', 'Reg', (219, 229))
307265	31911802	There was also no significant difference regarding FAT1 mutation, which played a role in regulating the migration and invasion of OSCC cells through the localization of beta-catenin.	('invasion of OSCC cells', 'CPA', (118, 140))	('migration', 'CPA', (104, 113))	('beta-catenin', 'Gene', (169, 181))	('FAT1', 'Gene', '2195', (51, 55))	('mutation', 'Var', (56, 64))	('beta-catenin', 'Gene', '1499', (169, 181))	('FAT1', 'Gene', (51, 55))
307266	31911802	Only frequent mutations in NSD1 (P=0.034) were significantly enriched in cases with higher risk score.	('NSD1', 'Gene', '64324', (27, 31))	('mutations', 'Var', (14, 23))	('NSD1', 'Gene', (27, 31))
307268	31911802	There were some differences in the gene-level CNV landscape; however, the frequently deleted genomic regions were located at the 9p21.3 region encompassing the CDKN2A/CDKN2B (mean deletion -0.002 vs -0.138, P=0.015).	('deletion', 'Var', (180, 188))	('CDKN2B', 'Gene', (167, 173))	('CDKN2A', 'Gene', (160, 166))	('CDKN2A', 'Gene', '1029', (160, 166))	('CDKN2B', 'Gene', '1030', (167, 173))
307279	31911802	This result of the mutated genes suggested that it was the inflammatory responses and microenvironment that mainly contribute to the different prognosis rather than well-known tumorigenesis progresses.	('tumor', 'Disease', (176, 181))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('tumor', 'Disease', 'MESH:D009369', (176, 181))	('mutated', 'Var', (19, 26))
307280	31911802	Only frequent mutations in NSD1 were significantly enriched in cases with higher risk scores.	('NSD1', 'Gene', '64324', (27, 31))	('mutations', 'Var', (14, 23))	('NSD1', 'Gene', (27, 31))
307281	31911802	It was reported that NSD1 was more mutated in laryngeal and pharyngeal squamous cell carcinoma (L/P-SCC) than in OC-SCC, and given the role of NSD1 as a chromatin modifier, these mutations could contribute to cancer formation through a combination of rare germline variants and somatic loss-of-heterozygosity (LOH).	('NSD1', 'Gene', (21, 25))	('laryngeal', 'Disease', (46, 55))	('loss-of-heterozygosity', 'NegReg', (286, 308))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (71, 94))	('OC-SCC', 'Disease', (113, 119))	('contribute', 'Reg', (195, 205))	('OC-SCC', 'Disease', 'MESH:D002294', (113, 119))	('cancer', 'Disease', 'MESH:D009369', (209, 215))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (71, 94))	('NSD1', 'Gene', '64324', (143, 147))	('cancer', 'Disease', (209, 215))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('squamous cell carcinoma', 'Disease', (71, 94))	('pharyngeal squamous cell carcinoma', 'Phenotype', 'HP:0012182', (60, 94))	('mutations', 'Var', (179, 188))	('NSD1', 'Gene', '64324', (21, 25))	('NSD1', 'Gene', (143, 147))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
307285	31911802	The deletion of CDKN2A, a tumor suppressor gene that functions in G1 cell cycle control, was associated with poor prognosis and low survival rate in OC-SCC, and EGFR amplification was shown to be associated with advanced clinical stage in OC-SCC patients.	('EGFR', 'Gene', (161, 165))	('OC-SCC', 'Disease', (239, 245))	('poor', 'NegReg', (109, 113))	('OC-SCC', 'Disease', 'MESH:D002294', (239, 245))	('CDKN2A', 'Gene', (16, 22))	('associated', 'Reg', (196, 206))	('CDKN2A', 'Gene', '1029', (16, 22))	('patients', 'Species', '9606', (246, 254))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('deletion', 'Var', (4, 12))	('low', 'NegReg', (128, 131))	('OC-SCC', 'Disease', (149, 155))	('EGFR', 'Gene', '1956', (161, 165))	('tumor', 'Disease', (26, 31))	('survival', 'CPA', (132, 140))	('OC-SCC', 'Disease', 'MESH:D002294', (149, 155))
307311	24386425	In the present study, we focus on the gene dysregulation about tumorigenesis and regional lymph node metastasis in LSCC.	('tumor', 'Disease', (63, 68))	('dysregulation', 'Var', (43, 56))	('regional lymph node metastasis', 'CPA', (81, 111))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('LSCC', 'Disease', (115, 119))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
307342	24386425	Two subgroups of tumor samples were distinguishable in the training set based on the expression profile of the different genes, which suggested regional lymph node metastasis was affected by gene regulation in LSCC.	('gene regulation', 'Var', (191, 206))	('tumor', 'Disease', (17, 22))	('LSCC', 'Disease', (210, 214))	('regional lymph node metastasis', 'CPA', (144, 174))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('affected by', 'Reg', (179, 190))
307374	24386425	Suppressing endogenous eIF3a expression had been shown to reverse the malignant phenotype of human cancer cells and overexpression of eIF3a had been found in many cancers such as cancers of lung, breast, cervix, stomach, and esophagus.	('stomach', 'Disease', (212, 219))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('overexpression', 'PosReg', (116, 130))	('cancer', 'Disease', 'MESH:D009369', (163, 169))	('cancers', 'Disease', 'MESH:D009369', (163, 170))	('breast', 'Disease', (196, 202))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('lung', 'Disease', (190, 194))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('cancers', 'Disease', 'MESH:D009369', (179, 186))	('Suppressing', 'Var', (0, 11))	('human', 'Species', '9606', (93, 98))	('cancer', 'Disease', (163, 169))	('cancers', 'Phenotype', 'HP:0002664', (163, 170))	('cancers', 'Disease', (163, 170))	('found', 'Reg', (149, 154))	('cervix', 'Disease', (204, 210))	('eIF3a', 'Gene', (23, 28))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('cancer', 'Disease', (99, 105))	('esophagus', 'Disease', (225, 234))	('eIF3a', 'Gene', '8669', (23, 28))	('cancers', 'Phenotype', 'HP:0002664', (179, 186))	('eIF3a', 'Gene', (134, 139))	('eIF3a', 'Gene', '8669', (134, 139))	('cancers', 'Disease', (179, 186))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('cancer', 'Disease', (179, 185))
307398	33927753	In addition, the pathology of several thoracic malignancies, including lung cancer, esophageal cancer, and breast cancer, is found to exhibit dysregulated lncRNA expression in a variety of malignancies.	('thoracic malignancies', 'Disease', (38, 59))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('lung cancer', 'Disease', 'MESH:D008175', (71, 82))	('cancer', 'Disease', (95, 101))	('breast cancer', 'Phenotype', 'HP:0003002', (107, 120))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('thoracic malignancies', 'Disease', 'MESH:D013896', (38, 59))	('lung cancer', 'Phenotype', 'HP:0100526', (71, 82))	('malignancies', 'Disease', 'MESH:D009369', (47, 59))	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('malignancies', 'Disease', (47, 59))	('malignancies', 'Disease', 'MESH:D009369', (189, 201))	('breast cancer', 'Disease', 'MESH:D001943', (107, 120))	('breast cancer', 'Disease', (107, 120))	('malignancies', 'Disease', (189, 201))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('dysregulated', 'Var', (142, 154))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('lncRNA expression', 'MPA', (155, 172))	('lung cancer', 'Disease', (71, 82))	('cancer', 'Disease', (114, 120))
307422	33927753	When considering the interaction between lncRNAs and clinical features, only five lncRNAs (RP11_71E19.5, RP11_722E23.2, RP11_796E2.4, RP11_95O2.1, and AC004528.4) were significantly associated with patient survival (Figure 1C).	('RP11', 'Gene', '26121', (134, 138))	('patient', 'Species', '9606', (198, 205))	('AC004528.4', 'Var', (151, 161))	('associated with', 'Reg', (182, 197))	('RP11', 'Gene', (105, 109))	('RP11', 'Gene', (91, 95))	('RP11', 'Gene', (120, 124))	('RP11', 'Gene', (134, 138))	('RP11', 'Gene', '26121', (105, 109))	('RP11', 'Gene', '26121', (120, 124))	('patient survival', 'CPA', (198, 214))	('RP11', 'Gene', '26121', (91, 95))
307437	33927753	We found many biological pathways (BPs) influenced by mRNAs that correlate with biomarker lncRNA.	('mRNAs', 'Var', (54, 59))	('biological pathways', 'Pathway', (14, 33))	('influenced', 'Reg', (40, 50))	('BPs', 'Chemical', '-', (35, 38))
307439	33927753	Variation in lncRNA RP11-796E2.4 and RP11-95O2.1 expression mainly affects immune regulation, which is essential for the recognition and elimination of gastric tumor cells (Figures 5C,D).	('RP11', 'Gene', '26121', (20, 24))	('lncRNA', 'Gene', (13, 19))	('affects', 'Reg', (67, 74))	('gastric tumor', 'Disease', 'MESH:D013274', (152, 165))	('gastric tumor', 'Phenotype', 'HP:0006753', (152, 165))	('RP11', 'Gene', (37, 41))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('RP11', 'Gene', '26121', (37, 41))	('Variation', 'Var', (0, 9))	('immune regulation', 'MPA', (75, 92))	('gastric tumor', 'Disease', (152, 165))	('RP11', 'Gene', (20, 24))
307440	33927753	AC004528.4 was mainly involved in the epithelial-mesenchymal transition, which regulates the invasion and metastasis of cancer cells (; Figure 5E).	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('involved', 'Reg', (22, 30))	('AC004528.4', 'Var', (0, 10))	('epithelial-mesenchymal transition', 'CPA', (38, 71))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('invasion', 'CPA', (93, 101))
307506	33668046	Gene-specific TaqMan MicroRNA probes (Thermo Fisher Scientific) were utilized for quantitative analyses of miRNA transcript levels of miR-10a, miR-28, miR-99b, miR-141, miR-320b, and miR-3120.	('miR-99b', 'Gene', (151, 158))	('miR-3120', 'Gene', (183, 191))	('miR-10a', 'Gene', (134, 141))	('miR-99b', 'Gene', '407056', (151, 158))	('miR-141', 'Gene', (160, 167))	('miR-320b', 'Var', (169, 177))	('miR-28', 'Gene', (143, 149))	('miR-10a', 'Gene', '406902', (134, 141))	('miR-28', 'Gene', '407020', (143, 149))	('miR-141', 'Gene', '406933', (160, 167))	('miR-3120', 'Gene', '100422882', (183, 191))
307513	33668046	Of the 13 miRNAs, 6 genes (miR-10a, miR-28, miR-99b, miR-107, miR-320b, and miR-3120) were selected for further validation analyses because the 6 miRNAs obtained from a set of linear discriminant coefficients indicated an area in proximity of the LSQCC lineage.	('miR-28', 'Gene', '407020', (36, 42))	('miR-3120', 'Gene', '100422882', (76, 84))	('miR-107', 'Gene', '406901', (53, 60))	('miR-99b', 'Gene', (44, 51))	('LSQCC', 'Disease', (247, 252))	('miR-107', 'Gene', (53, 60))	('miR-10a', 'Gene', (27, 34))	('miR-99b', 'Gene', '407056', (44, 51))	('miR-10a', 'Gene', '406902', (27, 34))	('miR-28', 'Gene', (36, 42))	('miR-3120', 'Gene', (76, 84))	('miR-320b', 'Var', (62, 70))
307528	33668046	reported that loss of heterozygosity analysis might be useful if performed together with conventional clinico-histological assessments for the differential diagnosis of the 2 types of tumors.	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('tumors', 'Disease', 'MESH:D009369', (184, 190))	('tumors', 'Phenotype', 'HP:0002664', (184, 190))	('tumors', 'Disease', (184, 190))	('loss of heterozygosity analysis', 'Var', (14, 45))
307545	33668046	Therefore, our study's results support the notion that individual metastases express both different and common phenotypes, and genetic instability leads to clonal metastases becoming heterogeneous.	('metastases', 'Disease', (66, 76))	('metastases', 'Disease', (163, 173))	('metastases', 'Disease', 'MESH:D009362', (66, 76))	('genetic instability', 'Var', (127, 146))	('metastases', 'Disease', 'MESH:D009362', (163, 173))
307601	32207067	For example, in a 5-year cohort study of patients with psoriasis, use of the immunosuppressive therapy cyclosporine was associated with a 2-fold greater incidence of malignancy and a 6-fold greater incidence of nonmelanoma skin cancer (NMSC) compared with incidence in the general population.	('psoriasis', 'Phenotype', 'HP:0003765', (55, 64))	('cyclosporine', 'Var', (103, 115))	('cyclosporine', 'Chemical', 'MESH:D016572', (103, 115))	('skin cancer', 'Phenotype', 'HP:0008069', (223, 234))	('psoriasis', 'Disease', (55, 64))	('melanoma', 'Phenotype', 'HP:0002861', (214, 222))	('nonmelanoma skin cancer', 'Disease', (211, 234))	('malignancy', 'Disease', 'MESH:D009369', (166, 176))	('patients', 'Species', '9606', (41, 49))	('nonmelanoma skin cancer', 'Disease', 'MESH:D012878', (211, 234))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('malignancy', 'Disease', (166, 176))	('psoriasis', 'Disease', 'MESH:D011565', (55, 64))
307610	32207067	Consistent with this role of IL-12 in cancer surveillance, inhibition of IL-12/23p40 in a preclinical model enhanced tumor outgrowth.	('IL-12/23p40', 'Gene', (73, 84))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumor', 'Disease', (117, 122))	('enhanced', 'PosReg', (108, 116))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('inhibition', 'Var', (59, 69))	('cancer', 'Disease', (38, 44))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
307629	32207067	From week 12 to week 266, patients assigned to brodalumab received brodalumab 140 mg Q2W, Q4W, or Q8W or brodalumab 210 mg Q2W.	('Q8W', 'Mutation', 'p.Q8W', (98, 101))	('patients', 'Species', '9606', (26, 34))	('Q8W', 'Var', (98, 101))	('brodalumab', 'Chemical', 'MESH:C571216', (67, 77))	('Q4W', 'Var', (90, 93))	('brodalumab', 'Chemical', 'MESH:C571216', (105, 115))	('brodalumab', 'Chemical', 'MESH:C571216', (47, 57))
307657	32207067	Through week 12, one SEER-adjudicated malignancy (prostate cancer) occurred in a patient receiving ustekinumab, and one (penile squamous cell cancer) occurred among all patients receiving brodalumab.	('brodalumab', 'Chemical', 'MESH:C571216', (188, 198))	('malignancy', 'Disease', 'MESH:D009369', (38, 48))	('patients', 'Species', '9606', (169, 177))	('patient', 'Species', '9606', (81, 88))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (128, 148))	('malignancy', 'Disease', (38, 48))	('penile squamous cell cancer', 'Disease', 'MESH:D002294', (121, 148))	('penile squamous cell cancer', 'Disease', (121, 148))	('prostate cancer', 'Disease', (50, 65))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('ustekinumab', 'Var', (99, 110))	('ustekinumab', 'Chemical', 'MESH:D000069549', (99, 110))	('patient', 'Species', '9606', (169, 176))	('prostate cancer', 'Disease', 'MESH:D011471', (50, 65))	('prostate cancer', 'Phenotype', 'HP:0012125', (50, 65))
307706	32207067	There were also 972 reports of melanoma associated with TNFalpha inhibitors in the US Food and Drug Administration Adverse Events Reporting System database (from the date of approval for each drug through August 2012).	('TNFalpha', 'Gene', (56, 64))	('inhibitors', 'Var', (65, 75))	('melanoma', 'Disease', 'MESH:D008545', (31, 39))	('melanoma', 'Phenotype', 'HP:0002861', (31, 39))	('TNFalpha', 'Gene', '7124', (56, 64))	('melanoma', 'Disease', (31, 39))
307809	29617659	The recently published sarcoma TCGA marker paper utilized automated feature extraction of nuclear properties for correlation with copy number load and genomic doubling.	('copy', 'Var', (130, 134))	('sarcoma', 'Phenotype', 'HP:0100242', (23, 30))	('sarcoma', 'Disease', 'MESH:D012509', (23, 30))	('sarcoma', 'Disease', (23, 30))
307818	29617659	Integrated analysis of TIL maps and molecular data reveals patterns and associations that can improve our understanding of the tumor microenvironment, and we illustrate some emerging relationships in this work.	('tumor', 'Disease', (127, 132))	('associations', 'Var', (72, 84))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))
307867	29617659	If over half of a 50x50 patch intersects with a necrotic region, the patch is classified as non-lymphocyte-infiltrated.	('necrotic', 'Disease', (48, 56))	('50x50', 'Var', (18, 23))	('necrotic', 'Disease', 'MESH:D009336', (48, 56))
307904	27694893	These effects are mediated by activation of the ERK1/2 signalling pathway, and inhibition of this pathway with a specific ERK1/2 inhibitor (U0126) significantly impairs the tumour-promoting effects induced by TBL1XR1.	('ERK1/2', 'Gene', '5595;5594', (122, 128))	('ERK1/2', 'Gene', (48, 54))	('tumour', 'Disease', (173, 179))	('tumour', 'Disease', 'MESH:D009369', (173, 179))	('ERK1/2', 'Gene', '5595;5594', (48, 54))	('impairs', 'NegReg', (161, 168))	('tumour', 'Phenotype', 'HP:0002664', (173, 179))	('inhibition', 'NegReg', (79, 89))	('ERK1/2', 'Gene', (122, 128))	('U0126', 'Chemical', 'MESH:C113580', (140, 145))	('TBL1XR1', 'Var', (209, 216))
307905	27694893	Moreover, TBL1XR1 mediated ERK1/2 activation is dependent on the beta-catenin/MMP7/EGFR signalling pathway.	('EGFR', 'Gene', '1956', (83, 87))	('ERK1/2', 'Gene', (27, 33))	('MMP7', 'Gene', (78, 82))	('MMP7', 'Gene', '4316', (78, 82))	('ERK1/2', 'Gene', '5595;5594', (27, 33))	('EGFR', 'Gene', (83, 87))	('beta-catenin', 'Gene', '1499', (65, 77))	('TBL1XR1', 'Var', (10, 17))	('beta-catenin', 'Gene', (65, 77))
307906	27694893	In conclusion, TBL1XR1 contributes to GC tumorigenesis and progression through the activation of the beta-catenin/MMP7/EGFR/ERK signalling pathway and may act as a new therapeutic target for GC.	('GC', 'Phenotype', 'HP:0012126', (38, 40))	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('ERK', 'Gene', (124, 127))	('ERK', 'Gene', '5594', (124, 127))	('MMP7', 'Gene', '4316', (114, 118))	('tumor', 'Disease', (41, 46))	('beta-catenin', 'Gene', (101, 113))	('progression', 'CPA', (59, 70))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('GC', 'Phenotype', 'HP:0012126', (191, 193))	('EGFR', 'Gene', '1956', (119, 123))	('beta-catenin', 'Gene', '1499', (101, 113))	('TBL1XR1', 'Var', (15, 22))	('MMP7', 'Gene', (114, 118))	('EGFR', 'Gene', (119, 123))	('activation', 'PosReg', (83, 93))
307910	27694893	TBL1XR1 is an essential component of the SMRT (silencing mediator of retinoic acid and thyroid hormone receptors)/N-CoR (nuclear receptor corepressor)/HDAC3 (histone deacetylase 3)/TBL1 (transducin (beta)-like 1)/GPS2 (G-protein pathway suppressor 2) nuclear receptor corepressor complex, and overexpression of TBL1XR1 can induce gene repression by targeting gene promoters through transcription factors (TFs) and nuclear receptors (NRs).	('SMRT', 'Gene', '9612', (41, 45))	('GPS2', 'Gene', (213, 217))	('HDAC3', 'Gene', (151, 156))	('histone deacetylase 3', 'Gene', '8841', (158, 179))	('TBL1', 'Gene', '90665', (311, 315))	('TBL1', 'Gene', '90665', (0, 4))	('histone deacetylase 3', 'Gene', (158, 179))	('SMRT', 'Gene', (41, 45))	('TBL1', 'Gene', '90665', (181, 185))	('N-CoR', 'Gene', '9611', (114, 119))	('gene repression', 'MPA', (330, 345))	('HDAC3', 'Gene', '8841', (151, 156))	('N-CoR', 'Gene', (114, 119))	('TBL1', 'Gene', (311, 315))	('transducin (beta)-like 1', 'Gene', '90665', (187, 211))	('TBL1', 'Gene', (0, 4))	('GPS2', 'Gene', '2874', (213, 217))	('nuclear', 'Protein', (414, 421))	('overexpression', 'Var', (293, 307))	('induce', 'PosReg', (323, 329))	('TBL1', 'Gene', (181, 185))	('transducin (beta)-like 1', 'Gene', (187, 211))
307911	27694893	Many recurrent mutations and de novo deletions have been found in the TBL1XR1 gene, which are associated with intellectual disability.	('deletions', 'Var', (37, 46))	('intellectual disability', 'Phenotype', 'HP:0001249', (110, 133))	('mutations', 'Var', (15, 24))	('TBL1XR1', 'Gene', (70, 77))	('associated', 'Reg', (94, 104))	('intellectual disability', 'Disease', (110, 133))	('intellectual disability', 'Disease', 'MESH:D008607', (110, 133))
307912	27694893	Studies have shown that TBL1XR1 can mediate the activation of many different transduction pathways, such as NF-kappaB, NRs, Wnt/beta-catenin and Notch pathways.	('NRs', 'Pathway', (119, 122))	('Notch pathways', 'Pathway', (145, 159))	('beta-catenin', 'Gene', (128, 140))	('TBL1XR1', 'Var', (24, 31))	('NF-kappaB', 'Pathway', (108, 117))	('beta-catenin', 'Gene', '1499', (128, 140))	('activation', 'PosReg', (48, 58))	('transduction pathways', 'Pathway', (77, 98))
307917	27694893	A recent study showed that TBL1XR1 can also serve as an androgen receptor coactivator and suppress prostate cancer growth by directly activating androgen receptor target genes involved in cell differentiation and growth suppression, instead of cell proliferation.	('cell', 'CPA', (188, 192))	('androgen receptor', 'Gene', (145, 162))	('androgen receptor', 'Gene', (56, 73))	('suppress', 'NegReg', (90, 98))	('TBL1XR1', 'Var', (27, 34))	('prostate cancer', 'Disease', (99, 114))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('androgen receptor', 'Gene', '367', (145, 162))	('androgen receptor', 'Gene', '367', (56, 73))	('prostate cancer', 'Disease', 'MESH:D011471', (99, 114))	('activating', 'PosReg', (134, 144))	('prostate cancer', 'Phenotype', 'HP:0012125', (99, 114))
307920	27694893	Studies of TBL1XR1 with gain- and loss-of-function approaches in GC cells reveal that TBL1XR1 regulates cell growth, migration, invasion and epithelial-mesenchymal transition (EMT) in vitro, as well as tumorigenesis and peritoneal metastasis in vivo through the activation of the beta-catenin/MMP7/EGFR/ERK pathway in GC cells.	('GC', 'Phenotype', 'HP:0012126', (65, 67))	('ERK', 'Gene', '5594', (303, 306))	('cell growth', 'CPA', (104, 115))	('GC', 'Phenotype', 'HP:0012126', (318, 320))	('migration', 'CPA', (117, 126))	('tumor', 'Disease', (202, 207))	('activation', 'PosReg', (262, 272))	('peritoneal metastasis', 'CPA', (220, 241))	('EGFR', 'Gene', '1956', (298, 302))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('MMP7', 'Gene', (293, 297))	('invasion', 'CPA', (128, 136))	('ERK', 'Gene', (303, 306))	('TBL1XR1', 'Var', (86, 93))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('beta-catenin', 'Gene', (280, 292))	('epithelial-mesenchymal transition', 'CPA', (141, 174))	('beta-catenin', 'Gene', '1499', (280, 292))	('regulates', 'Reg', (94, 103))	('MMP7', 'Gene', '4316', (293, 297))	('EGFR', 'Gene', (298, 302))
307925	27694893	Furthermore, Kaplan-Meier survival analysis showed that patients with high TBL1XR1 expression had a shorter overall survival (Figure 1e).	('patients', 'Species', '9606', (56, 64))	('overall survival', 'MPA', (108, 124))	('TBL1XR1', 'Gene', (75, 82))	('shorter', 'NegReg', (100, 107))	('high', 'Var', (70, 74))
307926	27694893	To further elucidate the biological functions of TBL1XR1 in GC progression, TBL1XR1 expression in GC cells was silenced by transfecting TBL1XR1-shRNA (sh#1, sh#2, sh#3 and sh#4) into NCI-N87 and SGC7901 cells expressing high levels of TBL1XR1 (Figures 2a-c).	('GC', 'Phenotype', 'HP:0012126', (60, 62))	('sh#2', 'Gene', '100125854', (157, 161))	('silenced', 'NegReg', (111, 119))	('GC', 'Phenotype', 'HP:0012126', (196, 198))	('sh#3', 'Gene', (163, 167))	('TBL1XR1-shRNA', 'Var', (136, 149))	('sh#1', 'Gene', (151, 155))	('sh#4', 'Gene', (172, 176))	('sh#4', 'Gene', '100125850', (172, 176))	('sh#2', 'Gene', (157, 161))	('sh#3', 'Gene', '100125849', (163, 167))	('GC', 'Phenotype', 'HP:0012126', (98, 100))	('sh#1', 'Gene', '100125848', (151, 155))	('TBL1XR1', 'Gene', (76, 83))
307930	27694893	As shown in Figures 3g and h, TBL1XR1 knockdown significantly increased the expression levels of epithelial cell markers (alpha-catenin and E-cadherin), and decreased the expression levels of mesenchymal cell markers (N-cadherin and ZEB2), which suggests that TBL1XR1 silencing could reverse the EMT phenotypes of GC cells.	('increased', 'PosReg', (62, 71))	('silencing', 'Var', (268, 277))	('N-cadherin', 'Gene', '1000', (218, 228))	('TBL1XR1', 'Gene', (30, 37))	('ZEB2', 'Gene', '9839', (233, 237))	('expression levels', 'MPA', (76, 93))	('GC', 'Phenotype', 'HP:0012126', (314, 316))	('E-cadherin', 'Gene', (140, 150))	('E-cadherin', 'Gene', '999', (140, 150))	('decreased', 'NegReg', (157, 166))	('expression levels', 'MPA', (171, 188))	('ZEB2', 'Gene', (233, 237))	('knockdown', 'Var', (38, 47))	('N-cadherin', 'Gene', (218, 228))
307933	27694893	We first examined the TBL1XR1 and pERK1/2 (Thr202/Tyr204 phosphorylation of ERK) protein expression levels in GC and patient-matched normal gastric tissues by IHC and immunofluorescence staining, and found that the pERK1/2 expression level was positively correlated with TBL1XR1 (Figures 4a and b, Supplementary Figure S1).	('Tyr204', 'Chemical', '-', (50, 56))	('correlated', 'Reg', (255, 265))	('ERK', 'Gene', (35, 38))	('ERK1/2', 'Gene', (216, 222))	('expression level', 'MPA', (223, 239))	('ERK', 'Gene', (76, 79))	('ERK1/2', 'Gene', (35, 41))	('ERK1/2', 'Gene', '5595;5594', (35, 41))	('TBL1XR1', 'Var', (271, 278))	('ERK1/2', 'Gene', '5595;5594', (216, 222))	('GC', 'Phenotype', 'HP:0012126', (110, 112))	('ERK', 'Gene', '5594', (216, 219))	('patient', 'Species', '9606', (117, 124))	('ERK', 'Gene', '5594', (35, 38))	('Thr202', 'Chemical', '-', (43, 49))	('ERK', 'Gene', (216, 219))	('ERK', 'Gene', '5594', (76, 79))
307934	27694893	We next investigated the protein expression levels of pERK1/2 and TBL1XR1 in four GC cell lines, and found that both proteins were highly expressed in SGC7901 and NCI-N87 cells, while expression levels were significantly lower in MKN45 and BGC823 cells (Figure 4c), suggesting that the ERK1/2 signalling pathway may be involved in tumour-promotion effects induced by TBL1XR1.	('TBL1XR1', 'Var', (367, 374))	('tumour', 'Disease', 'MESH:D009369', (331, 337))	('SGC7901', 'Var', (151, 158))	('ERK1/2', 'Gene', (286, 292))	('GC', 'Phenotype', 'HP:0012126', (241, 243))	('tumour', 'Disease', (331, 337))	('ERK1/2', 'Gene', (55, 61))	('ERK1/2', 'Gene', '5595;5594', (55, 61))	('ERK1/2', 'Gene', '5595;5594', (286, 292))	('GC', 'Phenotype', 'HP:0012126', (152, 154))	('tumour', 'Phenotype', 'HP:0002664', (331, 337))	('GC', 'Phenotype', 'HP:0012126', (82, 84))
307935	27694893	To explore the involvement and functional effect of ERK1/2 activation in tumour promotion induced by TBL1XR1 in GC, we first treated SGC7901 cells and NCI-N87 cells expressing high levels of TBL1XR1 with a specific ERK1/2 inhibitor U0126.	('tumour', 'Disease', (73, 79))	('ERK1/2', 'Gene', '5595;5594', (52, 58))	('ERK1/2', 'Gene', (52, 58))	('GC', 'Phenotype', 'HP:0012126', (112, 114))	('tumour', 'Phenotype', 'HP:0002664', (73, 79))	('TBL1XR1', 'Var', (191, 198))	('ERK1/2', 'Gene', (215, 221))	('U0126', 'Chemical', 'MESH:C113580', (232, 237))	('tumour', 'Disease', 'MESH:D009369', (73, 79))	('ERK1/2', 'Gene', '5595;5594', (215, 221))	('GC', 'Phenotype', 'HP:0012126', (134, 136))
307936	27694893	We demonstrated that U0126 (20 muM) significantly suppressed GC cell proliferation, migration and invasion (Figures 4d-f).	('suppressed', 'NegReg', (50, 60))	('U0126', 'Chemical', 'MESH:C113580', (21, 26))	('muM', 'Gene', '56925', (31, 34))	('invasion', 'CPA', (98, 106))	('migration', 'CPA', (84, 93))	('U0126', 'Var', (21, 26))	('muM', 'Gene', (31, 34))	('GC', 'Phenotype', 'HP:0012126', (61, 63))	('GC cell proliferation', 'CPA', (61, 82))
307937	27694893	Additionally, U0126 also reversed the EMT of GC cells (Figure 4g).	('U0126', 'Chemical', 'MESH:C113580', (14, 19))	('GC', 'Phenotype', 'HP:0012126', (45, 47))	('EMT of GC cells', 'CPA', (38, 53))	('U0126', 'Var', (14, 19))
307938	27694893	We then determined whether knockdown of TBL1XR1 expression could inhibit the phosphorylation of ERK1/2 in GC cells.	('phosphorylation', 'MPA', (77, 92))	('ERK1/2', 'Gene', (96, 102))	('knockdown', 'Var', (27, 36))	('GC', 'Phenotype', 'HP:0012126', (106, 108))	('TBL1XR1', 'Gene', (40, 47))	('ERK1/2', 'Gene', '5595;5594', (96, 102))	('inhibit', 'NegReg', (65, 72))
307939	27694893	As shown in Figures 4h and i, TBL1XR1 knockdown significantly reduced the phosphorylation of ERK1/2 in NCI-N87/TBL1XR1-shRNA and SGC7901/TBL1XR1-shRNA cells, while TBL1XR1 overexpression significantly increased the phosphorylation of ERK1/2 in BGC823/TBL1XR1 and MKN45/TBL1XR1 cells.	('phosphorylation', 'MPA', (74, 89))	('SGC7901/TBL1XR1-shRNA', 'Var', (129, 150))	('GC', 'Phenotype', 'HP:0012126', (245, 247))	('ERK1/2', 'Gene', (234, 240))	('ERK1/2', 'Gene', '5595;5594', (234, 240))	('ERK1/2', 'Gene', (93, 99))	('ERK1/2', 'Gene', '5595;5594', (93, 99))	('phosphorylation', 'MPA', (215, 230))	('GC', 'Phenotype', 'HP:0012126', (130, 132))	('knockdown', 'Var', (38, 47))	('TBL1XR1', 'Var', (30, 37))	('reduced', 'NegReg', (62, 69))
307940	27694893	We then explored whether TBL1XR1 could enhance GC cell proliferation, migration and invasion through the activation of the ERK1/2 signalling pathway.	('ERK1/2', 'Gene', '5595;5594', (123, 129))	('GC', 'Phenotype', 'HP:0012126', (47, 49))	('invasion', 'CPA', (84, 92))	('migration', 'CPA', (70, 79))	('TBL1XR1', 'Var', (25, 32))	('GC cell proliferation', 'CPA', (47, 68))	('ERK1/2', 'Gene', (123, 129))	('enhance', 'PosReg', (39, 46))
307941	27694893	After incubation with U0126, the proliferation, migration and invasion ability of BGC823/TBL1XR1 and MKN45/TBL1XR1 cells was significantly reduced in comparison with the control groups (Figures 4j-l).	('migration', 'CPA', (48, 57))	('U0126', 'Var', (22, 27))	('GC', 'Phenotype', 'HP:0012126', (83, 85))	('U0126', 'Chemical', 'MESH:C113580', (22, 27))	('invasion ability', 'CPA', (62, 78))	('BGC823/TBL1XR1', 'Gene', (82, 96))	('reduced', 'NegReg', (139, 146))
307944	27694893	Thus, these data suggest that TBL1XR1 regulates GC cell proliferation, migration, invasion and EMT by activating the ERK1/2 signalling pathway.	('GC', 'Phenotype', 'HP:0012126', (48, 50))	('ERK1/2', 'Gene', (117, 123))	('GC cell proliferation', 'CPA', (48, 69))	('activating', 'PosReg', (102, 112))	('ERK1/2', 'Gene', '5595;5594', (117, 123))	('regulates', 'Reg', (38, 47))	('invasion', 'CPA', (82, 90))	('migration', 'CPA', (71, 80))	('EMT', 'CPA', (95, 98))	('TBL1XR1', 'Var', (30, 37))
307945	27694893	Aberrant activation of beta-catenin signalling plays an important role in various cancers such as gastrointestinal and colorectal cancer.	('colorectal cancer', 'Phenotype', 'HP:0003003', (119, 136))	('activation', 'PosReg', (9, 19))	('gastrointestinal', 'Disease', 'MESH:D005767', (98, 114))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('Aberrant', 'Var', (0, 8))	('colorectal cancer', 'Disease', (119, 136))	('cancers', 'Phenotype', 'HP:0002664', (82, 89))	('gastrointestinal', 'Disease', (98, 114))	('cancers', 'Disease', (82, 89))	('beta-catenin', 'Gene', (23, 35))	('cancers', 'Disease', 'MESH:D009369', (82, 89))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('colorectal cancer', 'Disease', 'MESH:D015179', (119, 136))	('beta-catenin', 'Gene', '1499', (23, 35))
307947	27694893	TBL1XR1 can promote the EMT of tumour cells via activating beta-catenin signalling.	('promote', 'PosReg', (12, 19))	('activating', 'Reg', (48, 58))	('TBL1XR1', 'Var', (0, 7))	('beta-catenin', 'Gene', '1499', (59, 71))	('tumour', 'Phenotype', 'HP:0002664', (31, 37))	('tumour', 'Disease', 'MESH:D009369', (31, 37))	('tumour', 'Disease', (31, 37))	('beta-catenin', 'Gene', (59, 71))
307951	27694893	We then explored whether TBL1XR1 could promote the phosphorylation of ERK1/2 and EMT in GC cells through the activation of beta-catenin.	('beta-catenin', 'Gene', '1499', (123, 135))	('promote', 'PosReg', (39, 46))	('ERK1/2', 'Gene', (70, 76))	('ERK1/2', 'Gene', '5595;5594', (70, 76))	('TBL1XR1', 'Var', (25, 32))	('activation', 'PosReg', (109, 119))	('phosphorylation', 'MPA', (51, 66))	('EMT', 'CPA', (81, 84))	('beta-catenin', 'Gene', (123, 135))	('GC', 'Phenotype', 'HP:0012126', (88, 90))
307952	27694893	As shown in Figure 5c, after treatment with beta-catenin inhibitor XAV939 (10 muM), the phosphorylation of ERK1/2 induced by overexpression of TBL1XR1 in BGC823/TBL1XR1 and MKN45/TBL1XR1 cells was significantly inhibited.	('phosphorylation', 'MPA', (88, 103))	('ERK1/2', 'Gene', (107, 113))	('inhibited', 'NegReg', (211, 220))	('muM', 'Gene', (78, 81))	('TBL1XR1', 'Var', (143, 150))	('ERK1/2', 'Gene', '5595;5594', (107, 113))	('beta-catenin', 'Gene', '1499', (44, 56))	('beta-catenin', 'Gene', (44, 56))	('GC', 'Phenotype', 'HP:0012126', (155, 157))	('muM', 'Gene', '56925', (78, 81))	('overexpression', 'PosReg', (125, 139))	('XAV939', 'Chemical', 'MESH:C544261', (67, 73))
307955	27694893	Thus, these data suggest that TBL1XR1 promotes the activation of ERK1/2 and EMT in GC cells by activating the beta-catenin signalling.	('beta-catenin', 'Gene', (110, 122))	('TBL1XR1', 'Var', (30, 37))	('ERK1/2', 'Gene', (65, 71))	('ERK1/2', 'Gene', '5595;5594', (65, 71))	('beta-catenin', 'Gene', '1499', (110, 122))	('promotes', 'PosReg', (38, 46))	('GC', 'Phenotype', 'HP:0012126', (83, 85))	('EMT in', 'CPA', (76, 82))	('activation', 'PosReg', (51, 61))	('activating', 'PosReg', (95, 105))
307957	27694893	We showed that MMP7 was elevated or downregulated in TBL1XR1-overexpressing or TBL1XR1-silencing GC cells (Figures 6a and b).	('MMP7', 'Gene', (15, 19))	('MMP7', 'Gene', '4316', (15, 19))	('TBL1XR1-overexpressing', 'Var', (53, 75))	('GC', 'Phenotype', 'HP:0012126', (97, 99))	('elevated', 'PosReg', (24, 32))	('downregulated', 'NegReg', (36, 49))
307960	27694893	We showed that TBL1XR1 knockdown significantly decreased the expression of p-beta-catenin, MMP7, pEGFR and pERK1/2 in NCI-N87 cells (Figure 6a).	('EGFR', 'Gene', (98, 102))	('TBL1XR1', 'Gene', (15, 22))	('MMP7', 'Gene', (91, 95))	('ERK1/2', 'Gene', (108, 114))	('knockdown', 'Var', (23, 32))	('ERK1/2', 'Gene', '5595;5594', (108, 114))	('MMP7', 'Gene', '4316', (91, 95))	('beta-catenin', 'Gene', '1499', (77, 89))	('EGFR', 'Gene', '1956', (98, 102))	('beta-catenin', 'Gene', (77, 89))	('expression', 'MPA', (61, 71))	('decreased', 'NegReg', (47, 56))
307963	27694893	Thus, these results suggest that TBL1XR1 indirectly promotes the activation of ERK1/2 via the beta-catenin/MMP7/EGFR signalling pathway.	('EGFR', 'Gene', (112, 116))	('MMP7', 'Gene', '4316', (107, 111))	('ERK1/2', 'Gene', (79, 85))	('ERK1/2', 'Gene', '5595;5594', (79, 85))	('beta-catenin', 'Gene', (94, 106))	('MMP7', 'Gene', (107, 111))	('promotes', 'PosReg', (52, 60))	('beta-catenin', 'Gene', '1499', (94, 106))	('EGFR', 'Gene', '1956', (112, 116))	('TBL1XR1', 'Var', (33, 40))	('activation', 'PosReg', (65, 75))
307964	27694893	We further evaluated whether TBL1XR1 knockdown or overexpression could regulate gastric tumour growth and metastatic potential in vivo.	('regulate', 'Reg', (71, 79))	('TBL1XR1', 'Gene', (29, 36))	('gastric tumour growth', 'Disease', 'MESH:D013274', (80, 101))	('knockdown', 'Var', (37, 46))	('gastric tumour', 'Phenotype', 'HP:0006753', (80, 94))	('tumour', 'Phenotype', 'HP:0002664', (88, 94))	('metastatic potential', 'CPA', (106, 126))	('gastric tumour growth', 'Disease', (80, 101))
307968	27694893	As shown in Figure 7g, there were fewer Ki-67 antigen-positive cells in tumours derived from NCI-N87/TBL1XR1-sh cells than in tumours derived from NCI-N87/nc-shRNA cells.	('tumour', 'Phenotype', 'HP:0002664', (126, 132))	('tumours', 'Phenotype', 'HP:0002664', (126, 133))	('tumour', 'Phenotype', 'HP:0002664', (72, 78))	('tumours', 'Phenotype', 'HP:0002664', (72, 79))	('NCI-N87/TBL1XR1-sh', 'Var', (93, 111))	('tumours', 'Disease', 'MESH:D009369', (126, 133))	('tumours', 'Disease', (126, 133))	('tumours', 'Disease', 'MESH:D009369', (72, 79))	('fewer', 'NegReg', (34, 39))	('tumours', 'Disease', (72, 79))	('Ki-67', 'Gene', (40, 45))
307970	27694893	This further indicated that the knockdown of TBL1XR1 expression could inhibit cell growth and EMT of GC cells via the ERK1/2 pathway.	('knockdown', 'Var', (32, 41))	('cell growth', 'CPA', (78, 89))	('ERK1/2', 'Gene', (118, 124))	('ERK1/2', 'Gene', '5595;5594', (118, 124))	('TBL1XR1', 'Gene', (45, 52))	('GC', 'Phenotype', 'HP:0012126', (101, 103))	('inhibit', 'NegReg', (70, 77))	('EMT of GC cells', 'CPA', (94, 109))
307978	27694893	Liu et al found that overexpression of TBL1XR1 enhanced lymphangiogenesis and lymphatic metastasis in esophageal squamous cell carcinoma and was positively correlated with tumour stage and overall survival, which suggest that TBL1XR1 might serve as an independent unfavourable prognostic factor for outcome of esophageal squamous cell carcinoma patients.	('esophageal squamous cell carcinoma', 'Disease', (102, 136))	('lymphangiogenesis', 'CPA', (56, 73))	('tumour', 'Phenotype', 'HP:0002664', (172, 178))	('enhanced', 'PosReg', (47, 55))	('correlated', 'Reg', (156, 166))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (310, 344))	('tumour', 'Disease', 'MESH:D009369', (172, 178))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (321, 344))	('overexpression', 'PosReg', (21, 35))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (113, 136))	('tumour', 'Disease', (172, 178))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (102, 136))	('lymphatic metastasis', 'CPA', (78, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (335, 344))	('esophageal squamous cell carcinoma', 'Disease', (310, 344))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('TBL1XR1', 'Var', (39, 46))	('patients', 'Species', '9606', (345, 353))
307979	27694893	TBL1XR1 amplification has also been shown in breast cancer, and inactivation of TBL1XR1 attenuated tumour cell migration and invasion.	('inactivation', 'Var', (64, 76))	('TBL1XR1', 'Gene', (80, 87))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('attenuated tumour', 'Disease', (88, 105))	('breast cancer', 'Disease', 'MESH:D001943', (45, 58))	('TBL1XR1', 'Gene', (0, 7))	('breast cancer', 'Disease', (45, 58))	('attenuated tumour', 'Disease', 'MESH:C538265', (88, 105))	('breast cancer', 'Phenotype', 'HP:0003002', (45, 58))	('tumour', 'Phenotype', 'HP:0002664', (99, 105))
307980	27694893	Furthermore, Kaplan-Meier survival analysis shows that patients with high TBL1XR1 expression have a shorter overall survival.	('overall survival', 'MPA', (108, 124))	('TBL1XR1', 'Gene', (74, 81))	('shorter', 'NegReg', (100, 107))	('high', 'Var', (69, 73))	('patients', 'Species', '9606', (55, 63))
307982	27694893	In accordance with previous studies, we find that TBL1XR1 acts as a multifunctional protein that affects tumour cell proliferation, migration and invasion, and knockdown of TBL1XR1 significantly inhibited gastric tumour growth and metastatic potential both in vitro and in vivo.	('tumour', 'Disease', 'MESH:D009369', (105, 111))	('tumour', 'Phenotype', 'HP:0002664', (213, 219))	('knockdown', 'Var', (160, 169))	('gastric tumour growth', 'Disease', 'MESH:D013274', (205, 226))	('inhibited', 'NegReg', (195, 204))	('tumour', 'Disease', (105, 111))	('metastatic potential', 'CPA', (231, 251))	('tumour', 'Disease', 'MESH:D009369', (213, 219))	('migration', 'CPA', (132, 141))	('TBL1XR1', 'Var', (173, 180))	('tumour', 'Disease', (213, 219))	('gastric tumour', 'Phenotype', 'HP:0006753', (205, 219))	('tumour', 'Phenotype', 'HP:0002664', (105, 111))	('affects', 'Reg', (97, 104))	('gastric tumour growth', 'Disease', (205, 226))	('invasion', 'CPA', (146, 154))
307983	27694893	Aberrant apoptotic events are closely involved in oncogenesis and tumour regression in numerous cancers, including GC.	('tumour regression in numerous cancers', 'Disease', 'MESH:D009369', (66, 103))	('Aberrant', 'Var', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('tumour', 'Phenotype', 'HP:0002664', (66, 72))	('apoptotic events', 'CPA', (9, 25))	('involved', 'Reg', (38, 46))	('GC', 'Phenotype', 'HP:0012126', (115, 117))	('cancers', 'Phenotype', 'HP:0002664', (96, 103))	('tumour regression in numerous cancers', 'Disease', (66, 103))
307990	27694893	TBL1XR1 knockdown attenuated the phosphorylation of ERK1/2 and consequently led to decreased cell growth, migration, invasion and EMT in GC cells in vitro and in vivo.	('phosphorylation', 'MPA', (33, 48))	('cell growth', 'CPA', (93, 104))	('ERK1/2', 'Gene', (52, 58))	('ERK1/2', 'Gene', '5595;5594', (52, 58))	('knockdown', 'Var', (8, 17))	('decreased', 'NegReg', (83, 92))	('EMT in GC cells', 'CPA', (130, 145))	('attenuated', 'NegReg', (18, 28))	('TBL1XR1', 'Gene', (0, 7))	('invasion', 'CPA', (117, 125))	('GC', 'Phenotype', 'HP:0012126', (137, 139))
307991	27694893	In contrast, TBL1XR1 overexpression exhibited the opposite results, which supports that TBL1XR1 is an upstream activator of ERK1/2 and serves as an important regulator of cell growth and EMT.	('ERK1/2', 'Gene', '5595;5594', (124, 130))	('TBL1XR1', 'Var', (88, 95))	('ERK1/2', 'Gene', (124, 130))
307992	27694893	Additionally, we find that the inhibitory effects of ERK1/2 inhibitor U0126 on GC cells are much more significant than those of silencing TBL1XR1 alone.	('U0126', 'Chemical', 'MESH:C113580', (70, 75))	('GC', 'Phenotype', 'HP:0012126', (79, 81))	('ERK1/2', 'Gene', (53, 59))	('ERK1/2', 'Gene', '5595;5594', (53, 59))	('U0126', 'Var', (70, 75))
307993	27694893	First, ERK1/2 is known as a convergence point of multiple tumour-promoting cascades, and TBL1XR1 is one of these receptors that can activate the ERK1/2 signalling pathway in tumour microenvironment.	('tumour', 'Phenotype', 'HP:0002664', (174, 180))	('ERK1/2', 'Gene', (7, 13))	('ERK1/2', 'Gene', '5595;5594', (7, 13))	('tumour', 'Disease', 'MESH:D009369', (174, 180))	('tumour', 'Phenotype', 'HP:0002664', (58, 64))	('ERK1/2', 'Gene', (145, 151))	('ERK1/2', 'Gene', '5595;5594', (145, 151))	('tumour', 'Disease', 'MESH:D009369', (58, 64))	('tumour', 'Disease', (174, 180))	('tumour', 'Disease', (58, 64))	('activate', 'PosReg', (132, 140))	('TBL1XR1', 'Var', (89, 96))
307997	27694893	The activation of ERK1/2 mediated by TBL1XR1 was dependent on the phosphorylation of beta-catenin.	('beta-catenin', 'Gene', '1499', (85, 97))	('ERK1/2', 'Gene', (18, 24))	('ERK1/2', 'Gene', '5595;5594', (18, 24))	('beta-catenin', 'Gene', (85, 97))	('activation', 'PosReg', (4, 14))	('TBL1XR1', 'Var', (37, 44))
307998	27694893	Wang et al have indicated that TBL1XR1 could promote EMT via the beta-catenin signalling pathway in cervical cancer.	('beta-catenin', 'Gene', '1499', (65, 77))	('TBL1XR1', 'Var', (31, 38))	('EMT', 'CPA', (53, 56))	('promote', 'PosReg', (45, 52))	('cervical cancer', 'Disease', (100, 115))	('cervical cancer', 'Disease', 'MESH:D002583', (100, 115))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('beta-catenin', 'Gene', (65, 77))
308005	27694893	In conclusion, we demonstrated that TBL1XR1 plays a crucial role in tumour growth, metastasis and prognosis via activation of the beta-catenin/MMP7/EGFR/ERK pathway (Figure 8).	('tumour', 'Phenotype', 'HP:0002664', (68, 74))	('metastasis', 'CPA', (83, 93))	('MMP7', 'Gene', (143, 147))	('activation', 'PosReg', (112, 122))	('EGFR', 'Gene', '1956', (148, 152))	('ERK', 'Gene', '5594', (153, 156))	('ERK', 'Gene', (153, 156))	('EGFR', 'Gene', (148, 152))	('tumour', 'Disease', 'MESH:D009369', (68, 74))	('MMP7', 'Gene', '4316', (143, 147))	('tumour', 'Disease', (68, 74))	('beta-catenin', 'Gene', (130, 142))	('TBL1XR1', 'Var', (36, 43))	('beta-catenin', 'Gene', '1499', (130, 142))
308006	27694893	Thus, this study links TBL1XR1/beta-catenin/MMP7/EGFR/ERK signalling to the control of the progression of GC and establishes TBL1XR1 as a potential biomarker for clinical prognosis and a therapeutic target in GC.	('EGFR', 'Gene', '1956', (49, 53))	('MMP7', 'Gene', (44, 48))	('beta-catenin', 'Gene', (31, 43))	('MMP7', 'Gene', '4316', (44, 48))	('ERK', 'Gene', '5594', (54, 57))	('GC', 'Phenotype', 'HP:0012126', (106, 108))	('EGFR', 'Gene', (49, 53))	('beta-catenin', 'Gene', '1499', (31, 43))	('ERK', 'Gene', (54, 57))	('TBL1XR1', 'Var', (125, 132))	('GC', 'Phenotype', 'HP:0012126', (209, 211))
308033	27694893	51067-2-AP) and anti-MMP7 (10374-2-AP) antibodies were purchased from Proteintech (Rosemont, IL, USA).	('10374-2-AP', 'Var', (27, 37))	('MMP7', 'Gene', '4316', (21, 25))	('MMP7', 'Gene', (21, 25))
308045	27694893	Cells were treated with puromycin (1 mug/ml) (InvivoGen, San Diego, CA, USA) to produce stably transfected cells (NCI-N87/nc-shRNA, NCI-N87/TBL1XR1-shRNA, SGC7901/nc-shRNA and SGC7901/TBL1XR1-shRNA) for further experiments.	('puromycin', 'Chemical', 'MESH:D011691', (24, 33))	('SGC7901/nc-shRNA', 'Var', (155, 171))	('NCI-N87/nc-shRNA', 'Var', (114, 130))	('GC', 'Phenotype', 'HP:0012126', (177, 179))	('GC', 'Phenotype', 'HP:0012126', (156, 158))	('SGC7901/TBL1XR1-shRNA', 'Var', (176, 197))
308103	26196516	Lung cancer was coded by ICD-9-CM 162 or ICD 10 C34.0, C34.1, C34.2, C34.3, C34.8, and C34.9 in TCRD.	('C34.0', 'Var', (48, 53))	('Lung cancer', 'Phenotype', 'HP:0100526', (0, 11))	('C34.3', 'Var', (69, 74))	('C34.2', 'Var', (62, 67))	('C34.9', 'Var', (87, 92))	('Lung cancer', 'Disease', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))	('C34.8', 'Var', (76, 81))	('Lung cancer', 'Disease', 'MESH:D008175', (0, 11))	('C34.1', 'Var', (55, 60))
308174	26196516	Estrogen receptor interacts with the downstream mediators of EGFR signaling in NSCLC, and that mutation of EGFR correlate with clinical responsiveness to the tyrosine kinase inhibitor.	('interacts', 'Reg', (18, 27))	('Estrogen receptor', 'Gene', '2099', (0, 17))	('NSCLC', 'Disease', 'MESH:D002289', (79, 84))	('EGFR', 'Gene', '1956', (107, 111))	('EGFR', 'Gene', (107, 111))	('NSCLC', 'Disease', (79, 84))	('NSCLC', 'Phenotype', 'HP:0030358', (79, 84))	('Estrogen receptor', 'Gene', (0, 17))	('correlate with', 'Reg', (112, 126))	('EGFR', 'Gene', '1956', (61, 65))	('EGFR', 'Gene', (61, 65))	('mutation', 'Var', (95, 103))
308179	26196516	Statin may limit the availability of cholesterol required for tumor cell proliferation and metastasis, and simvastatin at a defined daily dose of over 150 reduced lung cancer risk compared with non-users (OR, 0.77; 95% CI, 0.62-0.97) in women.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('lung cancer', 'Disease', 'MESH:D008175', (163, 174))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('reduced', 'NegReg', (155, 162))	('cholesterol', 'Chemical', 'MESH:D002784', (37, 48))	('tumor', 'Disease', (62, 67))	('simvastatin', 'Var', (107, 118))	('lung cancer', 'Phenotype', 'HP:0100526', (163, 174))	('women', 'Species', '9606', (237, 242))	('lung cancer', 'Disease', (163, 174))	('simvastatin', 'Chemical', 'MESH:D019821', (107, 118))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
308211	33324542	The expression of miR-381 is downregulated in lung adenocarcinoma, epithelial ovarian cancer, colon cancer, and breast cancer, suggesting that miR-381 may play a role as a tumor suppressor.	('breast cancer', 'Disease', 'MESH:D001943', (112, 125))	('breast cancer', 'Disease', (112, 125))	('tumor', 'Disease', (172, 177))	('expression', 'MPA', (4, 14))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('miR-381', 'Gene', (18, 25))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (46, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (56, 65))	('ovarian cancer', 'Phenotype', 'HP:0100615', (78, 92))	('lung adenocarcinoma, epithelial ovarian cancer', 'Disease', 'MESH:D000077192', (46, 92))	('colon cancer', 'Disease', (94, 106))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('miR-381', 'Var', (143, 150))	('epithelial ovarian cancer', 'Phenotype', 'HP:0025318', (67, 92))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('downregulated', 'NegReg', (29, 42))	('colon cancer', 'Phenotype', 'HP:0003003', (94, 106))	('breast cancer', 'Phenotype', 'HP:0003002', (112, 125))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('colon cancer', 'Disease', 'MESH:D015179', (94, 106))
308212	33324542	On the other hand, miR-381 is upregulated in glioma, epithelial sarcoma, and osteosarcoma, suggesting that miR-381 might act as an oncogene.	('epithelial sarcoma', 'Disease', 'MESH:D012509', (53, 71))	('osteosarcoma', 'Disease', 'MESH:D012516', (77, 89))	('upregulated', 'PosReg', (30, 41))	('miR-381', 'Gene', (19, 26))	('glioma', 'Disease', 'MESH:D005910', (45, 51))	('glioma', 'Phenotype', 'HP:0009733', (45, 51))	('sarcoma', 'Phenotype', 'HP:0100242', (82, 89))	('osteosarcoma', 'Phenotype', 'HP:0002669', (77, 89))	('miR-381', 'Var', (107, 114))	('epithelial sarcoma', 'Disease', (53, 71))	('sarcoma', 'Phenotype', 'HP:0100242', (64, 71))	('glioma', 'Disease', (45, 51))	('osteosarcoma', 'Disease', (77, 89))
308219	33324542	In breast cancer cell lines, overexpression of miR-381 is associated with decreased levels of Wnt axis genes, including CTNNB1, RhoA, ROCK1, and c-MYC.	('RhoA', 'Gene', (128, 132))	('overexpression', 'PosReg', (29, 43))	('miR-381', 'Var', (47, 54))	('c-MYC', 'Gene', (145, 150))	('ROCK1', 'Gene', '6093', (134, 139))	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('CTNNB1', 'Gene', (120, 126))	('RhoA', 'Gene', '387', (128, 132))	('breast cancer', 'Disease', (3, 16))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('ROCK1', 'Gene', (134, 139))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('CTNNB1', 'Gene', '1499', (120, 126))	('decreased', 'NegReg', (74, 83))	('c-MYC', 'Gene', '4609', (145, 150))	('levels of', 'MPA', (84, 93))	('Wnt axis genes', 'Gene', (94, 108))
308234	33324542	In a xenograft mouse model, miR-381 inhibited tumor growth.	('inhibited', 'NegReg', (36, 45))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('miR-381', 'Var', (28, 35))	('tumor', 'Disease', (46, 51))	('mouse', 'Species', '10090', (15, 20))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
308236	33324542	MiR-381 also modulates cell proliferation via the PI3K/AKT/mTOR pathway, which plays a crucial role in cell proliferation, invasion, and survival.	('AKT', 'Gene', (55, 58))	('modulates', 'Reg', (13, 22))	('AKT', 'Gene', '207', (55, 58))	('mTOR', 'Gene', '2475', (59, 63))	('cell proliferation', 'CPA', (23, 41))	('MiR-381', 'Var', (0, 7))	('mTOR', 'Gene', (59, 63))
308237	33324542	MiR-381 acts as a tumor suppressor via inhibiting the ETS1/PI3K/AKT/mTOR pathway activity.	('tumor', 'Disease', (18, 23))	('ETS1', 'Gene', '2113', (54, 58))	('AKT', 'Gene', '207', (64, 67))	('mTOR', 'Gene', '2475', (68, 72))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('mTOR', 'Gene', (68, 72))	('activity', 'MPA', (81, 89))	('ETS1', 'Gene', (54, 58))	('inhibiting', 'NegReg', (39, 49))	('AKT', 'Gene', (64, 67))	('MiR-381', 'Var', (0, 7))
308241	33324542	Mechanistically, miR-381 regulates the PI3K/AKT pathway via inhibiting LMO3, and overexpression of miR-381 decreases the protein levels of p-PI3K and p-AKT in cell lines.	('inhibiting', 'NegReg', (60, 70))	('LMO3', 'Gene', (71, 75))	('protein levels', 'MPA', (121, 135))	('LMO3', 'Gene', '55885', (71, 75))	('AKT', 'Gene', '207', (152, 155))	('miR-381', 'Var', (17, 24))	('miR-381', 'Gene', (99, 106))	('decreases', 'NegReg', (107, 116))	('AKT', 'Gene', '207', (44, 47))	('AKT', 'Gene', (152, 155))	('regulates', 'Reg', (25, 34))	('AKT', 'Gene', (44, 47))	('p-PI3K', 'Pathway', (139, 145))
308242	33324542	By inhibiting PI3K/AKT pathway activity, miR-381 could be a tumor suppressor.	('inhibiting', 'NegReg', (3, 13))	('miR-381', 'Var', (41, 48))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('AKT', 'Gene', '207', (19, 22))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('AKT', 'Gene', (19, 22))	('tumor', 'Disease', (60, 65))
308245	33324542	PTTG1 is upregulated in pituitary tumors; in contrast, the levels of microRNA-655, miR-300, miR-381, and miR-329 are decreased in pituitary tumor tissues.	('levels', 'MPA', (59, 65))	('pituitary tumors', 'Disease', 'MESH:D010911', (24, 40))	('pituitary tumor', 'Disease', (130, 145))	('upregulated', 'PosReg', (9, 20))	('miR-381', 'MPA', (92, 99))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('microRNA-655', 'Gene', (69, 81))	('miR-329', 'Gene', '723842', (105, 112))	('PTTG1', 'Gene', (0, 5))	('miR-300', 'Var', (83, 90))	('decreased', 'NegReg', (117, 126))	('pituitary tumor', 'Disease', 'MESH:D010911', (130, 145))	('microRNA-655', 'Gene', '724025', (69, 81))	('pituitary tumors', 'Disease', (24, 40))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('pituitary tumor', 'Disease', 'MESH:D010911', (24, 39))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('miR-329', 'Gene', (105, 112))
308246	33324542	Overexpression of microRNA-655, miR-300, miR-381, and miR-329 decreases the viability and proliferation of human pituitary cells.	('decreases', 'NegReg', (62, 71))	('microRNA-655', 'Gene', (18, 30))	('miR-329', 'Gene', '723842', (54, 61))	('miR-381', 'Var', (41, 48))	('human', 'Species', '9606', (107, 112))	('microRNA-655', 'Gene', '724025', (18, 30))	('miR-300', 'Var', (32, 39))	('miR-329', 'Gene', (54, 61))
308247	33324542	In a xenograft mouse model, microRNA-655, miR-300, miR-381, and miR-329 inhibited tumor growth and PTTG1 expression.	('miR-329', 'Gene', (64, 71))	('microRNA-655', 'Gene', (28, 40))	('miR-300', 'Var', (42, 49))	('PTTG1', 'Gene', (99, 104))	('miR-329', 'Gene', '723842', (64, 71))	('microRNA-655', 'Gene', '724025', (28, 40))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('miR-381', 'Var', (51, 58))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('mouse', 'Species', '10090', (15, 20))	('inhibited', 'NegReg', (72, 81))	('tumor', 'Disease', (82, 87))	('expression', 'MPA', (105, 115))
308248	33324542	MicroRNA-655, miR-300, miR-381, and miR-329 target PTTG1 mRNA and inhibit PTTG1 expression.	('PTTG1', 'Gene', (74, 79))	('miR-381', 'Var', (23, 30))	('miR-329', 'Gene', '723842', (36, 43))	('miR-300', 'Var', (14, 21))	('MicroRNA-655', 'Gene', '724025', (0, 12))	('MicroRNA-655', 'Gene', (0, 12))	('mRNA', 'MPA', (57, 61))	('inhibit', 'NegReg', (66, 73))	('expression', 'MPA', (80, 90))	('miR-329', 'Gene', (36, 43))	('PTTG1', 'Gene', (51, 56))
308249	33324542	p53, which is one of the most important tumor suppressor genes and is mutated in a variety of human cancers, can bind to the promoters of microRNA-655, miR-300, miR-381, and miR-329, activating their transcription.	('bind', 'Interaction', (113, 117))	('microRNA-655', 'Gene', '724025', (138, 150))	('miR-300', 'Var', (152, 159))	('activating', 'PosReg', (183, 193))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('cancers', 'Disease', 'MESH:D009369', (100, 107))	('p53', 'Gene', '7157', (0, 3))	('microRNA-655', 'Gene', (138, 150))	('miR-381', 'Var', (161, 168))	('miR-329', 'Gene', '723842', (174, 181))	('p53', 'Gene', (0, 3))	('human', 'Species', '9606', (94, 99))	('tumor', 'Disease', (40, 45))	('cancers', 'Phenotype', 'HP:0002664', (100, 107))	('cancers', 'Disease', (100, 107))	('miR-329', 'Gene', (174, 181))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('transcription', 'MPA', (200, 213))
308257	33324542	In epithelial ovarian cancer tissues and cell lines, miR-381 expression is decreased, and overexpression of miR-381 significantly inhibits epithelial ovarian cancer cell proliferation, migration, and invasion.	('invasion', 'CPA', (200, 208))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('epithelial ovarian cancer', 'Disease', 'MESH:D000077216', (139, 164))	('miR-381', 'Gene', (53, 60))	('epithelial ovarian cancer', 'Disease', (139, 164))	('epithelial ovarian cancer', 'Phenotype', 'HP:0025318', (139, 164))	('expression', 'MPA', (61, 71))	('ovarian cancer', 'Phenotype', 'HP:0100615', (150, 164))	('ovarian cancer', 'Phenotype', 'HP:0100615', (14, 28))	('miR-381', 'Var', (108, 115))	('inhibits', 'NegReg', (130, 138))	('epithelial ovarian cancer', 'Disease', (3, 28))	('epithelial ovarian cancer', 'Disease', 'MESH:D000077216', (3, 28))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('migration', 'CPA', (185, 194))	('overexpression', 'PosReg', (90, 104))	('epithelial ovarian cancer', 'Phenotype', 'HP:0025318', (3, 28))	('decreased', 'NegReg', (75, 84))
308262	33324542	In gastric cancer cell lines, inhibition of miR-381 enhances cell proliferation, invasion, and migration.	('gastric cancer', 'Phenotype', 'HP:0012126', (3, 17))	('inhibition', 'Var', (30, 40))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('invasion', 'CPA', (81, 89))	('miR-381', 'Gene', (44, 51))	('gastric cancer', 'Disease', 'MESH:D013274', (3, 17))	('gastric cancer', 'Disease', (3, 17))	('migration', 'CPA', (95, 104))	('enhances', 'PosReg', (52, 60))	('cell proliferation', 'CPA', (61, 79))
308263	33324542	Mechanistically, miR-381 can target the 3'UTR of ROCK2, which plays an important role in actin cytoskeleton formation, cell proliferation, and cell migration, and inhibit its expression.	('ROCK2', 'Gene', '9475', (49, 54))	('inhibit', 'NegReg', (163, 170))	('expression', 'MPA', (175, 185))	('cell proliferation', 'CPA', (119, 137))	('cell migration', 'CPA', (143, 157))	('miR-381', 'Var', (17, 24))	('actin', 'MPA', (89, 94))	('ROCK2', 'Gene', (49, 54))
308264	33324542	Thus, via ROCK2, miR-381 can act as a tumor suppressor.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('miR-381', 'Var', (17, 24))	('ROCK2', 'Gene', (10, 15))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('ROCK2', 'Gene', '9475', (10, 15))
308265	33324542	However, in some types of cancers, miR-381 acts as an oncogene.	('cancers', 'Phenotype', 'HP:0002664', (26, 33))	('cancers', 'Disease', 'MESH:D009369', (26, 33))	('cancers', 'Disease', (26, 33))	('miR-381', 'Var', (35, 42))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))
308266	33324542	Gergo et al., identified another pathway, in which miR-381 targets SMARCB1, which encodes a subunit of the SWI/SNF ATP-dependent chromatin-remodeling complex.	('SMARCB1', 'Gene', (67, 74))	('SMARCB1', 'Gene', '6598', (67, 74))	('miR-381', 'Var', (51, 58))
308267	33324542	SMARCB1 expression is absent in 83% of epithelioid sarcomas, and inactivation of SMARCB1 results in aggressive tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('epithelioid sarcomas', 'Disease', 'MESH:D012509', (39, 59))	('sarcomas', 'Phenotype', 'HP:0100242', (51, 59))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('epithelioid sarcomas', 'Disease', (39, 59))	('inactivation', 'Var', (65, 77))	('SMARCB1', 'Gene', '6598', (81, 88))	('sarcoma', 'Phenotype', 'HP:0100242', (51, 58))	('results in', 'Reg', (89, 99))	('tumor', 'Disease', (111, 116))	('SMARCB1', 'Gene', (81, 88))	('SMARCB1', 'Gene', '6598', (0, 7))	('SMARCB1', 'Gene', (0, 7))
308274	33324542	The expression of LRRC4, which is targeted by both miR-381 and miR-182, is decreased in glioma cells.	('glioma', 'Disease', (88, 94))	('expression', 'MPA', (4, 14))	('miR-381', 'Var', (51, 58))	('miR-182', 'Gene', (63, 70))	('glioma', 'Disease', 'MESH:D005910', (88, 94))	('LRRC4', 'Gene', (18, 23))	('glioma', 'Phenotype', 'HP:0009733', (88, 94))	('miR-182', 'Gene', '406958', (63, 70))	('decreased', 'NegReg', (75, 84))
308281	33324542	In breast cancer, endometrial carcinoma, epithelial ovarian cancer, and pancreatic cancer, miR-381 acts as an antioncogene.	('endometrial carcinoma, epithelial ovarian cancer', 'Disease', 'MESH:D010051', (18, 66))	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('pancreatic cancer', 'Disease', (72, 89))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('breast cancer', 'Disease', (3, 16))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('pancreatic cancer', 'Disease', 'MESH:D010190', (72, 89))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('ovarian cancer', 'Phenotype', 'HP:0100615', (52, 66))	('epithelial ovarian cancer', 'Phenotype', 'HP:0025318', (41, 66))	('carcinoma', 'Phenotype', 'HP:0030731', (30, 39))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (18, 39))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('miR-381', 'Var', (91, 98))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (72, 89))
308282	33324542	In primary glioma, miR-381 acts as an oncogene and modulates the PI3K/AKT and ERK pathways.	('AKT', 'Gene', '207', (70, 73))	('ERK', 'Gene', '5594', (78, 81))	('glioma', 'Disease', 'MESH:D005910', (11, 17))	('modulates', 'Reg', (51, 60))	('glioma', 'Phenotype', 'HP:0009733', (11, 17))	('AKT', 'Gene', (70, 73))	('ERK', 'Gene', (78, 81))	('glioma', 'Disease', (11, 17))	('miR-381', 'Var', (19, 26))
308293	33324542	Overexpression of miR-381 in OSCC cell lines inhibits cell proliferation by increasing the proportion of G1/G0-phase cells, indicating that miR-381 acts as a tumor suppressor, possibly because miR-381 targets FGFR2 and downregulates it.	('FGFR2', 'Gene', '2263', (209, 214))	('tumor', 'Disease', (158, 163))	('cell proliferation', 'CPA', (54, 72))	('OS', 'Phenotype', 'HP:0002669', (29, 31))	('inhibits', 'NegReg', (45, 53))	('miR-381', 'Var', (140, 147))	('OSCC', 'CellLine', 'CVCL:L894', (29, 33))	('downregulates', 'NegReg', (219, 232))	('increasing', 'PosReg', (76, 86))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('FGFR2', 'Gene', (209, 214))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('miR-381', 'Var', (193, 200))
308296	33324542	Thus, by targeting FGFR2 and inhibiting EMT, miR-381-3p acts as a tumor suppressor.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Disease', (66, 71))	('miR-381-3p', 'Chemical', '-', (45, 55))	('FGFR2', 'Gene', (19, 24))	('FGFR2', 'Gene', '2263', (19, 24))	('miR-381-3p', 'Var', (45, 55))	('EMT', 'CPA', (40, 43))	('inhibiting', 'NegReg', (29, 39))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('targeting', 'Reg', (9, 18))
308297	33324542	MiR-381 can directly bind to the 3'UTR of CCAAT/enhancer-binding protein alpha (C/EBPalpha) and inhibit its expression.	('C/EBPalpha', 'Gene', '1050', (80, 90))	('CCAAT/enhancer-binding protein alpha', 'Gene', '1050', (42, 78))	('CCAAT/enhancer-binding protein alpha', 'Gene', (42, 78))	('expression', 'MPA', (108, 118))	('bind', 'Interaction', (21, 25))	('inhibit', 'NegReg', (96, 103))	('C/EBPalpha', 'Gene', (80, 90))	('MiR-381', 'Var', (0, 7))
308299	33324542	Thus, miR-381 inhibits Cx43 expression via the C/EBPalpha-binding element AATTGTC in the Cx43 promoter region.	('inhibits', 'NegReg', (14, 22))	('C/EBPalpha', 'Gene', (47, 57))	('Cx43', 'Gene', (23, 27))	('Cx43', 'Gene', '2697', (23, 27))	('miR-381', 'Var', (6, 13))	('C/EBPalpha', 'Gene', '1050', (47, 57))	('Cx43', 'Gene', '2697', (89, 93))	('Cx43', 'Gene', (89, 93))
308301	33324542	Thus, miR-381 can suppress the C/EBPalpha- and Cx43-dependent invasion of breast cancer cells.	('breast cancer', 'Disease', (74, 87))	('suppress', 'NegReg', (18, 26))	('C/EBPalpha', 'Gene', '1050', (31, 41))	('Cx43', 'Gene', '2697', (47, 51))	('miR-381', 'Var', (6, 13))	('Cx43', 'Gene', (47, 51))	('C/EBPalpha', 'Gene', (31, 41))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('breast cancer', 'Disease', 'MESH:D001943', (74, 87))	('breast cancer', 'Phenotype', 'HP:0003002', (74, 87))
308305	33324542	The absence of Cx43 can enhance the aggressiveness of pancreatic cancer, indicating its protective effects.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (54, 71))	('Cx43', 'Gene', '2697', (15, 19))	('Cx43', 'Gene', (15, 19))	('enhance', 'PosReg', (24, 31))	('aggressiveness', 'Phenotype', 'HP:0000718', (36, 50))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('aggressiveness of pancreatic cancer', 'Disease', (36, 71))	('absence', 'Var', (4, 11))	('aggressiveness of pancreatic cancer', 'Disease', 'MESH:D010190', (36, 71))
308320	33324542	Inhibition of miR-381 increases the expression of MMP-2 and MMP-9, indicating that downregulation of miR-381 leads to cancer cell migration and invasion.	('miR-381', 'Gene', (101, 108))	('cancer', 'Disease', (118, 124))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('expression', 'MPA', (36, 46))	('leads', 'Reg', (109, 114))	('invasion', 'CPA', (144, 152))	('MMP-2', 'Gene', '4313', (50, 55))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('downregulation', 'NegReg', (83, 97))	('Inhibition', 'Var', (0, 10))	('MMP-9', 'Gene', '4318', (60, 65))	('increases', 'PosReg', (22, 31))	('miR-381', 'Gene', (14, 21))	('MMP-9', 'Gene', (60, 65))	('MMP-2', 'Gene', (50, 55))
308333	33324542	By targeting FGF7, miR-381 also suppresses the migration and invasion of cervical cell lines.	('suppresses', 'NegReg', (32, 42))	('FGF7', 'Gene', '2252', (13, 17))	('targeting', 'Reg', (3, 12))	('FGF7', 'Gene', (13, 17))	('miR-381', 'Var', (19, 26))
308343	33324542	Another group found that Cullin 4B (CUL4B) is another crucial target of miR-381.	('miR-381', 'Var', (72, 79))	('CUL4B', 'Gene', (36, 41))	('Cullin 4B', 'Gene', (25, 34))	('CUL4B', 'Gene', '8450', (36, 41))	('Cullin 4B', 'Gene', '8450', (25, 34))
308346	33324542	CUL4B epigenetically inhibits many tumor suppressors, including insulin-like growth factor-binding protein 3 (IGFBP3), PTEN, and p16.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('CUL4B', 'Gene', '8450', (0, 5))	('inhibits', 'NegReg', (21, 29))	('p16', 'Gene', (129, 132))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('IGFBP3', 'Gene', (110, 116))	('epigenetically', 'Var', (6, 20))	('tumor', 'Disease', (35, 40))	('PTEN', 'Gene', (119, 123))	('CUL4B', 'Gene', (0, 5))	('insulin-like growth factor-binding protein 3', 'Gene', '3486', (64, 108))	('PTEN', 'Gene', '5728', (119, 123))	('p16', 'Gene', '1029', (129, 132))	('IGFBP3', 'Gene', '3486', (110, 116))	('insulin-like growth factor-binding protein 3', 'Gene', (64, 108))
308348	33324542	In gastric carcinoma, CUL4B is upregulated and targeted by miR-381 and miR-489, and silencing of CUL4B inhibits the proliferation and migration of gastric cancer cells via the Wnt/beta-catenin signaling pathway.	('gastric carcinoma', 'Phenotype', 'HP:0012126', (3, 20))	('inhibits', 'NegReg', (103, 111))	('miR-381', 'Var', (59, 66))	('CUL4B', 'Gene', '8450', (97, 102))	('gastric cancer', 'Phenotype', 'HP:0012126', (147, 161))	('silencing', 'Var', (84, 93))	('miR-489', 'Gene', '574442', (71, 78))	('proliferation', 'CPA', (116, 129))	('CUL4B', 'Gene', (22, 27))	('beta-catenin', 'Gene', (180, 192))	('beta-catenin', 'Gene', '1499', (180, 192))	('CUL4B', 'Gene', '8450', (22, 27))	('gastric cancer', 'Disease', (147, 161))	('miR-489', 'Gene', (71, 78))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('gastric carcinoma', 'Disease', 'MESH:D013274', (3, 20))	('upregulated', 'PosReg', (31, 42))	('gastric carcinoma', 'Disease', (3, 20))	('gastric cancer', 'Disease', 'MESH:D013274', (147, 161))	('carcinoma', 'Phenotype', 'HP:0030731', (11, 20))	('CUL4B', 'Gene', (97, 102))
308350	33324542	Thus, via the miR-381/489-CUL4B axis, miR-381 and miR-489 suppress cell proliferation, gastric carcinoma invasion, and EMT.	('miR-489', 'Gene', (50, 57))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (87, 104))	('gastric carcinoma invasion', 'Disease', 'MESH:D013274', (87, 113))	('CUL4B', 'Gene', (26, 31))	('miR-381', 'Var', (38, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('gastric carcinoma invasion', 'Disease', (87, 113))	('miR-489', 'Gene', '574442', (50, 57))	('EMT', 'CPA', (119, 122))	('cell proliferation', 'CPA', (67, 85))	('CUL4B', 'Gene', '8450', (26, 31))	('suppress', 'NegReg', (58, 66))
308356	33324542	Based on the results of a previous study showing that TMEM16A contributes to cell invasion via the TGF-beta signaling pathway, miR-381 suppresses the TGF-beta signaling pathway and, as a result, inhibits EMT.	('suppresses', 'NegReg', (135, 145))	('inhibits', 'NegReg', (195, 203))	('miR-381', 'Var', (127, 134))	('TGF-beta', 'Gene', '7039', (99, 107))	('TGF-beta', 'Gene', '7039', (150, 158))	('EMT', 'CPA', (204, 207))	('TMEM16A', 'Gene', (54, 61))	('cell invasion', 'CPA', (77, 90))	('TMEM16A', 'Gene', '55107', (54, 61))	('TGF-beta', 'Gene', (99, 107))	('TGF-beta', 'Gene', (150, 158))
308358	33324542	Thus, by targeting TMEM16A, miR-381 can suppress the TGF-beta signaling pathway and inhibit EMT progression, ultimately suppressing cell proliferation, migration, and invasion.	('TGF-beta', 'Gene', '7039', (53, 61))	('migration', 'CPA', (152, 161))	('suppressing', 'NegReg', (120, 131))	('TMEM16A', 'Gene', (19, 26))	('miR-381', 'Var', (28, 35))	('inhibit', 'NegReg', (84, 91))	('invasion', 'CPA', (167, 175))	('EMT progression', 'CPA', (92, 107))	('suppress', 'NegReg', (40, 48))	('cell proliferation', 'CPA', (132, 150))	('TGF-beta', 'Gene', (53, 61))	('TMEM16A', 'Gene', '55107', (19, 26))	('targeting', 'Reg', (9, 18))
308360	33324542	In gastric carcinoma cell lines, knockdown of CAT104 has effects similar to those of an miR-381 inhibitor, indicating that CAT104 inhibits the expression of miR-381, resulting in enhanced cell migration and invasion.	('cell migration', 'CPA', (188, 202))	('CAT104', 'Chemical', '-', (46, 52))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (3, 20))	('expression', 'MPA', (143, 153))	('enhanced', 'PosReg', (179, 187))	('gastric carcinoma', 'Disease', 'MESH:D013274', (3, 20))	('CAT104', 'Chemical', '-', (123, 129))	('carcinoma', 'Phenotype', 'HP:0030731', (11, 20))	('miR-381', 'Gene', (157, 164))	('gastric carcinoma', 'Disease', (3, 20))	('CAT104', 'Var', (123, 129))	('inhibits', 'NegReg', (130, 138))	('invasion', 'CPA', (207, 215))
308361	33324542	Furthermore, miR-381 targets ZEB1, which is involved in the Wnt/beta-catenin pathway, and induces apoptosis.	('apoptosis', 'CPA', (98, 107))	('ZEB1', 'Gene', '6935', (29, 33))	('induces', 'PosReg', (90, 97))	('miR-381', 'Var', (13, 20))	('ZEB1', 'Gene', (29, 33))	('beta-catenin', 'Gene', (64, 76))	('beta-catenin', 'Gene', '1499', (64, 76))
308378	33324542	In addition, inhibition of ID1 decreases tumor growth in animal models.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('decreases tumor', 'Disease', 'MESH:D002303', (31, 46))	('inhibition', 'Var', (13, 23))	('ID1', 'Gene', '3397', (27, 30))	('decreases tumor', 'Disease', (31, 46))	('ID1', 'Gene', (27, 30))
308382	33324542	Src inhibition can lead to increased miR-381 expression and ID1 downregulation.	('increased', 'PosReg', (27, 36))	('ID1', 'Gene', '3397', (60, 63))	('downregulation', 'NegReg', (64, 78))	('Src', 'Gene', (0, 3))	('Src', 'Gene', '6714', (0, 3))	('inhibition', 'Var', (4, 14))	('expression', 'MPA', (45, 55))	('miR-381', 'Protein', (37, 44))	('ID1', 'Gene', (60, 63))
308384	33324542	Thus, miR-381 is involved in the Src-ID1 pathway and may be a potential target via EMT inhibition.	('Src', 'Gene', (33, 36))	('Src', 'Gene', '6714', (33, 36))	('ID1', 'Gene', '3397', (37, 40))	('involved', 'Reg', (17, 25))	('miR-381', 'Var', (6, 13))	('ID1', 'Gene', (37, 40))
308385	33324542	Overexpression of miR-381-3p significantly inhibits cell proliferation and migration.	('miR-381-3p', 'Var', (18, 28))	('inhibits', 'NegReg', (43, 51))	('miR-381-3p', 'Chemical', '-', (18, 28))
308386	33324542	MiR-381 inhibits bladder cancer cell proliferation by regulating CDK6, resulting in G1-phase arrest.	('regulating', 'Reg', (54, 64))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('bladder cancer', 'Phenotype', 'HP:0009725', (17, 31))	('arrest', 'Disease', 'MESH:D006323', (93, 99))	('inhibits', 'NegReg', (8, 16))	('arrest', 'Disease', (93, 99))	('CDK6', 'Gene', (65, 69))	('bladder cancer', 'Disease', (17, 31))	('CDK6', 'Gene', '1021', (65, 69))	('bladder cancer', 'Disease', 'MESH:D001749', (17, 31))	('MiR-381', 'Var', (0, 7))
308387	33324542	MiR-381 can also inhibit migration by downregulating MET and CCNA2, thus resulting in EMT progression.	('CCNA2', 'Gene', '890', (61, 66))	('migration', 'CPA', (25, 34))	('resulting in', 'Reg', (73, 85))	('inhibit', 'NegReg', (17, 24))	('EMT progression', 'CPA', (86, 101))	('CCNA2', 'Gene', (61, 66))	('MET', 'Gene', '79811', (53, 56))	('MiR-381', 'Var', (0, 7))	('MET', 'Gene', (53, 56))	('downregulating', 'NegReg', (38, 52))
308389	33324542	Inhibition of miR-381 results in cell proliferation, and liver receptor homolog-1 (LRH-1) is the target of miR-381.	('liver receptor homolog-1', 'Gene', '2494', (57, 81))	('liver receptor homolog-1', 'Gene', (57, 81))	('LRH-1', 'Gene', '2494', (83, 88))	('LRH-1', 'Gene', (83, 88))	('Inhibition', 'Var', (0, 10))	('cell proliferation', 'CPA', (33, 51))	('miR-381', 'Gene', (14, 21))
308392	33324542	In conclusion, through LRH-1, miR-381 inhibits tumor progression in colon cancer.	('LRH-1', 'Gene', (23, 28))	('colon cancer', 'Phenotype', 'HP:0003003', (68, 80))	('inhibits', 'NegReg', (38, 46))	('colon cancer', 'Disease', 'MESH:D015179', (68, 80))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('colon cancer', 'Disease', (68, 80))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('LRH-1', 'Gene', '2494', (23, 28))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('tumor', 'Disease', (47, 52))	('miR-381', 'Var', (30, 37))
308393	33324542	In hepatocellular carcinoma tissues, miR-381 is downregulated, and overexpression of miR-381 in hepatocellular carcinoma cell lines results in decreased cell proliferation and invasion.	('carcinoma', 'Phenotype', 'HP:0030731', (18, 27))	('hepatocellular carcinoma', 'Disease', (3, 27))	('miR-381', 'Var', (85, 92))	('hepatocellular carcinoma', 'Disease', (96, 120))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (96, 120))	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('overexpression', 'PosReg', (67, 81))	('decreased', 'NegReg', (143, 152))	('downregulated', 'NegReg', (48, 61))	('miR-381', 'Gene', (37, 44))	('cell proliferation', 'CPA', (153, 171))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (3, 27))	('invasion', 'CPA', (176, 184))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (3, 27))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (96, 120))
308397	33324542	Overexpression of LRH-1 in breast cancer results in cell migration and invasion.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('cell migration', 'CPA', (52, 66))	('breast cancer', 'Disease', 'MESH:D001943', (27, 40))	('invasion', 'CPA', (71, 79))	('LRH-1', 'Gene', '2494', (18, 23))	('breast cancer', 'Disease', (27, 40))	('LRH-1', 'Gene', (18, 23))	('breast cancer', 'Phenotype', 'HP:0003002', (27, 40))	('Overexpression', 'Var', (0, 14))
308403	33324542	performed a computational analysis of cancer tissues from 103 breast cancer patients and similarly concluded that the levels of miR-381 and miR-486 are reduced in cancer tissues.	('patients', 'Species', '9606', (76, 84))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('miR-486', 'Gene', '619554', (140, 147))	('levels', 'MPA', (118, 124))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('reduced', 'NegReg', (152, 159))	('miR-486', 'Gene', (140, 147))	('breast cancer', 'Disease', 'MESH:D001943', (62, 75))	('breast cancer', 'Phenotype', 'HP:0003002', (62, 75))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('miR-381', 'Var', (128, 135))	('breast cancer', 'Disease', (62, 75))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('cancer', 'Disease', (38, 44))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Disease', (163, 169))	('cancer', 'Disease', 'MESH:D009369', (163, 169))	('cancer', 'Disease', (69, 75))
308407	33324542	Both miR-381 and miR-486 can target JARID1B and inhibit its expression, which can induce DNA damage accumulation.	('expression', 'MPA', (60, 70))	('induce', 'Reg', (82, 88))	('miR-486', 'Gene', (17, 24))	('JARID1B', 'Gene', (36, 43))	('miR-486', 'Gene', '619554', (17, 24))	('JARID1B', 'Gene', '10765', (36, 43))	('DNA damage accumulation', 'MPA', (89, 112))	('target', 'Reg', (29, 35))	('miR-381', 'Var', (5, 12))	('inhibit', 'NegReg', (48, 55))
308410	33324542	Thus, miR-381-induced JARID1B downregulation causes hypersensitivity to DNA damage and BRCA1 upregulation, which plays an important role in breast cancer migration.	('upregulation', 'PosReg', (93, 105))	('JARID1B', 'Gene', '10765', (22, 29))	('breast cancer', 'Disease', 'MESH:D001943', (140, 153))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('breast cancer', 'Disease', (140, 153))	('hypersensitivity', 'Disease', (52, 68))	('hypersensitivity', 'Disease', 'MESH:D004342', (52, 68))	('downregulation', 'NegReg', (30, 44))	('BRCA1', 'Gene', '672', (87, 92))	('breast cancer', 'Phenotype', 'HP:0003002', (140, 153))	('miR-381-induced', 'Var', (6, 21))	('BRCA1', 'Gene', (87, 92))	('JARID1B', 'Gene', (22, 29))
308412	33324542	WEE1 depletion blocks S phase completion.	('blocks', 'NegReg', (15, 21))	('depletion', 'Var', (5, 14))	('S phase completion', 'CPA', (22, 40))	('WEE1', 'Gene', '7465', (0, 4))	('WEE1', 'Gene', (0, 4))
308421	33324542	In vivo, a study in a xenograft mouse model showed that UBE2C promotes tumor growth, suggesting that UBE2C promotes cell proliferation, in rectal carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('rectal carcinoma', 'Phenotype', 'HP:0100743', (139, 155))	('UBE2C', 'Var', (101, 106))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('promotes', 'PosReg', (62, 70))	('promotes', 'PosReg', (107, 115))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('mouse', 'Species', '10090', (32, 37))	('rectal carcinoma', 'Disease', 'MESH:D012004', (139, 155))	('tumor', 'Disease', (71, 76))	('rectal carcinoma', 'Disease', (139, 155))	('cell proliferation', 'CPA', (116, 134))
308428	33324542	Thus, miR-381 can suppress the FYN-MAPK pathway.	('FYN', 'Gene', (31, 34))	('suppress', 'NegReg', (18, 26))	('miR-381', 'Var', (6, 13))	('FYN', 'Gene', '2534', (31, 34))
308430	33324542	Thus, miR-381 increases drug sensitivity in breast cancer via the FYN-MAPK pathway.	('breast cancer', 'Disease', 'MESH:D001943', (44, 57))	('increases', 'PosReg', (14, 23))	('breast cancer', 'Phenotype', 'HP:0003002', (44, 57))	('breast cancer', 'Disease', (44, 57))	('drug sensitivity', 'Phenotype', 'HP:0020174', (24, 40))	('miR-381', 'Var', (6, 13))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('FYN', 'Gene', (66, 69))	('FYN', 'Gene', '2534', (66, 69))	('drug sensitivity', 'MPA', (24, 40))
308433	33324542	Similar to its effect on DOX sensitivity, miR-381 targets MDR1 and promotes cisplatin sensitivity in breast cancer cells.	('promotes', 'PosReg', (67, 75))	('DOX', 'Chemical', 'MESH:D004317', (25, 28))	('cisplatin', 'Chemical', 'MESH:D002945', (76, 85))	('miR-381', 'Var', (42, 49))	('targets', 'Reg', (50, 57))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('MDR1', 'Gene', (58, 62))	('breast cancer', 'Disease', 'MESH:D001943', (101, 114))	('cisplatin sensitivity', 'MPA', (76, 97))	('MDR1', 'Gene', '5243', (58, 62))	('breast cancer', 'Disease', (101, 114))	('breast cancer', 'Phenotype', 'HP:0003002', (101, 114))
308436	33324542	Genetic knockdown of MDR1 enhances the chemosensitivity of breast cancer cells.	('breast cancer', 'Disease', 'MESH:D001943', (59, 72))	('knockdown', 'Var', (8, 17))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('breast cancer', 'Disease', (59, 72))	('MDR1', 'Gene', (21, 25))	('breast cancer', 'Phenotype', 'HP:0003002', (59, 72))	('enhances', 'PosReg', (26, 34))	('MDR1', 'Gene', '5243', (21, 25))
308437	33324542	Thus, targeting of MDR1 by miR-381 could be a therapeutic strategy.	('MDR1', 'Gene', (19, 23))	('miR-381', 'Var', (27, 34))	('MDR1', 'Gene', '5243', (19, 23))
308442	33324542	Both miR-381 and miR-495 target the 3'UTR of the MDR1 gene and inhibit its expression.	('miR-495', 'Gene', (17, 24))	('miR-495', 'Gene', '574453', (17, 24))	('MDR1', 'Gene', (49, 53))	('target', 'Reg', (25, 31))	('MDR1', 'Gene', '5243', (49, 53))	('inhibit', 'NegReg', (63, 70))	('expression', 'MPA', (75, 85))	('miR-381', 'Var', (5, 12))
308444	33324542	Thus, miR-381 and miR-495 provide a novel approach to leukemia therapy.	('leukemia', 'Phenotype', 'HP:0001909', (54, 62))	('miR-381', 'Var', (6, 13))	('miR-495', 'Gene', (18, 25))	('leukemia', 'Disease', (54, 62))	('leukemia', 'Disease', 'MESH:D007938', (54, 62))	('miR-495', 'Gene', '574453', (18, 25))
308447	33324542	In a mouse model, cells with miR-381 inhibition were injected into nude mice, and inhibition of miR-381 was found to promote chemoresistance to Ci and Pa. Drug resistance is also a major problem in NSCLC.	('NSCLC', 'Phenotype', 'HP:0030358', (198, 203))	('Drug resistance', 'Phenotype', 'HP:0020174', (155, 170))	('Ci', 'Chemical', 'MESH:D002945', (144, 146))	('nude mice', 'Species', '10090', (67, 76))	('inhibition', 'Var', (82, 92))	('mouse', 'Species', '10090', (5, 10))	('NSCLC', 'Disease', 'MESH:D002289', (198, 203))	('miR-381', 'Gene', (96, 103))	('NSCLC', 'Disease', (198, 203))	('promote', 'PosReg', (117, 124))	('Pa', 'Chemical', 'MESH:D017239', (151, 153))
308449	33324542	In NSCLC cell lines, activation of NF-kappaB leads to cisplatin chemoresistance, and inhibition of NF-kappaB can enhance cisplatin efficiency.	('cisplatin efficiency', 'CPA', (121, 141))	('NSCLC', 'Disease', (3, 8))	('NF-kappaB', 'Gene', '4790', (99, 108))	('cisplatin', 'Chemical', 'MESH:D002945', (121, 130))	('cisplatin chemoresistance', 'MPA', (54, 79))	('inhibition', 'Var', (85, 95))	('NSCLC', 'Disease', 'MESH:D002289', (3, 8))	('NF-kappaB', 'Gene', (99, 108))	('NF-kappaB', 'Gene', '4790', (35, 44))	('cisplatin', 'Chemical', 'MESH:D002945', (54, 63))	('NSCLC', 'Phenotype', 'HP:0030358', (3, 8))	('activation', 'PosReg', (21, 31))	('NF-kappaB', 'Gene', (35, 44))	('enhance', 'PosReg', (113, 120))
308450	33324542	MiR-381 suppresses the activation of NF-kappaB via ID1.	('suppresses', 'NegReg', (8, 18))	('ID1', 'Gene', (51, 54))	('NF-kappaB', 'Gene', (37, 46))	('ID1', 'Gene', '3397', (51, 54))	('NF-kappaB', 'Gene', '4790', (37, 46))	('MiR-381', 'Var', (0, 7))
308452	33324542	Moreover, delivery of miR-381 decreases the IC50 values of cisplatin by six fold in NSCLC cell lines, indicating that miR-381 induces cisplatin sensitivity in NSCLC cells.	('induces', 'PosReg', (126, 133))	('decreases', 'NegReg', (30, 39))	('NSCLC', 'Phenotype', 'HP:0030358', (84, 89))	('IC50 values of cisplatin', 'MPA', (44, 68))	('cisplatin sensitivity', 'MPA', (134, 155))	('NSCLC', 'Disease', (159, 164))	('NSCLC', 'Disease', 'MESH:D002289', (159, 164))	('NSCLC', 'Disease', (84, 89))	('miR-381', 'Var', (118, 125))	('NSCLC', 'Disease', 'MESH:D002289', (84, 89))	('cisplatin', 'Chemical', 'MESH:D002945', (134, 143))	('cisplatin', 'Chemical', 'MESH:D002945', (59, 68))	('NSCLC', 'Phenotype', 'HP:0030358', (159, 164))	('miR-381', 'Var', (22, 29))
308453	33324542	Thus, in NSCLC cells, miR-381 regulates the cell cycle and chemosensitivity, and restoration of miR-381 expression may be a therapeutic approach in NSCLC.	('chemosensitivity', 'CPA', (59, 75))	('NSCLC', 'Disease', (148, 153))	('NSCLC', 'Disease', (9, 14))	('regulates', 'Reg', (30, 39))	('NSCLC', 'Disease', 'MESH:D002289', (148, 153))	('NSCLC', 'Disease', 'MESH:D002289', (9, 14))	('NSCLC', 'Phenotype', 'HP:0030358', (9, 14))	('miR-381', 'Gene', (96, 103))	('restoration', 'Var', (81, 92))	('NSCLC', 'Phenotype', 'HP:0030358', (148, 153))	('cell cycle', 'CPA', (44, 54))
308454	33324542	Though in most occasions miR-381 exerts tumor suppressor functions, in some tumors, miR-381 exerts oncogenic functions.	('miR-381', 'Var', (84, 91))	('exerts', 'Reg', (92, 98))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('tumor', 'Disease', (76, 81))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('oncogenic functions', 'CPA', (99, 118))	('tumor', 'Disease', (40, 45))	('tumors', 'Disease', (76, 82))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('miR-381', 'Gene', (25, 32))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
308458	33324542	The filament light polypeptide (NEFL) gene, a tumor suppressor gene, is also a target of miR-381.	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Disease', (46, 51))	('NEFL', 'Gene', '4747', (32, 36))	('miR-381', 'Var', (89, 96))	('NEFL', 'Gene', (32, 36))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
308485	33324542	MiR-381 can bind to the 3'UTR of the VEGF-C gene and repress its expression, thus repressing VEGF-C-mediated lymphangiogenesis.	('VEGF-C', 'Gene', '7424', (37, 43))	('VEGF-C', 'Gene', (93, 99))	('VEGF-C', 'Gene', (37, 43))	('expression', 'MPA', (65, 75))	('repress', 'NegReg', (53, 60))	('repressing', 'NegReg', (82, 92))	('VEGF-C', 'Gene', '7424', (93, 99))	('MiR-381', 'Var', (0, 7))
308496	33324542	Inhibition of miRNA-381 leads to radioresistance and aggressive behaviors in esophageal squamous cell carcinoma cell lines.	('aggressive behaviors', 'Disease', 'MESH:D001523', (53, 73))	('miRNA-381', 'Chemical', '-', (14, 23))	('aggressive behavior', 'Phenotype', 'HP:0000718', (53, 72))	('esophageal squamous cell carcinoma', 'Disease', (77, 111))	('radioresistance', 'CPA', (33, 48))	('aggressive behaviors', 'Phenotype', 'HP:0000718', (53, 73))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (88, 111))	('aggressive behaviors', 'Disease', (53, 73))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (77, 111))	('Inhibition', 'Var', (0, 10))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('miRNA-381', 'Gene', (14, 23))
308497	33324542	In vivo, cell lines with higher miRNA-381 expression levels generate tumors less aggressively, supporting the hypothesis that miRNA-381 inhibits tumor growth and aggressive behaviors.	('expression', 'MPA', (42, 52))	('tumors less aggressively', 'Disease', 'MESH:D001523', (69, 93))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('tumor', 'Disease', (145, 150))	('aggressive behaviors', 'Phenotype', 'HP:0000718', (162, 182))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('aggressive behavior', 'Phenotype', 'HP:0000718', (162, 181))	('inhibits', 'NegReg', (136, 144))	('miRNA-381', 'Var', (32, 41))	('aggressive behaviors', 'Disease', (162, 182))	('tumor', 'Disease', (69, 74))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('miRNA-381', 'Var', (126, 135))	('miRNA-381', 'Chemical', '-', (32, 41))	('aggressive behaviors', 'Disease', 'MESH:D001523', (162, 182))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('tumors less aggressively', 'Disease', (69, 93))	('miRNA-381', 'Chemical', '-', (126, 135))
308498	33324542	One study showed that miRNA-381 is associated with radiosensitivity in esophageal squamous cell carcinoma; miRNA-381 was increased in radiosensitive but decreased in radioresistant esophageal squamous cell carcinoma cell lines.	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('carcinoma', 'Phenotype', 'HP:0030731', (206, 215))	('miRNA-381', 'Chemical', '-', (107, 116))	('esophageal squamous cell carcinoma', 'Disease', (71, 105))	('esophageal squamous cell carcinoma', 'Disease', (181, 215))	('decreased', 'NegReg', (153, 162))	('miRNA-381', 'Var', (107, 116))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (71, 105))	('miRNA-381', 'Chemical', '-', (22, 31))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (82, 105))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (192, 215))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (181, 215))
308500	33324542	MiRNA-381 sensitizes esophageal squamous cell carcinoma cells to irradiation and inhibits their proliferation, migration, and invasion, indicating that miRNA-381 is a potential biomarker and potential therapeutic target for esophageal squamous cell carcinoma.	('inhibits', 'NegReg', (81, 89))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (224, 258))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (21, 55))	('migration', 'CPA', (111, 120))	('miRNA-381', 'Chemical', '-', (152, 161))	('carcinoma', 'Phenotype', 'HP:0030731', (46, 55))	('proliferation', 'CPA', (96, 109))	('MiRNA-381', 'Chemical', '-', (0, 9))	('MiRNA-381', 'Var', (0, 9))	('esophageal squamous cell carcinoma', 'Disease', (21, 55))	('esophageal squamous cell carcinoma', 'Disease', (224, 258))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (235, 258))	('invasion', 'CPA', (126, 134))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (32, 55))	('carcinoma', 'Phenotype', 'HP:0030731', (249, 258))	('sensitizes', 'Reg', (10, 20))
308501	33324542	Moreover, another group found that miR-381 expression is downregulated in esophageal squamous cell carcinoma tissues and cells, and that restoration of miR-381 expression enhances the apoptosis of esophageal squamous cell carcinoma cells.	('expression', 'MPA', (160, 170))	('esophageal squamous cell carcinoma', 'Disease', (74, 108))	('esophageal squamous cell carcinoma', 'Disease', (197, 231))	('downregulated', 'NegReg', (57, 70))	('miR-381', 'Gene', (152, 159))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (208, 231))	('carcinoma', 'Phenotype', 'HP:0030731', (222, 231))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (85, 108))	('enhances', 'PosReg', (171, 179))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (74, 108))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (197, 231))	('miR-381', 'Gene', (35, 42))	('restoration', 'Var', (137, 148))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('expression', 'MPA', (43, 53))	('apoptosis', 'CPA', (184, 193))
308503	33324542	By targeting XIAP, which is upregulated in esophageal squamous cell carcinoma tissues, miR-381 induces caspase-3-dependent apoptosis in these cells.	('esophageal squamous cell carcinoma', 'Disease', (43, 77))	('caspase-3', 'Gene', '836', (103, 112))	('XIAP', 'Gene', '331', (13, 17))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (54, 77))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (43, 77))	('miR-381', 'Var', (87, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (68, 77))	('upregulated', 'PosReg', (28, 39))	('XIAP', 'Gene', (13, 17))	('induces', 'PosReg', (95, 102))	('caspase-3', 'Gene', (103, 112))
308507	33324542	LRH-1 is a direct target of miR-381.	('miR-381', 'Var', (28, 35))	('LRH-1', 'Gene', (0, 5))	('LRH-1', 'Gene', '2494', (0, 5))
308513	33324542	By binding to the 3'UTR of CD1c, miR-381 significantly reduces CD1c expression at both the mRNA and protein levels.	('CD1c', 'Gene', '911', (63, 67))	('expression', 'MPA', (68, 78))	('binding', 'Interaction', (3, 10))	('CD1c', 'Gene', (27, 31))	('reduces', 'NegReg', (55, 62))	('CD1c', 'Gene', (63, 67))	('CD1c', 'Gene', '911', (27, 31))	('miR-381', 'Var', (33, 40))
308516	33324542	MiR-381 can inhibit CD1c expression via IL-10.	('inhibit', 'NegReg', (12, 19))	('IL-10', 'Gene', (40, 45))	('CD1c', 'Gene', (20, 24))	('IL-10', 'Gene', '3586', (40, 45))	('CD1c', 'Gene', '911', (20, 24))	('MiR-381', 'Var', (0, 7))
308526	33324542	In OSCC, miR-381 suppresses EMT by inhibiting FGFR2.	('OSCC', 'CellLine', 'CVCL:L894', (3, 7))	('EMT', 'CPA', (28, 31))	('FGFR2', 'Gene', (46, 51))	('FGFR2', 'Gene', '2263', (46, 51))	('suppresses', 'NegReg', (17, 27))	('inhibiting', 'NegReg', (35, 45))	('OS', 'Phenotype', 'HP:0002669', (3, 5))	('miR-381', 'Var', (9, 16))
308530	33324542	In gastric carcinoma, miR-381 inhibits Sox4, TMEM16A, and ZEB1 and suppresses metastasis.	('gastric carcinoma', 'Phenotype', 'HP:0012126', (3, 20))	('suppresses', 'NegReg', (67, 77))	('TMEM16A', 'Gene', '55107', (45, 52))	('gastric carcinoma', 'Disease', 'MESH:D013274', (3, 20))	('carcinoma', 'Phenotype', 'HP:0030731', (11, 20))	('TMEM16A', 'Gene', (45, 52))	('gastric carcinoma', 'Disease', (3, 20))	('Sox4', 'Gene', (39, 43))	('Sox4', 'Gene', '6659', (39, 43))	('metastasis', 'CPA', (78, 88))	('ZEB1', 'Gene', (58, 62))	('ZEB1', 'Gene', '6935', (58, 62))	('inhibits', 'NegReg', (30, 38))	('miR-381', 'Var', (22, 29))
308531	33324542	In lung adenocarcinoma, miR-381 inhibits ID1 and suppresses EMT.	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (3, 22))	('carcinoma', 'Phenotype', 'HP:0030731', (13, 22))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (3, 22))	('miR-381', 'Var', (24, 31))	('inhibits', 'NegReg', (32, 40))	('EMT', 'CPA', (60, 63))	('ID1', 'Gene', '3397', (41, 44))	('suppresses', 'NegReg', (49, 59))	('lung adenocarcinoma', 'Disease', (3, 22))	('ID1', 'Gene', (41, 44))
308532	33324542	In colon cancer and hepatocellular carcinoma, miR-381 inhibits LRH-1 and suppresses cell growth.	('carcinoma', 'Phenotype', 'HP:0030731', (35, 44))	('hepatocellular carcinoma', 'Disease', (20, 44))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (20, 44))	('LRH-1', 'Gene', '2494', (63, 68))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('cell growth', 'CPA', (84, 95))	('LRH-1', 'Gene', (63, 68))	('colon cancer', 'Phenotype', 'HP:0003003', (3, 15))	('colon cancer', 'Disease', 'MESH:D015179', (3, 15))	('inhibits', 'NegReg', (54, 62))	('miR-381', 'Var', (46, 53))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (20, 44))	('colon cancer', 'Disease', (3, 15))	('suppresses', 'NegReg', (73, 83))
308534	33324542	In breast cancer, miR-381 inhibits WEE1 and blocks the G2/M transition.	('inhibits', 'NegReg', (26, 34))	('blocks', 'NegReg', (44, 50))	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('WEE1', 'Gene', (35, 39))	('WEE1', 'Gene', '7465', (35, 39))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('breast cancer', 'Disease', (3, 16))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('G2/M transition', 'CPA', (55, 70))	('miR-381', 'Var', (18, 25))
308535	33324542	In colon cancer, miR-381 inhibits UBE2C and, as a result, suppresses cell growth.	('UBE2C', 'Protein', (34, 39))	('inhibits', 'NegReg', (25, 33))	('miR-381', 'Var', (17, 24))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('colon cancer', 'Phenotype', 'HP:0003003', (3, 15))	('colon cancer', 'Disease', 'MESH:D015179', (3, 15))	('suppresses', 'NegReg', (58, 68))	('colon cancer', 'Disease', (3, 15))	('cell growth', 'CPA', (69, 80))
308537	33324542	MiR-381 can also increase cisplatin sensitivity in NSCLC.	('cisplatin sensitivity', 'MPA', (26, 47))	('NSCLC', 'Disease', (51, 56))	('NSCLC', 'Disease', 'MESH:D002289', (51, 56))	('cisplatin', 'Chemical', 'MESH:D002945', (26, 35))	('increase', 'PosReg', (17, 25))	('NSCLC', 'Phenotype', 'HP:0030358', (51, 56))	('MiR-381', 'Var', (0, 7))
308540	33324542	In chondrosarcoma, miR-381 inhibits VEGF-dependent lymphangiogenesis, and in esophageal squamous cell carcinoma, miR-381 increases radiosensitivity.	('miR-381', 'Var', (113, 120))	('inhibits', 'NegReg', (27, 35))	('chondrosarcoma', 'Disease', (3, 17))	('increases', 'PosReg', (121, 130))	('VEGF', 'Gene', (36, 40))	('esophageal squamous cell carcinoma', 'Disease', (77, 111))	('sarcoma', 'Phenotype', 'HP:0100242', (10, 17))	('radiosensitivity', 'MPA', (131, 147))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (3, 17))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (88, 111))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (77, 111))	('VEGF', 'Gene', '7422', (36, 40))	('increases radiosensitivity', 'Phenotype', 'HP:0010997', (121, 147))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('miR-381', 'Var', (19, 26))	('chondrosarcoma', 'Disease', 'MESH:D002813', (3, 17))
308541	33324542	In NSCLC, miR-381 suppresses the immune response.	('NSCLC', 'Disease', (3, 8))	('NSCLC', 'Disease', 'MESH:D002289', (3, 8))	('immune response', 'CPA', (33, 48))	('miR-381', 'Var', (10, 17))	('NSCLC', 'Phenotype', 'HP:0030358', (3, 8))	('suppresses', 'NegReg', (18, 28))
308543	33324542	However, under most conditions, miR-381 acts as an inhibitor of tumorigenesis.	('tumor', 'Disease', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('miR-381', 'Var', (32, 39))	('tumor', 'Disease', 'MESH:D009369', (64, 69))
308545	33324542	Considering that miR-381 can enhance chemo- and radiosensitivity, combination treatment with miR-381 and chemotherapy or radiation may be a novel and comprehensive therapeutic strategy for cancer.	('miR-381', 'Var', (17, 24))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('miR-381', 'Var', (93, 100))	('enhance', 'PosReg', (29, 36))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('cancer', 'Disease', (189, 195))
308546	33324542	The current methods for diagnosing cancer, including detection of serum tumor markers, such as CA125, CA199, and CEA, and traditional imaging techniques, such as CT, have low sensitivity and specificity.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('CA125', 'Gene', '94025', (95, 100))	('tumor', 'Disease', (72, 77))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('CA199', 'Var', (102, 107))	('CA125', 'Gene', (95, 100))	('CEA', 'Gene', (113, 116))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('CEA', 'Gene', '5670', (113, 116))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('cancer', 'Disease', (35, 41))
308547	33324542	The levels of miR-381 were assessed in multiple cancers, and studies have shown that in some cancers, miR-381 is associated with prognosis and is thus a novel biomarker (Table 4).	('cancers', 'Disease', (48, 55))	('cancers', 'Disease', (93, 100))	('associated with', 'Reg', (113, 128))	('prognosis', 'CPA', (129, 138))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('cancers', 'Phenotype', 'HP:0002664', (93, 100))	('miR-381', 'Var', (102, 109))	('cancers', 'Phenotype', 'HP:0002664', (48, 55))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('multiple cancers', 'Disease', (39, 55))	('cancers', 'Disease', 'MESH:D009369', (48, 55))	('cancers', 'Disease', 'MESH:D009369', (93, 100))	('multiple cancers', 'Disease', 'MESH:D009369', (39, 55))
308550	33324542	In another study that enrolled 103 breast cancer patients, miR-381 was expressed at lower levels in breast cancer samples than in normal tissues.	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('miR-381', 'Var', (59, 66))	('breast cancer', 'Disease', 'MESH:D001943', (35, 48))	('breast cancer', 'Disease', 'MESH:D001943', (100, 113))	('breast cancer', 'Disease', (100, 113))	('breast cancer', 'Phenotype', 'HP:0003002', (100, 113))	('breast cancer', 'Disease', (35, 48))	('lower', 'NegReg', (84, 89))	('patients', 'Species', '9606', (49, 57))	('breast cancer', 'Phenotype', 'HP:0003002', (35, 48))
308553	33324542	Patients with lower levels of miR-381 had poorer survival (P = 0.023) than those with high levels of miR-381.	('Patients', 'Species', '9606', (0, 8))	('poorer', 'NegReg', (42, 48))	('miR-381', 'Var', (30, 37))	('survival', 'MPA', (49, 57))
308570	33324542	Moreover, the Kaplan-Meier curve showed that patients with higher miR-381 expression exhibited better overall survival (P = 0.0001), and miR-381 is an independent prognostic factor for 5-year survival (P = 0.002).	('expression', 'MPA', (74, 84))	('miR-381', 'Var', (137, 144))	('patients', 'Species', '9606', (45, 53))	('miR-381', 'Gene', (66, 73))	('higher', 'PosReg', (59, 65))	('overall survival', 'CPA', (102, 118))	('better', 'PosReg', (95, 101))
308571	33324542	In a study of osteosarcoma, 60 patients were divided into two groups according to miR-381 expression, and miR-381 expression was found to be associated with survival time.	('survival time', 'CPA', (157, 170))	('osteosarcoma', 'Disease', (14, 26))	('osteosarcoma', 'Phenotype', 'HP:0002669', (14, 26))	('miR-381', 'Gene', (82, 89))	('osteosarcoma', 'Disease', 'MESH:D012516', (14, 26))	('associated', 'Reg', (141, 151))	('patients', 'Species', '9606', (31, 39))	('sarcoma', 'Phenotype', 'HP:0100242', (19, 26))	('miR-381 expression', 'Var', (106, 124))
308580	33324542	Although various studies have revealed that miR-381 is associated with cancer prognosis, miRNAs still have some disadvantages.	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('cancer', 'Disease', (71, 77))	('associated', 'Reg', (55, 65))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('miR-381', 'Var', (44, 51))
308581	33324542	MiR-381 can act as a tumor suppressor in various cancers and, in contrast, can act as an oncogene in other types of cancers.	('cancers', 'Phenotype', 'HP:0002664', (49, 56))	('tumor', 'Disease', (21, 26))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))	('cancers', 'Disease', 'MESH:D009369', (116, 123))	('cancers', 'Phenotype', 'HP:0002664', (116, 123))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cancers', 'Disease', (116, 123))	('cancers', 'Disease', 'MESH:D009369', (49, 56))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('cancers', 'Disease', (49, 56))	('MiR-381', 'Var', (0, 7))
308586	33324542	Various studies have been performed to explain the signaling pathways affected by miR-381 in cancer, and the findings have indicated that miR-381 could be a novel therapeutic target in cancer.	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('miR-381', 'Gene', (82, 89))	('miR-381', 'Var', (138, 145))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('cancer', 'Disease', (185, 191))
308590	33324550	Ectopic expression of collagens can regulate the tumor progression and disease outcome through remodeling of the extracellular matrix (ECM).	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('collagens', 'Protein', (22, 31))	('remodeling', 'CPA', (95, 105))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('Ectopic expression', 'Var', (0, 18))	('tumor', 'Disease', (49, 54))	('regulate', 'Reg', (36, 44))
308616	33324550	Anti-(FAK) (#13009), anti-P-FAK (#8556S), anti-DDR2 (#12133), anti-E-cadherin (#14472), anti-N-cadherin (#13116), anti-vimentin (#5741), and anti-beta-Actin (#3700) were purchased from Cell Signaling Technology (Danvers, MA, USA).	('E-cadherin', 'Gene', (67, 77))	('beta-Actin', 'Gene', (146, 156))	('#13009', 'Var', (12, 18))	('#5741', 'Var', (129, 134))	('beta-Actin', 'Gene', '728378', (146, 156))	('E-cadherin', 'Gene', '999', (67, 77))	('#12133', 'Var', (53, 59))	('#8556S', 'Var', (33, 39))	('#14472', 'Var', (79, 85))	('N-cadherin', 'Gene', (93, 103))	('vimentin', 'Gene', '7431', (119, 127))	('vimentin', 'Gene', (119, 127))	('N-cadherin', 'Gene', '1000', (93, 103))	('#13116', 'Var', (105, 111))
308638	33324550	Cancer cells were grown on coverslips, incubated with 5% milk for 1 h, and treated with antibodies specific for anti-E-cadherin (#14472), anti-N-cadherin (#13116), and anti-vimentin (#5741) at 4 C overnight, and these antibodies were purchased from Cell Signaling Technology (Danvers, MA, USA).	('#14472', 'Var', (129, 135))	('#5741', 'Var', (183, 188))	('N-cadherin', 'Gene', (143, 153))	('vimentin', 'Gene', '7431', (173, 181))	('#13116', 'Var', (155, 161))	('Cancer', 'Disease', (0, 6))	('N-cadherin', 'Gene', '1000', (143, 153))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('vimentin', 'Gene', (173, 181))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('E-cadherin', 'Gene', (117, 127))	('E-cadherin', 'Gene', '999', (117, 127))
308656	33324550	Using the COL10A1 vector or small interfering RNAs (siRNAs), we successfully overexpressed or knocked down COL10A1 in A549 cells or H1299 cells, respectively ( Supplementary Figure S1I ).	('H1299', 'CellLine', 'CVCL:0060', (132, 137))	('A549', 'CellLine', 'CVCL:0023', (118, 122))	('knocked down', 'Var', (94, 106))	('COL10A1', 'Gene', (107, 114))
308658	33324550	Meanwhile, the EdU assay revealed a significant downregulation in growth ability after transfection with si-COL10A1 compared with the negative control (si-scb) ( Figure 2F  and  Supplementary Figure S2A ).	('EdU', 'Chemical', '-', (15, 18))	('growth ability', 'CPA', (66, 80))	('downregulation', 'NegReg', (48, 62))	('si-COL10A1', 'Var', (105, 115))
308659	33324550	Further, we also observed that knockdown of COL10A1 promoted the apoptosis of H1299 cells in TUNEL assay.	('H1299', 'CellLine', 'CVCL:0060', (78, 83))	('COL10A1', 'Gene', (44, 51))	('apoptosis', 'CPA', (65, 74))	('promoted', 'PosReg', (52, 60))	('knockdown', 'Var', (31, 40))
308663	33324550	The results shown that knockdown of COL10A1 drastically decreased the tumor growth of H1299 cells.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('COL10A1', 'Gene', (36, 43))	('tumor', 'Disease', (70, 75))	('knockdown', 'Var', (23, 32))	('decreased', 'NegReg', (56, 65))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('H1299', 'CellLine', 'CVCL:0060', (86, 91))
308664	33324550	The growth rates of the tumors, in terms of volume and weight were decreased upon COL10A1 knockdown ( Figure 3A ).	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('growth rates', 'CPA', (4, 16))	('tumors', 'Disease', (24, 30))	('knockdown', 'Var', (90, 99))	('tumors', 'Disease', 'MESH:D009369', (24, 30))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('COL10A1', 'Gene', (82, 89))	('decreased', 'NegReg', (67, 76))
308666	33324550	In the sixth week, mice injected with COL10A1 knockdown H1299 cells showed fewer metastasis nodules than those injected with sh-scb in lung ( Figures 3C, D ).	('H1299', 'CellLine', 'CVCL:0060', (56, 61))	('knockdown', 'Var', (46, 55))	('sh-scb', 'Chemical', '-', (125, 131))	('fewer', 'NegReg', (75, 80))	('metastasis nodules', 'CPA', (81, 99))	('COL10A1', 'Gene', (38, 45))	('mice', 'Species', '10090', (19, 23))
308672	33324550	To explore whether COL10A1 could activate DDR2 by physical interaction, the western blot assays were applied to detect the expression level of phosphorylated DDR2 (p-DDR2) upon overexpressed and knocked COL10A1 down in A549 and H1299 cells, respectively.	('A549', 'CellLine', 'CVCL:0023', (219, 223))	('H1299', 'CellLine', 'CVCL:0060', (228, 233))	('COL10A1', 'Gene', (203, 210))	('knocked', 'Var', (195, 202))
308674	33324550	The expression level of FAK was significantly decreased upon knocked COL10A1 down in H1299 cells and was dramatically increased with ectopic expression of COL10A1 in A549 cells.	('expression level', 'MPA', (4, 20))	('down', 'NegReg', (77, 81))	('COL10A1', 'Gene', (155, 162))	('COL10A1', 'Gene', (69, 76))	('increased', 'PosReg', (118, 127))	('knocked', 'Var', (61, 68))	('A549', 'CellLine', 'CVCL:0023', (166, 170))	('FAK', 'Gene', (24, 27))	('decreased', 'NegReg', (46, 55))	('H1299', 'CellLine', 'CVCL:0060', (85, 90))
308679	33324550	After transfection of H1299 cells with si-COL10A1 and negative control, immunofluorescence analysis showed that E-cadherin was upregulated, but N-cadherin and vimentin were downregulated ( Figures 5A, B ); the western blot assays revealed the same results ( Figure 5C ).	('downregulated', 'NegReg', (173, 186))	('vimentin', 'Gene', '7431', (159, 167))	('vimentin', 'Gene', (159, 167))	('E-cadherin', 'Gene', (112, 122))	('si-COL10A1', 'Var', (39, 49))	('N-cadherin', 'Gene', (144, 154))	('E-cadherin', 'Gene', '999', (112, 122))	('upregulated', 'PosReg', (127, 138))	('H1299', 'CellLine', 'CVCL:0060', (22, 27))	('N-cadherin', 'Gene', '1000', (144, 154))
308687	33324550	The ectopic expression of COL10A1 is considered to be tightly associated with tumor metastasis.	('tumor metastasis', 'Disease', 'MESH:D009362', (78, 94))	('tumor metastasis', 'Disease', (78, 94))	('associated', 'Reg', (62, 72))	('COL10A1', 'Gene', (26, 33))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('ectopic expression', 'Var', (4, 22))
308689	33324550	We constructed stable lung adenocarcinoma cell lines with overexpression or knockdown of COL10A1 via cell transfection experiments.	('knockdown', 'Var', (76, 85))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (22, 41))	('carcinoma', 'Phenotype', 'HP:0030731', (32, 41))	('lung adenocarcinoma', 'Disease', (22, 41))	('COL10A1', 'Gene', (89, 96))	('overexpression', 'PosReg', (58, 72))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (22, 41))
308691	33324550	In contrast, the invasion and migration ability of H1299 cells with COL10A1 knockdown was significantly downregulated.	('H1299', 'CellLine', 'CVCL:0060', (51, 56))	('downregulated', 'NegReg', (104, 117))	('knockdown', 'Var', (76, 85))	('COL10A1', 'Gene', (68, 75))
308697	33324550	Research indicated that the inhibition of pyruvate metabolism could prevent collagen remodeling in the lung ECM thus reducing metastatic growth in the lung.	('prevent', 'NegReg', (68, 75))	('metastatic growth in the lung', 'CPA', (126, 155))	('pyruvate', 'Chemical', 'MESH:D019289', (42, 50))	('reducing', 'NegReg', (117, 125))	('inhibition', 'Var', (28, 38))	('pyruvate metabolism', 'MPA', (42, 61))	('collagen remodeling', 'CPA', (76, 95))
308849	31730285	We are planning to conduct a further study of SPMs using data from JCOG0502 (UMIN000000551) with an aim of comparing esophagectomy with definitive chemoradiotherapy for T1bN0 esophageal cancer.	('esophageal cancer', 'Disease', (175, 192))	('esophageal cancer', 'Disease', 'MESH:D004938', (175, 192))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('JCOG0502', 'Chemical', 'MESH:C525065', (67, 75))	('T1bN0', 'Var', (169, 174))
308852	30127948	Downregulation of ERBB3 decreases the proliferation, migration and invasion of cervical cancer cells though the interaction with MTK-1 Cervical cancer is a common malignancy in females.	('decreases', 'NegReg', (24, 33))	('cancer', 'Disease', (88, 94))	('proliferation', 'CPA', (38, 51))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('Cervical cancer', 'Disease', 'MESH:D002583', (135, 150))	('ERBB3', 'Gene', '2065', (18, 23))	('Cervical cancer', 'Disease', (135, 150))	('invasion', 'CPA', (67, 75))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('Downregulation', 'Var', (0, 14))	('ERBB3', 'Gene', (18, 23))	('malignancy', 'Disease', 'MESH:D009369', (163, 173))	('cancer', 'Disease', (144, 150))	('malignancy', 'Disease', (163, 173))	('migration', 'CPA', (53, 62))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
308856	30127948	The effects of ERBB3 small interfering RNA silencing on cell proliferation, migration and invasion were explored, and the interaction between ERBB3 and mitogen-activated protein kinase kinase kinase 4 (MTK-1) was also investigated.	('small interfering RNA', 'Var', (21, 42))	('ERBB3', 'Gene', '2065', (142, 147))	('ERBB3', 'Gene', (142, 147))	('MTK-1', 'Gene', '4216', (202, 207))	('ERBB3', 'Gene', '2065', (15, 20))	('mitogen-activated protein kinase kinase kinase 4', 'Gene', '4216', (152, 200))	('ERBB3', 'Gene', (15, 20))	('mitogen-activated protein kinase kinase kinase 4', 'Gene', (152, 200))	('MTK-1', 'Gene', (202, 207))
308858	30127948	In addition, the expression level of MTK-1 was also significantly decreased following MTK-1 siRNA silencing.	('MTK-1', 'Gene', (86, 91))	('decreased', 'NegReg', (66, 75))	('siRNA silencing', 'Var', (92, 107))	('MTK-1', 'Gene', (37, 42))	('MTK-1', 'Gene', '4216', (86, 91))	('expression level', 'MPA', (17, 33))	('MTK-1', 'Gene', '4216', (37, 42))
308921	30127948	The phosphorylation of ERBB3 was also demonstrated to be closely associated with the activation of the phosphoinositide 3-kinase/protein kinase B signaling pathway in the progression of a variety of types of cancer.	('cancer', 'Disease', (208, 214))	('associated', 'Reg', (65, 75))	('activation', 'PosReg', (85, 95))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('ERBB3', 'Gene', '2065', (23, 28))	('phosphorylation', 'Var', (4, 19))	('cancer', 'Disease', 'MESH:D009369', (208, 214))	('ERBB3', 'Gene', (23, 28))
308931	30127948	It is well-known that 15 out of 100 known HPV genotypes cause cervical cancer, and HPV 16 and 18 are responsible for ~70% of all cervical cancer cases.	('HPV 16', 'Species', '333760', (83, 89))	('HPV', 'Species', '10566', (42, 45))	('HPV', 'Species', '10566', (83, 86))	('cervical cancer', 'Disease', (129, 144))	('HPV', 'Var', (83, 86))	('cervical cancer', 'Disease', 'MESH:D002583', (129, 144))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('cervical cancer', 'Disease', (62, 77))	('cervical cancer', 'Disease', 'MESH:D002583', (62, 77))	('cause', 'Reg', (56, 61))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))
308971	28510121	The amino acid sequences for the two different terminal proteins are Arg358 and Ser359, which can be enzymatically lyzed releasing a soluble form of GPC3 (sGPC3).	('Arg358', 'Var', (69, 75))	('GPC3', 'Gene', '2719', (156, 160))	('GPC3', 'Gene', '2719', (149, 153))	('Ser359', 'Chemical', '-', (80, 86))	('Ser359', 'Var', (80, 86))	('Arg358', 'Chemical', '-', (69, 75))	('GPC3', 'Gene', (156, 160))	('GPC3', 'Gene', (149, 153))
309003	28510121	In addition, an early study demonstrated an increased apoptosis response caused by ectopic expression of GPC3 in human lung carcinoma tumor cell, and GPC3 would be a candidate lung tumor suppressor gene, although little has been known on accurate mechanisms of GPC3 in the carcinogenesis of lung cancer.	('lung tumor', 'Phenotype', 'HP:0100526', (176, 186))	('GPC3', 'Gene', '2719', (105, 109))	('cancer', 'Phenotype', 'HP:0002664', (296, 302))	('lung carcinoma tumor', 'Disease', (119, 139))	('apoptosis response', 'CPA', (54, 72))	('carcinogenesis of lung cancer', 'Disease', (273, 302))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('ectopic expression', 'Var', (83, 101))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('human', 'Species', '9606', (113, 118))	('increased', 'PosReg', (44, 53))	('lung tumor', 'Disease', 'MESH:D008175', (176, 186))	('GPC3', 'Gene', (150, 154))	('GPC3', 'Gene', '2719', (150, 154))	('GPC3', 'Gene', (261, 265))	('lung cancer', 'Phenotype', 'HP:0100526', (291, 302))	('GPC3', 'Gene', '2719', (261, 265))	('lung carcinoma tumor', 'Disease', 'MESH:D009369', (119, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('lung tumor', 'Disease', (176, 186))	('carcinogenesis of lung cancer', 'Disease', 'MESH:D063646', (273, 302))	('GPC3', 'Gene', (105, 109))
309068	32201516	Siglec-15 mutations are widely observed in tumors and interact with different genes in different cancer types.	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('interact', 'Reg', (54, 62))	('cancer', 'Disease', (97, 103))	('cancer', 'Disease', 'MESH:D009369', (97, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumors', 'Disease', (43, 49))	('mutations', 'Var', (10, 19))	('Siglec-15', 'Gene', (0, 9))	('tumors', 'Disease', 'MESH:D009369', (43, 49))
309090	32201516	It has a collection of data on millions of coding mutations, noncoding mutations, genomic rearrangements, fusion genes, copy number abnormalities and gene expression variants in the human genome all in one database so that researchers can explore these data more easily.	('copy number abnormalities', 'Disease', 'MESH:D007674', (120, 145))	('human', 'Species', '9606', (182, 187))	('copy number abnormalities', 'Disease', (120, 145))	('variants', 'Var', (166, 174))
309104	32201516	COSMIC provided information on Siglec-15 mutations in different cancers, which included substitution missense, nonsense and synonymous mutations, and the results are depicted in pie charts.	('mutations', 'Var', (41, 50))	('Siglec-15', 'Gene', (31, 40))	('cancers', 'Disease', 'MESH:D009369', (64, 71))	('cancers', 'Phenotype', 'HP:0002664', (64, 71))	('cancers', 'Disease', (64, 71))	('substitution missense', 'Var', (88, 109))	('nonsense', 'Var', (111, 119))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
309105	32201516	Nonsense substitutions were found in biliary tract cancer (33.33%), breast cancer (25%) and lung cancer (16.67%), while substitution missense mutations were observed in biliary tract cancer (33.33%), breast cancer (75%), central nervous system cancer (33.33%), hematopoietic and lymphoid cancer (100%), endometrial cancer (100%), large intestine cancer (68.42%), liver cancer (25%), lung cancer (83.33%), esophageal cancer (75%), prostate cancer (100%), skin cancer (100%), stomach cancer (75%), thyroid cancer (100%) and upper aerodigestive tract cancer (60%).	('cancer', 'Disease', 'MESH:D009369', (459, 465))	('endometrial cancer', 'Disease', (303, 321))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('stomach cancer', 'Disease', (474, 488))	('lung cancer', 'Phenotype', 'HP:0100526', (383, 394))	('cancer', 'Disease', 'MESH:D009369', (369, 375))	('biliary tract cancer', 'Disease', (37, 57))	('cancer', 'Disease', 'MESH:D009369', (504, 510))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('cancer', 'Disease', (388, 394))	('lymphoid cancer', 'Phenotype', 'HP:0002665', (279, 294))	('missense mutations', 'Var', (133, 151))	('cancer', 'Disease', (315, 321))	('central nervous system cancer', 'Phenotype', 'HP:0100006', (221, 250))	('biliary tract cancer', 'Phenotype', 'HP:0100574', (37, 57))	('breast cancer', 'Phenotype', 'HP:0003002', (200, 213))	('biliary tract cancer', 'Disease', 'MESH:D001661', (37, 57))	('breast cancer', 'Disease', 'MESH:D001943', (68, 81))	('cancer', 'Disease', (75, 81))	('cancer', 'Disease', (504, 510))	('breast cancer', 'Disease', (200, 213))	('cancer', 'Disease', (416, 422))	('liver cancer', 'Phenotype', 'HP:0002896', (363, 375))	('liver cancer', 'Disease', (363, 375))	('cancer', 'Disease', 'MESH:D009369', (482, 488))	('lymphoid cancer', 'Disease', 'MESH:D009369', (279, 294))	('upper aerodigestive tract cancer', 'Disease', (522, 554))	('cancer', 'Disease', (288, 294))	('thyroid cancer', 'Disease', (496, 510))	('cancer', 'Disease', 'MESH:D009369', (244, 250))	('prostate cancer', 'Disease', 'MESH:D011471', (430, 445))	('prostate cancer', 'Phenotype', 'HP:0012125', (430, 445))	('cancer', 'Disease', (97, 103))	('central nervous system cancer', 'Disease', (221, 250))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('biliary tract cancer', 'Disease', (169, 189))	('thyroid cancer', 'Disease', 'MESH:D013964', (496, 510))	('cancer', 'Disease', (482, 488))	('cancer', 'Disease', (459, 465))	('nervous system cancer', 'Phenotype', 'HP:0004375', (229, 250))	('esophageal cancer', 'Disease', (405, 422))	('cancer', 'Disease', (244, 250))	('cancer', 'Disease', 'MESH:D009369', (183, 189))	('cancer', 'Disease', 'MESH:D009369', (207, 213))	('cancer', 'Disease', (369, 375))	('substitutions', 'Var', (9, 22))	('biliary tract cancer', 'Phenotype', 'HP:0100574', (169, 189))	('breast cancer', 'Disease', 'MESH:D001943', (200, 213))	('endometrial cancer', 'Phenotype', 'HP:0012114', (303, 321))	('lung cancer', 'Disease', 'MESH:D008175', (92, 103))	('cancer', 'Disease', 'MESH:D009369', (548, 554))	('skin cancer', 'Disease', 'MESH:D012878', (454, 465))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('cancer', 'Disease', (51, 57))	('biliary tract cancer', 'Disease', 'MESH:D001661', (169, 189))	('cancer', 'Disease', 'MESH:D009369', (346, 352))	('upper aerodigestive tract cancer', 'Disease', 'MESH:D006258', (522, 554))	('cancer', 'Disease', (548, 554))	('cancer', 'Disease', 'MESH:D009369', (439, 445))	('skin cancer', 'Disease', (454, 465))	('prostate cancer', 'Disease', (430, 445))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('stomach cancer', 'Disease', 'MESH:D013274', (474, 488))	('lymphoid cancer', 'Disease', (279, 294))	('lung cancer', 'Disease', (92, 103))	('large intestine cancer', 'Phenotype', 'HP:0100834', (330, 352))	('stomach cancer', 'Phenotype', 'HP:0012126', (474, 488))	('cancer', 'Disease', (346, 352))	('breast cancer', 'Phenotype', 'HP:0003002', (68, 81))	('thyroid cancer', 'Phenotype', 'HP:0002890', (496, 510))	('central nervous system cancer', 'Disease', 'MESH:D002494', (221, 250))	('cancer', 'Disease', 'MESH:D009369', (388, 394))	('cancer', 'Disease', (439, 445))	('lung cancer', 'Phenotype', 'HP:0100526', (92, 103))	('cancer', 'Disease', 'MESH:D009369', (315, 321))	('lung cancer', 'Disease', 'MESH:D008175', (383, 394))	('endometrial cancer', 'Disease', 'MESH:D016889', (303, 321))	('cancer', 'Disease', (183, 189))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('cancer', 'Disease', (207, 213))	('cancer', 'Disease', 'MESH:D009369', (416, 422))	('esophageal cancer', 'Disease', 'MESH:D004938', (405, 422))	('cancer', 'Disease', 'MESH:D009369', (288, 294))	('skin cancer', 'Phenotype', 'HP:0008069', (454, 465))	('hematopoietic and', 'Disease', (261, 278))	('lung cancer', 'Disease', (383, 394))	('liver cancer', 'Disease', 'MESH:D006528', (363, 375))	('cancer', 'Disease', 'MESH:D009369', (97, 103))	('breast cancer', 'Disease', (68, 81))
309106	32201516	Additionally, synonymous substitution mutations appeared in biliary tract cancer (33.33%), central nervous system cancer (66.67%), large intestine cancer (36.84%), liver cancer (75%), esophageal cancer (25%), parathyroid cancer (100%), stomach cancer (25%) and upper aerodigestive tract cancer (40%).	('cancer', 'Disease', 'MESH:D009369', (221, 227))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('cancer', 'Disease', (170, 176))	('cancer', 'Disease', (287, 293))	('liver cancer', 'Disease', 'MESH:D006528', (164, 176))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('upper aerodigestive tract cancer', 'Disease', (261, 293))	('cancer', 'Disease', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('thyroid cancer', 'Phenotype', 'HP:0002890', (213, 227))	('synonymous substitution mutations', 'Var', (14, 47))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('cancer', 'Disease', 'MESH:D009369', (244, 250))	('nervous system cancer', 'Phenotype', 'HP:0004375', (99, 120))	('liver cancer', 'Phenotype', 'HP:0002896', (164, 176))	('biliary tract cancer', 'Disease', (60, 80))	('liver cancer', 'Disease', (164, 176))	('upper aerodigestive tract cancer', 'Disease', 'MESH:D006258', (261, 293))	('stomach cancer', 'Disease', 'MESH:D013274', (236, 250))	('stomach cancer', 'Phenotype', 'HP:0012126', (236, 250))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('esophageal cancer', 'Disease', 'MESH:D004938', (184, 201))	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('parathyroid cancer', 'Disease', 'MESH:D010282', (209, 227))	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('large intestine cancer', 'Phenotype', 'HP:0100834', (131, 153))	('parathyroid cancer', 'Disease', (209, 227))	('cancer', 'Disease', 'MESH:D009369', (287, 293))	('cancer', 'Disease', (221, 227))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Disease', (195, 201))	('esophageal cancer', 'Disease', (184, 201))	('biliary tract cancer', 'Phenotype', 'HP:0100574', (60, 80))	('cancer', 'Disease', (244, 250))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('central nervous system cancer', 'Disease', (91, 120))	('biliary tract cancer', 'Disease', 'MESH:D001661', (60, 80))	('parathyroid cancer', 'Phenotype', 'HP:0006780', (209, 227))	('appeared', 'Reg', (48, 56))	('central nervous system cancer', 'Phenotype', 'HP:0100006', (91, 120))	('cancer', 'Disease', (147, 153))	('stomach cancer', 'Disease', (236, 250))	('central nervous system cancer', 'Disease', 'MESH:D002494', (91, 120))	('cancer', 'Disease', (114, 120))
309107	32201516	C>T and G>A mutations were most common in the Siglec-15 coding strand, both of which were observed in eleven cancer types.	('G>A mutations', 'Var', (8, 21))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('C>T', 'Var', (0, 3))	('mutations', 'Var', (12, 21))	('cancer', 'Disease', (109, 115))	('common', 'Reg', (32, 38))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))
309108	32201516	A>T and T>A mutations in Siglec-15 were not found in the TCGA cancer samples.	('T>A', 'Var', (8, 11))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('Siglec-15', 'Gene', (25, 34))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))
309109	32201516	Other types of base mutations occurred sporadically in different cancers (Figure 3a).	('base mutations', 'Var', (15, 29))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('cancers', 'Disease', 'MESH:D009369', (65, 72))	('cancers', 'Phenotype', 'HP:0002664', (65, 72))	('occurred', 'Reg', (30, 38))	('cancers', 'Disease', (65, 72))
309123	32201516	Several lines of evidence have shown that interactions with sialic acid-binding receptors can influence cancer progression; for example, hypersialylation can induce changes in the physical properties of tumor cells and potentiate the evasion of apoptosis in cancer cells.	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('tumor', 'Disease', (203, 208))	('hypersialylation', 'Var', (137, 153))	('influence', 'Reg', (94, 103))	('cancer', 'Phenotype', 'HP:0002664', (258, 264))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('potentiate', 'PosReg', (219, 229))	('sialic acid', 'Chemical', 'MESH:D019158', (60, 71))	('interactions', 'Interaction', (42, 54))	('cancer', 'Disease', 'MESH:D009369', (258, 264))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('cancer', 'Disease', (258, 264))	('induce changes', 'Reg', (158, 172))	('cancer', 'Disease', (104, 110))	('evasion', 'MPA', (234, 241))
309131	32201516	Additionally, knockdown of Siglec-15 expression did not cause obvious physical abnormalities but did inhibit tumor growth.	('Siglec-15', 'Gene', (27, 36))	('inhibit', 'NegReg', (101, 108))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('knockdown', 'Var', (14, 23))	('tumor', 'Disease', (109, 114))
309132	32201516	Since no previous studies have focused on Siglec-15 mutations in human cancers, we explored this topic with the help of COSMIC and cBioPortal.	('mutations', 'Var', (52, 61))	('human', 'Species', '9606', (65, 70))	('cancers', 'Disease', 'MESH:D009369', (71, 78))	('cancers', 'Phenotype', 'HP:0002664', (71, 78))	('Siglec-15', 'Gene', (42, 51))	('cancers', 'Disease', (71, 78))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))
309133	32201516	As shown in Figure 3, the results from TCGA demonstrated that Siglec-15 mutations occurred widely in human cancers.	('mutations', 'Var', (72, 81))	('cancers', 'Disease', (107, 114))	('cancers', 'Disease', 'MESH:D009369', (107, 114))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('Siglec-15', 'Gene', (62, 71))	('occurred', 'Reg', (82, 90))	('human', 'Species', '9606', (101, 106))	('cancers', 'Phenotype', 'HP:0002664', (107, 114))
309134	32201516	The most common type of Siglec-15 mutation was missense substitution, which could be observed in all tumors with mutations.	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('Siglec-15', 'Gene', (24, 33))	('missense substitution', 'Var', (47, 68))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('tumors', 'Disease', (101, 107))	('tumors', 'Disease', 'MESH:D009369', (101, 107))
309135	32201516	At the base-pair level, C>T and G>A mutations were the most widely observed in tumors.	('observed', 'Reg', (67, 75))	('C>T', 'Var', (24, 27))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('G>A mutations', 'Var', (32, 45))	('tumors', 'Disease', (79, 85))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
309139	32201516	Alterations in the expression of Siglec-15 may cause a variety of gene changes across different cancers, which could lead to remarkably different results.	('cancers', 'Phenotype', 'HP:0002664', (96, 103))	('cause', 'Reg', (47, 52))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('Alterations', 'Var', (0, 11))	('gene changes', 'MPA', (66, 78))	('Siglec-15', 'Gene', (33, 42))	('cancers', 'Disease', 'MESH:D009369', (96, 103))	('cancers', 'Disease', (96, 103))
309143	32201516	For cutaneous melanoma patients, high Siglec-15 expression indicates a high risk of tumor aggressiveness and adverse clinical outcomes.	('high', 'Var', (33, 37))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (84, 104))	('patients', 'Species', '9606', (23, 31))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('expression', 'MPA', (48, 58))	('melanoma', 'Phenotype', 'HP:0002861', (14, 22))	('Siglec-15', 'Protein', (38, 47))	('tumor aggressiveness', 'Disease', (84, 104))	('cutaneous melanoma', 'Disease', (4, 22))	('aggressiveness', 'Phenotype', 'HP:0000718', (90, 104))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (4, 22))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (4, 22))
309153	32201516	Siglec-15 mutations are widely observed in tumors and interact with different genes in different cancer types, which might explain why high Siglec-15 expression does not necessarily indicate a poor prognosis in all cancers.	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('expression', 'MPA', (150, 160))	('cancer', 'Disease', (97, 103))	('cancer', 'Disease', (215, 221))	('cancer', 'Disease', 'MESH:D009369', (215, 221))	('cancers', 'Disease', 'MESH:D009369', (215, 222))	('cancer', 'Disease', 'MESH:D009369', (97, 103))	('cancers', 'Phenotype', 'HP:0002664', (215, 222))	('cancers', 'Disease', (215, 222))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('tumors', 'Disease', (43, 49))	('mutations', 'Var', (10, 19))	('Siglec-15', 'Gene', (0, 9))	('Siglec-15', 'Gene', (140, 149))	('tumors', 'Disease', 'MESH:D009369', (43, 49))
309214	31068568	Possible molecular genetic marker-based therapy targeting mutations involving PIK3CA in basaloid squamous cell carcinoma versus squamous cell carcinoma may provide a tailored therapeutic strategy as a treatment.	('mutations', 'Var', (58, 67))	('PIK3CA', 'Gene', (78, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (97, 120))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (128, 151))	('PIK3CA', 'Gene', '5290', (78, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (142, 151))	('basaloid squamous cell carcinoma', 'Phenotype', 'HP:0002671', (88, 120))	('basaloid squamous cell carcinoma versus squamous cell carcinoma', 'Disease', 'MESH:D002294', (88, 151))	('men', 'Species', '9606', (206, 209))
309221	28545451	We knocked down PTK7 in two esophageal squamous cell carcinoma cell lines, TE-5, and TE-9, by siRNA, and evaluated cell proliferation, apoptosis, and migration ofPTK7-defective cells.	('apoptosis', 'CPA', (135, 144))	('PTK7', 'Gene', '5754', (16, 20))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (28, 62))	('PTK7', 'Gene', (162, 166))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (39, 62))	('knocked', 'Var', (3, 10))	('esophageal squamous cell carcinoma', 'Disease', (28, 62))	('PTK7', 'Gene', '5754', (162, 166))	('carcinoma', 'Phenotype', 'HP:0030731', (53, 62))	('cell proliferation', 'CPA', (115, 133))	('migration', 'CPA', (150, 159))	('PTK7', 'Gene', (16, 20))
309235	28545451	Disruption of PTK7 expression can repress cell proliferation and can promote apoptosis in colon and liver cancers.	('PTK7', 'Gene', (14, 18))	('apoptosis', 'CPA', (77, 86))	('repress', 'NegReg', (34, 41))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('PTK7', 'Gene', '5754', (14, 18))	('cell proliferation', 'CPA', (42, 60))	('cancers', 'Phenotype', 'HP:0002664', (106, 113))	('liver cancers', 'Phenotype', 'HP:0002896', (100, 113))	('promote', 'PosReg', (69, 76))	('colon and liver cancers', 'Disease', 'MESH:D006528', (90, 113))	('Disruption', 'Var', (0, 10))
309238	28545451	Notably, given that Wnt signaling plays significant roles in human cancer and that a recent study has shown that knockdown of PTK7 can inhibit Wnt/beta-catenin activity, it is conceivable that PTK7 may also be involved in cancer development and progression.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('beta-catenin', 'Gene', '1499', (147, 159))	('PTK7', 'Gene', '5754', (193, 197))	('cancer', 'Disease', 'MESH:D009369', (222, 228))	('cancer', 'Disease', (67, 73))	('inhibit', 'NegReg', (135, 142))	('PTK7', 'Gene', (126, 130))	('cancer', 'Disease', (222, 228))	('involved', 'Reg', (210, 218))	('PTK7', 'Gene', '5754', (126, 130))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('knockdown', 'Var', (113, 122))	('PTK7', 'Gene', (193, 197))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('human', 'Species', '9606', (61, 66))	('beta-catenin', 'Gene', (147, 159))
309239	28545451	Although dysregulation of PTK7 has been reported in some cancers, its role in tumorigenesis and oncogenic progression awaits further demonstration.	('PTK7', 'Gene', (26, 30))	('PTK7', 'Gene', '5754', (26, 30))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('cancers', 'Phenotype', 'HP:0002664', (57, 64))	('cancers', 'Disease', (57, 64))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('cancers', 'Disease', 'MESH:D009369', (57, 64))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('tumor', 'Disease', (78, 83))	('reported', 'Reg', (40, 48))	('dysregulation', 'Var', (9, 22))
309253	28545451	We knocked down PTK7 in two esophageal squamous carcinoma cell lines and measured proliferation and apoptosis of these PTK7-deficient cells.	('measured', 'Reg', (73, 81))	('PTK7', 'Gene', '5754', (16, 20))	('esophageal squamous carcinoma', 'Disease', 'MESH:D000077277', (28, 57))	('PTK7', 'Gene', '5754', (119, 123))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (39, 57))	('PTK7', 'Gene', (16, 20))	('esophageal squamous carcinoma', 'Phenotype', 'HP:0011459', (28, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (48, 57))	('esophageal squamous carcinoma', 'Disease', (28, 57))	('knocked', 'Var', (3, 10))	('proliferation', 'CPA', (82, 95))	('apoptosis', 'CPA', (100, 109))	('PTK7', 'Gene', (119, 123))
309263	28545451	Absorbance at 450 nm at each time point was recorded for both targeted-knockdown (siPTK7) and knockdown control (siControl) cells.	('PTK7', 'Gene', (84, 88))	('targeted-knockdown', 'Var', (62, 80))	('PTK7', 'Gene', '5754', (84, 88))
309294	28545451	Notably, in both cases of TE-5 and TE-9, siPTK7 cells had increased populations of both early stage (Annexin V+/PI-) and late stage apoptotic (Annexin V+/PI+) cells (Fig.	('PTK7', 'Gene', '5754', (43, 47))	('Annexin V', 'Gene', '308', (143, 152))	('TE-9', 'Var', (35, 39))	('Annexin V', 'Gene', (143, 152))	('TE-5', 'Var', (26, 30))	('increased', 'PosReg', (58, 67))	('Annexin V', 'Gene', '308', (101, 110))	('Annexin V', 'Gene', (101, 110))	('PTK7', 'Gene', (43, 47))
309299	28545451	Transwell migration assay showed that, in both cases of TE-5 and TE-9, migration of siPTK7 cells was significantly reduced by 60% or more compared with siControl (p < 0.01) (Fig.	('reduced', 'NegReg', (115, 122))	('PTK7', 'Gene', '5754', (86, 90))	('migration', 'CPA', (71, 80))	('PTK7', 'Gene', (86, 90))	('TE-5', 'Var', (56, 60))	('TE-9', 'Var', (65, 69))
309307	28545451	Indeed, disruption of PTK7 expression by siRNA rendered the tumor cells lose the proliferative advantages to the undisturbed counterparts.	('disruption', 'Var', (8, 18))	('PTK7', 'Gene', (22, 26))	('lose', 'NegReg', (72, 76))	('PTK7', 'Gene', '5754', (22, 26))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('proliferative advantages', 'CPA', (81, 105))	('tumor', 'Disease', (60, 65))
309309	28545451	More interestingly, disruption of PTK7 further slowed down cellular migration in vitro, during which the epithelial-mesenchymal transition marker gene E-cadherin was upregulated, suggesting PTK7 may promote metastasis of esophageal squamous cell carcinoma.	('upregulated', 'PosReg', (166, 177))	('slowed down', 'NegReg', (47, 58))	('PTK7', 'Gene', (34, 38))	('PTK7', 'Gene', '5754', (34, 38))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (221, 255))	('metastasis', 'CPA', (207, 217))	('disruption', 'Var', (20, 30))	('promote', 'PosReg', (199, 206))	('cellular migration in vitro', 'CPA', (59, 86))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (232, 255))	('carcinoma', 'Phenotype', 'HP:0030731', (246, 255))	('PTK7', 'Gene', (190, 194))	('E-cadherin', 'Gene', (151, 161))	('esophageal squamous cell carcinoma', 'Disease', (221, 255))	('PTK7', 'Gene', '5754', (190, 194))	('E-cadherin', 'Gene', '999', (151, 161))
309312	28545451	When PTK7 expression was disrupted by RNAi, the tumor cells proliferated slowly and became prone to apoptosis.	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('tumor', 'Disease', (48, 53))	('PTK7', 'Gene', '5754', (5, 9))	('prone', 'Reg', (91, 96))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('PTK7', 'Gene', (5, 9))	('disrupted', 'Var', (25, 34))	('apoptosis', 'CPA', (100, 109))	('expression', 'Protein', (10, 20))	('slowly', 'NegReg', (73, 79))
309331	27631209	Circulating long noncoding RNA GAS5 is a novel biomarker for the diagnosis of nonsmall cell lung cancer The recently discovered long noncoding RNAs have the potential to regulate many biological processes, which are aberrantly expressed in many tumor types.	('biological processes', 'CPA', (184, 204))	('lung cancer', 'Phenotype', 'HP:0100526', (92, 103))	('tumor', 'Disease', (245, 250))	('GAS5', 'Gene', '60674', (31, 35))	('tumor', 'Disease', 'MESH:D009369', (245, 250))	('nonsmall cell lung cancer', 'Disease', (78, 103))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('nonsmall cell lung cancer', 'Disease', 'MESH:D002289', (78, 103))	('nonsmall cell lung cancer', 'Phenotype', 'HP:0030358', (78, 103))	('GAS5', 'Gene', (31, 35))	('long noncoding RNAs', 'Var', (128, 147))	('regulate', 'Reg', (170, 178))
309361	27631209	The high expression of MALAT1 was highly predictive of a poor prognosis in early-stage NSCLC.	('MALAT1', 'Gene', (23, 29))	('NSCLC', 'Disease', (87, 92))	('NSCLC', 'Disease', 'MESH:D002289', (87, 92))	('high', 'Var', (4, 8))	('NSCLC', 'Phenotype', 'HP:0030358', (87, 92))	('MALAT1', 'Gene', '378938', (23, 29))
309369	27631209	Meanwhile, the knockdown of GAS5 promoted tumor cell growth.	('promoted', 'PosReg', (33, 41))	('tumor', 'Disease', (42, 47))	('knockdown', 'Var', (15, 24))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('GAS5', 'Gene', (28, 32))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
309438	27631209	Furthermore, the AUC values obtained for GAS5 and CEA were 0.832 (95% CI 0.754-0.893) and 0.700 (95% CI 0.611-0.779), respectively.	('0.700', 'Var', (90, 95))	('CEA', 'Gene', '1084', (50, 53))	('AUC', 'MPA', (17, 20))	('CEA', 'Gene', (50, 53))
309493	26672675	Moreover, according to the final score (0-300), OSCCs/OPSCCs have been divided in two classes: CK19high scoreOSCCs/OPSCCCs (15 cases with score > 150) and CK19low scoreOSCCs/OPSCCs (23 cases with score < 150).	('score > 150', 'Var', (138, 149))	('CK19', 'Gene', (155, 159))	('CK19', 'Gene', '3880', (155, 159))	('CK19', 'Gene', (95, 99))	('CK19', 'Gene', '3880', (95, 99))
309495	26672675	Regarding HPV detection in OSCC/OPSCC, among 38 cases, 10 were HR-HPV+ cancers (as evaluated by ISH and/or consensus PCR) (Table 2): 6 cases were HPV16+, 1 case was infected by both HR- and LR-HPVs (HPV31/44+), 1 case was HPV31+ and 1 case HPV56+; the remaining positive case, at the ISH evaluation, showed an integrated status for HR-HPV, but it has not been possible to assess the viral genotype.	('HR-HPV', 'Disease', (63, 69))	('HPV', 'Species', '10566', (199, 202))	('HPV', 'Species', '10566', (10, 13))	('HPV', 'Species', '10566', (66, 69))	('cancers', 'Phenotype', 'HP:0002664', (71, 78))	('HPV', 'Species', '10566', (240, 243))	('HR-HPV+ cancers', 'Disease', (63, 78))	('HPV16', 'Species', '333760', (146, 151))	('HPV', 'Species', '10566', (193, 196))	('HPV', 'Species', '10566', (146, 149))	('HR-HPV', 'Disease', 'MESH:D030361', (332, 338))	('HR-HPV', 'Disease', 'MESH:D030361', (63, 69))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('HR-HPV+ cancers', 'Disease', 'MESH:D030361', (63, 78))	('HR-HPV', 'Disease', (332, 338))	('HPV', 'Species', '10566', (335, 338))	('HPV', 'Species', '10566', (222, 225))	('HPV16+', 'Var', (146, 152))
309497	26672675	Finally, among the 28 HR-HPV- cancers, 2 were HPV6+ (Low Risk- Human Papilloma Virus, LR-HPV), 1 was HPV53+ (Intermediate Risk- Human Papillloma Virus, IR-HPV) and the remaining cases (n.25) were HPV-.	('HPV', 'Species', '10566', (196, 199))	('HPV', 'Species', '10566', (25, 28))	('Human', 'Species', '9606', (63, 68))	('Human Papilloma Virus', 'Species', '10566', (63, 84))	('HPV53+', 'Var', (101, 107))	('HPV', 'Species', '10566', (155, 158))	('cancers', 'Phenotype', 'HP:0002664', (30, 37))	('HPV', 'Species', '10566', (46, 49))	('HPV', 'Species', '10566', (89, 92))	('Papilloma', 'Phenotype', 'HP:0012740', (69, 78))	('Papillloma Virus', 'Disease', (134, 150))	('HPV', 'Species', '10566', (101, 104))	('HR-HPV- cancers', 'Disease', (22, 37))	('Papillloma Virus', 'Disease', 'MESH:D001102', (134, 150))	('HPV6+', 'Disease', (46, 51))	('HR-HPV- cancers', 'Disease', 'MESH:D030361', (22, 37))	('Human', 'Species', '9606', (128, 133))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
309501	26672675	High scores (270-300), high percentages (90-100) of expressing cancer cells and a constant staining 3+ have been observed in all integrated HR-HPV+ OSCCs/OPSCCs.	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('HR-HPV', 'Disease', 'MESH:D030361', (140, 146))	('HR-HPV', 'Disease', (140, 146))	('270-300', 'Var', (13, 20))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('cancer', 'Disease', (63, 69))
309503	26672675	In perilesional areas, in HR-HPV-cancers, we observed CK19 positivity in 13 out 19 valuable cases (68.4 %) and a generally moderate-strong staining, localized in all epithelial layers (6 cases at basal level, 4 cases at the intermediate layer and the remaining 3 cases in the upper layer).	('cancers', 'Phenotype', 'HP:0002664', (33, 40))	('positivity', 'Var', (59, 69))	('CK19', 'Gene', (54, 58))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('HR-HPV-cancers', 'Disease', 'MESH:D030361', (26, 40))	('HR-HPV-cancers', 'Disease', (26, 40))	('CK19', 'Gene', '3880', (54, 58))
309518	26672675	The relative extent of CK19 expression, as revealed by the mean fluorescence intensity (MFI), varied among the analyzed cell lines, being lower for UPCI-SCC-131 (MFI = 60,62) in comparison to the UPCI-SCC-154 (MFI = 83,92) (Fig.	('fluorescence intensity', 'MPA', (64, 86))	('UPCI-SCC-131', 'Var', (148, 160))	('lower', 'NegReg', (138, 143))	('CK19', 'Gene', (23, 27))	('CK19', 'Gene', '3880', (23, 27))	('UPCI-SCC-131', 'CellLine', 'CVCL:2229', (148, 160))
309596	33712015	Ten small molecules were identified as potential drugs specifically for HPV-positive or HPV-negative patients; three:NVP-AUY922, fostamatinib and PP-2:greatly inhibited the proliferation of six HPV-negative HNSCC cell lines in vitro, and NVP-AUY922 inhibited three HPV-negative HNSCC xenografts in vivo.	('inhibited', 'NegReg', (249, 258))	('patients', 'Species', '9606', (101, 109))	('NVP-AUY922', 'Chemical', 'MESH:C528044', (238, 248))	('HPV', 'Species', '10566', (265, 268))	('NVP-AUY922', 'Var', (117, 127))	('PP-2', 'Gene', (146, 150))	('fostamatinib', 'Chemical', 'MESH:C523665', (129, 141))	('NVP-AUY922', 'Chemical', 'MESH:C528044', (117, 127))	('HPV', 'Species', '10566', (72, 75))	('proliferation', 'CPA', (173, 186))	('HPV', 'Species', '10566', (88, 91))	('HPV', 'Species', '10566', (194, 197))	('NVP-AUY922', 'Var', (238, 248))	('PP-2', 'Gene', '4888', (146, 150))	('inhibited', 'NegReg', (159, 168))
309646	33712015	Three GEO datasets (GSE39366, GSE40774, GSE55550) containing a total of 345 samples were analyzed by GEO2R, with the data divided into the HPV-positive and HPV-negative groups.	('GSE39366', 'Var', (20, 28))	('GSE40774', 'Var', (30, 38))	('HPV', 'Species', '10566', (156, 159))	('GSE55550', 'Var', (40, 48))	('HPV', 'Species', '10566', (139, 142))
309690	33712015	NVP-AUY922 was the most effective drug, followed by fostamatinib and PP-2.	('PP-2', 'Gene', (69, 73))	('fostamatinib', 'Chemical', 'MESH:C523665', (52, 64))	('NVP-AUY922', 'Var', (0, 10))	('NVP-AUY922', 'Chemical', 'MESH:C528044', (0, 10))	('PP-2', 'Gene', '4888', (69, 73))
309691	33712015	The IC50 values of NVP-AUY922, fostamatinib and PP-2 were range from 0.012 to 0.072 muM, 0.811 to 3.470 muM, 5.32 to 16.41 muM, respectively (Fig.	('NVP-AUY922', 'Var', (19, 29))	('PP-2', 'Gene', (48, 52))	('fostamatinib', 'Chemical', 'MESH:C523665', (31, 43))	('NVP-AUY922', 'Chemical', 'MESH:C528044', (19, 29))	('PP-2', 'Gene', '4888', (48, 52))
309695	33712015	As a result, NVP-AUY922 significantly inhibited the growth of all the three HNSCC xenografts in vivo compared with the control group (Fig.	('NVP-AUY922', 'Var', (13, 23))	('NVP-AUY922', 'Chemical', 'MESH:C528044', (13, 23))	('growth', 'CPA', (52, 58))	('inhibited', 'NegReg', (38, 47))
309698	33712015	Three of them, NVP-AUY922, PP-2 and fostamatinib showed therapeutic value in six HPV-negative HNSCC cell lines, besides, NVP-AUY922 inhibited three HPV-negative HNSCC xenografts in vivo.	('PP-2', 'Gene', (27, 31))	('inhibited', 'NegReg', (132, 141))	('HPV', 'Species', '10566', (148, 151))	('NVP-AUY922', 'Var', (121, 131))	('NVP-AUY922', 'Chemical', 'MESH:C528044', (121, 131))	('PP-2', 'Gene', '4888', (27, 31))	('NVP-AUY922', 'Chemical', 'MESH:C528044', (15, 25))	('fostamatinib', 'Chemical', 'MESH:C523665', (36, 48))	('HPV', 'Species', '10566', (81, 84))
309699	33712015	AREG is a ligand of the epidermal growth factor receptor (EGFR), AREG binds to EGFR can induce key intracellular signaling cascades controlling cell survival, proliferation and motility.	('cell survival', 'CPA', (144, 157))	('EGFR', 'Gene', '1956', (58, 62))	('AREG', 'Gene', '374', (65, 69))	('EGFR', 'Gene', '1956', (79, 83))	('EGFR', 'Gene', (79, 83))	('epidermal growth factor receptor', 'Gene', (24, 56))	('EGFR', 'Gene', (58, 62))	('key intracellular signaling cascades', 'MPA', (95, 131))	('induce', 'Reg', (88, 94))	('binds', 'Var', (70, 75))	('motility', 'CPA', (177, 185))	('AREG', 'Gene', '374', (0, 4))	('epidermal growth factor receptor', 'Gene', '1956', (24, 56))	('AREG', 'Gene', (0, 4))	('AREG', 'Gene', (65, 69))
309706	33712015	STAG3 is also required for chromosome pairing and synapsis, DNA repair and meiosis progression, and mutation of STAG3 may induce DNA repair process abnormalities.	('STAG3', 'Gene', (0, 5))	('STAG3', 'Gene', (112, 117))	('mutation', 'Var', (100, 108))	('STAG3', 'Gene', '10734', (112, 117))	('DNA repair process abnormalities', 'CPA', (129, 161))	('STAG3', 'Gene', '10734', (0, 5))	('induce', 'Reg', (122, 128))
309707	33712015	A previous study demonstrated that STAG3 may be a tumor suppressor gene, and that loss of STAG3 may cause drug resistance in melanoma.	('STAG3', 'Gene', '10734', (35, 40))	('melanoma', 'Phenotype', 'HP:0002861', (125, 133))	('melanoma', 'Disease', (125, 133))	('STAG3', 'Gene', '10734', (90, 95))	('drug resistance', 'Phenotype', 'HP:0020174', (106, 121))	('melanoma', 'Disease', 'MESH:D008545', (125, 133))	('STAG3', 'Gene', (35, 40))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('STAG3', 'Gene', (90, 95))	('cause', 'Reg', (100, 105))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('drug resistance', 'MPA', (106, 121))	('loss', 'Var', (82, 86))	('tumor', 'Disease', (50, 55))
309719	33712015	NVP-AUY922, PP-2, and fostamatinib inhibited cell proliferation in vitro in six HPV-negative cell lines, with low IC50 values.	('fostamatinib', 'Gene', (22, 34))	('PP-2', 'Gene', '4888', (12, 16))	('cell proliferation in vitro', 'CPA', (45, 72))	('NVP-AUY922', 'Var', (0, 10))	('NVP-AUY922', 'Chemical', 'MESH:C528044', (0, 10))	('PP-2', 'Gene', (12, 16))	('HPV', 'Species', '10566', (80, 83))	('inhibited', 'NegReg', (35, 44))	('fostamatinib', 'Chemical', 'MESH:C523665', (22, 34))
309721	33712015	NVP-AUY922 is an HSP inhibitor that suppresses the growth, angiogenesis and metastasis of several kinds of tumors, including oral squamous cell carcinoma.	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('growth', 'CPA', (51, 57))	('NVP-AUY922', 'Var', (0, 10))	('tumors', 'Disease', (107, 113))	('suppresses', 'NegReg', (36, 46))	('met', 'Gene', '79811', (76, 79))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('NVP-AUY922', 'Chemical', 'MESH:C528044', (0, 10))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (125, 153))	('tumors', 'Disease', 'MESH:D009369', (107, 113))	('met', 'Gene', (76, 79))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (130, 153))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('angiogenesis', 'CPA', (59, 71))	('oral squamous cell carcinoma', 'Disease', (125, 153))
309734	33712015	Three of the identified small molecule drugs (NVP-AUY922, PP-2 and fostamatinib) showed inhibitory effects on six HPV-negative HNSCC cell lines, and NVP-AUY922 inhibited three HPV-negative HNSCC xenografts in vivo.	('NVP-AUY922', 'Chemical', 'MESH:C528044', (149, 159))	('PP-2', 'Gene', (58, 62))	('HPV', 'Species', '10566', (114, 117))	('HPV', 'Species', '10566', (176, 179))	('NVP-AUY922', 'Var', (149, 159))	('PP-2', 'Gene', '4888', (58, 62))	('fostamatinib', 'Chemical', 'MESH:C523665', (67, 79))	('inhibitory', 'NegReg', (88, 98))	('inhibited', 'NegReg', (160, 169))	('NVP-AUY922', 'Chemical', 'MESH:C528044', (46, 56))
309738	33712015	In addition, NVP-AUY922, fostamatinib and PP-2 may be used as drugs to treat HPV-negative head and neck cancers.	('PP-2', 'Gene', (42, 46))	('neck cancers', 'Disease', 'MESH:D006258', (99, 111))	('fostamatinib', 'Chemical', 'MESH:C523665', (25, 37))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('NVP-AUY922', 'Var', (13, 23))	('NVP-AUY922', 'Chemical', 'MESH:C528044', (13, 23))	('HPV', 'Species', '10566', (77, 80))	('cancers', 'Phenotype', 'HP:0002664', (104, 111))	('neck cancers', 'Disease', (99, 111))	('head and neck cancers', 'Phenotype', 'HP:0012288', (90, 111))	('PP-2', 'Gene', '4888', (42, 46))
309766	33255394	showed that cell lines and patient samples of NSCLC overexpressed XIST and shown that XIST knockdown inhibits tumour growth in vivo.	('XIST', 'Gene', (86, 90))	('NSCLC', 'Disease', (46, 51))	('LC', 'Phenotype', 'HP:0100526', (49, 51))	('knockdown', 'Var', (91, 100))	('patient', 'Species', '9606', (27, 34))	('tumour', 'Phenotype', 'HP:0002664', (110, 116))	('tumour growth', 'Disease', (110, 123))	('NSCLC', 'Disease', 'MESH:D002289', (46, 51))	('inhibits', 'NegReg', (101, 109))	('tumour growth', 'Disease', 'MESH:D006130', (110, 123))	('NSCLC', 'Phenotype', 'HP:0030358', (46, 51))
309786	33255394	Following the sexual dimorphism of XIST, we investigated the change in the genome transcriptional landscape A549 (derived from male patient) and H1975 (derived from female patient) NSCLC cell lines upon silencing XIST using siRNA (Figure 6).	('silencing', 'Var', (203, 212))	('NSCLC', 'Disease', 'MESH:D002289', (181, 186))	('H1975', 'CellLine', 'CVCL:1511', (145, 150))	('patient', 'Species', '9606', (172, 179))	('A549', 'CellLine', 'CVCL:0023', (108, 112))	('LC', 'Phenotype', 'HP:0100526', (184, 186))	('NSCLC', 'Phenotype', 'HP:0030358', (181, 186))	('XIST', 'Gene', (213, 217))	('patient', 'Species', '9606', (132, 139))	('NSCLC', 'Disease', (181, 186))
309788	33255394	In the H1975, 751 genes were significantly dysregulated after the treatment with the siRNA XIST.	('dysregulated', 'Reg', (43, 55))	('H1975', 'Var', (7, 12))	('H1975', 'CellLine', 'CVCL:1511', (7, 12))
309789	33255394	The two cell lines had 34 downregulated genes in common with p < 0.05, 24 downregulated genes with p < 5 x 10-5, and one gene (RHOH) that was up-regulated in the H1975 and down-regulated for the A549 (Figure 6b).	('downregulated', 'NegReg', (26, 39))	('RHOH', 'Gene', '399', (127, 131))	('H1975', 'Var', (162, 167))	('up-regulated', 'PosReg', (142, 154))	('H1975', 'CellLine', 'CVCL:1511', (162, 167))	('down-regulated', 'NegReg', (172, 186))	('RHOH', 'Gene', (127, 131))	('A549', 'CellLine', 'CVCL:0023', (195, 199))
309804	33255394	Silencing XIST in vitro resulted in 944 DEGs for A549 and 751 DEGs for H1975 cell lines respectively.	('H1975', 'CellLine', 'CVCL:1511', (71, 76))	('XIST', 'Gene', (10, 14))	('Silencing', 'Var', (0, 9))	('A549', 'CellLine', 'CVCL:0023', (49, 53))
309815	33255394	In H1975 cells silencing XIST lead to a highly significant down-regulation of 113 genes.	('silencing', 'Var', (15, 24))	('H1975', 'CellLine', 'CVCL:1511', (3, 8))	('down-regulation', 'NegReg', (59, 74))	('XIST', 'Gene', (25, 29))
309820	33255394	Our current cell lines have an EGFR mutant phenotype harbouring a T790M resistance mutation and a L858R sensitizing mutation (H1975), whereas the A549 cell line is KRAS mutant.	('EGFR', 'Gene', '1956', (31, 35))	('L858R', 'Mutation', 'rs121434568', (98, 103))	('KRAS', 'Gene', '3845', (164, 168))	('EGFR', 'Gene', (31, 35))	('A549', 'CellLine', 'CVCL:0023', (146, 150))	('T790M', 'Mutation', 'rs121434569', (66, 71))	('KRAS', 'Gene', (164, 168))	('H1975', 'CellLine', 'CVCL:1511', (126, 131))	('T790M', 'Var', (66, 71))
309825	33255394	These involve genes like MUC16 (CA125) whose levels relate to different stages of NSCLC, and PTK7 that is associated with lymph node metastasis as well as ALK and EGFR mutations in lung cancer.	('ALK', 'Gene', '238', (155, 158))	('EGFR', 'Gene', (163, 167))	('ALK', 'Gene', (155, 158))	('LC', 'Phenotype', 'HP:0100526', (85, 87))	('CA125', 'Gene', '94025', (32, 37))	('mutations', 'Var', (168, 177))	('lymph node metastasis', 'Disease', (122, 143))	('associated with', 'Reg', (106, 121))	('lung cancer', 'Disease', (181, 192))	('PTK7', 'Gene', (93, 97))	('MUC16', 'Gene', '94025', (25, 30))	('NSCLC', 'Disease', 'MESH:D002289', (82, 87))	('EGFR', 'Gene', '1956', (163, 167))	('PTK7', 'Gene', '5754', (93, 97))	('NSCLC', 'Disease', (82, 87))	('MUC16', 'Gene', (25, 30))	('lung cancer', 'Disease', 'MESH:D008175', (181, 192))	('NSCLC', 'Phenotype', 'HP:0030358', (82, 87))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('CA125', 'Gene', (32, 37))	('lung cancer', 'Phenotype', 'HP:0100526', (181, 192))
309842	33255394	The co-expression of XIST, TSIX, hnRNPu, Bcl-2, and BRCA1 provided a strong collective feature to discriminate between controls and LC, implying a diagnostic potential.	('Bcl-2', 'Gene', (41, 46))	('hnRNPu', 'Gene', (33, 39))	('BRCA1', 'Gene', '672', (52, 57))	('Bcl-2', 'Gene', '596', (41, 46))	('co-expression', 'Var', (4, 17))	('BRCA1', 'Gene', (52, 57))	('TSIX', 'Gene', '9383', (27, 31))	('LC', 'Phenotype', 'HP:0100526', (132, 134))	('XIST', 'Gene', (21, 25))	('TSIX', 'Gene', (27, 31))	('hnRNPu', 'Gene', '3192', (33, 39))
309869	32382346	Although the side effects caused by cisplatin have been mildly alleviated by newly-developed antagonists, cisplatin resistance, which commonly originates from multiple cellular self-defense adaptations, often results in disease recurrence.	('disease', 'Disease', (220, 227))	('results in', 'Reg', (209, 219))	('cisplatin', 'Chemical', 'MESH:D002945', (36, 45))	('cisplatin', 'Chemical', 'MESH:D002945', (106, 115))	('cisplatin resistance', 'Var', (106, 126))
309911	32382346	The GEPIA analysis identified RHBG and NCAM1 as co-expressed genes of HOXD-AS2 and LNC01123, respectively.	('LNC01123', 'Var', (83, 91))	('HOXD-AS2', 'Gene', (70, 78))	('RHBG', 'Gene', (30, 34))	('HOXD-AS2', 'Gene', '100506783', (70, 78))	('NCAM1', 'Gene', '4684', (39, 44))	('NCAM1', 'Gene', (39, 44))
309941	32382346	Although NCAM1 has been associated with cisplatin resistance in ovarian cancer, the in vitro expression of NCAM improved the response of multiple myeloma cells to Bortezomib (Btz) treatment.	('associated', 'Reg', (24, 34))	('NCAM', 'Gene', '4684', (107, 111))	('improved', 'PosReg', (112, 120))	('expression', 'Var', (93, 103))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('NCAM1', 'Gene', (9, 14))	('NCAM', 'Gene', (107, 111))	('cisplatin', 'Chemical', 'MESH:D002945', (40, 49))	('multiple myeloma', 'Phenotype', 'HP:0006775', (137, 153))	('Btz', 'Chemical', 'MESH:D000069286', (175, 178))	('NCAM', 'Gene', '4684', (9, 13))	('ovarian cancer', 'Disease', 'MESH:D010051', (64, 78))	('Bortezomib', 'Chemical', 'MESH:D000069286', (163, 173))	('NCAM', 'Gene', (9, 13))	('multiple myeloma', 'Disease', 'MESH:D009101', (137, 153))	('response', 'MPA', (125, 133))	('NCAM1', 'Gene', '4684', (9, 14))	('ovarian cancer', 'Disease', (64, 78))	('multiple myeloma', 'Disease', (137, 153))	('ovarian cancer', 'Phenotype', 'HP:0100615', (64, 78))
309944	32382346	MED12 mutations are associated with tumorigenesis.	('associated', 'Reg', (20, 30))	('MED12', 'Gene', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('MED12', 'Gene', '9968', (0, 5))	('tumor', 'Disease', (36, 41))	('mutations', 'Var', (6, 15))
309945	32382346	Indeed, somatic mutations in MED12 exon 2 have been observed in uterine leiomyosarcoma, colorectal cancer (CRC), uterine leiomyoma, breast fibroadenoma, phyllodes tumors and prostate cancer.	('MED12', 'Gene', (29, 34))	('tumors and prostate cancer', 'Disease', 'MESH:D011471', (163, 189))	('colorectal cancer', 'Disease', 'MESH:D015179', (88, 105))	('CRC', 'Disease', (107, 110))	('colorectal cancer', 'Disease', (88, 105))	('breast fibroadenoma', 'Phenotype', 'HP:0010619', (132, 151))	('mutations', 'Var', (16, 25))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('leiomyoma', 'Disease', 'MESH:D007889', (121, 130))	('tumors', 'Phenotype', 'HP:0002664', (163, 169))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (72, 86))	('breast fibroadenoma', 'Disease', 'MESH:D001943', (132, 151))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (72, 86))	('prostate cancer', 'Phenotype', 'HP:0012125', (174, 189))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('MED12', 'Gene', '9968', (29, 34))	('CRC', 'Disease', 'MESH:D015179', (107, 110))	('colorectal cancer', 'Phenotype', 'HP:0003003', (88, 105))	('observed', 'Reg', (52, 60))	('leiomyoma', 'Disease', (121, 130))	('uterine leiomyosarcoma', 'Phenotype', 'HP:0002891', (64, 86))	('breast fibroadenoma', 'Disease', (132, 151))	('leiomyosarcoma', 'Disease', (72, 86))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('uterine leiomyoma', 'Phenotype', 'HP:0000131', (113, 130))
309947	32382346	This is consistent with the results of the present study, in which patients with high levels of MED12 had improved OS time.	('MED12', 'Gene', '9968', (96, 101))	('improved', 'PosReg', (106, 114))	('patients', 'Species', '9606', (67, 75))	('MED12', 'Gene', (96, 101))	('high levels', 'Var', (81, 92))	('OS time', 'CPA', (115, 122))
309949	32382346	Although the results of the present study suggested that ARF4 upregulation was associated with improved patient outcomes, it has been previously reported that high expression levels of ARF4 in patients with breast cancer are significantly associated with increased risk of distant metastasis and shorter OS time.	('associated', 'Reg', (239, 249))	('patients', 'Species', '9606', (193, 201))	('breast cancer', 'Disease', (207, 220))	('ARF4', 'Gene', '378', (57, 61))	('ARF4', 'Gene', (57, 61))	('distant metastasis', 'CPA', (273, 291))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('shorter OS time', 'CPA', (296, 311))	('high expression levels', 'Var', (159, 181))	('ARF4', 'Gene', '378', (185, 189))	('patient', 'Species', '9606', (104, 111))	('breast cancer', 'Disease', 'MESH:D001943', (207, 220))	('breast cancer', 'Phenotype', 'HP:0003002', (207, 220))	('patient', 'Species', '9606', (193, 200))	('ARF4', 'Gene', (185, 189))	('upregulation', 'PosReg', (62, 74))
309950	32382346	Conversely, ARF4 silencing reduces the colonization of the lung by metastatic breast cancer cells in vivo.	('breast cancer', 'Phenotype', 'HP:0003002', (78, 91))	('ARF4', 'Gene', (12, 16))	('ARF4', 'Gene', '378', (12, 16))	('reduces', 'NegReg', (27, 34))	('colonization of the lung by metastatic', 'CPA', (39, 77))	('breast cancer', 'Disease', 'MESH:D001943', (78, 91))	('silencing', 'Var', (17, 26))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('breast cancer', 'Disease', (78, 91))
309994	28984208	Most successful examples of DNA mutations as biomarkers were found in well-studied cancer genes, such as EGFR, KRAS, and BRAF.	('BRAF', 'Gene', (121, 125))	('KRAS', 'Gene', (111, 115))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('KRAS', 'Gene', '3845', (111, 115))	('EGFR', 'Gene', '1956', (105, 109))	('mutations', 'Var', (32, 41))	('EGFR', 'Gene', (105, 109))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('BRAF', 'Gene', '673', (121, 125))	('cancer', 'Disease', (83, 89))
310002	28984208	Notably, in KIRC it is the tumor-suppressor genes that are most prone to mutation, whereas in other cancer types mutation is most common in oncogenes.	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumor', 'Disease', (27, 32))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('mutation', 'Var', (73, 81))
310023	28984208	In KIRC, we found only one mutation biomarker, MTHFD1 (p adjust = 0.01), which was mutated in five of 414 samples.	('MTHFD1', 'Gene', (47, 53))	('mutated', 'Var', (83, 90))	('MTHFD1', 'Gene', '4522', (47, 53))
310024	28984208	Among all the cancers we examined, UCEC had the largest number of SNV survival biomarkers with somatic mutations in 31 genes.	('cancers', 'Disease', (14, 21))	('mutations', 'Var', (103, 112))	('cancers', 'Phenotype', 'HP:0002664', (14, 21))	('UCEC', 'Disease', (35, 39))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('cancers', 'Disease', 'MESH:D009369', (14, 21))
310039	28984208	Since most driver mutations previously reported in KIRC are in tumor-suppressor genes (i.e., are of limited clinical use), our finding of a large number of protein biomarkers has important implications for the development of precision medicine approaches to treat patients with KIRC.	('tumor', 'Disease', (63, 68))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('patients', 'Species', '9606', (264, 272))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('mutations', 'Var', (18, 27))
310052	28984208	Our results showed that the overlapping genes were involved in the KEGG's cancer-related signaling transduction pathways (hsa05215: prostate cancer, p = 2.2 x 10-3; hsa05223: non-small cell lung cancer, p = 0.024; and hsa04012: ErbB signaling pathway, p = 0.029).	('prostate cancer', 'Disease', (132, 147))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (179, 201))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('cancer', 'Disease', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('ErbB', 'Gene', '1956', (228, 232))	('cell lung cancer', 'Disease', 'MESH:D008175', (185, 201))	('cancer', 'Disease', (141, 147))	('cell lung cancer', 'Disease', (185, 201))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('cancer', 'Disease', (195, 201))	('lung cancer', 'Phenotype', 'HP:0100526', (190, 201))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (175, 201))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('ErbB', 'Gene', (228, 232))	('prostate cancer', 'Disease', 'MESH:D011471', (132, 147))	('involved', 'Reg', (51, 59))	('prostate cancer', 'Phenotype', 'HP:0012125', (132, 147))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('hsa05223', 'Var', (165, 173))
310071	28984208	As a result, we found seven stage-specific protein biomarkers among the 52 general biomarkers: ACC1, Cyclin_B1, FASN, GATA3, GAB2, MAPK_pT202_Y204, and Rad51.	('FASN', 'Gene', (112, 116))	('Cyclin_B1', 'Gene', '891', (101, 110))	('Rad51', 'Gene', (152, 157))	('GAB2', 'Gene', (125, 129))	('Rad51', 'Gene', '5888', (152, 157))	('FASN', 'Gene', '2194', (112, 116))	('GATA3', 'Gene', (118, 123))	('Cyclin_B1', 'Gene', (101, 110))	('ACC1', 'Gene', (95, 99))	('ACC1', 'Gene', '31', (95, 99))	('GATA3', 'Gene', '2625', (118, 123))	('MAPK_pT202_Y204', 'Var', (131, 146))	('GAB2', 'Gene', '9846', (125, 129))
310104	28984208	With nominal p value threshold at 0.01, frameshift deletions in SETD2 was found to be significant (p = 4.88 x 10-3).	('SETD2', 'Gene', (64, 69))	('frameshift deletions', 'Var', (40, 60))	('SETD2', 'Gene', '29072', (64, 69))
310113	28984208	For each cancer type, we included two somatic mutation types: insertion/deletion (indel) and SNV.	('insertion/deletion', 'Var', (62, 80))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('cancer', 'Disease', (9, 15))
310192	28325293	In addition, piR-L-138 directly interacted with p60-MDM2 and inhibited CDDP-activated apoptosis in p53-mutated LSCC.	('p60', 'Gene', (48, 51))	('inhibited', 'NegReg', (61, 70))	('p53-mutated', 'Var', (99, 110))	('LSCC', 'Phenotype', 'HP:0030359', (111, 115))	('CDDP', 'Chemical', '-', (71, 75))	('CDDP-activated', 'MPA', (71, 85))	('interacted', 'Interaction', (32, 42))	('LSCC', 'Disease', (111, 115))	('L-138', 'Chemical', '-', (17, 22))	('p60', 'Gene', '3437', (48, 51))
310210	28325293	In contrast, neither piR-L-138 in all four LADCs nor any non-LSCC-related piR-Ls in all four LSCCs were observed to show an obviously consistent and substantial increase upon CDDP, gemcitabine, or docetaxel treatment (Figure S1), indicating that the upregulated piR-L-138 was LSCC-related, which was consistent with the data obtained using RNA sequencing (RNA-seq) (Figure 1B) as we reported previously.	('LADC', 'Phenotype', 'HP:0030078', (43, 47))	('upregulated', 'PosReg', (250, 261))	('L', 'Chemical', '-', (266, 267))	('L', 'Chemical', '-', (78, 79))	('L', 'Chemical', '-', (25, 26))	('gemcitabine', 'Chemical', 'MESH:C056507', (181, 192))	('LSCC', 'Phenotype', 'HP:0030359', (61, 65))	('L', 'Chemical', '-', (93, 94))	('CDDP', 'Var', (175, 179))	('LSCC', 'Phenotype', 'HP:0030359', (93, 97))	('L-138', 'Chemical', '-', (266, 271))	('LSCC', 'Phenotype', 'HP:0030359', (276, 280))	('docetaxel', 'Chemical', 'MESH:D000077143', (197, 206))	('CDDP', 'Chemical', '-', (175, 179))	('L', 'Chemical', '-', (43, 44))	('L', 'Chemical', '-', (61, 62))	('L', 'Chemical', '-', (276, 277))	('L-138', 'Chemical', '-', (25, 30))
310219	28325293	Targeting piR-L-138 followed by CDDP treatment in two LSCC representative cell lines of H157 and SKMES-1, we found that blocking piR-L-138 resulted in decreased cell viability (Figure 2A), which was caused by an increased apoptotic cell population represented by a substantial increase of the sub-G1 fragment (Figure 2B; Figures S3A-S3C).	('blocking', 'Var', (120, 128))	('increased apoptotic cell population', 'Phenotype', 'HP:0030887', (212, 247))	('LSCC', 'Phenotype', 'HP:0030359', (54, 58))	('CDDP', 'Chemical', '-', (32, 36))	('cell viability', 'CPA', (161, 175))	('L-138', 'Chemical', '-', (133, 138))	('L-138', 'Chemical', '-', (14, 19))	('decreased', 'NegReg', (151, 160))	('sub-G1 fragment', 'CPA', (293, 308))	('increase', 'PosReg', (277, 285))	('SKMES-1', 'CellLine', 'CVCL:0630', (97, 104))	('piR-L-138', 'Gene', (129, 138))	('apoptotic cell population', 'CPA', (222, 247))	('increased', 'PosReg', (212, 221))
310220	28325293	In addition, H157 and SKMES-1 cells treated with Anti-138 showed a significantly increased percentage of Annexin V-positive cells, cleaved Capase-3, and cleaved poly ADP ribose polymerase (PARP) (Figure 2C; Figures S4A-S4C), further confirming that targeting piR-L-138 increases the sensitivity of LSCC cells to CDDP in vitro.	('Annexin V', 'Gene', '308', (105, 114))	('Annexin V', 'Gene', (105, 114))	('cleaved', 'MPA', (131, 138))	('L-138', 'Chemical', '-', (263, 268))	('poly ADP ribose polymerase', 'Gene', (161, 187))	('LSCC', 'Phenotype', 'HP:0030359', (298, 302))	('SKMES-1', 'CellLine', 'CVCL:0630', (22, 29))	('PARP', 'Gene', (189, 193))	('increases', 'PosReg', (269, 278))	('poly ADP ribose polymerase', 'Gene', '142', (161, 187))	('CDDP', 'Chemical', '-', (312, 316))	('piR-L-138', 'Gene', (259, 268))	('Anti-138', 'Var', (49, 57))	('sensitivity', 'MPA', (283, 294))	('increased', 'PosReg', (81, 90))	('PARP', 'Gene', '142', (189, 193))
310221	28325293	To further confirm the roles of CDDP-induced piR-L-138 in apoptosis, we used a tumor xenograft model to determine whether targeting piR-L-138 could enhance CDDP-induced cell apoptosis of tumors developed from H157 cells inoculated in Nu/Nu mice.	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('tumor', 'Disease', (79, 84))	('targeting', 'Var', (122, 131))	('CDDP', 'Chemical', '-', (32, 36))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('mice', 'Species', '10090', (240, 244))	('CDDP', 'Chemical', '-', (156, 160))	('tumor', 'Disease', (187, 192))	('L-138', 'Chemical', '-', (136, 141))	('L-138', 'Chemical', '-', (49, 54))	('tumors', 'Disease', (187, 193))	('enhance', 'PosReg', (148, 155))	('piR-L-138', 'Gene', (132, 141))	('tumors', 'Disease', 'MESH:D009369', (187, 193))	('tumors', 'Phenotype', 'HP:0002664', (187, 193))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('CDDP-induced', 'MPA', (156, 168))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
310225	28325293	Compared with tumors formed in untreated mice and in mice treated with CDDP plus Scr, the tumors in mice treated with CDDP plus Anti-138 were significantly smaller (Figure 3A, left and center and growth curves), indicating that targeting piR-L-138 inhibited tumor growth.	('tumor', 'Disease', (258, 263))	('mice', 'Species', '10090', (100, 104))	('tumors', 'Disease', 'MESH:D009369', (90, 96))	('tumor', 'Disease', 'MESH:D009369', (258, 263))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('mice', 'Species', '10090', (53, 57))	('tumor', 'Disease', (90, 95))	('CDDP', 'Chemical', '-', (71, 75))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('inhibited', 'NegReg', (248, 257))	('Scr', 'Gene', '109559', (81, 84))	('smaller', 'NegReg', (156, 163))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('tumor', 'Phenotype', 'HP:0002664', (258, 263))	('mice', 'Species', '10090', (41, 45))	('L-138', 'Chemical', '-', (242, 247))	('tumors', 'Disease', (14, 20))	('CDDP', 'Chemical', '-', (118, 122))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('targeting', 'Var', (228, 237))	('tumor', 'Disease', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumors', 'Disease', (90, 96))	('Scr', 'Gene', (81, 84))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('piR-L-138', 'Gene', (238, 247))
310226	28325293	Further, compared with tumors treated with CDDP and Scr control, tumors treated with CDDP plus Anti-138 exhibited higher expression of cleaved Caspase 3 (Figure 3B), indicating that targeting piR-L-138 enhanced CDDP-induced cell apoptosis in tumors.	('expression', 'MPA', (121, 131))	('tumors', 'Disease', (65, 71))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))	('cleaved', 'MPA', (135, 142))	('Scr', 'Gene', '109559', (52, 55))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('L-138', 'Chemical', '-', (196, 201))	('tumors', 'Phenotype', 'HP:0002664', (242, 248))	('cell apoptosis', 'CPA', (224, 238))	('tumors', 'Disease', (23, 29))	('CDDP', 'Chemical', '-', (211, 215))	('tumor', 'Phenotype', 'HP:0002664', (242, 247))	('CDDP', 'Chemical', '-', (85, 89))	('piR-L-138', 'Var', (192, 201))	('tumors', 'Disease', (242, 248))	('higher', 'PosReg', (114, 120))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('tumors', 'Disease', 'MESH:D009369', (23, 29))	('enhanced', 'PosReg', (202, 210))	('Scr', 'Gene', (52, 55))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('CDDP', 'Chemical', '-', (43, 47))	('tumors', 'Disease', 'MESH:D009369', (242, 248))
310227	28325293	In addition, we found that tumor areas that showed high concentrated Anti-138 also showed high levels of cleaved Caspase-3 and cleaved PARP (Figures 3C and 3D), further conforming that blocking CDDP-upregulated piR-L-138 accelerates CDDP-induced apoptosis of tumors derived from LSCC cells.	('tumor', 'Disease', 'MESH:D009369', (259, 264))	('L-138', 'Chemical', '-', (215, 220))	('tumors', 'Phenotype', 'HP:0002664', (259, 265))	('Caspase-3', 'Gene', (113, 122))	('CDDP-upregulated', 'Var', (194, 210))	('tumor', 'Disease', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (259, 264))	('tumors', 'Disease', (259, 265))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('piR-L-138', 'Gene', (211, 220))	('accelerates', 'PosReg', (221, 232))	('PARP', 'Gene', (135, 139))	('tumors', 'Disease', 'MESH:D009369', (259, 265))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('Caspase-3', 'Gene', '836', (113, 122))	('PARP', 'Gene', '142', (135, 139))	('CDDP', 'Chemical', '-', (194, 198))	('tumor', 'Disease', (259, 264))	('LSCC', 'Phenotype', 'HP:0030359', (279, 283))	('CDDP', 'Chemical', '-', (233, 237))
310229	28325293	Given that CDDP-induced piR-L-138 inhibits apoptosis and that these two LSCC-representative cell lines harbor p53 mutations, we hypothesized that piR-L-138 could be involved in regulating functions of mouse double minute 2 homolog (MDM2) because MDM2 and its three isoforms (90, 75, and 60 kDa) have been implicated in p53-independent apoptosis as well as in chemoresistance.	('chemoresistance', 'CPA', (359, 374))	('CDDP', 'Chemical', '-', (11, 15))	('apoptosis', 'CPA', (43, 52))	('mutations', 'Var', (114, 123))	('implicated', 'Reg', (305, 315))	('inhibits', 'NegReg', (34, 42))	('L-138', 'Chemical', '-', (28, 33))	('L-138', 'Chemical', '-', (150, 155))	('mouse', 'Species', '10090', (201, 206))	('LSCC', 'Phenotype', 'HP:0030359', (72, 76))
310231	28325293	As shown in Figure 4A, blocking piR-L-138 increased full-length MDM2 and decreased the 60-kDa cleaved isoform (referred to hereafter as p60-MDM2) upon CDDP treatment, and, in contrast, ectopic expression of piR-L-138 decreased total MDM2 and increased p60-MDM2 upon CDDP treatment (Figure 4B), indicating that the role of piR-L-138 in apoptosis inhibition was related to p60 MDM2.	('decreased', 'NegReg', (217, 226))	('blocking piR-L-138', 'Var', (23, 41))	('decreased', 'NegReg', (73, 82))	('CDDP', 'Chemical', '-', (151, 155))	('MDM2', 'MPA', (233, 237))	('increased', 'PosReg', (242, 251))	('p60', 'Gene', '3437', (136, 139))	('p60', 'Gene', (136, 139))	('increased', 'PosReg', (42, 51))	('60-kDa cleaved isoform', 'MPA', (87, 109))	('CDDP', 'Chemical', '-', (266, 270))	('p60', 'Gene', (252, 255))	('L-138', 'Chemical', '-', (211, 216))	('L-138', 'Chemical', '-', (36, 41))	('p60', 'Gene', '3437', (252, 255))	('p60', 'Gene', (371, 374))	('p60', 'Gene', '3437', (371, 374))	('apoptosis', 'CPA', (335, 344))	('L-138', 'Chemical', '-', (326, 331))	('piR-L-138', 'Var', (32, 41))
310240	28325293	We found that both piR-L-138 and p60-MDM2 were predominantly co-localized at the perinuclear area when unchallenged and showed an enhanced and polarized perinuclear pattern upon CDDP treatment in both H157 and SKMES-1 cells (Figure 4E).	('enhanced', 'PosReg', (130, 138))	('piR-L-138', 'Var', (19, 28))	('L-138', 'Chemical', '-', (23, 28))	('SKMES-1', 'CellLine', 'CVCL:0630', (210, 217))	('p60', 'Gene', (33, 36))	('p60', 'Gene', '3437', (33, 36))	('CDDP', 'Chemical', '-', (178, 182))
310241	28325293	Together, these results suggest that piR-L-138 directly interacts with p60-MDM2 in response to CDDP treatment in p53-mutated LSCC H157 and SKMES-1 cells.	('p60', 'Gene', (71, 74))	('p60', 'Gene', '3437', (71, 74))	('response to CDDP treatment', 'MPA', (83, 109))	('p53-mutated', 'Var', (113, 124))	('interacts', 'Interaction', (56, 65))	('CDDP', 'Chemical', '-', (95, 99))	('SKMES-1', 'CellLine', 'CVCL:0630', (139, 146))	('LSCC', 'Phenotype', 'HP:0030359', (125, 129))	('L-138', 'Chemical', '-', (41, 46))
310242	28325293	PIWI-interacting RNAs (piRNAs) have been identified to play roles in transposon silencing, heterochromatin modification, and germ cell maintenance.	('PIWI', 'Gene', '9271', (0, 4))	('heterochromatin modification', 'MPA', (91, 119))	('PIWI', 'Gene', (0, 4))	('transposon silencing', 'Var', (69, 89))
310253	28325293	Our results clearly showed that the upregulated piR-L-138 was critical in protecting LSCC cells from CDDP-induced apoptosis and that inhibiting piR-L-138 enhanced CDDP-mediated apoptosis, suggesting targeting piR-L-138 as a strategy to boost CDDP efficacy for patients with LSCC.	('L-138', 'Chemical', '-', (148, 153))	('upregulated', 'PosReg', (36, 47))	('inhibiting', 'Var', (133, 143))	('LSCC', 'Phenotype', 'HP:0030359', (274, 278))	('piR-L-138', 'Gene', (144, 153))	('enhanced', 'PosReg', (154, 162))	('CDDP', 'Chemical', '-', (101, 105))	('CDDP', 'Chemical', '-', (163, 167))	('CDDP', 'Chemical', '-', (242, 246))	('LSCC', 'Phenotype', 'HP:0030359', (85, 89))	('patients', 'Species', '9606', (260, 268))	('L-138', 'Chemical', '-', (213, 218))	('L-138', 'Chemical', '-', (52, 57))
310254	28325293	Our study provides a proof-of-concept result for the potential use of Anti-138 to enhance CDDP-mediated apoptosis of LSCC cells in vivo because we were using local injection with a sub-optimal dose, which produced only modest anti-tumor activity.	('Anti-138', 'Var', (70, 78))	('tumor', 'Disease', 'MESH:D009369', (231, 236))	('CDDP', 'Chemical', '-', (90, 94))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('tumor', 'Disease', (231, 236))	('CDDP-mediated', 'MPA', (90, 103))	('LSCC', 'Phenotype', 'HP:0030359', (117, 121))	('enhance', 'PosReg', (82, 89))
310255	28325293	We were, therefore, focusing on determining whether Anti-138 increased apoptosis at the sites of Anti-138 injection by analyzing tumor tissue sections for cleaved Caspase-3 and cleaved PARP, which are indicators of apoptosis.	('tumor', 'Disease', (129, 134))	('cleaved', 'MPA', (177, 184))	('PARP', 'Gene', (185, 189))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('Caspase-3', 'Gene', (163, 172))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('Caspase-3', 'Gene', '836', (163, 172))	('cleaved', 'MPA', (155, 162))	('Anti-138', 'Var', (52, 60))	('PARP', 'Gene', '142', (185, 189))
310256	28325293	The concept was supported by the close relationship between higher levels of cleaved Caspase-3 and cleaved PARP and higher concentrated Anti-138 (Figure 3).	('Caspase-3', 'Gene', '836', (85, 94))	('PARP', 'Gene', '142', (107, 111))	('cleaved', 'MPA', (77, 84))	('higher', 'PosReg', (60, 66))	('higher', 'PosReg', (116, 122))	('cleaved', 'Var', (99, 106))	('PARP', 'Gene', (107, 111))	('Caspase-3', 'Gene', (85, 94))
310258	28325293	In our previous study, we have shown that piR-L-163 could directly bind and regulate phosphorylated protein activities.	('phosphorylated protein activities', 'MPA', (85, 118))	('piR-L-163', 'Var', (42, 51))	('bind', 'Interaction', (67, 71))	('regulate', 'Reg', (76, 84))	('L', 'Chemical', '-', (46, 47))
310262	28325293	Strikingly and interestingly, we found that there was a negative correlation between p60-MDM2 and its serine-166 phosphorylation (Figure 4A), indicating the possibility that the interaction of piR-L-138 and p60-MDM2 could inhibit its phosphorylation to enhance apoptosis.	('interaction', 'Interaction', (178, 189))	('serine-166 phosphorylation', 'MPA', (102, 128))	('serine', 'Chemical', 'MESH:D012694', (102, 108))	('piR-L-138', 'Var', (193, 202))	('p60', 'Gene', (207, 210))	('p60', 'Gene', '3437', (207, 210))	('L-138', 'Chemical', '-', (197, 202))	('inhibit', 'NegReg', (222, 229))	('phosphorylation', 'MPA', (234, 249))	('p60', 'Gene', (85, 88))	('p60', 'Gene', '3437', (85, 88))	('apoptosis', 'CPA', (261, 270))	('enhance', 'PosReg', (253, 260))
310264	28325293	In addition, further studies are necessary to determine how piR-L-138 affects p60-MDM2 phosphorylation.	('p60', 'Gene', '3437', (78, 81))	('piR-L-138', 'Var', (60, 69))	('affects', 'Reg', (70, 77))	('L-138', 'Chemical', '-', (64, 69))	('p60', 'Gene', (78, 81))	('phosphorylation', 'MPA', (87, 102))
310343	32807122	AMPK inactivation is accompanied by the activation of multiple oncogenic pathways associated with cell adhesion, calcium signaling and extracellular matrix organization.	('AMPK', 'Gene', '5563', (0, 4))	('activation', 'PosReg', (40, 50))	('calcium', 'Chemical', 'MESH:D002118', (113, 120))	('AMPK', 'Gene', (0, 4))	('oncogenic pathways', 'Pathway', (63, 81))	('inactivation', 'Var', (5, 17))
310373	32807122	Focusing on the genomic and transcriptomic landscape of 92 genes associated with AMPK signaling retrieved from KEGG across 21 cancer types involving 18,484 patients (Additional file 1), we interrogated somatic copy number alterations (SCNA) and mRNA expression (see Additional file 2 for a flowchart illustrating the study design).	('patients', 'Species', '9606', (156, 164))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('AMPK', 'Gene', '5563', (81, 85))	('cancer', 'Disease', (126, 132))	('copy number alterations', 'Var', (210, 233))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('AMPK', 'Gene', (81, 85))
310374	32807122	To determine the effects of genomic alterations in AMPK pathway genes, we classified genes as having high-level amplifications (gains), low-level amplifications, deep (homozygous) deletions and shallow (heterozygous) deletions.	('deep', 'Var', (162, 166))	('AMPK', 'Gene', (51, 55))	('AMPK', 'Gene', '5563', (51, 55))
310379	32807122	In contrast, PPP2R2A was the most deleted gene found in > 20% of samples across 17 cancers, followed by the deletion of SLC2A4 in 16 cancers and five additional genes (FOXO3, PPP2CB, PPP2R2D, PPP2R5C and PPP2R5E) in 15 cancer types (Fig.	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('PPP2CB', 'Gene', (175, 181))	('FOXO3', 'Gene', (168, 173))	('cancer', 'Disease', 'MESH:D009369', (219, 225))	('cancers', 'Disease', 'MESH:D009369', (133, 140))	('PPP2CB', 'Gene', '5516', (175, 181))	('PPP2R5E', 'Gene', (204, 211))	('PPP2R2A', 'Gene', '5520', (13, 20))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('FOXO3', 'Gene', '2309', (168, 173))	('PPP2R5C', 'Gene', '5527', (192, 199))	('deletion', 'Var', (108, 116))	('cancers', 'Disease', 'MESH:D009369', (83, 90))	('PPP2R5C', 'Gene', (192, 199))	('SLC2A4', 'Gene', (120, 126))	('cancers', 'Phenotype', 'HP:0002664', (133, 140))	('cancer', 'Disease', (133, 139))	('cancers', 'Disease', (133, 140))	('PPP2R2D', 'Gene', (183, 190))	('cancer', 'Disease', (219, 225))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('cancers', 'Disease', (83, 90))	('SLC2A4', 'Gene', '6517', (120, 126))	('PPP2R2D', 'Gene', '55844', (183, 190))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('PPP2R2A', 'Gene', (13, 20))	('PPP2R5E', 'Gene', '5529', (204, 211))	('cancers', 'Phenotype', 'HP:0002664', (83, 90))	('cancer', 'Disease', (83, 89))
310387	32807122	1), none of the genes harbored prognostic information, suggesting that alterations in AMPK signaling components have minimal roles in driving tumor progression and patient outcomes.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('tumor', 'Disease', (142, 147))	('patient', 'Species', '9606', (164, 171))	('alterations', 'Var', (71, 82))	('AMPK', 'Gene', '5563', (86, 90))	('AMPK', 'Gene', (86, 90))	('tumor', 'Disease', 'MESH:D009369', (142, 147))
310395	32807122	As in glioma, log-rank tests revealed that patients with high 24-gene scores had significantly improved survival outcomes in breast cancer (P = 0,0026) and sarcoma (P = 0.021) (Fig.	('sarcoma', 'Disease', 'MESH:D012509', (156, 163))	('high', 'Var', (57, 61))	('patients', 'Species', '9606', (43, 51))	('glioma', 'Disease', 'MESH:D005910', (6, 12))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('sarcoma', 'Disease', (156, 163))	('glioma', 'Phenotype', 'HP:0009733', (6, 12))	('breast cancer', 'Disease', 'MESH:D001943', (125, 138))	('sarcoma', 'Phenotype', 'HP:0100242', (156, 163))	('improved', 'PosReg', (95, 103))	('breast cancer', 'Disease', (125, 138))	('breast cancer', 'Phenotype', 'HP:0003002', (125, 138))	('glioma', 'Disease', (6, 12))
310396	32807122	In contrast, high expression of the 24 genes was associated with increased mortality rates in stomach adenocarcinoma (P = 0.033) (Fig.	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('adenocarcinoma', 'Disease', (102, 116))	('mortality', 'Disease', 'MESH:D003643', (75, 84))	('high', 'Var', (13, 17))	('adenocarcinoma', 'Disease', 'MESH:D000230', (102, 116))	('mortality', 'Disease', (75, 84))
310404	32807122	3a); consistent with our previous observation that high pathway scores were associated with good prognosis in sarcoma (Fig.	('sarcoma', 'Disease', 'MESH:D012509', (110, 117))	('sarcoma', 'Phenotype', 'HP:0100242', (110, 117))	('high', 'Var', (51, 55))	('sarcoma', 'Disease', (110, 117))
310411	32807122	AMPK pathway inactivation was associated with altered survival outcomes in patients (Figs.	('AMPK', 'Gene', '5563', (0, 4))	('inactivation', 'Var', (13, 25))	('patients', 'Species', '9606', (75, 83))	('AMPK', 'Gene', (0, 4))	('survival', 'CPA', (54, 62))
310419	32807122	Five TFs, SUZ12, SMAD4, REST, EZH2 and NFE2L2, were found to be enriched in all four cancers, suggesting that transcriptional dysregulation of tumors with aberrant AMPK signaling involved direct physical associations of these TFs with target DEGs (Fig.	('NFE2L2', 'Gene', (39, 45))	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('cancers', 'Disease', 'MESH:D009369', (85, 92))	('AMPK', 'Gene', (164, 168))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('SMAD4', 'Gene', '4089', (17, 22))	('transcriptional', 'MPA', (110, 125))	('tumors', 'Disease', (143, 149))	('dysregulation', 'NegReg', (126, 139))	('SUZ12', 'Gene', (10, 15))	('tumors', 'Disease', 'MESH:D009369', (143, 149))	('aberrant', 'Var', (155, 163))	('cancers', 'Phenotype', 'HP:0002664', (85, 92))	('cancers', 'Disease', (85, 92))	('NFE2L2', 'Gene', '4780', (39, 45))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('EZH2', 'Gene', '2146', (30, 34))	('SUZ12', 'Gene', '23512', (10, 15))	('EZH2', 'Gene', (30, 34))	('AMPK', 'Gene', '5563', (164, 168))	('associations', 'Interaction', (204, 216))	('SMAD4', 'Gene', (17, 22))
310422	32807122	EZH2, NFE2L2, REST, SMAD4 and SUZ12 were all implicated as common transcriptional regulators of DEGs in glioma, sarcoma, breast and stomach cancers, suggesting that altered AMPK signaling converged on similar groups of transcriptional targets.	('AMPK', 'Gene', (173, 177))	('NFE2L2', 'Gene', '4780', (6, 12))	('stomach cancers', 'Phenotype', 'HP:0012126', (132, 147))	('sarcoma', 'Phenotype', 'HP:0100242', (112, 119))	('SUZ12', 'Gene', (30, 35))	('EZH2', 'Gene', '2146', (0, 4))	('EZH2', 'Gene', (0, 4))	('SMAD4', 'Gene', (20, 25))	('NFE2L2', 'Gene', (6, 12))	('SUZ12', 'Gene', '23512', (30, 35))	('breast and stomach cancers', 'Disease', 'MESH:D001943', (121, 147))	('glioma', 'Disease', (104, 110))	('glioma', 'Disease', 'MESH:D005910', (104, 110))	('stomach cancer', 'Phenotype', 'HP:0012126', (132, 146))	('AMPK', 'Gene', '5563', (173, 177))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('SMAD4', 'Gene', '4089', (20, 25))	('sarcoma', 'Disease', 'MESH:D012509', (112, 119))	('cancers', 'Phenotype', 'HP:0002664', (140, 147))	('glioma', 'Phenotype', 'HP:0009733', (104, 110))	('sarcoma', 'Disease', (112, 119))	('DEGs', 'Var', (96, 100))
310428	32807122	2), which mirrored the behavior of DEGs identified as a result of aberrant AMPK signaling (Fig.	('AMPK', 'Gene', (75, 79))	('aberrant', 'Var', (66, 74))	('AMPK', 'Gene', '5563', (75, 79))
310438	32807122	We subsequently categorized patients into four groups using the median cutoff of the AMPK scores and TF expression values: 1) low-low, 2) high-high, 3) low AMPK score and high TF expression and 4) high AMPK score and low TF expression.	('low', 'NegReg', (152, 155))	('AMPK', 'Gene', '5563', (202, 206))	('AMPK', 'Gene', '5563', (85, 89))	('AMPK', 'Gene', (156, 160))	('TF expression', 'MPA', (176, 189))	('TF expression', 'MPA', (221, 234))	('AMPK', 'Gene', (85, 89))	('low-low', 'Var', (126, 133))	('AMPK', 'Gene', (202, 206))	('AMPK', 'Gene', '5563', (156, 160))	('patients', 'Species', '9606', (28, 36))	('high-high', 'Var', (138, 147))
310458	32807122	These putative loss- or gain-of-function genes are more likely to impact tumor progression as they are altered at both macromolecular levels.	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('loss-', 'NegReg', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('gain-of-function', 'PosReg', (24, 40))	('tumor', 'Disease', (73, 78))	('genes', 'Var', (41, 46))
310465	32807122	Ablation of LKB1 results in enhanced risk of developing gastrointestinal, lung and skin squamous cell cancers.	('gastrointestinal', 'Disease', (56, 72))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('skin squamous cell cancers', 'Disease', 'MESH:D002294', (83, 109))	('Ablation', 'Var', (0, 8))	('skin squamous cell cancers', 'Disease', (83, 109))	('enhanced', 'PosReg', (28, 36))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))	('squamous cell cancers', 'Phenotype', 'HP:0002860', (88, 109))	('LKB1', 'Gene', (12, 16))	('lung', 'Disease', (74, 78))	('LKB1', 'Gene', '6794', (12, 16))
310469	32807122	However, when tested in mice models, metformin contributes to enhanced tumor progression and increased angiogenesis, providing us with a glimpse of potential pro-neoplastic effects of AMPK activation.	('metformin', 'Chemical', 'MESH:D008687', (37, 46))	('AMPK', 'Gene', (184, 188))	('mice', 'Species', '10090', (24, 28))	('increased', 'PosReg', (93, 102))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('enhanced', 'PosReg', (62, 70))	('AMPK', 'Gene', '5563', (184, 188))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Disease', (71, 76))	('angiogenesis', 'CPA', (103, 115))	('metformin', 'Var', (37, 46))
310475	32807122	AMPK knockdown in pancreatic cancer cells impairs anchorage-dependent growth and reduces cell viability under glucose deprived conditions.	('glucose', 'Chemical', 'MESH:D005947', (110, 117))	('anchorage-dependent growth', 'CPA', (50, 76))	('AMPK', 'Gene', '5563', (0, 4))	('pancreatic cancer', 'Disease', (18, 35))	('knockdown', 'Var', (5, 14))	('pancreatic cancer', 'Disease', 'MESH:D010190', (18, 35))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('impairs', 'NegReg', (42, 49))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (18, 35))	('AMPK', 'Gene', (0, 4))	('reduces', 'NegReg', (81, 88))	('cell viability', 'CPA', (89, 103))
310476	32807122	AMPK signaling induces cell migration in prostate cancer cells while AMPK knockdown inhibits cell proliferation and promotes apoptosis.	('prostate cancer', 'Disease', 'MESH:D011471', (41, 56))	('AMPK', 'Gene', '5563', (0, 4))	('prostate cancer', 'Phenotype', 'HP:0012125', (41, 56))	('promotes', 'PosReg', (116, 124))	('AMPK', 'Gene', '5563', (69, 73))	('knockdown', 'Var', (74, 83))	('cell proliferation', 'CPA', (93, 111))	('cell migration', 'CPA', (23, 37))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('apoptosis', 'CPA', (125, 134))	('AMPK', 'Gene', (0, 4))	('prostate cancer', 'Disease', (41, 56))	('inhibits', 'NegReg', (84, 92))	('AMPK', 'Gene', (69, 73))
310490	32807122	Restoration of SMAD4 expression in pancreatic cancer cells inhibits tumor function in vivo by influencing angiogenesis through decreased VEGF expression.	('tumor', 'Disease', (68, 73))	('SMAD4', 'Gene', (15, 20))	('decreased', 'NegReg', (127, 136))	('VEGF', 'Gene', '7422', (137, 141))	('inhibits', 'NegReg', (59, 67))	('Restoration', 'Var', (0, 11))	('influencing', 'Reg', (94, 105))	('pancreatic cancer', 'Disease', 'MESH:D010190', (35, 52))	('pancreatic cancer', 'Disease', (35, 52))	('VEGF', 'Gene', (137, 141))	('angiogenesis', 'CPA', (106, 118))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('SMAD4', 'Gene', '4089', (15, 20))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('expression', 'MPA', (142, 152))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (35, 52))
310498	32807122	Our study provides a comprehensive catalog of clinically actionable genetic variations which could be used for patient stratification in prospective clinical trials testing the capabilities of AMPK antagonists or agonists as potential treatments for cancer.	('cancer', 'Disease', 'MESH:D009369', (250, 256))	('cancer', 'Disease', (250, 256))	('variations', 'Var', (76, 86))	('AMPK', 'Gene', '5563', (193, 197))	('patient', 'Species', '9606', (111, 118))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))	('genetic variations', 'Var', (68, 86))	('AMPK', 'Gene', (193, 197))
310519	32356397	Although there have been controversies on the role of ERalpha on the pathogenesis of NSCLC, the majority of literature studies using resected NSCLC samples show that expression of ERalpha is associated with poorer overall survival after surgery (Kawai et al., 2005).	('NSCLC', 'Disease', (85, 90))	('expression', 'Var', (166, 176))	('NSCLC', 'Disease', 'MESH:D002289', (85, 90))	('NSCLC', 'Disease', (142, 147))	('NSCLC', 'Phenotype', 'HP:0030358', (85, 90))	('overall survival', 'MPA', (214, 230))	('NSCLC', 'Disease', 'MESH:D002289', (142, 147))	('ERalpha', 'Gene', (180, 187))	('poorer', 'NegReg', (207, 213))	('NSCLC', 'Phenotype', 'HP:0030358', (142, 147))
310521	32356397	Regarding the possible faults due to subjective measurement of immunohistochemistry in the above studies, a study employing qPCR shows similar results that ERalpha mRNA levels are significantly associated with worse NSCLC prognosis (Olivo-Marston et al., 2010).	('NSCLC', 'Disease', (216, 221))	('men', 'Species', '9606', (55, 58))	('NSCLC', 'Disease', 'MESH:D002289', (216, 221))	('NSCLC', 'Phenotype', 'HP:0030358', (216, 221))	('associated', 'Reg', (194, 204))	('ERalpha', 'Var', (156, 163))
310522	32356397	This study also proved a relationship between specific single nucleotide polymorphisms (SNPs) leading to high ERalpha expression and poor NSCLC outcomes.	('NSCLC', 'Disease', (138, 143))	('ERalpha expression', 'MPA', (110, 128))	('high', 'PosReg', (105, 109))	('single nucleotide polymorphisms', 'Var', (55, 86))	('NSCLC', 'Disease', 'MESH:D002289', (138, 143))	('NSCLC', 'Phenotype', 'HP:0030358', (138, 143))
310556	32356397	MK-2206 (CAS 1032350-13-2) and fulvestrant (CAS 129453-61-8) were from Selleckchem (Houston, TX, USA).	('fulvestrant', 'Chemical', 'MESH:D000077267', (31, 42))	('CAS 129453-61-8', 'Var', (44, 59))	('CAS 1032350-13-2', 'Var', (9, 25))	('MK-2206', 'Chemical', 'MESH:C548887', (0, 7))
310570	32356397	Briefly, the slices were first incubated with the primary antibodies, anti-ERalpha (Abcam, ab93021 for IHC, E115 for immunofluorescence, Cambridge, MA, USA), anti-CD68 (total human macrophage marker; Abcam, ab955), anti-CD163 (M2 macrophage marker; Abcam, ab87099), or anti-F4/80 (total mouse macrophage marker; Abcam, ab16911) in 3% BSA in PBS overnight at 4 C followed by secondary antibodies.	('human', 'Species', '9606', (175, 180))	('CD163', 'Gene', '9332', (220, 225))	('CD68', 'Gene', (163, 167))	('CD68', 'Gene', '968', (163, 167))	('CD163', 'Gene', (220, 225))	('mouse', 'Species', '10090', (287, 292))	('anti-F4/80', 'Var', (269, 279))	('PBS', 'Chemical', 'MESH:D007854', (341, 344))
310626	32356397	Results showed that THP-1 CM indeed could significantly increase A549 and H1299 invasion compared with control CM, and B6 Mphi CM could significantly increase LLC1 invasion compared with control CM.	('THP-1', 'Gene', '2736', (20, 25))	('THP-1', 'Gene', (20, 25))	('increase', 'PosReg', (56, 64))	('LLC1', 'Gene', (159, 163))	('B6 Mphi CM', 'Var', (119, 129))	('A549', 'CPA', (65, 69))	('increase', 'PosReg', (150, 158))	('LLC1', 'Gene', '128602', (159, 163))	('H1299 invasion', 'CPA', (74, 88))
310642	32356397	To dissect the mechanism of how ERalpha in the lung cancer cells increases the infiltrating M2 macrophages with higher MMP9 production, we then examined those cytokines that have been linked to the macrophage recruitment and polarization (Ao et al., 2017; Izumi et al., 2013; Lee et al., 2013; Murdoch et al., 2004; Nagarsheth et al., 2017; Sanchez-Martin et al., 2011; Su et al., 2014; Wang et al., 2013; Yeh et al., 2016).	('men', 'Species', '9606', (216, 219))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('lung cancer', 'Disease', (47, 58))	('increases', 'PosReg', (65, 74))	('lung cancer', 'Phenotype', 'HP:0100526', (47, 58))	('lung cancer', 'Disease', 'MESH:D008175', (47, 58))	('MMP9', 'Gene', '4318', (119, 123))	('ERalpha', 'Var', (32, 39))	('MMP9', 'Gene', (119, 123))
310648	32356397	Similar interruption effects were also observed when we replaced the CCL2-shRNA with C28H34F3N5O4S (CAS 445479-97-0), a CCR2-specific antagonist (Cherney et al., 2008; Ding et al., 2015; Izumi et al., 2013) in A549 cells (Fig.	('C28H34F3N5O4S', 'Var', (85, 98))	('C28H34F3N5O4S', 'Chemical', '-', (85, 98))	('CCL2', 'Gene', (69, 73))	('CCL2', 'Gene', '6347', (69, 73))
310650	32356397	4H), as well as ERalpha-increased MMP9 expression in the THP-1 cells (Fig.	('MMP9', 'Gene', '4318', (34, 38))	('MMP9', 'Gene', (34, 38))	('ERalpha-increased', 'Var', (16, 33))	('expression', 'MPA', (39, 49))	('THP-1', 'Gene', '2736', (57, 62))	('THP-1', 'Gene', (57, 62))
310673	32356397	Western blot data reveal that THP-1-CM-cultured A549 and H1299 show higher expression of phosphorylated ERK and Akt, while no change of phosphorylated STAT3 (Fig.	('THP-1', 'Gene', (30, 35))	('STAT3', 'Gene', (151, 156))	('ERK', 'Gene', (104, 107))	('H1299', 'Var', (57, 62))	('Akt', 'Gene', '207', (112, 115))	('higher', 'PosReg', (68, 74))	('ERK', 'Gene', '5594', (104, 107))	('Akt', 'Gene', (112, 115))	('STAT3', 'Gene', '6774', (151, 156))	('expression', 'MPA', (75, 85))	('THP-1', 'Gene', '2736', (30, 35))
310687	32356397	In the present study, we proved that ERalpha expression in lung cancer cells can promote NSCLC invasion through increase of and cross-talk with infiltrated macrophages via up-regulating the CCL2- and CXCL12-involved signal pathways.	('lung cancer', 'Disease', 'MESH:D008175', (59, 70))	('NSCLC', 'Disease', 'MESH:D002289', (89, 94))	('ERalpha', 'Gene', (37, 44))	('promote', 'PosReg', (81, 88))	('CXCL12', 'Gene', (200, 206))	('CCL2', 'Gene', '6347', (190, 194))	('lung cancer', 'Disease', (59, 70))	('NSCLC', 'Phenotype', 'HP:0030358', (89, 94))	('and cross-talk', 'MPA', (124, 138))	('CCL2', 'Gene', (190, 194))	('increase', 'PosReg', (112, 120))	('lung cancer', 'Phenotype', 'HP:0100526', (59, 70))	('CXCL12', 'Gene', '6387', (200, 206))	('up-regulating', 'PosReg', (172, 185))	('expression', 'Var', (45, 55))	('NSCLC', 'Disease', (89, 94))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
310696	32356397	Though commonly regarded as a tumor-promoting factor, ERalpha was found to inhibit breast cancer invasion (Gao et al., 2017; Padilla-Rodriguez et al., 2018; Plate t et al., 2004).	('Padilla-Rodriguez', 'Disease', (125, 142))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('inhibit', 'NegReg', (75, 82))	('breast cancer', 'Disease', 'MESH:D001943', (83, 96))	('Padilla-Rodriguez', 'Disease', 'MESH:C538183', (125, 142))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('breast cancer', 'Disease', (83, 96))	('breast cancer', 'Phenotype', 'HP:0003002', (83, 96))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('tumor', 'Disease', (30, 35))	('ERalpha', 'Var', (54, 61))
310710	32356397	Macrophages can secrete various factors to promote cancer cell invasion, and M2-type polarization is generally associated with greater invasion-promoting ability of macrophages (Shapouri-Moghaddam et al., 2018).	('promote', 'PosReg', (43, 50))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('M2-type', 'Var', (77, 84))	('invasion-promoting ability', 'CPA', (135, 161))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))
310815	32210363	In the analysis of different genes expressed by different experimental treatments, the heat map was used to show the changes in expression levels of multiple genes caused by dcEF treatment (300 mV/mm, 2 h) and untreated groups.	('dcEF', 'Gene', (174, 178))	('expression levels', 'MPA', (128, 145))	('men', 'Species', '9606', (76, 79))	('300 mV/mm', 'Var', (190, 199))	('dcEF', 'Chemical', '-', (174, 178))	('men', 'Species', '9606', (184, 187))	('changes', 'Reg', (117, 124))	('men', 'Species', '9606', (64, 67))
310833	32210363	For JUN and ITGA2, the main changes were amplification, deep deletion and missense mutation.	('deep deletion', 'Var', (56, 69))	('amplification', 'MPA', (41, 54))	('JUN', 'Gene', (4, 7))	('missense mutation', 'Var', (74, 91))	('ITGA2', 'Gene', (12, 17))	('ITGA2', 'Gene', '3673', (12, 17))
310834	32210363	Meanwhile, mutations occurred in CCND1, IL6 and KRAS were amplification and missense mutation.	('mutations', 'Var', (11, 20))	('KRAS', 'Gene', (48, 52))	('IL6', 'Gene', (40, 43))	('CCND1', 'Gene', (33, 38))	('KRAS', 'Gene', '3845', (48, 52))	('missense mutation', 'Var', (76, 93))	('CCND1', 'Gene', '595', (33, 38))	('IL6', 'Gene', '3569', (40, 43))
310840	32210363	Patients with high levels of several genes (JUN, FGF2, IL6 and MAPK13) have higher survival rates than patients with low expression.	('FGF2', 'Gene', '2247', (49, 53))	('MAPK13', 'Gene', (63, 69))	('IL6', 'Gene', '3569', (55, 58))	('high levels', 'Var', (14, 25))	('JUN', 'Gene', (44, 47))	('FGF2', 'Gene', (49, 53))	('rat', 'Species', '10116', (92, 95))	('Patients', 'Species', '9606', (0, 8))	('IL6', 'Gene', (55, 58))	('patients', 'Species', '9606', (103, 111))	('MAPK13', 'Gene', '5603', (63, 69))	('higher', 'PosReg', (76, 82))	('survival rates', 'CPA', (83, 97))
310847	32210363	12B), ITGA2, KRAS, MMP9, NRAS and MAPK13 (Figures S28B, S32B-35B) had higher levels in lung adenocarcinoma than in normal lung tissues.	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (87, 106))	('NRAS', 'Gene', (25, 29))	('higher', 'PosReg', (70, 76))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (87, 106))	('S32B', 'Var', (56, 60))	('S32B', 'SUBSTITUTION', 'None', (56, 60))	('MAPK13', 'Gene', '5603', (34, 40))	('MAPK13', 'Gene', (34, 40))	('ITGA2', 'Gene', '3673', (6, 11))	('S28B', 'Var', (50, 54))	('S28B', 'SUBSTITUTION', 'None', (50, 54))	('MMP9', 'Gene', '4318', (19, 23))	('MMP9', 'Gene', (19, 23))	('NRAS', 'Gene', '4893', (25, 29))	('KRAS', 'Gene', '3845', (13, 17))	('ITGA2', 'Gene', (6, 11))	('lung adenocarcinoma', 'Disease', (87, 106))	('KRAS', 'Gene', (13, 17))
310849	32210363	12C), FGF2, CCND1 and IL6 (Figures S29B-31B) expressed fewer mRNAs in lung cancer tissues than normal lung tissues.	('lung cancer', 'Disease', 'MESH:D008175', (70, 81))	('mRNAs', 'MPA', (61, 66))	('fewer', 'NegReg', (55, 60))	('CCND1', 'Gene', (12, 17))	('FGF2', 'Gene', (6, 10))	('lung cancer', 'Disease', (70, 81))	('lung cancer', 'Phenotype', 'HP:0100526', (70, 81))	('CCND1', 'Gene', '595', (12, 17))	('IL6', 'Gene', '3569', (22, 25))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('S29B', 'Var', (35, 39))	('IL6', 'Gene', (22, 25))	('FGF2', 'Gene', '2247', (6, 10))	('S29B', 'SUBSTITUTION', 'None', (35, 39))
310860	32210363	Noteworthy, the simulation of larger proteins (EGFR 1157 aa, ITGA2 1181 aa) were performed by running MD 3 times to refine the protein structures (300 K (20 ns)-350 K (20 ns)-300 K(100 ns) in MD process).	('ITGA2', 'Gene', (61, 66))	('300 K (20 ns', 'Var', (147, 159))	('ITGA2', 'Gene', '3673', (61, 66))
310905	32210363	Mutations in NRAS are often found in several hematological diseases and tumors, such as follicular thyroid cancer, somatic rectal cancer and myelomonocytic leukemia.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('hematological diseases and tumors', 'Disease', 'MESH:D006402', (45, 78))	('myelomonocytic leukemia', 'Disease', 'MESH:D054429', (141, 164))	('thyroid cancer', 'Phenotype', 'HP:0002890', (99, 113))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('follicular thyroid cancer', 'Disease', (88, 113))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('Mutations', 'Var', (0, 9))	('myelomonocytic leukemia', 'Disease', (141, 164))	('NRAS', 'Gene', (13, 17))	('found', 'Reg', (28, 33))	('rectal cancer', 'Phenotype', 'HP:0100743', (123, 136))	('follicular thyroid cancer', 'Disease', 'MESH:C572845', (88, 113))	('leukemia', 'Phenotype', 'HP:0001909', (156, 164))	('somatic rectal cancer', 'Disease', (115, 136))	('NRAS', 'Gene', '4893', (13, 17))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('somatic rectal cancer', 'Disease', 'MESH:D012004', (115, 136))
310955	32210363	In addition, data from molecular dynamics simulations show that four phenylalanine residues at the internal gate region on human calcium channel proteins are important for EF to activate ion channels.	('phenylalanine', 'Chemical', 'MESH:D010649', (69, 82))	('activate', 'PosReg', (178, 186))	('ion channels', 'MPA', (187, 199))	('human', 'Species', '9606', (123, 128))	('phenylalanine residues', 'Var', (69, 91))	('calcium', 'Chemical', 'MESH:D002118', (129, 136))
310977	32210363	According to the results of Kaplan Meier analysis, the survival rates of the patients expressing high levels of JUN, FGF2, IL6 and MAPK13 were higher than that of the low-expressing patients, whereas the patients expressing high levels of EGFR, CCND1, ITGA2, KRAS, MMP9 and NRAS showed no significance in comparison with the low-expressing groups.	('IL6', 'Gene', (123, 126))	('KRAS', 'Gene', (259, 263))	('high levels', 'Var', (97, 108))	('rat', 'Species', '10116', (64, 67))	('higher', 'PosReg', (143, 149))	('patients', 'Species', '9606', (182, 190))	('MAPK13', 'Gene', '5603', (131, 137))	('patients', 'Species', '9606', (204, 212))	('FGF2', 'Gene', '2247', (117, 121))	('survival rates', 'CPA', (55, 69))	('MAPK13', 'Gene', (131, 137))	('CCND1', 'Gene', '595', (245, 250))	('patients', 'Species', '9606', (77, 85))	('NRAS', 'Gene', '4893', (274, 278))	('CCND1', 'Gene', (245, 250))	('FGF2', 'Gene', (117, 121))	('ITGA2', 'Gene', '3673', (252, 257))	('IL6', 'Gene', '3569', (123, 126))	('NRAS', 'Gene', (274, 278))	('MMP9', 'Gene', '4318', (265, 269))	('MMP9', 'Gene', (265, 269))	('KRAS', 'Gene', '3845', (259, 263))	('ITGA2', 'Gene', (252, 257))
310980	32210363	In the present study, three levels of research have been integrated with an attempt to provide clues for understanding the molecular mechanisms by which dcEF stimulates tumor cells.	('dcEF', 'Chemical', '-', (153, 157))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('stimulates', 'PosReg', (158, 168))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('dcEF', 'Var', (153, 157))	('tumor', 'Disease', (169, 174))	('rat', 'Species', '10116', (62, 65))
311022	27081670	The search parameters were set as follows: taxonomy: Mouse; mass values, monoisotopic; precursor mass tolerance, +-1 Da; fragment mass tolerance, +-0.3 Da; enzyme, trypsin; maximum missed cleavage allowed, 1; modifications, carbamidomethyl Cys (permanent); methionine oxidation (variable); Ser, Thr, and Tyr phosphorylation.	('modifications', 'Var', (209, 222))	('Ser', 'MPA', (290, 293))	('carbamidomethyl Cys', 'MPA', (224, 243))	('Mouse', 'Species', '10090', (53, 58))	('Tyr phosphorylation', 'MPA', (304, 323))	('Thr', 'MPA', (295, 298))	('carbamidomethyl Cys', 'Chemical', '-', (224, 243))	('Thr', 'Chemical', 'MESH:D013912', (295, 298))	('methionine oxidation', 'MPA', (257, 277))	('methionine', 'Chemical', 'MESH:D008715', (257, 267))	('Ser', 'Chemical', 'MESH:D012694', (290, 293))	('Tyr', 'Chemical', 'MESH:D014443', (304, 307))
311047	33027769	According to a retrospective study of 218 NSCLC patients, dysregulated Olfactomedin 4 (OLFM4) expression correlates significantly with decreased overall and disease-specific survival (DSS).	('DSS', 'Gene', (184, 187))	('NSCLC', 'Disease', (42, 47))	('dysregulated', 'Var', (58, 70))	('Olfactomedin 4', 'Gene', '10562', (71, 85))	('OLFM4', 'Gene', (87, 92))	('disease-specific survival', 'CPA', (157, 182))	('NSCLC', 'Disease', 'MESH:D002289', (42, 47))	('DSS', 'Gene', '5376', (184, 187))	('Olfactomedin 4', 'Gene', (71, 85))	('expression', 'MPA', (94, 104))	('decreased', 'NegReg', (135, 144))	('patients', 'Species', '9606', (48, 56))	('OLFM4', 'Gene', '10562', (87, 92))
311089	33027769	Thus, model robustness was validated using four independent GEO cohorts: GSE30219, GSE4127, GSE42127 and GSE50081.	('GSE50081', 'Var', (105, 113))	('GSE42127', 'Var', (92, 100))	('GSE30219', 'Var', (73, 81))	('GSE4127', 'Chemical', '-', (83, 90))	('GSE4127', 'Var', (83, 90))
311095	31978896	Results: From the training set, we identified a eight-lncRNA signature (including AP000487, AC011997, LINC01592, LINC01497, LINC01711, FENDRR, AC087045, AC137770) which separated the patients into two groups with significantly different overall survival (hazard ratio, HR = 3.79, 95% confidence interval, 95% CI [2.56-5.62]; P < 0.001).	('AC087045', 'Var', (143, 151))	('LINC01497', 'Gene', '102723487', (113, 122))	('LINC01592', 'Gene', (102, 111))	('LINC01592', 'Gene', '100505718', (102, 111))	('LINC01711', 'Var', (124, 133))	('AC011997', 'Var', (92, 100))	('LINC01711', 'Chemical', '-', (124, 133))	('LINC01497', 'Gene', (113, 122))	('AP000487', 'Var', (82, 90))	('FENDRR', 'Gene', '400550', (135, 141))	('FENDRR', 'Gene', (135, 141))	('AC137770', 'Var', (153, 161))	('patients', 'Species', '9606', (183, 191))
311117	31978896	As above, it was suggested that the lncRNAs in the signature were all risk factors for OS.	('OS', 'Chemical', 'MESH:D009992', (87, 89))	('lncRNAs', 'Var', (36, 43))	('risk factors', 'Reg', (70, 82))
311119	31978896	For example, the influence of LINC01711 was greatest while that of LINC01592 was least.	('LINC01592', 'Gene', (67, 76))	('LINC01592', 'Gene', '100505718', (67, 76))	('LINC01711', 'Chemical', '-', (30, 39))	('LINC01711', 'Var', (30, 39))
311123	31978896	The area under the ROC curve (AUC) for 0.5-, 1-, 3-, and 5-year OS were 0.673, 0.734, 0.798, 0.816, 0.795 and 0.777, 0.644, 0.642, 0.649, 0.765 in the TCGA and GEO cohorts, respectively.	('0.798', 'Var', (86, 91))	('0.795', 'Var', (100, 105))	('0.816', 'Var', (93, 98))	('0.777', 'Var', (110, 115))	('0.734', 'Var', (79, 84))	('OS', 'Chemical', 'MESH:D009992', (64, 66))	('0.673', 'Var', (72, 77))
311140	31978896	Finally, eight lincRNAs (AP000487, AC011997, LINC01592, LINC01497, LINC01711, FENDRR, AC087045, AC137770) were selected to build a prognostic signature for ESCC.	('FENDRR', 'Gene', (78, 84))	('LINC01497', 'Gene', '102723487', (56, 65))	('AC137770', 'Var', (96, 104))	('LINC01592', 'Gene', (45, 54))	('AC087045', 'Var', (86, 94))	('AP000487', 'Var', (25, 33))	('LINC01711', 'Var', (67, 76))	('ESCC', 'Disease', 'MESH:C562729', (156, 160))	('LINC01592', 'Gene', '100505718', (45, 54))	('LINC01711', 'Chemical', '-', (67, 76))	('LINC01497', 'Gene', (56, 65))	('AC011997', 'Var', (35, 43))	('FENDRR', 'Gene', '400550', (78, 84))	('ESCC', 'Disease', (156, 160))
311177	31636653	While genetic alterations initiate tumorigenesis, how they affect the transcriptional program and ultimately drive the malignant phenotype remains elusive.	('affect', 'Reg', (59, 65))	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('drive', 'Reg', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumor', 'Disease', (35, 40))	('transcriptional', 'CPA', (70, 85))	('initiate', 'Reg', (26, 34))	('genetic alterations', 'Var', (6, 25))
311185	31636653	Four human ESCC cell lines [KYSE140, KYSE510, TE5, and Shantou human embryonic esophageal carcinoma (SHEEC)] and one normal immortalized esophageal squamous epithelial cell line (SHEE) were used in this study.	('KYSE510', 'Var', (37, 44))	('embryonic esophageal carcinoma', 'Disease', (69, 99))	('human', 'Species', '9606', (63, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('ESCC', 'Disease', 'MESH:D018307', (11, 15))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (79, 99))	('embryonic esophageal carcinoma', 'Disease', 'MESH:D004938', (69, 99))	('ESCC', 'Disease', (11, 15))	('human', 'Species', '9606', (5, 10))
311186	31636653	Among the five cell lines in this study, KYSE140, KYSE510, and TE5 are established from the resected specimens of patients with ESCC.	('KYSE510', 'Var', (50, 57))	('KYSE140', 'Var', (41, 48))	('ESCC', 'Disease', 'MESH:D018307', (128, 132))	('ESCC', 'Disease', (128, 132))	('patients', 'Species', '9606', (114, 122))
311187	31636653	We chose these three ESCC patient-derived cell lines as they cover all three types of cell differentiation of primary tumor: KYSE140 is derived from a patient with moderately differentiated squamous cell carcinoma, KYSE510 is derived from a patient with well-differentiated squamous cell carcinoma, and TE5 is derived from a patient with poorly differentiated squamous cell carcinoma.	('patient', 'Species', '9606', (26, 33))	('KYSE510', 'Var', (215, 222))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('carcinoma', 'Phenotype', 'HP:0030731', (288, 297))	('carcinoma', 'Phenotype', 'HP:0030731', (374, 383))	('squamous cell carcinoma', 'Disease', (274, 297))	('patient', 'Species', '9606', (325, 332))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (360, 383))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('patient', 'Species', '9606', (151, 158))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (190, 213))	('KYSE140', 'Var', (125, 132))	('carcinoma', 'Phenotype', 'HP:0030731', (204, 213))	('squamous cell carcinoma', 'Disease', (360, 383))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (274, 297))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (190, 213))	('ESCC', 'Disease', 'MESH:D018307', (21, 25))	('patient', 'Species', '9606', (241, 248))	('ESCC', 'Disease', (21, 25))	('tumor', 'Disease', (118, 123))	('squamous cell carcinoma', 'Disease', (190, 213))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (274, 297))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (360, 383))
311194	31636653	RNA was purified according to the following criteria: (1) with concentration >=300 ng/microl, (2) OD260/280 = 2.0-2.2 and OD260/230 = 1.8-2.1, and (3) RNA integrity number (RIN) >=9, which is assessed on the Agilent Bioanalyzer 2100 system.	('N', 'Chemical', 'MESH:D009584', (152, 153))	('OD260/280', 'Var', (98, 107))	('N', 'Chemical', 'MESH:D009584', (175, 176))	('N', 'Chemical', 'MESH:D009584', (1, 2))	('OD260/230', 'Var', (122, 131))
311205	31636653	We also compared the transcription start sites (TSS) of each transcript with the Cap Analysis of Gene Expression (CAGE) promoter tags and epigenetic marks that are typically associated with actively transcribed promoters (H3K4me1, H3K4me3, and H3K27ac).	('H3K4me3', 'Var', (231, 238))	('CAGE', 'Gene', (114, 118))	('H3K27ac', 'Var', (244, 251))	('H3K4me1', 'Var', (222, 229))	('epigenetic marks', 'Var', (138, 154))	('H3K4me1, H3K4me3', 'Chemical', 'MESH:C024755', (222, 238))	('CAGE', 'Gene', '168400', (114, 118))
311227	31636653	Totally, we identified 445,983, 477,033, 491,354, 327,459, 259,482 FLNC reads from KYSE140, KYSE510, SHEE, SHEEC, and TE5 cells, respectively, which cover ~80% of all circular-consensus sequences in each cell line (Table 1).	('KYSE510', 'Var', (92, 99))	('N', 'Chemical', 'MESH:D009584', (69, 70))	('KYSE140', 'Var', (83, 90))
311239	31636653	From current SMRT data, it is clear that, except for the three annotated VIL2 variants in reference genome, other 24 VIL2 variants with different expressions are also transcribed but have not been annotated in KYSE510 cells (Figures 3A, C).	('variants', 'Var', (122, 130))	('VIL2', 'Gene', (117, 121))	('VIL2', 'Gene', (73, 77))	('VIL2', 'Gene', '7430', (73, 77))	('VIL2', 'Gene', '7430', (117, 121))
311248	31636653	Under a stringent criterion (see Methods), 5,400, 5,210, 4,883, 4,756, and 2,274 lncRNAs were directly predicted from SHEE, KYSE140, KYSE510, SHEEC, and TE5 cells, respectively (Figure S2A).	('N', 'Chemical', 'MESH:D009584', (85, 86))	('KYSE510', 'Var', (133, 140))	('KYSE140', 'Var', (124, 131))
311281	31636653	During the onset of carcinogenesis, shifted splicing of DNA repair genes has previously been documented in several cancer studies, such as BRCA1 and FANCM in breast cancer and ERCC1 in ovarian cancer.	('shifted splicing', 'Var', (36, 52))	('cancer', 'Disease', (193, 199))	('ovarian cancer', 'Disease', 'MESH:D010051', (185, 199))	('BRCA1', 'Gene', '672', (139, 144))	('breast cancer', 'Phenotype', 'HP:0003002', (158, 171))	('ERCC1', 'Gene', '2067', (176, 181))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('carcinogenesis', 'Disease', (20, 34))	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('BRCA1', 'Gene', (139, 144))	('breast cancer', 'Disease', 'MESH:D001943', (158, 171))	('carcinogenesis', 'Disease', 'MESH:D063646', (20, 34))	('breast cancer', 'Disease', (158, 171))	('FANCM', 'Gene', '57697', (149, 154))	('ERCC1', 'Gene', (176, 181))	('ovarian cancer', 'Disease', (185, 199))	('FANCM', 'Gene', (149, 154))	('ovarian cancer', 'Phenotype', 'HP:0100615', (185, 199))	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('N', 'Chemical', 'MESH:D009584', (57, 58))	('cancer', 'Disease', (165, 171))	('DNA repair genes', 'Gene', (56, 72))	('cancer', 'Disease', (115, 121))	('documented', 'Reg', (93, 103))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('N', 'Chemical', 'MESH:D009584', (151, 152))
311286	31636653	Although the altered splicing pattern of this group of genes is not clear in clinical samples currently, several investigations have confirmed that a few regulators of GTPase use different variants in cancers.	('cancers', 'Disease', 'MESH:D009369', (201, 208))	('cancers', 'Phenotype', 'HP:0002664', (201, 208))	('cancers', 'Disease', (201, 208))	('variants', 'Var', (189, 197))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('clinical samples', 'Species', '191496', (77, 93))	('GTPase', 'Gene', (168, 174))
311333	29628790	Additionally, Fe2+ ions induce iron transporter (Fe-ATPase) responsible for iron efflux.	('iron efflux', 'MPA', (76, 87))	('iron', 'Chemical', 'MESH:D007501', (31, 35))	('iron', 'Chemical', 'MESH:D007501', (76, 80))	('Fe2+ ions', 'Var', (14, 23))	('Fe2+', 'Chemical', 'MESH:C038178', (14, 18))	('Fe-ATPase', 'Gene', (49, 58))
311361	29628790	It was also demonstrated that HO-1 can directly inhibit apoptosis via activation of Akt (protein kinase B) pathway and this, in turn, can lead to increased ratio of antiapoptotic Bcl-2 (B-cell lymphoma-2) to proapoptotic Bax (Bcl-2-associated X protein) proteins in colon cancer cell line.	('lymphoma', 'Phenotype', 'HP:0002665', (193, 201))	('cancer', 'Phenotype', 'HP:0002664', (272, 278))	('colon cancer', 'Disease', 'MESH:D015179', (266, 278))	('HO-1', 'Var', (30, 34))	('Bcl-2', 'Gene', (226, 231))	('Bcl-2', 'Gene', (179, 184))	('B-cell lymphoma-2', 'Gene', '596', (186, 203))	('inhibit', 'NegReg', (48, 55))	('increased', 'PosReg', (146, 155))	('colon cancer', 'Disease', (266, 278))	('Akt', 'Gene', (84, 87))	('Bcl-2', 'Gene', '596', (226, 231))	('Bcl-2', 'Gene', '596', (179, 184))	('Bax', 'Gene', (221, 224))	('Akt', 'Gene', '207', (84, 87))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (186, 201))	('Bax', 'Gene', '581', (221, 224))	('ratio', 'MPA', (156, 161))	('B-cell lymphoma-2', 'Gene', (186, 203))	('Bcl-2-associated X protein', 'Gene', '581', (226, 252))	('colon cancer', 'Phenotype', 'HP:0003003', (266, 278))	('antiapoptotic', 'MPA', (165, 178))	('apoptosis', 'CPA', (56, 65))	('Bcl-2-associated X protein', 'Gene', (226, 252))
311362	29628790	Furthermore, genetic inhibition of HO-1 in breast cancer cell lines resulted in augmented doxorubicin-induced apoptosis via downregulation of antiapoptotic proteins.	('breast cancer', 'Disease', (43, 56))	('breast cancer', 'Disease', 'MESH:D001943', (43, 56))	('breast cancer', 'Phenotype', 'HP:0003002', (43, 56))	('genetic inhibition', 'Var', (13, 31))	('HO-1', 'Gene', (35, 39))	('doxorubicin-induced', 'MPA', (90, 109))	('antiapoptotic', 'Protein', (142, 155))	('augmented', 'PosReg', (80, 89))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('doxorubicin', 'Chemical', 'MESH:D004317', (90, 101))	('downregulation', 'NegReg', (124, 138))
311370	29628790	Additionally, pharmacological inhibition of HO-1 resulted in suppressed angiogenesis and reduced VEGF level in mouse lung cancer in vivo.	('suppressed', 'NegReg', (61, 71))	('inhibition', 'Var', (30, 40))	('mouse', 'Species', '10090', (111, 116))	('VEGF level', 'MPA', (97, 107))	('lung cancer', 'Disease', (117, 128))	('HO-1', 'Gene', (44, 48))	('lung cancer', 'Phenotype', 'HP:0100526', (117, 128))	('reduced', 'NegReg', (89, 96))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('angiogenesis', 'CPA', (72, 84))	('lung cancer', 'Disease', 'MESH:D008175', (117, 128))
311376	29628790	Our initial experiments performed on murine C2C12 myoblasts suggested that HO-1 overexpression increases proliferation rate and the resistance to oxidative stress, however, it negatively regulates the differentiation of myoblasts to skeletal muscles.	('regulates', 'Reg', (187, 196))	('resistance to oxidative stress', 'MPA', (132, 162))	('differentiation of myoblasts to skeletal muscles', 'CPA', (201, 249))	('negatively', 'NegReg', (176, 186))	('murine', 'Species', '10090', (37, 43))	('overexpression', 'Var', (80, 94))	('HO-1', 'Gene', (75, 79))	('proliferation rate', 'CPA', (105, 123))	('oxidative stress', 'Phenotype', 'HP:0025464', (146, 162))	('increases', 'PosReg', (95, 104))
311378	29628790	Downregulation of myomirs as well as other muscle regulatory factors including a master regulatory switch for myogenesis, MyoD and myogenin, by HO-1 overexpression was mimicked by CO-releasing molecule.	('Downregulation', 'NegReg', (0, 14))	('MyoD', 'Gene', (122, 126))	('myogenin', 'Gene', (131, 139))	('CO', 'Chemical', 'MESH:D002248', (180, 182))	('overexpression', 'Var', (149, 163))	('MyoD', 'Gene', '4654', (122, 126))	('myogenin', 'Gene', '4656', (131, 139))	('HO-1', 'Gene', (144, 148))	('myomirs', 'Gene', (18, 25))
311388	29628790	Mutation of FH, a tricarboxylic acid cycle enzyme, results in a permanently increased level of fumarate, which is proposed to act as an oncometabolite through a various mechanism.	('increased', 'PosReg', (76, 85))	('Mutation', 'Var', (0, 8))	('fumarate', 'Chemical', 'MESH:D005650', (95, 103))	('FH', 'Gene', '2271', (12, 14))	('level of fumarate', 'MPA', (86, 103))	('tricarboxylic acid', 'Chemical', 'MESH:D014233', (18, 36))
311390	29628790	Moreover, silencing of HMOX1 in FH-deficient cell lines resulted in their synthetic lethality.	('HMOX1', 'Gene', (23, 28))	('FH-deficient', 'Disease', (32, 44))	('synthetic lethality', 'CPA', (74, 93))	('FH-deficient', 'Disease', 'MESH:D006938', (32, 44))	('silencing', 'Var', (10, 19))
311391	29628790	This term refers to the situation in which simultaneous defect in two genes causes cell death, whereas at the same time separate dysfunction or mutation of each gene does not affect cells viability.	('defect', 'Var', (56, 62))	('dysfunction', 'Disease', 'MESH:D006331', (129, 140))	('dysfunction', 'Disease', (129, 140))	('causes', 'Reg', (76, 82))	('cell death', 'CPA', (83, 93))
311394	29628790	Importantly, genetic or pharmacological inhibition of HMOX1 significantly diminished survival of FH-deficient cells.	('inhibition', 'Var', (40, 50))	('diminished', 'NegReg', (74, 84))	('HMOX1', 'Gene', (54, 59))	('FH-deficient', 'Disease', (97, 109))	('survival', 'CPA', (85, 93))	('FH-deficient', 'Disease', 'MESH:D006938', (97, 109))
311395	29628790	Also in our hands, genetic inhibition of HMOX1 in UOK262 cell line, which lacks FH activity, decreased cells viability, proliferation, and clonogenic potential (unpublished data).	('proliferation', 'CPA', (120, 133))	('clonogenic potential', 'CPA', (139, 159))	('genetic inhibition', 'Var', (19, 37))	('cells viability', 'CPA', (103, 118))	('FH', 'Gene', '2271', (80, 82))	('decreased', 'NegReg', (93, 102))	('UOK262', 'CellLine', 'CVCL:1D72', (50, 56))	('HMOX1', 'Gene', (41, 46))
311397	29628790	Noteworthy, genetic variation like polymorphism of HO-1 promoter and its association with cancer susceptibility was a subject of several studies.	('polymorphism', 'Var', (35, 47))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('HO-1 promoter', 'Gene', (51, 64))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))
311400	29628790	It has been demonstrated that shorter (GT)n repeats within the HMOX1 promoter results in higher transcriptional activity and this, in turn, attributes to the increased risk and poor prognosis of pancreatic cancer and gastric cancer.	('pancreatic cancer', 'Disease', 'MESH:D010190', (195, 212))	('gastric cancer', 'Disease', 'MESH:D013274', (217, 231))	('gastric cancer', 'Phenotype', 'HP:0012126', (217, 231))	('transcriptional activity', 'MPA', (96, 120))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('higher', 'PosReg', (89, 95))	('shorter', 'Var', (30, 37))	('HMOX1', 'Gene', (63, 68))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (195, 212))	('gastric cancer', 'Disease', (217, 231))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('attributes to', 'Reg', (140, 153))	('pancreatic cancer', 'Disease', (195, 212))
311401	29628790	Patients with a shorter version of the promotor are more susceptible to the development of pancreatic cancer and recurrence of the disease.	('susceptible', 'Reg', (57, 68))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('shorter', 'Var', (16, 23))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (91, 108))	('Patients', 'Species', '9606', (0, 8))	('pancreatic cancer', 'Disease', (91, 108))	('pancreatic cancer', 'Disease', 'MESH:D010190', (91, 108))
311404	29628790	More complicated, other studies showed no correlation between HMOX1 polymorphism and the risk of lung squamous cell carcinoma and sporadic colorectal cancer, indicating that the final outcome may depend on several factors including the type of the tumor, subject ethnicity, and many others.	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('tumor', 'Disease', (248, 253))	('colorectal cancer', 'Disease', 'MESH:D015179', (139, 156))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('tumor', 'Disease', 'MESH:D009369', (248, 253))	('HMOX1', 'Gene', (62, 67))	('polymorphism', 'Var', (68, 80))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (97, 125))	('lung squamous cell carcinoma', 'Disease', (97, 125))	('colorectal cancer', 'Phenotype', 'HP:0003003', (139, 156))	('tumor', 'Phenotype', 'HP:0002664', (248, 253))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (102, 125))	('colorectal cancer', 'Disease', (139, 156))
311406	29628790	As described above, inhibition of HO-1 may be considered as a mode for anticancer treatment.	('inhibition', 'Var', (20, 30))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('cancer', 'Disease', (75, 81))	('cancer', 'Disease', 'MESH:D009369', (75, 81))
311414	29628790	Direct, intraperitoneal injection of HO-1 siRNA resulted in the diminished growth of tumors in an orthotopic model of hepatocellular carcinoma.	('growth', 'MPA', (75, 81))	('tumors', 'Disease', 'MESH:D009369', (85, 91))	('diminished', 'NegReg', (64, 74))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (118, 142))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (118, 142))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('hepatocellular carcinoma', 'Disease', (118, 142))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('HO-1 siRNA', 'Var', (37, 47))	('tumors', 'Disease', (85, 91))
311415	29628790	Moreover, subcutaneous injection of human colon cancer cell line resistant to 5-fluorouracil (5-FU), transduced with shRNA against HO-1, significantly reduced tumor size and markedly increased the sensitivity of nude mice to 5-FU treatment.	('reduced', 'NegReg', (151, 158))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('increased', 'PosReg', (183, 192))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (78, 92))	('nude mice', 'Species', '10090', (212, 221))	('tumor', 'Disease', (159, 164))	('colon cancer', 'Phenotype', 'HP:0003003', (42, 54))	('colon cancer', 'Disease', 'MESH:D015179', (42, 54))	('5-FU', 'Chemical', 'MESH:D005472', (225, 229))	('5-FU', 'Chemical', 'MESH:D005472', (94, 98))	('sensitivity', 'MPA', (197, 208))	('human', 'Species', '9606', (36, 41))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('transduced', 'Var', (101, 111))	('colon cancer', 'Disease', (42, 54))
311418	29628790	Most recently, novel and extremely powerful genetic tool - CRISPR (clustered regularly interspaced short palindromic repeat) - Cas9 (CRISPR-associated nuclease 9) system, adopted from bacteria defense mechanism against viral infection, has opened new possibilities to specifically knock-out any desired gene at the genomic level.	('knock-out', 'Var', (281, 290))	('viral infection', 'Disease', (219, 234))	('viral infection', 'Disease', 'MESH:D001102', (219, 234))
311421	29628790	Although there are commercially available tools to generate HO-1 knock-out, there is a lack of studies evaluating the role of HO-1 in cancer using CRISPR/Cas9 technology, what, most probably, is just a matter of time.	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('knock-out', 'Var', (65, 74))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))
311432	29628790	Inhibition of HO-1 by ZnPPIX increased the sensitivity of nasopharyngeal carcinoma cells to radiotherapy and intensified effectiveness of cisplatin in liver cancer both in vitro and in vivo.	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (58, 82))	('intensified', 'PosReg', (109, 120))	('nasopharyngeal carcinoma', 'Disease', (58, 82))	('cisplatin', 'Chemical', 'MESH:D002945', (138, 147))	('liver cancer', 'Disease', 'MESH:D006528', (151, 163))	('ZnPPIX', 'Gene', (22, 28))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('liver cancer', 'Phenotype', 'HP:0002896', (151, 163))	('sensitivity', 'MPA', (43, 54))	('increased', 'PosReg', (29, 38))	('liver cancer', 'Disease', (151, 163))	('nasopharyngeal carcinoma', 'Disease', 'MESH:D000077274', (58, 82))	('Inhibition', 'Var', (0, 10))	('ZnPPIX', 'Chemical', 'MESH:C017803', (22, 28))	('effectiveness', 'MPA', (121, 134))	('HO-1', 'Gene', (14, 18))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
311440	29628790	observed that cytotoxic effect of ZnPPIX on human ovarian and prostate cancer cell lines was altered neither by overexpression nor by knockout of HO-1, suggesting HO-1 independent effect of this inhibitor.	('human', 'Species', '9606', (44, 49))	('ZnPPIX', 'Chemical', 'MESH:C017803', (34, 40))	('prostate cancer', 'Phenotype', 'HP:0012125', (62, 77))	('HO-1', 'Gene', (146, 150))	('ZnPPIX', 'Gene', (34, 40))	('cytotoxic effect', 'CPA', (14, 30))	('knockout', 'Var', (134, 142))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('ovarian and prostate cancer', 'Disease', 'MESH:D010051', (50, 77))
311446	29628790	Moreover, another group showed that overexpression of HO-1 in Treg cells is associated with better survival in hypoxia, typical for tumors, and inhibition of HO-1 using SnPP is able to revoke this effect, suggesting a protective role of the enzyme.	('hypoxia', 'Disease', (111, 118))	('overexpression', 'PosReg', (36, 50))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('HO-1', 'Gene', (54, 58))	('survival', 'CPA', (99, 107))	('inhibition', 'Var', (144, 154))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('tumors', 'Disease', (132, 138))	('hypoxia', 'Disease', 'MESH:D000860', (111, 118))	('HO-1', 'Gene', (158, 162))	('tumors', 'Disease', 'MESH:D009369', (132, 138))	('better', 'PosReg', (92, 98))
311453	29628790	have demonstrated that ZnPPIX specifically inhibits indoleamine 2,3-dioxygenase (IDO) enzyme, which is thought to favor immune escape in many types of tumors.	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('indoleamine 2,3-dioxygenase', 'Gene', '3620', (52, 79))	('tumors', 'Disease', (151, 157))	('tumors', 'Disease', 'MESH:D009369', (151, 157))	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('favor', 'PosReg', (114, 119))	('ZnPPIX', 'Var', (23, 29))	('immune escape', 'CPA', (120, 133))	('ZnPPIX', 'Chemical', 'MESH:C017803', (23, 29))	('inhibits', 'NegReg', (43, 51))
311463	29628790	Inhibition of HO-1 activity in hormone-refractory prostate cancer resulted in decreased proliferation, viability and invasiveness of cancer cell in vitro.	('invasiveness of cancer', 'Disease', (117, 139))	('invasiveness of cancer', 'Disease', 'MESH:D009362', (117, 139))	('prostate cancer', 'Disease', 'MESH:D011471', (50, 65))	('viability', 'CPA', (103, 112))	('prostate cancer', 'Disease', (50, 65))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('activity', 'MPA', (19, 27))	('Inhibition', 'Var', (0, 10))	('proliferation', 'CPA', (88, 101))	('decreased', 'NegReg', (78, 87))	('prostate cancer', 'Phenotype', 'HP:0012125', (50, 65))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('HO-1', 'Gene', (14, 18))
311465	29628790	As summarized in this review, inhibition of HO-1 can be considered as a potential anticancer strategy in various cancer types through several possible mechanisms (Fig.	('inhibition', 'Var', (30, 40))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('HO-1', 'Gene', (44, 48))	('cancer', 'Disease', (113, 119))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('cancer', 'Disease', (86, 92))
311494	33931045	Laboratory examinations revealed 64.6 mumol/L total bilirubin (normal, 5.1-22.2 mumol/L), 50.0 mumol/L direct bilirubin (normal, 0-6.8 mumol/L), elevated transaminase levels, including 38U/L alanine aminotransferase (normal, 7-40 U/L), 80U/L aspartate aminotransferase (normal, 13-35 U/L) and cholestasis parameters, including 1411U/L gamma-glutamyl transpeptidase (normal, 7-45 U/L), 314U/L alkaline phosphatase (normal 50-135 U/L).	('80U/L', 'MPA', (236, 241))	('elevated', 'PosReg', (145, 153))	('1411U/L', 'Var', (327, 334))	('38U/L', 'MPA', (185, 190))	('elevated transaminase', 'Phenotype', 'HP:0002910', (145, 166))	('50.0 mumol/L', 'Var', (90, 102))	('alanine aminotransferase', 'Enzyme', (191, 215))	('bilirubin', 'Chemical', 'MESH:D001663', (52, 61))	('bilirubin', 'Chemical', 'MESH:D001663', (110, 119))	('cholestasis', 'Phenotype', 'HP:0001396', (293, 304))	('aspartate', 'MPA', (242, 251))	('gamma-glutamyl transpeptidase', 'Gene', '102724197', (335, 364))	('transaminase levels', 'MPA', (154, 173))	('gamma-glutamyl transpeptidase', 'Gene', (335, 364))	('314U/L', 'Var', (385, 391))	('cholestasis', 'Disease', 'MESH:D002779', (293, 304))	('cholestasis', 'Disease', (293, 304))	('direct bilirubin', 'MPA', (103, 119))
311558	32660101	The additive or synergistic effect of epigallocatechin with chemopreventive agents has been verified as it reduces the toxicities and enhances the anti-cancerous effects.	('cancerous', 'Disease', (152, 161))	('toxicities', 'Disease', 'MESH:D064420', (119, 129))	('cancerous', 'Disease', 'MESH:D009369', (152, 161))	('epigallocatechin', 'Chemical', 'MESH:C057580', (38, 54))	('enhances', 'PosReg', (134, 142))	('reduces', 'NegReg', (107, 114))	('toxicities', 'Disease', (119, 129))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('epigallocatechin', 'Var', (38, 54))
311584	32660101	Moreover, EGCG suppresses TNF-alpha-induced MCP-1 expression in human umbilical vein endothelial cells and such effect was arbitrated by 67LR and was via the inhibition of NF-kappaB activation.	('suppresses', 'NegReg', (15, 25))	('human', 'Species', '9606', (64, 69))	('MCP-1', 'Gene', (44, 49))	('NF-kappaB', 'Gene', '4790', (172, 181))	('MCP-1', 'Gene', '6347', (44, 49))	('EGCG', 'Var', (10, 14))	('EGCG', 'Chemical', 'MESH:C045651', (10, 14))	('TNF-alpha', 'Gene', '7124', (26, 35))	('NF-kappaB', 'Gene', (172, 181))	('si', 'Chemical', 'MESH:D012825', (56, 58))	('rat', 'Species', '10116', (128, 131))	('expression', 'MPA', (50, 60))	('TNF-alpha', 'Gene', (26, 35))
311599	32660101	The apoptotic regulation by EGCG on colon cancer cells in the presence of low-dose H2O2 was investigated and it was observed to induced apoptosis and abolished the cell-proliferative effect.	('H2O2', 'Chemical', 'MESH:D006861', (83, 87))	('H2O2', 'Var', (83, 87))	('EGCG', 'Gene', (28, 32))	('rat', 'Species', '10116', (176, 179))	('si', 'Chemical', 'MESH:D012825', (142, 144))	('colon cancer', 'Disease', 'MESH:D015179', (36, 48))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('apoptosis', 'CPA', (136, 145))	('colon cancer', 'Disease', (36, 48))	('cell-proliferative effect', 'CPA', (164, 189))	('EGCG', 'Chemical', 'MESH:C045651', (28, 32))	('induced', 'Reg', (128, 135))	('abolished', 'NegReg', (150, 159))	('colon cancer', 'Phenotype', 'HP:0003003', (36, 48))
311621	32660101	EGCG was established to induce apoptosis in cells of the examined neoplastic cell lines in a concentration-related manner.	('si', 'Chemical', 'MESH:D012825', (37, 39))	('EGCG', 'Chemical', 'MESH:C045651', (0, 4))	('EGCG', 'Var', (0, 4))	('apoptosis', 'CPA', (31, 40))	('rat', 'Species', '10116', (100, 103))
311623	32660101	EGCG prompted apoptosis, diminished mitochondrial membrane potential and endorsed the G0/G1 phase cell cycle arrest of liver carcinoma cells whereas such activity was not observed on non-cancerous liver cells.	('arrest of liver carcinoma', 'Disease', 'MESH:D012131', (109, 134))	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('liver carcinoma', 'Phenotype', 'HP:0001402', (119, 134))	('cancerous', 'Disease', (187, 196))	('diminished', 'NegReg', (25, 35))	('diminished mitochondrial membrane potential', 'Phenotype', 'HP:0040013', (25, 68))	('mitochondrial membrane potential', 'MPA', (36, 68))	('endorsed', 'PosReg', (73, 81))	('apoptosis', 'CPA', (14, 23))	('EGCG', 'Chemical', 'MESH:C045651', (0, 4))	('si', 'Chemical', 'MESH:D012825', (20, 22))	('cancerous liver', 'Phenotype', 'HP:0002896', (187, 202))	('cancerous', 'Disease', 'MESH:D009369', (187, 196))	('EGCG', 'Var', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (98, 115))	('arrest of liver carcinoma', 'Disease', (109, 134))
311637	32660101	Furthermore, EGCG decreases the mRNA levels of innumerable cell cycle-related genes, but enhances the expression of the cell cycle inhibitor p21 and the apoptosis-related death receptor 5 (Table 1).	('si', 'Chemical', 'MESH:D012825', (159, 161))	('decreases', 'NegReg', (18, 27))	('expression', 'MPA', (102, 112))	('p21', 'Gene', (141, 144))	('EGCG', 'Chemical', 'MESH:C045651', (13, 17))	('p21', 'Gene', '644914', (141, 144))	('EGCG', 'Var', (13, 17))	('enhances', 'PosReg', (89, 97))	('mRNA levels of innumerable', 'MPA', (32, 58))	('si', 'Chemical', 'MESH:D012825', (108, 110))
311645	32660101	A dominant negative AKT or the phosphatidylinositol 3- kinase inhibitor, LY294002, powerfully inhibited surviving promoter activity, giving additional indications to support the hypothesis that the inhibitory effect of EGCG on survivin is arbitrated through the AKT pathway.	('AKT', 'Gene', (20, 23))	('AKT', 'Gene', (262, 265))	('LY294002', 'Var', (73, 81))	('si', 'Chemical', 'MESH:D012825', (46, 48))	('LY294002', 'Chemical', 'MESH:C085911', (73, 81))	('negative', 'NegReg', (11, 19))	('surviving promoter activity', 'MPA', (104, 131))	('EGCG', 'Chemical', 'MESH:C045651', (219, 223))	('AKT', 'Gene', '207', (20, 23))	('rat', 'Species', '10116', (244, 247))	('AKT', 'Gene', '207', (262, 265))	('si', 'Chemical', 'MESH:D012825', (185, 187))	('inhibited', 'NegReg', (94, 103))
311652	32660101	Another study result demonstrated that the Stat3-binding assay showed that EGCG meaningfully disturbed Stat3 peptide binding at micromolar concentrations, and the docking experiments showed that EGCG had a powerful relation with Arg-609, one of the chief residues in the STAT3 SH2 domain that it important for Stat3 and phosphorylated peptide binding.	('STAT3', 'Gene', (271, 276))	('Stat3', 'Gene', (103, 108))	('Stat3', 'Gene', (310, 315))	('Stat3', 'Gene', '6774', (310, 315))	('rat', 'Species', '10116', (146, 149))	('EGCG', 'Chemical', 'MESH:C045651', (75, 79))	('Stat3', 'Gene', '6774', (43, 48))	('disturbed', 'Reg', (93, 102))	('Arg', 'Chemical', 'MESH:D001120', (229, 232))	('men', 'Species', '9606', (177, 180))	('EGCG', 'Chemical', 'MESH:C045651', (195, 199))	('Stat3', 'Gene', (43, 48))	('Arg-609', 'Var', (229, 236))	('STAT3', 'Gene', '6774', (271, 276))	('si', 'Chemical', 'MESH:D012825', (257, 259))	('Stat3', 'Gene', '6774', (103, 108))	('rat', 'Species', '10116', (28, 31))
311659	32660101	Treatment of cells with 10 or 30 micrograms of epigalocathechin-3-gallate showed a 50% inhibition of growth, and decidedly inhibited the phosphorylation of HER-2 in both tested cell lines.	('growth', 'MPA', (101, 107))	('inhibition', 'NegReg', (87, 97))	('epigalocathechin-3-gallate', 'Chemical', '-', (47, 73))	('epigalocathechin-3-gallate', 'Var', (47, 73))	('phosphorylation', 'MPA', (137, 152))	('HER-2', 'Gene', (156, 161))	('HER-2', 'Gene', '2064', (156, 161))	('inhibited', 'NegReg', (123, 132))	('men', 'Species', '9606', (5, 8))
311686	32660101	It was shown that EGCG with eugenol-amrogentin could more effectively constrain the cellular proliferation and colony formation than individual actions.	('eugenol-amrogentin', 'Var', (28, 46))	('colony formation', 'CPA', (111, 127))	('cellular proliferation', 'CPA', (84, 106))	('eugenol', 'Chemical', 'MESH:D005054', (28, 35))	('amrogentin', 'Chemical', '-', (36, 46))	('constrain', 'NegReg', (70, 79))	('EGCG', 'Chemical', 'MESH:C045651', (18, 22))	('rat', 'Species', '10116', (100, 103))
311713	32660101	Correspondingly, Epigallocatechin gallate showed growth inhibitory effects in each cell line in a dose-dependent approach and induced apoptosis and cell cycle arrest.	('cell cycle arrest', 'Phenotype', 'HP:0011018', (148, 165))	('arrest', 'Disease', 'MESH:D006323', (159, 165))	('Epigallocatechin gallate', 'Var', (17, 41))	('apoptosis', 'CPA', (134, 143))	('arrest', 'Disease', (159, 165))	('induced', 'Reg', (126, 133))	('si', 'Chemical', 'MESH:D012825', (140, 142))	('Epigallocatechin gallate', 'Chemical', 'MESH:C045651', (17, 41))	('growth inhibitory effects', 'CPA', (49, 74))
311714	32660101	Besides, Epigallocatechin gallate causes a substantial decrease in ovarian cancer cell growth, showed dose dependent growth inhibitory effects, and induced apoptosis and cell cycle arrest.	('growth inhibitory effects', 'CPA', (117, 142))	('Epigallocatechin gallate', 'Chemical', 'MESH:C045651', (9, 33))	('si', 'Chemical', 'MESH:D012825', (2, 4))	('decrease in ovarian cancer', 'Disease', (55, 81))	('arrest', 'Disease', (181, 187))	('si', 'Chemical', 'MESH:D012825', (162, 164))	('arrest', 'Disease', 'MESH:D006323', (181, 187))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (170, 187))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('decrease in ovarian cancer', 'Disease', 'MESH:D002303', (55, 81))	('ovarian cancer', 'Phenotype', 'HP:0100615', (67, 81))	('Epigallocatechin gallate', 'Var', (9, 33))	('induced', 'Reg', (148, 155))	('apoptosis', 'CPA', (156, 165))
311721	32660101	Moreover, Epigallocatechin gallate caused the arrest of cells in the G0/G1 phase of the cell cycle.	('arrest', 'Disease', 'MESH:D006323', (46, 52))	('cells in the G0/G1 phase of the cell cycle', 'CPA', (56, 98))	('Epigallocatechin gallate', 'Var', (10, 34))	('arrest', 'Disease', (46, 52))	('Epigallocatechin gallate', 'Chemical', 'MESH:C045651', (10, 34))
311739	32660101	Gastric cancer-based studies have demonstrated that increasing the concentration of Epigallocatechin gallate inhibited cell proliferation under a hypoxia state and induced apoptosis in a dose-dependent manner.	('cell proliferation under a', 'CPA', (119, 145))	('Gastric cancer', 'Disease', (0, 14))	('rat', 'Species', '10116', (131, 134))	('hypoxia', 'Disease', 'MESH:D000860', (146, 153))	('Epigallocatechin gallate', 'Chemical', 'MESH:C045651', (84, 108))	('inhibited', 'NegReg', (109, 118))	('rat', 'Species', '10116', (74, 77))	('Gastric cancer', 'Disease', 'MESH:D013274', (0, 14))	('Epigallocatechin', 'Var', (84, 100))	('induced', 'Reg', (164, 171))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('si', 'Chemical', 'MESH:D012825', (178, 180))	('Gastric cancer', 'Phenotype', 'HP:0012126', (0, 14))	('rat', 'Species', '10116', (41, 44))	('apoptosis', 'CPA', (172, 181))	('increasing', 'PosReg', (52, 62))	('si', 'Chemical', 'MESH:D012825', (58, 60))	('hypoxia', 'Disease', (146, 153))
311743	32660101	Also, Epigallocatechin gallate was capable of inhibiting VEGF secretion and expression.	('inhibiting', 'NegReg', (46, 56))	('Epigallocatechin gallate', 'Var', (6, 30))	('si', 'Chemical', 'MESH:D012825', (82, 84))	('VEGF', 'Gene', (57, 61))	('expression', 'MPA', (76, 86))	('Epigallocatechin gallate', 'Chemical', 'MESH:C045651', (6, 30))	('VEGF', 'Gene', '7422', (57, 61))
311765	32660101	Both Epigallocatechin gallate and Poly E specially inhibited the growth of the various colon cancer cells when compared with the normal human fetal colon cell line.	('colon cancer', 'Disease', (87, 99))	('human', 'Species', '9606', (136, 141))	('Poly E', 'Var', (34, 40))	('growth', 'CPA', (65, 71))	('Poly E', 'Chemical', '-', (34, 40))	('Epigallocatechin gallate', 'Chemical', 'MESH:C045651', (5, 29))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('colon cancer', 'Phenotype', 'HP:0003003', (87, 99))	('inhibited', 'NegReg', (51, 60))	('colon cancer', 'Disease', 'MESH:D015179', (87, 99))
311766	32660101	Moreover, treatment of cancer cells with Epigallocatechin gallate or Poly E caused an increase of cells in G1 and induced apoptosis.	('increase', 'PosReg', (86, 94))	('si', 'Chemical', 'MESH:D012825', (128, 130))	('apoptosis', 'CPA', (122, 131))	('Epigallocatechin gallate', 'Var', (41, 65))	('men', 'Species', '9606', (15, 18))	('cancer', 'Disease', (23, 29))	('cancer', 'Disease', 'MESH:D009369', (23, 29))	('Epigallocatechin gallate', 'Chemical', 'MESH:C045651', (41, 65))	('cells in G1', 'CPA', (98, 109))	('Poly E', 'Var', (69, 75))	('Poly E', 'Chemical', '-', (69, 75))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))
311767	32660101	Both Epigallocatechin gallate and Poly E initiated a decrease in the phosphorylated forms of epidermal growth factor receptor and HER2 proteins, and successively caused a decrease in the phosphorylated forms of the extracellular signal-regulated kinase and Akt proteins.	('si', 'Chemical', 'MESH:D012825', (155, 157))	('Poly E', 'Var', (34, 40))	('decrease', 'NegReg', (53, 61))	('decrease', 'NegReg', (171, 179))	('Akt', 'Gene', '207', (257, 260))	('Poly E', 'Chemical', '-', (34, 40))	('phosphorylated forms', 'MPA', (69, 89))	('Epigallocatechin gallate', 'Chemical', 'MESH:C045651', (5, 29))	('extracellular signal-regulated kinase', 'Pathway', (215, 252))	('phosphorylated forms', 'MPA', (187, 207))	('HER2', 'Gene', (130, 134))	('si', 'Chemical', 'MESH:D012825', (229, 231))	('epidermal growth factor receptor', 'Gene', (93, 125))	('HER2', 'Gene', '2064', (130, 134))	('epidermal growth factor receptor', 'Gene', '1956', (93, 125))	('Akt', 'Gene', (257, 260))
311771	32660101	The inhibition rates on tumor growth in the EGCG groups were significantly different compared with the control group.	('tumor growth', 'Disease', (24, 36))	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumor growth', 'Disease', 'MESH:D006130', (24, 36))	('EGCG', 'Chemical', 'MESH:C045651', (44, 48))	('rat', 'Species', '10116', (15, 18))	('EGCG', 'Var', (44, 48))	('si', 'Chemical', 'MESH:D012825', (61, 63))	('inhibition', 'NegReg', (4, 14))
311780	32660101	Findings based on renal cancer revealed that Epigallocatechin gallate inhibit growth and induces apoptosis in the renal cell carcinoma cell line.	('renal cell carcinoma', 'Disease', (114, 134))	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('induces', 'Reg', (89, 96))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (114, 134))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (114, 134))	('Epigallocatechin gallate', 'Var', (45, 69))	('cancer', 'Disease', (24, 30))	('cancer', 'Disease', 'MESH:D009369', (24, 30))	('renal cancer', 'Phenotype', 'HP:0009726', (18, 30))	('Epigallocatechin gallate', 'Chemical', 'MESH:C045651', (45, 69))	('inhibit', 'NegReg', (70, 77))	('si', 'Chemical', 'MESH:D012825', (103, 105))	('growth', 'CPA', (78, 84))	('apoptosis', 'CPA', (97, 106))
311784	32660101	Moreover, Epigallocatechin gallate treatment caused in the downregulation of metalloproteinase-2 and metalloproteinase-9 in carcinoma cells and anticancer effect associated with Epigallocatechin gallate may involve the downregulation of metalloproteinase-2 and metalloproteinase-9.	('cancer', 'Disease', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('metalloproteinase-2', 'Enzyme', (77, 96))	('metalloproteinase-9', 'Enzyme', (101, 120))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('Epigallocatechin gallate', 'Chemical', 'MESH:C045651', (178, 202))	('downregulation', 'NegReg', (219, 233))	('carcinoma', 'Disease', (124, 133))	('carcinoma', 'Disease', 'MESH:D009369', (124, 133))	('downregulation', 'NegReg', (59, 73))	('metalloproteinase-2', 'Enzyme', (237, 256))	('men', 'Species', '9606', (40, 43))	('Epigallocatechin gallate', 'Chemical', 'MESH:C045651', (10, 34))	('Epigallocatechin', 'Var', (178, 194))	('metalloproteinase-9', 'Enzyme', (261, 280))
311790	32660101	Chemical sensitivity to vinblastine in cells was increased by EGCG pre-treatment, and this effect was withdrawn by siRNA-mediated knockdown of connexin 32.	('Chemical sensitivity to vinblastine', 'MPA', (0, 35))	('connexin 32', 'Gene', (143, 154))	('vinblastine', 'Chemical', 'MESH:D014747', (24, 35))	('si', 'Chemical', 'MESH:D012825', (12, 14))	('si', 'Chemical', 'MESH:D012825', (115, 117))	('increased', 'PosReg', (49, 58))	('connexin 32', 'Gene', '2705', (143, 154))	('men', 'Species', '9606', (76, 79))	('knockdown', 'Var', (130, 139))	('EGCG', 'Var', (62, 66))	('EGCG', 'Chemical', 'MESH:C045651', (62, 66))
311806	32660101	Epigallocatechin-3-gallate also inhibited cancer cell invasion and migration, and Epigallocatechin-3-gallate induced apoptosis in cancer cells.	('Epigallocatechin-3-gallate', 'Var', (82, 108))	('rat', 'Species', '10116', (70, 73))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('inhibited', 'NegReg', (32, 41))	('cancer', 'Disease', (130, 136))	('cancer', 'Disease', (42, 48))	('migration', 'CPA', (67, 76))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('Epigallocatechin-3-gallate', 'Chemical', 'MESH:C045651', (82, 108))	('apoptosis', 'CPA', (117, 126))	('si', 'Chemical', 'MESH:D012825', (123, 125))	('Epigallocatechin-3-gallate', 'Chemical', 'MESH:C045651', (0, 26))	('si', 'Chemical', 'MESH:D012825', (58, 60))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))
311808	32660101	Based on an in vitro study, Epigallocatechin-3-gallate caused morphological changes and increased growth inhibition in a dose- and time-dependent manner in bladder cancer cells.	('Epigallocatechin-3-gallate', 'Chemical', 'MESH:C045651', (28, 54))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('bladder cancer', 'Disease', 'MESH:D001749', (156, 170))	('bladder cancer', 'Disease', (156, 170))	('growth inhibition', 'CPA', (98, 115))	('Epigallocatechin-3-gallate', 'Var', (28, 54))	('increased', 'PosReg', (88, 97))	('morphological changes', 'CPA', (62, 83))	('bladder cancer', 'Phenotype', 'HP:0009725', (156, 170))
311816	32660101	Epigallocatechin-3-gallate caused significant inhibition of proliferation and induced apoptosis in cancer cells.	('rat', 'Species', '10116', (67, 70))	('Epigallocatechin-3-gallate', 'Var', (0, 26))	('inhibition', 'NegReg', (46, 56))	('induced', 'Reg', (78, 85))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('cancer', 'Disease', (99, 105))	('si', 'Chemical', 'MESH:D012825', (92, 94))	('si', 'Chemical', 'MESH:D012825', (34, 36))	('proliferation', 'CPA', (60, 73))	('Epigallocatechin-3-gallate', 'Chemical', 'MESH:C045651', (0, 26))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('apoptosis', 'CPA', (86, 95))
311824	32660101	The result confirmed that epigallocatechin-3-gallate induced growth inhibition and apoptosis.	('growth inhibition', 'CPA', (61, 78))	('si', 'Chemical', 'MESH:D012825', (89, 91))	('apoptosis', 'CPA', (83, 92))	('epigallocatechin-3-gallate', 'Var', (26, 52))	('epigallocatechin-3-gallate', 'Chemical', 'MESH:C045651', (26, 52))
311827	32660101	Cells treated with epigallocatechin-3-gallate or the mixture treatment had lower proliferative indices when compared to the other groups.	('lower', 'NegReg', (75, 80))	('men', 'Species', '9606', (66, 69))	('rat', 'Species', '10116', (88, 91))	('proliferative indices', 'CPA', (81, 102))	('epigallocatechin-3-gallate', 'Chemical', 'MESH:C045651', (19, 45))	('epigallocatechin-3-gallate', 'Var', (19, 45))
311831	32660101	Results demonstrated that epigallocatechin-3-gallate caused induction of cell death and reactive oxygen species generation in lymphoma cells.	('rat', 'Species', '10116', (15, 18))	('lymphoma', 'Disease', (126, 134))	('lymphoma', 'Disease', 'MESH:D008223', (126, 134))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (88, 111))	('rat', 'Species', '10116', (116, 119))	('lymphoma', 'Phenotype', 'HP:0002665', (126, 134))	('reactive oxygen species generation', 'MPA', (88, 122))	('cell death', 'CPA', (73, 83))	('epigallocatechin-3-gallate', 'Var', (26, 52))	('epigallocatechin-3-gallate', 'Chemical', 'MESH:C045651', (26, 52))
311832	32660101	The mechanism that epigallocatechin-3-gallate inhibits the growth of head and neck cancer, focused on the regulation of the expression and activity of beta-catenin showed epigallocatechin-3-gallate prompted apoptosis via the suppression of beta-catenin signaling.	('beta-catenin', 'Gene', (240, 252))	('apoptosis', 'CPA', (207, 216))	('growth', 'CPA', (59, 65))	('si', 'Chemical', 'MESH:D012825', (232, 234))	('si', 'Chemical', 'MESH:D012825', (130, 132))	('beta-catenin', 'Gene', '1499', (151, 163))	('beta-catenin', 'Gene', '1499', (240, 252))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('head and neck cancer', 'Phenotype', 'HP:0012288', (69, 89))	('inhibits', 'NegReg', (46, 54))	('suppression', 'NegReg', (225, 236))	('si', 'Chemical', 'MESH:D012825', (253, 255))	('epigallocatechin-3-gallate', 'Chemical', 'MESH:C045651', (19, 45))	('si', 'Chemical', 'MESH:D012825', (213, 215))	('epigallocatechin-3-gallate', 'Var', (171, 197))	('head and neck cancer', 'Disease', 'MESH:D006258', (69, 89))	('epigallocatechin-3-gallate', 'Chemical', 'MESH:C045651', (171, 197))	('beta-catenin', 'Gene', (151, 163))
311835	32660101	A pioneering study explaining the role epigallocatechin-3-gallate in cancer management as shRNA-mediated silencing of Bim meaningfully inhibited apoptosis prompted through the combination of erlotinib and epigallocatechin-3-gallate.	('apoptosis', 'CPA', (145, 154))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('erlotinib', 'Chemical', 'MESH:D000069347', (191, 200))	('si', 'Chemical', 'MESH:D012825', (105, 107))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('si', 'Chemical', 'MESH:D012825', (151, 153))	('epigallocatechin-3-gallate', 'Chemical', 'MESH:C045651', (205, 231))	('epigallocatechin-3-gallate', 'Chemical', 'MESH:C045651', (39, 65))	('Bim', 'Gene', (118, 121))	('silencing', 'Var', (105, 114))	('inhibited', 'NegReg', (135, 144))	('men', 'Species', '9606', (82, 85))	('cancer', 'Disease', (69, 75))	('Bim', 'Gene', '10018', (118, 121))
311847	32660101	Moreover, epigallocatechin-3-gallate caused an inhibitory effect on cell migration, motility, spread, and adhesion.	('cell migration', 'CPA', (68, 82))	('inhibitory', 'NegReg', (47, 57))	('si', 'Chemical', 'MESH:D012825', (110, 112))	('epigallocatechin-3-gallate', 'Chemical', 'MESH:C045651', (10, 36))	('rat', 'Species', '10116', (76, 79))	('epigallocatechin-3-gallate', 'Var', (10, 36))	('spread', 'CPA', (94, 100))	('motility', 'CPA', (84, 92))	('adhesion', 'CPA', (106, 114))
311865	32660101	Metformin inhibited HO-1 expression and increased the anti-tumor effect of epigallocatechin-3-gallate and metformin also enhanced ROS generation induced by epigallocatechin-3-gallate, consequently causing apoptosis.	('ROS', 'Chemical', 'MESH:D017382', (130, 133))	('tumor', 'Disease', (59, 64))	('enhanced', 'PosReg', (121, 129))	('causing', 'Reg', (197, 204))	('Metformin', 'Chemical', 'MESH:D008687', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('metformin', 'Var', (106, 115))	('ROS generation', 'MPA', (130, 144))	('metformin', 'Chemical', 'MESH:D008687', (106, 115))	('expression', 'MPA', (25, 35))	('inhibited', 'NegReg', (10, 19))	('si', 'Chemical', 'MESH:D012825', (200, 202))	('si', 'Chemical', 'MESH:D012825', (31, 33))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('rat', 'Species', '10116', (138, 141))	('HO-1', 'Gene', '3162', (20, 24))	('si', 'Chemical', 'MESH:D012825', (211, 213))	('increased', 'PosReg', (40, 49))	('epigallocatechin-3-gallate', 'Chemical', 'MESH:C045651', (75, 101))	('epigallocatechin-3-gallate', 'Chemical', 'MESH:C045651', (156, 182))	('HO-1', 'Gene', (20, 24))
311872	32660101	The cytotoxic effect of this green tea compound on both the parental lung cancer cells and their cisplatin-resistant cells explained that epigallocatechin-3-gallate was capable of increasing interlukine-6 production, while its downstream effector signal transducers and activators of transcription 3 phosphorylation were unaffected by epigallocatechin-3-gallate.	('epigallocatechin-3-gallate', 'Chemical', 'MESH:C045651', (138, 164))	('parental lung cancer', 'Disease', (60, 80))	('epigallocatechin-3-gallate', 'Var', (138, 164))	('cisplatin', 'Chemical', 'MESH:D002945', (97, 106))	('si', 'Chemical', 'MESH:D012825', (109, 111))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('interlukine-6 production', 'MPA', (191, 215))	('lung cancer', 'Phenotype', 'HP:0100526', (69, 80))	('increasing', 'PosReg', (180, 190))	('si', 'Chemical', 'MESH:D012825', (247, 249))	('parental lung cancer', 'Disease', 'MESH:D008175', (60, 80))	('epigallocatechin-3-gallate', 'Chemical', 'MESH:C045651', (335, 361))	('tea', 'Gene', (35, 38))	('si', 'Chemical', 'MESH:D012825', (186, 188))	('tea', 'Gene', '11988', (35, 38))
311880	32660101	Overall, the outcome of the study revealed that epigallocatechin-3-gallate has an anticancer effect on osteosarcoma cells.	('epigallocatechin-3-gallate', 'Chemical', 'MESH:C045651', (48, 74))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('osteosarcoma', 'Phenotype', 'HP:0002669', (103, 115))	('epigallocatechin-3-gallate', 'Var', (48, 74))	('osteosarcoma', 'Disease', 'MESH:D012516', (103, 115))	('osteosarcoma', 'Disease', (103, 115))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('cancer', 'Disease', (86, 92))
311886	32660101	Epigallocatechin-3-gallate confirmed its role in the inhibition of glioma and it was reported that epigallocatechin-3-gallate induced apoptosis.	('epigallocatechin-3-gallate', 'Var', (99, 125))	('glioma', 'Disease', (67, 73))	('apoptosis', 'CPA', (134, 143))	('si', 'Chemical', 'MESH:D012825', (140, 142))	('glioma', 'Disease', 'MESH:D005910', (67, 73))	('Epigallocatechin-3-gallate', 'Chemical', 'MESH:C045651', (0, 26))	('glioma', 'Phenotype', 'HP:0009733', (67, 73))	('epigallocatechin-3-gallate', 'Chemical', 'MESH:C045651', (99, 125))
311891	32660101	To analyze the study, two glioma cell lines were treated with epigallocatechin-3-gallate, and its effect on cell proliferation and invasive ability.	('si', 'Chemical', 'MESH:D012825', (135, 137))	('invasive ability', 'CPA', (131, 147))	('epigallocatechin-3-gallate', 'Chemical', 'MESH:C045651', (62, 88))	('epigallocatechin-3-gallate', 'Var', (62, 88))	('glioma', 'Disease', (26, 32))	('rat', 'Species', '10116', (120, 123))	('cell proliferation', 'CPA', (108, 126))	('glioma', 'Disease', 'MESH:D005910', (26, 32))	('glioma', 'Phenotype', 'HP:0009733', (26, 32))
311893	32660101	Besides, invasive ability was significantly suppressed in the EGCG-treated cells.	('suppressed', 'NegReg', (44, 54))	('si', 'Chemical', 'MESH:D012825', (2, 4))	('invasive ability', 'CPA', (9, 25))	('si', 'Chemical', 'MESH:D012825', (30, 32))	('EGCG-treated', 'Var', (62, 74))	('si', 'Chemical', 'MESH:D012825', (13, 15))	('EGCG', 'Chemical', 'MESH:C045651', (62, 66))
311897	32660101	Another study reported that epigallocatechin-3-gallate considerably suppresses invasion and migration in anaplastic thyroid carcinoma cells.	('epigallocatechin-3-gallate', 'Chemical', 'MESH:C045651', (28, 54))	('epigallocatechin-3-gallate', 'Var', (28, 54))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (116, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('rat', 'Species', '10116', (95, 98))	('anaplastic thyroid carcinoma', 'Disease', 'MESH:D065646', (105, 133))	('anaplastic thyroid carcinoma', 'Phenotype', 'HP:0011779', (105, 133))	('suppresses', 'NegReg', (68, 78))	('anaplastic thyroid carcinoma', 'Disease', (105, 133))	('si', 'Chemical', 'MESH:D012825', (58, 60))	('si', 'Chemical', 'MESH:D012825', (83, 85))
311908	32660101	It was reported that ECG or EGCG at higher doses had a minor inhibitory effect on cell proliferation in the resistant human HCC cell line and in vivo, whereas the administration of DOX with these compounds at lower doses significantly inhibited HCC cell proliferation in vitro and hepatoma growth in a xenograft mouse model, compared with treatment with either agent alone at the same dose.	('inhibited', 'NegReg', (235, 244))	('men', 'Species', '9606', (344, 347))	('HCC cell proliferation in vitro', 'CPA', (245, 276))	('rat', 'Species', '10116', (261, 264))	('hepatoma growth', 'Disease', 'MESH:D006528', (281, 296))	('rat', 'Species', '10116', (94, 97))	('HCC', 'Phenotype', 'HP:0001402', (245, 248))	('ECG', 'Var', (21, 24))	('EGCG', 'Var', (28, 32))	('inhibitory', 'NegReg', (61, 71))	('HCC', 'Phenotype', 'HP:0001402', (124, 127))	('si', 'Chemical', 'MESH:D012825', (110, 112))	('si', 'Chemical', 'MESH:D012825', (221, 223))	('rat', 'Species', '10116', (171, 174))	('human', 'Species', '9606', (118, 123))	('EGCG', 'Chemical', 'MESH:C045651', (28, 32))	('mouse', 'Species', '10090', (312, 317))	('DOX', 'Chemical', 'MESH:D004317', (181, 184))	('hepatoma growth', 'Disease', (281, 296))	('ECG', 'Chemical', 'MESH:C062669', (21, 24))
311910	32660101	The result of the study established that moderately increased body weights were noticed due to EGCG/TF treatment compared with carcinogen control mice.	('increased', 'PosReg', (52, 61))	('TF', 'Chemical', 'MESH:C056068', (100, 102))	('increased body weights', 'Phenotype', 'HP:0004324', (52, 74))	('men', 'Species', '9606', (108, 111))	('EGCG', 'Chemical', 'MESH:C045651', (95, 99))	('mice', 'Species', '10090', (146, 150))	('EGCG/TF treatment', 'Var', (95, 112))	('body weights', 'CPA', (62, 74))	('rat', 'Species', '10116', (45, 48))
311912	32660101	Treatment of mice with EGCG showed a noteworthy decrease in the mean number of aberrant crypt foci per mouse, when compared with the model mice treated with azoxymethane (AOM)/dextran sodium sulfate (DSS).	('mice', 'Species', '10090', (13, 17))	('men', 'Species', '9606', (5, 8))	('EGCG', 'Chemical', 'MESH:C045651', (23, 27))	('azoxymethane', 'Chemical', 'MESH:D001397', (157, 169))	('mouse', 'Species', '10090', (103, 108))	('EGCG', 'Var', (23, 27))	('dextran sodium sulfate', 'Chemical', '-', (176, 198))	('decrease', 'NegReg', (48, 56))	('mice', 'Species', '10090', (139, 143))	('DSS', 'Chemical', '-', (200, 203))	('AOM', 'Chemical', 'MESH:D001397', (171, 174))
311914	32660101	The results revealed that EGCG could inhibit colon carcinogenesis via decreasing the number of precancerous lesions and solid tumors, with reduced tumor load and delayed histological progression of colorectal cancer.	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('EGCG', 'Chemical', 'MESH:C045651', (26, 30))	('colon carcinogenesis', 'Disease', (45, 65))	('reduced', 'NegReg', (139, 146))	('solid tumors', 'Disease', 'MESH:D009369', (120, 132))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('si', 'Chemical', 'MESH:D012825', (190, 192))	('tumor', 'Disease', (147, 152))	('precancerous lesions', 'Disease', (95, 115))	('colorectal cancer', 'Disease', 'MESH:D015179', (198, 215))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('si', 'Chemical', 'MESH:D012825', (62, 64))	('colorectal cancer', 'Disease', (198, 215))	('si', 'Chemical', 'MESH:D012825', (110, 112))	('inhibit', 'NegReg', (37, 44))	('tumor', 'Disease', (126, 131))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('si', 'Chemical', 'MESH:D012825', (76, 78))	('precancerous lesions', 'Disease', 'MESH:D011230', (95, 115))	('solid tumors', 'Disease', (120, 132))	('colon carcinogenesis', 'Disease', 'MESH:D063646', (45, 65))	('EGCG', 'Var', (26, 30))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('decreasing', 'NegReg', (70, 80))	('colorectal cancer', 'Phenotype', 'HP:0003003', (198, 215))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
311919	32660101	Results confirmed that Epigallocatechin-gallate decreased in vivo growth and increased the sensitivity to GEM of Mz-ChA-1 cell xenografts in nude mice.	('Mz-ChA', 'Chemical', '-', (113, 119))	('nude mice', 'Species', '10090', (141, 150))	('Epigallocatechin-gallate', 'Chemical', 'MESH:C045651', (23, 47))	('sensitivity to GEM', 'MPA', (91, 109))	('decreased', 'NegReg', (48, 57))	('Epigallocatechin-gallate', 'Var', (23, 47))	('growth', 'MPA', (66, 72))	('increased', 'PosReg', (77, 86))	('si', 'Chemical', 'MESH:D012825', (94, 96))
311927	32660101	A laboratory experiment provided evidence that Epigallocatechin-3-gallate modulates numerous molecular targets and inhibit the pathogenesis of cancer through inhibition of initiation, promotion and progression.	('men', 'Species', '9606', (19, 22))	('pathogenesis', 'CPA', (127, 139))	('progression', 'CPA', (198, 209))	('rat', 'Species', '10116', (6, 9))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('inhibit', 'NegReg', (115, 122))	('Epigallocatechin-3-gallate', 'Var', (47, 73))	('si', 'Chemical', 'MESH:D012825', (205, 207))	('si', 'Chemical', 'MESH:D012825', (136, 138))	('molecular', 'Protein', (93, 102))	('initiation', 'CPA', (172, 182))	('Epigallocatechin-3-gallate', 'Chemical', 'MESH:C045651', (47, 73))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('inhibition', 'NegReg', (158, 168))	('promotion', 'CPA', (184, 193))	('modulates', 'Reg', (74, 83))
311933	32660101	This finding was determined by a decrease in atypical small acinar proliferation diagnoses on the Poly E (0/26) compared with the placebo arm (5/25).	('Poly', 'Var', (98, 102))	('decrease', 'NegReg', (33, 41))	('Poly E', 'Chemical', '-', (98, 104))	('rat', 'Species', '10116', (74, 77))	('atypical small acinar proliferation diagnoses', 'Disease', (45, 90))
311934	32660101	A decrease in serum prostate-specific antigen was observed on the PolyE arm.	('PolyE', 'Chemical', '-', (66, 71))	('decrease', 'NegReg', (2, 10))	('PolyE', 'Var', (66, 71))	('prostate-specific antigen', 'Gene', '354', (20, 45))	('prostate-specific antigen', 'Gene', (20, 45))
311962	32660101	No other reported acute toxicity was related with Epigallocatechin-3-gallate.	('Epigallocatechin-3-gallate', 'Var', (50, 76))	('Epigallocatechin-3-gallate', 'Chemical', 'MESH:C045651', (50, 76))	('toxicity', 'Disease', 'MESH:D064420', (24, 32))	('toxicity', 'Disease', (24, 32))
311985	32660101	The treatment of colorectal cancer cells with Epigallocatechin-3-gallate and cisplatin or oxaliplatin demonstrated a synergistic effect on inhibition of cell proliferation and induction of cell death.	('colorectal cancer', 'Phenotype', 'HP:0003003', (17, 34))	('Epigallocatechin-3-gallate', 'Var', (46, 72))	('inhibition', 'NegReg', (139, 149))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (90, 101))	('colorectal cancer', 'Disease', (17, 34))	('men', 'Species', '9606', (9, 12))	('cell death', 'CPA', (189, 199))	('cell proliferation', 'CPA', (153, 171))	('rat', 'Species', '10116', (109, 112))	('Epigallocatechin-3-gallate', 'Chemical', 'MESH:C045651', (46, 72))	('cisplatin', 'Chemical', 'MESH:D002945', (77, 86))	('rat', 'Species', '10116', (165, 168))	('colorectal cancer', 'Disease', 'MESH:D015179', (17, 34))
311997	32660101	The low concentrations of catechins are cytotoxic to ER alpha-human breast cancer cells, and the combination of Epigallocatechin-3-gallate and 4-hydroxytamoxifen provokes synergistic cytotoxicity in human breast cancer cells.	('ER alpha', 'Gene', (53, 61))	('breast cancer', 'Disease', 'MESH:D001943', (205, 218))	('cytotoxicity', 'Disease', (183, 195))	('breast cancer', 'Disease', (205, 218))	('ER alpha', 'Gene', '2099', (53, 61))	('cytotoxicity', 'Disease', 'MESH:D064420', (183, 195))	('rat', 'Species', '10116', (15, 18))	('human', 'Species', '9606', (199, 204))	('breast cancer', 'Phenotype', 'HP:0003002', (205, 218))	('4-hydroxytamoxifen', 'Chemical', 'MESH:C016601', (143, 161))	('human', 'Species', '9606', (62, 67))	('breast cancer', 'Phenotype', 'HP:0003002', (68, 81))	('Epigallocatechin-3-gallate', 'Chemical', 'MESH:C045651', (112, 138))	('catechins', 'Chemical', 'MESH:D002392', (26, 35))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))	('Epigallocatechin-3-gallate', 'Var', (112, 138))	('combination', 'Interaction', (97, 108))	('breast cancer', 'Disease', 'MESH:D001943', (68, 81))	('breast cancer', 'Disease', (68, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))
312003	32660101	The amount of epigallocatechin gallate needed for prevention according to both criteria was decreased ten times via combination with epicatechin (EC), epigallocatechin (EGC) or (-)-epicatechin-3-gallate (ECG).	('ECG', 'Chemical', 'MESH:C062669', (204, 207))	('epicatechin', 'Chemical', 'MESH:D002392', (133, 144))	('EC', 'Chemical', 'MESH:D002392', (204, 206))	('EC', 'Chemical', 'MESH:D002392', (146, 148))	('epigallocatechin gallate', 'Chemical', 'MESH:C045651', (14, 38))	('epicatechin', 'Chemical', 'MESH:D002392', (181, 192))	('epigallocatechin', 'Chemical', 'MESH:C057580', (151, 167))	('combination', 'Interaction', (116, 127))	('epigallocatechin', 'Chemical', 'MESH:C057580', (14, 30))	('-', 'Var', (178, 179))	('(-)-epicatechin-3-gallate', 'Chemical', 'MESH:C062669', (177, 202))	('EGC', 'Chemical', 'MESH:C057580', (169, 172))	('decreased', 'NegReg', (92, 101))
312005	32660101	Epicatechin increased apoptosis, the growth inhibition of the human lung cancer cell line, and the inhibition of tumor necrosis factor-alpha released from BALB/c-3T3 cells through epigallocatechin gallate and another tea polyphenol with a galloyl moiety in a dose-dependent way.	('si', 'Chemical', 'MESH:D012825', (28, 30))	('lung cancer', 'Phenotype', 'HP:0100526', (68, 79))	('galloyl', 'Chemical', '-', (239, 246))	('T3', 'CellLine', 'CVCL:0594', (163, 165))	('tea', 'Gene', '11988', (217, 220))	('growth inhibition', 'CPA', (37, 54))	('epigallocatechin', 'Var', (180, 196))	('apoptosis', 'CPA', (22, 31))	('epigallocatechin gallate', 'Chemical', 'MESH:C045651', (180, 204))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('increased', 'PosReg', (12, 21))	('tumor necrosis factor-alpha', 'Gene', (113, 140))	('lung cancer', 'Disease', (68, 79))	('Epicatechin', 'Chemical', 'MESH:D002392', (0, 11))	('human', 'Species', '9606', (62, 67))	('inhibition', 'NegReg', (99, 109))	('si', 'Chemical', 'MESH:D012825', (124, 126))	('tea', 'Gene', (217, 220))	('lung cancer', 'Disease', 'MESH:D008175', (68, 79))	('polyphenol', 'Chemical', 'MESH:D059808', (221, 231))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('tumor necrosis factor-alpha', 'Gene', '7124', (113, 140))
312039	32660101	The anticancer activity of the EGCG-adsorbed pNG was examined and EGCG-pNG was shown to inhibit tumor cell growth by means of cell apoptosis.	('cancer', 'Disease', (8, 14))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('cell apoptosis', 'CPA', (126, 140))	('tumor', 'Disease', (96, 101))	('inhibit', 'NegReg', (88, 95))	('EGCG-pNG', 'Var', (66, 74))	('EGCG', 'Chemical', 'MESH:C045651', (31, 35))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('si', 'Chemical', 'MESH:D012825', (137, 139))	('EGCG', 'Chemical', 'MESH:C045651', (66, 70))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('cancer', 'Disease', 'MESH:D009369', (8, 14))
312049	32660101	Results confirmed that both EGCG and nano-EGCG inhibited the growth of lung cancer cells, with half-maximal inhibitory concentrations of 36.03 and 4.71 muM, respectively.	('inhibited', 'NegReg', (47, 56))	('lung cancer', 'Phenotype', 'HP:0100526', (71, 82))	('lung cancer', 'Disease', 'MESH:D008175', (71, 82))	('rat', 'Species', '10116', (126, 129))	('nano-EGCG', 'Var', (37, 46))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('EGCG', 'Chemical', 'MESH:C045651', (42, 46))	('growth', 'CPA', (61, 67))	('lung cancer', 'Disease', (71, 82))	('EGCG', 'Chemical', 'MESH:C045651', (28, 32))
312051	32660101	Moreover, Nano-EGCG may inhibit lung cancer cell invasion and inhibit lung cancer cell proliferation, colony formation, migration, and invasion.	('lung cancer', 'Disease', (70, 81))	('colony formation', 'CPA', (102, 118))	('inhibit', 'NegReg', (62, 69))	('inhibit', 'NegReg', (24, 31))	('EGCG', 'Chemical', 'MESH:C045651', (15, 19))	('rat', 'Species', '10116', (94, 97))	('lung cancer', 'Disease', 'MESH:D008175', (32, 43))	('lung cancer', 'Phenotype', 'HP:0100526', (32, 43))	('lung cancer', 'Disease', 'MESH:D008175', (70, 81))	('si', 'Chemical', 'MESH:D012825', (53, 55))	('lung cancer', 'Phenotype', 'HP:0100526', (70, 81))	('rat', 'Species', '10116', (123, 126))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('invasion', 'CPA', (135, 143))	('si', 'Chemical', 'MESH:D012825', (139, 141))	('Nano-EGCG', 'Var', (10, 19))	('migration', 'CPA', (120, 129))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('lung cancer', 'Disease', (32, 43))
312063	32660101	Results demonstrated that cumulative amounts transported after encapsulation were significantly higher for C and EGCg, respectively.	('cumulative amounts transported', 'MPA', (26, 56))	('rat', 'Species', '10116', (15, 18))	('si', 'Chemical', 'MESH:D012825', (82, 84))	('EGCg', 'Var', (113, 117))	('EGCg', 'Chemical', 'MESH:C045651', (113, 117))	('higher', 'PosReg', (96, 102))
312064	32660101	This study establishes that encapsulation of catechins in chitosan nanoparticles improves their intestinal absorption and is an encouraging approach for improving their bioavailability.	('intestinal absorption', 'MPA', (96, 117))	('improving', 'PosReg', (153, 162))	('chitosan', 'Chemical', 'MESH:D048271', (58, 66))	('catechins', 'Chemical', 'MESH:D002392', (45, 54))	('improves', 'PosReg', (81, 89))	('bioavailability', 'MPA', (169, 184))	('encapsulation', 'Var', (28, 41))
312068	32660101	EGCG NPs could meaningfully modify the pharmacokinetic profile and increase the bioavailability of EGCG by more than 2.4-times in comparison with the EGCG powder group.	('NPs', 'Var', (5, 8))	('EGCG', 'Chemical', 'MESH:C045651', (99, 103))	('EGCG', 'Chemical', 'MESH:C045651', (150, 154))	('increase', 'PosReg', (67, 75))	('EGCG', 'Chemical', 'MESH:C045651', (0, 4))	('bioavailability', 'MPA', (80, 95))	('modify', 'Reg', (28, 34))	('pharmacokinetic profile', 'MPA', (39, 62))
312081	32660101	It was determined that EGCG3''Me has a significant inhibitory effect on the activity of angiotensin I-converting enzyme (ACE).	('angiotensin I-converting enzyme', 'Gene', (88, 119))	('EGCG', 'Chemical', 'MESH:C045651', (23, 27))	('activity', 'MPA', (76, 84))	('si', 'Chemical', 'MESH:D012825', (39, 41))	("EGCG3''Me", 'Var', (23, 32))	('angiotensin I-converting enzyme', 'Gene', '1636', (88, 119))	('ACE', 'Gene', '1636', (121, 124))	('inhibitory effect', 'NegReg', (51, 68))	('si', 'Chemical', 'MESH:D012825', (96, 98))	('ACE', 'Gene', (121, 124))
312082	32660101	The effect of Benifuuki tea on human hypertension is chiefly the result of the strong inhibitory effect of EGCG3''Me on angiotensin I-converting enzyme activity, its high rate of absorption, and its stability in the blood.	('inhibitory effect', 'MPA', (86, 103))	("EGCG3''", 'Var', (107, 114))	('EGCG', 'Chemical', 'MESH:C045651', (107, 111))	('angiotensin I-converting enzyme', 'Gene', (120, 151))	('activity', 'MPA', (152, 160))	('hypertension', 'Disease', (37, 49))	('hypertension', 'Phenotype', 'HP:0000822', (37, 49))	('human', 'Species', '9606', (31, 36))	('rat', 'Species', '10116', (171, 174))	('absorption', 'MPA', (179, 189))	('hypertension', 'Disease', 'MESH:D006973', (37, 49))	('angiotensin I-converting enzyme', 'Gene', '1636', (120, 151))	('tea', 'Gene', (24, 27))	('tea', 'Gene', '11988', (24, 27))
312101	32140600	Association of promoter methylation of RASSF1A and KRAS mutations in non-small cell lung carcinoma in Kashmiri population (India) Non-small cell lung carcinoma (NSCLC) incidence and progression is increasing because of genetic and epigenetic changes.	('KRAS', 'Gene', '3845', (51, 55))	('Non-small cell lung carcinoma', 'Disease', 'MESH:D002289', (130, 159))	('non-small cell lung carcinoma', 'Disease', (69, 98))	('small cell lung carcinoma', 'Phenotype', 'HP:0030357', (73, 98))	('promoter', 'MPA', (15, 23))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('Non-small cell lung carcinoma', 'Disease', (130, 159))	('KRAS', 'Gene', (51, 55))	('mutations', 'Var', (56, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (150, 159))	('non-small cell lung carcinoma', 'Disease', 'MESH:D002289', (69, 98))	('NSCLC', 'Disease', 'MESH:D002289', (161, 166))	('small cell lung carcinoma', 'Phenotype', 'HP:0030357', (134, 159))	('NSCLC', 'Disease', (161, 166))	('Non-small cell lung carcinoma', 'Phenotype', 'HP:0030358', (130, 159))	('RASSF1A', 'Gene', '11186', (39, 46))	('NSCLC', 'Phenotype', 'HP:0030358', (161, 166))	('RASSF1A', 'Gene', (39, 46))	('non-small cell lung carcinoma', 'Phenotype', 'HP:0030358', (69, 98))
312102	32140600	The mutations in the Kirsten rat sarcoma (KRAS) are the most frequently oncogene aberrations in lung carcinoma patients.	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('Kirsten rat sarcoma', 'Gene', '3845', (21, 40))	('sarcoma', 'Phenotype', 'HP:0100242', (33, 40))	('Kirsten rat sarcoma', 'Gene', (21, 40))	('mutations', 'Var', (4, 13))	('lung carcinoma', 'Disease', (96, 110))	('lung carcinoma', 'Disease', 'MESH:D008175', (96, 110))	('patients', 'Species', '9606', (111, 119))
312104	32140600	We hypothesized that RASSF1A methylation and KRAS mutations may play an important role in NSCLC.	('methylation', 'Var', (29, 40))	('RASSF1A', 'Gene', (21, 28))	('mutations', 'Var', (50, 59))	('NSCLC', 'Disease', (90, 95))	('play', 'Reg', (64, 68))	('RASSF1A', 'Gene', '11186', (21, 28))	('NSCLC', 'Disease', 'MESH:D002289', (90, 95))	('role', 'Reg', (82, 86))	('KRAS', 'Gene', (45, 49))	('NSCLC', 'Phenotype', 'HP:0030358', (90, 95))
312105	32140600	Non-small cell lung carcinoma patients (n = 100) and equal number of healthy controls were assessed for activating KRAS (exon 2) mutations using allele-specific oligonucleotide polymerase chain reaction (ASO-PCR) and promoter hypermethylation of RASSF1A using methylation specific PCR.	('RASSF1A', 'Gene', '11186', (246, 253))	('carcinoma', 'Phenotype', 'HP:0030731', (20, 29))	('Non-small cell lung carcinoma', 'Phenotype', 'HP:0030358', (0, 29))	('mutations', 'Var', (129, 138))	('small cell lung carcinoma', 'Phenotype', 'HP:0030357', (4, 29))	('Non-small cell lung carcinoma', 'Disease', 'MESH:D002289', (0, 29))	('patients', 'Species', '9606', (30, 38))	('activating', 'PosReg', (104, 114))	('RASSF1A', 'Gene', (246, 253))	('Non-small cell lung carcinoma', 'Disease', (0, 29))
312106	32140600	The frequency of mutations in Kirsten rat sarcoma (KRAS) were found in 31% of NSCLC patients in the Kashmiri population and occur most commonly, but not exclusively, in adenocarcinoma histology and life-long smokers.	('adenocarcinoma', 'Disease', 'MESH:D000230', (169, 183))	('Kirsten rat sarcoma', 'Gene', '3845', (30, 49))	('NSCLC', 'Disease', 'MESH:D002289', (78, 83))	('patients', 'Species', '9606', (84, 92))	('sarcoma', 'Phenotype', 'HP:0100242', (42, 49))	('NSCLC', 'Phenotype', 'HP:0030358', (78, 83))	('Kirsten rat sarcoma', 'Gene', (30, 49))	('NSCLC', 'Disease', (78, 83))	('adenocarcinoma', 'Disease', (169, 183))	('carcinoma', 'Phenotype', 'HP:0030731', (174, 183))	('mutations', 'Var', (17, 26))
312107	32140600	The NSCLC patients in advanced stage reported the higher frequency of mutation in KRAS (exon 2).	('NSCLC', 'Disease', 'MESH:D002289', (4, 9))	('NSCLC', 'Phenotype', 'HP:0030358', (4, 9))	('patients', 'Species', '9606', (10, 18))	('KRAS', 'Gene', (82, 86))	('mutation', 'Var', (70, 78))	('NSCLC', 'Disease', (4, 9))
312110	32140600	The frequency of KRAS mutation and RASSF1A promoter methylation were significantly different between adenocarcinomas (ADC) and squamous cell carcinomas (SCC) patients with NSCLC (P < 0.03).	('mutation', 'Var', (22, 30))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (127, 151))	('RASSF1A', 'Gene', '11186', (35, 42))	('adenocarcinomas', 'Disease', 'MESH:D000230', (101, 116))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (127, 150))	('patients', 'Species', '9606', (158, 166))	('adenocarcinomas', 'Disease', (101, 116))	('SCC', 'Phenotype', 'HP:0002860', (153, 156))	('carcinomas', 'Phenotype', 'HP:0030731', (106, 116))	('squamous cell carcinomas', 'Disease', (127, 151))	('RASSF1A', 'Gene', (35, 42))	('different', 'Reg', (83, 92))	('SCC', 'Disease', 'MESH:D002294', (153, 156))	('ADC', 'Disease', 'MESH:D000230', (118, 121))	('NSCLC', 'Disease', 'MESH:D002289', (172, 177))	('ADC', 'Disease', (118, 121))	('KRAS', 'Gene', (17, 21))	('SCC', 'Disease', (153, 156))	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('NSCLC', 'Disease', (172, 177))	('carcinomas', 'Phenotype', 'HP:0030731', (141, 151))	('NSCLC', 'Phenotype', 'HP:0030358', (172, 177))	('methylation', 'Var', (52, 63))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (127, 151))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))
312111	32140600	In addition, we reported that NSCLC patients having RASSF1A promoter methylation was significantly associated with smoking (P = 0.01).	('NSCLC', 'Disease', 'MESH:D002289', (30, 35))	('patients', 'Species', '9606', (36, 44))	('RASSF1A', 'Gene', (52, 59))	('NSCLC', 'Phenotype', 'HP:0030358', (30, 35))	('methylation', 'Var', (69, 80))	('smoking', 'Disease', (115, 122))	('NSCLC', 'Disease', (30, 35))	('RASSF1A', 'Gene', '11186', (52, 59))	('associated', 'Reg', (99, 109))
312112	32140600	It was identified that NSCLC patients with RASSF1A promoter region hypermethylation had poorer survival and faster disease progression compared with those without hypermethylation of RASSF1A promoter region (P = 0.0001).	('patients', 'Species', '9606', (29, 37))	('NSCLC', 'Phenotype', 'HP:0030358', (23, 28))	('RASSF1A', 'Gene', '11186', (43, 50))	('disease progression', 'CPA', (115, 134))	('faster', 'PosReg', (108, 114))	('RASSF1A', 'Gene', (183, 190))	('hypermethylation', 'Var', (67, 83))	('NSCLC', 'Disease', (23, 28))	('poorer', 'NegReg', (88, 94))	('NSCLC', 'Disease', 'MESH:D002289', (23, 28))	('RASSF1A', 'Gene', '11186', (183, 190))	('survival', 'CPA', (95, 103))	('RASSF1A', 'Gene', (43, 50))
312113	32140600	The Median survivals among with cases containing promoter region hypermethylation of RASSF1A were 17.20 and 42.13 months for patients without promoter region hypermethylation of RASSF1A and the patients with KRAS mutation with or without hypermethylation of the promoter region of RASSF1A a tumor suppressor gene had poorer survival compared with those patients with wild type KRAS gene, with or without hypermethylation of RASSF1A promoter region.	('RASSF1A', 'Gene', (85, 92))	('RASSF1A', 'Gene', (178, 185))	('RASSF1A', 'Gene', (281, 288))	('patients', 'Species', '9606', (194, 202))	('hypermethylation', 'Var', (65, 81))	('RASSF1A', 'Gene', '11186', (424, 431))	('RASSF1A', 'Gene', '11186', (85, 92))	('RASSF1A', 'Gene', '11186', (178, 185))	('patients', 'Species', '9606', (353, 361))	('hypermethylation', 'Var', (238, 254))	('tumor', 'Disease', 'MESH:D009369', (291, 296))	('mutation', 'Var', (213, 221))	('RASSF1A', 'Gene', '11186', (281, 288))	('tumor', 'Phenotype', 'HP:0002664', (291, 296))	('poorer', 'NegReg', (317, 323))	('tumor', 'Disease', (291, 296))	('RASSF1A', 'Gene', (424, 431))	('patients', 'Species', '9606', (125, 133))
312114	32140600	The median survivals among patients with mutation in KRAS protooncogene were 16 months and 42 months for NSCLC patients with wild type KRAS gene.	('NSCLC', 'Disease', 'MESH:D002289', (105, 110))	('NSCLC', 'Phenotype', 'HP:0030358', (105, 110))	('mutation', 'Var', (41, 49))	('patients', 'Species', '9606', (27, 35))	('KRAS', 'Gene', (53, 57))	('NSCLC', 'Disease', (105, 110))	('patients', 'Species', '9606', (111, 119))
312115	32140600	The aberrant RASSF1A gene promoter methylation with the subsequent mutation in KRAS gene (exon 2) plays a significant role in the pathogenesis and disease progression of non-small cell lung carcinoma (NSCLC).	('RASSF1A', 'Gene', (13, 20))	('NSCLC', 'Phenotype', 'HP:0030358', (201, 206))	('mutation', 'Var', (67, 75))	('carcinoma', 'Phenotype', 'HP:0030731', (190, 199))	('aberrant', 'Var', (4, 12))	('small cell lung carcinoma', 'Phenotype', 'HP:0030357', (174, 199))	('KRAS gene', 'Gene', (79, 88))	('non-small cell lung carcinoma', 'Disease', 'MESH:D002289', (170, 199))	('RASSF1A', 'Gene', '11186', (13, 20))	('NSCLC', 'Disease', (201, 206))	('non-small cell lung carcinoma', 'Phenotype', 'HP:0030358', (170, 199))	('non-small cell lung carcinoma', 'Disease', (170, 199))	('methylation', 'Var', (35, 46))	('NSCLC', 'Disease', 'MESH:D002289', (201, 206))
312120	32140600	Non-small cell lung carcinoma (NSCLC) arise as a result of molecular, genetic and epigenetic alterations alongside with additional morphological changes that gives rise to neoplastic tissue by the transformation of benign bronchial epithelium.	('neoplastic tissue', 'Phenotype', 'HP:0002664', (172, 189))	('Non-small cell lung carcinoma', 'Phenotype', 'HP:0030358', (0, 29))	('alterations', 'Var', (93, 104))	('NSCLC', 'Disease', (31, 36))	('small cell lung carcinoma', 'Phenotype', 'HP:0030357', (4, 29))	('Non-small cell lung carcinoma', 'Disease', 'MESH:D002289', (0, 29))	('NSCLC', 'Disease', 'MESH:D002289', (31, 36))	('carcinoma', 'Phenotype', 'HP:0030731', (20, 29))	('NSCLC', 'Phenotype', 'HP:0030358', (31, 36))	('Non-small cell lung carcinoma', 'Disease', (0, 29))
312121	32140600	Genetic alterations in tumour suppressor and proto-oncogenes genes have been detected to play important role in all stages of lung tumourigenesis.	('tumour', 'Phenotype', 'HP:0002664', (23, 29))	('Genetic alterations', 'Var', (0, 19))	('tumour', 'Disease', (131, 137))	('tumour', 'Disease', 'MESH:D009369', (23, 29))	('tumour', 'Disease', (23, 29))	('tumour', 'Phenotype', 'HP:0002664', (131, 137))	('tumour', 'Disease', 'MESH:D009369', (131, 137))	('lung tumour', 'Phenotype', 'HP:0100526', (126, 137))
312122	32140600	Hypermethylation of CpG Island causing epigenetic silencing in the promoter has been shown to be an important phenomenon in cancer formation.	('cancer', 'Disease', (124, 130))	('epigenetic silencing in the', 'MPA', (39, 66))	('Hypermethylation', 'Var', (0, 16))	('men', 'Species', '9606', (115, 118))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('CpG', 'Protein', (20, 23))	('cancer', 'Disease', 'MESH:D009369', (124, 130))
312123	32140600	DNA methylation is an alternative mechanism to mutations or deletions which disrupt the function of tumor suppressor gene.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('deletions', 'Var', (60, 69))	('tumor', 'Disease', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('mutations', 'Var', (47, 56))	('disrupt', 'NegReg', (76, 83))	('function', 'MPA', (88, 96))
312124	32140600	Aberrant gene methylation in the promoter region in the tumor suppressor gene has also been most frequently found in NSCLC.	('found', 'Reg', (108, 113))	('NSCLC', 'Disease', (117, 122))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('Aberrant gene methylation in', 'Var', (0, 28))	('tumor', 'Disease', (56, 61))	('NSCLC', 'Disease', 'MESH:D002289', (117, 122))	('NSCLC', 'Phenotype', 'HP:0030358', (117, 122))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
312128	32140600	In particular NSCLC patients with lung adenocarcinomas have been shown to harbor most of the KRAS mutations.	('NSCLC', 'Disease', (14, 19))	('KRAS', 'Gene', (93, 97))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (34, 54))	('NSCLC', 'Disease', 'MESH:D002289', (14, 19))	('mutations', 'Var', (98, 107))	('lung adenocarcinomas', 'Disease', 'MESH:C538231', (34, 54))	('patients', 'Species', '9606', (20, 28))	('NSCLC', 'Phenotype', 'HP:0030358', (14, 19))	('carcinoma', 'Phenotype', 'HP:0030731', (44, 53))	('carcinomas', 'Phenotype', 'HP:0030731', (44, 54))	('lung adenocarcinomas', 'Disease', (34, 54))
312133	32140600	Transcriptional repression by methylation of promoter region is an important means for silencing of number of cancer-associated genes including RASSF1A.	('cancer', 'Disease', (110, 116))	('Transcriptional', 'MPA', (0, 15))	('methylation', 'Var', (30, 41))	('RASSF1A', 'Gene', (144, 151))	('RASSF1A', 'Gene', '11186', (144, 151))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('silencing', 'NegReg', (87, 96))
312134	32140600	RASSF1A conataining a Ras effector domain is ceded inactivated by epigenetics silencing of its promoter in a variety of human cancers including lung, colon, breast, prostate, thyroid, and renal cell carcinomas.	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (188, 209))	('inactivated', 'NegReg', (51, 62))	('cancers', 'Disease', 'MESH:D009369', (126, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (199, 208))	('carcinomas', 'Phenotype', 'HP:0030731', (199, 209))	('lung', 'Disease', (144, 148))	('human', 'Species', '9606', (120, 125))	('thyroid', 'Disease', (175, 182))	('breast', 'Disease', (157, 163))	('prostate', 'Disease', (165, 173))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('cancers', 'Phenotype', 'HP:0002664', (126, 133))	('RASSF1A', 'Gene', '11186', (0, 7))	('cancers', 'Disease', (126, 133))	('RASSF1A', 'Gene', (0, 7))	('renal cell carcinomas', 'Disease', 'MESH:D002292', (188, 209))	('colon', 'Disease', (150, 155))	('epigenetics silencing', 'Var', (66, 87))	('renal cell carcinomas', 'Disease', (188, 209))
312135	32140600	The purpose of this study was to examine the association between KRAS mutation and RASSF1A hypermethylation in non-small cell lung carcinoma, and to determine their correlation with clinicopathological characteristics.	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('association', 'Interaction', (45, 56))	('non-small cell lung carcinoma', 'Disease', 'MESH:D002289', (111, 140))	('non-small cell lung carcinoma', 'Phenotype', 'HP:0030358', (111, 140))	('RASSF1A', 'Gene', (83, 90))	('non-small cell lung carcinoma', 'Disease', (111, 140))	('hypermethylation', 'Var', (91, 107))	('RASSF1A', 'Gene', '11186', (83, 90))	('small cell lung carcinoma', 'Phenotype', 'HP:0030357', (115, 140))	('mutation', 'Var', (70, 78))	('KRAS', 'Gene', (65, 69))
312138	32140600	We have critically examined prospectively all newly diagnosed patients with NSCLC (n = 100) analysed for KRAS mutations and RASSF1A methylation.	('mutations', 'Var', (110, 119))	('NSCLC', 'Disease', (76, 81))	('KRAS', 'Gene', (105, 109))	('RASSF1A', 'Gene', (124, 131))	('patients', 'Species', '9606', (62, 70))	('NSCLC', 'Disease', 'MESH:D002289', (76, 81))	('RASSF1A', 'Gene', '11186', (124, 131))	('methylation', 'Var', (132, 143))	('NSCLC', 'Phenotype', 'HP:0030358', (76, 81))
312150	32140600	10 mul of each PCR product were resolved by loading onto 1.5% agarose gel, and the bands were visualized under UV trans-illumination by ethidium bromide staining A band size of 169bp was observed for both RASSF1A methylated and unmethylated set (Figure 2).	('RASSF1A', 'Gene', '11186', (205, 212))	('methylated', 'Var', (213, 223))	('ethidium bromide', 'Chemical', 'MESH:D004996', (136, 152))	('agarose', 'Chemical', 'MESH:D012685', (62, 69))	('RASSF1A', 'Gene', (205, 212))
312151	32140600	The association between the KRAS (exon 2) mutations as well as between methylation status of RASSF1A promoter region and various clinicopathological characteristics were statistically computed using Chi Square test ( 2) or Fisher's exact test.	('RASSF1A', 'Gene', (93, 100))	('mutations', 'Var', (42, 51))	('RASSF1A', 'Gene', '11186', (93, 100))
312152	32140600	Kaplan Meier survival analysis plots were used to evaluate the effect of methylation of RASSF1A and KRAS (exon 2) mutations on overall survival of NSCLC patients, and differences in the survival rate between two groups were compared using the Log-rank (Mantel-cox) test.	('NSCLC', 'Disease', (147, 152))	('patients', 'Species', '9606', (153, 161))	('NSCLC', 'Disease', 'MESH:D002289', (147, 152))	('mutations', 'Var', (114, 123))	('RASSF1A', 'Gene', '11186', (88, 95))	('NSCLC', 'Phenotype', 'HP:0030358', (147, 152))	('RASSF1A', 'Gene', (88, 95))
312160	32140600	Out of hundred NSCLC patients, 31 (31%) were positive for KRAS (exon 2) gene mutations and 69 (69%) were negative.	('NSCLC', 'Phenotype', 'HP:0030358', (15, 20))	('positive', 'Reg', (45, 53))	('patients', 'Species', '9606', (21, 29))	('NSCLC', 'Disease', (15, 20))	('mutations', 'Var', (77, 86))	('NSCLC', 'Disease', 'MESH:D002289', (15, 20))
312161	32140600	KRAS gene mutation was found in higher frequency in patients Adenocarcinoma (ADC) (29.16%) than in squamous cell carcinoma (SCC) (10%) histological types of lung cancer.	('carcinoma', 'Phenotype', 'HP:0030731', (66, 75))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('Adenocarcinoma', 'Disease', (61, 75))	('squamous cell carcinoma', 'Disease', (99, 122))	('lung cancer', 'Disease', (157, 168))	('mutation', 'Var', (10, 18))	('ADC', 'Disease', 'MESH:D000230', (77, 80))	('ADC', 'Disease', (77, 80))	('patients', 'Species', '9606', (52, 60))	('KRAS gene', 'Gene', (0, 9))	('SCC', 'Phenotype', 'HP:0002860', (124, 127))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (99, 122))	('lung cancer', 'Disease', 'MESH:D008175', (157, 168))	('Adenocarcinoma', 'Disease', 'MESH:D000230', (61, 75))	('SCC', 'Disease', 'MESH:D002294', (124, 127))	('lung cancer', 'Phenotype', 'HP:0100526', (157, 168))	('SCC', 'Disease', (124, 127))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (99, 122))
312162	32140600	There was a much difference in frequency of KRAS gene mutation in NSCLC patients with respect to gender however also the higher frequency of those mutations was reported in higher age group >45 (32.18%) than lower age group <=45 (23.08%) (Table 2).	('mutation', 'Var', (54, 62))	('NSCLC', 'Disease', (66, 71))	('KRAS gene', 'Gene', (44, 53))	('NSCLC', 'Disease', 'MESH:D002289', (66, 71))	('NSCLC', 'Phenotype', 'HP:0030358', (66, 71))	('patients', 'Species', '9606', (72, 80))
312163	32140600	The higher frequency of KRAS (exon 2) mutation among the different stages, NSCLC patients were found in advanced stage (42.55%) than the early stages (20.75%).	('NSCLC', 'Phenotype', 'HP:0030358', (75, 80))	('patients', 'Species', '9606', (81, 89))	('NSCLC', 'Disease', (75, 80))	('mutation', 'Var', (38, 46))	('NSCLC', 'Disease', 'MESH:D002289', (75, 80))
312164	32140600	Also the development of NSCLC was reported to be faster among the patients in advanced stage with KRAS (exon 2) mutations (Table 2).	('NSCLC', 'Disease', (24, 29))	('NSCLC', 'Disease', 'MESH:D002289', (24, 29))	('faster', 'PosReg', (49, 55))	('mutations', 'Var', (112, 121))	('men', 'Species', '9606', (16, 19))	('NSCLC', 'Phenotype', 'HP:0030358', (24, 29))	('patients', 'Species', '9606', (66, 74))
312165	32140600	We observed statistically significant higher frequencies of KRAS gene (exon 2) mutations in NSCLC patients who were ex-smokers (50%) and current smokers (40%) (OR = 0.182, 95% CI: 0.047-0.697, P < 0.01) (Table 2).	('NSCLC', 'Phenotype', 'HP:0030358', (92, 97))	('patients', 'Species', '9606', (98, 106))	('higher', 'PosReg', (38, 44))	('NSCLC', 'Disease', (92, 97))	('NSCLC', 'Disease', 'MESH:D002289', (92, 97))	('mutations', 'Var', (79, 88))
312166	32140600	The significantly higher frequency of the KRAS gene (exon 2) mutation was reported in NSCLC patients positive for metastasis (33.33%) with metastasis (OR = 0.941, 95% CI: 0.319-2.775, P < 0.03) (Table 2).	('NSCLC', 'Disease', (86, 91))	('mutation', 'Var', (61, 69))	('patients', 'Species', '9606', (92, 100))	('NSCLC', 'Disease', 'MESH:D002289', (86, 91))	('KRAS gene', 'Gene', (42, 51))	('NSCLC', 'Phenotype', 'HP:0030358', (86, 91))
312167	32140600	As far as the mutation frequency is concerned, 100 patients were investigated through screening by direct sequencing, 31% showed mutation in exon 2 corresponding to codons 12 and 13 of the KRAS proto-oncogene.	('KRAS', 'Gene', (189, 193))	('patients', 'Species', '9606', (51, 59))	('mutation in', 'Var', (129, 140))
312169	32140600	The most common mutations that was found in NSCLC patients are glycine (G) to cysteine (C) on codon 12 (p.G12C, 32.25% of mutated samples; 10 of 31) Figure 4, glycine (G) to valine (V) on codon 12 (p.G12V, 22.58% of mutated samples; 07 of 31) Figure 5, glycine (G) to aspartate (D) on codon 12 (p.G12D, 19.04% of mutated samples; 05 of 31), glycine (G) to aspartate (D) on codon 13 (p.G13D, 9.67% of mutated samples; 03 of 31).	('codon 12', 'Chemical', '-', (188, 196))	('valine', 'Chemical', 'MESH:D014633', (174, 180))	('codon 12', 'Chemical', '-', (94, 102))	('p.G13D', 'Mutation', 'rs112445441', (383, 389))	('glycine', 'Chemical', 'MESH:D005998', (159, 166))	('mutations', 'Var', (16, 25))	('cysteine', 'Chemical', 'MESH:D003545', (78, 86))	('NSCLC', 'Disease', 'MESH:D002289', (44, 49))	('patients', 'Species', '9606', (50, 58))	('glycine', 'Chemical', 'MESH:D005998', (63, 70))	('glycine', 'Chemical', 'MESH:D005998', (341, 348))	('aspartate', 'Chemical', 'MESH:D001224', (356, 365))	('p.G12V', 'Mutation', 'rs121913529', (198, 204))	('glycine', 'Chemical', 'MESH:D005998', (253, 260))	('aspartate', 'Chemical', 'MESH:D001224', (268, 277))	('NSCLC', 'Disease', (44, 49))	('p.G12C', 'Mutation', 'rs121913530', (104, 110))	('codon 12', 'Chemical', '-', (285, 293))	('NSCLC', 'Phenotype', 'HP:0030358', (44, 49))	('p.G12D', 'Mutation', 'rs121913529', (295, 301))
312170	32140600	The three mutations G12C, G12V, G12D account 70.96% of all the mutations.	('G12C', 'Var', (20, 24))	('G12D', 'Var', (32, 36))	('G12D', 'Mutation', 'rs121913529', (32, 36))	('G12V', 'Var', (26, 30))	('G12V', 'SUBSTITUTION', 'None', (26, 30))	('G12C', 'SUBSTITUTION', 'None', (20, 24))
312172	32140600	However when compared with healthy controls a statistical significant difference was observed (P = 0.03) with patients having RASSF1A gene methylation.	('RASSF1A', 'Gene', '11186', (126, 133))	('RASSF1A', 'Gene', (126, 133))	('patients', 'Species', '9606', (110, 118))	('methylation', 'Var', (139, 150))
312173	32140600	The result illustrated that methylation of RASSF1A promoter region is more frequent (41.0%) in NSCLC cases as against those in healthy controls (3.0%) (Table 3).	('NSCLC', 'Disease', 'MESH:D002289', (95, 100))	('RASSF1A', 'Gene', '11186', (43, 50))	('frequent', 'Reg', (75, 83))	('NSCLC', 'Phenotype', 'HP:0030358', (95, 100))	('methylation', 'Var', (28, 39))	('NSCLC', 'Disease', (95, 100))	('RASSF1A', 'Gene', (43, 50))
312174	32140600	Our results indicate that NSCLC patients who show hypermethylation of promoter region of RASSF1A gene have a statistical significant increased risk of developing NSCLC and can be a useful candidate biomarker in studying the prognosis of the disease.	('patients', 'Species', '9606', (32, 40))	('NSCLC', 'Disease', (162, 167))	('RASSF1A', 'Gene', '11186', (89, 96))	('NSCLC', 'Phenotype', 'HP:0030358', (26, 31))	('hypermethylation', 'Var', (50, 66))	('NSCLC', 'Disease', 'MESH:D002289', (162, 167))	('NSCLC', 'Disease', (26, 31))	('RASSF1A', 'Gene', (89, 96))	('NSCLC', 'Phenotype', 'HP:0030358', (162, 167))	('NSCLC', 'Disease', 'MESH:D002289', (26, 31))
312175	32140600	The association of RASSF1A aberrant gene promoter hypermethylation and age at diagnosis is described in Table 2.	('RASSF1A', 'Gene', '11186', (19, 26))	('RASSF1A', 'Gene', (19, 26))	('aberrant gene', 'Var', (27, 40))
312176	32140600	although methylation of RASSF1A gene was observed to be more evident in the age group >45 years (43.67%) as compared to the age group <=45 years (23.08%) (Table 2).	('methylation', 'Var', (9, 20))	('RASSF1A', 'Gene', '11186', (24, 31))	('RASSF1A', 'Gene', (24, 31))
312179	32140600	RASSF1A aberrant gene methylation was found to be the highest in NSCLC patients with Adenocarcinoma (52.77%) as compared to squamous cell carcinoma (25%).	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('RASSF1A', 'Gene', (0, 7))	('Adenocarcinoma', 'Disease', 'MESH:D000230', (85, 99))	('highest', 'Reg', (54, 61))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (124, 147))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('patients', 'Species', '9606', (71, 79))	('NSCLC', 'Disease', 'MESH:D002289', (65, 70))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (124, 147))	('squamous cell carcinoma', 'Disease', (124, 147))	('RASSF1A', 'Gene', '11186', (0, 7))	('NSCLC', 'Phenotype', 'HP:0030358', (65, 70))	('aberrant gene methylation', 'Var', (8, 33))	('Adenocarcinoma', 'Disease', (85, 99))	('NSCLC', 'Disease', (65, 70))
312180	32140600	A statistical significant association was found between the methylation status of RASSF1A gene with different histological types (OR = 0.621, 95% CI = 0.157-2.183, P < 0.05) (Table 2).	('methylation status', 'Var', (60, 78))	('significant association', 'Reg', (14, 37))	('RASSF1A', 'Gene', '11186', (82, 89))	('RASSF1A', 'Gene', (82, 89))
312181	32140600	The Follow-up of the 100 primary NSCLCs patients regarding disease progression in terms of survival was performed by using Kaplan-Meier survival plot we observed NSCLCs patients with RASSF1A aberrant gene promoter region hypermethylation had a poorer survival compared with those without hypermethylation of promoter region of RASSF1A gene, however these differences were statistically significant based on Log-rank (Mantel-cox) test (P = 0.0001).	('RASSF1A', 'Gene', '11186', (327, 334))	('NSCLC', 'Phenotype', 'HP:0030358', (33, 38))	('patients', 'Species', '9606', (169, 177))	('patients', 'Species', '9606', (40, 48))	('hypermethylation', 'Var', (221, 237))	('NSCLCs', 'Disease', (33, 39))	('NSCLCs', 'Disease', (162, 168))	('RASSF1A', 'Gene', (183, 190))	('poorer', 'NegReg', (244, 250))	('NSCLCs', 'Disease', 'MESH:D002289', (162, 168))	('RASSF1A', 'Gene', (327, 334))	('aberrant', 'Var', (191, 199))	('survival', 'MPA', (251, 259))	('RASSF1A', 'Gene', '11186', (183, 190))	('NSCLC', 'Phenotype', 'HP:0030358', (162, 167))	('NSCLCs', 'Disease', 'MESH:D002289', (33, 39))
312182	32140600	Median survivals among with NSCLC patients containing hypermethylation of promoter region of RASSF1A were 17.20 and 42.13 months for NSCLC patients without hypermethylation of RASSF1A promoter Figure 6(a).	('NSCLC', 'Disease', (28, 33))	('RASSF1A', 'Gene', '11186', (93, 100))	('patients', 'Species', '9606', (139, 147))	('NSCLC', 'Phenotype', 'HP:0030358', (133, 138))	('NSCLC', 'Disease', 'MESH:D002289', (28, 33))	('RASSF1A', 'Gene', (176, 183))	('hypermethylation', 'Var', (54, 70))	('RASSF1A', 'Gene', (93, 100))	('NSCLC', 'Disease', (133, 138))	('patients', 'Species', '9606', (34, 42))	('NSCLC', 'Phenotype', 'HP:0030358', (28, 33))	('RASSF1A', 'Gene', '11186', (176, 183))	('NSCLC', 'Disease', 'MESH:D002289', (133, 138))
312183	32140600	The NSCLC patients with KRAS (exon 2) mutation with or without RASSF1A promoter region hypermethylation had poorer survival compared with those patients with wild type KRAS gene, with or without RASSF1A promoter region hypermethylation.	('NSCLC', 'Disease', 'MESH:D002289', (4, 9))	('survival', 'MPA', (115, 123))	('RASSF1A', 'Gene', (195, 202))	('RASSF1A', 'Gene', (63, 70))	('poorer', 'NegReg', (108, 114))	('patients', 'Species', '9606', (144, 152))	('RASSF1A', 'Gene', '11186', (195, 202))	('NSCLC', 'Phenotype', 'HP:0030358', (4, 9))	('RASSF1A', 'Gene', '11186', (63, 70))	('mutation', 'Var', (38, 46))	('patients', 'Species', '9606', (10, 18))	('NSCLC', 'Disease', (4, 9))
312185	32140600	The analysis of aberrant RASSF1A promoter methylation when combined with KRAS (exon 2) mutation data, we found that only 9 of 72 (12.5%) patients with adenocarcinoma contained both a KRAS mutation and RASSF1A aberrant gene promoter methylation.	('carcinoma', 'Phenotype', 'HP:0030731', (156, 165))	('KRAS', 'Gene', (183, 187))	('mutation', 'Var', (188, 196))	('RASSF1A', 'Gene', (25, 32))	('aberrant', 'Var', (209, 217))	('adenocarcinoma', 'Disease', (151, 165))	('patients', 'Species', '9606', (137, 145))	('RASSF1A', 'Gene', '11186', (25, 32))	('RASSF1A', 'Gene', (201, 208))	('adenocarcinoma', 'Disease', 'MESH:D000230', (151, 165))	('contained', 'Reg', (166, 175))	('RASSF1A', 'Gene', '11186', (201, 208))
312186	32140600	Patients with squamous cell carcinomas 1 of 28 (3.57%) with promoter region methylation of RASSF1A contained a KRAS mutation (Table 4).	('carcinomas', 'Phenotype', 'HP:0030731', (28, 38))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (14, 37))	('RASSF1A', 'Gene', '11186', (91, 98))	('contained', 'Reg', (99, 108))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (14, 38))	('squamous cell carcinomas', 'Disease', (14, 38))	('Patients', 'Species', '9606', (0, 8))	('methylation', 'Var', (76, 87))	('KRAS mutation', 'Var', (111, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (28, 37))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (14, 38))	('RASSF1A', 'Gene', (91, 98))
312187	32140600	Our results indicated that the majority of the NSCLC patients with adenocarcinomas containing KRAS mutations lack RASSF1A aberrant gene promoter methylation.	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('carcinomas', 'Phenotype', 'HP:0030731', (72, 82))	('KRAS', 'Gene', (94, 98))	('patients', 'Species', '9606', (53, 61))	('NSCLC', 'Phenotype', 'HP:0030358', (47, 52))	('RASSF1A', 'Gene', (114, 121))	('mutations', 'Var', (99, 108))	('NSCLC', 'Disease', (47, 52))	('adenocarcinomas', 'Disease', 'MESH:D000230', (67, 82))	('lack', 'NegReg', (109, 113))	('adenocarcinomas', 'Disease', (67, 82))	('NSCLC', 'Disease', 'MESH:D002289', (47, 52))	('RASSF1A', 'Gene', '11186', (114, 121))
312190	32140600	The most common molecular events in the NSCLC are mutations in the KRAS gene, suggesting a significant role in lung tumour carcinogenesis.	('lung tumour', 'Phenotype', 'HP:0100526', (111, 122))	('role', 'Reg', (103, 107))	('mutations', 'Var', (50, 59))	('common', 'Reg', (9, 15))	('NSCLC', 'Phenotype', 'HP:0030358', (40, 45))	('KRAS', 'Gene', (67, 71))	('lung tumour carcinogenesis', 'Disease', (111, 137))	('NSCLC', 'Disease', (40, 45))	('lung tumour carcinogenesis', 'Disease', 'MESH:D063646', (111, 137))	('tumour', 'Phenotype', 'HP:0002664', (116, 122))	('NSCLC', 'Disease', 'MESH:D002289', (40, 45))
312191	32140600	The mutations in codons 12 and 13 in the KRAS gene are the most common in lung cancers.	('mutations in codons', 'Var', (4, 23))	('lung cancer', 'Phenotype', 'HP:0100526', (74, 85))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('lung cancers', 'Disease', 'MESH:D008175', (74, 86))	('lung cancers', 'Disease', (74, 86))	('lung cancers', 'Phenotype', 'HP:0100526', (74, 86))	('common', 'Reg', (64, 70))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('KRAS', 'Gene', (41, 45))
312192	32140600	In present study the frequency of KRAS gene (exon 2) mutations in NSCLC patients was 31%.	('NSCLC', 'Disease', (66, 71))	('KRAS gene', 'Gene', (34, 43))	('NSCLC', 'Disease', 'MESH:D002289', (66, 71))	('mutations', 'Var', (53, 62))	('NSCLC', 'Phenotype', 'HP:0030358', (66, 71))	('patients', 'Species', '9606', (72, 80))
312193	32140600	The frequency of KRAS mutation reported in the study of Sameer et al, was 22.64%, 39% in study of Plesec et al,, 32.7% in Yunxia et al, study and it was 37% in work of Brink et al,.	('Yunxia', 'Disease', 'None', (122, 128))	('mutation', 'Var', (22, 30))	('KRAS', 'Gene', (17, 21))	('Yunxia', 'Disease', (122, 128))
312194	32140600	The significant higher frequency of KRAS (exon 2) gene mutation was seen in non-small cell lung cancer patients with ADC histological type of (21%) than SCC (10%), however the difference between the histological subtypes was statistically significant (OR = 0.81, 95% CI = 0.257-2.588, p < 0.01).	('lung cancer', 'Phenotype', 'HP:0100526', (91, 102))	('higher', 'PosReg', (16, 22))	('non-small cell lung cancer', 'Disease', (76, 102))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (80, 102))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('ADC', 'Disease', 'MESH:D000230', (117, 120))	('SCC', 'Disease', 'MESH:D002294', (153, 156))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (76, 102))	('ADC', 'Disease', (117, 120))	('mutation', 'Var', (55, 63))	('SCC', 'Phenotype', 'HP:0002860', (153, 156))	('patients', 'Species', '9606', (103, 111))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (76, 102))	('SCC', 'Disease', (153, 156))
312195	32140600	We observed higher frequency of KRAS mutations were detected largely in patients with lung adenocarcinomas than NSCLC patients with squamous cell carcinomas of the lung.	('NSCLC', 'Phenotype', 'HP:0030358', (112, 117))	('carcinomas', 'Phenotype', 'HP:0030731', (146, 156))	('squamous cell carcinomas of the lung', 'Disease', 'MESH:D002294', (132, 168))	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (132, 156))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (86, 106))	('carcinomas', 'Phenotype', 'HP:0030731', (96, 106))	('lung adenocarcinomas', 'Disease', (86, 106))	('carcinomas of the lung', 'Phenotype', 'HP:0100526', (146, 168))	('NSCLC', 'Disease', (112, 117))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (132, 155))	('KRAS', 'Gene', (32, 36))	('mutations', 'Var', (37, 46))	('lung adenocarcinomas', 'Disease', 'MESH:C538231', (86, 106))	('NSCLC', 'Disease', 'MESH:D002289', (112, 117))	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('squamous cell carcinomas of the lung', 'Phenotype', 'HP:0030359', (132, 168))	('squamous cell carcinomas of the lung', 'Disease', (132, 168))	('patients', 'Species', '9606', (118, 126))	('patients', 'Species', '9606', (72, 80))
312196	32140600	In fact, in the study conducted by Ju et al,; Herbest et al,; Brando et al, found patients with adenocarcinoma have common mutation in KRAS gene.	('mutation', 'Var', (123, 131))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('patients', 'Species', '9606', (82, 90))	('KRAS', 'Gene', (135, 139))	('adenocarcinoma', 'Disease', (96, 110))	('adenocarcinoma', 'Disease', 'MESH:D000230', (96, 110))
312197	32140600	There was a much difference in frequency of KRAS gene mutation in NSCLC patients with respect to age however also the higher frequency of those mutations was reported in higher age group >45 (32.18%) than lower age group <=45 (23.01%).	('mutation', 'Var', (54, 62))	('NSCLC', 'Disease', (66, 71))	('KRAS gene', 'Gene', (44, 53))	('NSCLC', 'Disease', 'MESH:D002289', (66, 71))	('NSCLC', 'Phenotype', 'HP:0030358', (66, 71))	('patients', 'Species', '9606', (72, 80))
312198	32140600	In this study, our results revealed that the higher frequency of KRAS (exon 2) mutations among the different stages was reported in NSCLC patients in advanced stage (III &IV) (42.55%) than the early stages (I & II) (20.75%).	('NSCLC', 'Phenotype', 'HP:0030358', (132, 137))	('NSCLC', 'Disease', (132, 137))	('NSCLC', 'Disease', 'MESH:D002289', (132, 137))	('patients', 'Species', '9606', (138, 146))	('mutations', 'Var', (79, 88))
312200	32140600	A similar studies conducted Mascaux et al,; Johnson et al, showed from a clinical perspective, KRAS-mutant lung carcinomas have been generally associated with type of tumours, particularly found mostly in the advanced-stage setting.	('tumour', 'Phenotype', 'HP:0002664', (167, 173))	('associated', 'Reg', (143, 153))	('tumours', 'Phenotype', 'HP:0002664', (167, 174))	('lung carcinomas', 'Disease', (107, 122))	('KRAS-mutant', 'Var', (95, 106))	('type of tumours', 'Disease', 'MESH:D009369', (159, 174))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('carcinomas', 'Phenotype', 'HP:0030731', (112, 122))	('type of tumours', 'Disease', (159, 174))	('lung carcinomas', 'Disease', 'MESH:D008175', (107, 122))
312201	32140600	found higher frequency of KRAS gene mutations in patients who are having history of long-life smoking and the study by El Osta et al, found KRAS mutations are typically found more often in the patients who are heavy smokers and KRAS mutations rarely occur in lung cancers in light or never smokers.	('patients', 'Species', '9606', (193, 201))	('lung cancer', 'Phenotype', 'HP:0100526', (259, 270))	('lung cancers', 'Disease', 'MESH:D008175', (259, 271))	('found', 'Reg', (169, 174))	('KRAS gene', 'Gene', (26, 35))	('Osta', 'Gene', '200931', (122, 126))	('mutations', 'Var', (145, 154))	('cancer', 'Phenotype', 'HP:0002664', (264, 270))	('lung cancers', 'Phenotype', 'HP:0100526', (259, 271))	('mutations', 'Var', (36, 45))	('Osta', 'Gene', (122, 126))	('lung cancers', 'Disease', (259, 271))	('patients', 'Species', '9606', (49, 57))	('cancers', 'Phenotype', 'HP:0002664', (264, 271))	('KRAS', 'Gene', (140, 144))
312202	32140600	Our results showed higher incidence KRAS gene (exon 2) mutations in patients with distant organ metastasis.	('patients', 'Species', '9606', (68, 76))	('distant organ metastasis', 'CPA', (82, 106))	('mutations', 'Var', (55, 64))
312203	32140600	Wagner et al, found a significant association of K-RAS mutation and metastasis in NSCLC patients.	('association', 'Interaction', (34, 45))	('NSCLC', 'Phenotype', 'HP:0030358', (82, 87))	('K-RAS', 'Gene', '3845', (49, 54))	('patients', 'Species', '9606', (88, 96))	('K-RAS', 'Gene', (49, 54))	('metastasis', 'CPA', (68, 78))	('mutation', 'Var', (55, 63))	('NSCLC', 'Disease', (82, 87))	('NSCLC', 'Disease', 'MESH:D002289', (82, 87))
312205	32140600	In a total of 100 primary NSCLC cases diagnosed, the KRAS (exon 2) mutations were found in 31 of 100 cases (30%).	('NSCLC', 'Phenotype', 'HP:0030358', (26, 31))	('found', 'Reg', (82, 87))	('mutations', 'Var', (67, 76))	('NSCLC', 'Disease', (26, 31))	('NSCLC', 'Disease', 'MESH:D002289', (26, 31))
312207	32140600	In another studies by Macerellia et al,; Riely et al,; Dogan et al, evaluated most activating KRAS (exon 2) mutations in NSCLC are sited in codons 12 or 13.	('mutations', 'Var', (108, 117))	('NSCLC', 'Disease', (121, 126))	('NSCLC', 'Disease', 'MESH:D002289', (121, 126))	('activating', 'PosReg', (83, 93))	('NSCLC', 'Phenotype', 'HP:0030358', (121, 126))
312208	32140600	Further, mutations in KRAS detected in this study were diverse comprising 31, out of which, 10 were KRAS c.34G > T transversion, and 8 were KRAS c.35G > T transversion, 5 were KRAS c.35G > A transition, 4 were KRAS c.34G > A transition, 2 was KRAS c.34G > C transversion on codon 12 and 2 were KRAS c.38G > A on codon 13.	('KRAS c.34G > C', 'Var', (243, 257))	('c.35G > A', 'Mutation', 'rs121913529', (181, 190))	('KRAS c.35G > A', 'Var', (176, 190))	('c.34G > C', 'Mutation', 'rs121913530', (248, 257))	('c.34G > T', 'Mutation', 'rs121913530', (105, 114))	('mutations', 'Var', (9, 18))	('c.38G > A', 'Mutation', 'rs112445441', (299, 308))	('KRAS c.34G > A', 'Var', (210, 224))	('KRAS', 'Gene', (22, 26))	('KRAS c.34G > T transversion', 'Var', (100, 127))	('c.35G > T', 'Mutation', 'rs121913529', (145, 154))	('KRAS c.35G > T', 'Var', (140, 154))	('codon 12', 'Chemical', '-', (274, 282))	('c.34G > A', 'Mutation', 'rs121913530', (215, 224))
312209	32140600	Riely et al, showed NSCLC KRAS mutations mainly occur as transversion mutations.	('NSCLC', 'Phenotype', 'HP:0030358', (20, 25))	('NSCLC', 'Disease', 'MESH:D002289', (20, 25))	('mutations', 'Var', (31, 40))	('NSCLC', 'Disease', (20, 25))
312210	32140600	The aberrant promoter hypermethylation of RASSF1A gene has been witnessed in a variety of human carcinomas such as pancreatic endocrine tumor, colorectal carcinoma, nasopharyngeal carcinoma, prostate carcinoma, ovary and renal carcinoma, hepatocellular carcinoma, breast cancer, NSCLC, gastric cancer as depicted in the Figure 7.	('carcinoma', 'Disease', 'MESH:D002277', (180, 189))	('carcinoma', 'Disease', (154, 163))	('endocrine tumor', 'Phenotype', 'HP:0100568', (126, 141))	('renal carcinoma', 'Phenotype', 'HP:0005584', (221, 236))	('carcinoma', 'Phenotype', 'HP:0030731', (200, 209))	('NSCLC', 'Disease', (279, 284))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (165, 189))	('human', 'Species', '9606', (90, 95))	('prostate carcinoma', 'Disease', (191, 209))	('hepatocellular carcinoma', 'Disease', (238, 262))	('carcinoma', 'Disease', (200, 209))	('promoter', 'MPA', (13, 21))	('NSCLC', 'Phenotype', 'HP:0030358', (279, 284))	('gastric cancer', 'Disease', 'MESH:D013274', (286, 300))	('carcinoma', 'Disease', 'MESH:D002277', (227, 236))	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('carcinomas', 'Phenotype', 'HP:0030731', (96, 106))	('carcinomas', 'Disease', 'MESH:D002277', (96, 106))	('cancer', 'Phenotype', 'HP:0002664', (271, 277))	('carcinoma', 'Disease', (96, 105))	('RASSF1A', 'Gene', '11186', (42, 49))	('carcinoma', 'Disease', 'MESH:D002277', (154, 163))	('carcinoma', 'Disease', (253, 262))	('pancreatic endocrine tumor', 'Disease', (115, 141))	('cancer', 'Phenotype', 'HP:0002664', (294, 300))	('carcinoma', 'Disease', 'MESH:D002277', (200, 209))	('carcinoma', 'Phenotype', 'HP:0030731', (180, 189))	('RASSF1A', 'Gene', (42, 49))	('gastric cancer', 'Phenotype', 'HP:0012126', (286, 300))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (238, 262))	('carcinoma', 'Disease', (180, 189))	('breast cancer', 'Phenotype', 'HP:0003002', (264, 277))	('prostate carcinoma', 'Disease', 'MESH:D011471', (191, 209))	('carcinoma', 'Disease', 'MESH:D002277', (96, 105))	('pancreatic endocrine tumor', 'Disease', 'MESH:D010190', (115, 141))	('pancreatic endocrine tumor', 'Phenotype', 'HP:0030405', (115, 141))	('carcinoma', 'Phenotype', 'HP:0030731', (227, 236))	('carcinoma', 'Disease', (227, 236))	('breast cancer', 'Disease', 'MESH:D001943', (264, 277))	('carcinomas', 'Disease', (96, 106))	('aberrant', 'Var', (4, 12))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (238, 262))	('carcinoma', 'Disease', 'MESH:D002277', (253, 262))	('breast cancer', 'Disease', (264, 277))	('NSCLC', 'Disease', 'MESH:D002289', (279, 284))	('colorectal carcinoma', 'Disease', (143, 163))	('prostate carcinoma', 'Phenotype', 'HP:0012125', (191, 209))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('ovary and renal carcinoma', 'Disease', 'MESH:D010051', (211, 236))	('carcinoma', 'Phenotype', 'HP:0030731', (154, 163))	('gastric cancer', 'Disease', (286, 300))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (143, 163))
312211	32140600	Most of the recent studies have reported that an epigenetic changes result in many types of carcinomas.	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('result in', 'Reg', (68, 77))	('carcinomas', 'Phenotype', 'HP:0030731', (92, 102))	('carcinomas', 'Disease', (92, 102))	('carcinomas', 'Disease', 'MESH:D002277', (92, 102))	('epigenetic changes', 'Var', (49, 67))
312213	32140600	The DNA hypomethylation is probable contributors to oncogenesis and are mediated by various mechanisms that include aberrant hyper-methylation of tumor suppressor genes and chromosomal instability in various human cancers.	('hyper-methylation', 'Var', (125, 142))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('cancers', 'Phenotype', 'HP:0002664', (214, 221))	('contributors', 'Reg', (36, 48))	('cancers', 'Disease', (214, 221))	('tumor', 'Disease', (146, 151))	('cancers', 'Disease', 'MESH:D009369', (214, 221))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('oncogenesis', 'CPA', (52, 63))	('human', 'Species', '9606', (208, 213))	('chromosomal instability', 'Phenotype', 'HP:0040012', (173, 196))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
312215	32140600	The aberrant methylation particularly in CpG islands of promoter regions the RASSF1A gene that may play an important role in the progression and development of lung carcinoma.	('methylation', 'MPA', (13, 24))	('RASSF1A', 'Gene', '11186', (77, 84))	('role', 'Reg', (117, 121))	('lung carcinoma', 'Disease', 'MESH:D008175', (160, 174))	('aberrant', 'Var', (4, 12))	('men', 'Species', '9606', (152, 155))	('lung carcinoma', 'Disease', (160, 174))	('carcinoma', 'Phenotype', 'HP:0030731', (165, 174))	('RASSF1A', 'Gene', (77, 84))
312216	32140600	In this study, we observed that RASSF1A promoter methylation was present in 41% in NSCLC patients.	('RASSF1A', 'Gene', '11186', (32, 39))	('NSCLC', 'Disease', (83, 88))	('NSCLC', 'Disease', 'MESH:D002289', (83, 88))	('RASSF1A', 'Gene', (32, 39))	('patients', 'Species', '9606', (89, 97))	('NSCLC', 'Phenotype', 'HP:0030358', (83, 88))	('methylation', 'Var', (49, 60))
312217	32140600	This frequency of RASSF1A aberrant gene promoter region hypermethylation according to the present study is consistent with the findings reported by other groups.	('aberrant', 'Var', (26, 34))	('RASSF1A', 'Gene', '11186', (18, 25))	('RASSF1A', 'Gene', (18, 25))
312218	32140600	The aberrant RASSF1A gene promoter region hypermethylation was found to be significantly associated with different histological types, however higher frequencies were found in adenocarcinoma subtype than squamous cell carcinoma sub type (P = 0.03).	('RASSF1A', 'Gene', (13, 20))	('associated', 'Reg', (89, 99))	('hypermethylation', 'Var', (42, 58))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (204, 227))	('aberrant', 'Var', (4, 12))	('carcinoma', 'Phenotype', 'HP:0030731', (218, 227))	('adenocarcinoma subtype than squamous cell carcinoma sub type', 'Disease', 'MESH:D002294', (176, 236))	('RASSF1A', 'Gene', '11186', (13, 20))	('higher', 'PosReg', (143, 149))	('carcinoma', 'Phenotype', 'HP:0030731', (181, 190))
312219	32140600	We also found that RASSF1A gene aberrant promoter region hypermethylation predominantly occurs in NSCLC patients with advanced stage of disease.	('RASSF1A', 'Gene', '11186', (19, 26))	('NSCLC', 'Phenotype', 'HP:0030358', (98, 103))	('NSCLC', 'Disease', (98, 103))	('aberrant', 'Var', (32, 40))	('RASSF1A', 'Gene', (19, 26))	('patients', 'Species', '9606', (104, 112))	('NSCLC', 'Disease', 'MESH:D002289', (98, 103))	('occurs', 'Reg', (88, 94))
312220	32140600	In the present study, we observed that an aberrant promoter methylation of the RASSF1A gene and distant organ metastasis status although could be of prognostic significance.	('RASSF1A', 'Gene', '11186', (79, 86))	('RASSF1A', 'Gene', (79, 86))	('promoter', 'MPA', (51, 59))	('aberrant', 'Var', (42, 50))
312221	32140600	These results suggest that aberrant RASSF1A gene methylation in promoter region accompanies the induction and progression toward a more aggressive form of NSCLC genesis process.	('RASSF1A', 'Gene', '11186', (36, 43))	('aberrant', 'Var', (27, 35))	('accompanies', 'Reg', (80, 91))	('NSCLC', 'Disease', (155, 160))	('NSCLC', 'Disease', 'MESH:D002289', (155, 160))	('RASSF1A', 'Gene', (36, 43))	('methylation', 'Var', (49, 60))	('NSCLC', 'Phenotype', 'HP:0030358', (155, 160))
312223	32140600	However there was no statistical significant correlation found between RASSF1A gene aberrant promoter region hypermethylation and other various clinicopathological characteristics like age, gender and smoking level (light, moderate and heavy).	('RASSF1A', 'Gene', (71, 78))	('aberrant', 'Var', (84, 92))	('RASSF1A', 'Gene', '11186', (71, 78))	('hypermethylation', 'Var', (109, 125))
312224	32140600	This study reveals that smoking is significantly associated with RASSF1A gene promoter region hypermethylation in NSCLC patients (OR = 3.099, 95%CI = 1.167-4.443, P = 0.01) and that hypermethylation of the RASSF1A gene in the promoter region may affect a patient's overall survival in NSCLC.	('overall', 'MPA', (265, 272))	('NSCLC', 'Phenotype', 'HP:0030358', (114, 119))	('RASSF1A', 'Gene', (206, 213))	('patient', 'Species', '9606', (120, 127))	('NSCLC', 'Disease', (285, 290))	('associated', 'Reg', (49, 59))	('RASSF1A', 'Gene', (65, 72))	('hypermethylation', 'Var', (94, 110))	('NSCLC', 'Disease', (114, 119))	('affect', 'Reg', (246, 252))	('patient', 'Species', '9606', (255, 262))	('NSCLC', 'Disease', 'MESH:D002289', (285, 290))	('RASSF1A', 'Gene', '11186', (206, 213))	('RASSF1A', 'Gene', '11186', (65, 72))	('NSCLC', 'Disease', 'MESH:D002289', (114, 119))	('patients', 'Species', '9606', (120, 128))	('NSCLC', 'Phenotype', 'HP:0030358', (285, 290))	('hypermethylation', 'Var', (182, 198))
312225	32140600	According to methylation status of RASSF1A gene promoter region in NSCLC patients indicated that the overall survival of NSCLC patients group with methylation in RASSF1A gene promoter region had an obviously shorter survival time than those in the un-methylation group (P = 0.001).	('RASSF1A', 'Gene', (35, 42))	('NSCLC', 'Phenotype', 'HP:0030358', (67, 72))	('survival time', 'CPA', (216, 229))	('NSCLC', 'Disease', (121, 126))	('NSCLC', 'Phenotype', 'HP:0030358', (121, 126))	('RASSF1A', 'Gene', (162, 169))	('methylation', 'Var', (147, 158))	('patients', 'Species', '9606', (127, 135))	('NSCLC', 'Disease', 'MESH:D002289', (121, 126))	('RASSF1A', 'Gene', '11186', (35, 42))	('NSCLC', 'Disease', (67, 72))	('shorter', 'NegReg', (208, 215))	('patients', 'Species', '9606', (73, 81))	('NSCLC', 'Disease', 'MESH:D002289', (67, 72))	('RASSF1A', 'Gene', '11186', (162, 169))
312226	32140600	Hypermethylation of the RASSF1A gene promoter and advanced stage (III and IV) disease were also associated with poorer overall survival among NSCLC patients.	('patients', 'Species', '9606', (148, 156))	('NSCLC', 'Disease', (142, 147))	('Hypermethylation', 'Var', (0, 16))	('RASSF1A', 'Gene', (24, 31))	('NSCLC', 'Disease', 'MESH:D002289', (142, 147))	('overall survival', 'MPA', (119, 135))	('RASSF1A', 'Gene', '11186', (24, 31))	('NSCLC', 'Phenotype', 'HP:0030358', (142, 147))	('poorer', 'NegReg', (112, 118))
312227	32140600	These results suggest that hypermethylation and staging of the RASSF1A are independent prognostic factors in NSCLC.	('hypermethylation', 'Var', (27, 43))	('NSCLC', 'Disease', 'MESH:D002289', (109, 114))	('RASSF1A', 'Gene', (63, 70))	('NSCLC', 'Phenotype', 'HP:0030358', (109, 114))	('RASSF1A', 'Gene', '11186', (63, 70))	('NSCLC', 'Disease', (109, 114))
312229	32140600	In conclusion, the data suggests that methylation of RASSF1A gene promoter region in NSCLC patients might be specifically closely associated to males patients, smokers, patients in advanced stage of the disease, patients who have adenocarcinoma histological type of NSCLC, metastatic stage of disease and patients aged >45years.	('NSCLC', 'Disease', (85, 90))	('adenocarcinoma', 'Disease', (230, 244))	('patients', 'Species', '9606', (169, 177))	('NSCLC', 'Disease', 'MESH:D002289', (266, 271))	('NSCLC', 'Disease', 'MESH:D002289', (85, 90))	('patients', 'Species', '9606', (91, 99))	('methylation', 'Var', (38, 49))	('NSCLC', 'Phenotype', 'HP:0030358', (85, 90))	('patients', 'Species', '9606', (212, 220))	('NSCLC', 'Phenotype', 'HP:0030358', (266, 271))	('adenocarcinoma', 'Disease', 'MESH:D000230', (230, 244))	('patients', 'Species', '9606', (305, 313))	('carcinoma', 'Phenotype', 'HP:0030731', (235, 244))	('patients', 'Species', '9606', (150, 158))	('RASSF1A', 'Gene', (53, 60))	('NSCLC', 'Disease', (266, 271))	('RASSF1A', 'Gene', '11186', (53, 60))	('associated', 'Reg', (130, 140))
312230	32140600	Although aberrant methylation of promoter region of RASSF1A gene located at 3p21is the region frequently methylated in non-small cell lung cancer, and it's also frequently hypermethylated in non-small cell lung cancer with a history of smoking (51.61%) the results were consistent with the studies conducted by Han et al and Huang et al http://clincancerres.aacrjournals.org/content/10/18/6119 - ref-17.	('cancer', 'Disease', 'MESH:D009369', (348, 354))	('aberrant', 'Var', (9, 17))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (123, 145))	('RASSF1A', 'Gene', '11186', (52, 59))	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (191, 217))	('cancer', 'Disease', 'MESH:D009369', (211, 217))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (119, 145))	('RASSF1A', 'Gene', (52, 59))	('cancer', 'Disease', (348, 354))	('lung cancer', 'Phenotype', 'HP:0100526', (134, 145))	('non-small cell lung cancer', 'Disease', (191, 217))	('methylation', 'MPA', (18, 29))	('lung cancer', 'Phenotype', 'HP:0100526', (206, 217))	('non-small cell lung cancer', 'Disease', (119, 145))	('cancer', 'Phenotype', 'HP:0002664', (348, 354))	('cancer', 'Disease', (139, 145))	('cancer', 'Disease', (211, 217))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (195, 217))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (191, 217))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (119, 145))	('methylated', 'Var', (105, 115))
312231	32140600	In the present study, we systematically evulated the correlation between activating KRAS (exon 2) mutations and RASSF1A aberrant promoter hypermethylation in the NSCLC patients were It was observed that 21 of 72 (29.16%) of the adenocarcinomas (ADC) and 10 of 28 (35.71%) of squamous cell carcinomas (SCC) histological subtypes contained activating KRAS (exon 2) mutations restricted to codon 12 or 13.	('codon 12', 'Chemical', '-', (387, 395))	('carcinoma', 'Phenotype', 'HP:0030731', (289, 298))	('carcinomas', 'Phenotype', 'HP:0030731', (289, 299))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (275, 299))	('SCC', 'Phenotype', 'HP:0002860', (301, 304))	('KRAS (exon 2', 'Gene', (349, 361))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (275, 299))	('SCC', 'Disease', 'MESH:D002294', (301, 304))	('NSCLC', 'Disease', 'MESH:D002289', (162, 167))	('mutations', 'Var', (363, 372))	('ADC', 'Disease', 'MESH:D000230', (245, 248))	('ADC', 'Disease', (245, 248))	('SCC', 'Disease', (301, 304))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (275, 298))	('RASSF1A', 'Gene', '11186', (112, 119))	('NSCLC', 'Disease', (162, 167))	('squamous cell carcinomas', 'Disease', (275, 299))	('activating', 'PosReg', (338, 348))	('NSCLC', 'Phenotype', 'HP:0030358', (162, 167))	('RASSF1A', 'Gene', (112, 119))	('patients', 'Species', '9606', (168, 176))	('adenocarcinomas', 'Disease', 'MESH:D000230', (228, 243))	('adenocarcinomas', 'Disease', (228, 243))	('carcinoma', 'Phenotype', 'HP:0030731', (233, 242))	('carcinomas', 'Phenotype', 'HP:0030731', (233, 243))
312233	32140600	Our results showed that aberrant RASSF1A promoter region methylation was observed in 38 of 72 (52.77%) of adenocarcinomas and 3 of 28 (10.71%) of squamous cell carcinomas histological subtypes in NSCLC patients.	('carcinoma', 'Phenotype', 'HP:0030731', (160, 169))	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('carcinomas', 'Phenotype', 'HP:0030731', (111, 121))	('NSCLC', 'Disease', 'MESH:D002289', (196, 201))	('aberrant', 'Var', (24, 32))	('patients', 'Species', '9606', (202, 210))	('methylation', 'MPA', (57, 68))	('carcinomas', 'Phenotype', 'HP:0030731', (160, 170))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (146, 170))	('adenocarcinomas', 'Disease', 'MESH:D000230', (106, 121))	('RASSF1A', 'Gene', '11186', (33, 40))	('NSCLC', 'Disease', (196, 201))	('adenocarcinomas', 'Disease', (106, 121))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (146, 170))	('NSCLC', 'Phenotype', 'HP:0030358', (196, 201))	('RASSF1A', 'Gene', (33, 40))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (146, 169))	('squamous cell carcinomas', 'Disease', (146, 170))	('observed', 'Reg', (73, 81))
312234	32140600	When KRAS mutations and RASSF1A gene methylation status data were combined, we observed that only 9 of 52 (12.5%) of lung adenocarcinomas and 1 of 28 (3.57%) of squamous cell carcinomas contains both a KRAS mutation and RASSF1A gene methylation (Table 4).	('lung adenocarcinomas', 'Disease', (117, 137))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (161, 185))	('squamous cell carcinomas', 'Disease', (161, 185))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (117, 137))	('RASSF1A', 'Gene', (220, 227))	('RASSF1A', 'Gene', (24, 31))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (161, 185))	('RASSF1A', 'Gene', '11186', (220, 227))	('RASSF1A', 'Gene', '11186', (24, 31))	('carcinoma', 'Phenotype', 'HP:0030731', (175, 184))	('carcinomas', 'Phenotype', 'HP:0030731', (175, 185))	('KRAS', 'Gene', (202, 206))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (161, 184))	('mutation', 'Var', (207, 215))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('lung adenocarcinomas', 'Disease', 'MESH:C538231', (117, 137))	('carcinomas', 'Phenotype', 'HP:0030731', (127, 137))
312235	32140600	In this study, the data evaluated together with previous study, specified that the majority of NSCLC patients with adenocarcinomas and squamous cell carcinomas containing activating KRAS gene mutations lack RASSF1A promoter methylation.	('lack', 'NegReg', (202, 206))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (135, 159))	('NSCLC', 'Disease', 'MESH:D002289', (95, 100))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (135, 158))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (135, 159))	('carcinomas', 'Phenotype', 'HP:0030731', (120, 130))	('mutations', 'Var', (192, 201))	('NSCLC', 'Disease', (95, 100))	('patients', 'Species', '9606', (101, 109))	('NSCLC', 'Phenotype', 'HP:0030358', (95, 100))	('squamous cell carcinomas', 'Disease', (135, 159))	('adenocarcinomas', 'Disease', 'MESH:D000230', (115, 130))	('adenocarcinomas', 'Disease', (115, 130))	('activating', 'PosReg', (171, 181))	('RASSF1A', 'Gene', '11186', (207, 214))	('carcinoma', 'Phenotype', 'HP:0030731', (149, 158))	('carcinomas', 'Phenotype', 'HP:0030731', (149, 159))	('RASSF1A', 'Gene', (207, 214))	('KRAS', 'Gene', (182, 186))
312238	31433976	LSD1 Inhibition Promotes Epithelial Differentiation through Derepression of Fate-Determining Transcription Factors Self-renewing somatic tissues depend upon the proper balance of chromatin-modifying enzymes to coordinate progenitor cell maintenance and differentiation, disruption of which can promote carcinogenesis.	('LSD1', 'Gene', '23028', (0, 4))	('disruption', 'Var', (270, 280))	('promote', 'PosReg', (294, 301))	('Derepression', 'MPA', (60, 72))	('Inhibition', 'Var', (5, 15))	('Epithelial Differentiation', 'CPA', (25, 51))	('LSD1', 'Gene', (0, 4))	('carcinogenesis', 'Disease', (302, 316))	('Promotes', 'PosReg', (16, 24))
312241	31433976	LSD1 inhibitors block both LSD1 binding to chromatin and its catalytic activity, driving significant increases in H3K4 methylation and gene transcription of these fate-determining transcription factors.	('LSD1', 'Gene', (27, 31))	('H3K4', 'Protein', (114, 118))	('LSD1', 'Gene', '23028', (0, 4))	('H3', 'Chemical', 'MESH:C012616', (114, 116))	('inhibitors', 'Var', (5, 15))	('increases', 'PosReg', (101, 110))	('catalytic activity', 'MPA', (61, 79))	('block', 'NegReg', (16, 21))	('gene transcription', 'MPA', (135, 153))	('binding', 'Interaction', (32, 39))	('methylation', 'MPA', (119, 130))	('LSD1', 'Gene', (0, 4))	('LSD1', 'Gene', '23028', (27, 31))
312243	31433976	Together these data highlight both LSD1's role in maintaining the epidermal progenitor state and the potential of LSD1 inhibitors for the treatment of keratinocyte cancers, which collectively outnumber all other cancers combined.	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('rat', 'Species', '10116', (153, 156))	('inhibitors', 'Var', (119, 129))	('LSD1', 'Gene', (35, 39))	('cancers', 'Phenotype', 'HP:0002664', (164, 171))	('LSD1', 'Gene', (114, 118))	('cancers', 'Phenotype', 'HP:0002664', (212, 219))	('LSD1', 'Gene', '23028', (35, 39))	('cancers', 'Disease', (164, 171))	('LSD1', 'Gene', '23028', (114, 118))	('cancers', 'Disease', 'MESH:D009369', (164, 171))	('cancers', 'Disease', 'MESH:D009369', (212, 219))	('cancers', 'Disease', (212, 219))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))
312244	31433976	demonstrate that inhibition of the epigenetic regulator and histone demethylase, LSD1, promotes activation of the epidermal differentiation transcriptional program and, in turn, represses the invasion of cutaneous squamous cell carcinoma, one of the most common of all human cancers.	('represses', 'NegReg', (178, 187))	('cutaneous squamous cell carcinoma', 'Disease', (204, 237))	('cancer', 'Phenotype', 'HP:0002664', (275, 281))	('carcinoma', 'Phenotype', 'HP:0030731', (228, 237))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (214, 237))	('inhibition', 'Var', (17, 27))	('invasion', 'CPA', (192, 200))	('human', 'Species', '9606', (269, 274))	('rat', 'Species', '10116', (7, 10))	('cancers', 'Phenotype', 'HP:0002664', (275, 282))	('cutaneous squamous cell carcinoma', 'Phenotype', 'HP:0006739', (204, 237))	('cutaneous squamous cell carcinoma', 'Disease', 'MESH:D002294', (204, 237))	('epidermal differentiation transcriptional program', 'Pathway', (114, 163))	('cancers', 'Disease', 'MESH:D009369', (275, 282))	('LSD1', 'Gene', '23028', (81, 85))	('LSD1', 'Gene', (81, 85))	('activation', 'PosReg', (96, 106))	('cancers', 'Disease', (275, 282))
312245	31433976	Mutations in chromatin modifiers occur in approximately 50% of all human cancers and are often associated with poor disease prognosis.	('cancers', 'Disease', (73, 80))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('occur', 'Reg', (33, 38))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('Mutations', 'Var', (0, 9))	('human', 'Species', '9606', (67, 72))	('associated', 'Reg', (95, 105))	('cancers', 'Disease', 'MESH:D009369', (73, 80))
312246	31433976	By altering chromatin structure, these mutations can give rise to each of the classic hallmarks of cancer.	('altering', 'Reg', (3, 11))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('give rise', 'Reg', (53, 62))	('mutations', 'Var', (39, 48))	('cancer', 'Disease', (99, 105))	('chromatin structure', 'MPA', (12, 31))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
312247	31433976	Subsequently, considerable work has explored the use of epigenetic enzyme inhibitors to overcome tumor differentiation blocks through epigenetic reprogramming.	('tumor', 'Disease', (97, 102))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('epigenetic', 'Var', (56, 66))
312249	31433976	Epigenetics plays a particularly crucial role in self-renewing somatic epithelia, where stem cell populations must continually undergo self-renewal.	('epithelia', 'Disease', 'None', (71, 80))	('Epigenetics', 'Var', (0, 11))	('epithelia', 'Disease', (71, 80))
312259	31433976	Together, these results highlight the potential therapeutic utility of targeting epigenetic reprogramming for keratinocyte cancers (i.e., cutaneous squamous cell carcinoma [cSCC] and basal cell carcinoma [BCC]), which collectively outnumber all other human malignancies combined.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('malignancies', 'Disease', 'MESH:D009369', (257, 269))	('carcinoma', 'Phenotype', 'HP:0030731', (162, 171))	('human', 'Species', '9606', (251, 256))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (148, 171))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (183, 203))	('basal cell carcinoma', 'Disease', 'MESH:D002280', (183, 203))	('carcinoma', 'Phenotype', 'HP:0030731', (194, 203))	('basal cell carcinoma', 'Disease', (183, 203))	('malignancies', 'Disease', (257, 269))	('cancers', 'Disease', 'MESH:D009369', (123, 130))	('cancers', 'Phenotype', 'HP:0002664', (123, 130))	('rat', 'Species', '10116', (112, 115))	('epigenetic', 'Var', (81, 91))	('cutaneous squamous cell carcinoma', 'Disease', 'MESH:D002294', (138, 171))	('cancers', 'Disease', (123, 130))	('cutaneous squamous cell carcinoma', 'Phenotype', 'HP:0006739', (138, 171))	('cutaneous squamous cell carcinoma', 'Disease', (138, 171))
312271	31433976	Intersection between the TFs upregulated by LSD1 inhibition and TFs deemed as critical for epidermal pro-genitor differentiation yielded a restricted number of TFs including all three members of the Grainyhead-like family of TFs (GRHL1, GRHL2, and GRHL3), together with OVOL2, NOTCH3, and KLF4 (Figures S1J and S1K).	('GRHL2', 'Gene', '79977', (237, 242))	('NOTCH3', 'Gene', (277, 283))	('GRHL3', 'Gene', (248, 253))	('GRHL1', 'Gene', (230, 235))	('upregulated', 'PosReg', (29, 40))	('GRHL3', 'Gene', '57822', (248, 253))	('NOTCH3', 'Gene', '4854', (277, 283))	('OVOL2', 'Gene', '58495', (270, 275))	('KLF4', 'Gene', '9314', (289, 293))	('KLF4', 'Gene', (289, 293))	('LSD1', 'Gene', (44, 48))	('OVOL2', 'Gene', (270, 275))	('LSD1', 'Gene', '23028', (44, 48))	('inhibition', 'Var', (49, 59))	('GRHL2', 'Gene', (237, 242))	('GRHL1', 'Gene', '29841', (230, 235))
312275	31433976	These changes include numerous TFs known as key determinants of epidermal progenitor differentiation, such as NOTCH3, OVOL1, ZNF750, GRHL1, and GRHL3 (Figure 1M).	('GRHL3', 'Gene', (144, 149))	('GRHL3', 'Gene', '57822', (144, 149))	('ZNF750', 'Gene', (125, 131))	('OVOL1', 'Gene', '5017', (118, 123))	('OVOL1', 'Gene', (118, 123))	('GRHL1', 'Gene', '29841', (133, 138))	('changes', 'Var', (6, 13))	('NOTCH3', 'Gene', (110, 116))	('GRHL1', 'Gene', (133, 138))	('NOTCH3', 'Gene', '4854', (110, 116))	('ZNF750', 'Gene', '79755', (125, 131))
312283	31433976	Furthermore, these differentiation gene expression programs can be unleashed with inhibition of LSD1.	('inhibition', 'Var', (82, 92))	('LSD1', 'Gene', '23028', (96, 100))	('LSD1', 'Gene', (96, 100))
312284	31433976	Having found LSD1 inhibitors induce a differentiation-related transcriptional program in EPs, we hypothesized that LSD1 may be enriched at the regulatory elements of key epidermal progenitor differentiation genes.	('inhibitors', 'Var', (18, 28))	('LSD1', 'Gene', (115, 119))	('induce', 'Reg', (29, 35))	('LSD1', 'Gene', '23028', (115, 119))	('LSD1', 'Gene', '23028', (13, 17))	('EPs', 'Chemical', '-', (89, 92))	('LSD1', 'Gene', (13, 17))	('EPs', 'Disease', (89, 92))	('differentiation-related', 'CPA', (38, 61))
312290	31433976	Together, this suggests that LSD1 is preferentially lost from regulatory elements upon LSD1 inhibition (Figure 2F).	('inhibition', 'Var', (92, 102))	('LSD1', 'Gene', (87, 91))	('LSD1', 'Gene', '23028', (87, 91))	('LSD1', 'Gene', '23028', (29, 33))	('LSD1', 'Gene', (29, 33))	('lost', 'NegReg', (52, 56))
312293	31433976	A total of 146 genes (Figure 2H), of which 23 were TFs (Figures 2I), were both upregulated by LSD1 inhibition and associated with LSD1 lost sites.	('inhibition', 'Var', (99, 109))	('LSD1', 'Gene', '23028', (94, 98))	('LSD1', 'Gene', (94, 98))	('upregulated', 'PosReg', (79, 90))	('LSD1', 'Gene', (130, 134))	('LSD1', 'Gene', '23028', (130, 134))
312302	31433976	Furthermore, transcriptional changes induced by LSD1 inhibition significantly overlap with those seen with SNAI2 inhibition (Figures S3G-S3J), including the upregulation of genes involved in epidermal differentiation and cornification (Figure S3K).	('inhibition', 'Var', (53, 63))	('LSD1', 'Gene', (48, 52))	('LSD1', 'Gene', '23028', (48, 52))	('cornification', 'CPA', (221, 234))	('inhibition', 'NegReg', (113, 123))	('SNAI2', 'Gene', '6591', (107, 112))	('SNAI2', 'Gene', (107, 112))	('upregulation', 'PosReg', (157, 169))	('transcriptional', 'MPA', (13, 28))	('epidermal differentiation', 'CPA', (191, 216))	('genes', 'Gene', (173, 178))
312303	31433976	Collectively, these observations suggest that inhibiting LSD1 in EPs may block LSD1/SNAI2 binding and induce differentiation via activation of SNAI2-repressed target genes.	('LSD1', 'Gene', (79, 83))	('EPs', 'Chemical', '-', (65, 68))	('induce', 'PosReg', (102, 108))	('SNAI2', 'Gene', '6591', (143, 148))	('SNAI2', 'Gene', (143, 148))	('LSD1', 'Gene', '23028', (79, 83))	('binding', 'Interaction', (90, 97))	('block', 'NegReg', (73, 78))	('LSD1', 'Gene', (57, 61))	('activation', 'PosReg', (129, 139))	('inhibiting', 'Var', (46, 56))	('SNAI2', 'Gene', (84, 89))	('differentiation', 'MPA', (109, 124))	('LSD1', 'Gene', '23028', (57, 61))	('SNAI2', 'Gene', '6591', (84, 89))
312310	31433976	We also demonstrate that LSD1 and SNAI2 directly interact, collectively suggesting that LSD1 is required for SNAI2-mediated transcriptional repression, and that LSD1 inhibitors may block this repressive function.	('LSD1', 'Gene', '23028', (25, 29))	('SNAI2', 'Gene', '6591', (109, 114))	('SNAI2', 'Gene', (109, 114))	('block', 'NegReg', (181, 186))	('rat', 'Species', '10116', (15, 18))	('SNAI2', 'Gene', '6591', (34, 39))	('SNAI2', 'Gene', (34, 39))	('LSD1', 'Gene', (88, 92))	('LSD1', 'Gene', (25, 29))	('LSD1', 'Gene', '23028', (88, 92))	('LSD1', 'Gene', (161, 165))	('transcriptional repression', 'MPA', (124, 150))	('inhibitors', 'Var', (166, 176))	('LSD1', 'Gene', '23028', (161, 165))
312314	31433976	Similar to the LSD1 binding sites, the increases in H3K4me1 and H3K4me2 were enriched at promoter regions in GSK-LSD1-treated samples (Figure 3C).	('H3K4me1', 'Protein', (52, 59))	('GSK-LSD1', 'Gene', '23028', (109, 117))	('H3K4me2', 'Var', (64, 71))	('H3', 'Chemical', 'MESH:C012616', (64, 66))	('H3', 'Chemical', 'MESH:C012616', (52, 54))	('LSD1', 'Gene', (15, 19))	('LSD1', 'Gene', (113, 117))	('LSD1', 'Gene', '23028', (15, 19))	('LSD1', 'Gene', '23028', (113, 117))	('increases', 'PosReg', (39, 48))	('GSK-LSD1', 'Gene', (109, 117))
312317	31433976	A total of 151 genes gained only H3K4me2 (Figures 3E and 3I; Table S2J), and 17 genes gained only H3K4me1 (Figures 3E and S4C; Table S2I).	('gained', 'PosReg', (21, 27))	('H3', 'Chemical', 'MESH:C012616', (33, 35))	('gained', 'PosReg', (86, 92))	('H3K4me2', 'Var', (33, 40))	('H3', 'Chemical', 'MESH:C012616', (98, 100))	('H3K4me1', 'MPA', (98, 105))
312318	31433976	There were some genes that gained H3K4me1 and/or H3K4me2 that were not bound by LSD1 in either DMSO- or GSK-LSD1-treated EPs (Tables S2G and S2H), as well as genes that lost LSD1 binding with GSK-LSD1 treatment but did not demonstrate any significant changes in H3K4 methylation (Figure S4D; Table S2F).	('EPs', 'Chemical', '-', (121, 124))	('GSK-LSD1', 'Gene', (192, 200))	('LSD1', 'Gene', '23028', (80, 84))	('LSD1', 'Gene', (80, 84))	('GSK-LSD1', 'Gene', (104, 112))	('H3K4', 'Protein', (262, 266))	('H3', 'Chemical', 'MESH:C012616', (34, 36))	('LSD1', 'Gene', (196, 200))	('H3K4me2', 'Var', (49, 56))	('rat', 'Species', '10116', (230, 233))	('LSD1', 'Gene', '23028', (196, 200))	('LSD1', 'Gene', (174, 178))	('H3K4me1', 'Var', (34, 41))	('gained', 'PosReg', (27, 33))	('LSD1', 'Gene', '23028', (174, 178))	('LSD1', 'Gene', (108, 112))	('binding', 'Interaction', (179, 186))	('DMSO', 'Chemical', 'MESH:D004121', (95, 99))	('LSD1', 'Gene', '23028', (108, 112))	('GSK-LSD1', 'Gene', '23028', (192, 200))	('GSK-LSD1', 'Gene', '23028', (104, 112))	('H3', 'Chemical', 'MESH:C012616', (49, 51))	('H3', 'Chemical', 'MESH:C012616', (262, 264))	('lost', 'NegReg', (169, 173))
312332	31433976	To test this, we utilized a model of human cSCC in which proliferating EPs are engineered to express two medically relevant oncodrivers, CDK4 (R24C) and tamoxifen-induced mutant H-RAS (G12V), which are sufficient to convert normal OTC epidermis into invasive cSCC.	('R24C', 'Mutation', 'rs11547328', (143, 147))	('G12V', 'Mutation', 'rs104894230', (185, 189))	('rat', 'Species', '10116', (64, 67))	('CDK4', 'Var', (137, 141))	('EPs', 'Chemical', '-', (71, 74))	('H-RAS', 'Gene', '3265', (178, 183))	('human', 'Species', '9606', (37, 42))	('mutant', 'Var', (171, 177))	('H-RAS', 'Gene', (178, 183))	('tamoxifen', 'Chemical', 'MESH:D013629', (153, 162))
312337	31433976	We next hypothesized that the expression of the pro-differentiation transcriptional programs upregulated by LSD1 inhibition would be suppressed in human patient cSCCs.	('expression', 'MPA', (30, 40))	('pro-differentiation', 'CPA', (48, 67))	('human', 'Species', '9606', (147, 152))	('suppressed', 'NegReg', (133, 143))	('LSD1', 'Gene', (108, 112))	('inhibition', 'Var', (113, 123))	('LSD1', 'Gene', '23028', (108, 112))	('patient', 'Species', '9606', (153, 160))	('upregulated', 'PosReg', (93, 104))
312343	31433976	Together, these data underscore the pro-differentiation gene expression effects of LSD1 inhibitors in both EPs and cSCC models, and highlight their potential as a pro-differentiation therapy in invasive SCC.	('LSD1', 'Gene', (83, 87))	('pro-differentiation gene expression', 'MPA', (36, 71))	('invasive SCC', 'Disease', (194, 206))	('EPs', 'Chemical', '-', (107, 110))	('LSD1', 'Gene', '23028', (83, 87))	('cSCC', 'Disease', (115, 119))	('EPs', 'Disease', (107, 110))	('inhibitors', 'Var', (88, 98))
312345	31433976	Epigenetic dysregulation disrupts differentiation and, in turn, can promote disease such as cancer.	('Epigenetic dysregulation', 'Var', (0, 24))	('cancer', 'Disease', (92, 98))	('disrupts', 'NegReg', (25, 33))	('promote', 'PosReg', (68, 75))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('differentiation', 'CPA', (34, 49))
312348	31433976	Interestingly, cSCC has been shown to share common mutational and transcriptional underpinnings with all other forms of SCC, and this ''pan-squamous'' group of cancers displays the highest rates of mutations in epigenetic modifiers.	('cancers', 'Disease', 'MESH:D009369', (160, 167))	('cancers', 'Phenotype', 'HP:0002664', (160, 167))	('cancers', 'Disease', (160, 167))	('cSCC', 'Disease', (15, 19))	('epigenetic modifiers', 'Var', (211, 231))	('mutations', 'Var', (198, 207))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('rat', 'Species', '10116', (189, 192))
312352	31433976	Inhibition of LSD1 results in a dramatic reduction of LSD1 binding genome-wide at known SNAI2-repressed canonical epithelial differentiation genes and TFs, and is coupled with broad increases in H3K4 methylation, as well as the expression of these genes.	('LSD1', 'Gene', (14, 18))	('epithelia', 'Disease', (114, 123))	('epithelia', 'Disease', 'None', (114, 123))	('binding', 'Interaction', (59, 66))	('increases', 'PosReg', (182, 191))	('LSD1', 'Gene', '23028', (14, 18))	('H3K4', 'Protein', (195, 199))	('methylation', 'MPA', (200, 211))	('LSD1', 'Gene', (54, 58))	('H3', 'Chemical', 'MESH:C012616', (195, 197))	('Inhibition', 'Var', (0, 10))	('reduction', 'NegReg', (41, 50))	('LSD1', 'Gene', '23028', (54, 58))	('expression', 'MPA', (228, 238))	('SNAI2', 'Gene', '6591', (88, 93))	('SNAI2', 'Gene', (88, 93))
312361	31433976	Along these lines, recent evidence has also highlighted the ability of LSD1 inhibitors to synergize with immunotherapies such as inhibitors of PD-1, suggesting even further potential when used in combination with other therapies that have demonstrated efficacy.	('PD-1', 'Gene', (143, 147))	('rat', 'Species', '10116', (246, 249))	('LSD1', 'Gene', (71, 75))	('inhibitors', 'Var', (76, 86))	('LSD1', 'Gene', '23028', (71, 75))
312389	31433976	Primary human keratinocytes with CDK4 R24C and ER-H-RAS G12V overexpression were seeded onto the basement membrane side at a density of 8x105 cells in a total volume of 80 microL.	('G12V', 'Mutation', 'rs104894230', (56, 60))	('R24C', 'Mutation', 'rs11547328', (38, 42))	('overexpression', 'PosReg', (61, 75))	('CDK4 R24C', 'Var', (33, 42))	('rat', 'Species', '10116', (16, 19))	('H-RAS', 'Gene', '3265', (50, 55))	('ER-H', 'Gene', (47, 51))	('ER-H', 'Gene', '13877', (47, 51))	('H-RAS', 'Gene', (50, 55))	('human', 'Species', '9606', (8, 13))
312394	31433976	Phoenix cells were used for retrovirus production containing ER-H-RAS G12V and CDK4 R24C constructs.	('CDK4 R24C constructs', 'Var', (79, 99))	('G12V', 'Mutation', 'rs104894230', (70, 74))	('H-RAS', 'Gene', '3265', (64, 69))	('ER-H', 'Gene', (61, 65))	('ER-H', 'Gene', '13877', (61, 65))	('H-RAS', 'Gene', (64, 69))	('R24C', 'Mutation', 'rs11547328', (84, 88))
312396	31433976	Cells were spun at 1000 rpm for 1 hour at room temperature and keratinocyte growth medium was replaced after 1 hour of incubation at 37 C. Primary human keratinocytes were first transduced with CDK4 R24C and then two days later were transduced with ER-H-RAS G12V.	('ER-H', 'Gene', '13877', (249, 253))	('ER-H', 'Gene', (249, 253))	('rat', 'Species', '10116', (52, 55))	('G12V', 'Mutation', 'rs104894230', (258, 262))	('human', 'Species', '9606', (147, 152))	('CDK4 R24C', 'Var', (194, 203))	('H-RAS', 'Gene', '3265', (252, 257))	('R24C', 'Mutation', 'rs11547328', (199, 203))	('H-RAS', 'Gene', (252, 257))	('rat', 'Species', '10116', (155, 158))	('rat', 'Species', '10116', (65, 68))
312411	31433976	Antibodies used for ChIP-seq include anti-LSD1, anti-Histone 3 (monomethyl K4), and anti-Histone 3 (dimethyl K4) as described in the KRT.	('LSD1', 'Gene', (42, 46))	('anti-Histone 3', 'Var', (48, 62))	('LSD1', 'Gene', '23028', (42, 46))	('anti-Histone 3', 'Var', (84, 98))	('KRT', 'Gene', '643865', (133, 136))	('monomethyl K4', 'Chemical', '-', (64, 77))	('KRT', 'Gene', (133, 136))	('dimethyl K4', 'Chemical', '-', (100, 111))
312448	31433976	LSD1 represses master epidermal transcription factors that promote differentiation LSD1 inhibition activates the epidermal differentiation transcriptional program LSD1 inhibition represses invasion in a model of cutaneous squamous cell carcinoma	('inhibition represses', 'NegReg', (168, 188))	('LSD1', 'Gene', (83, 87))	('LSD1', 'Gene', '23028', (0, 4))	('LSD1', 'Gene', '23028', (83, 87))	('cutaneous squamous cell carcinoma', 'Phenotype', 'HP:0006739', (212, 245))	('cutaneous squamous cell carcinoma', 'Disease', 'MESH:D002294', (212, 245))	('LSD1', 'Gene', (163, 167))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (222, 245))	('carcinoma', 'Phenotype', 'HP:0030731', (236, 245))	('LSD1', 'Gene', '23028', (163, 167))	('activates', 'PosReg', (99, 108))	('invasion', 'CPA', (189, 197))	('LSD1', 'Gene', (0, 4))	('cutaneous squamous cell carcinoma', 'Disease', (212, 245))	('inhibition', 'Var', (88, 98))
312451	29628290	Specific driver mutations correlated with lower (CTNNB1, NRAS, or IDH1) or higher (BRAF, TP53, or CASP8) leukocyte levels across all cancers.	('cancers', 'Disease', 'MESH:D009369', (133, 140))	('TP53', 'Gene', '7157', (89, 93))	('IDH1', 'Gene', '3417', (66, 70))	('CTNNB1', 'Gene', '1499', (49, 55))	('lower', 'NegReg', (42, 47))	('NRAS', 'Gene', (57, 61))	('leukocyte levels', 'MPA', (105, 121))	('mutations', 'Var', (16, 25))	('higher', 'PosReg', (75, 81))	('cancers', 'Phenotype', 'HP:0002664', (133, 140))	('cancers', 'Disease', (133, 140))	('CTNNB1', 'Gene', (49, 55))	('BRAF', 'Gene', '673', (83, 87))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('BRAF', 'Gene', (83, 87))	('CASP8', 'Gene', '841', (98, 103))	('TP53', 'Gene', (89, 93))	('NRAS', 'Gene', '4893', (57, 61))	('IDH1', 'Gene', (66, 70))	('CASP8', 'Gene', (98, 103))
312452	29628290	Multiple control modalities of the intracellular and extracellular networks (transcription, microRNAs, copy number and epigenetic processes) were involved in tumor-immune cell interactions, both across and within immune subtypes.	('tumor', 'Disease', (158, 163))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('involved', 'Reg', (146, 154))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('copy number', 'Var', (103, 114))
312460	29628290	Antibodies against CTLA-4, PD-1, and PD-L1 are effective in treating a variety of malignancies.	('Antibodies', 'Var', (0, 10))	('PD-L1', 'Gene', (37, 42))	('CTLA-4', 'Gene', '1493', (19, 25))	('malignancies', 'Disease', (82, 94))	('PD-1', 'Gene', (27, 31))	('PD-1', 'Gene', '5133', (27, 31))	('PD-L1', 'Gene', '29126', (37, 42))	('CTLA-4', 'Gene', (19, 25))	('malignancies', 'Disease', 'MESH:D009369', (82, 94))
312475	29628290	The six resulting clusters "Immune Subtypes", C1-C6 (with 2416, 2591, 2397, 1157, 385 and 180 cases, respectively) were characterized by a distinct distribution of scores over the five representative signatures (Figure 1A, bottom panel), and showed distinct immune signatures based on the dominant sample characteristics of their tumor samples (Figure 1B-C).	('C1-C6', 'Var', (46, 51))	('tumor', 'Phenotype', 'HP:0002664', (330, 335))	('tumor', 'Disease', (330, 335))	('tumor', 'Disease', 'MESH:D009369', (330, 335))
312485	29628290	IDH mutations were enriched in C5 over C4 (80% of IDH mutations, p<2x10-16, Fisher's exact test), suggesting an association of IDH-mutations with favorable immune composition.	('association', 'Interaction', (112, 123))	('IDH', 'Gene', (127, 130))	('IDH', 'Gene', '3417', (127, 130))	('IDH', 'Gene', (0, 3))	('IDH', 'Gene', '3417', (0, 3))	('mutations', 'Var', (54, 63))	('IDH', 'Gene', (50, 53))	('mutations', 'Var', (4, 13))	('IDH', 'Gene', '3417', (50, 53))
312498	29628290	The spatial fraction of tumor regions with tumor infiltrating lymphocytes (TILs), estimated by analysis of digitized TCGA H&E stained slides, varied by immune subtype, with C2 the highest (p<10-16, Figure 2D).	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumor', 'Disease', (24, 29))	('with', 'Var', (168, 172))	('H&E', 'Chemical', '-', (122, 125))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Disease', (43, 48))
312511	29628290	The immune infiltrate was related to measures of DNA damage, including copy number variation (CNV) burden (both in terms of number of segments and fraction of genome alterations), aneuploidy, loss of heterozygosity (LOH), homologous recombination deficiency (HRD), and intratumor heterogeneity (ITH) (Figure 4A).	('aneuploidy', 'Disease', (180, 190))	('loss of heterozygosity', 'Var', (192, 214))	('copy number variation', 'MPA', (71, 92))	('homologous recombination deficiency', 'Disease', (222, 257))	('tumor', 'Disease', 'MESH:D009369', (274, 279))	('HRD', 'Disease', (259, 262))	('aneuploidy', 'Disease', 'MESH:D000782', (180, 190))	('tumor', 'Phenotype', 'HP:0002664', (274, 279))	('tumor', 'Disease', (274, 279))	('HRD', 'Disease', 'None', (259, 262))	('men', 'Species', '9606', (137, 140))
312512	29628290	LF correlated negatively with CNV segment burden, with strongest correlation in C6 and C2, and positively with aneuploidy, LOH, HRD, and mutation load, particularly in C3.	('HRD', 'Disease', (128, 131))	('LOH', 'Var', (123, 126))	('aneuploidy', 'Disease', (111, 121))	('negatively', 'NegReg', (14, 24))	('men', 'Species', '9606', (37, 40))	('HRD', 'Disease', 'None', (128, 131))	('aneuploidy', 'Disease', 'MESH:D000782', (111, 121))	('CNV segment burden', 'MPA', (30, 48))	('mutation load', 'Var', (137, 150))
312513	29628290	Chromosome 1p (including TNFRS9 and VTCN1) amplification associated with higher LF, while its deletion did the opposite.	('VTCN1', 'Gene', '79679', (36, 41))	('TNFRS9', 'Gene', (25, 31))	('amplification', 'Var', (43, 56))	('VTCN1', 'Gene', (36, 41))	('higher', 'PosReg', (73, 79))
312515	29628290	Amplification of chr2, 20q, and 22q (including CTLA4, CD40, and ADORA2 respectively), and deletions of 5q, 9p, and chr19 (including IL13 and IL4, IFNA1 and IFNA2, and ICAM1 respectively) associated with changes in macrophage polarity (Figure S4A).	('macrophage polarity', 'CPA', (214, 233))	('IFNA1', 'Gene', '3439', (146, 151))	('ADORA2', 'Gene', (64, 70))	('chr19', 'Gene', (115, 120))	('CTLA4', 'Gene', (47, 52))	('chr2', 'Gene', (17, 21))	('IL13', 'Gene', (132, 136))	('ICAM1', 'Gene', (167, 172))	('deletions', 'Var', (90, 99))	('ICAM1', 'Gene', '3383', (167, 172))	('IFNA2', 'Gene', (156, 161))	('CD40', 'Gene', (54, 58))	('IFNA2', 'Gene', '3440', (156, 161))	('associated', 'Reg', (187, 197))	('changes', 'Reg', (203, 210))	('ADORA2', 'Gene', '135', (64, 70))	('IFNA1', 'Gene', (146, 151))	('CD40', 'Gene', '958', (54, 58))	('IL4', 'Gene', '3565', (141, 144))	('IL4', 'Gene', (141, 144))	('IL13', 'Gene', '3596', (132, 136))	('CTLA4', 'Gene', '1493', (47, 52))
312516	29628290	IL-13 influences macrophage polarization, implying a possible basis for our observation that IL13 deletions associated with altered M0 macrophage fractions.	('IL-13', 'Gene', '3596', (0, 5))	('influences', 'Reg', (6, 16))	('IL13', 'Gene', (93, 97))	('IL13', 'Gene', '3596', (93, 97))	('macrophage polarization', 'CPA', (17, 40))	('IL-13', 'Gene', (0, 5))	('deletions', 'Var', (98, 107))
312519	29628290	We correlated mutations in 299 cancer driver genes with immune subtypes, and found 33 significant associations (q<0.1) (Figure 4C, Table S2).	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('associations', 'Interaction', (98, 110))	('cancer', 'Disease', (31, 37))	('mutations', 'Var', (14, 23))
312520	29628290	C1 was enriched in mutations in driver genes, such as TP53, PIK3CA, PTEN or KRAS.	('PIK3CA', 'Gene', (60, 66))	('KRAS', 'Gene', (76, 80))	('PIK3CA', 'Gene', '5290', (60, 66))	('mutations', 'Var', (19, 28))	('KRAS', 'Gene', '3845', (76, 80))	('PTEN', 'Gene', (68, 72))	('TP53', 'Gene', '7157', (54, 58))	('PTEN', 'Gene', '5728', (68, 72))	('TP53', 'Gene', (54, 58))
312522	29628290	C3 was enriched in BRAF, CDH1 and PBRM1 mutations, a finding of note since patients with PBRM1 mutations respond particularly well to IM therapy.	('BRAF', 'Gene', '673', (19, 23))	('CDH1', 'Gene', '999', (25, 29))	('BRAF', 'Gene', (19, 23))	('PBRM1', 'Gene', (89, 94))	('PBRM1', 'Gene', (34, 39))	('PBRM1', 'Gene', '55193', (89, 94))	('PBRM1', 'Gene', '55193', (34, 39))	('patients', 'Species', '9606', (75, 83))	('mutations', 'Var', (40, 49))	('mutations', 'Var', (95, 104))	('CDH1', 'Gene', (25, 29))
312523	29628290	C4 was enriched in CTNNB1, EGFR, and IDH1 mutations.	('CTNNB1', 'Gene', (19, 25))	('EGFR', 'Gene', '1956', (27, 31))	('EGFR', 'Gene', (27, 31))	('IDH1', 'Gene', (37, 41))	('CTNNB1', 'Gene', '1499', (19, 25))	('IDH1', 'Gene', '3417', (37, 41))	('mutations', 'Var', (42, 51))
312525	29628290	C6 only showed an enrichment in KRAS G12 mutations.	('mutations', 'Var', (41, 50))	('men', 'Species', '9606', (24, 27))	('KRAS', 'Gene', (32, 36))	('KRAS', 'Gene', '3845', (32, 36))
312526	29628290	Mutations in 23 driver genes associated with increased LF either in specific tumor types or across them, including TP53, HLA-B, BRAF, PTEN, NF1, APC and CASP8.	('BRAF', 'Gene', '673', (128, 132))	('HLA-B', 'Gene', '3106', (121, 126))	('HLA-B', 'Gene', (121, 126))	('TP53', 'Gene', '7157', (115, 119))	('PTEN', 'Gene', '5728', (134, 138))	('tumor type', 'Disease', (77, 87))	('NF1', 'Gene', (140, 143))	('Mutations', 'Var', (0, 9))	('TP53', 'Gene', (115, 119))	('APC', 'Disease', 'MESH:D011125', (145, 148))	('tumor type', 'Disease', 'MESH:D009369', (77, 87))	('NF1', 'Gene', '4763', (140, 143))	('CASP8', 'Gene', (153, 158))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('CASP8', 'Gene', '841', (153, 158))	('APC', 'Disease', (145, 148))	('PTEN', 'Gene', (134, 138))	('BRAF', 'Gene', (128, 132))
312527	29628290	Twelve other events were associated with lower LF, including the IDH1 R132H mutation, GATA3, KRAS, NRAS, CTNNB1 and NOTCH1 (Figure 4D).	('IDH1', 'Gene', '3417', (65, 69))	('GATA3', 'Gene', (86, 91))	('R132H', 'Var', (70, 75))	('KRAS', 'Gene', (93, 97))	('NOTCH1', 'Gene', '4851', (116, 122))	('NOTCH1', 'Gene', (116, 122))	('R132H', 'Mutation', 'rs121913500', (70, 75))	('GATA3', 'Gene', '2625', (86, 91))	('lower', 'NegReg', (41, 46))	('KRAS', 'Gene', '3845', (93, 97))	('CTNNB1', 'Gene', '1499', (105, 111))	('NRAS', 'Gene', (99, 103))	('NRAS', 'Gene', '4893', (99, 103))	('IDH1', 'Gene', (65, 69))	('CTNNB1', 'Gene', (105, 111))
312529	29628290	PI3K, NOTCH and RTK/RAS pathway disruptions showed variable, tumor type specific effects on immune factors, while TGF-beta pathway disruptions more consistently associated with lower LF (most prominently in C2 and C6; Figure S4C), higher eosinophils (C2), and increased macrophages.	('lower', 'NegReg', (177, 182))	('TGF-beta', 'Gene', '7040', (114, 122))	('disruptions', 'Var', (131, 142))	('disruptions', 'Var', (32, 43))	('RTK/RAS pathway', 'Gene', (16, 31))	('eosinophils', 'MPA', (238, 249))	('higher', 'PosReg', (231, 237))	('TGF-beta', 'Gene', (114, 122))	('tumor type', 'Disease', (61, 71))	('eosin', 'Chemical', 'MESH:D004801', (238, 243))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor type', 'Disease', 'MESH:D009369', (61, 71))	('macrophages', 'CPA', (270, 281))	('increased', 'PosReg', (260, 269))
312531	29628290	Thus, TGF-beta pathway disruption has context-dependent effects on LF, but may promote increased macrophages, particularly M1.	('TGF-beta', 'Gene', (6, 14))	('disruption', 'Var', (23, 33))	('promote increased', 'PosReg', (79, 96))	('macrophages', 'CPA', (97, 108))	('TGF-beta', 'Gene', '7040', (6, 14))
312537	29628290	No single cis-eQTL significantly correlated with PD-L1 expression, although the SNP rs822337, approximately 1KB upstream of CD274 transcription start, correlated weakly (p=0.074;1.3x10-4 unadjusted; Figure S4G).	('CD274', 'Gene', (124, 129))	('PD-L1', 'Gene', '29126', (49, 54))	('CD274', 'Gene', '29126', (124, 129))	('rs822337', 'Var', (84, 92))	('PD-L1', 'Gene', (49, 54))	('rs822337', 'Mutation', 'rs822337', (84, 92))
312538	29628290	Lymphocyte fractions tended to be lower in people of Asian ancestry, particularly in UCEC and BLCA (Figure S4H).	('BLCA', 'Disease', (94, 98))	('lower', 'NegReg', (34, 39))	('Asian ancestry', 'Var', (53, 67))	('Lymphocyte fractions', 'CPA', (0, 20))	('UCEC', 'Disease', (85, 89))	('people', 'Species', '9606', (43, 49))	('BLCA', 'Chemical', '-', (94, 98))
312539	29628290	Peptides predicted to bind with MHC proteins (pMHCs) and induce antitumor adaptive immunity were identified from SNV and indel mutations.	('tumor', 'Disease', (68, 73))	('MHC proteins', 'Protein', (32, 44))	('indel mutations', 'Var', (121, 136))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('bind', 'Interaction', (22, 26))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('induce', 'PosReg', (57, 63))
312541	29628290	Neoantigen load also associated with higher content of CD8 T cells, M1 macrophages, and CD4 memory T cells, and lower Tregs, mast, dendritic, and memory B cells in multiple tumor types (Figure S4K).	('content', 'MPA', (44, 51))	('CD8', 'Gene', '925', (55, 58))	('higher', 'PosReg', (37, 43))	('CD4 memory T cells', 'CPA', (88, 106))	('tumor type', 'Disease', (173, 183))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumor type', 'Disease', 'MESH:D009369', (173, 183))	('CD8', 'Gene', (55, 58))	('Neoantigen', 'Var', (0, 10))	('multiple tumor', 'Disease', 'MESH:D009369', (164, 178))	('multiple tumor', 'Disease', (164, 178))	('Tregs', 'CPA', (118, 123))	('lower', 'NegReg', (112, 117))
312549	29628290	In a regression model of all tumors, high load of each virus type associated with immune features (Figure S5C, cancer-type adjusted).	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('associated', 'Reg', (66, 76))	('immune', 'Disease', (82, 88))	('cancer', 'Disease', (111, 117))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('tumors', 'Disease', 'MESH:D009369', (29, 35))	('tumors', 'Disease', (29, 35))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('high load', 'Var', (37, 46))
312568	29628290	CD40 (Figure 6C), IL10 and IDO1, inversely correlated with gene expression, suggesting epigenetic silencing.	('IL10', 'Gene', (18, 22))	('IDO1', 'Gene', (27, 31))	('CD40', 'Gene', (0, 4))	('IL10', 'Gene', '3586', (18, 22))	('correlated', 'Reg', (43, 53))	('gene expression', 'MPA', (59, 74))	('epigenetic silencing', 'Var', (87, 107))	('IDO1', 'Gene', '3620', (27, 31))	('CD40', 'Gene', '958', (0, 4))
312571	29628290	In particular, IMs SLAMF7, SELP, TNFSF4 (OX40L), IL10, and CD40 were amplified less frequently in C5 relative to all samples, while TGFB1, KIR2DL1, and KIR2DL3 deletions were enriched in C5 (Figure 6D), consistent with our observation of lower immune infiltration with TGFB1 deletion (Figure S4A).	('CD40', 'Gene', (59, 63))	('IL10', 'Gene', '3586', (49, 53))	('TGFB1', 'Gene', '7040', (269, 274))	('TGFB1', 'Gene', (269, 274))	('SELP', 'Gene', '6403', (27, 31))	('CD40', 'Gene', '958', (59, 63))	('TNFSF4', 'Gene', '7292', (33, 39))	('SELP', 'Gene', (27, 31))	('TGFB1', 'Gene', '7040', (132, 137))	('deletion', 'Var', (275, 283))	('KIR2DL1', 'Gene', '3802', (139, 146))	('TGFB1', 'Gene', (132, 137))	('OX40L', 'Gene', (41, 46))	('KIR2DL3', 'Gene', (152, 159))	('TNFSF4', 'Gene', (33, 39))	('KIR2DL3', 'Gene', '3804', (152, 159))	('lower', 'NegReg', (238, 243))	('IL10', 'Gene', (49, 53))	('SLAMF7', 'Gene', '57823', (19, 25))	('KIR2DL1', 'Gene', (139, 146))	('OX40L', 'Gene', '7292', (41, 46))	('SLAMF7', 'Gene', (19, 25))
312585	29628290	Some T cell associated ligands were subtype specific, such as CD276 (C2, C6), IL1B (C6), and VEGFB (C4).	('VEGFB', 'Gene', '7423', (93, 98))	('IL1B', 'Gene', (78, 82))	('VEGFB', 'Gene', (93, 98))	('IL1B', 'Gene', '3553', (78, 82))	('CD276', 'Var', (62, 67))
312590	29628290	Somatic alterations in AKAP9, HRAS, KRAS and PREX2 were inferred to modulate the activity of IMs according to both the MR- and SYGNAL-PanImmune, a significant overlap (p=1.6x10-7, Fisher's exact test).	('HRAS', 'Gene', (30, 34))	('PREX2', 'Gene', (45, 50))	('alterations', 'Var', (8, 19))	('KRAS', 'Gene', (36, 40))	('modulate', 'Reg', (68, 76))	('KRAS', 'Gene', '3845', (36, 40))	('AKAP9', 'Gene', '10142', (23, 28))	('activity', 'MPA', (81, 89))	('AKAP9', 'Gene', (23, 28))	('HRAS', 'Gene', '3265', (30, 34))	('PREX2', 'Gene', '80243', (45, 50))
312595	29628290	Conversely, causal mutations shared across tumor types may associate with different tumor-specific downstream regulators.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('mutations', 'Var', (19, 28))	('tumor type', 'Disease', (43, 53))	('tumor', 'Disease', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor type', 'Disease', 'MESH:D009369', (43, 53))	('tumor', 'Disease', (43, 48))	('associate', 'Reg', (59, 68))
312600	29628290	C3 was regulated by KLF15 and miR-141-3p.	('KLF15', 'Gene', (20, 25))	('miR-141-3p', 'Var', (30, 40))	('KLF15', 'Gene', '28999', (20, 25))
312620	29628290	For example, KRAS mutations were enriched in C1 and but infrequent in C5, suggesting that mutations in driver oncogenes alter pathways that affect immune cells.	('mutations', 'Var', (90, 99))	('alter', 'Reg', (120, 125))	('pathways', 'Pathway', (126, 134))	('affect', 'Reg', (140, 146))	('KRAS', 'Gene', (13, 17))	('KRAS', 'Gene', '3845', (13, 17))	('mutations', 'Var', (18, 27))
312621	29628290	Driver mutations such as TP53, by inducing genomic instability, may alter the immune landscape via the generation of neoantigens.	('TP53', 'Gene', (25, 29))	('mutations', 'Var', (7, 16))	('inducing', 'Reg', (34, 42))	('alter', 'Reg', (68, 73))	('genomic instability', 'MPA', (43, 62))	('immune landscape', 'MPA', (78, 94))	('TP53', 'Gene', '7157', (25, 29))	('neoantigens', 'MPA', (117, 128))
312622	29628290	Our findings confirmed previous work showing that mutations in BRAF enhance the immune infiltrate while those in IDH1 diminish it.	('diminish', 'NegReg', (118, 126))	('immune infiltrate', 'CPA', (80, 97))	('mutations', 'Var', (50, 59))	('IDH1', 'Gene', (113, 117))	('IDH1', 'Gene', '3417', (113, 117))	('BRAF', 'Gene', '673', (63, 67))	('BRAF', 'Gene', (63, 67))	('enhance', 'PosReg', (68, 75))
312630	29628290	Predicted intracellular networks implied that seven immune related TFs(including interferon and STAT-family transcription factors) may play an active role in transcriptional events related to leukocyte infiltration, and that mutations in six genes (including Ras-family proteins) may influence immune infiltration.	('influence', 'Reg', (284, 293))	('mutations', 'Var', (225, 234))	('STAT', 'Disease', (96, 100))	('immune infiltration', 'CPA', (294, 313))	('STAT', 'Disease', 'None', (96, 100))
312692	29628290	Comparing functional annotations of these clusters, we found that overlap to be reflected in the concordant distribution of mean scores of IFN-gamma, TGF-beta, mutation load and overall leukocyte infiltrate among the overlapping clusters.	('IFN-gamma', 'Gene', '3458', (139, 148))	('IFN-gamma', 'Gene', (139, 148))	('TGF-beta', 'Gene', '7040', (150, 158))	('mutation load', 'Var', (160, 173))	('TGF-beta', 'Gene', (150, 158))
312721	29628290	All clonality calls for quantifying intratumoral heterogeneity (ITH) were also determined by ABSOLUTE, which models tumor copy number alterations and mutations as mixtures of subclonal and clonal components of varying ploidy.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Disease', (41, 46))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('mutations', 'Var', (150, 159))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('tumor', 'Disease', (116, 121))
312723	29628290	Scores for copy number burden, aneuploidy, loss of heterozygosity, and homologous recombination deficiency (HRD) were derived.	('aneuploidy', 'Disease', (31, 41))	('aneuploidy', 'Disease', 'MESH:D000782', (31, 41))	('HRD', 'Disease', 'None', (108, 111))	('copy number burden', 'Var', (11, 29))	('loss of heterozygosity', 'Var', (43, 65))	('HRD', 'Disease', (108, 111))
312724	29628290	Copy number burden scores frac_altered and n_segs ("fraction altered", and "number of segments", respectively) represent the fraction of bases deviating from baseline ploidy (defined as above 0.1 or below - 0.1 in log2 relative copy number (CN) space), and the total number of segments in each sample's copy number profile, respectively.	('men', 'Species', '9606', (89, 92))	('deviating', 'NegReg', (143, 152))	('frac_altered', 'Var', (26, 38))	('men', 'Species', '9606', (280, 283))
312725	29628290	LOH_n_seg and LOH_frac_altered are the number of segments with LOH events and fraction of bases with LOH events, respectively.	('LOH_n_seg', 'Var', (0, 9))	('men', 'Species', '9606', (52, 55))	('LOH_frac_altered', 'Var', (14, 30))
312726	29628290	HRD score is a measure quantifying defects in homologous recombination that sums 3 separate metrics of genomic scarring: large (>15 Mb) non-arm-level regions with LOH, large-scale state transitions (breaks between adjacent segments of >10 Mb), and subtelomeric regions with allelic imbalance.	('imbalance', 'Phenotype', 'HP:0002172', (282, 291))	('HRD', 'Disease', 'None', (0, 3))	('scarring', 'Phenotype', 'HP:0100699', (111, 119))	('defects', 'Var', (35, 42))	('HRD', 'Disease', (0, 3))	('LOH', 'NegReg', (163, 166))	('men', 'Species', '9606', (226, 229))
312727	29628290	Aneuploidy scores were calculated as the sum total of amplified or deleted (collectively "altered") arms.	('deleted', 'Var', (67, 74))	('Aneuploidy', 'Disease', 'MESH:D000782', (0, 10))	('Aneuploidy', 'Disease', (0, 10))
312728	29628290	To call arm alterations, sample chromosome arms were first stratified by sample tumor type, type of alteration being tested (amplification or deletion), and chromosome arm (1p, 1q, etc.).	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('alterations', 'Var', (12, 23))	('tumor type', 'Disease', 'MESH:D009369', (80, 90))	('tumor type', 'Disease', (80, 90))	('deletion', 'Var', (142, 150))
312734	29628290	Furthermore, for each gene, we similarly computed significances of differences of CIBERSORT-estimated relative immune cell subtype levels from their expected levels first in "amplified" and then in "deleted" samples in order to identify the effects of copy number amplification and deletion respectively on immune infiltrate composition while controlling for cancer disease type.	('cancer disease', 'Disease', 'MESH:D009369', (359, 373))	('deletion', 'Var', (282, 290))	('effects', 'Reg', (241, 248))	('cancer', 'Phenotype', 'HP:0002664', (359, 365))	('cancer disease', 'Disease', (359, 373))	('copy number amplification', 'Var', (252, 277))
312735	29628290	Contributors: Galen Gao, Andrew Cherniack We focused our analysis on genes identified as drivers by the TCGA PanCancer Atlas Driver Mutation Working Group (the CGAT list; TCGA Research Network, "Comprehensive Discovery and Characterization of Driver Genes and Mutations in Human Cancers", unpublished data) that were identified as 1) having 10 or more mutations overall and 2) mutated in two or more tissues.	('CGAT', 'Gene', (160, 164))	('Human', 'Species', '9606', (273, 278))	('Cancer', 'Disease', 'MESH:D009369', (112, 118))	('Cancer', 'Disease', (112, 118))	('Cancer', 'Phenotype', 'HP:0002664', (112, 118))	('mutations', 'Var', (352, 361))	('Cancer', 'Phenotype', 'HP:0002664', (279, 285))	('Cancers', 'Disease', (279, 286))	('Cancer', 'Disease', (279, 285))	('Cancers', 'Disease', 'MESH:D009369', (279, 286))	('Cancers', 'Phenotype', 'HP:0002664', (279, 286))	('Cancer', 'Disease', 'MESH:D009369', (279, 285))	('CGAT', 'Gene', '6570', (160, 164))
312738	29628290	Contributor: Eduard Porta Pardo We used domainXplorer to identify driver genes and mutations that correlate with the leukocyte fraction of the tumor sample.	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('mutations', 'Var', (83, 92))	('tumor', 'Disease', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
312739	29628290	The algorithm uses a linear model that takes into account potential biases caused by differences in the immune responses between the tissues of origin of the tumors, the gender of the patient, the total number of missense mutations in the sample or the patient's age as covariates.	('tumors', 'Disease', (158, 164))	('tumors', 'Phenotype', 'HP:0002664', (158, 164))	('patient', 'Species', '9606', (253, 260))	('tumors', 'Disease', 'MESH:D009369', (158, 164))	('missense mutations', 'Var', (213, 231))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('patient', 'Species', '9606', (184, 191))
312743	29628290	For each pathway, samples from each of 30 tumor types were divided into two groups of altered and intact cases based on acquisition of non-silent or frameshift mutations, heterozygous or homozygous deletions, or amplifications, in at least one member of the pathway.	('tumor type', 'Disease', (42, 52))	('amplifications', 'Var', (212, 226))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('tumor type', 'Disease', 'MESH:D009369', (42, 52))
312753	29628290	To perform association analyses with single nucleotide polymorphisms (SNPs) at the PDL1 locus, we imputed the genotype data using the Haplotype Reference Consortium as a reference.	('PDL1', 'Gene', '29126', (83, 87))	('single nucleotide polymorphisms', 'Var', (37, 68))	('PDL1', 'Gene', (83, 87))
312762	29628290	Variation in sequencing coverage and tumor purity require careful consideration in order to mitigate the risk of impacting mutation calls and on pMHC, and prior to pMHC calling, sequencing data was subjected to rigorous harmonization efforts, performed by the PanCancer MC3 Consortium.	('Cancer', 'Disease', (263, 269))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('impacting', 'Reg', (113, 122))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('Cancer', 'Phenotype', 'HP:0002664', (263, 269))	('mutation calls', 'Var', (123, 137))	('Cancer', 'Disease', 'MESH:D009369', (263, 269))
312789	29628290	Using output from a PanCan GISTIC2.0 run on ISAR-corrected Affymetrix genome-wide human SNP6.0 array data, deep amplifications, shallow amplifications, non-alterations, shallow deletions, and deep deletions of each immunomodulator gene were called as described in "Genomic Correlations with Immune Phenotype" above for 8461 tumors that both were immune subtyped and had ABSOLUTE purity and ploidy calls.	('tumor', 'Phenotype', 'HP:0002664', (324, 329))	('non-alterations', 'Var', (152, 167))	('human', 'Species', '9606', (82, 87))	('tumors', 'Disease', (324, 330))	('tumors', 'Phenotype', 'HP:0002664', (324, 330))	('shallow deletions', 'Var', (169, 186))	('tumors', 'Disease', 'MESH:D009369', (324, 330))	('deep deletions', 'Var', (192, 206))	('shallow amplifications', 'Var', (128, 150))
312805	29628290	Mutation or copy-number events identified by the domainXplorer algorithm were tested for statistical association with the 32 cMRs identified, using the DIGGIT algorithm (above), and retained if associated with one or more of the 32 cMRs in at least one tumor-specific context.	('tumor', 'Disease', 'MESH:D009369', (253, 258))	('tumor', 'Phenotype', 'HP:0002664', (253, 258))	('tumor', 'Disease', (253, 258))	('copy-number', 'Var', (12, 23))
312872	29636077	The keywords were used to search the literature of miR-182-5p in LUSC from PubMed, Wiley Online Library, EBSCO, Cochrane Central Register of Controlled Trials, Web of Science, Google Scholar, Ovid, EMBASE, and LILACS, until 5 October 2017, and the keywords were as follows: (cancer OR carcinoma OR adenocarcinoma OR tumour OR tumor OR malignanc* OR neoplas*) AND (Lung OR pulmonary OR respiratory OR respiration OR aspiration OR bronchi OR bronchioles OR alveoli OR pneumocytes OR "air way") AND (miR-182 OR miRNA-182 OR microRNA-182 OR miR182 OR miRNA182 OR microRNA182 OR "miR 182" OR "miRNA 182" OR "microRNA 182"OR miR-182-5p OR miRNA-182-5p OR microRNA-182-5p).	('carcinoma OR adenocarcinoma OR tumour', 'Disease', 'MESH:D000230', (285, 322))	('LUSC', 'Phenotype', 'HP:0030359', (65, 69))	('miRNA-182', 'Gene', '406958', (633, 642))	('miR', 'Gene', '220972', (497, 500))	('miR', 'Gene', (619, 622))	('miR-182', 'Gene', '406958', (619, 626))	('miRNA-182', 'Gene', (508, 517))	('miR', 'Gene', '220972', (51, 54))	('carcinoma OR adenocarcinoma OR tumour', 'Disease', (285, 322))	('miR', 'Gene', (537, 540))	('miR-182-5p', 'Gene', '100302183', (619, 629))	('cancer', 'Disease', 'MESH:D009369', (275, 281))	('miR', 'Gene', '220972', (575, 578))	('miRNA182', 'Gene', '406958', (547, 555))	('miR', 'Gene', (497, 500))	('miR182', 'Gene', (537, 543))	('miR-182-5p', 'Gene', (51, 61))	('miR', 'Gene', (51, 54))	('pulmonary', 'Disease', 'MESH:D008171', (372, 381))	('miR182', 'Gene', '406958', (537, 543))	('aspiration', 'Phenotype', 'HP:0002835', (415, 425))	('tumor', 'Disease', (326, 331))	('miR', 'Gene', '220972', (588, 591))	('miRNA-182', 'Gene', (633, 642))	('miR', 'Gene', (575, 578))	('miR-182', 'Gene', (497, 504))	('carcinoma', 'Phenotype', 'HP:0030731', (285, 294))	('tumor', 'Disease', 'MESH:D009369', (326, 331))	('miR', 'Gene', (633, 636))	('miR-182', 'Gene', '406958', (497, 504))	('miR', 'Gene', '220972', (508, 511))	('miR-182', 'Gene', (51, 58))	('miR-182-5p', 'Gene', (619, 629))	('miR', 'Gene', (588, 591))	('miR', 'Gene', '220972', (633, 636))	('miR', 'Gene', '220972', (547, 550))	('miR-182', 'Gene', '406958', (51, 58))	('miRNA-182', 'Gene', '406958', (508, 517))	('cancer', 'Disease', (275, 281))	('miR', 'Gene', '220972', (619, 622))	('cancer', 'Phenotype', 'HP:0002664', (275, 281))	('miRNA182', 'Gene', (547, 555))	('tumour', 'Phenotype', 'HP:0002664', (316, 322))	('miR-182-5p', 'Gene', '100302183', (51, 61))	('tumor', 'Phenotype', 'HP:0002664', (326, 331))	('miR', 'Gene', (508, 511))	('miR-182', 'Gene', (619, 626))	('microRNA-182-5p', 'Var', (649, 664))	('miR', 'Gene', (547, 550))	('miR', 'Gene', '220972', (537, 540))	('pulmonary', 'Disease', (372, 381))	('carcinoma', 'Phenotype', 'HP:0030731', (303, 312))
312893	29636077	Four microarrays (GSE16025, GSE19945, GSE51853, and GSE74190) showed statistical significance in which the miR-182-5p expression level was remarkably increased in LUSC tissues.	('miR-182-5p', 'Gene', '100302183', (107, 117))	('miR-182-5p', 'Gene', (107, 117))	('GSE51853', 'Var', (38, 46))	('GSE74190', 'Var', (52, 60))	('LUSC', 'Phenotype', 'HP:0030359', (163, 167))	('increased', 'PosReg', (150, 159))	('GSE19945', 'Var', (28, 36))	('GSE16025', 'Var', (18, 26))
312944	29636077	According to recent studies, the high level of EPAS1 expression could lead to a poor prognosis by increasing the tumor size and angiogenesis.	('tumor', 'Disease', (113, 118))	('EPAS1', 'Gene', '2034', (47, 52))	('high', 'Var', (33, 37))	('increasing', 'PosReg', (98, 108))	('EPAS1', 'Gene', (47, 52))	('lead to', 'Reg', (70, 77))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('angiogenesis', 'CPA', (128, 140))
312966	33912452	In this report, we identified two novel tumor types from TCGA with LINC00460 deregulation.	('LINC00460', 'Gene', '728192', (67, 76))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('LINC00460', 'Gene', (67, 76))	('deregulation', 'Var', (77, 89))
312982	33912452	Several reports have shown that sponge lncRNAs play a pivotal role in various cancer types, including BRCA and abnormal expression of lncRNAs can significantly contribute to BRCA initiation and progression.	('BRCA', 'Gene', (174, 178))	('BRCA', 'Gene', '672', (174, 178))	('BRCA', 'Gene', (102, 106))	('BRCA initiation', 'Disease', (174, 189))	('BRCA initiation', 'Disease', 'MESH:D007319', (174, 189))	('contribute', 'Reg', (160, 170))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('abnormal expression', 'Var', (111, 130))	('BRCA', 'Gene', '672', (102, 106))
312995	33912452	We identified two novel (not previously reported) tumor types from the TCGA cohort with LINC00460 deregulation.	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('deregulation', 'Var', (98, 110))	('tumor', 'Disease', (50, 55))	('LINC00460', 'Gene', '728192', (88, 97))	('LINC00460', 'Gene', (88, 97))
139762	33912452	GAPDH (Hs99999905) and SCARNA5 (Hs03391742_cn) transcripts were used as endogenous controls.	('SCARNA5', 'Gene', '677775', (23, 30))	('SCARNA5', 'Gene', (23, 30))	('GAPDH', 'Gene', '2597', (0, 5))	('Hs03391742_cn', 'Var', (32, 45))	('Hs99999905', 'Var', (7, 17))	('GAPDH', 'Gene', (0, 5))
313074	33912452	These data strongly suggest that LINC00460 might play a dual prognostic role across different tumors, as high LINC00460 expression predicts an increased OS, RFS and DMFS in the BRCA model, but it is also a marker for poor prognosis in at least eight distinct solid tumors (see  Figure 3C ).	('increased', 'PosReg', (143, 152))	('tumors', 'Disease', 'MESH:D009369', (265, 271))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('LINC00460', 'Gene', '728192', (33, 42))	('RFS', 'Disease', (157, 160))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('LINC00460', 'Gene', (110, 119))	('tumors', 'Disease', (94, 100))	('DMFS', 'Chemical', '-', (165, 169))	('tumors', 'Phenotype', 'HP:0002664', (265, 271))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('BRCA', 'Gene', '672', (177, 181))	('LINC00460', 'Gene', '728192', (110, 119))	('high', 'Var', (105, 109))	('tumor', 'Phenotype', 'HP:0002664', (265, 270))	('tumors', 'Disease', (265, 271))	('LINC00460', 'Gene', (33, 42))	('DMFS', 'MPA', (165, 169))	('BRCA', 'Gene', (177, 181))
313079	33912452	Analysis with LINC00460 predicted an increased OS in the TNBC GEO derived cohort GSE16446 (using all TNBC samples; n= 107; HR = 0.26; 95% CI [0.09 - 0.72]; logrank p = 0.0053) ( Figure 5D ).	('LINC00460', 'Gene', (14, 23))	('LINC00460', 'Gene', '728192', (14, 23))	('TNBC', 'Gene', (57, 61))	('GSE16446', 'Var', (81, 89))
313085	33912452	Interestingly, in aggressive BRCA subtypes, high LINC00460 expression is able to predict a favorable clinical course, further strengthening the dual role for this lncRNA in OS and RFS prediction in cancer.	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('high', 'Var', (44, 48))	('cancer', 'Disease', (198, 204))	('BRCA', 'Gene', '672', (29, 33))	('LINC00460', 'Gene', (49, 58))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('BRCA', 'Gene', (29, 33))	('LINC00460', 'Gene', '728192', (49, 58))
313120	33912452	We have also confirmed LINC00460 deregulation in BRCA using two independent cohorts.	('BRCA', 'Gene', '672', (49, 53))	('BRCA', 'Gene', (49, 53))	('deregulation', 'Var', (33, 45))	('LINC00460', 'Gene', '728192', (23, 32))	('LINC00460', 'Gene', (23, 32))
313124	33912452	In addition, we describe here that LINC00460 high expression is significantly associated with poor survival in three different tumors (GBM, LGG and SARC) but related with a favorable survival rate in BRCA, i.e., its association to clinical outcome varies between tumors.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumors', 'Disease', (127, 133))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('tumors', 'Phenotype', 'HP:0002664', (263, 269))	('BRCA', 'Gene', '672', (200, 204))	('tumor', 'Phenotype', 'HP:0002664', (263, 268))	('tumors', 'Disease', 'MESH:D009369', (127, 133))	('BRCA', 'Gene', (200, 204))	('LINC00460', 'Gene', (35, 44))	('LINC00460', 'Gene', '728192', (35, 44))	('tumors', 'Disease', 'MESH:D009369', (263, 269))	('high expression', 'Var', (45, 60))	('tumors', 'Disease', (263, 269))	('poor', 'NegReg', (94, 98))
313127	33912452	For example, high MALAT-1 expression has been reported as a marker for poor prognosis in various tumors, including COAD, NSCLC, STAD, PAAD, ESCA, among others, but also as a good prognosis factor for BRCA, acting as a metastasis suppressor.	('expression', 'MPA', (26, 36))	('COAD', 'Disease', 'MESH:D029424', (115, 119))	('MALAT-1', 'Gene', (18, 25))	('ESCA', 'Disease', (140, 144))	('high', 'Var', (13, 17))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('BRCA', 'Gene', '672', (200, 204))	('NSCLC', 'Disease', (121, 126))	('STAD', 'Disease', (128, 132))	('PAAD', 'Disease', (134, 138))	('BRCA', 'Gene', (200, 204))	('COAD', 'Disease', (115, 119))	('NSCLC', 'Disease', 'MESH:D002289', (121, 126))	('tumors', 'Disease', (97, 103))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('tumors', 'Disease', 'MESH:D009369', (97, 103))	('MALAT-1', 'Gene', '378938', (18, 25))
313129	33912452	It has been shown that high expression of this lncRNA is related to poor clinical outcome in different cancers, but in another study, authors demonstrate that high XIST expression is related to an increased brain metastasis-free survival in BRCA patients.	('cancers', 'Disease', 'MESH:D009369', (103, 110))	('brain metastasis-free survival', 'CPA', (207, 237))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('patients', 'Species', '9606', (246, 254))	('BRCA', 'Gene', '672', (241, 245))	('XIST', 'Gene', '7503', (164, 168))	('BRCA', 'Gene', (241, 245))	('increased', 'PosReg', (197, 206))	('XIST', 'Gene', (164, 168))	('cancers', 'Phenotype', 'HP:0002664', (103, 110))	('high', 'Var', (159, 163))	('cancers', 'Disease', (103, 110))
313141	33912452	High expression of SFRP5 is significantly associated with a better prognosis in PAAD and BRCA.	('PAAD', 'Disease', (80, 84))	('SFRP5', 'Gene', '6425', (19, 24))	('High', 'Var', (0, 4))	('BRCA', 'Gene', (89, 93))	('associated', 'Reg', (42, 52))	('SFRP5', 'Gene', (19, 24))	('BRCA', 'Gene', '672', (89, 93))
313148	33912452	It has been previously shown that the presence of TILs improves prognosis as it modulates cancer progression and enhances chemotherapy response in TNBC, conferring a protective immunity in these patients.	('presence', 'Var', (38, 46))	('chemotherapy response', 'CPA', (122, 143))	('enhances', 'PosReg', (113, 121))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('modulates', 'Reg', (80, 89))	('prognosis', 'CPA', (64, 73))	('patients', 'Species', '9606', (195, 203))	('TILs', 'Gene', (50, 54))	('improves', 'PosReg', (55, 63))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))
313156	33912452	In this regard, although there have been reports that suggest that WNT7A is an oncoprotein, it has also been shown that loss of WNT7A expression is significantly associated with poor RFS in BRCA and it is also involved in tumor cell differentiation.	('WNT7A', 'Gene', (67, 72))	('tumor', 'Disease', 'MESH:D009369', (222, 227))	('involved', 'Reg', (210, 218))	('RFS', 'MPA', (183, 186))	('WNT7A', 'Gene', '7476', (128, 133))	('BRCA', 'Gene', '672', (190, 194))	('associated', 'Reg', (162, 172))	('BRCA', 'Gene', (190, 194))	('tumor', 'Disease', (222, 227))	('WNT7A', 'Gene', '7476', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('loss', 'Var', (120, 124))	('WNT7A', 'Gene', (128, 133))
313162	33912452	This finding further strengthens the beneficial role of both transcripts in patient's prediction and prognosis as, it has been demonstrated that ER-negative breast cancers with high levels of TILs have heightened sensitivity to anthracycline-based chemotherapy, and that TILs are an independent predictor of good response to anthracycline/taxane neoadjuvant chemotherapy.	('breast cancers', 'Phenotype', 'HP:0003002', (157, 171))	('breast cancers', 'Disease', 'MESH:D001943', (157, 171))	('heightened', 'PosReg', (202, 212))	('breast cancers', 'Disease', (157, 171))	('high', 'Var', (177, 181))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('breast cancer', 'Phenotype', 'HP:0003002', (157, 170))	('cancers', 'Phenotype', 'HP:0002664', (164, 171))	('ER', 'Gene', '2099', (145, 147))	('anthracycline', 'Chemical', 'MESH:D018943', (228, 241))	('patient', 'Species', '9606', (76, 83))	('anthracycline', 'Chemical', 'MESH:D018943', (325, 338))	('sensitivity to anthracycline-based chemotherapy', 'MPA', (213, 260))	('taxane', 'Chemical', 'MESH:C080625', (339, 345))
313168	33912452	In gastric cancer patients, high expression of miR-103 was significantly associated with poor overall survival and disease-free survival and is a key factor that contributes to tumor progression.	('miR-103', 'Var', (47, 54))	('gastric cancer', 'Phenotype', 'HP:0012126', (3, 17))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('overall survival', 'CPA', (94, 110))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('gastric cancer', 'Disease', 'MESH:D013274', (3, 17))	('disease-free survival', 'CPA', (115, 136))	('contributes', 'Reg', (162, 173))	('poor', 'NegReg', (89, 93))	('expression', 'MPA', (33, 43))	('gastric cancer', 'Disease', (3, 17))	('patients', 'Species', '9606', (18, 26))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('tumor', 'Disease', (177, 182))
313174	33912452	LINC00460:WNT7A ratio is a composite marker that can predict a favorable OS and DMFS in TNBC, and combination of LINC00460 and WNT7A over-expression is associated with complete pathological response (pCR) after anthracycline therapy in ER- BRCA patients.	('over-expression', 'PosReg', (133, 148))	('LINC00460', 'Gene', (0, 9))	('BRCA', 'Gene', '672', (240, 244))	('combination', 'Var', (98, 109))	('WNT7A', 'Gene', '7476', (127, 132))	('LINC00460', 'Gene', (113, 122))	('LINC00460', 'Gene', '728192', (113, 122))	('BRCA', 'Gene', (240, 244))	('LINC00460', 'Gene', '728192', (0, 9))	('DMFS', 'Chemical', '-', (80, 84))	('anthracycline', 'Chemical', 'MESH:D018943', (211, 224))	('patients', 'Species', '9606', (245, 253))	('WNT7A', 'Gene', (10, 15))	('WNT7A', 'Gene', (127, 132))	('ER', 'Gene', '2099', (236, 238))	('associated with', 'Reg', (152, 167))	('WNT7A', 'Gene', '7476', (10, 15))	('complete pathological response', 'Disease', (168, 198))
313185	33331418	In vitro, KIF2A expression in AML cell lines and CD34+ cells (from healthy donors) was measured, and the effect of KIF2A knockdown on AML cell proliferation and apoptosis in HL-60 and KG-1 cells was detected.	('knockdown', 'Var', (121, 130))	('KIF2A', 'Gene', '3796', (115, 120))	('AML', 'Disease', 'MESH:D015470', (30, 33))	('CD34', 'Gene', '947', (49, 53))	('AML', 'Disease', 'MESH:D015470', (134, 137))	('AML', 'Disease', (30, 33))	('KIF2A', 'Gene', (10, 15))	('KIF2A', 'Gene', '3796', (10, 15))	('HL-60', 'CellLine', 'CVCL:0002', (174, 179))	('AML', 'Disease', (134, 137))	('CD34', 'Gene', (49, 53))	('KG-1', 'CellLine', 'CVCL:0374', (184, 188))	('KIF2A', 'Gene', (115, 120))
313190	33331418	In vitro experiments showed that KIF2A was overexpressed in AML cell lines (KG-1, HL-60, ME-1, and HT-93) compared to CD34+ cells, moreover, cell proliferation was reduced but apoptosis was increased by KIF2A knockdown in HL-60 and KG-1 cells.	('HL-60', 'CellLine', 'CVCL:0002', (222, 227))	('KG-1', 'CellLine', 'CVCL:0374', (232, 236))	('overexpressed', 'PosReg', (43, 56))	('KIF2A', 'Gene', (33, 38))	('CD34', 'Gene', '947', (118, 122))	('KIF2A', 'Gene', '3796', (203, 208))	('knockdown', 'Var', (209, 218))	('HT-93', 'CellLine', 'CVCL:E331', (99, 104))	('HL-60', 'CellLine', 'CVCL:0002', (82, 87))	('ME-1', 'Gene', (89, 93))	('cell proliferation', 'CPA', (141, 159))	('apoptosis', 'CPA', (176, 185))	('reduced', 'NegReg', (164, 171))	('KG-1', 'CellLine', 'CVCL:0374', (76, 80))	('ME-1', 'Gene', '4199', (89, 93))	('AML', 'Disease', 'MESH:D015470', (60, 63))	('CD34', 'Gene', (118, 122))	('KIF2A', 'Gene', '3796', (33, 38))	('increased', 'PosReg', (190, 199))	('AML', 'Disease', (60, 63))	('KIF2A', 'Gene', (203, 208))
313212	33331418	CR was defined as follows (all criteria need to be fulfilled): bone marrow blasts <5%, absence of blasts with Auer rods, absence of extramedullary disease, absolute neutrophil count >1.0x109/L (1,000/muL), platelet count >100x109/L (100,000/muL), and independence of red cell transfusions.	('muL', 'Gene', (200, 203))	('bone marrow blasts', 'CPA', (63, 81))	('muL', 'Gene', '4591', (241, 244))	('red cell transfusions', 'Phenotype', 'HP:0011888', (267, 288))	('muL', 'Gene', (241, 244))	('muL', 'Gene', '4591', (200, 203))	('>100x109/L', 'Var', (221, 231))
313240	33331418	KIF2A high expression was associated with shorter EFS (P<0.001) (Figure 3A) and decreased OS in AML patients (P=0.001) (Figure 3B).	('AML', 'Disease', (96, 99))	('EFS', 'MPA', (50, 53))	('shorter', 'NegReg', (42, 49))	('high expression', 'Var', (6, 21))	('KIF2A', 'Gene', (0, 5))	('decreased', 'NegReg', (80, 89))	('KIF2A', 'Gene', '3796', (0, 5))	('patients', 'Species', '9606', (100, 108))	('AML', 'Disease', 'MESH:D015470', (96, 99))
313245	33331418	Univariate Cox proportional hazards regression model analysis indicated that KIF2A high expression (P=0.002), WBC >10x109/L (P=0.044), monosomal karyotype (P<0.001), NPM1 mutation (P=0.046), and high risk stratification were associated with worse OS and multivariate Cox proportional hazards regression model analysis showed that WBC >10x109/L (P=0.002) and high risk stratification were independent factors predicting worse OS in AML patients (Table 4).	('worse OS', 'Disease', (419, 427))	('monosomal karyotype', 'Var', (135, 154))	('AML', 'Disease', 'MESH:D015470', (431, 434))	('mutation', 'Var', (171, 179))	('KIF2A', 'Gene', (77, 82))	('worse OS', 'Disease', (241, 249))	('NPM1', 'Gene', '4869', (166, 170))	('patients', 'Species', '9606', (435, 443))	('KIF2A', 'Gene', '3796', (77, 82))	('AML', 'Disease', (431, 434))	('NPM1', 'Gene', (166, 170))
313248	33331418	In our preliminary experiments, we used three shRNAs to knockdown KIF2A, and the one that presented the best efficiency in silencing KIF2A was chosen for further assays.	('KIF2A', 'Gene', (133, 138))	('KIF2A', 'Gene', '3796', (133, 138))	('KIF2A', 'Gene', (66, 71))	('KIF2A', 'Gene', '3796', (66, 71))	('knockdown', 'Var', (56, 65))
313253	33331418	These data suggested that KIF2A knockdown inhibited cell proliferation but enhanced cell apoptosis in AML.	('enhanced', 'PosReg', (75, 83))	('cell proliferation', 'CPA', (52, 70))	('AML', 'Disease', 'MESH:D015470', (102, 105))	('KIF2A', 'Gene', (26, 31))	('knockdown', 'Var', (32, 41))	('KIF2A', 'Gene', '3796', (26, 31))	('inhibited', 'NegReg', (42, 51))	('AML', 'Disease', (102, 105))	('cell apoptosis', 'CPA', (84, 98))
313254	33331418	In this study, we observed that: 1) KIF2A expression was significantly increased in AML patients compared to healthy controls, and correlated with increased WBC level, presence of monosomal karyotype, as well as high risk stratification in AML patients; 2) KIF2A high expression predicted low EFS and OS in AML patients; and 3) KIF2A was overexpressed in various human AML cell lines and its knockdown repressed cell proliferation but enhanced cell apoptosis in AML cells.	('AML', 'Disease', 'MESH:D015470', (462, 465))	('low', 'Disease', (289, 292))	('AML', 'Disease', 'MESH:D015470', (369, 372))	('KIF2A', 'Gene', (328, 333))	('KIF2A', 'Gene', (36, 41))	('AML', 'Disease', (462, 465))	('expression', 'MPA', (42, 52))	('AML', 'Disease', (369, 372))	('AML', 'Disease', 'MESH:D015470', (240, 243))	('patients', 'Species', '9606', (244, 252))	('KIF2A', 'Gene', (257, 262))	('knockdown', 'Var', (392, 401))	('AML', 'Disease', (240, 243))	('human', 'Species', '9606', (363, 368))	('WBC level', 'MPA', (157, 166))	('cell apoptosis', 'CPA', (444, 458))	('KIF2A', 'Gene', '3796', (328, 333))	('cell proliferation', 'CPA', (412, 430))	('KIF2A', 'Gene', '3796', (36, 41))	('KIF2A', 'Gene', '3796', (257, 262))	('AML', 'Disease', 'MESH:D015470', (307, 310))	('AML', 'Disease', (307, 310))	('enhanced', 'PosReg', (435, 443))	('AML', 'Disease', 'MESH:D015470', (84, 87))	('patients', 'Species', '9606', (88, 96))	('patients', 'Species', '9606', (311, 319))	('AML', 'Disease', (84, 87))	('increased', 'PosReg', (71, 80))
313258	33331418	For example, KIF2A knockdown inhibits lymphoma cell proliferation through positively regulating PI3K/AKT signaling pathway in SCCOT Tca8113 cells.	('AKT', 'Gene', '207', (101, 104))	('knockdown', 'Var', (19, 28))	('lymphoma', 'Disease', (38, 46))	('regulating', 'Reg', (85, 95))	('KIF2A', 'Gene', (13, 18))	('AKT', 'Gene', (101, 104))	('lymphoma', 'Disease', 'MESH:D008223', (38, 46))	('inhibits', 'NegReg', (29, 37))	('KIF2A', 'Gene', '3796', (13, 18))	('lymphoma', 'Phenotype', 'HP:0002665', (38, 46))
313259	33331418	Furthermore, silencing KIF2A promotes cell apoptosis via inhibiting PI3K/Akt signaling pathway in squamous cell carcinoma of the oral tongue.	('squamous cell carcinoma', 'Disease', (98, 121))	('inhibiting', 'NegReg', (57, 67))	('Akt', 'Gene', (73, 76))	('KIF2A', 'Gene', (23, 28))	('KIF2A', 'Gene', '3796', (23, 28))	('cell apoptosis', 'CPA', (38, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (98, 121))	('squamous cell carcinoma of the oral tongue', 'Phenotype', 'HP:0030413', (98, 140))	('Akt', 'Gene', '207', (73, 76))	('carcinoma of the oral', 'Phenotype', 'HP:0100649', (112, 133))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (98, 121))	('silencing', 'Var', (13, 22))	('promotes', 'PosReg', (29, 37))
313260	33331418	Moreover, silencing KIF2A reduces cell proliferation and migration, enhances cell apoptosis, and induces G2/M phase arrest through inhibiting PI3K/AKT and MAPK/ERK pathways in lung adenocarcinoma cells.	('cell proliferation', 'CPA', (34, 52))	('MAPK', 'Gene', (155, 159))	('inhibiting', 'NegReg', (131, 141))	('reduces', 'NegReg', (26, 33))	('arrest', 'Disease', (116, 122))	('lung adenocarcinoma', 'Disease', (176, 195))	('ERK', 'Gene', '5594', (160, 163))	('MAPK', 'Gene', '5594', (155, 159))	('KIF2A', 'Gene', '3796', (20, 25))	('AKT', 'Gene', (147, 150))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (176, 195))	('arrest', 'Disease', 'MESH:D006323', (116, 122))	('ERK', 'Gene', (160, 163))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (176, 195))	('silencing', 'Var', (10, 19))	('cell apoptosis', 'CPA', (77, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (186, 195))	('enhances', 'PosReg', (68, 76))	('KIF2A', 'Gene', (20, 25))	('AKT', 'Gene', '207', (147, 150))	('induces', 'Reg', (97, 104))
313261	33331418	KIF2A knockdown suppresses cell proliferation, cell invasion, and cell migration through regulating matrix metalloproteinases-2 (MMP-2) activity in human malignant glioma cell lines.	('malignant glioma', 'Disease', 'MESH:D005910', (154, 170))	('suppresses', 'NegReg', (16, 26))	('glioma', 'Phenotype', 'HP:0009733', (164, 170))	('cell migration', 'CPA', (66, 80))	('matrix metalloproteinases-2', 'Gene', '4313', (100, 127))	('cell proliferation', 'CPA', (27, 45))	('MMP-2', 'Gene', '4313', (129, 134))	('matrix metalloproteinases-2', 'Gene', (100, 127))	('KIF2A', 'Gene', (0, 5))	('cell invasion', 'CPA', (47, 60))	('KIF2A', 'Gene', '3796', (0, 5))	('human', 'Species', '9606', (148, 153))	('malignant glioma', 'Disease', (154, 170))	('knockdown', 'Var', (6, 15))	('MMP-2', 'Gene', (129, 134))	('activity', 'MPA', (136, 144))
313265	33331418	For example, a study reports that KIF2A high expression is associated with elevated Ann Arbor stage and international prognostic index score in DLBCL patients.	('high expression', 'Var', (40, 55))	('elevated', 'PosReg', (75, 83))	('KIF2A', 'Gene', (34, 39))	('patients', 'Species', '9606', (150, 158))	('Ann Arbor stage', 'MPA', (84, 99))	('international prognostic index score', 'MPA', (104, 140))	('KIF2A', 'Gene', '3796', (34, 39))
313266	33331418	Also, one study reports that KIF2A high expression is correlated with lymph node metastasis and HER2 positive cancer in breast cancer patients, and another study shows that KIF2A high expression is associated with increased pathological grade in glioma patients.	('breast cancer', 'Disease', (120, 133))	('breast cancer', 'Disease', 'MESH:D001943', (120, 133))	('patients', 'Species', '9606', (253, 261))	('patients', 'Species', '9606', (134, 142))	('KIF2A', 'Gene', '3796', (173, 178))	('KIF2A', 'Gene', '3796', (29, 34))	('HER2', 'Gene', (96, 100))	('cancer', 'Disease', (127, 133))	('lymph node metastasis', 'CPA', (70, 91))	('cancer', 'Disease', (110, 116))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('glioma', 'Disease', (246, 252))	('high', 'Var', (179, 183))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('glioma', 'Disease', 'MESH:D005910', (246, 252))	('KIF2A', 'Gene', (173, 178))	('KIF2A', 'Gene', (29, 34))	('breast cancer', 'Phenotype', 'HP:0003002', (120, 133))	('glioma', 'Phenotype', 'HP:0009733', (246, 252))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('increased', 'PosReg', (214, 223))	('correlated', 'Reg', (54, 64))	('pathological grade', 'CPA', (224, 242))	('HER2', 'Gene', '2064', (96, 100))	('cancer', 'Disease', 'MESH:D009369', (110, 116))
313268	33331418	Moreover, KIF2A expression was positively correlated with WBC level, monosomal karyotype possibility, and risk stratification in AML patients.	('monosomal', 'Var', (69, 78))	('AML', 'Disease', 'MESH:D015470', (129, 132))	('patients', 'Species', '9606', (133, 141))	('WBC level', 'MPA', (58, 67))	('AML', 'Disease', (129, 132))	('KIF2A', 'Gene', (10, 15))	('KIF2A', 'Gene', '3796', (10, 15))	('correlated', 'Reg', (42, 52))	('expression', 'MPA', (16, 26))
313275	33331418	In our study, KIF2A knockdown inhibited cell proliferation and promoted cell apoptosis in both HL-60 and KG-1 cell lines.	('inhibited', 'NegReg', (30, 39))	('cell apoptosis', 'CPA', (72, 86))	('HL-60', 'CellLine', 'CVCL:0002', (95, 100))	('promoted', 'PosReg', (63, 71))	('KIF2A', 'Gene', '3796', (14, 19))	('KIF2A', 'Gene', (14, 19))	('knockdown', 'Var', (20, 29))	('cell proliferation', 'CPA', (40, 58))	('KG-1', 'CellLine', 'CVCL:0374', (105, 109))
313276	33331418	These data suggested that KIF2A knockdown might serve as an anti-tumor approach by inhibiting cell proliferation and enhancing cell apoptosis in AML cells, which provided indications for further explorations on treatment for AML.	('AML', 'Disease', (145, 148))	('tumor', 'Disease', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('KIF2A', 'Gene', (26, 31))	('knockdown', 'Var', (32, 41))	('KIF2A', 'Gene', '3796', (26, 31))	('cell apoptosis', 'CPA', (127, 141))	('AML', 'Disease', (225, 228))	('enhancing', 'PosReg', (117, 126))	('inhibiting', 'NegReg', (83, 93))	('cell proliferation', 'CPA', (94, 112))	('AML', 'Disease', 'MESH:D015470', (145, 148))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('AML', 'Disease', 'MESH:D015470', (225, 228))
313280	33331418	In conclusion, KIF2A high expression predicted increased AML risk, and correlated with elevated WBC level, presence of monosomal karyotype, worse risk stratification, shorter EFS, as well as worse OS.	('KIF2A', 'Gene', (15, 20))	('KIF2A', 'Gene', '3796', (15, 20))	('AML', 'Disease', 'MESH:D015470', (57, 60))	('WBC level', 'MPA', (96, 105))	('increased', 'PosReg', (47, 56))	('high expression', 'Var', (21, 36))	('AML', 'Disease', (57, 60))	('EFS', 'MPA', (175, 178))	('elevated', 'PosReg', (87, 95))
313281	33331418	Moreover, its knockdown inhibited cell proliferation but enhanced cell apoptosis in AML.	('cell proliferation', 'CPA', (34, 52))	('AML', 'Disease', 'MESH:D015470', (84, 87))	('inhibited', 'NegReg', (24, 33))	('AML', 'Disease', (84, 87))	('cell apoptosis', 'CPA', (66, 80))	('knockdown', 'Var', (14, 23))	('enhanced', 'PosReg', (57, 65))
313288	32571328	miR-130a-5p was diminished in NSCLC tissues and cells versus their counterparts.	('diminished', 'NegReg', (16, 26))	('NSCLC', 'Disease', 'MESH:D002289', (30, 35))	('miR-130a-5p', 'Chemical', '-', (0, 11))	('NSCLC', 'Disease', (30, 35))	('miR-130a-5p', 'Var', (0, 11))
313289	32571328	miR-130a-5p exerted its repressive role in NSCLC by curtailing cell viability, migration, invasion as well as EMT, while facilitating apoptosis.	('facilitating', 'PosReg', (121, 133))	('EMT', 'CPA', (110, 113))	('apoptosis', 'CPA', (134, 143))	('cell viability', 'CPA', (63, 77))	('miR-130a-5p', 'Chemical', '-', (0, 11))	('miR-130a-5p', 'Var', (0, 11))	('curtailing', 'NegReg', (52, 62))	('NSCLC', 'Disease', (43, 48))	('invasion', 'CPA', (90, 98))	('NSCLC', 'Disease', 'MESH:D002289', (43, 48))
313290	32571328	miR-130a-5p directly targeted RUNX2, a transcription factor, and conversely regulated its expression.	('regulated', 'Reg', (76, 85))	('targeted', 'Reg', (21, 29))	('RUNX2', 'Gene', (30, 35))	('miR-130a-5p', 'Chemical', '-', (0, 11))	('expression', 'MPA', (90, 100))	('miR-130a-5p', 'Var', (0, 11))
313292	32571328	Following the validation of the supporting role of STK32A in NSCLC cells and NF-kappaB p65 phosphorylation, RUNX2 overexpression was monitored to reverse miR-130a-5p-inhibited NSCLC tumor volume and weight through enhancing STK32A expression in vivo.	('NF-kappaB p65', 'Gene', '5970', (77, 90))	('NSCLC', 'Disease', (176, 181))	('NSCLC tumor', 'Disease', 'MESH:D009369', (176, 187))	('NSCLC tumor', 'Disease', (176, 187))	('STK32A', 'Gene', (51, 57))	('STK32A', 'Gene', (224, 230))	('NSCLC', 'Disease', 'MESH:D002289', (176, 181))	('miR-130a-5p', 'Chemical', '-', (154, 165))	('miR-130a-5p-inhibited', 'Var', (154, 175))	('NSCLC', 'Disease', (61, 66))	('STK32A', 'Gene', '202374', (224, 230))	('STK32A', 'Gene', '202374', (51, 57))	('NF-kappaB p65', 'Gene', (77, 90))	('NSCLC', 'Disease', 'MESH:D002289', (61, 66))	('expression', 'MPA', (231, 241))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))	('enhancing', 'PosReg', (214, 223))
313293	32571328	miR-130a-5p diminished the growth and EMT of NSCLC cells by regulating the RUNX2/STK32A/NF-kappaB p65 axis, offering possible targets for the treatment for NSCLC.	('STK32A', 'Gene', (81, 87))	('regulating', 'Reg', (60, 70))	('growth', 'CPA', (27, 33))	('EMT', 'CPA', (38, 41))	('STK32A', 'Gene', '202374', (81, 87))	('NSCLC', 'Disease', (45, 50))	('miR-130a-5p', 'Chemical', '-', (0, 11))	('NSCLC', 'Disease', 'MESH:D002289', (45, 50))	('NF-kappaB p65', 'Gene', (88, 101))	('NF-kappaB p65', 'Gene', '5970', (88, 101))	('NSCLC', 'Disease', (156, 161))	('miR-130a-5p', 'Var', (0, 11))	('NSCLC', 'Disease', 'MESH:D002289', (156, 161))	('diminished', 'NegReg', (12, 22))
313301	32571328	The dysfunction of miR-130a-5p has been implicated in breast cancer, esophageal squamous cell carcinoma as well as glioma.	('breast cancer', 'Disease', (54, 67))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (69, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('glioma', 'Disease', (115, 121))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (80, 103))	('miR-130a-5p', 'Gene', (19, 30))	('miR-130a-5p', 'Chemical', '-', (19, 30))	('dysfunction', 'Var', (4, 15))	('esophageal squamous cell carcinoma', 'Disease', (69, 103))	('implicated', 'Reg', (40, 50))	('glioma', 'Phenotype', 'HP:0009733', (115, 121))	('glioma', 'Disease', 'MESH:D005910', (115, 121))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('breast cancer', 'Disease', 'MESH:D001943', (54, 67))	('breast cancer', 'Phenotype', 'HP:0003002', (54, 67))
313303	32571328	Meanwhile, miR-130a-3p suppressed malignant phenotype of gastric carcinoma cells and subsequent EMT process.	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('gastric carcinoma', 'Disease', 'MESH:D013274', (57, 74))	('suppressed', 'NegReg', (23, 33))	('gastric carcinoma', 'Disease', (57, 74))	('EMT process', 'CPA', (96, 107))	('miR-130a-3p', 'Chemical', '-', (11, 22))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (57, 74))	('miR-130a-3p', 'Var', (11, 22))
313337	32571328	The primary antibodies included E-cadherin (1:30000, ab40772), N-cadherin (1:100, ab18203), vimentin (1:3000, ab92547), RUNX 2 (1:100, ab23981), GAPDH (1:2500, ab9485), Phospho-NF-kappaB (p65, Ser536; 1:1000, #3033, Cell Signaling Technologies (CST), Beverly, MA, USA), NF-kappaB (p65, 1:1000, #8242, CST) and the corresponding horseradish peroxidase-labelled secondary antibody (1:50000, ab205718).	('NF-kappaB', 'Gene', (177, 186))	('GAPDH', 'Gene', '2597', (145, 150))	('p65', 'Gene', '5970', (188, 191))	('NF-kappaB', 'Gene', '4790', (177, 186))	('1:100', 'Var', (128, 133))	('NF-kappaB', 'Gene', (270, 279))	('GAPDH', 'Gene', (145, 150))	('p65', 'Gene', (281, 284))	('horseradish', 'Species', '3704', (328, 339))	('NF-kappaB', 'Gene', '4790', (270, 279))	('1:3000', 'Var', (102, 108))	('p65', 'Gene', '5970', (281, 284))	('E-cadherin', 'Gene', (32, 42))	('p65', 'Gene', (188, 191))	('E-cadherin', 'Gene', '999', (32, 42))	('N-cadherin', 'Gene', (63, 73))	('vimentin', 'Gene', '7431', (92, 100))	('N-cadherin', 'Gene', '1000', (63, 73))	('vimentin', 'Gene', (92, 100))
313339	32571328	The wild-type (WT) RUNX2 sequence, 3'untraslated region (3'UTR) sequences of RUNX2 containing the predicted binding sites for miR-130a-5p, or mutated RUNX2 sequence, 3'UTR sequences of RUNX2 without miR-130a-5p binding sites were inserted into pMIR-REPORT  promoter vectors (Thermo Fisher Scientific Inc., Waltham, MA, USA).	('miR-130a-5p', 'Chemical', '-', (199, 210))	('miR-130a-5p', 'Chemical', '-', (126, 137))	('mutated', 'Var', (142, 149))	('RUNX2', 'Gene', (150, 155))
313348	32571328	Meanwhile, we performed RT-qPCR experiments on lung adenocarcinoma cells A549, H1650, a lung squamous cell line SK-MES-1 and normal lung cells WI-38, and found significantly reduced expression of miR-130a-5p (Fig.	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (47, 66))	('expression', 'MPA', (182, 192))	('A549', 'CellLine', 'CVCL:0023', (73, 77))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (47, 66))	('carcinoma', 'Phenotype', 'HP:0030731', (57, 66))	('SK-MES-1', 'CellLine', 'CVCL:0630', (112, 120))	('miR-130a-5p', 'Var', (196, 207))	('miR-130a-5p', 'Chemical', '-', (196, 207))	('lung adenocarcinoma', 'Disease', (47, 66))	('reduced', 'NegReg', (174, 181))
313351	32571328	Meanwhile, the five-year survival curve showed that patients with higher miR-130a-5p expression had higher survival (Fig.	('miR-130a-5p', 'Var', (73, 84))	('survival', 'MPA', (107, 115))	('higher', 'PosReg', (100, 106))	('patients', 'Species', '9606', (52, 60))	('miR-130a-5p', 'Chemical', '-', (73, 84))
313352	32571328	All in all, miR-130a-5p maybe act as a tumor inhibitor in NSCLC.	('NSCLC', 'Disease', (58, 63))	('miR-130a-5p', 'Chemical', '-', (12, 23))	('NSCLC', 'Disease', 'MESH:D002289', (58, 63))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumor', 'Disease', (39, 44))	('miR-130a-5p', 'Var', (12, 23))
313355	32571328	miR-130a-5p mimic significantly inhibited proliferation of NSCLC cell lines and reduced the number of colonies formed, while miR-130a-5p inhibitor contributed to increased proliferation of NSCLC cell lines and more colonies formed (Fig.	('NSCLC', 'Disease', (189, 194))	('miR-130a-5p', 'Var', (125, 136))	('NSCLC', 'Disease', 'MESH:D002289', (59, 64))	('proliferation', 'CPA', (172, 185))	('miR-130a-5p', 'Chemical', '-', (125, 136))	('increased', 'PosReg', (162, 171))	('inhibited', 'NegReg', (32, 41))	('proliferation', 'CPA', (42, 55))	('NSCLC', 'Disease', 'MESH:D002289', (189, 194))	('reduced', 'NegReg', (80, 87))	('more', 'PosReg', (210, 214))	('colonies formed', 'CPA', (215, 230))	('miR-130a-5p', 'Chemical', '-', (0, 11))	('NSCLC', 'Disease', (59, 64))
313358	32571328	Flow cytometry clearly displayed a promoting effect of miR-130a-5p mimic on apoptosis of NSCLC cells (Fig.	('NSCLC', 'Disease', 'MESH:D002289', (89, 94))	('miR-130a-5p mimic', 'Var', (55, 72))	('miR-130a-5p', 'Chemical', '-', (55, 66))	('promoting', 'PosReg', (35, 44))	('apoptosis', 'CPA', (76, 85))	('NSCLC', 'Disease', (89, 94))
313359	32571328	Together, these results suggest that miR-130a-5p overexpression suppresses development of NSCLC cells.	('miR-130a-5p overexpression', 'Var', (37, 63))	('NSCLC', 'Disease', (90, 95))	('miR-130a-5p', 'Chemical', '-', (37, 48))	('suppresses', 'NegReg', (64, 74))	('NSCLC', 'Disease', 'MESH:D002289', (90, 95))
313361	32571328	We found that the higher the N grade (i.e., the higher the degree of lymph node metastasis), the lower the expression of miR-130a-5p (Fig.	('miR-130a-5p', 'Chemical', '-', (121, 132))	('miR-130a-5p', 'Var', (121, 132))	('expression', 'MPA', (107, 117))	('lower', 'NegReg', (97, 102))
313363	32571328	We monitored that miR-130a-5p significantly inhibited Vimentin and N-cadherin expression, while facilitated E-cadherin expression (Fig.	('E-cadherin', 'Gene', (108, 118))	('E-cadherin', 'Gene', '999', (108, 118))	('miR-130a-5p', 'Chemical', '-', (18, 29))	('inhibited', 'NegReg', (44, 53))	('Vimentin', 'Gene', (54, 62))	('facilitated', 'PosReg', (96, 107))	('N-cadherin', 'Gene', (67, 77))	('Vimentin', 'Gene', '7431', (54, 62))	('miR-130a-5p', 'Var', (18, 29))	('N-cadherin', 'Gene', '1000', (67, 77))
313364	32571328	Taken together, miR-130a-5p inhibited metastasis in NSCLC.	('miR-130a-5p', 'Var', (16, 27))	('NSCLC', 'Disease', (52, 57))	('miR-130a-5p', 'Chemical', '-', (16, 27))	('NSCLC', 'Disease', 'MESH:D002289', (52, 57))	('inhibited', 'NegReg', (28, 37))	('metastasis', 'CPA', (38, 48))
313365	32571328	The potential binding sites of miR-130a-5p to RUNX2 (Fig.	('miR-130a-5p', 'Var', (31, 42))	('miR-130a-5p', 'Chemical', '-', (31, 42))	('binding', 'Interaction', (14, 21))	('RUNX2', 'Gene', (46, 51))
313367	32571328	We thus speculated that miR-130a-5p played a tumor suppressor role in NSCLC cells by targeting RUNX2.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('targeting', 'Reg', (85, 94))	('RUNX2', 'Gene', (95, 100))	('NSCLC', 'Disease', (70, 75))	('tumor', 'Disease', (45, 50))	('NSCLC', 'Disease', 'MESH:D002289', (70, 75))	('miR-130a-5p', 'Var', (24, 35))	('miR-130a-5p', 'Chemical', '-', (24, 35))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
313368	32571328	Next, we measured the RUNX2 expression in A549 and SK-MES-1 cells delivered with miR-130a-5p mimic or inhibitor by RT-qPCR and western blot analysis.	('SK-MES-1', 'CellLine', 'CVCL:0630', (51, 59))	('expression', 'MPA', (28, 38))	('A549', 'CellLine', 'CVCL:0023', (42, 46))	('miR-130a-5p', 'Chemical', '-', (81, 92))	('miR-130a-5p mimic', 'Var', (81, 98))	('RUNX2', 'Gene', (22, 27))
313369	32571328	The obtained results revealed that miR-130a-5p could negatively modulated the expression of RUNX2 (Fig.	('RUNX2', 'Gene', (92, 97))	('expression', 'MPA', (78, 88))	('miR-130a-5p', 'Chemical', '-', (35, 46))	('negatively', 'NegReg', (53, 63))	('modulated', 'Reg', (64, 73))	('miR-130a-5p', 'Var', (35, 46))
313370	32571328	To further validate the interaction between RUNX2 and miR-130a-5p, RUNX2-WT or RUNX2-MT reporters containing wild or mutant miR-130a-5p binding sites were generated, respectively.	('miR-130a-5p', 'Gene', (124, 135))	('mutant', 'Var', (117, 123))	('miR-130a-5p', 'Chemical', '-', (54, 65))	('miR-130a-5p', 'Chemical', '-', (124, 135))
313371	32571328	Subsequent luciferase assay disclosed that the introduction of miR-130a-5p mimic led to a notable decline of luciferase activity of RUNX2-WT reporter, but had no much influence on luciferase activity of RUNX2-MT reporter (Fig.	('miR-130a-5p mimic', 'Var', (63, 80))	('luciferase', 'Enzyme', (109, 119))	('decline', 'NegReg', (98, 105))	('activity', 'MPA', (120, 128))	('miR-130a-5p', 'Chemical', '-', (63, 74))
313372	32571328	4d), which implied that miR-130a-5p could interact with RUNX2s.	('miR-130a-5p', 'Var', (24, 35))	('miR-130a-5p', 'Chemical', '-', (24, 35))	('RUNX2s', 'Protein', (56, 62))	('interact', 'Interaction', (42, 50))
313381	32571328	Also, STK32A mRNA expression was assessed in NSCLC cells following those transfections, which demonstrated that pcDNA RUNX2 promoted STK32A mRNA expression, while silencing of RUNX2 decreased STK32A expression (Fig.	('STK32A', 'Gene', (133, 139))	('STK32A', 'Gene', (192, 198))	('decreased', 'NegReg', (182, 191))	('STK32A', 'Gene', '202374', (133, 139))	('silencing', 'Var', (163, 172))	('NSCLC', 'Disease', (45, 50))	('STK32A', 'Gene', '202374', (192, 198))	('STK32A', 'Gene', (6, 12))	('NSCLC', 'Disease', 'MESH:D002289', (45, 50))	('STK32A', 'Gene', '202374', (6, 12))	('pcDNA', 'Var', (112, 117))	('promoted', 'PosReg', (124, 132))	('RUNX2', 'Gene', (118, 123))
313382	32571328	To explore the role of STK32A on NSCLC progress, we overexpressed or silenced STK32A in A549 and SK-MES-1 cells, the efficiency of which was validated through RT-qPCR (Fig.	('STK32A', 'Gene', (78, 84))	('SK-MES-1', 'CellLine', 'CVCL:0630', (97, 105))	('STK32A', 'Gene', (23, 29))	('STK32A', 'Gene', '202374', (78, 84))	('STK32A', 'Gene', '202374', (23, 29))	('silenced', 'Var', (69, 77))	('NSCLC', 'Disease', (33, 38))	('A549', 'CellLine', 'CVCL:0023', (88, 92))	('NSCLC', 'Disease', 'MESH:D002289', (33, 38))
313388	32571328	Finally, we set to explore the regulatory mechanisms of miR-130a-5p, RUNX2, STK32A in NSCLC.	('miR-130a-5p', 'Chemical', '-', (56, 67))	('NSCLC', 'Disease', (86, 91))	('RUNX2', 'Gene', (69, 74))	('NSCLC', 'Disease', 'MESH:D002289', (86, 91))	('STK32A', 'Gene', (76, 82))	('STK32A', 'Gene', '202374', (76, 82))	('miR-130a-5p', 'Var', (56, 67))
313389	32571328	The expression of STK32A in A549 and SK-MES-1 cells delivered with miR-130a-5p mimic and miR-130a-5p mimic + pcDNA RUNX2 and their controls was measured (Fig.	('miR-130a-5p', 'Chemical', '-', (67, 78))	('SK-MES-1', 'CellLine', 'CVCL:0630', (37, 45))	('A549', 'CellLine', 'CVCL:0023', (28, 32))	('miR-130a-5p mimic', 'Var', (67, 84))	('STK32A', 'Gene', (18, 24))	('miR-130a-5p', 'Chemical', '-', (89, 100))	('STK32A', 'Gene', '202374', (18, 24))	('miR-130a-5p mimic', 'Var', (89, 106))
313395	32571328	Therefore, we supposed that overexpression of RUNX2 reversed its degradation caused by miR-130a-5p, through which RUNX2 mimic reversed miR-130a-5p-mediated effects.	('miR-130a-5p', 'Chemical', '-', (135, 146))	('degradation', 'MPA', (65, 76))	('miR-130a-5p', 'Chemical', '-', (87, 98))	('miR-130a-5p', 'Var', (87, 98))
313396	32571328	After administration of A549 cells stably transfected with miR-130a-5p mimic, miR-130a-5p mimic + pcDNA RUNX2 or their controls into nude mice, quantification displayed that miR-130a-5p mimic reduced the tumor weight and volume.	('A549', 'CellLine', 'CVCL:0023', (24, 28))	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('nude mice', 'Species', '10090', (133, 142))	('miR-130a-5p', 'Chemical', '-', (78, 89))	('tumor', 'Disease', (204, 209))	('miR-130a-5p', 'Chemical', '-', (174, 185))	('miR-130a-5p', 'Chemical', '-', (59, 70))	('reduced', 'NegReg', (192, 199))	('miR-130a-5p mimic', 'Var', (174, 191))
313398	32571328	The above experiments demonstrated that miR-130a-5p downregulated the expression of STK32A by targeting the transcription factor RUNX2, thus exerting its inhibitory effect on NSCLC.	('NSCLC', 'Disease', 'MESH:D002289', (175, 180))	('miR-130a-5p', 'Var', (40, 51))	('targeting', 'NegReg', (94, 103))	('miR-130a-5p', 'Chemical', '-', (40, 51))	('RUNX2', 'Gene', (129, 134))	('downregulated', 'NegReg', (52, 65))	('expression', 'MPA', (70, 80))	('inhibitory', 'MPA', (154, 164))	('STK32A', 'Gene', '202374', (84, 90))	('NSCLC', 'Disease', (175, 180))	('STK32A', 'Gene', (84, 90))
313403	32571328	In addition, overexpression of miR-130a-5p diminished the growth, migration, invasion and EMT event, while promoted apoptosis of A549 and SK-MES-1 cells.	('SK-MES-1', 'CellLine', 'CVCL:0630', (138, 146))	('apoptosis', 'CPA', (116, 125))	('invasion', 'CPA', (77, 85))	('A549', 'CellLine', 'CVCL:0023', (129, 133))	('miR-130a-5p', 'Chemical', '-', (31, 42))	('EMT event', 'CPA', (90, 99))	('miR-130a-5p', 'Var', (31, 42))	('promoted', 'PosReg', (107, 115))	('diminished', 'NegReg', (43, 53))	('growth', 'CPA', (58, 64))
313406	32571328	Furthermore, RUNX2 upregulation rescued the suppressive effects of miR-130a-5p on the tumorigenesis of A549 cells.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('miR-130a-5p', 'Var', (67, 78))	('miR-130a-5p', 'Chemical', '-', (67, 78))	('tumor', 'Disease', (86, 91))	('RUNX2', 'Gene', (13, 18))	('A549', 'CellLine', 'CVCL:0023', (103, 107))	('upregulation', 'PosReg', (19, 31))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
313408	32571328	The expression of miR-130a-5p in gastric cancer cell lines was found to be repressed relative to normal gastric epithelial mucosa cells.	('miR-130a-5p', 'Chemical', '-', (18, 29))	('gastric cancer', 'Disease', (33, 47))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('gastric cancer', 'Disease', 'MESH:D013274', (33, 47))	('gastric cancer', 'Phenotype', 'HP:0012126', (33, 47))	('miR-130a-5p', 'Var', (18, 29))
313411	32571328	Moreover, miR-130a-3p was participated in suppression of glioma cell migration, invasion as well as EMT process with declines in N-cadherin and Vimentin expression by H19 knockdown.	('N-cadherin', 'Gene', (129, 139))	('H19', 'Gene', (167, 170))	('invasion', 'CPA', (80, 88))	('glioma', 'Phenotype', 'HP:0009733', (57, 63))	('declines', 'NegReg', (117, 125))	('suppression', 'NegReg', (42, 53))	('Vimentin', 'Gene', '7431', (144, 152))	('glioma', 'Disease', (57, 63))	('N-cadherin', 'Gene', '1000', (129, 139))	('EMT process', 'CPA', (100, 111))	('knockdown', 'Var', (171, 180))	('miR-130a-3p', 'Chemical', '-', (10, 21))	('expression', 'MPA', (153, 163))	('glioma', 'Disease', 'MESH:D005910', (57, 63))	('H19', 'Gene', '283120', (167, 170))	('Vimentin', 'Gene', (144, 152))	('miR-130a-3p', 'Var', (10, 21))
313413	32571328	However, the detailed mechanism of miR-130a-5p in NSCLC remains exclusive.	('miR-130a-5p', 'Chemical', '-', (35, 46))	('miR-130a-5p', 'Var', (35, 46))	('NSCLC', 'Disease', (50, 55))	('NSCLC', 'Disease', 'MESH:D002289', (50, 55))
313415	32571328	Further bioinformatics and dual-luciferase assays revealed that RUNX2 is a target of miR-130a-5p.	('miR-130a-5p', 'Chemical', '-', (85, 96))	('RUNX2', 'Gene', (64, 69))	('miR-130a-5p', 'Var', (85, 96))
313416	32571328	We also established that RUNX2 expression was decreased following miR-130a-5p restoration in A549 and SK-MES-1 cells.	('A549', 'CellLine', 'CVCL:0023', (93, 97))	('expression', 'MPA', (31, 41))	('miR-130a-5p restoration', 'Var', (66, 89))	('SK-MES-1', 'CellLine', 'CVCL:0630', (102, 110))	('RUNX2', 'Gene', (25, 30))	('decreased', 'NegReg', (46, 55))	('miR-130a-5p', 'Chemical', '-', (66, 77))
313417	32571328	In line with our findings, RUNX2, which was upregulated in breast cancer, was substantiated as a target of miR-153 and negatively modulated by miR-153 in breast cancer tissues.	('breast cancer', 'Disease', 'MESH:D001943', (154, 167))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('miR-153', 'Chemical', '-', (107, 114))	('miR-153', 'Var', (107, 114))	('breast cancer', 'Disease', (154, 167))	('upregulated', 'PosReg', (44, 55))	('breast cancer', 'Disease', 'MESH:D001943', (59, 72))	('RUNX2', 'Gene', (27, 32))	('breast cancer', 'Phenotype', 'HP:0003002', (154, 167))	('breast cancer', 'Disease', (59, 72))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('breast cancer', 'Phenotype', 'HP:0003002', (59, 72))	('miR-153', 'Chemical', '-', (143, 150))	('modulated', 'Reg', (130, 139))	('negatively', 'NegReg', (119, 129))
313419	32571328	While in cervical cancer, knockdown of CCAT1 prevented the tumor progression by blocking the cell growth, migration, invasion and EMT by downregulating RUNX2.	('cancer', 'Disease', (18, 24))	('cell growth', 'CPA', (93, 104))	('tumor', 'Disease', (59, 64))	('invasion', 'CPA', (117, 125))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('CCAT1', 'Gene', '100507056', (39, 44))	('prevented', 'NegReg', (45, 54))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('RUNX2', 'Gene', (152, 157))	('blocking', 'NegReg', (80, 88))	('knockdown', 'Var', (26, 35))	('CCAT1', 'Gene', (39, 44))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('migration', 'CPA', (106, 115))	('downregulating', 'NegReg', (137, 151))	('cancer', 'Disease', 'MESH:D009369', (18, 24))	('EMT', 'CPA', (130, 133))
313422	32571328	Therefore, we may conclude that miR-130a-5p plays tumor-suppressing properties in NSCLC by downregulating RUNX2 expression.	('miR-130a-5p', 'Var', (32, 43))	('RUNX2', 'Gene', (106, 111))	('NSCLC', 'Disease', 'MESH:D002289', (82, 87))	('miR-130a-5p', 'Chemical', '-', (32, 43))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('downregulating', 'NegReg', (91, 105))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('NSCLC', 'Disease', (82, 87))	('tumor', 'Disease', (50, 55))	('expression', 'MPA', (112, 122))
313424	32571328	Our further western blot analysis revealed that miR-130a-5p mimic contributed to the lowered extent of NF-kappaB p65 phosphorylation, while RUNX2 overexpression enhanced its activation.	('miR-130a-5p mimic', 'Var', (48, 65))	('lowered', 'NegReg', (85, 92))	('NF-kappaB p65', 'Gene', (103, 116))	('NF-kappaB p65', 'Gene', '5970', (103, 116))	('phosphorylation', 'MPA', (117, 132))	('miR-130a-5p', 'Chemical', '-', (48, 59))
313433	32571328	By contrast, STK32A knockdown culminated in the opposite trends.	('knockdown', 'Var', (20, 29))	('STK32A', 'Gene', '202374', (13, 19))	('STK32A', 'Gene', (13, 19))
313436	32571328	However, our data only hint the vital roles of miR-130a-5p and STK32A in NSCLC cells.	('miR-130a-5p', 'Var', (47, 58))	('NSCLC', 'Disease', (73, 78))	('STK32A', 'Gene', (63, 69))	('miR-130a-5p', 'Chemical', '-', (47, 58))	('STK32A', 'Gene', '202374', (63, 69))	('NSCLC', 'Disease', 'MESH:D002289', (73, 78))
313447	31652722	Evidence suggests that variations in RAD52 expression can influence HR activity and, subsequently, influence the predisposition and treatment efficacy of cancer.	('treatment efficacy', 'CPA', (132, 150))	('influence', 'Reg', (99, 108))	('cancer', 'Disease', (154, 160))	('RAD52', 'Gene', (37, 42))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('predisposition', 'CPA', (113, 127))	('HR activity', 'MPA', (68, 79))	('influence', 'Reg', (58, 67))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('variations', 'Var', (23, 33))
313451	31652722	Causes of DNA-damaging insults include errors in DNA replication, telomeric shortening, and reactive oxygen species (ROS) which, in turn, are induced by endogenous and exogenous factors.	('telomeric shortening', 'CPA', (66, 86))	('DNA', 'Gene', (49, 52))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (92, 115))	('ROS', 'Chemical', 'MESH:D017382', (117, 120))	('errors', 'Var', (39, 45))	('reactive oxygen species', 'MPA', (92, 115))	('telomeric shortening', 'Phenotype', 'HP:0031413', (66, 86))
313455	31652722	On the other hand, the effects of DNA damage signaling deregulation can have implications in cancer therapy resulting in hypersensitive or resistant tumor cells to therapeutic agents.	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('hypersensitive', 'Disease', (121, 135))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('deregulation', 'Var', (55, 67))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('tumor', 'Disease', (149, 154))	('implications', 'Reg', (77, 89))	('hypersensitive', 'Disease', 'MESH:D004342', (121, 135))
313459	31652722	Per day, various DNA-damaging agents can attack the cells and, consequently, originate a wide range of damages including single base lesions, DNA adducts, DNA crosslinks, single-strand breaks (SSBs), and double-strand breaks (DSBs).	('crosslinks', 'Var', (159, 169))	('originate', 'Reg', (77, 86))	('single base lesions', 'MPA', (121, 140))	('single-strand breaks', 'MPA', (171, 191))	('double-strand breaks', 'MPA', (204, 224))	('DSBs', 'Chemical', '-', (226, 230))	('adducts', 'Var', (146, 153))
313461	31652722	However, if the DDR process is inefficient or nonfunctional, accumulation of DNA damage may result in genetic mutations and aberrant chromosomal segregations that can increase genomic instability, contributing to a higher risk of cancer development.	('cancer', 'Disease', 'MESH:D009369', (230, 236))	('mutations', 'Var', (110, 119))	('aberrant chromosomal segregations', 'CPA', (124, 157))	('result in', 'Reg', (92, 101))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('DDR', 'Chemical', '-', (16, 19))	('cancer', 'Disease', (230, 236))	('increase', 'PosReg', (167, 175))	('genomic instability', 'MPA', (176, 195))
313478	31652722	Unpaired or incorrectly repaired DSBs can cause loss of genetic information, cell growth arrest, cell death, and carcinogenesis.	('arrest', 'Disease', (89, 95))	('loss', 'NegReg', (48, 52))	('carcinogenesis', 'Disease', 'MESH:D063646', (113, 127))	('death', 'Disease', 'MESH:D003643', (102, 107))	('death', 'Disease', (102, 107))	('DSBs', 'Chemical', '-', (33, 37))	('DSBs', 'Gene', (33, 37))	('carcinogenesis', 'Disease', (113, 127))	('Unpaired', 'Var', (0, 8))	('genetic', 'MPA', (56, 63))	('growth arrest', 'Phenotype', 'HP:0001510', (82, 95))	('arrest', 'Disease', 'MESH:D006323', (89, 95))
313484	31652722	After that, through the joint action of RAD51 paralogs (RAD51B, RAD51C, RAD51D, XRCC2, and XRCC3), RAD52, RAD54, and BRCA2 occurs the formation of the RAD51-ssDNA filament.	('RAD51C', 'Gene', '5889', (64, 70))	('XRCC2', 'Gene', (80, 85))	('RAD51B', 'Gene', (56, 62))	('RAD51', 'Gene', (72, 77))	('RAD51D', 'Gene', '5892', (72, 78))	('RAD51', 'Gene', (56, 61))	('XRCC3', 'Gene', '7517', (91, 96))	('RAD54', 'Gene', (106, 111))	('RAD51', 'Gene', '5888', (72, 77))	('RAD51', 'Gene', '5888', (56, 61))	('RAD51C', 'Gene', (64, 70))	('RAD51', 'Gene', (40, 45))	('BRCA2', 'Gene', (117, 122))	('RAD51', 'Gene', '5888', (40, 45))	('RAD51', 'Gene', (64, 69))	('RAD51', 'Gene', '5888', (64, 69))	('RAD51', 'Gene', (151, 156))	('RAD51', 'Gene', '5888', (151, 156))	('XRCC2', 'Gene', '7516', (80, 85))	('XRCC3', 'Gene', (91, 96))	('RAD51B', 'Gene', '5890', (56, 62))	('BRCA2', 'Gene', '675', (117, 122))	('RAD51D', 'Gene', (72, 78))	('RAD54', 'Gene', '8438', (106, 111))	('RAD52', 'Var', (99, 104))
313492	31652722	When BRCA2 and PALB2 genes are depleted, defective activity of the human RAD52 can be synthetically lethal.	('PALB2', 'Gene', '79728', (15, 20))	('PALB2', 'Gene', (15, 20))	('RAD52', 'Gene', (73, 78))	('BRCA2', 'Gene', (5, 10))	('defective', 'Var', (41, 50))	('depleted', 'NegReg', (31, 39))	('BRCA2', 'Gene', '675', (5, 10))	('human', 'Species', '9606', (67, 72))
313506	31652722	This discordance between expression and activity of RAD52 gene suggests that altered DNA repair mechanism promotes prostate tumor progression.	('prostate tumor', 'Phenotype', 'HP:0100787', (115, 129))	('RAD52', 'Gene', (52, 57))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('promotes', 'PosReg', (106, 114))	('prostate tumor', 'Disease', 'MESH:D011471', (115, 129))	('altered', 'Var', (77, 84))	('prostate tumor', 'Disease', (115, 129))
313514	31652722	Tyr-104 residue is located in the N-terminal domain of RAD52 which is responsible for enhancing RAD52 activity and stimulation of RAD52 foci formation.	('Tyr', 'Chemical', 'MESH:D014443', (0, 3))	('RAD52', 'Gene', (55, 60))	('Tyr-104 residue', 'Var', (0, 15))	('enhancing', 'PosReg', (86, 95))	('activity', 'MPA', (102, 110))	('RAD52', 'Enzyme', (96, 101))	('RAD52', 'Protein', (130, 135))	('stimulation', 'PosReg', (115, 126))
313524	31652722	Later, Barlow group developed a study that established that murine RAD52 gene expression is associated with Ataxia Telangiectasia (A-T).	('murine', 'Var', (60, 66))	('murine', 'Species', '10090', (60, 66))	('RAD52', 'Gene', (67, 72))	('Ataxia Telangiectasia (A-T', 'Disease', 'MESH:D001260', (108, 134))	('associated', 'Reg', (92, 102))	('Telangiectasia', 'Phenotype', 'HP:0001009', (115, 129))	('Ataxia', 'Phenotype', 'HP:0001251', (108, 114))
313525	31652722	Therefore, tumor formation can occur with aberrant chromosome abnormalities due to loss of ATM kinase activity and uncontrolled HR, promoting an increased risk of cancer caused by A-T. Another study developed by this group, showed, using an in vivo ATM-/- mouse model, that RAD52 knockout seems to confer a longer latency period in T-cell lymphoma development, as well as an increase lifespan and decrease of tumor incidence when compared with the RAD52 wildtype model.	('tumor', 'Disease', (409, 414))	('decrease', 'NegReg', (397, 405))	('ATM', 'Gene', (249, 252))	('tumor', 'Disease', 'MESH:D009369', (409, 414))	('cancer', 'Disease', 'MESH:D009369', (163, 169))	('chromosome abnormalities', 'Phenotype', 'HP:0031411', (51, 75))	('ATM', 'Gene', '11920', (249, 252))	('knockout', 'Var', (280, 288))	('tumor', 'Disease', (11, 16))	('T-cell lymphoma', 'Disease', 'MESH:D016399', (332, 347))	('lifespan', 'CPA', (384, 392))	('tumor', 'Phenotype', 'HP:0002664', (409, 414))	('tumor', 'Disease', 'MESH:D009369', (11, 16))	('chromosome abnormalities', 'Disease', (51, 75))	('chromosome abnormalities', 'Disease', 'MESH:D002869', (51, 75))	('T-cell lymphoma', 'Phenotype', 'HP:0012190', (332, 347))	('T-cell lymphoma', 'Disease', (332, 347))	('cancer', 'Disease', (163, 169))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('increase', 'PosReg', (375, 383))	('ATM', 'Gene', (91, 94))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('lymphoma', 'Phenotype', 'HP:0002665', (339, 347))	('cell lymphoma', 'Phenotype', 'HP:0012191', (334, 347))	('RAD52', 'Gene', (274, 279))	('ATM', 'Gene', '11920', (91, 94))	('mouse', 'Species', '10090', (256, 261))
313526	31652722	This new evidence associated with the capacity to promote carcinogenesis and favor survival through RAD52 inactivation in a tumorigenic environment was speculated to be a consequence of reduction in disproportionate intrachromosomal recombination found in the ATM absence.	('inactivation', 'Var', (106, 118))	('ATM', 'Gene', '11920', (260, 263))	('RAD52', 'Gene', (100, 105))	('promote', 'PosReg', (50, 57))	('ATM', 'Gene', (260, 263))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('carcinogenesis', 'Disease', 'MESH:D063646', (58, 72))	('tumor', 'Disease', (124, 129))	('favor', 'PosReg', (77, 82))	('carcinogenesis', 'Disease', (58, 72))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
313532	31652722	used a TCGA database and showed a significant association between amplification of the genomic region where the RAD52 gene is located (locus 12p13.33) and development of lung squamous cell carcinoma (LUSC).	('amplification', 'Var', (66, 79))	('LUSC', 'Phenotype', 'HP:0030359', (200, 204))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (170, 198))	('RAD52', 'Gene', (112, 117))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (175, 198))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (170, 198))	('lung squamous cell carcinoma', 'Disease', (170, 198))	('carcinoma', 'Phenotype', 'HP:0030731', (189, 198))
313538	31652722	In addition, several evidences have demonstrated that genetic variants in DNA repair genes, such as single nucleotide polymorphisms (SNPs), can influence cancer progression and treatment response.	('DNA repair genes', 'Gene', (74, 90))	('treatment response', 'CPA', (177, 195))	('single nucleotide polymorphisms', 'Var', (100, 131))	('influence', 'Reg', (144, 153))	('cancer', 'Disease', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))
313539	31652722	analyzed three RAD52 SNPs with potential functional effect and evaluated, in an in vitro model, their association with platinum resistance and clinical outcome in cervical squamous cell carcinoma (CSCC) patients.	('association', 'Interaction', (102, 113))	('cervical squamous cell carcinoma', 'Disease', 'MESH:D002294', (163, 195))	('carcinoma', 'Phenotype', 'HP:0030731', (186, 195))	('platinum resistance', 'CPA', (119, 138))	('RAD52', 'Gene', (15, 20))	('platinum', 'Chemical', 'MESH:D010984', (119, 127))	('cervical squamous cell carcinoma', 'Disease', (163, 195))	('patients', 'Species', '9606', (203, 211))	('SNPs', 'Var', (21, 25))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (172, 195))
313541	31652722	Furthermore, these authors observed that patients with at least one variant allele have a significantly lower progression-free survival.	('patients', 'Species', '9606', (41, 49))	('lower', 'NegReg', (104, 109))	('variant', 'Var', (68, 75))	('progression-free survival', 'CPA', (110, 135))
313547	31652722	In literature, it is described that DNA repair-defective tumor cells are associated with high genomic instability which can induce the acquisition of genetic alterations in specific genes, promoting treatment resistance.	('promoting', 'PosReg', (189, 198))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('genetic alterations', 'Var', (150, 169))	('specific genes', 'Gene', (173, 187))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('treatment resistance', 'CPA', (199, 219))	('tumor', 'Disease', (57, 62))
313548	31652722	In addition, the presence of additional DNA modifications in DNA damage signaling pathways may also promote resistance to therapy in tumor cells with defective DDR activity.	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('modifications', 'Var', (44, 57))	('resistance to therapy', 'CPA', (108, 129))	('tumor', 'Disease', (133, 138))	('DNA damage signaling pathways', 'Pathway', (61, 90))	('presence', 'Var', (17, 25))	('promote', 'PosReg', (100, 107))	('DDR', 'Chemical', '-', (160, 163))
313550	31652722	This concept assumes that, in the presence of a defective repair pathway, the inactivation of an additional pathway can result in cell death by DNA damage accumulation caused by the inactivation of two complementary repair pathways.	('inactivation', 'Var', (182, 194))	('defective', 'Var', (48, 57))	('death', 'Disease', 'MESH:D003643', (135, 140))	('death', 'Disease', (135, 140))	('DNA damage accumulation', 'MPA', (144, 167))	('inactivation', 'NegReg', (78, 90))
313551	31652722	On the other hand, the depletion of a single pathway is not enough to cause cell death, given that, in the presence of a defective repair activity, the cell remains capable of tolerating damage and promoting cell survival.	('death', 'Disease', 'MESH:D003643', (81, 86))	('activity', 'MPA', (138, 146))	('death', 'Disease', (81, 86))	('defective', 'Var', (121, 130))	('cell survival', 'CPA', (208, 221))	('promoting', 'PosReg', (198, 207))	('tolerating damage', 'MPA', (176, 193))
313552	31652722	In clinical practice, this concept is frequently exploited, when tumor cells are deficient in one of the repair mechanisms owing to a genetic alteration and another mechanism is pharmacologically inactivated by the targeted cytotoxic agent.	('deficient', 'NegReg', (81, 90))	('tumor', 'Disease', (65, 70))	('genetic alteration', 'Var', (134, 152))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
313556	31652722	Initially, synthetic lethality concept development was encouraged to kill cancer cells with inactivating mutations in BRCA1 and BRAC2 by poly adenosine 5'-disphosphate ribose polymerase (PARP) inhibition.	('adenosine', 'Chemical', 'MESH:D000241', (142, 151))	('PARP', 'Gene', '142', (187, 191))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('BRCA1', 'Gene', '672', (118, 123))	('cancer', 'Disease', (74, 80))	('BRAC2', 'Gene', (128, 133))	('PARP', 'Gene', (187, 191))	('inactivating mutations', 'Var', (92, 114))	('BRCA1', 'Gene', (118, 123))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
313557	31652722	Actually, there are preliminary evidence reporting the application of synthetic lethality dependent of RAD52 gene in cells with mutations in BRCA1 and BRCA2 genes, as well as in cells with suppressed BRCA1-RAD51 pathway due to oncogenes activation or epigenetic modifications associated to malignancy of phenotypes.	('RAD51', 'Gene', (206, 211))	('malignancy', 'Disease', (290, 300))	('mutations', 'Var', (128, 137))	('BRCA1', 'Gene', '672', (141, 146))	('epigenetic modifications', 'Var', (251, 275))	('BRCA1', 'Gene', '672', (200, 205))	('BRCA2', 'Gene', '675', (151, 156))	('RAD51', 'Gene', '5888', (206, 211))	('BRCA1', 'Gene', (141, 146))	('suppressed', 'NegReg', (189, 199))	('BRCA1', 'Gene', (200, 205))	('malignancy', 'Disease', 'MESH:D009369', (290, 300))	('activation', 'PosReg', (237, 247))	('BRCA2', 'Gene', (151, 156))	('RAD52', 'Gene', (103, 108))
313559	31652722	In practical context, it was possible to observe that in hereditary ovarian and breast cancers with a defective activity of BRCA1/2 genes and inactivation of RAD52 function, by specific inhibitors, there was an induced suppression of tumor cells progression (Figure 3).	('tumor', 'Disease', (234, 239))	('BRCA1/2', 'Gene', (124, 131))	('breast cancers', 'Phenotype', 'HP:0003002', (80, 94))	('hereditary ovarian and breast cancers', 'Disease', 'MESH:D061325', (57, 94))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('suppression', 'NegReg', (219, 230))	('inactivation', 'Var', (142, 154))	('tumor', 'Disease', 'MESH:D009369', (234, 239))	('defective activity', 'NegReg', (102, 120))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('cancers', 'Phenotype', 'HP:0002664', (87, 94))	('RAD52', 'Gene', (158, 163))
313564	31652722	However, in BRCA1, PALB2 or BRCA2 mutant cells, the decrease on RAD52 activity can lead to cell death.	('RAD52', 'Protein', (64, 69))	('PALB2', 'Gene', (19, 24))	('PALB2', 'Gene', '79728', (19, 24))	('activity', 'MPA', (70, 78))	('BRCA2', 'Gene', '675', (28, 33))	('death', 'Disease', 'MESH:D003643', (96, 101))	('BRCA1', 'Gene', '672', (12, 17))	('decrease', 'NegReg', (52, 60))	('death', 'Disease', (96, 101))	('BRCA2', 'Gene', (28, 33))	('mutant', 'Var', (34, 40))	('BRCA1', 'Gene', (12, 17))
313565	31652722	Therapeutically, these data allow to reinforce the fact that any cancer type, with BRCA1-PALB2-BRCA2 pathway suppressed, may be targeted by inactivation of RAD52.	('BRCA2', 'Gene', '675', (95, 100))	('inactivation', 'Var', (140, 152))	('suppressed', 'NegReg', (109, 119))	('BRCA1', 'Gene', '672', (83, 88))	('PALB2', 'Gene', '79728', (89, 94))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('BRCA1', 'Gene', (83, 88))	('PALB2', 'Gene', (89, 94))	('RAD52', 'Gene', (156, 161))	('BRCA2', 'Gene', (95, 100))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))
313566	31652722	Despite the development of other therapeutic approaches that take advantage of the synthetic lethality concept in cancers carrying BRCAs genes alterations, such as poly-(ADP-ribose) polymerase (PARP) inhibition, this strategy using RAD52 inhibitors to target depleted BRCA-pathway is different.	('PARP', 'Gene', (194, 198))	('cancers', 'Disease', 'MESH:D009369', (114, 121))	('cancers', 'Phenotype', 'HP:0002664', (114, 121))	('cancers', 'Disease', (114, 121))	('BRCA', 'Gene', '672', (268, 272))	('poly-(ADP-ribose) polymerase', 'Gene', '142', (164, 192))	('BRCA', 'Gene', '672', (131, 135))	('poly-(ADP-ribose) polymerase', 'Gene', (164, 192))	('BRCA', 'Gene', (268, 272))	('PARP', 'Gene', '142', (194, 198))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('BRCA', 'Gene', (131, 135))	('inhibition', 'Var', (200, 210))	('alterations', 'Var', (143, 154))
313567	31652722	Some studies have demonstrated that personalized synthetic lethality induced by targeting RAD52 is achieved in BRCA-deficient carcinomas and leukemias, while normal cells and tissues remain unaffected.	('carcinomas', 'Phenotype', 'HP:0030731', (126, 136))	('leukemias', 'Phenotype', 'HP:0001909', (141, 150))	('RAD52', 'Gene', (90, 95))	('BRCA-deficient carcinomas and leukemias', 'Disease', 'MESH:D007938', (111, 150))	('leukemia', 'Phenotype', 'HP:0001909', (141, 149))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('targeting', 'Var', (80, 89))
313573	31652722	Finally, this study also showed that the therapeutic outcome may be improved by RAD52 inactivation of BRCA genes-defective cancers and treated with agents that inhibit PARP, while inducing a minimal toxicity to normal cells.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('BRCA', 'Gene', '672', (102, 106))	('BRCA', 'Gene', (102, 106))	('inhibit', 'NegReg', (160, 167))	('toxicity', 'Disease', 'MESH:D064420', (199, 207))	('toxicity', 'Disease', (199, 207))	('cancers', 'Disease', 'MESH:D009369', (123, 130))	('cancers', 'Phenotype', 'HP:0002664', (123, 130))	('PARP', 'Gene', (168, 172))	('inactivation', 'Var', (86, 98))	('cancers', 'Disease', (123, 130))	('improved', 'PosReg', (68, 76))	('PARP', 'Gene', '142', (168, 172))
313576	31652722	Therefore, a therapeutic strategy that targets tumor-specific DNA repair pathways through RAD52 inactivation may be a promising approach to improve therapy efficacy since it can result in an increased tumor cells sensitization to cell death and a decreased toxicity to normal cells.	('decreased', 'NegReg', (247, 256))	('toxicity', 'Disease', 'MESH:D064420', (257, 265))	('RAD52', 'Gene', (90, 95))	('inactivation', 'Var', (96, 108))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('toxicity', 'Disease', (257, 265))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('increased', 'PosReg', (191, 200))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor', 'Disease', (201, 206))	('death', 'Disease', 'MESH:D003643', (235, 240))	('tumor', 'Disease', (47, 52))	('death', 'Disease', (235, 240))
313617	29340065	In addition, we observed that the path:05215_1 from Prostate cancer displayed significantly higher activity in PRAD than other tumor types.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('higher', 'PosReg', (92, 98))	('Prostate cancer', 'Disease', 'MESH:D011471', (52, 67))	('tumor', 'Disease', (127, 132))	('Prostate cancer', 'Phenotype', 'HP:0012125', (52, 67))	('PRAD', 'Enzyme', (111, 115))	('path:05215_1', 'Var', (34, 46))	('Prostate cancer', 'Disease', (52, 67))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('activity', 'MPA', (99, 107))
313619	29340065	For example, Path: 05219 (Bladder cancer) corresponded to BLCA, Path: 05223 (Non-small cell lung cancer) corresponded to LUAD and LUSC, and Path: 05215 (Prostate cancer) corresponded to PRAD.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('Bladder cancer', 'Disease', (26, 40))	('Prostate cancer', 'Disease', 'MESH:D011471', (153, 168))	('lung cancer', 'Phenotype', 'HP:0100526', (92, 103))	('Non-small cell lung cancer', 'Phenotype', 'HP:0030358', (77, 103))	('Prostate cancer', 'Phenotype', 'HP:0012125', (153, 168))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('PRAD', 'Disease', (186, 190))	('Path: 05215', 'Var', (140, 151))	('LUAD', 'Disease', (121, 125))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (81, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('Bladder cancer', 'Phenotype', 'HP:0009725', (26, 40))	('Prostate cancer', 'Disease', (153, 168))	('Path: 05223', 'Var', (64, 75))	('Non-small cell lung cancer', 'Disease', 'MESH:D002289', (77, 103))	('BLCA', 'Disease', (58, 62))	('Non-small cell lung cancer', 'Disease', (77, 103))	('Bladder cancer', 'Disease', 'MESH:D001749', (26, 40))	('Path: 05219', 'Var', (13, 24))
313624	29340065	As shown in Figure 2A, entire pathways displayed higher activities in tumor samples than normal samples, with P-value = 2.99e-07 in BLCA, P-value = 3.19e-04 in LUAD, P-value = 5.69e-11 in LUSC, and P-value = 7.87e-10 in PRAD.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('activities', 'MPA', (56, 66))	('tumor', 'Disease', (70, 75))	('P-value', 'Var', (138, 145))	('higher', 'PosReg', (49, 55))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('P-value', 'Var', (110, 117))
313626	29340065	In addition, the path:05223_8 and path:05215_8 displayed opposite subpathway patterns with higher activities in normal samples than tumor samples, showing that novel biological patterns were observed at the subpathway levels.	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumor', 'Disease', (132, 137))	('activities', 'MPA', (98, 108))	('path:05215_8', 'Var', (34, 46))
313667	28078827	By comparing the gene expression levels of FAM83 family members in cancers from 17 different tumor types with those in their corresponding normal tissues, we identified consistent upregulation of FAM83D and FAM83H across the majority of tumor types, which is largely driven by increased DNA copy number.	('cancers', 'Phenotype', 'HP:0002664', (67, 74))	('tumor', 'Disease', (237, 242))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('cancers', 'Disease', (67, 74))	('upregulation', 'PosReg', (180, 192))	('cancers', 'Disease', 'MESH:D009369', (67, 74))	('FAM83', 'Chemical', '-', (207, 212))	('FAM83D', 'Gene', (196, 202))	('tumor', 'Disease', (93, 98))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))	('FAM83', 'Chemical', '-', (43, 48))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('FAM83H', 'Var', (207, 213))	('tumor', 'Disease', 'MESH:D009369', (237, 242))	('FAM83D', 'Gene', '81610', (196, 202))	('FAM83', 'Chemical', '-', (196, 201))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
313669	28078827	In breast cancer, we found that alterations in FAM83 family genes correlated significantly with TP53 mutation, whereas significant, but inverse correlation was observed with PIK3CA and CDH1 (E-cadherin) mutations.	('CDH1', 'Gene', (185, 189))	('correlated', 'Reg', (66, 76))	('E-cadherin', 'Gene', (191, 201))	('PIK3CA', 'Gene', (174, 180))	('TP53', 'Gene', (96, 100))	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('breast cancer', 'Disease', (3, 16))	('CDH1', 'Gene', '999', (185, 189))	('E-cadherin', 'Gene', '999', (191, 201))	('FAM83', 'Chemical', '-', (47, 52))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('alterations', 'Var', (32, 43))	('PIK3CA', 'Gene', '5290', (174, 180))	('FAM83 family genes', 'Gene', (47, 65))	('mutation', 'Var', (101, 109))	('TP53', 'Gene', '7157', (96, 100))
313670	28078827	We also identified that expression levels of 55 proteins were significantly associated with alterations in FAM83 family genes including a decrease in GATA3, ESR1, and PGR proteins in tumors with alterations in FAM83.	('ESR1', 'Gene', (157, 161))	('expression levels', 'MPA', (24, 41))	('FAM83', 'Gene', (210, 215))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('alterations', 'Var', (92, 103))	('PGR', 'Gene', (167, 170))	('tumors', 'Disease', (183, 189))	('GATA3', 'Gene', '2625', (150, 155))	('alterations', 'Var', (195, 206))	('FAM83', 'Chemical', '-', (210, 215))	('FAM83 family genes', 'Gene', (107, 125))	('GATA3', 'Gene', (150, 155))	('decrease', 'NegReg', (138, 146))	('tumors', 'Disease', 'MESH:D009369', (183, 189))	('PGR', 'Gene', '5241', (167, 170))	('proteins', 'Protein', (48, 56))	('ESR1', 'Gene', '2099', (157, 161))	('tumors', 'Phenotype', 'HP:0002664', (183, 189))	('FAM83', 'Chemical', '-', (107, 112))
313674	28078827	FAM83A is downstream of EGFR and PI3K pathways and is associated with RAS/RAF/MEK/ERK and PI3K/AKT/mTOR pathways (Lee et al., 2012).	('MEK', 'Gene', (78, 81))	('MEK', 'Gene', '5609', (78, 81))	('AKT', 'Gene', '207', (95, 98))	('FAM83A', 'Var', (0, 6))	('ERK', 'Gene', '5594', (82, 85))	('RAF', 'Gene', '22882', (74, 77))	('AKT', 'Gene', (95, 98))	('RAF', 'Gene', (74, 77))	('ERK', 'Gene', (82, 85))	('mTOR', 'Gene', '2475', (99, 103))	('mTOR', 'Gene', (99, 103))	('associated', 'Reg', (54, 64))
313675	28078827	Importantly, FAM83A interacts with c-RAF and PI3K p85 components of the EGFR pathway, and FAM83A expression was correlated with tumor growth rate (Lee et al., 2012).	('tumor', 'Disease', (128, 133))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('FAM83A', 'Var', (13, 19))	('c-RAF', 'Gene', (35, 40))	('correlated', 'Reg', (112, 122))	('FAM83A', 'Var', (90, 96))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('p85', 'Gene', '5296', (50, 53))	('interacts', 'Reg', (20, 29))	('EGFR pathway', 'Pathway', (72, 84))	('c-RAF', 'Gene', '5894', (35, 40))	('expression', 'MPA', (97, 107))	('p85', 'Gene', (50, 53))
313688	28078827	Gene transcript data of normal and tumor tissues across seventeen different tumor types were obtained from the National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO) (brain: GSE4290; breast: GSE10780, GSE21422, GSE29044, and GSE3744; colon: GSE8671; gastric: GSE13911; head-and-neck: GSE6791; liver: GSE6764, GSE40367, GSE45267, GSE55092, and GSE62232; nasopharyngeal: GSE12452; lung: GSE31210, GSE19804, and GSE19188; ovarian: GSE14407; cervical: GSE6791; pancreatic: GSE16515; and prostate cancer: GSE3325).	('cervical', 'Disease', (466, 474))	('GSE3325', 'Var', (528, 535))	('GSE19188', 'Var', (437, 445))	('tumor', 'Disease', (76, 81))	('prostate cancer', 'Disease', 'MESH:D011471', (511, 526))	('ovarian', 'Disease', (447, 454))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('prostate cancer', 'Phenotype', 'HP:0012125', (511, 526))	('GSE19804', 'Var', (423, 431))	('tumor', 'Disease', (35, 40))	('prostate cancer', 'Disease', (511, 526))	('GSE6791', 'Var', (476, 483))	('pancreatic', 'Disease', 'MESH:D010195', (485, 495))	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('GSE16515', 'Var', (497, 505))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('GSE14407', 'Var', (456, 464))	('GSE31210', 'Var', (413, 421))	('pancreatic', 'Disease', (485, 495))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('cancer', 'Phenotype', 'HP:0002664', (520, 526))
313689	28078827	Survival multivariate analysis and risk assessment for individual FAM83 family genes and gene signatures in human cancer data sets were performed using SurvExpress (Aguirre-Gamboa et al., 2013) in the following data sets: ovarian (GSE9891 and GSE32062), head-and-neck (TCGA and E-MTAB-1328), breast (TCGA and GSE20685), liver (TCGA), lung adenocarcinoma (TCGA), lung squamous cell carcinoma (TCGA), pancreatic (GSE28735 and GSE21501), stomach (TCGA), colon (TCGA and GSE17536), brain low-grade glioma (TCGA), and brain glioblastoma multiforme (GSE16011).	('breast', 'Disease', (292, 298))	('carcinoma', 'Phenotype', 'HP:0030731', (344, 353))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('brain glioblastoma multiforme', 'Disease', (513, 542))	('FAM83', 'Chemical', '-', (66, 71))	('pancreatic', 'Disease', 'MESH:D010195', (399, 409))	('glioma', 'Disease', (494, 500))	('glioblastoma', 'Phenotype', 'HP:0012174', (519, 531))	('carcinoma', 'Phenotype', 'HP:0030731', (381, 390))	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('glioma', 'Disease', 'MESH:D005910', (494, 500))	('lung adenocarcinoma', 'Disease', (334, 353))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (367, 390))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (362, 390))	('pancreatic', 'Disease', (399, 409))	('colon', 'Disease', (451, 456))	('GSE28735', 'Var', (411, 419))	('liver', 'Disease', (320, 325))	('glioma', 'Phenotype', 'HP:0009733', (494, 500))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (334, 353))	('human', 'Species', '9606', (108, 113))	('stomach', 'Disease', (435, 442))	('brain glioblastoma multiforme', 'Disease', 'MESH:D005909', (513, 542))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (362, 390))	('GSE21501', 'Var', (424, 432))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (334, 353))	('lung squamous cell carcinoma', 'Disease', (362, 390))	('cancer', 'Disease', (114, 120))
313698	28078827	Specifically, FAM83D and FAM83H were upregulated in 21 of 27 data sets (78%) and 16 of 27 data sets (59%) data sets, respectively.	('FAM83D', 'Gene', (14, 20))	('upregulated', 'PosReg', (37, 48))	('FAM83D', 'Gene', '81610', (14, 20))	('FAM83H', 'Var', (25, 31))
313702	28078827	Changes in DNA copy number are often observed in tumors, and DNA copy number aberrations are one of the mechanisms that can result in a change in gene expression in tumor progression.	('change', 'Reg', (136, 142))	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('tumor', 'Disease', (49, 54))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('aberrations', 'Var', (77, 88))	('tumors', 'Disease', (49, 55))	('tumors', 'Disease', 'MESH:D009369', (49, 55))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('gene expression', 'MPA', (146, 161))	('tumor', 'Disease', (165, 170))
313704	28078827	For each of the eight FAM83 family genes, we used a rank-based nonparametric test to determine whether the transcriptional expression levels are significantly associated with their copy number.	('FAM83', 'Chemical', '-', (22, 27))	('associated', 'Reg', (159, 169))	('copy number', 'Var', (181, 192))	('FAM83', 'Gene', (22, 27))	('transcriptional expression levels', 'MPA', (107, 140))
313706	28078827	In addition, FAM83D and FAM83H showed a significant association between DNA copy number and expression in 10/19 and 16/19 tumor types, respectively (P < 0.01).	('FAM83D', 'Gene', (13, 19))	('FAM83H', 'Var', (24, 30))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('DNA', 'Gene', (72, 75))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('FAM83D', 'Gene', '81610', (13, 19))	('tumor', 'Disease', (122, 127))	('expression', 'MPA', (92, 102))
313707	28078827	Examples of the association of DNA copy number and gene expression are shown for FAM83H in ovarian cancer (P = 1.77E-19), prostate adenocarcinoma (P = 5.17E-19), and breast cancer (P = 4.29E-83) (Fig.	('ovarian cancer', 'Disease', 'MESH:D010051', (91, 105))	('ovarian cancer', 'Disease', (91, 105))	('breast cancer', 'Disease', 'MESH:D001943', (166, 179))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('prostate adenocarcinoma', 'Disease', (122, 145))	('breast cancer', 'Disease', (166, 179))	('association', 'Interaction', (16, 27))	('breast cancer', 'Phenotype', 'HP:0003002', (166, 179))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('prostate adenocarcinoma', 'Disease', 'MESH:D011471', (122, 145))	('FAM83H', 'Var', (81, 87))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('ovarian cancer', 'Phenotype', 'HP:0100615', (91, 105))
313711	28078827	In uterine cancer, increased expression levels of FAM83A, B, D, and F-H were associated with decreased survival (Fig.	('FAM83A', 'Var', (50, 56))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('decreased', 'NegReg', (93, 102))	('increased', 'PosReg', (19, 28))	('expression levels', 'MPA', (29, 46))	('cancer', 'Disease', 'MESH:D009369', (11, 17))	('survival', 'CPA', (103, 111))	('cancer', 'Disease', (11, 17))	('uterine cancer', 'Phenotype', 'HP:0010784', (3, 17))
313718	28078827	As we observed a strong association between gene expression and DNA copy number in breast cancer across all FAM83 family members, we chose to further investigate the functional consequences of tumors with FAM83 family gene alterations in breast cancer.	('FAM83', 'Chemical', '-', (108, 113))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('FAM83', 'Chemical', '-', (205, 210))	('breast cancer', 'Disease', 'MESH:D001943', (83, 96))	('tumors', 'Phenotype', 'HP:0002664', (193, 199))	('breast cancer', 'Disease', (83, 96))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('breast cancer', 'Phenotype', 'HP:0003002', (83, 96))	('alterations', 'Var', (223, 234))	('breast cancer', 'Disease', 'MESH:D001943', (238, 251))	('tumors', 'Disease', (193, 199))	('tumors', 'Disease', 'MESH:D009369', (193, 199))	('breast cancer', 'Disease', (238, 251))	('cancer', 'Phenotype', 'HP:0002664', (245, 251))	('breast cancer', 'Phenotype', 'HP:0003002', (238, 251))
313719	28078827	We investigated the types of aberrations in FAM83 family genes in 960 breast tumor samples (TCGA) including changes in gene expression, mutations, and DNA copy number changes.	('FAM83 family', 'Gene', (44, 56))	('breast tumor', 'Disease', 'MESH:D001943', (70, 82))	('gene expression', 'MPA', (119, 134))	('breast tumor', 'Disease', (70, 82))	('FAM83', 'Chemical', '-', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('mutations', 'Var', (136, 145))	('changes', 'Reg', (108, 115))	('breast tumor', 'Phenotype', 'HP:0100013', (70, 82))
313721	28078827	Interestingly, more than half of all tumors harbored at least one alteration in a FAM83 family gene, with amplification and/or overexpression being the most common aberration (Fig.	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('FAM83', 'Chemical', '-', (82, 87))	('amplification', 'Var', (106, 119))	('alteration', 'Var', (66, 76))	('FAM83 family gene', 'Gene', (82, 99))	('overexpression', 'PosReg', (127, 141))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumors', 'Disease', (37, 43))	('tumors', 'Disease', 'MESH:D009369', (37, 43))
313722	28078827	To search for the mechanisms for FAM83 family members contributing to tumor development, we investigated whether mutations in any genes were enriched in tumors with alterations of FAM83 family members and found that tumors with alterations in FAM83 family members were significantly more likely to also have a TP53 mutation (P = 2.04E-14), whereas they were significantly less likely to have mutations in PIK3CA (P = 8.73E-6) and CDH1 (E-cadherin) (P = 2.13E-05) (Fig.	('PIK3CA', 'Gene', '5290', (405, 411))	('mutation', 'Var', (315, 323))	('tumors', 'Disease', (216, 222))	('FAM83', 'Chemical', '-', (243, 248))	('tumors', 'Disease', 'MESH:D009369', (153, 159))	('tumor', 'Disease', (216, 221))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('FAM83', 'Chemical', '-', (33, 38))	('TP53', 'Gene', '7157', (310, 314))	('tumors', 'Disease', 'MESH:D009369', (216, 222))	('tumor', 'Disease', (153, 158))	('tumor', 'Disease', 'MESH:D009369', (216, 221))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('FAM83', 'Gene', (180, 185))	('PIK3CA', 'Gene', (405, 411))	('CDH1', 'Gene', '999', (430, 434))	('tumors', 'Phenotype', 'HP:0002664', (153, 159))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('FAM83', 'Chemical', '-', (180, 185))	('CDH1', 'Gene', (430, 434))	('tumor', 'Disease', (70, 75))	('alterations', 'Var', (228, 239))	('tumors', 'Phenotype', 'HP:0002664', (216, 222))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('TP53', 'Gene', (310, 314))	('tumors', 'Disease', (153, 159))	('E-cadherin', 'Gene', (436, 446))	('E-cadherin', 'Gene', '999', (436, 446))	('FAM83', 'Gene', (243, 248))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
313723	28078827	Finally, we investigated whether protein expression of any genes was significantly different between the breast cancer group with FAM83 family alterations and those without any alteration.	('different', 'Reg', (83, 92))	('FAM83', 'Chemical', '-', (130, 135))	('family alterations', 'Var', (136, 154))	('breast cancer', 'Disease', 'MESH:D001943', (105, 118))	('breast cancer', 'Disease', (105, 118))	('FAM83', 'Gene', (130, 135))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('alterations', 'Var', (143, 154))	('breast cancer', 'Phenotype', 'HP:0003002', (105, 118))
313724	28078827	For example, protein levels of CCNB1 (cyclin B1) were significantly higher (P = 7.28E-13) in breast tumors with alterations in FAM83 family genes, whereas protein levels of GATA3 (P = 3.79E-07), PGR (P = 5.77E-07), and ESR1 (P = 9.20E-07) were significantly lower (Fig.	('CCNB1', 'Gene', (31, 36))	('cyclin B1', 'Gene', '891', (38, 47))	('cyclin B1', 'Gene', (38, 47))	('lower', 'NegReg', (258, 263))	('ESR1', 'Gene', '2099', (219, 223))	('PGR', 'Gene', '5241', (195, 198))	('ESR1', 'Gene', (219, 223))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('GATA3', 'Gene', '2625', (173, 178))	('protein levels', 'MPA', (13, 27))	('breast tumors', 'Disease', 'MESH:D001943', (93, 106))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('breast tumors', 'Disease', (93, 106))	('CCNB1', 'Gene', '891', (31, 36))	('GATA3', 'Gene', (173, 178))	('higher', 'PosReg', (68, 74))	('breast tumors', 'Phenotype', 'HP:0100013', (93, 106))	('breast tumor', 'Phenotype', 'HP:0100013', (93, 105))	('FAM83', 'Chemical', '-', (127, 132))	('alterations', 'Var', (112, 123))	('PGR', 'Gene', (195, 198))	('FAM83 family genes', 'Gene', (127, 145))
313728	28078827	FAM83A was found to be upregulated in lung, ovarian, pancreatic, and certain brain tumors (Fig.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('upregulated', 'PosReg', (23, 34))	('brain tumors', 'Phenotype', 'HP:0030692', (77, 89))	('lung', 'Disease', (38, 42))	('pancreatic', 'Disease', 'MESH:D010195', (53, 63))	('pancreatic', 'Disease', (53, 63))	('FAM83A', 'Var', (0, 6))	('brain tumors', 'Disease', 'MESH:D001932', (77, 89))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('brain tumors', 'Disease', (77, 89))	('ovarian', 'Disease', (44, 51))
313730	28078827	In addition, overexpression of FAM83A increases cancer cell proliferation and invasion, phosphorylates c-RAF and PI3K p85, upstream of MAPK and downstream of EGFR, and confers resistance to EGFR-TKI (Lee et al., 2012; Li et al., 2015).	('c-RAF', 'Gene', (103, 108))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('invasion', 'CPA', (78, 86))	('p85', 'Gene', '5296', (118, 121))	('increases cancer', 'Disease', 'MESH:D009369', (38, 54))	('FAM83A', 'Var', (31, 37))	('overexpression', 'PosReg', (13, 27))	('c-RAF', 'Gene', '5894', (103, 108))	('p85', 'Gene', (118, 121))	('increases cancer', 'Disease', (38, 54))
313743	28078827	FAM83H was found to be required for tooth enamel calcification (Lee et al., 2008), and mutations in FAM83H were shown to correlate with amelogenesis imperfecta (Zhang et al., 2015).	('tooth enamel calcification', 'Disease', 'MESH:D002114', (36, 62))	('amelogenesis imperfecta', 'Phenotype', 'HP:0000705', (136, 159))	('FAM83H', 'Gene', (100, 106))	('amelogenesis imperfecta', 'Disease', (136, 159))	('tooth enamel calcification', 'Disease', (36, 62))	('correlate with', 'Reg', (121, 135))	('amelogenesis imperfecta', 'Disease', 'MESH:D000567', (136, 159))	('mutations', 'Var', (87, 96))
313745	28078827	Subsequent knockdown of FAM83H in LNCaP cells significantly inhibited colony formation (Nalla et al., 2016).	('inhibited', 'NegReg', (60, 69))	('LNCaP', 'CellLine', 'CVCL:0395', (34, 39))	('knockdown', 'Var', (11, 20))	('FAM83H', 'Var', (24, 30))	('colony formation', 'CPA', (70, 86))
313746	28078827	A study in colorectal cancer identified FAM83H as an important regulator of keratin cytoskeletal organization, and that overexpression of FAM83H is accompanied by keratin filament disassembly and subsequently leads to loss of epithelial cell polarity (Kuga et al., 2013).	('colorectal cancer', 'Disease', 'MESH:D015179', (11, 28))	('overexpression', 'PosReg', (120, 134))	('colorectal cancer', 'Phenotype', 'HP:0003003', (11, 28))	('loss', 'NegReg', (218, 222))	('epithelial cell polarity', 'CPA', (226, 250))	('FAM83H', 'Var', (138, 144))	('colorectal cancer', 'Disease', (11, 28))	('keratin filament', 'Protein', (163, 179))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))
313750	28078827	However, we found no correlation between MYC and FAM83H gene expression in breast, ovarian, and prostate cancer (Pearson correlation < 0.25), suggesting strongly that FAM83H by itself is an important driver gene on chromosome 8q.	('prostate cancer', 'Disease', 'MESH:D011471', (96, 111))	('ovarian', 'Disease', (83, 90))	('prostate cancer', 'Phenotype', 'HP:0012125', (96, 111))	('prostate cancer', 'Disease', (96, 111))	('MYC', 'Gene', '4609', (41, 44))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('FAM83H', 'Var', (167, 173))	('breast', 'Disease', (75, 81))	('MYC', 'Gene', (41, 44))
313753	28078827	In a recent study, it was found that FAM83F expression was increased in esophageal SCC, and introduction of miR-143 into esophageal cancer cells downregulated FAM83F expression, which results in inhibition of cell proliferation, migration, and invasion (Mao et al., 2016).	('expression', 'MPA', (44, 54))	('cell proliferation', 'CPA', (209, 227))	('migration', 'CPA', (229, 238))	('FAM83F', 'Gene', (159, 165))	('SCC', 'Gene', '6317', (83, 86))	('FAM83F', 'Gene', '113828', (37, 43))	('increased', 'PosReg', (59, 68))	('downregulated', 'NegReg', (145, 158))	('SCC', 'Gene', (83, 86))	('inhibition', 'NegReg', (195, 205))	('esophageal cancer', 'Disease', 'MESH:D004938', (121, 138))	('FAM83F', 'Gene', (37, 43))	('esophageal cancer', 'Disease', (121, 138))	('expression', 'MPA', (166, 176))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('introduction', 'Var', (92, 104))	('FAM83F', 'Gene', '113828', (159, 165))	('miR-143', 'Gene', '406935', (108, 115))	('invasion', 'CPA', (244, 252))	('miR-143', 'Gene', (108, 115))
313765	32580473	Potential Prognostic Role of SPARC Methylation in Non-Small-Cell Lung Cancer The silencing of SPARC (secreted protein acid and rich in cysteine) gene through methylation of its promoter region represents a common event in many solid tumors and it is frequently associated with tumor progression and an aggressive clinical outcome.	('tumors', 'Disease', 'MESH:D009369', (233, 239))	('methylation', 'Var', (158, 169))	('tumor', 'Phenotype', 'HP:0002664', (277, 282))	('Non-Small-Cell Lung Cancer', 'Phenotype', 'HP:0030358', (50, 76))	('Non-Small-Cell Lung Cancer', 'Disease', (50, 76))	('tumor', 'Disease', (233, 238))	('associated', 'Reg', (261, 271))	('cysteine', 'Chemical', 'MESH:D003545', (135, 143))	('Small-Cell Lung Cancer', 'Phenotype', 'HP:0030357', (54, 76))	('tumor', 'Disease', 'MESH:D009369', (233, 238))	('tumors', 'Phenotype', 'HP:0002664', (233, 239))	('Non-Small-Cell Lung Cancer', 'Disease', 'MESH:D002289', (50, 76))	('silencing', 'NegReg', (81, 90))	('Cancer', 'Phenotype', 'HP:0002664', (70, 76))	('tumor', 'Disease', (277, 282))	('SPARC', 'Gene', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('SPARC', 'Gene', (29, 34))	('tumors', 'Disease', (233, 239))	('tumor', 'Disease', 'MESH:D009369', (277, 282))	('SPARC', 'Gene', '6678', (94, 99))	('SPARC', 'Gene', '6678', (29, 34))	('Lung Cancer', 'Phenotype', 'HP:0100526', (65, 76))
313766	32580473	Anyhow, the data concerning the epigenetic mechanism of SPARC deregulation and its prognostic value in lung cancer are still incomplete.	('lung cancer', 'Disease', 'MESH:D008175', (103, 114))	('SPARC', 'Gene', '6678', (56, 61))	('deregulation', 'Var', (62, 74))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('lung cancer', 'Disease', (103, 114))	('lung cancer', 'Phenotype', 'HP:0100526', (103, 114))	('SPARC', 'Gene', (56, 61))
313769	32580473	An inverse correlation between the epigenetic silencing and SPARC expression was confirmed by 5-Aza-2'-deoxycytidine ((5-Aza-CdR) treatment that also significantly induced a reduction in cell viability, proliferation and tumor cell migration.	('SPARC', 'Gene', '6678', (60, 65))	('proliferation', 'CPA', (203, 216))	('SPARC', 'Gene', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('tumor', 'Disease', (221, 226))	('epigenetic silencing', 'Var', (35, 55))	("5-Aza-2'-deoxycytidine", 'Chemical', 'MESH:D000077209', (94, 116))	('cell viability', 'CPA', (187, 201))	('reduction', 'NegReg', (174, 183))	('tumor', 'Disease', 'MESH:D009369', (221, 226))
313773	32580473	Promoter methylation of SPARC gene should represent an interesting prognostic biomarker in NSCLC, with potential application in the squamous early-stage context.	('NSCLC', 'Disease', 'MESH:D002289', (91, 96))	('SPARC', 'Gene', '6678', (24, 29))	('SPARC', 'Gene', (24, 29))	('Promoter methylation', 'Var', (0, 20))	('NSCLC', 'Disease', (91, 96))
313787	32580473	At present, the data concerning methylation as possible epigenetic mechanisms of SPARC deregulation in lung cancer are incomplete and correlation analysis with disease clinical course in a specific subset of patients or specific therapeutic strategies is lacking.	('patients', 'Species', '9606', (208, 216))	('lung cancer', 'Disease', 'MESH:D008175', (103, 114))	('SPARC', 'Gene', (81, 86))	('deregulation', 'Var', (87, 99))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('lung cancer', 'Disease', (103, 114))	('lung cancer', 'Phenotype', 'HP:0100526', (103, 114))	('SPARC', 'Gene', '6678', (81, 86))
313788	32580473	Here we hypothesized that the silencing of SPARC gene by aberrant methylation of its promoter CpG island during lung carcinogenesis was responsible for the downregulation of its expression in NSCLC cells.	('NSCLC', 'Disease', (192, 197))	('downregulation', 'NegReg', (156, 170))	('SPARC', 'Gene', (43, 48))	('aberrant methylation', 'Var', (57, 77))	('expression', 'MPA', (178, 188))	('NSCLC', 'Disease', 'MESH:D002289', (192, 197))	('methylation', 'Var', (66, 77))	('silencing', 'NegReg', (30, 39))	('lung carcinogenesis', 'Disease', (112, 131))	('SPARC', 'Gene', '6678', (43, 48))	('lung carcinogenesis', 'Disease', 'MESH:D063646', (112, 131))
313806	32580473	From the FFPE of the learning cohort of 21 NSCLCs, 3 microm sections were selected for IHC analysis and incubated with 1:200 rabbit monoclonal anti-SPARC antibody (D10F10, Cell Signaling, Danvers, MA) for 60 min at RT.	('SPARC', 'Gene', '6678', (148, 153))	('NSCLCs', 'Disease', (43, 49))	('SPARC', 'Gene', (148, 153))	('NSCLCs', 'Disease', 'MESH:D002289', (43, 49))	('D10F10', 'Var', (164, 170))
313813	32580473	The Primer/Probe sets for SPARC and RPLPO genes expression were as follows: Hs00234160_m1 and 4326314E (Thermo Fisher, Life Technologies).	('SPARC', 'Gene', '6678', (26, 31))	('Hs00234160_m1', 'Var', (76, 89))	('SPARC', 'Gene', (26, 31))	('RPLPO genes', 'Gene', (36, 47))	('4326314E', 'Var', (94, 102))
313841	32580473	The SPARC methylation status was assessed by designing a primers/probe set that amplifies the CpG region in the gene promoter region showing the highest frequency of methylation and that contains a consensus sequence for the transcriptional Sp1 and AP1 regulatory elements.	('SPARC', 'Gene', '6678', (4, 9))	('AP1', 'Gene', '2353', (249, 252))	('SPARC', 'Gene', (4, 9))	('methylation', 'Var', (166, 177))	('AP1', 'Gene', (249, 252))
313851	32580473	Variable levels of methylation of SPARC were observed in the tumor cell lines ranged as follows: 0-292.5 +- 60.6 (A549), 23.4 +- 7.4 (H2228), 148 +- 6.8 (H1573) and 179.3 +- 20.4 (H460), (Figure 4A), whereas in normal cells no methylation was detected.	('tumor', 'Disease', (61, 66))	('SPARC', 'Gene', '6678', (34, 39))	('SPARC', 'Gene', (34, 39))	('H2228', 'CellLine', 'CVCL:1543', (134, 139))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('A549', 'CellLine', 'CVCL:0023', (114, 118))	('methylation', 'MPA', (19, 30))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('H1573', 'CellLine', 'CVCL:1478', (154, 159))	('H1573', 'Var', (154, 159))	('H2228', 'Var', (134, 139))
313854	32580473	In A549 cell line that resulted methylated for SPARC gene, the cell migration significantly decreased after 5-Aza-Cdr treatment at 24 h and 48 h (p < 0.001, t-test) (Figure 5).	('SPARC', 'Gene', (47, 52))	('A549', 'CellLine', 'CVCL:0023', (3, 7))	('cell migration', 'CPA', (63, 77))	('decreased', 'NegReg', (92, 101))	('SPARC', 'Gene', '6678', (47, 52))	('methylated', 'Var', (32, 42))
313857	32580473	A highly significant inverse correlation between aberrant SPARC promoter methylation and its mRNA expression was found in both LUAD and LUSC (Figure 7).	('mRNA expression', 'MPA', (93, 108))	('SPARC', 'Gene', '6678', (58, 63))	('aberrant', 'Var', (49, 57))	('SPARC', 'Gene', (58, 63))	('inverse', 'NegReg', (21, 28))
313858	32580473	Specifically, in LUAD samples almost all CpG were inversely correlated with the expression of SPARC (except cg07539983 and cg08879559), whereas in LUSC all but cg07539983 CpGs were inversely correlated with the expression of SPARC (Supplemental Materials Figure S2).	('SPARC', 'Gene', (94, 99))	('cg07539983', 'Var', (160, 170))	('SPARC', 'Gene', '6678', (225, 230))	('SPARC', 'Gene', '6678', (94, 99))	('cg08879559', 'Var', (123, 133))	('cg07539983', 'Var', (108, 118))	('SPARC', 'Gene', (225, 230))
313859	32580473	To assess in tissues a possible correlation between the SPARC protein levels in NSCLC cells and the epigenetic silencing of the SPARC gene, the learning cohort of paired non-neoplastic/NSCLC tumors were also analyzed by immunohistochemistry.	('NSCLC tumors', 'Disease', (185, 197))	('tumors', 'Phenotype', 'HP:0002664', (191, 197))	('NSCLC', 'Disease', 'MESH:D002289', (185, 190))	('epigenetic silencing', 'Var', (100, 120))	('SPARC', 'Gene', '6678', (56, 61))	('NSCLC', 'Disease', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('NSCLC', 'Disease', 'MESH:D002289', (80, 85))	('NSCLC tumors', 'Disease', 'MESH:D009369', (185, 197))	('SPARC', 'Gene', '6678', (128, 133))	('SPARC', 'Gene', (56, 61))	('SPARC', 'Gene', (128, 133))	('NSCLC', 'Disease', (185, 190))
313861	32580473	By consequence, no significant correlation between epigenetic silencing and SPARC protein levels was possible.	('SPARC', 'Gene', '6678', (76, 81))	('SPARC', 'Gene', (76, 81))	('epigenetic silencing', 'Var', (51, 71))
313870	32580473	No statistically significant associations were found between methylation (status and levels) and any clinic-pathological feature both in the whole sample of NSCLC patients and within tumor histology groups.	('patients', 'Species', '9606', (163, 171))	('methylation', 'Var', (61, 72))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('tumor', 'Disease', (183, 188))	('NSCLC', 'Disease', (157, 162))	('NSCLC', 'Disease', 'MESH:D002289', (157, 162))
313877	32580473	KRAS mutations were identified in five cases (20%), (Supplemental Table S2), but no significant correlation between KRAS mutated status and methylation of SPARC gene was found.	('mutations', 'Var', (5, 14))	('SPARC', 'Gene', '6678', (155, 160))	('KRAS', 'Gene', (116, 120))	('SPARC', 'Gene', (155, 160))	('identified', 'Reg', (20, 30))	('KRAS', 'Gene', (0, 4))	('KRAS', 'Gene', '3845', (116, 120))	('KRAS', 'Gene', '3845', (0, 4))
313883	32580473	We demonstrated here that aberrant methylation of SPARC promoter region should be considered a frequent event in lung cancer cell lines from different histologies and NSCLC patients.	('aberrant methylation', 'Var', (26, 46))	('NSCLC', 'Disease', 'MESH:D002289', (167, 172))	('lung cancer', 'Disease', (113, 124))	('SPARC', 'Gene', (50, 55))	('lung cancer', 'Phenotype', 'HP:0100526', (113, 124))	('patients', 'Species', '9606', (173, 181))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('lung cancer', 'Disease', 'MESH:D008175', (113, 124))	('NSCLC', 'Disease', (167, 172))	('SPARC', 'Gene', '6678', (50, 55))
313888	32580473	In tumor tissues, we found SPARC promoter hypermethylation in the 58% of NSCLCs analyzed; in particular, it was detected in 68% of SqCCs and 53% of ADCs.	('hypermethylation', 'Var', (42, 58))	('tumor', 'Disease', (3, 8))	('NSCLCs', 'Disease', (73, 79))	('SPARC', 'Gene', '6678', (27, 32))	('ADCs', 'Disease', (148, 152))	('SPARC', 'Gene', (27, 32))	('detected', 'Reg', (112, 120))	('tumor', 'Disease', 'MESH:D009369', (3, 8))	('NSCLCs', 'Disease', 'MESH:D002289', (73, 79))	('SqCCs', 'Disease', (131, 136))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))
313898	32580473	Moreover, in solid tumors, aberrant methylation frequently involves DNA CpG dinucleotides at the 5' end of tumor suppressor genes and it is related to the gene silencing and neoplastic process.	('tumors', 'Disease', (19, 25))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('dinucleotides', 'Chemical', 'MESH:D015226', (76, 89))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('aberrant methylation', 'Var', (27, 47))	('related', 'Reg', (140, 147))	('tumor', 'Disease', (19, 24))	('neoplastic process', 'Phenotype', 'HP:0002664', (174, 192))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))
313900	32580473	As SPARC is a protein involved in many cellular processes, such as proliferation, spreading, adhesion, motility and invasion, the silencing of SPARC gene in lung tumor cells could have a great impact on the neoplastic enhancement.	('impact', 'Reg', (193, 199))	('lung tumor', 'Phenotype', 'HP:0100526', (157, 167))	('SPARC', 'Gene', '6678', (3, 8))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('SPARC', 'Gene', '6678', (143, 148))	('SPARC', 'Gene', (143, 148))	('lung tumor', 'Disease', (157, 167))	('SPARC', 'Gene', (3, 8))	('lung tumor', 'Disease', 'MESH:D008175', (157, 167))	('silencing', 'Var', (130, 139))	('neoplastic enhancement', 'CPA', (207, 229))
313902	32580473	To our knowledge, this is the first evidence of a potential utility of SPARC epigenetic silencing as prognostic marker in early stage lung cancer.	('epigenetic silencing', 'Var', (77, 97))	('SPARC', 'Gene', (71, 76))	('lung cancer', 'Disease', (134, 145))	('lung cancer', 'Phenotype', 'HP:0100526', (134, 145))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('lung cancer', 'Disease', 'MESH:D008175', (134, 145))	('SPARC', 'Gene', '6678', (71, 76))
313904	32580473	In support of this hypothesis, we observed that, under the 5-Aza-CdR treatment, the cell proliferation, invasion and migration in the lung cell line A549 were inhibited as for cell viability.	('migration in the', 'CPA', (117, 133))	('5-Aza-CdR', 'Var', (59, 68))	('A549', 'CellLine', 'CVCL:0023', (149, 153))	('invasion', 'CPA', (104, 112))	('cell proliferation', 'CPA', (84, 102))	('inhibited', 'NegReg', (159, 168))
313912	32580473	Finally, if demonstrated that SPARC methylation can be detected in cfDNA of NSCLC, it could represent an interesting non-invasive marker of early diagnosis of NSCLC to test in liquid biopsy or to monitoring cancer evolution in NSCLC patients.	('cancer', 'Disease', 'MESH:D009369', (207, 213))	('detected', 'Reg', (55, 63))	('NSCLC', 'Disease', (227, 232))	('cancer', 'Disease', (207, 213))	('NSCLC', 'Disease', (159, 164))	('SPARC', 'Gene', (30, 35))	('NSCLC', 'Disease', (76, 81))	('NSCLC', 'Disease', 'MESH:D002289', (227, 232))	('NSCLC', 'Disease', 'MESH:D002289', (159, 164))	('NSCLC', 'Disease', 'MESH:D002289', (76, 81))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('patients', 'Species', '9606', (233, 241))	('SPARC', 'Gene', '6678', (30, 35))	('methylation', 'Var', (36, 47))
313923	32547744	Pretreatment differences in immune cell composition in NSCLC are associated with survival and depend on smoking status and histological subtype.	('differences', 'Var', (13, 24))	('NSCLC', 'Disease', (55, 60))	('NSCLC', 'Disease', 'MESH:D002289', (55, 60))	('associated', 'Reg', (65, 75))	('NSCLC', 'Phenotype', 'HP:0030358', (55, 60))
313985	32547744	Cytotoxic CD8 T cells can be associated either with better or with worse survival, depending on the subtype of NSCLC.	('Cytotoxic', 'Var', (0, 9))	('NSCLC', 'Disease', (111, 116))	('CD8', 'Gene', (10, 13))	('NSCLC', 'Disease', 'MESH:D002289', (111, 116))	('CD8', 'Gene', '925', (10, 13))	('NSCLC', 'Phenotype', 'HP:0030358', (111, 116))
314023	31725680	This meta-analysis was carried out to quantitatively evaluate the prognostic values of partial KIF members in cancer patients.	('cancer', 'Disease', (110, 116))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('partial', 'Var', (87, 94))	('patients', 'Species', '9606', (117, 125))	('cancer', 'Disease', 'MESH:D009369', (110, 116))
314027	31725680	Our results indicated that patients with high expression of KIF2 and KIF20A tended to have shorter OS than those with low expression (HR = 2.23, 95% CI = 1.87-2.65, P < .001; HR = 1.77, 95% CI = 1.57-1.99, P < .001, respectively).	('KIF20A', 'Gene', (69, 75))	('KIF2', 'Gene', (60, 64))	('KIF20A', 'Gene', '10112', (69, 75))	('KIF2', 'Gene', '3796', (69, 73))	('high expression', 'Var', (41, 56))	('patients', 'Species', '9606', (27, 35))	('KIF2', 'Gene', (69, 73))	('KIF2', 'Gene', '3796', (60, 64))	('shorter', 'NegReg', (91, 98))
314044	31725680	In recent years, a large number of studies have suggested that abnormal expression of KIF2A and KIF20A is involved in the carcinogenesis of various tumors, such as epithelial ovarian cancer (EOC), breast cancer (BC), colorectal cancer (CRC), and laryngeal squamous cell carcinoma (LSCC).	('abnormal', 'Var', (63, 71))	('KIF20A', 'Gene', '10112', (96, 102))	('involved', 'Reg', (106, 114))	('EOC', 'Phenotype', 'HP:0025318', (191, 194))	('colorectal cancer', 'Disease', (217, 234))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (256, 279))	('CRC', 'Disease', 'MESH:D015179', (236, 239))	('KIF2A', 'Gene', '3796', (86, 91))	('carcinogenesis of various tumors', 'Disease', (122, 154))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('breast cancer', 'Phenotype', 'HP:0003002', (197, 210))	('carcinogenesis of various tumors', 'Disease', 'MESH:D063646', (122, 154))	('epithelial ovarian cancer', 'Disease', 'MESH:D010051', (164, 189))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('carcinoma', 'Phenotype', 'HP:0030731', (270, 279))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('squamous cell carcinoma', 'Disease', (256, 279))	('breast cancer', 'Disease', 'MESH:D001943', (197, 210))	('epithelial ovarian cancer', 'Phenotype', 'HP:0025318', (164, 189))	('breast cancer', 'Disease', (197, 210))	('EOC', 'Disease', (191, 194))	('colorectal cancer', 'Phenotype', 'HP:0003003', (217, 234))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('BC', 'Disease', 'MESH:D001943', (212, 214))	('KIF2A', 'Gene', (86, 91))	('epithelial ovarian cancer', 'Disease', (164, 189))	('KIF20A', 'Gene', (96, 102))	('ovarian cancer', 'Phenotype', 'HP:0100615', (175, 189))	('CRC', 'Disease', (236, 239))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (256, 279))	('BC', 'Phenotype', 'HP:0003002', (212, 214))	('CRC', 'Phenotype', 'HP:0003003', (236, 239))	('colorectal cancer', 'Disease', 'MESH:D015179', (217, 234))	('EOC', 'Disease', 'MESH:D010051', (191, 194))
314060	31725680	As shown in Figure 2, the results of 9 studies involving 1839 cancer patients demonstrated that high KIF2A expression was significantly related to a shorter OS (HR = 2.23, 95% CI = 1.87-2.65, P < .001).	('KIF2A', 'Gene', '3796', (101, 106))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('shorter', 'Disease', (149, 156))	('expression', 'MPA', (107, 117))	('high', 'Var', (96, 100))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('patients', 'Species', '9606', (69, 77))	('KIF2A', 'Gene', (101, 106))
314063	31725680	The results showed that patients with cancer and high KIF20A expression had a significantly poor OS compared to those with low KIF20A expression (HR = 1.77, 95% CI = 1.57-1.99, P < .001).	('KIF20A', 'Gene', '10112', (127, 133))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('poor', 'NegReg', (92, 96))	('patients', 'Species', '9606', (24, 32))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('KIF20A', 'Gene', (54, 60))	('high', 'Var', (49, 53))	('cancer', 'Disease', (38, 44))	('KIF20A', 'Gene', '10112', (54, 60))	('KIF20A', 'Gene', (127, 133))
314064	31725680	Overall, high expression of KIF2A and KIF20A was associated with shorter OS, and these two KIF members can serve as independent factors for predicting the survival outcomes of patients with cancer.	('cancer', 'Disease', (190, 196))	('patients', 'Species', '9606', (176, 184))	('high expression', 'Var', (9, 24))	('cancer', 'Disease', 'MESH:D009369', (190, 196))	('KIF20A', 'Gene', '10112', (38, 44))	('shorter', 'Disease', (65, 72))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('KIF2A', 'Gene', (28, 33))	('KIF2A', 'Gene', '3796', (28, 33))	('KIF20A', 'Gene', (38, 44))
314074	31725680	Mutations in some members of KIF may lead to congenital and hereditary diseases, including cancer.	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('lead to', 'Reg', (37, 44))	('hereditary diseases', 'Disease', (60, 79))	('hereditary diseases', 'Disease', 'MESH:D030342', (60, 79))	('Mutations', 'Var', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('KIF', 'Gene', (29, 32))
314077	31725680	We identified 25 recently published articles and found that patients with cancer and high KIF2 and KIF20A expression tended to have shorter OS than those with low expression.	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('KIF2', 'Gene', (99, 103))	('expression', 'MPA', (106, 116))	('patients', 'Species', '9606', (60, 68))	('high', 'Var', (85, 89))	('KIF20A', 'Gene', (99, 105))	('cancer', 'Disease', (74, 80))	('KIF2', 'Gene', '3796', (90, 94))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('KIF20A', 'Gene', '10112', (99, 105))	('KIF2', 'Gene', '3796', (99, 103))	('KIF2', 'Gene', (90, 94))
314089	31725680	Second, the expression of these 2 proteins can be suppressed by certain miRNAs, which may provide candidate novel molecular targets for precise cancer treatment.	('suppressed', 'NegReg', (50, 60))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('cancer', 'Disease', (144, 150))	('expression', 'MPA', (12, 22))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('miRNAs', 'Var', (72, 78))
314099	31725680	Similarly, Wang and colleagues reported that gene silencing of KIF2A suppressed cell proliferation and improved the anti-tumor effect of 5-fluorouracil in squamous cell carcinoma of the oral tongue, suggesting that KIF2A can be developed as a drug target for treating this cancer type.	('squamous cell carcinoma of the oral tongue', 'Disease', (155, 197))	('carcinoma', 'Phenotype', 'HP:0030731', (169, 178))	('KIF2A', 'Gene', '3796', (215, 220))	('gene silencing', 'Var', (45, 59))	('cancer', 'Disease', 'MESH:D009369', (273, 279))	('improved', 'PosReg', (103, 111))	('tumor', 'Disease', (121, 126))	('cell proliferation', 'CPA', (80, 98))	('KIF2A', 'Gene', (63, 68))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (137, 151))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (155, 178))	('tumor', 'Disease', 'MESH:D009369', (121, 126))	('KIF2A', 'Gene', (215, 220))	('carcinoma of the oral', 'Phenotype', 'HP:0100649', (169, 190))	('squamous cell carcinoma of the oral tongue', 'Disease', 'MESH:D002294', (155, 197))	('suppressed', 'NegReg', (69, 79))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('cancer', 'Disease', (273, 279))	('cancer', 'Phenotype', 'HP:0002664', (273, 279))	('KIF2A', 'Gene', '3796', (63, 68))
314127	28049499	Regulatory ncRNAs have been classified by length as follows: small noncoding RNAs (<200 bp), which includes microRNAs (miRNAs), snRNAs, piRNAs, siRNAs, and others, and long ncRNAs (lncRNAs) (>200 bp).	('miR', 'Gene', (119, 122))	('miR', 'Gene', '220972', (119, 122))	('<200', 'Var', (83, 87))
314144	28049499	explored internal components including alternative splicing events (AS) such as exon skipping (ES), intron retention (IR), and alternative 5' or 3' splicing site (A5SS and A3SS) within circRNAs.	('A5SS', 'Chemical', '-', (163, 167))	('exo', 'Gene', (80, 83))	('exo', 'Gene', '24127', (80, 83))	('intron retention', 'MPA', (100, 116))	('cir', 'Gene', '3762', (185, 188))	('cir', 'Gene', (185, 188))	('A3SS', 'Var', (172, 176))
314151	28049499	They discovered that circRNAs are abundant in the nucleus with little enrichment for miRNA target sites, and knockdown of ciRNAs could lead to the reduced expression of their parental genes.	('miR', 'Gene', '220972', (85, 88))	('miR', 'Gene', (85, 88))	('ciRNAs', 'Gene', (122, 128))	('expression', 'MPA', (155, 165))	('cir', 'Gene', '3762', (21, 24))	('cir', 'Gene', (21, 24))	('knockdown', 'Var', (109, 118))	('reduced', 'NegReg', (147, 154))
314168	28049499	Here, we discuss recent discoveries that implicate aberrant circRNAs in cancer (Table 1).	('cir', 'Gene', '3762', (60, 63))	('aberrant', 'Var', (51, 59))	('cir', 'Gene', (60, 63))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('cancer', 'Disease', (72, 78))
314190	28049499	Researchers showed that well-established cancer-associated chromosomal translocations gave rise to fusion circRNAs (f-circRNA) that were produced from transcribed exons of distinct genes affected by the translocations.	('cir', 'Gene', '3762', (118, 121))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('exo', 'Gene', (163, 166))	('exo', 'Gene', '24127', (163, 166))	('cir', 'Gene', (106, 109))	('translocations', 'Var', (71, 85))	('cir', 'Gene', '3762', (106, 109))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('cir', 'Gene', (118, 121))
314195	28049499	Previous research showed that mRNA sequencing of tumor-educated blood platelets could distinguish cancer patients from healthy population with 96% accuracy, and the location of the primary tumor was correctly identified with 71% accuracy across six different tumor types.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('tumor', 'Disease', (189, 194))	('patients', 'Species', '9606', (105, 113))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor', 'Disease', 'MESH:D009369', (259, 264))	('tumor', 'Disease', (49, 54))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('tumor', 'Phenotype', 'HP:0002664', (259, 264))	('mRNA', 'Var', (30, 34))	('cancer', 'Disease', (98, 104))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('tumor', 'Disease', (259, 264))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))
314227	28049499	During DNA replication, circRNAs enriched in the nucleus may interact with the opposite strand of its genomic DNA through base-pairing and thus form a DNA-RNA triple helix affecting DNA replication.	('form', 'Reg', (144, 148))	('base-pairing', 'Var', (122, 134))	('DNA replication', 'MPA', (182, 197))	('cir', 'Gene', '3762', (24, 27))	('cir', 'Gene', (24, 27))	('interact', 'Interaction', (61, 69))
314241	28049499	CircRNAs were considered untranslatable, but recent studies prove that most circRNAs carry open reading frames, and some of them have IRES elements.	('cir', 'Gene', '3762', (76, 79))	('cir', 'Gene', (76, 79))	('open reading frames', 'Var', (91, 110))
314274	33677681	Patients with a TPS >= 1% had an increased ORR compared to those < 1%, with the highest benefit in the patients with >= 50% TPS.	('Patients', 'Species', '9606', (0, 8))	('ORR', 'MPA', (43, 46))	('>= 1%', 'Var', (20, 25))	('patients', 'Species', '9606', (103, 111))
314275	33677681	The indication for metastatic NSCLC was expanded in 2016, to include patients with TPS >= 1% with disease progression on or after platinum-containing chemotherapy and metastatic NSCLC with high PD-L1 expression (TPS >= 50%) with no EGFR or ALK genomic tumor aberrations, and no prior systemic chemotherapy treatment.	('PD-L1', 'Gene', (194, 199))	('NSCLC', 'Disease', (178, 183))	('NSCLC', 'Disease', 'MESH:D002289', (30, 35))	('EGFR', 'Gene', '1956', (232, 236))	('tumor aberrations', 'Disease', (252, 269))	('ALK', 'Gene', '238', (240, 243))	('NSCLC', 'Disease', 'MESH:D002289', (178, 183))	('NSCLC', 'Phenotype', 'HP:0030358', (30, 35))	('high', 'Var', (189, 193))	('tumor', 'Phenotype', 'HP:0002664', (252, 257))	('ALK', 'Gene', (240, 243))	('NSCLC', 'Phenotype', 'HP:0030358', (178, 183))	('platinum', 'Chemical', 'MESH:D010984', (130, 138))	('patients', 'Species', '9606', (69, 77))	('EGFR', 'Gene', (232, 236))	('NSCLC', 'Disease', (30, 35))	('tumor aberrations', 'Disease', 'MESH:D002869', (252, 269))
314276	33677681	An improved overall survival rate was seen in patients with high PD-L1 expression.	('patients', 'Species', '9606', (46, 54))	('overall survival', 'MPA', (12, 28))	('improved', 'PosReg', (3, 11))	('high', 'Var', (60, 64))	('PD-L1', 'Gene', (65, 70))
314282	33677681	Patients with a positive PD-L1 expression (CPS > 1) derived benefit, and those patients who expressed a CPS > 20 were found to have the most benefit, with an increase in OS when treated with pembrolizumab with chemotherapy compared to cetuximab with chemotherapy.	('CPS', 'Chemical', '-', (104, 107))	('cetuximab', 'Chemical', 'MESH:D000068818', (235, 244))	('pembrolizumab', 'Chemical', 'MESH:C582435', (191, 204))	('Patients', 'Species', '9606', (0, 8))	('patients', 'Species', '9606', (79, 87))	('CPS', 'Chemical', '-', (43, 46))	('expression', 'Var', (31, 41))	('PD-L1', 'Gene', (25, 30))
314288	33677681	Mutations in the mismatch repair genes (MLH1, MSH2, MSH6, and PMS2) can lead to MSI due to errors in the DNA microsatellites.	('MSH6', 'Gene', (52, 56))	('MSI', 'Gene', (80, 83))	('PMS2', 'Gene', (62, 66))	('MSI', 'Gene', '5928', (80, 83))	('PMS2', 'Gene', '5395', (62, 66))	('MSH6', 'Gene', '2956', (52, 56))	('Mutations', 'Var', (0, 9))	('lead to', 'Reg', (72, 79))	('MSH2', 'Gene', (46, 50))	('MLH1', 'Gene', (40, 44))	('MSH2', 'Gene', '4436', (46, 50))	('MLH1', 'Gene', '4292', (40, 44))	('errors', 'Reg', (91, 97))
314289	33677681	Tumors with high levels of mismatch repair mutations are commonly associated with higher levels of neoantigen production, rendering the tumors susceptible to the ICI therapy.	('tumors', 'Disease', (136, 142))	('tumors', 'Disease', 'MESH:D009369', (136, 142))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('mismatch repair', 'Protein', (27, 42))	('higher', 'PosReg', (82, 88))	('Tumors', 'Disease', (0, 6))	('levels of neoantigen production', 'MPA', (89, 120))	('mutations', 'Var', (43, 52))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))
314292	33677681	Within the Keynote-158 (NCT02628067) clinical trial, retrospective analysis was performed on tumor samples and the TMB of >= 10 or >= 13 mutations (mut) per Mb was analyzed by the Foundation One CDx.	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Disease', (93, 98))	('mutations', 'Var', (137, 146))	('TMB', 'Chemical', '-', (115, 118))	('CDx', 'Chemical', '-', (195, 198))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
314294	33677681	The higher mutational burden within a tumor is expected to correspond to a higher level of immunogenic neopeptides that would drive T cell-mediated anti-tumor immunity.	('mutational', 'Var', (11, 21))	('tumor', 'Disease', (38, 43))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('higher', 'PosReg', (75, 81))	('drive', 'PosReg', (126, 131))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('level of immunogenic neopeptides', 'MPA', (82, 114))
314299	33677681	In the CheckMate 057 and CheckMate 063, similar retrospective stratification was performed, which demonstrated that PD-L1 expression was predictive of benefit to treatment with nivolumab.	('benefit', 'PosReg', (151, 158))	('nivolumab', 'Chemical', 'MESH:D000077594', (177, 186))	('expression', 'Var', (122, 132))	('PD-L1', 'Gene', (116, 121))
314304	33677681	TMB stratification was divided into three groups, with low < 85, medium 85-169, and high >= 170 missense somatic mutations per tumor.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('low < 85', 'Var', (55, 63))	('tumor', 'Disease', (127, 132))	('TMB', 'Chemical', '-', (0, 3))	('high >= 170 missense somatic', 'Var', (84, 112))	('tumor', 'Disease', 'MESH:D009369', (127, 132))
314308	33677681	Recurrence-free survival was higher in patients with a higher PD-L1 expression, though all patients experienced greater benefit when treated with nivolumab compared to ipilimumab.	('higher', 'PosReg', (29, 35))	('patients', 'Species', '9606', (91, 99))	('patients', 'Species', '9606', (39, 47))	('higher', 'Var', (55, 61))	('expression', 'MPA', (68, 78))	('nivolumab', 'Chemical', 'MESH:D000077594', (146, 155))	('Recurrence-free survival', 'CPA', (0, 24))	('PD-L1', 'Gene', (62, 67))	('ipilimumab', 'Chemical', 'MESH:D000074324', (168, 178))
314333	33677681	Tumor specimens were prospectively evaluated using the Ventana PD-L1 (SP142) assay and patients with high levels of PD-L1 expression had improved PR, CR, and ORR.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('ORR', 'MPA', (158, 161))	('patients', 'Species', '9606', (87, 95))	('PD-L1', 'Gene', (116, 121))	('high levels', 'Var', (101, 112))	('improved', 'PosReg', (137, 145))
314337	33677681	PD-L1 positivity correlated with improved OS, PFS, and ORR when treated with atezolizumab as a single agent.	('atezolizumab', 'Chemical', 'MESH:C000594389', (77, 89))	('positivity', 'Var', (6, 16))	('PFS', 'Disease', (46, 49))	('PD-L1', 'Gene', (0, 5))	('improved', 'PosReg', (33, 41))	('ORR', 'Disease', (55, 58))
314338	33677681	In May 2020, following the IMpower110 (NCT02409342) clinical trial, the inclusion criteria of high PD-L1 expression >= 50% of tumor cells or >= 10% of tumor-infiltrating immune cells as defined by an FDA-approved device were approved for the treatment of adult metastatic NSCLC with no EGFR or ALK genomic aberrations.	('NSCLC', 'Disease', (272, 277))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('NSCLC', 'Disease', 'MESH:D002289', (272, 277))	('EGFR', 'Gene', '1956', (286, 290))	('ALK', 'Gene', (294, 297))	('tumor', 'Disease', (151, 156))	('PD-L1', 'Gene', (99, 104))	('EGFR', 'Gene', (286, 290))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('NSCLC', 'Phenotype', 'HP:0030358', (272, 277))	('ALK', 'Gene', '238', (294, 297))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('high', 'Var', (94, 98))	('tumor', 'Disease', 'MESH:D009369', (151, 156))	('tumor', 'Disease', (126, 131))
314347	33677681	In the urothelial carcinoma cohort, the PD-L1 high patients experienced an improved disease control rate but patients treated with durvalumab experienced response regardless of PD-L1 status.	('improved', 'PosReg', (75, 83))	('high', 'Var', (46, 50))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (7, 27))	('carcinoma', 'Phenotype', 'HP:0030731', (18, 27))	('patients', 'Species', '9606', (109, 117))	('PD-L1', 'Gene', (40, 45))	('patients', 'Species', '9606', (51, 59))	('urothelial carcinoma', 'Disease', (7, 27))	('disease control', 'CPA', (84, 99))	('durvalumab', 'Chemical', 'MESH:C000613593', (131, 141))
314367	33677681	As PD-L1 positivity is still being evaluated as a predictive biomarker in clinical trials, in which patients with negative or non-evaluable tumor samples have also demonstrated a response, additional biomarkers are being assessed to determine their correlation with response rates and to better identify those patients who will respond.	('patients', 'Species', '9606', (310, 318))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('positivity', 'Var', (9, 19))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('patients', 'Species', '9606', (100, 108))	('PD-L1', 'Gene', (3, 8))	('tumor', 'Disease', (140, 145))
314375	33677681	The cancer immunity cycle is initiated when the accumulation of genetic mutations within cancer cell results in the production of neoantigens, which are able to bind to major histocompatibility complex (MHC) molecules on the cancer cell plasma membrane.	('cancer', 'Disease', 'MESH:D009369', (225, 231))	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('cancer', 'Disease', (225, 231))	('genetic mutations', 'Var', (64, 81))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('cancer', 'Disease', (89, 95))	('cancer', 'Disease', 'MESH:D009369', (4, 10))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('bind', 'Interaction', (161, 165))	('cancer', 'Disease', (4, 10))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
314381	33677681	Various clinical trials are studying the sequential treatment of ICIs either prior to or following chemotherapies, to determine if this treatment can turn "cold" non-immunogenic tumor to a "hot" tumor, which would respond to ICI treatment (NCT00527735, NCT02499367).	('tumor', 'Disease', (178, 183))	('tumor', 'Disease', (195, 200))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('NCT00527735', 'Var', (240, 251))
314382	33677681	The goal of these combinations is to modulate the immune suppressive microenvironment and initiate tumor cell death, recruiting effector T cells to the tumor and increasing the efficacy of the ICIs.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('tumor', 'Disease', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('ICIs', 'CPA', (193, 197))	('combinations', 'Var', (18, 30))	('tumor', 'Disease', (152, 157))	('recruiting', 'PosReg', (117, 127))	('tumor cell death', 'Disease', (99, 115))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('increasing', 'PosReg', (162, 172))	('tumor cell death', 'Disease', 'MESH:D003643', (99, 115))
314479	30799199	To examine whether prognosis-ranked GSEA is capable of identifying biologically relevant gene sets, a pan-cancer prognosis-ranked GSEA was carried out in gene sets that were up- or down-regulated by specific chemical and genetic perturbations (CGP, Table S2).	('perturbations', 'Var', (229, 242))	('up-', 'PosReg', (174, 177))	('down-regulated', 'NegReg', (181, 195))	('pan-cancer', 'Disease', (102, 112))	('GSEA', 'Chemical', '-', (36, 40))	('GSEA', 'Chemical', '-', (130, 134))	('pan-cancer', 'Disease', 'MESH:C537931', (102, 112))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
314488	30799199	Consistently, "Rapamycin response DN", "Response to APLIDIN DN" and "Response to GSK3 inhibitor SB216763 DN" were associated with adverse prognoses in the majority of tumor cohorts (log-rank P < .05, 41/42 datasets for Rapamycin, 43/46 datasets for GSK3i, Figs.	('SB216763 DN', 'Var', (96, 107))	('Rapamycin', 'Chemical', 'MESH:D020123', (219, 228))	('APLIDIN', 'Disease', (52, 59))	('GS', 'Disease', 'MESH:D011125', (249, 251))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('GS', 'Disease', 'MESH:D011125', (81, 83))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('Rapamycin', 'Chemical', 'MESH:D020123', (15, 24))	('tumor', 'Disease', (167, 172))	('APLIDIN', 'Disease', 'None', (52, 59))
314497	30799199	Notably, in contrast to their AdvP enrichment in major cancer types, cell-proliferation programs were enriched in FavP in colon cancer, small cell lung carcinoma and glioblastoma (cancer types labeled in blue, Fig.	('carcinoma', 'Phenotype', 'HP:0030731', (152, 161))	('glioblastoma', 'Phenotype', 'HP:0012174', (166, 178))	('colon cancer', 'Phenotype', 'HP:0003003', (122, 134))	('cell-proliferation programs', 'CPA', (69, 96))	('cancer', 'Disease', (128, 134))	('small cell lung carcinoma', 'Phenotype', 'HP:0030357', (136, 161))	('colon cancer', 'Disease', 'MESH:D015179', (122, 134))	('enriched', 'Reg', (102, 110))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('cancer', 'Disease', (180, 186))	('cancer', 'Disease', (55, 61))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('colon cancer', 'Disease', (122, 134))	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('small cell lung carcinoma and glioblastoma', 'Disease', 'MESH:D055752', (136, 178))	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('FavP', 'Var', (114, 118))
314509	30799199	Using data from the Human Pathology Atlas, we found that cancer-type dependent prognostic variations in the cell-proliferation program were consistent with prognostic NES (Fig.	('Human', 'Species', '9606', (20, 25))	('cancer-type', 'Disease', 'MESH:D009369', (57, 68))	('cell-proliferation program', 'CPA', (108, 134))	('variations', 'Var', (90, 100))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('cancer-type', 'Disease', (57, 68))
314524	30799199	To confirm the functional roles of stress response genes in treatment resistance, we validated three of these genes (PLAT, PLAU and SERPINE1) in MDA-MB-231 cells in response to MLN8237 (AURKA inhibitor) and Palbociclib (CDK4/6 inhibitor).	('PLAU', 'Gene', '5328', (123, 127))	('MLN8237', 'Var', (177, 184))	('PLAT', 'Gene', '5327', (117, 121))	('AURKA', 'Gene', '6790', (186, 191))	('SERPINE1', 'Gene', '5054', (132, 140))	('SERPINE1', 'Gene', (132, 140))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (145, 155))	('CDK4/6', 'Gene', '1019;1021', (220, 226))	('AURKA', 'Gene', (186, 191))	('PLAT', 'Gene', (117, 121))	('CDK4/6', 'Gene', (220, 226))	('PLAU', 'Gene', (123, 127))
314525	30799199	Consistently, cells were more sensitive to both inhibitors after knocking-down PLAT, PLAU or SERPINE1 by conditional shRNA (Figs.	('PLAT', 'Gene', '5327', (79, 83))	('PLAU', 'Gene', (85, 89))	('PLAU', 'Gene', '5328', (85, 89))	('more', 'PosReg', (25, 29))	('SERPINE1', 'Gene', (93, 101))	('sensitive', 'MPA', (30, 39))	('SERPINE1', 'Gene', '5054', (93, 101))	('PLAT', 'Gene', (79, 83))	('knocking-down', 'Var', (65, 78))
314534	30799199	To determine whether CycleC and CycleR are associated with established molecular subtyping, we examined the correlation of CycleC and CycleR with molecular subtypes and IDH1 mutation in the TCGA glioblastoma dataset.	('mutation', 'Var', (174, 182))	('glioblastoma', 'Disease', (195, 207))	('IDH1', 'Gene', (169, 173))	('IDH1', 'Gene', '3417', (169, 173))	('glioblastoma', 'Disease', 'MESH:D005909', (195, 207))	('glioblastoma', 'Phenotype', 'HP:0012174', (195, 207))
314537	30799199	In addition, CycleC was enriched IDH1 mutant subset, while CycleR was enriched in IDH1 wild-type subtype (Figs.	('mutant', 'Var', (38, 44))	('IDH1', 'Gene', (33, 37))	('IDH1', 'Gene', (82, 86))	('IDH1', 'Gene', '3417', (33, 37))	('IDH1', 'Gene', '3417', (82, 86))
314538	30799199	3j and S3l), consistent with previous report that IDH1 mutant glioblastoma patients were more sensitive to radiochemotherapy.	('glioblastoma', 'Phenotype', 'HP:0012174', (62, 74))	('IDH1', 'Gene', (50, 54))	('IDH1', 'Gene', '3417', (50, 54))	('patients', 'Species', '9606', (75, 83))	('mutant', 'Var', (55, 61))	('glioblastoma', 'Disease', (62, 74))	('glioblastoma', 'Disease', 'MESH:D005909', (62, 74))	('sensitive', 'MPA', (94, 103))
314552	30799199	S4f and S4g), the prognoses of favorable LSF gene sets again varied among cancer types (Fig.	('varied', 'Reg', (61, 67))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('S4f', 'Var', (0, 3))	('cancer', 'Disease', (74, 80))	('S4g', 'Var', (8, 11))	('LSF', 'Gene', (41, 44))	('LSF', 'Gene', '7024', (41, 44))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
314565	30799199	To test this possibility, we performed ssGSEA on transcriptional profiles of individual patients treated with anti-PD-1 immunotherapy (GSE78220, GSE67501, GSE91061 and Aa5951).	('GS', 'Disease', 'MESH:D011125', (135, 137))	('GS', 'Disease', 'MESH:D011125', (145, 147))	('patients', 'Species', '9606', (88, 96))	('PD-1', 'Gene', (115, 119))	('Aa5951', 'Var', (168, 174))	('PD-1', 'Gene', '5133', (115, 119))	('GSEA', 'Chemical', '-', (41, 45))	('GS', 'Disease', 'MESH:D011125', (155, 157))	('GS', 'Disease', 'MESH:D011125', (41, 43))
314598	30799199	The prognostic variations not only strengthen the importance of our cancer type-specific prognostic resource, but also provide an opportunity to establish the determinants for prognosis and treatment response.	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('variations', 'Var', (15, 25))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('cancer', 'Disease', (68, 74))
314606	30799199	For example, mutational loads have been demonstrated to benefit anti-CTLA4 responses in melanoma and anti-PD1 response in lung cancer, while another study reports that mutational loads benefit survival, but not anti-PD-1 response.	('PD1', 'Gene', (106, 109))	('benefit', 'PosReg', (185, 192))	('PD-1', 'Gene', (216, 220))	('lung cancer', 'Disease', (122, 133))	('CTLA4', 'Gene', '1493', (69, 74))	('PD-1', 'Gene', '5133', (216, 220))	('lung cancer', 'Phenotype', 'HP:0100526', (122, 133))	('survival', 'MPA', (193, 201))	('melanoma', 'Disease', (88, 96))	('melanoma', 'Phenotype', 'HP:0002861', (88, 96))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('CTLA4', 'Gene', (69, 74))	('benefit', 'PosReg', (56, 63))	('mutational loads', 'Var', (13, 29))	('melanoma', 'Disease', 'MESH:D008545', (88, 96))	('lung cancer', 'Disease', 'MESH:D008175', (122, 133))	('mutational loads', 'Var', (168, 184))	('PD1', 'Gene', '5133', (106, 109))
314626	29843367	The combination of low CD151 expression and high RNASEH2A expression resulted in impaired proliferation in four kidney cancer cell lines, suggesting potential synthetic dosage lethality (SDL) interactions between the two genes.	('high', 'Var', (44, 48))	('kidney cancer', 'Disease', (112, 125))	('proliferation', 'CPA', (90, 103))	('RNASEH2A', 'Gene', (49, 57))	('low', 'NegReg', (19, 22))	('CD151', 'Gene', (23, 28))	('RNASEH2A', 'Gene', '10535', (49, 57))	('impaired', 'NegReg', (81, 89))	('si', 'Chemical', 'MESH:D012825', (64, 66))	('kidney cancer', 'Phenotype', 'HP:0009726', (112, 125))	('kidney cancer', 'Disease', 'MESH:D007680', (112, 125))	('expression', 'MPA', (29, 39))	('si', 'Chemical', 'MESH:D012825', (35, 37))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
314630	29843367	Genomic instability facilitates tumor initiation and progression.	('progression', 'CPA', (53, 64))	('facilitates', 'PosReg', (20, 31))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('si', 'Chemical', 'MESH:D012825', (60, 62))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('Genomic instability', 'Var', (0, 19))	('tumor', 'Disease', (32, 37))
314632	29843367	Loss-of-function mutations in the nucleotide degrading enzymes sterile alpha motif (SAM) domain and HD domain-containing protein 1 (SAMHD1), Three prime repair exonuclease 1 (TREX1), and ribonuclease H2 subunits A, B, and C (RNASEH2A, RNASEH2B, RNASEH2C) in human germline mainly result in a hyper-inflammatory Aicardi-Goutieres syndrome (AGS), and in the development of malignancy in AGS patient is rare.	('HD', 'Disease', 'MESH:D006816', (100, 102))	('AGS', 'Disease', (339, 342))	('hyper-inflammatory Aicardi-Goutieres syndrome', 'Disease', 'MESH:C535607', (292, 337))	('SAMHD1', 'Gene', '25939', (132, 138))	('patient', 'Species', '9606', (389, 396))	('RNASEH2A', 'Gene', '10535', (225, 233))	('SAMHD1', 'Gene', (132, 138))	('mutations', 'Var', (17, 26))	('malignancy', 'Disease', 'MESH:D009369', (371, 381))	('result in', 'Reg', (280, 289))	('RNASEH2C', 'Gene', (245, 253))	('RNASEH2B', 'Gene', '79621', (235, 243))	('AGS', 'Disease', (385, 388))	('hyper-inflammatory Aicardi-Goutieres syndrome', 'Disease', (292, 337))	('AGS', 'Disease', 'MESH:C535607', (339, 342))	('TREX1', 'Gene', '11277', (175, 180))	('RNASEH2C', 'Gene', '84153', (245, 253))	('RNASEH2B', 'Gene', (235, 243))	('malignancy', 'Disease', (371, 381))	('Three prime repair exonuclease 1', 'Gene', (141, 173))	('HD', 'Disease', 'MESH:D006816', (135, 137))	('RNASEH2A', 'Gene', (225, 233))	('TREX1', 'Gene', (175, 180))	('AGS', 'Disease', 'MESH:C535607', (385, 388))	('Three prime repair exonuclease 1', 'Gene', '11277', (141, 173))	('Loss-of-function', 'NegReg', (0, 16))	('human', 'Species', '9606', (258, 263))
314642	29843367	It has been reported that certain genes have synthetic dosage lethality (SDL) interactions with genes that are frequently overexpressed in tumors and that inhibition of the SDL partners can decrease cancer proliferation.	('decrease', 'NegReg', (190, 198))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('tumors', 'Disease', (139, 145))	('cancer', 'Disease', (199, 205))	('tumors', 'Disease', 'MESH:D009369', (139, 145))	('inhibition', 'Var', (155, 165))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('interactions', 'Interaction', (78, 90))
314651	29843367	In search of an alternative pathway that promotes tumor proliferation, we performed gene correlation studies in five kidney cancer patient samples with high RNASEH2A expression, low CDK1 expression, and bad clinical outcomes (death).	('death', 'Disease', 'MESH:D003643', (226, 231))	('si', 'Chemical', 'MESH:D012825', (193, 195))	('RNASEH2A', 'Gene', (157, 165))	('tumor', 'Disease', (50, 55))	('death', 'Disease', (226, 231))	('kidney cancer', 'Disease', 'MESH:D007680', (117, 130))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('si', 'Chemical', 'MESH:D012825', (172, 174))	('expression', 'MPA', (166, 176))	('RNASEH2A', 'Gene', '10535', (157, 165))	('low', 'NegReg', (178, 181))	('kidney cancer', 'Phenotype', 'HP:0009726', (117, 130))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('kidney cancer', 'Disease', (117, 130))	('CDK1', 'Gene', '983', (182, 186))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('patient', 'Species', '9606', (131, 138))	('expression', 'MPA', (187, 197))	('CDK1', 'Gene', (182, 186))	('high', 'Var', (152, 156))
314655	29843367	To study the interactions among RNASEH2A, CDK1, and CD151 and their impact on tumor proliferation, we performed si-RNA knockdown studies on three ccRCC cell lines (786O, A704, KMRC3, all with VHL mutation) and one kidney urothelial carcinoma cell line (BFTC909, without VHL mutation).	('RCC', 'Disease', (148, 151))	('si', 'Chemical', 'MESH:D012825', (112, 114))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('carcinoma', 'Phenotype', 'HP:0030731', (232, 241))	('VHL', 'Disease', (192, 195))	('RCC', 'Disease', 'MESH:C538614', (148, 151))	('CDK1', 'Gene', '983', (42, 46))	('RNASEH2A', 'Gene', '10535', (32, 40))	('CDK1', 'Gene', (42, 46))	('BFTC909', 'CellLine', 'CVCL:1084', (253, 260))	('VHL', 'Disease', (270, 273))	('kidney urothelial carcinoma', 'Disease', 'MESH:D007674', (214, 241))	('kidney urothelial carcinoma', 'Phenotype', 'HP:0030409', (214, 241))	('kidney urothelial carcinoma', 'Disease', (214, 241))	('tumor', 'Disease', (78, 83))	('VHL', 'Disease', 'MESH:D006623', (192, 195))	('mutation', 'Var', (196, 204))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('RNASEH2A', 'Gene', (32, 40))	('one kidney', 'Phenotype', 'HP:0000122', (210, 220))	('ccRCC', 'Phenotype', 'HP:0006770', (146, 151))	('VHL', 'Disease', 'MESH:D006623', (270, 273))
314656	29843367	As shown in Figure 3A, CDK1 knockdown resulted in the upregulation of RNASEH2A and CD151 in all cell lines, however it did not significantly impair tumor proliferation (except for a mild effect on A704).	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('CDK1', 'Gene', (23, 27))	('CDK1', 'Gene', '983', (23, 27))	('RNASEH2A', 'Gene', (70, 78))	('tumor', 'Disease', (148, 153))	('upregulation', 'PosReg', (54, 66))	('RNASEH2A', 'Gene', '10535', (70, 78))	('si', 'Chemical', 'MESH:D012825', (127, 129))	('knockdown', 'Var', (28, 37))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('CD151', 'Gene', (83, 88))
314657	29843367	Interestingly, in BFTC909, CDK1 could not be knocked down after a 96-hour si-CDK1 transfection, and the tumor survival rate even increased.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('transfection', 'Var', (82, 94))	('CDK1', 'Gene', (77, 81))	('CDK1', 'Gene', '983', (77, 81))	('tumor', 'Disease', (104, 109))	('increased', 'PosReg', (129, 138))	('si', 'Chemical', 'MESH:D012825', (74, 76))	('CDK1', 'Gene', '983', (27, 31))	('CDK1', 'Gene', (27, 31))	('BFTC909', 'CellLine', 'CVCL:1084', (18, 25))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
314658	29843367	Furthermore, RNASEH2A knockdown resulted in CD151 upregulation and decreased proliferation in all ccRCC cell lines.	('ccRCC', 'Phenotype', 'HP:0006770', (98, 103))	('RNASEH2A', 'Gene', '10535', (13, 21))	('upregulation', 'PosReg', (50, 62))	('RCC', 'Disease', 'MESH:C538614', (100, 103))	('knockdown', 'Var', (22, 31))	('CD151', 'Gene', (44, 49))	('decreased', 'NegReg', (67, 76))	('RNASEH2A', 'Gene', (13, 21))	('RCC', 'Disease', (100, 103))	('proliferation', 'CPA', (77, 90))
314661	29843367	Cell viability assays were performed in ccRCC cell line 786O after transfection with si-CDK1, si-RNASEH2A, and si-CD151, which showed comparable results to the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays (Figure 4).	('RCC', 'Disease', 'MESH:C538614', (42, 45))	('CDK1', 'Gene', '983', (88, 92))	('MTT', 'Chemical', 'MESH:C070243', (222, 225))	('si', 'Chemical', 'MESH:D012825', (111, 113))	('CDK1', 'Gene', (88, 92))	('RNASEH2A', 'Gene', (97, 105))	('ccRCC', 'Phenotype', 'HP:0006770', (40, 45))	('3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide', 'Chemical', 'MESH:C022616', (160, 220))	('si', 'Chemical', 'MESH:D012825', (85, 87))	('RNASEH2A', 'Gene', '10535', (97, 105))	('si-CD151', 'Var', (111, 119))	('RCC', 'Disease', (42, 45))	('si', 'Chemical', 'MESH:D012825', (94, 96))
314666	29843367	In KIRC, patients with scores lower than the cutoff (-1.925) had a significantly worse overall survival rate compared to those with scores above the cutoff value (mean survival of 955.3 days versus 2242.2 days, hazard ratio (HR) = 4.53 (3.05-6.73), p = 2.2 x 10-16, Figure 6A).	('lower', 'NegReg', (30, 35))	('patients', 'Species', '9606', (9, 17))	('overall survival', 'CPA', (87, 103))	('scores', 'Var', (23, 29))	('si', 'Chemical', 'MESH:D012825', (67, 69))	('worse', 'NegReg', (81, 86))
314668	29843367	In another ccRCC cohort, namely, the E-GEOD-22541 expression array data (n = 44), patients with scores lower than -1.596 also showed lower disease-free survival when compared to those with higher scores (mean survival of 390.0 days versus 1889.2 days, HR = 2.99 (1.07-8.35), p = 7.1 x 10-4, Figure 6C).	('si', 'Chemical', 'MESH:D012825', (56, 58))	('patients', 'Species', '9606', (82, 90))	('scores lower than -1.596', 'Var', (96, 120))	('RCC', 'Disease', 'MESH:C538614', (13, 16))	('ccRCC', 'Phenotype', 'HP:0006770', (11, 16))	('RCC', 'Disease', (13, 16))	('disease-free survival', 'CPA', (139, 160))	('lower', 'NegReg', (133, 138))
314676	29843367	Similarly, in our study, CDK1 knockdown in RCC cell lines did not have a pronounced effect on tumor growth.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Disease', (94, 99))	('CDK1', 'Gene', (25, 29))	('RCC', 'Disease', 'MESH:C538614', (43, 46))	('RCC', 'Disease', (43, 46))	('CDK1', 'Gene', '983', (25, 29))	('knockdown', 'Var', (30, 39))
314679	29843367	In contrast to CDK1 knockdown, transfection of RCC cell lines with either si-RNASEH2A or si-CD151 resulted in impaired tumor proliferation.	('CDK1', 'Gene', '983', (15, 19))	('RNASEH2A', 'Gene', '10535', (77, 85))	('impaired tumor', 'Disease', (110, 124))	('CDK1', 'Gene', (15, 19))	('si-CD151', 'Var', (89, 97))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('si', 'Chemical', 'MESH:D012825', (74, 76))	('si', 'Chemical', 'MESH:D012825', (89, 91))	('RCC', 'Disease', 'MESH:C538614', (47, 50))	('RCC', 'Disease', (47, 50))	('RNASEH2A', 'Gene', (77, 85))	('impaired tumor', 'Disease', 'MESH:D015417', (110, 124))
314680	29843367	Upregulation of CD151 and RNASEH2A was noted 48 h after si-RNASEH2A and si-CD151 knockdown, respectively, in all kidney cancer cell lines.	('Upregulation', 'PosReg', (0, 12))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('kidney cancer', 'Phenotype', 'HP:0009726', (113, 126))	('RNASEH2A', 'Gene', (59, 67))	('RNASEH2A', 'Gene', '10535', (26, 34))	('kidney cancer', 'Disease', (113, 126))	('RNASEH2A', 'Gene', '10535', (59, 67))	('CD151', 'Gene', (16, 21))	('si-CD151', 'Var', (72, 80))	('si', 'Chemical', 'MESH:D012825', (72, 74))	('si', 'Chemical', 'MESH:D012825', (56, 58))	('kidney cancer', 'Disease', 'MESH:D007680', (113, 126))	('RNASEH2A', 'Gene', (26, 34))
314688	29843367	Furthermore, according to the potential SDL relationships between CD151 and RNASEH2A identified by this study, CD151-high RCCs could be treated with RNASEH2A inhibitors.	('RNASEH2A', 'Gene', (76, 84))	('RNASEH2A', 'Gene', (149, 157))	('CD151-high', 'Var', (111, 121))	('RNASEH2A', 'Gene', '10535', (76, 84))	('RNASEH2A', 'Gene', '10535', (149, 157))	('RCCs', 'Phenotype', 'HP:0005584', (122, 126))	('RCC', 'Disease', 'MESH:C538614', (122, 125))	('RCC', 'Disease', (122, 125))
314781	29399193	Finally, factors, including age >60 years, non-glottic carcinoma, high histologic grade, high staging, extensive treatment and recurrence were associated with increased probability of overall mortality (Fig.	('high', 'Disease', (89, 93))	('overall mortality', 'MPA', (184, 201))	('carcinoma', 'Phenotype', 'HP:0030731', (55, 64))	('non-glottic carcinoma', 'Disease', 'MESH:C563636', (43, 64))	('high', 'Var', (66, 70))	('non-glottic carcinoma', 'Disease', (43, 64))
314843	28604784	Consequently, CD13 can affect prognosis in various tumor subtypes.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor', 'Disease', (51, 56))	('CD13', 'Var', (14, 18))	('prognosis', 'CPA', (30, 39))	('affect', 'Reg', (23, 29))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
314845	28604784	At present, two NGR-coupled molecules are under study: (1) NGR-tumor necrosis factor (NGR-hTNF) and (2) truncated tissue factor-NGR (tTF-NGR).	('tumor', 'Disease', (63, 68))	('NGR (tTF-', 'Gene', '399', (128, 137))	('truncated', 'Var', (104, 113))	('necrosis factor (NGR-', 'Gene', '65078', (69, 90))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
314846	28604784	Upon the intravenous infusion of tTF-NGR, we could demonstrate vascular infarction in tumor blood vessels with subsequent retardation of tumor growth.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tTF-NGR', 'Var', (33, 40))	('tumor', 'Disease', (137, 142))	('tumor', 'Disease', (86, 91))	('vascular infarction', 'Disease', 'MESH:D007238', (63, 82))	('retardation of tumor', 'Disease', 'MESH:D009369', (122, 142))	('vascular infarction', 'Disease', (63, 82))	('retardation of tumor', 'Disease', (122, 142))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
314865	28604784	Sections were incubated over night at 4 C with a CD13 antibody (SP187, Cell Marque; dilution 1:300) and a CD31 antibody (JC70A, DAKO, dilution 1:200) followed by a 60 min incubation with a Cy3-labelled goat anti-rabbit-IgG antibody (#111-165-003, Dianova; dilution 1:200) and a FITC-labelled goat anti-mouse-IgG (#554001, BD Pharmingen; dilution 1:500).	('FITC', 'Chemical', 'MESH:D016650', (278, 282))	('#554001', 'Var', (313, 320))	('goat', 'Species', '9925', (202, 206))	('mouse', 'Species', '10090', (302, 307))	('CD31', 'Gene', (106, 110))	('CD31', 'Gene', '5175', (106, 110))	('goat', 'Species', '9925', (292, 296))	('rabbit', 'Species', '9986', (212, 218))	('IgG antibody', 'Phenotype', 'HP:0003237', (219, 231))	('#111-165-003', 'Var', (233, 245))
314896	28604784	In subgroup analyses lung cancer patients in tumor stage I (n = 577 patients) had an increased overall survival in case CD13 mRNA expression was observed (p = 0.0035; HR = 0.67 (95%-CI: 0.51-0.88)).	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('patients', 'Species', '9606', (33, 41))	('CD13 mRNA expression', 'Var', (120, 140))	('lung cancer', 'Disease', (21, 32))	('tumor', 'Disease', (45, 50))	('lung cancer', 'Phenotype', 'HP:0100526', (21, 32))	('patients', 'Species', '9606', (68, 76))	('overall survival', 'MPA', (95, 111))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('increased', 'PosReg', (85, 94))	('lung cancer', 'Disease', 'MESH:D008175', (21, 32))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
314913	28604784	Likewise, for subcutaneous CD13+ A549 xenotransplants in CD-1 nude mice similar results were found with a significant reduction of tumor growth after application of tTF-NGR in comparison to the saline control group, which reproduces earlier results (22).	('NGR ', 'Gene', '399', (169, 173))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('A549', 'CellLine', 'CVCL:0023', (33, 37))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('reduction', 'NegReg', (118, 127))	('tumor', 'Disease', (131, 136))	('NGR ', 'Gene', (169, 173))	('saline', 'Chemical', 'MESH:D012965', (194, 200))	('CD13+ A549', 'Var', (27, 37))	('nude mice', 'Species', '10090', (62, 71))
314941	32872133	Therefore, deep learning should be a promising approach to successfully handling the mapping between genotype and phenotype, leading to the data-driven discovery of the critical signatures of somatic mutations involved in cancer genesis.	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('cancer', 'Disease', (222, 228))	('cancer', 'Disease', 'MESH:D009369', (222, 228))	('mutations', 'Var', (200, 209))
314945	32872133	In particular, many researchers in the field of biomedicine are interested more in the biological insights, such as genetic variants associated with a cancer phenotype, than in the model accuracy.	('biomedicine', 'Chemical', '-', (48, 59))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('variants', 'Var', (124, 132))	('cancer', 'Disease', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (151, 157))
314947	32872133	To investigate the practical performance of the proposed method compared with other configurations of Diet Networks and MLP with the same architecture, we defined a simple task:predicting the histological types of lung cancer from somatic mutations (i.e., SNVs, insertions and deletions).	('deletions', 'Var', (277, 286))	('lung cancer', 'Phenotype', 'HP:0100526', (214, 225))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('insertions', 'Var', (262, 272))	('lung cancer', 'Disease', 'MESH:D008175', (214, 225))	('SNVs', 'Var', (256, 260))	('lung cancer', 'Disease', (214, 225))
314962	32872133	Notably, KRAS has shown mutation with a frequency 26 times higher in LUAD than in LUSC.	('LUAD', 'Phenotype', 'HP:0030078', (69, 73))	('LUAD', 'Disease', (69, 73))	('KRAS', 'Gene', (9, 13))	('KRAS', 'Gene', '3845', (9, 13))	('LUSC', 'Phenotype', 'HP:0030359', (82, 86))	('mutation', 'Var', (24, 32))	('higher', 'PosReg', (59, 65))
314964	32872133	What needs to be discussed carefully here is that TP53, ZFHX4, and MUC5B are known to be significantly mutated in both LUAD and LUSC.	('ZFHX4', 'Gene', (56, 61))	('mutated', 'Var', (103, 110))	('MUC5B', 'Gene', '727897', (67, 72))	('MUC5B', 'Gene', (67, 72))	('LUSC', 'Phenotype', 'HP:0030359', (128, 132))	('LUAD', 'Phenotype', 'HP:0030078', (119, 123))	('TP53', 'Gene', '7157', (50, 54))	('ZFHX4', 'Gene', '79776', (56, 61))	('TP53', 'Gene', (50, 54))
314965	32872133	For example, mutations in MUC5B have also been detected in both LUAD and LUSC.	('MUC5B', 'Gene', '727897', (26, 31))	('MUC5B', 'Gene', (26, 31))	('LUAD', 'Phenotype', 'HP:0030078', (64, 68))	('LUAD', 'Disease', (64, 68))	('detected', 'Reg', (47, 55))	('mutations', 'Var', (13, 22))	('LUSC', 'Phenotype', 'HP:0030359', (73, 77))
314969	32872133	The task of predicting the histological type of lung cancer from somatic mutations (i.e., SNVs, insertions, and deletions) is simple yet fundamental to the practice of cancer medicine.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('cancer', 'Disease', (53, 59))	('deletions', 'Var', (112, 121))	('lung cancer', 'Disease', 'MESH:D008175', (48, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('insertions', 'Var', (96, 106))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('lung cancer', 'Disease', (48, 59))	('cancer', 'Disease', (168, 174))	('lung cancer', 'Phenotype', 'HP:0100526', (48, 59))
314978	32793396	FBXO22 exerts oncogenetic functions via promoting the ubiquitination and degradation of its substrates, including KDM4A, KDM4B, methylated p53, p21, KLF4, LKB1, Snail, CD147, Bach1, PTEN, and HDM2.	('HDM2', 'Gene', '4193', (192, 196))	('FBXO22', 'Gene', (0, 6))	('methylated', 'Var', (128, 138))	('KDM4B', 'Gene', (121, 126))	('Snail', 'Gene', (161, 166))	('p21', 'Gene', (144, 147))	('LKB1', 'Gene', (155, 159))	('p21', 'Gene', '644914', (144, 147))	('CD147', 'Gene', '682', (168, 173))	('Bach1', 'Gene', '571', (175, 180))	('KDM4B', 'Gene', '23030', (121, 126))	('KLF4', 'Gene', (149, 153))	('CD147', 'Gene', (168, 173))	('Bach1', 'Gene', (175, 180))	('KDM4A', 'Gene', '9682', (114, 119))	('ubiquitination', 'MPA', (54, 68))	('KDM4A', 'Gene', (114, 119))	('degradation', 'MPA', (73, 84))	('HDM2', 'Gene', (192, 196))	('Snail', 'Gene', '6615', (161, 166))	('KLF4', 'Gene', '9314', (149, 153))	('promoting', 'PosReg', (40, 49))
314979	32793396	FBXO22 is also regulated by several regulatory factors such as p53, miR-155, SNHG14, and circ_0006282.	('miR-155', 'Gene', '406947', (68, 75))	('SNHG14', 'Gene', (77, 83))	('circ_0006282', 'Var', (89, 101))	('miR-155', 'Gene', (68, 75))	('regulated', 'Reg', (15, 24))	('FBXO22', 'Gene', (0, 6))	('p53', 'Var', (63, 66))	('SNHG14', 'Gene', '104472715', (77, 83))
314986	32793396	Post-translational modification (PTM) is one of the critical pathways in regulation of cellular events such as proliferation, apoptotic death, cell cycle, mitosis, motility, and innate immunity.	('mitosis', 'Disease', 'None', (155, 162))	('death', 'Disease', 'MESH:D003643', (136, 141))	('motility', 'CPA', (164, 172))	('death', 'Disease', (136, 141))	('cell cycle', 'CPA', (143, 153))	('Post-translational modification', 'Var', (0, 31))	('apoptotic', 'CPA', (126, 135))	('mitosis', 'Disease', (155, 162))
314994	32793396	The p53 protein as a traditional tumor suppressor has been identified to be mutated in a variety of human malignancies.	('malignancies', 'Disease', 'MESH:D009369', (106, 118))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('mutated', 'Var', (76, 83))	('protein', 'Protein', (8, 15))	('malignancies', 'Disease', (106, 118))	('human', 'Species', '9606', (100, 105))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumor', 'Disease', (33, 38))	('p53', 'Gene', (4, 7))
314995	32793396	Mutant p53 proteins lose anticancer function due to impaired cellular homeostasis and damaged genome stability, leading to enhancement of survival, invasion, and metastasis.	('cancer', 'Disease', (29, 35))	('impaired', 'NegReg', (52, 60))	('proteins', 'Protein', (11, 19))	('genome stability', 'CPA', (94, 110))	('cellular homeostasis', 'MPA', (61, 81))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('enhancement', 'PosReg', (123, 134))	('survival', 'CPA', (138, 146))	('Mutant', 'Var', (0, 6))	('lose', 'NegReg', (20, 24))	('damaged', 'NegReg', (86, 93))	('p53', 'Gene', (7, 10))	('cancer', 'Disease', 'MESH:D009369', (29, 35))	('invasion', 'CPA', (148, 156))
314997	32793396	Since FBXO22 might target numerous substrates for degradation or inactivation, p53 exerts its tumor suppressive activity partly via induction of FBXO22 expression.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Disease', (94, 99))	('p53', 'Var', (79, 82))	('FBXO22', 'Gene', (145, 151))	('expression', 'MPA', (152, 162))	('induction', 'PosReg', (132, 141))
315010	32793396	Specifically, circ_0006282 functions as a ceRNA to spong miR-155 and cause the upregulation of its target, FBXO22, resulting in enhancement of proliferation and metastasis of gastric cancer cells (Fig.	('enhancement', 'PosReg', (128, 139))	('miR-155', 'Gene', (57, 64))	('gastric cancer', 'Disease', (175, 189))	('circ_0006282', 'Var', (14, 26))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('gastric cancer', 'Disease', 'MESH:D013274', (175, 189))	('FBXO22', 'Gene', (107, 113))	('miR-155', 'Gene', '406947', (57, 64))	('upregulation', 'PosReg', (79, 91))	('proliferation', 'CPA', (143, 156))	('gastric cancer', 'Phenotype', 'HP:0012126', (175, 189))	('metastasis', 'CPA', (161, 171))
315012	32793396	KDM4A, also termed as JMJD2A and JHDM3A, can demethylate histone H3 lysine 9 (H3K9) and 36 (H3K36) and H1.4K26, leading to regulation of genome replication and stability.	('KDM4A', 'Gene', '9682', (0, 5))	('stability', 'CPA', (160, 169))	('JHDM3A', 'Gene', (33, 39))	('JMJD2A', 'Gene', '9682', (22, 28))	('JMJD2A', 'Gene', (22, 28))	('KDM4A', 'Gene', (0, 5))	('H1.4K26', 'Var', (103, 110))	('histone H3 lysine', 'Protein', (57, 74))	('genome replication', 'CPA', (137, 155))	('JHDM3A', 'Gene', '9682', (33, 39))	('lysine', 'Chemical', 'MESH:D008239', (68, 74))	('regulation', 'Reg', (123, 133))
315032	32793396	It is worth noting that Snail/Slug and ZEB-1/SIP1 families not only control EMT process, but also inhibit cell cycle progression by repression of cyclin D. This study indicated that FBXO22 may act as an upstream regulator and play a dual role in mammary cancer by inducing Snail degradation: promotion of proliferation and suppression of metastasis.	('Slug', 'Gene', '6591', (30, 34))	('Snail', 'Gene', '6615', (24, 29))	('cancer', 'Disease', (254, 260))	('SIP1', 'Gene', (45, 49))	('Snail', 'Gene', (273, 278))	('cancer', 'Phenotype', 'HP:0002664', (254, 260))	('inducing', 'PosReg', (264, 272))	('FBXO22', 'Var', (182, 188))	('ZEB-1', 'Gene', (39, 44))	('ZEB-1', 'Gene', '6935', (39, 44))	('promotion', 'PosReg', (292, 301))	('metastasis', 'CPA', (338, 348))	('Snail', 'Gene', (24, 29))	('Slug', 'Gene', (30, 34))	('suppression', 'NegReg', (323, 334))	('cancer', 'Disease', 'MESH:D009369', (254, 260))	('SIP1', 'Gene', '9839', (45, 49))	('proliferation', 'CPA', (305, 318))	('Snail', 'Gene', '6615', (273, 278))
315038	32793396	LKB1 expression level is regulated by FBXO22 via proteasome-mediated degradation in non-small cell lung cancer (NSCLC) cells.	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (84, 110))	('FBXO22', 'Var', (38, 44))	('proteasome-mediated degradation', 'MPA', (49, 80))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('non-small cell lung cancer', 'Disease', (84, 110))	('LKB1', 'Gene', (0, 4))	('NSCLC', 'Phenotype', 'HP:0030358', (112, 117))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (88, 110))	('expression level', 'MPA', (5, 21))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (84, 110))	('NSCLC', 'Disease', (112, 117))	('regulated', 'Reg', (25, 34))	('NSCLC', 'Disease', 'MESH:D002289', (112, 117))	('lung cancer', 'Phenotype', 'HP:0100526', (99, 110))
315040	32793396	FBXO22-mediated inactivation of LKB1 causes promotion of cell growth via modulation of AMPK and mTOR pathways in NSCLC cells.	('mTOR', 'Gene', (96, 100))	('cell growth', 'CPA', (57, 68))	('NSCLC', 'Phenotype', 'HP:0030358', (113, 118))	('inactivation', 'Var', (16, 28))	('LKB1', 'Gene', (32, 36))	('mTOR', 'Gene', '2475', (96, 100))	('AMPK', 'Gene', (87, 91))	('NSCLC', 'Disease', (113, 118))	('AMPK', 'Gene', '5564', (87, 91))	('promotion', 'PosReg', (44, 53))	('modulation', 'Reg', (73, 83))	('NSCLC', 'Disease', 'MESH:D002289', (113, 118))
315062	32793396	Fbxo22 deletion promoting or blocking tumorigenesis in these mouse models will elucidate the physiological role of FBXO22 in tumorigenesis in a given organ.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('blocking', 'NegReg', (29, 37))	('Fbxo22', 'Gene', (0, 6))	('tumor', 'Disease', (125, 130))	('mouse', 'Species', '10090', (61, 66))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('promoting', 'PosReg', (16, 25))	('Fbxo22', 'Gene', '71999', (0, 6))	('deletion', 'Var', (7, 15))
315067	32793396	Furthermore, high expression of FBXO22 is associated with poor prognosis in patients with HCC.	('HCC', 'Phenotype', 'HP:0001402', (90, 93))	('patients', 'Species', '9606', (76, 84))	('FBXO22', 'Gene', (32, 38))	('high', 'Var', (13, 17))	('HCC', 'Disease', (90, 93))
315072	32793396	In support of the oncogenic role of FBXO22 in lung cancer, the high expression of FBO22 is correlated with poor overall survival in lung cancer patients.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('lung cancer', 'Disease', 'MESH:D008175', (132, 143))	('lung cancer', 'Phenotype', 'HP:0100526', (132, 143))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('lung cancer', 'Disease', 'MESH:D008175', (46, 57))	('patients', 'Species', '9606', (144, 152))	('high', 'Var', (63, 67))	('lung cancer', 'Disease', (132, 143))	('FBO22', 'Gene', (82, 87))	('poor', 'NegReg', (107, 111))	('lung cancer', 'Disease', (46, 57))	('overall', 'MPA', (112, 119))	('lung cancer', 'Phenotype', 'HP:0100526', (46, 57))
315084	32793396	FBXO22 exerts its tumor promoting role in HCC, lung cancer, breast cancer, but inhibits migration and metastasis in lung cancer and breast cancer, indicating FBXO22 either acting as a tumor suppressor or acting as an oncogene.	('lung cancer', 'Phenotype', 'HP:0100526', (116, 127))	('inhibits', 'NegReg', (79, 87))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('FBXO22', 'Gene', (0, 6))	('breast cancer', 'Phenotype', 'HP:0003002', (60, 73))	('FBXO22', 'Var', (158, 164))	('lung cancer', 'Disease', (47, 58))	('tumor', 'Disease', (18, 23))	('tumor', 'Disease', (184, 189))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('breast cancer', 'Disease', 'MESH:D001943', (60, 73))	('breast cancer', 'Phenotype', 'HP:0003002', (132, 145))	('breast cancer', 'Disease', (60, 73))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('lung cancer', 'Disease', (116, 127))	('breast cancer', 'Disease', 'MESH:D001943', (132, 145))	('lung cancer', 'Disease', 'MESH:D008175', (47, 58))	('breast cancer', 'Disease', (132, 145))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('lung cancer', 'Phenotype', 'HP:0100526', (47, 58))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('lung cancer', 'Disease', 'MESH:D008175', (116, 127))	('HCC', 'Disease', (42, 45))	('HCC', 'Phenotype', 'HP:0001402', (42, 45))
315090	32793396	A complementary chemical and genomic screening approach might be a novel strategy for achieving FBXO22 inhibitors for treating cancer patients.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('patients', 'Species', '9606', (134, 142))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('inhibitors', 'Var', (103, 113))	('FBXO22', 'Gene', (96, 102))	('cancer', 'Disease', (127, 133))
315108	31921623	Recent studies suggest that long non-coding RNAs (lncRNAs), which are RNAs >200 nucleotides in length that have no coding potential and represent the majority of non-coding RNAs, are extensively involved in the initiation and progression of cancer.	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('involved', 'Reg', (195, 203))	('cancer', 'Disease', (241, 247))	('cancer', 'Disease', 'MESH:D009369', (241, 247))	('long non-coding RNAs', 'Var', (28, 48))
315127	31921623	To inhibit TGF-beta signaling, 5 muM SB505124 (Selleck) was added to the culture medium 30 min prior to the specified treatments.	('TGF-beta', 'Gene', '7040', (11, 19))	('TGF-beta', 'Gene', (11, 19))	('SB505124', 'Chemical', 'MESH:C519132', (37, 45))	('inhibit', 'NegReg', (3, 10))	('SB505124', 'Var', (37, 45))
315158	31921623	Mice injected with cells overexpressing TBULC showed higher rates of lung colonization and more metastatic tumor nodules in the lung than did mice injected with control cells (Figures 3E,F).	('higher', 'PosReg', (53, 59))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('lung colonization', 'Disease', 'MESH:D008175', (69, 86))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('mice', 'Species', '10090', (142, 146))	('TBULC', 'Var', (40, 45))	('Mice', 'Species', '10090', (0, 4))	('lung colonization', 'Disease', (69, 86))
315179	31921623	By utilizing subcutaneous injections of lncRNA MALAT1 translational oligonucleotides to treat breast cancer in mice, the Gayatri Arun team found that the suppression of MALAT1 by antisense oligonucleotides significantly inhibited the growth of mouse breast cancer and promoted tumor transition from solid nodules to cystic components; this approach could inhibit the invasion and migration ability of tumor cells in vitro in 3D-like organ cultures.	('growth', 'CPA', (234, 240))	('cancer', 'Phenotype', 'HP:0002664', (257, 263))	('tumor', 'Disease', 'MESH:D009369', (401, 406))	('antisense', 'Var', (179, 188))	('tumor', 'Phenotype', 'HP:0002664', (277, 282))	('breast cancer', 'Phenotype', 'HP:0003002', (94, 107))	('mouse', 'Species', '10090', (244, 249))	('tumor', 'Phenotype', 'HP:0002664', (401, 406))	('breast cancer', 'Disease', 'MESH:D001943', (94, 107))	('promoted', 'PosReg', (268, 276))	('breast cancer', 'Disease', (94, 107))	('inhibit', 'NegReg', (355, 362))	('breast cancer', 'Phenotype', 'HP:0003002', (250, 263))	('suppression', 'NegReg', (154, 165))	('tumor', 'Disease', (277, 282))	('breast cancer', 'Disease', 'MESH:D001943', (250, 263))	('breast cancer', 'Disease', (250, 263))	('tumor', 'Disease', 'MESH:D009369', (277, 282))	('mice', 'Species', '10090', (111, 115))	('inhibited', 'NegReg', (220, 229))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('MALAT1', 'Gene', (169, 175))	('tumor', 'Disease', (401, 406))
315198	28093071	We furthermore observed re-expression of both genes after treatment with epigenetically active drugs in most NSCLC cell lines with downregulated SPAG6 and L1TD1 mRNA expression.	('NSCLC', 'Disease', 'MESH:D002289', (109, 114))	('SPAG6', 'Gene', (145, 150))	('N', 'Chemical', 'MESH:D009584', (109, 110))	('expression', 'Species', '29278', (27, 37))	('epigenetically active drugs', 'Var', (73, 100))	('L1TD1', 'Gene', (155, 160))	('mRNA expression', 'MPA', (161, 176))	('NSCLC', 'Phenotype', 'HP:0030358', (109, 114))	('SPAG6', 'Gene', '9576', (145, 150))	('expression', 'Species', '29278', (166, 176))	('downregulated', 'NegReg', (131, 144))	('N', 'Chemical', 'MESH:D009584', (163, 164))	('NSCLC', 'Disease', (109, 114))
315200	28093071	ROC curve analyses demonstrated that methylation of both genes is able to distinguish between TU and NL samples of these patients.	('methylation', 'Var', (37, 48))	('distinguish', 'Reg', (74, 85))	('TU', 'Phenotype', 'HP:0002664', (94, 96))	('N', 'Chemical', 'MESH:D009584', (101, 102))	('patients', 'Species', '9606', (121, 129))
315201	28093071	Immunohistochemistry revealed a close association between SPAG6/L1TD1 methylation and downregulated protein expression of these genes.	('SPAG6', 'Gene', '9576', (58, 63))	('protein expression', 'MPA', (100, 118))	('expression', 'Species', '29278', (108, 118))	('downregulated', 'NegReg', (86, 99))	('methylation', 'Var', (70, 81))	('SPAG6', 'Gene', (58, 63))
315202	28093071	Moreover, by performing functional assays we observed reduced cell growth, proliferation and viability of pCMV6-L1TD1 transfected NSCLC cells.	('NSCLC', 'Disease', 'MESH:D002289', (130, 135))	('pCMV6-L1TD1', 'Gene', (106, 117))	('transfected', 'Var', (118, 129))	('NSCLC', 'Phenotype', 'HP:0030358', (130, 135))	('reduced', 'NegReg', (54, 61))	('viability', 'CPA', (93, 102))	('proliferation', 'CPA', (75, 88))	('NSCLC', 'Disease', (130, 135))	('cell growth', 'CPA', (62, 73))
315203	28093071	In addition, reduced volumes of tumors derived from pCMV6-L1TD1 compared to pCMV6-ENTRY transfected NCI-H1975 cells were seen in a xenograft tumor model.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('pCMV6-L1TD1', 'Var', (52, 63))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('tumor', 'Disease', (141, 146))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('reduced', 'NegReg', (13, 20))	('NCI-H1975 cells', 'CellLine', 'CVCL:1511', (100, 115))	('N', 'Chemical', 'MESH:D009584', (83, 84))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumors', 'Disease', (32, 38))	('N', 'Chemical', 'MESH:D009584', (100, 101))	('tumor', 'Disease', (32, 37))	('tumors', 'Disease', 'MESH:D009369', (32, 38))
315207	28093071	It has been shown that methylation plays an important role in various molecular and cellular processes including embryonic development and genomic imprinting as well as in the pathogenesis of malignant diseases.	('methylation', 'Var', (23, 34))	('role', 'Reg', (54, 58))	('malignant diseases', 'Disease', 'MESH:D009369', (192, 210))	('malignant diseases', 'Disease', (192, 210))
315210	28093071	A synergistic effect on re-expression of by methylation silenced genes by DNMT inhibitors in combination with histone deacetylase inhibitors like trichostatin A (TSA) was reported.	('trichostatin A', 'Chemical', 'MESH:C012589', (146, 160))	('N', 'Chemical', 'MESH:D009584', (75, 76))	('re-expression', 'MPA', (24, 37))	('expression', 'Species', '29278', (27, 37))	('inhibitors', 'Var', (79, 89))	('DNMT', 'Gene', (74, 78))	('TSA', 'Chemical', 'MESH:C012589', (162, 165))	('by methylation', 'MPA', (41, 55))
315228	28093071	Furthermore, our results indicate that L1TD1 functions as a tumor cell growth suppressor in NSCLC cells.	('NSCLC', 'Phenotype', 'HP:0030358', (92, 97))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('NSCLC', 'Disease', (92, 97))	('L1TD1', 'Var', (39, 44))	('tumor', 'Disease', (60, 65))	('NSCLC', 'Disease', 'MESH:D002289', (92, 97))
315230	28093071	For analyses of single nucleotide variants (SNVs) and deletions of SPAG6 and L1TD1 lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) datasets were used.	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('LUAD', 'Phenotype', 'HP:0030078', (104, 108))	('lung adenocarcinoma', 'Disease', (83, 102))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (114, 142))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (83, 102))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('N', 'Chemical', 'MESH:D009584', (45, 46))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (83, 102))	('SPAG6', 'Gene', (67, 72))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (114, 142))	('L1TD1', 'Gene', (77, 82))	('SPAG6', 'Gene', '9576', (67, 72))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (119, 142))	('deletions', 'Var', (54, 63))	('lung squamous cell carcinoma', 'Disease', (114, 142))	('LUSC', 'Phenotype', 'HP:0030359', (144, 148))
315237	28093071	In addition, DNA of breast cancer (MCF-7, MDA-MB-453, MDA-MB-468, MDA-MB-231, BT20), colon cancer (HCT-15, HT29), ovarian cancer (SK-OV3, A2780), pancreatic cancer (AsPC-1, BxPC-3) as well as head and neck cancer cell lines (CAL27, FaDu) were provided by various members of the Medical University of Vienna, Austria.	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('colon cancer', 'Disease', 'MESH:D015179', (85, 97))	('ovarian cancer', 'Disease', 'MESH:D010051', (114, 128))	('HT29', 'CellLine', 'CVCL:0320', (107, 111))	('MDA-MB-468', 'CellLine', 'CVCL:0419', (54, 64))	('BxPC-3', 'CellLine', 'CVCL:0186', (173, 179))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (66, 76))	('breast cancer', 'Phenotype', 'HP:0003002', (20, 33))	('pancreatic cancer', 'Disease', 'MESH:D010190', (146, 163))	('colon cancer', 'Disease', (85, 97))	('head and neck cancer', 'Phenotype', 'HP:0012288', (192, 212))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('neck cancer', 'Disease', 'MESH:D006258', (201, 212))	('MDA-MB-468', 'Var', (54, 64))	('neck cancer', 'Disease', (201, 212))	('ovarian cancer', 'Disease', (114, 128))	('breast cancer', 'Disease', 'MESH:D001943', (20, 33))	('breast cancer', 'Disease', (20, 33))	('pancreatic cancer', 'Disease', (146, 163))	('MDA-MB-453', 'CellLine', 'CVCL:0418', (42, 52))	('ovarian cancer', 'Phenotype', 'HP:0100615', (114, 128))	('CAL27', 'CellLine', 'CVCL:1107', (225, 230))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('colon cancer', 'Phenotype', 'HP:0003003', (85, 97))	('MCF-7', 'CellLine', 'CVCL:0031', (35, 40))	('N', 'Chemical', 'MESH:D009584', (14, 15))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('SK-OV3', 'CellLine', 'CVCL:0532', (130, 136))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (146, 163))
315245	28093071	Expression of SPAG6 was determined using Taqman Gene Expression Assays Hs00542625_m1 (SPAG6) and Hs03929097_g1 (GAPDH) in a StepOne cycler (Applied Biosystems) and expression of L1TD1 was determined using Qiagen's QuantiTect  SYBR Green PCR Kit (primer sequences see Additional file 1: Table S3).	('Hs03929097_g1', 'Var', (97, 110))	('SPAG6', 'Gene', (14, 19))	('SYBR Green', 'Chemical', '-', (226, 236))	('expression', 'Species', '29278', (164, 174))	('SPAG6', 'Gene', (86, 91))	('SPAG6', 'Gene', '9576', (14, 19))	('SPAG6', 'Gene', '9576', (86, 91))	('Hs00542625_m1', 'Var', (71, 84))	('Expression', 'Species', '29278', (0, 10))	('GAPDH', 'Gene', '2597', (112, 117))	('GAPDH', 'Gene', (112, 117))	('Expression', 'Species', '29278', (53, 63))
315248	28093071	Samples were stained with the rabbit polyclonal antibodies HPA038440 (SPAG6 1:100, Sigma Aldrich) and HPA028501 (L1TD1 1:100, Sigma Aldrich).	('SPAG6', 'Gene', (70, 75))	('HPA028501', 'Var', (102, 111))	('rabbit', 'Species', '9986', (30, 36))	('SPAG6', 'Gene', '9576', (70, 75))
315250	28093071	NCI-H1975 cells were transfected with pCMV6-ENTRY (PS100001, Origene) and pCMV6-L1TD1 (RC219014, Origene) expression vectors using Lipofectamine  LTX reagent (Invitrogen).	('NCI-H1975 cells', 'CellLine', 'CVCL:1511', (0, 15))	('RC219014', 'Var', (87, 95))	('expression vectors', 'Species', '29278', (106, 124))	('N', 'Chemical', 'MESH:D009584', (0, 1))	('PS100001', 'Var', (51, 59))	('N', 'Chemical', 'MESH:D009584', (45, 46))	('Lipofectamine  LTX', 'Chemical', '-', (131, 149))
315284	28093071	While most of the 56 CpG sites analysed were found to be SPAG6 methylated in A549 (79%) and in NCI-H1975 (92%) cells, only a few CpG sites were methylated in NHBECs (4%, Fig.	('N', 'Chemical', 'MESH:D009584', (95, 96))	('SPAG6', 'Gene', (57, 62))	('NCI-H1975', 'CellLine', 'CVCL:1511', (95, 104))	('methylated', 'Var', (63, 73))	('N', 'Chemical', 'MESH:D009584', (158, 159))	('SPAG6', 'Gene', '9576', (57, 62))	('A549', 'CellLine', 'CVCL:0023', (77, 81))
315285	28093071	Differences in the percentage of SPAG6 methylated CpG sites between NSCLC cells and NHBECs were statistically significant (p < 0.0001).	('N', 'Chemical', 'MESH:D009584', (84, 85))	('NSCLC', 'Disease', 'MESH:D002289', (68, 73))	('SPAG6', 'Gene', (33, 38))	('N', 'Chemical', 'MESH:D009584', (68, 69))	('NSCLC', 'Phenotype', 'HP:0030358', (68, 73))	('SPAG6', 'Gene', '9576', (33, 38))	('methylated', 'Var', (39, 49))	('NSCLC', 'Disease', (68, 73))
315288	28093071	Moreover, we determined methylation of SPAG6 and L1TD1 in 5 breast cancer, 2 colon cancer, 2 ovarian cancer, 2 pancreatic cancer as well as 2 head and neck cancer cell lines.	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('colon cancer', 'Disease', 'MESH:D015179', (77, 89))	('methylation', 'Var', (24, 35))	('pancreatic cancer', 'Disease', (111, 128))	('breast cancer', 'Phenotype', 'HP:0003002', (60, 73))	('ovarian cancer', 'Disease', (93, 107))	('SPAG6', 'Gene', (39, 44))	('ovarian cancer', 'Phenotype', 'HP:0100615', (93, 107))	('colon cancer', 'Disease', (77, 89))	('breast cancer', 'Disease', 'MESH:D001943', (60, 73))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (111, 128))	('breast cancer', 'Disease', (60, 73))	('determined', 'Reg', (13, 23))	('L1TD1', 'Gene', (49, 54))	('head and neck cancer', 'Phenotype', 'HP:0012288', (142, 162))	('colon cancer', 'Phenotype', 'HP:0003003', (77, 89))	('pancreatic cancer', 'Disease', 'MESH:D010190', (111, 128))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('ovarian cancer', 'Disease', 'MESH:D010051', (93, 107))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('SPAG6', 'Gene', '9576', (39, 44))	('neck cancer', 'Disease', 'MESH:D006258', (151, 162))	('neck cancer', 'Disease', (151, 162))
315289	28093071	All these tumor cell lines were found to be SPAG6 and L1TD1 methylated with percentages of methylation ranging between 71% (SK-OV3 cells) and 98% (FaDu cells) for SPAG6 methylation and between 88% (BxPC-3 cells) and 100% (FaDu cells) for L1TD1 methylation (Additional file 1: Table S4).	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('tumor', 'Disease', (10, 15))	('SPAG6', 'Gene', (163, 168))	('BxPC-3', 'CellLine', 'CVCL:0186', (198, 204))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('SK-OV3', 'CellLine', 'CVCL:0532', (124, 130))	('SPAG6', 'Gene', '9576', (163, 168))	('methylation', 'Var', (169, 180))	('SPAG6', 'Gene', (44, 49))	('L1TD1', 'Gene', (54, 59))	('methylation', 'MPA', (91, 102))	('SPAG6', 'Gene', '9576', (44, 49))
315291	28093071	Differences in SPAG6 and L1TD1 methylation between TU and NL samples were statistically significant (p < 0.0001, respectively) demonstrating that both genes are tumor-specifically methylated (Fig.	('Differences', 'Reg', (0, 11))	('L1TD1', 'Gene', (25, 30))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('SPAG6', 'Gene', (15, 20))	('N', 'Chemical', 'MESH:D009584', (58, 59))	('methylation', 'Var', (31, 42))	('SPAG6', 'Gene', '9576', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('TU', 'Phenotype', 'HP:0002664', (51, 53))	('tumor', 'Disease', (161, 166))
315294	28093071	Considering patients with a T/N ratio >= 1.5 as methylated, 79% of them were SPAG6 methylated and 81% of them were L1TD1 methylated, respectively.	('patients', 'Species', '9606', (12, 20))	('N', 'Chemical', 'MESH:D009584', (30, 31))	('SPAG6', 'Gene', (77, 82))	('methylated', 'Var', (83, 93))	('SPAG6', 'Gene', '9576', (77, 82))
315298	28093071	To investigate if other mechanisms besides methylation are involved in transcriptional regulation of SPAG6 and L1TD1, we analysed SNVs as well as homozygous and heterozygous deletions in LUAD and LUSC SNP and aCGH datasets of NSCLC patients.	('LUSC', 'Phenotype', 'HP:0030359', (196, 200))	('NSCLC', 'Disease', 'MESH:D002289', (226, 231))	('N', 'Chemical', 'MESH:D009584', (226, 227))	('SPAG6', 'Gene', (101, 106))	('patients', 'Species', '9606', (232, 240))	('SPAG6', 'Gene', '9576', (101, 106))	('deletions', 'Var', (174, 183))	('LUAD', 'Phenotype', 'HP:0030078', (187, 191))	('NSCLC', 'Phenotype', 'HP:0030358', (226, 231))	('LUAD', 'Disease', (187, 191))	('N', 'Chemical', 'MESH:D009584', (202, 203))	('N', 'Chemical', 'MESH:D009584', (131, 132))	('NSCLC', 'Disease', (226, 231))
315302	28093071	Homozygous SPAG6 deletions were detected in only 1% and heterozygous SPAG6 deletions were found in 40% of these patients.	('SPAG6', 'Gene', '9576', (69, 74))	('deletions', 'Var', (17, 26))	('SPAG6', 'Gene', '9576', (11, 16))	('patients', 'Species', '9606', (112, 120))	('SPAG6', 'Gene', (69, 74))	('SPAG6', 'Gene', (11, 16))
315303	28093071	Similar frequencies of SNVs and deletions were found for L1TD1 (Additional file 4: Figure S3).	('deletions', 'Var', (32, 41))	('L1TD1', 'Gene', (57, 62))	('N', 'Chemical', 'MESH:D009584', (24, 25))
315306	28093071	SPAG6 and L1TD1 protein expression was observed in bronchial and bronchiolar epithelial cells of NL samples.	('expression', 'Species', '29278', (24, 34))	('L1TD1', 'Var', (10, 15))	('N', 'Chemical', 'MESH:D009584', (97, 98))	('SPAG6', 'Gene', (0, 5))	('SPAG6', 'Gene', '9576', (0, 5))
315311	28093071	When we compared SPAG6 and L1TD1 methylation with their protein expression in TU samples, we observed downregulated SPAG6 protein expression in 77% of SPAG6 methylated TU samples and downregulated L1TD1 protein expression in 52% of L1TD1 methylated TU samples, respectively (Fig.	('protein', 'Protein', (122, 129))	('expression', 'MPA', (130, 140))	('L1TD1', 'Gene', (197, 202))	('SPAG6', 'Gene', '9576', (151, 156))	('SPAG6', 'Gene', '9576', (116, 121))	('SPAG6', 'Gene', (17, 22))	('TU', 'Phenotype', 'HP:0002664', (78, 80))	('expression', 'Species', '29278', (211, 221))	('expression', 'Species', '29278', (130, 140))	('downregulated', 'NegReg', (183, 196))	('SPAG6', 'Gene', (151, 156))	('downregulated', 'NegReg', (102, 115))	('methylated', 'Var', (157, 167))	('SPAG6', 'Gene', (116, 121))	('TU', 'Phenotype', 'HP:0002664', (249, 251))	('SPAG6', 'Gene', '9576', (17, 22))	('protein', 'Protein', (203, 210))	('TU', 'Phenotype', 'HP:0002664', (168, 170))	('expression', 'MPA', (211, 221))	('expression', 'Species', '29278', (64, 74))
315313	28093071	We found a strong reduction in tumor cell growth of pCMV6-L1TD1 compared to pCMV6-ENTRY transfected cells (Fig.	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('pCMV6-L1TD1', 'Var', (52, 63))	('tumor', 'Disease', (31, 36))	('N', 'Chemical', 'MESH:D009584', (83, 84))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('reduction', 'NegReg', (18, 27))
315315	28093071	Moreover, we analysed tumor cell proliferation in a time-dependent manner and observed a reduced proliferation rate of pCMV6-L1TD1 compared to pCMV6-ENTRY and to pCMV6-GFP transfected cells (Fig.	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('proliferation rate', 'CPA', (97, 115))	('N', 'Chemical', 'MESH:D009584', (150, 151))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('tumor', 'Disease', (22, 27))	('reduced', 'NegReg', (89, 96))	('pCMV6-L1TD1', 'Var', (119, 130))
315316	28093071	In addition, we found a reduced colony-forming ability and tumor cell viability of pCMV6-L1TD1 transfected cells compared to control cells (Fig.	('tumor', 'Disease', (59, 64))	('pCMV6-L1TD1', 'Var', (83, 94))	('reduced', 'NegReg', (24, 31))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('colony-forming ability', 'CPA', (32, 54))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
315317	28093071	Differences in tumor cell viability between pCMV6-L1TD1 and pCMV6-ENTRY transfected cells were statistically significant after 48 (p = 0.0064) and 72 h (p < 0.0001), while differences between pCMV6-L1TD1 and pCMV6-GFP transfected cells did not reach statistical significance.	('N', 'Chemical', 'MESH:D009584', (67, 68))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumor', 'Disease', (15, 20))	('pCMV6-L1TD1', 'Var', (44, 55))
315319	28093071	However, no impact of ectopic SPAG6 expression on tumor cell growth, proliferation, viability or colony-forming abilities were seen (data not shown).	('ectopic', 'Var', (22, 29))	('colony-forming abilities', 'CPA', (97, 121))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Disease', (50, 55))	('SPAG6', 'Gene', (30, 35))	('expression', 'Species', '29278', (36, 46))	('SPAG6', 'Gene', '9576', (30, 35))
315325	28093071	Size measurement of dissected tumors confirmed size differences of tumors derived from pCMV6-L1TD1 and from pCMV6-ENTRY transfected cells which were seen during the experiment (Fig.	('tumors', 'Disease', (30, 36))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('tumors', 'Disease', 'MESH:D009369', (67, 73))	('pCMV6-L1TD1', 'Var', (87, 98))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('tumors', 'Disease', (67, 73))	('N', 'Chemical', 'MESH:D009584', (115, 116))
315326	28093071	Expression of L1TD1 in tumors derived from pCMV6-L1TD1 transfected NCI-H1975 cells was confirmed by RT-PCR (Additional file 5: Figure S4).	('tumors', 'Disease', 'MESH:D009369', (23, 29))	('tumors', 'Disease', (23, 29))	('Expression', 'Species', '29278', (0, 10))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('pCMV6-L1TD1', 'Var', (43, 54))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))	('NCI-H1975 cells', 'CellLine', 'CVCL:1511', (67, 82))
315336	28093071	While tumor-specific downregulation of SPAG6 mRNA expression was observed in all tumor types investigated except hepatocellular and prostate carcinomas, downregulated L1TD1 mRNA expression was found in NSCLCs, breast, colorectal and prostate carcinomas but not in head and neck, kidney and hepatocellular carcinomas.	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (290, 314))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('downregulated', 'NegReg', (153, 166))	('mRNA expression', 'MPA', (45, 60))	('prostate carcinomas', 'Disease', 'MESH:D011472', (132, 151))	('SPAG6', 'Gene', (39, 44))	('downregulation', 'NegReg', (21, 35))	('prostate carcinomas', 'Disease', 'MESH:D011472', (233, 252))	('N', 'Chemical', 'MESH:D009584', (202, 203))	('kidney and hepatocellular carcinomas', 'Disease', 'MESH:D006528', (279, 315))	('tumor', 'Disease', (81, 86))	('colorectal and prostate carcinomas', 'Disease', 'MESH:D015179', (218, 252))	('L1TD1', 'Var', (167, 172))	('hepatocellular', 'Disease', (113, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('expression', 'Species', '29278', (178, 188))	('breast', 'Disease', (210, 216))	('carcinomas', 'Phenotype', 'HP:0030731', (141, 151))	('NSCLC', 'Disease', 'MESH:D002289', (202, 207))	('N', 'Chemical', 'MESH:D009584', (175, 176))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('prostate carcinomas', 'Disease', (132, 151))	('expression', 'Species', '29278', (50, 60))	('tumor', 'Disease', (6, 11))	('NSCLC', 'Disease', (202, 207))	('N', 'Chemical', 'MESH:D009584', (47, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (242, 251))	('prostate carcinomas', 'Disease', (233, 252))	('NSCLCs', 'Phenotype', 'HP:0030358', (202, 208))	('tumor', 'Disease', 'MESH:D009369', (6, 11))	('hepatocellular carcinomas', 'Phenotype', 'HP:0001402', (290, 315))	('carcinomas', 'Phenotype', 'HP:0030731', (242, 252))	('carcinoma', 'Phenotype', 'HP:0030731', (305, 314))	('carcinomas', 'Phenotype', 'HP:0030731', (305, 315))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('SPAG6', 'Gene', '9576', (39, 44))	('NSCLC', 'Phenotype', 'HP:0030358', (202, 207))
315337	28093071	Overall, these data suggest that deregulated expression of SPAG6 and L1TD1 may play a role not only in the pathogenesis of NSCLCs but also in tumors of other entities and that expression of these 2 genes differs between certain tumor types.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('tumor', 'Disease', 'MESH:D009369', (228, 233))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))	('play', 'Reg', (79, 83))	('role', 'Reg', (86, 90))	('SPAG6', 'Gene', '9576', (59, 64))	('expression', 'Species', '29278', (45, 55))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('tumors', 'Disease', (142, 148))	('deregulated', 'Var', (33, 44))	('tumor', 'Disease', (142, 147))	('NSCLC', 'Disease', 'MESH:D002289', (123, 128))	('expression', 'Species', '29278', (176, 186))	('tumors', 'Disease', 'MESH:D009369', (142, 148))	('SPAG6', 'Gene', (59, 64))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('NSCLC', 'Disease', (123, 128))	('NSCLCs', 'Phenotype', 'HP:0030358', (123, 129))	('L1TD1', 'Gene', (69, 74))	('NSCLC', 'Phenotype', 'HP:0030358', (123, 128))	('expression', 'MPA', (45, 55))	('tumor', 'Disease', (228, 233))
315342	28093071	In addition, we found an association between SPAG6 and L1TD1 methylation and loss of SPAG6 and L1TD1 protein expression when we performed IHC of FFPE tissue samples from NSCLC patients.	('patients', 'Species', '9606', (176, 184))	('SPAG6', 'Gene', '9576', (85, 90))	('NSCLC', 'Phenotype', 'HP:0030358', (170, 175))	('expression', 'MPA', (109, 119))	('methylation', 'Var', (61, 72))	('SPAG6', 'Gene', (45, 50))	('SPAG6', 'Gene', '9576', (45, 50))	('L1TD1', 'Gene', (55, 60))	('NSCLC', 'Disease', (170, 175))	('protein', 'Protein', (101, 108))	('loss', 'NegReg', (77, 81))	('SPAG6', 'Gene', (85, 90))	('NSCLC', 'Disease', 'MESH:D002289', (170, 175))	('L1TD1', 'Gene', (95, 100))	('expression', 'Species', '29278', (109, 119))
315343	28093071	While most of the SPAG6 or L1TD1 methylated TU samples did not express these proteins, not methylated TU samples mostly expressed SPAG6 or L1TD1.	('TU', 'Phenotype', 'HP:0002664', (44, 46))	('SPAG6', 'Gene', '9576', (18, 23))	('TU', 'Phenotype', 'HP:0002664', (102, 104))	('SPAG6', 'Gene', (18, 23))	('SPAG6', 'Gene', (130, 135))	('L1TD1', 'Var', (139, 144))	('SPAG6', 'Gene', '9576', (130, 135))
315345	28093071	Our hypothesis that methylation is one of the mechanisms responsible for inactivation of these genes is further supported by the fact that SNVs and homozygous deletions of SPAG6 and L1TD1 were rarely detected in LUAD and LUSC SNP and in aCGH datasets of NSCLC patients.	('LUAD', 'Phenotype', 'HP:0030078', (212, 216))	('NSCLC', 'Disease', (254, 259))	('L1TD1', 'Gene', (182, 187))	('LUSC', 'Phenotype', 'HP:0030359', (221, 225))	('NSCLC', 'Disease', 'MESH:D002289', (254, 259))	('SPAG6', 'Gene', '9576', (172, 177))	('patients', 'Species', '9606', (260, 268))	('N', 'Chemical', 'MESH:D009584', (140, 141))	('NSCLC', 'Phenotype', 'HP:0030358', (254, 259))	('N', 'Chemical', 'MESH:D009584', (254, 255))	('N', 'Chemical', 'MESH:D009584', (227, 228))	('deletions', 'Var', (159, 168))	('SPAG6', 'Gene', (172, 177))
315348	28093071	Methylation of certain TSGs in NSCLCs is tumor-subtype specific.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Disease', (41, 46))	('Methylation', 'Var', (0, 11))	('NSCLC', 'Disease', (31, 36))	('NSCLCs', 'Phenotype', 'HP:0030358', (31, 37))	('NSCLC', 'Disease', 'MESH:D002289', (31, 36))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('NSCLC', 'Phenotype', 'HP:0030358', (31, 36))
315349	28093071	While for instance APC and CDH13 methylation was detected more frequently in lung adenocarcinomas compared to lung squamous cell carcinomas, p16 methylation was detected more frequently in lung squamous cell carcinomas than in lung adenocarcinomas.	('methylation', 'Var', (33, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (208, 217))	('carcinomas', 'Phenotype', 'HP:0030731', (208, 218))	('lung squamous cell carcinomas', 'Disease', 'MESH:D002294', (189, 218))	('CDH13', 'Gene', (27, 32))	('carcinomas', 'Phenotype', 'HP:0030731', (129, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))	('lung squamous cell carcinomas', 'Disease', (110, 139))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (77, 96))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (110, 138))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (227, 246))	('p16 methylation', 'Var', (141, 156))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (77, 97))	('detected', 'Reg', (161, 169))	('carcinoma', 'Phenotype', 'HP:0030731', (237, 246))	('lung squamous cell carcinomas', 'Disease', (189, 218))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (115, 139))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (194, 218))	('detected', 'Reg', (49, 57))	('carcinomas', 'Phenotype', 'HP:0030731', (237, 247))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (189, 217))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (227, 247))	('carcinomas', 'Phenotype', 'HP:0030731', (87, 97))	('methylation', 'Var', (145, 156))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (77, 97))	('APC', 'Disease', 'MESH:D011125', (19, 22))	('APC', 'Disease', (19, 22))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (227, 247))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (115, 138))	('lung adenocarcinomas', 'Disease', (77, 97))	('lung squamous cell carcinomas', 'Disease', 'MESH:D002294', (110, 139))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (194, 217))	('lung adenocarcinomas', 'Disease', (227, 247))
315351	28093071	These observations suggest that methylation of SPAG6 and L1TD1 is a common feature in all histological subtypes of NSCLCs.	('NSCLC', 'Phenotype', 'HP:0030358', (115, 120))	('methylation', 'Var', (32, 43))	('SPAG6', 'Gene', '9576', (47, 52))	('NSCLC', 'Disease', (115, 120))	('NSCLC', 'Disease', 'MESH:D002289', (115, 120))	('SPAG6', 'Gene', (47, 52))	('NSCLCs', 'Phenotype', 'HP:0030358', (115, 121))	('L1TD1', 'Gene', (57, 62))	('common', 'Reg', (68, 74))
315352	28093071	Methylation of several genes was shown to be associated with shorter survival of NSCLC patients (e.g.	('shorter', 'NegReg', (61, 68))	('Methylation', 'Var', (0, 11))	('NSCLC', 'Phenotype', 'HP:0030358', (81, 86))	('NSCLC', 'Disease', (81, 86))	('patients', 'Species', '9606', (87, 95))	('NSCLC', 'Disease', 'MESH:D002289', (81, 86))	('survival', 'MPA', (69, 77))
315354	28093071	In our study, we did not find a correlation between SPAG6 or L1TD1 methylation and OS as well as DFS of NSCLC patients or any other clinico-pathological characteristic of these patients.	('SPAG6', 'Gene', (52, 57))	('OS', 'Chemical', '-', (83, 85))	('patients', 'Species', '9606', (110, 118))	('patients', 'Species', '9606', (177, 185))	('NSCLC', 'Disease', (104, 109))	('SPAG6', 'Gene', '9576', (52, 57))	('NSCLC', 'Disease', 'MESH:D002289', (104, 109))	('L1TD1', 'Gene', (61, 66))	('NSCLC', 'Phenotype', 'HP:0030358', (104, 109))	('methylation', 'Var', (67, 78))
315355	28093071	However, analyses of gene expression microarray data indicate that low SPAG6 expression is associated with a shorter OS of lung squamous cell carcinoma patients and low L1TD1 expression with a shorter OS of lung adenocarcinoma patients.	('low', 'Var', (67, 70))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (207, 226))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (128, 151))	('OS of lung squamous cell carcinoma', 'Disease', (117, 151))	('expression', 'Species', '29278', (77, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (142, 151))	('OS of lung squamous cell carcinoma', 'Disease', 'MESH:C567932', (117, 151))	('SPAG6', 'Gene', (71, 76))	('OS of lung adenocarcinoma', 'Disease', 'MESH:C567932', (201, 226))	('L1TD1', 'Gene', (169, 174))	('patients', 'Species', '9606', (227, 235))	('low', 'NegReg', (165, 168))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (123, 151))	('expression', 'Species', '29278', (26, 36))	('expression', 'Species', '29278', (175, 185))	('patients', 'Species', '9606', (152, 160))	('expression', 'MPA', (77, 87))	('OS of lung adenocarcinoma', 'Disease', (201, 226))	('SPAG6', 'Gene', '9576', (71, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (217, 226))
315359	28093071	Indeed, in vitro experiments showed reduced cell growth, proliferation, viability and colony-forming abilities of pCMV6-L1TD1 transfected cells suggesting that it may be a potential TSG in NSCLCs.	('colony-forming abilities', 'CPA', (86, 110))	('NSCLC', 'Disease', (189, 194))	('transfected', 'Var', (126, 137))	('NSCLC', 'Disease', 'MESH:D002289', (189, 194))	('viability', 'CPA', (72, 81))	('NSCLCs', 'Phenotype', 'HP:0030358', (189, 195))	('cell growth', 'CPA', (44, 55))	('NSCLC', 'Phenotype', 'HP:0030358', (189, 194))	('pCMV6-L1TD1 transfected', 'Var', (114, 137))	('reduced', 'NegReg', (36, 43))
315360	28093071	Because of these encouraging results and to further support our hypothesis that L1TD1 has tumor-cell growth suppressing properties, we additionally performed xenograft experiments to investigate the growth of tumors induced by L1TD1-overexpressing and wildtype NSCLC cells.	('tumors', 'Disease', (209, 215))	('tumors', 'Phenotype', 'HP:0002664', (209, 215))	('tumor', 'Disease', (209, 214))	('NSCLC', 'Disease', (261, 266))	('tumors', 'Disease', 'MESH:D009369', (209, 215))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('NSCLC', 'Disease', 'MESH:D002289', (261, 266))	('L1TD1-overexpressing', 'Gene', (227, 247))	('L1TD1', 'Var', (80, 85))	('tumor', 'Disease', 'MESH:D009369', (209, 214))	('NSCLC', 'Phenotype', 'HP:0030358', (261, 266))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
315361	28093071	Interestingly, we observed significantly smaller tumors induced by pCMV6-L1TD1 compared to pCMV6-ENTRY transfected NCI-H1975 cells indicating that L1TD1 indeed has tumor-cell growth suppressing properties.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Disease', (164, 169))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('N', 'Chemical', 'MESH:D009584', (98, 99))	('L1TD1', 'Var', (147, 152))	('smaller', 'NegReg', (41, 48))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('tumor', 'Disease', (49, 54))	('pCMV6-L1TD1', 'Var', (67, 78))	('tumors', 'Disease', (49, 55))	('tumors', 'Disease', 'MESH:D009369', (49, 55))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('NCI-H1975 cells', 'CellLine', 'CVCL:1511', (115, 130))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('N', 'Chemical', 'MESH:D009584', (115, 116))
315366	28093071	Our results demonstrate that tumor-specific methylation of SPAG6 and L1TD1 is a frequently occurring event in NSCLCs and they suggest that methylation plays an important role in the transcriptional regulation of these genes.	('methylation', 'Var', (44, 55))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('SPAG6', 'Gene', '9576', (59, 64))	('L1TD1', 'Gene', (69, 74))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('NSCLC', 'Disease', (110, 115))	('occurring', 'Reg', (91, 100))	('NSCLC', 'Disease', 'MESH:D002289', (110, 115))	('tumor', 'Disease', (29, 34))	('NSCLCs', 'Phenotype', 'HP:0030358', (110, 116))	('SPAG6', 'Gene', (59, 64))	('NSCLC', 'Phenotype', 'HP:0030358', (110, 115))
315368	28093071	In addition, or findings indicate that methylation of these genes may be of relevance not only in NSCLCs but also in other malignancies.	('malignancies', 'Disease', 'MESH:D009369', (123, 135))	('methylation', 'Var', (39, 50))	('NSCLCs', 'Phenotype', 'HP:0030358', (98, 104))	('NSCLC', 'Phenotype', 'HP:0030358', (98, 103))	('relevance', 'Reg', (76, 85))	('malignancies', 'Disease', (123, 135))	('NSCLC', 'Disease', (98, 103))	('NSCLC', 'Disease', 'MESH:D002289', (98, 103))
315369	28093071	Moreover, in vitro and in vivo experiments showed that L1TD1 has tumor-cell growth suppressing properties in NSCLC cells.	('NSCLC', 'Disease', 'MESH:D002289', (109, 114))	('tumor', 'Disease', (65, 70))	('L1TD1', 'Var', (55, 60))	('NSCLC', 'Phenotype', 'HP:0030358', (109, 114))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('NSCLC', 'Disease', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
315370	28093071	Taken together we identified methylation as a potential mechanism for frequent downregulation of SPAG6 and L1TD1 in NSCLCs and suggest a putative role of L1TD1 in tumor cell development.	('NSCLC', 'Disease', 'MESH:D002289', (116, 121))	('methylation', 'Var', (29, 40))	('NSCLCs', 'Phenotype', 'HP:0030358', (116, 122))	('SPAG6', 'Gene', (97, 102))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('L1TD1', 'Gene', (107, 112))	('NSCLC', 'Phenotype', 'HP:0030358', (116, 121))	('SPAG6', 'Gene', '9576', (97, 102))	('downregulation', 'NegReg', (79, 93))	('tumor', 'Disease', (163, 168))	('NSCLC', 'Disease', (116, 121))
315408	32144446	To assess the functional status of these BMDCs, we also analyzed the surface expression of the activation markers MHC class II (MHC II), CD40, and CD80.	('MHC II', 'Gene', (128, 134))	('MHC class II', 'Gene', '111364', (114, 126))	('MHC II', 'Gene', '111364', (128, 134))	('CD40', 'Gene', (137, 141))	('CD80', 'Var', (147, 151))	('MHC class II', 'Gene', (114, 126))
315410	32144446	Mice treated with anti-PD-1 and TTFields monotherapies demonstrated decreased tumor volume as compared to the control group, although statistical significance was not reached (Fig.	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('anti-PD-1', 'Var', (18, 27))	('decreased tumor', 'Disease', (68, 83))	('decreased tumor', 'Disease', 'MESH:D002303', (68, 83))
315414	32144446	TTFields were shown to lead to mitotic catastrophe resulting in the formation of abnormal aneuploid progeny.	('TTFields', 'Var', (0, 8))	('lead to', 'Reg', (23, 30))	('abnormal aneuploid', 'Disease', (81, 99))	('mitotic catastrophe', 'CPA', (31, 50))	('abnormal aneuploid', 'Disease', 'MESH:D000782', (81, 99))
315432	27129219	Cellular senescence is characterized by permanent cell cycle arrest and distinct morphological, physiological, and epigenetic changes in response to events such as telomere attrition, aberrant oncogene activation, and abrogation of tumor suppressor gene functions.	('activation', 'PosReg', (202, 212))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (50, 67))	('tumor', 'Disease', 'MESH:D009369', (232, 237))	('Cellular senescence', 'Disease', (0, 19))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('abrogation', 'NegReg', (218, 228))	('changes', 'Reg', (126, 133))	('aberrant', 'Var', (184, 192))	('cell cycle arrest', 'CPA', (50, 67))	('tumor', 'Disease', (232, 237))	('oncogene', 'Protein', (193, 201))
315435	27129219	A number of key senescence-associated factors, such as p53/p21 and RB/p16, have been found to prevent tumorigenesis.	('p16', 'Gene', '1029', (70, 73))	('p53/p21', 'Var', (55, 62))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('RB', 'Disease', 'MESH:D012175', (67, 69))	('prevent', 'NegReg', (94, 101))	('p16', 'Gene', (70, 73))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))
315438	27129219	In addition to direct transcriptional regulation, epigenetic alterations also play an essential role in determining gene expression patterns and in setting the environment for activators or repressors to function appropriately.	('determining', 'Reg', (104, 115))	('gene expression patterns', 'MPA', (116, 140))	('epigenetic alterations', 'Var', (50, 72))	('expression', 'Species', '29278', (121, 131))
315453	27129219	The GSK3beta inhibitor SB415286 was purchased from Sigma, and LiCl was purchased from M&C Gene Technology.	('GSK3beta', 'Gene', '2932', (4, 12))	('SB415286', 'Chemical', 'MESH:C417520', (23, 31))	('SB415286', 'Var', (23, 31))	('LiCl', 'Chemical', 'MESH:D018021', (62, 66))	('GSK3beta', 'Gene', (4, 12))
315466	27129219	The His-tagged recombinant protein expression vectors pET-HBP1, pET-Mdm2, and pET-p53, were constructed on the base of the pET-28b (+) vector.	('Mdm2', 'Gene', (68, 72))	('His', 'Chemical', 'MESH:D006639', (4, 7))	('Mdm2', 'Gene', '4193', (68, 72))	('pET-p53', 'Var', (78, 85))	('expression vectors', 'Species', '29278', (35, 53))
315500	27129219	Additionally, other work suggested that histone methyltransferase EZH2 depletion promotes cellular senescence by activation of p21 in gastric cancer cells.	('depletion', 'Var', (71, 80))	('gastric cancer', 'Phenotype', 'HP:0012126', (134, 148))	('promotes', 'PosReg', (81, 89))	('gastric cancer', 'Disease', (134, 148))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('EZH2', 'Gene', (66, 70))	('EZH2', 'Gene', '2146', (66, 70))	('gastric cancer', 'Disease', 'MESH:D013274', (134, 148))	('activation', 'PosReg', (113, 123))	('cellular senescence', 'CPA', (90, 109))	('p21', 'Protein', (127, 130))
315507	27129219	HBP1 knockdown decreased p21 protein and mRNA, only decreased p53 protein, did not change p53 mRNA, and increased EZH2 protein and mRNA.	('mRNA', 'MPA', (131, 135))	('increased', 'PosReg', (104, 113))	('p21 protein', 'MPA', (25, 36))	('knockdown', 'Var', (5, 14))	('decreased', 'NegReg', (52, 61))	('decreased', 'NegReg', (15, 24))	('mRNA', 'MPA', (41, 45))	('EZH2', 'Gene', '2146', (114, 118))	('p53 protein', 'MPA', (62, 73))	('EZH2', 'Gene', (114, 118))	('HBP1', 'Gene', (0, 4))
315521	27129219	However, EZH2 overexpression could partially attenuate increased p53 binding to the p21 promoter caused by HBP1 overexpression.	('EZH2', 'Gene', '2146', (9, 13))	('HBP1', 'Gene', (107, 111))	('expression', 'Species', '29278', (18, 28))	('attenuate', 'NegReg', (45, 54))	('binding', 'Interaction', (69, 76))	('overexpression', 'Var', (112, 126))	('EZH2', 'Gene', (9, 13))	('expression', 'Species', '29278', (116, 126))	('p53', 'Protein', (65, 68))
315523	27129219	1, B and C, and 2A, HBP1 overexpression and knockdown had no effect on either Mdm2 protein or mRNA levels.	('Mdm2', 'Gene', (78, 82))	('mRNA levels', 'MPA', (94, 105))	('Mdm2', 'Gene', '4193', (78, 82))	('expression', 'Species', '29278', (29, 39))	('knockdown', 'Var', (44, 53))	('HBP1', 'Gene', (20, 24))
315524	27129219	Although occasionally it could be seen that Mdm2 levels were slightly up-regulated by HBP1 expression (data not shown), this may be caused by p53 transcriptional activation.	('HBP1', 'Gene', (86, 90))	('Mdm2', 'Gene', (44, 48))	('up-regulated', 'PosReg', (70, 82))	('expression', 'Var', (91, 101))	('Mdm2', 'Gene', '4193', (44, 48))	('activation', 'PosReg', (162, 172))	('expression', 'Species', '29278', (91, 101))
315533	27129219	3, C-E, the Western blotting results indicated that GST-p53 and GST-Mdm2, but not GST alone, pulled down HBP1 in vitro.	('GST-p53', 'Var', (52, 59))	('Mdm2', 'Gene', (68, 72))	('pulled down', 'NegReg', (93, 104))	('HBP1', 'Gene', (105, 109))	('Mdm2', 'Gene', '4193', (68, 72))
315536	27129219	To further determine the specific domain required for their interaction, a set of deletion mutants of HBP1, p53, and Mdm2 were constructed in the pGEX-4T-1 vector, followed by GST pulldown assay as described above.	('Mdm2', 'Gene', '4193', (117, 121))	('p53', 'Gene', (108, 111))	('deletion mutants', 'Var', (82, 98))	('HBP1', 'Gene', (102, 106))	('Mdm2', 'Gene', (117, 121))
315538	27129219	For Mdm2, only mutant 237-288 did not bind HBP1 protein, whereas the other mutants all bound HBP1 (Fig.	('mutant 237-288', 'Var', (15, 29))	('bound', 'Interaction', (87, 92))	('Mdm2', 'Gene', (4, 8))	('Mdm2', 'Gene', '4193', (4, 8))	('bind', 'Interaction', (38, 42))
315546	27129219	4B, overexpression of HBP1 disrupted the interaction between exogenous p53 and Mdm2 (left panel), whereas knockdown of HBP1 enhanced exogenous p53 interaction with Mdm2 (center panel).	('interaction', 'Interaction', (41, 52))	('interaction', 'Interaction', (147, 158))	('enhanced', 'PosReg', (124, 132))	('HBP1', 'Gene', (22, 26))	('Mdm2', 'Gene', (164, 168))	('Mdm2', 'Gene', (79, 83))	('knockdown', 'Var', (106, 115))	('expression', 'Species', '29278', (8, 18))	('Mdm2', 'Gene', '4193', (164, 168))	('HBP1', 'Gene', (119, 123))	('exogenous', 'MPA', (133, 142))	('disrupted', 'NegReg', (27, 36))	('Mdm2', 'Gene', '4193', (79, 83))
315549	27129219	4B, knockdown of HBP1 also enhanced endogenous p53 interaction with Mdm2 in A549 cells (right panel).	('Mdm2', 'Gene', (68, 72))	('enhanced', 'PosReg', (27, 35))	('interaction', 'Interaction', (51, 62))	('A549', 'CellLine', 'CVCL:0023', (76, 80))	('Mdm2', 'Gene', '4193', (68, 72))	('HBP1', 'Gene', (17, 21))	('knockdown', 'Var', (4, 13))	('endogenous', 'MPA', (36, 46))
315552	27129219	Hence, disruption of p53/Mdm2 interaction by HBP1 might also release the p53 transcriptional activity inhibited by Mdm2 and thus promote p21 transcription.	('p53', 'Protein', (73, 76))	('promote', 'PosReg', (129, 136))	('Mdm2', 'Gene', '4193', (115, 119))	('p21', 'Gene', (137, 140))	('Mdm2', 'Gene', (25, 29))	('disruption', 'Var', (7, 17))	('HBP1', 'Gene', (45, 49))	('interaction', 'Interaction', (30, 41))	('Mdm2', 'Gene', '4193', (25, 29))	('release', 'PosReg', (61, 68))	('Mdm2', 'Gene', (115, 119))
315564	27129219	In fact, accumulating evidence indicates that histone methylation also regulates gene transcription via local chromatin reorganization, in which the histone methyltransferase EZH2 plays an important part.	('histone', 'Var', (46, 53))	('EZH2', 'Gene', '2146', (175, 179))	('regulates', 'Reg', (71, 80))	('methylation', 'Var', (54, 65))	('EZH2', 'Gene', (175, 179))	('gene transcription', 'MPA', (81, 99))	('local chromatin reorganization', 'MPA', (104, 134))
315566	27129219	1, B and C, and 5, A and B, overexpression of HBP1 decreased both EZH2 protein and mRNA levels, whereas knockdown of HBP1 elevated EZH2 protein and mRNA levels, which were observed both in the presence and absence of p53.	('mRNA levels', 'MPA', (83, 94))	('HBP1', 'Gene', (117, 121))	('mRNA levels', 'MPA', (148, 159))	('HBP1', 'Gene', (46, 50))	('EZH2', 'Gene', (66, 70))	('decreased', 'NegReg', (51, 60))	('EZH2', 'Gene', '2146', (66, 70))	('elevated', 'PosReg', (122, 130))	('expression', 'Species', '29278', (32, 42))	('EZH2', 'Gene', (131, 135))	('EZH2', 'Gene', '2146', (131, 135))	('knockdown', 'Var', (104, 113))
315572	27129219	However, when EZH2 was also knocked down, the decrease of p21 and increase of H3K27me3 caused by HBP1 knockdown were partially rescued (Fig.	('increase', 'PosReg', (66, 74))	('HBP1', 'Gene', (97, 101))	('H3K27me3', 'Protein', (78, 86))	('EZH2', 'Gene', (14, 18))	('EZH2', 'Gene', '2146', (14, 18))	('p21', 'MPA', (58, 61))	('knockdown', 'Var', (102, 111))	('decrease', 'NegReg', (46, 54))
315573	27129219	In addition, EZH2 knockdown also attenuated the increases in cell growth and colony formation in soft agar caused by HBP1 knockdown, as assessed by MTT assay and soft agar assay (supplemental Fig.	('knockdown', 'Var', (18, 27))	('EZH2', 'Gene', (13, 17))	('EZH2', 'Gene', '2146', (13, 17))	('HBP1', 'Gene', (117, 121))	('agar', 'Chemical', 'MESH:D000362', (102, 106))	('increases', 'PosReg', (48, 57))	('MTT', 'Chemical', '-', (148, 151))	('cell growth', 'CPA', (61, 72))	('knockdown', 'Var', (122, 131))	('attenuated', 'NegReg', (33, 43))	('colony formation in soft agar', 'CPA', (77, 106))	('agar', 'Chemical', 'MESH:D000362', (167, 171))
315574	27129219	Our data indicated that depletion of EZH2 could rescue the protein changes of p21 and H3K27me3 caused by HBP1 knockdown, thus rescuing the phenotype in HBP1-depleted cells.	('knockdown', 'Var', (110, 119))	('HBP1', 'Gene', (105, 109))	('p21', 'Protein', (78, 81))	('EZH2', 'Gene', '2146', (37, 41))	('depletion', 'MPA', (24, 33))	('protein changes', 'MPA', (59, 74))	('H3K27me3', 'Protein', (86, 94))	('EZH2', 'Gene', (37, 41))
315576	27129219	These results suggest that HBP1 decreases the level of H3K27me3 on the p21 promoter by inhibiting EZH2 expression, thus activating p21 transcription.	('decreases', 'NegReg', (32, 41))	('expression', 'Species', '29278', (103, 113))	('EZH2', 'Gene', (98, 102))	('expression', 'MPA', (103, 113))	('p21', 'Gene', (131, 134))	('transcription', 'MPA', (135, 148))	('level', 'MPA', (46, 51))	('inhibiting', 'NegReg', (87, 97))	('H3K27me3', 'Var', (55, 63))	('HBP1', 'Gene', (27, 31))	('activating', 'PosReg', (120, 130))	('EZH2', 'Gene', '2146', (98, 102))
315581	27129219	We designed two EZH2 promoter-luciferase reporters with either a native EZH2 segment (2608 bp, from +50 bp to -2558 bp, Luc-EZH2) or with a deletion that abolishes the TCF4 affinity site (2601 bp, from +50 bp to -2558 bp, Luc-DeltaEZH2) (Fig.	('EZH2', 'Gene', (16, 20))	('TCF4', 'Gene', (168, 172))	('TCF4', 'Gene', '6925', (168, 172))	('EZH2', 'Gene', '2146', (124, 128))	('EZH2', 'Gene', '2146', (72, 76))	('abolishes', 'NegReg', (154, 163))	('EZH2', 'Gene', (124, 128))	('deletion', 'Var', (140, 148))	('EZH2', 'Gene', (72, 76))	('EZH2', 'Gene', '2146', (231, 235))	('EZH2', 'Gene', '2146', (16, 20))	('EZH2', 'Gene', (231, 235))
315586	27129219	LiCl and SB415286 are specific inhibitors of GSK3beta, which can inhibit Wnt/beta-catenin signaling.	('SB415286', 'Chemical', 'MESH:C417520', (9, 17))	('GSK3beta', 'Gene', '2932', (45, 53))	('LiCl', 'Chemical', 'MESH:D018021', (0, 4))	('SB415286', 'Var', (9, 17))	('inhibit', 'NegReg', (65, 72))	('beta-catenin', 'Gene', (77, 89))	('GSK3beta', 'Gene', (45, 53))	('beta-catenin', 'Gene', '1499', (77, 89))
315587	27129219	Therefore, LiCl and SB415286 can specifically activate Wnt/beta-catenin signaling.	('beta-catenin', 'Gene', '1499', (59, 71))	('LiCl', 'Chemical', 'MESH:D018021', (11, 15))	('activate', 'PosReg', (46, 54))	('SB415286', 'Chemical', 'MESH:C417520', (20, 28))	('SB415286', 'Var', (20, 28))	('beta-catenin', 'Gene', (59, 71))
315589	27129219	6C, both LiCl and SB415286 activated the wild-type Luc-EZH2 but had no effect on the Luc-DeltaEZH2 (left panel).	('SB415286', 'Chemical', 'MESH:C417520', (18, 26))	('SB415286', 'Var', (18, 26))	('EZH2', 'Gene', '2146', (55, 59))	('EZH2', 'Gene', '2146', (94, 98))	('EZH2', 'Gene', (55, 59))	('EZH2', 'Gene', (94, 98))	('LiCl', 'Chemical', 'MESH:D018021', (9, 13))	('activated', 'PosReg', (27, 36))
315590	27129219	Accordingly, EZH2 protein and mRNA levels were increased by LiCl and SB415286 (Fig.	('LiCl', 'Chemical', 'MESH:D018021', (60, 64))	('EZH2', 'Gene', (13, 17))	('EZH2', 'Gene', '2146', (13, 17))	('mRNA levels', 'MPA', (30, 41))	('increased', 'PosReg', (47, 56))	('SB415286', 'Chemical', 'MESH:C417520', (69, 77))	('SB415286', 'Var', (69, 77))
315591	27129219	In the meantime, beta-catenin, the downstream target of GSK3beta in the Wnt/beta-catenin signaling pathway, was also elevated by LiCl and SB415286 (Fig.	('SB415286', 'Chemical', 'MESH:C417520', (138, 146))	('GSK3beta', 'Gene', (56, 64))	('SB415286', 'Var', (138, 146))	('beta-catenin', 'Gene', '1499', (17, 29))	('beta-catenin', 'Gene', (76, 88))	('GSK3beta', 'Gene', '2932', (56, 64))	('beta-catenin', 'Gene', '1499', (76, 88))	('elevated', 'PosReg', (117, 125))	('beta-catenin', 'Gene', (17, 29))	('LiCl', 'Chemical', 'MESH:D018021', (129, 133))	('LiCl', 'Var', (129, 133))
315592	27129219	Overexpression or knockdown of beta-catenin led to the increase or decrease of EZH2 protein, respectively (Fig.	('knockdown', 'Var', (18, 27))	('beta-catenin', 'Gene', (31, 43))	('decrease', 'NegReg', (67, 75))	('expression', 'Species', '29278', (4, 14))	('beta-catenin', 'Gene', '1499', (31, 43))	('EZH2', 'Gene', (79, 83))	('EZH2', 'Gene', '2146', (79, 83))
315595	27129219	6E, the p21 promoter was inhibited by LiCl and SB415286 (left panel), and accordingly, p21 mRNA and protein levels were decreased by LiCl and SB415286 (center and right panels).	('decreased', 'NegReg', (120, 129))	('LiCl', 'Chemical', 'MESH:D018021', (133, 137))	('SB415286', 'Var', (142, 150))	('LiCl', 'Chemical', 'MESH:D018021', (38, 42))	('inhibited', 'NegReg', (25, 34))	('p21', 'Gene', (8, 11))	('SB415286', 'Chemical', 'MESH:C417520', (47, 55))	('SB415286', 'Var', (47, 55))	('SB415286', 'Chemical', 'MESH:C417520', (142, 150))
315603	27129219	In addition, HBP1 could also inhibit Luc-EZH2 transcription activated by SB415286 or LiCl but had no effect on Luc-DeltaEZH2 (Fig.	('SB415286', 'Chemical', 'MESH:C417520', (73, 81))	('EZH2', 'Gene', (120, 124))	('LiCl', 'Chemical', 'MESH:D018021', (85, 89))	('SB415286', 'Var', (73, 81))	('EZH2', 'Gene', (41, 45))	('EZH2', 'Gene', '2146', (41, 45))	('inhibit', 'NegReg', (29, 36))	('transcription', 'MPA', (46, 59))	('EZH2', 'Gene', '2146', (120, 124))
315609	27129219	Furthermore, when beta-catenin was knocked down by siRNA, the inhibition of EZH2 expression by HBP1 was enhanced (Fig.	('expression', 'Species', '29278', (81, 91))	('beta-catenin', 'Gene', (18, 30))	('beta-catenin', 'Gene', '1499', (18, 30))	('enhanced', 'PosReg', (104, 112))	('EZH2', 'Gene', '2146', (76, 80))	('inhibition', 'NegReg', (62, 72))	('HBP1', 'Gene', (95, 99))	('EZH2', 'Gene', (76, 80))	('knocked', 'Var', (35, 42))
315610	27129219	To define the functional domains of HBP1 that might be working here, we cotransfected HEK293T cells with Luc-EZH2 and wild-type HBP1 or mutant HBP1, such as mutated HMG box (pmHMG) or deleted repression domain (Delrepression), respectively.	('EZH2', 'Gene', '2146', (109, 113))	('HBP1', 'Gene', (143, 147))	('HEK293T', 'CellLine', 'CVCL:0063', (86, 93))	('deleted', 'Var', (184, 191))	('mutated', 'Var', (157, 164))	('mutant', 'Var', (136, 142))	('EZH2', 'Gene', (109, 113))
315621	27129219	However, when TCF4 was knocked down by siRNA, the binding of Delrepression to the EZH2 promoter was drastically decreased.	('EZH2', 'Gene', (82, 86))	('knocked down', 'Var', (23, 35))	('EZH2', 'Gene', '2146', (82, 86))	('TCF4', 'Gene', (14, 18))	('TCF4', 'Gene', '6925', (14, 18))	('binding', 'Interaction', (50, 57))	('decreased', 'NegReg', (112, 121))
315634	27129219	As a matter of fact, when p53 was knocked down by shRNA, HBP1 still increased the level of p21 by inhibiting EZH2 (Fig.	('level', 'MPA', (82, 87))	('inhibiting', 'NegReg', (98, 108))	('knocked down', 'Var', (34, 46))	('HBP1', 'Gene', (57, 61))	('EZH2', 'Gene', '2146', (109, 113))	('increased', 'PosReg', (68, 77))	('EZH2', 'Gene', (109, 113))	('p21', 'MPA', (91, 94))
315636	27129219	We used a lentivirus to overexpress HBP1, EZH2, and/or p53 shRNA in WI-38 cells.	('HBP1', 'Gene', (36, 40))	('EZH2', 'Gene', '2146', (42, 46))	('overexpress', 'PosReg', (24, 35))	('EZH2', 'Gene', (42, 46))	('p53', 'Var', (55, 58))
315642	27129219	In addition, it has been found that HBP1 can suppress tumorigenesis by inducing cellular senescence, so we next investigated whether p21 activation by HBP1 also participates in inhibiting tumorigenesis.	('inducing', 'Reg', (71, 79))	('inhibiting', 'NegReg', (177, 187))	('suppress', 'NegReg', (45, 53))	('tumor', 'Disease', (188, 193))	('HBP1', 'Var', (36, 40))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor', 'Disease', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('cellular senescence', 'CPA', (80, 99))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('HBP1', 'Gene', (151, 155))
315643	27129219	8H, overexpression of HBP1 inhibited the growth of A549 cells, whereas, in p53-null H1299 cells, HBP1 also caused cell growth arrest.	('growth', 'CPA', (41, 47))	('cell growth', 'CPA', (114, 125))	('H1299', 'CellLine', 'CVCL:0060', (84, 89))	('A549', 'CellLine', 'CVCL:0023', (51, 55))	('HBP1', 'Gene', (22, 26))	('expression', 'Species', '29278', (8, 18))	('inhibited', 'NegReg', (27, 36))	('overexpression', 'PosReg', (4, 18))	('HBP1', 'Var', (97, 101))	('growth arrest', 'Phenotype', 'HP:0001510', (119, 132))
315647	27129219	Finally, HBP1 inhibited tumorigenesis in nude mice inoculated with A549 or H1299 cells, whereas overexpression of EZH2 in H1299 cells rescued tumorigenesis inhibition caused by HBP1 (Fig.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('tumor', 'Disease', (24, 29))	('tumor', 'Disease', (142, 147))	('expression', 'Species', '29278', (100, 110))	('HBP1', 'Gene', (177, 181))	('inhibited', 'NegReg', (14, 23))	('H1299', 'CellLine', 'CVCL:0060', (122, 127))	('H1299', 'CellLine', 'CVCL:0060', (75, 80))	('EZH2', 'Gene', '2146', (114, 118))	('A549', 'CellLine', 'CVCL:0023', (67, 71))	('nude mice', 'Species', '10090', (41, 50))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('EZH2', 'Gene', (114, 118))	('HBP1', 'Var', (9, 13))
315668	27129219	In separate transgenic mouse models, both HBP1 and p21 blocked G1 progression in liver regeneration.	('liver regeneration', 'CPA', (81, 99))	('p21', 'Var', (51, 54))	('mouse', 'Species', '10090', (23, 28))	('blocked', 'NegReg', (55, 62))
315685	27129219	Our work underscores the importance of the HBP1-EZH2/p53-p21 axis for regulating cellular senescence because its abrogation disrupts senescence and promotes tumorigenesis.	('tumor', 'Disease', (157, 162))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('EZH2', 'Gene', '2146', (48, 52))	('abrogation', 'Var', (113, 123))	('senescence', 'CPA', (133, 143))	('disrupts', 'NegReg', (124, 132))	('EZH2', 'Gene', (48, 52))	('promotes', 'PosReg', (148, 156))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))
315691	27129219	The variation in the expression levels of HBP1, p21, and EZH2, which are all associated with premature senescence, could have a lasting impact on tumorigenic progression.	('EZH2', 'Gene', (57, 61))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('variation', 'Var', (4, 13))	('expression levels', 'MPA', (21, 38))	('expression', 'Species', '29278', (21, 31))	('impact', 'Reg', (136, 142))	('tumor', 'Disease', (146, 151))	('p21', 'Gene', (48, 51))	('EZH2', 'Gene', '2146', (57, 61))	('HBP1', 'Gene', (42, 46))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
315696	33859174	Interestingly, while ectopic expression of FCN3 led to cell cycle arrest and apoptosis in A549 and H23 cells derived from LUAD, the secreted form of the protein had no effect on the cells.	('cell cycle arrest', 'Phenotype', 'HP:0011018', (55, 72))	('arrest', 'Disease', 'MESH:D006323', (66, 72))	('apoptosis', 'CPA', (77, 86))	('FCN3', 'Gene', '8547', (43, 47))	('arrest', 'Disease', (66, 72))	('FCN3', 'Gene', (43, 47))	('H23', 'CellLine', 'CVCL:1547', (99, 102))	('ectopic expression', 'Var', (21, 39))	('LUAD', 'Phenotype', 'HP:0030078', (122, 126))
315697	33859174	Rather, we found evidence indicating that activation of the unfolded protein response from endoplasmic reticulum (ER) stress is induced by ectopic expression of FCN3.	('ectopic expression', 'Var', (139, 157))	('ER', 'Gene', '2069', (114, 116))	('FCN3', 'Gene', '8547', (161, 165))	('activation', 'PosReg', (42, 52))	('FCN3', 'Gene', (161, 165))	('unfolded protein response', 'MPA', (60, 85))
315698	33859174	Consistently, inhibition of ER stress response led to enhanced survival of the LUAD cells.	('survival of the LUAD cells', 'CPA', (63, 89))	('ER', 'Gene', '2069', (28, 30))	('LUAD', 'Phenotype', 'HP:0030078', (79, 83))	('inhibition', 'Var', (14, 24))	('enhanced', 'PosReg', (54, 62))
315704	33859174	This applies to tumor suppressors as well as oncogenes given that presumptive loss-of-function mutations bearing nonsense mutations and DEGs with decreased expression in tumor tissues are found in large numbers.	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('decreased', 'NegReg', (146, 155))	('tumor', 'Disease', (170, 175))	('tumor', 'Disease', (16, 21))	('mutations', 'Var', (95, 104))	('expression', 'MPA', (156, 166))	('nonsense mutations', 'Var', (113, 131))	('loss-of-function', 'NegReg', (78, 94))
315776	33859174	FCN3 expression on A549 and H23 cells led to G1 and G2/M arrest, respectively, and showed consistent changes in levels of cell cycle protein markers (Fig.	('expression', 'Var', (5, 15))	('arrest', 'Disease', 'MESH:D006323', (57, 63))	('FCN3', 'Gene', '8547', (0, 4))	('arrest', 'Disease', (57, 63))	('FCN3', 'Gene', (0, 4))	('led to', 'Reg', (38, 44))	('levels of cell cycle protein markers', 'MPA', (112, 148))	('H23', 'CellLine', 'CVCL:1547', (28, 31))	('changes', 'Reg', (101, 108))
315780	33859174	It has been reported that lack of wild-type p53 protein can lead to bypassing of G1 checkpoint and to G2/M arrest phenotype instead.	('arrest', 'Disease', 'MESH:D006323', (107, 113))	('lack', 'Var', (26, 30))	('lead', 'Reg', (60, 64))	('protein', 'Protein', (48, 55))	('arrest', 'Disease', (107, 113))	('bypassing', 'CPA', (68, 77))	('p53', 'Gene', (44, 47))	('p53', 'Gene', '7157', (44, 47))	('G1 checkpoint', 'CPA', (81, 94))
315781	33859174	Delayed cell cycle upon FCN3 expression appears to ultimately lead to apoptosis as can be seen from increased proportions of Annexin V positive cells in both A549 and H23 cells (Fig.	('expression', 'Var', (29, 39))	('Delayed cell cycle', 'CPA', (0, 18))	('increased', 'PosReg', (100, 109))	('Annexin V', 'Gene', '308', (125, 134))	('Annexin V', 'Gene', (125, 134))	('lead to', 'Reg', (62, 69))	('FCN3', 'Gene', '8547', (24, 28))	('H23', 'CellLine', 'CVCL:1547', (167, 170))	('apoptosis', 'CPA', (70, 79))	('FCN3', 'Gene', (24, 28))
315782	33859174	This was corroborated by the enhanced appearance of cleaved PARP upon FCN3 expression (Fig.	('FCN3', 'Gene', '8547', (70, 74))	('FCN3', 'Gene', (70, 74))	('expression', 'Var', (75, 85))	('enhanced', 'PosReg', (29, 37))	('PARP', 'Gene', '1302', (60, 64))	('PARP', 'Gene', (60, 64))
315792	33859174	This strongly suggests that ectopic expression of FCN3 caused ER stress which in turn activated the UPR process.	('FCN3', 'Gene', '8547', (50, 54))	('FCN3', 'Gene', (50, 54))	('ER', 'Gene', '2069', (62, 64))	('UPR process', 'CPA', (100, 111))	('ectopic expression', 'Var', (28, 46))	('activated', 'PosReg', (86, 95))
315794	33859174	We confirmed the induction of the two genes by ectopic expression of FCN3 at the protein level as well (Fig.	('FCN3', 'Gene', (69, 73))	('ectopic expression', 'Var', (47, 65))	('FCN3', 'Gene', '8547', (69, 73))
315832	33159673	Autophagy modulating agents as chemosensitizers for cisplatin therapy in cancer Although cisplatin is one of the most common antineoplastic drug, its successful utilisation in cancer treatment is limited by the drug resistance.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('cisplatin', 'Chemical', 'MESH:D002945', (52, 61))	('cisplatin', 'Var', (89, 98))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('drug resistance', 'Phenotype', 'HP:0020174', (211, 226))	('cisplatin', 'Chemical', 'MESH:D002945', (89, 98))	('cancer', 'Disease', (176, 182))	('cancer', 'Disease', 'MESH:D009369', (176, 182))
315869	33159673	Interestingly another mechanism responsible for single-strand DNA damage repair - mismatch repair (MMR) plays an opposite role in cisplatin resistance.	('single-strand DNA', 'Var', (48, 65))	('cisplatin resistance', 'MPA', (130, 150))	('cisplatin', 'Chemical', 'MESH:D002945', (130, 139))
315878	33159673	Among others p53, p73 and insulin-like growth factor-binding protein-3 promoters' hypermethylation was strongly correlated with cisplatin resistance.	('p73', 'Gene', '7161', (18, 21))	('p73', 'Gene', (18, 21))	('p53', 'Gene', '7157', (13, 16))	('correlated', 'Reg', (112, 122))	('cisplatin', 'Chemical', 'MESH:D002945', (128, 137))	('insulin-like growth factor-binding protein-3', 'Gene', (26, 70))	('p53', 'Gene', (13, 16))	('hypermethylation', 'Var', (82, 98))	('insulin-like growth factor-binding protein-3', 'Gene', '3486', (26, 70))	('cisplatin resistance', 'Disease', (128, 148))
315898	33159673	Aberrant function and expression of the lysosomal H + -pump in cisplatin-resistant cells result in decreased lysosomal acidification.	('decreased', 'NegReg', (99, 108))	('cisplatin', 'Chemical', 'MESH:D002945', (63, 72))	('Aberrant function', 'Var', (0, 17))	('lysosomal acidification', 'MPA', (109, 132))	('expression', 'MPA', (22, 32))	('lysosomal H + -pump', 'Gene', (40, 59))
315969	33159673	The latter is most visible during treatment with high concentrations of CQ (40-160 muM) whereas at lower concentrations (10-20 muM) autophagy inhibition is a predominant effect.	('autophagy inhibition', 'CPA', (132, 152))	('CQ (40-160 muM', 'Var', (72, 86))	('CQ', 'Chemical', 'MESH:D002738', (72, 74))
315979	33159673	Conversely in the same experiment ATG5 knockout efficiently reversed CPT resistance.	('reversed', 'Reg', (60, 68))	('knockout', 'Var', (39, 47))	('ATG5', 'Gene', (34, 38))	('CPT', 'Gene', '79947', (69, 72))	('CPT', 'Gene', (69, 72))	('ATG5', 'Gene', '9474', (34, 38))
315988	33159673	Consistently ATG genes knock down and CQ treatment sensitizes cancer cells to CPT.	('CPT', 'Gene', '79947', (78, 81))	('sensitizes', 'Reg', (51, 61))	('ATG genes', 'Gene', (13, 22))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('CPT', 'Gene', (78, 81))	('cancer', 'Disease', (62, 68))	('knock down', 'Var', (23, 33))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('CQ', 'Chemical', 'MESH:D002738', (38, 40))
315989	33159673	Subsequently ATG5/7 knockout inhibits CQ (in monotherapy) antineoplastic activity.	('ATG5/7', 'Gene', (13, 19))	('ATG5/7', 'Gene', '9474;10533', (13, 19))	('inhibits', 'NegReg', (29, 37))	('knockout', 'Var', (20, 28))	('CQ', 'Chemical', 'MESH:D002738', (38, 40))
315993	33159673	Off note experiments with oxaliplatin (OXA) proved that CQ or 3-MA addition augments OXA induced ROS generation.	('CQ', 'Chemical', 'MESH:D002738', (56, 58))	('3-MA addition', 'Var', (62, 75))	('3-MA', 'Chemical', 'MESH:C025946', (62, 66))	('OXA', 'Chemical', 'MESH:D000077150', (85, 88))	('ROS', 'Chemical', 'MESH:D017382', (97, 100))	('OXA', 'Chemical', 'MESH:D000077150', (39, 42))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (26, 37))	('augments', 'NegReg', (76, 84))	('OXA induced ROS generation', 'MPA', (85, 111))
316004	33159673	Conversely, CPT induces lysosomal biogenesis by c-Abl/TFEB pathway and TFEB knock-down successfully increased the cytotoxic effect of CPT.	('CPT', 'Gene', '79947', (134, 137))	('TFEB', 'Gene', (54, 58))	('CPT', 'Gene', (12, 15))	('increased', 'PosReg', (100, 109))	('TFEB', 'Gene', '7942', (71, 75))	('c-Abl', 'Gene', '25', (48, 53))	('TFEB', 'Gene', (71, 75))	('knock-down', 'Var', (76, 86))	('lysosomal biogenesis', 'MPA', (24, 44))	('cytotoxic effect', 'CPA', (114, 130))	('CPT', 'Gene', '79947', (12, 15))	('CPT', 'Gene', (134, 137))	('induces', 'Reg', (16, 23))	('c-Abl', 'Gene', (48, 53))	('TFEB', 'Gene', '7942', (54, 58))
316011	33159673	In addition 3-MA was shown to induce caspase-dependent cell death independently of autophagy modulating effect.	('3-MA', 'Var', (12, 16))	('3-MA', 'Chemical', 'MESH:C025946', (12, 16))	('caspase', 'Gene', '837;841', (37, 44))	('caspase', 'Gene', (37, 44))
316015	33159673	In the latter experiment ATG5 knockout was also incapable of augmenting CPT sensitivity.	('CPT', 'Gene', (72, 75))	('ATG5', 'Gene', (25, 29))	('knockout', 'Var', (30, 38))	('CPT', 'Gene', '79947', (72, 75))	('ATG5', 'Gene', '9474', (25, 29))
316018	33159673	Off note in the same experiment Beclin-1 (autophagy regulation protein) knockdown enhanced cisplatin-induced cell death and apoptosis.	('enhanced', 'PosReg', (82, 90))	('Beclin-1', 'Gene', '8678', (32, 40))	('cisplatin-induced', 'MPA', (91, 108))	('cisplatin', 'Chemical', 'MESH:D002945', (91, 100))	('Beclin-1', 'Gene', (32, 40))	('apoptosis', 'CPA', (124, 133))	('knockdown', 'Var', (72, 81))
316032	33159673	PKI-402 addition to CPT was shown to further increase lysosomes number as well as it induced mitochondrial depolarization, mtROS generation and led to apoptosis through LMP induction.	('CPT', 'Gene', '79947', (20, 23))	('PKI-402', 'Var', (0, 7))	('lysosomes number', 'MPA', (54, 70))	('LMP', 'MPA', (169, 172))	('mitochondrial depolarization', 'MPA', (93, 121))	('induced', 'Reg', (85, 92))	('ROS', 'Chemical', 'MESH:D017382', (125, 128))	('mtROS generation', 'MPA', (123, 139))	('CPT', 'Gene', (20, 23))	('LMP', 'Chemical', '-', (169, 172))	('apoptosis', 'CPA', (151, 160))	('led to', 'Reg', (144, 150))	('increase', 'PosReg', (45, 53))
316034	33159673	However it is important to note that whereas low ROS accumulation may lead to compensatory lysosomal biogenesis and act protectively, high amounts may itself facilitate LMP.	('facilitate', 'PosReg', (158, 168))	('ROS', 'Chemical', 'MESH:D017382', (49, 52))	('ROS', 'Protein', (49, 52))	('LMP', 'Chemical', '-', (169, 172))	('lead to', 'Reg', (70, 77))	('compensatory', 'MPA', (78, 90))	('LMP', 'MPA', (169, 172))	('low', 'Var', (45, 48))
316039	33159673	U0126 is a selective MEK1/2 (kinases upstream of ERK) inhibitor.	('MEK1/2', 'Gene', '5604;5605', (21, 27))	('MEK1/2', 'Gene', (21, 27))	('U0126', 'Var', (0, 5))	('U0126', 'Chemical', 'MESH:C113580', (0, 5))	('ERK', 'Gene', '5594', (49, 52))	('ERK', 'Gene', (49, 52))
316041	33159673	Co-treatment with U0126 overcame drug resistance, reduced autophagy and promoted CPT induced apoptosis.	('U0126', 'Chemical', 'MESH:C113580', (18, 23))	('autophagy', 'CPA', (58, 67))	('CPT', 'Gene', (81, 84))	('overcame', 'PosReg', (24, 32))	('U0126', 'Var', (18, 23))	('drug resistance', 'Phenotype', 'HP:0020174', (33, 48))	('reduced', 'NegReg', (50, 57))	('CPT', 'Gene', '79947', (81, 84))	('drug resistance', 'CPA', (33, 48))	('promoted', 'PosReg', (72, 80))
316042	33159673	Similar results were obtained upon 3-MA treatment as well as ERK1/2 or ATG5 knockdown.	('knockdown', 'Var', (76, 85))	('3-MA', 'Chemical', 'MESH:C025946', (35, 39))	('ATG5', 'Gene', '9474', (71, 75))	('ERK1/2', 'Gene', '5595;5594', (61, 67))	('ERK1/2', 'Gene', (61, 67))	('ATG5', 'Gene', (71, 75))
316044	33159673	U0126 was also shown to increase sensitivity towards CPT in NSCLC.	('increase', 'PosReg', (24, 32))	('CPT', 'Gene', '79947', (53, 56))	('CPT', 'Gene', (53, 56))	('U0126', 'Var', (0, 5))	('NSCLC', 'Disease', (60, 65))	('U0126', 'Chemical', 'MESH:C113580', (0, 5))	('NSCLC', 'Disease', 'MESH:D002289', (60, 65))
316046	33159673	Inconsistently a study in the oesophageal cancer cell line showed that the addition of U0126 to CPT alleviates CPT-induced growth inhibition suppressing both senescence and apoptosis.	('CPT', 'Gene', (111, 114))	('apoptosis', 'CPA', (173, 182))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('U0126', 'Chemical', 'MESH:C113580', (87, 92))	('CPT', 'Gene', '79947', (96, 99))	('growth inhibition', 'MPA', (123, 140))	('suppressing', 'NegReg', (141, 152))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('U0126', 'Var', (87, 92))	('CPT', 'Gene', '79947', (111, 114))	('CPT', 'Gene', (96, 99))	('senescence', 'CPA', (158, 168))	('alleviates', 'NegReg', (100, 110))
316048	33159673	MPT0L145 was designed as a selective FGF-R inhibitor and is capable of inducing non-apoptotic autophagy-dependent cell death.	('non-apoptotic autophagy-dependent cell death', 'CPA', (80, 124))	('inducing', 'PosReg', (71, 79))	('MPT0L145', 'Chemical', 'MESH:C000625862', (0, 8))	('MPT0L145', 'Var', (0, 8))
316049	33159673	As it occurred MPT0L145 possesses second activity to inhibit PIK3C3 - a membrane protein implicated in endosome and autophagosome maturation process.	('PIK3C3', 'Gene', (61, 67))	('inhibit', 'NegReg', (53, 60))	('MPT0L145', 'Chemical', 'MESH:C000625862', (15, 23))	('MPT0L145', 'Var', (15, 23))	('PIK3C3', 'Gene', '5289', (61, 67))
316050	33159673	MPT0L145 was found to reduce the viability of bladder cancer cell lines in vitro.	('reduce', 'NegReg', (22, 28))	('bladder cancer', 'Disease', 'MESH:D001749', (46, 60))	('bladder cancer', 'Disease', (46, 60))	('viability', 'CPA', (33, 42))	('bladder cancer', 'Phenotype', 'HP:0009725', (46, 60))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('MPT0L145', 'Chemical', 'MESH:C000625862', (0, 8))	('MPT0L145', 'Var', (0, 8))
316052	33159673	Moreover enhanced induction with concomitant impairment of late-stage autophagy (resulting in incomplete autophagic flux) and perinuclear accumulation of enlarged and deacidified late-endosomes were found after MPT0L145 stimulation.	('incomplete', 'NegReg', (94, 104))	('MPT0L145', 'Chemical', 'MESH:C000625862', (211, 219))	('MPT0L145', 'Var', (211, 219))	('late-stage autophagy', 'CPA', (59, 79))	('induction', 'MPA', (18, 27))	('enhanced', 'PosReg', (9, 17))
316054	33159673	Furthermore, ATG5-knockout rescued cells from MPT0L145 induced cell death which indicates the importance of autophagic cell death in MPT0L145 cytotoxicity.	('ATG5', 'Gene', (13, 17))	('cytotoxicity', 'Disease', 'MESH:D064420', (142, 154))	('MPT0L145', 'Chemical', 'MESH:C000625862', (46, 54))	('MPT0L145', 'Var', (46, 54))	('cell death', 'CPA', (63, 73))	('MPT0L145', 'Chemical', 'MESH:C000625862', (133, 141))	('ATG5', 'Gene', '9474', (13, 17))	('cytotoxicity', 'Disease', (142, 154))
316055	33159673	In the same study, MPT0L145 addition was found to markedly diminish cell viability in CPT-treated CPT-resistant bladder cancer cell line.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('cell viability', 'CPA', (68, 82))	('CPT', 'Gene', '79947', (98, 101))	('CPT', 'Gene', '79947', (86, 89))	('bladder cancer', 'Disease', 'MESH:D001749', (112, 126))	('bladder cancer', 'Disease', (112, 126))	('CPT', 'Gene', (98, 101))	('MPT0L145', 'Chemical', 'MESH:C000625862', (19, 27))	('MPT0L145 addition', 'Var', (19, 36))	('bladder cancer', 'Phenotype', 'HP:0009725', (112, 126))	('CPT', 'Gene', (86, 89))	('diminish', 'NegReg', (59, 67))
316058	33159673	In oesophageal squamous cell carcinoma cell line nimotuzumab was found to enhance the sensitivity towards CPT or paclitaxel-induced viability reduction.	('carcinoma', 'Phenotype', 'HP:0030731', (29, 38))	('CPT', 'Gene', '79947', (106, 109))	('nimotuzumab', 'Var', (49, 60))	('oesophageal squamous cell carcinoma', 'Disease', 'MESH:D002294', (3, 38))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (15, 38))	('CPT', 'Gene', (106, 109))	('paclitaxel', 'Chemical', 'MESH:D017239', (113, 123))	('nimotuzumab', 'Chemical', 'MESH:C501466', (49, 60))	('oesophageal squamous cell carcinoma', 'Disease', (3, 38))	('enhance', 'PosReg', (74, 81))
316061	33159673	Notably, chemosensitising effects of nimotuzumab was abrogated by ATG-5 knock-down indicating for the importance of autophagy induction in cytotoxicity.	('chemosensitising effects', 'CPA', (9, 33))	('nimotuzumab', 'Gene', (37, 48))	('cytotoxicity', 'Disease', 'MESH:D064420', (139, 151))	('nimotuzumab', 'Chemical', 'MESH:C501466', (37, 48))	('abrogated', 'NegReg', (53, 62))	('ATG-5', 'Gene', (66, 71))	('knock-down', 'Var', (72, 82))	('ATG-5', 'Gene', '9474', (66, 71))	('cytotoxicity', 'Disease', (139, 151))
316064	33159673	SAR405 belongs to specific inhibitors of PIK3C3/Vps34.	('Vps34', 'Gene', (48, 53))	('PIK3C3', 'Gene', '5289', (41, 47))	('SAR405', 'Var', (0, 6))	('PIK3C3', 'Gene', (41, 47))	('Vps34', 'Gene', '5289', (48, 53))	('SAR405', 'Chemical', 'MESH:C000594652', (0, 6))
316077	33159673	Particularly metformin was showed to improve neo-adjuvant therapy outcomes in neck, cervix and breast cancer.	('neo-adjuvant therapy', 'CPA', (45, 65))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('neck', 'Disease', (78, 82))	('improve', 'PosReg', (37, 44))	('breast cancer', 'Disease', (95, 108))	('metformin', 'Var', (13, 22))	('breast cancer', 'Phenotype', 'HP:0003002', (95, 108))	('cervix', 'Disease', (84, 90))	('metformin', 'Chemical', 'MESH:D008687', (13, 22))	('breast cancer', 'Disease', 'MESH:D001943', (95, 108))
316087	33159673	Consistently metformin in micromolar concentrations diminished ammonia production as well as it reduced MAP1LC3B-II, GABARAP, BECN1 and ATG12/ATG5 expression.	('ATG5', 'Gene', '9474', (142, 146))	('ammonia production', 'MPA', (63, 81))	('metformin', 'Var', (13, 22))	('GABARAP', 'Gene', (117, 124))	('ATG12', 'Gene', (136, 141))	('GABARAP', 'Gene', '11337', (117, 124))	('ammonia', 'Chemical', 'MESH:D000641', (63, 70))	('LC3B', 'Gene', (108, 112))	('BECN1', 'Gene', (126, 131))	('ATG5', 'Gene', (142, 146))	('LC3B', 'Gene', '81631', (108, 112))	('metformin', 'Chemical', 'MESH:D008687', (13, 22))	('diminished', 'NegReg', (52, 62))	('BECN1', 'Gene', '8678', (126, 131))	('ATG12', 'Gene', '9140', (136, 141))	('reduced', 'NegReg', (96, 103))
316090	33159673	Interestingly metformin increased BCL2-BECN1 binding thus sequestering the first and possibly preventing its antiapoptotic action.	('BCL2', 'Gene', '596', (34, 38))	('preventing', 'NegReg', (94, 104))	('BECN1', 'Gene', (39, 44))	('binding', 'Interaction', (45, 52))	('metformin', 'Var', (14, 23))	('BCL2', 'Gene', (34, 38))	('BECN1', 'Gene', '8678', (39, 44))	('metformin', 'Chemical', 'MESH:D008687', (14, 23))	('sequestering', 'NegReg', (58, 70))	('increased', 'PosReg', (24, 33))	('antiapoptotic action', 'MPA', (109, 129))
316102	33159673	This suggests glycolysis inhibition by 2-DG leads to ER-stress and its effect on cell growth depends on the direction of subsequent changes in autophagic flux.	('ER', 'Gene', '2069', (53, 55))	('2-DG', 'Var', (39, 43))	('2-DG', 'Chemical', 'MESH:D003847', (39, 43))	('glycolysis', 'CPA', (14, 24))	('inhibition', 'NegReg', (25, 35))
316108	33159673	Even more strikingly co-treatment with CPT and 2-DG led to the reduction of both ER-stress (measured by BIP expression) and autophagy.	('BIP', 'Gene', (104, 107))	('autophagy', 'CPA', (124, 133))	('2-DG', 'Var', (47, 51))	('CPT', 'Gene', (39, 42))	('2-DG', 'Chemical', 'MESH:D003847', (47, 51))	('ER', 'Gene', '2069', (81, 83))	('reduction', 'NegReg', (63, 72))	('CPT', 'Gene', '79947', (39, 42))	('BIP', 'Gene', '3309', (104, 107))
316109	33159673	Of note the this effect was replicated by co-treatment with 2-DG and Akt inhibitor LY294002.	('Akt', 'Gene', (69, 72))	('LY294002', 'Var', (83, 91))	('2-DG', 'Chemical', 'MESH:D003847', (60, 64))	('LY294002', 'Chemical', 'MESH:C085911', (83, 91))	('Akt', 'Gene', '207', (69, 72))
316119	33159673	FK866 is a specific Nampt inhibitor.	('Nampt', 'Gene', (20, 25))	('Nampt', 'Gene', '10135', (20, 25))	('FK866', 'Chemical', 'MESH:C480543', (0, 5))	('FK866', 'Var', (0, 5))
316123	33159673	FK866 addition to CPT or etoposide was suggested to unmask mitochondrial NAD depletion.	('mitochondrial NAD depletion', 'MPA', (59, 86))	('etoposide', 'Chemical', 'MESH:D005047', (25, 34))	('CPT', 'Gene', '79947', (18, 21))	('NAD', 'Chemical', 'MESH:D009243', (73, 76))	('unmask', 'Reg', (52, 58))	('FK866', 'Chemical', 'MESH:C480543', (0, 5))	('FK866 addition', 'Var', (0, 14))	('CPT', 'Gene', (18, 21))
316139	33159673	Interestingly siRNA knockdown of XIAP was shown to conversely enhance autophagy in response to CPT and was less efficient in sensitizing cells towards drug-induced growth inhibition.	('autophagy', 'CPA', (70, 79))	('CPT', 'Gene', (95, 98))	('enhance', 'PosReg', (62, 69))	('XIAP', 'Gene', (33, 37))	('XIAP', 'Gene', '331', (33, 37))	('knockdown', 'Var', (20, 29))	('CPT', 'Gene', '79947', (95, 98))
316141	33159673	In addition, PXD conferred protection against CPT-induced neurotoxicity in vitro proving it may simultaneously limit adverse effects of therapy.	('CPT', 'Gene', (46, 49))	('neurotoxicity', 'Disease', (58, 71))	('PXD', 'Chemical', '-', (13, 16))	('neurotoxicity', 'Disease', 'MESH:D020258', (58, 71))	('CPT', 'Gene', '79947', (46, 49))	('PXD', 'Var', (13, 16))
316151	33159673	However these results require cautious interpretation as both wortmannin and PTEN transfection may act on various pathways.	('transfection', 'Var', (82, 94))	('wortmannin', 'Chemical', 'MESH:D000077191', (62, 72))	('PTEN', 'Gene', (77, 81))	('PTEN', 'Gene', '5728', (77, 81))	('act', 'Reg', (99, 102))
316154	33159673	Moreover silencing Beclin-1 or ATG-7 impairs andrographolide activity suggesting that its activity depends on late flux stalling rather than complete autophagy inhibition The latter also indicates andrographolide may be more efficient in cells with a higher level of autophagy for instance due to CPT stimulation.	('Beclin-1', 'Gene', (19, 27))	('ATG-7', 'Gene', (31, 36))	('andrographolide', 'Chemical', 'MESH:C030419', (45, 60))	('Beclin-1', 'Gene', '8678', (19, 27))	('activity', 'MPA', (90, 98))	('silencing', 'Var', (9, 18))	('impairs', 'NegReg', (37, 44))	('ATG-7', 'Gene', '10533', (31, 36))	('andrographolide', 'Chemical', 'MESH:C030419', (197, 212))	('CPT', 'Gene', '79947', (297, 300))	('activity', 'MPA', (61, 69))	('CPT', 'Gene', (297, 300))
316155	33159673	Off note in the same study ATG-7 knock-down itself sensitizes cells towards CPT.	('ATG-7', 'Gene', (27, 32))	('sensitizes', 'Reg', (51, 61))	('CPT', 'Gene', (76, 79))	('ATG-7', 'Gene', '10533', (27, 32))	('CPT', 'Gene', '79947', (76, 79))	('knock-down', 'Var', (33, 43))
316160	33159673	Simultaneously 4-AAQB was shown to reduce Akt and mTOR phosphorylation which is known to induce rather than reduce autophagy yet the opposite effect was noted.	('Akt', 'Gene', (42, 45))	('mTOR', 'Gene', (50, 54))	('4-AAQB', 'Var', (15, 21))	('mTOR', 'Gene', '2475', (50, 54))	('reduce', 'NegReg', (35, 41))	('Akt', 'Gene', '207', (42, 45))	('4-AAQB', 'Chemical', 'MESH:C555021', (15, 21))
316162	33159673	Molecularly pristimerin was shown to directly inhibit proteasome and telomerase activity, to diminish MEK/ERK, EGF-R, PI3K/Akt, Wnt/beta-catenin, NfxB pathways as well as to induce JNK.	('MEK', 'Gene', '5609', (102, 105))	('diminish', 'NegReg', (93, 101))	('ERK', 'Gene', '5594', (106, 109))	('MEK', 'Gene', (102, 105))	('inhibit', 'NegReg', (46, 53))	('activity', 'MPA', (80, 88))	('Akt', 'Gene', (123, 126))	('pristimerin', 'Var', (12, 23))	('JNK', 'Gene', (181, 184))	('ERK', 'Gene', (106, 109))	('NfxB pathways', 'Pathway', (146, 159))	('JNK', 'Gene', '5599', (181, 184))	('induce', 'PosReg', (174, 180))	('beta-catenin', 'Gene', (132, 144))	('Akt', 'Gene', '207', (123, 126))	('proteasome', 'Protein', (54, 64))	('beta-catenin', 'Gene', '1499', (132, 144))	('pristimerin', 'Chemical', 'MESH:C009043', (12, 23))	('EGF-R', 'Gene', (111, 116))	('telomerase', 'Protein', (69, 79))	('EGF-R', 'Gene', '1956', (111, 116))
316211	33159673	BZYQD was shown to sensitize resistant NSCLC cell line towards CPT mediated apoptosis.	('BZYQD', 'Var', (0, 5))	('sensitize', 'Reg', (19, 28))	('CPT', 'Gene', '79947', (63, 66))	('NSCLC', 'Disease', (39, 44))	('CPT', 'Gene', (63, 66))	('NSCLC', 'Disease', 'MESH:D002289', (39, 44))
316225	33159673	Importantly siRNA knock-down of autophagy-related ATG genes was shown to reverse EGCG chemosensitising effect which suggests the involvement of autophagic cell death.	('reverse', 'NegReg', (73, 80))	('EGCG', 'Chemical', 'MESH:C045651', (81, 85))	('knock-down', 'Var', (18, 28))	('EGCG chemosensitising effect', 'MPA', (81, 109))	('autophagy-related ATG genes', 'Gene', (32, 59))
316227	33159673	Chal-24 efficiently induces cell death in a cancer cell in vitro and in vivo without signs of toxicity in mice.	('mice', 'Species', '10090', (106, 110))	('Chal-24', 'Chemical', 'MESH:C576272', (0, 7))	('cancer', 'Disease', (44, 50))	('cell death', 'CPA', (28, 38))	('induces', 'Reg', (20, 27))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('toxicity', 'Disease', 'MESH:D064420', (94, 102))	('Chal-24', 'Var', (0, 7))	('toxicity', 'Disease', (94, 102))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
316228	33159673	Chal-24 was found to synergistically induce apoptosis with CPT in NSCLC cell lines.	('Chal-24', 'Chemical', 'MESH:C576272', (0, 7))	('NSCLC', 'Disease', (66, 71))	('CPT', 'Gene', '79947', (59, 62))	('apoptosis', 'CPA', (44, 53))	('NSCLC', 'Disease', 'MESH:D002289', (66, 71))	('CPT', 'Gene', (59, 62))	('induce', 'PosReg', (37, 43))	('Chal-24', 'Var', (0, 7))
316229	33159673	CPT/Chal-24 co-treatment led to an increase in JNK/Bcl-2/Beclin 1 dependent autophagy induction, facilitated ERK-dependent proteasomal degradation of cellular inhibitor of apoptosis proteins (c-IAPs) and triggered Ripoptosome (RIP1/FADD/caspase 8) complex assembly as well as it dramatically reduced levels of Riopotosome inhibitor - cFLIPL.	('caspase 8', 'Gene', (237, 246))	('assembly', 'MPA', (256, 264))	('RIP1', 'Gene', '8737', (227, 231))	('Beclin 1', 'Gene', (57, 65))	('Beclin 1', 'Gene', '8678', (57, 65))	('co-treatment', 'Var', (12, 24))	('JNK', 'Gene', (47, 50))	('caspase 8', 'Gene', '841', (237, 246))	('levels of Riopotosome inhibitor - cFLIPL', 'MPA', (300, 340))	('JNK', 'Gene', '5599', (47, 50))	('facilitated', 'PosReg', (97, 108))	('FADD', 'Gene', '8772', (232, 236))	('increase', 'PosReg', (35, 43))	('RIP1', 'Gene', (227, 231))	('reduced', 'NegReg', (292, 299))	('Chal-24', 'Chemical', 'MESH:C576272', (4, 11))	('Bcl-2', 'Gene', (51, 56))	('ERK', 'Gene', '5594', (109, 112))	('CPT', 'Gene', '79947', (0, 3))	('autophagy induction', 'CPA', (76, 95))	('Ripoptosome', 'Pathway', (214, 225))	('Bcl-2', 'Gene', '596', (51, 56))	('ERK', 'Gene', (109, 112))	('CPT', 'Gene', (0, 3))	('FADD', 'Gene', (232, 236))
316252	33159673	Arachidonic acid (AA), eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) were shown to enhance CPT mediated viability reduction in NSCLC cell line in vitro.	('reduction', 'NegReg', (124, 133))	('CPT', 'Gene', (101, 104))	('NSCLC', 'Disease', (137, 142))	('eicosapentaenoic acid', 'Chemical', 'MESH:D015118', (23, 44))	('NSCLC', 'Disease', 'MESH:D002289', (137, 142))	('docosahexaenoic', 'Var', (52, 67))	('enhance', 'PosReg', (93, 100))	('EPA', 'Chemical', 'MESH:D015118', (46, 49))	('Arachidonic acid', 'Chemical', 'MESH:D016718', (0, 16))	('CPT', 'Gene', '79947', (101, 104))	('docosahexaenoic acid', 'Chemical', 'MESH:D004281', (52, 72))	('DHA', 'Chemical', 'MESH:D004281', (74, 77))
316263	33159673	Interestingly the reduction of p62 linked to increased autophagic flux was suggested to play a role in the aforementioned actions as p62 knock-down reproduced QC effect.	('p62', 'Gene', (133, 136))	('p62', 'Gene', '23636', (31, 34))	('increased', 'PosReg', (45, 54))	('knock-down', 'Var', (137, 147))	('autophagic flux', 'CPA', (55, 70))	('p62', 'Gene', (31, 34))	('p62', 'Gene', '23636', (133, 136))	('reduction', 'NegReg', (18, 27))
316275	33159673	Furthermore, knock-down of ULK1 or Atg-7 but not inhibition of autophagosome-lysosome fusion comprises LC-3/GO nuclear localization suggesting autophagosome formation and elongation are required for GO nuclear trafficking.	('knock-down', 'Var', (13, 23))	('GO', 'Chemical', 'MESH:C000628730', (199, 201))	('Atg-7', 'Gene', (35, 40))	('GO', 'Chemical', 'MESH:C000628730', (108, 110))	('Atg-7', 'Gene', '10533', (35, 40))	('LC-3/GO nuclear localization', 'MPA', (103, 131))	('ULK1', 'Gene', (27, 31))	('ULK1', 'Gene', '8408', (27, 31))
316289	33159673	Furthermore, ROS scavenging with N-acetylcysteine, autophagy inhibition by Beclin-1 knockdown or pre-treatment with 3-MA reduced ZA monotherapy effect on apoptosis.	('3-MA', 'Chemical', 'MESH:C025946', (116, 120))	('autophagy', 'CPA', (51, 60))	('Beclin-1', 'Gene', (75, 83))	('inhibition', 'NegReg', (61, 71))	('knockdown', 'Var', (84, 93))	('apoptosis', 'CPA', (154, 163))	('Beclin-1', 'Gene', '8678', (75, 83))	('ROS', 'MPA', (13, 16))	('ZA', 'Chemical', '-', (129, 131))	('N-acetylcysteine', 'Chemical', 'MESH:D000111', (33, 49))	('ROS', 'Chemical', 'MESH:D017382', (13, 16))
316294	33159673	Li was shown to chemosensitise cancer cells towards CPT or 5-FU which was also accompanied by enhanced accumulation of cytoplasmic vesicles.	('CPT', 'Gene', (52, 55))	('5-FU', 'Var', (59, 63))	('chemosensitise cancer', 'Disease', (16, 37))	('5-FU', 'Chemical', 'MESH:D005472', (59, 63))	('chemosensitise cancer', 'Disease', 'MESH:D009369', (16, 37))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('CPT', 'Gene', '79947', (52, 55))	('enhanced accumulation', 'PosReg', (94, 115))
316299	33159673	C60 were shown to induce cytotoxic autophagy and to sensitize cancer cells towards chemotherapeutics.	('sensitize', 'Reg', (52, 61))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('induce', 'PosReg', (18, 24))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('cytotoxic autophagy', 'CPA', (25, 44))	('C60', 'Var', (0, 3))
316300	33159673	Pre-treatment of cervical cancer cell lines with non-toxic concentrations of C60(Nd) was showed to greatly potentiate CPT mediated cell death.	('CPT', 'Gene', (118, 121))	('cancer', 'Disease', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('C60(Nd', 'Var', (77, 83))	('potentiate', 'PosReg', (107, 117))	('CPT', 'Gene', '79947', (118, 121))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('Nd', 'Chemical', 'MESH:D009354', (81, 83))
316308	33159673	Inhibition of lysosomes biogenesis would restrict vesicular cisplatin accumulation and its efflux via exocytosis/extracellular vesicles.	('efflux', 'MPA', (91, 97))	('restrict', 'NegReg', (41, 49))	('Inhibition', 'Var', (0, 10))	('cisplatin', 'Chemical', 'MESH:D002945', (60, 69))	('vesicular cisplatin accumulation', 'MPA', (50, 82))	('exocytosis/extracellular vesicles', 'MPA', (102, 135))
316315	33159673	Furthermore, cisplatin may affect lysosomal stability both directly (f.i.	('lysosomal', 'MPA', (34, 43))	('cisplatin', 'Var', (13, 22))	('cisplatin', 'Chemical', 'MESH:D002945', (13, 22))	('affect', 'Reg', (27, 33))
316317	33159673	This convergence of different molecular events characteristic for cancer and further augmented by cisplatin/cisplatin resistance on lysosomes makes them a potential target for cancer therapy.	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('cisplatin', 'Chemical', 'MESH:D002945', (108, 117))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('cisplatin', 'Chemical', 'MESH:D002945', (98, 107))	('cisplatin/cisplatin', 'Var', (98, 117))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('cancer', 'Disease', (176, 182))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('cancer', 'Disease', (66, 72))
316337	33664813	LUAD, for example, arising from the distal airway, is often associated with the mutation of the KRAS gene.	('KRAS', 'Gene', '3845', (96, 100))	('LUAD', 'Disease', (0, 4))	('associated', 'Reg', (60, 70))	('mutation', 'Var', (80, 88))	('KRAS', 'Gene', (96, 100))
316411	33664813	The key role of p53 mutation in malignant transformation, histological progress, invasion and metastasis of lung cancer has been confirmed in lung cancer models in vitro and in vivo.	('lung cancer', 'Disease', 'MESH:D008175', (108, 119))	('lung cancer', 'Disease', 'MESH:D008175', (142, 153))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('p53', 'Gene', (16, 19))	('mutation', 'Var', (20, 28))	('malignant transformation', 'CPA', (32, 56))	('p53', 'Gene', '7157', (16, 19))	('lung cancer', 'Disease', (142, 153))	('metastasis of lung cancer', 'Disease', (94, 119))	('lung cancer', 'Phenotype', 'HP:0100526', (142, 153))	('lung cancer', 'Phenotype', 'HP:0100526', (108, 119))	('metastasis of lung cancer', 'Disease', 'MESH:D008175', (94, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
316412	33664813	Smoking is closely associated with p53 mutation, which may explain the universality of p53 alterations in LUSC.	('associated', 'Reg', (19, 29))	('p53', 'Gene', (35, 38))	('mutation', 'Var', (39, 47))	('p53', 'Gene', '7157', (35, 38))	('p53', 'Gene', (87, 90))	('p53', 'Gene', '7157', (87, 90))
316432	32971741	Deregulated microRNAs Are Associated with Patient Survival and Predicted to Target Genes That Modulate Lung Cancer Signaling Pathways Lung cancer is the leading cause of cancer death, worldwide.	('Lung Cancer', 'Phenotype', 'HP:0100526', (103, 114))	('Lung Cancer', 'Disease', (103, 114))	('Deregulated', 'Var', (0, 11))	('Lung cancer', 'Disease', (134, 145))	('cancer death', 'Disease', (170, 182))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('Lung cancer', 'Disease', 'MESH:D008175', (134, 145))	('cancer death', 'Disease', 'MESH:D009369', (170, 182))	('Lung Cancer', 'Disease', 'MESH:D008175', (103, 114))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('Associated', 'Reg', (26, 36))	('Cancer', 'Phenotype', 'HP:0002664', (108, 114))	('Patient', 'Species', '9606', (42, 49))	('Lung cancer', 'Phenotype', 'HP:0100526', (134, 145))
316447	32971741	Enrichment analysis confirmed that genes targeted by the 33 miRNAs are aberrantly expressed in lung AD and SCC, and modulate known pathways in lung cancer.	('known pathways', 'Pathway', (125, 139))	('lung cancer', 'Disease', (143, 154))	('lung AD', 'Disease', (95, 102))	('lung cancer', 'Phenotype', 'HP:0100526', (143, 154))	('SCC', 'Gene', (107, 110))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('miRNAs', 'Var', (60, 66))	('modulate', 'Reg', (116, 124))	('lung cancer', 'Disease', 'MESH:D008175', (143, 154))	('SCC', 'Gene', '6317', (107, 110))	('men', 'Species', '9606', (6, 9))
316448	32971741	Additionally, high expression of miR-25-3p was significantly associated (p < 0.05) with poor patient survival, when considering both tumor histologies.	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('poor', 'NegReg', (88, 92))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('high', 'Var', (14, 18))	('patient survival', 'CPA', (93, 109))	('patient', 'Species', '9606', (93, 100))	('miR-25-3p', 'Chemical', '-', (33, 42))	('tumor', 'Disease', (133, 138))	('miR-25-3p', 'Var', (33, 42))
316449	32971741	(4) Conclusions: miR-25-3p may be a potential prognostic biomarker in non-small cell lung cancer.	('miR-25-3p', 'Chemical', '-', (17, 26))	('lung cancer', 'Disease', (85, 96))	('lung cancer', 'Phenotype', 'HP:0100526', (85, 96))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('miR-25-3p', 'Var', (17, 26))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (74, 96))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (70, 96))	('lung cancer', 'Disease', 'MESH:D008175', (85, 96))
316450	32971741	Genes targeted by miRNAs regulate EGFR and TGFbeta signaling, among other known pathways relevant to lung tumorigenesis.	('miRNAs', 'Var', (18, 24))	('lung tumor', 'Disease', (101, 111))	('EGFR', 'Gene', (34, 38))	('TGFbeta', 'Gene', (43, 50))	('lung tumor', 'Disease', 'MESH:D008175', (101, 111))	('regulate', 'Reg', (25, 33))	('lung tumor', 'Phenotype', 'HP:0100526', (101, 111))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('TGFbeta', 'Gene', '7039', (43, 50))	('EGFR', 'Gene', '1956', (34, 38))
316454	32971741	Global efforts have been made, in order to determine actionable mutations in NSCLC, including The Cancer Genome Atlas (TCGA) project and the Lung Cancer Mutation Consortium (LCMC).	('NSCLC', 'Disease', 'MESH:D002289', (77, 82))	('Lung Cancer', 'Disease', 'MESH:D008175', (141, 152))	('Cancer', 'Phenotype', 'HP:0002664', (98, 104))	('Cancer', 'Disease', (98, 104))	('Cancer', 'Disease', 'MESH:D009369', (98, 104))	('Cancer', 'Phenotype', 'HP:0002664', (146, 152))	('mutations', 'Var', (64, 73))	('Cancer', 'Disease', (146, 152))	('NSCLC', 'Disease', (77, 82))	('Lung Cancer', 'Disease', (141, 152))	('Lung Cancer', 'Phenotype', 'HP:0100526', (141, 152))	('Cancer', 'Disease', 'MESH:D009369', (146, 152))
316455	32971741	TCGA comprehensively mapped mutations and transcriptome changes, as well as their frequency in large sample sets of lung AD and SCC, and demonstrated that mutations in oncogenes such as EGFR, K-RAS, ALK and BRAF occur in >60% of lung AD cases, with driver mutations targetable by tyrosine kinase inhibitors.	('BRAF', 'Gene', (207, 211))	('BRAF', 'Gene', '673', (207, 211))	('ALK', 'Gene', '238', (199, 202))	('K-RAS', 'Gene', (192, 197))	('mutations', 'Var', (155, 164))	('SCC', 'Gene', (128, 131))	('lung AD', 'Disease', (229, 236))	('ALK', 'Gene', (199, 202))	('EGFR', 'Gene', '1956', (186, 190))	('EGFR', 'Gene', (186, 190))	('SCC', 'Gene', '6317', (128, 131))	('lung AD', 'Disease', (116, 123))	('K-RAS', 'Gene', '3845', (192, 197))
316463	32971741	Our data adds to the current literature by showing that deregulated miRNAs modulate a number of genes encoding transcription factors, as well as common driver genes involved in lung tumor development and progression.	('deregulated', 'Var', (56, 67))	('lung tumor', 'Disease', (177, 187))	('lung tumor', 'Disease', 'MESH:D008175', (177, 187))	('modulate', 'Reg', (75, 83))	('miRNAs', 'Gene', (68, 74))	('lung tumor', 'Phenotype', 'HP:0100526', (177, 187))	('men', 'Species', '9606', (195, 198))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
316478	32971741	Two miRNAs (miR-20a-5p and miR-93-5p) had higher expression levels in tumors from smokers compared to non-smokers (p < 0.05).	('expression levels', 'MPA', (49, 66))	('had', 'Gene', (38, 41))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('miR-93', 'Gene', '407051', (27, 33))	('miR-93', 'Gene', (27, 33))	('tumors', 'Disease', (70, 76))	('higher', 'PosReg', (42, 48))	('tumors', 'Disease', 'MESH:D009369', (70, 76))	('had', 'Gene', '23498', (38, 41))	('miR-20a-5p', 'Var', (12, 22))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))
316480	32971741	miR-25-3p overexpression was significantly associated with overall survival, when considering patients with both tumor histologies (Figure 2).	('tumor', 'Disease', (113, 118))	('miR-25-3p', 'Var', (0, 9))	('patients', 'Species', '9606', (94, 102))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('associated', 'Reg', (43, 53))	('overexpression', 'PosReg', (10, 24))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('miR-25-3p', 'Chemical', '-', (0, 9))	('overall survival', 'MPA', (59, 75))
316488	32971741	Interestingly, miRNAs validated in the TCGA dataset (miR-15a-5p, miR-25-3p, miR-205-5p, miR-196b-5p and miR-411-5p) were related to genes in cancer pathways.	('related', 'Reg', (121, 128))	('miR-411', 'Gene', '693121', (104, 111))	('miR-25-3p', 'Chemical', '-', (65, 74))	('miR-205', 'Gene', '406988', (76, 83))	('miR-15a-5p', 'Var', (53, 63))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('miR-25-3p', 'Var', (65, 74))	('miR-411', 'Gene', (104, 111))	('miR-196b', 'Gene', '442920', (88, 96))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('miR-196b', 'Gene', (88, 96))	('cancer', 'Disease', (141, 147))	('miR-205', 'Gene', (76, 83))
316491	32971741	miRNA alterations often lead to target gene deregulation and deregulated signaling pathways with roles in tumor development and progression.	('deregulated', 'Reg', (61, 72))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('lead to', 'Reg', (24, 31))	('signaling pathways', 'Pathway', (73, 91))	('men', 'Species', '9606', (119, 122))	('deregulation', 'Var', (44, 56))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('miRNA', 'Var', (0, 5))	('tumor', 'Disease', (106, 111))
316497	32971741	Deregulated miR-25 expression has been reported in human cancer, and overexpressed in NSCLC primary tumors and cell lines, associated with increased cell proliferation, migration and invasion.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('overexpressed', 'PosReg', (69, 82))	('miR-25', 'Gene', (12, 18))	('Deregulated', 'Var', (0, 11))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('cancer', 'Disease', (57, 63))	('migration', 'CPA', (169, 178))	('increased', 'PosReg', (139, 148))	('NSCLC primary tumors', 'Disease', 'MESH:D001932', (86, 106))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('human', 'Species', '9606', (51, 56))	('NSCLC primary tumors', 'Disease', (86, 106))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('cell proliferation', 'CPA', (149, 167))	('invasion', 'CPA', (183, 191))	('miR-25', 'Gene', '407014', (12, 18))
316512	32971741	Based on TCGA data, pathways activated by EGFR mutations were found in 11% of tumors, K-RAS mutations in 32%, PI3K mutations in 4%, HER2 in 3% and PTEN inactivation in 3% of lung adenocarcinoma samples.	('carcinoma', 'Phenotype', 'HP:0030731', (184, 193))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (174, 193))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('HER2', 'Gene', (132, 136))	('PTEN', 'Gene', (147, 151))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('EGFR', 'Gene', (42, 46))	('inactivation', 'NegReg', (152, 164))	('mutations', 'Var', (47, 56))	('PTEN', 'Gene', '5728', (147, 151))	('tumors', 'Disease', (78, 84))	('HER2', 'Gene', '2064', (132, 136))	('PI3K', 'Var', (110, 114))	('mutations', 'Var', (92, 101))	('K-RAS', 'Gene', (86, 91))	('lung adenocarcinoma', 'Disease', (174, 193))	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('EGFR', 'Gene', '1956', (42, 46))	('K-RAS', 'Gene', '3845', (86, 91))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (174, 193))
316513	32971741	In lung SCC, TCGA data showed that pathways are often activated by mutations in TP53 in 81% of tumors, PI3K in 16%, PTEN in 15%, EGFR in 9%, KRAS in 3% and HER2 in 4% of tumors.	('HER2', 'Gene', (156, 160))	('KRAS', 'Gene', (141, 145))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('PTEN', 'Gene', (116, 120))	('EGFR', 'Gene', (129, 133))	('tumors', 'Disease', (95, 101))	('tumors', 'Disease', 'MESH:D009369', (170, 176))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('TP53', 'Gene', '7157', (80, 84))	('SCC', 'Gene', '6317', (8, 11))	('PTEN', 'Gene', '5728', (116, 120))	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('HER2', 'Gene', '2064', (156, 160))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('pathways', 'Pathway', (35, 43))	('SCC', 'Gene', (8, 11))	('EGFR', 'Gene', '1956', (129, 133))	('tumors', 'Phenotype', 'HP:0002664', (170, 176))	('activated', 'PosReg', (54, 63))	('KRAS', 'Gene', '3845', (141, 145))	('mutations', 'Var', (67, 76))	('TP53', 'Gene', (80, 84))	('tumors', 'Disease', (170, 176))
316514	32971741	Although we did not find mutations associated with miRNA changes, likely due to our small sample set, we identified common, mutually exclusive driver mutations in EGFR, K-RAS and N-RAS.	('EGFR', 'Gene', '1956', (163, 167))	('K-RAS', 'Gene', '3845', (169, 174))	('N-RAS', 'Gene', (179, 184))	('mutations', 'Var', (150, 159))	('EGFR', 'Gene', (163, 167))	('K-RAS', 'Gene', (169, 174))	('N-RAS', 'Gene', '4893', (179, 184))
316515	32971741	In Brazilian patients, mutational frequency of driver genes was reported in a large number of lung adenocarcinoma cases (n = 444), with EGFR mutated in 22.7% and K-RAS in 20.4% of the cases.	('mutated', 'Var', (141, 148))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('lung adenocarcinoma', 'Disease', (94, 113))	('patients', 'Species', '9606', (13, 21))	('K-RAS', 'Gene', '3845', (162, 167))	('K-RAS', 'Gene', (162, 167))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (94, 113))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (94, 113))	('EGFR', 'Gene', '1956', (136, 140))	('EGFR', 'Gene', (136, 140))
316516	32971741	By computational analyses, we showed that deregulated miRNAs modulate a number of genes encoding transcription factors, as well as common driver genes in lung cancer.	('lung cancer', 'Disease', (154, 165))	('lung cancer', 'Phenotype', 'HP:0100526', (154, 165))	('deregulated miRNAs', 'Var', (42, 60))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('miRNAs', 'Var', (54, 60))	('lung cancer', 'Disease', 'MESH:D008175', (154, 165))	('modulate', 'Reg', (61, 69))
316536	32971741	In addition, our data support the existing literature by identifying miRNAs predicted to modulate transcription factors and known driver genes with a role in lung cancer pathways.	('lung cancer', 'Disease', (158, 169))	('lung cancer', 'Phenotype', 'HP:0100526', (158, 169))	('transcription', 'Protein', (98, 111))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('modulate', 'Reg', (89, 97))	('lung cancer', 'Disease', 'MESH:D008175', (158, 169))	('miRNAs', 'Var', (69, 75))
316567	31358054	IFN-beta gene-modified MSCs via systemic administration have also been demonstrated to successfully migrate to the tumor environment and attenuate tumor growth in experimental animal models such as hepatocellular carcinoma, bronchioloalveolar carcinoma, and melanoma.	('tumor', 'Disease', (115, 120))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (198, 222))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('melanoma', 'Disease', 'MESH:D008545', (258, 266))	('tumor', 'Disease', (147, 152))	('gene-modified', 'Var', (9, 22))	('IFN-beta', 'Gene', (0, 8))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('carcinoma', 'Phenotype', 'HP:0030731', (213, 222))	('hepatocellular carcinoma', 'Disease', (198, 222))	('attenuate', 'NegReg', (137, 146))	('bronchioloalveolar carcinoma', 'Disease', (224, 252))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('carcinoma', 'Phenotype', 'HP:0030731', (243, 252))	('melanoma', 'Phenotype', 'HP:0002861', (258, 266))	('melanoma', 'Disease', (258, 266))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('bronchioloalveolar carcinoma', 'Disease', 'MESH:D002282', (224, 252))	('IFN-beta', 'Gene', '3456', (0, 8))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (198, 222))
316581	31358054	GMSCs were incubated with FITC-conjugated mouse monoclonal antibodies specific for human CD73, CD166 (Becton Dickinson Biosciences, CA, USA), and CD90 (R&D Systems, Inc., MN, USA); CD44, CD105, CD14, CD34, and CD45 (eBioscience, CA, USA); or isotype-matched control immunoglobulin Gs.	('CD73', 'Gene', '4907', (89, 93))	('GMSCs', 'Chemical', '-', (0, 5))	('CD45', 'Gene', '5788', (210, 214))	('CD73', 'Gene', (89, 93))	('and', 'Var', (206, 209))	('FITC', 'Chemical', 'MESH:D016650', (26, 30))	('CD34', 'Gene', (200, 204))	('CD90', 'Gene', (146, 150))	('CD166', 'Gene', (95, 100))	('CD14', 'Gene', (194, 198))	('CD14', 'Gene', '929', (194, 198))	('CD90', 'Gene', '7070', (146, 150))	('CD44', 'Gene', '960', (181, 185))	('CD44', 'Gene', (181, 185))	('MN', 'CellLine', 'CVCL:U508', (171, 173))	('CD34', 'Gene', '947', (200, 204))	('mouse', 'Species', '10090', (42, 47))	('human', 'Species', '9606', (83, 88))	('CD166', 'Gene', '214', (95, 100))	('CD45', 'Gene', (210, 214))
316583	31358054	After 28 days of incubation, mineral deposition was detected by Alizarin Red (Sigma-Aldrich, A5533-25G) staining.	('A5533-25G', 'SUBSTITUTION', 'None', (93, 102))	('A5533-25G', 'Var', (93, 102))	('Alizarin Red', 'Chemical', 'MESH:C010078', (64, 76))	('mineral deposition', 'CPA', (29, 47))
316635	31358054	There was no change in cell shape for IFN-beta gene-modified GMSC.	('IFN-beta', 'Gene', '3456', (38, 46))	('gene-modified', 'Var', (47, 60))	('IFN-beta', 'Gene', (38, 46))
316658	31358054	The weights of the dissected tumors in the GMSCs (0.596 +- 0.0941 g), GMSCs/vector (0.614 +- 0.128 g), and GMSCs/IFN-beta groups (0.155 +- 0.0444 g) were significantly decreased compared with the PBS group (1.03 +- 0.237 g) (P < 0.01) (Fig.	('0.614', 'Var', (84, 89))	('IFN-beta', 'Gene', '3456', (113, 121))	('0.155', 'Var', (130, 135))	('decreased', 'NegReg', (168, 177))	('GMSCs', 'Chemical', '-', (43, 48))	('IFN-beta', 'Gene', (113, 121))	('weights', 'CPA', (4, 11))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('tumors', 'Disease', 'MESH:D009369', (29, 35))	('PBS', 'Chemical', '-', (196, 199))	('tumors', 'Disease', (29, 35))	('GMSCs', 'Chemical', '-', (70, 75))	('GMSCs', 'Chemical', '-', (107, 112))
316662	31358054	The results indicated that the number of Ki67-positive cells was significantly higher in the PBS group (125.9 +- 9.04 cells/field) than in the GMSCs (83.6 +- 7.28 cells/field), GMSCs/vector (77.5 +- 8.26 cells/field), or GMSCs/IFN-beta group (44.5 +- 5.84 cells/field) (P < 0.05).	('PBS', 'Chemical', '-', (93, 96))	('GMSCs', 'Chemical', '-', (221, 226))	('Ki67-positive', 'Var', (41, 54))	('PBS', 'Disease', (93, 96))	('GMSCs', 'Chemical', '-', (177, 182))	('IFN-beta', 'Gene', '3456', (227, 235))	('GMSCs', 'Chemical', '-', (143, 148))	('higher', 'PosReg', (79, 85))	('IFN-beta', 'Gene', (227, 235))
316675	31358054	IFN-beta gene-modified MSCs have been demonstrated to possess consistent anticancer effects for multiple tumors, such as bronchioloalveolar carcinoma, ovarian carcinoma, breast cancer, pancreatic cancer, and prostate cancer.	('cancer', 'Disease', (177, 183))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (196, 202))	('prostate cancer', 'Disease', 'MESH:D011471', (208, 223))	('prostate cancer', 'Phenotype', 'HP:0012125', (208, 223))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (185, 202))	('prostate cancer', 'Disease', (208, 223))	('carcinoma', 'Phenotype', 'HP:0030731', (159, 168))	('multiple tumors', 'Disease', (96, 111))	('gene-modified', 'Var', (9, 22))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (151, 168))	('IFN-beta', 'Gene', (0, 8))	('cancer', 'Disease', 'MESH:D009369', (217, 223))	('breast cancer', 'Phenotype', 'HP:0003002', (170, 183))	('ovarian carcinoma', 'Disease', (151, 168))	('pancreatic cancer', 'Disease', 'MESH:D010190', (185, 202))	('cancer', 'Disease', 'MESH:D009369', (177, 183))	('cancer', 'Disease', (77, 83))	('bronchioloalveolar carcinoma', 'Disease', (121, 149))	('breast cancer', 'Disease', 'MESH:D001943', (170, 183))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (151, 168))	('cancer', 'Disease', (196, 202))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('breast cancer', 'Disease', (170, 183))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('pancreatic cancer', 'Disease', (185, 202))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('multiple tumors', 'Disease', 'MESH:D009369', (96, 111))	('IFN-beta', 'Gene', '3456', (0, 8))	('bronchioloalveolar carcinoma', 'Disease', 'MESH:D002282', (121, 149))	('cancer', 'Disease', (217, 223))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))
316682	31358054	IFN-beta gene-modified MSCs displayed consistent anticancer effects for its long-term IFN-beta expression capability.	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('gene-modified', 'Var', (9, 22))	('IFN-beta', 'Gene', '3456', (0, 8))	('IFN-beta', 'Gene', '3456', (86, 94))	('IFN-beta', 'Gene', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('expression', 'MPA', (95, 105))	('IFN-beta', 'Gene', (86, 94))
316687	31358054	Therefore, Ki67 can be used as a tumor cell proliferation and tumor diagnostic marker.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('tumor', 'Disease', (62, 67))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('Ki67', 'Var', (11, 15))	('tumor', 'Disease', (33, 38))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
316702	31358054	In summary, IFN-beta gene-modified GMSCs inhibit the proliferation of TSCC cells in vitro and in vivo.	('IFN-beta', 'Gene', (12, 20))	('TSCC', 'Phenotype', 'HP:0030413', (70, 74))	('proliferation', 'CPA', (53, 66))	('IFN-beta', 'Gene', '3456', (12, 20))	('inhibit', 'NegReg', (41, 48))	('GMSCs', 'Chemical', '-', (35, 40))	('gene-modified', 'Var', (21, 34))
316713	30247749	In a subset analysis of clinically T1-2N0M0 OCSCC, we demonstrate that the MS subtype was predictive of occult nodal metastasis (RR=3.38, 95% CI 1.08-10.69).	('occult nodal', 'Disease', (104, 116))	('T1-2N0M0', 'Var', (35, 43))	('OCSCC', 'Disease', (44, 49))	('OCSCC', 'Disease', 'MESH:D002294', (44, 49))
316736	30247749	Deregulation of the KEAP1/NRF2 oxidative stress pathway appears to be a critical element of carcinogenesis in the classical subtype, and there is growing evidence to suggest that the KEAP1-NRF2 mediated oxidative stress response plays a role in resistance to radiation in several human cancers.	('carcinogenesis', 'Disease', 'MESH:D063646', (92, 106))	('cancers', 'Phenotype', 'HP:0002664', (286, 293))	('NRF2', 'Gene', (189, 193))	('cancers', 'Disease', (286, 293))	('Deregulation', 'Var', (0, 12))	('KEAP1', 'Gene', (20, 25))	('carcinogenesis', 'Disease', (92, 106))	('human', 'Species', '9606', (280, 285))	('cancer', 'Phenotype', 'HP:0002664', (286, 292))	('KEAP1', 'Gene', '9817', (183, 188))	('KEAP1', 'Gene', (183, 188))	('oxidative stress', 'Phenotype', 'HP:0025464', (203, 219))	('oxidative stress', 'Phenotype', 'HP:0025464', (31, 47))	('NRF2', 'Gene', '4780', (26, 30))	('NRF2', 'Gene', (26, 30))	('KEAP1', 'Gene', '9817', (20, 25))	('NRF2', 'Gene', '4780', (189, 193))	('cancers', 'Disease', 'MESH:D009369', (286, 293))
316791	30247749	Another recent analysis of epithelial to mesenchymal transition markers found that high expression of Vimentin was associated with poor disease-specific survival in oral tongue squamous cell carcinoma.	('Vimentin', 'Gene', '7431', (102, 110))	('poor', 'NegReg', (131, 135))	('oral tongue squamous cell carcinoma', 'Disease', 'MESH:D002294', (165, 200))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (177, 200))	('carcinoma', 'Phenotype', 'HP:0030731', (191, 200))	('Vimentin', 'Gene', (102, 110))	('high', 'Var', (83, 87))	('oral tongue squamous cell carcinoma', 'Disease', (165, 200))	('tongue squamous cell carcinoma', 'Phenotype', 'HP:0030413', (170, 200))
316803	30247749	Loss of function mutations in the KEAP1 tumor suppressor gene and activating mutations in the KEAP1 binding domain of NFE2L2 have been described in multiple cancers, and result in the constitutive activation of NRF2.	('multiple cancers', 'Disease', (148, 164))	('KEAP1', 'Gene', (34, 39))	('NRF2', 'Gene', (211, 215))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('mutations', 'Var', (17, 26))	('NFE2L2', 'Gene', (118, 124))	('multiple cancers', 'Disease', 'MESH:D009369', (148, 164))	('KEAP1', 'Gene', '9817', (94, 99))	('cancers', 'Phenotype', 'HP:0002664', (157, 164))	('mutations', 'Var', (77, 86))	('KEAP1', 'Gene', (94, 99))	('tumor', 'Disease', (40, 45))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('NRF2', 'Gene', '4780', (211, 215))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('Loss of function', 'NegReg', (0, 16))	('constitutive activation', 'MPA', (184, 207))	('NFE2L2', 'Gene', '4780', (118, 124))	('KEAP1', 'Gene', '9817', (34, 39))
316814	30247749	KEAP1/NRF2 pathway alterations have been associated with radiation resistance, and may be contributing to the poor survival noted in classical subtype tumors.	('NRF2', 'Gene', (6, 10))	('associated', 'Reg', (41, 51))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('KEAP1', 'Gene', (0, 5))	('radiation resistance', 'CPA', (57, 77))	('tumors', 'Disease', (151, 157))	('tumors', 'Disease', 'MESH:D009369', (151, 157))	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('alterations', 'Var', (19, 30))	('NRF2', 'Gene', '4780', (6, 10))	('KEAP1', 'Gene', '9817', (0, 5))
316840	29966864	The standard treatment for metastatic PCs is androgen-deprivation therapy (ADT); inevitably the cancer mutates to escape the effect of ADT and develops into castration resistant prostate cancer (CRPC).	('cancer', 'Disease', 'MESH:D009369', (187, 193))	('prostate cancer', 'Phenotype', 'HP:0012125', (178, 193))	('PC', 'Phenotype', 'HP:0012125', (38, 40))	('develops', 'Reg', (143, 151))	('cancer', 'Disease', (187, 193))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('prostate cancer', 'Disease', (178, 193))	('ADT', 'Chemical', '-', (135, 138))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('rat', 'Species', '10116', (161, 164))	('ADT', 'Chemical', '-', (75, 78))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('PC', 'Phenotype', 'HP:0012125', (197, 199))	('mutates', 'Var', (103, 110))	('cancer', 'Disease', (96, 102))	('prostate cancer', 'Disease', 'MESH:D011471', (178, 193))
316914	29966864	Castration was associated with an initial decline in serum PSA for 3 weeks, followed with elevations by 4 weeks, indicative of CRPC status.	('decline', 'NegReg', (42, 49))	('PC', 'Phenotype', 'HP:0012125', (129, 131))	('PSA', 'Gene', '354', (59, 62))	('PSA', 'Gene', (59, 62))	('Castration', 'Var', (0, 10))	('rat', 'Species', '10116', (4, 7))	('elevations', 'PosReg', (90, 100))
316929	29966864	This demonstrated that cut-off point-positive PCs were associated with a significant reduction in disease free survival (DFS) (Figure 6C).	('rat', 'Species', '10116', (12, 15))	('reduction in disease', 'Disease', (85, 105))	('PCs', 'Var', (46, 49))	('reduction in disease', 'Disease', 'MESH:D015431', (85, 105))	('PC', 'Phenotype', 'HP:0012125', (46, 48))
316934	29966864	This concept is becoming even more attractive by the recent demonstration that BChE hydrolyzes ghrelin, thus regulating metabolism.	('hydrolyzes', 'Var', (84, 94))	('rat', 'Species', '10116', (67, 70))	('ghrelin', 'Protein', (95, 102))	('regulating', 'Reg', (109, 119))	('ghrelin', 'Chemical', 'MESH:D054439', (95, 102))	('metabolism', 'MPA', (120, 130))
316935	29966864	Alteration of metabolism is a major contributor of tumorigenesis and cancer progression.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('metabolism', 'MPA', (14, 24))	('Alteration', 'Var', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('tumor', 'Disease', (51, 56))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('rat', 'Species', '10116', (4, 7))	('cancer', 'Disease', (69, 75))
316942	29966864	This reverse pattern is supported by a recent report in which ectopic expression of an AR type 3a variant was found to inhibit LNCaP cell proliferation and reduce BChE expression.	('reduce', 'NegReg', (156, 162))	('LNCaP cell proliferation', 'CPA', (127, 151))	('inhibit', 'NegReg', (119, 126))	('variant', 'Var', (98, 105))	('AR type 3a', 'Gene', (87, 97))	('BChE expression', 'MPA', (163, 178))	('LNCaP', 'CellLine', 'CVCL:0395', (127, 132))	('rat', 'Species', '10116', (145, 148))
316967	33931030	This study suggested the role of pseudogenes in tumorigenesis and progression, potentially functioning as therapeutic targets to NPC.	('tumor', 'Disease', (48, 53))	('NPC', 'Phenotype', 'HP:0100630', (129, 132))	('progression', 'CPA', (66, 77))	('NPC', 'Gene', (129, 132))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('pseudogenes', 'Var', (33, 44))	('NPC', 'Gene', '4864', (129, 132))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
316975	33931030	Moreover, these pseudogenes play important roles in tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumor', 'Disease', (52, 57))	('roles', 'Reg', (43, 48))	('pseudogenes', 'Var', (16, 27))	('tumor', 'Disease', 'MESH:D009369', (52, 57))
316982	33931030	These CYP450 pseudogenes participated in arachidonic acid metabolism pathway.	('pseudogenes', 'Var', (13, 24))	('participated', 'Reg', (25, 37))	('arachidonic', 'Enzyme', (41, 52))	('CYP', 'Gene', (6, 9))	('CYP', 'Gene', '4051', (6, 9))	('arachidonic acid', 'Chemical', 'MESH:D016718', (41, 57))
316986	33931030	Thus, the differentially expressed pseudogenes in NPC suggested their unique roles in tumorigenesis and progression.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Disease', (86, 91))	('NPC', 'Phenotype', 'HP:0100630', (50, 53))	('pseudogenes', 'Var', (35, 46))	('NPC', 'Gene', (50, 53))	('NPC', 'Gene', '4864', (50, 53))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
316996	33931030	Sections at 4 mum thickness were prepared and immunostained with antibodies against CKpan, P63, P40, KI67, LCA, EGFR, P16 and 34betaE12, as well as by in situ hybridization for EBV-encoded RNAs (EBERs) to determine the EBV positivity.	('EGFR', 'Gene', (112, 116))	('LCA', 'Gene', (107, 110))	('EBV', 'Species', '10376', (219, 222))	('EBV', 'Species', '10376', (177, 180))	('P63', 'Gene', (91, 94))	('LCA', 'Gene', '5788', (107, 110))	('P40', 'Gene', (96, 99))	('P63', 'Gene', '8626', (91, 94))	('EGFR', 'Gene', '1956', (112, 116))	('CKpan', 'Gene', (84, 89))	('P40', 'Gene', '3578', (96, 99))	('CKpan', 'Chemical', '-', (84, 89))	('P16', 'Gene', (118, 121))	('P16', 'Gene', '1029', (118, 121))	('KI67', 'Var', (101, 105))
317017	33931030	All primary NPC samples (13/13) were positively immunostained with CKpan, P63, P40, KI67 and EGFR, but negatively with LCA.	('KI67', 'Var', (84, 88))	('EGFR', 'Gene', '1956', (93, 97))	('NPC', 'Gene', (12, 15))	('P63', 'Gene', (74, 77))	('NPC', 'Phenotype', 'HP:0100630', (12, 15))	('P40', 'Gene', (79, 82))	('EGFR', 'Gene', (93, 97))	('LCA', 'Gene', (119, 122))	('NPC', 'Gene', '4864', (12, 15))	('P40', 'Gene', '3578', (79, 82))	('LCA', 'Gene', '5788', (119, 122))	('P63', 'Gene', '8626', (74, 77))	('CKpan', 'Gene', (67, 72))	('CKpan', 'Chemical', '-', (67, 72))
317024	33931030	The top 10 upregulated pseudogenes were HNRNPA1P21, AACSP1, FCGR1CP, CCR5, CXCR2P1, AC097527.1, OR7E28P, CCNYL2, IGKV2OR22-4 and GBP1P1 (Fig.	('FCGR1CP', 'Gene', (60, 67))	('FCGR1CP', 'Gene', '100132417', (60, 67))	('OR7E28P', 'Gene', '26645', (96, 103))	('IGKV2OR22-4', 'Gene', (113, 124))	('AACSP1', 'Gene', (52, 58))	('IGKV2OR22-4', 'Gene', '28847', (113, 124))	('CXCR2P1', 'Gene', (75, 82))	('GBP1P1', 'Gene', '400759', (129, 135))	('CCR5', 'Gene', '1234', (69, 73))	('upregulated', 'PosReg', (11, 22))	('CXCR2P1', 'Gene', '3580', (75, 82))	('GBP1P1', 'Gene', (129, 135))	('AACSP1', 'Gene', '729522', (52, 58))	('CCR5', 'Gene', (69, 73))	('HNRNPA1P21', 'Gene', '344697', (40, 50))	('CCNYL2', 'Gene', '414194', (105, 111))	('HNRNPA1P21', 'Gene', (40, 50))	('OR7E28P', 'Gene', (96, 103))	('CCNYL2', 'Gene', (105, 111))	('AC097527.1', 'Var', (84, 94))
317025	33931030	2a, marked by rectangles), while the top 10 downregulated ones were STRA6LP, AC084879.1, AC116562.4, RNU6-696P, OR7E155P, RPS3AP15, AC104852.1, FRMPD2B, AC139769.1 and AC105233.3 (Fig.	('OR7E155P', 'Gene', '403297', (112, 120))	('AC084879.1', 'Var', (77, 87))	('FRMPD2B', 'Gene', (144, 151))	('AC116562.4', 'Var', (89, 99))	('STRA6LP', 'Gene', (68, 75))	('OR7E155P', 'Gene', (112, 120))	('RPS3AP15', 'Gene', '652670', (122, 130))	('RPS3AP15', 'Gene', (122, 130))	('AC139769.1', 'Var', (153, 163))	('RNU6', 'Gene', '26827', (101, 105))	('AC104852.1', 'Var', (132, 142))	('FRMPD2B', 'Gene', '728798', (144, 151))	('AC105233.3', 'Var', (168, 178))	('RNU6', 'Gene', (101, 105))	('STRA6LP', 'Gene', '112272565', (68, 75))
317026	33931030	The top 20 enriched GO terms of up-regulated pseudogenes belonged to BP and MF classes, while 18 of the top 20 GO terms were associated with BP class of Fc-gamma receptor, immune system process and other related signaling pathway terms (Fig.S2).	('Fc-gamma receptor', 'Gene', (153, 170))	('up-regulated', 'PosReg', (32, 44))	('Fc-gamma receptor', 'Gene', '2209', (153, 170))	('pseudogenes', 'Var', (45, 56))
317028	33931030	The significantly down-regulated pseudogenes CYP2F2P, CYP2G1P, CYP4F24P, CYP2B7P and CYP2G2P were enriched into another 7 GO terms, including arachidonic acid metabolic process (GO:0019369), epoxygenase P450 pathway (GO:0019373), unsaturated fatty acid metabolic process (GO:0033559) and others that were shown in GO chord plot (Fig.	('CYP4F24P', 'Gene', (63, 71))	('CYP2G1P', 'Gene', (54, 61))	('CYP4F24P', 'Gene', '388514', (63, 71))	('arachidonic acid', 'Chemical', 'MESH:D016718', (142, 158))	('GO:0033559', 'Var', (272, 282))	('CYP2B7P', 'Gene', '1556', (73, 80))	('unsaturated fatty acid metabolic process', 'Enzyme', (230, 270))	('CYP2G2P', 'Gene', (85, 92))	('CYP2G1P', 'Gene', '22952', (54, 61))	('unsaturated fatty acid', 'Chemical', 'MESH:D005231', (230, 252))	('CYP2G2P', 'Gene', '83757', (85, 92))	('epoxygenase P450 pathway', 'Enzyme', (191, 215))	('down-regulated', 'NegReg', (18, 32))	('arachidonic acid metabolic process', 'Enzyme', (142, 176))	('CYP2B7P', 'Gene', (73, 80))	('CYP2F2P', 'Gene', '171427', (45, 52))	('GO:0019373', 'Var', (217, 227))	('CYP2F2P', 'Gene', (45, 52))
317031	33931030	We performed KEGG pathway enrichment analysis on differentially expressed pseudogenes and filtrated out three most statistically significant pathways participated by down-regulated pseudogenes, including arachidonic acid metabolism (map 00590), olfactory transduction (map 04740) and fat digestion and absorption (map 04975).	('pseudogenes', 'Var', (181, 192))	('olfactory', 'MPA', (245, 254))	('arachidonic acid metabolism', 'MPA', (204, 231))	('arachidonic acid', 'Chemical', 'MESH:D016718', (204, 220))	('down-regulated', 'NegReg', (166, 180))	('map 00590', 'Var', (233, 242))	('map 04975', 'Var', (314, 323))	('map 04740', 'Var', (269, 278))	('fat', 'CPA', (284, 287))
317032	33931030	The down-regulated pseudogenes involved in arachidonic acid metabolism pathway were AC136433.1, CYP4F26P, AC145285.4, AL390726.5 and CYP2B7P (Fig.S3).	('AC136433.1', 'Var', (84, 94))	('CYP2B7P', 'Gene', (133, 140))	('CYP4F26P', 'Gene', (96, 104))	('CYP4F26P', 'Gene', '106478958', (96, 104))	('CYP2B7P', 'Gene', '1556', (133, 140))	('down-regulated', 'NegReg', (4, 18))	('arachidonic acid', 'Chemical', 'MESH:D016718', (43, 59))	('AL390726', 'Chemical', '-', (118, 126))	('AC145285.4', 'Var', (106, 116))	('AL390726.5', 'Var', (118, 128))
317035	33931030	The significantly up-regulated pseudogenes in KEGG chord plot included HLA-DPA3, IGHV1OR15-2, IGHV3-11, FCGR1CP and IGHV3-69-1 (Fig.	('IGHV3-11', 'Gene', (94, 102))	('IGHV3-69-1', 'Gene', (116, 126))	('IGHV3-69-1', 'Gene', '28402', (116, 126))	('up-regulated', 'PosReg', (18, 30))	('pseudogenes', 'Var', (31, 42))	('IGHV3-11', 'Gene', '28450;102723407', (94, 102))	('HLA-DPA3', 'Gene', '267013', (71, 79))	('IGHV1OR15-2', 'Gene', '100287128', (81, 92))	('IGHV1OR15-2', 'Gene', (81, 92))	('FCGR1CP', 'Gene', (104, 111))	('FCGR1CP', 'Gene', '100132417', (104, 111))	('HLA-DPA3', 'Gene', (71, 79))
317038	33931030	Significantly up-regulated pseudogenes such as IGHV1OR15-2, IGHV3-11, FCGR1CP and IGHV3-69-1 belonged to or regulated Fc gamma receptor.	('up-regulated', 'PosReg', (14, 26))	('IGHV3-11', 'Gene', (60, 68))	('IGHV3-69-1', 'Gene', (82, 92))	('Fc gamma receptor', 'Gene', (118, 135))	('IGHV3-69-1', 'Gene', '28402', (82, 92))	('pseudogenes', 'Var', (27, 38))	('IGHV3-11', 'Gene', '28450;102723407', (60, 68))	('FCGR1CP', 'Gene', (70, 77))	('IGHV1OR15-2', 'Gene', '100287128', (47, 58))	('Fc gamma receptor', 'Gene', '2209', (118, 135))	('FCGR1CP', 'Gene', '100132417', (70, 77))	('IGHV1OR15-2', 'Gene', (47, 58))
317040	33931030	Significantly down-regulated pseudogenes, such as AC136433.1, CYP4F26P, AC145285.4, AL390726.5 and CYP2B7P were involved in epoxygenase P450 pathway and participated in arachidonic acid metabolic process (Figs.	('AL390726', 'Chemical', '-', (84, 92))	('arachidonic acid metabolic process', 'Enzyme', (169, 203))	('arachidonic acid', 'Chemical', 'MESH:D016718', (169, 185))	('CYP2B7P', 'Gene', (99, 106))	('epoxygenase P450 pathway', 'Enzyme', (124, 148))	('AC136433.1', 'Var', (50, 60))	('down-regulated', 'NegReg', (14, 28))	('CYP4F26P', 'Gene', (62, 70))	('CYP2B7P', 'Gene', '1556', (99, 106))	('CYP4F26P', 'Gene', '106478958', (62, 70))	('AL390726.5', 'Var', (84, 94))	('participated', 'Reg', (153, 165))	('AC145285.4', 'Var', (72, 82))
317041	33931030	These down-regulated pseudogenes were mapped into the arachidonic acid metabolism KEGG pathway (Fig.	('down-regulated', 'NegReg', (6, 20))	('pseudogenes', 'Var', (21, 32))	('arachidonic acid', 'Chemical', 'MESH:D016718', (54, 70))	('arachidonic', 'Pathway', (54, 65))
317044	33931030	In order to validate this hypothesis, we plotted correlation among CYP2B7P and CYP4F26P, CYP2F2P, AC136443.1 and AC145285.4, illustrating a constitutive association among expression levels of CYP2B7P, CYP2F2P, CYP4F26P, AC136443.1 and AC145285.4 (Fig.	('CYP2B7P', 'Gene', (67, 74))	('CYP2B7P', 'Gene', '1556', (67, 74))	('CYP2F2P', 'Gene', '171427', (201, 208))	('CYP4F26P', 'Gene', (79, 87))	('AC145285.4', 'Var', (235, 245))	('CYP2B7P', 'Gene', (192, 199))	('CYP4F26P', 'Gene', (210, 218))	('CYP2F2P', 'Gene', (201, 208))	('CYP2F2P', 'Gene', '171427', (89, 96))	('CYP4F26P', 'Gene', '106478958', (210, 218))	('CYP2B7P', 'Gene', '1556', (192, 199))	('CYP4F26P', 'Gene', '106478958', (79, 87))	('CYP2F2P', 'Gene', (89, 96))	('AC136443.1', 'Var', (220, 230))
317056	33931030	In this study, we detected 251 differentially expressed pseudogenes between primary NPC and paracancerous control tissues.	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('NPC', 'Gene', (84, 87))	('NPC', 'Phenotype', 'HP:0100630', (84, 87))	('pseudogenes', 'Var', (56, 67))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('NPC', 'Gene', '4864', (84, 87))	('cancer', 'Disease', (96, 102))
317057	33931030	CYP450 pseudogenes were significantly down-regulated, while pseudogenes of Fc gamma receptors were up-regulated in NPC tissues.	('Fc gamma receptor', 'Gene', (75, 92))	('NPC', 'Gene', (115, 118))	('down-regulated', 'NegReg', (38, 52))	('NPC', 'Phenotype', 'HP:0100630', (115, 118))	('up-regulated', 'PosReg', (99, 111))	('CYP', 'Gene', (0, 3))	('NPC', 'Gene', '4864', (115, 118))	('CYP', 'Gene', '4051', (0, 3))	('Fc gamma receptor', 'Gene', '2209', (75, 92))	('pseudogenes', 'Var', (60, 71))
317060	33931030	Thus, pseudogenes might participate in the tumorigenesis of NPC.	('pseudogenes', 'Var', (6, 17))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('NPC', 'Gene', (60, 63))	('NPC', 'Phenotype', 'HP:0100630', (60, 63))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('participate', 'Reg', (24, 35))	('tumor', 'Disease', (43, 48))	('NPC', 'Gene', '4864', (60, 63))
317062	33931030	Some of them contribute to the activation of pre-carcinogens with genetic polymorphism that have been implicated in susceptibility to NPC.	('genetic polymorphism', 'Var', (66, 86))	('NPC', 'Phenotype', 'HP:0100630', (134, 137))	('NPC', 'Gene', (134, 137))	('activation', 'PosReg', (31, 41))	('NPC', 'Gene', '4864', (134, 137))
317067	33931030	However, very limited study reported whether CYP450 pseudogenes were associated with NPC tumorigenesis.	('CYP', 'Gene', '4051', (45, 48))	('associated', 'Reg', (69, 79))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('pseudogenes', 'Var', (52, 63))	('NPC', 'Phenotype', 'HP:0100630', (85, 88))	('CYP', 'Gene', (45, 48))	('NPC', 'Gene', (85, 88))	('NPC', 'Gene', '4864', (85, 88))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
317074	33931030	6), these findings suggest that CYP450 pseudogenes are correlated with disease diagnosis and prognosis.	('pseudogenes', 'Var', (39, 50))	('correlated', 'Reg', (55, 65))	('CYP', 'Gene', (32, 35))	('CYP', 'Gene', '4051', (32, 35))
317075	33931030	Our work provided evidence to support the potential role of CYP450 pseudogenes in NPC tumorigenesis, thus supplementing the function of CYP450 in cancer pathogenesis and progression.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('CYP', 'Gene', (60, 63))	('tumor', 'Disease', (86, 91))	('CYP', 'Gene', '4051', (60, 63))	('NPC', 'Phenotype', 'HP:0100630', (82, 85))	('CYP', 'Gene', (136, 139))	('NPC', 'Gene', (82, 85))	('NPC', 'Gene', '4864', (82, 85))	('CYP', 'Gene', '4051', (136, 139))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('pseudogenes', 'Var', (67, 78))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
317082	33931030	Critical factors taking part in arachidonic acid metabolism regulate tumor growth and therapeutic resistance, such as Acyl-CoA synthetase 4 (ACSL4) in prostate tumor, hypermethylated genes in esophageal squamous cell carcinoma, the coding gene of epoxide hydrolase 2 (EPHX2) in prostate cancer, 12-lipoxygenase (12LOX) in ovarian cancer, etc.	('ACSL4', 'Gene', '2182', (141, 146))	('ovarian cancer', 'Disease', (322, 336))	('cancer', 'Phenotype', 'HP:0002664', (287, 293))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('12-lipoxygenase', 'Gene', (295, 310))	('ovarian cancer', 'Phenotype', 'HP:0100615', (322, 336))	('epoxide hydrolase 2', 'Gene', '2053', (247, 266))	('Acyl-CoA synthetase 4', 'Gene', (118, 139))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('12LOX', 'Gene', '246', (312, 317))	('EPHX2', 'Gene', (268, 273))	('esophageal squamous cell carcinoma', 'Disease', (192, 226))	('12LOX', 'Gene', (312, 317))	('epoxide hydrolase 2', 'Gene', (247, 266))	('12-lipoxygenase', 'Gene', '246', (295, 310))	('prostate tumor', 'Disease', (151, 165))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (203, 226))	('ACSL4', 'Gene', (141, 146))	('prostate tumor', 'Disease', 'MESH:D011471', (151, 165))	('prostate cancer', 'Disease', 'MESH:D011471', (278, 293))	('hypermethylated genes', 'Var', (167, 188))	('arachidonic acid', 'Chemical', 'MESH:D016718', (32, 48))	('prostate cancer', 'Phenotype', 'HP:0012125', (278, 293))	('EPHX2', 'Gene', '2053', (268, 273))	('tumor', 'Disease', (160, 165))	('prostate tumor', 'Phenotype', 'HP:0100787', (151, 165))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (192, 226))	('prostate cancer', 'Disease', (278, 293))	('ovarian cancer', 'Disease', 'MESH:D010051', (322, 336))	('cancer', 'Phenotype', 'HP:0002664', (330, 336))	('tumor', 'Disease', (69, 74))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('Acyl-CoA synthetase 4', 'Gene', '2182', (118, 139))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (217, 226))
317085	33931030	The polymorphism of Cyclooxygenase-2 (Cox-2), a key enzyme in the conversion of arachidonic acid to prostaglandins is proved to mediate susceptibility to NPC.	('Cox-2', 'Gene', (38, 43))	('susceptibility', 'Reg', (136, 150))	('arachidonic acid', 'Chemical', 'MESH:D016718', (80, 96))	('NPC', 'Gene', '4864', (154, 157))	('Cyclooxygenase-2', 'Gene', '5743', (20, 36))	('prostaglandins', 'Chemical', 'MESH:D011453', (100, 114))	('NPC', 'Phenotype', 'HP:0100630', (154, 157))	('Cyclooxygenase-2', 'Gene', (20, 36))	('NPC', 'Gene', (154, 157))	('mediate', 'Reg', (128, 135))	('Cox-2', 'Gene', '5743', (38, 43))	('polymorphism', 'Var', (4, 16))
317086	33931030	Our data showed that down-regulated CYP450 pseudogenes were mapped into the arachidonic acid metabolism pathway, suggesting the potential role of arachidonic acid pathway in regulation of NPC tumorigenesis.	('NPC', 'Gene', '4864', (188, 191))	('pseudogenes', 'Var', (43, 54))	('tumor', 'Disease', (192, 197))	('arachidonic acid', 'Chemical', 'MESH:D016718', (146, 162))	('arachidonic acid metabolism pathway', 'Enzyme', (76, 111))	('CYP', 'Gene', '4051', (36, 39))	('arachidonic acid', 'Chemical', 'MESH:D016718', (76, 92))	('down-regulated', 'NegReg', (21, 35))	('NPC', 'Gene', (188, 191))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('NPC', 'Phenotype', 'HP:0100630', (188, 191))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('CYP', 'Gene', (36, 39))
317094	33931030	Thus, the differential pseudogenes expression pattern might lead to the NPC relapse.	('pseudogenes', 'Var', (23, 34))	('NPC', 'Gene', (72, 75))	('NPC', 'Phenotype', 'HP:0100630', (72, 75))	('lead to', 'Reg', (60, 67))	('NPC', 'Gene', '4864', (72, 75))
317097	33931030	In summary, we displayed a RNA-seq analysis on pseudogene expression in NPC and paracancerous tissues.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('NPC', 'Gene', (72, 75))	('NPC', 'Phenotype', 'HP:0100630', (72, 75))	('cancer', 'Disease', (84, 90))	('NPC', 'Gene', '4864', (72, 75))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('pseudogene', 'Var', (47, 57))
317108	33299035	Mutation in tumor suppressor genes (KEAP1, PBRM1) and genes involved in extrinsic apoptosis (CASP8), antigen-presentation (HLA-A, HLA-B), immune regulation (SMAD4) or DNA repair (BRCA1, BRCA2, TP53BP1) correlated with TLS alteration in multiple tumor types, indicating the interaction between mutation landscape and TLS formation.	('KEAP1', 'Gene', (36, 41))	('TP53BP1', 'Gene', (193, 200))	('PBRM1', 'Gene', (43, 48))	('BRCA1', 'Gene', (179, 184))	('BRCA', 'Phenotype', 'HP:0003002', (186, 190))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('SMAD4', 'Gene', (157, 162))	('BRCA2', 'Gene', '675', (186, 191))	('tumor', 'Disease', (12, 17))	('TLS alteration', 'Disease', (218, 232))	('correlated', 'Reg', (202, 212))	('HLA-B', 'Gene', '3106', (130, 135))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('CASP8', 'Gene', '841', (93, 98))	('HLA-A', 'Gene', (123, 128))	('SMAD4', 'Gene', '4089', (157, 162))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('CASP8', 'Gene', (93, 98))	('tumor', 'Disease', (245, 250))	('HLA-B', 'Gene', (130, 135))	('BRCA2', 'Gene', (186, 191))	('TP53BP1', 'Gene', '7158', (193, 200))	('tumor', 'Disease', 'MESH:D009369', (245, 250))	('HLA-A', 'Gene', '3105', (123, 128))	('PBRM1', 'Gene', '55193', (43, 48))	('Mutation', 'Var', (0, 8))	('KEAP1', 'Gene', '9817', (36, 41))	('BRCA', 'Phenotype', 'HP:0003002', (179, 183))	('BRCA1', 'Gene', '672', (179, 184))
317114	33299035	The presence of TLS had been reported to be associated with favorable prognosis in multiple solid tumors, which might be associated with their capacity in inducing a long-lasting antitumor response.	('tumors', 'Disease', (98, 104))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('inducing', 'Reg', (155, 163))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumors', 'Disease', 'MESH:D009369', (98, 104))	('TLS', 'Gene', (16, 19))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumor', 'Disease', (183, 188))	('tumor', 'Disease', (98, 103))	('presence', 'Var', (4, 12))
317140	33299035	Among all the tumor sample applied to the viral detection, the presence of viral genome was frequently observed in certain tumor types including BLCA, CESC, CRC, HNSC, LIHC and STAD.	('BLCA', 'Disease', (145, 149))	('tumor', 'Disease', (14, 19))	('tumor', 'Disease', (123, 128))	('HNSC', 'Disease', (162, 166))	('presence', 'Reg', (63, 71))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('BLCA', 'Phenotype', 'HP:0002862', (145, 149))	('CRC', 'Disease', (157, 160))	('CESC', 'Disease', (151, 155))	('STAD', 'Disease', (177, 181))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('CRC', 'Phenotype', 'HP:0003003', (157, 160))	('viral genome', 'Var', (75, 87))	('observed', 'Reg', (103, 111))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('LIHC', 'Disease', (168, 172))
317151	33299035	Genomic alteration of certain oncogenic pathway of tumor cells can help shape the immune microenvironment as the intrinsic factors.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('Genomic alteration', 'Var', (0, 18))	('tumor', 'Disease', (51, 56))	('oncogenic pathway', 'Pathway', (30, 47))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
317153	33299035	We therefore asked whether driver gene mutations were associated with TLS density in tumor microenvironment.	('tumor', 'Disease', (85, 90))	('mutations', 'Var', (39, 48))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('associated', 'Reg', (54, 64))
317154	33299035	By focusing on the known driver genes with annotated mutation information (gain-of-function, loss-of-function, switch-of-function), we first identified 35 driver genes whose mutation significantly correlated with alteration in TLS signature expression in pan-cancer (P < 0.01).	('cancer', 'Disease', 'MESH:D009369', (259, 265))	('mutation', 'Var', (174, 182))	('expression', 'MPA', (241, 251))	('correlated', 'Reg', (197, 207))	('cancer', 'Phenotype', 'HP:0002664', (259, 265))	('TLS signature', 'Gene', (227, 240))	('alteration', 'Reg', (213, 223))	('cancer', 'Disease', (259, 265))
317157	33299035	Higher TLS scoring was also associated with loss-of-function mutations in tumor suppressor genes (KEAP1, PBRM1), genes involved in extrinsic apoptosis (CASP8), antigen-presentation (HLA-A, HLA-B) or immune regulation (SMAD4), indicating the mechanism by which the tumor cells survive or escape the immune surveillance.	('KEAP1', 'Gene', (98, 103))	('PBRM1', 'Gene', '55193', (105, 110))	('tumor', 'Disease', (74, 79))	('CASP8', 'Gene', (152, 157))	('HLA-B', 'Gene', (189, 194))	('PBRM1', 'Gene', (105, 110))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Disease', (264, 269))	('HLA-A', 'Gene', '3105', (182, 187))	('tumor', 'Disease', 'MESH:D009369', (264, 269))	('TLS', 'Disease', (7, 10))	('SMAD4', 'Gene', (218, 223))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('mutations', 'Var', (61, 70))	('HLA-B', 'Gene', '3106', (189, 194))	('tumor', 'Phenotype', 'HP:0002664', (264, 269))	('Higher', 'PosReg', (0, 6))	('HLA-A', 'Gene', (182, 187))	('CASP8', 'Gene', '841', (152, 157))	('SMAD4', 'Gene', '4089', (218, 223))	('KEAP1', 'Gene', '9817', (98, 103))	('loss-of-function', 'NegReg', (44, 60))
317158	33299035	Mutation in a few genes like IDH1, NRAS, CTNNB1 etc.	('NRAS', 'Gene', (35, 39))	('IDH1', 'Gene', (29, 33))	('Mutation', 'Var', (0, 8))	('CTNNB1', 'Gene', (41, 47))	('NRAS', 'Gene', '4893', (35, 39))	('IDH1', 'Gene', '3417', (29, 33))	('CTNNB1', 'Gene', '1499', (41, 47))
317164	33299035	Tumors with high TLS scoring also exhibited tendency of improved survival in BRCA, LIHC, UCEC, although the association of which failed to achieve statistical significance.	('high', 'Var', (12, 16))	('BRCA', 'Disease', (77, 81))	('improved', 'PosReg', (56, 64))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('UCEC', 'Disease', (89, 93))	('TLS', 'Gene', (17, 20))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('BRCA', 'Phenotype', 'HP:0003002', (77, 81))	('LIHC', 'Disease', (83, 87))
317167	33299035	Similarly, tumor with high TLS exhibited significant improved overall survival in LIHC (P = 0.051, Fig.	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('high TLS', 'Var', (22, 30))	('tumor', 'Disease', (11, 16))	('LIHC', 'Disease', (82, 86))	('improved', 'PosReg', (53, 61))	('tumor', 'Disease', 'MESH:D009369', (11, 16))
317176	33299035	Patients with high TLS scoring also demonstrated significant improved overall survival (P = 0.024) (Fig.	('improved', 'PosReg', (61, 69))	('overall survival', 'MPA', (70, 86))	('TLS', 'Gene', (19, 22))	('high', 'Var', (14, 18))	('Patients', 'Species', '9606', (0, 8))
317179	33299035	Also, NSCLC patients with high TLS scoring were associated with significantly prolonged progression-free survival (P < 0.0001) (Fig.	('patients', 'Species', '9606', (12, 20))	('NSCLC', 'Disease', 'MESH:D002289', (6, 11))	('high', 'Var', (26, 30))	('NSCLC', 'Phenotype', 'HP:0030358', (6, 11))	('progression-free survival', 'CPA', (88, 113))	('TLS', 'Gene', (31, 34))	('NSCLC', 'Disease', (6, 11))	('prolonged', 'PosReg', (78, 87))
317183	33299035	Our findings suggested that neoantigen load, oncovirus infection and diver gene mutations may play a role in the formation of TLS, which in turn also interact with tumor cells and help to shape the oncogene mutation landscape across different tumor types.	('tumor', 'Disease', (164, 169))	('mutations', 'Var', (80, 89))	('interact', 'Reg', (150, 158))	('tumor', 'Disease', 'MESH:D009369', (243, 248))	('diver gene', 'Gene', (69, 79))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('oncovirus infection', 'Disease', (45, 64))	('oncovirus infection', 'Disease', 'MESH:D007239', (45, 64))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))	('tumor', 'Disease', (243, 248))
317201	33299035	Also, tumor types with high mutation/neoantigen load tend to have higher expression of TLS signature.	('mutation/neoantigen', 'Var', (28, 47))	('TLS signature', 'Protein', (87, 100))	('tumor', 'Disease', 'MESH:D009369', (6, 11))	('expression', 'MPA', (73, 83))	('higher', 'PosReg', (66, 72))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('tumor', 'Disease', (6, 11))
317203	33299035	Certain oncogenic events caused by driver gene mutation like CTNNB1, FGFR3 etc.	('CTNNB1', 'Gene', (61, 67))	('caused', 'Reg', (25, 31))	('FGFR3', 'Gene', '2261', (69, 74))	('mutation', 'Var', (47, 55))	('FGFR3', 'Gene', (69, 74))	('CTNNB1', 'Gene', '1499', (61, 67))
317208	33299035	Of note, a recent study had demonstrated the involvement of caspase-8 (encoded by CASP8) in the cleavage of immune regulator, RIPK1, the accumulation of which can cause autoinflammatory diseases.	('autoinflammatory diseases', 'Disease', (169, 194))	('caspase-8', 'Gene', (60, 69))	('CASP8', 'Gene', (82, 87))	('CASP8', 'Gene', '841', (82, 87))	('caspase-8', 'Gene', '841', (60, 69))	('RIPK1', 'Gene', (126, 131))	('autoinflammatory diseases', 'Disease', 'MESH:D056660', (169, 194))	('cleavage', 'MPA', (96, 104))	('RIPK1', 'Gene', '8737', (126, 131))	('involvement', 'Reg', (45, 56))	('accumulation', 'Var', (137, 149))	('cause', 'Reg', (163, 168))
317209	33299035	Thus, overexpression of TLS signature in tumor with genomic loss in CASP8 could also be associated with its immune dysregulation function.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('immune dysregulation function', 'MPA', (108, 137))	('CASP8', 'Gene', (68, 73))	('tumor', 'Disease', (41, 46))	('CASP8', 'Gene', '841', (68, 73))	('genomic loss', 'Var', (52, 64))	('immune dysregulation', 'Phenotype', 'HP:0002958', (108, 128))	('overexpression', 'PosReg', (6, 20))	('associated', 'Reg', (88, 98))	('tumor', 'Disease', 'MESH:D009369', (41, 46))
317210	33299035	Tumors with high TLS scoring were also frequently correlated with loss of function mutation on genes associated with antigen presentation, like HLA-A, HLA-B, or genes involved in immune regulation like SMAD4, which could be the mechanism by which tumor cells escape the immune surveillance.	('tumor', 'Phenotype', 'HP:0002664', (247, 252))	('HLA-B', 'Gene', (151, 156))	('SMAD4', 'Gene', '4089', (202, 207))	('HLA-B', 'Gene', '3106', (151, 156))	('tumor', 'Disease', (247, 252))	('HLA-A', 'Gene', '3105', (144, 149))	('loss of function', 'NegReg', (66, 82))	('HLA-A', 'Gene', (144, 149))	('mutation', 'Var', (83, 91))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('SMAD4', 'Gene', (202, 207))	('tumor', 'Disease', 'MESH:D009369', (247, 252))
317211	33299035	Intriguingly, several genes associated with DNA repair, like BRCA1, BRCA2 and TP53BP1, were also frequently mutated (loss-of-function) in tumors with high TLS scoring.	('mutated', 'Var', (108, 115))	('BRCA1', 'Gene', (61, 66))	('BRCA2', 'Gene', '675', (68, 73))	('TP53BP1', 'Gene', '7158', (78, 85))	('TP53BP1', 'Gene', (78, 85))	('tumors', 'Disease', (138, 144))	('loss-of-function', 'NegReg', (117, 133))	('tumors', 'Disease', 'MESH:D009369', (138, 144))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('BRCA', 'Phenotype', 'HP:0003002', (68, 72))	('BRCA', 'Phenotype', 'HP:0003002', (61, 65))	('BRCA2', 'Gene', (68, 73))	('BRCA1', 'Gene', '672', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
317212	33299035	We speculated that high TLS density in tumors with mutated BRCA1, BRCA2 or TP53BP1 could be attributed to the genomic instability and the subsequent increase in mutation burden.	('BRCA2', 'Gene', (66, 71))	('BRCA1', 'Gene', '672', (59, 64))	('BRCA', 'Phenotype', 'HP:0003002', (66, 70))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('TP53BP1', 'Gene', (75, 82))	('increase', 'PosReg', (149, 157))	('high', 'PosReg', (19, 23))	('BRCA1', 'Gene', (59, 64))	('BRCA2', 'Gene', '675', (66, 71))	('TP53BP1', 'Gene', '7158', (75, 82))	('TLS density', 'MPA', (24, 35))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('mutation burden', 'MPA', (161, 176))	('tumors', 'Disease', (39, 45))	('BRCA', 'Phenotype', 'HP:0003002', (59, 63))	('mutated', 'Var', (51, 58))
317218	33299035	We also found that tumor subtypes with copy number alteration (CN low or CN high) demonstrated significantly lower TLS scoring as compared to MSI (hypermutated) subtype and POLE (ultramutated) subtype.	('TLS scoring', 'MPA', (115, 126))	('lower', 'NegReg', (109, 114))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('copy number alteration', 'Var', (39, 61))	('tumor', 'Disease', (19, 24))
317220	33299035	We didn't observe any survival benefit in lung cancers with high TLS scoring, which though had been reported in published studies.	('lung cancers', 'Disease', (42, 54))	('high TLS scoring', 'Var', (60, 76))	('cancers', 'Phenotype', 'HP:0002664', (47, 54))	('lung cancers', 'Disease', 'MESH:D008175', (42, 54))	('lung cancer', 'Phenotype', 'HP:0100526', (42, 53))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('lung cancers', 'Phenotype', 'HP:0100526', (42, 54))
317287	32150096	Among them, cardia lymph nodes (0/2), esophageal lymph nodes (0/13); immunohistochemistry (IHC): EGFR (+), P53 (80%+), Ki67 (70%+); Tumor Node Metastasis (TNM) staging was pT1bN0M0, stage I. Twenty months later, he unconsciously found mass on the left neck.	('P53', 'Gene', '7157', (107, 110))	('pT1bN0M0', 'Var', (172, 180))	('cardia lymph', 'Disease', 'MESH:D004938', (12, 24))	('EGFR', 'Gene', '1956', (97, 101))	('EGFR', 'Gene', (97, 101))	('Tumor', 'Phenotype', 'HP:0002664', (132, 137))	('P53', 'Gene', (107, 110))	('cardia lymph', 'Disease', (12, 24))
317288	32150096	Only left cervical lymph nodes (size: 4.7 x 3.7 cm) showed hypermetabolism by whole body Positron Emission Computed Tomography (PET-CT) (February 23, 2017), squamous cell carcinoma was verified by needle biopsy, so it was diagnosed as solitary left cervical lymph node metastasis, at this time, the TNM stage of the patient was cT0N0M1, stage IV.	('cervical lymph node metastasis', 'Phenotype', 'HP:0025289', (249, 279))	('squamous cell carcinoma', 'Disease', (157, 180))	('cT0N0M1', 'Var', (328, 335))	('carcinoma', 'Phenotype', 'HP:0030731', (171, 180))	('hypermetabolism', 'Disease', 'MESH:C565498', (59, 74))	('patient', 'Species', '9606', (316, 323))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (157, 180))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (157, 180))	('hypermetabolism', 'Disease', (59, 74))
317301	32150096	The number of insertion mutations and deletion mutations (Indels) is 58, and the ratio of Indels/TMB is 25.66%.	('TMB', 'Chemical', '-', (97, 100))	('deletion mutations', 'Var', (38, 56))	('insertion mutations', 'Var', (14, 33))
317317	32150096	Meanwhile, due to few studies on esophageal cancer, it remains controversial about the prognostic and predictive value of PD-L1 expression in ESCC, as some studies associate high PD-L1 expression with poor differentiation of tumor and poor prognosis, while others postulate better response to PD-1/PD-L1 blockade with high PD-L1 expression.	('poor differentiation', 'CPA', (201, 221))	('tumor', 'Disease', 'MESH:D009369', (225, 230))	('expression', 'MPA', (185, 195))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('high', 'Var', (174, 178))	('tumor', 'Disease', (225, 230))	('PD-L1', 'Gene', (179, 184))	('esophageal cancer', 'Disease', (33, 50))	('ESCC', 'Disease', (142, 146))	('PD-1/PD-L1 blockade', 'Disease', (293, 312))	('esophageal cancer', 'Disease', 'MESH:D004938', (33, 50))	('PD-1/PD-L1 blockade', 'Disease', 'MESH:D010300', (293, 312))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
317325	32150096	In addition to the common point mutations in cancer cells, insertion mutations, deletion mutations, together is Indels, result in the production of abnormal proteins, which increase the immunogenicity and thus activate the immune system.	('cancer', 'Disease', (45, 51))	('deletion mutations', 'Var', (80, 98))	('production', 'MPA', (134, 144))	('activate', 'PosReg', (210, 218))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('immunogenicity', 'MPA', (186, 200))	('result in', 'Reg', (120, 129))	('insertion mutations', 'Var', (59, 78))	('increase', 'PosReg', (173, 181))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('immune system', 'CPA', (223, 236))	('proteins', 'Protein', (157, 165))	('abnormal proteins', 'Protein', (148, 165))
317326	32150096	It showed that the number and percentage of Indels in renal cancer are the highest.	('Indels', 'Var', (44, 50))	('renal cancer', 'Disease', (54, 66))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('renal cancer', 'Disease', 'MESH:D007680', (54, 66))	('renal cancer', 'Phenotype', 'HP:0009726', (54, 66))
317328	32150096	TILs is found to be an independent prognostic factor for prolonging progression free survival (PFS) and overall survival (OS) in tumor immunity, thus indicating the critical role of T cells in tumor immunity.	('TILs', 'Var', (0, 4))	('overall', 'MPA', (104, 111))	('tumor', 'Disease', (193, 198))	('progression', 'MPA', (68, 79))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('prolonging', 'PosReg', (57, 67))	('tumor', 'Disease', (129, 134))
317330	32150096	Some patients with MDM2 family amplification or EGFR aberrations had poor clinical outcome and significantly increased rate of tumor growth after single-agent ICIs (PD-1/PD-L1) treatment.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('MDM2', 'Gene', '4193', (19, 23))	('EGFR', 'Gene', '1956', (48, 52))	('patients', 'Species', '9606', (5, 13))	('MDM2', 'Gene', (19, 23))	('tumor', 'Disease', (127, 132))	('EGFR', 'Gene', (48, 52))	('aberrations', 'Var', (53, 64))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('increased', 'PosReg', (109, 118))
317331	32150096	In 2017, European Society for Medical Oncology (ESMO) conducted a comprehensive genetic analysis of patients with hyperprogression on immunotherapy, and found that MDM2/4 amplification, EGFR amplification, and CCND1/FGF3/FGF4/FGF19 amplification were associated with hyperprogression after ICIs treatment.	('CCND1', 'Gene', '595', (210, 215))	('EGFR', 'Gene', (186, 190))	('patients', 'Species', '9606', (100, 108))	('FGF3', 'Gene', (216, 220))	('amplification', 'Var', (171, 184))	('FGF3', 'Gene', '2248', (216, 220))	('MDM2/4', 'Gene', '4193;4194', (164, 170))	('FGF19', 'Gene', (226, 231))	('CCND1', 'Gene', (210, 215))	('FGF19', 'Gene', '9965', (226, 231))	('FGF4', 'Gene', '2249', (221, 225))	('Oncology', 'Phenotype', 'HP:0002664', (38, 46))	('MDM2/4', 'Gene', (164, 170))	('amplification', 'Var', (232, 245))	('EGFR', 'Gene', '1956', (186, 190))	('hyperprogression', 'Disease', (267, 283))	('amplification', 'Var', (191, 204))	('associated with', 'Reg', (251, 266))	('FGF4', 'Gene', (221, 225))
317343	31399552	The long noncoding RNA MIR210HG promotes tumor metastasis by acting as a ceRNA of miR-1226-3p to regulate mucin-1c expression in invasive breast cancer Background: Long noncoding RNAs have been known to be involved in multiple types of malignancies, including invasive breast cancer (IBC).	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('mucin', 'Gene', (106, 111))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('breast cancer', 'Phenotype', 'HP:0003002', (269, 282))	('mucin', 'Gene', '100508689', (106, 111))	('invasive breast cancer', 'Disease', (260, 282))	('invasive breast cancer', 'Disease', 'MESH:D001943', (260, 282))	('involved', 'Reg', (206, 214))	('breast cancer', 'Disease', 'MESH:D001943', (269, 282))	('breast cancer', 'Phenotype', 'HP:0003002', (138, 151))	('tumor', 'Disease', (41, 46))	('Long noncoding RNAs', 'Var', (164, 183))	('MIR210HG', 'Gene', '100506211', (23, 31))	('breast cancer', 'Disease', 'MESH:D001943', (138, 151))	('cancer', 'Phenotype', 'HP:0002664', (276, 282))	('promotes', 'PosReg', (32, 40))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('BC', 'Phenotype', 'HP:0003002', (285, 287))	('malignancies', 'Disease', 'MESH:D009369', (236, 248))	('invasive breast cancer', 'Disease', (129, 151))	('malignancies', 'Disease', (236, 248))	('invasive breast cancer', 'Disease', 'MESH:D001943', (129, 151))	('MIR210HG', 'Gene', (23, 31))
317347	31399552	Results: The aberrantly enhanced MiR210HG expression predicted poor prognosis and lower survival rate.	('MiR210HG', 'Gene', (33, 41))	('poor prognosis', 'CPA', (63, 77))	('expression', 'MPA', (42, 52))	('enhanced', 'PosReg', (24, 32))	('aberrantly', 'Var', (13, 23))	('survival rate', 'CPA', (88, 101))	('MiR210HG', 'Gene', '100506211', (33, 41))	('lower', 'NegReg', (82, 87))
317349	31399552	MiR-1226-3p was identified and validated to be the target miRNA of MiR210HG.	('MiR210HG', 'Gene', (67, 75))	('MiR-1226-3p', 'Var', (0, 11))	('MiR210HG', 'Gene', '100506211', (67, 75))
317367	31399552	We first detected the expression of MIR210HG and miR-1226-3p in tumor tissues from IBC patients as well as in IBC cell lines.	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('tumor', 'Disease', (64, 69))	('patients', 'Species', '9606', (87, 95))	('MIR210HG', 'Gene', '100506211', (36, 44))	('BC', 'Phenotype', 'HP:0003002', (111, 113))	('miR-1226', 'Chemical', '-', (49, 57))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('IBC', 'Disease', (83, 86))	('MIR210HG', 'Gene', (36, 44))	('miR-1226-3p', 'Var', (49, 60))	('BC', 'Phenotype', 'HP:0003002', (84, 86))
317371	31399552	Through GEO array data analysis, we found that a series of lncRNAs including MIR210HG were significantly up-regulated, while miRNAs including miR-1226-3p were significantly down-regulated in IBC compared with normal tissues (Figure 1A and 1B).	('MIR210HG', 'Gene', '100506211', (77, 85))	('miR-1226-3p', 'Var', (142, 153))	('MIR210HG', 'Gene', (77, 85))	('up-regulated', 'PosReg', (105, 117))	('BC', 'Phenotype', 'HP:0003002', (192, 194))	('miR-1226', 'Chemical', '-', (142, 150))	('down-regulated', 'NegReg', (173, 187))	('IBC', 'Disease', (191, 194))
317372	31399552	Next, we selected 115 differentially expressed genes (DEGs) and found that two ncRNAs (MIR210HG and miR-1226-3p) may overlap (Figure 1C).	('MIR210HG', 'Gene', (87, 95))	('MIR210HG', 'Gene', '100506211', (87, 95))	('miR-1226', 'Chemical', '-', (100, 108))	('miR-1226-3p', 'Var', (100, 111))
317393	31399552	Furthermore, MTT assay results showed that in both MDA-MB-231 and MCF-7 cells MIR210HG knockdown inhibited the breast cancer cell proliferation (Figure 2E and 2F, P < 0.05) and colony formation (Figure 2H, P < 0.05).	('MIR210HG', 'Gene', (78, 86))	('MTT', 'Chemical', 'MESH:C070243', (13, 16))	('MCF-7', 'CellLine', 'CVCL:0031', (66, 71))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('colony formation', 'CPA', (177, 193))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (51, 61))	('breast cancer', 'Disease', 'MESH:D001943', (111, 124))	('MIR210HG', 'Gene', '100506211', (78, 86))	('breast cancer', 'Phenotype', 'HP:0003002', (111, 124))	('inhibited', 'NegReg', (97, 106))	('breast cancer', 'Disease', (111, 124))	('knockdown', 'Var', (87, 96))
317400	31399552	MiR-1226-3p and MIR210HG shared complementary sequences (Figure 3C).	('MIR210HG', 'Gene', (16, 24))	('MIR210HG', 'Gene', '100506211', (16, 24))	('MiR-1226-3p', 'Var', (0, 11))
317401	31399552	Thus, we focused on the interaction between MIR210HG and miR-1226-3p.	('MIR210HG', 'Gene', (44, 52))	('miR-1226', 'Chemical', '-', (57, 65))	('interaction', 'Interaction', (24, 35))	('miR-1226-3p', 'Var', (57, 68))	('MIR210HG', 'Gene', '100506211', (44, 52))
317402	31399552	FISH analysis showed that MIR210HG and miR-1226-3p colocalized in the cytoplasm in MDA-MB-231 (Figure 3A).	('miR-1226', 'Chemical', '-', (39, 47))	('MIR210HG', 'Gene', (26, 34))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (83, 93))	('miR-1226-3p', 'Var', (39, 50))	('MDA-MB-231', 'Gene', (83, 93))	('MIR210HG', 'Gene', '100506211', (26, 34))
317403	31399552	This result suggested that MIR210HG may bind to miR-1226-3p in the cytoplasm.	('miR-1226-3p', 'Var', (48, 59))	('MIR210HG', 'Gene', (27, 35))	('bind', 'Reg', (40, 44))	('miR-1226', 'Chemical', '-', (48, 56))	('MIR210HG', 'Gene', '100506211', (27, 35))
317404	31399552	qRT-PCR results showed an inverse correlation between the expression levels of miR-1226-3p and MIR210HG in 45 paired IBC tissues (Figure 3B, P = 0.0313).	('BC', 'Phenotype', 'HP:0003002', (118, 120))	('miR-1226-3p', 'Var', (79, 90))	('inverse', 'NegReg', (26, 33))	('MIR210HG', 'Gene', '100506211', (95, 103))	('miR-1226', 'Chemical', '-', (79, 87))	('MIR210HG', 'Gene', (95, 103))
317405	31399552	To ascertain whether MIR210HG can bind directly to miR-1226-3p at its miRNA response element (MRE), we constructed luciferase reporter plasmids, that contained wild-type (WT) or mutated (Mut) miR-1226-3p binding sites.	('MIR210HG', 'Gene', (21, 29))	('miR-1226', 'Chemical', '-', (192, 200))	('miR-1226', 'Chemical', '-', (51, 59))	('MIR210HG', 'Gene', '100506211', (21, 29))	('mutated', 'Var', (178, 185))	('ether', 'Chemical', 'MESH:D004986', (15, 20))
317410	31399552	In contrast to MIR210HG, miR-1226-3p expression was significantly lower in MDA-MB-231 and MCF-7 cells than that in CAL-148, BT-549 and HCC38 (Figure 3E, P < 0.05).	('MIR210HG', 'Gene', '100506211', (15, 23))	('lower', 'NegReg', (66, 71))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (75, 85))	('miR-1226', 'Chemical', '-', (25, 33))	('HCC38', 'CellLine', 'CVCL:1267', (135, 140))	('MCF-7', 'CellLine', 'CVCL:0031', (90, 95))	('BT-549', 'CellLine', 'CVCL:1092', (124, 130))	('MIR210HG', 'Gene', (15, 23))	('miR-1226-3p', 'Var', (25, 36))	('expression', 'MPA', (37, 47))
317412	31399552	To further investigate the mechanism of miR-1226-3p modulating tumor progression of IBC, we searched for potential downstream target genes of miR-1226-3p using three independent miRNA target-predicting algorithms (TargetScan, miRTarBase, and miRDB).	('tumor', 'Disease', (63, 68))	('IBC', 'Disease', (84, 87))	('miR-1226', 'Chemical', '-', (40, 48))	('miR-1226-3p', 'Var', (142, 153))	('BC', 'Phenotype', 'HP:0003002', (85, 87))	('modulating', 'Reg', (52, 62))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('miR-1226', 'Chemical', '-', (142, 150))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
317414	31399552	Next, bioinformatic prediction (TargetScan and miRDB) revealed a putative binding site for miR-1226-3p in the MUC1-C 3'- UTR with high complementarity (Figure 4B).	('miR-1226-3p', 'Var', (91, 102))	('MUC1', 'Gene', (110, 114))	('MUC1', 'Gene', '4582', (110, 114))	('binding', 'Interaction', (74, 81))	('miR-1226', 'Chemical', '-', (91, 99))
317416	31399552	Expectedly, the miR-1226-3p expression level was negatively associated with that of MUC1-C (Figure 4C, P = 0.0268).	('miR-1226', 'Chemical', '-', (16, 24))	('negatively', 'NegReg', (49, 59))	('miR-1226-3p', 'Var', (16, 27))	('MUC1', 'Gene', (84, 88))	('MUC1', 'Gene', '4582', (84, 88))
317417	31399552	Similarly, we constructed luciferase reporter plasmids harboring wild type 3'-UTR of MUC1-C or the mutant on predicted binding site of miR-1226-3p.	('mutant', 'Var', (99, 105))	('miR-1226', 'Chemical', '-', (135, 143))	('MUC1', 'Gene', (85, 89))	('MUC1', 'Gene', '4582', (85, 89))
317418	31399552	The results showed that miR-1226-3p mimic transfection suppressed the luciferase activity of MUC1-C-WT reporter in MDA-MB-231 cells (Figure 4D, P < 0.05), suggesting that MUC1-C was directly targeted by miR-1226-3p.	('MUC1', 'Gene', (93, 97))	('MUC1', 'Gene', '4582', (93, 97))	('miR-1226', 'Chemical', '-', (203, 211))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (115, 125))	('miR-1226', 'Chemical', '-', (24, 32))	('MUC1', 'Gene', (171, 175))	('suppressed', 'NegReg', (55, 65))	('MUC1', 'Gene', '4582', (171, 175))	('luciferase', 'Enzyme', (70, 80))	('miR-1226-3p', 'Var', (24, 35))
317420	31399552	Moreover, western blot analysis showed that miR-1226-3p mimics transfection suppressed the protein expression of MUC1-C, while miR-1226-3p inhibitors upregulated MUC1-C expression (Figure 4F-4G).	('miR-1226', 'Chemical', '-', (44, 52))	('MUC1', 'Gene', '4582', (162, 166))	('miR-1226-3p inhibitors', 'Var', (127, 149))	('upregulated', 'PosReg', (150, 161))	('MUC1', 'Gene', (113, 117))	('MUC1', 'Gene', '4582', (113, 117))	('miR-1226', 'Chemical', '-', (127, 135))	('suppressed', 'NegReg', (76, 86))	('expression', 'MPA', (169, 179))	('protein expression', 'MPA', (91, 109))	('MUC1', 'Gene', (162, 166))
317430	31399552	Correlations between the genes of interest (MIR210HG and MUC1-C) and functional states in 3 different single-cell datasets (CancerSEA), EXP0052, EXP0053 and EXP0054 were plotted.	('MIR210HG', 'Gene', (44, 52))	('MIR210HG', 'Gene', '100506211', (44, 52))	('EXP0053', 'Var', (145, 152))	('MUC1', 'Gene', (57, 61))	('EXP0052', 'Var', (136, 143))	('MUC1', 'Gene', '4582', (57, 61))	('Cancer', 'Phenotype', 'HP:0002664', (124, 130))	('EXP0054', 'Var', (157, 164))
317439	31399552	Consistent with previous experiments, miR-1226-3p over-expression decreased the expression of MUC1-C, SMAD2, p-ERK, Snail, E-cadherin, while increased N-cadherin.	('SMAD2', 'Gene', '4087', (102, 107))	('MUC1', 'Gene', (94, 98))	('Snail', 'Gene', (116, 121))	('MUC1', 'Gene', '4582', (94, 98))	('increased', 'PosReg', (141, 150))	('decreased', 'NegReg', (66, 75))	('Snail', 'Gene', '6615', (116, 121))	('N-cadherin', 'Gene', (151, 161))	('E-cadherin', 'Gene', (123, 133))	('E-cadherin', 'Gene', '999', (123, 133))	('miR-1226', 'Chemical', '-', (38, 46))	('N-cadherin', 'Gene', '1000', (151, 161))	('over-expression', 'PosReg', (50, 65))	('miR-1226-3p', 'Var', (38, 49))	('expression', 'MPA', (80, 90))	('p-ERK', 'Gene', '9451', (109, 114))	('p-ERK', 'Gene', (109, 114))	('SMAD2', 'Gene', (102, 107))
317451	31399552	Previous studies have shown that, compared with healthy controls, the expression of miR-1226-3p was significantly higher in stomach tumors but lower in colorectal tumors.	('stomach tumors', 'Phenotype', 'HP:0006753', (124, 138))	('miR-1226', 'Chemical', '-', (84, 92))	('colorectal tumors', 'Disease', 'MESH:D015179', (152, 169))	('lower', 'NegReg', (143, 148))	('miR-1226-3p', 'Var', (84, 95))	('colorectal tumors', 'Disease', (152, 169))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('stomach tumors', 'Disease', 'MESH:D013274', (124, 138))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('expression', 'MPA', (70, 80))	('tumors', 'Phenotype', 'HP:0002664', (163, 169))	('higher', 'PosReg', (114, 120))	('stomach tumors', 'Disease', (124, 138))
317452	31399552	We further demonstrated that miR-1226-3p expression levels were noticeably downregulated in IBC tissues and cells.	('BC', 'Phenotype', 'HP:0003002', (93, 95))	('expression levels', 'MPA', (41, 58))	('downregulated', 'NegReg', (75, 88))	('IBC', 'Disease', (92, 95))	('miR-1226-3p', 'Var', (29, 40))	('miR-1226', 'Chemical', '-', (29, 37))
317453	31399552	Furthermore, miR-1226-3p expression levels were negatively correlated with those of MIR210HG in IBC tissues.	('negatively', 'NegReg', (48, 58))	('miR-1226', 'Chemical', '-', (13, 21))	('MIR210HG', 'Gene', '100506211', (84, 92))	('BC', 'Phenotype', 'HP:0003002', (97, 99))	('miR-1226-3p', 'Var', (13, 24))	('MIR210HG', 'Gene', (84, 92))
317454	31399552	Bioinformatic analysis showed that MIR210HG possesses one conserved target site for miR-1226-3p binding.	('miR-1226', 'Chemical', '-', (84, 92))	('binding', 'Interaction', (96, 103))	('MIR210HG', 'Gene', (35, 43))	('miR-1226-3p', 'Var', (84, 95))	('MIR210HG', 'Gene', '100506211', (35, 43))
317455	31399552	Further, FISH results showed intracellular colocalization of MIR210HG and miR-1226-3p, both of which were mainly concentrated in the cytoplasm.	('MIR210HG', 'Gene', (61, 69))	('MIR210HG', 'Gene', '100506211', (61, 69))	('miR-1226', 'Chemical', '-', (74, 82))	('miR-1226-3p', 'Var', (74, 85))
317456	31399552	A dual-luciferase reporter assay confirmed that miR-1226-3p reduced the luciferase activity of MIR210HG.	('miR-1226-3p', 'Var', (48, 59))	('activity', 'MPA', (83, 91))	('MIR210HG', 'Gene', '100506211', (95, 103))	('reduced', 'NegReg', (60, 67))	('miR-1226', 'Chemical', '-', (48, 56))	('MIR210HG', 'Gene', (95, 103))	('luciferase', 'Enzyme', (72, 82))
317458	31399552	In our study, miR-1226-3p overexpression decreased MUC1-C expression, which could be upregulated by miR-1226-3p inhibitors.	('upregulated', 'PosReg', (85, 96))	('expression', 'MPA', (58, 68))	('decreased', 'NegReg', (41, 50))	('miR-1226', 'Chemical', '-', (100, 108))	('miR-1226', 'Chemical', '-', (14, 22))	('MUC1', 'Gene', (51, 55))	('MUC1', 'Gene', '4582', (51, 55))	('miR-1226-3p', 'Var', (14, 25))
317459	31399552	Also, miR-1226-3p notably decreased the luciferase activity of MUC1-C.	('activity', 'MPA', (51, 59))	('luciferase', 'Enzyme', (40, 50))	('miR-1226', 'Chemical', '-', (6, 14))	('miR-1226-3p', 'Var', (6, 17))	('decreased', 'NegReg', (26, 35))	('MUC1', 'Gene', (63, 67))	('MUC1', 'Gene', '4582', (63, 67))
317460	31399552	These results indicated that MUC1-C was a direct target of miR-1226-3p.	('miR-1226', 'Chemical', '-', (59, 67))	('miR-1226-3p', 'Var', (59, 70))	('MUC1', 'Gene', '4582', (29, 33))	('MUC1', 'Gene', (29, 33))
317486	31399552	To construct luciferase reporter vectors, MUC1-C 3'-untranslated regions (UTR) and MIR210HG cDNA fragment containing the predicted potential miR-1226-3p binding sites or mutant sites were amplified by PCR.	('MUC1', 'Gene', '4582', (42, 46))	('MIR210HG', 'Gene', (83, 91))	('binding', 'Interaction', (153, 160))	('mutant', 'Var', (170, 176))	('miR-1226', 'Chemical', '-', (141, 149))	('miR-1226-3p', 'Gene', (141, 152))	('MIR210HG', 'Gene', '100506211', (83, 91))	('MUC1', 'Gene', (42, 46))
317503	31399552	FISH assay was performed to detect subcellular location of MIR210HG and miR-1226-3p.	('MIR210HG', 'Gene', (59, 67))	('miR-1226', 'Chemical', '-', (72, 80))	('MIR210HG', 'Gene', '100506211', (59, 67))	('miR-1226-3p', 'Var', (72, 83))
317516	31399552	Spearman Pearson correlation analysis was conducted to assess the correlation between MIR210HG and miR-1226-3p expression.	('miR-1226', 'Chemical', '-', (99, 107))	('MIR210HG', 'Gene', (86, 94))	('MIR210HG', 'Gene', '100506211', (86, 94))	('miR-1226-3p', 'Var', (99, 110))
317521	31399552	MIR210HG functions as a ceRNA for miR-1226-3p to promote IBC progression partially through mucin-1c signaling.	('mucin', 'Gene', (91, 96))	('MIR210HG', 'Gene', (0, 8))	('IBC', 'Disease', (57, 60))	('miR-1226', 'Chemical', '-', (34, 42))	('BC', 'Phenotype', 'HP:0003002', (58, 60))	('miR-1226-3p', 'Var', (34, 45))	('mucin', 'Gene', '100508689', (91, 96))	('promote', 'PosReg', (49, 56))	('MIR210HG', 'Gene', '100506211', (0, 8))
317575	29729234	In our patient's case, we submit that N. niwae caused the initial lung lesion:or cohabitated with a possible malignancy:and then spread systemically following exposure to steroids and chemotherapy.	('steroids', 'Chemical', 'MESH:D013256', (171, 179))	('malignancy', 'Disease', (109, 119))	('N. niwae', 'Var', (38, 46))	('patient', 'Species', '9606', (7, 14))	('lung lesion', 'Disease', 'MESH:D008171', (66, 77))	('malignancy', 'Disease', 'MESH:D009369', (109, 119))	('lung lesion', 'Disease', (66, 77))	('caused', 'Reg', (47, 53))
317585	30791942	shRNA-mediated depletion of LPCAT1 not only abrogated cell proliferation, migration and invasion in vitro, but also arrested tumor growth and brain metastases in vivo.	('depletion', 'Var', (15, 24))	('cell proliferation', 'CPA', (54, 72))	('arrested', 'NegReg', (116, 124))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('brain metastases', 'Disease', 'MESH:D009362', (142, 158))	('brain metastases', 'Disease', (142, 158))	('tumor', 'Disease', (125, 130))	('LPCAT1', 'Gene', (28, 34))	('abrogated', 'NegReg', (44, 53))
317594	30791942	Some previous studies suggested female gender, non-smoking, EGFR mutation and age under 60 years are high-risk factors for brain metastasis of NSCLC with stage IIIB/IV.	('NSCLC', 'Disease', (143, 148))	('NSCLC', 'Disease', 'MESH:D002289', (143, 148))	('NSCLC', 'Phenotype', 'HP:0030358', (143, 148))	('EGFR', 'Gene', '1956', (60, 64))	('mutation', 'Var', (65, 73))	('brain metastasis', 'CPA', (123, 139))	('EGFR', 'Gene', (60, 64))
317599	30791942	Inhibition of PI3K/AKT pathway might block brain metastasis of melanoma.	('brain metastasis of melanoma', 'Disease', (43, 71))	('brain metastasis of melanoma', 'Disease', 'MESH:D009362', (43, 71))	('AKT', 'Gene', '207', (19, 22))	('Inhibition', 'Var', (0, 10))	('block', 'NegReg', (37, 42))	('AKT', 'Gene', (19, 22))	('melanoma', 'Phenotype', 'HP:0002861', (63, 71))
317616	30791942	Microarray datasets of LUAD patients for gene expression analysis were acquired from online data repositories (Gene Express Omnibus, GEO) dataset (GSE32863 and GSE7670).	('GSE7670', 'Var', (160, 167))	('GSE32863', 'Var', (147, 155))	('GSE7670', 'Chemical', '-', (160, 167))	('patients', 'Species', '9606', (28, 36))	('LUAD', 'Phenotype', 'HP:0030078', (23, 27))
317643	30791942	The antibodies used were as follows: LPCAT1 (16112-1-AP, ProteinTech, Chicago, IL, USA), MYC (10828-1-AP, Proteintech), GAPDH (60004-1-Ig, Proteintech), AKT (4691, Cell Signaling Technology, MA, USA), p-AKT (4060, Cell Signaling Technology), PI3K (4249, Cell Signaling Technology), MMP-9 (10375-2-AP, Proteintech).	('GAPDH', 'Gene', (120, 125))	('60004-1-Ig', 'Var', (127, 137))	('AKT', 'Gene', (203, 206))	('4060', 'Var', (208, 212))	('AKT', 'Gene', '207', (153, 156))	('MYC', 'Gene', '4609', (89, 92))	('MMP-9', 'Gene', '4318', (282, 287))	('MMP-9', 'Gene', (282, 287))	('10375-2-AP', 'Var', (289, 299))	('AKT', 'Gene', (153, 156))	('GAPDH', 'Gene', '2597', (120, 125))	('AKT', 'Gene', '207', (203, 206))	('MYC', 'Gene', (89, 92))
317663	30791942	Antibodies used were as following: LPCAT1 (16112-1-AP, Proteintech), PCNA (10205-2-AP, Proteintech), CD34 (ab81289, Abcam, Cambridge, MA, USA) and MMP9 (10375-2-AP, Proteintech).	('PCNA', 'Gene', '5111', (69, 73))	('10205-2-AP', 'Var', (75, 85))	('MMP9', 'Gene', (147, 151))	('16112-1-AP', 'Var', (43, 53))	('ab81289', 'Var', (107, 114))	('10375-2-AP', 'Var', (153, 163))	('PCNA', 'Gene', (69, 73))	('CD34', 'Gene', '947', (101, 105))	('CD34', 'Gene', (101, 105))	('MMP9', 'Gene', '4318', (147, 151))
317673	30791942	We tried to find candidate genes involved in lung cancer by analyzing GEO dataset (GSE32863 and GSE7670) and LUAD dataset from the TCGA.	('lung cancer', 'Disease', 'MESH:D008175', (45, 56))	('GSE7670', 'Chemical', '-', (96, 103))	('lung cancer', 'Disease', (45, 56))	('lung cancer', 'Phenotype', 'HP:0100526', (45, 56))	('GSE32863', 'Var', (83, 91))	('LUAD', 'Phenotype', 'HP:0030078', (109, 113))	('GSE7670', 'Var', (96, 103))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))
317683	30791942	We found LPCAT1 amplification in 17% of the patients, which was the most frequent event among the 15 candidate genes (Fig.	('patients', 'Species', '9606', (44, 52))	('LPCAT1', 'Gene', (9, 15))	('amplification', 'Var', (16, 29))
317693	30791942	Patients with EGFR mutation were reportedly susceptible to BM.	('EGFR', 'Gene', '1956', (14, 18))	('mutation', 'Var', (19, 27))	('EGFR', 'Gene', (14, 18))	('susceptible', 'Reg', (44, 55))	('Patients', 'Species', '9606', (0, 8))
317694	30791942	Thus, we used HCC827 cell lines with EGFR mutation at exon 19 and PC-9 cell line with EGFR mutation at exon L858R to investigate the function of LPCAT1.	('PC-9', 'CellLine', 'CVCL:B260', (66, 70))	('EGFR', 'Gene', '1956', (86, 90))	('EGFR', 'Gene', (86, 90))	('mutation', 'Var', (42, 50))	('EGFR', 'Gene', '1956', (37, 41))	('HCC827', 'CellLine', 'CVCL:2063', (14, 20))	('EGFR', 'Gene', (37, 41))	('L858R', 'Mutation', 'rs121434568', (108, 113))
317696	30791942	HCC827 and PC-9 cell lines were then transduced with lentivirus bearing shRNA to knockdown LPCAT1 expression.	('knockdown', 'Var', (81, 90))	('PC-9', 'CellLine', 'CVCL:B260', (11, 15))	('HCC827', 'CellLine', 'CVCL:2063', (0, 6))	('LPCAT1', 'Gene', (91, 97))
317699	30791942	Since GSEA analysis showed that LPCAT1 amplification was positively correlated with genes related to "KEGG CELL CYCLE" and "GO CELL CYCLE G1-S TRANSITION" (Fig.	('LPCAT1', 'Gene', (32, 38))	('amplification', 'Var', (39, 52))	('GO CELL CYCLE G1-S TRANSITION', 'CPA', (124, 153))	('correlated', 'Reg', (68, 78))	('GSEA', 'Chemical', '-', (6, 10))
317703	30791942	We found that LPCAT1 knockdown inhibited cell migration and invasion of HCC827 and PC-9 cells (Fig.	('PC-9', 'CellLine', 'CVCL:B260', (83, 87))	('invasion', 'CPA', (60, 68))	('cell migration', 'CPA', (41, 55))	('HCC827', 'CellLine', 'CVCL:2063', (72, 78))	('inhibited', 'NegReg', (31, 40))	('knockdown', 'Var', (21, 30))	('LPCAT1', 'Gene', (14, 20))
317704	30791942	Since MMP-9 expression was associated with metastatic potential, we examined the expression of MMP-9 by Western blotting, and found that loss of LPCAT1 inhibited MMP-9 expression (Fig.	('MMP-9', 'Gene', (6, 11))	('MMP-9', 'Gene', (95, 100))	('MMP-9', 'Gene', '4318', (95, 100))	('expression', 'MPA', (168, 178))	('MMP-9', 'Gene', '4318', (162, 167))	('associated', 'Reg', (27, 37))	('MMP-9', 'Gene', (162, 167))	('metastatic potential', 'CPA', (43, 63))	('loss', 'Var', (137, 141))	('MMP-9', 'Gene', '4318', (6, 11))	('inhibited', 'NegReg', (152, 161))	('LPCAT1', 'Gene', (145, 151))
317707	30791942	The result indicated that tumor growth was substantially inhibited in LPCAT1 depletion group, as shown by smaller tumor size and lighter tumor weight (Fig.	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('lighter', 'NegReg', (129, 136))	('tumor', 'Disease', (137, 142))	('smaller', 'NegReg', (106, 113))	('depletion', 'Var', (77, 86))	('inhibited', 'NegReg', (57, 66))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('tumor', 'Disease', (114, 119))	('LPCAT1', 'Gene', (70, 76))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
317708	30791942	GSEA analysis of LUAD datasets showed that amplification of LPCAT1, in LUAD patients, was correlated with the gene-set of "GNF2_PCNA" (Fig.	('PCNA', 'Gene', '5111', (128, 132))	('patients', 'Species', '9606', (76, 84))	('LPCAT1', 'Gene', (60, 66))	('amplification', 'Var', (43, 56))	('LUAD', 'Phenotype', 'HP:0030078', (71, 75))	('PCNA', 'Gene', (128, 132))	('LUAD', 'Phenotype', 'HP:0030078', (17, 21))	('GSEA', 'Chemical', '-', (0, 4))
317710	30791942	Consistent with tumor growth inhibition, the result showed that in tumors with depleted LPCAT1 the expression of PCNA, CD34 and MMP9 were diminished (P < 0.05, Fig.	('PCNA', 'Gene', (113, 117))	('expression', 'MPA', (99, 109))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('tumor', 'Disease', (67, 72))	('diminished', 'NegReg', (138, 148))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('PCNA', 'Gene', '5111', (113, 117))	('depleted', 'Var', (79, 87))	('CD34', 'Gene', (119, 123))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Disease', (16, 21))	('tumors', 'Disease', (67, 73))	('LPCAT1', 'Gene', (88, 94))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('MMP9', 'Gene', (128, 132))	('MMP9', 'Gene', '4318', (128, 132))	('CD34', 'Gene', '947', (119, 123))	('tumors', 'Disease', 'MESH:D009369', (67, 73))
317712	30791942	Our result indicated that the mice were burdened with more brain metastatic lesions in shNC group than in LPCAT1 depletion group (Fig.	('shNC', 'Var', (87, 91))	('mice', 'Species', '10090', (30, 34))	('brain metastatic lesions', 'CPA', (59, 83))
317713	30791942	Together, these results showed that blockade of LPCAT1 activation suppressed tumor growth and brain metastasis of NSCLC cells in vivo.	('NSCLC', 'Phenotype', 'HP:0030358', (114, 119))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('NSCLC', 'Disease', (114, 119))	('brain metastasis', 'CPA', (94, 110))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('suppressed', 'NegReg', (66, 76))	('NSCLC', 'Disease', 'MESH:D002289', (114, 119))	('LPCAT1', 'Gene', (48, 54))	('tumor', 'Disease', (77, 82))	('blockade', 'Var', (36, 44))
317714	30791942	To explore the mechanism underlying the involvement of LPCAT1 in tumor metastasis, we set out to identify the relevant signaling pathways accounting for tumor growth inhibition caused by LPCAT1 knockdown.	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('LPCAT1', 'Gene', (187, 193))	('tumor', 'Disease', (65, 70))	('knockdown', 'Var', (194, 203))	('tumor metastasis', 'Disease', 'MESH:D009362', (65, 81))	('tumor', 'Disease', (153, 158))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor metastasis', 'Disease', (65, 81))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
317716	30791942	Importantly, GSEA analysis showed LPCAT1 amplification status was correlated with MYC-activated target gene set and negatively correlated with MYC-suppressed target gene set (Fig.	('correlated', 'Reg', (66, 76))	('MYC', 'Gene', '4609', (82, 85))	('amplification status', 'Var', (41, 61))	('LPCAT1', 'Gene', (34, 40))	('MYC', 'Gene', '4609', (143, 146))	('GSEA', 'Chemical', '-', (13, 17))	('negatively', 'NegReg', (116, 126))	('MYC', 'Gene', (143, 146))	('MYC', 'Gene', (82, 85))
317718	30791942	Notably, loss of LPCAT1 inhibited the expression of p-AKT and MYC in vitro (Fig.	('MYC', 'Gene', (62, 65))	('expression', 'MPA', (38, 48))	('AKT', 'Gene', '207', (54, 57))	('LPCAT1', 'Gene', (17, 23))	('inhibited', 'NegReg', (24, 33))	('loss', 'Var', (9, 13))	('MYC', 'Gene', '4609', (62, 65))	('AKT', 'Gene', (54, 57))
317721	30791942	To further confirm these findings, we treated the cells with exogenous IGF-1 (2 mug/ml) for 24 h, and found that the IGF-1 reversed the reduced expression of p-AKT and MYC induced by LPCAT1 knockdown (Fig.	('LPCAT1', 'Gene', (183, 189))	('MYC', 'Gene', (168, 171))	('AKT', 'Gene', '207', (160, 163))	('knockdown', 'Var', (190, 199))	('expression', 'MPA', (144, 154))	('IGF-1', 'Gene', '3479', (71, 76))	('IGF-1', 'Gene', (71, 76))	('MYC', 'Gene', '4609', (168, 171))	('reduced', 'NegReg', (136, 143))	('AKT', 'Gene', (160, 163))	('IGF-1', 'Gene', '3479', (117, 122))	('IGF-1', 'Gene', (117, 122))
317755	30791942	We further studied the roles of LPCAT1 in the proliferation, migration, invasion of NSCLC cells and tumorigenesis and found that knockdown of LPCAT1 inhibited proliferation, migration, invasion of NSCLC cells and NSCLC tumorigenesis and induced G1 phase arrest.	('NSCLC', 'Disease', 'MESH:D002289', (213, 218))	('tumor', 'Disease', (219, 224))	('tumor', 'Disease', (100, 105))	('proliferation', 'CPA', (159, 172))	('G1 phase arrest', 'CPA', (245, 260))	('NSCLC', 'Disease', 'MESH:D002289', (84, 89))	('tumor', 'Disease', 'MESH:D009369', (219, 224))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('NSCLC', 'Disease', 'MESH:D002289', (197, 202))	('LPCAT1', 'Gene', (142, 148))	('migration', 'CPA', (174, 183))	('NSCLC', 'Disease', (213, 218))	('knockdown', 'Var', (129, 138))	('NSCLC', 'Disease', (84, 89))	('induced', 'Reg', (237, 244))	('invasion', 'CPA', (185, 193))	('NSCLC', 'Phenotype', 'HP:0030358', (213, 218))	('NSCLC', 'Disease', (197, 202))	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('NSCLC', 'Phenotype', 'HP:0030358', (84, 89))	('NSCLC', 'Phenotype', 'HP:0030358', (197, 202))	('inhibited', 'NegReg', (149, 158))
317756	30791942	IHC analysis showed that LPCAT1 knockdown inhibited MMP-9 and CD34 expression in xenograft tumors.	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('MMP-9', 'Gene', '4318', (52, 57))	('MMP-9', 'Gene', (52, 57))	('xenograft tumors', 'Disease', (81, 97))	('CD34', 'Gene', '947', (62, 66))	('knockdown', 'Var', (32, 41))	('inhibited', 'NegReg', (42, 51))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('LPCAT1', 'Gene', (25, 31))	('CD34', 'Gene', (62, 66))	('xenograft tumors', 'Disease', 'MESH:D009369', (81, 97))	('expression', 'MPA', (67, 77))
317758	30791942	Moreover, we found that LPCAT1 knockdown inhibited brain metastatic lesions in the mice model of brain metastasis.	('mice', 'Species', '10090', (83, 87))	('LPCAT1', 'Gene', (24, 30))	('inhibited', 'NegReg', (41, 50))	('brain metastatic lesions', 'CPA', (51, 75))	('knockdown', 'Var', (31, 40))
317760	30791942	Phosphorylated AKT may contribute to biological behaviors of cancer cells, such as viability, proliferation, invasion and migration.	('Phosphorylated', 'Var', (0, 14))	('invasion', 'CPA', (109, 117))	('AKT', 'Gene', '207', (15, 18))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('cancer', 'Disease', (61, 67))	('contribute', 'Reg', (23, 33))	('proliferation', 'CPA', (94, 107))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('AKT', 'Gene', (15, 18))	('migration', 'CPA', (122, 131))	('biological behaviors', 'CPA', (37, 57))
317763	30791942	In this study, we found that p-AKT expression was inhibited in NSCLC cells with LPCAT1 knockdown.	('NSCLC', 'Disease', (63, 68))	('NSCLC', 'Disease', 'MESH:D002289', (63, 68))	('AKT', 'Gene', (31, 34))	('expression', 'MPA', (35, 45))	('NSCLC', 'Phenotype', 'HP:0030358', (63, 68))	('LPCAT1', 'Gene', (80, 86))	('AKT', 'Gene', '207', (31, 34))	('inhibited', 'NegReg', (50, 59))	('knockdown', 'Var', (87, 96))
317768	30791942	Our results showed that MYC expression decreased in LPCAT1 knockdown group, and inhibition of MYC expression was reversed upon treatment of NSCLC cells with exogenous IGF-1.	('NSCLC', 'Disease', 'MESH:D002289', (140, 145))	('MYC', 'Gene', (24, 27))	('MYC', 'Gene', (94, 97))	('IGF-1', 'Gene', '3479', (167, 172))	('IGF-1', 'Gene', (167, 172))	('NSCLC', 'Phenotype', 'HP:0030358', (140, 145))	('LPCAT1', 'Gene', (52, 58))	('knockdown', 'Var', (59, 68))	('decreased', 'NegReg', (39, 48))	('MYC', 'Gene', '4609', (24, 27))	('MYC', 'Gene', '4609', (94, 97))	('NSCLC', 'Disease', (140, 145))
317780	30791942	Previous studies also found that the expression of AKT and p-AKT was significantly higher in NSCLC tissue with KRAS mutation compared to those with wild-type KRAS.	('KRAS', 'Gene', '3845', (158, 162))	('NSCLC', 'Disease', (93, 98))	('KRAS', 'Gene', (111, 115))	('mutation', 'Var', (116, 124))	('AKT', 'Gene', (51, 54))	('NSCLC', 'Disease', 'MESH:D002289', (93, 98))	('KRAS', 'Gene', '3845', (111, 115))	('AKT', 'Gene', '207', (61, 64))	('expression', 'MPA', (37, 47))	('AKT', 'Gene', (61, 64))	('NSCLC', 'Phenotype', 'HP:0030358', (93, 98))	('KRAS', 'Gene', (158, 162))	('higher', 'PosReg', (83, 89))	('AKT', 'Gene', '207', (51, 54))
317782	30791942	Therefore, we speculated that LPCAT1 could promote KRAS-mutated NSCLC cells progress.	('LPCAT1', 'Var', (30, 36))	('NSCLC', 'Disease', 'MESH:D002289', (64, 69))	('KRAS', 'Gene', '3845', (51, 55))	('promote', 'PosReg', (43, 50))	('NSCLC', 'Phenotype', 'HP:0030358', (64, 69))	('NSCLC', 'Disease', (64, 69))	('KRAS', 'Gene', (51, 55))
317785	30791942	LPCAT1 promoted NSCLC proliferation, metastasis and tumorigenesis both in vitro and in vivo and, LPCAT1 promoted NSCLC progression, in part, via the PI3K/AKT/MYC pathway.	('MYC', 'Gene', (158, 161))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('NSCLC', 'Disease', 'MESH:D002289', (16, 21))	('NSCLC', 'Phenotype', 'HP:0030358', (16, 21))	('tumor', 'Disease', (52, 57))	('AKT', 'Gene', '207', (154, 157))	('NSCLC', 'Phenotype', 'HP:0030358', (113, 118))	('metastasis', 'CPA', (37, 47))	('MYC', 'Gene', '4609', (158, 161))	('NSCLC', 'Disease', (16, 21))	('AKT', 'Gene', (154, 157))	('promoted', 'PosReg', (7, 15))	('LPCAT1', 'Var', (97, 103))	('NSCLC', 'Disease', (113, 118))	('promoted', 'PosReg', (104, 112))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('NSCLC', 'Disease', 'MESH:D002289', (113, 118))
317795	26486077	Mutations in EGFR kinase domain, HER2 kinase domain, KRAS, BRAF, ALK, ROS1 and RET were mutually exclusive.	('ALK', 'Gene', '238', (65, 68))	('RET', 'Gene', '5979', (79, 82))	('HER2', 'Gene', (33, 37))	('HER2', 'Gene', '2064', (33, 37))	('RET', 'Gene', (79, 82))	('Mutations', 'Var', (0, 9))	('BRAF', 'Gene', (59, 63))	('ALK', 'Gene', (65, 68))	('ROS1', 'Gene', (70, 74))	('KRAS', 'Gene', (53, 57))	('BRAF', 'Gene', '673', (59, 63))	('KRAS', 'Gene', '3845', (53, 57))	('ROS1', 'Gene', '6098', (70, 74))	('EGFR', 'Gene', '1956', (13, 17))	('EGFR', 'Gene', (13, 17))
317796	26486077	In lung adenocarcinoma cases "pan-negative" for the seven above-mentioned driver mutations, we also detected two oncogenic EGFR extracellular domain mutations (A289D and R324L), two HER2 extracellular and transmembrane domain mutations (S310Y and V659E), one ARAF S214C mutation and two CD74-NRG1 fusions.	('EGFR', 'Gene', (123, 127))	('CD74', 'Gene', '972', (287, 291))	('ARAF', 'Gene', (259, 263))	('V659E', 'Var', (247, 252))	('lung adenocarcinoma', 'Disease', (3, 22))	('S310Y', 'Mutation', 'rs1057519816', (237, 242))	('A289D', 'Mutation', 'rs149840192', (160, 165))	('R324L', 'Var', (170, 175))	('EGFR', 'Gene', '1956', (123, 127))	('R324L', 'Mutation', 'rs750429622', (170, 175))	('CD74', 'Gene', (287, 291))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (3, 22))	('HER2', 'Gene', '2064', (182, 186))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (3, 22))	('NRG1', 'Gene', (292, 296))	('A289D', 'Var', (160, 165))	('S214C', 'Mutation', 'rs1057519786', (264, 269))	('carcinoma', 'Phenotype', 'HP:0030731', (13, 22))	('NRG1', 'Gene', '3084', (292, 296))	('S310Y', 'Var', (237, 242))	('V659E', 'Mutation', 'p.V659E', (247, 252))	('HER2', 'Gene', (182, 186))	('ARAF', 'Gene', '369', (259, 263))
317797	26486077	Six (1.2%) FGFR3 activating mutations were identified in lung squamous cell carcinoma (five S249C and one R248C).	('R248C', 'Mutation', 'rs121913482', (106, 111))	('lung squamous cell carcinoma', 'Disease', (57, 85))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (57, 85))	('FGFR3', 'Gene', '2261', (11, 16))	('S249C', 'Mutation', 'rs121913483', (92, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('activating', 'PosReg', (17, 27))	('FGFR3', 'Gene', (11, 16))	('R248C', 'Var', (106, 111))	('S249C', 'Var', (92, 97))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (57, 85))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (62, 85))
317798	26486077	There were three (15.8%) EGFR mutations and four (21.1%) KRAS mutations in large cell carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('EGFR', 'Gene', (25, 29))	('cell carcinoma', 'Disease', (81, 95))	('KRAS', 'Gene', (57, 61))	('large cell carcinoma', 'Phenotype', 'HP:0030360', (75, 95))	('mutations', 'Var', (30, 39))	('KRAS', 'Gene', '3845', (57, 61))	('cell carcinoma', 'Disease', 'MESH:C538614', (81, 95))	('EGFR', 'Gene', '1956', (25, 29))
317799	26486077	Three (37.5%) KRAS mutations were detected in sarcomatoid carcinoma.	('detected', 'Reg', (34, 42))	('sarcomatoid carcinoma', 'Disease', (46, 67))	('KRAS', 'Gene', '3845', (14, 18))	('mutations', 'Var', (19, 28))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))	('KRAS', 'Gene', (14, 18))	('sarcomatoid carcinoma', 'Phenotype', 'HP:0100242', (46, 67))	('sarcomatoid carcinoma', 'Disease', 'MESH:C538614', (46, 67))
317803	26486077	Treatment strategies for non-small cell lung cancer (NSCLC) have been revolutionized since the identification of EGFR activating mutations which predict response to EGFR tyrosine kinase inhibitors (TKIs) in 2004.	('EGFR', 'Gene', (165, 169))	('non-small cell lung cancer', 'Disease', (25, 51))	('NSCLC', 'Phenotype', 'HP:0030358', (53, 58))	('lung cancer', 'Phenotype', 'HP:0100526', (40, 51))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (29, 51))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('mutations', 'Var', (129, 138))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (25, 51))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (25, 51))	('EGFR', 'Gene', '1956', (113, 117))	('EGFR', 'Gene', (113, 117))	('NSCLC', 'Disease', (53, 58))	('NSCLC', 'Disease', 'MESH:D002289', (53, 58))	('EGFR', 'Gene', '1956', (165, 169))
317804	26486077	Over the last decade, various oncogenic driver mutations have been identified in NSCLC, which enables this disease to be classified into clinically relevant molecular subgroups.	('NSCLC', 'Phenotype', 'HP:0030358', (81, 86))	('NSCLC', 'Disease', 'MESH:D002289', (81, 86))	('NSCLC', 'Disease', (81, 86))	('mutations', 'Var', (47, 56))
317805	26486077	Large phase III randomized clinical trials have proved the efficacy of targeted therapies over conventional cytotoxic chemotherapy for NSCLC patients harboring EGFR mutations or ALK fusions.	('ALK', 'Gene', (178, 181))	('NSCLC', 'Disease', (135, 140))	('EGFR', 'Gene', '1956', (160, 164))	('NSCLC', 'Disease', 'MESH:D002289', (135, 140))	('EGFR', 'Gene', (160, 164))	('mutations', 'Var', (165, 174))	('ALK', 'Gene', '238', (178, 181))	('patients', 'Species', '9606', (141, 149))	('NSCLC', 'Phenotype', 'HP:0030358', (135, 140))
317806	26486077	In this study, we presented our sequencing results of a comprehensive panel of oncogenic driver mutations in a large prospective series of NSCLC patients who received surgical resection.	('patients', 'Species', '9606', (145, 153))	('NSCLC', 'Phenotype', 'HP:0030358', (139, 144))	('NSCLC', 'Disease', (139, 144))	('NSCLC', 'Disease', 'MESH:D002289', (139, 144))	('mutations', 'Var', (96, 105))
317807	26486077	A total of 1356 lung adenocarcinoma cases from April 2007 to May 2013 were sequenced for EGFR kinase domain mutations, KRAS mutations, HER2 kinase domain mutations, BRAF mutations, ALK fusions, ROS1 fusions, RET fusions and AKT1 mutations.	('ALK', 'Gene', (181, 184))	('RET', 'Gene', '5979', (208, 211))	('carcinoma', 'Phenotype', 'HP:0030731', (26, 35))	('ROS1', 'Gene', '6098', (194, 198))	('HER2', 'Gene', '2064', (135, 139))	('mutations', 'Var', (229, 238))	('BRAF', 'Gene', '673', (165, 169))	('BRAF', 'Gene', (165, 169))	('KRAS', 'Gene', '3845', (119, 123))	('RET', 'Gene', (208, 211))	('EGFR', 'Gene', (89, 93))	('AKT1', 'Gene', '207', (224, 228))	('lung adenocarcinoma', 'Disease', (16, 35))	('KRAS', 'Gene', (119, 123))	('ROS1', 'Gene', (194, 198))	('HER2', 'Gene', (135, 139))	('mutations', 'Var', (124, 133))	('AKT1', 'Gene', (224, 228))	('mutations', 'Var', (170, 179))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (16, 35))	('fusions', 'Var', (199, 206))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (16, 35))	('EGFR', 'Gene', '1956', (89, 93))	('ALK', 'Gene', '238', (181, 184))
317808	26486077	There were 855 (63.1%) EGFR kinase domain mutations (including 361 exon 19 deletions, 402 L858R and 92 other mutations), 108 (8.0%) KRAS mutations, 32 (2.4%) HER2 kinase domain mutations (all were exon 20 insertion mutations), 18 (1.3%) BRAF mutations (5 V600E and 13 non-V600E mutations), 70 (5.2%) ALK fusions, 11 (0.8%) ROS1 fusions and 17 (1.3%) RET fusions (Figure 1A).	('KRAS', 'Gene', (132, 136))	('V600E', 'Var', (255, 260))	('ALK', 'Gene', '238', (300, 303))	('EGFR', 'Gene', '1956', (23, 27))	('ALK', 'Gene', (300, 303))	('RET', 'Gene', '5979', (350, 353))	('ROS1', 'Gene', (323, 327))	('HER2', 'Gene', '2064', (158, 162))	('L858R', 'Mutation', 'rs121434568', (90, 95))	('V600E', 'Mutation', 'rs113488022', (272, 277))	('BRAF', 'Gene', '673', (237, 241))	('kinase domain', 'Gene', (28, 41))	('BRAF', 'Gene', (237, 241))	('RET', 'Gene', (350, 353))	('EGFR', 'Gene', (23, 27))	('V600E', 'Mutation', 'rs113488022', (255, 260))	('KRAS', 'Gene', '3845', (132, 136))	('mutations', 'Var', (137, 146))	('HER2', 'Gene', (158, 162))	('ROS1', 'Gene', '6098', (323, 327))
317809	26486077	We also identified 2 (0.1%) AKT1 mutations, both were E17K mutations.	('AKT1', 'Gene', '207', (28, 32))	('AKT1', 'Gene', (28, 32))	('mutations', 'Var', (33, 42))	('E17K', 'Mutation', 'rs121434592', (54, 58))
317810	26486077	One patient with AKT1 E17K mutation also harbored BRAF V600E mutation; the other did not harbor any of the seven above-mentioned mutations.	('E17K', 'Var', (22, 26))	('BRAF', 'Gene', (50, 54))	('AKT1', 'Gene', (17, 21))	('patient', 'Species', '9606', (4, 11))	('E17K', 'Mutation', 'rs121434592', (22, 26))	('AKT1', 'Gene', '207', (17, 21))	('BRAF', 'Gene', '673', (50, 54))	('V600E', 'Mutation', 'rs113488022', (55, 60))
317811	26486077	Six FGFR3-TACC3 fusions were detected out of 1016 lung adenocarcinomas, accounting for a mutation rate of 0.6%.	('fusions', 'Var', (16, 23))	('TACC3', 'Gene', '10460', (10, 15))	('lung adenocarcinomas', 'Disease', (50, 70))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (50, 69))	('TACC3', 'Gene', (10, 15))	('detected', 'Reg', (29, 37))	('FGFR3', 'Gene', (4, 9))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (50, 70))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (50, 70))	('carcinoma', 'Phenotype', 'HP:0030731', (60, 69))	('FGFR3', 'Gene', '2261', (4, 9))
317812	26486077	In cases "pan-negative" for mutations in EGFR, HER2, KRAS, BRAF, ALK, ROS1 and RET, we also sequenced for activating mutations in EGFR extracellular domain (ECD), HER2 ECD and transmembrane domain, ERBB3, ARAF and NRG1 (a total of 183 cases for ERBB family genes, and 219 cases for ARAF and NRG1) (Figure 1B).	('ECD', 'Disease', 'MESH:C574275', (157, 160))	('ECD', 'Disease', (157, 160))	('activating', 'PosReg', (106, 116))	('ERBB', 'Gene', '1956;2064;2065', (245, 249))	('ARAF', 'Gene', '369', (282, 286))	('KRAS', 'Gene', (53, 57))	('ERBB', 'Gene', '1956;2064;2065', (198, 202))	('ARAF', 'Gene', (282, 286))	('EGFR', 'Gene', (130, 134))	('EGFR', 'Gene', (41, 45))	('HER2', 'Gene', (163, 167))	('RET', 'Gene', '5979', (79, 82))	('HER2', 'Gene', '2064', (47, 51))	('ROS1', 'Gene', (70, 74))	('NRG1', 'Gene', '3084', (291, 295))	('ERBB3', 'Gene', (198, 203))	('ECD', 'Disease', 'MESH:C574275', (168, 171))	('ALK', 'Gene', '238', (65, 68))	('mutations', 'Var', (117, 126))	('NRG1', 'Gene', (214, 218))	('ECD', 'Disease', (168, 171))	('NRG1', 'Gene', '3084', (214, 218))	('RET', 'Gene', (79, 82))	('BRAF', 'Gene', (59, 63))	('BRAF', 'Gene', '673', (59, 63))	('ALK', 'Gene', (65, 68))	('EGFR', 'Gene', '1956', (130, 134))	('EGFR', 'Gene', '1956', (41, 45))	('mutations', 'Var', (28, 37))	('ARAF', 'Gene', '369', (205, 209))	('ARAF', 'Gene', (205, 209))	('ERBB', 'Gene', (245, 249))	('ERBB', 'Gene', (198, 202))	('HER2', 'Gene', '2064', (163, 167))	('NRG1', 'Gene', (291, 295))	('HER2', 'Gene', (47, 51))	('ERBB3', 'Gene', '2065', (198, 203))	('KRAS', 'Gene', '3845', (53, 57))	('ROS1', 'Gene', '6098', (70, 74))
317813	26486077	Oncogenic EGFR ECD mutations were detected in two cases (1.1%): one was A289D, and the other was R324L.	('detected', 'Reg', (34, 42))	('EGFR', 'Gene', '1956', (10, 14))	('EGFR', 'Gene', (10, 14))	('A289D', 'Var', (72, 77))	('A289D', 'Mutation', 'rs149840192', (72, 77))	('R324L', 'Mutation', 'rs750429622', (97, 102))	('ECD', 'Disease', (15, 18))	('ECD', 'Disease', 'MESH:C574275', (15, 18))	('R324L', 'Var', (97, 102))
317814	26486077	One S310Y mutation and one V659E mutation was detected in HER2 extracellular and transmembrane domain (1.1%), respectively.	('V659E', 'Mutation', 'p.V659E', (27, 32))	('V659E', 'Var', (27, 32))	('S310Y', 'Var', (4, 9))	('HER2', 'Gene', (58, 62))	('S310Y', 'Mutation', 'rs1057519816', (4, 9))	('HER2', 'Gene', '2064', (58, 62))
317815	26486077	There was one (0.5%) ARAF S214C mutation.	('S214C', 'Var', (26, 31))	('S214C', 'Mutation', 'rs1057519786', (26, 31))	('ARAF', 'Gene', (21, 25))	('ARAF', 'Gene', '369', (21, 25))
317818	26486077	In lung squamous cell carcinoma, the mutation rate of EGFR (12 out of 310, 3.9%), KRAS (8 out of 310, 2.6%), HER2 (1 out of 310, 0.3%), BRAF (1 out of 310, 0.3%), ALK (2 out of 310, 0.6%), DDR2 (1 out of 310, 0.3%), AKT1 (1 out of 310, 0.3%), FGFR1 fusions (2 out of 312, 0.6%) and FGFR3 fusions (9 out of 312, 2.9%) has been reported in our previous studies.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (8, 31))	('mutation', 'Var', (37, 45))	('lung squamous cell carcinoma', 'Disease', (3, 31))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (3, 31))	('BRAF', 'Gene', '673', (136, 140))	('ALK', 'Gene', '238', (163, 166))	('BRAF', 'Gene', (136, 140))	('EGFR', 'Gene', '1956', (54, 58))	('KRAS', 'Gene', '3845', (82, 86))	('ALK', 'Gene', (163, 166))	('HER2', 'Gene', '2064', (109, 113))	('FGFR1', 'Gene', '2260', (243, 248))	('FGFR3', 'Gene', (282, 287))	('DDR2', 'Gene', '4921', (189, 193))	('KRAS', 'Gene', (82, 86))	('AKT1', 'Gene', '207', (216, 220))	('FGFR3', 'Gene', '2261', (282, 287))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('DDR2', 'Gene', (189, 193))	('EGFR', 'Gene', (54, 58))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (3, 31))	('AKT1', 'Gene', (216, 220))	('HER2', 'Gene', (109, 113))	('FGFR1', 'Gene', (243, 248))
317819	26486077	We sequenced 503 lung squamous cell carcinoma resected from October 2007 to March 2013 for the prevalence of activating FGFR2 and FGFR3 mutations.	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (17, 45))	('lung squamous cell carcinoma', 'Disease', (17, 45))	('FGFR3', 'Gene', (130, 135))	('FGFR2', 'Gene', '2263', (120, 125))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (17, 45))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (22, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (36, 45))	('mutations', 'Var', (136, 145))	('FGFR2', 'Gene', (120, 125))	('FGFR3', 'Gene', '2261', (130, 135))	('activating', 'PosReg', (109, 119))
317820	26486077	Six (1.2%) FGFR3 activating mutations were identified, including 5 S249C mutations and 1 R248C mutation (Figure 2A).	('R248C', 'Mutation', 'rs121913482', (89, 94))	('S249C', 'Mutation', 'rs121913483', (67, 72))	('S249C mutations', 'Var', (67, 82))	('FGFR3', 'Gene', '2261', (11, 16))	('activating', 'PosReg', (17, 27))	('FGFR3', 'Gene', (11, 16))	('R248C', 'Var', (89, 94))
317822	26486077	Fifty-seven adenosquamous lung carcinoma resected between October 2007 to January 2013 were analyzed for mutations in EGFR kinase domain, HER2 kinase domain, KRAS, BRAF, ALK, RET and AKT1.	('RET', 'Gene', '5979', (175, 178))	('HER2', 'Gene', '2064', (138, 142))	('KRAS', 'Gene', '3845', (158, 162))	('carcinoma', 'Phenotype', 'HP:0030731', (31, 40))	('adenosquamous lung carcinoma', 'Disease', (12, 40))	('AKT1', 'Gene', '207', (183, 187))	('RET', 'Gene', (175, 178))	('adenosquamous lung carcinoma', 'Disease', 'MESH:D018196', (12, 40))	('BRAF', 'Gene', '673', (164, 168))	('AKT1', 'Gene', (183, 187))	('EGFR', 'Gene', '1956', (118, 122))	('mutations', 'Var', (105, 114))	('EGFR', 'Gene', (118, 122))	('ALK', 'Gene', '238', (170, 173))	('BRAF', 'Gene', (164, 168))	('KRAS', 'Gene', (158, 162))	('HER2', 'Gene', (138, 142))	('ALK', 'Gene', (170, 173))
317823	26486077	There were 20 (35.1%) EGFR mutations, 6 (10.5%) KRAS mutations, 1 (1.8%) HER2 mutation, 4 (7.0%) ALK fusions, 2 (3.5%) RET fusions and 2 (3.5%) AKT1 E17K mutations (Figure 2B).	('mutations', 'Var', (27, 36))	('HER2', 'Gene', '2064', (73, 77))	('AKT1', 'Gene', '207', (144, 148))	('KRAS', 'Gene', (48, 52))	('RET', 'Gene', (119, 122))	('E17K', 'Mutation', 'rs121434592', (149, 153))	('KRAS', 'Gene', '3845', (48, 52))	('AKT1', 'Gene', (144, 148))	('ALK', 'Gene', '238', (97, 100))	('mutations', 'Var', (53, 62))	('EGFR', 'Gene', '1956', (22, 26))	('ALK', 'Gene', (97, 100))	('E17K', 'Var', (149, 153))	('RET', 'Gene', '5979', (119, 122))	('HER2', 'Gene', (73, 77))	('EGFR', 'Gene', (22, 26))
317824	26486077	We also sequenced 19 large cell carcinoma samples resected from November 2007 to May 2012 to detect mutations in EGFR kinase domain, HER2 kinase domain, KRAS, BRAF, ALK, RET and AKT1.	('ALK', 'Gene', '238', (165, 168))	('ALK', 'Gene', (165, 168))	('cell carcinoma', 'Disease', (27, 41))	('EGFR', 'Gene', (113, 117))	('BRAF', 'Gene', '673', (159, 163))	('large cell carcinoma', 'Phenotype', 'HP:0030360', (21, 41))	('RET', 'Gene', (170, 173))	('BRAF', 'Gene', (159, 163))	('carcinoma', 'Phenotype', 'HP:0030731', (32, 41))	('HER2', 'Gene', '2064', (133, 137))	('KRAS', 'Gene', '3845', (153, 157))	('cell carcinoma', 'Disease', 'MESH:C538614', (27, 41))	('AKT1', 'Gene', '207', (178, 182))	('KRAS', 'Gene', (153, 157))	('EGFR', 'Gene', '1956', (113, 117))	('mutations', 'Var', (100, 109))	('HER2', 'Gene', (133, 137))	('AKT1', 'Gene', (178, 182))	('RET', 'Gene', '5979', (170, 173))
317825	26486077	There were 3 (15.8%) EGFR mutations and 4 (21.1%) KRAS mutations (Figure 2C).	('EGFR', 'Gene', '1956', (21, 25))	('EGFR', 'Gene', (21, 25))	('KRAS', 'Gene', (50, 54))	('mutations', 'Var', (26, 35))	('KRAS', 'Gene', '3845', (50, 54))
317826	26486077	Eight sarcomatoid carcinoma were analyzed for the presence of EGFR kinase domain mutations, KRAS mutations, HER2 kinase domain mutations, BRAF mutations, ALK fusions, RET fusions and AKT1 mutations.	('HER2', 'Gene', (108, 112))	('mutations', 'Var', (97, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (18, 27))	('KRAS', 'Gene', (92, 96))	('sarcomatoid carcinoma', 'Disease', (6, 27))	('ALK', 'Gene', '238', (154, 157))	('sarcomatoid carcinoma', 'Disease', 'MESH:C538614', (6, 27))	('mutations', 'Var', (81, 90))	('RET', 'Gene', '5979', (167, 170))	('EGFR', 'Gene', '1956', (62, 66))	('ALK', 'Gene', (154, 157))	('mutations', 'Var', (143, 152))	('HER2', 'Gene', '2064', (108, 112))	('RET', 'Gene', (167, 170))	('AKT1', 'Gene', '207', (183, 187))	('sarcomatoid carcinoma', 'Phenotype', 'HP:0100242', (6, 27))	('mutations', 'Var', (188, 197))	('BRAF', 'Gene', '673', (138, 142))	('BRAF', 'Gene', (138, 142))	('EGFR', 'Gene', (62, 66))	('AKT1', 'Gene', (183, 187))	('KRAS', 'Gene', '3845', (92, 96))
317827	26486077	Three (37.5%) KRAS mutations were detected, including 2 G12C and 1 G12V (Figure 2D).	('KRAS', 'Gene', '3845', (14, 18))	('G12C', 'Var', (56, 60))	('G12V', 'Var', (67, 71))	('G12C', 'Mutation', 'rs121913530', (56, 60))	('G12V', 'Mutation', 'rs121913529', (67, 71))	('KRAS', 'Gene', (14, 18))
317828	26486077	All the 6 lung squamous cell carcinoma patients with oncogenic FGFR3 mutations were male, and 5 of them were ever smokers.	('mutations', 'Var', (69, 78))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (10, 38))	('FGFR3', 'Gene', '2261', (63, 68))	('patients', 'Species', '9606', (39, 47))	('carcinoma', 'Phenotype', 'HP:0030731', (29, 38))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (10, 38))	('FGFR3', 'Gene', (63, 68))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (15, 38))	('lung squamous cell carcinoma', 'Disease', (10, 38))
317830	26486077	Both of the two adenocarcinoma cases with CD74-NRG1 fusions were female never-smoking stage I invasive mucinous adenocarcinoma.	('adenocarcinoma', 'Disease', (112, 126))	('invasive mucinous adenocarcinoma', 'Disease', 'MESH:D002288', (94, 126))	('adenocarcinoma', 'Disease', 'MESH:D000230', (16, 30))	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('CD74', 'Gene', (42, 46))	('adenocarcinoma', 'Disease', 'MESH:D000230', (112, 126))	('NRG1', 'Gene', (47, 51))	('fusions', 'Var', (52, 59))	('CD74', 'Gene', '972', (42, 46))	('NRG1', 'Gene', '3084', (47, 51))	('carcinoma', 'Phenotype', 'HP:0030731', (21, 30))	('invasive mucinous adenocarcinoma', 'Disease', (94, 126))	('adenocarcinoma', 'Disease', (16, 30))
317833	26486077	We then compared clinicopathologic characteristics between the 17 lung squamous cell carcinoma patients harboring FGFR fusions or FGFR mutations and 138 lung squamous cell carcinoma cases (both FGFR fusions and FGFR mutations were negative) from October 2007 to April 2010.	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (66, 94))	('FGFR', 'Gene', (130, 134))	('patients', 'Species', '9606', (95, 103))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (71, 94))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (66, 94))	('mutations', 'Var', (135, 144))	('lung squamous cell carcinoma', 'Disease', (66, 94))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (153, 181))	('fusions', 'Var', (119, 126))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (153, 181))	('lung squamous cell carcinoma', 'Disease', (153, 181))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (158, 181))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('FGFR', 'Gene', (114, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (172, 181))
317836	26486077	RFS of lung adenocarcinoma patients harboring EGFR mutations, KRAS mutations or ALK fusions were compared to that of wild-type patients (Supplementary Figure S1).	('KRAS', 'Gene', (62, 66))	('mutations', 'Var', (51, 60))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (7, 26))	('KRAS', 'Gene', '3845', (62, 66))	('EGFR', 'Gene', '1956', (46, 50))	('mutations', 'Var', (67, 76))	('ALK', 'Gene', '238', (80, 83))	('patients', 'Species', '9606', (27, 35))	('patients', 'Species', '9606', (127, 135))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (7, 26))	('EGFR', 'Gene', (46, 50))	('carcinoma', 'Phenotype', 'HP:0030731', (17, 26))	('lung adenocarcinoma', 'Disease', (7, 26))	('Supplementary Figure S1', 'Disease', (137, 160))	('ALK', 'Gene', (80, 83))	('Supplementary Figure S1', 'Disease', 'MESH:D017034', (137, 160))
317837	26486077	A total of 190 lung adenocarcinoma patients with classic EGFR exon 19 deletions or L858R experienced disease recurrence.	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (15, 34))	('L858R', 'Var', (83, 88))	('EGFR', 'Gene', '1956', (57, 61))	('lung adenocarcinoma', 'Disease', (15, 34))	('L858R', 'Mutation', 'rs121434568', (83, 88))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (15, 34))	('patients', 'Species', '9606', (35, 43))	('deletions', 'Var', (70, 79))	('EGFR', 'Gene', (57, 61))	('exon 19 deletions', 'Var', (62, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (25, 34))
317840	26486077	Patients treated with targeted therapies had significantly better survival outcomes both in the stage I-II group (P = 0.005) and the stage III group (P < 0.001).	('better', 'PosReg', (59, 65))	('survival', 'CPA', (66, 74))	('targeted therapies', 'Var', (22, 40))	('Patients', 'Species', '9606', (0, 8))
317843	26486077	Here, we performed a comprehensive analysis of oncogenic driver mutations in a large series of Chinese NSCLC patients.	('patients', 'Species', '9606', (109, 117))	('NSCLC', 'Disease', (103, 108))	('NSCLC', 'Disease', 'MESH:D002289', (103, 108))	('mutations', 'Var', (64, 73))	('NSCLC', 'Phenotype', 'HP:0030358', (103, 108))
317844	26486077	EGFR (15.8%) and KRAS (21.1%) mutations were present in a considerable proportion in lung large cell carcinoma.	('EGFR', 'Gene', (0, 4))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('large cell carcinoma', 'Phenotype', 'HP:0030360', (90, 110))	('present', 'Reg', (45, 52))	('lung large cell carcinoma', 'Phenotype', 'HP:0030360', (85, 110))	('lung large cell carcinoma', 'Disease', 'MESH:D018287', (85, 110))	('lung large cell carcinoma', 'Disease', (85, 110))	('mutations', 'Var', (30, 39))	('KRAS', 'Gene', (17, 21))	('KRAS', 'Gene', '3845', (17, 21))	('EGFR', 'Gene', '1956', (0, 4))
317845	26486077	De Pas and colleagues reported a case of lung large cell carcinoma patient harboring EGFR mutation having dramatic response to gefitinib treatment.	('EGFR', 'Gene', (85, 89))	('EGFR', 'Gene', '1956', (85, 89))	('gefitinib', 'Chemical', 'MESH:D000077156', (127, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (57, 66))	('large cell carcinoma', 'Phenotype', 'HP:0030360', (46, 66))	('lung large cell carcinoma', 'Phenotype', 'HP:0030360', (41, 66))	('lung large cell carcinoma', 'Disease', 'MESH:D018287', (41, 66))	('lung large cell carcinoma', 'Disease', (41, 66))	('mutation', 'Var', (90, 98))	('patient', 'Species', '9606', (67, 74))
317846	26486077	We further found that lung sarcomatoid carcinoma had a high frequency (37.5%) of KRAS mutations.	('KRAS', 'Gene', '3845', (81, 85))	('mutations', 'Var', (86, 95))	('lung sarcomatoid carcinoma', 'Disease', (22, 48))	('lung sarcomatoid carcinoma', 'Disease', 'MESH:C538614', (22, 48))	('sarcomatoid carcinoma', 'Phenotype', 'HP:0100242', (27, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (39, 48))	('KRAS', 'Gene', (81, 85))
317848	26486077	Liao and colleagues reported in 2013 the identification of inhibitor-sensitive oncogenic FGFR2 and FGFR3 mutations in lung squamous cell carcinoma from the Cancer Genome Atlas (TCGA) dataset.	('FGFR2', 'Gene', '2263', (89, 94))	('Cancer Genome Atlas', 'Disease', (156, 175))	('Cancer', 'Phenotype', 'HP:0002664', (156, 162))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (156, 175))	('FGFR3', 'Gene', (99, 104))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (118, 146))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('mutations', 'Var', (105, 114))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (123, 146))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (118, 146))	('lung squamous cell carcinoma', 'Disease', (118, 146))	('FGFR2', 'Gene', (89, 94))	('FGFR3', 'Gene', '2261', (99, 104))
317849	26486077	However, we screened more than 500 Chinese lung squamous cell carcinoma samples, and found that oncogenic FGFR3 mutations were present in only 1.2% (5 S249C and 1 R248C).	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (43, 71))	('lung squamous cell carcinoma', 'Disease', (43, 71))	('FGFR3', 'Gene', (106, 111))	('S249C', 'Var', (151, 156))	('R248C', 'Var', (163, 168))	('S249C', 'Mutation', 'rs121913483', (151, 156))	('R248C', 'Mutation', 'rs121913482', (163, 168))	('FGFR3', 'Gene', '2261', (106, 111))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (43, 71))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (48, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (62, 71))
317851	26486077	In addition to the 3.5% (11 out of 312) of FGFR fusions in lung squamous cell carcinoma, approximately 5% of Chinese lung squamous cell carcinoma could be defined by oncogenic alterations in the FGFR family genes.	('fusions', 'Var', (48, 55))	('FGFR', 'Gene', (43, 47))	('FGFR family', 'Gene', (195, 206))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (59, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (117, 145))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (59, 87))	('lung squamous cell carcinoma', 'Disease', (59, 87))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (117, 145))	('lung squamous cell carcinoma', 'Disease', (117, 145))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (122, 145))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (64, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))
317852	26486077	Through clinicopathologic analysis, we also found that patients with oncogenic FGFR3 mutations were characterized by male, smokers, and larger tumor size without mediastinal lymph node metastasis.	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('FGFR3', 'Gene', '2261', (79, 84))	('mediastinal lymph node metastasis', 'Phenotype', 'HP:0100721', (162, 195))	('tumor', 'Disease', (143, 148))	('FGFR3', 'Gene', (79, 84))	('mutations', 'Var', (85, 94))	('patients', 'Species', '9606', (55, 63))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
317853	26486077	Currently, the detection of mutations in ERBB family genes is mainly limited to the kinase domains of EGFR and HER2.	('HER2', 'Gene', (111, 115))	('ERBB', 'Gene', '1956;2064;2065', (41, 45))	('HER2', 'Gene', '2064', (111, 115))	('ERBB', 'Gene', (41, 45))	('EGFR', 'Gene', '1956', (102, 106))	('EGFR', 'Gene', (102, 106))	('mutations', 'Var', (28, 37))
317854	26486077	However, the identification of oncogenic driver mutations in other sites of the ERBB family genes has continuously been reported.	('mutations', 'Var', (48, 57))	('ERBB', 'Gene', '1956;2064;2065', (80, 84))	('ERBB', 'Gene', (80, 84))
317855	26486077	For example, oncogenic HER2 extracellular domain mutations were found in 0.8% (2 out of 258) of lung adenocarcinoma in the TCGA dataset.	('lung adenocarcinoma', 'Disease', (96, 115))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (96, 115))	('HER2', 'Gene', (23, 27))	('extracellular domain mutations', 'Var', (28, 58))	('HER2', 'Gene', '2064', (23, 27))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (96, 115))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('found', 'Reg', (64, 69))
317856	26486077	Jaiswal and colleagues reported oncogenic ERBB3 mutations were present in approximately 1% of lung adenocarcinoma from a Western cohort.	('ERBB3', 'Gene', '2065', (42, 47))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('lung adenocarcinoma', 'Disease', (94, 113))	('ERBB3', 'Gene', (42, 47))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (94, 113))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (94, 113))	('mutations', 'Var', (48, 57))
317857	26486077	Here we found two EGFR ECD mutations (A289D and R324L), one HER2 ECD mutation (S310Y), one HER2 transmembrane domain mutation (V659E) and no ERBB3 activating mutations, suggesting that oncogenic driver mutations in non-EGFR or HER2 kinase domain of ERBB family genes do exist, but in a very small proportion of Chinese lung adenocarcinoma patients.	('S310Y', 'Mutation', 'rs1057519816', (79, 84))	('EGFR', 'Gene', (219, 223))	('HER2', 'Gene', (60, 64))	('ERBB3', 'Gene', '2065', (141, 146))	('V659E', 'Mutation', 'p.V659E', (127, 132))	('HER2', 'Gene', (227, 231))	('ERBB', 'Gene', (249, 253))	('ERBB', 'Gene', '1956;2064;2065', (141, 145))	('EGFR', 'Gene', (18, 22))	('patients', 'Species', '9606', (339, 347))	('HER2', 'Gene', (91, 95))	('lung adenocarcinoma', 'Disease', (319, 338))	('A289D', 'Mutation', 'rs149840192', (38, 43))	('R324L', 'Var', (48, 53))	('EGFR', 'Gene', '1956', (219, 223))	('ERBB', 'Gene', (141, 145))	('S310Y', 'Var', (79, 84))	('ECD', 'Disease', 'MESH:C574275', (65, 68))	('HER2', 'Gene', '2064', (60, 64))	('ECD', 'Disease', (65, 68))	('ERBB', 'Gene', '1956;2064;2065', (249, 253))	('ERBB3', 'Gene', (141, 146))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (319, 338))	('HER2', 'Gene', '2064', (227, 231))	('A289D', 'Var', (38, 43))	('EGFR', 'Gene', '1956', (18, 22))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (319, 338))	('R324L', 'Mutation', 'rs750429622', (48, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (329, 338))	('HER2', 'Gene', '2064', (91, 95))	('ECD', 'Disease', 'MESH:C574275', (23, 26))	('ECD', 'Disease', (23, 26))
317858	26486077	Imielinski and colleagues reported that oncogenic and sorafenib-sensitive ARAF mutations were present in 1% of lung adenocarcinoma cases in the TCGA samples.	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (111, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('ARAF', 'Gene', '369', (74, 78))	('ARAF', 'Gene', (74, 78))	('lung adenocarcinoma', 'Disease', (111, 130))	('sorafenib', 'Chemical', 'MESH:D000077157', (54, 63))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (111, 130))	('mutations', 'Var', (79, 88))
317859	26486077	NRG1 fusions were also identified as novel oncogenic driver mutations in lung adenocarcinoma.	('lung adenocarcinoma', 'Disease', (73, 92))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (73, 92))	('fusions', 'Var', (5, 12))	('NRG1', 'Gene', (0, 4))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (73, 92))	('NRG1', 'Gene', '3084', (0, 4))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))
317860	26486077	The frequency of NRG1 fusions was reported to be approximately 1.7% in lung adenocarcinomas from an Asian population.	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (71, 90))	('NRG1', 'Gene', (17, 21))	('lung adenocarcinomas', 'Disease', (71, 91))	('fusions', 'Var', (22, 29))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (71, 91))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (71, 91))	('NRG1', 'Gene', '3084', (17, 21))
317861	26486077	Here, we found one ARAF mutation (S214C) and two CD74-NRG1 fusions in 219 "pan-negative" lung adenocarcinoma cases.	('CD74', 'Gene', (49, 53))	('ARAF', 'Gene', '369', (19, 23))	('NRG1', 'Gene', (54, 58))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (89, 108))	('ARAF', 'Gene', (19, 23))	('CD74', 'Gene', '972', (49, 53))	('NRG1', 'Gene', '3084', (54, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('S214C', 'Var', (34, 39))	('S214C', 'Mutation', 'rs1057519786', (34, 39))	('lung adenocarcinoma', 'Disease', (89, 108))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (89, 108))
317862	26486077	Both of the two cases with NRG1 fusions were invasive mucinous adenocarcinoma, which was consistent with previous reports that NRG1 fusions were characterized by invasive mucinous adenocarcinoma histology.	('fusions', 'Var', (32, 39))	('invasive mucinous adenocarcinoma', 'Disease', 'MESH:D002288', (162, 194))	('NRG1', 'Gene', (127, 131))	('NRG1', 'Gene', (27, 31))	('invasive mucinous adenocarcinoma', 'Disease', (45, 77))	('carcinoma', 'Phenotype', 'HP:0030731', (68, 77))	('NRG1', 'Gene', '3084', (127, 131))	('invasive mucinous adenocarcinoma', 'Disease', 'MESH:D002288', (45, 77))	('carcinoma', 'Phenotype', 'HP:0030731', (185, 194))	('NRG1', 'Gene', '3084', (27, 31))	('invasive mucinous adenocarcinoma', 'Disease', (162, 194))
317863	26486077	Targeting oncogenic driver mutations has transformed the management of lung adenocarcinoma patients.	('mutations', 'Var', (27, 36))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (71, 90))	('patients', 'Species', '9606', (91, 99))	('lung adenocarcinoma', 'Disease', (71, 90))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (71, 90))
317871	26486077	In conclusion, we determined the frequency of driver mutations in a large series of Chinese NSCLC patients.	('NSCLC', 'Phenotype', 'HP:0030358', (92, 97))	('patients', 'Species', '9606', (98, 106))	('mutations', 'Var', (53, 62))	('NSCLC', 'Disease', (92, 97))	('NSCLC', 'Disease', 'MESH:D002289', (92, 97))
317877	26486077	For the detection of ALK, ROS1, RET, NRG1, FGFR1, FGFR2 and FGFR3 fusions, we designed multiple pairs of primers to cover all the known fusion variants.	('FGFR1', 'Gene', (43, 48))	('ROS1', 'Gene', (26, 30))	('NRG1', 'Gene', (37, 41))	('ALK', 'Gene', '238', (21, 24))	('FGFR3', 'Gene', (60, 65))	('ROS1', 'Gene', '6098', (26, 30))	('FGFR1', 'Gene', '2260', (43, 48))	('ALK', 'Gene', (21, 24))	('FGFR2', 'Gene', '2263', (50, 55))	('RET', 'Gene', '5979', (32, 35))	('NRG1', 'Gene', '3084', (37, 41))	('fusions', 'Var', (66, 73))	('FGFR2', 'Gene', (50, 55))	('FGFR3', 'Gene', '2261', (60, 65))	('RET', 'Gene', (32, 35))
317974	26413213	Proteins containing JmjC domain are implicated in the regulation of chromatin remodeling and are predicted to be metallo-enzymes adopting the cupin fold.	('metal', 'Chemical', 'MESH:D008670', (113, 118))	('chromatin', 'MPA', (68, 77))	('implicated', 'Reg', (36, 46))	('Proteins', 'Protein', (0, 8))	('JmjC domain', 'Var', (20, 31))
317976	26413213	MINA (Tyrosine 209C) residue readily cross-links and crystallizes in complex with RPL27A (G37C).	('RPL27A', 'Gene', '6157', (82, 88))	('G37C', 'Mutation', 'c.37G>C', (90, 94))	('RPL27A', 'Gene', (82, 88))	('Tyrosine', 'Chemical', 'MESH:D014443', (6, 14))	('cross-links', 'Interaction', (37, 48))	('Tyrosine 209C', 'Var', (6, 19))
317981	26413213	Tissue distribution of mdig/MINA mRNA in normal human tissues as revealed by northern blot analysis showed the presence of mdig/MINA in liver, skeletal muscle, heart, pancreas and placenta whereas in brain, lung and kidney it was undetectable.	('human', 'Species', '9606', (48, 53))	('mdig/MINA', 'Var', (123, 132))	('pancreas', 'Disease', (167, 175))	('pancreas', 'Disease', 'MESH:D010190', (167, 175))
318005	26413213	It is well-known that genetic aberrations contribute to tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Disease', (56, 61))	('contribute', 'Reg', (42, 52))	('genetic aberrations', 'Var', (22, 41))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
318006	26413213	Emerging evidence in the past decade also suggested important contributions of epigenetic alterations on histone proteins and DNA to carcinogenesis.	('histone proteins', 'Protein', (105, 121))	('carcinogenesis', 'Disease', (133, 147))	('carcinogenesis', 'Disease', 'MESH:D063646', (133, 147))	('epigenetic alterations', 'Var', (79, 101))
318008	26413213	By establishing stably transfected cell lines through overexpressing mdig-GFP protein in A549 cells, we have demonstrated the mdig/MINA's ability in decreasing the heterochromatin conformation of A549 cells and derepressing the transcription of genes present in the tandemly repeated DNA regions.	('A549', 'CellLine', 'CVCL:0023', (196, 200))	('A549', 'CellLine', 'CVCL:0023', (89, 93))	('derepressing', 'Reg', (211, 223))	('mdig/MINA', 'Var', (126, 135))	('transcription', 'MPA', (228, 241))	('heterochromatin conformation', 'MPA', (164, 192))	('decreasing', 'NegReg', (149, 159))
318012	26413213	Vice versa, silencing mdig/MINA resulted in a 6.2-fold increase of H19 transcript.	('H19', 'Gene', '283120', (67, 70))	('increase', 'PosReg', (55, 63))	('H19', 'Gene', (67, 70))	('silencing', 'Var', (12, 21))
318024	26413213	Mdig/MINA has also been linked to lymphoma, especially the tumor progression of B cell lymphoma.	('B cell lymphoma', 'Phenotype', 'HP:0012191', (80, 95))	('tumor', 'Disease', (59, 64))	('lymphoma', 'Phenotype', 'HP:0002665', (87, 95))	('lymphoma', 'Disease', (34, 42))	('Mdig/MINA', 'Var', (0, 9))	('lymphoma', 'Disease', 'MESH:D008223', (87, 95))	('lymphoma', 'Disease', (87, 95))	('lymphoma', 'Disease', 'MESH:D008223', (34, 42))	('lymphoma', 'Phenotype', 'HP:0002665', (34, 42))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('B cell lymphoma', 'Disease', 'MESH:D016393', (80, 95))	('B cell lymphoma', 'Disease', (80, 95))	('linked', 'Reg', (24, 30))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
318025	26413213	It is overexpressed in gastric carcinoma and has been associated with tumor proliferation and anti-oncogene inactivation.	('gastric carcinoma', 'Disease', (23, 40))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('tumor', 'Disease', (70, 75))	('inactivation', 'Var', (108, 120))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (23, 40))	('gastric carcinoma', 'Disease', 'MESH:D013274', (23, 40))	('associated', 'Reg', (54, 64))	('carcinoma', 'Phenotype', 'HP:0030731', (31, 40))	('overexpressed', 'PosReg', (6, 19))
318055	26413213	Similarly, our mdig/MINA gene knockout studies in a model of experimental silicosis revealed that the deficiency of mdig/MINA ameliorated silica-induced lung fibrosis and the infiltration of macrophages and Th17 cells by altering the balance between Th17 and Treg cells in the lung.	('Th1', 'Gene', '51497', (207, 210))	('silica-induced', 'Disease', (138, 152))	('Th1', 'Gene', '51497', (250, 253))	('silica', 'Chemical', 'MESH:D012822', (138, 144))	('lung fibrosis', 'Disease', 'MESH:D005355', (153, 166))	('deficiency', 'Var', (102, 112))	('silicosis', 'Disease', 'MESH:D012829', (74, 83))	('silicosis', 'Disease', (74, 83))	('ameliorated', 'PosReg', (126, 137))	('infiltration', 'CPA', (175, 187))	('Th1', 'Gene', (207, 210))	('mdig/MINA', 'Gene', (116, 125))	('lung fibrosis', 'Disease', (153, 166))	('altering', 'Reg', (221, 229))	('Th1', 'Gene', (250, 253))	('lung fibrosis', 'Phenotype', 'HP:0002206', (153, 166))
318058	26413213	Our studies revealed that the deficiency of mdig/MINA gene attenuated silica-induced lung fibrosis and infiltration of macrophages and Th17 cells.	('silica-induced', 'Disease', (70, 84))	('lung fibrosis', 'Disease', (85, 98))	('Th1', 'Gene', '51497', (135, 138))	('silica', 'Chemical', 'MESH:D012822', (70, 76))	('deficiency', 'Var', (30, 40))	('lung fibrosis', 'Phenotype', 'HP:0002206', (85, 98))	('attenuated', 'NegReg', (59, 69))	('mdig/MINA gene', 'Gene', (44, 58))	('lung fibrosis', 'Disease', 'MESH:D005355', (85, 98))	('Th1', 'Gene', (135, 138))
318060	26413213	Nevertheless both the in vivo studies pertaining to mdig/MINA deficiency revealed an attenuated immune response in murine airways, with our studies indicating this observation might result from an impaired function of Th17 cells.	('mdig/MINA', 'Gene', (52, 61))	('Th1', 'Gene', '51497', (218, 221))	('deficiency', 'Var', (62, 72))	('immune response', 'CPA', (96, 111))	('Th1', 'Gene', (218, 221))	('murine', 'Species', '10090', (115, 121))	('attenuated', 'NegReg', (85, 95))
318066	26413213	In our previous studies using lung cancer cell lines and lung epithelial cell line, we found that mdig/MINA enhanced cell proliferation but repressed migration and invasion in in-vitro assays.	('lung cancer', 'Phenotype', 'HP:0100526', (30, 41))	('lung cancer', 'Disease', (30, 41))	('mdig/MINA', 'Var', (98, 107))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('cell proliferation', 'CPA', (117, 135))	('enhanced', 'PosReg', (108, 116))	('lung cancer', 'Disease', 'MESH:D008175', (30, 41))	('invasion', 'CPA', (164, 172))	('migration', 'CPA', (150, 159))	('repressed', 'NegReg', (140, 149))
318067	26413213	This might support the notion that mdig/MINA predicts better survival of patients with lymph node positive, an indication of cancer cell metastasis.	('lymph', 'Var', (87, 92))	('survival', 'CPA', (61, 69))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('patients', 'Species', '9606', (73, 81))	('better', 'PosReg', (54, 60))
318071	26413213	Using an online database containing gene profiling information from 2,437 cases of lung cancer, we found that high level of mdig/MINA predicts poorer overall survival (OS) of the lung cancer patients who had no lymph node metastasis or had only possible proximal lymph node metastasis.	('lung cancer', 'Disease', 'MESH:D008175', (83, 94))	('patients', 'Species', '9606', (191, 199))	('poorer', 'NegReg', (143, 149))	('lung cancer', 'Disease', (179, 190))	('lung cancer', 'Phenotype', 'HP:0100526', (179, 190))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('overall survival', 'MPA', (150, 166))	('lung cancer', 'Disease', (83, 94))	('lung cancer', 'Phenotype', 'HP:0100526', (83, 94))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('lung cancer', 'Disease', 'MESH:D008175', (179, 190))	('mdig/MINA', 'Var', (124, 133))
318081	26413213	revealed that patients who stained negative for mdig/MINA had significantly shorter survival than those who were stained positive for mdig/MINA, especially in stage I or squamous cell carcinoma, indicating that increase of the protein level of mdig/MINA may be associated with a favorable prognosis of lung cancer patients.	('lung cancer', 'Disease', 'MESH:D008175', (302, 313))	('carcinoma', 'Phenotype', 'HP:0030731', (184, 193))	('patients', 'Species', '9606', (314, 322))	('protein level', 'MPA', (227, 240))	('increase', 'PosReg', (211, 219))	('cancer', 'Phenotype', 'HP:0002664', (307, 313))	('survival', 'MPA', (84, 92))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (170, 193))	('lung cancer', 'Disease', (302, 313))	('squamous cell carcinoma', 'Disease', (170, 193))	('lung cancer', 'Phenotype', 'HP:0100526', (302, 313))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (170, 193))	('mdig/MINA', 'Var', (244, 253))	('shorter', 'NegReg', (76, 83))	('patients', 'Species', '9606', (14, 22))
318085	26413213	In both H226B cells and A549 cells, overexpression of mdig/MINA inhibited cell migration and invasion, whereas silencing mdig/MINA with shRNA enhanced migration and invasion of these cancer cells.	('migration', 'CPA', (151, 160))	('A549', 'CellLine', 'CVCL:0023', (24, 28))	('cancer', 'Disease', (183, 189))	('silencing', 'Var', (111, 120))	('H226B', 'CellLine', 'CVCL:J621', (8, 13))	('inhibited', 'NegReg', (64, 73))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('invasion', 'CPA', (165, 173))	('enhanced', 'PosReg', (142, 150))	('cancer', 'Disease', 'MESH:D009369', (183, 189))
318087	26413213	A study evaluated two myc gene-regulated proteins, mdig/MINA and Cap 43, in neuroblastoma revealed that mdig/MINA is a clinico-pathological prognostic predicator of neuroblastoma, one of the common pediatric solid cancers.	('neuroblastoma', 'Disease', (76, 89))	('cancers', 'Phenotype', 'HP:0002664', (214, 221))	('neuroblastoma', 'Phenotype', 'HP:0003006', (76, 89))	('cancers', 'Disease', (214, 221))	('Cap 43', 'Gene', (65, 71))	('cancers', 'Disease', 'MESH:D009369', (214, 221))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('neuroblastoma', 'Disease', 'MESH:D009447', (165, 178))	('Cap 43', 'Gene', '10397', (65, 71))	('neuroblastoma', 'Disease', (165, 178))	('mdig/MINA', 'Var', (104, 113))	('neuroblastoma', 'Phenotype', 'HP:0003006', (165, 178))	('neuroblastoma', 'Disease', 'MESH:D009447', (76, 89))
318096	26413213	Silencing of mdig/MINA by siRNA in human pancreatic cell line, PANC-1, induced cell cycle arrest in G2/M phase and apoptosis, resulting in diminished growth of the cells.	('PANC-1', 'CellLine', 'CVCL:0480', (63, 69))	('human', 'Species', '9606', (35, 40))	('cell cycle arrest in G2/M phase', 'CPA', (79, 110))	('apoptosis', 'CPA', (115, 124))	('pancreatic', 'Disease', (41, 51))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (79, 96))	('pancreatic', 'Disease', 'MESH:D010195', (41, 51))	('growth', 'CPA', (150, 156))	('Silencing', 'Var', (0, 9))	('diminished', 'NegReg', (139, 149))	('mdig/MINA', 'Gene', (13, 22))
318113	26413213	Altogether, high mdig/MINA expression predicted poor prognosis in patients with gastric carcinoma.	('gastric carcinoma', 'Disease', (80, 97))	('high', 'Var', (12, 16))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (80, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('gastric carcinoma', 'Disease', 'MESH:D013274', (80, 97))	('patients', 'Species', '9606', (66, 74))	('mdig/MINA', 'Gene', (17, 26))
318123	26413213	Mdig/MINA is a known oncogene that exerts a proliferative effect in several cancer cell lines and abrogation of mdig/MINA inhibits cell proliferation.	('inhibits', 'NegReg', (122, 130))	('abrogation', 'Var', (98, 108))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('mdig/MINA', 'Gene', (112, 121))	('cell proliferation', 'CPA', (131, 149))	('proliferative effect', 'MPA', (44, 64))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))
318145	26413213	Our earlier reports stated that mdig/MINA predicts poorer overall survival in patients with earlier stages of lung cancer.	('overall survival', 'MPA', (58, 74))	('lung cancer', 'Disease', 'MESH:D008175', (110, 121))	('mdig/MINA', 'Var', (32, 41))	('poorer', 'NegReg', (51, 57))	('patients', 'Species', '9606', (78, 86))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('lung cancer', 'Disease', (110, 121))	('lung cancer', 'Phenotype', 'HP:0100526', (110, 121))
318174	26413213	Recently, studies performed in heterozygous myc knockout mice (myc+/-) revealed that decreased myc expression promoted longevity and benefited multiple organs and physiological process thereby enhancing the health span of the animals.	('mice', 'Species', '10090', (57, 61))	('expression', 'MPA', (99, 109))	('longevity', 'CPA', (119, 128))	('decreased', 'Var', (85, 94))	('benefited', 'PosReg', (133, 142))	('health span of', 'CPA', (207, 221))	('myc', 'Gene', (95, 98))	('enhancing', 'PosReg', (193, 202))	('promoted', 'PosReg', (110, 118))
318175	26413213	Age-related pathologies, notably cardiac fibrosis and immunosenescence were found to be attenuated in the myc+/- mice.	('cardiac fibrosis', 'Disease', (33, 49))	('cardiac fibrosis', 'Disease', 'MESH:D005355', (33, 49))	('attenuated', 'NegReg', (88, 98))	('mice', 'Species', '10090', (113, 117))	('immunosenescence', 'CPA', (54, 70))	('myc+/-', 'Var', (106, 112))
318176	26413213	This is an important finding that further strengthens our mdig/MINA knockout studies reporting that mdig/MINA deficiency ameliorated silica-induced pulmonary fibrosis in mice by altering the balance between Th17 and Treg cells.	('altering', 'Reg', (178, 186))	('Th1', 'Gene', '51497', (207, 210))	('mdig/MINA', 'Gene', (100, 109))	('pulmonary fibrosis', 'Disease', (148, 166))	('Th1', 'Gene', (207, 210))	('deficiency', 'Var', (110, 120))	('ameliorated', 'PosReg', (121, 132))	('mice', 'Species', '10090', (170, 174))	('pulmonary fibrosis', 'Phenotype', 'HP:0002206', (148, 166))	('silica', 'Chemical', 'MESH:D012822', (133, 139))	('pulmonary fibrosis', 'Disease', 'MESH:D011658', (148, 166))	('balance', 'MPA', (191, 198))
318182	26413213	High level of mdig/MINA is an indicator for poor diagnosis of multiple myeloma, possibly due to the enhanced Jak-STAT signaling by mdig/MINA (Wu et al.	('multiple myeloma', 'Disease', 'MESH:D009101', (62, 78))	('STAT', 'Gene', (113, 117))	('STAT', 'Gene', '6774', (113, 117))	('multiple myeloma', 'Phenotype', 'HP:0006775', (62, 78))	('enhanced', 'PosReg', (100, 108))	('multiple myeloma', 'Disease', (62, 78))	('mdig/MINA', 'Var', (131, 140))
318187	33232910	Moreover, YTHDC2 exhibited antitumor activity in human LUAD cells.	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('LUAD', 'Phenotype', 'HP:0030078', (55, 59))	('tumor', 'Disease', (31, 36))	('human', 'Species', '9606', (49, 54))	('YTHDC2', 'Var', (10, 16))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
318188	33232910	Mechanistically, YTHDC2, via its m6A-recognizing YTH domain, suppressed cystine uptake and blocked the downstream antioxidant program.	('suppressed', 'NegReg', (61, 71))	('cystine', 'Chemical', 'MESH:D003553', (72, 79))	('blocked', 'NegReg', (91, 98))	('YTHDC2', 'Var', (17, 23))	('cystine uptake', 'MPA', (72, 86))
318204	33232910	In this study, we found that YTHDC2 inhibits LUAD tumorigenesis in vivo and in vitro and is largely dependent on its YTH domain.	('LUAD', 'Phenotype', 'HP:0030078', (45, 49))	('LUAD', 'Disease', (45, 49))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('inhibits', 'NegReg', (36, 44))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('YTHDC2', 'Var', (29, 35))	('tumor', 'Disease', (50, 55))
318210	33232910	KrasLSL-G12D/+; p53LSL-R172H/+ (KP) strains were purchased from the Jackson Laboratory.	('R172H', 'Mutation', 'p.R172H', (23, 28))	('G12D', 'Mutation', 'rs121913529', (8, 12))	('Kras', 'Gene', '16653', (0, 4))	('Kras', 'Gene', (0, 4))	('p53LSL-R172H/+', 'Var', (16, 30))
318212	33232910	The mice were also simultaneously intranasal infected with AAV5 encoding YTHDC2WT (WT indicates wide-type of YTHDC2) or YTHDC2 DeltaYTH (DeltaYTH indicates YTH domain dele of YTHDC2) under anaesthesia.	('infected', 'Disease', 'MESH:D007239', (45, 53))	('mice', 'Species', '10090', (4, 8))	('YTHDC2 DeltaYTH', 'Var', (120, 135))	('infected', 'Disease', (45, 53))	('YTHDC2WT', 'Var', (73, 81))	('AAV5', 'Var', (59, 63))
318228	33232910	For crispr/cas9 knockout of YTHDC2, NRF2, XRN2 and EXOSC10, single guide RNAs (sgRNAs) were cloned into the LentiCrisprV2 plasmid (Addgene, Cambridge, MA, USA).	('XRN2', 'Gene', (42, 46))	('XRN2', 'Gene', '22803', (42, 46))	('EXOSC10', 'Gene', (51, 58))	('knockout', 'Var', (16, 24))	('NRF2', 'Gene', (36, 40))	('YTHDC2', 'Gene', (28, 34))	('EXOSC10', 'Gene', '5394', (51, 58))
318230	33232910	SLC7A11-expressing and METTL3 shRNA-expressing plasmids were purchased from Zuorun Biotech Ltd. YTHDC2WT-HA and YTHDC2 DeltaYTH-HA were also cloned into pCDNA3.1(+).	('YTHDC2WT-HA', 'Var', (96, 107))	('YTHDC2 DeltaYTH-HA', 'Var', (112, 130))	('METTL3', 'Gene', '56339', (23, 29))	('METTL3', 'Gene', (23, 29))
318231	33232910	The primary antibodies used for IB were: anti-YTHDC2 (Abcam, #ab176846, Cambridge, MA, USA), anti-SLC7A11 (#ab175186), anti-ATF4 (#ab184909), anti-NRF2 (#ab89443), anti-XRN2 (#ab72181), anti-EXOSC10 (#ab94981), anti-METTL3 (#ab195352), anti-METTL14 (#ab220030), anti-WTAP (#ab195380), anti-HA (#ab1424), anti-FLAG (#ab125243, #ab236777), anti-XRN1 (#ab70259), and anti-GAPDH (#ab181602).	('#ab70259', 'Var', (349, 357))	('#ab220030', 'Var', (250, 259))	('#ab94981', 'Var', (200, 208))	('METTL3', 'Gene', '56339', (216, 222))	('METTL14', 'Gene', (241, 248))	('XRN2', 'Gene', (169, 173))	('GAPDH', 'Gene', (369, 374))	('EXOSC10', 'Gene', (191, 198))	('#ab195380', 'Var', (273, 282))	('WTAP', 'Gene', (267, 271))	('XRN2', 'Gene', '22803', (169, 173))	('XRN1', 'Gene', (343, 347))	('EXOSC10', 'Gene', '5394', (191, 198))	('#ab195352', 'Var', (224, 233))	('#ab125243', 'Var', (315, 324))	('#ab89443', 'Var', (153, 161))	('#ab72181', 'Var', (175, 183))	('#ab181602', 'Var', (376, 385))	('METTL14', 'Gene', '57721', (241, 248))	('GAPDH', 'Gene', '2597', (369, 374))	('METTL3', 'Gene', (216, 222))	('WTAP', 'Gene', '9589', (267, 271))	('XRN1', 'Gene', '54464', (343, 347))
318232	33232910	The antibodies used for IHC were: anti-YTHDC2 (#ab176846), anti-SLC7A11 (#ab175186), anti-PCNA (#ab92742) and anti-4-HNE (#ab48506).	('4-HNE', 'Chemical', 'MESH:C027576', (115, 120))	('#ab48506', 'Var', (122, 130))	('PCNA', 'Gene', '5111', (90, 94))	('#ab175186', 'Var', (73, 82))	('#ab92742', 'Var', (96, 104))	('PCNA', 'Gene', (90, 94))	('#ab176846', 'Var', (47, 56))
318238	33232910	For luciferase experiments, CDS and partial 3'UTR contain consensus m6A motif of SLC7A11 mRNA were cloned into the pmir-GLO plasmids.	('SLC7A11', 'Gene', (81, 88))	('CDS', 'Chemical', 'MESH:D002104', (28, 31))	('m6A motif', 'Var', (68, 77))
318239	33232910	For mutant reporter vectors, adenosine (A) in the m6A motif was replaced by a cytosine (C).	('cytosine', 'Chemical', 'MESH:D003596', (78, 86))	('adenosine', 'Chemical', 'MESH:D000241', (29, 38))	('mutant', 'Var', (4, 10))	('adenosine', 'MPA', (29, 38))
318243	33232910	For photoactivatable ribonucleotide crosslinking and immunoprecipitation (PAR-CLIP), control cells and cells stably expressing YTHDC2WT-HA or YTHDC2 DeltaYTH-HA were cultured with 4-SU (250 muM, Sigma) for 16 h, then irradiated with 365 nm UV light for crosslinking.	('4-SU', 'Chemical', '-', (180, 184))	('YTHDC2 DeltaYTH-HA', 'Var', (142, 160))	('ribonucleotide', 'Chemical', 'MESH:D012265', (21, 35))	('YTHDC2WT-HA', 'Var', (127, 138))
318247	33232910	About 1 x 107 H1299 cells with control, YTHDC2WT-HA or YTHDC2 DeltaYTH-HA groups were washed with cold PBS and lysed in protein lysis buffer.	('YTHDC2 DeltaYTH-HA', 'Var', (55, 73))	('H1299', 'CellLine', 'CVCL:0060', (14, 19))	('cold PBS', 'Disease', (98, 106))	('cold PBS', 'Disease', 'MESH:D011535', (98, 106))
318248	33232910	To ascertain the involvement of lipid peroxidation in lung tumorigenesis, the cells were stained by 5 muM fluorescent probe C11-BODIPY581/591 for 30 min at 37  C followed by flow cytometry.	('lung tumor', 'Phenotype', 'HP:0100526', (54, 64))	('lung tumor', 'Disease', (54, 64))	('lung tumor', 'Disease', 'MESH:D008175', (54, 64))	('C11-BODIPY581', 'Chemical', '-', (124, 137))	('C11-BODIPY581/591', 'Var', (124, 141))	('lipid', 'Chemical', 'MESH:D008055', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
318251	33232910	The malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE) concentration were assessed using lipid peroxidation assay kits (Abcam, #ab118970 and #ab238538).	('malondialdehyde', 'MPA', (4, 19))	('malondialdehyde', 'Chemical', 'MESH:D008315', (4, 19))	('lipid', 'Chemical', 'MESH:D008055', (89, 94))	('4-hydroxynonenal', 'Chemical', 'MESH:C027576', (30, 46))	('4-HNE', 'Chemical', 'MESH:C027576', (48, 53))	('#ab238538', 'Var', (141, 150))	('#ab118970', 'Var', (127, 136))	('MDA', 'Chemical', 'MESH:D008315', (21, 24))
318268	33232910	Conditional activation of oncogenic Kras and inactivation of p53 in KP mice by viruses that express Cre in lung epithelial cells results in a rapid development of LUAD.	('mice', 'Species', '10090', (71, 75))	('Kras', 'Gene', (36, 40))	('inactivation', 'Var', (45, 57))	('LUAD', 'Phenotype', 'HP:0030078', (163, 167))	('LUAD', 'Disease', (163, 167))	('p53', 'Gene', (61, 64))	('Kras', 'Gene', '16653', (36, 40))
318270	33232910	In addition to strong GFP signals, YTHDC2 was confirmed to be upregulated for a sustained period in tumors from KPYWT and KPYDeltaYTH mice compared to those of KPE mice 25 wk post infection (Fig.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('mice', 'Species', '10090', (134, 138))	('mice', 'Species', '10090', (164, 168))	('tumors', 'Disease', (100, 106))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('upregulated', 'PosReg', (62, 73))	('YTHDC2', 'Gene', (35, 41))	('infection', 'Disease', (180, 189))	('infection', 'Disease', 'MESH:D007239', (180, 189))	('KPYDeltaYTH', 'Var', (122, 133))
318271	33232910	Although YTHDC2 was unable to stop lung tumorigenesis, the tumor occurrence time was delayed, the overwhelming lung tumor burden was significantly suppressed, and the survival time was longer in KPYWT mice than in KPE mice and KPYDeltaYTH mice (Fig.	('tumor', 'Disease', (59, 64))	('lung tumor', 'Phenotype', 'HP:0100526', (35, 45))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('lung tumor', 'Disease', (111, 121))	('lung tumor', 'Phenotype', 'HP:0100526', (111, 121))	('mice', 'Species', '10090', (201, 205))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('mice', 'Species', '10090', (218, 222))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('lung tumor', 'Disease', 'MESH:D008175', (35, 45))	('longer', 'PosReg', (185, 191))	('tumor', 'Disease', (40, 45))	('mice', 'Species', '10090', (239, 243))	('delayed', 'NegReg', (85, 92))	('lung tumor', 'Disease', 'MESH:D008175', (111, 121))	('survival time', 'CPA', (167, 180))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('suppressed', 'NegReg', (147, 157))	('KPYWT', 'Var', (195, 200))	('lung tumor', 'Disease', (35, 45))	('tumor', 'Disease', (116, 121))
318274	33232910	While the number and size of the 3D spheroids and the tumor growth of xenografts decreased following YTHDC2WT overexpression in H1299 cells, these effects were not observed upon YTHDC2DeltaYTH overexpression (Fig.	('decreased', 'NegReg', (81, 90))	('overexpression', 'Var', (110, 124))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('H1299', 'CellLine', 'CVCL:0060', (128, 133))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('YTHDC2WT overexpression', 'Var', (101, 124))	('tumor', 'Disease', (54, 59))
318275	33232910	In contrast, knocking out YTHDC2 in H1975 cells increased spheroid formation and xenograft growth in mice (Figs.	('increased', 'PosReg', (48, 57))	('spheroid formation', 'CPA', (58, 76))	('YTHDC2', 'Gene', (26, 32))	('mice', 'Species', '10090', (101, 105))	('knocking out', 'Var', (13, 25))	('H1975', 'CellLine', 'CVCL:1511', (36, 41))	('xenograft growth', 'CPA', (81, 97))
318276	33232910	Notably, when YTHDC2 expression was reconstituted using YTHDC2sg2-resistant (res), the positive roles of YTHDC2-sg2 in tumorigenesis were restored (Figs.	('tumor', 'Disease', (119, 124))	('YTHDC2-sg2', 'Var', (105, 115))	('YTHDC2sg2', 'Gene', (56, 65))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('YTHDC2sg2', 'Gene', '64848', (56, 65))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))
318277	33232910	Thus, YTHDC2 exerts a tumor suppressive function in LUAD via its m6A reading domain.	('LUAD', 'Disease', (52, 56))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('LUAD', 'Phenotype', 'HP:0030078', (52, 56))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('tumor', 'Disease', (22, 27))	('YTHDC2', 'Var', (6, 12))
318278	33232910	To exclude potential competitive interference with endogenous YTHDC2 function in our overexpression experiments, YTHDC2 activity was reconstituted by FLAG-tagged YTHDC2sg2-res in YTHDC2-sg2-mediated YTHDC2 knockout H1299 cells, and its expression was adjusted to a similar level in NC-sg-treated control cells before further overexpressing HA-tagged YTHDC2sg2-res or YTHDC2 YTH (sg2-res) (Fig.	('YTHDC2sg2', 'Gene', (350, 359))	('YTHDC2', 'Gene', (113, 119))	('YTHDC2', 'Var', (367, 373))	('H1299', 'CellLine', 'CVCL:0060', (215, 220))	('YTHDC2sg2', 'Gene', '64848', (350, 359))	('YTHDC2sg2', 'Gene', (162, 171))	('YTHDC2sg2', 'Gene', '64848', (162, 171))
318285	33232910	Among the significantly altered metabolites, a 3.975-fold increase in cystine was observed in YTHDC2low tumors compared to YTHDC2high tumors (Fig.	('tumors', 'Disease', (134, 140))	('increase', 'PosReg', (58, 66))	('tumors', 'Disease', 'MESH:D009369', (134, 140))	('cystine', 'Chemical', 'MESH:D003553', (70, 77))	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('tumors', 'Disease', (104, 110))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('cystine', 'MPA', (70, 77))	('YTHDC2low', 'Var', (94, 103))	('metabolites', 'MPA', (32, 43))
318286	33232910	Moreover, a negative correlation between YTHDC2 and intracellular cystine was observed in cohort #1 (n = 100) (Fig.	('negative', 'NegReg', (12, 20))	('cystine', 'Chemical', 'MESH:D003553', (66, 73))	('YTHDC2', 'Var', (41, 47))	('intracellular cystine', 'MPA', (52, 73))
318287	33232910	These data indicate that YTHDC2 reduces intracellular cystine.	('reduces', 'NegReg', (32, 39))	('cystine', 'Chemical', 'MESH:D003553', (54, 61))	('intracellular cystine', 'MPA', (40, 61))	('YTHDC2', 'Var', (25, 31))
318288	33232910	To verify whether YTHDC2 reduces cystine uptake, we cultured primary patient-derived LUAD cells with either high (pHY#1-8) or low (pLY#1-8) YTHDC2 expression levels (Fig.	('reduces', 'NegReg', (25, 32))	('YTHDC2', 'Gene', (140, 146))	('expression', 'MPA', (147, 157))	('patient', 'Species', '9606', (69, 76))	('cystine', 'Chemical', 'MESH:D003553', (33, 40))	('YTHDC2', 'Var', (18, 24))	('LUAD', 'Phenotype', 'HP:0030078', (85, 89))	('cystine uptake', 'MPA', (33, 47))
318289	33232910	Extracellular cystine levels in the culture medium were lower in pLY#1-8 cells than in pHY#1-8 cells, while intracellular cystine levels were higher (Figs.	('pLY#1-8', 'Var', (65, 72))	('intracellular cystine levels', 'MPA', (108, 136))	('cystine', 'Chemical', 'MESH:D003553', (14, 21))	('cystine', 'Chemical', 'MESH:D003553', (122, 129))	('lower', 'NegReg', (56, 61))	('Extracellular cystine levels in the', 'MPA', (0, 35))	('higher', 'PosReg', (142, 148))
318292	33232910	Indeed, in the present, YTHDC2 was observed to increase CHAC1 mRNA levels (Figs.	('CHAC1', 'Gene', (56, 61))	('CHAC1', 'Gene', '79094', (56, 61))	('YTHDC2', 'Var', (24, 30))	('increase', 'PosReg', (47, 55))
318294	33232910	The glutamate release assay results showed that YTHDC2 suppresses glutamate release (Fig.	('glutamate', 'Chemical', 'MESH:D018698', (4, 13))	('glutamate', 'Chemical', 'MESH:D018698', (66, 75))	('YTHDC2', 'Var', (48, 54))	('glutamate release', 'MPA', (66, 83))	('suppresses', 'NegReg', (55, 65))
318295	33232910	These results suggest that YTHDC2 impairs cystine uptake via the inhibition of system Xc-.	('inhibition', 'NegReg', (65, 75))	('cystine', 'Chemical', 'MESH:D003553', (42, 49))	('system Xc-', 'Enzyme', (79, 89))	('cystine uptake', 'MPA', (42, 56))	('YTHDC2', 'Var', (27, 33))	('impairs', 'NegReg', (34, 41))
318298	33232910	Data from patient-derived LUAD cells and tumors in mice demonstrated that GSH was indeed reduced by YTHDC2 (Figs.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('mice', 'Species', '10090', (51, 55))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('tumors', 'Disease', (41, 47))	('patient', 'Species', '9606', (10, 17))	('tumors', 'Disease', 'MESH:D009369', (41, 47))	('GSH', 'Chemical', '-', (74, 77))	('YTHDC2', 'Var', (100, 106))	('reduced', 'NegReg', (89, 96))	('LUAD', 'Phenotype', 'HP:0030078', (26, 30))	('GSH', 'MPA', (74, 77))
318300	33232910	The tumor burden in the lung was significantly higher in KPYWT mice with NAC and GSH administration than in the vehicle-treated control mice, and the levels were similar to that of the KPE mice (Fig.	('tumor', 'Disease', (4, 9))	('mice', 'Species', '10090', (136, 140))	('mice', 'Species', '10090', (189, 193))	('higher', 'PosReg', (47, 53))	('NAC', 'Var', (73, 76))	('KPYWT', 'Var', (57, 62))	('mice', 'Species', '10090', (63, 67))	('GSH', 'Chemical', '-', (81, 84))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('NAC', 'Chemical', 'MESH:D000111', (73, 76))
318302	33232910	A potential reason for this result is that YTHDC2 impairs system Xc-, and we proposed that the impairment of system Xc- function might be critical for the facilitation of GSH and its raw materials other than cystine, such as cysteine or its precursor to enter into cell.	('system Xc-', 'MPA', (58, 68))	('cysteine', 'Chemical', 'MESH:D003545', (225, 233))	('impairs', 'NegReg', (50, 57))	('cystine', 'Chemical', 'MESH:D003553', (208, 215))	('GSH', 'Chemical', '-', (171, 174))	('YTHDC2', 'Var', (43, 49))
318304	33232910	3G, the lack of GSH leads to an increase in lipid peroxidation.	('lack', 'Var', (8, 12))	('increase', 'PosReg', (32, 40))	('lipid peroxidation', 'MPA', (44, 62))	('GSH', 'Chemical', '-', (16, 19))	('lipid', 'Chemical', 'MESH:D008055', (44, 49))	('GSH', 'Gene', (16, 19))
318307	33232910	S3O, the fraction of oxidized C11-BODIPY581/591 (green) was largely increased in the tumors of KPYWT mice compared to those of KPE mice; however, these levels were similar in the tumors of KPE and KPYDeltaYTH mice.	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('mice', 'Species', '10090', (209, 213))	('tumors', 'Disease', 'MESH:D009369', (85, 91))	('tumors', 'Disease', (179, 185))	('C11-BODIPY581', 'Chemical', '-', (30, 43))	('tumors', 'Phenotype', 'HP:0002664', (179, 185))	('C11-BODIPY581/591', 'Var', (30, 47))	('tumors', 'Disease', 'MESH:D009369', (179, 185))	('mice', 'Species', '10090', (101, 105))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('mice', 'Species', '10090', (131, 135))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('increased', 'PosReg', (68, 77))	('tumors', 'Disease', (85, 91))
318310	33232910	Overall, these results indicate the m6A reading function of YTHDC2 is essential to reduce the cystine downstream antioxidant program.	('YTHDC2', 'Gene', (60, 66))	('cystine', 'Chemical', 'MESH:D003553', (94, 101))	('m6A reading function', 'Var', (36, 56))	('cystine downstream antioxidant program', 'MPA', (94, 132))	('reduce', 'NegReg', (83, 89))
318316	33232910	Subsequently, we investigated whether YTHDC2 inhibits cystine uptake via SLC7A11.	('cystine', 'Chemical', 'MESH:D003553', (54, 61))	('YTHDC2', 'Var', (38, 44))	('cystine uptake', 'MPA', (54, 68))	('inhibits', 'NegReg', (45, 53))
318318	33232910	In contrast, YTHDC2 deletion-induced cystine uptake was reversed by shRNA targeting SLC7A11 in H1975 cells (Figs.	('deletion-induced', 'Var', (20, 36))	('YTHDC2', 'Gene', (13, 19))	('cystine', 'Chemical', 'MESH:D003553', (37, 44))	('H1975', 'CellLine', 'CVCL:1511', (95, 100))	('SLC7A11', 'Gene', (84, 91))	('cystine uptake', 'MPA', (37, 51))
318320	33232910	Hence, YTHDC2 impairs cystine uptake dependent on SLC7A11.	('cystine uptake', 'MPA', (22, 36))	('SLC7A11', 'Gene', (50, 57))	('YTHDC2', 'Var', (7, 13))	('impairs', 'NegReg', (14, 21))	('cystine', 'Chemical', 'MESH:D003553', (22, 29))
318325	33232910	Knocking out YTHDC2 followed by reconstituting its expression in H1975 cells also voted that YTHDC2 regulates SLC7A11 transcription (Fig.	('SLC7A11', 'Gene', (110, 117))	('transcription', 'MPA', (118, 131))	('regulates', 'Reg', (100, 109))	('H1975', 'CellLine', 'CVCL:1511', (65, 70))	('YTHDC2', 'Var', (93, 99))
318327	33232910	Loss of function of YTHDC2 by CRISPR/Cas9 technology followed by YTHDC2 reconstitution in H1975 cells further confirmed that YTHDC2 accelerates SLC7A11 mRNA decay (Fig.	('H1975', 'CellLine', 'CVCL:1511', (90, 95))	('SLC7A11 mRNA decay', 'MPA', (144, 162))	('Loss', 'NegReg', (0, 4))	('YTHDC2', 'Var', (125, 131))	('accelerates', 'PosReg', (132, 143))
318329	33232910	Deletion of EXOSC10, but not XRN2, diminished the effects of YTHDC2 on shortening the SLC7A11 mRNA half-life (Fig.	('EXOSC10', 'Gene', '5394', (12, 19))	('SLC7A11 mRNA half-life', 'MPA', (86, 108))	('YTHDC2', 'Gene', (61, 67))	('XRN2', 'Gene', (29, 33))	('XRN2', 'Gene', '22803', (29, 33))	('EXOSC10', 'Gene', (12, 19))	('shortening', 'NegReg', (71, 81))	('Deletion', 'Var', (0, 8))
318333	33232910	Among the three major writers, i.e., METTL3, METTL14, and WTAP, only a higher METTL3 expression level was found to correlate with a higher global m6A methylation level in H1975 cells compared to H1299 cells (Figs.	('higher', 'PosReg', (132, 138))	('expression', 'MPA', (85, 95))	('METTL3', 'Gene', (78, 84))	('METTL14', 'Gene', (45, 52))	('WTAP', 'Gene', '9589', (58, 62))	('WTAP', 'Gene', (58, 62))	('METTL14', 'Gene', '57721', (45, 52))	('H1975', 'Var', (171, 176))	('H1975', 'CellLine', 'CVCL:1511', (171, 176))	('METTL3', 'Gene', (37, 43))	('H1299', 'CellLine', 'CVCL:0060', (195, 200))	('METTL3', 'Gene', '56339', (78, 84))	('METTL3', 'Gene', '56339', (37, 43))	('m6A methylation level', 'MPA', (146, 167))
318336	33232910	Knocking down METTL3 in H1975 cells prolonged the half-life of SLC7A11 mRNA, whereas overexpressing METTL3 in H1299 cells accelerated SLC7A11 mRNA degradation (Fig.	('SLC7A11 mRNA', 'MPA', (63, 75))	('SLC7A11 mRNA degradation', 'MPA', (134, 158))	('Knocking', 'Var', (0, 8))	('METTL3', 'Gene', '56339', (100, 106))	('H1299', 'CellLine', 'CVCL:0060', (110, 115))	('half-life', 'MPA', (50, 59))	('METTL3', 'Gene', '56339', (14, 20))	('METTL3', 'Gene', (100, 106))	('METTL3', 'Gene', (14, 20))	('accelerated', 'PosReg', (122, 133))	('prolonged', 'PosReg', (36, 45))	('H1975', 'CellLine', 'CVCL:1511', (24, 29))
318340	33232910	m6A modification in SLC7A11 mRNA was significantly reduced specifically around the putative m6A site after METTL3 was knocked down in H1975 cells.	('reduced', 'NegReg', (51, 58))	('METTL3', 'Gene', '56339', (107, 113))	('METTL3', 'Gene', (107, 113))	('SLC7A11', 'Gene', (20, 27))	('knocked down', 'Var', (118, 130))	('H1975', 'CellLine', 'CVCL:1511', (134, 139))	('m6A', 'Var', (0, 3))
318343	33232910	In contrast, the SLC7A11 mRNA-YTHDC2 interaction was remarkably suppressed once METTL3 was knocked down in H1975 cells (Fig.	('H1975', 'CellLine', 'CVCL:1511', (107, 112))	('suppressed', 'NegReg', (64, 74))	('SLC7A11', 'Gene', (17, 24))	('METTL3', 'Gene', '56339', (80, 86))	('METTL3', 'Gene', (80, 86))	('knocked down', 'Var', (91, 103))	('interaction', 'Interaction', (37, 48))
318344	33232910	Regardless of whether METTL3 was overexpressed or knocked down, deletion of the YTH domain blocked the SLC7A11 mRNA-YTHDC2 interaction (Fig.	('blocked', 'NegReg', (91, 98))	('SLC7A11 mRNA-YTHDC2 interaction', 'MPA', (103, 134))	('deletion', 'Var', (64, 72))	('METTL3', 'Gene', '56339', (22, 28))	('METTL3', 'Gene', (22, 28))
318346	33232910	YTHDC2WT, but not YTHDC2DeltaYTH, bound preferentially to the 3'UTR of SLC7A11 mRNA containing an m6A compared to the one with an unmethylated adenosine (Fig.	('SLC7A11', 'Gene', (71, 78))	('bound', 'Interaction', (34, 39))	('preferentially', 'PosReg', (40, 54))	('m6A', 'Var', (98, 101))	('adenosine', 'Chemical', 'MESH:D000241', (143, 152))
318347	33232910	Indeed, higher global m6A methylation caused a stronger SLC7A11 mRNA-YTHDC2 interaction in H1975 cells than in H1299 cells (Fig.	('H1299', 'CellLine', 'CVCL:0060', (111, 116))	('stronger', 'PosReg', (47, 55))	('interaction', 'Interaction', (76, 87))	('H1975', 'CellLine', 'CVCL:1511', (91, 96))	('global m6A methylation', 'MPA', (15, 37))	('H1975', 'Var', (91, 96))	('SLC7A11', 'Gene', (56, 63))	('higher', 'PosReg', (8, 14))
318350	33232910	The results suggested that only overexpression of YTHDC2WT but not YTHDC2DeltaYTH reduced SLC7A11 mRNA stability in H1299 cells and that knocking out YTHDC2 could increase its stability in H1975 cells.	('H1975', 'CellLine', 'CVCL:1511', (189, 194))	('SLC7A11 mRNA stability', 'MPA', (90, 112))	('increase', 'PosReg', (163, 171))	('YTHDC2', 'Gene', (150, 156))	('stability', 'MPA', (176, 185))	('H1299', 'CellLine', 'CVCL:0060', (116, 121))	('knocking out', 'Var', (137, 149))	('reduced', 'NegReg', (82, 89))
318352	33232910	Overall survival was much shorter among acinar LUAD patients with YTHDC2low compared to those without this expression pattern (Fig.	('LUAD', 'Phenotype', 'HP:0030078', (47, 51))	('acinar LUAD', 'Disease', (40, 51))	('YTHDC2low', 'Var', (66, 75))	('Overall', 'MPA', (0, 7))	('shorter', 'NegReg', (26, 33))	('patients', 'Species', '9606', (52, 60))
318365	33232910	7M), confirming that suppression of YTHDC2 in LUAD prevents lipid peroxidation by upregulating SLC7A11.	('YTHDC2', 'Gene', (36, 42))	('upregulating', 'PosReg', (82, 94))	('lipid', 'Chemical', 'MESH:D008055', (60, 65))	('LUAD', 'Phenotype', 'HP:0030078', (46, 50))	('lipid peroxidation', 'MPA', (60, 78))	('prevents', 'NegReg', (51, 59))	('suppression', 'Var', (21, 32))	('SLC7A11', 'MPA', (95, 102))
318376	33232910	Furthermore, we showed that YTHDC2 impairs system XC- activity and cystine uptake through downregulation of SLC7A11.	('system XC- activity', 'MPA', (43, 62))	('cystine uptake', 'MPA', (67, 81))	('YTHDC2', 'Var', (28, 34))	('impairs', 'NegReg', (35, 42))	('cystine', 'Chemical', 'MESH:D003553', (67, 74))	('SLC7A11', 'Gene', (108, 115))	('downregulation', 'NegReg', (90, 104))
318377	33232910	m6A methylation by METTL3 is a prerequisite for YTHDC2 to accelerate SLC7A11 mRNA decay.	('METTL3', 'Gene', (19, 25))	('accelerate', 'PosReg', (58, 68))	('METTL3', 'Gene', '56339', (19, 25))	('SLC7A11 mRNA decay', 'MPA', (69, 87))	('m6A', 'Var', (0, 3))
318378	33232910	Because cystine is indispensable for the downstream antioxidant program, suppression of YTHDC2 thus promotes tumorigenesis by protecting LUAD cells from oxidative damage.	('promotes', 'PosReg', (100, 108))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('cystine', 'Chemical', 'MESH:D003553', (8, 15))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('LUAD', 'Phenotype', 'HP:0030078', (137, 141))	('suppression', 'Var', (73, 84))	('tumor', 'Disease', (109, 114))	('YTHDC2', 'Gene', (88, 94))
318387	33232910	The application of small molecular inhibitors targeting these proteins in clinical oncology has shown great potential to improve patient outcomes.	('patient outcomes', 'CPA', (129, 145))	('small molecular', 'Var', (19, 34))	('oncology', 'Phenotype', 'HP:0002664', (83, 91))	('improve', 'PosReg', (121, 128))	('patient', 'Species', '9606', (129, 136))
318398	29563911	The seroprevalence of NAbs against AdC68 was much lower than that against AdHu5 in cancer subjects (43.64 vs. 67.05%, P < 0.01).	('lower', 'NegReg', (50, 55))	('AdHu5', 'Chemical', '-', (74, 79))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('AdC68', 'Chemical', '-', (35, 40))	('seroprevalence', 'MPA', (4, 18))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('AdC68', 'Var', (35, 40))	('cancer', 'Disease', (83, 89))
318403	29563911	The percentage of NAbs against AdC68 was significantly lower than that against AdHu5 (P < 0.05) in stage-I, -II, and -III cancer patients.	('stage-I', 'Disease', (99, 106))	('patients', 'Species', '9606', (129, 137))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('AdC68', 'Chemical', '-', (31, 36))	('AdHu5', 'Chemical', '-', (79, 84))	('lower', 'NegReg', (55, 60))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('AdC68', 'Var', (31, 36))
318407	29563911	Also, the titer of NAbs against AdC68 was significantly lower than that against AdHu5 in the same clinical stage and age group (P < 0.05).	('AdHu5', 'Chemical', '-', (80, 85))	('AdC68', 'Var', (32, 37))	('titer', 'MPA', (10, 15))	('lower', 'NegReg', (56, 61))	('AdC68', 'Chemical', '-', (32, 37))
318408	29563911	Taken together, the present study showed that NAbs against AdC68 is much lower than AdHu5, especially in lung adenocarcinoma, laryngeal cancer, esophageal cancer, and cervical cancer patients.	('laryngeal cancer', 'Phenotype', 'HP:0012118', (126, 142))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('cervical cancer', 'Disease', (167, 182))	('cervical cancer', 'Disease', 'MESH:D002583', (167, 182))	('NAbs', 'MPA', (46, 50))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('lung adenocarcinoma', 'Disease', (105, 124))	('AdC68', 'Chemical', '-', (59, 64))	('esophageal cancer', 'Disease', 'MESH:D004938', (144, 161))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (105, 124))	('lower', 'NegReg', (73, 78))	('patients', 'Species', '9606', (183, 191))	('esophageal cancer', 'Disease', (144, 161))	('AdHu5', 'Chemical', '-', (84, 89))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (105, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('AdC68', 'Var', (59, 64))	('laryngeal cancer', 'Disease', 'MESH:D007822', (126, 142))	('laryngeal cancer', 'Disease', (126, 142))
318422	29563911	The AdC68-based vaccine could also induce protective effector and memory T-cell responses against malignant melanoma cells in mice.	('AdC68', 'Chemical', '-', (4, 9))	('malignant melanoma', 'Disease', 'MESH:D008545', (98, 116))	('malignant melanoma', 'Disease', (98, 116))	('mice', 'Species', '10090', (126, 130))	('AdC68-based', 'Var', (4, 15))	('induce', 'PosReg', (35, 41))	('malignant melanoma', 'Phenotype', 'HP:0002861', (98, 116))
318462	29563911	The percentages of NAbs against AdC68 were significantly lower than those against AdHu5 (P < 0.05) in subjects of stages I, II, and III.	('AdC68', 'Chemical', '-', (32, 37))	('AdHu5', 'Chemical', '-', (82, 87))	('AdC68', 'Var', (32, 37))	('lower', 'NegReg', (57, 62))
318490	29563911	In addition, the titer of NAbs against AdC68 was significantly lower than that against AdHu5 in the same age groups (P < 0.05, Table 8).	('AdC68', 'Var', (39, 44))	('lower', 'NegReg', (63, 68))	('titer', 'MPA', (17, 22))	('AdC68', 'Chemical', '-', (39, 44))	('AdHu5', 'Chemical', '-', (87, 92))
318503	29563911	The seroprevalence rates of AdC68 NAbs were significantly higher than AdHu5 NAbs in stages I, II, and III.	('AdC68 NAbs', 'Chemical', '-', (28, 38))	('seroprevalence', 'MPA', (4, 18))	('AdHu5 NAbs', 'Chemical', '-', (70, 80))	('higher', 'PosReg', (58, 64))	('AdC68', 'Var', (28, 33))
318504	29563911	Although the seroprevalence rate of AdC68 NAbs was much lower than that of AdHu5 NAbs in stage-IV subjects, there was no significant difference between them.	('seroprevalence', 'MPA', (13, 27))	('AdHu5 NAbs', 'Chemical', '-', (75, 85))	('AdC68', 'Var', (36, 41))	('lower', 'NegReg', (56, 61))	('AdC68 NAbs', 'Chemical', '-', (36, 46))
318525	27333808	Here, we present and evaluate a method for prioritizing cancer genes accounting not only for mutations in individual genes but also in their neighbors in functional networks, MUFFINN (MUtations For Functional Impact on Network Neighbors).	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('mutations', 'Var', (93, 102))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))
318536	27333808	SIFT (Sorting Intolerant From Tolerant) and PolyPhen-2 (Polymorphism Phenotyping v2) are two commonly used methods for assessing the functional impact of protein variants, but they are not specialized for cancer gene prediction.	('cancer', 'Disease', 'MESH:D009369', (205, 211))	('ran', 'Gene', (34, 37))	('ran', 'Gene', (20, 23))	('ran', 'Gene', '5901', (20, 23))	('ran', 'Gene', '5901', (34, 37))	('cancer', 'Disease', (205, 211))	('SIFT', 'Disease', 'None', (0, 4))	('variants', 'Var', (162, 170))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('SIFT', 'Disease', (0, 4))
318537	27333808	Therefore, MutationAssessor and CHASM (Cancer-specific High-throughput Annotation of Somatic Mutations) were developed specifically for the assessment of the functional impact of variants in cancer.	('Cancer', 'Disease', 'MESH:D009369', (39, 45))	('cancer', 'Disease', (191, 197))	('cancer', 'Disease', 'MESH:D009369', (191, 197))	('variants', 'Var', (179, 187))	('Cancer', 'Phenotype', 'HP:0002664', (39, 45))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('Cancer', 'Disease', (39, 45))
318542	27333808	An important observation from analyses of the landscape of cancer mutation genomes performed to date has been the convergence of individual mutations into cellular pathways.	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('mutations', 'Var', (140, 149))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('cellular pathways', 'Pathway', (155, 172))
318543	27333808	Although somatic mutations in different genes are observed in different patients, these mutated genes tend to fall into a limited number of recurrently mutated pathways and processes in any particular type of cancer.	('fall', 'Reg', (110, 114))	('particular type of cancer', 'Disease', (190, 215))	('particular type of cancer', 'Disease', 'MESH:D009369', (190, 215))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))	('mutated', 'Var', (88, 95))	('fall', 'Phenotype', 'HP:0002527', (110, 114))	('patients', 'Species', '9606', (72, 80))
318555	27333808	From the observed clustering of genes somatically mutated in cancers into pathways, we hypothesized that a gene is more likely to represent a true cancer driver if it is functionally associated with other genes mutated in cancer.	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('cancer', 'Disease', 'MESH:D009369', (222, 228))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('cancer', 'Disease', (222, 228))	('gene', 'Var', (107, 111))	('cancer', 'Disease', (61, 67))	('cancers', 'Disease', 'MESH:D009369', (61, 68))	('cancers', 'Phenotype', 'HP:0002664', (61, 68))	('cancers', 'Disease', (61, 68))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('cancer', 'Disease', (147, 153))
318557	27333808	If a gene with low probability of being involved in cancer due to its low mutation frequency has many mutations among its network neighbors, MUFFINN will reprioritize it as a highly probable candidate.	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('mutations', 'Var', (102, 111))	('cancer', 'Disease', (52, 58))
318560	27333808	Unfortunately, such a cancer gene set is not available so we generated five distinct gold-standard cancer gene sets from various sources of annotations: (i) 422 cancer genes from the Cancer Genome Census database (CGC) as of October 2012; (ii) a CGC subset of 118 cancer genes which act in cancer via point mutations (CGCpointMut); (iii) 124 cancer genes based on the characteristic mutational patterns for oncogenes and tumor suppressor genes (20/20 rule); (iv) 288 high-confidence driver genes based on a rule-based approach (HCD); and (v) 797 human orthologs of mouse cancer genes identified by insertional mutagenesis (MouseMut).	('HCD', 'Disease', (528, 531))	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('cancer', 'Disease', (342, 348))	('tumor', 'Phenotype', 'HP:0002664', (421, 426))	('cancer', 'Disease', (161, 167))	('insertional mutagenesis', 'Var', (598, 621))	('cancer', 'Disease', (264, 270))	('cancer', 'Disease', (571, 577))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('cancer', 'Disease', 'MESH:D009369', (290, 296))	('HCD', 'Disease', 'MESH:D065630', (528, 531))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('cancer', 'Phenotype', 'HP:0002664', (264, 270))	('Cancer Genome Census', 'Disease', 'MESH:D009369', (183, 203))	('Cancer Genome Census', 'Disease', (183, 203))	('Cancer', 'Phenotype', 'HP:0002664', (183, 189))	('cancer', 'Disease', 'MESH:D009369', (342, 348))	('cancer', 'Disease', (22, 28))	('human', 'Species', '9606', (546, 551))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('tumor', 'Disease', (421, 426))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('cancer', 'Disease', 'MESH:D009369', (571, 577))	('cancer', 'Disease', 'MESH:D009369', (264, 270))	('tumor', 'Disease', 'MESH:D009369', (421, 426))	('cancer', 'Disease', (290, 296))	('cancer', 'Disease', (99, 105))	('mouse', 'Species', '10090', (565, 570))	('cancer', 'Phenotype', 'HP:0002664', (290, 296))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
318583	27333808	If mutations are evenly spread among members of cancer-related pathways for the given cancer type, DNsum works more effectively.	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('mutations', 'Var', (3, 12))	('cancer', 'Disease', (86, 92))
318584	27333808	Conversely, if mutations concentrate on a few hubs of cancer-related pathways for the given cancer type, adding more importance to the mutational information of the hub, DNmax, could be more effective for identifying additional cancer genes.	('cancer', 'Disease', (228, 234))	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('mutations', 'Var', (15, 24))	('cancer', 'Disease', (54, 60))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('cancer', 'Disease', 'MESH:D009369', (228, 234))
318589	27333808	Notably, mutation data for some types even outperformed the pan-cancer data in prediction of known cancer genes within the top 100, 500, or 1000 candidates (Fig.	('mutation', 'Var', (9, 17))	('pan-cancer', 'Disease', (60, 70))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('cancer', 'Disease', (99, 105))	('pan-cancer', 'Disease', 'MESH:C537931', (60, 70))	('outperformed', 'NegReg', (43, 55))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
318600	27333808	To test if correction of mutation frequencies by those factors can also improve our network-based cancer driver gene predictions, we compared MUFFINN predictions for the five gold-standard cancer gene sets when using raw mutation frequencies and MutsigCV scores.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('mutation', 'Var', (25, 33))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('cancer', 'Disease', (98, 104))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('cancer', 'Disease', (189, 195))
318616	27333808	Class 2 includes 14 genes known to increase cancer susceptibility through germline variants.	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('germline variants', 'Var', (74, 91))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
318617	27333808	For example, HIF1A (16th by MUFFINN yet below 8000th by all three gene-centric methods in BRCA samples) polymorphism contributes to the risk of gastrointestinal cancer and modulates the response to chemotherapy after surgery in patients with colorectal cancer.	('gastrointestinal cancer', 'Disease', 'MESH:D004067', (144, 167))	('polymorphism', 'Var', (104, 116))	('response', 'MPA', (186, 194))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('BRCA', 'Phenotype', 'HP:0003002', (90, 94))	('HIF1A', 'Gene', (13, 18))	('modulates', 'Reg', (172, 181))	('HIF1A', 'Gene', '3091', (13, 18))	('cancer', 'Phenotype', 'HP:0002664', (253, 259))	('patients', 'Species', '9606', (228, 236))	('contributes', 'Reg', (117, 128))	('colorectal cancer', 'Disease', 'MESH:D015179', (242, 259))	('gastrointestinal cancer', 'Disease', (144, 167))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (144, 167))	('colorectal cancer', 'Phenotype', 'HP:0003003', (242, 259))	('colorectal cancer', 'Disease', (242, 259))
318619	27333808	Likewise, germline variants in APEX1 (14th by MUFFINN yet below 13,000th by the gene-centric methods in head and neck squamous cell carcinoma (HNSC) samples) is known to increase the risk of breast cancer development by contributing apurinic/apyrimidinic (AP) site accumulation in DNA.	('APEX1', 'Gene', (31, 36))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('apurinic/apyrimidinic', 'MPA', (233, 254))	('breast cancer', 'Disease', 'MESH:D001943', (191, 204))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (118, 141))	('increase', 'PosReg', (170, 178))	('breast cancer', 'Phenotype', 'HP:0003002', (191, 204))	('accumulation', 'PosReg', (265, 277))	('contributing', 'PosReg', (220, 232))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('APEX1', 'Gene', '328', (31, 36))	('neck squamous cell carcinoma', 'Disease', (113, 141))	('breast cancer', 'Disease', (191, 204))	('variants', 'Var', (19, 27))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (113, 141))
318623	27333808	Class 3 includes 14 genes known to be involved in cancer by copy number variation (CNV) or structural variation (SV).	('copy number variation', 'Var', (60, 81))	('SV', 'Disease', 'None', (113, 115))	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('structural variation', 'Var', (91, 111))
318624	27333808	For example, deletion of PTP4A3 (49th by MUFFINN yet below 10,000th by the gene-centric methods in KIRP samples) reduces the tumor-initiation ability in cancer and PPAPDC1B (45th by MUFFINN yet below 16,000th by the gene-centric methods in colon and rectal adenocarcinoma (COADREAD) samples) is suggested to be a common driver in the 8p11-12 amplicon in breast, pancreatic, and lung cancer.	('PTP4A3', 'Gene', (25, 31))	('pancreatic', 'Disease', 'MESH:D010195', (362, 372))	('lung cancer', 'Disease', 'MESH:D008175', (378, 389))	('cancer', 'Phenotype', 'HP:0002664', (383, 389))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('lung cancer', 'Phenotype', 'HP:0100526', (378, 389))	('tumor-initiation ability in cancer', 'Disease', (125, 159))	('reduces', 'NegReg', (113, 120))	('carcinoma', 'Phenotype', 'HP:0030731', (262, 271))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('pancreatic', 'Disease', (362, 372))	('deletion', 'Var', (13, 21))	('breast', 'Disease', (354, 360))	('PPAPDC1B', 'Gene', '84513', (164, 172))	('tumor-initiation ability in cancer', 'Disease', 'MESH:D009369', (125, 159))	('PPAPDC1B', 'Gene', (164, 172))	('PTP4A3', 'Gene', '11156', (25, 31))	('lung cancer', 'Disease', (378, 389))	('colon and rectal adenocarcinoma', 'Disease', 'MESH:D012004', (240, 271))
318631	27333808	DCC (32nd by MUFFINN yet below 7000th by the gene-centric methods in HNSC samples), a putative candidate tumor suppressor, is inactivated by promoter hypermethylation in head and neck cancer and loss of PPM1A (23rd by MUFFINN yet below 5000th by the gene-centric methods in stomach adenocarcinoma (STAD) samples) expression enhances invasion and epithelial-to-mesenchymal transition in bladder cancer.	('cancer', 'Disease', (184, 190))	('stomach adenocarcinoma', 'Disease', 'MESH:D013274', (274, 296))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('cancer', 'Disease', 'MESH:D009369', (394, 400))	('carcinoma', 'Phenotype', 'HP:0030731', (287, 296))	('head and neck cancer', 'Phenotype', 'HP:0012288', (170, 190))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('tumor', 'Disease', (105, 110))	('loss', 'Var', (195, 199))	('ran', 'Gene', (373, 376))	('ran', 'Gene', '5901', (373, 376))	('stomach adenocarcinoma', 'Disease', (274, 296))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('cancer', 'Disease', (394, 400))	('PPM1A', 'Gene', '5494', (203, 208))	('cancer', 'Phenotype', 'HP:0002664', (394, 400))	('enhances', 'PosReg', (324, 332))	('bladder cancer', 'Disease', 'MESH:D001749', (386, 400))	('bladder cancer', 'Disease', (386, 400))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('bladder cancer', 'Phenotype', 'HP:0009725', (386, 400))	('PPM1A', 'Gene', (203, 208))
318648	27333808	Since HotNet2 did not provide prediction scores, we simply compared the number of retrieved gold-standard cancer genes for the 144 candidates predicted by HotNet2 and for the top 144 candidates predicted by MUFFINN.	('HotNet2', 'Var', (155, 162))	('cancer', 'Disease', (106, 112))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
318660	27333808	Frequently mutated cancer genes can be detected by sequencing only dozens of cancer samples.	('cancer', 'Disease', 'MESH:D009369', (19, 25))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('cancer', 'Disease', (19, 25))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('mutated', 'Var', (11, 18))
318665	27333808	For example, it has recently been reported that synonymous mutations contribute to cancer risk and future algorithms need to account for such less well-characterized cancer-related mutations.	('cancer', 'Disease', (166, 172))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('synonymous mutations', 'Var', (48, 68))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('contribute', 'Reg', (69, 79))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('cancer', 'Disease', (83, 89))
318669	27333808	Interestingly, many known cancer genes predicted by MUFFINN with no significant evidence of somatic exonic mutations among TCGA samples are supported by their involvement in other types of genetic alterations, such as germline genetic variation, chromosomal rearrangement, and altered gene expression regulation.	('involvement', 'Reg', (159, 170))	('exonic mutations', 'Var', (100, 116))	('cancer', 'Disease', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('ran', 'Gene', (262, 265))	('ran', 'Gene', '5901', (262, 265))	('TCGA', 'Gene', (123, 127))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('gene expression regulation', 'MPA', (285, 311))	('altered', 'Reg', (277, 284))
318674	27333808	First, 422 cancer genes were downloaded in October 2012 from the Cancer Genome Census (CGC) database, which includes the genes for which mutations have been causally implicated in cancer.	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('Cancer Genome Census', 'Disease', 'MESH:D009369', (65, 85))	('mutations', 'Var', (137, 146))	('Cancer Genome Census', 'Disease', (65, 85))	('cancer', 'Disease', 'MESH:D009369', (11, 17))	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('Cancer', 'Phenotype', 'HP:0002664', (65, 71))	('cancer', 'Disease', (11, 17))	('cancer', 'Disease', (180, 186))
318676	27333808	Since we benchmark cancer gene classifiers based on information of sequence alterations rather than structural rearrangement, we generated a second gold-standard comprising 118 cancer genes altered by point mutations, CGCpointMut.	('cancer', 'Disease', (177, 183))	('cancer', 'Disease', 'MESH:D009369', (177, 183))	('cancer', 'Disease', 'MESH:D009369', (19, 25))	('cancer', 'Disease', (19, 25))	('ran', 'Gene', (115, 118))	('altered', 'Reg', (190, 197))	('ran', 'Gene', '5901', (115, 118))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('point mutations', 'Var', (201, 216))
318677	27333808	Other classes of mutations, such as translocation, large amplifications, and deletions, were excluded from CGCpointMut.	('ran', 'Gene', (37, 40))	('deletions', 'Var', (77, 86))	('ran', 'Gene', '5901', (37, 40))	('large amplifications', 'Var', (51, 71))
318678	27333808	The third gold-standard set was composed of 124 cancer genes based on the patterns of mutations that oncogenes are recurrently mutated at the positions while tumor suppressor genes are mutated through protein truncating alterations.	('mutations', 'Var', (86, 95))	('oncogenes', 'Gene', (101, 110))	('tumor', 'Disease', (158, 163))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('mutated', 'Var', (127, 134))
318679	27333808	In particular, >20 % of the mutations in the gene need to be at recurrent positions to be classified as oncogenes and >20 % of the mutations need to be inactivated to be classified as tumor suppressor genes (20/20).	('tumor', 'Disease', (184, 189))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('mutations', 'Var', (28, 37))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))
318696	28377632	Genomic aberrations in 138 known cancer driver genes and 491 established fusion genes were found in 1,127 tumors (78%).	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('cancer', 'Disease', (33, 39))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('tumors', 'Disease', (106, 112))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('found', 'Reg', (91, 96))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('Genomic aberrations', 'Var', (0, 19))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))
318700	28377632	Examples of such therapies include EGFR inhibitors, which target point mutations in EGFR , anti-HER2 antibodies recognizing the product of the ERBB2 gene amplification, and ALK inhibitors, which target the EML4-ALK fusion gene.	('EML4', 'Gene', (206, 210))	('EGFR', 'Gene', '1956', (35, 39))	('ERBB2', 'Gene', (143, 148))	('EGFR', 'Gene', (35, 39))	('ERBB2', 'Gene', '2064', (143, 148))	('point mutations', 'Var', (65, 80))	('EGFR', 'Gene', (84, 88))	('ALK', 'Gene', '238', (211, 214))	('EGFR', 'Gene', '1956', (84, 88))	('EML4', 'Gene', '27436', (206, 210))	('ALK', 'Gene', '238', (173, 176))	('HER2', 'Gene', (96, 100))	('ALK', 'Gene', (173, 176))	('HER2', 'Gene', '2064', (96, 100))	('ALK', 'Gene', (211, 214))
318706	28377632	Gene expression analysis is requisite to confirm the status of tumor-specific genomic alterations, including mutations and amplifications, as actionable cancer driver genes.	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('tumor', 'Disease', (63, 68))	('cancer', 'Disease', (153, 159))	('amplifications', 'Var', (123, 137))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('mutations', 'Var', (109, 118))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
318716	28377632	(37% for variant 2 and 35% for variant 4), FLT3 (44%) and ERBB2  (34%) in breast cancer; CSF1R (47%), DNMT1 (42%), and MYD88 (31%) in sarcoma; KIT  (100%), AR (71%), SMO (50%), PDGFRA  (43%), and BCL2  (variant alpha) (42%) in gastrointestinal stromal tumors (GISTs).	('gastrointestinal stromal tumors', 'Disease', (227, 258))	('BCL2', 'Gene', (196, 200))	('ERBB2', 'Gene', '2064', (58, 63))	('SMO', 'Gene', (166, 169))	('DNMT1', 'Gene', (102, 107))	('tumors', 'Phenotype', 'HP:0002664', (252, 258))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('sarcoma', 'Phenotype', 'HP:0100242', (134, 141))	('MYD88', 'Gene', '4615', (119, 124))	('variant', 'Var', (9, 16))	('tumor', 'Phenotype', 'HP:0002664', (252, 257))	('FLT3', 'Gene', (43, 47))	('MYD88', 'Gene', (119, 124))	('breast cancer', 'Phenotype', 'HP:0003002', (74, 87))	('GISTs', 'Phenotype', 'HP:0100723', (260, 265))	('CSF1R', 'Gene', '1436', (89, 94))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (227, 258))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (227, 258))	('FLT3', 'Gene', '2322', (43, 47))	('PDGFRA', 'Gene', '5156', (177, 183))	('DNMT1', 'Gene', '1786', (102, 107))	('PDGFRA', 'Gene', (177, 183))	('CSF1R', 'Gene', (89, 94))	('BCL2', 'Gene', '596', (196, 200))	('breast cancer', 'Disease', 'MESH:D001943', (74, 87))	('breast cancer', 'Disease', (74, 87))	('sarcoma', 'Disease', 'MESH:D012509', (134, 141))	('SMO', 'Gene', '6608', (166, 169))	('ERBB2', 'Gene', (58, 63))	('sarcoma', 'Disease', (134, 141))
318718	28377632	These include nine genes frequently overexpressed with copy number gain, including six amplification-based oncogenes (MYC, MYCL, MYCN, MDM2, NKX2-1, and SKP2) and three mutation-based oncogenes (HIST1H3B, EZH2, and CARD11) (Supplementary Fig.	('MYC', 'Gene', (129, 132))	('overexpressed', 'PosReg', (36, 49))	('CARD11', 'Gene', (215, 221))	('MYC', 'Gene', '4609', (123, 126))	('EZH2', 'Gene', (205, 209))	('EZH2', 'Gene', '2146', (205, 209))	('copy number', 'Var', (55, 66))	('MYCN', 'Gene', (129, 133))	('CARD11', 'Gene', '84433', (215, 221))	('HIST1H3B', 'Gene', (195, 203))	('HIST1H3B', 'Gene', '8358', (195, 203))	('MYC', 'Gene', '4609', (129, 132))	('SKP2', 'Gene', (153, 157))	('NKX2-1', 'Gene', '7080', (141, 147))	('MYC', 'Gene', (118, 121))	('MYCL', 'Gene', (123, 127))	('MDM2', 'Gene', (135, 139))	('SKP2', 'Gene', '6502', (153, 157))	('NKX2-1', 'Gene', (141, 147))	('MYCL', 'Gene', '4610', (123, 127))	('MDM2', 'Gene', '4193', (135, 139))	('MYC', 'Gene', (123, 126))	('MYCN', 'Gene', '4613', (129, 133))	('MYC', 'Gene', '4609', (118, 121))
318720	28377632	One group contained genes where overexpression was frequent among those with high genomic amplification (copy number >=6), and included EGFR (variant 1), ERBB2, and MDM2.	('overexpression', 'PosReg', (32, 46))	('high genomic amplification', 'Var', (77, 103))	('ERBB2', 'Gene', (154, 159))	('ERBB2', 'Gene', '2064', (154, 159))	('MDM2', 'Gene', '4193', (165, 169))	('MDM2', 'Gene', (165, 169))	('EGFR', 'Gene', '1956', (136, 140))	('EGFR', 'Gene', (136, 140))
318722	28377632	In addition to EGFR variant 1, ERBB2, and MDM2, samples overexpressing FGFR2, KRAS, and EGFR variant 3 were abundant among those high-level genomic amplification of these genes, specifically in stomach cancer (FGFR2), colorectal and stomach cancer (KRAS), and lung, and head and neck cancer (EGFR variant 3) samples (Fig.	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('head and neck cancer', 'Disease', 'MESH:D006258', (270, 290))	('colorectal and stomach cancer', 'Disease', 'MESH:D015179', (218, 247))	('EGFR', 'Gene', '1956', (15, 19))	('stomach cancer', 'Disease', (194, 208))	('KRAS', 'Gene', '3845', (249, 253))	('EGFR', 'Gene', '1956', (292, 296))	('stomach cancer', 'Disease', (233, 247))	('FGFR2', 'Gene', (210, 215))	('KRAS', 'Gene', (249, 253))	('MDM2', 'Gene', (42, 46))	('ERBB2', 'Gene', (31, 36))	('EGFR', 'Gene', (88, 92))	('stomach cancer', 'Disease', 'MESH:D013274', (194, 208))	('FGFR2', 'Gene', '2263', (210, 215))	('stomach cancer', 'Phenotype', 'HP:0012126', (194, 208))	('MDM2', 'Gene', '4193', (42, 46))	('EGFR', 'Gene', (15, 19))	('ERBB2', 'Gene', '2064', (31, 36))	('FGFR2', 'Gene', (71, 76))	('head and neck cancer', 'Phenotype', 'HP:0012288', (270, 290))	('cancer', 'Phenotype', 'HP:0002664', (284, 290))	('KRAS', 'Gene', '3845', (78, 82))	('stomach cancer', 'Disease', 'MESH:D013274', (233, 247))	('stomach cancer', 'Phenotype', 'HP:0012126', (233, 247))	('variant', 'Var', (93, 100))	('lung', 'Disease', (260, 264))	('EGFR', 'Gene', (292, 296))	('KRAS', 'Gene', (78, 82))	('EGFR', 'Gene', '1956', (88, 92))	('FGFR2', 'Gene', '2263', (71, 76))
318723	28377632	When samples overexpressing EGFR variants 1 and 3 included samples with both high and moderate-levels of genomic amplification, samples in which both EGFR variants were overexpressed with genomic amplification were abundant in lung, and head and neck cancer samples (Fig.	('EGFR', 'Gene', '1956', (28, 32))	('EGFR', 'Gene', (150, 154))	('head and neck cancer', 'Phenotype', 'HP:0012288', (237, 257))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('variants', 'Var', (155, 163))	('EGFR', 'Gene', (28, 32))	('lung', 'Disease', (227, 231))	('head and neck cancer', 'Disease', 'MESH:D006258', (237, 257))	('EGFR', 'Gene', '1956', (150, 154))
318725	28377632	EGFR variant 3 mRNA translates a soluble EGFR protein, p60 (isoform C), lacking transmembrane and tyrosine kinase domains, whereas EGFR variant 1 mRNA translates the full-length p170 EGFR (isoform A).	('EGFR', 'Gene', (41, 45))	('EGFR', 'Gene', (0, 4))	('EGFR', 'Gene', '1956', (183, 187))	('EGFR', 'Gene', (183, 187))	('lacking', 'NegReg', (72, 79))	('p60', 'Gene', '29997', (55, 58))	('variant', 'Var', (5, 12))	('EGFR', 'Gene', '1956', (131, 135))	('EGFR', 'Gene', (131, 135))	('EGFR', 'Gene', '1956', (41, 45))	('EGFR', 'Gene', '1956', (0, 4))	('p60', 'Gene', (55, 58))
318726	28377632	Because the formation of inactive heterodimers between different isoforms competitively prevents the formation of functional holoreceptors, this result suggested that oncogenesis involving the EGFR pathway differs in samples with or without overexpressing EGFR variant 3 exhibiting genomic amplification.	('prevents', 'NegReg', (88, 96))	('EGFR', 'Gene', '1956', (193, 197))	('EGFR', 'Gene', (193, 197))	('EGFR', 'Gene', '1956', (256, 260))	('formation of functional holoreceptors', 'MPA', (101, 138))	('variant', 'Var', (261, 268))	('inactive heterodimers', 'MPA', (25, 46))	('EGFR', 'Gene', (256, 260))
318727	28377632	Using Pearson correlation coefficient, ERBB2 and MDM2 showed moderate relationships between copy number and FC (r = 0.53 and 0.49, respectively), whereas SKP2 (r = 0.35), EGFR variant 1 (r = 0.28), MYCL variants 1 and 2 (r = 0.26), and EZH2 (r = 0.20) were in the range between 0.2 and 0.4, indicating weak relationships.	('EGFR', 'Gene', (171, 175))	('relationships', 'Interaction', (70, 83))	('EZH2', 'Gene', (236, 240))	('ERBB2', 'Gene', '2064', (39, 44))	('EZH2', 'Gene', '2146', (236, 240))	('MYCL', 'Gene', '4610', (198, 202))	('copy number', 'Var', (92, 103))	('SKP2', 'Gene', '6502', (154, 158))	('MYCL', 'Gene', (198, 202))	('MDM2', 'Gene', '4193', (49, 53))	('EGFR', 'Gene', '1956', (171, 175))	('MDM2', 'Gene', (49, 53))	('SKP2', 'Gene', (154, 158))	('ERBB2', 'Gene', (39, 44))
318728	28377632	In particular, the majority of samples with high-level amplification of MYC were not overexpressed (r = 0.13), suggesting that these amplifications were passenger-like.	('amplification', 'Var', (55, 68))	('MYC', 'Gene', '4609', (72, 75))	('MYC', 'Gene', (72, 75))
318730	28377632	For these eight genes, Pearson correlation coefficient between copy number and FC among the samples overexpressed with FC >=5 demonstrated moderate and weak relationships in EGFR variant 1 (r = 0.52) and MYC (r = 0.33), respectively (Supplementary Fig.	('EGFR', 'Gene', (174, 178))	('MYC', 'Gene', '4609', (204, 207))	('variant 1', 'Var', (179, 188))	('relationships', 'Interaction', (157, 170))	('MYC', 'Gene', (204, 207))	('EGFR', 'Gene', '1956', (174, 178))
318731	28377632	This result indicates that overexpression with FC >=5 of EGFR variant 1 and MYC is frequently involved in copy number gain.	('variant 1', 'Var', (62, 71))	('MYC', 'Gene', (76, 79))	('EGFR', 'Gene', '1956', (57, 61))	('EGFR', 'Gene', (57, 61))	('MYC', 'Gene', '4609', (76, 79))
318733	28377632	The frequency of amplification-dependent overexpression, in which overexpression was accompanied by either high or moderate levels of genomic amplification, was calculated for individual tumor types (Table 2).	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('tumor', 'Disease', (187, 192))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('amplification-dependent', 'Var', (17, 40))
318741	28377632	Since amplification-dependent overexpression is predicted to be involved in oncogenesis, the genes amplified with overexpression are potential target molecules for anti-cancer agents.	('involved', 'Reg', (64, 72))	('cancer', 'Disease', (169, 175))	('amplification-dependent', 'Var', (6, 29))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('cancer', 'Disease', 'MESH:D009369', (169, 175))
318749	28377632	INHBA overexpression promotes cell proliferation in esophageal adenocarcinoma, while RECQL4 is associated with breast cancer tumor aggressiveness, due to both amplification and overexpression.	('breast cancer tumor aggressiveness', 'Disease', 'MESH:D001943', (111, 145))	('overexpression', 'Var', (6, 20))	('promotes', 'PosReg', (21, 29))	('INHBA', 'Gene', (0, 5))	('associated', 'Reg', (95, 105))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (52, 77))	('RECQL4', 'Gene', '9401', (85, 91))	('overexpression', 'PosReg', (177, 191))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (52, 77))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('RECQL4', 'Gene', (85, 91))	('esophageal adenocarcinoma', 'Disease', (52, 77))	('breast cancer tumor aggressiveness', 'Disease', (111, 145))	('breast cancer tumor', 'Phenotype', 'HP:0100013', (111, 130))	('amplification', 'Var', (159, 172))	('cell proliferation', 'CPA', (30, 48))	('INHBA', 'Gene', '3624', (0, 5))	('breast cancer', 'Phenotype', 'HP:0003002', (111, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (68, 77))	('aggressiveness', 'Phenotype', 'HP:0000718', (131, 145))
318755	28377632	Among the 1,454 tumors, 327 were categorized as having undetermined driver origins following mutation, copy number, and expression analyses of 138 driver and 491 fusion genes (Fig.	('tumors', 'Disease', (16, 22))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('tumors', 'Disease', 'MESH:D009369', (16, 22))	('mutation', 'Var', (93, 101))
318764	28377632	In addition, SKP2 overexpression and amplification has been related to metastasis in lung squamous cell carcinoma.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (90, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('related', 'Reg', (60, 67))	('SKP2', 'Gene', '6502', (13, 17))	('amplification', 'Var', (37, 50))	('metastasis in lung squamous cell carcinoma', 'Disease', (71, 113))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (85, 113))	('SKP2', 'Gene', (13, 17))	('metastasis in lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (71, 113))	('overexpression', 'PosReg', (18, 32))
318774	28377632	Although LMO1 duplication was associated with more advanced disease and survival in neuroblastoma, our analysis identified four samples from lung adenocarcinoma exhibiting LMO1 amplification and overexpression, three of which were derived from stage I and no stage information provided for the remaining sample.	('associated', 'Reg', (30, 40))	('lung adenocarcinoma', 'Disease', (141, 160))	('LMO1', 'Gene', (172, 176))	('neuroblastoma', 'Disease', 'MESH:D009447', (84, 97))	('LMO1', 'Gene', '4004', (172, 176))	('LMO1', 'Gene', (9, 13))	('neuroblastoma', 'Disease', (84, 97))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (141, 160))	('overexpression', 'PosReg', (195, 209))	('LMO1', 'Gene', '4004', (9, 13))	('neuroblastoma', 'Phenotype', 'HP:0003006', (84, 97))	('duplication', 'Var', (14, 25))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (141, 160))	('carcinoma', 'Phenotype', 'HP:0030731', (151, 160))
318779	28377632	Recurrent amplification-dependent overexpression of AXL was observed only in two sarcomas (myxofibrosarcoma and leiomyosarcoma).	('amplification-dependent', 'Var', (10, 33))	('sarcomas', 'Disease', (81, 89))	('AXL', 'Gene', (52, 55))	('sarcoma', 'Phenotype', 'HP:0100242', (100, 107))	('sarcoma', 'Phenotype', 'HP:0100242', (81, 88))	('AXL', 'Gene', '558', (52, 55))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (112, 126))	('overexpression', 'PosReg', (34, 48))	('sarcoma', 'Phenotype', 'HP:0100242', (119, 126))	('myxofibrosarcoma and leiomyosarcoma', 'Disease', 'MESH:D007890', (91, 126))	('sarcomas', 'Disease', 'MESH:D012509', (81, 89))	('sarcomas', 'Phenotype', 'HP:0100242', (81, 89))
318802	28377632	Driver mutations in 138 known driver genes were defined as those identified as pathogenic in the ClinVar database, or those contained in the Database of Curated Mutations (DoCM, http://docm.genome.wustl.edu) or the UMD TP53 mutation database.	('TP53', 'Gene', (219, 223))	('TP53', 'Gene', '7157', (219, 223))	('mutations', 'Var', (7, 16))
318810	25015643	Amplification of fibroblast growth factor receptor 1 (FGFR1), which aberrantly increases FGFR signaling, is a common genetic alteration in hLSCCs.	('Amplification', 'Var', (0, 13))	('fibroblast growth factor receptor 1', 'Gene', '14182', (17, 52))	('FGFR signaling', 'MPA', (89, 103))	('increases', 'PosReg', (79, 88))	('FGFR1', 'Gene', (54, 59))	('fibroblast growth factor receptor 1', 'Gene', (17, 52))	('hLSCCs', 'Disease', (139, 145))
318837	25015643	In all 17 cases, knockdown of the TSG with the second shRNA also resulted in tumor formation (Supplementary Fig.	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('resulted in', 'Reg', (65, 76))	('knockdown', 'Var', (17, 26))	('tumor', 'Disease', (77, 82))
318853	25015643	Remarkably, knockdown of 17 of the 24 TSGs resulted in increased levels of phosphorylated FRS2-Y436 (pFRS2-Y436) relative to that obtained with a non-silencing shRNA control, indicative of increased FGFR signaling (Fig.	('levels', 'MPA', (65, 71))	('FRS2', 'Gene', '327826', (90, 94))	('increased', 'PosReg', (55, 64))	('knockdown', 'Var', (12, 21))	('FRS2', 'Gene', (90, 94))	('FRS2', 'Gene', '327826', (102, 106))	('FRS2', 'Gene', (102, 106))	('increased', 'PosReg', (189, 198))
318867	25015643	For the seven TSGs that affected tFGFR1 levels, we investigated specificity by asking whether their knockdown also affected the levels of other FGF receptors (FGFR2, FGFR3 and FGFR4) and growth factor receptors (epidermal growth factor receptor [EGFR] and insulin receptor [IR]).	('knockdown', 'Var', (100, 109))	('FGFR4', 'Gene', '14186', (176, 181))	('levels', 'MPA', (128, 134))	('epidermal growth factor receptor', 'Gene', (212, 244))	('FGFR4', 'Gene', (176, 181))	('FGFR2', 'Gene', (159, 164))	('tFGFR1', 'Gene', (33, 39))	('EGFR', 'Gene', (246, 250))	('FGFR3', 'Gene', '14184', (166, 171))	('insulin receptor', 'Gene', '16337', (256, 272))	('epidermal growth factor receptor', 'Gene', '13649', (212, 244))	('FGFR2', 'Gene', '14183', (159, 164))	('FGFR3', 'Gene', (166, 171))	('affected', 'Reg', (24, 32))	('insulin receptor', 'Gene', (256, 272))	('IR', 'Gene', '16337', (274, 276))	('affected', 'Reg', (115, 123))	('EGFR', 'Gene', '13649', (246, 250))
318871	25015643	S8A and S8B) reduced proliferation, as measured in a soft agar colony formation assay (Supplementary Fig.	('S8B', 'Var', (8, 11))	('proliferation', 'CPA', (21, 34))	('soft agar colony formation assay', 'CPA', (53, 85))	('agar', 'Chemical', 'MESH:D000362', (58, 62))	('reduced', 'NegReg', (13, 20))
318872	25015643	As expected, the decreased colony formation resulting from ectopic expression of the TSG was counteracted by co-expression of FRS2 (Supplementary Fig.	('FRS2', 'Gene', (126, 130))	('decreased', 'NegReg', (17, 26))	('TSG', 'Gene', (85, 88))	('colony formation', 'CPA', (27, 43))	('FRS2', 'Gene', '327826', (126, 130))	('ectopic expression', 'Var', (59, 77))
318875	25015643	We also selected a representative subset of eight of these 14 TSGs and tested their ability to inhibit tumor growth in mouse xenografts.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('mouse', 'Species', '10090', (119, 124))	('tested', 'Reg', (71, 77))	('tumor', 'Disease', (103, 108))	('inhibit', 'NegReg', (95, 102))	('TSGs', 'Var', (62, 66))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
318885	25015643	Human cancer cell lines in which FGFR1 is amplified or contains an activating mutation are sensitive to FGFR pharmacological inhibitors.	('Human', 'Species', '9606', (0, 5))	('mutation', 'Var', (78, 86))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('cancer', 'Disease', 'MESH:D009369', (6, 12))	('activating', 'PosReg', (67, 77))	('cancer', 'Disease', (6, 12))	('FGFR1', 'Gene', (33, 38))
318891	25015643	S10B and S10C).	('S10B', 'SUBSTITUTION', 'None', (0, 4))	('S10C', 'Var', (9, 13))	('S10C', 'Mutation', 'p.S10C', (9, 13))	('S10B', 'Var', (0, 4))
318906	25015643	We then knocked down these three TSGs in SA cells, both singly and in combination, and measured ponatinib sensitivity in a soft agar colony formation assay.	('knocked', 'Var', (8, 15))	('measured', 'Reg', (87, 95))	('SA', 'Chemical', 'MESH:C012546', (41, 43))	('agar', 'Chemical', 'MESH:D000362', (128, 132))	('ponatinib', 'Chemical', 'MESH:C545373', (96, 105))
318907	25015643	5E show that TSG knockdown resulted in increased ponatinib sensitivity and this effect was greater with multiple compared to single knockdowns.	('ponatinib sensitivity', 'MPA', (49, 70))	('increased', 'PosReg', (39, 48))	('TSG', 'Gene', (13, 16))	('knockdown', 'Var', (17, 26))	('ponatinib', 'Chemical', 'MESH:C545373', (49, 58))
318909	25015643	TSG knockdown also increased the proliferation rate of SA cells and again this effect was greater with multiple compared to single knockdowns (Supplementary Fig.	('increased', 'PosReg', (19, 28))	('SA', 'Chemical', 'MESH:C012546', (55, 57))	('TSG', 'Gene', (0, 3))	('knockdown', 'Var', (4, 13))	('proliferation rate of SA cells', 'CPA', (33, 63))
318911	25015643	Using stringent selection criteria (see Methods), we identified 10 pre-mRNAs whose splicing was significantly altered in SRSF9 knockdown cells, several of which, including EIF3C, BCL2L11 and APC, encode proteins that have been implicated in transformation-related activities (Supplementary Table S4).	('BCL2L11', 'Gene', '12125', (179, 186))	('APC', 'Disease', (191, 194))	('BCL2L11', 'Gene', (179, 186))	('altered', 'Reg', (110, 117))	('APC', 'Disease', 'MESH:D011125', (191, 194))	('EIF3C', 'Gene', (172, 177))	('SRSF9', 'Gene', (121, 126))	('splicing', 'MPA', (83, 91))	('EIF3C', 'Gene', '56347', (172, 177))	('encode', 'Reg', (196, 202))	('knockdown', 'Var', (127, 136))
318913	25015643	6D show that full-length SH3BP2 protein levels were reduced in SRSF9 knockdown SA cells.	('SRSF9', 'Gene', (63, 68))	('reduced', 'NegReg', (52, 59))	('protein levels', 'MPA', (32, 46))	('SH3BP2', 'Gene', (25, 31))	('SA', 'Chemical', 'MESH:C012546', (79, 81))	('knockdown', 'Var', (69, 78))
318916	25015643	Notably, similar to SRSF9 knockdown, knockdown of SH3BP2 promoted colony formation in soft agar (Fig.	('SH3BP2', 'Gene', (50, 56))	('agar', 'Chemical', 'MESH:D000362', (91, 95))	('colony formation in soft agar', 'CPA', (66, 95))	('promoted', 'PosReg', (57, 65))	('knockdown', 'Var', (37, 46))
318919	25015643	Consistent with this idea, knockdown of FRS2 or treatment with ponatinib significantly suppressed growth of tumors derived from SRSF9 knockdown SA cells (Supplementary Fig.	('SA', 'Chemical', 'MESH:C012546', (144, 146))	('ponatinib', 'Chemical', 'MESH:C545373', (63, 72))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('FRS2', 'Gene', (40, 44))	('FRS2', 'Gene', '327826', (40, 44))	('knockdown', 'Var', (134, 143))	('tumors', 'Disease', (108, 114))	('SRSF9', 'Gene', (128, 133))	('tumors', 'Disease', 'MESH:D009369', (108, 114))	('suppressed', 'NegReg', (87, 97))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('growth', 'CPA', (98, 104))
318924	25015643	Analysis of the original 28 human TSG candidates using the NCBI SKY/M-FISH and CGH database (National Center for Biotechnology Information Spectral Karyotyping, Multiplex Fluorescence In Situ Hybridization and Comparative Genomic Hybridization) revealed that all the genes have been found to harbor deletions in either one or both copies in multiple cancer types (Supplementary Table S5).	('M-FISH', 'Species', '119488', (68, 74))	('multiple cancer', 'Disease', 'MESH:D009369', (341, 356))	('human', 'Species', '9606', (28, 33))	('deletions', 'Var', (299, 308))	('multiple cancer', 'Disease', (341, 356))	('cancer', 'Phenotype', 'HP:0002664', (350, 356))
318925	25015643	Similarly, analysis of the COSMIC (Catalogue of Somatic Mutations in Cancer) database revealed that all of the TSG candidates have been found to have loss of heterozygosity in one or more cancer types, six have been found to harbor homozygous deletions, and 11 have been found to be recurrently mutated in various cancers (Supplementary Table S6).	('deletions', 'Var', (243, 252))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('cancer', 'Disease', (314, 320))	('cancers', 'Disease', 'MESH:D009369', (314, 321))	('cancers', 'Disease', (314, 321))	('TSG', 'Gene', (111, 114))	('cancers', 'Phenotype', 'HP:0002664', (314, 321))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('cancer', 'Phenotype', 'HP:0002664', (314, 320))	('Cancer', 'Phenotype', 'HP:0002664', (69, 75))	('Cancer', 'Disease', (69, 75))	('cancer', 'Disease', (188, 194))	('loss', 'NegReg', (150, 154))	('Cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Disease', 'MESH:D009369', (314, 320))
318934	25015643	Consistent with this idea, both NIH 3T3 cells and HBECs are transformed by ectopic expression of FGFR1 or knockdown of FGFR signaling repressors (Figs.	('HBEC', 'CellLine', 'CVCL:X489', (50, 54))	('FGFR1', 'Gene', (97, 102))	('NIH 3T3', 'CellLine', 'CVCL:0594', (32, 39))	('knockdown', 'Var', (106, 115))
318937	25015643	Several considerations allow us to conclude that the basis of transformation of HBECs following knockdown of the 17 TSGs that encode repressors of FGFR signaling is, in fact, increased FGFR signaling.	('knockdown', 'Var', (96, 105))	('TSGs', 'Gene', (116, 120))	('FGFR signaling', 'MPA', (185, 199))	('HBEC', 'CellLine', 'CVCL:X489', (80, 84))	('increased', 'PosReg', (175, 184))
318938	25015643	First, ectopic expression of FGFR1 is sufficient to transform HBECs (Fig.	('HBEC', 'CellLine', 'CVCL:X489', (62, 66))	('HBECs', 'Disease', (62, 67))	('ectopic expression', 'Var', (7, 25))	('transform', 'Reg', (52, 61))	('FGFR1', 'Gene', (29, 34))
318940	25015643	5A and B) or FRS2 knockdown (Fig.	('knockdown', 'Var', (18, 27))	('FRS2', 'Gene', (13, 17))	('FRS2', 'Gene', '327826', (13, 17))
318941	25015643	An important implication of our results is that aberrantly increased FGFR signaling may drive tumorigenesis of many hLSCCs that lack FGFR1 amplification or activating mutations.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('drive', 'PosReg', (88, 93))	('activating mutations', 'Var', (156, 176))	('FGFR1', 'Gene', (133, 138))	('FGFR', 'MPA', (69, 73))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('hLSCCs', 'Disease', (116, 122))	('tumor', 'Disease', (94, 99))	('lack', 'NegReg', (128, 132))	('increased', 'PosReg', (59, 68))	('aberrantly', 'Var', (48, 58))
318943	25015643	We note, however, that to date FGFR inhibitors have not been proven to be clinically effective, which may be due to several factors including improper patient selection, use of non-optimized drugs, and not using appropriate drug combinations.	('inhibitors', 'Var', (36, 46))	('patient', 'Species', '9606', (151, 158))	('FGFR', 'Gene', (31, 35))
318944	25015643	For example, a recent hLSCC genomic sequencing study reported statistically recurrent mutations in 11 genes but only one of these, STK11, was in common with the 24 TSGs identified in this study.	('STK11', 'Gene', (131, 136))	('mutations', 'Var', (86, 95))	('STK11', 'Gene', '20869', (131, 136))
318957	25015643	For all 32 genes whose knockdown promoted tumor formation, a second, unrelated shRNA directed against the same target gene was tested for promotion of colony formation in soft agar and knockdown efficiency of the target gene.	('promoted', 'PosReg', (33, 41))	('tumor', 'Disease', (42, 47))	('knockdown', 'Var', (23, 32))	('agar', 'Chemical', 'MESH:D000362', (176, 180))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
318968	25015643	pFRS2-Y436 (Abcam), pFRS2-Y196 (Cell Signaling), tFRS2 (Santa Cruz), tIR (Cell Signaling), tPLC gamma (Santa Cruz), SH3BP2 (Abcam), pY (Invitrogen), and alpha-tubulin.	('IR', 'Gene', '16337', (70, 72))	('FRS2', 'Gene', '327826', (50, 54))	('FRS2', 'Gene', (21, 25))	('FRS2', 'Gene', '327826', (1, 5))	('FRS2', 'Gene', (50, 54))	('tPLC gamma', 'Var', (91, 101))	('alpha-tubulin', 'Gene', (153, 166))	('FRS2', 'Gene', (1, 5))	('alpha-tubulin', 'Gene', '10376', (153, 166))	('SH3BP2', 'Var', (116, 122))	('FRS2', 'Gene', '327826', (21, 25))
318970	25015643	The human or mouse FGFR1 cDNA clone (MHS1010-7429513 or MMM1013-7510432, respectively; Open Biosystems/Thermo Scientific) and empty vector (pCMV-SPORT6; Open Biosystems) were transfected into SA or NIH 3T3 cells twice with 3 days in between to achieve maximum transfection efficiency.	('mouse', 'Species', '10090', (13, 18))	('human', 'Species', '9606', (4, 9))	('SA', 'Chemical', 'MESH:C012546', (192, 194))	('NIH 3T3', 'CellLine', 'CVCL:0594', (198, 205))	('transfection', 'MPA', (260, 272))	('MHS1010-7429513', 'Var', (37, 52))	('MMM1013-7510432', 'Var', (56, 71))	('FGFR1', 'Gene', (19, 24))
318977	25015643	Total RNA from non-silencing or SRSF9 knockdown SA cells was isolated using TriPure Isolation Reagent (Roche), and mRNA purification, cDNA synthesis and amplification were carried out according to the TrueSeq RNA sample preparation guide (Illumina).	('SRSF9', 'Gene', (32, 37))	('SA', 'Chemical', 'MESH:C012546', (48, 50))	('knockdown', 'Var', (38, 47))
318986	32545894	Multiple reports have shown that mis-regulation of HOX gene expression plays key roles in the development of cancers.	('roles', 'Reg', (81, 86))	('cancers', 'Disease', 'MESH:D009369', (109, 116))	('cancers', 'Phenotype', 'HP:0002664', (109, 116))	('cancers', 'Disease', (109, 116))	('HOX gene', 'Gene', (51, 59))	('mis-regulation', 'Var', (33, 47))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))
318993	32545894	Multiple reports have demonstrated that mis-regulation of HOX genes expression plays key roles in the development of cancers.	('mis-regulation', 'Var', (40, 54))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('roles', 'Reg', (89, 94))	('cancers', 'Phenotype', 'HP:0002664', (117, 124))	('HOX genes', 'Gene', (58, 67))	('cancers', 'Disease', 'MESH:D009369', (117, 124))	('cancers', 'Disease', (117, 124))
319048	32545894	The expression correlation observed between HOXB5, HOXB6, and HOXB7 in ESCA, is in line with a previous report that showed that expression changes in the three "midcluster" HOXB genes, namely HOXB5, HOXB6, and HOXB7, can trigger changes in the transcriptional program of adult esophageal cells, with implications to the early stages of esophageal carcinogenesis.	('HOXB', 'Gene', (62, 66))	('HOXB7', 'Gene', '3217', (210, 215))	('HOXB7', 'Gene', (210, 215))	('HOXB', 'Gene', (44, 48))	('HOXB', 'Gene', (173, 177))	('HOXB', 'Gene', '3210', (199, 203))	('HOXB', 'Gene', (51, 55))	('HOXB', 'Gene', (210, 214))	('HOXB6', 'Gene', '3216', (51, 56))	('HOXB6', 'Gene', (51, 56))	('HOXB5', 'Gene', (44, 49))	('HOXB', 'Gene', (192, 196))	('HOXB6', 'Gene', '3216', (199, 204))	('HOXB7', 'Gene', '3217', (62, 67))	('trigger changes', 'Reg', (221, 236))	('esophageal carcinogenesis', 'Disease', (336, 361))	('HOXB7', 'Gene', (62, 67))	('HOXB', 'Gene', '3210', (62, 66))	('changes', 'Var', (139, 146))	('HOXB6', 'Gene', (199, 204))	('HOXB', 'Gene', '3210', (44, 48))	('HOXB', 'Gene', '3210', (173, 177))	('transcriptional program', 'MPA', (244, 267))	('HOXB5', 'Gene', '3215', (44, 49))	('HOXB5', 'Gene', (192, 197))	('HOXB', 'Gene', '3210', (51, 55))	('HOXB', 'Gene', '3210', (210, 214))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (336, 361))	('HOXB', 'Gene', (199, 203))	('HOXB', 'Gene', '3210', (192, 196))	('ESCA', 'Phenotype', 'HP:0011459', (71, 75))	('HOXB5', 'Gene', '3215', (192, 197))
319153	32265897	Based on the identified literature, IFI30, GBP1, and GBP4 suppress mouse primary T cell activation in vitro and mouse innate immune response in vivo while IFI30 and GBP1 appear to increase cell proliferation in a glioma cell line and two breast cancer cell lines but diminish cell proliferation in a colon cancer cell line.	('glioma', 'Phenotype', 'HP:0009733', (213, 219))	('diminish', 'NegReg', (267, 275))	('breast cancer', 'Disease', 'MESH:D001943', (238, 251))	('breast cancer', 'Disease', (238, 251))	('IFI30', 'Var', (155, 160))	('suppress', 'NegReg', (58, 66))	('colon cancer', 'Disease', (300, 312))	('increase', 'PosReg', (180, 188))	('IFI30', 'Var', (36, 41))	('GBP1', 'Var', (165, 169))	('mouse innate immune response', 'CPA', (112, 140))	('cell proliferation', 'CPA', (189, 207))	('mouse primary T cell activation', 'CPA', (67, 98))	('colon cancer', 'Phenotype', 'HP:0003003', (300, 312))	('mouse', 'Species', '10090', (67, 72))	('glioma', 'Disease', (213, 219))	('cancer', 'Phenotype', 'HP:0002664', (245, 251))	('glioma', 'Disease', 'MESH:D005910', (213, 219))	('GBP4', 'Gene', (53, 57))	('cancer', 'Phenotype', 'HP:0002664', (306, 312))	('GBP1', 'Gene', (43, 47))	('colon cancer', 'Disease', 'MESH:D015179', (300, 312))	('mouse', 'Species', '10090', (112, 117))	('breast cancer', 'Phenotype', 'HP:0003002', (238, 251))
319154	32265897	Intriguingly, however, IFI30 RNA expression is associated with better patient survival in breast cancer and diffuse large B cell lymphomas (DLBCL) while GPB1 RNA is associated with better patient survival in melanoma but poorer prognosis in human glioblastoma.	('lymphoma', 'Phenotype', 'HP:0002665', (129, 137))	('melanoma', 'Phenotype', 'HP:0002861', (208, 216))	('melanoma', 'Disease', (208, 216))	('human', 'Species', '9606', (241, 246))	('B cell lymphomas', 'Disease', (122, 138))	('B cell lymphomas', 'Phenotype', 'HP:0012191', (122, 138))	('IFI30 RNA expression', 'Var', (23, 43))	('patient', 'Species', '9606', (70, 77))	('B cell lymphoma', 'Phenotype', 'HP:0012191', (122, 137))	('large B cell', 'Phenotype', 'HP:0005404', (116, 128))	('glioblastoma', 'Disease', 'MESH:D005909', (247, 259))	('B cell lymphomas', 'Disease', 'MESH:D016393', (122, 138))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('lymphomas', 'Phenotype', 'HP:0002665', (129, 138))	('glioblastoma', 'Disease', (247, 259))	('patient', 'Species', '9606', (188, 195))	('melanoma', 'Disease', 'MESH:D008545', (208, 216))	('glioblastoma', 'Phenotype', 'HP:0012174', (247, 259))	('breast cancer', 'Phenotype', 'HP:0003002', (90, 103))	('GPB1 RNA', 'Var', (153, 161))	('breast cancer', 'Disease', 'MESH:D001943', (90, 103))	('breast cancer', 'Disease', (90, 103))	('better', 'PosReg', (63, 69))
319174	32265897	Ten thousand two hundred fifty-five genes (40% of total genes) had an average FPKM > 1 and differential expression between tumors and normal controls (False Discovery Rate (FDR) < 0.05 in ANOVA).	('tumors', 'Disease', 'MESH:D009369', (123, 129))	('tumors', 'Disease', (123, 129))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('expression', 'MPA', (104, 114))	('differential', 'Reg', (91, 103))	('FPKM', 'Var', (78, 82))
319190	32265897	In IFNgamma positive tumors, IFI30, GBP1, and GBP4 were significantly upregulated (p < 0.0001) at 2.7-, 4.2-, and 6.2-fold, respectively (Figure 3A) while only IFI30 and GBP1 were upregulated (p < 0.05) at 1.4- and 1.2-fold, respectively in IFNgamma negative tumors compared to their matched normal controls (Figure 3B).	('IFNgamma', 'Gene', '3458', (241, 249))	('IFI30', 'Var', (29, 34))	('GBP4', 'Gene', (46, 50))	('GBP1', 'Gene', (36, 40))	('tumors', 'Disease', (21, 27))	('tumors', 'Disease', 'MESH:D009369', (21, 27))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('tumor', 'Phenotype', 'HP:0002664', (259, 264))	('tumors', 'Disease', (259, 265))	('tumors', 'Disease', 'MESH:D009369', (259, 265))	('upregulated', 'PosReg', (70, 81))	('tumors', 'Phenotype', 'HP:0002664', (259, 265))	('IFNgamma', 'Gene', (3, 11))	('IFNgamma', 'Gene', (241, 249))	('IFNgamma', 'Gene', '3458', (3, 11))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
319191	32265897	Notably, the abundance of IFI30, GBP1 and GBP4 was substantially higher in IFNgamma positive tumors (362, 51, 25 FPKM, respectively) than in IFNgamma negative tumors (207, 18, 7 FPKM, respectively) (Table S9).	('positive', 'Var', (84, 92))	('IFNgamma', 'Gene', (141, 149))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('IFI30', 'Gene', (26, 31))	('IFNgamma', 'Gene', '3458', (141, 149))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('IFNgamma', 'Gene', (75, 83))	('tumors', 'Disease', 'MESH:D009369', (93, 99))	('tumors', 'Disease', (159, 165))	('GBP1', 'Gene', (33, 37))	('IFNgamma', 'Gene', '3458', (75, 83))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('GBP4', 'Gene', (42, 46))	('tumors', 'Phenotype', 'HP:0002664', (159, 165))	('tumors', 'Disease', 'MESH:D009369', (159, 165))	('tumors', 'Disease', (93, 99))	('higher', 'PosReg', (65, 71))	('abundance', 'MPA', (13, 22))
319207	32265897	In contrast, there were no differences (p > 0.05) in expression of the above 9 immune cell specific genes in normal tissues from patients with IFNgamma positive vs. negative CRC (Figure 4B).	('patients', 'Species', '9606', (129, 137))	('IFNgamma', 'Gene', '3458', (143, 151))	('IFNgamma', 'Gene', (143, 151))	('positive', 'Var', (152, 160))
319215	32265897	Although the MSS/MSI status was available for only 7 CRCs in our cohort, 5 MSS CRCs, and two MSI CRC (Table S1), we found that all 10 genes (IFNgamma, six ICPs, and three ICPRGs) were upregulated in MSI CRC compared to MSS CRC but this did not reach statistical significance (P = 0.31) in this small sample size (Figure S3F).	('IFNgamma', 'Gene', '3458', (141, 149))	('MSI', 'Var', (199, 202))	('IFNgamma', 'Gene', (141, 149))	('upregulated', 'PosReg', (184, 195))
319217	32265897	To further define the dosage impact of IFNgamma on the expression of six ICPs and three ICPRGs, we generated six IFNgamma expression level gradients 1 IFNgamma: FPKM > 5 (4 CRCs); IFNgamma: FPKM = 4.9-2 (20 CRCs); IFNgamma: FPKM = 1.99-1(44 CRCs); IFNgamma: FPKM = 0.99-0.5 (73 CRCs); IFNgamma: FPKM = 0.49-0.01 (467 CRC); and IFNgamma: FPKM < 0.009 (107 CRCs) in 716 CRCs (Indivumed [79 CRCs] and TCGA [637 CRCs]) (Figure 5A) and examined the impact of the levels on expression of the ICPs and ICPRGs examined in our more limited cohort.	('IFNgamma', 'Gene', '3458', (285, 293))	('IFNgamma', 'Gene', '3458', (327, 335))	('IFNgamma', 'Gene', (327, 335))	('IFNgamma', 'Gene', (180, 188))	('FPKM = 0.49-0.01', 'Var', (295, 311))	('IFNgamma', 'Gene', '3458', (180, 188))	('IFNgamma', 'Gene', (113, 121))	('IFNgamma', 'Gene', '3458', (214, 222))	('IFNgamma', 'Gene', (214, 222))	('IFNgamma', 'Gene', (39, 47))	('FPKM < 0.009', 'Var', (337, 349))	('IFNgamma', 'Gene', '3458', (113, 121))	('IFNgamma', 'Gene', '3458', (39, 47))	('IFNgamma', 'Gene', '3458', (151, 159))	('IFNgamma', 'Gene', (151, 159))	('IFNgamma', 'Gene', (248, 256))	('IFNgamma', 'Gene', (285, 293))	('IFNgamma', 'Gene', '3458', (248, 256))
319249	32265897	In fact, GBP1 and GBP4 were associated with a favorable prognosis in 4 types of cancer (CRC, SKCM, BC, and STC) according to the Pathology Atlas analysis.	('SKCM', 'Disease', (93, 97))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('GBP1', 'Var', (9, 13))	('CRC', 'Disease', (88, 91))	('GBP4', 'Var', (18, 22))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('cancer', 'Disease', (80, 86))
319250	32265897	These data are consistent with the evidence [KEYNOTE-001 trial/pembrolizumab (anti-PDL1) treatment] that high expression of PDL1, a classical immune suppressive check point molecule was associated with better survival among pembrolizumab-treated NSCLC and melanoma patients.	('NSCLC', 'Disease', 'MESH:D002289', (246, 251))	('PDL1', 'Gene', '29126', (83, 87))	('better', 'PosReg', (202, 208))	('PDL1', 'Gene', '29126', (124, 128))	('NSCLC', 'Disease', (246, 251))	('melanoma', 'Disease', (256, 264))	('melanoma', 'Phenotype', 'HP:0002861', (256, 264))	('patients', 'Species', '9606', (265, 273))	('PDL1', 'Gene', (83, 87))	('melanoma', 'Disease', 'MESH:D008545', (256, 264))	('survival', 'MPA', (209, 217))	('PDL1', 'Gene', (124, 128))	('pembrolizumab', 'Chemical', 'MESH:C582435', (224, 237))	('pembrolizumab', 'Chemical', 'MESH:C582435', (63, 76))	('high expression', 'Var', (105, 120))
319337	28562351	In order to study where there is an age trend of second cancer, the SIRs were stratified according to three age groups (<=50, 50-60 and >60) at initial diagnosis of the primary cancer.	('cancer', 'Disease', (177, 183))	('<=50', 'Var', (120, 124))	('cancer', 'Disease', 'MESH:D009369', (177, 183))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('primary cancer', 'Disease', (169, 183))	('primary cancer', 'Disease', 'MESH:D009369', (169, 183))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))
319359	28562351	The epigenetic alterations of some genes, such as HOXA9, have been implicated in both oral cancer and esophageal cancer patients as potential biomarkers for the early detection of the field of cancerization.	('esophageal cancer', 'Disease', 'MESH:D004938', (102, 119))	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('HOXA9', 'Gene', (50, 55))	('implicated', 'Reg', (67, 77))	('cancer', 'Disease', (193, 199))	('oral cancer', 'Disease', 'MESH:D009062', (86, 97))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('oral cancer', 'Disease', (86, 97))	('cancer', 'Disease', (113, 119))	('epigenetic alterations', 'Var', (4, 26))	('patients', 'Species', '9606', (120, 128))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('esophageal cancer', 'Disease', (102, 119))	('HOXA9', 'Gene', '3205', (50, 55))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
319362	28562351	For example, the tumour suppressor gene TP53 plays an important role in the multi-step carcinogenesis for both cancers, and TP53 mutations were found in 93% of esophageal squamous cell carcinoma and 57% of oral squamous cell carcinoma in Chinese patients, particularly those who had alcohol drinking, betel quid chewing or cigarette smoking.	('cancers', 'Disease', 'MESH:D009369', (111, 118))	('patients', 'Species', '9606', (246, 254))	('TP53', 'Gene', (124, 128))	('TP53', 'Gene', '7157', (40, 44))	('esophageal squamous cell carcinoma', 'Disease', (160, 194))	('alcohol', 'Chemical', 'MESH:D000438', (283, 290))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (206, 234))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('found', 'Reg', (144, 149))	('oral squamous cell carcinoma', 'Disease', (206, 234))	('cancers', 'Phenotype', 'HP:0002664', (111, 118))	('alcohol drinking', 'Phenotype', 'HP:0030955', (283, 299))	('cancers', 'Disease', (111, 118))	('TP53', 'Gene', '7157', (124, 128))	('tumour', 'Phenotype', 'HP:0002664', (17, 23))	('tumour', 'Disease', 'MESH:D009369', (17, 23))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (211, 234))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (160, 194))	('TP53', 'Gene', (40, 44))	('tumour', 'Disease', (17, 23))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (171, 194))	('carcinoma', 'Phenotype', 'HP:0030731', (225, 234))	('mutations', 'Var', (129, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (185, 194))
319363	28562351	Recently, genetic polymorphisms of acetaldehyde dehydrogenases (ALDH2) gene is recognized as a key factor regarding the susceptibility to both esophageal and oral squamous cell carcinomas.	('susceptibility', 'Reg', (120, 134))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (163, 186))	('ALDH2', 'Gene', '217', (64, 69))	('ALDH2', 'Gene', (64, 69))	('esophageal and oral squamous cell carcinomas', 'Disease', 'MESH:D000077277', (143, 187))	('carcinoma', 'Phenotype', 'HP:0030731', (177, 186))	('carcinomas', 'Phenotype', 'HP:0030731', (177, 187))	('acetaldehyde', 'Chemical', 'MESH:D000079', (35, 47))	('genetic polymorphisms', 'Var', (10, 31))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (163, 187))
319365	28562351	Inactive heterozygous ALDH2 alleles cause a deficiency of the enzyme and were shown to increase the risk of esophageal squamous cell carcinoma (SCC) and metachronous head and neck cancer.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (119, 142))	('ALDH2', 'Gene', (22, 27))	('increase', 'PosReg', (87, 95))	('deficiency of the enzyme', 'Disease', 'MESH:D008661', (44, 68))	('SCC', 'Gene', (144, 147))	('alleles', 'Var', (28, 35))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('SCC', 'Phenotype', 'HP:0002860', (144, 147))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (108, 142))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('SCC', 'Gene', '6317', (144, 147))	('head and neck cancer', 'Phenotype', 'HP:0012288', (166, 186))	('neck cancer', 'Disease', 'MESH:D006258', (175, 186))	('ALDH2', 'Gene', '217', (22, 27))	('neck cancer', 'Disease', (175, 186))	('esophageal squamous cell carcinoma', 'Disease', (108, 142))	('deficiency of the enzyme', 'Disease', (44, 68))
319370	28562351	On top of that, the in vitro and animal studies showed that HPV16 E6-E7 can induce cancer stem-like cells phenotypes in esophageal squamous cell carcinoma through activation of the PI3K/Akt signalling pathway.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (131, 154))	('Akt', 'Gene', '207', (186, 189))	('activation', 'PosReg', (163, 173))	('carcinoma', 'Phenotype', 'HP:0030731', (145, 154))	('HPV16', 'Species', '333760', (60, 65))	('E6-E7', 'Var', (66, 71))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('esophageal squamous cell carcinoma', 'Disease', (120, 154))	('Akt', 'Gene', (186, 189))	('HPV16', 'Gene', (60, 65))	('induce', 'PosReg', (76, 82))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (120, 154))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('cancer', 'Disease', (83, 89))
319409	27108527	Thus, high IL-6 expression correlated to poor prognosis and acquired cisplatin resistance, but it did not mediate cisplatin resistance in the HNSCC cell lines.	('cisplatin', 'Chemical', 'MESH:D002945', (69, 78))	('HNSCC', 'Phenotype', 'HP:0012288', (142, 147))	('cisplatin', 'Chemical', 'MESH:D002945', (114, 123))	('high', 'Var', (6, 10))	('expression', 'MPA', (16, 26))	('acquired cisplatin resistance', 'MPA', (60, 89))	('IL-6', 'Gene', (11, 15))
319419	27108527	Moreover, IL-6 gene knock-down reverses cisplatin resistance in esophageal carcinoma cell lines and increased IL-6 production is associated with resistance to other chemotherapy drugs, such as fluorouracil, doxorubicin and VP-16.	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (64, 84))	('reverses', 'NegReg', (31, 39))	('increased', 'PosReg', (100, 109))	('IL-6 production', 'MPA', (110, 125))	('fluorouracil', 'Chemical', 'MESH:D005472', (193, 205))	('knock-down', 'Var', (20, 30))	('VP-16', 'Gene', '3054', (223, 228))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('cisplatin', 'Chemical', 'MESH:D002945', (40, 49))	('IL-6', 'Gene', (10, 14))	('VP-16', 'Gene', (223, 228))	('esophageal carcinoma', 'Disease', (64, 84))	('cisplatin resistance', 'MPA', (40, 60))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (64, 84))	('doxorubicin', 'Chemical', 'MESH:D004317', (207, 218))	('increased IL-6', 'Phenotype', 'HP:0030783', (100, 114))
319453	27108527	Further investigation of 70 cis-/carboplatin treated patients showed that those with high IL-6 mRNA expression levels tended to have a lower 5-year survival rate, suggesting reduced response to platinum-based treatment (Fig.	('carboplatin', 'Chemical', 'MESH:D016190', (33, 44))	('IL-6', 'Gene', (90, 94))	('5-year survival rate', 'CPA', (141, 161))	('patients', 'Species', '9606', (53, 61))	('mRNA expression levels', 'MPA', (95, 117))	('platinum', 'Chemical', 'MESH:D010984', (194, 202))	('high', 'Var', (85, 89))	('lower', 'NegReg', (135, 140))	('men', 'Species', '9606', (214, 217))	('reduced', 'NegReg', (174, 181))
319459	27108527	The IC50 values for cisplatin treated cells (i.e., C12cis and D2cis) were more than three times higher than in the parental cells (Fig.	('D2', 'Gene', '28503', (62, 64))	('cisplatin', 'Chemical', 'MESH:D002945', (20, 29))	('IC50', 'MPA', (4, 8))	('higher', 'PosReg', (96, 102))	('C12cis', 'Var', (51, 57))
319477	27108527	However, unlike IL-6, the mRNA and protein levels of its receptor were downregulated in both C12cis and D2cis cells in comparison with the parental cells (Fig.	('downregulated', 'NegReg', (71, 84))	('C12cis', 'Var', (93, 99))	('D2', 'Gene', '28503', (104, 106))
319493	27108527	A few alternative spliced IL-6 variants exist in human, some of which have antagonistic activities and a tissue-specific expression pattern, similar to IL-4.	('IL-4', 'Gene', '3565', (152, 156))	('variants', 'Var', (31, 39))	('human', 'Species', '9606', (49, 54))	('IL-6', 'Gene', (26, 30))	('IL-4', 'Gene', (152, 156))
319494	27108527	For example, lung tissue, renal tissue, renal carcinomas and fibroblasts produce three IL-6 inhibitory variants lacking either exon 4 (IL-6delta4), exon 2 (IL-6delta2) or both exons (IL-6delta2delta4).	('6delta2', 'Mutation', 'c.6del2', (186, 193))	('lacking', 'NegReg', (112, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (46, 55))	('renal carcinomas', 'Disease', (40, 56))	('6delta4', 'Mutation', 'c.6del4', (138, 145))	('exon 2', 'MPA', (148, 154))	('variants', 'Var', (103, 111))	('renal carcinomas', 'Phenotype', 'HP:0005584', (40, 56))	('carcinomas', 'Phenotype', 'HP:0030731', (46, 56))	('exon 4', 'MPA', (127, 133))	('IL-6', 'Gene', (87, 91))	('6delta2', 'Mutation', 'c.6del2', (159, 166))	('renal carcinomas', 'Disease', 'MESH:C538614', (40, 56))
319499	27108527	Dysregulated microRNA expression is common in various malignancies where miRNAs regulate cell proliferation, apoptosis and invasion by controlling downstream target genes.	('malignancies', 'Disease', (54, 66))	('regulate', 'Reg', (80, 88))	('cell proliferation', 'CPA', (89, 107))	('invasion', 'CPA', (123, 131))	('apoptosis', 'CPA', (109, 118))	('Dysregulated', 'Var', (0, 12))	('malignancies', 'Disease', 'MESH:D009369', (54, 66))	('microRNA', 'Protein', (13, 21))
319513	27108527	In conclusion, high tumor IL-6 transcription levels were associated with poor prognosis and acquired cisplatin resistance in HNSCC, but IL-6 did not itself mediate cisplatin resistance.	('high', 'Var', (15, 19))	('acquired cisplatin resistance', 'MPA', (92, 121))	('HNSCC', 'Phenotype', 'HP:0012288', (125, 130))	('cisplatin', 'Chemical', 'MESH:D002945', (101, 110))	('IL-6', 'Gene', (26, 30))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('transcription levels', 'MPA', (31, 51))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('tumor', 'Disease', (20, 25))	('cisplatin', 'Chemical', 'MESH:D002945', (164, 173))
319514	27108527	Thus, inhibiting IL-6 signaling may not reduce cisplatin resistance in HNSCC.	('inhibiting', 'Var', (6, 16))	('cisplatin resistance', 'MPA', (47, 67))	('IL-6', 'Protein', (17, 21))	('cisplatin', 'Chemical', 'MESH:D002945', (47, 56))	('HNSCC', 'Disease', (71, 76))	('HNSCC', 'Phenotype', 'HP:0012288', (71, 76))
319529	33935618	Women affected by BRCA1/BRCA2 gene mutations, who were subjected to preventive bilateral oophorectomy in reproductive age, face a similar problem.	('BRCA1', 'Gene', '672', (18, 23))	('BRCA2', 'Gene', '675', (24, 29))	('Women', 'Species', '9606', (0, 5))	('BRCA1', 'Gene', (18, 23))	('BRCA2', 'Gene', (24, 29))	('mutations', 'Var', (35, 44))
319548	33935618	Taking into account that most endometrial cancers are estrogen-sensitive, and the fact that prolonged exposition to estrogens increases the risk of disease, the use of ET in women after endometrial cancer potentially causes cancer recurrence as a result of stimulation of cancer cells remaining after treatment.	('cancer', 'Phenotype', 'HP:0002664', (272, 278))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('cancers', 'Phenotype', 'HP:0002664', (42, 49))	('cancer', 'Disease', (224, 230))	('endometrial cancer', 'Phenotype', 'HP:0012114', (30, 48))	('cancer', 'Disease', (198, 204))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('cancer', 'Disease', 'MESH:D009369', (272, 278))	('women', 'Species', '9606', (174, 179))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('endometrial cancer', 'Phenotype', 'HP:0012114', (186, 204))	('estrogen', 'Gene', '2069', (54, 62))	('endometrial cancer', 'Disease', 'MESH:D016889', (30, 48))	('endometrial cancer', 'Disease', (186, 204))	('estrogen', 'Gene', (54, 62))	('use', 'Var', (161, 164))	('cancer', 'Disease', 'MESH:D009369', (224, 230))	('endometrial cancer', 'Disease', 'MESH:D016889', (186, 204))	('endometrial cancers', 'Disease', 'MESH:D016889', (30, 49))	('estrogen', 'Gene', '2069', (116, 124))	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('endometrial cancers', 'Disease', (30, 49))	('stimulation', 'PosReg', (257, 268))	('causes', 'Reg', (217, 223))	('estrogen', 'Gene', (116, 124))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', (272, 278))
319575	33935618	The BRCA1 and BRCA2 gene mutations are associated with the increased risk of developing invasive EOC and breast cancer.	('mutations', 'Var', (25, 34))	('BRCA1', 'Gene', (4, 9))	('BRCA2', 'Gene', '675', (14, 19))	('EOC', 'Phenotype', 'HP:0025318', (97, 100))	('invasive EOC', 'Disease', (88, 100))	('associated', 'Reg', (39, 49))	('BRCA1', 'Gene', '672', (4, 9))	('breast cancer', 'Disease', 'MESH:D001943', (105, 118))	('breast cancer', 'Disease', (105, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('BRCA2', 'Gene', (14, 19))	('breast cancer', 'Phenotype', 'HP:0003002', (105, 118))
319576	33935618	In patients showing these gene mutations, risk-reducing salpingo-oophorectomy (RRSO) is recommended.	('patients', 'Species', '9606', (3, 11))	('mutations', 'Var', (31, 40))	('salpingo-oophorectomy', 'Disease', (56, 77))
319633	32268925	Biological evidence suggests that cisplatin causes the inhibition of the repair of radiation-induced DNA damage via both homologous recombination and nonhomologous end-joining.	('cisplatin', 'Chemical', 'MESH:D002945', (34, 43))	('repair', 'MPA', (73, 79))	('homologous recombination', 'MPA', (121, 145))	('nonhomologous', 'Var', (150, 163))	('inhibition', 'NegReg', (55, 65))
319710	32268925	In the present study, we incorporated DP weekly concurrentwith radiotherapy to treat patients with T4 or M1 LNM esophageal SCC.	('SCC', 'Phenotype', 'HP:0002860', (123, 126))	('SCC', 'Gene', '6317', (123, 126))	('patients', 'Species', '9606', (85, 93))	('M1 LNM', 'Var', (105, 111))	('DP', 'Chemical', 'MESH:D004176', (38, 40))	('SCC', 'Gene', (123, 126))
319729	32268925	If LN metastases could be covered by a single radiation field and treated appropriately with a potent radiosensitizer, the survival of patients with M1a and M1b nonvisceral LN disease would be improved.	('M1b', 'Var', (157, 160))	('patients', 'Species', '9606', (135, 143))	('metastases', 'Disease', 'MESH:D009362', (6, 16))	('improved', 'PosReg', (193, 201))	('M1a', 'Var', (149, 152))	('LN disease', 'Disease', (173, 183))	('metastases', 'Disease', (6, 16))	('LN disease', 'Disease', 'MESH:D003141', (173, 183))
319770	30216350	We found increasing lung cancer risk with increasing PM10 category (P-value for trend: 0.04).	('lung cancer', 'Disease', 'MESH:D008175', (20, 31))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('PM10', 'Var', (53, 57))	('lung cancer', 'Disease', (20, 31))	('lung cancer', 'Phenotype', 'HP:0100526', (20, 31))
319776	30216350	Some of those studies (cohort and case-control, ecological studies were not included), were later included in a meta-analysis to calculate the quantitative relationships between the risk of lung cancer and exposure to PM with aerodynamic diameter <=2.5 mum (PM2.5) and <=10 mum (PM10).	('<=10 mum', 'Var', (269, 277))	('lung cancer', 'Disease', 'MESH:D008175', (190, 201))	('<=2.5 mum', 'Var', (247, 256))	('lung cancer', 'Disease', (190, 201))	('lung cancer', 'Phenotype', 'HP:0100526', (190, 201))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
319825	30216350	Overall, we found an increasing trend of lung cancer with increasing PM10 concentration (P-value for trend for OR2: 0.04), with ORs moderately increased in the 4th (OR2 1.24, 95% CI: 0.85-1.80) and clearly elevated in the 5th PM10 category (OR 1.52, 95% CI: 1.04-2.21) (Table 3 and Fig 2).	('lung cancer', 'Disease', (41, 52))	('lung cancer', 'Phenotype', 'HP:0100526', (41, 52))	('elevated', 'PosReg', (206, 214))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('PM10', 'Var', (69, 73))	('lung cancer', 'Disease', 'MESH:D008175', (41, 52))
319841	30216350	The meta-analysis included nine cohort studies (three from Europe, five from the USA, and one from New Zealand) which provided quantitative relative risk estimates of lung cancer (per 10 mug/m3 of PM10).	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('PM10', 'Var', (197, 201))	('lung cancer', 'Disease', (167, 178))	('lung cancer', 'Phenotype', 'HP:0100526', (167, 178))	('lung cancer', 'Disease', 'MESH:D008175', (167, 178))
319851	30216350	The lung cancer estimates for these two cities were higher than the overall HR in the ESCAPE study (EPIC-Athens, RR 1.55 (95% CI: 1.00-2.40, 18 cases); EPIC-Turin, RR 1.45 (95% CI: 0.69-3.04, 48 cases), SIDRIA-Turin, RR = 1.41, 95% CI: 0.46-4.31, 19 cases).The ESCAPE study found ORs for adenocarcinoma (based on 663 cases) and squamous cell carcinoma (322 cases) respectively of 1.51 (95% CI: 1.10-2.08) and 0.84 (95% CI: 0.50-1.40) per 10 mug/m3 of PM10.	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (328, 351))	('adenocarcinoma', 'Disease', (288, 302))	('SIDRIA', 'Disease', (203, 209))	('carcinoma', 'Phenotype', 'HP:0030731', (293, 302))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('adenocarcinoma', 'Disease', 'MESH:D000230', (288, 302))	('carcinoma', 'Phenotype', 'HP:0030731', (342, 351))	('lung cancer', 'Disease', (4, 15))	('SIDRIA', 'Disease', 'None', (203, 209))	('lung cancer', 'Phenotype', 'HP:0100526', (4, 15))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (328, 351))	('lung cancer', 'Disease', 'MESH:D008175', (4, 15))	('squamous cell carcinoma', 'Disease', (328, 351))	('PM10', 'Var', (451, 455))
319862	30216350	In men only (2278 subjects, 16 lung cancer cases) the HR was 5.21 (95% CI: 1.94-13.99) for an interquartile range of 24 mug/m3 of PM10.	('lung cancer', 'Disease', 'MESH:D008175', (31, 42))	('PM10', 'Var', (130, 134))	('lung cancer', 'Disease', (31, 42))	('lung cancer', 'Phenotype', 'HP:0100526', (31, 42))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('men', 'Species', '9606', (3, 6))
319864	30216350	We were able to find only one RR (slightly greater than 1.00) for PM10 and lung cancer in the period 1987-1996 in Fig 5C of the original paper.	('lung cancer', 'Disease', (75, 86))	('lung cancer', 'Phenotype', 'HP:0100526', (75, 86))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('lung cancer', 'Disease', 'MESH:D008175', (75, 86))	('PM10', 'Var', (66, 70))
319877	30216350	The only case-control study on lung cancer which calculated quantitative relative risk estimates (per 10 mug/m3 of PM10) we are aware of was recently performed in South Korea.	('lung cancer', 'Disease', 'MESH:D008175', (31, 42))	('PM10', 'Var', (115, 119))	('lung cancer', 'Disease', (31, 42))	('lung cancer', 'Phenotype', 'HP:0100526', (31, 42))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))
319890	30216350	AOD aerosol optical depth (AOD) ARPA Regional Environmental Protection Agency CI confidence interval; EAGLE: Environment And Genetics in Lung cancer Etiology OR odds ratio PM10 particulate matter with aerodynamic diameter <=10 mum	('Lung cancer', 'Phenotype', 'HP:0100526', (137, 148))	('Lung cancer', 'Disease', (137, 148))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('Lung cancer', 'Disease', 'MESH:D008175', (137, 148))	('men', 'Species', '9606', (53, 56))	('PM10', 'Var', (172, 176))	('men', 'Species', '9606', (116, 119))
319907	27364315	Lung cancer histology and molecular markers, such as genetic mutations, are important when classifying lung cancers for treatment and preventive strategies.	('lung cancers', 'Disease', (103, 115))	('men', 'Species', '9606', (125, 128))	('genetic mutations', 'Var', (53, 70))	('Lung cancer', 'Phenotype', 'HP:0100526', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('Lung cancer', 'Disease', (0, 11))	('lung cancer', 'Phenotype', 'HP:0100526', (103, 114))	('lung cancers', 'Phenotype', 'HP:0100526', (103, 115))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))	('lung cancers', 'Disease', 'MESH:D008175', (103, 115))	('cancers', 'Phenotype', 'HP:0002664', (108, 115))	('Lung cancer', 'Disease', 'MESH:D008175', (0, 11))
319912	27364315	Lung cancer was defined as ICD-10/ICD-O3 codes C33-C34 and ICD-9 code 162, which include malignant neoplasms of the trachea, bronchus, and lung.	('malignant neoplasms of the trachea', 'Disease', (89, 123))	('C33-C34', 'Var', (47, 54))	('Lung cancer', 'Phenotype', 'HP:0100526', (0, 11))	('neoplasms', 'Phenotype', 'HP:0002664', (99, 108))	('malignant neoplasms of the trachea', 'Disease', 'MESH:D009369', (89, 123))	('Lung cancer', 'Disease', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))	('Lung cancer', 'Disease', 'MESH:D008175', (0, 11))	('neoplasms of the trachea', 'Phenotype', 'HP:0100551', (99, 123))
319954	27364315	An explanation for this is likely the result of several factors including a high relative proportion of epithelial growth factor receptor (EGFR)-mutation positive lung tumors for targeted therapies, the standardized long-term surveillance of lung cancer survivors, and the coordinated efforts on a national level to monitor and improve cancer care in Japan.	('cancer', 'Disease', (247, 253))	('cancer', 'Disease', (336, 342))	('EGFR', 'Gene', (139, 143))	('-mutation', 'Var', (144, 153))	('epithelial growth factor receptor', 'Gene', (104, 137))	('cancer', 'Phenotype', 'HP:0002664', (336, 342))	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('lung cancer', 'Disease', (242, 253))	('epithelial growth factor receptor', 'Gene', '1956', (104, 137))	('lung tumors', 'Disease', 'MESH:D008175', (163, 174))	('EGFR', 'Gene', '1956', (139, 143))	('cancer', 'Disease', 'MESH:D009369', (247, 253))	('cancer', 'Disease', 'MESH:D009369', (336, 342))	('lung tumors', 'Phenotype', 'HP:0100526', (163, 174))	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('lung cancer', 'Disease', 'MESH:D008175', (242, 253))	('lung tumors', 'Disease', (163, 174))	('lung cancer', 'Phenotype', 'HP:0100526', (242, 253))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
319969	27364315	The proportions of the genetic events, either mutations, amplifications, translocations, vary considerably across published studies and by histologic subtype, leading to both common pathway alterations (cell cycle regulation, DNA repair and divergent effects (RAS/RAf, mTOR and Jak-STAT in adenocarcinoma versus squamous differentiation, oxidative stress and PIK3CA in squamous cell carcinoma).	('leading', 'Reg', (159, 166))	('carcinoma', 'Phenotype', 'HP:0030731', (383, 392))	('mTOR', 'Gene', '2475', (269, 273))	('DNA repair', 'MPA', (226, 236))	('RAf', 'Gene', '22882', (264, 267))	('squamous cell carcinoma', 'Disease', (369, 392))	('alterations', 'Reg', (190, 201))	('carcinoma', 'Phenotype', 'HP:0030731', (295, 304))	('mutations', 'Var', (46, 55))	('PIK3CA', 'Gene', (359, 365))	('oxidative stress', 'Phenotype', 'HP:0025464', (338, 354))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (369, 392))	('adenocarcinoma', 'Disease', (290, 304))	('RAf', 'Gene', (264, 267))	('cell cycle', 'CPA', (203, 213))	('mTOR', 'Gene', (269, 273))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (369, 392))	('adenocarcinoma', 'Disease', 'MESH:D000230', (290, 304))	('PIK3CA', 'Gene', '5290', (359, 365))	('Jak-STAT', 'Gene', (278, 286))
319970	27364315	Supplemental Figure 1 summarizes the difference in the distribution of mutations in adenocarcinoma in a Chinese population and in U.S./European populations.	('mutations', 'Var', (71, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('adenocarcinoma', 'Disease', (84, 98))	('men', 'Species', '9606', (6, 9))	('adenocarcinoma', 'Disease', 'MESH:D000230', (84, 98))
319973	27364315	In a pooled analysis to describe the spectrum of somatic mutations in African Americans (AA), while the frequency of EGFR and KRAS mutations is comparable, AA have a distinct mutational pattern from Caucasian Americans, with a significantly higher proportion of unknown driver mutations that are not yet fully characterized (77% of NSCLC and 70% of non-squamous cell lung cancer).	('KRAS', 'Gene', '3845', (126, 130))	('mutations', 'Var', (131, 140))	('NSCLC', 'Disease', 'MESH:D002289', (332, 337))	('squamous cell lung cancer', 'Phenotype', 'HP:0030359', (353, 378))	('lung cancer', 'Phenotype', 'HP:0100526', (367, 378))	('EGFR', 'Gene', '1956', (117, 121))	('EGFR', 'Gene', (117, 121))	('cancer', 'Phenotype', 'HP:0002664', (372, 378))	('mutations', 'Var', (57, 66))	('cell lung cancer', 'Disease', (362, 378))	('non-squamous cell lung cancer', 'Phenotype', 'HP:0030358', (349, 378))	('NSCLC', 'Disease', (332, 337))	('cell lung cancer', 'Disease', 'MESH:D008175', (362, 378))	('KRAS', 'Gene', (126, 130))
319974	27364315	The frequency of mutations in squamous cell carcinoma, without a mixed histology, is summarized in Supplemental Figure 2.	('men', 'Species', '9606', (105, 108))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (30, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (44, 53))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (30, 53))	('mutations', 'Var', (17, 26))	('squamous cell carcinoma', 'Disease', (30, 53))
319975	27364315	In addition to these distinct mutations, as with adenocarcinoma, there are other genes that are frequently amplified that are also actionable, either directly or indirectly, including FGFR1 (20%), SOX (20%), MDM2 (10%), MET (6%) and PDGFRA (8-10%).	('PDGFRA', 'Gene', '5156', (233, 239))	('PDGFRA', 'Gene', (233, 239))	('FGFR1', 'Gene', '2260', (184, 189))	('MDM2', 'Gene', '4193', (208, 212))	('MDM2', 'Gene', (208, 212))	('carcinoma', 'Phenotype', 'HP:0030731', (54, 63))	('MET', 'Gene', (220, 223))	('adenocarcinoma', 'Disease', (49, 63))	('mutations', 'Var', (30, 39))	('FGFR1', 'Gene', (184, 189))	('adenocarcinoma', 'Disease', 'MESH:D000230', (49, 63))
320046	27364315	In addition, genetic testing, which screens actionable genetic alterations including EGFR mutations for targeted therapy, will likely provide important information about the treatment and prognosis of lung cancer although the treatment only affects a small minority of lung cancer patients overall.	('men', 'Species', '9606', (179, 182))	('EGFR', 'Gene', (85, 89))	('lung cancer', 'Disease', 'MESH:D008175', (269, 280))	('mutations', 'Var', (90, 99))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('lung cancer', 'Disease', 'MESH:D008175', (201, 212))	('cancer', 'Phenotype', 'HP:0002664', (274, 280))	('patients', 'Species', '9606', (281, 289))	('lung cancer', 'Disease', (269, 280))	('men', 'Species', '9606', (231, 234))	('lung cancer', 'Phenotype', 'HP:0100526', (269, 280))	('lung cancer', 'Phenotype', 'HP:0100526', (201, 212))	('EGFR', 'Gene', '1956', (85, 89))	('lung cancer', 'Disease', (201, 212))
320050	27364315	For example, in China, survey data showed that only 9.6% of non-small cell lung cancer cases were tested for EGFR mutation, while in Sweden, 49% of cases received testing.	('lung cancer', 'Phenotype', 'HP:0100526', (75, 86))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (60, 86))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('tested', 'Reg', (98, 104))	('EGFR', 'Gene', '1956', (109, 113))	('non-small cell lung cancer', 'Disease', (60, 86))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (64, 86))	('mutation', 'Var', (114, 122))	('EGFR', 'Gene', (109, 113))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (60, 86))
320279	32218847	Collectively, these results confirmed that exogenous BCL11A knockdown inhibited tumor progression in TNBC, and support the tumorigenic role of BCL11A in TNBC cell function.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor', 'Disease', (123, 128))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('TNBC', 'Disease', (101, 105))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('tumor', 'Disease', (80, 85))	('knockdown', 'Var', (60, 69))	('BCL11A', 'Gene', (53, 59))	('inhibited', 'NegReg', (70, 79))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
320283	32218847	To address it, the present study evaluated if inhibiting BCL11A could influence AR expression level in TNBC cell lines.	('AR', 'Gene', '367', (80, 82))	('BCL11A', 'Gene', (57, 63))	('inhibiting', 'Var', (46, 56))	('influence', 'Reg', (70, 79))
320285	32218847	Furthermore, knockdown of BCL11A expression significantly down-regulated the expression level of AR in TNBC cells (Fig.	('down-regulated', 'NegReg', (58, 72))	('BCL11A', 'Gene', (26, 32))	('knockdown', 'Var', (13, 22))	('AR', 'Gene', '367', (97, 99))
320294	32218847	Subsequent experimentation also revealed that knockdown of BCL11A expression significantly down-regulated the expression level of AR in TNBC cell lines and further had an influence on cell function in TNBC.	('down-regulated', 'NegReg', (91, 105))	('cell function', 'CPA', (184, 197))	('knockdown', 'Var', (46, 55))	('TNBC', 'Disease', (201, 205))	('had', 'Reg', (164, 167))	('BCL11A', 'Gene', (59, 65))	('influence', 'Reg', (171, 180))	('AR', 'Gene', '367', (130, 132))
320309	32218847	To gain more solid evidence, we designed the following experiment in TNBC cell lines to further investigate if inhibiting BCL11A could influence AR expression level and subsequently influence tumor cell function.	('influence', 'Reg', (135, 144))	('AR', 'Gene', '367', (145, 147))	('tumor', 'Disease', (192, 197))	('inhibiting', 'Var', (111, 121))	('influence', 'Reg', (182, 191))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('BCL11A', 'Gene', (122, 128))
320310	32218847	The present study showed that BCL11A knockdown significantly down-regulated the expression level of AR in TNBC cells and further had an influence on cell function, which suggests that AR may be a downstream target of BCL11A.	('cell function', 'CPA', (149, 162))	('AR', 'Gene', '367', (100, 102))	('AR', 'Gene', '367', (184, 186))	('BCL11A', 'Gene', (30, 36))	('expression level', 'MPA', (80, 96))	('influence', 'Reg', (136, 145))	('knockdown', 'Var', (37, 46))	('down-regulated', 'NegReg', (61, 75))
320316	32101536	Individualized genetic network analysis reveals new therapeutic vulnerabilities in 6,700 cancer genomes Tumor-specific genomic alterations allow systematic identification of genetic interactions that promote tumorigenesis and tumor vulnerabilities, offering novel strategies for development of targeted therapies for individual patients.	('tumor', 'Disease', 'MESH:D009369', (208, 213))	('interactions', 'Interaction', (182, 194))	('patients', 'Species', '9606', (328, 336))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('tumor', 'Disease', 'MESH:D009369', (226, 231))	('Tumor', 'Phenotype', 'HP:0002664', (104, 109))	('cancer', 'Disease', (89, 95))	('tumor', 'Disease', (208, 213))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('alterations', 'Var', (127, 138))	('promote', 'PosReg', (200, 207))	('tumor', 'Disease', (226, 231))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
320320	32101536	By analyzing drug pharmacogenomics profiles from the Genomics of Drug Sensitivity in Cancer database, we show that the network-predicted putative genetic interactions (e.g., BRCA2-TP53) are significantly correlated with sensitivity/resistance of multiple therapeutic agents.	('sensitivity/resistance', 'CPA', (220, 242))	('correlated', 'Reg', (204, 214))	('Drug Sensitivity', 'Phenotype', 'HP:0020174', (65, 81))	('Cancer', 'Disease', (85, 91))	('Cancer', 'Phenotype', 'HP:0002664', (85, 91))	('BRCA2-TP53', 'Gene', (174, 184))	('Cancer', 'Disease', 'MESH:D009369', (85, 91))	('interactions', 'Var', (154, 166))	('BRCA2-TP53', 'Gene', '7157;675', (174, 184))	('BRCA', 'Phenotype', 'HP:0003002', (174, 178))
320325	32101536	Tumor-specific genomic alterations derived from multi-center cancer genome projects allow identification of genetic interactions that promote tumor vulnerabilities, offering novel strategies for development of targeted cancer therapies.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('promote', 'PosReg', (134, 141))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('tumor', 'Disease', (142, 147))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('cancer', 'Disease', (61, 67))	('cancer', 'Disease', 'MESH:D009369', (219, 225))	('alterations', 'Var', (23, 34))	('cancer', 'Disease', (219, 225))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('multi-center cancer', 'Disease', (48, 67))	('multi-center cancer', 'Disease', 'MESH:D009369', (48, 67))
320329	32101536	By analyzing drug pharmacogenomics profiles, we showed that the network-predicted putative genetic interactions (e.g., BRCA2-TP53) were significantly correlated with sensitivity/resistance of anticancer drugs (e.g., afatinib) and we experimentally validated it in breast cancer cell lines.	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('afatinib', 'Chemical', 'MESH:D000077716', (216, 224))	('interactions', 'Var', (99, 111))	('sensitivity/resistance', 'MPA', (166, 188))	('cancer', 'Phenotype', 'HP:0002664', (271, 277))	('breast cancer', 'Disease', 'MESH:D001943', (264, 277))	('BRCA2-TP53', 'Gene', (119, 129))	('cancer', 'Disease', 'MESH:D009369', (196, 202))	('breast cancer', 'Disease', (264, 277))	('breast cancer', 'Phenotype', 'HP:0003002', (264, 277))	('cancer', 'Disease', (196, 202))	('correlated', 'Reg', (150, 160))	('BRCA2-TP53', 'Gene', '7157;675', (119, 129))	('cancer', 'Disease', 'MESH:D009369', (271, 277))	('BRCA', 'Phenotype', 'HP:0003002', (119, 123))	('cancer', 'Disease', (271, 277))	('genetic interactions', 'Var', (91, 111))
320335	32101536	Somatic alterations identified in tumor exomes/genomes are commonly grouped into two classes: gain-of-function mutations on oncogenes and loss-of-function mutations on tumor suppressor genes (TSGs).	('mutations', 'Var', (111, 120))	('oncogenes', 'Protein', (124, 133))	('tumor', 'Disease', (34, 39))	('mutations', 'Var', (155, 164))	('tumor', 'Disease', (168, 173))	('loss-of-function', 'NegReg', (138, 154))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('gain-of-function', 'PosReg', (94, 110))
320339	32101536	A synthetic lethal interaction occurring between a tumor-specific somatic mutation and a gene that drives tumorigenesis and tumor progression offers an ideal therapeutic target in cancer.	('mutation', 'Var', (74, 82))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('tumor', 'Disease', (51, 56))	('tumor', 'Disease', (124, 129))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('cancer', 'Disease', (180, 186))	('tumor', 'Disease', (106, 111))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
320344	32101536	For example, several computational approaches, such as MEMo and WeSME, were reported to identify mutually exclusive mutations in cancer.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('mutations', 'Var', (116, 125))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))
320348	32101536	We computationally identified hundreds of new putative genetic interactions in multiple cancer types via INCM.	('cancer', 'Disease', (88, 94))	('genetic', 'Var', (55, 62))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))
320353	32101536	Previous studies have shown that gene pairs with high co-mutation rate in cancer populations and with the closest network topological distance in the human protein-protein interactome can have high likelihood to promote tumorigenesis and anticancer drug responses.	('human', 'Species', '9606', (150, 155))	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('cancer', 'Disease', (242, 248))	('cancer', 'Disease', 'MESH:D009369', (242, 248))	('tumor', 'Disease', (220, 225))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('promote', 'PosReg', (212, 219))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('cancer', 'Disease', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (242, 248))	('tumor', 'Disease', 'MESH:D009369', (220, 225))	('co-mutation', 'Var', (54, 65))
320380	32101536	We found that genes in the INCM-predicted putative genetic interactions were enriched to be in the CGC gene set (P < 0.01) across all 14 cancer types, in SMGs across 12 cancer types with the exception of BLCA and OV, in the DDR genes across 12 cancer types with the exception of PRAD and SKCM, and in the CRF genes across 8 cancer types with the exception of BLCA, BRCA, COAD, GBM, LAML and OV (Fig 3C and 3D).	('cancer', 'Disease', (169, 175))	('OV', 'Phenotype', 'HP:0012887', (391, 393))	('DDR', 'Gene', (224, 227))	('interactions', 'Var', (59, 71))	('COAD', 'Disease', 'MESH:D029424', (371, 375))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('BRCA', 'Gene', (365, 369))	('cancer', 'Disease', (137, 143))	('cancer', 'Disease', 'MESH:D009369', (244, 250))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('OV', 'Phenotype', 'HP:0012887', (213, 215))	('cancer', 'Disease', 'MESH:D009369', (169, 175))	('cancer', 'Disease', (324, 330))	('COAD', 'Disease', (371, 375))	('BRCA', 'Phenotype', 'HP:0003002', (365, 369))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('cancer', 'Phenotype', 'HP:0002664', (324, 330))	('CGC', 'Gene', (99, 102))	('cancer', 'Disease', (244, 250))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('BRCA', 'Gene', '672', (365, 369))	('cancer', 'Disease', 'MESH:D009369', (324, 330))
320388	32101536	Fig 4C reveals that melanoma patients harboring nonsynonymous somatic mutations on BACH2-KRAS have poor survival rate compared with the wild-type group (P = 0.001, log-rank test).	('patients', 'Species', '9606', (29, 37))	('BACH2', 'Gene', '60468', (83, 88))	('BACH2', 'Gene', (83, 88))	('poor', 'NegReg', (99, 103))	('survival rate', 'CPA', (104, 117))	('nonsynonymous', 'Var', (48, 61))	('melanoma', 'Phenotype', 'HP:0002861', (20, 28))	('melanoma', 'Disease', (20, 28))	('KRAS', 'Gene', (89, 93))	('melanoma', 'Disease', 'MESH:D008545', (20, 28))	('KRAS', 'Gene', '3845', (89, 93))
320390	32101536	In addition to HRAS and KRAS, we also computationally identified several significantly mutated genetic interactions for new gene families, such as SEPT1-BRIP1 in melanoma (Fig 4D).	('genetic', 'Var', (95, 102))	('KRAS', 'Gene', '3845', (24, 28))	('melanoma', 'Disease', 'MESH:D008545', (162, 170))	('melanoma', 'Phenotype', 'HP:0002861', (162, 170))	('melanoma', 'Disease', (162, 170))	('HRAS', 'Gene', '3265', (15, 19))	('SEPT1', 'Gene', (147, 152))	('BRIP1', 'Gene', (153, 158))	('mutated', 'Reg', (87, 94))	('SEPT1', 'Gene', '1731', (147, 152))	('BRIP1', 'Gene', '83990', (153, 158))	('HRAS', 'Gene', (15, 19))	('KRAS', 'Gene', (24, 28))
320392	32101536	For BRCA, in total we identified 82 significantly mutated genetic interactions with adjusted P-value < 0.05 (S4 Table).	('mutated', 'Var', (50, 57))	('BRCA', 'Gene', (4, 8))	('BRCA', 'Gene', '672', (4, 8))	('BRCA', 'Phenotype', 'HP:0003002', (4, 8))
320397	32101536	Interestingly, breast cancer patients harboring nonsynonymous somatic mutations on BCL2L1-HRAS reveals poor survival rate compared to the wild-type status on both BCL2L1 and HRAS (P = 0, log-rank test, S6C Fig).	('BCL2L1', 'Gene', '598', (163, 169))	('patients', 'Species', '9606', (29, 37))	('BCL2L1', 'Gene', '598', (83, 89))	('HRAS', 'Gene', (174, 178))	('HRAS', 'Gene', '3265', (90, 94))	('HRAS', 'Gene', (90, 94))	('nonsynonymous somatic mutations', 'Var', (48, 79))	('survival rate', 'CPA', (108, 121))	('breast cancer', 'Disease', 'MESH:D001943', (15, 28))	('breast cancer', 'Phenotype', 'HP:0003002', (15, 28))	('BCL2L1', 'Gene', (83, 89))	('poor', 'NegReg', (103, 107))	('breast cancer', 'Disease', (15, 28))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('BCL2L1', 'Gene', (163, 169))	('HRAS', 'Gene', '3265', (174, 178))
320409	32101536	We next turned to examine the correlation between the network-predicted putative genetic interactions and anticancer drug responses.	('genetic', 'Var', (81, 88))	('cancer', 'Disease', (110, 116))	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))
320410	32101536	By analyzing drug pharmacogenomic profiles across over 1,000 cancer cell lines from the Genomics of Drug Sensitivity in Cancer (GDSC) database (see Methods), we found that the network-predicted putative genetic interactions were highly correlated to sensitivity/resistance of multiple therapeutic agents (S7 Table).	('Drug Sensitivity', 'Phenotype', 'HP:0020174', (100, 116))	('Cancer', 'Disease', (120, 126))	('Cancer', 'Disease', 'MESH:D009369', (120, 126))	('Cancer', 'Phenotype', 'HP:0002664', (120, 126))	('genetic interactions', 'Var', (203, 223))	('correlated', 'Reg', (236, 246))	('000 cancer', 'Disease', 'MESH:D009369', (57, 67))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('000 cancer', 'Disease', (57, 67))
320421	32101536	Fig 5A and 5D reveal that cancer cell lines have both somatic mutations on BRCA2 and TP53 (BRCA2-TP53) are sensitive to afatinib.	('TP53', 'Gene', (85, 89))	('afatinib', 'Chemical', 'MESH:D000077716', (120, 128))	('BRCA2-TP53', 'Gene', (91, 101))	('cancer', 'Disease', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('TP53', 'Gene', '7157', (97, 101))	('BRCA2', 'Gene', (91, 96))	('BRCA2', 'Gene', (75, 80))	('sensitive', 'Reg', (107, 116))	('TP53', 'Gene', (97, 101))	('BRCA2-TP53', 'Gene', '7157;675', (91, 101))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('BRCA', 'Phenotype', 'HP:0003002', (91, 95))	('BRCA', 'Phenotype', 'HP:0003002', (75, 79))	('BRCA2', 'Gene', '675', (91, 96))	('TP53', 'Gene', '7157', (85, 89))	('BRCA2', 'Gene', '675', (75, 80))	('mutations', 'Var', (62, 71))
320425	32101536	In addition, co-mutations on BRCA2 and TP53 (BRCA2-TP53) are sensitive to JQ1 (a BET inhibitor) compared to wild-type cell lines (Fig 5C).	('BRCA2', 'Gene', (45, 50))	('sensitive', 'MPA', (61, 70))	('TP53', 'Gene', (51, 55))	('BRCA2', 'Gene', '675', (45, 50))	('BRCA2', 'Gene', (29, 34))	('JQ1', 'MPA', (74, 77))	('BET', 'Gene', '92737', (81, 84))	('BRCA', 'Phenotype', 'HP:0003002', (45, 49))	('co-mutations', 'Var', (13, 25))	('BRCA', 'Phenotype', 'HP:0003002', (29, 33))	('BET', 'Gene', (81, 84))	('TP53', 'Gene', '7157', (39, 43))	('BRCA2-TP53', 'Gene', (45, 55))	('BRCA2', 'Gene', '675', (29, 34))	('BRCA2-TP53', 'Gene', '7157;675', (45, 55))	('TP53', 'Gene', '7157', (51, 55))	('TP53', 'Gene', (39, 43))
320426	32101536	Clinical studies showed that mutations on TP53 reduce responsiveness to first-line tyrosine kinase inhibitors in EGFR-mutated non-small cell lung cancer (NSCLC) patients.	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (126, 152))	('small cell lung cancer', 'Disease', (130, 152))	('TP53', 'Gene', '7157', (42, 46))	('NSCLC', 'Disease', 'MESH:D002289', (154, 159))	('reduce', 'NegReg', (47, 53))	('NSCLC', 'Phenotype', 'HP:0030358', (154, 159))	('mutations', 'Var', (29, 38))	('TP53', 'Gene', (42, 46))	('SCLC', 'Phenotype', 'HP:0030357', (155, 159))	('patients', 'Species', '9606', (161, 169))	('small cell lung cancer', 'Disease', 'MESH:D055752', (130, 152))	('EGFR', 'Gene', '1956', (113, 117))	('EGFR', 'Gene', (113, 117))	('lung cancer', 'Phenotype', 'HP:0100526', (141, 152))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (130, 152))	('NSCLC', 'Disease', (154, 159))
320429	32101536	Collectively, INCM-predicted putative genetic interactions offer potential pharmacogenomics biomarkers for guiding personalized cancer treatment.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('genetic interactions', 'Var', (38, 58))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('cancer', 'Disease', (128, 134))
320435	32101536	In addition, phosphorylation of centrin during the cell cycle process preceded centrosome duplication, and centrosome duplication played essential roles in genomic instability and cancer.	('phosphorylation', 'MPA', (13, 28))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('roles', 'Reg', (147, 152))	('genomic instability', 'CPA', (156, 175))	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('cancer', 'Disease', (180, 186))	('centrosome duplication', 'Var', (107, 129))
320436	32101536	Thus, network-based INCM analysis generates a hypothesis for a potential synthetic lethal interaction for CETN2 and CDK4 co-mutated ovarian cancer.	('ovarian cancer', 'Disease', (132, 146))	('CETN2', 'Gene', (106, 111))	('co-mutated', 'Var', (121, 131))	('CETN2', 'Gene', '1069', (106, 111))	('CDK4', 'Gene', '1019', (116, 120))	('CDK4', 'Gene', (116, 120))	('ovarian cancer', 'Phenotype', 'HP:0100615', (132, 146))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('ovarian cancer', 'Disease', 'MESH:D010051', (132, 146))
320438	32101536	Here, we found that 159 samples have somatic mutations in both PTEN and PIK3CA (PIK3CA-PTEN [P < 1.0x10-4] by INCM analysis) in UCEC from TCGA.	('PTEN', 'Gene', '5728', (63, 67))	('PTEN', 'Gene', (87, 91))	('mutations', 'Var', (45, 54))	('PTEN', 'Gene', '5728', (87, 91))	('PIK3CA', 'Gene', (72, 78))	('PIK3CA', 'Gene', (80, 86))	('PIK3CA', 'Gene', '5290', (80, 86))	('PIK3CA', 'Gene', '5290', (72, 78))	('PTEN', 'Gene', (63, 67))
320439	32101536	In addition, the mutation burden is significantly increased in PIK3CA-PTEN co-mutated samples compared to tumors with single-mutant PTEN or PIK3CA alone in UCEC (Fig 6B).	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('PTEN', 'Gene', (132, 136))	('PIK3CA', 'Gene', (140, 146))	('co-mutated', 'Var', (75, 85))	('PTEN', 'Gene', '5728', (132, 136))	('PTEN', 'Gene', (70, 74))	('tumors', 'Disease', (106, 112))	('mutant', 'Gene', '4594', (125, 131))	('PTEN', 'Gene', '5728', (70, 74))	('increased', 'PosReg', (50, 59))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('PIK3CA', 'Gene', '5290', (140, 146))	('PIK3CA', 'Gene', (63, 69))	('mutant', 'Gene', (125, 131))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('PIK3CA', 'Gene', '5290', (63, 69))	('mutation burden', 'MPA', (17, 32))
320441	32101536	Thus, detection of co-mutations of both PIK3CA and PTEN may offer potential biomarkers or targets for individualized treatment of tumors in uterine cancer or other cancer types (Fig 6C).	('tumors', 'Disease', (130, 136))	('cancer', 'Disease', (148, 154))	('tumors', 'Disease', 'MESH:D009369', (130, 136))	('co-mutations', 'Var', (19, 31))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('PIK3CA', 'Gene', (40, 46))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('PIK3CA', 'Gene', '5290', (40, 46))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('cancer', 'Disease', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('uterine cancer', 'Phenotype', 'HP:0010784', (140, 154))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('PTEN', 'Gene', (51, 55))	('PTEN', 'Gene', '5728', (51, 55))
320443	32101536	Integrating large-scale somatic mutations with known genetic interaction networks, INCM can be used to build cancer type-specific genetic subnetworks which are significantly enriched in known cancer genes and well-established cancer pathways.	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('cancer', 'Disease', (109, 115))	('cancer', 'Disease', (192, 198))	('mutations', 'Var', (32, 41))	('cancer', 'Disease', (226, 232))	('cancer', 'Disease', 'MESH:D009369', (192, 198))	('cancer', 'Disease', 'MESH:D009369', (226, 232))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
320454	32101536	The publicly available copy number variation profiles, gene fusions, and large-scale somatic mutations from TCGA pan-cancer project and ICGC project would significantly enhance the applications of INCM in the future.	('copy number variation', 'Var', (23, 44))	('TCGA', 'Gene', (108, 112))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('enhance', 'PosReg', (169, 176))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('cancer', 'Disease', (117, 123))	('applications', 'MPA', (181, 193))
320480	32101536	The reference C-score distribution was generated by calculating the C-score based on the reshuffled mutations for each individual tumor, and the process was independently repeated 10,000 times.	('mutations', 'Var', (100, 109))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumor', 'Disease', (130, 135))	('tumor', 'Disease', 'MESH:D009369', (130, 135))
320513	30628709	The primary mechanism is the direct effect on tumor cells, by increased drug accumulation in the cells after electroporation.	('increased', 'PosReg', (62, 71))	('drug accumulation', 'MPA', (72, 89))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Disease', (46, 51))	('electroporation', 'Var', (109, 124))	('increased drug accumulation', 'Phenotype', 'HP:0020170', (62, 89))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
320655	30628709	P3-0003 and P3-0307) and performed within the scope of LEA-EBAM (French-Slovenian European Associated Laboratory: Pulsed Electric Fields Applications in Biology and Medicine).	('P3-0307', 'Var', (12, 19))	('Slovenia', 'Disease', (72, 80))	('Slovenia', 'Disease', 'None', (72, 80))	('P3-0003', 'Var', (0, 7))
320658	25487617	The negative regulators of Wnt pathway:DACH1, DKK1, and WIF1 are methylated in oral and oropharyngeal cancer and WIF1 methylation predicts shorter survival The deregulation of Wnt signaling has recently emerged as one of the drivers of head and neck cancers.	('DACH1', 'Gene', (39, 44))	('WIF1', 'Gene', (56, 60))	('Wnt signaling', 'Pathway', (176, 189))	('oral and oropharyngeal cancer', 'Disease', 'MESH:D009959', (79, 108))	('methylation', 'Var', (118, 129))	('DACH1', 'Gene', '1602', (39, 44))	('WIF1', 'Gene', '11197', (113, 117))	('shorter', 'NegReg', (139, 146))	('WIF1', 'Gene', (113, 117))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('cancers', 'Phenotype', 'HP:0002664', (250, 257))	('head and neck cancers', 'Phenotype', 'HP:0012288', (236, 257))	('WIF1', 'Gene', '11197', (56, 60))	('deregulation', 'Var', (160, 172))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))	('neck cancers', 'Disease', (245, 257))	('DKK1', 'Gene', '22943', (46, 50))	('DKK1', 'Gene', (46, 50))	('neck cancers', 'Disease', 'MESH:D006258', (245, 257))
320663	25487617	On the other hand, RUNX3 was methylated only in one cell line, while LKB1 and PPP2R2B were not methylated in any of the cell lines.	('methylated', 'Var', (29, 39))	('LKB1', 'Gene', (69, 73))	('LKB1', 'Gene', '6794', (69, 73))	('RUNX3', 'Gene', (19, 24))	('RUNX3', 'Gene', '864', (19, 24))	('PPP2R2B', 'Gene', '5521', (78, 85))	('PPP2R2B', 'Gene', (78, 85))
320664	25487617	The biallelic methylation of DKK1 correlated with the low level of expression of this gene.	('biallelic methylation', 'Var', (4, 25))	('DKK1', 'Gene', '22943', (29, 33))	('low level of expression', 'MPA', (54, 77))	('DKK1', 'Gene', (29, 33))
320666	25487617	Importantly, the methylation of WIF-1 correlated with shorter survival in oral cancer patients.	('oral cancer', 'Disease', 'MESH:D009062', (74, 85))	('oral cancer', 'Disease', (74, 85))	('survival', 'MPA', (62, 70))	('WIF-1', 'Gene', '11197', (32, 37))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('methylation', 'Var', (17, 28))	('WIF-1', 'Gene', (32, 37))	('shorter', 'NegReg', (54, 61))	('patients', 'Species', '9606', (86, 94))
320667	25487617	Overall, the methylation of the antagonists of Wnt pathway is frequently detected in oral squamous cell carcinomas.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (90, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('detected', 'Reg', (73, 81))	('Wnt pathway', 'Pathway', (47, 58))	('methylation', 'Var', (13, 24))	('carcinomas', 'Phenotype', 'HP:0030731', (104, 114))	('oral squamous cell carcinomas', 'Disease', (85, 114))	('oral squamous cell carcinomas', 'Disease', 'MESH:D002294', (85, 114))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (90, 114))
320668	25487617	The methylation of WIF1 may be considered a prognostic marker in oral cancers.	('oral cancers', 'Disease', 'MESH:D009062', (65, 77))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('methylation', 'Var', (4, 15))	('WIF1', 'Gene', (19, 23))	('cancers', 'Phenotype', 'HP:0002664', (70, 77))	('WIF1', 'Gene', '11197', (19, 23))	('oral cancers', 'Disease', (65, 77))
320677	25487617	Mutations in the genes coding for proteins in the Wnt pathway are rare in HNSCC, and thus, this pathway was not believed to be significant for the pathogenesis of head and neck carcinomas.	('head and neck carcinomas', 'Phenotype', 'HP:0012288', (163, 187))	('neck carcinomas', 'Disease', 'MESH:D006258', (172, 187))	('HNSCC', 'Disease', (74, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (177, 186))	('carcinomas', 'Phenotype', 'HP:0030731', (177, 187))	('HNSCC', 'Phenotype', 'HP:0012288', (74, 79))	('Mutations', 'Var', (0, 9))	('neck carcinomas', 'Disease', (172, 187))
320678	25487617	The genes which encode the extracellular antagonists of Wnt ligands or Frizzled/LRP receptors, such as SFRP1-5, WIF1, or DKK1-3, are frequently silenced in HNSCC cells through the methylation of their promoter regions.	('WIF1', 'Gene', '11197', (112, 116))	('SFRP1-5', 'Gene', '6422;6423;2487;6424;6425', (103, 110))	('methylation', 'Var', (180, 191))	('DKK1-3', 'Gene', (121, 127))	('SFRP1-5', 'Gene', (103, 110))	('DKK1-3', 'Gene', '22943;27123;27122', (121, 127))	('HNSCC', 'Phenotype', 'HP:0012288', (156, 161))	('WIF1', 'Gene', (112, 116))	('silenced', 'NegReg', (144, 152))
320679	25487617	Also, the function of the intracellular negative Wnt regulators such as DACH1, PPP2R2B, or RUNX3 may be lost due to the hypermethylation of their gene promoters.	('PPP2R2B', 'Gene', '5521', (79, 86))	('function', 'MPA', (10, 18))	('PPP2R2B', 'Gene', (79, 86))	('lost', 'NegReg', (104, 108))	('DACH1', 'Gene', (72, 77))	('DACH1', 'Gene', '1602', (72, 77))	('RUNX3', 'Gene', (91, 96))	('RUNX3', 'Gene', '864', (91, 96))	('hypermethylation', 'Var', (120, 136))
320687	25487617	In line with this observation, the knockdown of beta-catenin reduced the growth of HN cancer cells and tumors.	('knockdown', 'Var', (35, 44))	('growth of', 'CPA', (73, 82))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('beta-catenin', 'Gene', (48, 60))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('HN cancer', 'Disease', 'MESH:D009369', (83, 92))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('tumors', 'Disease', (103, 109))	('tumors', 'Disease', 'MESH:D009369', (103, 109))	('HN cancer', 'Disease', (83, 92))	('beta-catenin', 'Gene', '1499', (48, 60))	('reduced', 'NegReg', (61, 68))
320690	25487617	Another study showed that the hyperactivation of beta-catenin affects cell morphology and cell adhesion leading to the higher capacity of cells for invasion and migration driven i.a.	('beta-catenin', 'Gene', (49, 61))	('cell adhesion', 'CPA', (90, 103))	('beta-catenin', 'Gene', '1499', (49, 61))	('higher', 'PosReg', (119, 125))	('cell morphology', 'CPA', (70, 85))	('affects', 'Reg', (62, 69))	('hyperactivation', 'Var', (30, 45))
320719	25487617	On the other hand, complete gene silencing (methylation of both alleles) was usually observed in the cell lines positive for DKK1 methylation.	('DKK1', 'Gene', (125, 129))	('gene', 'MPA', (28, 32))	('DKK1', 'Gene', '22943', (125, 129))	('methylation', 'Var', (130, 141))
320720	25487617	This biallelic methylation of DKK1 was accompanied by low transcript level when compared with cell lines showing the lack of methylation of this gene.	('transcript level', 'MPA', (58, 74))	('methylation', 'Var', (15, 26))	('biallelic methylation', 'Var', (5, 26))	('low', 'NegReg', (54, 57))	('DKK1', 'Gene', '22943', (30, 34))	('DKK1', 'Gene', (30, 34))
320724	25487617	On the other hand, only rare cases of methylation of DKK1 (7.1 %) were observed.	('DKK1', 'Gene', '22943', (53, 57))	('DKK1', 'Gene', (53, 57))	('methylation', 'Var', (38, 49))
320730	25487617	The methylation of WIF1 significantly correlated (p = 0.036) with shorter survival (Fig.	('WIF1', 'Gene', '11197', (19, 23))	('WIF1', 'Gene', (19, 23))	('methylation', 'Var', (4, 15))	('shorter', 'NegReg', (66, 73))
320733	25487617	The effectiveness is higher in patients with low-grade tumor and dramatically decreases in advanced cancer.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('low-grade', 'Var', (45, 54))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('tumor', 'Disease', (55, 60))	('effectiveness', 'MPA', (4, 17))	('higher', 'PosReg', (21, 27))	('patients', 'Species', '9606', (31, 39))	('decreases', 'NegReg', (78, 87))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))
320753	25487617	Another study showed that RUNX3 was hypermethylated in 70 % OSCC and that the downregulation of RUNX3 protein correlated with poor differentiation.	('RUNX3', 'Gene', '864', (96, 101))	('hypermethylated', 'Var', (36, 51))	('OSCC', 'Disease', (60, 64))	('downregulation', 'NegReg', (78, 92))	('RUNX3', 'Gene', (96, 101))	('OSCC', 'Phenotype', 'HP:0012182', (60, 64))	('poor differentiation', 'CPA', (126, 146))	('RUNX3', 'Gene', (26, 31))	('OSCC', 'Chemical', '-', (60, 64))	('RUNX3', 'Gene', '864', (26, 31))	('protein', 'Protein', (102, 109))
320754	25487617	Additionally, another study showed that RUNX3 was methylated in 60 % of cases of oral dysplasia and 100 % cases of OSCC.	('methylated', 'Var', (50, 60))	('OSCC', 'Phenotype', 'HP:0012182', (115, 119))	('oral dysplasia', 'Disease', (81, 95))	('OSCC', 'Disease', (115, 119))	('oral dysplasia', 'Disease', 'MESH:D020820', (81, 95))	('OSCC', 'Chemical', '-', (115, 119))	('RUNX3', 'Gene', (40, 45))	('RUNX3', 'Gene', '864', (40, 45))
320756	25487617	Of all the antagonists of Wnt pathway, the methylation of genes encoding SFRP proteins was most frequently reported in oral carcinomas.	('oral carcinomas', 'Disease', (119, 134))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('methylation', 'Var', (43, 54))	('carcinomas', 'Phenotype', 'HP:0030731', (124, 134))	('reported', 'Reg', (107, 115))	('oral carcinomas', 'Disease', 'MESH:D020820', (119, 134))	('SFRP', 'Gene', (73, 77))
320763	25487617	So far, the methylation of this gene was detected in colorectal carcinomas where it correlated with late tumor stage, poor differentiation, and lymph node metastasis.	('poor differentiation', 'CPA', (118, 138))	('colorectal carcinomas', 'Disease', (53, 74))	('colorectal carcinomas', 'Disease', 'MESH:D015179', (53, 74))	('correlated', 'Reg', (84, 94))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))	('lymph node metastasis', 'CPA', (144, 165))	('carcinomas', 'Phenotype', 'HP:0030731', (64, 74))	('methylation', 'Var', (12, 23))	('tumor', 'Disease', (105, 110))	('detected', 'Reg', (41, 49))
320764	25487617	Recently, DACH1 emerged as an important tumor suppressor gene and its frequent methylation in OSCC underscores the potential anti-cancer effects of epigenetic therapies via suppression of Wnt signaling.	('Wnt signaling', 'Pathway', (188, 201))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('OSCC', 'Disease', (94, 98))	('cancer', 'Disease', (130, 136))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('epigenetic', 'Var', (148, 158))	('DACH1', 'Gene', (10, 15))	('suppression', 'NegReg', (173, 184))	('methylation', 'Var', (79, 90))	('OSCC', 'Chemical', '-', (94, 98))	('DACH1', 'Gene', '1602', (10, 15))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('OSCC', 'Phenotype', 'HP:0012182', (94, 98))
320765	25487617	Indeed, it has been shown that the inhibition of Wnt pathway blocks tumor growth in head and neck cancers.	('tumor', 'Disease', (68, 73))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('blocks', 'NegReg', (61, 67))	('cancers', 'Phenotype', 'HP:0002664', (98, 105))	('neck cancers', 'Disease', (93, 105))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('Wnt pathway', 'Pathway', (49, 60))	('neck cancers', 'Disease', 'MESH:D006258', (93, 105))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('inhibition', 'Var', (35, 45))	('head and neck cancers', 'Phenotype', 'HP:0012288', (84, 105))
320768	25487617	However, it was found that the expression of DKK1 correlated significantly with a low risk of regional lymph node metastasis and that its knockdown increased the cellular migration and invasiveness in oral cancer cells.	('knockdown', 'Var', (138, 147))	('cellular migration', 'CPA', (162, 180))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('increased', 'PosReg', (148, 157))	('DKK1', 'Gene', '22943', (45, 49))	('DKK1', 'Gene', (45, 49))	('invasiveness in oral cancer', 'Disease', 'MESH:D009062', (185, 212))	('invasiveness in oral cancer', 'Disease', (185, 212))
320769	25487617	This suggests a potential prognostic significance of the methylation of this gene in oral carcinomas.	('oral carcinomas', 'Disease', (85, 100))	('methylation', 'Var', (57, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('carcinomas', 'Phenotype', 'HP:0030731', (90, 100))	('oral carcinomas', 'Disease', 'MESH:D020820', (85, 100))
320770	25487617	Although no evidence in favor of this hypothesis was found in our study, this may be attributed to a relatively small cohort of patients regarding the low frequency of methylation in the group of primary OSCC patients.	('OSCC', 'Phenotype', 'HP:0012182', (204, 208))	('methylation', 'Var', (168, 179))	('patients', 'Species', '9606', (209, 217))	('OSCC', 'Chemical', '-', (204, 208))	('patients', 'Species', '9606', (128, 136))	('primary OSCC', 'Disease', (196, 208))
320772	25487617	It was previously reported to be methylated in 18 % OSCC and 35 % of tongue carcinoma patients.	('tongue carcinoma', 'Phenotype', 'HP:0030415', (69, 85))	('OSCC', 'Phenotype', 'HP:0012182', (52, 56))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('OSCC', 'Chemical', '-', (52, 56))	('tongue carcinoma', 'Disease', 'MESH:D014062', (69, 85))	('tongue carcinoma', 'Disease', (69, 85))	('methylated', 'Var', (33, 43))	('OSCC', 'Disease', (52, 56))	('patients', 'Species', '9606', (86, 94))
320773	25487617	Moreover, the methylation of this gene can be considered as a marker of progression of carcinogenesis since its methylation was observed to be twice more frequent in OSCC (80 %) than in oral dysplasia (40 %).	('OSCC', 'Disease', (166, 170))	('OSCC', 'Phenotype', 'HP:0012182', (166, 170))	('carcinogenesis', 'Disease', 'MESH:D063646', (87, 101))	('oral dysplasia', 'Disease', 'MESH:D020820', (186, 200))	('frequent', 'Reg', (154, 162))	('methylation', 'Var', (14, 25))	('OSCC', 'Chemical', '-', (166, 170))	('carcinogenesis', 'Disease', (87, 101))	('oral dysplasia', 'Disease', (186, 200))	('methylation', 'MPA', (112, 123))
320774	25487617	Importantly, we observed that the methylation of the gene correlated with shorter overall survival of the patients.	('shorter', 'NegReg', (74, 81))	('overall survival', 'MPA', (82, 98))	('patients', 'Species', '9606', (106, 114))	('methylation', 'Var', (34, 45))
320776	25487617	The results presented in this study corroborate that the epigenetic abnormalities may frequently affect Wnt signaling in oral carcinomas.	('affect', 'Reg', (97, 103))	('oral carcinomas', 'Disease', (121, 136))	('epigenetic abnormalities', 'Var', (57, 81))	('Wnt signaling', 'Pathway', (104, 117))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('carcinomas', 'Phenotype', 'HP:0030731', (126, 136))	('oral carcinomas', 'Disease', 'MESH:D020820', (121, 136))
320779	25487617	In summary, our current study showed that DACH1, DKK1, and WIF-1 are methylated in oral and oropharyngeal squamous cell carcinomas.	('oropharyngeal squamous cell carcinomas', 'Phenotype', 'HP:0012182', (92, 130))	('oropharyngeal squamous cell carcinoma', 'Phenotype', 'HP:0012182', (92, 129))	('WIF-1', 'Gene', (59, 64))	('squamous cell carcinomas', 'Disease', (106, 130))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (106, 130))	('WIF-1', 'Gene', '11197', (59, 64))	('DACH1', 'Gene', (42, 47))	('DKK1', 'Gene', '22943', (49, 53))	('DKK1', 'Gene', (49, 53))	('methylated', 'Var', (69, 79))	('DACH1', 'Gene', '1602', (42, 47))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (106, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('carcinomas', 'Phenotype', 'HP:0030731', (120, 130))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (106, 129))
320781	25487617	The possible prognostic significance of the methylation of DKK1 and WIF1 needs to be further evaluated in prospective studies.	('methylation', 'Var', (44, 55))	('DKK1', 'Gene', '22943', (59, 63))	('DKK1', 'Gene', (59, 63))	('WIF1', 'Gene', (68, 72))	('WIF1', 'Gene', '11197', (68, 72))
320813	33498755	After maturation, DCs upregulate their antigen presentation machinery and co-stimulatory molecules, such as CD40, CD80 or CD86, becoming potent T-cell activators.	('CD86', 'Gene', '942', (122, 126))	('CD40', 'Var', (108, 112))	('antigen presentation machinery', 'MPA', (39, 69))	('CD80', 'Gene', '941', (114, 118))	('upregulate', 'PosReg', (22, 32))	('CD86', 'Gene', (122, 126))	('DC', 'Gene', '13179', (18, 20))	('CD80', 'Gene', (114, 118))
320827	33498755	Murine cDC1s express CD11c, MHC-II, CD103, CD8alpha, XCR1, CLEC9A and DNGR1 and are developmentally dependent on IRF8, ID2, and BATF3.	('XCR1', 'Gene', (53, 57))	('CD103', 'Gene', (36, 41))	('CD8alpha', 'Gene', (43, 51))	('IRF8', 'Gene', (113, 117))	('IRF8', 'Gene', '15900', (113, 117))	('MHC-II', 'Gene', (28, 34))	('ID2', 'Gene', (119, 122))	('CD11c', 'Var', (21, 26))	('BATF3', 'Gene', (128, 133))	('den', 'Chemical', 'MESH:D004052', (105, 108))	('Murine', 'Species', '10090', (0, 6))	('ID2', 'Gene', '15902', (119, 122))	('BATF3', 'Gene', '381319', (128, 133))	('CD8alpha', 'Gene', '12525', (43, 51))	('MHC-II', 'Gene', '111364', (28, 34))	('DC', 'Gene', '13179', (8, 10))
320828	33498755	Human cDC1s express CD11c, HLA-DR, XCR1, CLEC9A, DNGR1, and CD141.	('Human', 'Species', '9606', (0, 5))	('DNGR1', 'Gene', (49, 54))	('CD141', 'Gene', (60, 65))	('CD141', 'Gene', '7056', (60, 65))	('CD11c', 'Var', (20, 25))	('DC', 'Gene', '13179', (7, 9))
320836	33498755	A substantial fraction of intratumoral CD103+ cDC1s does not migrate to the lymph nodes, but still plays a crucial role in cancer immunity.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('CD103+', 'Var', (39, 45))	('DC', 'Gene', '13179', (47, 49))	('tumor', 'Disease', (31, 36))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('cancer', 'Disease', (123, 129))	('plays', 'Reg', (99, 104))
320837	33498755	demonstrated that, in mouse models, non-migrating CD103+ cDC1s mediate their effects directly in the TME by producing distinct chemokines.	('DC', 'Gene', '13179', (58, 60))	('mouse', 'Species', '10090', (22, 27))	('producing', 'Reg', (108, 117))	('CD103+', 'Var', (50, 56))
320843	33498755	Murine cDC2s express CD11c, MHC-II, CD11b and CD172a, whereas human cDC2s are characterized by the expression of CD11c, HLA-DR, CD1c, CD1a and CD172a.	('CD1a', 'Gene', '909', (134, 138))	('cDC2', 'Gene', (7, 11))	('CD1c', 'Gene', '911', (128, 132))	('cDC2', 'Gene', '983', (7, 11))	('human', 'Species', '9606', (62, 67))	('CD172a', 'Gene', (143, 149))	('CD11c', 'Var', (113, 118))	('MHC-II', 'Gene', '111364', (28, 34))	('MHC-II', 'Gene', (28, 34))	('CD11c', 'Var', (21, 26))	('CD1c', 'Gene', (128, 132))	('CD1a', 'Gene', (134, 138))	('Murine', 'Species', '10090', (0, 6))	('cDC2', 'Gene', (68, 72))	('CD172a', 'Gene', (46, 52))	('cDC2', 'Gene', '983', (68, 72))	('CD11b', 'Gene', (36, 41))	('CD11b', 'Gene', '16409', (36, 41))
320858	33498755	Therefore, the presence of pDCs in the TME of these tumors is associated with a poor prognosis.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('presence', 'Var', (15, 23))	('tumors', 'Disease', (52, 58))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('DC', 'Gene', '13179', (28, 30))
320862	33498755	Murine moDCs express CD11c, MHC-II, CD11b, Ly6C, CD14, CD64, CD206, CD209 and CCR2, while human moDC additionally express CD1c and CD1a (Table 1).	('human', 'Species', '9606', (90, 95))	('CD1c', 'Gene', '911', (122, 126))	('Ly6C', 'Gene', '17067', (43, 47))	('MHC-II', 'Gene', '111364', (28, 34))	('CD64', 'Gene', (55, 59))	('DC', 'Gene', '13179', (98, 100))	('CD1a', 'Gene', (131, 135))	('CD209', 'Gene', (68, 73))	('Ly6C', 'Gene', (43, 47))	('DC', 'Gene', '13179', (9, 11))	('CD1c', 'Gene', (122, 126))	('CD14', 'Gene', (49, 53))	('CD11c', 'Var', (21, 26))	('CD206', 'Gene', '17533', (61, 66))	('CD11b', 'Gene', '16409', (36, 41))	('CD14', 'Gene', '12475', (49, 53))	('CCR2', 'Gene', (78, 82))	('CD209', 'Gene', '170786', (68, 73))	('MHC-II', 'Gene', (28, 34))	('CD1a', 'Gene', '909', (131, 135))	('Murine', 'Species', '10090', (0, 6))	('CD64', 'Gene', '14129', (55, 59))	('CD206', 'Gene', (61, 66))	('CD11b', 'Gene', (36, 41))	('CCR2', 'Gene', '12772', (78, 82))
320877	33498755	The importance of these chemokines has been demonstrated in mouse models in which the absence of CXCL9 and CXCL10 prevents CD8+ T-cell recall within the tumor.	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('CD8', 'Gene', (123, 126))	('CXCL10', 'Var', (107, 113))	('CD8', 'Gene', '925', (123, 126))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('absence', 'Var', (86, 93))	('prevents', 'NegReg', (114, 122))	('mouse', 'Species', '10090', (60, 65))
320883	33498755	TME may also affect the function and stimulation of DCs.	('TME', 'Var', (0, 3))	('DC', 'Gene', '13179', (52, 54))	('function', 'MPA', (24, 32))	('stimulation', 'MPA', (37, 48))	('affect', 'Reg', (13, 19))
320890	33498755	Indeed, in mouse mammary tumors, IL-10 production by macrophages can suppress IL-12 expression by CD103+ cDC1s resulting in activation of tumor-specific CD8+ T cells.	('CD8', 'Gene', (153, 156))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('activation', 'PosReg', (124, 134))	('mouse', 'Species', '10090', (11, 16))	('CD8', 'Gene', '925', (153, 156))	('tumor', 'Disease', (138, 143))	('tumors', 'Disease', (25, 31))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('tumor', 'Disease', (25, 30))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('DC', 'Gene', '13179', (106, 108))	('CD103+', 'Var', (98, 104))	('tumors', 'Disease', 'MESH:D009369', (25, 31))	('IL-12', 'Gene', (78, 83))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('suppress', 'NegReg', (69, 77))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
320917	33498755	It has been hypothesized that this cross-interaction could be further supported by chemokines secreted by cDC1s such as CXCL9 and CXCL10, which can attract NK cells to TME via CXCR3.	('CXCR3', 'Gene', '2833', (176, 181))	('CXCL10', 'Var', (130, 136))	('DC', 'Gene', '13179', (107, 109))	('CXCR3', 'Gene', (176, 181))
320919	33498755	Genetic and cellular ablation of NK cells has provided evidence that these cells are essential in regulating DC accumulation within the tumor through the production of FLT3L.	('DC', 'Gene', '13179', (109, 111))	('den', 'Chemical', 'MESH:D004052', (58, 61))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('FLT3L', 'Gene', (168, 173))	('ablation', 'Var', (21, 29))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('tumor', 'Disease', (136, 141))
320943	33498755	Broz and colleagues were among the first to demonstrate the importance of CD103+ cDC1 in stimulating tumor-specific CD8+ T cell responses within the TME.	('stimulating', 'PosReg', (89, 100))	('CD8', 'Gene', (116, 119))	('DC', 'Gene', '13179', (82, 84))	('CD103+', 'Var', (74, 80))	('tumor', 'Disease', (101, 106))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('CD8', 'Gene', '925', (116, 119))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
320950	33498755	The authors also demonstrated that TLR3 engagement is able to induce IFN-lambda production from tumor-associated cDC1s, thus proposing TLR3 activation as a potential therapeutic strategy.	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('induce', 'PosReg', (62, 68))	('TLR3', 'Gene', (35, 39))	('tumor', 'Disease', (96, 101))	('engagement', 'Var', (40, 50))	('DC', 'Gene', '13179', (114, 116))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('IFN-lambda production', 'MPA', (69, 90))
320969	33498755	Human CD141+ DCs express high levels of TLR3, and treatment with TLR3 agonists, such as polyinosinic-polycytidylic acid (Poly I:C) and its derivates Poly-ICLC (Hiltonol) and poly-IC12U (Ampligen), have been shown to efficiently activate DCs by inducing cross-presentation, pro-inflammatory cytokines, Th1 cell immunity, NK cells and cytotoxic CD8+ T cell responses.	('Human', 'Species', '9606', (0, 5))	('cross-presentation', 'MPA', (253, 271))	('activate', 'PosReg', (228, 236))	('polyinosinic-polycytidylic', 'Var', (88, 114))	('NK cells', 'CPA', (320, 328))	('CD8', 'Gene', (343, 346))	('CD141', 'Gene', (6, 11))	('-IC12U', 'Chemical', '-', (178, 184))	('Poly-ICLC', 'Var', (149, 158))	('Poly I:C', 'Chemical', 'MESH:D011070', (121, 129))	('Hiltonol', 'Chemical', 'MESH:C019531', (160, 168))	('poly-IC12U', 'Var', (174, 184))	('CD141', 'Gene', '7056', (6, 11))	('DC', 'Gene', '13179', (237, 239))	('pro-inflammatory cytokines', 'MPA', (273, 299))	('inducing', 'PosReg', (244, 252))	('CD8', 'Gene', '925', (343, 346))	('DC', 'Gene', '13179', (13, 15))	('Th1 cell immunity', 'CPA', (301, 318))	('polyinosinic-polycytidylic acid', 'Chemical', 'MESH:D011070', (88, 119))	('Ampligen', 'Chemical', 'MESH:C047490', (186, 194))
320975	33498755	The interaction between CD40 and CD40L may also increase cross-presentation by DCs.	('interaction', 'Interaction', (4, 15))	('CD40L', 'Gene', '959', (33, 38))	('DC', 'Gene', '13179', (79, 81))	('CD40L', 'Gene', (33, 38))	('CD40', 'Var', (24, 28))	('cross-presentation', 'MPA', (57, 75))	('increase', 'PosReg', (48, 56))
320985	33498755	The addition of anti-CD40 antibody to FLT3L, radiotherapy and Poly-ICLC has been shown to induce regression of poorly T cell-infiltrated tumors refractory to PD-1/PD-L1 therapy in four syngeneic mouse models: colon adenocarcinoma, melanoma and two triple-negative mammary cancers of melanoma.	('tumors', 'Disease', (137, 143))	('cancer', 'Phenotype', 'HP:0002664', (272, 278))	('melanoma', 'Phenotype', 'HP:0002861', (231, 239))	('melanoma', 'Disease', (231, 239))	('melanoma', 'Disease', 'MESH:D008545', (283, 291))	('cancers', 'Phenotype', 'HP:0002664', (272, 279))	('cancers', 'Disease', (272, 279))	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('anti-CD40', 'Var', (16, 25))	('Poly-ICLC', 'Var', (62, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (220, 229))	('mouse', 'Species', '10090', (195, 200))	('colon adenocarcinoma', 'Disease', 'MESH:D003110', (209, 229))	('melanoma', 'Disease', 'MESH:D008545', (231, 239))	('melanoma', 'Phenotype', 'HP:0002861', (283, 291))	('melanoma', 'Disease', (283, 291))	('FLT3L', 'Gene', (38, 43))	('cancers', 'Disease', 'MESH:D009369', (272, 279))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('colon adenocarcinoma', 'Disease', (209, 229))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
320987	33498755	These very encouraging results were followed by a Phase I clinical trial initiated on December 1th, 2020 to evaluate the safety of in situ immunomodulation with recombinant CDX-301, radiotherapy, anti-CD40 mAb and Poly-ICLC in patients with unresectable and metastatic breast cancer (NCT04616248).	('breast cancer', 'Disease', 'MESH:D001943', (269, 282))	('cancer', 'Phenotype', 'HP:0002664', (276, 282))	('anti-CD40', 'Var', (196, 205))	('breast cancer', 'Disease', (269, 282))	('breast cancer', 'Phenotype', 'HP:0003002', (269, 282))	('unresectable', 'Disease', (241, 253))	('patients', 'Species', '9606', (227, 235))
320995	33498755	Radiation therapy causes cell death in highly replicating cancer cells by creating breaks in the DNA double-strand.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('death', 'Disease', 'MESH:D003643', (30, 35))	('death', 'Disease', (30, 35))	('cancer', 'Disease', (58, 64))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('DNA double-strand', 'Protein', (97, 114))	('breaks', 'Var', (83, 89))
321006	33498755	Cryoablation induces tumor cell death by necrosis and osmosis.	('death', 'Disease', (32, 37))	('tumor', 'Disease', (21, 26))	('necrosis and osmosis', 'Disease', 'MESH:D009336', (41, 61))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('death', 'Disease', 'MESH:D003643', (32, 37))	('Cryoablation', 'Var', (0, 12))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
321010	33498755	In liver tumors, cryoablation in more than 20% of the tissue causes a systemic inflammatory response due to the release of IL-6, IL-10 and TNFalpha.	('systemic inflammatory response', 'MPA', (70, 100))	('causes', 'Reg', (61, 67))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('liver tumors', 'Disease', 'MESH:D008113', (3, 15))	('release', 'MPA', (112, 119))	('IL-6', 'Gene', (123, 127))	('cryoablation', 'Var', (17, 29))	('liver tumors', 'Phenotype', 'HP:0002896', (3, 15))	('IL-6', 'Gene', '3569', (123, 127))	('liver tumors', 'Disease', (3, 15))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('TNFalpha', 'Gene', (139, 147))	('TNFalpha', 'Gene', '7124', (139, 147))
321012	33498755	The preclinical study by den Brok showed that cryoablation leads to maturation of DCs, which resulted in a tumor-specific immune response that protected half of the mice from a new infusion of tumor cells.	('mice', 'Species', '10090', (165, 169))	('tumor', 'Disease', (107, 112))	('DC', 'Gene', '13179', (82, 84))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('cryoablation', 'Var', (46, 58))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('den', 'Chemical', 'MESH:D004052', (25, 28))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('tumor', 'Disease', (193, 198))	('resulted in', 'Reg', (93, 104))
321024	33498755	Notably, deletion of PD-L1 in DCs, but not in macrophages, significantly reduced tumor growth and led to enhanced antitumor CD8+ T-cell responses.	('DC', 'Gene', '13179', (30, 32))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('deletion', 'Var', (9, 17))	('reduced', 'NegReg', (73, 80))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('CD8', 'Gene', (124, 127))	('PD-L1', 'Gene', (21, 26))	('tumor', 'Disease', (118, 123))	('CD8', 'Gene', '925', (124, 127))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('enhanced', 'PosReg', (105, 113))	('tumor', 'Disease', (81, 86))
321029	33498755	These recent findings suggest that ICB therapy is effective not only by directly activating T cells, but also by triggering a complex network, in which DCs play a pivotal role at the interface between innate and adaptive antitumor responses, and that blocking the PD-1 pathway early with immune checkpoint inhibitors, at the time of priming and expansion of memory T cells, could be critical for enhancing antitumor immunity.	('tumor', 'Disease', 'MESH:D009369', (225, 230))	('tumor', 'Disease', 'MESH:D009369', (410, 415))	('blocking', 'Var', (251, 259))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('PD-1 pathway', 'Pathway', (264, 276))	('triggering', 'Reg', (113, 123))	('tumor', 'Phenotype', 'HP:0002664', (410, 415))	('tumor', 'Disease', (225, 230))	('tumor', 'Disease', (410, 415))	('enhancing', 'PosReg', (396, 405))	('DC', 'Gene', '13179', (152, 154))
321075	33490290	The miRNA-target network was associated with (TCCGTCC) MIR-184, (TGCACGA) MIR-517, (GTGGTGA) MIR-197, (CCAGGGG) MIR-331, and (CAGCAGG) MIR-370.	('MIR-331', 'Gene', '442903', (112, 119))	('associated', 'Interaction', (29, 39))	('MIR-197', 'Gene', '406974', (93, 100))	('MIR-331', 'Gene', (112, 119))	('TGCACGA', 'Gene', (65, 72))	('MIR-370', 'Gene', (135, 142))	('MIR-184', 'Gene', (55, 62))	('MIR-184', 'Gene', '406960', (55, 62))	('MIR-370', 'Gene', '442915', (135, 142))	('MIR-197', 'Gene', (93, 100))	('MIR-517', 'Var', (74, 81))
321087	32727606	Different driver gene mutations in patients with synchronous multiple primary lung cancers: a case report Routine clinical and pathological examinations usually cannot fully conclusively determine the relationship between different lesions of lung cancer.	('synchronous multiple primary lung cancers', 'Disease', (49, 90))	('lung cancer', 'Disease', (243, 254))	('lung cancer', 'Phenotype', 'HP:0100526', (243, 254))	('lung cancer', 'Phenotype', 'HP:0100526', (78, 89))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('cancer', 'Phenotype', 'HP:0002664', (248, 254))	('lung cancers', 'Phenotype', 'HP:0100526', (78, 90))	('lung cancer', 'Disease', 'MESH:D008175', (78, 89))	('lung cancer', 'Disease', 'MESH:D008175', (243, 254))	('mutations', 'Var', (22, 31))	('synchronous multiple primary lung cancers', 'Disease', 'MESH:D008175', (49, 90))	('patients', 'Species', '9606', (35, 43))	('cancers', 'Phenotype', 'HP:0002664', (83, 90))
321089	32727606	In the present study, we report a case of synchronous multiple primary lung cancer (MPLC) composed of two distinct pathological subtypes with epidermal growth factor receptor (EGFR) gene mutations L858R of the acinar adenocarcinoma subtype and EML4-ALK rearrangement of the squamous cell carcinoma.	('L858R', 'Mutation', 'rs121434568', (197, 202))	('acinar adenocarcinoma', 'Disease', 'MESH:D018267', (210, 231))	('EML4', 'Gene', (244, 248))	('epidermal growth factor receptor', 'Gene', (142, 174))	('carcinoma', 'Phenotype', 'HP:0030731', (288, 297))	('EML4', 'Gene', '27436', (244, 248))	('epidermal growth factor receptor', 'Gene', '1956', (142, 174))	('squamous cell carcinoma', 'Disease', (274, 297))	('synchronous multiple primary lung cancer', 'Disease', (42, 82))	('acinar adenocarcinoma', 'Disease', (210, 231))	('carcinoma', 'Phenotype', 'HP:0030731', (222, 231))	('EGFR', 'Gene', (176, 180))	('ALK', 'Gene', '238', (249, 252))	('synchronous multiple primary lung cancer', 'Disease', 'MESH:D008175', (42, 82))	('L858R', 'Var', (197, 202))	('lung cancer', 'Phenotype', 'HP:0100526', (71, 82))	('ALK', 'Gene', (249, 252))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (274, 297))	('EGFR', 'Gene', '1956', (176, 180))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (274, 297))
321094	32727606	The distinct pathogenesis of lung cancer has not been fully clarified, in spite of somatic or germline mutations are believed to drive the development of lung adenocarcinoma.	('drive', 'PosReg', (129, 134))	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('mutations', 'Var', (103, 112))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (154, 173))	('lung cancer', 'Disease', 'MESH:D008175', (29, 40))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (154, 173))	('carcinoma', 'Phenotype', 'HP:0030731', (164, 173))	('lung adenocarcinoma', 'Disease', (154, 173))	('lung cancer', 'Disease', (29, 40))	('lung cancer', 'Phenotype', 'HP:0100526', (29, 40))
321096	32727606	In the present study, we report the cases of two synchronous lung adenocarcinomas, composed of two distinct pathological subtypes harboring epidermal growth factor receptor (EGFR) gene mutation and echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) rearrangement.	('synchronous lung adenocarcinomas', 'Disease', (49, 81))	('EML4', 'Gene', (275, 279))	('EML4', 'Gene', '27436', (275, 279))	('EGFR', 'Gene', '1956', (174, 178))	('epidermal growth factor receptor', 'Gene', (140, 172))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (61, 80))	('epidermal growth factor receptor', 'Gene', '1956', (140, 172))	('lymphoma', 'Disease', (258, 266))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('mutation', 'Var', (185, 193))	('ALK', 'Gene', '238', (280, 283))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (247, 266))	('synchronous lung adenocarcinomas', 'Disease', 'MESH:D000077192', (49, 81))	('lymphoma', 'Disease', 'MESH:D008223', (258, 266))	('ALK', 'Gene', (280, 283))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (61, 81))	('EGFR', 'Gene', (174, 178))	('rearrangement', 'Var', (285, 298))	('lymphoma', 'Phenotype', 'HP:0002665', (258, 266))
321104	32727606	Real-time polymerase chain reaction (PCR) analysis showed that the adenocarcinoma had an epidermal growth factor receptor (EGFR) mutation presenting as point mutation L858R, while the squamous cell carcinoma suffered from ALK fusion.	('EGFR', 'Gene', (123, 127))	('adenocarcinoma', 'Disease', (67, 81))	('EGFR', 'Gene', '1956', (123, 127))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (184, 207))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('adenocarcinoma', 'Disease', 'MESH:D000230', (67, 81))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (184, 207))	('L858R', 'Mutation', 'rs121434568', (167, 172))	('ALK', 'Gene', (222, 225))	('carcinoma', 'Phenotype', 'HP:0030731', (198, 207))	('squamous cell carcinoma', 'Disease', (184, 207))	('epidermal growth factor receptor', 'Gene', '1956', (89, 121))	('ALK', 'Gene', '238', (222, 225))	('L858R', 'Var', (167, 172))	('epidermal growth factor receptor', 'Gene', (89, 121))
321111	32727606	The EGFR gene mutation and ALK-EML4 rearrangement in the lung adenocarcinoma and squamous cell carcinoma encouraged us to explore the tumor origin, and both tumors presented as treatment-naive mutants occurring synchronously.	('EGFR', 'Gene', (4, 8))	('EML4', 'Gene', (31, 35))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('EML4', 'Gene', '27436', (31, 35))	('ALK', 'Gene', '238', (27, 30))	('rearrangement', 'Var', (36, 49))	('tumors', 'Phenotype', 'HP:0002664', (157, 163))	('lung adenocarcinoma', 'Disease', (57, 76))	('ALK', 'Gene', (27, 30))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('EGFR', 'Gene', '1956', (4, 8))	('tumors', 'Disease', (157, 163))	('adenocarcinoma and squamous cell carcinoma', 'Disease', 'MESH:D002294', (62, 104))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (57, 76))	('tumor', 'Disease', (134, 139))	('tumor', 'Disease', (157, 162))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (57, 76))	('tumors', 'Disease', 'MESH:D009369', (157, 163))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('mutation', 'Var', (14, 22))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (81, 104))
321112	32727606	ALK rearrangement is one of the crucial molecular alterations in NSCLC, especially in adenocarcinoma with the incidence between 2 and 13%.	('rearrangement', 'Var', (4, 17))	('NSCLC', 'Disease', 'MESH:D002289', (65, 70))	('NSCLC', 'Disease', (65, 70))	('adenocarcinoma', 'Disease', (86, 100))	('ALK', 'Gene', (0, 3))	('NSCLC', 'Phenotype', 'HP:0030358', (65, 70))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('adenocarcinoma', 'Disease', 'MESH:D000230', (86, 100))	('ALK', 'Gene', '238', (0, 3))
321113	32727606	However, ALK rearrangement was detected with a frequency of lower than 1% in squamous cell carcinoma, thus was not routinely received molecular testing.	('ALK', 'Gene', (9, 12))	('rearrangement', 'Var', (13, 26))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (77, 100))	('ALK', 'Gene', '238', (9, 12))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (77, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('squamous cell carcinoma', 'Disease', (77, 100))
321117	32727606	The relationship between squamous cell carcinoma and ALK gene status (including rearrangement, mutation, and copy number gain) still needs to be elucidated.	('ALK', 'Gene', (53, 56))	('squamous cell carcinoma', 'Disease', (25, 48))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (25, 48))	('copy number gain', 'Var', (109, 125))	('carcinoma', 'Phenotype', 'HP:0030731', (39, 48))	('ALK', 'Gene', '238', (53, 56))	('rearrangement', 'Var', (80, 93))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (25, 48))	('mutation', 'Var', (95, 103))
321119	32727606	Similarly to the uncertain clinical efficacy of EGFR-tyrosine kinase inhibitor in squamous cell carcinoma, it is also controversy whether ALK rearrangement squamous cell carcinoma patients could benefit from ALK inhibitor.	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('squamous cell carcinoma', 'Disease', (82, 105))	('ALK', 'Gene', (208, 211))	('EGFR', 'Gene', '1956', (48, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (170, 179))	('ALK', 'Gene', '238', (138, 141))	('EGFR', 'Gene', (48, 52))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (156, 179))	('ALK', 'Gene', '238', (208, 211))	('rearrangement', 'Var', (142, 155))	('squamous cell carcinoma', 'Disease', (156, 179))	('ALK', 'Gene', (138, 141))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (156, 179))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (82, 105))	('patients', 'Species', '9606', (180, 188))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (82, 105))
321123	32727606	In our case, the postoperative pathology revealed that the squamous cell carcinoma suffered from ALK fusion mutation.	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (59, 82))	('squamous cell carcinoma', 'Disease', (59, 82))	('suffered from', 'Reg', (83, 96))	('ALK', 'Gene', '238', (97, 100))	('ALK', 'Gene', (97, 100))	('mutation', 'Var', (108, 116))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (59, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
321125	32727606	EGFR mutations have also frequently been reported in MPLC patients, whereas complicated mutations (L858R/S768I, G719X/T790M, L858R/20ins, 19del/T790M, 19del/L858R, and 19del/20ins) were only found in female patients.	('T790M', 'Mutation', 'rs121434569', (118, 123))	('G719X', 'Var', (112, 117))	('L858R', 'SUBSTITUTION', 'None', (157, 162))	('19del/T790M', 'Var', (138, 149))	('L858R', 'Var', (157, 162))	('reported', 'Reg', (41, 49))	('L858R', 'SUBSTITUTION', 'None', (125, 130))	('L858R', 'Mutation', 'rs121434568', (99, 104))	('19del/20ins', 'Mutation', 'c.19,20delins/', (168, 179))	('L858R', 'Var', (125, 130))	('MPLC', 'Disease', (53, 57))	('EGFR', 'Gene', (0, 4))	('S768I', 'SUBSTITUTION', 'None', (105, 110))	('T790M', 'Mutation', 'rs121434569', (144, 149))	('patients', 'Species', '9606', (58, 66))	('EGFR', 'Gene', '1956', (0, 4))	('L858R', 'SUBSTITUTION', 'None', (99, 104))	('S768I', 'Var', (105, 110))	('L858R', 'Var', (99, 104))	('patients', 'Species', '9606', (207, 215))	('L858R', 'Mutation', 'rs121434568', (157, 162))	('G719X', 'SUBSTITUTION', 'None', (112, 117))	('L858R', 'Mutation', 'rs121434568', (125, 130))
321126	32727606	Our male patient was an unusual case of synchronous double primary NSCLC with EGFR L858R mutations in adenocarcinoma and EML-4ALK rearrangement in squamous cell carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('ALK', 'Gene', '238', (126, 129))	('squamous cell carcinoma', 'Disease', (147, 170))	('adenocarcinoma', 'Disease', (102, 116))	('patient', 'Species', '9606', (9, 16))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (147, 170))	('adenocarcinoma', 'Disease', 'MESH:D000230', (102, 116))	('NSCLC', 'Phenotype', 'HP:0030358', (67, 72))	('ALK', 'Gene', (126, 129))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (147, 170))	('mutations', 'Var', (89, 98))	('NSCLC', 'Disease', (67, 72))	('EGFR', 'Gene', '1956', (78, 82))	('EGFR', 'Gene', (78, 82))	('L858R', 'Mutation', 'rs121434568', (83, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (161, 170))	('NSCLC', 'Disease', 'MESH:D002289', (67, 72))
321127	32727606	Our case was confirmed as stage I for adenocarcinoma (T1aN0M0), and thus the EGFR-TKI was not indicated.	('adenocarcinoma', 'Disease', (38, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (43, 52))	('adenocarcinoma', 'Disease', 'MESH:D000230', (38, 52))	('EGFR', 'Gene', '1956', (77, 81))	('T1aN0M0', 'Var', (54, 61))	('EGFR', 'Gene', (77, 81))
321129	32727606	Second, to the best of our knowledge, ALK fusion and EGFR L858R mutations in separate squamous cell carcinoma and adenocarcinoma diagnosed at the same time has not been reported.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (86, 109))	('ALK', 'Gene', '238', (38, 41))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('adenocarcinoma', 'Disease', 'MESH:D000230', (114, 128))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (86, 109))	('L858R', 'Var', (58, 63))	('squamous cell carcinoma', 'Disease', (86, 109))	('L858R', 'Mutation', 'rs121434568', (58, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('ALK', 'Gene', (38, 41))	('EGFR', 'Gene', '1956', (53, 57))	('EGFR', 'Gene', (53, 57))	('adenocarcinoma', 'Disease', (114, 128))
321130	32727606	Complex mutations suggested that tumor heterogeneity can exist in different tumors at the same time.	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('mutations', 'Var', (8, 17))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumors', 'Disease', (76, 82))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('tumor', 'Disease', (33, 38))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
321146	31861759	Negative and positive charges in ECL1 contribute to pore formation.	('pore formation', 'MPA', (52, 66))	('ECL1', 'Gene', (33, 37))	('N', 'Chemical', 'MESH:D009584', (0, 1))	('Negative', 'Var', (0, 8))
321150	31861759	Aberrant expressions of claudins have been reported in various cancers.	('Aberrant', 'Var', (0, 8))	('claudins', 'Protein', (24, 32))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('cancers', 'Disease', 'MESH:D009369', (63, 70))	('cancers', 'Phenotype', 'HP:0002664', (63, 70))	('reported', 'Reg', (43, 51))	('cancers', 'Disease', (63, 70))	('expressions', 'MPA', (9, 20))
321163	31861759	Similarly, claudin-4 accelerates cell migration and invasion in ovarian tumor cell lines, in support of this, peptide-mediated silencing of claudin-4 in ovarian cancer cells exhibited lower tumor burden.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('claudin-4', 'Gene', (11, 20))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('ovarian cancer', 'Disease', 'MESH:D010051', (153, 167))	('invasion', 'CPA', (52, 60))	('peptide-mediated silencing', 'Var', (110, 136))	('claudin-4', 'Gene', '1364', (11, 20))	('ovarian tumor', 'Disease', (64, 77))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('ovarian tumor', 'Disease', 'MESH:D010051', (64, 77))	('cell migration', 'CPA', (33, 47))	('lower', 'NegReg', (184, 189))	('ovarian cancer', 'Disease', (153, 167))	('tumor', 'Disease', (72, 77))	('accelerates', 'PosReg', (21, 32))	('tumor', 'Disease', (190, 195))	('ovarian cancer', 'Phenotype', 'HP:0100615', (153, 167))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('claudin-4', 'Gene', (140, 149))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('ovarian tumor', 'Phenotype', 'HP:0100615', (64, 77))	('claudin-4', 'Gene', '1364', (140, 149))
321164	31861759	Claudin-6 was shown to be a tumor suppressor through genetic manipulation studies in cervical carcinoma cells wherein loss of claudin-6 exacerbated cell proliferation and tumor growth.	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('tumor', 'Disease', (28, 33))	('cervical carcinoma', 'Disease', (85, 103))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('Claudin-6', 'Gene', '9074', (0, 9))	('claudin-6', 'Gene', (126, 135))	('Claudin-6', 'Gene', (0, 9))	('cell proliferation', 'CPA', (148, 166))	('loss', 'Var', (118, 122))	('exacerbated', 'PosReg', (136, 147))	('cervical carcinoma', 'Disease', 'MESH:D002583', (85, 103))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', (171, 176))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
321170	31861759	Recently, mutations of claudin-1 have been reported in breast cancer, which has led to claudin-1 transcript variants shorter than classical claudin-1 transcript.	('breast cancer', 'Phenotype', 'HP:0003002', (55, 68))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('claudin-1', 'Gene', (23, 32))	('variants', 'Var', (108, 116))	('shorter', 'NegReg', (117, 124))	('breast cancer', 'Disease', 'MESH:D001943', (55, 68))	('breast cancer', 'Disease', (55, 68))	('mutations', 'Var', (10, 19))	('reported', 'Reg', (43, 51))	('claudin-1', 'Gene', (87, 96))
321185	31861759	The phosphorylation of claudin-1 at different serine sites (192, 205, 206, and T191) regulates its assembly at tight junctions.	('assembly', 'MPA', (99, 107))	('regulates', 'Reg', (85, 94))	('claudin-1', 'Gene', (23, 32))	('T191', 'Var', (79, 83))	('192', 'Var', (60, 63))	('serine', 'Chemical', 'MESH:C047902', (46, 52))
321187	31861759	Claudin-4 is phosphorylated by atypical PKC (aPKC) at serine195.	('serine195', 'Var', (54, 63))	('Claudin-4', 'Gene', (0, 9))	('serine', 'Chemical', 'MESH:C047902', (54, 60))	('Claudin-4', 'Gene', '1364', (0, 9))
321194	31861759	Dysregulated pluripotent stem cells in tumors are more aggressive and have the potential to reform the whole tumor.	('more', 'PosReg', (50, 54))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('aggressive', 'CPA', (55, 65))	('Dysregulated pluripotent', 'Var', (0, 24))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumor', 'Disease', (39, 44))	('tumors', 'Disease', (39, 45))	('tumor', 'Disease', (109, 114))
321210	31861759	In contrast, other claudins negatively regulate WNTsignaling cascades, such as loss of claudin-3 inducing WNT/beta-catenin activation, thus aiding in the promotion of colon cancer.	('loss', 'Var', (79, 83))	('beta-catenin', 'Gene', (110, 122))	('colon cancer', 'Phenotype', 'HP:0003003', (167, 179))	('beta-catenin', 'Gene', '1499', (110, 122))	('promotion', 'PosReg', (154, 163))	('aid', 'Gene', (140, 143))	('claudin-3', 'Gene', '1365', (87, 96))	('inducing', 'Reg', (97, 105))	('colon cancer', 'Disease', 'MESH:D015179', (167, 179))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('N', 'Chemical', 'MESH:D009584', (107, 108))	('N', 'Chemical', 'MESH:D009584', (49, 50))	('colon cancer', 'Disease', (167, 179))	('claudin-3', 'Gene', (87, 96))	('aid', 'Gene', '57379', (140, 143))
321219	31861759	The depletion of claudin-3 was able to combat the formation of spheres and tumor formation as well as increased sensitivity to cisplatin.	('combat', 'NegReg', (39, 45))	('depletion', 'Var', (4, 13))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('cisplatin', 'Chemical', 'MESH:D002945', (127, 136))	('claudin-3', 'Gene', '1365', (17, 26))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('increased', 'PosReg', (102, 111))	('formation of spheres', 'CPA', (50, 70))	('claudin-3', 'Gene', (17, 26))	('sensitivity to cisplatin', 'MPA', (112, 136))	('tumor', 'Disease', (75, 80))
321230	31861759	Claudin-1 and -7 have proved to have an inverse role in colon cancer, wherein claudin-1 elevates the metastasis of colon cancer cells.	('Claudin-1 and -7', 'Gene', '9076;1366', (0, 16))	('colon cancer', 'Disease', (56, 68))	('colon cancer', 'Disease', (115, 127))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('claudin-1', 'Var', (78, 87))	('colon cancer', 'Phenotype', 'HP:0003003', (115, 127))	('elevates', 'PosReg', (88, 96))	('colon cancer', 'Phenotype', 'HP:0003003', (56, 68))	('colon cancer', 'Disease', 'MESH:D015179', (56, 68))	('colon cancer', 'Disease', 'MESH:D015179', (115, 127))
321245	31861759	The role of claudin-7 in drug resistance has also been reported, wherein decreased drug resistance, increased apoptosis and diminished anti-apoptotic PI3K/Akt pathway was achieved by knocking down claudin-7, proving the potentiality in chemo-resistance.	('anti-apoptotic', 'CPA', (135, 149))	('claudin-7', 'Gene', (197, 206))	('increased', 'PosReg', (100, 109))	('drug resistance', 'Phenotype', 'HP:0020174', (25, 40))	('decreased', 'NegReg', (73, 82))	('drug resistance', 'CPA', (83, 98))	('drug resistance', 'Phenotype', 'HP:0020174', (83, 98))	('knocking down', 'Var', (183, 196))	('Akt', 'Gene', '207', (155, 158))	('diminished', 'NegReg', (124, 134))	('apoptosis', 'CPA', (110, 119))	('Akt', 'Gene', (155, 158))
321247	31861759	have provided evidence for the increased migratory potential of pancreatic cancer cells upon EPCAM and claudin-7 association influencing cell-cell adhesion.	('cell-cell adhesion', 'CPA', (137, 155))	('migratory potential', 'CPA', (41, 60))	('EPCAM', 'Gene', '4072', (93, 98))	('claudin-7', 'Gene', (103, 112))	('increased', 'PosReg', (31, 40))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('cancer', 'Disease', (75, 81))	('pancreatic', 'Disease', 'MESH:D010195', (64, 74))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (64, 81))	('influencing', 'Reg', (125, 136))	('association', 'Var', (113, 124))	('pancreatic', 'Disease', (64, 74))	('EPCAM', 'Gene', (93, 98))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))
321260	31861759	In this report, the patients with low claudin-6 had a lower survival rate than the patients with high claudin-6.	('claudin-6', 'Gene', (38, 47))	('patients', 'Species', '9606', (20, 28))	('low', 'Var', (34, 37))	('patients', 'Species', '9606', (83, 91))	('survival rate', 'CPA', (60, 73))	('lower', 'NegReg', (54, 59))
321268	31861759	Claudin-3 cytoplasmic expression is an indicator of poor survival in triple-negative breast cancer.	('breast cancer', 'Disease', 'MESH:D001943', (85, 98))	('Claudin-3', 'Gene', (0, 9))	('Claudin-3', 'Gene', '1365', (0, 9))	('breast cancer', 'Disease', (85, 98))	('breast cancer', 'Phenotype', 'HP:0003002', (85, 98))	('cytoplasmic', 'Var', (10, 21))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
321269	31861759	In addition, epigenetic modifications of claudins are reported to be a promising prognosis marker of various cancers.	('epigenetic modifications', 'Var', (13, 37))	('claudins', 'Protein', (41, 49))	('cancers', 'Disease', 'MESH:D009369', (109, 116))	('cancers', 'Phenotype', 'HP:0002664', (109, 116))	('cancers', 'Disease', (109, 116))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))
321270	31861759	recently demonstrated that the methylation of claudin-3 is a prognostic factor in gastric adenocarcinoma.	('claudin-3', 'Gene', '1365', (46, 55))	('gastric adenocarcinoma', 'Disease', 'MESH:D013274', (82, 104))	('claudin-3', 'Gene', (46, 55))	('gastric adenocarcinoma', 'Disease', (82, 104))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('methylation', 'Var', (31, 42))
321276	31861759	It was reported that claudin-3 expression was correlated with a Breast cancer type 1 (BRCA1) mutation.	('BRCA1', 'Gene', '672', (86, 91))	('correlated', 'Reg', (46, 56))	('BRCA1', 'Gene', (86, 91))	('Breast cancer type 1', 'Gene', '672', (64, 84))	('expression', 'MPA', (31, 41))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('Breast cancer', 'Phenotype', 'HP:0003002', (64, 77))	('mutation', 'Var', (93, 101))	('claudin-3', 'Gene', (21, 30))	('Breast cancer type 1', 'Gene', (64, 84))	('claudin-3', 'Gene', '1365', (21, 30))
321281	31861759	Patients with lymph node metastasis with an advanced clinical stage showed more methylation in the claudin-11 promoter, which associated with poor overall survival of LSCC patients.	('poor', 'NegReg', (142, 146))	('LSCC', 'Disease', (167, 171))	('associated with', 'Reg', (126, 141))	('claudin-11', 'Gene', '5010', (99, 109))	('claudin-11', 'Gene', (99, 109))	('Patients', 'Species', '9606', (0, 8))	('methylation', 'Var', (80, 91))	('patients', 'Species', '9606', (172, 180))
321283	31861759	Claudin-4 high/claudin-1 low, claudin-4 high/claudin-7 low, and claudin-4 high/claudin-1 low/claudin-7 low types were also significantly correlated with lymph node metastasis, and showed worse survival.	('high/claudin-1', 'Var', (10, 24))	('lymph node metastasis', 'CPA', (153, 174))	('correlated with', 'Reg', (137, 152))	('Claudin-4', 'Gene', '1364', (0, 9))	('Claudin-4', 'Gene', (0, 9))	('low', 'NegReg', (25, 28))	('claudin-4', 'Gene', '1364', (30, 39))	('claudin-4', 'Gene', '1364', (64, 73))	('claudin-4', 'Gene', (30, 39))	('claudin-4', 'Gene', (64, 73))
321287	31861759	There is a long-lasting history of antibody-mediated targeting of claudin-1 against hepatitis C virus (HCV) infections, and wherein many researchers have provided proof for the importance of claudins in HCV infections as viral entry point.	('hepatitis C virus (HCV) infections', 'Disease', 'MESH:D006526', (84, 118))	('hepatitis', 'Phenotype', 'HP:0012115', (84, 93))	('antibody-mediated', 'Var', (35, 52))	('claudin-1', 'Gene', (66, 75))	('HCV infection', 'Disease', (203, 216))	('HCV infection', 'Disease', 'MESH:D006526', (203, 216))
321289	31861759	It was promising to see the antibodies raised against claudin-1 was able to block HCV entry.	('claudin-1', 'Gene', (54, 63))	('HCV', 'Disease', 'MESH:D006526', (82, 85))	('HCV', 'Disease', (82, 85))	('block', 'NegReg', (76, 81))	('antibodies', 'Var', (28, 38))
321343	31861759	Recently, small molecules inhibitors have been gaining more attention in cancer biology, as they aid in targeted therapy.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('aid', 'Gene', '57379', (97, 100))	('small molecules', 'Var', (10, 25))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('aid', 'Gene', (97, 100))	('targeted therapy', 'CPA', (104, 120))
321346	31861759	Further funding came from a pilot project award from the Fred and Pamela Buffet Cancer Center, which was funded by a National Cancer Institute Cancer Center Support Grant, under award number P30 CA036727 to P.D., BX002761 (VA merit) to A.B.S., and Nebraska research initiative (NRI to P.D and A.B.S).	('P30', 'Gene', '201161', (191, 194))	('P30', 'Gene', (191, 194))	('Cancer', 'Phenotype', 'HP:0002664', (126, 132))	('BX002761', 'Chemical', 'MESH:C067968', (213, 221))	('N', 'Chemical', 'MESH:D009584', (278, 279))	('N', 'Chemical', 'MESH:D009584', (117, 118))	('N', 'Chemical', 'MESH:D009584', (248, 249))	('BX002761', 'Var', (213, 221))	('Cancer', 'Phenotype', 'HP:0002664', (80, 86))	('Cancer', 'Phenotype', 'HP:0002664', (143, 149))	('P.D.', 'Var', (207, 211))
321347	30696442	NLRP3 deletion inhibits inflammation-driven mouse lung tumorigenesis induced by benzo(a)pyrene and lipopolysaccharide Inflammatory micro-environment has been proposed to play a critical role in lung tumorigenesis.	('lung tumor', 'Disease', (194, 204))	('benzo(a)pyrene', 'Chemical', 'MESH:D001564', (80, 94))	('lung tumor', 'Disease', 'MESH:D008175', (194, 204))	('NLRP3', 'Gene', '216799', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('lung tumor', 'Disease', (50, 60))	('NLRP3', 'Gene', (0, 5))	('lung tumor', 'Disease', 'MESH:D008175', (50, 60))	('lung tumor', 'Phenotype', 'HP:0100526', (194, 204))	('deletion', 'Var', (6, 14))	('inhibits', 'NegReg', (15, 23))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('lung tumor', 'Phenotype', 'HP:0100526', (50, 60))	('mouse', 'Species', '10090', (44, 49))
321350	30696442	NLRP3-/- mice and C57BL/6J mice (wide-type, WT) were instilled intratracheally with B(a)p (1 mg/mouse) once a week for 4 times [the week of the last time of B(a)p treatment named Week 0], and mice were then instilled intratracheally with LPS at Week 3, 2.5 mug/mouse, once every three weeks for 5 times.	('mice', 'Species', '10090', (192, 196))	('NLRP3-/-', 'Gene', (0, 8))	('mouse', 'Species', '10090', (96, 101))	('LPS', 'Gene', '21898', (238, 241))	('mouse', 'Species', '10090', (261, 266))	('B(a)p', 'Gene', (84, 89))	('B(a)p', 'Gene', '12034', (157, 162))	('mice', 'Species', '10090', (27, 31))	('C57BL/6J', 'Var', (18, 26))	('LPS', 'Gene', (238, 241))	('B(a)p', 'Gene', (157, 162))	('mice', 'Species', '10090', (9, 13))	('B(a)p', 'Gene', '12034', (84, 89))
321353	30696442	In WT mice, B(a)p plus LPS exposure significantly increased tumor incidence, mean tumor count and tumor size of visible tumors of lungs compared with B(a)p treatment alone, and NLRP3 deletion inhibited lung tumorigenesis induced by B(a)p or B(a)p plus LPS.	('tumors', 'Disease', (120, 126))	('lung tumor', 'Phenotype', 'HP:0100526', (202, 212))	('B(a)p', 'Gene', '12034', (150, 155))	('tumors of lungs', 'Phenotype', 'HP:0100526', (120, 135))	('mice', 'Species', '10090', (6, 10))	('LPS', 'Gene', '21898', (252, 255))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('LPS', 'Gene', '21898', (23, 26))	('B(a)p', 'Gene', (150, 155))	('tumor', 'Disease', (98, 103))	('LPS', 'Gene', (252, 255))	('tumor', 'Disease', (60, 65))	('tumor', 'Disease', (82, 87))	('LPS', 'Gene', (23, 26))	('tumors', 'Disease', 'MESH:D009369', (120, 126))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('increased', 'PosReg', (50, 59))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('lung tumor', 'Disease', 'MESH:D008175', (202, 212))	('tumor', 'Disease', (120, 125))	('B(a)p', 'Gene', '12034', (12, 17))	('B(a)p', 'Gene', (12, 17))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('inhibited', 'NegReg', (192, 201))	('B(a)p', 'Gene', '12034', (241, 246))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumor', 'Disease', (207, 212))	('B(a)p', 'Gene', (241, 246))	('NLRP3', 'Gene', (177, 182))	('B(a)p', 'Gene', '12034', (232, 237))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('B(a)p', 'Gene', (232, 237))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('lung tumor', 'Disease', (202, 212))	('deletion', 'Var', (183, 191))
321354	30696442	Histopathological examination found LPS-induced pulmonary inflammatory changes enhanced lung tumorigenesis induced by B(a)p in WT mice, deletion of NLRP3 improved the inflammatory changes induced by LPS and the number and size of pathological tumor nests induced by B(a)p or B(a)p plus LPS.	('LPS', 'Gene', '21898', (199, 202))	('improved', 'PosReg', (154, 162))	('LPS', 'Gene', (199, 202))	('lung tumor', 'Disease', (88, 98))	('LPS', 'Gene', '21898', (286, 289))	('lung tumor', 'Phenotype', 'HP:0100526', (88, 98))	('deletion', 'Var', (136, 144))	('LPS', 'Gene', (286, 289))	('NLRP3', 'Gene', (148, 153))	('B(a)p', 'Gene', '12034', (118, 123))	('tumor', 'Disease', (243, 248))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('inflammatory', 'MPA', (167, 179))	('LPS', 'Gene', '21898', (36, 39))	('B(a)p', 'Gene', (118, 123))	('enhanced', 'PosReg', (79, 87))	('tumor', 'Disease', 'MESH:D009369', (243, 248))	('B(a)p', 'Gene', '12034', (275, 280))	('LPS', 'Gene', (36, 39))	('B(a)p', 'Gene', (275, 280))	('mice', 'Species', '10090', (130, 134))	('lung tumor', 'Disease', 'MESH:D008175', (88, 98))	('B(a)p', 'Gene', '12034', (266, 271))	('B(a)p', 'Gene', (266, 271))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))	('tumor', 'Disease', (93, 98))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
321356	30696442	LPS enhanced B(a)p-induced lung tumorigenesis in WT and NLRP3-/- mice of C57BL/6J strain, and NLRP3 deletion inhibits lung tumorigenesis induced by B(a)p or B(a)p plus LPS.	('lung tumor', 'Phenotype', 'HP:0100526', (27, 37))	('LPS', 'Gene', (0, 3))	('lung tumor', 'Disease', 'MESH:D008175', (118, 128))	('B(a)p', 'Gene', '12034', (157, 162))	('B(a)p', 'Gene', (157, 162))	('inhibits', 'NegReg', (109, 117))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('B(a)p', 'Gene', '12034', (148, 153))	('NLRP3', 'Gene', (94, 99))	('B(a)p', 'Gene', (148, 153))	('B(a)p', 'Gene', '12034', (13, 18))	('lung tumor', 'Disease', 'MESH:D008175', (27, 37))	('deletion', 'Var', (100, 108))	('B(a)p', 'Gene', (13, 18))	('lung tumor', 'Disease', (118, 128))	('mice', 'Species', '10090', (65, 69))	('lung tumor', 'Phenotype', 'HP:0100526', (118, 128))	('LPS', 'Gene', '21898', (168, 171))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('LPS', 'Gene', (168, 171))	('lung tumor', 'Disease', (27, 37))	('LPS', 'Gene', '21898', (0, 3))
321405	30696442	In addition, NLRP3 deletion mainly reduced the growth of B(a)p or B(a)p plus LPS-induced lung tumors (P < 0.05).	('lung tumor', 'Phenotype', 'HP:0100526', (89, 99))	('B(a)p', 'Gene', (66, 71))	('B(a)p', 'Gene', '12034', (57, 62))	('NLRP3', 'Gene', (13, 18))	('reduced', 'NegReg', (35, 42))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('growth', 'MPA', (47, 53))	('deletion', 'Var', (19, 27))	('lung tumors', 'Phenotype', 'HP:0100526', (89, 100))	('B(a)p', 'Gene', '12034', (66, 71))	('B(a)p', 'Gene', (57, 62))	('LPS-induced lung tumors', 'Disease', 'MESH:C536528', (77, 100))	('LPS-induced lung tumors', 'Disease', (77, 100))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))
321406	30696442	Taken together, these results demonstrate that NLRP3 deletion significantly inhibits lung tumorigenesis induced by B(a)p or B(a)p plus LPS in mice.	('NLRP3', 'Gene', (47, 52))	('B(a)p', 'Gene', (115, 120))	('B(a)p', 'Gene', (124, 129))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('deletion', 'Var', (53, 61))	('lung tumor', 'Disease', (85, 95))	('inhibits', 'NegReg', (76, 84))	('LPS', 'Gene', '21898', (135, 138))	('mice', 'Species', '10090', (142, 146))	('lung tumor', 'Disease', 'MESH:D008175', (85, 95))	('LPS', 'Gene', (135, 138))	('B(a)p', 'Gene', '12034', (115, 120))	('B(a)p', 'Gene', '12034', (124, 129))	('lung tumor', 'Phenotype', 'HP:0100526', (85, 95))
321411	30696442	Interestingly, deletion of NLRP3 improved the inflammatory changes induced by LPS, but vehicles-induced inflammatory changes still persist.	('inflammatory changes', 'MPA', (46, 66))	('deletion', 'Var', (15, 23))	('NLRP3', 'Gene', (27, 32))	('LPS', 'Gene', '21898', (78, 81))	('improved', 'PosReg', (33, 41))	('LPS', 'Gene', (78, 81))
321413	30696442	The number and size of pathological tumor nests in cross-section of the left lobes of lungs induced by LPS plus B(a)p in WT mice were increased than mice exposed to B(a)p alone, whereas deletion of NLRP3 attenuated the number and size of pathological tumor nests induced by B(a)p or B(a)p plus LPS compared with WT mice, respectively.	('LPS', 'Gene', (294, 297))	('LPS', 'Gene', '21898', (103, 106))	('tumor', 'Disease', (251, 256))	('B(a)p', 'Gene', '12034', (165, 170))	('mice', 'Species', '10090', (124, 128))	('LPS', 'Gene', (103, 106))	('mice', 'Species', '10090', (149, 153))	('tumor', 'Disease', 'MESH:D009369', (251, 256))	('B(a)p', 'Gene', (165, 170))	('tumor', 'Disease', (36, 41))	('B(a)p', 'Gene', '12034', (283, 288))	('mice', 'Species', '10090', (315, 319))	('B(a)p', 'Gene', (283, 288))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (251, 256))	('B(a)p', 'Gene', '12034', (274, 279))	('attenuated', 'NegReg', (204, 214))	('B(a)p', 'Gene', (274, 279))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('B(a)p', 'Gene', '12034', (112, 117))	('deletion', 'Var', (186, 194))	('B(a)p', 'Gene', (112, 117))	('LPS', 'Gene', '21898', (294, 297))	('increased', 'PosReg', (134, 143))	('NLRP3', 'Gene', (198, 203))
321415	30696442	These results indicated that LPS exposure induces marked lung inflammation and damage, and play a critical role in promoting B(a)p-induced lung tumorigenesis.	('exposure', 'Var', (33, 41))	('B(a)p', 'Gene', (125, 130))	('lung tumor', 'Disease', (139, 149))	('promoting', 'PosReg', (115, 124))	('lung tumor', 'Disease', 'MESH:D008175', (139, 149))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('lung inflammation', 'Disease', 'MESH:D011014', (57, 74))	('LPS', 'Gene', '21898', (29, 32))	('lung tumor', 'Phenotype', 'HP:0100526', (139, 149))	('damage', 'CPA', (79, 85))	('LPS', 'Gene', (29, 32))	('B(a)p', 'Gene', '12034', (125, 130))	('lung inflammation', 'Disease', (57, 74))
321416	30696442	Moreover, NLRP3 deletion prevented lung tumorigenesis induced by B(a)p or B(a)p plus LPS.	('LPS', 'Gene', (85, 88))	('deletion', 'Var', (16, 24))	('lung tumor', 'Phenotype', 'HP:0100526', (35, 45))	('prevented', 'NegReg', (25, 34))	('B(a)p', 'Gene', (74, 79))	('NLRP3', 'Gene', (10, 15))	('B(a)p', 'Gene', '12034', (65, 70))	('B(a)p', 'Gene', '12034', (74, 79))	('LPS', 'Gene', '21898', (85, 88))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('lung tumor', 'Disease', (35, 45))	('lung tumor', 'Disease', 'MESH:D008175', (35, 45))	('B(a)p', 'Gene', (65, 70))
321428	30696442	Similarly, a mouse model of inflammation-driven lung squamous cell carcinoma (LSCC) with A/J mice was induced by Nnitroso-trischloroethylurea (NTCU) and enhanced by LPS.	('mouse', 'Species', '10090', (13, 18))	('Nnitroso-trischloroethylurea', 'Chemical', 'MESH:C572573', (113, 141))	('LPS', 'Gene', (165, 168))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (53, 76))	('inflammation-driven lung squamous cell carcinoma', 'Disease', 'MESH:D011014', (28, 76))	('Nnitroso-trischloroethylurea', 'Var', (113, 141))	('mice', 'Species', '10090', (93, 97))	('NTCU', 'Chemical', 'MESH:C572573', (143, 147))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('inflammation-driven lung squamous cell carcinoma', 'Disease', (28, 76))	('LPS', 'Gene', '21898', (165, 168))
321434	30696442	NLRP3 deletion significantly suppressed the tumor incidence, mean tumor count and tumor size of visible tumors on the surface of lungs induced by B(a)p or B(a)p plus LPS, implying NLRP3 inflammasome may be involved in the enhancement of pulmonary inflammation in lung tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('lung tumor', 'Disease', (263, 273))	('LPS', 'Gene', '21898', (166, 169))	('tumors', 'Disease', (104, 110))	('LPS', 'Gene', (166, 169))	('lung tumor', 'Phenotype', 'HP:0100526', (263, 273))	('tumor', 'Disease', (82, 87))	('tumor', 'Disease', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (268, 273))	('tumor', 'Disease', (66, 71))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('pulmonary inflammation', 'Disease', (237, 259))	('deletion', 'Var', (6, 14))	('B(a)p', 'Gene', '12034', (146, 151))	('B(a)p', 'Gene', '12034', (155, 160))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('suppressed', 'NegReg', (29, 39))	('pulmonary inflammation', 'Disease', 'MESH:D011014', (237, 259))	('lung tumor', 'Disease', 'MESH:D008175', (263, 273))	('B(a)p', 'Gene', (146, 151))	('B(a)p', 'Gene', (155, 160))	('tumor', 'Disease', (104, 109))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('NLRP3', 'Gene', (0, 5))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('tumor', 'Disease', (268, 273))	('tumor', 'Disease', 'MESH:D009369', (268, 273))
321441	30696442	Histopathological observation not only confirmed that LPS-induced lung inflammatory changes and pathological injury enhanced B(a)p-induced lung tumorigenesis, and NLRP3 deletion significantly improved these changes, but also found that B(a)p exposure and B(a)p plus LPS exposure predominately induced the occurrence of lung adenoma in this study.	('improved', 'PosReg', (192, 200))	('B(a)p', 'Gene', (255, 260))	('deletion', 'Var', (169, 177))	('LPS', 'Gene', '21898', (54, 57))	('LPS', 'Gene', (54, 57))	('B(a)p', 'Gene', '12034', (125, 130))	('B(a)p', 'Gene', (125, 130))	('B(a)p', 'Gene', '12034', (236, 241))	('lung tumor', 'Disease', 'MESH:D008175', (139, 149))	('LPS', 'Gene', '21898', (266, 269))	('B(a)p', 'Gene', (236, 241))	('LPS', 'Gene', (266, 269))	('NLRP3', 'Gene', (163, 168))	('induced', 'Reg', (293, 300))	('lung adenoma', 'Disease', (319, 331))	('enhanced', 'PosReg', (116, 124))	('lung tumor', 'Disease', (139, 149))	('lung adenoma', 'Disease', 'MESH:D000236', (319, 331))	('lung tumor', 'Phenotype', 'HP:0100526', (139, 149))	('B(a)p', 'Gene', '12034', (255, 260))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))
321446	30696442	Our results from this study demonstrated that LPS enhanced B(a)p-induced lung tumorigenesis in WT and NLRP3-/- mice of C57BL/6J strain, and NLRP3 deletion inhibits lung tumorigenesis induced by B(a)p or B(a)p plus LPS.	('LPS', 'Gene', '21898', (46, 49))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('LPS', 'Gene', (46, 49))	('lung tumor', 'Disease', 'MESH:D008175', (164, 174))	('LPS', 'Gene', '21898', (214, 217))	('LPS', 'Gene', (214, 217))	('lung tumor', 'Disease', (73, 83))	('NLRP3', 'Gene', (140, 145))	('inhibits', 'NegReg', (155, 163))	('B(a)p', 'Gene', '12034', (203, 208))	('lung tumor', 'Phenotype', 'HP:0100526', (73, 83))	('B(a)p', 'Gene', '12034', (59, 64))	('B(a)p', 'Gene', (59, 64))	('B(a)p', 'Gene', (203, 208))	('B(a)p', 'Gene', '12034', (194, 199))	('B(a)p', 'Gene', (194, 199))	('lung tumor', 'Disease', (164, 174))	('lung tumor', 'Phenotype', 'HP:0100526', (164, 174))	('deletion', 'Var', (146, 154))	('lung tumor', 'Disease', 'MESH:D008175', (73, 83))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('mice', 'Species', '10090', (111, 115))
321453	29456509	FOXA2 expression was decreased in LSCC tissues compared with adjacent normal tissues and knockdown of FOXA2 increased NCI-H292 cells proliferation.	('NCI-H292 cells proliferation', 'CPA', (118, 146))	('NCI-H292 cells', 'CellLine', 'CVCL:0455', (118, 132))	('LSCC', 'Disease', (34, 38))	('decreased', 'NegReg', (21, 30))	('expression', 'MPA', (6, 16))	('increased', 'PosReg', (108, 117))	('LSCC', 'Phenotype', 'HP:0030359', (34, 38))	('FOXA2', 'Gene', '3170', (102, 107))	('knockdown', 'Var', (89, 98))	('FOXA2', 'Gene', '3170', (0, 5))	('FOXA2', 'Gene', (102, 107))	('FOXA2', 'Gene', (0, 5))
321454	29456509	Inhibition of cell proliferation by curcumin was attenuated by FOXA2 knockdown.	('FOXA2', 'Gene', (63, 68))	('curcumin', 'Chemical', 'MESH:D003474', (36, 44))	('attenuated', 'NegReg', (49, 59))	('cell proliferation', 'CPA', (14, 32))	('FOXA2', 'Gene', '3170', (63, 68))	('knockdown', 'Var', (69, 78))
321466	29456509	Therefore, FOXA2 may be an important target protein for therapies against LSCC since LSCCs are linked more strongly with smoking than other forms of NSCLC, and activation of FOXA2 may be useful for treating human LSCC.	('SCLC', 'Phenotype', 'HP:0030357', (150, 154))	('FOXA2', 'Gene', (11, 16))	('LSCC', 'Phenotype', 'HP:0030359', (74, 78))	('NSCLC', 'Phenotype', 'HP:0030358', (149, 154))	('LSCCs', 'Disease', (85, 90))	('NSCLC', 'Disease', (149, 154))	('LSCC', 'Phenotype', 'HP:0030359', (85, 89))	('FOXA2', 'Gene', '3170', (11, 16))	('LSCC', 'Phenotype', 'HP:0030359', (213, 217))	('human', 'Species', '9606', (207, 212))	('linked', 'Reg', (95, 101))	('NSCLC', 'Disease', 'MESH:D002289', (149, 154))	('FOXA2', 'Gene', '3170', (174, 179))	('activation', 'Var', (160, 170))	('FOXA2', 'Gene', (174, 179))
321475	29456509	Thus, STAT3 has been regarded as a key target for lung cancer prevention, and inhibition of STAT3 signal showed great anticancer and antiangiogenic effects in vitro and in vivo.	('lung cancer', 'Disease', (50, 61))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('cancer', 'Disease', (122, 128))	('antiangiogenic effects', 'CPA', (133, 155))	('lung cancer', 'Disease', 'MESH:D008175', (50, 61))	('inhibition', 'Var', (78, 88))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('STAT3', 'Gene', '6774', (92, 97))	('STAT3', 'Gene', '6774', (6, 11))	('STAT3', 'Gene', (92, 97))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('STAT3', 'Gene', (6, 11))	('lung cancer', 'Phenotype', 'HP:0100526', (50, 61))	('cancer', 'Disease', (55, 61))
321476	29456509	Recent study showed that activation of STAT3 by Mycoplasma pneumoniae inhibited FOXA2 expression in human NCI-H292 LSCC cells.	('NCI-H292 LSCC', 'CellLine', 'CVCL:0455', (106, 119))	('FOXA2', 'Gene', '3170', (80, 85))	('STAT3', 'Gene', '6774', (39, 44))	('human', 'Species', '9606', (100, 105))	('FOXA2', 'Gene', (80, 85))	('Mycoplasma pneumoniae', 'Var', (48, 69))	('expression', 'MPA', (86, 96))	('STAT3', 'Gene', (39, 44))	('inhibited', 'NegReg', (70, 79))	('activation', 'PosReg', (25, 35))	('LSCC', 'Phenotype', 'HP:0030359', (115, 119))
321506	29456509	The PVDF membrane was blocked with 5% BSA, washed three times with TBST, and then incubated with the antibodies separately overnight at 4 C. Antibodies to beta-actin, P-STAT3, and P-STAT6 were from Cell Signaling (Cell Signaling Technology, Danvers, MA, United States) and antibodies to FOXA2 were from Santa Cruz (Santa Cruz Biotechnology, Dallas, TX, United States).	('STAT3', 'Gene', '6774', (169, 174))	('TBST', 'Chemical', '-', (67, 71))	('Antibodies', 'Var', (141, 151))	('STAT6', 'Gene', '6778', (182, 187))	('STAT3', 'Gene', (169, 174))	('PVDF', 'Chemical', 'MESH:C024865', (4, 8))	('FOXA2', 'Gene', '3170', (287, 292))	('FOXA2', 'Gene', (287, 292))	('beta-actin', 'Gene', (155, 165))	('beta-actin', 'Gene', '728378', (155, 165))	('STAT6', 'Gene', (182, 187))
321520	29456509	Curcumin-induced cell proliferation inhibition was rescued after FOXA2 knockdown compared to controls (Figure 3A).	('Curcumin', 'Chemical', 'MESH:D003474', (0, 8))	('FOXA2', 'Gene', (65, 70))	('cell proliferation', 'CPA', (17, 35))	('knockdown', 'Var', (71, 80))	('FOXA2', 'Gene', '3170', (65, 70))
321521	29456509	The inhibitory rate of curcumin was significantly decreased in FOXA2 knockdown cells compared to controls (inhibitory rate: 40% vs. 60%).	('FOXA2', 'Gene', (63, 68))	('inhibitory rate', 'MPA', (4, 19))	('curcumin', 'Chemical', 'MESH:D003474', (23, 31))	('FOXA2', 'Gene', '3170', (63, 68))	('decreased', 'NegReg', (50, 59))	('knockdown', 'Var', (69, 78))
321526	29456509	These results suggested that loss of FOXA2 expression might play important roles in the tumourigenesis of LSCC.	('LSCC', 'Disease', (106, 110))	('LSCC', 'Phenotype', 'HP:0030359', (106, 110))	('FOXA2', 'Gene', '3170', (37, 42))	('FOXA2', 'Gene', (37, 42))	('loss', 'Var', (29, 33))	('tumourigenesis', 'CPA', (88, 102))
321531	29456509	Also, we found pro-apoptotic Bax protein and mRNA decreased after FOXA2 knockdown in NCI-H292 cells (Figures 5D,E).	('FOXA2', 'Gene', '3170', (66, 71))	('FOXA2', 'Gene', (66, 71))	('Bax', 'Gene', (29, 32))	('decreased', 'NegReg', (50, 59))	('NCI-H292 cells', 'CellLine', 'CVCL:0455', (85, 99))	('mRNA', 'MPA', (45, 49))	('Bax', 'Gene', '581', (29, 32))	('knockdown', 'Var', (72, 81))
321546	29456509	Unlike lung adenocarcinoma, activating mutations in EGFR and ALK fusion are typically not present in LSCC, so targeted agents are largely ineffective against LSCC.	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (7, 26))	('EGFR', 'Gene', '1956', (52, 56))	('EGFR', 'Gene', (52, 56))	('ALK', 'Gene', (61, 64))	('LSCC', 'Phenotype', 'HP:0030359', (158, 162))	('mutations', 'Var', (39, 48))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (7, 26))	('carcinoma', 'Phenotype', 'HP:0030731', (17, 26))	('ALK', 'Gene', '238', (61, 64))	('lung adenocarcinoma', 'Disease', (7, 26))	('LSCC', 'Phenotype', 'HP:0030359', (101, 105))
321554	29456509	We confirmed that Bax was regulated by FOXA2, which decreased after FOXA2 knockdown.	('Bax', 'Gene', '581', (18, 21))	('decreased', 'NegReg', (52, 61))	('FOXA2', 'Gene', '3170', (39, 44))	('knockdown', 'Var', (74, 83))	('FOXA2', 'Gene', (39, 44))	('FOXA2', 'Gene', '3170', (68, 73))	('Bax', 'Gene', (18, 21))	('FOXA2', 'Gene', (68, 73))
321736	31958696	N6-Methyladenosine: A Potential Breakthrough for Human Cancer Among more than 100 types of identified RNA modification, N6-methyladenosine (m6A) modification is the predominant mRNA modification, which regulates RNA splicing, translocation, stability, and translation.	('translocation', 'MPA', (226, 239))	('translation', 'MPA', (256, 267))	('N6-methyladenosine', 'Chemical', 'MESH:C010223', (120, 138))	('N6-Methyladenosine', 'Chemical', 'MESH:C010223', (0, 18))	('stability', 'MPA', (241, 250))	('Cancer', 'Phenotype', 'HP:0002664', (55, 61))	('N6-methyladenosine', 'Var', (120, 138))	('regulates', 'Reg', (202, 211))	('Human', 'Species', '9606', (49, 54))	('Cancer', 'Disease', (55, 61))	('m6A', 'Gene', (140, 143))	('Cancer', 'Disease', 'MESH:D009369', (55, 61))	('RNA splicing', 'MPA', (212, 224))	('m6A', 'Gene', '56339', (140, 143))
321737	31958696	m6A modification plays critical roles in the growth, differentiation, and metabolism of cells.	('m6A', 'Gene', '56339', (0, 3))	('growth', 'CPA', (45, 51))	('differentiation', 'CPA', (53, 68))	('modification', 'Var', (4, 16))	('metabolism', 'CPA', (74, 84))	('m6A', 'Gene', (0, 3))
321740	31958696	An increasing number of studies have implicated the correlation between m6A modification and human cancers.	('m6A', 'Gene', (72, 75))	('human', 'Species', '9606', (93, 98))	('cancers', 'Disease', 'MESH:D009369', (99, 106))	('cancers', 'Phenotype', 'HP:0002664', (99, 106))	('cancers', 'Disease', (99, 106))	('m6A', 'Gene', '56339', (72, 75))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('modification', 'Var', (76, 88))
321743	31958696	N6-adenosine is the most prevalent epigenetic modification in RNA, originally identified in mRNAs in the 1970s.	('N6-adenosine', 'Var', (0, 12))	('N6-adenosine', 'Chemical', 'MESH:C054123', (0, 12))	('RNA', 'Gene', (62, 65))
321744	31958696	Similar to the methylation of DNA, N6-methyladenosine (m6A) methylation regulates post-transcriptional expression without changing the base sequence.	('m6A', 'Gene', (55, 58))	('m6A', 'Gene', '56339', (55, 58))	('methylation', 'Var', (60, 71))	('regulates', 'Reg', (72, 81))	('post-transcriptional expression', 'MPA', (82, 113))	('N6-methyladenosine', 'Chemical', 'MESH:C010223', (35, 53))
321757	31958696	Accumulating studies indicate that aberrant m6A levels closely correlate with carcinogenesis and the progression and metastasis of cancer cells.	('metastasis of cancer', 'Disease', (117, 137))	('metastasis of cancer', 'Disease', 'MESH:D009362', (117, 137))	('carcinogenesis', 'Disease', 'MESH:D063646', (78, 92))	('aberrant', 'Var', (35, 43))	('carcinogenesis', 'Disease', (78, 92))	('m6A', 'Gene', (44, 47))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('correlate', 'Reg', (63, 72))	('m6A', 'Gene', '56339', (44, 47))	('progression', 'CPA', (101, 112))
321798	31958696	Demethylation of m6Am at the sites adjacent to snRNA cap lead to relatively decreased m6Am-snRNA levels.	('m6A', 'Gene', '56339', (86, 89))	('decreased', 'NegReg', (76, 85))	('Demethylation', 'Var', (0, 13))	('m6A', 'Gene', (17, 20))	('m6A', 'Gene', (86, 89))	('m6A', 'Gene', '56339', (17, 20))
321804	31958696	m6A modification exerts biological functions by binding to YTH domain-containing proteins (YTHDC1-2), YTH-family proteins (YTHDF1-3), and other interacting factors.	('m6A', 'Gene', '56339', (0, 3))	('YTH domain-containing proteins', 'Protein', (59, 89))	('binding', 'Interaction', (48, 55))	('modification', 'Var', (4, 16))	('YTHDC1-2', 'Gene', (91, 99))	('m6A', 'Gene', (0, 3))	('YTHDC1-2', 'Gene', '64848', (91, 99))
321811	31958696	YTHDC2 enhances translation efficiency of target mRNA, while knockdown of YTHDC2 results in an upregulation of m6A-modified transcripts.	('YTHDC2', 'Gene', '64848', (74, 80))	('YTHDC2', 'Gene', (74, 80))	('m6A', 'Gene', (111, 114))	('translation efficiency', 'MPA', (16, 38))	('YTHDC2', 'Gene', '64848', (0, 6))	('YTHDC2', 'Gene', (0, 6))	('knockdown', 'Var', (61, 70))	('m6A', 'Gene', '56339', (111, 114))	('upregulation', 'PosReg', (95, 107))	('enhances', 'PosReg', (7, 15))
321814	31958696	In addition, diverse cellular stresses selectively result in an increase in mRNAs with 5' UTR m6A.	('m6A', 'Gene', (94, 97))	('m6A', 'Gene', '56339', (94, 97))	('increase', 'PosReg', (64, 72))	("5' UTR", 'Var', (87, 93))	('mRNAs', 'MPA', (76, 81))
321821	31958696	However, elevated non-functional METTL3 also activates the PI3K/AKT pathway, which implicated that there are certain mechanisms independent of m6A modification.	('m6A', 'Gene', '56339', (143, 146))	('elevated', 'PosReg', (9, 17))	('activates', 'PosReg', (45, 54))	('AKT', 'Gene', '207', (64, 67))	('non-functional', 'Var', (18, 32))	('METTL3', 'Protein', (33, 39))	('m6A', 'Gene', (143, 146))	('AKT', 'Gene', (64, 67))
321823	31958696	METTL14 is essential for maintaining self-renewal of AML cells, while knockdown of METTL14 promotes myeloid differentiation.	('promotes', 'PosReg', (91, 99))	('myeloid differentiation', 'CPA', (100, 123))	('knockdown', 'Var', (70, 79))	('METTL14', 'Gene', (0, 7))	('METTL14', 'Gene', '57721', (0, 7))	('METTL14', 'Gene', (83, 90))	('METTL14', 'Gene', '57721', (83, 90))
321826	31958696	However, YTHDF proteins are not involved in promoting stability and translation of target mRNAs, while knockdown of METTL14 has an effect on the quantity of MYB and MYC mRNA.	('METTL14', 'Gene', '57721', (116, 123))	('MYC', 'Gene', (165, 168))	('METTL14', 'Gene', (116, 123))	('quantity', 'MPA', (145, 153))	('effect', 'Reg', (131, 137))	('MYB', 'Gene', '4602', (157, 160))	('MYC', 'Gene', '4609', (165, 168))	('MYB', 'Gene', (157, 160))	('knockdown', 'Var', (103, 112))
321836	31958696	FTO is overexpressed in AML with MLL rearrangements, PML-RARA, FLT3-ITD, or NPM1 mutations.	('FLT3', 'Gene', (63, 67))	('MLL', 'Gene', (33, 36))	('FLT3', 'Gene', '2322', (63, 67))	('NPM1', 'Gene', '4869', (76, 80))	('MLL', 'Gene', '4297', (33, 36))	('PML', 'Gene', (53, 56))	('RARA', 'Gene', '5914', (57, 61))	('PML', 'Gene', '5371', (53, 56))	('mutations', 'Var', (81, 90))	('RARA', 'Gene', (57, 61))	('NPM1', 'Gene', (76, 80))
321840	31958696	Similarly, CAPAM (cap-specific adenosine methyltransferase) mediating m6A modification at the 5' cap in mRNA may correlate with AML, but the hypothesizes have yet to be identified.	('m6A', 'Gene', (70, 73))	('adenosine', 'Chemical', 'MESH:D000241', (31, 40))	('modification', 'Var', (74, 86))	('correlate', 'Reg', (113, 122))	('m6A', 'Gene', '56339', (70, 73))	('AML', 'MPA', (128, 131))
321841	31958696	Recently, an investigation in leukemia patients indicated that genetic alterations of m6A regulatory genes were associated with p53 mutations in AML.	('genetic alterations', 'Var', (63, 82))	('m6A', 'Gene', '56339', (86, 89))	('leukemia', 'Disease', (30, 38))	('p53', 'Gene', (128, 131))	('p53', 'Gene', '7157', (128, 131))	('patients', 'Species', '9606', (39, 47))	('leukemia', 'Disease', 'MESH:D007938', (30, 38))	('AML', 'Gene', (145, 148))	('mutations', 'Var', (132, 141))	('leukemia', 'Phenotype', 'HP:0001909', (30, 38))	('m6A', 'Gene', (86, 89))	('associated', 'Reg', (112, 122))
321846	31958696	According to clinical and laboratory data, high YTHDF1 expression in patients signaled poorer overall survival, while silencing of YTHDF1 in vitro resulted in poor efficacy of anticancer drugs and suppression of cancer proliferation.	('poor', 'NegReg', (159, 163))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))	('YTHDF1', 'Gene', (131, 137))	('overall', 'MPA', (94, 101))	('high', 'Var', (43, 47))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('expression', 'MPA', (55, 65))	('silencing', 'Var', (118, 127))	('suppression', 'NegReg', (197, 208))	('cancer', 'Disease', (212, 218))	('poorer', 'NegReg', (87, 93))	('cancer', 'Disease', 'MESH:D009369', (212, 218))	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('patients', 'Species', '9606', (69, 77))	('efficacy', 'MPA', (164, 172))	('cancer', 'Disease', (180, 186))	('YTHDF1', 'Gene', (48, 54))
321850	31958696	Confirmed as an m6A methyltransferase (as previously mentioned), METTL3 is capable of methylating SRY (sex determining region Y)-box 2 (SOX2), which is essential for maintaining self-renewal.	('m6A', 'Gene', (16, 19))	('methylating', 'Var', (86, 97))	('m6A', 'Gene', '56339', (16, 19))	('METTL3', 'Gene', (65, 71))	('SOX2', 'Gene', '6657', (136, 140))	('SOX2', 'Gene', (136, 140))
321851	31958696	IGF2BP2 subsequently recognizes the methylated SOX2 transcripts, thereby preventing SOX2 mRNA degradation.	('methylated', 'Var', (36, 46))	('preventing', 'NegReg', (73, 83))	('IGF2BP2', 'Gene', '10644', (0, 7))	('SOX2', 'Gene', '6657', (84, 88))	('SOX2', 'Gene', (84, 88))	('SOX2', 'Gene', '6657', (47, 51))	('IGF2BP2', 'Gene', (0, 7))	('SOX2', 'Gene', (47, 51))
321857	31958696	Some studies have given way to the idea that METTL3 is a carcinogenic factor of GC.	('carcinogenic', 'Disease', 'MESH:D063646', (57, 69))	('GC', 'Disease', 'MESH:D013274', (80, 82))	('carcinogenic', 'Disease', (57, 69))	('GC', 'Phenotype', 'HP:0012126', (80, 82))	('METTL3', 'Var', (45, 51))
321860	31958696	METTL3 leads to inactivation of the AKT signaling pathway, while knockdown of METTL3 activated the apoptotic pathway in GC cells.	('METTL3', 'Gene', (78, 84))	('AKT', 'Gene', '207', (36, 39))	('inactivation', 'NegReg', (16, 28))	('activated', 'PosReg', (85, 94))	('METTL3', 'Var', (0, 6))	('AKT', 'Gene', (36, 39))	('GC', 'Disease', 'MESH:D013274', (120, 122))	('knockdown', 'Var', (65, 74))	('apoptotic pathway', 'Pathway', (99, 116))	('GC', 'Phenotype', 'HP:0012126', (120, 122))
321868	31958696	Mechanistically, FTO inhibits the function of BNIP3, which acts as a tumor suppressor.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('inhibits', 'NegReg', (21, 29))	('function', 'MPA', (34, 42))	('tumor', 'Disease', (69, 74))	('FTO', 'Var', (17, 20))	('BNIP3', 'Gene', (46, 51))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('BNIP3', 'Gene', '664', (46, 51))
321873	31958696	However, increased m6A levels in transformed cells, resulting from overexpression of METTL3 and METTL14, or deletion of ALKBH5, promoted proliferation and migration.	('METTL3', 'Gene', (85, 91))	('migration', 'CPA', (155, 164))	('METTL14', 'Gene', '57721', (96, 103))	('overexpression', 'PosReg', (67, 81))	('METTL14', 'Gene', (96, 103))	('m6A', 'Gene', (19, 22))	('increased', 'PosReg', (9, 18))	('ALKBH5', 'Gene', '54890', (120, 126))	('ALKBH5', 'Gene', (120, 126))	('m6A', 'Gene', '56339', (19, 22))	('promoted', 'PosReg', (128, 136))	('proliferation', 'CPA', (137, 150))	('deletion', 'Var', (108, 116))
321875	31958696	Deregulation of FTO and METTL3 has been detected in lung cancer, which indicated their significant roles in tumorigenesis and development.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('lung cancer', 'Disease', 'MESH:D008175', (52, 63))	('FTO', 'Gene', (16, 19))	('Deregulation', 'Var', (0, 12))	('METTL3', 'Gene', (24, 30))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('detected', 'Reg', (40, 48))	('tumor', 'Disease', (108, 113))	('lung cancer', 'Disease', (52, 63))	('lung cancer', 'Phenotype', 'HP:0100526', (52, 63))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))
321879	31958696	Mechanistically, FTO decreased m6A levels and mRNA stability in the MZF1 mRNA transcript, thereby promoting expression of MZF1 and mediating carcinogenesis.	('MZF1', 'Gene', (122, 126))	('m6A', 'Gene', '56339', (31, 34))	('decreased', 'NegReg', (21, 30))	('carcinogenesis', 'Disease', (141, 155))	('MZF1', 'Gene', '7593', (68, 72))	('mediating', 'Reg', (131, 140))	('carcinogenesis', 'Disease', 'MESH:D063646', (141, 155))	('promoting', 'PosReg', (98, 107))	('MZF1', 'Gene', '7593', (122, 126))	('expression', 'MPA', (108, 118))	('FTO', 'Var', (17, 20))	('m6A', 'Gene', (31, 34))	('mRNA stability', 'MPA', (46, 60))	('MZF1', 'Gene', (68, 72))
321886	31958696	Depletion of UBE2C induces attenuated proliferation, clonogenicity, and invasive growth of NSCLC cells.	('NSCLC', 'Disease', 'MESH:D002289', (91, 96))	('attenuated', 'NegReg', (27, 37))	('UBE2C', 'Gene', '11065', (13, 18))	('UBE2C', 'Gene', (13, 18))	('invasive growth', 'CPA', (72, 87))	('Depletion', 'Var', (0, 9))	('clonogenicity', 'CPA', (53, 66))	('NSCLC', 'Disease', (91, 96))
321888	31958696	Overexpression of METTL3 is a signal of poor prognosis in HCC, and upregulated YTHDF1 is positively correlated with TNM stage, indicating their important roles in HCC cells metastasis and progression.	('YTHDF1', 'Gene', (79, 85))	('HCC', 'Phenotype', 'HP:0001402', (163, 166))	('HCC', 'Disease', 'MESH:D006528', (58, 61))	('HCC', 'Disease', (58, 61))	('METTL3', 'Gene', (18, 24))	('Overexpression', 'Var', (0, 14))	('HCC', 'Phenotype', 'HP:0001402', (58, 61))	('HCC', 'Disease', 'MESH:D006528', (163, 166))	('upregulated', 'PosReg', (67, 78))	('HCC', 'Disease', (163, 166))	('TNM stage', 'Disease', (116, 125))
321895	31958696	FTO-mediated m6A mRNA demethylation promotes melanoma tumorigenesis and anti-PD-1 resistance.	('melanoma tumorigenesis', 'Disease', (45, 67))	('anti-PD-1 resistance', 'CPA', (72, 92))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('mRNA', 'Var', (17, 21))	('m6A', 'Gene', (13, 16))	('melanoma tumorigenesis', 'Disease', 'MESH:D063646', (45, 67))	('melanoma', 'Phenotype', 'HP:0002861', (45, 53))	('m6A', 'Gene', '56339', (13, 16))	('promotes', 'PosReg', (36, 44))
321897	31958696	In mice, knockdown of FTO markedly enhances melanoma cell sensitivity to interferon (IFN)-gamma and anti-PD-1 treatment, which suggested a promising anti-cancer therapy.	('interferon (IFN)-gamma', 'Gene', (73, 95))	('interferon (IFN)-gamma', 'Gene', '15978', (73, 95))	('knockdown', 'Var', (9, 18))	('FTO', 'Gene', (22, 25))	('melanoma', 'Phenotype', 'HP:0002861', (44, 52))	('mice', 'Species', '10090', (3, 7))	('melanoma', 'Disease', (44, 52))	('cancer', 'Disease', (154, 160))	('melanoma', 'Disease', 'MESH:D008545', (44, 52))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('enhances', 'PosReg', (35, 43))
321902	31958696	Upregulated m6A mRNA modification was identified to induce the suppression of GSC self-renewal and tumorigenesis.	('tumor', 'Disease', (99, 104))	('suppression', 'NegReg', (63, 74))	('GSC self-renewal', 'CPA', (78, 94))	('mRNA modification', 'Var', (16, 33))	('m6A', 'Gene', (12, 15))	('m6A', 'Gene', '56339', (12, 15))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('Upregulated', 'PosReg', (0, 11))
321909	31958696	It is becoming increasingly clear that deregulated m6A modification is a key factor in growth, metastasis, and drug resistance of various tumors.	('m6A', 'Gene', '56339', (51, 54))	('deregulated', 'Var', (39, 50))	('tumors', 'Disease', (138, 144))	('tumors', 'Disease', 'MESH:D009369', (138, 144))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('drug resistance', 'Phenotype', 'HP:0020174', (111, 126))	('m6A', 'Gene', (51, 54))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
321916	31958696	Moreover, METTL3 participates in the mutagenesis of p53 proteins, which promotes proliferation, metastasis, and drug resistance of cancer cells.	('cancer', 'Disease', (131, 137))	('drug resistance', 'Phenotype', 'HP:0020174', (112, 127))	('metastasis', 'CPA', (96, 106))	('p53', 'Gene', (52, 55))	('proteins', 'Protein', (56, 64))	('p53', 'Gene', '7157', (52, 55))	('METTL3', 'Gene', (10, 16))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('mutagenesis', 'Var', (37, 48))	('promotes', 'PosReg', (72, 80))	('proliferation', 'CPA', (81, 94))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('drug resistance', 'CPA', (112, 127))
321917	31958696	METTL3 catalyzes the formation of m6A at the point-mutated codon 273 (G>A) of p53 pre-mRNA, promoting aberrant splicing of p53 pre-mRNA and expression of p53 R273H mutant protein.	('m6A', 'Gene', '56339', (34, 37))	('expression', 'MPA', (140, 150))	('codon 273 (G>A)', 'Mutation', 'c.CODON273G>A', (59, 74))	('protein', 'Protein', (171, 178))	('promoting', 'PosReg', (92, 101))	('p53', 'Gene', (78, 81))	('p53', 'Gene', (123, 126))	('p53', 'Gene', (154, 157))	('p53', 'Gene', '7157', (154, 157))	('p53', 'Gene', '7157', (123, 126))	('splicing', 'MPA', (111, 119))	('p53', 'Gene', '7157', (78, 81))	('R273H', 'Var', (158, 163))	('R273H', 'Mutation', 'rs28934576', (158, 163))	('m6A', 'Gene', (34, 37))
321919	31958696	Reduction of m6A methylation caused by abnormal MAC has been found in about 70% of human endometrial cancer samples, resulting in activation of the AKT pathway by upregulating the negative AKT regulator PHLPP2 and downregulating the positive AKT regulator mTORC2.	('endometrial cancer', 'Disease', 'MESH:D016889', (89, 107))	('mTORC2', 'Gene', (256, 262))	('activation', 'PosReg', (130, 140))	('abnormal MAC', 'Var', (39, 51))	('m6A', 'Gene', '56339', (13, 16))	('AKT', 'Gene', (189, 192))	('PHLPP2', 'Gene', (203, 209))	('mTORC2', 'Gene', '74343', (256, 262))	('AKT', 'Gene', (148, 151))	('AKT', 'Gene', (242, 245))	('m6A', 'Gene', (13, 16))	('PHLPP2', 'Gene', '23035', (203, 209))	('methylation', 'MPA', (17, 28))	('Reduction', 'NegReg', (0, 9))	('AKT', 'Gene', '207', (189, 192))	('AKT', 'Gene', '207', (242, 245))	('AKT', 'Gene', '207', (148, 151))	('endometrial cancer', 'Phenotype', 'HP:0012114', (89, 107))	('human', 'Species', '9606', (83, 88))	('abnormal MAC', 'Phenotype', 'HP:0001103', (39, 51))	('upregulating', 'PosReg', (163, 175))	('downregulating', 'NegReg', (214, 228))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('endometrial cancer', 'Disease', (89, 107))
321920	31958696	The alteration of MAC can be caused by METTL14 mutation (hotspot R298P mutation) or reduced expression of METTL3.	('R298P mutation', 'Var', (65, 79))	('METTL14', 'Gene', '57721', (39, 46))	('mutation', 'Var', (47, 55))	('METTL3', 'Gene', (106, 112))	('reduced', 'NegReg', (84, 91))	('R298P', 'Mutation', 'p.R298P', (65, 70))	('METTL14', 'Gene', (39, 46))	('expression', 'MPA', (92, 102))	('MAC', 'Disease', (18, 21))
321924	31958696	In the emerging FTO-m6A-MYC-CEBPA axis, FTO is the target of R-2HG (R-enantiomer of 2-hydroxyglutarate), which has anticancer activity in AML.	('MYC', 'Gene', (24, 27))	('m6A', 'Gene', '56339', (20, 23))	('MYC', 'Gene', '4609', (24, 27))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (84, 102))	('cancer', 'Disease', (119, 125))	('CEBPA', 'Gene', (28, 33))	('CEBPA', 'Gene', '1050', (28, 33))	('R-2HG', 'Var', (61, 66))	('m6A', 'Gene', (20, 23))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
321925	31958696	R-2HG disabled FTO and upregulated m6A level in MYC/CEBPA mRNA, reducing the stability and translation of MYC and CEBPA transcripts.	('m6A', 'Gene', (35, 38))	('disabled', 'NegReg', (6, 14))	('CEBPA', 'Gene', (114, 119))	('reducing', 'NegReg', (64, 72))	('upregulated', 'PosReg', (23, 34))	('MYC', 'Gene', (106, 109))	('FTO', 'Gene', (15, 18))	('CEBPA', 'Gene', '1050', (114, 119))	('m6A', 'Gene', '56339', (35, 38))	('MYC', 'Gene', (48, 51))	('translation', 'MPA', (91, 102))	('MYC', 'Gene', '4609', (106, 109))	('MYC', 'Gene', '4609', (48, 51))	('CEBPA', 'Gene', (52, 57))	('R-2HG', 'Var', (0, 5))	('stability', 'MPA', (77, 86))	('CEBPA', 'Gene', '1050', (52, 57))
321927	31958696	Similarly, in R-2HG-sensitive leukemia cells, mutant IDH1R132H also induced cell-cycle arrest, apoptosis, and proliferation inhibition.	('cell-cycle arrest', 'CPA', (76, 93))	('leukemia', 'Disease', (30, 38))	('leukemia', 'Phenotype', 'HP:0001909', (30, 38))	('leukemia', 'Disease', 'MESH:D007938', (30, 38))	('apoptosis', 'CPA', (95, 104))	('induced', 'Reg', (68, 75))	('IDH1R132H', 'Gene', (53, 62))	('mutant', 'Var', (46, 52))	('proliferation inhibition', 'CPA', (110, 134))
321928	31958696	Besides improving sensitivity to cancer suppressors, FTO also enhances resistance to chemoradiotherapy.	('improving', 'PosReg', (8, 17))	('cancer', 'Disease', (33, 39))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('resistance to chemoradiotherapy', 'CPA', (71, 102))	('FTO', 'Var', (53, 56))	('sensitivity', 'MPA', (18, 29))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('enhances', 'PosReg', (62, 70))
321929	31958696	In cervical squamous cell carcinoma (CSCC) tissues, FTO decreased the m6A level in beta-catenin mRNA transcripts and regulated expression of beta-catenin, thereby promoting activity of excision repair cross-complementation group 1 (ERCC1).	('carcinoma', 'Phenotype', 'HP:0030731', (26, 35))	('squamous cell carcinoma', 'Disease', (12, 35))	('ERCC1', 'Gene', '2067', (232, 237))	('FTO', 'Var', (52, 55))	('cervical', 'Disease', (3, 11))	('m6A', 'Gene', '56339', (70, 73))	('decreased', 'NegReg', (56, 65))	('promoting', 'PosReg', (163, 172))	('excision repair cross-complementation group 1', 'Gene', '2067', (185, 230))	('ERCC1', 'Gene', (232, 237))	('excision repair cross-complementation group 1', 'Gene', (185, 230))	('m6A', 'Gene', (70, 73))	('expression', 'MPA', (127, 137))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (12, 35))	('beta-catenin', 'Gene', (141, 153))	('beta-catenin', 'Gene', '1499', (141, 153))	('activity', 'MPA', (173, 181))	('regulated', 'Reg', (117, 126))	('beta-catenin', 'Gene', (83, 95))	('beta-catenin', 'Gene', '1499', (83, 95))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (12, 35))
321949	31958696	m6A modification provides a new idea for cancer therapy.	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('m6A', 'Gene', '56339', (0, 3))	('modification', 'Var', (4, 16))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('m6A', 'Gene', (0, 3))
321999	31642468	It was confirmed in mouse microglial cell line that amyloid-beta peptide can induce up-regulation of gamma-enolase, which plays a protective role in amyloid-beta-related neurotoxicity.	('gamma-enolase', 'Protein', (101, 114))	('neurotoxicity', 'Disease', (170, 183))	('amyloid-beta peptide', 'Var', (52, 72))	('up-regulation', 'PosReg', (84, 97))	('neurotoxicity', 'Disease', 'MESH:D020258', (170, 183))	('mouse', 'Species', '10090', (20, 25))
322008	31642468	observed that knocking-out gamma-enolase significantly reduced migration of tumour cells.	('gamma-enolase', 'Protein', (27, 40))	('reduced', 'NegReg', (55, 62))	('tumour', 'Phenotype', 'HP:0002664', (76, 82))	('knocking-out', 'Var', (14, 26))	('tumour', 'Disease', 'MESH:D009369', (76, 82))	('rat', 'Species', '10116', (66, 69))	('tumour', 'Disease', (76, 82))
322084	31642468	proposed that the combined detection of Hp, CEA, NSE and CYFRA21-1 could significantly improve the sensitivity and specificity of lung cancer diagnosis and could be used for pathological typing.	('lung cancer', 'Phenotype', 'HP:0100526', (130, 141))	('specificity of lung cancer', 'Disease', (115, 141))	('specificity of lung cancer', 'Disease', 'MESH:D008175', (115, 141))	('CEA', 'Gene', '1048', (44, 47))	('CEA', 'Gene', (44, 47))	('C', 'Chemical', 'MESH:D002244', (57, 58))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('improve', 'PosReg', (87, 94))	('C', 'Chemical', 'MESH:D002244', (44, 45))	('CYFRA21-1', 'Var', (57, 66))
322093	31642468	Compared with patients in stable disease (SD) and progress disease (PD), NSE and LDH level declined in patients who achieved CR + PR.	('C', 'Chemical', 'MESH:D002244', (125, 126))	('declined', 'NegReg', (91, 99))	('patients', 'Species', '9606', (103, 111))	('LDH level', 'MPA', (81, 90))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('patients', 'Species', '9606', (14, 22))	('CR + PR', 'Var', (125, 132))
322094	31642468	Multivariate regression analysis revealed that NSE > 50.324 ng/ml and distant metastases were independent risk factors for patients achieving CR + PR and were independently correlated with worse overall survival (OS).	('metastases', 'Disease', 'MESH:D009362', (78, 88))	('patients', 'Species', '9606', (123, 131))	('metastases', 'Disease', (78, 88))	('overall survival', 'MPA', (195, 211))	('CR + PR', 'Var', (142, 149))	('C', 'Chemical', 'MESH:D002244', (142, 143))
322165	31642468	A combination assay of SCC, CEA, CYFRA21-1 and NSE increased sensitivity to 43.4%, which was still low in diagnosing lung cancer but was higher than any other single tumour marker.	('C', 'Chemical', 'MESH:D002244', (28, 29))	('tumour', 'Disease', 'MESH:D009369', (166, 172))	('tumour', 'Disease', (166, 172))	('lung cancer', 'Disease', (117, 128))	('CEA', 'Gene', (28, 31))	('NSE', 'Gene', (47, 50))	('C', 'Chemical', 'MESH:D002244', (33, 34))	('C', 'Chemical', 'MESH:D002244', (24, 25))	('lung cancer', 'Disease', 'MESH:D008175', (117, 128))	('C', 'Chemical', 'MESH:D002244', (25, 26))	('increased', 'PosReg', (51, 60))	('lung cancer', 'Phenotype', 'HP:0100526', (117, 128))	('sensitivity', 'MPA', (61, 72))	('CEA', 'Gene', '1048', (28, 31))	('SCC', 'Gene', '6317', (23, 26))	('tumour', 'Phenotype', 'HP:0002664', (166, 172))	('CYFRA21-1', 'Var', (33, 42))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('SCC', 'Gene', (23, 26))
322185	31642468	also demonstrated inhibition of glycolysis alleviates LPS-induced ALI in a mouse model in 2016.	('rat', 'Species', '10116', (12, 15))	('alleviates', 'NegReg', (43, 53))	('glycolysis', 'MPA', (32, 42))	('ALI', 'Disease', 'MESH:D055371', (66, 69))	('mouse', 'Species', '10090', (75, 80))	('LPS', 'Gene', '21898', (54, 57))	('inhibition', 'Var', (18, 28))	('LPS', 'Gene', (54, 57))	('ALI', 'Disease', (66, 69))
322201	29617666	Systematic Analysis of Splice-Site-Creating Mutations in Cancer For the past decade, cancer genomic studies have focused on mutations leading to splice-site disruption, overlooking those having splice-creating potential.	('Cancer', 'Disease', (57, 63))	('ding', 'Gene', '6045', (137, 141))	('mutations', 'Var', (124, 133))	('Cancer', 'Disease', 'MESH:D009369', (57, 63))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('cancer', 'Disease', (85, 91))	('Mutations', 'Var', (44, 53))	('ding', 'Gene', (137, 141))	('splice-site disruption', 'MPA', (145, 167))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('Cancer', 'Phenotype', 'HP:0002664', (57, 63))
322204	29617666	Mutations in 11 genes, including PARP1, BRCA1, and BAP1, were experimentally validated for splice-site-creating function.	('BAP1', 'Gene', (51, 55))	('BRCA1', 'Gene', (40, 45))	('BRCA', 'Phenotype', 'HP:0003002', (40, 44))	('PARP1', 'Gene', (33, 38))	('PARP1', 'Gene', '142', (33, 38))	('Mutations', 'Var', (0, 9))	('BRCA1', 'Gene', '672', (40, 45))	('ding', 'Gene', '6045', (28, 32))	('BAP1', 'Gene', '8314', (51, 55))	('ding', 'Gene', (28, 32))
322208	29617666	identify nearly 2,000 splice-site-creating mutations (SCMs) from over 8,000 tumor samples across 33 cancer types.	('000 tumor', 'Disease', (72, 81))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('mutations', 'Var', (43, 52))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('000 tumor', 'Disease', 'MESH:D009369', (72, 81))
322210	29617666	Large-scale sequencing studies, such as The Cancer Genome Atlas (TCGA) project, have worked to address the functional consequences of genomic mutations in tumors, with the larger goal of determining the underlying mechanisms of cancer initiation and progression.	('mutations', 'Var', (142, 151))	('Cancer', 'Disease', (44, 50))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('Cancer', 'Disease', 'MESH:D009369', (44, 50))	('Cancer', 'Phenotype', 'HP:0002664', (44, 50))	('cancer initiation', 'Disease', 'MESH:D009369', (228, 245))	('tumors', 'Phenotype', 'HP:0002664', (155, 161))	('cancer initiation', 'Disease', (228, 245))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('tumors', 'Disease', (155, 161))	('tumors', 'Disease', 'MESH:D009369', (155, 161))
322211	29617666	Many studies have focused on characterizing (1) non-synonymous somatic mutations that alter amino acid sequence and (2) splice-disrupting mutations at splice donors and acceptors.	('donor', 'Species', '9606', (158, 163))	('amino', 'MPA', (92, 97))	('alter', 'Reg', (86, 91))	('mutations', 'Var', (138, 147))
322212	29617666	Current annotation methods typically classify mutations as disruptors of splicing if they fall on either the consensus intronic dinucleotide splice donor, GT, or the splice acceptor, AG.	('mutations', 'Var', (46, 55))	('fall', 'Reg', (90, 94))	('dinucleotide', 'Chemical', 'MESH:D015226', (128, 140))	('splicing', 'MPA', (73, 81))	('fall', 'Phenotype', 'HP:0002527', (90, 94))	('donor', 'Species', '9606', (148, 153))
322213	29617666	One such example is the c.190 mutation in BRCA1.	('BRCA1', 'Gene', '672', (42, 47))	('c.190', 'Var', (24, 29))	('BRCA1', 'Gene', (42, 47))	('BRCA', 'Phenotype', 'HP:0003002', (42, 46))
322214	29617666	Conventional annotation had predicted a missense mutation, p.C64G, but our analysis of RNA sequencing (RNA-seq) data in ovarian tumors harboring p.C64G and a published mouse model suggested the germline c.190 mutation leads to the creation of an alternative splice junction, resulting in a truncated null protein.	('truncated null protein', 'MPA', (290, 312))	('p.C64G', 'Mutation', 'rs80357064', (145, 151))	('p.C64G', 'Mutation', 'rs80357064', (59, 65))	('mouse', 'Species', '10090', (168, 173))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('p.C64G', 'Var', (145, 151))	('ovarian tumors', 'Disease', (120, 134))	('c.190', 'Gene', (203, 208))	('ovarian tumors', 'Phenotype', 'HP:0100615', (120, 134))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('ovarian tumors', 'Disease', 'MESH:D010051', (120, 134))	('alternative splice junction', 'MPA', (246, 273))
322215	29617666	Several case studies have reported observations of missense and silent mutations activating cryptic splice sites in MLH1, LMNA, RB1, RNASEH2A, MECP2, BAP1, and KIT, and other studies relate missense and silent mutations to splicing changes.	('BAP1', 'Gene', (150, 154))	('MLH1', 'Gene', (116, 120))	('RB1', 'Gene', (128, 131))	('silent mutations', 'Var', (64, 80))	('LMNA', 'Gene', (122, 126))	('missense', 'Var', (51, 59))	('MECP2', 'Gene', '4204', (143, 148))	('cryptic', 'Gene', '55997', (92, 99))	('MLH1', 'Gene', '4292', (116, 120))	('cryptic', 'Gene', (92, 99))	('RB1', 'Gene', '5925', (128, 131))	('RNASEH2A', 'Gene', (133, 141))	('LMNA', 'Gene', '4000', (122, 126))	('BAP1', 'Gene', '8314', (150, 154))	('RNASEH2A', 'Gene', '10535', (133, 141))	('activating', 'PosReg', (81, 91))	('MECP2', 'Gene', (143, 148))
322217	29617666	In our large-scale analysis across 8,656 tumor samples, we report 1,964 such somatic mutations that had originally been mis-annotated.	('tumor', 'Disease', (41, 46))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('mutations', 'Var', (85, 94))	('tumor', 'Phenotype', 'HP:0002664', (41, 46))
322221	29617666	We collected high-quality mutation calls from 8,656 tumors across 33 cancer types derived from The Cancer Genome Atlas having available TCGA RNA-seq data (STAR Methods).	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('Cancer', 'Disease', 'MESH:D009369', (99, 105))	('Cancer', 'Disease', (99, 105))	('mutation', 'Var', (26, 34))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('Cancer', 'Phenotype', 'HP:0002664', (99, 105))	('tumors', 'Disease', (52, 58))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Disease', (69, 75))
322222	29617666	For every mutation, we defined a set of control samples in the same cancer cohort that lacked the same mutation in the gene of interest.	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('cancer', 'Disease', (68, 74))	('mutation', 'Var', (10, 18))
322223	29617666	We sought to assess the landscape of SCMs across cancer genomes by evaluating all mutations already having conventional annotations and their potential splice-site-creating effects (Figure 1A).	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('mutations', 'Var', (82, 91))	('cancer', 'Disease', (49, 55))	('cancer', 'Disease', 'MESH:D009369', (49, 55))
322226	29617666	In addition, we found 58 insertions or deletions, 46 nonsense, and 123 non-coding region mutations that likewise create cryptic splicing sites.	('deletions', 'Var', (39, 48))	('ding', 'Gene', '6045', (77, 81))	('insertions', 'Var', (25, 35))	('ding', 'Gene', (77, 81))	('cryptic', 'Gene', '55997', (120, 127))	('mutations', 'Var', (89, 98))	('cryptic', 'Gene', (120, 127))
322227	29617666	Next, we characterized the sequence context for the 1,790 SCMs corresponding to single nucleotide mutations.	('single nucleotide mutations', 'Var', (80, 107))	('ding', 'Gene', (72, 76))	('ding', 'Gene', '6045', (72, 76))
322230	29617666	Mutations at the -3 position of the alternative acceptor site would potentially enhance U2AF1 recognition of the acceptor splice site.	('recognition of the acceptor splice site', 'MPA', (94, 133))	('U2AF1', 'Gene', '7307', (88, 93))	('Mutations', 'Var', (0, 9))	('enhance', 'PosReg', (80, 87))	('U2AF1', 'Gene', (88, 93))
322231	29617666	Previous studies have reported S34F U2AF1 mutants preferentially skip exons that contain a T nucleotide at the -3 position.	('S34F', 'Var', (31, 35))	('mutants', 'Var', (42, 49))	('U2AF1', 'Gene', (36, 41))	('U2AF1', 'Gene', '7307', (36, 41))	('skip', 'NegReg', (65, 69))	('S34F', 'Mutation', 'rs371769427', (31, 35))
322232	29617666	Of the 192 mutations located at the -3 position from the alternative junction and that contain an AG in the -2 and -1 positions, 56% undergo a G > C transversion (21%G > A, 18%G > T,3%C > T,2%A > C, 1% A > T), with C being the preferred base at the -3 position for U2AF1 binding (Figure 2D).	('mutations', 'Var', (11, 20))	('U2AF1', 'Gene', (265, 270))	('U2AF1', 'Gene', '7307', (265, 270))	('ding', 'Gene', '6045', (274, 278))	('undergo', 'Reg', (133, 140))	('18%G > T', 'Mutation', 'c.18G>T', (173, 181))	('ding', 'Gene', (274, 278))	('G > A', 'Var', (166, 171))
322233	29617666	These cases are a good illustration of the fact that many other genomic splicing features are also relevant, including exonic splicing enhancers (ESE), polypyrimidine tract, branch point, and RNA-binding proteins.	('exonic splicing', 'Var', (119, 134))	('ding', 'Gene', (114, 118))	('polypyrimidine tract', 'Var', (152, 172))	('ding', 'Gene', '6045', (199, 203))	('ding', 'Gene', (199, 203))	('ding', 'Gene', '6045', (114, 118))	('polypyrimidine', 'Chemical', '-', (152, 166))
322237	29617666	Both the truncated and normal spliced products can be observed for many variants, due to either the wild-type allele or leaky splicing, for example, as observed in RNASEH2A, NFU1, SMN1, CFTR, and NF2.	('RNASEH2A', 'Gene', (164, 172))	('leaky splicing', 'Var', (120, 134))	('NFU1', 'Gene', '27247', (174, 178))	('CFTR', 'Gene', '1080', (186, 190))	('NF2', 'Gene', '4771', (196, 199))	('RNASEH2A', 'Gene', '10535', (164, 172))	('SMN1', 'Gene', '6606', (180, 184))	('NFU1', 'Gene', (174, 178))	('CFTR', 'Gene', (186, 190))	('SMN1', 'Gene', (180, 184))	('NF2', 'Gene', (196, 199))
322238	29617666	Overall, most of the reads supporting the alternative junction also support the mutation, a finding that suggests a strong association between the mutation and alternative splice junction.	('ding', 'Gene', '6045', (95, 99))	('ding', 'Gene', (95, 99))	('mutation', 'Var', (80, 88))
322239	29617666	Regarding the 5' splice site, mutations within the first 6 bp of the new exon junction have a much higher fraction of alternative junction reads supporting them; and we see an inverse correlation between the mutation and the junction as the distance between them increases.	('ding', 'Gene', '6045', (5, 9))	('ding', 'Gene', (5, 9))	('mutations', 'Var', (30, 39))	('alternative junction reads', 'MPA', (118, 144))
322241	29617666	While most SCMs were found outside the current cancer gene compendium (Table S1), Figure 4A shows that a remarkable number of cancer genes harbor splice altering variants, a phenomenon supported in the literature.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('cancer', 'Disease', (47, 53))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('splice altering variants', 'Var', (146, 170))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))
322242	29617666	A pan-cancer view reveals that TP53 was the most mutated across cancer types, while 18 GATA3 mutations and 6 ATRX mutations were specific to breast cancer (BRCA) and lower-grade glioma (LGG), respectively.	('mutations', 'Var', (114, 123))	('GATA3', 'Gene', '2625', (87, 92))	('ATRX', 'Gene', '546', (109, 113))	('TP53', 'Gene', (31, 35))	('BRCA', 'Gene', '672', (156, 160))	('cancer', 'Disease', 'MESH:D009369', (6, 12))	('breast cancer', 'Phenotype', 'HP:0003002', (141, 154))	('glioma', 'Disease', (178, 184))	('GATA3', 'Gene', (87, 92))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('glioma', 'Disease', 'MESH:D005910', (178, 184))	('cancer', 'Disease', (64, 70))	('breast cancer', 'Disease', 'MESH:D001943', (141, 154))	('BRCA', 'Gene', (156, 160))	('breast cancer', 'Disease', (141, 154))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('mutations', 'Var', (93, 102))	('glioma', 'Phenotype', 'HP:0009733', (178, 184))	('TP53', 'Gene', '7157', (31, 35))	('cancer', 'Disease', (6, 12))	('cancer', 'Disease', (148, 154))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('BRCA', 'Phenotype', 'HP:0003002', (156, 160))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('ATRX', 'Gene', (109, 113))
322243	29617666	We observed 137 mutations nearby to one another (+-5 bp) which lead to the creation of the same recurrent splice-site-creating events, not only in TP53 but also in GATA3, DDX5, KDM6A, SETD2, PTEN, SPOP, and BAP1.	('DDX5', 'Gene', '1655', (171, 175))	('TP53', 'Gene', (147, 151))	('KDM6A', 'Gene', '7403', (177, 182))	('BAP1', 'Gene', '8314', (207, 211))	('PTEN', 'Gene', (191, 195))	('mutations', 'Var', (16, 25))	('PTEN', 'Gene', '5728', (191, 195))	('BAP1', 'Gene', (207, 211))	('GATA3', 'Gene', '2625', (164, 169))	('KDM6A', 'Gene', (177, 182))	('DDX5', 'Gene', (171, 175))	('SETD2', 'Gene', '29072', (184, 189))	('TP53', 'Gene', '7157', (147, 151))	('GATA3', 'Gene', (164, 169))	('SETD2', 'Gene', (184, 189))
322244	29617666	While some mutations did not occur at the same position, 14 mutations creating the same alternative splice junction were found in the same exon, including 2 mutations in the third exon of BAK1.	('BAK1', 'Gene', (188, 192))	('ding', 'Gene', '6045', (150, 154))	('ding', 'Gene', (150, 154))	('mutations', 'Var', (60, 69))	('BAK1', 'Gene', '578', (188, 192))
322245	29617666	While most mutations in close proximity created the same alternative splice junction, two adjacent SCMs in CTNND1 and 2 nearby exonic mutations in ACP2 and GMPPB created different alternative junctions.	('GMPPB', 'Gene', '29925', (156, 161))	('mutations', 'Var', (11, 20))	('created', 'Reg', (40, 47))	('GMPPB', 'Gene', (156, 161))	('ACP2', 'Gene', (147, 151))	('ACP2', 'Gene', '53', (147, 151))	('CTNND1 and 2', 'Gene', '1500;1501', (107, 119))	('alternative splice junction', 'MPA', (57, 84))
322248	29617666	PARP1 inhibitors targeting the catalytic domain disrupt DNA repair mechanisms thereby increasing the effectiveness of chemotherapeutic agents (Figure 4D).	('effectiveness', 'MPA', (101, 114))	('disrupt', 'Reg', (48, 55))	('DNA', 'MPA', (56, 59))	('inhibitors', 'Var', (6, 16))	('PARP1', 'Gene', '142', (0, 5))	('increasing', 'PosReg', (86, 96))	('PARP1', 'Gene', (0, 5))
322249	29617666	Identifying mutations that disrupt inhibitor binding are essential to properly evaluate treatment options.	('ding', 'Gene', (48, 52))	('inhibitor', 'Protein', (35, 44))	('mutations', 'Var', (12, 21))	('ding', 'Gene', '6045', (48, 52))
322250	29617666	MiSplice identified a conventionally annotated silent PARP1 mutation (p.S939S) in a lung squamous cell carcinoma (LUSC) patient that acts as a splice-site-creating variant by creating a de novo donor site (Figure 5A).	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (84, 112))	('lung squamous cell carcinoma', 'Disease', (84, 112))	('donor', 'Species', '9606', (194, 199))	('LUSC', 'Phenotype', 'HP:0030359', (114, 118))	('patient', 'Species', '9606', (120, 127))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (84, 112))	('PARP1', 'Gene', '142', (54, 59))	('p.S939S', 'Var', (70, 77))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (89, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('PARP1', 'Gene', (54, 59))	('p.S939S', 'Mutation', 'p.S939S', (70, 77))
322252	29617666	Out of 173 LUSC control samples, none contained reads supporting the alternative junction, providing strong evidence that the annotated ''silent'' mutation is actually a SCM.	('mutation', 'Var', (147, 155))	('ding', 'Gene', (96, 100))	('LUSC', 'Phenotype', 'HP:0030359', (11, 15))	('ding', 'Gene', '6045', (96, 100))
322253	29617666	Previous reports of missense mutations at p.940 are predicted to reduce PARP1 enzymatic activity by disrupting the binding affinity of PARP1 to its substrate NAD+.	('missense mutations at p.940', 'Var', (20, 47))	('PARP1', 'Gene', '142', (72, 77))	('ding', 'Gene', (118, 122))	('PARP1', 'Gene', (72, 77))	('PARP1', 'Gene', '142', (135, 140))	('PARP1', 'Gene', (135, 140))	('NAD+', 'Chemical', 'MESH:D009243', (158, 162))	('disrupting', 'NegReg', (100, 110))	('p.940', 'Var', (42, 47))	('reduce', 'NegReg', (65, 71))	('enzymatic activity', 'MPA', (78, 96))	('ding', 'Gene', '6045', (118, 122))
322255	29617666	We identified two kidney renal clear cell carcinoma (KIRC) samples having the same conventionally annotated missense mutation (c.233A > G, p.N78S) in BAP1, a nuclear deubiquitinase, that created the same spliced-out alternative splicing product (Figure 5B).	('BAP1', 'Gene', (150, 154))	('kidney renal clear cell carcinoma', 'Disease', 'MESH:C538614', (18, 51))	('c.233A > G', 'Var', (127, 137))	('kidney renal clear cell carcinoma', 'Disease', (18, 51))	('c.233A > G', 'Mutation', 'rs1319729011', (127, 137))	('BAP1', 'Gene', '8314', (150, 154))	('p.N78S', 'Mutation', 'rs1319729011', (139, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (42, 51))
322256	29617666	Inactivation of BAP1 is prevalent among renal cell carcinomas and an annotated missense mutation (p.L570V) has been reported to create a cryptic splice site in melanoma.	('renal cell carcinomas', 'Disease', 'MESH:C538614', (40, 61))	('p.L570V', 'Var', (98, 105))	('melanoma', 'Phenotype', 'HP:0002861', (160, 168))	('carcinomas', 'Phenotype', 'HP:0030731', (51, 61))	('melanoma', 'Disease', (160, 168))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (40, 61))	('cryptic', 'Gene', '55997', (137, 144))	('melanoma', 'Disease', 'MESH:D008545', (160, 168))	('cryptic', 'Gene', (137, 144))	('BAP1', 'Gene', '8314', (16, 20))	('renal cell carcinomas', 'Disease', (40, 61))	('p.L570V', 'Mutation', 'p.L570V', (98, 105))	('Inactivation', 'Var', (0, 12))	('BAP1', 'Gene', (16, 20))	('prevalent', 'Reg', (24, 33))	('carcinoma', 'Phenotype', 'HP:0030731', (51, 60))
322257	29617666	This result suggests the conventionally annotated missense mutations in BAP1 likely create an alternatively spliced transcript that is not readily expressed at the protein level.	('BAP1', 'Gene', (72, 76))	('BAP1', 'Gene', '8314', (72, 76))	('missense mutations', 'Var', (50, 68))	('create', 'Reg', (84, 90))
322258	29617666	We used a pCAS2.1 splicing reporter mini-gene functional assay that was adapted from previous publications, to validate SCMs in 11 cancer genes, including two originally annotated silent mutations in PARP1, RAD51C, two splice site mutations in TP53 and BRCA1, and several missense mutations in ARID2, BAP1, BCOR, CDH1, KMT2A, PTEN, and TSC2.	('TP53', 'Gene', (244, 248))	('RAD51C', 'Gene', '5889', (207, 213))	('BAP1', 'Gene', '8314', (301, 305))	('ding', 'Gene', (150, 154))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('CDH1', 'Gene', '999', (313, 317))	('RAD51C', 'Gene', (207, 213))	('PARP1', 'Gene', (200, 205))	('KMT2A', 'Gene', (319, 324))	('ding', 'Gene', '6045', (150, 154))	('ARID2', 'Gene', '196528', (294, 299))	('TSC2', 'Gene', '7249', (336, 340))	('BAP1', 'Gene', (301, 305))	('TP53', 'Gene', '7157', (244, 248))	('CDH1', 'Gene', (313, 317))	('BCOR', 'Gene', '54880', (307, 311))	('BRCA', 'Phenotype', 'HP:0003002', (253, 257))	('BRCA1', 'Gene', '672', (253, 258))	('PTEN', 'Gene', (326, 330))	('BRCA1', 'Gene', (253, 258))	('ARID2', 'Gene', (294, 299))	('TSC2', 'Gene', (336, 340))	('cancer', 'Disease', (131, 137))	('BCOR', 'Gene', (307, 311))	('PARP1', 'Gene', '142', (200, 205))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('missense mutations', 'Var', (272, 290))	('KMT2A', 'Gene', '4297', (319, 324))	('PTEN', 'Gene', '5728', (326, 330))
322260	29617666	Examining the change in the MaxEntScan score for the 11 genes revealed mutations in ARID2, BAP1, BCOR, CDH1, PARP1, RAD51C, PTEN, and TSC2 having dramatically stronger splice scores in the presence of the mutation, while mutations in BRCA1, KMT2A, and TP53 did not (Figure 5D).	('BRCA1', 'Gene', '672', (234, 239))	('BAP1', 'Gene', (91, 95))	('CDH1', 'Gene', (103, 107))	('PTEN', 'Gene', (124, 128))	('BRCA1', 'Gene', (234, 239))	('BCOR', 'Gene', '54880', (97, 101))	('KMT2A', 'Gene', (241, 246))	('stronger', 'PosReg', (159, 167))	('TP53', 'Gene', (252, 256))	('BCOR', 'Gene', (97, 101))	('TSC2', 'Gene', (134, 138))	('PTEN', 'Gene', '5728', (124, 128))	('RAD51C', 'Gene', '5889', (116, 122))	('mutations', 'Var', (71, 80))	('PARP1', 'Gene', '142', (109, 114))	('BRCA', 'Phenotype', 'HP:0003002', (234, 238))	('ARID2', 'Gene', '196528', (84, 89))	('splice scores', 'MPA', (168, 181))	('RAD51C', 'Gene', (116, 122))	('TP53', 'Gene', '7157', (252, 256))	('BAP1', 'Gene', '8314', (91, 95))	('KMT2A', 'Gene', '4297', (241, 246))	('mutation', 'Var', (205, 213))	('ARID2', 'Gene', (84, 89))	('CDH1', 'Gene', '999', (103, 107))	('TSC2', 'Gene', '7249', (134, 138))	('PARP1', 'Gene', (109, 114))
322261	29617666	Except for PTEN, variants with stronger splice scores showed higher levels of the alternatively spliced product in the mini-gene assay when compared to the wild-type.	('PTEN', 'Gene', (11, 15))	('PTEN', 'Gene', '5728', (11, 15))	('variants', 'Var', (17, 25))	('higher', 'PosReg', (61, 67))	('levels', 'MPA', (68, 74))
322263	29617666	We found that alternative splice forms for some important genes related to tumorigenesis, including SMARC1, KDM6A, and NOTCH1, are highly immunogenic and can contain 40 or more unique neoantigens (Figure 6A).	('alternative splice forms', 'Var', (14, 38))	('SMARC1', 'Gene', (100, 106))	('ding', 'Gene', '6045', (95, 99))	('neoantigens', 'MPA', (184, 195))	('NOTCH1', 'Gene', '4851', (119, 125))	('NOTCH1', 'Gene', (119, 125))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('KDM6A', 'Gene', (108, 113))	('ding', 'Gene', (95, 99))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('KDM6A', 'Gene', '7403', (108, 113))	('tumor', 'Disease', (75, 80))	('contain', 'Reg', (158, 165))
322264	29617666	In addition, the mean number of neoantigens across SCMs from NetMHCpan-4.0 and NetMHCpan-3.0 are 2.0 and 2.5, respectively, which are both higher than the average number of around 1 for non-synonymous mutations.	('NetMHCpan', 'Chemical', '-', (61, 70))	('NetMHCpan', 'Chemical', '-', (79, 88))	('NetMHCpan-3.0', 'Var', (79, 92))	('NetMHCpan-4.0', 'Gene', (61, 74))
322273	29617666	Our analysis shows MiSplice reliably identifies SCMs across multiple cancer types.	('SCMs', 'Disease', (48, 52))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('MiSplice', 'Var', (19, 27))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('identifies', 'Reg', (37, 47))	('cancer', 'Disease', (69, 75))
322275	29617666	Many important cancer-related genes harbor these mutations, such as TP53, ATRX, BAP1, CTNNB1, RB1, etc.	('mutations', 'Var', (49, 58))	('RB1', 'Gene', (94, 97))	('cancer', 'Disease', (15, 21))	('cancer', 'Disease', 'MESH:D009369', (15, 21))	('ATRX', 'Gene', '546', (74, 78))	('BAP1', 'Gene', '8314', (80, 84))	('RB1', 'Gene', '5925', (94, 97))	('CTNNB1', 'Gene', (86, 92))	('BAP1', 'Gene', (80, 84))	('TP53', 'Gene', '7157', (68, 72))	('TP53', 'Gene', (68, 72))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('ATRX', 'Gene', (74, 78))	('CTNNB1', 'Gene', '1499', (86, 92))
322277	29617666	A previous study has shown that loss of wild-type ATRX is associated with tumor growth in glioma.	('ATRX', 'Gene', '546', (50, 54))	('glioma', 'Disease', (90, 96))	('associated', 'Reg', (58, 68))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('glioma', 'Disease', 'MESH:D005910', (90, 96))	('glioma', 'Phenotype', 'HP:0009733', (90, 96))	('loss', 'Var', (32, 36))	('tumor', 'Disease', (74, 79))	('ATRX', 'Gene', (50, 54))
322278	29617666	This suggests silent and missense mutations instead act as modifiers of splicing by creating or strengthening cryptic sites within the exon as opposed to disrupting the canonical splice site.	('cryptic', 'Gene', (110, 117))	('silent', 'Var', (14, 20))	('canonical splice site', 'MPA', (169, 190))	('missense mutations', 'Var', (25, 43))	('strengthening', 'PosReg', (96, 109))	('cryptic', 'Gene', '55997', (110, 117))
322280	29617666	For example, we found high concordance for RNA-seq reads supporting alternatively spliced junctions and mutations, suggesting the association between mutations and cryptic splicing forms.	('cryptic', 'Gene', '55997', (164, 171))	('mutations', 'Var', (104, 113))	('cryptic', 'Gene', (164, 171))
322281	29617666	These events were conventionally annotated as missense, silent, splice site, nonsense, or other mutations when, in fact, we have shown that they often create cryptic splice sites.	('missense', 'Var', (46, 54))	('mutations', 'Var', (96, 105))	('cryptic', 'Gene', (158, 165))	('cryptic', 'Gene', '55997', (158, 165))
322282	29617666	This relative abundance of the alternative and wild-type product suggests varying levels of junction usage, depending on the context of the mutation, and emphasizes the importance of validating predictions using a functional assay to understand the full biological consequence.	('ding', 'Gene', (113, 117))	('ding', 'Gene', '6045', (113, 117))	('mutation', 'Var', (140, 148))
322299	29617666	It executes the following steps:  For each cryptic splice site and nearby canonical splice site, the corresponding nucleotide sequences were first extracted for both the mutant and reference sequences (9-mer and 23-mer for donor and acceptor, respectively).	('cryptic', 'Gene', '55997', (43, 50))	('ding', 'Gene', '6045', (110, 114))	('cryptic', 'Gene', (43, 50))	('mutant', 'Var', (170, 176))	('ding', 'Gene', (110, 114))	('donor', 'Species', '9606', (223, 228))
322313	29617666	MiSplice applied to PanCancer data identifies 1,964 splice-site-creating mutations 26% and 11% of SCMs had been previously mis-annotated as missense and silent mutations SCMs may be more immunogenic than are missense mutations A mini-gene functional assay validates 10 of 11 predicted SCMs	('missense', 'Var', (140, 148))	('Cancer', 'Disease', (23, 29))	('Cancer', 'Disease', 'MESH:D009369', (23, 29))	('Cancer', 'Phenotype', 'HP:0002664', (23, 29))	('immunogenic', 'CPA', (187, 198))	('more', 'PosReg', (182, 186))	('mutations', 'Var', (73, 82))
322318	29844930	Here, we show that NOS2 ablation inhibits macrophage infiltration, fibrosis, and SCC development in the lungs of KA/KA mice.	('SCC', 'Gene', '6317', (81, 84))	('mice', 'Species', '10090', (119, 123))	('fibrosis', 'Disease', 'MESH:D005355', (67, 75))	('macrophage infiltration', 'CPA', (42, 65))	('NOS2', 'Gene', (19, 23))	('inhibits', 'NegReg', (33, 41))	('SCC', 'Gene', (81, 84))	('SCC', 'Phenotype', 'HP:0002860', (81, 84))	('ablation', 'Var', (24, 32))	('fibrosis', 'Disease', (67, 75))
322322	29844930	This finding sheds light on a new mechanism by which macrophage NOS2 increases pulmonary inflammatory responses and macrophage survival and impairs macrophage lipid metabolism, thereby promoting lung SCC formation.	('SCC', 'Gene', '6317', (200, 203))	('pulmonary inflammatory responses', 'CPA', (79, 111))	('increases', 'PosReg', (69, 78))	('impairs', 'NegReg', (140, 147))	('macrophage survival', 'CPA', (116, 135))	('lipid', 'Chemical', 'MESH:D008055', (159, 164))	('macrophage', 'Var', (53, 63))	('NOS2', 'Gene', (64, 68))	('SCC', 'Gene', (200, 203))	('macrophage lipid metabolism', 'MPA', (148, 175))	('SCC', 'Phenotype', 'HP:0002860', (200, 203))	('promoting', 'PosReg', (185, 194))
322344	29844930	In this study, we show that NOS2 ablation inhibits pulmonary inflammation, lung epithelial cell overgrowth, and lung SCC development associated with markedly decreased pulmonary macrophage/foamy macrophage numbers in KA/KA mice.	('NOS2', 'Gene', (28, 32))	('decreased', 'NegReg', (158, 167))	('pulmonary macrophage/foamy macrophage numbers', 'CPA', (168, 213))	('inhibits', 'NegReg', (42, 50))	('ablation', 'Var', (33, 41))	('SCC', 'Gene', (117, 120))	('pulmonary inflammation', 'Disease', 'MESH:D011014', (51, 73))	('mice', 'Species', '10090', (223, 227))	('SCC', 'Phenotype', 'HP:0002860', (117, 120))	('SCC', 'Gene', '6317', (117, 120))	('overgrowth', 'Phenotype', 'HP:0001548', (96, 106))	('pulmonary inflammation', 'Disease', (51, 73))	('foamy macrophage', 'Phenotype', 'HP:0003651', (189, 205))	('lung epithelial cell overgrowth', 'CPA', (75, 106))
322347	29844930	Together, these results reveal a crucial role of macrophage NOS2 for circulating inflammatory responses and promoting lung SCC development.	('SCC', 'Phenotype', 'HP:0002860', (123, 126))	('SCC', 'Gene', '6317', (123, 126))	('promoting', 'PosReg', (108, 117))	('macrophage', 'Var', (49, 59))	('circulating inflammatory responses', 'CPA', (69, 103))	('SCC', 'Gene', (123, 126))
322352	29844930	Lung SCCs derived from KA/KA and KA/KA;Nos2-/- mice expressed K5 and TRIM29, but NOS2 deletion reduced TRIM29 and COX2 expression in KA/KA lungs (Fig.	('TRIM29', 'Gene', (69, 75))	('SCC', 'Gene', '6317', (5, 8))	('expression', 'MPA', (119, 129))	('COX2', 'Gene', '17709', (114, 118))	('K5', 'Gene', '110308', (62, 64))	('mice', 'Species', '10090', (47, 51))	('deletion', 'Var', (86, 94))	('Nos2', 'Gene', (39, 43))	('SCC', 'Gene', (5, 8))	('reduced', 'NegReg', (95, 102))	('TRIM29', 'Gene', (103, 109))	('TRIM29', 'Gene', '72169', (103, 109))	('TRIM29', 'Gene', '72169', (69, 75))	('NOS2', 'Gene', (81, 85))	('Nos2', 'Gene', '18126', (39, 43))	('SCC', 'Phenotype', 'HP:0002860', (5, 8))	('COX2', 'Gene', (114, 118))
322358	29844930	Together, these results suggest that NOS2 deletion decreases lung SCC incidence.	('SCC', 'Gene', (66, 69))	('SCC', 'Phenotype', 'HP:0002860', (66, 69))	('decreases', 'NegReg', (51, 60))	('SCC', 'Gene', '6317', (66, 69))	('NOS2', 'Gene', (37, 41))	('deletion', 'Var', (42, 50))
322360	29844930	Ki67-stained proliferative cells in the basal layer of upper airway epithelium were significantly increased in KA/KA lungs, compared to WT lungs, and NOS2 deletion decreased Ki67-positive basal epithelial cells in the upper airways of KA/KA;Nos2-/- lungs compared to KA/KA lungs (Fig.	('Ki67', 'Gene', '17345', (174, 178))	('decreased', 'NegReg', (164, 173))	('Ki67', 'Gene', '17345', (0, 4))	('Nos2', 'Gene', (241, 245))	('Nos2', 'Gene', '18126', (241, 245))	('Ki67', 'Gene', (0, 4))	('increased', 'PosReg', (98, 107))	('Ki67', 'Gene', (174, 178))	('deletion', 'Var', (155, 163))	('NOS2', 'Gene', (150, 154))
322364	29844930	Masson's trichrome staining for collagen, a fibrosis marker, showed increased collagen staining in KA/KA lungs compared to WT and that NOS2 deletion reduced collagen expression (Fig.	('fibrosis', 'Disease', 'MESH:D005355', (44, 52))	('NOS2', 'Gene', (135, 139))	('reduced', 'NegReg', (149, 156))	('collagen expression', 'MPA', (157, 176))	('increased', 'PosReg', (68, 77))	('deletion', 'Var', (140, 148))	('fibrosis', 'Disease', (44, 52))	('collagen staining', 'MPA', (78, 95))
322367	29844930	NOS2 deletion-mediated changes include reduced expression of many chemokines (CXC and CC), cytokines (IL), matrix metalloproteinases, stemness cell markers, cell cycle/mitogenic activators, and TNF and Jak inflammatory signaling pathways, but increased molecules that were involved in regulating cellular events, such as cell growth and adhesion (Fig.	('chemokines', 'MPA', (66, 76))	('molecules', 'MPA', (253, 262))	('deletion-mediated', 'Var', (5, 22))	('stemness', 'Disease', (134, 142))	('stemness', 'Disease', 'MESH:D020295', (134, 142))	('cytokines', 'MPA', (91, 100))	('increased', 'PosReg', (243, 252))	('TNF', 'Gene', (194, 197))	('reduced', 'NegReg', (39, 46))	('NOS2', 'Gene', (0, 4))	('expression', 'MPA', (47, 57))	('TNF', 'Gene', '21926', (194, 197))
322368	29844930	These major inflammation-related molecular alterations may contribute to the reduction of lung SCC and fibrosis development although KA/KA;Nos2-/- mice still remain other phenotypes.	('inflammation', 'Disease', 'MESH:D007249', (12, 24))	('mice', 'Species', '10090', (147, 151))	('inflammation', 'Disease', (12, 24))	('Nos2', 'Gene', (139, 143))	('fibrosis', 'Disease', (103, 111))	('fibrosis', 'Disease', 'MESH:D005355', (103, 111))	('alterations', 'Var', (43, 54))	('reduction of lung SCC', 'Disease', (77, 98))	('reduction of lung SCC', 'Disease', 'MESH:D008171', (77, 98))	('SCC', 'Phenotype', 'HP:0002860', (95, 98))	('Nos2', 'Gene', '18126', (139, 143))
322372	29844930	Flow cytometric analysis revealed that KA/KA lungs had markedly increased numbers of CD45+CD11b+Gr-1- macrophages compared to WT and that NOS2 deletion significantly reduced macrophage numbers in KA/KA;Nos2-/- lungs (Fig.	('Nos2', 'Gene', '18126', (202, 206))	('NOS2', 'Gene', (138, 142))	('CD11b', 'Gene', (90, 95))	('reduced', 'NegReg', (166, 173))	('deletion', 'Var', (143, 151))	('CD11b', 'Gene', '16409', (90, 95))	('CD45', 'Gene', (85, 89))	('CD45', 'Gene', '19264', (85, 89))	('increased', 'PosReg', (64, 73))	('macrophage numbers', 'CPA', (174, 192))	('Nos2', 'Gene', (202, 206))
322373	29844930	We observed many large foamy macrophages that are characterized by a pink color and needle-shaped crystalline bodies in the cytoplasm due to lipid protein accumulation in KA/KA lungs but not in WT lungs, as examined by hematoxylin and eosin (H&E) histological examination (Fig.	('accumulation', 'PosReg', (155, 167))	('foamy macrophages', 'Phenotype', 'HP:0003651', (23, 40))	('hematoxylin', 'Chemical', 'MESH:D006416', (219, 230))	('lipid protein', 'MPA', (141, 154))	('foamy macrophage', 'Phenotype', 'HP:0003651', (23, 39))	('lipid', 'Chemical', 'MESH:D008055', (141, 146))	('eosin', 'Chemical', 'MESH:D004801', (235, 240))	('KA/KA', 'Var', (171, 176))	('H&E', 'Chemical', '-', (242, 245))	('needle-shaped crystalline bodies', 'CPA', (84, 116))
322375	29844930	NOS2 deletion reduced foamy macrophage numbers and sizes in KA/KA;Nos2-/- lungs compared to KA/KA (Fig.	('reduced', 'NegReg', (14, 21))	('deletion', 'Var', (5, 13))	('Nos2', 'Gene', (66, 70))	('foamy macrophage numbers', 'CPA', (22, 46))	('Nos2', 'Gene', '18126', (66, 70))	('foamy macrophage', 'Phenotype', 'HP:0003651', (22, 38))	('NOS2', 'Gene', (0, 4))
322377	29844930	NOS2 deletion attenuated the intensity of oil red staining in the macrophages and reduced the foamy macrophage numbers, suggesting that NOS2-mediated changes modulate lipid metabolism in the macrophages.	('foamy macrophage', 'Phenotype', 'HP:0003651', (94, 110))	('foamy macrophage numbers', 'CPA', (94, 118))	('deletion', 'Var', (5, 13))	('attenuated', 'NegReg', (14, 24))	('oil red staining', 'MPA', (42, 58))	('lipid metabolism', 'MPA', (167, 183))	('modulate', 'Reg', (158, 166))	('oil red', 'Chemical', 'MESH:C009213', (42, 49))	('reduced', 'NegReg', (82, 89))	('NOS2', 'Gene', (0, 4))	('intensity', 'MPA', (29, 38))	('lipid', 'Chemical', 'MESH:D008055', (167, 172))
322385	29844930	NOS2 deletion markedly reduced Ym-1 expression in KA/KA macrophages.	('Ym-1', 'Gene', '12655', (31, 35))	('deletion', 'Var', (5, 13))	('Ym-1', 'Gene', (31, 35))	('reduced', 'NegReg', (23, 30))	('NOS2', 'Gene', (0, 4))
322388	29844930	KA/KA and KA/KA;Nos2-/- macrophages expressed comparable levels of arginase 1, another M2 macrophage marker, and treatment with LPS decreased expression of arginase 1 in KA/KA;Nos2-/- and WT macrophages (Fig.	('arginase 1', 'Gene', '11846', (67, 77))	('arginase 1', 'Gene', '11846', (156, 166))	('LPS', 'Gene', '21898', (128, 131))	('arginase 1', 'Gene', (156, 166))	('arginase 1', 'Gene', (67, 77))	('KA/KA', 'Var', (170, 175))	('LPS', 'Gene', (128, 131))	('Nos2', 'Gene', (176, 180))	('Nos2', 'Gene', '18126', (176, 180))	('decreased', 'NegReg', (132, 141))	('expression', 'MPA', (142, 152))	('Nos2', 'Gene', (16, 20))	('Nos2', 'Gene', '18126', (16, 20))
322389	29844930	Of note, the effect of LPS treatment on reduced Ym-1 and arginase 1 expression was more in KA/KA;Nos2-/- macrophages than in KA/KA macrophages, suggesting that NOS2 deletion may reduce the macrophage potential in response to inflammation.	('macrophage potential in response to', 'CPA', (189, 224))	('Ym-1', 'Gene', '12655', (48, 52))	('inflammation', 'Disease', 'MESH:D007249', (225, 237))	('arginase 1', 'Gene', '11846', (57, 67))	('expression', 'MPA', (68, 78))	('NOS2', 'Gene', (160, 164))	('arginase 1', 'Gene', (57, 67))	('inflammation', 'Disease', (225, 237))	('reduce', 'NegReg', (178, 184))	('Nos2', 'Gene', (97, 101))	('Nos2', 'Gene', '18126', (97, 101))	('reduced', 'NegReg', (40, 47))	('LPS', 'Gene', '21898', (23, 26))	('deletion', 'Var', (165, 173))	('Ym-1', 'Gene', (48, 52))	('LPS', 'Gene', (23, 26))
322396	29844930	The analysis showed increased expression of multiple cytokines in KA/KA compared to KA/KA;Nos2-/- peritoneal macrophages (Fig.	('increased', 'PosReg', (20, 29))	('expression', 'MPA', (30, 40))	('KA/KA', 'Var', (66, 71))	('Nos2', 'Gene', (90, 94))	('Nos2', 'Gene', '18126', (90, 94))
322401	29844930	6a, bottom panel), suggesting that NOS2 deletion-mediated Cxcl5 induction may contribute to the reduction of foamy macrophage numbers.	('Cxcl5', 'Gene', '20311', (58, 63))	('foamy macrophage', 'Phenotype', 'HP:0003651', (109, 125))	('deletion-mediated', 'Var', (40, 57))	('NOS2', 'Gene', (35, 39))	('Cxcl5', 'Gene', (58, 63))	('foamy macrophage numbers', 'CPA', (109, 133))	('reduction', 'NegReg', (96, 105))
322402	29844930	To determine a physiological effect of macrophage NOS2 deletion on lung SCC development, we performed BM transplant experiments by injecting KA/KA BM cells into irradiated KA/KA mice or KA/KA;Nos2-/- mice, or by injecting KA/KA;Nos2-/- BM cells into irradiated KA/KA mice or KA/KA;Nos2-/- mice (Fig.	('Nos2', 'Gene', '18126', (192, 196))	('mice', 'Species', '10090', (178, 182))	('NOS2', 'Gene', (50, 54))	('mice', 'Species', '10090', (289, 293))	('SCC', 'Gene', (72, 75))	('SCC', 'Phenotype', 'HP:0002860', (72, 75))	('Nos2', 'Gene', (228, 232))	('mice', 'Species', '10090', (200, 204))	('Nos2', 'Gene', '18126', (228, 232))	('deletion', 'Var', (55, 63))	('Nos2', 'Gene', '18126', (281, 285))	('SCC', 'Gene', '6317', (72, 75))	('Nos2', 'Gene', (281, 285))	('mice', 'Species', '10090', (267, 271))	('Nos2', 'Gene', (192, 196))
322410	29844930	In this study, we demonstrate that macrophage NOS2 promotes lung SCC development by circulating inflammatory signaling, enhancing macrophage migration and survival, and impairing lipid metabolism.	('circulating inflammatory signaling', 'MPA', (84, 118))	('SCC', 'Gene', (65, 68))	('enhancing', 'PosReg', (120, 129))	('lipid', 'Chemical', 'MESH:D008055', (179, 184))	('NOS2', 'Gene', (46, 50))	('macrophage', 'Var', (35, 45))	('impairing', 'NegReg', (169, 178))	('lipid metabolism', 'MPA', (179, 195))	('survival', 'CPA', (155, 163))	('SCC', 'Gene', '6317', (65, 68))	('SCC', 'Phenotype', 'HP:0002860', (65, 68))	('promotes', 'PosReg', (51, 59))	('macrophage migration', 'CPA', (130, 150))
322411	29844930	Our results also explain that an increased inflammatory microenvironment can induce NOS2 expression in KA/KA lungs; in turn, NOS2 circulates inflammatory signals between macrophages and epithelial cells, promoting carcinogenesis.	('carcinogenesis', 'Disease', (214, 228))	('circulates inflammatory signals', 'MPA', (130, 161))	('increased inflammatory microenvironment', 'Phenotype', 'HP:0012649', (33, 72))	('promoting', 'PosReg', (204, 213))	('NOS2', 'Gene', (84, 88))	('NOS2', 'Var', (125, 129))	('carcinogenesis', 'Disease', 'MESH:D063646', (214, 228))
322412	29844930	Although we demonstrated that macrophage NOS2 promoted lung SCC development in KA/KA mice, BM transplant experiments showed that NOS2 deletion in the epithelial cells reduced lung tumorigenesis associated with decreased infiltrating macrophage numbers in the lungs of irradiated KA/KA;Nos2-/- mice receiving KA/KA BM, compared to irradiated KA/KA mice receiving KA/KA BM, suggesting that epithelial cell NOS2 is required for circulating inflammation.	('Nos2', 'Gene', (285, 289))	('SCC', 'Gene', '6317', (60, 63))	('mice', 'Species', '10090', (347, 351))	('lung tumor', 'Disease', (175, 185))	('decreased', 'NegReg', (210, 219))	('lung tumor', 'Phenotype', 'HP:0100526', (175, 185))	('SCC', 'Gene', (60, 63))	('infiltrating macrophage numbers', 'CPA', (220, 251))	('mice', 'Species', '10090', (85, 89))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('deletion', 'Var', (134, 142))	('reduced', 'NegReg', (167, 174))	('inflammation', 'Disease', 'MESH:D007249', (437, 449))	('lung tumor', 'Disease', 'MESH:D008175', (175, 185))	('SCC', 'Phenotype', 'HP:0002860', (60, 63))	('Nos2', 'Gene', '18126', (285, 289))	('inflammation', 'Disease', (437, 449))	('NOS2', 'Gene', (129, 133))	('mice', 'Species', '10090', (293, 297))
322413	29844930	Furthermore, Ki67-stained proliferating basal cells of the lung bronchi in KA/KA;Nos2-/- mice were significantly decreased compared to KA/KA lungs, suggesting that NOS2 deletion reduces the basal cell growth in the lung bronchi or that NOS2 promotes epithelial cell growth in KA/KA lungs through a loop of inflammatory cells and epithelial cells.	('NOS2', 'Gene', (164, 168))	('reduces', 'NegReg', (178, 185))	('epithelial cell growth', 'CPA', (250, 272))	('deletion', 'Var', (169, 177))	('mice', 'Species', '10090', (89, 93))	('Ki67', 'Gene', (13, 17))	('promotes', 'PosReg', (241, 249))	('Ki67', 'Gene', '17345', (13, 17))	('basal cell growth in the lung bronchi', 'CPA', (190, 227))	('Nos2', 'Gene', (81, 85))	('Nos2', 'Gene', '18126', (81, 85))
322415	29844930	NOS2 deletion decreased the expression of Ym-1 in KA/KA;Nos2-/- macrophages compared to KA/KA macrophages and LPS treatment in vitro further reduced Ym-1 and arginase 1 expression in KA/KA;Nos2-/- macrophages, indicating that NOS2 deletion attenuates the M2 potential of KA/KA macrophages, as well as reduces responses to inflammatory signaling in macrophages in vivo.	('deletion', 'Var', (231, 239))	('LPS', 'Gene', '21898', (110, 113))	('Nos2', 'Gene', '18126', (189, 193))	('LPS', 'Gene', (110, 113))	('Nos2', 'Gene', (56, 60))	('expression', 'MPA', (169, 179))	('NOS2', 'Gene', (0, 4))	('responses to inflammatory signaling in macrophages', 'MPA', (309, 359))	('M2 potential', 'MPA', (255, 267))	('Nos2', 'Gene', (189, 193))	('Ym-1', 'Gene', '12655', (149, 153))	('Ym-1', 'Gene', (42, 46))	('reduces', 'NegReg', (301, 308))	('deletion', 'Var', (5, 13))	('decreased', 'NegReg', (14, 23))	('reduced', 'NegReg', (141, 148))	('attenuates', 'NegReg', (240, 250))	('arginase 1', 'Gene', (158, 168))	('NOS2', 'Gene', (226, 230))	('Ym-1', 'Gene', '12655', (42, 46))	('expression', 'MPA', (28, 38))	('arginase 1', 'Gene', '11846', (158, 168))	('Nos2', 'Gene', '18126', (56, 60))	('Ym-1', 'Gene', (149, 153))
322420	29844930	NOS2 deletion reduced foamy macrophage numbers and sizes and NOS2 null BM transplantation reduced lung tumorigenesis with decreased pulmonary macrophage infiltration, suggesting that increased NOS2 may impair the lipid metabolism in macrophages during lung carcinogenesis.	('decreased pulmonary macrophage infiltration', 'Disease', (122, 165))	('lipid', 'Chemical', 'MESH:D008055', (213, 218))	('reduced', 'NegReg', (14, 21))	('deletion', 'Var', (5, 13))	('reduced', 'NegReg', (90, 97))	('decreased pulmonary macrophage infiltration', 'Disease', 'MESH:D017254', (122, 165))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('impair', 'NegReg', (202, 208))	('lung tumor', 'Disease', 'MESH:D008175', (98, 108))	('foamy macrophage', 'Phenotype', 'HP:0003651', (22, 38))	('lung tumor', 'Disease', (98, 108))	('NOS2', 'Gene', (0, 4))	('lipid metabolism in macrophages', 'MPA', (213, 244))	('lung carcinogenesis', 'Disease', (252, 271))	('NOS2', 'Gene', (61, 65))	('lung tumor', 'Phenotype', 'HP:0100526', (98, 108))	('lung carcinogenesis', 'Disease', 'MESH:D063646', (252, 271))
322422	29844930	NOS2 deletion increased Cxcl5 expression in KA/KA macrophages, suggesting that NOS2's effect on the macrophage property may be associated with Cxcl5 regulation.	('increased', 'PosReg', (14, 23))	('deletion', 'Var', (5, 13))	('Cxcl5', 'Gene', '20311', (143, 148))	('Cxcl5', 'Gene', '20311', (24, 29))	('Cxcl5', 'Gene', (143, 148))	('Cxcl5', 'Gene', (24, 29))	('NOS2', 'Gene', (0, 4))
322427	29844930	L-IkkalphaKA/KA (KA/KA) mice express a kinase-dead IKKalpha with an amino acid K44 > A44 substitution, and also specifically express a WT IKKalpha in the skin under the loricrin promoter control for protecting the skin integrity, which was previously described.	('IKKalpha', 'Gene', (138, 146))	('mice', 'Species', '10090', (24, 28))	('amino acid K44 > A44', 'Var', (68, 88))	('IKKalpha', 'Gene', (51, 59))	('IKKalpha', 'Gene', '12675', (51, 59))	('IKKalpha', 'Gene', '12675', (138, 146))
322487	28253859	A genetic variant in long non-coding RNA MALAT1 associated with survival outcome among patients with advanced lung adenocarcinoma: a survival cohort analysis Recently studies have demonstrated that the long non-coding RNA (lncRNA) metastasis associated lung adenocarcinoma transcript 1 (MALAT1) may participate in the development and progression of lung cancer.	('lung cancer', 'Disease', (349, 360))	('carcinoma', 'Phenotype', 'HP:0030731', (263, 272))	('associated', 'Reg', (48, 58))	('MALAT1', 'Gene', (41, 47))	('MALAT1', 'Gene', '378938', (287, 293))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (110, 129))	('variant', 'Var', (10, 17))	('advanced lung adenocarcinoma', 'Disease', 'MESH:D000077192', (101, 129))	('MALAT1', 'Gene', '378938', (41, 47))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (253, 272))	('lung cancer', 'Disease', 'MESH:D008175', (349, 360))	('lung cancer', 'Phenotype', 'HP:0100526', (349, 360))	('metastasis associated lung adenocarcinoma transcript 1', 'Gene', '378938', (231, 285))	('advanced lung adenocarcinoma', 'Disease', (101, 129))	('participate', 'Reg', (299, 310))	('cancer', 'Phenotype', 'HP:0002664', (354, 360))	('MALAT1', 'Gene', (287, 293))	('patients', 'Species', '9606', (87, 95))
322488	28253859	In this study, we hypothesized that genetic variant of this lncRNA may affect the prognosis of lung cancer patients.	('lung cancer', 'Disease', (95, 106))	('lung cancer', 'Phenotype', 'HP:0100526', (95, 106))	('genetic variant', 'Var', (36, 51))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('prognosis', 'CPA', (82, 91))	('affect', 'Reg', (71, 77))	('lung cancer', 'Disease', 'MESH:D008175', (95, 106))	('patients', 'Species', '9606', (107, 115))
322490	28253859	The genetic variant rs3200401 in MALAT1 was then genotyped among this population by using TaqMan assay.	('MALAT1', 'Gene', (33, 39))	('rs3200401', 'Var', (20, 29))	('rs3200401', 'Mutation', 'rs3200401', (20, 29))	('MALAT1', 'Gene', '378938', (33, 39))
322492	28253859	It was shown that among the advanced lung adenoma patients, subjects carrying rs3200401 CT and CT + TT genotypes had significantly longer median survival time (MST = 29.9, 28.9 vs. 19.3 month, Long-rank P = 0.019 and 0.024, respectively) and decreased death risks [crude HR (95% CI) = 0.65 (0.43-0.98) and 0.64 (0.44-0.95), P = 0.040 and 0.025, respectively], when compared to subjects wtih the MALAT1 rs3200401 CC genotype.	('rs3200401', 'Mutation', 'rs3200401', (402, 411))	('decreased death', 'Disease', 'MESH:D003643', (242, 257))	('patients', 'Species', '9606', (50, 58))	('median survival time', 'CPA', (138, 158))	('MALAT1', 'Gene', (395, 401))	('rs3200401', 'Mutation', 'rs3200401', (78, 87))	('rs3200401', 'Var', (78, 87))	('lung adenoma', 'Disease', (37, 49))	('longer', 'PosReg', (131, 137))	('lung adenoma', 'Disease', 'MESH:D000236', (37, 49))	('decreased death', 'Disease', (242, 257))	('MALAT1', 'Gene', '378938', (395, 401))
322493	28253859	However, the beneficial effect of rs3200401 was not seen among early NSCLC and advanced lung squamous cell carcinoma patients.	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('rs3200401', 'Var', (34, 43))	('lung squamous cell carcinoma', 'Disease', (88, 116))	('NSCLC', 'Disease', (69, 74))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (93, 116))	('NSCLC', 'Disease', 'MESH:D002289', (69, 74))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (88, 116))	('patients', 'Species', '9606', (117, 125))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (88, 116))	('rs3200401', 'Mutation', 'rs3200401', (34, 43))
322495	28253859	The rs3200401 T allele located on the lncRNA MALAT1 was associated with a better survival for advanced lung adenocarcinoma patients, which may offer a novel prognostic biomarker for this patient subgroup.	('better', 'PosReg', (74, 80))	('rs3200401', 'Mutation', 'rs3200401', (4, 13))	('patient', 'Species', '9606', (123, 130))	('rs3200401 T', 'Var', (4, 15))	('lung adenocarcinoma', 'Disease', (103, 122))	('MALAT1', 'Gene', (45, 51))	('patients', 'Species', '9606', (123, 131))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (103, 122))	('survival', 'MPA', (81, 89))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('patient', 'Species', '9606', (187, 194))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (103, 122))	('MALAT1', 'Gene', '378938', (45, 51))
322509	28253859	In this study, we genotyped the single nucleotide polymorphism (SNP) rs3200401 located in lncRNA MALAT1 and aimed to investigate its association with the survival outcome of 398 advanced NSCLC patients.	('patients', 'Species', '9606', (193, 201))	('rs3200401', 'Mutation', 'rs3200401', (69, 78))	('association', 'Interaction', (133, 144))	('rs3200401', 'Var', (69, 78))	('MALAT1', 'Gene', '378938', (97, 103))	('NSCLC', 'Disease', (187, 192))	('NSCLC', 'Disease', 'MESH:D002289', (187, 192))	('MALAT1', 'Gene', (97, 103))	('investigate', 'Reg', (117, 128))	('single nucleotide polymorphism', 'Var', (32, 62))
322515	28253859	It was indicated by the dbSNP database that there are 16 SNPs located on MALAT1 gene with the MAF > 0.01, however, only rs3200401 had the MAF > 0.10 in all the 1000 Genome, the NHLBI "Grand Opportunity" Exome Sequencing Project (GO-ESP), and Exome Aggregation Consortium (ExAC) projects (https://www.ncbi.nlm.nih.gov/variation/view/) (Additional file 1: Table S1).	('MALAT1', 'Gene', '378938', (73, 79))	('MAF', 'Gene', '4094', (138, 141))	('MAF', 'Gene', '4094', (94, 97))	('MALAT1', 'Gene', (73, 79))	('MAF', 'Gene', (138, 141))	('MAF', 'Gene', (94, 97))	('rs3200401', 'Mutation', 'rs3200401', (120, 129))	('rs3200401', 'Var', (120, 129))
322516	28253859	Thus, to acquire adequate statistical power, the SNP rs3200401 was investigated in the present study, while the other SNPs with MAF < 0.10 were not selected.	('MAF', 'Gene', (128, 131))	('rs3200401', 'Mutation', 'rs3200401', (53, 62))	('rs3200401', 'Var', (53, 62))	('MAF', 'Gene', '4094', (128, 131))
322517	28253859	The MALAT1 polymorphism, rs3200401 C > T, was genotyped by TaqMan assay among all study subjects using ABI 7900HT Sequence Detection System (Applied Biosystems, Waltham, Massachusetts, USA) and each sample was analyzed in duplicate.	('MALAT1', 'Gene', (4, 10))	('rs3200401', 'Mutation', 'rs3200401', (25, 34))	('rs3200401 C > T', 'Var', (25, 40))	('MALAT1', 'Gene', '378938', (4, 10))
322518	28253859	Kaplan-Meier analysis and log-rank test were used to assess the associations between survival time and demographic characteristics, clinical features, and MALAT1 rs3200401 genotypes.	('rs3200401', 'Mutation', 'rs3200401', (162, 171))	('MALAT1', 'Gene', '378938', (155, 161))	('rs3200401', 'Var', (162, 171))	('MALAT1', 'Gene', (155, 161))	('associations', 'Interaction', (64, 76))
322520	28253859	The multivariate Cox regression models, with adjustment for age, sex, smoking status, histology, TNM stage, and therapy treatments of surgical resection, chemotherapy, and radiotherapy, were used to estimate the adjusted hazard ratio (HR) and 95% CIs for the effect of MALAT1 rs3200401 genotypes on death risk for NSCLC patients.	('MALAT1', 'Gene', '378938', (269, 275))	('rs3200401', 'Mutation', 'rs3200401', (276, 285))	('rs3200401', 'Var', (276, 285))	('NSCLC', 'Disease', (314, 319))	('MALAT1', 'Gene', (269, 275))	('death', 'Disease', (299, 304))	('TNM', 'Gene', '10178', (97, 100))	('death', 'Disease', 'MESH:D003643', (299, 304))	('NSCLC', 'Disease', 'MESH:D002289', (314, 319))	('TNM', 'Gene', (97, 100))	('patients', 'Species', '9606', (320, 328))
322526	28253859	The statistical power analysis showed that, as for the SNP rs3200401 (MAF = 0.187) analyzed in this study, it had the statistical power of 0.913 to detect the association with HR = 1.4 by using 398 subjects in the survival analysis.	('MAF', 'Gene', '4094', (70, 73))	('MAF', 'Gene', (70, 73))	('rs3200401', 'Var', (59, 68))	('rs3200401', 'Mutation', 'rs3200401', (59, 68))
322530	28253859	The associations between lncRNA MALAT1 rs3200401 genotypes and survival outcome of early-staged NSCLC patients were shown in Table 2.	('NSCLC', 'Disease', (96, 101))	('patients', 'Species', '9606', (102, 110))	('NSCLC', 'Disease', 'MESH:D002289', (96, 101))	('MALAT1', 'Gene', '378938', (32, 38))	('rs3200401', 'Mutation', 'rs3200401', (39, 48))	('rs3200401', 'Var', (39, 48))	('MALAT1', 'Gene', (32, 38))	('associations', 'Interaction', (4, 16))
322531	28253859	No significant associations were found between rs3200401 genotypes and the MST and death risk of early NSCLC patients, either in adenocarcinoma or squamous cell carcinoma.	('patients', 'Species', '9606', (109, 117))	('NSCLC', 'Disease', (103, 108))	('NSCLC', 'Disease', 'MESH:D002289', (103, 108))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('adenocarcinoma or squamous cell carcinoma', 'Disease', 'MESH:D002294', (129, 170))	('rs3200401', 'Var', (47, 56))	('death', 'Disease', (83, 88))	('death', 'Disease', 'MESH:D003643', (83, 88))	('MST', 'Disease', (75, 78))	('rs3200401', 'Mutation', 'rs3200401', (47, 56))	('carcinoma', 'Phenotype', 'HP:0030731', (161, 170))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (147, 170))	('adenocarcinoma or squamous cell carcinoma', 'Disease', (129, 170))
322532	28253859	Among the advanced NSCLC patients, those carrying MALAT1 rs3200401 CT and rs3200401 CT + TT genotypes have significantly longer MST than those with rs3200401 CC genotype (MST = 22.6, 21.8 vs.15.9 months, and log-rank P = 0.045 and 0.034, respectively) (Table 3).	('rs3200401', 'Mutation', 'rs3200401', (148, 157))	('rs3200401 CT', 'Var', (57, 69))	('MALAT1', 'Gene', '378938', (50, 56))	('rs3200401', 'Var', (74, 83))	('patients', 'Species', '9606', (25, 33))	('longer', 'PosReg', (121, 127))	('NSCLC', 'Disease', (19, 24))	('rs3200401', 'Mutation', 'rs3200401', (57, 66))	('rs3200401', 'Mutation', 'rs3200401', (74, 83))	('MALAT1', 'Gene', (50, 56))	('NSCLC', 'Disease', 'MESH:D002289', (19, 24))	('MST', 'CPA', (128, 131))
322533	28253859	The univariate cox proportional hazard models showed that, when compared to the rs3200401 CC genotype, the rs3200401 CT and CT + TT genotypes were associated with significant lower death risk for advanced NSCLC patients [crude HR (95% CI) = 0.78 (0.61-0.99) and 0.78 (0.61-0.98), P = 0.046 and 0.034, respectively].	('patients', 'Species', '9606', (211, 219))	('rs3200401', 'Mutation', 'rs3200401', (107, 116))	('lower', 'NegReg', (175, 180))	('rs3200401', 'Mutation', 'rs3200401', (80, 89))	('rs3200401', 'Var', (107, 116))	('death', 'Disease', 'MESH:D003643', (181, 186))	('death', 'Disease', (181, 186))	('NSCLC', 'Disease', (205, 210))	('NSCLC', 'Disease', 'MESH:D002289', (205, 210))
322535	28253859	We further analyzed the associations of MALAT1 rs3200401 with survival outcomes among advanced patients with lung adenocarcinoma and squamous cell carcinoma separately (Table 3).	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (133, 156))	('MALAT1', 'Gene', (40, 46))	('associations', 'Interaction', (24, 36))	('patients', 'Species', '9606', (95, 103))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (109, 128))	('lung adenocarcinoma', 'Disease', (109, 128))	('MALAT1', 'Gene', '378938', (40, 46))	('rs3200401', 'Var', (47, 56))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('rs3200401', 'Mutation', 'rs3200401', (47, 56))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (133, 156))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (109, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (147, 156))	('squamous cell carcinoma', 'Disease', (133, 156))
322536	28253859	Compared to advanced lung adenocarcinoma patients carrying the rs3200401 CC genotype, those with rs3200401 CT and CT + TT genotypes had significant longer MST and lower risk of death (MST = 29.9 and 28.9 months vs. 19.3 months, log-rank P = 0.019 and 0.024) [crude HR (95% CI) = 0.62 (0.41-0.93) and 0.65 (0.44-0.95); adjusted HR (95% CI) = 0.65 (0.43-0.98) and 0.64 (0.44-0.95), respectively] (Table 3) (Fig.	('rs3200401', 'Mutation', 'rs3200401', (63, 72))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (21, 40))	('death', 'Disease', (177, 182))	('rs3200401', 'Var', (97, 106))	('rs3200401 CC', 'Var', (63, 75))	('rs3200401', 'Mutation', 'rs3200401', (97, 106))	('MST', 'MPA', (155, 158))	('patients', 'Species', '9606', (41, 49))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (21, 40))	('longer', 'PosReg', (148, 154))	('lower', 'NegReg', (163, 168))	('lung adenocarcinoma', 'Disease', (21, 40))	('death', 'Disease', 'MESH:D003643', (177, 182))	('carcinoma', 'Phenotype', 'HP:0030731', (31, 40))
322539	28253859	We found the rs3200401 CT + TT genotype was associated with a decreased death risk at a borderline significance among lung adenocarcinoma patients with age <= 65 [HR (95% CI) = 0.59 (0.35-1.00), P = 0.054]) and stage IIIA-IIIB [HR (95% CI) = 0.54 (0.29-1.01), P = 0.053].	('rs3200401', 'Mutation', 'rs3200401', (13, 22))	('patients', 'Species', '9606', (138, 146))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('decreased death', 'Disease', (62, 77))	('lung adenocarcinoma', 'Disease', (118, 137))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (118, 137))	('decreased death', 'Disease', 'MESH:D003643', (62, 77))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (118, 137))	('rs3200401 CT + TT', 'Var', (13, 30))
322540	28253859	No significant associations between rs3200401 genotypes and survival were seen among squamous cell carcinoma patients in each stratum.	('patients', 'Species', '9606', (109, 117))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (85, 108))	('rs3200401', 'Var', (36, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('rs3200401', 'Mutation', 'rs3200401', (36, 45))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (85, 108))	('squamous cell carcinoma', 'Disease', (85, 108))
322541	28253859	In this follow-up study for case-only survival analysis, we investigated the association of the genetic variation rs3200401 in lncRNA MALAT1 with the survival outcome of NSCLC patients.	('MALAT1', 'Gene', (134, 140))	('patients', 'Species', '9606', (176, 184))	('rs3200401', 'Var', (114, 123))	('NSCLC', 'Disease', (170, 175))	('rs3200401', 'Mutation', 'rs3200401', (114, 123))	('NSCLC', 'Disease', 'MESH:D002289', (170, 175))	('MALAT1', 'Gene', '378938', (134, 140))	('association', 'Interaction', (77, 88))
322542	28253859	We found that among advanced lung adenocarcinoma patients, those carrying MALAT1 rs3200401 CT or CT + TT genotypes had significant longer survival time and decreased death risks than those carrying rs3200401 CC genotype.	('decreased death', 'Disease', 'MESH:D003643', (156, 171))	('rs3200401', 'Mutation', 'rs3200401', (81, 90))	('lung adenocarcinoma', 'Disease', (29, 48))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (29, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (39, 48))	('survival time', 'CPA', (138, 151))	('rs3200401', 'Mutation', 'rs3200401', (198, 207))	('MALAT1', 'Gene', '378938', (74, 80))	('decreased death', 'Disease', (156, 171))	('patients', 'Species', '9606', (49, 57))	('longer', 'PosReg', (131, 137))	('rs3200401', 'Var', (81, 90))	('MALAT1', 'Gene', (74, 80))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (29, 48))
322543	28253859	This finding suggested that rs3200401 C > T variant of MALAT1 might be a potential prognostic biomarker for predicting the survival of advanced lung adenocarcinoma patients.	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (144, 163))	('MALAT1', 'Gene', '378938', (55, 61))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (144, 163))	('carcinoma', 'Phenotype', 'HP:0030731', (154, 163))	('MALAT1', 'Gene', (55, 61))	('patients', 'Species', '9606', (164, 172))	('lung adenocarcinoma', 'Disease', (144, 163))	('rs3200401', 'Mutation', 'rs3200401', (28, 37))	('rs3200401 C > T', 'Var', (28, 43))
322546	28253859	Increased MALAT1 expression in tumor tissues of NSCLC patients is associated with an unfavorable overall survival, while the high expression of MALAT1 in tumor tissues was also found to be associated with an increased risk of metastasis and a poor overall survival among colorectal cancer, pancreatic cancer, glioma, and clear cell renal cell carcinoma.	('MALAT1', 'Gene', (144, 150))	('NSCLC', 'Disease', (48, 53))	('MALAT1', 'Gene', (10, 16))	('patients', 'Species', '9606', (54, 62))	('glioma', 'Phenotype', 'HP:0009733', (309, 315))	('colorectal cancer', 'Disease', (271, 288))	('poor', 'NegReg', (243, 247))	('carcinoma', 'Phenotype', 'HP:0030731', (343, 352))	('MALAT1', 'Gene', '378938', (144, 150))	('pancreatic cancer', 'Disease', 'MESH:D010190', (290, 307))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (321, 352))	('tumor', 'Disease', (154, 159))	('MALAT1', 'Gene', '378938', (10, 16))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('expression', 'MPA', (17, 27))	('pancreatic cancer', 'Disease', (290, 307))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('cancer', 'Phenotype', 'HP:0002664', (301, 307))	('colorectal cancer', 'Phenotype', 'HP:0003003', (271, 288))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (321, 352))	('Increased', 'PosReg', (0, 9))	('high expression', 'Var', (125, 140))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('metastasis', 'CPA', (226, 236))	('glioma', 'Disease', (309, 315))	('overall survival', 'CPA', (248, 264))	('cancer', 'Phenotype', 'HP:0002664', (282, 288))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (290, 307))	('NSCLC', 'Disease', 'MESH:D002289', (48, 53))	('tumor', 'Disease', (31, 36))	('associated with', 'Reg', (189, 204))	('clear cell renal cell carcinoma', 'Disease', (321, 352))	('glioma', 'Disease', 'MESH:D005910', (309, 315))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (332, 352))	('colorectal cancer', 'Disease', 'MESH:D015179', (271, 288))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
322549	28253859	Inhibition of MALAT1 was seen to have an anti-proliferative effect and controls phenotypic switch in endothelial cells, indicating that MALAT1 may regulate angiogenesis and result in metastasis.	('angiogenesis', 'CPA', (156, 168))	('MALAT1', 'Gene', '378938', (14, 20))	('metastasis', 'CPA', (183, 193))	('result in', 'Reg', (173, 182))	('regulate', 'Reg', (147, 155))	('MALAT1', 'Gene', (14, 20))	('Inhibition', 'Var', (0, 10))	('MALAT1', 'Gene', '378938', (136, 142))	('MALAT1', 'Gene', (136, 142))
322551	28253859	Although MALAT1 expression in lung cancer tissue was reported to be associated with poor prognosis in lung squamous cell carcinoma, our findings indicated that the SNP rs3200401 cannot affect the survival outcome of lung squamous cell carcinoma patients.	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (216, 244))	('patients', 'Species', '9606', (245, 253))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('MALAT1', 'Gene', '378938', (9, 15))	('rs3200401', 'Var', (168, 177))	('lung cancer', 'Disease', (30, 41))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (221, 244))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (216, 244))	('lung squamous cell carcinoma', 'Disease', (216, 244))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (102, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (235, 244))	('lung cancer', 'Disease', 'MESH:D008175', (30, 41))	('SNP', 'Var', (164, 167))	('rs3200401', 'Mutation', 'rs3200401', (168, 177))	('lung cancer', 'Phenotype', 'HP:0100526', (30, 41))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (102, 130))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (107, 130))	('lung squamous cell carcinoma', 'Disease', (102, 130))	('MALAT1', 'Gene', (9, 15))
322562	28253859	Large studies have reported that genetic polymorphisms on certain genes may affect the susceptibility of lung cancer, sensitivity of chemo- or radiotherapy, and length of survival or prognosis.	('lung cancer', 'Phenotype', 'HP:0100526', (105, 116))	('affect', 'Reg', (76, 82))	('prognosis', 'CPA', (183, 192))	('genetic polymorphisms', 'Var', (33, 54))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('lung cancer', 'Disease', 'MESH:D008175', (105, 116))	('length of survival', 'CPA', (161, 179))	('lung cancer', 'Disease', (105, 116))
322563	28253859	found a borderline significant association between rs619586 in MALAT1 and decreased hepatocellular carcinoma risk.	('decreased hepatocellular carcinoma', 'Disease', (74, 108))	('MALAT1', 'Gene', '378938', (63, 69))	('MALAT1', 'Gene', (63, 69))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (84, 108))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('rs619586', 'Mutation', 'rs619586', (51, 59))	('rs619586', 'Var', (51, 59))	('decreased hepatocellular carcinoma', 'Disease', 'MESH:D006528', (74, 108))
322564	28253859	did not found any association between rs619586 genotype and lung cancer risk, but patients with rs619586 A allele had more chance of response to platinum-based chemotherapy.	('more', 'PosReg', (118, 122))	('lung cancer', 'Disease', (60, 71))	('platinum', 'Chemical', 'MESH:D010984', (145, 153))	('lung cancer', 'Phenotype', 'HP:0100526', (60, 71))	('response', 'CPA', (133, 141))	('patients', 'Species', '9606', (82, 90))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('lung cancer', 'Disease', 'MESH:D008175', (60, 71))	('rs619586', 'Mutation', 'rs619586', (96, 104))	('rs619586', 'Mutation', 'rs619586', (38, 46))	('rs619586 A', 'Var', (96, 106))
322566	28253859	Further studies with larger sample sized populations could investigate the low-frequency SNPs of MALAT1 with higher detection power, and the biological functions for the positive variants of MALAT1 also warrant further deep investigation.	('MALAT1', 'Gene', '378938', (97, 103))	('MALAT1', 'Gene', '378938', (191, 197))	('SNPs', 'Var', (89, 93))	('MALAT1', 'Gene', (191, 197))	('MALAT1', 'Gene', (97, 103))
322568	28253859	We found that the C > T variation of rs3200401 caused 1.62 kcal/mol minimal free energy (MFE, DeltaG) change, which may alter structural features of MALAT1 (Additional file 2: Figure S1), resulting in weaken interaction between MALAT1 and its binding protein SRSF2.	('SRSF2', 'Gene', (259, 264))	('change', 'Reg', (102, 108))	('minimal free energy', 'MPA', (68, 87))	('MALAT1', 'Gene', '378938', (149, 155))	('MALAT1', 'Gene', '378938', (228, 234))	('alter', 'Reg', (120, 125))	('MALAT1', 'Gene', (149, 155))	('SRSF2', 'Gene', '6427', (259, 264))	('rs3200401', 'Mutation', 'rs3200401', (37, 46))	('DeltaG', 'Mutation', 'c.delG', (94, 100))	('rs3200401', 'Var', (37, 46))	('MALAT1', 'Gene', (228, 234))	('interaction', 'Interaction', (208, 219))	('weaken', 'NegReg', (201, 207))
322570	28253859	SRSF2 and phosphorylated SRSF2 were reported to correlate with aggressive features of lung adenocarcinoma but not with lung squamous cell carcinoma patients.	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('patients', 'Species', '9606', (148, 156))	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('lung adenocarcinoma', 'Disease', (86, 105))	('SRSF2', 'Gene', '6427', (25, 30))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (119, 147))	('lung squamous cell carcinoma', 'Disease', (119, 147))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (86, 105))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (124, 147))	('SRSF2', 'Gene', (0, 5))	('phosphorylated', 'Var', (10, 24))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (86, 105))	('SRSF2', 'Gene', (25, 30))	('SRSF2', 'Gene', '6427', (0, 5))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (119, 147))
322571	28253859	It was biologically possible that SNP rs3200401 C > T variant may cause MALAT1-SRSF2 binding loss, affect phosphorylation of SRSF2, down-regulate phosphorylation of SRSF2, change the alternative splicing of pre-mRNAs, and then alter the expression levels of metastasis associated genes.	('rs3200401', 'Mutation', 'rs3200401', (38, 47))	('alternative splicing', 'MPA', (183, 203))	('loss', 'NegReg', (93, 97))	('SRSF2', 'Gene', '6427', (125, 130))	('phosphorylation', 'MPA', (106, 121))	('MALAT1', 'Gene', (72, 78))	('SRSF2', 'Gene', (165, 170))	('SRSF2', 'Gene', (125, 130))	('SNP', 'Var', (34, 37))	('MALAT1', 'Gene', '378938', (72, 78))	('expression levels', 'MPA', (237, 254))	('change', 'Reg', (172, 178))	('affect', 'Reg', (99, 105))	('down-regulate', 'NegReg', (132, 145))	('SRSF2', 'Gene', '6427', (79, 84))	('SRSF2', 'Gene', (79, 84))	('alter', 'Reg', (227, 232))	('SRSF2', 'Gene', '6427', (165, 170))	('phosphorylation', 'MPA', (146, 161))	('binding', 'Interaction', (85, 92))
322574	28253859	First, this study used a single-institution cohort to investigate the association between MALAT1 variant and the survival outcome of lung cancer patients for practical reason.	('patients', 'Species', '9606', (145, 153))	('variant', 'Var', (97, 104))	('lung cancer', 'Disease', (133, 144))	('MALAT1', 'Gene', '378938', (90, 96))	('lung cancer', 'Phenotype', 'HP:0100526', (133, 144))	('investigate', 'Reg', (54, 65))	('association', 'Interaction', (70, 81))	('MALAT1', 'Gene', (90, 96))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('lung cancer', 'Disease', 'MESH:D008175', (133, 144))
322575	28253859	Second, to get adequate statistical power by using this moderate cohort of lung cancer patients, we only choose the SNP with MAF > 0.1 (rs3200401) to investigate in the present study.	('lung cancer', 'Disease', (75, 86))	('lung cancer', 'Phenotype', 'HP:0100526', (75, 86))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('lung cancer', 'Disease', 'MESH:D008175', (75, 86))	('MAF', 'Gene', '4094', (125, 128))	('rs3200401', 'Mutation', 'rs3200401', (136, 145))	('rs3200401', 'Var', (136, 145))	('patients', 'Species', '9606', (87, 95))	('MAF', 'Gene', (125, 128))
322578	28253859	To give a clue for further interpretation and explanation of the biological function of rs3200401, we still analyzed the TCGA data and found that a higher MALAT1 expression level was associated with a worse survival outcome among advanced lung adenocarcinoma patients.	('expression level', 'MPA', (162, 178))	('patients', 'Species', '9606', (259, 267))	('MALAT1', 'Gene', '378938', (155, 161))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (239, 258))	('carcinoma', 'Phenotype', 'HP:0030731', (249, 258))	('MALAT1', 'Gene', (155, 161))	('rs3200401', 'Var', (88, 97))	('rs3200401', 'Mutation', 'rs3200401', (88, 97))	('lung adenocarcinoma', 'Disease', (239, 258))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (239, 258))	('higher', 'PosReg', (148, 154))
322580	28253859	In conclusion, this study revealed that the genetic variation SNP rs3200401 T allele located on lncRNA MALAT1 was associated with a better survival of advanced lung adenocarcinoma patient, while this effect was not seen among lung squamous cell carcinoma patients.	('SNP', 'Var', (62, 65))	('rs3200401', 'Mutation', 'rs3200401', (66, 75))	('MALAT1', 'Gene', '378938', (103, 109))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (160, 179))	('carcinoma', 'Phenotype', 'HP:0030731', (170, 179))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (226, 254))	('lung squamous cell carcinoma', 'Disease', (226, 254))	('carcinoma', 'Phenotype', 'HP:0030731', (245, 254))	('MALAT1', 'Gene', (103, 109))	('lung adenocarcinoma', 'Disease', (160, 179))	('patient', 'Species', '9606', (255, 262))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (231, 254))	('patients', 'Species', '9606', (255, 263))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (160, 179))	('better', 'PosReg', (132, 138))	('patient', 'Species', '9606', (180, 187))	('survival', 'CPA', (139, 147))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (226, 254))
322581	28253859	The protective effect of rs3200401 T allele may because it can influence the secondary structure of lncRNA MALAT1, or influence the interaction between MALAT1 and SR proteins thus by altering the expression levels of metastasis associated genes.	('expression levels', 'MPA', (196, 213))	('rs3200401', 'Mutation', 'rs3200401', (25, 34))	('rs3200401', 'Var', (25, 34))	('metastasis', 'MPA', (217, 227))	('MALAT1', 'Gene', '378938', (107, 113))	('MALAT1', 'Gene', '378938', (152, 158))	('MALAT1', 'Gene', (107, 113))	('interaction', 'Interaction', (132, 143))	('influence', 'Reg', (63, 72))	('altering', 'Reg', (183, 191))	('MALAT1', 'Gene', (152, 158))	('secondary structure', 'MPA', (77, 96))	('SR proteins', 'Protein', (163, 174))	('influence', 'Reg', (118, 127))
322582	28253859	The MALAT1 rs3200401 T allele may serve as a novel biomarker for predicting clinical outcomes of lung adenocarcinoma.	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (97, 116))	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('rs3200401 T', 'Var', (11, 22))	('rs3200401', 'Mutation', 'rs3200401', (11, 20))	('MALAT1', 'Gene', (4, 10))	('lung adenocarcinoma', 'Disease', (97, 116))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (97, 116))	('MALAT1', 'Gene', '378938', (4, 10))
322630	33649335	In a study of lung cancer, the dysregulations of DMRT3 along with other two proteins were considered specific for lung squamous cell carcinoma .	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (119, 142))	('lung cancer', 'Disease', (14, 25))	('lung cancer', 'Phenotype', 'HP:0100526', (14, 25))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (114, 142))	('DMRT3', 'Gene', (49, 54))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('dysregulations', 'Var', (31, 45))	('lung squamous cell carcinoma', 'Disease', (114, 142))	('lung cancer', 'Disease', 'MESH:D008175', (14, 25))
322648	33649335	The biological roles of the gatekeepers proposed set are marked as cell cycle regulation, DNA-repair breaks, nucleosome assembly and processes that occur in the mitotic phase.	('DNA-repair', 'Gene', (90, 100))	('gatekeepers', 'Species', '111938', (28, 39))	('breaks', 'Var', (101, 107))	('nucleosome assembly', 'CPA', (109, 128))	('cell cycle', 'CPA', (67, 77))
322705	31970154	As shown in Figure 2D, more than one-fifth of all HNSC samples harbored PGRMC1 amplification, and consistently, HNSC samples harboring PGRMC1 amplification exhibited higher mRNA expression than those that exhibit diploid PGRMC1.	('higher', 'PosReg', (166, 172))	('PGRMC1', 'Gene', (221, 227))	('HNSC', 'Disease', (112, 116))	('HNSC', 'Phenotype', 'HP:0012288', (50, 54))	('HNSC', 'Disease', (50, 54))	('PGRMC1', 'Gene', '10857', (221, 227))	('HNSC', 'Disease', 'MESH:C535575', (50, 54))	('HNSC', 'Phenotype', 'HP:0012288', (112, 116))	('PGRMC1', 'Gene', '10857', (72, 78))	('PGRMC1', 'Gene', (135, 141))	('HNSC', 'Disease', 'MESH:C535575', (112, 116))	('PGRMC1', 'Gene', '10857', (135, 141))	('amplification', 'Var', (79, 92))	('PGRMC1', 'Gene', (72, 78))	('amplification', 'Var', (142, 155))	('mRNA expression', 'MPA', (173, 188))
322707	31970154	In summary, a positive correlation between PGRMC1 copy number amplification and mRNA over-expression was found among HNSC samples, and its over-expression is an adverse prognostic factor for HNSC patients.	('HNSC', 'Phenotype', 'HP:0012288', (117, 121))	('mRNA', 'MPA', (80, 84))	('PGRMC1', 'Gene', (43, 49))	('HNSC', 'Phenotype', 'HP:0012288', (191, 195))	('HNSC', 'Disease', (117, 121))	('HNSC', 'Disease', 'MESH:C535575', (117, 121))	('HNSC', 'Disease', (191, 195))	('positive', 'Reg', (14, 22))	('HNSC', 'Disease', 'MESH:C535575', (191, 195))	('patients', 'Species', '9606', (196, 204))	('copy number amplification', 'Var', (50, 75))	('over-expression', 'PosReg', (139, 154))	('PGRMC1', 'Gene', '10857', (43, 49))	('over-expression', 'PosReg', (85, 100))
322724	31970154	Remarkably, as shown in Figure 7B, the genomic alterations rate of PIK3CA in the PGRMC1 high-expression sub-group is 1.5-fold higher than the samples of low-expression sub-group, which reached nearly 45% of the total samples for HNSC cohort.	('PIK3CA', 'Gene', '5290', (67, 73))	('PGRMC1', 'Gene', (81, 87))	('HNSC', 'Phenotype', 'HP:0012288', (229, 233))	('PGRMC1', 'Gene', '10857', (81, 87))	('higher', 'PosReg', (126, 132))	('high-expression', 'Var', (88, 103))	('HNSC', 'Disease', (229, 233))	('HNSC', 'Disease', 'MESH:C535575', (229, 233))	('PIK3CA', 'Gene', (67, 73))	('genomic alterations', 'MPA', (39, 58))
322726	31970154	As many studies reported that HNSC with concurrent mutation of multiple PI3K pathway genes were advanced (stage IV), implicating concerted PI3K pathway aberrations in HNSC progression (Qiu et al.,; Lui et al.,), these data revealed the positive correlation between PGRMC1 over-expression and PIK3CA genomic alterations, known for its association of cancer progression and metastasis, which provided further support for the oncogenic role of PGRMC1 and the potential interaction with PIK3CA.	('HNSC', 'Disease', (30, 34))	('PGRMC1', 'Gene', (441, 447))	('PIK3CA', 'Gene', (483, 489))	('HNSC', 'Phenotype', 'HP:0012288', (30, 34))	('PGRMC1', 'Gene', (265, 271))	('mutation', 'Var', (51, 59))	('HNSC', 'Disease', 'MESH:C535575', (30, 34))	('over-expression', 'PosReg', (272, 287))	('cancer', 'Disease', (349, 355))	('PIK3CA', 'Gene', '5290', (292, 298))	('HNSC', 'Disease', (167, 171))	('cancer', 'Phenotype', 'HP:0002664', (349, 355))	('PGRMC1', 'Gene', '10857', (441, 447))	('PIK3CA', 'Gene', '5290', (483, 489))	('HNSC', 'Phenotype', 'HP:0012288', (167, 171))	('HNSC', 'Disease', 'MESH:C535575', (167, 171))	('PGRMC1', 'Gene', '10857', (265, 271))	('PIK3CA', 'Gene', (292, 298))	('cancer', 'Disease', 'MESH:D009369', (349, 355))
322732	31970154	Remarkably, the tumors harboring PGRMC1 high-expression showed the more abundant counts of somatic mutations and the fraction of genomic copy number alterations compared with PGRMC1 low-expression tumors (Figure 8C).	('tumors', 'Disease', 'MESH:D009369', (197, 203))	('PGRMC1', 'Gene', '10857', (33, 39))	('PGRMC1', 'Gene', (175, 181))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('PGRMC1', 'Gene', '10857', (175, 181))	('high-expression', 'Var', (40, 55))	('tumors', 'Disease', (197, 203))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('tumors', 'Phenotype', 'HP:0002664', (197, 203))	('tumors', 'Disease', 'MESH:D009369', (16, 22))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('tumors', 'Disease', (16, 22))	('PGRMC1', 'Gene', (33, 39))
322736	31970154	In this present study, we assessed the prognostic impact of aberrant PGRMC1 expression in head and neck cancer and other cancers to identify patients who may benefit from anti-cancer therapy targeting PGRMC1 and also investigated the oncogenic mechanism of PGRMC1 over-expression in cancer cells.	('cancer', 'Disease', 'MESH:D009369', (283, 289))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('PGRMC1', 'Gene', (257, 263))	('PGRMC1', 'Gene', (201, 207))	('cancer', 'Disease', (104, 110))	('patients', 'Species', '9606', (141, 149))	('cancers', 'Phenotype', 'HP:0002664', (121, 128))	('cancers', 'Disease', (121, 128))	('head and neck cancer', 'Phenotype', 'HP:0012288', (90, 110))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('PGRMC1', 'Gene', '10857', (69, 75))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('cancer', 'Disease', (283, 289))	('PGRMC1', 'Gene', '10857', (257, 263))	('cancer', 'Phenotype', 'HP:0002664', (283, 289))	('head and neck cancer', 'Disease', 'MESH:D006258', (90, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('PGRMC1', 'Gene', '10857', (201, 207))	('aberrant', 'Var', (60, 68))	('cancers', 'Disease', 'MESH:D009369', (121, 128))	('PGRMC1', 'Gene', (69, 75))	('cancer', 'Disease', (176, 182))	('cancer', 'Disease', (121, 127))
322737	31970154	Considering the amplification is one of the major genetic mechanisms that could increase the gene expression of oncogenes (Savelyeva and Schwab,; Lockwood et al.,; Zhang et al.,), it suggested that the copy number amplification of PGRMC1 could serve as a potential genetic driver for its over-expression.	('PGRMC1', 'Gene', '10857', (231, 237))	('PGRMC1', 'Gene', (231, 237))	('increase', 'PosReg', (80, 88))	('over-expression', 'PosReg', (288, 303))	('gene expression', 'MPA', (93, 108))	('copy number amplification', 'Var', (202, 227))
322738	31970154	Our data revealed, previously undescribed, the oncogenic and prognosis value of PGRMC1 over-expression and copy number amplification in the head and neck cancer.	('head and neck cancer', 'Phenotype', 'HP:0012288', (140, 160))	('copy number amplification', 'Var', (107, 132))	('over-expression', 'PosReg', (87, 102))	('head and neck cancer', 'Disease', 'MESH:D006258', (140, 160))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('PGRMC1', 'Gene', (80, 86))	('PGRMC1', 'Gene', '10857', (80, 86))
322739	31970154	It is convinced that the status of PGRMC1 copy number amplification and over-expression will probably influence response to head and neck cancer treatment strategy.	('copy number amplification', 'Var', (42, 67))	('influence', 'Reg', (102, 111))	('over-expression', 'MPA', (72, 87))	('head and neck cancer', 'Phenotype', 'HP:0012288', (124, 144))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('PGRMC1', 'Gene', (35, 41))	('PGRMC1', 'Gene', '10857', (35, 41))	('head and neck cancer', 'Disease', 'MESH:D006258', (124, 144))
322751	31686911	This study was designed to validate the prognostic value of microRNA-195 in human tumors.	('microRNA-195', 'Var', (60, 72))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('tumors', 'Disease', (82, 88))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('human', 'Species', '9606', (76, 81))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))
322754	31686911	The results showed that patients with high expression of miR-195 had favorable tumor-node-metastasis (late vs early: pooled OR =0.16, 95% CI: 0.11-0.22, P<0.001), lymph node metastasis (pooled OR =0.25, 95% CI: 0.18-0.35, P<0.001) and distant metastasis (pooled OR =0.26, 95% CI: 0.13-0.52, P<0.001).	('miR-195', 'Gene', (57, 64))	('miR-195', 'Gene', '406971', (57, 64))	('lymph node metastasis', 'CPA', (163, 184))	('high expression', 'Var', (38, 53))	('distant metastasis', 'CPA', (235, 253))	('tumor-node-metastasis', 'Disease', (79, 100))	('tumor-node-metastasis', 'Disease', 'MESH:D009362', (79, 100))	('patients', 'Species', '9606', (24, 32))	('favorable', 'PosReg', (69, 78))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
322769	31686911	So far, numerous studies have shown that the clinicopathological features and the overall survival of patients in various cancers are closely related to the dysregulation of miR-195.	('miR-195', 'Gene', (174, 181))	('miR-195', 'Gene', '406971', (174, 181))	('dysregulation', 'Var', (157, 170))	('patients', 'Species', '9606', (102, 110))	('cancers', 'Disease', 'MESH:D009369', (122, 129))	('cancers', 'Phenotype', 'HP:0002664', (122, 129))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('cancers', 'Disease', (122, 129))	('related', 'Reg', (142, 149))
322797	31686911	A large number of miRNAs have been found to be associated with clinical features of a variety of cancers.	('cancers', 'Disease', 'MESH:D009369', (97, 104))	('cancers', 'Phenotype', 'HP:0002664', (97, 104))	('miRNAs', 'Var', (18, 24))	('cancers', 'Disease', (97, 104))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('associated', 'Reg', (47, 57))
322798	31686911	For example, high expression of miR-21 has been confirmed to correlate with worse overall survival significantly in carcinomas of the digestive system.	('carcinomas', 'Disease', (116, 126))	('carcinomas', 'Phenotype', 'HP:0030731', (116, 126))	('high', 'Var', (13, 17))	('miR-21', 'Gene', '406991', (32, 38))	('worse', 'NegReg', (76, 81))	('miR-21', 'Gene', (32, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('overall', 'MPA', (82, 89))	('carcinomas', 'Disease', 'MESH:D002277', (116, 126))
322821	31255659	We obtained significant predictive performance for RNA-defined HPV+ (AUC = 0.73), DNA methylation subtypes MethylMix HPV+ (AUC = 0.79), non-CIMP-atypical (AUC = 0.77) and Stem-like-Smoking (AUC = 0.71), and mutation of NSD1 (AUC = 0.73).	('CIMP', 'Chemical', '-', (140, 144))	('mutation', 'Var', (207, 215))	('NSD1', 'Gene', '64324', (219, 223))	('NSD1', 'Gene', (219, 223))
322822	31255659	When compared to clinical models, radiomic models were superior to subtypes such as NOTCH1 mutation and DNA methylation subtype non-CIMP-atypical while were inferior for DNA methylation subtype CIMP-atypical and NSD1 mutation.	('mutation', 'Var', (91, 99))	('NSD1', 'Gene', (212, 216))	('NOTCH1', 'Gene', (84, 90))	('CIMP', 'Chemical', '-', (194, 198))	('NSD1', 'Gene', '64324', (212, 216))	('NOTCH1', 'Gene', '4851', (84, 90))	('CIMP', 'Chemical', '-', (132, 136))
322854	31255659	The atypical subtype is defined as lacking either EGFR amplification or deletion of 9p.	('lacking', 'NegReg', (35, 42))	('EGFR', 'Gene', (50, 54))	('deletion', 'Var', (72, 80))	('EGFR', 'Gene', '1956', (50, 54))
322856	31255659	focal amplification of both EGFR and CCND1, amplification of 3q, and deletion of 3p and 9p.	('EGFR', 'Gene', '1956', (28, 32))	('CCND1', 'Gene', (37, 42))	('EGFR', 'Gene', (28, 32))	('amplification', 'Var', (44, 57))	('CCND1', 'Gene', '595', (37, 42))	('deletion', 'Var', (69, 77))
322857	31255659	This resulted in five DNA methylation subtypes based on DNA methylation aberrations defined as non-CIMP-atypical, NSD1-Smoking, CIMP-atypical, MethylMix HPV+ and stem-like-smoking.	('stem-like-smoking', 'Disease', (162, 179))	('resulted', 'Reg', (5, 13))	('NSD1', 'Gene', '64324', (114, 118))	('MethylMix HPV+', 'Var', (143, 157))	('CIMP', 'Chemical', '-', (99, 103))	('NSD1', 'Gene', (114, 118))	('CIMP', 'Chemical', '-', (128, 132))
322881	31255659	Next, models using only clinical data showed higher performance for CIMP-Atypical (AUC = 0.75) and NSD1-Smoking (AUC = 0.73) compared to the radiomic models, while clinical models for Non-CIMP-Atypical (AUC = 0.53) and Stem-like-Smoking (AUC = 0.66) were inferior to the corresponding radiomic models.	('CIMP-Atypical', 'Var', (68, 81))	('performance', 'MPA', (52, 63))	('CIMP', 'Chemical', '-', (188, 192))	('CIMP', 'Chemical', '-', (68, 72))	('NSD1', 'Gene', '64324', (99, 103))	('higher', 'PosReg', (45, 51))	('NSD1', 'Gene', (99, 103))
322908	31255659	The subtype atypical contains all MethylMix HPV+ cases and 86% of the RNA-defined HPV+ cases, and is thus heavily linked with HPV infection.	('HPV infection', 'Disease', (126, 139))	('linked', 'Reg', (114, 120))	('MethylMix', 'Var', (34, 43))	('HPV infection', 'Disease', 'MESH:D030361', (126, 139))
322909	31255659	Besides enrichment of HPV+, atypical cases are characterized by lack of chromosome 7 amplifications and mutations in the helical domain of PIK3CA.	('PIK3CA', 'Gene', '5290', (139, 145))	('PIK3CA', 'Gene', (139, 145))	('mutations in', 'Var', (104, 116))
322910	31255659	As for non-HPV-related subtypes, our results show that quantitative image features have moderate ability to identify the DNA methylation subtypes including the non-CIMP-Atypical, and the mutation NSD1.	('NSD1', 'Gene', '64324', (196, 200))	('CIMP', 'Chemical', '-', (164, 168))	('mutation', 'Var', (187, 195))	('non-CIMP-Atypical', 'Disease', (160, 177))	('NSD1', 'Gene', (196, 200))
322911	31255659	The CIMP, 'CpG island methylator phenotype', is a driver for cancer developments related to epigenetic silence of tumor suppressor genes.	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('cancer', 'Disease', (61, 67))	('tumor', 'Disease', (114, 119))	('epigenetic silence', 'Var', (92, 110))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('CIMP', 'Chemical', '-', (4, 8))
322912	31255659	The non-CIMP-atypical subtype was mostly found with CASP8 and NOTCH1 mutations.	('found', 'Reg', (41, 46))	('mutations', 'Var', (69, 78))	('CIMP', 'Chemical', '-', (8, 12))	('CASP8', 'Gene', (52, 57))	('CASP8', 'Gene', '841', (52, 57))	('NOTCH1', 'Gene', '4851', (62, 68))	('non-CIMP-atypical subtype', 'Disease', (4, 29))	('NOTCH1', 'Gene', (62, 68))
322913	31255659	It is interesting that radiomic models for DNA methylation subtypes non-CIMP-atypical and Stem-like-Smoking, gene expression subtype classical, and mutation NOTCH1 performed better than clinical models, suggesting the CT imaging features are more representative of the tumors and the inter-tumor and intra-tumor characteristics can be much better captured by the imaging than semantic clinical features for these subtypes.	('tumor', 'Disease', 'MESH:D009369', (269, 274))	('CIMP', 'Chemical', '-', (72, 76))	('tumor', 'Disease', 'MESH:D009369', (306, 311))	('intra-tumor', 'Disease', (300, 311))	('tumor', 'Phenotype', 'HP:0002664', (269, 274))	('tumor', 'Phenotype', 'HP:0002664', (306, 311))	('tumors', 'Phenotype', 'HP:0002664', (269, 275))	('tumor', 'Disease', (269, 274))	('tumor', 'Disease', (306, 311))	('tumor', 'Disease', 'MESH:D009369', (290, 295))	('NOTCH1', 'Gene', '4851', (157, 163))	('tumors', 'Disease', (269, 275))	('NOTCH1', 'Gene', (157, 163))	('tumors', 'Disease', 'MESH:D009369', (269, 275))	('intra-tumor', 'Disease', 'MESH:D009369', (300, 311))	('tumor', 'Phenotype', 'HP:0002664', (290, 295))	('mutation', 'Var', (148, 156))	('tumor', 'Disease', (290, 295))
322920	31142332	Acumulating evidence shows that, m6A RNA methylation has an outsize effect on RNA production/metabolism and participates in the pathogenesis of multiple diseases including cancers.	('outsize effect', 'MPA', (60, 74))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('participates in', 'Reg', (108, 123))	('RNA production/metabolism', 'MPA', (78, 103))	('m6A', 'Gene', (33, 36))	('methylation', 'Var', (41, 52))	('cancers', 'Disease', 'MESH:D009369', (172, 179))	('cancers', 'Phenotype', 'HP:0002664', (172, 179))	('m6A', 'Gene', '56339', (33, 36))	('cancers', 'Disease', (172, 179))
322922	31142332	In this review, we mainly summarize the recent advances in biological function of m6A modifications in human cancer and discuss the potential therapeutic strategies.	('modifications', 'Var', (86, 99))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('human', 'Species', '9606', (103, 108))	('cancer', 'Disease', (109, 115))	('m6A', 'Gene', (82, 85))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('m6A', 'Gene', '56339', (82, 85))
322931	31142332	In this review, we summarize the function and therapeutic advances of m6A modifications in human cancer and provide their promising applications in the treatment of these malignant tumors (Table 1).	('m6A', 'Gene', (70, 73))	('cancer', 'Disease', (97, 103))	('tumors', 'Phenotype', 'HP:0002664', (181, 187))	('cancer', 'Disease', 'MESH:D009369', (97, 103))	('malignant tumors', 'Disease', (171, 187))	('m6A', 'Gene', '56339', (70, 73))	('modifications', 'Var', (74, 87))	('malignant tumors', 'Disease', 'MESH:D018198', (171, 187))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('human', 'Species', '9606', (91, 96))
322936	31142332	M6A modifications promote the initiation of miRNA biogenesis and regulate nuclear mRNA processing events.	('modifications', 'Var', (4, 17))	('M6A', 'Gene', '56339', (0, 3))	('miRNA biogenesis', 'MPA', (44, 60))	('nuclear mRNA processing events', 'MPA', (74, 104))	('M6A', 'Gene', (0, 3))	('initiation', 'MPA', (30, 40))	('regulate', 'Reg', (65, 73))	('promote', 'PosReg', (18, 25))
322940	31142332	M6A RNA modifications that overlap in space with the splicing enhancer regions affect alternative RNA splicing by acting as key pre-mRNA splicing regulators.	('affect', 'Reg', (79, 85))	('M6A', 'Gene', '56339', (0, 3))	('modifications', 'Var', (8, 21))	('M6A', 'Gene', (0, 3))	('alternative RNA splicing', 'MPA', (86, 110))
322941	31142332	Inhibiton of m6A methyltransferase impacts gene expression and alternative splicing patterns.	('gene expression', 'MPA', (43, 58))	('Inhibiton', 'Var', (0, 9))	('alternative splicing patterns', 'MPA', (63, 92))	('m6A', 'Gene', (13, 16))	('impacts', 'Reg', (35, 42))	('m6A', 'Gene', '56339', (13, 16))
322943	31142332	FTO and ALKBH5 regulate m6A around splice sites to control the splicing of Runt-related transcription factor 1 (RUNX1T1) in exon, and removal of m6A by FTO reduces the recruitment of SRSF2 and prompts the skipping of exon 6, leading to a short isoform of RUNX1T1.	('SRSF2', 'Gene', (183, 188))	('RUNX1T1', 'Gene', (112, 119))	('m6A', 'Gene', '56339', (24, 27))	('Runt-related transcription factor 1', 'Gene', '861', (75, 110))	('m6A', 'Gene', (24, 27))	('ALKBH5', 'Gene', (8, 14))	('FTO', 'Gene', '79068', (152, 155))	('RUNX1T1', 'Gene', '862', (255, 262))	('FTO', 'Gene', (152, 155))	('ALKBH5', 'Gene', '54890', (8, 14))	('FTO', 'Gene', '79068', (0, 3))	('m6A', 'Gene', '56339', (145, 148))	('splicing', 'MPA', (63, 71))	('RUNX1T1', 'Gene', '862', (112, 119))	('FTO', 'Gene', (0, 3))	('skipping', 'MPA', (205, 213))	('removal', 'Var', (134, 141))	('recruitment', 'MPA', (168, 179))	('m6A', 'Gene', (145, 148))	('short isoform', 'MPA', (238, 251))	('RUNX1T1', 'Gene', (255, 262))	('SRSF2', 'Gene', '6427', (183, 188))	('reduces', 'NegReg', (156, 163))	('Runt-related transcription factor 1', 'Gene', (75, 110))
322953	31142332	M6A modifications occur in mRNA and noncoding RNA (ncRNAs) to regulate gene expression in its 5' or 3' UTR.	('gene expression', 'MPA', (71, 86))	('M6A', 'Gene', '56339', (0, 3))	('M6A', 'Gene', (0, 3))	('regulate', 'Reg', (62, 70))	('modifications', 'Var', (4, 17))
322954	31142332	METTL3 enhances mRNA translation, while depletion of METTL3 selectively inhibits mRNAs translation in 5'UTR and reduces AFF4 and MYC translation in bladder cancer but increase that of zinc finger protein 750 and fibroblast growth factor 14 in nasopharyngeal carcinoma.	("mRNAs translation in 5'UTR", 'MPA', (81, 107))	('METTL3', 'Gene', (0, 6))	('inhibits', 'NegReg', (72, 80))	('MYC', 'Gene', (129, 132))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (243, 267))	('METTL3', 'Gene', (53, 59))	('zinc finger protein 750', 'Gene', (184, 207))	('mRNA translation', 'MPA', (16, 32))	('METTL3', 'Gene', '56339', (0, 6))	('METTL3', 'Gene', '56339', (53, 59))	('reduces', 'NegReg', (112, 119))	('AFF4', 'Gene', (120, 124))	('MYC', 'Gene', '4609', (129, 132))	('AFF4', 'Gene', '27125', (120, 124))	('fibroblast growth factor 14', 'Gene', '2259', (212, 239))	('enhances', 'PosReg', (7, 15))	('carcinoma', 'Phenotype', 'HP:0030731', (258, 267))	('nasopharyngeal carcinoma', 'Disease', (243, 267))	('bladder cancer', 'Disease', 'MESH:D001749', (148, 162))	('bladder cancer', 'Disease', (148, 162))	('depletion', 'Var', (40, 49))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('zinc finger protein 750', 'Gene', '79755', (184, 207))	('increase', 'PosReg', (167, 175))	('bladder cancer', 'Phenotype', 'HP:0009725', (148, 162))	('nasopharyngeal carcinoma', 'Disease', 'MESH:D000077274', (243, 267))	('fibroblast growth factor 14', 'Gene', (212, 239))
322955	31142332	M6A modifications facilitate the initiated translation through interacting with the initiation factors eIF3, CBP80 and eIF4E in an RNA-independent manner.	('eIF3', 'Gene', (103, 107))	('M6A', 'Gene', '56339', (0, 3))	('CBP80', 'Gene', '4686', (109, 114))	('eIF4E', 'Gene', '1977', (119, 124))	('facilitate', 'PosReg', (18, 28))	('M6A', 'Gene', (0, 3))	('initiated translation', 'MPA', (33, 54))	('CBP80', 'Gene', (109, 114))	('eIF3', 'Gene', '8661', (103, 107))	('eIF4E', 'Gene', (119, 124))	('interacting', 'Interaction', (63, 74))	('modifications', 'Var', (4, 17))
322960	31142332	The methyltransferases and demethylases of m6A are associated with a variety of diseases, such as obesity, type 2 diabetes mellitus (T2DM), growth retardation, developmental delay, facial dysmorphism.	('type 2 diabetes', 'Phenotype', 'HP:0005978', (107, 122))	('developmental delay', 'Phenotype', 'HP:0001263', (160, 179))	('methyltransferases', 'Enzyme', (4, 22))	('growth retardation', 'Disease', 'MESH:D006130', (140, 158))	('growth retardation', 'Disease', (140, 158))	('diabetes mellitus', 'Disease', (114, 131))	('facial dysmorphism', 'Disease', 'None', (181, 199))	('facial dysmorphism', 'Phenotype', 'HP:0001999', (181, 199))	('facial dysmorphism', 'Disease', (181, 199))	('obesity', 'Disease', (98, 105))	('diabetes mellitus', 'Disease', 'MESH:D003920', (114, 131))	('diabetes mellitus', 'Phenotype', 'HP:0000819', (114, 131))	('obesity', 'Disease', 'MESH:D009765', (98, 105))	('growth retardation', 'Phenotype', 'HP:0001510', (140, 158))	('m6A', 'Gene', '56339', (43, 46))	('demethylases', 'Var', (27, 39))	('developmental delay', 'Disease', (160, 179))	('associated', 'Reg', (51, 61))	('m6A', 'Gene', (43, 46))	('obesity', 'Phenotype', 'HP:0001513', (98, 105))
322961	31142332	Besides, m6A modification affects infertility, developmental arrest, neuronal disorder and infectious diseases.	('infertility', 'Disease', (34, 45))	('neuronal disorder', 'Disease', (69, 86))	('affects', 'Reg', (26, 33))	('infectious diseases', 'Disease', (91, 110))	('m6A', 'Gene', (9, 12))	('modification', 'Var', (13, 25))	('developmental arrest', 'Disease', (47, 67))	('developmental arrest', 'Disease', 'MESH:D006323', (47, 67))	('m6A', 'Gene', '56339', (9, 12))	('neuronal disorder', 'Disease', 'MESH:D009410', (69, 86))	('developmental arrest', 'Phenotype', 'HP:0007281', (47, 67))	('infertility', 'Disease', 'MESH:D007247', (34, 45))	('infectious diseases', 'Disease', 'MESH:D003141', (91, 110))	('infertility', 'Phenotype', 'HP:0000789', (34, 45))
322966	31142332	Deficiency of demethylase ALKBH5 leads to the aberrant spermatogenesis and apoptosis with impaired fertility in testes and striking changes in DNA methyltransferase 1 (Dnmt1) and ubiquitin-like with PHD and RING finger domains 1 (Uhrf1).	('changes', 'Reg', (132, 139))	('Uhrf1', 'Gene', (230, 235))	('ubiquitin-like with PHD and RING finger domains 1', 'Gene', '29128', (179, 228))	('DNA methyltransferase 1', 'Gene', '1786', (143, 166))	('apoptosis', 'CPA', (75, 84))	('spermatogenesis', 'CPA', (55, 70))	('ALKBH5', 'Gene', '54890', (26, 32))	('Dnmt1', 'Gene', (168, 173))	('ALKBH5', 'Gene', (26, 32))	('Dnmt1', 'Gene', '1786', (168, 173))	('Uhrf1', 'Gene', '29128', (230, 235))	('impaired fertility', 'Phenotype', 'HP:0000144', (90, 108))	('aberrant spermatogenesis', 'Phenotype', 'HP:0008669', (46, 70))	('DNA methyltransferase 1', 'Gene', (143, 166))	('Deficiency', 'Var', (0, 10))
322969	31142332	M6A modification regulates the pace of cerebral cortex development and m6A-regulated histone modifications enhances self-renewal of neural stem cells by METTL3/14.	('enhances', 'PosReg', (107, 115))	('pace', 'CPA', (31, 35))	('self-renewal of neural stem cells', 'CPA', (116, 149))	('M6A', 'Gene', '56339', (0, 3))	('modifications', 'Var', (93, 106))	('histone', 'Protein', (85, 92))	('m6A', 'Gene', (71, 74))	('M6A', 'Gene', (0, 3))	('regulates', 'Reg', (17, 26))	('m6A', 'Gene', '56339', (71, 74))	('METTL3', 'Gene', '56339', (153, 159))	('METTL3', 'Gene', (153, 159))
322971	31142332	M6A depletion decreases the decay of radial glia cells associated with stem cell maintenance, neurogenesis and differentiation.	('decreases', 'NegReg', (14, 23))	('neurogenesis', 'CPA', (94, 106))	('decay of radial glia cells', 'CPA', (28, 54))	('M6A', 'Gene', '56339', (0, 3))	('differentiation', 'CPA', (111, 126))	('M6A', 'Gene', (0, 3))	('depletion', 'Var', (4, 13))
322972	31142332	Cacinogenesis is characterized by stepwise accumulation of genetic/epigenetic alterations of different proto-oncogenes and tumor-suppressor genes following other diseases including chronic inflammation and metabolic diseases.	('inflammation', 'Disease', (189, 201))	('metabolic diseases', 'Disease', (206, 224))	('tumor', 'Disease', (123, 128))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('genetic/epigenetic alterations', 'Var', (59, 89))	('Cacinogenesis', 'Disease', (0, 13))	('inflammation', 'Disease', 'MESH:D007249', (189, 201))	('metabolic diseases', 'Disease', 'MESH:D008659', (206, 224))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
322973	31142332	METTL3/14 and FTO influence Hepatitis C virus replication and production, and endogenous mediators of inflammatory responses (proinflammatory cytokines, reactive oxygen, et al) can promote genetic/epigenetic alterations.	('METTL3', 'Gene', '56339', (0, 6))	('Hepatitis', 'Phenotype', 'HP:0012115', (28, 37))	('genetic/epigenetic alterations', 'Var', (189, 219))	('FTO influence Hepatitis C virus', 'Disease', (14, 45))	('METTL3', 'Gene', (0, 6))	('promote', 'PosReg', (181, 188))	('production', 'MPA', (62, 72))	('FTO influence Hepatitis C virus', 'Disease', 'MESH:D006526', (14, 45))	('replication', 'MPA', (46, 57))
322976	31142332	Emerging evidence suggests that, m6A modification is associated with the tumor proliferation, differentiation, tumorigenesis, proliferation, invasion and metastasis and functions as oncogenes or anti-oncogenes in malignant tumors (Table 1 and Fig.	('invasion', 'CPA', (141, 149))	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('modification', 'Var', (37, 49))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('m6A', 'Gene', (33, 36))	('malignant tumors', 'Disease', (213, 229))	('proliferation', 'CPA', (126, 139))	('associated', 'Reg', (53, 63))	('tumor', 'Disease', (223, 228))	('tumor', 'Disease', (111, 116))	('tumor', 'Disease', (73, 78))	('tumor', 'Disease', 'MESH:D009369', (223, 228))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumors', 'Phenotype', 'HP:0002664', (223, 229))	('differentiation', 'CPA', (94, 109))	('m6A', 'Gene', '56339', (33, 36))	('malignant tumors', 'Disease', 'MESH:D018198', (213, 229))
322977	31142332	FTO is highly expressed in AML with t(11q23)/MLL rearrangements, t(15;17)/PML-RARA, FLT3-ITD and/or NPM1 mutations and promotes leukemic cell transformation and tumorigenesis.	('AML', 'Phenotype', 'HP:0004808', (27, 30))	('PML', 'Gene', (74, 77))	('FLT3', 'Gene', (84, 88))	('mutations', 'Var', (105, 114))	('tumor', 'Disease', (161, 166))	('FLT3', 'Gene', '2322', (84, 88))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('NPM1', 'Gene', (100, 104))	('RARA', 'Gene', '5914', (78, 82))	('PML', 'Gene', '5371', (74, 77))	('FTO', 'Gene', '79068', (0, 3))	('MLL', 'Gene', '4297', (45, 48))	('MLL', 'Gene', (45, 48))	('FTO', 'Gene', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('RARA', 'Gene', (78, 82))	('promotes', 'PosReg', (119, 127))	('leukemic', 'Disease', 'MESH:D007938', (128, 136))	('AML', 'Disease', 'MESH:D015470', (27, 30))	('leukemic', 'Disease', (128, 136))	('AML', 'Disease', (27, 30))	('NPM1', 'Gene', '4869', (100, 104))
322984	31142332	Collectively, these studies corroborate the functional importance of m6A modifications in leukemia, such as METTL3, METTL14, FTO and YTHDF2 and they provide profound insights into development and maintenance of AML and self-renewal of leukemia stem/initiation cells through the downstream MYC and Tal1 pathways.	('FTO', 'Gene', (125, 128))	('Tal1', 'Gene', (297, 301))	('METTL14', 'Gene', (116, 123))	('modifications', 'Var', (73, 86))	('MYC', 'Gene', (289, 292))	('YTHDF2', 'Gene', (133, 139))	('leukemia', 'Disease', 'MESH:D007938', (90, 98))	('leukemia', 'Disease', (90, 98))	('m6A', 'Gene', '56339', (69, 72))	('self-renewal', 'CPA', (219, 231))	('METTL3', 'Gene', (108, 114))	('MYC', 'Gene', '4609', (289, 292))	('leukemia', 'Phenotype', 'HP:0001909', (235, 243))	('m6A', 'Gene', (69, 72))	('YTHDF2', 'Gene', '51441', (133, 139))	('METTL3', 'Gene', '56339', (108, 114))	('Tal1', 'Gene', '6886', (297, 301))	('leukemia', 'Disease', (235, 243))	('leukemia', 'Disease', 'MESH:D007938', (235, 243))	('AML', 'Disease', 'MESH:D015470', (211, 214))	('METTL14', 'Gene', '57721', (116, 123))	('AML', 'Phenotype', 'HP:0004808', (211, 214))	('AML', 'Disease', (211, 214))	('FTO', 'Gene', '79068', (125, 128))	('leukemia', 'Phenotype', 'HP:0001909', (90, 98))
322990	31142332	Besides, SUMOylation of METTL3 is of importance for the promotion of tumor growth at lysine residues K177, K211, K212 and K215 in non-small cell lung carcinoma (NSCLC).	('lysine', 'Chemical', 'MESH:D008239', (85, 91))	('K215', 'Var', (122, 126))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('promotion', 'PosReg', (56, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (150, 159))	('non-small cell lung carcinoma', 'Phenotype', 'HP:0030358', (130, 159))	('NSCLC', 'Disease', 'MESH:D002289', (161, 166))	('non-small cell lung carcinoma', 'Disease', (130, 159))	('small cell lung carcinoma', 'Phenotype', 'HP:0030357', (134, 159))	('K211', 'Var', (107, 111))	('K212', 'Var', (113, 117))	('NSCLC', 'Disease', (161, 166))	('METTL3', 'Gene', (24, 30))	('tumor', 'Disease', (69, 74))	('K177', 'Var', (101, 105))	('NSCLC', 'Phenotype', 'HP:0030358', (161, 166))	('non-small cell lung carcinoma', 'Disease', 'MESH:D002289', (130, 159))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('METTL3', 'Gene', '56339', (24, 30))
322997	31142332	Thus, these studies suggest a new dimension of epigenetic alteration in liver carcinogenesis.	('liver carcinogenesis', 'Disease', 'MESH:D063646', (72, 92))	('liver carcinogenesis', 'Disease', (72, 92))	('epigenetic alteration', 'Var', (47, 68))
323002	31142332	On the one hand, m6A-modified genes usually act a oncogenic role in cancer, leading to alterations of mRNA translation and acceleration of tumor progression, and decreasing m6A modification results in tumor development.	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('m6A', 'Gene', (173, 176))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('alterations', 'Var', (87, 98))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('mRNA translation', 'MPA', (102, 118))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('m6A', 'Gene', '56339', (173, 176))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('cancer', 'Disease', (68, 74))	('m6A', 'Gene', (17, 20))	('tumor', 'Disease', (201, 206))	('acceleration', 'PosReg', (123, 135))	('decreasing', 'NegReg', (162, 172))	('modification', 'MPA', (177, 189))	('m6A', 'Gene', '56339', (17, 20))
323003	31142332	On the other hand, given that SUMOylation of METTL3 represses its m6A methyltransferase capacity and results in tumor growth of NSCLC, modification of m6A methylase can determine the tumor development.	('results in', 'Reg', (101, 111))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('NSCLC', 'Disease', (128, 133))	('m6A', 'Gene', (151, 154))	('NSCLC', 'Phenotype', 'HP:0030358', (128, 133))	('represses', 'NegReg', (52, 61))	('METTL3', 'Gene', (45, 51))	('tumor', 'Disease', (112, 117))	('m6A', 'Gene', '56339', (66, 69))	('METTL3', 'Gene', '56339', (45, 51))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('capacity', 'MPA', (88, 96))	('tumor', 'Disease', (183, 188))	('determine', 'Reg', (169, 178))	('m6A', 'Gene', (66, 69))	('modification', 'Var', (135, 147))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('NSCLC', 'Disease', 'MESH:D002289', (128, 133))	('SUMOylation', 'Var', (30, 41))	('m6A', 'Gene', '56339', (151, 154))
323005	31142332	Regulators or inhibitors of m6A modifications may provide the potential therapeutic strategies for cancers, such as MA2 in GBM, R-2HG/SPI1/FB23-2 in AML and CA4 in CRC.	('SPI1', 'Gene', '6688', (134, 138))	('MA2', 'Gene', '10687', (116, 119))	('R-2', 'Gene', '913', (128, 131))	('cancers', 'Disease', 'MESH:D009369', (99, 106))	('modifications', 'Var', (32, 45))	('AML', 'Disease', 'MESH:D015470', (149, 152))	('AML', 'Disease', (149, 152))	('AML', 'Phenotype', 'HP:0004808', (149, 152))	('R-2', 'Gene', (128, 131))	('m6A', 'Gene', '56339', (28, 31))	('CA4', 'Gene', (157, 160))	('CA4', 'Gene', '762', (157, 160))	('SPI1', 'Gene', (134, 138))	('m6A', 'Gene', (28, 31))	('cancers', 'Phenotype', 'HP:0002664', (99, 106))	('cancers', 'Disease', (99, 106))	('CRC', 'Disease', (164, 167))	('MA2', 'Gene', (116, 119))	('GBM', 'Disease', (123, 126))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
323011	31142332	ALKBH5 and FTO are alpha-ketoglutarate (alpha-KG)-dependent dioxygenases, which are competitively inhibited by D2-hydorxyglutarate (D2-HG) and elevated in isocitrate de-hydrogenases (IDH)-mutant cancers for transferring isocitrate to alpha-KG.	('FTO', 'Gene', '79068', (11, 14))	('IDH', 'Gene', (183, 186))	('FTO', 'Gene', (11, 14))	('alpha-KG', 'Chemical', 'MESH:D007656', (234, 242))	('-mutant', 'Var', (187, 194))	('-ketoglutarate', 'Chemical', '-', (24, 38))	('inhibited', 'NegReg', (98, 107))	('cancers', 'Disease', 'MESH:D009369', (195, 202))	('IDH', 'Gene', '3417', (183, 186))	('ALKBH5', 'Gene', (0, 6))	('D2-hydorxyglutarate', 'Chemical', '-', (111, 130))	('alpha-KG', 'Chemical', 'MESH:D007656', (40, 48))	('elevated', 'PosReg', (143, 151))	('ALKBH5', 'Gene', '54890', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('isocitrate', 'Chemical', 'MESH:C034219', (220, 230))	('isocitrate', 'Chemical', 'MESH:C034219', (155, 165))	('cancers', 'Phenotype', 'HP:0002664', (195, 202))	('cancers', 'Disease', (195, 202))
323012	31142332	R-2-hydroxyglutarate (R-2HG), an metabolite by mutating IDH1/2 enzyme, exhibits anti-leukemia effects through increasing m6A levels in R-2HG-sensitive AML.	('m6A', 'Gene', (121, 124))	('mutating', 'Var', (47, 55))	('increasing', 'PosReg', (110, 120))	('R-2', 'Gene', '913', (0, 3))	('AML', 'Disease', 'MESH:D015470', (151, 154))	('R-2-', 'Gene', '913', (0, 4))	('AML', 'Disease', (151, 154))	('R-2', 'Gene', '913', (135, 138))	('R-2', 'Gene', '913', (22, 25))	('AML', 'Phenotype', 'HP:0004808', (151, 154))	('leukemia', 'Phenotype', 'HP:0001909', (85, 93))	('R-2-', 'Gene', (0, 4))	('R-2', 'Gene', (0, 3))	('leukemia', 'Disease', 'MESH:D007938', (85, 93))	('leukemia', 'Disease', (85, 93))	('m6A', 'Gene', '56339', (121, 124))	('R-2', 'Gene', (135, 138))	('IDH1/2', 'Gene', '3417;3418', (56, 62))	('R-2', 'Gene', (22, 25))	('IDH1/2', 'Gene', (56, 62))
323013	31142332	S-adenosylmethionine (SAM) serves as a cofactor substrate in METTL3/14 complex and its product S-adenosylhomocysteine (SAH) inhibits the methyltransferases by competing with adenosylmethionine.	('METTL3', 'Gene', (61, 67))	('methyltransferases', 'Enzyme', (137, 155))	('inhibits', 'NegReg', (124, 132))	('adenosylmethionine', 'Chemical', 'MESH:D012436', (2, 20))	('S-adenosylhomocysteine', 'Var', (95, 117))	('SAM', 'Chemical', 'MESH:D012436', (22, 25))	('S-adenosylmethionine', 'Chemical', 'MESH:D012436', (0, 20))	('adenosylmethionine', 'Chemical', 'MESH:D012436', (174, 192))	('METTL3', 'Gene', '56339', (61, 67))
323023	31142332	Though some inhibitors of m6A methylation have shown promising effects on cancer development, novel therapeutic strategies for m6A RNA methylation should be further explored in the treatment of cancer.	('inhibitors', 'Var', (12, 22))	('m6A', 'Gene', '56339', (127, 130))	('cancer', 'Disease', (194, 200))	('effects', 'Reg', (63, 70))	('m6A', 'Gene', '56339', (26, 29))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Disease', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('m6A', 'Gene', (26, 29))	('m6A', 'Gene', (127, 130))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('cancer', 'Disease', 'MESH:D009369', (194, 200))
323029	28187435	Overexpression of GLUT1 was found to significantly correlate with poor 3-year OS (OR: 2.86; 95% CI, 1.90-4.32, P < 0.00001) and 5-year OS (OR: 2.52; 95% CI, 1.75-3.61, P < 0.00001) of solid tumors.	('solid tumors', 'Disease', 'MESH:D009369', (184, 196))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('GLUT1', 'Gene', (18, 23))	('OS', 'Chemical', '-', (135, 137))	('GLUT1', 'Gene', '6513', (18, 23))	('Overexpression', 'Var', (0, 14))	('OS', 'Chemical', '-', (78, 80))	('tumors', 'Phenotype', 'HP:0002664', (190, 196))	('solid tumors', 'Disease', (184, 196))	('poor', 'NegReg', (66, 70))
323057	28187435	In the stratified analysis, expression status of GLUT1 was associated with unfavorable clinical results of oral squamous cell carcinoma (OR: 3.79; 95% CI, 1.74-8.24, P = 0.0008) (Figure 3A), and breast carcinoma (OR: 2.32; 95% CI, 1.02-5.30, P = 0.04) (Figure 3B).	('breast carcinoma', 'Disease', (195, 211))	('breast carcinoma', 'Phenotype', 'HP:0003002', (195, 211))	('expression status', 'Var', (28, 45))	('breast carcinoma', 'Disease', 'MESH:D001943', (195, 211))	('associated', 'Reg', (59, 69))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (112, 135))	('carcinoma', 'Phenotype', 'HP:0030731', (202, 211))	('GLUT1', 'Gene', (49, 54))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (107, 135))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('GLUT1', 'Gene', '6513', (49, 54))	('oral squamous cell carcinoma', 'Disease', (107, 135))
323063	28187435	High expression status of GLUT1 was related to poor 5-year OS of oral squamous cell carcinoma (OR: 2.70; 95% CI, 1.57-4.65, P = 0.0003) (Figure 5A), and breast carcinoma (OR: 6.81; 95% CI, 1.94-23.98, P = 0.003) (Figure 5B).	('breast carcinoma', 'Disease', 'MESH:D001943', (153, 169))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (70, 93))	('OS', 'Chemical', '-', (59, 61))	('GLUT1', 'Gene', (26, 31))	('High', 'Var', (0, 4))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (65, 93))	('breast carcinoma', 'Phenotype', 'HP:0003002', (153, 169))	('carcinoma', 'Phenotype', 'HP:0030731', (160, 169))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('GLUT1', 'Gene', '6513', (26, 31))	('oral squamous cell carcinoma', 'Disease', (65, 93))	('breast carcinoma', 'Disease', (153, 169))
323098	28187435	In light of GLUT1 as a major receptor for uptake of Vitamin C, an interesting study discovered that cultured human colorectal cancer cells with BRAF or KRAS mutations are selectively exterminated after high dose of vitamin C treatment, as a result of elevated GLUT1-facilitated uptake of the oxidized form of vitamin C, namely dehydroascorbate, which indicates a potentially novel therapy for KRAS or BRAF mutant colorectal cancers.	('GLUT1', 'Gene', (260, 265))	('cancers', 'Phenotype', 'HP:0002664', (424, 431))	('BRAF', 'Gene', '673', (144, 148))	('KRAS', 'Gene', '3845', (393, 397))	('BRAF', 'Gene', (144, 148))	('GLUT1', 'Gene', (12, 17))	('KRAS', 'Gene', (393, 397))	('colorectal cancer', 'Disease', 'MESH:D015179', (413, 430))	('KRAS', 'Gene', '3845', (152, 156))	('mutations', 'Var', (157, 166))	('colorectal cancer', 'Phenotype', 'HP:0003003', (115, 132))	('mutant', 'Var', (406, 412))	('uptake', 'MPA', (278, 284))	('colorectal cancers', 'Disease', 'MESH:D015179', (413, 431))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('vitamin C', 'Chemical', 'MESH:D001205', (309, 318))	('BRAF', 'Gene', '673', (401, 405))	('KRAS', 'Gene', (152, 156))	('GLUT1', 'Gene', '6513', (260, 265))	('BRAF', 'Gene', (401, 405))	('vitamin C', 'Chemical', 'MESH:D001205', (215, 224))	('human', 'Species', '9606', (109, 114))	('colorectal cancer', 'Disease', 'MESH:D015179', (115, 132))	('GLUT1', 'Gene', '6513', (12, 17))	('dehydroascorbate', 'Chemical', 'MESH:D003683', (327, 343))	('colorectal cancer', 'Phenotype', 'HP:0003003', (413, 430))	('Vitamin C', 'Chemical', 'MESH:D001205', (52, 61))	('cancer', 'Phenotype', 'HP:0002664', (424, 430))	('elevated', 'PosReg', (251, 259))	('high dose of vitamin C', 'Phenotype', 'HP:0100510', (202, 224))	('colorectal cancer', 'Disease', (115, 132))	('colorectal cancers', 'Disease', (413, 431))
323155	27553942	A study shows that the prognostic value of CD3+ and CD8+ T-cells depends on the infiltration pattern.	('CD8', 'Gene', (52, 55))	('CD3+', 'Var', (43, 47))	('CD8', 'Gene', '925', (52, 55))
323161	27553942	In an analysis of 124 articles that focus on the prognostic values of T-cells, the presence of CD8 cytotoxic T-cells appears to be generally associated with an improved survival.	('survival', 'CPA', (169, 177))	('presence', 'Var', (83, 91))	('CD8', 'Gene', '925', (95, 98))	('improved', 'PosReg', (160, 168))	('CD8', 'Gene', (95, 98))
323183	27553942	Notably, microsatellite-instable tumors exhibited increased densities of TH1, effector, and memory T-cell populations.	('TH1', 'Gene', (73, 76))	('effector', 'CPA', (78, 86))	('densities', 'CPA', (60, 69))	('microsatellite-instable', 'Var', (9, 32))	('increased', 'PosReg', (50, 59))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumors', 'Disease', 'MESH:D009369', (33, 39))	('TH1', 'Gene', '51497', (73, 76))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('tumors', 'Disease', (33, 39))
323201	27553942	Interestingly, a recent comprehensive bioinformatics study involving ~18,000 human tumors of 39 types of malignancy revealed consistent results that neutrophils were markers for poor clinical responses.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('neutrophils', 'Var', (149, 160))	('tumors', 'Disease', (83, 89))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('tumors', 'Disease', 'MESH:D009369', (83, 89))	('malignancy', 'Disease', 'MESH:D009369', (105, 115))	('malignancy', 'Disease', (105, 115))	('human', 'Species', '9606', (77, 82))
323216	27553942	Epigenetic silencing of TH1 cytokines CXCL9 and CXCL10 in cancer cells severely compromised the recruitment of effector T-cells, and blockade of epigenetic repression improved checkpoint-targeted immunotherapy.	('improved', 'PosReg', (167, 175))	('CXCL9', 'Gene', (38, 43))	('recruitment of effector T-cells', 'MPA', (96, 127))	('checkpoint-targeted immunotherapy', 'CPA', (176, 209))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('compromised', 'NegReg', (80, 91))	('CXCL10', 'Gene', '3627', (48, 54))	('TH1', 'Gene', '51497', (24, 27))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('Epigenetic silencing', 'Var', (0, 20))	('cancer', 'Disease', (58, 64))	('CXCL10', 'Gene', (48, 54))	('epigenetic repression', 'Var', (145, 166))	('TH1', 'Gene', (24, 27))	('CXCL9', 'Gene', '4283', (38, 43))
323228	27553942	It has been suggested that the genomic mutations in melanoma drive the presentation of tumor-associated mutant neoantigens on the cell surface, which promotes the clonal diversity of anti-tumor immunity and underlies the successful clinical outcome of immunotherapy.	('tumor', 'Disease', (188, 193))	('melanoma', 'Phenotype', 'HP:0002861', (52, 60))	('melanoma', 'Disease', (52, 60))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('promotes', 'PosReg', (150, 158))	('melanoma', 'Disease', 'MESH:D008545', (52, 60))	('mutant', 'Var', (104, 110))	('tumor', 'Disease', (87, 92))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('genomic mutations', 'Var', (31, 48))	('presentation', 'MPA', (71, 83))
323229	27553942	Recent studies of HNSCC cancer genomics showed that every HNSCC cell harbors more than 200 mutations; yet patient responses to immunotherapeutic agents are not optimal.	('harbors', 'Reg', (69, 76))	('HNSCC cancer', 'Disease', (18, 30))	('HNSCC', 'Phenotype', 'HP:0012288', (18, 23))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('patient', 'Species', '9606', (106, 113))	('mutations', 'Var', (91, 100))	('HNSCC cancer', 'Disease', 'MESH:D000077195', (18, 30))	('HNSCC', 'Phenotype', 'HP:0012288', (58, 63))
323238	27553942	Knocking down autophagy-promoting proteins restored the level of GMZB in tumor cells and sensitized tumor to effector immune cells.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('GMZB', 'Chemical', '-', (65, 69))	('Knocking down', 'Var', (0, 13))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Disease', (100, 105))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Disease', (73, 78))	('level', 'MPA', (56, 61))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('restored', 'PosReg', (43, 51))
323240	27553942	Genetic evidence shows that autophagy prevents tumor initiation, as disruption of an autophagy-promoting gene BECN1 resulted in increased tumorigenesis.	('tumor', 'Disease', (47, 52))	('tumor', 'Disease', (138, 143))	('disruption', 'Var', (68, 78))	('increased', 'PosReg', (128, 137))	('BECN1', 'Gene', '8678', (110, 115))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumor initiation', 'Disease', 'MESH:D009369', (47, 63))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('BECN1', 'Gene', (110, 115))	('tumor initiation', 'Disease', (47, 63))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
323252	27553942	Importantly, recent genomic characterization of HNSCC revealed novel mutations involving cell death pathways, especially mutations affecting CASP8.	('mutations', 'Var', (69, 78))	('HNSCC', 'Phenotype', 'HP:0012288', (48, 53))	('mutations', 'Var', (121, 130))	('involving', 'Reg', (79, 88))	('cell', 'CPA', (89, 93))	('HNSCC', 'Gene', (48, 53))	('CASP8', 'Gene', (141, 146))	('CASP8', 'Gene', '841', (141, 146))
323254	27553942	Mutations of CASP8 in HNSCC were found to be diffuse and suggestive of loss-of-function in nature.	('loss-of-function', 'NegReg', (71, 87))	('CASP8', 'Gene', (13, 18))	('CASP8', 'Gene', '841', (13, 18))	('HNSCC', 'Gene', (22, 27))	('Mutations', 'Var', (0, 9))	('HNSCC', 'Phenotype', 'HP:0012288', (22, 27))
323272	27553942	However there are several urgent scientific challenges that need to be addressed to realize the potential of precision medicine-informed immunotherapy: (1) Although high CD3+ CD8+ T-cell and Treg counts appear to be prognostically beneficial, the current immunoscore scheme has not yet fully taken into account cancer cell factors that modulate tumor immunogenicity.	('tumor', 'Disease', 'MESH:D009369', (345, 350))	('CD8', 'Gene', (175, 178))	('tumor', 'Phenotype', 'HP:0002664', (345, 350))	('cancer', 'Disease', (311, 317))	('cancer', 'Disease', 'MESH:D009369', (311, 317))	('high', 'Var', (165, 169))	('tumor', 'Disease', (345, 350))	('CD3+', 'Gene', (170, 174))	('CD8', 'Gene', '925', (175, 178))	('cancer', 'Phenotype', 'HP:0002664', (311, 317))
323349	27832160	Detection was performed using 2 step Mach 3 Mouse HRP Polymer Detection (Biocare M3M530L, Biocare, Concord, CA, USA) 20/20 minutes.	('Biocare', 'Var', (73, 80))	('M3M530L', 'Var', (81, 88))	('Mouse', 'Species', '10090', (44, 49))
323361	27832160	The collagens CO1A1, CO1A2, CO3A1, CO5A1, CO6A1, CO6A2 and CO6A3 were distinguished by 17, 18, 7, 2, 20, 24 and 97 unique peptides respectively.	('CO6A1', 'Var', (42, 47))	('CO6A3', 'Var', (59, 64))	('CO6A2', 'Var', (49, 54))	('peptides', 'Chemical', 'MESH:D010455', (122, 130))
323431	27832160	High levels of stathmin have been associated with poor prognosis in multiple cancer types and resistance to drugs stabilizing microtubules, such as taxane.	('resistance', 'MPA', (94, 104))	('associated', 'Reg', (34, 44))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('High levels', 'Var', (0, 11))	('taxane', 'Chemical', 'MESH:C080625', (148, 154))	('stathmin', 'Gene', (15, 23))	('stathmin', 'Gene', '3925', (15, 23))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))
323432	27832160	Furthermore, depletion of stathmin leads to cell cycle arrest in the G2 phase and apoptosis.	('apoptosis', 'CPA', (82, 91))	('cell cycle arrest in the G2 phase', 'CPA', (44, 77))	('depletion', 'Var', (13, 22))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (44, 61))	('stathmin', 'Gene', '3925', (26, 34))	('stathmin', 'Gene', (26, 34))
323489	31592412	Furthermore, the IDH1 exon 4 mutation is identified as an unfavorable factor for anlotinib therapy under TMI-based stratification, and the TMI plus IDH1 exon 4 mutation status potentially predicts response to anlotinib.	('mutation', 'Var', (29, 37))	('response', 'MPA', (197, 205))	('IDH1', 'Gene', '3417', (148, 152))	('IDH1', 'Gene', (17, 21))	('predicts', 'Reg', (188, 196))	('IDH1', 'Gene', '3417', (17, 21))	('anlotinib', 'Chemical', 'None', (81, 90))	('anlotinib', 'Chemical', 'None', (209, 218))	('IDH1', 'Gene', (148, 152))
323502	31592412	Our results indicated that alterations in mutation burden (BL vs PD) could not determine anlotinib response, but the specific acquired mutations or numbers of metastases were correlated with the response of those NB patients (Figure  1 ; Table S1 and Figure S3, Supporting Information).	('metastases', 'Disease', (159, 169))	('mutations', 'Var', (135, 144))	('metastases', 'Disease', 'MESH:D009362', (159, 169))	('N', 'Chemical', 'MESH:D009584', (213, 214))	('patients', 'Species', '9606', (216, 224))	('anlotinib', 'Chemical', 'None', (89, 98))
323505	31592412	We hypothesized that the acquired mutations are correlated with acquired anlotinib resistance, and then analyzed the acquired mutations in the three subgroups independently.	('anlotinib resistance', 'MPA', (73, 93))	('mutations', 'Var', (34, 43))	('anlotinib', 'Chemical', 'None', (73, 82))
323506	31592412	Our results indicated that 14 LUAD patients (driver gene negative) acquired mutations (range: 1-13 mutations) in 17 cancer genes after resistance to anlotinib occurred (Figure 1B, left).	('LUAD', 'Disease', (30, 34))	('mutations', 'Var', (76, 85))	('LUAD', 'Disease', 'MESH:C538231', (30, 34))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('anlotinib', 'Chemical', 'None', (149, 158))	('acquired', 'Reg', (67, 75))	('patients', 'Species', '9606', (35, 43))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('LUAD', 'Phenotype', 'HP:0030078', (30, 34))
323509	31592412	Of the acquired mutations (range: 1-7 mutations) in 9 cancer genes, the mutation frequencies of ARID1A (50%) and BRCA2 (50%) were the highest (Figure 1C).	('highest', 'Reg', (134, 141))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('ARID1A', 'Gene', '8289', (96, 102))	('mutations', 'Var', (16, 25))	('ARID1A', 'Gene', (96, 102))	('cancer', 'Disease', (54, 60))	('BRCA2', 'Gene', (113, 118))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('BRCA2', 'Gene', '675', (113, 118))
323512	31592412	These results indicated that acquired mutations in ARID1A and BRCA2 may be associated with acquired anlotinib resistance.	('BRCA2', 'Gene', '675', (62, 67))	('anlotinib resistance', 'MPA', (100, 120))	('ARID1A', 'Gene', '8289', (51, 57))	('anlotinib', 'Chemical', 'None', (100, 109))	('ARID1A', 'Gene', (51, 57))	('mutations', 'Var', (38, 47))	('associated', 'Reg', (75, 85))	('BRCA2', 'Gene', (62, 67))
323513	31592412	We then investigated whether the mutations in ARID1A and BRCA2 were initially involved in the resistance to anlotinib in NSCLC.	('involved', 'Reg', (78, 86))	('resistance to anlotinib', 'MPA', (94, 117))	('BRCA2', 'Gene', (57, 62))	('NSCLC', 'Disease', (121, 126))	('mutations', 'Var', (33, 42))	('investigated', 'Reg', (8, 20))	('anlotinib', 'Chemical', 'None', (108, 117))	('NSCLC', 'Disease', 'MESH:D002289', (121, 126))	('BRCA2', 'Gene', '675', (57, 62))	('ARID1A', 'Gene', '8289', (46, 52))	('ARID1A', 'Gene', (46, 52))	('NSCLC', 'Phenotype', 'HP:0030358', (121, 126))
323514	31592412	Five point mutations in ARID1A and BRCA2 were examined in all 26 anlotinib NB patients (13 driver gene negative LUAD, 6 LUSC, and 7 driver gene positive LUAD) at BL, and the results indicated that 92% (24/26) of NB patients harbored ARID1A (A1850fs, chr 1: 26 779 439:TG/T and G766fs: chr 1: 26 762 190:TC/T) and BRCA2 (T3033fs: chr 13: 32 379 885:CA/C and chr 13: 32 379 885:C/CA) mutations, suggesting these acquired point mutations are potentially associated with anlotinib resistance (Figure 1E).	('ARID1A', 'Gene', (233, 239))	('BRCA2', 'Gene', '675', (313, 318))	('patients', 'Species', '9606', (78, 86))	('LUAD', 'Phenotype', 'HP:0030078', (153, 157))	('anlotinib', 'MPA', (467, 476))	('N', 'Chemical', 'MESH:D009584', (212, 213))	('LUSC', 'Disease', 'MESH:D002294', (120, 124))	('LUSC', 'Phenotype', 'HP:0030359', (120, 124))	('LUAD', 'Phenotype', 'HP:0030078', (112, 116))	('A1850fs', 'Mutation', 'p.A1850fsX', (241, 248))	('ARID1A', 'Gene', '8289', (233, 239))	('N', 'Chemical', 'MESH:D009584', (75, 76))	('ARID1A', 'Gene', (24, 30))	('BRCA2', 'Gene', '675', (35, 40))	('anlotinib', 'Chemical', 'None', (467, 476))	('LUAD', 'Disease', (153, 157))	('A1850fs', 'Var', (241, 248))	('LUAD', 'Disease', (112, 116))	('T3033fs', 'Var', (320, 327))	('G766fs', 'Mutation', 'p.G766fsX', (277, 283))	('ARID1A', 'Gene', '8289', (24, 30))	('G766fs', 'Var', (277, 283))	('LUAD', 'Disease', 'MESH:C538231', (153, 157))	('associated with', 'Reg', (451, 466))	('T3033fs', 'Mutation', 'p.T3033fsX', (320, 327))	('BRCA2', 'Gene', (313, 318))	('LUAD', 'Disease', 'MESH:C538231', (112, 116))	('patients', 'Species', '9606', (215, 223))	('anlotinib', 'Chemical', 'None', (65, 74))	('LUSC', 'Disease', (120, 124))	('BRCA2', 'Gene', (35, 40))
323522	31592412	These results demonstrated that mutation burden could potentially be used as a predictor for anlotinib response stratification in NDB and DCB patients.	('DCB', 'Disease', (138, 141))	('N', 'Chemical', 'MESH:D009584', (130, 131))	('anlotinib', 'Chemical', 'None', (93, 102))	('NDB', 'Disease', (130, 133))	('mutation burden', 'Var', (32, 47))	('patients', 'Species', '9606', (142, 150))
323528	31592412	For further stratification of these NDB and DCB patients, we assumed that specific mutations are associated with anlotinib response, and hence sought to screen for potential unfavorable mutations (Figures S4A and S7, Supporting Information).	('mutations', 'Var', (83, 92))	('N', 'Chemical', 'MESH:D009584', (36, 37))	('anlotinib', 'Chemical', 'None', (113, 122))	('anlotinib response', 'MPA', (113, 131))	('associated', 'Reg', (97, 107))	('patients', 'Species', '9606', (48, 56))
323529	31592412	The correlation analysis of anlotinib response and mutation in the discovery cohort identified 120 unfavorable mutations (Wilcoxon P value < 0.01).	('mutations', 'Var', (111, 120))	('mutation', 'Var', (51, 59))	('anlotinib', 'Chemical', 'None', (28, 37))
323530	31592412	These unfavorable mutations were distributed in 58 cancer genes, and each gene contained 1-14 mutations (Figure S7A, Supporting Information).	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('mutations', 'Var', (18, 27))
323531	31592412	The UMS was derived from patients harboring unfavorable mutation numbers, and ranged from 0 to 96 (Figure S5B, Supporting Information).	('S5B', 'Gene', (106, 109))	('mutation', 'Var', (56, 64))	('S5B', 'Gene', '5711', (106, 109))	('patients', 'Species', '9606', (25, 33))
323534	31592412	Further analysis demonstrated that NSCLC patients with a negative UMS benefited more from anlotinib therapy (Figure 2C; Figure S5G,H, Supporting Information).	('benefited', 'PosReg', (70, 79))	('NSCLC', 'Disease', (35, 40))	('anlotinib', 'Chemical', 'None', (90, 99))	('anlotinib', 'Var', (90, 99))	('patients', 'Species', '9606', (41, 49))	('NSCLC', 'Disease', 'MESH:D002289', (35, 40))	('NSCLC', 'Phenotype', 'HP:0030358', (35, 40))
323541	31592412	Vice versa, patients harboring low TMI scores were more responsive to anlotinib therapy than those with higher TMI scores (Figure 3B,C,F).	('patients', 'Species', '9606', (12, 20))	('anlotinib', 'Chemical', 'None', (70, 79))	('more', 'PosReg', (51, 55))	('responsive to anlotinib therapy', 'MPA', (56, 87))	('low', 'Var', (31, 34))
323544	31592412	As to the subgroups of nonsmokers and >3 metastases, imbalanced composition maybe contributes majority cause (Figure S6D, Supporting Information).	('metastases', 'Disease', (41, 51))	('imbalanced', 'Var', (53, 63))	('metastases', 'Disease', 'MESH:D009362', (41, 51))
323548	31592412	Genetic analysis revealed that 6 patients (with a higher response to anlotinib) did not have the IDH1 exon 4 mutation, and 9 of the remaining 10 patients (with a lower response to anlotinib) had the IDH1 exon 4 mutation.	('patients', 'Species', '9606', (145, 153))	('IDH1', 'Gene', '3417', (199, 203))	('IDH1', 'Gene', (97, 101))	('patients', 'Species', '9606', (33, 41))	('anlotinib', 'Chemical', 'None', (69, 78))	('IDH1', 'Gene', '3417', (97, 101))	('anlotinib', 'Chemical', 'None', (180, 189))	('IDH1', 'Gene', (199, 203))	('mutation', 'Var', (109, 117))
323558	31592412	This process has been demonstrated in multiregion tissue sequencing.22 Through sequencing of cfDNA and ctDNA, our study found that some NSCLC patients were harboring more mutations in plasma than in tissue, which confirmed the limitations of sequencing single tumor region.	('tumor', 'Disease', (260, 265))	('NSCLC', 'Disease', 'MESH:D002289', (136, 141))	('tumor', 'Disease', 'MESH:D009369', (260, 265))	('N', 'Chemical', 'MESH:D009584', (136, 137))	('N', 'Chemical', 'MESH:D009584', (106, 107))	('NSCLC', 'Phenotype', 'HP:0030358', (136, 141))	('N', 'Chemical', 'MESH:D009584', (96, 97))	('tumor', 'Phenotype', 'HP:0002664', (260, 265))	('mutations', 'Var', (171, 180))	('patients', 'Species', '9606', (142, 150))	('NSCLC', 'Disease', (136, 141))
323561	31592412	However, there is no suitable predictor that can be used to distinguish responders to antiangiogenic drugs, especially on multitargeted antiangiogenic drugs.29 Angiogenesis-related receptors (such as VEGFR, PDGFR, and FGFR) can be remarkably inhibited via exposing exposure to multitargeted antiangiogenic drugs, but no confirmed clinical evidence has validated the correlation between expression of angiogenesis-related factors and clinical outcome due to the complex architecture of angiogenic signaling.6, 8, 9, 11 Our results found that NSCLC patients are initially resistant to multitargeted antiangiogenic anlotinib, once they acquire ARID1A and BRCA2 mutations.	('ARID1A', 'Gene', (641, 647))	('BRCA2', 'Gene', '675', (652, 657))	('VEGFR', 'Gene', (200, 205))	('NSCLC', 'Disease', 'MESH:D002289', (541, 546))	('PDGFR', 'Gene', (207, 212))	('mutations', 'Var', (658, 667))	('NSCLC', 'Phenotype', 'HP:0030358', (541, 546))	('anlotinib', 'Chemical', 'None', (612, 621))	('PDGFR', 'Gene', '5159', (207, 212))	('VEGFR', 'Gene', '3791', (200, 205))	('BRCA2', 'Gene', (652, 657))	('patients', 'Species', '9606', (547, 555))	('ARID1A', 'Gene', '8289', (641, 647))	('NSCLC', 'Disease', (541, 546))	('acquire', 'Reg', (633, 640))
323567	31592412	A previous study indicated that tumors harboring more mutations produce extensive neoantigens, which enhances efficacy of checkpoint inhibitors.18 Unlike the findings regarding checkpoint inhibitors, the present findings indicated that multitargeted antiangiogenic therapy using anlotinib brings neglected survival benefit to the NSCLC patients harboring more mutations (especially with a high TMI), but provides significant survival benefit to those harboring fewer mutations (especially those with a low TMI).	('NSCLC', 'Disease', (330, 335))	('survival benefit', 'CPA', (306, 322))	('anlotinib', 'Gene', (279, 288))	('anlotinib', 'Chemical', 'None', (279, 288))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('patients', 'Species', '9606', (336, 344))	('NSCLC', 'Disease', 'MESH:D002289', (330, 335))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('mutations', 'Var', (360, 369))	('tumors', 'Disease', (32, 38))	('NSCLC', 'Phenotype', 'HP:0030358', (330, 335))	('tumors', 'Disease', 'MESH:D009369', (32, 38))
323568	31592412	A single predictor reflects most of events, but can be improved via other factors.16, 18, 30, 32 A previous study described NSCLC patients harboring STK11 mutation who had primary resistance to checkpoint inhibitors, although they had a high TMB.33 A similar phenomenon also exists in fist-generation TKI therapy for those patients harboring concomitant mutations.34, 35 While our results showed that TMI could predict anlotinib response effectively, further analysis indicated that not all TMI full scored patients had a poor response to anlotinib.	('patients', 'Species', '9606', (323, 331))	('men', 'Species', '9606', (264, 267))	('STK11', 'Gene', '6794', (149, 154))	('anlotinib', 'Chemical', 'None', (539, 548))	('anlotinib', 'Chemical', 'None', (419, 428))	('NSCLC', 'Disease', (124, 129))	('patients', 'Species', '9606', (507, 515))	('patients', 'Species', '9606', (130, 138))	('NSCLC', 'Disease', 'MESH:D002289', (124, 129))	('mutation', 'Var', (155, 163))	('STK11', 'Gene', (149, 154))	('NSCLC', 'Phenotype', 'HP:0030358', (124, 129))
323573	31592412	In addition to ongoing efforts to discuss circulating DNA-based sequencing for anlotinib stratification, there is a need to develop a greater understanding of proteomics and exosome omics, since the altered proteins possibly limit the efficacy of multitargeted antiangiogenic drugs.	('altered', 'Var', (199, 206))	('anlotinib', 'Chemical', 'None', (79, 88))	('efficacy', 'MPA', (235, 243))	('proteins', 'Protein', (207, 215))	('limit', 'NegReg', (225, 230))	('N', 'Chemical', 'MESH:D009584', (55, 56))
323582	31592412	Pathological Type and Staging: EGFR driver gene mutations were detected in tissue DNA by ADx-ARMS method, and ALK fusion or ROS1 rearrangement were detected in tissue RNA via RT-qPCR method.	('EGFR', 'Gene', '1956', (31, 35))	('men', 'Species', '9606', (138, 141))	('ALK', 'Gene', '238', (110, 113))	('EGFR', 'Gene', (31, 35))	('N', 'Chemical', 'MESH:D009584', (168, 169))	('ROS1', 'Gene', (124, 128))	('N', 'Chemical', 'MESH:D009584', (83, 84))	('ALK', 'Gene', (110, 113))	('ROS1', 'Gene', '6098', (124, 128))	('mutations', 'Var', (48, 57))
323583	31592412	The patient harboring any one of these positive mutations in EGFR, ALK, and ROS1 was defined as driver gene positive.	('ALK', 'Gene', '238', (67, 70))	('patient', 'Species', '9606', (4, 11))	('ROS1', 'Gene', (76, 80))	('ROS1', 'Gene', '6098', (76, 80))	('EGFR', 'Gene', '1956', (61, 65))	('mutations', 'Var', (48, 57))	('EGFR', 'Gene', (61, 65))	('ALK', 'Gene', (67, 70))
323597	31592412	According to the methods reported in a previous study, the mutations were filtered with VAF > 20%,23 the mutations were deleted with low effect (MODIFIER and LOW), and finally the mutations were obtained with relatively high effect (MODERATE and HIGH).	('mutations', 'Var', (105, 114))	('HIGH', 'Disease', (246, 250))	('HIGH', 'Disease', 'MESH:D052456', (246, 250))
323636	31952355	In some cancers, lower expression of CLDN-1 is shown to be associated with cancer progression and invasion, while in others, loss of CLDN-1 improves the patient survival.	('cancers', 'Disease', 'MESH:D009369', (8, 15))	('cancers', 'Phenotype', 'HP:0002664', (8, 15))	('cancers', 'Disease', (8, 15))	('cancer', 'Disease', (8, 14))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('loss', 'Var', (125, 129))	('lower', 'NegReg', (17, 22))	('invasion', 'CPA', (98, 106))	('cancer', 'Disease', (75, 81))	('CLDN-1', 'Gene', (37, 43))	('improves', 'PosReg', (140, 148))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('patient survival', 'CPA', (153, 169))	('patient', 'Species', '9606', (153, 160))	('CLDN-1', 'Gene', (133, 139))	('cancer', 'Disease', 'MESH:D009369', (8, 14))	('expression', 'MPA', (23, 33))
323642	31952355	Both defective tight junctions and the absence of tight junctions have shown to be associated with the development and progression of certain cancers.	('tight junctions', 'Protein', (50, 65))	('cancers', 'Disease', 'MESH:D009369', (142, 149))	('tight junctions', 'Protein', (15, 30))	('absence', 'NegReg', (39, 46))	('cancers', 'Disease', (142, 149))	('men', 'Species', '9606', (110, 113))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('associated', 'Reg', (83, 93))	('defective', 'Var', (5, 14))	('cancers', 'Phenotype', 'HP:0002664', (142, 149))
323664	31952355	Considering the importance of claudins in cancer, targeting claudin expression appears to have promise in the treatment of cancer.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('men', 'Species', '9606', (115, 118))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', (123, 129))	('claudin expression', 'Protein', (60, 78))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('targeting', 'Var', (50, 59))
323678	31952355	While one study reported that the activation of CLDN-1 was repressed by the binding of E-cadherin to CLDN-1 promoter, knockdown of CLDN-1 has been found to be associated with decreased cell migration and induction of EMT in breast cancer cells.	('cell migration', 'CPA', (185, 199))	('E-cadherin', 'Gene', (87, 97))	('E-cadherin', 'Gene', '999', (87, 97))	('EMT', 'CPA', (217, 220))	('CLDN-1', 'Gene', (131, 137))	('knockdown', 'Var', (118, 127))	('breast cancer', 'Disease', 'MESH:D001943', (224, 237))	('breast cancer', 'Phenotype', 'HP:0003002', (224, 237))	('breast cancer', 'Disease', (224, 237))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('decreased', 'NegReg', (175, 184))
323691	31952355	Several transcript variants for CLDN-1 were found in human invasive breast cancer as a result of splicing and mis splicing events suggesting that through alternative splicing CLDN-1 is downregulated in invasive type of breast cancers.	('breast cancers', 'Phenotype', 'HP:0003002', (219, 233))	('breast cancer', 'Phenotype', 'HP:0003002', (68, 81))	('breast cancer', 'Phenotype', 'HP:0003002', (219, 232))	('invasive breast cancer', 'Disease', (59, 81))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))	('cancers', 'Phenotype', 'HP:0002664', (226, 233))	('alternative splicing', 'Var', (154, 174))	('CLDN-1', 'Gene', (32, 38))	('invasive type of breast cancers', 'Disease', (202, 233))	('downregulated', 'NegReg', (185, 198))	('human', 'Species', '9606', (53, 58))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('CLDN-1', 'Gene', (175, 181))	('invasive breast cancer', 'Disease', 'MESH:D001943', (59, 81))	('invasive type of breast cancers', 'Disease', 'MESH:D001943', (202, 233))
323697	31952355	The same study demonstrated the increased pathogenic character of FTC-133 cells by RASV12 transfection was associated with high expression of CLDN-1 and enhanced cell proliferation and migration.	('CLDN-1', 'Gene', (142, 148))	('cell proliferation', 'CPA', (162, 180))	('FTC', 'Disease', 'MESH:C572845', (66, 69))	('RASV12', 'Gene', (83, 89))	('expression', 'MPA', (128, 138))	('transfection', 'Var', (90, 102))	('FTC', 'Disease', (66, 69))	('enhanced', 'PosReg', (153, 161))	('migration', 'CPA', (185, 194))
323698	31952355	Conversely, the downregulation of CLDN-1 by siRNA caused decreased cell invasion and migration accompanied by decreased phospho-PKC expression in the FTC-238 cells, suggesting that the aggressiveness of follicular thyroid carcinoma associated with high CLDN-1 expression can be influenced by PKC activity.	('downregulation', 'NegReg', (16, 30))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (214, 231))	('aggressiveness', 'Phenotype', 'HP:0000718', (185, 199))	('aggressiveness of follicular thyroid carcinoma', 'Disease', (185, 231))	('cell invasion', 'CPA', (67, 80))	('CLDN-1', 'Gene', (253, 259))	('decreased', 'NegReg', (57, 66))	('aggressiveness of follicular thyroid carcinoma', 'Disease', 'MESH:C572845', (185, 231))	('FTC', 'Disease', (150, 153))	('PKC', 'Gene', '112476', (128, 131))	('carcinoma', 'Phenotype', 'HP:0030731', (222, 231))	('CLDN-1', 'Gene', (34, 40))	('PKC', 'Gene', (128, 131))	('PKC', 'Gene', '112476', (292, 295))	('decreased', 'NegReg', (110, 119))	('FTC', 'Disease', 'MESH:C572845', (150, 153))	('PKC', 'Gene', (292, 295))	('follicular thyroid carcinoma', 'Phenotype', 'HP:0006731', (203, 231))	('high', 'Var', (248, 252))
323704	31952355	In mouse xenograft studies, tumor growth and metastasis is regulated by genetic modulation of CLDN-1.	('tumor', 'Disease', (28, 33))	('mouse', 'Species', '10090', (3, 8))	('genetic modulation', 'Var', (72, 90))	('CLDN-1', 'Gene', (94, 100))	('regulated', 'Reg', (59, 68))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
323716	31952355	Dhawan and colleagues reported that T84 cell transfection with CLDN -1 resulted in aggregation and multilayer formation in transfected T84 cells as compared to the T84 parent cells.	('resulted in', 'Reg', (71, 82))	('multilayer formation', 'CPA', (99, 119))	('CLDN -1', 'Gene', '9076', (63, 70))	('CLDN -1', 'Gene', (63, 70))	('transfection', 'Var', (45, 57))	('aggregation', 'Disease', 'MESH:D001791', (83, 94))	('aggregation', 'Disease', (83, 94))
323718	31952355	The progression of colon cancer has been linked with the dysregulation of the CLDN-1 expression causing disorganization of the tight junction fibrils leading to increased paracellular permeability.	('dysregulation', 'Var', (57, 70))	('colon cancer', 'Phenotype', 'HP:0003003', (19, 31))	('colon cancer', 'Disease', 'MESH:D015179', (19, 31))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('paracellular permeability', 'MPA', (171, 196))	('colon cancer', 'Disease', (19, 31))	('tight', 'Protein', (127, 132))	('increased', 'PosReg', (161, 170))	('CLDN-1', 'Gene', (78, 84))	('disorganization', 'MPA', (104, 119))
323723	31952355	Wnt signaling is activated by the loss of the adenomatous polyposis coli (APC) protein or by the activation of beta-catenin mutations.	('APC', 'Disease', 'MESH:D011125', (74, 77))	('adenomatous polyposis coli', 'Disease', (46, 72))	('APC', 'Disease', (74, 77))	('mutations', 'Var', (124, 133))	('activation', 'PosReg', (97, 107))	('beta-catenin', 'Gene', (111, 123))	('Wnt signaling', 'Pathway', (0, 13))	('adenomatous polyposis coli', 'Phenotype', 'HP:0005227', (46, 72))	('activated', 'PosReg', (17, 26))	('beta-catenin', 'Gene', '1499', (111, 123))	('loss', 'NegReg', (34, 38))	('adenomatous polyposis coli', 'Disease', 'MESH:D011125', (46, 72))
323747	31952355	However in another study reduced expression of CLDN-1 was reported to be a marker for a poor prognosis in HCC, and a further study showed that reduced expression of CLDN-1 reinforced the invasive and cancer stem cell (CSC) like properties of HCC cell lines (Huh7 and Hep3B) in vitro, while the forced expression of CLDN-1 diminished the CSC-like properties of HCC cells.	('HCC', 'Disease', (242, 245))	('CLDN-1', 'Gene', (165, 171))	('HCC', 'Disease', 'MESH:D006528', (242, 245))	('reduced', 'NegReg', (143, 150))	('reinforced', 'PosReg', (172, 182))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('Huh7', 'Gene', (258, 262))	('Huh7', 'Gene', '284424', (258, 262))	('HCC', 'Disease', 'MESH:D006528', (106, 109))	('HCC', 'Disease', 'MESH:D006528', (360, 363))	('HCC', 'Disease', (106, 109))	('HCC', 'Disease', (360, 363))	('Hep3B', 'CellLine', 'CVCL:0326', (267, 272))	('cancer', 'Disease', 'MESH:D009369', (200, 206))	('expression', 'Var', (151, 161))	('cancer', 'Disease', (200, 206))	('diminished', 'NegReg', (322, 332))
323753	31952355	Studies showed that the invasive ability of HOP62 lung adenocarcinoma cells is increased by knockdown of endogenous expression of CLDN-1.	('increased', 'PosReg', (79, 88))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (50, 69))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (50, 69))	('knockdown', 'Var', (92, 101))	('lung adenocarcinoma', 'Disease', (50, 69))	('HOP62', 'CellLine', 'CVCL:1285', (44, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (60, 69))	('CLDN-1', 'Gene', (130, 136))	('invasive ability', 'CPA', (24, 40))
323758	31952355	An experiment in human lung cancer cell lines, observed that TNFalpha induced the expression of CLDN-1, and knockdown of CLDN-1 blocked 75% of TNFalpha-induced gene expression.	('TNFalpha', 'Gene', (61, 69))	('knockdown', 'Var', (108, 117))	('TNFalpha', 'Gene', (143, 151))	('CLDN-1', 'Gene', (96, 102))	('lung cancer', 'Disease', (23, 34))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('expression', 'MPA', (82, 92))	('human', 'Species', '9606', (17, 22))	('lung cancer', 'Phenotype', 'HP:0100526', (23, 34))	('TNFalpha', 'Gene', '7124', (61, 69))	('men', 'Species', '9606', (9, 12))	('TNFalpha', 'Gene', '7124', (143, 151))	('lung cancer', 'Disease', 'MESH:D008175', (23, 34))
323759	31952355	In CL1-5 lung cancer cells, cell migration activity was inhibited by over-expression of CLDN-1 and restored by CLDN-1 knockdown in addition to cell invasion ability.	('restored', 'PosReg', (99, 107))	('knockdown', 'Var', (118, 127))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('over-expression', 'PosReg', (69, 84))	('lung cancer', 'Disease', 'MESH:D008175', (9, 20))	('CLDN-1', 'Gene', (88, 94))	('cell migration activity', 'CPA', (28, 51))	('inhibited', 'NegReg', (56, 65))	('lung cancer', 'Disease', (9, 20))	('lung cancer', 'Phenotype', 'HP:0100526', (9, 20))
323764	31952355	Another study found that enhanced cell migration by tumor necrosis factor and a similar morphology like fibroblast was found to be reduced by small CLDN-1 interfering RNA in the cells of lung cancer.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumor necrosis', 'Disease', 'MESH:D009336', (52, 66))	('cell migration', 'CPA', (34, 48))	('enhanced', 'PosReg', (25, 33))	('small', 'Var', (142, 147))	('lung cancer', 'Disease', 'MESH:D008175', (187, 198))	('CLDN-1', 'Gene', (148, 154))	('tumor necrosis', 'Disease', (52, 66))	('reduced', 'NegReg', (131, 138))	('lung cancer', 'Disease', (187, 198))	('lung cancer', 'Phenotype', 'HP:0100526', (187, 198))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))
323783	31952355	One study demonstrated the association of high CLDN-1 expression with aggressive histopathologic features such as perineural and vascular invasion and suggested that CLDN-1 might be directly or indirectly involved in the progression of OSCC.	('expression', 'MPA', (54, 64))	('OSCC', 'Disease', 'MESH:D002294', (236, 240))	('OSCC', 'Disease', (236, 240))	('high', 'Var', (42, 46))	('involved', 'Reg', (205, 213))	('CLDN-1', 'Gene', (47, 53))
323784	31952355	Another study found that the absence of CLDN-1 was associated with poorly differentiated tumors.	('tumors', 'Disease', (89, 95))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('absence', 'Var', (29, 36))	('associated', 'Reg', (51, 61))	('CLDN-1', 'Gene', (40, 46))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))
323785	31952355	Immunohistochemical analysis revealed that the presence of CLDN-1 in the invasive front of tumor islands was associated with neck mode metastasis.	('CLDN-1', 'Gene', (59, 65))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('presence', 'Var', (47, 55))	('neck mode metastasis', 'Disease', (125, 145))	('associated with', 'Reg', (109, 124))	('tumor', 'Disease', (91, 96))
323786	31952355	The results obtained from this study further suggested that the expression of CLDN-1 is linked with the recurrence of OSCC.	('OSCC', 'Disease', (118, 122))	('recurrence', 'Disease', (104, 114))	('linked', 'Reg', (88, 94))	('expression', 'Var', (64, 74))	('OSCC', 'Disease', 'MESH:D002294', (118, 122))	('CLDN-1', 'Gene', (78, 84))
323794	31952355	In melanoma patients with brain metastases, the expression of CLDN-1 was downregulated, and the introduction of CLDN-1 retrovirus reduced the tumor aggressiveness and tumor migration ability and diminished micro-metastasis in the brain.	('aggressiveness', 'Phenotype', 'HP:0000718', (148, 162))	('CLDN-1', 'Gene', (62, 68))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('retrovirus reduced the tumor aggressiveness', 'Disease', 'MESH:D001523', (119, 162))	('downregulated', 'NegReg', (73, 86))	('introduction', 'Var', (96, 108))	('patients', 'Species', '9606', (12, 20))	('expression', 'MPA', (48, 58))	('melanoma', 'Disease', 'MESH:D008545', (3, 11))	('tumor', 'Disease', (167, 172))	('tumor', 'Disease', (142, 147))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('CLDN-1', 'Gene', (112, 118))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('retrovirus reduced the tumor aggressiveness', 'Disease', (119, 162))	('micro-metastasis in the brain', 'CPA', (206, 235))	('diminished', 'NegReg', (195, 205))	('brain metastases', 'Disease', 'MESH:D009362', (26, 42))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('brain metastases', 'Disease', (26, 42))	('melanoma', 'Phenotype', 'HP:0002861', (3, 11))	('melanoma', 'Disease', (3, 11))
323804	31952355	Any defect in the expression of CLDN-1 can result in tight junction dysfunction causing increased paracellular permeability leading to various pathologies such as in Neonatal ichthyosis-sclerosing cholangitis (NISCH) syndrome.	('ichthyosis', 'Phenotype', 'HP:0008064', (175, 185))	('Neonatal ichthyosis-sclerosing cholangitis (NISCH) syndrome', 'Disease', 'MESH:C564365', (166, 225))	('junction dysfunction', 'Disease', 'MESH:D020511', (59, 79))	('junction dysfunction', 'Disease', (59, 79))	('result in', 'Reg', (43, 52))	('cholangitis', 'Phenotype', 'HP:0030151', (197, 208))	('paracellular permeability', 'MPA', (98, 123))	('increased', 'PosReg', (88, 97))	('CLDN-1', 'Gene', (32, 38))	('sclerosing cholangitis', 'Phenotype', 'HP:0030991', (186, 208))	('defect', 'Var', (4, 10))
323806	31952355	Besides, the other study reported that high expression of CLDN-1 resulted in blood-brain-barrier (BBB) leakiness during post-stroke recovery and targeting of CLDN-1 by a CLDN-1 peptide improved the permeability of brain endothelial barrier.	('permeability', 'MPA', (198, 210))	('improved', 'PosReg', (185, 193))	('high', 'Var', (39, 43))	('stroke', 'Phenotype', 'HP:0001297', (125, 131))	('leakiness', 'Disease', 'MESH:C535298', (103, 112))	('leakiness', 'Disease', (103, 112))	('stroke', 'Disease', (125, 131))	('resulted in', 'Reg', (65, 76))	('stroke', 'Disease', 'MESH:D020521', (125, 131))	('CLDN-1', 'Gene', (58, 64))
323814	31952355	Any disturbance in CLDN-1 expression or its partners may result in the manifestation of various diseases including cancers.	('expression', 'MPA', (26, 36))	('cancers', 'Disease', 'MESH:D009369', (115, 122))	('cancers', 'Phenotype', 'HP:0002664', (115, 122))	('cancers', 'Disease', (115, 122))	('result in', 'Reg', (57, 66))	('disturbance', 'Var', (4, 15))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('CLDN-1', 'Gene', (19, 25))
323819	31952355	One of the studies observed that the human hepatocytes treated with mouse anti-CLDN-1 monoclonal antibodies (mAbs), showed improved drug absorption and prevented hepatitis C virus (HCV) infection.	('mouse', 'Species', '10090', (68, 73))	('anti-CLDN-1', 'Var', (74, 85))	('hepatitis C virus (HCV) infection', 'Disease', 'MESH:D006526', (162, 195))	('hepatitis', 'Phenotype', 'HP:0012115', (162, 171))	('drug absorption', 'MPA', (132, 147))	('prevented', 'NegReg', (152, 161))	('anti-CLDN-1', 'Gene', (74, 85))	('human', 'Species', '9606', (37, 42))	('improved', 'PosReg', (123, 131))
323822	31952355	It was observed that blocking CLDN-1 with cCPE variants in the Huh7.5 hepatoma cell line inhibited infection of Huh7.5 cells with HCV in a dose-dependent manner and this also opened the epidermal barrier in the reconstructed human epidermis.	('HCV', 'Species', '11103', (130, 133))	('infection', 'Disease', (99, 108))	('opened', 'Reg', (175, 181))	('variants', 'Var', (47, 55))	('infection', 'Disease', 'MESH:D007239', (99, 108))	('Huh7.5', 'CellLine', 'CVCL:7927', (112, 118))	('hepatoma', 'Disease', (70, 78))	('hepatoma', 'Disease', 'MESH:D006528', (70, 78))	('inhibited', 'NegReg', (89, 98))	('epidermal barrier in the', 'CPA', (186, 210))	('cCPE', 'Gene', (42, 46))	('human', 'Species', '9606', (225, 230))	('Huh7.5', 'CellLine', 'CVCL:7927', (63, 69))	('CLDN-1', 'Gene', (30, 36))
323829	31952355	Several other studies have used CLDN-4 as a target for tumor therapy and showed the accumulation of anti-CLDN-4 mAbs specifically in the tumors and reduced the growth of human colorectal and gastric tumors in mice.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumors', 'Disease', (137, 143))	('tumors', 'Disease', (199, 205))	('colorectal and gastric tumors', 'Disease', 'MESH:D015179', (176, 205))	('anti-CLDN-4', 'Var', (100, 111))	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('tumors', 'Disease', 'MESH:D009369', (199, 205))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('gastric tumors', 'Phenotype', 'HP:0006753', (191, 205))	('growth', 'CPA', (160, 166))	('tumor', 'Disease', (199, 204))	('mice', 'Species', '10090', (209, 213))	('tumor', 'Disease', (137, 142))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('tumors', 'Phenotype', 'HP:0002664', (199, 205))	('reduced', 'NegReg', (148, 155))	('tumor', 'Disease', (55, 60))	('human', 'Species', '9606', (170, 175))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
323833	31952355	Besides the fact that the abnormal or deregulated expression of claudins has been associated with different human diseases like cancer, there are also other human disorders such as autosomal recessive disorders that have been reported due to clearly defined mutations in the corresponding claudin genes.	('mutations', 'Var', (258, 267))	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('autosomal recessive disorders', 'Disease', (181, 210))	('associated', 'Reg', (82, 92))	('human', 'Species', '9606', (157, 162))	('autosomal recessive disorders', 'Disease', 'MESH:D030342', (181, 210))	('claudins', 'Gene', (64, 72))	('deregulated expression', 'MPA', (38, 60))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('human', 'Species', '9606', (108, 113))	('claudin', 'Gene', (289, 296))	('cancer', 'Disease', (128, 134))
323834	31952355	The first evidence that showed a mutation in the claudin family of tight junction proteins causes human disorders were from the group of Lifton.	('causes', 'Reg', (91, 97))	('human disorders', 'Disease', (98, 113))	('mutation', 'Var', (33, 41))	('human', 'Species', '9606', (98, 103))
323835	31952355	In their study, they reported that the mutations in the human gene, paracellin-1 (PCLN-1)/CLDN-16 causes an autosomal recessive disorder called Familial hypomagnesemia with hypercalcinuria and nephrocalcinosis (FHHNC) characterized with renal Mg2+ and Ca+ wasting.	('PCLN-1', 'Gene', '10686', (82, 88))	('hypercalcinuria', 'Phenotype', 'HP:0002150', (173, 188))	('hypercalcinuria and nephrocalcinosis', 'Disease', 'MESH:D009397', (173, 209))	('Familial hypomagnesemia', 'Disease', 'MESH:C537153', (144, 167))	('hypomagnesemia', 'Phenotype', 'HP:0002917', (153, 167))	('causes', 'Reg', (98, 104))	('Mg2', 'Gene', (243, 246))	('Familial hypomagnesemia', 'Disease', (144, 167))	('mutations', 'Var', (39, 48))	('human', 'Species', '9606', (56, 61))	('autosomal recessive disorder', 'Disease', 'MESH:D030342', (108, 136))	('Mg2', 'Gene', '4589', (243, 246))	('paracellin-1', 'Gene', '10686', (68, 80))	('nephrocalcinosis', 'Phenotype', 'HP:0000121', (193, 209))	('autosomal recessive disorder', 'Disease', (108, 136))	('PCLN-1', 'Gene', (82, 88))	('paracellin-1', 'Gene', (68, 80))
323836	31952355	Later the same group revealed additional evidence that loss of function mutations in paracellin-1 PCLN-1/CLDN-16, are causative of FHHNC.	('mutations', 'Var', (72, 81))	('paracellin-1', 'Gene', (85, 97))	('FHHNC', 'Disease', (131, 136))	('PCLN-1', 'Gene', (98, 104))	('paracellin-1', 'Gene', '10686', (85, 97))	('PCLN-1', 'Gene', '10686', (98, 104))
323838	31952355	CLDN-16 is a cattle ortholog of PCLN-1 with ~ 90% sequence homology, and PCLN-1/CLDN16 mutations have been shown to be strongly associated with bovine chronic interstitial nephritis with diffuse zonal fibrosis (CINF).	('CINF', 'Gene', (211, 215))	('fibrosis', 'Disease', 'MESH:D005355', (201, 209))	('fibrosis', 'Disease', (201, 209))	('interstitial nephritis', 'Disease', 'MESH:D009395', (159, 181))	('nephritis', 'Phenotype', 'HP:0000123', (172, 181))	('mutations', 'Var', (87, 96))	('bovine', 'Species', '9913', (144, 150))	('interstitial nephritis', 'Disease', (159, 181))	('CLDN16', 'Gene', (80, 86))	('associated with', 'Reg', (128, 143))	('chronic interstitial nephritis', 'Phenotype', 'HP:0004743', (151, 181))	('CINF', 'Gene', '281074', (211, 215))	('cattle', 'Species', '9913', (13, 19))	('PCLN-1', 'Gene', '10686', (73, 79))	('PCLN-1', 'Gene', (73, 79))	('PCLN-1', 'Gene', (32, 38))	('CLDN16', 'Gene', '282184', (80, 86))	('PCLN-1', 'Gene', '10686', (32, 38))	('interstitial nephritis', 'Phenotype', 'HP:0001970', (159, 181))
323839	31952355	Although both renal disorders FHHN and CINF are caused by PCLN-1/CLDN16 mutations, but the clinical features of both diseases are quite different which may be due to specific mutations/deletions in the same gene or through species specificity.	('mutations', 'Var', (72, 81))	('PCLN-1', 'Gene', '10686', (58, 64))	('renal disorders FHHN and CINF', 'Disease', 'MESH:D007674', (14, 43))	('caused', 'Reg', (48, 54))	('CLDN16', 'Gene', (65, 71))	('CLDN16', 'Gene', '282184', (65, 71))	('PCLN-1', 'Gene', (58, 64))
323840	31952355	Since the first report, several other tight junction disorders have been shown to cause human diseases including mutations in claudin proteins such as CLDN-1, CLDN-9, CLDN-10, CLDN-14, CLDN-16, CLDN-19 (for detailed reviews see).	('CLDN-9', 'Gene', '9080', (159, 165))	('CLDN-1', 'Gene', (151, 157))	('CLDN-19', 'Gene', '149461', (194, 201))	('cause', 'Reg', (82, 87))	('junction disorders', 'Disease', 'MESH:D020511', (44, 62))	('CLDN-10', 'Gene', '9071', (167, 174))	('CLDN-19', 'Gene', (194, 201))	('CLDN-9', 'Gene', (159, 165))	('CLDN-14', 'Gene', '23562', (176, 183))	('junction disorders', 'Disease', (44, 62))	('mutations', 'Var', (113, 122))	('CLDN-10', 'Gene', (167, 174))	('CLDN-14', 'Gene', (176, 183))	('human', 'Species', '9606', (88, 93))	('CLDN-16', 'Gene', (185, 192))
323877	31534232	Efforts are also underway to integrate multiplex immunofluorescence imaging with FISH, in situ mRNA profiling, and DNA mutation detection as part of a multi-parametric approach to tumor characterization and human tumor atlas construction.	('tumor', 'Disease', (213, 218))	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('mutation', 'Var', (119, 127))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('tumor atlas construction', 'Disease', (213, 237))	('tumor', 'Disease', (180, 185))	('tumor', 'Disease', 'MESH:D009369', (213, 218))	('human', 'Species', '9606', (207, 212))	('rat', 'Species', '10116', (34, 37))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('tumor atlas construction', 'Disease', 'MESH:D000381', (213, 237))
323901	31534232	For example, one can use malignant peripheral nerve sheath tumors with EED or SUZ12 mutations for testing antibodies against H3K27me3, or mismatch repair-deficient tumors carrying inactivating alterations for testing antibodies against MSH2/MSH6 or MLH1/PMS2.	('malignant peripheral nerve sheath tumors', 'Phenotype', 'HP:0100697', (25, 65))	('sheath tumors', 'Disease', 'MESH:D018317', (52, 65))	('SUZ12', 'Gene', '23512', (78, 83))	('H3K27me3', 'Protein', (125, 133))	('sheath tumors', 'Disease', (52, 65))	('rat', 'Species', '10116', (197, 200))	('tumors', 'Phenotype', 'HP:0002664', (164, 170))	('mismatch repair-deficient tumors', 'Disease', (138, 170))	('PMS2', 'Gene', '5395', (254, 258))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('EED', 'Gene', (71, 74))	('MLH1', 'Gene', (249, 253))	('MSH2', 'Gene', (236, 240))	('mutations', 'Var', (84, 93))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('MLH1', 'Gene', '4292', (249, 253))	('PMS2', 'Gene', (254, 258))	('MSH6', 'Gene', (241, 245))	('MSH2', 'Gene', '4436', (236, 240))	('mismatch repair-deficient tumors', 'Disease', 'MESH:C536928', (138, 170))	('MSH6', 'Gene', '2956', (241, 245))	('EED', 'Gene', '8726', (71, 74))	('SUZ12', 'Gene', (78, 83))
323908	31534232	These approaches include (i) comparing patterns of staining by different antibodies on the same sample, which is particularly useful when highly qualified US Food and Drug Administration-approved antibody reagents are available as comparators (e.g., anti PD-1 antibodies); (ii) examining patterns of staining in tissues having stereotypical structures and spatial distributions of multiple cell types (e.g., immune cells in tonsil); and (iii) staining tissues with known genetic lesions such as HER2 overexpression or CDKN2A deletion.	('HER2', 'Gene', '2064', (495, 499))	('rat', 'Species', '10116', (180, 183))	('rat', 'Species', '10116', (236, 239))	('CDKN2A', 'Gene', (518, 524))	('overexpression', 'PosReg', (500, 514))	('deletion', 'Var', (525, 533))	('CDKN2A', 'Gene', '1029', (518, 524))	('HER2', 'Gene', (495, 499))
324039	31534232	By contrast, LUNG-3-PR was enriched in B cells (CD45+/CD20+) and Treg cells (CD45+/CD3+/CD4+/FOXP3+).	('CD45+/CD3+/CD4+/FOXP3+', 'Var', (77, 99))	('CD20', 'Gene', (54, 58))	('CD20', 'Gene', '54474', (54, 58))
324050	31534232	Similarly, double-positive PD-1/LAG3 cells (CD45+/CD3+/CD4-/CD8a+/PD-1+/LAG3+ cells and CD45+/CD3+/CD4+/CD8a-/PD-1+/LAG3+ cells) were substantially enriched in the tumor domain.	('tumor', 'Disease', (164, 169))	('CD45+/CD3+/CD4-/CD8a+/PD-1+/LAG3+ cells', 'Var', (44, 83))	('CD45+/CD3+/CD4+/CD8a-/PD-1+/LAG3+', 'Var', (88, 121))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))
324077	31534232	This analysis revealed co-segregation of markers such as PD-1 and CD3, CD8a and CD3, PD-L1 and IBA1, CD3 and CD45RB, and FOXP3 with both CD4 and CD3 (Fig.	('IBA1', 'Gene', (95, 99))	('CD3', 'Gene', (66, 69))	('IBA1', 'Gene', '199', (95, 99))	('FOXP3', 'Gene', (121, 126))	('PD-L1', 'Gene', (85, 90))	('CD45RB', 'Var', (109, 115))	('CD3', 'Gene', (80, 83))	('CD3', 'Gene', (101, 104))	('PD-1', 'Gene', (57, 61))	('CD8a', 'Gene', (71, 75))
324118	30342504	described a cT2N2M1 lung squamous cell carcinoma case with brain metastasis in which the symptoms of iris metastasis appeared during the second course of chemotherapy.	('iris metastasis', 'Disease', 'MESH:D009362', (101, 116))	('brain metastasis', 'Disease', (59, 75))	('cT2N2M1', 'Var', (12, 19))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (20, 48))	('iris metastasis', 'Disease', (101, 116))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (20, 48))	('lung squamous cell carcinoma', 'Disease', (20, 48))	('brain metastasis', 'Disease', 'MESH:D009362', (59, 75))	('carcinoma', 'Phenotype', 'HP:0030731', (39, 48))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (25, 48))
324203	28250368	to a human non-small lung adenocarcinoma cell line of bronchoalveolar origin (H358) with a homozygous deletion of p53; (iv) by Chiu et al.	('H358', 'CellLine', 'CVCL:1559', (78, 82))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (21, 40))	('small lung', 'Phenotype', 'HP:0002089', (15, 25))	('p53', 'Gene', (114, 117))	('p53', 'Gene', '7157', (114, 117))	('non-small lung adenocarcinoma', 'Phenotype', 'HP:0030358', (11, 40))	('deletion', 'Var', (102, 110))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (21, 40))	('human', 'Species', '9606', (5, 10))	('lung adenocarcinoma', 'Disease', (21, 40))	('carcinoma', 'Phenotype', 'HP:0030731', (31, 40))
324215	28250368	This is a human non-small lung adenocarcinoma cell line of bronchoalveolar origin with a homozygous deletion of p53, a major tumor suppressor protein very frequently mutated and/or inactivated in cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (26, 45))	('human', 'Species', '9606', (10, 15))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('cancer', 'Disease', 'MESH:D009369', (196, 202))	('tumor', 'Disease', (125, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (36, 45))	('lung adenocarcinoma', 'Disease', (26, 45))	('p53', 'Gene', (112, 115))	('cancer', 'Disease', (196, 202))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (26, 45))	('small lung', 'Phenotype', 'HP:0002089', (20, 30))	('deletion', 'Var', (100, 108))	('p53', 'Gene', '7157', (112, 115))	('non-small lung adenocarcinoma', 'Phenotype', 'HP:0030358', (16, 45))
324216	28250368	This proteomic analysis evidenced that the p53 deficient cells overexpressed a protein belonging to the fibroblast growth factor family (FGF-19) that binds the FGF-4 receptor only.	('overexpressed', 'PosReg', (63, 76))	('FGF-19', 'Gene', '9965', (137, 143))	('deficient', 'Var', (47, 56))	('FGF-4', 'Gene', '2249', (160, 165))	('FGF-19', 'Gene', (137, 143))	('p53', 'Gene', (43, 46))	('FGF-4', 'Gene', (160, 165))	('p53', 'Gene', '7157', (43, 46))	('binds', 'Interaction', (150, 155))
324229	28250368	In addition, upon scanning phosphorylation of EGFR across 31 lung cancer cell lines, they observed that higher stoichiometry of three phosphorylation sites was statistically correlated with EGFR sensitizing mutations.	('lung cancer', 'Disease', (61, 72))	('lung cancer', 'Phenotype', 'HP:0100526', (61, 72))	('EGFR', 'Gene', '1956', (190, 194))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('EGFR', 'Gene', '1956', (46, 50))	('stoichiometry', 'MPA', (111, 124))	('sensitizing', 'PosReg', (195, 206))	('EGFR', 'Gene', (190, 194))	('mutations', 'Var', (207, 216))	('EGFR', 'Gene', (46, 50))	('lung cancer', 'Disease', 'MESH:D008175', (61, 72))	('higher', 'PosReg', (104, 110))
324240	28250368	Based on their label-free quantitative approach, a total of 36 P-Tyr (30 P-Tyr with higher levels in CL1-5 cells and six P-Tyr with higher levels in CL1-0 cells) were considered to be associated with metastasis.	('Tyr', 'Chemical', 'MESH:D014443', (65, 68))	('metastasis', 'CPA', (200, 210))	('CL1', 'Gene', '9201', (149, 152))	('CL1-5', 'Gene', (101, 106))	('CL1-5', 'Gene', '9201;100862695;23284;100862696', (101, 106))	('CL1', 'Gene', '9201', (101, 104))	('P-Tyr', 'Var', (63, 68))	('CL1', 'Gene', (149, 152))	('CL1', 'Gene', (101, 104))	('Tyr', 'Chemical', 'MESH:D014443', (75, 78))	('associated', 'Reg', (184, 194))	('Tyr', 'Chemical', 'MESH:D014443', (123, 126))	('higher', 'PosReg', (84, 90))
324292	28250368	From the values of these variants, the amount of ProGRP isoform 2 could also be indirectly calculated.	('ProGRP', 'Gene', (49, 55))	('variants', 'Var', (25, 33))	('ProGRP', 'Gene', '2922', (49, 55))
324315	28250368	The validation of its aberrant expression using immunohistochemistry suggested for this protein a role as a potential biomarker in the detection of adenocarcinomas.	('aberrant', 'Var', (22, 30))	('carcinoma', 'Phenotype', 'HP:0030731', (153, 162))	('carcinomas', 'Phenotype', 'HP:0030731', (153, 163))	('adenocarcinomas', 'Disease', 'MESH:D000230', (148, 163))	('adenocarcinomas', 'Disease', (148, 163))
324372	28250368	This comparative study resulted in the finding of deregulated proteins involved in tissue remodeling, complement system dysfunction with consequent impairment on defense mechanisms and chronic inflammation, nutritional imbalance and P. aeruginosa colonization.	('deregulated', 'Var', (50, 61))	('proteins', 'Protein', (62, 70))	('complement system dysfunction', 'Disease', (102, 131))	('inflammation', 'Disease', 'MESH:D007249', (193, 205))	('inflammation', 'Disease', (193, 205))	('men', 'Species', '9606', (108, 111))	('complement system dysfunction', 'Disease', 'MESH:D007153', (102, 131))	('impairment', 'NegReg', (148, 158))	('defense mechanisms', 'CPA', (162, 180))	('men', 'Species', '9606', (154, 157))	('P. aeruginosa', 'Species', '287', (233, 246))	('imbalance', 'Phenotype', 'HP:0002172', (219, 228))
324418	28250368	A large-scale study of phosphoproteome in human lung cancer A549 cells allowed for the identification of a new phosphoprotein (YAP1), phosphorylated at Ser127, which seemed to be a promising lung adenocarcinoma biomarker.	('Ser127', 'Chemical', '-', (152, 158))	('YAP1', 'Gene', '10413', (127, 131))	('carcinoma', 'Phenotype', 'HP:0030731', (201, 210))	('lung cancer', 'Disease', 'MESH:D008175', (48, 59))	('human', 'Species', '9606', (42, 47))	('Ser127', 'Var', (152, 158))	('lung adenocarcinoma', 'Disease', (191, 210))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (191, 210))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('lung cancer', 'Disease', (48, 59))	('lung cancer', 'Phenotype', 'HP:0100526', (48, 59))	('A549', 'CellLine', 'CVCL:0023', (60, 64))	('YAP1', 'Gene', (127, 131))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (191, 210))
324421	28250368	Particularly intriguing was the finding that, while many of the overexpressed proteins secreted upon p53 expression prevented tumorigenesis, the p53 deficient cells over-secreted proteins involved in the progression of this event.	('prevented', 'NegReg', (116, 125))	('p53', 'Gene', (145, 148))	('p53', 'Gene', '7157', (145, 148))	('expression', 'Var', (105, 115))	('p53', 'Gene', (101, 104))	('p53', 'Gene', '7157', (101, 104))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('deficient', 'NegReg', (149, 158))	('over-secreted', 'PosReg', (165, 178))	('tumor', 'Disease', (126, 131))
324448	28250368	They underlined how the use of antibodies as highly selective capture agents, combined with the high resolving power of CE, permits the simultaneous quantification and characterization of several protein biomarkers, including variants, isoforms, peptide fragments and post-transaltional modifications (PTMs).	('men', 'Species', '9606', (258, 261))	('variants', 'Var', (226, 234))	('post-transaltional modifications', 'Var', (268, 300))
324501	27322459	Lastly, we confirmed that the lincRNAs are biologically functional, by measuring the reduction of cell proliferation and migration in breast cancer cell lines with siRNA knockdown on two of the homologous lincRNAs.	('cell proliferation', 'CPA', (98, 116))	('knockdown', 'Var', (170, 179))	('breast cancer', 'Disease', (134, 147))	('breast cancer', 'Phenotype', 'HP:0003002', (134, 147))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('siRNA', 'Gene', (164, 169))	('reduction', 'NegReg', (85, 94))	('breast cancer', 'Disease', 'MESH:D001943', (134, 147))
324509	27322459	These included GSE25599 (liver cancer), GSE58135 (breast cancer) and GSE50760 (colon cancer).	('colon cancer', 'Disease', (79, 91))	('liver cancer', 'Phenotype', 'HP:0002896', (25, 37))	('GSE50760', 'Var', (69, 77))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('liver cancer', 'Disease', 'MESH:D006528', (25, 37))	('liver cancer', 'Disease', (25, 37))	('colon cancer', 'Phenotype', 'HP:0003003', (79, 91))	('breast cancer', 'Disease', 'MESH:D001943', (50, 63))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('colon cancer', 'Disease', 'MESH:D015179', (79, 91))	('GSE58135', 'Var', (40, 48))	('breast cancer', 'Phenotype', 'HP:0003002', (50, 63))	('GSE25599', 'Var', (15, 23))	('breast cancer', 'Disease', (50, 63))
324510	27322459	In addition, normal breast tissue samples were taken from GSE52194, GSE45326 and GSE30611 for comparison with our cancer samples.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('GSE52194', 'Var', (58, 66))	('GSE45326', 'Var', (68, 76))	('GSE30611', 'Var', (81, 89))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('cancer', 'Disease', (114, 120))
324575	27322459	All three public RNA-Seq datasets (GSE58135 breast cancer, GSE50760 colon cancer, and GSE25599 liver cancer) show consistent directions of fold change for all six lincRNAs (Fig.	('GSE25599 liver cancer', 'Disease', 'MESH:D006528', (86, 107))	('breast cancer', 'Disease', 'MESH:D001943', (44, 57))	('GSE58135', 'Var', (35, 43))	('breast cancer', 'Phenotype', 'HP:0003002', (44, 57))	('colon cancer', 'Phenotype', 'HP:0003003', (68, 80))	('breast cancer', 'Disease', (44, 57))	('GSE25599 liver cancer', 'Disease', (86, 107))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('liver cancer', 'Phenotype', 'HP:0002896', (95, 107))	('GSE50760 colon cancer', 'Disease', (59, 80))	('GSE50760 colon cancer', 'Disease', 'MESH:D015179', (59, 80))
324589	27322459	To further verify the robustness of the five-lincRNA panel, we tested the TCGA data based RF model on four independent RNA-Seq datasets: GSE58135 breast cancer, GSE50760 colon cancer, GSE25599 liver cancer and our breast cancer dataset (Fig.	('breast cancer', 'Phenotype', 'HP:0003002', (214, 227))	('colon cancer', 'Phenotype', 'HP:0003003', (170, 182))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('GSE25599 liver cancer', 'Disease', 'MESH:D006528', (184, 205))	('GSE25599 liver cancer', 'Disease', (184, 205))	('breast cancer', 'Disease', 'MESH:D001943', (146, 159))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('liver cancer', 'Phenotype', 'HP:0002896', (193, 205))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('breast cancer', 'Disease', (146, 159))	('breast cancer', 'Phenotype', 'HP:0003002', (146, 159))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('breast cancer', 'Disease', 'MESH:D001943', (214, 227))	('tested', 'Reg', (63, 69))	('GSE50760 colon cancer', 'Disease', (161, 182))	('GSE50760 colon cancer', 'Disease', 'MESH:D015179', (161, 182))	('GSE58135', 'Var', (137, 145))	('breast cancer', 'Disease', (214, 227))
324598	27322459	Interestingly, the growth rate of fast proliferating MDA-MB-231 cells significantly decreased upon transfection with lincRNAs siRNA (Fig.	('transfection', 'Var', (99, 111))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (53, 63))	('fast proliferating', 'CPA', (34, 52))	('growth rate', 'CPA', (19, 30))	('decreased', 'NegReg', (84, 93))
324630	26483189	Additionally, cell migration and invasion abilities were higher in SP cells than MP cells, whereas there was no difference in proliferation.	('higher', 'PosReg', (57, 63))	('cell migration', 'CPA', (14, 28))	('SP', 'Chemical', '-', (67, 69))	('invasion abilities', 'CPA', (33, 51))	('SP cells', 'Var', (67, 75))
324673	26483189	Following another wash with PBS and blocking with 10 % (v/v) normal donkey serum in PBS for 1 h, the cells were incubated overnight at 4  C with primary antibodies against Oct3/4 (1:200, R&D Systems) and Nanog (1:200, R&D Systems).	('and', 'Var', (200, 203))	('PBS', 'Chemical', '-', (84, 87))	('donkey', 'Species', '9793', (68, 74))	('Oct3/4', 'Protein', (172, 178))	('PBS', 'Chemical', '-', (28, 31))
324744	26483189	Although Oct3/4 cannot maintain the undifferentiated state of ES cells without leukemia inhibitory factor (LIF), overexpression of Nanog allows ES cells to remain undifferentiated and to self-renew independently of LIF/STAT3 signaling.	('Nanog', 'Var', (131, 136))	('leukemia', 'Phenotype', 'HP:0001909', (79, 87))	('overexpression', 'PosReg', (113, 127))	('leukemia inhibitory factor', 'Gene', '3976', (79, 105))	('LIF', 'Gene', '3976', (107, 110))	('self-renew', 'CPA', (187, 197))	('LIF', 'Gene', (107, 110))	('LIF', 'Gene', (215, 218))	('LIF', 'Gene', '3976', (215, 218))	('leukemia inhibitory factor', 'Gene', (79, 105))
324754	26483189	More importantly, multivariate analysis of clinicopathological and immunohistochemical data demonstrated, for the first time, that expression of Oct3/4, as well as vascular invasion, are independently correlated with DNM in stage I/II TSCC following partial glossectomy.	('stage I/II TSCC', 'Disease', (224, 239))	('Oct3/4', 'Gene', (145, 151))	('TSCC', 'Phenotype', 'HP:0030413', (235, 239))	('DNM', 'Chemical', '-', (217, 220))	('DNM', 'Var', (217, 220))	('correlated with', 'Reg', (201, 216))
324757	26483189	Therefore, we suggest that Nanog could be an alternative independent predictor of DNM where Oct3/4 cannot be evaluated.	('DNM', 'Disease', (82, 85))	('DNM', 'Chemical', '-', (82, 85))	('Nanog', 'Var', (27, 32))
324760	26483189	Apart from the association with DNM, our results regarding the clinical significance of Oct3/4 and Nanog expression are seemingly inconsistent with a previous study of OSCC, in which increased expressions of Oct3/4 and Nanog were correlated with advanced stage and worse overall survival, but not with lymph node metastasis at the time of diagnosis.	('overall survival', 'CPA', (271, 287))	('Nanog', 'Gene', (219, 224))	('increased', 'PosReg', (183, 192))	('Oct3/4', 'Var', (208, 214))	('advanced stage', 'CPA', (246, 260))	('expressions', 'MPA', (193, 204))	('DNM', 'Chemical', '-', (32, 35))
324767	26483189	Recent studies have implicated EMT in the emergence of CSCs; for example, induction of EMT resulted in acquisition of stemness properties in immortalized mammary epithelial cells and, inversely, stem-like cells isolated from both mammary glands and carcinomas expressed a number of EMT markers.	('EMT', 'CPA', (282, 285))	('carcinomas', 'Disease', 'MESH:D002277', (249, 259))	('EMT', 'Gene', (87, 90))	('carcinoma', 'Phenotype', 'HP:0030731', (249, 258))	('carcinomas', 'Phenotype', 'HP:0030731', (249, 259))	('acquisition', 'PosReg', (103, 114))	('induction', 'Var', (74, 83))	('expressed', 'Reg', (260, 269))	('carcinomas', 'Disease', (249, 259))	('stemness properties', 'CPA', (118, 137))
324769	26483189	Intriguingly, a recent study showed that co-overexpression of Oct4 and Nanog in lung adenocarcinoma cells increased CSC-like properties and induced EMT by upregulating Slug and Snail expression, and thereby promoted tumorigenesis, drug resistance, and metastasis.	('Snail', 'Gene', '6615', (177, 182))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('Slug', 'Gene', (168, 172))	('drug resistance', 'CPA', (231, 246))	('tumor', 'Disease', (216, 221))	('Nanog', 'Var', (71, 76))	('EMT', 'CPA', (148, 151))	('metastasis', 'CPA', (252, 262))	('tumor', 'Disease', 'MESH:D009369', (216, 221))	('expression', 'MPA', (183, 193))	('Oct4', 'Gene', '5460', (62, 66))	('increased', 'PosReg', (106, 115))	('Snail', 'Gene', (177, 182))	('lung adenocarcinoma', 'Disease', (80, 99))	('Slug', 'Gene', '6591', (168, 172))	('drug resistance', 'Phenotype', 'HP:0020174', (231, 246))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (80, 99))	('CSC-like properties', 'CPA', (116, 135))	('Oct4', 'Gene', (62, 66))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (80, 99))	('upregulating', 'PosReg', (155, 167))	('promoted', 'PosReg', (207, 215))
324780	30588023	This study aimed to assess the value of NGS-based ctDNA analysis in detecting gene mutations in lung cancer patients.	('mutations', 'Var', (83, 92))	('lung cancer', 'Disease', 'MESH:D008175', (96, 107))	('lung cancer', 'Disease', (96, 107))	('lung cancer', 'Phenotype', 'HP:0100526', (96, 107))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('patients', 'Species', '9606', (108, 116))
324783	30588023	In addition, there were seven cases with double mutations and one case with triple mutations, with EGFR p.T790M mutation exhibiting the highest frequency.	('EGFR', 'Gene', '1956', (99, 103))	('EGFR', 'Gene', (99, 103))	('p.T790M', 'Mutation', 'rs121434569', (104, 111))	('p.T790M', 'Var', (104, 111))
324798	30588023	The major purpose of this study was to assess the value of NGS-based ctDNA in detecting gene mutations in lung cancer patients.	('mutations', 'Var', (93, 102))	('lung cancer', 'Disease', (106, 117))	('lung cancer', 'Phenotype', 'HP:0100526', (106, 117))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('lung cancer', 'Disease', 'MESH:D008175', (106, 117))	('patients', 'Species', '9606', (118, 126))
324813	30588023	Of all the plasma specimens, there were 31 specimens harboring known somatic mutations, and EGFR was the most frequently mutated gene (27.72%, 28/101).	('men', 'Species', '9606', (48, 51))	('mutations', 'Var', (77, 86))	('men', 'Species', '9606', (23, 26))	('EGFR', 'Gene', '1956', (92, 96))	('harboring', 'Reg', (53, 62))	('EGFR', 'Gene', (92, 96))
324814	30588023	Among the 66 cases with lung adenocarcinoma, there were 22, 1, and 1 cases harboring EGFR, KRAS, and ALK mutations, respectively; among the 26 cases with lung squamous cell carcinoma, five cases were detected to harbor EGFR mutation and one case harbored NRAS mutation, while only one of the nine cases with small-cell lung carcinoma was found to harbor EGFR mutation (Table 2).	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (159, 182))	('EGFR', 'Gene', (85, 89))	('lung squamous cell carcinoma', 'Disease', (154, 182))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (154, 182))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (24, 43))	('EGFR', 'Gene', (219, 223))	('ALK', 'Gene', '238', (101, 104))	('small-cell lung carcinoma', 'Disease', 'MESH:D055752', (308, 333))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (24, 43))	('NRAS', 'Gene', (255, 259))	('KRAS', 'Gene', '3845', (91, 95))	('ALK', 'Gene', (101, 104))	('EGFR', 'Gene', '1956', (354, 358))	('mutation', 'Var', (224, 232))	('EGFR', 'Gene', '1956', (85, 89))	('KRAS', 'Gene', (91, 95))	('EGFR', 'Gene', '1956', (219, 223))	('small-cell lung carcinoma', 'Phenotype', 'HP:0030357', (308, 333))	('carcinoma', 'Phenotype', 'HP:0030731', (324, 333))	('small-cell lung carcinoma', 'Disease', (308, 333))	('carcinoma', 'Phenotype', 'HP:0030731', (173, 182))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (154, 182))	('NRAS', 'Gene', '4893', (255, 259))	('lung adenocarcinoma', 'Disease', (24, 43))	('EGFR', 'Gene', (354, 358))	('carcinoma', 'Phenotype', 'HP:0030731', (34, 43))
324815	30588023	In addition, EGFR mutation was found to occur in exon 19 (n=18), exon 20 (n=6), and exon 21 (n=11).	('EGFR', 'Gene', '1956', (13, 17))	('EGFR', 'Gene', (13, 17))	('mutation', 'Var', (18, 26))
324816	30588023	Of the 101 lung cancer patients included in this study, there were eight cases (7.92%) harboring more than one clinically actionable genetic alternation, including seven cases with double mutations and one case with triple mutations (Table 3).	('double mutations', 'Var', (181, 197))	('patients', 'Species', '9606', (23, 31))	('lung cancer', 'Disease', (11, 22))	('lung cancer', 'Phenotype', 'HP:0100526', (11, 22))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('lung cancer', 'Disease', 'MESH:D008175', (11, 22))
324817	30588023	EGFR p.T790M mutation exhibited the highest frequency, followed by EGFR p.E746_A750delELREA and EGFR p.L747_T751delLREAT mutations.	('p.E746_A750del', 'Var', (72, 86))	('EGFR', 'Gene', '1956', (96, 100))	('EGFR', 'Gene', (0, 4))	('EGFR', 'Gene', (96, 100))	('p.L747_T751del', 'DELETION', 'None', (101, 115))	('p.L747_T751del', 'Var', (101, 115))	('EGFR', 'Gene', '1956', (67, 71))	('EGFR', 'Gene', (67, 71))	('p.T790M', 'Mutation', 'rs121434569', (5, 12))	('p.E746_A750del', 'DELETION', 'None', (72, 86))	('EGFR', 'Gene', '1956', (0, 4))	('p.T790M', 'Var', (5, 12))
324818	30588023	In addition, a case was detected to harbor double ALK mutations (p.F1174C and p.G1269A).	('p.G1269A', 'Mutation', 'rs1057519781', (78, 86))	('ALK', 'Gene', (50, 53))	('p.G1269A', 'Var', (78, 86))	('p.F1174C', 'Mutation', 'rs1057519697', (65, 73))	('p.F1174C', 'Var', (65, 73))	('ALK', 'Gene', '238', (50, 53))
324824	30588023	The overall rate of EGFR mutation was 27.72% in the study subjects.	('mutation', 'Var', (25, 33))	('EGFR', 'Gene', '1956', (20, 24))	('EGFR', 'Gene', (20, 24))
324825	30588023	In addition, the rate of EGFR mutation was detected to be higher in lung adenocarcinoma than in lung squamous cell carcinoma, which was in agreement with previous studies.	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (96, 124))	('men', 'Species', '9606', (144, 147))	('EGFR', 'Gene', (25, 29))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (96, 124))	('mutation', 'Var', (30, 38))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (101, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (68, 87))	('lung adenocarcinoma', 'Disease', (68, 87))	('lung squamous cell carcinoma', 'Disease', (96, 124))	('higher', 'Reg', (58, 64))	('EGFR', 'Gene', '1956', (25, 29))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (68, 87))
324826	30588023	It has been shown that the highest rate of EGFR mutation is 21.9%-36% in lung cancer, and more than 60% of non-small-cell lung carcinomas (NSCLCs) express EGFR.	('small-cell lung carcinoma', 'Disease', 'MESH:D055752', (111, 136))	('lung carcinomas', 'Disease', 'MESH:D008175', (122, 137))	('EGFR', 'Gene', (155, 159))	('EGFR', 'Gene', (43, 47))	('lung cancer', 'Disease', 'MESH:D008175', (73, 84))	('lung carcinomas', 'Disease', (122, 137))	('NSCLC', 'Disease', 'MESH:D002289', (139, 144))	('lung cancer', 'Phenotype', 'HP:0100526', (73, 84))	('small-cell lung carcinoma', 'Phenotype', 'HP:0030357', (111, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('carcinomas', 'Phenotype', 'HP:0030731', (127, 137))	('small-cell lung carcinoma', 'Disease', (111, 136))	('EGFR', 'Gene', '1956', (155, 159))	('NSCLC', 'Disease', (139, 144))	('non-small-cell lung carcinomas', 'Phenotype', 'HP:0030358', (107, 137))	('EGFR', 'Gene', '1956', (43, 47))	('mutation', 'Var', (48, 56))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('small-cell lung carcinomas', 'Phenotype', 'HP:0030357', (111, 137))	('lung cancer', 'Disease', (73, 84))
324828	30588023	More importantly, tyrosine kinase inhibitors (TKIs) are especially effective in cancer patients harboring activating EGFR mutations.	('EGFR', 'Gene', '1956', (117, 121))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('EGFR', 'Gene', (117, 121))	('activating', 'PosReg', (106, 116))	('mutations', 'Var', (122, 131))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('patients', 'Species', '9606', (87, 95))	('cancer', 'Disease', (80, 86))
324829	30588023	Previous studies have demonstrated that EGFR-TKIs are the standard treatment for advanced NSCLC, and identification of EGFR mutation is a standard procedure during the treatment of advanced NSCLC patients.	('men', 'Species', '9606', (72, 75))	('NSCLC', 'Disease', (90, 95))	('men', 'Species', '9606', (173, 176))	('patients', 'Species', '9606', (196, 204))	('NSCLC', 'Disease', (190, 195))	('EGFR', 'Gene', '1956', (40, 44))	('NSCLC', 'Disease', 'MESH:D002289', (90, 95))	('EGFR', 'Gene', (40, 44))	('mutation', 'Var', (124, 132))	('EGFR', 'Gene', '1956', (119, 123))	('NSCLC', 'Disease', 'MESH:D002289', (190, 195))	('EGFR', 'Gene', (119, 123))
324830	30588023	In this study, NGS-based ctDNA analysis revealed that EGFR mutation predominantly occurred in exons 19 and 21, and these mutations are the target sites of the first-generation EGFR-TKI gefitinib and erlotinib.	('erlotinib', 'Chemical', 'MESH:D000069347', (199, 208))	('EGFR', 'Gene', '1956', (176, 180))	('occurred', 'Reg', (82, 90))	('EGFR', 'Gene', '1956', (54, 58))	('mutation', 'Var', (59, 67))	('EGFR', 'Gene', (176, 180))	('EGFR', 'Gene', (54, 58))	('gefitinib', 'Chemical', 'MESH:D000077156', (185, 194))
324831	30588023	T790M mutation was detected in six patients, and all exhibited complex EGFR mutations, which may be explained by the following two reasons: 1) Four out of six of them received EGFR-TKI treatment, and therefore, T790M mutation may have conferred the acquired EGFR-TKI resistance in these four cases.	('EGFR', 'Gene', '1956', (258, 262))	('T790M', 'Mutation', 'rs121434569', (211, 216))	('T790M mutation', 'Var', (0, 14))	('EGFR', 'Gene', (258, 262))	('EGFR', 'Gene', '1956', (176, 180))	('T790M', 'Var', (211, 216))	('conferred', 'Reg', (235, 244))	('T790M', 'Mutation', 'rs121434569', (0, 5))	('EGFR', 'Gene', '1956', (71, 75))	('EGFR', 'Gene', (176, 180))	('men', 'Species', '9606', (190, 193))	('patients', 'Species', '9606', (35, 43))	('EGFR', 'Gene', (71, 75))
324832	30588023	In addition, a case was detected harboring both L858R and exon 19 deletion mutations in the EGFR gene, which is rarely detected.	('L858R', 'Var', (48, 53))	('L858R', 'Mutation', 'rs121434568', (48, 53))	('EGFR', 'Gene', '1956', (92, 96))	('EGFR', 'Gene', (92, 96))	('exon 19 deletion mutations', 'Var', (58, 84))
324833	30588023	Analysis of somatic genetic alterations in a set of 119 primary NSCLCs from Japan and the USA revealed multiple mutations in the EGFR gene; however, in this study, unfortunately, no novel EGFR mutations were identified.	('NSCLC', 'Disease', 'MESH:D002289', (64, 69))	('mutations', 'Var', (112, 121))	('EGFR', 'Gene', '1956', (129, 133))	('EGFR', 'Gene', '1956', (188, 192))	('EGFR', 'Gene', (129, 133))	('EGFR', 'Gene', (188, 192))	('NSCLC', 'Disease', (64, 69))
324834	30588023	NRAS, KRAS, and ALK mutations have been proved to be involved in the acquired resistance to TKIs in lung cancer, and KRAS mutation is the second most frequently mutated drug target gene in lung cancer.	('KRAS', 'Gene', (117, 121))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('KRAS', 'Gene', (6, 10))	('lung cancer', 'Disease', (100, 111))	('lung cancer', 'Disease', (189, 200))	('NRAS', 'Gene', (0, 4))	('acquired resistance', 'MPA', (69, 88))	('ALK', 'Gene', '238', (16, 19))	('mutations', 'Var', (20, 29))	('lung cancer', 'Disease', 'MESH:D008175', (100, 111))	('ALK', 'Gene', (16, 19))	('KRAS', 'Gene', '3845', (6, 10))	('lung cancer', 'Disease', 'MESH:D008175', (189, 200))	('involved', 'Reg', (53, 61))	('KRAS', 'Gene', '3845', (117, 121))	('lung cancer', 'Phenotype', 'HP:0100526', (100, 111))	('lung cancer', 'Phenotype', 'HP:0100526', (189, 200))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('NRAS', 'Gene', '4893', (0, 4))
324835	30588023	It is reported that KRAS has a mutation rate of 6.7%-13.5% in adenocarcinoma.	('KRAS', 'Gene', '3845', (20, 24))	('mutation', 'Var', (31, 39))	('adenocarcinoma', 'Disease', (62, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('adenocarcinoma', 'Disease', 'MESH:D000230', (62, 76))	('KRAS', 'Gene', (20, 24))
324839	30588023	In the present study, two cases were detected harboring ALK mutations.	('mutations', 'Var', (60, 69))	('ALK', 'Gene', '238', (56, 59))	('ALK', 'Gene', (56, 59))
324840	30588023	Multigene mutation is common in the cases of lung cancer.	('lung cancer', 'Disease', 'MESH:D008175', (45, 56))	('Multigene mutation', 'Var', (0, 18))	('lung cancer', 'Disease', (45, 56))	('lung cancer', 'Phenotype', 'HP:0100526', (45, 56))	('common', 'Reg', (22, 28))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))
324841	30588023	The frequency of double mutations, notably single-gene double mutations, is reported to be 3.13%-8.33% in lung cancer.	('double mutations', 'Var', (17, 33))	('lung cancer', 'Disease', (106, 117))	('lung cancer', 'Phenotype', 'HP:0100526', (106, 117))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('single-gene double mutations', 'Var', (43, 71))	('lung cancer', 'Disease', 'MESH:D008175', (106, 117))
324842	30588023	In this study, we found that all multiple mutations occurred in a single gene, and the most frequent mutations were EGFR 19 exon deletion and T790M mutations.	('EGFR', 'Gene', '1956', (116, 120))	('T790M', 'Mutation', 'rs121434569', (142, 147))	('EGFR', 'Gene', (116, 120))	('T790M mutations', 'Var', (142, 157))
324843	30588023	It has been shown that EGFR 19 exon deletion mutation and L858R mutation are the target sites of the first-generation EGFR-TKIs, and EGFR p.T190M mutation is involved in resistance to the first-generation EGFR-TKIs.	('p.T190M', 'Mutation', 'p.T190M', (138, 145))	('L858R', 'Var', (58, 63))	('p.T190M', 'Var', (138, 145))	('involved', 'Reg', (158, 166))	('EGFR', 'Gene', '1956', (205, 209))	('EGFR', 'Gene', (205, 209))	('L858R', 'Mutation', 'rs121434568', (58, 63))	('EGFR', 'Gene', '1956', (23, 27))	('EGFR', 'Gene', '1956', (118, 122))	('EGFR', 'Gene', (118, 122))	('EGFR', 'Gene', '1956', (133, 137))	('EGFR', 'Gene', (23, 27))	('EGFR', 'Gene', (133, 137))
324844	30588023	In the current study, the seven cases harboring double EGFR mutations had rapid clinical progression, of which six were detected with EGFR-TKI resistance mutations.	('EGFR', 'Gene', '1956', (55, 59))	('EGFR', 'Gene', (134, 138))	('EGFR', 'Gene', (55, 59))	('mutations', 'Var', (60, 69))	('EGFR', 'Gene', '1956', (134, 138))
324848	30588023	In summary, the results of the present study demonstrate that ctDNA panel sequencing can be used for lung cancer gene mutation identification, which highlights the potential to use peripheral blood samples as noninvasive biopsy specimens for lung cancer.	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('lung cancer', 'Disease', 'MESH:D008175', (101, 112))	('men', 'Species', '9606', (233, 236))	('lung cancer', 'Disease', 'MESH:D008175', (242, 253))	('mutation', 'Var', (118, 126))	('lung cancer', 'Phenotype', 'HP:0100526', (101, 112))	('lung cancer', 'Disease', (242, 253))	('lung cancer', 'Phenotype', 'HP:0100526', (242, 253))	('lung cancer', 'Disease', (101, 112))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
324860	29069808	Our data demonstrate the existence of a lung CSC population and suggest a role for targeting ALDH1 as a potential therapeutic strategy in re-sensitizing NSCLC cells to the cytotoxic effects of cisplatin.	('NSCLC', 'Phenotype', 'HP:0030358', (153, 158))	('NSCLC', 'Disease', (153, 158))	('NSCLC', 'Disease', 'MESH:D002289', (153, 158))	('cisplatin', 'Chemical', 'MESH:D002945', (193, 202))	('targeting', 'Var', (83, 92))	('SCLC', 'Phenotype', 'HP:0030357', (154, 158))	('ALDH1', 'Gene', (93, 98))
324891	29069808	Comparison of ALDH1 activity across PT and CisR sublines identified the presence of a significantly greater ALDH1+ve subpopulation in H460 (p<0.01), H1299 (p<0.001) and SKMES-1 (p<0.001) CisR sublines relative to their cisplatin sensitive counterparts.	('H1299', 'Var', (149, 154))	('cisplatin', 'Chemical', 'MESH:D002945', (219, 228))	('H460', 'CellLine', 'CVCL:0459', (134, 138))	('greater', 'PosReg', (100, 107))	('H1299', 'CellLine', 'CVCL:0060', (149, 154))	('SKMES-1', 'CellLine', 'CVCL:0630', (169, 176))	('ALDH1+ve subpopulation', 'MPA', (108, 130))
324899	29069808	Similarly, the CSC marker, CD133, was significantly up-regulated in H460 ALDH1+ve cells (11.12-fold, p<0.01) and SKMES-1 ALDH1+ve cells (2.25-fold, p<0.05) relative to their ALDH1-ve controls.	('CD133', 'Gene', (27, 32))	('CD133', 'Gene', '8842', (27, 32))	('up-regulated', 'PosReg', (52, 64))	('SKMES-1', 'Gene', (113, 120))	('H460', 'Var', (68, 72))	('H460', 'CellLine', 'CVCL:0459', (68, 72))	('SKMES-1', 'CellLine', 'CVCL:0630', (113, 120))
324915	29069808	Similar expansion of the ALDH1+ve subset was observed in SKMES-1 PT and CisR cells, where cisplatin significantly enhanced the presence of the ALDH1+ve subpopulations from 1.53+-0.03% to 11.31+-1.42% (p<0.01) in the SKMES-1 PT cell line and from 17.06+-0.96% to 25.46+-0.77% (p<0.01) in the SKMES-1 CisR subline.	('SKMES-1', 'CellLine', 'CVCL:0630', (216, 223))	('cisplatin', 'Chemical', 'MESH:D002945', (90, 99))	('ALDH1+ve', 'Var', (143, 151))	('enhanced', 'PosReg', (114, 122))	('SKMES-1', 'CellLine', 'CVCL:0630', (57, 64))	('SKMES-1', 'CellLine', 'CVCL:0630', (291, 298))
324919	29069808	In the H1299 PT cell line, cisplatin induced a significant induction of OCT-4 (p<0.05), SOX-2 (p<0.05), CD133 (p<0.05) and ALDH1 gene expression (p<0.05).	('cisplatin', 'Chemical', 'MESH:D002945', (27, 36))	('expression', 'MPA', (134, 144))	('induction', 'PosReg', (59, 68))	('OCT-4', 'Gene', (72, 77))	('CD133', 'Gene', (104, 109))	('CD133', 'Gene', '8842', (104, 109))	('cisplatin', 'Var', (27, 36))	('SOX-2', 'Gene', '6657', (88, 93))	('H1299', 'CellLine', 'CVCL:0060', (7, 12))	('OCT-4', 'Gene', '5460', (72, 77))	('SOX-2', 'Gene', (88, 93))	('ALDH1 gene', 'Gene', (123, 133))
324923	29069808	To assess whether inhibition of ALDH1 can overcome cisplatin resistance, CisR sublines were treated with the ALDH1 inhibitor, DEAB, for 72hrs and ALDH activity was reassessed by flow cytometry.	('cisplatin', 'Chemical', 'MESH:D002945', (51, 60))	('ALDH1', 'Gene', (32, 37))	('cisplatin resistance', 'MPA', (51, 71))	('DEAB', 'Chemical', '-', (126, 130))	('inhibition', 'Var', (18, 28))
324929	29069808	While this effect was evident across all three CisR sublines, albeit at different concentrations of cisplatin, DEAB significantly reduced the proliferation of H460, H1299 and SKMES-1 resistant cell lines at different concentrations of cisplatin (H460: 1muM; H1299: 40muM and 100muM; SKMES-1: 10muM).	('H460', 'CellLine', 'CVCL:0459', (246, 250))	('muM', 'Gene', (267, 270))	('proliferation', 'CPA', (142, 155))	('SKMES-1', 'CellLine', 'CVCL:0630', (175, 182))	('SKMES-1', 'CellLine', 'CVCL:0630', (283, 290))	('H1299', 'CellLine', 'CVCL:0060', (165, 170))	('DEAB', 'Chemical', '-', (111, 115))	('DEAB', 'Gene', (111, 115))	('muM', 'Gene', '56925', (294, 297))	('H1299', 'CellLine', 'CVCL:0060', (258, 263))	('muM', 'Gene', (294, 297))	('muM', 'Gene', '56925', (278, 281))	('muM', 'Gene', (278, 281))	('H1299', 'Var', (258, 263))	('cisplatin', 'Chemical', 'MESH:D002945', (235, 244))	('muM', 'Gene', '56925', (253, 256))	('muM', 'Gene', (253, 256))	('cisplatin', 'Chemical', 'MESH:D002945', (100, 109))	('reduced', 'NegReg', (130, 137))	('muM', 'Gene', '56925', (267, 270))	('H460', 'CellLine', 'CVCL:0459', (159, 163))
324935	29069808	Of interest, this effect was most significant in the H1299 CisR subline, where DEAB in combination with cisplatin at concentrations ranging from 1-100muM, resulted in significant increases in apoptotic cell death in these cells compared to cisplatin-only treated cells.	('increases', 'PosReg', (179, 188))	('cisplatin', 'Chemical', 'MESH:D002945', (240, 249))	('muM', 'Gene', (150, 153))	('cisplatin', 'Chemical', 'MESH:D002945', (104, 113))	('apoptotic cell death', 'CPA', (192, 212))	('H1299', 'CellLine', 'CVCL:0060', (53, 58))	('DEAB', 'Var', (79, 83))	('DEAB', 'Chemical', '-', (79, 83))	('muM', 'Gene', '56925', (150, 153))
324941	29069808	While this effect was most significant at lower concentrations of cisplatin (1-20muM) in H460, H1299 and SKMES-1 CisR cell lines, DSF was also shown to significantly enhance the cytotoxicity of cisplatin in H1299 cells at higher concentrations of cisplatin (40-100muM) when treated in combination.	('cytotoxicity', 'Disease', 'MESH:D064420', (178, 190))	('DSF', 'Chemical', 'MESH:D004221', (130, 133))	('cisplatin', 'Chemical', 'MESH:D002945', (66, 75))	('H460', 'CellLine', 'CVCL:0459', (89, 93))	('muM', 'Gene', '56925', (264, 267))	('cytotoxicity', 'Disease', (178, 190))	('muM', 'Gene', (264, 267))	('H1299', 'CellLine', 'CVCL:0060', (207, 212))	('cisplatin', 'Chemical', 'MESH:D002945', (194, 203))	('enhance', 'PosReg', (166, 173))	('muM', 'Gene', '56925', (81, 84))	('H1299', 'CellLine', 'CVCL:0060', (95, 100))	('SKMES-1', 'CellLine', 'CVCL:0630', (105, 112))	('DSF', 'Var', (130, 133))	('cisplatin', 'Chemical', 'MESH:D002945', (247, 256))	('muM', 'Gene', (81, 84))
324945	29069808	Of note, this was particularly significant in H460 CisR cells (p<0.001), in which case, DSF in combination with cisplatin at all concentrations (1-100muM) induced significant apoptosis, relative to cells treated with cisplatin and DSF alone.	('DSF', 'Chemical', 'MESH:D004221', (231, 234))	('muM', 'Gene', (150, 153))	('apoptosis', 'CPA', (175, 184))	('DSF', 'Var', (88, 91))	('cisplatin', 'Chemical', 'MESH:D002945', (112, 121))	('DSF', 'Chemical', 'MESH:D004221', (88, 91))	('H460', 'CellLine', 'CVCL:0459', (46, 50))	('muM', 'Gene', '56925', (150, 153))	('induced', 'Reg', (155, 162))	('cisplatin', 'Chemical', 'MESH:D002945', (217, 226))
324960	29069808	In ovarian cancer, ALDH+ve CSCs have been consistently shown to exhibit increased chemoresistance, where the extent of the ALDH+ve subpopulation often correlates with acquired taxane and platinum resistance.	('taxane', 'Chemical', 'MESH:C080625', (176, 182))	('increased', 'PosReg', (72, 81))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('ovarian cancer', 'Phenotype', 'HP:0100615', (3, 17))	('ALDH+ve CSCs', 'Var', (19, 31))	('ovarian cancer', 'Disease', 'MESH:D010051', (3, 17))	('chemoresistance', 'CPA', (82, 97))	('ovarian cancer', 'Disease', (3, 17))
324965	29069808	Similar observations were reported by Zakaria et al., in the lung adenocarcinoma cell lines, A549 and H2170 compared to the normal bronchial epithelial cell line, PHBEC, highlighting the cancer stem cell hypothesis as an important avenue of interest in lung cancer.	('cancer', 'Disease', 'MESH:D009369', (187, 193))	('lung cancer', 'Phenotype', 'HP:0100526', (253, 264))	('cancer', 'Phenotype', 'HP:0002664', (258, 264))	('lung cancer', 'Disease', (253, 264))	('cancer', 'Disease', (187, 193))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (61, 80))	('H2170', 'Var', (102, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('A549', 'CellLine', 'CVCL:0023', (93, 97))	('lung adenocarcinoma', 'Disease', (61, 80))	('lung cancer', 'Disease', 'MESH:D008175', (253, 264))	('cancer', 'Disease', 'MESH:D009369', (258, 264))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (61, 80))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('cancer', 'Disease', (258, 264))
324977	29069808	In more recent studies in head and neck squamous cell carcinoma (HNSCC), cisplatin enhanced the fraction of head and neck CSCs in vivo, despite the lack of a significant change in overall tumor volume.	('tumor', 'Disease', (188, 193))	('cisplatin', 'Chemical', 'MESH:D002945', (73, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (54, 63))	('neck squamous cell carcinoma', 'Disease', (35, 63))	('enhanced', 'PosReg', (83, 91))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (40, 63))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (26, 63))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (35, 63))	('cisplatin', 'Var', (73, 82))	('fraction', 'MPA', (96, 104))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('HNSCC', 'Phenotype', 'HP:0012288', (65, 70))
324978	29069808	Similarly, in ovarian cancer cells, following treatment with increasing concentrations of cisplatin, while there was a distinct dose-dependent decrease in the total number of viable cells, a significant increase in the percentage of ALDH+ve cells was observed, suggesting the chemoresistant nature of this ALDH+ve cell population and/or the induction of ALDH by cisplatin.	('ovarian cancer', 'Disease', (14, 28))	('chemoresistant', 'CPA', (276, 290))	('decrease', 'NegReg', (143, 151))	('cisplatin', 'Chemical', 'MESH:D002945', (90, 99))	('ovarian cancer', 'Phenotype', 'HP:0100615', (14, 28))	('cisplatin', 'Chemical', 'MESH:D002945', (362, 371))	('ovarian cancer', 'Disease', 'MESH:D010051', (14, 28))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('ALDH+ve', 'CPA', (233, 240))	('cisplatin', 'Var', (90, 99))	('increase', 'PosReg', (203, 211))
324986	29069808	Our data suggest that ALDH1+ve cells not only correlate with acquired cisplatin resistance but out-survive their ALDH1-ve counterparts during cisplatin therapy.	('ALDH1+ve', 'Var', (22, 30))	('cisplatin', 'Chemical', 'MESH:D002945', (142, 151))	('acquired cisplatin resistance', 'MPA', (61, 90))	('cisplatin', 'Chemical', 'MESH:D002945', (70, 79))	('out-survive', 'NegReg', (95, 106))	('correlate', 'Reg', (46, 55))
324996	29069808	We showed that both the ALDH1+ve and ALDH1-ve cell subsets could efficiently form tumors in vivo from low cell numbers.	('ALDH1-ve', 'Gene', (37, 45))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('tumors', 'Disease', (82, 88))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('ALDH1+ve', 'Var', (24, 32))
325001	29069808	It is noted that the literature tends to reflect ALDH1+ve lung cancer cells as being more tumorigenic relative to ALDH1-ve cells.	('more', 'PosReg', (85, 89))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('lung cancer', 'Disease', (58, 69))	('tumor', 'Disease', (90, 95))	('lung cancer', 'Phenotype', 'HP:0100526', (58, 69))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('ALDH1+ve', 'Var', (49, 57))	('lung cancer', 'Disease', 'MESH:D008175', (58, 69))
325021	29069808	To date, a number of clinical trials using Disulfiram have been initiated in lung cancer (NCT00312819), refractory solid tumors involving the liver (NCT00742911), metastatic melanoma (NCT00256230) and prostate cancer (NCT01118741).	('lung cancer', 'Phenotype', 'HP:0100526', (77, 88))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('Disulfiram', 'Chemical', 'MESH:D004221', (43, 53))	('solid tumors', 'Disease', 'MESH:D009369', (115, 127))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('prostate cancer', 'Disease', 'MESH:D011471', (201, 216))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('prostate cancer', 'Phenotype', 'HP:0012125', (201, 216))	('lung cancer', 'Disease', 'MESH:D008175', (77, 88))	('NCT00256230', 'Var', (184, 195))	('melanoma', 'Disease', 'MESH:D008545', (174, 182))	('melanoma', 'Phenotype', 'HP:0002861', (174, 182))	('solid tumors', 'Disease', (115, 127))	('melanoma', 'Disease', (174, 182))	('tumors involving the liver', 'Phenotype', 'HP:0002896', (121, 147))	('lung cancer', 'Disease', (77, 88))	('prostate cancer', 'Disease', (201, 216))
325033	29069808	In a study by You et al, high gene expression of the ALDH1 isoform, ALDH1A1, correlated with better overall survival (OS) in adenocarcinoma patients when studied in a cohort of 1,926 NSCLC patients followed over a period of 20 years (p=0.039).	('NSCLC', 'Phenotype', 'HP:0030358', (183, 188))	('high gene', 'Var', (25, 34))	('NSCLC', 'Disease', (183, 188))	('SCLC', 'Phenotype', 'HP:0030357', (184, 188))	('adenocarcinoma', 'Disease', (125, 139))	('NSCLC', 'Disease', 'MESH:D002289', (183, 188))	('patients', 'Species', '9606', (140, 148))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('patients', 'Species', '9606', (189, 197))	('ALDH1A1', 'Gene', (68, 75))	('better', 'PosReg', (93, 99))	('overall survival', 'MPA', (100, 116))	('adenocarcinoma', 'Disease', 'MESH:D000230', (125, 139))
325034	29069808	These data demonstrating an association of ALDH1 mRNA with better prognosis were further supported in an exploratory and retrospective study in NSCLC, which indicated that ALDH1 expression is associated with a more favourable outcome.	('NSCLC', 'Disease', (144, 149))	('ALDH1', 'Gene', (172, 177))	('associated with', 'Reg', (192, 207))	('NSCLC', 'Disease', 'MESH:D002289', (144, 149))	('SCLC', 'Phenotype', 'HP:0030357', (145, 149))	('ALDH1', 'Gene', (43, 48))	('expression', 'Var', (178, 188))	('NSCLC', 'Phenotype', 'HP:0030358', (144, 149))
325039	29069808	A multivariate analysis also identified expression of ALDH1 in NSCLC patients as a significant independent prognostic factor for disease-free survival.	('NSCLC', 'Disease', (63, 68))	('NSCLC', 'Disease', 'MESH:D002289', (63, 68))	('expression', 'Var', (40, 50))	('ALDH1', 'Gene', (54, 59))	('NSCLC', 'Phenotype', 'HP:0030358', (63, 68))	('SCLC', 'Phenotype', 'HP:0030357', (64, 68))	('patients', 'Species', '9606', (69, 77))
325040	29069808	The authors reported that the 5-year disease-free survival rate for patients with high ALDH1 expression levels in their cancer cells was significantly lower than those with low ALDH1 levels (47.3% vs. 21.5%, respectively; p=0.023).	('disease-free survival', 'CPA', (37, 58))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('high', 'Var', (82, 86))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('patients', 'Species', '9606', (68, 76))	('lower', 'NegReg', (151, 156))	('expression', 'MPA', (93, 103))	('ALDH1', 'Gene', (87, 92))
325053	29069808	For all cell lines, media was supplemented with 10% heat-inactivated foetal bovine serum (FBS), penicillin (100U/ml) and streptomycin (100mug/ml) (Lonza, UK).	('100U/ml', 'Var', (108, 115))	('FBS', 'Disease', (90, 93))	('streptomycin', 'Chemical', 'MESH:D013307', (121, 133))	('bovine', 'Species', '9913', (76, 82))	('penicillin', 'Chemical', 'MESH:D010406', (96, 106))	('FBS', 'Disease', 'MESH:D005198', (90, 93))
325056	29069808	Gene expression (mRNA) analysis of stem cell and CSC markers was carried out by RT-PCR using the following primers: NANOG (FWD 5'-TTGGAGC CTAATCAGCGAGGT-3', REV 5'-GCCTCCCAATCCCA AACAATA-3'), OCT-4 (FWD 5'-ATTCAGCCAAAC GACCATCT-3', REV 5'-GTTTTCTTACTAGTCAC GTGCGG-3'), SOX-2 (FWD 5'-GGAGCTTTGCACG AAGTTTG-3', REV 5'-GGAAAGTTGGGATCGA ACAA-3'), KLF4 (FWD 5'-CACACTTGTGATTACGC GGG-3', REV 5'-CCCGTGTGTTTACGGTAGTGC-3'), C-MYC (FWD 5'-CCTCGGATTCTCTGCTCTCCTC-3', REV 5'-AGGTTTGCTGTGGCCTCCAG-3'), ALDH1 (FWD 5'-GCCATAACAATCTCCTCTGCT-3', REV 5'-CATGGAAACCGTACTCTCCC-3') and CD133 (FWD 5'-GAGAAAGTGGCATCGTGCAA-3', REV 5'-CA CGTCCTCCGAATCCATTC-3').	('NANOG', 'Gene', '79923', (116, 121))	('KLF4', 'Gene', (343, 347))	('KLF4', 'Gene', '9314', (343, 347))	('NANOG', 'Gene', (116, 121))	('FWD', 'Var', (573, 576))	('C-MYC', 'Gene', (416, 421))	('SOX-2', 'Gene', '6657', (269, 274))	('OCT-4', 'Gene', '5460', (192, 197))	('OCT-4', 'Gene', (192, 197))	('CD133', 'Gene', (566, 571))	('ALDH1', 'Gene', (490, 495))	('SOX-2', 'Gene', (269, 274))	('CD133', 'Gene', '8842', (566, 571))	('C-MYC', 'Gene', '4609', (416, 421))
325075	29069808	Cells were trypsinized and re-stained using the Aldefluor assay to reassess the ALDH1 cell subsets, ALDH1+ve, ALDH1-ve and ALDH1+/-.	('ALDH1+ve', 'Var', (100, 108))	('ALDH1+/-', 'Var', (123, 131))	('Aldefluor', 'Chemical', '-', (48, 57))
325083	29069808	NOD/SCID mice (n=4 per group) were subcutaneously inoculated with ALDH1+ve and ALDH1-ve H460 CisR cell fractions at a density of 1x103 cells/mouse within a Matrigel plug (Corning, USA).	('ALDH1-ve', 'Var', (79, 87))	('mouse', 'Species', '10090', (141, 146))	('SCID', 'Disease', 'MESH:D053632', (4, 8))	('SCID', 'Disease', (4, 8))	('mice', 'Species', '10090', (9, 13))	('H460', 'CellLine', 'CVCL:0459', (88, 92))
325092	26858029	Deregulation of a pathway including MYCN, HMGA2 and CDKN2A, with the participation of DICER1, is of importance in several solid tumours, and may also be of significance in the pathogenesis of NSCLC.	('importance', 'Reg', (100, 110))	('NSCLC', 'Disease', (192, 197))	('Deregulation', 'Var', (0, 12))	('NSCLC', 'Disease', 'MESH:D002289', (192, 197))	('DICER1', 'Gene', (86, 92))	('DICER1', 'Gene', '23405', (86, 92))	('solid tumours', 'Disease', 'MESH:D009369', (122, 135))	('HMGA2', 'Gene', '8091', (42, 47))	('tumour', 'Phenotype', 'HP:0002664', (128, 134))	('MYCN', 'Gene', (36, 40))	('CDKN2A', 'Gene', (52, 58))	('solid tumours', 'Disease', (122, 135))	('significance', 'Reg', (156, 168))	('NSCLC', 'Phenotype', 'HP:0030358', (192, 197))	('HMGA2', 'Gene', (42, 47))	('tumours', 'Phenotype', 'HP:0002664', (128, 135))	('MYCN', 'Gene', '4613', (36, 40))	('CDKN2A', 'Gene', '1029', (52, 58))
325111	26858029	Epidermal growth factor receptor (EGFR) mutational testing has been performed routinely in Norway since 2010.	('EGFR', 'Gene', (34, 38))	('mutational testing', 'Var', (40, 58))	('Epidermal growth factor receptor', 'Gene', (0, 32))	('Epidermal growth factor receptor', 'Gene', '1956', (0, 32))	('EGFR', 'Gene', '1956', (34, 38))
325112	26858029	Targeted therapies such as EGFR inhibitors and anaplastic lymphoma kinase (ALK) inhibitors are currently in clinical use.	('EGFR', 'Gene', '1956', (27, 31))	('inhibitors', 'Var', (32, 42))	('EGFR', 'Gene', (27, 31))	('ALK', 'Gene', (75, 78))	('anaplastic lymphoma kinase', 'Gene', (47, 73))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (47, 66))	('ALK', 'Gene', '238', (75, 78))	('lymphoma', 'Phenotype', 'HP:0002665', (58, 66))	('anaplastic lymphoma kinase', 'Gene', '238', (47, 73))
325113	26858029	Increased understanding of different levels of tumour development, of genetic, epigenetic, protein alterations and their functional influence are of clinical importance.	('tumour', 'Disease', 'MESH:D009369', (47, 53))	('tumour', 'Disease', (47, 53))	('protein', 'Protein', (91, 98))	('men', 'Species', '9606', (61, 64))	('epigenetic', 'Var', (79, 89))	('tumour', 'Phenotype', 'HP:0002664', (47, 53))
325115	26858029	Overexpression of the HMGA2 gene is linked to the development of cancer.	('HMGA2', 'Gene', '8091', (22, 27))	('HMGA2', 'Gene', (22, 27))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('linked to', 'Reg', (36, 45))	('Overexpression', 'Var', (0, 14))	('men', 'Species', '9606', (57, 60))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))
325118	26858029	In NSCLC, however, re-expression of HMGA2 is proposed as a common event and considered as a molecular marker.	('HMGA2', 'Gene', '8091', (36, 41))	('NSCLC', 'Disease', (3, 8))	('NSCLC', 'Disease', 'MESH:D002289', (3, 8))	('HMGA2', 'Gene', (36, 41))	('re-expression', 'Var', (19, 32))	('NSCLC', 'Phenotype', 'HP:0030358', (3, 8))
325195	26858029	Compared to tumours with low HMGA2 mRNA expression, mean expression of let-7a, let-7c, let-7d and let-7f was significantly lower in tumours with high expression of HMGA2 whereas let-7d was higher.	('tumours', 'Disease', 'MESH:D009369', (12, 19))	('tumours', 'Disease', 'MESH:D009369', (132, 139))	('let-7c', 'Gene', (79, 85))	('tumour', 'Phenotype', 'HP:0002664', (132, 138))	('tumour', 'Phenotype', 'HP:0002664', (12, 18))	('let-7d', 'Gene', '406886', (87, 93))	('expression', 'MPA', (57, 67))	('let-7f', 'Var', (98, 104))	('let-7c', 'Gene', '406885', (79, 85))	('HMGA2', 'Gene', (29, 34))	('lower', 'NegReg', (123, 128))	('HMGA2', 'Gene', (164, 169))	('let-7d', 'Gene', (87, 93))	('let-7d', 'Gene', '406886', (178, 184))	('let-7a', 'Gene', (71, 77))	('HMGA2', 'Gene', '8091', (29, 34))	('tumours', 'Disease', (132, 139))	('tumours', 'Disease', (12, 19))	('HMGA2', 'Gene', '8091', (164, 169))	('let-7d', 'Gene', (178, 184))	('tumours', 'Phenotype', 'HP:0002664', (12, 19))	('tumours', 'Phenotype', 'HP:0002664', (132, 139))	('high', 'Var', (145, 149))
325196	26858029	Mean expression of let-7a and let-7d was significantly different depending on mRNA expression in all of the four genes in question, while mean let-7f was significantly different in MYCN, HMGA2 and CKDN2A (Table 4).	('MYCN', 'Gene', (181, 185))	('expression', 'MPA', (5, 15))	('HMGA2', 'Gene', (187, 192))	('different', 'Reg', (168, 177))	('MYCN', 'Gene', '4613', (181, 185))	('mRNA expression', 'MPA', (78, 93))	('let-7f', 'Var', (143, 149))	('let-7d', 'Gene', (30, 36))	('let-7d', 'Gene', '406886', (30, 36))	('let-7a', 'Gene', (19, 25))	('HMGA2', 'Gene', '8091', (187, 192))
325201	26858029	In tumours with apparent co-regulation of expression of HMGA2 and MYCN, there was a significantly better outcome when both genes were downregulated compared to the alternatives (log rank test, p = 0.040) (Fig.	('HMGA2', 'Gene', (56, 61))	('tumour', 'Phenotype', 'HP:0002664', (3, 9))	('downregulated', 'NegReg', (134, 147))	('co-regulation', 'Var', (25, 38))	('tumours', 'Phenotype', 'HP:0002664', (3, 10))	('MYCN', 'Gene', (66, 70))	('MYCN', 'Gene', '4613', (66, 70))	('HMGA2', 'Gene', '8091', (56, 61))	('tumours', 'Disease', 'MESH:D009369', (3, 10))	('tumours', 'Disease', (3, 10))
325206	26858029	The development of NSCLC includes multiple genetic and epigenetic alterations that may lead to activation of pathways promoting tumour growth as well as inhibition of pathways of tumour suppression.	('epigenetic alterations', 'Var', (55, 77))	('NSCLC', 'Phenotype', 'HP:0030358', (19, 24))	('pathways of', 'Pathway', (167, 178))	('inhibition', 'NegReg', (153, 163))	('tumour suppression', 'Disease', (179, 197))	('tumour suppression', 'Disease', 'OMIM:146850', (179, 197))	('tumour', 'Phenotype', 'HP:0002664', (179, 185))	('promoting', 'PosReg', (118, 127))	('activation', 'PosReg', (95, 105))	('men', 'Species', '9606', (11, 14))	('tumour', 'Phenotype', 'HP:0002664', (128, 134))	('tumour growth', 'Disease', (128, 141))	('NSCLC', 'Disease', (19, 24))	('tumour growth', 'Disease', 'MESH:D006130', (128, 141))	('NSCLC', 'Disease', 'MESH:D002289', (19, 24))	('pathways', 'Pathway', (109, 117))
325210	26858029	It is mainly expressed in embryos, and mutant mice with HMGA2 deficiency develop a pygmy phenotype.	('HMGA2 deficiency', 'Disease', 'MESH:D007153', (56, 72))	('HMGA2 deficiency', 'Disease', (56, 72))	('mice', 'Species', '10090', (46, 50))	('develop', 'Reg', (73, 80))	('mutant', 'Var', (39, 45))	('pygmy phenotype', 'CPA', (83, 98))
325217	26858029	Previous studies have indicated a role for thyroid transcription factor-1 (TTF-1) in the regulation of HMGA2 expression, as a loss of TTF-1 triggers overexpression of HMGA2.	('overexpression', 'MPA', (149, 163))	('HMGA2', 'Gene', '8091', (167, 172))	('TTF-1', 'Gene', '7080', (134, 139))	('HMGA2', 'Gene', (167, 172))	('thyroid transcription factor-1', 'Gene', (43, 73))	('HMGA2', 'Gene', '8091', (103, 108))	('TTF-1', 'Gene', '7080', (75, 80))	('HMGA2', 'Gene', (103, 108))	('TTF-1', 'Gene', (75, 80))	('TTF-1', 'Gene', (134, 139))	('thyroid transcription factor-1', 'Gene', '7080', (43, 73))	('loss', 'Var', (126, 130))
325230	26858029	We found several let-7 microRNAs to be differentially expressed comparing high and low HMGA2 gene expression; let-7a, let-7c and let-7f was seen inversely correlated, consistent with the biological presumption that loss of let-7 inhibition leads to HMGA2 overexpression in cancer.	('cancer', 'Disease', (273, 279))	('cancer', 'Disease', 'MESH:D009369', (273, 279))	('HMGA2', 'Gene', (249, 254))	('let-7c', 'Gene', (118, 124))	('inhibition', 'NegReg', (229, 239))	('let-7c', 'Gene', '406885', (118, 124))	('loss', 'Var', (215, 219))	('HMGA2', 'Gene', '8091', (87, 92))	('cancer', 'Phenotype', 'HP:0002664', (273, 279))	('let-7', 'Gene', (223, 228))	('overexpression', 'PosReg', (255, 269))	('HMGA2', 'Gene', (87, 92))	('HMGA2', 'Gene', '8091', (249, 254))
325231	26858029	It has also been shown that aberrant expression of let-7 is more common in squamous cell carcinoma compared to adenocarcinomas.	('common', 'Reg', (65, 71))	('adenocarcinomas', 'Disease', (111, 126))	('aberrant expression', 'Var', (28, 47))	('adenocarcinomas', 'Disease', 'MESH:D000230', (111, 126))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (75, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('squamous cell carcinoma', 'Disease', (75, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('carcinomas', 'Phenotype', 'HP:0030731', (116, 126))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (75, 98))	('let-7', 'Gene', (51, 56))
325244	26858029	The mRNA expression levels of MYCN and HMGA2 and DICER1 were significantly correlated, and co-regulation of expression of HMGA2 and MYCN, had a significant impact on survival.	('MYCN', 'Gene', (30, 34))	('impact', 'Reg', (156, 162))	('HMGA2', 'Gene', (39, 44))	('DICER1', 'Gene', (49, 55))	('HMGA2', 'Gene', '8091', (122, 127))	('MYCN', 'Gene', '4613', (30, 34))	('DICER1', 'Gene', '23405', (49, 55))	('mRNA expression levels', 'MPA', (4, 26))	('HMGA2', 'Gene', (122, 127))	('MYCN', 'Gene', (132, 136))	('MYCN', 'Gene', '4613', (132, 136))	('co-regulation', 'Var', (91, 104))	('survival', 'CPA', (166, 174))	('HMGA2', 'Gene', '8091', (39, 44))
325248	25398092	In many epithelial malignancies, altered integrin expression is associated with tumor progression and often correlates with unfavorable prognosis.	('associated', 'Reg', (64, 74))	('integrin', 'Protein', (41, 49))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('epithelial malignancies', 'Disease', 'MESH:D002277', (8, 31))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumor', 'Disease', (80, 85))	('epithelial malignancies', 'Disease', (8, 31))	('altered', 'Var', (33, 40))	('epithelial malignancies', 'Phenotype', 'HP:0031492', (8, 31))	('expression', 'MPA', (50, 60))
325253	25398092	In contrast, patients with reduced focal alpha6 expression at the tumor invasion front shared a significantly shortened relapse-free survival compared to patients with strong alpha6 expression at their stromal surfaces, as it was regularly observed in normal esophageal epithelium (p = 0.001).	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('reduced', 'NegReg', (27, 34))	('alpha6', 'Protein', (41, 47))	('tumor', 'Disease', (66, 71))	('focal', 'Var', (35, 40))	('patients', 'Species', '9606', (13, 21))	('patients', 'Species', '9606', (154, 162))	('relapse-free survival', 'CPA', (120, 141))	('shortened', 'NegReg', (110, 119))	('tumor', 'Disease', 'MESH:D009369', (66, 71))
325254	25398092	Our findings suggest that alterations in both pattern and magnitude of integrin expression may play a major role in the disease progression of ESCC patients.	('patients', 'Species', '9606', (148, 156))	('SCC', 'Gene', (144, 147))	('SCC', 'Phenotype', 'HP:0002860', (144, 147))	('play', 'Reg', (95, 99))	('alterations', 'Var', (26, 37))	('SCC', 'Gene', '6317', (144, 147))	('integrin', 'Protein', (71, 79))
325313	25398092	Seven (54%) of the 13 pN0 patients had an enhanced beta1 expression at the invasion front of their tumors compared to only two (12%) of 17 of the pN1 patients (p = 0.018).	('pN1', 'Gene', (146, 149))	('expression', 'MPA', (57, 67))	('tumors', 'Disease', 'MESH:D009369', (99, 105))	('enhanced', 'PosReg', (42, 50))	('beta1', 'Gene', '3779', (51, 56))	('patients', 'Species', '9606', (26, 34))	('pN0', 'Var', (22, 25))	('patients', 'Species', '9606', (150, 158))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))	('pN1', 'Gene', '5270', (146, 149))	('beta1', 'Gene', (51, 56))	('tumors', 'Disease', (99, 105))
325318	25398092	Thereby, patients with a down-regulated low to moderate (+/++) alpha6 immunostaining at the invasion front shared a 6.41 times increased risk for tumor relapse (95% CI: 1.88-21.78), a 5.11 times increased risk for shortened tumor-associated survival (95% CI: 1.47-17.81), and a 3.04 times increased risk for shortened overall survival (95% CI: 1.13-8.21) compared to patients with a distinct strong (+++) alpha6 staining.	('patients', 'Species', '9606', (9, 17))	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('tumor', 'Disease', (224, 229))	('tumor', 'Disease', (146, 151))	('down-regulated', 'NegReg', (25, 39))	('low to moderate (+/++', 'Var', (40, 61))	('patients', 'Species', '9606', (367, 375))	('overall', 'MPA', (318, 325))	('tumor', 'Disease', 'MESH:D009369', (146, 151))	('tumor', 'Disease', 'MESH:D009369', (224, 229))	('shortened', 'NegReg', (214, 223))
325348	25398092	Our results indicate that the abrogation of normal integrin expression characteristics, as they are observed in non-malignant squamous epithelium of the esophagus, is a frequent event in esophageal squamous cell carcinoma (ESCC) associated to an unfavorable disease outcome.	('expression', 'MPA', (60, 70))	('SCC', 'Gene', (224, 227))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (198, 221))	('SCC', 'Phenotype', 'HP:0002860', (224, 227))	('abrogation', 'Var', (30, 40))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (187, 221))	('SCC', 'Gene', '6317', (224, 227))	('carcinoma', 'Phenotype', 'HP:0030731', (212, 221))	('esophageal squamous cell carcinoma', 'Disease', (187, 221))
325365	25398092	In another study, the loss of polarized alpha6beta4 expression was suggested as a potential early marker of malignancy in oral SCC.	('SCC', 'Gene', (127, 130))	('SCC', 'Phenotype', 'HP:0002860', (127, 130))	('beta4', 'Gene', '10381', (46, 51))	('malignancy', 'Disease', 'MESH:D009369', (108, 118))	('malignancy in oral', 'Phenotype', 'HP:0100649', (108, 126))	('SCC', 'Gene', '6317', (127, 130))	('beta4', 'Gene', (46, 51))	('malignancy', 'Disease', (108, 118))	('loss', 'Var', (22, 26))
325369	25398092	In their in vitro experiments, the authors convincingly show that the molecular interference and down-regulation of alpha6 integrin expression in ESCC cell lines decreases cell proliferation and invasiveness.	('molecular interference', 'Var', (70, 92))	('SCC', 'Gene', (147, 150))	('alpha6 integrin', 'Protein', (116, 131))	('down-regulation', 'NegReg', (97, 112))	('SCC', 'Phenotype', 'HP:0002860', (147, 150))	('decreases', 'NegReg', (162, 171))	('cell proliferation', 'CPA', (172, 190))	('SCC', 'Gene', '6317', (147, 150))	('invasiveness', 'CPA', (195, 207))
325394	25398092	Particularly the expression of the two alpha6 integrins alpha6beta1 and alpha6beta4 appear to play a critical role in the malignant progression of ESCC reflecting its aggressiveness: The abrogation of a polarized expression pattern in the primary tumor with a loss of the focally enhanced integrin expression along the tumor invasion front represents an amendatory histopathological marker to further assess the malignancy of the individual tumor.	('tumor', 'Phenotype', 'HP:0002664', (247, 252))	('expression', 'MPA', (298, 308))	('malignancy', 'Disease', 'MESH:D009369', (412, 422))	('SCC', 'Gene', (148, 151))	('tumor', 'Disease', (441, 446))	('loss', 'NegReg', (260, 264))	('beta1', 'Gene', (62, 67))	('abrogation', 'Var', (187, 197))	('aggressiveness', 'Disease', (167, 181))	('malignancy', 'Disease', (412, 422))	('integrin', 'Protein', (289, 297))	('tumor', 'Disease', 'MESH:D009369', (441, 446))	('aggressiveness', 'Phenotype', 'HP:0000718', (167, 181))	('beta1', 'Gene', '3779', (62, 67))	('beta4', 'Gene', (78, 83))	('SCC', 'Gene', '6317', (148, 151))	('aggressiveness', 'Disease', 'MESH:D001523', (167, 181))	('tumor', 'Disease', (319, 324))	('tumor', 'Disease', (247, 252))	('tumor', 'Phenotype', 'HP:0002664', (441, 446))	('beta4', 'Gene', '10381', (78, 83))	('tumor', 'Disease', 'MESH:D009369', (319, 324))	('SCC', 'Phenotype', 'HP:0002860', (148, 151))	('tumor', 'Disease', 'MESH:D009369', (247, 252))	('polarized expression pattern', 'MPA', (203, 231))	('tumor', 'Phenotype', 'HP:0002664', (319, 324))	('enhanced', 'PosReg', (280, 288))
325402	30896821	In vitro experiments demonstrated that CASC9 knockdown by RNA interference attenuated the viability and proliferation of LUSC cells.	('LUSC', 'Phenotype', 'HP:0030359', (121, 125))	('CASC9', 'Gene', '101805492', (39, 44))	('CASC9', 'Gene', (39, 44))	('attenuated', 'NegReg', (75, 85))	('RNA interference', 'MPA', (58, 74))	('knockdown', 'Var', (45, 54))
325412	30896821	Drugs targeting mutated versions of the epidermal growth factor receptor (EGFR), GTPase KRas and ALK tyrosine kinase receptor proteins mutations have already demonstrated beneficial effects in patients with LUAD.	('patients', 'Species', '9606', (193, 201))	('KRas', 'Gene', (88, 92))	('KRas', 'Gene', '3845', (88, 92))	('epidermal growth factor receptor', 'Gene', '1956', (40, 72))	('ALK', 'Gene', '238', (97, 100))	('mutations', 'Var', (135, 144))	('LUAD', 'Phenotype', 'HP:0030078', (207, 211))	('mutated', 'Var', (16, 23))	('LUAD', 'Disease', (207, 211))	('beneficial', 'PosReg', (171, 181))	('EGFR', 'Gene', '1956', (74, 78))	('ALK', 'Gene', (97, 100))	('epidermal growth factor receptor', 'Gene', (40, 72))	('EGFR', 'Gene', (74, 78))
325413	30896821	Numerous studies have revealed that the ectopic expression of lncRNAs is implicated in human cancer.	('implicated', 'Reg', (73, 83))	('ectopic', 'Var', (40, 47))	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('human', 'Species', '9606', (87, 92))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('lncRNAs', 'Gene', (62, 69))
325447	30896821	The distribution of the CASC9 alteration in 179 sequenced patients with LUSC was visualized using the OncoPrint module of cBioPortal.	('alteration', 'Var', (30, 40))	('CASC9', 'Gene', '101805492', (24, 29))	('LUSC', 'Phenotype', 'HP:0030359', (72, 76))	('patients', 'Species', '9606', (58, 66))	('CASC9', 'Gene', (24, 29))
325470	30896821	Finally, 3 GSE datasets, GSE49155, GSE33479 and GSE51852, were included.	('GSE51852', 'Var', (48, 56))	('GSE', 'Chemical', '-', (35, 38))	('GSE', 'Chemical', '-', (48, 51))	('GSE49155', 'Var', (25, 33))	('GSE', 'Chemical', '-', (11, 14))	('GSE33479', 'Var', (35, 43))	('GSE', 'Chemical', '-', (25, 28))
325487	30896821	7 illustrates the behavioral changes in LUSC cells caused by the siRNA knockdown of CASC9 in terms of cell viability and proliferation.	('behavioral changes', 'Phenotype', 'HP:0000708', (18, 36))	('knockdown', 'Var', (71, 80))	('CASC9', 'Gene', '101805492', (84, 89))	('CASC9', 'Gene', (84, 89))	('LUSC', 'Phenotype', 'HP:0030359', (40, 44))	('behavioral changes', 'CPA', (18, 36))
325514	30896821	The 2.2% incidence of naturally occurring gene duplication of CASC9 in LUSC samples was consistent with the upregulation of this lncRNA, providing a possible explanation for its overexpression in this cancer type.	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('CASC9', 'Gene', (62, 67))	('CASC9', 'Gene', '101805492', (62, 67))	('gene duplication', 'Var', (42, 58))	('cancer', 'Disease', (201, 207))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('LUSC', 'Phenotype', 'HP:0030359', (71, 75))	('upregulation', 'PosReg', (108, 120))
325541	30896821	The datasets generated and/or analyzed during the current study were TCGA-LUSC (https://portal.gdc.cancer.gov/) GSE49155, GSE33479 and GSE51852 (https://www.ncbi.nlm.nih.gov/gds/).	('GSE51852', 'Var', (135, 143))	('GSE49155', 'Var', (112, 120))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('GSE', 'Chemical', '-', (135, 138))	('LUSC', 'Phenotype', 'HP:0030359', (74, 78))	('cancer', 'Disease', (99, 105))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('GSE33479', 'Var', (122, 130))	('GSE', 'Chemical', '-', (112, 115))	('GSE', 'Chemical', '-', (122, 125))
325567	29515689	The in-depth studies of chromosome discovered Philadelphia chromosome that was resulted from the translocation between chromosome 9 and 22 in chronic myelogenous leukemia (CML) cells.	('CML', 'Disease', 'MESH:D015464', (172, 175))	('chronic myelogenous leukemia', 'Disease', 'MESH:D015464', (142, 170))	('translocation', 'Var', (97, 110))	('chronic myelogenous leukemia', 'Disease', (142, 170))	('chronic myelogenous leukemia', 'Phenotype', 'HP:0005506', (142, 170))	('CML', 'Disease', (172, 175))	('leukemia', 'Phenotype', 'HP:0001909', (162, 170))	('myelogenous leukemia', 'Phenotype', 'HP:0012324', (150, 170))	('resulted from', 'Reg', (79, 92))
325569	29515689	Those findings promote scientists to increasingly understand cancers that are derived from accumulation of genomic alternations, including base substitutions, small insertions and deletions, chromosomal rearrangements and copy number alterations and microbial infections.	('base substitutions', 'Var', (139, 157))	('copy number alterations', 'Var', (222, 245))	('cancers', 'Disease', 'MESH:D009369', (61, 68))	('cancers', 'Phenotype', 'HP:0002664', (61, 68))	('cancers', 'Disease', (61, 68))	('microbial infections', 'Disease', 'MESH:D015163', (250, 270))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('chromosomal', 'Disease', (191, 202))	('microbial infections', 'Disease', (250, 270))	('deletions', 'Var', (180, 189))	('small insertions', 'Var', (159, 175))
325580	29515689	The study of lung squamous cell carcinoma (LSCC) found a mean of 360 exonic mutations, 165 genomic rearrangements, and 323 segments of copy number alteration per tumor, and loss-of-function mutations that are not reported previously.	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (13, 41))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (18, 41))	('tumor', 'Disease', (162, 167))	('lung squamous cell carcinoma', 'Disease', (13, 41))	('copy number alteration', 'Var', (135, 157))	('carcinoma', 'Phenotype', 'HP:0030731', (32, 41))	('loss-of-function', 'NegReg', (173, 189))	('tumor', 'Disease', 'MESH:D009369', (162, 167))
325583	29515689	For example, gene fusions resulting from chromosome translocations have an important role in the initial steps of tumorigenesis with evidence of discovery of gene fusions in all malignancies.	('malignancies', 'Disease', 'MESH:D009369', (178, 190))	('gene', 'Var', (13, 17))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('chromosome translocations', 'Var', (41, 66))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('malignancies', 'Disease', (178, 190))	('tumor', 'Disease', (114, 119))
325584	29515689	Functionally recurrent gene fusions provide more precisely clinical-related subclassifications of traditionaly morphological classification of tumors and accelerate the development of specific targeted therapies.	('accelerate', 'PosReg', (154, 164))	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('tumors', 'Disease', (143, 149))	('tumors', 'Disease', 'MESH:D009369', (143, 149))	('gene fusions', 'Var', (23, 35))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
325596	29515689	EGFR mutants were the most common genomic alteration underlying NSCLC, and patients with EGFR mutants were routinely treated with EGFR kinase inhibitor.	('NSCLC', 'Disease', 'MESH:D002289', (64, 69))	('EGFR', 'Gene', '1956', (89, 93))	('EGFR', 'Gene', (89, 93))	('EGFR', 'Gene', (0, 4))	('mutants', 'Var', (94, 101))	('EGFR', 'Gene', (130, 134))	('patients', 'Species', '9606', (75, 83))	('mutants', 'Var', (5, 12))	('EGFR', 'Gene', '1956', (0, 4))	('EGFR', 'Gene', '1956', (130, 134))	('NSCLC', 'Disease', (64, 69))	('common', 'Reg', (27, 33))
325598	29515689	These forms of molecular abnormalities have distinct mechanisms of tumorigenesis from EGFR mutants.	('EGFR', 'Gene', '1956', (86, 90))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('EGFR', 'Gene', (86, 90))	('mutants', 'Var', (91, 98))	('molecular abnormalities', 'Disease', (15, 38))	('tumor', 'Disease', (67, 72))	('molecular abnormalities', 'Disease', 'MESH:C567116', (15, 38))
325603	29515689	Splicing abnormalities are a common characteristics of cancer, occurring in every category of cancer hallmarks.	('Splicing abnormalities', 'Var', (0, 22))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('cancer hallmarks', 'Disease', (94, 110))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('occurring', 'Reg', (63, 72))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('cancer hallmarks', 'Disease', 'MESH:D009369', (94, 110))	('cancer', 'Disease', (55, 61))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
325605	29515689	RNA-seq can directly and readily detect RNA splicing events relative to standard gene expression microarray, so it is a power tool in discovering cancer-related alternative splicing, which might be a diagnostic or prognostic marker and potential personalized therapy target.	('alternative splicing', 'Var', (161, 181))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('cancer', 'Disease', (146, 152))
325606	29515689	In the research of NSCLC, a comprehensive study of prognosis-related alternative mRNA splicing using RNA-seq data identified a large number of alternative splicing events that are associated with the prognosis of NSCLC.	('NSCLC', 'Disease', 'MESH:D002289', (213, 218))	('alternative splicing events', 'Var', (143, 170))	('NSCLC', 'Disease', (19, 24))	('associated with', 'Reg', (180, 195))	('NSCLC', 'Disease', 'MESH:D002289', (19, 24))	('NSCLC', 'Disease', (213, 218))
325619	29515689	The miRNA-mRNA regulatory network was studied in peripheral blood mononuclear cells of small cell osteosarcoma (SCO) with RNA-seq, which identified 37 dysregulated miRNA (27 upregulated and 10 downregulated) and 1636 dysregulated mRNAs (555 upregulated and 1081 downregulated), two important signaling pathways including mTOR signaling and cell cycle signaling, and dysregulation of three miRNAs (has-miR-26b-5p, has-miR-221-3p, and has-miR-125b-2-3p) that might be involved in SCO tumorigenesis.	('osteosarcoma', 'Phenotype', 'HP:0002669', (98, 110))	('SCO', 'Gene', (112, 115))	('tumor', 'Disease', 'MESH:D009369', (482, 487))	('mTOR', 'Gene', (321, 325))	('downregulated', 'NegReg', (262, 275))	('sarcoma', 'Phenotype', 'HP:0100242', (103, 110))	('upregulated', 'PosReg', (241, 252))	('mTOR', 'Gene', '2475', (321, 325))	('tumor', 'Phenotype', 'HP:0002664', (482, 487))	('has-miR-26b-5p', 'Var', (397, 411))	('dysregulation', 'Var', (366, 379))	('SCO', 'Gene', '619469', (478, 481))	('has-miR-125b-2-3p', 'Var', (433, 450))	('small cell osteosarcoma', 'Disease', (87, 110))	('small cell osteosarcoma', 'Disease', 'MESH:D012516', (87, 110))	('cell cycle', 'CPA', (340, 350))	('has-miR-221-3p', 'Var', (413, 427))	('SCO', 'Gene', '619469', (112, 115))	('SCO', 'Gene', (478, 481))	('tumor', 'Disease', (482, 487))
325627	29515689	Another study identified a signature of five lncRNAs (CYP4F26P, RP11-108M12.3, RP11-38M8.1, RP11-54H7.4 and ZNF503-AS1), which might act as an independent prognostic indicator for LUSC with RNA-seq data from TCGA.	('ZNF503-AS1', 'Gene', (108, 118))	('ncRNA', 'Gene', '220202', (46, 51))	('H7.4', 'CellLine', 'CVCL:1934', (99, 103))	('RP11', 'Gene', '26121', (79, 83))	('ZNF503-AS1', 'Gene', '253264', (108, 118))	('RP11', 'Gene', (92, 96))	('RP11', 'Gene', (64, 68))	('LUSC', 'Disease', (180, 184))	('CYP4F26P', 'Var', (54, 62))	('RP11', 'Gene', '26121', (64, 68))	('RP11', 'Gene', '26121', (92, 96))	('ncRNA', 'Gene', (46, 51))	('RP11', 'Gene', (79, 83))
325635	29515689	For example, glycosylated proteins represented 50% of the secreted proteome and abnormal glycosylation of proteins has been implicated to play a critical role in cancerous progression.	('proteins', 'Protein', (106, 114))	('glycosylation', 'MPA', (89, 102))	('cancerous', 'Disease', 'MESH:D009369', (162, 171))	('abnormal glycosylation', 'Phenotype', 'HP:0012345', (80, 102))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('abnormal', 'Var', (80, 88))	('role', 'Reg', (154, 158))	('play', 'Reg', (138, 142))	('cancerous', 'Disease', (162, 171))
325649	29515689	Since phosphorylated PGRMC1 will active a series of intracellular signaling, it is a potential therapeutic target.	('PGRMC1', 'Gene', (21, 27))	('PGRMC1', 'Gene', '10857', (21, 27))	('phosphorylated', 'Var', (6, 20))	('active a series of intracellular signaling', 'MPA', (33, 75))
325653	29515689	Besides biomarkers, proteomics approach is also a guiding tool for the discovery of more potential therapeutic targets, for example, BIRC6 in colon cancer stem cells, bone marrow stromal antigen 2 and cyclophilin A in endometrial cancers, phosphoglycerate mutase 1 in HCCs, anaplastic lymphoma kinase in ovarian cancer, and hypusination of eukaryotic initiation factor 5A in BCR-ABL-positive leukemias.	('endometrial cancers', 'Disease', (218, 237))	('eukaryotic initiation factor 5A', 'Gene', (340, 371))	('colon cancer', 'Disease', (142, 154))	('bone marrow stromal antigen 2', 'Gene', '684', (167, 196))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (274, 293))	('hypusination', 'Var', (324, 336))	('eukaryotic initiation factor 5A', 'Gene', '1984', (340, 371))	('cancer', 'Phenotype', 'HP:0002664', (312, 318))	('ovarian cancer', 'Disease', 'MESH:D010051', (304, 318))	('leukemias', 'Disease', 'MESH:D007938', (392, 401))	('BIRC6', 'Gene', '57448', (133, 138))	('cancers', 'Phenotype', 'HP:0002664', (230, 237))	('lymphoma', 'Phenotype', 'HP:0002665', (285, 293))	('colon cancer', 'Phenotype', 'HP:0003003', (142, 154))	('leukemias', 'Phenotype', 'HP:0001909', (392, 401))	('HCC', 'Gene', '619501', (268, 271))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('ovarian cancer', 'Disease', (304, 318))	('leukemia', 'Phenotype', 'HP:0001909', (392, 400))	('HCC', 'Gene', (268, 271))	('phosphoglycerate mutase 1', 'Gene', (239, 264))	('colon cancer', 'Disease', 'MESH:D015179', (142, 154))	('BIRC6', 'Gene', (133, 138))	('ovarian cancer', 'Phenotype', 'HP:0100615', (304, 318))	('leukemias', 'Disease', (392, 401))	('bone marrow stromal antigen 2', 'Gene', (167, 196))	('phosphoglycerate mutase 1', 'Gene', '5223', (239, 264))	('anaplastic', 'Enzyme', (274, 284))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('lymphoma', 'Disease', (285, 293))	('lymphoma', 'Disease', 'MESH:D008223', (285, 293))	('endometrial cancers', 'Disease', 'MESH:D016889', (218, 237))
325657	29515689	For example, pathway network analysis based on multiple sets of pituitary adenoma proteomics data (DEP data, nitroproteomics data, and protein mapping data) revealed mitochondrial dysfunction, oxidative stress, cell cycle dysregulation, and MAPK-signaling abnormality were significantly associated with pituitary adenoma pathogenesis, wich provides new clues to in-depth investigation of pituitary adenoma and discovery of effective biomarkers.	('pituitary adenoma', 'Phenotype', 'HP:0002893', (64, 81))	('pituitary adenoma', 'Disease', (303, 320))	('pituitary adenoma', 'Disease', (64, 81))	('pituitary adenoma', 'Disease', 'MESH:D010911', (388, 405))	('oxidative stress', 'MPA', (193, 209))	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (166, 191))	('pituitary adenoma', 'Phenotype', 'HP:0002893', (388, 405))	('pituitary adenoma', 'Disease', (388, 405))	('cell cycle dysregulation', 'Phenotype', 'HP:0011018', (211, 235))	('mitochondrial dysfunction', 'Disease', 'MESH:D028361', (166, 191))	('mitochondrial dysfunction', 'Disease', (166, 191))	('MAPK-signaling', 'MPA', (241, 255))	('oxidative stress', 'Phenotype', 'HP:0025464', (193, 209))	('abnormality', 'Var', (256, 267))	('pituitary adenoma', 'Disease', 'MESH:D010911', (303, 320))	('pituitary adenoma', 'Phenotype', 'HP:0002893', (303, 320))	('cell cycle', 'CPA', (211, 221))	('pituitary adenoma', 'Disease', 'MESH:D010911', (64, 81))	('associated', 'Reg', (287, 297))
325695	29515689	Mutated IDH1/2 was found a neomorphic enzymatic activity to catalyze alpha-ketoglutarate to (R)2-hydroglutarate [(R)2-HG] in gliomas.	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (69, 88))	('gliomas', 'Disease', (125, 132))	('gliomas', 'Disease', 'MESH:D005910', (125, 132))	('(R)2-HG', 'Chemical', '-', (113, 120))	('gliomas', 'Phenotype', 'HP:0009733', (125, 132))	('glioma', 'Phenotype', 'HP:0009733', (125, 131))	('IDH1/2', 'Gene', '3417;3418', (8, 14))	('Mutated', 'Var', (0, 7))	('catalyze', 'MPA', (60, 68))	('(R)2-hydroglutarate', 'Chemical', '-', (92, 111))	('IDH1/2', 'Gene', (8, 14))
325697	29515689	Tumor with IDH mutation constructs a distinct clinical subset in both leukemia and gliomas.	('mutation', 'Var', (15, 23))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('IDH', 'Gene', '3417', (11, 14))	('IDH', 'Gene', (11, 14))	('leukemia and gliomas', 'Disease', 'MESH:D005910', (70, 90))	('gliomas', 'Phenotype', 'HP:0009733', (83, 90))	('glioma', 'Phenotype', 'HP:0009733', (83, 89))	('leukemia', 'Phenotype', 'HP:0001909', (70, 78))
325698	29515689	IDH mutations were also identified in multiple cancers, including chondrosarcoma, sarcoma, and cholangiocarcinoma.	('sarcoma', 'Phenotype', 'HP:0100242', (73, 80))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (66, 80))	('IDH', 'Gene', (0, 3))	('identified', 'Reg', (24, 34))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (95, 113))	('multiple cancers', 'Disease', 'MESH:D009369', (38, 54))	('IDH', 'Gene', '3417', (0, 3))	('sarcoma', 'Disease', 'MESH:D012509', (82, 89))	('cancers', 'Phenotype', 'HP:0002664', (47, 54))	('mutations', 'Var', (4, 13))	('sarcoma', 'Disease', (82, 89))	('cholangiocarcinoma', 'Disease', (95, 113))	('sarcoma', 'Disease', 'MESH:D012509', (73, 80))	('chondrosarcoma', 'Disease', 'MESH:D002813', (66, 80))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (95, 113))	('chondrosarcoma', 'Disease', (66, 80))	('sarcoma', 'Disease', (73, 80))	('sarcoma', 'Phenotype', 'HP:0100242', (82, 89))	('multiple cancers', 'Disease', (38, 54))
325699	29515689	IDH mutants become promising candidates of therapeutic targets.	('IDH', 'Gene', '3417', (0, 3))	('IDH', 'Gene', (0, 3))	('mutants', 'Var', (4, 11))
325700	29515689	A selective R 132H-IDH1 inhibitor (AGI-5198) demonstrated that mIDH1 inhibitor was able to block the production of R-2HG, and induce demethylation of histone and the expression of gliogenic differentiation associated genes, but it did not influence the functions of IDH1 wild-type in a glioma.	('histone', 'Protein', (150, 157))	('IDH1', 'Gene', (64, 68))	('IDH1', 'Gene', '3417', (19, 23))	('R-2HG', 'MPA', (115, 120))	('inhibitor', 'Var', (69, 78))	('IDH1', 'Gene', '3417', (64, 68))	('block', 'NegReg', (91, 96))	('glioma', 'Disease', (286, 292))	('induce', 'Reg', (126, 132))	('mIDH1', 'Gene', '15926', (63, 68))	('mIDH1', 'Gene', (63, 68))	('IDH1', 'Gene', (266, 270))	('glioma', 'Disease', 'MESH:D005910', (286, 292))	('expression', 'MPA', (166, 176))	('AGI-5198', 'Chemical', 'MESH:C581156', (35, 43))	('production', 'MPA', (101, 111))	('IDH1', 'Gene', (19, 23))	('demethylation', 'MPA', (133, 146))	('IDH1', 'Gene', '3417', (266, 270))	('glioma', 'Phenotype', 'HP:0009733', (286, 292))	('R 132H', 'Mutation', 'rs121913500', (12, 18))	('gliogenic differentiation associated genes', 'Gene', (180, 222))
325703	29515689	More and more IDH inhibitors are being developed such as AG-120 and AG-221 in cancers.	('IDH', 'Gene', (14, 17))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('IDH', 'Gene', '3417', (14, 17))	('cancers', 'Disease', 'MESH:D009369', (78, 85))	('cancers', 'Phenotype', 'HP:0002664', (78, 85))	('cancers', 'Disease', (78, 85))	('AG-120', 'Var', (57, 63))	('AG-221', 'Gene', (68, 74))
325717	29515689	For example,a PET/CT imaging study in NSCLC showed that abnormal texture as measured by coarseness, contrast, and busyness is associated with nonresponse to chemoradiotherapy and with poorer prognosis.	('NSCLC', 'Disease', (38, 43))	('abnormal', 'Var', (56, 64))	('associated', 'Reg', (126, 136))	('NSCLC', 'Disease', 'MESH:D002289', (38, 43))
325721	29515689	Another study assessed T2-weighted MRI-derived textural features demonstrated that these features corrected significantly with Gleason score and could distinguish Gleason score 3+4 from 4+3 cancers with high sensitive to the pathological difference.	('cancers', 'Phenotype', 'HP:0002664', (190, 197))	('cancers', 'Disease', (190, 197))	('cancers', 'Disease', 'MESH:D009369', (190, 197))	('Gleason', 'Var', (163, 170))	('distinguish', 'Reg', (151, 162))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('Gleason score', 'MPA', (127, 140))	('corrected', 'Reg', (98, 107))
325733	29515689	Another glioblastoma study based on MRI-derived tumor imaging features demonstrated that TP53 mutant tumors had smaller enhancing and necrotic volumes (p = 0.012 and 0.017, respectively) and RB1 mutant tumors had smaller edema volumes (p = 0.015).	('smaller', 'NegReg', (112, 119))	('edema', 'Disease', 'MESH:D004487', (221, 226))	('smaller', 'NegReg', (213, 220))	('tumors', 'Disease', 'MESH:D009369', (202, 208))	('edema', 'Disease', (221, 226))	('RB1', 'Gene', '5925', (191, 194))	('enhancing', 'MPA', (120, 129))	('TP53', 'Gene', '7157', (89, 93))	('tumor', 'Disease', (202, 207))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('glioblastoma', 'Disease', 'MESH:D005909', (8, 20))	('tumor', 'Disease', (48, 53))	('tumors', 'Phenotype', 'HP:0002664', (202, 208))	('mutant', 'Var', (94, 100))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('necrotic', 'Disease', (134, 142))	('mutant', 'Var', (195, 201))	('glioblastoma', 'Disease', (8, 20))	('tumors', 'Disease', (101, 107))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('TP53', 'Gene', (89, 93))	('necrotic', 'Disease', 'MESH:D009336', (134, 142))	('glioblastoma', 'Phenotype', 'HP:0012174', (8, 20))	('edema', 'Phenotype', 'HP:0000969', (221, 226))	('RB1', 'Gene', (191, 194))	('tumor', 'Disease', (101, 106))	('tumors', 'Disease', (202, 208))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('tumors', 'Disease', 'MESH:D009369', (101, 107))
325749	29515689	Another integrative analysis of genomic and proteomic data demonstrated that PI3K pathway aberrations are particularly common in hormone receptor-positive breast cancer, which might be important in clinical selection of targeted therapies.	('aberrations', 'Var', (90, 101))	('breast cancer', 'Disease', 'MESH:D001943', (155, 168))	('PI3K pathway', 'Pathway', (77, 89))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('breast cancer', 'Disease', (155, 168))	('breast cancer', 'Phenotype', 'HP:0003002', (155, 168))	('common', 'Reg', (119, 125))
325760	29515689	Several studies have demonstrated the ability of whole genome sequencing in detecting chromosomal copy number changes, rearrangements, DNA hypomethylation, SNP and tumor heterogeneity.	('chromosomal copy number changes', 'Var', (86, 117))	('tumor', 'Disease', (164, 169))	('SNP', 'Disease', (156, 159))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('rearrangements', 'Var', (119, 133))
325765	29515689	Non-squamous NSCLC patients with EGFR mutation benefited from gefitinib and afatinib with increased tumor response rate and prolonged progression-free survival compared to cytotoxic chemotherapy, while sorafenib may derive clinical benefit to NSCLC patients with wild-type EGFR.	('tumor', 'Disease', (100, 105))	('progression-free', 'CPA', (134, 150))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('EGFR', 'Gene', (273, 277))	('NSCLC', 'Disease', 'MESH:D002289', (13, 18))	('gefitinib', 'Chemical', 'MESH:D000077156', (62, 71))	('EGFR', 'Gene', (33, 37))	('NSCLC', 'Disease', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('sorafenib', 'Chemical', 'MESH:D000077157', (202, 211))	('NSCLC', 'Disease', 'MESH:D002289', (243, 248))	('patients', 'Species', '9606', (19, 27))	('increased', 'PosReg', (90, 99))	('patients', 'Species', '9606', (249, 257))	('afatinib', 'Chemical', 'MESH:D000077716', (76, 84))	('EGFR', 'Gene', '1956', (273, 277))	('Non-squamous NSCLC', 'Disease', (0, 18))	('NSCLC', 'Disease', (243, 248))	('benefited', 'PosReg', (47, 56))	('Non-squamous NSCLC', 'Disease', 'MESH:D002294', (0, 18))	('EGFR', 'Gene', '1956', (33, 37))	('mutation', 'Var', (38, 46))
325766	29515689	Although a series of potential biomarkers generated by proteomics, metabolomics, and radiomics have not been approved in the clinical application, some of these candidates (such as AFP-L3 and des-gamma-carboxyprothrombin in HCC, and sarcosine in Pca) show better sensitivity and specificity compared to the FDA-approved biomarkers.	('des-gamma-carboxyprothrombin', 'Var', (192, 220))	('sarcosine', 'Chemical', 'MESH:D012521', (233, 242))	('specificity', 'MPA', (279, 290))	('HCC', 'Gene', (224, 227))	('HCC', 'Gene', '619501', (224, 227))	('better', 'PosReg', (256, 262))	('sensitivity', 'MPA', (263, 274))
325782	31475450	In this review, we summarize recent studies and findings of myoferlin and suggest that myoferlin is a novel potential candidate for clinical diagnosis and targeted cancer therapy.	('cancer', 'Disease', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('myoferlin', 'Var', (87, 96))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))
325784	31475450	It was initially found to have a high degree of homology to dysferlin, and the percentage of similarity between myoferlin and dysferlin sequences is 69%.1 Dysferlin gene mutations cause Miyoshi myopathy and limb girdle muscular dystrophy type 2B,2 while mutations in myoferlin are not correlated with human disease in previous studies.	('Miyoshi myopathy', 'Disease', 'MESH:C537480', (186, 202))	('human', 'Species', '9606', (301, 306))	('Dysferlin', 'Gene', '8291', (155, 164))	('limb girdle muscular dystrophy', 'Disease', 'MESH:D049288', (207, 237))	('limb girdle muscular dystrophy', 'Disease', (207, 237))	('muscular dystrophy', 'Phenotype', 'HP:0003560', (219, 237))	('myopathy', 'Phenotype', 'HP:0003198', (194, 202))	('Dysferlin', 'Gene', (155, 164))	('mutations', 'Var', (170, 179))	('limb girdle muscular dystrophy', 'Phenotype', 'HP:0006785', (207, 237))	('dysferlin', 'Gene', (126, 135))	('dysferlin', 'Gene', (60, 69))	('dysferlin', 'Gene', '8291', (60, 69))	('cause', 'Reg', (180, 185))	('Miyoshi myopathy', 'Disease', (186, 202))	('dysferlin', 'Gene', '8291', (126, 135))
325805	31475450	The loss of myoferlin reduces the autophosphorylation and expression of VEGF receptor-2 (VEGFR-2) in native ECs.	('VEGF receptor-2', 'Gene', (72, 87))	('VEGFR-2', 'Gene', (89, 96))	('expression', 'MPA', (58, 68))	('autophosphorylation', 'MPA', (34, 53))	('myoferlin', 'Protein', (12, 21))	('reduces', 'NegReg', (22, 29))	('VEGFR-2', 'Gene', '3791', (89, 96))	('VEGF receptor-2', 'Gene', '3791', (72, 87))	('loss', 'Var', (4, 8))
325806	31475450	The transfection of myoferlin increases autophosphorylation in response to VEGF and VEGFR-2 membrane expression in a reconstituted cell system.	('VEGF', 'Gene', '7422', (75, 79))	('autophosphorylation', 'MPA', (40, 59))	('VEGF', 'Gene', '7422', (84, 88))	('VEGFR-2', 'Gene', (84, 91))	('transfection', 'Var', (4, 16))	('myoferlin', 'Protein', (20, 29))	('VEGF', 'Gene', (84, 88))	('VEGFR-2', 'Gene', '3791', (84, 91))	('VEGF', 'Gene', (75, 79))	('increases', 'PosReg', (30, 39))
325830	31475450	For migration, researchers found that myoferlin depletion enhances cell adhesion, enlarges focal adhesion,64 enhances cell-matrix adhesion through elevating focal adhesion kinase and paxillin phosphorylation,65 redirects cancer cell motility35 and subsequently inhibits migration.	('myoferlin', 'Protein', (38, 47))	('cancer', 'Disease', 'MESH:D009369', (221, 227))	('inhibits', 'NegReg', (261, 269))	('enhances', 'PosReg', (109, 117))	('elevating', 'PosReg', (147, 156))	('cancer', 'Disease', (221, 227))	('focal', 'MPA', (91, 96))	('paxillin', 'Protein', (183, 191))	('migration', 'CPA', (270, 279))	('cell-matrix adhesion', 'CPA', (118, 138))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('cell adhesion', 'CPA', (67, 80))	('redirects', 'Reg', (211, 220))	('depletion', 'Var', (48, 57))	('focal adhesion kinase', 'MPA', (157, 178))	('enhances', 'PosReg', (58, 66))	('enlarges', 'PosReg', (82, 90))
325832	31475450	After knocking-down myoferlin, mesenchymal to epithelial transition occurred,40 and selective changes in MMPs were observed (which included remarkable down-regulation of MMP140, 50 and MMP3, 8, 12, 13, 14, 1640 and up-regulation of MMP940), EGF-induced cell migration and EMT were blocked66 (verified by impaired degradation of phosphorylated EGFR via dysfunctional plasma membrane caveolae and alteration of caveolin homo-oligomerization) and bio-mechanical properties were altered65 (cell stiffness decreased, cell-substrate adhesion increased, and cells subsequently migrated directionally, collectively and slowly).	('altered65', 'Reg', (475, 484))	('down-regulation', 'NegReg', (151, 166))	('EGFR', 'Gene', (343, 347))	('cell stiffness', 'CPA', (486, 500))	('MMPs', 'Gene', '4313;4314', (105, 109))	('increased', 'PosReg', (536, 545))	('EMT', 'Gene', (272, 275))	('decreased', 'NegReg', (501, 510))	('EMT', 'Gene', '3702', (272, 275))	('MMP3', 'Gene', (185, 189))	('up-regulation', 'PosReg', (215, 228))	('cell-substrate adhesion', 'CPA', (512, 535))	('bio-mechanical properties', 'CPA', (444, 469))	('cell migration', 'CPA', (253, 267))	('EGFR', 'Gene', '1956', (343, 347))	('MMP940', 'Var', (232, 238))	('MMP3', 'Gene', '4314', (185, 189))	('MMPs', 'Gene', (105, 109))	('slowly', 'NegReg', (611, 617))	('knocking-down', 'Var', (6, 19))
325836	31475450	Pancreatic cancer is one of the deadliest cancers given its poor prognosis.62 Similarly, high myoferlin levels are a risk factor in pancreatic adenocarcinoma (PAC).	('cancers', 'Disease', (42, 49))	('PAC', 'Phenotype', 'HP:0006725', (159, 162))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (132, 157))	('Pancreatic cancer', 'Disease', (0, 17))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('PAC', 'Phenotype', 'HP:0006699', (159, 162))	('carcinoma', 'Phenotype', 'HP:0030731', (148, 157))	('Pancreatic cancer', 'Disease', 'MESH:D010190', (0, 17))	('PAC', 'Disease', 'MESH:D010195', (159, 162))	('pancreatic adenocarcinoma', 'Disease', (132, 157))	('high', 'Var', (89, 93))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D010195', (132, 157))	('cancers', 'Phenotype', 'HP:0002664', (42, 49))	('PAC', 'Disease', (159, 162))	('cancers', 'Disease', 'MESH:D009369', (42, 49))	('Pancreatic cancer', 'Phenotype', 'HP:0002894', (0, 17))
325847	31475450	Melanoma is the most aggressive type of skin cancer, and the appearance of vasculogenic mimicry (VM) in this type of cancer always indicates a poor prognosis.72 In VM, tumour cells mimic true vascular endothelium cells and form microvascular channels.73 Myoferlin knockdown significantly impaired the capability of A375 cells to form VM structures and subsequently inhibit cell invasion and migration in vitro.	('Melanoma', 'Disease', 'MESH:D008545', (0, 8))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('aggressive type of skin cancer', 'Disease', (21, 51))	('aggressive type of skin cancer', 'Disease', 'MESH:D012878', (21, 51))	('inhibit', 'NegReg', (365, 372))	('Melanoma', 'Disease', (0, 8))	('impaired', 'NegReg', (288, 296))	('cancer', 'Disease', (117, 123))	('knockdown', 'Var', (264, 273))	('Myoferlin', 'Gene', '26509', (254, 263))	('Melanoma', 'Phenotype', 'HP:0002861', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('tumour', 'Phenotype', 'HP:0002664', (168, 174))	('tumour', 'Disease', 'MESH:D009369', (168, 174))	('tumour', 'Disease', (168, 174))	('cancer', 'Disease', (45, 51))	('skin cancer', 'Phenotype', 'HP:0008069', (40, 51))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('Myoferlin', 'Gene', (254, 263))
325852	31475450	Myoferlin knockdown significantly decreases tumour growth and metastasis of HNSCC.	('metastasis', 'CPA', (62, 72))	('decreases', 'NegReg', (34, 43))	('HNSCC', 'Disease', (76, 81))	('tumour', 'Disease', 'MESH:D009369', (44, 50))	('HNSCC', 'Disease', 'MESH:C535575', (76, 81))	('HNSCC', 'Phenotype', 'HP:0012288', (76, 81))	('Myoferlin', 'Gene', (0, 9))	('tumour', 'Disease', (44, 50))	('knockdown', 'Var', (10, 19))	('Myoferlin', 'Gene', '26509', (0, 9))	('tumour', 'Phenotype', 'HP:0002664', (44, 50))
325861	31475450	The latest research shows that myoferlin regulates cancer-derived exosomes and functions as a new player in exosome biology.41 As mentioned above, myoferlin impacts tumour-associated angiogenesis by affecting VEGFA secretion and EGFR activity.36, 66 These findings suggest that myoferlin induces the malignant phenotype of cancers by altering the tumour microenvironment.	('myoferlin', 'Var', (278, 287))	('tumour', 'Phenotype', 'HP:0002664', (165, 171))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('EGFR', 'Gene', '1956', (229, 233))	('tumour', 'Disease', 'MESH:D009369', (165, 171))	('tumour', 'Disease', (165, 171))	('cancer', 'Disease', 'MESH:D009369', (323, 329))	('cancers', 'Disease', 'MESH:D009369', (323, 330))	('VEGFA', 'Gene', '7422', (209, 214))	('impacts tumour', 'Disease', (157, 171))	('impacts tumour', 'Disease', 'MESH:D014095', (157, 171))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('altering', 'Reg', (334, 342))	('EGFR', 'Gene', (229, 233))	('cancers', 'Phenotype', 'HP:0002664', (323, 330))	('cancers', 'Disease', (323, 330))	('induces', 'Reg', (288, 295))	('cancer', 'Disease', (323, 329))	('tumour', 'Phenotype', 'HP:0002664', (347, 353))	('cancer', 'Phenotype', 'HP:0002664', (323, 329))	('tumour', 'Disease', 'MESH:D009369', (347, 353))	('malignant phenotype', 'CPA', (300, 319))	('tumour', 'Disease', (347, 353))	('cancer', 'Disease', (51, 57))	('VEGFA', 'Gene', (209, 214))
325862	31475450	Zhang et al13 found that WJ460 directly targets myoferlin, interacts with myoferlin C2 domain and hampers the proper function of myoferlin.13 WJ460 represents a potentially effective therapeutic molecule for preventing myoferlin-related cancers and provides an opportunity for developing myoferlin-targeted agents.	('WJ460', 'Var', (142, 147))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('preventing', 'NegReg', (208, 218))	('cancers', 'Phenotype', 'HP:0002664', (237, 244))	('cancers', 'Disease', (237, 244))	('cancers', 'Disease', 'MESH:D009369', (237, 244))
325898	31336613	In some kinds of cancer cells, tigecycline also induces autophagy and apoptosis, and inhibits angiogenesis and migration/invasion.	('inhibits', 'NegReg', (85, 93))	('autophagy', 'CPA', (56, 65))	('tigecycline', 'Var', (31, 42))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('induces', 'PosReg', (48, 55))	('cancer', 'Disease', (17, 23))	('tigecycline', 'Chemical', 'MESH:D000078304', (31, 42))	('apoptosis', 'CPA', (70, 79))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
325913	31336613	Further study reveals that primary CD34+ CML cells cultured with 13C 6-glucose significantly decrease the incorporation of 13C isotopes into citrate, glutamate and aspartate as well as the enzymatic activities of pyruvate dehydrogenase (PDH) and pyruvate carboxylase (PC) after tigecycline treatment, resulting in a robust decrease in glucose oxidation and extra cellular acidification.	('13C', 'Chemical', '-', (65, 68))	('citrate', 'Chemical', 'MESH:D019343', (141, 148))	('CML', 'Disease', 'MESH:D015464', (41, 44))	('PDH', 'Gene', (237, 240))	('CML', 'Disease', (41, 44))	('decrease', 'NegReg', (93, 101))	('pyruvate carboxylase', 'Gene', '5091', (246, 266))	('decrease', 'NegReg', (323, 331))	('glutamate', 'Chemical', 'MESH:D018698', (150, 159))	('tigecycline', 'Chemical', 'MESH:D000078304', (278, 289))	('CD34', 'Gene', (35, 39))	('glucose oxidation', 'Disease', 'MESH:D004194', (335, 352))	('pyruvate carboxylase', 'Gene', (246, 266))	('extra cellular acidification', 'MPA', (357, 385))	('CML', 'Phenotype', 'HP:0005506', (41, 44))	('13C 6-glucose', 'Chemical', '-', (65, 78))	('PDH', 'Gene', '54704', (237, 240))	('13C', 'Chemical', '-', (123, 126))	('glucose oxidation', 'Disease', (335, 352))	('13C 6-glucose', 'Var', (65, 78))	('CD34', 'Gene', '947', (35, 39))	('aspartate', 'Chemical', 'MESH:D001224', (164, 173))	('incorporation of 13C isotopes into citrate', 'MPA', (106, 148))	('pyruvate dehydrogenase', 'Gene', '54704', (213, 235))	('pyruvate dehydrogenase', 'Gene', (213, 235))
325914	31336613	Meanwhile, there is a significant decrease in the fraction of isotopologues with 2 or more 13C atoms following incubation with 13C 5-glutamine and 13C 16-palmitate, and the overall steady-state levels of aspartate, which plays an anaplerotic role for OxPhos in the leukemic stem cells (LSCs)-enriched population.	('13C', 'Chemical', '-', (127, 130))	('13C', 'Chemical', '-', (147, 150))	('leukemic', 'Disease', 'MESH:D007938', (265, 273))	('fraction', 'MPA', (50, 58))	('levels', 'MPA', (194, 200))	('aspartate', 'MPA', (204, 213))	('13C 16-palmitate', 'Chemical', '-', (147, 163))	('13C', 'Var', (127, 130))	('decrease', 'NegReg', (34, 42))	('13C', 'Var', (147, 150))	('13C 5-glutamine', 'Chemical', '-', (127, 142))	('13C', 'Chemical', '-', (91, 94))	('leukemic', 'Disease', (265, 273))	('isotopologues', 'MPA', (62, 75))	('aspartate', 'Chemical', 'MESH:D001224', (204, 213))
325928	31336613	Tigecycline also induces mitochondrial ROS, which was significantly more prominent in OxPhos-DLBCLs compared with BCR-DLBCLs with glycolytic phenotype.	('ROS', 'Chemical', 'MESH:D017382', (39, 42))	('induces', 'Reg', (17, 24))	('Tigecycline', 'Chemical', 'MESH:D000078304', (0, 11))	('more', 'PosReg', (68, 72))	('OxPhos-DLBCLs', 'Var', (86, 99))	('mitochondrial ROS', 'MPA', (25, 42))
325937	31336613	However, lymphoma samples with more mitochondrial mass are more sensitive to this drug treatment and the levels of some mtRNAs such as AtpP6, CytB, Nd2, and Nd3 are increased after tigecycline treatment, indicating it promotes mitochondrial biogenesis.	('AtpP6', 'MPA', (135, 140))	('lymphoma', 'Phenotype', 'HP:0002665', (9, 17))	('promotes', 'PosReg', (218, 226))	('tigecycline', 'Var', (181, 192))	('Nd3', 'Gene', '4537', (157, 160))	('Nd2', 'Gene', (148, 151))	('CytB', 'Gene', (142, 146))	('levels', 'MPA', (105, 111))	('mitochondrial biogenesis', 'MPA', (227, 251))	('tigecycline', 'Chemical', 'MESH:D000078304', (181, 192))	('Nd3', 'Gene', (157, 160))	('lymphoma', 'Disease', (9, 17))	('Nd2', 'Gene', '4536', (148, 151))	('mtRNAs', 'MPA', (120, 126))	('CytB', 'Gene', '4519', (142, 146))	('increased', 'PosReg', (165, 174))	('lymphoma', 'Disease', 'MESH:D008223', (9, 17))
325941	31336613	Our group demonstrate as tigecycline induces cell cycle arrest at G0/G1 phase in multiple malignant tumors, including melanoma, glioma, neuroblastoma, oral squamous cell carcinoma, and multiple myeloma.	('multiple myeloma', 'Disease', (185, 201))	('neuroblastoma', 'Disease', (136, 149))	('malignant tumors', 'Disease', 'MESH:D018198', (90, 106))	('neuroblastoma', 'Phenotype', 'HP:0003006', (136, 149))	('melanoma', 'Phenotype', 'HP:0002861', (118, 126))	('melanoma', 'Disease', (118, 126))	('cell cycle arrest', 'CPA', (45, 62))	('tigecycline', 'Var', (25, 36))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (151, 179))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('neuroblastoma', 'Disease', 'MESH:D009447', (136, 149))	('malignant tumors', 'Disease', (90, 106))	('oral squamous cell carcinoma', 'Disease', (151, 179))	('multiple myeloma', 'Phenotype', 'HP:0006775', (185, 201))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('glioma', 'Disease', (128, 134))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (156, 179))	('glioma', 'Disease', 'MESH:D005910', (128, 134))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (45, 62))	('multiple myeloma', 'Disease', 'MESH:D009101', (185, 201))	('carcinoma', 'Phenotype', 'HP:0030731', (170, 179))	('melanoma', 'Disease', 'MESH:D008545', (118, 126))	('tigecycline', 'Chemical', 'MESH:D000078304', (25, 36))	('glioma', 'Phenotype', 'HP:0009733', (128, 134))
325947	31336613	However, a recent study shows that tigecycline also induces cell cycle arrest at G2/M phase in human ovarian cancers.	('human', 'Species', '9606', (95, 100))	('ovarian cancers', 'Phenotype', 'HP:0100615', (101, 116))	('ovarian cancers', 'Disease', 'MESH:D010051', (101, 116))	('ovarian cancers', 'Disease', (101, 116))	('cancers', 'Phenotype', 'HP:0002664', (109, 116))	('tigecycline', 'Var', (35, 46))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (60, 77))	('induces', 'Reg', (52, 59))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('ovarian cancer', 'Phenotype', 'HP:0100615', (101, 115))	('cell cycle arrest at G2/M phase', 'CPA', (60, 91))	('tigecycline', 'Chemical', 'MESH:D000078304', (35, 46))
325949	31336613	In several kinds of tumors, tigecycline induces significant autophagy.	('tumors', 'Disease', 'MESH:D009369', (20, 26))	('tumors', 'Disease', (20, 26))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('tigecycline', 'Var', (28, 39))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('tigecycline', 'Chemical', 'MESH:D000078304', (28, 39))	('autophagy', 'CPA', (60, 69))
325952	31336613	However, in CML, tigecycline induces autophagy by downregulating the PI3K-AKT-mTOR pathway.	('tigecycline', 'Var', (17, 28))	('CML', 'Disease', (12, 15))	('AKT', 'Gene', '207', (74, 77))	('downregulating', 'NegReg', (50, 64))	('autophagy', 'CPA', (37, 46))	('induces', 'PosReg', (29, 36))	('AKT', 'Gene', (74, 77))	('CML', 'Disease', 'MESH:D015464', (12, 15))	('tigecycline', 'Chemical', 'MESH:D000078304', (17, 28))	('CML', 'Phenotype', 'HP:0005506', (12, 15))
325954	31336613	In multiple myeloma and CML, inhibition of autophagy with autophagy inhibitors like bafilomycin A1, chloroquine (CQ) and 3-methyladenine (3-MA) or ATG5 knockdown promotes the anti-cancer activity of this drug, suggesting that autophagy plays a cytoprotective role during tigecycline treatment.	('ATG5', 'Gene', (147, 151))	('3-methyladenine', 'Chemical', 'MESH:C025946', (121, 136))	('multiple myeloma', 'Phenotype', 'HP:0006775', (3, 19))	('3-MA', 'Chemical', 'MESH:C025946', (138, 142))	('inhibition', 'NegReg', (29, 39))	('CML', 'Disease', 'MESH:D015464', (24, 27))	('CQ', 'Chemical', 'MESH:D002738', (113, 115))	('promotes', 'PosReg', (162, 170))	('CML', 'Disease', (24, 27))	('cancer', 'Disease', (180, 186))	('multiple myeloma', 'Disease', 'MESH:D009101', (3, 19))	('bafilomycin', 'Chemical', '-', (84, 95))	('knockdown', 'Var', (152, 161))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('autophagy', 'CPA', (43, 52))	('ATG5', 'Gene', '9474', (147, 151))	('multiple myeloma', 'Disease', (3, 19))	('chloroquine', 'Chemical', 'MESH:D002738', (100, 111))	('CML', 'Phenotype', 'HP:0005506', (24, 27))	('tigecycline', 'Chemical', 'MESH:D000078304', (271, 282))	('cancer', 'Disease', 'MESH:D009369', (180, 186))
325985	31336613	Mechanically, tigecycline binds to 70S ribosome through interacting with 16S rRNA nucleobase C1054 which is located at the decoding site of the ribosome, thereby blocking the initial codon recognition step of tRNA accommodation.	('interacting', 'Interaction', (56, 67))	('tRNA accommodation', 'MPA', (209, 227))	('blocking', 'NegReg', (162, 170))	('C1054', 'Var', (93, 98))	('initial codon recognition step', 'MPA', (175, 205))	('tigecycline', 'Chemical', 'MESH:D000078304', (14, 25))
325990	31336613	In AML and renal cell carcinoma, inhibition of mitochondrial translation by EF-Tu knockdown mimics the inhibitory effects of tigecycline via promoting mRNA expression and inhibiting protein expression of COX I and COX II, without changing COX IV protein or mRNA levels.	('COX IV', 'Gene', (239, 245))	('COX IV', 'Gene', '1327', (239, 245))	('inhibiting', 'NegReg', (171, 181))	('promoting', 'PosReg', (141, 150))	('renal cell carcinoma', 'Disease', (11, 31))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (11, 31))	('knockdown', 'Var', (82, 91))	('tigecycline', 'Chemical', 'MESH:D000078304', (125, 136))	('mitochondrial translation', 'MPA', (47, 72))	('EF-Tu', 'Gene', (76, 81))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('mRNA expression', 'MPA', (151, 166))	('EF-Tu', 'Gene', '1915', (76, 81))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (11, 31))	('protein expression', 'MPA', (182, 200))	('inhibition', 'NegReg', (33, 43))	('AML', 'Disease', 'MESH:D015470', (3, 6))	('AML', 'Phenotype', 'HP:0004808', (3, 6))	('AML', 'Disease', (3, 6))
326006	31336613	In neuroblastoma, this drug also decreases the phosphorylation of AKT at position Ser473, while not Thr308, thereby inhibiting the phosphorylation of its target FOXO3a at Ser253, while not Thr32.	('neuroblastoma', 'Phenotype', 'HP:0003006', (3, 16))	('inhibiting', 'NegReg', (116, 126))	('Thr32', 'Chemical', '-', (189, 194))	('AKT', 'Gene', (66, 69))	('Ser253', 'Chemical', '-', (171, 177))	('FOXO3a', 'Gene', '2309', (161, 167))	('phosphorylation', 'MPA', (47, 62))	('phosphorylation', 'MPA', (131, 146))	('Thr308', 'Chemical', '-', (100, 106))	('Ser473', 'Var', (82, 88))	('neuroblastoma', 'Disease', 'MESH:D009447', (3, 16))	('FOXO3a', 'Gene', (161, 167))	('decreases', 'NegReg', (33, 42))	('neuroblastoma', 'Disease', (3, 16))	('Ser473', 'Chemical', '-', (82, 88))	('AKT', 'Gene', '207', (66, 69))
326011	31336613	In gastric cancer cells, ovarian cancer and multiple myeloma, AMPK pathway is activated via phosphorylating at Thr172 and subsequently inactivates mTOR with dephosphorylation at Ser2448 and its downstream targets including p70S6K (dephosphorylation at Thr389), 4E-BP1 (dephosphorylation at Thr37/46) and p-rS6 (dephosphorylation at Thr37/46) after tigecycline treatment, thereby inducing cell autophagy or overcoming chemoresistance.	('cell autophagy', 'CPA', (388, 402))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('phosphorylating', 'Var', (92, 107))	('inactivates', 'NegReg', (135, 146))	('4E-BP1', 'Gene', '1978', (261, 267))	('p70S6K', 'Gene', (223, 229))	('inducing', 'NegReg', (379, 387))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('multiple myeloma', 'Phenotype', 'HP:0006775', (44, 60))	('tigecycline', 'Chemical', 'MESH:D000078304', (348, 359))	('gastric cancer', 'Phenotype', 'HP:0012126', (3, 17))	('chemoresistance', 'CPA', (417, 432))	('ovarian cancer', 'Disease', 'MESH:D010051', (25, 39))	('multiple myeloma', 'Disease', 'MESH:D009101', (44, 60))	('AMPK', 'Gene', '5562', (62, 66))	('4E-BP1', 'Gene', (261, 267))	('p70S6K', 'Gene', '6198', (223, 229))	('gastric cancer', 'Disease', (3, 17))	('multiple myeloma', 'Disease', (44, 60))	('ovarian cancer', 'Disease', (25, 39))	('overcoming', 'PosReg', (406, 416))	('p-rS6', 'Var', (304, 309))	('ovarian cancer', 'Phenotype', 'HP:0100615', (25, 39))	('AMPK', 'Gene', (62, 66))	('gastric cancer', 'Disease', 'MESH:D013274', (3, 17))	('mTOR', 'Gene', (147, 151))
326017	31336613	Our previous study also reveals that both mRNA and protein levels of p21 is significant declined after tigecycline treatment in a dose- and time-dependent manner, and restoration of p21 in melanoma can rescue cell cycle arrest, cell proliferation inhibition, migration, and migration blockade induced by tigecycline treatment.	('p21', 'Gene', (182, 185))	('tigecycline', 'Chemical', 'MESH:D000078304', (103, 114))	('migration blockade', 'CPA', (274, 292))	('cell cycle arrest', 'CPA', (209, 226))	('p21', 'Gene', (69, 72))	('cell proliferation inhibition', 'CPA', (228, 257))	('migration', 'CPA', (259, 268))	('declined', 'NegReg', (88, 96))	('tigecycline', 'Chemical', 'MESH:D000078304', (304, 315))	('melanoma', 'Disease', 'MESH:D008545', (189, 197))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (209, 226))	('p21', 'Gene', '1026', (182, 185))	('melanoma', 'Phenotype', 'HP:0002861', (189, 197))	('melanoma', 'Disease', (189, 197))	('restoration', 'Var', (167, 178))	('p21', 'Gene', '1026', (69, 72))
326029	31336613	Actually, Wnt/beta-Catenin and PI3K/Akt signaling crosstalk with each other through their common target GSK3beta, and inhibition of PI3K/Akt signaling also suppresses GSK3beta phosphorylation and beta-catenin expression.	('crosstalk', 'Reg', (50, 59))	('suppresses', 'NegReg', (156, 166))	('beta-catenin', 'Gene', '1499', (196, 208))	('GSK3beta', 'Gene', '2932', (104, 112))	('phosphorylation', 'MPA', (176, 191))	('Akt', 'Gene', '207', (36, 39))	('Akt', 'Gene', '207', (137, 140))	('Akt', 'Gene', (36, 39))	('GSK3beta', 'Gene', (167, 175))	('Akt', 'Gene', (137, 140))	('beta-Catenin', 'Gene', (14, 26))	('beta-Catenin', 'Gene', '1499', (14, 26))	('GSK3beta', 'Gene', (104, 112))	('inhibition', 'Var', (118, 128))	('GSK3beta', 'Gene', '2932', (167, 175))	('beta-catenin', 'Gene', (196, 208))
326032	31336613	Recent studies reveal that tigecycline can enhance susceptibility of various tumors, especially hematological neoplasms to chemotherapy or targeted therapy (Figure 4), suggesting the suitability of the drug in combination with chemotherapy.	('tumors', 'Disease', (77, 83))	('tumors', 'Disease', 'MESH:D009369', (77, 83))	('neoplasms', 'Phenotype', 'HP:0002664', (110, 119))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('tigecycline', 'Var', (27, 38))	('susceptibility', 'MPA', (51, 65))	('hematological neoplasms', 'Phenotype', 'HP:0004377', (96, 119))	('hematological neoplasms', 'Disease', (96, 119))	('hematological neoplasms', 'Disease', 'MESH:D019337', (96, 119))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tigecycline', 'Chemical', 'MESH:D000078304', (27, 38))	('enhance', 'PosReg', (43, 50))
326043	31336613	A recent clinical study shows that tigecycline is associated with a significant decrease in fibrinogen levels, which is a marker for malignant phenotype, following cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC), compared to imipenem-cilastatin.	('tigecycline', 'Chemical', 'MESH:D000078304', (35, 46))	('tigecycline', 'Var', (35, 46))	('fibrinogen', 'Gene', '2244', (92, 102))	('fibrinogen', 'Gene', (92, 102))	('imipenem', 'Chemical', 'MESH:D015378', (259, 267))	('cilastatin', 'Chemical', 'MESH:D015377', (268, 278))	('decrease in fibrinogen levels', 'Phenotype', 'HP:0011900', (80, 109))	('decrease', 'NegReg', (80, 88))
326047	31336613	Tigecycline can also enhance susceptibility of some hematological malignancies target therapy, such as imatinib, a small molecule that specifically targets the TK domain in abl (the Abelson proto-oncogene), c-kit, and PDGF-R (platelet-derived growth factor receptor).	('platelet-derived growth factor receptor', 'Gene', '5159', (226, 265))	('TK domain', 'Var', (160, 169))	('enhance', 'PosReg', (21, 28))	('Tigecycline', 'Chemical', 'MESH:D000078304', (0, 11))	('imatinib', 'Chemical', 'MESH:D000068877', (103, 111))	('Abelson proto-oncogene), c-kit', 'Gene', '3815', (182, 212))	('platelet-derived growth factor receptor', 'Gene', (226, 265))	('hematological malignancies', 'Disease', (52, 78))	('susceptibility', 'MPA', (29, 43))	('hematological malignancies', 'Disease', 'MESH:D019337', (52, 78))	('abl', 'Gene', (173, 176))	('PDGF-R', 'Gene', '5159', (218, 224))	('PDGF-R', 'Gene', (218, 224))	('hematological malignancies', 'Phenotype', 'HP:0004377', (52, 78))
326048	31336613	For instance, tigecycline inhibits cell proliferation and induces apoptosis in KBM5 CML cells with T315I mutations (KBM5-STI cells), which is an imatinib-resistant genotype.	('inhibits', 'NegReg', (26, 34))	('imatinib', 'Chemical', 'MESH:D000068877', (145, 153))	('CML', 'Disease', (84, 87))	('induces', 'Reg', (58, 65))	('cell proliferation', 'CPA', (35, 53))	('T315I mutations', 'Var', (99, 114))	('apoptosis', 'CPA', (66, 75))	('T315I', 'Mutation', 'rs1414524659', (99, 104))	('tigecycline', 'Chemical', 'MESH:D000078304', (14, 25))	('CML', 'Disease', 'MESH:D015464', (84, 87))	('CML', 'Phenotype', 'HP:0005506', (84, 87))
326056	31336613	A clinical study on tigecycline antibacterial activity shows that once daily high dose this drug, i.e., 200-400 mg (IV) x 1, then 100-200 mg (IV) q24 h, can effectively eliminate the multi-drug resistant (MDR) Klebsiella Pneumoniae in the urine in 5 days and Enterobacter aerogenes in 12 days without gastrointestinal or other side effects.	('200-400 mg', 'Var', (104, 114))	('Klebsiella Pneumoniae', 'Species', '573', (210, 231))	('Klebsiella Pneumoniae in the urine', 'Phenotype', 'HP:0002742', (210, 244))	('eliminate', 'NegReg', (169, 178))	('multi-drug resistant', 'MPA', (183, 203))	('gastrointestinal', 'Disease', (301, 317))	('Enterobacter aerogenes', 'Disease', (259, 281))	('Enterobacter aerogenes', 'Species', '548', (259, 281))	('gastrointestinal', 'Disease', 'MESH:D005767', (301, 317))	('tigecycline', 'Chemical', 'MESH:D000078304', (20, 31))	('Klebsiella Pneumoniae', 'Disease', (210, 231))
326072	31336613	Previous studies have revealed that mitochondrial ribosome seems to be a specific target of tigecycline, because deletion of EF-Tu mimics the effect of this drug in cancer cells.	('EF-Tu', 'Gene', (125, 130))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('deletion', 'Var', (113, 121))	('tigecycline', 'Chemical', 'MESH:D000078304', (92, 103))	('cancer', 'Disease', (165, 171))	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('EF-Tu', 'Gene', '1915', (125, 130))
326098	29158988	We downloaded five gene expression data sets from GEO database, including GSE2280, GSE3524, GSE6631, GSE9844 and GSE31056.	('GSE3524', 'Chemical', '-', (83, 90))	('GSE2280', 'Var', (74, 81))	('GSE9844', 'Chemical', '-', (101, 108))	('GSE31056', 'Var', (113, 121))	('GSE6631', 'Var', (92, 99))	('GSE6631', 'Chemical', '-', (92, 99))	('GSE2280', 'Chemical', '-', (74, 81))	('GSE9844', 'Var', (101, 108))
326100	29158988	Patients with OTSCC were extracted with ICD-O-3 (International Classification of Diseases for Oncology, Third Edition) code of C01.9, C02.0, C02.1, C02.2, C02.3, C02.4, C02.5, C02.6, C02.7, C02.8, C02.9.	('Oncology', 'Phenotype', 'HP:0002664', (94, 102))	('C02.5', 'Var', (169, 174))	('C02.7', 'Var', (183, 188))	('C02.6', 'Var', (176, 181))	('C02.3', 'Var', (155, 160))	('C02.4', 'Var', (162, 167))	('C02.2', 'Var', (148, 153))	('C01.9', 'CellLine', 'CVCL:E303', (127, 132))	('Patients', 'Species', '9606', (0, 8))	('C02.9', 'Var', (197, 202))	('C02.1', 'Var', (141, 146))	('C02.0', 'Var', (134, 139))	('C02.8', 'Var', (190, 195))
326101	29158988	Moreover, histological types were limited to squamous cell carcinoma (code 8050, 8051, 8052, 8070, 8071, 8072, 8073, 8074, 8075, 8076, 8081, 8082, 8083 and 8084).	('squamous cell carcinoma', 'Disease', (45, 68))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (45, 68))	('8071', 'Var', (99, 103))	('8052', 'Var', (87, 91))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (45, 68))	('8070', 'Var', (93, 97))	('8073', 'Var', (111, 115))	('8081', 'Var', (135, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (59, 68))	('8074', 'Var', (117, 121))	('8084', 'Var', (156, 160))	('8075', 'Var', (123, 127))
326105	29158988	For each patient, the risk score was calculated by the summation of the mRNA expression intensities weighted by corresponding coefficients, which were derived from univariate Cox regression analysis associated with survival outcomes as follows: Risk score =betagene1 x expression-valuegene1 + betagene2 x expression-valuegene2 +   + betageneN x expression-valuegeneN.	('Cox', 'Gene', '1351', (175, 178))	('Cox', 'Gene', (175, 178))	('expression-valuegene1 + betagene2', 'Var', (269, 302))	('=betagene1', 'Var', (256, 266))	('expression-valuegene2 +   + betageneN', 'Var', (305, 342))	('patient', 'Species', '9606', (9, 16))
326118	29158988	Table S2 showed that the top five significant KEGG pathways of DEGs enriched in ribosome, viral myocarditis, protein export, lysosome and natural killer cell mediated cytotoxicity.	('viral myocarditis', 'Disease', 'MESH:D009205', (90, 107))	('cytotoxicity', 'Disease', (167, 179))	('myocarditis', 'Phenotype', 'HP:0012819', (96, 107))	('protein export', 'MPA', (109, 123))	('cytotoxicity', 'Disease', 'MESH:D064420', (167, 179))	('DEGs', 'Var', (63, 67))	('viral myocarditis', 'Disease', (90, 107))
326144	29158988	Transcription factor HNF1B is a master regulator of gene expression, and loss of HNF1B may enhance cellular survival and exacerbate the development of chromophobe renal cell carcinomas.	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (163, 184))	('HNF1B', 'Gene', (21, 26))	('development', 'CPA', (136, 147))	('loss', 'Var', (73, 77))	('carcinoma', 'Phenotype', 'HP:0030731', (174, 183))	('exacerbate', 'PosReg', (121, 131))	('HNF1B', 'Gene', '6928', (81, 86))	('chromophobe renal cell carcinomas', 'Disease', (151, 184))	('HNF1B', 'Gene', (81, 86))	('HNF1B', 'Gene', '6928', (21, 26))	('enhance', 'PosReg', (91, 98))	('cellular survival', 'CPA', (99, 116))	('carcinomas', 'Phenotype', 'HP:0030731', (174, 184))	('chromophobe renal cell carcinomas', 'Disease', 'MESH:C538614', (151, 184))
326145	29158988	NPY, a neuropeptide abundantly produced by enteric neurons, is important in the regulation of intestinal inflammation, and the aberrant methylation of NPY is associated with intestinal tumor.	('NPY', 'Gene', '4852', (0, 3))	('NPY', 'Gene', '4852', (151, 154))	('methylation', 'Var', (136, 147))	('associated with', 'Reg', (158, 173))	('intestinal tumor', 'Disease', (174, 190))	('intestinal tumor', 'Disease', 'MESH:D007414', (174, 190))	('aberrant methylation', 'Var', (127, 147))	('NPY', 'Gene', (0, 3))	('NPY', 'Gene', (151, 154))	('intestinal inflammation', 'Disease', 'MESH:D007249', (94, 117))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('intestinal inflammation', 'Disease', (94, 117))
326230	28061796	In a complementary model, GLUT4 gene silencing significantly reduced the GLUT4 protein levels in HSC-3-M3 and HSC-2 cells, which expressed a high level of endogenous GLUT4 (Fig.	('GLUT4 protein levels', 'MPA', (73, 93))	('HSC-3', 'Gene', '150353', (97, 102))	('GLUT4', 'Gene', (26, 31))	('HSC-2', 'CellLine', 'CVCL:1287', (110, 115))	('reduced', 'NegReg', (61, 68))	('HSC-3', 'Gene', (97, 102))	('gene silencing', 'Var', (32, 46))
326231	28061796	GLUT4 knockdown in these two cell lines significantly inhibited the migratory/invasive capabilities of the highly metastatic HSC-3-M3 and HSC-2 cells (Fig.	('inhibited', 'NegReg', (54, 63))	('highly metastatic', 'CPA', (107, 124))	('HSC-3', 'Gene', '150353', (125, 130))	('HSC-2', 'CellLine', 'CVCL:1287', (138, 143))	('GLUT4', 'Protein', (0, 5))	('migratory/invasive capabilities', 'CPA', (68, 99))	('knockdown', 'Var', (6, 15))	('HSC-3', 'Gene', (125, 130))
326235	28061796	Our results showed that stronger bioluminescence could be observed in 4 out of 5 mice injected with the GLUT4-overexpressing cells compared to only 1 mouse exhibiting weak bioluminescence in the vector control group (Fig.	('mice', 'Species', '10090', (81, 85))	('GLUT4-overexpressing cells', 'Var', (104, 130))	('stronger', 'PosReg', (24, 32))	('bioluminescence', 'MPA', (33, 48))	('mouse', 'Species', '10090', (150, 155))
326252	28061796	5c, left panel) and that the knockdown of GLUT4 expression in HSC-2 cells resulted in the higher expression of the DDX58 and OASL proteins (Fig.	('DDX58', 'Protein', (115, 120))	('OASL', 'Gene', (125, 129))	('knockdown', 'Var', (29, 38))	('HSC-2', 'CellLine', 'CVCL:1287', (62, 67))	('OASL', 'Gene', '8638', (125, 129))	('higher', 'PosReg', (90, 96))	('GLUT4', 'Gene', (42, 47))	('expression', 'MPA', (97, 107))
326255	28061796	The subsequent knockdown of DDX58 could significantly restore the migration potential of GLUT4-knockdown HSC-2 cells by 1.5-fold (Fig.	('knockdown', 'Var', (15, 24))	('migration potential', 'CPA', (66, 85))	('HSC-2', 'CellLine', 'CVCL:1287', (105, 110))	('restore', 'PosReg', (54, 61))	('DDX58', 'Gene', (28, 33))
326256	28061796	5e, P < 0.001); however, OASL knockdown did not restore the migration capability (Additional file 1: Figure S5).	('OASL', 'Gene', '8638', (25, 29))	('migration capability', 'CPA', (60, 80))	('OASL', 'Gene', (25, 29))	('knockdown', 'Var', (30, 39))
326257	28061796	The results showed that high GLUT4 RNA expression in combination with low DDX58 RNA expression levels was significantly correlated with the worst HNSCC patient survival (Fig.	('HNSCC', 'Phenotype', 'HP:0012288', (146, 151))	('correlated', 'Reg', (120, 130))	('GLUT4 RNA', 'Protein', (29, 38))	('high', 'Var', (24, 28))	('patient', 'Species', '9606', (152, 159))
326266	28061796	Second, TRIM24 interacts with nuclear receptor, such as RAR or ER, to regulate gene expression.	('RAR', 'Gene', (56, 59))	('interacts', 'Reg', (15, 24))	('gene expression', 'MPA', (79, 94))	('RAR', 'Gene', '5914', (56, 59))	('regulate', 'Reg', (70, 78))	('TRIM24', 'Var', (8, 14))
326268	28061796	Because our signaling analysis was generated using GLUT4-silenced HNSCC cells, we proposed that GLUT4 triggers TRIM24 to repress several downstream tumor suppressors.	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('HNSCC', 'Phenotype', 'HP:0012288', (66, 71))	('tumor', 'Disease', (148, 153))	('repress', 'NegReg', (121, 128))	('GLUT4', 'Var', (96, 101))	('TRIM24', 'Gene', (111, 117))	('tumor', 'Disease', 'MESH:D009369', (148, 153))
326293	25968125	Fortunately, all of the other statements about cancer remain intact since the coding error effectively added an offset term to predicted age that changed little with chronological age (Figure 1).	('offset term', 'MPA', (112, 123))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('cancer', 'Disease', (47, 53))	('added', 'PosReg', (103, 108))	('coding error', 'Var', (78, 90))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))
326297	25968125	Third, the results for TP53 become more significant, that is TP53 mutations are associated with lower age acceleration in colorectal cancer.	('mutations', 'Var', (66, 75))	('colorectal cancer', 'Phenotype', 'HP:0003003', (122, 139))	('lower', 'NegReg', (96, 101))	('colorectal cancer', 'Disease', (122, 139))	('colorectal cancer', 'Disease', 'MESH:D015179', (122, 139))	('TP53', 'Gene', '7157', (23, 27))	('TP53', 'Gene', (23, 27))	('TP53', 'Gene', '7157', (61, 65))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('TP53', 'Gene', (61, 65))
326304	25968125	Additional file seventeen in the original publication; Additional file 6 here: Effect of TP53 mutation on age acceleration.	('TP53', 'Gene', (89, 93))	('TP53', 'Gene', '7157', (89, 93))	('age', 'Disease', (106, 109))	('mutation', 'Var', (94, 102))
326312	25968125	But I have to revise the following paragraph: "Further, TP53 mutation is associated with significantly lower age acceleration in five different cancer types including AML (p = 0.0023), breast cancer (p = 1.4E-5 and p = 3.7E-8), ovarian cancer (p = 0.03), and uterine corpus endometrioid (p = 0.00093).	('uterine corpus endometrioid', 'Disease', (259, 286))	('cancer', 'Disease', 'MESH:D009369', (236, 242))	('ovarian cancer', 'Disease', (228, 242))	('mutation', 'Var', (61, 69))	('cancer', 'Disease', (144, 150))	('cancer', 'Disease', (192, 198))	('ovarian cancer', 'Phenotype', 'HP:0100615', (228, 242))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('TP53', 'Gene', '7157', (56, 60))	('AML', 'Disease', 'MESH:D015470', (167, 170))	('AML', 'Disease', (167, 170))	('cancer', 'Disease', (236, 242))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('lower', 'NegReg', (103, 108))	('breast cancer', 'Phenotype', 'HP:0003002', (185, 198))	('cancer', 'Disease', 'MESH:D009369', (192, 198))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('ovarian cancer', 'Disease', 'MESH:D010051', (228, 242))	('breast cancer', 'Disease', 'MESH:D001943', (185, 198))	('breast cancer', 'Disease', (185, 198))	('TP53', 'Gene', (56, 60))
326314	25968125	I could only find one cancer type (GBM) where mutations in TP53 are associated with a nominally significant increased age acceleration (p = 0.02)".	('mutations', 'Var', (46, 55))	('TP53', 'Gene', (59, 63))	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('cancer', 'Disease', (22, 28))	('age', 'Disease', (118, 121))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('TP53', 'Gene', '7157', (59, 63))	('increased age acceleration', 'Phenotype', 'HP:0007495', (108, 134))
326315	25968125	as follows: TP53 mutation is associated with significantly lower age acceleration in six data sets (Additional file 6) including AML (P = 0.0041), breast cancer (P = 7.8x10-12 and P = 1.4x10-12), ovarian cancer (P = 0.04), uterine corpus endometrioid (P = 0.0012), and colorectal cancer (P = 0.036, Figure 4B).	('AML', 'Disease', 'MESH:D015470', (129, 132))	('lower', 'NegReg', (59, 64))	('colorectal cancer', 'Phenotype', 'HP:0003003', (269, 286))	('AML', 'Disease', (129, 132))	('cancer', 'Phenotype', 'HP:0002664', (280, 286))	('ovarian cancer', 'Disease', (196, 210))	('breast cancer', 'Phenotype', 'HP:0003002', (147, 160))	('ovarian cancer', 'Phenotype', 'HP:0100615', (196, 210))	('mutation', 'Var', (17, 25))	('TP53', 'Gene', (12, 16))	('age', 'MPA', (65, 68))	('breast cancer', 'Disease', 'MESH:D001943', (147, 160))	('colorectal cancer', 'Disease', 'MESH:D015179', (269, 286))	('breast cancer', 'Disease', (147, 160))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('uterine corpus endometrioid', 'Disease', (223, 250))	('colorectal cancer', 'Disease', (269, 286))	('TP53', 'Gene', '7157', (12, 16))	('ovarian cancer', 'Disease', 'MESH:D010051', (196, 210))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))
326317	25968125	The following original statement remains unchanged: "Age acceleration differs greatly across different breast cancer types (Figure 4N): Luminal A tumors (typically ER+ or PR+, HER2-, low Ki67), show the highest positive age acceleration".	('HER2', 'Gene', (176, 180))	('low Ki67', 'Var', (183, 191))	('PR+', 'Var', (171, 174))	('A tumors', 'Disease', 'MESH:D009369', (144, 152))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('HER2', 'Gene', '2064', (176, 180))	('breast cancer', 'Disease', 'MESH:D001943', (103, 116))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('breast cancer', 'Disease', (103, 116))	('breast cancer', 'Phenotype', 'HP:0003002', (103, 116))	('tumors', 'Phenotype', 'HP:0002664', (146, 152))	('A tumors', 'Disease', (144, 152))
326318	25968125	But I retract the statement that luminal B tumors (typically ER+ or PR+, HER2+ or HER2- with high Ki67) show a similar effect.	('HER2', 'Gene', '2064', (73, 77))	('PR+', 'Var', (68, 71))	('luminal B tumors', 'Disease', (33, 49))	('luminal B tumors', 'Disease', 'MESH:D006509', (33, 49))	('HER2', 'Gene', (82, 86))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('HER2', 'Gene', '2064', (82, 86))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('HER2', 'Gene', (73, 77))
326319	25968125	The p-value in the following statement "Echoing previous results, TP53 mutations appear to be associated with decreased age acceleration (p = 0.073)" needs to be revised to (p = 0.036, Figure 4B).	('TP53', 'Gene', '7157', (66, 70))	('TP53', 'Gene', (66, 70))	('age acceleration', 'CPA', (120, 136))	('decreased', 'NegReg', (110, 119))	('mutations', 'Var', (71, 80))
326320	25968125	The p-value in the following statement "Promoter hypermethylation of the mismatch repair gene MLH1 leads to the most significant increase in age acceleration (P = 5.7x10-5)" needs to be revised to (p = 3.9x10-7, Figure 4D).	('increase', 'PosReg', (129, 137))	('Promoter hypermethylation', 'Var', (40, 65))	('MLH1', 'Gene', '4292', (94, 98))	('MLH1', 'Gene', (94, 98))	('age acceleration', 'CPA', (141, 157))
326322	25968125	The p-value in the following statement "Interestingly, age acceleration in GBM samples is highly significantly (p = 3.3x10-7) associated with certain mutations in H3F3A" needs to be revised to (p = 0.0015, Figure 4J).	('H3F3A', 'Gene', (163, 168))	('associated', 'Reg', (126, 136))	('H3F3A', 'Gene', '3020', (163, 168))	('mutations', 'Var', (150, 159))	('acceleration', 'PosReg', (59, 71))
326323	25968125	The following statement remains unchanged: "Mutations in FLT3, RAS, NPMc, and various well characterized translocations do not seem to relate to age acceleration in AML samples".	('AML', 'Disease', (165, 168))	('NPMc', 'Gene', (68, 72))	('FLT3', 'Gene', '2322', (57, 61))	('Mutations', 'Var', (44, 53))	('AML', 'Disease', 'MESH:D015470', (165, 168))	('FLT3', 'Gene', (57, 61))
326324	25968125	But I have to retract the claim that mutations in IDH1 do not relate to age acceleration.	('IDH1', 'Gene', (50, 54))	('age acceleration', 'Disease', (72, 88))	('IDH1', 'Gene', '3417', (50, 54))	('mutations', 'Var', (37, 46))	('relate', 'Reg', (62, 68))
326325	25968125	Rather, IDH1 mutations are nominally significantly related with age acceleration (p = 0.036, Figure 4S).	('IDH1', 'Gene', (8, 12))	('IDH1', 'Gene', '3417', (8, 12))	('age acceleration', 'Disease', (64, 80))	('mutations', 'Var', (13, 22))	('related', 'Reg', (51, 58))
326419	33896245	Consistent with these observations, inhibition of TIAL1 or MYOD1 expression attenuated the effects of MBNL1 in SSCC.	('MYOD1', 'Gene', (59, 64))	('TIAL1', 'Gene', (50, 55))	('inhibition', 'Var', (36, 46))	('attenuated', 'NegReg', (76, 86))	('MYOD1', 'Gene', '4654', (59, 64))	('MBNL1', 'Gene', (102, 107))	('MBNL1', 'Gene', '4154', (102, 107))	('TIAL1', 'Gene', '7073', (50, 55))	('SSCC', 'Disease', (111, 115))
326449	33896245	Over-expression of MBNL1 reduced cell growth and migration rate, and increased LDH activity level in vitro, compared with negative mimics group ( Figure 1A-1D).	('reduced', 'NegReg', (25, 32))	('increased', 'PosReg', (69, 78))	('MBNL1', 'Gene', (19, 24))	('LDH activity level', 'MPA', (79, 97))	('MBNL1', 'Gene', '4154', (19, 24))	('Over-expression', 'Var', (0, 15))
326457	33896245	Over-expression of MBNL1 increased Caspase-9/3 activity levels, in comparison with negative group ( Figure 3G-3 H ).	('increased', 'PosReg', (25, 34))	('MBNL1', 'Gene', (19, 24))	('MBNL1', 'Gene', '4154', (19, 24))	('Over-expression', 'Var', (0, 15))	('Caspase-9/3', 'Gene', (35, 46))	('Caspase-9/3', 'Gene', '842;836', (35, 46))
326466	33896245	To identify the function of MYOD1 in the effects of MBNL1 on SSCC, si-MYOD1 mimics could suppress the protein expression MYOD1 protein expression in in vitro model of SSCC, compared with negative group ( Figure 6A-6B ).	('MYOD1', 'Gene', '4654', (121, 126))	('MYOD1', 'Gene', (28, 33))	('MYOD1', 'Gene', (70, 75))	('MBNL1', 'Gene', '4154', (52, 57))	('MYOD1', 'Gene', (121, 126))	('SSCC', 'Disease', (167, 171))	('mimics', 'Var', (76, 82))	('MYOD1', 'Gene', '4654', (28, 33))	('suppress', 'NegReg', (89, 97))	('protein expression', 'MPA', (102, 120))	('MYOD1', 'Gene', '4654', (70, 75))	('MBNL1', 'Gene', (52, 57))
326471	33896245	In recent years, studies on the dysregulation of cell proliferation and division, the inactivation of tumor suppressor genes, the activation of oncogenes and the apoptosis of cancer cells have all become research hotspots.	('dysregulation', 'Var', (32, 45))	('cancer', 'Disease', (175, 181))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('cell proliferation', 'CPA', (49, 67))	('inactivation', 'Var', (86, 98))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
326501	30754676	Reduced skin-tumorigenic potential was also observed in v-Ha-Ras transgenic mice when C/EBPbeta was deficient, thereby suggesting C/EBPbeta plays an oncogenic role in the downstream Ras signaling pathway.	('transgenic mice', 'Species', '10090', (65, 80))	('tumor', 'Disease', (13, 18))	('C/EBPbeta', 'Var', (130, 139))	('Reduced', 'NegReg', (0, 7))	('C/EBPbeta', 'Gene', (86, 95))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('deficient', 'Var', (100, 109))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
326510	30754676	In human cancers, mutation or dysregulated expression of genes involved in cell cycle regulation are frequently observed, which is attributed to accelerated cancer cell growth, leading to more malignant progression.	('cancer', 'Disease', (9, 15))	('cancers', 'Disease', 'MESH:D009369', (9, 16))	('cancers', 'Phenotype', 'HP:0002664', (9, 16))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('cancers', 'Disease', (9, 16))	('more', 'PosReg', (188, 192))	('human', 'Species', '9606', (3, 8))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('cancer', 'Disease', (157, 163))	('mutation', 'Var', (18, 26))	('dysregulated', 'Var', (30, 42))	('expression', 'MPA', (43, 53))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('accelerated', 'PosReg', (145, 156))
326515	30754676	These observations imply that dysregulation of cell cycle is critical to lung cancer development, and altered cell cycle regulatory proteins could be important therapeutic targets or prognostic markers.	('lung cancer', 'Disease', 'MESH:D008175', (73, 84))	('dysregulation', 'Var', (30, 43))	('dysregulation of cell cycle', 'Phenotype', 'HP:0011018', (30, 57))	('lung cancer', 'Disease', (73, 84))	('lung cancer', 'Phenotype', 'HP:0100526', (73, 84))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))
326516	30754676	Lung cancer is a genetically heterogeneous disease, and in lung adenocarcinoma, K-RAS and epidermal growth factor receptor (EGFR) are most commonly activated by mutations.	('EGFR', 'Gene', '1956', (124, 128))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (59, 78))	('Lung cancer', 'Phenotype', 'HP:0100526', (0, 11))	('epidermal growth factor receptor', 'Gene', (90, 122))	('EGFR', 'Gene', (124, 128))	('K-RAS', 'Gene', '3845', (80, 85))	('K-RAS', 'Gene', (80, 85))	('Lung cancer', 'Disease', (0, 11))	('mutations', 'Var', (161, 170))	('epidermal growth factor receptor', 'Gene', '1956', (90, 122))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (59, 78))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))	('activated', 'PosReg', (148, 157))	('Lung cancer', 'Disease', 'MESH:D008175', (0, 11))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))	('lung adenocarcinoma', 'Disease', (59, 78))
326557	30754676	Chromatin immunoprecipitation was performed with anti-C/EBPbeta (sc-150X, Santacruz Biotechnology, Santa Cruz, CA, USA) or HDAC2 (sc-9959X, Santacruz Biotechnology, Santa Cruz, CA, USA) and protein G agarose.	('C', 'Gene', '1051', (171, 172))	('C', 'Gene', '1051', (54, 55))	('agarose', 'Chemical', 'MESH:D012685', (200, 207))	('C', 'Gene', '1051', (105, 106))	('C', 'Gene', '1051', (0, 1))	('C', 'Gene', '1051', (126, 127))	('sc-9959X', 'Var', (130, 138))	('HDAC2', 'Gene', (123, 128))	('HDAC2', 'Gene', '3066', (123, 128))	('C', 'Gene', '1051', (111, 112))	('sc-150X', 'Var', (65, 72))	('C', 'Gene', '1051', (177, 178))
326561	30754676	The constructs of Wee1 promoter region were cloned into pGL3-promoter firefly luciferase vector (Promega, Madison, WI, USA), which were named R3 (-4932 to -4679), and R2 (-4543 to -4380), C/EBPbeta and HDAC2 cDNA clones purchased from OriGene were sub-cloned into pcDNA3.1 vector (Invitrogen, Waltham, MA, USA).	('pGL3', 'Gene', (56, 60))	('Wee1', 'Gene', '7465', (18, 22))	('Wee1', 'Gene', (18, 22))	('-4543', 'Var', (171, 176))	('HDAC2', 'Gene', (202, 207))	('HDAC2', 'Gene', '3066', (202, 207))	('pGL3', 'Gene', '6391', (56, 60))	('-4932', 'Var', (146, 151))
326599	30754676	K-Ras and EGFR is frequently activated by mutation and they are mutually exclusive in lung adenocarcinomas, and these oncogenes might act as upstream regulator of C/EBPbeta.	('EGFR', 'Gene', '1956', (10, 14))	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('activated', 'PosReg', (29, 38))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (86, 106))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (86, 106))	('K-Ras', 'Gene', '3845', (0, 5))	('carcinomas', 'Phenotype', 'HP:0030731', (96, 106))	('EGFR', 'Gene', (10, 14))	('K-Ras', 'Gene', (0, 5))	('mutation', 'Var', (42, 50))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (86, 105))	('lung adenocarcinomas', 'Disease', (86, 106))
326600	30754676	However, the levels of C/EBPbeta protein were not very different among adenocarcinomas with mutant K-RAS (A549, H23, A427, NCI-H358), mutant EGFR (NCI-H1975, HCC827) and wild-type K-RAS and EGFR (NCI-H1703, NCI-H522, Calu-3), even though A549 and H23 cells displayed relatively high levels of C/EBPbeta (Figure 2A).	('K-RAS', 'Gene', (99, 104))	('EGFR', 'Gene', '1956', (190, 194))	('C', 'Gene', '1051', (159, 160))	('C', 'Gene', '1051', (23, 24))	('K-RAS', 'Gene', '3845', (99, 104))	('NCI-H358', 'CellLine', 'CVCL:1559', (123, 131))	('C', 'Gene', '1051', (160, 161))	('EGFR', 'Gene', '1956', (141, 145))	('A549', 'CellLine', 'CVCL:0023', (238, 242))	('C', 'Gene', '1051', (293, 294))	('C', 'Gene', '1051', (197, 198))	('K-RAS', 'Gene', (180, 185))	('EGFR', 'Gene', (190, 194))	('C', 'Gene', '1051', (124, 125))	('H23', 'CellLine', 'CVCL:1547', (247, 250))	('mutant', 'Var', (92, 98))	('C', 'Gene', '1051', (148, 149))	('adenocarcinomas', 'Disease', 'MESH:D000230', (71, 86))	('NCI-H522', 'CellLine', 'CVCL:1567', (207, 215))	('NCI-H1975', 'CellLine', 'CVCL:1511', (147, 156))	('adenocarcinomas', 'Disease', (71, 86))	('NCI-H1703', 'CellLine', 'CVCL:1490', (196, 205))	('C', 'Gene', '1051', (217, 218))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('K-RAS', 'Gene', '3845', (180, 185))	('carcinomas', 'Phenotype', 'HP:0030731', (76, 86))	('EGFR', 'Gene', (141, 145))	('H23', 'CellLine', 'CVCL:1547', (112, 115))	('C', 'Gene', '1051', (208, 209))	('A549', 'CellLine', 'CVCL:0023', (106, 110))
326601	30754676	To examine the function of C/EBPbeta in lung cancer cells, we knocked down C/EBPbeta using two different siRNAs in NSCLC cell lines.	('C/EBPbeta', 'Gene', (75, 84))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('NSCLC', 'Disease', (115, 120))	('NSCLC', 'Disease', 'MESH:D002289', (115, 120))	('knocked', 'Var', (62, 69))	('EBPbeta in lung cancer', 'Disease', (29, 51))	('EBPbeta in lung cancer', 'Disease', 'MESH:D008175', (29, 51))	('lung cancer', 'Phenotype', 'HP:0100526', (40, 51))
326606	30754676	Neither histological subtypes nor EGFR and K-Ras mutation status of the cell lines produced significant differences in the growth arrest induced by C/EBPbeta-knockdown (Figure 2E).	('K-Ras', 'Gene', '3845', (43, 48))	('EGFR', 'Gene', (34, 38))	('K-Ras', 'Gene', (43, 48))	('C/EBPbeta-knockdown', 'Var', (148, 167))	('growth arrest', 'Disease', (123, 136))	('growth arrest', 'Disease', 'MESH:D006323', (123, 136))	('growth arrest', 'Phenotype', 'HP:0001510', (123, 136))	('EGFR', 'Gene', '1956', (34, 38))
326647	30754676	Treatment with MK1775 induced a rapid decrease in Y15-pCDK1 with little changes in total levels of CDK1.	('CDK1', 'Gene', (99, 103))	('MK1775', 'Chemical', 'MESH:C549567', (15, 21))	('decrease', 'NegReg', (38, 46))	('CDK1', 'Gene', '983', (99, 103))	('CDK1', 'Gene', (55, 59))	('CDK1', 'Gene', '983', (55, 59))	('MK1775', 'Var', (15, 21))
326668	30754676	For example, Wee1 kinase activity is regulated by Akt-mediated phosphorylation on Ser642 and phosphorylated Wee1 binds to 14-3-3theta and translocates to the cytoplasm, resulting in G2/M cell cycle progression.	('Akt', 'Gene', '207', (50, 53))	('Wee1', 'Gene', (108, 112))	('translocates', 'MPA', (138, 150))	('Ser642', 'Var', (82, 88))	('Wee1', 'Gene', '7465', (108, 112))	('activity', 'MPA', (25, 33))	('Akt', 'Gene', (50, 53))	('Ser642', 'Chemical', '-', (82, 88))	('Wee1', 'Gene', (13, 17))	('phosphorylated', 'Var', (93, 107))	('G2/M cell cycle progression', 'CPA', (182, 209))	('Wee1', 'Gene', '7465', (13, 17))	('binds', 'Interaction', (113, 118))
326669	30754676	In late G2 phase, phosphorylation of Wee1 by CDK1 and polo-like kinase 1 creates a phosphodegron which targets Wee1 for SCF-beta-TrCP ubiquitin ligase-mediated proteasomal degradation.	('polo-like kinase 1', 'Gene', '5347', (54, 72))	('Wee1', 'Gene', (111, 115))	('polo-like kinase 1', 'Gene', (54, 72))	('C', 'Gene', '1051', (121, 122))	('CDK1', 'Gene', (45, 49))	('Wee1', 'Gene', '7465', (111, 115))	('C', 'Gene', '1051', (45, 46))	('CDK1', 'Gene', '983', (45, 49))	('Wee1', 'Gene', (37, 41))	('C', 'Gene', '1051', (131, 132))	('Wee1', 'Gene', '7465', (37, 41))	('phosphorylation', 'Var', (18, 33))
326682	30754676	Rather acute lung injury is induced by lipopolysaccharide (LPS)-induced C/EBPbeta mRNA, suggesting C/EBPbeta might play a distinct role in pathological status.	('C/EBPbeta mRNA', 'Var', (72, 86))	('lipopolysaccharide', 'Chemical', 'MESH:D008070', (39, 57))	('induced', 'Reg', (28, 35))	('lung injury', 'Disease', 'MESH:D055370', (13, 24))	('lung injury', 'Disease', (13, 24))
326683	30754676	Loss in the function mutations were found in acute myeloid leukemia, suggesting C/EBPalpha as potential human tumor suppressor.	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (45, 67))	('tumor', 'Disease', 'MESH:D009369', (110, 115))	('leukemia', 'Phenotype', 'HP:0001909', (59, 67))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (45, 67))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (51, 67))	('Loss', 'NegReg', (0, 4))	('human', 'Species', '9606', (104, 109))	('acute myeloid leukemia', 'Disease', (45, 67))	('mutations', 'Var', (21, 30))
326700	27889930	Receptor tyrosine kinase amplification is predictive of distant metastasis in patients with oral squamous cell carcinoma This study aimed to clarify the genomic factors associated with the diagnosis and prognosis of oral squamous cell carcinoma via next-generation sequencing.	('distant metastasis', 'CPA', (56, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (97, 120))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (216, 244))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (221, 244))	('oral squamous cell carcinoma', 'Disease', (92, 120))	('patients', 'Species', '9606', (78, 86))	('carcinoma', 'Phenotype', 'HP:0030731', (235, 244))	('oral squamous cell carcinoma', 'Disease', (216, 244))	('Receptor tyrosine kinase', 'Gene', (0, 24))	('Receptor tyrosine kinase', 'Gene', '5979', (0, 24))	('amplification', 'Var', (25, 38))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (92, 120))
326704	27889930	Genes carrying mutations included TP53, CDKN2A, and PIK3CA in 79 (35.9%), 35 (15.9%), and 19 patients (8.6%), respectively.	('TP53', 'Gene', (34, 38))	('mutations', 'Var', (15, 24))	('CDKN2A', 'Gene', (40, 46))	('PIK3CA', 'Gene', (52, 58))	('CDKN2A', 'Gene', '1029', (40, 46))	('PIK3CA', 'Gene', '5290', (52, 58))	('patients', 'Species', '9606', (93, 101))	('TP53', 'Gene', '7157', (34, 38))
326705	27889930	Copy number analysis detected amplification of PIK3CA and AKT1 in 38 (17.3%) and 11 patients (5.0%), respectively.	('PIK3CA', 'Gene', (47, 53))	('PIK3CA', 'Gene', '5290', (47, 53))	('patients', 'Species', '9606', (84, 92))	('AKT1', 'Gene', '207', (58, 62))	('amplification', 'Var', (30, 43))	('AKT1', 'Gene', (58, 62))
326706	27889930	Amplification of receptor tyrosine kinases was found in 37 patients (16.8%).	('receptor tyrosine kinase', 'Gene', (17, 41))	('Amplification', 'Var', (0, 13))	('patients', 'Species', '9606', (59, 67))	('receptor tyrosine kinase', 'Gene', '5979', (17, 41))
326714	27889930	Annually, approximately 300 000 people worldwide develop oral cancer.1 The majority of oral malignancies arise from epithelial tissue, and squamous cell carcinoma is the predominant tumor type.2 Despite advances in diagnostic technology and therapeutic techniques, the survival rate of oral squamous cell carcinoma (OSCC) has improved by only 5% in the past 20 years, and the 5-year survival rate of OSCC is 60%.3 Comprehensive analyses of gene mutations in head and neck squamous cell carcinoma (HNSCC) including OSCC using NGS have also been conducted, revealing substantial information about genomic alterations in HNSCC.4, 5, 6, 7, 8 However, there is little evidence for selecting stratified therapies based on genomic alterations.	('carcinoma', 'Phenotype', 'HP:0030731', (153, 162))	('squamous cell carcinoma', 'Disease', (139, 162))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (458, 495))	('OS', 'Chemical', '-', (400, 402))	('carcinoma', 'Phenotype', 'HP:0030731', (486, 495))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))	('neck squamous cell carcinoma', 'Disease', (467, 495))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (467, 495))	('people', 'Species', '9606', (32, 38))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (291, 314))	('mutations', 'Var', (445, 454))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (286, 314))	('oral cancer', 'Disease', 'MESH:D009062', (57, 68))	('oral squamous cell carcinoma', 'Disease', (286, 314))	('oral cancer', 'Disease', (57, 68))	('OS', 'Chemical', '-', (316, 318))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (139, 162))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (472, 495))	('oral malignancies', 'Disease', 'MESH:D020820', (87, 104))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (291, 314))	('HNSCC', 'Phenotype', 'HP:0012288', (618, 623))	('OS', 'Chemical', '-', (514, 516))	('tumor', 'Disease', (182, 187))	('oral malignancies', 'Disease', (87, 104))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (139, 162))	('HNSCC', 'Phenotype', 'HP:0012288', (497, 502))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (472, 495))	('carcinoma', 'Phenotype', 'HP:0030731', (305, 314))	('tumor', 'Disease', 'MESH:D009369', (182, 187))
326721	27889930	The panel target's hotspot regions included more than 2800 COSMIC mutations of 50 cancer-related genes (Table [Link], [Link]a and b).	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('COSMIC mutations', 'Var', (59, 75))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('OS', 'Chemical', '-', (60, 62))
326730	27889930	Figure 1 presents the results for the detection of somatic mutations (SMs) and copy number alterations (CNAs).	('somatic mutations', 'Var', (51, 68))	('copy number alterations', 'Var', (79, 102))	('SMs', 'Chemical', '-', (70, 73))
326732	27889930	Genes detected to have a mutation included TP53 in 79 patients (35.9%), CDKN2A in 35 patients (15.9%), PIK3CA in 19 patients (8.6%), NOTCH1 in nine patients (4.1%), HRAS in four patients (1.8%), RB1 in three patients (1.4%), FBXW7 in one patient (0.5%), and PTEN in onde patient (0.5%).	('HRAS', 'Gene', (165, 169))	('patients', 'Species', '9606', (54, 62))	('patient', 'Species', '9606', (271, 278))	('FBXW7', 'Gene', '55294', (225, 230))	('patient', 'Species', '9606', (238, 245))	('PIK3CA', 'Gene', '5290', (103, 109))	('PTEN', 'Gene', (258, 262))	('patients', 'Species', '9606', (148, 156))	('patient', 'Species', '9606', (208, 215))	('patients', 'Species', '9606', (116, 124))	('mutation', 'Var', (25, 33))	('patients', 'Species', '9606', (178, 186))	('NOTCH1', 'Gene', (133, 139))	('patients', 'Species', '9606', (85, 93))	('TP53', 'Gene', (43, 47))	('CDKN2A', 'Gene', (72, 78))	('patient', 'Species', '9606', (54, 61))	('RB1', 'Gene', (195, 198))	('PTEN', 'Gene', '5728', (258, 262))	('patient', 'Species', '9606', (85, 92))	('NOTCH1', 'Gene', '4851', (133, 139))	('PIK3CA', 'Gene', (103, 109))	('patient', 'Species', '9606', (148, 155))	('FBXW7', 'Gene', (225, 230))	('CDKN2A', 'Gene', '1029', (72, 78))	('patients', 'Species', '9606', (208, 216))	('RB1', 'Gene', '5925', (195, 198))	('patient', 'Species', '9606', (116, 123))	('patient', 'Species', '9606', (178, 185))	('TP53', 'Gene', '7157', (43, 47))	('HRAS', 'Gene', '3265', (165, 169))
326734	27889930	Copy number analysis uncovered deletions of tumor suppressor genes, namely CDKN2A in 25 patients (11.4%), NOTCH1 in eight patients (3.6%), and SMAD4 in three patients (1.4%).	('SMAD4', 'Gene', '4089', (143, 148))	('CDKN2A', 'Gene', (75, 81))	('patients', 'Species', '9606', (88, 96))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('NOTCH1', 'Gene', '4851', (106, 112))	('NOTCH1', 'Gene', (106, 112))	('deletions', 'Var', (31, 40))	('patients', 'Species', '9606', (122, 130))	('CDKN2A', 'Gene', '1029', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('SMAD4', 'Gene', (143, 148))	('patients', 'Species', '9606', (158, 166))	('tumor', 'Disease', (44, 49))
326736	27889930	Amplification of receptor tyrosine kinases (RTKs) was found in 37 patients (16.8%).	('receptor tyrosine kinase', 'Gene', (17, 41))	('RTK', 'Gene', '5979', (44, 47))	('Amplification', 'Var', (0, 13))	('receptor tyrosine kinase', 'Gene', '5979', (17, 41))	('RTK', 'Gene', (44, 47))	('patients', 'Species', '9606', (66, 74))
326742	27889930	Examination of these frequencies separately for T- and N-factors used for stage classification revealed that the frequency of PIK3CA SMs was significantly higher for patients with T3/4 lesions (P = 0.015), whereas the frequency of PIK3CA amplification was significantly higher in patients with N0 lesions (P = 0.028) (Table 1).	('PIK3CA', 'Gene', (231, 237))	('T3/4 lesions', 'Var', (180, 192))	('PIK3CA', 'Gene', (126, 132))	('patients', 'Species', '9606', (280, 288))	('PIK3CA', 'Gene', '5290', (231, 237))	('PIK3CA', 'Gene', '5290', (126, 132))	('SMs', 'Chemical', '-', (133, 136))	('higher', 'PosReg', (155, 161))	('patients', 'Species', '9606', (166, 174))
326743	27889930	Regarding mutations of TP53 and CDKN2A, no significant difference was detected between stages.	('TP53', 'Gene', (23, 27))	('CDKN2A', 'Gene', (32, 38))	('CDKN2A', 'Gene', '1029', (32, 38))	('TP53', 'Gene', '7157', (23, 27))	('mutations', 'Var', (10, 19))
326748	27889930	In addition, comparisons of each gene revealed that deletion of CDKN2A was exclusive with SMs of TP53, whereas amplification of PIK3CA was cooperative with SMs of TP53.	('PIK3CA', 'Gene', '5290', (128, 134))	('TP53', 'Gene', '7157', (97, 101))	('SMs', 'Chemical', '-', (90, 93))	('CDKN2A', 'Gene', (64, 70))	('TP53', 'Gene', '7157', (163, 167))	('SMs', 'Chemical', '-', (156, 159))	('TP53', 'Gene', (97, 101))	('CDKN2A', 'Gene', '1029', (64, 70))	('TP53', 'Gene', (163, 167))	('PIK3CA', 'Gene', (128, 134))	('deletion', 'Var', (52, 60))
326753	27889930	In univariate analysis for OS, a statistically significant difference was detected for RTK amplification (hazard ratio [HR] = 2.662, 95% confidence interval [CI] = 1.290-5.491, P = 0.008) and CDKN2A deletion (HR = 2.442, 95% CI = 1.059-5.634, P = 0.036).	('OS', 'Chemical', '-', (27, 29))	('RTK', 'Gene', (87, 90))	('CDKN2A', 'Gene', (192, 198))	('RTK', 'Gene', '5979', (87, 90))	('deletion', 'Var', (199, 207))	('CDKN2A', 'Gene', '1029', (192, 198))
326755	27889930	3a) and 63.7% (95% CI = 41.6-85.8) in the CDNK2A deletion group (Fig.	('CDNK2A', 'Gene', (42, 48))	('CDNK2A', 'Chemical', '-', (42, 48))	('deletion', 'Var', (49, 57))
326761	27889930	Additionally, similar comparisons among the four groups detected significantly poorer prognosis associated with the presence of RTK amplifications irrespective of CDKN2A deletion (no CDKN2A deletion/RTK amplification: HR = 2.626, 95% CI = 1.103-6.248, P = 0.029; CDKN2A deletion/RTK amplification: HR = 3.517, 95% CI = 1.196-10.34, P = 0.022) (Table 5).	('RTK', 'Gene', (128, 131))	('CDKN2A', 'Gene', (263, 269))	('CDKN2A', 'Gene', (183, 189))	('RTK', 'Gene', (279, 282))	('CDKN2A', 'Gene', '1029', (163, 169))	('CDKN2A', 'Gene', '1029', (263, 269))	('CDKN2A', 'Gene', '1029', (183, 189))	('RTK', 'Gene', '5979', (199, 202))	('poorer', 'NegReg', (79, 85))	('RTK', 'Gene', '5979', (279, 282))	('presence', 'Var', (116, 124))	('RTK', 'Gene', '5979', (128, 131))	('amplifications', 'Var', (132, 146))	('CDKN2A', 'Gene', (163, 169))	('RTK', 'Gene', (199, 202))
326762	27889930	Examination of the cause of death in 25 cases in which CDKN2A deletion was detected revealed that two, one, two, and two patients died because of the primary lesion, cervical metastasis, distant metastasis, and another disease, respectively (data not shown).	('CDKN2A', 'Gene', '1029', (55, 61))	('distant metastasis', 'CPA', (187, 205))	('deletion', 'Var', (62, 70))	('death', 'Disease', 'MESH:D003643', (28, 33))	('death', 'Disease', (28, 33))	('cervical metastasis', 'CPA', (166, 185))	('CDKN2A', 'Gene', (55, 61))	('patients', 'Species', '9606', (121, 129))
326765	27889930	The most prevalent genetic alteration detected in our cohort comprised a broad spectrum of TP53 mutations (35.9%).	('prevalent', 'Reg', (9, 18))	('TP53', 'Gene', '7157', (91, 95))	('TP53', 'Gene', (91, 95))	('mutations', 'Var', (96, 105))
326769	27889930	Regulation failure induced by RTK alteration is known to cause intercellular/intracellular signaling perturbation, and RTK alterations have been reported in many cancers.15, 16 In HNSCC, genetic alterations of not only EGFR but also ERBB2, FGFR1, FGFR3, and MET have been reported.17, 18, 19, 20, 21 RTK gene alterations induce epithelial-mesenchymal transition,22 allowing tumor cells to acquire migration capabilities.	('FGFR3', 'Gene', '2261', (247, 252))	('cancers', 'Disease', (162, 169))	('EGFR', 'Gene', (219, 223))	('ERBB2', 'Gene', '2064', (233, 238))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('RTK', 'Gene', (119, 122))	('FGFR1', 'Gene', '2260', (240, 245))	('RTK', 'Gene', '5979', (119, 122))	('EGFR', 'Gene', '1956', (219, 223))	('cancers', 'Disease', 'MESH:D009369', (162, 169))	('tumor', 'Disease', (374, 379))	('tumor', 'Disease', 'MESH:D009369', (374, 379))	('RTK', 'Gene', (30, 33))	('RTK', 'Gene', '5979', (30, 33))	('HNSCC', 'Phenotype', 'HP:0012288', (180, 185))	('RTK', 'Gene', (300, 303))	('alterations', 'Var', (309, 320))	('cancers', 'Phenotype', 'HP:0002664', (162, 169))	('FGFR1', 'Gene', (240, 245))	('FGFR3', 'Gene', (247, 252))	('ERBB2', 'Gene', (233, 238))	('RTK', 'Gene', '5979', (300, 303))	('induce', 'Reg', (321, 327))	('tumor', 'Phenotype', 'HP:0002664', (374, 379))
326770	27889930	Overexpression of EGFR was demonstrated to be an adverse prognostic factor in HNSCC.23 In addition, HER2 overexpression in breast and gastric cancers and FGFR1 overexpression in lung cancer have been identified as adverse prognostic factors.24, 25, 26 EGFR amplification was detected most frequently in this study, similar to previous reports.4, 19 Meanwhile, amplification of other RTKs such as ERBB2, FRFR1, and FGFR3 was also detected, albeit in a small number of patients, demonstrating that RTKs are adverse prognostic factors.	('lung cancer', 'Phenotype', 'HP:0100526', (178, 189))	('patients', 'Species', '9606', (467, 475))	('ERBB2', 'Gene', (396, 401))	('EGFR', 'Gene', (18, 22))	('FGFR1', 'Gene', '2260', (154, 159))	('RTK', 'Gene', (383, 386))	('amplification', 'Var', (360, 373))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('ERBB2', 'Gene', '2064', (396, 401))	('EGFR', 'Gene', '1956', (252, 256))	('cancers', 'Phenotype', 'HP:0002664', (142, 149))	('RTK', 'Gene', '5979', (383, 386))	('HER2', 'Gene', '2064', (100, 104))	('lung cancer', 'Disease', (178, 189))	('gastric cancers', 'Phenotype', 'HP:0012126', (134, 149))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('HNSCC', 'Phenotype', 'HP:0012288', (78, 83))	('breast and gastric cancers', 'Disease', 'MESH:D013274', (123, 149))	('FGFR3', 'Gene', (414, 419))	('EGFR', 'Gene', '1956', (18, 22))	('FGFR1', 'Gene', (154, 159))	('RTK', 'Gene', (496, 499))	('FGFR3', 'Gene', '2261', (414, 419))	('FRFR1', 'Gene', (403, 408))	('lung cancer', 'Disease', 'MESH:D008175', (178, 189))	('HER2', 'Gene', (100, 104))	('EGFR', 'Gene', (252, 256))	('RTK', 'Gene', '5979', (496, 499))
326771	27889930	Moreover, it was demonstrated that the group with both RTK amplification and TP53 mutations had significantly poorer prognosis than the other groups, although no significant difference was detected in OS regarding the presence or absence of TP53 mutations alone.	('TP53', 'Gene', '7157', (241, 245))	('RTK', 'Gene', '5979', (55, 58))	('TP53', 'Gene', (241, 245))	('OS', 'Chemical', '-', (201, 203))	('mutations', 'Var', (82, 91))	('poorer', 'NegReg', (110, 116))	('TP53', 'Gene', '7157', (77, 81))	('TP53', 'Gene', (77, 81))	('prognosis', 'CPA', (117, 126))	('RTK', 'Gene', (55, 58))
326773	27889930	Meanwhile, CDKN2A, another tumor suppressor gene, has also been reported to undergo deletion in HNSCC.27 However, it was not demonstrated that a synergistic effect of CDKN2A deletion and RTK amplification on OS.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('HNSCC', 'Phenotype', 'HP:0012288', (96, 101))	('RTK', 'Gene', (187, 190))	('tumor', 'Disease', (27, 32))	('CDKN2A', 'Gene', (167, 173))	('CDKN2A', 'Gene', '1029', (167, 173))	('OS', 'Chemical', '-', (208, 210))	('deletion', 'Var', (174, 182))	('RTK', 'Gene', '5979', (187, 190))	('CDKN2A', 'Gene', (11, 17))	('HNSCC.27', 'CellLine', 'CVCL:8807', (96, 104))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('CDKN2A', 'Gene', '1029', (11, 17))
326774	27889930	Our examination of stages detected a statistically significant difference in the frequency of genetic alterations in PIK3CA between stages as well as their factors, namely local tumor progression (T status) and cervical lymph node metastasis (N status), separately.	('genetic alterations', 'Var', (94, 113))	('tumor', 'Disease', (178, 183))	('PIK3CA', 'Gene', (117, 123))	('PIK3CA', 'Gene', '5290', (117, 123))	('cervical lymph node', 'Disease', (211, 230))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))
326776	27889930	It has been found that precursor lesions of invasive cancers also exhibit PIK3CA amplification.29, 30 Given our result that the frequency of PIK3CA amplification was significantly higher in patients free of cervical lymph node metastasis, PIK3CA amplification is likely to reflect a tumor's early characteristics.	('PIK3CA', 'Gene', (239, 245))	('cancers', 'Phenotype', 'HP:0002664', (53, 60))	('tumor', 'Disease', 'MESH:D009369', (283, 288))	('patients', 'Species', '9606', (190, 198))	('invasive cancers', 'Disease', (44, 60))	('PIK3CA', 'Gene', '5290', (74, 80))	('PIK3CA', 'Gene', '5290', (239, 245))	('invasive cancers', 'Disease', 'MESH:D009362', (44, 60))	('tumor', 'Phenotype', 'HP:0002664', (283, 288))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('PIK3CA', 'Gene', (141, 147))	('tumor', 'Disease', (283, 288))	('PIK3CA', 'Gene', '5290', (141, 147))	('higher', 'PosReg', (180, 186))	('amplification', 'Var', (148, 161))	('PIK3CA', 'Gene', (74, 80))
326784	27889930	The mutational events linked to smoking are traditionally reported as an increase in C>A mutations and a decrease in C>T mutations.39 However, Pickering et al.40 reported that smoking has only a minor impact on the types of mutations observed in oral tongue SCC and TCGA data also demonstrate that the genomic effects of smoking are tumor-site specific.	('tumor', 'Disease', (333, 338))	('oral tongue SCC', 'Disease', (246, 261))	('tumor', 'Disease', 'MESH:D009369', (333, 338))	('mutations', 'Var', (224, 233))	('tumor', 'Phenotype', 'HP:0002664', (333, 338))
326788	27889930	Oncogenes are recurrently mutated at the same amino acid positions, whereas tumor suppressor genes are mutated through truncating mutations throughout their length.41 Regarding NOTCH1, most of the mutations in hematopoietic tumors have been identified in the heterodimerization and C-terminal polypeptide-enriched proline, glutamate, serine, and threonine domain,42, 43 and the panel we used only targeted these regions.	('NOTCH1', 'Gene', '4851', (177, 183))	('NOTCH1', 'Gene', (177, 183))	('hematopoietic tumors', 'Disease', 'MESH:D019337', (210, 230))	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('mutations', 'Var', (197, 206))	('tumor', 'Disease', (224, 229))	('serine', 'Chemical', 'MESH:D012694', (334, 340))	('tumors', 'Phenotype', 'HP:0002664', (224, 230))	('hematopoietic tumors', 'Disease', (210, 230))	('glutamate', 'Chemical', 'MESH:D018698', (323, 332))	('threonine', 'Chemical', 'MESH:D013912', (346, 355))	('proline', 'Chemical', 'MESH:D011392', (314, 321))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('tumor', 'Disease', 'MESH:D009369', (224, 229))
326793	26810754	Epigenetic silencing of CREB3L1 by DNA methylation is associated with high-grade metastatic breast cancers with poor prognosis and is prevalent in triple negative breast cancers CREB3L1 (cAMP-responsive element-binding protein 3-like protein 1), a member of the unfolded protein response, has recently been identified as a metastasis suppressor in both breast and bladder cancer.	('CREB3L1', 'Gene', '90993', (24, 31))	('cancers', 'Phenotype', 'HP:0002664', (170, 177))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('breast cancers', 'Disease', 'MESH:D001943', (163, 177))	('breast cancers', 'Phenotype', 'HP:0003002', (92, 106))	('breast cancers', 'Disease', (163, 177))	('breast and bladder cancer', 'Disease', 'MESH:D001749', (353, 378))	('CREB3L1', 'Gene', (178, 185))	('breast cancer', 'Phenotype', 'HP:0003002', (92, 105))	('breast cancers', 'Phenotype', 'HP:0003002', (163, 177))	('prevalent', 'Reg', (134, 143))	('CREB3L1', 'Gene', '90993', (178, 185))	('breast cancer', 'Phenotype', 'HP:0003002', (163, 176))	('associated', 'Reg', (54, 64))	('bladder cancer', 'Phenotype', 'HP:0009725', (364, 378))	('cancer', 'Phenotype', 'HP:0002664', (372, 378))	('Epigenetic silencing', 'Var', (0, 20))	('CREB3L1', 'Gene', (24, 31))	('cAMP-responsive element-binding protein 3-like protein 1', 'Gene', '90993', (187, 243))	('cancers', 'Phenotype', 'HP:0002664', (99, 106))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('breast cancers', 'Disease', 'MESH:D001943', (92, 106))	('breast cancers', 'Disease', (92, 106))
326797	26810754	This study demonstrates that the low CREB3L1 expression previously seen in highly metastatic breast cancer cell lines is caused in part by epigenetic silencing.	('rat', 'Species', '10116', (18, 21))	('low', 'NegReg', (33, 36))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('breast cancer', 'Disease', 'MESH:D001943', (93, 106))	('expression', 'MPA', (45, 55))	('CREB3L1', 'Gene', (37, 44))	('breast cancer', 'Disease', (93, 106))	('epigenetic silencing', 'Var', (139, 159))	('breast cancer', 'Phenotype', 'HP:0003002', (93, 106))
326801	26810754	Importantly, bioinformatics analyses of tumor databases support these findings, with methylation of the CREB3L1 gene associated with TNBCs, and strongly negatively correlated with CREB3L1 mRNA expression.	('CREB3L1', 'Gene', (104, 111))	('methylation', 'Var', (85, 96))	('associated', 'Reg', (117, 127))	('TNBCs', 'Disease', (133, 138))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('mRNA expression', 'MPA', (188, 203))	('negatively correlated', 'NegReg', (153, 174))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))
326804	26810754	Our data further strengthens the role for CREB3L1 as a metastasis suppressor in breast cancer and demonstrates that epigenetic silencing is a major regulator of the loss of CREB3L1 expression.	('epigenetic silencing', 'Var', (116, 136))	('expression', 'MPA', (181, 191))	('CREB3L1', 'Gene', (173, 180))	('rat', 'Species', '10116', (105, 108))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('breast cancer', 'Disease', 'MESH:D001943', (80, 93))	('breast cancer', 'Disease', (80, 93))	('breast cancer', 'Phenotype', 'HP:0003002', (80, 93))	('loss', 'NegReg', (165, 169))
326807	26810754	This process can be disrupted by endoplasmic reticulum stress resulting from hypoxia, glucose or nutrient depletion, change in calcium homeostasis, or expression of mutant or misfolded proteins, and can lead to the accumulation of unfolded proteins that if released from the endoplasmic reticulum can have detrimental effects.	('mutant', 'Var', (165, 171))	('hypoxia', 'Disease', (77, 84))	('change', 'Reg', (117, 123))	('unfolded proteins', 'Protein', (231, 248))	('calcium', 'Chemical', 'MESH:D002118', (127, 134))	('lead to', 'Reg', (203, 210))	('accumulation', 'PosReg', (215, 227))	('glucose', 'Chemical', 'MESH:D005947', (86, 93))	('hypoxia', 'Disease', 'MESH:D000860', (77, 84))
326814	26810754	Activated IRE1 cleaves the mRNA of X-box binding protein 1 (XBP1).	('cleaves', 'Var', (15, 22))	('mRNA of', 'MPA', (27, 34))	('IRE1', 'Gene', (10, 14))	('X-box binding protein 1', 'Gene', '7494', (35, 58))	('XBP1', 'Gene', '7494', (60, 64))	('IRE1', 'Gene', '2081', (10, 14))	('X-box binding protein 1', 'Gene', (35, 58))	('XBP1', 'Gene', (60, 64))
326817	26810754	Paradoxically, phosphorylated eIF2alpha also selectively promotes the translation of specific mRNAs, such as ATF4, which activates the transcription of genes involved in amino acid metabolism and apoptosis.	('ATF4', 'Gene', (109, 113))	('activates', 'PosReg', (121, 130))	('eIF2alpha', 'Gene', '83939', (30, 39))	('ATF4', 'Gene', '468', (109, 113))	('transcription', 'MPA', (135, 148))	('phosphorylated', 'Var', (15, 29))	('translation', 'MPA', (70, 81))	('eIF2alpha', 'Gene', (30, 39))	('promotes', 'PosReg', (57, 65))
326820	26810754	It is an endoplasmic reticulum transmembrane protein and activated in a similar manner to ATF6, via Site-1-protease (S1P) and S2P cleavage in the Golgi apparatus followed by translocation to the nucleus.	('Site-1-protease', 'Gene', (100, 115))	('S1P', 'Gene', '8720', (117, 120))	('cleavage', 'Var', (130, 138))	('rat', 'Species', '10116', (156, 159))	('S1P', 'Gene', (117, 120))	('S2P', 'Gene', (126, 129))	('ATF6', 'Gene', '22926', (90, 94))	('translocation', 'MPA', (174, 187))	('ATF6', 'Gene', (90, 94))	('S2P', 'Gene', '51360', (126, 129))	('Site-1-protease', 'Gene', '8720', (100, 115))
326824	26810754	Inhibition of PERK expression in animal models results in an increase in reactive oxygen species leading to increased DNA damage and a halting of the cell cycle.	('reactive oxygen species', 'Chemical', 'MESH:D017382', (73, 96))	('PERK', 'Gene', (14, 18))	('halting', 'NegReg', (135, 142))	('DNA damage', 'MPA', (118, 128))	('PERK', 'Gene', '9451', (14, 18))	('increased', 'PosReg', (108, 117))	('reactive oxygen species', 'MPA', (73, 96))	('Inhibition', 'Var', (0, 10))	('increase', 'PosReg', (61, 69))
326830	26810754	Epigenetic downregulation of CREB3L1 mRNA expression by DNA methylation is associated with increased tumor grade and aggressive phenotype in bladder cancer.	('bladder cancer', 'Disease', (141, 155))	('mRNA expression', 'MPA', (37, 52))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('CREB3L1', 'Gene', (29, 36))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('bladder cancer', 'Phenotype', 'HP:0009725', (141, 155))	('Epigenetic', 'Var', (0, 10))	('increased', 'PosReg', (91, 100))	('bladder cancer', 'Disease', 'MESH:D001749', (141, 155))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
326836	26810754	We further showed that re-expression of CREB3L1 reduced the in vitro metastatic cell properties, including cell migration, invasion, survival under hypoxic conditions and anchorage-independent growth.	('rat', 'Species', '10116', (115, 118))	('re-expression', 'Var', (23, 36))	('invasion', 'CPA', (123, 131))	('reduced', 'NegReg', (48, 55))	('anchorage-independent growth', 'CPA', (171, 199))	('cell migration', 'CPA', (107, 121))	('CREB3L1', 'Gene', (40, 47))	('survival under', 'CPA', (133, 147))	('hypoxic conditions', 'Disease', (148, 166))	('hypoxic conditions', 'Disease', 'MESH:D009135', (148, 166))
326856	26810754	Samples were transferred to nitrocellulose and were probed with CREB3L1 (11235-2-AP from Protein Tech, Rosemont, IL, USA; rabbit, 1:500) or ss-actin (C-4 from Santa Cruz Biotechnology, Dallas, TX, USA; mouse, 1:500) primary antibodies, followed by infrared 680 nm or 800 nm dye-tagged secondary antibodies (LI-COR Biosciences, Lincoln, NE, USA; 200 ng/ml).	('mouse', 'Species', '10090', (202, 207))	('11235-2-AP', 'Var', (73, 83))	('COR', 'Gene', (310, 313))	('rabbit', 'Species', '9986', (122, 128))	('COR', 'Gene', '108031', (310, 313))
326865	26810754	Only sequences containing efficient C to T conversions, indicative of effective sodium bisulfite conversion at the non-CpG sites (that would not be methylated) were used for methylation analyses.	('sodium bisulfite conversion', 'MPA', (80, 107))	('sodium bisulfite', 'Chemical', 'MESH:C009279', (80, 96))	('C to', 'Var', (36, 40))
326911	26810754	The presence of MG132 increased CREB3L1 protein levels more robustly (Fig.	('MG132', 'Var', (16, 21))	('increased', 'PosReg', (22, 31))	('CREB3L1 protein levels', 'MPA', (32, 54))	('MG132', 'Chemical', 'MESH:C072553', (16, 21))
326912	26810754	These results suggest that both epigenetic and post-translational mechanisms can contribute to reduced CREB3L1 in human breast cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('CREB3L1', 'Gene', (103, 110))	('breast cancer', 'Disease', (120, 133))	('breast cancer', 'Disease', 'MESH:D001943', (120, 133))	('breast cancer', 'Phenotype', 'HP:0003002', (120, 133))	('epigenetic', 'Var', (32, 42))	('human', 'Species', '9606', (114, 119))	('reduced', 'NegReg', (95, 102))
326926	26810754	Although the sample size within each group was small, there was a larger proportion of HER2 amplified tumor samples with cytoplasmic CREB3L1 protein, rather than nuclear CREB3L1 (Additional file 6: Figure S4b).	('HER2', 'Gene', '2064', (87, 91))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('rat', 'Species', '10116', (150, 153))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('HER2', 'Gene', (87, 91))	('cytoplasmic CREB3L1', 'Var', (121, 140))
326930	26810754	In parallel, luminal breast cancers with nuclear CREB3L1 were most frequently of low-medium grade, whereas those with cytoplasmic CREB3L1 were often high-grade tumors (Fig.	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('breast cancers', 'Phenotype', 'HP:0003002', (21, 35))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('luminal breast cancers', 'Disease', 'MESH:D001943', (13, 35))	('nuclear CREB3L1', 'Var', (41, 56))	('breast cancer', 'Phenotype', 'HP:0003002', (21, 34))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('cancers', 'Phenotype', 'HP:0002664', (28, 35))	('tumors', 'Disease', (160, 166))	('luminal breast cancers', 'Disease', (13, 35))	('tumors', 'Disease', 'MESH:D009369', (160, 166))
326932	26810754	These results suggest that in HER2 amplified breast cancers about half express CREB3L1, and the CREB3L1 is primarily localized in the cytoplasm where its transcriptional regulation would not be active.	('CREB3L1', 'Gene', (79, 86))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('breast cancers', 'Phenotype', 'HP:0003002', (45, 59))	('amplified', 'Var', (35, 44))	('breast cancers', 'Disease', 'MESH:D001943', (45, 59))	('HER2', 'Gene', (30, 34))	('breast cancers', 'Disease', (45, 59))	('breast cancer', 'Phenotype', 'HP:0003002', (45, 58))	('HER2', 'Gene', '2064', (30, 34))	('cancers', 'Phenotype', 'HP:0002664', (52, 59))
326939	26810754	These results suggest that loss of CREB3L1 is more frequently seen in high-grade, more aggressive breast cancers that lack ER and PR expression.	('loss', 'Var', (27, 31))	('breast cancer', 'Phenotype', 'HP:0003002', (98, 111))	('cancers', 'Phenotype', 'HP:0002664', (105, 112))	('seen', 'Reg', (62, 66))	('aggressive breast cancers', 'Disease', 'MESH:D001943', (87, 112))	('PR', 'Gene', '5241', (130, 132))	('breast cancers', 'Phenotype', 'HP:0003002', (98, 112))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('ER', 'Gene', '2099', (123, 125))	('high-grade', 'Disease', (70, 80))	('CREB3L1', 'Gene', (35, 42))	('aggressive breast cancers', 'Disease', (87, 112))
326940	26810754	Our breast cancer cell line data suggested that CREB3L1 expression can be regulated in part by DNA methylation.	('methylation', 'Var', (99, 110))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('breast cancer', 'Disease', 'MESH:D001943', (4, 17))	('regulated', 'Reg', (74, 83))	('breast cancer', 'Phenotype', 'HP:0003002', (4, 17))	('DNA methylation', 'Var', (95, 110))	('breast cancer', 'Disease', (4, 17))	('expression', 'MPA', (56, 66))	('CREB3L1', 'Gene', (48, 55))
326943	26810754	In all we analyzed 201 tumor samples and found 35 contained CREB3L1 methylation.	('methylation', 'Var', (68, 79))	('tumor', 'Disease', (23, 28))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))
326946	26810754	In our samples there were only a few breast tumors with alterations in CREB3L1 copy number; 9 % had increased copy number (3-5 copies), 4 % had a decreased copy number of 1 and 86 % had a normal copy number of 2.	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('breast tumor', 'Phenotype', 'HP:0100013', (37, 49))	('copy number', 'MPA', (156, 167))	('increased', 'PosReg', (100, 109))	('alterations', 'Var', (56, 67))	('CREB3L1', 'Gene', (71, 78))	('breast tumors', 'Disease', 'MESH:D001943', (37, 50))	('rat', 'Species', '10116', (60, 63))	('decreased', 'NegReg', (146, 155))	('breast tumors', 'Disease', (37, 50))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('breast tumors', 'Phenotype', 'HP:0100013', (37, 50))
326948	26810754	We observed that CREB3L1 DNA methylation was found in some samples within all tumor grades (Fig.	('methylation', 'Var', (29, 40))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Disease', (78, 83))	('CREB3L1', 'Gene', (17, 24))	('found', 'Reg', (45, 50))
326950	26810754	Overall, CREB3L1 methylation was weakly, positively correlated with tumor type (r = 0.150, p <0.05) and tumor grade (r = 0.146, p <0.05) (Table 2).	('tumor', 'Disease', (68, 73))	('correlated', 'Reg', (52, 62))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('CREB3L1', 'Gene', (9, 16))	('methylation', 'Var', (17, 28))	('tumor', 'Disease', (104, 109))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
326951	26810754	In addition, CREB3L1 methylation was weakly, negatively correlated with age of diagnosis (r = -0.166, p <0.05), ER expression (r = -0.168, p <0.05) and PR expression (r = -0.143, p <0.05).	('negatively', 'NegReg', (45, 55))	('PR', 'Gene', '5241', (152, 154))	('methylation', 'Var', (21, 32))	('CREB3L1', 'Gene', (13, 20))	('ER', 'Gene', '2099', (112, 114))
326952	26810754	These results suggest that the majority of the breast tumor samples with DNA methylation had reduced CREB3L1 mRNA expression, implicating methylation as a mechanism of CREB3L1 gene silencing.	('mRNA expression', 'MPA', (109, 124))	('breast tumor', 'Phenotype', 'HP:0100013', (47, 59))	('CREB3L1', 'Gene', (101, 108))	('DNA methylation', 'Var', (73, 88))	('reduced', 'NegReg', (93, 100))	('breast tumor', 'Disease', 'MESH:D001943', (47, 59))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('breast tumor', 'Disease', (47, 59))
326960	26810754	Region number 2 showed the largest significant difference in methylation between normal breast and breast tumors, suggesting that changes in methylation in this region may have the largest influence on CREB3L1 mRNA expression.	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('breast tumor', 'Phenotype', 'HP:0100013', (99, 111))	('methylation', 'MPA', (141, 152))	('changes', 'Var', (130, 137))	('breast tumors', 'Phenotype', 'HP:0100013', (99, 112))	('breast tumors', 'Disease', 'MESH:D001943', (99, 112))	('mRNA expression', 'MPA', (210, 225))	('influence', 'Reg', (189, 198))	('breast tumors', 'Disease', (99, 112))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('CREB3L1', 'Gene', (202, 209))
326974	26810754	Thus, the loss of CREB3L1 is a frequent occurrence and could play an important role in tumor progression and metastasis in many cancer types.	('loss', 'Var', (10, 14))	('CREB3L1', 'Gene', (18, 25))	('role', 'Reg', (79, 83))	('metastasis in many cancer', 'Disease', 'MESH:D009362', (109, 134))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Disease', (87, 92))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('play', 'Reg', (61, 65))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('metastasis in many cancer', 'Disease', (109, 134))
326977	26810754	Consistent with these effects, knockdown of endogenous CREB3L1 in cells demonstrated that loss of CREB3L1 expression significantly increased migration, invasion, anchorage-independent growth, and tolerance of hypoxia.	('invasion', 'CPA', (152, 160))	('migration', 'CPA', (141, 150))	('increased', 'PosReg', (131, 140))	('hypoxia', 'Disease', (209, 216))	('hypoxia', 'Disease', 'MESH:D000860', (209, 216))	('loss', 'Var', (90, 94))	('rat', 'Species', '10116', (79, 82))	('CREB3L1', 'Gene', (98, 105))	('anchorage-independent growth', 'CPA', (162, 190))	('rat', 'Species', '10116', (144, 147))
326983	26810754	Viral infections and treatment with the chemotherapy agent, doxorubicin, have also been shown to induce cell stress and the activation of CREB3L1.	('CREB3L1', 'Gene', (138, 145))	('activation', 'PosReg', (124, 134))	('Viral infections', 'Disease', (0, 16))	('doxorubicin', 'Chemical', 'MESH:D004317', (60, 71))	('cell stress', 'CPA', (104, 115))	('induce', 'Reg', (97, 103))	('doxorubicin', 'Var', (60, 71))	('Viral infections', 'Disease', 'MESH:D001102', (0, 16))
326988	26810754	As doxorubicin was only effective in blocking cell proliferation in CREB3L1-expressing cells, this suggests that only patients expressing CREB3L1 are likely to benefit from doxorubicin treatment.	('patients', 'Species', '9606', (118, 126))	('doxorubicin', 'Chemical', 'MESH:D004317', (3, 14))	('CREB3L1', 'Var', (138, 145))	('rat', 'Species', '10116', (58, 61))	('cell proliferation', 'CPA', (46, 64))	('doxorubicin', 'Chemical', 'MESH:D004317', (173, 184))
326990	26810754	These results also suggest that the loss of CREB3L1 may contribute to doxorubicin treatment resistance.	('doxorubicin treatment resistance', 'MPA', (70, 102))	('loss', 'Var', (36, 40))	('CREB3L1', 'Gene', (44, 51))	('doxorubicin', 'Chemical', 'MESH:D004317', (70, 81))	('contribute', 'Reg', (56, 66))
326994	26810754	PERK and XBP1 are both important factors in tolerance of hypoxia; loss of expression of either factor inhibits tumor growth and increased apoptosis following hypoxia.	('PERK', 'Gene', (0, 4))	('loss of expression', 'Var', (66, 84))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('XBP1', 'Gene', '7494', (9, 13))	('PERK', 'Gene', '9451', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('hypoxia', 'Disease', (57, 64))	('hypoxia', 'Disease', 'MESH:D000860', (57, 64))	('increased', 'PosReg', (128, 137))	('hypoxia', 'Disease', (158, 165))	('hypoxia', 'Disease', 'MESH:D000860', (158, 165))	('tumor', 'Disease', (111, 116))	('XBP1', 'Gene', (9, 13))	('apoptosis', 'CPA', (138, 147))	('inhibits', 'NegReg', (102, 110))
327007	26810754	Our data in human breast cancer cell lines suggest that epigenetic silencing of CREB3L1 contributes to reducing CREB3L1 mRNA expression for at least some cell lines, an effect that was reversed by the inhibition of histone acetylation with TSA and/or inhibition of DNA methylation with DAC.	('DAC', 'Chemical', '-', (286, 289))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('inhibition', 'NegReg', (201, 211))	('histone', 'Protein', (215, 222))	('CREB3L1', 'Gene', (80, 87))	('breast cancer', 'Disease', 'MESH:D001943', (18, 31))	('acetylation', 'MPA', (223, 234))	('breast cancer', 'Disease', (18, 31))	('epigenetic silencing', 'Var', (56, 76))	('mRNA expression', 'MPA', (120, 135))	('CREB3L1', 'Gene', (112, 119))	('TSA', 'Chemical', 'MESH:C012589', (240, 243))	('reducing', 'NegReg', (103, 111))	('breast cancer', 'Phenotype', 'HP:0003002', (18, 31))	('human', 'Species', '9606', (12, 17))
327015	26810754	The analysis of CREB3L1 DNA methylation in breast tumors in the TCGA database, also with suggested CpG sites 238 and 259 (i.e., region number 2), were usually more methylated in tumors with low CREB3L1 mRNA expression (Additional file 11: Figure S7), but were generally less methylated in breast tumors than in normal breast tissue (Additional file 9: Figure S5a).	('breast tumors', 'Phenotype', 'HP:0100013', (43, 56))	('breast tumors', 'Disease', (289, 302))	('tumors', 'Disease', 'MESH:D009369', (178, 184))	('breast tumor', 'Phenotype', 'HP:0100013', (43, 55))	('tumors', 'Disease', 'MESH:D009369', (296, 302))	('breast tumors', 'Phenotype', 'HP:0100013', (289, 302))	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('CREB3L1', 'Gene', (194, 201))	('methylated', 'MPA', (164, 174))	('more', 'PosReg', (159, 163))	('low', 'NegReg', (190, 193))	('tumors', 'Phenotype', 'HP:0002664', (178, 184))	('CREB3L1', 'Gene', (16, 23))	('tumors', 'Phenotype', 'HP:0002664', (296, 302))	('methylation', 'Var', (28, 39))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('tumor', 'Phenotype', 'HP:0002664', (296, 301))	('tumors', 'Disease', (178, 184))	('breast tumors', 'Disease', 'MESH:D001943', (43, 56))	('breast tumors', 'Disease', (43, 56))	('tumors', 'Disease', (296, 302))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('breast tumor', 'Phenotype', 'HP:0100013', (289, 301))	('tumors', 'Disease', (50, 56))	('breast tumors', 'Disease', 'MESH:D001943', (289, 302))
327023	26810754	who found that CREB3L1 gene expression was downregulated in bladder cancer and that the loss of expression was associated with DNA methylation of the gene.	('downregulated', 'NegReg', (43, 56))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('bladder cancer', 'Phenotype', 'HP:0009725', (60, 74))	('expression', 'MPA', (28, 38))	('expression', 'MPA', (96, 106))	('bladder cancer', 'Disease', 'MESH:D001749', (60, 74))	('bladder cancer', 'Disease', (60, 74))	('DNA', 'Var', (127, 130))	('CREB3L1 gene', 'Gene', (15, 27))
327030	26810754	This raises the possibility that loss of CREB3L1 could play a key role in cancer progression and metastasis across a broad group of cancer types.	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('role', 'Reg', (66, 70))	('cancer', 'Disease', (132, 138))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('metastasis', 'CPA', (97, 107))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('cancer', 'Disease', (74, 80))	('loss', 'Var', (33, 37))	('play', 'Reg', (55, 59))	('CREB3L1', 'Gene', (41, 48))
327036	26810754	In addition, loss of CREB3L1 expression could have prognostic value for multiple forms of cancer.	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('loss', 'Var', (13, 17))	('CREB3L1', 'Gene', (21, 28))	('expression', 'MPA', (29, 39))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))
327124	33840169	Genetic alterations in Wnt family of genes and their putative association with head and neck squamous cell carcinoma Head and neck squamous cell carcinoma (HNSCC) is the most frequent type of head and neck cancer that usually arises from the mucosal surfaces of several organs including nasal cavity, paranasal sinuses, oral cavity, tongue, pharynx, and larynx.	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('Genetic alterations', 'Var', (0, 19))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (131, 154))	('carcinoma', 'Phenotype', 'HP:0030731', (145, 154))	('neck squamous cell carcinoma', 'Disease', (126, 154))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (88, 116))	('association', 'Interaction', (62, 73))	('neck cancer', 'Disease', (201, 212))	('neck cancer', 'Disease', 'MESH:D006258', (201, 212))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (126, 154))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (93, 116))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('HNSCC', 'Phenotype', 'HP:0012288', (156, 161))	('Wnt family of genes', 'Gene', (23, 42))	('neck squamous cell carcinoma', 'Disease', (88, 116))	('head and neck cancer', 'Phenotype', 'HP:0012288', (192, 212))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (79, 116))
327125	33840169	Dysregulation of this pathway correlates with oncogenesis in various tissues including breast, colon, pancreatic as well as head and neck cancers.	('colon', 'Disease', (95, 100))	('neck cancers', 'Disease', 'MESH:D006258', (133, 145))	('Dysregulation', 'Var', (0, 13))	('head and neck cancer', 'Phenotype', 'HP:0012288', (124, 144))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('oncogenesis', 'Disease', (46, 57))	('breast', 'Disease', (87, 93))	('pancreatic', 'Disease', 'MESH:D010195', (102, 112))	('head and neck cancers', 'Phenotype', 'HP:0012288', (124, 145))	('cancers', 'Phenotype', 'HP:0002664', (138, 145))	('neck cancers', 'Disease', (133, 145))	('colon', 'Disease', 'MESH:D003110', (95, 100))	('pancreatic', 'Disease', (102, 112))
327126	33840169	Gene amplification, deep deletions, missense and truncating mutations were observed in HNSCC patients.	('truncating', 'MPA', (49, 59))	('HNSCC', 'Phenotype', 'HP:0012288', (87, 92))	('missense and', 'Var', (36, 48))	('deep deletions', 'Var', (20, 34))	('patients', 'Species', '9606', (93, 101))	('HNSCC', 'Disease', (87, 92))
327130	33840169	Taken together, the present study provides clues on the possible association of WNT11 gene alterations with HNSCC, which has to be further validated using experimental approaches.	('WNT11', 'Gene', '7481', (80, 85))	('HNSCC', 'Disease', (108, 113))	('HNSCC', 'Phenotype', 'HP:0012288', (108, 113))	('association', 'Interaction', (65, 76))	('alterations', 'Var', (91, 102))	('WNT11', 'Gene', (80, 85))
327149	33840169	The oncoprint data analysis revealed alterations in 19 genes, of which WNT11 (5%) harbored the highest frequency of gene amplification and deep deletion.	('WNT11', 'Gene', (71, 76))	('WNT11', 'Gene', '7481', (71, 76))	('alterations', 'Reg', (37, 48))	('deep deletion', 'Var', (139, 152))
327150	33840169	The variations in WNT3 (R85Q), WNT5A (I93V, G341S), WNT6 (R46W, T105M), WNT7A (R90C), WNT10A (A240V), and WNT11 (L65P, R202H) genes were reported.	('WNT7A', 'Gene', '7476', (72, 77))	('R85Q', 'Var', (24, 28))	('I93V', 'Mutation', 'rs750646727', (38, 42))	('WNT7A', 'Gene', (72, 77))	('T105M', 'Var', (64, 69))	('WNT10A', 'Gene', '80326', (86, 92))	('WNT6', 'Gene', (52, 56))	('WNT6', 'Gene', '7475', (52, 56))	('R85Q', 'Mutation', 'rs1483494147', (24, 28))	('R90C', 'Var', (79, 83))	('R46W', 'Var', (58, 62))	('WNT3', 'Gene', '7473', (18, 22))	('L65P', 'Mutation', 'rs748458884', (113, 117))	('WNT3', 'Gene', (18, 22))	('WNT11', 'Gene', (106, 111))	('G341S', 'Mutation', 'rs1370251695', (44, 49))	('WNT5A', 'Gene', (31, 36))	('A240V', 'Var', (94, 99))	('T105M', 'Mutation', 'rs759013954', (64, 69))	('R46W', 'Mutation', 'rs766635655', (58, 62))	('R202H', 'Mutation', 'rs374455490', (119, 124))	('WNT11', 'Gene', '7481', (106, 111))	('A240V', 'Mutation', 'rs201578578', (94, 99))	('I93V', 'Var', (38, 42))	('WNT10A', 'Gene', (86, 92))	('R202H', 'Var', (119, 124))	('R90C', 'Mutation', 'rs751362548', (79, 83))	('G341S', 'Var', (44, 49))	('WNT5A', 'Gene', '7474', (31, 36))
327162	33840169	These results add to the association of WNT11 gene alterations with HNSCC.	('alterations', 'Var', (51, 62))	('WNT11', 'Gene', (40, 45))	('association', 'Interaction', (25, 36))	('WNT11', 'Gene', '7481', (40, 45))	('HNSCC', 'Disease', (68, 73))	('HNSCC', 'Phenotype', 'HP:0012288', (68, 73))
327163	33840169	Genetic variations such as single nucleotide variants and copy number variants have long been associated with oral cancer and other devastating diseases.	('single nucleotide variants', 'Var', (27, 53))	('cancer', 'Disease', (115, 121))	('copy number variants', 'Var', (58, 78))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('associated', 'Reg', (94, 104))	('cancer', 'Disease', 'MESH:D009369', (115, 121))
327167	33840169	Altered Wnt/beta-catenin signaling has been considered a promoting event for various types of cancers.	('cancers', 'Disease', 'MESH:D009369', (94, 101))	('beta-catenin', 'Gene', (12, 24))	('Altered', 'Var', (0, 7))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('beta-catenin', 'Gene', '1499', (12, 24))	('cancers', 'Phenotype', 'HP:0002664', (94, 101))	('cancers', 'Disease', (94, 101))
327176	33840169	Numerous novel variants and reported variants were identified in HNSCC patients.	('HNSCC', 'Disease', (65, 70))	('variants', 'Var', (15, 23))	('HNSCC', 'Phenotype', 'HP:0012288', (65, 70))	('patients', 'Species', '9606', (71, 79))
327177	33840169	Computational tools provide a cost-effective alternative for analyzing the genetic alterations especially in a complex disorder such as cancer.	('genetic alterations', 'Var', (75, 94))	('cancer', 'Disease', (136, 142))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
327185	32457800	In conclusion, MFAP5, miR-200b-3p, and AC005154.6 may have potential prognostic value in CRC and may provide a prognostic reference for this patient population.	('miR-200b', 'Gene', '406984', (22, 30))	('AC005154.6', 'Var', (39, 49))	('MFAP5', 'Gene', (15, 20))	('miR-200b', 'Gene', (22, 30))	('patient', 'Species', '9606', (141, 148))	('CRC', 'Disease', (89, 92))	('MFAP5', 'Gene', '8076', (15, 20))	('CRC', 'Phenotype', 'HP:0003003', (89, 92))
327197	32457800	For example, Ki-67 and p53 have potential prognostic value in Dukes' B and C colon cancer, KRAS and BRAF have potential prognostic value in stage II and III resected colon cancer, the BRAF V600E mutation has been shown to be an independent prognostic factor for survival in stage II and stage III colon cancer patients, and SNORA42 may be a prognostic biomarker in CRC.	('patients', 'Species', '9606', (310, 318))	('colon cancer', 'Phenotype', 'HP:0003003', (297, 309))	('BRAF', 'Gene', (184, 188))	('colon cancer', 'Disease', (166, 178))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('colon cancer', 'Disease', 'MESH:D015179', (77, 89))	('KRAS', 'Gene', '3845', (91, 95))	('V600E', 'Var', (189, 194))	('stage III colon cancer', 'Disease', (287, 309))	('stage III colon cancer', 'Disease', 'MESH:D015179', (287, 309))	("Dukes' B", 'Disease', (62, 70))	('colon cancer', 'Disease', 'MESH:D015179', (297, 309))	('BRAF', 'Gene', '673', (100, 104))	('cancer', 'Phenotype', 'HP:0002664', (303, 309))	('p53', 'Gene', '7157', (23, 26))	('BRAF', 'Gene', (100, 104))	('KRAS', 'Gene', (91, 95))	('colon cancer', 'Phenotype', 'HP:0003003', (166, 178))	('stage II', 'Disease', (274, 282))	('SNORA42', 'Gene', '677823', (324, 331))	('p53', 'Gene', (23, 26))	('colon cancer', 'Disease', 'MESH:D015179', (166, 178))	('C colon cancer', 'Disease', (75, 89))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('SNORA42', 'Gene', (324, 331))	('colon cancer', 'Phenotype', 'HP:0003003', (77, 89))	('C colon cancer', 'Disease', 'MESH:D015179', (75, 89))	('V600E', 'Mutation', 'rs113488022', (189, 194))	('CRC', 'Phenotype', 'HP:0003003', (365, 368))	('BRAF', 'Gene', '673', (184, 188))
327206	32457800	To determine the DEGs common to different CRC samples, CRC datasets were also collected from GEO, including GSE32323 ( with 17 normal and 17 tumor samples, GSE21510 with 44 normal and 104 tumor samples, and GSE8671 with 32 normal and 32 tumor samples (Supplementary Table S1).	('tumor', 'Disease', (188, 193))	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('tumor', 'Disease', (237, 242))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('CRC', 'Phenotype', 'HP:0003003', (55, 58))	('CRC', 'Phenotype', 'HP:0003003', (42, 45))	('DEGs', 'Gene', '8560', (17, 21))	('tumor', 'Disease', (141, 146))	('GSE21510', 'Var', (156, 164))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('tumor', 'Disease', 'MESH:D009369', (237, 242))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('DEGs', 'Gene', (17, 21))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))
327244	32457800	For example, miR-92a and miR-144* may be potential biomarkers of non-invasive colorectal cancer, and miR-103a may be a new regulator of Wnt signaling as an onco-miRNA.	('miR-144', 'Gene', (25, 32))	('colorectal cancer', 'Disease', 'MESH:D015179', (78, 95))	('miR-103a', 'Var', (101, 109))	('miR-144', 'Gene', '406936', (25, 32))	('colorectal cancer', 'Phenotype', 'HP:0003003', (78, 95))	('miR-92a', 'Var', (13, 20))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('colorectal cancer', 'Disease', (78, 95))
327247	32457800	Among the miRNAs, miR-93-5p had the most interacting lncRNAs (177), followed by miR-103a-3p (126), and miR-181c-5p (99).	('miR-93', 'Gene', '407051', (18, 24))	('miR-181c', 'Gene', (103, 111))	('miR-181c', 'Gene', '406957', (103, 111))	('miR-93', 'Gene', (18, 24))	('interacting', 'Interaction', (41, 52))	('miR-103a-3p', 'Var', (80, 91))
327251	32457800	According to StarBase, there were four pairs of miRNA-mRNA interactions with significant negative correlations, including miR-93-5p:CNN1, miR-378-3p:MFAP5, miR-93-5p:MFAP5, and miR-200b-3p:MFAP5 (Figure 6A).	('miR-378-3p', 'Var', (138, 148))	('MFAP5', 'Gene', (166, 171))	('MFAP5', 'Gene', '8076', (189, 194))	('MFAP5', 'Gene', (149, 154))	('negative', 'NegReg', (89, 97))	('miR-200b', 'Gene', (177, 185))	('MFAP5', 'Gene', '8076', (166, 171))	('miRNA-mRNA interactions', 'MPA', (48, 71))	('CNN1', 'Gene', '1264', (132, 136))	('MFAP5', 'Gene', '8076', (149, 154))	('CNN1', 'Gene', (132, 136))	('miR-93', 'Gene', '407051', (156, 162))	('MFAP5', 'Gene', (189, 194))	('miR-93', 'Gene', (156, 162))	('miR-93', 'Gene', '407051', (122, 128))	('miR-200b', 'Gene', '406984', (177, 185))	('miR-93', 'Gene', (122, 128))
327253	32457800	The expression patterns of these three miRNAs showed that miR-200b-3p was significantly up-regulated, while miR-378a-3p was significantly down-regulated (Figure 6B).	('miR-200b', 'Gene', '406984', (58, 66))	('miR-378a-3p', 'Var', (108, 119))	('up-regulated', 'PosReg', (88, 100))	('down-regulated', 'NegReg', (138, 152))	('miR-200b', 'Gene', (58, 66))
327259	32457800	Finally, we found that AC005154.6 had a consistent expression pattern with MFAP5 (significantly down-regulated in CRC), and both had opposing expression patterns with the mediating miRNA, miR-200b-3p (Figure 6E).	('miR-200b', 'Gene', '406984', (188, 196))	('AC005154.6', 'Var', (23, 33))	('down-regulated', 'NegReg', (96, 110))	('miR-200b', 'Gene', (188, 196))	('CRC', 'Phenotype', 'HP:0003003', (114, 117))	('MFAP5', 'Gene', (75, 80))	('MFAP5', 'Gene', '8076', (75, 80))
327266	32457800	MFAP5 blockade can inhibit fibrosis and enhance chemosensitivity in ovarian and pancreatic cancer, and can promote basal-like breast cancer progression by activating epithelial-to-mesenchymal transition.	('MFAP5', 'Gene', '8076', (0, 5))	('fibrosis', 'Disease', (27, 35))	('breast cancer', 'Disease', 'MESH:D001943', (126, 139))	('inhibit', 'NegReg', (19, 26))	('breast cancer', 'Phenotype', 'HP:0003002', (126, 139))	('chemosensitivity', 'CPA', (48, 64))	('breast cancer', 'Disease', (126, 139))	('activating', 'PosReg', (155, 165))	('epithelial-to-mesenchymal transition', 'CPA', (166, 202))	('fibrosis', 'Disease', 'MESH:D005355', (27, 35))	('blockade', 'Var', (6, 14))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('enhance', 'PosReg', (40, 47))	('MFAP5', 'Gene', (0, 5))	('promote', 'PosReg', (107, 114))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (80, 97))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('ovarian and pancreatic cancer', 'Disease', 'MESH:D010195', (68, 97))
327281	32457800	Aberrant lncRNA expression is associated with tumorigenesis, tumor progression, and metastasis.	('associated', 'Reg', (30, 40))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('Aberrant', 'Var', (0, 8))	('tumor', 'Disease', (46, 51))	('lncRNA expression', 'Protein', (9, 26))	('metastasis', 'CPA', (84, 94))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Disease', (61, 66))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
327285	32457800	MFAP5 promotes tumor progression and bone metastasis in several cancers, and miR-200b-3p negatively regulates MFAP5 expression; finally, AC005154.6 interacts with miRNA-200b-3p.	('MFAP5', 'Gene', '8076', (0, 5))	('miR-200b', 'Gene', '406984', (77, 85))	('bone metastasis', 'CPA', (37, 52))	('promotes', 'PosReg', (6, 14))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('regulates', 'Reg', (100, 109))	('MFAP5', 'Gene', (110, 115))	('cancers', 'Phenotype', 'HP:0002664', (64, 71))	('AC005154.6', 'Var', (137, 147))	('MFAP5', 'Gene', '8076', (110, 115))	('cancers', 'Disease', (64, 71))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('miR-200b', 'Gene', (77, 85))	('tumor', 'Disease', (15, 20))	('expression', 'MPA', (116, 126))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('cancers', 'Disease', 'MESH:D009369', (64, 71))	('MFAP5', 'Gene', (0, 5))	('interacts', 'Reg', (148, 157))
327289	32294127	We aimed to determine the safety of S-1 adjuvant chemotherapy and the potential differences in the disease-free survival (DFS) between patients with T2N0 (stage II) OSCC treated with S-1 adjuvant therapy (S-1) and those treated with SA.	('S-1', 'Gene', (205, 208))	('patients', 'Species', '9606', (135, 143))	('S-1', 'Gene', (36, 39))	('T2N0', 'Var', (149, 153))	('S-1', 'Gene', '5707', (205, 208))	('S-1', 'Gene', '5707', (183, 186))	('S-1', 'Gene', '5707', (36, 39))	('OSCC', 'Disease', (165, 169))	('SA', 'Chemical', '-', (233, 235))	('S-1', 'Gene', (183, 186))
327397	32294127	Reviewer #3: 1.The eligibility criteria in the study were patients with cT2N0 oral cancer, but cervical lymph node metastases were found in both the S-1 and the two groups of patients undergoing surgery alone (Table 1).	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('metastases', 'Disease', (115, 125))	('S-1', 'Gene', '5707', (149, 152))	('metastases', 'Disease', 'MESH:D009362', (115, 125))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('cT2N0', 'Var', (72, 77))	('cervical lymph node metastases', 'Phenotype', 'HP:0025289', (95, 125))	('patients', 'Species', '9606', (175, 183))	('patients', 'Species', '9606', (58, 66))	('S-1', 'Gene', (149, 152))	('cancer', 'Disease', (83, 89))
327427	32294127	Comment #1: The eligibility criteria in the study were patients with cT2N0 oral cancer, but cervical lymph node metastases were found in both the S-1 and the two groups of patients undergoing surgery alone (Table 1).	('S-1', 'Gene', (146, 149))	('cT2N0', 'Var', (69, 74))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('S-1', 'Gene', '5707', (146, 149))	('metastases', 'Disease', (112, 122))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('metastases', 'Disease', 'MESH:D009362', (112, 122))	('patients', 'Species', '9606', (172, 180))	('cervical lymph node metastases', 'Phenotype', 'HP:0025289', (92, 122))	('patients', 'Species', '9606', (55, 63))	('cancer', 'Disease', (80, 86))
327499	29868604	Any CNB entails the risk of tumor seeding along the needle tract and the risk seems to depend on the needle size.	('CNB', 'Var', (4, 7))	('tumor', 'Disease', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('tumor', 'Disease', 'MESH:D009369', (28, 33))
327554	29868604	It is presumed that dissecting along the tumor increases the risk of cutting of or leaving microscopic parts of the tumor in situ.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Disease', (41, 46))	('dissecting', 'Var', (20, 30))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('tumor', 'Disease', (116, 121))
327633	29868604	Similarly, a multivariate analysis based on the Surveillance, Epidemiology, and End Results (SEER) data found in 2170 parotid malignancies a survival benefit associated with adjuvant RT (HR, 1.20; 95% CI, 0.98-1.47; P = 0.08).	('parotid malignancies', 'Disease', 'MESH:D010309', (118, 138))	('parotid malignancies', 'Disease', (118, 138))	('survival', 'MPA', (141, 149))	('benefit', 'PosReg', (150, 157))	('adjuvant', 'Var', (174, 182))
327635	29868604	In this unique entity, adjuvant RT was associated with improved local control and survival rates in several large retrospective cohorts , e.g., in a cohort of 1784 patients registered in the NCDB and in a recent Japanese retrospective multicenter analysis including 103 patients with adenoid-cystic carcinoma of the head and neck.	('carcinoma', 'Phenotype', 'HP:0030731', (299, 308))	('improved', 'PosReg', (55, 63))	('survival', 'CPA', (82, 90))	('patients', 'Species', '9606', (270, 278))	('local control', 'CPA', (64, 77))	('adenoid-cystic carcinoma', 'Disease', (284, 308))	('adenoid-cystic carcinoma', 'Disease', 'MESH:D003528', (284, 308))	('patients', 'Species', '9606', (164, 172))	('adjuvant', 'Var', (23, 31))
327738	28386192	Tumor marker is chemical substance reflecting tumor's existence and commonly used markers are carcino-embryonic antigen (CEA), carbohydrate antigen (CA) (like CA125, CA199 and CA153) and neuron-specific enolase (NSE).	('tumor', 'Disease', 'MESH:D009369', (46, 51))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('CA125', 'Gene', (159, 164))	('CEA', 'Gene', (121, 124))	('NSE', 'Gene', '2026', (212, 215))	('neuron-specific enolase', 'Gene', '2026', (187, 210))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('CEA', 'Gene', '5670', (121, 124))	('tumor', 'Disease', (46, 51))	('CA153', 'Gene', '4582', (176, 181))	('neuron-specific enolase', 'Gene', (187, 210))	('NSE', 'Gene', (212, 215))	('CA125', 'Gene', '94025', (159, 164))	('CA199', 'Var', (166, 171))	('CA153', 'Gene', (176, 181))
327740	28386192	Our preliminary study analyzed the structural and functional changes of erbB4 before and after mutation, and based on the original signal pathway of erbB4, tumor marker genes were added to the regulatory network in this study to uncover the internal molecular regulatory mechanism for prediction of tumor occurrence and development, which lays foundation for in-depth cancer suppressor research in the future.	('cancer', 'Disease', (368, 374))	('tumor', 'Disease', (299, 304))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('cancer', 'Phenotype', 'HP:0002664', (368, 374))	('erbB4', 'Gene', '2066', (72, 77))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('erbB4', 'Gene', (72, 77))	('erbB4', 'Gene', '2066', (149, 154))	('tumor', 'Disease', (156, 161))	('tumor', 'Disease', 'MESH:D009369', (299, 304))	('cancer', 'Disease', 'MESH:D009369', (368, 374))	('erbB4', 'Gene', (149, 154))	('tumor', 'Phenotype', 'HP:0002664', (299, 304))	('mutation', 'Var', (95, 103))
327745	28386192	The detection of every index was in accordance with instruction on kit; CEA and CYFRA21-1 were detected by ELISA method; CA125, CA199, CA724, SCC-Ag and CA153 were detected by Roche E601 automatic immuno-analyzer and NSE was detected by radio immunoassay.	('CA125', 'Gene', (121, 126))	('CA199', 'Var', (128, 133))	('CA153', 'Gene', (153, 158))	('CEA', 'Gene', (72, 75))	('SCC', 'Gene', (142, 145))	('NSE', 'Gene', '2026', (217, 220))	('CA724', 'Var', (135, 140))	('CEA', 'Gene', '5670', (72, 75))	('CA125', 'Gene', '94025', (121, 126))	('SCC', 'Gene', '6317', (142, 145))	('NSE', 'Gene', (217, 220))	('CA153', 'Gene', '4582', (153, 158))	('CA724', 'Chemical', '-', (135, 140))
327752	28386192	Measurement results of eight tumor markers for totally 260 patients in malignant SPN group and benign SPN group are listed in Table 1 and the eight tumor markers were CEA, NSE, CYFRA21-1, CA125, CA199, CA724, SCC-Ag and CA153.	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('SCC', 'Gene', '6317', (209, 212))	('CA199', 'Var', (195, 200))	('CA125', 'Gene', (188, 193))	('CA153', 'Gene', (220, 225))	('SCC', 'Gene', (209, 212))	('NSE', 'Gene', '2026', (172, 175))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('NSE', 'Gene', (172, 175))	('patients', 'Species', '9606', (59, 67))	('CA724', 'Chemical', '-', (202, 207))	('CA724', 'Var', (202, 207))	('CA125', 'Gene', '94025', (188, 193))	('CA153', 'Gene', '4582', (220, 225))	('CEA', 'Gene', (167, 170))	('CEA', 'Gene', '5670', (167, 170))	('tumor', 'Disease', (148, 153))	('tumor', 'Disease', (29, 34))	('CYFRA21-1', 'Var', (177, 186))	('tumor', 'Disease', 'MESH:D009369', (148, 153))
327754	28386192	According to clinical test results, CEA, NSE, CYFRA21-1, CA125, CA199, CA724, SCC-Ag and CA153 were regarded as variables included in discriminant analysis model.	('NSE', 'Gene', '2026', (41, 44))	('CA153', 'Gene', '4582', (89, 94))	('CEA', 'Gene', (36, 39))	('SCC', 'Gene', '6317', (78, 81))	('CA724', 'Chemical', '-', (71, 76))	('CA125', 'Gene', (57, 62))	('CA125', 'Gene', '94025', (57, 62))	('NSE', 'Gene', (41, 44))	('CA199', 'Var', (64, 69))	('CA153', 'Gene', (89, 94))	('CEA', 'Gene', '5670', (36, 39))	('CA724', 'Var', (71, 76))	('CYFRA21-1', 'Var', (46, 55))	('SCC', 'Gene', (78, 81))
327755	28386192	Wilks' lambda method was employed to conduct a stepwise discriminative analysis for these variables with F value being discriminative statistics standard and totally four predictors with statistical significance were screened out which were CYFRA21-1, CA125, SCC-Ag and CA153 (see Table 2, Table 3).	('CA153', 'Gene', '4582', (270, 275))	('SCC', 'Gene', '6317', (259, 262))	('CYFRA21-1', 'Var', (241, 250))	('CA153', 'Gene', (270, 275))	('CA125', 'Gene', (252, 257))	('SCC', 'Gene', (259, 262))	('CA125', 'Gene', '94025', (252, 257))
327757	28386192	CYFRA21-1, a soluble fragment of cytokeratin 19 which is the expression product of KRT19 gene, is mainly applied for detection of tumor marker of non-small-cell lung cancer.	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (150, 172))	('cytokeratin 19', 'Gene', '3880', (33, 47))	('cytokeratin 19', 'Gene', (33, 47))	('KRT19', 'Gene', (83, 88))	('non-small-cell lung cancer', 'Disease', (146, 172))	('KRT19', 'Gene', '3880', (83, 88))	('non-small-cell lung cancer', 'Disease', 'MESH:D002289', (146, 172))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('lung cancer', 'Phenotype', 'HP:0100526', (161, 172))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (146, 172))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('tumor', 'Disease', (130, 135))	('CYFRA21-1', 'Var', (0, 9))
327777	28386192	Serological tumor marker is significant for determination of begin and malignant SPN, and the commonly used markers are CYFRA21-1, CA125, CA153 and SCC-Ag.	('CA125', 'Gene', (131, 136))	('CA153', 'Gene', '4582', (138, 143))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('SCC', 'Gene', (148, 151))	('CA125', 'Gene', '94025', (131, 136))	('tumor', 'Disease', (12, 17))	('CA153', 'Gene', (138, 143))	('SCC', 'Gene', '6317', (148, 151))	('CYFRA21-1', 'Var', (120, 129))
327784	28386192	In this study four serological tumor markers which are significant for malignant and benign SPN detection were screened out through clinical cases, and the four markers are CYFRA21-1, CA125, CA153 and SCC-Ag.	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('CA125', 'Gene', (184, 189))	('CA153', 'Gene', (191, 196))	('SCC', 'Gene', (201, 204))	('tumor', 'Disease', (31, 36))	('SCC', 'Gene', '6317', (201, 204))	('CA125', 'Gene', '94025', (184, 189))	('CYFRA21-1', 'Var', (173, 182))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('CA153', 'Gene', '4582', (191, 196))
327786	28386192	Our previous research mainly studied the structures and function of erbB4 before and after its mutation and found that erbB4 expressed high in non-small-cell lung cancer and that it's closely correlated to the metastasis of cancer cells and to patients' prognosis, which indicates that erbB4 is a possible candidate of targeted molecular therapy.	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (143, 169))	('erbB4', 'Gene', (68, 73))	('patients', 'Species', '9606', (244, 252))	('cancer', 'Disease', (224, 230))	('cancer', 'Disease', 'MESH:D009369', (163, 169))	('erbB4', 'Gene', '2066', (68, 73))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('high', 'Reg', (135, 139))	('erbB4', 'Gene', (286, 291))	('correlated', 'Reg', (192, 202))	('mutation', 'Var', (95, 103))	('non-small-cell lung cancer', 'Disease', (143, 169))	('non-small-cell lung cancer', 'Disease', 'MESH:D002289', (143, 169))	('lung cancer', 'Phenotype', 'HP:0100526', (158, 169))	('erbB4', 'Gene', (119, 124))	('erbB4', 'Gene', '2066', (286, 291))	('cancer', 'Disease', 'MESH:D009369', (224, 230))	('cancer', 'Disease', (163, 169))	('erbB4', 'Gene', '2066', (119, 124))	('metastasis', 'CPA', (210, 220))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (147, 169))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))
327795	28386192	Aberrant activation of Wnt signaling pathway plays a crucial role in cell canceration, tumor growth and tumor invasion, thus any change of Wnt gene itself or its any member may induce tumor.	('activation', 'PosReg', (9, 19))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('Aberrant', 'Var', (0, 8))	('change', 'Var', (129, 135))	('Wnt gene', 'Gene', (139, 147))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('tumor', 'Disease', (104, 109))	('tumor', 'Disease', (87, 92))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('cancer', 'Disease', (74, 80))	('tumor', 'Disease', (184, 189))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('induce', 'Reg', (177, 183))	('Wnt signaling pathway', 'Pathway', (23, 44))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
327802	28386192	Mutant p53 gene can cause its original function loss which means it cannot regulate cell proliferation, growth or DNA repair thus it becomes an oncogene.	('Mutant', 'Var', (0, 6))	('p53', 'Gene', '7157', (7, 10))	('p53', 'Gene', (7, 10))	('function', 'MPA', (39, 47))
327818	26818118	We also identified MIs in cancer cell lines from Cancer Cell Line Encyclopedia (CCLE).	('n', 'Chemical', 'MESH:D009584', (67, 68))	('Cancer Cell Line Encyclopedia', 'Disease', 'MESH:C538614', (49, 78))	('n', 'Chemical', 'MESH:D009584', (40, 41))	('MIs', 'Var', (19, 22))	('cancer', 'Disease', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('n', 'Chemical', 'MESH:D009584', (63, 64))	('n', 'Chemical', 'MESH:D009584', (24, 25))	('n', 'Chemical', 'MESH:D009584', (28, 29))	('Cancer Cell Line Encyclopedia', 'Disease', (49, 78))	('CCLE', 'Chemical', '-', (80, 84))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('n', 'Chemical', 'MESH:D009584', (11, 12))	('n', 'Chemical', 'MESH:D009584', (51, 52))	('Cancer', 'Phenotype', 'HP:0002664', (49, 55))
327822	26818118	Genomic structural variations (SVs), including insertion, deletion, rearrangement, and duplication are important sources of human genetic diversity and may be responsible for human diseases.	('n', 'Chemical', 'MESH:D009584', (132, 133))	('n', 'Chemical', 'MESH:D009584', (74, 75))	('n', 'Chemical', 'MESH:D009584', (44, 45))	('n', 'Chemical', 'MESH:D009584', (27, 28))	('n', 'Chemical', 'MESH:D009584', (97, 98))	('human', 'Species', '9606', (175, 180))	('n', 'Chemical', 'MESH:D009584', (2, 3))	('insertion', 'Var', (47, 56))	('rearrangement', 'Var', (68, 81))	('n', 'Chemical', 'MESH:D009584', (48, 49))	('n', 'Chemical', 'MESH:D009584', (79, 80))	('duplication', 'Var', (87, 98))	('n', 'Chemical', 'MESH:D009584', (65, 66))	('n', 'Chemical', 'MESH:D009584', (128, 129))	('n', 'Chemical', 'MESH:D009584', (38, 39))	('n', 'Chemical', 'MESH:D009584', (149, 150))	('n', 'Chemical', 'MESH:D009584', (110, 111))	('n', 'Chemical', 'MESH:D009584', (55, 56))	('n', 'Chemical', 'MESH:D009584', (84, 85))	('n', 'Chemical', 'MESH:D009584', (179, 180))	('SV', 'Disease', 'None', (31, 33))	('n', 'Chemical', 'MESH:D009584', (164, 165))	('human', 'Species', '9606', (124, 129))	('deletion', 'Var', (58, 66))
327838	26818118	For example, the sample NA12878, provided by 1KGP from two paired-end libraries with 15X coverage, has been frequently selected by variant detection tools for performance comparisons (642 deletions, 271 duplications and 30 insertions).	('n', 'Chemical', 'MESH:D009584', (67, 68))	('n', 'Chemical', 'MESH:D009584', (136, 137))	('n', 'Chemical', 'MESH:D009584', (167, 168))	('n', 'Chemical', 'MESH:D009584', (106, 107))	('insertions', 'Var', (223, 233))	('n', 'Chemical', 'MESH:D009584', (213, 214))	('deletions', 'Var', (188, 197))	('n', 'Chemical', 'MESH:D009584', (217, 218))	('n', 'Chemical', 'MESH:D009584', (195, 196))	('duplications', 'Var', (203, 215))	('n', 'Chemical', 'MESH:D009584', (224, 225))	('n', 'Chemical', 'MESH:D009584', (147, 148))	('NA12878', 'Var', (24, 31))	('n', 'Chemical', 'MESH:D009584', (180, 181))	('n', 'Chemical', 'MESH:D009584', (114, 115))	('n', 'Chemical', 'MESH:D009584', (231, 232))
327842	26818118	Our algorithm, named MID (Micro-Inversion Detector), specifically detects MIs shorter than the read length.	('n', 'Chemical', 'MESH:D009584', (15, 16))	('n', 'Chemical', 'MESH:D009584', (33, 34))	('n', 'Chemical', 'MESH:D009584', (40, 41))	('n', 'Chemical', 'MESH:D009584', (102, 103))	('n', 'Chemical', 'MESH:D009584', (89, 90))	('MID', 'Disease', 'None', (21, 24))	('MID', 'Disease', (21, 24))	('detects', 'Reg', (66, 73))	('MIs shorter', 'Var', (74, 85))
327846	26818118	The simulation results showed that MID can detect MIs efficiently and reliably using unmapped NGS short reads with low false positives.	('n', 'Chemical', 'MESH:D009584', (67, 68))	('n', 'Chemical', 'MESH:D009584', (82, 83))	('MIs', 'Var', (50, 53))	('n', 'Chemical', 'MESH:D009584', (61, 62))	('n', 'Chemical', 'MESH:D009584', (13, 14))	('GS', 'Disease', 'MESH:D011125', (95, 97))	('MID', 'Disease', (35, 38))	('n', 'Chemical', 'MESH:D009584', (41, 42))	('n', 'Chemical', 'MESH:D009584', (86, 87))	('MID', 'Disease', 'None', (35, 38))
327847	26818118	By applying MID to 1KGP data, we identified 721 MIs, 349 of which are intergenic, 342 MIs are intronic, and 30 MIs are exonic.	('MID', 'Disease', (12, 15))	('n', 'Chemical', 'MESH:D009584', (36, 37))	('n', 'Chemical', 'MESH:D009584', (71, 72))	('n', 'Chemical', 'MESH:D009584', (105, 106))	('n', 'Chemical', 'MESH:D009584', (77, 78))	('n', 'Chemical', 'MESH:D009584', (122, 123))	('n', 'Chemical', 'MESH:D009584', (95, 96))	('MID', 'Disease', 'None', (12, 15))	('n', 'Chemical', 'MESH:D009584', (99, 100))	('MIs', 'Var', (86, 89))	('MIs', 'Var', (48, 51))	('n', 'Chemical', 'MESH:D009584', (9, 10))
327856	26818118	For Dataset 2, we simulated 1,000 MIs surrounded by 4,000 other structural variants (including SNVs, deletions, insertions, and duplications) following a normal distribution for MI size randomly on chr10, with a size range of 15-40 bp.	('insertions', 'Var', (112, 122))	('n', 'Chemical', 'MESH:D009584', (108, 109))	('n', 'Chemical', 'MESH:D009584', (92, 93))	('duplications', 'Var', (128, 140))	('deletions', 'Var', (101, 110))	('n', 'Chemical', 'MESH:D009584', (120, 121))	('n', 'Chemical', 'MESH:D009584', (154, 155))	('n', 'Chemical', 'MESH:D009584', (44, 45))	('n', 'Chemical', 'MESH:D009584', (113, 114))	('n', 'Chemical', 'MESH:D009584', (188, 189))	('n', 'Chemical', 'MESH:D009584', (219, 220))	('n', 'Chemical', 'MESH:D009584', (172, 173))	('n', 'Chemical', 'MESH:D009584', (196, 197))	('n', 'Chemical', 'MESH:D009584', (138, 139))	('n', 'Chemical', 'MESH:D009584', (86, 87))	('n', 'Chemical', 'MESH:D009584', (149, 150))	('n', 'Chemical', 'MESH:D009584', (80, 81))	('n', 'Chemical', 'MESH:D009584', (125, 126))
327943	26818118	What makes MID different from other SV detecting tools is that our approach is sensitive to very small size MIs, and capable of detecting MIs with multiple breakpoints in one read due to flexible segment mapping process, as well as scoring system in distinguishing MIs from palindromic sequence and other incorrect matches.	('MID', 'Disease', (11, 14))	('n', 'Chemical', 'MESH:D009584', (209, 210))	('n', 'Chemical', 'MESH:D009584', (248, 249))	('n', 'Chemical', 'MESH:D009584', (296, 297))	('n', 'Chemical', 'MESH:D009584', (114, 115))	('n', 'Chemical', 'MESH:D009584', (201, 202))	('SV', 'Disease', 'None', (36, 38))	('n', 'Chemical', 'MESH:D009584', (169, 170))	('n', 'Chemical', 'MESH:D009584', (81, 82))	('n', 'Chemical', 'MESH:D009584', (262, 263))	('n', 'Chemical', 'MESH:D009584', (255, 256))	('n', 'Chemical', 'MESH:D009584', (278, 279))	('n', 'Chemical', 'MESH:D009584', (135, 136))	('palindromic sequence', 'Var', (274, 294))	('MID', 'Disease', 'None', (11, 14))	('n', 'Chemical', 'MESH:D009584', (237, 238))	('n', 'Chemical', 'MESH:D009584', (22, 23))	('n', 'Chemical', 'MESH:D009584', (46, 47))	('n', 'Chemical', 'MESH:D009584', (291, 292))	('n', 'Chemical', 'MESH:D009584', (172, 173))	('n', 'Chemical', 'MESH:D009584', (164, 165))	('n', 'Chemical', 'MESH:D009584', (306, 307))	('MIs', 'Var', (265, 268))	('MIs', 'Var', (138, 141))
327949	26818118	In conclusion, MID is suitable for large-scale short reads produced by present high-throughput sequencing technologies (e.g., Illumina), especially for low coverage data, and MID might have positive impact on identifying key genetic variants in human diseases with the further development of sequencing technologies.	('n', 'Chemical', 'MESH:D009584', (249, 250))	('n', 'Chemical', 'MESH:D009584', (297, 298))	('n', 'Chemical', 'MESH:D009584', (132, 133))	('n', 'Chemical', 'MESH:D009584', (12, 13))	('n', 'Chemical', 'MESH:D009584', (218, 219))	('n', 'Chemical', 'MESH:D009584', (5, 6))	('n', 'Chemical', 'MESH:D009584', (243, 244))	('MID', 'Disease', 'None', (175, 178))	('n', 'Chemical', 'MESH:D009584', (1, 2))	('MID', 'Disease', 'None', (15, 18))	('variants', 'Var', (233, 241))	('impact', 'Reg', (199, 205))	('human', 'Species', '9606', (245, 250))	('n', 'Chemical', 'MESH:D009584', (286, 287))	('n', 'Chemical', 'MESH:D009584', (103, 104))	('n', 'Chemical', 'MESH:D009584', (207, 208))	('n', 'Chemical', 'MESH:D009584', (238, 239))	('MID', 'Disease', (175, 178))	('n', 'Chemical', 'MESH:D009584', (300, 301))	('n', 'Chemical', 'MESH:D009584', (110, 111))	('MID', 'Disease', (15, 18))	('n', 'Chemical', 'MESH:D009584', (172, 173))	('n', 'Chemical', 'MESH:D009584', (212, 213))	('n', 'Chemical', 'MESH:D009584', (227, 228))	('n', 'Chemical', 'MESH:D009584', (100, 101))	('n', 'Chemical', 'MESH:D009584', (76, 77))	('n', 'Chemical', 'MESH:D009584', (307, 308))
327961	26818118	Owing to the possible combination of variants including unbalanced variants such as small indels, insertions, deletions and duplications, we set the range of distance between two anchors to be in a range from 15 bp to 65 bp, which is denoted as the insert size for the paired-end read in Bowtie.	('n', 'Chemical', 'MESH:D009584', (194, 195))	('n', 'Chemical', 'MESH:D009584', (250, 251))	('n', 'Chemical', 'MESH:D009584', (91, 92))	('n', 'Chemical', 'MESH:D009584', (106, 107))	('n', 'Chemical', 'MESH:D009584', (99, 100))	('n', 'Chemical', 'MESH:D009584', (3, 4))	('n', 'Chemical', 'MESH:D009584', (42, 43))	('n', 'Chemical', 'MESH:D009584', (121, 122))	('n', 'Chemical', 'MESH:D009584', (27, 28))	('n', 'Chemical', 'MESH:D009584', (200, 201))	('insertions', 'Var', (98, 108))	('n', 'Chemical', 'MESH:D009584', (57, 58))	('n', 'Chemical', 'MESH:D009584', (286, 287))	('n', 'Chemical', 'MESH:D009584', (72, 73))	('n', 'Chemical', 'MESH:D009584', (32, 33))	('n', 'Chemical', 'MESH:D009584', (277, 278))	('n', 'Chemical', 'MESH:D009584', (47, 48))	('n', 'Chemical', 'MESH:D009584', (134, 135))	('n', 'Chemical', 'MESH:D009584', (62, 63))	('n', 'Chemical', 'MESH:D009584', (151, 152))	('n', 'Chemical', 'MESH:D009584', (117, 118))	('n', 'Chemical', 'MESH:D009584', (180, 181))	('n', 'Chemical', 'MESH:D009584', (173, 174))	('n', 'Chemical', 'MESH:D009584', (236, 237))	('n', 'Chemical', 'MESH:D009584', (53, 54))	('variants', 'Var', (37, 45))	('n', 'Chemical', 'MESH:D009584', (163, 164))	('deletions', 'Var', (110, 119))
327984	26818118	While we set the threshold of i (2 as default) mismatches in one seed, if the SNVs occur at the edges of MSPs and a k-mer covering the SNVs reach the threshold of i mismatches, then this k-mer fails to be aligned.	('MSPs', 'Gene', (105, 109))	('mismatches', 'Var', (47, 57))	('n', 'Chemical', 'MESH:D009584', (209, 210))	('n', 'Chemical', 'MESH:D009584', (59, 60))	('n', 'Chemical', 'MESH:D009584', (62, 63))	('n', 'Chemical', 'MESH:D009584', (111, 112))	('MSPs', 'Gene', '84000', (105, 109))	('n', 'Chemical', 'MESH:D009584', (180, 181))	('n', 'Chemical', 'MESH:D009584', (128, 129))
328011	26818118	MS[i]: The number of mismatches in MSP[i].	('mismatches', 'Var', (21, 31))	('MSP[i]', 'Gene', (35, 41))	('n', 'Chemical', 'MESH:D009584', (33, 34))	('n', 'Chemical', 'MESH:D009584', (11, 12))
328019	26818118	4c, the path starting with MSP[1] and ending with MSP[4] denotes a short read to be detected, and the path in red is the max-score path.	('n', 'Chemical', 'MESH:D009584', (19, 20))	('MSP[', 'Var', (27, 31))	('n', 'Chemical', 'MESH:D009584', (39, 40))	('n', 'Chemical', 'MESH:D009584', (95, 96))	('n', 'Chemical', 'MESH:D009584', (42, 43))	('n', 'Chemical', 'MESH:D009584', (59, 60))	('MSP[', 'Var', (50, 54))	('n', 'Chemical', 'MESH:D009584', (35, 36))	('n', 'Chemical', 'MESH:D009584', (108, 109))
328025	26818118	In summary, MID is generated based on flexible segment mapping, including non-overlapping MSPs identification, which is capable of identifying very small size MIs, regardless of multiple breakpoints in one read, and scoring system which can distinguish false positives caused by palindromic sequence and other incorrect matches.	('MID', 'Disease', (12, 15))	('n', 'Chemical', 'MESH:D009584', (74, 75))	('palindromic sequence', 'Var', (279, 299))	('n', 'Chemical', 'MESH:D009584', (36, 37))	('n', 'Chemical', 'MESH:D009584', (98, 99))	('n', 'Chemical', 'MESH:D009584', (60, 61))	('n', 'Chemical', 'MESH:D009584', (296, 297))	('n', 'Chemical', 'MESH:D009584', (200, 201))	('n', 'Chemical', 'MESH:D009584', (1, 2))	('n', 'Chemical', 'MESH:D009584', (311, 312))	('MSPs', 'Gene', '84000', (90, 94))	('n', 'Chemical', 'MESH:D009584', (65, 66))	('n', 'Chemical', 'MESH:D009584', (87, 88))	('MID', 'Disease', 'None', (12, 15))	('n', 'Chemical', 'MESH:D009584', (221, 222))	('n', 'Chemical', 'MESH:D009584', (301, 302))	('n', 'Chemical', 'MESH:D009584', (246, 247))	('n', 'Chemical', 'MESH:D009584', (71, 72))	('n', 'Chemical', 'MESH:D009584', (239, 240))	('n', 'Chemical', 'MESH:D009584', (134, 135))	('n', 'Chemical', 'MESH:D009584', (213, 214))	('n', 'Chemical', 'MESH:D009584', (283, 284))	('MSPs', 'Gene', (90, 94))	('n', 'Chemical', 'MESH:D009584', (140, 141))	('n', 'Chemical', 'MESH:D009584', (203, 204))	('n', 'Chemical', 'MESH:D009584', (195, 196))	('n', 'Chemical', 'MESH:D009584', (21, 22))	('n', 'Chemical', 'MESH:D009584', (52, 53))	('n', 'Chemical', 'MESH:D009584', (76, 77))	('n', 'Chemical', 'MESH:D009584', (108, 109))
328027	26818118	1KGP 1000 Genomes project CCLE Cancer cell line encyclopedia CDS Coding sequence MI Micro-inversion MID Micro-inversion detector MS Matching segment MSP Matching segment pair NGS Next-generation sequencing PPV Positive predictive value SD Standard deviation SN Sensitivity SNV Single nucleotide variation SV Structural variation TFBS Transcription factor binding site UTR Untranslated region	('GS', 'Disease', 'MESH:D011125', (176, 178))	('n', 'Chemical', 'MESH:D009584', (242, 243))	('n', 'Chemical', 'MESH:D009584', (98, 99))	('n', 'Chemical', 'MESH:D009584', (12, 13))	('n', 'Chemical', 'MESH:D009584', (91, 92))	('n', 'Chemical', 'MESH:D009584', (360, 361))	('TFBS Transcription', 'Gene', (329, 347))	('n', 'Chemical', 'MESH:D009584', (377, 378))	('CDS', 'Gene', '1040', (61, 64))	('Cancer', 'Disease', 'MESH:D009369', (31, 37))	('n', 'Chemical', 'MESH:D009584', (327, 328))	('SV', 'Disease', 'None', (305, 307))	('n', 'Chemical', 'MESH:D009584', (200, 201))	('n', 'Chemical', 'MESH:D009584', (193, 194))	('n', 'Chemical', 'MESH:D009584', (263, 264))	('n', 'Chemical', 'MESH:D009584', (33, 34))	('CCLE', 'Chemical', '-', (26, 30))	('n', 'Chemical', 'MESH:D009584', (167, 168))	('n', 'Chemical', 'MESH:D009584', (256, 257))	('Single nucleotide variation', 'Var', (277, 304))	('MID', 'Disease', 'None', (100, 103))	('n', 'Chemical', 'MESH:D009584', (111, 112))	('n', 'Chemical', 'MESH:D009584', (279, 280))	('n', 'Chemical', 'MESH:D009584', (49, 50))	('n', 'Chemical', 'MESH:D009584', (303, 304))	('CDS', 'Gene', (61, 64))	('n', 'Chemical', 'MESH:D009584', (159, 160))	('n', 'Chemical', 'MESH:D009584', (390, 391))	('n', 'Chemical', 'MESH:D009584', (373, 374))	('Cancer', 'Phenotype', 'HP:0002664', (31, 37))	('n', 'Chemical', 'MESH:D009584', (357, 358))	('TFBS', 'Chemical', '-', (329, 333))	('MID', 'Disease', (100, 103))	('n', 'Chemical', 'MESH:D009584', (118, 119))	('n', 'Chemical', 'MESH:D009584', (346, 347))	('n', 'Chemical', 'MESH:D009584', (77, 78))	('n', 'Chemical', 'MESH:D009584', (284, 285))	('n', 'Chemical', 'MESH:D009584', (186, 187))	('n', 'Chemical', 'MESH:D009584', (203, 204))	('Cancer', 'Disease', (31, 37))	('n', 'Chemical', 'MESH:D009584', (138, 139))	('n', 'Chemical', 'MESH:D009584', (337, 338))	('n', 'Chemical', 'MESH:D009584', (45, 46))	('n', 'Chemical', 'MESH:D009584', (146, 147))	('n', 'Chemical', 'MESH:D009584', (69, 70))
328031	25745359	We then study whether knockdown of S100A7 in lung squamous cell carcinoma cells would reduce cell proliferation and NF-kappaB activity in vitro and attenuate tumor growth in vivo.	('tumor', 'Disease', (158, 163))	('S100A7', 'Gene', (35, 41))	('NF-kappaB', 'Gene', '4790', (116, 125))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (45, 73))	('S100A7', 'Gene', '6278', (35, 41))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('NF-kappaB', 'Gene', (116, 125))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (50, 73))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (45, 73))	('cell proliferation', 'CPA', (93, 111))	('attenuate', 'NegReg', (148, 157))	('knockdown', 'Var', (22, 31))	('lung squamous cell carcinoma', 'Disease', (45, 73))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))	('reduce', 'NegReg', (86, 92))	('activity', 'MPA', (126, 134))
328034	25745359	Quantitative reverse transcriptase-polymerase chain reaction and immunoblotting confirmed knockdown of S100A7 messenger RNA and protein, respectively.	('knockdown', 'Var', (90, 99))	('S100A7', 'Gene', '6278', (103, 109))	('S100A7', 'Gene', (103, 109))
328041	25745359	In vitro data showed that inhibition of S100A7 decreased proliferation of NCI-H520 cells.	('inhibition', 'Var', (26, 36))	('S100A7', 'Gene', '6278', (40, 46))	('S100A7', 'Gene', (40, 46))	('NCI-H520', 'CellLine', 'CVCL:1566', (74, 82))	('proliferation', 'CPA', (57, 70))	('decreased', 'NegReg', (47, 56))
328042	25745359	S100A7 knockdown reduced NF-kappaB phosphorylation and tumor growth in vivo and vivo.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('S100A7', 'Gene', '6278', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('NF-kappaB', 'Gene', '4790', (25, 34))	('tumor', 'Disease', (55, 60))	('phosphorylation', 'MPA', (35, 50))	('NF-kappaB', 'Gene', (25, 34))	('knockdown', 'Var', (7, 16))	('reduced', 'NegReg', (17, 24))	('S100A7', 'Gene', (0, 6))
328057	25745359	In cancer cells, breakdown of NF-kappaB feedback loops or constitutive activation of NF-kappaB leads to increased proliferation, angiogenesis, and metastasis.	('NF-kappaB', 'Gene', '4790', (85, 94))	('NF-kappaB', 'Gene', '4790', (30, 39))	('increased', 'PosReg', (104, 113))	('activation', 'PosReg', (71, 81))	('angiogenesis', 'CPA', (129, 141))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('NF-kappaB', 'Gene', (85, 94))	('NF-kappaB', 'Gene', (30, 39))	('cancer', 'Disease', (3, 9))	('proliferation', 'CPA', (114, 127))	('breakdown', 'Var', (17, 26))	('metastasis', 'CPA', (147, 157))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
328061	25745359	We hypothesize that the knockdown of S100A7 in SCC cells will reduce cell proliferation and that this effect will correlate with decreased NF-kappaB activity.	('NF-kappaB', 'Gene', (139, 148))	('SCC', 'Phenotype', 'HP:0002860', (47, 50))	('decreased', 'NegReg', (129, 138))	('SCC', 'Gene', '6317', (47, 50))	('S100A7', 'Gene', '6278', (37, 43))	('S100A7', 'Gene', (37, 43))	('reduce', 'NegReg', (62, 68))	('activity', 'MPA', (149, 157))	('cell proliferation', 'CPA', (69, 87))	('NF-kappaB', 'Gene', '4790', (139, 148))	('knockdown', 'Var', (24, 33))	('SCC', 'Gene', (47, 50))
328062	25745359	Furthermore, we propose S100A7 knockdown in SCC cells will attenuate tumor growth in vivo.	('SCC', 'Gene', '6317', (44, 47))	('SCC', 'Phenotype', 'HP:0002860', (44, 47))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('attenuate', 'NegReg', (59, 68))	('tumor', 'Disease', (69, 74))	('SCC', 'Gene', (44, 47))	('S100A7', 'Gene', '6278', (24, 30))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('S100A7', 'Gene', (24, 30))	('knockdown', 'Var', (31, 40))
328124	25745359	The results also indicated that male sex, older age and positive S100A7 expression were associated with worse prognosis (Table 2).	('expression', 'MPA', (72, 82))	('positive', 'Var', (56, 64))	('S100A7', 'Gene', '6278', (65, 71))	('S100A7', 'Gene', (65, 71))
328133	25745359	All subsequent experiments used NCI-H520 cells transduced with sequence S4 shRNA targeting S100A7, or nontargeted shRNA, compared.	('S100A7', 'Gene', '6278', (91, 97))	('sequence S4', 'Var', (63, 74))	('NCI-H520', 'CellLine', 'CVCL:1566', (32, 40))	('S100A7', 'Gene', (91, 97))
328137	25745359	Results showed a stable reduction by approximately 48% in the growth rate of NCI-H520 knockdown cells compared with both control groups (Figure 4B).	('knockdown', 'Var', (86, 95))	('NCI-H520', 'Gene', (77, 85))	('growth rate', 'CPA', (62, 73))	('reduction', 'NegReg', (24, 33))	('NCI-H520', 'CellLine', 'CVCL:1566', (77, 85))
328143	25745359	Analysis of S100A7 expression in xenograft tumors confirmed persistent decrease in S100A7 in knockdown tumors compared with wild-type tumors (data not shown).	('knockdown', 'Var', (93, 102))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('decrease', 'NegReg', (71, 79))	('S100A7', 'Gene', (12, 18))	('tumors', 'Disease', (103, 109))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('type tumors', 'Disease', 'MESH:D009369', (129, 140))	('S100A7', 'Gene', (83, 89))	('tumors', 'Disease', (134, 140))	('tumors', 'Disease', 'MESH:D009369', (103, 109))	('S100A7', 'Gene', '6278', (12, 18))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('xenograft tumors', 'Disease', (33, 49))	('tumors', 'Disease', 'MESH:D009369', (134, 140))	('S100A7', 'Gene', '6278', (83, 89))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('xenograft tumors', 'Disease', 'MESH:D009369', (33, 49))	('tumors', 'Disease', (43, 49))	('type tumors', 'Disease', (129, 140))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('tumors', 'Disease', 'MESH:D009369', (43, 49))
328152	25745359	In our study, we found overexpression of S100A7 in SCC tissues was observed when comparing SCC tissues with adjacent normal tissues, and this aberrant accumulation of S100A7 in SCC cells was associated with a shorter survival time and identified as a novel risk factor for poor prognosis.	('S100A7', 'Gene', '6278', (41, 47))	('SCC', 'Gene', (51, 54))	('accumulation', 'PosReg', (151, 163))	('SCC', 'Gene', (177, 180))	('survival time', 'CPA', (217, 230))	('aberrant', 'Var', (142, 150))	('S100A7', 'Gene', (167, 173))	('S100A7', 'Gene', '6278', (167, 173))	('SCC', 'Gene', '6317', (51, 54))	('SCC', 'Phenotype', 'HP:0002860', (51, 54))	('SCC', 'Gene', (91, 94))	('SCC', 'Phenotype', 'HP:0002860', (177, 180))	('SCC', 'Gene', '6317', (177, 180))	('shorter', 'NegReg', (209, 216))	('SCC', 'Phenotype', 'HP:0002860', (91, 94))	('S100A7', 'Gene', (41, 47))	('SCC', 'Gene', '6317', (91, 94))
328154	25745359	This is the first study that demonstrates decreased proliferation and tumor growth in vivo and vitro with knockdown of S100A7 mRNA.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('proliferation', 'CPA', (52, 65))	('decreased', 'NegReg', (42, 51))	('tumor', 'Disease', (70, 75))	('knockdown', 'Var', (106, 115))	('S100A7', 'Gene', (119, 125))	('S100A7', 'Gene', '6278', (119, 125))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
328158	25745359	Our RNAi data revealed that inhibition of S100A7 affects expression of NF-kB activation, which are involved in cell proliferation.	('expression', 'MPA', (57, 67))	('inhibition', 'Var', (28, 38))	('NF-kB activation', 'Gene', (71, 87))	('S100A7', 'Gene', '6278', (42, 48))	('S100A7', 'Gene', (42, 48))
328160	25745359	Our study shows that knockdown of S100A7 decreases NF-kappaB activity, further supporting the hypothesis of a role for S100A7 and NF-kappaB interaction that slows tumor growth.	('S100A7', 'Gene', '6278', (34, 40))	('NF-kappaB', 'Gene', '4790', (130, 139))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('decreases', 'NegReg', (41, 50))	('NF-kappaB', 'Gene', (130, 139))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('NF-kappaB', 'Gene', '4790', (51, 60))	('tumor', 'Disease', (163, 168))	('S100A7', 'Gene', (119, 125))	('knockdown', 'Var', (21, 30))	('activity', 'MPA', (61, 69))	('S100A7', 'Gene', (34, 40))	('NF-kappaB', 'Gene', (51, 60))	('S100A7', 'Gene', '6278', (119, 125))	('slows', 'NegReg', (157, 162))	('interaction', 'Interaction', (140, 151))
328174	32700817	TOX shows significant impacts on survival of LUAD with early stage, ever-smoking, or low-TMB status.	('LUAD', 'Phenotype', 'HP:0030078', (45, 49))	('impacts', 'Reg', (22, 29))	('LUAD', 'Disease', (45, 49))	('low-TMB status', 'Var', (85, 99))	('TMB', 'Chemical', '-', (89, 92))
328185	32700817	1 ,  2  Specific targeted therapies like tyrosine kinase inhibitors (TKIs) confer significant survival benefit in a minority of NSCLC patients with EGFR-mutant, ALK-rearranged, ROS1-rearranged, or BRAF (V600E)-mutant.	('NSCLC', 'Phenotype', 'HP:0030358', (128, 133))	('ROS1', 'Gene', '6098', (177, 181))	('ALK', 'Gene', '238', (161, 164))	('ALK', 'Gene', (161, 164))	('EGFR', 'Gene', '1956', (148, 152))	('EGFR', 'Gene', (148, 152))	('benefit', 'PosReg', (103, 110))	('patients', 'Species', '9606', (134, 142))	('NSCLC', 'Disease', (128, 133))	('NSCLC', 'Disease', 'MESH:D002289', (128, 133))	('V600E', 'Mutation', 'rs113488022', (203, 208))	('survival', 'CPA', (94, 102))	('ROS1', 'Gene', (177, 181))	('BRAF (V600E)-mutant', 'Var', (197, 216))
328187	32700817	11 ,  12 ,  13 ,  14  Some biomarkers, such as the PD-L1 expression, tumor-infiltration lymphocytes (TILs), TP53, and KRAS mutation status and tumor mutation burden (TMB), were reported for their predictive value for clinical responses in ICIs therapy.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor', 'Disease', (143, 148))	('mutation', 'Var', (123, 131))	('TP53', 'Gene', (108, 112))	('KRAS', 'Gene', (118, 122))	('tumor', 'Disease', (69, 74))	('TMB', 'Chemical', '-', (166, 169))	('KRAS', 'Gene', '100518251', (118, 122))	('PD-L1', 'Gene', '574058', (51, 56))	('TP53', 'Gene', '397276', (108, 112))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('PD-L1', 'Gene', (51, 56))
328213	32700817	LUAD patients (P0616A, P0616P, P0617, P0619, P0729, P1010, P1118, P1120, P1202, P1208, and P1219) were selected and the expression of TOX was normalized.	('P0729', 'Var', (45, 50))	('P1120', 'Var', (66, 71))	('P1208', 'Var', (80, 85))	('patients', 'Species', '9606', (5, 13))	('P1010', 'Var', (52, 57))	('P1219', 'Var', (91, 96))	('P1118', 'Var', (59, 64))	('P0616A', 'Var', (15, 21))	('P1202', 'Var', (73, 78))	('P0617', 'Var', (31, 36))	('P0616P', 'Var', (23, 29))	('P0616A', 'Mutation', 'p.P0616A', (15, 21))	('P0616P', 'Mutation', 'p.P0616P', (23, 29))	('P0619', 'Var', (38, 43))	('LUAD', 'Phenotype', 'HP:0030078', (0, 4))
328242	32700817	Notably, normal copy number or deletions spanning the TOX gene locus correlate with increased immune cell infiltration except CD8+ T cell.	('TOX', 'Gene', (54, 57))	('CD8', 'Gene', (126, 129))	('CD8', 'Gene', '925', (126, 129))	('deletions', 'Var', (31, 40))	('increased', 'PosReg', (84, 93))	('immune cell infiltration', 'CPA', (94, 118))
328270	32700817	21   Interestingly, our findings suggest that TOX has dual functions that high expression level of TOX is positively correlated with better prognosis in multiple cancer types included LUAD and, meanwhile, induces T cells exhaustion which causes the inefficiency of antitumor immunity.	('tumor', 'Disease', 'MESH:D009369', (269, 274))	('T cells exhaustion', 'CPA', (213, 231))	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('T cells exhaustion', 'Phenotype', 'HP:0005435', (213, 231))	('tumor', 'Phenotype', 'HP:0002664', (269, 274))	('cancer', 'Disease', (162, 168))	('high', 'Var', (74, 78))	('TOX', 'Gene', (99, 102))	('LUAD', 'Phenotype', 'HP:0030078', (184, 188))	('tumor', 'Disease', (269, 274))	('LUAD', 'Disease', (184, 188))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('induces', 'Reg', (205, 212))
328402	27347166	Ptch-1 mutations contribute to the development of cutaneous eyelid basal cell carcinoma.	('men', 'Species', '9606', (42, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (67, 87))	('cutaneous eyelid basal cell carcinoma', 'Disease', (50, 87))	('contribute', 'Reg', (17, 27))	('Ptch-1', 'Gene', '5727', (0, 6))	('cutaneous eyelid basal cell carcinoma', 'Disease', 'MESH:D002280', (50, 87))	('Ptch-1', 'Gene', (0, 6))	('mutations', 'Var', (7, 16))
328403	27347166	The present study provides evidence that alterations in hedgehog signaling pathways may lead to transformation of the conjunctival intraepithelial neoplasia into invasive squamous cell carcinoma.	('neoplasia', 'Phenotype', 'HP:0002664', (147, 156))	('invasive squamous cell carcinoma', 'Disease', (162, 194))	('intraepithelial neoplasia', 'Phenotype', 'HP:0032187', (131, 156))	('lead to', 'Reg', (88, 95))	('conjunctival intraepithelial neoplasia', 'Disease', (118, 156))	('invasive squamous cell carcinoma', 'Disease', 'MESH:D002294', (162, 194))	('conjunctival intraepithelial neoplasia', 'Disease', 'MESH:D019048', (118, 156))	('hedgehog signaling pathways', 'Pathway', (56, 83))	('carcinoma', 'Phenotype', 'HP:0030731', (185, 194))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (171, 194))	('alterations', 'Var', (41, 52))
328413	27347166	In the misregulation of Hedgehog pathway, cell self-renewal cycle fails and tumorigenesis is initiated.	('fails', 'NegReg', (66, 71))	('Hedgehog pathway', 'Pathway', (24, 40))	('misregulation', 'Var', (7, 20))	('tumor', 'Disease', (76, 81))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('initiated', 'PosReg', (93, 102))	('cell self-renewal cycle', 'CPA', (42, 65))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
328418	27347166	Disruptions in the Shh pathway has an effective role in the abnormal development of stem cells.	('Disruptions', 'Var', (0, 11))	('Shh', 'Gene', (19, 22))	('men', 'Species', '9606', (76, 79))	('Shh', 'Gene', '6469', (19, 22))	('abnormal development of stem cells', 'CPA', (60, 94))
328422	27347166	Ptch-1 inactivation is responsible for basal cell nevus syndrome.	('basal cell nevus syndrome', 'Disease', 'MESH:D001478', (39, 64))	('inactivation', 'Var', (7, 19))	('responsible', 'Reg', (23, 34))	('nevus', 'Phenotype', 'HP:0003764', (50, 55))	('Ptch-1', 'Gene', '5727', (0, 6))	('basal cell nevus', 'Phenotype', 'HP:0002671', (39, 55))	('basal cell nevus syndrome', 'Disease', (39, 64))	('Ptch-1', 'Gene', (0, 6))
328457	27347166	In the present study, the low Ptch-1 expression score in the BCC group was found to be statistically significant and this evidence also supports the evidence that Ptch-1 mutations may serve a role in the development of sporadic BCC, hypothesized by Kim et al.	('low', 'NegReg', (26, 29))	('Ptch-1', 'Gene', (163, 169))	('mutations', 'Var', (170, 179))	('Ptch-1', 'Gene', '5727', (30, 36))	('men', 'Species', '9606', (211, 214))	('Ptch-1', 'Gene', (30, 36))	('expression', 'MPA', (37, 47))	('Ptch-1', 'Gene', '5727', (163, 169))	('role', 'Reg', (192, 196))	('BCC', 'Disease', (228, 231))
328459	27347166	De Grujil et al suggested that UV radiation may result in Ptch-1 mutations and long-term effects of UV radiation on the development of BCC may also be effective through Ptch-1 mutation.	('Ptch-1', 'Gene', '5727', (169, 175))	('Ptch-1', 'Gene', (169, 175))	('result in', 'Reg', (48, 57))	('Ptch-1', 'Gene', '5727', (58, 64))	('mutation', 'Var', (176, 184))	('men', 'Species', '9606', (127, 130))	('Ptch-1', 'Gene', (58, 64))	('mutations', 'Var', (65, 74))
328461	27347166	In 5 BCC cases where exenteration was performed, the Ptch-1 score was <=2 and this also supports the idea that Ptch-1 mutation may contribute to BCC development.	('Ptch-1', 'Gene', (111, 117))	('BCC', 'Disease', (5, 8))	('Ptch-1', 'Gene', '5727', (53, 59))	('Ptch-1', 'Gene', (53, 59))	('men', 'Species', '9606', (156, 159))	('mutation', 'Var', (118, 126))	('Ptch-1', 'Gene', '5727', (111, 117))	('contribute', 'Reg', (131, 141))	('BCC', 'Disease', (145, 148))
328462	27347166	In a previous study on sporadic BCC conducted by Holikova et al, Ptch-1 mutations were identified with increased inactive Ptch-1 mRNA in cytoplasm by in situ hybridization method and this was detected in particular in the outer tumor layers with palisade formation; increase of Gli-1 activity was also observed in tumor areas.	('Ptch-1', 'Gene', (65, 71))	('mutations', 'Var', (72, 81))	('tumor', 'Disease', 'MESH:D009369', (314, 319))	('BCC', 'Disease', (32, 35))	('palisade', 'Chemical', 'MESH:C478127', (246, 254))	('increased', 'PosReg', (103, 112))	('tumor', 'Phenotype', 'HP:0002664', (314, 319))	('tumor', 'Disease', 'MESH:D009369', (228, 233))	('Gli-1', 'Gene', (278, 283))	('Ptch-1', 'Gene', '5727', (122, 128))	('mRNA', 'MPA', (129, 133))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('tumor', 'Disease', (314, 319))	('Ptch-1', 'Gene', (122, 128))	('Gli-1', 'Gene', '2735', (278, 283))	('inactive', 'MPA', (113, 121))	('tumor', 'Disease', (228, 233))	('Ptch-1', 'Gene', '5727', (65, 71))
328463	27347166	The authors pointed out that Ptch-1 mutation increases Shh signaling, initiating cell proliferation through the Gli family of transcriptional factors.	('cell proliferation', 'CPA', (81, 99))	('Ptch-1', 'Gene', '5727', (29, 35))	('increases', 'PosReg', (45, 54))	('Ptch-1', 'Gene', (29, 35))	('Shh', 'Gene', '6469', (55, 58))	('initiating', 'Reg', (70, 80))	('Gli', 'Gene', (112, 115))	('Shh', 'Gene', (55, 58))	('mutation', 'Var', (36, 44))	('Gli', 'Gene', '2735', (112, 115))
328466	27347166	Lupi showed BCC development after just a single somatic mutation through the Shh pathway and suggested that Ptch-1 mutation was responsible for the development of sporadic and hereditary BCC.	('men', 'Species', '9606', (155, 158))	('Ptch-1', 'Gene', (108, 114))	('BCC', 'Disease', (187, 190))	('Shh', 'Gene', (77, 80))	('men', 'Species', '9606', (23, 26))	('Shh', 'Gene', '6469', (77, 80))	('mutation', 'Var', (115, 123))	('BCC development', 'CPA', (12, 27))	('responsible', 'Reg', (128, 139))	('Ptch-1', 'Gene', '5727', (108, 114))
328484	27347166	The present study present evidence that Ptch-1 mutations contribute to the development of cutaneous eyelid basal cell carcinoma.	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (107, 127))	('contribute', 'Reg', (57, 67))	('cutaneous eyelid basal cell carcinoma', 'Disease', (90, 127))	('mutations', 'Var', (47, 56))	('Ptch-1', 'Gene', '5727', (40, 46))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('Ptch-1', 'Gene', (40, 46))	('cutaneous eyelid basal cell carcinoma', 'Disease', 'MESH:D002280', (90, 127))	('men', 'Species', '9606', (82, 85))
328485	27347166	Alterations in hedgehog signaling pathways may lead to transformation of the conjunctival intraepithelial neoplasia into invasive squamous cell carcinoma.	('intraepithelial neoplasia', 'Phenotype', 'HP:0032187', (90, 115))	('hedgehog signaling pathways', 'Pathway', (15, 42))	('invasive squamous cell carcinoma', 'Disease', (121, 153))	('lead to', 'Reg', (47, 54))	('Alterations', 'Var', (0, 11))	('invasive squamous cell carcinoma', 'Disease', 'MESH:D002294', (121, 153))	('conjunctival intraepithelial neoplasia', 'Disease', (77, 115))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (130, 153))	('conjunctival intraepithelial neoplasia', 'Disease', 'MESH:D019048', (77, 115))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('neoplasia', 'Phenotype', 'HP:0002664', (106, 115))
328489	32188144	We found that DMC suppressed cell proliferation via simultaneously inducing G2/M-phase arrest and cell apoptosis.	('cell apoptosis', 'CPA', (98, 112))	('arrest', 'Disease', 'MESH:D006323', (87, 93))	('DMC', 'Var', (14, 17))	('DMC', 'Chemical', 'MESH:C050229', (14, 17))	('inducing', 'PosReg', (67, 75))	('cell proliferation', 'CPA', (29, 47))	('arrest', 'Disease', (87, 93))	('suppressed', 'NegReg', (18, 28))
328492	32188144	The analyses of clinical datasets revealed that patients with head and neck cancers expressing high HO-1 and low cIAP1 had the most favorable prognoses.	('neck cancers', 'Disease', 'MESH:D006258', (71, 83))	('cancers', 'Phenotype', 'HP:0002664', (76, 83))	('high', 'Var', (95, 99))	('head and neck cancer', 'Phenotype', 'HP:0012288', (62, 82))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('head and neck cancers', 'Phenotype', 'HP:0012288', (62, 83))	('cIAP1', 'Gene', (113, 118))	('head and neck cancer', 'Disease', 'MESH:D006258', (62, 82))	('patients', 'Species', '9606', (48, 56))	('HO-1', 'Gene', (100, 104))	('neck cancers', 'Disease', (71, 83))	('cIAP1', 'Gene', '329', (113, 118))
328501	32188144	For instance, studies demonstrated that LCL161, a cIAP1 antagonist, sensitizes a panel of OSCC cell lines to Fas ligand (FasL) treatment.	('Fas ligand', 'Gene', '356', (109, 119))	('FasL', 'Gene', (121, 125))	('FasL', 'Gene', '356', (121, 125))	('cIAP1', 'Gene', '329', (50, 55))	('sensitizes', 'Reg', (68, 78))	('LCL161', 'Var', (40, 46))	('cIAP1', 'Gene', (50, 55))	('Fas ligand', 'Gene', (109, 119))
328521	32188144	In addition, the long-term growth of HSC-3 and SCC-9 cells was also significantly reduced following treatment with 12.5-50 muM of DMC, and the IC50 values were lower than 12.5 muM (Figure 1C).	('long-term growth', 'CPA', (17, 33))	('HSC-3', 'Gene', (37, 42))	('muM', 'Gene', (123, 126))	('DMC', 'Var', (130, 133))	('DMC', 'Chemical', 'MESH:C050229', (130, 133))	('SCC-9', 'CellLine', 'CVCL:1685', (47, 52))	('muM', 'Gene', '56925', (176, 179))	('HSC-3', 'Gene', '150353', (37, 42))	('muM', 'Gene', (176, 179))	('reduced', 'NegReg', (82, 89))	('muM', 'Gene', '56925', (123, 126))
328524	32188144	After 24 h of DMC (12.5-50 muM) treatment in HSC-3 and SCC-9 cells, the cell cycle distribution in the G0/G1 phase had markedly attenuated, whereas the distribution of cells in the G2/M phase had markedly increased in DMC-treated cells compared to vehicle-treated cells (Figure 1D,E), suggesting that cell cycle arrest in the G2/M phase may contribute to the suppressive effects of DMC on cell viability.	('arrest', 'Disease', (312, 318))	('muM', 'Gene', '56925', (27, 30))	('DMC', 'Chemical', 'MESH:C050229', (382, 385))	('HSC-3', 'Gene', '150353', (45, 50))	('DMC-treated', 'Var', (218, 229))	('DMC', 'Chemical', 'MESH:C050229', (218, 221))	('SCC-9', 'CellLine', 'CVCL:1685', (55, 60))	('muM', 'Gene', (27, 30))	('increased', 'PosReg', (205, 214))	('attenuated', 'NegReg', (128, 138))	('DMC', 'Chemical', 'MESH:C050229', (14, 17))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (301, 318))	('HSC-3', 'Gene', (45, 50))	('arrest', 'Disease', 'MESH:D006323', (312, 318))	('cell cycle distribution', 'CPA', (72, 95))
328528	32188144	Apoptosis induced by DMC was further checked by Annexin V-FITC/PI (propidium iodide) double-staining analysis.	('DMC', 'Chemical', 'MESH:C050229', (21, 24))	('DMC', 'Var', (21, 24))	('propidium iodide', 'Chemical', 'MESH:D011419', (67, 83))	('Annexin V', 'Gene', '308', (48, 57))	('Annexin V', 'Gene', (48, 57))	('FITC', 'Chemical', 'MESH:D016650', (58, 62))
328530	32188144	Percentages of total apoptotic cells treated with DMC ranged 8.9-52.2% in HSC-3 cells and 5.1-46% in SCC-9 cells (Figure 2C).	('HSC-3', 'Gene', (74, 79))	('SCC-9', 'CellLine', 'CVCL:1685', (101, 106))	('HSC-3', 'Gene', '150353', (74, 79))	('DMC', 'Chemical', 'MESH:C050229', (50, 53))	('DMC', 'Var', (50, 53))
328531	32188144	These results are all hallmarks of apoptosis and demonstrated the ability of DMC to induce the apoptotic cell death of OSCC cells.	('DMC', 'Var', (77, 80))	('DMC', 'Chemical', 'MESH:C050229', (77, 80))	('apoptotic cell death', 'CPA', (95, 115))
328533	32188144	Several apoptosis-related proteins were respectively upregulated and downregulated in DMC-treated HSC-3 cells compared to vehicle-treated cells (Figure 3A).	('DMC', 'Chemical', 'MESH:C050229', (86, 89))	('HSC-3', 'Gene', (98, 103))	('downregulated', 'NegReg', (69, 82))	('DMC-treated', 'Var', (86, 97))	('apoptosis-related proteins', 'Protein', (8, 34))	('HSC-3', 'Gene', '150353', (98, 103))	('upregulated', 'PosReg', (53, 64))
328537	32188144	The cleavage of poly(ADP-ribose) polymerase (PARP) by caspase-3 was also concentration-dependently induced by DMC treatment (Figure 3F,G).	('caspase-3', 'Gene', (54, 63))	('induced', 'Reg', (99, 106))	('PARP', 'Gene', (45, 49))	('cleavage', 'MPA', (4, 12))	('DMC', 'Chemical', 'MESH:C050229', (110, 113))	('poly(ADP-ribose) polymerase', 'Gene', '142', (16, 43))	('caspase-3', 'Gene', '836', (54, 63))	('DMC treatment', 'Var', (110, 123))	('PARP', 'Gene', '142', (45, 49))	('poly(ADP-ribose) polymerase', 'Gene', (16, 43))
328540	32188144	To further determine the role of upregulated HO-1 induced by DMC in DMC-mediated growth inhibition and apoptosis in OSCC cells, we knocked down HO-1 with HO-1-specific siRNA.	('upregulated', 'PosReg', (33, 44))	('DMC', 'Chemical', 'MESH:C050229', (61, 64))	('knocked', 'Var', (131, 138))	('HO-1', 'Gene', (144, 148))	('HO-1', 'Gene', (45, 49))	('DMC', 'Chemical', 'MESH:C050229', (68, 71))
328542	32188144	Moreover, the silencing of HO-1 significantly rescued DMC-mediated growth inhibition (Figure 4D).	('silencing', 'Var', (14, 23))	('HO-1', 'Gene', (27, 31))	('rescued', 'NegReg', (46, 53))	('DMC', 'Chemical', 'MESH:C050229', (54, 57))
328544	32188144	We found the induction of caspase-3 activation by DMC in SCC-9 cells was reversed by the SnPP pretreatment (Figure 4E).	('DMC', 'Var', (50, 53))	('SnPP', 'Chemical', '-', (89, 93))	('SCC-9', 'CellLine', 'CVCL:1685', (57, 62))	('activation', 'PosReg', (36, 46))	('caspase-3', 'Gene', (26, 35))	('DMC', 'Chemical', 'MESH:C050229', (50, 53))	('caspase-3', 'Gene', '836', (26, 35))
328547	32188144	The Kaplan-Meier (KM) plot revealed a longer overall survival of head and neck cancer patients with high HO-1 (HMOX1) expression than patients with low HO-1 expression (p = 0.04; Figure 4H).	('expression', 'Var', (118, 128))	('HMOX1', 'Gene', '3162', (111, 116))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('head and neck cancer', 'Phenotype', 'HP:0012288', (65, 85))	('patients', 'Species', '9606', (134, 142))	('longer', 'PosReg', (38, 44))	('high', 'Var', (100, 104))	('head and neck cancer', 'Disease', 'MESH:D006258', (65, 85))	('HMOX1', 'Gene', (111, 116))	('overall survival', 'MPA', (45, 61))	('patients', 'Species', '9606', (86, 94))
328548	32188144	These data suggest that upregulating HO-1 is crucial for DMC-induced caspase-mediated apoptotic cell death, and that high HO-1 levels predict a favorable prognosis in patients with head and neck cancer.	('head and neck cancer', 'Phenotype', 'HP:0012288', (181, 201))	('caspase', 'Gene', '841;842', (69, 76))	('patients', 'Species', '9606', (167, 175))	('upregulating', 'PosReg', (24, 36))	('head and neck cancer', 'Disease', 'MESH:D006258', (181, 201))	('high', 'Var', (117, 121))	('caspase', 'Gene', (69, 76))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('DMC', 'Chemical', 'MESH:C050229', (57, 60))
328554	32188144	Therefore, we examined whether DMC can induce the activation of three major MAPKs including extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38.	('p38', 'Gene', (172, 175))	('c-Jun N-terminal kinase', 'Gene', '5599', (137, 160))	('ERK', 'Gene', '5594', (131, 134))	('JNK', 'Gene', (162, 165))	('DMC', 'Var', (31, 34))	('JNK', 'Gene', '5599', (162, 165))	('DMC', 'Chemical', 'MESH:C050229', (31, 34))	('ERK', 'Gene', (131, 134))	('activation', 'PosReg', (50, 60))	('p38', 'Gene', '1432', (172, 175))	('MAPK', 'Gene', '1432', (76, 80))	('MAPK', 'Gene', (76, 80))	('extracellular signal-regulated kinase', 'Gene', '5594', (92, 129))	('extracellular signal-regulated kinase', 'Gene', (92, 129))	('c-Jun N-terminal kinase', 'Gene', (137, 160))
328555	32188144	As shown in Figure 5A,B, DMC significantly activated JNK1/2 and p38 MAPK, but not ERK1/2, in concentration-dependent manners.	('ERK1/2', 'Gene', '5595;5594', (82, 88))	('ERK1/2', 'Gene', (82, 88))	('p38', 'Gene', '1432', (64, 67))	('activated', 'PosReg', (43, 52))	('DMC', 'Var', (25, 28))	('DMC', 'Chemical', 'MESH:C050229', (25, 28))	('p38', 'Gene', (64, 67))	('MAPK', 'Gene', '1432', (68, 72))	('JNK1/2', 'Gene', '5599;5601', (53, 59))	('JNK1/2', 'Gene', (53, 59))	('MAPK', 'Gene', (68, 72))
328556	32188144	To further determine the role of JNK1/2 and p38 MAPK activation in DMC-induced HO-1 upregulation and cell apoptosis, 1 h of pretreatment of 10 muM SB203580 (a p38 inhibitor) or 1 muM JNK-in-8 (a JNK inhibitor) with HSC-3 cells was followed by 50 muM DMC treatment for another 24 h, and then cells were subjected to Western blotting analysis (Figure 5C).	('muM', 'Gene', '56925', (179, 182))	('JNK', 'Gene', (183, 186))	('SB203580', 'Chemical', 'MESH:C093642', (147, 155))	('JNK', 'Gene', (33, 36))	('muM', 'Gene', (179, 182))	('JNK', 'Gene', '5599', (183, 186))	('p38', 'Gene', (44, 47))	('JNK', 'Gene', '5599', (33, 36))	('HSC-3', 'Gene', '150353', (215, 220))	('SB203580', 'Var', (147, 155))	('muM', 'Gene', '56925', (246, 249))	('muM', 'Gene', (246, 249))	('p38', 'Gene', (159, 162))	('muM', 'Gene', '56925', (143, 146))	('HSC-3', 'Gene', (215, 220))	('muM', 'Gene', (143, 146))	('p38', 'Gene', '1432', (44, 47))	('upregulation', 'PosReg', (84, 96))	('MAPK', 'Gene', (48, 52))	('JNK1/2', 'Gene', '5599;5601', (33, 39))	('DMC', 'Chemical', 'MESH:C050229', (67, 70))	('JNK', 'Gene', (195, 198))	('DMC', 'Chemical', 'MESH:C050229', (250, 253))	('JNK', 'Gene', '5599', (195, 198))	('MAPK', 'Gene', '1432', (48, 52))	('p38', 'Gene', '1432', (159, 162))	('JNK1/2', 'Gene', (33, 39))
328559	32188144	Overall, these results suggest that DMC induces caspase-mediated cell apoptosis through activating the p38 MAPK-HO-1 signaling cascade in OSCC cells.	('induces', 'Reg', (40, 47))	('p38', 'Gene', (103, 106))	('MAPK', 'Gene', '1432', (107, 111))	('caspase', 'Gene', '841;842', (48, 55))	('MAPK', 'Gene', (107, 111))	('activating', 'PosReg', (88, 98))	('DMC', 'Var', (36, 39))	('DMC', 'Chemical', 'MESH:C050229', (36, 39))	('caspase', 'Gene', (48, 55))	('p38', 'Gene', '1432', (103, 106))
328561	32188144	In the present study, we observed that DMC exhibited strong oncostatic effects on OSCC cells respectively derived from primary and metastatic sites, including G2/M cell-cycle arrest and apoptotic cell death.	('DMC', 'Chemical', 'MESH:C050229', (39, 42))	('arrest', 'Disease', 'MESH:D006323', (175, 181))	('DMC', 'Var', (39, 42))	('apoptotic cell death', 'CPA', (186, 206))	('arrest', 'Disease', (175, 181))
328564	32188144	The present study first revealed that the exposure of OSCC cells to DMC resulted in an increased percentage of cells in the G2/M phase together with a decrease in the G0/G1 phase.	('increased', 'PosReg', (87, 96))	('decrease', 'NegReg', (151, 159))	('G0/G1 phase', 'CPA', (167, 178))	('DMC', 'Chemical', 'MESH:C050229', (68, 71))	('cells in the G2/M phase', 'CPA', (111, 134))	('DMC', 'Var', (68, 71))
328566	32188144	These results are supported by other published studies which indicate that DMC markedly induced G2/M arrest in brain and prostate cancers.	('brain and prostate cancers', 'Disease', 'MESH:D011471', (111, 137))	('cancers', 'Phenotype', 'HP:0002664', (130, 137))	('induced', 'Reg', (88, 95))	('prostate cancer', 'Phenotype', 'HP:0012125', (121, 136))	('M arrest', 'Disease', 'MESH:D006323', (99, 107))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('M arrest', 'Disease', (99, 107))	('prostate cancers', 'Phenotype', 'HP:0012125', (121, 137))	('DMC', 'Var', (75, 78))	('DMC', 'Chemical', 'MESH:C050229', (75, 78))
328568	32188144	In addition, other positive regulators that participate in the G2/M transition, such as CDC25C phosphatase and cyclin B1, were downregulated by DMC through inducing reactive oxygen species (ROS) production in brain tumor cells.	('brain tumor', 'Disease', 'MESH:D001932', (209, 220))	('cyclin B1', 'Gene', '891', (111, 120))	('cyclin B1', 'Gene', (111, 120))	('inducing', 'PosReg', (156, 164))	('brain tumor', 'Disease', (209, 220))	('DMC', 'Var', (144, 147))	('DMC', 'Chemical', 'MESH:C050229', (144, 147))	('downregulated', 'NegReg', (127, 140))	('ROS', 'Chemical', 'MESH:D017382', (190, 193))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('brain tumor', 'Phenotype', 'HP:0030692', (209, 220))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (165, 188))	('CDC25C', 'Gene', (88, 94))
328578	32188144	Furthermore, DMC was recently shown to inhibit NF-kappaB activity in OSCC cells.	('DMC', 'Var', (13, 16))	('DMC', 'Chemical', 'MESH:C050229', (13, 16))	('inhibit', 'NegReg', (39, 46))	('NF-kappaB', 'Gene', (47, 56))	('activity', 'MPA', (57, 65))	('NF-kappaB', 'Gene', '4790', (47, 56))
328579	32188144	Taken together, DMC might enhance the therapeutic effect of chemotherapeutic agents in OSCC treatment via targeting NF-kappaB-mediated IAP expression, and this hypothesis is worthy of further investigation in the future.	('therapeutic', 'MPA', (38, 49))	('NF-kappaB', 'Gene', '4790', (116, 125))	('NF-kappaB', 'Gene', (116, 125))	('IAP expression', 'MPA', (135, 149))	('DMC', 'Var', (16, 19))	('DMC', 'Chemical', 'MESH:C050229', (16, 19))	('OSCC', 'Disease', (87, 91))	('targeting', 'NegReg', (106, 115))	('enhance', 'PosReg', (26, 33))
328580	32188144	In addition to cIAP1/XIAP targeting, DMC was found to significantly induce the upregulation of HO-1 from the apoptosis array in OSCC cells.	('DMC', 'Chemical', 'MESH:C050229', (37, 40))	('cIAP1', 'Gene', '329', (15, 20))	('cIAP1', 'Gene', (15, 20))	('HO-1', 'Gene', (95, 99))	('upregulation', 'PosReg', (79, 91))	('XIAP', 'Gene', '331', (21, 25))	('DMC', 'Var', (37, 40))	('XIAP', 'Gene', (21, 25))
328594	32188144	Herein, we also observed that head and neck cancer patients harboring high HO-1 (HMOX1) expression in tumor tissues had significantly more favorable overall survival than those with a lower level.	('favorable', 'PosReg', (139, 148))	('HMOX1', 'Gene', (81, 86))	('head and neck cancer', 'Disease', 'MESH:D006258', (30, 50))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('overall survival', 'CPA', (149, 165))	('HMOX1', 'Gene', '3162', (81, 86))	('patients', 'Species', '9606', (51, 59))	('high', 'Var', (70, 74))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('head and neck cancer', 'Phenotype', 'HP:0012288', (30, 50))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
328605	32188144	We observed that p38 MAPK activity was essential for HO-1 expression induced by DMC.	('p38', 'Gene', (17, 20))	('MAPK', 'Gene', (21, 25))	('expression', 'MPA', (58, 68))	('p38', 'Gene', '1432', (17, 20))	('HO-1', 'Gene', (53, 57))	('DMC', 'Chemical', 'MESH:C050229', (80, 83))	('DMC', 'Var', (80, 83))	('MAPK', 'Gene', '1432', (21, 25))
328611	32188144	Furthermore, after screening 36 CUR analogues, DMC was demonstrated to show the best inhibitory effects on both wild-type and mutant EGFR.	('DMC', 'Chemical', 'MESH:C050229', (47, 50))	('inhibitory effects', 'MPA', (85, 103))	('CUR', 'Chemical', 'MESH:D003474', (32, 35))	('EGFR', 'Gene', (133, 137))	('mutant', 'Var', (126, 132))
328613	32188144	In addition to targeting EGFR, another CUR analogue, BDMC, was reported to promote the suppressive effect of PDL-1 antibody on bladder cancer progression via stimulating cytotoxic T-cell activity and suppressing myeloid-derived suppressor cells (MDSCs) in an immunocompetent mice model, suggesting that DMC might be also an immunomodulatory compound in the tumor microenvironment.	('stimulating', 'PosReg', (158, 169))	('antibody', 'Var', (115, 123))	('mice', 'Species', '10090', (275, 279))	('DMC', 'Chemical', 'MESH:C050229', (303, 306))	('tumor', 'Phenotype', 'HP:0002664', (357, 362))	('iron', 'Chemical', 'MESH:D007501', (371, 375))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('suppressing', 'NegReg', (200, 211))	('bladder cancer', 'Disease', (127, 141))	('bladder cancer', 'Disease', 'MESH:D001749', (127, 141))	('DMC', 'Chemical', 'MESH:C050229', (54, 57))	('bladder cancer', 'Phenotype', 'HP:0009725', (127, 141))	('PDL-1', 'Gene', (109, 114))	('PDL-1', 'Gene', '60533', (109, 114))	('CUR', 'Chemical', 'MESH:D003474', (39, 42))	('BDMC', 'Chemical', 'MESH:C034786', (53, 57))	('tumor', 'Disease', (357, 362))	('promote', 'PosReg', (75, 82))	('cytotoxic T-cell activity', 'CPA', (170, 195))	('tumor', 'Disease', 'MESH:D009369', (357, 362))	('myeloid-derived suppressor cells', 'CPA', (212, 244))
328623	32188144	The primary antibodies against cleaved Caspase-8 (#9496), cleaved Caspase-9 (#9505), cleaved Caspase-3 (#9664), Caspase-8 (#9746), Caspase-9 (#9502), PARP (#9542), Phospho-Erk1/2 (#4370), Erk1/2 (#9102), Phospho-JNK (#4668), JNK2 (#9258), Phospho-EGFR (#2220), EGFR (#2239), c-IAP1 (#7065), and XIAP (#2045) were obtained from Cell Signaling Technology (Danvers, MA, USA).	('Erk1/2', 'Gene', '5595;5594', (172, 178))	('PARP', 'Gene', (150, 154))	('#9496', 'Var', (50, 55))	('#9746', 'Var', (123, 128))	('Caspase-3', 'Gene', '836', (93, 102))	('Caspase-8', 'Gene', '841', (112, 121))	('JNK2', 'Gene', '5601', (225, 229))	('XIAP', 'Gene', '331', (295, 299))	('#2239', 'Var', (267, 272))	('c-IAP1', 'Gene', '329', (275, 281))	('#2220', 'Var', (253, 258))	('Caspase-8', 'Gene', '841', (39, 48))	('JNK2', 'Gene', (225, 229))	('JNK', 'Gene', (212, 215))	('#9102', 'Var', (196, 201))	('JNK', 'Gene', '5599', (212, 215))	('c-IAP1', 'Gene', (275, 281))	('#9502', 'Var', (142, 147))	('Erk1/2', 'Gene', (188, 194))	('Erk1/2', 'Gene', (172, 178))	('Caspase-3', 'Gene', (93, 102))	('Caspase-9', 'Gene', '842', (131, 140))	('#9258', 'Var', (231, 236))	('Caspase-9', 'Gene', (131, 140))	('Caspase-8', 'Gene', (112, 121))	('XIAP', 'Gene', (295, 299))	('#4370', 'Var', (180, 185))	('#7065', 'Var', (283, 288))	('Caspase-9', 'Gene', '842', (66, 75))	('JNK', 'Gene', (225, 228))	('JNK', 'Gene', '5599', (225, 228))	('#9505', 'Var', (77, 82))	('Caspase-9', 'Gene', (66, 75))	('PARP', 'Gene', '142', (150, 154))	('#9664', 'Var', (104, 109))	('Caspase-8', 'Gene', (39, 48))	('Erk1/2', 'Gene', '5595;5594', (188, 194))
328624	32188144	Anti-Caspase-3 (610323), anti-phospho-p38 (612281), and anti-p38 (612168) were purchased from BD biosciences (San Jose, CA, USA).	('612168', 'Var', (66, 72))	('p38', 'Gene', '1432', (61, 64))	('610323', 'Var', (16, 22))	('p38', 'Gene', '1432', (38, 41))	('Caspase-3', 'Gene', (5, 14))	('Caspase-3', 'Gene', '836', (5, 14))	('p38', 'Gene', (61, 64))	('612281', 'Var', (43, 49))	('p38', 'Gene', (38, 41))
328638	32188144	HMOX1 gene silencing was performed using siRNAs targeting HMOX1 (#4390824, s6674 Ambion) and a negative control (#4390844, Ambion).	('#4390824', 'Var', (65, 73))	('HMOX1', 'Gene', (0, 5))	('s6674 Ambion', 'Var', (75, 87))	('HMOX1', 'Gene', (58, 63))	('HMOX1', 'Gene', '3162', (0, 5))	('HMOX1', 'Gene', '3162', (58, 63))
328643	32188144	Moreover, the cell apoptotic effect was also possibly contributed by G2/M cycle arrest induced by DMC, and the mechanism is schematically illustrated in Figure 6.	('arrest', 'Disease', 'MESH:D006323', (80, 86))	('DMC', 'Var', (98, 101))	('DMC', 'Chemical', 'MESH:C050229', (98, 101))	('arrest', 'Disease', (80, 86))	('contributed', 'Reg', (54, 65))	('cell apoptotic effect', 'CPA', (14, 35))
328646	32188144	The following are available online at , Figure S1: Effect of demethoxycurcumin (DMC) on apoptosis-related proteins in oral squamous cell carcinoma (OSCC) cells, Figure S2: Activation of p38 mitogen-activated protein kinase (MAPK) is involved in demethoxycurcumin (DMC)-induced heme oxygenase (HO)-1 expression and cell apoptosis in SCC9 cells, Figure S3: Levels of endogenous epidermal growth factor receptor (EGFR) were analyzed by Western blot analysis in HSC-3 and SCC-9 oral squamous cell carcinoma (OSCC) cells, Figure S4: Demethoxycurcumin (DMC) potentiates the growth inhibitory effect of gefitinib on oral squamous cell carcinoma (OSCC) cells.	('Demethoxycurcumin', 'Chemical', 'MESH:C050229', (528, 545))	('carcinoma', 'Phenotype', 'HP:0030731', (493, 502))	('DMC', 'Chemical', 'MESH:C050229', (264, 267))	('heme oxygenase (HO)-1', 'Gene', (277, 298))	('gefitinib', 'Chemical', 'MESH:D000077156', (596, 605))	('SCC-9', 'CellLine', 'CVCL:1685', (468, 473))	('heme oxygenase (HO)-1', 'Gene', '3162', (277, 298))	('demethoxycurcumin', 'Chemical', 'MESH:C050229', (245, 262))	('carcinoma', 'Phenotype', 'HP:0030731', (628, 637))	('MAPK', 'Gene', (224, 228))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (609, 637))	('HSC-3', 'Gene', '150353', (458, 463))	('DMC', 'Chemical', 'MESH:C050229', (547, 550))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (118, 146))	('oral squamous cell carcinoma', 'Disease', (118, 146))	('DMC', 'Chemical', 'MESH:C050229', (80, 83))	('demethoxycurcumin', 'Chemical', 'MESH:C050229', (61, 78))	('oral squamous cell carcinoma', 'Disease', (609, 637))	('MAPK', 'Gene', '1432', (224, 228))	('growth inhibitory effect', 'MPA', (568, 592))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (474, 502))	('SCC9', 'CellLine', 'CVCL:1685', (332, 336))	('epidermal growth factor receptor', 'Gene', (376, 408))	('potentiates', 'PosReg', (552, 563))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (123, 146))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (614, 637))	('oral squamous cell carcinoma', 'Disease', (474, 502))	('Demethoxycurcumin', 'Var', (528, 545))	('p38 mitogen-activated protein kinase', 'Gene', (186, 222))	('epidermal growth factor receptor', 'Gene', '1956', (376, 408))	('HSC-3', 'Gene', (458, 463))	('p38 mitogen-activated protein kinase', 'Gene', '1432', (186, 222))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (479, 502))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))
328700	32266150	Of 69 patients enrolled in this study, immunohistological examination revealed that 52 (75.4%) tumors were classified as high BCL11A expression, while 15 (37.5%) paracancer tissues expressed high BCL11A (p < 0.01) (Figures 1A,B) (Table 1).	('cancer', 'Disease', (166, 172))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('patients', 'Species', '9606', (6, 14))	('high BCL11A', 'Var', (121, 132))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumors', 'Disease', (95, 101))
328702	32266150	In accordance with previous studies, high expression of BCL11A was associated with significantly higher loco-regional recurrence or mortality (hazard ratio: 12; 95% CI, 1.43-100.8, P = 0.009) (Table 2).	('higher', 'PosReg', (97, 103))	('high expression', 'Var', (37, 52))	('mortality', 'Disease', (132, 141))	('BCL11A', 'Gene', (56, 62))	('mortality', 'Disease', 'MESH:D003643', (132, 141))	('loco-regional recurrence', 'CPA', (104, 128))
328706	32266150	BCL11A overexpression promoted proliferation in AMC-HN-8 cells (Figure 2A).	('BCL11A', 'Gene', (0, 6))	('overexpression', 'Var', (7, 21))	('proliferation', 'CPA', (31, 44))	('promoted', 'PosReg', (22, 30))	('AMC-HN-8', 'CellLine', 'CVCL:5966', (48, 56))
328709	32266150	We next addressed whether changes in BCL11A in AMC-HN-8 cells could have an impact on chemosensitivity to cisplatin.	('chemosensitivity to cisplatin', 'MPA', (86, 115))	('changes', 'Var', (26, 33))	('BCL11A', 'Gene', (37, 43))	('cisplatin', 'Chemical', 'MESH:D002945', (106, 115))	('impact', 'Reg', (76, 82))	('AMC-HN-8', 'CellLine', 'CVCL:5966', (47, 55))
328734	32266150	reported that knockdown of BCL11A expression in TNBC cells in a mouse model markedly decreased cancer development.	('decreased', 'NegReg', (85, 94))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('BCL11A', 'Gene', (27, 33))	('cancer', 'Disease', (95, 101))	('knockdown', 'Var', (14, 23))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('mouse', 'Species', '10090', (64, 69))
328736	32266150	They also reported that the survival rates of triple-negative breast cancer patients with either copy number gains or high expression of BCL11A were poorer than those of the remainder of the group.	('patients', 'Species', '9606', (76, 84))	('BCL11A', 'Gene', (137, 143))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('breast cancer', 'Disease', 'MESH:D001943', (62, 75))	('copy number gains', 'Var', (97, 114))	('high', 'Reg', (118, 122))	('breast cancer', 'Phenotype', 'HP:0003002', (62, 75))	('breast cancer', 'Disease', (62, 75))	('poorer', 'NegReg', (149, 155))	('survival rates', 'CPA', (28, 42))
328737	32266150	In addition to lower survival rates, the patients with copy number gains of BCL11A had a higher rate of metastasis and relapse.	('BCL11A', 'Gene', (76, 82))	('copy number gains', 'Var', (55, 72))	('patients', 'Species', '9606', (41, 49))	('lower', 'NegReg', (15, 20))	('survival rates', 'CPA', (21, 35))
328738	32266150	In our study, LSCC patients with high expression of BCL11A were significantly more likely to suffer loco-regional recurrence or to become moribund than those with low expression of BCL11A (hazard ratio: 12, P = 0.009) (Table 2).	('patients', 'Species', '9606', (19, 27))	('high expression', 'Var', (33, 48))	('BCL11A', 'Gene', (52, 58))	('LSCC', 'Disease', (14, 18))	('loco-regional recurrence', 'CPA', (100, 124))	('SCC', 'Phenotype', 'HP:0002860', (15, 18))
328739	32266150	Furthermore, the vast majority of patients with high expression of BCL11A were diagnosed with advanced clinical N1/N2 lymphatic metastasis (P = 0.023) (Table 2).	('patients', 'Species', '9606', (34, 42))	('high expression', 'Var', (48, 63))	('BCL11A', 'Gene', (67, 73))
328745	32266150	Furthermore, overexpressing Mdm2 rescued both apoptosis and proliferation defects caused by Bcl11a knockdown in B cells.	('Bcl11a', 'Gene', (92, 98))	('apoptosis', 'CPA', (46, 55))	('Mdm2', 'Gene', '4193', (28, 32))	('knockdown', 'Var', (99, 108))	('proliferation defects', 'CPA', (60, 81))	('Mdm2', 'Gene', (28, 32))
328746	32266150	In addition, Bcl11a deletion resulted in p53 accumulation in lymphocytes, likely due to reduced Mdm2/Mdm4.	('Mdm2', 'Gene', '4193', (96, 100))	('p53', 'Gene', '7157', (41, 44))	('Mdm4', 'Gene', (101, 105))	('Bcl11a', 'Gene', (13, 19))	('accumulation', 'PosReg', (45, 57))	('Mdm4', 'Gene', '4194', (101, 105))	('deletion', 'Var', (20, 28))	('Mdm2', 'Gene', (96, 100))	('p53', 'Gene', (41, 44))
328778	28717185	LncRNAs can also contribute to carcinogenesis or tumor suppression and play a role in regulating cell cycle, apoptosis, proliferation, invasion and migration through their aberrant expression in different cancers.	('proliferation', 'CPA', (120, 133))	('cancers', 'Disease', 'MESH:D009369', (205, 212))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('migration', 'CPA', (148, 157))	('cancers', 'Disease', (205, 212))	('apoptosis', 'CPA', (109, 118))	('aberrant', 'Var', (172, 180))	('carcinogenesis or tumor', 'Disease', 'MESH:D063646', (31, 54))	('LncRNAs', 'Protein', (0, 7))	('contribute', 'Reg', (17, 27))	('regulating', 'Reg', (86, 96))	('carcinogenesis or tumor', 'Disease', (31, 54))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('cell cycle', 'CPA', (97, 107))	('cancers', 'Phenotype', 'HP:0002664', (205, 212))	('invasion', 'CPA', (135, 143))
328781	28717185	The migration and growth of tumors was inhibited after silencing MALAT-1 expression, whereas the forced expression of MALAT-1 significantly increased migration in NSCLC cells.	('SCLC', 'Phenotype', 'HP:0030357', (164, 168))	('MALAT-1', 'Gene', (118, 125))	('inhibited', 'NegReg', (39, 48))	('MALAT-1', 'Gene', (65, 72))	('tumors', 'Disease', (28, 34))	('tumors', 'Disease', 'MESH:D009369', (28, 34))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('NSCLC', 'Disease', (163, 168))	('silencing', 'Var', (55, 64))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('NSCLC', 'Disease', 'MESH:D002289', (163, 168))	('MALAT-1', 'Gene', '378938', (65, 72))	('migration', 'CPA', (150, 159))	('increased', 'PosReg', (140, 149))	('migration', 'CPA', (4, 13))	('MALAT-1', 'Gene', '378938', (118, 125))	('NSCLC', 'Phenotype', 'HP:0030358', (163, 168))
328836	28717185	The results demonstrated that the migration ability was significantly inhibited after knockdown of HOXA11-AS, especially in A549 cells (P < 0.01, Fig.	('HOXA11-AS', 'Gene', '221883', (99, 108))	('knockdown', 'Var', (86, 95))	('HOXA11-AS', 'Gene', (99, 108))	('A549', 'CellLine', 'CVCL:0023', (124, 128))	('migration ability', 'CPA', (34, 51))	('inhibited', 'NegReg', (70, 79))
328839	28717185	Overall, these results indicated that the migration of NSCLC cells was inhibited due to knockdown of HOXA11-AS.	('migration of', 'CPA', (42, 54))	('NSCLC', 'Disease', (55, 60))	('inhibited', 'NegReg', (71, 80))	('NSCLC', 'Disease', 'MESH:D002289', (55, 60))	('knockdown', 'Var', (88, 97))	('SCLC', 'Phenotype', 'HP:0030357', (56, 60))	('HOXA11-AS', 'Gene', (101, 110))	('HOXA11-AS', 'Gene', '221883', (101, 110))	('NSCLC', 'Phenotype', 'HP:0030358', (55, 60))
328874	28717185	Additionally, we found that the AUC of HOXA11-AS was 0.878 (95% CI: 0.786-0.969) for lung adenocarcinoma and 0.962 (95% CI: 0.928-0.996) for lung squamous cell carcinoma, which predicted a diagnostic value of HOXA11-AS in NSCLC.	('SCLC', 'Phenotype', 'HP:0030357', (223, 227))	('HOXA11-AS', 'Gene', (209, 218))	('HOXA11-AS', 'Gene', '221883', (209, 218))	('NSCLC', 'Phenotype', 'HP:0030358', (222, 227))	('carcinoma', 'Phenotype', 'HP:0030731', (160, 169))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (141, 169))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (141, 169))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (146, 169))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (85, 104))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('lung squamous cell carcinoma', 'Disease', (141, 169))	('NSCLC', 'Disease', (222, 227))	('lung adenocarcinoma', 'Disease', (85, 104))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (85, 104))	('NSCLC', 'Disease', 'MESH:D002289', (222, 227))	('0.962', 'Var', (109, 114))	('HOXA11-AS', 'Gene', (39, 48))	('HOXA11-AS', 'Gene', '221883', (39, 48))
328878	28717185	The proliferation, migration, invasion and tumorigenic and angiogenic ability of NSCLC cells were all inhibited and apoptosis was induced after silencing the expression of HOXA11-AS.	('angiogenic ability', 'CPA', (59, 77))	('induced', 'Reg', (130, 137))	('inhibited', 'NegReg', (102, 111))	('HOXA11-AS', 'Gene', '221883', (172, 181))	('migration', 'CPA', (19, 28))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('NSCLC', 'Phenotype', 'HP:0030358', (81, 86))	('invasion', 'CPA', (30, 38))	('HOXA11-AS', 'Gene', (172, 181))	('SCLC', 'Phenotype', 'HP:0030357', (82, 86))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('NSCLC', 'Disease', (81, 86))	('silencing', 'Var', (144, 153))	('expression', 'Protein', (158, 168))	('tumor', 'Disease', (43, 48))	('NSCLC', 'Disease', 'MESH:D002289', (81, 86))
328882	28717185	In our study, HOXA11-AS knockdown causes G0/G1 or G2/M arrest and cell cycle could not progress to the following phase, which indicate that the silencing of HOXA11-AS inhibit cell cycle progression, also, the different phenotypes of HOXA11-AS RNAi may cause a minor difference on different phases arrest.	('HOXA11-AS', 'Gene', '221883', (157, 166))	('M arrest', 'Disease', 'MESH:D006323', (53, 61))	('HOXA11-AS', 'Gene', '221883', (233, 242))	('HOXA11-AS', 'Gene', (14, 23))	('HOXA11-AS', 'Gene', '221883', (14, 23))	('M arrest', 'Disease', (53, 61))	('HOXA11-AS', 'Gene', (233, 242))	('inhibit', 'NegReg', (167, 174))	('cell cycle progression', 'CPA', (175, 197))	('silencing', 'Var', (144, 153))	('G0/G1', 'CPA', (41, 46))	('knockdown', 'Var', (24, 33))	('HOXA11-AS', 'Gene', (157, 166))
328883	28717185	In addition, as reported, deregulated cell-cycle control is a fundamental aspect for the treatment of malignancies.	('malignancies', 'Disease', (102, 114))	('deregulated', 'Var', (26, 37))	('malignancies', 'Disease', 'MESH:D009369', (102, 114))
328887	28717185	In addition, angiogenesis is the basis of tumor growth, metastasis, invasion and recidivism, and the results of the CAM model confirmed that the tumorigenic and angiogenic ability of NSCLC cells was weakened after silencing the expression of HOXA11-AS, indicating that HOXA11-AS has a promoting effect on angiogenesis.	('NSCLC', 'Phenotype', 'HP:0030358', (183, 188))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('tumor', 'Disease', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('silencing', 'Var', (214, 223))	('NSCLC', 'Disease', (183, 188))	('angiogenesis', 'CPA', (305, 317))	('promoting', 'PosReg', (285, 294))	('SCLC', 'Phenotype', 'HP:0030357', (184, 188))	('tumor', 'Disease', (145, 150))	('weakened', 'NegReg', (199, 207))	('NSCLC', 'Disease', 'MESH:D002289', (183, 188))	('HOXA11-AS', 'Gene', (269, 278))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('HOXA11-AS', 'Gene', '221883', (269, 278))	('HOXA11-AS', 'Gene', '221883', (242, 251))	('HOXA11-AS', 'Gene', (242, 251))
328893	28717185	Methylation of HOXA11 was significantly associated with poor prognosis in cancer patients.	('Methylation', 'Var', (0, 11))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('patients', 'Species', '9606', (81, 89))	('cancer', 'Disease', (74, 80))	('HOXA11', 'Gene', (15, 21))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('associated', 'Reg', (40, 50))
328894	28717185	Hypermethylation of HOXA11 was associated with NSCLC progression by effecting cell proliferation or migration.	('migration', 'CPA', (100, 109))	('NSCLC', 'Phenotype', 'HP:0030358', (47, 52))	('Hypermethylation', 'Var', (0, 16))	('SCLC', 'Phenotype', 'HP:0030357', (48, 52))	('associated', 'Reg', (31, 41))	('NSCLC', 'Disease', (47, 52))	('effecting', 'Reg', (68, 77))	('NSCLC', 'Disease', 'MESH:D002289', (47, 52))	('HOXA11', 'Gene', (20, 26))	('cell proliferation', 'CPA', (78, 96))
328906	28717185	In addition, they found that HOXA11-AS could affect p16, p21 and p27 expression via competitive endogenous RNAs, epigenetic modification, or chromatin modification methods to regulate proliferation and cell cycle of glioma cells.	('affect', 'Reg', (45, 51))	('p16', 'Gene', '1029', (52, 55))	('p21', 'Gene', '644914', (57, 60))	('glioma', 'Disease', 'MESH:D005910', (216, 222))	('cell cycle', 'CPA', (202, 212))	('glioma', 'Phenotype', 'HP:0009733', (216, 222))	('proliferation', 'CPA', (184, 197))	('regulate', 'Reg', (175, 183))	('p27', 'Gene', (65, 68))	('expression', 'MPA', (69, 79))	('p27', 'Gene', '3429', (65, 68))	('glioma', 'Disease', (216, 222))	('p16', 'Gene', (52, 55))	('HOXA11-AS', 'Gene', (29, 38))	('p21', 'Gene', (57, 60))	('HOXA11-AS', 'Gene', '221883', (29, 38))	('epigenetic modification', 'Var', (113, 136))
328955	33684886	Dysregulation of proteasome-related protein degradation leads to tumorigenesis, while Exendin-4, a glucagon-like peptide 1 receptor (GLP-1R) agonist, possesses anti-cancer effects.	('proteasome-related protein degradation', 'MPA', (17, 55))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('Dysregulation', 'Var', (0, 13))	('Exendin-4', 'Chemical', 'MESH:D000077270', (86, 95))	('leads to', 'Reg', (56, 64))	('Exendin-4', 'Gene', (86, 95))	('cancer', 'Disease', (165, 171))	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('tumorigenesis', 'CPA', (65, 78))	('glucagon-like peptide 1 receptor', 'Gene', (99, 131))	('glucagon-like peptide 1 receptor', 'Gene', '2740', (99, 131))
328957	33684886	PSMA2 expression was increased in 12 cancer types in TCGA database and cervical cancer specimens from patients with T2D (T2D vs non-T2D: 3.22 (95% confidence interval CI: 1.38, 5.05) vs 1.00 (0.66, 1.34) fold change, P = 0.01).	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('PSMA2', 'Gene', (0, 5))	('increased', 'PosReg', (21, 30))	('cancer', 'Disease', (37, 43))	('T2D', 'Phenotype', 'HP:0005978', (132, 135))	('patients', 'Species', '9606', (102, 110))	('expression', 'MPA', (6, 16))	('T2D', 'Phenotype', 'HP:0005978', (121, 124))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('T2D', 'Phenotype', 'HP:0005978', (116, 119))	('T2D', 'Var', (116, 119))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('cancer', 'Disease', (80, 86))
328958	33684886	psma2-shRNA decreased cell proliferation in vitro, and tumour volume and Ki67 expression in vivo.	('tumour', 'Disease', (55, 61))	('expression', 'MPA', (78, 88))	('Ki67', 'Gene', '17345', (73, 77))	('psma2-shRNA', 'Var', (0, 11))	('tumour', 'Phenotype', 'HP:0002664', (55, 61))	('decreased', 'NegReg', (12, 21))	('tumour', 'Disease', 'MESH:D009369', (55, 61))	('Ki67', 'Gene', (73, 77))	('cell proliferation', 'CPA', (22, 40))
328962	33684886	This correlation was corroborated by in vitro experiments where silencing glp-1r decreased psma2 expression.	('decreased', 'NegReg', (81, 90))	('psma2 expression', 'MPA', (91, 107))	('glp-1r', 'Gene', (74, 80))	('glp-1r', 'Gene', '2740', (74, 80))	('silencing', 'Var', (64, 73))
328980	33684886	Genetic mutations, chemical irritation, irradiation, toxins, bacteria, and virus infections are amongst the common causes of tumorigenesis.	('virus infections', 'Disease', (75, 91))	('irritation', 'Disease', (28, 38))	('virus infections', 'Disease', 'MESH:D001102', (75, 91))	('Genetic mutations', 'Var', (0, 17))	('irritation', 'Disease', 'MESH:D001523', (28, 38))
328984	33684886	Inhibition of the proteasome results in cell-cycle arrest and apoptosis, and is a target for anticancer therapy.	('proteasome', 'Protein', (18, 28))	('cancer', 'Disease', (97, 103))	('arrest', 'Disease', 'MESH:D006323', (51, 57))	('arrest', 'Disease', (51, 57))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('apoptosis', 'CPA', (62, 71))	('Inhibition', 'Var', (0, 10))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
328986	33684886	A single nucleotide polymorphism (SNPs) c.328C>G, contributing to missense protein-coding in PSMA2, has been implicated in human breast and colorectal cancer.	('colorectal cancer', 'Disease', (140, 157))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('human', 'Species', '9606', (123, 128))	('implicated', 'Reg', (109, 119))	('PSMA2', 'Gene', (93, 98))	('missense protein-coding', 'Var', (66, 89))	('c.328C>G', 'Mutation', 'c.328C>G', (40, 48))	('colorectal cancer', 'Disease', 'MESH:D015179', (140, 157))	('colorectal cancer', 'Phenotype', 'HP:0003003', (140, 157))	('breast', 'Disease', (129, 135))
329006	33684886	The CUP-1 is an immortal mouse epithelial cancer cell line generated from the kidney of baby C57BL/6J mice with the insertion of the HPV-16 E7 oncogene.	('mice', 'Species', '10090', (102, 106))	('epithelial cancer', 'Disease', (31, 48))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('insertion', 'Var', (116, 125))	('mouse', 'Species', '10090', (25, 30))	('HPV-16', 'Species', '333760', (133, 139))	('epithelial cancer', 'Disease', 'MESH:D009369', (31, 48))	('epithelial cancer', 'Phenotype', 'HP:0031492', (31, 48))	('HPV-16', 'Gene', (133, 139))
329014	33684886	Secondly, PSMA2-O/E and -shRNA increased and decreased cell proliferation under high glucose condition and tumour volume in db/db mice, respectively.	('mice', 'Species', '10090', (130, 134))	('decreased', 'NegReg', (45, 54))	('tumour', 'Phenotype', 'HP:0002664', (107, 113))	('cell proliferation', 'CPA', (55, 73))	('PSMA2-O/E', 'Var', (10, 19))	('tumour', 'Disease', 'MESH:D009369', (107, 113))	('glucose', 'Chemical', 'MESH:D005947', (85, 92))	('high glucose', 'Phenotype', 'HP:0003074', (80, 92))	('tumour', 'Disease', (107, 113))
329019	33684886	Secondly, we generated stable cell lines with psma2-O/E or -shRNA transfection in CUP-1 cells to explore the role of psma2 in cell proliferation and tumour growth.	('tumour growth', 'Disease', (149, 162))	('psma2-O/E', 'Var', (46, 55))	('tumour', 'Phenotype', 'HP:0002664', (149, 155))	('tumour growth', 'Disease', 'MESH:D006130', (149, 162))
329031	33684886	Our group established CUP-1 by incorporating HPV-16 E7 and activated EJ-ras oncogene into baby mouse kidney epithelial cells from C57BL/KSJ mice, which shares the same genetic background of db/db mice.	('C57BL/KSJ', 'Var', (130, 139))	('mice', 'Species', '10090', (140, 144))	('mice', 'Species', '10090', (196, 200))	('HPV-16', 'Species', '333760', (45, 51))	('EJ-ras oncogene', 'Gene', (69, 84))	('EJ', 'CellLine', 'CVCL:7039', (69, 71))	('mouse', 'Species', '10090', (95, 100))
329041	33684886	Diabetes was defined based on physician-diagnosed T2D and/or prescription of glucose-lowering drugs and/or abnormal laboratory values as defined by the American Diabetes Association guidelines: HbA1c >= 6.5%, or fasting plasma glucose >= 7.0 mmol/L, or 2-h plasma glucose >= 11.1 mmol/L during a 75 g oral glucose tolerance test (OGTT), or random plasma glucose >= 11.1 mmol/L with typical symptoms of hyperglycemia or hyperglycaemic crisis.	('glucose', 'Chemical', 'MESH:D005947', (227, 234))	('glucose', 'Chemical', 'MESH:D005947', (264, 271))	('abnormal laboratory', 'Phenotype', 'HP:0001939', (107, 126))	('glucose', 'Chemical', 'MESH:D005947', (354, 361))	('hyperglycemia', 'Phenotype', 'HP:0003074', (402, 415))	('glucose', 'Chemical', 'MESH:D005947', (306, 313))	('>= 11.1', 'Var', (272, 279))	('glucose', 'Chemical', 'MESH:D005947', (77, 84))	('hyperglycemia', 'Disease', 'MESH:D006943', (402, 415))	('>= 7.0', 'Var', (235, 241))	('Diabetes', 'Disease', 'MESH:D003920', (161, 169))	('Diabetes', 'Disease', 'MESH:D003920', (0, 8))	('T2D', 'Phenotype', 'HP:0005978', (50, 53))	('HbA1c', 'Var', (194, 199))	('hyperglycemia', 'Disease', (402, 415))	('Diabetes', 'Disease', (161, 169))	('Diabetes', 'Disease', (0, 8))
329054	33684886	For psma2 knockdown, shRNA lentivirus particles were purchased from Sigma (Cat.	('knockdown', 'Var', (10, 19))	('psma2', 'Gene', (4, 9))	('Cat', 'Gene', '847', (75, 78))	('Cat', 'Gene', (75, 78))
329056	33684886	For GLP-1R knockdown, siRNA was purchased from Invitrogen (Cat.	('Cat', 'Gene', '847', (59, 62))	('Cat', 'Gene', (59, 62))	('knockdown', 'Var', (11, 20))	('GLP-1R', 'Gene', (4, 10))
329070	33684886	The primary antibodies included PSMA2, GLP-1R, phospho-P65, P65, phospho-IkappaB, IkappaB, and GAPDH.	('P65', 'Gene', '5970', (55, 58))	('P65', 'Gene', (55, 58))	('phospho-IkappaB', 'Var', (65, 80))	('P65', 'Gene', '5970', (60, 63))	('P65', 'Gene', (60, 63))
329073	33684886	In animal experiments, we calculated the sample size to be 7 in each group (28 in total) based on the mean and standard deviation (SD) (mean+-SD) of tumour volume in the Exendin-4 group (500+-110 mm2) and control group (700+-120 mm2) in a pilot study (n = 3 in each group), to achieve 90% power with an alpha (p) value less than 0.05.	('tumour', 'Phenotype', 'HP:0002664', (149, 155))	('Exendin-4', 'Chemical', 'MESH:D000077270', (170, 179))	('500+-110 mm2', 'Var', (187, 199))	('tumour', 'Disease', 'MESH:D009369', (149, 155))	('tumour', 'Disease', (149, 155))
329096	33684886	Consistent with the above results, psma2-shRNA reduced cell viability and proliferation in normal and in high glucose conditions in vitro (Fig.	('glucose', 'Chemical', 'MESH:D005947', (110, 117))	('psma2-shRNA', 'Var', (35, 46))	('cell viability', 'CPA', (55, 69))	('high glucose', 'Phenotype', 'HP:0003074', (105, 117))	('reduced', 'NegReg', (47, 54))
329099	33684886	Tumour with psma2-shRNA-CUP-1 cells had decreased Ki67 expression, indicative of reduced tumour proliferation in vivo (PSMA2-shRNA vehicle: 0.26%, 95% CI: 0.09-0.42; vector control: 0.46%, 95% CI: 0.32-0.60; P = 0.028, t-test) (Fig.	('Ki67', 'Gene', (50, 54))	('tumour', 'Phenotype', 'HP:0002664', (89, 95))	('Tumour', 'Phenotype', 'HP:0002664', (0, 6))	('expression', 'MPA', (55, 65))	('psma2-shRNA-CUP-1 cells', 'Var', (12, 35))	('Ki67', 'Gene', '17345', (50, 54))	('reduced', 'NegReg', (81, 88))	('tumour proliferation', 'Disease', 'MESH:D009369', (89, 109))	('decreased', 'NegReg', (40, 49))	('tumour proliferation', 'Disease', (89, 109))
329100	33684886	Downregulation of psma2 did not alter blood glucose level in vivo, suggesting that the anti-cancer effect was not glucose-mediated (SFig.	('psma2', 'Gene', (18, 23))	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('glucose', 'Chemical', 'MESH:D005947', (114, 121))	('Downregulation', 'Var', (0, 14))	('glucose', 'Chemical', 'MESH:D005947', (44, 51))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
329118	33684886	Upon knockdown of GLP-1R, there was correspondingly reduced expression of PSMA2 under normal and high glucose conditions (Fig.	('expression', 'MPA', (60, 70))	('reduced', 'NegReg', (52, 59))	('knockdown', 'Var', (5, 14))	('high glucose', 'Phenotype', 'HP:0003074', (97, 109))	('GLP-1R', 'Gene', (18, 24))	('PSMA2', 'Gene', (74, 79))	('glucose', 'Chemical', 'MESH:D005947', (102, 109))
329127	33684886	In vivo, psma2-shRNA attenuated tumour growth and cell proliferation.	('attenuated tumour', 'Disease', 'MESH:C538265', (21, 38))	('tumour growth', 'Disease', 'MESH:D006130', (32, 45))	('tumour', 'Phenotype', 'HP:0002664', (32, 38))	('attenuated tumour', 'Disease', (21, 38))	('tumour growth', 'Disease', (32, 45))	('psma2-shRNA', 'Var', (9, 20))	('cell proliferation', 'CPA', (50, 68))
329137	33684886	On the other hand, MG132, a proteasome inhibitor, attenuated diabetic nephropathy by enhancing renal antioxidative capacity and histone degradation.	('diabetic nephropathy', 'Disease', (61, 81))	('enhancing', 'PosReg', (85, 94))	('diabetic nephropathy', 'Disease', 'MESH:D003928', (61, 81))	('histone degradation', 'MPA', (128, 147))	('renal antioxidative capacity', 'MPA', (95, 123))	('nephropathy', 'Phenotype', 'HP:0000112', (70, 81))	('MG132', 'Chemical', 'MESH:C072553', (19, 24))	('attenuated', 'NegReg', (50, 60))	('MG132', 'Var', (19, 24))
329146	33684886	The proto-oncogenic role of psma2 was confirmed by transfection studies where psma2-O/E enhanced, and psma2-shRNA reduced cancer growth.	('psma2-shRNA', 'Var', (102, 113))	('reduced', 'NegReg', (114, 121))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))
329149	33684886	These original findings suggested that dysregulation of PSMA2 might underlie the high risk of cancer in T2D.	('dysregulation', 'Var', (39, 52))	('T2D', 'Phenotype', 'HP:0005978', (104, 107))	('T2D', 'Disease', (104, 107))	('PSMA2', 'Gene', (56, 61))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
329181	33684886	In sum, our consistent results allow us to conclude that high glucose increased PSMA2 expression and promoted tumour growth, which could be attenuated by Exendin-4.	('promoted', 'PosReg', (101, 109))	('Exendin-4', 'Chemical', 'MESH:D000077270', (154, 163))	('increased', 'PosReg', (70, 79))	('tumour', 'Phenotype', 'HP:0002664', (110, 116))	('expression', 'MPA', (86, 96))	('tumour growth', 'Disease', (110, 123))	('high glucose', 'Var', (57, 69))	('PSMA2', 'Gene', (80, 85))	('high glucose', 'Phenotype', 'HP:0003074', (57, 69))	('tumour growth', 'Disease', 'MESH:D006130', (110, 123))	('glucose', 'Chemical', 'MESH:D005947', (62, 69))
329191	28814486	Overall, low serum ghrelin was significantly associated with increased risk of colorectal cancer (Q1 vs Q4: OR:1.57, 95% CI: 1.05, 2.34).	('low', 'Var', (9, 12))	('ghrelin', 'Protein', (19, 26))	('colorectal cancer', 'Phenotype', 'HP:0003003', (79, 96))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('colorectal cancer', 'Disease', (79, 96))	('ghrelin', 'Chemical', 'MESH:D054439', (19, 26))	('rectal cancer', 'Phenotype', 'HP:0100743', (83, 96))	('serum ghrelin', 'Protein', (13, 26))	('colorectal cancer', 'Disease', 'MESH:D015179', (79, 96))
329194	28814486	Low serum ghrelin was associated with an increased colorectal cancer risk within 10 years of blood draw with a decreased risk for developing colorectal cancer more than 20 years after blood draw.	('ghrelin', 'Chemical', 'MESH:D054439', (10, 17))	('colorectal cancer', 'Disease', 'MESH:D015179', (51, 68))	('colorectal cancer', 'Disease', 'MESH:D015179', (141, 158))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('colorectal cancer', 'Phenotype', 'HP:0003003', (51, 68))	('decreased', 'NegReg', (111, 120))	('colorectal cancer', 'Phenotype', 'HP:0003003', (141, 158))	('colorectal cancer', 'Disease', (51, 68))	('Low serum', 'Var', (0, 9))	('ghrelin', 'Protein', (10, 17))	('colorectal cancer', 'Disease', (141, 158))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('rectal cancer', 'Phenotype', 'HP:0100743', (55, 68))	('rectal cancer', 'Phenotype', 'HP:0100743', (145, 158))
329241	28814486	Surprisingly we observed substantial differences in the associations between low serum ghrelin and cancers occurring in each time period.	('low', 'Var', (77, 80))	('ghrelin', 'Chemical', 'MESH:D054439', (87, 94))	('cancers', 'Disease', 'MESH:D009369', (99, 106))	('cancers', 'Phenotype', 'HP:0002664', (99, 106))	('cancers', 'Disease', (99, 106))	('serum ghrelin', 'Protein', (81, 94))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
329245	28814486	However, low serum ghrelin was associated with a statistically significant decrease in risk of both colon (OR: 0.33, 95% CI: 0.11, 1.03) and rectal (OR: 0.18, 95% CI: 0.04, 0.82) cancers occurring more than 20 years after blood draw (CRC:0.26; 95% CI: 0.11, 0.64).	('low', 'Var', (9, 12))	('ghrelin', 'Protein', (19, 26))	('decrease', 'NegReg', (75, 83))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('rectal', 'Disease', (141, 147))	('ghrelin', 'Chemical', 'MESH:D054439', (19, 26))	('colon', 'Disease', (100, 105))	('cancers', 'Disease', 'MESH:D009369', (179, 186))	('cancers', 'Phenotype', 'HP:0002664', (179, 186))	('cancers', 'Disease', (179, 186))	('serum ghrelin', 'Protein', (13, 26))
329259	28814486	Whereas low ghrelin was associated with an increased risk among cancers occurring within 10 years of blood draw, it was associated with a decreased risk in cancers occurring more than 20 years after blood draw.	('ghrelin', 'Protein', (12, 19))	('low', 'Var', (8, 11))	('cancers', 'Phenotype', 'HP:0002664', (156, 163))	('cancers', 'Disease', (156, 163))	('cancers', 'Disease', 'MESH:D009369', (156, 163))	('decreased', 'NegReg', (138, 147))	('cancers', 'Disease', 'MESH:D009369', (64, 71))	('ghrelin', 'Chemical', 'MESH:D054439', (12, 19))	('cancers', 'Phenotype', 'HP:0002664', (64, 71))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('cancers', 'Disease', (64, 71))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
329263	28814486	It is also possible that the metabolic repercussions of low serum ghrelin may contribute to a pro-carcinogenic environment during cancer initiation while the pro-inflammatory effect of low serum ghrelin may enhance subsequent tumor development.	('carcinogenic', 'Disease', 'MESH:D063646', (98, 110))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('low serum', 'Var', (185, 194))	('carcinogenic', 'Disease', (98, 110))	('low serum', 'Var', (56, 65))	('cancer', 'Disease', (130, 136))	('contribute', 'Reg', (78, 88))	('metabolic', 'MPA', (29, 38))	('men', 'Species', '9606', (118, 121))	('men', 'Species', '9606', (239, 242))	('tumor', 'Disease', 'MESH:D009369', (226, 231))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('enhance', 'PosReg', (207, 214))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('ghrelin', 'Chemical', 'MESH:D054439', (66, 73))	('tumor', 'Disease', (226, 231))	('ghrelin', 'Chemical', 'MESH:D054439', (195, 202))
329270	28814486	Also, we measured total ghrelin, but there are two isoforms of ghrelin: acylated ghrelin, which binds to the growth hormone secretagogue receptor 1a, and des-acylated ghrelin.	('ghrelin', 'Chemical', 'MESH:D054439', (63, 70))	('binds', 'Interaction', (96, 101))	('ghrelin', 'Chemical', 'MESH:D054439', (24, 31))	('ghrelin', 'Chemical', 'MESH:D054439', (81, 88))	('ghrelin', 'Chemical', 'MESH:D054439', (167, 174))	('des-acylated', 'Var', (154, 166))
329280	28814486	Ghrelin concentrations might be altered in conditions of chronic inflammation Low serum ghrelin concentrations have been associated with an increased risk of development of esophageal and gastric cancers in prospective studies Individuals with low serum ghrelin concentrations had a 10-fold increase in risk of colorectal cancers for tumors developing within 10 years of blood draw Conversely, for individuals with tumors developing more than 20 years later, low serum ghrelin concentration was associated with a significantly decreased risk of colorectal cancer Ghrelin concentrations may vary across the carcinogenic process, and this variation may have clinical utility.	('decreased', 'NegReg', (527, 536))	('gastric cancer', 'Phenotype', 'HP:0012126', (188, 202))	('tumor', 'Phenotype', 'HP:0002664', (334, 339))	('chronic inflammation', 'Disease', 'MESH:D007249', (57, 77))	('chronic inflammation', 'Disease', (57, 77))	('tumors', 'Disease', (334, 340))	('tumors', 'Disease', (415, 421))	('carcinogenic process', 'Disease', (606, 626))	('colorectal cancer', 'Disease', 'MESH:D015179', (311, 328))	('rectal cancer', 'Phenotype', 'HP:0100743', (549, 562))	('carcinogenic process', 'Disease', 'MESH:D009385', (606, 626))	('esophageal', 'Disease', (173, 183))	('colorectal cancer', 'Phenotype', 'HP:0003003', (545, 562))	('colorectal cancers', 'Disease', 'MESH:D015179', (311, 329))	('tumors', 'Disease', 'MESH:D009369', (334, 340))	('tumors', 'Disease', 'MESH:D009369', (415, 421))	('cancer', 'Phenotype', 'HP:0002664', (556, 562))	('Ghrelin', 'Chemical', 'MESH:D054439', (563, 570))	('esophageal', 'Disease', 'MESH:D004941', (173, 183))	('Ghrelin', 'Chemical', 'MESH:D054439', (0, 7))	('rectal cancer', 'Phenotype', 'HP:0100743', (315, 328))	('cancers', 'Phenotype', 'HP:0002664', (196, 203))	('ghrelin', 'Chemical', 'MESH:D054439', (469, 476))	('ghrelin', 'Chemical', 'MESH:D054439', (88, 95))	('cancer', 'Phenotype', 'HP:0002664', (322, 328))	('Low', 'Var', (78, 81))	('colorectal cancer', 'Disease', 'MESH:D015179', (545, 562))	('colorectal cancer', 'Phenotype', 'HP:0003003', (311, 328))	('tumor', 'Phenotype', 'HP:0002664', (415, 420))	('men', 'Species', '9606', (165, 168))	('ghrelin', 'Chemical', 'MESH:D054439', (254, 261))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('gastric cancers', 'Disease', 'MESH:D013274', (188, 203))	('colorectal cancers', 'Disease', (311, 329))	('gastric cancers', 'Disease', (188, 203))	('colorectal cancer', 'Disease', (545, 562))	('gastric cancers', 'Phenotype', 'HP:0012126', (188, 203))	('cancers', 'Phenotype', 'HP:0002664', (322, 329))	('tumors', 'Phenotype', 'HP:0002664', (334, 340))	('tumors', 'Phenotype', 'HP:0002664', (415, 421))	('low', 'Var', (244, 247))
329288	33579235	A mixed effects (ANOVA) test was used to determine the correlation between DeltaNp63alpha and ERK3 expression levels (MFI).	('ERK3 expression levels', 'MPA', (94, 116))	('DeltaNp63alpha', 'Chemical', '-', (75, 89))	('DeltaNp63alpha', 'Var', (75, 89))
329290	33579235	The effect of ERK3 regulation by DeltaNp63alpha on cell migration was measured by performing trans-well migration assay.	('DeltaNp63alpha', 'Chemical', '-', (33, 47))	('DeltaNp63alpha', 'Var', (33, 47))	('cell migration', 'CPA', (51, 65))	('ERK3', 'Gene', (14, 18))
329294	33579235	Moreover, similar to the effect of  Np63alpha depletion, silencing ERK3 greatly enhanced A431 cell migration.	('p63', 'Gene', '8626', (37, 40))	('A431', 'CellLine', 'CVCL:0037', (89, 93))	('A431 cell migration', 'CPA', (89, 108))	('silencing', 'Var', (57, 66))	('enhanced', 'PosReg', (80, 88))	('ERK3', 'Gene', (67, 71))	('p63', 'Gene', (37, 40))
329300	33579235	As DeltaNp63alpha is a critical regulator in epithelial development, alterations in its expression and functions are implicated in tumor development.	('DeltaNp63alpha', 'Gene', (3, 17))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('alterations', 'Var', (69, 80))	('functions', 'MPA', (103, 112))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumor', 'Disease', (131, 136))	('DeltaNp63alpha', 'Chemical', '-', (3, 17))	('implicated', 'Reg', (117, 127))	('expression', 'MPA', (88, 98))
329304	33579235	DeltaNp63alpha promotes tumor initiation by activating signaling pathways involved in cell survival.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('activating', 'PosReg', (44, 54))	('tumor', 'Disease', (24, 29))	('signaling pathways', 'Pathway', (55, 73))	('DeltaNp63alpha', 'Chemical', '-', (0, 14))	('DeltaNp63alpha', 'Var', (0, 14))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('promotes', 'PosReg', (15, 23))
329305	33579235	For example, DeltaNp63alpha promotes the activation of AKT pathway, which in turn enhances cell proliferation of pancreatic cancer and squamous cell carcinoma of the lung.	('DeltaNp63alpha', 'Var', (13, 27))	('pancreatic cancer', 'Disease', 'MESH:D010190', (113, 130))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (135, 158))	('AKT', 'Gene', (55, 58))	('squamous cell carcinoma of the lung', 'Phenotype', 'HP:0030359', (135, 170))	('carcinoma', 'Phenotype', 'HP:0030731', (149, 158))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (113, 130))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (135, 158))	('enhances', 'PosReg', (82, 90))	('squamous cell carcinoma', 'Disease', (135, 158))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('carcinoma of the lung', 'Phenotype', 'HP:0100526', (149, 170))	('AK', 'Phenotype', 'HP:0025127', (55, 57))	('pancreatic cancer', 'Disease', (113, 130))	('DeltaNp63alpha', 'Chemical', '-', (13, 27))	('activation', 'PosReg', (41, 51))	('AKT', 'Gene', '207', (55, 58))	('cell proliferation', 'CPA', (91, 109))
329306	33579235	Premalignant lesions and epidermal cysts were observed in the basal layer of the epidermis upon DeltaNp63alpha induction, indicating an oncogenic role for DeltaNp63alpha in the initiation of SCC tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('tumor', 'Disease', (195, 200))	('Premalignant lesions', 'Disease', 'MESH:D001768', (0, 20))	('epidermal cysts', 'Phenotype', 'HP:0200040', (25, 40))	('Premalignant lesions', 'Disease', (0, 20))	('SCC', 'Gene', (191, 194))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('SCC', 'Phenotype', 'HP:0002860', (191, 194))	('DeltaNp63alpha', 'Chemical', '-', (96, 110))	('DeltaNp63alpha', 'Chemical', '-', (155, 169))	('DeltaNp63alpha', 'Var', (96, 110))	('SCC', 'Gene', '6317', (191, 194))
329307	33579235	Nevertheless, an inhibitory effect of DeltaNp63alpha on cancer cell invasion has been reported in breast, bladder, and prostate cancers.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('cancers', 'Phenotype', 'HP:0002664', (128, 135))	('prostate cancers', 'Phenotype', 'HP:0012125', (119, 135))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('prostate cancers', 'Disease', (119, 135))	('inhibitory effect', 'NegReg', (17, 34))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('DeltaNp63alpha', 'Chemical', '-', (38, 52))	('bladder', 'Disease', (106, 113))	('DeltaNp63alpha', 'Var', (38, 52))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('prostate cancers', 'Disease', 'MESH:D011471', (119, 135))	('breast', 'Disease', (98, 104))	('cancer', 'Disease', (128, 134))
329321	33579235	We also showed that DeltaNp63alpha directly upregulates ERK3 gene transcription and expression levels in NMSC and that ERK3 mediates the role of DeltaNp63alpha in regulating cancer cell migration.	('ERK3 gene', 'Gene', (56, 65))	('cancer', 'Disease', (174, 180))	('transcription', 'MPA', (66, 79))	('expression levels', 'MPA', (84, 101))	('upregulates', 'PosReg', (44, 55))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('DeltaNp63alpha', 'Chemical', '-', (20, 34))	('DeltaNp63alpha', 'Var', (20, 34))	('NMSC', 'Disease', (105, 109))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('DeltaNp63alpha', 'Chemical', '-', (145, 159))
329351	33579235	DeltaNp63alpha has been previously shown to be upregulated in NMSC.	('upregulated', 'PosReg', (47, 58))	('DeltaNp63alpha', 'Chemical', '-', (0, 14))	('DeltaNp63alpha', 'Var', (0, 14))	('NMSC', 'Disease', (62, 66))
329359	33579235	We next examined whether there is a correlation between the expression of DeltaNp63alpha and ERK3 in AK and SCC specimens when compared to normal skin tissues (Fig.	('ERK3', 'Gene', (93, 97))	('SCC', 'Gene', (108, 111))	('DeltaNp63alpha', 'Chemical', '-', (74, 88))	('DeltaNp63alpha', 'Var', (74, 88))	('SCC', 'Phenotype', 'HP:0002860', (108, 111))	('SCC', 'Gene', '6317', (108, 111))	('AK', 'Phenotype', 'HP:0025127', (101, 103))
329361	33579235	This indicates that DeltaNp63alpha might positively regulate ERK3 in normal skin and NMSC.	('ERK3', 'Protein', (61, 65))	('DeltaNp63alpha', 'Chemical', '-', (20, 34))	('DeltaNp63alpha', 'Var', (20, 34))
329362	33579235	Since both DeltaNp63alpha and ERK3 are upregulated and positively correlated in NMSC tissues, we examined whether DeltaNp63alpha upregulates the expression levels of ERK3.	('DeltaNp63alpha', 'Chemical', '-', (114, 128))	('DeltaNp63alpha', 'Var', (114, 128))	('DeltaNp63alpha', 'Gene', (11, 25))	('upregulated', 'PosReg', (39, 50))	('NMSC', 'Disease', (80, 84))	('DeltaNp63alpha', 'Chemical', '-', (11, 25))	('ERK3', 'Gene', (30, 34))
329364	33579235	We observed that silencing DeltaNp63alpha resulted in a significant reduction of DeltaNp63alpha at both transcript and protein levels in both cell lines as expected (Fig.	('DeltaNp63alpha', 'Gene', (27, 41))	('DeltaNp63alpha', 'Chemical', '-', (81, 95))	('reduction', 'NegReg', (68, 77))	('silencing', 'Var', (17, 26))	('DeltaNp63alpha', 'Gene', (81, 95))	('DeltaNp63alpha', 'Chemical', '-', (27, 41))
329365	33579235	Importantly, ERK3 transcript level was significantly reduced upon silencing of DeltaNp63alpha in A431 and HaCaT cell lines (Fig.	('DeltaNp63alpha', 'Gene', (79, 93))	('silencing', 'Var', (66, 75))	('transcript level', 'MPA', (18, 34))	('HaCaT', 'CellLine', 'CVCL:0038', (106, 111))	('reduced', 'NegReg', (53, 60))	('A431', 'CellLine', 'CVCL:0037', (97, 101))	('DeltaNp63alpha', 'Chemical', '-', (79, 93))	('ERK3', 'Gene', (13, 17))
329366	33579235	Consistent with the change in mRNA transcript level, immunoblot analysis shows that ERK3 protein expression was also substantially decreased upon DeltaNp63alpha silencing (Fig.	('DeltaNp63alpha', 'Chemical', '-', (146, 160))	('DeltaNp63alpha silencing', 'Var', (146, 170))	('decreased', 'NegReg', (131, 140))	('ERK3', 'Gene', (84, 88))	('protein', 'Protein', (89, 96))	('expression', 'MPA', (97, 107))
329367	33579235	These findings suggest that DeltaNp63alpha positively regulates ERK3 levels in normal skin and SCC cells.	('SCC', 'Gene', '6317', (95, 98))	('ERK3 levels', 'MPA', (64, 75))	('SCC', 'Phenotype', 'HP:0002860', (95, 98))	('DeltaNp63alpha', 'Var', (28, 42))	('SCC', 'Gene', (95, 98))	('DeltaNp63alpha', 'Chemical', '-', (28, 42))	('regulates', 'Reg', (54, 63))
329369	33579235	The first binding site (BS1) is 15 kb (chr15:52004994-52005013) upstream and the second site (BS2) is 3.4 kb (chr15:52069703-52069722) downstream the transcription start site (TSS) of the ERK3 gene.	('chr15:52069703-52069722', 'STRUCTURAL_ABNORMALITY', 'None', (110, 133))	('chr15:52004994-52005013', 'Var', (39, 62))	('chr15:52004994-52005013', 'STRUCTURAL_ABNORMALITY', 'None', (39, 62))	('ERK3', 'Gene', (188, 192))	('chr15:52069703-52069722', 'Var', (110, 133))
329379	33579235	As we have found that DeltaNp63alpha upregulates ERK3 expression and that both DeltaNp63alpha and ERK3 suppress cell migration of A431 cells, we examined whether ERK3, as a downstream target of DeltaNp63alpha, mediates the latter's role in cell migration.	('expression', 'MPA', (54, 64))	('ERK3', 'Gene', (49, 53))	('DeltaNp63alpha', 'Chemical', '-', (194, 208))	('suppress', 'NegReg', (103, 111))	('cell migration of A431 cells', 'CPA', (112, 140))	('DeltaNp63alpha', 'Chemical', '-', (22, 36))	('upregulates', 'PosReg', (37, 48))	('DeltaNp63alpha', 'Var', (22, 36))	('DeltaNp63alpha', 'Var', (79, 93))	('ERK3', 'Gene', (98, 102))	('DeltaNp63alpha', 'Chemical', '-', (79, 93))	('A431', 'CellLine', 'CVCL:0037', (130, 134))
329381	33579235	As expected, DeltaNp63alpha silencing greatly decreased the protein level of ERK3 (Fig.	('ERK3', 'Protein', (77, 81))	('DeltaNp63alpha silencing', 'Var', (13, 37))	('protein level', 'MPA', (60, 73))	('DeltaNp63alpha', 'Chemical', '-', (13, 27))	('decreased', 'NegReg', (46, 55))
329383	33579235	These findings suggest that ERK3 is an important downstream mediator of DeltaNp63alpha in suppressing A431cell migration.	('A431', 'CellLine', 'CVCL:0037', (102, 106))	('ERK3', 'Gene', (28, 32))	('suppressing', 'NegReg', (90, 101))	('DeltaNp63alpha', 'Var', (72, 86))	('DeltaNp63alpha', 'Chemical', '-', (72, 86))
329387	33579235	We generated HaCaT and A431 stable cell lines with stable knockdown of ERK3 by lentiviral transduction of shRNA against ERK3 (shERK3) or non-targeting lenti-GIPZ shRNA (shGIPZ) as a control.	('HaCaT', 'CellLine', 'CVCL:0038', (13, 18))	('ERK3', 'Gene', (71, 75))	('ERK3', 'Gene', (120, 124))	('A431', 'CellLine', 'CVCL:0037', (23, 27))	('knockdown', 'Var', (58, 67))
329388	33579235	We confirmed the silencing of ERK3 in HaCaT-shERK3 or A431-shERK3 when compared with HaCaT-shGIPZ or A431-shGIPZ (Fig.	('HaCaT', 'CellLine', 'CVCL:0038', (85, 90))	('A431', 'CellLine', 'CVCL:0037', (101, 105))	('silencing', 'NegReg', (17, 26))	('HaCaT', 'CellLine', 'CVCL:0038', (38, 43))	('A431', 'CellLine', 'CVCL:0037', (54, 58))	('ERK3', 'Gene', (30, 34))	('A431-shERK3', 'Var', (54, 65))
329389	33579235	6b and c, ERK3 silencing did not cause a significant difference in proliferation between cells stably expressing shERK3 and cells expressing shGIPZ control in both HaCaT and A431 cell lines.	('silencing', 'Var', (15, 24))	('HaCaT', 'CellLine', 'CVCL:0038', (164, 169))	('A431', 'CellLine', 'CVCL:0037', (174, 178))	('shERK3', 'Gene', (113, 119))
329391	33579235	F-actin staining clearly showed that cells with ERK3 overexpression had a remarkable decrease in the formation of filopodia structures on cell surface and stress fibers assembly inside cells as compared to cells with expression of CDH empty vector (Fig.	('ERK3', 'Gene', (48, 52))	('stress', 'Disease', (155, 161))	('stress', 'Disease', 'MESH:D000079225', (155, 161))	('decrease', 'NegReg', (85, 93))	('formation of filopodia structures on cell surface', 'CPA', (101, 150))	('overexpression', 'Var', (53, 67))
329393	33579235	We have previously reported that DeltaNp63alpha inhibits cell migration and invasion via downregulating Rac1 phosphorylation.	('DeltaNp63alpha', 'Chemical', '-', (33, 47))	('DeltaNp63alpha', 'Var', (33, 47))	('inhibits', 'NegReg', (48, 56))	('Rac1', 'Gene', '5879', (104, 108))	('Rac1', 'Gene', (104, 108))	('cell migration', 'CPA', (57, 71))	('downregulating', 'NegReg', (89, 103))	('invasion', 'CPA', (76, 84))
329394	33579235	These findings prompted us to examine whether DeltaNp63alpha-ERK3 signaling downregulates cell migration through inhibiting Rac1 phosphorylation.	('inhibiting', 'NegReg', (113, 123))	('DeltaNp63alpha', 'Chemical', '-', (46, 60))	('DeltaNp63alpha-ERK3', 'Var', (46, 65))	('cell migration', 'CPA', (90, 104))	('Rac1', 'Gene', (124, 128))	('Rac1', 'Gene', '5879', (124, 128))	('downregulates', 'NegReg', (76, 89))
329397	33579235	As expected, silencing DeltaNp63alpha increased pRac1 (Lane 3 versus Lane 1, Fig.	('DeltaNp63alpha', 'Protein', (23, 37))	('DeltaNp63alpha', 'Chemical', '-', (23, 37))	('pRac1', 'Gene', '84366', (48, 53))	('pRac1', 'Gene', (48, 53))	('increased', 'PosReg', (38, 47))	('silencing', 'Var', (13, 22))
329398	33579235	Importantly, ERK3 overexpression counteracted the increase of pRac1 induced by silencing DeltaNp63alpha (Lane 4 versus Lane 3, Fig.	('pRac1', 'Gene', '84366', (62, 67))	('pRac1', 'Gene', (62, 67))	('increase', 'PosReg', (50, 58))	('DeltaNp63alpha', 'Chemical', '-', (89, 103))	('DeltaNp63alpha', 'Gene', (89, 103))	('silencing', 'Var', (79, 88))	('overexpression', 'PosReg', (18, 32))
329399	33579235	These results suggest that DeltaNp63alpha -ERK3 axis inhibits Rac1 phosphorylation, thereby suppressing NMSC cell migration.	('suppressing', 'NegReg', (92, 103))	('NMSC cell migration', 'CPA', (104, 123))	('Rac1', 'Gene', '5879', (62, 66))	('inhibits', 'NegReg', (53, 61))	('Rac1', 'Gene', (62, 66))	('DeltaNp63alpha', 'Chemical', '-', (27, 41))	('DeltaNp63alpha', 'Var', (27, 41))
329400	33579235	DeltaNp63alpha plays an important role in the development of skin, lung and mammary gland.	('mammary gland', 'CPA', (76, 89))	('lung', 'CPA', (67, 71))	('DeltaNp63alpha', 'Var', (0, 14))	('DeltaNp63alpha', 'Chemical', '-', (0, 14))
329402	33579235	DeltaNp63alpha exhibits an inhibitory role on cell migration and invasion, in part by downregulating EMT and Akt pathway.	('Akt', 'Gene', '207', (109, 112))	('downregulating', 'NegReg', (86, 100))	('DeltaNp63alpha', 'Chemical', '-', (0, 14))	('DeltaNp63alpha', 'Var', (0, 14))	('EMT', 'Gene', (101, 104))	('Akt', 'Gene', (109, 112))	('EMT', 'Gene', '3702', (101, 104))	('invasion', 'CPA', (65, 73))	('cell migration', 'CPA', (46, 60))
329404	33579235	The underlying molecular mechanisms by which DeltaNp63alpha plays different roles in different cancers are still largely unknown and need to be further explored.	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('cancers', 'Phenotype', 'HP:0002664', (95, 102))	('cancers', 'Disease', (95, 102))	('cancers', 'Disease', 'MESH:D009369', (95, 102))	('DeltaNp63alpha', 'Chemical', '-', (45, 59))	('DeltaNp63alpha', 'Var', (45, 59))
329415	33579235	More importantly, our results demonstrate a highly significant positive correlation between DeltaNp63alpha expression and ERK3 expression in normal skin and NMSC specimens.	('expression', 'MPA', (127, 137))	('DeltaNp63alpha', 'Chemical', '-', (92, 106))	('ERK3', 'Gene', (122, 126))	('DeltaNp63alpha', 'Var', (92, 106))
329416	33579235	These findings raise an intriguing possibility that DeltaNp63alpha, as a transcriptional factor, may regulate the expression of ERK3 in skin and indicates a cooperative role between DeltaNp63alpha and ERK3 in promoting the initiation and development of cutaneous SCC.	('SCC', 'Gene', '6317', (263, 266))	('cooperative', 'Interaction', (157, 168))	('ERK3', 'Gene', (128, 132))	('promoting', 'PosReg', (209, 218))	('SCC', 'Phenotype', 'HP:0002860', (263, 266))	('DeltaNp63alpha', 'Var', (182, 196))	('expression', 'MPA', (114, 124))	('development', 'CPA', (238, 249))	('SCC', 'Gene', (263, 266))	('DeltaNp63alpha', 'Chemical', '-', (182, 196))	('DeltaNp63alpha', 'Chemical', '-', (52, 66))	('regulate', 'Reg', (101, 109))
329417	33579235	Indeed, we have found that DeltaNp63alpha positively regulates ERK3 gene expression in both HaCaT keratinocyte and A431 skin SCC cells.	('regulates', 'Reg', (53, 62))	('HaCaT', 'CellLine', 'CVCL:0038', (92, 97))	('ERK3 gene', 'Gene', (63, 72))	('SCC', 'Gene', (125, 128))	('SCC', 'Phenotype', 'HP:0002860', (125, 128))	('expression', 'MPA', (73, 83))	('A431', 'CellLine', 'CVCL:0037', (115, 119))	('SCC', 'Gene', '6317', (125, 128))	('DeltaNp63alpha', 'Chemical', '-', (27, 41))	('DeltaNp63alpha', 'Var', (27, 41))
329418	33579235	The inhibitory role of DeltaNp63alpha on cell migration is attributed to its function in sustaining the epithelial integrity by blocking pathways that promote EMT.	('blocking', 'NegReg', (128, 136))	('pathways', 'Pathway', (137, 145))	('EMT', 'Gene', (159, 162))	('DeltaNp63alpha', 'Chemical', '-', (23, 37))	('cell migration', 'CPA', (41, 55))	('DeltaNp63alpha', 'Var', (23, 37))	('EMT', 'Gene', '3702', (159, 162))	('promote', 'PosReg', (151, 158))	('epithelial integrity', 'CPA', (104, 124))
329421	33579235	In this study, we found that knockdown of ERK3 significantly increased the migration of A431 cutaneous SCC cells, suggesting that both DeltaNp63alpha and ERK3 play inhibitory roles in skin cell migration.	('DeltaNp63alpha', 'Chemical', '-', (135, 149))	('knockdown', 'Var', (29, 38))	('ERK3', 'Gene', (42, 46))	('SCC', 'Gene', (103, 106))	('increased', 'PosReg', (61, 70))	('SCC', 'Phenotype', 'HP:0002860', (103, 106))	('SCC', 'Gene', '6317', (103, 106))	('A431', 'CellLine', 'CVCL:0037', (88, 92))
329425	33579235	Taken together, these findings demonstrate that ERK3 is a mediator for DeltaNp63alpha-mediated inhibition of NMSC cell migration.	('DeltaNp63alpha', 'Chemical', '-', (71, 85))	('NMSC cell migration', 'CPA', (109, 128))	('inhibition', 'NegReg', (95, 105))	('DeltaNp63alpha-mediated', 'Var', (71, 94))
329427	33579235	In line with these clinical findings, ERK3 transcript levels are positively regulated by DeltaNp63alpha, and ERK3 acts as an important downstream mediator of DeltaNp63alpha in regulating cell migration.	('regulated', 'Reg', (76, 85))	('positively', 'PosReg', (65, 75))	('ERK3', 'Gene', (38, 42))	('transcript levels', 'MPA', (43, 60))	('DeltaNp63alpha', 'Chemical', '-', (158, 172))	('DeltaNp63alpha', 'Chemical', '-', (89, 103))	('DeltaNp63alpha', 'Var', (89, 103))	('cell migration', 'CPA', (187, 201))
329428	33579235	To our knowledge, our study is the first to reveal the molecular regulation of ERK3 by DeltaNp63alpha in cutaneous SCC and provides an additional mechanism by which DeltaNp63alpha regulates cancer cell migration.	('cancer', 'Disease', (190, 196))	('DeltaNp63alpha', 'Gene', (87, 101))	('cancer', 'Disease', 'MESH:D009369', (190, 196))	('ERK3', 'Gene', (79, 83))	('DeltaNp63alpha', 'Chemical', '-', (165, 179))	('SCC', 'Gene', (115, 118))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('SCC', 'Phenotype', 'HP:0002860', (115, 118))	('regulates', 'Reg', (180, 189))	('DeltaNp63alpha', 'Chemical', '-', (87, 101))	('DeltaNp63alpha', 'Var', (165, 179))	('SCC', 'Gene', '6317', (115, 118))
329431	33579235	This work was supported by grants from the National Cancer Institute to M.P.K [1R01CA154715] and W.L [5R01CA193264].	('W.L [5R01CA193264]', 'Var', (97, 115))	('Cancer', 'Disease', 'MESH:D009369', (52, 58))	('Cancer', 'Phenotype', 'HP:0002664', (52, 58))	('Cancer', 'Disease', (52, 58))
329437	31391008	Ten mRNAs (CSRP2, CKS2, ADGRG6, MB21D1, GMNN, RIPOR3, RAD51, PCLAF, ORC1, NAGS), 9 lncRNAs (LINC02560, HOXC13 - AS, FOXD2 - AS1, AC105277.1, AC099850.3, STARD4 - AS1, SLC16A1 - AS1, MIR503HG, MIR100HG) and 8 miRNAs (miR - 654, miR - 503, miR - 450a, miR - 379, miR - 369, miR - 190a, miR - 101, and let-7c) were found to be significantly associated with overall survival (log-rank p < 0.05).	('AS1', 'Gene', '5729', (177, 180))	('GMNN', 'Gene', (40, 44))	('miR - 379', 'Gene', '494328', (250, 259))	('AS1', 'Gene', '5729', (162, 165))	('MIR503HG', 'Gene', '84848', (182, 190))	('ORC1', 'Gene', '4998', (68, 72))	('NAGS', 'Gene', (74, 78))	('AS1', 'Gene', (124, 127))	('FOXD2', 'Gene', '2306', (116, 121))	('NAGS', 'Gene', '162417', (74, 78))	('ORC1', 'Gene', (68, 72))	('let-7c', 'Gene', (299, 305))	('CSRP2', 'Gene', '1466', (11, 16))	('MIR100HG', 'Gene', '399959', (192, 200))	('MIR503HG', 'Gene', (182, 190))	('miR - 369', 'Gene', '442914', (261, 270))	('STARD4', 'Gene', (153, 159))	('HOXC13', 'Gene', '3229', (103, 109))	('miR - 503', 'Gene', (227, 236))	('CSRP2', 'Gene', (11, 16))	('MIR100HG', 'Gene', (192, 200))	('MB21D1', 'Gene', (32, 38))	('AS1', 'Gene', (162, 165))	('CKS2', 'Gene', '1164', (18, 22))	('AS1', 'Gene', (177, 180))	('FOXD2', 'Gene', (116, 121))	('CKS2', 'Gene', (18, 22))	('miR - 369', 'Gene', (261, 270))	('miR - 654', 'Gene', '724024', (216, 225))	('let-7c', 'Gene', '406885', (299, 305))	('ADGRG6', 'Gene', '57211', (24, 30))	('RAD51', 'Gene', (54, 59))	('AS1', 'Gene', '5729', (124, 127))	('RAD51', 'Gene', '5888', (54, 59))	('GMNN', 'Gene', '51053', (40, 44))	('LINC02560', 'Var', (92, 101))	('miR - 503', 'Gene', '574506', (227, 236))	('ADGRG6', 'Gene', (24, 30))	('miR - 654', 'Gene', (216, 225))	('STARD4', 'Gene', '134429', (153, 159))	('miR - 190a', 'Gene', '406965', (272, 282))	('overall', 'MPA', (354, 361))	('miR - 450a', 'Var', (238, 248))	('MB21D1', 'Gene', '115004', (32, 38))	('associated with', 'Reg', (338, 353))	('miR - 190a', 'Gene', (272, 282))	('SLC16A1', 'Gene', (167, 174))	('SLC16A1', 'Gene', '6566', (167, 174))	('miR - 379', 'Gene', (250, 259))	('miR - 101', 'Var', (284, 293))	('HOXC13', 'Gene', (103, 109))
329446	31391008	For instance, expression of the lncRNA SNHG6 is significantly increased in tongue cancer, and interference with SNHG6 expression can inhibit the proliferation and epithelial-mesenchymal transition (EMT) of tongue cancer cells.	('increased', 'PosReg', (62, 71))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('tongue cancer', 'Disease', (75, 88))	('interference', 'Var', (94, 106))	('tongue cancer', 'Disease', 'MESH:D014062', (75, 88))	('SNHG6', 'Gene', '641638', (39, 44))	('proliferation', 'CPA', (145, 158))	('SNHG6', 'Gene', '641638', (112, 117))	('inhibit', 'NegReg', (133, 140))	('expression', 'MPA', (14, 24))	('tongue cancer', 'Disease', (206, 219))	('tongue cancer', 'Disease', 'MESH:D014062', (206, 219))	('SNHG6', 'Gene', (39, 44))	('SNHG6', 'Gene', (112, 117))
329474	31391008	Through survival analysis, we identified 10 mRNAs (CSRP2, CKS2, ADGRG6, MB21D1, GMNN, RIPOR3, RAD51, PCLAF, ORC1, NAGS), 9 lncRNAs (LINC02560, HOXC13 - AS, FOXD2 - AS1, AC105277.1, AC099850.3, STARD4 - AS1, SLC16A1 - AS1, MIR503HG, MIR100HG) and 8 miRNAs (miR - 654, miR - 503, miR - 450a, miR - 379, miR - 369, miR - 190a, miR - 101, let-7c) that were significantly related to the overall survival of patients with SCCT.	('ADGRG6', 'Gene', (64, 70))	('miR - 654', 'Gene', (256, 265))	('miR - 190a', 'Gene', '406965', (312, 322))	('let-7c', 'Gene', '406885', (335, 341))	('ORC1', 'Gene', '4998', (108, 112))	('miR - 379', 'Gene', '494328', (290, 299))	('miR - 190a', 'Gene', (312, 322))	('miR - 101', 'Var', (324, 333))	('ORC1', 'Gene', (108, 112))	('AS1', 'Gene', (164, 167))	('HOXC13', 'Gene', (143, 149))	('AS1', 'Gene', '5729', (217, 220))	('GMNN', 'Gene', (80, 84))	('MIR503HG', 'Gene', (222, 230))	('miR - 369', 'Gene', '442914', (301, 310))	('miR - 503', 'Gene', (267, 276))	('NAGS', 'Gene', (114, 118))	('MB21D1', 'Gene', (72, 78))	('AS1', 'Gene', (202, 205))	('STARD4', 'Gene', (193, 199))	('miR - 369', 'Gene', (301, 310))	('FOXD2', 'Gene', '2306', (156, 161))	('patients', 'Species', '9606', (402, 410))	('NAGS', 'Gene', '162417', (114, 118))	('CSRP2', 'Gene', (51, 56))	('CKS2', 'Gene', '1164', (58, 62))	('CKS2', 'Gene', (58, 62))	('MIR100HG', 'Gene', '399959', (232, 240))	('related', 'Reg', (367, 374))	('RAD51', 'Gene', (94, 99))	('miR - 503', 'Gene', '574506', (267, 276))	('AS1', 'Gene', '5729', (164, 167))	('RAD51', 'Gene', '5888', (94, 99))	('HOXC13', 'Gene', '3229', (143, 149))	('SCCT', 'Phenotype', 'HP:0030413', (416, 420))	('miR - 450a', 'Var', (278, 288))	('let-7c', 'Gene', (335, 341))	('MIR100HG', 'Gene', (232, 240))	('AS1', 'Gene', (217, 220))	('SLC16A1', 'Gene', (207, 214))	('FOXD2', 'Gene', (156, 161))	('MB21D1', 'Gene', '115004', (72, 78))	('SLC16A1', 'Gene', '6566', (207, 214))	('STARD4', 'Gene', '134429', (193, 199))	('miR - 654', 'Gene', '724024', (256, 265))	('ADGRG6', 'Gene', '57211', (64, 70))	('AS1', 'Gene', '5729', (202, 205))	('CSRP2', 'Gene', '1466', (51, 56))	('GMNN', 'Gene', '51053', (80, 84))	('miR - 379', 'Gene', (290, 299))	('LINC02560', 'Var', (132, 141))	('MIR503HG', 'Gene', '84848', (222, 230))
329490	24916928	The presumption was that evidence of dysregulation of certain genes within the excised primary tumor could be used to improve the prognostic discrimination of clinical and pathologic staging alone, by indicating the likelihood that dissemination of the tumor had already occured.	('dysregulation', 'Var', (37, 50))	('tumor', 'Disease', 'MESH:D009369', (253, 258))	('tumor', 'Phenotype', 'HP:0002664', (253, 258))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Disease', (253, 258))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('improve', 'PosReg', (118, 125))	('tumor', 'Disease', (95, 100))
329502	24916928	For the breast study, a total of 2874 HGU133A Affymetrix CEL files was obtained from GEO data sets GSE31519, GSE11121, GSE2034, GSE2990, GSE3494, GSE5327, GSE6532, and GSE7390, and the 98 of those that were triple negative cases were selected.	('GSE2990', 'Var', (128, 135))	('GSE2034', 'Chemical', '-', (119, 126))	('GSE31519', 'Var', (99, 107))	('GSE2990', 'Chemical', '-', (128, 135))	('GSE11121', 'Var', (109, 117))	('GSE3494', 'Chemical', '-', (137, 144))	('GSE6532', 'Var', (155, 162))	('GSE3494', 'Var', (137, 144))	('GSE7390', 'Chemical', '-', (168, 175))	('GSE5327', 'Chemical', '-', (146, 153))	('GSE7390', 'Var', (168, 175))	('GSE5327', 'Var', (146, 153))	('GSE2034', 'Var', (119, 126))	('GSE6532', 'Chemical', '-', (155, 162))
329588	24916928	Genome sequencing of tumors has led to the realization that mutations in a relatively small number of driver genes promote tumor development by influencing only a few key signaling pathways, which in turn affect cell survival, cell fate or genome maintenance.	('promote', 'PosReg', (115, 122))	('tumor', 'Disease', (123, 128))	('key signaling pathways', 'Pathway', (167, 189))	('tumor', 'Disease', (21, 26))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('cell fate', 'CPA', (227, 236))	('genome maintenance', 'CPA', (240, 258))	('tumors', 'Disease', (21, 27))	('tumors', 'Disease', 'MESH:D009369', (21, 27))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('affect', 'Reg', (205, 211))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('mutations', 'Var', (60, 69))	('cell survival', 'CPA', (212, 225))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('influencing', 'Reg', (144, 155))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
329589	24916928	Nearly all solid tumors in adults carry, in addition to driver mutations, appreciable numbers of mutations which do not confer a growth advantage; non-small-cell-lung-cancers are especially rich in these passenger mutations because of exposure to carcinogens before and during tumor cell development.	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('tumor', 'Disease', (17, 22))	('tumor', 'Disease', 'MESH:D009369', (277, 282))	('lung-cancers', 'Disease', 'MESH:D008175', (162, 174))	('mutations', 'Var', (214, 223))	('cancers', 'Phenotype', 'HP:0002664', (167, 174))	('tumor', 'Phenotype', 'HP:0002664', (277, 282))	('solid tumors', 'Disease', (11, 23))	('lung-cancers', 'Disease', (162, 174))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('tumor', 'Disease', (277, 282))	('solid tumors', 'Disease', 'MESH:D009369', (11, 23))
329590	24916928	Many of the mutations, of driver and passenger genes alike, can be presumed to influence the gene expression profile of each lung cancer cell, adding to the difficulty of finding common gene profiles; the signal of cancer-related changes must be found against a large, variable background of noise.	('lung cancer', 'Disease', 'MESH:D008175', (125, 136))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('cancer', 'Disease', (215, 221))	('cancer', 'Disease', 'MESH:D009369', (215, 221))	('cancer', 'Disease', (130, 136))	('mutations', 'Var', (12, 21))	('gene expression profile', 'MPA', (93, 116))	('influence', 'Reg', (79, 88))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('lung cancer', 'Disease', (125, 136))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('lung cancer', 'Phenotype', 'HP:0100526', (125, 136))
329610	31930386	Aberrant miRNA expression is associated with many diseases, including cancer.	('Aberrant', 'Var', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('miRNA expression', 'Protein', (9, 25))	('associated', 'Reg', (29, 39))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))
329617	31930386	We also performed in vitro cell-based assays for a novel miRNA miR-335-3p in uterine corpus endometrial carcinoma (UCEC) for further validation of MDEHT.	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (92, 113))	('miR-335-3p', 'Var', (63, 73))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('miR-335-3p', 'Chemical', '-', (63, 73))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (92, 113))	('endometrial carcinoma', 'Disease', (92, 113))
329653	31930386	The primary antibodies used are phospho-Wee1 (Ser642), Wee1, Cyclin E2, CDK2, cdc42, p21, p16 and GAPDH obtained from Cell Signaling Technology (Danvers, MA, USA).	('p16', 'Gene', '1029', (90, 93))	('cdc42', 'Gene', (78, 83))	('Wee1', 'Gene', (55, 59))	('GAPDH', 'Gene', '2597', (98, 103))	('Ser642', 'Chemical', '-', (46, 52))	('Cyclin E2', 'Gene', (61, 70))	('Wee1', 'Gene', '7465', (55, 59))	('cdc42', 'Gene', '998', (78, 83))	('CDK2', 'Gene', (72, 76))	('Wee1', 'Gene', (40, 44))	('p16', 'Gene', (90, 93))	('Wee1', 'Gene', '7465', (40, 44))	('Cyclin E2', 'Gene', '9134', (61, 70))	('GAPDH', 'Gene', (98, 103))	('p21', 'Gene', (85, 88))	('Ser642', 'Var', (46, 52))	('CDK2', 'Gene', '1017', (72, 76))	('p21', 'Gene', '644914', (85, 88))
329662	31930386	DESeq and DESeq2 slightly inflated the Type I error rate in all scenarios; whereas the other three methods (edgeR, NBPSeq and TSPM) substantially inflated Type I error rate.	('inflated', 'Reg', (26, 34))	('inflated Type I error', 'Disease', 'MESH:D005776', (146, 167))	('Type I error rate', 'MPA', (39, 56))	('DESeq', 'Var', (0, 5))	('inflated Type I error', 'Disease', (146, 167))	('DESeq2', 'Var', (10, 16))
329684	31930386	We first performed qRT-PCR to examine the miR-335-3p expression in 47 cases of UCEC tissues and their matched adjacent non-tumor tissues.	('miR-335-3p', 'Chemical', '-', (42, 52))	('tumor', 'Disease', (123, 128))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('miR-335-3p', 'Var', (42, 52))	('UCEC', 'Disease', (79, 83))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
329686	31930386	To further investigate the potential role of miR-335-3p in UCEC, HEC-1-B cells were transfected with a miR-335-3p inhibitor to knock down its expression, and the expression level of miR-335-3p was decreased after the transfection when compared with the NC group (Fig.	('miR-335-3p', 'Chemical', '-', (182, 192))	('decreased', 'NegReg', (197, 206))	('expression level', 'MPA', (162, 178))	('miR-335-3p', 'Chemical', '-', (103, 113))	('HEC-1-B', 'CellLine', 'CVCL:0294', (65, 72))	('miR-335-3p', 'Chemical', '-', (45, 55))	('knock', 'Var', (127, 132))	('expression', 'MPA', (142, 152))	('miR-335-3p', 'Var', (182, 192))
329687	31930386	As a result, the knockdown of miR-335-3p significantly suppressed HEC-1-B cell proliferation (Fig.	('HEC-1-B', 'CellLine', 'CVCL:0294', (66, 73))	('HEC-1-B cell proliferation', 'CPA', (66, 92))	('miR-335-3p', 'Var', (30, 40))	('suppressed', 'NegReg', (55, 65))	('knockdown', 'Var', (17, 26))	('miR-335-3p', 'Chemical', '-', (30, 40))
329688	31930386	6D), suggesting that the cancer-related roles of miR-335-3p might be partly restricted to the regulation of cancer cell proliferation.	('miR-335-3p', 'Var', (49, 59))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('miR-335-3p', 'Chemical', '-', (49, 59))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (25, 31))	('cancer', 'Disease', (25, 31))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
329689	31930386	As shown in Figure 6E, downregulation of miR-335-3p caused a significant cell cycle arrest at the S stage.	('downregulation', 'NegReg', (23, 37))	('miR-335-3p', 'Chemical', '-', (41, 51))	('arrest', 'Disease', 'MESH:D006323', (84, 90))	('arrest', 'Disease', (84, 90))	('miR-335-3p', 'Var', (41, 51))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (73, 90))
329690	31930386	Meanwhile, the expression levels of cell cycle-related proteins, such as phospho-Wee1 (Ser642), Wee1, Cyclin E2, cdc42, p21 and p16, were significantly affected when miR-335-3p was knockdown (Fig.	('Ser642', 'Chemical', '-', (87, 93))	('cdc42', 'Gene', (113, 118))	('expression levels', 'MPA', (15, 32))	('miR-335-3p', 'Chemical', '-', (166, 176))	('p21', 'Gene', (120, 123))	('Wee1', 'Gene', (96, 100))	('cdc42', 'Gene', '998', (113, 118))	('p21', 'Gene', '644914', (120, 123))	('Cyclin E2', 'Gene', (102, 111))	('p16', 'Gene', (128, 131))	('Wee1', 'Gene', (81, 85))	('p16', 'Gene', '1029', (128, 131))	('Wee1', 'Gene', '7465', (96, 100))	('Wee1', 'Gene', '7465', (81, 85))	('cell', 'MPA', (36, 40))	('miR-335-3p', 'Var', (166, 176))	('knockdown', 'Var', (181, 190))	('affected', 'Reg', (152, 160))	('Cyclin E2', 'Gene', '9134', (102, 111))
329691	31930386	Our data demonstrated that miR-335-3p could play a role in promoting cell proliferation via enhancing cell cycle progression in UCEC.	('promoting', 'PosReg', (59, 68))	('enhancing', 'PosReg', (92, 101))	('UCEC', 'Disease', (128, 132))	('miR-335-3p', 'Chemical', '-', (27, 37))	('cell proliferation', 'CPA', (69, 87))	('cell cycle progression', 'CPA', (102, 124))	('miR-335-3p', 'Var', (27, 37))
329697	31930386	MiR-335-3p has rarely been studied, and its role in cancer remains elusive.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('MiR-335-3p', 'Chemical', '-', (0, 10))	('MiR-335-3p', 'Var', (0, 10))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))
329698	31930386	For the first time, our preliminary data demonstrated that miR-335-3p play a role in promoting cell proliferation via enhancing cell cycle progression in UCEC.	('cell proliferation', 'CPA', (95, 113))	('miR-335-3p', 'Chemical', '-', (59, 69))	('enhancing', 'PosReg', (118, 127))	('cell cycle progression', 'CPA', (128, 150))	('UCEC', 'Disease', (154, 158))	('promoting', 'PosReg', (85, 94))	('miR-335-3p', 'Var', (59, 69))
329725	32070309	The study hypotheses are that: (i) the adjuvant-treatment group (PORT/POCRT) can increase the disease-free survival (DFS) rate compared with the surgery alone (SA) group; (ii) a reduction in the radiation field using POCRT will not increase the out-of-field regional recurrence rate (OoFRRR) compared with that using PORT.	('POCRT', 'Var', (217, 222))	('regional recurrence', 'CPA', (258, 277))	('POCRT', 'Chemical', '-', (217, 222))	('SA', 'Chemical', '-', (160, 162))	('POCRT', 'Chemical', '-', (70, 75))	('disease-free survival', 'CPA', (94, 115))	('increase', 'PosReg', (81, 89))
329739	32070309	The CTV borders will be defined inferiorly as 3-cm below the subcarina or the lower margin of the tumor bed (only for T4 lesions), including the lower cervical and bilateral supraclavicular region and mediastinal stations 1R/L, 2R/L, 3p, 4R/L, and 7 (Fig.	('tumor', 'Disease', (98, 103))	('2R/L', 'SUBSTITUTION', 'None', (228, 232))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('1R/L', 'Var', (222, 226))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('4R/L', 'SUBSTITUTION', 'None', (238, 242))	('1R/L', 'SUBSTITUTION', 'None', (222, 226))	('2R/L', 'Var', (228, 232))	('4R/L', 'Var', (238, 242))
329758	32070309	National Comprehensive Cancer Network guidelines (2016-2019) recommend observation for pathologic T1-4aN0-1 M0 esophageal squamous cell carcinomas.	('esophageal squamous cell carcinomas', 'Disease', 'MESH:C562729', (111, 146))	('esophageal squamous cell carcinomas', 'Disease', (111, 146))	('Cancer', 'Phenotype', 'HP:0002664', (23, 29))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (122, 146))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (122, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('carcinomas', 'Phenotype', 'HP:0030731', (136, 146))	('T1-4aN0-1 M0', 'Var', (98, 110))
329793	26291987	The overall survival rate in patients with Psf3 overexpression was significantly lower than that in patients without Psf3 overexpression (P = 0.006).	('patients', 'Species', '9606', (29, 37))	('lower', 'NegReg', (81, 86))	('Psf3', 'Gene', (117, 121))	('overexpression', 'Var', (48, 62))	('Psf3', 'Gene', '64785', (117, 121))	('patients', 'Species', '9606', (100, 108))	('Psf3', 'Gene', (43, 47))	('Psf3', 'Gene', '64785', (43, 47))
329794	26291987	Multivariate survival analysis revealed Psf3 expression to be an independent risk factor for an unfavorable outcome (P = 0.049).	('Psf3', 'Gene', (40, 44))	('expression', 'Var', (45, 55))	('Psf3', 'Gene', '64785', (40, 44))
329801	26291987	It was observed that loss of Psf1 lead to embryonic lethality around the implantation stage, which was caused by the inability of cells in the inner cell mass to proliferate.7 Moreover, GINS components not only play a role in immature cells, but also play a role in cancer cells.	('loss', 'Var', (21, 25))	('cancer', 'Disease', 'MESH:D009369', (266, 272))	('embryonic lethality', 'Disease', 'MESH:D020964', (42, 61))	('cancer', 'Disease', (266, 272))	('embryonic lethality', 'Disease', (42, 61))	('Psf1', 'Gene', (29, 33))	('GINS', 'Chemical', '-', (186, 190))	('play', 'Reg', (251, 255))	('cancer', 'Phenotype', 'HP:0002664', (266, 272))
329804	26291987	These findings suggested that the aberrant accumulation of Psf3 was related to the malignant behavior of tumors in a cell cycle-independent manner, at least in the case of lung adenocarcinoma.	('tumors', 'Disease', (105, 111))	('tumors', 'Disease', 'MESH:D009369', (105, 111))	('Psf3', 'Gene', (59, 63))	('accumulation', 'PosReg', (43, 55))	('Psf3', 'Gene', '64785', (59, 63))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (172, 191))	('aberrant', 'Var', (34, 42))	('related', 'Reg', (68, 75))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (172, 191))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('carcinoma', 'Phenotype', 'HP:0030731', (182, 191))	('lung adenocarcinoma', 'Disease', (172, 191))
329808	26291987	Moreover, we used RNAi methodology to knock down the expression of Psf3 and thereby determine the significance of abnormal Psf3 expression in NSCLC.	('Psf3', 'Gene', '64785', (123, 127))	('NSCLC', 'Disease', (142, 147))	('NSCLC', 'Disease', 'MESH:D002289', (142, 147))	('knock', 'Var', (38, 43))	('Psf3', 'Gene', (67, 71))	('NSCLC', 'Phenotype', 'HP:0030358', (142, 147))	('Psf3', 'Gene', '64785', (67, 71))	('Psf3', 'Gene', (123, 127))
329870	26291987	Multivariate analysis indicated that Psf3 expression was an independent prognostic factor in NSCLC (P = 0.049).	('NSCLC', 'Disease', (93, 98))	('NSCLC', 'Disease', 'MESH:D002289', (93, 98))	('expression', 'Var', (42, 52))	('Psf3', 'Gene', (37, 41))	('NSCLC', 'Phenotype', 'HP:0030358', (93, 98))	('Psf3', 'Gene', '64785', (37, 41))
329878	26291987	These findings suggested that some part of the abnormal Psf3 expression interacted with Cdc45 and Mcm2, and functioned as the CMG complex in NSCLC.	('interacted', 'Interaction', (72, 82))	('Psf3', 'Gene', (56, 60))	('Psf3', 'Gene', '64785', (56, 60))	('NSCLC', 'Disease', (141, 146))	('CMG', 'Chemical', '-', (126, 129))	('NSCLC', 'Disease', 'MESH:D002289', (141, 146))	('NSCLC', 'Phenotype', 'HP:0030358', (141, 146))	('abnormal', 'Var', (47, 55))
329889	26291987	In both cell lines, a Psf3-positive signal was clearly detected in anti-Mcm2 and anti-Cdc45 precipitates, but not in precipitates incubated with control rabbit IgG (Fig.	('detected', 'Reg', (55, 63))	('rabbit', 'Species', '9986', (153, 159))	('anti-Mcm2', 'Var', (67, 76))	('Psf3', 'Gene', (22, 26))	('Psf3', 'Gene', '64785', (22, 26))
329896	26291987	The number of cells in each transfected cell line was counted every 24 h from culture initiation for 72 h. The cells transfected with Psf3 RNAi grew more slowly than other cell lines, which revealed that the knockdown of Psf3 inhibits the proliferation of A549 and EBC1 (Fig.	('inhibits', 'NegReg', (226, 234))	('knockdown', 'Var', (208, 217))	('Psf3', 'Gene', (221, 225))	('Psf3', 'Gene', '64785', (221, 225))	('proliferation', 'CPA', (239, 252))	('Psf3', 'Gene', (134, 138))	('A549', 'CellLine', 'CVCL:0023', (256, 260))	('Psf3', 'Gene', '64785', (134, 138))
329897	26291987	Moreover, we used BrdU-FACS to evaluate whether the knockdown of Psf3 led to delayed S phase.	('Psf3', 'Gene', (65, 69))	('Psf3', 'Gene', '64785', (65, 69))	('delayed', 'Disease', (77, 84))	('BrdU', 'Chemical', 'MESH:D001973', (18, 22))	('knockdown', 'Var', (52, 61))
329898	26291987	The percentages in the S-phase gating zone were decreased by Psf3 gene knockdown in both cell lines (Fig.	('S-phase gating zone', 'CPA', (23, 42))	('knockdown', 'Var', (71, 80))	('decreased', 'NegReg', (48, 57))	('Psf3', 'Gene', (61, 65))	('gene knockdown', 'Var', (66, 80))	('Psf3', 'Gene', '64785', (61, 65))
329899	26291987	Thus, Psf3 gene knockdown in human lung carcinoma cell lines resulted in growth inhibition characterized by delayed S-phase progression.	('growth', 'MPA', (73, 79))	('Psf3', 'Gene', (6, 10))	('Psf3', 'Gene', '64785', (6, 10))	('knockdown', 'Var', (16, 25))	('carcinoma', 'Phenotype', 'HP:0030731', (40, 49))	('lung carcinoma', 'Disease', 'MESH:D008175', (35, 49))	('human', 'Species', '9606', (29, 34))	('lung carcinoma', 'Disease', (35, 49))
329904	26291987	Ki67 expression showed a scattered staining pattern in the nuclei of cancer cells because it increased during the middle of cell division and was detected in a cell cycle-dependent manner.19 However, the Psf3 expression showed a clustered staining pattern, indicating that the aberrant accumulation of Psf3 might play a role in cancer cells, irrespective of the cell cycle.	('cancer', 'Phenotype', 'HP:0002664', (328, 334))	('aberrant', 'Var', (277, 285))	('Psf3', 'Gene', (302, 306))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('Psf3', 'Gene', '64785', (302, 306))	('Psf3', 'Gene', (204, 208))	('cancer', 'Disease', (328, 334))	('cancer', 'Disease', 'MESH:D009369', (328, 334))	('Psf3', 'Gene', '64785', (204, 208))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('play', 'Reg', (313, 317))	('cancer', 'Disease', (69, 75))
329908	26291987	These results indicated that abnormal Psf3 expression could lead to excessive proliferation in cancer cells.	('Psf3', 'Gene', '64785', (38, 42))	('lead to', 'Reg', (60, 67))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('cancer', 'Disease', (95, 101))	('abnormal', 'Var', (29, 37))	('excessive proliferation', 'CPA', (68, 91))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('expression', 'MPA', (43, 53))	('Psf3', 'Gene', (38, 42))
329923	26291987	In this study, Psf3 gene knockdown resulted in growth inhibition in human lung carcinoma cell lines.	('human', 'Species', '9606', (68, 73))	('growth', 'MPA', (47, 53))	('Psf3', 'Gene', (15, 19))	('lung carcinoma', 'Disease', (74, 88))	('lung carcinoma', 'Disease', 'MESH:D008175', (74, 88))	('Psf3', 'Gene', '64785', (15, 19))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('knockdown', 'Var', (25, 34))
329936	32638267	Moreover, we found that hypo-DNA methylation, DNA amplification, and TP53 mutation were contributing to the high expression levels of pyrimidine metabolic rate-limiting enzymes in lung cancer cells.	('mutation', 'Var', (74, 82))	('pyrimidine', 'Chemical', 'MESH:C030986', (134, 144))	('TP53', 'Gene', '7157', (69, 73))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('TP53', 'Gene', (69, 73))	('lung cancer', 'Disease', 'MESH:D008175', (180, 191))	('expression levels', 'MPA', (113, 130))	('lung cancer', 'Disease', (180, 191))	('lung cancer', 'Phenotype', 'HP:0100526', (180, 191))	('high', 'PosReg', (108, 112))
329954	32638267	Also, inhibition of pyrimidine synthesis sensitizes triple-negative breast cancer cells to chemotherapy.	('breast cancer', 'Disease', 'MESH:D001943', (68, 81))	('breast cancer', 'Phenotype', 'HP:0003002', (68, 81))	('pyrimidine', 'Chemical', 'MESH:C030986', (20, 30))	('breast cancer', 'Disease', (68, 81))	('pyrimidine synthesis', 'MPA', (20, 40))	('inhibition', 'Var', (6, 16))	('sensitizes', 'Reg', (41, 51))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))
329961	32638267	The gene expression series matrix of normal and cancerous lung tissues was downloaded from the GEO website (www.ncbi.nlm.nih.gov/geo) and included GSE7670, GSE10072, GSE18842, GSE19188, GSE27262, GSE30219, GSE31210, GSE31908, GSE33532, and GSE75324 datasets.	('GSE10072', 'Var', (156, 164))	('GSE19188', 'Var', (176, 184))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('cancerous', 'Disease', 'MESH:D009369', (48, 57))	('GSE31908', 'Var', (216, 224))	('GSE7670', 'Var', (147, 154))	('GSE27262', 'Var', (186, 194))	('GSE18842', 'Var', (166, 174))	('GSE7670', 'Chemical', '-', (147, 154))	('cancerous', 'Disease', (48, 57))
329979	32638267	Among all the enriched metabolic signaling pathways, the pyrimidine metabolism signaling pathway was significantly enriched in seven out of ten datasets, including GSE10072, GSE18842, GSE19188, GSE27262, GSE30219, GSE31210, and GSE75324 datasets, representing the most frequently enriched metabolic signaling pathway (Fig.	('pyrimidine', 'Chemical', 'MESH:C030986', (57, 67))	('GSE30219', 'Var', (204, 212))	('GSE75324', 'Var', (228, 236))	('GSE19188', 'Var', (184, 192))	('GSE18842', 'Var', (174, 182))	('pyrimidine metabolism signaling pathway', 'Pathway', (57, 96))	('GSE10072', 'Var', (164, 172))	('GSE27262', 'Var', (194, 202))	('enriched', 'Reg', (115, 123))	('GSE31210', 'Var', (214, 222))
329980	32638267	Only in GSE7670, GSE31908, and GSE33532 three datasets, the pyrimidine metabolism signaling pathway was not significantly correlated with the transcriptional profiling of lung cancer (Fig.	('pyrimidine', 'Chemical', 'MESH:C030986', (60, 70))	('lung cancer', 'Disease', (171, 182))	('GSE31908', 'Var', (17, 25))	('GSE7670', 'Chemical', '-', (8, 15))	('lung cancer', 'Phenotype', 'HP:0100526', (171, 182))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('GSE33532', 'Var', (31, 39))	('lung cancer', 'Disease', 'MESH:D008175', (171, 182))	('GSE7670', 'Var', (8, 15))
329986	32638267	The expression levels of those pyrimidine metabolic rate-limiting enzymes in lung normal and tumor tissues were investigated in GSE7670, GSE10072, GSE18842, GSE19188, GSE27262, GSE31908, GSE33532, and GSE75324 datasets.	('GSE7670', 'Var', (128, 135))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('GSE10072', 'Var', (137, 145))	('GSE7670', 'Chemical', '-', (128, 135))	('tumor', 'Disease', (93, 98))	('pyrimidine', 'Chemical', 'MESH:C030986', (31, 41))	('GSE19188', 'Var', (157, 165))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
330019	32638267	Also, TK1 amplification occurred in 2.2% lung cancer patients (Fig.	('TK1', 'Gene', (6, 9))	('patients', 'Species', '9606', (53, 61))	('lung cancer', 'Disease', (41, 52))	('TK1', 'Gene', '7083', (6, 9))	('lung cancer', 'Phenotype', 'HP:0100526', (41, 52))	('amplification', 'Var', (10, 23))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('lung cancer', 'Disease', 'MESH:D008175', (41, 52))
330024	32638267	We found that pyrimidine metabolic rate-limiting enzymes CAD, CTPS, DTYMK, RRM1, RRM2, TYMS, UCK2, and TK1 were all highly expressed in TP53 mutant lung cancer patients (Fig.	('UCK2', 'Gene', '7371', (93, 97))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('TYMS', 'Gene', '7298', (87, 91))	('DTYMK', 'Gene', '1841', (68, 73))	('pyrimidine', 'Chemical', 'MESH:C030986', (14, 24))	('TP53', 'Gene', '7157', (136, 140))	('RRM1', 'Gene', '6240', (75, 79))	('CTPS', 'Gene', (62, 66))	('highly expressed', 'PosReg', (116, 132))	('RRM2', 'Gene', (81, 85))	('DTYMK', 'Gene', (68, 73))	('TK1', 'Gene', (103, 106))	('TK1', 'Gene', '7083', (103, 106))	('CAD', 'Chemical', 'MESH:C075764', (57, 60))	('lung cancer', 'Disease', (148, 159))	('mutant', 'Var', (141, 147))	('TYMS', 'Gene', (87, 91))	('UCK2', 'Gene', (93, 97))	('TP53', 'Gene', (136, 140))	('RRM1', 'Gene', (75, 79))	('patients', 'Species', '9606', (160, 168))	('lung cancer', 'Disease', 'MESH:D008175', (148, 159))	('lung cancer', 'Phenotype', 'HP:0100526', (148, 159))	('CTPS', 'Gene', '1503', (62, 66))	('RRM2', 'Gene', '6241', (81, 85))
330026	32638267	The expression levels of pyrimidine metabolic rate-limiting enzymes CAD, CTPS, DTYMK, RRM1, RRM2, TYMS, UCK2, and TK1 were particularly higher in TP53 mutant lung cancer patients (Fig.	('lung cancer', 'Disease', (158, 169))	('UCK2', 'Gene', (104, 108))	('TYMS', 'Gene', (98, 102))	('TP53', 'Gene', (146, 150))	('RRM1', 'Gene', (86, 90))	('lung cancer', 'Disease', 'MESH:D008175', (158, 169))	('RRM2', 'Gene', '6241', (92, 96))	('CTPS', 'Gene', '1503', (73, 77))	('DTYMK', 'Gene', '1841', (79, 84))	('UCK2', 'Gene', '7371', (104, 108))	('expression levels', 'MPA', (4, 21))	('patients', 'Species', '9606', (170, 178))	('mutant', 'Var', (151, 157))	('lung cancer', 'Phenotype', 'HP:0100526', (158, 169))	('DTYMK', 'Gene', (79, 84))	('pyrimidine', 'Chemical', 'MESH:C030986', (25, 35))	('RRM2', 'Gene', (92, 96))	('CTPS', 'Gene', (73, 77))	('TP53', 'Gene', '7157', (146, 150))	('higher', 'PosReg', (136, 142))	('RRM1', 'Gene', '6240', (86, 90))	('TYMS', 'Gene', '7298', (98, 102))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('TK1', 'Gene', (114, 117))	('TK1', 'Gene', '7083', (114, 117))	('CAD', 'Chemical', 'MESH:C075764', (68, 71))
330028	32638267	Overall, our results suggested that hypo-DNA methylation, DNA amplification, and TP53 mutation were combined contributing to the high expression levels of pyrimidine metabolic rate-limiting enzymes in lung cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('lung cancer', 'Disease', 'MESH:D008175', (201, 212))	('high', 'PosReg', (129, 133))	('TP53', 'Gene', (81, 85))	('pyrimidine', 'Chemical', 'MESH:C030986', (155, 165))	('lung cancer', 'Phenotype', 'HP:0100526', (201, 212))	('mutation', 'Var', (86, 94))	('lung cancer', 'Disease', (201, 212))	('contributing', 'Reg', (109, 121))	('TP53', 'Gene', '7157', (81, 85))	('expression levels', 'MPA', (134, 151))
330085	30933315	Mutation of Chromatin Regulators and Focal Hotspot Alterations Characterize HPV Positive Oropharyngeal Squamous Cell Carcinoma HPV associated oropharyngeal cancer is a clinically and biologically distinct disease from smoking related Head and Neck Squamous Cell Carcinoma (HNSCC).	('Head and Neck Squamous Cell Carcinoma', 'Phenotype', 'HP:0012288', (234, 271))	('Oropharyngeal Squamous Cell Carcinoma', 'Phenotype', 'HP:0012182', (89, 126))	('Neck Squamous Cell Carcinoma', 'Disease', (243, 271))	('Squamous Cell Carcinoma', 'Disease', (103, 126))	('Neck Squamous Cell Carcinoma', 'Disease', 'MESH:D000077195', (243, 271))	('cancer', 'Disease', (156, 162))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (103, 126))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (248, 271))	('Mutation', 'Var', (0, 8))	('HPV', 'Gene', (76, 79))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('Carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('HNSCC', 'Phenotype', 'HP:0012288', (273, 278))	('Carcinoma', 'Phenotype', 'HP:0030731', (262, 271))	('Squamous Cell Carcinoma', 'Disease', 'MESH:D002294', (103, 126))	('Squamous Cell Carcinoma', 'Disease', 'MESH:D002294', (248, 271))
330089	30933315	There was a strikingly high 33% frequency of mutations within genes associated with chromatin regulation, including mutations in KMT2C, KMT2D, NSD1, CREBBP, EP300, and CTCF.	('mutations', 'Var', (45, 54))	('EP300', 'Gene', (157, 162))	('EP300', 'Gene', '2033', (157, 162))	('CTCF', 'Gene', (168, 172))	('CREBBP', 'Gene', '1387', (149, 155))	('KMT2C', 'Gene', '58508', (129, 134))	('KMT2C', 'Gene', (129, 134))	('CTCF', 'Gene', '10664', (168, 172))	('KMT2D', 'Gene', (136, 141))	('mutations', 'Var', (116, 125))	('KMT2D', 'Gene', '8085', (136, 141))	('NSD1', 'Gene', '64324', (143, 147))	('CREBBP', 'Gene', (149, 155))	('NSD1', 'Gene', (143, 147))
330090	30933315	In addition, the commonly altered genes PIK3CA and FGFR3 show distinct domain-specific hotspot mutations as compared to their HPV negative counterparts.	('PIK3CA', 'Gene', (40, 46))	('FGFR3', 'Gene', '2261', (51, 56))	('PIK3CA', 'Gene', '5290', (40, 46))	('hotspot', 'PosReg', (87, 94))	('altered', 'Reg', (26, 33))	('mutations', 'Var', (95, 104))	('FGFR3', 'Gene', (51, 56))
330091	30933315	PIK3CA shows a uniquely high rate of mutation within the helicase domain, and FGFR3 contains a predominance of hotspot S249C alterations that are not found in HPV-negative HNSCC.	('FGFR3', 'Gene', (78, 83))	('HNSCC', 'Phenotype', 'HP:0012288', (172, 177))	('mutation', 'Var', (37, 45))	('S249C', 'Mutation', 'rs121913483', (119, 124))	('S249C alterations', 'Var', (119, 136))	('PIK3CA', 'Gene', (0, 6))	('FGFR3', 'Gene', '2261', (78, 83))	('PIK3CA', 'Gene', '5290', (0, 6))	('helicase domain', 'Protein', (57, 72))
330092	30933315	A high frequency of mutations within chromatin regulatory genes, as well as domain specific alterations within PIK3CA and FGFR3, are novel findings that distinguish the molecular signature of HPV positive oropharyngeal squamous cell carcinoma from its smoking-related counterpart.	('squamous cell carcinoma', 'Disease', (219, 242))	('chromatin regulatory genes', 'Gene', (37, 63))	('FGFR3', 'Gene', (122, 127))	('PIK3CA', 'Gene', (111, 117))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (219, 242))	('PIK3CA', 'Gene', '5290', (111, 117))	('carcinoma', 'Phenotype', 'HP:0030731', (233, 242))	('oropharyngeal squamous cell carcinoma', 'Phenotype', 'HP:0012182', (205, 242))	('mutations', 'Var', (20, 29))	('FGFR3', 'Gene', '2261', (122, 127))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (219, 242))
330100	30933315	The prior TCGA HPV+ analysis revealed 56% of tumors to contain PIK3CA somatic mutations and only one tumor of the cohort to contain a TP53 alteration, both hallmarks of HPV+ disease.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('TP53', 'Gene', (134, 138))	('hallmarks of HPV+ disease', 'Disease', (156, 181))	('tumors', 'Disease', (45, 51))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('tumor', 'Disease', (45, 50))	('tumor', 'Disease', (101, 106))	('hallmarks of HPV+ disease', 'Disease', 'MESH:D030361', (156, 181))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('mutations', 'Var', (78, 87))	('tumors', 'Disease', 'MESH:D009369', (45, 51))	('PIK3CA', 'Gene', (63, 69))	('PIK3CA', 'Gene', '5290', (63, 69))	('TP53', 'Gene', '7157', (134, 138))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
330105	30933315	Although HPV+ oropharynx tumors have clinically favorable outcomes compared to their HPV-negative counterparts, the low mutational rate and tumor heterogeneity suggests limited options for targeted therapeutic intervention, and a need for further focused genomic analysis of this unique oncologic entity.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumors', 'Disease', (25, 31))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('tumor', 'Disease', (25, 30))	('oropharynx tumors', 'Phenotype', 'HP:0100638', (14, 31))	('tumors', 'Disease', 'MESH:D009369', (25, 31))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('HPV+', 'Var', (9, 13))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('tumor', 'Disease', (140, 145))
330115	30933315	Subsequent processing was carried out with SAMtools v.1.1, Picard Tools v.1.96, Genome Analysis Toolkit (GATK) v2.4-9 and, which consisted of the following steps: sorting and splitting of the BAM files, marking of duplicate reads, local realignment, indel realignment and recalibration of base quality scores.	('v2.4-9', 'Gene', (111, 117))	('v2.4-9', 'Gene', '28804;28803;28802', (111, 117))	('indel realignment', 'Var', (250, 267))
330128	30933315	Two tumors contained PIK3CA mutations, and there were separate mutations of HRAS, FGFR3, KMT2D, CASP8, and FBXW7 within one sample each.	('FGFR3', 'Gene', (82, 87))	('HRAS', 'Gene', '3265', (76, 80))	('tumors', 'Disease', (4, 10))	('PIK3CA', 'Gene', (21, 27))	('CASP8', 'Gene', (96, 101))	('FBXW7', 'Gene', '55294', (107, 112))	('CASP8', 'Gene', '841', (96, 101))	('PIK3CA', 'Gene', '5290', (21, 27))	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('HRAS', 'Gene', (76, 80))	('KMT2D', 'Gene', (89, 94))	('KMT2D', 'Gene', '8085', (89, 94))	('FGFR3', 'Gene', '2261', (82, 87))	('contained', 'Reg', (11, 20))	('FBXW7', 'Gene', (107, 112))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('mutations', 'Var', (28, 37))
330130	30933315	There was an average rate of 2.45 mutations per tumor, similar to the low rate of mutagenesis within HPV+ tumors reported in other studies.	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('tumor', 'Disease', (48, 53))	('tumors', 'Disease', (106, 112))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('mutations', 'Var', (34, 43))	('tumor', 'Disease', (106, 111))
330134	30933315	There is a particular predominance of TpC mutations (5.45 per Mb) compared to CpG mutations (3.94 per Mb).	('mutations', 'Var', (42, 51))	('TpC', 'Gene', (38, 41))	('TpC', 'Gene', '8030', (38, 41))
330135	30933315	This phenomena is also seen in HPV related cervical cancer, whereas CpG dinucleotide alterations predominate in non-HPV related cancers such as colorectal, pancreatic, and glioblastoma multiforme.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('cancers', 'Disease', 'MESH:D009369', (128, 135))	('dinucleotide alterations', 'Var', (72, 96))	('cancers', 'Phenotype', 'HP:0002664', (128, 135))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('cancers', 'Disease', (128, 135))	('pancreatic', 'Disease', (156, 166))	('colorectal', 'Disease', 'MESH:D015179', (144, 154))	('glioblastoma multiforme', 'Disease', (172, 195))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('colorectal', 'Disease', (144, 154))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (172, 195))	('glioblastoma', 'Phenotype', 'HP:0012174', (172, 184))	('cancer', 'Disease', (128, 134))
330136	30933315	There was a strong predominance of amplifications within 3q25-28 containing PIK3CA, and consistent with prior reports.	('PIK3CA', 'Gene', (76, 82))	('PIK3CA', 'Gene', '5290', (76, 82))	('amplifications', 'Var', (35, 49))
330142	30933315	NSD1 is mutated within 9% (4 of 46 tumors) of the JHU cohort, and 2 tumors within the TCGA samples.	('NSD1', 'Gene', (0, 4))	('tumors', 'Disease', (68, 74))	('tumors', 'Disease', 'MESH:D009369', (68, 74))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('mutated', 'Var', (8, 15))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('tumors', 'Disease', (35, 41))	('tumors', 'Disease', 'MESH:D009369', (35, 41))	('NSD1', 'Gene', '64324', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))
330144	30933315	This putative tumor suppressor gene is correlated with significant increased patient survival when the mutation is present, possibly related to a known strong association with genome-wide hypomethylation and corresponding platinum sensitivity .	('tumor', 'Disease', (14, 19))	('platinum', 'Chemical', 'MESH:D010984', (222, 230))	('increased', 'PosReg', (67, 76))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('mutation', 'Var', (103, 111))	('patient', 'Species', '9606', (77, 84))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('patient survival', 'CPA', (77, 93))
330145	30933315	Mutations of the tumor suppressor CREBBP and its closely related paralogue EP300 have not been previously identified in genome-wide studies of HPV-positive HNSCC.	('EP300', 'Gene', (75, 80))	('EP300', 'Gene', '2033', (75, 80))	('tumor', 'Disease', (17, 22))	('CREBBP', 'Gene', (34, 40))	('Mutations', 'Var', (0, 9))	('HNSCC', 'Phenotype', 'HP:0012288', (156, 161))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('CREBBP', 'Gene', '1387', (34, 40))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
330148	30933315	Within our JHU cohort, CREBBP is mutated in 4 of 46 tumors (8.7%), and EP300 in 1 subject (2.2%).	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('tumors', 'Disease', (52, 58))	('CREBBP', 'Gene', (23, 29))	('mutated', 'Var', (33, 40))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('CREBBP', 'Gene', '1387', (23, 29))	('EP300', 'Gene', (71, 76))	('EP300', 'Gene', '2033', (71, 76))
330149	30933315	CREBBP/EP300 are acetyltransferases which modulate chromatin accessibility within enhancer networks, and inactivating mutations of these genes are highly recurrent within multiple types of lymphoma where they have been most studied.	('CREBBP', 'Gene', '1387', (0, 6))	('EP300', 'Gene', (7, 12))	('EP300', 'Gene', '2033', (7, 12))	('lymphoma', 'Disease', (189, 197))	('chromatin accessibility', 'MPA', (51, 74))	('lymphoma', 'Disease', 'MESH:D008223', (189, 197))	('lymphoma', 'Phenotype', 'HP:0002665', (189, 197))	('inactivating mutations', 'Var', (105, 127))	('CREBBP', 'Gene', (0, 6))	('modulate', 'Reg', (42, 50))
330150	30933315	As global transcriptional coactivators they act on both proto-oncogenes and tumor suppressor genes, and loss of CREBBP/EP300 confers a clonal proliferative advantage within tumor cells.	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('loss', 'Var', (104, 108))	('CREBBP', 'Gene', (112, 118))	('EP300', 'Gene', (119, 124))	('EP300', 'Gene', '2033', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumor', 'Disease', (173, 178))	('CREBBP', 'Gene', '1387', (112, 118))	('clonal proliferative advantage', 'CPA', (135, 165))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
330151	30933315	CTCF was also found to be mutated in 1 JHU subject and 1 TCGA tumor.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('CTCF', 'Gene', (0, 4))	('tumor', 'Disease', (62, 67))	('CTCF', 'Gene', '10664', (0, 4))	('mutated', 'Var', (26, 33))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
330153	30933315	Interestingly, Rb1 is mutated within 2 JHU samples (4.4%) and 4 TCGA samples (8.8%).	('mutated', 'Var', (22, 29))	('Rb1', 'Gene', '5925', (15, 18))	('Rb1', 'Gene', (15, 18))
330155	30933315	An Rb1 mutation may similarly act to disrupt binding to E2F independent of E7, but its dependence on E7 in this case remains unclear.	('Rb1', 'Gene', '5925', (3, 6))	('binding', 'Interaction', (45, 52))	('E2F', 'Protein', (56, 59))	('mutation', 'Var', (7, 15))	('Rb1', 'Gene', (3, 6))	('disrupt', 'NegReg', (37, 44))
330156	30933315	Interestingly, one of the Rb1 mutated samples within the JHU cohort does contain expression of viral oncoproteins E245.	('E245', 'Var', (114, 118))	('Rb1', 'Gene', (26, 29))	('mutated', 'Var', (30, 37))	('Rb1', 'Gene', '5925', (26, 29))	('expression', 'MPA', (81, 91))
330158	30933315	Specifically, Rb plays an important role in histone modification and stabilization of the genome through epigenetic control, and may represent an alternate role for Rb mutation in HPV+ cancer progression.	('epigenetic control', 'MPA', (105, 123))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('HPV+', 'Disease', (180, 184))	('Rb', 'Chemical', 'MESH:D012413', (14, 16))	('mutation', 'Var', (168, 176))	('Rb', 'Chemical', 'MESH:D012413', (165, 167))	('stabilization', 'MPA', (69, 82))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('cancer', 'Disease', (185, 191))	('histone modification', 'MPA', (44, 64))
330159	30933315	In our JHU cohort, the highest frequency of mutation was found within the PIK3CA gene, at a rate of 28% (13 of 46 subjects).	('PIK3CA', 'Gene', '5290', (74, 80))	('mutation', 'Var', (44, 52))	('PIK3CA', 'Gene', (74, 80))
330161	30933315	Ten of the 13 subjects contain mutations within the helical domain, whereby only one mutation is located within the kinase domain at G1049R, immediately adjacent to the H1047R hotspot.	('G1049R', 'Mutation', 'rs121913277', (133, 139))	('H1047R', 'SUBSTITUTION', 'None', (169, 175))	('H1047R', 'Var', (169, 175))	('G1049R', 'Var', (133, 139))
330162	30933315	TCGA analysis of HPV+ oropharynx tumors is markedly similar, with a likewise 28% frequency (13 of 46 tumors) of missense mutation of the PIK3CA gene.	('oropharynx tumors', 'Phenotype', 'HP:0100638', (22, 39))	('PIK3CA', 'Gene', (137, 143))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('PIK3CA', 'Gene', '5290', (137, 143))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumors', 'Disease', 'MESH:D009369', (33, 39))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('tumors', 'Disease', (101, 107))	('missense mutation', 'Var', (112, 129))	('tumors', 'Disease', (33, 39))	('tumors', 'Disease', 'MESH:D009369', (101, 107))
330163	30933315	Notably, twelve of the 13 mutations were located within the E545K or E542K helical hotspot domain, and none within the kinase domain (Figure 4).	('E545K', 'Mutation', 'rs104886003', (60, 65))	('E542K', 'Var', (69, 74))	('E545K', 'Var', (60, 65))	('E542K', 'Mutation', 'rs121913273', (69, 74))
330164	30933315	In contrast, Liu et al showed that the majority of HPV-negative tumors contain mutations within the kinase domain of PIK3CA, highlighting a potentially distinct mechanistic difference despite alterations within the same gene.	('tumors', 'Disease', (64, 70))	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('PIK3CA', 'Gene', (117, 123))	('PIK3CA', 'Gene', '5290', (117, 123))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('mutations', 'Var', (79, 88))
330167	30933315	5 of 6 mutations within the JHU cohort occur at the S249C hotspot, and 4 of 5 mutations within TCGA occur at the same locus.	('TCGA', 'Gene', (95, 99))	('S249C', 'Mutation', 'rs121913483', (52, 57))	('mutations', 'Var', (7, 16))
330168	30933315	FGFR3 mutational domain variants have not been previously reported within TCGA.	('FGFR3', 'Gene', '2261', (0, 5))	('mutational domain variants', 'Var', (6, 32))	('FGFR3', 'Gene', (0, 5))
330169	30933315	In contrast to HPV+ tumors, TCGA HPV-negative tumors have only a 1.5% (7 of 466 samples) FGFR3 mutagenic rate, with only one of these located at the S249C hotspot.	('mutagenic', 'Var', (95, 104))	('tumors', 'Disease', (20, 26))	('tumors', 'Disease', 'MESH:D009369', (20, 26))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('FGFR3', 'Gene', (89, 94))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('tumors', 'Disease', 'MESH:D009369', (46, 52))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('tumors', 'Disease', (46, 52))	('S249C', 'Mutation', 'rs121913483', (149, 154))	('FGFR3', 'Gene', '2261', (89, 94))
330170	30933315	PIK3CA and FGFR3 mutations predominate in HPV+ OPSCC, with a lesser role played by other mutations within the PIK3CA pathway.	('FGFR3', 'Gene', '2261', (11, 16))	('PIK3CA', 'Gene', (0, 6))	('FGFR3', 'Gene', (11, 16))	('PIK3CA', 'Gene', '5290', (0, 6))	('OPSCC', 'Phenotype', 'HP:0012182', (47, 52))	('PIK3CA', 'Gene', (110, 116))	('HPV+ OPSCC', 'Disease', (42, 52))	('mutations', 'Var', (17, 26))	('PIK3CA', 'Gene', '5290', (110, 116))
330171	30933315	For example, only 2 tumors (4.4%, 2 of 46) contain HRAS mutations within the JHU samples.	('tumors', 'Disease', 'MESH:D009369', (20, 26))	('mutations', 'Var', (56, 65))	('HRAS', 'Gene', (51, 55))	('tumors', 'Disease', (20, 26))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('HRAS', 'Gene', '3265', (51, 55))
330172	30933315	There was one HRAS mutation within TCGA HPV+ OPSCC.	('OPSCC', 'Phenotype', 'HP:0012182', (45, 50))	('mutation', 'Var', (19, 27))	('TCGA', 'Gene', (35, 39))	('HRAS', 'Gene', (14, 18))	('HRAS', 'Gene', '3265', (14, 18))
330173	30933315	Two tumors contained PTEN mutations and two contained a PIK3R1 mutation in both our cohort and TCGA, respectively.	('PIK3R1', 'Gene', '5295', (56, 62))	('tumors', 'Disease', (4, 10))	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('PIK3R1', 'Gene', (56, 62))	('mutation', 'Var', (63, 71))	('mutations', 'Var', (26, 35))	('contained', 'Reg', (11, 20))	('PTEN', 'Gene', (21, 25))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('PTEN', 'Gene', '5728', (21, 25))
330174	30933315	We have identified potential driver mutations within HPV associated HNSCC that have only previously been identified within non-HPV associated carcinomas, suggesting a smoking-independent biological overlap between these anatomically related but distinct cancers.	('cancer', 'Phenotype', 'HP:0002664', (254, 260))	('HPV', 'Gene', (53, 56))	('carcinomas', 'Disease', 'MESH:D009369', (142, 152))	('HNSCC', 'Gene', (68, 73))	('mutations', 'Var', (36, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (142, 151))	('carcinomas', 'Phenotype', 'HP:0030731', (142, 152))	('carcinomas', 'Disease', (142, 152))	('cancers', 'Phenotype', 'HP:0002664', (254, 261))	('cancers', 'Disease', (254, 261))	('cancers', 'Disease', 'MESH:D009369', (254, 261))	('HNSCC', 'Phenotype', 'HP:0012288', (68, 73))
330175	30933315	Three of the JHU tumors carried the CASP8 alteration.	('JHU tumors', 'Disease', (13, 23))	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('CASP8', 'Gene', (36, 41))	('CASP8', 'Gene', '841', (36, 41))	('JHU tumors', 'Disease', 'MESH:D009369', (13, 23))	('alteration', 'Var', (42, 52))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
330176	30933315	CASP8 mutations are a significant finding in HPV negative OSCC, yet to be identified in HPV+ HNSCC.	('HNSCC', 'Phenotype', 'HP:0012288', (93, 98))	('CASP8', 'Gene', (0, 5))	('mutations', 'Var', (6, 15))	('CASP8', 'Gene', '841', (0, 5))
330177	30933315	The loss-of-function of the apoptosis gene CASP8 is notable for its strong correlation with an HRAS co-mutation in oral cavity cancer , but there was no concurrent HRAS mutation within our study.	('CASP8', 'Gene', (43, 48))	('CASP8', 'Gene', '841', (43, 48))	('HRAS', 'Gene', (95, 99))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('loss-of-function', 'NegReg', (4, 20))	('HRAS', 'Gene', (164, 168))	('co-mutation', 'Var', (100, 111))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('HRAS', 'Gene', '3265', (95, 99))	('cancer', 'Disease', (127, 133))	('HRAS', 'Gene', '3265', (164, 168))
330178	30933315	Indeed, we found one recurrent G13D HRAS mutation in two subjects, and no KRAS or NRAS mutations within our entire cohort.	('G13D', 'Mutation', 'rs112445441', (31, 35))	('HRAS', 'Gene', '3265', (36, 40))	('NRAS', 'Gene', (82, 86))	('KRAS', 'Gene', (74, 78))	('KRAS', 'Gene', '3845', (74, 78))	('HRAS', 'Gene', (36, 40))	('NRAS', 'Gene', '4893', (82, 86))	('G13D', 'Var', (31, 35))
330179	30933315	The TCGA analysis revealed no CASP8, KRAS, or NRAS mutations within HPV+ OPSCC tumors.	('CASP8', 'Gene', (30, 35))	('mutations', 'Var', (51, 60))	('NRAS', 'Gene', (46, 50))	('CASP8', 'Gene', '841', (30, 35))	('OPSCC', 'Phenotype', 'HP:0012182', (73, 78))	('NRAS', 'Gene', '4893', (46, 50))	('KRAS', 'Gene', (37, 41))	('tumors', 'Disease', (79, 85))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('KRAS', 'Gene', '3845', (37, 41))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
330181	30933315	SERPINB5 is notable in our population for containing a high rate of co-occurring mutations (Figure 3), existing concurrently with NOTCH1, FAT1, USP6, PDE4DIP, TRAF3 and HLA-A.	('FAT1', 'Gene', (138, 142))	('USP6', 'Gene', '9098', (144, 148))	('HLA-A', 'Gene', (169, 174))	('PDE4DIP', 'Gene', '9659', (150, 157))	('USP6', 'Gene', (144, 148))	('NOTCH1', 'Gene', '4851', (130, 136))	('NOTCH1', 'Gene', (130, 136))	('SERPINB5', 'Gene', (0, 8))	('SERPINB5', 'Gene', '5268', (0, 8))	('PDE4DIP', 'Gene', (150, 157))	('TRAF3', 'Gene', '7187', (159, 164))	('mutations', 'Var', (81, 90))	('HLA-A', 'Gene', '3105', (169, 174))	('FAT1', 'Gene', '2195', (138, 142))	('TRAF3', 'Gene', (159, 164))
330183	30933315	We have identified mutations in FBXW7 within 8 of 46 tumors (17.4%) of the JHU cohort.	('FBXW7', 'Gene', (32, 37))	('mutations', 'Var', (19, 28))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('FBXW7', 'Gene', '55294', (32, 37))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('tumors', 'Disease', (53, 59))
330188	30933315	Notch1 itself is mutated within 6.5% (3 of 46) of patients within the JHU cohort and 6.5% (3 of 46) within TCGA.	('Notch1', 'Gene', (0, 6))	('Notch1', 'Gene', '4851', (0, 6))	('patients', 'Species', '9606', (50, 58))	('mutated', 'Var', (17, 24))
330189	30933315	Notably, CYLD is mutated within the TCGA cohort at a rate of 13% (6 of 46).	('CYLD', 'Gene', '1540', (9, 13))	('CYLD', 'Gene', (9, 13))	('mutated', 'Var', (17, 24))
330191	30933315	PTCH1, a novel gene alteration, is mutated in 2 JHU tumor samples and one TCGA tumor.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('mutated', 'Var', (35, 42))	('tumor', 'Disease', (79, 84))	('PTCH1', 'Gene', (0, 5))	('tumor', 'Disease', (52, 57))	('PTCH1', 'Gene', '5727', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
330197	30933315	H3K27ac) in HPV+ oropharyngeal cancer.	('H3K27ac', 'Var', (0, 7))	('cancer', 'Disease', (31, 37))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))
330205	30933315	Only within the past decade have PMTs been implicated as drivers of carcinogenesis, with mutations strongly implicated in metastatic spread of squamous cell carcinoma.	('squamous cell carcinoma', 'Disease', (143, 166))	('implicated in', 'Reg', (108, 121))	('carcinogenesis', 'Disease', 'MESH:D063646', (68, 82))	('carcinogenesis', 'Disease', (68, 82))	('metastatic spread', 'CPA', (122, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (157, 166))	('mutations', 'Var', (89, 98))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (143, 166))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (143, 166))
330207	30933315	In squamous cell carcinoma of the esophagus, there is a higher rate of KMT2D mutations identified within metastases as compared to primary tumors.	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (3, 26))	('KMT2D', 'Gene', (71, 76))	('KMT2D', 'Gene', '8085', (71, 76))	('carcinoma of the esophagus', 'Phenotype', 'HP:0011459', (17, 43))	('metastases', 'Disease', (105, 115))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('mutations', 'Var', (77, 86))	('tumors', 'Disease', (139, 145))	('tumors', 'Disease', 'MESH:D009369', (139, 145))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('metastases', 'Disease', 'MESH:D009362', (105, 115))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (3, 26))	('carcinoma', 'Phenotype', 'HP:0030731', (17, 26))	('squamous cell carcinoma', 'Disease', (3, 26))
330208	30933315	In our JHU study population, KMT2C is altered in a statistically significant 28% of subjects, and all subjects within this cohort presented with locoregional metastases.	('KMT2C', 'Gene', '58508', (29, 34))	('KMT2C', 'Gene', (29, 34))	('altered', 'Var', (38, 45))	('metastases', 'Disease', (158, 168))	('presented with', 'Reg', (130, 144))	('metastases', 'Disease', 'MESH:D009362', (158, 168))
330210	30933315	In sum, the dysregulation of enhancer chromatin within HPV+ OPSCC oncogenic progression has not been well characterized previously, and here, we highlight its high rate of mutagenesis along with its potential mechanistic connection to HPV+ carcinoma.	('carcinoma', 'Disease', (240, 249))	('carcinoma', 'Disease', 'MESH:D009369', (240, 249))	('HPV+', 'Gene', (55, 59))	('carcinoma', 'Phenotype', 'HP:0030731', (240, 249))	('OPSCC', 'Phenotype', 'HP:0012182', (60, 65))	('mutagenesis', 'Var', (172, 183))
330217	30933315	Somewhat contradictory, within the JHU cohort there were no EGFR specific mutations, and only two tumors harbored an HRAS mutation, highlighting the need for more in-depth genomic investigations of driver events in order to bridge understanding with empiric clinical data.	('tumors', 'Disease', (98, 104))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('HRAS', 'Gene', '3265', (117, 121))	('mutation', 'Var', (122, 130))	('tumors', 'Disease', 'MESH:D009369', (98, 104))	('mutations', 'Var', (74, 83))	('HRAS', 'Gene', (117, 121))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('EGFR', 'Gene', '1956', (60, 64))	('EGFR', 'Gene', (60, 64))
330220	30933315	Within our HPV+ cohort, mutations within the PIK3CA helical domain predominate, whereby kinase domain mutations are more prevalent within HPV negative tumors.	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumors', 'Disease', (151, 157))	('tumors', 'Disease', 'MESH:D009369', (151, 157))	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('PIK3CA', 'Gene', (45, 51))	('PIK3CA', 'Gene', '5290', (45, 51))	('mutations', 'Var', (24, 33))
330223	30933315	This suggests that despite having a similar rate of PIK3CA mutations, HPV positive and negative disease may be specifically driven by domain alterations.	('domain alterations', 'Var', (134, 152))	('PIK3CA', 'Gene', (52, 58))	('driven by', 'Reg', (124, 133))	('mutations', 'Var', (59, 68))	('PIK3CA', 'Gene', '5290', (52, 58))	('HPV positive', 'Disease', (70, 82))
330224	30933315	In several other cancers, the specific PIK3CA domain alteration has been shown to be predictive of tumor response to treatment and survival.	('tumor', 'Disease', (99, 104))	('domain alteration', 'Var', (46, 63))	('PIK3CA', 'Gene', '5290', (39, 45))	('cancers', 'Phenotype', 'HP:0002664', (17, 24))	('cancers', 'Disease', (17, 24))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('cancers', 'Disease', 'MESH:D009369', (17, 24))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('PIK3CA', 'Gene', (39, 45))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
330225	30933315	In urothelial carcinoma, mutations within the PIK3CA kinase domain correspond with high levels of AKT activation as compared to mutations within the helical domain .	('mutations', 'Var', (25, 34))	('PIK3CA', 'Gene', '5290', (46, 52))	('urothelial carcinoma', 'Disease', (3, 23))	('AKT', 'Gene', '207', (98, 101))	('activation', 'PosReg', (102, 112))	('AKT', 'Gene', (98, 101))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (3, 23))	('carcinoma', 'Phenotype', 'HP:0030731', (14, 23))	('PIK3CA', 'Gene', (46, 52))
330226	30933315	And in an early phase clinical trial, patients with the kinase domain H1047R mutation had a significantly higher partial response rate to PI3K/AKT/mTOR inhibitors as compared to patients with helical domain E545K and E542K mutations.	('H1047R', 'SUBSTITUTION', 'None', (70, 76))	('E542K', 'Mutation', 'rs121913273', (217, 222))	('patients', 'Species', '9606', (178, 186))	('AKT', 'Gene', '207', (143, 146))	('higher', 'PosReg', (106, 112))	('partial response', 'MPA', (113, 129))	('patients', 'Species', '9606', (38, 46))	('mTOR', 'Gene', '2475', (147, 151))	('E545K', 'Mutation', 'rs104886003', (207, 212))	('H1047R', 'Var', (70, 76))	('AKT', 'Gene', (143, 146))	('mTOR', 'Gene', (147, 151))
330227	30933315	In breast cancer, patients with helical domain mutant tumors have been associated with poorer recurrence-free and overall survival, and conversely, those patients with kinase alterations had a better prognosis than those with even PIK3CA wild-type tumors.	('tumors', 'Disease', (248, 254))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('PIK3CA', 'Gene', '5290', (231, 237))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('recurrence-free', 'CPA', (94, 109))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumors', 'Disease', 'MESH:D009369', (248, 254))	('tumors', 'Disease', (54, 60))	('overall survival', 'CPA', (114, 130))	('patients', 'Species', '9606', (154, 162))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('patients', 'Species', '9606', (18, 26))	('tumor', 'Phenotype', 'HP:0002664', (248, 253))	('tumors', 'Disease', 'MESH:D009369', (54, 60))	('PIK3CA', 'Gene', (231, 237))	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('breast cancer', 'Disease', (3, 16))	('tumors', 'Phenotype', 'HP:0002664', (248, 254))	('helical domain mutant', 'Var', (32, 53))	('poorer', 'NegReg', (87, 93))
330229	30933315	Mechanistically, PIK3CA domain specific alterations have been linked with differential downstream pathway activations - mutations in the helical domain located on exon 9 corresponds strongly with features enabling cell migration and dissemination, while kinase alterations located on exon 20 are associated with aberrant proliferation.	('PIK3CA', 'Gene', (17, 23))	('PIK3CA', 'Gene', '5290', (17, 23))	('cell migration', 'CPA', (214, 228))	('mutations', 'Var', (120, 129))
330231	30933315	Kinase mutants act via a different mechanism, directly activating the PI3K catalytic subunit, while still being acted upon by p85 inhibition.	('mutants', 'Var', (7, 14))	('p85', 'Gene', (126, 129))	('activating', 'PosReg', (55, 65))	('PI3K', 'Protein', (70, 74))	('p85', 'Gene', '5295', (126, 129))
330232	30933315	As the case with targetable BRAF V600E mutations, importance of selective inhibition against point mutations have become possible with deep genome-wide investigations.	('V600E', 'Var', (33, 38))	('BRAF', 'Gene', (28, 32))	('BRAF', 'Gene', '673', (28, 32))	('V600E', 'Mutation', 'rs113488022', (33, 38))
330235	30933315	The S249C variant is prognostic, and correlates with significantly worse disease-free survival within HPV+ OPSCC.	('S249C', 'Var', (4, 9))	('OPSCC', 'Phenotype', 'HP:0012182', (107, 112))	('S249C', 'Mutation', 'rs121913483', (4, 9))	('disease-free survival', 'CPA', (73, 94))	('worse', 'NegReg', (67, 72))
330236	30933315	This is not true of the other FGFR3 domain variants.	('variants', 'Var', (43, 51))	('FGFR3', 'Gene', (30, 35))	('FGFR3', 'Gene', '2261', (30, 35))
330237	30933315	Within lung SCC, S249C mutations have been shown to drive cellular transformation in culture, and growth of cells expressing this mutation were inhibited by the FGFR kinase inhibitor ponatinib.	('S249C mutations', 'Var', (17, 32))	('ponatinib', 'Chemical', 'MESH:C545373', (183, 192))	('inhibited', 'NegReg', (144, 153))	('S249C', 'Mutation', 'rs121913483', (17, 22))	('drive', 'Reg', (52, 57))	('cellular transformation', 'CPA', (58, 81))	('growth', 'CPA', (98, 104))
330239	30933315	The S249C variant correlates with higher FGFR3 protein expression, non-16/18 HPV subtypes, and unfavorable clinical outcome .	('S249C', 'Var', (4, 9))	('protein', 'Protein', (47, 54))	('S249C', 'Mutation', 'rs121913483', (4, 9))	('FGFR3', 'Gene', '2261', (41, 46))	('higher', 'PosReg', (34, 40))	('expression', 'MPA', (55, 65))	('non-16/18 HPV subtypes', 'CPA', (67, 89))	('FGFR3', 'Gene', (41, 46))
330243	30933315	Particularly, KMT2C mutational burden reaches statistical significance, with other notably high mutagenic rates seen within CREBBP, EP300, and NSD1.	('EP300', 'Gene', '2033', (132, 137))	('CREBBP', 'Gene', '1387', (124, 130))	('CREBBP', 'Gene', (124, 130))	('NSD1', 'Gene', '64324', (143, 147))	('KMT2C', 'Gene', '58508', (14, 19))	('KMT2C', 'Gene', (14, 19))	('mutagenic rates', 'MPA', (96, 111))	('mutational', 'Var', (20, 30))	('EP300', 'Gene', (132, 137))	('NSD1', 'Gene', (143, 147))
330256	29440874	Cytotoxicity to DNA is postulated to occur by DNA cross-linking, nucleic acid depurination, or abnormal base paring.	('nucleic acid', 'Var', (65, 77))	('Cytotoxicity', 'Disease', 'MESH:D064420', (0, 12))	('Cytotoxicity', 'Disease', (0, 12))
330500	30761122	Results: A cohort (GSE17536) of colorectal cancer patients showed that high LAYN expression was associated with poorer overall survival (OS), disease-specific survival (DSS), and disease-free survival (DFS).	('colorectal cancer', 'Disease', (32, 49))	('disease-free survival', 'CPA', (179, 200))	('high', 'Var', (71, 75))	('patients', 'Species', '9606', (50, 58))	('colorectal cancer', 'Disease', 'MESH:D015179', (32, 49))	('LAYN', 'Gene', '143903', (76, 80))	('DSS', 'Chemical', '-', (169, 172))	('disease-specific survival', 'CPA', (142, 167))	('overall survival', 'MPA', (119, 135))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('colorectal cancer', 'Phenotype', 'HP:0003003', (32, 49))	('LAYN', 'Gene', (76, 80))	('poorer', 'NegReg', (112, 118))
330501	30761122	In addition, high LAYN expression was significantly correlated with poor OS and progression-free survival (PFS) in gastric cancers (OS HR = 1.97, P = 3.6e-10; PFS HR = 2.12, P = 2.3e-10).	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('poor OS', 'Disease', (68, 75))	('high', 'Var', (13, 17))	('LAYN', 'Gene', '143903', (18, 22))	('gastric cancer', 'Phenotype', 'HP:0012126', (115, 129))	('cancers', 'Phenotype', 'HP:0002664', (123, 130))	('OS HR', 'Disease', (132, 137))	('progression-free survival', 'CPA', (80, 105))	('gastric cancers', 'Phenotype', 'HP:0012126', (115, 130))	('OS HR', 'Disease', 'MESH:C567932', (132, 137))	('LAYN', 'Gene', (18, 22))	('gastric cancers', 'Disease', (115, 130))	('gastric cancers', 'Disease', 'MESH:D013274', (115, 130))	('expression', 'MPA', (23, 33))
330503	30761122	Specifically, high LAYN expression was correlated with worse OS and PFS in stage 2 to 4 but not stage 1 and stage N0 gastric cancer patients (P = 0.28, 0.34; P = 0.073, 0.092).	('worse OS', 'Disease', (55, 63))	('gastric cancer', 'Phenotype', 'HP:0012126', (117, 131))	('LAYN', 'Gene', (19, 23))	('expression', 'MPA', (24, 34))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('gastric cancer', 'Disease', 'MESH:D013274', (117, 131))	('high', 'Var', (14, 18))	('LAYN', 'Gene', '143903', (19, 23))	('gastric cancer', 'Disease', (117, 131))	('PFS', 'Disease', (68, 71))	('patients', 'Species', '9606', (132, 140))
330520	30761122	LAYN was first shown to be associated with cancer in a report demonstrating that low levels of LAYN protein can reduce cell invasion and lymph node metastasis A549 lung cancer cells.	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('cancer', 'Disease', (169, 175))	('protein', 'Protein', (100, 107))	('reduce', 'NegReg', (112, 118))	('cancer', 'Disease', (43, 49))	('lymph node metastasis A549 lung cancer', 'Disease', (137, 175))	('lung cancer', 'Phenotype', 'HP:0100526', (164, 175))	('associated', 'Reg', (27, 37))	('LAYN', 'Gene', (95, 99))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('lymph node metastasis A549 lung cancer', 'Disease', 'MESH:D009362', (137, 175))	('LAYN', 'Gene', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('LAYN', 'Gene', '143903', (95, 99))	('low levels', 'Var', (81, 91))	('cancer', 'Disease', 'MESH:D009369', (169, 175))	('LAYN', 'Gene', '143903', (0, 4))
330562	30761122	Notably, LAYN expression significantly impacts prognosis in 4 type cancers, including colorectal, breast, eye and ovarian cancers (Figures 2A-H).	('expression', 'Var', (14, 24))	('LAYN', 'Gene', (9, 13))	('cancers', 'Phenotype', 'HP:0002664', (67, 74))	('colorectal, breast, eye and ovarian cancers', 'Disease', 'MESH:D001943', (86, 129))	('impacts', 'Reg', (39, 46))	('ovarian cancers', 'Phenotype', 'HP:0100615', (114, 129))	('type cancers', 'Disease', (62, 74))	('ovarian cancer', 'Phenotype', 'HP:0100615', (114, 128))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('cancers', 'Phenotype', 'HP:0002664', (122, 129))	('LAYN', 'Gene', '143903', (9, 13))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('type cancers', 'Disease', 'MESH:D009369', (62, 74))
330563	30761122	Two cohorts (GSE17536, GSE14333) included 177 samples and 226 samples at different stages of colorectal cancer and showed that high LAYN expression was marginally associated with poorer prognosis (OS HR = 1.50, 95% CI = 0.98 to 2.29, Cox P = 0.06; DSS HR = 1.84, 95% CI=1.15 to 2.97, Cox P = 0.012; DFS HR = 2.32, 95% CI=1.27 to 4.25, Cox P = 0.006; DFS HR = 1.72, 95% CI = 1.21 to 2.46, Cox P = 0.003) (Figures 2A-D).	('Cox', 'Gene', (388, 391))	('high', 'Var', (127, 131))	('LAYN', 'Gene', '143903', (132, 136))	('colorectal cancer', 'Phenotype', 'HP:0003003', (93, 110))	('Cox', 'Gene', (284, 287))	('LAYN', 'Gene', (132, 136))	('GSE17536', 'Var', (13, 21))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('Cox', 'Gene', '1351', (234, 237))	('poorer', 'NegReg', (179, 185))	('colorectal cancer', 'Disease', 'MESH:D015179', (93, 110))	('Cox', 'Gene', '1351', (335, 338))	('Cox', 'Gene', (234, 237))	('GSE14333', 'Var', (23, 31))	('colorectal cancer', 'Disease', (93, 110))	('Cox', 'Gene', '1351', (388, 391))	('Cox', 'Gene', (335, 338))	('DSS', 'Chemical', '-', (248, 251))	('OS HR', 'Disease', 'MESH:C567932', (197, 202))	('OS HR', 'Disease', (197, 202))	('Cox', 'Gene', '1351', (284, 287))
330564	30761122	Therefore, it is conceivable that high LAYN expression is an independent risk factor and leads to a poor prognosis in CRC patients.	('LAYN', 'Gene', (39, 43))	('CRC', 'Disease', (118, 121))	('high', 'Var', (34, 38))	('patients', 'Species', '9606', (122, 130))	('CRC', 'Disease', 'MESH:D015179', (118, 121))	('CRC', 'Phenotype', 'HP:0003003', (118, 121))	('LAYN', 'Gene', '143903', (39, 43))
330572	30761122	Meanwhile, high LAYN expression was correlated with better prognosis of DFS in KIRP and THCA (thyroid carcinoma) as well as OS in SKCM (skin cutaneous melanoma).	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (94, 111))	('skin cutaneous melanoma', 'Disease', (136, 159))	('LAYN', 'Gene', '143903', (16, 20))	('LAYN', 'Gene', (16, 20))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (141, 159))	('thyroid carcinoma', 'Disease', (94, 111))	('expression', 'MPA', (21, 31))	('melanoma', 'Phenotype', 'HP:0002861', (151, 159))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('high', 'Var', (11, 15))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (136, 159))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (94, 111))
330575	30761122	Overexpression of LAYN was associated with worse OS and PFS in male and female patients as well as two types of Lauren classification and differentiation (P < 0.05).	('LAYN', 'Gene', '143903', (18, 22))	('PFS', 'Disease', (56, 59))	('Lauren classification', 'Disease', (112, 133))	('Overexpression', 'Var', (0, 14))	('patients', 'Species', '9606', (79, 87))	('LAYN', 'Gene', (18, 22))
330577	30761122	Here the N category refers to lymph node involvement; N0 indicates no regional lymph node metastasis, and N1-N3 indicate regional lymph node metastasis.	('men', 'Species', '9606', (48, 51))	('N1-N3', 'Var', (106, 111))	('regional lymph node metastasis', 'CPA', (121, 151))
330606	30761122	DCs can promote tumor metastasis by increasing Treg cells and reducing CD8+ T cell cytotoxicity.	('tumor metastasis', 'Disease', (16, 32))	('DCs', 'Var', (0, 3))	('CD8', 'Gene', '925', (71, 74))	('increasing', 'PosReg', (36, 46))	('cytotoxicity', 'Disease', 'MESH:D064420', (83, 95))	('tumor metastasis', 'Disease', 'MESH:D009362', (16, 32))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('reducing', 'NegReg', (62, 70))	('Treg cells', 'CPA', (47, 57))	('cytotoxicity', 'Disease', (83, 95))	('promote', 'PosReg', (8, 15))	('CD8', 'Gene', (71, 74))
330615	30761122	Here, we report that variations in LAYN expression level correlate to prognosis in different types of cancer.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('variations', 'Var', (21, 31))	('expression level', 'MPA', (40, 56))	('LAYN', 'Gene', '143903', (35, 39))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('LAYN', 'Gene', (35, 39))
330627	30761122	KIRP, SKCM, and THCA were exeptions where high levels of LAYN expression showed a better prognosis.	('LAYN', 'Gene', (57, 61))	('LAYN', 'Gene', '143903', (57, 61))	('high levels', 'Var', (42, 53))
330629	30761122	In three datasets of PrognoScan, high LAYN expression levels can be used as an independent risk factor for poor prognosis in colorectal and ovarian cancers (Figures 2A-D,H).	('ovarian cancer', 'Phenotype', 'HP:0100615', (140, 154))	('colorectal and ovarian cancers', 'Disease', 'MESH:D015179', (125, 155))	('high', 'Var', (33, 37))	('LAYN', 'Gene', '143903', (38, 42))	('cancers', 'Phenotype', 'HP:0002664', (148, 155))	('ovarian cancers', 'Phenotype', 'HP:0100615', (140, 155))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('LAYN', 'Gene', (38, 42))
330686	27898614	Proposed theories of carcinogenesis include dysregulation of limbal stem cells and alterations in transcription factor activation due to phosphorylation of receptor sites for cytokines and growth factors.	('carcinogenesis', 'Disease', 'MESH:D063646', (21, 35))	('activation', 'PosReg', (119, 129))	('transcription factor', 'Gene', (98, 118))	('phosphorylation', 'Var', (137, 152))	('carcinogenesis', 'Disease', (21, 35))	('alterations', 'Reg', (83, 94))
330688	27898614	Mutation of p53, with resultant dysregulation of tumor suppression, has been identified in a portion of OSSN cases.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('OSSN', 'Disease', (104, 108))	('Mutation', 'Var', (0, 8))	('tumor', 'Disease', (49, 54))	('p53', 'Gene', (12, 15))	('p53', 'Gene', '7157', (12, 15))	('identified', 'Reg', (77, 87))	('OSSN', 'Chemical', '-', (104, 108))
330727	27898614	Furthermore, xenografts of human foreskin infected with HPV type 16 develop intraepithelial neoplasia in severe combined immunodeficiency mice.	('intraepithelial neoplasia', 'Phenotype', 'HP:0032187', (76, 101))	('develop', 'Reg', (68, 75))	('immunodeficiency', 'Phenotype', 'HP:0002721', (121, 137))	('intraepithelial neoplasia', 'Disease', (76, 101))	('combined immunodeficiency', 'Phenotype', 'HP:0005387', (112, 137))	('immunodeficiency', 'Disease', 'MESH:D007153', (121, 137))	('HPV type', 'Var', (56, 64))	('mice', 'Species', '10090', (138, 142))	('human', 'Species', '9606', (27, 32))	('HPV', 'Species', '10566', (56, 59))	('immunodeficiency', 'Disease', (121, 137))	('severe combined immunodeficiency', 'Phenotype', 'HP:0004430', (105, 137))	('neoplasia', 'Phenotype', 'HP:0002664', (92, 101))	('intraepithelial neoplasia', 'Disease', 'MESH:D019048', (76, 101))
330765	27898614	A systematic evidence review concluded that the incidence of infections due to vaccine-strain HPV, incidence of anogenital warts, and incidence of cervical dysplasia were declining and that the decline was likely due to HPV vaccination programs.	('vaccine-strain', 'Var', (79, 93))	('infections', 'Disease', 'MESH:D007239', (61, 71))	('cervical dysplasia', 'Disease', 'MESH:D002575', (147, 165))	('HPV', 'Species', '10566', (220, 223))	('HPV', 'Species', '10566', (94, 97))	('cervical dysplasia', 'Phenotype', 'HP:0032131', (147, 165))	('HPV', 'Gene', (94, 97))	('infections', 'Disease', (61, 71))	('warts', 'Phenotype', 'HP:0200043', (123, 128))	('declining', 'NegReg', (171, 180))	('cervical dysplasia', 'Disease', (147, 165))	('anogenital warts', 'Disease', (112, 128))
330799	29335437	We further report that genetic or pharmacological inhibition of USP13 considerably reduces MCL1 protein abundance and significantly increases tumor cell sensitivity to BH3 mimetic inhibitors targeting BCL-2 and BCL-XL.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('BCL-2', 'Gene', (201, 206))	('MCL1', 'Gene', (91, 95))	('inhibition', 'Var', (50, 60))	('USP13', 'Gene', (64, 69))	('tumor', 'Disease', (142, 147))	('MCL1', 'Gene', '4170', (91, 95))	('BH3', 'Chemical', 'MESH:C006008', (168, 171))	('BCL-XL', 'Gene', '598', (211, 217))	('reduces', 'NegReg', (83, 90))	('increases', 'PosReg', (132, 141))	('BCL-2', 'Gene', '596', (201, 206))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('BCL-XL', 'Gene', (211, 217))
330808	29335437	For example, P5091, a small-molecule inhibitor of USP7, activates HDM2/p53/p21 signaling axis and exerts cytotoxicity in several multiple myeloma (MM) cell models, supporting future clinical investigations of USP7 inhibitors for the treatment of malignant hematological diseases.	('activates', 'PosReg', (56, 65))	('USP7', 'Gene', (50, 54))	('malignant hematological diseases', 'Disease', (246, 278))	('P5091', 'Chemical', 'MESH:C576408', (13, 18))	('malignant hematological diseases', 'Disease', 'MESH:D019337', (246, 278))	('cytotoxicity', 'Disease', 'MESH:D064420', (105, 117))	('p53', 'Gene', (71, 74))	('p53', 'Gene', '7157', (71, 74))	('multiple myeloma', 'Disease', 'MESH:D009101', (129, 145))	('P5091', 'Var', (13, 18))	('multiple myeloma', 'Phenotype', 'HP:0006775', (129, 145))	('multiple myeloma', 'Disease', (129, 145))	('cytotoxicity', 'Disease', (105, 117))	('clinical', 'Species', '191496', (182, 190))
330819	29335437	In this study, we find that in certain lung and ovarian cancer cell lines, USP9X knockdown does not alter MCL1 protein levels.	('USP9X', 'Gene', (75, 80))	('MCL1', 'Gene', '4170', (106, 110))	('MCL1', 'Gene', (106, 110))	('USP9X', 'Gene', '8239', (75, 80))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('ovarian cancer', 'Phenotype', 'HP:0100615', (48, 62))	('lung and ovarian cancer', 'Disease', 'MESH:D010051', (39, 62))	('knockdown', 'Var', (81, 90))
330822	29335437	In addition, genetic depletion of USP13 using clustered regularly interspaced palindromic repeats (CRISPR)/Cas9, or pharmacological inhibition of USP13 by a small-molecule inhibitor spautin-1, markedly downregulates MCL1 protein expression and shows synergistic effects against tumor cells in combination with ABT-263, a selective antagonist of BCL-2 and BCL-XL.	('tumor', 'Phenotype', 'HP:0002664', (278, 283))	('tumor', 'Disease', 'MESH:D009369', (278, 283))	('BCL-XL', 'Gene', '598', (355, 361))	('genetic depletion', 'Var', (13, 30))	('ABT-263', 'Chemical', 'MESH:C528561', (310, 317))	('MCL1', 'Gene', '4170', (216, 220))	('tumor', 'Disease', (278, 283))	('USP13', 'Gene', (34, 39))	('MCL1', 'Gene', (216, 220))	('USP13', 'Gene', (146, 151))	('downregulates', 'NegReg', (202, 215))	('BCL-2', 'Gene', '596', (345, 350))	('BCL-XL', 'Gene', (355, 361))	('spautin-1', 'Chemical', 'MESH:C000591235', (182, 191))	('expression', 'Species', '29278', (229, 239))	('BCL-2', 'Gene', (345, 350))	('expression', 'MPA', (229, 239))
330827	29335437	In parallel, given the important role of MCL1 in neoplasm, we conducted TCGA pan-cancer genomic interrogation of copy number alterations (Supplementary Fig.	('neoplasm', 'Disease', (49, 57))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('neoplasm', 'Disease', 'MESH:D009369', (49, 57))	('neoplasm', 'Phenotype', 'HP:0002664', (49, 57))	('cancer', 'Disease', (81, 87))	('MCL1', 'Gene', (41, 45))	('MCL1', 'Gene', '4170', (41, 45))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('copy number alterations', 'Var', (113, 136))
330831	29335437	We confirmed the siRNA screen results by transfecting each of the four oligos against USP13 into HEK293T cells, and indeed found that USP13 knockdown decreased the endogenous protein levels of MCL1, while modulating USP9X or OTUB2 with different siRNAs had no consistent effects on MCL1 expression (Fig.	('HEK293T', 'CellLine', 'CVCL:0063', (97, 104))	('OTUB2', 'Gene', '78990', (225, 230))	('USP13', 'Gene', (134, 139))	('USP9X', 'Gene', (216, 221))	('expression', 'Species', '29278', (287, 297))	('modulating', 'Var', (205, 215))	('USP9X', 'Gene', '8239', (216, 221))	('MCL1', 'Gene', '4170', (193, 197))	('MCL1', 'Gene', '4170', (282, 286))	('endogenous protein levels', 'MPA', (164, 189))	('MCL1', 'Gene', (282, 286))	('knockdown', 'Var', (140, 149))	('OTUB2', 'Gene', (225, 230))	('decreased', 'NegReg', (150, 159))	('MCL1', 'Gene', (193, 197))
330850	29335437	As expected, USP13 knockdown resulted in uniform downregulation of endogenous MCL1 protein (Fig.	('MCL1', 'Gene', (78, 82))	('MCL1', 'Gene', '4170', (78, 82))	('knockdown', 'Var', (19, 28))	('USP13', 'Gene', (13, 18))	('downregulation', 'NegReg', (49, 63))
330855	29335437	3c), arguing that USP13 instead of USP9X served as a regulator of MCL1 stability.	('USP13', 'Var', (18, 23))	('USP9X', 'Gene', (35, 40))	('MCL1', 'Gene', (66, 70))	('MCL1', 'Gene', '4170', (66, 70))	('USP9X', 'Gene', '8239', (35, 40))
330856	29335437	HUWE1 (encoding MULE) and FBXW7 (encoding SCFFbw7), two putative E3 ubiquitin ligases of MCL1, was knocked down individually or combinatorially in SW-1573 and HEY cells.	('knocked down', 'Var', (99, 111))	('HUWE1', 'Gene', (0, 5))	('HUWE1', 'Gene', '10075', (0, 5))	('FBXW7', 'Gene', (26, 31))	('MCL1', 'Gene', '4170', (89, 93))	('MCL1', 'Gene', (89, 93))	('MULE', 'Species', '319699', (16, 20))	('FBXW7', 'Gene', '55294', (26, 31))	('SW-1573', 'CellLine', 'CVCL:1720', (147, 154))
330858	29335437	As a complimentary approach, we lentivirally expressed ectopic USP13 into OVCAR5, PC9 and NCI-H2170 cells, whose endogenous USP13 levels were relatively low (Fig.	('USP13', 'Gene', (63, 68))	('NCI-H2170', 'CellLine', 'CVCL:1535', (90, 99))	('ectopic', 'Var', (55, 62))	('PC9', 'Gene', (82, 85))	('PC9', 'Gene', '255738', (82, 85))
330861	29335437	USP13 knockdown by siRNA markedly reduced the half-life of MCL1 in TOV-21G (Fig.	('reduced', 'NegReg', (34, 41))	('USP13', 'Gene', (0, 5))	('MCL1', 'Gene', '4170', (59, 63))	('MCL1', 'Gene', (59, 63))	('half-life', 'MPA', (46, 55))	('knockdown', 'Var', (6, 15))
330876	29335437	Finally, we determined whether MCL1 was a deubiquitination substrate of USP13 by transfecting expression vectors encoding MCL1, HA-tagged ubiquitin and wild type or mutant USP13-C345A into HEK293T cells.	('expression vectors', 'Species', '29278', (94, 112))	('mutant', 'Var', (165, 171))	('C345A', 'Mutation', 'c.345C>A', (178, 183))	('MCL1', 'Gene', (122, 126))	('MCL1', 'Gene', '4170', (122, 126))	('USP13-C345A', 'Gene', (172, 183))	('MCL1', 'Gene', (31, 35))	('MCL1', 'Gene', '4170', (31, 35))	('HEK293T', 'CellLine', 'CVCL:0063', (189, 196))
330878	29335437	Consistent with USP13 removing ubiquitin from MCL1, wild type USP13, but not catalytically inactive mutant USP13-C345A, markedly reduced the amount of ubiquitinated MCL1 (Fig.	('MCL1', 'Gene', (46, 50))	('MCL1', 'Gene', (165, 169))	('MCL1', 'Gene', '4170', (165, 169))	('USP13', 'Var', (16, 21))	('reduced', 'NegReg', (129, 136))	('MCL1', 'Gene', '4170', (46, 50))	('C345A', 'Mutation', 'c.345C>A', (113, 118))
330888	29335437	Indeed, when we subcutaneously implanted TOV-21G and SW-1573 cells into nude mice, USP13 knockout dramatically retarded tumor growth in xenograft models.	('retarded tumor', 'Disease', 'MESH:D009369', (111, 125))	('USP13', 'Gene', (83, 88))	('retarded tumor', 'Disease', (111, 125))	('SW-1573', 'CellLine', 'CVCL:1720', (53, 60))	('knockout', 'Var', (89, 97))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('nude mice', 'Species', '10090', (72, 81))
330901	29335437	These data suggested that genetic inactivation of USP13 could improve tumor cell susceptibility to BH3 mimetic inhibitors such as ABT-263.	('USP13', 'Gene', (50, 55))	('genetic inactivation', 'Var', (26, 46))	('BH3', 'Chemical', 'MESH:C006008', (99, 102))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('ABT-263', 'Chemical', 'MESH:C528561', (130, 137))	('improve', 'PosReg', (62, 69))	('tumor', 'Disease', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
330904	29335437	We treated SW-1573 and TOV-21G cells with spautin-1 and found that spautin-1 reduced the protein level of MCL1 (Fig.	('MCL1', 'Gene', '4170', (106, 110))	('SW-1573', 'CellLine', 'CVCL:1720', (11, 18))	('spautin-1', 'Var', (67, 76))	('MCL1', 'Gene', (106, 110))	('spautin-1', 'Chemical', 'MESH:C000591235', (67, 76))	('reduced', 'NegReg', (77, 84))	('spautin-1', 'Chemical', 'MESH:C000591235', (42, 51))
330934	29335437	Finally, USP13 inhibition reduced MCL1 protein abundance and thereby increased tumor cell sensitivity to BH3 mimetic inhibitor ABT-263.	('increased', 'PosReg', (69, 78))	('tumor', 'Disease', (79, 84))	('MCL1', 'Gene', '4170', (34, 38))	('MCL1', 'Gene', (34, 38))	('reduced', 'NegReg', (26, 33))	('ABT-263', 'Chemical', 'MESH:C528561', (127, 134))	('USP13', 'Gene', (9, 14))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('BH3', 'Chemical', 'MESH:C006008', (105, 108))	('inhibition', 'Var', (15, 25))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
330936	29335437	Importantly, in addition to apply genetic approaches to modulate USP13 expression, we have tested a preclinical lead compound spautin-1 and evaluated the impact of pharmacologically inhibiting USP13 activity on MCL1 protein expression and tumor cell sensitivity to ABT-263.	('modulate', 'Var', (56, 64))	('MCL1', 'Gene', (211, 215))	('activity', 'MPA', (199, 207))	('clinical', 'Species', '191496', (103, 111))	('tumor', 'Disease', 'MESH:D009369', (239, 244))	('inhibiting', 'NegReg', (182, 192))	('expression', 'Species', '29278', (224, 234))	('tumor', 'Phenotype', 'HP:0002664', (239, 244))	('spautin-1', 'Chemical', 'MESH:C000591235', (126, 135))	('tumor', 'Disease', (239, 244))	('ABT-263', 'Chemical', 'MESH:C528561', (265, 272))	('expression', 'Species', '29278', (71, 81))	('MCL1', 'Gene', '4170', (211, 215))	('USP13', 'Gene', (193, 198))
330942	29335437	Although recent development of MCL1 inhibitors such as S63845 suggests that the specific targeting of MCL1 in vivo is possible, the optimal clinical use is yet to be determined, considering that one inevitable concern regarding inhibitors of the BCL-2 family proteins is the potential unacceptable toxicity associated with complete functional shutdown, especially when combined with other cytotoxic agents to treat solid tumors.	('toxicity', 'Disease', 'MESH:D064420', (298, 306))	('toxicity', 'Disease', (298, 306))	('MCL1', 'Gene', (102, 106))	('MCL1', 'Gene', '4170', (102, 106))	('S63845', 'Var', (55, 61))	('solid tumors', 'Disease', (415, 427))	('tumor', 'Phenotype', 'HP:0002664', (421, 426))	('solid tumors', 'Disease', 'MESH:D009369', (415, 427))	('MCL1', 'Gene', (31, 35))	('MCL1', 'Gene', '4170', (31, 35))	('tumors', 'Phenotype', 'HP:0002664', (421, 427))	('BCL-2', 'Gene', '596', (246, 251))	('BCL-2', 'Gene', (246, 251))	('clinical', 'Species', '191496', (140, 148))
330946	29335437	Our study has provided a rational basis for designing clinical trials of USP13 inhibitors in the future to control solid tumors including lung and ovarian cancer.	('ovarian cancer', 'Phenotype', 'HP:0100615', (147, 161))	('solid tumors', 'Disease', 'MESH:D009369', (115, 127))	('lung and ovarian cancer', 'Disease', 'MESH:D010051', (138, 161))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('inhibitors', 'Var', (79, 89))	('clinical', 'Species', '191496', (54, 62))	('solid tumors', 'Disease', (115, 127))	('USP13', 'Gene', (73, 78))	('control', 'PosReg', (107, 114))
330948	29335437	Hence, pharmaceutical intervention of USP13 activity is expected to antagonize the tumorigenic potential of MCL1 oncoprotein, and combined administration of USP13 inhibitors with clinically approved venetoclax therapy may represent a promising targeting strategy for the treatment of human cancer by inducing tumor cell death.	('tumor', 'Disease', (83, 88))	('MCL1', 'Gene', '4170', (108, 112))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('cancer', 'Disease', 'MESH:D009369', (290, 296))	('venetoclax', 'Chemical', 'MESH:C579720', (199, 209))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumor', 'Disease', (309, 314))	('tumor', 'Disease', 'MESH:D009369', (309, 314))	('antagonize', 'NegReg', (68, 78))	('human', 'Species', '9606', (284, 289))	('inhibitors', 'Var', (163, 173))	('clinical', 'Species', '191496', (179, 187))	('USP13', 'Gene', (157, 162))	('inducing', 'PosReg', (300, 308))	('USP13', 'Gene', (38, 43))	('cancer', 'Disease', (290, 296))	('MCL1', 'Gene', (108, 112))	('cancer', 'Phenotype', 'HP:0002664', (290, 296))	('tumor', 'Phenotype', 'HP:0002664', (309, 314))
330960	29335437	For FBXW7 knockdown, the siRNA sequences were: FBXW7-siRNA-1 GGAUCUCUUGAUACAUCAA; FBXW7-siRNA-2 GGAGUAUGGUCAUCACAAA.	('FBXW7', 'Gene', (82, 87))	('FBXW7', 'Gene', '55294', (4, 9))	('FBXW7', 'Gene', (47, 52))	('FBXW7', 'Gene', (4, 9))	('FBXW7', 'Gene', '55294', (47, 52))	('FBXW7', 'Gene', '55294', (82, 87))	('knockdown', 'Var', (10, 19))
330973	29335437	Antibodies against the following proteins were used: USP13 (sc-514416, 1:1000), MCL1 (sc-819, 1:1000) (Santa Cruz); USP9X (#14898, 1:1000), PTEN (#9188, 1:1000), MULE (#5695, 1:1000), BCL-XL (#2764, 1:1000), BAX (#5023, 1:1000), BAK (#6947, 1:1000), Vimentin (#5741, 1:1000), GAPDH (#8884, 1:1000), H3 (#12648, 1:2000), beta-tubulin (#5346, 1:1000), Actin (#5125, 1:1000) (Cell Signaling Technology); OTUB2 (ab74371, 1:1000) (Abcam).	('BCL-XL', 'Gene', '598', (184, 190))	('USP9X', 'Gene', (116, 121))	('OTUB2', 'Gene', (401, 406))	('MULE', 'Species', '319699', (162, 166))	('OTUB2', 'Gene', '78990', (401, 406))	('USP9X', 'Gene', '8239', (116, 121))	('BAK', 'Gene', (229, 232))	('#5346', 'Var', (334, 339))	('BCL-XL', 'Gene', (184, 190))	('BAX', 'Gene', '581', (208, 211))	('MCL1', 'Gene', '4170', (80, 84))	('BAX', 'Gene', (208, 211))	('MCL1', 'Gene', (80, 84))	('PTEN', 'Gene', (140, 144))	('BAK', 'Gene', '578', (229, 232))	('PTEN', 'Gene', '5728', (140, 144))
330989	29335437	After 48 h, the cells were treated with 20 muM proteasome inhibitor MG132 (Selleck) for 8 h. The cells were then washed with PBS and lysed in HEPES buffer (20 mM HEPES, pH 7.2, 50 mM NaCl, 1 mM NaF, 0.5% Triton X-100) supplemented with 0.1% SDS, 20 muM MG132 and protease inhibitor cocktail (Roche).	('muM', 'Gene', (43, 46))	('muM', 'Gene', (249, 252))	('NaF', 'Gene', (194, 197))	('MG132', 'Chemical', 'MESH:C072553', (68, 73))	('Triton X-100', 'Chemical', 'MESH:D017830', (204, 216))	('NaCl', 'Chemical', 'MESH:D012965', (183, 187))	('SDS', 'Chemical', 'MESH:D012967', (241, 244))	('HEPES', 'Chemical', 'MESH:D006531', (142, 147))	('HEPES', 'Chemical', 'MESH:D006531', (162, 167))	('muM', 'Gene', '56925', (43, 46))	('muM', 'Gene', '56925', (249, 252))	('MG132', 'Chemical', 'MESH:C072553', (253, 258))	('MG132', 'Var', (253, 258))	('NaF', 'Gene', '3576', (194, 197))	('PBS', 'Chemical', 'MESH:D007854', (125, 128))
331002	27751354	Mutant TP53 disrupts age-related accumulation patterns of somatic mutations in multiple cancer types Most cancers are driven by somatic mutations in proto-oncogenes and tumor suppressor genes.	('accumulation', 'MPA', (33, 45))	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('TP53', 'Gene', '7157', (7, 11))	('TP53', 'Gene', (7, 11))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('cancers', 'Phenotype', 'HP:0002664', (106, 113))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('cancers', 'Disease', (106, 113))	('cancer', 'Disease', (106, 112))	('tumor', 'Disease', (169, 174))	('disrupts', 'NegReg', (12, 20))	('cancers', 'Disease', 'MESH:D009369', (106, 113))	('Mutant', 'Var', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
331003	27751354	Genetic changes in a tumor may accumulate in the tissue self-renewal phase prior to neoplasm.	('tissue self-renewal phase', 'CPA', (49, 74))	('accumulate', 'PosReg', (31, 41))	('tumor', 'Disease', (21, 26))	('Genetic changes', 'Var', (0, 15))	('neoplasm', 'Disease', (84, 92))	('neoplasm', 'Phenotype', 'HP:0002664', (84, 92))	('neoplasm', 'Disease', 'MESH:D009369', (84, 92))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
331007	27751354	Hereby, we speculate that mutant TP53 can disrupt the age-related accumulation patterns of somatic mutations in tumors.	('disrupt', 'NegReg', (42, 49))	('accumulation patterns', 'MPA', (66, 87))	('TP53', 'Gene', '7157', (33, 37))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('TP53', 'Gene', (33, 37))	('mutant', 'Var', (26, 32))	('tumors', 'Disease', 'MESH:D009369', (112, 118))	('tumors', 'Disease', (112, 118))
331008	27751354	We found that there was a significant interaction between TP53 genotype (mutant versus wild-type) and patient age at the initial clinical date on somatic mutation burden for five cancers.	('TP53', 'Gene', '7157', (58, 62))	('patient', 'Species', '9606', (102, 109))	('TP53', 'Gene', (58, 62))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('mutant', 'Var', (73, 79))	('cancers', 'Disease', 'MESH:D009369', (179, 186))	('cancers', 'Phenotype', 'HP:0002664', (179, 186))	('cancers', 'Disease', (179, 186))
331013	27751354	In light of the classical multi-mutation theory of tumorigenesis, which states that cancer is the result of accumulated mutations in a cell's DNA, the age-related pattern of cancer incidences can be explained by several mutually complementary mechanisms.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('cancer', 'Disease', (84, 90))	('tumor', 'Disease', (51, 56))	('cancer', 'Disease', (174, 180))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('mutations', 'Var', (120, 129))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
331015	27751354	In this regard, a positive association between patient age and the number of accumulated mutations in tumors could exist across a wide spectrum of cancer types.	('patient', 'Species', '9606', (47, 54))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('tumors', 'Disease', 'MESH:D009369', (102, 108))	('tumors', 'Disease', (102, 108))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('mutations', 'Var', (89, 98))	('cancer', 'Disease', (147, 153))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))
331018	27751354	no age-mutation association was found in chronic myelomonocytic leukemia (CMML) for which <5% of patients have a TP53 mutation, although such a relationship was reported in acute myeloid leukemia (AML).	('chronic myelomonocytic leukemia', 'Disease', (41, 72))	('acute myeloid leukemia', 'Disease', (173, 195))	('leukemia', 'Phenotype', 'HP:0001909', (187, 195))	('TP53', 'Gene', (113, 117))	('chronic myelomonocytic leukemia', 'Disease', 'MESH:D015477', (41, 72))	('AML', 'Disease', 'MESH:D015470', (197, 200))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (173, 195))	('AML', 'Phenotype', 'HP:0004808', (197, 200))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (179, 195))	('AML', 'Disease', (197, 200))	('mutation', 'Var', (118, 126))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (173, 195))	('patients', 'Species', '9606', (97, 105))	('CMML', 'Disease', 'MESH:D054429', (74, 78))	('chronic myelomonocytic leukemia', 'Phenotype', 'HP:0012325', (41, 72))	('TP53', 'Gene', '7157', (113, 117))	('leukemia', 'Phenotype', 'HP:0001909', (64, 72))	('CMML', 'Disease', (74, 78))	('CMML', 'Phenotype', 'HP:0012325', (74, 78))
331020	27751354	The loss or disruption of p53 function due to a mutation can lead to uncontrolled cell proliferation and eventually cancer.	('function', 'MPA', (30, 38))	('lead to', 'Reg', (61, 68))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('uncontrolled cell proliferation', 'CPA', (69, 100))	('disruption', 'NegReg', (12, 22))	('p53', 'Gene', (26, 29))	('mutation', 'Var', (48, 56))	('p53', 'Gene', '7157', (26, 29))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('loss', 'NegReg', (4, 8))
331021	27751354	Considering the crucial roles of normal p53 in conserving genome stability, we speculate that its aberration can disrupt or reshape age-related accumulation patterns of somatic mutations in tumors.	('tumors', 'Disease', 'MESH:D009369', (190, 196))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('accumulation', 'MPA', (144, 156))	('p53', 'Gene', (40, 43))	('disrupt', 'Reg', (113, 120))	('reshape', 'Reg', (124, 131))	('p53', 'Gene', '7157', (40, 43))	('tumors', 'Disease', (190, 196))	('tumors', 'Phenotype', 'HP:0002664', (190, 196))	('aberration', 'Var', (98, 108))
331023	27751354	Among the 33 cancer types with clinically-annotated multiomic data (available at TCGA database by April 24, 2015), twelve were studied in this work by considering the genetic diversity of patients and the prevalence of somatic TP53 mutations in these tumors.	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('TP53', 'Gene', '7157', (227, 231))	('tumors', 'Disease', (251, 257))	('tumors', 'Disease', 'MESH:D009369', (251, 257))	('tumors', 'Phenotype', 'HP:0002664', (251, 257))	('TP53', 'Gene', (227, 231))	('cancer', 'Disease', (13, 19))	('mutations', 'Var', (232, 241))	('cancer', 'Disease', 'MESH:D009369', (13, 19))	('patients', 'Species', '9606', (188, 196))	('tumor', 'Phenotype', 'HP:0002664', (251, 256))
331025	27751354	black American or Asian) besides the dominant white Americans, and the ratio of samples with TP53 non-synonymous mutations was over 25%.	('TP53', 'Gene', '7157', (93, 97))	('non-synonymous mutations', 'Var', (98, 122))	('TP53', 'Gene', (93, 97))
331036	27751354	wild-type versus mutant) of a tumor (patient) was indexed by i (i = 1, 2).	('patient', 'Species', '9606', (37, 44))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('mutant', 'Var', (17, 23))	('tumor', 'Disease', (30, 35))
331037	27751354	(1), yij and xj represented the status-specific mutation burden on the jth tumor sample and the age of the jth patient, respectively.	('yij', 'Var', (5, 8))	('jth tumor', 'Disease', 'MESH:D009369', (71, 80))	('jth tumor', 'Disease', (71, 80))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('patient', 'Species', '9606', (111, 118))
331038	27751354	I was a binary variable with a value of 1 or 0, indicating the mutant or wild-type TP53 tumors.	('TP53', 'Gene', '7157', (83, 87))	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('mutant', 'Var', (63, 69))	('TP53', 'Gene', (83, 87))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('tumors', 'Disease', (88, 94))
331039	27751354	The baseline was denoted by mu and could be considered as the expected mutation burden for a TP53 wild-type tumor carried by a patient aged at x. alpha represented the effect of TP53 mutation on y, i.e.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('TP53', 'Gene', '7157', (178, 182))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('patient', 'Species', '9606', (127, 134))	('TP53', 'Gene', (178, 182))	('TP53', 'Gene', '7157', (93, 97))	('TP53', 'Gene', (93, 97))	('tumor', 'Disease', (108, 113))	('mutation', 'Var', (183, 191))
331040	27751354	the age-adjusted average increase or decrease (when the value was negative) in mutation burden for a tumor with mutated TP53.	('decrease', 'NegReg', (37, 45))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('increase', 'PosReg', (25, 33))	('mutated', 'Var', (112, 119))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('TP53', 'Gene', '7157', (120, 124))	('mutation burden', 'MPA', (79, 94))	('TP53', 'Gene', (120, 124))
331041	27751354	mu + alpha stood for the expected mutation burden for a mutant TP53 tumor carried by a patient aged at x.	('tumor', 'Disease', (68, 73))	('TP53', 'Gene', '7157', (63, 67))	('TP53', 'Gene', (63, 67))	('mutant', 'Var', (56, 62))	('patient', 'Species', '9606', (87, 94))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))
331049	27751354	LUAD, in which the slope was negative and significant in the mutant TP53 tumors but not in the wild-type counterparts.	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('tumors', 'Disease', (73, 79))	('mutant', 'Var', (61, 67))	('tumors', 'Disease', 'MESH:D009369', (73, 79))	('TP53', 'Gene', '7157', (68, 72))	('TP53', 'Gene', (68, 72))	('LUAD', 'Phenotype', 'HP:0030078', (0, 4))
331050	27751354	The third group, consisting of BRCA, GBM and HNSC, demonstrated consistent positive association between mutation burden and patient age.	('BRCA', 'Phenotype', 'HP:0003002', (31, 35))	('BRCA', 'Gene', '672', (31, 35))	('positive', 'PosReg', (75, 83))	('mutation burden', 'Var', (104, 119))	('BRCA', 'Gene', (31, 35))	('patient', 'Species', '9606', (124, 131))	('HNSC', 'Phenotype', 'HP:0012288', (45, 49))
331058	27751354	Here, we repeated our linear model analysis on an "alternative" dataset similar to that used in Ref., in which the tumors with more than 200 (or 250) mutations in UCEC (or COAD) were also eliminated.	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('COAD', 'Disease', (172, 176))	('tumors', 'Disease', (115, 121))	('tumors', 'Disease', 'MESH:D009369', (115, 121))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('mutations', 'Var', (150, 159))	('UCEC', 'Gene', (163, 167))	('COAD', 'Disease', 'MESH:D029424', (172, 176))
331059	27751354	As shown in Supplemental Figure S2, this reanalysis confirmed our results that the TP53 genotype-dependent positive association between mutation burden and patient age did exist in UCEC.	('TP53', 'Gene', '7157', (83, 87))	('TP53', 'Gene', (83, 87))	('positive association', 'PosReg', (107, 127))	('UCEC', 'Disease', (181, 185))	('mutation burden', 'Var', (136, 151))	('patient', 'Species', '9606', (156, 163))
331061	27751354	was observed in the mutant TP53 tumors, with the p-value being smaller and significant (i.e.	('TP53', 'Gene', '7157', (27, 31))	('TP53', 'Gene', (27, 31))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumors', 'Disease', (32, 38))	('mutant', 'Var', (20, 26))	('tumors', 'Disease', 'MESH:D009369', (32, 38))
331065	27751354	More importantly, the fact that most of these patterns only appeared in TP53 wild-type tumors confirmed our hypothesis about the interference of TP53 alteration to the mutation accumulation process.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('alteration', 'Var', (150, 160))	('TP53', 'Gene', '7157', (72, 76))	('TP53', 'Gene', '7157', (145, 149))	('TP53', 'Gene', (72, 76))	('TP53', 'Gene', (145, 149))	('tumors', 'Disease', (87, 93))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('tumors', 'Disease', 'MESH:D009369', (87, 93))
331066	27751354	Considering that mutant-TP53 tumors had a heavier mutation burden than TP53 wild-type tumors in ten cancers (alpha in Supplemental Table S3), it is plausible to predict a burst of genetic alterations in cells following the disruption of function of the TP53 gene.	('tumors in ten cancers', 'Disease', (86, 107))	('heavier', 'PosReg', (42, 49))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('TP53', 'Gene', '7157', (24, 28))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('mutation burden', 'MPA', (50, 65))	('tumors', 'Disease', (86, 92))	('TP53', 'Gene', '7157', (253, 257))	('TP53', 'Gene', '7157', (71, 75))	('tumors', 'Disease', (29, 35))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('tumors', 'Disease', 'MESH:D009369', (29, 35))	('cancers', 'Phenotype', 'HP:0002664', (100, 107))	('TP53', 'Gene', (24, 28))	('tumors in ten cancers', 'Disease', 'MESH:D009369', (86, 107))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('disruption', 'Var', (223, 233))	('TP53', 'Gene', (71, 75))	('TP53', 'Gene', (253, 257))
331069	27751354	In the case that the altered TP53 is DM-a, many genetic changes from the subsequent mutation burst will be fixed as hitchhikers in forming new clone(s) that get additional fitness advantage from DM-b.	('altered', 'Var', (21, 28))	('DM-a', 'Gene', '3108', (37, 41))	('DM-a', 'Gene', (37, 41))	('TP53', 'Gene', '7157', (29, 33))	('TP53', 'Gene', (29, 33))
331070	27751354	On the other hand, when the altered TP53 is DM-b or DM-c, the fixation of genetic changes arising from the mutation burst will happen during a time period close to the initial clinical date (or the tumor tissue sampling date).	('altered', 'Var', (28, 35))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('TP53', 'Gene', '7157', (36, 40))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('DM-c', 'Gene', (52, 56))	('DM-b', 'Var', (44, 48))	('DM-c', 'Gene', '284340', (52, 56))	('TP53', 'Gene', (36, 40))	('tumor', 'Disease', (198, 203))
331072	27751354	In COAD, ESCA and LUSC, the TP53 wild-type tumors did not demonstrate the expected age-related accumulation patterns for somatic mutations, suggesting the existence of other "mutators" that, similar to TP53 mutation, could impact the stability of other genes.	('TP53', 'Gene', (202, 206))	('TP53', 'Gene', '7157', (28, 32))	('LUSC', 'Phenotype', 'HP:0030359', (18, 22))	('stability', 'MPA', (234, 243))	('mutators', 'Var', (175, 183))	('COAD', 'Disease', (3, 7))	('TP53', 'Gene', (28, 32))	('TP53', 'Gene', '7157', (202, 206))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('impact', 'Reg', (223, 229))	('ESCA', 'Phenotype', 'HP:0011459', (9, 13))	('tumors', 'Disease', (43, 49))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('COAD', 'Disease', 'MESH:D029424', (3, 7))	('tumors', 'Disease', 'MESH:D009369', (43, 49))
331075	27751354	In this study, we found that mutant TP53 could disrupt or reshape age-related accumulation patterns of somatic mutations present in tumors.	('disrupt', 'NegReg', (47, 54))	('reshape', 'Reg', (58, 65))	('accumulation patterns', 'MPA', (78, 99))	('mutant', 'Var', (29, 35))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('TP53', 'Gene', '7157', (36, 40))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('TP53', 'Gene', (36, 40))	('tumors', 'Disease', (132, 138))	('tumors', 'Disease', 'MESH:D009369', (132, 138))
331122	28035402	The membranes were probed with the primary antibodies, including rabbit anti-Smad1 (#6944) and rabbit anti-Smad5 (#9517; both from Cell Signaling Technology, Beverly, MA, USA), rabbit anti-Smad9 [Smad8 (R-64); Santa Cruz Biotechnology, Inc., Santa Cruz, CA, USA] and rabbit anti-phospho-Smad1 (Ser463/465)/Smad5 (Ser463/465)/Smad9 (Ser465/467) (#13820; Cell Signaling Technology).	('Smad9', 'Gene', (325, 330))	('Smad9', 'Gene', '4093', (325, 330))	('Smad9', 'Gene', '4093', (189, 194))	('Smad9', 'Gene', (189, 194))	('Smad8', 'Gene', (196, 201))	('Smad8', 'Gene', '4093', (196, 201))	('Smad1', 'Gene', (77, 82))	('rabbit', 'Species', '9986', (177, 183))	('Smad1', 'Gene', '4086', (77, 82))	('rabbit', 'Species', '9986', (65, 71))	('Smad5', 'Gene', '4090', (107, 112))	('rabbit', 'Species', '9986', (95, 101))	('Smad5', 'Gene', (107, 112))	('Smad5', 'Gene', '4090', (306, 311))	('Smad5', 'Gene', (306, 311))	('Smad1', 'Gene', (287, 292))	('Ser463/465', 'Var', (294, 304))	('rabbit', 'Species', '9986', (267, 273))	('Smad1', 'Gene', '4086', (287, 292))
331203	32571479	Combined deletion of Glut1 and Glut3 impairs lung adenocarcinoma growth Glucose utilization increases in tumors, a metabolic process that is observed clinically by 18F-fluorodeoxyglucose positron emission tomography (18F-FDG-PET).	('tumors', 'Disease', (105, 111))	('tumors', 'Disease', 'MESH:D009369', (105, 111))	('impairs lung adenocarcinoma growth', 'Disease', (37, 71))	('deletion', 'Var', (9, 17))	('impairs lung adenocarcinoma growth', 'Disease', 'MESH:D006130', (37, 71))	('Glut3', 'Gene', (31, 36))	('18F-fluorodeoxyglucose', 'Chemical', 'MESH:D019788', (164, 186))	('18F-FDG', 'Chemical', 'MESH:D019788', (217, 224))	('Glucose', 'Chemical', 'MESH:D005947', (72, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (55, 64))	('Glut3', 'Gene', '20527', (31, 36))	('Glut1', 'Gene', '20525', (21, 26))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (45, 64))	('increases', 'PosReg', (92, 101))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('Glut1', 'Gene', (21, 26))
331205	32571479	In a genetically-engineered mouse model of lung adenocarcinoma, we show that the deletion of only one highly expressed glucose transporter, Glut1 or Glut3, in cancer cells does not impair tumor growth, whereas their combined loss diminishes tumor development.	('tumor', 'Disease', (188, 193))	('deletion', 'Var', (81, 89))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('Glut1', 'Gene', (140, 145))	('cancer', 'Disease', (159, 165))	('tumor', 'Disease', (241, 246))	('impair', 'NegReg', (181, 187))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('tumor', 'Disease', 'MESH:D009369', (241, 246))	('lung adenocarcinoma', 'Disease', (43, 62))	('loss diminishes', 'NegReg', (225, 240))	('mouse', 'Species', '10090', (28, 33))	('carcinoma', 'Phenotype', 'HP:0030731', (53, 62))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (43, 62))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (43, 62))	('Glut3', 'Gene', (149, 154))	('glucose', 'Chemical', 'MESH:D005947', (119, 126))
331214	32571479	We show that the deletion of Glut1 or Glut3 is not sufficient to decrease tumor progression, which is only affected significantly upon combined Glut1 and Glut3 loss.	('Glut3', 'Gene', (38, 43))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('Glut1', 'Gene', (29, 34))	('deletion', 'Var', (17, 25))	('tumor', 'Disease', (74, 79))	('decrease', 'NegReg', (65, 73))
331216	32571479	SLC2A1 (GLUT1) followed by SLC2A3 (GLUT3) were the most expressed members, (Figure 1a) and high SLC2A1 expression was correlated with poor overall survival (Figure 1:figure supplement 1a).	('SLC2A1', 'Gene', '20525', (96, 102))	('SLC2A1', 'Gene', (0, 6))	('SLC2A1', 'Gene', (96, 102))	('high', 'Var', (91, 95))	('expression', 'MPA', (103, 113))	('overall survival', 'CPA', (139, 155))	('poor', 'NegReg', (134, 138))	('SLC2A3', 'Gene', (27, 33))	('SLC2A3', 'Gene', '20527', (27, 33))	('SLC2A1', 'Gene', '20525', (0, 6))
331222	32571479	In the immunocompetent KrasLSL-G12D/WT; Trp53Flox/Flox (KP) mouse model where tumors consist of pure LUADs all harboring Trp53 gene deletion, RNA sequencing analyses of bulk tumor samples revealed a predominance of NMF4-like lesions (Figure 1:figure supplement 1c).	('tumor', 'Disease', (174, 179))	('G12D', 'Mutation', 'rs121913529', (31, 35))	('tumors', 'Disease', (78, 84))	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('NMF4', 'Gene', (215, 219))	('gene deletion', 'Var', (127, 140))	('Trp53', 'Gene', (121, 126))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('Trp53', 'Gene', '22059', (40, 45))	('NMF4', 'Gene', '20739', (215, 219))	('Trp53', 'Gene', '22059', (121, 126))	('mouse', 'Species', '10090', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('tumor', 'Disease', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('Trp53', 'Gene', (40, 45))
331226	32571479	To determine the contribution of Glut1 for tumor development, we crossed KP mice to Slc2a1Flox/Flox (G1) animals, and initiated tumors in the resulting KPG1 mice and control KP mice by intratracheal lentiviral-Cre instillation (Lenti.PGK-Cre, Figure 1:figure supplement 2c-d).	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('mice', 'Species', '10090', (157, 161))	('mice', 'Species', '10090', (177, 181))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('mice', 'Species', '10090', (76, 80))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumors', 'Disease', (128, 134))	('Slc2a1', 'Gene', (84, 90))	('tumor', 'Disease', (128, 133))	('tumors', 'Disease', 'MESH:D009369', (128, 134))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('tumor', 'Disease', (43, 48))	('initiated', 'PosReg', (118, 127))	('KPG1', 'Var', (152, 156))	('Slc2a1', 'Gene', '20525', (84, 90))
331229	32571479	Because there was no significant increase in KPG1 mouse survival (Figure 1h), these data together fail to reveal a clear impact of Glut1 deletion in the tumor epithelial cells on disease progression.	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('Glut1', 'Gene', (131, 136))	('mouse', 'Species', '10090', (50, 55))	('deletion', 'Var', (137, 145))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('B', 'Chemical', 'MESH:D001895', (0, 1))
331230	32571479	To detect if there are measurable changes in glucose utilization secondary to Glut1 deletion in vivo, we decided to monitor glucose-derived biomass accumulation in tumors with ultrastructural resolution.	('glucose', 'Chemical', 'MESH:D005947', (124, 131))	('glucose utilization', 'MPA', (45, 64))	('deletion', 'Var', (84, 92))	('tumors', 'Disease', (164, 170))	('tumors', 'Disease', 'MESH:D009369', (164, 170))	('tumors', 'Phenotype', 'HP:0002664', (164, 170))	('Glut1', 'Gene', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('glucose', 'Chemical', 'MESH:D005947', (45, 52))
331236	32571479	Quantitative NanoSIMS images of these organelles revealed a lower 13C-enrichment signal intensity in KPG1 compared to KP tumor cells (Figure 2d), demonstrating the consequence of Glut1 loss in vivo.	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumor', 'Disease', (121, 126))	('tumor', 'Disease', 'MESH:D009369', (121, 126))	('13C', 'Chemical', 'MESH:C000615229', (66, 69))	('Glut1', 'Protein', (179, 184))	('13C-enrichment signal intensity', 'MPA', (66, 97))	('loss', 'NegReg', (185, 189))	('KPG1', 'Var', (101, 105))	('lower', 'NegReg', (60, 65))
331237	32571479	Despite the differences measured by NanoSIMS, Glut1 deficiency only minimally affected tumor progression (see Figure 1d-h).	('Glut1', 'Protein', (46, 51))	('affected', 'Reg', (78, 86))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Disease', (87, 92))	('deficiency', 'Var', (52, 62))	('tumor', 'Disease', 'MESH:D009369', (87, 92))
331252	32571479	Global gene expression analyses from tumor samples confirmed the functionality of the PPARalphaDelta13 construct in both KP and KPG1 tumors, as 'Hallmark_bile acid metabolism', 'Hallmark_fatty acid metabolism', 'KEGG_peroxisome' and 'KEGG_ fatty acid metabolism' pathways were repressed in tumors harboring this construct compared to tumors from KP-rtTA or KPG1-rtTA mice not fed on a doxycycline diet (Figure 3:figure supplement 3d).	('tumors', 'Disease', 'MESH:D009369', (290, 296))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (334, 339))	('fatty acid', 'Chemical', 'MESH:D005227', (187, 197))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumors', 'Disease', (334, 340))	('repressed', 'NegReg', (277, 286))	('tumor', 'Disease', (290, 295))	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('doxycycline', 'Chemical', 'MESH:D004318', (385, 396))	('tumors', 'Disease', 'MESH:D009369', (334, 340))	('tumor', 'Disease', 'MESH:D009369', (290, 295))	('KPG1 tumors', 'Disease', (128, 139))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumors', 'Phenotype', 'HP:0002664', (290, 296))	('mice', 'Species', '10090', (367, 371))	('fatty acid', 'Chemical', 'MESH:D005227', (240, 250))	('tumors', 'Disease', (133, 139))	('tumor', 'Disease', (334, 339))	('tumor', 'Disease', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (290, 295))	('tumor', 'Disease', 'MESH:D009369', (334, 339))	('tumors', 'Disease', (290, 296))	('PPARalphaDelta13', 'Gene', (86, 102))	('tumors', 'Disease', 'MESH:D009369', (133, 139))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('construct', 'Var', (312, 321))	('tumors', 'Phenotype', 'HP:0002664', (334, 340))	('KPG1 tumors', 'Disease', 'MESH:D009369', (128, 139))	('tumor', 'Disease', (37, 42))	("'KEGG_ fatty acid metabolism' pathways", 'Pathway', (233, 271))
331263	32571479	Although this indicates that Glut3 deletion alone does not affect tumors in a detectable manner, we next wanted to evaluate its importance in a Glut1-deficient context.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('tumors', 'Disease', (66, 72))	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('Glut3', 'Gene', (29, 34))	('deletion', 'Var', (35, 43))
331265	32571479	Deletion of the two glucose transporters, Glut1 and Glut3, from the tumor epithelial cell compartment resulted in a decreased number of tumors (Figure 4b).	('tumor', 'Disease', (68, 73))	('tumors', 'Disease', (136, 142))	('tumors', 'Disease', 'MESH:D009369', (136, 142))	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('Glut3', 'Protein', (52, 57))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('Glut1', 'Protein', (42, 47))	('tumor', 'Disease', (136, 141))	('decreased', 'NegReg', (116, 125))	('glucose', 'Chemical', 'MESH:D005947', (20, 27))	('Deletion', 'Var', (0, 8))
331266	32571479	Furthermore, contrasting with our data obtained from each separately-targeted Gluts, combined Glut1 and Glut3 deletion led to a significant reduction of tumor growth rates monitored by muCT scans, to a reduced tumor size with an absence of big (>50 mg) lesions at sacrifice, to a decrease of high grade tumors, and to an extended mouse survival (Figure 4c-g and Figure 4:figure supplement 3a-b).	('reduced', 'NegReg', (202, 209))	('tumor', 'Phenotype', 'HP:0002664', (303, 308))	('Glut1', 'Gene', (94, 99))	('tumors', 'Disease', (303, 309))	('deletion', 'Var', (110, 118))	('mouse survival', 'CPA', (330, 344))	('tumor', 'Disease', (210, 215))	('tumor', 'Disease', (153, 158))	('tumors', 'Disease', 'MESH:D009369', (303, 309))	('tumor', 'Disease', 'MESH:D009369', (210, 215))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('decrease', 'NegReg', (280, 288))	('reduction of tumor', 'Disease', 'MESH:D007022', (140, 158))	('extended', 'PosReg', (321, 329))	('reduction of tumor', 'Disease', (140, 158))	('Glut3', 'Gene', (104, 109))	('mouse', 'Species', '10090', (330, 335))	('tumor', 'Disease', (303, 308))	('tumor', 'Disease', 'MESH:D009369', (303, 308))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumors', 'Phenotype', 'HP:0002664', (303, 309))
331267	32571479	This synergistic action of the dual Glut1 and Glut3 deletion was also demonstrated in vitro with four different human NSCLC cell lines, on which the strongest reduction of tumor cell viability resulted from the combined knockdown of these glucose transporters (Figure 4:figure supplement 3c-f).	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('Glut3', 'Gene', (46, 51))	('reduction of tumor', 'Disease', 'MESH:D007022', (159, 177))	('glucose', 'Chemical', 'MESH:D005947', (239, 246))	('NSCLC', 'Disease', (118, 123))	('Glut1', 'Gene', (36, 41))	('knockdown', 'Var', (220, 229))	('NSCLC', 'Disease', 'MESH:D002289', (118, 123))	('reduction of tumor', 'Disease', (159, 177))	('human', 'Species', '9606', (112, 117))	('deletion', 'Var', (52, 60))
331269	32571479	To trace and compare directly glucose uptake in tumors from the different mouse genotypes, we used positron emission tomography with 18F-fluorodeoxyglucose (18F-FDG-PET) in KP, KPG1, KPG3, and KPG1G3 tumors.	('glucose', 'Chemical', 'MESH:D005947', (148, 155))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('18F-FDG', 'Chemical', 'MESH:D019788', (157, 164))	('tumors', 'Disease', (48, 54))	('tumors', 'Disease', 'MESH:D009369', (48, 54))	('18F-fluorodeoxyglucose', 'Chemical', 'MESH:D019788', (133, 155))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('tumors', 'Phenotype', 'HP:0002664', (200, 206))	('glucose', 'Chemical', 'MESH:D005947', (30, 37))	('KPG1G3', 'Var', (193, 199))	('tumors', 'Disease', (200, 206))	('mouse', 'Species', '10090', (74, 79))	('tumors', 'Disease', 'MESH:D009369', (200, 206))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
331275	32571479	Because glucose uptake was not significantly lower in KPG3 compared to KP tumors, and in KPG1G3 compared to KPG1 tumors, a possible explanation is that most tumors analyzed had not yet gained Glut3 expression and become dependent on it, which agrees with an elevated Glut3 expression specifically in big lesions (see Figure 4:figure supplement 1c).	('tumors', 'Disease', (113, 119))	('Glut3', 'Protein', (192, 197))	('lower', 'NegReg', (45, 50))	('elevated', 'PosReg', (258, 266))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('tumors', 'Disease', 'MESH:D009369', (74, 80))	('tumors', 'Phenotype', 'HP:0002664', (157, 163))	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('KPG1 tumors', 'Disease', 'MESH:D009369', (108, 119))	('KP tumors', 'Disease', (71, 80))	('expression', 'MPA', (198, 208))	('KPG1G3', 'Var', (89, 95))	('gained', 'PosReg', (185, 191))	('tumors', 'Disease', (157, 163))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('B', 'Chemical', 'MESH:D001895', (0, 1))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))	('glucose uptake', 'MPA', (8, 22))	('KP tumors', 'Disease', 'MESH:D009369', (71, 80))	('glucose', 'Chemical', 'MESH:D005947', (8, 15))	('tumors', 'Disease', 'MESH:D009369', (157, 163))	('big lesions', 'Disease', (300, 311))	('KPG1 tumors', 'Disease', (108, 119))	('KPG3', 'Var', (54, 58))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('tumors', 'Disease', (74, 80))
331277	32571479	This analysis showed that the expression of no other glucose transporter was changed upon dual Glut1 and Glut3 deletion in KP tumors (Figure 4:figure supplement 4a).	('expression', 'MPA', (30, 40))	('dual Glut1', 'Protein', (90, 100))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('glucose', 'Chemical', 'MESH:D005947', (53, 60))	('changed', 'Reg', (77, 84))	('KP tumors', 'Disease', 'MESH:D009369', (123, 132))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('Glut3', 'Gene', (105, 110))	('KP tumors', 'Disease', (123, 132))	('deletion', 'Var', (111, 119))
331278	32571479	Altogether, these data demonstrate that deleting Glut1 and Glut3 in KP tumors reduces glucose uptake, and that Glut1 highly contributes to glucose uptake in KP tumors.	('deleting', 'Var', (40, 48))	('KP tumors reduces glucose uptake', 'Disease', (68, 100))	('KP tumors', 'Disease', (157, 166))	('Glut3', 'Protein', (59, 64))	('KP tumors reduces glucose uptake', 'Disease', 'MESH:C536778', (68, 100))	('KP tumors', 'Disease', 'MESH:D009369', (157, 166))	('glucose', 'Chemical', 'MESH:D005947', (139, 146))	('KP tumors', 'Disease', 'MESH:D009369', (68, 77))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('contributes', 'Reg', (124, 135))	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('glucose', 'Chemical', 'MESH:D005947', (86, 93))	('Glut1', 'Protein', (49, 54))	('glucose uptake', 'MPA', (139, 153))
331282	32571479	In the KL model, Glut1 deletion impairs LUSC development, and we find that Lkb1-deficient lung tumors lack detectable Glut3, precluding any compensation occurring through this transporter.	('LUSC development', 'CPA', (40, 56))	('lack', 'NegReg', (102, 106))	('Glut1', 'Gene', (17, 22))	('deficient lung', 'Phenotype', 'HP:0002089', (80, 94))	('deficient lung tumors', 'Disease', (80, 101))	('deletion', 'Var', (23, 31))	('LUSC', 'Chemical', '-', (40, 44))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('Lkb1', 'Gene', (75, 79))	('lung tumor', 'Phenotype', 'HP:0100526', (90, 100))	('deficient lung tumors', 'Disease', 'MESH:D008175', (80, 101))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('Glut3', 'Protein', (118, 123))	('impairs', 'NegReg', (32, 39))	('lung tumors', 'Phenotype', 'HP:0100526', (90, 101))	('Lkb1', 'Gene', '20869', (75, 79))
331289	32571479	Correspondence to the three subtypes found by the Cancer Genome Atlas Research Network (proximal proliferative, proximal inflammatory and terminal respiratory unit) and presence of TP53 mutation are shown on top bars.	('Cancer', 'Disease', 'MESH:D009369', (50, 56))	('Cancer', 'Disease', (50, 56))	('TP53', 'Gene', (181, 185))	('Cancer', 'Phenotype', 'HP:0002664', (50, 56))	('TP53', 'Gene', '22059', (181, 185))	('mutation', 'Var', (186, 194))
331334	32571479	Antibodies used are anti-PPARalpha (PA1-822A, ThermoFisher Scientific, 1:1000; RRID:AB_2165595), anti-GLUT1 (07-1401, Millipore, 1:1000; RRID:AB_1587074), anti-GLUT3 (ab41525, Abcam, 1:1000; RRID:AB_732609), anti-beta-tubulin (sc-9104, Santa Cruz Biotechnology, 1:1000; RRID:AB_2241191), and anti-gamma-tubulin (T6557, Sigma-Aldrich, 1:10'000; RRID:AB_477584).	('B', 'Chemical', 'MESH:D001895', (143, 144))	('PPARalpha', 'Gene', '19013', (25, 34))	('B', 'Chemical', 'MESH:D001895', (197, 198))	('B', 'Chemical', 'MESH:D001895', (276, 277))	('T6557', 'Var', (312, 317))	('B', 'Chemical', 'MESH:D001895', (85, 86))	('B', 'Chemical', 'MESH:D001895', (350, 351))	('B', 'Chemical', 'MESH:D001895', (247, 248))	('PPARalpha', 'Gene', (25, 34))
331335	32571479	For histological analyses, lung lobes from tumor-bearing mice were fixed in 3,6% formaldehyde (VWR Chemicals, 20909.290) at 4 C for 24 hr, then rinsed once in PBS1x followed by a washing and a keeping in 70% absolute ethanol (VWR, C20820.362) before paraffin embedding.	('mice', 'Species', '10090', (57, 61))	('formaldehyde', 'Chemical', 'MESH:D005557', (81, 93))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('PBS1x', 'Chemical', '-', (159, 164))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('C20820.362', 'Var', (231, 241))	('ethanol', 'Chemical', 'MESH:D000431', (217, 224))	('tumor', 'Disease', (43, 48))	('paraffin', 'Chemical', 'MESH:D010232', (250, 258))
331348	32571479	The ngTMA block was cut at 4 mum and a double IHC using anti-GLUT1 (AEC chromogen, red staining) and anti-HIF1alpha (DAB chromogen, brown staining) was performed.	('anti-GLUT1', 'Var', (56, 66))	('HIF1alpha', 'Gene', (106, 115))	('TMA', 'Disease', (6, 9))	('DAB', 'Chemical', 'MESH:D015100', (117, 120))	('HIF1alpha', 'Gene', '15251', (106, 115))	('TMA', 'Disease', 'MESH:D000783', (6, 9))
331357	32571479	Real-time PCR was done using Taqman universal PCR master mix (4324018, ThermoFisher Scientific) and Taqman probes for the following genes: Slc2a1: Mm00441480_m1; Slc2a3: Mm00441483_m1; Slc2a2: Mm00446229_m1; Slc2a4: Mm00436615_m1; Slc2a5: Mm00600311_m1; Slc2a6: Mm00554217_m1; Slc2a7: Mm01260610_m1; Slc2a8: Mm00444634_m1; Slc2a9: Mm00455122_m1; Slc2a10: Mm01249519_m1; Slc2a12: Mm02375931_s1; Slc2a13: Mm01306489_m1; Slc5a2: Mm00453831_m1; Slc50a1: Mm00485707_m1; gene expression level normalization gene Rpl30: Mm01611464_g1 (all from ThermoFisher Scientific, Catalog number: 4331182).	('Slc2a7', 'Gene', (277, 283))	('Slc50a1', 'Gene', (441, 448))	('Rpl30', 'Gene', (506, 511))	('Slc2a10', 'Gene', '170441', (346, 353))	('Slc2a4', 'Gene', '20528', (208, 214))	('Slc2a9', 'Gene', '117591', (323, 329))	('Slc5a2', 'Gene', (418, 424))	('Slc2a6', 'Gene', '227659', (254, 260))	('Slc2a8', 'Gene', (300, 306))	('Slc2a3', 'Gene', '20527', (162, 168))	('Mm00485707_m1', 'Var', (450, 463))	('Slc2a8', 'Gene', '56017', (300, 306))	('Mm01306489_m1', 'Var', (403, 416))	('Slc50a1', 'Gene', '19729', (441, 448))	('Rpl30', 'Gene', '19946', (506, 511))	('Slc2a2', 'Gene', (185, 191))	('Slc2a13', 'Gene', '239606', (394, 401))	('Slc2a1', 'Gene', (346, 352))	('Slc2a1', 'Gene', (370, 376))	('Slc2a7', 'Gene', '435818', (277, 283))	('Slc2a1', 'Gene', (394, 400))	('Slc2a13', 'Gene', (394, 401))	('Slc2a5', 'Gene', (231, 237))	('Slc2a4', 'Gene', (208, 214))	('Slc2a1', 'Gene', (139, 145))	('Slc2a6', 'Gene', (254, 260))	('Slc2a2', 'Gene', '20526', (185, 191))	('Slc2a9', 'Gene', (323, 329))	('Slc2a12', 'Gene', (370, 377))	('Mm01611464_g1', 'Var', (513, 526))	('Slc2a1', 'Gene', '20525', (346, 352))	('Slc2a3', 'Gene', (162, 168))	('Slc2a5', 'Gene', '56485', (231, 237))	('Slc2a1', 'Gene', '20525', (370, 376))	('Slc5a2', 'Gene', '246787', (418, 424))	('Slc2a10', 'Gene', (346, 353))	('Slc2a1', 'Gene', '20525', (394, 400))	('Slc2a12', 'Gene', '353169', (370, 377))	('Slc2a1', 'Gene', '20525', (139, 145))
331368	32571479	Fragment analysis was done on an ABI3730xl (Life Technologies) and the resulting data were analyzed with GeneMarker HID software (Softgenetics).	('HID', 'Disease', (116, 119))	('B', 'Chemical', 'MESH:D001895', (34, 35))	('ABI3730xl', 'Var', (33, 42))	('HID', 'Disease', 'MESH:C566528', (116, 119))
331381	32571479	The last time frame (labeling steady-state) was used to derive standardized uptake values (SUV) images and measure maximal SUV (SUVmax) values over tumor regions.where RROI represents the radioactivity concentration measured in the region of interest (ROI),  is the injected activity corrected for the radiotracer decay and w is the mouse weight.	('mouse', 'Species', '10090', (333, 338))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('tumor', 'Disease', (148, 153))	('RROI', 'Var', (168, 172))	('tumor', 'Disease', 'MESH:D009369', (148, 153))
331389	32571479	Acceptance summary: This study uses conditional mice to show that GLUT1 inactivation is dispensable for tumor growth in a mouse model of lung cancer, while combined GLUT1/GLUT3 deletion leads to smaller tumors and longer survival.	('tumor', 'Disease', (203, 208))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('GLUT1/GLUT3', 'Gene', (165, 176))	('deletion', 'Var', (177, 185))	('lung cancer', 'Disease', 'MESH:D008175', (137, 148))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('tumors', 'Phenotype', 'HP:0002664', (203, 209))	('lung cancer', 'Phenotype', 'HP:0100526', (137, 148))	('GLUT1', 'Gene', (66, 71))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('tumors', 'Disease', (203, 209))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('tumor', 'Disease', (104, 109))	('smaller', 'NegReg', (195, 202))	('inactivation', 'NegReg', (72, 84))	('mouse', 'Species', '10090', (122, 127))	('longer', 'PosReg', (214, 220))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('lung cancer', 'Disease', (137, 148))	('tumors', 'Disease', 'MESH:D009369', (203, 209))	('mice', 'Species', '10090', (48, 52))
331391	32571479	Decision letter after peer review: Thank you for submitting your article "Combined deletion of Glut1 and Glut3 impairs lung adenocarcinoma growth" for consideration by eLife.	('impairs lung adenocarcinoma growth', 'Disease', 'MESH:D006130', (111, 145))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (119, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('deletion', 'Var', (83, 91))	('Glut3', 'Gene', (105, 110))	('Glut1', 'Gene', (95, 100))	('impairs lung adenocarcinoma growth', 'Disease', (111, 145))
331395	32571479	More evidence on how tumor histopathology is altered by GLUT1 and GLUT3 knockout should be included.	('altered', 'Reg', (45, 52))	('knockout', 'Var', (72, 80))	('tumor', 'Disease', (21, 26))	('GLUT3', 'Protein', (66, 71))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('GLUT1', 'Protein', (56, 61))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
331398	32571479	Reviewer #1: The authors show that GLUT1 inactivation does not significant affect the growth of tumors in the KP GEM model of lung cancer, whereas combined GLUT1/GLUT3 deletion leads to smaller tumors and longer survival.	('longer', 'PosReg', (205, 211))	('lung cancer', 'Disease', 'MESH:D008175', (126, 137))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumors', 'Disease', (96, 102))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('lung cancer', 'Disease', (126, 137))	('lung cancer', 'Phenotype', 'HP:0100526', (126, 137))	('tumors', 'Disease', 'MESH:D009369', (194, 200))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('tumors', 'Phenotype', 'HP:0002664', (194, 200))	('smaller', 'NegReg', (186, 193))	('GLUT1/GLUT3', 'Gene', (156, 167))	('tumors', 'Disease', (194, 200))	('deletion', 'Var', (168, 176))
331404	32571479	The finding that co-deletion of GLU1 and GLUT3 does impact tumor growth in the KP model is interesting, but provides an overall incremental advance.	('tumor', 'Disease', (59, 64))	('GLU1', 'Gene', (32, 36))	('impact', 'Reg', (52, 58))	('GLUT3', 'Gene', (41, 46))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('co-deletion', 'Var', (17, 28))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
331409	32571479	proved that Glut1 deficiency fails to suppress tumorigenesis and they identified Glut3 as a compensatory mechanism.	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('Glut1', 'Gene', (12, 17))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('deficiency', 'Var', (18, 28))	('tumor', 'Disease', (47, 52))
331410	32571479	The combined deletion of Glut1 and Glut3 suppressed tumor growth, decreased tumor number and increased mouse survival.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('decreased tumor', 'Disease', (66, 81))	('Glut1', 'Gene', (25, 30))	('tumor', 'Disease', (52, 57))	('mouse survival', 'CPA', (103, 117))	('increased', 'PosReg', (93, 102))	('mouse', 'Species', '10090', (103, 108))	('tumor', 'Disease', (76, 81))	('suppressed', 'NegReg', (41, 51))	('Glut3', 'Gene', (35, 40))	('decreased tumor', 'Disease', 'MESH:D002303', (66, 81))	('deletion', 'Var', (13, 21))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
331417	32571479	They show that either transporter alone is dispensible for tumor growth, but deletion of both transporters extends mouse survival.	('tumor', 'Disease', (59, 64))	('extends', 'PosReg', (107, 114))	('mouse', 'Species', '10090', (115, 120))	('deletion', 'Var', (77, 85))	('mouse survival', 'CPA', (115, 129))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
331421	32571479	1) The Abstract implies that glucose uptake may not be important based on Glut1 deletion, although then suggests it is important since Glut3 is required if Glut1 is absent.	('Glut1', 'Gene', (74, 79))	('deletion', 'Var', (80, 88))	('glucose', 'Chemical', 'MESH:D005947', (29, 36))
331424	32571479	2) The use of nanoSIMS to assess glucose fate following glucose transporter deletion is interesting, however this is a poor surrogate for glucose uptake (see below).	('glucose transporter', 'Gene', (56, 75))	('deletion', 'Var', (76, 84))	('glucose', 'Chemical', 'MESH:D005947', (138, 145))	('glucose', 'Chemical', 'MESH:D005947', (56, 63))	('glucose', 'Chemical', 'MESH:D005947', (33, 40))
331434	32571479	7) The extension in mouse survival with dual deletion of Glut1 and Glut3 is fairly modest.	('mouse', 'Species', '10090', (20, 25))	('dual deletion', 'Var', (40, 53))	('Glut3', 'Gene', (67, 72))	('Glut1', 'Gene', (57, 62))
331437	32571479	In response to this comment and to those of the reviewer #3, we have now used 18F-FDG PET to trace glucose uptake in KP, KPG1, KPG3 and KPG1G3 lung tumors.	('lung tumors', 'Disease', 'MESH:D008175', (143, 154))	('lung tumor', 'Phenotype', 'HP:0100526', (143, 153))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('trace glucose uptake', 'MPA', (93, 113))	('18F-FDG', 'Chemical', 'MESH:D019788', (78, 85))	('lung tumors', 'Phenotype', 'HP:0100526', (143, 154))	('lung tumors', 'Disease', (143, 154))	('glucose', 'Chemical', 'MESH:D005947', (99, 106))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('KPG3', 'Var', (127, 131))	('KPG1G3', 'Var', (136, 142))
331443	32571479	These overall data suggest, as expected, that deleting glucose transporters in KP tumors reduces glucose uptake and that Glut1 mainly contributes to glucose uptake in KP tumors (Figure 4H-IA).	('contributes', 'Reg', (134, 145))	('glucose', 'Chemical', 'MESH:D005947', (55, 62))	('glucose uptake', 'MPA', (149, 163))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('glucose', 'Chemical', 'MESH:D005947', (149, 156))	('KP tumors', 'Disease', 'MESH:D009369', (167, 176))	('glucose', 'Chemical', 'MESH:D005947', (97, 104))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('KP tumors reduces glucose uptake', 'Disease', 'MESH:C536778', (79, 111))	('KP tumors reduces glucose uptake', 'Disease', (79, 111))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('KP tumors', 'Disease', (167, 176))	('tumors', 'Phenotype', 'HP:0002664', (170, 176))	('KP tumors', 'Disease', 'MESH:D009369', (79, 88))	('deleting', 'Var', (46, 54))
331448	32571479	Our results showed a significant decrease of high tumor grades (grades 4 and 5) in KPG1 vs. KP lesions and in KPG1G3 vs. KP tumors.	('KP tumors', 'Disease', (121, 130))	('decrease', 'NegReg', (33, 41))	('KPG1', 'Disease', (83, 87))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('KPG1G3', 'Var', (110, 116))	('tumor', 'Disease', (124, 129))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('KP tumors', 'Disease', 'MESH:D009369', (121, 130))	('tumor', 'Disease', (50, 55))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
331457	32571479	In all cell lines, the combination of GLUT1 and GLUT3 knockdown more strongly diminished tumor cell viability when compared to individual gene knockdown, which corroborates our in vivo data.	('knockdown', 'Var', (54, 63))	('diminished', 'NegReg', (78, 88))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('GLUT1', 'Protein', (38, 43))	('GLUT3', 'Gene', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
331464	32571479	Glut1 and/or Glut3 gene deletion in the KP model of pure lung adenocarcinomas has never been reported before, and even if expression data show high Glut1 expression in advanced tumors this does not mean it is functionally implicated.	('Glut3', 'Gene', (13, 18))	('Glut1', 'Protein', (148, 153))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (57, 76))	('tumors', 'Phenotype', 'HP:0002664', (177, 183))	('tumors', 'Disease', 'MESH:D009369', (177, 183))	('lung adenocarcinomas', 'Disease', (57, 77))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (57, 77))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('carcinomas', 'Phenotype', 'HP:0030731', (67, 77))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('deletion', 'Var', (24, 32))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (57, 77))	('tumors', 'Disease', (177, 183))	('Glut1', 'Gene', (0, 5))	('expression', 'MPA', (154, 164))
331466	32571479	Finally, thanks to this revision we increased our knowledge about in vivo tumor glucose uptake in the different genotypes (18F-FDG-PET imaging), and we report an unexpected accelerated KLG1 tumor growth compared to that of KL tumors (see our response to the reviewer #3 point 6), that we interpret as a sustained proliferative capacity consequent to the impaired LUAD-to-LUSC transdifferentiation caused by Glut1 deletion.	('KL tumors', 'Disease', 'MESH:D009369', (223, 232))	('deletion', 'Var', (413, 421))	('tumors', 'Phenotype', 'HP:0002664', (226, 232))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('LUSC', 'Chemical', '-', (371, 375))	('glucose', 'Chemical', 'MESH:D005947', (80, 87))	('18F-FDG', 'Chemical', 'MESH:D019788', (123, 130))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor', 'Disease', 'MESH:D009369', (226, 231))	('KL tumors', 'Disease', (223, 232))	('tumor', 'Disease', (190, 195))	('tumor', 'Disease', (74, 79))	('Glut1', 'Gene', (407, 412))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('tumor', 'Disease', (226, 231))	('accelerated', 'PosReg', (173, 184))
331468	32571479	First, to address this comment we have now used human tumor cell lines from non-small cell lung cancer (NSCLC) with GLUT1, GLUT3 or both knockdown, as described in Essential revisions point 3.	('lung cancer', 'Phenotype', 'HP:0100526', (91, 102))	('GLUT3', 'Protein', (123, 128))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (80, 102))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('human', 'Species', '9606', (48, 53))	('GLUT1', 'Protein', (116, 121))	('NSCLC', 'Disease', (104, 109))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (76, 102))	('lung cancer', 'Disease', 'MESH:D008175', (91, 102))	('NSCLC', 'Disease', 'MESH:D002289', (104, 109))	('knockdown', 'Var', (137, 146))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumor', 'Disease', (54, 59))	('lung cancer', 'Disease', (91, 102))
331478	32571479	Longitudinal muCT-based tumor growth rate measurements (n = 5 tumors from control-treated mice and n = 3 tumors from tamoxifen-treated mice) revealed that acute Glut1 deletion in established tumors seems to decrease tumor growth (Author response image 2D).	('tumors', 'Disease', (105, 111))	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('deletion', 'Var', (167, 175))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('tumors', 'Disease', (191, 197))	('tumors', 'Disease', 'MESH:D009369', (105, 111))	('tumor', 'Disease', (216, 221))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumors', 'Disease', (62, 68))	('tumor', 'Disease', 'MESH:D009369', (216, 221))	('tumors', 'Disease', 'MESH:D009369', (191, 197))	('tamoxifen', 'Chemical', 'MESH:D013629', (117, 126))	('tumor', 'Disease', (105, 110))	('Glut1', 'Gene', (161, 166))	('tumor', 'Disease', (24, 29))	('tumors', 'Disease', 'MESH:D009369', (62, 68))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('mice', 'Species', '10090', (90, 94))	('tumor', 'Disease', (191, 196))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('decrease', 'NegReg', (207, 215))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('tumor', 'Disease', (62, 67))	('mice', 'Species', '10090', (135, 139))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumors', 'Phenotype', 'HP:0002664', (191, 197))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
331480	32571479	Thus, these results suggest that acute Glut1 deletion in established KP tumors reduce tumor growth, which might be partially compensated by an increased Glut3 protein expression.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('increased', 'PosReg', (143, 152))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('Glut3', 'MPA', (153, 158))	('Glut1', 'Gene', (39, 44))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('KP tumors reduce tumor', 'Disease', (69, 91))	('deletion', 'Var', (45, 53))	('KP tumors reduce tumor', 'Disease', 'MESH:D009369', (69, 91))
331489	32571479	2017, who reported an association between high GLUT1 and poor prognosis in LUSC.	('high', 'Var', (42, 46))	('association', 'Interaction', (22, 33))	('LUSC', 'Chemical', '-', (75, 79))	('LUSC', 'Disease', (75, 79))
331492	32571479	In response to this comment, we have now used human tumor cell lines from non-small cell lung cancer with GLUT1, GLUT3 or both knockdown, as described in Essential revisions point 3.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('GLUT1', 'Var', (106, 111))	('GLUT3', 'Gene', (113, 118))	('lung cancer', 'Disease', (89, 100))	('tumor', 'Disease', (52, 57))	('lung cancer', 'Phenotype', 'HP:0100526', (89, 100))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (78, 100))	('human', 'Species', '9606', (46, 51))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (74, 100))	('lung cancer', 'Disease', 'MESH:D008175', (89, 100))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('knockdown', 'Var', (127, 136))
331494	32571479	Unfortunately, cleaved caspase-3 staining did not reveal any apoptotic cell, which may be explained by the fact that we focused on a quick apoptotic process, the cleaved caspase-3 detection, at a specific time windows, the sacrifice.	('caspase-3', 'Gene', '12367', (23, 32))	('caspase-3', 'Gene', (170, 179))	('cleaved', 'Var', (162, 169))	('caspase-3', 'Gene', (23, 32))	('caspase-3', 'Gene', '12367', (170, 179))
331495	32571479	Concerning cell proliferation, we surprisingly quantified an increased proliferation rate of KPG1G3 tumors compared to control KP lesions (Author response image 5), which was particularly evident in small lesions.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('KPG1G3', 'Var', (93, 99))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('tumors', 'Disease', (100, 106))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('increased', 'PosReg', (61, 70))	('proliferation', 'CPA', (71, 84))
331496	32571479	We then hypothesised, but unfortunately were not able to test it, that the immune microenvironment of KPG1G3 tumors might be more active than the one of the KP lesions.	('KPG1G3', 'Var', (102, 108))	('tumors', 'Disease', 'MESH:D009369', (109, 115))	('tumors', 'Disease', (109, 115))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))
331501	32571479	To respond to this critical point, raised as Essential revision point 1, we have now used 18F-FDG-PET imaging and have compared tumors from KP, KPG1, KPG3 and KPG1G3 mice.	('KPG1G3', 'Var', (159, 165))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('mice', 'Species', '10090', (166, 170))	('18F-FDG', 'Chemical', 'MESH:D019788', (90, 97))	('tumors', 'Disease', (128, 134))	('tumors', 'Disease', 'MESH:D009369', (128, 134))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('KPG3', 'Var', (150, 154))
331513	32571479	Accordingly to Hsieh et al., 2019 study, we confirmed that Glut1 deletion in KL tumors impacts neither overall mouse survival, nor tumor initiation (Author response image 7A-B).	('deletion', 'Var', (65, 73))	('KL tumors impacts', 'Disease', 'MESH:D014095', (77, 94))	('tumor initiation', 'Disease', 'MESH:D009369', (131, 147))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('mouse', 'Species', '10090', (111, 116))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('KL tumors impacts', 'Disease', (77, 94))	('tumor initiation', 'Disease', (131, 147))	('Hsieh', 'Disease', (15, 20))	('Hsieh', 'Disease', 'None', (15, 20))	('B', 'Chemical', 'MESH:D001895', (174, 175))	('Glut1', 'Gene', (59, 64))
331514	32571479	Unexpectedly, after having used X-rays micro-computed tomography (muCT) analysis to longitudinally follow KLG1 and KL tumor development, we observed that Glut1 deficiency led to a significantly accelerated tumor growth rate (Author response image 7C).	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('deficiency', 'Var', (160, 170))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('accelerated', 'PosReg', (194, 205))	('tumor', 'Disease', (206, 211))	('KL tumor', 'Disease', 'MESH:D009369', (115, 123))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumor', 'Disease', (118, 123))	('Glut1', 'Gene', (154, 159))	('KL tumor', 'Disease', (115, 123))	('tumor', 'Disease', 'MESH:D009369', (206, 211))
331517	32571479	We interpret these data as follows: KL tumors require Glut1 for LUAD-to-LUSC transdifferentiation, and Glut1 deletion prevents this, as reported by Hsieh et al., 2019.	('Glut1', 'Gene', (103, 108))	('KL tumors', 'Disease', (36, 45))	('deletion', 'Var', (109, 117))	('LUAD-to-LUSC transdifferentiation', 'CPA', (64, 97))	('Hsieh', 'Disease', 'None', (148, 153))	('Hsieh', 'Disease', (148, 153))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('KL tumors', 'Disease', 'MESH:D009369', (36, 45))	('LUSC', 'Chemical', '-', (72, 76))	('prevents', 'NegReg', (118, 126))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))
331519	32571479	Accordingly, our data demonstrate that tumor cell proliferation marks are more elevated in absence of Glut1 and that in vivo tumor growth is faster: KLG1 LUAD tumors keep growing.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('absence', 'Var', (91, 98))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('KLG1', 'Var', (149, 153))	('LUAD tumors', 'Disease', 'MESH:D009369', (154, 165))	('tumors', 'Phenotype', 'HP:0002664', (159, 165))	('tumor', 'Disease', (125, 130))	('tumor', 'Disease', (159, 164))	('Glut1', 'Protein', (102, 107))	('LUAD tumors', 'Disease', (154, 165))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('elevated', 'PosReg', (79, 87))	('tumor', 'Disease', (39, 44))	('tumor', 'Disease', 'MESH:D009369', (159, 164))
331525	32571479	The extension in mouse survival corresponds to a median survival of 172 days and 211.5 days post-tumor initiation in KP and KPG1G3 mice, respectively.	('mouse survival', 'CPA', (17, 31))	('tumor initiation', 'Disease', 'MESH:D009369', (97, 113))	('mouse', 'Species', '10090', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('KPG1G3', 'Var', (124, 130))	('extension', 'PosReg', (4, 13))	('tumor initiation', 'Disease', (97, 113))	('mice', 'Species', '10090', (131, 135))
331526	32571479	In other words, KPG1G3 mice lifespan is about 23% longer than the one of the control mice.	('mice', 'Species', '10090', (85, 89))	('KPG1G3', 'Var', (16, 22))	('lifespan', 'CPA', (28, 36))	('longer', 'PosReg', (50, 56))	('mice', 'Species', '10090', (23, 27))
331530	32571479	This analysis revealed that no other glucose transporter is induced upon Glut1 and Glut3 deletion in KP tumors.	('glucose transporter', 'MPA', (37, 56))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('induced', 'Reg', (60, 67))	('Glut1', 'Gene', (73, 78))	('Glut3', 'Gene', (83, 88))	('KP tumors', 'Disease', (101, 110))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('deletion', 'Var', (89, 97))	('glucose', 'Chemical', 'MESH:D005947', (37, 44))	('KP tumors', 'Disease', 'MESH:D009369', (101, 110))
331562	30597654	Results also suggested significant prognostic effect of high NLR on poor DFS in squamous cell carcinoma of oral cavity (HR = 1.69; 95% CI, 1.24-2.30; P = .001) and larynx (HR = 1.36; 95% CI, 1.13-1.63; P = .001) (Table 3).	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('NLR', 'Gene', (61, 64))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (80, 103))	('squamous cell carcinoma of oral cavity', 'Phenotype', 'HP:0030413', (80, 118))	('squamous cell carcinoma', 'Disease', (80, 103))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (80, 103))	('carcinoma of oral cavity', 'Phenotype', 'HP:0100649', (94, 118))	('larynx', 'Disease', (164, 170))	('high', 'Var', (56, 60))
331564	30597654	As shown in Table 3, stratified analyses based on sample size, cutoff value of NLR, tumor TNM classification, and statistical model showed that these factors had no significant effect on the association between high NLR and poor DFS.	('high', 'Var', (211, 215))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('TNM', 'Gene', '10178', (90, 93))	('tumor', 'Disease', (84, 89))	('association', 'Interaction', (191, 202))	('TNM', 'Gene', (90, 93))	('poor DFS', 'Disease', (224, 232))
331567	30597654	And results indicated that high NLR was significantly correlated with worse CSS in HNSCC (HR = 1.45; 95% CI, 1.23-1.71; P < .001) (Figure 3C).	('HNSCC', 'Disease', (83, 88))	('HNSCC', 'Phenotype', 'HP:0012288', (83, 88))	('CSS', 'Chemical', '-', (76, 79))	('high', 'Var', (27, 31))	('NLR', 'Gene', (32, 35))	('CSS', 'Disease', (76, 79))
331591	30897760	A Systematic Pan-Cancer Analysis of Genetic Heterogeneity Reveals Associations with Epigenetic Modifiers Intratumor genetic heterogeneity (ITH) is the main obstacle to effective cancer treatment and a major mechanism of drug resistance.	('Epigenetic Modifiers', 'Var', (84, 104))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('drug resistance', 'Phenotype', 'HP:0020174', (220, 235))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('Associations', 'Interaction', (66, 78))	('Cancer', 'Phenotype', 'HP:0002664', (17, 23))	('cancer', 'Disease', (178, 184))	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
331594	30897760	Integration of ITH scores and somatic variants detected in each tumor sample revealed that mutations in epigenetic modifier genes are associated with higher ITH levels.	('associated', 'Reg', (134, 144))	('tumor', 'Disease', (64, 69))	('higher', 'PosReg', (150, 156))	('ITH levels', 'MPA', (157, 167))	('mutations', 'Var', (91, 100))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
331595	30897760	Indeed, the knockout of histone methyltransferase SETD2 or DNA methyltransferase DNMT3A using the CRISPR/Cas9 system on cancer cells led to significant expansion of genetically-distinct clones and culminated in highly heterogeneous cell populations.	('genetically-distinct clones', 'CPA', (165, 192))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('expansion', 'PosReg', (152, 161))	('knockout', 'Var', (12, 20))	('SETD2', 'Gene', '29072', (50, 55))	('DNMT3A', 'Gene', (81, 87))	('DNMT3A', 'Gene', '1788', (81, 87))	('SETD2', 'Gene', (50, 55))	('culminated in', 'Reg', (197, 210))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))
331602	30897760	By facilitating the emergence of nucleotide sequence mutations, copy-number alterations, chromosomal translocations or aneuploidies, genomic instability has been regarded as the major source of ITH.	('copy-number alterations', 'Var', (64, 87))	('aneuploidies', 'Disease', (119, 131))	('aneuploidies', 'Disease', 'MESH:D000782', (119, 131))	('nucleotide sequence mutations', 'Var', (33, 62))	('chromosomal translocations', 'Var', (89, 115))
331604	30897760	Besides mutations, cancer cells invariably present with some degree of epigenetic alterations that contribute to the acquisition of the cancer hallmarks.	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('cancer', 'Disease', 'MESH:D009369', (19, 25))	('cancer hallmarks', 'Disease', 'MESH:D009369', (136, 152))	('cancer', 'Disease', (19, 25))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('epigenetic alterations', 'Var', (71, 93))	('cancer', 'Disease', (136, 142))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('cancer hallmarks', 'Disease', (136, 152))
331605	30897760	Indeed, there is evidence that epigenomic reprogramming plays a seminal role in tumorigenesis by creating a progenitor-like cell state that facilitates expression of driver mutations and tumor initiation.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('driver mutations', 'Var', (166, 182))	('epigenomic', 'Var', (31, 41))	('tumor', 'Disease', (80, 85))	('tumor', 'Disease', (187, 192))	('expression', 'MPA', (152, 162))	('facilitates', 'PosReg', (140, 151))
331606	30897760	For instance, acute monocytic leukemias frequently (20.5%) carry mutations in the de novo DNA methyltransferase gene DNMT3A, displaying aberrant genome-wide DNA methylation profiles.	('monocytic leukemias', 'Disease', (20, 39))	('leukemias', 'Phenotype', 'HP:0001909', (30, 39))	('acute monocytic leukemias', 'Phenotype', 'HP:0004845', (14, 39))	('DNMT3A', 'Gene', (117, 123))	('DNMT3A', 'Gene', '1788', (117, 123))	('monocytic leukemias', 'Disease', 'MESH:D007951', (20, 39))	('mutations', 'Var', (65, 74))
331607	30897760	Ten percent of kidney renal clear cell carcinomas (KIRC) have mutations in SETD2, the methyltransferase responsible for trimethylation of Lys36 in histone H3 (H3K36me3), which is necessary for accurate gene expression and DNA repair.	('kidney renal clear cell carcinomas', 'Disease', (15, 49))	('kidney renal clear cell carcinomas', 'Disease', 'MESH:C538614', (15, 49))	('SETD2', 'Gene', '29072', (75, 80))	('SETD2', 'Gene', (75, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (39, 48))	('carcinomas', 'Phenotype', 'HP:0030731', (39, 49))	('mutations', 'Var', (62, 71))	('Lys36', 'Chemical', '-', (138, 143))
331608	30897760	H3K36me3 is also involved in targeting DNMT3A to chromatin, highlighting the finely tuned epigenetic interplay between histone and DNA methylation that is needed for normal cell function and is frequently disrupted in cancer cells.	('DNMT3A', 'Gene', (39, 45))	('cancer', 'Disease', 'MESH:D009369', (218, 224))	('DNMT3A', 'Gene', '1788', (39, 45))	('H3K36me3', 'Var', (0, 8))	('cancer', 'Disease', (218, 224))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))
331609	30897760	While epigenetic deregulation in cancer arises primarily as a consequence of DNA mutations, the view that altered epigenomes may also change DNA mutation rates highlights reciprocal interactions that contribute to cancer development.	('change', 'Reg', (134, 140))	('cancer', 'Disease', (33, 39))	('cancer', 'Disease', (214, 220))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('DNA', 'Gene', (141, 144))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('mutations', 'Var', (81, 90))	('DNA', 'Gene', (77, 80))	('cancer', 'Disease', 'MESH:D009369', (214, 220))
331610	30897760	Accordingly, epigenomic disruption should favor the development of genetically-diverse tumor cell populations, fueling ITH.	('favor', 'PosReg', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Disease', (87, 92))	('epigenomic disruption', 'Var', (13, 34))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('development', 'CPA', (52, 63))
331613	30897760	Our integrative pan-cancer characterization of somatic variants and ITH identified mutations in epigenetic modifier genes that display an association with increased clonal evolution across several cancer types.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('mutations', 'Var', (83, 92))	('cancer', 'Disease', 'MESH:D009369', (197, 203))	('variants', 'Var', (55, 63))	('cancer', 'Disease', (197, 203))	('epigenetic modifier genes', 'Gene', (96, 121))	('cancer', 'Disease', 'MESH:D009369', (20, 26))	('cancer', 'Disease', (20, 26))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))
331618	30897760	The ITH score was obtained using the mutant-allele tumor heterogeneity (MATH) method (Figure 1A and Table S1).	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('mutant-allele', 'Var', (37, 50))	('tumor', 'Disease', (51, 56))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
331623	30897760	Individual analysis of each cancer type revealed that only thyroid carcinoma (THCA), pancreatic adenocarcinoma (PAAD) and kidney renal clear cell carcinoma (KIRC) exhibited a statistically significant positive correlation between genomic instability and ITH (Figure 1B).	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D010190', (85, 110))	('kidney renal clear cell carcinoma', 'Disease', (122, 155))	('ITH', 'Disease', (254, 257))	('pancreatic adenocarcinoma', 'Disease', (85, 110))	('only thyroid carcinoma', 'Disease', 'MESH:D013964', (54, 76))	('PAAD', 'Phenotype', 'HP:0006725', (112, 116))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('only thyroid carcinoma', 'Disease', (54, 76))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (85, 110))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('genomic', 'Var', (230, 237))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('cancer', 'Disease', (28, 34))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (59, 76))	('kidney renal clear cell carcinoma', 'Disease', 'MESH:C538614', (122, 155))	('THCA', 'Phenotype', 'HP:0002890', (78, 82))
331626	30897760	To investigate whether epigenomic deregulation drives the development of tumors with high levels of ITH, we focused our analysis on KIRC, the cancer type with the highest frequency of mutations in epigenetic modifiers (Figure 2A).	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('mutations', 'Var', (184, 193))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('tumors', 'Disease', (73, 79))	('tumors', 'Disease', 'MESH:D009369', (73, 79))	('cancer', 'Disease', (142, 148))
331627	30897760	The important role of epigenomic deregulation in the development and progression of KIRC is illustrated by the finding that patients with mutations in epigenetic modifiers have worse overall survival compared to those without mutations in these genes (p < 0.05, log-rank test; Figure 2B).	('overall survival', 'MPA', (183, 199))	('worse', 'NegReg', (177, 182))	('mutations', 'Var', (138, 147))	('patients', 'Species', '9606', (124, 132))	('epigenetic', 'Gene', (151, 161))
331628	30897760	Moreover, the presence of mutations in epigenetic modifier genes correlates positively with increased ITH across different cancer types (Figure 2D and Table S2).	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('epigenetic modifier genes', 'Gene', (39, 64))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('mutations', 'Var', (26, 35))	('increased', 'PosReg', (92, 101))	('cancer', 'Disease', (123, 129))	('ITH', 'Disease', (102, 105))
331629	30897760	The strongest predictor of high ITH in both KIRC alone or across several cancer types was the presence of mutations in SETD2, DNMT1 and DNTM3A (Figure 2E).	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('SETD2', 'Gene', '29072', (119, 124))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('SETD2', 'Gene', (119, 124))	('DNMT1', 'Gene', (126, 131))	('mutations', 'Var', (106, 115))	('DNMT1', 'Gene', '1786', (126, 131))	('DNTM3A', 'Gene', (136, 142))
331630	30897760	Importantly, we could model 32% of variability in KIRC ITH using only mutations in SETD2, DNMT1 and DNTM3A (Figure 2F).	('mutations', 'Var', (70, 79))	('DNMT1', 'Gene', (90, 95))	('DNTM3A', 'Gene', (100, 106))	('DNMT1', 'Gene', '1786', (90, 95))	('SETD2', 'Gene', '29072', (83, 88))	('SETD2', 'Gene', (83, 88))
331632	30897760	These data suggest that epigenomic deregulation is an important determinant of ITH and identify mutations in SETD2, DNMT1 and DNTM3A as candidate drivers of ITH.	('ITH', 'Disease', (79, 82))	('SETD2', 'Gene', '29072', (109, 114))	('DNMT1', 'Gene', (116, 121))	('SETD2', 'Gene', (109, 114))	('DNMT1', 'Gene', '1786', (116, 121))	('mutations', 'Var', (96, 105))	('DNTM3A', 'Gene', (126, 132))
331633	30897760	We next sought to experimentally validate the role of SETD2, DNMT1 and DNMT3A mutations in driving the emergence of genetically-distinct subclonal cell populations.	('DNMT3A', 'Gene', (71, 77))	('DNMT3A', 'Gene', '1788', (71, 77))	('SETD2', 'Gene', '29072', (54, 59))	('SETD2', 'Gene', (54, 59))	('DNMT1', 'Gene', (61, 66))	('mutations', 'Var', (78, 87))	('DNMT1', 'Gene', '1786', (61, 66))
331636	30897760	Importantly, knockout of DNMT1 rendered KIRC cells senescent (Figure 3B), in contrast to DNMT3A and SETD2 depletion, which were well tolerated and did not significantly affect cell proliferation (Figure 3C).	('DNMT1', 'Gene', '1786', (25, 30))	('knockout', 'Var', (13, 21))	('DNMT3A', 'Gene', (89, 95))	('DNMT3A', 'Gene', '1788', (89, 95))	('senescent', 'CPA', (51, 60))	('SETD2', 'Gene', '29072', (100, 105))	('DNMT1', 'Gene', (25, 30))	('SETD2', 'Gene', (100, 105))
331637	30897760	This finding suggests that additional compensatory mutations are required to allow the proliferation of DNMT1 mutant cells within tumors.	('tumors', 'Disease', (130, 136))	('tumors', 'Disease', 'MESH:D009369', (130, 136))	('DNMT1', 'Gene', (104, 109))	('DNMT1', 'Gene', '1786', (104, 109))	('mutant', 'Var', (110, 116))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))
331638	30897760	Alternatively, DNMT1 mutant clones could be selected during tumor evolution due their ability to promote carcinogenesis through the senescence-associated secretory phenotype.	('carcinogenesis', 'Disease', 'MESH:D063646', (105, 119))	('mutant', 'Var', (21, 27))	('DNMT1', 'Gene', (15, 20))	('carcinogenesis', 'Disease', (105, 119))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('DNMT1', 'Gene', '1786', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Disease', (60, 65))	('senescence-associated secretory phenotype', 'MPA', (132, 173))	('promote', 'PosReg', (97, 104))
331639	30897760	To investigate whether loss of DNMT3A or SETD2 drives the acquisition of genetically-heterogeneous cell populations over time, we performed whole-exome sequencing of control and knockout cells cultured during 1, 3 and 6 months (Figure 4A).	('DNMT3A', 'Gene', (31, 37))	('SETD2', 'Gene', '29072', (41, 46))	('DNMT3A', 'Gene', '1788', (31, 37))	('loss', 'Var', (23, 27))	('SETD2', 'Gene', (41, 46))
331642	30897760	However, while ITH rose for up to three months after SETD2 depletion, it remained constant through time in DNMT3A knockout cells (Figure 4B).	('SETD2', 'Gene', (53, 58))	('depletion', 'Var', (59, 68))	('rose', 'PosReg', (19, 23))	('DNMT3A', 'Gene', (107, 113))	('DNMT3A', 'Gene', '1788', (107, 113))	('SETD2', 'Gene', '29072', (53, 58))
331645	30897760	Altogether, these data suggest that loss of SETD2 or DNMT3A drives specific patterns of clonal evolution that culminate in tumors with increased levels of ITH.	('DNMT3A', 'Gene', (53, 59))	('tumors', 'Disease', (123, 129))	('DNMT3A', 'Gene', '1788', (53, 59))	('tumors', 'Disease', 'MESH:D009369', (123, 129))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('SETD2', 'Gene', '29072', (44, 49))	('loss', 'Var', (36, 40))	('increased', 'PosReg', (135, 144))	('SETD2', 'Gene', (44, 49))	('culminate in', 'Reg', (110, 122))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
331646	30897760	The increased ITH observed knockout of SETD2 or DNMT3A knockout suggests that new clones carrying phenotypic traits that confer selective advantage within the cell populations have expanded and were selected.	('SETD2', 'Gene', (39, 44))	('DNMT3A', 'Gene', (48, 54))	('DNMT3A', 'Gene', '1788', (48, 54))	('knockout', 'Var', (55, 63))	('SETD2', 'Gene', '29072', (39, 44))
331650	30897760	Basal mitochondrial respiration in knockout and parental cells was equally efficient (Figure 5B), indicating that no major intrinsic metabolic alterations were caused upon loss of either SETD2 or DNMT3A.	('SETD2', 'Gene', (187, 192))	('loss', 'Var', (172, 176))	('DNMT3A', 'Gene', (196, 202))	('DNMT3A', 'Gene', '1788', (196, 202))	('SETD2', 'Gene', '29072', (187, 192))
331652	30897760	Both parameters were significantly increased in SETD2 and DNMT3A knockout cells when compared to parental cells under similar conditions (Figure 5C,D).	('increased', 'PosReg', (35, 44))	('DNMT3A', 'Gene', (58, 64))	('SETD2', 'Gene', '29072', (48, 53))	('DNMT3A', 'Gene', '1788', (58, 64))	('knockout', 'Var', (65, 73))	('SETD2', 'Gene', (48, 53))
331653	30897760	Analysis of SETD2 and DNMT3A knockout cells revealed mutations in genes involved in mitochondria biogenesis and function (Table S5); however, inspection of mitochondria network in knockout cells using fluorescence confocal microscopy did not reveal any major alterations (Figure 5E).	('SETD2', 'Gene', '29072', (12, 17))	('SETD2', 'Gene', (12, 17))	('DNMT3A', 'Gene', (22, 28))	('DNMT3A', 'Gene', '1788', (22, 28))	('mutations', 'Var', (53, 62))
331660	30897760	Recently, high concordance was observed between the evolution of genetic and epigenetic diversification in esophageal squamous cell carcinoma and in glioma, disclosing possible relationships between genomic and epigenomic alterations during the clonal evolution of tumors.	('tumor', 'Phenotype', 'HP:0002664', (265, 270))	('glioma', 'Disease', (149, 155))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (107, 141))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (118, 141))	('epigenetic', 'Var', (77, 87))	('tumors', 'Disease', (265, 271))	('tumors', 'Disease', 'MESH:D009369', (265, 271))	('tumors', 'Phenotype', 'HP:0002664', (265, 271))	('esophageal squamous cell carcinoma', 'Disease', (107, 141))	('glioma', 'Phenotype', 'HP:0009733', (149, 155))	('glioma', 'Disease', 'MESH:D005910', (149, 155))
331661	30897760	An interesting hypothesis linking DNA mutations and epigenetics in cancer is that altered DNA methylation or chromatin modifications may accelerate mutation rates.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('cancer', 'Disease', (67, 73))	('accelerate', 'PosReg', (137, 147))	('chromatin', 'MPA', (109, 118))	('DNA', 'Protein', (90, 93))	('mutation rates', 'MPA', (148, 162))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('altered', 'Var', (82, 89))
331662	30897760	For example, abnormal DNA hypomethylation near guanine quadruplexes (G4s)-rich regions is a common signature for many DNA breakpoints associated with somatic copy-number alterations.	('G4s', 'Gene', (69, 72))	('DNA', 'Disease', (118, 121))	('abnormal', 'Var', (13, 21))	('guanine', 'Chemical', 'MESH:D006147', (47, 54))	('G4s', 'Gene', '411', (69, 72))
331663	30897760	This finding suggests that DNA hypomethylation in genomic regions enriched for G4s acts as a mutagenic factor in cancer.	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('hypomethylation', 'Var', (31, 46))	('cancer', 'Disease', (113, 119))	('mutagenic', 'Reg', (93, 102))	('G4s', 'Gene', '411', (79, 82))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('G4s', 'Gene', (79, 82))
331665	30897760	Together, these data establish a strong association between epigenomic deregulation:namely, DNA and histone methylation and genomic mutations, which we show play important roles during clonal evolution and genetic diversification of tumors.	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('tumors', 'Disease', 'MESH:D009369', (233, 239))	('tumors', 'Phenotype', 'HP:0002664', (233, 239))	('tumors', 'Disease', (233, 239))	('mutations', 'Var', (132, 141))
331666	30897760	Particularly, we identified and validated mutations in the methyltransferase genes SETD2 and DNMT3A as potent drivers of ITH.	('ITH', 'Disease', (121, 124))	('SETD2', 'Gene', '29072', (83, 88))	('SETD2', 'Gene', (83, 88))	('mutations', 'Var', (42, 51))	('DNMT3A', 'Gene', (93, 99))	('DNMT3A', 'Gene', '1788', (93, 99))
331671	30897760	We thus reasoned that the increased ITH observed upon SETD2 or DNMT3A knockout likely underpins phenotypic variations in mitochondrial metabolism upon which natural selection could act.	('ITH', 'MPA', (36, 39))	('SETD2', 'Gene', '29072', (54, 59))	('mitochondrial metabolism', 'MPA', (121, 145))	('SETD2', 'Gene', (54, 59))	('increased', 'PosReg', (26, 35))	('DNMT3A', 'Gene', (63, 69))	('DNMT3A', 'Gene', '1788', (63, 69))	('knockout', 'Var', (70, 78))
331672	30897760	In agreement with this, we observed that both SETD2 and DNMT3A depleted cell populations have increased bioenergetic performance under stress conditions, a phenotype that was accompanied by mutations in genes involved in mitochondria function.	('SETD2', 'Gene', (46, 51))	('mutations', 'Var', (190, 199))	('increased', 'PosReg', (94, 103))	('bioenergetic', 'MPA', (104, 116))	('DNMT3A', 'Gene', (56, 62))	('DNMT3A', 'Gene', '1788', (56, 62))	('SETD2', 'Gene', '29072', (46, 51))
331673	30897760	Caki-2 cells (Cell Line Services, Eppelheim, Germany) that do not have SETD2 mutations were selected as a cellular model of KIRC.	('SETD2', 'Gene', (71, 76))	('SETD2', 'Gene', '29072', (71, 76))	('mutations', 'Var', (77, 86))	('Caki-2', 'CellLine', 'CVCL:0235', (0, 6))
331682	30897760	After 1 h blocking with 5% non-fat dry milk in 1x PBS, 0.1% Tween20 at room temperature, membranes were incubated with antibodies as follows: anti-DNMT1 (2 microg/mL, Active Motif, Carlsbad, CA, USA), anti-DNMT3A (1:1000, Cell Signaling), anti-H3K36me3 (1:500, Abcam, Cambridge, UK), alpha-tubulin (1:15,000, Sigma-Aldrich) and anti-histone H3 (1:1000, Abcam).	('DNMT1', 'Gene', '1786', (147, 152))	('alpha-tubulin', 'Protein', (284, 297))	('anti-H3K36me3', 'Var', (239, 252))	('DNMT3A', 'Gene', (206, 212))	('DNMT3A', 'Gene', '1788', (206, 212))	('anti-histone', 'Var', (328, 340))	('DNMT1', 'Gene', (147, 152))	('PBS', 'Chemical', 'MESH:D007854', (50, 53))
331701	30897760	Genomic instability was calculated as the absolute number of mutations and INDEL observed in each tumor sample.	('tumor', 'Disease', (98, 103))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('mutations', 'Var', (61, 70))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))
331704	30897760	To identify driver-gene mutations, a binary matrix was produced representing the presence/absence of mutations for each gene on each tumor sample, eliminating the bias introduced by hypermutated genes.	('mutations', 'Var', (24, 33))	('tumor', 'Disease', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumor', 'Disease', 'MESH:D009369', (133, 138))
331717	30897760	Single-nucleotide variants reported in dbSNP150 were filtered out from VCF output files, unless they were also present in COSMICv85.	('dbSNP150', 'Gene', (39, 47))	('Single-nucleotide variants', 'Var', (0, 26))	('dbSNP150', 'Chemical', '-', (39, 47))
331718	30897760	The ITH from control and knockout cell lines was determined using the mutant-allele tumor heterogeneity (MATH) approach.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('tumor', 'Disease', (84, 89))	('mutant-allele', 'Var', (70, 83))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))
331720	30897760	Our pan-cancer analyses revealed that mutations in epigenetic modifiers, namely SETD2 and DNMT3A, are major determinants of ITH.	('SETD2', 'Gene', (80, 85))	('ITH', 'Disease', (124, 127))	('cancer', 'Disease', (8, 14))	('determinants', 'Reg', (108, 120))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('DNMT3A', 'Gene', (90, 96))	('DNMT3A', 'Gene', '1788', (90, 96))	('mutations', 'Var', (38, 47))	('SETD2', 'Gene', '29072', (80, 85))	('cancer', 'Disease', 'MESH:D009369', (8, 14))
331722	30897760	For instance, SETD2 mutations are found in 10% of KIRC, 9% of non-small cell lung carcinomas, 15% of pediatric high-grade gliomas and 8% of adult high-grade gliomas, whereas mutations in DNMT3A are observed in over 20% acute monocytic leukemias.	('non-small cell lung carcinomas', 'Phenotype', 'HP:0030358', (62, 92))	('gliomas', 'Disease', 'MESH:D005910', (157, 164))	('carcinomas', 'Phenotype', 'HP:0030731', (82, 92))	('DNMT3A', 'Gene', (187, 193))	('leukemias', 'Phenotype', 'HP:0001909', (235, 244))	('monocytic leukemias', 'Disease', 'MESH:D007951', (225, 244))	('glioma', 'Phenotype', 'HP:0009733', (157, 163))	('gliomas', 'Disease', (122, 129))	('gliomas', 'Phenotype', 'HP:0009733', (157, 164))	('glioma', 'Phenotype', 'HP:0009733', (122, 128))	('cell lung carcinomas', 'Disease', (72, 92))	('cell lung carcinomas', 'Disease', 'MESH:D055752', (72, 92))	('acute monocytic leukemias', 'Phenotype', 'HP:0004845', (219, 244))	('monocytic leukemias', 'Disease', (225, 244))	('SETD2', 'Gene', (14, 19))	('gliomas', 'Disease', 'MESH:D005910', (122, 129))	('mutations', 'Var', (20, 29))	('DNMT3A', 'Gene', '1788', (187, 193))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('SETD2', 'Gene', '29072', (14, 19))	('gliomas', 'Disease', (157, 164))	('small cell lung carcinomas', 'Phenotype', 'HP:0030357', (66, 92))	('gliomas', 'Phenotype', 'HP:0009733', (122, 129))
331724	30897760	Our experimental validation of the role of specific epigenetic modifier genes in driving ITH reveals novel biomarkers and/or therapeutic targets that may contribute to more effective cancer prognoses and treatment.	('cancer', 'Disease', (183, 189))	('epigenetic modifier genes', 'Var', (52, 77))	('contribute', 'Reg', (154, 164))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('cancer', 'Disease', 'MESH:D009369', (183, 189))
331725	30897760	The following are available online at , Method S1: Pan-Cancer Data Sets, Method S2: Intratumor heterogeneity score using mutant-allele tumor heterogeneity (MATH) score, Method S3: Identification of deregulated cancer pathways associated with ITH, Method S4: Pan-cancer discovery of driver-gene mutations of ITH, Method S5: Whole-exome sequencing and variant calling for human cancer cell lines, Method S6: Clonality analyses.	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('cancer', 'Disease', (376, 382))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('cancer', 'Phenotype', 'HP:0002664', (376, 382))	('deregulated', 'MPA', (198, 209))	('Pan-cancer', 'Disease', 'MESH:C537931', (258, 268))	('cancer', 'Disease', 'MESH:D009369', (210, 216))	('mutations', 'Var', (294, 303))	('tumor', 'Disease', (89, 94))	('cancer', 'Disease', (262, 268))	('cancer', 'Disease', 'MESH:D009369', (376, 382))	('cancer', 'Phenotype', 'HP:0002664', (262, 268))	('tumor', 'Disease', (135, 140))	('ITH', 'Gene', (307, 310))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('Cancer', 'Phenotype', 'HP:0002664', (55, 61))	('tumor', 'Disease', 'MESH:D009369', (135, 140))	('human', 'Species', '9606', (370, 375))	('cancer', 'Disease', 'MESH:D009369', (262, 268))	('cancer', 'Disease', (210, 216))	('Pan-cancer', 'Disease', (258, 268))
331726	30897760	This file contains the description of the computational methods used in this study, Table S1: Clinical data and genomic features (genomic instability and MATH values) for samples from 16 different TCGA cancer types, Table S2: Linear models associating mutations in functional groups and ITH for each cancer type, Table S3: Predicted effect of DNMT1, DNMT3A and SETD2 mutations in KIRC samples from cBioportal, Table S4: ITH values (MATH) estimated for control, DNTM3A and SETD2 KO cell lines, Table S5: Mutations generated after SETD2 and DNMT3A knockouts (not present in controls), including the mutations with GO terms associated with mitochondria, Table S6: Material and Methods Table (e.g., plasmids, gRNAs, antibodies, primers and other products), Table S7: Read length, total reads and mapped reads for each condition.	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('SETD2', 'Gene', (361, 366))	('SETD2', 'Gene', (472, 477))	('DNMT3A', 'Gene', '1788', (350, 356))	('SETD2', 'Gene', '29072', (361, 366))	('SETD2', 'Gene', '29072', (472, 477))	('DNMT3A', 'Gene', '1788', (539, 545))	('cancer', 'Disease', 'MESH:D009369', (202, 208))	('DNMT1', 'Gene', '1786', (343, 348))	('cancer', 'Disease', (300, 306))	('cancer', 'Phenotype', 'HP:0002664', (300, 306))	('DNMT3A', 'Gene', (350, 356))	('SETD2', 'Gene', (529, 534))	('DNMT3A', 'Gene', (539, 545))	('DNMT1', 'Gene', (343, 348))	('SETD2', 'Gene', '29072', (529, 534))	('mutations', 'Var', (367, 376))	('cancer', 'Disease', (202, 208))	('cancer', 'Disease', 'MESH:D009369', (300, 306))
331794	30984771	However, radiosensitization can also increase normal tissue toxicity and bone marrow suppression, resulting in undesirable breaks in treatment.	('toxicity', 'Disease', (60, 68))	('bone marrow suppression', 'Disease', (73, 96))	('increase', 'PosReg', (37, 45))	('bone marrow suppression', 'Disease', 'MESH:D001855', (73, 96))	('toxicity', 'Disease', 'MESH:D064420', (60, 68))	('radiosensitization', 'Var', (9, 27))	('bone marrow suppression', 'Phenotype', 'HP:0005528', (73, 96))
331945	26291010	Recently, using a homogeneous large cohort of stage I lung adenocarcinoma patients, we have identified high tumor-infiltrating FoxP3/CD3 lymphocytes ratio in tumor-related stroma, overexpression of interleukin-7 receptor (IL-7R), and loss of IL-12Rbeta2 expression in tumor cells as independent prognostic factors of stage I lung adenocarcinoma.	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (325, 344))	('IL-7R', 'Gene', (222, 227))	('tumor', 'Disease', (108, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (335, 344))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('IL-7R', 'Gene', '3575', (222, 227))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (54, 73))	('tumor', 'Phenotype', 'HP:0002664', (268, 273))	('interleukin-7 receptor', 'Gene', '3575', (198, 220))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))	('IL-12Rbeta2', 'Gene', '3595', (242, 253))	('IL-12Rbeta2', 'Gene', (242, 253))	('loss', 'Var', (234, 238))	('I lung adenocarcinoma', 'Disease', (323, 344))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('FoxP3', 'Gene', (127, 132))	('patients', 'Species', '9606', (74, 82))	('I lung adenocarcinoma', 'Disease', 'MESH:D000077192', (323, 344))	('FoxP3', 'Gene', '50943', (127, 132))	('tumor', 'Disease', (158, 163))	('I lung adenocarcinoma', 'Disease', (52, 73))	('tumor', 'Disease', (268, 273))	('interleukin-7 receptor', 'Gene', (198, 220))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('I lung adenocarcinoma', 'Disease', 'MESH:D000077192', (52, 73))	('tumor', 'Disease', 'MESH:D009369', (268, 273))	('overexpression', 'PosReg', (180, 194))
331990	26291010	The OS of patients with high CD10+ neutrophil and low CD20+ lymphocyte infiltration (5-year OS, 42%) was significantly worse compared with those with low CD10/low CD20 (5-year OS, 62%; P = 0.001; hazard ratio [HR] = 0.55; 95% confidence interval [CI] = 0.38 - 0.79), low CD10/high CD20 (5-year OS, 55%; P = 0.026; HR = 0.58; 95% CI = 0.36 - 0.94), and high CD10/high CD20 (5-year OS, 70%; P = 0.043; HR = 0.60; 95% CI = 0.36 - 0.98) (Fig.	('CD10', 'Gene', (29, 33))	('low', 'Var', (267, 270))	('CD20', 'Gene', (163, 167))	('CD10', 'Gene', '4311', (271, 275))	('CD10', 'Gene', '4311', (154, 158))	('low CD20+ lymphocyte', 'Phenotype', 'HP:0001888', (50, 70))	('CD20', 'Gene', (367, 371))	('CD20', 'Gene', (281, 285))	('CD20', 'Gene', '931', (163, 167))	('CD10', 'Gene', '4311', (357, 361))	('CD10', 'Gene', (154, 158))	('CD10', 'Gene', (271, 275))	('CD20', 'Gene', '931', (367, 371))	('CD20', 'Gene', '931', (281, 285))	('CD10', 'Gene', (357, 361))	('patients', 'Species', '9606', (10, 18))	('CD20', 'Gene', (54, 58))	('CD10', 'Gene', '4311', (29, 33))	('CD20', 'Gene', '931', (54, 58))
331992	26291010	Using this risk index in the training cohort, OS of patients with high CD10/CD20 risk index was significantly worse (n = 72; 5-year OS, 42%) than those with low risk index (n = 228; 5-year OS, 62%; P < 0.001; HR = 0.56; 95% CI = 0.4-0.78) (Fig.	('CD10', 'Gene', (71, 75))	('worse', 'NegReg', (110, 115))	('high', 'Var', (66, 70))	('CD10', 'Gene', '4311', (71, 75))	('CD20', 'Gene', (76, 80))	('CD20', 'Gene', '931', (76, 80))	('patients', 'Species', '9606', (52, 60))
331994	26291010	OS of patients with high CD10/CD20 risk index was significantly worse (n = 30; 5-year OS, 46%) than those with low risk index (n = 112; 5-year OS, 66%; P = 0.032; HR = 0.58; 95% CI = 0.35-0.96) (Fig.	('CD10', 'Gene', '4311', (25, 29))	('worse', 'NegReg', (64, 69))	('CD20', 'Gene', (30, 34))	('CD20', 'Gene', '931', (30, 34))	('high', 'Var', (20, 24))	('patients', 'Species', '9606', (6, 14))	('CD10', 'Gene', (25, 29))
332000	26291010	With regard to type of tumor-infiltrating lymphocyte evaluated by immunohistochemistry, we have recently reported that high FoxP3 to CD3+ tumor-infiltrating lymphocyte ratio in tumor-related stroma was an independent prognostic factor for patients with stage I lung adenocarcinoma.	('I lung adenocarcinoma', 'Disease', 'MESH:D000077192', (259, 280))	('tumor', 'Disease', (138, 143))	('high', 'Var', (119, 123))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('patients', 'Species', '9606', (239, 247))	('FoxP3', 'Gene', '50943', (124, 129))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (261, 280))	('I lung adenocarcinoma', 'Disease', (259, 280))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('FoxP3', 'Gene', (124, 129))	('tumor', 'Disease', (23, 28))	('tumor', 'Disease', (177, 182))	('carcinoma', 'Phenotype', 'HP:0030731', (271, 280))
332002	26291010	However, in our current study of lung squamous cell carcinoma no single type of tumor-infiltrating lymphocytes nor any combination of tumor-infiltrating lymphocytes (including combinations of FoxP3/CD3 or CD4/CD8) were significantly associated with patient clinical outcomes.	('patient', 'Species', '9606', (249, 256))	('CD8', 'Gene', (209, 212))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('CD4', 'Gene', (205, 208))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (33, 61))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (38, 61))	('FoxP3', 'Gene', (192, 197))	('FoxP3', 'Gene', '50943', (192, 197))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (33, 61))	('lung squamous cell carcinoma', 'Disease', (33, 61))	('CD8', 'Gene', '925', (209, 212))	('tumor', 'Disease', (80, 85))	('combinations', 'Var', (176, 188))	('tumor', 'Disease', (134, 139))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (52, 61))	('associated', 'Reg', (233, 243))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('CD4', 'Gene', '920', (205, 208))
332029	26291010	The biological interaction of TANs with CD20+ B cells in the tumor immune microenvironment is unclear; however, it was demonstrated that B cells inhibit neutrophil migration and, in contrast, B cell deficiency leads to increased infiltration of neutrophil in the non-tumoral inflammatory process.	('tumor', 'Disease', (61, 66))	('men', 'Species', '9606', (86, 89))	('CD20', 'Gene', '931', (40, 44))	('infiltration', 'MPA', (229, 241))	('tumor', 'Disease', 'MESH:D009369', (267, 272))	('deficiency', 'Var', (199, 209))	('tumor', 'Phenotype', 'HP:0002664', (267, 272))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('neutrophil migration', 'CPA', (153, 173))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Disease', (267, 272))	('CD20', 'Gene', (40, 44))	('increased', 'PosReg', (219, 228))	('inhibit', 'NegReg', (145, 152))
332036	24628993	We have previously shown that the receptor tyrosine kinase (RTK) MET frequently suffers gain-of-function mutations that significantly promote lung tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('lung tumor', 'Disease', (142, 152))	('gain-of-function', 'PosReg', (88, 104))	('promote', 'PosReg', (134, 141))	('receptor tyrosine kinase', 'Gene', (34, 58))	('lung tumor', 'Disease', 'MESH:D008175', (142, 152))	('receptor tyrosine kinase', 'Gene', '5979', (34, 58))	('RTK', 'Gene', (60, 63))	('mutations', 'Var', (105, 114))	('lung tumor', 'Phenotype', 'HP:0100526', (142, 152))	('RTK', 'Gene', '5979', (60, 63))
332043	24628993	The combinatorial effect of PAX8 knockdown and MET inhibition using SU11274 was investigated in NSCLC cell viability assay.	('NSCLC', 'Disease', (96, 101))	('SU11274', 'Var', (68, 75))	('NSCLC', 'Disease', 'MESH:D002289', (96, 101))	('SU11274', 'Chemical', 'MESH:C478479', (68, 75))	('PAX8', 'Gene', (28, 32))
332049	24628993	Most importantly, knockdown of PAX8 in A549 cells resulted in enhanced apoptosis (~6 fold) and decreased cell motility (~45%), thereby making PAX8 a potential therapeutic target.	('decreased', 'NegReg', (95, 104))	('knockdown', 'Var', (18, 27))	('apoptosis', 'CPA', (71, 80))	('enhanced', 'PosReg', (62, 70))	('PAX8', 'Gene', (31, 35))	('A549', 'CellLine', 'CVCL:0023', (39, 43))	('cell motility', 'CPA', (105, 118))
332050	24628993	However, the combinatorial approach of PAX8 knockdown and treatment with MET inhibitor, SU11274, had marginal additive effect on loss of NSCLC cell viability.	('NSCLC', 'Disease', (137, 142))	('SU11274', 'Chemical', 'MESH:C478479', (88, 95))	('NSCLC', 'Disease', 'MESH:D002289', (137, 142))	('loss', 'NegReg', (129, 133))	('knockdown', 'Var', (44, 53))	('PAX8', 'Gene', (39, 43))
332055	24628993	Most recently, EGFR mutations, ALK/ROS1 translocation and MET amplification have been shown in a subset of NSCLC.	('ALK', 'Gene', '238', (31, 34))	('NSCLC', 'Disease', (107, 112))	('shown', 'Reg', (86, 91))	('NSCLC', 'Disease', 'MESH:D002289', (107, 112))	('ROS1', 'Gene', '6098', (35, 39))	('EGFR', 'Gene', '1956', (15, 19))	('ALK', 'Gene', (31, 34))	('EGFR', 'Gene', (15, 19))	('ROS1', 'Gene', (35, 39))	('mutations', 'Var', (20, 29))
332063	24628993	In follicular thyroid carcinoma, PAX8 undergoes gene rearrangement as a result of (2;3) (q13;p25) chromosomal translocation with peroxisome proliferator-activated receptor- gamma(PPARgamma).	('peroxisome proliferator-activated receptor- gamma', 'Gene', '5468', (129, 178))	('gene rearrangement', 'MPA', (48, 66))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (14, 31))	('undergoes', 'Reg', (38, 47))	('p25', 'Gene', (93, 96))	('PPARgamma', 'Gene', (179, 188))	('follicular thyroid carcinoma', 'Disease', (3, 31))	('follicular thyroid carcinoma', 'Phenotype', 'HP:0006731', (3, 31))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('2;', 'Var', (83, 85))	('follicular thyroid carcinoma', 'Disease', 'MESH:D018263', (3, 31))	('PPARgamma', 'Gene', '5468', (179, 188))	('p25', 'Gene', '11076', (93, 96))	('peroxisome proliferator-activated receptor- gamma', 'Gene', (129, 178))	('PAX8', 'Gene', (33, 37))
332067	24628993	Our previous work demonstrated that the forced expression of a MET mutant, originally discovered in human NSCLC, results in an abnormal vulval phenotype with marked hyperplasia.	('NSCLC', 'Disease', 'MESH:D002289', (106, 111))	('hyperplasia', 'Disease', 'MESH:D006965', (165, 176))	('human', 'Species', '9606', (100, 105))	('results in', 'Reg', (113, 123))	('mutant', 'Var', (67, 73))	('abnormal vulval phenotype', 'MPA', (127, 152))	('rat', 'Species', '10116', (25, 28))	('hyperplasia', 'Disease', (165, 176))	('NSCLC', 'Disease', (106, 111))
332071	24628993	Silencing of PAX8 resulted in a significant decrease in not only PAX8 levels but also that of MET and RON expression.	('PAX8', 'Gene', (13, 17))	('decrease', 'NegReg', (44, 52))	('PAX8 levels', 'MPA', (65, 76))	('RON', 'Gene', (102, 105))	('Silencing', 'Var', (0, 9))	('RON', 'Gene', '4486', (102, 105))
332092	24628993	The A549 cells were plated in 60 mm plates and PAX8 was knocked down using PAX8 specific siRNA.	('A549', 'CellLine', 'CVCL:0023', (4, 8))	('knocked', 'Var', (56, 63))	('PAX8', 'Gene', (47, 51))
332097	24628993	Cell migration was determined in A549 cells transfected with PAX8 siRNA or scrambled siRNA.	('rat', 'Species', '10116', (8, 11))	('A549', 'CellLine', 'CVCL:0023', (33, 37))	('Cell migration', 'CPA', (0, 14))	('PAX8', 'Var', (61, 65))
332152	24628993	The effect of PAX8 knock down in A549 cells on apoptosis was investigated using flow cytometry based analysis after staining with Annexin V and PI and representative results are shown in Figure 4.	('Annexin V', 'Gene', (130, 139))	('PAX8', 'Gene', (14, 18))	('knock down', 'Var', (19, 29))	('A549', 'CellLine', 'CVCL:0023', (33, 37))	('Annexin V', 'Gene', '308', (130, 139))
332154	24628993	There was a clear loss in cell motility as reflected by prominent gaps in the scratches made in PAX8 knock down plate compared to control cell monolayer.	('cell motility', 'CPA', (26, 39))	('loss', 'NegReg', (18, 22))	('rat', 'Species', '10116', (80, 83))	('PAX8', 'Gene', (96, 100))	('gaps', 'NegReg', (66, 70))	('knock down plate', 'Var', (101, 117))
332156	24628993	The dramatic decrease in cell migration in PAX8 knockdown cells compared to control cells can be appreciated from representative photographs shown in Figure 5C and the summary results shown as bar graphs in Figure 5D.	('PAX8', 'Gene', (43, 47))	('cell migration', 'CPA', (25, 39))	('decrease', 'NegReg', (13, 21))	('rat', 'Species', '10116', (33, 36))	('knockdown', 'Var', (48, 57))
332157	24628993	Treatment of A549 cells with small molecule inhibitor of MET, SU11274, however resulted in an almost 50% loss in cell viability that further decreased to 43% in PAX8 knocked down cells under comparable conditions.	('SU11274', 'Var', (62, 69))	('loss', 'NegReg', (105, 109))	('decreased', 'NegReg', (141, 150))	('SU11274', 'Chemical', 'MESH:C478479', (62, 69))	('cell viability', 'CPA', (113, 127))	('A549', 'CellLine', 'CVCL:0023', (13, 17))
332170	24628993	Although site directed loss-of-function mutants have been reported in hypothyroidism, no gain-of-function mutants have been reported for PAX8 in any cancers.	('hypothyroidism', 'Disease', 'MESH:D007037', (70, 84))	('loss-of-function', 'NegReg', (23, 39))	('hypothyroidism', 'Phenotype', 'HP:0000821', (70, 84))	('cancers', 'Disease', (149, 156))	('cancers', 'Phenotype', 'HP:0002664', (149, 156))	('hypothyroidism', 'Disease', (70, 84))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('mutants', 'Var', (40, 47))	('cancers', 'Disease', 'MESH:D009369', (149, 156))
332174	24628993	The silencing of PAX8 in NSCLC cells not only resulted in decreased levels of MET, but also that of RON.	('PAX8', 'Gene', (17, 21))	('RON', 'Gene', '4486', (100, 103))	('levels of MET', 'MPA', (68, 81))	('NSCLC', 'Disease', (25, 30))	('decreased', 'NegReg', (58, 67))	('NSCLC', 'Disease', 'MESH:D002289', (25, 30))	('RON', 'Gene', (100, 103))	('silencing', 'Var', (4, 13))
332188	24628993	It is not surprising that PAX8 knockdown results in significant loss in A549 cell viability; as such a role was demonstrated for PAX transcription factors including PAX8 in the promotion of cancer cell growth.	('cancer', 'Disease', (190, 196))	('cancer', 'Disease', 'MESH:D009369', (190, 196))	('PAX', 'Gene', (165, 168))	('PAX', 'Gene', '19303', (26, 29))	('rat', 'Species', '10116', (119, 122))	('A549', 'CellLine', 'CVCL:0023', (72, 76))	('loss', 'NegReg', (64, 68))	('PAX', 'Gene', '19303', (129, 132))	('A549 cell viability', 'CPA', (72, 91))	('promotion', 'PosReg', (177, 186))	('PAX', 'Gene', '19303', (165, 168))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('PAX', 'Gene', (129, 132))	('PAX', 'Gene', (26, 29))	('knockdown', 'Var', (31, 40))
332191	24628993	For instance, knockdown of PAX8 in H1993 cells resulted in a loss in the ability to close the gap created in scratch assay by about 20% at 12 h that was comparable to that seen in PAX8 knockdown A549 cells in relation to respective scrambled RNA treated controls, although actual values were somewhat different.	('rat', 'Species', '10116', (111, 114))	('PAX8', 'Gene', (27, 31))	('H1993', 'CellLine', 'CVCL:1512', (35, 40))	('knockdown', 'Var', (14, 23))	('loss', 'NegReg', (61, 65))	('A549', 'CellLine', 'CVCL:0023', (195, 199))
332192	24628993	In terms of cell viability, PAX8 knockdown had a marginal inhibitory effect in both A549 and H1993 cells.	('A549', 'CellLine', 'CVCL:0023', (84, 88))	('knockdown', 'Var', (33, 42))	('PAX8', 'Gene', (28, 32))	('H1993', 'CellLine', 'CVCL:1512', (93, 98))
332193	24628993	Inhibition of MET using specific inhibitors is also known to adversely affect NSCLC cell viability and is the basis for several ongoing clinical trials aimed at testing the efficacy of MET inhibitors in NSCLC and other cancers.	('NSCLC', 'Disease', (203, 208))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('NSCLC', 'Disease', 'MESH:D002289', (203, 208))	('affect', 'Reg', (71, 77))	('cancers', 'Disease', 'MESH:D009369', (219, 226))	('MET', 'Gene', (14, 17))	('cancers', 'Phenotype', 'HP:0002664', (219, 226))	('Inhibition', 'Var', (0, 10))	('NSCLC', 'Disease', (78, 83))	('cancers', 'Disease', (219, 226))	('NSCLC', 'Disease', 'MESH:D002289', (78, 83))	('inhibitors', 'Var', (33, 43))
332196	24628993	Also in H1993 cells, it was the MET inhibitor (SU11274) that had maximum inhibitory effect on cell viability that was comparable to that observed in A549 cells.	('SU11274', 'Var', (47, 54))	('SU11274', 'Chemical', 'MESH:C478479', (47, 54))	('cell viability', 'CPA', (94, 108))	('H1993', 'CellLine', 'CVCL:1512', (8, 13))	('A549', 'CellLine', 'CVCL:0023', (149, 153))
332198	24628993	These observations substantiate our contention that PAX8 knockdown effects in NSCLC cells are consistent and due to the use of any select NSCLC cell line.	('NSCLC', 'Disease', (138, 143))	('NSCLC', 'Disease', 'MESH:D002289', (138, 143))	('knockdown', 'Var', (57, 66))	('effects', 'Reg', (67, 74))	('PAX8', 'Gene', (52, 56))	('NSCLC', 'Disease', (78, 83))	('NSCLC', 'Disease', 'MESH:D002289', (78, 83))
332200	24628993	Synergy in killing NSCLC is more likely to be achieved by combining PAX8 knockdown with a non-overlapping disparate approach such as cisplatin that forms DNA adducts.	('PAX8', 'Gene', (68, 72))	('rat', 'Species', '10116', (111, 114))	('NSCLC', 'Disease', (19, 24))	('cisplatin', 'Chemical', 'MESH:D002945', (133, 142))	('NSCLC', 'Disease', 'MESH:D002289', (19, 24))	('knockdown', 'Var', (73, 82))
332201	24628993	In conclusion, we report here a potential therapeutic target PAX8 whose silencing in NSCLC cells promotes loss in viability and motility; most likely through the deprivation of essential signals from MET and RON RTKs.	('NSCLC', 'Disease', (85, 90))	('PAX8', 'Gene', (61, 65))	('silencing', 'Var', (72, 81))	('NSCLC', 'Disease', 'MESH:D002289', (85, 90))	('RTK', 'Gene', '5979', (212, 215))	('RON', 'Gene', (208, 211))	('RON', 'Gene', '4486', (208, 211))	('deprivation', 'NegReg', (162, 173))	('loss', 'NegReg', (106, 110))	('essential signals', 'MPA', (177, 194))	('RTK', 'Gene', (212, 215))
332209	32657049	The frequency of mutations in EGFR, MET, and RET were significantly higher in nonsmokers than in smokers.	('RET', 'Gene', '5979', (45, 48))	('EGFR', 'Gene', (30, 34))	('higher', 'PosReg', (68, 74))	('RET', 'Gene', (45, 48))	('MET', 'Gene', '79811', (36, 39))	('MET', 'Gene', (36, 39))	('EGFR', 'Gene', '1956', (30, 34))	('mutations', 'Var', (17, 26))
332210	32657049	Besides, Pearson correlation analysis found that ALK, BRAF, and MET mutations had a strong correlation with age.	('ALK', 'Gene', '238', (49, 52))	('MET', 'Gene', (64, 67))	('BRAF', 'Gene', (54, 58))	('BRAF', 'Gene', '673', (54, 58))	('ALK', 'Gene', (49, 52))	('mutations', 'Var', (68, 77))	('MET', 'Gene', '79811', (64, 67))
332211	32657049	Notably, higher frequencies of ALK and BRAF alterations were associated with younger age, while more frequent MET mutations appear in the patients at age 55 or older.	('ALK', 'Gene', '238', (31, 34))	('BRAF', 'Gene', '673', (39, 43))	('BRAF', 'Gene', (39, 43))	('MET', 'Gene', '79811', (110, 113))	('alterations', 'Var', (44, 55))	('ALK', 'Gene', (31, 34))	('MET', 'Gene', (110, 113))	('patients', 'Species', '9606', (138, 146))
332215	32657049	We found that the median variant allele frequency (VAF) in adenocarcinoma was significantly lower than those in squamous cell carcinoma and the median VAF was significantly higher in stage II-IV than in stage I.	('adenocarcinoma', 'Disease', (59, 73))	('stage II-IV', 'Disease', (183, 194))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (112, 135))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('variant', 'Var', (25, 32))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (112, 135))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))	('adenocarcinoma', 'Disease', 'MESH:D000230', (59, 73))	('squamous cell carcinoma', 'Disease', (112, 135))	('lower', 'NegReg', (92, 97))	('higher', 'PosReg', (173, 179))
332216	32657049	Besides, we found that ALK and BRAF mutations had a strong correlation with younger age.	('ALK', 'Gene', (23, 26))	('mutations', 'Var', (36, 45))	('ALK', 'Gene', '238', (23, 26))	('BRAF', 'Gene', '673', (31, 35))	('BRAF', 'Gene', (31, 35))
332224	32657049	The latest version of the National Comprehensive Cancer Network (NCCN) guidelines for NSCLC recommends that, in addition to detecting EGFR, KRAS, BRAF, HER2 mutations, MET amplification/exon 14 skipping mutations and gene rearrangements involving ROS1, RET, ALK, etc., NTRK gene fusion should also be genetically tested.	('KRAS', 'Gene', '3845', (140, 144))	('skipping', 'NegReg', (194, 202))	('MET', 'Gene', (168, 171))	('HER2', 'Gene', '2064', (152, 156))	('NSCLC', 'Disease', 'MESH:D002289', (86, 91))	('KRAS', 'Gene', (140, 144))	('EGFR', 'Gene', '1956', (134, 138))	('ALK', 'Gene', '238', (258, 261))	('NSCLC', 'Disease', (86, 91))	('ROS1', 'Gene', '6098', (247, 251))	('mutations', 'Var', (157, 166))	('RET', 'Gene', '5979', (253, 256))	('ALK', 'Gene', (258, 261))	('Cancer', 'Phenotype', 'HP:0002664', (49, 55))	('NSCLC', 'Phenotype', 'HP:0030358', (86, 91))	('MET', 'Gene', '79811', (168, 171))	('HER2', 'Gene', (152, 156))	('Cancer', 'Disease', (49, 55))	('BRAF', 'Gene', '673', (146, 150))	('BRAF', 'Gene', (146, 150))	('ROS1', 'Gene', (247, 251))	('EGFR', 'Gene', (134, 138))	('RET', 'Gene', (253, 256))	('Cancer', 'Disease', 'MESH:D009369', (49, 55))
332226	32657049	The gene mutations in lung cancer have different results among different countries, for example, the frequency of EGFR mutation of Asian female never-smokers higher than female never-smokers of the west countries.	('lung cancer', 'Disease', (22, 33))	('lung cancer', 'Phenotype', 'HP:0100526', (22, 33))	('mutation', 'Var', (119, 127))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('lung cancer', 'Disease', 'MESH:D008175', (22, 33))	('EGFR', 'Gene', '1956', (114, 118))	('EGFR', 'Gene', (114, 118))
332229	32657049	We also describe the correlation of age, gender, smoking, tumor stage, histological type with genetic mutations.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('genetic mutations', 'Var', (94, 111))	('tumor', 'Disease', 'MESH:D009369', (58, 63))
332249	32657049	The majority of mutations appeared in EGFR, ERBB2 and TP53.	('EGFR', 'Gene', '1956', (38, 42))	('ERBB2', 'Gene', '2064', (44, 49))	('EGFR', 'Gene', (38, 42))	('ERBB2', 'Gene', (44, 49))	('appeared', 'Reg', (26, 34))	('mutations', 'Var', (16, 25))	('TP53', 'Gene', '7157', (54, 58))	('TP53', 'Gene', (54, 58))
332251	32657049	In total, 69.5% of the 256 patients were identified to have EGFR mutations, which excluded 1.9% amplification of EGFR.	('patients', 'Species', '9606', (27, 35))	('EGFR', 'Gene', '1956', (60, 64))	('EGFR', 'Gene', '1956', (113, 117))	('EGFR', 'Gene', (113, 117))	('EGFR', 'Gene', (60, 64))	('mutations', 'Var', (65, 74))
332252	32657049	For EGFR mutations, we found that its mutations mainly occurred in exon19 and exon21 (Figure 1c), which was consistent with the results of many other studies (Gou & Wu, 2014).	('EGFR', 'Gene', '1956', (4, 8))	('EGFR', 'Gene', (4, 8))	('mutations', 'Var', (9, 18))	('exon21', 'Var', (78, 84))	('mutations', 'Var', (38, 47))	('occurred', 'Reg', (55, 63))
332256	32657049	We compared the frequency of mutations between lung adenocarcinoma and lung squamous cell carcinoma, in addition to this, compared between stage I and stage II or higher.	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (47, 66))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (76, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('mutations', 'Var', (29, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (57, 66))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (47, 66))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (71, 99))	('lung adenocarcinoma', 'Disease', (47, 66))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (71, 99))	('lung squamous cell carcinoma', 'Disease', (71, 99))
332259	32657049	Similarly, we compared the VAF of patients with stage I and stage II or higher and found that patients with stage II-IV had significantly higher VAF than patients with stage I (Figure 2c, p = 8.4e-06).	('patients', 'Species', '9606', (94, 102))	('patients', 'Species', '9606', (154, 162))	('VAF', 'CPA', (145, 148))	('patients', 'Species', '9606', (34, 42))	('stage II-IV', 'Var', (108, 119))	('higher', 'PosReg', (138, 144))
332269	32657049	Otherwise, we found that the EGFR mutation frequency in female patients was significantly higher than that in male (Figure 3c).	('mutation', 'Var', (34, 42))	('EGFR', 'Gene', '1956', (29, 33))	('EGFR', 'Gene', (29, 33))	('patients', 'Species', '9606', (63, 71))	('higher', 'PosReg', (90, 96))
332270	32657049	While the frequency of mutations in PTEN was significantly lower in female than in male (Figure 3c).	('PTEN', 'Gene', '5728', (36, 40))	('mutations', 'Var', (23, 32))	('lower', 'NegReg', (59, 64))	('PTEN', 'Gene', (36, 40))
332271	32657049	Next, we found that the frequency of mutations in EGRR, MET, RET, and TP53 were significantly higher in nonsmoker patients than in smokers (Figure 3d).	('RET', 'Gene', '5979', (61, 64))	('RET', 'Gene', (61, 64))	('TP53', 'Gene', '7157', (70, 74))	('MET', 'Gene', '79811', (56, 59))	('mutations', 'Var', (37, 46))	('TP53', 'Gene', (70, 74))	('MET', 'Gene', (56, 59))	('patients', 'Species', '9606', (114, 122))	('EGRR', 'Gene', (50, 54))	('higher', 'PosReg', (94, 100))
332274	32657049	Among the gene mutations investigated, only ALK rearrangements (p = .00079) and BRAF (p = .0067) mutation genotypes were significantly associated with age at diagnosis, while mutations such as EGFR, KRAS and MET were no longer significantly associated with age (Figure 4b-f).	('KRAS', 'Gene', '3845', (199, 203))	('BRAF', 'Gene', (80, 84))	('ALK', 'Gene', (44, 47))	('rearrangements', 'Var', (48, 62))	('KRAS', 'Gene', (199, 203))	('EGFR', 'Gene', '1956', (193, 197))	('associated', 'Reg', (135, 145))	('MET', 'Gene', '79811', (208, 211))	('ALK', 'Gene', '238', (44, 47))	('EGFR', 'Gene', (193, 197))	('mutation', 'Var', (97, 105))	('BRAF', 'Gene', '673', (80, 84))	('MET', 'Gene', (208, 211))	('age', 'Disease', (151, 154))
332276	32657049	In addition, smoking history was positively correlated with MET, ROS1, PIK3CA, and PETN gene mutations (Pearson's r = .87-.95) whereas RET (Pearson's r = -.85) and BRAF (Pearson's r = -.84) were negatively correlated.	('PIK3CA', 'Gene', '5290', (71, 77))	('mutations', 'Var', (93, 102))	('PETN gene', 'Gene', (83, 92))	('ROS1', 'Gene', (65, 69))	('RET', 'Gene', '5979', (135, 138))	('BRAF', 'Gene', '673', (164, 168))	('ROS1', 'Gene', '6098', (65, 69))	('RET', 'Gene', (135, 138))	('BRAF', 'Gene', (164, 168))	('MET', 'Gene', '79811', (60, 63))	('correlated', 'Interaction', (44, 54))	('MET', 'Gene', (60, 63))	('PIK3CA', 'Gene', (71, 77))
332278	32657049	Notably, BRAF and ALK mutations in the younger and older groups were significantly different (Figure 4b,c).	('ALK', 'Gene', '238', (18, 21))	('BRAF', 'Gene', (9, 13))	('ALK', 'Gene', (18, 21))	('mutations', 'Var', (22, 31))	('BRAF', 'Gene', '673', (9, 13))
332287	32657049	The top three driver gene mutations in NSCLC are EGFR, ERBB2, and KRAS.	('EGFR', 'Gene', '1956', (49, 53))	('NSCLC', 'Phenotype', 'HP:0030358', (39, 44))	('EGFR', 'Gene', (49, 53))	('KRAS', 'Gene', '3845', (66, 70))	('mutations', 'Var', (26, 35))	('NSCLC', 'Disease', (39, 44))	('ERBB2', 'Gene', (55, 60))	('ERBB2', 'Gene', '2064', (55, 60))	('NSCLC', 'Disease', 'MESH:D002289', (39, 44))	('KRAS', 'Gene', (66, 70))
332289	32657049	Among the patients with two gene mutations, we found that one patient was co-mutated with EGFR and KRAS.	('EGFR', 'Gene', '1956', (90, 94))	('patient', 'Species', '9606', (62, 69))	('mutations', 'Var', (33, 42))	('patient', 'Species', '9606', (10, 17))	('EGFR', 'Gene', (90, 94))	('patients', 'Species', '9606', (10, 18))	('KRAS', 'Gene', (99, 103))	('KRAS', 'Gene', '3845', (99, 103))
332291	32657049	Once they co-exist, KRAS mutations might develop resistance to EGFR inhibitors (Pao et al., 2005).	('KRAS', 'Gene', '3845', (20, 24))	('EGFR', 'Gene', '1956', (63, 67))	('mutations', 'Var', (25, 34))	('EGFR', 'Gene', (63, 67))	('KRAS', 'Gene', (20, 24))	('resistance', 'MPA', (49, 59))
332297	32657049	The average variant allele frequency (VAF) of adenocarcinoma was lower than that of squamous cell carcinoma, we speculated that the oncogenesis and development of squamous cell carcinoma were more closely related to genetic mutations than adenocarcinoma.	('related', 'Reg', (205, 212))	('adenocarcinoma', 'Disease', (46, 60))	('variant', 'Var', (12, 19))	('adenocarcinoma', 'Disease', (239, 253))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (163, 186))	('adenocarcinoma', 'Disease', 'MESH:D000230', (46, 60))	('adenocarcinoma', 'Disease', 'MESH:D000230', (239, 253))	('lower', 'NegReg', (65, 70))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (163, 186))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (177, 186))	('squamous cell carcinoma', 'Disease', (163, 186))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (84, 107))	('squamous cell carcinoma', 'Disease', (84, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (244, 253))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (84, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (51, 60))
332298	32657049	In Asia, the most common gene mutation in adenocarcinoma patients is EGFR, and most of EGFR mutations occur in never smoker.	('EGFR', 'Gene', '1956', (69, 73))	('EGFR', 'Gene', '1956', (87, 91))	('patients', 'Species', '9606', (57, 65))	('mutation', 'Var', (30, 38))	('EGFR', 'Gene', (69, 73))	('adenocarcinoma', 'Disease', (42, 56))	('EGFR', 'Gene', (87, 91))	('mutations', 'Var', (92, 101))	('carcinoma', 'Phenotype', 'HP:0030731', (47, 56))	('adenocarcinoma', 'Disease', 'MESH:D000230', (42, 56))
332300	32657049	To date, no targetable driver gene mutations have been found due to smoking, and the number of squamous cell histology mutations is higher than adenocarcinoma (2012; 2014).	('carcinoma', 'Phenotype', 'HP:0030731', (149, 158))	('adenocarcinoma', 'Disease', (144, 158))	('squamous cell histology', 'Disease', (95, 118))	('adenocarcinoma', 'Disease', 'MESH:D000230', (144, 158))	('mutations', 'Var', (119, 128))
332303	32657049	Our results had first discovered that the average mutation frequency of stage I cancer was lower than that of advanced stage, we speculated that the accumulation of genetic mutations was associated with the evoluation of tumor clones.	('lower', 'NegReg', (91, 96))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('tumor', 'Disease', (221, 226))	('mutations', 'Var', (173, 182))	('tumor', 'Disease', 'MESH:D009369', (221, 226))	('associated', 'Reg', (187, 197))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('cancer', 'Disease', (80, 86))
332304	32657049	While the frequency of mutations in NSCLC-associated driver genes is consistent with previous studies (Gou & Wu, 2014; Wang et al., 2011).	('NSCLC', 'Phenotype', 'HP:0030358', (36, 41))	('mutations', 'Var', (23, 32))	('NSCLC', 'Disease', 'MESH:D002289', (36, 41))	('NSCLC', 'Disease', (36, 41))
332305	32657049	Our results indicated that early NSCLC patients should also undergo genetic testing, which was beneficial to targeted treatment of patients.	('patients', 'Species', '9606', (131, 139))	('NSCLC', 'Phenotype', 'HP:0030358', (33, 38))	('genetic', 'Var', (68, 75))	('patients', 'Species', '9606', (39, 47))	('NSCLC', 'Disease', (33, 38))	('NSCLC', 'Disease', 'MESH:D002289', (33, 38))
332307	32657049	Many studies have shown that mutations in EGFR are associated with smoking status and specific histological types (Li et al., 2013; Ren et al., 2012; San Tam et al., 2006; Xu et al., 2012).	('EGFR', 'Gene', '1956', (42, 46))	('mutations', 'Var', (29, 38))	('EGFR', 'Gene', (42, 46))	('associated', 'Reg', (51, 61))	('Ren', 'Gene', (132, 135))	('Ren', 'Gene', '5972', (132, 135))
332308	32657049	A study of 506 cases of NSCLC showed that the mutation rate of EGFR was higher in nonsmoking patients than in smoking patients, and higher in female patients than in male patients (Wu et al., 2007).	('NSCLC', 'Disease', (24, 29))	('higher', 'Reg', (72, 78))	('EGFR', 'Gene', '1956', (63, 67))	('patients', 'Species', '9606', (149, 157))	('higher', 'Reg', (132, 138))	('NSCLC', 'Disease', 'MESH:D002289', (24, 29))	('EGFR', 'Gene', (63, 67))	('patients', 'Species', '9606', (118, 126))	('patients', 'Species', '9606', (171, 179))	('NSCLC', 'Phenotype', 'HP:0030358', (24, 29))	('mutation', 'Var', (46, 54))	('patients', 'Species', '9606', (93, 101))
332309	32657049	Another study of 524 patients with NSCLC also found that the rate of EGFR mutation vary with smoking status and histological subtypes, EGFR being the most frequently altered gene in nonsmoking adenocarcinoma patients (An et al., 2012).	('EGFR', 'Gene', '1956', (69, 73))	('mutation', 'Var', (74, 82))	('patients', 'Species', '9606', (208, 216))	('NSCLC', 'Disease', (35, 40))	('adenocarcinoma', 'Disease', 'MESH:D000230', (193, 207))	('altered', 'Reg', (166, 173))	('EGFR', 'Gene', (69, 73))	('EGFR', 'Gene', '1956', (135, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (198, 207))	('patients', 'Species', '9606', (21, 29))	('NSCLC', 'Disease', 'MESH:D002289', (35, 40))	('EGFR', 'Gene', (135, 139))	('NSCLC', 'Phenotype', 'HP:0030358', (35, 40))	('adenocarcinoma', 'Disease', (193, 207))
332313	32657049	A recent study of young patients with nonsmall cell lung cancer showed that higher frequency of ALK and HER2 genetic alterations were associated with young age, while, mutations in KRAS, STK11, and EGFR exon 20 are more common in older patients (Hou et al., 2018).	('EGFR', 'Gene', '1956', (198, 202))	('lung cancer', 'Phenotype', 'HP:0100526', (52, 63))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('STK11', 'Gene', (187, 192))	('nonsmall cell lung cancer', 'Disease', 'MESH:D002289', (38, 63))	('mutations', 'Var', (168, 177))	('KRAS', 'Gene', (181, 185))	('patients', 'Species', '9606', (236, 244))	('HER2', 'Gene', (104, 108))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (41, 63))	('STK11', 'Gene', '6794', (187, 192))	('ALK', 'Gene', '238', (96, 99))	('ALK', 'Gene', (96, 99))	('EGFR', 'Gene', (198, 202))	('nonsmall cell lung cancer', 'Disease', (38, 63))	('KRAS', 'Gene', '3845', (181, 185))	('alterations', 'Var', (117, 128))	('patients', 'Species', '9606', (24, 32))	('HER2', 'Gene', '2064', (104, 108))
332314	32657049	It is clear that we found a higher frequency of ALK mutations and a lower frequency of KRAS mutations in young patients (below 55) which is consistent with previous studies (Hou et al., 2018; Sacher et al., 2016; Tanaka et al., 2017).	('mutations', 'Var', (52, 61))	('KRAS', 'Gene', (87, 91))	('KRAS', 'Gene', '3845', (87, 91))	('ALK', 'Gene', '238', (48, 51))	('ALK', 'Gene', (48, 51))	('patients', 'Species', '9606', (111, 119))
332315	32657049	In addition, a higher frequency of BRAF mutations and a lower frequency of MET are also found in young patients.	('BRAF', 'Gene', (35, 39))	('mutations', 'Var', (40, 49))	('MET', 'Gene', '79811', (75, 78))	('patients', 'Species', '9606', (103, 111))	('BRAF', 'Gene', '673', (35, 39))	('MET', 'Gene', (75, 78))
332318	32657049	The above findings highlighted that the targeted alterations of ALK and BRAF, could be a valuable target in young patients with nonsmall cell lung cancer.	('nonsmall cell lung cancer', 'Disease', (128, 153))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (131, 153))	('alterations', 'Var', (49, 60))	('BRAF', 'Gene', (72, 76))	('nonsmall cell lung cancer', 'Disease', 'MESH:D002289', (128, 153))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('ALK', 'Gene', (64, 67))	('lung cancer', 'Phenotype', 'HP:0100526', (142, 153))	('ALK', 'Gene', '238', (64, 67))	('BRAF', 'Gene', '673', (72, 76))	('patients', 'Species', '9606', (114, 122))
332319	32657049	In addition, although we described that there was a significantly higher EGFR mutation rate and other unique mutation features of cancer driver genes in the NSCLC patients, the majority of them were early stage (175 patients in stage I) which is still unnecessary to undergo targeted therapy.	('patients', 'Species', '9606', (163, 171))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('mutation', 'Var', (78, 86))	('EGFR', 'Gene', '1956', (73, 77))	('cancer', 'Disease', (130, 136))	('NSCLC', 'Phenotype', 'HP:0030358', (157, 162))	('EGFR', 'Gene', (73, 77))	('patients', 'Species', '9606', (216, 224))	('higher', 'PosReg', (66, 72))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('NSCLC', 'Disease', (157, 162))	('NSCLC', 'Disease', 'MESH:D002289', (157, 162))
332331	32751160	Consequently, the aberrant regulation or expression of DYRK kinases has been associated with several human pathologies, including cancer.	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('aberrant regulation', 'Var', (18, 37))	('expression', 'MPA', (41, 51))	('DYRK', 'Gene', '1859', (55, 59))	('cancer', 'Disease', (130, 136))	('DYRK', 'Gene', (55, 59))	('human', 'Species', '9606', (101, 106))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('associated', 'Reg', (77, 87))
332338	32751160	Moreover, a DYRK1A-specific run of histidine residues targets this family member to the subnuclear splicing compartment, and the noncatalytic N-terminal domain of DYRK3 serves to localize it to stress granules.	('DYRK3', 'Gene', '8444', (163, 168))	('DYRK3', 'Gene', (163, 168))	('run', 'Var', (28, 31))	('targets', 'Reg', (54, 61))	('histidine', 'Chemical', 'MESH:D006639', (35, 44))
332344	32751160	DYRKs are also subject to other post-transcriptional events, such as microRNAs (miR)-mediated gene silencing or local translation.	('DYRK', 'Gene', '1859', (0, 4))	('DYRK', 'Gene', (0, 4))	('local translation', 'MPA', (112, 129))	('gene', 'Var', (94, 98))	('microRNAs', 'Var', (69, 78))
332348	32751160	In this regard, and given the constitutive nature of DYRK kinase activity, the regulation of their intracellular levels becomes crucial to modulate their functions, and thus, altering the DYRK expression acquires additional importance in terms of their impact on normal cell fitness.	('altering', 'Var', (175, 183))	('impact', 'Reg', (253, 259))	('modulate', 'Reg', (139, 147))	('DYRK', 'Gene', '1859', (53, 57))	('DYRK', 'Gene', '1859', (188, 192))	('DYRK', 'Gene', (53, 57))	('functions', 'MPA', (154, 163))	('DYRK', 'Gene', (188, 192))
332351	32751160	Subsequently, it was proposed as a driver in liver cancer through a study that identified such drivers according to mutations in unusual nucleotide contexts.	('liver cancer', 'Phenotype', 'HP:0002896', (45, 57))	('liver cancer', 'Disease', 'MESH:D006528', (45, 57))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('liver cancer', 'Disease', (45, 57))	('mutations in', 'Var', (116, 128))
332355	32751160	On the other hand, DYRK1A haploinsufficiency caused by de novo truncation or by missense-inactivating mutations was recently seen to underlie a rare, severe disorder, the DYRK1A haploinsufficiency syndrome (also known as MRD7 or Mental Retardation, Autosomal Dominant 7: OMIM#614104 and ORPHA:464311 and 268261; and references therein).	('MRD7', 'Gene', (221, 225))	('Mental Retardation', 'Disease', 'MESH:D008607', (229, 247))	('haploinsufficiency syndrome', 'Disease', (178, 205))	('severe disorder', 'Disease', 'MESH:D045169', (150, 165))	('haploinsufficiency', 'Disease', 'MESH:D058495', (26, 44))	('MRD7', 'Gene', '1859', (221, 225))	('Mental Retardation', 'Phenotype', 'HP:0001249', (229, 247))	('haploinsufficiency', 'Disease', 'MESH:D058495', (178, 196))	('haploinsufficiency', 'Disease', (26, 44))	('haploinsufficiency syndrome', 'Disease', 'MESH:D058495', (178, 205))	('severe disorder', 'Disease', (150, 165))	('haploinsufficiency', 'Disease', (178, 196))	('DYRK1A', 'Gene', (19, 25))	('missense-inactivating mutations', 'Var', (80, 111))	('Mental Retardation', 'Disease', (229, 247))	('DYRK1A', 'Gene', (171, 177))
332357	32751160	For instance, DYRK1A stimulates the transcriptional activity of the Hh-signaling effector GLI1 through direct phosphorylation (Figure 3), although it also represses the Hh pathway through an indirect mechanism involving regulators of the actin cytoskeleton.	('DYRK1A', 'Var', (14, 20))	('GLI1', 'Gene', '2735', (90, 94))	('GLI1', 'Gene', (90, 94))	('represses', 'NegReg', (155, 164))	('stimulates', 'PosReg', (21, 31))	('phosphorylation', 'MPA', (110, 125))	('Hh pathway', 'Pathway', (169, 179))	('transcriptional activity', 'MPA', (36, 60))
332358	32751160	Likewise, DYRK1A negatively regulates the nuclear factor of activated T-cell (NFAT) transcription factors by inducing their phosphorylation-dependent nuclear export, yet it serves as a positive modulator of NFAT signaling in primary endothelial cells stimulated by vascular endothelial growth factor (VEGF) (Figure 3).	('DYRK1A', 'Var', (10, 16))	('NFAT', 'Gene', '32321', (78, 82))	('NFAT', 'Gene', (207, 211))	('inducing', 'PosReg', (109, 117))	('regulates', 'Reg', (28, 37))	('VEGF', 'Gene', (301, 305))	('nuclear factor', 'MPA', (42, 56))	('NFAT', 'Gene', (78, 82))	('vascular endothelial growth factor', 'Gene', (265, 299))	('vascular endothelial growth factor', 'Gene', '7422', (265, 299))	('NFAT', 'Gene', '32321', (207, 211))	('phosphorylation-dependent nuclear export', 'MPA', (124, 164))	('VEGF', 'Gene', '7422', (301, 305))	('negatively', 'NegReg', (17, 27))
332359	32751160	Finally, DYRK1A may induce cells to either enter or exit the cell cycle by controlling the Cyclin D1-to-p21 ratio.	('induce', 'Reg', (20, 26))	('DYRK1A', 'Var', (9, 15))	('controlling', 'Reg', (75, 86))	('Cyclin D1', 'Gene', '595', (91, 100))	('p21', 'Gene', (104, 107))	('p21', 'Gene', '644914', (104, 107))	('Cyclin D1', 'Gene', (91, 100))	('exit the cell cycle', 'CPA', (52, 71))
332361	32751160	Therefore, as will become evident below, it remains unclear as to whether DYRK1A acts as a tumor suppressor or a tumor promoter or, more probably, as either, depending on the tumor context.	('tumor', 'Disease', (113, 118))	('tumor', 'Disease', (175, 180))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('DYRK1A', 'Var', (74, 80))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('tumor', 'Disease', (91, 96))
332362	32751160	The first indications of a role for DYRK1A in cell immortalization were obtained in studies on oncogenic viruses, indicating that DYRK1A potentially affects cell transformation in oncovirus-associated cancer models.	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('cell transformation', 'CPA', (157, 176))	('cancer', 'Disease', (201, 207))	('DYRK1A', 'Var', (130, 136))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('affects', 'Reg', (149, 156))
332364	32751160	Mutations in E1A that interfere with DYRK1A binding produce hyper-transformation in conjunction with G12V HRAS proto-oncogene.	('hyper-transformation', 'Disease', (60, 80))	('hyper-transformation', 'Disease', 'MESH:D002472', (60, 80))	('HRAS', 'Gene', (106, 110))	('G12V', 'Mutation', 'rs104894230', (101, 105))	('E1A', 'Gene', (13, 16))	('Mutations', 'Var', (0, 9))	('DYRK1A', 'Protein', (37, 43))	('HRAS', 'Gene', '3265', (106, 110))	('binding', 'Interaction', (44, 51))
332370	32751160	Moreover, DYRK1A interacts with beta-HPV E6 proteins (Figure 3), and this DYRK1A interaction is defective in HPV E6 variants found in invasive cervical carcinoma.	('variants', 'Var', (116, 124))	('HPV', 'Species', '10566', (37, 40))	('carcinoma', 'Phenotype', 'HP:0030731', (152, 161))	('invasive cervical carcinoma', 'Disease', (134, 161))	('HPV E6', 'Gene', (109, 115))	('defective', 'NegReg', (96, 105))	('HPV', 'Species', '10566', (109, 112))	('interacts', 'Interaction', (17, 26))	('invasive cervical carcinoma', 'Disease', 'MESH:D009361', (134, 161))
332374	32751160	DYRK1A promotes the assembly of this complex by phosphorylating the DREAM component Lin52 on S28, thereby triggering cell cycle exit (Figure 3).	('DREAM', 'Gene', (68, 73))	('cell cycle exit', 'CPA', (117, 132))	('assembly', 'MPA', (20, 28))	('DYRK1A', 'Gene', (0, 6))	('triggering', 'Reg', (106, 116))	('S28', 'Gene', '6234', (93, 96))	('Lin52', 'Gene', '91750', (84, 89))	('promotes', 'PosReg', (7, 15))	('phosphorylating', 'Var', (48, 63))	('DREAM', 'Gene', '30818', (68, 73))	('Lin52', 'Gene', (84, 89))	('S28', 'Gene', (93, 96))
332377	32751160	DYRK1A positively regulates p53 transcriptional activity by the direct phosphorylation of S15, but it also negatively regulates this factor by enhancing sirtuin (Sirt)1-dependent deacetylation.	('phosphorylation', 'MPA', (71, 86))	('Sirt)1', 'Gene', '23411', (162, 168))	('negatively', 'NegReg', (107, 117))	('S15', 'Gene', (90, 93))	('enhancing', 'PosReg', (143, 152))	('regulates', 'Reg', (18, 27))	('transcriptional activity', 'MPA', (32, 56))	('S15', 'Gene', '6209', (90, 93))	('p53', 'Protein', (28, 31))	('DYRK1A', 'Var', (0, 6))
332383	32751160	Thus, DYRK1A prevents epidermal growth factor receptor (EGFR) endocytosis-mediated degradation in neural stem cells and indeed, DYRK1A-dependent EGFR stabilization has been described in glioblastoma (GBM) and non-small cell lung cancer (NSCLC) cell lines.	('prevents', 'NegReg', (13, 21))	('NSCLC', 'Disease', 'MESH:D002289', (237, 242))	('EGFR', 'Gene', '1956', (56, 60))	('non-small cell lung cancer', 'Disease', (209, 235))	('epidermal growth factor receptor', 'Gene', (22, 54))	('glioblastoma', 'Disease', 'MESH:D005909', (186, 198))	('NSCLC', 'Disease', (237, 242))	('epidermal growth factor receptor', 'Gene', '1956', (22, 54))	('EGFR', 'Gene', (145, 149))	('lung cancer', 'Phenotype', 'HP:0100526', (224, 235))	('DYRK1A-dependent', 'Var', (128, 144))	('NSCLC', 'Phenotype', 'HP:0030358', (237, 242))	('glioblastoma', 'Disease', (186, 198))	('DYRK1A', 'Var', (6, 12))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (209, 235))	('glioblastoma', 'Phenotype', 'HP:0012174', (186, 198))	('EGFR', 'Gene', (56, 60))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (213, 235))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('GBM', 'Phenotype', 'HP:0012174', (200, 203))	('EGFR', 'Gene', '1956', (145, 149))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (209, 235))
332387	32751160	Given that RTKs are common targets in cancer therapy, the inhibition of DYRK1A (and its paralog DYRK1B) could be considered an element in combinatorial therapies to simultaneously target several deregulated RTKs.	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('RTK', 'Gene', '5979', (11, 14))	('RTK', 'Gene', (207, 210))	('inhibition', 'Var', (58, 68))	('DYRK1A', 'Gene', (72, 78))	('DYRK1B', 'Gene', (96, 102))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('DYRK1B', 'Gene', '9149', (96, 102))	('RTK', 'Gene', '5979', (207, 210))	('cancer', 'Disease', (38, 44))	('RTK', 'Gene', (11, 14))
332388	32751160	Finally, DYRK1A depletion reduces the levels of membrane-bound VEGF receptor 2 (VEGFR2), and it causes defects in VEGFR2-dependent signaling and the downstream NFAT-dependent transcriptional response in endothelial cells.	('NFAT', 'Gene', '32321', (160, 164))	('DYRK1A depletion', 'Var', (9, 25))	('VEGF receptor 2', 'Gene', (63, 78))	('depletion', 'Var', (16, 25))	('VEGFR2', 'Gene', '3791', (80, 86))	('VEGFR2', 'Gene', '3791', (114, 120))	('NFAT', 'Gene', (160, 164))	('levels of', 'MPA', (38, 47))	('VEGF receptor 2', 'Gene', '3791', (63, 78))	('VEGFR2', 'Gene', (80, 86))	('VEGFR2', 'Gene', (114, 120))	('reduces', 'NegReg', (26, 33))	('defects', 'NegReg', (103, 110))
332389	32751160	These results are correlated with the defects in developmental angiogenesis in a mouse model in which the Dyrk1a dosage is reduced, although whether DYRK1A has a proangiogenic role in the tumor microenvironment needs to be further explored.	('tumor', 'Disease', (188, 193))	('dosage', 'Var', (113, 119))	('developmental angiogenesis', 'CPA', (49, 75))	('Dyrk1a', 'Gene', (106, 112))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('mouse', 'Species', '10090', (81, 86))	('reduced', 'NegReg', (123, 130))
332393	32751160	Indeed, a weaker DYRK1A expression was correlated with a worse overall survival in breast cancer patients and a poorer prognosis in CRC and GBM patients, whereas more DYRK1A was associated with a reduced survival time in patients with lung cancer.	('CRC', 'Disease', (132, 135))	('patients', 'Species', '9606', (221, 229))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('CRC', 'Phenotype', 'HP:0003003', (132, 135))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('expression', 'MPA', (24, 34))	('GBM', 'Phenotype', 'HP:0012174', (140, 143))	('breast cancer', 'Phenotype', 'HP:0003002', (83, 96))	('CRC', 'Disease', 'MESH:D015179', (132, 135))	('weaker', 'NegReg', (10, 16))	('lung cancer', 'Disease', (235, 246))	('DYRK1A', 'Protein', (17, 23))	('breast cancer', 'Disease', 'MESH:D001943', (83, 96))	('breast cancer', 'Disease', (83, 96))	('patients', 'Species', '9606', (97, 105))	('worse', 'NegReg', (57, 62))	('lung cancer', 'Disease', 'MESH:D008175', (235, 246))	('DYRK1A', 'Var', (167, 173))	('patients', 'Species', '9606', (144, 152))	('lung cancer', 'Phenotype', 'HP:0100526', (235, 246))
332397	32751160	In cell models, DYRK1A knockdown or enzymatic inhibition reduced the proliferation of HNSCC cell lines, luminal/HER2 breast cancer or PDAC, as well as impaired the self-renewal capacity of GBM cells and compromised ovarian cancer spheroid cell viability.	('ovarian cancer', 'Phenotype', 'HP:0100615', (215, 229))	('GBM', 'Phenotype', 'HP:0012174', (189, 192))	('PDAC', 'Phenotype', 'HP:0006725', (134, 138))	('HER2', 'Gene', '2064', (112, 116))	('breast cancer', 'Phenotype', 'HP:0003002', (117, 130))	('proliferation', 'CPA', (69, 82))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('breast cancer', 'Disease', 'MESH:D001943', (117, 130))	('breast cancer', 'Disease', (117, 130))	('reduced', 'NegReg', (57, 64))	('ovarian cancer spheroid', 'Disease', 'MESH:C000598645', (215, 238))	('self-renewal capacity', 'CPA', (164, 185))	('HER2', 'Gene', (112, 116))	('ovarian cancer spheroid', 'Disease', (215, 238))	('impaired', 'NegReg', (151, 159))	('inhibition', 'Var', (46, 56))	('HNSCC', 'Phenotype', 'HP:0012288', (86, 91))	('knockdown', 'Var', (23, 32))	('compromised', 'NegReg', (203, 214))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('DYRK1A', 'Gene', (16, 22))
332400	32751160	The antitumor role of DYRK1A was suggested to be related to the lower incidence of cancer in DS individuals, deviating from that observed in the normal population.	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('lower', 'NegReg', (64, 69))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('DYRK1A', 'Var', (22, 28))	('tumor', 'Disease', (8, 13))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('cancer', 'Disease', (83, 89))
332403	32751160	In this regard, DYRK1A was proposed to be a potent, megakaryoblastic oncogene, suggesting that NFAT-negative regulation through an imbalance in DYRK1A might perturb myeloid differentiation and promote AMKL in DS individuals.	('DYRK1A', 'Gene', (144, 150))	('promote', 'PosReg', (193, 200))	('AMKL', 'CPA', (201, 205))	('imbalance', 'Var', (131, 140))	('perturb', 'NegReg', (157, 164))	('imbalance', 'Phenotype', 'HP:0002172', (131, 140))	('NFAT', 'Gene', '32321', (95, 99))	('NFAT', 'Gene', (95, 99))	('AMKL', 'Phenotype', 'HP:0006733', (201, 205))	('myeloid differentiation', 'CPA', (165, 188))
332405	32751160	Thus, more research is clearly required to fully understand how DYRK1A contributes to tumor initiation or progression.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor initiation', 'Disease', (86, 102))	('progression', 'CPA', (106, 117))	('DYRK1A', 'Var', (64, 70))	('contributes', 'Reg', (71, 82))	('tumor initiation', 'Disease', 'MESH:D009369', (86, 102))
332407	32751160	Although both kinases share substrates (Table 1), the distinct clinical outcome of inactivating mutations indicates they are not functionally redundant, i.e., a disorder within the autism spectrum for DYRK1A and a metabolic syndrome for DYRK1B (abdominal obesity metabolic syndrome-3, OMIM#615812).	('abdominal obesity', 'Phenotype', 'HP:0012743', (245, 262))	('autism', 'Phenotype', 'HP:0000717', (181, 187))	('inactivating mutations', 'Var', (83, 105))	('autism', 'Disease', 'MESH:D001321', (181, 187))	('obesity metabolic syndrome-3', 'Phenotype', 'HP:0025501', (255, 283))	('obesity', 'Phenotype', 'HP:0001513', (255, 262))	('autism', 'Disease', (181, 187))	('DYRK1B', 'Gene', (237, 243))	('DYRK1B', 'Gene', '9149', (237, 243))	('metabolic syndrome', 'Disease', (214, 232))	('abdominal obesity metabolic syndrome', 'Disease', 'MESH:C535554', (245, 281))	('metabolic syndrome', 'Disease', 'MESH:D024821', (214, 232))	('metabolic syndrome', 'Disease', 'MESH:D024821', (263, 281))	('abdominal obesity metabolic syndrome', 'Disease', (245, 281))
332412	32751160	Furthermore, we confirmed previous reports on the amplification of the DYRK1B genomic region (19q13.2) in ovarian cancer and PDAC (Table S1).	('DYRK1B', 'Gene', '9149', (71, 77))	('amplification', 'Var', (50, 63))	('ovarian cancer', 'Disease', 'MESH:D010051', (106, 120))	('ovarian cancer', 'Disease', (106, 120))	('PDAC', 'Phenotype', 'HP:0006725', (125, 129))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('PDAC', 'Disease', (125, 129))	('DYRK1B', 'Gene', (71, 77))	('ovarian cancer', 'Phenotype', 'HP:0100615', (106, 120))
332415	32751160	Several findings point to an antagonistic role of DYRK1B and MAPK signaling, with an increase in DYRK1B in response to inhibitors of the MAPK kinase (MEK) in CRC and melanoma cell lines and a reduction following the mitogen activation of the RAS-MEK-extracellular signal-regulated kinase (ERK) pathway in skeletal myoblasts.	('CRC', 'Disease', 'MESH:D015179', (158, 161))	('DYRK1B', 'Gene', '9149', (50, 56))	('DYRK1B', 'Gene', '9149', (97, 103))	('DYRK1B', 'Gene', (50, 56))	('melanoma', 'Phenotype', 'HP:0002861', (166, 174))	('melanoma', 'Disease', (166, 174))	('ERK', 'Gene', (289, 292))	('inhibitors', 'Var', (119, 129))	('mitogen', 'MPA', (216, 223))	('RAS-MEK-extracellular signal-regulated kinase', 'Gene', (242, 287))	('response', 'MPA', (107, 115))	('DYRK1B', 'Gene', (97, 103))	('increase', 'PosReg', (85, 93))	('CRC', 'Disease', (158, 161))	('RAS-MEK-extracellular signal-regulated kinase', 'Gene', '5594', (242, 287))	('MEK', 'Gene', '5609', (246, 249))	('reduction', 'NegReg', (192, 201))	('CRC', 'Phenotype', 'HP:0003003', (158, 161))	('MEK', 'Gene', '5609', (150, 153))	('melanoma', 'Disease', 'MESH:D008545', (166, 174))	('MEK', 'Gene', (246, 249))	('MEK', 'Gene', (150, 153))	('ERK', 'Gene', '5594', (289, 292))
332416	32751160	The cross-talk between DYRK1B and the MAPK pathway was further explored in ovarian cancer and NSCLC cell lines, where DYRK1B knockdown increased c-RAF and ERK activation.	('ovarian cancer', 'Disease', 'MESH:D010051', (75, 89))	('knockdown', 'Var', (125, 134))	('ERK', 'Gene', (155, 158))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('NSCLC', 'Disease', 'MESH:D002289', (94, 99))	('increased c-RAF', 'Phenotype', 'HP:0040178', (135, 150))	('c-RAF', 'Gene', (145, 150))	('ovarian cancer', 'Disease', (75, 89))	('NSCLC', 'Disease', (94, 99))	('ovarian cancer', 'Phenotype', 'HP:0100615', (75, 89))	('DYRK1B', 'Gene', '9149', (118, 124))	('activation', 'PosReg', (159, 169))	('NSCLC', 'Phenotype', 'HP:0030358', (94, 99))	('DYRK1B', 'Gene', '9149', (23, 29))	('c-RAF', 'Gene', '5894', (145, 150))	('ERK', 'Gene', '5594', (155, 158))	('DYRK1B', 'Gene', (118, 124))	('DYRK1B', 'Gene', (23, 29))	('increased', 'PosReg', (135, 144))
332417	32751160	This DYRK1B-MAPK cross-talk might be even more complex, since DYRK1B is an ERK substrate at a residue that potentiates DYRK1B activity, and accordingly, oncogenic KRAS mutants act as positive modulators of DYRK1B activity.	('DYRK1B', 'Gene', '9149', (5, 11))	('potentiates', 'PosReg', (107, 118))	('ERK', 'Gene', '5594', (75, 78))	('DYRK1B', 'Gene', (5, 11))	('DYRK1B', 'Gene', '9149', (119, 125))	('KRAS', 'Gene', (163, 167))	('ERK', 'Gene', (75, 78))	('DYRK1B', 'Gene', (119, 125))	('KRAS', 'Gene', '3845', (163, 167))	('DYRK1B', 'Gene', (62, 68))	('DYRK1B', 'Gene', '9149', (62, 68))	('DYRK1B', 'Gene', (206, 212))	('DYRK1B', 'Gene', '9149', (206, 212))	('activity', 'MPA', (126, 134))	('mutants', 'Var', (168, 175))
332423	32751160	In addition, the depletion or inhibition of DYRK1B enhances the DNA damage, apoptosis and sensitivity to reactive oxygen species (ROS) or chemotherapeutic drugs targeting proliferating cells, as well as the sensitivity to compounds that target pathways favoring proliferation in cell lines of different tumor origins, such as mTOR and MEK inhibitors (Figure 2).	('tumor', 'Disease', 'MESH:D009369', (303, 308))	('ROS', 'Chemical', 'MESH:D017382', (130, 133))	('MEK', 'Gene', '5609', (335, 338))	('DYRK1B', 'Gene', (44, 50))	('tumor', 'Phenotype', 'HP:0002664', (303, 308))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (105, 128))	('DYRK1B', 'Gene', '9149', (44, 50))	('apoptosis', 'CPA', (76, 85))	('sensitivity', 'MPA', (90, 101))	('DNA damage', 'MPA', (64, 74))	('tumor', 'Disease', (303, 308))	('depletion', 'Var', (17, 26))	('inhibition', 'NegReg', (30, 40))	('mTOR', 'Gene', '2475', (326, 330))	('sensitivity', 'MPA', (207, 218))	('mTOR', 'Gene', (326, 330))	('enhances', 'PosReg', (51, 59))	('MEK', 'Gene', (335, 338))
332425	32751160	Thus, DYRK1B knockdown negatively affects different aspects of ovarian cancer cell malignancy, including viability, proliferative potential and migratory capacity.	('viability', 'CPA', (105, 114))	('proliferative potential', 'CPA', (116, 139))	('ovarian cancer cell malignancy', 'Disease', 'MESH:D009369', (63, 93))	('migratory capacity', 'CPA', (144, 162))	('ovarian cancer', 'Phenotype', 'HP:0100615', (63, 77))	('ovarian cancer cell malignancy', 'Disease', (63, 93))	('DYRK1B', 'Gene', '9149', (6, 12))	('ovarian cancer cell malignancy', 'Phenotype', 'HP:0025318', (63, 93))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('DYRK1B', 'Gene', (6, 12))	('affects', 'Reg', (34, 41))	('negatively', 'NegReg', (23, 33))	('knockdown', 'Var', (13, 22))
332426	32751160	Likewise, DYRK1B knockdown negatively affects PDAC cell proliferation, migration and invasion, whereas a treatment of PANC1 xenografts with a DYRK1B inhibitor impairs tumor growth.	('PDAC', 'Phenotype', 'HP:0006725', (46, 50))	('negatively', 'NegReg', (27, 37))	('impairs tumor', 'Disease', 'MESH:D060825', (159, 172))	('PDAC cell proliferation', 'CPA', (46, 69))	('migration', 'CPA', (71, 80))	('DYRK1B', 'Gene', '9149', (142, 148))	('DYRK1B', 'Gene', (10, 16))	('invasion', 'CPA', (85, 93))	('affects', 'Reg', (38, 45))	('DYRK1B', 'Gene', '9149', (10, 16))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('knockdown', 'Var', (17, 26))	('PANC1', 'CellLine', 'CVCL:0480', (118, 123))	('DYRK1B', 'Gene', (142, 148))	('impairs tumor', 'Disease', (159, 172))
332430	32751160	The first hints that DYRK2 may influence carcinogenesis were derived from a genomic analysis and differential gene expression studies, highlighting DYRK2 overexpression in association with the amplification of its genomic locus in esophageal and lung adenocarcinomas, GIST, gastric adenocarcinoma and liposarcoma.	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (246, 265))	('lung adenocarcinomas', 'Disease', (246, 266))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (246, 266))	('GIST', 'Disease', (268, 272))	('amplification', 'Var', (193, 206))	('gastric adenocarcinoma and liposarcoma', 'Disease', 'MESH:D013274', (274, 312))	('liposarcoma', 'Phenotype', 'HP:0012034', (301, 312))	('overexpression', 'PosReg', (154, 168))	('DYRK2', 'Gene', (148, 153))	('carcinogenesis', 'Disease', 'MESH:D063646', (41, 55))	('carcinoma', 'Phenotype', 'HP:0030731', (256, 265))	('carcinoma', 'Phenotype', 'HP:0030731', (287, 296))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (246, 266))	('GIST', 'Phenotype', 'HP:0100723', (268, 272))	('influence', 'Reg', (31, 40))	('carcinogenesis', 'Disease', (41, 55))	('sarcoma', 'Phenotype', 'HP:0100242', (305, 312))
332435	32751160	An analysis of CNAs indicated that DYRK2 upregulation might be associated with gene amplification in BLCA, BRCA, LUAD, LUSC and STAD (Table S1).	('gene amplification', 'Var', (79, 97))	('BRCA', 'Gene', '672', (107, 111))	('BRCA', 'Gene', (107, 111))	('DYRK2', 'Gene', (35, 40))	('upregulation', 'PosReg', (41, 53))	('BLCA', 'Disease', (101, 105))
332440	32751160	Besides the alterations to the DYRK2 expression, it has been proposed that this kinase may represent a prognostic marker for different types of cancer, based on a correlation analysis between the gene/protein expressions and distinct clinical features like the degree of malignancy, relapse, response to chemotherapy or patient survival.	('alterations', 'Var', (12, 23))	('malignancy', 'Disease', (271, 281))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('patient', 'Species', '9606', (320, 327))	('cancer', 'Disease', (144, 150))	('DYRK2', 'Gene', (31, 36))	('relapse', 'Disease', (283, 290))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('malignancy', 'Disease', 'MESH:D009369', (271, 281))
332444	32751160	As such, DYRK2 protein levels were shown to inversely correlate with tumor invasiveness, and enhanced 10-year disease-free survival was evident in DYRK2-positive breast cancer patients when compared to DYRK2-negative patients, while a stronger DYRK2 mRNA expression was associated with a worse prognosis in another study of breast cancer patients.	('patients', 'Species', '9606', (176, 184))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor invasiveness', 'Disease', (69, 87))	('tumor invasiveness', 'Disease', 'MESH:D009361', (69, 87))	('patients', 'Species', '9606', (217, 225))	('DYRK2 protein levels', 'MPA', (9, 29))	('breast cancer', 'Phenotype', 'HP:0003002', (324, 337))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('breast cancer', 'Disease', 'MESH:D001943', (162, 175))	('disease-free survival', 'CPA', (110, 131))	('enhanced', 'PosReg', (93, 101))	('breast cancer', 'Disease', 'MESH:D001943', (324, 337))	('breast cancer', 'Phenotype', 'HP:0003002', (162, 175))	('cancer', 'Phenotype', 'HP:0002664', (331, 337))	('breast cancer', 'Disease', (162, 175))	('breast cancer', 'Disease', (324, 337))	('patients', 'Species', '9606', (338, 346))	('DYRK2-positive', 'Var', (147, 161))
332445	32751160	This model is consistent with experimental data when DYRK2 levels are manipulated in carcinoma cell lines (ovary, CRC and HCC) that are then used as xenografts in mice, whereby DYRK2 gene silencing confers an enhanced proliferative capacity and metastatic potential in vivo.	('gene silencing', 'Var', (183, 197))	('carcinoma', 'Disease', (85, 94))	('proliferative capacity', 'CPA', (218, 240))	('carcinoma', 'Disease', 'MESH:D009369', (85, 94))	('metastatic potential', 'CPA', (245, 265))	('enhanced', 'PosReg', (209, 217))	('CRC', 'Phenotype', 'HP:0003003', (114, 117))	('CRC', 'Disease', 'MESH:D015179', (114, 117))	('mice', 'Species', '10090', (163, 167))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('HCC', 'Phenotype', 'HP:0001402', (122, 125))	('DYRK2', 'Gene', (177, 182))	('CRC', 'Disease', (114, 117))
332449	32751160	Moreover, the DNA-methyltransferase 1-dependent methylation of the DYRK2 promoter provokes transcriptional downregulation that may influence DYRK2 expression in CRC cells.	('DNA-methyltransferase 1', 'Gene', '1786', (14, 37))	('CRC', 'Disease', 'MESH:D015179', (161, 164))	('DNA-methyltransferase 1', 'Gene', (14, 37))	('CRC', 'Phenotype', 'HP:0003003', (161, 164))	('expression', 'MPA', (147, 157))	('DYRK2', 'Gene', (67, 72))	('transcriptional', 'MPA', (91, 106))	('DYRK2', 'Gene', (141, 146))	('downregulation', 'NegReg', (107, 121))	('CRC', 'Disease', (161, 164))	('methylation', 'Var', (48, 59))	('influence', 'Reg', (131, 140))
332457	32751160	The relevance of this interaction is highlighted by the alterations in the assembly of the EDVP complex detected in the analysis of certain DYRK2 mutants found in cancer samples.	('DYRK2', 'Gene', (140, 145))	('alterations', 'Reg', (56, 67))	('mutants', 'Var', (146, 153))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('cancer', 'Disease', (163, 169))	('cancer', 'Disease', 'MESH:D009369', (163, 169))	('assembly', 'MPA', (75, 83))
332458	32751160	In addition, it is worth noting that many of the proteins that are degraded following DYRK2 phosphorylation are targets of the tumor suppressor F-box/WD repeat-containing protein 7 (FBXW7) (Figure 5A), suggesting possible cross-talk with E3 ubiquitin ligase protein complexes made up of this factor.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('proteins', 'Protein', (49, 57))	('DYRK2', 'Var', (86, 91))	('F-box/WD repeat-containing protein 7', 'Gene', (144, 180))	('tumor', 'Disease', (127, 132))	('FBXW7', 'Gene', '55294', (182, 187))	('FBXW7', 'Gene', (182, 187))	('F-box/WD repeat-containing protein 7', 'Gene', '55294', (144, 180))	('phosphorylation', 'Var', (92, 107))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('degraded', 'NegReg', (67, 75))
332461	32751160	In conjunction with the reduced expression of DYRK2 in tumor samples, DYRK2 depletion promotes the proliferation of cell lines originating from distinct tumor types, including breast, lymphoma, osteosarcoma, CRC and HCC, suggesting that DYRK2 may acts as a brake on proliferation.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('promotes', 'PosReg', (86, 94))	('depletion', 'Var', (76, 85))	('sarcoma', 'Phenotype', 'HP:0100242', (199, 206))	('lymphoma', 'Phenotype', 'HP:0002665', (184, 192))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('CRC', 'Disease', 'MESH:D015179', (208, 211))	('tumor', 'Disease', (153, 158))	('DYRK2', 'Gene', (70, 75))	('osteosarcoma', 'Disease', (194, 206))	('osteosarcoma', 'Disease', 'MESH:D012516', (194, 206))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('CRC', 'Disease', (208, 211))	('breast', 'Disease', (176, 182))	('CRC', 'Phenotype', 'HP:0003003', (208, 211))	('lymphoma', 'Disease', (184, 192))	('lymphoma', 'Disease', 'MESH:D008223', (184, 192))	('proliferation', 'CPA', (99, 112))	('tumor', 'Disease', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('HCC', 'Disease', (216, 219))	('osteosarcoma', 'Phenotype', 'HP:0002669', (194, 206))	('HCC', 'Phenotype', 'HP:0001402', (216, 219))
332462	32751160	In this regard, DYRK2 phosphorylates the oncogenic pro-proliferative transcription factors c-Jun and Myc, increasing their rate of degradation.	('c-Jun', 'Gene', '3725', (91, 96))	('DYRK2', 'Var', (16, 21))	('c-Jun', 'Gene', (91, 96))	('increasing', 'PosReg', (106, 116))	('Myc', 'Gene', '4609', (101, 104))	('Myc', 'Gene', (101, 104))	('rate of degradation', 'MPA', (123, 142))
332466	32751160	The interaction between DYRK2 and the E3 ubiquitin ligase RNF8 was proposed to influence DYRK2 recruitment to the DNA repair machinery, and the phosphorylation of p53 by DYRK2 promotes apoptosis in response to DNA damage, with ATM acting upstream by increasing the DYRK2 nuclear accumulation.	('interaction', 'Interaction', (4, 15))	('increasing', 'PosReg', (250, 260))	('promotes', 'PosReg', (176, 184))	('response to DNA damage', 'MPA', (198, 220))	('ATM', 'Gene', '472', (227, 230))	('p53', 'Gene', (163, 166))	('RNF8', 'Gene', '9025', (58, 62))	('apoptosis', 'CPA', (185, 194))	('phosphorylation', 'Var', (144, 159))	('influence', 'Reg', (79, 88))	('DYRK2', 'Gene', (170, 175))	('RNF8', 'Gene', (58, 62))	('nuclear accumulation', 'MPA', (271, 291))	('ATM', 'Gene', (227, 230))
332467	32751160	The modulation of p53 and Myc was also proposed as a DYRK2-mediated mechanism in leukemia stem cells and CML cell lines.	('leukemia', 'Phenotype', 'HP:0001909', (81, 89))	('leukemia', 'Disease', 'MESH:D007938', (81, 89))	('CML', 'Disease', (105, 108))	('leukemia', 'Disease', (81, 89))	('modulation', 'Var', (4, 14))	('CML', 'Disease', 'MESH:D015464', (105, 108))	('CML', 'Phenotype', 'HP:0005506', (105, 108))	('p53', 'Protein', (18, 21))	('Myc', 'Gene', '4609', (26, 29))	('Myc', 'Gene', (26, 29))
332468	32751160	The putative regulatory activity during DDR and/or the ability of DYRK2 to increase components of the xenobiotic response system, such as the PXR/NR1I2 nuclear receptor (Figure 5A), may contribute to enhance the resistance to chemotherapy drugs observed upon DYRK2 silencing.	('DYRK2', 'Var', (66, 71))	('silencing', 'Var', (265, 274))	('resistance to chemotherapy drugs', 'MPA', (212, 244))	('DDR', 'Disease', (40, 43))	('components of the xenobiotic response system', 'MPA', (84, 128))	('regulatory activity', 'MPA', (13, 32))	('PXR', 'Gene', (142, 145))	('increase', 'PosReg', (75, 83))	('enhance', 'PosReg', (200, 207))	('PXR', 'Gene', '8856', (142, 145))
332470	32751160	In this regard, DYRK2 phosphorylates the EMT transcription factor Snail, priming it for ubiquitination-mediated degradation (Figure 5A), which provides additional evidence that DYRK2 prevents the activation of aggressive phenotypes in breast and ovarian cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (254, 260))	('breast and ovarian cancer', 'Disease', 'MESH:D001943', (235, 260))	('ubiquitination-mediated degradation', 'MPA', (88, 123))	('Snail', 'Gene', (66, 71))	('DYRK2', 'Var', (177, 182))	('Snail', 'Gene', '6615', (66, 71))	('ovarian cancer', 'Phenotype', 'HP:0100615', (246, 260))	('prevents', 'NegReg', (183, 191))
332474	32751160	Similarly, DYRK2 silencing increased the invasion, metastasis and breast cancer cell stemness.	('metastasis', 'CPA', (51, 61))	('increased', 'PosReg', (27, 36))	('breast cancer cell stemness', 'Disease', (66, 93))	('DYRK2', 'Gene', (11, 16))	('invasion', 'CPA', (41, 49))	('breast cancer cell stemness', 'Disease', 'MESH:D001943', (66, 93))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('breast cancer', 'Phenotype', 'HP:0003002', (66, 79))	('silencing', 'Var', (17, 26))
332475	32751160	Conversely, using a clustered regularly interspaced short palindromic repeats (CRISPR)-based approach to generate DYRK2-knock out MDA-MB-468 breast cancer cells, DYRK2 was seen to promote breast cancer cell proliferation and tumor growth in xenografts.	('tumor', 'Disease', 'MESH:D009369', (225, 230))	('breast cancer', 'Disease', 'MESH:D001943', (188, 201))	('DYRK2', 'Var', (162, 167))	('breast cancer', 'Phenotype', 'HP:0003002', (188, 201))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('breast cancer', 'Disease', (188, 201))	('MDA-MB-468', 'CellLine', 'CVCL:0419', (130, 140))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('tumor', 'Disease', (225, 230))	('breast cancer', 'Disease', 'MESH:D001943', (141, 154))	('breast cancer', 'Disease', (141, 154))	('breast cancer', 'Phenotype', 'HP:0003002', (141, 154))	('promote', 'PosReg', (180, 187))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
332477	32751160	In this context, two DYRK2 inhibitors, the natural drug curcumin and the small-molecule LDN192960, impaired cell proliferation and invasion and induced apoptosis in multiple myeloma and TNBC cell lines.	('multiple myeloma', 'Disease', (165, 181))	('invasion', 'CPA', (131, 139))	('TNBC', 'Disease', 'None', (186, 190))	('LDN192960', 'Var', (88, 97))	('TNBC', 'Disease', (186, 190))	('DYRK2', 'Protein', (21, 26))	('induced', 'Reg', (144, 151))	('impaired', 'NegReg', (99, 107))	('cell proliferation', 'CPA', (108, 126))	('apoptosis', 'CPA', (152, 161))	('curcumin', 'Chemical', 'MESH:D003474', (56, 64))	('multiple myeloma', 'Phenotype', 'HP:0006775', (165, 181))	('LDN192960', 'Chemical', '-', (88, 97))	('multiple myeloma', 'Disease', 'MESH:D009101', (165, 181))
332487	32751160	In addition, manipulating the DYRK3 expression in HCC cells demonstrated an inverse correlation with proliferation rates both in vitro and in tumor xenograft models, as well as with the metastatic potential of the tumor cells, further evidencing that DYRK3 fulfills a tumor-suppressor role in this type of cancer.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('cancer', 'Disease', 'MESH:D009369', (306, 312))	('tumor', 'Phenotype', 'HP:0002664', (268, 273))	('metastatic potential', 'CPA', (186, 206))	('inverse', 'NegReg', (76, 83))	('tumor', 'Disease', (142, 147))	('DYRK3', 'Gene', (30, 35))	('DYRK3', 'Gene', (251, 256))	('tumor', 'Disease', (214, 219))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('cancer', 'Disease', (306, 312))	('tumor', 'Disease', 'MESH:D009369', (214, 219))	('cancer', 'Phenotype', 'HP:0002664', (306, 312))	('tumor', 'Disease', (268, 273))	('HCC', 'Phenotype', 'HP:0001402', (50, 53))	('manipulating', 'Var', (13, 25))	('DYRK3', 'Gene', '8444', (30, 35))	('proliferation rates', 'CPA', (101, 120))	('DYRK3', 'Gene', '8444', (251, 256))	('tumor', 'Disease', 'MESH:D009369', (268, 273))
332494	32751160	In the case of DYRK1A, the search for both naturally occurring and synthetic inhibitors has been extensive given that DYRK1A may be a potential pharmacological target not only in cancer but, also, in neurodegenerative diseases (reviewed in), DS and diabetes (reviewed in).	('DYRK1A', 'Var', (118, 124))	('neurodegenerative diseases', 'Disease', 'MESH:D019636', (200, 226))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('neurodegenerative diseases', 'Disease', (200, 226))	('neurodegenerative diseases', 'Phenotype', 'HP:0002180', (200, 226))	('diabetes', 'Disease', 'MESH:D003920', (249, 257))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('diabetes', 'Disease', (249, 257))	('cancer', 'Disease', (179, 185))
332503	32751160	For instance, the DYRK1B inhibitor AZ191 increases the anticancer effects of doxorubicin in liposarcoma cell lines or sensitizes the PDAC cell lines to mTOR inhibition.	('sarcoma', 'Phenotype', 'HP:0100242', (96, 103))	('liposarcoma', 'Disease', (92, 103))	('mTOR', 'Gene', (152, 156))	('AZ191', 'Var', (35, 40))	('sensitizes', 'Reg', (118, 128))	('increases', 'PosReg', (41, 50))	('DYRK1B', 'Gene', '9149', (18, 24))	('mTOR', 'Gene', '2475', (152, 156))	('liposarcoma', 'Disease', 'MESH:D008080', (92, 103))	('doxorubicin', 'Chemical', 'MESH:D004317', (77, 88))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('PDAC', 'Phenotype', 'HP:0006725', (133, 137))	('liposarcoma', 'Phenotype', 'HP:0012034', (92, 103))	('AZ191', 'Chemical', '-', (35, 40))	('DYRK1B', 'Gene', (18, 24))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))
332504	32751160	However, AZ191 has been also shown to counteract the antitumor effects of the lysosome inhibitor Bafilomycin A1 in HCC cell lines.	('HCC', 'Phenotype', 'HP:0001402', (115, 118))	('Bafilomycin A1', 'Chemical', 'MESH:C040929', (97, 111))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('AZ191', 'Var', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Disease', (57, 62))	('AZ191', 'Chemical', '-', (9, 14))
332506	32751160	Finally, better understanding the role of DYRKs in tumor cells has proven valuable by helping to identify combinatorial therapeutic approaches, as in the cases of the DYRK1B inhibitors that enhance the inhibitory efficiency of MEK and mTOR or DYRK2 inhibition sensitizing MDA-MB-468 cells to the proteasome inhibitor bortezomib.	('DYRK1B', 'Gene', '9149', (167, 173))	('DYRK', 'Gene', '1859', (42, 46))	('mTOR', 'Gene', '2475', (235, 239))	('inhibitory efficiency', 'MPA', (202, 223))	('enhance', 'PosReg', (190, 197))	('DYRK', 'Gene', '1859', (167, 171))	('DYRK1B', 'Gene', (167, 173))	('inhibition', 'Var', (249, 259))	('tumor', 'Disease', (51, 56))	('DYRK', 'Gene', (42, 46))	('inhibitors', 'Var', (174, 184))	('bortezomib', 'Chemical', 'MESH:D000069286', (317, 327))	('MEK', 'Gene', '5609', (227, 230))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('DYRK', 'Gene', (167, 171))	('sensitizing', 'Reg', (260, 271))	('MDA-MB-468', 'CellLine', 'CVCL:0419', (272, 282))	('MEK', 'Gene', (227, 230))	('DYRK', 'Gene', '1859', (243, 247))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('mTOR', 'Gene', (235, 239))	('DYRK', 'Gene', (243, 247))
332509	32751160	In particular, compound CX-4945 was initially identified as a casein kinase 2 inhibitor, but it was subsequently shown to be a potent DYRK1A and DYRK1B inhibitor, and it is currently in phase I and II clinical studies for medulloblastoma, cholangiocarcinoma and basal cell carcinoma (NCT02128282, NCT03904862 and NCT03897036).	('medulloblastoma', 'Disease', 'MESH:D008527', (222, 237))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (262, 282))	('cholangiocarcinoma and basal cell carcinoma', 'Disease', 'MESH:D002280', (239, 282))	('NCT03904862', 'Var', (297, 308))	('NCT03897036', 'Var', (313, 324))	('medulloblastoma', 'Phenotype', 'HP:0002885', (222, 237))	('CX-4945', 'Chemical', 'MESH:C555142', (24, 31))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (239, 257))	('medulloblastoma', 'Disease', (222, 237))	('carcinoma', 'Phenotype', 'HP:0030731', (273, 282))	('NCT02128282', 'Var', (284, 295))	('DYRK1B', 'Gene', '9149', (145, 151))	('DYRK1B', 'Gene', (145, 151))	('carcinoma', 'Phenotype', 'HP:0030731', (248, 257))	('CX-4945', 'Var', (24, 31))
332512	32751160	Finally, two other DYRK inhibitors have been assessed in clinical trials for non-neoplastic disorders: GSK-626616 completed a phase I clinical trial to evaluate its action on anemia (NCT00443170), and lorecivivint, a potent CLK2 inhibitor that also inhibits DYRK1A, is being studied in a phase II trial for the treatment of moderate-to-severe symptomatic osteoarthritis (NCT03706521).	('osteoarthritis', 'Disease', 'MESH:D010003', (355, 369))	('non-neoplastic disorders', 'Disease', (77, 101))	('non-neoplastic disorders', 'Disease', 'MESH:C580335', (77, 101))	('DYRK', 'Gene', (258, 262))	('anemia', 'Disease', (175, 181))	('lorecivivint', 'Chemical', 'MESH:C000627701', (201, 213))	('NCT00443170', 'Var', (183, 194))	('DYRK', 'Gene', (19, 23))	('NCT03706521', 'Var', (371, 382))	('osteoarthritis', 'Phenotype', 'HP:0002758', (355, 369))	('CLK2', 'Gene', (224, 228))	('osteoarthritis', 'Disease', (355, 369))	('anemia', 'Disease', 'MESH:D000740', (175, 181))	('GSK-626616', 'Chemical', '-', (103, 113))	('inhibits', 'NegReg', (249, 257))	('DYRK', 'Gene', '1859', (258, 262))	('CLK2', 'Gene', '1196', (224, 228))	('DYRK', 'Gene', '1859', (19, 23))	('anemia', 'Phenotype', 'HP:0001903', (175, 181))
332515	32751160	However, this evidence mostly comes from studies exploring DYRK expressions in tumor tissues and/or the phenotypic changes triggered by manipulating the DYRK protein in cancer cell lines.	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('cancer', 'Disease', (169, 175))	('DYRK', 'Gene', '1859', (59, 63))	('tumor', 'Disease', (79, 84))	('DYRK', 'Gene', (59, 63))	('manipulating', 'Var', (136, 148))	('DYRK', 'Gene', '1859', (153, 157))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('DYRK', 'Gene', (153, 157))	('cancer', 'Disease', 'MESH:D009369', (169, 175))
332520	32751160	Nevertheless, putative side effects due to the inhibition of members that are essential to maintaining cellular homeostasis in normal cells, such as the dosage-sensitive DYRK1A or DYRK1B, should be carefully monitored.	('DYRK1A', 'Var', (170, 176))	('DYRK1B', 'Gene', '9149', (180, 186))	('DYRK1B', 'Gene', (180, 186))
332529	29884221	In the cancer context, tICA identifies gene modules whose expression variation across tumours is driven by copy-number or DNA methylation changes, but whose deregulation relative to normal tissue is independent of such alterations, a result we validate by direct analysis of individual data types.	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('expression', 'MPA', (58, 68))	('tumour', 'Phenotype', 'HP:0002664', (86, 92))	('driven', 'Reg', (97, 103))	('tumours', 'Phenotype', 'HP:0002664', (86, 93))	('DNA', 'MPA', (122, 125))	('copy-number', 'Var', (107, 118))	('ICA', 'Chemical', '-', (24, 27))	('tumours', 'Disease', 'MESH:D009369', (86, 93))	('cancer', 'Disease', (7, 13))	('cancer', 'Disease', 'MESH:D009369', (7, 13))	('changes', 'Var', (138, 145))	('tumours', 'Disease', (86, 93))
332535	29884221	We further illustrate potential uses of our tensorial BSS algorithm (i) to detect cell-type-independent and cell-type-specific methylation quantitative trait loci (mQTLs) in multi-cell-type or multi-tissue EWAS and (ii) to detect cancer gene modules deregulated by copy-number and DNA methylation changes.	('detect', 'Reg', (223, 229))	('cancer', 'Disease', 'MESH:D009369', (230, 236))	('copy-number', 'Var', (265, 276))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('cancer', 'Disease', (230, 236))	('tensorial BSS algorithm', 'Disease', 'MESH:C537908', (44, 67))	('tensorial BSS algorithm', 'Disease', (44, 67))
332562	29884221	As expected, with an increase in the number of CpGs, the SE of all algorithms dropped, likely driven by increased confounding due to genetic variation (Fig.	('SE', 'Disease', 'None', (57, 59))	('CpGs', 'Var', (47, 51))	('dropped', 'NegReg', (78, 85))
332563	29884221	With the increase in probe number, tICA (tWFOBI and tWJADE) outperformed not only JIVE, PARAFAC and CCA/SCCA, but also tPCA (Fig.	('ICA', 'Chemical', '-', (36, 39))	('outperformed', 'PosReg', (60, 72))	('increase', 'PosReg', (9, 17))	('probe number', 'Var', (21, 33))
332586	29884221	Strikingly, we observed that while variations in copy number and DNAm of STX6 modulate expression differences between colon cancers, that the deregulation of STX6 expression between normal and cancer is clearly independent of copy-number and DNAm state (Fig.	('colon cancers', 'Disease', (118, 131))	('cancer', 'Disease', (193, 199))	('variations', 'Var', (35, 45))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('cancer', 'Disease', 'MESH:D009369', (124, 130))	('STX6', 'Gene', (158, 162))	('STX6', 'Gene', '10228', (158, 162))	('colon cancer', 'Phenotype', 'HP:0003003', (118, 130))	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('expression differences', 'MPA', (87, 109))	('colon cancers', 'Phenotype', 'HP:0003003', (118, 131))	('cancers', 'Phenotype', 'HP:0002664', (124, 131))	('cancer', 'Disease', (124, 130))	('STX6', 'Gene', (73, 77))	('modulate', 'Reg', (78, 86))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('colon cancers', 'Disease', 'MESH:D015179', (118, 131))	('expression', 'MPA', (163, 173))	('STX6', 'Gene', '10228', (73, 77))
332589	29884221	For those overexpressed in cancer, we then asked if individual tumours exhibiting a neutral CNV state (the CNV state of the normal samples) or a CNV loss still exhibited overexpression relative to the normal samples.	('tumours', 'Disease', (63, 70))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('overexpression', 'MPA', (170, 184))	('loss', 'NegReg', (149, 153))	('tumour', 'Phenotype', 'HP:0002664', (63, 69))	('tumours', 'Phenotype', 'HP:0002664', (63, 70))	('CNV', 'Var', (145, 148))	('cancer', 'Disease', (27, 33))	('cancer', 'Disease', 'MESH:D009369', (27, 33))	('tumours', 'Disease', 'MESH:D009369', (63, 70))
332592	29884221	Indeed, restricting to cancers with neutral or copy-number gain (Fig.	('cancers', 'Disease', 'MESH:D009369', (23, 30))	('cancers', 'Phenotype', 'HP:0002664', (23, 30))	('cancers', 'Disease', (23, 30))	('copy-number gain', 'Var', (47, 63))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))
332599	29884221	This was demonstrated not only on simulated data, but also in the context of two real EWAS, where tICA methods were significantly more powerful in detecting differentially methylated CpGs associated with an epidemiological factor (smoking) and single-nucleotide polymorphisms (SNPs; mQTLs).	('single-nucleotide polymorphisms', 'Var', (244, 275))	('associated', 'Reg', (188, 198))	('CpGs', 'Gene', (183, 187))	('differentially methylated', 'MPA', (157, 182))	('ICA', 'Chemical', '-', (99, 102))
332615	29884221	In other words, although CNV and DNAm variation strongly modulates expression variation of these DEGs across individuals tumours, for most of the genes exhibiting this CNV or DNAm dosage-dependent expression pattern, their deregulation relative to normal cells appears to be independent of the underlying CNV or promoter DNAm state.	('tumours', 'Disease', 'MESH:D009369', (121, 128))	('tumours', 'Disease', (121, 128))	('tumour', 'Phenotype', 'HP:0002664', (121, 127))	('variation', 'Var', (38, 47))	('expression variation', 'MPA', (67, 87))	('modulates', 'Reg', (57, 66))	('tumours', 'Phenotype', 'HP:0002664', (121, 128))
332698	33115703	Inhibition of autophagy may be a novel clinical treatment strategy to surmount the antagonistic effects between the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) (EGFR-TKIs) and chemotherapeutic agents.	('autophagy', 'CPA', (14, 23))	('EGFR', 'Gene', '1956', (189, 193))	('epidermal growth factor receptor', 'Gene', (116, 148))	('EGFR', 'Gene', (150, 154))	('epidermal growth factor receptor', 'Gene', '1956', (116, 148))	('EGFR', 'Gene', (189, 193))	('Inhibition', 'Var', (0, 10))	('EGFR', 'Gene', '1956', (150, 154))
332701	33115703	It has been reported that HA15 played an anti-tumor role in melanoma, breast, pancreatic and adrenocortical carcinoma, even overcoming drug resistance.	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('drug resistance', 'MPA', (135, 150))	('pancreatic and adrenocortical carcinoma', 'Disease', 'MESH:D018268', (78, 117))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('breast', 'Disease', (70, 76))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (93, 117))	('tumor', 'Disease', (46, 51))	('HA15', 'Var', (26, 30))	('melanoma', 'Disease', 'MESH:D008545', (60, 68))	('melanoma', 'Disease', (60, 68))	('melanoma', 'Phenotype', 'HP:0002861', (60, 68))	('overcoming', 'PosReg', (124, 134))	('drug resistance', 'Phenotype', 'HP:0020174', (135, 150))	('HA15', 'Chemical', '-', (26, 30))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
332704	33115703	Our data suggest that GRP78 plays a pro-survival role in human lung cancer cells and is related to poor prognosis; inhibition of GRP78 by HA15 might be effective as a novel therapy in clinical settings.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('lung cancer', 'Disease', 'MESH:D008175', (63, 74))	('HA15', 'Chemical', '-', (138, 142))	('lung cancer', 'Disease', (63, 74))	('lung cancer', 'Phenotype', 'HP:0100526', (63, 74))	('inhibition', 'Var', (115, 125))	('GRP78', 'Protein', (129, 134))	('human', 'Species', '9606', (57, 62))
332712	33115703	We found that, compared with the control group (0 muM), the viability of HA15-treated lung cancer cells decreased significantly with increasing concentrations of HA15 (Fig.	('viability', 'CPA', (60, 69))	('HA15', 'Chemical', '-', (162, 166))	('HA15', 'Chemical', '-', (73, 77))	('decreased', 'NegReg', (104, 113))	('lung cancer', 'Phenotype', 'HP:0100526', (86, 97))	('lung cancer', 'Disease', (86, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('HA15', 'Var', (162, 166))	('lung cancer', 'Disease', 'MESH:D008175', (86, 97))
332715	33115703	To further explore the role of GRP78 in lung cancer cells, we used the EdU assay and flow cytometry to analyze the proliferation rates, cell cycle arrests and apoptosis rates of A549, H460, and H1975 cells after treatment with 10 muM HA15 for 24 h. We found that the proliferation of all lung cancer cells was inhibited by HA15 (Fig.	('lung cancer', 'Disease', (288, 299))	('A549', 'CellLine', 'CVCL:0023', (178, 182))	('HA15', 'Chemical', '-', (234, 238))	('lung cancer', 'Phenotype', 'HP:0100526', (288, 299))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('EdU', 'Chemical', '-', (71, 74))	('HA15', 'Chemical', '-', (323, 327))	('H1975', 'CellLine', 'CVCL:1511', (194, 199))	('lung cancer', 'Disease', 'MESH:D008175', (288, 299))	('lung cancer', 'Disease', 'MESH:D008175', (40, 51))	('proliferation', 'CPA', (267, 280))	('H460', 'CellLine', 'CVCL:0459', (184, 188))	('cancer', 'Phenotype', 'HP:0002664', (293, 299))	('inhibited', 'NegReg', (310, 319))	('lung cancer', 'Disease', (40, 51))	('lung cancer', 'Phenotype', 'HP:0100526', (40, 51))	('HA15', 'Var', (323, 327))
332721	33115703	5C) cells were significantly higher in HA15-treated cells than the respective control groups.	('higher', 'PosReg', (29, 35))	('HA15-treated', 'Var', (39, 51))	('HA15', 'Chemical', '-', (39, 43))
332728	33115703	6D), electron microscopy revealed that the A549 cells exposed to HA15 (10 muM) displayed typically dilated ER cisternae, a classical feature of ER stress (Fig.	('dilated', 'Reg', (99, 106))	('stress', 'Disease', 'MESH:D000079225', (147, 153))	('stress', 'Disease', (147, 153))	('HA15', 'Chemical', '-', (65, 69))	('ER', 'Gene', '2069', (144, 146))	('ER', 'Gene', '2069', (107, 109))	('HA15', 'Var', (65, 69))	('A549', 'CellLine', 'CVCL:0023', (43, 47))
332733	33115703	Furthermore, HA15 upregulated the protein expression of Beclin-1, which is essential for initiating the formation of the autophagosome in autophagy.	('protein expression', 'MPA', (34, 52))	('HA15', 'Var', (13, 17))	('Beclin-1', 'Gene', (56, 64))	('upregulated', 'PosReg', (18, 29))	('Beclin-1', 'Gene', '8678', (56, 64))	('HA15', 'Chemical', '-', (13, 17))
332734	33115703	At the same time, the protein expression of p62 was downregulated by HA15, which indirectly reflects the decreased level of autophagosome clearance.	('HA15', 'Chemical', '-', (69, 73))	('downregulated', 'NegReg', (52, 65))	('p62', 'Gene', (44, 47))	('p62', 'Gene', '23636', (44, 47))	('HA15', 'Var', (69, 73))	('protein expression', 'MPA', (22, 40))	('decreased', 'NegReg', (105, 114))
332740	33115703	Furthermore, inhibition of GRP78 by HA15 significantly decreased the viability of A549, H460, and H1975 cells in a dose- and time-dependent manner.	('HA15', 'Var', (36, 40))	('GRP78', 'Protein', (27, 32))	('viability', 'CPA', (69, 78))	('decreased', 'NegReg', (55, 64))	('HA15', 'Chemical', '-', (36, 40))	('inhibition', 'NegReg', (13, 23))	('H1975', 'CellLine', 'CVCL:1511', (98, 103))	('A549', 'CellLine', 'CVCL:0023', (82, 86))	('H460', 'CellLine', 'CVCL:0459', (88, 92))
332741	33115703	HA15 inhibited A549, H460, and H1975 cell proliferation and promoted apoptosis.	('A549', 'CPA', (15, 19))	('inhibited', 'NegReg', (5, 14))	('HA15', 'Chemical', '-', (0, 4))	('promoted', 'PosReg', (60, 68))	('H460', 'CellLine', 'CVCL:0459', (21, 25))	('H1975', 'CellLine', 'CVCL:1511', (31, 36))	('HA15', 'Var', (0, 4))	('A549', 'CellLine', 'CVCL:0023', (15, 19))	('apoptosis', 'CPA', (69, 78))
332742	33115703	ER stress and autophagy were triggered by HA15 in A549 cells and these processes were involved in HA15-induced apoptosis.	('stress', 'Disease', (3, 9))	('autophagy', 'CPA', (14, 23))	('HA15', 'Chemical', '-', (98, 102))	('stress', 'Disease', 'MESH:D000079225', (3, 9))	('HA15', 'Chemical', '-', (42, 46))	('A549', 'CellLine', 'CVCL:0023', (50, 54))	('involved', 'Reg', (86, 94))	('triggered', 'Reg', (29, 38))	('ER', 'Gene', '2069', (0, 2))	('HA15', 'Var', (42, 46))
332743	33115703	It has been reported that high expression of GRP78 could promote tumorigenesis and drug resistance, and inhibition of GRP78 could improve the efficacy of chemotherapy drugs.	('improve', 'PosReg', (130, 137))	('high expression', 'Var', (26, 41))	('tumor', 'Disease', (65, 70))	('promote', 'PosReg', (57, 64))	('drug resistance', 'CPA', (83, 98))	('drug resistance', 'Phenotype', 'HP:0020174', (83, 98))	('GRP78', 'Protein', (45, 50))	('GRP78', 'Gene', (118, 123))	('inhibition', 'Var', (104, 114))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('efficacy of chemotherapy drugs', 'CPA', (142, 172))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
332746	33115703	It has been reported that HA15, a novel inhibitor targeting GRP78, could upregulate ER stress levels in malignant pleural mesothelioma cells, induce the pro-apoptotic UPR and autophagy, and induce cell death.	('ER', 'Gene', '2069', (84, 86))	('cell death', 'CPA', (197, 207))	('pro-apoptotic UPR', 'CPA', (153, 170))	('stress', 'Disease', (87, 93))	('HA15', 'Var', (26, 30))	('stress', 'Disease', 'MESH:D000079225', (87, 93))	('malignant pleural mesothelioma', 'Disease', (104, 134))	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (104, 134))	('induce', 'Reg', (190, 196))	('induce', 'PosReg', (142, 148))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (114, 134))	('GRP78', 'Gene', (60, 65))	('HA15', 'Chemical', '-', (26, 30))	('upregulate', 'PosReg', (73, 83))	('autophagy', 'CPA', (175, 184))
332747	33115703	Similarly, lung cancer cell apoptosis induced by HA15 was concomitant with ER stress.	('stress', 'Disease', (78, 84))	('ER', 'Gene', '2069', (75, 77))	('HA15', 'Chemical', '-', (49, 53))	('lung cancer', 'Disease', (11, 22))	('lung cancer', 'Phenotype', 'HP:0100526', (11, 22))	('HA15', 'Var', (49, 53))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('stress', 'Disease', 'MESH:D000079225', (78, 84))	('lung cancer', 'Disease', 'MESH:D008175', (11, 22))
332748	33115703	In this study, we found that after HA15 treatment, the pro-apoptotic UPR signaling was activated, resulting in significantly increased expression of CHOP.	('HA15', 'Var', (35, 39))	('increased', 'PosReg', (125, 134))	('CHOP', 'Gene', (149, 153))	('pro-apoptotic UPR signaling', 'MPA', (55, 82))	('HA15', 'Chemical', '-', (35, 39))	('expression', 'MPA', (135, 145))	('CHOP', 'Gene', '1649', (149, 153))	('activated', 'PosReg', (87, 96))
332751	33115703	demonstrated that while HA15 induced dissociation of the GRP78, protein kinase RNA (PER)-like ER kinase (PERK), IRE1alpha, and ATF6 complex, thus inducing ER stress, GRP78 binds ATP with high affinity and its ATPase activity, stimulated by binding to the unfolded protein, catalyzes re-folding.	('binds', 'Interaction', (172, 177))	('dissociation', 'MPA', (37, 49))	('ER', 'Gene', '2069', (106, 108))	('GRP78', 'Protein', (57, 62))	('ATF6', 'Gene', (127, 131))	('IRE1alpha', 'Gene', (112, 121))	('ATP', 'Chemical', 'MESH:D000255', (178, 181))	('ATP', 'Chemical', 'MESH:D000255', (209, 212))	('PERK', 'Gene', (105, 109))	('ER', 'Gene', '2069', (94, 96))	('HA15', 'Chemical', '-', (24, 28))	('ER', 'Gene', '2069', (85, 87))	('ATF6', 'Gene', '22926', (127, 131))	('binding', 'Interaction', (240, 247))	('PERK', 'Gene', '9451', (105, 109))	('ER', 'Gene', '2069', (155, 157))	('stress', 'Disease', 'MESH:D000079225', (158, 164))	('IRE1alpha', 'Gene', '2081', (112, 121))	('GRP78', 'Gene', (166, 171))	('ATPase', 'Enzyme', (209, 215))	('inducing', 'Reg', (146, 154))	('HA15', 'Var', (24, 28))	('activity', 'MPA', (216, 224))	('stress', 'Disease', (158, 164))
332752	33115703	HA15 is able to inhibit the ATPase activity of GRP78 in a dose-dependent manner, leading to the accumulation of unfolded proteins and aggravating ER stress.	('ATPase', 'Protein', (28, 34))	('inhibit', 'NegReg', (16, 23))	('activity', 'MPA', (35, 43))	('HA15', 'Chemical', '-', (0, 4))	('ER', 'Gene', '2069', (146, 148))	('accumulation', 'PosReg', (96, 108))	('unfolded proteins', 'MPA', (112, 129))	('stress', 'Disease', 'MESH:D000079225', (149, 155))	('stress', 'Disease', (149, 155))	('aggravating', 'PosReg', (134, 145))	('HA15', 'Var', (0, 4))	('ATP', 'Chemical', 'MESH:D000255', (28, 31))	('GRP78', 'Protein', (47, 52))
332753	33115703	HA15-induced apoptosis is not only related closely to ER stress but also to autophagy.	('HA15', 'Chemical', '-', (0, 4))	('autophagy', 'CPA', (76, 85))	('ER', 'Gene', '2069', (54, 56))	('HA15-induced', 'Var', (0, 12))	('apoptosis', 'CPA', (13, 22))	('stress', 'Disease', (57, 63))	('stress', 'Disease', 'MESH:D000079225', (57, 63))
332757	33115703	Interestingly, we found that ATF4 and CHOP were upregulated after treatment with HA15, which may increase autophagy.	('increase', 'PosReg', (97, 105))	('ATF4', 'Gene', (29, 33))	('HA15', 'Var', (81, 85))	('CHOP', 'Gene', '1649', (38, 42))	('ATF4', 'Gene', '468', (29, 33))	('upregulated', 'PosReg', (48, 59))	('CHOP', 'Gene', (38, 42))	('autophagy', 'CPA', (106, 115))	('HA15', 'Chemical', '-', (81, 85))
332791	33115703	After treating with 10 muM HA15 for 24 h, cells were fixed with 4% paraformaldehyde, then stained with a primary antibody ATF4 (60035, 1:200, Protein tech, Wuhan, China) or CHOP (15204, 1:200, Protein tech, Wuhan, China) overnight at 4 C. The next day, a FITC-tagged secondary antibody (ZF0311 or ZF0312, 1:1000, ZSGB-BIO, Beijing, China) and DAPI (C1002, Beyotime, Shanghai, China), were added.	('paraformaldehyde', 'Chemical', 'MESH:C003043', (67, 83))	('HA15', 'Chemical', '-', (27, 31))	('CHOP', 'Gene', (173, 177))	('C1002', 'Var', (349, 354))	('ATF4', 'Gene', (122, 126))	('ZF0311', 'Var', (287, 293))	('ZF0312', 'Var', (297, 303))	('ATF4', 'Gene', '468', (122, 126))	('DAPI', 'Chemical', 'MESH:C007293', (343, 347))	('CHOP', 'Gene', '1649', (173, 177))
332923	30944296	Immunohistochemical analysis of specimens from the esophageal tissue and cell block of pleural effusion showed that they positively expressed p63 and p40 and negatively expressed calretinin and D2-40 (Figure 3A-3D).	('calretinin', 'Gene', '794', (179, 189))	('pleural effusion', 'Disease', 'MESH:D010996', (87, 103))	('p63', 'Gene', (142, 145))	('D2-40', 'Var', (194, 199))	('pleural effusion', 'Disease', (87, 103))	('p40', 'Gene', '8626', (150, 153))	('pleural effusion', 'Phenotype', 'HP:0002202', (87, 103))	('p63', 'Gene', '8626', (142, 145))	('men', 'Species', '9606', (37, 40))	('p40', 'Gene', (150, 153))	('calretinin', 'Gene', (179, 189))	('negatively', 'NegReg', (158, 168))
333128	27913747	The 1-, 3-, and 5-year survival rates were higher for patients with ER-positive tumours than for patients with ER-negative tumours.	('tumours', 'Disease', 'MESH:D009369', (80, 87))	('tumours', 'Disease', (80, 87))	('higher', 'PosReg', (43, 49))	('patients', 'Species', '9606', (54, 62))	('tumours', 'Phenotype', 'HP:0002664', (123, 130))	('tumours', 'Disease', 'MESH:D009369', (123, 130))	('tumour', 'Phenotype', 'HP:0002664', (80, 86))	('tumour', 'Phenotype', 'HP:0002664', (123, 129))	('ER-positive', 'Var', (68, 79))	('tumours', 'Disease', (123, 130))	('tumours', 'Phenotype', 'HP:0002664', (80, 87))	('patients', 'Species', '9606', (97, 105))
333176	27913747	In the current study, the postoperative 1-, 3- and 5-year survival rates of NSCLC patients were higher in patients with ER-positive tumours than in patients with ER-negative tumours.	('patients', 'Species', '9606', (148, 156))	('tumour', 'Phenotype', 'HP:0002664', (174, 180))	('tumours', 'Disease', 'MESH:D009369', (132, 139))	('tumours', 'Disease', (132, 139))	('higher', 'PosReg', (96, 102))	('tumours', 'Phenotype', 'HP:0002664', (174, 181))	('patients', 'Species', '9606', (82, 90))	('NSCLC', 'Disease', (76, 81))	('tumours', 'Disease', 'MESH:D009369', (174, 181))	('NSCLC', 'Disease', 'MESH:D002289', (76, 81))	('tumours', 'Disease', (174, 181))	('patients', 'Species', '9606', (106, 114))	('tumour', 'Phenotype', 'HP:0002664', (132, 138))	('tumours', 'Phenotype', 'HP:0002664', (132, 139))	('ER-positive', 'Var', (120, 131))	('survival rates', 'CPA', (58, 72))	('NSCLC', 'Phenotype', 'HP:0030358', (76, 81))
333213	27835574	As shown in Figure 1, high-risk miRNAs tended to up-regulated in patients with high scores, whereas protective miRNAs tended to high expressed in patients with low scores (Figure 1A and 1B).	('patients', 'Species', '9606', (146, 154))	('patients', 'Species', '9606', (65, 73))	('up-regulated', 'PosReg', (49, 61))	('high scores', 'Var', (79, 90))
333233	27835574	MiR-101 was also reported to suppress lung tumorigenesis through inhibition of DNMT3a.	('inhibition', 'NegReg', (65, 75))	('lung', 'Disease', (38, 42))	('suppress', 'NegReg', (29, 37))	('MiR-101', 'Var', (0, 7))	('MiR-101', 'Chemical', '-', (0, 7))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('DNMT3a', 'Gene', (79, 85))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('DNMT3a', 'Gene', '1788', (79, 85))	('tumor', 'Disease', (43, 48))
333253	27835574	ATRX is the predicted target of miR-101, miR-139 and miR-944.	('miR-944', 'Gene', '100126340', (53, 60))	('ATRX', 'Gene', (0, 4))	('miR-139', 'Gene', (41, 48))	('miR-101', 'Chemical', '-', (32, 39))	('miR-101', 'Var', (32, 39))	('miR-944', 'Gene', (53, 60))	('miR-139', 'Gene', '406931', (41, 48))	('ATRX', 'Gene', '546', (0, 4))
333255	27835574	Dysregulation of TGF-beta signaling pathway is important in cancer progression and cell invasion.	('Dysregulation', 'Var', (0, 13))	('cell invasion', 'CPA', (83, 96))	('TGF-beta signaling pathway', 'Pathway', (17, 43))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('cancer', 'Disease', (60, 66))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
333258	27835574	found that high expression levels of VEGF-B is associated poor survival of LUSC patients.	('VEGF-B', 'Gene', (37, 43))	('patients', 'Species', '9606', (80, 88))	('high', 'Var', (11, 15))	('LUSC', 'Phenotype', 'HP:0030359', (75, 79))	('VEGF-B', 'Gene', '7423', (37, 43))
333274	27765924	Kaplan-Meier survival curves showed that high expression of MTDH predicted reduced survival of lung SCC patients.	('SCC', 'Gene', (100, 103))	('MTDH', 'Gene', '92140', (60, 64))	('SCC', 'Gene', '6317', (100, 103))	('high', 'Var', (41, 45))	('reduced', 'NegReg', (75, 82))	('MTDH', 'Gene', (60, 64))	('patients', 'Species', '9606', (104, 112))	('survival', 'MPA', (83, 91))
333284	27765924	Aberrantly expressed miRNAs can dysregulate cellular RNA networks critical for normal cell function.	('Aberrantly expressed', 'Var', (0, 20))	('miR', 'Gene', '220972', (21, 24))	('miR', 'Gene', (21, 24))	('cellular RNA networks', 'Pathway', (44, 65))	('dysregulate', 'Reg', (32, 43))
333286	27765924	Identification of aberrantly expressed miRNAs is the first step to defining the oncogenic RNA networks in cancer cells.	('miR', 'Gene', '220972', (39, 42))	('miR', 'Gene', (39, 42))	('aberrantly', 'Var', (18, 28))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('cancer', 'Disease', (106, 112))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
333301	27765924	Kaplan-Meier survival curves showed that high expression of MTDH predicted poorer survival of lung SCC patients.	('SCC', 'Gene', '6317', (99, 102))	('MTDH', 'Gene', '92140', (60, 64))	('high', 'Var', (41, 45))	('patients', 'Species', '9606', (103, 111))	('survival', 'MPA', (82, 90))	('MTDH', 'Gene', (60, 64))	('SCC', 'Gene', (99, 102))	('poorer', 'NegReg', (75, 81))
333330	27765924	The TargetScan database identified two putative target sites in the 3'-UTR of MTDH for miR-145-5p (position 3151-3157 and position 3503-3510) and one site for miR-145-3p (position 147-153) (Figure 3C).	('miR-145', 'Gene', '406937', (159, 166))	('miR-145', 'Gene', '406937', (87, 94))	('MTDH', 'Gene', '92140', (78, 82))	('position 3151-3157', 'Var', (99, 117))	('MTDH', 'Gene', (78, 82))	('3p', 'Chemical', '-', (167, 169))	('miR-145', 'Gene', (159, 166))	('miR-145', 'Gene', (87, 94))
333338	27765924	Wound healing and Matrigel invasion assays showed significant inhibition of cell migration and invasion by si-MTDH transfectants (P < 0.001, Figures 4D and 4E).	('invasion', 'CPA', (95, 103))	('MTDH', 'Gene', (110, 114))	('cell migration', 'CPA', (76, 90))	('MTDH', 'Gene', '92140', (110, 114))	('transfectants', 'Var', (115, 128))	('inhibition', 'NegReg', (62, 72))
333340	27765924	As for MTDH copy number variation (CNV), our study showed that 60% of lung SCC patients had a genetic alteration (Figure 5B and 5C).	('SCC', 'Gene', '6317', (75, 78))	('MTDH', 'Gene', (7, 11))	('patients', 'Species', '9606', (79, 87))	('MTDH', 'Gene', '92140', (7, 11))	('SCC', 'Gene', (75, 78))	('genetic alteration', 'Var', (94, 112))
333342	27765924	We assessed the Kaplan-Meier univariate survival of patients groups, comparing those with an MTDH alteration (CNV amplification or gain, or mRNA Z-score > 1.5) and those without an MTDH alteration (diploid or heterozygous loss, and mRNA Z-score equal or less than 1.5).	('alteration', 'Var', (98, 108))	('MTDH', 'Gene', (181, 185))	('MTDH', 'Gene', (93, 97))	('gain', 'PosReg', (131, 135))	('MTDH', 'Gene', '92140', (181, 185))	('MTDH', 'Gene', '92140', (93, 97))	('patients', 'Species', '9606', (52, 60))
333355	27765924	Moreover, we showed that UHRF1 was overexpressed in BC clinical specimens and that the high UHRF1 expression group had a significantly poorer cause-specific survival rate in comparison with the low expression group.	('cause-specific survival rate', 'CPA', (142, 170))	('UHRF1', 'Gene', (92, 97))	('UHRF1', 'Gene', '29128', (92, 97))	('clinical', 'Species', '191496', (55, 63))	('high', 'Var', (87, 91))	('poorer', 'NegReg', (135, 141))	('UHRF1', 'Gene', (25, 30))	('UHRF1', 'Gene', '29128', (25, 30))	('expression', 'MPA', (98, 108))
333367	27765924	Our function assays showed that knockdown of MTDH inhibited cancer cell aggressiveness and affected downstream signal pathways under the following headings: "focal adhesion", "pathways in cancer", "endocytosis" and "cell cycle".	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('affected', 'Reg', (91, 99))	('MTDH', 'Gene', (45, 49))	('cancer cell aggressiveness', 'Disease', 'MESH:C538614', (60, 86))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('knockdown', 'Var', (32, 41))	('cancer', 'Disease', (60, 66))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('MTDH', 'Gene', '92140', (45, 49))	('cancer', 'Disease', (188, 194))	('aggressiveness', 'Phenotype', 'HP:0000718', (72, 86))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('inhibited', 'NegReg', (50, 59))	('cancer cell aggressiveness', 'Disease', (60, 86))
333371	27765924	Furthermore, Kaplan-Meier survival curves showed that high expression of MTDH predicted poorer survival of lung SCC patients.	('high', 'Var', (54, 58))	('SCC', 'Gene', '6317', (112, 115))	('MTDH', 'Gene', (73, 77))	('patients', 'Species', '9606', (116, 124))	('survival', 'MPA', (95, 103))	('poorer', 'NegReg', (88, 94))	('MTDH', 'Gene', '92140', (73, 77))	('SCC', 'Gene', (112, 115))
333372	27765924	Our functional study showed that silencing of MTDH inhibited lung-SCC cell migration and invasion.	('SCC', 'Gene', (66, 69))	('MTDH', 'Gene', '92140', (46, 50))	('silencing', 'Var', (33, 42))	('SCC', 'Gene', '6317', (66, 69))	('invasion', 'CPA', (89, 97))	('MTDH', 'Gene', (46, 50))	('inhibited', 'NegReg', (51, 60))
333394	27765924	TaqMan probes and primers for MTDH (assay ID: Hs00757841_m1, Applied Biosystems, Foster City, CA, USA), EPN3 (HS00978957_m1), TPD52 (Hs00893105_m1), CYP27B1 (Hs01096154_m1), LMAN1 (Hs01557542), STAT1 (Hs01013996_m1) and TXNDC12 (Hs00210841_m1) were assay-on-demand gene expression products.	('MTDH', 'Gene', (30, 34))	('LMAN1', 'Gene', (174, 179))	('MTDH', 'Gene', '92140', (30, 34))	('TPD52', 'Gene', '7163', (126, 131))	('STAT1', 'Gene', '6772', (194, 199))	('Hs00893105_m1', 'Var', (133, 146))	('TXNDC12', 'Gene', '51060', (220, 227))	('HS00978957_m1', 'Var', (110, 123))	('Hs00210841_m1', 'Var', (229, 242))	('CYP27B1', 'Gene', (149, 156))	('Hs01013996_m1', 'Var', (201, 214))	('TPD52', 'Gene', (126, 131))	('TXNDC12', 'Gene', (220, 227))	('EPN3', 'Gene', '55040', (104, 108))	('Hs01557542', 'Var', (181, 191))	('Hs01096154_m1', 'Var', (158, 171))	('STAT1', 'Gene', (194, 199))	('EPN3', 'Gene', (104, 108))	('LMAN1', 'Gene', '3998', (174, 179))	('CYP27B1', 'Gene', '1594', (149, 156))
333398	27765924	We also purchased the following from Invitrogen (Carlsbad, CA, USA): Stealth Select RNAi siRNA, si-MTDH (assay ID: HSS 150644, and P/N: HSS 150646.	('MTDH', 'Gene', '92140', (99, 103))	('P/N: HSS 150646', 'Var', (131, 146))	('MTDH', 'Gene', (99, 103))
333411	27765924	Alternatively, we used sequences that were missing the miR-145-5p target sites (position 3151-3157 or position 3503-3510) or the miR-145-3p target site (position 147-153).	('miR-145', 'Gene', '406937', (55, 62))	('miR-145', 'Gene', (129, 136))	('miR-145', 'Gene', '406937', (129, 136))	('position 3151-3157', 'Var', (80, 98))	('miR-145', 'Gene', (55, 62))	('3p', 'Chemical', '-', (137, 139))
333432	27826043	Persistent, high level expression of E6 and E7 is often associated with integration of the viral genome where disruption of the E2 coding region leads to deregulated expression of E6 and E7 oncoproteins, yet viral genome integration is not a prerequisite for cancer.	('cancer', 'Disease', 'MESH:D009369', (259, 265))	('deregulated expression', 'MPA', (154, 176))	('associated', 'Reg', (56, 66))	('cancer', 'Phenotype', 'HP:0002664', (259, 265))	('disruption', 'Var', (110, 120))	('cancer', 'Disease', (259, 265))
333445	27826043	In the United States, HIV-infected women with T cell counts less than 200 have a 7-fold increased incidence of cervical carcinoma compared to the general population.	('women', 'Species', '9606', (35, 40))	('HIV-infected', 'Disease', (22, 34))	('HIV-infected', 'Disease', 'MESH:D015658', (22, 34))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('cervical carcinoma', 'Disease', 'MESH:D002575', (111, 129))	('cervical carcinoma', 'Disease', (111, 129))	('less than 200', 'Var', (60, 73))
333460	27826043	In both men and women worldwide, infection with any HPV type has been shown to double the risk for HIV infection.	('infection', 'Var', (33, 42))	('HIV infection', 'Disease', (99, 112))	('women', 'Species', '9606', (16, 21))	('men', 'Species', '9606', (18, 21))	('men', 'Species', '9606', (8, 11))	('HIV infection', 'Disease', 'MESH:D015658', (99, 112))	('HPV', 'Species', '10566', (52, 55))
333473	27826043	Although both HSV-1 and HSV-2 can infect oral or genital mucosa, HSV-2 is typically associated with genital herpes.	('associated with', 'Reg', (84, 99))	('genital herpes', 'Disease', (100, 114))	('HSV-2', 'Species', '10310', (65, 70))	('HSV-1 and HSV-2 can infect oral', 'Disease', 'MESH:C536395', (14, 45))	('HSV-2', 'Species', '10310', (24, 29))	('genital herpes', 'Phenotype', 'HP:0032157', (100, 114))	('HSV-2', 'Var', (65, 70))
333482	27826043	In regards to cervical cancer, HSV-2 seropositive women have been shown to have a 2- to 9-fold increased risk of developing cervical squamous cell carcinoma or adenocarcinoma.	('HSV-2', 'Gene', (31, 36))	('seropositive', 'Var', (37, 49))	('squamous cell carcinoma or adenocarcinoma', 'Disease', (133, 174))	('to 9', 'Species', '1214577', (85, 89))	('women', 'Species', '9606', (50, 55))	('squamous cell carcinoma or adenocarcinoma', 'Disease', 'MESH:D002294', (133, 174))	('carcinoma', 'Phenotype', 'HP:0030731', (165, 174))	('cervical cancer', 'Disease', 'MESH:D002583', (14, 29))	('HSV-2', 'Species', '10310', (31, 36))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('carcinoma', 'Phenotype', 'HP:0030731', (147, 156))	('cervical cancer', 'Disease', (14, 29))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (133, 156))
333497	27826043	Subsequent tissue repair, deregulated HPV oncogene expression and DNA replication, or HPV integration would be the early carcinogenic events that would not rely on the continued presence of HSV, setting up a scenario for HSV "hit-and-run" oncogenesis.	('deregulated', 'Var', (26, 37))	('HPV', 'Species', '10566', (86, 89))	('HPV', 'Species', '10566', (38, 41))	('tissue repair', 'CPA', (11, 24))	('HPV oncogene expression', 'Gene', (38, 61))	('DNA replication', 'CPA', (66, 81))	('carcinogenic', 'Disease', 'MESH:D063646', (121, 133))	('carcinogenic', 'Disease', (121, 133))
333499	27826043	T-Vec (talimogene laheraprepvec) is a second-generation HSV-1 virus engineered with deletions in the HSV-1 gamma34.5 and alpha47, which attenuate neurovirulence and enhance replication in cancer cells.	('HSV-1', 'Species', '10298', (56, 61))	('attenuate', 'NegReg', (136, 145))	('HSV-1', 'Species', '10298', (101, 106))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('enhance', 'PosReg', (165, 172))	('HSV-1 virus engineered', 'Disease', (56, 78))	('neurovirulence', 'MPA', (146, 160))	('HSV-1 virus engineered', 'Disease', 'MESH:C536395', (56, 78))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('cancer', 'Disease', (188, 194))	('deletions', 'Var', (84, 93))	('replication', 'MPA', (173, 184))	('HSV-1', 'Gene', (101, 106))
333500	27826043	T-Vec also carries an insertion of the human granulocyte-macrophage colony-stimulating gene in the HSV genome to enhance tumor specific immunity.	('insertion', 'Var', (22, 31))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumor', 'Disease', (121, 126))	('enhance', 'PosReg', (113, 120))	('human', 'Species', '9606', (39, 44))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
333509	27826043	Similar to HSV, HCMV co-infection with HPV16 or HPV18 was more frequent in high grade CIN and invasive carcinoma than in normal or control cervical tissues The presence of HCMV in HPV16-positive cervical tumors correlated with a 2-fold increase in lymph node metastasis and has also been associated with integrated forms of HPV16 in cervical lesions.	('presence', 'Var', (160, 168))	('invasive carcinoma', 'Disease', (94, 112))	('lymph node metastasis', 'Disease', 'MESH:D009362', (248, 269))	('cervical tumors', 'Disease', 'MESH:D002583', (195, 210))	('HPV', 'Species', '10566', (180, 183))	('tumors', 'Phenotype', 'HP:0002664', (204, 210))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('invasive carcinoma', 'Disease', 'MESH:D009361', (94, 112))	('CIN', 'Phenotype', 'HP:0032242', (86, 89))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('lymph node metastasis', 'Disease', (248, 269))	('HPV16-positive', 'Gene', (180, 194))	('CIN', 'Disease', 'MESH:D007674', (86, 89))	('increase', 'PosReg', (236, 244))	('HCMV', 'Species', '10359', (16, 20))	('cervical tumors', 'Phenotype', 'HP:0030159', (195, 210))	('cervical tumors', 'Disease', (195, 210))	('HPV16', 'Species', '333760', (39, 44))	('HPV', 'Species', '10566', (48, 51))	('HPV', 'Species', '10566', (324, 327))	('HCMV', 'Species', '10359', (172, 176))	('CIN', 'Disease', (86, 89))	('HPV', 'Species', '10566', (39, 42))	('HPV16', 'Species', '333760', (180, 185))	('HPV16', 'Species', '333760', (324, 329))
333560	27826043	EBV LMP2A has been shown to induce a delay in epithelial differentiation; a phenotype also observed in EBV-infected keratinocytes.	('EBV-infected', 'Disease', (103, 115))	('EBV', 'Var', (0, 3))	('EBV', 'Species', '10376', (103, 106))	('EBV-infected', 'Disease', 'MESH:D020031', (103, 115))	('LMP2A', 'Gene', (4, 9))	('LMP2A', 'Gene', '17494231', (4, 9))	('EBV', 'Species', '10376', (0, 3))	('delay', 'NegReg', (37, 42))	('epithelial differentiation', 'CPA', (46, 72))
333570	27826043	Although both low-risk and high-risk HPVs (6, 11, 16, and 18) were detected, HPV16 and 18 were more prevalent, accounting for 66.7% of HPV-positive NPC tumors in a Chinese cohort.	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('HPV16', 'Species', '333760', (77, 82))	('NPC', 'Phenotype', 'HP:0100630', (148, 151))	('HPV16', 'Var', (77, 82))	('HPV', 'Species', '10566', (135, 138))	('HPV', 'Species', '10566', (77, 80))	('HPV', 'Species', '10566', (37, 40))	('HPV-positive NPC tumors', 'Disease', 'MESH:D052556', (135, 158))	('tumors', 'Phenotype', 'HP:0002664', (152, 158))	('HPV-positive NPC tumors', 'Disease', (135, 158))
333581	27826043	For example, HPV E7 degradation of the retinoblastoma protein stimulates cell cycle progression independent of p16 inhibition of cyclin D/cyclin-dependent kinase complexes, recapitulating the events shown to establish EBV latency in NPE cells.	('E7 degradation', 'Var', (17, 31))	('cell cycle progression', 'CPA', (73, 95))	('retinoblastoma', 'Disease', (39, 53))	('retinoblastoma', 'Disease', 'MESH:D012175', (39, 53))	('EBV', 'Species', '10376', (218, 221))	('stimulates', 'PosReg', (62, 72))	('HPV', 'Species', '10566', (13, 16))	('retinoblastoma', 'Phenotype', 'HP:0009919', (39, 53))
333585	27826043	Regardless of the outcome, these observations provide evidence for co-infection increasing EBV persistence through either latency or enhanced viral replication and by extending HPV oncogene expression.	('extending', 'PosReg', (167, 176))	('persistence', 'MPA', (95, 106))	('HPV oncogene', 'Gene', (177, 189))	('co-infection', 'Var', (67, 79))	('HPV', 'Species', '10566', (177, 180))	('viral replication', 'CPA', (142, 159))	('EBV', 'Species', '10376', (91, 94))	('expression', 'MPA', (190, 200))	('enhanced', 'PosReg', (133, 141))	('increasing', 'PosReg', (80, 90))	('EBV', 'Gene', (91, 94))
333591	27826043	It is therefore conceivable that polyomaviruses could possibly augment the transformative properties of HPV during viral co-infection.	('transformative properties', 'CPA', (75, 100))	('men', 'Species', '9606', (66, 69))	('HPV', 'Species', '10566', (104, 107))	('augment', 'PosReg', (63, 70))	('polyomaviruses', 'Var', (33, 47))	('polyomaviruses', 'Species', '36362', (33, 47))
333630	27826043	Co-infection, through expression of additional viral oncogenes or epigenetic reprogramming, can replace deleterious mutations required for tumor progression.	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('Co-infection', 'Disease', (0, 12))	('Co-infection', 'Disease', 'MESH:D060085', (0, 12))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('epigenetic', 'Var', (66, 76))
333631	27826043	As epigenetic modifications result in heritable changes to gene expression, epigenetic alterations would have long-term effects on tumor progression in the absence of viral gene expression or infection.	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('epigenetic modifications', 'Var', (3, 27))	('gene expression', 'MPA', (59, 74))	('tumor', 'Disease', (131, 136))	('changes', 'Reg', (48, 55))	('effects', 'Reg', (120, 127))
333644	32629423	Inhibition of system XC-, which is a membrane Na+-dependent cysteine-glutamate exchange transporter, and GPX4 can disrupt the oxidation-reduction balance and cause overwhelming lipid peroxidation that ultimately results in cell death.	('death', 'Disease', (228, 233))	('GPX4', 'Gene', '2879', (105, 109))	('death', 'Disease', 'MESH:D003643', (228, 233))	('lipid peroxidation', 'MPA', (177, 195))	('oxidation-reduction balance', 'MPA', (126, 153))	('cause', 'Reg', (158, 163))	('disrupt', 'NegReg', (114, 121))	('Inhibition', 'Var', (0, 10))	('results in', 'Reg', (212, 222))	('lipid', 'Chemical', 'MESH:D008055', (177, 182))	('GPX4', 'Gene', (105, 109))
333649	32629423	Ductal pancreatic cancer cells with a mutant KRAS gene are more susceptible to ferroptosis than wild-type cells.	('mutant', 'Var', (38, 44))	('KRAS', 'Gene', '3845', (45, 49))	('Ductal pancreatic cancer', 'Disease', (0, 24))	('ferroptosis', 'MPA', (79, 90))	('susceptible', 'Reg', (64, 75))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (7, 24))	('Ductal pancreatic cancer', 'Disease', 'MESH:D010190', (0, 24))	('KRAS', 'Gene', (45, 49))
333651	32629423	In addition, changes in the gene expression of tumor cells also affect ferroptosis, and a number of genes have been confirmed to regulate ferroptosis.	('changes', 'Var', (13, 20))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('ferroptosis', 'CPA', (71, 82))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('affect', 'Reg', (64, 70))	('tumor', 'Disease', (47, 52))
333662	32629423	The analysis of nonsynonymous mutations in 20 cancer types showed that the mutation frequencies for FRGs were generally low in almost all cancers and relatively high in UCEC (Figure S1A).	('FRGs', 'Gene', (100, 104))	('cancer', 'Disease', (138, 144))	('UCEC', 'Disease', (169, 173))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('cancer', 'Disease', (46, 52))	('mutation', 'Var', (75, 83))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('low', 'NegReg', (120, 123))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('cancers', 'Phenotype', 'HP:0002664', (138, 145))	('high', 'Reg', (161, 165))	('cancers', 'Disease', (138, 145))	('cancer', 'Disease', 'MESH:D009369', (138, 144))	('cancers', 'Disease', 'MESH:D009369', (138, 145))
333663	32629423	Furthermore, NFE2L2, which encodes NRF2 and plays a master regulator role in antioxidant responses and has been shown to cause resistance to ferroptosis, showed relatively high mutation frequencies in multiple cancers including BLCA, CESC, ESCA, HNSC, LUSC, and UCEC (Figure S1A).	('LUSC', 'Disease', (252, 256))	('mutation', 'Var', (177, 185))	('NRF2', 'Gene', '4780', (35, 39))	('NFE2L2', 'Gene', '4780', (13, 19))	('multiple cancers', 'Disease', (201, 217))	('BLCA', 'Disease', (228, 232))	('ESCA', 'Disease', (240, 244))	('cancers', 'Phenotype', 'HP:0002664', (210, 217))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('NFE2L2', 'Gene', (13, 19))	('NRF2', 'Gene', (35, 39))	('multiple cancers', 'Disease', 'MESH:D009369', (201, 217))	('HNSC', 'Disease', (246, 250))	('resistance', 'MPA', (127, 137))	('UCEC', 'Disease', (262, 266))	('CESC', 'Disease', (234, 238))
333665	32629423	For example, TTC35, HSPB1, TFRC, and RPL8 were more prone to copy number gain than copy number loss in almost all tumors, but SCL7A11 and ALOX15 showed the opposite profile.	('RPL8', 'Gene', '6132', (37, 41))	('copy number', 'Var', (61, 72))	('RPL8', 'Gene', (37, 41))	('gain', 'PosReg', (73, 77))	('TFRC', 'Gene', (27, 31))	('HSPB1', 'Gene', '3315', (20, 25))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('HSPB1', 'Gene', (20, 25))	('TFRC', 'Gene', '7037', (27, 31))	('tumors', 'Disease', (114, 120))	('ALOX15', 'Gene', (138, 144))	('TTC35', 'Gene', (13, 18))	('tumors', 'Disease', 'MESH:D009369', (114, 120))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('TTC35', 'Gene', '9694', (13, 18))	('ALOX15', 'Gene', '246', (138, 144))
333681	32629423	This result indicates that the aberrance of copy number for FRGs is common in most cancers and can influence gene expression.	('cancers', 'Disease', 'MESH:D009369', (83, 90))	('cancers', 'Phenotype', 'HP:0002664', (83, 90))	('cancers', 'Disease', (83, 90))	('gene expression', 'MPA', (109, 124))	('copy number', 'Var', (44, 55))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('influence', 'Reg', (99, 108))	('aberrance', 'Var', (31, 40))	('FRGs', 'Gene', (60, 64))	('common', 'Reg', (68, 74))
333682	32629423	In addition to SCNA, the methylation of promoter can regulate gene expression and aberrant DNA methylation of the promoter is associated with tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('regulate', 'Reg', (53, 61))	('associated with', 'Reg', (126, 141))	('tumor', 'Disease', (142, 147))	('gene expression', 'MPA', (62, 77))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('aberrant', 'Var', (82, 90))
333693	32629423	This suggests that miRNAs play a regulatory role in FRGs expression, and the aberrant expression of miRNAs in tumors could impact ferroptosis.	('impact', 'NegReg', (123, 129))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumors', 'Disease', (110, 116))	('tumors', 'Disease', 'MESH:D009369', (110, 116))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('ferroptosis', 'CPA', (130, 141))	('miRNAs', 'Gene', (100, 106))	('aberrant expression', 'Var', (77, 96))
333720	32629423	Strikingly, somatic mutations, namely, NFE2L2, BRAF, and TP53, were positively associated with FPI in pancancer associations, but a mutation in TP53 was negatively correlated with ferroptosis in LUSC.	('TP53', 'Gene', '7157', (144, 148))	('TP53', 'Gene', (144, 148))	('associated', 'Reg', (79, 89))	('NFE2L2', 'Gene', (39, 45))	('cancer', 'Disease', (105, 111))	('BRAF', 'Gene', (47, 51))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('BRAF', 'Gene', '673', (47, 51))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('TP53', 'Gene', '7157', (57, 61))	('NFE2L2', 'Gene', '4780', (39, 45))	('TP53', 'Gene', (57, 61))	('mutation', 'Var', (132, 140))	('FPI', 'Disease', (95, 98))
333721	32629423	This observation was verified by the comparison of FPI between the TP53 mutant and wild-type groups (Figure S3B), consistent with previous findings that showed that TP53 played a dual role in regulating ferroptosis.	('TP53', 'Gene', (165, 169))	('mutant', 'Var', (72, 78))	('ferroptosis', 'Disease', (203, 214))	('TP53', 'Gene', '7157', (67, 71))	('TP53', 'Gene', (67, 71))	('TP53', 'Gene', '7157', (165, 169))
333722	32629423	The influences of KRAS mutations on FPI were also investigated, and the results showed that the relationship between KRAS mutation and FPI was significantly negative in gastric tumors (Figure S3C) but slightly positive in hepatocellular carcinoma (Figures S3A and S3C).	('KRAS', 'Gene', (117, 121))	('tumors', 'Phenotype', 'HP:0002664', (177, 183))	('negative', 'NegReg', (157, 165))	('KRAS', 'Gene', (18, 22))	('positive', 'Reg', (210, 218))	('mutation', 'Var', (122, 130))	('KRAS', 'Gene', '3845', (18, 22))	('KRAS', 'Gene', '3845', (117, 121))	('gastric tumors', 'Phenotype', 'HP:0006753', (169, 183))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (222, 246))	('gastric tumors', 'Disease', (169, 183))	('gastric tumors', 'Disease', 'MESH:D013274', (169, 183))	('hepatocellular carcinoma', 'Disease', (222, 246))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (222, 246))	('carcinoma', 'Phenotype', 'HP:0030731', (237, 246))
333724	32629423	Furthermore, differential expression of FRGs between wild-type and tumors with mutant TP53 (Figure S3D) and KRAS (Figure S3E) was found to be ubiquitous in most cancers.	('KRAS', 'Gene', (108, 112))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('TP53', 'Gene', '7157', (86, 90))	('tumors', 'Disease', 'MESH:D009369', (67, 73))	('mutant', 'Var', (79, 85))	('KRAS', 'Gene', '3845', (108, 112))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('TP53', 'Gene', (86, 90))	('cancers', 'Disease', 'MESH:D009369', (161, 168))	('cancers', 'Phenotype', 'HP:0002664', (161, 168))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('cancers', 'Disease', (161, 168))	('tumors', 'Disease', (67, 73))
333728	32629423	For example, terpenoid backbone biosynthesis and steroid biosynthesis were enriched in the low-FPI group in 19 and 16 cancers, respectively (Figure 3A).	('terpenoid backbone biosynthesis', 'MPA', (13, 44))	('cancers', 'Disease', (118, 125))	('low-FPI', 'Var', (91, 98))	('cancers', 'Disease', 'MESH:D009369', (118, 125))	('steroid biosynthesis', 'MPA', (49, 69))	('steroid', 'Chemical', 'MESH:D013256', (49, 56))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('terpenoid', 'Chemical', 'MESH:D013729', (13, 22))	('cancers', 'Phenotype', 'HP:0002664', (118, 125))
333740	32629423	Based on the clinical data from TCGA, survival analysis was performed and the results were consistent since it was found that the lower FPI predicted a better survival in five cancers including GBM, KIRC, KIRP, LIHC, and LUAD (Figure 4).	('cancers', 'Disease', (176, 183))	('survival', 'MPA', (159, 167))	('cancers', 'Disease', 'MESH:D009369', (176, 183))	('lower', 'Var', (130, 135))	('LIHC', 'Disease', (211, 215))	('KIRP', 'Disease', (205, 209))	('LUAD', 'Disease', (221, 225))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('GBM', 'Disease', (194, 197))	('KIRC', 'Disease', (199, 203))	('better', 'PosReg', (152, 158))	('cancers', 'Phenotype', 'HP:0002664', (176, 183))
333752	32629423	However, high expression of CARS and MT1G showed consistently better survival among cancers including KICH, UCEC, PAAD, and HNSC (Figure S3I).	('MT1G', 'Gene', (37, 41))	('high expression', 'Var', (9, 24))	('CARS', 'Gene', (28, 32))	('PAAD', 'Disease', (114, 118))	('cancers', 'Disease', 'MESH:D009369', (84, 91))	('MT1G', 'Gene', '4495', (37, 41))	('better', 'PosReg', (62, 68))	('HNSC', 'Disease', (124, 128))	('cancers', 'Disease', (84, 91))	('KICH', 'Disease', 'None', (102, 106))	('cancers', 'Phenotype', 'HP:0002664', (84, 91))	('CARS', 'Gene', '833', (28, 32))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('KICH', 'Disease', (102, 106))	('UCEC', 'Disease', (108, 112))
333804	29956740	Furthermore, Sox2 was overexpressed and inhibited using full-length Sox2 cDNA and short hairpin RNA (shRNA) transfection in UM2 and Cal27 cell lines, respectively.	('inhibited', 'NegReg', (40, 49))	('Sox2', 'Gene', '6657', (68, 72))	('Sox2', 'Gene', '6657', (13, 17))	('transfection', 'Var', (108, 120))	('Sox2', 'Gene', (68, 72))	('Sox2', 'Gene', (13, 17))
333809	29956740	Moreover, when the expression of Sox2 was decreased by shRNA transduction, beta-catenin expression was attenuated.	('beta-catenin', 'Gene', '1499', (75, 87))	('expression', 'MPA', (19, 29))	('attenuated', 'NegReg', (103, 113))	('decreased', 'NegReg', (42, 51))	('Sox2', 'Gene', '6657', (33, 37))	('shRNA', 'Var', (55, 60))	('Sox2', 'Gene', (33, 37))	('beta-catenin', 'Gene', (75, 87))
333879	29956740	The results showed that patients with tumors with high Sox2 expression had a significantly worse prognosis than those with low Sox2 expression (P=0.006; Fig.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('Sox2', 'Gene', (55, 59))	('tumors', 'Disease', (38, 44))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('Sox2', 'Gene', '6657', (55, 59))	('tumors', 'Disease', 'MESH:D009369', (38, 44))	('Sox2', 'Gene', '6657', (127, 131))	('patients', 'Species', '9606', (24, 32))	('Sox2', 'Gene', (127, 131))	('high', 'Var', (50, 54))
333886	29956740	Silencing of Sox2 significantly inhibited the proliferation of the Cal27 cells (P<0.05; Fig.	('inhibited', 'NegReg', (32, 41))	('Sox2', 'Gene', '6657', (13, 17))	('proliferation', 'CPA', (46, 59))	('Sox2', 'Gene', (13, 17))	('Silencing', 'Var', (0, 9))
333887	29956740	Following knockdown of Sox2, the colony number was also decreased.	('Sox2', 'Gene', '6657', (23, 27))	('decreased', 'NegReg', (56, 65))	('Sox2', 'Gene', (23, 27))	('colony number', 'CPA', (33, 46))	('knockdown', 'Var', (10, 19))
333888	29956740	In addition, knockdown of Sox2 significantly reduced the cell invasion and wound-healing ability (P<0.05; Fig.	('reduced', 'NegReg', (45, 52))	('wound-healing ability', 'CPA', (75, 96))	('Sox2', 'Gene', '6657', (26, 30))	('knockdown', 'Var', (13, 22))	('cell invasion', 'CPA', (57, 70))	('Sox2', 'Gene', (26, 30))
333899	29956740	These results suggest that beta-catenin may associated with a higher malignant phenotype and EMT progression in TSCC cells with alterations in Sox2 expression.	('associated', 'Reg', (44, 54))	('alterations', 'Var', (128, 139))	('beta-catenin', 'Gene', '1499', (27, 39))	('Sox2', 'Gene', '6657', (143, 147))	('higher', 'PosReg', (62, 68))	('malignant phenotype', 'CPA', (69, 88))	('beta-catenin', 'Gene', (27, 39))	('TSCC', 'Phenotype', 'HP:0030413', (112, 116))	('Sox2', 'Gene', (143, 147))	('EMT progression', 'CPA', (93, 108))
333904	29956740	Overexpression of Sox2 is often associated with increased cancer aggressiveness, resistance to chemo-radiation therapy and decreased survival rate, which have been reported in various cancer types, including breast, prostate, lung, ovarian and colon cancer.	('cancer', 'Disease', (184, 190))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('decreased', 'NegReg', (123, 132))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('Overexpression', 'Var', (0, 14))	('cancer aggressiveness', 'Disease', 'MESH:D009369', (58, 79))	('Sox2', 'Gene', '6657', (18, 22))	('ovarian and colon cancer', 'Disease', 'MESH:D010051', (232, 256))	('resistance', 'CPA', (81, 91))	('cancer', 'Disease', 'MESH:D009369', (250, 256))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('aggressiveness', 'Phenotype', 'HP:0000718', (65, 79))	('cancer aggressiveness', 'Disease', (58, 79))	('colon cancer', 'Phenotype', 'HP:0003003', (244, 256))	('breast', 'Disease', (208, 214))	('lung', 'Disease', (226, 230))	('increased', 'PosReg', (48, 57))	('cancer', 'Disease', (250, 256))	('Sox2', 'Gene', (18, 22))	('prostate', 'Disease', (216, 224))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))	('cancer', 'Disease', (58, 64))	('survival rate', 'CPA', (133, 146))
333912	29956740	To confirm this hypothesis, two TSCC cell lines were constructed to evaluate the role of Sox2 through lentiviral-mediated overexpression and lentiviral-mediated knockdown.	('Sox2', 'Gene', '6657', (89, 93))	('Sox2', 'Gene', (89, 93))	('knockdown', 'Var', (161, 170))	('TSCC', 'Phenotype', 'HP:0030413', (32, 36))
333914	29956740	Nevertheless, when the same modifications occur in cancer cells, metastasis can happen.	('modifications', 'Var', (28, 41))	('metastasis', 'CPA', (65, 75))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('happen', 'Reg', (80, 86))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))
333921	29956740	In addition, silencing of Sox2 could attenuate the expression of mesenchymal markers, and could elevate the epithelial marker expression in Cal27 tongue cancer cells.	('mesenchymal', 'CPA', (65, 76))	('elevate', 'PosReg', (96, 103))	('Sox2', 'Gene', '6657', (26, 30))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('expression', 'MPA', (51, 61))	('epithelial marker expression', 'MPA', (108, 136))	('tongue cancer', 'Disease', (146, 159))	('attenuate', 'NegReg', (37, 46))	('tongue cancer', 'Disease', 'MESH:D014062', (146, 159))	('Sox2', 'Gene', (26, 30))	('silencing', 'Var', (13, 22))
333929	29956740	In the present study, the results revealed that beta-catenin expression was closely associated with Sox2 expression, which suggests that beta-catenin may be associated with a higher malignant phenotype and EMT progression in TSCC cells with alteration of Sox2 expression.	('associated', 'Reg', (157, 167))	('beta-catenin', 'Gene', (48, 60))	('beta-catenin', 'Gene', '1499', (137, 149))	('Sox2', 'Gene', (100, 104))	('higher', 'PosReg', (175, 181))	('beta-catenin', 'Gene', '1499', (48, 60))	('alteration', 'Var', (241, 251))	('Sox2', 'Gene', '6657', (100, 104))	('TSCC', 'Phenotype', 'HP:0030413', (225, 229))	('EMT progression', 'CPA', (206, 221))	('Sox2', 'Gene', '6657', (255, 259))	('beta-catenin', 'Gene', (137, 149))	('Sox2', 'Gene', (255, 259))
333934	29021619	Pan-cancer analysis of bi-allelic alterations in homologous recombination DNA repair genes BRCA1 and BRCA2 are involved in homologous recombination (HR) DNA repair and are germ-line cancer pre-disposition genes that result in a syndrome of hereditary breast and ovarian cancer (HBOC).	('hereditary breast and ovarian cancer', 'Disease', 'MESH:D061325', (240, 276))	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('BRCA', 'Gene', '672', (101, 105))	('Pan-cancer', 'Disease', 'MESH:C537931', (0, 10))	('BRCA1', 'Gene', '672', (91, 96))	('BRCA1', 'Gene', (91, 96))	('cancer', 'Disease', (270, 276))	('ovarian cancer', 'Disease', 'MESH:D010051', (262, 276))	('result in', 'Reg', (216, 225))	('cancer', 'Disease', (182, 188))	('BRCA', 'Gene', (101, 105))	('cancer', 'Disease', 'MESH:D009369', (4, 10))	('breast and ovarian cancer', 'Disease', 'MESH:D010051', (251, 276))	('cancer', 'Phenotype', 'HP:0002664', (270, 276))	('BRCA', 'Gene', '672', (91, 95))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('BRCA2', 'Gene', (101, 106))	('ovarian cancer', 'Disease', (262, 276))	('BRCA', 'Gene', (91, 95))	('Pan-cancer', 'Disease', (0, 10))	('ovarian cancer', 'Phenotype', 'HP:0100615', (262, 276))	('cancer', 'Disease', 'MESH:D009369', (270, 276))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('BRCA2', 'Gene', '675', (101, 106))	('bi-allelic', 'Var', (23, 33))	('cancer', 'Disease', (4, 10))
333936	29021619	Here, we perform a pan-cancer analysis of The Cancer Genome Atlas (TCGA) data set and observe that bi-allelic pathogenic alterations in homologous recombination (HR) DNA repair-related genes are prevalent across many malignancies.	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (46, 65))	('alterations', 'Var', (121, 132))	('malignancies', 'Disease', 'MESH:D009369', (217, 229))	('HR) DNA repair-related genes', 'Gene', (162, 190))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('malignancies', 'Disease', (217, 229))	('prevalent', 'Reg', (195, 204))	('Cancer Genome Atlas', 'Disease', (46, 65))	('Cancer', 'Phenotype', 'HP:0002664', (46, 52))
333937	29021619	These bi-allelic alterations often associate with genomic features of HR deficiency.	('HR deficiency', 'Disease', 'MESH:D001919', (70, 83))	('associate', 'Reg', (35, 44))	('bi-allelic', 'Var', (6, 16))	('HR deficiency', 'Disease', (70, 83))
333939	29021619	Germline mutations in BRCA1/BRCA2 are associated with an increased risk of breast, ovarian, prostate and/or pancreatic cancer.	('BRCA1/BRCA2', 'Gene', (22, 33))	('Germline mutations', 'Var', (0, 18))	('and/or', 'Disease', (101, 107))	('associated', 'Reg', (38, 48))	('prostate', 'Disease', (92, 100))	('ovarian', 'Disease', (83, 90))	('pancreatic cancer', 'Disease', (108, 125))	('pancreatic cancer', 'Disease', 'MESH:D010190', (108, 125))	('breast', 'Disease', (75, 81))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (108, 125))
333940	29021619	Pathogenic mutations in these genes not only predispose to cancer, but can also be exploited therapeutically with homologous recombination (HR) directed therapies, such as PARP inhibitors and platinum salts.	('mutations', 'Var', (11, 20))	('predispose', 'Reg', (45, 55))	('PARP', 'Gene', '1302', (172, 176))	('PARP', 'Gene', (172, 176))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('cancer', 'Disease', (59, 65))
333942	29021619	Hereditary cancers associated with germ-line mutations in BRCA1/2 have recently been found to display specific patterns of genomic alterations that likely result from defective HR DNA repair.	('associated', 'Reg', (19, 29))	('mutations', 'Var', (45, 54))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('Hereditary cancers', 'Disease', 'MESH:D009369', (0, 18))	('Hereditary cancers', 'Disease', (0, 18))	('cancers', 'Phenotype', 'HP:0002664', (11, 18))	('BRCA1/2', 'Gene', (58, 65))
333943	29021619	Certain types of structural abnormalities, such as patterns of loss-of-heterozygosity in long segments (e.g., large-scale state transitions (LST)), have been shown to be associated with mutations in BRCA1/2 and may be employed as surrogates for sensitivity to HR-directed therapies.	('mutations', 'Var', (186, 195))	('structural abnormalities', 'Disease', 'MESH:C566527', (17, 41))	('loss-of-heterozygosity', 'NegReg', (63, 85))	('structural abnormalities', 'Disease', (17, 41))	('BRCA1/2', 'Gene', (199, 206))
333945	29021619	POLQ was associated with highest number of mono-allelic pathogenic mutations, with a single-nucleotide polymorphism (SNP) lle1421fs displaying a prevalence of 0.6% in the cohort; however, this SNP was not enriched in TCGA when compared with a cohort of patients from exome aggregation consortium.	('POLQ', 'Gene', '10721', (0, 4))	('lle1421fs', 'Var', (122, 131))	('patients', 'Species', '9606', (253, 261))	('single-nucleotide', 'Var', (85, 102))	('POLQ', 'Gene', (0, 4))
333946	29021619	Further studies are warranted to define the functional impact of mono and bi-allelic alterations of POLQ on HR DNA repair in human cancers.	('mono', 'Var', (65, 69))	('cancers', 'Phenotype', 'HP:0002664', (131, 138))	('POLQ', 'Gene', (100, 104))	('bi-allelic alterations', 'Var', (74, 96))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('human', 'Species', '9606', (125, 130))
333950	29021619	Over 5% of all cancers have a bi-allelic pathogenic alteration in HR-related genes, with 25% and 10% of ovarian and breast cancers, respectively, having this pathway altered (Fig.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('breast cancers', 'Disease', 'MESH:D001943', (116, 130))	('breast cancers', 'Disease', (116, 130))	('breast cancer', 'Phenotype', 'HP:0003002', (116, 129))	('altered', 'Reg', (166, 173))	('cancers', 'Phenotype', 'HP:0002664', (15, 22))	('bi-allelic', 'Var', (30, 40))	('cancers', 'Phenotype', 'HP:0002664', (123, 130))	('breast cancers', 'Phenotype', 'HP:0003002', (116, 130))	('ovarian and breast cancers', 'Disease', 'MESH:D010051', (104, 130))	('HR-related genes', 'Gene', (66, 82))	('breast cancer', 'Disease', 'MESH:D001943', (116, 129))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))
333951	29021619	Across all cancer types, only 45% of bi-allelic alterations in HR-related genes occurred in traditional BRCA1/2-associated hereditary cancers (hereditary breast and ovarian cancer (HBOC), namely breast, ovarian, and prostate cancer), suggesting that this pathway is altered in other malignancies (Fig.	('bi-allelic alterations', 'Var', (37, 59))	('ovarian', 'Disease', (203, 210))	('prostate cancer', 'Phenotype', 'HP:0012125', (216, 231))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('cancers', 'Phenotype', 'HP:0002664', (134, 141))	('BRCA1/2-associated', 'Gene', (104, 122))	('occurred', 'Reg', (80, 88))	('ovarian cancer', 'Phenotype', 'HP:0100615', (165, 179))	('hereditary cancers', 'Disease', (123, 141))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('HR-related genes', 'Gene', (63, 79))	('breast', 'Disease', (195, 201))	('ovarian cancer', 'Disease', (165, 179))	('hereditary cancers', 'Disease', 'MESH:D009369', (123, 141))
333954	29021619	We first examined if bi-allelic alterations were associated with phenotypic consequences in HBOC cancers.	('cancers', 'Phenotype', 'HP:0002664', (97, 104))	('HBOC cancers', 'Disease', 'MESH:D061325', (92, 104))	('associated', 'Reg', (49, 59))	('HBOC cancers', 'Disease', (92, 104))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('bi-allelic alterations', 'Var', (21, 43))
333957	29021619	Of these 15 mutations, the pathogenicity of the BRCA1 p.G1788V mutation and the CDK12 p.L996F mutation is supported by previous clinical pre-disposition analysis and functional studies, respectively (Fig.	('CDK12', 'Gene', (80, 85))	('BRCA1', 'Gene', (48, 53))	('p.L996F', 'Var', (86, 93))	('p.L996F', 'Mutation', 'p.L996F', (86, 93))	('p.G1788V', 'Var', (54, 62))	('p.G1788V', 'Mutation', 'rs80357069', (54, 62))
333958	29021619	Massively parallel sequencing of some cancer types (e.g., non-small-cell lung cancer and melanoma) have revealed frequent, and often hotspot, mutations in oncogenes that are therapeutically targetable.	('lung cancer', 'Disease', 'MESH:D008175', (73, 84))	('mutations', 'Var', (142, 151))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('lung cancer', 'Disease', (73, 84))	('lung cancer', 'Phenotype', 'HP:0100526', (73, 84))	('melanoma', 'Phenotype', 'HP:0002861', (89, 97))	('melanoma', 'Disease', (89, 97))	('oncogenes', 'Gene', (155, 164))	('melanoma', 'Disease', 'MESH:D008545', (89, 97))
333960	29021619	For example, cancers with mismatch repair have long been known to harbor microsatellite instability (MSI) and a disproportionately high number of somatic genetic alterations.	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('harbor', 'Reg', (66, 72))	('cancers', 'Phenotype', 'HP:0002664', (13, 20))	('MSI', 'Disease', 'None', (101, 104))	('mismatch repair', 'Var', (26, 41))	('microsatellite instability', 'Disease', (73, 99))	('MSI', 'Disease', (101, 104))
333962	29021619	Intriguingly, a pan-cancer basket study of MSI tumors demonstrated that these cancers display a marked response to immunotherapy, suggesting that DNA-repair deficiencies can be targeted regardless of their site of origin.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('cancers', 'Phenotype', 'HP:0002664', (78, 85))	('MSI tumors', 'Disease', 'MESH:D009369', (43, 53))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('MSI tumors', 'Disease', (43, 53))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))	('deficiencies', 'Var', (157, 169))
333963	29021619	Although we found a correlation between bi-allelic pathogenic mutations in HR-related DNA repair genes and genomic evidence of HR deficiency (signature 3 and LST) across cancer types, the basis of HR deficiency remains unexplained in a large number of cases.	('HR-related DNA repair genes', 'Gene', (75, 102))	('HR deficiency remains unexplained', 'Disease', 'MESH:D000071298', (197, 230))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('HR deficiency remains unexplained', 'Disease', (197, 230))	('mutations', 'Var', (62, 71))
333964	29021619	Although we cannot rule out other causes of HR deficiency (e.g., some dominant negative or haploinsufficient mono-allelic alterations, gene rearrangements and epigenetic effects), our observations support bi-allelic genetic alterations affecting HR-related genes as a major etiology of HR DNA repair deficiency not only in cancers linked to HBOC, but across cancer types.	('etiology', 'Reg', (274, 282))	('haploinsufficient', 'Disease', 'MESH:D058495', (91, 108))	('HR-related genes', 'Gene', (246, 262))	('haploinsufficient', 'Disease', (91, 108))	('HR DNA repair', 'Gene', (286, 299))	('cancer', 'Phenotype', 'HP:0002664', (358, 364))	('cancer', 'Phenotype', 'HP:0002664', (323, 329))	('cancers', 'Phenotype', 'HP:0002664', (323, 330))	('deficiency', 'NegReg', (300, 310))	('bi-allelic genetic alterations', 'Var', (205, 235))
333966	29021619	Tumors that had bi-allelic alterations in an HR-related gene where one of the alterations was not inactivating were considered to have bi-allelic VUS alterations.	('bi-allelic', 'Var', (16, 26))	('HR-related gene', 'Gene', (45, 60))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))
333968	29021619	We then determined which signature was responsible for the majority of mutations, and deemed that the dominant signature in a particular cancer.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('mutations', 'Var', (71, 80))	('particular cancer', 'Disease', (126, 143))	('particular cancer', 'Disease', 'MESH:D009369', (126, 143))
333970	29021619	We also performed simulations (N = 100,000) randomly selecting 102 genes (the size of the HR gene panel) and deriving an empirical p-value for the association of alterations in HR genes and phenotypic genomic measures of HR deficiency in breast, prostate, and ovarian cancers.	('ovarian cancers', 'Phenotype', 'HP:0100615', (260, 275))	('association', 'Interaction', (147, 158))	('ovarian cancers', 'Disease', (260, 275))	('alterations', 'Var', (162, 173))	('HR genes', 'Gene', (177, 185))	('ovarian cancers', 'Disease', 'MESH:D010051', (260, 275))	('cancer', 'Phenotype', 'HP:0002664', (268, 274))	('ovarian cancer', 'Phenotype', 'HP:0100615', (260, 274))	('cancers', 'Phenotype', 'HP:0002664', (268, 275))	('HR deficiency in breast, prostate', 'Disease', 'MESH:D011472', (221, 254))
333985	32810311	These include an immune-inflamed phenotype, 15 ,  16  expression of T cell signaling pathway genes such as IFNgamma, 17  microsatellite instability, 18  somatic copy-number alterations, 19  human leukocyte antigen (HLA) class I diversity, 20  T cell repertoire clonality change, 21  WNT-beta-catenin signaling, 22  TGFbeta expression, 23  and even commensal microbiota.	('IFNgamma', 'Gene', '3458', (107, 115))	('beta-catenin', 'Gene', '1499', (287, 299))	('T cell signaling pathway genes', 'Gene', (68, 98))	('TGFbeta', 'Gene', (315, 322))	('alterations', 'Var', (173, 184))	('TGFbeta', 'Gene', '7039', (315, 322))	('beta-catenin', 'Gene', (287, 299))	('human', 'Species', '9606', (190, 195))	('IFNgamma', 'Gene', (107, 115))
334044	32810311	We analyzed RNA-Seq data of 28 pretreatment tumors from melanoma patients who received anti-PD-1 ICI.	('tumors', 'Disease', (44, 50))	('tumors', 'Disease', 'MESH:D009369', (44, 50))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('melanoma', 'Disease', 'MESH:D008545', (56, 64))	('melanoma', 'Phenotype', 'HP:0002861', (56, 64))	('melanoma', 'Disease', (56, 64))	('anti-PD-1', 'Var', (87, 96))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('patients', 'Species', '9606', (65, 73))
334050	32810311	35  Axis 6 (Treg) and axis 7 (MDSC) were high in Pt25 and Pt16, respectively, suggesting that the strategies to deplete Treg or MDSC might be recommended to these patients.	('Pt16', 'Var', (58, 62))	('Treg', 'Chemical', '-', (12, 16))	('Pt25', 'Var', (49, 53))	('patients', 'Species', '9606', (163, 171))	('Treg', 'Chemical', '-', (120, 124))
334065	32810311	For example, immunograms for hallmarks of cancer could also be compiled by adopting gene sets for the eight hallmarks: sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, activating invasion and metastasis, reprogramming of energy metabolism, and evading immune destruction.	('death', 'Disease', 'MESH:D003643', (198, 203))	('death', 'Disease', (198, 203))	('hallmarks of cancer', 'Disease', (29, 48))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('replicative immortality', 'CPA', (214, 237))	('evading', 'Var', (155, 162))	('invasion', 'CPA', (273, 281))	('immune destruction', 'CPA', (346, 364))	('activating', 'PosReg', (262, 272))	('enabling', 'PosReg', (205, 213))	('inducing', 'PosReg', (239, 247))	('reprogramming', 'Reg', (298, 311))	('angiogenesis', 'CPA', (248, 260))	('proliferative signaling', 'MPA', (130, 153))	('hallmarks of cancer', 'Disease', 'MESH:D009369', (29, 48))	('sustaining', 'PosReg', (119, 129))
334072	32435155	Association of human XPA rs1800975 polymorphism and cancer susceptibility: an integrative analysis of 71 case-control studies The objective of the present study is to comprehensively evaluate the impact of the rs1800975 A/G polymorphism within the human xeroderma pigmentosum group A (XPA) gene on susceptibility to overall cancer by performing an integrative analysis of the current evidence.	('cancer', 'Disease', (324, 330))	('rs1800975', 'Mutation', 'rs1800975', (210, 219))	('XPA', 'Gene', '7507', (285, 288))	('human', 'Species', '9606', (15, 20))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('XPA', 'Gene', (285, 288))	('human', 'Species', '9606', (248, 253))	('rs1800975', 'Mutation', 'rs1800975', (25, 34))	('rs1800975 A/G', 'Var', (210, 223))	('cancer', 'Phenotype', 'HP:0002664', (324, 330))	('xeroderma pigmentosum', 'Disease', 'MESH:D014983', (254, 275))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('XPA', 'Gene', (21, 24))	('cancer', 'Disease', 'MESH:D009369', (324, 330))	('XPA', 'Gene', '7507', (21, 24))	('xeroderma pigmentosum', 'Disease', (254, 275))
334077	32435155	However, our eQTL/sQTL data did not support the strong links of rs1800975 with the gene expression or splicing changes of XPA in the skin tissue.	('rs1800975', 'Mutation', 'rs1800975', (64, 73))	('XPA', 'Gene', (122, 125))	('rs1800975', 'Var', (64, 73))	('XPA', 'Gene', '7507', (122, 125))
334078	32435155	In addition, even though we observed a decreased risk of lung cancer under the homozygotic, heterozygotic and dominant models (P < 0.05, OR < 1) and an enhanced risk of colorectal cancer under the allelic, homozygotic, heterozygotic, dominant (P < 0.05, OR > 1), our data from FPRP analysis and another pooling analysis with only the population-based controls in the Caucasian population did not support the strong links between the XPA rs1800975 A/G polymorphism and the risk of lung or colorectal cancer.	('XPA', 'Gene', '7507', (433, 436))	('colorectal cancer', 'Phenotype', 'HP:0003003', (488, 505))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('XPA', 'Gene', (433, 436))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('colorectal cancer', 'Disease', 'MESH:D015179', (169, 186))	('colorectal cancer', 'Disease', (488, 505))	('rs1800975 A/G', 'Var', (437, 450))	('lung cancer', 'Disease', 'MESH:D008175', (57, 68))	('cancer', 'Phenotype', 'HP:0002664', (499, 505))	('rs1800975', 'Mutation', 'rs1800975', (437, 446))	('colorectal cancer', 'Phenotype', 'HP:0003003', (169, 186))	('colorectal cancer', 'Disease', (169, 186))	('lung', 'Disease', (480, 484))	('decreased', 'NegReg', (39, 48))	('colorectal cancer', 'Disease', 'MESH:D015179', (488, 505))	('lung cancer', 'Disease', (57, 68))	('lung cancer', 'Phenotype', 'HP:0100526', (57, 68))
334079	32435155	Our findings provide evidence of the close relationship between the XPA rs1800975 A/G polymorphism and susceptibility to skin cancer in the Caucasian population.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('rs1800975', 'Mutation', 'rs1800975', (72, 81))	('skin cancer', 'Phenotype', 'HP:0008069', (121, 132))	('susceptibility', 'Reg', (103, 117))	('rs1800975 A/G', 'Var', (72, 85))	('skin cancer', 'Disease', (121, 132))	('XPA', 'Gene', '7507', (68, 71))	('skin cancer', 'Disease', 'MESH:D012878', (121, 132))	('XPA', 'Gene', (68, 71))
334080	32435155	The potential effect of XPA rs1800975 on the risk of developing lung or colorectal cancer still merits the enrollment of larger well-scaled studies.	('colorectal cancer', 'Disease', 'MESH:D015179', (72, 89))	('rs1800975', 'Mutation', 'rs1800975', (28, 37))	('XPA', 'Gene', (24, 27))	('XPA', 'Gene', '7507', (24, 27))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('colorectal cancer', 'Phenotype', 'HP:0003003', (72, 89))	('lung', 'Disease', (64, 68))	('colorectal cancer', 'Disease', (72, 89))	('rs1800975', 'Var', (28, 37))
334083	32435155	The human XPA rs1800975 T/C polymorphism is a common single nucleotide polymorphism (SNP) in the 5'-untranslated region of the XPA gene.	('rs1800975', 'Mutation', 'rs1800975', (14, 23))	('XPA', 'Gene', (10, 13))	('human', 'Species', '9606', (4, 9))	('rs1800975 T/C polymorphism', 'Var', (14, 40))	('XPA', 'Gene', '7507', (127, 130))	('XPA', 'Gene', (127, 130))	('XPA', 'Gene', '7507', (10, 13))
334084	32435155	In the present study, we are interested in comprehensively exploring the possible effect of the XPA rs1800975 genetic variant on the susceptibility to different cancer diseases, such as skin cancer, lung cancer, breast cancer, esophageal cancer, gastric cancer, colorectal cancer or endometrial cancer.	('XPA', 'Gene', (96, 99))	('breast cancer', 'Phenotype', 'HP:0003002', (212, 225))	('gastric cancer', 'Disease', (246, 260))	('esophageal cancer', 'Disease', 'MESH:D004938', (227, 244))	('lung cancer', 'Disease', (199, 210))	('cancer diseases', 'Disease', 'MESH:D009369', (161, 176))	('endometrial cancer', 'Phenotype', 'HP:0012114', (283, 301))	('skin cancer', 'Disease', (186, 197))	('breast cancer', 'Disease', 'MESH:D001943', (212, 225))	('colorectal cancer', 'Disease', 'MESH:D015179', (262, 279))	('esophageal cancer', 'Disease', (227, 244))	('breast cancer', 'Disease', (212, 225))	('rs1800975', 'Mutation', 'rs1800975', (100, 109))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('gastric cancer', 'Disease', 'MESH:D013274', (246, 260))	('endometrial cancer', 'Disease', (283, 301))	('colorectal cancer', 'Disease', (262, 279))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('skin cancer', 'Phenotype', 'HP:0008069', (186, 197))	('endometrial cancer', 'Disease', 'MESH:D016889', (283, 301))	('lung cancer', 'Disease', 'MESH:D008175', (199, 210))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('lung cancer', 'Phenotype', 'HP:0100526', (199, 210))	('gastric cancer', 'Phenotype', 'HP:0012126', (246, 260))	('rs1800975', 'Var', (100, 109))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('skin cancer', 'Disease', 'MESH:D012878', (186, 197))	('colorectal cancer', 'Phenotype', 'HP:0003003', (262, 279))	('cancer diseases', 'Disease', (161, 176))	('XPA', 'Gene', '7507', (96, 99))
334085	32435155	There are different reports with distinct conclusions regarding the genetic relationship between the XPA rs1800975 polymorphism and cancer susceptibility in varied populations.	('cancer', 'Disease', (132, 138))	('XPA', 'Gene', (101, 104))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('XPA', 'Gene', '7507', (101, 104))	('rs1800975', 'Var', (105, 114))	('rs1800975', 'Mutation', 'rs1800975', (105, 114))	('cancer', 'Disease', 'MESH:D009369', (132, 138))
334086	32435155	For example, the XPA rs1800975 polymorphism was reported to be related to the risk of lung cancer in Norwegian, Germany or Korean populations but not in patients from Belgium or the USA.	('rs1800975', 'Var', (21, 30))	('patients', 'Species', '9606', (153, 161))	('lung cancer', 'Phenotype', 'HP:0100526', (86, 97))	('lung cancer', 'Disease', (86, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('XPA', 'Gene', '7507', (17, 20))	('related', 'Reg', (63, 70))	('rs1800975', 'Mutation', 'rs1800975', (21, 30))	('lung cancer', 'Disease', 'MESH:D008175', (86, 97))	('XPA', 'Gene', (17, 20))
334087	32435155	To the best of our knowledge, to date, only two meta-analyses regarding the association between the XPA rs1800975 polymorphism and susceptibility to overall cancer diseases have been previously reported in 2012.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('XPA', 'Gene', (100, 103))	('polymorphism', 'Var', (114, 126))	('rs1800975', 'Mutation', 'rs1800975', (104, 113))	('cancer diseases', 'Disease', (157, 172))	('cancer diseases', 'Disease', 'MESH:D009369', (157, 172))	('XPA', 'Gene', '7507', (100, 103))
334090	32435155	The inclusion criteria were as follows: genotypic frequency data for the XPA rs1800975 polymorphism in both cases and controls.	('XPA', 'Gene', '7507', (73, 76))	('rs1800975', 'Mutation', 'rs1800975', (77, 86))	('rs1800975', 'Var', (77, 86))	('XPA', 'Gene', (73, 76))
334092	32435155	If the FPRP value < 0.2 under the prior probability level of 0.1, a worthy outcome between XPA rs1800975 and cancer risk was considered.	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('cancer', 'Disease', (109, 115))	('XPA', 'Gene', (91, 94))	('XPA', 'Gene', '7507', (91, 94))	('rs1800975', 'Var', (95, 104))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('rs1800975', 'Mutation', 'rs1800975', (95, 104))
334099	32435155	Based on the dataset of GTEx, we also analyzed the "Significant Single-Tissue" eQTL (expression quantitative trait loci) and sQTL (splicing quantitative trait loci) in all tissues, for the XPA gene and the rs1800975 SNP.	('GTEx', 'Chemical', '-', (24, 28))	('XPA', 'Gene', (189, 192))	('rs1800975', 'Mutation', 'rs1800975', (206, 215))	('sQTL', 'Gene', (125, 129))	('rs1800975 SNP', 'Var', (206, 219))	('XPA', 'Gene', '7507', (189, 192))
334101	32435155	We failed to obtain evidence regarding the relationship between the XPA rs1800975 polymorphism and the overall risk of cancer in the overall population.	('rs1800975', 'Var', (72, 81))	('rs1800975', 'Mutation', 'rs1800975', (72, 81))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('cancer', 'Disease', (119, 125))	('XPA', 'Gene', '7507', (68, 71))	('XPA', 'Gene', (68, 71))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
334107	32435155	Moreover, we observed an enhanced risk of colorectal cancer under allelic (Table 4, P = 0.021, OR = 1.20), homozygotic (P = 0.007, OR = 1.68), heterozygotic (Table 5, P = 0.041, OR = 1.46), and dominant (P = 0.016, OR = 1.54) conditions, implying the potential effect of the AG genotype of XPA rs1800975 on the risk of colorectal cancer.	('colorectal cancer', 'Phenotype', 'HP:0003003', (42, 59))	('cancer', 'Phenotype', 'HP:0002664', (330, 336))	('colorectal cancer', 'Disease', (319, 336))	('colorectal cancer', 'Disease', (42, 59))	('XPA', 'Gene', (290, 293))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('XPA', 'Gene', '7507', (290, 293))	('rs1800975', 'Mutation', 'rs1800975', (294, 303))	('colorectal cancer', 'Disease', 'MESH:D015179', (319, 336))	('rs1800975', 'Var', (294, 303))	('colorectal cancer', 'Disease', 'MESH:D015179', (42, 59))	('colorectal cancer', 'Phenotype', 'HP:0003003', (319, 336))
334109	32435155	These data suggested that XPA rs1800975 may be associated with a high susceptibility to skin cancer, especially skin BCC.	('skin cancer', 'Disease', (88, 99))	('skin cancer', 'Disease', 'MESH:D012878', (88, 99))	('skin BCC', 'Disease', (112, 120))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('XPA', 'Gene', '7507', (26, 29))	('XPA', 'Gene', (26, 29))	('rs1800975', 'Var', (30, 39))	('rs1800975', 'Mutation', 'rs1800975', (30, 39))	('associated', 'Reg', (47, 57))	('skin cancer', 'Phenotype', 'HP:0008069', (88, 99))
334110	32435155	There were no significant differences between cases and controls in the majority of comparisons (Tables 2, 3, 4, P > 0.05), indicating that XPA rs1800975 does not seem to contribute to the risk of specific cancer types, such as breast cancer, esophageal cancer, gastric cancer, reproductive system cancer, endometrial cancer, or head and neck cancer.	('cancer', 'Disease', (318, 324))	('cancer', 'Disease', (343, 349))	('cancer', 'Disease', (254, 260))	('esophageal cancer', 'Disease', (243, 260))	('gastric cancer', 'Disease', 'MESH:D013274', (262, 276))	('rs1800975', 'Var', (144, 153))	('head and neck cancer', 'Phenotype', 'HP:0012288', (329, 349))	('breast cancer', 'Phenotype', 'HP:0003002', (228, 241))	('cancer', 'Phenotype', 'HP:0002664', (254, 260))	('cancer', 'Disease', 'MESH:D009369', (235, 241))	('cancer', 'Disease', (270, 276))	('cancer', 'Disease', 'MESH:D009369', (298, 304))	('endometrial cancer', 'Phenotype', 'HP:0012114', (306, 324))	('breast cancer', 'Disease', 'MESH:D001943', (228, 241))	('cancer', 'Phenotype', 'HP:0002664', (270, 276))	('cancer', 'Disease', (206, 212))	('cancer', 'Phenotype', 'HP:0002664', (298, 304))	('breast cancer', 'Disease', (228, 241))	('cancer', 'Disease', 'MESH:D009369', (318, 324))	('gastric cancer', 'Phenotype', 'HP:0012126', (262, 276))	('endometrial cancer', 'Disease', (306, 324))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('head and neck cancer', 'Disease', 'MESH:D006258', (329, 349))	('cancer', 'Disease', 'MESH:D009369', (343, 349))	('cancer', 'Disease', 'MESH:D009369', (254, 260))	('endometrial cancer', 'Disease', 'MESH:D016889', (306, 324))	('XPA', 'Gene', '7507', (140, 143))	('rs1800975', 'Mutation', 'rs1800975', (144, 153))	('XPA', 'Gene', (140, 143))	('cancer', 'Disease', (235, 241))	('cancer', 'Disease', 'MESH:D009369', (270, 276))	('cancer', 'Disease', (298, 304))	('gastric cancer', 'Disease', (262, 276))	('cancer', 'Disease', 'MESH:D009369', (206, 212))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))	('esophageal cancer', 'Disease', 'MESH:D004938', (243, 260))
334117	32435155	Collectively, this evidence did not support the strong association between lung cancer risk and XPA rs1800975.	('lung cancer', 'Disease', (75, 86))	('XPA', 'Gene', (96, 99))	('rs1800975', 'Var', (100, 109))	('lung cancer', 'Phenotype', 'HP:0100526', (75, 86))	('rs1800975', 'Mutation', 'rs1800975', (100, 109))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('lung cancer', 'Disease', 'MESH:D008175', (75, 86))	('XPA', 'Gene', '7507', (96, 99))
334120	32435155	We cannot obtain a relatively scientific conclusion regarding the potential links of XPA rs1800975 and colorectal cancer risk.	('links', 'Interaction', (76, 81))	('colorectal cancer', 'Disease', 'MESH:D015179', (103, 120))	('colorectal cancer', 'Phenotype', 'HP:0003003', (103, 120))	('colorectal cancer', 'Disease', (103, 120))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('XPA', 'Gene', (85, 88))	('rs1800975', 'Var', (89, 98))	('XPA', 'Gene', '7507', (85, 88))	('rs1800975', 'Mutation', 'rs1800975', (89, 98))
334124	32435155	4 shows that the cumulative Z-curve of the dominant model can cross both the lines of the TSA monitoring boundary and the required information size, suggesting a credible conclusion regarding the association between XPA rs1800975 and skin susceptibility.	('rs1800975', 'Mutation', 'rs1800975', (220, 229))	('XPA', 'Gene', (216, 219))	('association', 'Interaction', (196, 207))	('rs1800975', 'Var', (220, 229))	('TSA', 'Chemical', '-', (90, 93))	('skin susceptibility', 'Disease', (234, 253))	('XPA', 'Gene', '7507', (216, 219))
334125	32435155	Finally, based on GTEx datasets, we analyzed the expression profile of the XPA gene in different tissues, and the correlation between the gene expression and rs1800975 SNP of XPA.	('GTEx', 'Chemical', '-', (18, 22))	('XPA', 'Gene', (75, 78))	('rs1800975 SNP', 'Var', (158, 171))	('XPA', 'Gene', '7507', (75, 78))	('XPA', 'Gene', '7507', (175, 178))	('XPA', 'Gene', (175, 178))	('rs1800975', 'Mutation', 'rs1800975', (158, 167))
334127	32435155	6), we observed the potential association between XPA gene expression and rs1800975 SNP, in the tissues of artery aorta (P-value = 1.8e-9), artery tibial (P-value = 1.55e-6), esophagus muscularis (P-value = 3.59e-9), muscle skeletal (P-value = 6.39e-12), but not the skin tissue of ["not sun exposed (suprapubic)", P-value = 7.87e-1) or ["sun exposed (lower leg)", P-value = 5.16e-1).	('rs1800975 SNP', 'Var', (74, 87))	('lower leg', 'Phenotype', 'HP:0006385', (352, 361))	('XPA', 'Gene', (50, 53))	('rs1800975', 'Mutation', 'rs1800975', (74, 83))	('XPA', 'Gene', '7507', (50, 53))
334128	32435155	Cross-tissue meta-analysis further showed a potential overall correlation between gene expression and rs1800975 SNP of XPA (Fig.	('correlation', 'Interaction', (62, 73))	('rs1800975 SNP', 'Var', (102, 115))	('XPA', 'Gene', (119, 122))	('rs1800975', 'Mutation', 'rs1800975', (102, 111))	('XPA', 'Gene', '7507', (119, 122))
334129	32435155	In addition, our sQTL data further showed a potential association between rs1800975 SNP and the splicing changes of XPA gene in the thyroid tissue (Fig.	('rs1800975 SNP', 'Var', (74, 87))	('splicing', 'MPA', (96, 104))	('rs1800975', 'Mutation', 'rs1800975', (74, 83))	('XPA', 'Gene', (116, 119))	('XPA', 'Gene', '7507', (116, 119))
334130	32435155	Although we observed a group of publications regarding the influence of XPA rs1800975 on the risk of certain specific cancers, such as lung cancer, head and neck cancer, breast cancer, and digestive system cancer, the evaluation strategies, study number and statistical power differed.	('cancer', 'Disease', (177, 183))	('cancers', 'Disease', 'MESH:D009369', (118, 125))	('cancer', 'Disease', (162, 168))	('head and neck cancer', 'Phenotype', 'HP:0012288', (148, 168))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('lung cancer', 'Disease', (135, 146))	('rs1800975', 'Mutation', 'rs1800975', (76, 85))	('XPA', 'Gene', (72, 75))	('XPA', 'Gene', '7507', (72, 75))	('cancer', 'Disease', (206, 212))	('breast cancer', 'Phenotype', 'HP:0003002', (170, 183))	('cancers', 'Phenotype', 'HP:0002664', (118, 125))	('head and neck cancer', 'Disease', 'MESH:D006258', (148, 168))	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('cancers', 'Disease', (118, 125))	('cancer', 'Disease', (118, 124))	('cancer', 'Disease', 'MESH:D009369', (177, 183))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('cancer', 'Disease', (140, 146))	('lung cancer', 'Disease', 'MESH:D008175', (135, 146))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('breast cancer', 'Disease', 'MESH:D001943', (170, 183))	('breast cancer', 'Disease', (170, 183))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('lung cancer', 'Phenotype', 'HP:0100526', (135, 146))	('rs1800975', 'Var', (76, 85))	('cancer', 'Disease', 'MESH:D009369', (206, 212))	('cancer', 'Disease', 'MESH:D009369', (118, 124))
334131	32435155	We were interested in comprehensively exploring the impact of XPA rs1800975 on overall cancer susceptibility by pooling all currently available evidence.	('XPA', 'Gene', (62, 65))	('rs1800975', 'Var', (66, 75))	('cancer', 'Disease', (87, 93))	('rs1800975', 'Mutation', 'rs1800975', (66, 75))	('XPA', 'Gene', '7507', (62, 65))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cancer', 'Disease', 'MESH:D009369', (87, 93))
334132	32435155	To date, there are only two reported meta-analyses from 2012 describing the association between XPA rs1800975 and susceptibility to overall cancer diseases.	('XPA', 'Gene', (96, 99))	('rs1800975', 'Var', (100, 109))	('rs1800975', 'Mutation', 'rs1800975', (100, 109))	('cancer diseases', 'Disease', (140, 155))	('cancer diseases', 'Disease', 'MESH:D009369', (140, 155))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('XPA', 'Gene', '7507', (96, 99))
334134	32435155	Based on six genetic models (allelic, carrier, homozygotic, heterozygotic, dominant and recessive), a series of overall meta-analyses and subgroup analyses using the factors of race, control source and genotyping method, were used to scientifically assess the association between XPA rs1800975 polymorphism and the risk of cancer.	('cancer', 'Disease', 'MESH:D009369', (323, 329))	('cancer', 'Disease', (323, 329))	('rs1800975', 'Mutation', 'rs1800975', (284, 293))	('XPA', 'Gene', '7507', (280, 283))	('cancer', 'Phenotype', 'HP:0002664', (323, 329))	('XPA', 'Gene', (280, 283))	('polymorphism', 'Var', (294, 306))	('rs1800975 polymorphism', 'Var', (284, 306))
334137	32435155	included a total of thirty-six case-control or case-cohort studies from twenty-eight publications to conduct a meta-analysis for the genetic effect of XPA rs1800975 on the susceptibility to overall cancer.	('XPA', 'Gene', (151, 154))	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('rs1800975', 'Mutation', 'rs1800975', (155, 164))	('cancer', 'Disease', (198, 204))	('rs1800975', 'Var', (155, 164))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('XPA', 'Gene', '7507', (151, 154))
334141	32435155	The sample size contributes to the inconsistency with the data of Ding et al.. Additionally, we detected a decreased lung cancer risk in cases under the GG vs. AA, AG vs. AA, AG + GG vs. AA models but an increased risk of colorectal cancer under the allelic, homozygotic, heterozygotic, dominant models, indicating the possible effect of the AG genotype of XPA rs1800975 on the susceptibility to colorectal cancer.	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('lung cancer', 'Disease', (117, 128))	('cancer', 'Phenotype', 'HP:0002664', (407, 413))	('XPA', 'Gene', (357, 360))	('XPA', 'Gene', '7507', (357, 360))	('colorectal cancer', 'Disease', 'MESH:D015179', (396, 413))	('rs1800975', 'Mutation', 'rs1800975', (361, 370))	('colorectal cancer', 'Disease', 'MESH:D015179', (222, 239))	('decreased lung', 'Phenotype', 'HP:0002089', (107, 121))	('colorectal cancer', 'Disease', (396, 413))	('lung cancer', 'Disease', 'MESH:D008175', (117, 128))	('colorectal cancer', 'Disease', (222, 239))	('lung cancer', 'Phenotype', 'HP:0100526', (117, 128))	('Ding', 'Gene', '6045', (66, 70))	('Ding', 'Gene', (66, 70))	('rs1800975', 'Var', (361, 370))	('colorectal cancer', 'Phenotype', 'HP:0003003', (396, 413))	('decreased', 'NegReg', (107, 116))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('colorectal cancer', 'Phenotype', 'HP:0003003', (222, 239))
334142	32435155	Nevertheless, our data from FPRP analysis and another pooling analysis with only the population-based controls in the Caucasian population did not strongly support the protective role of the G allele within the XPA rs1800975 polymorphism in the risk of lung or colorectal cancer.	('cancer', 'Phenotype', 'HP:0002664', (272, 278))	('XPA', 'Gene', '7507', (211, 214))	('colorectal cancer', 'Phenotype', 'HP:0003003', (261, 278))	('XPA', 'Gene', (211, 214))	('rs1800975', 'Var', (215, 224))	('rs1800975', 'Mutation', 'rs1800975', (215, 224))	('colorectal cancer', 'Disease', (261, 278))	('lung', 'Disease', (253, 257))	('colorectal cancer', 'Disease', 'MESH:D015179', (261, 278))
334143	32435155	Our data from the pooling analysis, FPRP analysis and TSA demonstrated a significant difference between skin cancer cases and negative controls under six genetic models, suggesting the contribution of the G allele within XPA rs1800975 to an enhanced susceptibility to skin cancer.	('TSA', 'Chemical', '-', (54, 57))	('rs1800975', 'Var', (225, 234))	('rs1800975', 'Mutation', 'rs1800975', (225, 234))	('XPA', 'Gene', (221, 224))	('skin cancer', 'Phenotype', 'HP:0008069', (268, 279))	('enhanced', 'PosReg', (241, 249))	('XPA', 'Gene', '7507', (221, 224))	('skin cancer', 'Phenotype', 'HP:0008069', (104, 115))	('cancer', 'Phenotype', 'HP:0002664', (273, 279))	('skin cancer', 'Disease', (268, 279))	('skin cancer', 'Disease', (104, 115))	('skin cancer', 'Disease', 'MESH:D012878', (104, 115))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('skin cancer', 'Disease', 'MESH:D012878', (268, 279))
334144	32435155	Our eQTL and sQTL analysis data of GTEx showed that the XPA rs1800975 might not be associated with the gene expression or splicing changes of XPA in the skin tissue, suggesting the existence of other molecular mechanisms.	('XPA', 'Gene', (142, 145))	('XPA', 'Gene', '7507', (142, 145))	('GTEx', 'Chemical', '-', (35, 39))	('XPA', 'Gene', '7507', (56, 59))	('XPA', 'Gene', (56, 59))	('rs1800975', 'Mutation', 'rs1800975', (60, 69))	('rs1800975', 'Var', (60, 69))
334149	32435155	Thus, it is meaningful to explore the potential genetic influence of all XPA genetic variants or the combined variants of XPA and other relevant genes (such as xeroderma pigmentosum group D, XPD) in the pathogenesis of the above tumors, arterial or muscular system-related diseases.	('tumors', 'Disease', 'MESH:D009369', (229, 235))	('XPA', 'Gene', (73, 76))	('variants', 'Var', (85, 93))	('XPA', 'Gene', '7507', (73, 76))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('xeroderma pigmentosum', 'Disease', (160, 181))	('xeroderma pigmentosum', 'Disease', 'MESH:D014983', (160, 181))	('XPD', 'Gene', (191, 194))	('tumors', 'Disease', (229, 235))	('tumors', 'Phenotype', 'HP:0002664', (229, 235))	('arterial or muscular system-related diseases', 'Disease', (237, 281))	('XPD', 'Gene', '2068', (191, 194))	('XPA', 'Gene', (122, 125))	('XPA', 'Gene', '7507', (122, 125))
334150	32435155	To summarize, our comprehensive integrative analysis data demonstrated statistical evidence on the association between the XPA rs1800975 A/G polymorphism and susceptibility to skin cancer, especially skin BCC, in the Caucasian population.	('skin cancer', 'Disease', 'MESH:D012878', (176, 187))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('rs1800975 A/G', 'Var', (127, 140))	('susceptibility', 'Reg', (158, 172))	('skin BCC', 'Disease', (200, 208))	('skin cancer', 'Phenotype', 'HP:0008069', (176, 187))	('XPA', 'Gene', '7507', (123, 126))	('XPA', 'Gene', (123, 126))	('skin cancer', 'Disease', (176, 187))	('association', 'Interaction', (99, 110))	('rs1800975', 'Mutation', 'rs1800975', (127, 136))
334151	32435155	The enrollment of more case-control studies following the HWE principle in diverse ethnicities will help researchers to further verify the potential genetic role of the XPA rs1800975 polymorphism in the risk of lung or colorectal cancer.	('colorectal cancer', 'Phenotype', 'HP:0003003', (219, 236))	('XPA', 'Gene', (169, 172))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('XPA', 'Gene', '7507', (169, 172))	('rs1800975', 'Mutation', 'rs1800975', (173, 182))	('colorectal cancer', 'Disease', (219, 236))	('rs1800975', 'Var', (173, 182))	('lung', 'Disease', (211, 215))	('colorectal cancer', 'Disease', 'MESH:D015179', (219, 236))
334157	31270960	High linc00152 expression levels are associated with chemoresistance as well as poor prognosis and shorter survival.	('High', 'Var', (0, 4))	('chemoresistance', 'CPA', (53, 68))	('linc00152', 'Gene', (5, 14))	('expression levels', 'MPA', (15, 32))	('associated', 'Reg', (37, 47))	('linc00152', 'Gene', '112597', (5, 14))
334178	31270960	Their qRT-PCR and transwell assay results indicated that the knockdown of linc00152 prevents PDAC cell proliferation and invasion, thereby verifying the oncogenic property of linc00152.	('linc00152', 'Gene', '112597', (74, 83))	('prevents', 'NegReg', (84, 92))	('linc00152', 'Gene', '112597', (175, 184))	('knockdown', 'Var', (61, 70))	('linc00152', 'Gene', (74, 83))	('invasion', 'CPA', (121, 129))	('PDAC', 'Disease', (93, 97))	('PDAC', 'Phenotype', 'HP:0006725', (93, 97))	('linc00152', 'Gene', (175, 184))
334188	31270960	Specifically, Zhang et al 41 determined the knockdown of linc00152 can inhibit the cell cycle (especially the G1 phase) to delay cell proliferation.	('cell proliferation', 'CPA', (129, 147))	('linc00152', 'Gene', '112597', (57, 66))	('inhibit', 'NegReg', (71, 78))	('delay', 'NegReg', (123, 128))	('linc00152', 'Gene', (57, 66))	('knockdown', 'Var', (44, 53))
334201	31270960	Additionally, downregulated linc00152 expression decreases cell proliferation and shortens the S phase, possibly because of the epigenetic suppression of P16 and inhibition of miR-205.	('inhibition', 'NegReg', (162, 172))	('S phase', 'CPA', (95, 102))	('epigenetic', 'Var', (128, 138))	('miR-205', 'Gene', '406988', (176, 183))	('linc00152', 'Gene', (28, 37))	('P16', 'Gene', '1029', (154, 157))	('downregulated', 'NegReg', (14, 27))	('decreases', 'NegReg', (49, 58))	('cell proliferation', 'CPA', (59, 77))	('linc00152', 'Gene', '112597', (28, 37))	('shortens', 'NegReg', (82, 90))	('miR-205', 'Gene', (176, 183))	('P16', 'Gene', (154, 157))
334203	31270960	A cell viability assay indicated that inhibited linc00152 expression can disrupt cell proliferation.	('cell proliferation', 'CPA', (81, 99))	('inhibited', 'Var', (38, 47))	('linc00152', 'Gene', (48, 57))	('disrupt', 'NegReg', (73, 80))	('expression', 'MPA', (58, 68))	('linc00152', 'Gene', '112597', (48, 57))
334211	31270960	When we investigated the relationship between linc00152 and gastric carcinogenesis, we observed that linc00152 can specifically recognize the EGFR-binding site and activate the PI3K/AKT signaling pathway to promote the proliferation of gastric cancer cells.31 Moreover, PI3K signals help regulate many cellular functions such as proliferation, differentiation, apoptosis, and glucose transport.	('EGFR', 'Gene', '1956', (142, 146))	('linc00152', 'Gene', (101, 110))	('gastric carcinogenesis', 'Disease', (60, 82))	('gastric carcinogenesis', 'Disease', 'MESH:D063646', (60, 82))	('gastric cancer', 'Disease', (236, 250))	('differentiation', 'CPA', (344, 359))	('cellular functions', 'CPA', (302, 320))	('AKT', 'Gene', '207', (182, 185))	('PI3K', 'Var', (270, 274))	('apoptosis', 'CPA', (361, 370))	('glucose', 'Chemical', 'MESH:D005947', (376, 383))	('regulate', 'Reg', (288, 296))	('EGFR', 'Gene', (142, 146))	('gastric cancer', 'Disease', 'MESH:D013274', (236, 250))	('linc00152', 'Gene', '112597', (46, 55))	('proliferation', 'CPA', (329, 342))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('linc00152', 'Gene', (46, 55))	('gastric cancer', 'Phenotype', 'HP:0012126', (236, 250))	('glucose transport', 'CPA', (376, 393))	('linc00152', 'Gene', '112597', (101, 110))	('AKT', 'Gene', (182, 185))
334212	31270960	The signaling pathway comprising type IA PI3K and its downstream molecular protein kinase B (PKB or AKT) was recently determined to be closely related to the development and progression of human tumors.32 This pathway regulates the proliferation and survival of tumor cells, and its abnormal activity can lead to the development of malignant cells, while also facilitating cellular migration, adhesion, tumor angiogenesis, and the degradation of the extracellular matrix (Figure 3).	('tumor', 'Phenotype', 'HP:0002664', (262, 267))	('tumor', 'Disease', (195, 200))	('tumor', 'Disease', 'MESH:D009369', (403, 408))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('lead to', 'Reg', (305, 312))	('tumors', 'Phenotype', 'HP:0002664', (195, 201))	('regulates', 'Reg', (218, 227))	('AKT', 'Gene', (100, 103))	('tumor', 'Phenotype', 'HP:0002664', (403, 408))	('facilitating', 'PosReg', (360, 372))	('abnormal', 'Var', (283, 291))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('tumors', 'Disease', (195, 201))	('cellular migration', 'CPA', (373, 391))	('human', 'Species', '9606', (189, 194))	('tumor', 'Disease', (262, 267))	('adhesion', 'CPA', (393, 401))	('AKT', 'Gene', '207', (100, 103))	('tumor', 'Disease', 'MESH:D009369', (262, 267))	('survival', 'CPA', (250, 258))	('tumors', 'Disease', 'MESH:D009369', (195, 201))	('development of malignant cells', 'CPA', (317, 347))	('PKB', 'Gene', '207', (93, 96))	('degradation of the extracellular matrix', 'MPA', (431, 470))	('proliferation', 'CPA', (232, 245))	('PKB', 'Gene', (93, 96))	('tumor', 'Disease', (403, 408))
334217	31270960	Therefore, inhibiting linc00152 activity may be a viable strategy for treating esophageal cancer.	('esophageal cancer', 'Disease', (79, 96))	('linc00152', 'Gene', '112597', (22, 31))	('inhibiting', 'Var', (11, 21))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('esophageal cancer', 'Disease', 'MESH:D004938', (79, 96))	('activity', 'MPA', (32, 40))	('linc00152', 'Gene', (22, 31))
334241	31089135	In vivo Lkb1 ablation alone is sufficient to induce LSCC development by reducing MKK7 levels and JNK1/2 activities, independent of the AMPKalpha and mTOR pathways.	('SCC', 'Gene', '6317', (53, 56))	('JNK1/2 activities', 'MPA', (97, 114))	('Lkb1', 'Gene', (8, 12))	('induce', 'PosReg', (45, 51))	('ablation', 'Var', (13, 21))	('mTOR', 'Gene', (149, 153))	('MKK7 levels', 'MPA', (81, 92))	('reducing', 'NegReg', (72, 80))	('mTOR', 'Gene', '56717', (149, 153))	('SCC', 'Gene', (53, 56))	('Lkb1', 'Gene', '20869', (8, 12))
334243	31089135	Pharmaceutically elevated JNK1/2 activities abates Lkb1 dependent LSCC formation while compound mutations of Jnk1/2 and Lkb1 further accelerate LSCC progression.	('compound mutations', 'Var', (87, 105))	('accelerate', 'PosReg', (133, 143))	('Lkb1', 'Gene', '20869', (51, 55))	('Jnk1/2', 'Gene', '26419;26420', (109, 115))	('SCC', 'Gene', (145, 148))	('Lkb1', 'Gene', (120, 124))	('Lkb1', 'Gene', (51, 55))	('SCC', 'Gene', (67, 70))	('Jnk1/2', 'Gene', (109, 115))	('SCC', 'Gene', '6317', (145, 148))	('abates', 'NegReg', (44, 50))	('SCC', 'Gene', '6317', (67, 70))	('Lkb1', 'Gene', '20869', (120, 124))
334247	31089135	Here, the authors show that sole LKB1 depletion is sufficient to drive the development of this cancer, where downstream defective MKK7-JNK1/2 signalling activates the  Np63/p63 pathway to induce subsequent epithelial cells transformation and tumour progression.	('Np63/p63 pathway', 'Pathway', (168, 184))	('defective', 'Var', (120, 129))	('tumour', 'Disease', 'MESH:D009369', (242, 248))	('induce', 'PosReg', (188, 194))	('tumour', 'Disease', (242, 248))	('activates', 'PosReg', (153, 162))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('drive', 'Reg', (65, 70))	('cancer', 'Disease', (95, 101))	('depletion', 'Var', (38, 47))	('tumour', 'Phenotype', 'HP:0002664', (242, 248))	('MKK7-JNK1/2', 'MPA', (130, 141))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('epithelial cells transformation', 'CPA', (206, 237))
334250	31089135	Therefore, identifying cancer driver mutations in human cancers is valuable for targeted therapy.	('cancers', 'Disease', (56, 63))	('cancers', 'Disease', 'MESH:D009369', (56, 63))	('cancers', 'Phenotype', 'HP:0002664', (56, 63))	('cancer', 'Disease', (23, 29))	('cancer', 'Disease', 'MESH:D009369', (23, 29))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('mutations', 'Var', (37, 46))	('human', 'Species', '9606', (50, 55))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))
334255	31089135	Several preclinical models show that mice carrying compound mutations develop LSCC, as evidenced by studies on KrasG12D/Lkb1loss, Sox2OX/Lkb1loss, Ptenloss/Lkb1loss, and Cdkn2aloss/Ptenloss/Sox2OX mice.	('Lkb1', 'Gene', (137, 141))	('Sox2', 'Gene', '20674', (130, 134))	('Sox2', 'Gene', (190, 194))	('Lkb1', 'Gene', '20869', (156, 160))	('Pten', 'Gene', (147, 151))	('Pten', 'Gene', '19211', (147, 151))	('mice', 'Species', '10090', (197, 201))	('mice', 'Species', '10090', (37, 41))	('develop', 'PosReg', (70, 77))	('Lkb1', 'Gene', (120, 124))	('Kras', 'Gene', (111, 115))	('Lkb1', 'Gene', '20869', (137, 141))	('Sox2', 'Gene', '20674', (190, 194))	('SCC', 'Gene', '6317', (79, 82))	('Sox2', 'Gene', (130, 134))	('Kras', 'Gene', '16653', (111, 115))	('Lkb1', 'Gene', '20869', (120, 124))	('Lkb1', 'Gene', (156, 160))	('SCC', 'Gene', (79, 82))	('Pten', 'Gene', (181, 185))	('Pten', 'Gene', '19211', (181, 185))	('mutations', 'Var', (60, 69))
334256	31089135	In contrast, mutations in one single gene lead to lung adenocarcinomas (ADs), as shown by Trp53 deficiency, Pten ablation, KrasG12D or EgfrL858R activation and Sox2 overexpression (Sox2OX).	('lung adenocarcinomas', 'Disease', (50, 70))	('Kras', 'Gene', '16653', (123, 127))	('overexpression', 'PosReg', (165, 179))	('AD', 'Disease', 'MESH:D000544', (72, 74))	('Sox2', 'Gene', (181, 185))	('activation', 'PosReg', (145, 155))	('Sox2', 'Gene', '20674', (160, 164))	('deficiency', 'NegReg', (96, 106))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (50, 70))	('Sox2', 'Gene', '20674', (181, 185))	('lead to', 'Reg', (42, 49))	('mutations', 'Var', (13, 22))	('Trp53', 'Gene', '22059', (90, 95))	('EgfrL858R', 'Mutation', 'rs121434568', (135, 144))	('Kras', 'Gene', (123, 127))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (50, 69))	('Trp53', 'Gene', (90, 95))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (50, 70))	('Sox2', 'Gene', (160, 164))	('ablation', 'NegReg', (113, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (60, 69))	('carcinomas', 'Phenotype', 'HP:0030731', (60, 70))	('Pten', 'Gene', (108, 112))	('AD', 'Disease', (72, 74))	('Pten', 'Gene', '19211', (108, 112))
334264	31089135	LKB1 has been shown as an important suppressor of LSCC, supported by observations that Lkb1 deficiency in mouse lungs drives LSCC development in conjunction with additional mutations.	('deficiency', 'Var', (92, 102))	('SCC', 'Gene', (51, 54))	('Lkb1', 'Gene', '20869', (87, 91))	('SCC', 'Gene', '6317', (126, 129))	('SCC', 'Gene', '6317', (51, 54))	('Lkb1', 'Gene', (87, 91))	('drives', 'PosReg', (118, 124))	('mouse', 'Species', '10090', (106, 111))	('SCC', 'Gene', (126, 129))
334265	31089135	However, ablation of Lkb1 alone in mouse lung using adenovirus-Cre (Ad-Cre) via intranasal delivery does not cause pulmonary neoplasia.	('pulmonary neoplasia', 'Disease', 'MESH:D009369', (115, 134))	('Lkb1', 'Gene', '20869', (21, 25))	('pulmonary neoplasia', 'Disease', (115, 134))	('ablation', 'Var', (9, 17))	('pulmonary neoplasia', 'Phenotype', 'HP:0100526', (115, 134))	('neoplasia', 'Phenotype', 'HP:0002664', (125, 134))	('mouse', 'Species', '10090', (35, 40))	('Lkb1', 'Gene', (21, 25))
334267	31089135	Using a previously generated codon-optimized Cre recombinase under the control of the Club Cell Secretory Protein promoter (CCSPiCre) for all airway epithelial cells, including cells of large airways, we found that Lkb1 deficiency by itself is sufficient to induce LSCC.	('Lkb1', 'Gene', (215, 219))	('induce', 'Reg', (258, 264))	('deficiency', 'Var', (220, 230))	('Club', 'Phenotype', 'HP:0001217', (86, 90))	('Lkb1', 'Gene', '20869', (215, 219))	('SCC', 'Gene', (266, 269))	('SCC', 'Gene', '6317', (266, 269))
334268	31089135	In contrast, no LSCC was induced after manipulation of other five candidate genes that have frequent mutations in human LSCCs, including TP53, PTEN, ERRFI1, SMAD4 and KRAS.	('mutations', 'Var', (101, 110))	('SCC', 'Gene', '6317', (17, 20))	('SCC', 'Gene', (121, 124))	('SMAD4', 'Gene', (157, 162))	('SMAD4', 'Gene', '4089', (157, 162))	('KRAS', 'Gene', (167, 171))	('human', 'Species', '9606', (114, 119))	('PTEN', 'Gene', (143, 147))	('TP53', 'Gene', '7157', (137, 141))	('KRAS', 'Gene', '3845', (167, 171))	('SCC', 'Gene', '6317', (121, 124))	('ERRFI1', 'Gene', '54206', (149, 155))	('ERRFI1', 'Gene', (149, 155))	('SCC', 'Gene', (17, 20))	('TP53', 'Gene', (137, 141))
334274	31089135	Cells in the lesions exhibited positive staining of LSCC clinical markers (p63, DeltaNp63 and CK5) and lack of lung AD marker TTF1 expression (Fig.	('SCC', 'Gene', '6317', (53, 56))	('DeltaNp63', 'Var', (80, 89))	('TTF1', 'Gene', '22130', (126, 130))	('DeltaNp63', 'Chemical', '-', (80, 89))	('TTF1', 'Gene', (126, 130))	('lack', 'NegReg', (103, 107))	('lack of lung', 'Phenotype', 'HP:0005944', (103, 115))	('CK5', 'Gene', '110308', (94, 97))	('AD', 'Disease', 'MESH:D000544', (116, 118))	('p63', 'Var', (75, 78))	('AD', 'Disease', (116, 118))	('expression', 'MPA', (131, 141))	('CK5', 'Gene', (94, 97))	('SCC', 'Gene', (53, 56))
334278	31089135	1c-d) have relatively lower expression of p63 and DeltaNp63, which could be cells at the early phase of LSCC.	('p63', 'Var', (42, 45))	('DeltaNp63', 'Var', (50, 59))	('expression', 'MPA', (28, 38))	('DeltaNp63', 'Chemical', '-', (50, 59))	('SCC', 'Gene', (105, 108))	('lower', 'NegReg', (22, 27))	('SCC', 'Gene', '6317', (105, 108))
334279	31089135	Meanwhile, progressive lung SCC developmental stages (SCC-DSs) were also observed after Lkb1 ablation (Supplementary Data 1-2), including epithelial hyperplasia (5.4%) (Supplementary Fig.	('ablation', 'Var', (93, 101))	('SCC', 'Gene', '6317', (54, 57))	('Lkb1', 'Gene', (88, 92))	('SCC', 'Gene', (28, 31))	('DSs', 'Chemical', '-', (58, 61))	('epithelial hyperplasia', 'Disease', 'MESH:D017573', (138, 160))	('Lkb1', 'Gene', '20869', (88, 92))	('SCC', 'Gene', '6317', (28, 31))	('epithelial hyperplasia', 'Disease', (138, 160))	('SCC', 'Gene', (54, 57))
334285	31089135	Instead, lungs of Pten deletion, P53 ablation, Errfi1 knockout or KrasG12D activation had AD tumors, adenomas and atypical adenomatous hyperplasia that showed opposite profiles of marker expression compared with lung SCCs in Lkb1d/d mice (Table 1 and Supplementary Fig.	('Lkb1', 'Gene', (225, 229))	('P53', 'Gene', (33, 36))	('P53', 'Gene', '22059', (33, 36))	('AD tumors', 'Disease', (90, 99))	('Errfi1', 'Gene', (47, 53))	('Kras', 'Gene', (66, 70))	('adenomatous hyperplasia', 'Disease', (123, 146))	('adenomas', 'Disease', 'MESH:D000236', (101, 109))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('deletion', 'Var', (23, 31))	('adenomas', 'Disease', (101, 109))	('adenomatous hyperplasia', 'Disease', 'MESH:D011125', (123, 146))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('SCC', 'Gene', '6317', (217, 220))	('Kras', 'Gene', '16653', (66, 70))	('Lkb1', 'Gene', '20869', (225, 229))	('Pten', 'Gene', (18, 22))	('Pten', 'Gene', '19211', (18, 22))	('mice', 'Species', '10090', (233, 237))	('SCC', 'Gene', (217, 220))	('Errfi1', 'Gene', '74155', (47, 53))	('AD tumors', 'Disease', 'MESH:D000544', (90, 99))
334286	31089135	Moreover, loss of Smad4 exhibited no histomorphologic change in lungs (Supplementary Fig.	('loss', 'Var', (10, 14))	('Smad4', 'Gene', '17128', (18, 23))	('Smad4', 'Gene', (18, 23))
334287	31089135	In summary, these findings reveal a unique capacity of Lkb1 deficiency in the induction of lung SCCs and SCC-DSs.	('deficiency', 'Var', (60, 70))	('SCC', 'Gene', (96, 99))	('Lkb1', 'Gene', '20869', (55, 59))	('DSs', 'Chemical', '-', (109, 112))	('SCC', 'Gene', '6317', (96, 99))	('SCC', 'Gene', (105, 108))	('Lkb1', 'Gene', (55, 59))	('SCC', 'Gene', '6317', (105, 108))
334290	31089135	Functionally, Lkb1 deficiency altered expression of genes that are enriched in functions of cell movement, morphology, death and survival (Supplementary Table 1), reflecting the histological observations.	('expression of genes', 'MPA', (38, 57))	('deficiency', 'Var', (19, 29))	('Lkb1', 'Gene', '20869', (14, 18))	('Lkb1', 'Gene', (14, 18))	('altered', 'Reg', (30, 37))
334293	31089135	Like the observations in SCCs, no significant changes of AMPKalpha and mTOR phosphorylation levels were found in 1- and 3-month old mouse lungs at the pretumor stage in response to Lkb1 deficiency (Fig.	('SCC', 'Gene', (25, 28))	('Lkb1', 'Gene', '20869', (181, 185))	('Lkb1', 'Gene', (181, 185))	('SCC', 'Gene', '6317', (25, 28))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('mTOR', 'Gene', (71, 75))	('mouse', 'Species', '10090', (132, 137))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('deficiency', 'Var', (186, 196))	('mTOR', 'Gene', '56717', (71, 75))	('AMPKalpha', 'MPA', (57, 66))	('tumor', 'Disease', (154, 159))
334295	31089135	Close examination of genes altered by Lkb1 deficiency via ingenuity pathway analysis (IPA) revealed JNK1/2, P38, NFkB and ERK1/2 as the common downstream pathways for candidate upstream regulators of Lkb1 responsive genes (Table 2 and Supplementary Data 3).	('Lkb1', 'Gene', (200, 204))	('Lkb1', 'Gene', '20869', (38, 42))	('ERK1/2', 'Gene', '26417;26413', (122, 128))	('P38', 'Gene', (108, 111))	('P38', 'Gene', '26416', (108, 111))	('Lkb1', 'Gene', '20869', (200, 204))	('Lkb1', 'Gene', (38, 42))	('ERK1/2', 'Gene', (122, 128))	('deficiency', 'Var', (43, 53))
334297	31089135	These observations establish an association between Lkb1 deficiency and reduced JNK1/2 activities in LSCC.	('reduced', 'NegReg', (72, 79))	('deficiency', 'Var', (57, 67))	('JNK1/2 activities', 'MPA', (80, 97))	('SCC', 'Gene', '6317', (102, 105))	('Lkb1', 'Gene', '20869', (52, 56))	('Lkb1', 'Gene', (52, 56))	('SCC', 'Gene', (102, 105))
334303	31089135	Next, the timing of change of JNK1/2 activities in response to Lkb1 deficiency was examined to determine the sequence of events between JNK1/2 inactivation and LSCC development.	('JNK1/2', 'Gene', (136, 142))	('SCC', 'Gene', (161, 164))	('deficiency', 'Var', (68, 78))	('Lkb1', 'Gene', '20869', (63, 67))	('SCC', 'Gene', '6317', (161, 164))	('Lkb1', 'Gene', (63, 67))	('inactivation', 'NegReg', (143, 155))
334314	31089135	This suggests that the impact of Lkb1 deletion on p-JNK1/2 levels does not appear to be entirely direct, implying that proliferation induced by Lkb1 loss occurs prior to the decline in p-JNK1/2 levels.	('Lkb1', 'Gene', (33, 37))	('Lkb1', 'Gene', '20869', (144, 148))	('loss', 'NegReg', (149, 153))	('p-JNK1/2', 'MPA', (185, 193))	('Lkb1', 'Gene', (144, 148))	('deletion', 'Var', (38, 46))	('Lkb1', 'Gene', '20869', (33, 37))	('proliferation', 'CPA', (119, 132))
334316	31089135	To investigate the underlying mechanism of JNK1/2 inactivation during LSCC development, we examined expression levels of MKK7, which phosphorylates JNK1/2 at T183/Y185 to regulate JNK1/2 activities in previous reports.	('MKK7', 'Gene', (121, 125))	('regulate', 'Reg', (171, 179))	('activities', 'MPA', (187, 197))	('SCC', 'Gene', (71, 74))	('T183/Y185', 'Var', (158, 167))	('SCC', 'Gene', '6317', (71, 74))
334322	31089135	Similar results were observed in H157 cells, which are human LSCC cells with the mutations of LKB1 and PTEN (Supplementary Fig.	('PTEN', 'Gene', (103, 107))	('SCC', 'Gene', '6317', (62, 65))	('human', 'Species', '9606', (55, 60))	('LKB1', 'Gene', (94, 98))	('H157', 'CellLine', 'CVCL:2458', (33, 37))	('mutations', 'Var', (81, 90))	('SCC', 'Gene', (62, 65))
334323	31089135	Meanwhile, at the pretumor stage modeled by a nontumorigenic human bronchial epithelial cell line NL20 and Beas-2B, the MKK7 knockout also had reduced JNK1/2 phosphorylation levels (Fig.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('knockout', 'Var', (125, 133))	('NL20', 'CellLine', 'CVCL:3756', (98, 102))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor', 'Disease', (21, 26))	('Beas-2B', 'CellLine', 'CVCL:0168', (107, 114))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))	('tumor', 'Disease', (49, 54))	('MKK7', 'Gene', (120, 124))	('JNK1/2 phosphorylation levels', 'MPA', (151, 180))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('human', 'Species', '9606', (61, 66))	('reduced', 'NegReg', (143, 150))
334325	31089135	Furthermore, ablation of LKB1 and MKK7 in NL20 and Beas-2b promoted cell growth (Fig.	('LKB1', 'Gene', (25, 29))	('NL20', 'CellLine', 'CVCL:3756', (42, 46))	('ablation', 'Var', (13, 21))	('cell growth', 'CPA', (68, 79))	('MKK7', 'Gene', (34, 38))	('promoted', 'PosReg', (59, 67))
334329	31089135	As anticipated, Jnk1/2 ablation increased cell growth in mLSCC cells (Fig.	('cell growth', 'CPA', (42, 53))	('SCC', 'Gene', (59, 62))	('Jnk1/2', 'Gene', (16, 22))	('Jnk1/2', 'Gene', '26419;26420', (16, 22))	('ablation', 'Var', (23, 31))	('SCC', 'Gene', '6317', (59, 62))	('increased', 'PosReg', (32, 41))
334340	31089135	1a, b) (Supplementary Data 1-2), and loss of Jnk1/2 in the Lkb1-deficient background accelerated LSCC development in vivo.	('Lkb1', 'Gene', '20869', (59, 63))	('accelerated', 'PosReg', (85, 96))	('SCC', 'Gene', '6317', (98, 101))	('Lkb1', 'Gene', (59, 63))	('Jnk1/2', 'Gene', '26419;26420', (45, 51))	('loss', 'Var', (37, 41))	('Jnk1/2', 'Gene', (45, 51))	('SCC', 'Gene', (98, 101))
334346	31089135	Taken together, these results reveal that compound mutations of Jnk1/2 and Lkb1 facilitate LSCC development and demonstrate that JNK1/2 act as major suppressors for Lkb1-dependent LSCC progression.	('Lkb1', 'Gene', '20869', (165, 169))	('compound mutations', 'Var', (42, 60))	('SCC', 'Gene', (181, 184))	('SCC', 'Gene', '6317', (92, 95))	('Jnk1/2', 'Gene', '26419;26420', (64, 70))	('Lkb1', 'Gene', (75, 79))	('facilitate', 'PosReg', (80, 90))	('Lkb1', 'Gene', (165, 169))	('Jnk1/2', 'Gene', (64, 70))	('SCC', 'Gene', '6317', (181, 184))	('Lkb1', 'Gene', '20869', (75, 79))	('SCC', 'Gene', (92, 95))
334354	31089135	Conversely, treatment with stimuli of JNK1/2 pathway, IL-1beta, TNFalpha or Anisomycin raised JNK1/2 phosphorylation levels and decreased the expression of DeltaNp63 and p63 in parental or gRNA-Control mLSCC cells (Fig.	('IL-1beta', 'Gene', (54, 62))	('JNK1/2 phosphorylation levels', 'MPA', (94, 123))	('raised', 'PosReg', (87, 93))	('TNFalpha', 'Gene', '21926', (64, 72))	('DeltaNp63', 'Chemical', '-', (156, 165))	('p63', 'Var', (170, 173))	('DeltaNp63', 'Gene', (156, 165))	('SCC', 'Gene', (204, 207))	('decreased', 'NegReg', (128, 137))	('Anisomycin', 'Chemical', 'MESH:D000841', (76, 86))	('IL-1beta', 'Gene', '16176', (54, 62))	('expression', 'MPA', (142, 152))	('TNFalpha', 'Gene', (64, 72))	('SCC', 'Gene', '6317', (204, 207))
334356	31089135	Global assessment of the impact of Jnk1/2 ablation on gene expression revealed increased P63 mRNA levels, altered expression of downstream targets of TP63, and changes in genes that are enriched for regulating cancer and cell proliferation (Table 4; Supplementary Table 7 and Supplementary Data 3).	('changes', 'Reg', (160, 167))	('altered', 'Reg', (106, 113))	('increased', 'PosReg', (79, 88))	('Jnk1/2', 'Gene', (35, 41))	('genes', 'Gene', (171, 176))	('P63', 'Gene', '22061', (89, 92))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('P63', 'Gene', (89, 92))	('P63', 'Gene', '22061', (151, 154))	('P63', 'Gene', (151, 154))	('expression', 'MPA', (114, 124))	('cancer', 'Disease', 'MESH:D009369', (210, 216))	('ablation', 'Var', (42, 50))	('Jnk1/2', 'Gene', '26419;26420', (35, 41))	('cell', 'CPA', (221, 225))	('cancer', 'Disease', (210, 216))
334357	31089135	Downstream targets of TNF and IL-1beta are also impacted by Jnk1/2 ablation (Table 4 and Supplementary Data 3), which is in accordance with the well-known role of JNK1/2 in mediating activities of these two cytokines.	('IL-1beta', 'Gene', '16176', (30, 38))	('ablation', 'Var', (67, 75))	('IL-1beta', 'Gene', (30, 38))	('Jnk1/2', 'Gene', (60, 66))	('impacted', 'Reg', (48, 56))	('Jnk1/2', 'Gene', '26419;26420', (60, 66))	('TNF', 'Gene', (22, 25))	('TNF', 'Gene', '21926', (22, 25))
334358	31089135	In summary, these results indicate that JNK1/2 inactivation activates the DeltaNp63/p63 pathway to promote LSCC development.	('inactivation', 'Var', (47, 59))	('JNK1/2', 'Gene', (40, 46))	('promote', 'PosReg', (99, 106))	('SCC', 'Gene', (108, 111))	('DeltaNp63', 'Chemical', '-', (74, 83))	('SCC', 'Gene', '6317', (108, 111))	('activates', 'PosReg', (60, 69))	('DeltaNp63/p63 pathway', 'Pathway', (74, 95))
334375	31089135	JNK1/2 activities were defined by a gene signature that was generated using these DEGs induced by knocking out Jnk1/2 in mLSCC cells (Supplementary Data 3).	('SCC', 'Gene', '6317', (123, 126))	('knocking out', 'Var', (98, 110))	('Jnk1/2', 'Gene', (111, 117))	('Jnk1/2', 'Gene', '26419;26420', (111, 117))	('SCC', 'Gene', (123, 126))
334384	31089135	In this study, we generated a mouse lung SCC model in which the sole ablation of Lkb1 in mouse lung airways is sufficient to induce LSCC and have established Lkb1 as a key suppressor gene of LSCC.	('SCC', 'Gene', (41, 44))	('Lkb1', 'Gene', '20869', (158, 162))	('SCC', 'Gene', (133, 136))	('SCC', 'Gene', '6317', (133, 136))	('SCC', 'Gene', '6317', (192, 195))	('mouse', 'Species', '10090', (30, 35))	('induce', 'Reg', (125, 131))	('SCC', 'Gene', '6317', (41, 44))	('Lkb1', 'Gene', (81, 85))	('Lkb1', 'Gene', (158, 162))	('ablation', 'Var', (69, 77))	('SCC', 'Gene', (192, 195))	('mouse', 'Species', '10090', (89, 94))	('Lkb1', 'Gene', '20869', (81, 85))
334385	31089135	Lkb1 deficiency results in decreased expression of MKK7, a reduction of JNK1/2 phosphorylation, lower JNK1/2 activities and elevated DeltaNp63 signaling, which subsequently leads to epithelial cells transformation and progression into LSCC (Fig.	('SCC', 'Gene', '6317', (236, 239))	('deficiency', 'Var', (5, 15))	('JNK1/2 phosphorylation', 'MPA', (72, 94))	('Lkb1', 'Gene', '20869', (0, 4))	('decreased', 'NegReg', (27, 36))	('lower', 'NegReg', (96, 101))	('DeltaNp63 signaling', 'MPA', (133, 152))	('JNK1/2 activities', 'MPA', (102, 119))	('expression', 'MPA', (37, 47))	('reduction', 'NegReg', (59, 68))	('SCC', 'Gene', (236, 239))	('Lkb1', 'Gene', (0, 4))	('DeltaNp63', 'Chemical', '-', (133, 142))	('epithelial cells transformation', 'CPA', (182, 213))	('MKK7', 'Protein', (51, 55))	('leads to', 'Reg', (173, 181))	('elevated', 'PosReg', (124, 132))
334386	31089135	Loss of Lkb1 however does not automatically cause loss of p-JNK1/2 in normal mouse airway epithelial cells.	('Lkb1', 'Gene', '20869', (8, 12))	('Loss', 'Var', (0, 4))	('mouse', 'Species', '10090', (77, 82))	('Lkb1', 'Gene', (8, 12))
334391	31089135	Although Lkb1 is involved in three of these mouse models, ablating Lkb1 alone using adenovirus-Cre (Ad-Cre) fails to cause pulmonary neoplasia.	('Lkb1', 'Gene', (9, 13))	('Lkb1', 'Gene', (67, 71))	('ablating', 'Var', (58, 66))	('pulmonary neoplasia', 'Disease', 'MESH:D009369', (123, 142))	('Lkb1', 'Gene', '20869', (9, 13))	('cause', 'Reg', (117, 122))	('neoplasia', 'Phenotype', 'HP:0002664', (133, 142))	('pulmonary neoplasia', 'Disease', (123, 142))	('Lkb1', 'Gene', '20869', (67, 71))	('mouse', 'Species', '10090', (44, 49))	('pulmonary neoplasia', 'Phenotype', 'HP:0100526', (123, 142))
334394	31089135	Results based on the CCSPiCre system indeed revealed a previously underestimated role of Lkb1 lost-of-function mutation that by itself Lkb1 deficiency is sufficient to initiate LSCC, in comparison with any single mutation in either Trp53, Pten, Errfi1, Smad4 or KrasG12D (Table 1).	('SCC', 'Gene', '6317', (178, 181))	('SCC', 'Gene', (178, 181))	('deficiency', 'Var', (140, 150))	('Errfi1', 'Gene', (245, 251))	('Lkb1', 'Gene', (89, 93))	('Smad4', 'Gene', '17128', (253, 258))	('Kras', 'Gene', (262, 266))	('Lkb1', 'Gene', (135, 139))	('Pten', 'Gene', (239, 243))	('Pten', 'Gene', '19211', (239, 243))	('mutation', 'Var', (111, 119))	('Kras', 'Gene', '16653', (262, 266))	('Trp53', 'Gene', '22059', (232, 237))	('Lkb1', 'Gene', '20869', (89, 93))	('Errfi1', 'Gene', '74155', (245, 251))	('lost-of-function', 'NegReg', (94, 110))	('Smad4', 'Gene', (253, 258))	('Trp53', 'Gene', (232, 237))	('Lkb1', 'Gene', '20869', (135, 139))
334395	31089135	Furthermore, the merit that Lkb1 ablation alone induces LSCC offers a simplified platform for screening other regulators of LSCC development.	('SCC', 'Gene', '6317', (57, 60))	('ablation', 'Var', (33, 41))	('Lkb1', 'Gene', '20869', (28, 32))	('SCC', 'Gene', (125, 128))	('SCC', 'Gene', '6317', (125, 128))	('induces', 'Reg', (48, 55))	('Lkb1', 'Gene', (28, 32))	('SCC', 'Gene', (57, 60))
334399	31089135	1c), close to the trachea, after the deletion of Lkb1 in large airways (Supplementary Figs.	('Lkb1', 'Gene', '20869', (49, 53))	('Lkb1', 'Gene', (49, 53))	('deletion', 'Var', (37, 45))
334403	31089135	JNK1/2 inactivation is associated with not only LSCC but also cervical and head and neck SCC (Fig.	('SCC', 'Gene', (49, 52))	('SCC', 'Gene', '6317', (89, 92))	('inactivation', 'Var', (7, 19))	('cervical', 'Disease', (62, 70))	('JNK1/2', 'Gene', (0, 6))	('SCC', 'Gene', '6317', (49, 52))	('associated', 'Reg', (23, 33))	('SCC', 'Gene', (89, 92))
334406	31089135	These results suggest that JNK1/2 inactivation in vivo may promote or lead to SCC formation and progression besides lung SCC.	('inactivation', 'Var', (34, 46))	('SCC', 'Gene', '6317', (78, 81))	('JNK1/2', 'Gene', (27, 33))	('SCC', 'Gene', (121, 124))	('progression', 'CPA', (96, 107))	('lead to', 'Reg', (70, 77))	('promote', 'PosReg', (59, 66))	('SCC', 'Gene', '6317', (121, 124))	('SCC', 'Gene', (78, 81))
334409	31089135	In addition to lung SCCs, LKB1 and MKK7, as upstream regulators of P-JNK1/2, are also found to be frequently mutated in other human SCCs, such as cervical, cutaneous, head and neck and esophageal SCCs (cBioPortal databases).	('SCC', 'Gene', (196, 199))	('MKK7', 'Gene', (35, 39))	('esophageal SCCs', 'Disease', (185, 200))	('human', 'Species', '9606', (126, 131))	('SCC', 'Gene', (20, 23))	('cutaneous', 'Disease', (156, 165))	('esophageal SCCs', 'Disease', 'MESH:D004941', (185, 200))	('SCC', 'Gene', '6317', (196, 199))	('SCC', 'Gene', (132, 135))	('SCC', 'Gene', '6317', (20, 23))	('mutated', 'Var', (109, 116))	('cervical', 'Disease', (146, 154))	('SCC', 'Gene', '6317', (132, 135))	('LKB1', 'Gene', (26, 30))
334410	31089135	Meanwhile, we showed that the DeltaNp63 pathway, a well-proven oncogenic and squamous linage pathway, was activated after JNK1/2 inactivation.	('JNK1/2', 'Gene', (122, 128))	('activated', 'PosReg', (106, 115))	('DeltaNp63 pathway', 'Pathway', (30, 47))	('DeltaNp63', 'Chemical', '-', (30, 39))	('inactivation', 'Var', (129, 141))
334411	31089135	This further suggests that JNK1/2 inactivation promotes SCC development through a common downstream target p63 since TP63 was also amplified in human cervical and head and neck SCCs (cBioPortal databases).	('human', 'Species', '9606', (144, 149))	('inactivation', 'Var', (34, 46))	('promotes', 'PosReg', (47, 55))	('SCC', 'Gene', (56, 59))	('JNK1/2', 'Gene', (27, 33))	('SCC', 'Gene', (177, 180))	('SCC', 'Gene', '6317', (56, 59))	('SCC', 'Gene', '6317', (177, 180))
334414	31089135	Although the Ikka mutant (K44A) knock-in mice does develop spontaneous LSCCs, K44A mutation has not been identified in human LSCC, and the copy number losses and other genomic mutations in IKKa are also rare in human LSCCs.	('K44A', 'Mutation', 'p.K44A', (78, 82))	('copy number losses', 'Var', (139, 157))	('SCC', 'Gene', '6317', (218, 221))	('develop', 'PosReg', (51, 58))	('K44A', 'Mutation', 'p.K44A', (26, 30))	('mice', 'Species', '10090', (41, 45))	('SCC', 'Gene', '6317', (126, 129))	('human', 'Species', '9606', (119, 124))	('Ikka', 'Gene', (13, 17))	('mutant', 'Var', (18, 24))	('SCC', 'Gene', (72, 75))	('human', 'Species', '9606', (211, 216))	('Ikka', 'Gene', '12675', (13, 17))	('IKKa', 'Gene', '1147', (189, 193))	('SCC', 'Gene', (218, 221))	('SCC', 'Gene', '6317', (72, 75))	('IKKa', 'Gene', (189, 193))	('SCC', 'Gene', (126, 129))
334415	31089135	Here, we demonstrated the potential to target JNK1/2 for human SCC treatment in preclinical models in that activation of P-JNK1/2 using Anisomycin induced LSCC cell death and inhibited LSCC development (Fig.	('SCC', 'Gene', '6317', (186, 189))	('SCC', 'Gene', (63, 66))	('Anisomycin', 'Chemical', 'MESH:D000841', (136, 146))	('inhibited', 'NegReg', (175, 184))	('activation', 'Var', (107, 117))	('SCC', 'Gene', (156, 159))	('SCC', 'Gene', '6317', (63, 66))	('SCC', 'Gene', (186, 189))	('P-JNK1/2', 'Gene', (121, 129))	('SCC', 'Gene', '6317', (156, 159))	('human', 'Species', '9606', (57, 62))
334425	31089135	Hence, the mechanism of LSCC formation and progression regulated by genetic alternations are largely unknown.	('SCC', 'Gene', (25, 28))	('SCC', 'Gene', '6317', (25, 28))	('genetic alternations', 'Var', (68, 88))
334430	31089135	Consistent with the observations in human lung cancers, these mouse results show that epithelial hyperplasia can develop into SCC, AD or ASC, and the developmental direction of epithelial hyperplasia can be reflected by expression of these markers, such as p63 and CK5 for SCC and TTF1 for AD.	('epithelial hyperplasia', 'Disease', (177, 199))	('CK5', 'Gene', (265, 268))	('lung cancers', 'Disease', 'MESH:D008175', (42, 54))	('epithelial hyperplasia', 'Disease', 'MESH:D017573', (177, 199))	('SCC', 'Gene', '6317', (273, 276))	('mouse', 'Species', '10090', (62, 67))	('lung cancers', 'Disease', (42, 54))	('CK5', 'Gene', '110308', (265, 268))	('lung cancer', 'Phenotype', 'HP:0100526', (42, 53))	('SCC', 'Gene', (273, 276))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('lung cancers', 'Phenotype', 'HP:0100526', (42, 54))	('AD', 'Disease', (131, 133))	('epithelial hyperplasia', 'Disease', (86, 108))	('TTF1', 'Gene', (281, 285))	('cancers', 'Phenotype', 'HP:0002664', (47, 54))	('AD', 'Disease', (290, 292))	('epithelial hyperplasia', 'Disease', 'MESH:D017573', (86, 108))	('AD', 'Disease', 'MESH:D000544', (131, 133))	('TTF1', 'Gene', '22130', (281, 285))	('ASC', 'Disease', (137, 140))	('SCC', 'Gene', '6317', (126, 129))	('AD', 'Disease', 'MESH:D000544', (290, 292))	('human', 'Species', '9606', (36, 41))	('p63', 'Var', (257, 260))	('SCC', 'Gene', (126, 129))
334440	31089135	As we described in Table 5, Jnk1/2 knockout under Lkb1-loss background not only shortened the average developing time of LSCC-DSs from 13 months to 4 months, but also increased the incidence of LSCC-DSs from 25 to 100%, besides the promotion of LSCCs.	('Lkb1', 'Gene', (50, 54))	('SCC', 'Gene', (122, 125))	('SCC', 'Gene', (195, 198))	('SCC', 'Gene', '6317', (122, 125))	('SCC', 'Gene', '6317', (195, 198))	('Lkb1', 'Gene', '20869', (50, 54))	('increased', 'PosReg', (167, 176))	('SCC', 'Gene', (246, 249))	('DSs', 'Chemical', '-', (126, 129))	('DSs', 'Chemical', '-', (199, 202))	('Jnk1/2', 'Gene', (28, 34))	('Jnk1/2', 'Gene', '26419;26420', (28, 34))	('shortened', 'NegReg', (80, 89))	('knockout', 'Var', (35, 43))	('SCC', 'Gene', '6317', (246, 249))
334441	31089135	Unlike Lkb1d/d mouse lungs in which only some of epithelial hyperplasia were positive for staining of p63 and CK5 (Supplementary Fig.	('Lkb1', 'Gene', '20869', (7, 11))	('Lkb1', 'Gene', (7, 11))	('CK5', 'Gene', (110, 113))	('mouse', 'Species', '10090', (15, 20))	('CK5', 'Gene', '110308', (110, 113))	('p63', 'Var', (102, 105))	('epithelial hyperplasia', 'Disease', 'MESH:D017573', (49, 71))	('epithelial hyperplasia', 'Disease', (49, 71))
334444	31089135	These results conclude that JNK1/2 inactivation drives LSCC formation and development in response to Lkb1 deficiency.	('development', 'CPA', (74, 85))	('drives', 'PosReg', (48, 54))	('JNK1/2', 'Gene', (28, 34))	('inactivation', 'Var', (35, 47))	('SCC', 'Gene', (56, 59))	('deficiency', 'Var', (106, 116))	('Lkb1', 'Gene', '20869', (101, 105))	('SCC', 'Gene', '6317', (56, 59))	('Lkb1', 'Gene', (101, 105))
334451	31089135	These results suggest inactivation of the JNK1/2 pathway induces DeltaNp63 expression partially due to the decrease of c-Jun.	('inactivation', 'Var', (22, 34))	('induces', 'Reg', (57, 64))	('DeltaNp63', 'Chemical', '-', (65, 74))	('DeltaNp63', 'Gene', (65, 74))	('c-Jun', 'Gene', '16476', (119, 124))	('JNK1/2 pathway', 'Pathway', (42, 56))	('decrease', 'NegReg', (107, 115))	('c-Jun', 'Gene', (119, 124))	('expression', 'MPA', (75, 85))
334464	31089135	Interestingly, the COSMIC database (https://cancer.sanger.ac.uk/cosmic), which includes 1588 SCC and 36 ASC samples among 8018 patients, shows that the frequency of LKB1 mutations in pure human SCC and ASC is 1.89% and 11.11%, respectively.	('LKB1', 'Gene', (165, 169))	('human', 'Species', '9606', (188, 193))	('mutations', 'Var', (170, 179))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('SCC', 'Gene', (93, 96))	('patients', 'Species', '9606', (127, 135))	('SCC', 'Gene', (194, 197))	('SCC', 'Gene', '6317', (93, 96))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('SCC', 'Gene', '6317', (194, 197))
334465	31089135	In other words, the mutation rate in ASC is much higher (5.89 fold) than SCC.	('ASC', 'Disease', (37, 40))	('mutation', 'Var', (20, 28))	('SCC', 'Gene', (73, 76))	('SCC', 'Gene', '6317', (73, 76))	('higher', 'PosReg', (49, 55))
334467	31089135	Meanwhile, we observed one common mutation (CDS: c.1062C > G; AA: p.F354L) between SCC and ASC, which may indicate the potential for transdifferentiating.	('SCC', 'Gene', (83, 86))	('c.1062C > G', 'Mutation', 'c.1062C>G', (49, 60))	('p.F354L', 'Mutation', 'p.F354L', (66, 73))	('CDS', 'Chemical', 'MESH:D002104', (44, 47))	('SCC', 'Gene', '6317', (83, 86))	('p.F354L', 'Var', (66, 73))
334475	31089135	The deletion or overexpression of those genes in mouse lung was achieved by breeding conditional genetic mice with CCSPiCre mice.	('overexpression', 'PosReg', (16, 30))	('mice', 'Species', '10090', (124, 128))	('mouse', 'Species', '10090', (49, 54))	('deletion', 'Var', (4, 12))	('mice', 'Species', '10090', (105, 109))
334486	31089135	NL20 was cultured using complete growth medium: Ham's F12 medium, 2.7 g/L glucose, 0.005 mg/mL insulin, 10 ng/mL epidermal growth factor, 0.001 mg/mL transferrin, 500 ng/mL hydrocortisone and 4% FBS.	('NL20', 'CellLine', 'CVCL:3756', (0, 4))	('hydrocortisone', 'Chemical', 'MESH:D006854', (173, 187))	('FBS', 'Disease', 'MESH:D005198', (195, 198))	('0.005 mg/mL', 'Var', (83, 94))	('glucose', 'Chemical', 'MESH:D005947', (74, 81))	('0.001 mg/mL', 'Var', (138, 149))	('transferrin', 'Gene', (150, 161))	('FBS', 'Disease', (195, 198))	('transferrin', 'Gene', '22041', (150, 161))
334494	31089135	H157 cells are human LSCC cells with mutations of LKB1 and PTEN.	('H157', 'CellLine', 'CVCL:2458', (0, 4))	('SCC', 'Gene', (22, 25))	('mutations', 'Var', (37, 46))	('LKB1', 'Gene', (50, 54))	('human', 'Species', '9606', (15, 20))	('SCC', 'Gene', '6317', (22, 25))	('PTEN', 'Gene', (59, 63))
334515	31089135	p63 and DeltaNp63 and TTF1 are nuclear staining and multifocal.	('TTF1', 'Gene', '22130', (22, 26))	('DeltaNp63', 'Var', (8, 17))	('DeltaNp63', 'Chemical', '-', (8, 17))	('TTF1', 'Gene', (22, 26))
334517	31089135	Within the SCCs, the compact arrangements of basal-appearing cells with scant cytoplasm tended to show nuclear staining of p63.	('SCC', 'Gene', (11, 14))	('p63', 'Var', (123, 126))	('SCC', 'Gene', '6317', (11, 14))
334533	31089135	The Taqman probes for 18s (4310893E) and Lkb1 (Mm00488470_m1) were purchased from Applied Biosystems.	('Lkb1', 'Gene', '20869', (41, 45))	('Lkb1', 'Gene', (41, 45))	('4310893E', 'Var', (27, 35))
334541	31089135	The gene signature score (also known as a "t-score") was defined for each sample as the two-sided t statistic comparison of the high Jnk1/2-signature genes' expression profile with the low Jnk1/2-signature genes' profile.	('Jnk1/2', 'Gene', '26419;26420', (133, 139))	('Jnk1/2', 'Gene', (133, 139))	('high', 'Var', (128, 132))	('Jnk1/2', 'Gene', (189, 195))	('Jnk1/2', 'Gene', '26419;26420', (189, 195))
334542	31089135	Samples with a gene signature score (t-score) higher than 0, which share a similar gene signature profile of Jnk1/2 knockout in mLSCCLP.3 cells, were classified as having low JNK1/2 activities and vice versa.	('SCC', 'Gene', (130, 133))	('activities', 'MPA', (182, 192))	('Jnk1/2', 'Gene', '26419;26420', (109, 115))	('low', 'NegReg', (171, 174))	('knockout', 'Var', (116, 124))	('SCC', 'Gene', '6317', (130, 133))	('Jnk1/2', 'Gene', (109, 115))	('JNK1/2', 'Enzyme', (175, 181))
334557	29512696	Several important molecules were identified in celecoxib-treated LSQCC cell lines, such as VEGFA, ATF4, FN1, lnc-AP000769.1-2:10 and lnc-HFE2-2:1, which may enhance the anti-cancer effects of celecoxib on LSQCC.	('LSQCC', 'Chemical', '-', (205, 210))	('lnc-HFE2-2:1', 'Var', (133, 145))	('LSQCC', 'Disease', (205, 210))	('enhance', 'PosReg', (157, 164))	('celecoxib', 'Chemical', 'MESH:D000068579', (47, 56))	('VEGFA', 'Gene', '7422', (91, 96))	('celecoxib', 'Chemical', 'MESH:D000068579', (192, 201))	('ATF4', 'Gene', (98, 102))	('LSQCC', 'Chemical', '-', (65, 70))	('cancer', 'Disease', (174, 180))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('FN1', 'Gene', '2335', (104, 107))	('VEGFA', 'Gene', (91, 96))	('FN1', 'Gene', (104, 107))	('ATF4', 'Gene', '468', (98, 102))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))
334562	29512696	Cyclooxygenase (COX)-2 serves an important role in the tumorigenesis of various types of cancer, and COX-2 inhibitors may effectively prevent tumor progression.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('COX-2', 'Gene', (101, 106))	('COX-2', 'Gene', '5743', (101, 106))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Disease', (142, 147))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('tumor', 'Disease', (55, 60))	('Cyclooxygenase (COX)-2', 'Gene', '4513', (0, 22))	('cancer', 'Disease', (89, 95))	('inhibitors', 'Var', (107, 117))	('Cyclooxygenase (COX)-2', 'Gene', (0, 22))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
334563	29512696	Celecoxib is a selective COX-2 inhibitor; at the early stages of non-small-cell lung cancer (NSCLC), celecoxib was reported to increase the anti-cancer properties of preoperative chemotherapies, such as paclitaxel and carboplatin.	('cancer', 'Disease', (145, 151))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('NSCLC', 'Disease', 'MESH:D002289', (93, 98))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('carboplatin', 'Chemical', 'MESH:D016190', (218, 229))	('lung cancer', 'Disease', 'MESH:D008175', (80, 91))	('NSCLC', 'Disease', (93, 98))	('COX-2', 'Gene', '5743', (25, 30))	('lung cancer', 'Phenotype', 'HP:0100526', (80, 91))	('celecoxib', 'Var', (101, 110))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (65, 91))	('Celecoxib', 'Chemical', 'MESH:D000068579', (0, 9))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (69, 91))	('cancer', 'Disease', (85, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('lung cancer', 'Disease', (80, 91))	('celecoxib', 'Chemical', 'MESH:D000068579', (101, 110))	('increase', 'PosReg', (127, 135))	('paclitaxel', 'Chemical', 'MESH:D017239', (203, 213))	('COX-2', 'Gene', (25, 30))
334592	29512696	According to the enrichment analysis results of the co-expressed DEGs, the co-expressed DE-LNRs were mainly enriched in the 'p53 signaling pathway' (for example, lnc-HES1-10:1, lnc-HFE2-2:1, lnc-KIAA1257-3:1 and lnc-KSR1-1:1; Fig.	('HES1', 'Gene', (166, 170))	('lnc-HFE2-2:1', 'Var', (177, 189))	('KSR1', 'Gene', '8844', (216, 220))	('KSR1', 'Gene', (216, 220))	('HES1', 'Gene', '3280', (166, 170))	('p53', 'Gene', (125, 128))	('p53', 'Gene', '7157', (125, 128))	('lnc-KIAA1257-3:1', 'Var', (191, 207))
334598	29512696	Notably, many of the identified DEGs and DE-LNRs were significantly enriched in pathways like 'protein processing in endoplasmic reticulum', 'mTOR signaling pathway' and 'ECM-receptor interaction'.	('DEGs', 'Var', (32, 36))	('enriched', 'Reg', (68, 76))	('mTOR', 'Gene', (142, 146))	('mTOR', 'Gene', '2475', (142, 146))
334600	29512696	A previous study reported that by upregulating the expression of FLJ10540, VEGFA activates the phosphatidylinositol 3-kinase/AKT signaling pathway, subsequently promoting cell invasion and migration in lung cancer.	('AKT', 'Gene', '207', (125, 128))	('cell invasion', 'CPA', (171, 184))	('FLJ10540', 'Var', (65, 73))	('VEGFA', 'Gene', '7422', (75, 80))	('lung cancer', 'Disease', (202, 213))	('AKT', 'Gene', (125, 128))	('upregulating', 'PosReg', (34, 46))	('lung cancer', 'Phenotype', 'HP:0100526', (202, 213))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('activates', 'PosReg', (81, 90))	('VEGFA', 'Gene', (75, 80))	('lung cancer', 'Disease', 'MESH:D008175', (202, 213))	('promoting', 'PosReg', (161, 170))	('migration', 'CPA', (189, 198))
334618	29512696	In the present study, lnc-AP000769.1-2:10 was closely correlated with VEGFA, which was enriched in the mTOR signaling pathway following celecoxib treatment.	('celecoxib', 'Chemical', 'MESH:D000068579', (136, 145))	('mTOR', 'Gene', (103, 107))	('VEGFA', 'Gene', (70, 75))	('lnc-AP000769.1-2:10', 'Var', (22, 41))	('correlated', 'Reg', (54, 64))	('VEGFA', 'Gene', '7422', (70, 75))	('mTOR', 'Gene', '2475', (103, 107))
334628	29512696	In lung cancer, knockdown of FN1 was previously reported to increase the chemosensitivity of cisplatin and promote apoptosis in tumor cells.	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('chemosensitivity of cisplatin', 'MPA', (73, 102))	('FN1', 'Gene', (29, 32))	('lung cancer', 'Disease', (3, 14))	('cisplatin', 'Chemical', 'MESH:D002945', (93, 102))	('lung cancer', 'Phenotype', 'HP:0100526', (3, 14))	('increase', 'PosReg', (60, 68))	('knockdown', 'Var', (16, 25))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('lung cancer', 'Disease', 'MESH:D008175', (3, 14))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('tumor', 'Disease', (128, 133))	('apoptosis', 'CPA', (115, 124))	('promote', 'PosReg', (107, 114))	('FN1', 'Gene', '2335', (29, 32))
334636	29512696	In conclusion, genes (such as VEGFA, ATF4 and FN1), and lncRNAs (such as lnc-AP000769.1-2:10 and lnc-HFE2-2:1) may be crucial molecules to enhance the anti-cancer effects of celecoxib treatment on LSQCC, and may be used as predictors for chemosensitivity of celecoxib.	('FN1', 'Gene', (46, 49))	('LSQCC', 'Chemical', '-', (197, 202))	('cancer', 'Disease', (156, 162))	('celecoxib', 'Chemical', 'MESH:D000068579', (174, 183))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('ATF4', 'Gene', (37, 41))	('VEGFA', 'Gene', '7422', (30, 35))	('celecoxib', 'Chemical', 'MESH:D000068579', (258, 267))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('ATF4', 'Gene', '468', (37, 41))	('lnc-HFE2-2:1', 'Var', (97, 109))	('VEGFA', 'Gene', (30, 35))	('FN1', 'Gene', '2335', (46, 49))	('enhance', 'PosReg', (139, 146))
334639	26767073	In last two decades, treatment of melanoma took a dramatic turn with the discovery of targeted therapy which targets the mutations in mitogen-activated protein kinase (MAPK) pathway and immune checkpoint inhibitors.	('mutations', 'Var', (121, 130))	('MAPK', 'Gene', (168, 172))	('men', 'Species', '9606', (26, 29))	('melanoma', 'Disease', 'MESH:D008545', (34, 42))	('melanoma', 'Phenotype', 'HP:0002861', (34, 42))	('melanoma', 'Disease', (34, 42))
334661	26767073	These include immunotherapy (anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4) monoclonal antibodies; anti-programmed cell death-1 protein (PD-1) monoclonal antibodies), targeted therapy like BRAF inhibitors and MEK inhibitors.	('BRAF', 'Gene', '673', (189, 193))	('MEK', 'Gene', (209, 212))	('anti-cytotoxic T-lymphocyte antigen-4', 'Gene', (29, 66))	('MEK', 'Gene', '5609', (209, 212))	('anti-programmed', 'Var', (99, 114))	('anti-cytotoxic T-lymphocyte antigen-4', 'Gene', '1493', (29, 66))	('BRAF', 'Gene', (189, 193))	('CTLA-4', 'Gene', (68, 74))
334710	26767073	The ability of ipilimumab-refractory disease to respond to pembrolizumab is probably a reflection of the different mechanisms by which anti-CTLA-4 and anti-PD-1 therapies stimulate an anti-tumor T-cell response.	('ipilimumab-refractory', 'Disease', (15, 36))	('tumor', 'Disease', (189, 194))	('anti-PD-1', 'Gene', (151, 160))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('stimulate', 'PosReg', (171, 180))	('ipilimumab', 'Chemical', 'MESH:D000074324', (15, 25))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('pembrolizumab', 'Chemical', 'MESH:C582435', (59, 72))	('anti-CTLA-4', 'Var', (135, 146))
334711	26767073	CTLA-4 blockade broadens the immune response, evidenced by an increased T-cell receptor repertoire leading to increased tumor infiltration, whereas PD-1 blockade induces intratumoral T-cell proliferation without detectable changes in the peripheral immune repertoire.	('immune response', 'CPA', (29, 44))	('increased', 'PosReg', (62, 71))	('tumor', 'Disease', (175, 180))	('CTLA-4', 'Gene', (0, 6))	('increased', 'PosReg', (110, 119))	('increased T-cell', 'Phenotype', 'HP:0100828', (62, 78))	('broadens', 'CPA', (16, 24))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('blockade', 'Var', (7, 15))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('T-cell receptor', 'Protein', (72, 87))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('tumor', 'Disease', (120, 125))
334714	26767073	The 6-month PFS rates were 47.3% for pembrolizumab Q2W, 46.4% for pembrolizumab Q3W, and 26.5% for ipilimumab.	('pembrolizumab', 'Chemical', 'MESH:C582435', (66, 79))	('Q3W', 'Var', (80, 83))	('PFS', 'Disease', (12, 15))	('pembrolizumab', 'Chemical', 'MESH:C582435', (37, 50))	('Q2W', 'Var', (51, 54))	('ipilimumab', 'Chemical', 'MESH:D000074324', (99, 109))
334724	26767073	Four hundred eighteen previously untreated MM patients without BRAF mutation were randomly assigned to nivolumab (at a dose of 3 mg/kg Q2W and dacarbazine-matched placebo Q3W) or dacarbazine (at a dose of 1000 mg/m2 of body-surface area Q3W and nivolumab-matched placebo Q2W).	('patients', 'Species', '9606', (46, 54))	('mutation', 'Var', (68, 76))	('dacarbazine', 'Chemical', 'MESH:D003606', (179, 190))	('dacarbazine', 'Chemical', 'MESH:D003606', (143, 154))	('nivolumab', 'Chemical', 'MESH:D000077594', (103, 112))	('BRAF', 'Gene', '673', (63, 67))	('MM', 'Phenotype', 'HP:0002861', (43, 45))	('BRAF', 'Gene', (63, 67))	('nivolumab', 'Chemical', 'MESH:D000077594', (245, 254))
334726	26767073	PFS was also increased with nivolumab (median 5.1 versus 2.2 months), as was the ORR (40% versus 14%).	('PFS', 'MPA', (0, 3))	('nivolumab', 'Chemical', 'MESH:D000077594', (28, 37))	('increased', 'PosReg', (13, 22))	('nivolumab', 'Var', (28, 37))
334730	26767073	All patients had received prior anti-CTLA-4 therapy and a BRAF inhibitor if a V600 mutation was present in their tumor.	('tumor', 'Disease', (113, 118))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('V600 mutation', 'Var', (78, 91))	('patients', 'Species', '9606', (4, 12))	('BRAF', 'Gene', '673', (58, 62))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('BRAF', 'Gene', (58, 62))
334760	26767073	Mutations in BRAF gene can occur in two ways.	('BRAF', 'Gene', '673', (13, 17))	('Mutations', 'Var', (0, 9))	('BRAF', 'Gene', (13, 17))
334762	26767073	The frequency of BRAF mutations varies widely in human cancers, from more than 80% in melanomas and nevi, to as little as 0-18% in other tumors, such as 1-3% in lung cancers and 5% in colorectal cancer.	('cancers', 'Disease', 'MESH:D009369', (55, 62))	('tumors', 'Disease', (137, 143))	('cancers', 'Disease', 'MESH:D009369', (166, 173))	('colorectal cancer', 'Disease', 'MESH:D015179', (184, 201))	('lung cancers', 'Disease', 'MESH:D008175', (161, 173))	('colorectal cancer', 'Disease', (184, 201))	('nevi', 'Phenotype', 'HP:0003764', (100, 104))	('lung cancers', 'Disease', (161, 173))	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('melanomas', 'Phenotype', 'HP:0002861', (86, 95))	('human', 'Species', '9606', (49, 54))	('lung cancer', 'Phenotype', 'HP:0100526', (161, 172))	('lung cancers', 'Phenotype', 'HP:0100526', (161, 173))	('cancers', 'Phenotype', 'HP:0002664', (55, 62))	('cancers', 'Disease', (55, 62))	('cancers', 'Phenotype', 'HP:0002664', (166, 173))	('cancers', 'Disease', (166, 173))	('melanoma', 'Phenotype', 'HP:0002861', (86, 94))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('colorectal cancer', 'Phenotype', 'HP:0003003', (184, 201))	('mutations', 'Var', (22, 31))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('melanomas', 'Disease', 'MESH:D008545', (86, 95))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('BRAF', 'Gene', '673', (17, 21))	('nevi', 'Disease', (100, 104))	('BRAF', 'Gene', (17, 21))	('melanomas', 'Disease', (86, 95))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
334763	26767073	In 90% of cases, thymine is substituted with adenine at nucleotide 1799 which leads to valine (V) being substituted for by glutamate (E) at codon 600 referred to as V600E mutation that activates the MAPK pathway.	('V600E', 'Var', (165, 170))	('adenine', 'Chemical', 'MESH:D000225', (45, 52))	('valine', 'Chemical', 'MESH:D014633', (87, 93))	('glutamate', 'Chemical', 'MESH:D018698', (123, 132))	('thymine', 'Chemical', 'MESH:D013941', (17, 24))	('V600E', 'Mutation', 'rs113488022', (165, 170))	('activates', 'PosReg', (185, 194))	('MAPK pathway', 'Pathway', (199, 211))
334764	26767073	The V600K mutation results in an amino acid substitution at codon 600 in BRAF, from a valine (V) to lysine (K).	('BRAF', 'Gene', '673', (73, 77))	('BRAF', 'Gene', (73, 77))	('V600K', 'Mutation', 'rs121913227', (4, 9))	('lysine', 'Chemical', 'MESH:D008239', (100, 106))	('valine', 'Chemical', 'MESH:D014633', (86, 92))	('results in', 'Reg', (19, 29))	('V600K', 'Var', (4, 9))
334765	26767073	This mutation has been widely associated with papillary thyroid cancer, NSCLC, colorectal cancer and melanoma.	('associated', 'Reg', (30, 40))	('colorectal cancer', 'Phenotype', 'HP:0003003', (79, 96))	('melanoma', 'Phenotype', 'HP:0002861', (101, 109))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('melanoma', 'Disease', (101, 109))	('NSCLC', 'Disease', (72, 77))	('colorectal cancer', 'Disease', 'MESH:D015179', (79, 96))	('papillary thyroid cancer', 'Phenotype', 'HP:0002895', (46, 70))	('melanoma', 'Disease', 'MESH:D008545', (101, 109))	('colorectal cancer', 'Disease', (79, 96))	('NSCLC', 'Disease', 'MESH:D002289', (72, 77))	('thyroid cancer', 'Phenotype', 'HP:0002890', (56, 70))	('papillary thyroid cancer', 'Disease', (46, 70))	('NSCLC', 'Phenotype', 'HP:0030358', (72, 77))	('papillary thyroid cancer', 'Disease', 'MESH:D000077273', (46, 70))	('mutation', 'Var', (5, 13))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
334769	26767073	Among them, NRAS mutations are found in about 10-15% of melanoma patients.	('melanoma', 'Disease', 'MESH:D008545', (56, 64))	('melanoma', 'Phenotype', 'HP:0002861', (56, 64))	('melanoma', 'Disease', (56, 64))	('NRAS', 'Gene', (12, 16))	('NRAS', 'Gene', '4893', (12, 16))	('mutations', 'Var', (17, 26))	('patients', 'Species', '9606', (65, 73))	('found', 'Reg', (31, 36))
334770	26767073	Activated RAS results in a cascade of phosphorylation events involving the serine/threonine kinases RAF (encoded by ARAF, BRAF and CRAF).	('RAF', 'Gene', '22882', (100, 103))	('RAF', 'Gene', (100, 103))	('phosphorylation', 'MPA', (38, 53))	('RAF', 'Gene', '22882', (117, 120))	('BRAF', 'Gene', '673', (122, 126))	('RAF', 'Gene', '22882', (132, 135))	('RAF', 'Gene', (117, 120))	('ARAF', 'Gene', '369', (116, 120))	('CRAF', 'Gene', (131, 135))	('ARAF', 'Gene', (116, 120))	('BRAF', 'Gene', (122, 126))	('Activated', 'Var', (0, 9))	('RAF', 'Gene', (132, 135))	('RAF', 'Gene', '22882', (123, 126))	('CRAF', 'Gene', '5894', (131, 135))	('RAF', 'Gene', (123, 126))	('serine/threonine kinases', 'MPA', (75, 99))
334772	26767073	About 50% of melanomas harbor an activating mutation in BRAF, the most common being BRAF V600E, which renders the kinase constitutively active.	('BRAF', 'Gene', '673', (84, 88))	('BRAF', 'Gene', '673', (56, 60))	('melanomas', 'Disease', (13, 22))	('BRAF', 'Gene', (84, 88))	('melanoma', 'Phenotype', 'HP:0002861', (13, 21))	('V600E', 'Mutation', 'rs113488022', (89, 94))	('melanomas', 'Phenotype', 'HP:0002861', (13, 22))	('activating', 'PosReg', (33, 43))	('melanomas', 'Disease', 'MESH:D008545', (13, 22))	('V600E', 'Var', (89, 94))	('BRAF', 'Gene', (56, 60))
334773	26767073	Vemurafenib is a potent inhibitor of the kinase domain in mutant BRAF, a mutation carried by half of melanomas.	('melanomas', 'Phenotype', 'HP:0002861', (101, 110))	('mutant', 'Var', (58, 64))	('melanomas', 'Disease', 'MESH:D008545', (101, 110))	('melanoma', 'Phenotype', 'HP:0002861', (101, 109))	('Vemurafenib', 'Chemical', 'MESH:D000077484', (0, 11))	('BRAF', 'Gene', '673', (65, 69))	('melanomas', 'Disease', (101, 110))	('BRAF', 'Gene', (65, 69))
334774	26767073	It was approved by US FDA and European Medicines Agency for the treatment of unresectable or MM with mutant BRAF V600E at a dose of 960 mg orally twice a day.	('men', 'Species', '9606', (69, 72))	('unresectable or MM', 'Disease', (77, 95))	('V600E', 'Mutation', 'rs113488022', (113, 118))	('mutant', 'Var', (101, 107))	('MM', 'Phenotype', 'HP:0002861', (93, 95))	('BRAF', 'Gene', '673', (108, 112))	('BRAF', 'Gene', (108, 112))
334778	26767073	A follow-up, multicenter, phase II study enrolled 132 patients with previously treated BRAF V600-mutant MM without brain metastases.	('patients', 'Species', '9606', (54, 62))	('MM', 'Phenotype', 'HP:0002861', (104, 106))	('brain metastases', 'Disease', 'MESH:D009362', (115, 131))	('V600-mutant MM', 'Var', (92, 106))	('brain metastases', 'Disease', (115, 131))	('BRAF', 'Gene', (87, 91))	('BRAF', 'Gene', '673', (87, 91))
334781	26767073	In the international, multicenter, randomized, phase III BRIM-3 trial, 675 patients with previously untreated, MM with the BRAF V600E mutation were randomly assigned to either vemurafenib (960 mg twice a day) or dacarbazine (1,000 mg/m2 IV Q3W) in patients who had either metastatic disease or unresectable stage IIIC disease.	('V600E', 'Mutation', 'rs113488022', (128, 133))	('BRAF', 'Gene', (123, 127))	('dacarbazine', 'Chemical', 'MESH:D003606', (212, 223))	('BRAF', 'Gene', '673', (123, 127))	('patients', 'Species', '9606', (75, 83))	('V600E', 'Var', (128, 133))	('vemurafenib', 'Chemical', 'MESH:D000077484', (176, 187))	('MM', 'Phenotype', 'HP:0002861', (111, 113))	('metastatic disease', 'Disease', (272, 290))	('patients', 'Species', '9606', (248, 256))	('metastatic disease', 'Disease', 'MESH:C538445', (272, 290))
334782	26767073	The results of this study showed that OS was significantly prolonged with vemurafenib compared with dacarbazine (13.6 versus 9.7 months).	('prolonged', 'PosReg', (59, 68))	('vemurafenib', 'Var', (74, 85))	('dacarbazine', 'Chemical', 'MESH:D003606', (100, 111))	('OS', 'Chemical', '-', (38, 40))	('vemurafenib', 'Chemical', 'MESH:D000077484', (74, 85))
334783	26767073	Vemurafenib produced improved rates of OS and PFS in patients with previously untreated melanoma with the BRAF V600E mutation.	('improved', 'PosReg', (21, 29))	('patients', 'Species', '9606', (53, 61))	('melanoma', 'Phenotype', 'HP:0002861', (88, 96))	('melanoma', 'Disease', (88, 96))	('V600E', 'Var', (111, 116))	('BRAF', 'Gene', '673', (106, 110))	('PFS', 'Disease', (46, 49))	('melanoma', 'Disease', 'MESH:D008545', (88, 96))	('Vemurafenib', 'Chemical', 'MESH:D000077484', (0, 11))	('OS', 'Chemical', '-', (39, 41))	('BRAF', 'Gene', (106, 110))	('V600E', 'Mutation', 'rs113488022', (111, 116))
334785	26767073	Mechanisms of primary resistance include RAC1P29S mutations (RAC 1 regulates cell proliferation and migration), COT overexpression (COT activates ERK through mechanism that does not depend on RAF signaling), alterations in RTK signaling (RTK activation can signal either through CRAF or through the PI3K pathway), and alterations in the PI3K-AKT-mTOR pathway (loss of function of PTEN).	('ERK', 'Gene', '5594', (146, 149))	('PI3K-AKT-mTOR pathway', 'Pathway', (337, 358))	('overexpression', 'PosReg', (116, 130))	('RAF', 'Gene', (280, 283))	('PTEN', 'Gene', '5728', (380, 384))	('RAF', 'Gene', (192, 195))	('PI3K pathway', 'Pathway', (299, 311))	('RTK', 'Gene', (238, 241))	('RAC 1', 'Gene', '5879', (61, 66))	('ERK', 'Gene', (146, 149))	('RTK', 'Gene', '5979', (238, 241))	('RTK', 'Gene', (223, 226))	('migration', 'CPA', (100, 109))	('CRAF', 'Gene', (279, 283))	('RTK', 'Gene', '5979', (223, 226))	('alterations', 'Var', (208, 219))	('cell proliferation', 'CPA', (77, 95))	('RAC1P29S', 'Gene', (41, 49))	('mutations', 'Var', (50, 59))	('CRAF', 'Gene', '5894', (279, 283))	('alterations', 'Reg', (318, 329))	('RAC 1', 'Gene', (61, 66))	('RAF', 'Gene', '22882', (280, 283))	('PTEN', 'Gene', (380, 384))	('COT', 'Disease', (112, 115))	('RAF', 'Gene', '22882', (192, 195))
334786	26767073	The reactivation of the MAPK pathway is the most frequent cause of acquired/secondary resistance; it may be driven by events that occur upstream (upregulation and activation of the RTK, NRAS activating mutations) or downstream (activating MEK1/2 mutation, or at the level of BRAF).	('activation', 'PosReg', (163, 173))	('MAPK pathway', 'Pathway', (24, 36))	('mutation', 'Var', (246, 254))	('NRAS', 'Gene', (186, 190))	('upregulation', 'PosReg', (146, 158))	('MEK1/2', 'Gene', (239, 245))	('RTK', 'Gene', '5979', (181, 184))	('NRAS', 'Gene', '4893', (186, 190))	('BRAF', 'Gene', '673', (275, 279))	('BRAF', 'Gene', (275, 279))	('MEK1/2', 'Gene', '5604;5605', (239, 245))	('RTK', 'Gene', (181, 184))	('acquired/secondary', 'Disease', (67, 85))
334789	26767073	Knock-down of eIF4E significantly repressed the proliferation of a subset of melanoma cell lines.	('Knock-down', 'Var', (0, 10))	('melanoma', 'Phenotype', 'HP:0002861', (77, 85))	('melanoma', 'Disease', (77, 85))	('melanoma', 'Disease', 'MESH:D008545', (77, 85))	('eIF4E', 'Gene', '1977', (14, 19))	('repressed', 'NegReg', (34, 43))	('eIF4E', 'Gene', (14, 19))
334793	26767073	Moreover, increasing eIF4E activity by silencing of 4E-BP1/2 renders vemurafenib responsive cells more resistant to BRAF inhibition.	('BRAF', 'Gene', '673', (116, 120))	('vemurafenib', 'Chemical', 'MESH:D000077484', (69, 80))	('4E-BP1', 'Gene', '1978', (52, 58))	('BRAF', 'Gene', (116, 120))	('eIF4E', 'Gene', '1977', (21, 26))	('silencing', 'Var', (39, 48))	('increasing', 'PosReg', (10, 20))	('activity', 'MPA', (27, 35))	('4E-BP1', 'Gene', (52, 58))	('eIF4E', 'Gene', (21, 26))
334796	26767073	A vemurafenib analog (PLX4720) accelerated the growth of the lesions harboring HRAS mutations, and this growth was inhibited by concomitant treatment with an MEK inhibitor.	('MEK', 'Gene', (158, 161))	('MEK', 'Gene', '5609', (158, 161))	('men', 'Species', '9606', (145, 148))	('growth', 'MPA', (47, 53))	('HRAS', 'Gene', (79, 83))	('PLX4720', 'Chemical', 'MESH:C528407', (22, 29))	('mutations', 'Var', (84, 93))	('vemurafenib', 'Chemical', 'MESH:D000077484', (2, 13))	('accelerated', 'PosReg', (31, 42))	('HRAS', 'Gene', '3265', (79, 83))
334800	26767073	Dabrafenib was approved by the US FDA in May 2013 for the treatment of patients with advanced melanoma that contains the V600E mutation of BRAF at a dose of 150 mg orally twice a day.	('men', 'Species', '9606', (63, 66))	('advanced melanoma', 'Disease', (85, 102))	('BRAF', 'Gene', (139, 143))	('V600E', 'Var', (121, 126))	('patients', 'Species', '9606', (71, 79))	('melanoma', 'Phenotype', 'HP:0002861', (94, 102))	('Dabrafenib', 'Chemical', 'MESH:C561627', (0, 10))	('advanced melanoma', 'Disease', 'MESH:D008545', (85, 102))	('V600E', 'Mutation', 'rs113488022', (121, 126))	('BRAF', 'Gene', '673', (139, 143))
334803	26767073	A total of 76 patients with BRAF V600E and 16 patients with V600K mutations were treated with dabrafenib 150 mg twice daily.	('dabrafenib', 'Chemical', 'MESH:C561627', (94, 104))	('BRAF', 'Gene', '673', (28, 32))	('patients', 'Species', '9606', (46, 54))	('V600E', 'Mutation', 'rs113488022', (33, 38))	('V600E', 'Var', (33, 38))	('V600K', 'Var', (60, 65))	('BRAF', 'Gene', (28, 32))	('patients', 'Species', '9606', (14, 22))	('V600K', 'Mutation', 'rs121913227', (60, 65))
334805	26767073	Median OS was 13.1 months for the V600E patients and 12.9 months for the V600K patients.	('OS', 'Chemical', '-', (7, 9))	('patients', 'Species', '9606', (40, 48))	('V600K', 'Var', (73, 78))	('V600E', 'Mutation', 'rs113488022', (34, 39))	('V600K', 'Mutation', 'rs121913227', (73, 78))	('patients', 'Species', '9606', (79, 87))	('V600E', 'Var', (34, 39))
334811	26767073	All patients had the V600E mutation in BRAF, the patients in the dacarbazine arm being allowed to crossover at the time of disease progression.	('V600E', 'Var', (21, 26))	('BRAF', 'Gene', '673', (39, 43))	('BRAF', 'Gene', (39, 43))	('dacarbazine', 'Chemical', 'MESH:D003606', (65, 76))	('patients', 'Species', '9606', (4, 12))	('V600E', 'Mutation', 'rs113488022', (21, 26))	('patients', 'Species', '9606', (49, 57))
334824	26767073	Trametinib, an MEK inhibitor, was first approved by FDA in 2013 for treatment of patients with unresectable or MM with BRAF V600E or V600K mutation.	('Trametinib', 'Chemical', 'MESH:C560077', (0, 10))	('V600E', 'Mutation', 'rs113488022', (124, 129))	('men', 'Species', '9606', (73, 76))	('BRAF', 'Gene', '673', (119, 123))	('patients', 'Species', '9606', (81, 89))	('V600K', 'Var', (133, 138))	('BRAF', 'Gene', (119, 123))	('MM', 'Phenotype', 'HP:0002861', (111, 113))	('MEK', 'Gene', (15, 18))	('V600K', 'Mutation', 'rs121913227', (133, 138))	('MEK', 'Gene', '5609', (15, 18))
334826	26767073	Based on the below mentioned trial, trametinib was approved by the FDA in 2013 for the treatment of patients with unresectable stage IIIC or MM with BRAF V600E/K mutations.	('BRAF', 'Gene', (149, 153))	('BRAF', 'Gene', '673', (149, 153))	('trametinib', 'Chemical', 'MESH:C560077', (36, 46))	('V600E', 'SUBSTITUTION', 'None', (154, 159))	('MM', 'Phenotype', 'HP:0002861', (141, 143))	('patients', 'Species', '9606', (100, 108))	('men', 'Species', '9606', (19, 22))	('men', 'Species', '9606', (92, 95))	('V600E', 'Var', (154, 159))
334827	26767073	In an open-label phase III trial (METRIC), 322 patients with BRAF V600E/K-mutant MM were randomized to receive either trametinib (n = 214) or chemotherapy with either dacarbazine or paclitaxel (n = 108).	('paclitaxel', 'Chemical', 'MESH:D017239', (182, 192))	('V600E', 'Var', (66, 71))	('V600E', 'SUBSTITUTION', 'None', (66, 71))	('BRAF', 'Gene', '673', (61, 65))	('dacarbazine', 'Chemical', 'MESH:D003606', (167, 178))	('patients', 'Species', '9606', (47, 55))	('BRAF', 'Gene', (61, 65))	('trametinib', 'Chemical', 'MESH:C560077', (118, 128))	('MM', 'Phenotype', 'HP:0002861', (81, 83))
334847	26767073	The visual acuity of this patient improved after intraocular treatments of antibodies against VEGF.	('patient', 'Species', '9606', (26, 33))	('improved', 'PosReg', (34, 42))	('men', 'Species', '9606', (66, 69))	('antibodies', 'Var', (75, 85))	('VEGF', 'Gene', (94, 98))	('visual', 'MPA', (4, 10))	('VEGF', 'Gene', '7422', (94, 98))
334849	26767073	The mechanism of reduced left ventricular ejection fraction in relation to MEK inhibition is unknown, but cardiac toxicity has previously been reported in association with MEK inhibitors; this could represent a class effect.	('cardiac toxicity', 'Disease', 'MESH:D066126', (106, 122))	('cardiac toxicity', 'Disease', (106, 122))	('left ventricular ejection fraction', 'MPA', (25, 59))	('MEK', 'Gene', (172, 175))	('MEK', 'Gene', '5609', (172, 175))	('MEK', 'Gene', '5609', (75, 78))	('inhibition', 'Var', (79, 89))	('MEK', 'Gene', (75, 78))	('reduced', 'NegReg', (17, 24))
334859	26767073	In a phase III double-blinded study conducted by Long et al, 423 patients with unresectable stage IIIC or stage IV melanoma with BRAF V600E/K mutation were randomized to receive the combination of oral BRAF inhibitor dabrafenib and MEK inhibitor trametinib (n = 211) (combination therapy group) or dabrafenib and placebo (n = 212) (dabrafenib group).	('V600E', 'SUBSTITUTION', 'None', (134, 139))	('IV melanoma', 'Disease', (112, 123))	('BRAF', 'Gene', (129, 133))	('BRAF', 'Gene', '673', (129, 133))	('melanoma', 'Phenotype', 'HP:0002861', (115, 123))	('IV melanoma', 'Disease', 'MESH:D008545', (112, 123))	('BRAF', 'Gene', '673', (202, 206))	('dabrafenib', 'Chemical', 'MESH:C561627', (298, 308))	('dabrafenib', 'Chemical', 'MESH:C561627', (332, 342))	('BRAF', 'Gene', (202, 206))	('dabrafenib', 'Chemical', 'MESH:C561627', (217, 227))	('MEK', 'Gene', (232, 235))	('V600E', 'Var', (134, 139))	('patients', 'Species', '9606', (65, 73))	('MEK', 'Gene', '5609', (232, 235))	('trametinib', 'Chemical', 'MESH:C560077', (246, 256))
334860	26767073	Patients who had previous systemic anticancer treatment and those without the BRAF V600E/K mutation were excluded from the study.	('V600E', 'Var', (83, 88))	('BRAF', 'Gene', '673', (78, 82))	('cancer', 'Disease', (39, 45))	('men', 'Species', '9606', (51, 54))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('V600E', 'SUBSTITUTION', 'None', (83, 88))	('BRAF', 'Gene', (78, 82))	('Patients', 'Species', '9606', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))
334871	26767073	Secondary cancers such as cutaneous squamous cell carcinoma were also lower in the combination therapy group vs. monotherapy (2% vs. 9%).	('cutaneous squamous cell carcinoma', 'Disease', 'MESH:D002294', (26, 59))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('carcinoma', 'Phenotype', 'HP:0030731', (50, 59))	('combination', 'Var', (83, 94))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (36, 59))	('lower', 'NegReg', (70, 75))	('cancers', 'Phenotype', 'HP:0002664', (10, 17))	('cutaneous squamous cell carcinoma', 'Disease', (26, 59))	('cancers', 'Disease', 'MESH:D009369', (10, 17))	('cancers', 'Disease', (10, 17))
334872	26767073	A phase III randomized trial conducted by Larkin et al on 495 patients with BRAF V600E/K-mutated metastatic or locally invasive melanoma showed similar results to the above study.	('BRAF', 'Gene', (76, 80))	('BRAF', 'Gene', '673', (76, 80))	('V600E', 'SUBSTITUTION', 'None', (81, 86))	('metastatic', 'Disease', (97, 107))	('invasive melanoma', 'Disease', (119, 136))	('melanoma', 'Phenotype', 'HP:0002861', (128, 136))	('V600E', 'Var', (81, 86))	('patients', 'Species', '9606', (62, 70))	('invasive melanoma', 'Disease', 'MESH:D008545', (119, 136))
334873	26767073	Patients who had received prior cancer treatment and those with wild type BRAF mutation were excluded from the study.	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('BRAF', 'Gene', (74, 78))	('cancer', 'Disease', (32, 38))	('BRAF', 'Gene', '673', (74, 78))	('Patients', 'Species', '9606', (0, 8))	('mutation', 'Var', (79, 87))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('men', 'Species', '9606', (44, 47))
334886	26767073	Subgroup analysis showed that men who were treated with ipilimumab plus sargramostim had greater OS compared to ipilimumab alone while the opposite trend was seen in women.	('women', 'Species', '9606', (166, 171))	('ipilimumab', 'Chemical', 'MESH:D000074324', (56, 66))	('ipilimumab', 'Chemical', 'MESH:D000074324', (112, 122))	('OS', 'Chemical', '-', (97, 99))	('men', 'Species', '9606', (30, 33))	('ipilimumab', 'Var', (56, 66))	('men', 'Species', '9606', (168, 171))	('greater', 'PosReg', (89, 96))
334901	26767073	Postow et al recently conducted a double-blinded study involving 142 patients (109 with BRAF wild type and 33 with BRAF V600E mutation positive) with MM who had not previously received treatment.	('BRAF', 'Gene', '673', (115, 119))	('BRAF', 'Gene', (115, 119))	('BRAF', 'Gene', (88, 92))	('BRAF', 'Gene', '673', (88, 92))	('patients', 'Species', '9606', (69, 77))	('V600E', 'Mutation', 'rs113488022', (120, 125))	('men', 'Species', '9606', (190, 193))	('V600E', 'Var', (120, 125))	('MM', 'Phenotype', 'HP:0002861', (150, 152))
334918	26767073	Anti-PD-1 antibodies like pembrolizumab and nivolumab have become the preferred approach to immunotherapy in patients with advanced melanoma, even though they are associated with various autoimmune AEs.	('melanoma', 'Phenotype', 'HP:0002861', (132, 140))	('patients', 'Species', '9606', (109, 117))	('advanced melanoma', 'Disease', (123, 140))	('nivolumab', 'Chemical', 'MESH:D000077594', (44, 53))	('autoimmune AEs', 'Disease', 'MESH:D001327', (187, 201))	('Anti-PD-1', 'Var', (0, 9))	('pembrolizumab', 'Chemical', 'MESH:C582435', (26, 39))	('autoimmune AEs', 'Disease', (187, 201))	('advanced melanoma', 'Disease', 'MESH:D008545', (123, 140))
334941	31462771	Silencing ZDHHC19 blocks STAT3 palmitoylation and dimerization, impairing cytokine and fatty acid-induced STAT3 activation.	('fatty acid', 'Chemical', 'MESH:D005227', (87, 97))	('dimerization', 'MPA', (50, 62))	('blocks', 'NegReg', (18, 24))	('Silencing', 'Var', (0, 9))	('ZDHHC19', 'Gene', (10, 17))	('STAT3 palmitoylation', 'MPA', (25, 45))	('impairing', 'NegReg', (64, 73))
334944	31462771	In addition, ZDHHC19 knockout in LSCC cells significantly blocks STAT3 activity, and inhibits fatty acid-induced tumorsphere formation and high-fat diet (HFD)-induced tumorigenesis in vivo.	('tumor', 'Disease', (113, 118))	('inhibits', 'NegReg', (85, 93))	('tumors', 'Disease', (113, 119))	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('fatty acid', 'Chemical', 'MESH:D005227', (94, 104))	('blocks', 'NegReg', (58, 64))	('STAT3 activity', 'MPA', (65, 79))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('knockout', 'Var', (21, 29))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('fatty acid-induced', 'MPA', (94, 112))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('ZDHHC19', 'Gene', (13, 20))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('tumor', 'Disease', (167, 172))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
334945	31462771	Taken together, we reveal that fatty acid and ZDHHC19-mediated palmitoylation are additional signals regulating STAT3, linking deregulation of palmitoylation to inflammation and cancer.	('fatty acid', 'Chemical', 'MESH:D005227', (31, 41))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('palmitoylation', 'MPA', (143, 157))	('inflammation', 'Disease', 'MESH:D007249', (161, 173))	('cancer', 'Disease', (178, 184))	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('ZDHHC19-mediated', 'Gene', (46, 62))	('palmitoylation', 'MPA', (63, 77))	('inflammation', 'Disease', (161, 173))	('deregulation', 'Var', (127, 139))
334948	31462771	Posttranslational S-palmitoylation or S-fatty acylation attaches fatty acids, such as palmitate, to the cysteine residues of a protein, and regulates diverse functions of proteins under physiological and pathological conditions.	('cysteine', 'Chemical', 'MESH:D003545', (104, 112))	('fatty acids', 'Chemical', 'MESH:D005227', (65, 76))	('regulates', 'Reg', (140, 149))	('S-fatty acylation', 'Var', (38, 55))	('palmitate', 'Chemical', 'MESH:D010168', (86, 95))	('S-palmitoylation', 'Var', (18, 34))	('proteins', 'Protein', (171, 179))	('functions', 'MPA', (158, 167))
334951	31462771	Moreover, STAT3 can be efficiently labeled by palmitoylation (Alk-C16) or stearoylation (Alk-C18) probes, but much less efficiently labeled by probes with C14 or C20 chain length (Fig.	('Alk', 'Gene', '238', (62, 65))	('palmitoylation', 'MPA', (46, 60))	('C20 chain', 'Var', (162, 171))	('C18', 'Gene', (93, 96))	('Alk', 'Gene', (89, 92))	('Alk', 'Gene', (62, 65))	('C18', 'Gene', '27241', (93, 96))	('stearoylation', 'MPA', (74, 87))	('C14', 'Var', (155, 158))	('Alk', 'Gene', '238', (89, 92))
334954	31462771	Mutating the evolutionarily conserved C687 and C712 located in this region to serine, singly (C687S, C712S) or in combination (C687/712S, or 2CS) could markedly block palmitoylation (Fig.	('serine', 'Chemical', 'MESH:D012694', (78, 84))	('Mutating', 'Var', (0, 8))	('C687S', 'Mutation', 'p.C687S', (94, 99))	('C712S', 'Mutation', 'p.C712S', (101, 106))	('palmitoylation', 'MPA', (167, 181))	('C687S', 'Var', (94, 99))	('C712S', 'Var', (101, 106))	('C687/712S', 'Var', (127, 136))	('C712', 'Var', (47, 51))	('block', 'NegReg', (161, 166))	('C687', 'Var', (38, 42))
334957	31462771	Moreover, the enhanced palmitoylation following IL-6 stimulation was attenuated by C687S mutation (Extended Data Fig.	('C687S', 'Var', (83, 88))	('palmitoylation', 'MPA', (23, 37))	('IL-6', 'Gene', '3569', (48, 52))	('attenuated', 'NegReg', (69, 79))	('enhanced', 'PosReg', (14, 22))	('C687S', 'Mutation', 'p.C687S', (83, 88))	('IL-6', 'Gene', (48, 52))
334958	31462771	Interestingly, the phosphorylation-deficient, dominant-negative STAT3 mutant (DN-STAT3, Y705F) showed decreased palmitoylation levels compared to the WT, but the mutation did not completely abolish its palmitoylation (Fig.	('Y705F', 'Var', (88, 93))	('palmitoylation levels', 'MPA', (112, 133))	('Y705F', 'Mutation', 'p.Y705F', (88, 93))	('palmitoylation', 'MPA', (202, 216))	('abolish', 'NegReg', (190, 197))	('STAT3', 'Gene', (64, 69))	('phosphorylation-deficient', 'MPA', (19, 44))	('decreased', 'NegReg', (102, 111))
334959	31462771	Interestingly, palmitoylation-deficient STAT3 2CS mutant can still be phosphorylated at Y705 at similar levels as WT upon IL-6 stimulation, but showed significantly decreased nuclear localization (Extended Data Fig.	('decreased', 'NegReg', (165, 174))	('palmitoylation-deficient', 'Disease', 'MESH:C535589', (15, 39))	('STAT3 2CS', 'Gene', (40, 49))	('IL-6', 'Gene', (122, 126))	('Y705', 'Var', (88, 92))	('IL-6', 'Gene', '3569', (122, 126))	('palmitoylation-deficient', 'Disease', (15, 39))	('nuclear localization', 'MPA', (175, 195))
334965	31462771	Indeed, STAT3 A651V mutant showed significantly reduced palmitoylation levels and homodimerization (Extended Data Fig.	('homodimerization', 'MPA', (82, 98))	('A651V', 'Mutation', 'p.A651V', (14, 19))	('reduced', 'NegReg', (48, 55))	('A651V mutant', 'Var', (14, 26))	('STAT3', 'Gene', (8, 13))	('palmitoylation levels', 'MPA', (56, 77))
334966	31462771	Therefore, it is possible that palmitoylation could enhance STAT3 dimerization through engaging the lipid-binding pocket in SH2 domain.	('lipid-binding pocket', 'MPA', (100, 120))	('STAT3 dimerization', 'MPA', (60, 78))	('lipid', 'Chemical', 'MESH:D008055', (100, 105))	('engaging', 'PosReg', (87, 95))	('enhance', 'PosReg', (52, 59))	('palmitoylation', 'Var', (31, 45))
334967	31462771	To test the function of STAT3 palmitoylation, we re-expressed STAT3 WT and 2CS mutant in STAT3-/- mouse embryonic fibroblast (MEF) cells.	('STAT3', 'Gene', (62, 67))	('mutant', 'Var', (79, 85))	('2CS', 'Gene', (75, 78))	('MEF', 'Disease', (126, 129))	('mouse', 'Species', '10090', (98, 103))	('MEF', 'Disease', 'None', (126, 129))
334968	31462771	Consistently, the STAT3 2CS mutant lost palmitoylation in basal and IL-6-induced conditions (Extended Data Fig.	('palmitoylation', 'MPA', (40, 54))	('mutant', 'Var', (28, 34))	('IL-6', 'Gene', (68, 72))	('IL-6', 'Gene', '3569', (68, 72))	('lost', 'NegReg', (35, 39))	('STAT3 2CS', 'Gene', (18, 27))
334972	31462771	We found that HFD notably increased STAT3 palmitoylation and phosphorylation levels compared to normal-fat diet (NFD) in mouse lung and liver tissues (Fig.	('HFD', 'Var', (14, 17))	('phosphorylation levels', 'MPA', (61, 83))	('STAT3 palmitoylation', 'MPA', (36, 56))	('mouse', 'Species', '10090', (121, 126))	('increased', 'PosReg', (26, 35))
334974	31462771	Indeed, exogenous palmitic acid could increase STAT3 palmitoylation levels in a dose-dependent manner (Fig.	('palmitic acid', 'Chemical', 'MESH:D019308', (18, 31))	('exogenous', 'Var', (8, 17))	('STAT3 palmitoylation levels', 'MPA', (47, 74))	('increase', 'PosReg', (38, 46))
334977	31462771	Depalmitoylation by hydroxylamine treatment or C687S mutation could almost abolish STAT3 homodimerization in response to palmitic acid (Extended Data Fig.	('STAT3 homodimerization', 'MPA', (83, 105))	('palmitic acid', 'Chemical', 'MESH:D019308', (121, 134))	('hydroxylamine', 'Chemical', 'MESH:D019811', (20, 33))	('C687S', 'Mutation', 'p.C687S', (47, 52))	('response to palmitic acid', 'MPA', (109, 134))	('C687S', 'Var', (47, 52))	('Depalmitoylation', 'MPA', (0, 16))
334983	31462771	We generated the catalytically inactive mutant of ZDHHC19 (C142S) by mutating active site cysteine residue to serine (Extended Data Fig.	('mutating', 'Var', (69, 77))	('cysteine', 'Chemical', 'MESH:D003545', (90, 98))	('ZDHHC19', 'Gene', (50, 57))	('C142S', 'Var', (59, 64))	('serine', 'Chemical', 'MESH:D012694', (110, 116))	('active', 'MPA', (78, 84))	('C142S', 'Mutation', 'p.C142S', (59, 64))
334985	31462771	Consistently, ectopic expressing ZDHHC19 WT, but not C142S mutant, could significantly induce the activation of STAT3 reporter (Extended Data Fig.	('STAT3 reporter', 'MPA', (112, 126))	('activation', 'PosReg', (98, 108))	('ZDHHC19', 'Gene', (33, 40))	('C142S', 'Mutation', 'p.C142S', (53, 58))	('C142S', 'Var', (53, 58))	('induce', 'PosReg', (87, 93))
334987	31462771	Loss of ZDHHC19 also abolished STAT3 target gene expression induced by IL-6, palmitic acid, or their combination (Extended Data Fig.	('ZDHHC19', 'Gene', (8, 15))	('IL-6', 'Gene', (71, 75))	('abolished', 'NegReg', (21, 30))	('palmitic acid', 'MPA', (77, 90))	('IL-6', 'Gene', '3569', (71, 75))	('palmitic acid', 'Chemical', 'MESH:D019308', (77, 90))	('Loss', 'Var', (0, 4))	('STAT3 target gene expression', 'MPA', (31, 59))
334991	31462771	ZDHHC19 SH3 binding motif mutant (P18A) showed significantly reduced interaction with Grb2 and STAT3 (Extended Data Fig.	('P18A', 'Mutation', 'rs121913248', (34, 38))	('ZDHHC19', 'Gene', (0, 7))	('Grb2', 'Protein', (86, 90))	('interaction', 'Interaction', (69, 80))	('SH3', 'Gene', (8, 11))	('mutant', 'Var', (26, 32))	('reduced', 'NegReg', (61, 68))	('SH3', 'Gene', '100125849', (8, 11))
334997	31462771	Oncogenic HRAS (G12V) and NRAS (G12V or Q61R), or their palmitoylation did not affect STAT3 transcriptional activities either (Extended Data Fig.	('Q61R', 'Var', (40, 44))	('HRAS', 'Gene', (10, 14))	('Q61R', 'Mutation', 'rs11554290', (40, 44))	('G12V', 'Mutation', 'rs104894230', (32, 36))	('NRAS', 'Gene', (26, 30))	('G12V', 'Mutation', 'rs104894230', (16, 20))	('NRAS', 'Gene', '4893', (26, 30))	('STAT3 transcriptional activities', 'MPA', (86, 118))	('HRAS', 'Gene', '3265', (10, 14))
335002	31462771	In addition, high ZDHHC19 expression correlated significantly with poor patient survival (Extended Data Fig.	('expression', 'MPA', (26, 36))	('ZDHHC19', 'Gene', (18, 25))	('high', 'Var', (13, 17))	('poor', 'NegReg', (67, 71))	('patient', 'Species', '9606', (72, 79))	('patient survival', 'CPA', (72, 88))
335006	31462771	Knocking down ZDHHC19 in multiple LSCC cell lines (HCC95, KNS-62 and/or SK-MES) reduced STAT3 palmitoylation and its nuclear localization (Extended Data Fig.	('Knocking down', 'Var', (0, 13))	('nuclear localization', 'MPA', (117, 137))	('SK-MES', 'CellLine', 'CVCL:0630', (72, 78))	('STAT3 palmitoylation', 'MPA', (88, 108))	('reduced', 'NegReg', (80, 87))	('HCC95', 'CellLine', 'CVCL:5137', (51, 56))	('ZDHHC19', 'Gene', (14, 21))
335010	31462771	In addition, loss of STAT3 or ZDHHC19 significantly blocked tumorsphere formation under basal conditions or with palmitic acid stimulation (Extended Data Fig.	('blocked', 'NegReg', (52, 59))	('STAT3', 'Gene', (21, 26))	('ZDHHC19', 'Gene', (30, 37))	('tumors', 'Disease', 'MESH:D009369', (60, 66))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('palmitic acid', 'Chemical', 'MESH:D019308', (113, 126))	('loss', 'Var', (13, 17))	('tumors', 'Disease', (60, 66))
335011	31462771	Interestingly, ectopic expression of STAT3C could rescue the inhibitory effects of ZDHHC19 knockdown in tumorsphere formation (Extended Data Fig.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('knockdown', 'Var', (91, 100))	('inhibitory effects', 'MPA', (61, 79))	('tumors', 'Disease', (104, 110))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('ZDHHC19', 'Gene', (83, 90))
335014	31462771	ZDHHC19 knockout significantly blocked HFD-induced tumor growth (Fig.4d, and Extended Data Fig.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('ZDHHC19', 'Gene', (0, 7))	('tumor', 'Disease', (51, 56))	('blocked', 'NegReg', (31, 38))	('knockout', 'Var', (8, 16))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
335035	31462771	cOmplete EDTA-free protease inhibitors cocktail (05892791001) and Liberase DL (05401160001) were purchased from Roche.	('05401160001', 'Var', (79, 90))	('EDTA', 'Chemical', 'MESH:D004492', (9, 13))	('05892791001', 'Var', (49, 60))
335039	31462771	Flag-tag (14793S), HA-tag (3724S), phospho-STAT3 (Tyr705) (9145S), STAT3 (9139S), Grb2 (3972), Lamin B1(68591S), HDAC1 (5356S), Ki67 (9027S), Anti-Rabbit HRP (7074S), Anti-Mouse HRP (7076S) were purchased from Cell Signaling.	('HDAC1', 'Gene', '100355156', (113, 118))	('Mouse', 'Species', '10090', (172, 177))	('HDAC1', 'Gene', (113, 118))	('3724S', 'Var', (27, 32))	('Rabbit', 'Species', '9986', (147, 153))	('3972', 'Var', (88, 92))	('Tyr705', 'Chemical', '-', (50, 56))	('9027S', 'Var', (134, 139))	('9139S', 'Var', (74, 79))	('68591S', 'Var', (104, 110))
335045	31462771	All the mutants (STAT3 C687S, C712S, C687/712S; ZDHHC19 C142S, P18A) were generated by site-directed mutagenesis using the QuickChange II Site-Directed Mutagenesis kit (Agilent) following manufacturer's instructions.	('ZDHHC19', 'Gene', (48, 55))	('C687S', 'Mutation', 'p.C687S', (23, 28))	('P18A', 'Mutation', 'rs121913248', (63, 67))	('C142S', 'Var', (56, 61))	('C687/712S', 'Var', (37, 46))	('C142S', 'Mutation', 'p.C142S', (56, 61))	('C712S', 'Var', (30, 35))	('C712S', 'Mutation', 'p.C712S', (30, 35))
335068	31462771	Antibody and dilutions used in the studies: anti-FLAG M2 (1:2000), anti-HA (1:1000), anti-GFP (1:1000), anti-STAT3 (1:1000), anti-pSTAT3 (1:1000), anti-ZDHHC19 (1:500), anti-GAPDH (1:2000), anti-c-Myc (1:1000), streptavidin-HRP antibody (1:5000).	('anti-pSTAT3', 'Var', (125, 136))	('anti-ZDHHC19', 'Var', (147, 159))	('anti-HA', 'Var', (67, 74))	('anti-GAPDH', 'Var', (169, 179))	('anti-GFP', 'Var', (85, 93))	('c-Myc', 'Gene', '4609', (195, 200))	('anti-STAT3', 'Var', (104, 114))	('c-Myc', 'Gene', (195, 200))	('anti-FLAG', 'Var', (44, 53))
335135	31462771	The mice were fed with autoclaved regular chow diet (normal fat diet, NFD, composed of 10% fat based on caloric content) or high-fat diet (HFD, composed of 60% fat based on caloric content) (Research Diet Cat#D12492, D12450J New Brunswick, NJ) for one week before cancer cell transplantation and their specific diet were maintained until the experiments were terminated.	('mice', 'Species', '10090', (4, 8))	('cancer', 'Phenotype', 'HP:0002664', (264, 270))	('D12450J', 'Var', (217, 224))	('D12450J', 'SUBSTITUTION', 'None', (217, 224))	('cancer', 'Disease', (264, 270))	('cancer', 'Disease', 'MESH:D009369', (264, 270))
335154	29805077	NRF2 directly controls TRPA1 expression and TRPA1 inhibition suppresses xenograft tumor growth and enhances chemosensitivity.	('TRPA1', 'Gene', (44, 49))	('NRF2', 'Gene', (0, 4))	('inhibition', 'Var', (50, 60))	('chemosensitivity', 'CPA', (108, 124))	('suppresses', 'NegReg', (61, 71))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('TRPA1', 'Protein', (23, 28))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('enhances', 'PosReg', (99, 107))	('NRF2', 'Gene', '4780', (0, 4))	('tumor', 'Disease', (82, 87))
335155	29805077	Tumor suppressor and oncogenic pathways frequently mutated in cancer commonly cause increased accumulation of reactive oxygen species (ROS).	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('Tumor suppressor', 'Pathway', (0, 16))	('oncogenic pathways', 'Pathway', (21, 39))	('increased', 'PosReg', (84, 93))	('cancer', 'Disease', (62, 68))	('accumulation of reactive oxygen species', 'MPA', (94, 133))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('ROS', 'Chemical', 'MESH:D017382', (135, 138))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (110, 133))	('mutated', 'Var', (51, 58))
335163	29805077	Through disruption of Gclm encoding a rate-limiting enzyme for the synthesis of glutathione (GSH) that can neutralize ROS, GSH was shown to be required for cancer initiation in the MMTV-PyMT mouse breast cancer model.	('disruption', 'Var', (8, 18))	('breast cancer', 'Disease', (197, 210))	('cancer initiation', 'Disease', (156, 173))	('Gclm', 'Gene', (22, 26))	('GSH', 'Chemical', '-', (93, 96))	('breast cancer', 'Phenotype', 'HP:0003002', (197, 210))	('ROS', 'MPA', (118, 121))	('Gclm', 'Gene', '2730', (22, 26))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('P', 'Chemical', 'MESH:D010758', (186, 187))	('glutathione', 'Chemical', 'MESH:D005978', (80, 91))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('mouse', 'Species', '10090', (191, 196))	('ROS', 'Chemical', 'MESH:D017382', (118, 121))	('GSH', 'Chemical', '-', (123, 126))	('MMTV', 'Species', '11757', (181, 185))	('breast cancer', 'Disease', 'MESH:D001943', (197, 210))	('cancer initiation', 'Disease', 'MESH:D009369', (156, 173))
335182	29805077	TRPA1 mutations were found in some cancers; however, none (among 61 mutants tested) led to a constitutive TRPA1 activation (Figure S1F and Table S2).	('TRPA1', 'Gene', (0, 5))	('TRPA1', 'Gene', (106, 111))	('activation', 'PosReg', (112, 122))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('S', 'Chemical', 'MESH:D013455', (131, 132))	('S', 'Chemical', 'MESH:D013455', (145, 146))	('cancers', 'Disease', 'MESH:D009369', (35, 42))	('cancers', 'Phenotype', 'HP:0002664', (35, 42))	('cancers', 'Disease', (35, 42))	('mutations', 'Var', (6, 15))
335190	29805077	Mustard oil elicited increases in intracellular Ca2+ concentration ([Ca2+]i), which were abolished by either the TRPA1 specific inhibitor AP-18, TRPA1 knockdown by short hairpin RNA (shRNA), or removal of extracellular Ca2+ (Figures 1D-1I and S1M).	('increases', 'PosReg', (21, 30))	('Ca2', 'Gene', (219, 222))	('Ca2', 'Gene', (69, 72))	('TRPA1', 'Gene', (113, 118))	('Mustard oil', 'Chemical', 'MESH:C027793', (0, 11))	('Ca2', 'Gene', (48, 51))	('AP-18', 'Chemical', '-', (138, 143))	('TRPA1', 'Gene', (145, 150))	('Ca2', 'Gene', '760', (219, 222))	('S', 'Chemical', 'MESH:D013455', (243, 244))	('Ca2', 'Gene', '760', (48, 51))	('Ca2', 'Gene', '760', (69, 72))	('knockdown', 'Var', (151, 160))
335192	29805077	H2O2 induced an increase in [Ca2+]i and also oscillatory Ca2+ responses that were suppressed by TRPA1 inhibition in TRPA1-enriched cancer cell lines (Figures 2A-2C and S2A-S2C), indicating that TRPA1 is the major channel responsible for Ca2+ entry in response to H2O2 in these cancer cells.	('suppressed', 'NegReg', (82, 92))	('increase', 'PosReg', (16, 24))	('Ca2', 'Gene', (29, 32))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('S', 'Chemical', 'MESH:D013455', (172, 173))	('cancer', 'Disease', (277, 283))	('TRPA1', 'Gene', (96, 101))	('Ca2', 'Gene', '760', (57, 60))	('Ca2', 'Gene', '760', (237, 240))	('inhibition', 'NegReg', (102, 112))	('cancer', 'Phenotype', 'HP:0002664', (277, 283))	('H2O2', 'Chemical', 'MESH:D006861', (263, 267))	('H2O2', 'Chemical', 'MESH:D006861', (0, 4))	('Ca2', 'Gene', (57, 60))	('Ca2', 'Gene', (237, 240))	('cancer', 'Disease', (131, 137))	('S', 'Chemical', 'MESH:D013455', (168, 169))	('Ca2', 'Gene', '760', (29, 32))	('cancer', 'Disease', 'MESH:D009369', (277, 283))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('H2O2', 'Var', (0, 4))
335193	29805077	This is consistent with evidence that knockdown of TRPM2, another redox-sensitive channel whose expression partially overlaps that of TRPA1 in human tumors (Figure 1A), does not affect Ca2+ responses to H2O2 in HCC1569 and H1792 cells (Figures S2D and S2E).	('H1792', 'CellLine', 'CVCL:1495', (223, 228))	('H2O2', 'Chemical', 'MESH:D006861', (203, 207))	('Ca2', 'Gene', (185, 188))	('human', 'Species', '9606', (143, 148))	('Ca2', 'Gene', '760', (185, 188))	('S', 'Chemical', 'MESH:D013455', (244, 245))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('TRPM2', 'Gene', '7226', (51, 56))	('TRPM2', 'Gene', (51, 56))	('tumors', 'Disease', (149, 155))	('S', 'Chemical', 'MESH:D013455', (252, 253))	('tumors', 'Disease', 'MESH:D009369', (149, 155))	('tumors', 'Phenotype', 'HP:0002664', (149, 155))	('knockdown', 'Var', (38, 47))	('HCC1569', 'CellLine', 'CVCL:1255', (211, 218))	('affect', 'Reg', (178, 184))
335194	29805077	Notably, AP-18 or TRPA1 knockdown, which did not affect normal cell growth in monolayer culture (Figure S2F), decreased live cell number and increased cell death in response to H2O2 in TRPA1-enriched cancer cells, but not in those with low TRPA1 expression (Figures 2D-2I, S2G, and S2H).	('S', 'Chemical', 'MESH:D013455', (282, 283))	('AP-18', 'Chemical', '-', (9, 14))	('AP-18', 'Gene', (9, 14))	('TRPA1', 'Gene', (18, 23))	('increased', 'PosReg', (141, 150))	('S', 'Chemical', 'MESH:D013455', (104, 105))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('decreased', 'NegReg', (110, 119))	('live cell number', 'CPA', (120, 136))	('S', 'Chemical', 'MESH:D013455', (273, 274))	('H2O2', 'Chemical', 'MESH:D006861', (177, 181))	('cell death', 'CPA', (151, 161))	('response', 'MPA', (165, 173))	('cancer', 'Disease', 'MESH:D009369', (200, 206))	('knockdown', 'Var', (24, 33))	('cancer', 'Disease', (200, 206))
335195	29805077	Ectopic TRPA1 expression increased the survival of H2O2-treated cells with low basal TRPA1 expression (Figures 2J and S2I), further supporting that TRPA1 promotes oxidative-stress defense.	('survival', 'CPA', (39, 47))	('increased', 'PosReg', (25, 34))	('oxidative-stress', 'MPA', (163, 179))	('promotes', 'PosReg', (154, 162))	('S', 'Chemical', 'MESH:D013455', (118, 119))	('oxidative-stress', 'Phenotype', 'HP:0025464', (163, 179))	('Ectopic', 'Var', (0, 7))	('TRPA1', 'Gene', (8, 13))	('H2O2', 'Chemical', 'MESH:D006861', (51, 55))
335197	29805077	We next examined whether ectopic TRPA1 expression induces oxidative-stress defense in MCF-10A cells, a well-established immortalized mammary epithelial cell line used for the analysis of phenotypic changes induced by oncogene transduction.	('MCF-10A', 'CellLine', 'CVCL:0598', (86, 93))	('oxidative-stress defense', 'MPA', (58, 82))	('oxidative-stress', 'Phenotype', 'HP:0025464', (58, 74))	('ectopic', 'Var', (25, 32))	('induces', 'PosReg', (50, 57))	('TRPA1', 'Gene', (33, 38))
335200	29805077	BAPTA-AM suppressed viability of TRPA1-expressing cells treated with H2O2 (Figure S2N), indicating the importance of [Ca2+]i rises in cell survival.	('H2O2', 'Chemical', 'MESH:D006861', (69, 73))	('H2O2', 'Var', (69, 73))	('Ca2', 'Gene', '760', (118, 121))	('viability', 'CPA', (20, 29))	('BAPTA-AM', 'Chemical', 'MESH:C070379', (0, 8))	('TRPA1-expressing', 'Gene', (33, 49))	('Ca2', 'Gene', (118, 121))	('S', 'Chemical', 'MESH:D013455', (82, 83))	('suppressed', 'NegReg', (9, 19))
335203	29805077	Both HCC1569 and H1792 formed solid spheroids.	('H1792', 'CellLine', 'CVCL:1495', (17, 22))	('solid spheroids', 'CPA', (30, 45))	('HCC1569', 'Var', (5, 12))	('H1792', 'Var', (17, 22))	('HCC1569', 'CellLine', 'CVCL:1255', (5, 12))
335208	29805077	TRPA1 inhibition increased apoptosis of cells localized in the inner region of spheroids (Figures 3C, 3D, and S3B).	('TRPA1', 'Gene', (0, 5))	('S3B', 'Gene', '11778', (110, 113))	('apoptosis', 'CPA', (27, 36))	('inhibition', 'Var', (6, 16))	('S3B', 'Gene', (110, 113))
335212	29805077	Indeed, TRPA1 inhibition impaired the anchorage-independent growth of HCC1569 cells, reducing both the number and average size of colonies (Figures 3G and 3H).	('reducing', 'NegReg', (85, 93))	('HCC1569', 'CellLine', 'CVCL:1255', (70, 77))	('anchorage-independent growth', 'CPA', (38, 66))	('impaired', 'NegReg', (25, 33))	('TRPA1', 'Gene', (8, 13))	('inhibition', 'Var', (14, 24))
335213	29805077	Furthermore, TRPA1 expression increased live cell number and suppressed anoikis in suspended MCF-10A cells (Figure S3D), which do not possess anchorage-independent ability.	('suppressed', 'NegReg', (61, 71))	('TRPA1', 'Gene', (13, 18))	('live cell number', 'CPA', (40, 56))	('anoikis', 'CPA', (72, 79))	('S', 'Chemical', 'MESH:D013455', (115, 116))	('expression', 'Var', (19, 29))	('MCF-10A', 'CellLine', 'CVCL:0598', (93, 100))	('increased', 'PosReg', (30, 39))
335221	29805077	In 3D culture, the wild-type but not the C199S Hyper-2 mutant, which is unable to react with ROS, showed increased signal in the inner cells of MCF-10A acini (Figures S3L-S3N), which was abolished by NAC but not by TRPA1 expression or AP-18.	('S', 'Chemical', 'MESH:D013455', (167, 168))	('Hyper-2', 'Gene', (47, 54))	('MCF-10A', 'CellLine', 'CVCL:0598', (144, 151))	('S', 'Chemical', 'MESH:D013455', (45, 46))	('S', 'Chemical', 'MESH:D013455', (171, 172))	('ROS', 'Chemical', 'MESH:D017382', (93, 96))	('AP-18', 'Chemical', '-', (235, 240))	('C199S', 'Var', (41, 46))	('C199S', 'Mutation', 'rs1217962638', (41, 46))	('increased', 'PosReg', (105, 114))	('S', 'Chemical', 'MESH:D013455', (95, 96))	('signal', 'MPA', (115, 121))	('NAC', 'Gene', (200, 203))	('NAC', 'Gene', '7504', (200, 203))
335223	29805077	Moreover, TRPA1 expression suppressed apoptosis of the cells localized in the inner region of the MCF-10A acini (Figure S3O).	('TRPA1', 'Gene', (10, 15))	('expression', 'Var', (16, 26))	('suppressed', 'NegReg', (27, 37))	('apoptosis', 'CPA', (38, 47))	('S', 'Chemical', 'MESH:D013455', (120, 121))	('MCF-10A', 'CellLine', 'CVCL:0598', (98, 105))
335229	29805077	TRPM2 knockdown did not affect Ca2+ responses to carboplatin (Figure S4D).	('TRPM2', 'Gene', '7226', (0, 5))	('TRPM2', 'Gene', (0, 5))	('Ca2', 'Gene', (31, 34))	('S', 'Chemical', 'MESH:D013455', (69, 70))	('carboplatin', 'Chemical', 'MESH:D016190', (49, 60))	('knockdown', 'Var', (6, 15))	('Ca2', 'Gene', '760', (31, 34))
335232	29805077	Carboplatin-induced ROS generation was unaffected by TRPA1 knockdown (Figure S4G).	('Carboplatin', 'Chemical', 'MESH:D016190', (0, 11))	('ROS', 'Chemical', 'MESH:D017382', (20, 23))	('S', 'Chemical', 'MESH:D013455', (22, 23))	('S', 'Chemical', 'MESH:D013455', (77, 78))	('knockdown', 'Var', (59, 68))	('TRPA1', 'Gene', (53, 58))
335234	29805077	In 3D culture, TRPA1 inhibition strongly enhanced apoptosis of HCC1569 cells localized in the inner region of day 7 spheroids treated with carboplatin (Figures 4M and 4N).	('enhanced', 'PosReg', (41, 49))	('HCC1569', 'CellLine', 'CVCL:1255', (63, 70))	('inhibition', 'Var', (21, 31))	('TRPA1', 'Protein', (15, 20))	('carboplatin', 'Chemical', 'MESH:D016190', (139, 150))	('apoptosis', 'CPA', (50, 59))
335239	29805077	TRPA1 knockdown not only suppressed tumor growth (Figure 5A, vehicle controls) but also sensitized tumors to carboplatin treatment, which was associated with increased apoptosis (Figures 5A-5C).	('tumor', 'Disease', (99, 104))	('TRPA1', 'Gene', (0, 5))	('tumors', 'Disease', 'MESH:D009369', (99, 105))	('suppressed', 'NegReg', (25, 35))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('apoptosis', 'CPA', (168, 177))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('knockdown', 'Var', (6, 15))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))	('carboplatin', 'Chemical', 'MESH:D016190', (109, 120))	('sensitized', 'NegReg', (88, 98))	('tumor', 'Disease', (36, 41))	('increased', 'PosReg', (158, 167))	('tumors', 'Disease', (99, 105))
335241	29805077	Although several TRPA1 inhibitors have been developed as pain and respiratory therapies, their pharmacokinetics are not optimal.	('TRPA1', 'Protein', (17, 22))	('inhibitors', 'Var', (23, 33))	('pain', 'Phenotype', 'HP:0012531', (57, 61))	('pain', 'Disease', 'MESH:D010146', (57, 61))	('pain', 'Disease', (57, 61))
335243	29805077	Despite this limitation, oral administration of AM-0902 twice daily reduced both tumor volume and mass in EL-12-58 xenograft models without significant side toxicities (0.188% +- 2.42% weight loss at day 32) (Figures 5D and 5E).	('side toxicities', 'Disease', 'MESH:D064420', (152, 167))	('weight loss', 'Disease', 'MESH:D015431', (185, 196))	('EL-12-58', 'CellLine', 'CVCL:3680', (106, 114))	('side toxicities', 'Disease', (152, 167))	('AM-0902', 'Var', (48, 55))	('AM-0902', 'Chemical', 'MESH:C000609916', (48, 55))	('weight loss', 'Disease', (185, 196))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('mass', 'CPA', (98, 102))	('weight loss', 'Phenotype', 'HP:0001824', (185, 196))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('reduced', 'NegReg', (68, 75))	('tumor', 'Disease', (81, 86))
335245	29805077	Although 3 of 10 animals treated with AM-0902 + carboplatin exhibited significant weight loss during the last 3 days (from day 29 to day 32), most likely due to diarrhea, animals treated with either AM-0902 + carboplatin or carboplatin alone showed comparable weight loss until day 29 and there was no correlation between weight loss and tumor growth at any time points (Figure S5A).	('weight loss', 'Disease', (260, 271))	('weight loss', 'Phenotype', 'HP:0001824', (322, 333))	('carboplatin', 'Chemical', 'MESH:D016190', (209, 220))	('AM-0902', 'Chemical', 'MESH:C000609916', (38, 45))	('tumor', 'Disease', (338, 343))	('AM-0902 + carboplatin', 'Var', (38, 59))	('S', 'Chemical', 'MESH:D013455', (378, 379))	('weight loss', 'Disease', 'MESH:D015431', (82, 93))	('tumor', 'Disease', 'MESH:D009369', (338, 343))	('diarrhea', 'Phenotype', 'HP:0002014', (161, 169))	('weight loss', 'Disease', (322, 333))	('carboplatin', 'Chemical', 'MESH:D016190', (224, 235))	('weight loss', 'Phenotype', 'HP:0001824', (82, 93))	('diarrhea', 'Disease', (161, 169))	('weight loss', 'Disease', (82, 93))	('AM-0902 +', 'Var', (199, 208))	('tumor', 'Phenotype', 'HP:0002664', (338, 343))	('carboplatin', 'Chemical', 'MESH:D016190', (48, 59))	('weight loss', 'Disease', 'MESH:D015431', (260, 271))	('weight loss', 'Phenotype', 'HP:0001824', (260, 271))	('AM-0902', 'Chemical', 'MESH:C000609916', (199, 206))	('diarrhea', 'Disease', 'MESH:D003967', (161, 169))	('weight loss', 'Disease', 'MESH:D015431', (322, 333))
335246	29805077	H&E staining of tumor sections revealed that AM-0902 treatment reduced live tumor cell area relative to total area, compared with vehicle or single carboplatin treatment (Figures 5F and 5G).	('AM-0902', 'Chemical', 'MESH:C000609916', (45, 52))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('H&E', 'Chemical', '-', (0, 3))	('tumor', 'Disease', (76, 81))	('that', 'Var', (40, 44))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('carboplatin', 'Chemical', 'MESH:D016190', (148, 159))	('tumor', 'Disease', (16, 21))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('treatment', 'NegReg', (53, 62))
335247	29805077	Furthermore, Masson trichrome staining showed that the population of collagenous stroma was enhanced by AM-0902 + carboplatin treatment (Figures 5F and 5H), probably due to a desmoplastic response to tumor cell death.	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('AM-0902', 'Chemical', 'MESH:C000609916', (104, 111))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('desmoplastic', 'Disease', 'MESH:D018220', (175, 187))	('tumor', 'Disease', (200, 205))	('enhanced', 'PosReg', (92, 100))	('population of collagenous stroma', 'CPA', (55, 87))	('carboplatin', 'Chemical', 'MESH:D016190', (114, 125))	('desmoplastic', 'Disease', (175, 187))	('AM-0902 + carboplatin', 'Var', (104, 125))
335258	29805077	In MCF-10A cells treated with H2O2 or deprived of matrix attachment, ectopic TRPA1 expression increased the phosphorylation of multiple pro-survival proteins, including components of the RAS-ERK (p-MAPK, p-B-RAF, p-p90RSK, p-MEK1, or p-ELK), PI3K/AKT (p-AKT, p-GSK-3alpha-beta, or p-PRAS40), and mammalian target of rapamycin (mTOR) signaling pathways (p-S6, p-eIF4E, p-4E-BP1, or p-mTOR), as well as upstream components of these pathways (p-SRC, p-SHP-2, or p-SHC) (Figure 6A).	('eIF4E', 'Gene', (361, 366))	('S', 'Chemical', 'MESH:D013455', (355, 356))	('AKT', 'Gene', (254, 257))	('increased', 'PosReg', (94, 103))	('ectopic TRPA1', 'Gene', (69, 82))	('S', 'Chemical', 'MESH:D013455', (442, 443))	('AKT', 'Gene', '207', (247, 250))	('eIF4E', 'Gene', '1977', (361, 366))	('H2O2', 'Chemical', 'MESH:D006861', (30, 34))	('S', 'Chemical', 'MESH:D013455', (219, 220))	('PRAS40', 'Gene', (283, 289))	('PI3K/AKT', 'Gene', (242, 250))	('P', 'Chemical', 'MESH:D010758', (242, 243))	('4E-BP1', 'Gene', '1978', (370, 376))	('mTOR', 'Gene', (327, 331))	('mTOR', 'Gene', (383, 387))	('p90RSK', 'Gene', '6195', (215, 221))	('P', 'Chemical', 'MESH:D010758', (200, 201))	('S', 'Chemical', 'MESH:D013455', (449, 450))	('H2O2', 'Var', (30, 34))	('MEK', 'Gene', '5609', (225, 228))	('AKT', 'Gene', '207', (254, 257))	('P', 'Chemical', 'MESH:D010758', (283, 284))	('MCF-10A', 'CellLine', 'CVCL:0598', (3, 10))	('P', 'Chemical', 'MESH:D010758', (374, 375))	('mTOR', 'Gene', '2475', (327, 331))	('P', 'Chemical', 'MESH:D010758', (79, 80))	('mTOR', 'Gene', '2475', (383, 387))	('SHP-2', 'Gene', '5781', (449, 454))	('4E-BP1', 'Gene', (370, 376))	('phosphorylation', 'MPA', (108, 123))	('mammalian target of rapamycin', 'Gene', '2475', (296, 325))	('P', 'Chemical', 'MESH:D010758', (451, 452))	('MEK', 'Gene', (225, 228))	('PI3K/AKT', 'Gene', '5293;207', (242, 250))	('PRAS40', 'Gene', '84335', (283, 289))	('AKT', 'Gene', (247, 250))	('TRPA1', 'Gene', (77, 82))	('S', 'Chemical', 'MESH:D013455', (262, 263))	('S', 'Chemical', 'MESH:D013455', (461, 462))	('S', 'Chemical', 'MESH:D013455', (286, 287))	('p90RSK', 'Gene', (215, 221))	('mammalian target of rapamycin', 'Gene', (296, 325))	('S', 'Chemical', 'MESH:D013455', (189, 190))	('SHP-2', 'Gene', (449, 454))
335262	29805077	Consistent with these observations, TRPA1 inhibition decreased the phosphorylation of RAS-ERK/AKT/mTOR signaling proteins and expression of MCL-1 in HCC1569 and H1792 cells (Figures 6E-6I, S6G, and S6H).	('AKT', 'Gene', '207', (94, 97))	('S6G', 'Mutation', 'p.S6G', (189, 192))	('S6H', 'Mutation', 'p.S6H', (198, 201))	('expression', 'MPA', (126, 136))	('MCL-1', 'Gene', '4170', (140, 145))	('AKT', 'Gene', (94, 97))	('inhibition', 'Var', (42, 52))	('mTOR', 'Gene', '2475', (98, 102))	('HCC1569', 'CellLine', 'CVCL:1255', (149, 156))	('MCL-1', 'Gene', (140, 145))	('H1792', 'CellLine', 'CVCL:1495', (161, 166))	('decreased', 'NegReg', (53, 62))	('mTOR', 'Gene', (98, 102))	('TRPA1', 'Protein', (36, 41))	('phosphorylation', 'MPA', (67, 82))
335264	29805077	Interestingly, phosphorylation of PI3K/AKT signaling proteins was unaffected by TRPA1 knockdown in HCC1569 cells treated with H2O2 or carboplatin (Figures 6E and 6G), raising the possibility that this pathway is already maximally activated due to PTEN deletion and HER2 overexpression present in these cells.	('HER2', 'Gene', (265, 269))	('HCC1569', 'CellLine', 'CVCL:1255', (99, 106))	('carboplatin', 'Chemical', 'MESH:D016190', (134, 145))	('overexpression', 'PosReg', (270, 284))	('deletion', 'Var', (252, 260))	('PI3K/AKT', 'Gene', '5293;207', (34, 42))	('HER2', 'Gene', '2064', (265, 269))	('TRPA1', 'Gene', (80, 85))	('PI3K/AKT', 'Gene', (34, 42))	('PTEN', 'Gene', (247, 251))	('PTEN', 'Gene', '5728', (247, 251))	('H2O2', 'Chemical', 'MESH:D006861', (126, 130))	('phosphorylation', 'MPA', (15, 30))
335266	29805077	In support of these findings, the phosphorylation of RAS-ERK and mTOR signaling proteins and MCL-1 mRNA were increased in BRCA with high TRPA1 expression (Figures S7A and S7B).	('mTOR', 'Gene', (65, 69))	('mTOR', 'Gene', '2475', (65, 69))	('TRPA1', 'Protein', (137, 142))	('phosphorylation', 'MPA', (34, 49))	('increased', 'PosReg', (109, 118))	('expression', 'MPA', (143, 153))	('MCL-1', 'Gene', (93, 98))	('MCL-1', 'Gene', '4170', (93, 98))	('S', 'Chemical', 'MESH:D013455', (55, 56))	('S', 'Chemical', 'MESH:D013455', (163, 164))	('S', 'Chemical', 'MESH:D013455', (171, 172))	('RAS-ERK', 'Protein', (53, 60))	('BRCA', 'Gene', '672', (122, 126))	('high', 'Var', (132, 136))	('BRCA', 'Gene', (122, 126))
335269	29805077	W-7, trifluoperazine (TFP; another CaM inhibitor structurally distinct from W-7), PD325901 (MEK inhibitor), Torin1 (mTOR inhibitor), A-1210477 (MCL-1 inhibitor), or PYK2 knockdown, but not KN-93 (CaM kinase II inhibitor), suppressed the enhanced viability of TRPA1-expressing MCF-10A cells treated with H2O2 or HCC1569 cells treated with H2O2 or carboplatin (Figures 6J-6M).	('carboplatin', 'Chemical', 'MESH:D016190', (346, 357))	('H2O2', 'Chemical', 'MESH:D006861', (338, 342))	('MCF-10A', 'CellLine', 'CVCL:0598', (276, 283))	('mTOR', 'Gene', '2475', (116, 120))	('viability', 'CPA', (246, 255))	('MCL-1', 'Gene', (144, 149))	('suppressed', 'NegReg', (222, 232))	('P', 'Chemical', 'MESH:D010758', (82, 83))	('knockdown', 'Var', (170, 179))	('MEK', 'Gene', '5609', (92, 95))	('PYK2', 'Gene', '2185', (165, 169))	('H2O2', 'Chemical', 'MESH:D006861', (303, 307))	('MEK', 'Gene', (92, 95))	('P', 'Chemical', 'MESH:D010758', (24, 25))	('enhanced', 'PosReg', (237, 245))	('TRPA1-expressing', 'Gene', (259, 275))	('PD325901', 'Var', (82, 90))	('PYK2', 'Gene', (165, 169))	('P', 'Chemical', 'MESH:D010758', (165, 166))	('HCC1569', 'CellLine', 'CVCL:1255', (311, 318))	('P', 'Chemical', 'MESH:D010758', (261, 262))	('A-1210477', 'Var', (133, 142))	('mTOR', 'Gene', (116, 120))	('MCL-1', 'Gene', '4170', (144, 149))
335270	29805077	Notably, A-1210477 abolished TRPA1-mediated inhibition of apoptosis in MCF-10A or HCC1569 cells localized in the inner region of spheroids (Figures S7D-S7G) and increased clearance of cells from the inner space in shGFP-transduced control HCC1569 spheroids but not in shTRPA1-transduced spheroids (Figures 6N, 6O, S7H, and S7I).	('HCC1569', 'CellLine', 'CVCL:1255', (82, 89))	('S', 'Chemical', 'MESH:D013455', (323, 324))	('HCC1569', 'CellLine', 'CVCL:1255', (239, 246))	('P', 'Chemical', 'MESH:D010758', (218, 219))	('S', 'Chemical', 'MESH:D013455', (314, 315))	('P', 'Chemical', 'MESH:D010758', (272, 273))	('S7I', 'Mutation', 'p.S7I', (323, 326))	('MCF-10A', 'CellLine', 'CVCL:0598', (71, 78))	('P', 'Chemical', 'MESH:D010758', (31, 32))	('S', 'Chemical', 'MESH:D013455', (152, 153))	('S7H', 'Mutation', 'p.S7H', (314, 317))	('A-1210477', 'Var', (9, 18))	('S', 'Chemical', 'MESH:D013455', (148, 149))	('apoptosis', 'CPA', (58, 67))	('clearance', 'CPA', (171, 180))	('increased', 'PosReg', (161, 170))	('abolished', 'NegReg', (19, 28))
335273	29805077	In HCC1569 and EL-12-58 tumors treated with vehicle or carboplatin, TRPA1 knockdown or AM-0902 suppressed phosphorylation of PYK2, MAPK, and 4E-BP1 and expression of MCL-1 (Figure 6Q), suggesting that TRPA1 is activated and upregulates Ca2+-dependent anti-apoptotic programs in tumors.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumor', 'Phenotype', 'HP:0002664', (278, 283))	('TRPA1', 'Gene', (68, 73))	('P', 'Chemical', 'MESH:D010758', (133, 134))	('tumors', 'Disease', (24, 30))	('tumors', 'Disease', (278, 284))	('phosphorylation', 'MPA', (106, 121))	('MCL-1', 'Gene', '4170', (166, 171))	('P', 'Chemical', 'MESH:D010758', (203, 204))	('4E-BP1', 'Gene', '1978', (141, 147))	('upregulates', 'PosReg', (224, 235))	('suppressed', 'NegReg', (95, 105))	('MCL-1', 'Gene', (166, 171))	('tumors', 'Disease', 'MESH:D009369', (24, 30))	('AM-0902', 'Var', (87, 94))	('knockdown', 'Var', (74, 83))	('tumors', 'Disease', 'MESH:D009369', (278, 284))	('P', 'Chemical', 'MESH:D010758', (145, 146))	('expression', 'MPA', (152, 162))	('4E-BP1', 'Gene', (141, 147))	('Ca2', 'Gene', '760', (236, 239))	('PYK2', 'Gene', '2185', (125, 129))	('HCC1569', 'CellLine', 'CVCL:1255', (3, 10))	('carboplatin', 'Chemical', 'MESH:D016190', (55, 66))	('MAPK', 'Protein', (131, 135))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('tumors', 'Phenotype', 'HP:0002664', (278, 284))	('PYK2', 'Gene', (125, 129))	('AM-0902', 'Chemical', 'MESH:C000609916', (87, 94))	('Ca2', 'Gene', (236, 239))	('P', 'Chemical', 'MESH:D010758', (125, 126))	('P', 'Chemical', 'MESH:D010758', (70, 71))	('EL-12-58', 'CellLine', 'CVCL:3680', (15, 23))
335276	29805077	In cancer cells with low basal TRPA1 expression, H2O2 increased TRPA1 expression substantially in serum-starved conditions (Figures S1K, S1L, and 7A) and marginally in complete media (Figure S8A).	('H2O2', 'Var', (49, 53))	('TRPA1', 'Gene', (64, 69))	('S', 'Chemical', 'MESH:D013455', (132, 133))	('S', 'Chemical', 'MESH:D013455', (191, 192))	('increased', 'PosReg', (54, 63))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('S1L', 'Mutation', 'p.S1L', (137, 140))	('expression', 'MPA', (70, 80))	('cancer', 'Disease', (3, 9))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))	('S', 'Chemical', 'MESH:D013455', (137, 138))	('H2O2', 'Chemical', 'MESH:D006861', (49, 53))
335279	29805077	Indeed, H2O2-induced TRPA1 expression was abolished by NRF2 knockdown (Figure 7C).	('TRPA1', 'Protein', (21, 26))	('NRF2', 'Gene', (55, 59))	('abolished', 'NegReg', (42, 51))	('H2O2', 'Chemical', 'MESH:D006861', (8, 12))	('expression', 'MPA', (27, 37))	('knockdown', 'Var', (60, 69))	('NRF2', 'Gene', '4780', (55, 59))
335280	29805077	Furthermore, H2O2 increased not only TRPA1 but also MCL-1 expression, which was suppressed by either TRPA1 inhibition or NRF2 knockdown (Figure 7D).	('NRF2', 'Gene', '4780', (121, 125))	('increased', 'PosReg', (18, 27))	('MCL-1', 'Gene', '4170', (52, 57))	('MCL-1', 'Gene', (52, 57))	('expression', 'MPA', (58, 68))	('NRF2', 'Gene', (121, 125))	('TRPA1', 'Protein', (37, 42))	('knockdown', 'Var', (126, 135))	('H2O2', 'Var', (13, 17))	('H2O2', 'Chemical', 'MESH:D006861', (13, 17))
335282	29805077	Mutations or deletions in NFE2L2 (encoding NRF2), KEAP1, or CUL3 (both encoding negative regulators of NRF2) that lead to a constitutive activation of NRF2, are frequently observed in LUSC (32.8%), LUAD (22.6%), and head-neck squamous carcinoma (HNSC, 14.3%), but rarely occur in BRCA (1.8%).	('CUL3', 'Gene', (60, 64))	('LUSC', 'Phenotype', 'HP:0030359', (184, 188))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (226, 244))	('NRF2', 'Gene', '4780', (43, 47))	('deletions', 'Var', (13, 22))	('KEAP1', 'Gene', '9817', (50, 55))	('KEAP1', 'Gene', (50, 55))	('S', 'Chemical', 'MESH:D013455', (186, 187))	('BRCA', 'Gene', '672', (280, 284))	('Mutations', 'Var', (0, 9))	('LUAD', 'Phenotype', 'HP:0030078', (198, 202))	('activation', 'PosReg', (137, 147))	('NRF2', 'Gene', (43, 47))	('NRF2', 'Gene', '4780', (151, 155))	('NFE2L2', 'Gene', '4780', (26, 32))	('S', 'Chemical', 'MESH:D013455', (248, 249))	('NRF2', 'Gene', '4780', (103, 107))	('CUL3', 'Gene', '8452', (60, 64))	('carcinoma', 'Phenotype', 'HP:0030731', (235, 244))	('BRCA', 'Gene', (280, 284))	('LUAD', 'Disease', (198, 202))	('NRF2', 'Gene', (151, 155))	('NFE2L2', 'Gene', (26, 32))	('NRF2', 'Gene', (103, 107))	('LUSC', 'Disease', (184, 188))	('head-neck squamous carcinoma', 'Disease', 'MESH:D000077195', (216, 244))	('head-neck squamous carcinoma', 'Disease', (216, 244))
335283	29805077	Notably, in LUSC and HNSC, TRPA1 expression was highly upregulated in those harboring NFE2L2 or KEAP1 mutations (Figures 7E and S8C).	('KEAP1', 'Gene', '9817', (96, 101))	('S', 'Chemical', 'MESH:D013455', (128, 129))	('NFE2L2', 'Gene', '4780', (86, 92))	('TRPA1', 'Gene', (27, 32))	('LUSC', 'Phenotype', 'HP:0030359', (12, 16))	('KEAP1', 'Gene', (96, 101))	('mutations', 'Var', (102, 111))	('upregulated', 'PosReg', (55, 66))	('NFE2L2', 'Gene', (86, 92))	('expression', 'MPA', (33, 43))	('S', 'Chemical', 'MESH:D013455', (23, 24))	('S', 'Chemical', 'MESH:D013455', (14, 15))
335284	29805077	Moreover, based on data from the COSMIC - Cell Lines Project (http://cancer.sanger.ac.uk/cell_lines), all TRPA1-enriched lung cancer cell lines (Figure 1C), except for HLF-a cells, whose genetic information is not available in the database, harbor KEAP1 mutations that cause constitutive activation of NRF2.	('lung cancer', 'Disease', 'MESH:D008175', (121, 132))	('KEAP1', 'Gene', '9817', (248, 253))	('P', 'Chemical', 'MESH:D010758', (251, 252))	('KEAP1', 'Gene', (248, 253))	('lung cancer', 'Phenotype', 'HP:0100526', (121, 132))	('P', 'Chemical', 'MESH:D010758', (108, 109))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('mutations', 'Var', (254, 263))	('cancer', 'Disease', (126, 132))	('activation', 'PosReg', (288, 298))	('HLF-a', 'CellLine', 'CVCL:2255', (168, 173))	('NRF2', 'Gene', '4780', (302, 306))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('S', 'Chemical', 'MESH:D013455', (35, 36))	('lung cancer', 'Disease', (121, 132))	('cancer', 'Disease', (69, 75))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('NRF2', 'Gene', (302, 306))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('TRPA1-enriched', 'Gene', (106, 120))	('P', 'Chemical', 'MESH:D010758', (53, 54))
335286	29805077	NRF2 knockdown strongly suppressed the expression of TRPA1 as well as NQO1 in lung cancer H1792, H647, and A549 cells but not in breast cancer HCC1569 cells harboring five copies of TRPA1 (Figures 7F, 7G, and S8D), indicating that constitutive NRF2 activation supports TRPA1 expression in these lung cancer cell lines.	('NQO1', 'Gene', '1728', (70, 74))	('lung cancer', 'Disease', (295, 306))	('NRF2', 'Gene', (244, 248))	('HCC1569', 'CellLine', 'CVCL:1255', (143, 150))	('knockdown', 'Var', (5, 14))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('suppressed', 'NegReg', (24, 34))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('lung cancer', 'Disease', (78, 89))	('NQO1', 'Gene', (70, 74))	('expression', 'MPA', (39, 49))	('lung cancer', 'Disease', 'MESH:D008175', (295, 306))	('NRF2', 'Gene', '4780', (0, 4))	('S', 'Chemical', 'MESH:D013455', (209, 210))	('breast cancer', 'Phenotype', 'HP:0003002', (129, 142))	('lung cancer', 'Phenotype', 'HP:0100526', (295, 306))	('cancer', 'Phenotype', 'HP:0002664', (300, 306))	('lung cancer', 'Disease', 'MESH:D008175', (78, 89))	('breast cancer', 'Disease', 'MESH:D001943', (129, 142))	('TRPA1', 'Gene', (53, 58))	('NRF2', 'Gene', '4780', (244, 248))	('breast cancer', 'Disease', (129, 142))	('lung cancer', 'Phenotype', 'HP:0100526', (78, 89))	('NRF2', 'Gene', (0, 4))	('H1792', 'CellLine', 'CVCL:1495', (90, 95))	('A549', 'CellLine', 'CVCL:0023', (107, 111))
335287	29805077	NRF2 knockdown did not suppress expression of other TRP channels, including TRPC3 and TRPV1 (Figures S8E and S8F).	('TRPV1', 'Gene', '7442', (86, 91))	('P', 'Chemical', 'MESH:D010758', (78, 79))	('P', 'Chemical', 'MESH:D010758', (54, 55))	('NRF2', 'Gene', (0, 4))	('TRPV1', 'Gene', (86, 91))	('knockdown', 'Var', (5, 14))	('S', 'Chemical', 'MESH:D013455', (101, 102))	('TRPC3', 'Gene', (76, 81))	('NRF2', 'Gene', '4780', (0, 4))	('S', 'Chemical', 'MESH:D013455', (109, 110))	('expression', 'MPA', (32, 42))	('P', 'Chemical', 'MESH:D010758', (88, 89))	('TRPC3', 'Gene', '7222', (76, 81))
335288	29805077	These results indicate that in addition to oxidative stress, genetic alterations also trigger TRPA1 expression through constitutive activation of NRF2 in lung tumors.	('NRF2', 'Gene', '4780', (146, 150))	('activation', 'PosReg', (132, 142))	('oxidative stress', 'Phenotype', 'HP:0025464', (43, 59))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('lung tumors', 'Disease', (154, 165))	('NRF2', 'Gene', (146, 150))	('tumors', 'Phenotype', 'HP:0002664', (159, 165))	('expression', 'MPA', (100, 110))	('genetic alterations', 'Var', (61, 80))	('lung tumors', 'Phenotype', 'HP:0100526', (154, 165))	('TRPA1', 'Gene', (94, 99))	('trigger', 'Reg', (86, 93))	('lung tumors', 'Disease', 'MESH:D008175', (154, 165))
335291	29805077	We disrupted these regions by CRISPR-Cas9 technology and found that TRPA1 expression was suppressed substantially by sgPeak1-targeted constructs and marginally by sgPeak3-targeted constructs, but not by sgPeak2-targeted constructs (Figures 7I and S8H).	('expression', 'MPA', (74, 84))	('S', 'Chemical', 'MESH:D013455', (247, 248))	('P', 'Chemical', 'MESH:D010758', (165, 166))	('TRPA1', 'Gene', (68, 73))	('P', 'Chemical', 'MESH:D010758', (119, 120))	('Peak1', 'Gene', '79834', (119, 124))	('P', 'Chemical', 'MESH:D010758', (34, 35))	('Peak1', 'Gene', (119, 124))	('suppressed', 'NegReg', (89, 99))	('Peak2', 'Gene', (205, 210))	('sgPeak3-targeted', 'Var', (163, 179))	('S', 'Chemical', 'MESH:D013455', (33, 34))	('P', 'Chemical', 'MESH:D010758', (70, 71))	('Peak2', 'Gene', '157285', (205, 210))	('P', 'Chemical', 'MESH:D010758', (205, 206))
335293	29805077	Given that the Peak3 is located in intron 21 of TRPA1 (Figure S8G), the marginal suppression of TRPA1 expression by sgPeak3 targeting could be at least in part due to defects in splicing or other intron-mediated enhancement mechanisms, independent of NRF2 binding.	('intron-mediated', 'MPA', (196, 211))	('P', 'Chemical', 'MESH:D010758', (98, 99))	('NRF2', 'Gene', '4780', (251, 255))	('S', 'Chemical', 'MESH:D013455', (62, 63))	('NRF2', 'Gene', (251, 255))	('expression', 'MPA', (102, 112))	('TRPA1', 'Gene', (96, 101))	('splicing', 'MPA', (178, 186))	('defects', 'NegReg', (167, 174))	('suppression', 'NegReg', (81, 92))	('P', 'Chemical', 'MESH:D010758', (118, 119))	('P', 'Chemical', 'MESH:D010758', (15, 16))	('sgPeak3', 'Gene', (116, 123))	('enhancement', 'PosReg', (212, 223))	('targeting', 'Var', (124, 133))	('P', 'Chemical', 'MESH:D010758', (50, 51))
335294	29805077	Furthermore, H2O2-induced TRPA1 expression was abolished by sgPeak1-targeted constructs in BT-549 and H358 cells (Figure 7K).	('BT-549', 'CellLine', 'CVCL:1092', (91, 97))	('constructs', 'Var', (77, 87))	('Peak1', 'Gene', '79834', (62, 67))	('Peak1', 'Gene', (62, 67))	('TRPA1', 'Protein', (26, 31))	('H2O2', 'Chemical', 'MESH:D006861', (13, 17))	('expression', 'MPA', (32, 42))	('H2O2-induced', 'Gene', (13, 25))	('abolished', 'NegReg', (47, 56))
335298	29805077	In TRPA1-amplified HCC1569 cells, inhibition of either TRPA1 or NRF2 suppressed cell survival, and inhibition of both reduced cell survival more than inhibition of each one (Figure 7L), suggesting that TRPA1-dependent and TRPA1-independent NRF2-mediated programs separately contribute to oxidative-stress defense in this cell line.	('oxidative-stress', 'Phenotype', 'HP:0025464', (288, 304))	('cell survival', 'CPA', (126, 139))	('NRF2', 'Gene', (240, 244))	('inhibition', 'Var', (34, 44))	('NRF2', 'Gene', '4780', (64, 68))	('reduced', 'NegReg', (118, 125))	('cell survival', 'CPA', (80, 93))	('inhibition', 'NegReg', (99, 109))	('TRPA1-amplified', 'Gene', (3, 18))	('TRPA1', 'Gene', (55, 60))	('suppressed', 'NegReg', (69, 79))	('NRF2', 'Gene', (64, 68))	('NRF2', 'Gene', '4780', (240, 244))	('HCC1569', 'CellLine', 'CVCL:1255', (19, 26))
335306	29805077	The increased ROS level in inner spheroid cells, together with our finding that inhibition of TRPA1 or MCL-1 induces clearance of cells from the inner space, suggests not only that TRPA1 and MCL-1 are essential for the survival of these cells but also that there are detrimental levels of oxidative stress on these inner cells.	('MCL-1', 'Gene', (103, 108))	('MCL-1', 'Gene', '4170', (103, 108))	('ROS level', 'MPA', (14, 23))	('clearance', 'CPA', (117, 126))	('ROS', 'Chemical', 'MESH:D017382', (14, 17))	('MCL-1', 'Gene', '4170', (191, 196))	('MCL-1', 'Gene', (191, 196))	('oxidative stress', 'Phenotype', 'HP:0025464', (289, 305))	('inhibition', 'Var', (80, 90))	('increased ROS level', 'Phenotype', 'HP:0025464', (4, 23))
335314	29805077	Interestingly, mutations or deletions in NFE2L2, KEAP1, or CUL3 are frequently observed in LUSC, LUAD, HNSC, and esophageal carcinoma, all of which are directly in contact with external environment.	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (113, 133))	('S', 'Chemical', 'MESH:D013455', (93, 94))	('deletions', 'Var', (28, 37))	('LUAD', 'Phenotype', 'HP:0030078', (97, 101))	('CUL3', 'Gene', (59, 63))	('observed', 'Reg', (79, 87))	('KEAP1', 'Gene', '9817', (49, 54))	('mutations', 'Var', (15, 24))	('LUAD', 'Disease', (97, 101))	('KEAP1', 'Gene', (49, 54))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (113, 133))	('HNSC', 'Disease', (103, 107))	('NFE2L2', 'Gene', '4780', (41, 47))	('CUL3', 'Gene', '8452', (59, 63))	('S', 'Chemical', 'MESH:D013455', (105, 106))	('LUSC', 'Disease', (91, 95))	('esophageal carcinoma', 'Disease', (113, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('NFE2L2', 'Gene', (41, 47))	('LUSC', 'Phenotype', 'HP:0030359', (91, 95))
335315	29805077	Given that these tissues can be exposed to strong oxidative stress due to cigarette smoke or higher partial pressure of O2 compared with other tissues, it is possible that the cells possessing genetic alterations of these genes are selected to constitutively upregulate TRPA1 and ROS-neutralizing factors in these tumors.	('upregulate', 'PosReg', (259, 269))	('tumor', 'Phenotype', 'HP:0002664', (314, 319))	('genetic alterations', 'Var', (193, 212))	('O2', 'Chemical', '-', (120, 122))	('tumors', 'Disease', (314, 320))	('tumors', 'Disease', 'MESH:D009369', (314, 320))	('ROS', 'Chemical', 'MESH:D017382', (280, 283))	('tumors', 'Phenotype', 'HP:0002664', (314, 320))	('oxidative stress', 'Phenotype', 'HP:0025464', (50, 66))	('TRPA1', 'Protein', (270, 275))
335324	29805077	In mammals, TRPA1 activation by dicarbonyls is associated with metabolic neuropathy and insulin release in sensory neurons and pancreatic beta cells, respectively.	('insulin', 'Gene', (88, 95))	('dicarbonyls', 'Chemical', '-', (32, 43))	('TRPA1', 'Protein', (12, 17))	('metabolic neuropathy', 'Disease', 'MESH:D001928', (63, 83))	('insulin', 'Gene', '3630', (88, 95))	('pancreatic', 'Disease', 'MESH:D010195', (127, 137))	('dicarbonyls', 'Var', (32, 43))	('neuropathy', 'Phenotype', 'HP:0009830', (73, 83))	('pancreatic', 'Disease', (127, 137))	('activation', 'PosReg', (18, 28))	('metabolic neuropathy', 'Disease', (63, 83))
335332	29805077	In contrast, TRPA1 inhibitors are currently under clinical evaluation as pain and respiratory therapies and have not shown any evidence of central nervous system or other drug-related side effects to date.	('pain', 'Disease', 'MESH:D010146', (73, 77))	('pain', 'Disease', (73, 77))	('inhibitors', 'Var', (19, 29))	('pain', 'Phenotype', 'HP:0012531', (73, 77))	('TRPA1', 'Protein', (13, 18))
335348	29805077	H1792, H647, A549, H23, H358, and sNF96.2 were obtained from, and authenticated by, ATCC.	('ATCC', 'Chemical', '-', (84, 88))	('A549', 'Var', (13, 17))	('H647', 'Var', (7, 11))	('sNF96.2', 'Gene', (34, 41))	('sNF96', 'Chemical', '-', (34, 39))	('H1792', 'CellLine', 'CVCL:1495', (0, 5))	('A549', 'CellLine', 'CVCL:0023', (13, 17))
335364	29805077	Inducible NRF2 shRNAs were obtained from GE Healthcare (Clone ID: V3THS_306092 and V3THS_306096).	('S', 'Chemical', 'MESH:D013455', (70, 71))	('S', 'Chemical', 'MESH:D013455', (87, 88))	('NRF2', 'Gene', (10, 14))	('V3THS_306096', 'Var', (83, 95))	('V3THS_306092', 'Var', (66, 78))	('NRF2', 'Gene', '4780', (10, 14))
335376	29805077	SMARTpool siRNA for Pyk2 (L-003165-00), NRF2 (L-003755-00), TRPM2 (L-004193-00), and siGENOME Non-Targeting siRNA Pool #2 (D-001206-14) were purchased from GE Healthcare and was transfected according to standard protocol and experiments were performed within 48-96 hr of transfection.	('TRPM2', 'Gene', (60, 65))	('L-004193-00', 'Var', (67, 78))	('NRF2', 'Gene', '4780', (40, 44))	('P', 'Chemical', 'MESH:D010758', (20, 21))	('L-003165-00', 'Var', (26, 37))	('Pyk2', 'Gene', '2185', (20, 24))	('P', 'Chemical', 'MESH:D010758', (62, 63))	('Pyk2', 'Gene', (20, 24))	('NRF2', 'Gene', (40, 44))	('L-003755-00', 'Var', (46, 57))	('P', 'Chemical', 'MESH:D010758', (114, 115))	('S', 'Chemical', 'MESH:D013455', (0, 1))	('TRPM2', 'Gene', '7226', (60, 65))
335402	29805077	For the measurement of ROS levels in HCC1569 and H1792 spheroids and MCF-10A acini, cells were transduced with a lentiviral vector encoding Hyper-2 or Hyper-2 (C199S).	('H1792', 'CellLine', 'CVCL:1495', (49, 54))	('C199S', 'Mutation', 'rs1217962638', (160, 165))	('Hyper-2', 'Var', (140, 147))	('HCC1569', 'CellLine', 'CVCL:1255', (37, 44))	('MCF-10A', 'CellLine', 'CVCL:0598', (69, 76))	('Hyper-2 (C199S', 'Var', (151, 165))	('ROS', 'Chemical', 'MESH:D017382', (23, 26))
335448	33176581	The 5-year cumulative survival rates of LC3B+, CD8+/CD39+, and CD8+/CD163+ patients were significantly higher than those of other group patients.	('higher', 'PosReg', (103, 109))	('CD163', 'Gene', '9332', (68, 73))	('cumulative survival', 'CPA', (11, 30))	('CD8', 'Gene', (47, 50))	('CD8', 'Gene', '925', (47, 50))	('patients', 'Species', '9606', (75, 83))	('CD163', 'Gene', (68, 73))	('patients', 'Species', '9606', (136, 144))	('CD8', 'Gene', (63, 66))	('CD39', 'Gene', (52, 56))	('LC3B+', 'Var', (40, 45))	('CD8', 'Gene', '925', (63, 66))	('CD39', 'Gene', '953', (52, 56))
335506	33176581	According to Kaplan Meier curves and the Log-rank test, we found that patients with HSCC tissue LC3B+ overall survival rate is higher than that of negative patients (P < 0.05, Figure 2A), and the CD8+/CD39+ and CD8+/CD163+ overall survival rate of patients was higher than other groups (P < 0.05 and P < 0.05, respectively; Figure 2B and 2C, respectively).	('HSCC', 'Chemical', '-', (84, 88))	('patients', 'Species', '9606', (70, 78))	('patients', 'Species', '9606', (156, 164))	('LC3B+', 'Var', (96, 101))	('CD8', 'Gene', '925', (211, 214))	('CD163', 'Gene', '9332', (216, 221))	('patients', 'Species', '9606', (248, 256))	('CD163', 'Gene', (216, 221))	('CD8', 'Gene', (196, 199))	('CD8', 'Gene', '925', (196, 199))	('HSCC', 'Phenotype', 'HP:0012182', (84, 88))	('higher', 'PosReg', (127, 133))	('CD39', 'Gene', (201, 205))	('CD8', 'Gene', (211, 214))	('CD39', 'Gene', '953', (201, 205))
335507	33176581	Moreover, in adjacent non-tumor mucosa tissue patients, the LC3B+ overall survival rate was better than that of negative patients.	('patients', 'Species', '9606', (46, 54))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('LC3B+', 'Var', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('patients', 'Species', '9606', (121, 129))	('better', 'PosReg', (92, 98))
335509	33176581	Further analysis showed that the overall survival rate of LC3B+ and CD8+/CD39+, LC3B+, and CD8+/CD163+ tumor tissue patients was significantly higher than those of other groups (P < 0.05, Figure 3A and 3B), and the overall survival rate of patients in the above 2 groups, in adjacent non-tumor mucosa tissues, was also significantly higher than that of other groups; however the difference was not statistically significant (P > 0.05, Figure 3C and 3D).	('CD8', 'Gene', (91, 94))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('CD8', 'Gene', (68, 71))	('LC3B+', 'Var', (80, 85))	('higher', 'PosReg', (333, 339))	('higher', 'PosReg', (143, 149))	('patients', 'Species', '9606', (116, 124))	('tumor', 'Disease', (288, 293))	('CD8', 'Gene', '925', (91, 94))	('CD163', 'Gene', (96, 101))	('CD8', 'Gene', '925', (68, 71))	('CD163', 'Gene', '9332', (96, 101))	('tumor', 'Disease', (103, 108))	('tumor', 'Disease', 'MESH:D009369', (288, 293))	('patients', 'Species', '9606', (240, 248))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('LC3B+', 'Var', (58, 63))	('survival', 'CPA', (41, 49))	('CD39', 'Gene', (73, 77))	('CD39', 'Gene', '953', (73, 77))	('tumor', 'Phenotype', 'HP:0002664', (288, 293))
335510	33176581	Kaplan Meier curves and the Log-rank test showed that with LC3B+, CD8+/CD39+, and CD8+/CD163+ patients, with co-positive expression of LC3B and CD8+/CD39+, CD8+/CD163+, regardless of in HSCC tissues or adjacent non-tumor mucosa tissues all had a higher relapse-free survival rate than other patient groups; however, the difference was not statistically significant (P > 0.05 Figures 4 and 5).	('higher', 'PosReg', (246, 252))	('CD8', 'Gene', (66, 69))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('CD8', 'Gene', '925', (144, 147))	('CD163', 'Gene', '9332', (161, 166))	('CD39', 'Gene', (71, 75))	('CD8', 'Gene', (82, 85))	('CD39', 'Gene', '953', (71, 75))	('patients', 'Species', '9606', (94, 102))	('patient', 'Species', '9606', (94, 101))	('LC3B+', 'Var', (59, 64))	('CD39', 'Gene', (149, 153))	('CD8', 'Gene', '925', (156, 159))	('CD39', 'Gene', '953', (149, 153))	('CD163', 'Gene', (161, 166))	('CD163', 'Gene', '9332', (87, 92))	('CD8', 'Gene', (144, 147))	('CD8', 'Gene', '925', (66, 69))	('relapse-free survival rate', 'CPA', (253, 279))	('HSCC', 'Chemical', '-', (186, 190))	('tumor', 'Disease', (215, 220))	('LC3B', 'Var', (135, 139))	('patient', 'Species', '9606', (291, 298))	('CD8', 'Gene', '925', (82, 85))	('tumor', 'Disease', 'MESH:D009369', (215, 220))	('HSCC', 'Phenotype', 'HP:0012182', (186, 190))	('CD163', 'Gene', (87, 92))	('CD8', 'Gene', (156, 159))
335515	33176581	reported 62 patients with low-risk head and neck squamous carcinoma (HNSCC) and high CD8 expression, who had a higher survival rate after first stage surgery and external radiotherapy.	('patients', 'Species', '9606', (12, 20))	('HNSCC', 'Disease', (69, 74))	('expression', 'MPA', (89, 99))	('neck squamous carcinoma', 'Disease', 'MESH:D000077195', (44, 67))	('CD8', 'Gene', (85, 88))	('neck squamous carcinoma', 'Disease', (44, 67))	('CD8', 'Gene', '925', (85, 88))	('HNSCC', 'Disease', 'MESH:D000077195', (69, 74))	('low-risk head', 'Phenotype', 'HP:0000252', (26, 39))	('higher', 'PosReg', (111, 117))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))	('high', 'Var', (80, 84))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (49, 67))
335530	33176581	We found that in patients with intra-tumor co-positive LC3B+ and CD8+/CD39+ and co-positive LC3B+ and CD8+/CD163+, the overall 5-year survival rate was higher than that of the other groups.	('higher', 'PosReg', (152, 158))	('intra-tumor', 'Disease', (31, 42))	('LC3B+', 'Var', (55, 60))	('CD8', 'Gene', (102, 105))	('CD8', 'Gene', '925', (102, 105))	('CD163', 'Gene', '9332', (107, 112))	('CD8', 'Gene', (65, 68))	('intra-tumor', 'Disease', 'MESH:D009369', (31, 42))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('LC3B+', 'Var', (92, 97))	('CD8', 'Gene', '925', (65, 68))	('patients', 'Species', '9606', (17, 25))	('CD163', 'Gene', (107, 112))	('CD39', 'Gene', (70, 74))	('CD39', 'Gene', '953', (70, 74))
335533	33176581	We found that LC3B+, CD8+/CD39+, CD8+/CD163+, LC3B+, CD8+/CD39+, and LC3B+ and CD8+/CD163+ co-positive patients had higher RFS than other groupsin both intra and peritumor immune infiltrates, but the effect was not significant (P > 0.05), possibly due to an insufficient number of cases.	('CD8', 'Gene', (53, 56))	('CD8', 'Gene', '925', (33, 36))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('CD39', 'Gene', (26, 30))	('LC3B+', 'Var', (46, 51))	('CD39', 'Gene', '953', (26, 30))	('RFS', 'Disease', 'MESH:D005198', (123, 126))	('CD163', 'Gene', (38, 43))	('CD8', 'Gene', '925', (79, 82))	('LC3B+', 'Var', (14, 19))	('CD163', 'Gene', (84, 89))	('LC3B+', 'Var', (69, 74))	('higher', 'PosReg', (116, 122))	('CD8', 'Gene', '925', (21, 24))	('CD8', 'Gene', (33, 36))	('CD8', 'Gene', '925', (53, 56))	('RFS', 'Disease', (123, 126))	('tumor', 'Disease', (166, 171))	('CD8', 'Gene', (79, 82))	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('CD163', 'Gene', '9332', (38, 43))	('CD8', 'Gene', (21, 24))	('CD39', 'Gene', (58, 62))	('CD163', 'Gene', '9332', (84, 89))	('patients', 'Species', '9606', (103, 111))	('CD39', 'Gene', '953', (58, 62))
335545	32284762	In this study, OSCC cells with stable overexpression or silencing of Per2 were established to explore their biological functions and mechanism in vivo and in vitro.	('silencing', 'Var', (56, 65))	('overexpression', 'PosReg', (38, 52))	('Per2', 'Gene', (69, 73))	('OSCC', 'CellLine', 'CVCL:L894', (15, 19))
335554	32284762	In conclusion, our research results demonstrate that Per2 suppresses OSCC progression by motivating autophagy, as well as inhibiting cell proliferation and promoting apoptosis, which were mediated by autophagy, in a PI3K/AKT/mTOR pathway-dependent manner.	('OSCC', 'CellLine', 'CVCL:L894', (69, 73))	('inhibiting', 'NegReg', (122, 132))	('Per2', 'Var', (53, 57))	('cell proliferation', 'CPA', (133, 151))	('AKT', 'Gene', '207', (221, 224))	('motivating', 'Reg', (89, 99))	('mTOR', 'Gene', '2475', (225, 229))	('autophagy', 'CPA', (100, 109))	('promoting', 'PosReg', (156, 165))	('AKT', 'Gene', (221, 224))	('mTOR', 'Gene', (225, 229))	('suppresses', 'NegReg', (58, 68))	('apoptosis', 'CPA', (166, 175))	('OSCC', 'Disease', (69, 73))
335565	32284762	Abnormal expression of the clock gene is strongly linked to the occurrence and development of various diseases, such as tumors.	('tumors', 'Disease', (120, 126))	('tumors', 'Disease', 'MESH:D009369', (120, 126))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('linked to', 'Reg', (50, 59))	('clock', 'Gene', (27, 32))	('expression', 'MPA', (9, 19))	('clock', 'Gene', '9575', (27, 32))	('Abnormal', 'Var', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))
335579	32284762	In order to knock down Per2 expression, according to the human Per2 mRNA sequence (Gene ID: NM_022817), three sequences for different targets of Per2 were designed by siRNA design software to synthesize shRNA-I~III.	('knock', 'Var', (12, 17))	('Per2', 'Gene', (23, 27))	('human', 'Species', '9606', (57, 62))	('expression', 'MPA', (28, 38))
335590	32284762	The LC3B (ab192890, Abcam, UK) or p62 (ab109012, Abcam, UK) antibody was incubated separately overnight at 4 C, followed by Cy3-labeled goat anti-rabbit IgG (H+L, A23320, Abbkine, China) for 1 hour in the dark at room temperature.	('Cy3', 'Chemical', '-', (124, 127))	('LC3B', 'Gene', (4, 8))	('p62', 'Gene', '23636', (34, 37))	('p62', 'Gene', (34, 37))	('LC3B', 'Gene', '81631', (4, 8))	('ab109012', 'Var', (39, 47))	('ab192890', 'Var', (10, 18))
335622	32284762	The results of the CCK-8 assay and flow cytometry showed that the proliferation of TSCCA cells was significantly decreased after overexpression of Per2 (P < 0.01), and it was significantly improved in Per2-RNAi cells (P < 0.01) (Figure 2A, 2B).	('improved', 'PosReg', (189, 197))	('Per2', 'Var', (147, 151))	('overexpression', 'PosReg', (129, 143))	('CCK-8', 'Chemical', 'MESH:D012844', (19, 24))	('proliferation', 'CPA', (66, 79))	('decreased', 'NegReg', (113, 122))
335623	32284762	Immunofluorescence analysis showed that the fluorescence intensity of LC3B protein was significantly enhanced in Per2-OE cells (P < 0.05), while the fluorescence intensity of p62 protein was significantly reduced (P < 0.05).	('fluorescence intensity', 'MPA', (44, 66))	('Per2-OE', 'Var', (113, 120))	('p62', 'Gene', (175, 178))	('LC3B', 'Gene', '81631', (70, 74))	('LC3B', 'Gene', (70, 74))	('protein', 'Protein', (75, 82))	('enhanced', 'PosReg', (101, 109))	('fluorescence', 'MPA', (149, 161))	('p62', 'Gene', '23636', (175, 178))
335625	32284762	In addition, as detected by western blotting, the ratio of LC3B II/I was significantly increased in the Per2-OE group (P < 0.05), and the expression levels of p62 and Beclin1 were notably decreased (P < 0.01) (Figure 3C).	('Beclin1', 'Gene', (167, 174))	('increased', 'PosReg', (87, 96))	('decreased', 'NegReg', (188, 197))	('expression levels', 'MPA', (138, 155))	('LC3B', 'Gene', (59, 63))	('p62', 'Gene', '23636', (159, 162))	('p62', 'Gene', (159, 162))	('Beclin1', 'Gene', '8678', (167, 174))	('Per2-OE', 'Var', (104, 111))	('LC3B', 'Gene', '81631', (59, 63))
335626	32284762	In contrast, the LC3B II/I ratio was significantly decreased (P < 0.05) in the Per2-RNAi group, and the p62 and Beclin1 expression levels were significantly elevated (P < 0.05) (Figure 3C).	('LC3B', 'Gene', (17, 21))	('Beclin1', 'Gene', (112, 119))	('p62', 'Gene', '23636', (104, 107))	('Per2-RNAi', 'Var', (79, 88))	('p62', 'Gene', (104, 107))	('decreased', 'NegReg', (51, 60))	('LC3B', 'Gene', '81631', (17, 21))	('elevated', 'PosReg', (157, 165))	('Beclin1', 'Gene', '8678', (112, 119))
335629	32284762	Nevertheless, the expression of PIK3CA, p-AKT and p-mTOR was obviously downregulated in the Per2-OE group in contrast with the control groups (P < 0.05).	('downregulated', 'NegReg', (71, 84))	('mTOR', 'Gene', (52, 56))	('PIK3CA', 'Gene', '5290', (32, 38))	('Per2-OE', 'Var', (92, 99))	('mTOR', 'Gene', '2475', (52, 56))	('AKT', 'Gene', (42, 45))	('expression', 'MPA', (18, 28))	('AKT', 'Gene', '207', (42, 45))	('PIK3CA', 'Gene', (32, 38))
335631	32284762	These consequences imply that overexpression of Per2 prevents activation of the PI3K/AKT/mTOR signaling pathway; meanwhile, silencing of Per2 enhances the PI3K/AKT/mTOR signaling pathway.	('mTOR', 'Gene', '2475', (89, 93))	('Per2', 'Gene', (137, 141))	('enhances', 'PosReg', (142, 150))	('AKT', 'Gene', '207', (160, 163))	('silencing', 'Var', (124, 133))	('AKT', 'Gene', '207', (85, 88))	('AKT', 'Gene', (160, 163))	('AKT', 'Gene', (85, 88))	('mTOR', 'Gene', (164, 168))	('mTOR', 'Gene', (89, 93))	('mTOR', 'Gene', '2475', (164, 168))
335633	32284762	The results revealed that, compared with the control group, the increase mediated by Per2-overexpression in autophagic density, LC3B II/I ratio and apoptosis index were significantly decreased to return (P < 0.05) (Figure 5A, 5B, 5C) due to the addition of SC79.	('LC3B', 'Gene', '81631', (128, 132))	('apoptosis index', 'CPA', (148, 163))	('LC3B', 'Gene', (128, 132))	('Per2-overexpression', 'Var', (85, 104))	('decreased', 'NegReg', (183, 192))	('increase', 'PosReg', (64, 72))	('autophagic density', 'CPA', (108, 126))
335637	32284762	In vivo tumorigenesis assays in nude mice revealed that tumor weight and volume in the Per2-OE group were significantly smaller than those in the NC group (Figure 7A).	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('smaller', 'NegReg', (120, 127))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('tumor', 'Disease', (56, 61))	('nude mice', 'Species', '10090', (32, 41))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('tumor', 'Disease', (8, 13))	('Per2-OE', 'Var', (87, 94))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
335638	32284762	As seen from the growth curve of subcutaneous tumors, tumor growth was slower in the Per2-OE group compared with that in the controls (P < 0.05) (Figure 7B).	('slower', 'NegReg', (71, 77))	('tumor', 'Disease', 'MESH:D009369', (46, 51))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('subcutaneous tumors', 'Phenotype', 'HP:0001482', (33, 52))	('Per2-OE', 'Var', (85, 92))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor', 'Disease', (46, 51))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumors', 'Disease', (46, 52))	('tumor', 'Disease', (54, 59))	('tumors', 'Disease', 'MESH:D009369', (46, 52))
335659	32042113	Loss of CD177 leads to hyperproliferative mammary epithelium and contributes to breast cancer pathogenesis.	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('contributes', 'Reg', (65, 76))	('leads to', 'Reg', (14, 22))	('breast cancer', 'Disease', 'MESH:D001943', (80, 93))	('hyperproliferative mammary epithelium', 'CPA', (23, 60))	('breast cancer', 'Disease', (80, 93))	('breast cancer', 'Phenotype', 'HP:0003002', (80, 93))	('Loss', 'Var', (0, 4))	('CD177', 'Gene', (8, 13))
335664	32042113	Cd177-/- mice at 8 weeks of age exhibited slightly lower blood neutrophil, but they appear to have a normal function in clearance of bacterial infection and chemotaxis.	('bacterial infection', 'Disease', (133, 152))	('bacterial infection', 'Phenotype', 'HP:0002718', (133, 152))	('Cd177-/-', 'Var', (0, 8))	('blood neutrophil', 'CPA', (57, 73))	('lower blood neutrophil', 'Phenotype', 'HP:0001875', (51, 73))	('lower', 'NegReg', (51, 56))	('mice', 'Species', '10090', (9, 13))	('bacterial infection', 'Disease', 'MESH:D001424', (133, 152))	('chemotaxis', 'CPA', (157, 167))
335667	32042113	Dysregulation of beta-Catenin plays a role in the development of several types of cancer, including breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('Dysregulation', 'Var', (0, 13))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('beta-Catenin', 'Protein', (17, 29))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('breast cancer', 'Disease', 'MESH:D001943', (100, 113))	('breast cancer', 'Phenotype', 'HP:0003002', (100, 113))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('breast cancer', 'Disease', (100, 113))	('cancer', 'Disease', (107, 113))
335678	32042113	All comparisons between WT and CD177-/- as well as those between MMTV-ErbB2/CD177+/- and MMTV-ErbB2/CD177-/- were made between littermates or aged-related mice.	('MMTV', 'Species', '11757', (65, 69))	('CD177-/-', 'Var', (31, 39))	('mice', 'Species', '10090', (155, 159))	('MMTV-ErbB2/CD177+/-', 'Var', (65, 84))	('MMTV', 'Species', '11757', (89, 93))
335707	32042113	cells were transfected with pRL-RLuc-Myc (Promega, Madison WI) and M50 Super8x TOPflash (Addgene Plasmid # 12456), plasmids at a 1:16 ratio.	('M50 Super8x', 'Var', (67, 78))	('Myc', 'Gene', (37, 40))	('Myc', 'Gene', '17869', (37, 40))
335726	32042113	CD177 had one of the highest correlations between expression and RFS, higher than many other makers for immune cells with known anti-cancer functions, including those for NK cells (CD314/NKG2d, CD94), toxic T cells (CD8), macrophages (CD163), etc.	('CD163', 'Gene', (235, 240))	('CD177', 'Var', (0, 5))	('CD94', 'Gene', (194, 198))	('CD94', 'Gene', '16643', (194, 198))	('correlations', 'Interaction', (29, 41))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('NKG2d', 'Gene', (187, 192))	('NKG2d', 'Gene', '27007', (187, 192))	('CD163', 'Gene', '93671', (235, 240))	('cancer', 'Disease', (133, 139))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('expression', 'MPA', (50, 60))
335727	32042113	CD177 is also positively correlated with metastasis-free survival (MFS), in two well-established datasets, GSE2034 (n = 286, Figure 1B, Figure S1A) and GSE2603 (n = 81, Figure S1B), irrelative of bone or lung metastasis (Figure S1A-B).	('GSE2603', 'Chemical', '-', (152, 159))	('GSE2034', 'Chemical', '-', (107, 114))	('CD177', 'Var', (0, 5))	('metastasis-free survival', 'CPA', (41, 65))	('GSE2034', 'Var', (107, 114))	('bone or lung metastasis', 'CPA', (196, 219))	('correlated', 'Reg', (25, 35))	('GSE2603', 'Var', (152, 159))
335742	32042113	However, mammary glands from 10-months old Cd177-/- mice exhibited significantly increased side branching and ductal structures (Figure 2A-B).	('side branching', 'CPA', (91, 105))	('Cd177-/-', 'Var', (43, 51))	('mice', 'Species', '10090', (52, 56))	('ductal structures', 'CPA', (110, 127))	('increased', 'PosReg', (81, 90))
335745	32042113	The mammary epithelium from the Cd177-/- mice had increased proliferation indicated by Ki-67 IHC (Figure 2D, Figure S3B, upper panels).	('mice', 'Species', '10090', (41, 45))	('Ki-67', 'Gene', (87, 92))	('mammary epithelium', 'CPA', (4, 22))	('increased', 'PosReg', (50, 59))	('S3B', 'Gene', (116, 119))	('Cd177-/-', 'Var', (32, 40))	('proliferation', 'CPA', (60, 73))	('Ki-67', 'Gene', '17345', (87, 92))	('S3B', 'Gene', '11778', (116, 119))
335748	32042113	Normal mammary ducts from both Cd177-/- and WT mice contained a single layer of keratin (Krt) 5-positive basal cells and Krt-8-postive luminal cells, whereas the filled mammary ducts from Cd177-/- mice had multiple layers of basal and luminal cells (Figure S3B, lower panels).	('Cd177-/-', 'Var', (188, 196))	('S3B', 'Gene', '11778', (257, 260))	('keratin (Krt) 5', 'Gene', (80, 95))	('Cd177-/-', 'Var', (31, 39))	('Krt-8', 'Gene', '16691', (121, 126))	('S3B', 'Gene', (257, 260))	('luminal', 'Chemical', 'MESH:D010634', (235, 242))	('Krt-8', 'Gene', (121, 126))	('luminal', 'Chemical', 'MESH:D010634', (135, 142))	('keratin (Krt) 5', 'Gene', '110308', (80, 95))	('mice', 'Species', '10090', (197, 201))	('mice', 'Species', '10090', (47, 51))
335755	32042113	Likewise, silencing Cd177 in 67NR cells (Figure 3E, Figure S4A) resulted in the increased tumor growth compared to 67NR control cells (Figure 4C).	('increased', 'PosReg', (80, 89))	('tumor', 'Disease', (90, 95))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('silencing', 'Var', (10, 19))	('Cd177', 'Gene', (20, 25))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
335758	32042113	The MMTV-ErbB2/Cd177-/- mice did not shown difference in first tumor onset (Figure S4C), but had increased tumor multiplicity compared to MMTV-ErbB2/Cd177+/- littermates (Figure 4D, P = 0.023); 41% of the MMTV-ErbB2/Cd177-/- mice but only 4.5% of the MMTV-ErbB2/Cd177+/- mice had more than 3 tumors (Figure 4E).	('tumor', 'Disease', (107, 112))	('tumors', 'Phenotype', 'HP:0002664', (292, 298))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('MMTV', 'Species', '11757', (4, 8))	('tumor', 'Phenotype', 'HP:0002664', (292, 297))	('MMTV', 'Species', '11757', (138, 142))	('tumors', 'Disease', (292, 298))	('mice', 'Species', '10090', (225, 229))	('tumor', 'Disease', (63, 68))	('mice', 'Species', '10090', (271, 275))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumors', 'Disease', 'MESH:D009369', (292, 298))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('MMTV-ErbB2/Cd177-/-', 'Var', (205, 224))	('MMTV', 'Species', '11757', (205, 209))	('mice', 'Species', '10090', (24, 28))	('tumor', 'Disease', (292, 297))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('tumor', 'Disease', 'MESH:D009369', (292, 297))	('MMTV', 'Species', '11757', (251, 255))
335760	32042113	As expected, no CD177 was observed in tumors from MMTV-ErbB2/Cd177-/- mice (Figure 4F).	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumors', 'Disease', (38, 44))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('tumors', 'Disease', 'MESH:D009369', (38, 44))	('MMTV', 'Species', '11757', (50, 54))	('mice', 'Species', '10090', (70, 74))	('MMTV-ErbB2/Cd177-/-', 'Var', (50, 69))
335765	32042113	Next generation RNA sequencing also revealed that Cd177-deficiency led to decreased expression of WNT/beta-Catenin-targeted genes within ErbB2-induced tumors from Figure 4D-F (Supplementary Table 4, Figure 5C) and further validated by real-time PCR (Figure 5D, Figure S5A).	('ErbB2-induced', 'Gene', (137, 150))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('WNT/beta-Catenin-targeted genes', 'Gene', (98, 129))	('tumors', 'Disease', (151, 157))	('tumors', 'Disease', 'MESH:D009369', (151, 157))	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('Cd177-deficiency', 'Var', (50, 66))	('decreased', 'NegReg', (74, 83))	('expression', 'MPA', (84, 94))	('Cd177-deficiency', 'Gene', (50, 66))
335767	32042113	Using an antibody that specifically recognizes active beta-Catenin, we did not find significant nuclear beta-Catenin staining on tissue sections of these ErbB2-induced tumors, either within Cd177+/- or Cd177-KO genotypes.	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('Cd177+/-', 'Var', (190, 198))	('ErbB2-induced', 'Gene', (154, 167))	('tumors', 'Disease', (168, 174))	('tumors', 'Disease', 'MESH:D009369', (168, 174))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('ErbB2-induced', 'Reg', (154, 167))
335769	32042113	In H146 cells with intrinsic CD177 expression (Figure S2C, S2E), silencing CD177 by siRNA (Figure S5B) significantly increased both basal and Wnt3a-induced beta-Catenin transcriptional activity compared to control cells (Figure S5B).	('S5B', 'Gene', (228, 231))	('silencing', 'Var', (65, 74))	('CD177', 'Gene', (75, 80))	('S5B', 'Gene', '5711', (98, 101))	('increased', 'PosReg', (117, 126))	('S5B', 'Gene', (98, 101))	('S5B', 'Gene', '5711', (228, 231))
335770	32042113	Further supporting the sufficiency of CD177 in attenuation of beta-Catenin activity, overexpression of CD177 in the CD177- MDA-MB-436 cells significantly reduced Wnt3a-mediated beta-Catenin activity (first two open bars in Figure 5H, S5C).	('Wnt3a-mediated beta-Catenin activity', 'MPA', (162, 198))	('overexpression', 'PosReg', (85, 99))	('MDA-MB-436', 'CellLine', 'CVCL:0623', (123, 133))	('CD177', 'Var', (103, 108))	('reduced', 'NegReg', (154, 161))
335771	32042113	As we have seen silencing CD177 in 67NR cells resulted in the increased in vitro (Figure 3F) and in vivo (Figure 4C) tumor growth, we further silenced beta-Catenin in 67NR sh1 cells to determine the causative role of beta-catenin downstream of CD177-deficiency.	('CD177', 'Gene', (26, 31))	('increased', 'PosReg', (62, 71))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumor', 'Disease', (117, 122))	('silencing', 'Var', (16, 25))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
335776	32042113	Co-incubation with cell lysates from MCF-7 (E-Cadherin positive), MDA-MB-231 (E-Cadherin negative) (Figure 6E), or HEK293T (Figure S6D) induced the interaction between CD177 and beta-Catenin.	('HEK293T', 'CellLine', 'CVCL:0063', (115, 122))	('MDA-MB-231', 'Var', (66, 76))	('HEK293T', 'Var', (115, 122))	('induced', 'Reg', (136, 143))	('beta-Catenin', 'Protein', (178, 190))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (66, 76))	('CD177', 'Protein', (168, 173))	('interaction', 'Interaction', (148, 159))	('MCF-7', 'CellLine', 'CVCL:0031', (37, 42))	('MCF-7', 'Gene', (37, 42))
335779	32042113	CD177-dependent suppression of beta-Catenin activity was independent of E-Cadherin in an E-Cadherin-negative MA-MB-436 cells (Figure 5H).	('beta-Catenin activity', 'MPA', (31, 52))	('suppression', 'NegReg', (16, 27))	('MB-436', 'CellLine', 'CVCL:0623', (112, 118))	('CD177-dependent', 'Var', (0, 15))
335783	32042113	While the loss of CD177 alone was insufficient to induce tumorigenesis, it did induce hyperproliferation of mammary epithelial cells.	('loss', 'Var', (10, 14))	('hyperproliferation of mammary epithelial', 'CPA', (86, 126))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('CD177', 'Gene', (18, 23))	('induce', 'Reg', (79, 85))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Disease', (57, 62))
335784	32042113	Mammary ducts from 10-month Cd177-/- mice exhibited multiple layers of epithelial cells with some filled ducts, a phenotype observed in the early stages of tumorigenesis and puberty.	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('Cd177-/-', 'Var', (28, 36))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumor', 'Disease', (156, 161))	('mice', 'Species', '10090', (37, 41))
335786	32042113	Nuclear beta-Catenin is also elevated within the mammary epithelial cells from 10-month Cd177-/- mice relative to WT mice.	('Nuclear beta-Catenin', 'Protein', (0, 20))	('elevated', 'PosReg', (29, 37))	('mice', 'Species', '10090', (97, 101))	('mice', 'Species', '10090', (117, 121))	('Cd177-/-', 'Var', (88, 96))
335827	29194401	For instance, in breast cancer, the addition of Twist, Snail and FOXC2 increased the mesenchymal properties of cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('breast cancer', 'Disease', 'MESH:D001943', (17, 30))	('FOXC2', 'Gene', (65, 70))	('Twist', 'Gene', '7291', (48, 53))	('breast cancer', 'Disease', (17, 30))	('Snail', 'Gene', (55, 60))	('FOXC2', 'Gene', '2303', (65, 70))	('breast cancer', 'Phenotype', 'HP:0003002', (17, 30))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('cancer', 'Disease', (24, 30))	('Twist', 'Gene', (48, 53))	('addition', 'Var', (36, 44))	('cancer', 'Disease', 'MESH:D009369', (24, 30))	('increased', 'PosReg', (71, 80))	('Snail', 'Gene', '6615', (55, 60))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))
335830	29194401	Drug resistance represents an ongoing challenge in cancer treatment and is doubtless the main reason for treatment failure.	('Drug resistance', 'Phenotype', 'HP:0020174', (0, 15))	('Drug resistance', 'Var', (0, 15))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))
335869	29194401	In multiple gastric cancer cells lines and hematopoietic malignances, ALDH expression levels were significantly higher in ROS-low than in ROS-high cells and most of these cells were quiescent.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('ROS-low', 'Var', (122, 129))	('gastric cancer', 'Disease', (12, 26))	('higher', 'PosReg', (112, 118))	('hematopoietic malignances', 'Disease', (43, 68))	('expression levels', 'MPA', (75, 92))	('ROS', 'Chemical', 'MESH:D017382', (122, 125))	('gastric cancer', 'Disease', 'MESH:D013274', (12, 26))	('multiple gastric cancer', 'Phenotype', 'HP:0004394', (3, 26))	('ROS', 'Chemical', 'MESH:D017382', (138, 141))	('gastric cancer', 'Phenotype', 'HP:0012126', (12, 26))	('hematopoietic malignances', 'Disease', 'MESH:D019337', (43, 68))	('ALDH', 'Gene', (70, 74))
335870	29194401	Tumors expressing high levels of ALDH are tumorigenic and resistant to chemotherapy in cancers of colon, breast, lung, pancreas, bladder, prostate and ovary.	('cancers of colon', 'Disease', (87, 103))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('high levels', 'Var', (18, 29))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('ALDH', 'Gene', (33, 37))	('tumor', 'Disease', (42, 47))	('Tumors', 'Disease', (0, 6))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('cancers', 'Phenotype', 'HP:0002664', (87, 94))	('bladder', 'Disease', (129, 136))	('ovary', 'Disease', (151, 156))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('breast', 'Disease', (105, 111))	('prostate', 'Disease', (138, 146))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('pancreas', 'Disease', (119, 127))	('cancers of colon', 'Disease', 'MESH:D015179', (87, 103))	('lung', 'Disease', (113, 117))
335881	29194401	MicroRNAs have been described to participate in cancer progression, malignance, drug resistance and even in CSCs properties acquisition.	('MicroRNAs', 'Var', (0, 9))	('malignance', 'CPA', (68, 78))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('participate', 'Reg', (33, 44))	('drug resistance', 'CPA', (80, 95))	('drug resistance', 'Phenotype', 'HP:0020174', (80, 95))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))
335882	29194401	One exemplification is the microRNA-22, which increases the hematopoietic stem cells self-renewal though the inactivation of TET2 in myelodysplastic syndrome and leukemia, where was found upregulated.	('TET2', 'Gene', (125, 129))	('microRNA-22', 'Gene', '407004', (27, 38))	('microRNA-22', 'Gene', (27, 38))	('myelodysplastic syndrome', 'Phenotype', 'HP:0002863', (133, 157))	('increases', 'PosReg', (46, 55))	('leukemia', 'Disease', (162, 170))	('leukemia', 'Phenotype', 'HP:0001909', (162, 170))	('leukemia', 'Disease', 'MESH:D007938', (162, 170))	('myelodysplastic syndrome', 'Disease', (133, 157))	('inactivation', 'Var', (109, 121))	('myelodysplastic syndrome', 'Disease', 'MESH:D009190', (133, 157))	('TET2', 'Gene', '54790', (125, 129))	('hematopoietic stem cells self-renewal', 'CPA', (60, 97))
335887	29194401	Importantly the authors identified the active secretion of microRNA-34a within exosomes, membrane vesicles approximately 100 nm in diameter and essential for cell-to-cell communications, indicating a role of microRNA in the surrounding environment.	('iron', 'Chemical', 'MESH:D007501', (239, 243))	('secretion', 'MPA', (46, 55))	('microRNA-34a', 'Var', (59, 71))
335890	29194401	Loss of microRNA-27b was found to increase docetaxel resistance in Luminal A breast-type cancer by increasing the expression and membrane location of ABCG2.	('microRNA-27b', 'Gene', '407019', (8, 20))	('ABCG2', 'Gene', '9429', (150, 155))	('docetaxel resistance', 'MPA', (43, 63))	('microRNA-27b', 'Gene', (8, 20))	('breast-type cancer', 'Disease', (77, 95))	('increasing', 'PosReg', (99, 109))	('breast-type cancer', 'Disease', 'MESH:D001943', (77, 95))	('membrane location', 'MPA', (129, 146))	('docetaxel', 'Chemical', 'MESH:D000077143', (43, 52))	('ABCG2', 'Gene', (150, 155))	('expression', 'MPA', (114, 124))	('increase', 'PosReg', (34, 42))	('Loss', 'Var', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
335895	29194401	The cells within the tumor are considered an ecosystem in which spontaneous mutations and epigenetic changes may confer cells with greater fitness for a specific tumor microenvironment; likewise, the fittest clone will repopulate the tumor after a treatment.	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('tumor', 'Disease', (234, 239))	('tumor', 'Disease', (21, 26))	('tumor', 'Disease', (162, 167))	('iron', 'Chemical', 'MESH:D007501', (176, 180))	('spontaneous mutations', 'Var', (64, 85))	('epigenetic changes', 'Var', (90, 108))	('tumor', 'Disease', 'MESH:D009369', (234, 239))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
335945	29194401	MSCs: Breast CSCs recruit MSCs by secreting IL6, which induces CXCL7 production in MSCs.	('IL6', 'Gene', (44, 47))	('induces', 'Reg', (55, 62))	('secreting', 'Var', (34, 43))	('CXCL7 production', 'MPA', (63, 79))	('IL6', 'Gene', '3569', (44, 47))
335964	29194401	In phase II clinical trials, vismodegib treatment resulted in an increased median survival of one year in comparison with patients receiving a standard treatment.	('vismodegib', 'Var', (29, 39))	('median survival', 'MPA', (75, 90))	('increased', 'PosReg', (65, 74))	('patients', 'Species', '9606', (122, 130))
335983	29194401	Previous studies showed that simultaneous knockdown of two ALDH isoforms results in increased cyclophosphamide sensitivity of lung cancer cells, suggesting the possible utility of ALDH-targeting treatments.	('cyclophosphamide', 'Chemical', 'MESH:D003520', (94, 110))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('lung cancer', 'Disease', (126, 137))	('ALDH', 'Gene', (59, 63))	('lung cancer', 'Phenotype', 'HP:0100526', (126, 137))	('increased', 'PosReg', (84, 93))	('cyclophosphamide sensitivity', 'MPA', (94, 122))	('lung cancer', 'Disease', 'MESH:D008175', (126, 137))	('knockdown', 'Var', (42, 51))
335990	29194401	In an animal model of pancreatic cancer, stroma reduction through the enzymatic destruction of hyaluronic acid led to reduced interstitial pressure, re-expanding the vasculature and enabling increased delivery of standard chemotherapy with concomitant increased efficacy, suggesting that not only cancer cells or CSCs are possible anticancer targets.	('re-expanding', 'PosReg', (149, 161))	('cancer', 'Disease', (33, 39))	('cancer', 'Disease', (335, 341))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('interstitial pressure', 'MPA', (126, 147))	('pancreatic cancer', 'Disease', 'MESH:D010190', (22, 39))	('delivery', 'MPA', (201, 209))	('cancer', 'Phenotype', 'HP:0002664', (335, 341))	('cancer', 'Disease', 'MESH:D009369', (297, 303))	('enabling increased', 'PosReg', (182, 200))	('stroma reduction', 'Disease', 'MESH:D015431', (41, 57))	('stroma reduction', 'Disease', (41, 57))	('pancreatic cancer', 'Disease', (22, 39))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('reduced', 'NegReg', (118, 125))	('cancer', 'Disease', 'MESH:D009369', (335, 341))	('hyaluronic acid', 'Protein', (95, 110))	('hyaluronic acid', 'Chemical', 'MESH:D006820', (95, 110))	('efficacy', 'MPA', (262, 270))	('vasculature', 'MPA', (166, 177))	('cancer', 'Disease', (297, 303))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (22, 39))	('destruction', 'Var', (80, 91))	('cancer', 'Phenotype', 'HP:0002664', (297, 303))
336070	31289600	Low-quality drinking water might raise the risk of having EPLs.	('Low-quality', 'Var', (0, 11))	('drinking water', 'Chemical', 'MESH:D060766', (12, 26))	('EPLs', 'Disease', (58, 62))
336078	29085449	In addition, patients with TSCC with higher PRR11 expression exhibited substantially shorter survival times compared with patients with lower PRR11 expression (P<0.001).	('TSCC', 'Disease', (27, 31))	('higher', 'Var', (37, 43))	('PRR11', 'Gene', (44, 49))	('shorter', 'NegReg', (85, 92))	('PRR11', 'Gene', '55771', (142, 147))	('survival times', 'CPA', (93, 107))	('patients', 'Species', '9606', (13, 21))	('expression', 'Var', (50, 60))	('PRR11', 'Gene', (142, 147))	('patients', 'Species', '9606', (122, 130))	('PRR11', 'Gene', '55771', (44, 49))	('TSCC', 'Phenotype', 'HP:0030413', (27, 31))
336112	29085449	The optimal cut-off value was determined: A staining index score >=6 was used to define tumors with high PRR11 expression; and a score <=4 indicated low PRR11 expression.	('PRR11', 'Gene', (105, 110))	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('PRR11', 'Gene', '55771', (153, 158))	('high', 'Var', (100, 104))	('expression', 'MPA', (111, 121))	('expression', 'MPA', (159, 169))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('PRR11', 'Gene', (153, 158))	('PRR11', 'Gene', '55771', (105, 110))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('tumors', 'Disease', (88, 94))	('low', 'NegReg', (149, 152))
336131	29085449	Kaplan-Meier analysis indicated that high PRR11 expression was associated with shorter overall survival time (P<0.001; Fig.	('high', 'Var', (37, 41))	('PRR11', 'Gene', (42, 47))	('shorter', 'NegReg', (79, 86))	('expression', 'MPA', (48, 58))	('overall survival', 'MPA', (87, 103))	('PRR11', 'Gene', '55771', (42, 47))
336146	29085449	Additionally, in lung, breast and numerous types of digestive system cancer, silencing of PRR11 expression induced S-phase arrest, and inhibited cell proliferation, migration, invasion and particularly tumor growth.	('tumor', 'Disease', (202, 207))	('migration', 'CPA', (165, 174))	('PRR11', 'Gene', '55771', (90, 95))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('S-phase arrest', 'CPA', (115, 129))	('system cancer', 'Disease', 'MESH:D009369', (62, 75))	('silencing', 'Var', (77, 86))	('PRR11', 'Gene', (90, 95))	('cell proliferation', 'CPA', (145, 163))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('invasion', 'CPA', (176, 184))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('inhibited', 'NegReg', (135, 144))	('system cancer', 'Disease', (62, 75))	('lung', 'Disease', (17, 21))	('breast', 'Disease', (23, 29))	('induced', 'Reg', (107, 114))
336149	29085449	Lung cancer-associated genes dehydrogenase/reductase 2 (DHRS2), erythrocyte membrane protein band 4.1 like 3 (EPB41L3), cyclin A1 (CCNA1), mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4), nuclear factor I B (NFIB) and ribonucleotide reductase catalytic subunit M1 (RRM1) are deregulated following PRR11 knockdown.	('CCNA1', 'Gene', (131, 136))	('RRM1', 'Gene', '6240', (282, 286))	('NFIB', 'Gene', (225, 229))	('MAP4K4', 'Gene', (196, 202))	('nuclear factor I B', 'Gene', (205, 223))	('erythrocyte membrane protein band 4.1 like 3', 'Gene', (64, 108))	('dehydrogenase/reductase 2', 'Gene', (29, 54))	('dehydrogenase/reductase 2', 'Gene', '10202', (29, 54))	('cancer', 'Disease', 'MESH:D009369', (5, 11))	('ribonucleotide reductase catalytic subunit M1', 'Gene', (235, 280))	('cyclin A1', 'Gene', '8900', (120, 129))	('Lung cancer', 'Phenotype', 'HP:0100526', (0, 11))	('NFIB', 'Gene', '4781', (225, 229))	('CCNA1', 'Gene', '8900', (131, 136))	('EPB41L3', 'Gene', '23136', (110, 117))	('cyclin A1', 'Gene', (120, 129))	('knockdown', 'Var', (320, 329))	('erythrocyte membrane protein band 4.1 like 3', 'Gene', '23136', (64, 108))	('DHRS2', 'Gene', (56, 61))	('PRR11', 'Gene', '55771', (314, 319))	('RRM1', 'Gene', (282, 286))	('EPB41L3', 'Gene', (110, 117))	('PRR11', 'Gene', (314, 319))	('mitogen-activated protein kinase kinase kinase kinase 4', 'Gene', '9448', (139, 194))	('nuclear factor I B', 'Gene', '4781', (205, 223))	('cancer', 'Disease', (5, 11))	('MAP4K4', 'Gene', '9448', (196, 202))	('deregulated', 'PosReg', (292, 303))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))	('ribonucleotide reductase catalytic subunit M1', 'Gene', '6240', (235, 280))	('DHRS2', 'Gene', '10202', (56, 61))
336153	29085449	Additionally, in breast cancer, PRR11 depletion reduces the expression of epithelial-mesenchymal transition (EMT)-associated transcription factors snail family transcriptional repressor (SNAI) 1, SNAI2, zinc finger-box-binding homeobox (ZEB) 1 and ZEB2.	('expression', 'MPA', (60, 70))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('breast cancer', 'Disease', 'MESH:D001943', (17, 30))	('snail family transcriptional repressor (SNAI) 1', 'Gene', '6615', (147, 194))	('SNAI2', 'Gene', '6591', (196, 201))	('SNAI2', 'Gene', (196, 201))	('breast cancer', 'Disease', (17, 30))	('ZEB2', 'Gene', '9839', (248, 252))	('depletion', 'Var', (38, 47))	('PRR11', 'Gene', '55771', (32, 37))	('breast cancer', 'Phenotype', 'HP:0003002', (17, 30))	('reduces', 'NegReg', (48, 55))	('PRR11', 'Gene', (32, 37))	('ZEB2', 'Gene', (248, 252))
336160	29085449	The results of the present study indicated that patients with high levels of PRR11 expression exhibited a shorter survival time, and PRR11 expression was also associated with regional draining lymph nodes metastasis.	('PRR11', 'Gene', (77, 82))	('survival time', 'CPA', (114, 127))	('shorter', 'NegReg', (106, 113))	('regional draining lymph nodes metastasis', 'CPA', (175, 215))	('high levels', 'Var', (62, 73))	('associated with', 'Reg', (159, 174))	('PRR11', 'Gene', '55771', (133, 138))	('patients', 'Species', '9606', (48, 56))	('PRR11', 'Gene', '55771', (77, 82))	('PRR11', 'Gene', (133, 138))
336174	26640587	The dysregulation of miRNAs might play pivotal roles in tumorigenesis in breast cancer, liver cancer, gastric cancer, and colorectal cancer.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('dysregulation', 'Var', (4, 17))	('colorectal cancer', 'Disease', (122, 139))	('miR', 'Gene', (21, 24))	('gastric cancer', 'Disease', (102, 116))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('gastric cancer', 'Disease', 'MESH:D013274', (102, 116))	('liver cancer', 'Disease', 'MESH:D006528', (88, 100))	('colorectal cancer', 'Phenotype', 'HP:0003003', (122, 139))	('roles', 'Reg', (47, 52))	('tumor', 'Disease', (56, 61))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('breast cancer', 'Phenotype', 'HP:0003002', (73, 86))	('liver cancer', 'Phenotype', 'HP:0002896', (88, 100))	('gastric cancer', 'Phenotype', 'HP:0012126', (102, 116))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('liver cancer', 'Disease', (88, 100))	('miR', 'Gene', '220972', (21, 24))	('breast cancer', 'Disease', 'MESH:D001943', (73, 86))	('breast cancer', 'Disease', (73, 86))	('colorectal cancer', 'Disease', 'MESH:D015179', (122, 139))
336256	26640587	MTS assay results showed that cell proliferation ability in Hep-2 or Tu-177 was lower in the Smad4 group than in the blank and vector groups (Figure 4C, 4D).	('Smad4', 'Gene', (93, 98))	('Smad4', 'Gene', '4089', (93, 98))	('Hep-2', 'CellLine', 'CVCL:1906', (60, 65))	('cell proliferation ability', 'CPA', (30, 56))	('lower', 'NegReg', (80, 85))	('MTS', 'Gene', (0, 3))	('Tu-177', 'CellLine', 'CVCL:4913', (69, 75))	('Tu-177', 'Var', (69, 75))	('MTS', 'Gene', '8201', (0, 3))
336292	26640587	Dysregulated miRNAs may play an important role by acting as oncogenes or anti-oncogenes.	('Dysregulated', 'Var', (0, 12))	('miR', 'Gene', '220972', (13, 16))	('miR', 'Gene', (13, 16))
336303	26640587	Cancer cell growth, proliferation, migration, and invasion were suppressed by the repression of miR-301a-3p; apoptosis was enhanced; and the cell cycle was arrested at the G0/G1 phase.	('enhanced', 'PosReg', (123, 131))	('invasion', 'CPA', (50, 58))	('migration', 'CPA', (35, 44))	('301a', 'Chemical', '-', (100, 104))	('suppressed', 'NegReg', (64, 74))	('apoptosis', 'CPA', (109, 118))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('cell cycle', 'CPA', (141, 151))	('Cancer', 'Disease', (0, 6))	('miR', 'Gene', '220972', (96, 99))	('miR', 'Gene', (96, 99))	('repression', 'Var', (82, 92))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))
336309	26640587	Deletion or degradation of Smad4 in tumors can specifically inhibit the tumor suppressor effect of TGF-beta.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('Smad4', 'Gene', (27, 32))	('Smad4', 'Gene', '4089', (27, 32))	('inhibit', 'NegReg', (60, 67))	('degradation', 'MPA', (12, 23))	('tumor', 'Disease', (72, 77))	('tumors', 'Disease', 'MESH:D009369', (36, 42))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('TGF-beta', 'Gene', '7040', (99, 107))	('tumors', 'Disease', (36, 42))	('TGF-beta', 'Gene', (99, 107))	('tumor', 'Disease', (36, 41))	('Deletion', 'Var', (0, 8))
336325	26640587	This illustrates that dysregulation of miR-301a-3p and Smad4 affect EMT in LSCC.	('dysregulation', 'Var', (22, 35))	('miR', 'Gene', '220972', (39, 42))	('miR', 'Gene', (39, 42))	('LSCC', 'Disease', (75, 79))	('Smad4', 'Gene', (55, 60))	('Smad4', 'Gene', '4089', (55, 60))	('affect', 'Reg', (61, 67))	('EMT', 'CPA', (68, 71))	('301a', 'Chemical', '-', (43, 47))
336331	24122205	Characterization of CD44 variant expression in head and neck squamous cell carcinomas CD44 is a complex family of molecules, associated with aggressive malignancies and cancer stem cells.	('cancer', 'Disease', (169, 175))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('variant', 'Var', (25, 32))	('aggressive malignancies', 'Disease', (141, 164))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (61, 85))	('associated', 'Reg', (125, 135))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (61, 84))	('cancer', 'Disease', 'MESH:D009369', (169, 175))	('head and neck squamous cell carcinomas', 'Phenotype', 'HP:0012288', (47, 85))	('CD44', 'Gene', '960', (86, 90))	('CD44', 'Gene', (86, 90))	('neck squamous cell carcinomas', 'Disease', (56, 85))	('CD44', 'Gene', '960', (20, 24))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (47, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('carcinomas', 'Phenotype', 'HP:0030731', (75, 85))	('CD44', 'Gene', (20, 24))	('aggressive malignancies', 'Disease', 'MESH:D009369', (141, 164))	('neck squamous cell carcinomas', 'Disease', 'MESH:D000077195', (56, 85))
336332	24122205	However, the role of CD44 variants in tumor progression and treatment resistance is not clear.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('CD44', 'Gene', '960', (21, 25))	('CD44', 'Gene', (21, 25))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('variants', 'Var', (26, 34))
336334	24122205	Furthermore, subpopulations of cells expressing high amounts of CD44 variants were identified and characterized, for e.g., cell cycle phase and radioresistance.	('cell cycle phase', 'CPA', (123, 139))	('CD44', 'Gene', '960', (64, 68))	('radioresistance', 'CPA', (144, 159))	('variants', 'Var', (69, 77))	('CD44', 'Gene', (64, 68))
336340	24122205	Our results demonstrate that the heterogeneity of tumor cells has important clinical implications for the treatment of HNSCC and that some of the CD44 variants may be associated with increased radioresistance.	('variants', 'Var', (151, 159))	('CD44', 'Gene', (146, 150))	('increased', 'PosReg', (183, 192))	('SCC', 'Gene', (121, 124))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('rat', 'Species', '10116', (19, 22))	('CD44', 'Gene', '960', (146, 150))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('SCC', 'Gene', '6317', (121, 124))	('HNSCC', 'Phenotype', 'HP:0012288', (119, 124))	('associated', 'Reg', (167, 177))	('tumor', 'Disease', (50, 55))	('radioresistance', 'CPA', (193, 208))
336341	24122205	Highly expressed CD44 variants could make interesting candidates for selective cancer targeting.	('CD44', 'Gene', '960', (17, 21))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('CD44', 'Gene', (17, 21))	('variants', 'Var', (22, 30))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))
336364	24122205	If one or several CD44 splice variants are found to be associated with cancer progression or treatment resistance, the possibility of targeting such a population will increase immensely, since these isoforms are not as abundantly expressed in the normal tissue as the standard CD44s molecule.	('variants', 'Var', (30, 38))	('CD44', 'Gene', '960', (277, 281))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('CD44s', 'Gene', (277, 282))	('cancer', 'Disease', (71, 77))	('CD44', 'Gene', (277, 281))	('associated', 'Reg', (55, 65))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('CD44', 'Gene', '960', (18, 22))	('CD44s', 'Gene', '960', (277, 282))	('treatment resistance', 'CPA', (93, 113))	('CD44', 'Gene', (18, 22))
336368	24122205	The scope of this study was to study the expression of potential cancer stem cell markers CD133, CD24, and CD44, with focus on CD44 exon variants in head and neck squamous cell carcinoma, in order to find attractive molecular targets for selective cancer targeting.	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (149, 186))	('CD133', 'Gene', (90, 95))	('CD133', 'Gene', '8842', (90, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (177, 186))	('cancer', 'Disease', (65, 71))	('neck squamous cell carcinoma', 'Disease', (158, 186))	('variants', 'Var', (137, 145))	('CD24', 'Gene', '100133941', (97, 101))	('cancer', 'Disease', (248, 254))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (158, 186))	('CD44', 'Gene', '960', (127, 131))	('cancer', 'Phenotype', 'HP:0002664', (248, 254))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('CD44', 'Gene', (127, 131))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (163, 186))	('cancer', 'Disease', 'MESH:D009369', (248, 254))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('CD24', 'Gene', (97, 101))	('CD44', 'Gene', '960', (107, 111))	('CD44', 'Gene', (107, 111))
336384	24122205	For analysis of CD44 and CD44 variant expression through the different phases of the cell cycle, cells were detached with nonenzymatic cell dissociation solution (Sigma-Aldrich, Stockholm, Sweden), washed in PBS with 0.5 % BSA, and fixed in ice-cold 70 % ethanol.	('CD44', 'Gene', '960', (16, 20))	('PBS', 'Chemical', '-', (208, 211))	('CD44', 'Gene', '960', (25, 29))	('CD44', 'Gene', (16, 20))	('variant', 'Var', (30, 37))	('CD44', 'Gene', (25, 29))	('ethanol', 'Chemical', 'MESH:D000431', (255, 262))
336413	24122205	Moreover, v4++ cells were extensively more resistant to radiation treatment than CD44v4+ cells.	('v4++', 'Var', (10, 14))	('resistant', 'CPA', (43, 52))	('CD44', 'Gene', '960', (81, 85))	('CD44', 'Gene', (81, 85))
336424	24122205	Here, the CD44v4/5 variant increased with about 15 %; v3 expression, with 60 %; v6, with 75 %; and v7, with about 21 % (Fig.	('increased', 'PosReg', (27, 36))	('variant', 'Var', (19, 26))	('v3 expression', 'MPA', (54, 67))	('CD44', 'Gene', '960', (10, 14))	('CD44', 'Gene', (10, 14))
336425	24122205	Furthermore, to determine if the CD44 variant expression pattern was consistent through the cell cycle, cell cycle studies were performed.	('variant', 'Var', (38, 45))	('CD44', 'Gene', '960', (33, 37))	('CD44', 'Gene', (33, 37))
336431	24122205	The purpose of this study was to examine the expression of the cancer stem cell markers CD133, CD24, CD44, and CD44 variants, in head and neck squamous cell carcinoma.	('CD44', 'Gene', (111, 115))	('variants', 'Var', (116, 124))	('CD44', 'Gene', (101, 105))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('CD24', 'Gene', '100133941', (95, 99))	('CD24', 'Gene', (95, 99))	('neck squamous cell carcinoma', 'Disease', (138, 166))	('CD133', 'Gene', (88, 93))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (138, 166))	('CD133', 'Gene', '8842', (88, 93))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (129, 166))	('carcinoma', 'Phenotype', 'HP:0030731', (157, 166))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (143, 166))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('CD44', 'Gene', '960', (111, 115))	('CD44', 'Gene', '960', (101, 105))	('cancer', 'Disease', (63, 69))
336437	24122205	Whereas some tumors such as gliomas exclusively express CD44s, other neoplasms including gastrointestinal cancer, bladder cancer, uterine cervical cancer, breast cancer, and HNSCC also express CD44 variants.	('bladder cancer', 'Disease', 'MESH:D001749', (114, 128))	('CD44', 'Gene', (193, 197))	('bladder cancer', 'Disease', (114, 128))	('gastrointestinal cancer', 'Disease', 'MESH:D004067', (89, 112))	('cancer', 'Disease', (162, 168))	('CD44s', 'Gene', '960', (56, 61))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('gastrointestinal cancer', 'Disease', (89, 112))	('cancer', 'Disease', (106, 112))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (89, 112))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('bladder cancer', 'Phenotype', 'HP:0009725', (114, 128))	('gliomas', 'Disease', (28, 35))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('neoplasms', 'Disease', 'MESH:D009369', (69, 78))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('breast cancer', 'Phenotype', 'HP:0003002', (155, 168))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('CD44', 'Gene', '960', (56, 60))	('SCC', 'Gene', '6317', (176, 179))	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('gliomas', 'Disease', 'MESH:D005910', (28, 35))	('CD44', 'Gene', (56, 60))	('neoplasms', 'Disease', (69, 78))	('tumors', 'Disease', (13, 19))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('breast cancer', 'Disease', 'MESH:D001943', (155, 168))	('SCC', 'Gene', (176, 179))	('breast cancer', 'Disease', (155, 168))	('variants', 'Var', (198, 206))	('CD44s', 'Gene', (56, 61))	('HNSCC', 'Phenotype', 'HP:0012288', (174, 179))	('gliomas', 'Phenotype', 'HP:0009733', (28, 35))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('cancer', 'Disease', (122, 128))	('neoplasms', 'Phenotype', 'HP:0002664', (69, 78))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('cancer', 'Disease', (147, 153))	('CD44', 'Gene', '960', (193, 197))
336440	24122205	Hence, CD44, particularly its variants, may be used as diagnostic or prognostic markers of at least some human malignant diseases, even enabling specific targeting of aggressive, resistant, or regrowing subpopulations.	('CD44', 'Gene', (7, 11))	('human', 'Species', '9606', (105, 110))	('variants', 'Var', (30, 38))	('CD44', 'Gene', '960', (7, 11))
336441	24122205	However, not much is known today about the role of most of these variants in malignancies, cancer stem cells, and HNSCC.	('SCC', 'Gene', (116, 119))	('cancer', 'Disease', (91, 97))	('malignancies', 'Disease', (77, 89))	('SCC', 'Gene', '6317', (116, 119))	('variants', 'Var', (65, 73))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('HNSCC', 'Phenotype', 'HP:0012288', (114, 119))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('malignancies', 'Disease', 'MESH:D009369', (77, 89))
336442	24122205	In this study, flow cytometry analysis was first used to assess the extent of CD133, CD24, and CD44 variant expression in four HNSCC cell lines.	('SCC', 'Gene', '6317', (129, 132))	('CD44', 'Gene', '960', (95, 99))	('CD44', 'Gene', (95, 99))	('CD24', 'Gene', (85, 89))	('CD24', 'Gene', '100133941', (85, 89))	('CD133', 'Gene', (78, 83))	('CD133', 'Gene', '8842', (78, 83))	('SCC', 'Gene', (129, 132))	('variant', 'Var', (100, 107))	('HNSCC', 'Phenotype', 'HP:0012288', (127, 132))
336451	24122205	However, a much larger panel of cell lines, preferably complemented with expression studies in patient tumor tissue, would be needed in order to draw any conclusions on CD44 variant expression correlated to tumor origin or tumor progression.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('tumor', 'Disease', (223, 228))	('patient', 'Species', '9606', (95, 102))	('CD44', 'Gene', (169, 173))	('tumor', 'Disease', (103, 108))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('variant', 'Var', (174, 181))	('tumor', 'Disease', 'MESH:D009369', (223, 228))	('tumor', 'Disease', (207, 212))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('CD44', 'Gene', '960', (169, 173))
336481	24122205	Even though IHC is commonly used for the analysis of patient biopsies, it is a comparatively blunt method and might be unable to satisfactorily distinguish between moderately and highly CD44 variant-expressing cells within the same biopsy.	('CD44', 'Gene', (186, 190))	('patient', 'Species', '9606', (53, 60))	('rat', 'Species', '10116', (84, 87))	('rat', 'Species', '10116', (168, 171))	('variant-expressing', 'Var', (191, 209))	('CD44', 'Gene', '960', (186, 190))
336482	24122205	Another important aspect is the molecular mechanism underlying the radioresistance of highly CD44 variant-expressing cells, which warrants further investigation.	('variant-expressing', 'Var', (98, 116))	('CD44', 'Gene', '960', (93, 97))	('CD44', 'Gene', (93, 97))	('radioresistance', 'CPA', (67, 82))
336483	24122205	In conclusion, we have identified several markers that are highly expressed in cultured HNSCC cells, and we have also identified splice variants associated with increased radioresistance and migration rate.	('rat', 'Species', '10116', (201, 204))	('rat', 'Species', '10116', (194, 197))	('radioresistance', 'CPA', (171, 186))	('migration rate', 'CPA', (191, 205))	('SCC', 'Gene', (90, 93))	('HNSCC', 'Phenotype', 'HP:0012288', (88, 93))	('SCC', 'Gene', '6317', (90, 93))	('increased', 'PosReg', (161, 170))	('splice variants', 'Var', (129, 144))
336484	24122205	Highly expressed variants of CD44 may also be a more specific marker than standard CD44s, which is present to high extent also in normal tissue.	('CD44', 'Gene', (29, 33))	('variants', 'Var', (17, 25))	('CD44s', 'Gene', '960', (83, 88))	('CD44', 'Gene', '960', (83, 87))	('CD44s', 'Gene', (83, 88))	('CD44', 'Gene', (83, 87))	('CD44', 'Gene', '960', (29, 33))
336486	24122205	In the future, CD44 variants may be used as prognostic markers or therapeutic targets.	('CD44', 'Gene', '960', (15, 19))	('CD44', 'Gene', (15, 19))	('variants', 'Var', (20, 28))
336518	24660084	A hybridization of the probe with integrated HPV in the tumor was defined as a positive signal demonstrated by dark brown dot-like staining in the nucleus of the tumor cells.	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('HPV', 'Species', '10566', (45, 48))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('HPV', 'Var', (45, 48))	('tumor', 'Disease', (162, 167))	('tumor', 'Disease', (56, 61))	('tumor', 'Disease', 'MESH:D009369', (162, 167))
336530	24660084	These include marker-affected tumors being considered concomitant if 50% or more of the same markers are mutated, the same gene copy is affected, and the temporal sequence of mutation is similar.	('tumors', 'Disease', (30, 36))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('affected', 'Reg', (136, 144))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('mutated', 'Var', (105, 112))
336569	31568516	Analysis of millions of mutations in APOBEC-hypermutated cancer genomes revealed that cancer tolerance to formation of hypermutable ssDNA is similar to yeast and that the predominant pattern of clustered mutagenesis is the same as in resection-defective yeast, suggesting that cluster formation in cancers is driven by a BIR-like mechanism.	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('APOBEC-hypermutated', 'Gene', (37, 56))	('cancer', 'Disease', (57, 63))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('cancer', 'Disease', 'MESH:D009369', (298, 304))	('cancers', 'Disease', 'MESH:D009369', (298, 305))	('yeast', 'Species', '4932', (254, 259))	('cancers', 'Phenotype', 'HP:0002664', (298, 305))	('cancer', 'Disease', (298, 304))	('cancers', 'Disease', (298, 305))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('yeast', 'Species', '4932', (152, 157))	('mutations', 'Var', (24, 33))	('cancer', 'Phenotype', 'HP:0002664', (298, 304))	('cancer', 'Disease', (86, 92))
336570	31568516	The phenomenon of genome-wide burst of clustered mutagenesis revealed by our study can play an important role in generating somatic hypermutation in cancers as well as in noncancerous cells.	('cancer', 'Disease', (149, 155))	('cancers', 'Disease', (149, 156))	('cancers', 'Phenotype', 'HP:0002664', (149, 156))	('clustered mutagenesis', 'Var', (39, 60))	('somatic hypermutation', 'MPA', (124, 145))	('cancer', 'Disease', (174, 180))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('cancer', 'Disease', 'MESH:D009369', (149, 155))	('cancers', 'Disease', 'MESH:D009369', (149, 156))
336573	31568516	The most striking form of clustered mutagenesis has been associated with ssDNA-specific apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like (APOBEC) cytidine deaminases normally acting as a part of the innate immunity by converting cytosines to uracils in ssDNA intermediates of retroviruses and retrotransposons that accidentally gain access to genomic DNA in human cancers.	('human', 'Species', '9606', (374, 379))	('cancers', 'Disease', 'MESH:D009369', (380, 387))	('cancers', 'Phenotype', 'HP:0002664', (380, 387))	('cancers', 'Disease', (380, 387))	('cytosines', 'Chemical', 'MESH:D003596', (245, 254))	('uracils', 'Chemical', 'MESH:D014498', (258, 265))	('mutagenesis', 'Var', (36, 47))	('cancer', 'Phenotype', 'HP:0002664', (380, 386))	('apolipoprotein B mRNA', 'Protein', (88, 109))
336577	31568516	Moreover, cancers can contain hundreds of APOBEC-induced mutation clusters with varying extents of strand coordination.	('mutation', 'Var', (57, 65))	('APOBEC-induced', 'Gene', (42, 56))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('cancers', 'Phenotype', 'HP:0002664', (10, 17))	('cancers', 'Disease', 'MESH:D009369', (10, 17))	('cancers', 'Disease', (10, 17))
336579	31568516	Studies in yeast models have indicated that long clusters of multiple mutations can stem from ssDNA intermediates formed during repair of a double-strand break (DSB) by homologous recombination (HR) (reviewed in and Fig 1).	('mutations', 'Var', (70, 79))	('yeast', 'Species', '4932', (11, 16))	('stem', 'Reg', (84, 88))
336582	31568516	Colocalization of APOBEC mutation clusters with breakpoints of chromosomal rearrangements in human cancers has been documented in several studies.	('human', 'Species', '9606', (93, 98))	('cancers', 'Disease', 'MESH:D009369', (99, 106))	('mutation', 'Var', (25, 33))	('cancers', 'Phenotype', 'HP:0002664', (99, 106))	('cancers', 'Disease', (99, 106))	('APOBEC', 'Gene', (18, 24))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
336584	31568516	In addition, bursts of DSBs occurring in the same or in several subsequent cell generations were implicated in chromothripsis, a common feature of cancers characterized by catastrophic multiple rearrangements in the cancer genome.	('cancer', 'Disease', (147, 153))	('implicated', 'Reg', (97, 107))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('chromothripsis', 'Disease', (111, 125))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('cancers', 'Disease', 'MESH:D009369', (147, 154))	('cancers', 'Phenotype', 'HP:0002664', (147, 154))	('cancer', 'Disease', (216, 222))	('cancer', 'Disease', 'MESH:D009369', (216, 222))	('cancers', 'Disease', (147, 154))	('DSBs', 'Var', (23, 27))
336588	31568516	Also, A3A-like signatures prevailed in bursts of APOBEC mutagenesis during propagation of cancer cell lines as revealed by.	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('mutagenesis', 'Var', (56, 67))	('APOBEC', 'Gene', (49, 55))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))
336590	31568516	Using the strand-assignment patterns of clustered mutations arising from these ssDNA sources in yeast, we then scrutinized over 10,000 mutation clusters in cancers with a high level of APOBEC mutagenesis and found that clusters in cancers matched patterns of clustered mutations in resection-defective yeast, suggesting that bidirectional resection does not play a major role in cluster formation, but rather, clusters in cancer are formed by a BIR-like mechanism.	('cancers', 'Phenotype', 'HP:0002664', (156, 163))	('cancer', 'Phenotype', 'HP:0002664', (422, 428))	('cancer', 'Disease', (156, 162))	('cancers', 'Disease', (156, 163))	('mutations', 'Var', (50, 59))	('cancer', 'Disease', 'MESH:D009369', (231, 237))	('cancers', 'Disease', 'MESH:D009369', (156, 163))	('cancers', 'Disease', 'MESH:D009369', (231, 238))	('cancers', 'Disease', (231, 238))	('cancer', 'Disease', (231, 237))	('yeast', 'Species', '4932', (302, 307))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('cancer', 'Disease', 'MESH:D009369', (422, 428))	('cancers', 'Phenotype', 'HP:0002664', (231, 238))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('cancer', 'Disease', (422, 428))	('yeast', 'Species', '4932', (96, 101))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))
336591	31568516	We tested whether bursts of DSBs could result in the vast formation of hypermutable ssDNA that leads to clustered mutations using Saccharomyces cerevisiae yeast strains harboring a triple reporter system (CAN1-ADE2-URA3) located in the midregion of chromosome II (Fig 2A).	('CAN1', 'Gene', (205, 209))	('leads', 'Reg', (95, 100))	('mutations', 'Var', (114, 123))	('ADE2', 'Gene', (210, 214))	('result in', 'Reg', (39, 48))	('URA3', 'Gene', '856692', (215, 219))	('URA3', 'Gene', (215, 219))	('CAN1', 'Gene', '856646', (205, 209))	('yeast', 'Species', '4932', (155, 160))	('Saccharomyces cerevisiae', 'Species', '4932', (130, 154))	('ADE2', 'Gene', '854295', (210, 214))
336593	31568516	While a similar construct expressing APOBEC3B was also highly mutagenic in yeast, we chose A3A for these experiments because, based on our prior experience, A3A caused lower level of background mutagenesis in proliferating yeast but produced similar size and density of mutation clusters in ssDNA artificially generated at uncapped telomeres.	('APOBEC3B', 'Gene', (37, 45))	('yeast', 'Species', '4932', (75, 80))	('APOBEC3B', 'Gene', '9582', (37, 45))	('yeast', 'Species', '4932', (223, 228))	('background mutagenesis', 'MPA', (183, 205))	('A3A', 'Var', (157, 160))
336595	31568516	All uracils formed by A3A-induced deamination of cytosines would result in C:G to T:A transitions in a tCw context with even greater preference for the A3A-specific trinucleotide context ytCa (y = T or C; mutated base capitalized), leaving a permanent mark on transient regions of persistent ssDNA.	('deamination', 'Var', (34, 45))	('C:G to T:A', 'Var', (75, 85))	('cytosines', 'Chemical', 'MESH:D003596', (49, 58))	('uracils', 'Chemical', 'MESH:D014498', (4, 11))	('result', 'Reg', (65, 71))
336598	31568516	Colonies of CanR ade2 double-inactivation mutants were identified on the medium containing canavanine by red color (pigmentation resulting from complete or partial ADE2 inactivation) and will be referred to as Can1-Red hereafter.	('mutants', 'Var', (42, 49))	('ADE2', 'Gene', (164, 168))	('canavanine', 'Chemical', 'MESH:C410363', (91, 101))	('double-inactivation mutants', 'Var', (22, 49))	('ade2', 'Gene', (17, 21))	('Can1', 'Gene', '856646', (210, 214))	('Can1', 'Gene', (210, 214))	('inactivation', 'NegReg', (169, 181))	('ade2', 'Gene', '854295', (17, 21))	('ADE2', 'Gene', '854295', (164, 168))
336600	31568516	In haploids, Can1-Red would result from a pair of mutations, while in diploids, it would require a loss of heterozygosity (LOH) following mutagenesis.	('Can1', 'Gene', '856646', (13, 17))	('mutations', 'Var', (50, 59))	('heterozygosity', 'MPA', (107, 121))	('Can1', 'Gene', (13, 17))	('loss', 'NegReg', (99, 103))	('result from', 'Reg', (28, 39))
336602	31568516	Since these colonies likely had mutations in the closely spaced CAN1 and ADE2 genes, they were likely to have at least one mutation cluster per genome, which was confirmed by whole-genome sequencing (S2C Table).	('ADE2', 'Gene', (73, 77))	('CAN1', 'Gene', (64, 68))	('mutations', 'Var', (32, 41))	('CAN1', 'Gene', '856646', (64, 68))	('ADE2', 'Gene', '854295', (73, 77))
336604	31568516	In Can1-Red diploids and haploids, the percent of isolates that had at least one nonselected cluster was over 70% (Fig 2B, 2C and 2D).	('Can1', 'Gene', '856646', (3, 7))	('haploids', 'Var', (25, 33))	('Can1', 'Gene', (3, 7))
336612	31568516	Furthermore, there was no genome-wide induction of C:G to T:A scattered (nonclustered) mutations by A3A expression in G2-arrested cells in the absence of gamma exposure as defined by whole-genome sequencing of Can1-White, unselected small white colonies without rearrangements, and unselected large white colonies, suggesting that the mere presence of A3A in the cell is not sufficient for cluster formation, but rather, it is the presence of persistent ssDNA that is the rate-limiting factor (S2 Fig, S1F Table, S1 Data).	('large white', 'Species', '7116', (293, 304))	('A3A', 'Gene', (100, 103))	('Can1', 'Gene', '856646', (210, 214))	('Can1', 'Gene', (210, 214))	('mutations', 'Var', (87, 96))
336614	31568516	This outcome is more pronounced in the subpopulation (represented in our experiments by Can1-Red isolates) prone to APOBEC mutagenesis and cluster formation.	('APOBEC', 'Gene', (116, 122))	('Can1', 'Gene', (88, 92))	('cluster formation', 'CPA', (139, 156))	('mutagenesis', 'Var', (123, 134))	('Can1', 'Gene', '856646', (88, 92))
336620	31568516	Also, it was recently demonstrated that in cultured cancer cell lines, a high frequency of APOBEC mutagenesis and cluster formation also occurs in a subpopulation of cells.	('APOBEC', 'Gene', (91, 97))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('cluster formation', 'CPA', (114, 131))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('mutagenesis', 'Var', (98, 109))
336621	31568516	This suggests that tumors with multiple mutation clusters also develop from a subpopulation prone to clustered mutagenesis.	('mutation', 'Var', (40, 48))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('tumors', 'Disease', (19, 25))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('develop', 'Reg', (63, 70))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))
336623	31568516	For all resection-defective strains, the induction of Can1-Red mutants after 40 krad gamma exposure was observed, and the presence of selected and nonselected clusters was confirmed by whole-genome sequencing of multiple isolates (Fig 5A, S1E Table, S2B Table).	('Can1', 'Gene', (54, 58))	('mutants', 'Var', (63, 70))	('induction', 'Reg', (41, 50))	('S2B', 'Chemical', 'MESH:D013455', (250, 253))	('Can1', 'Gene', '856646', (54, 58))
336627	31568516	Since Sgs1 and Exo1 are known to participate in long-range resection at DSBs, we predicted, based on the switch from top to bottom strand expected at bidirectional resection, that eliminating these pathways would result in a decrease of single-switch clusters with mutated C's on the 5' end and G's on the 3' end, reading the top (Watson) strand (Fig 1B).	('decrease', 'NegReg', (225, 233))	('single-switch clusters', 'MPA', (237, 259))	('Sgs1', 'Gene', (6, 10))	('Sgs1', 'Gene', '855228', (6, 10))	('mutated', 'Var', (265, 272))
336630	31568516	Furthermore, single-switch clusters in all strains, including WT, predominantly conformed to the mutation pattern of 5'C followed by 3'G (as opposed to 5'G followed by 3'C) (Fig 5C, S2I Table).	("3'C", 'Chemical', 'MESH:D002244', (168, 171))	("5'C", 'Var', (117, 120))	('conformed', 'Reg', (80, 89))	("5'C", 'Chemical', 'MESH:D002244', (117, 120))
336638	31568516	We did, however, find that C- or G-coordinated clusters were significantly longer in pol32 mutants as compared to WT, though there was no difference in mutation density (S4 Fig, S2J Table).	('longer', 'PosReg', (75, 81))	('G-coordinated clusters', 'CPA', (33, 55))	('pol32', 'Gene', (85, 90))	('pol32', 'Gene', '853500', (85, 90))	('mutants', 'Var', (91, 98))
336639	31568516	Previous studies in yeast strains in which BIR can be stimulated by a site-specific DSB have shown that in the absence of Pol32, break repair involves long resection at one end of the break, which can explain the incidence of C- or G-coordinated clusters found in pol32Delta mutants (Fig 1A [ii]).	('mutants', 'Var', (275, 282))	('C- or G-coordinated clusters', 'MPA', (226, 254))	('Pol32', 'Gene', (122, 127))	('yeast', 'Species', '4932', (20, 25))	('pol32', 'Gene', (264, 269))	('pol32', 'Gene', '853500', (264, 269))	('Pol32', 'Gene', '853500', (122, 127))
336646	31568516	Therefore, it is likely that rare clusters found in the genomes of Can1-Red isolates from triple mutants were not gamma-induced.	('Can1', 'Gene', (67, 71))	('triple mutants', 'Var', (90, 104))	('Can1', 'Gene', '856646', (67, 71))
336652	31568516	Using the knowledge gained from our results in yeast about molecular mechanisms contributing to the formation of different cluster types, we next scrutinized mutation catalogs from whole-genome-sequenced tumors belonging to cancer types highly enriched with APOBEC mutagenesis ( and Materials and Methods).	('tumors belonging to cancer', 'Disease', (204, 230))	('yeast', 'Species', '4932', (47, 52))	('mutagenesis', 'Var', (265, 276))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('APOBEC', 'Gene', (258, 264))	('tumors', 'Phenotype', 'HP:0002664', (204, 210))	('tumors belonging to cancer', 'Disease', 'MESH:D009369', (204, 230))
336653	31568516	We hypothesized that, similar to yeast, clustered mutagenesis in APOBEC-enriched cancer types is likely to highlight genome locations where persistent long stretches of ssDNA have occurred.	('yeast', 'Species', '4932', (33, 38))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('APOBEC-enriched', 'Gene', (65, 80))	('cancer', 'Disease', (81, 87))	('mutagenesis', 'Var', (50, 61))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))
336654	31568516	Highly APOBEC-enriched cancer types:including bladder, breast, cervix, head and neck, and lung:had in some tumors over a hundred CG-containing clusters with greater than 3 mutations in a cluster (Fig 6A and 6B, S6B and S6C Table, S1 Data).	('mutations', 'Var', (172, 181))	('cervix', 'Disease', (63, 69))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('bladder', 'Disease', (46, 53))	('tumors', 'Disease', (107, 113))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('cancer', 'Disease', (23, 29))	('breast', 'Disease', (55, 61))	('cancer', 'Disease', 'MESH:D009369', (23, 29))	('lung', 'Disease', (90, 94))	('tumors', 'Disease', 'MESH:D009369', (107, 113))	('S6B', 'Chemical', 'MESH:C012008', (211, 214))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))
336655	31568516	Furthermore, the mutation clusters in these cancers were highly enriched with APOBEC signature mutations, indicating that many samples in these cancer types experienced conditions that resulted in multiple ssDNA regions throughout the genome that were vulnerable to hypermutation.	('APOBEC', 'Gene', (78, 84))	('cancers', 'Phenotype', 'HP:0002664', (44, 51))	('cancer', 'Disease', (44, 50))	('cancers', 'Disease', (44, 51))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('cancers', 'Disease', 'MESH:D009369', (44, 51))	('cancer', 'Disease', (144, 150))	('mutations', 'Var', (95, 104))	('ssDNA', 'Disease', (206, 211))	('resulted in', 'Reg', (185, 196))	('experienced', 'Reg', (157, 168))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
336656	31568516	We used CG clusters with >3 mutations to calculate the minimum estimate of hypermutable ssDNA formed through the history of a cancer sample (see Materials and Methods) and found that these estimates were close to values observed in yeast.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('yeast', 'Species', '4932', (232, 237))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('hypermutable ssDNA', 'Disease', (75, 93))	('mutations', 'Var', (28, 37))
336664	31568516	We found that only lung cancers had a high proportion of multiple-switch clusters, which possibly suggests that complex genetic events in these cancers contributed to cluster formation.	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('lung cancers', 'Disease', 'MESH:D008175', (19, 31))	('lung cancers', 'Phenotype', 'HP:0100526', (19, 31))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('multiple-switch', 'Var', (57, 72))	('cancers', 'Phenotype', 'HP:0002664', (24, 31))	('cancers', 'Phenotype', 'HP:0002664', (144, 151))	('lung cancers', 'Disease', (19, 31))	('cancers', 'Disease', (144, 151))	('cancers', 'Disease', 'MESH:D009369', (24, 31))	('cancers', 'Disease', 'MESH:D009369', (144, 151))	('cancers', 'Disease', (24, 31))
336669	31568516	The frequency of clusters as well as strand assignment of mutations in strains with diagnostic deficiencies in different branches of HR allowed us to highlight subpathways of DSB repair in which long hypermutable ssDNA is formed (Fig 1).	('mutations', 'Var', (58, 67))	('deficiencies in different branches of HR', 'Disease', 'MESH:D015356', (95, 135))	('deficiencies in different branches of HR', 'Disease', (95, 135))	('long hypermutable ssDNA', 'Disease', (195, 218))
336671	31568516	Considering the overall conservation of HR DSB repair pathways from yeast to humans, we compare cluster patterns in a yeast model with APOBEC mutation clusters in human tumors and propose a model of cluster formation in humans.	('yeast', 'Species', '4932', (118, 123))	('human', 'Species', '9606', (220, 225))	('humans', 'Species', '9606', (77, 83))	('tumors', 'Disease', 'MESH:D009369', (169, 175))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('yeast', 'Species', '4932', (68, 73))	('human', 'Species', '9606', (163, 168))	('tumors', 'Phenotype', 'HP:0002664', (169, 175))	('APOBEC', 'Gene', (135, 141))	('mutation', 'Var', (142, 150))	('humans', 'Species', '9606', (220, 226))	('tumors', 'Disease', (169, 175))	('human', 'Species', '9606', (77, 82))
336672	31568516	Our results indicate that several kinds of abnormal repair of DSBs generated hypermutable ssDNA susceptible to the formation of APOBEC mutation clusters in yeast and that cluster-prone ssDNA generation relied upon pathways of HR repair involving end resection and BIR.	('yeast', 'Species', '4932', (156, 161))	('abnormal', 'Var', (43, 51))	('mutation', 'Var', (135, 143))
336675	31568516	Previously, we have shown that such delayed repair after long-range resection can occur and results in vast mutation clusters when exogenous oligonucleotides are provided to yeast cells six hours after a site-specific DSB has been generated and DNA damage was applied.	('results in', 'Reg', (92, 102))	('yeast', 'Species', '4932', (174, 179))	('mutation', 'Var', (108, 116))
336679	31568516	The density of APOBEC-induced mutations in clusters (approximately 1 mutation/kb) was close to the density observed in artificially created yeast subtelomeric ssDNA exposed to endogenously expressed A3A for up to 48 hours.	('yeast', 'Species', '4932', (140, 145))	('mutations', 'Var', (30, 39))	('APOBEC-induced', 'Gene', (15, 29))
336683	31568516	However, in human cancers, mutagenesis associated with ssDNA-specific APOBEC enzymes was observed to be equally distributed in the transcribed and non-transcribed strands of genes.	('cancers', 'Disease', (18, 25))	('ssDNA-specific', 'Gene', (55, 69))	('mutagenesis', 'Var', (27, 38))	('cancers', 'Phenotype', 'HP:0002664', (18, 25))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('APOBEC enzymes', 'Gene', (70, 84))	('human', 'Species', '9606', (12, 17))	('cancers', 'Disease', 'MESH:D009369', (18, 25))
336684	31568516	Both clustered and scattered APOBEC mutagenesis in cancers were more prominent in early-replicating regions of cancer genomes, and this preference was similar in transcribed and non-transcribed regions.	('cancers', 'Disease', (51, 58))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('mutagenesis', 'Var', (36, 47))	('cancers', 'Phenotype', 'HP:0002664', (51, 58))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('APOBEC', 'Gene', (29, 35))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('cancers', 'Disease', 'MESH:D009369', (51, 58))
336687	31568516	Based on size (i.e., number of mutations in a cluster), length, and mutation density, many APOBEC clusters in human cancers (Fig 3 and S3 Fig) resemble clusters formed in yeast cells experiencing repair of multiple simultaneous DSBs.	('APOBEC', 'Gene', (91, 97))	('mutations', 'Var', (31, 40))	('yeast', 'Species', '4932', (171, 176))	('human', 'Species', '9606', (110, 115))	('cancers', 'Disease', 'MESH:D009369', (116, 123))	('cancers', 'Phenotype', 'HP:0002664', (116, 123))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cancers', 'Disease', (116, 123))
336691	31568516	Our results obtained in a yeast model indicated that symmetrical resection can frequently generate vast APOBEC mutation clusters identified as "single-switch" (Figs 1B, 4 and 5B).	('yeast', 'Species', '4932', (26, 31))	('APOBEC', 'Gene', (104, 110))	('mutation', 'Var', (111, 119))
336694	31568516	There was only a small fraction of single-switch APOBEC clusters in cancers, and many of these single-switch clusters had a G-stretch on the left and thus were inconsistent with 5' to 3' direction of bidirectional resection (Fig 6B and 6C).	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('cancers', 'Phenotype', 'HP:0002664', (68, 75))	('G-stretch', 'Var', (124, 133))	('cancers', 'Disease', (68, 75))	('cancers', 'Disease', 'MESH:D009369', (68, 75))	('APOBEC', 'Gene', (49, 55))
336695	31568516	Altogether, comparison between APOBEC mutation in cancers with APOBEC clusters formed in yeast performing HR repair of multiple gamma-induced DSBs suggests that bidirectional resection at DSBs plays essentially no role in the generation of clusters in cancers.	('cancers', 'Phenotype', 'HP:0002664', (252, 259))	('cancers', 'Disease', 'MESH:D009369', (50, 57))	('cancers', 'Phenotype', 'HP:0002664', (50, 57))	('cancers', 'Disease', (252, 259))	('cancers', 'Disease', 'MESH:D009369', (252, 259))	('cancers', 'Disease', (50, 57))	('yeast', 'Species', '4932', (89, 94))	('APOBEC', 'Gene', (31, 37))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('mutation', 'Var', (38, 46))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))
336697	31568516	While the bulk of ssDNA tracks formed during mammalian replication and DSB repair are smaller than many APOBEC mutation clusters in cancers, there could be a small fraction of unusually long persistent ssDNA formed by either resection or abnormal replication.	('cancers', 'Disease', (132, 139))	('cancers', 'Disease', 'MESH:D009369', (132, 139))	('mammalian', 'Species', '9606', (45, 54))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('resection', 'Var', (225, 234))	('abnormal replication', 'Var', (238, 258))	('cancers', 'Phenotype', 'HP:0002664', (132, 139))
336698	31568516	In mammalian cells, including cancers, HR is involved in repair of DSBs as well as in recovery of collapsed replication forks.	('DSBs', 'Var', (67, 71))	('cancers', 'Phenotype', 'HP:0002664', (30, 37))	('cancers', 'Disease', (30, 37))	('cancers', 'Disease', 'MESH:D009369', (30, 37))	('collapsed', 'MPA', (98, 107))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('mammalian', 'Species', '9606', (3, 12))
336701	31568516	Interestingly, both chromosome rearrangements and APOBEC mutation clusters in cancers occur more frequently in early-replicating regions of the genome.	('mutation', 'Var', (57, 65))	('cancers', 'Phenotype', 'HP:0002664', (78, 85))	('cancers', 'Disease', 'MESH:D009369', (78, 85))	('cancers', 'Disease', (78, 85))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('APOBEC', 'Gene', (50, 56))
336708	31568516	One possible source of explosive formation of chromosome breakage and APOBEC mutation clusters was recently discovered in cultured human cells experiencing telomere protection crisis.	('mutation', 'Var', (77, 85))	('APOBEC', 'Gene', (70, 76))	('chromosome breakage', 'Phenotype', 'HP:0040012', (46, 65))	('human', 'Species', '9606', (131, 136))
336710	31568516	Episodic bursts of APOBEC mutagenesis that could be associated with bursts of ssDNA formation were recently reported with in vitro-propagated cancer cell lines.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('APOBEC', 'Gene', (19, 25))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('mutagenesis', 'Var', (26, 37))	('cancer', 'Disease', (142, 148))
336712	31568516	APOBEC mutation clusters in cancers identify stretches of long persistent ssDNA transiently formed in the proliferative history of a tumor.	('cancers', 'Disease', (28, 35))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('APOBEC', 'Gene', (0, 6))	('cancers', 'Phenotype', 'HP:0002664', (28, 35))	('tumor', 'Disease', (133, 138))	('mutation', 'Var', (7, 15))	('cancers', 'Disease', 'MESH:D009369', (28, 35))
336717	31568516	However, in cancer types with low APOBEC mutagenesis, the APOBEC mutation signature can be detected mostly or even exclusively in clusters.	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('cancer', 'Disease', (12, 18))	('APOBEC', 'Gene', (58, 64))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('mutagenesis', 'Var', (41, 52))
336722	31568516	All diploid and haploid yeast S. cerevisiae used in this study were derivatives of ySR128 (MATalpha ura3Delta can1Delta ade2Delta his7-2 leu2-3,112 trp1-289 lys2::ADE2-URA3-CAN1), which were made ung1Delta by disruption of UNG1 with KANMX cassette, conferring resistance to geneticin.	('lys2', 'Gene', (157, 161))	('URA3', 'Gene', (168, 172))	('CAN1', 'Gene', (173, 177))	('yeast', 'Species', '4932', (24, 29))	('ung1', 'Gene', (196, 200))	('UNG1', 'Gene', (223, 227))	('ADE2', 'Gene', '854295', (163, 167))	('lys2', 'Gene', '852412', (157, 161))	('disruption', 'Var', (209, 219))	('leu2', 'Gene', (137, 141))	('ade2', 'Gene', '854295', (120, 124))	('CAN1', 'Gene', '856646', (173, 177))	('URA3', 'Gene', '856692', (168, 172))	('leu2', 'Gene', '850342', (137, 141))	('ung1', 'Gene', '854987', (196, 200))	('ade2', 'Gene', (120, 124))	('UNG1', 'Gene', '854987', (223, 227))	('ADE2', 'Gene', (163, 167))	('S. cerevisiae', 'Species', '4932', (30, 43))
336729	31568516	Strains containing pol32::KANMX were constructed by crossing MATa pol32::KANMX strains (yCS177 or yCS178) with MATalpha ung1::KANMX sgs1::NATMX exo1::BSD strain (yCS124 or yCS125), followed by tetrad dissection and confirmation of haploid strains with desired genotype by PCR and phenotypic analysis.	('exo1', 'Gene', (144, 148))	('sgs1', 'Gene', (132, 136))	('pol32', 'Gene', '853500', (19, 24))	('sgs1', 'Gene', '855228', (132, 136))	('ung1', 'Gene', '854987', (120, 124))	('pol32', 'Gene', (66, 71))	('exo1', 'Gene', '854198', (144, 148))	('pol32', 'Gene', '853500', (66, 71))	('ung1', 'Gene', (120, 124))	('yCS124', 'Var', (162, 168))	('pol32', 'Gene', (19, 24))
336740	31568516	Cells were also concentrated and plated onto synthetic medium with low adenine and lacking arginine but supplemented with 60 mg/L canavanine (Can-Low-Ade) to determine frequencies and to isolate single CanR and double CanR Red mutant frequencies.	('arginine', 'Chemical', 'MESH:D001127', (91, 99))	('canavanine', 'Chemical', 'MESH:C410363', (130, 140))	('adenine', 'Chemical', 'MESH:D000225', (71, 78))	('double CanR', 'Var', (211, 222))	('double CanR', 'Phenotype', 'HP:0000506', (211, 222))	('single CanR', 'Var', (195, 206))
336741	31568516	A CanR phenotype indicates a mutation inactivating the CAN1 gene, and a red color indicates a likely mutation in ADE2.	('ADE2', 'Gene', '854295', (113, 117))	('CAN1', 'Gene', '856646', (55, 59))	('mutation inactivating', 'Var', (29, 50))	('CAN1', 'Gene', (55, 59))	('ADE2', 'Gene', (113, 117))
336744	31568516	Since Can1-Red mutants had coincident inactivation of the closely spaced CAN1 and ADE2 genes, they were expected to have at least one mutation cluster that overlapped the triple reporter region, CAN1-ADE2-URA3.	('ADE2', 'Gene', (82, 86))	('URA3', 'Gene', '856692', (205, 209))	('inactivation', 'NegReg', (38, 50))	('ADE2', 'Gene', '854295', (200, 204))	('CAN1', 'Gene', '856646', (195, 199))	('URA3', 'Gene', (205, 209))	('Can1', 'Gene', '856646', (6, 10))	('ADE2', 'Gene', (200, 204))	('Can1', 'Gene', (6, 10))	('mutants', 'Var', (15, 22))	('CAN1', 'Gene', '856646', (73, 77))	('ADE2', 'Gene', '854295', (82, 86))	('CAN1', 'Gene', (195, 199))	('CAN1', 'Gene', (73, 77))
336755	31568516	In our experiments, yeast formed mutation clusters in conditions of high level of genome-wide APOBEC mutagenesis.	('formed', 'Reg', (26, 32))	('yeast', 'Species', '4932', (20, 25))	('APOBEC', 'Gene', (94, 100))	('mutagenesis', 'Var', (101, 112))
336757	31568516	Enrichment with APOBEC mutation signature in clustered mutations of these cancer types always exceeded enrichment in the catalog of total mutations or in scattered (not belonging to any cluster) mutations (S6A Table).	('mutation', 'Var', (23, 31))	('mutations', 'Var', (55, 64))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('cancer', 'Disease', (74, 80))	('APOBEC', 'Gene', (16, 22))
336759	31568516	Mutation clusters containing more than 3 mutations were used as a proxy for long persistent regions of ssDNA because these clusters always showed increased enrichment with APOBEC mutation signature in cancers.	('cancers', 'Disease', 'MESH:D009369', (201, 208))	('cancers', 'Phenotype', 'HP:0002664', (201, 208))	('cancers', 'Disease', (201, 208))	('APOBEC', 'Gene', (172, 178))	('increased', 'PosReg', (146, 155))	('mutation', 'Var', (179, 187))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))
336760	31568516	These clusters were categorized by nucleotides mutated in the top (Watson) strand as follows: C-coordinated, only cytosines mutated; G-coordinated, only guanines mutated; C-coordinated with a terminal G, a single G mutated either on the 5'-side or on the 3'-side of a cluster; G-coordinated with a terminal C, a single C mutated either on the 5'-side or on the 3'-side of a cluster; CG single-switch, contiguous stretch of at least two mutated G's next to a contiguous stretch of at least two mutated C's (in some analyses, this category was divided into two subcategories: 5' C single-switch clusters, mutated C-stretch on the 5'-side followed by a mutated G-stretch; and 5' G single-switch clusters, mutated G-stretch on 5'-side followed by a mutated C-stretch); and CG multiple-switch, clusters with mutated G's and C's with more than one contiguous stretch of mutated C's and/or mutated G's.	('cytosines', 'Chemical', 'MESH:D003596', (114, 123))	('mutated', 'Var', (803, 810))	('guanines', 'Chemical', 'MESH:D006147', (153, 161))	('mutated', 'Var', (883, 890))
336762	31568516	An example of the calculation for enrichment of mutations within ytCa   ytTa signature expected for A3A mutagenesis in ung1Delta yeast is presented below, where the context is derived from a 41-nucleotides region containing the mutated residue in the center:  For each motif, the reverse complement was also used in the calculations.	('yeast', 'Species', '4932', (129, 134))	('ytCa   ytTa', 'Disease', 'None', (65, 76))	('ung1', 'Gene', '854987', (119, 123))	('ytCa   ytTa', 'Disease', (65, 76))	('ung1', 'Gene', (119, 123))	('mutations', 'Var', (48, 57))
336773	31568516	The authors tackle this problem using a clever triple reporter system to identify yeast strains most likely to exhibit mutation clusters (selected mutation clusters are predictive of the presence of non-selected mutation clusters elsewhere in the genome).	('exhibit', 'Reg', (111, 118))	('yeast', 'Species', '4932', (82, 87))	('mutation clusters', 'Var', (119, 136))
336774	31568516	Using a series of yeast strains defective in specific repair pathways, the authors identify 3 pathways that contribute to cluster formation at DSBs: 5'-3' bi-directional resection, uni-directional resection, and break-induced replication (BIR).	('break-induced replication', 'CPA', (212, 237))	('uni-directional resection', 'Var', (181, 206))	('yeast', 'Species', '4932', (18, 23))
336776	31568516	The authors proposal that clustered mutagenesis in human cancer is driven by a BIR-like mechanism is interesting, but requires further investigation.	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('cancer', 'Disease', (57, 63))	('clustered', 'Var', (26, 35))	('human', 'Species', '9606', (51, 56))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))
336779	31568516	This is an interesting study that makes important observations regarding the genesis of APOBEC mutations in cancer genomes.	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('mutations', 'Var', (95, 104))	('APOBEC', 'Gene', (88, 94))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
336784	31568516	Can APOBEC3B also generate mutation clusters in their system?	('APOBEC3B', 'Gene', (4, 12))	('mutation', 'Var', (27, 35))	('APOBEC3B', 'Gene', '9582', (4, 12))	('generate', 'Reg', (18, 26))
336787	31568516	For proof of this they examine mutagenesis in yeast mutants that impair production of single-strand DNA in various DNA double-strand break repair pathways.	('production of single-strand DNA', 'MPA', (72, 103))	('impair', 'NegReg', (65, 71))	('mutants', 'Var', (52, 59))	('yeast', 'Species', '4932', (46, 51))
336789	31568516	It would be important to emphasize first, what is new in this paper and second, as the authors propose that this is a model for clustered mutation in cancer cells from DSB repair, when during the growth of a tumor cell there would be bursts of DSBs associated with long ssDNA repair intermediates.	('tumor', 'Disease', 'MESH:D009369', (208, 213))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('cancer', 'Disease', (150, 156))	('tumor', 'Disease', (208, 213))	('mutation', 'Var', (138, 146))	('DSBs', 'Disease', (244, 248))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
336798	31568516	--- Reviewer 3: This is a nicely presented and expertly performed study, where yeast experiments give some further mechanistic clues regarding APOBEC mutation clusters, which are already a well-established feature of cancer genomes.	('mutation', 'Var', (150, 158))	('APOBEC', 'Gene', (143, 149))	('yeast', 'Species', '4932', (79, 84))	('cancer', 'Disease', (217, 223))	('cancer', 'Disease', 'MESH:D009369', (217, 223))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))
336799	31568516	Specifically, APOBEC clustered mutations in tumors are here shown to have characteristics similar to BIR-related APOBEC clusters artificially induced in yeast.	('yeast', 'Species', '4932', (153, 158))	('tumors', 'Disease', 'MESH:D009369', (44, 50))	('mutations', 'Var', (31, 40))	('tumors', 'Disease', (44, 50))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('APOBEC', 'Gene', (14, 20))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))
336828	26720001	OPSCC sites included the oropharynx (C10.0-C10.4, C10.8-C10.9), tonsil (C02.4, C09.0-C09.1, C09.8-C09.9), base of tongue (C01.9), soft palate and uvula (C05.1-C05.2), and Waldeyer's ring (C14.2).	('uvula', 'Disease', 'MESH:C531732', (146, 151))	('C09.8-C09.9', 'Var', (92, 103))	('C10.8-C10.9', 'Var', (50, 61))	('C09.8-C09.9', 'CellLine', 'CVCL:E286', (92, 103))	('C01.9', 'CellLine', 'CVCL:E303', (122, 127))	('soft palate', 'Disease', (130, 141))	('C09.0-C09.1', 'Var', (79, 90))	('uvula', 'Disease', (146, 151))	('soft palate', 'Disease', 'MESH:C562950', (130, 141))	('C10.0-C10.4', 'Var', (37, 48))
336829	26720001	Non-OP HNC sites included other parts of the tongue (C02.0-C02.3, C02.8-C02.9), mouth (C04.0-C04.1, C04.8-C04.9; C06.0-C06.2, C06.8-C06.9), gum (C03.0-C03.1, C03.9), and hard palate (C05.0, C05.8-C05.9).	('hard palate', 'Disease', 'MESH:D018804', (170, 181))	('C04.0-C04.1', 'Var', (87, 98))	('C03.9', 'CellLine', 'CVCL:J167', (158, 163))	('C06.8-C06.9', 'CellLine', 'CVCL:AX49', (126, 137))	('hard palate', 'Disease', (170, 181))	('C02.8-C02.9', 'Var', (66, 77))	('C03.0-C03.1', 'Var', (145, 156))	('hard palate', 'Phenotype', 'HP:0410005', (170, 181))	('C02.0-C02.3', 'Var', (53, 64))
336830	26720001	OPSCC and non-OP HNC analyses were restricted to cancers with squamous cell histologies (ICD-O-3 codes: 8050 to 8076, 8078, 8083, 8084, 8094).	('squamous cell histologies', 'Disease', (62, 87))	('8078', 'Var', (118, 122))	('8084', 'Var', (130, 134))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('8083', 'Var', (124, 128))	('cancers', 'Disease', 'MESH:D009369', (49, 56))	('cancers', 'Phenotype', 'HP:0002664', (49, 56))	('cancers', 'Disease', (49, 56))
336999	33265245	CYP2C9 polymorphisms were associated with colorectal cancer risk and may influence breast cancer.	('colorectal cancer', 'Phenotype', 'HP:0003003', (42, 59))	('CYP2C9', 'Gene', '1559', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('breast cancer', 'Disease', 'MESH:D001943', (83, 96))	('colorectal cancer', 'Disease', (42, 59))	('breast cancer', 'Disease', (83, 96))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('breast cancer', 'Phenotype', 'HP:0003002', (83, 96))	('polymorphisms', 'Var', (7, 20))	('influence', 'Reg', (73, 82))	('CYP2C9', 'Gene', (0, 6))	('colorectal cancer', 'Disease', 'MESH:D015179', (42, 59))	('associated', 'Reg', (26, 36))
337008	33265245	CEACAM1 has 11 different splice variants, as reported in some studies in vivo, and restoration of its expression abolishes oncogenicity of tumor cell lines, but when it is expressed de novo it increases the risk of metastasis CEACAM1 has also been proposed as a potential biomarker for breast cancer.	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('oncogenicity', 'MPA', (123, 135))	('CEACAM1', 'Gene', '634', (0, 7))	('CEACAM1', 'Gene', '634', (226, 233))	('expression', 'MPA', (102, 112))	('restoration', 'Var', (83, 94))	('metastasis', 'CPA', (215, 225))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('breast cancer', 'Disease', 'MESH:D001943', (286, 299))	('increases', 'PosReg', (193, 202))	('cancer', 'Phenotype', 'HP:0002664', (293, 299))	('breast cancer', 'Disease', (286, 299))	('CEACAM1', 'Gene', (0, 7))	('CEACAM1', 'Gene', (226, 233))	('breast cancer', 'Phenotype', 'HP:0003002', (286, 299))
337013	33265245	A recent study showed that a knockdown of UBET2 induced an inhibition in the progression of gastric cancer in vivo and in vitro via WNT signal pathway.	('inhibition', 'NegReg', (59, 69))	('progression', 'CPA', (77, 88))	('knockdown', 'Var', (29, 38))	('gastric cancer', 'Disease', (92, 106))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('gastric cancer', 'Disease', 'MESH:D013274', (92, 106))	('gastric cancer', 'Phenotype', 'HP:0012126', (92, 106))	('UBET2', 'Gene', (42, 47))
337031	33265245	There is a wide field of cancer research such as non-coding-DNA/RNA, single nucleotide polymorphisms, copy number variations, and epigenetic factors such as methylation and acetylation, that could lead us to a better understanding of the dynamics of cancer diseases.	('cancer diseases', 'Disease', (250, 265))	('cancer diseases', 'Disease', 'MESH:D009369', (250, 265))	('cancer', 'Disease', 'MESH:D009369', (250, 256))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('single nucleotide polymorphisms', 'Var', (69, 100))	('cancer', 'Disease', (250, 256))	('copy number variations', 'Var', (102, 124))	('cancer', 'Disease', 'MESH:D009369', (25, 31))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))	('cancer', 'Disease', (25, 31))
337043	32855206	A comprehensive understanding of how cancer mutations rewire immune signaling networks and functional output across cancer types is instrumental to realize the full potential of immunotherapy.	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('immune signaling networks', 'Pathway', (61, 86))	('cancer', 'Disease', (37, 43))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('mutations', 'Var', (44, 53))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('rewire', 'Reg', (54, 60))
337044	32855206	Here we systematically interrogated somatic mutations involved in immune signaling that alter immune responses in cancer patients.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('alter', 'Reg', (88, 93))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('mutations', 'Var', (44, 53))	('immune', 'MPA', (94, 100))	('patients', 'Species', '9606', (121, 129))	('cancer', 'Disease', (114, 120))
337065	32855206	For an immune pathway i in cancer type j, the score is defined as following:  Where  is the number of mutated immune genes in pathway i;  is the total number of genes in pathway i;  is the number of patients of cancer j that with gene mutations in pathway i; and  is the total number of patients sequenced in cancer j.	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('cancer', 'Disease', 'MESH:D009369', (211, 217))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('cancer', 'Disease', 'MESH:D009369', (309, 315))	('cancer', 'Disease', (211, 217))	('cancer', 'Phenotype', 'HP:0002664', (309, 315))	('patients', 'Species', '9606', (287, 295))	('patients', 'Species', '9606', (199, 207))	('cancer', 'Disease', (27, 33))	('cancer', 'Disease', 'MESH:D009369', (27, 33))	('gene mutations', 'Var', (230, 244))	('cancer', 'Disease', (309, 315))
337093	32855206	Recombinant MAGE-A3 protein combined with immunostimulant AS02B or AS15, has been administered to patients with early metastatic melanoma.	('MAGE-A3', 'Gene', (12, 19))	('melanoma', 'Phenotype', 'HP:0002861', (129, 137))	('melanoma', 'Disease', (129, 137))	('patients', 'Species', '9606', (98, 106))	('AS02B', 'Var', (58, 63))	('melanoma', 'Disease', 'MESH:D008545', (129, 137))	('MAGE-A3', 'Gene', '4102', (12, 19))
337103	32855206	It has been suggested that the mutations in immune pathways could impact tumor-immune interactions.	('mutations', 'Var', (31, 40))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Disease', (73, 78))	('immune pathways', 'Pathway', (44, 59))	('impact', 'Reg', (66, 72))
337108	32855206	We found that the cancer types that are likely to respond well to immunotherapy had higher proportion of immune-related gene mutations, such as skin cutaneous melanoma (SKCM) and kidney cancer (Figure S2C).	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (144, 167))	('mutations', 'Var', (125, 134))	('kidney cancer', 'Disease', 'MESH:D007680', (179, 192))	('skin cutaneous melanoma', 'Disease', (144, 167))	('kidney cancer', 'Phenotype', 'HP:0009726', (179, 192))	('immune-related gene', 'Gene', (105, 124))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (149, 167))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('kidney cancer', 'Disease', (179, 192))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('melanoma', 'Phenotype', 'HP:0002861', (159, 167))	('cancer', 'Disease', (18, 24))	('cancer', 'Disease', 'MESH:D009369', (18, 24))	('cancer', 'Disease', (186, 192))	('cancer', 'Disease', 'MESH:D009369', (186, 192))
337113	32855206	The top-1 gene (PLXNA4) ranked by mutation frequency was mutated in approximately 19% of lung cancer patients.	('patients', 'Species', '9606', (101, 109))	('lung cancer', 'Disease', (89, 100))	('lung cancer', 'Phenotype', 'HP:0100526', (89, 100))	('PLXNA4', 'Gene', (16, 22))	('lung cancer', 'Disease', 'MESH:D008175', (89, 100))	('top-1', 'Gene', '7150', (4, 9))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('top-1', 'Gene', (4, 9))	('mutated', 'Var', (57, 64))	('PLXNA4', 'Gene', '91584', (16, 22))
337115	32855206	We further found that the expression of PLXNA4 was correlated with the patients' survival in LUSC (Figure S2E, p=0.017).	('PLXNA4', 'Gene', '91584', (40, 46))	('expression', 'Var', (26, 36))	('patients', 'Species', '9606', (71, 79))	('PLXNA4', 'Gene', (40, 46))	('correlated', 'Reg', (51, 61))
337116	32855206	These results suggest that the mutations in cytokine receptors pathway might play critical roles in cancer and the proposed PMB index could help prioritizing key mutations in cancer pathways.	('cancer', 'Disease', (100, 106))	('mutations', 'Var', (31, 40))	('cancer', 'Disease', (175, 181))	('play', 'Reg', (77, 81))	('PMB', 'Chemical', '-', (124, 127))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('cytokine receptors pathway', 'Pathway', (44, 70))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
337122	32855206	These results indicate that these genes could play a role in promoting tumor growth.	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('genes', 'Var', (34, 39))	('promoting', 'PosReg', (61, 70))	('tumor', 'Disease', (71, 76))
337136	32855206	Given the importance of the proposed immune-related scores in predicting immune response, we next determined whether cancer mutations in immunity candidate driver regions were significantly correlated with these scores (Table S3).	('correlated', 'Reg', (190, 200))	('mutations', 'Var', (124, 133))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('cancer', 'Disease', (117, 123))
337138	32855206	Specifically, mutations in seven genes (UBXN1, LTBP2, STAT1, NGFR, NRAS, MET and LTBP4) were significantly correlated with all of three types of immune-related scores.	('correlated', 'Reg', (107, 117))	('NGFR', 'Gene', (61, 65))	('MET', 'Gene', '79811', (73, 76))	('LTBP4', 'Gene', '8425', (81, 86))	('LTBP4', 'Gene', (81, 86))	('LTBP2', 'Gene', (47, 52))	('NRAS', 'Gene', (67, 71))	('NGFR', 'Gene', '4804', (61, 65))	('STAT1', 'Gene', '6772', (54, 59))	('LTBP2', 'Gene', '4053', (47, 52))	('MET', 'Gene', (73, 76))	('NRAS', 'Gene', '4893', (67, 71))	('UBXN1', 'Gene', (40, 45))	('STAT1', 'Gene', (54, 59))	('mutations', 'Var', (14, 23))	('UBXN1', 'Gene', '51035', (40, 45))
337141	32855206	Moreover, we also identified mutations of STAT1 significantly correlated with these scores, which was consistent with previous observation that STAT1 played an important role in the innate immune response.	('STAT1', 'Gene', (144, 149))	('STAT1', 'Gene', '6772', (144, 149))	('STAT1', 'Gene', (42, 47))	('STAT1', 'Gene', '6772', (42, 47))	('mutations', 'Var', (29, 38))	('correlated', 'Reg', (62, 72))
337144	32855206	We first identified the protein regions whose mutations were significantly correlated with the abundance of six tumor-infiltrating immune cells (TIIC) subsets (B cells, CD4 T cells, CD8 T cells, macrophages, neutrophils, and dendritic cells).	('mutations', 'Var', (46, 55))	('CD4', 'Gene', (169, 172))	('CD8', 'Gene', (182, 185))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('CD8', 'Gene', '925', (182, 185))	('correlated', 'Reg', (75, 85))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('CD4', 'Gene', '920', (169, 172))	('tumor', 'Disease', (112, 117))
337150	32855206	For example, patients with LTBP4 mutations exhibited significantly higher abundance of CD8 T cells and neutrophils (Figure 4E).	('higher', 'PosReg', (67, 73))	('patients', 'Species', '9606', (13, 21))	('mutations', 'Var', (33, 42))	('LTBP4', 'Gene', '8425', (27, 32))	('LTBP4', 'Gene', (27, 32))	('CD8', 'Gene', (87, 90))	('CD8', 'Gene', '925', (87, 90))
337152	32855206	Moreover, we found that not only the genomic variants in LTBP4 were correlated with immune cell abundance, but patients with copy number alterations also exhibited significantly different abundance (Figure S5C).	('different', 'Reg', (178, 187))	('LTBP4', 'Gene', (57, 62))	('copy number alterations', 'Var', (125, 148))	('LTBP4', 'Gene', '8425', (57, 62))	('genomic variants', 'Var', (37, 53))	('correlated', 'Reg', (68, 78))	('abundance', 'MPA', (188, 197))	('immune cell abundance', 'MPA', (84, 105))	('patients', 'Species', '9606', (111, 119))
337153	32855206	These results suggest that the genomic alterations might contribute to immunotherapy response through affecting the immune cell infiltration in cancer.	('genomic alterations', 'Var', (31, 50))	('affecting', 'Reg', (102, 111))	('contribute', 'Reg', (57, 67))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('immune cell infiltration', 'CPA', (116, 140))	('cancer', 'Disease', (144, 150))	('immunotherapy response', 'CPA', (71, 93))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
337156	32855206	Approximately 25% of the mutations in PIK3CA and HRAS could generate neoantigens (Figure 5B).	('mutations', 'Var', (25, 34))	('neoantigens', 'MPA', (69, 80))	('HRAS', 'Gene', (49, 53))	('generate', 'Reg', (60, 68))	('PIK3CA', 'Gene', (38, 44))	('PIK3CA', 'Gene', '5290', (38, 44))	('HRAS', 'Gene', '3265', (49, 53))
337157	32855206	Next, we focused on mutations in PIK3CA and EGFR that give rise to neoantigens.	('PIK3CA', 'Gene', '5290', (33, 39))	('neoantigens', 'MPA', (67, 78))	('EGFR', 'Gene', '1956', (44, 48))	('EGFR', 'Gene', (44, 48))	('PIK3CA', 'Gene', (33, 39))	('mutations', 'Var', (20, 29))	('give rise to', 'Reg', (54, 66))
337159	32855206	For example, we identified 46 missense mutations that could generate neoantigens in PIK3CA.	('PIK3CA', 'Gene', '5290', (84, 90))	('neoantigens', 'MPA', (69, 80))	('missense mutations', 'Var', (30, 48))	('generate', 'Reg', (60, 68))	('PIK3CA', 'Gene', (84, 90))
337160	32855206	Moreover, we identified a mutation cluster (including R38C/H, E81K, R88Q, R93W, K111E and R115L) in PIK3CA (Figure 5E).	('K111E', 'Mutation', 'rs1057519933', (80, 85))	('R115L', 'Mutation', 'rs200018596', (90, 95))	('R88Q', 'Mutation', 'rs121913287', (68, 72))	('E81K', 'Mutation', 'rs1057519929', (62, 66))	('R38C', 'Var', (54, 58))	('R115L', 'Var', (90, 95))	('R93W', 'Mutation', 'p.R93W', (74, 78))	('PIK3CA', 'Gene', (100, 106))	('E81K', 'Var', (62, 66))	('R88Q', 'Var', (68, 72))	('R93W', 'Var', (74, 78))	('K111E', 'Var', (80, 85))	('PIK3CA', 'Gene', '5290', (100, 106))	('R38C', 'SUBSTITUTION', 'None', (54, 58))
337161	32855206	For EGFR, we identified 17 mutations that could generate neoantigens.	('mutations', 'Var', (27, 36))	('neoantigens', 'MPA', (57, 68))	('EGFR', 'Gene', (4, 8))	('generate', 'Reg', (48, 56))	('EGFR', 'Gene', '1956', (4, 8))
337162	32855206	We also found seven mutations formed a cluster in 3D (including R108K, R252/P/C/H and A189V/D, Figure 5E).	('R108K', 'Var', (64, 69))	('R252/P/C/H', 'Mutation', 'rs751667358', (71, 81))	('R252/P/C/H', 'Var', (71, 81))	('A189V', 'Var', (86, 91))	('R108K', 'Mutation', 'rs1057519828', (64, 69))	('A189V', 'SUBSTITUTION', 'None', (86, 91))
337163	32855206	We hypothesize that functional mutations which cause a conformational change in the protein may be more likely to be recognized by MHC molecules for immune pruning, but if these mutations subsequently suppress inflammatory signaling it may allow for proliferation of tumor cells with activating mutations.	('mutations', 'Var', (31, 40))	('suppress', 'NegReg', (201, 209))	('tumor', 'Disease', 'MESH:D009369', (267, 272))	('allow', 'Reg', (240, 245))	('conformational change', 'MPA', (55, 76))	('tumor', 'Phenotype', 'HP:0002664', (267, 272))	('tumor', 'Disease', (267, 272))	('mutations', 'Var', (178, 187))	('inflammatory signaling', 'MPA', (210, 232))
337178	32855206	These mutations were distributed in various types of cancer.	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('distributed', 'Reg', (21, 32))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('mutations', 'Var', (6, 15))
337179	32855206	We identified six mutations in PIK3R1 (encoding p85alpha) that reduced binding of HLAs (Figure 7B) and some mutations clustered in a possibly functional spot (Figure 7C).	('p85alpha', 'Gene', '5295', (48, 56))	('mutations', 'Var', (108, 117))	('reduced', 'NegReg', (63, 70))	('PIK3R1', 'Gene', '5295', (31, 37))	('HLAs', 'Protein', (82, 86))	('PIK3R1', 'Gene', (31, 37))	('p85alpha', 'Gene', (48, 56))	('binding', 'Interaction', (71, 78))	('mutations', 'Var', (18, 27))
337180	32855206	Consistently, we identified two mutations (N564D and K567E) that increased growth of cancer cell lines (Figure 7D).	('increased', 'PosReg', (65, 74))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('N564D', 'Mutation', 'rs1057519841', (43, 48))	('K567E', 'Var', (53, 58))	('cancer', 'Disease', (85, 91))	('K567E', 'Mutation', 'rs946866092', (53, 58))	('N564D', 'Var', (43, 48))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
337181	32855206	These results suggest that our network-based method helps identify cancer functional mutations by their change in binding affinity to HLAs.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('cancer', 'Disease', (67, 73))	('HLAs', 'Protein', (134, 138))	('change', 'Reg', (104, 110))	('mutations', 'Var', (85, 94))	('binding', 'Interaction', (114, 121))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))
337197	32855206	For example, up-regulation of BIRC5 is correlated with CNV amplification; and down-regulation of CCL14 is correlated with CNV deletion across cancer types.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('BIRC5', 'Gene', '332', (30, 35))	('BIRC5', 'Gene', (30, 35))	('down-regulation', 'NegReg', (78, 93))	('CCL14', 'Gene', '6358', (97, 102))	('amplification', 'Var', (59, 72))	('up-regulation', 'PosReg', (13, 26))	('CNV deletion', 'Var', (122, 134))	('CCL14', 'Gene', (97, 102))	('cancer', 'Disease', (142, 148))
337198	32855206	Moreover, eQTLs analysis revealed a hotspot locus that modulates the expression of DEFB1 (Figure S10A-D), which might function through perturbation of CTCF binding.	('CTCF', 'Gene', (151, 155))	('S10A', 'SUBSTITUTION', 'None', (97, 101))	('perturbation', 'Var', (135, 147))	('CTCF', 'Gene', '10664', (151, 155))	('S10A', 'Var', (97, 101))	('expression', 'MPA', (69, 79))	('modulates', 'Reg', (55, 64))	('DEFB1', 'Gene', '1672', (83, 88))	('binding', 'Interaction', (156, 163))	('DEFB1', 'Gene', (83, 88))
337207	32149330	LncRNA XIST promotes the progression of laryngeal squamous cell carcinoma via sponging miR-125b-5p to modulate TRIB2 Objective: X inactivate-specific transcript (XIST) is an attractive long noncoding RNA (lncRNA) functioning as an indicator of various human tumors, including laryngeal squamous cell carcinoma (LSCC).	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (50, 73))	('XIST', 'Gene', (7, 11))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (286, 309))	('tumors', 'Phenotype', 'HP:0002664', (258, 264))	('SCC', 'Gene', '6317', (312, 315))	('XIST', 'Gene', '7503', (7, 11))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))	('squamous cell carcinoma', 'Disease', (50, 73))	('XIST', 'Gene', (162, 166))	('SCC', 'Gene', (312, 315))	('tumor', 'Phenotype', 'HP:0002664', (258, 263))	('carcinoma', 'Phenotype', 'HP:0030731', (300, 309))	('tumors', 'Disease', (258, 264))	('squamous cell carcinoma', 'Disease', (286, 309))	('inactivate-specific', 'Var', (130, 149))	('XIST', 'Gene', '7503', (162, 166))	('human', 'Species', '9606', (252, 257))	('tumors', 'Disease', 'MESH:D009369', (258, 264))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (50, 73))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (286, 309))
337209	32149330	Materials and methods: Quantitative real-time polymerase chain reaction (QRT-PCR) was used to detect the expression levels of XIST, miR-125b-5p and TRIB2 in LSCC cells and tissues.	('TRIB2', 'Gene', '28951', (148, 153))	('si', 'Chemical', 'MESH:D012825', (111, 113))	('SCC', 'Gene', '6317', (158, 161))	('miR-125b-5p', 'Var', (132, 143))	('PC', 'CellLine', 'CVCL:0152', (77, 79))	('TRIB2', 'Gene', (148, 153))	('expression', 'MPA', (105, 115))	('SCC', 'Gene', (158, 161))	('miR-125b-5p', 'Chemical', '-', (132, 143))
337211	32149330	The relationship among XIST, miR-125b-5p and tribbles homolog 2 (TRIB2) was predicted by starBase v2.0 or TargetScan and confirmed by Dual-luciferase reporter assay.	('tribbles homolog 2', 'Gene', '28951', (45, 63))	('tribbles homolog 2', 'Gene', (45, 63))	('miR-125b-5p', 'Chemical', '-', (29, 40))	('TRIB2', 'Gene', (65, 70))	('miR-125b-5p', 'Var', (29, 40))	('TRIB2', 'Gene', '28951', (65, 70))
337215	32149330	XIST knockdown markedly repressed cell proliferation, migration and invasion and promoted the apoptosis of LSCC cells and the effects were antagonized by loss of miR-125b-5p.	('miR-125b-5p', 'Chemical', '-', (162, 173))	('cell proliferation', 'CPA', (34, 52))	('knockdown', 'Var', (5, 14))	('SCC', 'Gene', (108, 111))	('promoted', 'PosReg', (81, 89))	('invasion', 'CPA', (68, 76))	('migration', 'CPA', (54, 63))	('miR-125b-5p', 'Var', (162, 173))	('SCC', 'Gene', '6317', (108, 111))	('si', 'Chemical', 'MESH:D012825', (72, 74))	('repressed', 'NegReg', (24, 33))	('apoptosis', 'CPA', (94, 103))	('si', 'Chemical', 'MESH:D012825', (100, 102))
337216	32149330	MiR-125b-5p was a target of XIST in LSCC cells, and it could bind to TRIB2 as well.	('MiR-125b-5p', 'Var', (0, 11))	('TRIB2', 'Gene', '28951', (69, 74))	('SCC', 'Gene', '6317', (37, 40))	('MiR-125b-5p', 'Chemical', '-', (0, 11))	('SCC', 'Gene', (37, 40))	('bind', 'Interaction', (61, 65))	('TRIB2', 'Gene', (69, 74))
337217	32149330	Moreover, XIST-loss-induced down-regulation of TRIB2 could be significantly reversed by miR-125b-5p knockdown.	('down-regulation', 'NegReg', (28, 43))	('miR-125b-5p', 'Chemical', '-', (88, 99))	('TRIB2', 'Gene', (47, 52))	('TRIB2', 'Gene', '28951', (47, 52))	('miR-125b-5p', 'Var', (88, 99))	('si', 'Chemical', 'MESH:D012825', (62, 64))
337219	32149330	Conclusion: LncRNA XIST promoted the malignance of LSCC cells partly through competitively binding to miR-125b-5p, which in turn increased TRIB2 expression.	('miR-125b-5p', 'Var', (102, 113))	('TRIB2', 'Gene', (139, 144))	('increased', 'PosReg', (129, 138))	('SCC', 'Gene', (52, 55))	('TRIB2', 'Gene', '28951', (139, 144))	('expression', 'MPA', (145, 155))	('miR-125b-5p', 'Chemical', '-', (102, 113))	('malignance', 'CPA', (37, 47))	('promoted', 'PosReg', (24, 32))	('binding', 'Interaction', (91, 98))	('SCC', 'Gene', '6317', (52, 55))	('si', 'Chemical', 'MESH:D012825', (6, 8))	('si', 'Chemical', 'MESH:D012825', (151, 153))
337232	32149330	Previous studies demonstrated that miR-125b-5p was notably down-regulated in esophageal squamous cell carcinoma (ESCC) and negatively regulated HMGA2 expression.	('expression', 'MPA', (150, 160))	('si', 'Chemical', 'MESH:D012825', (156, 158))	('esophageal squamous cell carcinoma', 'Disease', (77, 111))	('SCC', 'Gene', (114, 117))	('miR-125b-5p', 'Var', (35, 46))	('HMGA2', 'Gene', '8091', (144, 149))	('down-regulated', 'NegReg', (59, 73))	('negatively regulated', 'NegReg', (123, 143))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (88, 111))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (77, 111))	('SCC', 'Gene', '6317', (114, 117))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('HMGA2', 'Gene', (144, 149))	('miR-125b-5p', 'Chemical', '-', (35, 46))
337233	32149330	Other investigators discovered that miR-125b-5p was a potential biomarker of LSCC.	('miR-125b-5p', 'Chemical', '-', (36, 47))	('SCC', 'Gene', '6317', (78, 81))	('miR-125b-5p', 'Var', (36, 47))	('SCC', 'Gene', (78, 81))
337234	32149330	However, the potential regulatory role of miR-125b-5p and its association with XIST in LSCC have been rarely reported in LSCC.	('SCC', 'Gene', (122, 125))	('association', 'Interaction', (62, 73))	('miR-125b-5p', 'Var', (42, 53))	('SCC', 'Gene', '6317', (122, 125))	('SCC', 'Gene', (88, 91))	('miR-125b-5p', 'Chemical', '-', (42, 53))	('SCC', 'Gene', '6317', (88, 91))
337262	32149330	The pGL3-XIST-WT and pGL3-TRIB2-WT contained the predicted binding sites of miR-125b-5p.	('pGL3', 'Gene', '6391', (21, 25))	('si', 'Chemical', 'MESH:D012825', (67, 69))	('binding', 'Interaction', (59, 66))	('miR-125b-5p', 'Var', (76, 87))	('pGL3', 'Gene', '6391', (4, 8))	('TRIB2', 'Gene', (26, 31))	('TRIB2', 'Gene', '28951', (26, 31))	('pGL3', 'Gene', (4, 8))	('pGL3', 'Gene', (21, 25))	('miR-125b-5p', 'Chemical', '-', (76, 87))
337272	32149330	The volume was measured every 7 d, and the weight of LSCC tumors was measured following injection for 35 d. The tumor tissues were used for the detection of the expression of XIST, miR-125b-5p and TRIB2.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('miR-125b-5p', 'Var', (181, 192))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('LSCC tumors', 'Disease', (53, 64))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('TRIB2', 'Gene', (197, 202))	('XIST', 'Gene', (175, 179))	('si', 'Chemical', 'MESH:D012825', (167, 169))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('TRIB2', 'Gene', '28951', (197, 202))	('miR-125b-5p', 'Chemical', '-', (181, 192))	('tumor', 'Disease', (112, 117))	('LSCC tumors', 'Disease', 'MESH:D009369', (53, 64))
337277	32149330	Further, analysis of 5-year overall survival rate by Kaplan-Meier method revealed that high level XIST was correlated with low survival rate (P = 0.0423) (Figure 1B).	('survival rate', 'MPA', (127, 140))	('low', 'NegReg', (123, 126))	('si', 'Chemical', 'MESH:D012825', (14, 16))	('high level', 'Var', (87, 97))
337289	32149330	To explore whether miR-125b-5p was a target of XIST, Dual-luciferase reporter assay was conducted by co-transfecting wild-type and mutant form of XIST (XIST-WT and XIST-Mut) with miR-NC or miR-125b-5p mimic into AMC-HN-8 and M4E cells, separately.	('miR', 'Gene', '220972', (19, 22))	('miR', 'Gene', (19, 22))	('miR-125b-5p', 'Chemical', '-', (19, 30))	('AMC', 'Chemical', '-', (212, 215))	('mutant', 'Var', (131, 137))	('miR', 'Gene', '220972', (189, 192))	('miR', 'Gene', (189, 192))	('miR', 'Gene', '220972', (179, 182))	('miR', 'Gene', (179, 182))	('miR-125b-5p', 'Chemical', '-', (189, 200))	('M4E', 'CellLine', 'CVCL:U812', (225, 228))
337290	32149330	The luciferase activity was significantly declined in AMC-HN-8 and M4E cells co-transfected with XIST-WT and miR-125b-5p, but no difference occurred in other groups (Figure 3B,C).	('si', 'Chemical', 'MESH:D012825', (28, 30))	('miR-125b-5p', 'Chemical', '-', (109, 120))	('activity', 'MPA', (15, 23))	('AMC', 'Chemical', '-', (54, 57))	('miR-125b-5p', 'Var', (109, 120))	('M4E', 'CellLine', 'CVCL:U812', (67, 70))	('luciferase', 'Enzyme', (4, 14))	('declined', 'NegReg', (42, 50))
337291	32149330	Then the regulatory relationship between miR-125b-5p and XIST was further explored in LSCC cells by transfection of si-XIST.	('si', 'Chemical', 'MESH:D012825', (116, 118))	('SCC', 'Gene', (87, 90))	('si-XIST', 'Var', (116, 123))	('transfection', 'Var', (100, 112))	('SCC', 'Gene', '6317', (87, 90))	('miR-125b-5p', 'Chemical', '-', (41, 52))
337293	32149330	And then, we found that the level of miR-125b-5p was lower in LSCC cells and tissues (Figure 3F,G).	('SCC', 'Gene', (63, 66))	('miR-125b-5p', 'Chemical', '-', (37, 48))	('level', 'MPA', (28, 33))	('SCC', 'Gene', '6317', (63, 66))	('lower', 'NegReg', (53, 58))	('miR-125b-5p', 'Var', (37, 48))
337294	32149330	In general, miR-125b-5p might be a potential tumor suppressor, which was negatively regulated by XIST.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('miR-125b-5p', 'Chemical', '-', (12, 23))	('tumor', 'Disease', (45, 50))	('miR-125b-5p', 'Var', (12, 23))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
337295	32149330	The regulatory role of miR-125b-5p in XIST expression was further confirmed in AMC-HN-8 and M4E cells by transfection of si-XIST with or without anti-miR-125b-5p.	('transfection', 'Var', (105, 117))	('M4E', 'CellLine', 'CVCL:U812', (92, 95))	('AMC', 'Chemical', '-', (79, 82))	('miR-125b-5p', 'Chemical', '-', (150, 161))	('miR-125b-5p', 'Chemical', '-', (23, 34))	('si', 'Chemical', 'MESH:D012825', (121, 123))	('si', 'Chemical', 'MESH:D012825', (49, 51))	('si-XIST', 'Var', (121, 128))
337296	32149330	The qRT-PCR results indicated that miR-125b-5p expression was notably elevated in AMC-HN-8 and M4E cells with loss of XIST, but this phenomenon was obviously overturned by the introduction of anti-miR-125b-5p (Figure 4A,B).	('M4E', 'CellLine', 'CVCL:U812', (95, 98))	('elevated', 'PosReg', (70, 78))	('loss', 'NegReg', (110, 114))	('XIST', 'MPA', (118, 122))	('si', 'Chemical', 'MESH:D012825', (53, 55))	('miR-125b-5p', 'Chemical', '-', (197, 208))	('miR-125b-5p', 'Gene', (35, 46))	('PC', 'CellLine', 'CVCL:0152', (8, 10))	('miR-125b-5p', 'Chemical', '-', (35, 46))	('anti-miR-125b-5p', 'Var', (192, 208))	('AMC', 'Chemical', '-', (82, 85))	('expression', 'MPA', (47, 57))
337297	32149330	Meanwhile, cell proliferation was inhibited in AMC-HN-8 and M4E cells by the transfection of si-XIST, whereas knockdown of miR-125b-5p coupled with XIST down-regulation could abolish si-XIST-mediated cell proliferation arrest (Figure 4C,D).	('abolish', 'NegReg', (175, 182))	('si', 'Chemical', 'MESH:D012825', (93, 95))	('arrest', 'Disease', (219, 225))	('M4E', 'CellLine', 'CVCL:U812', (60, 63))	('down-regulation', 'NegReg', (153, 168))	('AMC', 'Chemical', '-', (47, 50))	('si', 'Chemical', 'MESH:D012825', (183, 185))	('inhibited', 'NegReg', (34, 43))	('cell proliferation', 'CPA', (11, 29))	('miR-125b-5p', 'Chemical', '-', (123, 134))	('arrest', 'Disease', 'MESH:D006323', (219, 225))	('miR-125b-5p', 'Var', (123, 134))	('si-XIST', 'Var', (93, 100))
337298	32149330	Flow cytometry assay demonstrated that anti-miR-125b-5preversed the promoting effect of XIST interference on the apoptosis of LSCC cells (Figure 4E,F; Supplementary Figure S1A,B).	('SCC', 'Gene', (127, 130))	('apoptosis', 'CPA', (113, 122))	('XIST interference', 'MPA', (88, 105))	('SCC', 'Gene', '6317', (127, 130))	('miR-125b-5p', 'Chemical', '-', (44, 55))	('si', 'Chemical', 'MESH:D012825', (119, 121))	('anti-miR-125b-5preversed', 'Var', (39, 63))	('promoting', 'PosReg', (68, 77))
337299	32149330	Similarly, the inhibition of migration and invasion in LSCC cells with XIST loss was restored by knockdown of miR-125b-5p (Figure 4G,H; Supplementary Figure S1C,D).	('inhibition', 'NegReg', (15, 25))	('knockdown', 'Var', (97, 106))	('SCC', 'Gene', (56, 59))	('miR-125b-5p', 'Var', (110, 121))	('migration', 'CPA', (29, 38))	('si', 'Chemical', 'MESH:D012825', (47, 49))	('SCC', 'Gene', '6317', (56, 59))	('miR-125b-5p', 'Chemical', '-', (110, 121))
337303	32149330	As shown in Figure 5B,C, the luciferase activity was markedly decreased in cells treated with TRIB2-WT and miR-125b-5p, compared with cells treated with miR-125b-5p and TRIB2-Mut.	('luciferase', 'Enzyme', (29, 39))	('miR-125b-5p', 'Chemical', '-', (153, 164))	('TRIB2', 'Gene', (169, 174))	('decreased', 'NegReg', (62, 71))	('TRIB2', 'Gene', '28951', (94, 99))	('TRIB2', 'Gene', '28951', (169, 174))	('miR-125b-5p', 'Var', (107, 118))	('activity', 'MPA', (40, 48))	('miR-125b-5p', 'Chemical', '-', (107, 118))	('TRIB2', 'Gene', (94, 99))
337304	32149330	Accordingly, it was found that overexpression of miR-125b-5p could effectively repress TRIB2 expression in AMC-HN-8 and M4E cells (Figure 5D,E).	('TRIB2', 'Gene', '28951', (87, 92))	('overexpression', 'PosReg', (31, 45))	('miR-125b-5p', 'Var', (49, 60))	('M4E', 'CellLine', 'CVCL:U812', (120, 123))	('repress', 'NegReg', (79, 86))	('AMC', 'Chemical', '-', (107, 110))	('si', 'Chemical', 'MESH:D012825', (99, 101))	('expression', 'MPA', (93, 103))	('si', 'Chemical', 'MESH:D012825', (41, 43))	('miR-125b-5p', 'Chemical', '-', (49, 60))	('TRIB2', 'Gene', (87, 92))
337307	32149330	Overall, our results demonstrated that TRIB2 expression could be directly repressed by miR-125b-5p.	('TRIB2', 'Gene', (39, 44))	('TRIB2', 'Gene', '28951', (39, 44))	('miR-125b-5p', 'Var', (87, 98))	('si', 'Chemical', 'MESH:D012825', (51, 53))	('miR-125b-5p', 'Chemical', '-', (87, 98))
337310	32149330	Synchronously, we found that miR-125b-5p repressed cell proliferation and induced cell apoptosis.	('repressed', 'NegReg', (41, 50))	('si', 'Chemical', 'MESH:D012825', (93, 95))	('miR-125b-5p', 'Chemical', '-', (29, 40))	('cell apoptosis', 'CPA', (82, 96))	('cell proliferation', 'CPA', (51, 69))	('miR-125b-5p', 'Var', (29, 40))	('induced', 'PosReg', (74, 81))
337312	32149330	The cell migration and invasion were remarkably suppressed in miR-125b-5p group, but the result was opposite in miR-125b-5p+TRIB2 group, detected by Transwell assay (Figure 6G,H; Supplementary Figure S2C,D).	('invasion', 'CPA', (23, 31))	('miR-125b-5p', 'Var', (62, 73))	('TRIB2', 'Gene', (124, 129))	('TRIB2', 'Gene', '28951', (124, 129))	('cell migration', 'CPA', (4, 18))	('miR-125b-5p', 'Chemical', '-', (112, 123))	('suppressed', 'NegReg', (48, 58))	('miR-125b-5p', 'Chemical', '-', (62, 73))	('si', 'Chemical', 'MESH:D012825', (104, 106))	('si', 'Chemical', 'MESH:D012825', (27, 29))
337313	32149330	To sum up, miR-125b-5p inhibited the malignant potential of LSCC cells through suppressing TRIB2.	('inhibited', 'NegReg', (23, 32))	('SCC', 'Gene', '6317', (61, 64))	('miR-125b-5p', 'Var', (11, 22))	('TRIB2', 'Gene', (91, 96))	('suppressing', 'NegReg', (79, 90))	('TRIB2', 'Gene', '28951', (91, 96))	('miR-125b-5p', 'Chemical', '-', (11, 22))	('SCC', 'Gene', (61, 64))	('si', 'Chemical', 'MESH:D012825', (86, 88))
337314	32149330	Finally, Western blot assay and qRT-PCR were conducted to explore the underlying relationship among lncRNA XIST, miR-125b-5p and TRIB2 in LSCC cells.	('miR-125b-5p', 'Var', (113, 124))	('SCC', 'Gene', '6317', (139, 142))	('TRIB2', 'Gene', (129, 134))	('miR-125b-5p', 'Chemical', '-', (113, 124))	('TRIB2', 'Gene', '28951', (129, 134))	('SCC', 'Gene', (139, 142))	('PC', 'CellLine', 'CVCL:0152', (36, 38))
337317	32149330	Based on the above results, we discovered that lncRNA XIST down-regulation could inhibit TRIB2 expression via directly sponging miR-125b-5p in LSCC cells.	('miR-125b-5p', 'Chemical', '-', (128, 139))	('si', 'Chemical', 'MESH:D012825', (101, 103))	('SCC', 'Gene', (144, 147))	('inhibit', 'NegReg', (81, 88))	('miR-125b-5p', 'Var', (128, 139))	('SCC', 'Gene', '6317', (144, 147))	('TRIB2', 'Gene', (89, 94))	('down-regulation', 'NegReg', (59, 74))	('TRIB2', 'Gene', '28951', (89, 94))	('expression', 'MPA', (95, 105))
337319	32149330	The volume and weight of LSCC tumors were markedly lesser in sh-XIST group in comparison with that in sh-NC group (Figure 8A,B).	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('sh-XIST', 'Var', (61, 68))	('LSCC tumors', 'Disease', 'MESH:D009369', (25, 36))	('lesser', 'NegReg', (51, 57))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('LSCC tumors', 'Disease', (25, 36))
337321	32149330	As shown in Figure 8C-E, the level of XIST and the RNA and protein expression of TRIB2 were decreased in sh-XIST group, while the expression of miR-125b-5p revealed an opposite phenomenon.	('si', 'Chemical', 'MESH:D012825', (73, 75))	('si', 'Chemical', 'MESH:D012825', (136, 138))	('miR-125b-5p', 'Chemical', '-', (144, 155))	('level of XIST', 'MPA', (29, 42))	('TRIB2', 'Gene', (81, 86))	('sh-XIST', 'Var', (105, 112))	('TRIB2', 'Gene', '28951', (81, 86))	('si', 'Chemical', 'MESH:D012825', (172, 174))	('decreased', 'NegReg', (92, 101))
337326	32149330	These discoveries were in conformity with the report of Xiao et al.. Additionally, silencing XIST gene slowed down cell proliferation, as well as weakened anti-apoptosis, migration and invasion abilities of LSCC cells, which further determined the promotion role of XIST in LSCC.	('XIST gene', 'Gene', (93, 102))	('si', 'Chemical', 'MESH:D012825', (189, 191))	('invasion abilities', 'CPA', (185, 203))	('silencing', 'Var', (83, 92))	('anti-apoptosis', 'CPA', (155, 169))	('SCC', 'Gene', (275, 278))	('si', 'Chemical', 'MESH:D012825', (166, 168))	('SCC', 'Gene', '6317', (208, 211))	('SCC', 'Gene', '6317', (275, 278))	('slowed down', 'NegReg', (103, 114))	('SCC', 'Gene', (208, 211))	('cell proliferation', 'CPA', (115, 133))	('si', 'Chemical', 'MESH:D012825', (83, 85))	('weakened', 'NegReg', (146, 154))
337328	32149330	Analogously, exosomal miRNA-503 was accumulated by loss of XIST resulting in tumor metastasis was repressed, which provided an attractive doctoring for breast cancer in the report of Xing et al..	('tumor metastasis', 'Disease', 'MESH:D009362', (77, 93))	('tumor metastasis', 'Disease', (77, 93))	('loss', 'Var', (51, 55))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('breast cancer', 'Disease', 'MESH:D001943', (152, 165))	('XIST', 'Gene', (59, 63))	('miRNA-503', 'Chemical', '-', (22, 31))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('breast cancer', 'Disease', (152, 165))	('breast cancer', 'Phenotype', 'HP:0003002', (152, 165))
337331	32149330	But oppositely, reduction of miR-125b-5p was detected in LSCC cells and miR-125b-5p regulated cell glycolysis and growth by directly targeted hexokinase-2 (HK2), a key enzyme for glycolysis process.	('hexokinase-2', 'Gene', (142, 154))	('SCC', 'Gene', (58, 61))	('HK2', 'Gene', (156, 159))	('regulated', 'Reg', (84, 93))	('HK2', 'Gene', '3099', (156, 159))	('miR-125b-5p', 'Var', (72, 83))	('si', 'Chemical', 'MESH:D012825', (8, 10))	('si', 'Chemical', 'MESH:D012825', (186, 188))	('miR-125b-5p', 'Chemical', '-', (29, 40))	('SCC', 'Gene', '6317', (58, 61))	('si', 'Chemical', 'MESH:D012825', (106, 108))	('targeted', 'Reg', (133, 141))	('cell glycolysis', 'MPA', (94, 109))	('hexokinase-2', 'Gene', '3099', (142, 154))	('miR-125b-5p', 'Chemical', '-', (72, 83))	('growth', 'MPA', (114, 120))
337332	32149330	Using online software, we manifested miR-125b-5p, as a target of XIST, was notably low-expressed in LSCC cells (AMC-HN-8 and M4E cells) and tissues corresponding to Lokman et al..	('miR-125b-5p', 'Chemical', '-', (37, 48))	('si', 'Chemical', 'MESH:D012825', (1, 3))	('SCC', 'Gene', (101, 104))	('M4E', 'CellLine', 'CVCL:U812', (125, 128))	('AMC', 'Chemical', '-', (112, 115))	('low-expressed', 'NegReg', (83, 96))	('SCC', 'Gene', '6317', (101, 104))	('miR-125b-5p', 'Var', (37, 48))
337333	32149330	The small interference XIST (si-XIST) was transfected into LSCC cells in our study, which induced obviously up-regulation of miR-125b-5p, thereby arresting LSCC cells growth and metastasis.	('SCC', 'Gene', (157, 160))	('miR-125b-5p', 'Chemical', '-', (125, 136))	('si', 'Chemical', 'MESH:D012825', (29, 31))	('SCC', 'Gene', '6317', (60, 63))	('up-regulation', 'PosReg', (108, 121))	('SCC', 'Gene', '6317', (157, 160))	('miR-125b-5p', 'Var', (125, 136))	('arrest', 'Disease', 'MESH:D006323', (146, 152))	('arrest', 'Disease', (146, 152))	('SCC', 'Gene', (60, 63))	('si', 'Chemical', 'MESH:D012825', (185, 187))
337334	32149330	Concurrently, anti-miR-125b-5p expression could overtly abolish the XIST-loss effect.	('miR-125b-5p', 'Chemical', '-', (19, 30))	('si', 'Chemical', 'MESH:D012825', (37, 39))	('abolish', 'NegReg', (56, 63))	('XIST-loss effect', 'MPA', (68, 84))	('anti-miR-125b-5p expression', 'Var', (14, 41))
337339	32149330	We found that has-miR-125b-5p bound to 3'UTR of TRIB2 and the low-expression of TRIB2 was detected in LSCC cells with up-regulated miR-125b-5p expression.	('miR-125b-5p', 'Chemical', '-', (18, 29))	('si', 'Chemical', 'MESH:D012825', (149, 151))	('TRIB2', 'Gene', '28951', (80, 85))	('miR-125b-5p', 'Chemical', '-', (131, 142))	('SCC', 'Gene', (103, 106))	('up-regulated', 'PosReg', (118, 130))	('has-miR-125b-5p', 'Var', (14, 29))	('SCC', 'Gene', '6317', (103, 106))	('TRIB2', 'Gene', (48, 53))	('miR-125b-5p', 'Var', (131, 142))	('si', 'Chemical', 'MESH:D012825', (72, 74))	('TRIB2', 'Gene', '28951', (48, 53))	('bound', 'Interaction', (30, 35))	('TRIB2', 'Gene', (80, 85))
337342	32149330	Furthermore, the results of our rescue experiments demonstrated that up-regulation of TRIB2 reversely adjusted the inhibitive effect of miR-125b-5p overexpression on proliferation, anti-apoptosis and metastasis in LSCC cells.	('inhibitive', 'NegReg', (115, 125))	('TRIB2', 'Gene', (86, 91))	('up-regulation', 'PosReg', (69, 82))	('anti-apoptosis', 'CPA', (181, 195))	('metastasis', 'CPA', (200, 210))	('TRIB2', 'Gene', '28951', (86, 91))	('miR-125b-5p', 'Chemical', '-', (136, 147))	('si', 'Chemical', 'MESH:D012825', (207, 209))	('proliferation', 'CPA', (166, 179))	('si', 'Chemical', 'MESH:D012825', (158, 160))	('SCC', 'Gene', (215, 218))	('si', 'Chemical', 'MESH:D012825', (192, 194))	('miR-125b-5p', 'Var', (136, 147))	('SCC', 'Gene', '6317', (215, 218))
337343	32149330	Mechanistically, TRIB2 expression was distinctly down-regulated in cells treated with si-XIST, whereas loss of miR-125b-5p evidently abolished the effect.	('miR-125b-5p', 'Chemical', '-', (111, 122))	('si', 'Chemical', 'MESH:D012825', (29, 31))	('loss', 'Var', (103, 107))	('down-regulated', 'NegReg', (49, 63))	('miR-125b-5p', 'Var', (111, 122))	('TRIB2', 'Gene', (17, 22))	('si-XIST', 'Var', (86, 93))	('si', 'Chemical', 'MESH:D012825', (86, 88))	('TRIB2', 'Gene', '28951', (17, 22))	('expression', 'MPA', (23, 33))
337345	32149330	Thus, these results revealed that silencing XIST down-regulated TRIB2 expression through sponging miR-125b-5p in LSCC cells.	('si', 'Chemical', 'MESH:D012825', (76, 78))	('SCC', 'Gene', (114, 117))	('down-regulated', 'NegReg', (49, 63))	('miR-125b-5p', 'Chemical', '-', (98, 109))	('expression', 'MPA', (70, 80))	('TRIB2', 'Gene', (64, 69))	('si', 'Chemical', 'MESH:D012825', (34, 36))	('SCC', 'Gene', '6317', (114, 117))	('silencing', 'Var', (34, 43))	('TRIB2', 'Gene', '28951', (64, 69))
337349	32149330	Both XIST and TRIB2 contained the binding sites of miR-125b-5p, which was firstly predicted in our study.	('binding', 'Interaction', (34, 41))	('miR-125b-5p', 'Var', (51, 62))	('si', 'Chemical', 'MESH:D012825', (42, 44))	('TRIB2', 'Gene', (14, 19))	('TRIB2', 'Gene', '28951', (14, 19))	('miR-125b-5p', 'Chemical', '-', (51, 62))
337351	32149330	On the other hand, miR-125b-5p negatively regulated TRIB2 and reversed the promotive action of XIST on TRIB2 expression in LSCC cells.	('TRIB2', 'Gene', '28951', (52, 57))	('TRIB2', 'Gene', '28951', (103, 108))	('promotive action of XIST', 'MPA', (75, 99))	('expression', 'MPA', (109, 119))	('negatively', 'NegReg', (31, 41))	('miR-125b-5p', 'Chemical', '-', (19, 30))	('si', 'Chemical', 'MESH:D012825', (115, 117))	('SCC', 'Gene', (124, 127))	('SCC', 'Gene', '6317', (124, 127))	('regulated', 'Reg', (42, 51))	('TRIB2', 'Gene', (103, 108))	('miR-125b-5p', 'Var', (19, 30))	('TRIB2', 'Gene', (52, 57))
337354	32149330	It was first proved that XIST acted as a novel sponge of miR-125b-5p that simultaneously targeted TRIB2.	('miR-125b-5p', 'Chemical', '-', (57, 68))	('TRIB2', 'Gene', (98, 103))	('si', 'Chemical', 'MESH:D012825', (74, 76))	('TRIB2', 'Gene', '28951', (98, 103))	('miR-125b-5p', 'Var', (57, 68))	('targeted', 'Reg', (89, 97))
337364	31490413	Decision curve analysis yielded a range of threshold probabilities (0.020-0.177 and 0.021-0.133 for patients with esophageal adenocarcinoma and squamous cell carcinoma, respectively) at which the clinical net benefit of the risk model was larger than those of hypothetical all-screening and no-screening scenarios.	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (144, 167))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004941', (114, 139))	('esophageal adenocarcinoma', 'Disease', (114, 139))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (114, 139))	('patients', 'Species', '9606', (100, 108))	('larger', 'PosReg', (239, 245))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (158, 167))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (144, 167))	('squamous cell carcinoma', 'Disease', (144, 167))	('0.021-0.133', 'Var', (84, 95))
337431	30651768	Downregulation of TBL1XR1 produced the opposite results.	('TBL1XR1', 'Gene', (18, 25))	('Downregulation', 'Var', (0, 14))	('TBL1XR1', 'Gene', '79718', (18, 25))
337443	30651768	Aberrant expression of TBLIXR1 was associated with carcinogenesis and tumor progression by regulating multiple signaling pathways, including the nuclear factor-kappaB, nuclear receptors, Wnt/beta-catenin, and Notch pathways.	('nuclear receptors', 'Pathway', (168, 185))	('Aberrant expression', 'Var', (0, 19))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('regulating', 'Reg', (91, 101))	('associated', 'Reg', (35, 45))	('tumor', 'Disease', (70, 75))	('beta-catenin', 'Gene', (191, 203))	('nuclear factor-kappaB', 'Pathway', (145, 166))	('beta-catenin', 'Gene', '1499', (191, 203))	('Notch pathways', 'Pathway', (209, 223))	('carcinogenesis', 'Disease', 'MESH:D063646', (51, 65))	('TBLIXR1', 'Gene', (23, 30))	('carcinogenesis', 'Disease', (51, 65))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
337457	30651768	Stable cell lines expressing TBL1XR1-siRNA [negative control, (H1703-NC), H1703-siRNA-1, H1703-siRNA-2] were generated with 1 ug/ml puromycin.	('puromycin', 'Chemical', 'MESH:D011691', (132, 141))	('TBL1XR1', 'Gene', '79718', (29, 36))	('H1703-siRNA-1', 'Var', (74, 87))	('TBL1XR1', 'Gene', (29, 36))
337482	30651768	Conversely, knockdown of TBL1XR1 (H1703-siRNA-1, H1703-siRNA-2) significantly attenuated lung SCC cell proliferation, leading to a decrease in cell number compared with H1703-NC (P<0.05; Fig.	('TBL1XR1', 'Gene', '79718', (25, 32))	('cell number', 'CPA', (143, 154))	('SCC', 'Gene', (94, 97))	('SCC', 'Gene', '6317', (94, 97))	('TBL1XR1', 'Gene', (25, 32))	('decrease', 'NegReg', (131, 139))	('H1703-siRNA-2', 'Var', (49, 62))	('attenuated', 'NegReg', (78, 88))
337488	30651768	The wound healing assays and Transwell invasion assays demonstrated that TBL1XR1 knockdown significantly decreased the migration and invasion ability of H1703 cells (Fig.	('invasion ability', 'CPA', (133, 149))	('TBL1XR1', 'Gene', '79718', (73, 80))	('knockdown', 'Var', (81, 90))	('TBL1XR1', 'Gene', (73, 80))	('decreased', 'NegReg', (105, 114))
337492	30651768	TBL1XR1 knockdown reduced the number of irregular branched structures in both H1703-siRNA cells.	('TBL1XR1', 'Gene', (0, 7))	('knockdown', 'Var', (8, 17))	('TBL1XR1', 'Gene', '79718', (0, 7))	('reduced', 'NegReg', (18, 25))
337503	30651768	Abnormal TBLIXR1 expression is associated with the occurrence and development of malignant tumors.	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('malignant tumors', 'Disease', (81, 97))	('expression', 'MPA', (17, 27))	('associated', 'Reg', (31, 41))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('Abnormal', 'Var', (0, 8))	('malignant tumors', 'Disease', 'MESH:D018198', (81, 97))	('TBLIXR1', 'Gene', (9, 16))
337509	30651768	Furthermore, overexpression of TBL1XR1 promoted the proliferation, invasion and migration of lung SCC cells in vitro, while knockdown of TBL1XR1 significantly inhibited tumorigenicity, by promoting invasion and migration, and proliferation in lung SCC cells.	('migration', 'CPA', (80, 89))	('TBL1XR1', 'Gene', (137, 144))	('promoting', 'PosReg', (188, 197))	('knockdown', 'Var', (124, 133))	('promoted', 'PosReg', (39, 47))	('TBL1XR1', 'Gene', '79718', (31, 38))	('invasion', 'CPA', (67, 75))	('SCC', 'Gene', '6317', (98, 101))	('tumor', 'Disease', (169, 174))	('SCC', 'Gene', '6317', (248, 251))	('TBL1XR1', 'Gene', (31, 38))	('proliferation', 'CPA', (226, 239))	('SCC', 'Gene', (98, 101))	('proliferation', 'CPA', (52, 65))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('SCC', 'Gene', (248, 251))	('migration', 'CPA', (211, 220))	('inhibited', 'NegReg', (159, 168))	('invasion', 'CPA', (198, 206))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('TBL1XR1', 'Gene', '79718', (137, 144))
337629	29872311	Aberrant gene promoter methylation contributes to NSCLC, and PRDM is a tumor suppressor gene family that possesses histone methyltransferase activity.	('PRDM', 'Gene', (61, 65))	('Aberrant', 'Var', (0, 8))	('NSCLC', 'Phenotype', 'HP:0030358', (50, 55))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('contributes', 'Reg', (35, 46))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('NSCLC', 'Disease', (50, 55))	('tumor', 'Disease', (71, 76))	('NSCLC', 'Disease', 'MESH:D002289', (50, 55))
337630	29872311	This study aimed to investigate whether aberrant methylation of PRDM promoter is involved in NSCLC.	('NSCLC', 'Disease', (93, 98))	('aberrant methylation', 'Var', (40, 60))	('involved', 'Reg', (81, 89))	('NSCLC', 'Disease', 'MESH:D002289', (93, 98))	('NSCLC', 'Phenotype', 'HP:0030358', (93, 98))	('PRDM promoter', 'Gene', (64, 77))
337635	29872311	In LSCC patients, methylation of PRDM2 and PRDM16 was correlated with smoking status and methylation of PRDM5 was correlated with tumor differentiation.	('PRDM2', 'Gene', (33, 38))	('PRDM2', 'Gene', '7799', (33, 38))	('correlated', 'Reg', (114, 124))	('methylation', 'Var', (89, 100))	('PRDM5', 'Gene', (104, 109))	('methylation', 'MPA', (18, 29))	('LSCC', 'Disease', (3, 7))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('PRDM16', 'Gene', (43, 49))	('correlated', 'Reg', (54, 64))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('LSCC', 'Phenotype', 'HP:0030359', (3, 7))	('PRDM16', 'Gene', '63976', (43, 49))	('PRDM5', 'Gene', '11107', (104, 109))	('tumor', 'Disease', (130, 135))	('patients', 'Species', '9606', (8, 16))
337637	29872311	Smoking may be an important cause of PRDM2 and PRDM16 methylation in NSCLC.	('PRDM16', 'Gene', '63976', (47, 53))	('methylation', 'Var', (54, 65))	('NSCLC', 'Disease', (69, 74))	('cause', 'Reg', (28, 33))	('NSCLC', 'Disease', 'MESH:D002289', (69, 74))	('PRDM2', 'Gene', '7799', (37, 42))	('PRDM16', 'Gene', (47, 53))	('NSCLC', 'Phenotype', 'HP:0030358', (69, 74))	('PRDM2', 'Gene', (37, 42))
337644	29872311	Epigenetic mechanisms such as aberrant DNA methylation, histone modification, chromatin remodeling, and functional non-coding RNAs have contributed to the pathogenesis of lung cancer, providing additional markers for early detection, monitoring, prognosis, risk assessment, and personalized treatment of lung cancer.	('lung cancer', 'Disease', (304, 315))	('lung cancer', 'Phenotype', 'HP:0100526', (304, 315))	('aberrant', 'Var', (30, 38))	('lung cancer', 'Disease', (171, 182))	('lung cancer', 'Phenotype', 'HP:0100526', (171, 182))	('cancer', 'Phenotype', 'HP:0002664', (309, 315))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('contributed', 'Reg', (136, 147))	('lung cancer', 'Disease', 'MESH:D008175', (304, 315))	('lung cancer', 'Disease', 'MESH:D008175', (171, 182))
337645	29872311	PR domain zinc finger proteins (PRDMs) are evolutionarily conserved zinc finger transcription factors with tissue-specific expression profile and they play key roles during cell differentiation, organ development, and human diseases.	('PR domain', 'Var', (0, 9))	('roles', 'Reg', (160, 165))	('human', 'Species', '9606', (218, 223))	('play', 'Reg', (151, 155))
337646	29872311	PRDM genes are usually inactivated in hematological malignancies and solid cancers, and the inactivation mechanisms include promoter methylation, homozygous deletions, frameshift mutation, missense mutations, and PR domain deletion.	('hematological malignancies and solid cancers', 'Disease', 'MESH:D019337', (38, 82))	('promoter methylation', 'MPA', (124, 144))	('cancers', 'Phenotype', 'HP:0002664', (75, 82))	('PR domain deletion', 'Var', (213, 231))	('missense mutations', 'Var', (189, 207))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('hematological malignancies', 'Phenotype', 'HP:0004377', (38, 64))	('PRDM genes', 'Gene', (0, 10))	('frameshift mutation', 'Var', (168, 187))	('inactivated', 'NegReg', (23, 34))
337649	29872311	We hypothesized that methylation-mediated PRDM inactivation may participate in the pathogenesis of NSCLC.	('methylation-mediated', 'Var', (21, 41))	('NSCLC', 'Phenotype', 'HP:0030358', (99, 104))	('participate', 'Reg', (64, 75))	('PRDM', 'Gene', (42, 46))	('NSCLC', 'Disease', (99, 104))	('inactivation', 'NegReg', (47, 59))	('NSCLC', 'Disease', 'MESH:D002289', (99, 104))
337651	29872311	Our results demonstrated that DNA methylation of PRDM2, PRDM5, and PRDM16 was correlated with the malignancy of NSCLC.	('methylation', 'Var', (34, 45))	('malignancy of NSCLC', 'Disease', (98, 117))	('NSCLC', 'Phenotype', 'HP:0030358', (112, 117))	('PRDM5', 'Gene', (56, 61))	('malignancy of NSCLC', 'Disease', 'MESH:D009369', (98, 117))	('PRDM16', 'Gene', (67, 73))	('PRDM2', 'Gene', '7799', (49, 54))	('correlated', 'Reg', (78, 88))	('PRDM2', 'Gene', (49, 54))	('PRDM16', 'Gene', '63976', (67, 73))	('PRDM5', 'Gene', '11107', (56, 61))
337675	29872311	In patients with LSCC, PRDM2 gene methylation (with fully methylated and partially methylated) frequency was 67.3%, 50.0%, and 17.3%, respectively, in tumor tissues, adjacent tissues, and distant lung tissues.	('PRDM2', 'Gene', (23, 28))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('methylation', 'Var', (34, 45))	('LSCC', 'Disease', (17, 21))	('LSCC', 'Phenotype', 'HP:0030359', (17, 21))	('tumor', 'Disease', (151, 156))	('patients', 'Species', '9606', (3, 11))	('PRDM2', 'Gene', '7799', (23, 28))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
337676	29872311	In patients with LAC, PRDM2 gene methylation frequency was 78.3%, 34.8%, and 21.7%, respectively, in tumor tissues, adjacent tissues, and distant lung tissues.	('PRDM2', 'Gene', (22, 27))	('PRDM2', 'Gene', '7799', (22, 27))	('methylation', 'Var', (33, 44))	('LAC', 'Disease', (17, 20))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('patients', 'Species', '9606', (3, 11))	('LAC', 'Phenotype', 'HP:0030078', (17, 20))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
337677	29872311	In patients with LSCC, PRDM5 gene methylation was 73.1%, 44.2%, and 21.1%, respectively, in tumor tissues, adjacent tissues, and distant lung tissues.	('PRDM5', 'Gene', '11107', (23, 28))	('methylation', 'Var', (34, 45))	('LSCC', 'Disease', (17, 21))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('LSCC', 'Phenotype', 'HP:0030359', (17, 21))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('patients', 'Species', '9606', (3, 11))	('tumor', 'Disease', (92, 97))	('PRDM5', 'Gene', (23, 28))
337678	29872311	In patients with LAC, PRDM5 gene methylation frequency was 82.6%, 47.8%, and 17.4%, respectively, in tumor tissues, adjacent tissues, and distant lung tissues.	('methylation', 'Var', (33, 44))	('PRDM5', 'Gene', '11107', (22, 27))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('patients', 'Species', '9606', (3, 11))	('PRDM5', 'Gene', (22, 27))	('LAC', 'Phenotype', 'HP:0030078', (17, 20))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
337679	29872311	In patients with LSCC, PRDM16 gene methylation was 80.8%, 40.4%, and 21.2%, respectively, in tumor tissues, adjacent tissues, and distant lung tissues.	('PRDM16', 'Gene', '63976', (23, 29))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('LSCC', 'Disease', (17, 21))	('LSCC', 'Phenotype', 'HP:0030359', (17, 21))	('tumor', 'Disease', (93, 98))	('patients', 'Species', '9606', (3, 11))	('methylation', 'Var', (35, 46))	('PRDM16', 'Gene', (23, 29))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
337680	29872311	In patients with LAC, PRDM16 gene methylation frequency was 82.6%, 52.2%, and 30.4%, respectively, in tumor tissues, adjacent tissues, and distant lung tissues.	('tumor', 'Disease', (102, 107))	('methylation', 'Var', (34, 45))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('patients', 'Species', '9606', (3, 11))	('PRDM16', 'Gene', (22, 28))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('PRDM16', 'Gene', '63976', (22, 28))	('LAC', 'Phenotype', 'HP:0030078', (17, 20))
337685	29872311	The results showed that PRDM2 and PRDM16 gene methylation in LSCC patients was related to smoking, and methylation status of PRDM5 gene was associated with tumor differentiation of LSCC (Table 8).	('methylation status', 'Var', (103, 121))	('methylation', 'Var', (46, 57))	('associated with', 'Reg', (140, 155))	('PRDM16', 'Gene', '63976', (34, 40))	('LSCC', 'Disease', (61, 65))	('LSCC', 'Disease', (181, 185))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('PRDM2', 'Gene', (24, 29))	('PRDM2', 'Gene', '7799', (24, 29))	('LSCC', 'Phenotype', 'HP:0030359', (61, 65))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('PRDM5', 'Gene', (125, 130))	('patients', 'Species', '9606', (66, 74))	('LSCC', 'Phenotype', 'HP:0030359', (181, 185))	('tumor', 'Disease', (156, 161))	('related', 'Reg', (79, 86))	('PRDM5', 'Gene', '11107', (125, 130))	('PRDM16', 'Gene', (34, 40))
337690	29872311	Tobacco exposure is directly related to gene methylation abnormality and the inactivation of tumor suppressor gene expression.	('gene methylation abnormality', 'Var', (40, 68))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Disease', (93, 98))	('Tobacco', 'Species', '4097', (0, 7))	('expression', 'MPA', (115, 125))	('inactivation', 'NegReg', (77, 89))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
337691	29872311	Thus, abnormal methylation plays an important role in the pathogenesis of lung cancer and provides a reference for early diagnosis and individualized treatment of lung cancer.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('lung cancer', 'Disease', 'MESH:D008175', (163, 174))	('lung cancer', 'Disease', (74, 85))	('abnormal', 'Var', (6, 14))	('lung cancer', 'Phenotype', 'HP:0100526', (74, 85))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('lung cancer', 'Disease', 'MESH:D008175', (74, 85))	('lung cancer', 'Phenotype', 'HP:0100526', (163, 174))	('lung cancer', 'Disease', (163, 174))	('methylation', 'MPA', (15, 26))
337696	29872311	These results suggest that PRDM2, PRDM5, and PRDM16 expression may be suppressed due to gene hypermethylation in lung cancer.	('PRDM16', 'Gene', (45, 51))	('PRDM5', 'Gene', (34, 39))	('lung cancer', 'Disease', (113, 124))	('lung cancer', 'Phenotype', 'HP:0100526', (113, 124))	('PRDM16', 'Gene', '63976', (45, 51))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('expression', 'MPA', (52, 62))	('suppressed', 'NegReg', (70, 80))	('PRDM5', 'Gene', '11107', (34, 39))	('PRDM2', 'Gene', (27, 32))	('PRDM2', 'Gene', '7799', (27, 32))	('lung cancer', 'Disease', 'MESH:D008175', (113, 124))	('gene hypermethylation', 'Var', (88, 109))
337698	29872311	Our results showed that in LSCC, PRDM2 and PRDM16 gene methylation was correlated with the smoking of the patients, indicating that smoking may be an important cause of PRDM2 and PRDM16 gene methylation in squamous cell carcinoma of the lung.	('PRDM2', 'Gene', (33, 38))	('PRDM2', 'Gene', '7799', (33, 38))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (206, 229))	('squamous cell carcinoma of the lung', 'Phenotype', 'HP:0030359', (206, 241))	('cause', 'Reg', (160, 165))	('PRDM16', 'Gene', (179, 185))	('carcinoma of the lung', 'Phenotype', 'HP:0100526', (220, 241))	('squamous cell carcinoma of the lung', 'Disease', 'MESH:D002294', (206, 241))	('PRDM16', 'Gene', '63976', (179, 185))	('PRDM16', 'Gene', (43, 49))	('patients', 'Species', '9606', (106, 114))	('PRDM2', 'Gene', '7799', (169, 174))	('LSCC', 'Phenotype', 'HP:0030359', (27, 31))	('carcinoma', 'Phenotype', 'HP:0030731', (220, 229))	('PRDM16', 'Gene', '63976', (43, 49))	('squamous cell carcinoma of the lung', 'Disease', (206, 241))	('methylation', 'Var', (191, 202))	('PRDM2', 'Gene', (169, 174))
337699	29872311	Yoon et al reported that the single-nucleotide polymorphism of PRDM2 gene was associated with the risk of lung cancer.	('associated', 'Reg', (78, 88))	('lung cancer', 'Disease', (106, 117))	('lung cancer', 'Phenotype', 'HP:0100526', (106, 117))	('PRDM2', 'Gene', '7799', (63, 68))	('PRDM2', 'Gene', (63, 68))	('single-nucleotide polymorphism', 'Var', (29, 59))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('lung cancer', 'Disease', 'MESH:D008175', (106, 117))
337703	29872311	PRDM5 may be involved in the regulation of differentiation of LSCC and PRDM5 gene methylation may help evaluate the prognosis of squamous cell carcinoma of the lung.	('PRDM5', 'Gene', '11107', (71, 76))	('methylation', 'Var', (82, 93))	('help', 'Reg', (98, 102))	('squamous cell carcinoma of the lung', 'Disease', (129, 164))	('PRDM5', 'Gene', '11107', (0, 5))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (129, 152))	('squamous cell carcinoma of the lung', 'Phenotype', 'HP:0030359', (129, 164))	('squamous cell carcinoma of the lung', 'Disease', 'MESH:D002294', (129, 164))	('LSCC', 'Phenotype', 'HP:0030359', (62, 66))	('carcinoma', 'Phenotype', 'HP:0030731', (143, 152))	('PRDM5', 'Gene', (71, 76))	('carcinoma of the lung', 'Phenotype', 'HP:0100526', (143, 164))	('PRDM5', 'Gene', (0, 5))
337704	29872311	The methylation of PRDM5 resulted in decreased expression of PRDM5 in nasopharyngeal carcinoma, esophageal cancer, gastric cancer, cervical cancer, colon cancer, and other tumors.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('PRDM5', 'Gene', '11107', (19, 24))	('gastric cancer', 'Phenotype', 'HP:0012126', (115, 129))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (70, 94))	('PRDM5', 'Gene', (61, 66))	('colon cancer', 'Disease', (148, 160))	('tumors', 'Phenotype', 'HP:0002664', (172, 178))	('PRDM5', 'Gene', (19, 24))	('cervical cancer', 'Disease', 'MESH:D002583', (131, 146))	('expression', 'MPA', (47, 57))	('cervical cancer', 'Disease', (131, 146))	('gastric cancer', 'Disease', (115, 129))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('tumors', 'Disease', (172, 178))	('methylation', 'Var', (4, 15))	('nasopharyngeal carcinoma', 'Disease', (70, 94))	('esophageal cancer', 'Disease', 'MESH:D004938', (96, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('colon cancer', 'Phenotype', 'HP:0003003', (148, 160))	('decreased', 'NegReg', (37, 46))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('gastric cancer', 'Disease', 'MESH:D013274', (115, 129))	('nasopharyngeal carcinoma', 'Disease', 'MESH:D000077274', (70, 94))	('tumors', 'Disease', 'MESH:D009369', (172, 178))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('PRDM5', 'Gene', '11107', (61, 66))	('esophageal cancer', 'Disease', (96, 113))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('colon cancer', 'Disease', 'MESH:D015179', (148, 160))
337706	29872311	Our study provided the first evidence that the methylation of PRDM5 gene is involved in the pathogenesis of lung cancer and is related to tumor differentiation in patients with LSCC.	('related to', 'Reg', (127, 137))	('patients', 'Species', '9606', (163, 171))	('lung cancer', 'Disease', 'MESH:D008175', (108, 119))	('tumor', 'Disease', (138, 143))	('LSCC', 'Phenotype', 'HP:0030359', (177, 181))	('methylation', 'Var', (47, 58))	('PRDM5', 'Gene', (62, 67))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('lung cancer', 'Disease', (108, 119))	('lung cancer', 'Phenotype', 'HP:0100526', (108, 119))	('involved', 'Reg', (76, 84))	('PRDM5', 'Gene', '11107', (62, 67))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('LSCC', 'Disease', (177, 181))
337729	28184177	Further array analysis demonstrated that the transfection of BNC2 into A549 cells resulted in the increased expression of 139 genes and the down-regulation of 13 genes.	('down-regulation', 'NegReg', (140, 155))	('transfection', 'Var', (45, 57))	('increased', 'PosReg', (98, 107))	('BNC2', 'Gene', (61, 65))	('expression', 'MPA', (108, 118))	('A549', 'CellLine', 'CVCL:0023', (71, 75))
337747	28184177	Genetic variations in the BNC2 gene have been associated with skin cancer risk, susceptibility to ovarian cancer and prostate cancer development.	('men', 'Species', '9606', (140, 143))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('ovarian cancer', 'Disease', 'MESH:D010051', (98, 112))	('prostate cancer', 'Disease', 'MESH:D011471', (117, 132))	('skin cancer', 'Phenotype', 'HP:0008069', (62, 73))	('prostate cancer', 'Phenotype', 'HP:0012125', (117, 132))	('ovarian cancer', 'Disease', (98, 112))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('skin cancer', 'Disease', 'MESH:D012878', (62, 73))	('skin cancer', 'Disease', (62, 73))	('BNC2', 'Gene', (26, 30))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('associated', 'Reg', (46, 56))	('Genetic variations', 'Var', (0, 18))	('ovarian cancer', 'Phenotype', 'HP:0100615', (98, 112))	('prostate cancer', 'Disease', (117, 132))
337748	28184177	The deletion of the BNC2 gene and the corresponding decreased expression of BNC2 mRNA have been detected in Barrett's esophagus, hepatocellular carcinoma and high-grade serous ovarian carcinoma.	('serous ovarian carcinoma', 'Disease', 'MESH:D010051', (169, 193))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (176, 193))	('detected', 'Reg', (96, 104))	('BNC2', 'Gene', (76, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (184, 193))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (129, 153))	('decreased', 'NegReg', (52, 61))	('expression', 'MPA', (62, 72))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (129, 153))	('mRNA', 'MPA', (81, 85))	('BNC2', 'Gene', (20, 24))	('deletion', 'Var', (4, 12))	('hepatocellular carcinoma', 'Disease', (129, 153))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('serous ovarian carcinoma', 'Disease', (169, 193))	("Barrett's esophagus", 'Disease', (108, 127))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (108, 127))
337795	28184177	The transfection of BNC2 to A549 cells led to the up-regulation of numerous ISGs, of which a subset (XAF1, IRF7, OAS family) is known to inhibit cancer growth and promote the apoptosis of cancer cells.	('cancer', 'Disease', (145, 151))	('XAF1', 'Gene', (101, 105))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('IRF7', 'Gene', '3665', (107, 111))	('ISGs', 'Protein', (76, 80))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('XAF1', 'Gene', '54739', (101, 105))	('IRF7', 'Gene', (107, 111))	('transfection', 'Var', (4, 16))	('BNC2', 'Gene', (20, 24))	('cancer', 'Disease', (188, 194))	('OAS', 'Disease', (113, 116))	('promote', 'PosReg', (163, 170))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('up-regulation', 'PosReg', (50, 63))	('apoptosis', 'CPA', (175, 184))	('OAS', 'Disease', 'MESH:C537769', (113, 116))	('A549', 'CellLine', 'CVCL:0023', (28, 32))	('inhibit', 'NegReg', (137, 144))
337819	27056547	In this study, we attempted to identify and validate the differential expression of miRNAs in oral squamous cell carcinoma (OSCC), to correlate their expression with the clinico-pathological profile of tumours and to identify the signaling pathways through which the aberrantly expressed miRNAs effect tumourigenesis.	('miR', 'Gene', '220972', (84, 87))	('tumours', 'Phenotype', 'HP:0002664', (202, 209))	('aberrantly expressed', 'Var', (267, 287))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('tumours', 'Disease', 'MESH:D009369', (202, 209))	('miR', 'Gene', (84, 87))	('miR', 'Gene', '220972', (288, 291))	('tumour', 'Phenotype', 'HP:0002664', (202, 208))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (94, 122))	('tumour', 'Disease', 'MESH:D009369', (202, 208))	('oral squamous cell carcinoma', 'Disease', (94, 122))	('tumour', 'Disease', (202, 208))	('miR', 'Gene', (288, 291))	('tumour', 'Phenotype', 'HP:0002664', (302, 308))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (99, 122))	('tumour', 'Disease', 'MESH:D009369', (302, 308))	('effect', 'Reg', (295, 301))	('tumour', 'Disease', (302, 308))	('tumours', 'Disease', (202, 209))
337901	27056547	Evidently, let-7a, let-7d and let-7f was downregulated across 95, 84 and 89 % of tumours respectively, with a strong tendency for co-occurrence.	('let-7f', 'Var', (30, 36))	('tumours', 'Phenotype', 'HP:0002664', (81, 88))	('let-7a', 'Gene', (11, 17))	('let-7d', 'Gene', '406886', (19, 25))	('downregulated', 'NegReg', (41, 54))	('let-7d', 'Gene', (19, 25))	('tumours', 'Disease', 'MESH:D009369', (81, 88))	('tumours', 'Disease', (81, 88))	('tumour', 'Phenotype', 'HP:0002664', (81, 87))
337909	27056547	The relative expression of let-7d was significantly high in males compared to females, while that of let-7a and let-7f was higher in tongue carcinoma compared to gingivo-buccal tumours.	('tongue carcinoma', 'Disease', 'MESH:D014062', (133, 149))	('tongue carcinoma', 'Disease', (133, 149))	('expression', 'MPA', (13, 23))	('higher', 'PosReg', (123, 129))	('let-7d', 'Gene', '406886', (27, 33))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))	('tongue carcinoma', 'Phenotype', 'HP:0030415', (133, 149))	('gingivo-buccal tumours', 'Disease', 'MESH:D055093', (162, 184))	('gingivo-buccal tumours', 'Disease', (162, 184))	('let-7d', 'Gene', (27, 33))	('tumours', 'Phenotype', 'HP:0002664', (177, 184))	('high', 'PosReg', (52, 56))	('tumour', 'Phenotype', 'HP:0002664', (177, 183))	('let-7f', 'Var', (112, 118))
337910	27056547	Significantly elevated levels of miR-223 and miR-1275 was seen in the advanced tumour group (III-IV and T3-T4) Vs the less severe group (I-II and T1-T2).	('miR-1275', 'Gene', '100302123', (45, 53))	('T3-T4', 'Var', (104, 109))	('miR-223', 'Gene', '407008', (33, 40))	('tumour', 'Phenotype', 'HP:0002664', (79, 85))	('miR-1275', 'Gene', (45, 53))	('levels', 'MPA', (23, 29))	('tumour', 'Disease', 'MESH:D009369', (79, 85))	('elevated', 'PosReg', (14, 22))	('miR-223', 'Gene', (33, 40))	('tumour', 'Disease', (79, 85))
337914	27056547	Further, high level of miR-29b was seen in the T3-T4 group relative to T1-T2 tumour category.	('tumour', 'Disease', 'MESH:D009369', (77, 83))	('miR-29b', 'Gene', (23, 30))	('tumour', 'Disease', (77, 83))	('miR-29b', 'Gene', '407024', (23, 30))	('T3-T4', 'Var', (47, 52))	('tumour', 'Phenotype', 'HP:0002664', (77, 83))
337924	27056547	Some of the notable oncogenes that had multiple miRNA interactions were BCL2 (let-7a, miR-16, and miR-143), HMGA2 (let-7a, let-7d, and let-7f), CCND1 (let-7f, miR-16), MYC (let-7a, let-7f), HRAS and KRAS (let-7a, miR-143), and KMT2A (let-d, miR-16).	('let-7a', 'Var', (173, 179))	('miR-16', 'Gene', (86, 92))	('miR', 'Gene', '220972', (241, 244))	('let-7a', 'Var', (205, 211))	('miR-16', 'Gene', '51573', (159, 165))	('MYC', 'Gene', (168, 171))	('CCND1', 'Gene', '595', (144, 149))	('let-7a', 'Var', (115, 121))	('miR', 'Gene', '220972', (98, 101))	('miR-143', 'Gene', '406935', (98, 105))	('miR-143', 'Gene', (98, 105))	('miR', 'Gene', (241, 244))	('let-7f', 'Var', (135, 141))	('miR-16', 'Gene', '51573', (86, 92))	('BCL2', 'Gene', (72, 76))	('miR', 'Gene', '220972', (159, 162))	('CCND1', 'Gene', (144, 149))	('KMT2A', 'Gene', '4297', (227, 232))	('KRAS', 'Gene', '3845', (199, 203))	('HMGA2', 'Gene', (108, 113))	('miR', 'Gene', '220972', (213, 216))	('miR-16', 'Gene', (241, 247))	('let-7f', 'Var', (151, 157))	('miR', 'Gene', (98, 101))	('BCL2', 'Gene', '596', (72, 76))	('miR', 'Gene', '220972', (86, 89))	('miR-143', 'Gene', (213, 220))	('miR-143', 'Gene', '406935', (213, 220))	('let-7d', 'Gene', '406886', (123, 129))	('MYC', 'Gene', '4609', (168, 171))	('miR', 'Gene', '220972', (48, 51))	('miR', 'Gene', (159, 162))	('KRAS', 'Gene', (199, 203))	('miR', 'Gene', (213, 216))	('HRAS', 'Gene', '3265', (190, 194))	('miR-16', 'Gene', (159, 165))	('miR', 'Gene', (86, 89))	('miR-16', 'Gene', '51573', (241, 247))	('HRAS', 'Gene', (190, 194))	('KMT2A', 'Gene', (227, 232))	('let-7d', 'Gene', (123, 129))	('miR', 'Gene', (48, 51))	('HMGA2', 'Gene', '8091', (108, 113))
337929	27056547	Remarkably, 48 genes at different levels of the PI3K/Akt signaling pathway were targeted by the tumour suppressor miRs let-7a, let-7d, let-7f, miR-16, and/or miR-143 (Fig.	('miR-16', 'Gene', (143, 149))	('miR', 'Gene', '220972', (114, 117))	('let-7d', 'Gene', '406886', (127, 133))	('miR-16', 'Gene', '51573', (143, 149))	('let-7f', 'Var', (135, 141))	('Akt', 'Gene', (53, 56))	('miR', 'Gene', (114, 117))	('let-7d', 'Gene', (127, 133))	('Akt', 'Gene', '207', (53, 56))	('miR', 'Gene', '220972', (158, 161))	('miR-143', 'Gene', '406935', (158, 165))	('miR', 'Gene', '220972', (143, 146))	('tumour', 'Phenotype', 'HP:0002664', (96, 102))	('miR-143', 'Gene', (158, 165))	('targeted', 'Reg', (80, 88))	('tumour', 'Disease', 'MESH:D009369', (96, 102))	('tumour', 'Disease', (96, 102))	('miR', 'Gene', (158, 161))	('miR', 'Gene', (143, 146))	('let-7a', 'Var', (119, 125))
337931	27056547	Based on these results, we propose that the aberrantly expressed miRNAs may simultaneously elicit the constitutive activation of PI3K/Akt pathway and the suppression of the p53 pathway.	('activation', 'PosReg', (115, 125))	('p53', 'Gene', (173, 176))	('Akt', 'Gene', '207', (134, 137))	('p53', 'Gene', '7157', (173, 176))	('aberrantly expressed', 'Var', (44, 64))	('miR', 'Gene', '220972', (65, 68))	('miR', 'Gene', (65, 68))	('suppression', 'NegReg', (154, 165))	('Akt', 'Gene', (134, 137))
337953	27056547	Even the precursor molecules of let-7a and let-7d were reported to be down regulated in HNSCC and additionally, low levels of let-7d had an association with poorer prognosis.	('let-7d', 'Gene', '406886', (43, 49))	('let-7d', 'Gene', (43, 49))	('HNSCC', 'Disease', (88, 93))	('let-7d', 'Gene', (126, 132))	('HNSCC', 'Phenotype', 'HP:0012288', (88, 93))	('down regulated', 'NegReg', (70, 84))	('let-7d', 'Gene', '406886', (126, 132))	('let-7a', 'Gene', (32, 38))	('low levels', 'Var', (112, 122))
337971	27056547	In oral cancer, miR-203 was observed to be downregulated due to DNA hypermethylation.	('downregulated', 'NegReg', (43, 56))	('oral cancer', 'Disease', 'MESH:D009062', (3, 14))	('DNA hypermethylation', 'Var', (64, 84))	('miR-203', 'Gene', (16, 23))	('miR-203', 'Gene', '406986', (16, 23))	('oral cancer', 'Disease', (3, 14))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))
337985	27056547	Considering that the human genome contains ~ 30,000 protein coding genes, there is a possibility of up to 7.07 % of them being deregulated by the cumulatively action of let-7a, let-7d, let-7f, miR-16, miR-29b, miR-142-3p, miR-144, miR-203, miR-223, miR-21 and miR-143.	('miR-29b', 'Gene', (201, 208))	('miR-144', 'Gene', (222, 229))	('let-7d', 'Gene', (177, 183))	('miR', 'Gene', (260, 263))	('miR', 'Gene', (222, 225))	('miR-223', 'Gene', (240, 247))	('to 7', 'Species', '1214577', (103, 107))	('miR', 'Gene', '220972', (210, 213))	('miR', 'Gene', '220972', (201, 204))	('miR', 'Gene', '220972', (193, 196))	('miR', 'Gene', '220972', (249, 252))	('let-7f', 'Var', (185, 191))	('miR', 'Gene', '220972', (240, 243))	('miR-21', 'Gene', '406991', (249, 255))	('miR', 'Gene', (210, 213))	('let-7a', 'Gene', (169, 175))	('miR', 'Gene', (201, 204))	('miR-223', 'Gene', '407008', (240, 247))	('miR', 'Gene', (193, 196))	('miR', 'Gene', '220972', (231, 234))	('miR', 'Gene', (249, 252))	('miR-29b', 'Gene', '407024', (201, 208))	('miR-144', 'Gene', '406936', (222, 229))	('miR-203', 'Gene', (231, 238))	('miR', 'Gene', (240, 243))	('miR-16', 'Gene', (193, 199))	('miR-21', 'Gene', (249, 255))	('miR', 'Gene', (231, 234))	('miR', 'Gene', '220972', (260, 263))	('miR-143', 'Gene', '406935', (260, 267))	('miR', 'Gene', '220972', (222, 225))	('miR-143', 'Gene', (260, 267))	('let-7d', 'Gene', '406886', (177, 183))	('human', 'Species', '9606', (21, 26))	('miR-203', 'Gene', '406986', (231, 238))	('deregulated', 'PosReg', (127, 138))	('miR-16', 'Gene', '51573', (193, 199))
337989	27056547	The PI3K/PTEN/AKT/mTOR signaling axis is critical for maintaining the homeostasis in proliferation, metabolism, migration, apoptosis, etc., and its deregulation or constitutive activation due to mutations has been implicated in oral carcinogenesis.	('mTOR', 'Gene', (18, 22))	('mTOR', 'Gene', '2475', (18, 22))	('oral carcinogenesis', 'Disease', 'MESH:D063646', (228, 247))	('rat', 'Species', '10116', (115, 118))	('oral carcinogenesis', 'Disease', (228, 247))	('AKT', 'Gene', (14, 17))	('PTEN', 'Gene', (9, 13))	('PTEN', 'Gene', '5728', (9, 13))	('rat', 'Species', '10116', (92, 95))	('deregulation', 'PosReg', (148, 160))	('mutations', 'Var', (195, 204))	('homeostasis', 'MPA', (70, 81))	('AKT', 'Gene', '207', (14, 17))
337994	27056547	The pivotal role of p53 in tumour suppression is evident from the fact that more than 50 % of HNSCCs harbour inactivating p53 mutations or loss of its genomic loci.	('p53', 'Gene', (20, 23))	('p53', 'Gene', '7157', (20, 23))	('HNSCCs', 'Disease', (94, 100))	('tumour', 'Phenotype', 'HP:0002664', (27, 33))	('loss', 'NegReg', (139, 143))	('p53', 'Gene', '7157', (122, 125))	('HNSCC', 'Phenotype', 'HP:0012288', (94, 99))	('inactivating', 'Var', (109, 121))	('tumour', 'Disease', 'MESH:D009369', (27, 33))	('mutations', 'Var', (126, 135))	('tumour', 'Disease', (27, 33))	('p53', 'Gene', (122, 125))
337997	27056547	Since p53 mutations are relatively infrequent in the Indian OSCC population compared to the world, we propose that miRNA mediated repression may operate as an alternate mechanism of p53 inactivation.	('p53', 'Gene', (6, 9))	('p53', 'Gene', '7157', (6, 9))	('rat', 'Species', '10116', (148, 151))	('p53', 'Gene', '7157', (182, 185))	('mutations', 'Var', (10, 19))	('p53', 'Gene', (182, 185))	('miR', 'Gene', '220972', (115, 118))	('miR', 'Gene', (115, 118))
337998	27056547	In summary, aberrant expression and dysfunction of miRNAs may be reckoned as a crucial step in oral cancer initiation and progression.	('oral cancer initiation', 'Disease', 'MESH:D009062', (95, 117))	('oral cancer initiation', 'Disease', (95, 117))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('miR', 'Gene', '220972', (51, 54))	('miR', 'Gene', (51, 54))	('dysfunction', 'Var', (36, 47))	('aberrant expression', 'Var', (12, 31))
338010	27056547	Taken together, the results suggest that alterations in the cellular level of miRNAs might have a major impact on the proteome of the cancer cell thereby contributing to oral tumorigenesis.	('tumor', 'Disease', (175, 180))	('contributing to', 'Reg', (154, 169))	('miR', 'Gene', '220972', (78, 81))	('miR', 'Gene', (78, 81))	('cellular level', 'MPA', (60, 74))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('proteome', 'MPA', (118, 126))	('rat', 'Species', '10116', (45, 48))	('impact', 'Reg', (104, 110))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('alterations', 'Var', (41, 52))
338012	31390735	Lasting DNA Damage and Aberrant DNA Repair Gene Expression Profile Are Associated with Post-Chronic Cadmium Exposure in Human Bronchial Epithelial Cells Cadmium (Cd) is a widespread environmental pollutant and carcinogen.	('Human', 'Species', '9606', (120, 125))	('Cd', 'Chemical', 'MESH:D002104', (162, 164))	('Cadmium', 'Chemical', 'MESH:D002104', (153, 160))	('DNA Repair Gene', 'Gene', (32, 47))	('Cadmium', 'Chemical', 'MESH:D002104', (100, 107))	('Aberrant DNA Repair Gene Expression', 'Phenotype', 'HP:0003254', (23, 58))	('Associated', 'Reg', (71, 81))	('Aberrant', 'Var', (23, 31))
338027	31390735	Although the exact mechanisms of Cd carcinogenesis remain elusive, researchers have unveiled that Cd is likely to exert its deleterious effects on cells through multiple mechanisms, including induction of oxidative stress and inflammation, inhibition of apoptosis, aberration of gene expression, alteration of DNA methylation, and interference with DNA repair system.	('inhibition', 'NegReg', (240, 250))	('gene expression', 'Protein', (279, 294))	('Cd', 'Chemical', 'MESH:D002104', (33, 35))	('induction', 'Reg', (192, 201))	('oxidative stress', 'MPA', (205, 221))	('interference', 'NegReg', (331, 343))	('DNA methylation', 'Protein', (310, 325))	('carcinogenesis', 'Disease', (36, 50))	('aberration', 'Var', (265, 275))	('apoptosis', 'CPA', (254, 263))	('Cd', 'Chemical', 'MESH:D002104', (98, 100))	('inflammation', 'Disease', 'MESH:D007249', (226, 238))	('oxidative stress', 'Phenotype', 'HP:0025464', (205, 221))	('inflammation', 'Disease', (226, 238))	('carcinogenesis', 'Disease', 'MESH:D063646', (36, 50))	('alteration', 'Reg', (296, 306))
338029	31390735	Interestingly, so far, evidence of Cd interference is overwhelmingly available only for the repair pathways of single-stranded DNA (ssDNA) damage (e.g., base excision repair (BER), nucleotide excision repair (NER), and mismatch repair (MMR)), but very limited for double-stranded DNA (dsDNA) damage such as homologous recombinational repair (HRR) and non-homologous end-joining (NHEJ).	('base excision', 'MPA', (153, 166))	('single-stranded', 'Var', (111, 126))	('Cd', 'Chemical', 'MESH:D002104', (35, 37))
338077	31390735	We compared the growth rates of both CR0 and PM cells and discovered that CR0 cells had decreased cell proliferation when cultured in normal Cd-free growth medium (Figure 1B).	('cell proliferation', 'CPA', (98, 116))	('CR0', 'Var', (74, 77))	('decreased', 'NegReg', (88, 97))	('CR0', 'Chemical', '-', (74, 77))	('Cd', 'Chemical', 'MESH:D002104', (141, 143))	('CR0', 'Chemical', '-', (37, 40))
338089	31390735	This was an expected result since H2O2 is known for inducing severe DNA damage and is often used as a positive control in comet assays.	('inducing', 'PosReg', (52, 60))	('H2O2', 'Chemical', 'MESH:D006861', (34, 38))	('H2O2', 'Var', (34, 38))	('comet', 'Species', '302767', (122, 127))
338091	31390735	Taken together, these results not only show that the CR0 cells have a lower DNA repair capacity, but also indicates that they were likely to be more susceptible to DNA damage-inducing agents.	('lower', 'NegReg', (70, 75))	('CR0', 'Var', (53, 56))	('CR0', 'Chemical', '-', (53, 56))	('DNA repair capacity', 'MPA', (76, 95))
338128	31390735	Results indicated that the % tail DNA and tail extent moment of the CR0 cells were always greater than the PM cells when treated with the same concentration of gemcitabine or vinorelbine tartrate.	('vinorelbine tartrate', 'Chemical', 'MESH:D000077235', (175, 195))	('greater', 'PosReg', (90, 97))	('CR0', 'Var', (68, 71))	('tail extent moment', 'CPA', (42, 60))	('gemcitabine', 'Chemical', 'MESH:C056507', (160, 171))	('CR0', 'Chemical', '-', (68, 71))
338178	31390735	We showed that the post-chronic Cd-exposed human lung cells had retained Cd-resistance property, aberrant expression of DNA repair genes, reduced DNA repair capacity, and were more susceptible to chemotherapeutic and DNA damaging agents.	('Cd', 'Chemical', 'MESH:D002104', (73, 75))	('DNA repair genes', 'Gene', (120, 136))	('reduced', 'NegReg', (138, 145))	('Cd', 'Chemical', 'MESH:D002104', (32, 34))	('expression', 'MPA', (106, 116))	('aberrant', 'Var', (97, 105))	('Cd-resistance property', 'CPA', (73, 95))	('more', 'PosReg', (176, 180))	('DNA repair', 'MPA', (146, 156))	('human', 'Species', '9606', (43, 48))
338184	31390735	Figure S2: Western blot of histones extracted from CR0 and PM cells probed with H2AFX (1:1000, A11361, ABClonal), gammaH2AFX (1:1000, AP0099, ABClonal), or H3 (1:2000, 4499, CST) antibody.	('H2AFX', 'Gene', (119, 124))	('H2AFX', 'Gene', '3014', (119, 124))	('CST', 'Gene', (174, 177))	('CR0', 'Chemical', '-', (51, 54))	('1:1000', 'Var', (87, 93))	('H2AFX', 'Gene', '3014', (80, 85))	('H2AFX', 'Gene', (80, 85))	('CST', 'Gene', '106478911', (174, 177))	('gammaH2AFX', 'Chemical', '-', (114, 124))	('1:1000', 'Var', (126, 132))
338188	31390735	Antibodies were purchased from Santa Cruz Biotechnology: ATR (sc-515173); ATM (sc-377293); CDK7 (sc-365075); ERCC1 (sc-17809); LIG3 (sc-390922); NEIL1 (sc-271164); NEIL3 (sc-393703); PARP1 (sc-8007); PMS2 (sc-25315); SMUG1 (sc-377370); SUMO1 (sc-5308), GeneTex: ERCC2 (GTX108948); TP53 (GTX70214), Sigma-Aldrich: ACTB (A5441), ABClonal: H2AFX (A11361), and Cell Signaling Technology: H3 (4499).	('CDK7', 'Gene', '1022', (91, 95))	('NEIL3', 'Gene', '55247', (164, 169))	('ERCC1', 'Gene', (109, 114))	('PARP1', 'Gene', '142', (183, 188))	('SUMO1', 'Gene', '7341', (236, 241))	('ATR', 'Gene', (57, 60))	('LIG3', 'Gene', '3980', (127, 131))	('PMS2', 'Gene', '5395', (200, 204))	('GTX108948', 'Var', (269, 278))	('A11361', 'Var', (344, 350))	('NEIL3', 'Gene', (164, 169))	('SUMO1', 'Gene', (236, 241))	('ERCC2', 'Gene', (262, 267))	('NEIL1', 'Gene', '79661', (145, 150))	('TP53', 'Gene', (281, 285))	('ERCC2', 'Gene', '2068', (262, 267))	('GTX70214', 'Var', (287, 295))	('H2AFX', 'Gene', (337, 342))	('SMUG1', 'Gene', (217, 222))	('ATR', 'Gene', '545', (57, 60))	('H2AFX', 'Gene', '3014', (337, 342))	('PARP1', 'Gene', (183, 188))	('ACTB', 'Gene', '60', (313, 317))	('PMS2', 'Gene', (200, 204))	('NEIL1', 'Gene', (145, 150))	('ERCC1', 'Gene', '2067', (109, 114))	('SMUG1', 'Gene', '23583', (217, 222))	('CDK7', 'Gene', (91, 95))	('ACTB', 'Gene', (313, 317))	('TP53', 'Gene', '7157', (281, 285))	('LIG3', 'Gene', (127, 131))
338205	29151950	And lung squamous cell carcinoma (SCC) patients presenting high MCM5 expression had shorter OS (P = 0.015).	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (4, 32))	('SCC', 'Gene', (34, 37))	('patients', 'Species', '9606', (39, 47))	('SCC', 'Phenotype', 'HP:0002860', (34, 37))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (4, 32))	('carcinoma', 'Phenotype', 'HP:0030731', (23, 32))	('SCC', 'Gene', '6317', (34, 37))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (9, 32))	('lung squamous cell carcinoma', 'Disease', (4, 32))	('high', 'Var', (59, 63))	('MCM5', 'Gene', '4174', (64, 68))	('OS', 'Chemical', '-', (92, 94))	('MCM5', 'Gene', (64, 68))
338229	29151950	The slides were blocked with 10% normal goat serum for 30 min at 37C and washed and incubated overnight at 4C with mouse monoclonal antibody against MCM2 (1:200; 10513-1-AP, Proteintech Group, Inc. Chicago, IL, USA), MCM5 (1:200; 11703-1-AP, Proteintech Group, Inc. Chicago, IL, USA), or MCM6 (1:200; 13347-2-AP, Proteintech Group, Inc. Chicago, IL, USA).	('MCM2', 'Gene', (149, 153))	('goat', 'Species', '9925', (40, 44))	('MCM6', 'Gene', (288, 292))	('1:200; 13347-2-AP', 'Var', (294, 311))	('mouse', 'Species', '10090', (115, 120))	('MCM5', 'Gene', (217, 221))	('MCM6', 'Gene', '4175', (288, 292))	('1:200; 10513-1-AP', 'Var', (155, 172))	('MCM5', 'Gene', '4174', (217, 221))	('MCM2', 'Gene', '4171', (149, 153))
338260	29151950	High MCM3 expression was reported to have association with poor prognosis in medulloblastoma and glioma, and showed high expression in carcinomas of colon, cervix, stomach, kidney, breast, but not in lung cancer.	('breast', 'Disease', (181, 187))	('medulloblastoma and glioma', 'Disease', 'MESH:D008527', (77, 103))	('lung cancer', 'Disease', 'MESH:D008175', (200, 211))	('medulloblastoma', 'Phenotype', 'HP:0002885', (77, 92))	('High', 'Var', (0, 4))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('carcinomas of colon', 'Disease', 'MESH:D015179', (135, 154))	('carcinomas', 'Phenotype', 'HP:0030731', (135, 145))	('expression', 'MPA', (121, 131))	('MCM3', 'Gene', (5, 9))	('MCM3', 'Gene', '4172', (5, 9))	('lung cancer', 'Disease', (200, 211))	('lung cancer', 'Phenotype', 'HP:0100526', (200, 211))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('glioma', 'Phenotype', 'HP:0009733', (97, 103))	('carcinomas of colon', 'Disease', (135, 154))
338263	29151950	Overexpression of MCM5 protein has been found to be significantly associated with the progression and prognosis of several human cancers, such as breast cancer, colorectal cancer, and oral squamous cell carcinoma.	('colorectal cancer', 'Disease', (161, 178))	('human', 'Species', '9606', (123, 128))	('cancers', 'Phenotype', 'HP:0002664', (129, 136))	('associated with', 'Reg', (66, 81))	('cancers', 'Disease', (129, 136))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('Overexpression', 'Var', (0, 14))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (184, 212))	('oral squamous cell carcinoma', 'Disease', (184, 212))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('protein', 'Protein', (23, 30))	('breast cancer', 'Phenotype', 'HP:0003002', (146, 159))	('colorectal cancer', 'Phenotype', 'HP:0003003', (161, 178))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (189, 212))	('MCM5', 'Gene', '4174', (18, 22))	('cancers', 'Disease', 'MESH:D009369', (129, 136))	('breast cancer', 'Disease', 'MESH:D001943', (146, 159))	('MCM5', 'Gene', (18, 22))	('breast cancer', 'Disease', (146, 159))	('carcinoma', 'Phenotype', 'HP:0030731', (203, 212))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('colorectal cancer', 'Disease', 'MESH:D015179', (161, 178))
338274	27321186	The PKCiota gene PRKCI is targeted for frequent tumor-specific copy number gain (CNG) in both lung squamous cell carcinoma (LSCC) and ovarian serous carcinoma (OSC).	('PKC', 'Gene', '112476', (4, 7))	('PRKCI', 'Gene', '5584', (17, 22))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('ovarian serous carcinoma', 'Disease', (134, 158))	('OSC', 'Phenotype', 'HP:0012887', (160, 163))	('gain', 'PosReg', (75, 79))	('PKC', 'Gene', (4, 7))	('ovarian serous carcinoma', 'Disease', 'MESH:D010051', (134, 158))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (94, 122))	('copy number', 'Var', (63, 74))	('LSCC', 'Phenotype', 'HP:0030359', (124, 128))	('tumor', 'Disease', (48, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (149, 158))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (99, 122))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (94, 122))	('lung squamous cell carcinoma', 'Disease', (94, 122))	('PRKCI', 'Gene', (17, 22))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
338279	27321186	Lentiviral shRNA-mediated knock down (KD) of PKCiota leads to decreased nuclear YAP1 and increased YAP1 binding to angiomotin (AMOT), which sequesters YAP1 in the cytoplasm.	('YAP1', 'Gene', (151, 155))	('PKC', 'Gene', (45, 48))	('YAP1', 'Gene', (99, 103))	('YAP1', 'Gene', '10413', (99, 103))	('YAP1', 'Gene', '10413', (151, 155))	('decreased', 'NegReg', (62, 71))	('PKC', 'Gene', '112476', (45, 48))	('angiomotin', 'Gene', '154796', (115, 125))	('binding', 'Interaction', (104, 111))	('YAP1', 'Gene', (80, 84))	('YAP1', 'Gene', '10413', (80, 84))	('knock down', 'Var', (26, 36))	('increased', 'PosReg', (89, 98))	('angiomotin', 'Gene', (115, 125))
338280	27321186	Biochemical analysis reveals that PKCiota directly phosphorylates AMOT at a unique site, Thr750, whose phosphorylation inhibits YAP1 binding.	('PKC', 'Gene', (34, 37))	('PKC', 'Gene', '112476', (34, 37))	('inhibits', 'NegReg', (119, 127))	('YAP1', 'Gene', (128, 132))	('YAP1', 'Gene', '10413', (128, 132))	('Thr750', 'Chemical', '-', (89, 95))	('binding', 'Interaction', (133, 140))	('phosphorylation', 'Var', (103, 118))
338288	27321186	LSCC tumors harbor frequent CNGs in the PKCiota gene, PRKCI.	('tumors', 'Disease', (5, 11))	('tumors', 'Disease', 'MESH:D009369', (5, 11))	('PRKCI', 'Gene', '5584', (54, 59))	('CNGs', 'Var', (28, 32))	('PRKCI', 'Gene', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('LSCC', 'Disease', (0, 4))	('LSCC', 'Phenotype', 'HP:0030359', (0, 4))	('PKC', 'Gene', (40, 43))	('PKC', 'Gene', '112476', (40, 43))	('tumors', 'Phenotype', 'HP:0002664', (5, 11))
338301	27321186	Lentiviral shRNA-mediated knock down (KD) of PKCiota using a previously characterized and validated shRNA targeting the 3'UTR of PKCiota3 led to a significant depletion of PKCiota mRNA (Fig 1B).	('PKC', 'Gene', (172, 175))	('PKC', 'Gene', (45, 48))	('depletion', 'MPA', (159, 168))	('PKC', 'Gene', '112476', (172, 175))	('PKC', 'Gene', '112476', (45, 48))	('PKC', 'Gene', (129, 132))	('knock down', 'Var', (26, 36))	('PKC', 'Gene', '112476', (129, 132))
338325	27321186	As expected, expression of a constitutively active WW domain YAP1 mutant, which is incapable of binding AMOT, rescues clonal expansion and soft agar colony formation in YAP1 KD OSC cells (Fig 3B and C).	('soft agar colony formation', 'CPA', (139, 165))	('mutant', 'Var', (66, 72))	('YAP1', 'Gene', '10413', (169, 173))	('agar', 'Chemical', 'MESH:D000362', (144, 148))	('YAP1', 'Gene', '10413', (61, 65))	('rescues', 'PosReg', (110, 117))	('OSC', 'Phenotype', 'HP:0012887', (177, 180))	('YAP1', 'Gene', (169, 173))	('clonal expansion', 'CPA', (118, 134))	('YAP1', 'Gene', (61, 65))
338329	27321186	To assess whether YAP1 is sufficient downstream of PKCiota to maintain transformed growth we knocked down PKCiota in YAP1 KD OVCAR3 cells (PKCiota/YAP1 KD), and then expressed wild-type YAP1, WW mutant YAP1 or an empty control vector in these cells (Fig 4A).	('PKC', 'Gene', (106, 109))	('YAP1', 'Gene', (202, 206))	('PKC', 'Gene', (51, 54))	('YAP1', 'Gene', (147, 151))	('PKC', 'Gene', '112476', (106, 109))	('YAP1', 'Gene', '10413', (202, 206))	('YAP1', 'Gene', '10413', (147, 151))	('YAP1', 'Gene', (18, 22))	('YAP1', 'Gene', '10413', (18, 22))	('PKC', 'Gene', '112476', (51, 54))	('YAP1', 'Gene', (117, 121))	('YAP1', 'Gene', '10413', (117, 121))	('YAP1', 'Gene', (186, 190))	('YAP1', 'Gene', '10413', (186, 190))	('PKC', 'Gene', (139, 142))	('PKC', 'Gene', '112476', (139, 142))	('knocked', 'Var', (93, 100))
338331	27321186	Expression of wild-type YAP1 was unable to rescue soft agar growth or clonal expansion, whereas constitutively active WW mutant YAP1 led to a partial rescue of these phenotypes.	('YAP1', 'Gene', (24, 28))	('mutant', 'Var', (121, 127))	('YAP1', 'Gene', '10413', (24, 28))	('YAP1', 'Gene', (128, 132))	('YAP1', 'Gene', '10413', (128, 132))	('agar', 'Chemical', 'MESH:D000362', (55, 59))	('soft agar growth', 'CPA', (50, 66))	('clonal expansion', 'CPA', (70, 86))
338334	27321186	Interestingly, expression of exogenous WW mutant YAP1, but not wild-type YAP1, in PKCiota/YAP1 KD cells restores expression of CYR61, ANKRD1, and CTGF; furthermore, neither YAP1 allele restores expression of MMP10 (Fig 4D).	('MMP10', 'Gene', (208, 213))	('CYR61', 'Gene', '3491', (127, 132))	('mutant', 'Var', (42, 48))	('ANKRD1', 'Gene', '27063', (134, 140))	('CTGF', 'Gene', '1490', (146, 150))	('YAP1', 'Gene', (73, 77))	('YAP1', 'Gene', (49, 53))	('YAP1', 'Gene', (90, 94))	('PKC', 'Gene', '112476', (82, 85))	('expression', 'MPA', (113, 123))	('ANKRD1', 'Gene', (134, 140))	('CTGF', 'Gene', (146, 150))	('CYR61', 'Gene', (127, 132))	('YAP1', 'Gene', '10413', (173, 177))	('restores', 'PosReg', (104, 112))	('PKC', 'Gene', (82, 85))	('YAP1', 'Gene', (173, 177))	('MMP10', 'Gene', '4319', (208, 213))	('YAP1', 'Gene', '10413', (49, 53))	('YAP1', 'Gene', '10413', (90, 94))	('YAP1', 'Gene', '10413', (73, 77))	('expression', 'MPA', (194, 204))
338348	27321186	The effect of AMOT130 on nuclear YAP1 was specific since only cells expressing Flag-tagged AMOT130 exhibited decreased nuclear YAP1 staining.	('decreased', 'NegReg', (109, 118))	('AMOT130', 'Var', (91, 98))	('YAP1', 'Gene', '10413', (127, 131))	('YAP1', 'Gene', '10413', (33, 37))	('YAP1', 'Gene', (33, 37))	('YAP1', 'Gene', (127, 131))
338353	27321186	Expression of AMOT130, but not AMOT80, led to significant inhibition of soft agar colony formation (Fig 6A), oncosphere growth (Fig 6B) and clonal expansion (Fig 6C) of OSC cells.	('soft agar colony formation', 'CPA', (72, 98))	('AMOT80', 'Gene', (31, 37))	('oncosphere', 'Chemical', '-', (109, 119))	('clonal expansion', 'CPA', (140, 156))	('oncosphere growth', 'CPA', (109, 126))	('OSC', 'Phenotype', 'HP:0012887', (169, 172))	('inhibition', 'NegReg', (58, 68))	('AMOT80', 'Gene', '154796', (31, 37))	('AMOT130', 'Var', (14, 21))	('agar', 'Chemical', 'MESH:D000362', (77, 81))
338357	27321186	Analysis revealed three phosphorylated sites on PKCiota-phosphorylated AMOT, Thr536, Ser538 and Thr750 (Fig 7A), that were not detected in AMOT in the absence of PKCiota.	('Thr536', 'Chemical', '-', (77, 83))	('Ser538', 'Var', (85, 91))	('PKC', 'Gene', (48, 51))	('PKC', 'Gene', '112476', (48, 51))	('PKC', 'Gene', (162, 165))	('PKC', 'Gene', '112476', (162, 165))	('Ser538', 'Chemical', '-', (85, 91))	('Thr750', 'Var', (96, 102))	('Thr750', 'Chemical', '-', (96, 102))	('Thr536', 'Var', (77, 83))
338358	27321186	To assess the functional role of these phosphorylation sites, we generated Flag-tagged AMOT130 mutants in which both T536 and S538, or T750, were mutagenized to alanine to ablate phosphorylation (T536/S538A and T750A), or aspartic acid to mimic phosphorylation (T536/538D and T750D).	('aspartic acid', 'Chemical', 'MESH:D001224', (222, 235))	('T750A', 'Var', (211, 216))	('S538A', 'Mutation', 'p.S538A', (201, 206))	('alanine', 'Chemical', 'MESH:D000409', (161, 168))	('AMOT130', 'Gene', (87, 94))	('T750D', 'Mutation', 'p.T750D', (276, 281))	('T750A', 'Mutation', 'c.750T>A', (211, 216))	('phosphorylation', 'MPA', (179, 194))	('T536', 'Var', (117, 121))	('T536/S538A', 'Var', (196, 206))	('ablate', 'NegReg', (172, 178))	('T536/538D', 'Var', (262, 271))	('T750D', 'Var', (276, 281))
338359	27321186	AMOT130 mutants, as well as wild-type AMOT130, were expressed in OSC cells and assessed for localization of Flag-AMOT and YAP1 (Fig 7B).	('AMOT130', 'Gene', (0, 7))	('YAP1', 'Gene', (122, 126))	('OSC', 'Phenotype', 'HP:0012887', (65, 68))	('mutants', 'Var', (8, 15))	('YAP1', 'Gene', '10413', (122, 126))
338361	27321186	Interestingly, T536A/S538A, T536D/S538D and T750A AMOT130 mutants induced loss of nuclear YAP1 indistinguishable from wild-type AMOT130 (Figure 7B, middle three panels).	('T536A', 'Var', (15, 20))	('S538D', 'Var', (34, 39))	('T536A', 'SUBSTITUTION', 'None', (15, 20))	('T750A', 'Var', (44, 49))	('T536D', 'SUBSTITUTION', 'None', (28, 33))	('YAP1', 'Gene', (90, 94))	('loss', 'NegReg', (74, 78))	('YAP1', 'Gene', '10413', (90, 94))	('T750A', 'Mutation', 'c.750T>A', (44, 49))	('S538D', 'SUBSTITUTION', 'None', (34, 39))	('AMOT130', 'Gene', (50, 57))	('S538A', 'Mutation', 'p.S538A', (21, 26))	('T536D', 'Var', (28, 33))
338362	27321186	In cells expressing these AMOT130 mutants, YAP1 co-localized with Flag-AMOT130 at the cell periphery.	('mutants', 'Var', (34, 41))	('YAP1', 'Gene', '10413', (43, 47))	('AMOT130', 'Gene', (26, 33))	('co-localized', 'Interaction', (48, 60))	('YAP1', 'Gene', (43, 47))
338363	27321186	In contrast, expression of T750D AMOT130 failed to induce loss of nuclear YAP1 (Fig 7B, right panels).	('T750D', 'Var', (27, 32))	('YAP1', 'Gene', '10413', (74, 78))	('YAP1', 'Gene', (74, 78))	('T750D', 'Mutation', 'p.T750D', (27, 32))
338364	27321186	Quantitative analysis confirmed significant loss of nuclear YAP1 in cells expressing WT, S536/T538A, S536/T538D and T750A AMOT mutants, and the continued presence of nuclear YAP1 in cells expressing the T750D AMOT mutant (Fig 7C).	('T750D', 'Mutation', 'p.T750D', (203, 208))	('YAP1', 'Gene', (174, 178))	('YAP1', 'Gene', '10413', (174, 178))	('S536/T538D', 'Var', (101, 111))	('AMOT', 'Disease', (122, 126))	('T750A', 'Var', (116, 121))	('T750A', 'Mutation', 'c.750T>A', (116, 121))	('loss', 'NegReg', (44, 48))	('S536/T538A', 'Var', (89, 99))	('YAP1', 'Gene', (60, 64))	('T750D', 'Var', (203, 208))	('T538D', 'Mutation', 'p.T538D', (106, 111))	('YAP1', 'Gene', '10413', (60, 64))	('T538A', 'Mutation', 'c.538T>A', (94, 99))
338367	27321186	Immunoprecipitation of WT, T750A and T750D AMOT130 followed by immunoblot analysis for YAP1 revealed that whereas all three AMOT130 alleles bound YAP1, T750A AMOT130 bound significantly more YAP1, and T750D AMOT130 bound significantly less YAP1, than WT AMOT130 (Fig.	('AMOT130', 'Gene', (124, 131))	('T750D', 'Var', (201, 206))	('YAP1', 'Gene', (240, 244))	('YAP1', 'Gene', '10413', (87, 91))	('YAP1', 'Gene', (191, 195))	('bound', 'Interaction', (166, 171))	('T750D', 'Mutation', 'p.T750D', (37, 42))	('YAP1', 'Gene', (87, 91))	('T750A', 'Mutation', 'c.750T>A', (27, 32))	('bound', 'Interaction', (140, 145))	('T750A', 'Mutation', 'c.750T>A', (152, 157))	('YAP1', 'Gene', '10413', (146, 150))	('T750D', 'Mutation', 'p.T750D', (201, 206))	('T750A', 'Var', (152, 157))	('AMOT130', 'Gene', (158, 165))	('YAP1', 'Gene', '10413', (240, 244))	('YAP1', 'Gene', (146, 150))	('YAP1', 'Gene', '10413', (191, 195))	('more', 'PosReg', (186, 190))
338368	27321186	Consistent with these results, expression of either WT or T750A AMOT130 significantly inhibited soft agar colony formation (Fig.	('T750A', 'Var', (58, 63))	('AMOT130', 'Gene', (64, 71))	('agar', 'Chemical', 'MESH:D000362', (101, 105))	('T750A', 'Mutation', 'c.750T>A', (58, 63))	('inhibited', 'NegReg', (86, 95))	('soft agar colony formation', 'CPA', (96, 122))
338371	27321186	Immunoblot analysis demonstrated that both WT and T750A AMOT130 inhibited CYR61 expression whereas T750D AMOT did not (Fig.	('CYR61', 'Gene', (74, 79))	('T750A', 'Var', (50, 55))	('AMOT130', 'Gene', (56, 63))	('T750A', 'Mutation', 'c.750T>A', (50, 55))	('inhibited', 'NegReg', (64, 73))	('CYR61', 'Gene', '3491', (74, 79))	('T750D', 'Mutation', 'p.T750D', (99, 104))
338384	27321186	Immunohistochemical analysis revealed decreased nuclear YAP1 staining intensity in ANF-treated tumors compared to diluent-treated tumors (Fig.	('tumors', 'Disease', (130, 136))	('tumors', 'Disease', 'MESH:D009369', (130, 136))	('ANF', 'Chemical', 'MESH:D001310', (83, 86))	('decreased', 'NegReg', (38, 47))	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('YAP1', 'Gene', (56, 60))	('nuclear', 'MPA', (48, 55))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('YAP1', 'Gene', '10413', (56, 60))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('staining intensity', 'MPA', (61, 79))	('ANF-treated', 'Var', (83, 94))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('tumors', 'Disease', (95, 101))
338395	27321186	A major genetic risk factor for ovarian cancer is germline mutation of the BRCA1 or BRCA2 DNA mismatch repair genes which is present in 10% of ovarian cancer cases.	('BRCA1', 'Gene', (75, 80))	('germline mutation', 'Var', (50, 67))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('ovarian cancer', 'Phenotype', 'HP:0100615', (143, 157))	('BRCA2', 'Gene', (84, 89))	('ovarian cancer', 'Disease', (32, 46))	('ovarian cancer', 'Disease', 'MESH:D010051', (143, 157))	('BRCA2', 'Gene', '675', (84, 89))	('ovarian cancer', 'Phenotype', 'HP:0100615', (32, 46))	('ovarian cancer', 'Disease', (143, 157))	('BRCA1', 'Gene', '672', (75, 80))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('ovarian cancer', 'Disease', 'MESH:D010051', (32, 46))
338396	27321186	PRKCI resides at 3q26 and is a major target of oncogenic activation associated with chromosome 3q26 CNGs.	('chromosome 3q26', 'Var', (84, 99))	('PRKCI', 'Gene', (0, 5))	('PRKCI', 'Gene', '5584', (0, 5))
338413	27321186	Our data indicate a specific role for PKCiota-mediated T750 AMOT130 phosphorylation in YAP1 regulation; however, we identified several other PKCiota-mediated phosphorylation sites (T536 and S538) on AMOT130.	('PKC', 'Gene', (141, 144))	('PKC', 'Gene', (38, 41))	('YAP1', 'Gene', (87, 91))	('PKC', 'Gene', '112476', (38, 41))	('YAP1', 'Gene', '10413', (87, 91))	('T536', 'Var', (181, 185))	('PKC', 'Gene', '112476', (141, 144))	('S538', 'Var', (190, 194))
338418	27321186	In this regard, OSC tumors exhibit low levels of PKCzeta, in stark contrast to PKCiota, which is overexpressed as a result of 3q26 CNG.	('3q26 CNG', 'Var', (126, 134))	('PKC', 'Gene', (79, 82))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('PKC', 'Gene', (49, 52))	('PKC', 'Gene', '112476', (49, 52))	('PKC', 'Gene', '112476', (79, 82))	('OSC tumors', 'Disease', 'MESH:D009369', (16, 26))	('OSC', 'Phenotype', 'HP:0012887', (16, 19))	('OSC tumors', 'Disease', (16, 26))	('PKCzeta', 'Gene', '5590', (49, 56))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('PKCzeta', 'Gene', (49, 56))
338422	27321186	Our finding that ANF, a compound that inhibits oncogenic PKCiota signaling, blocks PKCiota-YAP1 signaling and inhibits OSC growth in vitro and OSC tumorigenesis in vivo suggests a plausible therapeutic intervention strategy for treatment of OSC.	('inhibits', 'NegReg', (110, 118))	('OSC tumor', 'Disease', (143, 152))	('PKC', 'Gene', '112476', (83, 86))	('blocks', 'NegReg', (76, 82))	('OSC tumor', 'Disease', 'MESH:D009369', (143, 152))	('OSC', 'Phenotype', 'HP:0012887', (119, 122))	('PKC', 'Gene', (83, 86))	('OSC', 'Phenotype', 'HP:0012887', (143, 146))	('inhibits', 'NegReg', (38, 46))	('PKC', 'Gene', '112476', (57, 60))	('OSC', 'Disease', (241, 244))	('ANF', 'Chemical', 'MESH:D001310', (17, 20))	('ANF', 'Var', (17, 20))	('YAP1', 'Gene', '10413', (91, 95))	('PKC', 'Gene', (57, 60))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('OSC', 'Phenotype', 'HP:0012887', (241, 244))	('OSC', 'Disease', (119, 122))	('YAP1', 'Gene', (91, 95))
338430	27321186	DNA probes targeting chromosome 3q26 (clones RP11-1148M8, RP11-1012L11, CTD-2316F21 and RP11-994L2) were labeled with SpectrumGreen dUTP (Abbott Molecular/Vysis Products), and a probe targeting the chromosome 3 centromere (D3Z1) was labeled in SpectrumOrange (Abbott Molecular/Vysis Products).	('RP11-1012L11', 'Var', (58, 70))	('dUTP', 'Chemical', 'MESH:C027078', (132, 136))	('clones RP11-1148M8', 'Var', (38, 56))	('CTD-2316F21', 'Var', (72, 83))	('RP11-994L2', 'Var', (88, 98))
338443	27321186	pCMV 3Tag AMOT130 was used as template for site-directed mutagenesis to generate AMOT130 cDNAs in which both Thr536 and Ser538 were mutagenized to alanines (T536A/S538A) or aspartic acid (T536D/S538D), or in which Thr750 was mutagenized to alanine (T750A) or aspartic acid (T750D).	('Thr536', 'Gene', (109, 115))	('aspartic acid', 'Chemical', 'MESH:D001224', (259, 272))	('aspartic acid', 'MPA', (259, 272))	('aspartic acid', 'Chemical', 'MESH:D001224', (173, 186))	('Thr750', 'Chemical', '-', (214, 220))	('T750A', 'Mutation', 'c.750T>A', (249, 254))	('alanine', 'Chemical', 'MESH:D000409', (240, 247))	('T536D', 'SUBSTITUTION', 'None', (188, 193))	('T750D', 'Mutation', 'p.T750D', (274, 279))	('Ser538', 'Gene', (120, 126))	('alanines', 'Chemical', 'MESH:D000409', (147, 155))	('Thr536', 'Chemical', '-', (109, 115))	('S538A', 'Mutation', 'p.S538A', (163, 168))	('S538D', 'SUBSTITUTION', 'None', (194, 199))	('T536A', 'Var', (157, 162))	('T536A', 'SUBSTITUTION', 'None', (157, 162))	('T536D', 'Var', (188, 193))	('Ser538', 'Chemical', '-', (120, 126))	('S538D', 'Var', (194, 199))	('alanine', 'Chemical', 'MESH:D000409', (147, 154))
338444	27321186	Expression plasmids containing full length human wildtype (cat# 18881) and WW mutant (cat# 17792) YAP1 were obtained from Addgene.	('YAP1', 'Gene', (98, 102))	('YAP1', 'Gene', '10413', (98, 102))	('cat# 18881', 'Var', (59, 69))	('human', 'Species', '9606', (43, 48))	('cat# 17792', 'Var', (86, 96))
338453	27321186	Cover slips were washed twice with PBS, incubated in blocking solution (PBS containing 5% BSA) for 1 hour and then with primary antibodies in PBS containing 1% BSA (FLAG antibody 1:50; YAP1 antibody 1:50) for 1 hour at 37 C. Cover slips were washed twice for 5 min in PBS, and incubated with secondary antibodies in PBS containing 1% BSA (Alexa Fluor 488, #A11001 and Alexa Fluor 594, #R37117 from Thermo Fisher Scientific, 1:300) for 1 hour at 37 C in a humidified chamber in the dark.	('YAP1', 'Gene', (185, 189))	('YAP1', 'Gene', '10413', (185, 189))	('PBS', 'Chemical', 'MESH:D007854', (316, 319))	('PBS', 'Chemical', 'MESH:D007854', (35, 38))	('PBS', 'Chemical', 'MESH:D007854', (72, 75))	('PBS', 'Chemical', 'MESH:D007854', (142, 145))	('#R37117', 'Var', (385, 392))	('PBS', 'Chemical', 'MESH:D007854', (268, 271))
338470	25125259	Functional kinomics identifies candidate therapeutic targets in head and neck cancer To identify novel therapeutic drug targets for p53 mutant head and neck squamous cell carcinoma (HNSCC).	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('p53', 'Gene', (132, 135))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (143, 180))	('carcinoma', 'Phenotype', 'HP:0030731', (171, 180))	('neck squamous cell carcinoma', 'Disease', (152, 180))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (157, 180))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (152, 180))	('mutant', 'Var', (136, 142))	('head and neck cancer', 'Phenotype', 'HP:0012288', (64, 84))
338471	25125259	RNAi kinome viability screens were performed on HNSCC cells including autologous pairs from primary tumor and recurrent/metastatic lesions, and in parallel on murine squamous cell carcinoma (MSCC) cells derived from tumors of inbred mice bearing germline mutations in Trp53, and p53 regulatory genes: Atm, Prkdc, and p19Arf.	('murine', 'Species', '10090', (159, 165))	('tumor', 'Disease', (100, 105))	('Prkdc', 'Gene', (306, 311))	('tumors', 'Disease', (216, 222))	('Trp53', 'Gene', '22059', (268, 273))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('mutations', 'Var', (255, 264))	('tumor', 'Disease', (216, 221))	('p53', 'Gene', (279, 282))	('Trp53', 'Gene', (268, 273))	('p19Arf', 'Gene', (317, 323))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (166, 189))	('tumors', 'Disease', 'MESH:D009369', (216, 222))	('Atm', 'Gene', (301, 304))	('tumor', 'Disease', 'MESH:D009369', (216, 221))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('Prkdc', 'Gene', '19090', (306, 311))	('mice', 'Species', '10090', (233, 237))	('carcinoma', 'Phenotype', 'HP:0030731', (180, 189))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (166, 189))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('p19Arf', 'Gene', '12578', (317, 323))	('Atm', 'Gene', '11920', (301, 304))	('tumors', 'Phenotype', 'HP:0002664', (216, 222))	('squamous cell carcinoma', 'Disease', (166, 189))
338474	25125259	RNAi mediated knockdown and chemical inhibition of the WEE1 kinase with a specific inhibitor, MK-1775, had a significant effect on both viability and apoptosis.	('MK-1775', 'Chemical', 'MESH:C549567', (94, 101))	('WEE1', 'Gene', (55, 59))	('inhibition', 'NegReg', (37, 47))	('apoptosis', 'CPA', (150, 159))	('knockdown', 'Var', (14, 23))
338475	25125259	Sensitivity to the MK-1775 kinase inhibitor is in part determined by p53 mutational status, and due to unscheduled mitotic entry.	('mutational', 'Var', (73, 83))	('determined', 'Reg', (55, 65))	('p53', 'Gene', (69, 72))	('MK-1775', 'Chemical', 'MESH:C549567', (19, 26))
338476	25125259	MK-1775 displays single-agent activity and potentiates the efficacy of cisplatin in a p53 mutant HNSCC xenograft model.	('mutant', 'Var', (90, 96))	('potentiates', 'PosReg', (43, 54))	('MK-1775', 'Var', (0, 7))	('efficacy', 'MPA', (59, 67))	('MK-1775', 'Chemical', 'MESH:C549567', (0, 7))	('cisplatin', 'Chemical', 'MESH:D002945', (71, 80))	('p53', 'Gene', (86, 89))
338482	25125259	Mutations in the tumor suppressor gene p53 are very common in HNSCC, with an estimated frequency of >50%.	('tumor', 'Disease', (17, 22))	('HNSCC', 'Disease', (62, 67))	('Mutations', 'Var', (0, 9))	('p53', 'Gene', (39, 42))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('common', 'Reg', (52, 58))
338483	25125259	Disruptive p53 mutations have been associated with metastasis, resistance to radiation, and poor patient survival.	('p53', 'Gene', (11, 14))	('resistance to radiation', 'CPA', (63, 86))	('metastasis', 'CPA', (51, 61))	('mutations', 'Var', (15, 24))	('associated', 'Reg', (35, 45))	('patient', 'Species', '9606', (97, 104))
338484	25125259	Despite the strong implication of p53 in the biology and clinical outcome of HNSCC, there are no available therapies that specifically target p53 mutant cancer cells.	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('p53', 'Gene', (142, 145))	('cancer', 'Disease', (153, 159))	('mutant', 'Var', (146, 152))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('HNSCC', 'Disease', (77, 82))
338485	25125259	Here, we hypothesized that HNSCC cancer cells, in particular those with p53 mutations, are dependent on particular kinases for survival and that targeting these kinases could have therapeutic potential.	('mutations', 'Var', (76, 85))	('p53', 'Gene', (72, 75))	('HNSCC cancer', 'Disease', 'MESH:D000077195', (27, 39))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('HNSCC cancer', 'Disease', (27, 39))
338487	25125259	We surveyed the entire human kinome to identify those kinases that are required for survival of HNSCC cells stratified by p53 mutational status and metastatic propensity.	('mutational', 'Var', (126, 136))	('human', 'Species', '9606', (23, 28))	('p53', 'Gene', (122, 125))
338492	25125259	These enzymes regulate multiple cellular processes that contribute to tumor development and progression, and many human tumors display aberrant activation of kinases caused by genetic alterations.	('tumors', 'Disease', (120, 126))	('tumors', 'Disease', 'MESH:D009369', (120, 126))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', (70, 75))	('tumor', 'Disease', (120, 125))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('activation', 'PosReg', (144, 154))	('human', 'Species', '9606', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('kinases', 'Enzyme', (158, 165))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('genetic alterations', 'Var', (176, 195))
338498	25125259	Through an efficient in vitro and in vivo prioritization and validation scheme, we identified the G2/M cell cycle regulatory kinase WEE1 as one of several clinically promising targets, and show that inhibition of WEE1 with a highly specific small molecule inhibitor impaired growth of p53 mutant HNSCC tumors in vivo.	('HNSCC tumors', 'Disease', 'MESH:D000077195', (296, 308))	('p53', 'Gene', (285, 288))	('growth', 'CPA', (275, 281))	('tumor', 'Phenotype', 'HP:0002664', (302, 307))	('impaired', 'NegReg', (266, 274))	('inhibition', 'Var', (199, 209))	('tumors', 'Phenotype', 'HP:0002664', (302, 308))	('mutant', 'Var', (289, 295))	('HNSCC tumors', 'Disease', (296, 308))
338506	25125259	To determine if a p53 mutation is disruptive, we used criteria established by Poeta et al.. Murine squamous cell carcinoma (MSCC) cells were derived from NIH/Ola strain mice with germline mutations in p53 pathway genes and included: MSCC-CK101 (HrasQ61L Trp53+/+), MSCC-CK102 (HrasQ61L Trp53 +/-), MSCC-CK103 (Hraswt p19Arf -/-), MSCC-CK104 (KrasG13R Atm-/-), MSCC-CK1 (Hras Q61L p53+/+) and MSCC-CK4 (Hras Q61L p53-/- (Cre+ p53 lox/lox)).	('Trp53', 'Gene', (254, 259))	('p53', 'Gene', (201, 204))	('Murine', 'Species', '10090', (92, 98))	('Trp53', 'Gene', (286, 291))	('Q61L', 'Mutation', 'rs121913233', (249, 253))	('CK1', 'Species', '2498238', (303, 306))	('Kras', 'Gene', '3845', (342, 346))	('CK1', 'Species', '2498238', (238, 241))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('Q61L', 'Mutation', 'rs121913233', (281, 285))	('squamous cell carcinoma', 'Disease', (99, 122))	('Hras', 'Gene', (310, 314))	('CK1', 'Species', '2498238', (270, 273))	('Hras', 'Gene', (245, 249))	('Atm', 'Gene', (351, 354))	('Kras', 'Gene', (342, 346))	('p19Arf', 'Gene', (317, 323))	('Hras', 'Gene', (277, 281))	('Q61L', 'Mutation', 'rs121913233', (375, 379))	('Q61L', 'Mutation', 'rs121913233', (407, 411))	('Hras', 'Gene', '3265', (310, 314))	('Hras', 'Gene', '3265', (245, 249))	('CK1', 'Species', '2498238', (365, 368))	('Hras', 'Gene', '3265', (277, 281))	('Hras', 'Gene', (370, 374))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (99, 122))	('mice', 'Species', '10090', (169, 173))	('Hras', 'Gene', (402, 406))	('mutations', 'Var', (188, 197))	('Atm', 'Gene', '11920', (351, 354))	('Hras', 'Gene', '3265', (370, 374))	('p19Arf', 'Gene', '12578', (317, 323))	('Hras', 'Gene', '3265', (402, 406))	('Trp53', 'Gene', '22059', (254, 259))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (99, 122))	('Trp53', 'Gene', '22059', (286, 291))	('CK1', 'Species', '2498238', (335, 338))
338509	25125259	Tumors induced by this protocol principally harbor an activating mutation in the Hras oncogene, but mutations in Kras have also been noted.	('activating', 'PosReg', (54, 64))	('Kras', 'Gene', (113, 117))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('Kras', 'Gene', '3845', (113, 117))	('Hras', 'Gene', (81, 85))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('mutation', 'Var', (65, 73))	('Hras', 'Gene', '3265', (81, 85))
338518	25125259	An HFF exclusion plot was generated using this kinome screen information to determine whether RNAi mediated knockdown of kinase targets compromised cell viability in both HFF cultures, with < 70% viability (>30% cell death) as a threshold (Fig.	('knockdown', 'Var', (108, 117))	('HFF', 'CellLine', 'CVCL:3285', (3, 6))	('cell viability', 'CPA', (148, 162))	('HFF', 'CellLine', 'CVCL:3285', (171, 174))	('compromised', 'NegReg', (136, 147))
338525	25125259	Mean viabilities (mui2 All, mui3 p53 mutant, mui4 metastatic) and Z score transformations were calculated for both human and murine lines per genotype and phenotype: 1) all human and murine cell lines; 2) p53 mutant/deficient human and murine cell lines; and 3) metastatic human and murine cell lines (Table S8).	('human', 'Species', '9606', (226, 231))	('murine', 'Species', '10090', (283, 289))	('murine', 'Species', '10090', (183, 189))	('murine', 'Species', '10090', (236, 242))	('p53', 'Gene', (205, 208))	('mutant/deficient', 'Var', (209, 225))	('human', 'Species', '9606', (115, 120))	('human', 'Species', '9606', (173, 178))	('murine', 'Species', '10090', (125, 131))	('human', 'Species', '9606', (273, 278))
338531	25125259	Statistical significance of RNA interference mediated knockdown of the 28 kinases was assessed via ANOVA with Dunnetts post-test for multiple comparisons (P<0.05 as significant) on differential viability (day 4.5 - day 1.5), and area under the curve (AUC) analysis of caspase 3/7 dependent apoptosis versus universal negative siRNA control (UNI).	('caspase 3/7', 'Gene', (268, 279))	('RNA', 'MPA', (28, 31))	('knockdown', 'Var', (54, 63))	('apoptosis', 'CPA', (290, 299))	('caspase 3/7', 'Gene', '836;840', (268, 279))
338534	25125259	Statistical significance of RNA interference mediated knockdown of the 20 kinases was assessed via ANOVA with Dunnetts post-test for multiple comparisons on absolute viability (day 4.5), differential viability (day 4.5 - day 1.5), and area under the curve (AUC) analysis of caspase-dependent apoptosis versus the negative siRNA control (SINC) (Tables S18-S20).	('SINC', 'Disease', (337, 341))	('SINC', 'Disease', 'None', (337, 341))	('knockdown', 'Var', (54, 63))
338535	25125259	Kinase inhibition dose response curves were performed with six kinase inhibitors (MK-1775 (a.k.a., AZD-1775), TAE684, PI828, PIK93, PP2, PF-562271) against kinase targets (WEE1, ALK, PI3K, PIK4CB, FYN, FAK (ILK surrogate)), respectively.	('PIK4CB', 'Gene', (189, 195))	('FYN', 'Gene', (197, 200))	('ILK', 'Gene', (207, 210))	('PI828', 'Var', (118, 123))	('ILK', 'Gene', '3611', (207, 210))	('PP2', 'Gene', '4888', (132, 135))	('ALK', 'Gene', (178, 181))	('AZD-1775', 'Chemical', 'MESH:C549567', (99, 107))	('MK-1775', 'Var', (82, 89))	('FYN', 'Gene', '2534', (197, 200))	('MK-1775', 'Chemical', 'MESH:C549567', (82, 89))	('FAK', 'Gene', '5747', (202, 205))	('FAK', 'Gene', (202, 205))	('PP2', 'Gene', (132, 135))	('TAE684', 'Chemical', 'MESH:C516714', (110, 116))	('ALK', 'Gene', '238', (178, 181))	('PIK4CB', 'Gene', '5298', (189, 195))
338536	25125259	Kinase inhibitors: MK-1775 (S1525), PIK93 (S1489), TAE684 (S1108) were obtained from Selleck Chemicals (Houston, TX); PI828 (2814), PP2 (1407) from Tocris Bioscience (Mpls, MN), and PF-562271 from Synkinase (San Diego, CA).	('PI828 (2814', 'Var', (118, 129))	('S1489', 'Var', (43, 48))	('PP2', 'Gene', '4888', (132, 135))	('MK-1775', 'Chemical', 'MESH:C549567', (19, 26))	('S1525', 'Var', (28, 33))	('MN', 'CellLine', 'CVCL:U508', (173, 175))	('Tocris Bioscience', 'Disease', (148, 165))	('PF-562271', 'Var', (182, 191))	('PP2', 'Gene', (132, 135))	('S1108', 'Var', (59, 64))	('TAE684', 'Chemical', 'MESH:C516714', (51, 57))	('Tocris Bioscience', 'Disease', 'None', (148, 165))
338541	25125259	In addition, the Genomics of Drug Sensitivity Project (Release 2 July 2012) contains 541 cancer cell lines that were treated with a WEE1/CHK1 inhibitor, 681640 (EMD Millpore), a pyrrolocarbazole compound that acts as a potent, ATP-binding site inhibitor of WEE1 (IC50 = 11 nM).	('CHK1', 'Gene', (137, 141))	('CHK1', 'Gene', '1111', (137, 141))	('pyrrolocarbazole', 'Chemical', '-', (178, 194))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('681640', 'Var', (153, 159))	('cancer', 'Disease', (89, 95))	('Drug Sensitivity', 'Phenotype', 'HP:0020174', (29, 45))	('ATP', 'Chemical', 'MESH:D000255', (227, 230))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
338549	25125259	AUCs were calculated for all treatments and vehicle (DMSO) for all cell lines utilizing two measurements over a 48-hour period with three concentrations (30 nm, 100 nm, 1 muM) of MK-1775.	('muM', 'Gene', (171, 174))	('DMSO', 'Chemical', 'MESH:D004121', (53, 57))	('30 nm', 'Var', (154, 159))	('MK-1775', 'Gene', (179, 186))	('MK-1775', 'Chemical', 'MESH:C549567', (179, 186))	('muM', 'Gene', '56925', (171, 174))
338563	25125259	Two pairs of these cells (UM-SCC14A UM-SCC14C and PCI-15A, PCI-15B) were derived from primary and subsequent post-treatment recurrences or metastatic cervical lymph nodes from the same patients and all carried disruptive mutations in p53 (Table S1).	('p53', 'Gene', (234, 237))	('mutations', 'Var', (221, 230))	('patients', 'Species', '9606', (185, 193))	('PCI-15B', 'Chemical', '-', (59, 66))	('carried', 'Reg', (202, 209))
338567	25125259	Next, we derived an interspecies kinome (508 kinases shared between both species) to identify kinases in which RNA interference mediated knockdown negatively impacted cell viability in both human and mouse cells (see schematic in Fig.	('RNA interference', 'MPA', (111, 127))	('negatively impacted', 'NegReg', (147, 166))	('mouse', 'Species', '10090', (200, 205))	('knockdown', 'Var', (137, 146))	('human', 'Species', '9606', (190, 195))	('cell viability', 'CPA', (167, 181))
338572	25125259	RNAi mediated knockdown of NEK4 and WEE1 kinases led to a significant reduction in cell viability in all four cell lines tested, while targeting TRIB2 did so for three of the four lines.	('TRIB2', 'Gene', (145, 150))	('reduction', 'NegReg', (70, 79))	('NEK4', 'Gene', '6787', (27, 31))	('WEE1', 'Gene', (36, 40))	('cell viability', 'CPA', (83, 97))	('TRIB2', 'Gene', '28951', (145, 150))	('NEK4', 'Gene', (27, 31))	('knockdown', 'Var', (14, 23))
338574	25125259	UM-SCC22A and UM-SCC22B are an autologous pair of cells derived from a primary tumor and cervical lymph node metastasis from the same patient.	('UM-SCC22A', 'CellLine', 'CVCL:7731', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('tumor', 'Disease', (79, 84))	('cervical lymph node metastasis', 'Phenotype', 'HP:0025289', (89, 119))	('UM-SCC22B', 'CellLine', 'CVCL:7732', (14, 23))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('UM-SCC22B', 'Var', (14, 23))	('patient', 'Species', '9606', (134, 141))
338576	25125259	RNAi mediated knockdown of kinases that regulate the G2/M transition, NEK4, WEE1, AURKA, and CHK1, as well as FYN and CAM2KB significantly impaired viability in three or more of the five cell lines tested (Fig.	('FYN', 'Gene', '2534', (110, 113))	('NEK4', 'Gene', '6787', (70, 74))	('impaired', 'NegReg', (139, 147))	('knockdown', 'Var', (14, 23))	('AURKA', 'Gene', '6790', (82, 87))	('CHK1', 'Gene', (93, 97))	('AURKA', 'Gene', (82, 87))	('NEK4', 'Gene', (70, 74))	('FYN', 'Gene', (110, 113))	('viability', 'MPA', (148, 157))	('CHK1', 'Gene', '1111', (93, 97))
338577	25125259	2B) while knockdown of the WEE1, NEK4, and AURKA kinases induced the highest levels of apoptosis in all five HNSCC cell lines.	('NEK4', 'Gene', (33, 37))	('knockdown', 'Var', (10, 19))	('induced', 'Reg', (57, 64))	('NEK4', 'Gene', '6787', (33, 37))	('AURKA', 'Gene', '6790', (43, 48))	('apoptosis', 'MPA', (87, 96))	('WEE1', 'Gene', (27, 31))	('AURKA', 'Gene', (43, 48))
338578	25125259	Altogether, compiled primary and secondary validation data showed that RNA interference mediated knockdown of WEE1, NEK4, and AURKA kinases significantly reduced viability and increased apoptosis in over 75% of HNSCC cell lines (Fig.	('WEE1', 'Gene', (110, 114))	('AURKA', 'Gene', (126, 131))	('knockdown', 'Var', (97, 106))	('NEK4', 'Gene', (116, 120))	('increased', 'PosReg', (176, 185))	('RNA interference', 'MPA', (71, 87))	('viability', 'CPA', (162, 171))	('reduced', 'NegReg', (154, 161))	('NEK4', 'Gene', '6787', (116, 120))	('AURKA', 'Gene', '6790', (126, 131))	('apoptosis', 'CPA', (186, 195))
338579	25125259	A comparison of functional kinomic profiles between cell line pairs isolated from the same patients showed a high degree of concordance, but with a tendency for the metastatic/recurrent cells to be more resistant to kinase knockdown relative to their primary tumor cell pair (Fig.	('patients', 'Species', '9606', (91, 99))	('tumor', 'Disease', 'MESH:D009369', (259, 264))	('tumor', 'Phenotype', 'HP:0002664', (259, 264))	('tumor', 'Disease', (259, 264))	('knockdown', 'Var', (223, 232))
338580	25125259	For example, RNAi mediated knockdown of TK2 and TRIB2 was more effective in cells isolated from the primary vs. the recurrent/metastatic lesions (Fig.	('TK2', 'Gene', (40, 43))	('knockdown', 'Var', (27, 36))	('TRIB2', 'Gene', (48, 53))	('TRIB2', 'Gene', '28951', (48, 53))	('TK2', 'Gene', '7084', (40, 43))
338583	25125259	In agreement with our siRNA knockdown experiments, p53 mutant HNSCC cell lines were sensitive to small molecule inhibitors targeting WEE1, ALK, PIK4CB, and FAK.	('p53', 'Gene', (51, 54))	('ALK', 'Gene', (139, 142))	('FAK', 'Gene', '5747', (156, 159))	('mutant', 'Var', (55, 61))	('PIK4CB', 'Gene', '5298', (144, 150))	('ALK', 'Gene', '238', (139, 142))	('PIK4CB', 'Gene', (144, 150))	('WEE1', 'Gene', (133, 137))	('FAK', 'Gene', (156, 159))
338584	25125259	The WEE1 kinase inhibitor, MK-1775 had the broadest and most significant effect on cell survival in both primary and recurrent/metastasis derived HNSCC cells, with an IC50 ranging from 220 nM-3.1 muM (Fig.	('muM', 'Gene', '56925', (196, 199))	('cell survival', 'CPA', (83, 96))	('muM', 'Gene', (196, 199))	('MK-1775', 'Var', (27, 34))	('MK-1775', 'Chemical', 'MESH:C549567', (27, 34))
338585	25125259	To further explore the sensitivity of p53 deficient cells to WEE1 inhibition, we performed dose-response curves with MK-1775 in pairs of p53 wild type and p53 mutant/deficient SCC cells.	('MK-1775', 'Chemical', 'MESH:C549567', (117, 124))	('mutant/deficient', 'Var', (159, 175))	('p53', 'Gene', (155, 158))
338586	25125259	The IC50 for MK-1775 was 20-fold lower in p53-/- MSCC cells compared to p53 wild type cells (0.22 muM vs. 4.5 muM) (Fig.	('IC50', 'MPA', (4, 8))	('muM', 'Gene', (98, 101))	('muM', 'Gene', '56925', (110, 113))	('p53-/-', 'Var', (42, 48))	('MK-1775', 'Gene', (13, 20))	('MK-1775', 'Chemical', 'MESH:C549567', (13, 20))	('muM', 'Gene', (110, 113))	('muM', 'Gene', '56925', (98, 101))	('lower', 'NegReg', (33, 38))
338587	25125259	The IC50 for MK-1775 in p53 mutant PCI-15A and PCI-15B HNSCC cells (0.14 - 0.17 muM) and p53 wild type SCC-61 and UMSCC-17A cells (2.8 - 4.5 muM) showed a similar differential sensitivity to MK-1775 as the mouse SCC cells.	('mutant', 'Var', (28, 34))	('p53', 'Gene', (24, 27))	('MK-1775', 'Chemical', 'MESH:C549567', (191, 198))	('muM', 'Gene', '56925', (141, 144))	('mouse', 'Species', '10090', (206, 211))	('PCI-15B', 'Chemical', '-', (47, 54))	('muM', 'Gene', '56925', (80, 83))	('MK-1775', 'Chemical', 'MESH:C549567', (13, 20))	('muM', 'Gene', (141, 144))	('muM', 'Gene', (80, 83))
338590	25125259	Consistent with the WEE1 inhibitor results, p53 deficient MSCC cells were also more sensitive to the CHK1 inhibitor, AZD7762 than p53 wild type cells (IC50 0.13 muM vs. 2.2 muM) (Fig.	('sensitive', 'MPA', (84, 93))	('muM', 'Gene', (161, 164))	('muM', 'Gene', '56925', (161, 164))	('muM', 'Gene', '56925', (173, 176))	('p53', 'Gene', (44, 47))	('more', 'PosReg', (79, 83))	('deficient', 'Var', (48, 57))	('CHK1', 'Gene', (101, 105))	('AZD7762', 'Chemical', 'MESH:C532363', (117, 124))	('muM', 'Gene', (173, 176))	('CHK1', 'Gene', '1111', (101, 105))
338593	25125259	We used mutational profiling data from the Sanger Cancer Cell Line Project to classify cell lines based on p53 mutational status and tested for correlation with sensitivity to 681640 (Table S21).	('Cancer', 'Disease', 'MESH:D009369', (50, 56))	('Cancer', 'Disease', (50, 56))	('Cancer', 'Phenotype', 'HP:0002664', (50, 56))	('mutational', 'Var', (111, 121))	('p53', 'Gene', (107, 110))
338594	25125259	Examination of the 42 cells that were derived from squamous cell carcinomas of the head and neck, oesophagus, lung, cervix, vulva, and skin, showed that, despite a broad range of sensitivities in both wild-type and mutant groups, on average p53 mutant SCC cells had increased sensitivity to 681640 compared to p53 wild type cells (median IC50: 5.34 muM vs. 29.23 muM, P=0.005) (Fig.	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('muM', 'Gene', (349, 352))	('muM', 'Gene', (363, 366))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (51, 75))	('carcinomas', 'Phenotype', 'HP:0030731', (65, 75))	('squamous cell carcinomas', 'Disease', (51, 75))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (51, 75))	('mutant', 'Var', (245, 251))	('increased', 'PosReg', (266, 275))	('muM', 'Gene', '56925', (349, 352))	('muM', 'Gene', '56925', (363, 366))	('sensitivity', 'MPA', (276, 287))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (51, 74))	('p53', 'Gene', (241, 244))
338596	25125259	In fact, the trend between p53 mutant status and 681640 sensitivity was reversed (median IC50: 12.83 muM vs. 7.75 muM P=1.348x10-5) (Fig.	('681640 sensitivity', 'Var', (49, 67))	('muM', 'Gene', '56925', (114, 117))	('muM', 'Gene', '56925', (101, 104))	('p53', 'Gene', (27, 30))	('muM', 'Gene', (114, 117))	('muM', 'Gene', (101, 104))	('mutant status', 'Var', (31, 44))
338598	25125259	Treatment of cells with MK-1775 led to unscheduled mitotic entry in p53 mutant but not wild type cells as measured by phospho-histone H3 (serine 10) (Fig.	('mutant', 'Var', (72, 78))	('serine', 'Chemical', 'MESH:D012694', (138, 144))	('p53', 'Gene', (68, 71))	('unscheduled', 'MPA', (39, 50))	('MK-1775', 'Chemical', 'MESH:C549567', (24, 31))
338600	25125259	This indicates that WEE1 inhibition by MK-1775 in p53 mutant SCC cells caused unscheduled mitotic entry leading to mitotic catastrophe and apoptotic cell death.	('unscheduled', 'MPA', (78, 89))	('mitotic catastrophe', 'CPA', (115, 134))	('MK-1775', 'Gene', (39, 46))	('apoptotic cell death', 'CPA', (139, 159))	('MK-1775', 'Chemical', 'MESH:C549567', (39, 46))	('p53', 'Gene', (50, 53))	('mutant', 'Var', (54, 60))	('inhibition', 'NegReg', (25, 35))	('WEE1', 'Gene', (20, 24))
338604	25125259	When tumors reached a palpable mass of >50 mm3, mice were randomized into four treatment arms and treated with vehicle, MK-1775, cisplatin, or cisplatin plus MK-1775.	('tumors', 'Disease', (5, 11))	('cisplatin', 'Chemical', 'MESH:D002945', (143, 152))	('tumors', 'Disease', 'MESH:D009369', (5, 11))	('mice', 'Species', '10090', (48, 52))	('cisplatin', 'Chemical', 'MESH:D002945', (129, 138))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('MK-1775', 'Var', (120, 127))	('MK-1775', 'Chemical', 'MESH:C549567', (158, 165))	('MK-1775', 'Chemical', 'MESH:C549567', (120, 127))	('tumors', 'Phenotype', 'HP:0002664', (5, 11))
338605	25125259	Cisplatin is the standard chemotherapeutic agent for HNSCC and cisplatin plus MK-1775 was used to determine if inhibition of WEE1 would synergize with DNA damaging therapy, as p53 mutant tumor cells would be expected to depend on G2/M arrest after DNA damaging treatment to repair DNA.	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('cisplatin', 'Chemical', 'MESH:D002945', (63, 72))	('p53', 'Gene', (176, 179))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('mutant', 'Var', (180, 186))	('MK-1775', 'Chemical', 'MESH:C549567', (78, 85))	('Cisplatin', 'Chemical', 'MESH:D002945', (0, 9))	('tumor', 'Disease', (187, 192))	('M arrest', 'Disease', 'MESH:D006323', (233, 241))	('M arrest', 'Disease', (233, 241))
338612	25125259	Here we applied a functional kinomic approach to identify new candidate therapeutic targets for aggressive p53 mutant tumors.	('mutant', 'Var', (111, 117))	('p53', 'Gene', (107, 110))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('tumors', 'Disease', (118, 124))	('tumors', 'Disease', 'MESH:D009369', (118, 124))
338616	25125259	Moreover, p53 deficient MSCC and HNSCC cells were highly sensitive to the specific WEE1 inhibitor MK-1775 relative to p53 WT cells, a finding that has been observed in other settings.	('sensitive', 'MPA', (57, 66))	('MK-1775', 'Var', (98, 105))	('p53', 'Gene', (10, 13))	('MK-1775', 'Chemical', 'MESH:C549567', (98, 105))
338619	25125259	As preclinical validation, we demonstrated that oral administration of MK-1775 inhibited the growth of p53 mutant HNSCC xenografts and also cooperated with cisplatin to induce tumor regression.	('MK-1775', 'Gene', (71, 78))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('mutant', 'Var', (107, 113))	('p53', 'Gene', (103, 106))	('tumor', 'Disease', (176, 181))	('MK-1775', 'Chemical', 'MESH:C549567', (71, 78))	('cisplatin', 'Chemical', 'MESH:D002945', (156, 165))	('growth', 'CPA', (93, 99))	('inhibited', 'NegReg', (79, 88))	('tumor', 'Disease', 'MESH:D009369', (176, 181))
338620	25125259	This xenograft protocol was designed and implemented after careful examination of previous preclinical studies utilizing genotoxic agents and/or MK-1775, and it was determined that the greatest responses to the WEE1 inhibitor MK-1775 would likely be obtained in p53 mutant HNSCC when given after genotoxic treatment (i.e., cisplatin).	('cisplatin', 'Chemical', 'MESH:D002945', (323, 332))	('p53', 'Gene', (262, 265))	('responses', 'MPA', (194, 203))	('mutant', 'Var', (266, 272))	('MK-1775', 'Chemical', 'MESH:C549567', (226, 233))	('genotoxic', 'Chemical', '-', (296, 305))	('MK-1775', 'Chemical', 'MESH:C549567', (145, 152))	('genotoxic', 'Chemical', '-', (121, 130))
338625	25125259	Thus, the degree by which MK-1775 enhances response to cisplatin would not only increase the effectiveness of existing therapy, but would open the possibility of reducing cisplatin dosing to minimize side-effects and broaden patient candidacy to these regimens.	('cisplatin', 'Chemical', 'MESH:D002945', (171, 180))	('MK-1775', 'Var', (26, 33))	('increase', 'PosReg', (80, 88))	('MK-1775', 'Chemical', 'MESH:C549567', (26, 33))	('cisplatin', 'Chemical', 'MESH:D002945', (55, 64))	('response to cisplatin', 'MPA', (43, 64))	('enhances', 'PosReg', (34, 42))	('patient', 'Species', '9606', (225, 232))	('effectiveness', 'MPA', (93, 106))
338626	25125259	MK-1775 has been shown to sensitize other p53 mutant tumors to DNA damaging agents.	('p53', 'Gene', (42, 45))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('sensitize', 'Reg', (26, 35))	('mutant', 'Var', (46, 52))	('MK-1775', 'Chemical', 'MESH:C549567', (0, 7))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('tumors', 'Disease', (53, 59))
338627	25125259	Molecular analysis of HNSCC tumor lysates showed reduced phosphorylation of the WEE1 substrate CDC2, indicating that MK-1775 inhibited its intended target.	('MK-1775', 'Chemical', 'MESH:C549567', (117, 124))	('reduced', 'NegReg', (49, 56))	('HNSCC tumor', 'Disease', (22, 33))	('HNSCC tumor', 'Disease', 'MESH:D000077195', (22, 33))	('inhibited', 'NegReg', (125, 134))	('phosphorylation', 'MPA', (57, 72))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('CDC2', 'Protein', (95, 99))	('MK-1775', 'Var', (117, 124))
338628	25125259	We previously found amplification of 11q13.1 in metastatic HNSCC tumor cells with corresponding over-expression of cyclin B, the activating subunit of CDC2, which could exacerbate the sensitivity of HNSCC cells to WEE1 inhibition.	('over-expression', 'PosReg', (96, 111))	('cyclin B', 'Gene', (115, 123))	('11q13.1', 'Gene', (37, 44))	('exacerbate', 'PosReg', (169, 179))	('sensitivity', 'MPA', (184, 195))	('HNSCC tumor', 'Disease', 'MESH:D000077195', (59, 70))	('amplification', 'Var', (20, 33))	('HNSCC tumor', 'Disease', (59, 70))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
338635	25125259	In summary, our cross-species functional kinomic approach using autologous pairs of primary and recurrent/metastatic p53 mutant HNSCC lines, coupled with isogenic mouse SCC cells with defined mutations along the p53 pathway has identified several survival kinases as candidate therapeutic targets for aggressive HNSCC.	('mouse', 'Species', '10090', (163, 168))	('mutant', 'Var', (121, 127))	('p53', 'Gene', (117, 120))	('aggressive HNSCC', 'Disease', (301, 317))
338638	25125259	Our preclinical data on WEE1 illustrates not only the vulnerabilities of p53 mutant HNSCC cells to deregulation of G2/M transition, but also supports the initiation of clinical trials with MK-1775 or other G2/M checkpoint inhibitors for HNSCC, particularly in combination with cisplatin.	('MK-1775', 'Chemical', 'MESH:C549567', (189, 196))	('HNSCC', 'Gene', (84, 89))	('p53', 'Gene', (73, 76))	('G2/M transition', 'MPA', (115, 130))	('deregulation', 'MPA', (99, 111))	('cisplatin', 'Chemical', 'MESH:D002945', (277, 286))	('mutant', 'Var', (77, 83))
338640	25125259	In this study, we address the unmet need to find novel therapies for p53 mutant head and neck squamous cell carcinoma (HNSCC).	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (89, 117))	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('p53', 'Gene', (69, 72))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (94, 117))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (80, 117))	('mutant', 'Var', (73, 79))	('neck squamous cell carcinoma', 'Disease', (89, 117))
338643	25125259	Our findings reveal vulnerabilities of p53 mutant HNSCC cells to inhibition of G2/M, SFK, PI3K and FAK pathways.	('PI3K', 'Pathway', (90, 94))	('FAK', 'Gene', (99, 102))	('FAK', 'Gene', '5747', (99, 102))	('mutant', 'Var', (43, 49))	('p53', 'Gene', (39, 42))	('G2/M', 'Pathway', (79, 83))	('SFK', 'Pathway', (85, 88))
338644	25125259	Our preclinical data demonstrate the vulnerability of p53 mutant HNSCC cells to deregulation of G2/M transition, and support initiation of clinical trials with MK-1775 or other G2/M checkpoint inhibitors for HNSCC, particularly in combination with cisplatin.	('mutant', 'Var', (58, 64))	('cisplatin', 'Chemical', 'MESH:D002945', (248, 257))	('deregulation', 'MPA', (80, 92))	('MK-1775', 'Chemical', 'MESH:C549567', (160, 167))	('p53', 'Gene', (54, 57))	('HNSCC', 'Gene', (65, 70))	('G2/M transition', 'MPA', (96, 111))
338645	28241446	DNA Methylation Status of PAX1 and ZNF582 in Esophageal Squamous Cell Carcinoma Hypermethylation of specific gene promoters is an important mechanism of carcinogenesis.	('carcinogenesis', 'Disease', (153, 167))	('PAX1', 'Gene', '5075', (26, 30))	('Esophageal Squamous Cell Carcinoma', 'Disease', 'MESH:D000077277', (45, 79))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (56, 79))	('Carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('ZNF582', 'Gene', '147948', (35, 41))	('Esophageal Squamous Cell Carcinoma', 'Disease', (45, 79))	('carcinogenesis', 'Disease', 'MESH:D063646', (153, 167))	('Hypermethylation', 'Var', (80, 96))	('ZNF582', 'Gene', (35, 41))	('PAX1', 'Gene', (26, 30))
338654	28241446	The sensitivities and specificities of PAX1 and ZNF582 methylation for the detection of cancer were 100% and 85.7%, and 78.6% and 100%, respectively.	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('ZNF582', 'Gene', '147948', (48, 54))	('PAX1', 'Gene', (39, 43))	('methylation', 'Var', (55, 66))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('ZNF582', 'Gene', (48, 54))	('PAX1', 'Gene', '5075', (39, 43))
338656	28241446	DNA methylation status of these two genes showed a relatively good sensitivity and specificity for the detection of ESCC tumors.	('ESCC tumors', 'Disease', (116, 127))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('ESCC tumors', 'Disease', 'MESH:D004938', (116, 127))	('SCC', 'Phenotype', 'HP:0002860', (117, 120))	('methylation status', 'Var', (4, 22))
338664	28241446	The hypermethylation of CpG islands in the promoter region of tumor suppressor genes, a key mechanism in tumorigenesis, could impede gene transcription and result in a decrease or loss of gene function, a key mechanism in tumorigenesis.	('gene transcription', 'MPA', (133, 151))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', 'MESH:D009369', (222, 227))	('loss', 'NegReg', (180, 184))	('tumor', 'Disease', (62, 67))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('impede', 'NegReg', (126, 132))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('decrease', 'NegReg', (168, 176))	('tumor', 'Disease', (222, 227))	('hypermethylation', 'Var', (4, 20))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('tumor', 'Disease', (105, 110))	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('gene function', 'MPA', (188, 201))
338665	28241446	Similar to other cancers, epigenetic silencing of tumor suppressor genes by promoter hypermethylation is a common molecular alteration in ESCC.	('promoter hypermethylation', 'Var', (76, 101))	('cancers', 'Phenotype', 'HP:0002664', (17, 24))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('SCC', 'Phenotype', 'HP:0002860', (139, 142))	('cancers', 'Disease', (17, 24))	('cancers', 'Disease', 'MESH:D009369', (17, 24))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('epigenetic silencing', 'Var', (26, 46))	('ESCC', 'Disease', (138, 142))	('tumor', 'Disease', (50, 55))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
338666	28241446	Methylation of CpG islands in the tumor suppressor genes prevents the binding of transcription factors to the corresponding DNA response elements, resulting in a decrease in gene transcription, and ultimately, a loss of tumor suppressing function, leading to an uncontrolled cell growth and tumor development.	('gene transcription', 'MPA', (174, 192))	('leading to', 'Reg', (248, 258))	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('tumor', 'Disease', (34, 39))	('binding', 'Interaction', (70, 77))	('prevents', 'NegReg', (57, 65))	('Methylation', 'Var', (0, 11))	('tumor', 'Disease', (220, 225))	('tumor', 'Disease', 'MESH:D009369', (291, 296))	('tumor', 'Phenotype', 'HP:0002664', (291, 296))	('uncontrolled cell growth', 'CPA', (262, 286))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('loss', 'NegReg', (212, 216))	('decrease', 'NegReg', (162, 170))	('tumor', 'Disease', 'MESH:D009369', (220, 225))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('tumor', 'Disease', (291, 296))
338667	28241446	It has been shown that aberrant methylation of some tumor suppressor genes such as PTEN, SFRP1, RASSF1A, DAPK, RUNX3, UCHL1, CDH1, p16INK, FHIT, APC and MGMT occurs frequently in esophageal cancer.	('SFRP1', 'Gene', (89, 94))	('esophageal cancer', 'Disease', 'MESH:D004938', (179, 196))	('tumor', 'Disease', (52, 57))	('UCHL1', 'Gene', (118, 123))	('p16INK', 'Gene', (131, 137))	('CDH1', 'Gene', '999', (125, 129))	('RUNX3', 'Gene', (111, 116))	('MGMT', 'Gene', '4255', (153, 157))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('PTEN', 'Gene', (83, 87))	('DAPK', 'Gene', (105, 109))	('UCHL1', 'Gene', '7345', (118, 123))	('esophageal cancer', 'Disease', (179, 196))	('occurs', 'Reg', (158, 164))	('CDH1', 'Gene', (125, 129))	('RASSF1A', 'Gene', '11186', (96, 103))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('SFRP1', 'Gene', '6422', (89, 94))	('aberrant', 'Var', (23, 31))	('FHIT', 'Gene', (139, 143))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('DAPK', 'Gene', '1612', (105, 109))	('PTEN', 'Gene', '5728', (83, 87))	('RASSF1A', 'Gene', (96, 103))	('RUNX3', 'Gene', '864', (111, 116))	('MGMT', 'Gene', (153, 157))	('APC', 'Disease', 'MESH:D011125', (145, 148))	('methylation', 'MPA', (32, 43))	('APC', 'Disease', (145, 148))	('FHIT', 'Gene', '2272', (139, 143))
338668	28241446	It is therefore the case that alterations in DNA methylation of specific genes may be a useful biomarker for early esophageal cancer detection.	('esophageal cancer', 'Disease', (115, 132))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('alterations', 'Var', (30, 41))	('esophageal cancer', 'Disease', 'MESH:D004938', (115, 132))
338672	28241446	have reported that DNA methylation of PAX1 gene is a prognostic indicator for oral squamous cell carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (83, 106))	('PAX1', 'Gene', '5075', (38, 42))	('PAX1', 'Gene', (38, 42))	('oral squamous cell carcinoma', 'Disease', (78, 106))	('DNA methylation', 'Var', (19, 34))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (78, 106))
338674	28241446	Based on these facts, we hypothesized that alterations in DNA methylation of PAX1 and ZNF582 genes were associated with ESCC development and progression, which may serve as a potential biomarker for early ESCC detection.	('ZNF582', 'Gene', (86, 92))	('SCC', 'Phenotype', 'HP:0002860', (206, 209))	('PAX1', 'Gene', '5075', (77, 81))	('ESCC', 'Disease', (120, 124))	('SCC', 'Phenotype', 'HP:0002860', (121, 124))	('associated with', 'Reg', (104, 119))	('DNA methylation', 'MPA', (58, 73))	('progression', 'CPA', (141, 152))	('ZNF582', 'Gene', '147948', (86, 92))	('alterations', 'Var', (43, 54))	('PAX1', 'Gene', (77, 81))
338692	28241446	For each sample, the PCR allows to detect simultaneously the methylated strands of ZNF582 or PAX1 using a FAM-labeled probe, while a probe labeled with VIC amplifies a CpG free region of the COL2A gene as internal control, therefore normalizing for the DNA quantity.	('methylated', 'Var', (61, 71))	('detect', 'Reg', (35, 41))	('PAX1', 'Gene', (93, 97))	('COL2A', 'Gene', (191, 196))	('PAX1', 'Gene', '5075', (93, 97))	('ZNF582', 'Gene', '147948', (83, 89))	('ZNF582', 'Gene', (83, 89))
338700	28241446	Along the lines, log (meth-index) >= -2.376 for PAX1 or log (meth-index) >= -0.597 for ZNF582 were considered to be methylation positivity.	('log', 'Var', (17, 20))	('ZNF582', 'Gene', (87, 93))	('PAX1', 'Gene', (48, 52))	('PAX1', 'Gene', '5075', (48, 52))	('>= -2.376', 'Var', (34, 43))	('ZNF582', 'Gene', '147948', (87, 93))
338701	28241446	The frequency of PAX1 methylation was 100% (14/14) in the tumor tissues, which is significantly higher than that (21.4%, 3/14) in the paracancerous tissues.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('PAX1', 'Gene', '5075', (17, 21))	('paracancerous tissues', 'Disease', (134, 155))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('higher', 'PosReg', (96, 102))	('paracancerous tissues', 'Disease', 'MESH:D009380', (134, 155))	('PAX1', 'Gene', (17, 21))	('methylation', 'Var', (22, 33))
338704	28241446	The frequency of PAX1 methylation was 80.7% (151/187) in the tumor samples, which is significantly higher than that (25%, 4/16) in the paracancerous samples.	('paracancerous', 'Disease', (135, 148))	('PAX1', 'Gene', '5075', (17, 21))	('higher', 'PosReg', (99, 105))	('paracancerous', 'Disease', 'None', (135, 148))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('PAX1', 'Gene', (17, 21))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Disease', (61, 66))	('methylation', 'Var', (22, 33))
338705	28241446	The frequency of ZNF582 methylation was 88.2% (165/187) in the tumor samples, which is significantly higher than that (18.8%, 3/16) in the paracancerous samples.	('tumor', 'Disease', (63, 68))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('higher', 'PosReg', (101, 107))	('ZNF582', 'Gene', '147948', (17, 23))	('paracancerous', 'Disease', 'None', (139, 152))	('methylation', 'Var', (24, 35))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('ZNF582', 'Gene', (17, 23))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('paracancerous', 'Disease', (139, 152))
338709	28241446	The accuracies of PAX1 and ZNF582 methylation testing were 0.893 and 0.954, respectively (Table 2).	('methylation', 'Var', (34, 45))	('PAX1', 'Gene', '5075', (18, 22))	('PAX1', 'Gene', (18, 22))	('ZNF582', 'Gene', '147948', (27, 33))	('ZNF582', 'Gene', (27, 33))
338710	28241446	As shown in Figure 2 and Table 2, the sensitivity and specificity of PAX1 methylation testing achieved 100% and 78.6% at the best meth-index cut-off value of -2.376, respectively.	('PAX1', 'Gene', (69, 73))	('PAX1', 'Gene', '5075', (69, 73))	('methylation', 'Var', (74, 85))
338711	28241446	At the best meth-index cut-off value of -0.597, the sensitivity and specificity of ZNF582 methylation testing were 85.7% and 100%, respectively.	('methylation', 'Var', (90, 101))	('ZNF582', 'Gene', '147948', (83, 89))	('ZNF582', 'Gene', (83, 89))
338712	28241446	Additionally, as shown in Figure 3C, the results of the accuracies of PAX1 and ZNF582 methylation testing using TCGA datasets were 0.760 and 0.806, respectively (Table 2).	('PAX1', 'Gene', (70, 74))	('methylation', 'Var', (86, 97))	('PAX1', 'Gene', '5075', (70, 74))	('ZNF582', 'Gene', '147948', (79, 85))	('ZNF582', 'Gene', (79, 85))
338713	28241446	The sensitivity and specificity of PAX1 methylation testing achieved 80.7% and 75.0%, respectively, and the sensitivity and specificity of ZNF582 methylation testing were 88.2% and 81.2%, respectively.	('ZNF582', 'Gene', (139, 145))	('methylation', 'Var', (40, 51))	('PAX1', 'Gene', (35, 39))	('PAX1', 'Gene', '5075', (35, 39))	('ZNF582', 'Gene', '147948', (139, 145))
338715	28241446	However, there is a tendency that PAX1 methylation level was associated with TNM stage and lymph node metastasis with a p value of 0.068 and 0.073, respectively, while ZNF582 methylation level was associated with carcino-embryonic antigen (CEA) concentration with a p value of 0.076 (Table 4).	('CEA', 'Gene', '1084', (240, 243))	('PAX1', 'Gene', (34, 38))	('methylation', 'Var', (39, 50))	('PAX1', 'Gene', '5075', (34, 38))	('TNM', 'Gene', (77, 80))	('ZNF582', 'Gene', '147948', (168, 174))	('lymph node metastasis', 'CPA', (91, 112))	('TNM', 'Gene', '10178', (77, 80))	('ZNF582', 'Gene', (168, 174))	('carcino-embryonic antigen', 'Gene', '1084', (213, 238))	('associated', 'Reg', (197, 207))	('associated', 'Reg', (61, 71))	('CEA', 'Gene', (240, 243))	('carcino-embryonic antigen', 'Gene', (213, 238))
338716	28241446	However, there is no association between methylation occurrence frequency of PAX1 and ZNF582 and any clinical features as shown in Table 3.	('ZNF582', 'Gene', (86, 92))	('PAX1', 'Gene', '5075', (77, 81))	('methylation', 'Var', (41, 52))	('ZNF582', 'Gene', '147948', (86, 92))	('PAX1', 'Gene', (77, 81))
338718	28241446	Previous studies have shown that the methylation status of PAX1 and ZNF582 genes is a useful testing to distinguish tumor and non-tumor tissues in cervical and oral squamous cell carcinoma.	('tumor', 'Disease', (130, 135))	('oral squamous cell carcinoma', 'Disease', (160, 188))	('cervical', 'Disease', (147, 155))	('PAX1', 'Gene', (59, 63))	('PAX1', 'Gene', '5075', (59, 63))	('methylation', 'Var', (37, 48))	('ZNF582', 'Gene', '147948', (68, 74))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (160, 188))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('ZNF582', 'Gene', (68, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (179, 188))	('tumor', 'Disease', (116, 121))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (165, 188))
338719	28241446	In the present study, we have for the first time demonstrated that the levels and frequencies of PAX1 and ZNF582 methylation are markedly higher in the tumor tissues compared to non-tumor tissues from ESCC patients, and methylation testing of these two genes has an excellent accuracy and great sensitivity and specificity to detect ESCC tumors, suggesting that PAX1 and ZNF582 methylation testing may be a promising biomarker for the detection of ESCC.	('SCC', 'Phenotype', 'HP:0002860', (334, 337))	('tumor', 'Disease', (338, 343))	('ESCC tumors', 'Disease', 'MESH:D004938', (333, 344))	('PAX1', 'Gene', (97, 101))	('PAX1', 'Gene', '5075', (362, 366))	('tumor', 'Disease', 'MESH:D009369', (338, 343))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))	('ZNF582', 'Gene', '147948', (371, 377))	('tumor', 'Disease', (152, 157))	('tumors', 'Phenotype', 'HP:0002664', (338, 344))	('ZNF582', 'Gene', (106, 112))	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('ESCC tumors', 'Disease', (333, 344))	('PAX1', 'Gene', (362, 366))	('tumor', 'Phenotype', 'HP:0002664', (338, 343))	('PAX1', 'Gene', '5075', (97, 101))	('higher', 'PosReg', (138, 144))	('SCC', 'Phenotype', 'HP:0002860', (449, 452))	('tumor', 'Disease', (182, 187))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('methylation', 'Var', (113, 124))	('SCC', 'Phenotype', 'HP:0002860', (202, 205))	('ZNF582', 'Gene', '147948', (106, 112))	('patients', 'Species', '9606', (206, 214))	('ZNF582', 'Gene', (371, 377))	('tumor', 'Disease', 'MESH:D009369', (182, 187))
338723	28241446	On the other hand, PAX1 and PAX4 are silenced by DNA methylation in ovarian and cervical cancers and in melanoma, and may function as tumor suppressors.	('melanoma', 'Phenotype', 'HP:0002861', (104, 112))	('melanoma', 'Disease', (104, 112))	('ovarian and cervical cancers', 'Disease', 'MESH:D010051', (68, 96))	('cancers', 'Phenotype', 'HP:0002664', (89, 96))	('melanoma', 'Disease', 'MESH:D008545', (104, 112))	('silenced', 'NegReg', (37, 45))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('PAX4', 'Gene', (28, 32))	('PAX4', 'Gene', '5078', (28, 32))	('PAX1', 'Gene', (19, 23))	('PAX1', 'Gene', '5075', (19, 23))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('DNA methylation', 'Var', (49, 64))	('tumor', 'Disease', (134, 139))	('methylation', 'Var', (53, 64))
338725	28241446	Previous studies have reported that PAX1 methylation testing is a potential biomarker for the screening of cervical cancer with a sensitivity and specificity greater than 80% in the detection of grade III or higher cervical intraepithelial neoplasia (CIN3+) lesions.	('cervical cancer', 'Disease', (107, 122))	('higher', 'PosReg', (208, 214))	('methylation', 'Var', (41, 52))	('cervical intraepithelial neoplasia', 'Phenotype', 'HP:0032242', (215, 249))	('cervical intraepithelial neoplasia', 'Disease', 'MESH:D018290', (215, 249))	('cervical intraepithelial neoplasia', 'Disease', (215, 249))	('PAX1', 'Gene', (36, 40))	('PAX1', 'Gene', '5075', (36, 40))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cervical cancer', 'Disease', 'MESH:D002583', (107, 122))	('intraepithelial neoplasia', 'Phenotype', 'HP:0032187', (224, 249))	('neoplasia', 'Phenotype', 'HP:0002664', (240, 249))
338726	28241446	The efficacy of PAX1 methylation testing in detecting cervical cancer is significantly improved with a combination of cervical cell cytology or HPV 16, 18 genotyping.	('cervical cancer', 'Disease', (54, 69))	('cervical cancer', 'Disease', 'MESH:D002583', (54, 69))	('improved', 'PosReg', (87, 95))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('methylation testing', 'Var', (21, 40))	('HPV 16', 'Species', '333760', (144, 150))	('PAX1', 'Gene', (16, 20))	('PAX1', 'Gene', '5075', (16, 20))
338727	28241446	Consistent with the reports in cervical cancers, we observed in the current study that PAX1 methylation testing had a 100% sensitivity and a 78.6% specificity in the detection of ESCC tumors, indicating that PAX1 methylation is a valuable biomarker for ESCC diagnosis.	('cancers', 'Phenotype', 'HP:0002664', (40, 47))	('methylation', 'Var', (92, 103))	('ESCC tumors', 'Disease', (179, 190))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('PAX1', 'Gene', (87, 91))	('cervical cancers', 'Disease', (31, 47))	('PAX1', 'Gene', '5075', (87, 91))	('SCC', 'Phenotype', 'HP:0002860', (254, 257))	('tumors', 'Phenotype', 'HP:0002664', (184, 190))	('ESCC tumors', 'Disease', 'MESH:D004938', (179, 190))	('PAX1', 'Gene', (208, 212))	('cervical cancers', 'Disease', 'MESH:D002583', (31, 47))	('PAX1', 'Gene', '5075', (208, 212))	('SCC', 'Phenotype', 'HP:0002860', (180, 183))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))
338731	28241446	Consistent with the concept that ZNF582 is a tumor suppressor, ZNF582 hypermethylation has been reported in acute myeloid leukemia and various invasive cancers.	('acute myeloid leukemia', 'Disease', (108, 130))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('ZNF582', 'Gene', '147948', (33, 39))	('ZNF582', 'Gene', (33, 39))	('reported', 'Reg', (96, 104))	('leukemia', 'Phenotype', 'HP:0001909', (122, 130))	('hypermethylation', 'Var', (70, 86))	('tumor', 'Disease', (45, 50))	('invasive cancers', 'Disease', 'MESH:D009362', (143, 159))	('invasive cancers', 'Disease', (143, 159))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (108, 130))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (108, 130))	('ZNF582', 'Gene', '147948', (63, 69))	('cancers', 'Phenotype', 'HP:0002664', (152, 159))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (114, 130))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('ZNF582', 'Gene', (63, 69))
338732	28241446	reported that ZNF582 methylation testing had a 70% sensitivity and an 82% specificity for the detection of cervical cancer CIN3+ lesions, and a great sensitivity and specificity in the classification of low-grade squamous intraepithelial lesion (LSIL).	('cervical cancer', 'Disease', (107, 122))	('ZNF582', 'Gene', (14, 20))	('squamous intraepithelial lesion', 'Disease', 'MESH:D000081483', (213, 244))	('methylation', 'Var', (21, 32))	('CIN3+', 'Var', (123, 128))	('ZNF582', 'Gene', '147948', (14, 20))	('squamous intraepithelial lesion', 'Disease', (213, 244))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cervical cancer', 'Disease', 'MESH:D002583', (107, 122))
338733	28241446	In the present study, we demonstrated that ZNF582 gene was much more frequently methylated in ESCC tumor tissues compared to non-tumor paracancerous tissues.	('ESCC tumor', 'Disease', 'MESH:D004938', (94, 104))	('more', 'PosReg', (64, 68))	('non-tumor paracancerous', 'Disease', (125, 148))	('paracancerous tissues', 'Disease', (135, 156))	('ZNF582', 'Gene', (43, 49))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('non-tumor paracancerous', 'Disease', 'MESH:D009369', (125, 148))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('ESCC tumor', 'Disease', (94, 104))	('methylated', 'Var', (80, 90))	('paracancerous tissues', 'Disease', 'MESH:D009380', (135, 156))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('SCC', 'Phenotype', 'HP:0002860', (95, 98))	('ZNF582', 'Gene', '147948', (43, 49))
338734	28241446	ZNF582 methylation testing reaches a 100% specificity and an 85.7% sensitivity for the detection of ESCC tumors (see Table 2), suggesting that it is a useful biomarker for screening ESCC.	('ESCC tumors', 'Disease', (100, 111))	('methylation', 'Var', (7, 18))	('SCC', 'Phenotype', 'HP:0002860', (183, 186))	('ZNF582', 'Gene', '147948', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('SCC', 'Phenotype', 'HP:0002860', (101, 104))	('ESCC tumors', 'Disease', 'MESH:D004938', (100, 111))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('ZNF582', 'Gene', (0, 6))
338735	28241446	Moreover, a combination of PAX1 and ZNF582 methylation testing could reach a 100% sensitivity and specificity in the detection of ESCC tumors.	('PAX1', 'Gene', (27, 31))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('methylation testing', 'Var', (43, 62))	('ESCC tumors', 'Disease', 'MESH:D004938', (130, 141))	('PAX1', 'Gene', '5075', (27, 31))	('ZNF582', 'Gene', (36, 42))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))	('SCC', 'Phenotype', 'HP:0002860', (131, 134))	('ESCC tumors', 'Disease', (130, 141))	('ZNF582', 'Gene', '147948', (36, 42))
338736	28241446	To further evaluate the clinical significance of PAX1 and ZNF582 methylation in ESCC development and progression, the association of PAX1/ZNF582 methylation to the clinicopathological features of ESCC patients was analyzed, as a previous report indicated a significant association between PAX6 methylation and TNM stage of non-small cell lung cancer (NSCLC).	('PAX1', 'Gene', (49, 53))	('methylation', 'Var', (294, 305))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (323, 349))	('ZNF582', 'Gene', (58, 64))	('cancer', 'Phenotype', 'HP:0002664', (343, 349))	('ZNF582', 'Gene', (138, 144))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (327, 349))	('SCC', 'Phenotype', 'HP:0002860', (197, 200))	('PAX1', 'Gene', (133, 137))	('patients', 'Species', '9606', (201, 209))	('PAX1', 'Gene', '5075', (49, 53))	('ZNF582', 'Gene', '147948', (58, 64))	('cell lung cancer', 'Disease', 'MESH:D008175', (333, 349))	('NSCLC', 'Disease', 'MESH:D002289', (351, 356))	('ZNF582', 'Gene', '147948', (138, 144))	('lung cancer', 'Phenotype', 'HP:0100526', (338, 349))	('ESCC', 'Disease', (80, 84))	('cell lung cancer', 'Disease', (333, 349))	('NSCLC', 'Disease', (351, 356))	('PAX6', 'Gene', (289, 293))	('TNM', 'Gene', '10178', (310, 313))	('PAX6', 'Gene', '5080', (289, 293))	('SCC', 'Phenotype', 'HP:0002860', (81, 84))	('PAX1', 'Gene', '5075', (133, 137))	('NSCLC', 'Phenotype', 'HP:0030358', (351, 356))	('TNM', 'Gene', (310, 313))
338738	28241446	However, the associations of PAX1 methylation with TNM stage (p = 0.068) and LN metastasis (p = 0.073) and ZNF582 methylation with CEA concentration (p = 0.076) appear to be interesting.	('LN metastasis', 'CPA', (77, 90))	('TNM', 'Gene', '10178', (51, 54))	('methylation', 'Var', (34, 45))	('CEA', 'Gene', (131, 134))	('CEA', 'Gene', '1084', (131, 134))	('ZNF582', 'Gene', '147948', (107, 113))	('PAX1', 'Gene', (29, 33))	('PAX1', 'Gene', '5075', (29, 33))	('methylation', 'Var', (114, 125))	('associations', 'Interaction', (13, 25))	('TNM', 'Gene', (51, 54))	('ZNF582', 'Gene', (107, 113))
338743	28241446	The methylation of PAX1 and ZNF582 detected in these cells could act as biomarkers for esophageal cancer screening in the future, which could replace traditional endoscopy as an equally effective but less invasive way of diagnosing for esophageal cancer.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('esophageal cancer', 'Disease', 'MESH:D004938', (236, 253))	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('esophageal cancer', 'Disease', (87, 104))	('ZNF582', 'Gene', '147948', (28, 34))	('methylation', 'Var', (4, 15))	('esophageal cancer', 'Disease', 'MESH:D004938', (87, 104))	('PAX1', 'Gene', (19, 23))	('PAX1', 'Gene', '5075', (19, 23))	('esophageal cancer', 'Disease', (236, 253))	('ZNF582', 'Gene', (28, 34))
338746	28241446	PAX1 and ZNF582 methylation testing has an excellent accuracy, sensitivity and specificity in distinguishing ESCC tumor tissues from non-tumor tissues.	('ESCC tumor', 'Disease', (109, 119))	('ZNF582', 'Gene', (9, 15))	('PAX1', 'Gene', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('tumor', 'Disease', (137, 142))	('PAX1', 'Gene', '5075', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('ESCC tumor', 'Disease', 'MESH:D004938', (109, 119))	('tumor', 'Disease', (114, 119))	('SCC', 'Phenotype', 'HP:0002860', (110, 113))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('ZNF582', 'Gene', '147948', (9, 15))	('methylation', 'Var', (16, 27))
338747	28241446	The combination of PAX1 and ZNF582 methylation testing could reach a 100% sensitivity and specificity in detecting ESCC tumors, providing a promising biomarker for ESCC screening and diagnosis, although further studies with larger sample size or population-based investigation are necessary to confirm this intriguing finding.	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('SCC', 'Phenotype', 'HP:0002860', (116, 119))	('SCC', 'Phenotype', 'HP:0002860', (165, 168))	('ZNF582', 'Gene', '147948', (28, 34))	('ESCC', 'Disease', (164, 168))	('PAX1', 'Gene', (19, 23))	('methylation', 'Var', (35, 46))	('PAX1', 'Gene', '5075', (19, 23))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('ESCC tumors', 'Disease', (115, 126))	('ZNF582', 'Gene', (28, 34))	('ESCC tumors', 'Disease', 'MESH:D004938', (115, 126))
338774	28088212	One study made use of ddPCR for detection of oncogenic E6/E7 mRNA in fresh tissue OPSCC specimens and found 100% sensitivity compared to p16 IHC using target RNA 20-50 times lower than reported for RT-qPCR.	('E6/E7 mRNA', 'Var', (55, 65))	('p16', 'Gene', '1029', (137, 140))	('p16', 'Gene', (137, 140))
338775	28088212	Because of the accuracy and ultra-sensitivity of ddPCR for identification of oncogenic HPV E6/E7 mRNA, we hypothesized that ddPCR can be used for detection of oncogenic HPV in OPSCC using oral/oropharyngeal swabs as opposed to fresh tissue.	('HPV', 'Gene', (169, 172))	('HPV', 'Species', '10566', (87, 90))	('E6/E7 mRNA', 'Var', (91, 101))	('HPV', 'Species', '10566', (169, 172))
338801	28088212	ddPCR was carried out using the ddPCRTM Supermix for Probes (No dUTP) (BIO-RAD, Mississauga, ON, CAN), the QX200TM Droplet Generator (catalog #186-4002 BIO-RAD), the QX200 Droplet Reader (catalog #186-4003 BIO-RAD) the C1000 TouchTM Thermal Cycler (catalog #185-1197 BIO-RAD) and the PX1TM PCR Plate Sealer (catalog #181-4000 BIO-RAD) as per manufacturer's instructions.	('RAD', 'Gene', '6236', (75, 78))	('RAD', 'Gene', (271, 274))	('RAD', 'Gene', (330, 333))	('catalog #186-4003', 'Var', (188, 205))	('RAD', 'Gene', (210, 213))	('dUTP', 'Chemical', 'MESH:C027078', (64, 68))	('RAD', 'Gene', '6236', (271, 274))	('RAD', 'Gene', (156, 159))	('RAD', 'Gene', '6236', (210, 213))	('RAD', 'Gene', '6236', (330, 333))	('RAD', 'Gene', (75, 78))	('RAD', 'Gene', '6236', (156, 159))
338806	28088212	Reactions were set up in a 96 well plate, mixed using a Mixmate Vortex Shaker (Eppendorf, Mississauga, ON, CAN) and 20 mul of the reaction mixture was transferred to DG8TM Cartridge for QX200/QX100 Droplet Generator (catalog #186-4008 BIO-RAD) followed by 70 mul of Droplet Generation Oil for Probes (catalog #186-3005 BIO-RAD) into the oil wells, according to the QX200 Droplet Generator Instruction Manual (#10031907 BIO-RAD).	('RAD', 'Gene', (239, 242))	('oil', 'Chemical', 'MESH:D009821', (337, 340))	('catalog #186-3005', 'Var', (301, 318))	('RAD', 'Gene', '6236', (239, 242))	('RAD', 'Gene', (423, 426))	('RAD', 'Gene', (323, 326))	('RAD', 'Gene', '6236', (423, 426))	('RAD', 'Gene', '6236', (323, 326))
338819	28088212	33/36 (92%) of patients with p16+OPSCC tested positive for E6/E7 by ddPCR (Table 2).	('p16', 'Gene', (29, 32))	('E6/E7', 'Var', (59, 64))	('patients', 'Species', '9606', (15, 23))	('p16', 'Gene', '1029', (29, 32))	('positive', 'Reg', (46, 54))
338820	28088212	One patient with p16-OPSCC tested positive for E6/E7 by ddPCR.	('positive', 'Reg', (34, 42))	('E6/E7', 'Var', (47, 52))	('p16', 'Gene', (17, 20))	('patient', 'Species', '9606', (4, 11))	('p16', 'Gene', '1029', (17, 20))
338822	28088212	All 4 patients with p16+OCSCC tested negative for E6/E7 by ddPCR, as did all 41 patients with p16-OCSCC (Table 3).	('p16', 'Gene', '1029', (94, 97))	('ddPCR', 'Gene', (59, 64))	('patients', 'Species', '9606', (80, 88))	('p16', 'Gene', (20, 23))	('p16', 'Gene', '1029', (20, 23))	('patients', 'Species', '9606', (6, 14))	('p16', 'Gene', (94, 97))	('E6/E7', 'Var', (50, 55))	('negative', 'NegReg', (37, 45))
338823	28088212	All 25 healthy control patients tested negative for E6/E7 by ddPCR, for an overall specificity of 98% for OPSCC.	('patients', 'Species', '9606', (23, 31))	('E6/E7', 'Var', (52, 57))	('OPSCC', 'Disease', (106, 111))	('ddPCR', 'Gene', (61, 66))
338836	28088212	Our results also demonstrated a high degree of accuracy in determining HPV status in OCSCC, as all 4 patients with p16+OCSCC tested negative for E6/E7 by ddPCR.	('patients', 'Species', '9606', (101, 109))	('p16', 'Gene', '1029', (115, 118))	('E6/E7', 'Var', (145, 150))	('negative', 'NegReg', (132, 140))	('HPV', 'Species', '10566', (71, 74))	('p16', 'Gene', (115, 118))	('OCSCC', 'Disease', (85, 90))
338837	28088212	Other studies have shown that non-OPSCC that are p16 positive are usually unrelated to HPV, and that p16 positivity does not purport a better prognosis in non-OPSCC, and may in fact yield a worse prognosis in these patients.	('non-OPSCC', 'Disease', (155, 164))	('patients', 'Species', '9606', (215, 223))	('p16', 'Gene', '1029', (101, 104))	('HPV', 'Species', '10566', (87, 90))	('p16', 'Gene', (49, 52))	('yield', 'Reg', (182, 187))	('p16', 'Gene', (101, 104))	('positivity', 'Var', (105, 115))	('p16', 'Gene', '1029', (49, 52))
338851	28088212	We also only tested for HPV 16 as in other studies; however, HPV 16 is known to cause more than 95% of HPV-related OPSCC.	('HPV 16', 'Var', (61, 67))	('HPV', 'Species', '10566', (24, 27))	('HPV', 'Species', '10566', (103, 106))	('HPV 16', 'Species', '333760', (61, 67))	('HPV 16', 'Species', '333760', (24, 30))	('OPSCC', 'Disease', (115, 120))	('HPV-related OPSCC', 'Disease', (103, 120))	('cause', 'Reg', (80, 85))	('HPV', 'Species', '10566', (61, 64))
338857	27042257	In this paper, we found that the median somatic total mutation loads and the median somatic single nucleotide mutation loads exhibited significant inverse correlations with the median NEIL1 and NEIL2 expression levels and a significant positive correlation with the median NEIL3 expression level using data for 13 cancer types from the Cancer Genome Atlas (TCGA) database.	('if', 'Gene', '35045', (228, 230))	('mutation loads', 'Var', (54, 68))	('cancer', 'Disease', (314, 320))	('inverse', 'NegReg', (147, 154))	('Cancer Genome Atlas', 'Disease', (336, 355))	('NEIL2', 'Gene', '252969', (194, 199))	('expression levels', 'MPA', (200, 217))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (336, 355))	('NEIL1', 'Gene', '79661', (184, 189))	('cancer', 'Phenotype', 'HP:0002664', (314, 320))	('Cancer', 'Phenotype', 'HP:0002664', (336, 342))	('NEIL1', 'Gene', (184, 189))	('if', 'Gene', '35045', (139, 141))	('NEIL2', 'Gene', (194, 199))	('cancer', 'Disease', 'MESH:D009369', (314, 320))
338858	27042257	A subset of the cancer types exhibited reduced NEIL1 and NEIL2 expressions and elevated NEIL3 expression, and such abnormal expressions of NEIL1, NEIL2, and NEIL3 were also significantly associated with the mutation loads in cancer.	('abnormal expressions', 'Phenotype', 'HP:0100022', (115, 135))	('NEIL1', 'Gene', (47, 52))	('cancer', 'Disease', (225, 231))	('expressions', 'MPA', (63, 74))	('NEIL1', 'Gene', '79661', (139, 144))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('mutation loads', 'Var', (207, 221))	('NEIL2', 'Gene', (57, 62))	('NEIL2', 'Gene', '252969', (146, 151))	('cancer', 'Disease', (16, 22))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('NEIL1', 'Gene', (139, 144))	('cancer', 'Disease', 'MESH:D009369', (225, 231))	('NEIL2', 'Gene', '252969', (57, 62))	('associated', 'Reg', (187, 197))	('elevated', 'PosReg', (79, 87))	('expression', 'MPA', (94, 104))	('reduced', 'NegReg', (39, 46))	('NEIL1', 'Gene', '79661', (47, 52))	('NEIL3', 'Gene', (88, 93))	('if', 'Gene', '35045', (177, 179))	('cancer', 'Disease', 'MESH:D009369', (16, 22))	('NEIL2', 'Gene', (146, 151))
338859	27042257	As a mechanism underlying the reduced expression of NEIL1 in cancer, the epigenetic silencing of NEIL1 through promoter hypermethylation was found.	('promoter hypermethylation', 'Var', (111, 136))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('NEIL1', 'Gene', '79661', (52, 57))	('expression', 'MPA', (38, 48))	('cancer', 'Disease', (61, 67))	('NEIL1', 'Gene', '79661', (97, 102))	('epigenetic silencing', 'Var', (73, 93))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('reduced', 'NegReg', (30, 37))	('NEIL1', 'Gene', (52, 57))	('NEIL1', 'Gene', (97, 102))
338861	27042257	These results suggested that the abnormal expressions of NEIL1, NEIL2, and NEIL3 are involved in cancer through their association with the somatic mutation load.	('NEIL1', 'Gene', (57, 62))	('abnormal expressions', 'Phenotype', 'HP:0100022', (33, 53))	('cancer', 'Disease', (97, 103))	('cancer', 'Disease', 'MESH:D009369', (97, 103))	('NEIL2', 'Gene', (64, 69))	('involved', 'Reg', (85, 93))	('somatic', 'Var', (139, 146))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('abnormal', 'Var', (33, 41))	('association', 'Interaction', (118, 129))	('NEIL1', 'Gene', '79661', (57, 62))	('NEIL2', 'Gene', '252969', (64, 69))	('NEIL3', 'Gene', (75, 80))
338862	27042257	NEIL1 (ENSG00000140398, OMIM #608844), NEIL2 (ENSG00000154328, OMIM #608933), and NEIL3 (ENSG00000109674, OMIM #608934) are structural human homologues of Escherichia coli (E. coli) Nei and Fpg, the genes encoding a DNA glycosylase that initiates the base excision repair (BER) process.	('ENSG00000109674', 'Var', (89, 104))	('ENSG00000140398', 'Var', (7, 22))	('E. coli', 'Species', '562', (173, 180))	('NEIL1', 'Gene', (0, 5))	('ENSG00000154328', 'Var', (46, 61))	('NEIL2', 'Gene', '252969', (39, 44))	('human', 'Species', '9606', (135, 140))	('Escherichia coli', 'Species', '562', (155, 171))	('NEIL1', 'Gene', '79661', (0, 5))	('NEIL2', 'Gene', (39, 44))
338869	27042257	These findings indicate that NEIL1, NEIL2, and NEIL3 have the ability to suppress mutations in cells.	('NEIL1', 'Gene', (29, 34))	('NEIL2', 'Gene', (36, 41))	('mutations', 'Var', (82, 91))	('NEIL1', 'Gene', '79661', (29, 34))	('NEIL2', 'Gene', '252969', (36, 41))	('NEIL3', 'Gene', (47, 52))
338870	27042257	Therefore, NEIL1, NEIL2, and NEIL3 are important enzymes to maintain the stability of genomic DNA by preventing mutations.	('NEIL1', 'Gene', '79661', (11, 16))	('preventing', 'NegReg', (101, 111))	('NEIL2', 'Gene', (18, 23))	('mutations', 'Var', (112, 121))	('NEIL1', 'Gene', (11, 16))	('NEIL2', 'Gene', '252969', (18, 23))
338872	27042257	Such investigations have revealed that the inactivation of mismatch repair genes, inactivating mutations of BRCA1 (ENSG00000012048), BRCA2 (ENSG00000139618), POLE (ENSG00000177084), and POLK (ENSG00000122008), or the overexpression of APOBEC3B (ENSG00000179750) causes mutagenesis in cancer.	('cancer', 'Disease', 'MESH:D009369', (284, 290))	('BRCA1', 'Gene', '672', (108, 113))	('ENSG00000179750', 'Var', (245, 260))	('POLK', 'Gene', '51426', (186, 190))	('BRCA1', 'Gene', (108, 113))	('ENSG00000012048', 'Var', (115, 130))	('APOBEC3B', 'Gene', '9582', (235, 243))	('ENSG00000139618', 'Var', (140, 155))	('ENSG00000122008', 'Var', (192, 207))	('BRCA2', 'Gene', (133, 138))	('POLK', 'Gene', (186, 190))	('causes', 'Reg', (262, 268))	('overexpression', 'PosReg', (217, 231))	('inactivation', 'Var', (43, 55))	('inactivating mutations', 'Var', (82, 104))	('cancer', 'Disease', (284, 290))	('mismatch repair genes', 'Gene', (59, 80))	('ENSG00000177084', 'Var', (164, 179))	('BRCA', 'Phenotype', 'HP:0003002', (133, 137))	('BRCA2', 'Gene', '675', (133, 138))	('cancer', 'Phenotype', 'HP:0002664', (284, 290))	('BRCA', 'Phenotype', 'HP:0003002', (108, 112))	('APOBEC3B', 'Gene', (235, 243))	('mutagenesis', 'MPA', (269, 280))
338895	27042257	As expected, the median total mutation load and the median SNP-type mutation load showed a strong inverse correlation with the median NEIL1 expression level (rho = -0.6382, P = 0.0189 and rho = -0.6429, P = 0.0178, resp.)	('mutation load', 'Var', (30, 43))	('NEIL1', 'Gene', '79661', (134, 139))	('NEIL1', 'Gene', (134, 139))	('inverse', 'NegReg', (98, 105))
338896	27042257	In addition, the median total mutation load and the median SNP-type mutation load showed a strong inverse correlation with the median NEIL2 expression level (rho = -0.6713, P = 0.0120 and rho = -0.6758, P = 0.0112, resp.).	('NEIL2', 'Gene', '252969', (134, 139))	('mutation load', 'Var', (30, 43))	('NEIL2', 'Gene', (134, 139))	('inverse', 'NegReg', (98, 105))
338904	27042257	We next investigated whether the abnormal expressions of NEIL1, NEIL2, and NEIL3 were associated with the mutation load in each cancer type.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('NEIL1', 'Gene', (57, 62))	('abnormal expressions', 'Phenotype', 'HP:0100022', (33, 53))	('mutation load', 'Var', (106, 119))	('NEIL2', 'Gene', (64, 69))	('associated', 'Reg', (86, 96))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('NEIL3', 'Gene', (75, 80))	('NEIL1', 'Gene', '79661', (57, 62))	('NEIL2', 'Gene', '252969', (64, 69))	('cancer', 'Disease', (128, 134))
338907	27042257	These results suggested that the abnormal expressions of NEIL1, NEIL2, and NEIL3 are associated with the mutation load in cancer.	('NEIL1', 'Gene', (57, 62))	('abnormal expressions', 'Phenotype', 'HP:0100022', (33, 53))	('cancer', 'Disease', (122, 128))	('NEIL2', 'Gene', (64, 69))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('NEIL1', 'Gene', '79661', (57, 62))	('NEIL2', 'Gene', '252969', (64, 69))	('mutation load', 'Var', (105, 118))	('associated', 'Reg', (85, 95))	('NEIL3', 'Gene', (75, 80))
338909	27042257	Nine [breast invasive carcinoma, colon adenocarcinoma, HNSCC, clear cell renal cell carcinoma (RCC), papillary RCC, lung adenocarcinoma, lung squamous cell carcinoma, rectal adenocarcinoma, and stomach adenocarcinoma] of the 13 (69.2%) cancer types satisfied the 4 criteria for epigenetic silencing described in Section 2 for the NEIL1 gene, whereas none of the cancer types satisfied the criteria for the NEIL2 or NEIL3 gene (Table 2, Figures 2(a) and 2(b), Supplementary Figure S5, and Supplementary Table S6).	('cancer', 'Disease', 'MESH:D009369', (236, 242))	('RCC', 'Disease', 'MESH:C538614', (111, 114))	('NEIL1', 'Gene', '79661', (330, 335))	('epigenetic silencing', 'Var', (278, 298))	('colon adenocarcinoma', 'Disease', (33, 53))	('papillary RCC, lung adenocarcinoma, lung squamous cell carcinoma', 'Disease', 'MESH:D000077192', (101, 165))	('men', 'Species', '9606', (494, 497))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (62, 93))	('NEIL2', 'Gene', (406, 411))	('rectal adenocarcinoma', 'Disease', (167, 188))	('cancer', 'Disease', 'MESH:D009369', (362, 368))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (137, 165))	('breast invasive carcinoma', 'Disease', (6, 31))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (116, 135))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (142, 165))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('NEIL1', 'Gene', (330, 335))	('clear cell renal cell carcinoma', 'Disease', (62, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (156, 165))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (73, 93))	('NEIL2', 'Gene', '252969', (406, 411))	('stomach adenocarcinoma', 'Disease', (194, 216))	('cancer', 'Disease', (236, 242))	('RCC', 'Phenotype', 'HP:0005584', (95, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('RCC', 'Disease', (95, 98))	('colon adenocarcinoma', 'Disease', 'MESH:D003110', (33, 53))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('HNSC', 'Phenotype', 'HP:0012288', (55, 59))	('rectal adenocarcinoma', 'Disease', 'MESH:D012004', (167, 188))	('breast invasive carcinoma', 'Phenotype', 'HP:0003002', (6, 31))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (62, 93))	('HNSCC', 'Phenotype', 'HP:0012288', (55, 60))	('cancer', 'Disease', (362, 368))	('RCC', 'Disease', (111, 114))	('RCC', 'Phenotype', 'HP:0005584', (111, 114))	('RCC', 'Disease', 'MESH:C538614', (95, 98))	('cancer', 'Phenotype', 'HP:0002664', (362, 368))	('carcinoma', 'Phenotype', 'HP:0030731', (44, 53))	('men', 'Species', '9606', (465, 468))	('stomach adenocarcinoma', 'Disease', 'MESH:D013274', (194, 216))	('breast invasive carcinoma', 'Disease', 'MESH:D018270', (6, 31))
338910	27042257	Together with a previous finding that the region around the transcription start site of the NEIL1 gene exhibits promoter activity, these results suggest that these cancer types exhibit epigenetic silencing of the NEIL1 via promoter hypermethylation.	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('NEIL1', 'Gene', (92, 97))	('promoter activity', 'MPA', (112, 129))	('NEIL1', 'Gene', (213, 218))	('cancer', 'Disease', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('epigenetic', 'Var', (185, 195))	('NEIL1', 'Gene', '79661', (92, 97))	('NEIL1', 'Gene', '79661', (213, 218))
338912	27042257	The expression level of NEIL1, but not of NEIL3, was increased in both cell lines by the 5-aza-dC treatment, strengthening the notion of the epigenetic silencing of NEIL1 expression (Figure 2(c)).	('5-aza-dC', 'Var', (89, 97))	('expression level', 'MPA', (4, 20))	('NEIL1', 'Gene', '79661', (24, 29))	('men', 'Species', '9606', (103, 106))	('5-aza-dC', 'Chemical', 'MESH:D000077209', (89, 97))	('NEIL1', 'Gene', (165, 170))	('NEIL1', 'Gene', (24, 29))	('epigenetic silencing', 'Var', (141, 161))	('increased', 'PosReg', (53, 62))	('NEIL1', 'Gene', '79661', (165, 170))
338923	27042257	The APOBEC3B expression level was significantly higher in the group of cancers with a high NEIL3 expression level than in the group of cancers with a low NEIL3 expression level in 10 of the 13 (76.9%) cancer types (Table 3, Supplementary Figure S6).	('cancer', 'Disease', (201, 207))	('cancers', 'Disease', 'MESH:D009369', (135, 142))	('if', 'Gene', '35045', (38, 40))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('cancer', 'Disease', (135, 141))	('cancers', 'Phenotype', 'HP:0002664', (71, 78))	('cancers', 'Disease', (71, 78))	('cancer', 'Disease', (71, 77))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('APOBEC3B', 'Gene', '9582', (4, 12))	('expression level', 'MPA', (13, 29))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('men', 'Species', '9606', (230, 233))	('cancers', 'Phenotype', 'HP:0002664', (135, 142))	('cancers', 'Disease', (135, 142))	('high NEIL3 expression level', 'Var', (86, 113))	('cancer', 'Disease', 'MESH:D009369', (135, 141))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('cancers', 'Disease', 'MESH:D009369', (71, 78))	('APOBEC3B', 'Gene', (4, 12))	('higher', 'PosReg', (48, 54))
338928	27042257	We also showed that a subset of human cancers exhibited reduced NEIL1 and NEIL2 expression levels and an elevated NEIL3 expression level, and these abnormal expressions of NEIL1, NEIL2, and NEIL3 were associated with the mutation load in cancer.	('NEIL1', 'Gene', '79661', (172, 177))	('NEIL1', 'Gene', (64, 69))	('expression levels', 'MPA', (80, 97))	('NEIL2', 'Gene', '252969', (179, 184))	('cancers', 'Disease', 'MESH:D009369', (38, 45))	('mutation load', 'Var', (221, 234))	('cancer', 'Disease', (238, 244))	('elevated', 'PosReg', (105, 113))	('NEIL2', 'Gene', '252969', (74, 79))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('NEIL1', 'Gene', (172, 177))	('cancer', 'Disease', (38, 44))	('human', 'Species', '9606', (32, 37))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('reduced', 'NegReg', (56, 63))	('NEIL3 expression level', 'MPA', (114, 136))	('abnormal expressions', 'Phenotype', 'HP:0100022', (148, 168))	('cancers', 'Phenotype', 'HP:0002664', (38, 45))	('cancers', 'Disease', (38, 45))	('NEIL1', 'Gene', '79661', (64, 69))	('cancer', 'Disease', 'MESH:D009369', (238, 244))	('NEIL2', 'Gene', (179, 184))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('associated', 'Reg', (201, 211))	('NEIL2', 'Gene', (74, 79))
338931	27042257	Thus, our results suggest that the abnormal regulation of NEIL1, NEIL2, and NEIL3 expression is involved in the development of cancer via an increase in the prevalence of somatic mutations, providing a new and important link between abnormalities in the DNA glycosylases NEIL1, NEIL2, and NEIL3 and human cancer.	('involved', 'Reg', (96, 104))	('NEIL2', 'Gene', (65, 70))	('NEIL1', 'Gene', '79661', (58, 63))	('increase', 'PosReg', (141, 149))	('cancer', 'Disease', 'MESH:D009369', (305, 311))	('NEIL2', 'Gene', (278, 283))	('NEIL3', 'Gene', (76, 81))	('men', 'Species', '9606', (119, 122))	('cancer', 'Disease', (127, 133))	('NEIL2', 'Gene', '252969', (65, 70))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('abnormal', 'Var', (35, 43))	('human', 'Species', '9606', (299, 304))	('NEIL1', 'Gene', '79661', (271, 276))	('NEIL1', 'Gene', (58, 63))	('mutations', 'Var', (179, 188))	('NEIL2', 'Gene', '252969', (278, 283))	('cancer', 'Disease', (305, 311))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('NEIL1', 'Gene', (271, 276))	('cancer', 'Phenotype', 'HP:0002664', (305, 311))
338932	27042257	Using a TCGA-based analysis, associations between abnormal NEIL1, NEIL2, or NEIL3 expressions and the somatic mutation load were apparently demonstrated in various cancer types for the first time.	('NEIL1', 'Gene', '79661', (59, 64))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('NEIL1', 'Gene', (59, 64))	('associations', 'Interaction', (29, 41))	('cancer', 'Disease', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('NEIL3', 'Gene', (76, 81))	('abnormal', 'Var', (50, 58))	('NEIL2', 'Gene', (66, 71))	('NEIL2', 'Gene', '252969', (66, 71))
338933	27042257	The association between reductions in NEIL1 and NEIL2 expressions and the increased number of somatic mutations in cancer is understandable, but the association between an elevation in NEIL3 expression and an increased number of somatic mutations in cancer seems surprising at first glance, since NEIL1, NEIL2, and NEIL3 all have the ability to suppress mutations.	('NEIL1', 'Gene', '79661', (38, 43))	('cancer', 'Disease', (115, 121))	('NEIL1', 'Gene', (297, 302))	('cancer', 'Disease', 'MESH:D009369', (250, 256))	('NEIL3', 'Gene', (185, 190))	('mutations', 'Var', (354, 363))	('cancer', 'Disease', (250, 256))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('NEIL2', 'Gene', '252969', (304, 309))	('NEIL1', 'Gene', (38, 43))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('NEIL2', 'Gene', (48, 53))	('reductions', 'NegReg', (24, 34))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))	('NEIL1', 'Gene', '79661', (297, 302))	('expression', 'MPA', (191, 201))	('NEIL2', 'Gene', '252969', (48, 53))	('NEIL2', 'Gene', (304, 309))
338938	27042257	In this study, we found 9 cancer types that showed epigenetic silencing of the NEIL1 gene via promoter hypermethylation using data from the TCGA database.	('epigenetic', 'Var', (51, 61))	('NEIL1', 'Gene', '79661', (79, 84))	('cancer', 'Disease', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('promoter hypermethylation', 'Var', (94, 119))	('NEIL1', 'Gene', (79, 84))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))
338939	27042257	Among them, the epigenetic silencing of NEIL1 expression in HNSCC, lung adenocarcinoma, lung squamous cell carcinoma, colon adenocarcinoma, and rectal adenocarcinoma was consistent with the findings of previous reports, whereas the findings in the remaining 4 cancer types, that is, breast invasive carcinoma, clear cell RCC, papillary RCC, and stomach adenocarcinoma, were novel findings.	('NEIL1', 'Gene', (40, 45))	('cancer', 'Disease', 'MESH:D009369', (260, 266))	('HNSC', 'Phenotype', 'HP:0012288', (60, 64))	('RCC', 'Disease', (321, 324))	('RCC', 'Phenotype', 'HP:0005584', (321, 324))	('lung adenocarcinoma', 'Disease', (67, 86))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (88, 116))	('breast invasive carcinoma', 'Disease', 'MESH:D018270', (283, 308))	('HNSCC', 'Phenotype', 'HP:0012288', (60, 65))	('rectal adenocarcinoma', 'Disease', (144, 165))	('colon adenocarcinoma', 'Disease', (118, 138))	('RCC', 'Disease', 'MESH:C538614', (321, 324))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (67, 86))	('RCC', 'Phenotype', 'HP:0005584', (336, 339))	('breast invasive carcinoma', 'Disease', (283, 308))	('RCC', 'Disease', (336, 339))	('papillary RCC', 'Disease', 'MESH:C538614', (326, 339))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (88, 116))	('papillary RCC', 'Disease', (326, 339))	('carcinoma', 'Phenotype', 'HP:0030731', (299, 308))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (67, 86))	('stomach adenocarcinoma', 'Disease', (345, 367))	('lung squamous cell carcinoma', 'Disease', (88, 116))	('carcinoma', 'Phenotype', 'HP:0030731', (156, 165))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (93, 116))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('cancer', 'Disease', (260, 266))	('NEIL1', 'Gene', '79661', (40, 45))	('RCC', 'Disease', 'MESH:C538614', (336, 339))	('cancer', 'Phenotype', 'HP:0002664', (260, 266))	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('rectal adenocarcinoma', 'Disease', 'MESH:D012004', (144, 165))	('colon adenocarcinoma', 'Disease', 'MESH:D003110', (118, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('epigenetic silencing', 'Var', (16, 36))	('HNSCC', 'Disease', (60, 65))	('stomach adenocarcinoma', 'Disease', 'MESH:D013274', (345, 367))	('breast invasive carcinoma', 'Phenotype', 'HP:0003002', (283, 308))
338940	27042257	Although further experiments, such as 5-aza-dC treatment and a NEIL1 protein expression analysis for each of the latter 4 cancer types, are needed to determine the epigenetic silencing of the NEIL1 gene via promoter hypermethylation in these cancer types, we suspect that the epigenetic silencing of the NEIL1 gene via promoter hypermethylation might be the chief mechanism underlying the downregulation of NEIL1 expression in diverse human cancers.	('men', 'Species', '9606', (52, 55))	('promoter hypermethylation', 'Var', (319, 344))	('NEIL1', 'Gene', '79661', (304, 309))	('cancers', 'Disease', 'MESH:D009369', (441, 448))	('cancer', 'Disease', 'MESH:D009369', (242, 248))	('cancer', 'Disease', 'MESH:D009369', (441, 447))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('NEIL1', 'Gene', '79661', (407, 412))	('NEIL1', 'Gene', (304, 309))	('NEIL1', 'Gene', '79661', (63, 68))	('NEIL1', 'Gene', '79661', (192, 197))	('5-aza-dC', 'Chemical', 'MESH:D000077209', (38, 46))	('men', 'Species', '9606', (23, 26))	('human', 'Species', '9606', (435, 440))	('NEIL1', 'Gene', (407, 412))	('cancers', 'Phenotype', 'HP:0002664', (441, 448))	('cancer', 'Disease', (242, 248))	('cancers', 'Disease', (441, 448))	('cancer', 'Disease', (441, 447))	('cancer', 'Disease', (122, 128))	('epigenetic', 'Var', (276, 286))	('NEIL1', 'Gene', (192, 197))	('NEIL1', 'Gene', (63, 68))	('cancer', 'Phenotype', 'HP:0002664', (441, 447))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('cancer', 'Phenotype', 'HP:0002664', (242, 248))
338941	27042257	Interestingly, in breast invasive carcinoma, which is one of the cancers that shows the epigenetic silencing of NEIL1, a reduction in NEIL1 expression was shown to be an independent predictor of a poor survival outcome.	('carcinoma', 'Phenotype', 'HP:0030731', (34, 43))	('breast invasive carcinoma', 'Disease', 'MESH:D018270', (18, 43))	('NEIL1', 'Gene', (134, 139))	('expression', 'MPA', (140, 150))	('NEIL1', 'Gene', (112, 117))	('breast invasive carcinoma', 'Phenotype', 'HP:0003002', (18, 43))	('NEIL1', 'Gene', '79661', (134, 139))	('breast invasive carcinoma', 'Disease', (18, 43))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('cancers', 'Disease', 'MESH:D009369', (65, 72))	('NEIL1', 'Gene', '79661', (112, 117))	('cancers', 'Phenotype', 'HP:0002664', (65, 72))	('epigenetic silencing', 'Var', (88, 108))	('cancers', 'Disease', (65, 72))	('reduction', 'NegReg', (121, 130))
338944	27042257	Since a reduction in NEIL1 expression was associated with an increased somatic mutation level and mutations in cancer-associated genes can lead to the exaggeration of the malignant potential, such as an increase in the proliferation rate, this kind of phenotypic change might explain the difference in survival outcomes between patients with and those without a reduction in NEIL1 expression.	('somatic mutation level', 'MPA', (71, 93))	('reduction', 'NegReg', (8, 17))	('malignant potential', 'CPA', (171, 190))	('exaggeration', 'PosReg', (151, 163))	('NEIL1', 'Gene', '79661', (21, 26))	('patients', 'Species', '9606', (328, 336))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('NEIL1', 'Gene', '79661', (375, 380))	('expression', 'MPA', (27, 37))	('NEIL1', 'Gene', (21, 26))	('mutations', 'Var', (98, 107))	('increased', 'PosReg', (61, 70))	('if', 'Gene', '35045', (223, 225))	('NEIL1', 'Gene', (375, 380))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('if', 'Gene', '35045', (289, 291))	('increase', 'PosReg', (203, 211))
338945	27042257	So far, several forms of germline nonsynonymous NEIL1 or NEIL2 mutations have been experimentally demonstrated to actually have reduced or absent repair activity.	('mutations', 'Var', (63, 72))	('NEIL2', 'Gene', (57, 62))	('NEIL1', 'Gene', '79661', (48, 53))	('reduced', 'NegReg', (128, 135))	('repair activity', 'MPA', (146, 161))	('absent', 'NegReg', (139, 145))	('NEIL2', 'Gene', '252969', (57, 62))	('NEIL1', 'Gene', (48, 53))	('men', 'Species', '9606', (89, 92))
338946	27042257	Human cells containing such NEIL1 or NEIL2 mutations are considered to have a reduced capacity to repair mutagenic bases; thus, similar to cancers with a reduced NEIL1 or NEIL2 expression levels, a higher incidence of mutation is likely to occur in the cells, leading to cancer susceptibility.	('Human', 'Species', '9606', (0, 5))	('NEIL1', 'Gene', '79661', (28, 33))	('cancers', 'Phenotype', 'HP:0002664', (139, 146))	('NEIL1', 'Gene', '79661', (162, 167))	('cancers', 'Disease', (139, 146))	('NEIL2', 'Gene', '252969', (37, 42))	('NEIL2', 'Gene', '252969', (171, 176))	('cancer', 'Disease', (271, 277))	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('mutation', 'Var', (218, 226))	('cancer', 'Phenotype', 'HP:0002664', (271, 277))	('NEIL1', 'Gene', (28, 33))	('NEIL1', 'Gene', (162, 167))	('cancers', 'Disease', 'MESH:D009369', (139, 146))	('cancer', 'Disease', 'MESH:D009369', (271, 277))	('cancer', 'Disease', (139, 145))	('NEIL2', 'Gene', (37, 42))	('NEIL2', 'Gene', (171, 176))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('mutations', 'Var', (43, 52))	('expression levels', 'MPA', (177, 194))
338947	27042257	This scenario is compatible with a previous paper reporting a germline NEIL2 variant that is a marker for risk and the progression of squamous cell carcinomas of the oral cavity and oropharynx and that is selectively found in familial colorectal cancer patients, but not in healthy controls.	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (134, 158))	('NEIL2', 'Gene', (71, 76))	('variant', 'Var', (77, 84))	('squamous cell carcinomas', 'Disease', (134, 158))	('carcinomas of the oral cavity', 'Phenotype', 'HP:0100649', (148, 177))	('squamous cell carcinomas of the oral cavity', 'Phenotype', 'HP:0030413', (134, 177))	('patients', 'Species', '9606', (253, 261))	('carcinomas', 'Phenotype', 'HP:0030731', (148, 158))	('NEIL2', 'Gene', '252969', (71, 76))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (134, 158))	('familial colorectal cancer', 'Disease', 'MESH:D015179', (226, 252))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (134, 157))	('colorectal cancer', 'Phenotype', 'HP:0003003', (235, 252))	('found', 'Reg', (217, 222))	('familial colorectal cancer', 'Disease', (226, 252))	('carcinoma', 'Phenotype', 'HP:0030731', (148, 157))
338948	27042257	Future genome-wide analyses of cancers derived from individuals with germline NEIL1 or NEIL2 mutations should clarify the role of NEIL1 and NEIL2 in the prevention of mutations.	('NEIL2', 'Gene', '252969', (87, 92))	('mutations', 'Var', (93, 102))	('NEIL1', 'Gene', (78, 83))	('NEIL2', 'Gene', (140, 145))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('NEIL1', 'Gene', (130, 135))	('NEIL2', 'Gene', (87, 92))	('cancers', 'Phenotype', 'HP:0002664', (31, 38))	('NEIL1', 'Gene', '79661', (78, 83))	('NEIL2', 'Gene', '252969', (140, 145))	('cancers', 'Disease', (31, 38))	('if', 'Gene', '35045', (114, 116))	('cancers', 'Disease', 'MESH:D009369', (31, 38))	('NEIL1', 'Gene', '79661', (130, 135))
338951	27042257	In conclusion, our study indicates that the abnormal expressions of NEIL1, NEIL2, and NEIL3 are likely to be involved in mutagenesis in human cancer.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('human', 'Species', '9606', (136, 141))	('abnormal expressions', 'Phenotype', 'HP:0100022', (44, 64))	('NEIL2', 'Gene', (75, 80))	('NEIL3', 'Gene', (86, 91))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('NEIL1', 'Gene', (68, 73))	('NEIL2', 'Gene', '252969', (75, 80))	('abnormal', 'Var', (44, 52))	('NEIL1', 'Gene', '79661', (68, 73))	('involved', 'Reg', (109, 117))	('cancer', 'Disease', (142, 148))
338952	27042257	Since little is known about gene abnormalities identified by whole-exome sequencing data that induce mutations in cancer, our findings regarding these novel mutagenic factors should contribute to our general understanding of human cancer.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('mutations', 'Var', (101, 110))	('cancer', 'Disease', 'MESH:D009369', (231, 237))	('cancer', 'Disease', (231, 237))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('human', 'Species', '9606', (225, 230))	('if', 'Gene', '35045', (52, 54))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('cancer', 'Disease', (114, 120))
338984	32195180	Alterations of miR-186 expression were demonstrated in numerous cancers, shown to play a vital role in oncogenesis, invasion, metastasis, apoptosis, and drug resistance.	('numerous cancers', 'Disease', (55, 71))	('Alterations', 'Var', (0, 11))	('invasion', 'CPA', (116, 124))	('cancers', 'Phenotype', 'HP:0002664', (64, 71))	('miR-186', 'Gene', '406962', (15, 22))	('drug resistance', 'Phenotype', 'HP:0020174', (153, 168))	('miR-186', 'Gene', (15, 22))	('metastasis', 'CPA', (126, 136))	('numerous cancers', 'Disease', 'MESH:D009369', (55, 71))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('expression', 'MPA', (23, 33))
339004	32195180	Alterations of miR-186 expression were demonstrated in numerous cancer tissues or cell lines, which played a vital role in oncogenesis, invasion, metastasis, apoptosis, and drug resistance.	('numerous cancer', 'Disease', (55, 70))	('metastasis', 'CPA', (146, 156))	('oncogenesis', 'CPA', (123, 134))	('Alterations', 'Var', (0, 11))	('invasion', 'CPA', (136, 144))	('apoptosis', 'CPA', (158, 167))	('miR-186', 'Gene', '406962', (15, 22))	('numerous cancer', 'Disease', 'MESH:D009369', (55, 70))	('miR-186', 'Gene', (15, 22))	('drug resistance', 'Phenotype', 'HP:0020174', (173, 188))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('expression', 'MPA', (23, 33))
339036	32195180	Inhibition of RETREG1 led to the errors in folding of proteins in ER, resulting in impaired protein balance and disease.	('folding of', 'MPA', (43, 53))	('RETREG1', 'Gene', (14, 21))	('proteins', 'Protein', (54, 62))	('Inhibition', 'Var', (0, 10))	('errors', 'Reg', (33, 39))	('impaired protein balance and disease', 'Disease', 'MESH:D030342', (83, 119))
339040	32195180	Yang and his colleagues verified that upregulation of miR-186 significantly enhanced the growth rates of bladder cancer cells by targeting PPM1B, which consequently promoted expression of p21Cip1 and p27Kip, while decreasing cyclin D1 expression level, which facilitated G1-S phase transition.	('cyclin D1', 'Gene', '595', (225, 234))	('facilitated', 'PosReg', (259, 270))	('PPM1B', 'Gene', (139, 144))	('bladder cancer', 'Disease', 'MESH:D001749', (105, 119))	('bladder cancer', 'Disease', (105, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('bladder cancer', 'Phenotype', 'HP:0009725', (105, 119))	('p21Cip1', 'Gene', '1026', (188, 195))	('promoted', 'PosReg', (165, 173))	('upregulation', 'PosReg', (38, 50))	('p21Cip1', 'Gene', (188, 195))	('expression', 'MPA', (174, 184))	('expression level', 'MPA', (235, 251))	('miR-186', 'Gene', (54, 61))	('miR-186', 'Gene', '406962', (54, 61))	('growth rates', 'CPA', (89, 101))	('decreasing', 'NegReg', (214, 224))	('cyclin D1', 'Gene', (225, 234))	('G1-S phase transition', 'CPA', (271, 292))	('enhanced', 'PosReg', (76, 84))	('p27Kip', 'Var', (200, 206))	('PPM1B', 'Gene', '5495', (139, 144))
339063	32195180	In addition, miR-186 suppressed the proliferation, migration, invasiveness, and angiogenesis by targeting ST6GAL2 in follicular thyroid carcinoma cells, or targeting ATAD2 in retinoblastoma cells, and inhibited autophagy by targeting the autophagy-related proteins Atg7 and Beclin1 in glioma microvascular endothelial cells.	('Atg7', 'Gene', (265, 269))	('glioma', 'Phenotype', 'HP:0009733', (285, 291))	('Atg7', 'Gene', '10533', (265, 269))	('ATAD2', 'Gene', '29028', (166, 171))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('inhibited', 'NegReg', (201, 210))	('ST6GAL2', 'Gene', (106, 113))	('targeting', 'Reg', (224, 233))	('retinoblastoma', 'Disease', 'MESH:D012175', (175, 189))	('ST6GAL2', 'Gene', '84620', (106, 113))	('angiogenesis', 'CPA', (80, 92))	('suppressed', 'NegReg', (21, 31))	('ATAD2', 'Gene', (166, 171))	('Beclin1', 'Gene', '8678', (274, 281))	('autophagy', 'CPA', (211, 220))	('targeting', 'Reg', (96, 105))	('proliferation', 'CPA', (36, 49))	('miR-186', 'Gene', '406962', (13, 20))	('miR-186', 'Gene', (13, 20))	('follicular thyroid carcinoma', 'Phenotype', 'HP:0006731', (117, 145))	('targeting', 'Var', (156, 165))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (128, 145))	('invasiveness', 'CPA', (62, 74))	('glioma', 'Disease', (285, 291))	('follicular thyroid carcinoma', 'Disease', 'MESH:D018263', (117, 145))	('migration', 'CPA', (51, 60))	('retinoblastoma', 'Disease', (175, 189))	('retinoblastoma', 'Phenotype', 'HP:0009919', (175, 189))	('glioma', 'Disease', 'MESH:D005910', (285, 291))	('follicular thyroid carcinoma', 'Disease', (117, 145))	('Beclin1', 'Gene', (274, 281))
339087	32195180	Otherwise, miR-186 was downregulated in ovarian cancer cells A2780/Taxol and in NSCLC tissues which were resistant to paclitaxel.	('downregulated', 'NegReg', (23, 36))	('NSCLC', 'Phenotype', 'HP:0030358', (80, 85))	('ovarian cancer', 'Disease', 'MESH:D010051', (40, 54))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('A2780/Taxol', 'Var', (61, 72))	('paclitaxel', 'Chemical', 'MESH:D017239', (118, 128))	('NSCLC', 'Disease', (80, 85))	('ovarian cancer', 'Disease', (40, 54))	('NSCLC', 'Disease', 'MESH:D002289', (80, 85))	('ovarian cancer', 'Phenotype', 'HP:0100615', (40, 54))	('miR-186', 'Gene', '406962', (11, 18))	('miR-186', 'Gene', (11, 18))
339108	32195180	SNPs-rs66461782 in miR-186 was detected in patients with breast cancer.	('detected', 'Reg', (31, 39))	('breast cancer', 'Disease', (57, 70))	('breast cancer', 'Phenotype', 'HP:0003002', (57, 70))	('patients', 'Species', '9606', (43, 51))	('miR-186', 'Gene', '406962', (19, 26))	('miR-186', 'Gene', (19, 26))	('rs66461782', 'DBSNP_MENTION', 'None', (5, 15))	('rs66461782', 'Var', (5, 15))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('breast cancer', 'Disease', 'MESH:D001943', (57, 70))
339110	32195180	Rs1062577 was one of the miRNA-related ESR1 SNPs.	('ESR1', 'Gene', (39, 43))	('Rs1062577', 'Var', (0, 9))	('ESR1', 'Gene', '2099', (39, 43))
339111	32195180	The A allele, substitution for T at the site (rs1062577 A allele), attenuated the binding of miR-186 to ESR1 mRNA due to one hydrogen bond lost, then disturbed its negative regulatory effect of miR-186 on ESR1 transcripts.	('miR-186', 'Gene', '406962', (93, 100))	('miR-186', 'Gene', (93, 100))	('ESR1', 'Gene', '2099', (205, 209))	('hydrogen bond', 'MPA', (125, 138))	('ESR1', 'Gene', (104, 108))	('mRNA', 'Protein', (109, 113))	('negative regulatory effect', 'MPA', (164, 190))	('attenuated', 'NegReg', (67, 77))	('miR-186', 'Gene', '406962', (194, 201))	('ESR1', 'Gene', (205, 209))	('miR-186', 'Gene', (194, 201))	('binding', 'Interaction', (82, 89))	('rs1062577', 'Var', (46, 55))	('hydrogen', 'Chemical', 'MESH:D006859', (125, 133))	('rs1062577', 'DBSNP_MENTION', 'None', (46, 55))	('disturbed', 'Reg', (150, 159))	('ESR1', 'Gene', '2099', (104, 108))	('lost', 'NegReg', (139, 143))
339112	32195180	In a word, the function of miR-186 may be disturbed by SNP either in miR-186 or target mRNAs.	('miR-186', 'Gene', '406962', (69, 76))	('miR-186', 'Gene', '406962', (27, 34))	('miR-186', 'Gene', (27, 34))	('miR-186', 'Gene', (69, 76))	('disturbed', 'Reg', (42, 51))	('SNP', 'Var', (55, 58))	('function', 'MPA', (15, 23))
339117	32195180	verified FOXO1 was a direct target of 6 miRNAs (including miR-9, -27, -96, -153, -183, and -186) in endometrial cancer cells, and transfection of the anti-miRs effectively induced cell cycle arrest in Ishikawa cells (endometrial cancer cells with FOXO1 at low level), but no remarkable effects in HEC-1B cells (endometrial cancer cells with FOXO1 abundant) were found.	('endometrial cancer', 'Disease', 'MESH:D016889', (311, 329))	('FOXO1', 'Gene', (247, 252))	('FOXO1', 'Gene', (341, 346))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('HEC-1B', 'CellLine', 'CVCL:0294;0.01683336734570692', (297, 303))	('endometrial cancer', 'Phenotype', 'HP:0012114', (100, 118))	('cell cycle arrest', 'CPA', (180, 197))	('endometrial cancer', 'Phenotype', 'HP:0012114', (217, 235))	('endometrial cancer', 'Disease', (100, 118))	('endometrial cancer', 'Disease', 'MESH:D016889', (100, 118))	('induced', 'Reg', (172, 179))	('FOXO1', 'Gene', '2308', (9, 14))	('endometrial cancer', 'Disease', (217, 235))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('endometrial cancer', 'Disease', (311, 329))	('endometrial cancer', 'Phenotype', 'HP:0012114', (311, 329))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (180, 197))	('transfection', 'Var', (130, 142))	('endometrial cancer', 'Disease', 'MESH:D016889', (217, 235))	('FOXO1', 'Gene', '2308', (247, 252))	('cancer', 'Phenotype', 'HP:0002664', (323, 329))	('FOXO1', 'Gene', '2308', (341, 346))	('FOXO1', 'Gene', (9, 14))
339119	32195180	found miR-181a decreased the apoptosis of triple-negative breast cancer cells upon doxorubicin treatment through suppression of the pro-apoptotic protein BAX directly, while another report showed miR-181a enhanced adriamycin-induced apoptosis by targeting the anti-apoptotic protein Bcl-2 in low-invasive breast cancer cells.	('adriamycin', 'Chemical', 'MESH:D004317', (214, 224))	('miR-181a', 'Chemical', '-', (196, 204))	('Bcl-2', 'Gene', (283, 288))	('miR-181a', 'Chemical', '-', (6, 14))	('adriamycin-induced apoptosis', 'CPA', (214, 242))	('cancer', 'Phenotype', 'HP:0002664', (312, 318))	('apoptosis', 'CPA', (29, 38))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('Bcl-2', 'Gene', '596', (283, 288))	('decreased', 'NegReg', (15, 24))	('enhanced', 'PosReg', (205, 213))	('breast cancer', 'Phenotype', 'HP:0003002', (305, 318))	('breast cancer', 'Phenotype', 'HP:0003002', (58, 71))	('BAX', 'Gene', (154, 157))	('breast cancer', 'Disease', (305, 318))	('breast cancer', 'Disease', 'MESH:D001943', (305, 318))	('BAX', 'Gene', '581', (154, 157))	('breast cancer', 'Disease', 'MESH:D001943', (58, 71))	('breast cancer', 'Disease', (58, 71))	('doxorubicin', 'Chemical', 'MESH:D004317', (83, 94))	('miR-181a', 'Var', (196, 204))	('suppression', 'NegReg', (113, 124))	('miR-181a', 'Var', (6, 14))
339125	32195180	found that miR-181a significantly inhibited cell viability of breast cancer cells (MCF-7), dose-dependently.	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('inhibited', 'NegReg', (34, 43))	('breast cancer', 'Disease', 'MESH:D001943', (62, 75))	('breast cancer', 'Phenotype', 'HP:0003002', (62, 75))	('MCF-7', 'CellLine', 'CVCL:0031;-0.06415787969614392', (83, 88))	('breast cancer', 'Disease', (62, 75))	('miR-181a', 'Chemical', '-', (11, 19))	('miR-181a', 'Var', (11, 19))
339126	32195180	However, with a miR-181a dose higher than 50 nM, it promoted proliferation of several types of cancer cells rather than producing inhibitory effects.	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('miR-181a', 'Chemical', '-', (16, 24))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('cancer', 'Disease', (95, 101))	('miR-181a', 'Var', (16, 24))	('proliferation', 'CPA', (61, 74))	('promoted', 'PosReg', (52, 60))
339268	31661545	Setting D-N- type group as base line, D-N+ increased the ratio of high/low differentiated samples, while D-N+ reduced it.	('D-', 'Chemical', 'MESH:D003903', (38, 40))	('high/low differentiated samples', 'CPA', (66, 97))	('D-', 'Chemical', 'MESH:D003903', (8, 10))	('D-N+', 'Var', (38, 42))	('increased', 'PosReg', (43, 52))	('D-', 'Chemical', 'MESH:D003903', (105, 107))
339296	31661545	Studies have shown that interfering NCOR1 expression can enhance cell proliferation and invasion, which leads to tumor growth and metastasis.	('tumor', 'Disease', (113, 118))	('NCOR1', 'Gene', '9611', (36, 41))	('invasion', 'CPA', (88, 96))	('leads to', 'Reg', (104, 112))	('expression', 'MPA', (42, 52))	('interfering', 'Var', (24, 35))	('metastasis', 'CPA', (130, 140))	('NCOR1', 'Gene', (36, 41))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('cell proliferation', 'CPA', (65, 83))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('enhance', 'PosReg', (57, 64))
339314	27004405	We report the 20 genes most frequently with mutations (n > 19,689 tumor samples for each gene), CNVs (n > 1,556), or up- or down-regulated (n = 7,998).	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Disease', (66, 71))	('CNVs', 'Disease', (96, 100))	('down-regulated', 'NegReg', (124, 138))	('up-', 'PosReg', (117, 120))	('mutations', 'Var', (44, 53))	('tumor', 'Disease', 'MESH:D009369', (66, 71))
339316	27004405	Co-occurrence of mutations differed between cancers, and mutations in many DNA repair genes were associated with higher total mutation burden.	('cancers', 'Phenotype', 'HP:0002664', (44, 51))	('DNA repair genes', 'Gene', (75, 91))	('cancers', 'Disease', (44, 51))	('cancers', 'Disease', 'MESH:D009369', (44, 51))	('mutations', 'Var', (57, 66))	('total mutation burden', 'MPA', (120, 141))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
339318	27004405	Defective DNA repair is a common hallmark of cancer.	('hallmark of cancer', 'Disease', (33, 51))	('hallmark of cancer', 'Disease', 'MESH:D009369', (33, 51))	('Defective', 'Var', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))
339323	27004405	Aberrations in genes involved in these pathways are closely linked to the development of malignancies.	('malignancies', 'Disease', (89, 101))	('Aberrations', 'Var', (0, 11))	('linked', 'Reg', (60, 66))	('malignancies', 'Disease', 'MESH:D009369', (89, 101))
339325	27004405	Germline mutations in BRCA1 and BRCA2, involved in HR and FA repair, increase the risk of developing breast and ovarian cancer 40-80% and 11-40%, respectively, in addition to other cancer types.	('Germline mutations', 'Var', (0, 18))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('FA', 'Phenotype', 'HP:0001994', (58, 60))	('BRCA2', 'Gene', (32, 37))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('breast and ovarian cancer', 'Disease', 'MESH:D010051', (101, 126))	('increase', 'Reg', (69, 77))	('BRCA1', 'Gene', '672', (22, 27))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('BRCA2', 'Gene', '675', (32, 37))	('ovarian cancer', 'Phenotype', 'HP:0100615', (112, 126))	('cancer', 'Disease', (181, 187))	('BRCA1', 'Gene', (22, 27))
339326	27004405	Additional links include defects in the HR gene, ATM, being associated with ataxia telangiectasia and up to a 25% lifetime malignancy risk, while NER defects in xeroderma pigmentosum are associated with a 70% risk of skin cancer by 8 years of age.	('defects', 'Var', (25, 32))	('ATM', 'Gene', '472', (49, 52))	('malignancy', 'Disease', (123, 133))	('skin cancer', 'Phenotype', 'HP:0008069', (217, 228))	('ataxia telangiectasia', 'Disease', 'MESH:D001260', (76, 97))	('skin cancer', 'Disease', (217, 228))	('skin cancer', 'Disease', 'MESH:D012878', (217, 228))	('ataxia', 'Phenotype', 'HP:0001251', (76, 82))	('defects', 'Var', (150, 157))	('ATM', 'Gene', (49, 52))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('telangiectasia', 'Phenotype', 'HP:0001009', (83, 97))	('ataxia telangiectasia', 'Disease', (76, 97))	('xeroderma pigmentosum', 'Disease', 'MESH:D014983', (161, 182))	('xeroderma pigmentosum', 'Disease', (161, 182))	('associated', 'Reg', (60, 70))	('malignancy', 'Disease', 'MESH:D009369', (123, 133))
339327	27004405	However, it remains unclear whether all DNA repair mutations are truly causal in driving tumorigenesis, as "mountain" genes, or are a byproduct of the malignancy and represent more infrequently mutated "hills".	('mutations', 'Var', (51, 60))	('malignancy', 'Disease', 'MESH:D009369', (151, 161))	('malignancy', 'Disease', (151, 161))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))	('DNA repair', 'Gene', (40, 50))
339328	27004405	In support of the former is the 'mutator phenotype' and the concept that early mutations in critical genes, such as those involved in DNA repair, result in genomic instability and subsequent hypermutability, accounting for the high mutation rate seen in cancer.	('cancer', 'Phenotype', 'HP:0002664', (254, 260))	('cancer', 'Disease', 'MESH:D009369', (254, 260))	('hypermutability', 'MPA', (191, 206))	('cancer', 'Disease', (254, 260))	('genomic', 'MPA', (156, 163))	('mutations', 'Var', (79, 88))	('result in', 'Reg', (146, 155))
339329	27004405	This theory of causality is further supported by reports that MMR mutations and MSI are commonly seen in early adenomas and early stage CRC.	('mutations', 'Var', (66, 75))	('adenomas', 'Disease', 'MESH:D000236', (111, 119))	('CRC', 'Phenotype', 'HP:0003003', (136, 139))	('MMR', 'Gene', (62, 65))	('adenomas', 'Disease', (111, 119))	('seen', 'Reg', (97, 101))	('early stage CRC', 'Disease', (124, 139))	('MSI', 'Disease', 'None', (80, 83))	('MSI', 'Disease', (80, 83))
339330	27004405	Despite the uncertainty of whether all defects in the DNA damage response play a central role in cancer pathogenesis, they are highly significant in disease progression and treatment.	('cancer', 'Disease', (97, 103))	('significant', 'Reg', (134, 145))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('defects', 'Var', (39, 46))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
339333	27004405	This may explain why patients with muscle-invasive bladder cancer carrying at least one somatic mutation in a critical DNA repair gene had increased recurrence-free survival compared to patients without these mutations.	('recurrence-free survival', 'CPA', (149, 173))	('increased', 'PosReg', (139, 148))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('mutation', 'Var', (96, 104))	('bladder cancer', 'Phenotype', 'HP:0009725', (51, 65))	('patients', 'Species', '9606', (21, 29))	('invasive bladder', 'Phenotype', 'HP:0100645', (42, 58))	('muscle-invasive bladder cancer', 'Disease', 'MESH:D001749', (35, 65))	('muscle-invasive bladder cancer', 'Disease', (35, 65))	('patients', 'Species', '9606', (186, 194))
339335	27004405	PARP1, involved in the BER pathway through its ability to sense and repair SSB lesions via ADP-ribosylation, has become a successful therapeutic target.	('lesions', 'Var', (79, 86))	('ADP', 'Chemical', 'MESH:D000244', (91, 94))	('PARP1', 'Gene', '142', (0, 5))	('SSB', 'Gene', (75, 78))	('PARP1', 'Gene', (0, 5))	('SSB', 'Gene', '6741', (75, 78))
339336	27004405	Olaparib, a PARP1 inhibitor, is now approved for patients with advanced ovarian cancer harboring BRCA1 or BRCA2 deleterious mutations, as loss of BRCA sensitizes these tumors to further inhibition of DNA repair and results in a synthetic lethality.	('tumors', 'Disease', (168, 174))	('synthetic', 'MPA', (228, 237))	('Olaparib', 'Chemical', 'MESH:C531550', (0, 8))	('PARP1', 'Gene', (12, 17))	('BRCA2', 'Gene', '675', (106, 111))	('BRCA', 'Gene', '672', (146, 150))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('tumors', 'Disease', 'MESH:D009369', (168, 174))	('BRCA1', 'Gene', '672', (97, 102))	('ovarian cancer', 'Disease', 'MESH:D010051', (72, 86))	('BRCA1', 'Gene', (97, 102))	('BRCA', 'Gene', '672', (106, 110))	('sensitizes', 'Reg', (151, 161))	('inhibition', 'NegReg', (186, 196))	('loss', 'Var', (138, 142))	('BRCA', 'Gene', '672', (97, 101))	('PARP1', 'Gene', '142', (12, 17))	('BRCA', 'Gene', (146, 150))	('patients', 'Species', '9606', (49, 57))	('ovarian cancer', 'Disease', (72, 86))	('BRCA', 'Gene', (106, 110))	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('mutations', 'Var', (124, 133))	('ovarian cancer', 'Phenotype', 'HP:0100615', (72, 86))	('BRCA', 'Gene', (97, 101))	('BRCA2', 'Gene', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
339337	27004405	PAPR1 inhibitors also show potential in many other cancers harboring deficiencies in DNA repair, and inhibition of other DNA repair genes is being evaluated to induce synthetic lethality, including PRKDC inhibition in MYC-overexpressing tumors.	('cancers', 'Disease', 'MESH:D009369', (51, 58))	('PRKDC', 'Gene', '5591', (198, 203))	('tumors', 'Disease', (237, 243))	('tumors', 'Disease', 'MESH:D009369', (237, 243))	('MYC', 'Gene', '4609', (218, 221))	('tumors', 'Phenotype', 'HP:0002664', (237, 243))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('deficiencies', 'Var', (69, 81))	('inhibitors', 'Var', (6, 16))	('cancers', 'Phenotype', 'HP:0002664', (51, 58))	('PRKDC', 'Gene', (198, 203))	('cancers', 'Disease', (51, 58))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))	('MYC', 'Gene', (218, 221))	('PAPR1', 'Gene', (0, 5))
339340	27004405	A recent study analyzing the mutational landscape and copy number variation (CNV) alterations in 100 pancreatic tumors revealed a strong association between genomic instability and inactivation of DNA repair genes, and was able to identify new candidate genes in driving pancreatic tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (282, 287))	('pancreatic tumors', 'Disease', 'MESH:D010190', (101, 118))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor', 'Disease', (282, 287))	('genomic instability', 'MPA', (157, 176))	('tumor', 'Disease', 'MESH:D009369', (282, 287))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('pancreatic tumors', 'Disease', (101, 118))	('alterations', 'Var', (82, 93))	('tumor', 'Disease', (112, 117))	('pancreatic tumors', 'Phenotype', 'HP:0002894', (101, 118))	('DNA repair genes', 'Gene', (197, 213))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('inactivation', 'MPA', (181, 193))
339341	27004405	In this study, we analyzed a comprehensive list of DNA repair genes utilizing the large databases Catalogue Of Somatic Mutations In Cancer (COSMIC) and The Cancer Genome Atlas (TCGA) within cBioPortal.	('Cancer Genome Atlas', 'Disease', (156, 175))	('Cancer', 'Disease', 'MESH:D009369', (156, 162))	('Cancer', 'Phenotype', 'HP:0002664', (156, 162))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (156, 175))	('OS', 'Chemical', '-', (141, 143))	('Mutations', 'Var', (119, 128))	('Cancer', 'Phenotype', 'HP:0002664', (132, 138))	('Cancer', 'Disease', (132, 138))	('Cancer', 'Disease', (156, 162))	('Cancer', 'Disease', 'MESH:D009369', (132, 138))
339345	27004405	There were also genes frequently mutated specifically in 1 or 2 of the evaluated groups, including MSH4, MDC1, WRN, and LIG1 in lung cancer, PALB2, BLM, and FANCA in breast cancer, RAD50, MSH3, MLH3, BLM, CLK2, and ERCC2 in liver tumors, MLH1, LIG1, TTK, and MSH2 in LI cancer, and MDC1 and POLD1 in skin cancer.	('LI cancer', 'Disease', (267, 276))	('MSH3', 'Gene', (188, 192))	('WRN', 'Gene', (111, 114))	('WRN', 'Gene', '7486', (111, 114))	('MDC1', 'Gene', '9656', (105, 109))	('tumors', 'Phenotype', 'HP:0002664', (230, 236))	('liver tumors', 'Disease', (224, 236))	('TTK', 'Gene', (250, 253))	('breast cancer', 'Disease', 'MESH:D001943', (166, 179))	('MSH3', 'Gene', '4437', (188, 192))	('breast cancer', 'Disease', (166, 179))	('CLK2', 'Gene', '1196', (205, 209))	('skin cancer', 'Disease', 'MESH:D012878', (300, 311))	('PALB2', 'Gene', (141, 146))	('MLH1', 'Gene', '4292', (238, 242))	('lung cancer', 'Disease', 'MESH:D008175', (128, 139))	('BLM', 'Gene', (200, 203))	('FANCA', 'Gene', '2175', (157, 162))	('breast cancer', 'Phenotype', 'HP:0003002', (166, 179))	('POLD1', 'Gene', '5424', (291, 296))	('MSH4', 'Gene', (99, 103))	('lung cancer', 'Phenotype', 'HP:0100526', (128, 139))	('cancer', 'Phenotype', 'HP:0002664', (270, 276))	('ERCC2', 'Gene', (215, 220))	('MSH2', 'Gene', (259, 263))	('BLM', 'Gene', '641', (200, 203))	('PALB2', 'Gene', '79728', (141, 146))	('RAD50', 'Gene', (181, 186))	('LIG1', 'Gene', '3978', (120, 124))	('LIG1', 'Gene', (120, 124))	('MLH3', 'Gene', (194, 198))	('cancer', 'Phenotype', 'HP:0002664', (305, 311))	('MSH4', 'Gene', '4438', (99, 103))	('ERCC2', 'Gene', '2068', (215, 220))	('skin cancer', 'Disease', (300, 311))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('FANCA', 'Gene', (157, 162))	('TTK', 'Gene', '7272', (250, 253))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('MSH2', 'Gene', '4436', (259, 263))	('MDC1', 'Gene', (282, 286))	('RAD50', 'Gene', '10111', (181, 186))	('FA', 'Phenotype', 'HP:0001994', (157, 159))	('BLM', 'Gene', (148, 151))	('liver tumors', 'Disease', 'MESH:D008113', (224, 236))	('MDC1', 'Gene', (105, 109))	('LIG1', 'Gene', '3978', (244, 248))	('skin cancer', 'Phenotype', 'HP:0008069', (300, 311))	('LIG1', 'Gene', (244, 248))	('CLK2', 'Gene', (205, 209))	('mutated', 'Var', (33, 40))	('LI cancer', 'Disease', 'MESH:D009369', (267, 276))	('lung cancer', 'Disease', (128, 139))	('POLD1', 'Gene', (291, 296))	('liver tumors', 'Phenotype', 'HP:0002896', (224, 236))	('BLM', 'Gene', '641', (148, 151))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))	('MDC1', 'Gene', '9656', (282, 286))	('MLH3', 'Gene', '27030', (194, 198))	('MLH1', 'Gene', (238, 242))
339349	27004405	LI and skin cancer were the most heavily mutated cancers for all analyzed genes, in agreement with previous reports, with LI displaying a further 0.74% and 0.64% increased mutation frequency of direct and indirect DNA repair genes, respectively, in comparison to the LI cancer average mutation frequency of all COSMIC genes (Figure 1B).	('LI cancer', 'Disease', (267, 276))	('OS', 'Chemical', '-', (312, 314))	('increased', 'PosReg', (162, 171))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('skin cancer', 'Phenotype', 'HP:0008069', (7, 18))	('LI cancer', 'Disease', 'MESH:D009369', (267, 276))	('mutation', 'Var', (172, 180))	('skin cancer', 'Disease', (7, 18))	('skin cancer', 'Disease', 'MESH:D012878', (7, 18))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('cancer', 'Phenotype', 'HP:0002664', (270, 276))	('cancers', 'Disease', 'MESH:D009369', (49, 56))	('cancers', 'Phenotype', 'HP:0002664', (49, 56))	('cancers', 'Disease', (49, 56))
339353	27004405	Lung squamous cell carcinoma samples displayed 94 genes pairs with a tendency toward mutual exclusivity (none significant) and 96 gene pairs toward co-occurrence (9 significant) (Figure 1G), while the majority of mutated gene pairs (156) in liver hepatocellular carcinoma samples were trending towards mutual exclusivity (0 significant, 9 gene pairs significant for co-occurrence) (Figure 1H).	('liver hepatocellular carcinoma', 'Disease', (241, 271))	('carcinoma', 'Phenotype', 'HP:0030731', (19, 28))	('mutated', 'Var', (213, 220))	('liver hepatocellular carcinoma', 'Disease', 'MESH:D006528', (241, 271))	('Lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (0, 28))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (5, 28))	('squamous cell carcinoma', 'Disease', (5, 28))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (247, 271))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (5, 28))	('carcinoma', 'Phenotype', 'HP:0030731', (262, 271))
339356	27004405	RRM2B, RECQL4, RAD54B, and NBN were the most commonly amplified genes and NEIL2, WRN, FANCB, and POLI most frequently displayed copy number loss.	('copy number loss', 'Var', (128, 144))	('RECQL4', 'Gene', (7, 13))	('RRM2B', 'Gene', (0, 5))	('NEIL2', 'Gene', '252969', (74, 79))	('WRN', 'Gene', '7486', (81, 84))	('RAD54B', 'Gene', '25788', (15, 21))	('FANCB', 'Gene', (86, 91))	('FA', 'Phenotype', 'HP:0001994', (86, 88))	('FANCB', 'Gene', '2187', (86, 91))	('WRN', 'Gene', (81, 84))	('POLI', 'Gene', (97, 101))	('NBN', 'Gene', '4683', (27, 30))	('RRM2B', 'Gene', '50484', (0, 5))	('RAD54B', 'Gene', (15, 21))	('RECQL4', 'Gene', '9401', (7, 13))	('NEIL2', 'Gene', (74, 79))	('POLI', 'Gene', '11201', (97, 101))	('NBN', 'Gene', (27, 30))
339360	27004405	Cases with mutations (assuming loss of function) or CNV alterations (all CNV loss, other than 1 CNV gain lung cancer case) in NEIL2 displayed decreased OS in liver hepatocellular carcinoma and decreased DFS in bladder urothelial and lung squamous cell carcinoma (Figure 2D).	('mutations', 'Var', (11, 20))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (238, 261))	('CNV loss', 'Disease', 'MESH:D015431', (73, 81))	('decreased DFS in bladder urothelial and lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (193, 261))	('lung cancer', 'Phenotype', 'HP:0100526', (105, 116))	('liver hepatocellular carcinoma', 'Disease', 'MESH:D006528', (158, 188))	('decreased', 'NegReg', (142, 151))	('OS', 'Chemical', '-', (152, 154))	('CNV gain lung cancer', 'Disease', (96, 116))	('NEIL2', 'Gene', (126, 131))	('carcinoma', 'Phenotype', 'HP:0030731', (252, 261))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('carcinoma', 'Phenotype', 'HP:0030731', (179, 188))	('CNV gain lung cancer', 'Disease', 'MESH:D008175', (96, 116))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (233, 261))	('liver hepatocellular carcinoma', 'Disease', (158, 188))	('alterations', 'Var', (56, 67))	('CNV loss', 'Disease', (73, 81))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (164, 188))	('NEIL2', 'Gene', '252969', (126, 131))
339361	27004405	Cases with CNV alterations (all CNV gain, other than 1 CNV loss liver cancer case and 1 CNV loss breast cancer case) in RRM2B were associated with decreased OS in liver, breast, and prostate carcinoma, and ovarian serous cystadenocarcinoma (Figure 2E).	('decreased', 'NegReg', (147, 156))	('ovarian serous cystadenocarcinoma', 'Phenotype', 'HP:0012887', (206, 239))	('carcinoma', 'Phenotype', 'HP:0030731', (230, 239))	('prostate carcinoma', 'Disease', (182, 200))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('ovarian serous cystadenocarcinoma', 'Disease', (206, 239))	('carcinoma', 'Phenotype', 'HP:0030731', (191, 200))	('CNV gain', 'Disease', (32, 40))	('liver', 'Disease', (163, 168))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('RRM2B', 'Gene', (120, 125))	('CNV loss breast cancer', 'Disease', (88, 110))	('ovarian serous cystadenocarcinoma', 'Disease', 'MESH:D018284', (206, 239))	('CNV loss breast cancer', 'Disease', 'MESH:D001943', (88, 110))	('breast cancer', 'Phenotype', 'HP:0003002', (97, 110))	('breast', 'Disease', (170, 176))	('liver cancer', 'Phenotype', 'HP:0002896', (64, 76))	('OS', 'Chemical', '-', (157, 159))	('CNV gain', 'Disease', 'MESH:D015430', (32, 40))	('CNV loss liver cancer', 'Disease', (55, 76))	('prostate carcinoma', 'Disease', 'MESH:D011472', (182, 200))	('CNV loss liver cancer', 'Disease', 'MESH:D006528', (55, 76))	('alterations', 'Var', (15, 26))	('RRM2B', 'Gene', '50484', (120, 125))	('prostate carcinoma', 'Phenotype', 'HP:0012125', (182, 200))
339363	27004405	However, bladder cancer with NEIL2 CNV alterations and mutations was trending toward decreased OS, and those with RRM2B CNV alterations showed a non-significant decrease in OS in colorectal, esophageal, and head and neck squamous cell carcinoma and a non-significant decreased DFS in bladder, lung adenocarcinoma, and CRC (data not shown).	('bladder cancer', 'Disease', 'MESH:D001749', (9, 23))	('bladder cancer', 'Disease', (9, 23))	('neck squamous cell carcinoma', 'Disease', (216, 244))	('bladder', 'Disease', (284, 291))	('alterations', 'Var', (124, 135))	('colorectal', 'Disease', 'MESH:D015179', (179, 189))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (216, 244))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (293, 312))	('bladder cancer', 'Phenotype', 'HP:0009725', (9, 23))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (293, 312))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))	('DFS', 'MPA', (277, 280))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (221, 244))	('OS', 'Chemical', '-', (95, 97))	('RRM2B', 'Gene', (114, 119))	('mutations', 'Var', (55, 64))	('NEIL2 CNV alterations', 'Disease', (29, 50))	('decrease', 'NegReg', (161, 169))	('CRC', 'Disease', (318, 321))	('carcinoma', 'Phenotype', 'HP:0030731', (235, 244))	('OS', 'Chemical', '-', (173, 175))	('colorectal', 'Disease', (179, 189))	('decreased', 'NegReg', (267, 276))	('CRC', 'Phenotype', 'HP:0003003', (318, 321))	('decreased', 'NegReg', (85, 94))	('lung adenocarcinoma', 'Disease', (293, 312))	('RRM2B', 'Gene', '50484', (114, 119))	('NEIL2 CNV alterations', 'Disease', 'MESH:D004408', (29, 50))	('carcinoma', 'Phenotype', 'HP:0030731', (303, 312))	('esophageal', 'Disease', (191, 201))
339364	27004405	Potential oncogenes with high CNV gain also present in the top 20 most frequently mutated DNA repair genes (Table 1) include CDK12, PRKDC, CLK2, and EXO1, while potential tumor suppressors with high CNV loss found in Table 1 include TP53, ATM, TP53BP1, and WRN.	('CNV loss', 'Disease', (199, 207))	('TP53', 'Gene', (244, 248))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('EXO1', 'Gene', '9156', (149, 153))	('DNA', 'Gene', (90, 93))	('CNV loss', 'Disease', 'MESH:D015431', (199, 207))	('CDK12', 'Gene', (125, 130))	('ATM', 'Gene', (239, 242))	('CNV gain', 'Disease', 'MESH:D015430', (30, 38))	('CLK2', 'Gene', (139, 143))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('WRN', 'Gene', '7486', (257, 260))	('TP53BP1', 'Gene', '7158', (244, 251))	('TP53', 'Gene', '7157', (244, 248))	('WRN', 'Gene', (257, 260))	('TP53', 'Gene', (233, 237))	('CDK12', 'Gene', '51755', (125, 130))	('mutated', 'Var', (82, 89))	('TP53BP1', 'Gene', (244, 251))	('CLK2', 'Gene', '1196', (139, 143))	('PRKDC', 'Gene', '5591', (132, 137))	('PRKDC', 'Gene', (132, 137))	('ATM', 'Gene', '472', (239, 242))	('tumor', 'Disease', (171, 176))	('EXO1', 'Gene', (149, 153))	('CNV gain', 'Disease', (30, 38))	('TP53', 'Gene', '7157', (233, 237))
339368	27004405	To determine if the DNA repair genes analyzed in this study were linked to a higher mutational burden, as hypothesized in the 'mutator phenotype', we quantified the average mutation count from the populations of tumors containing mutations in individual DNA repair genes.	('mutational burden', 'MPA', (84, 101))	('tumors', 'Disease', (212, 218))	('tumors', 'Disease', 'MESH:D009369', (212, 218))	('DNA repair genes', 'Gene', (254, 270))	('tumors', 'Phenotype', 'HP:0002664', (212, 218))	('mutations', 'Var', (230, 239))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))
339369	27004405	CRC cases with mutations in any of the 13 most frequently mutated direct DNA repair genes in LI tumors (Table 1) contained a significantly increased average mutation burden relative to the average mutation count in all CRC samples (Figure 5A).	('CRC', 'Phenotype', 'HP:0003003', (0, 3))	('LI tumors', 'Disease', 'MESH:D016864', (93, 102))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('CRC', 'Phenotype', 'HP:0003003', (219, 222))	('mutations', 'Var', (15, 24))	('direct DNA repair genes', 'Gene', (66, 89))	('increased', 'PosReg', (139, 148))	('LI tumors', 'Disease', (93, 102))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('mutation burden', 'MPA', (157, 172))
339371	27004405	A similar trend was seen in melanoma, within SLX4, POLE, BRCA1, FANCD2, and ERCC6-mutated tumors containing a significantly higher mutational burden than overall melanoma (Figure 5B).	('mutational', 'Var', (131, 141))	('tumors', 'Disease', 'MESH:D009369', (90, 96))	('melanoma', 'Disease', 'MESH:D008545', (28, 36))	('melanoma', 'Disease', 'MESH:D008545', (162, 170))	('BRCA1', 'Gene', '672', (57, 62))	('BRCA1', 'Gene', (57, 62))	('FA', 'Phenotype', 'HP:0001994', (64, 66))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('FANCD2', 'Gene', (64, 70))	('ERCC6', 'Gene', '2074', (76, 81))	('ERCC6', 'Gene', (76, 81))	('melanoma', 'Phenotype', 'HP:0002861', (28, 36))	('melanoma', 'Disease', (28, 36))	('SLX4', 'Gene', (45, 49))	('melanoma', 'Phenotype', 'HP:0002861', (162, 170))	('melanoma', 'Disease', (162, 170))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('FANCD2', 'Gene', '2177', (64, 70))	('tumors', 'Disease', (90, 96))	('SLX4', 'Gene', '84464', (45, 49))
339374	27004405	Lung, breast, liver, LI, and skin cancers each revealed unique patterns of aberrations in DNA repair pathways.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('skin cancers', 'Disease', (29, 41))	('skin cancers', 'Phenotype', 'HP:0008069', (29, 41))	('skin cancers', 'Disease', 'MESH:D012878', (29, 41))	('DNA repair pathways', 'Pathway', (90, 109))	('breast', 'Disease', (6, 12))	('Lung', 'Disease', (0, 4))	('aberrations', 'Var', (75, 86))	('liver', 'Disease', (14, 19))	('cancers', 'Phenotype', 'HP:0002664', (34, 41))	('skin cancer', 'Phenotype', 'HP:0008069', (29, 40))
339375	27004405	Breast cancer displayed many mutations in HR and FA genes, LI cancer in BER, MMR, and NER, lung cancer in BER and HR, liver cancer in MMR and HR, and skin cancer in BER, NER, and FA pathway genes.	('lung cancer', 'Phenotype', 'HP:0100526', (91, 102))	('Breast cancer', 'Phenotype', 'HP:0003002', (0, 13))	('LI cancer', 'Disease', (59, 68))	('FA', 'Phenotype', 'HP:0001994', (179, 181))	('skin cancer', 'Disease', 'MESH:D012878', (150, 161))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('FA', 'Phenotype', 'HP:0001994', (49, 51))	('lung cancer', 'Disease', (91, 102))	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('skin cancer', 'Disease', (150, 161))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('mutations', 'Var', (29, 38))	('FA genes', 'Gene', (49, 57))	('liver cancer', 'Disease', 'MESH:D006528', (118, 130))	('skin cancer', 'Phenotype', 'HP:0008069', (150, 161))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('Breast cancer', 'Disease', 'MESH:D001943', (0, 13))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('lung cancer', 'Disease', 'MESH:D008175', (91, 102))	('liver cancer', 'Phenotype', 'HP:0002896', (118, 130))	('LI cancer', 'Disease', 'MESH:D009369', (59, 68))	('liver cancer', 'Disease', (118, 130))	('Breast cancer', 'Disease', (0, 13))
339376	27004405	Cancer types also differed in the degree to which mutations in DNA repair genes co-occurred or displayed mutual exclusivity in tumors, with CRC, melanoma, breast cancer, and lung adenocarcinoma trending toward the former and liver cancer heavily trending towards the latter.	('melanoma', 'Phenotype', 'HP:0002861', (145, 153))	('carcinoma', 'Phenotype', 'HP:0030731', (184, 193))	('melanoma', 'Disease', (145, 153))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (174, 193))	('CRC', 'Disease', (140, 143))	('liver cancer', 'Disease', 'MESH:D006528', (225, 237))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('CRC', 'Phenotype', 'HP:0003003', (140, 143))	('tumors', 'Disease', (127, 133))	('liver cancer', 'Phenotype', 'HP:0002896', (225, 237))	('breast cancer', 'Phenotype', 'HP:0003002', (155, 168))	('liver cancer', 'Disease', (225, 237))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('melanoma', 'Disease', 'MESH:D008545', (145, 153))	('tumors', 'Disease', 'MESH:D009369', (127, 133))	('DNA repair genes', 'Gene', (63, 79))	('breast cancer', 'Disease', 'MESH:D001943', (155, 168))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('breast cancer', 'Disease', (155, 168))	('lung adenocarcinoma', 'Disease', (174, 193))	('mutations', 'Var', (50, 59))	('Cancer', 'Disease', (0, 6))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (174, 193))
339377	27004405	These data not only revealed the large increase in mutation frequency in LI cancers, but also provided specific values that can be of great use in future clinical trial design.	('cancers', 'Phenotype', 'HP:0002664', (76, 83))	('LI cancers', 'Disease', (73, 83))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('LI cancers', 'Disease', 'MESH:D009369', (73, 83))	('increase', 'PosReg', (39, 47))	('mutation', 'Var', (51, 59))
339378	27004405	These values, which have not before been documented in this manner, can aid in estimating the number of DNA repair mutations to be expected within specific cancer populations when designing cohort sizes.	('mutations', 'Var', (115, 124))	('cancer', 'Disease', (156, 162))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('DNA repair', 'Gene', (104, 114))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))
339385	27004405	CNVs in these genes were significantly associated with decreased OS and DFS in multiple tumor types, although it is not clear whether the clinical association seen was solely due to the effect of CNV gain or loss of the analyzed genes themselves or due to gain or loss of copy number of neighboring genes.	('OS', 'Chemical', '-', (65, 67))	('DFS', 'CPA', (72, 75))	('decreased', 'NegReg', (55, 64))	('CNV gain or loss', 'Disease', 'MESH:D015430', (196, 212))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('CNV gain or loss', 'Disease', (196, 212))	('CNVs', 'Var', (0, 4))	('multiple tumor', 'Disease', (79, 93))	('multiple tumor', 'Disease', 'MESH:D009369', (79, 93))
339386	27004405	Interestingly, a previous study analyzing oncogenic signatures across 12 tumor types identified an inverse correlation between high rates of recurrent mutations and recurrent copy number alterations (including CNV gain and loss), with no tumors displaying a large number of both.	('copy', 'MPA', (175, 179))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Disease', 'MESH:D009369', (238, 243))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (238, 243))	('tumors', 'Phenotype', 'HP:0002664', (238, 244))	('tumor', 'Disease', (73, 78))	('tumor', 'Disease', (238, 243))	('tumors', 'Disease', 'MESH:D009369', (238, 244))	('CNV gain and loss', 'Disease', 'MESH:D015430', (210, 227))	('tumors', 'Disease', (238, 244))	('mutations', 'Var', (151, 160))
339388	27004405	High rates of mutations or CNV alterations appear to be mutually exclusive phenomena, termed genome hyperbola, between genes in multiple tumor types.	('multiple tumor', 'Disease', (128, 142))	('multiple tumor', 'Disease', 'MESH:D009369', (128, 142))	('CNV', 'Gene', (27, 30))	('mutations', 'Var', (14, 23))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
339391	27004405	In multiple clinical histologies, mutations predicted to be immunogenic were associated with increased CD8A expression and patient survival.	('CD8A', 'Gene', (103, 107))	('patient', 'Species', '9606', (123, 130))	('increased', 'PosReg', (93, 102))	('expression', 'MPA', (108, 118))	('CD8A', 'Gene', '925', (103, 107))	('patient survival', 'CPA', (123, 139))	('mutations', 'Var', (34, 43))
339392	27004405	Additionally, in melanoma patients who received adoptively transferred T cell therapy, tumor infiltrating lymphocytes (TILs) identified as recognizing candidate mutated peptides, as predicted by whole-exome sequencing and a major histocompatibility complex (MHC)-binding algorithm, were associated with tumor regression.	('tumor', 'Disease', 'MESH:D009369', (303, 308))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Phenotype', 'HP:0002664', (303, 308))	('tumor', 'Disease', (87, 92))	('tumor', 'Disease', (303, 308))	('patients', 'Species', '9606', (26, 34))	('melanoma', 'Phenotype', 'HP:0002861', (17, 25))	('melanoma', 'Disease', (17, 25))	('melanoma', 'Disease', 'MESH:D008545', (17, 25))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('associated', 'Reg', (287, 297))	('mutated', 'Var', (161, 168))
339396	27004405	In pembrolizumab treated non-small cell lung cancers, higher burden of nonsynonymous mutations was associated with increased clinical response and progression-free survival (PFS), and responders with the greatest number of mutations contained mutations in the DNA repair genes POLD1, POLE, MSH2, PRKDC, RAD17, BRCA2, RAD51C, and/or LIG3.	('PRKDC', 'Gene', (296, 301))	('contained', 'Reg', (233, 242))	('POLD1', 'Gene', '5424', (277, 282))	('RAD17', 'Gene', '5884', (303, 308))	('LIG3', 'Gene', (332, 336))	('mutations', 'Var', (223, 232))	('BRCA2', 'Gene', (310, 315))	('progression-free survival', 'CPA', (147, 172))	('RAD17', 'Gene', (303, 308))	('increased', 'PosReg', (115, 124))	('RAD51C', 'Gene', '5889', (317, 323))	('cell lung cancers', 'Disease', (35, 52))	('LIG3', 'Gene', '3980', (332, 336))	('MSH2', 'Gene', (290, 294))	('lung cancer', 'Phenotype', 'HP:0100526', (40, 51))	('RAD51C', 'Gene', (317, 323))	('lung cancers', 'Phenotype', 'HP:0100526', (40, 52))	('BRCA2', 'Gene', '675', (310, 315))	('mutations', 'Var', (243, 252))	('POLE', 'Gene', (284, 288))	('POLD1', 'Gene', (277, 282))	('cancers', 'Phenotype', 'HP:0002664', (45, 52))	('MSH2', 'Gene', '4436', (290, 294))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('non-small cell lung cancers', 'Phenotype', 'HP:0030358', (25, 52))	('cell lung cancers', 'Disease', 'MESH:D008175', (35, 52))	('pembrolizumab', 'Chemical', 'MESH:C582435', (3, 16))	('PRKDC', 'Gene', '5591', (296, 301))	('small cell lung cancers', 'Phenotype', 'HP:0030357', (29, 52))
339398	27004405	In muscle-invasive bladder cancer, mutations in the DNA repair genes including ATM, ERCC2, FANCD2, PALB2, BRCA1, or BRCA2 were associated with higher somatic mutation burden, as measured by nonsynonymous single nucleotide variants and higher T cell clonality (a lower T cell receptor diversity index).	('ATM', 'Gene', '472', (79, 82))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('lower T cell', 'Phenotype', 'HP:0005403', (262, 274))	('higher', 'PosReg', (143, 149))	('FANCD2', 'Gene', (91, 97))	('BRCA1', 'Gene', '672', (106, 111))	('somatic mutation burden', 'MPA', (150, 173))	('BRCA1', 'Gene', (106, 111))	('invasive bladder', 'Phenotype', 'HP:0100645', (10, 26))	('FANCD2', 'Gene', '2177', (91, 97))	('muscle-invasive bladder cancer', 'Disease', 'MESH:D001749', (3, 33))	('ATM', 'Gene', (79, 82))	('PALB2', 'Gene', (99, 104))	('ERCC2', 'Gene', (84, 89))	('BRCA2', 'Gene', (116, 121))	('ERCC2', 'Gene', '2068', (84, 89))	('PALB2', 'Gene', '79728', (99, 104))	('muscle-invasive bladder cancer', 'Disease', (3, 33))	('bladder cancer', 'Phenotype', 'HP:0009725', (19, 33))	('FA', 'Phenotype', 'HP:0001994', (91, 93))	('BRCA2', 'Gene', '675', (116, 121))	('mutations', 'Var', (35, 44))
339399	27004405	This hypermutable state generated by defects in the DNA repair mechanism may be responsible for altering the tumor mutanome, resulting in the production of highly tumor-specific mutated neo-antigens that may have contributed to the favorable recurrence-free survival after cystectomy in bladder cancer patients with DNA repair gene mutations.	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('DNA repair', 'Gene', (52, 62))	('bladder cancer', 'Disease', 'MESH:D001749', (287, 301))	('bladder cancer', 'Disease', (287, 301))	('DNA repair', 'Gene', (316, 326))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('mutations', 'Var', (332, 341))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumor', 'Disease', (163, 168))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('defects', 'Var', (37, 44))	('cancer', 'Phenotype', 'HP:0002664', (295, 301))	('patients', 'Species', '9606', (302, 310))	('tumor', 'Disease', (109, 114))	('bladder cancer', 'Phenotype', 'HP:0009725', (287, 301))
339401	27004405	Tumors with germline or somatic mutation in BRCA1/2 that harbored higher overall somatic mutational burden were associated with a much favorable overall prognosis compared with tumors with lower somatic mutational burden.	('BRCA1', 'Gene', (44, 49))	('tumors', 'Phenotype', 'HP:0002664', (177, 183))	('tumors', 'Disease', 'MESH:D009369', (177, 183))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('BRCA1', 'Gene', '672', (44, 49))	('tumors', 'Disease', (177, 183))	('germline', 'Var', (12, 20))
339408	27004405	In accordance with the above findings, we determined that many of these DNA repair mutations were significantly associated with a higher somatic mutational burden in cancer, including CRC and melanoma.	('mutations', 'Var', (83, 92))	('cancer', 'Disease', (166, 172))	('somatic mutational burden', 'MPA', (137, 162))	('CRC', 'Disease', (184, 187))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('DNA repair', 'Gene', (72, 82))	('higher', 'PosReg', (130, 136))	('melanoma', 'Phenotype', 'HP:0002861', (192, 200))	('melanoma', 'Disease', (192, 200))	('melanoma', 'Disease', 'MESH:D008545', (192, 200))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('CRC', 'Phenotype', 'HP:0003003', (184, 187))
339413	27004405	Within the COSMIC database (cancer.sanger.ac.uk), each gene was analyzed for frequency of somatic mutations (in all cancer types and specifically within sequenced lung, breast, liver, large intestine large intestine (LI; 86.9% of samples were CRC), or skin tumors), CNV gain, CNV loss, overexpression, and underexpression.	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('CNV loss', 'Disease', (276, 284))	('skin tumors', 'Disease', (252, 263))	('underexpression', 'Var', (306, 321))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('CRC', 'Phenotype', 'HP:0003003', (243, 246))	('CNV gain', 'Disease', 'MESH:D015430', (266, 274))	('CNV loss', 'Disease', 'MESH:D015431', (276, 284))	('skin tumors', 'Disease', 'MESH:D012878', (252, 263))	('cancer', 'Disease', (116, 122))	('skin tumors', 'Phenotype', 'HP:0008069', (252, 263))	('tumors', 'Phenotype', 'HP:0002664', (257, 263))	('breast', 'Disease', (169, 175))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('overexpression', 'PosReg', (286, 300))	('cancer', 'Disease', (28, 34))	('tumor', 'Phenotype', 'HP:0002664', (257, 262))	('liver', 'Disease', (177, 182))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('OS', 'Chemical', '-', (12, 14))	('lung', 'Disease', (163, 167))	('CNV gain', 'Disease', (266, 274))
339422	29540752	Finally, our results suggest that the functionally altering mutations in "double-agent" genes and oncogenes are the main driving force in cancer development, because non-silent mutations are biasedly distributed toward these two gene sets across all 12 major cancer types.	('cancer', 'Disease', 'MESH:D009369', (259, 265))	('cancer', 'Disease', (138, 144))	('altering', 'Reg', (51, 59))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('cancer', 'Phenotype', 'HP:0002664', (259, 265))	('mutations', 'Var', (60, 69))	('cancer', 'Disease', 'MESH:D009369', (138, 144))	('cancer', 'Disease', (259, 265))
339435	29540752	For a gene with both oncogenic and tumor-suppressor potentials, it is possible that one single mutation event would unleash its oncogenic power and abolish its tumor-suppressor function.	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('oncogenic power', 'CPA', (128, 143))	('tumor-suppressor', 'Gene', (160, 176))	('tumor-suppressor', 'Gene', '7248', (160, 176))	('abolish', 'NegReg', (148, 155))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('tumor-suppressor', 'Gene', '7248', (35, 51))	('tumor-suppressor', 'Gene', (35, 51))	('mutation', 'Var', (95, 103))
339436	29540752	Theoretically, one such mutation event would be enough to trigger the carcinogenic cascade in normal cells.	('carcinogenic', 'Disease', (70, 82))	('carcinogenic', 'Disease', 'MESH:D063646', (70, 82))	('mutation', 'Var', (24, 32))	('trigger', 'Reg', (58, 65))
339452	29540752	The data include 3281 cancer cases from 12 major cancer types with a total of 617,354 somatic mutations in 20,947 genes.	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('mutations', 'Var', (94, 103))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('cancer', 'Disease', (22, 28))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('cancer', 'Disease', (49, 55))
339510	29540752	Both the non-silent mutation distributions and mutation rates in four gene sets propose that different types of cancers underwent different mutation processes and potential cancerous mutations are more prone to happen in POTSFs and/or ONCs.	('mutations', 'Var', (183, 192))	('cancers', 'Phenotype', 'HP:0002664', (112, 119))	('cancerous', 'Disease', (173, 182))	('ONCs', 'Disease', (235, 239))	('cancers', 'Disease', 'MESH:D009369', (112, 119))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('cancers', 'Disease', (112, 119))	('POTSFs', 'Disease', (221, 227))	('cancerous', 'Disease', 'MESH:D009369', (173, 182))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))
339511	29540752	We also examined the distribution of potential gain-of-function mutations and potential loss-of-function mutations in POTSFs, ONCs, TSGs, NCRGs, and their non-silent and silent mutation rate across 12 cancer types in this study (Figure S4, S5, S6 and S7).	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('gain-of-function', 'PosReg', (47, 63))	('cancer', 'Disease', (201, 207))	('TSG', 'Gene', (132, 135))	('ONCs', 'Gene', (126, 130))	('mutations', 'Var', (105, 114))	('TSG', 'Gene', '57045', (132, 135))	('mutations', 'Var', (64, 73))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('POTSFs', 'Gene', (118, 124))	('loss-of-function', 'NegReg', (88, 104))	('NCRGs', 'Gene', (138, 143))
339524	29540752	In our expression analyses, we notice one phenomenon that the expression level of POTSFs is more akin to TSGs in both 12 cancer types and 6 human organs.	('human', 'Species', '9606', (140, 145))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('TSG', 'Gene', (105, 108))	('POTSFs', 'Var', (82, 88))	('TSG', 'Gene', '57045', (105, 108))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('cancer', 'Disease', (121, 127))
339530	29540752	It proposes that POTSFs, ONCs, and TSGs are more likely to form a biological module through PPI, while NCRGs are less likely.	('TSG', 'Gene', '57045', (35, 38))	('TSG', 'Gene', (35, 38))	('PPI', 'Var', (92, 95))
339537	29540752	Cancer is a disease driven by accumulated somatic mutations which lead to abnormal cell proliferation.	('abnormal cell proliferation', 'Phenotype', 'HP:0031377', (74, 101))	('mutations', 'Var', (50, 59))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))
339550	29540752	Since the number of mutations is positively correlated with age, the younger a cancer patient is, the less mutations his or her cancer has.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('less', 'NegReg', (102, 106))	('patient', 'Species', '9606', (86, 93))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('mutations', 'Var', (20, 29))	('cancer', 'Disease', (128, 134))
339551	29540752	POTSFs are oncogene and tumor-suppressor gene incorporated into one, and a single mutation event in these genes could theoretically promote its oncogenic function and inhibit its tumor-suppressor function at the same time.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('mutation', 'Var', (82, 90))	('tumor-suppressor', 'Gene', '7248', (179, 195))	('oncogenic function', 'CPA', (144, 162))	('inhibit', 'NegReg', (167, 174))	('tumor-suppressor', 'Gene', '7248', (24, 40))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('tumor-suppressor', 'Gene', (179, 195))	('promote', 'PosReg', (132, 139))	('tumor-suppressor', 'Gene', (24, 40))
339552	29540752	Thus, a very few mutations in POTSFs could be sufficient to trigger the cellular cascade of cancerous transformation in vivo.	('POTSFs', 'Gene', (30, 36))	('trigger', 'Reg', (60, 67))	('cellular', 'CPA', (72, 80))	('cancerous', 'Disease', (92, 101))	('cancerous', 'Disease', 'MESH:D009369', (92, 101))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('mutations', 'Var', (17, 26))
339553	29540752	Our analyses of the non-silent mutation patterns for POTSFs, ONCs, TSGs, and NCRGs show that POTSFs and ONCs accumulate more mutations than TSGs and NCRGs in all 12 cancer types examined in this study.	('mutations', 'Var', (125, 134))	('TSG', 'Gene', (67, 70))	('TSG', 'Gene', '57045', (140, 143))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('TSG', 'Gene', '57045', (67, 70))	('cancer', 'Disease', (165, 171))	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('TSG', 'Gene', (140, 143))
339554	29540752	This pattern is also observed in the distribution of potential gain-of-function mutations and potential loss-of-function mutations across 12 cancer types (Figure S4 and S5).	('mutations', 'Var', (121, 130))	('mutations', 'Var', (80, 89))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('loss-of-function', 'NegReg', (104, 120))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('gain-of-function', 'PosReg', (63, 79))	('cancer', 'Disease', (141, 147))
339555	29540752	One thing we want to mention is that in this study non-silent mutations far outnumber silent mutations by the ratio of 3 to 1 (472,060 vs. 145,294), which propose that these 12 cancers are mainly driven by functionally altering mutations in POTSFs and ONCs.	('cancers', 'Disease', 'MESH:D009369', (177, 184))	('cancers', 'Phenotype', 'HP:0002664', (177, 184))	('ONCs', 'Gene', (252, 256))	('cancers', 'Disease', (177, 184))	('mutations', 'Var', (228, 237))	('POTSFs', 'Gene', (241, 247))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('non-silent', 'Var', (51, 61))
339562	29540752	The question is how gain-of-function mutation events could down-regulate the expression of TSGs in cancer cells.	('expression', 'MPA', (77, 87))	('mutation', 'Var', (37, 45))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('down-regulate', 'NegReg', (59, 72))	('TSG', 'Gene', (91, 94))	('cancer', 'Disease', (99, 105))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('gain-of-function', 'PosReg', (20, 36))	('TSG', 'Gene', '57045', (91, 94))
339563	29540752	One possible scenario is that the gain-of-function mutations in POTSFs promote their oncogenic functions and then the mutated POTSFs negatively regulate TSG expression during cancer development.	('promote', 'PosReg', (71, 78))	('mutations', 'Var', (51, 60))	('POTSFs', 'Gene', (64, 70))	('expression', 'MPA', (157, 167))	('cancer', 'Disease', (175, 181))	('TSG', 'Gene', (153, 156))	('mutated', 'Var', (118, 125))	('gain-of-function', 'PosReg', (34, 50))	('regulate', 'Reg', (144, 152))	('oncogenic functions', 'CPA', (85, 104))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('TSG', 'Gene', '57045', (153, 156))	('negatively', 'NegReg', (133, 143))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
339568	29540752	TP53 plays an essential role in controlling cell cycle and its mutations have been proved to be associated with many cancer types.	('mutations', 'Var', (63, 72))	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('associated', 'Reg', (96, 106))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('cancer', 'Disease', (117, 123))
339575	25587191	Aberrant activation of epidermal growth factor receptor (EGFR) signaling contributes to diverse cancers.	('epidermal growth factor receptor', 'Gene', (23, 55))	('activation', 'PosReg', (9, 19))	('cancers', 'Phenotype', 'HP:0002664', (96, 103))	('Aberrant', 'Var', (0, 8))	('epidermal growth factor receptor', 'Gene', '1956', (23, 55))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('cancers', 'Disease', 'MESH:D009369', (96, 103))	('cancers', 'Disease', (96, 103))
339579	25587191	In tumor biopsies from three cohorts of lung cancer patients, positive EGFR:GRB2 PLA was observed in patients with and without EGFR mutations and the intensity of EGFR:GRB2 PLA was predictive of overall survival in an EGFR inhibitor-treated cohort.	('patients', 'Species', '9606', (101, 109))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))	('tumor', 'Disease', (3, 8))	('EGFR:GRB2 PLA', 'Gene', (163, 176))	('lung cancer', 'Phenotype', 'HP:0100526', (40, 51))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('mutations', 'Var', (132, 141))	('EGFR:GRB2 PLA', 'Gene', '1956', (163, 176))	('lung cancer', 'Disease', 'MESH:D008175', (40, 51))	('EGFR:GRB2 PLA', 'Gene', (71, 84))	('EGFR:GRB2 PLA', 'Gene', '1956', (71, 84))	('patients', 'Species', '9606', (52, 60))	('EGFR', 'Gene', (127, 131))	('tumor', 'Disease', 'MESH:D009369', (3, 8))	('lung cancer', 'Disease', (40, 51))	('overall survival', 'CPA', (195, 211))
339586	25587191	EGFR activation, either through ligand binding or cancer-associated mutations conferring constitutive kinase activity, results in receptor autophosphorylation.	('EGFR', 'Gene', (0, 4))	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('activation', 'PosReg', (5, 15))	('results in', 'Reg', (119, 129))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('mutations', 'Var', (68, 77))	('receptor autophosphorylation', 'MPA', (130, 158))
339587	25587191	GRB2 is required for survival of cells with mutant EGFR and the interaction between EGFR and GRB2 is abrogated by erlotinib, resulting in loss of downstream ERK signaling.	('loss', 'NegReg', (138, 142))	('mutant', 'Var', (44, 50))	('downstream ERK signaling', 'MPA', (146, 170))	('abrogated', 'NegReg', (101, 110))	('EGFR', 'Gene', (51, 55))	('erlotinib', 'Chemical', 'MESH:D000069347', (114, 123))	('EGFR', 'Gene', (84, 88))	('interaction', 'Interaction', (64, 75))	('GRB2', 'Protein', (93, 97))
339589	25587191	EGFR mutational testing has become a standard of care in lung cancer treatment and presence of activating mutations is clearly associated with response to erlotinib and gefitinib with tumor response rates up to 85%.	('presence', 'Var', (83, 91))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('associated with', 'Reg', (127, 142))	('EGFR', 'Gene', (0, 4))	('erlotinib', 'Chemical', 'MESH:D000069347', (155, 164))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('response', 'MPA', (143, 151))	('lung cancer', 'Disease', 'MESH:D008175', (57, 68))	('tumor', 'Disease', (184, 189))	('mutational', 'Var', (5, 15))	('gefitinib', 'Chemical', 'MESH:D000077156', (169, 178))	('mutations', 'Var', (106, 115))	('lung cancer', 'Disease', (57, 68))	('lung cancer', 'Phenotype', 'HP:0100526', (57, 68))
339597	25587191	We analyzed EGFR:GRB2 PLA in PC9 cells, which are a lung adenocarcinoma cell line with a deletion from Glu746 to Ala750 in the kinase domain of EGFR, which results in ligand-independent constitutive activity.	('ligand-independent constitutive activity', 'MPA', (167, 207))	('EGFR', 'Gene', (144, 148))	('Glu746', 'Chemical', '-', (103, 109))	('adenocarcinoma', 'Disease', (57, 71))	('adenocarcinoma', 'Disease', 'MESH:D000230', (57, 71))	('EGFR:GRB2 PLA', 'Gene', (12, 25))	('Glu746', 'Var', (103, 109))	('deletion', 'Var', (89, 97))	('EGFR:GRB2 PLA', 'Gene', '1956', (12, 25))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (52, 71))	('PC9', 'Gene', '255738', (29, 32))	('Ala750', 'Chemical', '-', (113, 119))	('PC9', 'Gene', (29, 32))	('carcinoma', 'Phenotype', 'HP:0030731', (62, 71))
339603	25587191	We hypothesized that EGFR:GRB2 PLA intensity would be reduced by EGFR inhibition.	('EGFR:GRB2 PLA', 'Gene', '1956', (21, 34))	('EGFR', 'Gene', (65, 69))	('reduced', 'NegReg', (54, 61))	('inhibition', 'Var', (70, 80))	('EGFR:GRB2 PLA', 'Gene', (21, 34))
339606	25587191	Likewise, we found that erlotinib decreased phosphorylation of Tyr1068 in EGFR, which is indicative of activation by EGF or activating mutations and is the major binding site for GRB2, in a similar concentration-dependent manner in PC9 cells (Fig.	('phosphorylation', 'MPA', (44, 59))	('Tyr1068', 'Chemical', '-', (63, 70))	('decreased', 'NegReg', (34, 43))	('Tyr1068', 'Var', (63, 70))	('PC9', 'Gene', '255738', (232, 235))	('PC9', 'Gene', (232, 235))	('erlotinib', 'Chemical', 'MESH:D000069347', (24, 33))	('activation', 'PosReg', (103, 113))	('EGFR', 'Gene', (74, 78))
339609	25587191	To test if EGFR:GRB2 PLA correlated with EGFR mutational status and thus reflected activation of EGFR, we examined seven NSCLC cell lines with either mutant (PC9, H1650, HCC827, HCC4006) or wild-type EGFR (H1648, H322, H23).	('EGFR:GRB2 PLA', 'Gene', (11, 24))	('HCC4006', 'CellLine', 'CVCL:1269', (178, 185))	('EGFR', 'Gene', (41, 45))	('EGFR:GRB2 PLA', 'Gene', '1956', (11, 24))	('H1648', 'CellLine', 'CVCL:1482', (206, 211))	('NSCLC', 'Disease', (121, 126))	('mutational', 'Var', (46, 56))	('NSCLC', 'Disease', 'MESH:D002289', (121, 126))	('H1650', 'Var', (163, 168))	('PC9', 'Gene', '255738', (158, 161))	('H322', 'CellLine', 'CVCL:1556', (213, 217))	('HCC827', 'CellLine', 'CVCL:2063', (170, 176))	('correlated', 'Reg', (25, 35))	('PC9', 'Gene', (158, 161))
339610	25587191	We consistently observed intense EGFR:GRB2 PLA signal in cell lines with mutant EGFR and low to undetectable EGFR:GRB2 PLA signal in cell lines with wild-type EGFR (Fig.	('intense', 'PosReg', (25, 32))	('EGFR:GRB2 PLA', 'Gene', (33, 46))	('EGFR:GRB2 PLA', 'Gene', '1956', (33, 46))	('EGFR', 'Gene', (80, 84))	('mutant', 'Var', (73, 79))	('EGFR:GRB2 PLA', 'Gene', (109, 122))	('EGFR:GRB2 PLA', 'Gene', '1956', (109, 122))
339611	25587191	Moreover, cell lines with increased EGFR:GRB2 PLA signal had increased abundance of Tyr1068 phosphorylated EGFR (Fig.	('Tyr1068', 'Chemical', '-', (84, 91))	('EGFR:GRB2 PLA', 'Gene', (36, 49))	('abundance', 'MPA', (71, 80))	('Tyr1068 phosphorylated', 'Var', (84, 106))	('increased', 'PosReg', (61, 70))	('EGFR:GRB2 PLA', 'Gene', '1956', (36, 49))
339615	25587191	The intensity of the EGFR:GRB2 PLA signal was greater in xenografts made with H1650 (EGFR-mutant) than H322 (EGFR wild-type) cells (Fig.	('EGFR:GRB2 PLA', 'Gene', '1956', (21, 34))	('H322', 'CellLine', 'CVCL:1556', (103, 107))	('intensity', 'MPA', (4, 13))	('greater', 'PosReg', (46, 53))	('H1650', 'Var', (78, 83))	('EGFR:GRB2 PLA', 'Gene', (21, 34))
339618	25587191	Moreover, we found that the abundance of phosphorylated Tyr1068 EGFR was increased in H1650 xenografts compared to H322 xenografts, and that EGFR Tyr1068 phosphorylation was reduced in xenografts of mice treated with erlotinib (fig.	('abundance', 'MPA', (28, 37))	('increased', 'PosReg', (73, 82))	('phosphorylation', 'MPA', (154, 169))	('phosphorylated', 'MPA', (41, 55))	('mice', 'Species', '10090', (199, 203))	('Tyr1068', 'Var', (56, 63))	('H1650', 'Var', (86, 91))	('Tyr1068', 'Var', (146, 153))	('H322', 'CellLine', 'CVCL:1556', (115, 119))	('erlotinib', 'Chemical', 'MESH:D000069347', (217, 226))	('EGFR', 'Gene', (64, 68))	('reduced', 'NegReg', (174, 181))	('Tyr1068', 'Chemical', '-', (56, 63))	('Tyr1068', 'Chemical', '-', (146, 153))
339624	25587191	EGFR:GRB2 PLA labeling was robust in PDXs established from a patient tumor with an activating mutation in exon 18 of EGFR (encoding a G719A amino acid substitution), and EGFR:GRB2 PLA was strongly reduced in these mice when treated with erlotinib (Fig.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('patient', 'Species', '9606', (61, 68))	('EGFR:GRB2 PLA', 'Gene', (170, 183))	('tumor', 'Disease', (69, 74))	('EGFR:GRB2 PLA', 'Gene', '1956', (170, 183))	('EGFR', 'Gene', (117, 121))	('reduced', 'NegReg', (197, 204))	('activating', 'PosReg', (83, 93))	('G719A', 'Mutation', 'rs121913428', (134, 139))	('erlotinib', 'Chemical', 'MESH:D000069347', (237, 246))	('EGFR:GRB2 PLA', 'Gene', (0, 13))	('mice', 'Species', '10090', (214, 218))	('EGFR:GRB2 PLA', 'Gene', '1956', (0, 13))	('mutation in', 'Var', (94, 105))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
339625	25587191	In contrast, PDXs established from a patient tumor with wild-type EGFR and an activating mutation in exon 1 of KRAS (encoding a G12V amino acid substitution) had markedly less intense EGFR:GRB2 PLA, which was minimally affected by erlotinib treatment (Fig.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('patient', 'Species', '9606', (37, 44))	('KRAS', 'Gene', (111, 115))	('EGFR:GRB2 PLA', 'Gene', (184, 197))	('EGFR:GRB2 PLA', 'Gene', '1956', (184, 197))	('mutation', 'Var', (89, 97))	('tumor', 'Disease', (45, 50))	('erlotinib', 'Chemical', 'MESH:D000069347', (231, 240))	('less', 'NegReg', (171, 175))	('G12V', 'Var', (128, 132))	('G12V', 'SUBSTITUTION', 'None', (128, 132))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
339626	25587191	The EGFR:GRB2 PLA status in EGFR-mutant or KRAS-mutant PDX samples was similar to IHC staining for Tyr1068 phosphorylated EGFR (fig.	('EGFR:GRB2 PLA', 'Gene', '1956', (4, 17))	('EGFR-mutant', 'Var', (28, 39))	('EGFR-mutant', 'Gene', (28, 39))	('Tyr1068', 'Chemical', '-', (99, 106))	('KRAS-mutant', 'Gene', (43, 54))	('EGFR:GRB2 PLA', 'Gene', (4, 17))
339633	25587191	We focused on PDX tumors from lung cancers in more detail because EGFR inhibitors are routinely considered as a therapeutic option in the treatment of NSCLC patients.	('lung cancers', 'Disease', (30, 42))	('lung cancer', 'Phenotype', 'HP:0100526', (30, 41))	('inhibitors', 'Var', (71, 81))	('NSCLC', 'Disease', (151, 156))	('EGFR', 'Gene', (66, 70))	('NSCLC', 'Disease', 'MESH:D002289', (151, 156))	('PDX tumors', 'Disease', (14, 24))	('lung cancers', 'Disease', 'MESH:D008175', (30, 42))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('patients', 'Species', '9606', (157, 165))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('lung cancers', 'Phenotype', 'HP:0100526', (30, 42))	('cancers', 'Phenotype', 'HP:0002664', (35, 42))	('PDX tumors', 'Disease', 'MESH:D009369', (14, 24))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
339637	25587191	Moreover, none of the NSCLC adenocarcinoma PDX tumors had activating mutations in EGFR, suggesting that active EGFR signaling is not limited to genomically-encoded aberrant kinase activity.	('mutations', 'Var', (69, 78))	('EGFR', 'Gene', (82, 86))	('carcinoma', 'Phenotype', 'HP:0030731', (33, 42))	('activating', 'MPA', (58, 68))	('NSCLC adenocarcinoma PDX tumors', 'Disease', (22, 53))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('NSCLC adenocarcinoma PDX tumors', 'Disease', 'MESH:D000230', (22, 53))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))
339671	25587191	6A), 69% (9 of 13) of tumors with mutant EGFR had high EGFR:GRB2 PLA scores (Fig.	('tumors', 'Phenotype', 'HP:0002664', (22, 28))	('EGFR', 'Gene', (41, 45))	('EGFR:GRB2 PLA', 'Gene', (55, 68))	('EGFR:GRB2 PLA', 'Gene', '1956', (55, 68))	('tumors', 'Disease', 'MESH:D009369', (22, 28))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('tumors', 'Disease', (22, 28))	('mutant', 'Var', (34, 40))
339673	25587191	Some patients with wild-type EGFR benefit from therapies involving EGFR inhibitors.	('patients', 'Species', '9606', (5, 13))	('wild-type', 'Var', (19, 28))	('benefit', 'PosReg', (34, 41))	('EGFR', 'Gene', (29, 33))	('EGFR', 'Gene', (67, 71))
339676	25587191	Thus, we evaluated overall survival using an endpoint of two years of follow-up.. High EGFR:GRB2 PLA was associated with improved overall survival and a doubling in median overall survival (Fig.	('overall survival', 'MPA', (172, 188))	('EGFR:GRB2 PLA', 'Gene', (87, 100))	('High', 'Var', (82, 86))	('EGFR:GRB2 PLA', 'Gene', '1956', (87, 100))	('improved', 'PosReg', (121, 129))	('overall survival', 'MPA', (130, 146))
339677	25587191	Analysis of survival in all patients with available outcome data revealed a similar, but not statistically significant, trend of the association between high EGFR:GRB2 PLA scores, but not EGFR AQUA scores, and improved overall survival (fig.	('overall survival', 'MPA', (219, 235))	('improved', 'PosReg', (210, 218))	('EGFR:GRB2 PLA', 'Gene', (158, 171))	('patients', 'Species', '9606', (28, 36))	('EGFR:GRB2 PLA', 'Gene', '1956', (158, 171))	('high', 'Var', (153, 157))
339681	25587191	We found that PDX tumorswith high EGFR:GRB2 PLA were more likely to respond to cetuximab, but EGFR:GRB2 PLA was not entirely predictive of response.	('high', 'Var', (29, 33))	('EGFR:GRB2 PLA', 'Gene', (94, 107))	('PDX tumors', 'Disease', (14, 24))	('EGFR:GRB2 PLA', 'Gene', '1956', (94, 107))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('EGFR:GRB2 PLA', 'Gene', (34, 47))	('respond to cetuximab', 'MPA', (68, 88))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('PDX tumors', 'Disease', 'MESH:D009369', (14, 24))	('EGFR:GRB2 PLA', 'Gene', '1956', (34, 47))	('cetuximab', 'Chemical', 'MESH:D000068818', (79, 88))
339685	25587191	Mutations in genes encoding proteins downstream of EGFR or aberrant phosphorylation and activation of Met, AKT, and ERBB3, occur in the PDX tumors used in the current study.	('ERBB3', 'Gene', (116, 121))	('ERBB3', 'Gene', '2065', (116, 121))	('activation', 'PosReg', (88, 98))	('AKT', 'Gene', '207', (107, 110))	('phosphorylation', 'MPA', (68, 83))	('EGFR', 'Gene', (51, 55))	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('AKT', 'Gene', (107, 110))	('PDX tumors', 'Disease', 'MESH:D009369', (136, 146))	('Mutations', 'Var', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('Met', 'Gene', (102, 105))	('PDX tumors', 'Disease', (136, 146))
339686	25587191	In particular, colorectal cancer-derived PDX tumors in cetuximab-treated mice comprise 60% with KRAS mutations, 15% with BRAF mutations, both of which are downstream of EGFR and can be drivers in colorectal cancer.	('BRAF', 'Gene', (121, 125))	('PDX tumors', 'Disease', (41, 51))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('mutations', 'Var', (101, 110))	('colorectal cancer', 'Disease', (196, 213))	('cetuximab', 'Chemical', 'MESH:D000068818', (55, 64))	('colorectal cancer', 'Disease', 'MESH:D015179', (15, 32))	('mice', 'Species', '10090', (73, 77))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('colorectal cancer', 'Disease', 'MESH:D015179', (196, 213))	('colorectal cancer', 'Phenotype', 'HP:0003003', (15, 32))	('colorectal cancer', 'Phenotype', 'HP:0003003', (196, 213))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('PDX tumors', 'Disease', 'MESH:D009369', (41, 51))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('mutations', 'Var', (126, 135))	('colorectal cancer', 'Disease', (15, 32))	('KRAS', 'Gene', (96, 100))
339688	25587191	In patient samples, one tumor from a patient in MCC2 had both an L858R mutation and a T790M "gatekeeper" mutation in EGFR, and thus would not be expected to respond to erlotinib, but had a high EGFR:GRB2 PLA score.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('erlotinib', 'Chemical', 'MESH:D000069347', (168, 177))	('patient', 'Species', '9606', (37, 44))	('L858R', 'Var', (65, 70))	('tumor', 'Disease', (24, 29))	('patient', 'Species', '9606', (3, 10))	('EGFR:GRB2 PLA', 'Gene', (194, 207))	('EGFR:GRB2 PLA', 'Gene', '1956', (194, 207))	('L858R', 'Mutation', 'rs121434568', (65, 70))	('MCC2', 'Gene', (48, 52))	('T790M', 'Mutation', 'rs121434569', (86, 91))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('MCC2', 'Gene', '83878', (48, 52))	('gatekeeper', 'Species', '111938', (93, 103))
339704	25587191	For example, PLA could be used to monitor activation of the receptor tyrosine kinases MET and FGFR by either genetic mutation or signals from the tumor microenvironment.	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('genetic mutation', 'Var', (109, 125))	('tumor', 'Disease', (146, 151))	('activation', 'PosReg', (42, 52))	('MET', 'Enzyme', (86, 89))	('FGFR', 'Gene', (94, 98))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
339798	30597925	Hierarchical clustering of gene expression data from lung cancer cell lines could further verify the association of high LINC00261/FOXA2 expression to an epithelial gene signature.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('expression', 'MPA', (137, 147))	('high', 'Var', (116, 120))	('lung cancer', 'Disease', 'MESH:D008175', (53, 64))	('LINC00261', 'Gene', '140828', (121, 130))	('LINC00261', 'Gene', (121, 130))	('lung cancer', 'Disease', (53, 64))	('lung cancer', 'Phenotype', 'HP:0100526', (53, 64))
339885	30597925	For LINC00261 and FOXA2 knockdown, NCI-H520 and Calu-6 cell were seeded in 6-well plates at a density of 5 x 105 and 2 x 105 cells per well, respectively.	('NCI-H520', 'CellLine', 'CVCL:1566', (35, 43))	('FOXA2', 'Gene', (18, 23))	('LINC00261', 'Gene', (4, 13))	('Calu-6', 'CellLine', 'CVCL:0236', (48, 54))	('LINC00261', 'Gene', '140828', (4, 13))	('knockdown', 'Var', (24, 33))
339926	28767580	They concluded that any new EKG changes should raise the suspicion of cardiac metastases in clinically stable patients with cancer and no cardiac symptoms suggestive of ischemia.	('cancer', 'Disease', (124, 130))	('ischemia', 'Disease', (169, 177))	('EKG', 'Gene', (28, 31))	('ischemia', 'Disease', 'MESH:D007511', (169, 177))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('cardiac metastases', 'Disease', 'MESH:D009362', (70, 88))	('cardiac metastases', 'Disease', (70, 88))	('patients', 'Species', '9606', (110, 118))	('cancer', 'Disease', 'MESH:D009369', (124, 130))	('changes', 'Var', (32, 39))
339928	28767580	From our experience, it is suggested that any new EKG changes should raise the suspicion of cardiac metastases not only in patients with preexisting cancer but also in previously healthy individuals with unexplained AF.	('cancer', 'Disease', (149, 155))	('changes', 'Var', (54, 61))	('cardiac metastases', 'Disease', (92, 110))	('AF', 'Disease', 'MESH:D001281', (216, 218))	('patients', 'Species', '9606', (123, 131))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('EKG', 'Gene', (50, 53))	('AF', 'Phenotype', 'HP:0005110', (216, 218))	('cancer', 'Disease', 'MESH:D009369', (149, 155))	('cardiac metastases', 'Disease', 'MESH:D009362', (92, 110))
339945	28978030	Our results showed that PinX1 deletion accounted for the most alterations, with the frequency of its deletion regularly occurring in pathological types of carcinosarcoma and adenocarcinoma.	('carcinosarcoma and adenocarcinoma', 'Disease', 'MESH:D002296', (155, 188))	('occurring', 'Reg', (120, 129))	('PinX1', 'Gene', (24, 29))	('deletion', 'Var', (30, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (179, 188))	('PinX1', 'Gene', '54984', (24, 29))
339946	28978030	We found few instances of PinX1 gene mutations and 3D structural analysis demonstrated that these mutation sites were always located within telomerase inhibitor domains.	('mutations', 'Var', (37, 46))	('PinX1', 'Gene', (26, 31))	('PinX1', 'Gene', '54984', (26, 31))
339948	28978030	The status of PinX1 genetic alterations was correlated with prognosis and may be tumor-type specific.	('PinX1', 'Gene', '54984', (14, 19))	('genetic alterations', 'Var', (20, 39))	('PinX1', 'Gene', (14, 19))	('correlated', 'Reg', (44, 54))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Disease', (81, 86))
339954	28978030	Many studies have shown that telomere shortening or dysfunction is often acquired during the process of tumorigenesis.	('tumor', 'Disease', (104, 109))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('telomere shortening', 'Var', (29, 48))
339965	28978030	Furthermore, PinX1 knockdown leads to chromosomal instability, as its loss can cause delayed mitotic entry during mitosis, thereby abrogating faithful chromosome segregation.	('chromosomal instability', 'Phenotype', 'HP:0040012', (38, 61))	('mitosis', 'Disease', (114, 121))	('loss', 'NegReg', (70, 74))	('PinX1', 'Gene', (13, 18))	('knockdown', 'Var', (19, 28))	('mitosis', 'Disease', 'None', (114, 121))	('cause', 'Reg', (79, 84))	('chromosomal instability', 'MPA', (38, 61))	('leads to', 'Reg', (29, 37))	('faithful chromosome segregation', 'CPA', (142, 173))	('abrogating', 'NegReg', (131, 141))	('PinX1', 'Gene', '54984', (13, 18))
339973	28978030	PinX1 gene alterations were detected in 105 separate studies using the online resource cBioportal Web.	('alterations', 'Var', (11, 22))	('PinX1', 'Gene', (0, 5))	('PinX1', 'Gene', '54984', (0, 5))
339974	28978030	PinX1 deletion accounted for the most alterations, with the highest ratio of 12.5% (Uterine Carcinosarcoma, TCGA, Provisional).	('PinX1', 'Gene', (0, 5))	('Uterine Carcinosarcoma', 'Phenotype', 'HP:0002891', (84, 106))	('deletion', 'Var', (6, 14))	('Carcinosarcoma', 'Disease', 'MESH:D002296', (92, 106))	('TCGA', 'Disease', (108, 112))	('PinX1', 'Gene', '54984', (0, 5))	('Carcinosarcoma', 'Disease', (92, 106))
339975	28978030	Furthermore, the frequency of PinX1 deletion often occurred in the two specific pathological types of carcinosarcoma and adenocarcinoma.	('PinX1', 'Gene', (30, 35))	('deletion', 'Var', (36, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('PinX1', 'Gene', '54984', (30, 35))	('occurred', 'Reg', (51, 59))	('carcinosarcoma and adenocarcinoma', 'Disease', 'MESH:D002296', (102, 135))
339976	28978030	In addition, the frequency of PinX1 gene deletion in adenocarcinoma was more than squamous carcinoma in some solid tumors, such as 6.1% (TCGA, Nature), 5.5% (Broad, Cell), and 5.7% (TCGA, Provisional) in lung adenocarcinoma versus 1.7% (TCGA, Provisional) in lung squamous cell carcinoma.	('lung squamous cell carcinoma', 'Disease', (259, 287))	('PinX1', 'Gene', (30, 35))	('solid tumors', 'Disease', (109, 121))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (264, 287))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (204, 223))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (204, 223))	('carcinoma', 'Phenotype', 'HP:0030731', (278, 287))	('adenocarcinoma', 'Disease', (53, 67))	('squamous carcinoma', 'Disease', (82, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (214, 223))	('solid tumors', 'Disease', 'MESH:D009369', (109, 121))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('adenocarcinoma', 'Disease', 'MESH:D000230', (53, 67))	('adenocarcinoma', 'Disease', (209, 223))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (82, 100))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (259, 287))	('squamous carcinoma', 'Disease', 'MESH:D002294', (82, 100))	('lung adenocarcinoma', 'Disease', (204, 223))	('deletion', 'Var', (41, 49))	('adenocarcinoma', 'Disease', 'MESH:D000230', (209, 223))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (259, 287))	('PinX1', 'Gene', '54984', (30, 35))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))
339977	28978030	When compared with the high frequency of PinX1 genetic deletions, there were few, frequent PinX1 gene mutations the in 105 studies examined using cBioportal Web.	('PinX1', 'Gene', (91, 96))	('PinX1', 'Gene', '54984', (41, 46))	('PinX1', 'Gene', (41, 46))	('PinX1', 'Gene', '54984', (91, 96))	('mutations', 'Var', (102, 111))
339978	28978030	Of these, only three sites (S161N/R, A175T, R209C/H) had reached mutation level 2 (the number of patients with the same mutation site).	('A175T', 'Var', (37, 42))	('R209C', 'Var', (44, 49))	('S161N', 'Var', (28, 33))	('R209C', 'SUBSTITUTION', 'None', (44, 49))	('A175T', 'Mutation', 'rs750737817', (37, 42))	('S161N', 'SUBSTITUTION', 'None', (28, 33))	('patients', 'Species', '9606', (97, 105))
339984	28978030	As shown in Figure 4, there were no significant correlations between PinX1 gene alteration and overall survival and/or disease-free survival in prostate adenocarcinoma (TCGA, Provisional) (P>0.05, Figure 4A), colorectal adenocarcinoma (TCGA, Provisional) (P>0.05, Figure 4B), head and neck squamous cell carcinoma (TCGA, Provisional) (P>0.05, Figure 4C), kidney renal clear cell carcinoma (TCGA, Provisional) (P>0.05, Figure 4D), and lung squamous cell carcinoma (TCGA, Provisional) (P>0.05, Figure 4F).	('lung squamous cell carcinoma', 'Disease', (434, 462))	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (209, 234))	('prostate adenocarcinoma', 'Disease', (144, 167))	('carcinoma', 'Phenotype', 'HP:0030731', (453, 462))	('neck squamous cell carcinoma', 'Disease', (285, 313))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (285, 313))	('carcinoma', 'Phenotype', 'HP:0030731', (158, 167))	('prostate adenocarcinoma', 'Disease', 'MESH:D011471', (144, 167))	('carcinoma', 'Phenotype', 'HP:0030731', (379, 388))	('kidney renal clear cell carcinoma', 'Disease', 'MESH:C538614', (355, 388))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (290, 313))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (434, 462))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (439, 462))	('alteration', 'Var', (80, 90))	('PinX1', 'Gene', '54984', (69, 74))	('colorectal adenocarcinoma', 'Disease', (209, 234))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (276, 313))	('carcinoma', 'Phenotype', 'HP:0030731', (225, 234))	('carcinoma', 'Phenotype', 'HP:0030731', (304, 313))	('kidney renal clear cell carcinoma', 'Disease', (355, 388))	('PinX1', 'Gene', (69, 74))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (434, 462))
339985	28978030	There was also no significant correlation between PinX1 gene alteration and overall survival in bladder urothelial carcinoma (TCGA, Provisional) (P>0.05, Figure 4G) and disease-free survival in ovarian serous cystadenocarcinoma (TCGA, Provisional) (P>0.05, Figure 4H).	('ovarian serous cystadenocarcinoma', 'Disease', (194, 227))	('PinX1', 'Gene', (50, 55))	('bladder urothelial carcinoma', 'Disease', (96, 124))	('ovarian serous cystadenocarcinoma', 'Phenotype', 'HP:0012887', (194, 227))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('alteration', 'Var', (61, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (218, 227))	('PinX1', 'Gene', '54984', (50, 55))	('ovarian serous cystadenocarcinoma', 'Disease', 'MESH:D018284', (194, 227))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (96, 124))
339986	28978030	However, PinX1 gene alteration was significantly correlated with poor overall survival and/or disease-free survival in lung adenocarcinoma (TCGA, Provisional) (P<0.05, Figure 4E), poor overall survival in bladder urothelial carcinoma (TCGA, Provisional) (P<0.05, Figure 4G), and poor disease-free survival ovarian serous cystadenocarcinoma (TCGA, Provisional) (P<0.05, Figure 4H).	('carcinoma', 'Phenotype', 'HP:0030731', (330, 339))	('poor', 'NegReg', (180, 184))	('alteration', 'Var', (20, 30))	('poor disease-free survival ovarian serous cystadenocarcinoma', 'Disease', 'MESH:D018284', (279, 339))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (205, 233))	('PinX1', 'Gene', '54984', (9, 14))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (119, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('bladder urothelial carcinoma', 'Disease', (205, 233))	('lung adenocarcinoma', 'Disease', (119, 138))	('PinX1', 'Gene', (9, 14))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (119, 138))	('ovarian serous cystadenocarcinoma', 'Phenotype', 'HP:0012887', (306, 339))	('carcinoma', 'Phenotype', 'HP:0030731', (224, 233))	('poor', 'NegReg', (65, 69))
339999	28978030	We then continued our study in vitro to investigate whether knock-down of PinX1 expression promotes cell proliferation in cancer cell lines.	('promotes', 'PosReg', (91, 99))	('knock-down', 'Var', (60, 70))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('PinX1', 'Gene', '54984', (74, 79))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('PinX1', 'Gene', (74, 79))
340005	28978030	For example, one study demonstrated that high expression of PinX1 in esophageal squamous cell carcinoma is associated with a patient's chemoradiotherapy resistance and can predict his/her survival.	('predict', 'Reg', (172, 179))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (69, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (80, 103))	('associated', 'Reg', (107, 117))	('high expression', 'Var', (41, 56))	('esophageal squamous cell carcinoma', 'Disease', (69, 103))	('patient', 'Species', '9606', (125, 132))	('PinX1', 'Gene', '54984', (60, 65))	('PinX1', 'Gene', (60, 65))
340013	28978030	Our results indicated that PinX1 deletion is a common genotype in human cancer patients, leading us to believe that insufficient PinX1 may be involved in the progression of a variety of human cancers.	('deletion', 'Var', (33, 41))	('human', 'Species', '9606', (66, 71))	('cancers', 'Phenotype', 'HP:0002664', (192, 199))	('PinX1', 'Gene', '54984', (129, 134))	('cancers', 'Disease', (192, 199))	('cancer', 'Disease', (192, 198))	('PinX1', 'Gene', (129, 134))	('PinX1', 'Gene', '54984', (27, 32))	('cancer', 'Disease', (72, 78))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('insufficient', 'Disease', (116, 128))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('PinX1', 'Gene', (27, 32))	('involved', 'Reg', (142, 150))	('cancers', 'Disease', 'MESH:D009369', (192, 199))	('cancer', 'Disease', 'MESH:D009369', (192, 198))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('insufficient', 'Disease', 'MESH:D000309', (116, 128))	('human', 'Species', '9606', (186, 191))	('patients', 'Species', '9606', (79, 87))
340016	28978030	With the exception of the high frequency of PinX1 gene deletion, we also found that PinX1 genetic mutations occurred in some types of human cancers, including bladder urothelial carcinoma, lung adenocarcinoma, and melanoma.	('lung adenocarcinoma', 'Disease', (189, 208))	('bladder urothelial carcinoma', 'Disease', (159, 187))	('deletion', 'Var', (55, 63))	('PinX1', 'Gene', '54984', (44, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (199, 208))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (159, 187))	('PinX1', 'Gene', (44, 49))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (189, 208))	('melanoma', 'Phenotype', 'HP:0002861', (214, 222))	('melanoma', 'Disease', (214, 222))	('cancers', 'Disease', 'MESH:D009369', (140, 147))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (189, 208))	('human', 'Species', '9606', (134, 139))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('occurred', 'Reg', (108, 116))	('PinX1', 'Gene', '54984', (84, 89))	('mutations', 'Var', (98, 107))	('melanoma', 'Disease', 'MESH:D008545', (214, 222))	('cancers', 'Phenotype', 'HP:0002664', (140, 147))	('cancers', 'Disease', (140, 147))	('PinX1', 'Gene', (84, 89))	('carcinoma', 'Phenotype', 'HP:0030731', (178, 187))
340017	28978030	However, the number of cases having a PinX1 gene mutation was very few.	('PinX1', 'Gene', '54984', (38, 43))	('PinX1', 'Gene', (38, 43))	('mutation', 'Var', (49, 57))
340020	28978030	Additional work performing 3D structural analysis showed that that these mutation sites may influence this structural domain, which is specifically recognized by the TRFH domain of TRF1 via both hydrophobic and hydrophilic interactions.	('TRF1', 'Gene', (181, 185))	('influence', 'Reg', (92, 101))	('mutation sites', 'Var', (73, 87))	('hydrophobic', 'MPA', (195, 206))	('structural domain', 'MPA', (107, 124))	('TRF1', 'Gene', '7013', (181, 185))
340021	28978030	Thus, such mutations could break the PinX1-TRF1-TERT complex, thereby promoting telomere elongation in cells.	('mutations', 'Var', (11, 20))	('promoting', 'PosReg', (70, 79))	('telomere elongation', 'CPA', (80, 99))	('TERT', 'Gene', (48, 52))	('PinX1', 'Gene', '54984', (37, 42))	('break', 'NegReg', (27, 32))	('TRF1', 'Gene', (43, 47))	('TRF1', 'Gene', '7013', (43, 47))	('TERT', 'Gene', '7015', (48, 52))	('PinX1', 'Gene', (37, 42))
340024	28978030	Since the deletion of PinX1 accounts for the most observed alterations, we next randomly selected six studies to better understand the relationship between PinX1 gene copy number and mRNA levels.	('mRNA levels', 'MPA', (183, 194))	('PinX1', 'Gene', '54984', (22, 27))	('PinX1', 'Gene', '54984', (156, 161))	('deletion', 'Var', (10, 18))	('PinX1', 'Gene', (22, 27))	('PinX1', 'Gene', (156, 161))
340025	28978030	Among the five types of copy numbers we examined (deep deletion, shallow deletion, diploid, gain and amplification), we found that the frequency of PinX1 homozygous depletion as well as PinX1 heterozygous deficiency were the main reasons for the frequency of PinX1 deletion in a wide variety of tumor tissues.	('PinX1', 'Gene', '54984', (148, 153))	('PinX1', 'Gene', '54984', (186, 191))	('PinX1', 'Gene', '54984', (259, 264))	('tumor', 'Disease', 'MESH:D009369', (295, 300))	('PinX1', 'Gene', (148, 153))	('PinX1', 'Gene', (186, 191))	('tumor', 'Phenotype', 'HP:0002664', (295, 300))	('deletion', 'Var', (265, 273))	('PinX1', 'Gene', (259, 264))	('tumor', 'Disease', (295, 300))
340028	28978030	According to our mutation data, PinX1 mutations in gastric, colorectal, prostate, breast, and lung carcinomas may not actually contribute to development of these carcinomas due to their low incidence of mutational events seen in the database.	('gastric', 'Disease', (51, 58))	('prostate', 'Disease', (72, 80))	('colorectal', 'Disease', 'MESH:D015179', (60, 70))	('carcinomas', 'Disease', (162, 172))	('mutations', 'Var', (38, 47))	('lung carcinomas', 'Disease', 'MESH:D008175', (94, 109))	('carcinomas', 'Disease', (99, 109))	('lung carcinomas', 'Disease', (94, 109))	('PinX1', 'Gene', '54984', (32, 37))	('carcinoma', 'Phenotype', 'HP:0030731', (162, 171))	('breast', 'Disease', (82, 88))	('PinX1', 'Gene', (32, 37))	('carcinomas', 'Phenotype', 'HP:0030731', (162, 172))	('carcinomas', 'Disease', 'MESH:D002277', (162, 172))	('colorectal', 'Disease', (60, 70))	('contribute', 'Reg', (127, 137))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('carcinomas', 'Phenotype', 'HP:0030731', (99, 109))	('carcinomas', 'Disease', 'MESH:D002277', (99, 109))
340030	28978030	Rather, loss of hetereozygosity seems to play a major role in the inactivation of PinX1 in human cancers.	('cancers', 'Disease', 'MESH:D009369', (97, 104))	('cancers', 'Phenotype', 'HP:0002664', (97, 104))	('cancers', 'Disease', (97, 104))	('hetereozygosity', 'Var', (16, 31))	('inactivation', 'NegReg', (66, 78))	('loss', 'NegReg', (8, 12))	('PinX1', 'Gene', '54984', (82, 87))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('human', 'Species', '9606', (91, 96))	('PinX1', 'Gene', (82, 87))
340032	28978030	Thus, we used a Kaplan-Meier analysis to determine the relationship between PinX1 gene alterations and patient survival.	('alterations', 'Var', (87, 98))	('PinX1', 'Gene', '54984', (76, 81))	('PinX1', 'Gene', (76, 81))	('patient', 'Species', '9606', (103, 110))
340033	28978030	Our results demonstrated that PinX1 gene alterations were correlated with poor survival in patients with lung adenocarcinoma (overall survival and disease-free survival) and as well as those diagnosed with bladder urothelial carcinoma (disease-free survival only).	('PinX1', 'Gene', (30, 35))	('bladder urothelial carcinoma', 'Disease', (206, 234))	('patients', 'Species', '9606', (91, 99))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (105, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (225, 234))	('poor', 'NegReg', (74, 78))	('lung adenocarcinoma', 'Disease', (105, 124))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (105, 124))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (206, 234))	('PinX1', 'Gene', '54984', (30, 35))	('alterations', 'Var', (41, 52))
340034	28978030	However, there were no significant correlations between PinX1 alterations and overall survival and/or disease-free survival in the other seven types of tested human cancers.	('disease-free survival', 'CPA', (102, 123))	('PinX1', 'Gene', '54984', (56, 61))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('human', 'Species', '9606', (159, 164))	('PinX1', 'Gene', (56, 61))	('alterations', 'Var', (62, 73))	('cancers', 'Disease', 'MESH:D009369', (165, 172))	('cancers', 'Phenotype', 'HP:0002664', (165, 172))	('cancers', 'Disease', (165, 172))
340035	28978030	These results showed that the status of PinX1 gene alteration was correlated with prognosis; importantly, that this correlation may be tumor-type specific.	('correlated', 'Reg', (66, 76))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('tumor', 'Disease', (135, 140))	('alteration', 'Var', (51, 61))	('PinX1', 'Gene', '54984', (40, 45))	('PinX1', 'Gene', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
340048	28978030	It has been reported that PinX1 suppress tumor growth and depletion of endogenous PinX1 can enhance tumorigenicity.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('PinX1', 'Gene', (26, 31))	('tumor', 'Disease', (41, 46))	('suppress', 'NegReg', (32, 40))	('tumor', 'Disease', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('PinX1', 'Gene', '54984', (82, 87))	('depletion', 'Var', (58, 67))	('PinX1', 'Gene', '54984', (26, 31))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('enhance', 'PosReg', (92, 99))	('PinX1', 'Gene', (82, 87))
340049	28978030	We also observed that knockdown of PinX1 could also enhance cell proliferation in nine types of cancer cell lines in vitro.	('PinX1', 'Gene', '54984', (35, 40))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('knockdown', 'Var', (22, 31))	('enhance', 'PosReg', (52, 59))	('PinX1', 'Gene', (35, 40))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Disease', (96, 102))
340053	28978030	Thus, loss of PinX1 abrogates faithful chromosome segregation, suggesting a novel function outside of its established roles.	('PinX1', 'Gene', '54984', (14, 19))	('loss', 'Var', (6, 10))	('PinX1', 'Gene', (14, 19))	('abrogates', 'NegReg', (20, 29))	('faithful chromosome segregation', 'CPA', (30, 61))
340059	28978030	Analysis of PinX1 gene alterations, mutation levels, genetic profiles, 3D structural analyses, clinical impacts, gene co-expression, and integrated networks from this database was then performed in silico.	('PinX1', 'Gene', '54984', (12, 17))	('alterations', 'Var', (23, 34))	('PinX1', 'Gene', (12, 17))
340074	26497366	Cases with both unamplified PBXIP1 and TERT had a median 34.32-month extension of overall survival and 34.55-month delay in disease progression when compared with both amplified CNVs.	('PBXIP1', 'Gene', '57326', (28, 34))	('TERT', 'Gene', (39, 43))	('disease progression', 'CPA', (124, 143))	('extension', 'PosReg', (69, 78))	('TERT', 'Gene', '7015', (39, 43))	('unamplified', 'Var', (16, 27))	('delay', 'NegReg', (115, 120))	('PBXIP1', 'Gene', (28, 34))	('overall survival', 'CPA', (82, 98))
340075	26497366	This study demonstrates that CNVs of TERT and PBXIP1 have the potential to translate into the clinic and be used to improve outcomes for patients with this fatal disease.	('TERT', 'Gene', (37, 41))	('improve', 'PosReg', (116, 123))	('TERT', 'Gene', '7015', (37, 41))	('PBXIP1', 'Gene', (46, 52))	('patients', 'Species', '9606', (137, 145))	('CNVs', 'Var', (29, 33))	('PBXIP1', 'Gene', '57326', (46, 52))
340077	26497366	In past decades, molecular biomarkers, especially single nucleotide polymorphisms (SNPs), assessing an individual's genetic predisposition for diseases have shown potential for guiding clinical treatment of lung cancer.	('lung cancer', 'Disease', 'MESH:D008175', (207, 218))	('single nucleotide polymorphisms', 'Var', (50, 81))	('lung cancer', 'Disease', (207, 218))	('lung cancer', 'Phenotype', 'HP:0100526', (207, 218))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))
340078	26497366	Recently, increasing evidence suggests that copy number variations (CNVs) may also account for a large proportion of the heritability of lung cancer.	('lung cancer', 'Disease', (137, 148))	('lung cancer', 'Phenotype', 'HP:0100526', (137, 148))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('lung cancer', 'Disease', 'MESH:D008175', (137, 148))	('copy number variations', 'Var', (44, 66))
340080	26497366	By whole genome sequencing (WGS) or target sequencing, some studies have demonstrated the prognostic prediction role of high copy number alteration burden in the prostate cancer relapse, FGFR1 and PIK3CA amplifications in oral cavity squamous cell carcinoma, and MYC amplification in pancreatic adenosquamous carcinoma and lung adenocarcinomas.	('PIK3CA', 'Gene', (197, 203))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (234, 257))	('amplification', 'Var', (267, 280))	('prostate cancer', 'Disease', 'MESH:D011471', (162, 177))	('high copy number alteration burden', 'Var', (120, 154))	('prostate cancer', 'Phenotype', 'HP:0012125', (162, 177))	('carcinoma', 'Phenotype', 'HP:0030731', (309, 318))	('prostate cancer', 'Disease', (162, 177))	('FGFR1', 'Gene', '2260', (187, 192))	('squamous cell carcinoma', 'Disease', (234, 257))	('MYC', 'Gene', (263, 266))	('amplifications', 'Var', (204, 218))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (323, 342))	('carcinoma', 'Phenotype', 'HP:0030731', (333, 342))	('carcinomas', 'Phenotype', 'HP:0030731', (333, 343))	('PIK3CA', 'Gene', '5290', (197, 203))	('pancreatic adenosquamous carcinoma and lung adenocarcinomas', 'Disease', 'MESH:D018196', (284, 343))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (323, 343))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('FGFR1', 'Gene', (187, 192))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (234, 257))	('carcinoma', 'Phenotype', 'HP:0030731', (248, 257))
340094	26497366	After matching CNV areas detected by the three algorithms, 2604 somatic CNVs were identified differently expressed between cancerous and noncancerous tissues, among which, 2488 were amplifications and 116 were deletions.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('cancerous', 'Disease', 'MESH:D009369', (123, 132))	('cancerous', 'Disease', 'MESH:D009369', (140, 149))	('amplifications', 'Var', (182, 196))	('deletions', 'Var', (210, 219))	('cancerous', 'Disease', (123, 132))	('cancerous', 'Disease', (140, 149))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))
340101	26497366	The 5-year overall survival rate of patients with an unamplified PBXIP1 was 47.0% (95% CI: 33.3%-56.7%) compared with 35.1% (95% CI: 21.7%-48.8%) in patients with an amplified PBXIP1 (Table 4 and Figure 2C).	('PBXIP1', 'Gene', (176, 182))	('PBXIP1', 'Gene', (65, 71))	('patients', 'Species', '9606', (149, 157))	('patients', 'Species', '9606', (36, 44))	('PBXIP1', 'Gene', '57326', (176, 182))	('PBXIP1', 'Gene', '57326', (65, 71))	('unamplified', 'Var', (53, 64))
340102	26497366	Further analysis found that CNV of TERT was correlated with progression free survival of lung adenocarcinoma.	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (89, 108))	('correlated', 'Reg', (44, 54))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('CNV', 'Var', (28, 31))	('lung adenocarcinoma', 'Disease', (89, 108))	('TERT', 'Gene', (35, 39))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (89, 108))	('TERT', 'Gene', '7015', (35, 39))
340107	26497366	Patients with no amplifications in either gene had a 34.32-month longer median survival time with an HR of 0.51(95% CI = 0.28-0.93) compared with those with both genes amplified.	('Patients', 'Species', '9606', (0, 8))	('amplifications', 'Var', (17, 31))	('longer', 'PosReg', (65, 71))
340112	26497366	Similarly, stage I-II patients with an unamplified TERT had a 65% lower risk (95% CI = 38%-81%) of death than stage III-IV patients with an amplified TERT and a 70% lower risk (95% CI = 48%-82%) of disease progression (Table 5 and Figure 2G-2J).	('lower', 'NegReg', (165, 170))	('TERT', 'Gene', (150, 154))	('TERT', 'Gene', (51, 55))	('death', 'Disease', 'MESH:D003643', (99, 104))	('death', 'Disease', (99, 104))	('lower', 'NegReg', (66, 71))	('patients', 'Species', '9606', (123, 131))	('patients', 'Species', '9606', (22, 30))	('TERT', 'Gene', '7015', (150, 154))	('TERT', 'Gene', '7015', (51, 55))	('unamplified', 'Var', (39, 50))
340122	26497366	Also, the CNVs of PBXIP1 and TERT presented significant upregulation of corresponding gene expressions and were found to be independently predictive of lung adenocarcinoma patient survival.	('TERT', 'Gene', '7015', (29, 33))	('PBXIP1', 'Gene', (18, 24))	('upregulation', 'PosReg', (56, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (162, 171))	('gene expressions', 'MPA', (86, 102))	('PBXIP1', 'Gene', '57326', (18, 24))	('patient', 'Species', '9606', (172, 179))	('lung adenocarcinoma', 'Disease', (152, 171))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (152, 171))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (152, 171))	('predictive of', 'Reg', (138, 151))	('CNVs', 'Var', (10, 14))	('TERT', 'Gene', (29, 33))
340127	26497366	Previous molecular cytogenetic studies have shown that chromosomal aberrations occur on 5p in all major lung tumor types.	('lung tumor', 'Disease', 'MESH:D008175', (104, 114))	('chromosomal aberrations', 'Var', (55, 78))	('lung tumor', 'Phenotype', 'HP:0100526', (104, 114))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (55, 78))	('lung tumor', 'Disease', (104, 114))
340128	26497366	Besides a role in carcinogenesis, aberrations in 5p are also biomarkers for cancer prognosis.	('aberrations', 'Var', (34, 45))	('carcinogenesis', 'Disease', (18, 32))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('carcinogenesis', 'Disease', 'MESH:D063646', (18, 32))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))
340129	26497366	A genome-wide analysis revealed that copy number gains in chromosome 5p were correlated with to the survival of early-stage non-small cell lung cancer.	('cell lung cancer', 'Disease', (134, 150))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (128, 150))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (124, 150))	('cell lung cancer', 'Disease', 'MESH:D008175', (134, 150))	('copy number gains', 'Var', (37, 54))	('lung cancer', 'Phenotype', 'HP:0100526', (139, 150))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
340130	26497366	even presented direct evidence for this with the finding that amplification of genes in chromosome 5p may be responsible for the malignant progression of bronchioloalveolar carcinoma, which is a subtype of lung adenocarcinoma.	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (206, 225))	('responsible', 'Reg', (109, 120))	('carcinoma', 'Phenotype', 'HP:0030731', (173, 182))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (206, 225))	('carcinoma', 'Phenotype', 'HP:0030731', (216, 225))	('bronchioloalveolar carcinoma', 'Disease', (154, 182))	('amplification', 'Var', (62, 75))	('bronchioloalveolar carcinoma', 'Disease', 'MESH:D002282', (154, 182))	('lung adenocarcinoma', 'Disease', (206, 225))
340133	26497366	However, recent identification of highly recurrent point mutations in the TERT promoter in multiple cancer types suggests one potential mechanism for up-regulation of telomerase via reactivation of TERT.	('TERT', 'Gene', '7015', (198, 202))	('TERT', 'Gene', '7015', (74, 78))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('point mutations', 'Var', (51, 66))	('telomerase', 'Enzyme', (167, 177))	('up-regulation', 'PosReg', (150, 163))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('reactivation', 'MPA', (182, 194))	('TERT', 'Gene', (198, 202))	('TERT', 'Gene', (74, 78))
340136	26497366	A recently published whole genome study directly supports our finding by demonstrating amplification of TERT in lung adenocarcinoma.	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (112, 131))	('TERT', 'Gene', (104, 108))	('lung adenocarcinoma', 'Disease', (112, 131))	('TERT', 'Gene', '7015', (104, 108))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (112, 131))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('amplification', 'Var', (87, 100))
340143	26497366	Moreover, an amplified copy number of PBXIP1 was found to be predictive of poor outcomes in undifferentiated pleomorphic sarcomas and leiomyosarcomas.	('leiomyosarcomas', 'Disease', 'MESH:D007890', (134, 149))	('sarcomas', 'Phenotype', 'HP:0100242', (121, 129))	('leiomyosarcomas', 'Disease', (134, 149))	('undifferentiated pleomorphic sarcomas', 'Disease', 'MESH:D002277', (92, 129))	('amplified copy number', 'Var', (13, 34))	('undifferentiated pleomorphic sarcomas', 'Disease', (92, 129))	('sarcomas', 'Phenotype', 'HP:0100242', (141, 149))	('PBXIP1', 'Gene', (38, 44))	('PBXIP1', 'Gene', '57326', (38, 44))	('leiomyosarcomas', 'Phenotype', 'HP:0100243', (134, 149))
340150	26497366	Furthermore, a prognostic significance for the CNVs of TERT and PBXIP1 in lung adenocarcinoma was found, which may lead to translation into the clinic and improve outcomes for patients with this fatal disease.	('patients', 'Species', '9606', (176, 184))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (74, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('translation', 'MPA', (123, 134))	('PBXIP1', 'Gene', (64, 70))	('improve', 'PosReg', (155, 162))	('TERT', 'Gene', (55, 59))	('CNVs', 'Var', (47, 51))	('lung adenocarcinoma', 'Disease', (74, 93))	('TERT', 'Gene', '7015', (55, 59))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (74, 93))	('PBXIP1', 'Gene', '57326', (64, 70))	('lead to', 'Reg', (115, 122))
340153	26497366	Discovery set was used to scan the differently expressed copy number variations between cancerous and paired noncancerous tissues by WGS.	('copy number variations', 'Var', (57, 79))	('cancerous', 'Disease', (88, 97))	('cancerous', 'Disease', (112, 121))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('cancerous', 'Disease', 'MESH:D009369', (88, 97))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('cancerous', 'Disease', 'MESH:D009369', (112, 121))
340154	26497366	Validation set II was applied to detect the correlation between mutant driver genes from target CNVs with prognosis of lung adenocarcinoma.	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (119, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('lung adenocarcinoma', 'Disease', (119, 138))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (119, 138))	('mutant', 'Var', (64, 70))
340175	26497366	Because none of the algorithms were optimal for the detection of CNV and to improve the power and compensate for the disadvantage of using a single algorithm, three algorithms, CNVseq, CNVer and BICseq, were used to identify CNVs in each tumor against the matched noncancerous tissues.	('tumor', 'Disease', 'MESH:D009369', (238, 243))	('CNVs', 'Var', (225, 229))	('BICseq', 'Chemical', '-', (195, 201))	('tumor', 'Phenotype', 'HP:0002664', (238, 243))	('cancerous', 'Disease', (267, 276))	('cancer', 'Phenotype', 'HP:0002664', (267, 273))	('tumor', 'Disease', (238, 243))	('cancerous', 'Disease', 'MESH:D009369', (267, 276))
340191	24816914	We also showed that inhibition of MT1-MMP expression by NSC405020 resulted in decrease of arsenic-mediated invasion of HSC5 cells involving decrease in phosphorylated extracellular signal-regulated kinases (pERK).	('decrease', 'NegReg', (78, 86))	('NSC405020', 'Var', (56, 65))	('arsenic', 'Chemical', 'MESH:D001151', (90, 97))	('decrease', 'NegReg', (140, 148))	('inhibition', 'NegReg', (20, 30))	('MT1-MMP expression', 'Protein', (34, 52))	('HSC5', 'CellLine', 'CVCL:0314', (119, 123))	('arsenic-mediated', 'MPA', (90, 106))
340212	24816914	Previous studies also reported that arsenic reduces expression of E-cadherins.	('arsenic', 'Var', (36, 43))	('expression', 'MPA', (52, 62))	('arsenic', 'Chemical', 'MESH:D001151', (36, 43))	('E-cadherin', 'Gene', (66, 76))	('E-cadherin', 'Gene', '999', (66, 76))	('reduces', 'NegReg', (44, 51))
340238	24816914	However, at 3 microM and 5 microM, arsenic caused decrease of cell viability almost 2 and 5 folds, respectively (Figure 1A).	('arsenic', 'Var', (35, 42))	('arsenic', 'Chemical', 'MESH:D001151', (35, 42))	('cell viability', 'CPA', (62, 76))	('decrease', 'NegReg', (50, 58))
340260	24816914	Our results in this study suggested that arsenic might cause apoptosis of HSC5 cells through downregulation of N-cadherin and/or upregulation of p21(WAF1/CIP1).	('apoptosis', 'CPA', (61, 70))	('p21', 'Protein', (145, 148))	('arsenic', 'Chemical', 'MESH:D001151', (41, 48))	('upregulation', 'PosReg', (129, 141))	('WAF1/CIP1', 'Gene', '1026', (149, 158))	('downregulation', 'NegReg', (93, 107))	('arsenic', 'Var', (41, 48))	('HSC5', 'CellLine', 'CVCL:0314', (74, 78))	('N-cadherin', 'Protein', (111, 121))	('WAF1/CIP1', 'Gene', (149, 158))
340262	24816914	Since MT1-MMP has been reported to be potential sited upstream of ERK and may be associated with arsenic-mediated invasion (Figure 2).	('MT1-MMP', 'Var', (6, 13))	('associated', 'Reg', (81, 91))	('arsenic', 'Chemical', 'MESH:D001151', (97, 104))	('arsenic-mediated', 'CPA', (97, 113))
340265	24816914	Arsenic-mediated invasion was blocked by treatment with 1 microM of NSC405020 (Figure 5A).	('blocked', 'NegReg', (30, 37))	('Arsenic', 'Chemical', 'MESH:D001151', (0, 7))	('NSC405020', 'Var', (68, 77))
340266	24816914	NSC405020 (1 microM) caused to decrease of expression level of MT1-MMP as well as decrease of phosphorylated of ERK in HSC5 cells (Figure 5B).	('NSC405020', 'Var', (0, 9))	('MT1-MMP', 'MPA', (63, 70))	('decrease', 'NegReg', (82, 90))	('phosphorylated', 'MPA', (94, 108))	('decrease', 'NegReg', (31, 39))	('expression level', 'MPA', (43, 59))	('HSC5', 'CellLine', 'CVCL:0314', (119, 123))	('ERK', 'Protein', (112, 115))
340272	24816914	Our result showed that arsenic simultaneously strongly induced apoptosis (Figure 1) and promoted invasion (Figure 2) of HSC5 cells.	('promoted', 'PosReg', (88, 96))	('arsenic', 'Var', (23, 30))	('apoptosis', 'CPA', (63, 72))	('induced', 'Reg', (55, 62))	('invasion', 'CPA', (97, 105))	('arsenic', 'Chemical', 'MESH:D001151', (23, 30))	('HSC5', 'CellLine', 'CVCL:0314', (120, 124))
340279	24816914	Further, we showed that NSC405020, a MT1-MMP inhibitor, inhibited the arsenic-mediated promotion of invasion HSC5 cells (Figure 5).	('promotion', 'PosReg', (87, 96))	('NSC405020', 'Var', (24, 33))	('invasion HSC5 cells', 'CPA', (100, 119))	('arsenic', 'Chemical', 'MESH:D001151', (70, 77))	('arsenic-mediated', 'MPA', (70, 86))	('HSC5', 'CellLine', 'CVCL:0314', (109, 113))	('inhibited', 'NegReg', (56, 65))
340281	24816914	Finally, downregulation of MT1-MMP and pERK by NSC405020 led to decreasing the invasion of HSC5 cells (Figure 5).	('downregulation', 'NegReg', (9, 23))	('MT1-MMP', 'Protein', (27, 34))	('invasion of HSC5 cells', 'CPA', (79, 101))	('decreasing', 'NegReg', (64, 74))	('HSC5', 'CellLine', 'CVCL:0314', (91, 95))	('NSC405020', 'Var', (47, 56))
340287	31181801	Somatic Mutations in miRNA Genes in Lung Cancer:Potential Functional Consequences of Non-Coding Sequence Variants A growing body of evidence indicates that miRNAs may either drive or suppress oncogenesis.	('suppress', 'NegReg', (183, 191))	('Lung Cancer', 'Phenotype', 'HP:0100526', (36, 47))	('Lung Cancer', 'Disease', (36, 47))	('miR', 'Gene', '220972', (21, 24))	('oncogenesis', 'CPA', (192, 203))	('miR', 'Gene', (21, 24))	('drive', 'PosReg', (174, 179))	('Variants', 'Var', (105, 113))	('Cancer', 'Phenotype', 'HP:0002664', (41, 47))	('Lung Cancer', 'Disease', 'MESH:D008175', (36, 47))	('miR', 'Gene', '220972', (156, 159))	('miR', 'Gene', (156, 159))
340289	31181801	To determine the frequency and potential consequences of miRNA gene mutations, we analyzed whole exome sequencing datasets of 569 lung adenocarcinoma (LUAD) and 597 lung squamous cell carcinoma (LUSC) samples generated in The Cancer Genome Atlas (TCGA) project.	('miR', 'Gene', '220972', (57, 60))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (130, 149))	('miR', 'Gene', (57, 60))	('carcinoma', 'Phenotype', 'HP:0030731', (184, 193))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (165, 193))	('Cancer Genome Atlas', 'Disease', (226, 245))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (170, 193))	('lung squamous cell carcinoma', 'Disease', (165, 193))	('Cancer', 'Phenotype', 'HP:0002664', (226, 232))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (226, 245))	('lung adenocarcinoma', 'Disease', (130, 149))	('mutations', 'Var', (68, 77))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (130, 149))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (165, 193))
340290	31181801	Altogether, we identified 1091 somatic sequence variants affecting 522 different miRNA genes and showed that half of all cancers had at least one such somatic variant/mutation.	('affecting', 'Reg', (57, 66))	('cancers', 'Disease', (121, 128))	('miR', 'Gene', '220972', (81, 84))	('miR', 'Gene', (81, 84))	('cancers', 'Disease', 'MESH:D009369', (121, 128))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('variants', 'Var', (48, 56))	('cancers', 'Phenotype', 'HP:0002664', (121, 128))
340291	31181801	These sequence variants occurred in most crucial parts of miRNA precursors, including mature miRNA and seed sequences.	('miR', 'Gene', '220972', (58, 61))	('miR', 'Gene', (58, 61))	('occurred', 'Reg', (24, 32))	('miR', 'Gene', '220972', (93, 96))	('variants', 'Var', (15, 23))	('miR', 'Gene', (93, 96))
340292	31181801	Due to our findings, we hypothesize that seed mutations may affect miRNA:target interactions, drastically changing the pool of predicted targets.	('mutations', 'Var', (46, 55))	('changing', 'Reg', (106, 114))	('affect', 'Reg', (60, 66))	('interactions', 'Interaction', (80, 92))	('pool of predicted targets', 'MPA', (119, 144))	('miR', 'Gene', '220972', (67, 70))	('miR', 'Gene', (67, 70))
340293	31181801	Mutations may also affect miRNA biogenesis by changing the structure of miRNA precursors, DROSHA and DICER cleavage sites, and regulatory sequence/structure motifs.	('DICER', 'Gene', '23405', (101, 106))	('miR', 'Gene', '220972', (26, 29))	('changing', 'Reg', (46, 54))	('miR', 'Gene', (26, 29))	('DICER', 'Gene', (101, 106))	('affect', 'Reg', (19, 25))	('Mutations', 'Var', (0, 9))	('DROSHA', 'Gene', '29102', (90, 96))	('DROSHA', 'Gene', (90, 96))	('miR', 'Gene', '220972', (72, 75))	('miR', 'Gene', (72, 75))
340294	31181801	We identified 10 significantly overmutated hotspot miRNA genes, including the miR-379 gene in LUAD enriched in mutations in the mature miRNA and regulatory sequences.	('miR', 'Gene', (135, 138))	('mutations', 'Var', (111, 120))	('miR-379', 'Gene', (78, 85))	('miR', 'Gene', '220972', (78, 81))	('miR', 'Gene', (78, 81))	('miR', 'Gene', '220972', (51, 54))	('miR', 'Gene', (51, 54))	('miR-379', 'Gene', '494328', (78, 85))	('overmutated', 'PosReg', (31, 42))	('miR', 'Gene', '220972', (135, 138))
340295	31181801	The occurrence of mutations in the hotspot miRNA genes was also shown experimentally.	('miR', 'Gene', '220972', (43, 46))	('miR', 'Gene', (43, 46))	('mutations', 'Var', (18, 27))
340296	31181801	We present a comprehensive analysis of somatic variants in miRNA genes and show that some of these genes are mutational hotspots, suggesting their potential role in cancer.	('variants', 'Var', (47, 55))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('miR', 'Gene', '220972', (59, 62))	('miR', 'Gene', (59, 62))	('cancer', 'Disease', (165, 171))	('cancer', 'Disease', 'MESH:D009369', (165, 171))
340300	31181801	Analysis of these mutations allowed the elucidation of several important protein-coding driver genes, including KRAS, EGFR, BRAF, MET, RIT1, ALK, and NF1 in LUAD and PIK3CA, FGFR1, and PTEN in LUSC.	('NF1', 'Gene', (150, 153))	('MET', 'Gene', (130, 133))	('RIT1', 'Gene', '6016', (135, 139))	('FGFR1', 'Gene', (174, 179))	('EGFR', 'Gene', '1956', (118, 122))	('KRAS', 'Gene', '3845', (112, 116))	('BRAF', 'Gene', '673', (124, 128))	('BRAF', 'Gene', (124, 128))	('PTEN', 'Gene', (185, 189))	('PIK3CA', 'Gene', '5290', (166, 172))	('KRAS', 'Gene', (112, 116))	('PTEN', 'Gene', '5728', (185, 189))	('RIT1', 'Gene', (135, 139))	('ALK', 'Gene', '238', (141, 144))	('NF1', 'Gene', '4763', (150, 153))	('FGFR1', 'Gene', '2260', (174, 179))	('EGFR', 'Gene', (118, 122))	('ALK', 'Gene', (141, 144))	('PIK3CA', 'Gene', (166, 172))	('mutations', 'Var', (18, 27))
340323	31181801	Important exceptions are (i) a recently published study reporting a tool (ADmiRE) for the annotation and prioritization of different genetic variants, including somatic mutations in miRNAs, (ii) a database of somatic mutations affecting the interactions of miRNAs with competing endogenous RNAs (SomamiR), including somatic mutations in miRNAs, and (iii) recent reports of somatic mutations in pre-miR-142 (the only example of recurrently mutated miRNA gene in cancer), shown to contribute to the development of diffuse large B-cell lymphoma, follicular lymphoma and acute myeloid leukemia.	('miR', 'Gene', '220972', (257, 260))	('miR', 'Gene', '220972', (337, 340))	('cancer', 'Disease', (461, 467))	('miR', 'Gene', '220972', (76, 79))	('lymphoma', 'Disease', (554, 562))	('miR', 'Gene', (300, 303))	('lymphoma', 'Disease', 'MESH:D008223', (554, 562))	('lymphoma', 'Phenotype', 'HP:0002665', (533, 541))	('miR', 'Gene', '220972', (398, 401))	('cancer', 'Phenotype', 'HP:0002664', (461, 467))	('miR', 'Gene', (257, 260))	('interactions', 'Interaction', (241, 253))	('miR', 'Gene', '220972', (447, 450))	('miR', 'Gene', (337, 340))	('acute myeloid leukemia', 'Disease', (567, 589))	('miR', 'Gene', (76, 79))	('mutations', 'Var', (381, 390))	('miR-142', 'Gene', (398, 405))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (526, 541))	('miR', 'Gene', (398, 401))	('miR', 'Gene', '220972', (182, 185))	('contribute', 'Reg', (479, 489))	('lymphoma', 'Disease', (533, 541))	('follicular lymphoma', 'Disease', 'MESH:D008224', (543, 562))	('miR', 'Gene', (447, 450))	('cancer', 'Disease', 'MESH:D009369', (461, 467))	('lymphoma', 'Disease', 'MESH:D008223', (533, 541))	('lymphoma', 'Phenotype', 'HP:0002665', (554, 562))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (567, 589))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (573, 589))	('miR', 'Gene', (182, 185))	('leukemia', 'Phenotype', 'HP:0001909', (581, 589))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (567, 589))	('follicular lymphoma', 'Disease', (543, 562))	('miR', 'Gene', '220972', (300, 303))	('miR-142', 'Gene', '406934', (398, 405))
340325	31181801	Previous studies by our group and others have shown that the density of single nucleotide polymorphisms (SNPs) is significantly lower in miRNA genes than in their flanking sequences or in the whole genome.	('miR', 'Gene', '220972', (137, 140))	('miR', 'Gene', (137, 140))	('single nucleotide polymorphisms', 'Var', (72, 103))	('lower', 'NegReg', (128, 133))
340327	31181801	On the other hand, SNPs located in miRNA genes may affect miRNA biogenesis and the specificity of miRNA target recognition.	('SNPs', 'Var', (19, 23))	('affect', 'Reg', (51, 57))	('miR', 'Gene', '220972', (98, 101))	('miR', 'Gene', (98, 101))	('miR', 'Gene', '220972', (58, 61))	('miR', 'Gene', (58, 61))	('miR', 'Gene', '220972', (35, 38))	('miR', 'Gene', (35, 38))
340328	31181801	For example, the G>C substitution (SNP rs138166791) in the penultimate position of pre-miR-890, significantly lowers the cleavage efficiency by DROSHA and, consequently, decreases the levels of mature miR-890-5p and miR-890-3p.	('miR-890', 'Gene', (216, 223))	('levels', 'MPA', (184, 190))	('miR-890', 'Gene', '100126303', (216, 223))	('DROSHA', 'Gene', '29102', (144, 150))	('DROSHA', 'Gene', (144, 150))	('lowers', 'NegReg', (110, 116))	('miR-890', 'Gene', (87, 94))	('cleavage efficiency', 'MPA', (121, 140))	('decreases', 'NegReg', (170, 179))	('miR-890', 'Gene', '100126303', (87, 94))	('miR-890', 'Gene', (201, 208))	('G>C', 'Var', (17, 20))	('miR-890', 'Gene', '100126303', (201, 208))	('rs138166791', 'Mutation', 'rs138166791', (39, 50))
340329	31181801	There is also evidence that some SNPs within miRNA genes may correlate with different diseases, including cancer.	('SNPs', 'Var', (33, 37))	('correlate', 'Reg', (61, 70))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('miR', 'Gene', '220972', (45, 48))	('miR', 'Gene', (45, 48))	('cancer', 'Disease', (106, 112))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
340330	31181801	Finally, there are a few examples of Mendelian diseases caused by germline mutations in miRNA genes.	('miR', 'Gene', (88, 91))	('Mendelian diseases', 'Disease', 'MESH:D030342', (37, 55))	('Mendelian diseases', 'Disease', (37, 55))	('caused', 'Reg', (56, 62))	('germline mutations', 'Var', (66, 84))	('miR', 'Gene', '220972', (88, 91))
340331	31181801	To determine the frequency and potential consequences of somatic sequence variants in miRNA genes, as well as to identify potential overmutated hotspot miRNA genes, we searched for sequence variants in 1642 miRNA genes using whole exome sequencing (WES) datasets of 1066 samples of the two most common types of lung cancer, i.e., LUAD and LUSC.	('lung cancer', 'Phenotype', 'HP:0100526', (311, 322))	('LUSC', 'Disease', (339, 343))	('LUAD', 'Disease', (330, 334))	('cancer', 'Phenotype', 'HP:0002664', (316, 322))	('miR', 'Gene', (152, 155))	('miR', 'Gene', '220972', (86, 89))	('miR', 'Gene', (86, 89))	('lung cancer', 'Disease', 'MESH:D008175', (311, 322))	('miR', 'Gene', '220972', (152, 155))	('variants', 'Var', (74, 82))	('miR', 'Gene', '220972', (207, 210))	('lung cancer', 'Disease', (311, 322))	('miR', 'Gene', (207, 210))
340332	31181801	As a result, we identified over 1000 somatic sequence variants in more than 500 different miRNA genes and showed that a substantial fraction of the mutated miRNA genes overlap in the two types of lung cancer.	('overlap', 'Reg', (168, 175))	('miR', 'Gene', '220972', (90, 93))	('lung cancer', 'Disease', (196, 207))	('lung cancer', 'Phenotype', 'HP:0100526', (196, 207))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('variants', 'Var', (54, 62))	('miR', 'Gene', '220972', (156, 159))	('miR', 'Gene', (90, 93))	('lung cancer', 'Disease', 'MESH:D008175', (196, 207))	('miR', 'Gene', (156, 159))
340334	31181801	Among the identified variants were mutations in well-known oncomiRs and suppressormiRs, including let-7, miR-21, and miR-205.	('variants', 'Var', (21, 29))	('miR', 'Gene', (105, 108))	('miR', 'Gene', '220972', (105, 108))	('miR-205', 'Gene', '406988', (117, 124))	('miR', 'Gene', '220972', (82, 85))	('miR', 'Gene', (82, 85))	('let-7', 'Gene', (98, 103))	('miR-21', 'Gene', '406991', (105, 111))	('miR', 'Gene', '220972', (63, 66))	('miR', 'Gene', (63, 66))	('miR', 'Gene', '220972', (117, 120))	('miR', 'Gene', (117, 120))	('miR-205', 'Gene', (117, 124))	('miR-21', 'Gene', (105, 111))	('mutations', 'Var', (35, 44))
340335	31181801	A substantial fraction of the identified variants were localized in sequences of mature miRNAs, including in seed sequences and DROSHA and DICER cleavage sites.	('miR', 'Gene', (88, 91))	('variants', 'Var', (41, 49))	('DICER', 'Gene', '23405', (139, 144))	('DICER', 'Gene', (139, 144))	('DROSHA', 'Gene', '29102', (128, 134))	('DROSHA', 'Gene', (128, 134))	('miR', 'Gene', '220972', (88, 91))
340336	31181801	We performed an analysis with a set of computational tools and showed that somatic mutations in miRNA genes may affect (i) target recognition, (ii) the structure of miRNA precursors, and (iii) structural/sequence motifs that play a role in RNA:protein interactions important for miRNA biogenesis.	('mutations', 'Var', (83, 92))	('interactions', 'Interaction', (252, 264))	('target', 'Interaction', (123, 129))	('structure', 'MPA', (152, 161))	('structural/sequence motifs', 'MPA', (193, 219))	('miR', 'Gene', (279, 282))	('miR', 'Gene', (165, 168))	('miR', 'Gene', (96, 99))	('affect', 'Reg', (112, 118))	('miR', 'Gene', '220972', (165, 168))	('miR', 'Gene', '220972', (96, 99))	('miR', 'Gene', '220972', (279, 282))
340338	31181801	To identify somatic sequence variants in miRNA genes, we took advantage of somatic mutation calls performed on WES datasets of 569 LUAD and 497 LUSC paired tumor/normal samples generated within The Cancer Genome Atlas (TCGA) project.	('Cancer Genome Atlas', 'Disease', (198, 217))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('miR', 'Gene', '220972', (41, 44))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (198, 217))	('miR', 'Gene', (41, 44))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('variants', 'Var', (29, 37))	('tumor', 'Disease', (156, 161))	('Cancer', 'Phenotype', 'HP:0002664', (198, 204))
340341	31181801	In the set of selected miRNA genes, we identified 545 and 546 somatic sequence variants in 350 and 353 miRNA genes in LUAD and LUSC, respectively (Figure 1A and Supplementary Table S2).	('miR', 'Gene', '220972', (23, 26))	('miR', 'Gene', (23, 26))	('variants', 'Var', (79, 87))	('miR', 'Gene', '220972', (103, 106))	('miR', 'Gene', (103, 106))
340342	31181801	More than half of the mutated miRNA genes are annotated as high confidence in miRBase.	('miR', 'Gene', '220972', (30, 33))	('miR', 'Gene', (30, 33))	('miR', 'Gene', '220972', (78, 81))	('miR', 'Gene', (78, 81))	('mutated', 'Var', (22, 29))
340346	31181801	The distribution of mutation types was similar between the two cancers, with substitutions, indels, and complex sequence changes accounting for ~91%, 4%, and 5%, respectively.	('indels', 'Var', (92, 98))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('substitutions', 'Var', (77, 90))	('cancers', 'Phenotype', 'HP:0002664', (63, 70))	('cancers', 'Disease', (63, 70))	('cancers', 'Disease', 'MESH:D009369', (63, 70))
340348	31181801	As shown in Figure 1C, the distribution of somatic sequence variants across chromosomes only roughly correlated with the number of miRNA genes located on a particular chromosome (LUAD: r2 = 0.465, p = 0.0003; LUSC: r2 = 0.443, p = 0.0005).	('variants', 'Var', (60, 68))	('miR', 'Gene', '220972', (131, 134))	('correlated', 'Reg', (101, 111))	('miR', 'Gene', (131, 134))
340349	31181801	Exceptions were overmutation of chromosomes 19 (in both cancer types) and 14 (in LUSC) and undermutation of chromosomes 1 and 2 (in LUSC and LUAD, respectively).	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('LUSC', 'Disease', (132, 136))	('LUAD', 'Disease', (141, 145))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('overmutation', 'Var', (16, 28))	('cancer', 'Disease', (56, 62))	('undermutation', 'Var', (91, 104))
340350	31181801	Overall, the most abundantly mutated chromosomes were 14, 19, and X, encompassing 20% of the analyzed miRNA genes, but cumulatively accounting for 40% of the identified variants (Figure 1D).	('variants', 'Var', (169, 177))	('miR', 'Gene', '220972', (102, 105))	('miR', 'Gene', (102, 105))
340351	31181801	To look closer at the localization of sequence variants in subregions of miRNA precursors, we superimposed the identified variants (substitutions only) on the consensus miRNA precursor structure (Figure 2A) and categorized them according to localization in the miRNA gene subregions (Table 1 and Supplementary Table S2).	('variants', 'Var', (122, 130))	('miR', 'Gene', '220972', (261, 264))	('miR', 'Gene', (261, 264))	('miR', 'Gene', '220972', (73, 76))	('miR', 'Gene', (73, 76))	('miR', 'Gene', '220972', (169, 172))	('miR', 'Gene', (169, 172))
340355	31181801	It may be expected that the effect of a miRNA gene mutation will strongly depend on its localization.	('miR', 'Gene', '220972', (40, 43))	('mutation', 'Var', (51, 59))	('miR', 'Gene', (40, 43))
340356	31181801	The most unequivocal effect is caused by variants in the miRNA seed region responsible for miRNA:target interactions.	('miR', 'Gene', (91, 94))	('variants', 'Var', (41, 49))	('miR', 'Gene', '220972', (57, 60))	('miR', 'Gene', (57, 60))	('interactions', 'Interaction', (104, 116))	('caused by', 'Reg', (31, 40))	('miR', 'Gene', '220972', (91, 94))
340357	31181801	To obtain deeper insight into the scale of changes in target recognition caused by seed variants, we employed TargetScan to identify potential targets of corresponding wild-type and mutated miRNAs (Figure 3 and Supplementary Figure S3).	('variants', 'Var', (88, 96))	('miR', 'Gene', '220972', (190, 193))	('miR', 'Gene', (190, 193))
340358	31181801	As expected, the target overlap between wild-type and mutated miRNAs was generally low and usually did not exceed a few percentage points.	('miR', 'Gene', '220972', (62, 65))	('mutated', 'Var', (54, 61))	('low', 'NegReg', (83, 86))	('miR', 'Gene', (62, 65))
340359	31181801	As shown for miR-518d-3p, two sequence changes located in adjacent positions of the seed sequence have completely different effects on the number of predicted targets (Figure 3).	('changes', 'Var', (39, 46))	('effects', 'Reg', (124, 131))	('miR', 'Gene', '220972', (13, 16))	('miR', 'Gene', (13, 16))
340362	31181801	Disruption of structural or sequence motifs recognized by these proteins may affect the interaction of miRNA precursors with proteins and, consequently, miRNA biogenesis.	('miR', 'Gene', '220972', (153, 156))	('miR', 'Gene', (153, 156))	('proteins', 'Protein', (125, 133))	('affect', 'Reg', (77, 83))	('miR', 'Gene', '220972', (103, 106))	('miR', 'Gene', (103, 106))	('interaction', 'Interaction', (88, 99))	('Disruption', 'Var', (0, 10))
340363	31181801	Therefore, we employed recently developed by one of us (M.O.U.T) miRNAmotif software to investigate whether the identified somatic sequence variants disrupt or create known sequence motifs recognized by the following regulatory proteins: hnRNPA1, HuR, KSRP, Lin28, MBNL1, MCPIP1, DGCR8, MATR3, ZC3H7, YBX1, TRIM71, PTBP1/3, DDX17, RBFOX, SMAD, CELF1/2, and ZC3H10.	('hnRNPA1', 'Gene', (238, 245))	('variants', 'Var', (140, 148))	('CELF1/2', 'Gene', '10658;10659', (344, 351))	('PTBP1/3', 'Gene', (315, 322))	('ZC3H7', 'Gene', (294, 299))	('ZC3H7', 'Gene', '29066', (294, 299))	('MBNL1', 'Gene', '4154', (265, 270))	('MCPIP1', 'Gene', '80149', (272, 278))	('TRIM71', 'Gene', (307, 313))	('DDX17', 'Gene', '10521', (324, 329))	('DDX17', 'Gene', (324, 329))	('KSRP', 'Gene', (252, 256))	('HuR', 'Gene', (247, 250))	('ZC3H10', 'Gene', '84872', (357, 363))	('hnRNPA1', 'Gene', '3178', (238, 245))	('MCPIP1', 'Gene', (272, 278))	('CELF1/2', 'Gene', (344, 351))	('ZC3H10', 'Gene', (357, 363))	('miR', 'Gene', '220972', (65, 68))	('KSRP', 'Gene', '8570', (252, 256))	('YBX1', 'Gene', (301, 305))	('U.T', 'CellLine', 'CVCL:M769', (60, 63))	('Lin28', 'Gene', (258, 263))	('HuR', 'Gene', '1994', (247, 250))	('Lin28', 'Gene', '79727', (258, 263))	('YBX1', 'Gene', '4904', (301, 305))	('PTBP1/3', 'Gene', '5725;9991', (315, 322))	('DGCR8', 'Gene', (280, 285))	('TRIM71', 'Gene', '131405', (307, 313))	('miR', 'Gene', (65, 68))	('MATR3', 'Gene', (287, 292))	('DGCR8', 'Gene', '54487', (280, 285))	('MBNL1', 'Gene', (265, 270))	('MATR3', 'Gene', '9782', (287, 292))
340366	31181801	To further evaluate the reliability of the identified hotspot miRNA genes, we re-calculated mutation enrichment significance, weighting the mutation occurrences by the following factors: 2x, mutations in seeds; 1.5x, mutations in miRNAs (guide-strand only); 1.5x, mutations affecting the functional motifs or DROSHA/DICER cleavage sites; 1x, other mutations.	('mutations', 'Var', (264, 273))	('DICER', 'Gene', (316, 321))	('affecting', 'Reg', (274, 283))	('miR', 'Gene', '220972', (62, 65))	('miR', 'Gene', (62, 65))	('mutations', 'Var', (191, 200))	('miR', 'Gene', (230, 233))	('miR', 'Gene', '220972', (230, 233))	('DROSHA', 'Gene', '29102', (309, 315))	('DROSHA', 'Gene', (309, 315))	('mutations', 'Var', (217, 226))	('DICER', 'Gene', '23405', (316, 321))
340367	31181801	As shown in Table 3 the p-value calculated based on the weighted-mutation values further decreased for 8 hotspot-miRNA-genes, including the miR-509-3, miR-1324 and miR-379 genes with an excess of mutations affecting the mature miRNA and functional motif sequences.	('miR', 'Gene', (164, 167))	('miR', 'Gene', '220972', (140, 143))	('miR', 'Gene', '220972', (227, 230))	('miR-509-3', 'Gene', '100847022', (140, 149))	('decreased', 'NegReg', (89, 98))	('miR', 'Gene', '220972', (113, 116))	('miR', 'Gene', (140, 143))	('miR-1324', 'Gene', '100302212', (151, 159))	('miR-1324', 'Gene', (151, 159))	('miR-379', 'Gene', '494328', (164, 171))	('miR', 'Gene', (227, 230))	('miR-379', 'Gene', (164, 171))	('miR', 'Gene', (113, 116))	('miR', 'Gene', '220972', (151, 154))	('mutations', 'Var', (196, 205))	('miR', 'Gene', '220972', (164, 167))	('miR', 'Gene', (151, 154))	('miR-509-3', 'Gene', (140, 149))	('p-value', 'MPA', (24, 31))
340369	31181801	As shown in Figure 4, there were no specific hotspot mutations but rather randomly distributed mutations over the sequences of hotspot miRNA genes.	('miR', 'Gene', (135, 138))	('miR', 'Gene', '220972', (135, 138))	('mutations', 'Var', (95, 104))	('mutations', 'Var', (53, 62))
340370	31181801	An exception may be the miR-890 and miR-887 gene, in which most mutations clustered within the DROSHA cleavage site and basal stem junction in the 5' flanking region, respectively.	('miR-887', 'Gene', (36, 43))	('DROSHA', 'Gene', '29102', (95, 101))	('DROSHA', 'Gene', (95, 101))	('miR-890', 'Gene', (24, 31))	('miR-890', 'Gene', '100126303', (24, 31))	('miR-887', 'Gene', '100126347', (36, 43))	('mutations', 'Var', (64, 73))
340372	31181801	A similar observation was made for mutations in the miR-664b gene, whereas mutations in other hotspot miRNA genes showed a more or less random distribution over the range of miRNA expression levels.	('miR-664b', 'Gene', (52, 60))	('miR', 'Gene', '220972', (102, 105))	('miR', 'Gene', (102, 105))	('miR', 'Gene', '220972', (174, 177))	('miR', 'Gene', (174, 177))	('miR-664b', 'Gene', '100847052', (52, 60))	('miR', 'Gene', '220972', (52, 55))	('miR', 'Gene', (52, 55))	('mutations', 'Var', (35, 44))
340374	31181801	The formal analysis (Supplementary Table S4), although of low statistical power, showed an association of miR-890 gene mutations with later tumor stage (LUAD: stage I-II vs. III-IV, p = 0.019), more frequent mutations in the miR-887 gene in males (p = 0.045), and a borderline significant correlation of miR-664b gene mutations with lower cigarette-per-day-smoking in LUAD.	('miR-890', 'Gene', (106, 113))	('miR-887', 'Gene', (225, 232))	('miR-890', 'Gene', '100126303', (106, 113))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('miR-664b', 'Gene', (304, 312))	('mutations', 'Var', (208, 217))	('mutations', 'Var', (318, 327))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('miR-887', 'Gene', '100126347', (225, 232))	('miR-664b', 'Gene', '100847052', (304, 312))	('mutations', 'Var', (119, 128))	('tumor', 'Disease', (140, 145))
340375	31181801	However, due to the low number of the identified variants in particular hotspot miRNA genes, the abovementioned associations (not corrected for multiple comparisons) must be interpreted cautiously and cannot be generalized without further validation.	('miR', 'Gene', '220972', (80, 83))	('miR', 'Gene', (80, 83))	('variants', 'Var', (49, 57))
340376	31181801	As shown in Figure 5B, although mutations in hotspot miRNA genes and known driver genes are not mutually exclusive, a substantial fraction of mutations in hotspot miRNA genes occurred in samples with no known driver gene mutations.	('miR', 'Gene', '220972', (53, 56))	('mutations', 'Var', (142, 151))	('miR', 'Gene', (53, 56))	('miR', 'Gene', '220972', (163, 166))	('occurred', 'Reg', (175, 183))	('miR', 'Gene', (163, 166))
340377	31181801	Another consequence of mutations in miRNA genes are structural changes that can be caused by mutations in any subregion of the miRNA precursor.	('mutations', 'Var', (93, 102))	('structural', 'MPA', (52, 62))	('miR', 'Gene', '220972', (127, 130))	('miR', 'Gene', (127, 130))	('mutations', 'Var', (23, 32))	('miR', 'Gene', '220972', (36, 39))	('miR', 'Gene', (36, 39))
340378	31181801	Using mutations in the hotspot miRNA genes as examples, we compared the secondary and spatial structures of wild-type and mutant miRNA precursors.	('miR', 'Gene', '220972', (129, 132))	('miR', 'Gene', (129, 132))	('miR', 'Gene', '220972', (31, 34))	('miR', 'Gene', (31, 34))	('mutant', 'Var', (122, 128))	('mutations', 'Var', (6, 15))
340379	31181801	An example of a mutation that induced serious structural aberrations in the hairpin structure of miRNA precursor is n.57C>A in the 3' arm of pre-miR-664b (Figure 6A).	('n.57C>A', 'Mutation', 'n.57C>A', (116, 123))	('miR-664b', 'Gene', (145, 153))	('hairpin structure', 'MPA', (76, 93))	('miR-664b', 'Gene', '100847052', (145, 153))	('miR', 'Gene', '220972', (145, 148))	('miR', 'Gene', (145, 148))	('n.57C>A', 'Var', (116, 123))	('miR', 'Gene', '220972', (97, 100))	('miR', 'Gene', (97, 100))
340380	31181801	Such mutations very likely affect miRNA biogenesis (processing by cellular RNases).	('miR', 'Gene', (34, 37))	('affect', 'Reg', (27, 33))	('mutations', 'Var', (5, 14))	('miR', 'Gene', '220972', (34, 37))
340381	31181801	Mutations that introduced enlarged internal loops, e.g., n.20G>T and n.58T>A in the miR-664b precursor and n.66G>T and n.21G>A in the miR-890 precursor although do not affect substantially the secondary structure of the precursors, may increase the flexibility of the helix axis, manifested by changes in the geometry of 3D structure.	('n.66G>T', 'Mutation', 'n.66G>T', (107, 114))	('man', 'Species', '9606', (280, 283))	('n.66G>T', 'Var', (107, 114))	('n.58T>A', 'Mutation', 'n.58T>A', (69, 76))	('changes', 'Reg', (294, 301))	('enlarged', 'PosReg', (26, 34))	('n.20G>T', 'Var', (57, 64))	('geometry', 'MPA', (309, 317))	('flexibility', 'MPA', (249, 260))	('internal loops', 'MPA', (35, 49))	('n.20G>T', 'SUBSTITUTION', 'None', (57, 64))	('miR-664b', 'Gene', (84, 92))	('n.58T>A', 'Var', (69, 76))	('increase', 'PosReg', (236, 244))	('miR-890', 'Gene', '100126303', (134, 141))	('miR-664b', 'Gene', '100847052', (84, 92))	('n.21G>A', 'Mutation', 'rs1012992693', (119, 126))	('n.21G>A', 'Var', (119, 126))	('miR-890', 'Gene', (134, 141))
340382	31181801	Changes in the predicted secondary structure, which affect pre-miRNA stability, are not always manifested in spatial geometry, as shown for the n.60T>C mutation in the miR-890 precursor, which caused the loss of two nucleotide internal loops and increased the rigidity of the precursor stem but did not affect the 3D structure of the precursor.	('miR-890', 'Gene', (168, 175))	('miR-890', 'Gene', '100126303', (168, 175))	('rigidity', 'Disease', 'MESH:D009127', (260, 268))	('n.60T>C', 'Var', (144, 151))	('miR', 'Gene', '220972', (168, 171))	('miR', 'Gene', (168, 171))	('loss', 'NegReg', (204, 208))	('two nucleotide internal loops', 'MPA', (212, 241))	('miR', 'Gene', '220972', (63, 66))	('miR', 'Gene', (63, 66))	('increased', 'PosReg', (246, 255))	('n.60T>C', 'Mutation', 'n.60T>C', (144, 151))	('rigidity', 'Disease', (260, 268))	('rigidity', 'Phenotype', 'HP:0002063', (260, 268))	('man', 'Species', '9606', (95, 98))
340383	31181801	In the next step, we used Sanger sequencing to screen a small group of ~80 NSCLC samples for somatic sequence variants in three of the identified hotspot miRNA genes, i.e., the most frequently mutated miR-890, and the most frequently annotated with cancer-related functions miR-379 and miR-1297 genes (Table 3).	('miR', 'Gene', '220972', (154, 157))	('miR', 'Gene', '220972', (274, 277))	('cancer', 'Disease', (249, 255))	('miR-1297', 'Gene', '100302187', (286, 294))	('miR', 'Gene', '220972', (201, 204))	('miR-890', 'Gene', '100126303', (201, 208))	('cancer', 'Phenotype', 'HP:0002664', (249, 255))	('miR', 'Gene', (154, 157))	('miR', 'Gene', (274, 277))	('miR', 'Gene', (201, 204))	('NSCLC', 'Disease', 'MESH:D002289', (75, 80))	('cancer', 'Disease', 'MESH:D009369', (249, 255))	('mutated', 'Var', (193, 200))	('variants', 'Var', (110, 118))	('miR-890', 'Gene', (201, 208))	('NSCLC', 'Disease', (75, 80))	('miR-379', 'Gene', '494328', (274, 281))	('miR', 'Gene', '220972', (286, 289))	('miR-379', 'Gene', (274, 281))	('miR-1297', 'Gene', (286, 294))	('miR', 'Gene', (286, 289))
340384	31181801	Among the identified sequence variants was n.66G>C in the miR-890 gene, identified in the hemizygous state in 3 independent cancer samples (Supplementary Figure S5A).	('miR-890', 'Gene', '100126303', (58, 65))	('cancer', 'Disease', (124, 130))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('n.66G>C', 'SUBSTITUTION', 'None', (43, 50))	('n.66G>C', 'Var', (43, 50))	('cancer', 'Disease', 'MESH:D009369', (124, 130))	('miR-890', 'Gene', (58, 65))
340386	31181801	Additionally, mutations (n.1-18A>G) in the 5' flanking region of the miR-890 gene were detected in two other samples.	('detected', 'Reg', (87, 95))	('n.1-18A>G', 'Var', (25, 34))	('miR-890', 'Gene', (69, 76))	('miR-890', 'Gene', '100126303', (69, 76))	('n.1-18A>G', 'SUBSTITUTION', 'None', (25, 34))
340387	31181801	In addition, a single mutation (n.77+26C>T) in 3' flanking region, 36 nucleotides upstream of the predicted pre-miRNA sequence was detected.	('miR', 'Gene', '220972', (112, 115))	('n.77+26C>T', 'Var', (32, 42))	('miR', 'Gene', (112, 115))	('n.77+26C>T', 'Mutation', 'c.77+26C>T', (32, 42))
340388	31181801	Mutations were also found in the miR-379 gene, one (n.13C>A) in the seed region (Supplementary Figure S3A and Supplementary Figure S5B) and the other (n.1-37C>T) in the 5' flanking region, 42 nucleotides upstream of the predicted pre-miRNA sequence.	('miR', 'Gene', '220972', (33, 36))	('miR', 'Gene', (33, 36))	('n.13C>A', 'Mutation', 'n.13C>A', (52, 59))	('n.1-37C>T', 'Var', (151, 160))	('miR', 'Gene', '220972', (234, 237))	('miR', 'Gene', (234, 237))	('miR-379', 'Gene', '494328', (33, 40))	('S5B', 'Gene', '5711', (131, 134))	('n.1-37C>T', 'SUBSTITUTION', 'None', (151, 160))	('S5B', 'Gene', (131, 134))	('n.13C>A', 'Var', (52, 59))	('miR-379', 'Gene', (33, 40))
340389	31181801	Cancer development is associated with the accumulation of numerous genetic aberrations, including point mutations, CNVs, and copy number-neutral genomic rearrangements.	('point mutations', 'Var', (98, 113))	('Cancer development', 'CPA', (0, 18))	('numerous genetic aberrations', 'Disease', 'MESH:D030342', (58, 86))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('numerous genetic aberrations', 'Disease', (58, 86))	('copy number-neutral genomic rearrangements', 'Var', (125, 167))	('associated', 'Reg', (22, 32))	('CNVs', 'Disease', (115, 119))
340390	31181801	Most of these alterations are neutral (passenger) changes occurring randomly throughout the genome, but others may be cancer-driving mutations.	('alterations', 'Var', (14, 25))	('cancer', 'Disease', (118, 124))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))
340391	31181801	The accumulation of such mutations in a particular gene or the recurrent occurrence of a particular mutation may indicate its importance in cancer development.	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('mutations', 'Var', (25, 34))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))
340392	31181801	To date, many driver genes/mutations have been identified, some of which are utilized as biomarkers in personalized cancer therapy.	('man', 'Species', '9606', (9, 12))	('genes/mutations', 'Var', (21, 36))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))
340393	31181801	Prominent examples include EGFR mutations in lung cancer and JAK2 mutations in myeloproliferative disorders.	('mutations', 'Var', (66, 75))	('EGFR', 'Gene', '1956', (27, 31))	('lung cancer', 'Disease', 'MESH:D008175', (45, 56))	('EGFR', 'Gene', (27, 31))	('JAK2', 'Gene', '3717', (61, 65))	('lung cancer', 'Disease', (45, 56))	('myeloproliferative disorders', 'Disease', (79, 107))	('lung cancer', 'Phenotype', 'HP:0100526', (45, 56))	('mutations', 'Var', (32, 41))	('JAK2', 'Gene', (61, 65))	('myeloproliferative disorders', 'Phenotype', 'HP:0005547', (79, 107))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('myeloproliferative disorders', 'Disease', 'MESH:D009196', (79, 107))
340394	31181801	It should also be noted that a recent increase in interest in non-coding genomic variation, most likely inspired by the identification of highly recurrent mutations in the promoter of the TERT gene in melanoma and other cancers, is focused mostly on regions playing a role in DNA:protein interactions (e.g., promoters and enhancers).	('melanoma', 'Disease', (201, 209))	('melanoma', 'Disease', 'MESH:D008545', (201, 209))	('TERT', 'Gene', (188, 192))	('mutations', 'Var', (155, 164))	('TERT', 'Gene', '7015', (188, 192))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('cancers', 'Phenotype', 'HP:0002664', (220, 227))	('cancers', 'Disease', (220, 227))	('cancers', 'Disease', 'MESH:D009369', (220, 227))	('melanoma', 'Phenotype', 'HP:0002861', (201, 209))
340395	31181801	Considering the role of miRNAs in regulating gene expression, it can be presumed that somatic mutations may affect numerous cellular processes through changes in miRNA functionality.	('mutations', 'Var', (94, 103))	('affect', 'Reg', (108, 114))	('changes', 'Reg', (151, 158))	('cellular processes', 'CPA', (124, 142))	('miR', 'Gene', (24, 27))	('miR', 'Gene', '220972', (24, 27))	('miR', 'Gene', '220972', (162, 165))	('miR', 'Gene', (162, 165))
340396	31181801	Somatic mutations in miRNA genes may manifest as aberrations in miRNA:target interactions induced predominantly by mutations in the miRNA guide strand sequence, especially but not exclusively in the seed region, or as aberrations in miRNA biogenesis caused either by mutations in essential regulatory motifs or mutations affecting miRNA precursor structure.	('interactions', 'Interaction', (77, 89))	('miR', 'Gene', '220972', (233, 236))	('miR', 'Gene', (21, 24))	('mutations', 'Var', (311, 320))	('miR', 'Gene', (132, 135))	('miR', 'Gene', (331, 334))	('aberrations', 'Reg', (49, 60))	('miR', 'Gene', (233, 236))	('mutations', 'Var', (8, 17))	('miR', 'Gene', '220972', (64, 67))	('mutations', 'Var', (267, 276))	('mutations', 'Var', (115, 124))	('man', 'Species', '9606', (37, 40))	('miR', 'Gene', (64, 67))	('miR', 'Gene', '220972', (21, 24))	('caused', 'Reg', (250, 256))	('miR', 'Gene', '220972', (132, 135))	('induced', 'Reg', (90, 97))	('miR', 'Gene', '220972', (331, 334))
340397	31181801	Somatic mutations in miRNA genes may, therefore, cripple or enhance their silencing properties or create new miRNAs, i.e., miRNAs recognizing new targets.	('create', 'Reg', (98, 104))	('miR', 'Gene', '220972', (109, 112))	('miR', 'Gene', (109, 112))	('miR', 'Gene', '220972', (123, 126))	('miR', 'Gene', (123, 126))	('miR', 'Gene', '220972', (21, 24))	('miR', 'Gene', (21, 24))	('mutations', 'Var', (8, 17))	('cripple', 'NegReg', (49, 56))	('enhance', 'PosReg', (60, 67))	('silencing properties', 'MPA', (74, 94))
340398	31181801	Thus, the accumulation of somatically acquired gain- or loss-of-function mutations in a specific miRNA gene may benefit cancer development and progression.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('gain-', 'PosReg', (47, 52))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('loss-of-function', 'NegReg', (56, 72))	('miR', 'Gene', '220972', (97, 100))	('benefit', 'PosReg', (112, 119))	('miR', 'Gene', (97, 100))	('mutations', 'Var', (73, 82))
340399	31181801	In this study, we detected 1091 somatic sequence variants in 521 miRNA genes (Figure 1A) and showed that approximately 50% of the analyzed cancers had at least one such sequence variant in at least one miRNA gene.	('variants', 'Var', (49, 57))	('cancers', 'Disease', 'MESH:D009369', (139, 146))	('cancers', 'Phenotype', 'HP:0002664', (139, 146))	('miR', 'Gene', '220972', (202, 205))	('cancers', 'Disease', (139, 146))	('miR', 'Gene', (202, 205))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('miR', 'Gene', '220972', (65, 68))	('miR', 'Gene', (65, 68))
340400	31181801	It has to be noted, however, that similarly, as in protein-coding genes, the great majority of sequence variants detected in miRNA genes constitute spontaneous mutations accumulating during cancer development and only a small fraction of these variants may be a potential driver or functional mutations.	('cancer', 'Disease', (190, 196))	('cancer', 'Disease', 'MESH:D009369', (190, 196))	('variants', 'Var', (244, 252))	('variants', 'Var', (104, 112))	('accumulating', 'PosReg', (170, 182))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('miR', 'Gene', '220972', (125, 128))	('miR', 'Gene', (125, 128))
340401	31181801	As some excess of miRNA-gene mutations at ChrX occurs both in man and woman, it is unlikely to be caused by the observed before hypermutation of the inactive ChrX.	('mutations', 'Var', (29, 38))	('man', 'Species', '9606', (62, 65))	('miR', 'Gene', '220972', (18, 21))	('miR', 'Gene', (18, 21))	('ChrX', 'Gene', (42, 46))	('man', 'Species', '9606', (72, 75))	('woman', 'Species', '9606', (70, 75))
340402	31181801	To better understand the potential function of the identified variants, we characterized them with respect to localization in different subregions of miRNA precursors, influence on miRNA precursor secondary and tertiary structures, impact on sequence motifs bound by different proteins that participate in miRNA maturation and changes in mature miRNA:target interactions.	('changes', 'Reg', (327, 334))	('miR', 'Gene', '220972', (150, 153))	('impact', 'Reg', (232, 238))	('miR', 'Gene', (150, 153))	('miR', 'Gene', '220972', (345, 348))	('miR', 'Gene', (345, 348))	('bound', 'Interaction', (258, 263))	('variants', 'Var', (62, 70))	('localization', 'MPA', (110, 122))	('miR', 'Gene', '220972', (181, 184))	('interactions', 'Interaction', (358, 370))	('miR', 'Gene', (181, 184))	('influence', 'Reg', (168, 177))	('sequence motifs', 'MPA', (242, 257))	('miR', 'Gene', '220972', (306, 309))	('proteins', 'Protein', (277, 285))	('miR', 'Gene', (306, 309))
340403	31181801	Our analysis identified well-recognized suppressormiRs or oncomiRs among the miRNA genes with the identified variants.	('miR', 'Gene', (77, 80))	('miR', 'Gene', '220972', (50, 53))	('miR', 'Gene', (50, 53))	('miR', 'Gene', '220972', (62, 65))	('miR', 'Gene', (62, 65))	('variants', 'Var', (109, 117))	('miR', 'Gene', '220972', (77, 80))
340404	31181801	Examples of the mutated suppressormiR genes may be the Let-7a-2, let-7c, and let-7e genes belonging to the let-7 family, known to have tumor suppressor function by repressing cell proliferation and regulating the cell cycle and the miR-205 gene, which may act either as suppresormiR inhibiting cancer progression by suppressing EMT or oncomiR accelerating cancer development by facilitating tumor initiation and proliferation.	('regulating', 'Reg', (198, 208))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('let-7c', 'Gene', '406885', (65, 71))	('miR', 'Gene', (339, 342))	('facilitating', 'PosReg', (378, 390))	('miR', 'Gene', '220972', (232, 235))	('tumor', 'Disease', (391, 396))	('accelerating', 'PosReg', (343, 355))	('Let-7a-2', 'Gene', '406882', (55, 63))	('Let-7a-2', 'Gene', (55, 63))	('cell proliferation', 'CPA', (175, 193))	('miR', 'Gene', '220972', (34, 37))	('cancer', 'Disease', (294, 300))	('miR', 'Gene', '220972', (279, 282))	('cancer', 'Disease', (356, 362))	('tumor', 'Disease', 'MESH:D009369', (391, 396))	('tumor initiation', 'Disease', 'MESH:D009369', (391, 407))	('cancer', 'Phenotype', 'HP:0002664', (294, 300))	('cancer', 'Phenotype', 'HP:0002664', (356, 362))	('miR', 'Gene', (232, 235))	('cell cycle', 'CPA', (213, 223))	('miR-205', 'Gene', '406988', (232, 239))	('tumor initiation', 'Disease', (391, 407))	('tumor', 'Disease', (135, 140))	('miR', 'Gene', (34, 37))	('miR', 'Gene', (279, 282))	('EMT', 'CPA', (328, 331))	('tumor', 'Phenotype', 'HP:0002664', (391, 396))	('let-7e', 'Gene', (77, 83))	('tumor', 'Disease', 'MESH:D009369', (135, 140))	('let-7c', 'Gene', (65, 71))	('miR', 'Gene', '220972', (339, 342))	('cancer', 'Disease', 'MESH:D009369', (294, 300))	('cancer', 'Disease', 'MESH:D009369', (356, 362))	('mutated', 'Var', (16, 23))	('suppressing', 'NegReg', (316, 327))	('let-7e', 'Gene', '406887', (77, 83))	('inhibiting', 'NegReg', (283, 293))	('miR-205', 'Gene', (232, 239))
340406	31181801	The same n.35C>T mutation in the miR-205 seed sequence was observed in two samples in our studies (Figure 3 and Supplementary Figure S3B).	('miR-205', 'Gene', (33, 40))	('n.35C>T', 'Var', (9, 16))	('n.35C>T', 'Mutation', 'n.35C>T', (9, 16))	('miR-205', 'Gene', '406988', (33, 40))
340407	31181801	As shown in Figure 3 the mutation causes the loss of many miR-205 targets, including well-validated MED1, ERBB3, VEGFA, E2F1, and PTEN, that are crucial for the cancer-related functions of miR-205.	('ERBB3', 'Gene', (106, 111))	('E2F1', 'Gene', (120, 124))	('cancer', 'Disease', (161, 167))	('VEGFA', 'Gene', (113, 118))	('miR-205', 'Gene', '406988', (189, 196))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('mutation', 'Var', (25, 33))	('E2F1', 'Gene', '1869', (120, 124))	('miR-205', 'Gene', '406988', (58, 65))	('MED1', 'Gene', (100, 104))	('PTEN', 'Gene', (130, 134))	('ERBB3', 'Gene', '2065', (106, 111))	('VEGFA', 'Gene', '7422', (113, 118))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('miR-205', 'Gene', (189, 196))	('MED1', 'Gene', '5469', (100, 104))	('PTEN', 'Gene', '5728', (130, 134))	('man', 'Species', '9606', (53, 56))	('miR-205', 'Gene', (58, 65))	('loss', 'NegReg', (45, 49))
340409	31181801	Mutations were also found in genes encoding known oncomiRs, such as the miR-21, miR-155 genes and in the genes (miR-17, miR-18a, miR-20a, R19b-1, and miR-92a-1) belonging to the miR-17-92 cluster, also known as OncomiR-1 (Supplementary Table S2).	('miR', 'Gene', (80, 83))	('miR', 'Gene', (54, 57))	('miR', 'Gene', '220972', (178, 181))	('miR-18a', 'Gene', '406953', (120, 127))	('R19b-1', 'Gene', (138, 144))	('miR-20a', 'Gene', (129, 136))	('miR-155', 'Gene', (80, 87))	('miR-17', 'Gene', (178, 184))	('miR-92a-1', 'Gene', (150, 159))	('miR', 'Gene', '220972', (129, 132))	('miR-20a', 'Gene', '406982', (129, 136))	('miR', 'Gene', (178, 181))	('miR-155', 'Gene', '406947', (80, 87))	('Mutations', 'Var', (0, 9))	('miR-17', 'Gene', (112, 118))	('miR-92a-1', 'Gene', '407048', (150, 159))	('miR', 'Gene', '220972', (215, 218))	('miR', 'Gene', '220972', (150, 153))	('miR-21', 'Gene', '406991', (72, 78))	('miR-17-92', 'Gene', (178, 187))	('miR', 'Gene', (129, 132))	('miR', 'Gene', '220972', (120, 123))	('miR', 'Gene', '220972', (112, 115))	('miR', 'Gene', '220972', (72, 75))	('miR', 'Gene', (215, 218))	('miR-18a', 'Gene', (120, 127))	('miR', 'Gene', '220972', (80, 83))	('miR', 'Gene', (150, 153))	('miR-17', 'Gene', '406952', (178, 184))	('miR', 'Gene', '220972', (54, 57))	('miR', 'Gene', (120, 123))	('miR', 'Gene', (112, 115))	('miR-21', 'Gene', (72, 78))	('miR-17-92', 'Gene', '407975', (178, 187))	('miR', 'Gene', (72, 75))	('miR-17', 'Gene', '406952', (112, 118))
340410	31181801	Finally, mutations were also detected in the miR-143 gene, which encodes the most abundantly expressed miRNA (accounting for ~30% of all expressed miRNAs) and, next to miR-21, contribute to the greatest changes (decreases) in miRNA levels in most cancer types.	('mutations', 'Var', (9, 18))	('miR', 'Gene', '220972', (147, 150))	('miR', 'Gene', '220972', (226, 229))	('cancer', 'Disease', (247, 253))	('miR', 'Gene', (45, 48))	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('miR', 'Gene', '220972', (168, 171))	('miR', 'Gene', (147, 150))	('miR', 'Gene', (226, 229))	('miR-21', 'Gene', '406991', (168, 174))	('miR', 'Gene', (168, 171))	('cancer', 'Disease', 'MESH:D009369', (247, 253))	('miR', 'Gene', '220972', (103, 106))	('changes', 'Reg', (203, 210))	('miR-21', 'Gene', (168, 174))	('miR-143', 'Gene', '406935', (45, 52))	('miR', 'Gene', '220972', (45, 48))	('miR', 'Gene', (103, 106))	('miR-143', 'Gene', (45, 52))	('decreases', 'NegReg', (212, 221))
340413	31181801	The dispersed distribution of mutations over the hotspot miRNA genes (without specific hotspot mutations) is consistent with the pattern of loss-of-function mutations typically observed in suppressor genes.	('mutations', 'Var', (30, 39))	('miR', 'Gene', (57, 60))	('miR', 'Gene', '220972', (57, 60))
340416	31181801	An exceptional mutation distribution pattern was the accumulation of mutations in a basal region of the miR-887 gene and the introduction of a basal UG motif, which may be associated with the oncogene-like pattern of mutations resulting in accelerated pre-miRNA processing and thus an elevated level of this miRNA in cells.	('mutations', 'Var', (69, 78))	('miR', 'Gene', '220972', (256, 259))	('miR', 'Gene', (256, 259))	('miR', 'Gene', '220972', (308, 311))	('miR', 'Gene', (308, 311))	('miR', 'Gene', (104, 107))	('miR-887', 'Gene', '100126347', (104, 111))	('miR-887', 'Gene', (104, 111))	('level of', 'MPA', (294, 302))	('miR', 'Gene', '220972', (104, 107))	('accelerated', 'PosReg', (240, 251))	('elevated', 'PosReg', (285, 293))
340419	31181801	We have shown that mutations in miRNA genes and known cancer driver genes are not mutually exclusive, but a substantial number of miRNA gene mutations were identified in samples without mutations in known protein-coding drivers.	('miR', 'Gene', (32, 35))	('mutations', 'Var', (141, 150))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('miR', 'Gene', '220972', (130, 133))	('miR', 'Gene', (130, 133))	('cancer', 'Disease', (54, 60))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('miR', 'Gene', '220972', (32, 35))
340420	31181801	We also showed that mutations in some hotspot miRNA genes correlated with different epidemiological and clinical characteristics of cancer and that miR-887 and miR-664b gene mutations were associated with lower expression of these specific miRNAs.	('miR', 'Gene', (46, 49))	('miR-664b', 'Gene', '100847052', (160, 168))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('correlated', 'Reg', (58, 68))	('miR', 'Gene', (148, 151))	('miR', 'Gene', '220972', (240, 243))	('mutations', 'Var', (174, 183))	('miR', 'Gene', '220972', (160, 163))	('miR-887', 'Gene', '100126347', (148, 155))	('miR', 'Gene', (240, 243))	('mutations', 'Var', (20, 29))	('miR', 'Gene', '220972', (46, 49))	('miR', 'Gene', (160, 163))	('cancer', 'Disease', (132, 138))	('miR-664b', 'Gene', (160, 168))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('miR', 'Gene', '220972', (148, 151))	('lower', 'NegReg', (205, 210))	('expression', 'MPA', (211, 221))	('miR-887', 'Gene', (148, 155))
340425	31181801	For example, the n.66G>T mutation in the 3' arm of the miR-890 precursor destabilizes the duplex structure and enlarges the internal loop at the predicted DROSHA cleavage site.	('destabilizes', 'NegReg', (73, 85))	('miR-890', 'Gene', (55, 62))	('miR-890', 'Gene', '100126303', (55, 62))	('duplex structure', 'MPA', (90, 106))	('internal loop', 'MPA', (124, 137))	('n.66G>T', 'Mutation', 'n.66G>T', (17, 24))	('DROSHA', 'Gene', '29102', (155, 161))	('enlarges', 'PosReg', (111, 119))	('DROSHA', 'Gene', (155, 161))	('n.66G>T', 'Var', (17, 24))
340427	31181801	It was shown before that the G>C substitution (SNP rs138166791) located at the same position significantly decreases the effectiveness of pre-miRNA processing and the level of mature miRNA.	('G>C', 'Var', (29, 32))	('decreases', 'NegReg', (107, 116))	('rs138166791', 'Mutation', 'rs138166791', (51, 62))	('miR', 'Gene', '220972', (142, 145))	('miR', 'Gene', (142, 145))	('miR', 'Gene', '220972', (183, 186))	('miR', 'Gene', (183, 186))	('effectiveness', 'MPA', (121, 134))	('level', 'MPA', (167, 172))
340428	31181801	Additionally, as we have previously shown, such nucleotide substitutions may alter DROSHA cleavage specificity and may change the pool of generated isomiRs.	('nucleotide substitutions', 'Var', (48, 72))	('change', 'Reg', (119, 125))	('alter', 'Reg', (77, 82))	('miR', 'Gene', '220972', (151, 154))	('miR', 'Gene', (151, 154))	('DROSHA', 'Gene', '29102', (83, 89))	('DROSHA', 'Gene', (83, 89))
340430	31181801	We have also shown that somatic mutations in miRNA genes may affect (destroy or create) sequence motifs recognized by proteins playing a role in miRNA maturation.	('sequence motifs recognized', 'MPA', (88, 114))	('proteins', 'Protein', (118, 126))	('create', 'Reg', (80, 86))	('miR', 'Gene', '220972', (45, 48))	('miR', 'Gene', (45, 48))	('mutations', 'Var', (32, 41))	('affect', 'Reg', (61, 67))	('miR', 'Gene', '220972', (145, 148))	('miR', 'Gene', (145, 148))
340436	31181801	As shown in Figure 4, mutations may also affect the SRSF3-binding CNNC motif involved in pri-miRNA processing.	('SRSF3', 'Gene', '6428', (52, 57))	('CNNC motif', 'Gene', (66, 76))	('mutations', 'Var', (22, 31))	('miR', 'Gene', '220972', (93, 96))	('SRSF3', 'Gene', (52, 57))	('miR', 'Gene', (93, 96))	('affect', 'Reg', (41, 47))
340438	31181801	Therefore, our results, as well as the recently published tool ADmiRE, may help to prioritize potentially functional mutations and to develop a better algorithm for the identification of driver mutations in regions coding for non-coding RNAs, particularly miRNAs.	('miR', 'Gene', '220972', (256, 259))	('mutations', 'Var', (117, 126))	('miR', 'Gene', (256, 259))	('miR', 'Gene', '220972', (65, 68))	('miR', 'Gene', (65, 68))
340439	31181801	For example, an analysis of mutations in hotspot miRNA genes detected in this study showed that excess mutations in the miR-509-3 gene occur in the mature miRNA sequences and that those in the miR-887 gene affect regulatory sequence motifs.	('mutations', 'Var', (103, 112))	('miR', 'Gene', '220972', (120, 123))	('miR', 'Gene', (120, 123))	('miR-887', 'Gene', '100126347', (193, 200))	('miR-509-3', 'Gene', (120, 129))	('regulatory sequence motifs', 'MPA', (213, 239))	('miR-887', 'Gene', (193, 200))	('miR', 'Gene', '220972', (155, 158))	('miR-509-3', 'Gene', '100847022', (120, 129))	('miR', 'Gene', (155, 158))	('miR', 'Gene', (193, 196))	('miR', 'Gene', (49, 52))	('miR', 'Gene', '220972', (49, 52))	('miR', 'Gene', '220972', (193, 196))	('affect', 'Reg', (206, 212))
340444	31181801	We analyzed somatic sequence variants in 1642 miRNA gene regions (Supplementary Table S1) including 1600 regions covered by the probes used for exome enrichment (SureSelect, Agilent, Santa Clara, CA, USA) and 42 regions co-captured during library enrichment but not directly covered by the SureSelect probes.	('miR', 'Gene', (46, 49))	('variants', 'Var', (29, 37))	('miR', 'Gene', '220972', (46, 49))
340452	31181801	To further increase the reliability of the identified somatic sequence variants (and avoid the identification of uncertain variants), we removed those that did not fulfill the following criteria: (i) at least two alternative allele-supporting reads in a tumor sample (if no alternative allele-supporting read was detected in the corresponding normal sample); (ii) at least 5x higher frequency of alternative allele-supporting reads in the tumor sample than in the corresponding normal sample; (iii) somatic score parameter (SSC) > 30 (for VarScan2 and SomaticSniper); and (iv) base quality (BQ) parameter for alternative allele-supporting reads in the tumor sample > 20 (for MuSE and MuTect2).	('variants', 'Var', (71, 79))	('tumor', 'Disease', (439, 444))	('higher', 'PosReg', (376, 382))	('tumor', 'Disease', (652, 657))	('tumor', 'Disease', (254, 259))	('tumor', 'Disease', 'MESH:D009369', (439, 444))	('tumor', 'Disease', 'MESH:D009369', (652, 657))	('tumor', 'Disease', 'MESH:D009369', (254, 259))	('tumor', 'Phenotype', 'HP:0002664', (439, 444))	('tumor', 'Phenotype', 'HP:0002664', (652, 657))	('tumor', 'Phenotype', 'HP:0002664', (254, 259))
340454	31181801	Finally, the average sequencing depth of the identified somatic sequence variants in miRNA genes was ~290 for LUAD and ~313 for LUSC.	('variants', 'Var', (73, 81))	('miR', 'Gene', '220972', (85, 88))	('LUAD', 'Disease', (110, 114))	('miR', 'Gene', (85, 88))
340457	31181801	Hotspot miRNA genes were identified based on the probability of occurrence of the observed number of mutations, which was calculated with the use of 2-tailed binomial distribution (VassarStats: web site for statistical computation ), assuming a background random occurrence of identified mutations in all analyzed miRNA genes and considering the miRNA gene length.	('miR', 'Gene', '220972', (314, 317))	('miR', 'Gene', (314, 317))	('miR', 'Gene', '220972', (346, 349))	('miR', 'Gene', (346, 349))	('mutations', 'Var', (288, 297))	('miR', 'Gene', '220972', (8, 11))	('miR', 'Gene', (8, 11))
340460	31181801	To identify mutations affecting sequence motifs recognized by pre-miRNA-interacting proteins, we modified miRNAmotif software , which is dedicated to the identification of sequence motifs in wild-type pre-miRNA sequences.	('miR', 'Gene', (205, 208))	('mutations', 'Var', (12, 21))	('miR', 'Gene', (106, 109))	('miR', 'Gene', (66, 69))	('miR', 'Gene', '220972', (106, 109))	('miR', 'Gene', '220972', (66, 69))	('miR', 'Gene', '220972', (205, 208))
340463	31181801	For the experimental identification of sequence variants in the miR-890, miR-379, and miR-1297 genes, we analyzed DNA from 84 tumor samples (formalin-fixed paraffin-embedded) with histopathologically confirmed NSCLC diagnosed at the Franciszek Lukaszczyk Oncology Center in Bydgoszcz (central Poland).	('miR-890', 'Gene', (64, 71))	('formalin', 'Chemical', 'MESH:D005557', (141, 149))	('miR-1297', 'Gene', (86, 94))	('miR-379', 'Gene', '494328', (73, 80))	('variants', 'Var', (48, 56))	('NSCLC', 'Disease', (210, 215))	('Oncology', 'Phenotype', 'HP:0002664', (255, 263))	('paraffin', 'Chemical', 'MESH:D010232', (156, 164))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('NSCLC', 'Disease', 'MESH:D002289', (210, 215))	('miR-1297', 'Gene', '100302187', (86, 94))	('miR-379', 'Gene', (73, 80))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('miR-890', 'Gene', '100126303', (64, 71))	('tumor', 'Disease', (126, 131))
340467	31181801	In summary, in this study involving WES data from human lung tumors, we revealed a plethora of somatic sequence variants within miRNA genes and addressed their potential functional consequences.	('lung tumors', 'Phenotype', 'HP:0100526', (56, 67))	('lung tumors', 'Disease', (56, 67))	('lung tumors', 'Disease', 'MESH:D008175', (56, 67))	('miR', 'Gene', '220972', (128, 131))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('miR', 'Gene', (128, 131))	('plethora', 'Phenotype', 'HP:0001050', (83, 91))	('human', 'Species', '9606', (50, 55))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('variants', 'Var', (112, 120))
340468	31181801	Although our results must be further evaluated and experimentally validated, they provide a good starting point for discussion and further research on the development of miRNA gene-dedicated computational approaches, which may help elucidate the role of somatic miRNA gene mutations in cancer in the future.	('cancer', 'Phenotype', 'HP:0002664', (286, 292))	('mutations', 'Var', (273, 282))	('miR', 'Gene', '220972', (262, 265))	('miR', 'Gene', (262, 265))	('cancer', 'Disease', 'MESH:D009369', (286, 292))	('miR', 'Gene', '220972', (170, 173))	('miR', 'Gene', (170, 173))	('cancer', 'Disease', (286, 292))
340473	30886542	Identification of DNA methylation-driven genes in esophageal squamous cell carcinoma: a study based on The Cancer Genome Atlas Aberrant DNA methylations are significantly associated with esophageal squamous cell carcinoma (ESCC).	('DNA', 'Gene', (136, 139))	('associated with', 'Reg', (171, 186))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (61, 84))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (198, 221))	('methylations', 'Var', (140, 152))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (50, 84))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (187, 221))	('carcinoma', 'Phenotype', 'HP:0030731', (212, 221))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('Cancer', 'Phenotype', 'HP:0002664', (107, 113))	('esophageal squamous cell carcinoma', 'Disease', (50, 84))	('esophageal squamous cell carcinoma', 'Disease', (187, 221))
340483	30886542	Epigenetic changes are identified as significant contributors to cancer progression.	('cancer', 'Disease', (65, 71))	('Epigenetic changes', 'Var', (0, 18))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))
340484	30886542	Selective hypermethylation or hypomethylation of genes to regulate the expression of genes and form specific tissue types during development are considered to be a hallmark in developing many carcinomas.	('carcinomas', 'Disease', (192, 202))	('carcinomas', 'Disease', 'MESH:D002277', (192, 202))	('hyper', 'Disease', (10, 15))	('hypomethylation', 'Var', (30, 45))	('expression of genes', 'MPA', (71, 90))	('hyper', 'Disease', 'MESH:D053307', (10, 15))	('carcinoma', 'Phenotype', 'HP:0030731', (192, 201))	('carcinomas', 'Phenotype', 'HP:0030731', (192, 202))
340490	30886542	stated out the function of epigenetic changes on malignant mesothelioma cell.	('epigenetic changes', 'Var', (27, 45))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (49, 71))	('mesothelioma', 'Disease', (59, 71))	('mesothelioma', 'Disease', 'MESH:D008654', (59, 71))
340515	30886542	Aberrant DNA methylation of genes can be served as noninvasive biomarkers for the diagnosis and detection of cancer.	('Aberrant DNA methylation', 'Var', (0, 24))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('cancer', 'Disease', (109, 115))	('cancer', 'Disease', 'MESH:D009369', (109, 115))
340516	30886542	Several reports have shown that the aberrant methylation of DNA affects genes involved in DNA damage, cell cycle, Wnt, NF-kappaB signaling pathways, including MGMT, P16, DACH1 and ZNF382.	('cell', 'CPA', (102, 106))	('aberrant methylation', 'Var', (36, 56))	('NF-kappaB signaling pathways', 'Pathway', (119, 147))	('affects', 'Reg', (64, 71))	('MGMT', 'Gene', '4255', (159, 163))	('P16', 'Gene', (165, 168))	('MGMT', 'Gene', (159, 163))	('methylation', 'Var', (45, 56))	('ZNF382', 'Gene', (180, 186))	('P16', 'Gene', '1029', (165, 168))	('ZNF382', 'Gene', '84911', (180, 186))	('DACH1', 'Gene', (170, 175))	('DNA', 'Gene', (60, 63))	('DACH1', 'Gene', '1602', (170, 175))
340517	30886542	Also, other studies have shown that methylated FHIT is correlated with poor prognosis in early ESCC.	('methylated', 'Var', (36, 46))	('FHIT', 'Gene', (47, 51))	('early ESCC', 'Disease', (89, 99))	('FHIT', 'Gene', '2272', (47, 51))
340525	30886542	Previous studies have suggested CCDC8 (coiled-coil domain containing 8) was frequently epigenetically dysregulated in renal cell carcinoma and in breast carcinomas that metastasis to the brain.	('renal cell carcinoma', 'Disease', (118, 138))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (118, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (153, 162))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (118, 138))	('CCDC8', 'Gene', (32, 37))	('carcinomas', 'Phenotype', 'HP:0030731', (153, 163))	('breast carcinomas', 'Disease', 'MESH:D001943', (146, 163))	('breast carcinomas', 'Disease', (146, 163))	('coiled-coil domain containing 8', 'Gene', (39, 70))	('epigenetically dysregulated', 'Var', (87, 114))	('CCDC8', 'Gene', '83987', (32, 37))	('coiled-coil domain containing 8', 'Gene', '83987', (39, 70))	('breast carcinomas', 'Phenotype', 'HP:0003002', (146, 163))
340527	30886542	The result may due to aberrant methylation of the sites leading to the dysregulation of the expression, which affects the generation and progression of cancers and the prognosis of patients.	('cancers', 'Disease', (152, 159))	('cancers', 'Disease', 'MESH:D009369', (152, 159))	('aberrant methylation', 'Var', (22, 42))	('dysregulation', 'MPA', (71, 84))	('methylation', 'Var', (31, 42))	('patients', 'Species', '9606', (181, 189))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('cancers', 'Phenotype', 'HP:0002664', (152, 159))	('affects', 'Reg', (110, 117))	('expression', 'MPA', (92, 102))
340528	30886542	Growing evidence demonstrated that the aberrant DNA methylation was associated tumors generation and progression via the bioinformatics analysis.	('associated', 'Reg', (68, 78))	('DNA', 'Protein', (48, 51))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('tumors', 'Disease', (79, 85))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('aberrant', 'Var', (39, 47))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
340530	30886542	used GEO database to study aberrant methylation genes as biomarkers for hepatocellular cancer.	('hepatocellular cancer', 'Phenotype', 'HP:0001402', (72, 93))	('aberrant', 'Var', (27, 35))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('hepatocellular cancer', 'Disease', 'MESH:D006528', (72, 93))	('hepatocellular cancer', 'Disease', (72, 93))
340545	28560415	For example, activating mutations in epidermal growth factor receptor and mutations in ALK fusion proteins usually occur in LUAD, but not LUSC, rendering medications targeted at these genes ineffective for LUSC.	('LUSC', 'Phenotype', 'HP:0030359', (138, 142))	('ALK', 'Gene', '238', (87, 90))	('activating', 'PosReg', (13, 23))	('epidermal growth factor receptor', 'Gene', '1956', (37, 69))	('LUAD', 'Phenotype', 'HP:0030078', (124, 128))	('mutations', 'Var', (74, 83))	('LUAD', 'Disease', (124, 128))	('epidermal growth factor receptor', 'Gene', (37, 69))	('mutations', 'Var', (24, 33))	('ALK', 'Gene', (87, 90))	('LUSC', 'Phenotype', 'HP:0030359', (206, 210))
340561	28560415	The upregulated DEGs in LUSC vs. LUAD were enriched in 285 GOs, such as extracellular matrix organization (GO:0030198) and cell differentiation (GO:0030154), and in 25 pathways, such as cell adhesion molecules (id:04514) and p53 signaling pathway (id:04115).	('GO:0030198', 'Var', (107, 117))	('id:04514', 'Var', (211, 219))	('cell adhesion molecules', 'Pathway', (186, 209))	('p53', 'Gene', (225, 228))	('extracellular matrix organization', 'CPA', (72, 105))	('GO:0030154', 'Var', (145, 155))	('LUAD', 'Phenotype', 'HP:0030078', (33, 37))	('upregulated', 'PosReg', (4, 15))	('p53', 'Gene', '7157', (225, 228))	('cell differentiation', 'CPA', (123, 143))	('LUSC', 'Phenotype', 'HP:0030359', (24, 28))
340581	28560415	The p53 signaling pathway was also identified as upregulated in LUSC; a critical role of the p53 mutation in malignant transformation, histologic progression, invasion, and metastasis has been previously demonstrated in both in vitro and in vivo models of lung cancer.	('lung cancer', 'Disease', (256, 267))	('lung cancer', 'Phenotype', 'HP:0100526', (256, 267))	('p53', 'Gene', '7157', (4, 7))	('p53', 'Gene', (93, 96))	('p53', 'Gene', '7157', (93, 96))	('lung cancer', 'Disease', 'MESH:D008175', (256, 267))	('cancer', 'Phenotype', 'HP:0002664', (261, 267))	('metastasis', 'CPA', (173, 183))	('LUSC', 'Phenotype', 'HP:0030359', (64, 68))	('upregulated', 'PosReg', (49, 60))	('malignant transformation', 'CPA', (109, 133))	('invasion', 'CPA', (159, 167))	('mutation', 'Var', (97, 105))	('p53', 'Gene', (4, 7))
340582	28560415	Smoking was revealed to be closely related to p53 mutation, which may explain the prevalence of p53 alterations in LUSC.	('p53', 'Gene', (96, 99))	('p53', 'Gene', '7157', (96, 99))	('p53', 'Gene', (46, 49))	('LUSC', 'Phenotype', 'HP:0030359', (115, 119))	('p53', 'Gene', '7157', (46, 49))	('related', 'Reg', (35, 42))	('mutation', 'Var', (50, 58))
340586	28560415	Previous studies have suggested that miR-1 functions through the regulation of oncogenic coronin 1C, and the silencing miR-1 resulted in sensitization of LUSC to traditional chemotherapeutics.	('miR', 'Gene', '220972', (37, 40))	('miR', 'Gene', (37, 40))	('coronin 1C', 'Gene', (89, 99))	('miR', 'Gene', '220972', (119, 122))	('miR', 'Gene', (119, 122))	('coronin 1C', 'Gene', '23603', (89, 99))	('silencing', 'Var', (109, 118))	('LUSC', 'Phenotype', 'HP:0030359', (154, 158))	('sensitization', 'Reg', (137, 150))
340594	28039461	NFKB1-94insertion/deletion ATTG polymorphism and cancer risk: Evidence from 50 case-control studies Nuclear factor-kappa B1 (NF-kappaB1) is a pleiotropic transcription factor and key contributor to tumorigenesis in many types of cancer.	('NFKB1', 'Gene', (0, 5))	('NFKB1', 'Gene', '4790', (0, 5))	('cancer', 'Disease', (229, 235))	('cancer', 'Disease', 'MESH:D009369', (229, 235))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('polymorphism', 'Var', (32, 44))	('NF-kappaB', 'Gene', '4790', (125, 134))	('Nuclear factor-kappa B', 'Gene', '4790', (100, 122))	('Nuclear factor-kappa B', 'Gene', (100, 122))	('tumor', 'Disease', (198, 203))	('ATTG', 'Gene', (27, 31))	('cancer', 'Disease', (49, 55))	('NF-kappaB', 'Gene', (125, 134))
340595	28039461	Numerous studies have addressed the association of a functional insertion (I)/deletion (D) polymorphism (-94ins/delATTG, rs28362491) in the promoter region of NFKB1 gene with the risk of various types of cancer; however, their conclusions have been inconsistent.	('cancer', 'Disease', (204, 210))	('cancer', 'Disease', 'MESH:D009369', (204, 210))	('NFKB1', 'Gene', '4790', (159, 164))	('insertion', 'Var', (64, 73))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('NFKB1', 'Gene', (159, 164))	('rs28362491', 'Var', (121, 131))	('-94ins/delATTG', 'Mutation', 'rs28362491', (105, 119))	('rs28362491', 'Mutation', 'rs28362491', (121, 131))	('-94ins/delATTG', 'Var', (105, 119))
340601	28039461	In view of this, it is plausible that genetic polymorphisms in inflammation-related genes could modify cancer susceptibility.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('inflammation', 'Disease', 'MESH:D007249', (63, 75))	('genetic polymorphisms', 'Var', (38, 59))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('modify', 'Reg', (96, 102))	('inflammation', 'Disease', (63, 75))
340609	28039461	Among these, NFKB1 rs28362491, namely the -94insertion/deletion ATTG polymorphism, is potentially functional and the most widely investigated.	('NFKB1', 'Gene', (13, 18))	('rs28362491', 'Mutation', 'rs28362491', (19, 29))	('rs28362491', 'Var', (19, 29))	('NFKB1', 'Gene', '4790', (13, 18))
340611	28039461	The deletion of four bases (ATTG) reduces or prevents the binding to nuclear proteins and leads to lower transcript levels of the NFKB1 gene, thereby changing mRNA stability and regulating translation efficiency.	('NFKB1', 'Gene', (130, 135))	('binding', 'Interaction', (58, 65))	('lower', 'NegReg', (99, 104))	('transcript levels', 'MPA', (105, 122))	('reduces', 'NegReg', (34, 41))	('regulating', 'Reg', (178, 188))	('prevents', 'NegReg', (45, 53))	('mRNA stability', 'MPA', (159, 173))	('changing', 'Reg', (150, 158))	('deletion', 'Var', (4, 12))	('translation efficiency', 'MPA', (189, 211))	('NFKB1', 'Gene', '4790', (130, 135))	('nuclear proteins', 'Protein', (69, 85))
340617	28039461	Overall, the pooled analysis demonstrated a significant, negative association between the NFKB1 -94ins/delATTG polymorphism and overall cancer risk under all five genetic models (described in the Materials and Methods section): DD vs. II: OR = 0.75, 95% CI = 0.64-0.87; ID vs. II: OR = 0.91, 95% CI = 0.83-0.99; DD vs. ID/II: OR = 0.81, 95% CI = 0.71-0.91; ID/DD vs. II: OR = 0.86, 95% CI = 0.78-0.95; and D vs.	('-94ins/delATTG', 'Mutation', 'rs28362491', (96, 110))	('NFKB1', 'Gene', '4790', (90, 95))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('ID/DD', 'Var', (357, 362))	('cancer', 'Disease', (136, 142))	('NFKB1', 'Gene', (90, 95))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('negative', 'NegReg', (57, 65))
340622	28039461	However, no correlation was observed between NFKB1 -94ins/delATTG polymorphism and other types of cancer.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('-94ins/delATTG', 'Mutation', 'rs28362491', (51, 65))	('polymorphism', 'Var', (66, 78))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('NFKB1', 'Gene', (45, 50))	('cancer', 'Disease', (98, 104))	('NFKB1', 'Gene', '4790', (45, 50))
340623	28039461	When stratified by population, a significant association between NFKB1 -94ins/delATTG polymorphism and decreased cancer risk among Asians was detected under all genetic models (DD vs. II: OR = 0.67, 95% CI = 0.55-0.80; ID vs. II: OR = 0.86, 95% CI = 0.79-0.94; DD vs. ID/II: OR = 0.75, 95% CI = 0.65-0.86; ID/DD vs. II: OR = 0.80, 95% CI = 0.72-0.89; D vs.	('NFKB1', 'Gene', (65, 70))	('decreased cancer', 'Disease', 'MESH:D009369', (103, 119))	('polymorphism', 'Var', (86, 98))	('-94ins/delATTG', 'Mutation', 'rs28362491', (71, 85))	('decreased cancer', 'Disease', (103, 119))	('NFKB1', 'Gene', '4790', (65, 70))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
340624	28039461	As most of the studies were performed on the Chinese population, we determined the association of NFKB1 -94ins/delATTG polymorphism with cancer risk on Chinese subjects.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('-94ins/delATTG', 'Mutation', 'rs28362491', (104, 118))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('association', 'Interaction', (83, 94))	('NFKB1', 'Gene', '4790', (98, 103))	('cancer', 'Disease', (137, 143))	('polymorphism', 'Var', (119, 131))	('NFKB1', 'Gene', (98, 103))
340627	28039461	After stratification by quality score, a significantly decreased cancer risk was observed for studies with quality scores <=9 (DD vs. II: OR = 0.68, 95% CI = 0.53-0.86; DD vs. ID/II: OR = 0.73, 95% CI = 0.60-0.88; ID/DD vs. II: OR = 0.83, 95% CI = 0.71-0.96; D vs.	('decreased cancer', 'Disease', 'MESH:D009369', (55, 71))	('ID/DD', 'Var', (214, 219))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('decreased cancer', 'Disease', (55, 71))
340630	28039461	Numerous studies have suggested that polymorphisms in genes encoding inflammatory response factors, such as TNF-alpha -308G>A, IL6 -174G>C, and NFKBIA -826C>T may contribute to cancer susceptibility.	('polymorphisms', 'Var', (37, 50))	('-826C>T', 'Mutation', 'rs2233406', (151, 158))	('IL6', 'Gene', '3569', (127, 130))	('cancer', 'Disease', (177, 183))	('NFKBIA', 'Gene', '4792', (144, 150))	('-174G>C', 'Mutation', 'rs1800795', (131, 138))	('TNF-alpha', 'Gene', '7124', (108, 117))	('cancer', 'Disease', 'MESH:D009369', (177, 183))	('IL6', 'Gene', (127, 130))	('TNF-alpha', 'Gene', (108, 117))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('-308G>A', 'Mutation', 'rs1800629', (118, 125))	('NFKBIA', 'Gene', (144, 150))	('contribute', 'Reg', (163, 173))
340631	28039461	reported that the NFKB1 -94ins/delATTG polymorphism analyzed here (rs28362491) increased the risk of colorectal cancer in a Southern Chinese population; this association was also observed in several publications.	('rs28362491', 'Var', (67, 77))	('rs28362491', 'Mutation', 'rs28362491', (67, 77))	('increased', 'PosReg', (79, 88))	('colorectal cancer', 'Disease', 'MESH:D015179', (101, 118))	('NFKB1', 'Gene', '4790', (18, 23))	('NFKB1', 'Gene', (18, 23))	('colorectal cancer', 'Phenotype', 'HP:0003003', (101, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('colorectal cancer', 'Disease', (101, 118))	('-94ins/delATTG', 'Mutation', 'rs28362491', (24, 38))
340633	28039461	They did not observe any association between the -94ins/delATTG variant and overall cancer.	('the -94ins/delATTG', 'Var', (45, 63))	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('cancer', 'Disease', (84, 90))	('-94ins/delATTG', 'Mutation', 'rs28362491', (49, 63))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))
340635	28039461	They found that variant homozygotes (DD) had a decreased risk of cancer compared with wild-type homozygotes (II).	('variant', 'Var', (16, 23))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('decreased', 'NegReg', (47, 56))
340639	28039461	Ethnicity subgroup analysis indicated that the polymorphism contributed to cancer risk in the Asian, but not the Caucasian, population.	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('cancer', 'Disease', (75, 81))	('contributed', 'Reg', (60, 71))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('polymorphism', 'Var', (47, 59))
340641	28039461	Stratified analysis revealed a significant association between the polymorphism and ovarian, oral, and prostate cancers.	('cancers', 'Phenotype', 'HP:0002664', (112, 119))	('prostate cancers', 'Disease', 'MESH:D011471', (103, 119))	('oral', 'Disease', (93, 97))	('prostate cancer', 'Phenotype', 'HP:0012125', (103, 118))	('ovarian', 'Disease', (84, 91))	('prostate cancers', 'Phenotype', 'HP:0012125', (103, 119))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('prostate cancers', 'Disease', (103, 119))	('polymorphism', 'Var', (67, 79))
340644	28039461	Stratified analysis revealed that the polymorphism was associated with increased risk for oral squamous cell carcinoma and ovarian cancer, but not for colorectal cancer, bladder cancer, or renal cell cancer.	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('polymorphism', 'Var', (38, 50))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (95, 118))	('ovarian cancer', 'Disease', 'MESH:D010051', (123, 137))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('colorectal cancer', 'Disease', 'MESH:D015179', (151, 168))	('colorectal cancer', 'Disease', (151, 168))	('ovarian cancer', 'Disease', (123, 137))	('renal cell cancer', 'Disease', 'MESH:C538614', (189, 206))	('renal cell cancer', 'Disease', (189, 206))	('ovarian cancer', 'Phenotype', 'HP:0100615', (123, 137))	('renal cell cancer', 'Phenotype', 'HP:0005584', (189, 206))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('bladder cancer', 'Disease', 'MESH:D001749', (170, 184))	('bladder cancer', 'Disease', (170, 184))	('colorectal cancer', 'Phenotype', 'HP:0003003', (151, 168))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (90, 118))	('bladder cancer', 'Phenotype', 'HP:0009725', (170, 184))	('oral squamous cell carcinoma', 'Disease', (90, 118))
340646	28039461	Subgroups analysis based on ethnicity revealed that the polymorphism conferred decreased cancer susceptibility in the Asian population.	('polymorphism', 'Var', (56, 68))	('decreased cancer', 'Disease', (79, 95))	('decreased cancer', 'Disease', 'MESH:D009369', (79, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
340649	28039461	Conversely, we found that the del allele of the NFKB1 -94ins/delATTG polymorphism conferred a significantly decreased risk of cancer in the pooled analysis.	('NFKB1', 'Gene', '4790', (48, 53))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('NFKB1', 'Gene', (48, 53))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('decreased', 'NegReg', (108, 117))	('-94ins/delATTG', 'Mutation', 'rs28362491', (54, 68))	('del allele', 'Var', (30, 40))
340652	28039461	In line with previous data, our study detected a significant association between the -94ins/delATTG polymorphism and cancer risk in Asians, but not in Caucasians, under all five genetic models.	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('the -94ins/delATTG', 'Var', (81, 99))	('cancer', 'Disease', (117, 123))	('-94ins/delATTG', 'Mutation', 'rs28362491', (85, 99))
340655	28039461	Stratification by cancer type showed that the NFKB1 -94ins/delATTG polymorphism was inversely associated with the risk of lung cancer, nasopharyngeal carcinoma, prostate cancer, ovarian cancer, and oral squamous cell carcinoma, but no association was found for hepatocellular carcinoma, colorectal cancer, bladder cancer, gastric cancer, cervical cancer, breast cancer, or other cancers.	('cancers', 'Disease', 'MESH:D009369', (379, 386))	('inversely', 'NegReg', (84, 93))	('cancer', 'Disease', (170, 176))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (261, 285))	('ovarian cancer', 'Disease', 'MESH:D010051', (178, 192))	('colorectal cancer', 'Disease', 'MESH:D015179', (287, 304))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('cancer', 'Disease', 'MESH:D009369', (330, 336))	('lung cancer', 'Disease', 'MESH:D008175', (122, 133))	('breast cancer', 'Phenotype', 'HP:0003002', (355, 368))	('cancer', 'Disease', (18, 24))	('prostate cancer', 'Disease', 'MESH:D011471', (161, 176))	('cancer', 'Disease', 'MESH:D009369', (314, 320))	('cancer', 'Disease', 'MESH:D009369', (186, 192))	('cancer', 'Disease', 'MESH:D009369', (362, 368))	('-94ins/delATTG', 'Mutation', 'rs28362491', (52, 66))	('carcinoma', 'Phenotype', 'HP:0030731', (276, 285))	('colorectal cancer', 'Disease', (287, 304))	('gastric cancer', 'Disease', (322, 336))	('hepatocellular carcinoma', 'Disease', (261, 285))	('lung cancer', 'Phenotype', 'HP:0100526', (122, 133))	('prostate cancer', 'Phenotype', 'HP:0012125', (161, 176))	('cancer', 'Disease', 'MESH:D009369', (298, 304))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('prostate cancer', 'Disease', (161, 176))	('carcinoma', 'Phenotype', 'HP:0030731', (150, 159))	('associated', 'Reg', (94, 104))	('ovarian cancer', 'Disease', (178, 192))	('nasopharyngeal carcinoma', 'Disease', (135, 159))	('cancer', 'Disease', (347, 353))	('cancer', 'Disease', (127, 133))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (198, 226))	('breast cancer', 'Disease', 'MESH:D001943', (355, 368))	('cervical cancer', 'Disease', 'MESH:D002583', (338, 353))	('breast cancer', 'Disease', (355, 368))	('polymorphism', 'Var', (67, 79))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (203, 226))	('cancers', 'Phenotype', 'HP:0002664', (379, 386))	('cancer', 'Disease', (379, 385))	('cervical cancer', 'Disease', (338, 353))	('cancers', 'Disease', (379, 386))	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('ovarian cancer', 'Phenotype', 'HP:0100615', (178, 192))	('oral squamous cell carcinoma', 'Disease', (198, 226))	('NFKB1', 'Gene', '4790', (46, 51))	('gastric cancer', 'Disease', 'MESH:D013274', (322, 336))	('nasopharyngeal carcinoma', 'Disease', 'MESH:D000077274', (135, 159))	('cancer', 'Disease', (330, 336))	('bladder cancer', 'Disease', 'MESH:D001749', (306, 320))	('cancer', 'Disease', (186, 192))	('cancer', 'Disease', 'MESH:D009369', (18, 24))	('colorectal cancer', 'Phenotype', 'HP:0003003', (287, 304))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (261, 285))	('bladder cancer', 'Disease', (306, 320))	('lung cancer', 'Disease', (122, 133))	('cancer', 'Disease', (314, 320))	('cancer', 'Disease', (362, 368))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('bladder cancer', 'Phenotype', 'HP:0009725', (306, 320))	('cancer', 'Disease', (298, 304))	('NFKB1', 'Gene', (46, 51))	('gastric cancer', 'Phenotype', 'HP:0012126', (322, 336))	('cancer', 'Disease', 'MESH:D009369', (347, 353))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (135, 159))	('cancer', 'Disease', 'MESH:D009369', (379, 385))	('carcinoma', 'Phenotype', 'HP:0030731', (217, 226))	('cancer', 'Phenotype', 'HP:0002664', (298, 304))
340659	28039461	In conclusion, despite these limitations, and in agreement with several previous studies, this meta-analysis draws the robust conclusion that NFKB1 -94ins/delATTG polymorphism is associated with decreased cancer risk, especially in the Asian population.	('NFKB1', 'Gene', '4790', (142, 147))	('polymorphism', 'Var', (163, 175))	('-94ins/delATTG', 'Mutation', 'rs28362491', (148, 162))	('NFKB1', 'Gene', (142, 147))	('decreased cancer', 'Disease', (195, 211))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('decreased cancer', 'Disease', 'MESH:D009369', (195, 211))
340661	28039461	The following search terms were used: "polymorphism or SNP or single nucleotide polymorphism or variant" and "NFKB1/NF-kappaB1 or nuclear factor kappa B1", and "tumor or cancer or neoplasm or carcinoma".	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('NF-kappaB', 'Gene', '4790', (116, 125))	('cancer', 'Disease', (170, 176))	('neoplasm or carcinoma', 'Disease', 'MESH:D009369', (180, 201))	('NFKB1', 'Gene', '4790', (110, 115))	('NF-kappaB', 'Gene', (116, 125))	('neoplasm or carcinoma', 'Disease', (180, 201))	('"tumor', 'Disease', (160, 166))	('neoplasm', 'Phenotype', 'HP:0002664', (180, 188))	('single nucleotide polymorphism', 'Var', (62, 92))	('"tumor', 'Disease', 'MESH:D009369', (160, 166))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('NFKB1', 'Gene', (110, 115))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('variant', 'Var', (96, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (192, 201))
340683	26606135	Additionally, there is growing evidence suggesting that long non-coding RNA (lncRNA) and DNA methylation can mediate oncogenic or tumor suppressive outcomes, representing new classes of promising biomarkers.	('oncogenic', 'CPA', (117, 126))	('ncRNA', 'Gene', (78, 83))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('ncRNA', 'Gene', '54719', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('long non-coding RNA', 'Var', (56, 75))	('tumor', 'Disease', (130, 135))	('methylation', 'Var', (93, 104))
340724	26606135	DNA methylation was the second best predictor of BRCA (test set accuracy: 0.76, N test set = 73), COAD (test set accuracy: 0.79, N test set = 67), LUSC (test set accuracy: 0.77, N test set = 42), ovarian cancer (test set accuracy: 0.7, N test set = 146), and the third best predictors in UCEC (test set accuracy: 0.8, N test set = 81).	('BRCA', 'Gene', '672', (49, 53))	('ovarian cancer', 'Phenotype', 'HP:0100615', (196, 210))	('UCEC', 'Disease', (288, 292))	('BRCA', 'Gene', (49, 53))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('methylation', 'Var', (4, 15))	('COAD', 'Disease', 'MESH:D029424', (98, 102))	('ovarian cancer', 'Disease', 'MESH:D010051', (196, 210))	('ovarian cancer', 'Disease', (196, 210))	('LUSC', 'Disease', (147, 151))	('COAD', 'Disease', (98, 102))
340730	26606135	As integrative models require samples not only comprised of multi-omic profiles, but also those that fulfill the prognostic criteria, we observed a final of 20 integrated multi-omic data groups in the five cancer types, including 15 double-combination groups and 5 triple-combination groups (see Table C in S1 File).	('cancer', 'Disease', (206, 212))	('double-combination', 'Var', (233, 251))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('cancer', 'Disease', 'MESH:D009369', (206, 212))
340754	26606135	As is well known, cancer prognosis is likely caused by a series of factors, for example, clinical variables, genetic mutations, and aberrant gene expression.	('caused', 'Reg', (45, 51))	('genetic mutations', 'Var', (109, 126))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('aberrant gene expression', 'Var', (132, 156))	('cancer', 'Disease', (18, 24))	('cancer', 'Disease', 'MESH:D009369', (18, 24))
340778	33680068	The ablation of ROM1 leads to a change from the macular/pattern dystrophy (MD/PD) phenotype characterized by a defect in cone function to a retinitis pigmentosa (RP) phenotype characterized by a dominant defect in rod function, and the formation of abnormal Prph2/ROM1 complex and total Prph2 protein decreased.	('Prph2', 'Gene', '5961', (258, 263))	('defect in cone function', 'Phenotype', 'HP:0030637', (111, 134))	('pattern dystrophy', 'Disease', (56, 73))	('retinitis pigmentosa', 'Disease', 'MESH:C538365', (140, 160))	('pattern dystrophy', 'Disease', 'MESH:D008268', (56, 73))	('ablation', 'Var', (4, 12))	('MD/PD', 'Phenotype', 'HP:0007754', (75, 80))	('RP', 'Phenotype', 'HP:0000510', (162, 164))	('defect', 'NegReg', (111, 117))	('macular/pattern dystrophy', 'Phenotype', 'HP:0007754', (48, 73))	('Prph2', 'Gene', '5961', (287, 292))	('Prph2', 'Gene', (258, 263))	('retinitis pigmentosa', 'Disease', (140, 160))	('decreased', 'NegReg', (301, 310))	('retinitis', 'Phenotype', 'HP:0032118', (140, 149))	('PD', 'Disease', 'MESH:D010300', (78, 80))	('ROM1', 'Gene', (16, 20))	('formation', 'MPA', (236, 245))	('Prph2', 'Gene', (287, 292))	('retinitis pigmentosa', 'Phenotype', 'HP:0000510', (140, 160))	('change', 'Reg', (32, 38))
340786	33680068	The second was the Gene Expression Omnibus (GEO, http://www.ncbi.nlm.nih.gov/geo/), containing GSE4573, GSE31210, GSE50081, GSE37745, and GSE30219.	('GSE4573', 'Chemical', '-', (95, 102))	('GSE4573', 'Var', (95, 102))	('GSE31210', 'Var', (104, 112))	('GSE30219', 'Var', (138, 146))	('GSE50081', 'Var', (114, 122))	('GSE37745', 'Var', (124, 132))
340807	33680068	Kaplan-Meier analysis revealed that patients with lowly expressed ROM1 demonstrated shorter overall survival (OS) time and disease-free survival (DFS) (Figures 1(d) and 1(e)).	('patients', 'Species', '9606', (36, 44))	('disease-free survival', 'CPA', (123, 144))	('lowly expressed', 'Var', (50, 65))	('shorter', 'NegReg', (84, 91))	('overall', 'MPA', (92, 99))	('ROM1', 'Gene', (66, 70))
340824	33680068	CCK-8 assay deeply demonstrated that ablated ROM1 induced cell proliferation, indicating that ROM1 modulated lung cancer cell proliferation (Figures 5(b) and 5(c)).	('lung cancer', 'Disease', (109, 120))	('ablated', 'Var', (37, 44))	('lung cancer', 'Phenotype', 'HP:0100526', (109, 120))	('ROM1', 'Gene', (94, 98))	('modulated', 'Reg', (99, 108))	('CCK-8', 'Chemical', 'MESH:D012844', (0, 5))	('lung cancer', 'Disease', 'MESH:D008175', (109, 120))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('ROM1', 'Gene', (45, 49))
340826	33680068	Transwell analysis results indicated that a significantly increased number of migrated and invaded lung cancer cells were demonstrated in ROM1 knockdown group (Figures 5(d) and 5(e)).	('lung cancer', 'Disease', (99, 110))	('increased', 'PosReg', (58, 67))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('lung cancer', 'Disease', 'MESH:D008175', (99, 110))	('knockdown', 'Var', (143, 152))	('ROM1', 'Gene', (138, 142))	('lung cancer', 'Phenotype', 'HP:0100526', (99, 110))
340846	33680068	We found that knocking out ROM1 significantly promoted lung cancer cell proliferation.	('promoted', 'PosReg', (46, 54))	('lung cancer', 'Disease', 'MESH:D008175', (55, 66))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('lung cancer', 'Disease', (55, 66))	('lung cancer', 'Phenotype', 'HP:0100526', (55, 66))	('ROM1', 'Gene', (27, 31))	('knocking out', 'Var', (14, 26))
340848	33680068	The Transwell test showed that knocking out ROM1 significantly promoted lung cancer cell migration and invasion.	('ROM1', 'Gene', (44, 48))	('lung cancer', 'Disease', (72, 83))	('promoted', 'PosReg', (63, 71))	('lung cancer', 'Phenotype', 'HP:0100526', (72, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('invasion', 'CPA', (103, 111))	('knocking out', 'Var', (31, 43))	('lung cancer', 'Disease', 'MESH:D008175', (72, 83))
340924	31482686	The results identified a total of 21 signal pathways associated with the T1-T2 DEGs with maturity-onset diabetes of the young ranked first (adjusted P = 1.63E-06) (Complementary Table 3).	('diabetes', 'Disease', (104, 112))	('DEG', 'Chemical', 'MESH:C042934', (79, 82))	('signal pathways', 'Pathway', (37, 52))	('diabetes', 'Disease', 'MESH:D003920', (104, 112))	('T1-T2', 'Var', (73, 78))	('maturity-onset diabetes of the young', 'Phenotype', 'HP:0004904', (89, 125))
340935	31482686	Among them, seven drugs might inhibit lymph node metastases (raloxifene, iproniazid, exisulind, arachidonyltrifluoromethane, 16-phenyltetranorprostaglandin E2, econazole, and fluoxetine).	('econazole', 'Chemical', 'MESH:D004464', (160, 169))	('arachidonyltrifluoromethane', 'Chemical', 'MESH:C081565', (96, 123))	('inhibit', 'NegReg', (30, 37))	('arachidonyltrifluoromethane', 'Var', (96, 123))	('iproniazid', 'Chemical', 'MESH:D007490', (73, 83))	('metastases', 'Disease', 'MESH:D009362', (49, 59))	('fluoxetine', 'Chemical', 'MESH:D005473', (175, 185))	('16-phenyltetranorprostaglandin E2', 'Chemical', 'MESH:C063035', (125, 158))	('raloxifene', 'Chemical', 'MESH:D020849', (61, 71))	('metastases', 'Disease', (49, 59))
340936	31482686	In contrast, five drugs might promote lymph node metastases (AH-6809, ticarcillin, 5255229, mesoridazine, and stachydrine) (Complementary Table 5).	('5255229', 'Var', (83, 90))	('AH-6809', 'Chemical', 'MESH:C053876', (61, 68))	('promote', 'PosReg', (30, 37))	('stachydrine', 'Chemical', 'None', (110, 121))	('5255229, mesoridazine', 'Chemical', 'MESH:D008653', (83, 104))	('metastases', 'Disease', 'MESH:D009362', (49, 59))	('AH-6809', 'Var', (61, 68))	('metastases', 'Disease', (49, 59))
340958	31482686	The discovery of this pathway is consistent with recent studies that have demonstrated that altered glucose metabolism is closely related to the occurrence and development of lung cancer,24, 25, 26 and may suggest that it might also be related to lymph node metastasis.	('related', 'Reg', (130, 137))	('related', 'Reg', (236, 243))	('glucose metabolism', 'Disease', 'MESH:D044882', (100, 118))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('lung cancer', 'Disease', (175, 186))	('lung cancer', 'Phenotype', 'HP:0100526', (175, 186))	('lung cancer', 'Disease', 'MESH:D008175', (175, 186))	('altered', 'Var', (92, 99))	('glucose metabolism', 'Disease', (100, 118))
340961	31482686	There were also seven signaling pathways involved with the T3-T4 DEGs with the neuroactive ligand-receptor interaction (ID: hsa04080) ranked first.	('signaling pathways', 'Pathway', (22, 40))	('DEG', 'Chemical', 'MESH:C042934', (65, 68))	('T3-T4', 'Var', (59, 64))	('involved', 'Reg', (41, 49))
340966	31482686	Actually, we plan to identify all DEGs may cause premature tumor metastasis first and explore their function in the EMT signaling pathway, tumor microenvironment and epigenetic changes in further research.	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('cause', 'Reg', (43, 48))	('tumor', 'Disease', (59, 64))	('DEG', 'Chemical', 'MESH:C042934', (34, 37))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('premature tumor metastasis', 'Disease', 'MESH:D009362', (49, 75))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('DEGs', 'Var', (34, 38))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('premature tumor metastasis', 'Disease', (49, 75))
340969	31482686	Furthermore, signaling pathways, such as hsa04080 (neuroactive ligand-receptor interaction) and hsa04950 (maturity onset diabetes of the young), mediate the effects of these DEGs.	('diabetes', 'Disease', (121, 129))	('signaling pathways', 'Pathway', (13, 31))	('hsa04950', 'Var', (96, 104))	('hsa04080', 'Var', (41, 49))	('diabetes', 'Disease', 'MESH:D003920', (121, 129))	('maturity onset diabetes of the young', 'Phenotype', 'HP:0004904', (106, 142))	('DEG', 'Chemical', 'MESH:C042934', (174, 177))
341014	31214489	Three major histologic types of lung cancer (International Classification of Diseases for Oncology, Third Edition; topography code C34) were classified according to a morphology code: small cell carcinoma (8041-8045), adenocarcinoma (8140, 8211, 8230-8231, 8250-8260, 8323, 8480-8490, 8550-8551, 8570-8574, 8576), and squamous cell carcinoma (8050-8078, 8083-8084).	('8480-8490', 'Var', (274, 283))	('8570-8574', 'Var', (296, 305))	('8041-8045', 'Var', (206, 215))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (318, 341))	('carcinoma', 'Phenotype', 'HP:0030731', (223, 232))	('small cell carcinoma', 'Disease', (184, 204))	('lung cancer', 'Disease', 'MESH:D008175', (32, 43))	('carcinoma', 'Phenotype', 'HP:0030731', (332, 341))	('small cell carcinoma', 'Disease', 'MESH:D018288', (184, 204))	('8550-8551', 'Var', (285, 294))	('adenocarcinoma', 'Disease', (218, 232))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (318, 341))	('lung cancer', 'Phenotype', 'HP:0100526', (32, 43))	('8083-8084', 'Var', (354, 363))	('8230-8231', 'Var', (246, 255))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('carcinoma', 'Phenotype', 'HP:0030731', (195, 204))	('squamous cell carcinoma', 'Disease', (318, 341))	('adenocarcinoma', 'Disease', 'MESH:D000230', (218, 232))	('8140', 'Var', (234, 238))	('8050-8078', 'Var', (343, 352))	('8250-8260', 'Var', (257, 266))	('lung cancer', 'Disease', (32, 43))	('Oncology', 'Phenotype', 'HP:0002664', (90, 98))	('small cell carcinoma', 'Phenotype', 'HP:0030357', (184, 204))
341115	31093355	Excisional biopsy of two right cervical lymph nodes unexpectedly demonstrated squamous cell cancer (SCC) that was positive for p16 and HPV.	('p16', 'Var', (127, 130))	('SCC', 'Gene', (100, 103))	('squamous cell cancer', 'Disease', 'MESH:D002294', (78, 98))	('SCC', 'Phenotype', 'HP:0002860', (100, 103))	('SCC', 'Gene', '6317', (100, 103))	('squamous cell cancer', 'Disease', (78, 98))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (78, 98))	('HPV', 'Species', '10566', (135, 138))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
341120	31093355	Therefore, a diagnosis of synchronous stage IV T2N2bM0 HPV+ SCC of right BOT and stage IIAX follicular lymphoma was made.	('T2N2bM0', 'Var', (47, 54))	('follicular lymphoma', 'Disease', (92, 111))	('SCC', 'Gene', '6317', (60, 63))	('HPV', 'Species', '10566', (55, 58))	('lymphoma', 'Phenotype', 'HP:0002665', (103, 111))	('SCC', 'Gene', (60, 63))	('SCC', 'Phenotype', 'HP:0002860', (60, 63))	('follicular lymphoma', 'Disease', 'MESH:D008224', (92, 111))
341175	31093355	Therefore HPV positivity may confer a more favorable prognosis in a "platform-independent" manner.	('positivity', 'Var', (14, 24))	('HPV', 'Species', '10566', (10, 13))	('HPV', 'Gene', (10, 13))
341192	24324343	In this study, we conjugated RGD with quantum dots with emission wavelength of 800 nm (QD800) to generate QD800-RGD, and used it via intravenous injection as a probe to image tumors in nude mice bearing head and neck squamous cell carcinoma (HNSCC).	('tumors', 'Disease', (175, 181))	('tumors', 'Disease', 'MESH:D009369', (175, 181))	('QD800', 'Chemical', '-', (87, 92))	('neck squamous cell carcinoma', 'Disease', (212, 240))	('rat', 'Species', '10116', (101, 104))	('tumors', 'Phenotype', 'HP:0002664', (175, 181))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (212, 240))	('QD800', 'Chemical', '-', (106, 111))	('carcinoma', 'Phenotype', 'HP:0030731', (231, 240))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (203, 240))	('nude mice', 'Species', '10090', (185, 194))	('HNSCC', 'Phenotype', 'HP:0012288', (242, 247))	('QD800-RGD', 'Var', (106, 115))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (217, 240))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))
341194	24324343	The results showed that QD800-RGD was specifically targeted to integrin alphavbeta3 in vitro and in vivo, producing clear tumor fluorescence images after the intravenous injection.	('QD800-RGD', 'Var', (24, 33))	('integrin alphavbeta3', 'Gene', '3685', (63, 83))	('producing', 'Reg', (106, 115))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('QD800', 'Chemical', '-', (24, 29))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('integrin alphavbeta3', 'Gene', (63, 83))	('tumor', 'Disease', (122, 127))
341196	24324343	The greatest amount of QD800-RGD was found in liver and spleen, followed by tumor and lung, and a weak fluorescence signal was seen in tibia.	('QD800', 'Chemical', '-', (23, 28))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('QD800-RGD', 'Var', (23, 32))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
341207	24324343	In vivo optical imaging of NIR-QDs is particularly useful in personalized tumor treatment and diagnosis as compared with other currently available technologies due to its ability to be imaged in real-time.	('NIR-QDs', 'Var', (27, 34))	('tumor', 'Disease', (74, 79))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))
341218	24324343	Integrin alphavbeta3 specifically binds to the peptide containing the arginine-glycine-aspartic acid (RGD) sequence.	('binds', 'Interaction', (34, 39))	('arginine-glycine-aspartic acid', 'Chemical', '-', (70, 100))	('arginine-glycine-aspartic', 'Var', (70, 95))	('Integrin alphavbeta3', 'Gene', '3685', (0, 20))	('Integrin alphavbeta3', 'Gene', (0, 20))
341247	24324343	The targeting efficiency of QD800-RGD to integrin alphavbeta3 under the three experimental conditions was evaluated under a laser scanning confocal microscope (TCS-SP5; Leica Microsystems, Wetzlar, Germany).	('SP5', 'Gene', '64406', (164, 167))	('integrin alphavbeta3', 'Gene', '3685', (41, 61))	('integrin alphavbeta3', 'Gene', (41, 61))	('QD800', 'Chemical', '-', (28, 33))	('QD800-RGD', 'Var', (28, 37))	('SP5', 'Gene', (164, 167))
341248	24324343	DAPI was excited at 405 nm and bright blue fluorescence was captured through a filter at 455 nm; FITC was excited at 488 nm to capture bright green fluorescence with a 505 nm filter; QD800 was excited at 405 nm and the emission was captured at 800 nm.	('QD800', 'Chemical', '-', (183, 188))	('FITC', 'Chemical', 'MESH:D016650', (97, 101))	('QD800', 'Var', (183, 188))	('DAPI', 'Chemical', 'MESH:C007293', (0, 4))	('bright green fluorescence', 'MPA', (135, 160))
341249	24324343	The invisible infrared fluorescence emitted from QD800 was pseudocolored as red.	('invisible infrared fluorescence', 'MPA', (4, 35))	('QD800', 'Chemical', '-', (49, 54))	('QD800', 'Var', (49, 54))	('pseudocolored', 'MPA', (59, 72))
341262	24324343	The other pieces of the organs were frozen in optimal cutting temperature medium, cryosectioned at -20 C into 7 mum sections, viewed, and the image recorded under the laser scanning confocal microscope with excitation and emission set at 405 nm and 800 nm, respectively, for QD800 fluorescence in tumors and organs.	('rat', 'Species', '10116', (67, 70))	('tumors', 'Disease', 'MESH:D009369', (297, 303))	('tumor', 'Phenotype', 'HP:0002664', (297, 302))	('QD800', 'Var', (275, 280))	('tumors', 'Disease', (297, 303))	('QD800', 'Chemical', '-', (275, 280))	('tumors', 'Phenotype', 'HP:0002664', (297, 303))
341271	24324343	No QD800 fluorescence signal was seen in the tissues from control groups I and II, indicating that QD800-RGD but not QD800 was able to bind to the tumor angiogenic vessel endothelial cells, while QD800-RGD was not able to bind to integrin alphavbeta3 blocked by RGD in the endothelial cells.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('integrin alphavbeta3', 'Gene', '3685', (230, 250))	('bind', 'Interaction', (135, 139))	('QD800', 'Chemical', '-', (99, 104))	('integrin alphavbeta3', 'Gene', (230, 250))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('QD800', 'Chemical', '-', (117, 122))	('QD800', 'Chemical', '-', (3, 8))	('QD800', 'Chemical', '-', (196, 201))	('QD800-RGD', 'Var', (99, 108))
341272	24324343	The results also demonstrated that RGD was still able to recognize integrin alphavbeta3 with excellent specificity after being linked to QD800, enabling QD800 to bind to the surfaces of endothelial cells in the tumor angiogenic vessels.	('integrin alphavbeta3', 'Gene', (67, 87))	('bind', 'Interaction', (162, 166))	('QD800', 'Chemical', '-', (153, 158))	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('QD800', 'Chemical', '-', (137, 142))	('integrin alphavbeta3', 'Gene', '3685', (67, 87))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('tumor', 'Disease', (211, 216))	('rat', 'Species', '10116', (24, 27))	('QD800', 'Var', (153, 158))
341273	24324343	At 0.5 hour pi of QD800-RGD, clear fluorescence signals were detected in tumors in animals in the experimental group.	('QD800-RGD', 'Var', (18, 27))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('fluorescence signals', 'MPA', (35, 55))	('QD800', 'Chemical', '-', (18, 23))	('tumors', 'Disease', (73, 79))	('tumors', 'Disease', 'MESH:D009369', (73, 79))
341289	24324343	However, QD800 fluorescence signal was not found in the samples from control groups I and II but was clearly seen within tumor angiogenic vessels from the experimental group (Figure 6), demonstrating the well-targeted, in vivo binding of QD800-RGD to integrin alphavbeta3 in tumor angiogenic vessels.	('rat', 'Species', '10116', (193, 196))	('integrin alphavbeta3', 'Gene', '3685', (251, 271))	('QD800', 'Chemical', '-', (238, 243))	('tumor', 'Disease', (275, 280))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumor', 'Phenotype', 'HP:0002664', (275, 280))	('QD800-RGD', 'Var', (238, 247))	('tumor', 'Disease', (121, 126))	('integrin alphavbeta3', 'Gene', (251, 271))	('binding', 'Interaction', (227, 234))	('tumor', 'Disease', 'MESH:D009369', (275, 280))	('QD800', 'Chemical', '-', (9, 14))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
341294	24324343	The results from in vivo and ex vivo imaging and histochemical studies of the tumors and major organs indicated that QD800-RGD is capable of targeting to integrin alphavbeta3 in vivo, and the fluorescence can be captured ex vivo to produce clear tumor fluorescence images.	('integrin alphavbeta3', 'Gene', '3685', (154, 174))	('tumors', 'Disease', (78, 84))	('QD800-RGD', 'Var', (117, 126))	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('integrin alphavbeta3', 'Gene', (154, 174))	('tumor', 'Disease', 'MESH:D009369', (246, 251))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('QD800', 'Chemical', '-', (117, 122))	('tumor', 'Disease', (78, 83))	('tumor', 'Disease', (246, 251))	('targeting', 'Interaction', (141, 150))
341295	24324343	Our results showed that complete tumor images can be obtained 0.5 hour pi of QD800-RGD, and the size and fluorescence intensity of the images did not change from 0.5-6 hours pi and were reduced remarkably at 9 hours pi.	('QD800', 'Chemical', '-', (77, 82))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('QD800-RGD', 'Var', (77, 86))	('tumor', 'Disease', (33, 38))
341300	24324343	This is because QD800-RGD, a type of nanoparticle, is easily phagocytosed by the mononuclear phagocytic system, leading to the accumulation of QD800-RGD in the liver and spleen, organs containing large amounts of mononuclear phagocytic cells.	('accumulation', 'PosReg', (127, 139))	('QD800', 'Chemical', '-', (16, 21))	('QD800', 'Chemical', '-', (143, 148))	('QD800-RGD', 'Var', (16, 25))	('QD800-RGD', 'Var', (143, 152))
341301	24324343	In this study, we did not observe any acute toxicity of the animals to QD800 or QD800-RGD, nor did we see any abnormal behavior following the injection.	('QD800', 'Chemical', '-', (80, 85))	('QD800', 'Chemical', '-', (71, 76))	('QD800', 'Var', (71, 76))	('QD800-RGD', 'Var', (80, 89))	('toxicity', 'Disease', 'MESH:D064420', (44, 52))	('toxicity', 'Disease', (44, 52))
341304	24324343	These animals were successfully imaged in situ to obtain visual tumor images after intravenous injection of QD800-RGD.	('visual tumor', 'Disease', 'MESH:D014786', (57, 69))	('QD800-RGD', 'Var', (108, 117))	('QD800', 'Chemical', '-', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('visual tumor', 'Disease', (57, 69))
341306	24324343	That is, the most clear and intact tumor images, with the highest tumor-to-background ratio, were achieved within 6 hours after the QD800-RGD injection.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('QD800', 'Chemical', '-', (132, 137))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumor', 'Disease', (66, 71))	('QD800-RGD', 'Var', (132, 141))	('tumor', 'Disease', (35, 40))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('rat', 'Species', '10116', (86, 89))
341308	24324343	Results from both the early study and this study suggest that QD800-RGD may be applicable for in vivo imaging of different types of tumor in different parts of the body, with similar imaging-time response and in vivo QD800-RGD distribution.	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('QD800-RGD', 'Var', (62, 71))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumor', 'Disease', (132, 137))	('QD800', 'Chemical', '-', (217, 222))	('QD800', 'Chemical', '-', (62, 67))
341311	24324343	This study demonstrates that QD800-RGD can specifically target and bind to integrin alphavbeta3 expressed in the endothelial cells of tumor angiogenic vessels in vivo, producing clear visual and in situ fluorescence images of HNSCC after the intravenous injection.	('rat', 'Species', '10116', (18, 21))	('QD800', 'Chemical', '-', (29, 34))	('integrin alphavbeta3', 'Gene', (75, 95))	('QD800-RGD', 'Var', (29, 38))	('bind', 'Interaction', (67, 71))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('integrin alphavbeta3', 'Gene', '3685', (75, 95))	('HNSCC', 'Phenotype', 'HP:0012288', (226, 231))	('tumor', 'Disease', (134, 139))
341323	31031810	Through this discovery, a mutation in LDLR in FH patient's fibroblast cells was observed where it lacked high-affinity sites when compared to the normal cultured fibroblast cells.	('mutation', 'Var', (26, 34))	('LDLR', 'Gene', (38, 42))	('lacked', 'NegReg', (98, 104))	('FH', 'Gene', '3949', (46, 48))	('high-affinity sites', 'MPA', (105, 124))	('Thr', 'Chemical', 'MESH:D013912', (0, 3))	('LDLR', 'Gene', '3949', (38, 42))	('patient', 'Species', '9606', (49, 56))
341324	31031810	Approximately, one in 500 patients has this mutation and, to date, nearly 900 LDLR mutations were associated with FH.	('mutations', 'Var', (83, 92))	('LDLR', 'Gene', '3949', (78, 82))	('FH', 'Gene', '3949', (114, 116))	('patients', 'Species', '9606', (26, 34))	('associated', 'Reg', (98, 108))	('LDLR', 'Gene', (78, 82))
341336	31031810	On the contrary, LDL-B contains four-amino-acid sequence of Tyr-Trp-Thr-Asp (YWTD).	('Tyr-Trp-Thr-Asp', 'Var', (60, 75))	('LDL-B', 'Gene', (17, 22))	('Trp', 'Chemical', 'MESH:D014364', (64, 67))	('LDL-B', 'Gene', '9382', (17, 22))	('Thr', 'Chemical', 'MESH:D013912', (68, 71))	('Tyr', 'Chemical', 'MESH:D014443', (60, 63))	('Asp', 'Chemical', 'MESH:D001224', (72, 75))
341344	31031810	In addition, mutations of this protein were shown to cause defects in synthesis, transport, binding, internalisation, and recycling of LDLR proteins.	('binding', 'Interaction', (92, 99))	('LDLR', 'Gene', '3949', (135, 139))	('internalisation', 'MPA', (101, 116))	('transport', 'MPA', (81, 90))	('recycling', 'MPA', (122, 131))	('synthesis', 'MPA', (70, 79))	('LDLR', 'Gene', (135, 139))	('defects', 'NegReg', (59, 66))	('mutations', 'Var', (13, 22))
341363	31031810	The mutation of LRP5 has been said to be associated with osteoporosis and the change in bone mass syndrome.	('osteoporosis', 'Disease', (57, 69))	('change', 'Reg', (78, 84))	('bone mass syndrome', 'Disease', 'MESH:D001847', (88, 106))	('associated', 'Reg', (41, 51))	('bone mass syndrome', 'Disease', (88, 106))	('osteoporosis', 'Phenotype', 'HP:0000939', (57, 69))	('mutation', 'Var', (4, 12))	('LRP5', 'Gene', (16, 20))	('osteoporosis', 'Disease', 'MESH:D010024', (57, 69))
341368	31031810	The presence of LRP5 has also been linked significantly with tumor metastasis such as chondroblastic subtype of OS.	('chondroblastic subtype of OS', 'Disease', (86, 114))	('linked', 'Reg', (35, 41))	('OS', 'Phenotype', 'HP:0002669', (112, 114))	('LRP5', 'Gene', (16, 20))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('presence', 'Var', (4, 12))	('tumor', 'Disease', (61, 66))
341372	31031810	In a separate study, the decreased cell invasion and motility were observed in OS cell lines where dominant-negative LRP5 and Dickkopf-3 (Dkk-3) were found to be mutated.	('Dkk-3', 'Gene', (138, 143))	('mutated', 'Var', (162, 169))	('decreased', 'NegReg', (25, 34))	('Dickkopf-3', 'Gene', (126, 136))	('cell invasion', 'CPA', (35, 48))	('LRP5', 'Protein', (117, 121))	('Dkk-3', 'Gene', '27122', (138, 143))	('Dickkopf-3', 'Gene', '27122', (126, 136))	('motility', 'CPA', (53, 61))	('OS', 'Phenotype', 'HP:0002669', (79, 81))
341374	31031810	Interestingly, in contradiction to the above studies, recent study has shown that dominant-negative LRP5 failed to block OS formation, metastatic disease, and even maintenance of Wnt signaling in mice.	('mice', 'Species', '10090', (196, 200))	('metastatic disease', 'CPA', (135, 153))	('OS', 'Phenotype', 'HP:0002669', (121, 123))	('LRP5', 'Gene', (100, 104))	('dominant-negative', 'Var', (82, 99))
341383	31031810	The expression of LRP6 was found to be upregulated in these cancers and altered LRP6 leads to abnormal Wnt protein activation.	('activation', 'PosReg', (115, 125))	('Wnt protein', 'MPA', (103, 114))	('altered', 'Var', (72, 79))	('cancers', 'Phenotype', 'HP:0002664', (60, 67))	('upregulated', 'PosReg', (39, 50))	('cancers', 'Disease', (60, 67))	('cancers', 'Disease', 'MESH:D009369', (60, 67))	('expression', 'MPA', (4, 14))	('LRP6', 'Gene', (18, 22))	('LRP6', 'Gene', (80, 84))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
341388	31031810	Besides, the knockout of LRP6 expression has fundamentally diminished the cell migration and invasion of TNBC MDA-MB-231 and BT549.	('cell migration', 'CPA', (74, 88))	('LRP6', 'Gene', (25, 29))	('BT549', 'CellLine', 'CVCL:1092', (125, 130))	('knockout', 'Var', (13, 21))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (110, 120))	('diminished', 'NegReg', (59, 69))	('invasion', 'CPA', (93, 101))
341389	31031810	In another study, overexpressed LRP6 was also observed in a subpopulation of the human breast cancers suggesting that the Wnt signaling pathway activation by the overexpressed LRP6 was enough to induce the formation of breast cancer.	('induce', 'PosReg', (195, 201))	('Wnt signaling pathway', 'Pathway', (122, 143))	('overexpressed', 'Var', (162, 175))	('breast cancers', 'Phenotype', 'HP:0003002', (87, 101))	('breast cancer', 'Disease', 'MESH:D001943', (219, 232))	('breast cancers', 'Disease', 'MESH:D001943', (87, 101))	('breast cancer', 'Phenotype', 'HP:0003002', (219, 232))	('breast cancers', 'Disease', (87, 101))	('breast cancer', 'Disease', 'MESH:D001943', (87, 100))	('breast cancer', 'Disease', (219, 232))	('LRP6', 'Gene', (176, 180))	('activation', 'PosReg', (144, 154))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('breast cancer', 'Phenotype', 'HP:0003002', (87, 100))	('cancers', 'Phenotype', 'HP:0002664', (94, 101))	('human', 'Species', '9606', (81, 86))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
341390	31031810	LRP6 polymorphisms were validated to play a role in the predisposition of the nonsmall cell lung cancer (NSCLS) in previous study.	('lung cancer', 'Phenotype', 'HP:0100526', (92, 103))	('LRP6', 'Gene', (0, 4))	('NSCL', 'Disease', (105, 109))	('NSCL', 'Disease', 'None', (105, 109))	('nonsmall cell lung cancer', 'Disease', (78, 103))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (81, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('nonsmall cell lung cancer', 'Disease', 'MESH:D002289', (78, 103))	('nonsmall cell lung cancer', 'Phenotype', 'HP:0030358', (78, 103))	('NSCL', 'Phenotype', 'HP:0030358', (105, 109))	('polymorphisms', 'Var', (5, 18))
341391	31031810	These polymorphisms were also found associated with a reduced risk of lung squamous cell carcinoma (SCC) where LRP6 rs6488507 synergistically increased the risk of NSCLS in tobacco smokers in Chinese populations.	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (70, 98))	('increased', 'PosReg', (142, 151))	('rs6488507', 'Mutation', 'rs6488507', (116, 125))	('NSCL', 'Phenotype', 'HP:0030358', (164, 168))	('SCC', 'Phenotype', 'HP:0002860', (100, 103))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (70, 98))	('LRP6', 'Gene', (111, 115))	('NSCL', 'Disease', (164, 168))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (75, 98))	('lung squamous cell carcinoma', 'Disease', (70, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('tobacco', 'Species', '4097', (173, 180))	('rs6488507', 'Var', (116, 125))	('NSCL', 'Disease', 'None', (164, 168))
341394	31031810	From these previous studies, it is evidently showed that mutations in LRP6 have been linked to a wide variety of cancers.	('cancers', 'Disease', 'MESH:D009369', (113, 120))	('cancers', 'Phenotype', 'HP:0002664', (113, 120))	('cancers', 'Disease', (113, 120))	('LRP6', 'Gene', (70, 74))	('mutations', 'Var', (57, 66))	('linked', 'Reg', (85, 91))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
341395	31031810	It also showed its critical role in Wnt signaling pathway which confirmed that the LRP6 variants are related to the risk of cancer and tumor progression.	('cancer', 'Disease', (124, 130))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('LRP6', 'Gene', (83, 87))	('tumor', 'Disease', (135, 140))	('tumor', 'Disease', 'MESH:D009369', (135, 140))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('variants', 'Var', (88, 96))	('cancer', 'Disease', 'MESH:D009369', (124, 130))	('related', 'Reg', (101, 108))
341402	31031810	Previous study has reported that LRP8 might have been associated with Alzheimer's disease when LRP8 gene polymorphism occurred.	("Alzheimer's disease", 'Disease', 'MESH:D000544', (70, 89))	('LRP8', 'Gene', (33, 37))	("Alzheimer's disease", 'Phenotype', 'HP:0002511', (70, 89))	("Alzheimer's disease", 'Disease', (70, 89))	('LRP8', 'Gene', (95, 99))	('polymorphism', 'Var', (105, 117))	('associated', 'Reg', (54, 64))
341408	31031810	In another study, LRP8 was knocked down to investigate the molecular mechanisms in ApoE suppressed metastasis.	('knocked down', 'Var', (27, 39))	('ApoE', 'Gene', '348', (83, 87))	('ApoE', 'Gene', (83, 87))	('metastasis', 'CPA', (99, 109))	('LRP8', 'Gene', (18, 22))	('suppressed', 'NegReg', (88, 98))
341420	29158797	Multivariate analysis showed patients with high PD-L1 expression had significantly shorter disease free survival (DFS, HR 1.411, P = 0.025) and overall survival (OS, HR 1.659, P = 0.004) than those with low PD-L1 expression at a 50% cutoff value.	('patients', 'Species', '9606', (29, 37))	('high', 'Var', (43, 47))	('OS', 'Chemical', '-', (162, 164))	('shorter', 'NegReg', (83, 90))	('disease free survival', 'CPA', (91, 112))	('PD-L1', 'Gene', (48, 53))	('overall survival', 'CPA', (144, 160))
341429	29158797	Immunotherapy with anti-PD-L1 or anti-PD-1 antibodies has successfully shown significant antitumor activities in various cancers including NSCLC.	('cancers', 'Disease', (121, 128))	('NSCLC', 'Phenotype', 'HP:0030358', (139, 144))	('cancers', 'Disease', 'MESH:D009369', (121, 128))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('tumor', 'Disease', (93, 98))	('NSCLC', 'Disease', (139, 144))	('NSCLC', 'Disease', 'MESH:D002289', (139, 144))	('anti-PD-L1', 'Var', (19, 29))	('anti-PD-1', 'Var', (33, 42))	('cancers', 'Phenotype', 'HP:0002664', (121, 128))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
341444	29158797	The cut-offs for serum marker levels were stipulated as follows according to manufacturer's recommendation: CEA 5.0 ng/ml, NSE 15.2 ng/ml, SCCA 1.5 ng/ml, and Cyfra21-1 3.3 ng/ml.	('CEA', 'Gene', '1048', (108, 111))	('CEA', 'Gene', (108, 111))	('NSE', 'Gene', (123, 126))	('NSE', 'Gene', '2026', (123, 126))	('SCCA 1', 'Gene', '6317', (139, 145))	('SCCA 1', 'Gene', (139, 145))	('Cyfra21-1', 'Var', (159, 168))
341445	29158797	EGFR mutations, including EGFR exon 19 deletion (del19) and exon 21 Leu858Arg substitution (L858R), were identified by real-time PCR or DNA sequencing as previously described.	('EGFR', 'Gene', (26, 30))	('L858R', 'Mutation', 'rs121434568', (92, 97))	('EGFR', 'Gene', (0, 4))	('Leu858Arg', 'Chemical', '-', (68, 77))	('del19', 'Mutation', 'c.del19', (49, 54))	('Leu858Arg', 'Var', (68, 77))	('EGFR', 'Gene', '1956', (26, 30))	('EGFR', 'Gene', '1956', (0, 4))
341446	29158797	Other EGFR mutations were not tested for.	('mutations', 'Var', (11, 20))	('EGFR', 'Gene', '1956', (6, 10))	('EGFR', 'Gene', (6, 10))
341459	29158797	The EGFR mutation rate was 17.6% (64/364) among all NSCLC patients, 29.1% (60/206) within adenocarcinoma (Table S1) and 2.5% (4/158) within squamous cell carcinoma cohorts (Table S2), respectively.	('mutation', 'Var', (9, 17))	('NSCLC', 'Phenotype', 'HP:0030358', (52, 57))	('NSCLC', 'Disease', (52, 57))	('EGFR', 'Gene', (4, 8))	('NSCLC', 'Disease', 'MESH:D002289', (52, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('adenocarcinoma', 'Disease', (90, 104))	('adenocarcinoma', 'Disease', 'MESH:D000230', (90, 104))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (140, 163))	('patients', 'Species', '9606', (58, 66))	('carcinoma', 'Phenotype', 'HP:0030731', (154, 163))	('squamous cell carcinoma', 'Disease', (140, 163))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (140, 163))	('EGFR', 'Gene', '1956', (4, 8))
341468	29158797	Univariate analysis showed that patients with high PD-L1 positivity shared significantly shorter DFS (hazard ratio [HR] 1.546, P = 0.004) and OS (HR 1.704, P = 0.002) than those with low PD-L1 expression at a 50% cutoff value (Table 3) (Figure 2), but not at 1%, 5% or 10% (Figure S1).	('high', 'Var', (46, 50))	('patients', 'Species', '9606', (32, 40))	('OS', 'Chemical', '-', (142, 144))	('DFS', 'MPA', (97, 100))	('positivity', 'Var', (57, 67))	('shorter', 'NegReg', (89, 96))	('PD-L1', 'Gene', (51, 56))
341473	29158797	PD-L1 positivity remained a predictor of DFS and OS at the 50% cutoff value.	('PD-L1', 'Gene', (0, 5))	('positivity', 'Var', (6, 16))	('DFS', 'Disease', (41, 44))	('OS', 'Chemical', '-', (49, 51))
341475	29158797	To investigate PD-L1's clinical significance, patients were further divided into subgroups according to histology (adenocarcinoma vs. squamous cell carcinoma), serum SCCA level (<= 1.5 ng/ml vs. > 1.5 ng/ml) and smoking history (SI < 400 vs. SI >= 400).	('patients', 'Species', '9606', (46, 54))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('SI', 'Disease', 'None', (242, 244))	('adenocarcinoma', 'Disease', (115, 129))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (134, 157))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (134, 157))	('squamous cell carcinoma', 'Disease', (134, 157))	('adenocarcinoma', 'Disease', 'MESH:D000230', (115, 129))	('<= 1.5 ng/ml', 'Var', (178, 190))	('serum SCCA level', 'MPA', (160, 176))	('SI', 'Disease', 'None', (229, 231))	('carcinoma', 'Phenotype', 'HP:0030731', (148, 157))
341476	29158797	Univariate analysis showed that PD-L1 expression at a 50% cutoff was associated with significantly short DFS and OS only in patients with squamous cell carcinoma (DFS: HR 2.149, P = 0.001; OS: HR 2.380, P < 0.001) but not adenocarcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (227, 236))	('carcinoma', 'Phenotype', 'HP:0030731', (152, 161))	('DFS', 'MPA', (105, 108))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (138, 161))	('short', 'NegReg', (99, 104))	('PD-L1', 'Gene', (32, 37))	('OS', 'Chemical', '-', (189, 191))	('adenocarcinoma', 'Disease', 'MESH:D000230', (222, 236))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (138, 161))	('squamous cell carcinoma', 'Disease', (138, 161))	('expression', 'Var', (38, 48))	('OS', 'Chemical', '-', (113, 115))	('patients', 'Species', '9606', (124, 132))	('adenocarcinoma', 'Disease', (222, 236))
341478	29158797	Moreover, high PD-L1 expression was also associated with poor survival in patients with moderate/heavy smoking history (SI >= 400, DFS: HR 1.704, P = 0.010; OS: HR 2.028, P = 0.002) (Table 4) (Figure 2).	('PD-L1', 'Gene', (15, 20))	('poor', 'NegReg', (57, 61))	('patients', 'Species', '9606', (74, 82))	('expression', 'MPA', (21, 31))	('high', 'Var', (10, 14))	('SI', 'Disease', 'None', (120, 122))	('OS', 'Chemical', '-', (157, 159))
341481	29158797	Recent studies have investigated PD-L1 protein expression in association with EGFR mutation.	('EGFR', 'Gene', (78, 82))	('PD-L1', 'Gene', (33, 38))	('mutation', 'Var', (83, 91))	('EGFR', 'Gene', '1956', (78, 82))
341482	29158797	However, some reports found that PD-L1 expression was higher in patients with EGFR mutations compared to those with wild-type EGFR, while in other studies the reverse was true.	('mutations', 'Var', (83, 92))	('higher', 'PosReg', (54, 60))	('EGFR', 'Gene', (126, 130))	('patients', 'Species', '9606', (64, 72))	('PD-L1', 'Protein', (33, 38))	('EGFR', 'Gene', '1956', (78, 82))	('expression', 'MPA', (39, 49))	('EGFR', 'Gene', (78, 82))	('EGFR', 'Gene', '1956', (126, 130))
341483	29158797	We found no significant correlation between PD-L1 expression and EGFR mutation status in NSCLC, which was consistent with other groups.	('NSCLC', 'Disease', 'MESH:D002289', (89, 94))	('EGFR', 'Gene', '1956', (65, 69))	('EGFR', 'Gene', (65, 69))	('NSCLC', 'Phenotype', 'HP:0030358', (89, 94))	('mutation', 'Var', (70, 78))	('NSCLC', 'Disease', (89, 94))
341484	29158797	Therefore, more studies are required to verify the association between PD-L1 expression and mutant EGFR status in NSCLC patients.	('EGFR', 'Gene', (99, 103))	('NSCLC', 'Phenotype', 'HP:0030358', (114, 119))	('PD-L1', 'Gene', (71, 76))	('NSCLC', 'Disease', (114, 119))	('patients', 'Species', '9606', (120, 128))	('NSCLC', 'Disease', 'MESH:D002289', (114, 119))	('mutant', 'Var', (92, 98))	('EGFR', 'Gene', '1956', (99, 103))
341490	29158797	Because PD-L1 expression improves likelihood of NSCLC patient response to anti-PD-1/PD-L1 treatment, it is reasonable to hypothesize that moderate/heavy smoking history and high serum SCCA level may also have predictive value to this PD-1/PD-L1 blockade.	('patient', 'Species', '9606', (54, 61))	('expression', 'Var', (14, 24))	('NSCLC', 'Disease', (48, 53))	('PD-L1', 'Gene', (8, 13))	('NSCLC', 'Disease', 'MESH:D002289', (48, 53))	('improves', 'PosReg', (25, 33))	('NSCLC', 'Phenotype', 'HP:0030358', (48, 53))
341609	25340041	Additionally, the vascular injury and ensuing chaotic intratumor environment, such as hypoxic, acidic, and nutritionally deprived environment caused by high-dose fraction SBRT, may significantly hinder the repair of radiation damage.	('hinder', 'NegReg', (195, 201))	('vascular injury', 'Disease', (18, 33))	('tumor', 'Disease', (59, 64))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('hypoxic', 'Disease', (86, 93))	('hypoxic', 'Disease', 'MESH:D000860', (86, 93))	('SBRT', 'Gene', (171, 175))	('vascular injury', 'Disease', 'MESH:D057772', (18, 33))	('radiation damage', 'Disease', (216, 232))	('radiation damage', 'Disease', 'MESH:D004194', (216, 232))	('high-dose fraction', 'Var', (152, 170))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
341614	25340041	Similarly for brainstem, Dmax < 12.5 Gy in a single fraction is predicted to be associated with <5% risk for cranial neuropathy or necrosis.	('cranial neuropathy', 'Phenotype', 'HP:0006824', (109, 127))	('cranial neuropathy', 'Disease', 'MESH:D003389', (109, 127))	('necrosis', 'Disease', (131, 139))	('neuropathy', 'Phenotype', 'HP:0009830', (117, 127))	('cranial neuropathy', 'Disease', (109, 127))	('necrosis', 'Disease', 'MESH:D009336', (131, 139))	('Dmax < 12.5 Gy', 'Var', (25, 39))
341623	25340041	In addition, incorporation of biologically based agents such as EGFR inhibitors, DNA repair inhibitors, or immunomodulation may enhance local-regional effectiveness of SBRT without a significant increase in acute toxicity.	('local-regional effectiveness', 'CPA', (136, 164))	('toxicity', 'Disease', 'MESH:D064420', (213, 221))	('toxicity', 'Disease', (213, 221))	('enhance', 'PosReg', (128, 135))	('inhibitors', 'Var', (69, 79))	('EGFR', 'Gene', (64, 68))	('DNA repair', 'Gene', (81, 91))
341630	31434692	The in vitro studies indicated that knockdown of LINC00511 inhibited cervical cancer cell proliferation, migration, and invasion.	('inhibited', 'NegReg', (59, 68))	('invasion', 'CPA', (120, 128))	('knockdown', 'Var', (36, 45))	('LINC00511', 'Gene', (49, 58))	('cervical cancer', 'Disease', 'MESH:D002583', (69, 84))	('migration', 'CPA', (105, 114))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('cervical cancer', 'Disease', (69, 84))	('LINC00511', 'Gene', '400619', (49, 58))
341663	31434692	As shown in Table 1, we observed that high LINC00511 expression was correlated with advanced clinical stage, large tumor size, histological type of adenocarcinoma, and present lymph node metastasis and distant metastasis in cervical cancer patients.	('LINC00511', 'Gene', (43, 52))	('lymph node metastasis', 'CPA', (176, 197))	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('clinical', 'Species', '191496', (93, 101))	('carcinoma', 'Phenotype', 'HP:0030731', (153, 162))	('LINC00511', 'Gene', '400619', (43, 52))	('tumor', 'Disease', (115, 120))	('high', 'Var', (38, 42))	('type of adenocarcinoma', 'Disease', (140, 162))	('patients', 'Species', '9606', (240, 248))	('distant metastasis', 'CPA', (202, 220))	('cervical cancer', 'Disease', (224, 239))	('correlated', 'Reg', (68, 78))	('cervical cancer', 'Disease', 'MESH:D002583', (224, 239))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('type of adenocarcinoma', 'Disease', 'MESH:D000230', (140, 162))	('expression', 'MPA', (53, 63))
341666	31434692	We analyzed the relationship between LINC00511 expression and overall survival of cervical cancer patients, and found patients in high LINC00511 expression group had obviously short overall survival compared with those in low LINC00511 expression group (Figure 2).	('LINC00511', 'Gene', (226, 235))	('LINC00511', 'Gene', '400619', (135, 144))	('high', 'Var', (130, 134))	('LINC00511', 'Gene', '400619', (37, 46))	('cervical cancer', 'Disease', (82, 97))	('patients', 'Species', '9606', (98, 106))	('LINC00511', 'Gene', '400619', (226, 235))	('short', 'NegReg', (176, 181))	('cervical cancer', 'Disease', 'MESH:D002583', (82, 97))	('LINC00511', 'Gene', (135, 144))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('LINC00511', 'Gene', (37, 46))	('overall survival', 'MPA', (182, 198))	('patients', 'Species', '9606', (118, 126))
341668	31434692	Meanwhile, high LINC00511 expression was showed to be an independent poor prognostic factor in multivariate Cox regression model (Table 2).	('expression', 'MPA', (26, 36))	('Cox', 'Gene', '1351', (108, 111))	('LINC00511', 'Gene', '400619', (16, 25))	('Cox', 'Gene', (108, 111))	('high', 'Var', (11, 15))	('LINC00511', 'Gene', (16, 25))
341672	31434692	The results of CCK-8 suggested knockdown of LINC00511 obviously suppressed cell proliferation ability of HeLa and C33A cells (Figure 3B).	('suppressed', 'NegReg', (64, 74))	('LINC00511', 'Gene', (44, 53))	('LINC00511', 'Gene', '400619', (44, 53))	('knockdown', 'Var', (31, 40))
341673	31434692	Moreover, cell migration and invasion assays revealed knockdown of LINC00511 also markedly inhibited cell migration and invasion abilities of HeLa and C33A cells (Figure 3C,D).	('LINC00511', 'Gene', '400619', (67, 76))	('inhibited', 'NegReg', (91, 100))	('LINC00511', 'Gene', (67, 76))	('knockdown', 'Var', (54, 63))
341690	31434692	congruously showed breast cancer patients with high-expression of LINC00511 had poorer overall survival than patients with low-expression of LINC00511.	('breast cancer', 'Phenotype', 'HP:0003002', (19, 32))	('patients', 'Species', '9606', (33, 41))	('patients', 'Species', '9606', (109, 117))	('LINC00511', 'Gene', (141, 150))	('LINC00511', 'Gene', (66, 75))	('poorer', 'NegReg', (80, 86))	('high-expression', 'Var', (47, 62))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('breast cancer', 'Disease', 'MESH:D001943', (19, 32))	('LINC00511', 'Gene', '400619', (66, 75))	('breast cancer', 'Disease', (19, 32))	('overall survival', 'MPA', (87, 103))	('LINC00511', 'Gene', '400619', (141, 150))
341691	31434692	demonstrated that high LINC00511 expression predicted poor progression-free survival and overall survival, and served as independent prognostic indicator for overall survival of pancreatic ductal adenocarcinoma patients.	('patients', 'Species', '9606', (211, 219))	('carcinoma', 'Phenotype', 'HP:0030731', (201, 210))	('progression-free survival', 'CPA', (59, 84))	('poor', 'NegReg', (54, 58))	('LINC00511', 'Gene', '400619', (23, 32))	('pancreatic ductal adenocarcinoma', 'Disease', (178, 210))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (178, 210))	('high', 'Var', (18, 22))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (178, 210))	('overall survival', 'CPA', (89, 105))	('LINC00511', 'Gene', (23, 32))
341696	31434692	We found knockdown of LINC00511 markedly inhibited cervical cancer cell proliferation, migration and invasion.	('knockdown', 'Var', (9, 18))	('LINC00511', 'Gene', '400619', (22, 31))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('inhibited', 'NegReg', (41, 50))	('cervical cancer', 'Disease', (51, 66))	('cervical cancer', 'Disease', 'MESH:D002583', (51, 66))	('LINC00511', 'Gene', (22, 31))	('invasion', 'CPA', (101, 109))
341711	28903408	Derlin-1 depletion inhibited cell growth while its overexpression facilitated cell growth.	('inhibited', 'NegReg', (19, 28))	('cell growth', 'CPA', (29, 40))	('cell growth', 'CPA', (78, 89))	('Derlin-1', 'Gene', (0, 8))	('facilitated', 'PosReg', (66, 77))	('Derlin-1', 'Gene', '79139', (0, 8))	('depletion', 'Var', (9, 18))
341715	28903408	Blockage of AKT signaling attenuated the role of Derlin-1 on radioresistance.	('radioresistance', 'CPA', (61, 76))	('Blockage', 'Var', (0, 8))	('AKT', 'Gene', '207', (12, 15))	('AKT', 'Gene', (12, 15))	('attenuated', 'NegReg', (26, 36))	('Derlin-1', 'Gene', (49, 57))	('Derlin-1', 'Gene', '79139', (49, 57))
341730	28903408	There was one report identifying microRNA-181d as a tumor suppressor in human esophageal squamous cell carcinoma by downregulating Derlin-1.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('esophageal squamous cell carcinoma', 'Disease', (78, 112))	('Derlin-1', 'Gene', (131, 139))	('tumor', 'Disease', (52, 57))	('Derlin-1', 'Gene', '79139', (131, 139))	('human', 'Species', '9606', (72, 77))	('microRNA-181d', 'Var', (33, 46))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (89, 112))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (78, 112))	('downregulating', 'NegReg', (116, 130))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))
341741	28903408	We found that patients with a high expression of Derlin-1 tended to have a advanced TNM stage and T stage than other patients (Table 1).	('TNM', 'Gene', (84, 87))	('advanced', 'PosReg', (75, 83))	('T stage', 'CPA', (98, 105))	('high expression', 'Var', (30, 45))	('TNM', 'Gene', '10178', (84, 87))	('patients', 'Species', '9606', (117, 125))	('patients', 'Species', '9606', (14, 22))	('Derlin-1', 'Gene', (49, 57))	('Derlin-1', 'Gene', '79139', (49, 57))
341746	28903408	The patients with a high Derlin-1 expression exhibited a significantly lower overall survival (p = 0.0003, Log-Rank test).	('expression', 'MPA', (34, 44))	('high', 'Var', (20, 24))	('overall survival', 'MPA', (77, 93))	('patients', 'Species', '9606', (4, 12))	('Derlin-1', 'Gene', (25, 33))	('Derlin-1', 'Gene', '79139', (25, 33))	('lower', 'NegReg', (71, 76))
341751	28903408	As shown in Table 3 and Table 4, high Derlin-1 status serves as independent risk factors for postoperative survival in the both groups.	('high', 'Var', (33, 37))	('postoperative survival', 'CPA', (93, 115))	('Derlin-1', 'Gene', (38, 46))	('Derlin-1', 'Gene', '79139', (38, 46))
341756	28903408	The effect of siRNA knockdown was confirmed in TE-1 cells (Figure 2B).	('knockdown', 'Var', (20, 29))	('siRNA', 'Gene', (14, 19))	('TE-1', 'CellLine', 'CVCL:1759', (47, 51))
341757	28903408	CCK-8 demonstrated that Derlin-1 transfection facilitated cell proliferation while its siRNA blocked proliferation (Figure 3A).	('blocked', 'NegReg', (93, 100))	('transfection', 'Var', (33, 45))	('facilitated', 'PosReg', (46, 57))	('cell proliferation', 'CPA', (58, 76))	('Derlin-1', 'Gene', (24, 32))	('Derlin-1', 'Gene', '79139', (24, 32))
341766	28903408	Derlin-1 depletion dramatically reduced the proportion of apoptotic TE-1 cells induced by radiation (Figure 4A).	('reduced', 'NegReg', (32, 39))	('Derlin-1', 'Gene', (0, 8))	('Derlin-1', 'Gene', '79139', (0, 8))	('TE-1', 'CellLine', 'CVCL:1759', (68, 72))	('depletion', 'Var', (9, 18))
341767	28903408	Consistent with previous results, Derlin-1 depletion induced significant upregulation in cleaved caspase3 in TE-1 cells treated with 4 Gy IR.	('depletion', 'Var', (43, 52))	('caspase3', 'Gene', (97, 105))	('caspase3', 'Gene', '836', (97, 105))	('Derlin-1', 'Gene', (34, 42))	('TE-1', 'CellLine', 'CVCL:1759', (109, 113))	('Derlin-1', 'Gene', '79139', (34, 42))	('upregulation', 'PosReg', (73, 85))
341771	28903408	In addition, Derlin-1 overexpression also upregulated p-PI3K p85, p-GSK3beta and p -ERK.	('p85', 'Gene', (61, 64))	('ERK', 'Gene', '5594', (84, 87))	('overexpression', 'PosReg', (22, 36))	('p-GSK3beta', 'Var', (66, 76))	('ERK', 'Gene', (84, 87))	('Derlin-1', 'Gene', (13, 21))	('p-PI3K', 'Protein', (54, 60))	('Derlin-1', 'Gene', '79139', (13, 21))	('upregulated', 'PosReg', (42, 53))	('p85', 'Gene', '5296', (61, 64))
341778	28903408	Cells transfected with either Derlin-1 plasmid or siRNA were treated with LY294005 (5 mumol/L).	('Derlin-1', 'Gene', '79139', (30, 38))	('LY294005', 'Chemical', 'MESH:C477931', (74, 82))	('LY294005', 'Var', (74, 82))	('Derlin-1', 'Gene', (30, 38))
341779	28903408	LY294002 effectively blocked AKT phosphorylation in both cell lines.	('LY294002', 'Var', (0, 8))	('AKT', 'Gene', '207', (29, 32))	('LY294002', 'Chemical', 'MESH:C085911', (0, 8))	('blocked', 'NegReg', (21, 28))	('AKT', 'Gene', (29, 32))
341780	28903408	CCK-8 assay demonstrated that LY294002 dramatically reduced the effect of Derlin-1 on cell viability (Figure 5A).	('reduced', 'NegReg', (52, 59))	('Derlin-1', 'Gene', (74, 82))	('cell viability', 'CPA', (86, 100))	('LY294002', 'Chemical', 'MESH:C085911', (30, 38))	('effect', 'MPA', (64, 70))	('Derlin-1', 'Gene', '79139', (74, 82))	('LY294002', 'Var', (30, 38))
341781	28903408	Annexin V/PI staining showed that LY294002 treatment significantly upregulated the percentage of apoptosis.	('LY294002', 'Var', (34, 42))	('Annexin V', 'Gene', '308', (0, 9))	('Annexin V', 'Gene', (0, 9))	('LY294002', 'Chemical', 'MESH:C085911', (34, 42))	('upregulated', 'PosReg', (67, 78))
341782	28903408	In LY294002 treated Eca-109 cells, the effect of Derlin-1 was not significant as that in untreated group.	('LY294002 treated', 'Var', (3, 19))	('Derlin-1', 'Gene', (49, 57))	('LY294002', 'Chemical', 'MESH:C085911', (3, 11))	('Derlin-1', 'Gene', '79139', (49, 57))
341784	28903408	Next, we examined the effect of LY294002 on caspase3 cleavage and Bcl-2.	('cleavage', 'MPA', (53, 61))	('Bcl-2', 'Gene', (66, 71))	('Bcl-2', 'Gene', '596', (66, 71))	('caspase3', 'Gene', (44, 52))	('LY294002', 'Var', (32, 40))	('caspase3', 'Gene', '836', (44, 52))	('LY294002', 'Chemical', 'MESH:C085911', (32, 40))
341813	28903408	PI3K functions upstream of AKT and was composed of a catalytic subunit (p110) and a regulatory subunit.	('PI3K', 'Var', (0, 4))	('AKT', 'Gene', (27, 30))	('p110', 'Gene', (72, 76))	('p110', 'Gene', '100616443', (72, 76))	('AKT', 'Gene', '207', (27, 30))
341815	28903408	Moreover, LY294002, an AKT inhibitor, blocked the effects of Derlin-1 on Bcl-2 and IR resistance, indicating that PI3K/AKT/Bcl-2 signaling mediated the biological effects of Derlin-1.	('Bcl-2', 'Gene', (123, 128))	('Derlin-1', 'Gene', '79139', (174, 182))	('LY294002', 'Var', (10, 18))	('Bcl-2', 'Gene', (73, 78))	('AKT', 'Gene', '207', (23, 26))	('Bcl-2', 'Gene', '596', (73, 78))	('AKT', 'Gene', '207', (119, 122))	('Derlin-1', 'Gene', (174, 182))	('Derlin-1', 'Gene', (61, 69))	('LY294002', 'Chemical', 'MESH:C085911', (10, 18))	('Derlin-1', 'Gene', '79139', (61, 69))	('AKT', 'Gene', (23, 26))	('IR resistance', 'MPA', (83, 96))	('AKT', 'Gene', (119, 122))	('blocked', 'NegReg', (38, 45))	('Bcl-2', 'Gene', '596', (123, 128))
341817	28903408	Inhibition of the PI3K/AKT pathway could also induce mitotic catastrophe.	('AKT', 'Gene', '207', (23, 26))	('Inhibition', 'Var', (0, 10))	('AKT', 'Gene', (23, 26))	('induce', 'Reg', (46, 52))	('mitotic catastrophe', 'CPA', (53, 72))
341822	28903408	High Derlin-1 status might be a predictor of cancer aggressiveness and serve as an independent prognostic factor for ESCC patients with chemoradiotherapy.	('aggressiveness', 'Phenotype', 'HP:0000718', (52, 66))	('High', 'Var', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('Derlin-1', 'Gene', (5, 13))	('cancer aggressiveness', 'Disease', (45, 66))	('Derlin-1', 'Gene', '79139', (5, 13))	('patients', 'Species', '9606', (122, 130))	('cancer aggressiveness', 'Disease', 'MESH:D009369', (45, 66))	('ESCC', 'Disease', (117, 121))	('predictor', 'Reg', (32, 41))
341864	26681983	Additionally, intratumoral injection of the STAT3 decoy has been shown to inhibit STAT3 signaling in HNSCC tumors in humans.	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('STAT3 signaling', 'MPA', (82, 97))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('HNSCC tumors', 'Disease', 'MESH:D000077195', (101, 113))	('HNSCC', 'Phenotype', 'HP:0012288', (101, 106))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('inhibit', 'NegReg', (74, 81))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('STAT3 decoy', 'Var', (44, 55))	('SCC', 'Phenotype', 'HP:0002860', (103, 106))	('tumor', 'Disease', (19, 24))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('humans', 'Species', '9606', (117, 123))	('HNSCC tumors', 'Disease', (101, 113))
341901	26681983	For assessment of STAT3 downstream target gene knockdown (N=8 mice per group), UTMD treatment was performed when tumors reached 60-100 mm3, and mice were euthanized and tumors harvested 24 hours after treatment.	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('tumors', 'Disease', (113, 119))	('mice', 'Species', '10090', (144, 148))	('mice', 'Species', '10090', (62, 66))	('tumors', 'Disease', 'MESH:D009369', (169, 175))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('knockdown', 'Var', (47, 56))	('tumors', 'Phenotype', 'HP:0002664', (169, 175))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('tumors', 'Disease', (169, 175))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
341908	26681983	Tumors were homogenized in buffer containing 10 mM Tris, 5 mM EDTA, 50 mM NaCl, 30 mM Na4P2O7, 1 mM Na3VO4, 1% triton x-100, pH 7.6 supplemented with 1 Complete Mini Tablet (Roche Applied Science, Penzberg, Germany) per 10 ml.	('triton x-100', 'Chemical', 'MESH:D017830', (111, 123))	('Tris', 'Chemical', '-', (51, 55))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('NaCl', 'Chemical', 'MESH:D012965', (74, 78))	('EDTA', 'Chemical', 'MESH:D004492', (62, 66))	('Tumors', 'Disease', (0, 6))	('Na4P2O7', 'Var', (86, 93))	('Na4P2O7', 'Chemical', 'MESH:C107241', (86, 93))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('Na3VO4', 'Chemical', '-', (100, 106))
341923	26681983	Western blot analysis 24 hours after treatment on tumors from 8 animals per group indicated that relative to mutant decoy MB + UTMD treatment, Bcl-xL and cyclin D1 expression were reduced by 34 +- 8% and 39 +-10%, respectively, in tumors after STAT3 decoy MB + UTMD treatment (Fig.	('tumors', 'Disease', 'MESH:D009369', (231, 237))	('tumors', 'Phenotype', 'HP:0002664', (231, 237))	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('Bcl-xL', 'MPA', (143, 149))	('reduced', 'NegReg', (180, 187))	('cyclin D1 expression', 'MPA', (154, 174))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('mutant', 'Var', (109, 115))	('tumors', 'Disease', (50, 56))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('tumors', 'Disease', (231, 237))
341924	26681983	Representative 3D reconstructions of tumor volumes indicate that tumor growth was inhibited after STAT3 decoy MB + UTMD treatment compared to mutant decoy MB + UTMD treatment (Fig.	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('tumor', 'Disease', (65, 70))	('inhibited', 'NegReg', (82, 91))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('STAT3 decoy MB', 'Var', (98, 112))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
341926	26681983	6B), tumor doubling time was significantly prolonged after STAT3 decoy MB + UTMD treatment (4.6 +- 1.6 days) compared to control groups receiving STAT3 decoy only (2.5 +- 0.8 days), saline only (2.7 +- 0.5 days), or mutant decoy MB + UTMD treatment (2.9 +- 0.8 days).	('saline', 'Chemical', 'MESH:D012965', (182, 188))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('STAT3 decoy MB', 'Var', (59, 73))	('tumor', 'Disease', (5, 10))	('prolonged', 'PosReg', (43, 52))
341929	26681983	Tumor volumes in mice receiving STAT3 decoy MB + UTMD treatment were 31-51% smaller than mutant decoy MB + UTMD treatment at 4, 7, and 10 days after the first treatment.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('mice', 'Species', '10090', (17, 21))	('STAT3', 'Var', (32, 37))	('smaller', 'NegReg', (76, 83))	('Tumor volumes', 'CPA', (0, 13))
341932	26681983	The main finding of this study is that in the presence of ultrasound directed at a murine squamous cell carcinoma, MBs carrying STAT3 decoy significantly inhibited tumor growth compared to control treatment groups.	('tumor', 'Disease', (164, 169))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (90, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('squamous cell carcinoma', 'Disease', (90, 113))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (90, 113))	('inhibited', 'NegReg', (154, 163))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('MBs', 'Var', (115, 118))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('murine', 'Species', '10090', (83, 89))
341933	26681983	There were no statistically significant differences in tumor growth among the control groups that received saline infusion only, STAT3 decoy infusion only, or mutant decoy MB + UTMD.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('saline', 'Chemical', 'MESH:D012965', (107, 113))	('tumor', 'Disease', (55, 60))	('mutant decoy MB', 'Var', (159, 174))
341934	26681983	Importantly, we found preferential intratumoral accumulation of STAT3 decoy compared to that seen when an equivalent amount of unbound decoy was intravenously delivered, or was bound to MBs but not insonified.	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('STAT3 decoy', 'Var', (64, 75))	('bound', 'Interaction', (177, 182))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('preferential', 'PosReg', (22, 34))
341938	26681983	However, attachment of the STAT3 decoy to microbubbles provided further protection against nuclease attack and may reduce the required dose for therapeutic effect while enhancing concentration in the tumor(s).	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('attachment', 'Var', (9, 19))	('required dose for therapeutic effect', 'MPA', (126, 162))	('tumor', 'Disease', (200, 205))	('concentration in', 'MPA', (179, 195))	('enhancing', 'PosReg', (169, 178))	('reduce', 'NegReg', (115, 121))
341943	26681983	Specifically, STAT3 target genes Bcl-xL and cyclin D1 expression were reduced by about 1/3 upon treatment (when compared to mutant decoy MB + UTMD) and it took about twice as long for tumors to double (when compared to i.v.	('Bcl-xL', 'Gene', (33, 39))	('expression', 'MPA', (54, 64))	('reduced', 'NegReg', (70, 77))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('mutant', 'Var', (124, 130))	('tumors', 'Disease', (184, 190))	('tumors', 'Disease', 'MESH:D009369', (184, 190))	('tumors', 'Phenotype', 'HP:0002664', (184, 190))	('cyclin D1', 'Gene', (44, 53))
341947	26681983	Delivery of a Bcl-xL antisense oligonucleotide to carboplatin-resistant squamous cell carcinomas resulted in inhibition of cell growth with carboplatin treatment.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (72, 95))	('carboplatin', 'Chemical', 'MESH:D016190', (140, 151))	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('carcinomas', 'Phenotype', 'HP:0030731', (86, 96))	('oligonucleotide', 'Chemical', 'MESH:D009841', (31, 46))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (72, 96))	('squamous cell carcinomas', 'Disease', (72, 96))	('inhibition', 'NegReg', (109, 119))	('cell growth', 'CPA', (123, 134))	('antisense oligonucleotide', 'Var', (21, 46))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (72, 96))	('carboplatin', 'Chemical', 'MESH:D016190', (50, 61))
341948	26681983	Inhibition of cyclin D1 with shRNA reduced the cisplatin dose required to induce squamous cell carcinoma death.	('cyclin D1', 'Protein', (14, 23))	('squamous cell carcinoma death', 'Disease', (81, 110))	('squamous cell carcinoma death', 'Disease', 'MESH:D002294', (81, 110))	('reduced', 'NegReg', (35, 42))	('cisplatin', 'MPA', (47, 56))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('cisplatin', 'Chemical', 'MESH:D002945', (47, 56))	('Inhibition', 'Var', (0, 10))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (81, 104))
342143	24418859	P16 positivity was observed in 4 of 37 (11%) SCs including 3 of 11 (27%) SCs of the oropharynx and 1 of 26 (4%) SCs of nonoropharyngeal sites.	('SCs', 'Disease', (45, 48))	('SC', 'Phenotype', 'HP:0100242', (73, 75))	('observed', 'Reg', (19, 27))	('P16', 'Gene', (0, 3))	('positivity', 'Var', (4, 14))	('SC', 'Phenotype', 'HP:0100242', (112, 114))	('P16', 'Gene', '1029', (0, 3))	('SC', 'Phenotype', 'HP:0100242', (45, 47))
342252	28472511	gene clustering analysis, cancer genome mutation analysis or pull-down assays in protein complex analyses, etc.	('cancer', 'Disease', (26, 32))	('mutation', 'Var', (40, 48))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (26, 32))
342410	31576252	And in a related genomic study of Hodgkin's lymphoma, HCG9 was recognized to be associated with genetic variation.	('lymphoma', 'Phenotype', 'HP:0002665', (44, 52))	('genetic variation', 'Var', (96, 113))	("Hodgkin's lymphoma", 'Disease', 'MESH:D006689', (34, 52))	("Hodgkin's lymphoma", 'Disease', (34, 52))	('associated', 'Reg', (80, 90))	('HCG9', 'Gene', (54, 58))	("Hodgkin's lymphoma", 'Phenotype', 'HP:0012189', (34, 52))	('HCG9', 'Gene', '10255', (54, 58))
342414	31576252	After reviewing the relevant literature, we found that LNIC00261 plays a non-negligible role in the development and prognosis of cancer similarly.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('LNIC00261', 'Var', (55, 64))	('LNIC00261', 'Chemical', 'None', (55, 64))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))
342417	31576252	AC022148.1 and C5orf17 are two newly discovered lncRNAs associated with LUSC prognosis in this study and no scholars have studied their role and mechanism in cancers.	('C5orf17', 'Gene', (15, 22))	('LUSC', 'Disease', 'MESH:D002294', (72, 76))	('LUSC', 'Disease', (72, 76))	('C5orf17', 'Gene', '439936', (15, 22))	('cancers', 'Phenotype', 'HP:0002664', (158, 165))	('LUSC', 'Phenotype', 'HP:0030359', (72, 76))	('associated', 'Reg', (56, 66))	('AC022148.1', 'Var', (0, 10))	('cancers', 'Disease', (158, 165))	('cancers', 'Disease', 'MESH:D009369', (158, 165))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
342431	31576252	Based on a number of previous studies, the expression of FGF9 showed carcinogenicity in human tumors.	('FGF9', 'Gene', '2254', (57, 61))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('expression', 'Var', (43, 53))	('carcinogenicity', 'CPA', (69, 84))	('tumors', 'Disease', (94, 100))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('FGF9', 'Gene', (57, 61))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('human', 'Species', '9606', (88, 93))
342441	29560133	Cumulative meta-analysis and trial sequential analysis of correlation between hOGG1 Ser326Cys polymorphism and the risk of head and neck squamous cell carcinoma The human 8-oxoguanine glycosylase 1 (hOGG1) Ser326Cys polymorphism has been involved in the risk of head and neck squamous cell carcinoma (HNSCC), but the results of published studies on this topic still inconsistent.	('neck squamous cell carcinoma', 'Disease', (271, 299))	('hOGG1', 'Gene', (78, 83))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (123, 160))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (271, 299))	('involved', 'Reg', (238, 246))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (276, 299))	('carcinoma', 'Phenotype', 'HP:0030731', (151, 160))	('Ser326Cys', 'Var', (206, 215))	('Ser326Cys', 'SUBSTITUTION', 'None', (206, 215))	('human', 'Species', '9606', (165, 170))	('Ser326Cys', 'Var', (84, 93))	('Ser326Cys', 'SUBSTITUTION', 'None', (84, 93))	('neck squamous cell carcinoma', 'Disease', (132, 160))	('HNSCC', 'Phenotype', 'HP:0012288', (301, 306))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (132, 160))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (262, 299))	('hOGG1', 'Gene', '4968', (199, 204))	('hOGG1', 'Gene', (199, 204))	('hOGG1', 'Gene', '4968', (78, 83))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (137, 160))	('carcinoma', 'Phenotype', 'HP:0030731', (290, 299))
342445	29560133	Our meta-analysis results indicated that hOGG1 Ser326Cys polymorphism may be associated with increased risk of HNSCC, especially in Caucasians, alcohol drinkers and the patients with laryngeal squamous cell carcinoma.	('alcohol drinkers', 'Phenotype', 'HP:0030955', (144, 160))	('laryngeal squamous cell carcinoma', 'Disease', 'MESH:D002294', (183, 216))	('patients', 'Species', '9606', (169, 177))	('HNSCC', 'Phenotype', 'HP:0012288', (111, 116))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (193, 216))	('HNSCC', 'Disease', (111, 116))	('hOGG1', 'Gene', '4968', (41, 46))	('Ser326Cys', 'Var', (47, 56))	('carcinoma', 'Phenotype', 'HP:0030731', (207, 216))	('alcohol', 'Chemical', 'MESH:D000438', (144, 151))	('laryngeal squamous cell carcinoma', 'Disease', (183, 216))	('Ser326Cys', 'SUBSTITUTION', 'None', (47, 56))	('hOGG1', 'Gene', (41, 46))
342452	29560133	Base excision repair (BER), which is an important DNA repair pathway, plays a vital role in the repair of mutations generated by reactive oxygen species (ROS).	('reactive oxygen species', 'MPA', (129, 152))	('ROS', 'Chemical', 'MESH:D017382', (154, 157))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (129, 152))	('mutations', 'Var', (106, 115))
342453	29560133	The 8-hydroxy-2 deoxyguanine (8-OH-dG) is one of the most abundant oxidative products of high mutagenesis among numerous factors of oxidative DNA damage, because it has the tendency to mispair with adenine during DNA replication and finally result in GC to TA mutation.	('mispair', 'Var', (185, 192))	('8-OH-dG', 'Chemical', 'MESH:C067134', (30, 37))	('adenine', 'Chemical', 'MESH:D000225', (198, 205))	('result in', 'Reg', (241, 250))	('8-hydroxy-2 deoxyguanine', 'Chemical', '-', (4, 28))
342456	29560133	It has been hypothesized that the polymorphism in hOGG1 gene may affect the risk of developing HNSCC because of the critical roles in stabilizing genome integrity.	('affect', 'Reg', (65, 71))	('polymorphism', 'Var', (34, 46))	('hOGG1', 'Gene', (50, 55))	('hOGG1', 'Gene', '4968', (50, 55))	('HNSCC', 'Phenotype', 'HP:0012288', (95, 100))
342457	29560133	The hOGG1 gene has a G1245C polymorphism in exon 7 making the codon 326 coding Ser or Cys (rs1052133), and Cys326 has lower ability to prevent mutagenesis by 8-OH-dG than Ser326 in human cells in vivo.	('human', 'Species', '9606', (181, 186))	('G1245C', 'Var', (21, 27))	('prevent mutagenesis', 'MPA', (135, 154))	('Cys', 'Chemical', 'MESH:D003545', (86, 89))	('Ser', 'Chemical', 'MESH:D012694', (79, 82))	('8-OH-dG', 'Chemical', 'MESH:C067134', (158, 165))	('hOGG1', 'Gene', (4, 9))	('rs1052133', 'Var', (91, 100))	('Cys326', 'Chemical', '-', (107, 113))	('G1245C', 'Mutation', 'c.1245G>C', (21, 27))	('Cys326', 'Var', (107, 113))	('rs1052133', 'Mutation', 'rs1052133', (91, 100))	('lower', 'NegReg', (118, 123))	('Ser326', 'Chemical', '-', (171, 177))	('hOGG1', 'Gene', '4968', (4, 9))	('Ser', 'Chemical', 'MESH:D012694', (171, 174))	('Cys', 'Chemical', 'MESH:D003545', (107, 110))
342458	29560133	Many studies have suggested that this mutation may be associated with increased risk of several cancers.	('cancers', 'Phenotype', 'HP:0002664', (96, 103))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('mutation', 'Var', (38, 46))	('cancers', 'Disease', 'MESH:D009369', (96, 103))	('cancers', 'Disease', (96, 103))	('associated', 'Reg', (54, 64))
342459	29560133	Several of them have focused on the association of hOGG1 Ser326Cys polymorphism with head and neck cancer risk.	('head and neck cancer', 'Phenotype', 'HP:0012288', (85, 105))	('hOGG1', 'Gene', '4968', (51, 56))	('Ser326Cys', 'Var', (57, 66))	('Ser326Cys', 'SUBSTITUTION', 'None', (57, 66))	('association', 'Interaction', (36, 47))	('hOGG1', 'Gene', (51, 56))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('neck cancer', 'Disease', 'MESH:D006258', (94, 105))	('neck cancer', 'Disease', (94, 105))
342460	29560133	However, we observe that the results of the association between hOGG1 Ser326Cys polymorphism and HNSCC susceptibility remain controversial.	('hOGG1', 'Gene', '4968', (64, 69))	('Ser326Cys', 'Var', (70, 79))	('HNSCC', 'Phenotype', 'HP:0012288', (97, 102))	('Ser326Cys', 'SUBSTITUTION', 'None', (70, 79))	('HNSCC', 'Disease', (97, 102))	('hOGG1', 'Gene', (64, 69))
342461	29560133	In 2011, Wei et al performed a meta-analysis based on 6 case-control studies indicating that hOGG1 Ser326Cys polymorphism was significantly associated with HNSCC risk only under CysCys vs. SerSer model.	('associated', 'Reg', (140, 150))	('hOGG1', 'Gene', '4968', (93, 98))	('SerSer', 'Chemical', '-', (189, 195))	('Ser326Cys', 'Var', (99, 108))	('HNSCC', 'Disease', (156, 161))	('hOGG1', 'Gene', (93, 98))	('HNSCC', 'Phenotype', 'HP:0012288', (156, 161))	('polymorphism', 'Var', (109, 121))	('Ser326Cys', 'SUBSTITUTION', 'None', (99, 108))
342462	29560133	Obviously, the results of these meta-analyses were inconsistent (Supplementary Table 1), which might be attributed to the small effect of the Ser326Cys variation on HNSCC risk or the relatively low statistical power of published papers.	('Ser326Cys', 'Var', (142, 151))	('HNSCC', 'Disease', (165, 170))	('HNSCC', 'Phenotype', 'HP:0012288', (165, 170))	('Ser326Cys', 'SUBSTITUTION', 'None', (142, 151))
342463	29560133	Hence, in order to more systematically investigate the association between hOGG1 Ser326Cys polymorphism and risk of HNSCC, we included these eleven articles and performed present updated meta-analysis through combing the different studies which a quantitative approach.	('hOGG1', 'Gene', (75, 80))	('association', 'Interaction', (55, 66))	('Ser326Cys', 'SUBSTITUTION', 'None', (81, 90))	('Ser326Cys', 'Var', (81, 90))	('HNSCC', 'Disease', (116, 121))	('HNSCC', 'Phenotype', 'HP:0012288', (116, 121))	('hOGG1', 'Gene', '4968', (75, 80))
342468	29560133	The estimation of the association between hOGG1 Ser326Cys polymorphism and HNSCC risk is presented in Table 2.	('hOGG1', 'Gene', '4968', (42, 47))	('Ser326Cys', 'SUBSTITUTION', 'None', (48, 57))	('HNSCC', 'Disease', (75, 80))	('hOGG1', 'Gene', (42, 47))	('HNSCC', 'Phenotype', 'HP:0012288', (75, 80))	('Ser326Cys', 'Var', (48, 57))
342472	29560133	Of them, we observed increased risks of Ser326Cys polymorphism for Caucasians, laryngeal squamous cell carcinoma (LSCC), alcohol drinkers and controls agreement with HWE under corresponding models.	('laryngeal squamous cell carcinoma', 'Disease', 'MESH:D002294', (79, 112))	('alcohol drinkers', 'Phenotype', 'HP:0030955', (121, 137))	('Ser326Cys', 'SUBSTITUTION', 'None', (40, 49))	('laryngeal squamous cell carcinoma', 'Disease', (79, 112))	('Ser326Cys', 'Var', (40, 49))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (89, 112))	('alcohol', 'Chemical', 'MESH:D000438', (121, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))
342475	29560133	The present meta-analysis including 3,875 HNSCC cases and 4,696 controls indicated that hOGG1 Ser326Cys polymorphism might be associated with increased risk of HNSCC, and the TSA results also provided firm evidence.	('HNSCC', 'Phenotype', 'HP:0012288', (42, 47))	('hOGG1', 'Gene', (88, 93))	('polymorphism', 'Var', (104, 116))	('Ser326Cys', 'Var', (94, 103))	('Ser326Cys', 'SUBSTITUTION', 'None', (94, 103))	('HNSCC', 'Phenotype', 'HP:0012288', (160, 165))	('TSA', 'Chemical', '-', (175, 178))	('HNSCC', 'Disease', (160, 165))	('hOGG1', 'Gene', '4968', (88, 93))
342476	29560133	Based on stratified analysis by tumor site, we observed that the hOGG1 Ser326Cys polymorphism was significantly associated with LSCC.	('hOGG1', 'Gene', '4968', (65, 70))	('Ser326Cys', 'Var', (71, 80))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('Ser326Cys', 'SUBSTITUTION', 'None', (71, 80))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('hOGG1', 'Gene', (65, 70))	('LSCC', 'Disease', (128, 132))	('tumor', 'Disease', (32, 37))	('associated', 'Reg', (112, 122))
342478	29560133	There were four and two studies involving hOGG1 Ser326Cys polymorphism and HNSCC in smokers and alcohol drinkers, respectively.	('hOGG1', 'Gene', '4968', (42, 47))	('Ser326Cys', 'SUBSTITUTION', 'None', (48, 57))	('alcohol', 'Chemical', 'MESH:D000438', (96, 103))	('hOGG1', 'Gene', (42, 47))	('HNSCC', 'Phenotype', 'HP:0012288', (75, 80))	('Ser326Cys', 'Var', (48, 57))	('alcohol drinkers', 'Phenotype', 'HP:0030955', (96, 112))
342479	29560133	Interestingly, we found no significant association between hOGG1 Ser326Cys polymorphism and HNSCC in smokers but statistically significant relationship in alcohol drinkers.	('hOGG1', 'Gene', '4968', (59, 64))	('alcohol drinkers', 'Phenotype', 'HP:0030955', (155, 171))	('HNSCC', 'Disease', (92, 97))	('hOGG1', 'Gene', (59, 64))	('HNSCC', 'Phenotype', 'HP:0012288', (92, 97))	('alcohol', 'Chemical', 'MESH:D000438', (155, 162))	('Ser326Cys', 'SUBSTITUTION', 'None', (65, 74))	('Ser326Cys', 'Var', (65, 74))
342481	29560133	Of them, Wang et al conducted a subgroup analysis focused on HNSCC containing six studies, which showed that hOGG1 Ser326Cys polymorphism increased HNSCC risk under all comparisons.	('Ser326Cys', 'SUBSTITUTION', 'None', (115, 124))	('Ser326Cys', 'Var', (115, 124))	('increased', 'PosReg', (138, 147))	('HNSCC', 'Disease', (148, 153))	('HNSCC', 'Phenotype', 'HP:0012288', (148, 153))	('hOGG1', 'Gene', (109, 114))	('HNSCC', 'Phenotype', 'HP:0012288', (61, 66))	('hOGG1', 'Gene', '4968', (109, 114))
342482	29560133	The meta-analysis from Wei et al, included six studies and indicated a significant association between hOGG1 Ser326Cys polymorphism and HNSCC under CysCys vs. SerSer model.	('hOGG1', 'Gene', '4968', (103, 108))	('Ser326Cys', 'Var', (109, 118))	('Ser326Cys', 'SUBSTITUTION', 'None', (109, 118))	('SerSer', 'Chemical', '-', (159, 165))	('hOGG1', 'Gene', (103, 108))	('HNSCC', 'Phenotype', 'HP:0012288', (136, 141))	('polymorphism', 'Var', (119, 131))	('HNSCC under', 'Disease', (136, 147))
342483	29560133	Our meta-analysis incorporated 13 studies, which showed that hOGG1 Ser326Cys polymorphism was associated with the elevated risk of HNSCC under CysCys vs. SerSer and CysCys vs. (CysSer + SerSer) contrasts.	('SerSer', 'Chemical', '-', (154, 160))	('CysSer', 'Chemical', '-', (177, 183))	('HNSCC', 'Phenotype', 'HP:0012288', (131, 136))	('HNSCC', 'Disease', (131, 136))	('hOGG1', 'Gene', (61, 66))	('Ser326Cys', 'Var', (67, 76))	('Ser326Cys', 'SUBSTITUTION', 'None', (67, 76))	('SerSer', 'Chemical', '-', (186, 192))	('hOGG1', 'Gene', '4968', (61, 66))
342487	29560133	In summary, our meta-analysis suggests that hOGG1 Ser326Cys polymorphism may contribute to the occurrence of HNSCC, especially in Caucasians, alcohol drinkers and the patients with LSCC.	('Ser326Cys', 'SUBSTITUTION', 'None', (50, 59))	('Ser326Cys', 'Var', (50, 59))	('alcohol drinkers', 'Phenotype', 'HP:0030955', (142, 158))	('contribute', 'Reg', (77, 87))	('hOGG1', 'Gene', (44, 49))	('patients', 'Species', '9606', (167, 175))	('hOGG1', 'Gene', '4968', (44, 49))	('HNSCC', 'Disease', (109, 114))	('alcohol', 'Chemical', 'MESH:D000438', (142, 149))	('HNSCC', 'Phenotype', 'HP:0012288', (109, 114))
342489	29560133	Each study included in the present meta-analysis was required to meet all the following criteria: (i) the study focused on the association between hOGG1 Ser326Cys polymorphism and risk of HNSCC; (ii) the study design was a cohort or case-control study; and (iii) the data of genotype distributions in case and control groups were available.	('association', 'Interaction', (127, 138))	('hOGG1', 'Gene', '4968', (147, 152))	('Ser326Cys', 'Var', (153, 162))	('Ser326Cys', 'SUBSTITUTION', 'None', (153, 162))	('polymorphism', 'Var', (163, 175))	('hOGG1', 'Gene', (147, 152))	('HNSCC', 'Disease', (188, 193))	('HNSCC', 'Phenotype', 'HP:0012288', (188, 193))
342552	27432208	In multivariable analysis, HPV(+) nonsmokers compared to HPV(+) smokers had improvements in outcome that did not achieve statistical significance (HR (95% CI): 0.22 (0.05, 1.04), 0.34 (0.11, 1.06), 0.15 (0.02, 1.31) for OST, RFT, DST respectively), after adjustment for confounding factors.	('HPV', 'Species', '10566', (27, 30))	('DST', 'Disease', (230, 233))	('HPV(+', 'Var', (27, 32))	('improvements', 'PosReg', (76, 88))	('OST', 'Gene', (220, 223))	('RFT', 'Gene', '4152', (225, 228))	('RFT', 'Gene', (225, 228))	('outcome', 'MPA', (92, 99))	('HPV', 'Species', '10566', (57, 60))	('OST', 'Gene', '23263', (220, 223))
342572	27432208	Low BMI, as a measure of nutritional status, was prospectively associated with increased risk of HNSCC mortality among smokers, increased risk of death during chemoradiation, and a negative prognostic factor post-treatment.	('Low BMI', 'Phenotype', 'HP:0045082', (0, 7))	('HNSCC', 'Phenotype', 'HP:0012288', (97, 102))	('HNSCC mortality', 'Disease', (97, 112))	('death', 'Disease', 'MESH:D003643', (146, 151))	('death', 'Disease', (146, 151))	('BMI', 'MPA', (4, 7))	('Low', 'Var', (0, 3))
342647	33568653	High overall SSV burden associates with TP53 mutations, histone H3.3 gene H3F3C mutations, and the transcription of DNA damage response genes.	('mutations', 'Var', (45, 54))	('SSV', 'Chemical', '-', (13, 16))	('SSV', 'Disease', (13, 16))	('histone H3.3', 'Gene', (56, 68))	('mutations', 'Var', (80, 89))	('transcription', 'MPA', (99, 112))	('H3F3C', 'Gene', (74, 79))	('histone H3.3', 'Gene', '3020', (56, 68))	('TP53', 'Gene', '7157', (40, 44))	('TP53', 'Gene', (40, 44))	('H3F3C', 'Gene', '440093', (74, 79))
342653	33568653	All classes of somatic structural variants (SSVs):including tandem duplications, insertions, deletions, inversions, and translocations:can potentially alter the regulation of specific genes through several possible mechanisms, including gene fusion, promoter element disruption, enhancer hijacking, disruption of topologically associated domains (TADs), and altered DNA methylation.	('variants', 'Var', (34, 42))	('disruption', 'Reg', (299, 309))	('DNA methylation', 'MPA', (366, 381))	('altered', 'Reg', (358, 365))	('tandem duplications', 'Var', (60, 79))	('disruption', 'Reg', (267, 277))	('gene', 'CPA', (237, 241))	('TADs', 'Disease', (347, 351))	('enhancer hijacking', 'PosReg', (279, 297))	('deletions', 'Var', (93, 102))	('promoter', 'MPA', (250, 258))	('TADs', 'Disease', 'None', (347, 351))	('alter', 'Reg', (151, 156))	('regulation', 'MPA', (161, 171))	('specific genes', 'Gene', (175, 189))	('SSV', 'Chemical', '-', (44, 47))	('insertions', 'Var', (81, 91))
342654	33568653	Also, cancers harboring a high overall structural variation burden may exhibit an altered molecular profile reflective of extensive DNA damage.	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('molecular profile', 'MPA', (90, 107))	('cancers', 'Disease', 'MESH:D009369', (6, 13))	('cancers', 'Phenotype', 'HP:0002664', (6, 13))	('cancers', 'Disease', (6, 13))	('altered', 'Reg', (82, 89))	('structural variation', 'Var', (39, 59))
342672	33568653	Here, a high SSV burden is associated with TP53 mutations, histone H3.3 gene H3F3C mutations, and increased expression of DNA damage response genes.	('mutations', 'Var', (83, 92))	('DNA damage response genes', 'Gene', (122, 147))	('SSV', 'Chemical', '-', (13, 16))	('SSV burden', 'Disease', (13, 23))	('histone H3.3', 'Gene', '3020', (59, 71))	('H3F3C', 'Gene', (77, 82))	('increased', 'PosReg', (98, 107))	('expression', 'MPA', (108, 118))	('TP53', 'Gene', '7157', (43, 47))	('histone H3.3', 'Gene', (59, 71))	('TP53', 'Gene', (43, 47))	('H3F3C', 'Gene', '440093', (77, 82))	('mutations', 'Var', (48, 57))
342682	33568653	In line with previous observations in adult cancers, here, genomic rearrangements could be associated with widespread CNA patterns in pediatric brain tumors (Fig.	('tumors', 'Phenotype', 'HP:0002664', (150, 156))	('cancers', 'Phenotype', 'HP:0002664', (44, 51))	('widespread CNA patterns', 'Disease', (107, 130))	('adult cancers', 'Disease', (38, 51))	('brain tumors', 'Disease', 'MESH:D001932', (144, 156))	('brain tumors', 'Phenotype', 'HP:0030692', (144, 156))	('genomic rearrangements', 'Var', (59, 81))	('brain tumors', 'Disease', (144, 156))	('brain tumor', 'Phenotype', 'HP:0030692', (144, 155))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('adult cancers', 'Disease', 'MESH:D009369', (38, 51))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('associated', 'Reg', (91, 101))
342683	33568653	When we considered the set of all SSV-gene associations involving an SSV breakpoint falling within 1 Mb of gene start site for a given tumor, we found these associations to be highly enriched for gene-level amplification or deletion, though more so for the former.	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('SSV', 'Chemical', '-', (34, 37))	('SSV', 'Chemical', '-', (69, 72))	('tumor', 'Disease', (135, 140))	('falling', 'Phenotype', 'HP:0002527', (84, 91))	('deletion', 'Var', (224, 232))	('fall', 'Phenotype', 'HP:0002527', (84, 88))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
342684	33568653	While a significant proportion of SSVs associated with gene amplification involved tandem duplication SSVs as might be expected, all classes of SSV were involved with altered CNA patterns (Supplementary Fig.	('SSV', 'Chemical', '-', (102, 105))	('SSV', 'Chemical', '-', (34, 37))	('SSV', 'Chemical', '-', (144, 147))	('CNA patterns', 'MPA', (175, 187))	('gene amplification', 'Var', (55, 73))	('involved with altered', 'Reg', (153, 174))	('SSVs', 'Disease', (34, 38))	('tandem duplication', 'Var', (83, 101))	('involved', 'Reg', (74, 82))
342685	33568653	The intra-chromosomal, non-translocation SSVs associated with CNA showed enrichment for SSVs of larger DNA sizes (>100 kb, Supplementary Fig.	('CNA', 'Disease', (62, 65))	('non-translocation', 'Var', (23, 40))	('SSV', 'Chemical', '-', (41, 44))	('SSV', 'Chemical', '-', (88, 91))
342691	33568653	SSV patterns:together with patterns of CNA, insertion/deletion of nucleotide bases (indels), and Single Nucleotide Variants (SNVs):revealed both concordant and discordant patterns among tumors from the same patient.	('SSV', 'Chemical', '-', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('insertion/deletion', 'Var', (44, 62))	('tumors', 'Phenotype', 'HP:0002664', (186, 192))	('tumors', 'Disease', (186, 192))	('tumors', 'Disease', 'MESH:D009369', (186, 192))	('patient', 'Species', '9606', (207, 214))
342697	33568653	In principle, SSVs with breakpoints nearby a gene could lead to altered cis-regulation, e.g., by enhancer hijacking or altered DNA methylation, and SSV breakpoints within a gene could result in gene disruption or a gene fusion (Fig.	('lead to altered', 'Reg', (56, 71))	('result in', 'Reg', (184, 193))	('SSV', 'Var', (148, 151))	('SSV', 'Chemical', '-', (14, 17))	('DNA methylation', 'MPA', (127, 142))	('enhancer', 'PosReg', (97, 105))	('breakpoints', 'Var', (24, 35))	('SSV', 'Chemical', '-', (148, 151))	('cis-regulation', 'MPA', (72, 86))	('altered', 'Reg', (119, 126))	('gene', 'CPA', (194, 198))	('gene fusion', 'CPA', (215, 226))
342726	33568653	For particular genes of interest, including oncogenes TERT and MYB and tumor suppressor gene NF1, the relative expression changes in tumors harboring an SSV breakpoint were more dramatic as compared to tumors with CNA (Fig.	('TERT', 'Gene', '7015', (54, 58))	('tumors', 'Disease', 'MESH:D009369', (202, 208))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('SSV', 'Chemical', '-', (153, 156))	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('NF1', 'Gene', '4763', (93, 96))	('tumor', 'Disease', (202, 207))	('expression', 'MPA', (111, 121))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('MYB', 'Gene', '4602', (63, 66))	('NF1', 'Gene', (93, 96))	('MYB', 'Gene', (63, 66))	('tumors', 'Phenotype', 'HP:0002664', (202, 208))	('tumors', 'Disease', (133, 139))	('breakpoint', 'Var', (157, 167))	('tumor', 'Disease', (133, 138))	('tumor', 'Disease', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('tumors', 'Disease', 'MESH:D009369', (133, 139))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumors', 'Disease', (202, 208))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('TERT', 'Gene', (54, 58))
342731	33568653	Similarly, SSV breakpoints involving gene overexpression were enriched (p < 1E-15, chi-squared test) for putative enhancer translocation events, with the rearrangement bringing an enhancer within 500 kb of the gene (Fig.	('enhancer', 'PosReg', (180, 188))	('SSV', 'Chemical', '-', (11, 14))	('rearrangement', 'Var', (154, 167))
342748	33568653	We found a highly significant degree of overlapping gene-to-tumor associations involving predicted fusions using RNA-seq chimeric reads, gene overexpression, and SSVs breakpoint falling within the boundary of a gene (Supplementary Fig.	('SSVs breakpoint falling', 'Disease', 'MESH:D002303', (162, 185))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('SSVs breakpoint falling', 'Disease', (162, 185))	('fall', 'Phenotype', 'HP:0002527', (178, 182))	('fusions', 'Var', (99, 106))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('falling', 'Phenotype', 'HP:0002527', (178, 185))	('tumor', 'Disease', (60, 65))
342751	33568653	This set of 1208 fusion calls with the highest level of support involved 974 distinct gene fusions, 368 tumors, and 331 patients (Supplementary Data 4), as well as the majority of gene body-associated SSV breakpoints with overexpression (Fig.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('overexpression', 'PosReg', (222, 236))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('fusions', 'Var', (91, 98))	('tumors', 'Disease', (104, 110))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('SSV', 'Chemical', '-', (201, 204))	('patients', 'Species', '9606', (120, 128))
342752	33568653	Of the 368 tumors, 182 had fusions both detectable in two or more tumors and including a known cancer-associated gene by COSMIC (Fig.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('tumors', 'Phenotype', 'HP:0002664', (11, 17))	('tumors', 'Disease', (66, 72))	('cancer', 'Disease', (95, 101))	('tumors', 'Disease', 'MESH:D009369', (11, 17))	('tumors', 'Disease', (11, 17))	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('fusions', 'Var', (27, 34))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))
342759	33568653	Alterations considered were gene fusion, SSV-mediated altered cis-regulation or gene disruption (taking from the genes significant for 1 Mb region), SNV or indel, and deep deletion or high-level amplification (Supplementary Data 5).	('high-level amplification', 'Var', (184, 208))	('SSV', 'Chemical', '-', (41, 44))	('deep deletion', 'Var', (167, 180))	('gene fusion', 'Var', (28, 39))	('cis-regulation', 'MPA', (62, 76))	('gene', 'CPA', (80, 84))	('SNV', 'Var', (149, 152))	('altered', 'Reg', (54, 61))	('indel', 'Var', (156, 161))
342764	33568653	Some tumor types showed particularly high enrichment for alterations affecting a specific pathway (Fig.	('alterations', 'Var', (57, 68))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('tumor', 'Disease', (5, 10))
342765	33568653	RTK-related alterations showed enrichment within PLGG; p53/Rb-related alterations, within PHGG; alterations involving chromatin modifiers, TERT, and MYC family, within MBL; SWI/SNF alterations, within ATRT; Wnt/beta-catenin alterations, within CRANIO; and HIPPO pathway alterations, within MNG.	('alterations', 'Var', (70, 81))	('MBL', 'Disease', (168, 171))	('TERT', 'Gene', '7015', (139, 143))	('p53', 'Gene', (55, 58))	('MBL', 'Disease', 'MESH:C563602', (168, 171))	('p53', 'Gene', '7157', (55, 58))	('RTK', 'Gene', '5979', (0, 3))	('MYC', 'Gene', (149, 152))	('beta-catenin', 'Gene', (211, 223))	('SWI/SNF', 'Gene', (173, 180))	('HIPPO pathway', 'Pathway', (256, 269))	('beta-catenin', 'Gene', '1499', (211, 223))	('MYC', 'Gene', '4609', (149, 152))	('RTK', 'Gene', (0, 3))	('TERT', 'Gene', (139, 143))
342786	33568653	We searched for genes with inactivating SNVs or indels correlated with high SSV burden, with 17 genes being significant (Fig.	('SNVs', 'Var', (40, 44))	('high SSV burden', 'Disease', (71, 86))	('indels', 'Var', (48, 54))	('SSV', 'Chemical', '-', (76, 79))
342789	33568653	TP53 hotspot SNVs and inactivating SNVs and indels, along with single-copy loss, were associated with higher SSV burden, in both the CBTTC pediatric brain and TCGA adult pan-cancer cohorts (Fig.	('SSV', 'Chemical', '-', (109, 112))	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('higher', 'PosReg', (102, 108))	('cancer', 'Disease', (174, 180))	('pan', 'Gene', (170, 173))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('SNVs', 'Var', (13, 17))	('inactivating', 'Var', (22, 34))	('pan', 'Gene', '51816', (170, 173))	('SSV', 'Disease', (109, 112))
342791	33568653	TP53 mutation also corresponded to increases in detected SNVs and indels, in addition to SSV burden (Supplementary Figs.	('SNVs', 'MPA', (57, 61))	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('increases', 'PosReg', (35, 44))	('indels', 'MPA', (66, 72))	('SSV burden', 'MPA', (89, 99))	('mutation', 'Var', (5, 13))	('SSV', 'Chemical', '-', (89, 92))
342792	33568653	6b), with mutation and copy loss events mostly occurring in PHGG and MBL tumors.	('occurring', 'Reg', (47, 56))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('MBL tumors', 'Disease', 'MESH:C563602', (69, 79))	('MBL tumors', 'Disease', (69, 79))	('PHGG', 'Disease', (60, 64))	('copy loss', 'Var', (23, 32))
342802	33568653	A survey of Histone H3 genes showed frequent mutations in H3F3A and H3F3C across CBTTC tumors (Supplementary Fig.	('H3F3C', 'Gene', '440093', (68, 73))	('mutations', 'Var', (45, 54))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('H3F3A', 'Gene', '3020', (58, 63))	('H3F3A', 'Gene', (58, 63))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('H3F3C', 'Gene', (68, 73))	('tumors', 'Disease', (87, 93))	('tumors', 'Disease', 'MESH:D009369', (87, 93))
342803	33568653	While H3F3A mutations are commonly associated with pediatric brain tumors, particularly with PHGG and DIPG, H3F3C, which also encodes for an H3.3 histone component, appears to be much less studied in the context of cancer, including pediatric brain cancer.	('H3F3C', 'Gene', (108, 113))	('brain cancer', 'Phenotype', 'HP:0030692', (243, 255))	('cancer', 'Disease', (249, 255))	('brain tumors', 'Disease', (61, 73))	('cancer', 'Phenotype', 'HP:0002664', (249, 255))	('brain cancer', 'Disease', 'MESH:D001932', (243, 255))	('H3F3A', 'Gene', '3020', (6, 11))	('cancer', 'Disease', (215, 221))	('H3F3C', 'Gene', '440093', (108, 113))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('cancer', 'Disease', 'MESH:D009369', (249, 255))	('H3F3A', 'Gene', (6, 11))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('brain tumor', 'Phenotype', 'HP:0030692', (61, 72))	('brain cancer', 'Disease', (243, 255))	('cancer', 'Disease', 'MESH:D009369', (215, 221))	('brain tumors', 'Disease', 'MESH:D001932', (61, 73))	('mutations', 'Var', (12, 21))	('associated', 'Reg', (35, 45))	('brain tumors', 'Phenotype', 'HP:0030692', (61, 73))
342805	33568653	7b), with no hypermutated tumors having H3F3C mutations.	('mutations', 'Var', (46, 55))	('H3F3C', 'Gene', (40, 45))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('H3F3C', 'Gene', '440093', (40, 45))	('tumors', 'Disease', (26, 32))
342806	33568653	While H3F3A mutations in CBTTC tumors primarily involved the known K28M/K27M hotspot (n = 30 tumors), followed by the G35R/G34R hotspot (n = 4), H3F3C mutations followed another distinctive pattern.	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('H3F3C', 'Gene', (145, 150))	('K27M', 'Var', (72, 76))	('G35R', 'SUBSTITUTION', 'None', (118, 122))	('H3F3A', 'Gene', '3020', (6, 11))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumors', 'Disease', (31, 37))	('K28M', 'SUBSTITUTION', 'None', (67, 71))	('involved', 'Reg', (48, 56))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('G34R', 'SUBSTITUTION', 'None', (123, 127))	('G34R', 'Var', (123, 127))	('H3F3A', 'Gene', (6, 11))	('H3F3C', 'Gene', '440093', (145, 150))	('tumors', 'Disease', 'MESH:D009369', (31, 37))	('tumors', 'Disease', (93, 99))	('K28M', 'Var', (67, 71))	('CBTTC', 'Disease', (25, 30))	('mutations', 'Var', (12, 21))	('G35R', 'Var', (118, 122))	('K27M', 'SUBSTITUTION', 'None', (72, 76))	('tumors', 'Disease', 'MESH:D009369', (93, 99))
342807	33568653	All nine impacted tumors (three PLGG, two EPMT, and one each for ATRT, MNG, PHGG, and SARCNOS; two progressive, two recurrent, and one second malignancy) had nucleotide changes involving both K37 duplication and N79K amino acid change (Fig.	('K37', 'Gene', '8688', (192, 195))	('N79K', 'Mutation', 'rs768711923', (212, 216))	('N79K amino acid change', 'Var', (212, 234))	('malignancy', 'Disease', 'MESH:D009369', (142, 152))	('tumors', 'Disease', (18, 24))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('malignancy', 'Disease', (142, 152))	('K37', 'Gene', (192, 195))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
342808	33568653	Two of the nine tumors also harbored amino acid changes L104F and V89I.	('L104F', 'Mutation', 'rs765335762', (56, 61))	('L104F', 'Var', (56, 61))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('tumors', 'Disease', 'MESH:D009369', (16, 22))	('V89I', 'Mutation', 'rs148314204', (66, 70))	('tumors', 'Disease', (16, 22))	('V89I', 'Var', (66, 70))
342809	33568653	H3F3C mutations were mutually exclusive with TP53 alterations (Fig.	('TP53', 'Gene', (45, 49))	('H3F3C', 'Gene', (0, 5))	('TP53', 'Gene', '7157', (45, 49))	('H3F3C', 'Gene', '440093', (0, 5))	('mutations', 'Var', (6, 15))
342813	33568653	We went on to survey whole-exome sequencing data from 10,224 TCGA adult cancers for H3F3C mutations.	('adult cancers', 'Disease', 'MESH:D009369', (66, 79))	('H3F3C', 'Gene', (84, 89))	('mutations', 'Var', (90, 99))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('H3F3C', 'Gene', '440093', (84, 89))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('adult cancers', 'Disease', (66, 79))
342814	33568653	Of all TCGA tumors, 49:representing many different tissues of origin:harbored a mutation in H3F3C (Fig.	('H3F3C', 'Gene', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('tumors', 'Disease', (12, 18))	('H3F3C', 'Gene', '440093', (92, 97))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('mutation', 'Var', (80, 88))	('tumors', 'Disease', 'MESH:D009369', (12, 18))
342817	33568653	The TCGA H3F3C mutations did not show the same tight hotspot pattern found in CBTTC tumors, although TCGA mutations did include G35R (two patients), N79K (one patient), and V89I (four patients).	('V89I', 'Mutation', 'rs148314204', (173, 177))	('G35R', 'Var', (128, 132))	('N79K', 'Mutation', 'rs768711923', (149, 153))	('V89I', 'Var', (173, 177))	('TCGA', 'Gene', (101, 105))	('patients', 'Species', '9606', (184, 192))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('patient', 'Species', '9606', (184, 191))	('G35R', 'Mutation', 'rs748979871', (128, 132))	('H3F3C', 'Gene', '440093', (9, 14))	('patient', 'Species', '9606', (138, 145))	('tumors', 'Disease', (84, 90))	('tumors', 'Disease', 'MESH:D009369', (84, 90))	('patient', 'Species', '9606', (159, 166))	('N79K', 'Var', (149, 153))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('patients', 'Species', '9606', (138, 146))	('H3F3C', 'Gene', (9, 14))
342820	33568653	Aspects of this phenomenon, as observed in both PCAWG and CBTTC cohorts, include: hundreds of genes recurrently impacted, SSV breakpoints as far as 1 Mb from the gene contributing to deregulation, rearrangements involving widespread CNA patterns, many more genes with increased over decreased expression associated with SSV breakpoints, and overexpressed and under-expressed genes respectively representing known oncogenes and tumor suppressor genes.	('SSV', 'Chemical', '-', (122, 125))	('tumor', 'Disease', 'MESH:D009369', (427, 432))	('SSV', 'Chemical', '-', (320, 323))	('tumor', 'Phenotype', 'HP:0002664', (427, 432))	('tumor', 'Disease', (427, 432))	('rearrangements', 'Var', (197, 211))	('expression', 'MPA', (293, 303))	('increased over', 'PosReg', (268, 282))	('impacted', 'Reg', (112, 120))
342835	33568653	For a given patient, the overall numbers of SSVs and other somatic mutations tend to increase in a recurrent or progressive tumor as compared to the primary tumor.	('tumor', 'Disease', (157, 162))	('recurrent', 'CPA', (99, 108))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('SSVs', 'Gene', (44, 48))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('tumor', 'Disease', (124, 129))	('mutations', 'Var', (67, 76))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('patient', 'Species', '9606', (12, 19))	('increase', 'PosReg', (85, 93))	('SSV', 'Chemical', '-', (44, 47))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
342840	33568653	DNA mutation correlates of high SSV burden included mutations in TP53 and histone H3.3 genes.	('mutations', 'Var', (52, 61))	('histone H3.3', 'Gene', '3020', (74, 86))	('TP53', 'Gene', '7157', (65, 69))	('TP53', 'Gene', (65, 69))	('histone H3.3', 'Gene', (74, 86))	('SSV', 'Chemical', '-', (32, 35))
342841	33568653	Our TP53-related findings would be consistent with those of an adult pan-cancer study of TCGA data, in which TP53 mutational status was associated with global increases in DNA copy number instability and somatic SNV/indel frequency.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('pan', 'Gene', '51816', (69, 72))	('TP53', 'Gene', (4, 8))	('pan', 'Gene', (69, 72))	('increases', 'PosReg', (159, 168))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('TP53', 'Gene', '7157', (109, 113))	('mutational status', 'Var', (114, 131))	('DNA copy number instability', 'MPA', (172, 199))	('TP53', 'Gene', (109, 113))	('TP53', 'Gene', '7157', (4, 8))
342842	33568653	Other studies have also linked TP53 mutation with increased numbers of chromosome rearrangements in pediatric cancers.	('cancers', 'Disease', (110, 117))	('TP53', 'Gene', '7157', (31, 35))	('TP53', 'Gene', (31, 35))	('mutation', 'Var', (36, 44))	('chromosome rearrangements', 'MPA', (71, 96))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('cancers', 'Phenotype', 'HP:0002664', (110, 117))	('cancers', 'Disease', 'MESH:D009369', (110, 117))
342843	33568653	While H3F3A mutations are commonly associated with pediatric brain cancers, H3F3C appears to be much less studied in cancer, including pediatric brain cancer.	('brain cancer', 'Disease', (145, 157))	('brain cancer', 'Phenotype', 'HP:0030692', (61, 73))	('brain cancer', 'Disease', 'MESH:D001932', (61, 73))	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('H3F3A', 'Gene', '3020', (6, 11))	('H3F3C', 'Gene', '440093', (76, 81))	('cancer', 'Disease', (151, 157))	('cancer', 'Disease', (117, 123))	('brain cancer', 'Phenotype', 'HP:0030692', (145, 157))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('H3F3A', 'Gene', (6, 11))	('brain cancer', 'Disease', 'MESH:D001932', (145, 157))	('brain cancers', 'Disease', (61, 74))	('cancers', 'Phenotype', 'HP:0002664', (67, 74))	('cancer', 'Disease', (67, 73))	('mutations', 'Var', (12, 21))	('associated', 'Reg', (35, 45))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('brain cancers', 'Disease', 'MESH:D001932', (61, 74))	('H3F3C', 'Gene', (76, 81))
342844	33568653	Interestingly, a search of the PeCan (https://pecan.stjude.cloud/) and PedCBioportal (https://pedcbioportal.kidsfirstdrc.org/) databases:representing more than 1000 additional pediatric brain tumors:did not uncover additional cases of H3F3C hotspot mutation.	('mutation', 'Var', (249, 257))	('brain tumors', 'Disease', 'MESH:D001932', (186, 198))	('brain tumors', 'Phenotype', 'HP:0030692', (186, 198))	('H3F3C', 'Gene', (235, 240))	('tumors', 'Phenotype', 'HP:0002664', (192, 198))	('brain tumor', 'Phenotype', 'HP:0030692', (186, 197))	('brain tumors', 'Disease', (186, 198))	('PeCan', 'Species', '32201', (31, 36))	('H3F3C', 'Gene', '440093', (235, 240))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('pecan', 'Species', '32201', (46, 51))
342845	33568653	This may be because mutations in CBTTC cohort were few and spread among multiple histologic types and involving progressive or recurrent or second malignancy cases.	('malignancy', 'Disease', 'MESH:D009369', (147, 157))	('CBTTC', 'Gene', (33, 38))	('malignancy', 'Disease', (147, 157))	('spread', 'Reg', (59, 65))	('mutations', 'Var', (20, 29))	('involving', 'Reg', (102, 111))
342846	33568653	At the same time, the observations in adult tumors would suggest that alteration of histone H3.3 genes (including H3F3C) may cumulatively involve many patients, with the functional impact not being limited to hotspot mutations.	('tumors', 'Disease', (44, 50))	('tumors', 'Disease', 'MESH:D009369', (44, 50))	('H3F3C', 'Gene', (114, 119))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('histone H3.3', 'Gene', (84, 96))	('patients', 'Species', '9606', (151, 159))	('H3F3C', 'Gene', '440093', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('alteration', 'Var', (70, 80))	('histone H3.3', 'Gene', '3020', (84, 96))	('involve', 'Reg', (138, 145))
342863	33568653	Manta algorithm classified each SSV call as one of the following: tandem duplications, insertions, deletions, inversions, and translocations.	('deletions', 'Var', (99, 108))	('insertions', 'Var', (87, 97))	('SSV', 'Chemical', '-', (32, 35))
342872	33568653	This aspect would include treating SSV breakpoints representing different classes (tandem duplications, insertions, deletions, inversions, and translocations) and insert sizes the same in the integration with gene expression.	('deletions', 'Var', (116, 125))	('insertions', 'Var', (104, 114))	('SSV', 'Chemical', '-', (35, 38))
342895	33568653	We considered all inactivating SNVs (nonstop/nonsense) and indels in putative tumor suppressor genes (e.g., TP53) in the analyses.	('TP53', 'Gene', '7157', (108, 112))	('TP53', 'Gene', (108, 112))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('nonstop/nonsense', 'Var', (37, 53))	('tumor', 'Disease', (78, 83))
342897	33568653	At both the gene and pathway levels, we tabulated somatic alterations in the following order: SNV or indel, gene fusion, deep deletion (approximating homozygous loss), high-level amplification (approximating five or more copies), and SSV (for oncogenes, breakpoint falling with 1 Mb of gene and associated with expression >0.4 SD from median for the given tumor; for tumor suppressors, breakpoint falling within the gene body and expression < -0.4 SD).	('fall', 'Phenotype', 'HP:0002527', (397, 401))	('expression', 'MPA', (311, 321))	('tumor', 'Disease', (367, 372))	('SSV', 'Var', (234, 237))	('deep deletion', 'Var', (121, 134))	('SSV', 'Chemical', '-', (234, 237))	('falling', 'Phenotype', 'HP:0002527', (265, 272))	('falling', 'Phenotype', 'HP:0002527', (397, 404))	('high-level amplification', 'Var', (168, 192))	('tumor', 'Disease', 'MESH:D009369', (356, 361))	('gene fusion', 'Var', (108, 119))	('tumor', 'Disease', 'MESH:D009369', (367, 372))	('SNV', 'Var', (94, 97))	('fall', 'Phenotype', 'HP:0002527', (265, 269))	('tumor', 'Phenotype', 'HP:0002664', (367, 372))	('tumor', 'Phenotype', 'HP:0002664', (356, 361))	('tumor', 'Disease', (356, 361))
342905	33568653	For CBTTC datasets, we constructed a [gene x tumor] matrix, involving 567 genes with nonsense/nonstop/indel mutations in at least three tumors.	('tumors', 'Disease', (136, 142))	('tumors', 'Disease', 'MESH:D009369', (136, 142))	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('nonsense/nonstop/indel mutations', 'Var', (85, 117))	('x tumor', 'Disease', 'MESH:C562844', (43, 50))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('x tumor', 'Disease', (43, 50))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))
342917	33390818	Overexpression of CENPF is associated with progression and poor prognosis of lung adenocarcinoma Background and aim: The molecular signatures of lung adenocarcinoma (LUAD) are not well understood.	('carcinoma', 'Phenotype', 'HP:0030731', (155, 164))	('lung adenocarcinoma', 'Disease', (145, 164))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (77, 96))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (145, 164))	('associated', 'Reg', (27, 37))	('CENPF', 'Gene', (18, 23))	('lung adenocarcinoma', 'Disease', (77, 96))	('LUAD', 'Phenotype', 'HP:0030078', (166, 170))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (145, 164))	('Overexpression', 'Var', (0, 14))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (77, 96))	('CENPF', 'Gene', '1063', (18, 23))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))
342923	33390818	Besides, CENPF knockdown greatly suppressed A549 cell proliferation, induced S phase arrest, promoted apoptosis and decreased colony numbers of LUAD cells.	('LUAD', 'Phenotype', 'HP:0030078', (144, 148))	('knockdown', 'Var', (15, 24))	('apoptosis', 'CPA', (102, 111))	('colony numbers of LUAD cells', 'CPA', (126, 154))	('arrest', 'Disease', (85, 91))	('A549 cell proliferation', 'CPA', (44, 67))	('CENPF', 'Gene', (9, 14))	('arrest', 'Disease', 'MESH:D006323', (85, 91))	('induced', 'Reg', (69, 76))	('A549', 'CellLine', 'CVCL:0023', (44, 48))	('promoted', 'PosReg', (93, 101))	('suppressed', 'NegReg', (33, 43))	('decreased', 'NegReg', (116, 125))
342924	33390818	Furthermore, knockdown of CENPF significantly inhibited the tumor growth of the LUAD cells in an experimental xenograft lung cancer model of nude mice armpit of right forelimb.	('nude mice', 'Species', '10090', (141, 150))	('lung cancer', 'Disease', (120, 131))	('lung cancer', 'Phenotype', 'HP:0100526', (120, 131))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('LUAD', 'Phenotype', 'HP:0030078', (80, 84))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('lung cancer', 'Disease', 'MESH:D008175', (120, 131))	('tumor', 'Disease', (60, 65))	('knockdown', 'Var', (13, 22))	('inhibited', 'NegReg', (46, 55))	('CENPF', 'Gene', (26, 31))
342933	33390818	Gene expression profiles (GSE3141, GSE8894, GSE4573, GSE17710 and GSE31210) for NSCLC, LUSC and LUAD were also searched in the Gene Expression Omnibus (GEO) database for prognostic analysis.	('NSCLC', 'Phenotype', 'HP:0030358', (80, 85))	('LUAD', 'Phenotype', 'HP:0030078', (96, 100))	('GSE8894', 'Var', (35, 42))	('NSCLC', 'Disease', (80, 85))	('GSE3141', 'Var', (26, 33))	('GSE3141', 'Chemical', '-', (26, 33))	('GSE4573', 'Var', (44, 51))	('NSCLC', 'Disease', 'MESH:D002289', (80, 85))	('GSE8894', 'Chemical', '-', (35, 42))	('GSE17710', 'Var', (53, 61))	('GSE31210', 'Var', (66, 74))	('GSE4573', 'Chemical', '-', (44, 51))	('LUSC', 'Phenotype', 'HP:0030359', (87, 91))
342972	33390818	A total of 111 (GSE3141) and 138 (GSE8894) NSCLC patients, 129 (GSE4573) and 56 (GSE17710) LUSC patients, 204 (GSE31210) LUAD patients were used to validate the relationship between CENPF expression and OS as well as RFS, respectively.	('GSE4573', 'Chemical', '-', (64, 71))	('GSE3141', 'Chemical', '-', (16, 23))	('LUAD', 'Phenotype', 'HP:0030078', (121, 125))	('GSE3141', 'Var', (16, 23))	('CENPF', 'Gene', (182, 187))	('NSCLC', 'Phenotype', 'HP:0030358', (43, 48))	('GSE4573', 'Var', (64, 71))	('GSE8894', 'Chemical', '-', (34, 41))	('patients', 'Species', '9606', (126, 134))	('patients', 'Species', '9606', (96, 104))	('patients', 'Species', '9606', (49, 57))	('LUSC', 'Phenotype', 'HP:0030359', (91, 95))	('NSCLC', 'Disease', (43, 48))	('NSCLC', 'Disease', 'MESH:D002289', (43, 48))
342981	33390818	We noticed that knockdown of CENPF greatly suppressed A549 cell proliferation (Fig.	('CENPF', 'Gene', (29, 34))	('A549', 'CellLine', 'CVCL:0023', (54, 58))	('knockdown', 'Var', (16, 25))	('suppressed', 'NegReg', (43, 53))
342984	33390818	The qRT-PCR results revealed that CENPF expression was downregulated for nearly 80% in LUAD cells by the shCENPF lentivirus infection compared with shCtrl (P = 0.007) (Fig.	('expression', 'MPA', (40, 50))	('shCENPF', 'Var', (105, 112))	('LUAD', 'Phenotype', 'HP:0030078', (87, 91))	('CENPF', 'Gene', (34, 39))	('lentivirus infection', 'Disease', (113, 133))	('downregulated', 'NegReg', (55, 68))	('lentivirus infection', 'Disease', 'MESH:D016180', (113, 133))
342985	33390818	CENPF knockdown significantly impacted cell cycle distribution with induction of the G2/M fraction (P < 0.001) as well as the S phase fraction (P < 0.001) the in A549 cell lines, while the percentage of cells in the G1 phase did not change significantly (P = 0.154).	('impacted', 'Reg', (30, 38))	('CENPF', 'Gene', (0, 5))	('induction', 'PosReg', (68, 77))	('cell cycle distribution', 'CPA', (39, 62))	('A549', 'CellLine', 'CVCL:0023', (162, 166))	('S phase fraction', 'MPA', (126, 142))	('knockdown', 'Var', (6, 15))	('G2/M fraction', 'MPA', (85, 98))
342986	33390818	According to our results, we speculated that CENPF knockdown induced S phase arrest, which in turn contributes to the stimulating growth properties of LUAD cells (Fig.	('LUAD', 'Phenotype', 'HP:0030078', (151, 155))	('induced', 'Reg', (61, 68))	('arrest', 'Disease', 'MESH:D006323', (77, 83))	('CENPF', 'Gene', (45, 50))	('stimulating', 'PosReg', (118, 129))	('growth properties', 'CPA', (130, 147))	('arrest', 'Disease', (77, 83))	('knockdown', 'Var', (51, 60))
342991	33390818	Taken together, these results indicated that the knockdown of CENPF significantly inhibited the tumor growth of the LUAD cells in vitro and in vivo.	('knockdown', 'Var', (49, 58))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('inhibited', 'NegReg', (82, 91))	('CENPF', 'Gene', (62, 67))	('tumor', 'Disease', (96, 101))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('LUAD', 'Phenotype', 'HP:0030078', (116, 120))
342997	33390818	After CENPF knockdown, the cell proliferation of A549 cells slowed down, the cell cycle process was blocked, and the cell apoptosis rates increased, which indicated that CENPF could affect the function of A549 cells.	('increased', 'PosReg', (138, 147))	('CENPF', 'Gene', (6, 11))	('slowed down', 'NegReg', (60, 71))	('A549', 'CellLine', 'CVCL:0023', (49, 53))	('cell proliferation', 'CPA', (27, 45))	('knockdown', 'Var', (12, 21))	('A549', 'CellLine', 'CVCL:0023', (205, 209))	('function', 'MPA', (193, 201))	('cell apoptosis rates', 'CPA', (117, 137))	('affect', 'Reg', (182, 188))	('blocked', 'NegReg', (100, 107))	('cell cycle process', 'CPA', (77, 95))
343004	33390818	CENPF knockdown can decrease HCC cells ability, form colonies and induce tumor formation in nude mice.	('CENPF', 'Gene', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('HCC cells ability', 'CPA', (29, 46))	('nude mice', 'Species', '10090', (92, 101))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('induce', 'Reg', (66, 72))	('decrease', 'NegReg', (20, 28))	('tumor', 'Disease', (73, 78))	('form colonies', 'CPA', (48, 61))	('knockdown', 'Var', (6, 15))
343006	33390818	Furthermore, different kinds of experiments have confirmed that the high expression of CEPNF is a prognostic indicator of survival and metastasis in ESCA patients.	('metastasis', 'CPA', (135, 145))	('high', 'Var', (68, 72))	('patients', 'Species', '9606', (154, 162))	('ESCA', 'Disease', (149, 153))	('CEPNF', 'Gene', (87, 92))
343009	33390818	Besides, after CENPF knockdown in A549 cells, we performed vitro experiments to evaluate the role of CENPF in colony formation, cell cycle and apoptosis of lung cancer cell lines.	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('A549', 'CellLine', 'CVCL:0023', (34, 38))	('lung cancer', 'Disease', 'MESH:D008175', (156, 167))	('cell cycle', 'CPA', (128, 138))	('apoptosis', 'CPA', (143, 152))	('knockdown', 'Var', (21, 30))	('CENPF', 'Gene', (15, 20))	('lung cancer', 'Disease', (156, 167))	('colony formation', 'CPA', (110, 126))	('lung cancer', 'Phenotype', 'HP:0100526', (156, 167))
343011	33390818	The size and weight of the tumors formed by the A549-shCENPF cells significantly decreased compared with A549-shCtrl cells.	('decreased', 'NegReg', (81, 90))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('A549', 'CellLine', 'CVCL:0023', (48, 52))	('tumors', 'Disease', (27, 33))	('tumors', 'Disease', 'MESH:D009369', (27, 33))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('A549', 'CellLine', 'CVCL:0023', (105, 109))	('A549-shCENPF', 'Var', (48, 60))
343036	33143094	Blockade of this axis releases the brake and reinvigorates T cells, resulting in their antitumor activity.	('Blockade', 'Var', (0, 8))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('brake', 'MPA', (35, 40))	('tumor', 'Disease', (91, 96))
343044	33143094	TNAs are a result of mutant peptides mostly resulting from somatic mutations in cancer DNA, and overall tumor mutation burden (TMB) has been shown to correlate with response to anti-PD-1 antibodies across multiple cancers, including HNSCC.	('HNSCC', 'Disease', (233, 238))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('cancers', 'Disease', 'MESH:D009369', (214, 221))	('cancer', 'Disease', (80, 86))	('HNSCC', 'Phenotype', 'HP:0012288', (233, 238))	('cancer', 'Disease', (214, 220))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('peptides', 'Protein', (28, 36))	('TNAs', 'Disease', (0, 4))	('resulting from', 'Reg', (44, 58))	('TNAs', 'Chemical', '-', (0, 4))	('cancers', 'Phenotype', 'HP:0002664', (214, 221))	('cancers', 'Disease', (214, 221))	('tumor', 'Disease', (104, 109))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('cancer', 'Disease', 'MESH:D009369', (214, 220))	('mutant', 'Var', (21, 27))	('TMB', 'Chemical', '-', (127, 130))	('mutations', 'Var', (67, 76))
343045	33143094	Despite HNSCC ranking in the upper quartile of cancers by TMB with five mutations per million base pairs, this by itself is only a prerequisite for effective neoantigen presentation.	('TMB', 'Chemical', '-', (58, 61))	('mutations', 'Var', (72, 81))	('HNSCC', 'Gene', (8, 13))	('upper quartile of cancers', 'Disease', 'MESH:D009369', (29, 54))	('cancers', 'Phenotype', 'HP:0002664', (47, 54))	('HNSCC', 'Phenotype', 'HP:0012288', (8, 13))	('upper quartile of cancers', 'Disease', (29, 54))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))
343047	33143094	The significance of APM is evident from the lack of CD8+ TIL recognition of HNSCC despite expressed MHC I in the case of defective APM which is deficient in 20-80% of HNSCC.	('HNSCC', 'Phenotype', 'HP:0012288', (76, 81))	('defective', 'Var', (121, 130))	('HNSCC', 'Phenotype', 'HP:0012288', (167, 172))	('CD8', 'Gene', (52, 55))	('CD8', 'Gene', '925', (52, 55))
343049	33143094	beta2-microglobulin gene mutation is uncommon in non-HPV mediated (HPV-) HNSCC in contrast to HPV mediated (HPV+) HNSCC, where genes of the immune presentation pathway, such as beta2-microglobulin and HLA, are more often mutated.	('beta2-microglobulin', 'Gene', (0, 19))	('beta2-microglobulin', 'Gene', '567', (177, 196))	('HNSCC', 'Phenotype', 'HP:0012288', (73, 78))	('HPV', 'Species', '10566', (108, 111))	('HPV', 'Species', '10566', (94, 97))	('mutation', 'Var', (25, 33))	('HNSCC', 'Phenotype', 'HP:0012288', (114, 119))	('beta2-microglobulin', 'Gene', '567', (0, 19))	('HPV', 'Species', '10566', (67, 70))	('beta2-microglobulin', 'Gene', (177, 196))	('HPV', 'Species', '10566', (53, 56))	('non-HPV mediated', 'Disease', (49, 65))
343050	33143094	Furthermore, inhibition of the PD-1/PD-L1 axis in HNSCC can lead to compensatory upregulation of alternative immune checkpoints, such as TIM-3, LAG-3, CTLA-4, TIGIT, GITR, and VISTA.	('CTLA-4', 'Gene', (151, 157))	('TIGIT', 'Gene', (159, 164))	('VISTA', 'Gene', '64115', (176, 181))	('TIM-3', 'Gene', '84868', (137, 142))	('alternative immune checkpoints', 'MPA', (97, 127))	('inhibition', 'Var', (13, 23))	('VISTA', 'Gene', (176, 181))	('upregulation', 'PosReg', (81, 93))	('LAG-3', 'Gene', '3902', (144, 149))	('HNSCC', 'Phenotype', 'HP:0012288', (50, 55))	('GITR', 'Gene', '8784', (166, 170))	('LAG-3', 'Gene', (144, 149))	('TIGIT', 'Gene', '201633', (159, 164))	('GITR', 'Gene', (166, 170))	('TIM-3', 'Gene', (137, 142))
343052	33143094	Nevertheless, RT can increase the concentration of immunosuppressive cells in HNSCC TME and the magnitude of this effect seems to depend on RT details (e.g., hypofractionated RT increases T cell tumor infiltration, downregulates intratumoral immunosuppressive VEGF, and leads to lesser increase in MDSC as compared to conventionally fractionated RT) and on tumor characteristics (e.g., increase of CSCs in TME after RT is more prominent in HPV- HNSCC as compared to HPV+).	('HPV- HNSCC', 'Var', (440, 450))	('tumor', 'Disease', (195, 200))	('tumor', 'Disease', (234, 239))	('hypofractionated RT increases T cell tumor', 'Disease', (158, 200))	('VEGF', 'Gene', '7422', (260, 264))	('increase', 'PosReg', (286, 294))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('tumor', 'Disease', 'MESH:D009369', (234, 239))	('VEGF', 'Gene', (260, 264))	('increase', 'PosReg', (21, 29))	('tumor', 'Phenotype', 'HP:0002664', (357, 362))	('concentration', 'MPA', (34, 47))	('HPV', 'Species', '10566', (440, 443))	('increase', 'PosReg', (386, 394))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('CSCs', 'MPA', (398, 402))	('increases T cell', 'Phenotype', 'HP:0100828', (178, 194))	('HNSCC', 'Phenotype', 'HP:0012288', (78, 83))	('HNSCC', 'Phenotype', 'HP:0012288', (445, 450))	('hypofractionated RT increases T cell tumor', 'Disease', 'MESH:C563738', (158, 200))	('tumor', 'Disease', (357, 362))	('downregulates', 'NegReg', (215, 228))	('HPV', 'Species', '10566', (466, 469))	('MDSC', 'MPA', (298, 302))	('tumor', 'Disease', 'MESH:D009369', (357, 362))
343110	33143094	It seems that application of anti-PD-1 preceding RT could also be of benefit, as was shown in retrospective analysis of 758 patients with different metastatic solid cancers treated with either anti-CTLA-4 or anti-PD-1/L1, and RT within 30 days of immunotherapy.	('metastatic', 'Disease', (148, 158))	('solid cancers', 'Disease', 'MESH:D009369', (159, 172))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('anti-PD-1/L1', 'Var', (208, 220))	('anti-PD-1', 'Var', (29, 38))	('cancers', 'Phenotype', 'HP:0002664', (165, 172))	('anti-CTLA-4', 'Var', (193, 204))	('patients', 'Species', '9606', (124, 132))	('solid cancers', 'Disease', (159, 172))
343116	33143094	Nevertheless, prolonging inter-fractional interval results in reoxygenation (largely due to reduced oxygen consumption that follows extensive cancer cell death), thus removing hypoxia-induced immunosuppressive stimuli and radioresistance, which can be an issue particularly in bulky tumors.	('oxygen', 'Chemical', 'MESH:D010100', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('prolonging', 'Var', (14, 24))	('cancer', 'Disease', (142, 148))	('radioresistance', 'CPA', (222, 237))	('tumors', 'Disease', 'MESH:D009369', (283, 289))	('hypoxia', 'Disease', 'MESH:D000860', (176, 183))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('oxygen', 'Chemical', 'MESH:D010100', (100, 106))	('tumor', 'Phenotype', 'HP:0002664', (283, 288))	('removing', 'NegReg', (167, 175))	('reduced', 'NegReg', (92, 99))	('tumors', 'Disease', (283, 289))	('oxygen consumption', 'MPA', (100, 118))	('hypoxia', 'Disease', (176, 183))	('tumors', 'Phenotype', 'HP:0002664', (283, 289))	('reoxygenation', 'MPA', (62, 75))
343126	33143094	Hemi-irradiation also elicited abscopal effect which was of comparable magnitude to that after whole tumor irradiation.	('abscopal effect', 'CPA', (31, 46))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('Hemi-irradiation', 'Var', (0, 16))	('elicited', 'Reg', (22, 30))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
343153	33143094	In patients with CPS >= 1 pembrolizumab monotherapy resulted in significantly superior overall survival compared to standard of care systemic treatment.	('CPS >= 1', 'Var', (17, 25))	('superior', 'PosReg', (78, 86))	('patients', 'Species', '9606', (3, 11))	('pembrolizumab', 'Chemical', 'MESH:C582435', (26, 39))	('overall survival', 'MPA', (87, 103))
343169	33143094	Interestingly, the addition of one or two applications of low-dose cisplatin, a backbone of the standard HNSCC chemoradiation regimen, was also shown to strongly enhance the abscopal effect when used in combination with RT and anti-PD-1 in murine melanoma, adenocarcinoma, breast cancer, and colon cancer models.	('cancer', 'Phenotype', 'HP:0002664', (280, 286))	('carcinoma', 'Phenotype', 'HP:0030731', (262, 271))	('colon cancer', 'Disease', (292, 304))	('abscopal effect', 'MPA', (174, 189))	('HNSCC', 'Phenotype', 'HP:0012288', (105, 110))	('melanoma', 'Disease', 'MESH:D008545', (247, 255))	('breast cancer', 'Phenotype', 'HP:0003002', (273, 286))	('low-dose', 'Var', (58, 66))	('adenocarcinoma', 'Disease', (257, 271))	('enhance', 'PosReg', (162, 169))	('colon cancer', 'Phenotype', 'HP:0003003', (292, 304))	('breast cancer', 'Disease', 'MESH:D001943', (273, 286))	('breast cancer', 'Disease', (273, 286))	('cisplatin', 'Chemical', 'MESH:D002945', (67, 76))	('melanoma', 'Phenotype', 'HP:0002861', (247, 255))	('melanoma', 'Disease', (247, 255))	('colon cancer', 'Disease', 'MESH:D015179', (292, 304))	('adenocarcinoma', 'Disease', 'MESH:D000230', (257, 271))	('murine', 'Species', '10090', (240, 246))	('cancer', 'Phenotype', 'HP:0002664', (298, 304))
343176	31325708	Dysregulation of miRNAs can lead to tumorigenesis through changes in regulation of key cellular processes such as cell proliferation, cell survival, and apoptosis.	('cell survival', 'CPA', (134, 147))	('Dysregulation', 'Var', (0, 13))	('miR', 'Gene', '220972', (17, 20))	('miR', 'Gene', (17, 20))	('regulation of key cellular processes', 'MPA', (69, 105))	('changes', 'Reg', (58, 65))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('lead to', 'Reg', (28, 35))	('cell proliferation', 'CPA', (114, 132))	('tumor', 'Disease', (36, 41))	('apoptosis', 'CPA', (153, 162))
343182	31325708	We then demonstrated that miR-125a-5p regulates cell proliferation through cell cycle regulation at the G1/S transition.	('miR-125a-5p', 'Var', (26, 37))	('regulates', 'Reg', (38, 47))	('cell proliferation', 'CPA', (48, 66))	('5p', 'Chemical', '-', (35, 37))	('cell cycle regulation at the G1/S transition', 'CPA', (75, 119))
343183	31325708	We also show that miR-125a-5p can alter cell migration and modulate sensitivity to ionizing radiation.	('sensitivity to ionizing radiation', 'Phenotype', 'HP:0011133', (68, 101))	('alter', 'Reg', (34, 39))	('miR-125a-5p', 'Var', (18, 29))	('cell migration', 'CPA', (40, 54))	('sensitivity to ionizing radiation', 'MPA', (68, 101))	('modulate', 'Reg', (59, 67))	('5p', 'Chemical', '-', (27, 29))
343184	31325708	Finally, we identified putative mRNA targets of miR-125a-5p, including ERBB2, EIF4EBP1, and TXNRD1, which support the tumor suppressive mechanism of miR-125a-5p.	('ERBB2', 'Gene', '2064', (71, 76))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('EIF4EBP1', 'Gene', (78, 86))	('5p', 'Chemical', '-', (57, 59))	('ERBB2', 'Gene', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('EIF4EBP1', 'Gene', '1978', (78, 86))	('5p', 'Chemical', '-', (158, 160))	('tumor', 'Disease', (118, 123))	('miR-125a-5p', 'Var', (48, 59))	('miR-125a-5p', 'Var', (149, 160))	('TXNRD1', 'Gene', (92, 98))	('TXNRD1', 'Gene', '7296', (92, 98))
343185	31325708	Functional validation of ERBB2 suggests that miR-125a-5p affects cell proliferation and sensitivity to ionizing radiation, in part, through ERBB2.	('sensitivity to ionizing radiation', 'Phenotype', 'HP:0011133', (88, 121))	('ERBB2', 'Gene', '2064', (140, 145))	('miR-125a-5p', 'Var', (45, 56))	('affects', 'Reg', (57, 64))	('ERBB2', 'Gene', (140, 145))	('5p', 'Chemical', '-', (54, 56))	('ERBB2', 'Gene', '2064', (25, 30))	('cell proliferation', 'CPA', (65, 83))	('ERBB2', 'Gene', (25, 30))	('sensitivity to ionizing radiation', 'MPA', (88, 121))
343192	31325708	In the context of cancer, dysregulation of miRNA expression can lead to alteration in expression of oncogenes or tumor suppressor protein coding genes, leading to tumorigenesis or potentiation of a cancer-related phenotype.	('tumor', 'Disease', (113, 118))	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('dysregulation', 'Var', (26, 39))	('miR', 'Gene', '220972', (43, 46))	('miR', 'Gene', (43, 46))	('lead to alteration', 'Reg', (64, 82))	('cancer', 'Disease', (198, 204))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('expression', 'MPA', (86, 96))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Disease', (163, 168))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('cancer', 'Disease', (18, 24))	('cancer', 'Disease', 'MESH:D009369', (18, 24))	('potentiation', 'PosReg', (180, 192))
343215	31325708	In brief, synthetic microRNAs of miR-125a-5p and miR-551a, used as a non-specific control, was biotinylated at the 3' end of the RNA.	('miR-125a-5p', 'Var', (33, 44))	('synthetic', 'Species', '32630', (10, 19))	('miR-551a', 'Gene', (49, 57))	('miR-551a', 'Gene', '693135', (49, 57))	('5p', 'Chemical', '-', (42, 44))	('biotin', 'Chemical', 'MESH:D001710', (95, 101))
343254	31325708	This results suggests that miR-125a-5p is a potential marker associating low expression levels with local recurrence.	('miR-125a-5p', 'Var', (27, 38))	('5p', 'Chemical', '-', (36, 38))	('low expression levels', 'MPA', (73, 94))	('local recurrence', 'Disease', (100, 116))
343256	31325708	We did not observe any differences in between patients with no evidence of disease and patients with locoregional recurrence with the aforementioned risk factors, suggesting that miR-125a-5p expression is the only analyzed risk factor that is associated with locoregional recurrence.	('locoregional', 'Disease', (259, 271))	('associated', 'Reg', (243, 253))	('patients', 'Species', '9606', (46, 54))	('miR-125a-5p expression', 'Var', (179, 201))	('5p', 'Chemical', '-', (188, 190))	('patients', 'Species', '9606', (87, 95))
343258	31325708	Using OncoLnc, which links RNA-seq expression data with survival in The Cancer Genome Atlas (https://cancergenome.nih.gov), we find that patients with low levels of miR-125a-5p is associated with a worse overall survival than patients with high levels of miR-125a-5p (P = .006) (Figure 1B).	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('5p', 'Chemical', '-', (264, 266))	('cancer', 'Disease', (101, 107))	('overall survival', 'MPA', (204, 220))	('miR-125a-5p', 'Var', (165, 176))	('patients', 'Species', '9606', (137, 145))	('low', 'NegReg', (151, 154))	('patients', 'Species', '9606', (226, 234))	('5p', 'Chemical', '-', (174, 176))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('Cancer', 'Phenotype', 'HP:0002664', (72, 78))
343267	31325708	In both HN5 and UM-SCC-22B cell lines, there was an increase in the proportion of cells in the G1 phase with transfection of miR-125a-5p, with a concomitant proportion of cells decreased in S phase, in HN5 and UM-SCC-22B cells with miR-125a-5p mimic transfected, compared to controls (Figure 2C).	('G1 phase', 'CPA', (95, 103))	('transfection', 'Var', (109, 121))	('HN5', 'Gene', '100463289', (8, 11))	('HN5', 'Gene', (202, 205))	('increase', 'PosReg', (52, 60))	('UM-SCC-22B', 'CellLine', 'CVCL:7732', (16, 26))	('5p', 'Chemical', '-', (134, 136))	('HN5', 'Gene', (8, 11))	('5p', 'Chemical', '-', (241, 243))	('decreased', 'NegReg', (177, 186))	('miR-125a-5p', 'Var', (125, 136))	('HN5', 'Gene', '100463289', (202, 205))	('UM-SCC-22B', 'CellLine', 'CVCL:7732', (210, 220))	('S phase', 'CPA', (190, 197))
343270	31325708	Our data suggests that miR-125a-5p affects cell proliferation by regulating transit through the G1/S transition through p27 but does not affect DNA synthesis.	('transit', 'MPA', (76, 83))	('miR-125a-5p', 'Var', (23, 34))	('p27', 'Gene', (120, 123))	('5p', 'Chemical', '-', (32, 34))	('p27', 'Gene', '3429', (120, 123))	('affects', 'Reg', (35, 42))	('regulating', 'Reg', (65, 75))	('cell proliferation', 'CPA', (43, 61))
343274	31325708	We observed that there was decreased in vitro cell invasion with transfection of miR-125a-5p, compared to the control miRNA (Figure 3, C and D).	('5p', 'Chemical', '-', (90, 92))	('miR', 'Gene', '220972', (81, 84))	('miR', 'Gene', (81, 84))	('decreased', 'NegReg', (27, 36))	('vitro cell invasion', 'CPA', (40, 59))	('transfection', 'Var', (65, 77))	('miR', 'Gene', '220972', (118, 121))	('miR', 'Gene', (118, 121))
343277	31325708	With transfection of miR-125a-5p mimics, we observed a decrease in surviving fraction in response to ionizing radiation, compared to the control miRNA, in HN5 (Figure 4A) and UM-SCC-22B cells (Figure 4B).	('transfection', 'Var', (5, 17))	('HN5', 'Gene', '100463289', (155, 158))	('HN5', 'Gene', (155, 158))	('UM-SCC-22B', 'CellLine', 'CVCL:7732', (175, 185))	('5p', 'Chemical', '-', (30, 32))	('miR', 'Gene', '220972', (21, 24))	('miR', 'Gene', (21, 24))	('decrease', 'NegReg', (55, 63))	('miR', 'Gene', '220972', (145, 148))	('surviving fraction', 'CPA', (67, 85))	('miR', 'Gene', (145, 148))	('response to ionizing radiation', 'MPA', (89, 119))
343283	31325708	There was no increase in double-stranded DNA break formation without any ionizing radiation, in response to transfection of miR-125a-5p, suggesting that there is no contribution by miR-125a-5p by itself to double-stranded DNA damage (Figure 5 and Supplementary Fig.	('5p', 'Chemical', '-', (190, 192))	('miR-125a-5p', 'Var', (181, 192))	('double-stranded DNA break', 'MPA', (25, 50))	('5p', 'Chemical', '-', (133, 135))
343284	31325708	Our data suggests that miR-125a-5p has a role in modulating sensitivity to ionizing radiation in head and neck squamous cell carcinoma through delaying resolution of double-stranded DNA breaks.	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (97, 134))	('resolution of double-stranded DNA breaks', 'MPA', (152, 192))	('neck squamous cell carcinoma', 'Disease', (106, 134))	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (111, 134))	('miR-125a-5p', 'Var', (23, 34))	('delaying', 'NegReg', (143, 151))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (106, 134))	('5p', 'Chemical', '-', (32, 34))	('sensitivity to ionizing radiation', 'Phenotype', 'HP:0011133', (60, 93))	('modulating', 'Reg', (49, 59))	('sensitivity to ionizing radiation', 'MPA', (60, 93))
343290	31325708	In the end, we identified 41 mRNAs that were upregulated in tumor samples that contained a binding site for miR-125a-5p, as predicted by at least two prediction algorithms (Supplementary Table 2).	('miR-125a-5p', 'Var', (108, 119))	('binding', 'Interaction', (91, 98))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('upregulated', 'PosReg', (45, 56))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('mRNAs', 'MPA', (29, 34))	('5p', 'Chemical', '-', (117, 119))	('tumor', 'Disease', (60, 65))
343294	31325708	Analysis of the 3' untranslated region of TXNRD1 and EIF4EBP1 mRNA reveals putative, canonical binding sites for miR-125a-5p.	('TXNRD1', 'Gene', '7296', (42, 48))	('TXNRD1', 'Gene', (42, 48))	('EIF4EBP1', 'Gene', (53, 61))	('miR-125a-5p', 'Var', (113, 124))	('EIF4EBP1', 'Gene', '1978', (53, 61))	('5p', 'Chemical', '-', (122, 124))	('binding', 'Interaction', (95, 102))
343297	31325708	We then transfected miR-125a-5p into HN5 and UM-SCC-22B cell lines and then blotted for 4E-BP1 and TXNRD1 protein.	('TXNRD1', 'Gene', '7296', (99, 105))	('5p', 'Chemical', '-', (29, 31))	('4E-BP1', 'Gene', (88, 94))	('miR-125a-5p', 'Var', (20, 31))	('HN5', 'Gene', '100463289', (37, 40))	('UM-SCC-22B', 'CellLine', 'CVCL:7732', (45, 55))	('HN5', 'Gene', (37, 40))	('4E-BP1', 'Gene', '1978', (88, 94))	('TXNRD1', 'Gene', (99, 105))
343298	31325708	We found that miR-125a-5p was able to repress protein levels of TXNRD1 and EIF4EBP1 mRNA targets (Figure 6E).	('TXNRD1', 'Gene', (64, 70))	('EIF4EBP1', 'Gene', (75, 83))	('repress protein levels', 'MPA', (38, 60))	('miR-125a-5p', 'Var', (14, 25))	('5p', 'Chemical', '-', (23, 25))	('EIF4EBP1', 'Gene', '1978', (75, 83))	('TXNRD1', 'Gene', '7296', (64, 70))
343301	31325708	We also investigated ERBB2 mRNA as a target of miR-125a-5p, as it is an important signaling molecule in many cancers, including head and neck cancer.	('miR-125a-5p', 'Var', (47, 58))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('cancers', 'Disease', 'MESH:D009369', (109, 116))	('cancers', 'Phenotype', 'HP:0002664', (109, 116))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('cancers', 'Disease', (109, 116))	('head and neck cancer', 'Phenotype', 'HP:0012288', (128, 148))	('ERBB2', 'Gene', '2064', (21, 26))	('neck cancer', 'Disease', 'MESH:D006258', (137, 148))	('neck cancer', 'Disease', (137, 148))	('ERBB2', 'Gene', (21, 26))	('5p', 'Chemical', '-', (56, 58))
343303	31325708	We then analyzed the 3' untranslated region of ERBB2 and found that it contains a binding site for miR-125a-5p (Figure 7B).	('miR-125a-5p', 'Var', (99, 110))	('ERBB2', 'Gene', (47, 52))	('ERBB2', 'Gene', '2064', (47, 52))	('binding', 'Interaction', (82, 89))	('5p', 'Chemical', '-', (108, 110))
343308	31325708	7), and we also found that overexpression of ERBB2 results in increased resistance to ionizing radiation, compared to transfection of a control cDNA plasmid, suggesting that miR-125a-5p modulates sensitivity to radiation therapy, in part, through ERBB2 (Figure 7G).	('increased', 'PosReg', (62, 71))	('5p', 'Chemical', '-', (183, 185))	('miR-125a-5p', 'Var', (174, 185))	('sensitivity to radiation therapy', 'MPA', (196, 228))	('modulates', 'Reg', (186, 195))	('ERBB2', 'Gene', (247, 252))	('ERBB2', 'Gene', '2064', (247, 252))	('ERBB2', 'Gene', '2064', (45, 50))	('overexpression', 'PosReg', (27, 41))	('ERBB2', 'Gene', (45, 50))	('resistance to ionizing radiation', 'MPA', (72, 104))	('sensitivity to radiation', 'Phenotype', 'HP:0011133', (196, 220))
343318	31325708	This report has also identified three mRNA targets of miR-125a-5p in head and neck squamous cell carcinoma, specifically, ERBB2, which encodes for the erbB-2, otherwise known as HER2/neu, receptor tyrosine kinase, TXNRD1, which encodes for thioredoxin reductase 1, and EIF4EBP1, which encodes for the 4E-BP1 translation initiation factor.	('5p', 'Chemical', '-', (63, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('ERBB2', 'Gene', '2064', (122, 127))	('TXNRD1', 'Gene', (214, 220))	('neu', 'Gene', '2064', (183, 186))	('miR-125a-5p', 'Var', (54, 65))	('EIF4EBP1', 'Gene', '1978', (269, 277))	('thioredoxin reductase 1', 'Gene', '7296', (240, 263))	('4E-BP1', 'Gene', (301, 307))	('erbB-2', 'Gene', '2064', (151, 157))	('HER2', 'Gene', (178, 182))	('neck squamous cell carcinoma', 'Disease', (78, 106))	('EIF4EBP1', 'Gene', (269, 277))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (78, 106))	('TXNRD1', 'Gene', '7296', (214, 220))	('thioredoxin reductase 1', 'Gene', (240, 263))	('erbB-2', 'Gene', (151, 157))	('receptor tyrosine kinase', 'Gene', '5979', (188, 212))	('neu', 'Gene', (183, 186))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (83, 106))	('ERBB2', 'Gene', (122, 127))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (69, 106))	('receptor tyrosine kinase', 'Gene', (188, 212))	('4E-BP1', 'Gene', '1978', (301, 307))	('HER2', 'Gene', '2064', (178, 182))
343321	31325708	Our functional assays evaluating cell proliferation and sensitivity to ionization radiation suggest that miR-125a-5p acts, in part, through ERBB2.	('ionization radiation', 'Disease', (71, 91))	('miR-125a-5p', 'Var', (105, 116))	('5p', 'Chemical', '-', (114, 116))	('ERBB2', 'Gene', '2064', (140, 145))	('ERBB2', 'Gene', (140, 145))	('ionization radiation', 'Disease', 'MESH:D004194', (71, 91))
343336	31325708	In nasopharyngeal cancer, the detection of Epstein-Barr virus DNA after primary therapy with chemotherapy and radiotherapy was associated with worse survival than patients with undetectable levels of Epstein-Barr virus DNA, suggesting that there is a subset of patients that can potentially benefit from treatment escalation, which is the basis of the currently accruing NRG Oncology trial, NRG HN-001.	('patients', 'Species', '9606', (261, 269))	('Oncology', 'Phenotype', 'HP:0002664', (375, 383))	('patients', 'Species', '9606', (163, 171))	('worse', 'NegReg', (143, 148))	('Epstein-Barr virus', 'Species', '10376', (200, 218))	('nasopharyngeal cancer', 'Phenotype', 'HP:0100630', (3, 24))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('nasopharyngeal cancer', 'Disease', 'MESH:D009303', (3, 24))	('nasopharyngeal cancer', 'Disease', (3, 24))	('Epstein-Barr virus DNA', 'Var', (43, 65))	('Epstein-Barr virus', 'Species', '10376', (43, 61))
343364	30379847	For example, recurrent copy number aberrations or recurrent point mutations may reveal the drivers of carcinogenesis.	('copy number aberrations', 'Var', (23, 46))	('carcinogenesis', 'Disease', (102, 116))	('carcinogenesis', 'Disease', 'MESH:D063646', (102, 116))	('point mutations', 'Var', (60, 75))
343367	30379847	Examples include the PAM50 subtypes in breast cancer and the consensus subtypes in colorectal cancer.	('colorectal cancer', 'Disease', 'MESH:D015179', (83, 100))	('breast cancer', 'Phenotype', 'HP:0003002', (39, 52))	('colorectal cancer', 'Phenotype', 'HP:0003003', (83, 100))	('colorectal cancer', 'Disease', (83, 100))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('breast cancer', 'Disease', 'MESH:D001943', (39, 52))	('PAM50', 'Var', (21, 26))	('breast cancer', 'Disease', (39, 52))
343382	30379847	Here the power of integration of multiple data types is highlighted by the fact that the activity of this factor is associated with mutations in NFE2L2 as well as its inhibitor KEAP.	('activity', 'MPA', (89, 97))	('mutations', 'Var', (132, 141))	('NFE2L2', 'Gene', '4780', (145, 151))	('NFE2L2', 'Gene', (145, 151))	('associated', 'Reg', (116, 126))
343404	30379847	Third, the HER2 factor shows the expected strong association with ERBB2 copy number gain and protein upregulation, GRB7 copy number gain as well as EGFR protein upregulation.	('upregulation', 'PosReg', (101, 113))	('ERBB2', 'Gene', (66, 71))	('GRB7', 'Gene', '2886', (115, 119))	('EGFR', 'Gene', '1956', (148, 152))	('copy number', 'Var', (120, 131))	('EGFR', 'Gene', (148, 152))	('gain', 'PosReg', (132, 136))	('protein', 'MPA', (93, 100))	('GRB7', 'Gene', (115, 119))	('ERBB2', 'Gene', '2064', (66, 71))	('upregulation', 'PosReg', (161, 173))	('copy number', 'Var', (72, 83))	('gain', 'PosReg', (84, 88))	('HER2', 'Gene', (11, 15))	('HER2', 'Gene', '2064', (11, 15))
343406	30379847	The HER2, Luminal-Proliferative and 8q-gained factors, explain more variation in copy number data than in RNA expression data.	('HER2', 'Gene', '2064', (4, 8))	('copy number', 'Var', (81, 92))	('HER2', 'Gene', (4, 8))
343423	30379847	Consistent with the known prognostic value of ER status, a high value of the ER factor is associated with better survival in the METABRIC dataset (S12 Fig).	('high value', 'Var', (59, 69))	('better', 'PosReg', (106, 112))	('ER', 'Gene', '2099', (77, 79))	('ER', 'Gene', '2099', (46, 48))
343425	30379847	The gene-set enrichment analysis shows enrichment for signatures of ERBB2 amplification and the HER2-enriched PAM50 subtype.	('amplification', 'Var', (74, 87))	('ERBB2', 'Gene', '2064', (68, 73))	('ERBB2', 'Gene', (68, 73))	('HER2', 'Gene', (96, 100))	('HER2', 'Gene', '2064', (96, 100))
343430	30379847	Indeed, on the METABRIC data set, we find that samples characterized by a high value of the HER2 factor show worse survival (S12 Fig).	('worse', 'NegReg', (109, 114))	('HER2', 'Gene', '2064', (92, 96))	('HER2', 'Gene', (92, 96))	('high value', 'Var', (74, 84))
343456	30379847	One potential complication in identifying the 8q-gained factor is that it is strongly related to the Luminal-Proliferative factor (which is clearly identified in both sets): 8q-gains are associated with both factors and are often observed in Luminal tumors where they can increase proliferation through activation of MYC.	('increase', 'PosReg', (272, 280))	('MYC', 'Gene', (317, 320))	('Luminal tumors', 'Disease', 'MESH:D009369', (242, 256))	('proliferation', 'CPA', (281, 294))	('tumor', 'Phenotype', 'HP:0002664', (250, 255))	('Luminal tumors', 'Disease', (242, 256))	('8q-gains', 'Var', (174, 182))	('tumors', 'Phenotype', 'HP:0002664', (250, 256))	('MYC', 'Gene', '4609', (317, 320))	('activation', 'PosReg', (303, 313))
343462	30379847	We employed the same data types (gene expression, RPPA and copy number) as we employed in the breast cancer analysis.	('copy number', 'Var', (59, 70))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('breast cancer', 'Disease', 'MESH:D001943', (94, 107))	('breast cancer', 'Phenotype', 'HP:0003002', (94, 107))	('breast cancer', 'Disease', (94, 107))
343466	30379847	Finally, the Adenocarcinoma factor shows association with the RNA expression of a number of keratins, negative coefficients for both copy number and RNA expression of SOX2 and positive association with both RNA expression and copy number of NKX2-1 (also known as TTF1).	('negative', 'NegReg', (102, 110))	('carcinoma', 'Phenotype', 'HP:0030731', (18, 27))	('NKX2-1', 'Gene', (241, 247))	('Adenocarcinoma', 'Disease', (13, 27))	('TTF1', 'Gene', '7270', (263, 267))	('Adenocarcinoma', 'Disease', 'MESH:D000230', (13, 27))	('association', 'Interaction', (41, 52))	('NKX2-1', 'Gene', '7080', (241, 247))	('coefficients', 'MPA', (111, 123))	('copy number', 'Var', (226, 237))	('SOX2', 'Gene', '6657', (167, 171))	('SOX2', 'Gene', (167, 171))	('RNA expression', 'MPA', (62, 76))	('TTF1', 'Gene', (263, 267))
343467	30379847	As in breast cancer, most factors explain variation in each of the data types, with the largest proportion of the variation explained by a given factor mostly being the variation in RNA expression with the exceptions being the 8p11-gained and BSCC factors where the largest portion of the variance explained by these factors is the variation in the RPPA data.	('RNA expression', 'Protein', (182, 196))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('breast cancer', 'Disease', 'MESH:D001943', (6, 19))	('breast cancer', 'Disease', (6, 19))	('breast cancer', 'Phenotype', 'HP:0003002', (6, 19))	('variation', 'Var', (169, 178))
343479	30379847	Interestingly, in the primitive subtype of squamous cell carcinoma, tumors with high and low values for this factor exist (Fig 7B.2 and 7B.3, and S10 Fig).	('tumors', 'Disease', 'MESH:D009369', (68, 74))	('tumors', 'Disease', (68, 74))	('S10', 'Var', (146, 149))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (57, 66))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (43, 66))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('squamous cell carcinoma', 'Disease', (43, 66))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (43, 66))
343481	30379847	We also observe the expected associations between this factor and mutations in NFE2L2, STK11, KEAP1.	('mutations', 'Var', (66, 75))	('STK11', 'Gene', (87, 92))	('NFE2L2', 'Gene', '4780', (79, 85))	('KEAP1', 'Gene', '9817', (94, 99))	('associations', 'Interaction', (29, 41))	('NFE2L2', 'Gene', (79, 85))	('KEAP1', 'Gene', (94, 99))	('STK11', 'Gene', '6794', (87, 92))
343501	30379847	This conclusion is confirmed by a strong association of this factor with mutations in NFE2L2 and in its inhibitor KEAP1 (Fig 9A).	('association', 'Interaction', (41, 52))	('NFE2L2', 'Gene', '4780', (86, 92))	('KEAP1', 'Gene', '9817', (114, 119))	('NFE2L2', 'Gene', (86, 92))	('KEAP1', 'Gene', (114, 119))	('mutations', 'Var', (73, 82))
343502	30379847	Interestingly, the factor is depleted for EGFR mutations, although EGFR activates the NFE2L2 pathway by inhibiting KEAP1.	('activates', 'PosReg', (72, 81))	('EGFR', 'Gene', '1956', (42, 46))	('KEAP1', 'Gene', '9817', (115, 120))	('EGFR', 'Gene', (42, 46))	('NFE2L2', 'Gene', '4780', (86, 92))	('mutations', 'Var', (47, 56))	('inhibiting', 'NegReg', (104, 114))	('NFE2L2', 'Gene', (86, 92))	('KEAP1', 'Gene', (115, 120))	('EGFR', 'Gene', '1956', (67, 71))	('EGFR', 'Gene', (67, 71))
343623	24942260	Using an optimal cut-point of 10 buds/1 HPF, the 5-year OS of patients with a high grade (>=10 buds /1 HPF) for maximum tumor budding was significantly worse (n = 76; 39%) than those with a low grade (<10 buds /1 HPF; n = 409; 62%; p < 0.001) (Fig.	('OS', 'Chemical', '-', (56, 58))	('worse', 'NegReg', (152, 157))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('>=10 buds /1 HPF', 'Var', (90, 106))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('patients', 'Species', '9606', (62, 70))	('tumor', 'Disease', (120, 125))
343624	24942260	Using an optimal cut-point of 8 buds/10 HPFs, the 5-year OS of patients with high grade (>=8 buds /10 HPFs) for total tumor budding was significantly worse (n = 181; 46%) than those with a low grade (<8 buds /10 HPFs; n = 304; 67%; p = 0.007) (Fig.	('worse', 'NegReg', (150, 155))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('>=8 buds /10', 'Var', (89, 101))	('tumor', 'Disease', (118, 123))	('OS', 'Chemical', '-', (57, 59))	('patients', 'Species', '9606', (63, 71))
343625	24942260	The 5-year OS of patients with single cell invasion in the entire tumor was significantly worse (n = 197; 47%) than those without single cell invasion (n = 288; 67%; p = 0.002) (Fig.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('OS', 'Chemical', '-', (11, 13))	('tumor', 'Disease', (66, 71))	('single cell invasion', 'Var', (31, 51))	('worse', 'NegReg', (90, 95))	('patients', 'Species', '9606', (17, 25))	('tumor', 'Disease', 'MESH:D009369', (66, 71))
343626	24942260	Similarly, the 5-year OS of patients with single cell invasion in the tumor edge was significantly worse (n = 134; 42%) than those without single cell invasion (n = 351; 65%; p = 0.001) (Fig.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', (70, 75))	('OS', 'Chemical', '-', (22, 24))	('single cell invasion', 'Var', (42, 62))	('patients', 'Species', '9606', (28, 36))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('worse', 'NegReg', (99, 104))
343635	24942260	In each multivariate model, high grade for maximum budding (>=10 buds /1 HPF /1 HPF; Hazard ratio [HR] = 1.04; p = 0.014), high grade for total tumor budding (>=8 buds /1 HPF /10 HPFs; HR = 1.04; p = 0.029), single cell invasion in the entire tumor (HR = 1.47; p = 0.003), and single cell invasion at the tumor edge (HR = 1.49; p = 0.004) were independent prognostic factors of worse OS.	('tumor', 'Disease', (144, 149))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('tumor', 'Disease', 'MESH:D009369', (305, 310))	('tumor', 'Disease', 'MESH:D009369', (243, 248))	('tumor', 'Phenotype', 'HP:0002664', (305, 310))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('tumor', 'Disease', (305, 310))	('OS', 'Chemical', '-', (384, 386))	('single', 'Var', (277, 283))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))	('tumor', 'Disease', (243, 248))
343654	24942260	With regard to the size of the smallest tumor nest, our study demonstrated that single cell invasion (in both the entire tumor and the tumor edge) was an independent prognostic factor.	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('smallest tumor', 'Disease', (31, 45))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('tumor', 'Disease', (135, 140))	('tumor', 'Disease', (121, 126))	('tumor', 'Disease', 'MESH:D009369', (135, 140))	('single', 'Var', (80, 86))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('smallest tumor', 'Disease', 'MESH:D009369', (31, 45))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
343685	24942260	In multivariate analysis of OS adjusting for clinical and pathological factors (including pathologic stage and lymphovascular invasion) which were significantly prognostic in univariate analyses, maximum budding (HR = 1.04), total tumor budding (HR = 1.04), single cell invasion in the entire tumor (HR = 1.47), and single cell invasion in the tumor edge (HR = 1.49) were found to be independent prognostic factors for worse outcomes.	('maximum budding', 'CPA', (196, 211))	('OS', 'Chemical', '-', (28, 30))	('tumor', 'Disease', 'MESH:D009369', (231, 236))	('tumor', 'Disease', 'MESH:D009369', (293, 298))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('tumor', 'Phenotype', 'HP:0002664', (293, 298))	('single', 'Var', (258, 264))	('tumor', 'Phenotype', 'HP:0002664', (344, 349))	('tumor', 'Disease', (344, 349))	('single', 'Var', (316, 322))	('tumor', 'Disease', (231, 236))	('tumor', 'Disease', (293, 298))	('tumor', 'Disease', 'MESH:D009369', (344, 349))
343725	33925308	In NSCLC, it is estimated that activating mutations of epidermal growth factor receptor (EGFR) occur in 10% to 20% of Caucasian and at least 50% of Asian cases, with the most common EGFR mutations including deletion in exon 19 (19 Del) or point mutation in exon 21 (L858R).	('NSCLC', 'Disease', (3, 8))	('EGFR', 'Gene', (89, 93))	('L858R', 'Mutation', 'rs121434568', (266, 271))	('EGFR', 'Gene', (182, 186))	('EGFR', 'Gene', '1956', (182, 186))	('NSCLC', 'Disease', 'MESH:D002289', (3, 8))	('epidermal growth factor receptor', 'Gene', (55, 87))	('SCLC', 'Phenotype', 'HP:0030357', (4, 8))	('epidermal growth factor receptor', 'Gene', '1956', (55, 87))	('NSCLC', 'Phenotype', 'HP:0030358', (3, 8))	('deletion in', 'Var', (207, 218))	('point mutation', 'Var', (239, 253))	('EGFR', 'Gene', '1956', (89, 93))
343726	33925308	Targeted therapies have been developed using tyrosine kinase inhibitors (TKIs) for treatment of patients harboring EGFR mutations.	('patients', 'Species', '9606', (96, 104))	('EGFR', 'Gene', '1956', (115, 119))	('EGFR', 'Gene', (115, 119))	('mutations', 'Var', (120, 129))
343727	33925308	After the first-line treatment, a secondary resistant mutation (T90M) often occurs, estimated to affect 48-62% of EGFR TKI-resistant patients, to whom third-generation TKI may be administered.	('T90M', 'Mutation', 'p.T90M', (64, 68))	('patients', 'Species', '9606', (133, 141))	('EGFR', 'Gene', '1956', (114, 118))	('T90M', 'Var', (64, 68))	('EGFR', 'Gene', (114, 118))
343728	33925308	Thus, early detection of activating and resistant EGFR mutations may allow for personalized treatment of NSCLC patients and improve clinical outcome.	('NSCLC', 'Disease', 'MESH:D002289', (105, 110))	('NSCLC', 'Phenotype', 'HP:0030358', (105, 110))	('mutations', 'Var', (55, 64))	('activating', 'PosReg', (25, 35))	('allow', 'Reg', (69, 74))	('EGFR', 'Gene', '1956', (50, 54))	('improve', 'PosReg', (124, 131))	('EGFR', 'Gene', (50, 54))	('NSCLC', 'Disease', (105, 110))	('SCLC', 'Phenotype', 'HP:0030357', (106, 110))	('patients', 'Species', '9606', (111, 119))
343729	33925308	Other identified mutations such as anaplastic lymphoma kinase (ALK) or ROS proto-oncogene 1 (ROS1) rearrangements also constitute therapeutic targets in NSCLC patients.	('ROS1', 'Gene', '6098', (93, 97))	('NSCLC', 'Phenotype', 'HP:0030358', (153, 158))	('ALK', 'Gene', '238', (63, 66))	('lymphoma', 'Phenotype', 'HP:0002665', (46, 54))	('anaplastic lymphoma kinase', 'Gene', '238', (35, 61))	('NSCLC', 'Disease', (153, 158))	('NSCLC', 'Disease', 'MESH:D002289', (153, 158))	('ALK', 'Gene', (63, 66))	('ROS1', 'Gene', (93, 97))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (35, 54))	('anaplastic lymphoma kinase', 'Gene', (35, 61))	('patients', 'Species', '9606', (159, 167))	('rearrangements', 'Var', (99, 113))	('SCLC', 'Phenotype', 'HP:0030357', (154, 158))
343731	33925308	Mutations in other genes such as KRAS proto-oncogene GTPase (KRAS), tumor protein p53 (TP53), and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) are also reported in NSCLC, with co-existing mutations implicating lower progression free survival (PFS).	('PIK3CA', 'Gene', '5290', (170, 176))	('NSCLC', 'Phenotype', 'HP:0030358', (199, 204))	('KRAS', 'Gene', (61, 65))	('p53', 'Gene', (82, 85))	('phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha', 'Gene', '5290', (98, 168))	('mutations', 'Var', (223, 232))	('tumor', 'Disease', (68, 73))	('TP53', 'Gene', '7157', (87, 91))	('progression free survival', 'CPA', (251, 276))	('KRAS', 'Gene', '3845', (33, 37))	('Mutations', 'Var', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('PIK3CA', 'Gene', (170, 176))	('KRAS', 'Gene', (33, 37))	('SCLC', 'Phenotype', 'HP:0030357', (200, 204))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('lower', 'NegReg', (245, 250))	('NSCLC', 'Disease', 'MESH:D002289', (199, 204))	('TP53', 'Gene', (87, 91))	('reported', 'Reg', (187, 195))	('p53', 'Gene', '7157', (82, 85))	('NSCLC', 'Disease', (199, 204))	('KRAS', 'Gene', '3845', (61, 65))
343741	33925308	SCLC is also characterized by high incidence of inactivating mutations of TP53 and retinoblastoma 1 gene (RB1).	('SCLC', 'Gene', '7864', (0, 4))	('SCLC', 'Phenotype', 'HP:0030357', (0, 4))	('inactivating mutations', 'Var', (48, 70))	('RB1', 'Gene', '5925', (106, 109))	('retinoblastoma 1', 'Gene', '5925', (83, 99))	('retinoblastoma', 'Phenotype', 'HP:0009919', (83, 97))	('TP53', 'Gene', '7157', (74, 78))	('TP53', 'Gene', (74, 78))	('SCLC', 'Gene', (0, 4))	('RB1', 'Gene', (106, 109))	('retinoblastoma 1', 'Gene', (83, 99))
343742	33925308	Additional mutations have been detected at lower frequencies and in smaller populations of SCLC patients, such as amplification of MYC, MYCN, MYCL1, and FGR1 or inactivation of PTEN.	('MYC', 'Gene', (131, 134))	('MYCN', 'Gene', '4613', (136, 140))	('SCLC', 'Phenotype', 'HP:0030357', (91, 95))	('FGR1', 'Gene', (153, 157))	('MYCL1', 'Gene', (142, 147))	('MYC', 'Gene', (136, 139))	('amplification', 'Var', (114, 127))	('MYC', 'Gene', '4609', (131, 134))	('inactivation', 'Var', (161, 173))	('MYC', 'Gene', (142, 145))	('PTEN', 'Gene', (177, 181))	('patients', 'Species', '9606', (96, 104))	('SCLC', 'Gene', '7864', (91, 95))	('MYCL1', 'Gene', '4610', (142, 147))	('SCLC', 'Gene', (91, 95))	('MYCN', 'Gene', (136, 140))	('MYC', 'Gene', '4609', (136, 139))	('PTEN', 'Gene', '5728', (177, 181))	('MYC', 'Gene', '4609', (142, 145))
343750	33925308	Liquid biopsies have already proved to be efficient for assessing tumor mutations in SCLC and NSCLC as acquired resistance mechanisms.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('mutations', 'Var', (72, 81))	('NSCLC', 'Phenotype', 'HP:0030358', (94, 99))	('tumor', 'Disease', (66, 71))	('NSCLC', 'Disease', (94, 99))	('NSCLC', 'Disease', 'MESH:D002289', (94, 99))	('SCLC', 'Gene', (85, 89))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('SCLC', 'Gene', '7864', (95, 99))	('SCLC', 'Phenotype', 'HP:0030357', (95, 99))	('SCLC', 'Gene', (95, 99))	('SCLC', 'Gene', '7864', (85, 89))	('SCLC', 'Phenotype', 'HP:0030357', (85, 89))
343771	33925308	Despite variability among different investigations, such as the method used for cell isolation, disease subtype, patient stage, and CTCs cut-off value, most studies demonstrated that CTC quantification is strongly associated with survival, emphasizing its value for LCa prognostication.	('patient', 'Species', '9606', (113, 120))	('LCa', 'Phenotype', 'HP:0100526', (266, 269))	('quantification', 'Var', (187, 201))	('survival', 'MPA', (230, 238))	('associated with', 'Reg', (214, 229))	('CTC', 'MPA', (183, 186))
343773	33925308	Heterogeneity arises from different parameters: epithelial-mesenchymal transition (EMT) process, cellular size, intact or apoptotic state, and the presence of somatic oncogenic mutations, commonly affecting EGFR and TP53, and ALK rearrangements.	('ALK', 'Gene', '238', (226, 229))	('TP53', 'Gene', (216, 220))	('affecting', 'Reg', (197, 206))	('EGFR', 'Gene', '1956', (207, 211))	('ALK', 'Gene', (226, 229))	('epithelial-mesenchymal transition', 'CPA', (48, 81))	('mutations', 'Var', (177, 186))	('EGFR', 'Gene', (207, 211))	('TP53', 'Gene', '7157', (216, 220))
343783	33925308	In their study, 31% of patients with T790M-negative tissue samples, tested positive for T790M mutation in plasma.	('T790M', 'Mutation', 'rs121434569', (37, 42))	('T790M', 'Mutation', 'rs121434569', (88, 93))	('positive', 'Reg', (75, 83))	('patients', 'Species', '9606', (23, 31))	('T790M', 'Var', (88, 93))
343784	33925308	Objective response rate (ORR) and PFS were similar for patients with T90M detected in tumor or plasma, when treated with the third-generation EGFR-TKI Osimertinib.	('T90M', 'Var', (69, 73))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Disease', (86, 91))	('EGFR', 'Gene', '1956', (142, 146))	('EGFR', 'Gene', (142, 146))	('patients', 'Species', '9606', (55, 63))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('T90M', 'Mutation', 'p.T90M', (69, 73))
343787	33925308	first reported on a liquid biopsy assay to quantify somatic variants in cfDNA with a custom SCLC-specific gene panel.	('cfDNA', 'Gene', (72, 77))	('SCLC', 'Gene', '7864', (92, 96))	('SCLC', 'Phenotype', 'HP:0030357', (92, 96))	('SCLC', 'Gene', (92, 96))	('variants', 'Var', (60, 68))
343789	33925308	In 59% of patients with ES SCLC, the most common mutations were detected in TP53 (70%) and RB1 (52%).	('SCLC', 'Phenotype', 'HP:0030357', (27, 31))	('SCLC', 'Gene', (27, 31))	('RB1', 'Gene', '5925', (91, 94))	('mutations', 'Var', (49, 58))	('TP53', 'Gene', '7157', (76, 80))	('RB1', 'Gene', (91, 94))	('TP53', 'Gene', (76, 80))	('detected', 'Reg', (64, 72))	('patients', 'Species', '9606', (10, 18))	('SCLC', 'Gene', '7864', (27, 31))
343792	33925308	Aberrant DNA methylation, commonly found in cancer and leading to dysregulated gene expression, has shown as a promising biomarker assessed in ctDNA.	('Aberrant', 'Var', (0, 8))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('DNA', 'Protein', (9, 12))	('dysregulated gene expression', 'MPA', (66, 94))	('ctDNA', 'Disease', (143, 148))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
343805	33925308	reported on its application for the detection of the EGFR mutation in NSCLC patients by combining with the allele-specific Scorpion Amplification Refractory Mutation System (SARMS) assay.	('patients', 'Species', '9606', (76, 84))	('NSCLC', 'Disease', (70, 75))	('mutation', 'Var', (58, 66))	('NSCLC', 'Disease', 'MESH:D002289', (70, 75))	('SCLC', 'Phenotype', 'HP:0030357', (71, 75))	('EGFR', 'Gene', '1956', (53, 57))	('EGFR', 'Gene', (53, 57))	('NSCLC', 'Phenotype', 'HP:0030358', (70, 75))
343807	33925308	The activating mutation was found in 11 out of 12 patients with corresponding tissue analysis, and the T90M mutation was detected in 2 of 6 patients which showed response to TKIs and 9 of 14 who presented disease progression.	('T90M', 'Var', (103, 107))	('patients', 'Species', '9606', (50, 58))	('activating', 'PosReg', (4, 14))	('patients', 'Species', '9606', (140, 148))	('T90M', 'Mutation', 'p.T90M', (103, 107))
343839	33925308	In some cases, KRAS mutations were detected in plasma of negative tissue samples.	('KRAS', 'Gene', (15, 19))	('KRAS', 'Gene', '3845', (15, 19))	('mutations', 'Var', (20, 29))
343847	33925308	The system proved effective in detecting specific cancer mutations in SF3B1, NOTCH1, and TP53 genes in five samples, with 25 microL of plasma.	('TP53', 'Gene', '7157', (89, 93))	('TP53', 'Gene', (89, 93))	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('NOTCH1', 'Gene', '4851', (77, 83))	('NOTCH1', 'Gene', (77, 83))	('SF3B1', 'Gene', (70, 75))	('mutations', 'Var', (57, 66))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('SF3B1', 'Gene', '23451', (70, 75))
343850	33925308	When applied to the continuous monitoring of HER-2 type breast cancer, a point mutation in phosphatidylinositol-4,5-bisphosphate 3-kinase (PIK3CA) was detected, in a liver metastasis.	('HER-2', 'Gene', (45, 50))	('PIK3CA', 'Gene', '5290', (139, 145))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('point mutation', 'Var', (73, 87))	('phosphatidylinositol', 'Chemical', 'MESH:D010716', (91, 111))	('breast cancer', 'Disease', 'MESH:D001943', (56, 69))	('PIK3CA', 'Gene', (139, 145))	('breast cancer', 'Phenotype', 'HP:0003002', (56, 69))	('breast cancer', 'Disease', (56, 69))	('HER-2', 'Gene', '2064', (45, 50))
343851	33925308	presented a chip-based digital-PCR (dPCR) to detect and quantify cfDNA and ctDNA based on KRAS mutation of plasma from metastatic colorectal cancer patients.	('colorectal cancer', 'Phenotype', 'HP:0003003', (130, 147))	('patients', 'Species', '9606', (148, 156))	('colorectal cancer', 'Disease', (130, 147))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('KRAS', 'Gene', (90, 94))	('cfDNA', 'Disease', (65, 70))	('KRAS', 'Gene', '3845', (90, 94))	('colorectal cancer', 'Disease', 'MESH:D015179', (130, 147))	('mutation', 'Var', (95, 103))
343884	33925308	Clinical trial NCT01193829 (Development of Circulating Tumor Cell Molecular Diagnostics Using a Novel Microfluidic Device) aimed at comparing EGFR mutations in primary NSCLC tumors of respective CTCs isolated via a label-free microfluidic device.	('NSCLC tumors', 'Disease', (168, 180))	('mutations', 'Var', (147, 156))	('EGFR', 'Gene', '1956', (142, 146))	('EGFR', 'Gene', (142, 146))	('Tumor', 'Phenotype', 'HP:0002664', (55, 60))	('NSCLC', 'Phenotype', 'HP:0030358', (168, 173))	('SCLC', 'Phenotype', 'HP:0030357', (169, 173))	('NSCLC tumors', 'Disease', 'MESH:D009369', (168, 180))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('tumors', 'Phenotype', 'HP:0002664', (174, 180))
343885	33925308	Additionally, the clinical response of patients treated with gefitinib and its effect on CTCs EGFR mutations detected by the platform was also assessed.	('patients', 'Species', '9606', (39, 47))	('EGFR', 'Gene', '1956', (94, 98))	('EGFR', 'Gene', (94, 98))	('mutations', 'Var', (99, 108))	('gefitinib', 'Chemical', 'MESH:D000077156', (61, 70))
343886	33925308	Similarly, clinical trial NCT01734915 (Detecting EGFR T790M Mutations from Circulating Tumor Cells) was initiated in 2012 and intended to assess EGFR mutations in CTCs isolated using the microfluidic CTC-chip.	('EGFR', 'Gene', '1956', (49, 53))	('EGFR', 'Gene', (49, 53))	('EGFR', 'Gene', '1956', (145, 149))	('T790M', 'Mutation', 'rs121434569', (54, 59))	('Tumor', 'Phenotype', 'HP:0002664', (87, 92))	('Mutations', 'Var', (60, 69))	('EGFR', 'Gene', (145, 149))	('T790M Mutations', 'Var', (54, 69))
343887	33925308	The study aimed at comparing the EGFR mutation found in tissue biopsy and CTCs and matching genotyping, with the long-term goal of developing a less invasive liquid biopsy method to detect the EGFR mutation.	('EGFR', 'Gene', '1956', (193, 197))	('EGFR', 'Gene', '1956', (33, 37))	('EGFR', 'Gene', (193, 197))	('mutation', 'Var', (38, 46))	('EGFR', 'Gene', (33, 37))
343888	33925308	T790M mutation was observed in 30 (75%) tumor biopsies, 28 (70%) isolated CTCs samples, and 32 (80%) ctDNA samples, with the authors reporting on mostly comparable results between CTCs/ctDNA and tissue-based genotyping.	('observed', 'Reg', (19, 27))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('T790M', 'Mutation', 'rs121434569', (0, 5))	('T790M', 'Var', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))
343889	33925308	Interestingly, while CTCs and ctDNA genotyping showed to be unsuccessful in 20 to 30% of the cases, the combination of both assays enabled genotyping of all patients, even identifying the T90M mutation in 35% of patients in whom tissue biopsy was negative or indeterminate, and further demonstrating the usefulness of combining circulating biomarkers characterization.	('enabled', 'Reg', (131, 138))	('T90M', 'Mutation', 'p.T90M', (188, 192))	('patients', 'Species', '9606', (212, 220))	('patients', 'Species', '9606', (157, 165))	('T90M', 'Var', (188, 192))
343892	33925308	The Cobas  EGFR Mutation Test v2 was the first method approved by the FDA, a PCR-based liquid biopsy test to detect EGFR mutations in NSCLC.	('NSCLC', 'Disease', 'MESH:D002289', (134, 139))	('mutations', 'Var', (121, 130))	('EGFR', 'Gene', '1956', (11, 15))	('NSCLC', 'Phenotype', 'HP:0030358', (134, 139))	('EGFR', 'Gene', (11, 15))	('SCLC', 'Phenotype', 'HP:0030357', (135, 139))	('EGFR', 'Gene', '1956', (116, 120))	('EGFR', 'Gene', (116, 120))	('NSCLC', 'Disease', (134, 139))
343893	33925308	In vitro diagnostics (IVD) tests to detect activating and resistance EGFR mutations in plasma, using allele-specific real-time PCR assays are currently employed and recommended for cfDNA EGFR testing to complement tissue biopsy or as an alternative when tumor tissue is limited or non-accessible.	('EGFR', 'Gene', '1956', (69, 73))	('tumor', 'Disease', (254, 259))	('EGFR', 'Gene', (69, 73))	('EGFR', 'Gene', '1956', (187, 191))	('mutations', 'Var', (74, 83))	('IVD', 'Disease', 'MESH:C538167', (22, 25))	('IVD', 'Disease', (22, 25))	('EGFR', 'Gene', (187, 191))	('tumor', 'Disease', 'MESH:D009369', (254, 259))	('activating', 'PosReg', (43, 53))	('tumor', 'Phenotype', 'HP:0002664', (254, 259))
343894	33925308	While these methods disclose high specificity, sensitivity remains relatively low with false negatives being reported, as circulating tumor DNA may not express EGFR mutations in all patients whose tumors harbor mutations.	('tumors', 'Disease', 'MESH:D009369', (197, 203))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('EGFR', 'Gene', '1956', (160, 164))	('tumors', 'Phenotype', 'HP:0002664', (197, 203))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('EGFR', 'Gene', (160, 164))	('patients', 'Species', '9606', (182, 190))	('mutations', 'Var', (165, 174))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('tumors', 'Disease', (197, 203))	('tumor', 'Disease', (197, 202))	('tumor', 'Disease', (134, 139))
343895	33925308	The ASSESS clinical trial (NCT01785888) performed an international, multicenter, and non-comparative study to evaluate the utility of plasma ctDNA in EGFR mutation testing in NSCLC patients with locally advanced or metastatic disease, across Europe and Japan (Table 2).	('NSCLC', 'Disease', 'MESH:D002289', (175, 180))	('EGFR', 'Gene', (150, 154))	('EGFR', 'Gene', '1956', (150, 154))	('NSCLC', 'Phenotype', 'HP:0030358', (175, 180))	('metastatic', 'CPA', (215, 225))	('locally', 'Disease', (195, 202))	('SCLC', 'Phenotype', 'HP:0030357', (176, 180))	('patients', 'Species', '9606', (181, 189))	('mutation', 'Var', (155, 163))	('NSCLC', 'Disease', (175, 180))
343898	33925308	EGFR mutation was detected in 16% of tissue and 9% of total plasma samples.	('mutation', 'Var', (5, 13))	('detected', 'Reg', (18, 26))	('EGFR', 'Gene', '1956', (0, 4))	('EGFR', 'Gene', (0, 4))
343899	33925308	False negative results were detected in 102 patients and 25 patients disclosed EGFR mutation positive result only in plasma.	('patients', 'Species', '9606', (44, 52))	('EGFR', 'Gene', '1956', (79, 83))	('EGFR', 'Gene', (79, 83))	('patients', 'Species', '9606', (60, 68))	('mutation', 'Var', (84, 92))
343901	33925308	assessed the EGFR T790M mutation in circulating tumor DNA in the plasma of NSCLC patients receiving TKI treatment.	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('tumor', 'Disease', (48, 53))	('NSCLC', 'Phenotype', 'HP:0030358', (75, 80))	('SCLC', 'Phenotype', 'HP:0030357', (76, 80))	('patients', 'Species', '9606', (81, 89))	('T790M', 'Mutation', 'rs121434569', (18, 23))	('NSCLC', 'Disease', (75, 80))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('EGFR', 'Gene', '1956', (13, 17))	('NSCLC', 'Disease', 'MESH:D002289', (75, 80))	('EGFR', 'Gene', (13, 17))	('T790M', 'Var', (18, 23))
343902	33925308	Overall survival correlated with the initial TKI treatment and the T790M mutation status.	('T790M', 'Mutation', 'rs121434569', (67, 72))	('TKI', 'Disease', (45, 48))	('T790M', 'Var', (67, 72))	('Overall', 'MPA', (0, 7))
343906	33925308	The detection of T90M mutation in ctDNA had an influence on clinical prognosis and subsequent treatment with AZD9291 related to the longest patient survival.	('influence', 'Reg', (47, 56))	('patient', 'Species', '9606', (140, 147))	('T90M', 'Mutation', 'p.T90M', (17, 21))	('T90M', 'Var', (17, 21))	('ctDNA', 'Gene', (34, 39))	('AZD9291', 'Chemical', 'MESH:C000596361', (109, 116))
343908	33925308	The lab-on-a-disc ability to purify cfDNA from peripheral blood of NSCLC patients with EGFR L858R mutations was compared with a commercial kit (Qiagen QIAamp Circulating Nucleic Acid Kit), demonstrating the same performance.	('L858R', 'Mutation', 'rs121434568', (92, 97))	('Kit', 'Gene', (183, 186))	('EGFR', 'Gene', '1956', (87, 91))	('NSCLC', 'Phenotype', 'HP:0030358', (67, 72))	('EGFR', 'Gene', (87, 91))	('kit', 'Gene', '3815', (139, 142))	('Kit', 'Gene', '3815', (183, 186))	('NSCLC', 'Disease', (67, 72))	('kit', 'Gene', (139, 142))	('L858R mutations', 'Var', (92, 107))	('patients', 'Species', '9606', (73, 81))	('NSCLC', 'Disease', 'MESH:D002289', (67, 72))	('SCLC', 'Phenotype', 'HP:0030357', (68, 72))
343909	33925308	Additionally, a patient follow-up was performed were the occurrence of resistance to TKI treatment for EGFR mediated by T790M was detected earlier than with the second tissue biopsy, improving patient personalized treatment selection.	('EGFR', 'Gene', '1956', (103, 107))	('EGFR', 'Gene', (103, 107))	('T790M', 'Mutation', 'rs121434569', (120, 125))	('T790M', 'Var', (120, 125))	('patient', 'Species', '9606', (193, 200))	('patient', 'Species', '9606', (16, 23))
343917	33925308	Whereas CTCs allow for the study of whole cells, DNA and RNA molecular profiling as well as protein expression, ctDNA can assess mutations, DNA methylation and copy number aberrations, with both supporting patient stratification, understanding and estimation of metastasis, estimate OS, characterize tumor's mutational profile with real-time monitoring of disease progression and response to therapies, as well as detection of MRD.	('tumor', 'Phenotype', 'HP:0002664', (300, 305))	('tumor', 'Disease', (300, 305))	('mutations', 'Var', (129, 138))	('patient', 'Species', '9606', (206, 213))	('tumor', 'Disease', 'MESH:D009369', (300, 305))
343925	31514474	Conversely, in liver and gastric cancers, high levels of MMP8 worsen the prognosis.	('MMP8', 'Gene', (57, 61))	('liver', 'Disease', (15, 20))	('cancers', 'Phenotype', 'HP:0002664', (33, 40))	('high levels', 'Var', (42, 53))	('gastric cancer', 'Phenotype', 'HP:0012126', (25, 39))	('gastric cancers', 'Disease', (25, 40))	('gastric cancers', 'Disease', 'MESH:D013274', (25, 40))	('gastric cancers', 'Phenotype', 'HP:0012126', (25, 40))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('worsen', 'NegReg', (62, 68))	('prognosis', 'CPA', (73, 82))	('Co', 'Chemical', 'MESH:C065987', (0, 2))
343926	31514474	Expression and genetic alterations of MMP8 can be used as a prognostic factor by examination of the tumor and serum/plasma.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('MMP8', 'Gene', (38, 42))	('tumor', 'Disease', (100, 105))	('genetic alterations', 'Var', (15, 34))	('tumor', 'Disease', 'MESH:D009369', (100, 105))
343936	31514474	MMP8, also known as neutrophil collagenase or collagenase-2, cleaves triple helical type I collagen and numerous other ECM and non-ECM substrates.	('collagenase-2', 'Gene', '4317', (46, 59))	('cleaves', 'Var', (61, 68))	('triple helical type I collagen', 'Protein', (69, 99))	('MMP8', 'Gene', (0, 4))	('neutrophil collagenase', 'Gene', (20, 42))	('neutrophil collagenase', 'Gene', '4317', (20, 42))	('collagenase-2', 'Gene', (46, 59))
343943	31514474	We aim to create an overview of the potential prognostic value of MMP8 in blood and tumor samples as well as highlight the effect of genetic changes in MMP8 for prognosis.	('genetic changes', 'Var', (133, 148))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumor', 'Disease', (84, 89))	('MMP8', 'Gene', (152, 156))
343959	31514474	A higher level of MMP8 in the epidermal-dermal border correlates with melanoma invasiveness.	('melanoma invasiveness', 'Disease', (70, 91))	('melanoma invasiveness', 'Disease', 'MESH:D008545', (70, 91))	('melanoma', 'Phenotype', 'HP:0002861', (70, 78))	('MMP8', 'Var', (18, 22))
343974	31514474	It can be concluded, that high MMP8 seems to have a tumor-predicting role in both liver and ovarian cancers.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('cancers', 'Phenotype', 'HP:0002664', (100, 107))	('ovarian cancers', 'Phenotype', 'HP:0100615', (92, 107))	('tumor', 'Disease', (52, 57))	('high MMP8', 'Var', (26, 35))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('liver and ovarian cancers', 'Disease', 'MESH:D010051', (82, 107))	('ovarian cancer', 'Phenotype', 'HP:0100615', (92, 106))	('tumor', 'Disease', 'MESH:D009369', (52, 57))
343978	31514474	found that negative MMP8 staining was associated with stage I cancer, T1 tumor stage as well as no lymph node metastasis and furthermore, women with negative MMP8 staining had a better prognosis.	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('associated', 'Reg', (38, 48))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('MMP8', 'Gene', (158, 162))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('MMP8', 'Gene', (20, 24))	('negative', 'Var', (11, 19))	('tumor', 'Disease', (73, 78))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('women', 'Species', '9606', (138, 143))
344002	31514474	Interestingly, low or high MMP8 serum levels correlated with poor prognosis in gastric cancer patients.	('patients', 'Species', '9606', (94, 102))	('gastric cancer', 'Phenotype', 'HP:0012126', (79, 93))	('MMP8', 'Gene', (27, 31))	('serum levels', 'MPA', (32, 44))	('high', 'Var', (22, 26))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('gastric cancer', 'Disease', (79, 93))	('gastric cancer', 'Disease', 'MESH:D013274', (79, 93))
344013	31514474	Studies on MMP8 genetics in cancer have focused largely on single nucleotide polymorphisms (SNPs), which are collected in Table 3.	('cancer', 'Disease', (28, 34))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('single nucleotide polymorphisms', 'Var', (59, 90))
344015	31514474	SNP rs11225395 is associated with a lower risk of developing breast cancer and a higher overall survival from breast cancer as shown by three independent studies.	('lower', 'NegReg', (36, 41))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('breast cancer', 'Disease', (61, 74))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('rs11225395', 'Mutation', 'rs11225395', (4, 14))	('breast cancer', 'Phenotype', 'HP:0003002', (61, 74))	('higher', 'PosReg', (81, 87))	('breast cancer', 'Disease', 'MESH:D001943', (110, 123))	('breast cancer', 'Phenotype', 'HP:0003002', (110, 123))	('SNP rs11225395', 'Var', (0, 14))	('breast cancer', 'Disease', (110, 123))	('breast cancer', 'Disease', 'MESH:D001943', (61, 74))
344020	31514474	In the case of HNSCC, no correlation between SNP rs11225395 and survival of the patients was found, nor was this SNP associated with risk of oral cancer.	('rs11225395', 'Var', (49, 59))	('patients', 'Species', '9606', (80, 88))	('associated', 'Reg', (117, 127))	('SCC', 'Phenotype', 'HP:0002860', (17, 20))	('SCC', 'Disease', (17, 20))	('oral cancer', 'Disease', 'MESH:D009062', (141, 152))	('oral cancer', 'Disease', (141, 152))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('SCC', 'Disease', 'MESH:D002294', (17, 20))	('rs11225395', 'Mutation', 'rs11225395', (49, 59))
344021	31514474	Studies on the susceptibility to hepatocellular carcinoma, bladder cancer, acute lymphatic leukemia in children and lung cancer revealed no correlation to SNP rs11225395.	('lung cancer', 'Phenotype', 'HP:0100526', (116, 127))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('bladder cancer', 'Phenotype', 'HP:0009725', (59, 73))	('hepatocellular carcinoma', 'Disease', (33, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (48, 57))	('lymphatic leukemia', 'Phenotype', 'HP:0005526', (81, 99))	('acute lymphatic leukemia', 'Disease', (75, 99))	('acute lymphatic leukemia', 'Disease', 'MESH:D015451', (75, 99))	('leukemia', 'Phenotype', 'HP:0001909', (91, 99))	('lung cancer', 'Disease', (116, 127))	('acute lymphatic leukemia', 'Phenotype', 'HP:0006721', (75, 99))	('children', 'Species', '9606', (103, 111))	('SNP rs11225395', 'Var', (155, 169))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (33, 57))	('bladder cancer', 'Disease', (59, 73))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (33, 57))	('lung cancer', 'Disease', 'MESH:D008175', (116, 127))	('bladder cancer', 'Disease', 'MESH:D001749', (59, 73))	('rs11225395', 'Mutation', 'rs11225395', (159, 169))
344022	31514474	The SNP rs1940475 (A259G) is located in the pro-domain of MMP8 and alters the structural stability of the domain, thus decreasing the activation of MMP8.	('alters', 'Reg', (67, 73))	('activation', 'MPA', (134, 144))	('decreasing', 'NegReg', (119, 129))	('MMP8', 'Gene', (58, 62))	('rs1940475 (A259G', 'Var', (8, 24))	('structural stability of the', 'MPA', (78, 105))	('A259G', 'Mutation', 'rs1940475', (19, 24))	('MMP8', 'MPA', (148, 152))	('rs1940475', 'Mutation', 'rs1940475', (8, 17))
344023	31514474	revealed that 73.6-88.8% of their thyroid carcinoma tumor samples harbored SNP rs1940475 and the authors postulated, based on the location of this SNP, an effect on the function of MMP8.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('effect', 'Reg', (155, 161))	('thyroid carcinoma tumor', 'Disease', (34, 57))	('SNP', 'Var', (75, 78))	('thyroid carcinoma tumor', 'Disease', 'MESH:D013964', (34, 57))	('rs1940475', 'Mutation', 'rs1940475', (79, 88))	('rs1940475', 'Var', (79, 88))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (34, 51))	('function', 'MPA', (169, 177))	('carcinoma', 'Phenotype', 'HP:0030731', (42, 51))
344024	31514474	showed decreased enzymatic activity of MMP8 harboring this SNP as well as increased recurrence and lower survival of gastric adenocarcinoma patients.	('enzymatic activity', 'MPA', (17, 35))	('lower', 'NegReg', (99, 104))	('SNP', 'Var', (59, 62))	('decreased', 'NegReg', (7, 16))	('increased', 'PosReg', (74, 83))	('gastric adenocarcinoma', 'Disease', 'MESH:D013274', (117, 139))	('gastric adenocarcinoma', 'Disease', (117, 139))	('patients', 'Species', '9606', (140, 148))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('survival', 'CPA', (105, 113))	('MMP8', 'Gene', (39, 43))	('recurrence', 'CPA', (84, 94))
344025	31514474	found no correlation with the risk of bladder cancer or its type to SNP rs1940475.	('bladder cancer', 'Phenotype', 'HP:0009725', (38, 52))	('bladder cancer', 'Disease', 'MESH:D001749', (38, 52))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('bladder cancer', 'Disease', (38, 52))	('rs1940475', 'Mutation', 'rs1940475', (72, 81))	('rs1940475', 'Var', (72, 81))
344027	31514474	associated SNP rs1940475 with the risk of basal cell carcinoma (but not SCC or melanoma) but the association was not significant in age-adjusted analysis.	('SNP rs1940475', 'Var', (11, 24))	('rs1940475', 'Mutation', 'rs1940475', (15, 24))	('basal cell carcinoma', 'Disease', (42, 62))	('SCC', 'Disease', 'MESH:D002294', (72, 75))	('basal cell carcinoma', 'Disease', 'MESH:D002280', (42, 62))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (42, 62))	('carcinoma', 'Phenotype', 'HP:0030731', (53, 62))	('SCC', 'Phenotype', 'HP:0002860', (72, 75))	('SCC', 'Disease', (72, 75))	('melanoma', 'Phenotype', 'HP:0002861', (79, 87))	('melanoma', 'Disease', (79, 87))	('melanoma', 'Disease', 'MESH:D008545', (79, 87))
344029	31514474	found that SNP rs2155052 (C17G) in the MMP8 promoter region is associated with decreased risk of lung cancer, especially in high-risk patients such as ever-smokers.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('decreased', 'NegReg', (79, 88))	('lung cancer', 'Disease', 'MESH:D008175', (97, 108))	('patients', 'Species', '9606', (134, 142))	('C17G', 'Var', (26, 30))	('rs2155052', 'Mutation', 'rs2155052', (15, 24))	('C17G', 'SUBSTITUTION', 'None', (26, 30))	('lung cancer', 'Disease', (97, 108))	('lung cancer', 'Phenotype', 'HP:0100526', (97, 108))	('MMP8', 'Gene', (39, 43))
344030	31514474	An intronic SNP rs1892886 is associated with breast cancer and was also found to have a lower frequency in patients with lymph node metastasis, along with SNPs rs11225395, rs1940475 and rs1276284.	('rs1276284', 'Mutation', 'rs1276284', (186, 195))	('lymph node metastasis', 'CPA', (121, 142))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('rs11225395', 'Mutation', 'rs11225395', (160, 170))	('rs1892886', 'Mutation', 'rs1892886', (16, 25))	('breast cancer', 'Disease', 'MESH:D001943', (45, 58))	('rs1940475', 'Mutation', 'rs1940475', (172, 181))	('rs11225395', 'Var', (160, 170))	('breast cancer', 'Disease', (45, 58))	('rs1892886', 'Var', (16, 25))	('breast cancer', 'Phenotype', 'HP:0003002', (45, 58))	('associated', 'Reg', (29, 39))	('rs1276284', 'Var', (186, 195))	('rs1940475', 'Var', (172, 181))	('patients', 'Species', '9606', (107, 115))
344031	31514474	On the contrary to other studies, SNP rs17099462 decreased the expression of MMP8 and was shown to be associated with the increased risk of death from ovarian cancer.	('associated', 'Reg', (102, 112))	('SNP rs17099462', 'Var', (34, 48))	('death', 'Disease', 'MESH:D003643', (140, 145))	('death', 'Disease', (140, 145))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('ovarian cancer', 'Phenotype', 'HP:0100615', (151, 165))	('expression', 'MPA', (63, 73))	('ovarian cancer', 'Disease', 'MESH:D010051', (151, 165))	('decreased', 'NegReg', (49, 58))	('MMP8', 'Protein', (77, 81))	('ovarian cancer', 'Disease', (151, 165))	('rs17099462', 'Mutation', 'rs17099462', (38, 48))
344032	31514474	MMP8 SNPs rs35866072 and rs34009635 have no effect on the risks of childhood acute lymphocytic leukemia, breast, bladder, oral or lung cancer.	('lung cancer', 'Phenotype', 'HP:0100526', (130, 141))	('rs35866072', 'Mutation', 'rs35866072', (10, 20))	('acute lymphocytic leukemia', 'Disease', 'MESH:D054198', (77, 103))	('bladder', 'Disease', (113, 120))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('rs35866072', 'Var', (10, 20))	('lung cancer', 'Disease', 'MESH:D008175', (130, 141))	('oral', 'Disease', (122, 126))	('acute lymphocytic leukemia', 'Phenotype', 'HP:0006721', (77, 103))	('rs34009635', 'Mutation', 'rs34009635', (25, 35))	('breast', 'Disease', (105, 111))	('acute lymphocytic leukemia', 'Disease', (77, 103))	('leukemia', 'Phenotype', 'HP:0001909', (95, 103))	('lung cancer', 'Disease', (130, 141))	('rs34009635', 'Var', (25, 35))
344034	31514474	found that melanomas harbor somatic MMP8 mutations, which decrease MMP8 activity and lead to increased colony formation and cell migration in vitro as well as metastasis formation in vivo.	('mutations', 'Var', (41, 50))	('melanomas', 'Disease', 'MESH:D008545', (11, 20))	('increased', 'PosReg', (93, 102))	('activity', 'MPA', (72, 80))	('cell migration', 'CPA', (124, 138))	('decrease', 'NegReg', (58, 66))	('melanomas', 'Disease', (11, 20))	('metastasis formation', 'CPA', (159, 179))	('MMP8', 'Gene', (36, 40))	('MMP8', 'Protein', (67, 71))	('melanomas', 'Phenotype', 'HP:0002861', (11, 20))	('melanoma', 'Phenotype', 'HP:0002861', (11, 19))	('colony formation', 'CPA', (103, 119))
344042	31514474	Subsequently, MMP8 KO mice were also shown to be susceptible to melanoma.	('MMP8 KO', 'Var', (14, 21))	('mice', 'Species', '10090', (22, 26))	('melanoma', 'Phenotype', 'HP:0002861', (64, 72))	('melanoma', 'Disease', (64, 72))	('melanoma', 'Disease', 'MESH:D008545', (64, 72))	('susceptible', 'Reg', (49, 60))
344044	31514474	MMP8 was also upregulated in the secretome of DNA-dependent protein kinase, catalytic subunit (DNA-PKcs)-silenced melanoma cells that metastasized less in vivo and migrated/invaded less in vitro, providing indirect evidence for the protective role of MMP8.	('melanoma', 'Disease', 'MESH:D008545', (114, 122))	('DNA-PKcs', 'Gene', '5591', (95, 103))	('migrated/invaded', 'CPA', (164, 180))	('DNA-dependent protein kinase, catalytic subunit', 'Gene', '5591', (46, 93))	('MMP8', 'Gene', (0, 4))	('metastasized', 'CPA', (134, 146))	('-silenced', 'Var', (104, 113))	('DNA-PKcs', 'Gene', (95, 103))	('less', 'NegReg', (147, 151))	('less', 'NegReg', (181, 185))	('upregulated', 'PosReg', (14, 25))	('melanoma', 'Phenotype', 'HP:0002861', (114, 122))	('melanoma', 'Disease', (114, 122))
344050	31514474	Systemic MMP8 expression was found to decrease tumor size, hinder tumorigenesis and protect from metastasis formation.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('expression', 'Var', (14, 24))	('tumor', 'Disease', (66, 71))	('protect', 'NegReg', (84, 91))	('decrease', 'NegReg', (38, 46))	('hinder', 'NegReg', (59, 65))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('MMP8', 'Gene', (9, 13))	('metastasis formation', 'CPA', (97, 117))	('tumor', 'Disease', (47, 52))
344053	31514474	MMP8 has also been shown to affect the protease web by, e.g., decreasing the levels of MMP3 and MMP9 in breast cancer cells, which was speculated to decrease the malignant behavior of the cells.	('affect', 'Reg', (28, 34))	('MMP9', 'Gene', '4318', (96, 100))	('MMP9', 'Gene', (96, 100))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('breast cancer', 'Disease', 'MESH:D001943', (104, 117))	('levels', 'MPA', (77, 83))	('breast cancer', 'Disease', (104, 117))	('MMP3', 'Gene', (87, 91))	('protease web', 'Enzyme', (39, 51))	('decreasing', 'NegReg', (62, 72))	('breast cancer', 'Phenotype', 'HP:0003002', (104, 117))	('decrease', 'NegReg', (149, 157))	('MMP8', 'Var', (0, 4))	('MMP3', 'Gene', '4314', (87, 91))	('malignant behavior of', 'CPA', (162, 183))
344054	31514474	Furthermore, MMP8 overexpression was shown to increase the expression of interleukins 6 and 8 in breast cancer cells, which was postulated to be connected to inflammatory response rather than cancer progression.	('MMP8', 'Gene', (13, 17))	('increase', 'PosReg', (46, 54))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('interleukins 6 and 8', 'Gene', '3569', (73, 93))	('breast cancer', 'Disease', 'MESH:D001943', (97, 110))	('overexpression', 'Var', (18, 32))	('cancer', 'Disease', (192, 198))	('expression', 'MPA', (59, 69))	('cancer', 'Disease', 'MESH:D009369', (192, 198))	('breast cancer', 'Phenotype', 'HP:0003002', (97, 110))	('breast cancer', 'Disease', (97, 110))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))
344063	31514474	found that female MMP8 KO mice are especially prone to carcinogen-induced tongue cancer and that MMP8 cleaves estrogen receptors alpha and beta.	('tongue cancer', 'Disease', 'MESH:D014062', (74, 87))	('estrogen receptors alpha', 'Protein', (110, 134))	('prone', 'Reg', (46, 51))	('cleaves', 'Var', (102, 109))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('tongue cancer', 'Disease', (74, 87))	('estrogen', 'Chemical', 'MESH:D004967', (110, 118))	('mice', 'Species', '10090', (26, 30))
344064	31514474	Later, MMP8 overexpression was shown to reduce the invasion and migration of OTSCC cells in vitro and to change the gene and protein expression of various factors, including a decrease in VEGF-C.	('reduce', 'NegReg', (40, 46))	('MMP8', 'Gene', (7, 11))	('VEGF-C', 'Gene', '7424', (188, 194))	('SCC', 'Phenotype', 'HP:0002860', (79, 82))	('SCC', 'Disease', (79, 82))	('overexpression', 'Var', (12, 26))	('invasion', 'CPA', (51, 59))	('decrease', 'NegReg', (176, 184))	('SCC', 'Disease', 'MESH:D002294', (79, 82))	('VEGF-C', 'Gene', (188, 194))	('change', 'Reg', (105, 111))
344065	31514474	Lung adenocarcinoma cells treated with hepatocyte growth factor variants showed inhibition of proliferation, reduced invasion and increased amounts of active MMP8, which was suggested to facilitate the tumor-protective effects.	('MMP8', 'Protein', (158, 162))	('inhibition', 'NegReg', (80, 90))	('reduced', 'NegReg', (109, 116))	('tumor', 'Disease', (202, 207))	('amounts', 'MPA', (140, 147))	('facilitate', 'PosReg', (187, 197))	('proliferation', 'CPA', (94, 107))	('Lung adenocarcinoma', 'Disease', 'MESH:C538231', (0, 19))	('Lung adenocarcinoma', 'Phenotype', 'HP:0030078', (0, 19))	('increased', 'PosReg', (130, 139))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('Lung adenocarcinoma', 'Disease', (0, 19))	('carcinoma', 'Phenotype', 'HP:0030731', (10, 19))	('invasion', 'CPA', (117, 125))	('variants', 'Var', (64, 72))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))
344067	31514474	showed that silencing of MMP8 in prostate cancer cells led to increased ligand binding of beta1 integrin and higher prostate cancer cell invasion in vitro as well as increased breast cancer lung extravasation in vivo.	('increased', 'PosReg', (62, 71))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('prostate cancer', 'Disease', (116, 131))	('beta1 integrin', 'Gene', (90, 104))	('beta1 integrin', 'Gene', '3688', (90, 104))	('ligand binding', 'Interaction', (72, 86))	('higher', 'PosReg', (109, 115))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('prostate cancer', 'Disease', 'MESH:D011471', (33, 48))	('prostate cancer', 'Phenotype', 'HP:0012125', (33, 48))	('MMP8', 'Gene', (25, 29))	('prostate cancer', 'Disease', (33, 48))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('silencing', 'Var', (12, 21))	('breast cancer', 'Phenotype', 'HP:0003002', (176, 189))	('increased', 'PosReg', (166, 175))	('breast cancer', 'Disease', 'MESH:D001943', (176, 189))	('breast cancer', 'Disease', (176, 189))	('prostate cancer', 'Disease', 'MESH:D011471', (116, 131))	('prostate cancer', 'Phenotype', 'HP:0012125', (116, 131))
344068	31514474	Yet overexpression of integrin alpha6beta4 in OSCC cells did not change MMP8 mRNA expression, which shows, that MMP8 affects integrin but not vice versa.	('integrin', 'MPA', (125, 133))	('OSCC', 'Disease', (46, 50))	('SCC', 'Phenotype', 'HP:0002860', (47, 50))	('OSCC', 'Disease', 'MESH:D002294', (46, 50))	('MMP8', 'Var', (112, 116))	('affects', 'Reg', (117, 124))
344074	31514474	Bone marrow cells produce MMP8 along with other MMPs during multiple myeloma progression in vivo and the tumor growth can be reduced with the broad spectrum MMP inhibitor; SC-964.	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('multiple myeloma', 'Phenotype', 'HP:0006775', (60, 76))	('reduced', 'NegReg', (125, 132))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('multiple myeloma', 'Disease', 'MESH:D009101', (60, 76))	('MMP8', 'Var', (26, 30))	('tumor', 'Disease', (105, 110))	('multiple myeloma', 'Disease', (60, 76))
344084	31514474	Three independent studies show that MMP8 reduces interstitial tumor fluid pressure, increases fluid flow in various murine tumors, namely lung cancer, soft tissue sarcoma and HNSCC, and enhances the efficacies of oncolytic virus therapy and liposomal drugs.	('enhances', 'PosReg', (186, 194))	('tumors', 'Disease', 'MESH:D009369', (123, 129))	('SCC', 'Disease', 'MESH:D002294', (177, 180))	('lung cancer', 'Disease', 'MESH:D008175', (138, 149))	('lung cancer', 'Phenotype', 'HP:0100526', (138, 149))	('SCC', 'Disease', (177, 180))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('fluid flow', 'MPA', (94, 104))	('reduces', 'NegReg', (41, 48))	('interstitial tumor', 'Disease', (49, 67))	('murine', 'Species', '10090', (116, 122))	('MMP8', 'Var', (36, 40))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (151, 170))	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (151, 170))	('soft tissue sarcoma', 'Disease', (151, 170))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('sarcoma', 'Phenotype', 'HP:0100242', (163, 170))	('lung cancer', 'Disease', (138, 149))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('tumors', 'Disease', (123, 129))	('efficacies', 'CPA', (199, 209))	('oncolytic virus therapy', 'CPA', (213, 236))	('interstitial tumor', 'Disease', 'MESH:D007984', (49, 67))	('increases', 'PosReg', (84, 93))	('liposomal', 'Protein', (241, 250))	('SCC', 'Phenotype', 'HP:0002860', (177, 180))
344101	31514474	showed that prostate cancer patients with MMP8 SNP rs11225395 benefit more from androgen deprivation therapy than other patients.	('prostate cancer', 'Disease', (12, 27))	('benefit', 'PosReg', (62, 69))	('rs11225395', 'Var', (51, 61))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('androgen', 'Chemical', 'MESH:D000728', (80, 88))	('androgen', 'Disease', (80, 88))	('prostate cancer', 'Disease', 'MESH:D011471', (12, 27))	('patients', 'Species', '9606', (120, 128))	('prostate cancer', 'Phenotype', 'HP:0012125', (12, 27))	('rs11225395', 'Mutation', 'rs11225395', (51, 61))	('patients', 'Species', '9606', (28, 36))
344104	31514474	Inhibition of MMPs has been considered as a potential clinical intervention in cancer treatment.	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('MMPs', 'Protein', (14, 18))	('Inhibition', 'Var', (0, 10))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))
344114	31514474	The studies published to date, suggest that high MMP8 protein levels might predict better survival for tongue and some breast cancer patients, but they provide a worse prognosis in hepatocellular and ovarian cancers.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('high', 'Var', (44, 48))	('breast cancer', 'Disease', 'MESH:D001943', (119, 132))	('cancers', 'Phenotype', 'HP:0002664', (208, 215))	('breast cancer', 'Disease', (119, 132))	('MMP8 protein', 'Protein', (49, 61))	('patients', 'Species', '9606', (133, 141))	('breast cancer', 'Phenotype', 'HP:0003002', (119, 132))	('tongue', 'Disease', (103, 109))	('ovarian cancer', 'Phenotype', 'HP:0100615', (200, 214))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('better', 'PosReg', (83, 89))	('survival', 'CPA', (90, 98))	('ovarian cancers', 'Phenotype', 'HP:0100615', (200, 215))	('hepatocellular and ovarian cancers', 'Disease', 'MESH:D010051', (181, 215))
344119	31514474	SNPs, which modulate MMP8 transcription and activity, seem to play the strongest role in cancer prognosis and are beneficial for breast, bladder and gastric cancer patients but detrimental in ovarian cancer patients.	('transcription', 'MPA', (26, 39))	('MMP8', 'Gene', (21, 25))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('cancer', 'Disease', (89, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('gastric cancer', 'Disease', (149, 163))	('cancer', 'Disease', 'MESH:D009369', (200, 206))	('patients', 'Species', '9606', (164, 172))	('detrimental in ovarian cancer', 'Disease', (177, 206))	('gastric cancer', 'Disease', 'MESH:D013274', (149, 163))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('bladder', 'Disease', (137, 144))	('activity', 'MPA', (44, 52))	('cancer', 'Disease', (157, 163))	('breast', 'Disease', (129, 135))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('patients', 'Species', '9606', (207, 215))	('ovarian cancer', 'Phenotype', 'HP:0100615', (192, 206))	('detrimental in ovarian cancer', 'Disease', 'MESH:D010051', (177, 206))	('gastric cancer', 'Phenotype', 'HP:0012126', (149, 163))	('SNPs', 'Var', (0, 4))	('cancer', 'Disease', (200, 206))
344122	31514474	In these cancers, MMP8 slows the metastatic process both in vivo and in vitro, which explains why patients benefit from MMP8.	('cancers', 'Disease', 'MESH:D009369', (9, 16))	('cancers', 'Phenotype', 'HP:0002664', (9, 16))	('cancers', 'Disease', (9, 16))	('MMP8', 'Var', (18, 22))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('patients', 'Species', '9606', (98, 106))	('slows', 'NegReg', (23, 28))	('metastatic process', 'CPA', (33, 51))
344139	31514474	DFS Disease-free survival  ECM Extracellular matrix  EMT Epithelial-mesenchymal transition  HNSCC Head and neck squamous cell carcinoma  MMP Matrix metalloproteinase  MMP8 Matrix metalloproteinase 8  MMPI Matrix metalloproteinase inhibitor  OS Overall survival  OSCC Oral squamous cell carcinoma  OTSCC Oral tongue squamous cell carcinoma  PMN Polymorphonuclear neutrophils  RFS Recurrence- or relapse-free survival  SCC Squamous cell carcinoma  SNP Single nucleotide polymorphism  TGF-beta1 Transforming growth factor beta1  TIMP-1 Metalloproteinase inhibitor 1  VEGF-C Vascular endothelial growth factor C	('Squamous cell carcinoma', 'Disease', (421, 444))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (272, 295))	('Single nucleotide polymorphism', 'Var', (450, 480))	('Squamous cell carcinoma', 'Disease', 'MESH:D002294', (421, 444))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (112, 135))	('OSCC', 'Disease', (262, 266))	('SCC', 'Phenotype', 'HP:0002860', (263, 266))	('carcinoma', 'Phenotype', 'HP:0030731', (286, 295))	('squamous cell carcinoma', 'Disease', (272, 295))	('Matrix metalloproteinase 8', 'Gene', '4317', (172, 198))	('Transforming growth factor beta1', 'Gene', (492, 524))	('SCC', 'Disease', 'MESH:D002294', (263, 266))	('SCC', 'Phenotype', 'HP:0002860', (94, 97))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (315, 338))	('Metalloproteinase inhibitor 1', 'Gene', (533, 562))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('Transforming growth factor beta1', 'Gene', '7040', (492, 524))	('SCC', 'Disease', (263, 266))	('SCC', 'Disease', 'MESH:D002294', (94, 97))	('SCC', 'Phenotype', 'HP:0002860', (299, 302))	('SCC', 'Phenotype', 'HP:0002860', (417, 420))	('carcinoma', 'Phenotype', 'HP:0030731', (435, 444))	('Metalloproteinase inhibitor 1', 'Gene', '7076', (533, 562))	('SCC', 'Disease', (94, 97))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (272, 295))	('TGF-beta1', 'Gene', (482, 491))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (315, 338))	('TIMP-1', 'Gene', (526, 532))	('SCC', 'Disease', 'MESH:D002294', (299, 302))	('TIMP-1', 'Gene', '7076', (526, 532))	('SCC', 'Disease', 'MESH:D002294', (417, 420))	('Matrix metalloproteinase 8', 'Gene', (172, 198))	('VEGF-C', 'Gene', (564, 570))	('OSCC', 'Disease', 'MESH:D002294', (262, 266))	('neck squamous cell carcinoma', 'Disease', 'MESH:C535575', (107, 135))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (112, 135))	('carcinoma', 'Phenotype', 'HP:0030731', (329, 338))	('SCC', 'Disease', (299, 302))	('neck squamous cell carcinoma', 'Disease', (107, 135))	('TGF-beta1', 'Gene', '7040', (482, 491))	('Squamous cell carcinoma', 'Phenotype', 'HP:0002860', (421, 444))	('squamous cell carcinoma', 'Disease', (315, 338))	('VEGF-C', 'Gene', '7424', (564, 570))	('SCC', 'Disease', (417, 420))
344141	29034103	Similar to other cancers associated with prolonged exposure to carcinogens, HNSCCs often have a high burden of mutations, contributing to substantial inter- and intra-tumor heterogeneity.	('intra-tumor', 'Disease', (161, 172))	('mutations', 'Var', (111, 120))	('HNSCCs', 'Disease', (76, 82))	('cancers', 'Phenotype', 'HP:0002664', (17, 24))	('intra-tumor', 'Disease', 'MESH:D009369', (161, 172))	('cancers', 'Disease', (17, 24))	('cancers', 'Disease', 'MESH:D009369', (17, 24))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
344145	29034103	Frequent activating mutations in PIK3CA and inactivating mutations in NOTCH1 are seen in both subtypes of HNSCC, emphasizing the importance of these pathways.	('PIK3CA', 'Gene', '5290', (33, 39))	('HNSCC', 'Disease', (106, 111))	('activating', 'PosReg', (9, 19))	('NOTCH1', 'Gene', (70, 76))	('PIK3CA', 'Gene', (33, 39))	('inactivating mutations', 'Var', (44, 66))
344147	29034103	Targets of these alterations including AJUBA and FAT1, both involved in the regulation of NOTCH/CTNNB1 signaling.	('AJUBA', 'Gene', '84962', (39, 44))	('FAT1', 'Gene', (49, 53))	('AJUBA', 'Gene', (39, 44))	('rat', 'Species', '10116', (21, 24))	('alterations', 'Var', (17, 28))	('FAT1', 'Gene', '2195', (49, 53))
344166	29034103	Amongst non-lung and non-skin tumor types, head and neck cancer has one of the highest rates of non-synonymous mutations and a high degree of genomic instability, which contribute to the enormous heterogeneity of HNSCC.	('neck cancer', 'Disease', 'MESH:D006258', (52, 63))	('neck cancer', 'Disease', (52, 63))	('non-synonymous mutations', 'Var', (96, 120))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('skin tumor', 'Phenotype', 'HP:0008069', (25, 35))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('highest', 'Reg', (79, 86))	('head and neck cancer', 'Phenotype', 'HP:0012288', (43, 63))	('tumor', 'Disease', (30, 35))	('rat', 'Species', '10116', (87, 90))
344191	29034103	Copy number alterations (CNA) are frequent in HNSCC and are highly concordant across most of the genome for HPV- and HPV+ cases.	('HNSCC', 'Disease', (46, 51))	('rat', 'Species', '10116', (16, 19))	('HPV', 'Species', '10566', (108, 111))	('HPV', 'Species', '10566', (117, 120))	('Copy number alterations', 'Var', (0, 23))
344194	29034103	Commonly seen deletions prominently cover parts of chromosome 3p and 8p, impacting two tumor suppressor genes: FHIT (3p; expression loss is associated with worse survival in HNSCC) and CSMD1 (8p).	('FHIT', 'Gene', '2272', (111, 115))	('tumor suppressor', 'Gene', '7248', (87, 103))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('loss', 'NegReg', (132, 136))	('expression', 'MPA', (121, 131))	('deletions', 'Var', (14, 23))	('impacting', 'Reg', (73, 82))	('CSMD1', 'Gene', (185, 190))	('FHIT', 'Gene', (111, 115))	('CSMD1', 'Gene', '64478', (185, 190))	('worse', 'NegReg', (156, 161))	('tumor suppressor', 'Gene', (87, 103))
344205	29034103	Functionally, PIK3CA regulates phosphorylation of AKT1, and mutated PIK3CA has been shown to attenuate apoptotic signals and support tumor invasion.	('AKT1', 'Protein', (50, 54))	('PIK3CA', 'Gene', (68, 74))	('support', 'PosReg', (125, 132))	('apoptotic signals', 'CPA', (103, 120))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('PIK3CA', 'Gene', '5290', (68, 74))	('phosphorylation', 'MPA', (31, 46))	('regulates', 'Reg', (21, 30))	('attenuate', 'NegReg', (93, 102))	('mutated', 'Var', (60, 67))	('tumor', 'Disease', (133, 138))	('PIK3CA', 'Gene', (14, 20))	('PIK3CA', 'Gene', '5290', (14, 20))
344206	29034103	Additionally, mutationally activated PIK3CA has been shown to support cyclin D activity; thus, further emphasizing the tremendous relevance of cell cycle dysregulation in head and neck cancers.	('PIK3CA', 'Gene', '5290', (37, 43))	('head and neck cancers', 'Phenotype', 'HP:0012288', (171, 192))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('cyclin D activity', 'MPA', (70, 87))	('neck cancers', 'Disease', (180, 192))	('support', 'PosReg', (62, 69))	('cancers', 'Phenotype', 'HP:0002664', (185, 192))	('cell cycle dysregulation', 'Phenotype', 'HP:0011018', (143, 167))	('dysregulation in head', 'Phenotype', 'HP:0000234', (154, 175))	('mutationally activated', 'Var', (14, 36))	('neck cancers', 'Disease', 'MESH:D006258', (180, 192))	('PIK3CA', 'Gene', (37, 43))	('head and neck cancer', 'Phenotype', 'HP:0012288', (171, 191))
344209	29034103	PIK3CA in particular was mutated in 12.6 % of cases (19/151), which is substantially less than the number of cases with mutated PIK3CA (21 %, 58/279) reported by the TCGA.	('PIK3CA', 'Gene', '5290', (128, 134))	('PIK3CA', 'Gene', (0, 6))	('PIK3CA', 'Gene', '5290', (0, 6))	('PIK3CA', 'Gene', (128, 134))	('mutated', 'Var', (25, 32))
344210	29034103	Nevertheless, assessment of patient derived xenografts expressing wild type PI3KCA or mutant PI3KCA and treated with vehicle or the mTOR/PI3K inhibitor BEZ-235 indicated tumors with mutated PI3KCA were exquisitely sensitive to the small molecule inhibitor, whereas tumors without the mutation did not respond to the treatment.	('mutated', 'Var', (182, 189))	('BEZ-235', 'Chemical', 'MESH:C531198', (152, 159))	('mTOR', 'Gene', '2475', (132, 136))	('PI3', 'Gene', (93, 96))	('PI3', 'Gene', '5266', (137, 140))	('tumors', 'Disease', 'MESH:D009369', (265, 271))	('tumors', 'Disease', 'MESH:D009369', (170, 176))	('raf', 'Gene', (49, 52))	('PI3', 'Gene', (76, 79))	('PI3', 'Gene', (137, 140))	('PI3', 'Gene', '5266', (190, 193))	('mutant', 'Var', (86, 92))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('tumors', 'Phenotype', 'HP:0002664', (265, 271))	('PI3', 'Gene', '5266', (93, 96))	('tumors', 'Phenotype', 'HP:0002664', (170, 176))	('sensitive to', 'MPA', (214, 226))	('raf', 'Gene', '22882', (49, 52))	('tumor', 'Phenotype', 'HP:0002664', (265, 270))	('mTOR', 'Gene', (132, 136))	('PI3', 'Gene', (190, 193))	('tumors', 'Disease', (265, 271))	('patient', 'Species', '9606', (28, 35))	('PI3', 'Gene', '5266', (76, 79))	('tumors', 'Disease', (170, 176))
344213	29034103	NOTCH1 is a transmembrane kinase frequently mutationally inactivated (most commonly via missense or truncating mutation) in both HPV+ and HPV- cases (13-26 % and 8-17 %, respectively; Table 1).	('HPV', 'Species', '10566', (138, 141))	('mutationally', 'Var', (44, 56))	('NOTCH1', 'Gene', (0, 6))	('inactivated', 'NegReg', (57, 68))	('missense', 'Var', (88, 96))	('truncating mutation', 'Var', (100, 119))	('HPV', 'Species', '10566', (129, 132))
344214	29034103	Exome sequencing of HNSCC strongly implicated NOTCH1 as a tumor suppressor in this malignancy, as close to 40 % (11/28) of NOTCH1 mutations were truncating mutations predicted to be inactivating.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('truncating', 'MPA', (145, 155))	('tumor suppressor', 'Gene', '7248', (58, 74))	('malignancy', 'Disease', 'MESH:D009369', (83, 93))	('NOTCH1', 'Gene', (123, 129))	('mutations', 'Var', (130, 139))	('malignancy', 'Disease', (83, 93))	('tumor suppressor', 'Gene', (58, 74))
344220	29034103	Of note, p63 is transcriptionally activated by two distinct promoters; one of the two resulting p63 variants contains an N-terminal transactivation domain (TAp63), whereas, the other transcript lacks the N-terminal domain and is termed DeltaNp63.	('p63', 'Gene', '8626', (242, 245))	('p63', 'Gene', '8626', (9, 12))	('variants', 'Var', (100, 108))	('p63', 'Gene', (96, 99))	('p63', 'Gene', '8626', (158, 161))	('p63', 'Gene', '8626', (96, 99))	('p63', 'Gene', (242, 245))	('p63', 'Gene', (9, 12))	('p63', 'Gene', (158, 161))
344223	29034103	Well prior to the advent of high throughput sequencing, alterations in several genes, including inactivation or deletion of the tumor suppressors CDKN2A (p16) and TP53 (p53), and overexpression (via amplification and elevated transcription) of the epidermal growth factor receptor EGFR had been identified as relevant to the pathogenesis of HPV-negative HNSCC.	('p16', 'Gene', (154, 157))	('p53', 'Gene', (169, 172))	('deletion', 'Var', (112, 120))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('overexpression', 'PosReg', (179, 193))	('p16', 'Gene', '1029', (154, 157))	('EGFR', 'Gene', (281, 285))	('CDKN2A', 'Gene', (146, 152))	('tumor suppressor', 'Gene', '7248', (128, 144))	('TP53', 'Gene', (163, 167))	('elevated', 'PosReg', (217, 225))	('transcription', 'MPA', (226, 239))	('CDKN2A', 'Gene', '1029', (146, 152))	('inactivation', 'Var', (96, 108))	('rat', 'Species', '10116', (60, 63))	('EGFR', 'Gene', '1956', (281, 285))	('alterations', 'Var', (56, 67))	('HNSCC', 'Disease', (354, 359))	('epidermal growth factor receptor', 'Gene', (248, 280))	('TP53', 'Gene', '7157', (163, 167))	('HPV', 'Species', '10566', (341, 344))	('p53', 'Gene', '7157', (169, 172))	('epidermal growth factor receptor', 'Gene', '1956', (248, 280))	('tumor suppressor', 'Gene', (128, 144))
344228	29034103	Due to the high frequency of mutations in TP53 (Table 1), significant effort has been focused on elucidating the prognostic potential of this gene.	('TP53', 'Gene', '7157', (42, 46))	('TP53', 'Gene', (42, 46))	('mutations', 'Var', (29, 38))
344229	29034103	Some work suggests improved overall survival for patients with wild type TP53 compared to patients with TP53 mutations predicted to be functionally disruptive (i.e., nonsense mutations or missense mutations disruptive to the L2 or L3 DNA-binding domains).	('TP53', 'Gene', '7157', (73, 77))	('TP53', 'Gene', '7157', (104, 108))	('TP53', 'Gene', (104, 108))	('missense mutations', 'Var', (188, 206))	('overall', 'MPA', (28, 35))	('nonsense mutations', 'Var', (166, 184))	('TP53', 'Gene', (73, 77))	('mutations', 'Var', (109, 118))	('patients', 'Species', '9606', (49, 57))	('improved', 'PosReg', (19, 27))	('patients', 'Species', '9606', (90, 98))
344231	29034103	A multi-tiered genomic analysis of 250 HPV-negative tumors in 2014 (TCGA dataset; approximately corresponding to the cohort described above) confirmed that disruptive TP53 mutations correlated with reduced survival; however, in this analysis, cases with TP53 mutations predicted to be non-disruptive also had significantly worse survival outcomes compared to cases with wild type TP53.	('TP53', 'Gene', (380, 384))	('mutations', 'Var', (172, 181))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('TP53', 'Gene', '7157', (254, 258))	('TP53', 'Gene', (254, 258))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('mutations', 'Var', (259, 268))	('worse', 'NegReg', (323, 328))	('tumors', 'Disease', (52, 58))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('HPV', 'Species', '10566', (39, 42))	('TP53', 'Gene', '7157', (167, 171))	('reduced', 'NegReg', (198, 205))	('survival', 'MPA', (206, 214))	('survival', 'MPA', (329, 337))	('TP53', 'Gene', (167, 171))	('TP53', 'Gene', '7157', (380, 384))
344232	29034103	Strikingly, this study identified TP53 mutations as frequently co-occurring with deletions of chromosomal region 3p (179 out of 250 cases), with the combination associated with significantly worse survival than was predicted for TP53 mutations or 3p deletions considered independently.	('TP53', 'Gene', (229, 233))	('TP53', 'Gene', (34, 38))	('deletions', 'Var', (81, 90))	('associated', 'Reg', (161, 171))	('co-occurring', 'Reg', (63, 75))	('survival', 'MPA', (197, 205))	('mutations', 'Var', (39, 48))	('TP53', 'Gene', '7157', (229, 233))	('worse', 'NegReg', (191, 196))	('TP53', 'Gene', '7157', (34, 38))
344234	29034103	Efforts to elucidate the prognostic value of different TP53 mutations have also led to the development of a novel computation approach termed the Evolutionary Action score of TP53-coding variants (EAp53).	('p53', 'Gene', (199, 202))	('TP53', 'Gene', (175, 179))	('p53', 'Gene', '7157', (199, 202))	('TP53', 'Gene', '7157', (55, 59))	('TP53', 'Gene', (55, 59))	('EAp', 'Gene', (197, 200))	('mutations', 'Var', (60, 69))	('TP53', 'Gene', '7157', (175, 179))	('EAp', 'Gene', '6146', (197, 200))
344235	29034103	EAp53 stratifies HNSCC patients with tumors harboring TP53 missense mutations based on an estimated degree of risk assigned to each mutation.	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('rat', 'Species', '10116', (8, 11))	('EAp', 'Gene', (0, 3))	('patients', 'Species', '9606', (23, 31))	('p53', 'Gene', (2, 5))	('EAp', 'Gene', '6146', (0, 3))	('TP53', 'Gene', '7157', (54, 58))	('missense mutations', 'Var', (59, 77))	('p53', 'Gene', '7157', (2, 5))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumors', 'Disease', (37, 43))	('TP53', 'Gene', (54, 58))	('tumors', 'Disease', 'MESH:D009369', (37, 43))
344236	29034103	The foundational principles of this approach are based on previously identified TP53 "gain of function" mutations that enhanced cell transformation and chemotherapy resistance.	('mutations', 'Var', (104, 113))	('cell transformation', 'CPA', (128, 147))	('TP53', 'Gene', '7157', (80, 84))	('TP53', 'Gene', (80, 84))	('gain of function', 'PosReg', (86, 102))	('chemotherapy resistance', 'CPA', (152, 175))	('enhanced', 'PosReg', (119, 127))
344237	29034103	EAp53 assigns functional sensitivity to sequence variations based on evolutionary substitutions for every sequence position and calculates if substitutions correlate with larger or smaller phylogenetic divergences to determine "risk".	('EAp', 'Gene', (0, 3))	('p53', 'Gene', (2, 5))	('variations', 'Var', (49, 59))	('EAp', 'Gene', '6146', (0, 3))	('p53', 'Gene', '7157', (2, 5))	('substitutions', 'Var', (82, 95))
344238	29034103	HNSCC patients with p53 mutations classified using EAp53 as high-risk had significantly worse survival outcomes and reduced periods until distant metastases developed, as well as increased resistance to chemotherapy.	('p53', 'Gene', (20, 23))	('periods', 'CPA', (124, 131))	('p53', 'Gene', '7157', (20, 23))	('metastases', 'Disease', (146, 156))	('resistance to chemotherapy', 'CPA', (189, 215))	('EAp', 'Gene', (51, 54))	('metastases', 'Disease', 'MESH:D009362', (146, 156))	('EAp', 'Gene', '6146', (51, 54))	('p53', 'Gene', (53, 56))	('worse', 'NegReg', (88, 93))	('patients', 'Species', '9606', (6, 14))	('p53', 'Gene', '7157', (53, 56))	('mutations', 'Var', (24, 33))	('reduced', 'NegReg', (116, 123))	('increased', 'PosReg', (179, 188))	('survival', 'CPA', (94, 102))
344240	29034103	CDKN2A regulates cell cycle progression by blocking the activity of CCND1 (cyclin D1) and its associated kinases, CDK6 and CDK4, which phosphorylate and inactivate the tumor suppressor RB1 (Fig.	('CCND1', 'Gene', '595', (68, 73))	('CDKN2A', 'Gene', '1029', (0, 6))	('CDK6', 'Gene', '1021', (114, 118))	('RB1', 'Gene', '5925', (185, 188))	('cyclin D1', 'Gene', '595', (75, 84))	('CDK4', 'Gene', (123, 127))	('blocking', 'NegReg', (43, 51))	('tumor suppressor', 'Gene', (168, 184))	('CCND1', 'Gene', (68, 73))	('CDK6', 'Gene', (114, 118))	('activity', 'MPA', (56, 64))	('CDK4', 'Gene', '1019', (123, 127))	('tumor suppressor', 'Gene', '7248', (168, 184))	('CDKN2A', 'Gene', (0, 6))	('RB1', 'Gene', (185, 188))	('cell cycle progression', 'CPA', (17, 39))	('cyclin D1', 'Gene', (75, 84))	('inactivate', 'Var', (153, 163))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
344241	29034103	Inactivation of the CDKN2A gene was found in 57 % of HPV- cases in the TCGA cohort; however, other studies produced discordant values for genomic alterations of CDKN2A (ranging from 4 to 74 %; Table 1).	('rat', 'Species', '10116', (150, 153))	('CDKN2A', 'Gene', (20, 26))	('HPV-', 'Disease', (53, 57))	('CDKN2A', 'Gene', (161, 167))	('HPV', 'Species', '10566', (53, 56))	('CDKN2A', 'Gene', '1029', (20, 26))	('Inactivation', 'Var', (0, 12))	('CDKN2A', 'Gene', '1029', (161, 167))
344244	29034103	Methylation-associated inactivation of CDKN2A (further discussed below) is another important factor potentially complicating assessment of the function status of this gene.	('Methylation-associated inactivation', 'Var', (0, 35))	('CDKN2A', 'Gene', (39, 45))	('inactivation', 'Var', (23, 35))	('CDKN2A', 'Gene', '1029', (39, 45))
344245	29034103	Direct comparison of cases in the TCGA cohort with homozygous deletions or predicted inactivating mutations in CDKN2A versus wild type CDKN2A did not indicate a survival difference.	('CDKN2A', 'Gene', (135, 141))	('CDKN2A', 'Gene', '1029', (135, 141))	('deletions', 'Var', (62, 71))	('CDKN2A', 'Gene', (111, 117))	('inactivating mutations', 'Var', (85, 107))	('CDKN2A', 'Gene', '1029', (111, 117))
344249	29034103	reported that high RNA expression of CCND1 (z > 2-fold) not only correlated with reduced survival in the TCGA dataset, but also co-occurred frequently with CDKN2A deletions (co-occurrence ratio: 0.817).	('RNA expression', 'MPA', (19, 33))	('CDKN2A', 'Gene', (156, 162))	('survival', 'CPA', (89, 97))	('CCND1', 'Gene', (37, 42))	('CDKN2A', 'Gene', '1029', (156, 162))	('rat', 'Species', '10116', (188, 191))	('CCND1', 'Gene', '595', (37, 42))	('reduced', 'NegReg', (81, 88))	('deletions', 'Var', (163, 172))
344250	29034103	Cases harboring both, amplified CCND1 and deleted CDK2N2A had much worse prognosis than cases without these alterations.	('CDK', 'Gene', (50, 53))	('CCND1', 'Gene', (32, 37))	('deleted', 'Var', (42, 49))	('rat', 'Species', '10116', (112, 115))	('CCND1', 'Gene', '595', (32, 37))	('amplified', 'Var', (22, 31))	('CDK', 'Gene', '1019;1021', (50, 53))
344253	29034103	Nevertheless, alterations in ERBB2 or ERBB3 have been directly linked to resistance to EGFR-targeted therapy and are thus of therapeutic relevance.	('alterations', 'Var', (14, 25))	('rat', 'Species', '10116', (18, 21))	('ERBB2', 'Gene', (29, 34))	('EGFR', 'Gene', '1956', (87, 91))	('ERBB3', 'Gene', '2065', (38, 43))	('linked', 'Reg', (63, 69))	('EGFR', 'Gene', (87, 91))	('ERBB3', 'Gene', (38, 43))	('ERBB2', 'Gene', '2064', (29, 34))
344255	29034103	In addition, the RTKs FGFR1 and IGF1R were identified with activating mutations in 10 and 4 % of HPV- HNSCC, respectively, while no mutations of these kinases were identified in HPV+ HNSCC tumors (Fig.	('mutations', 'Var', (70, 79))	('HNSCC tumors', 'Disease', 'MESH:D000077195', (183, 195))	('FGFR1', 'Gene', '2260', (22, 27))	('HPV', 'Species', '10566', (97, 100))	('activating', 'PosReg', (59, 69))	('tumors', 'Phenotype', 'HP:0002664', (189, 195))	('IGF1', 'Gene', '3479', (32, 36))	('HPV- HNSCC', 'Disease', (97, 107))	('HNSCC tumors', 'Disease', (183, 195))	('IGF1', 'Gene', (32, 36))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('HPV', 'Species', '10566', (178, 181))	('FGFR1', 'Gene', (22, 27))
344263	29034103	FAT1 had previously been shown to be mutated in roughly 7 % of 60 head and neck tumors, but was detected to be inactivated (missense/truncating mutations and homozygous deletions) in a much greater percentage of HPV- cases (32 %; versus inactivated in only 3 % of HPV+ cases; Fig.	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('HPV-', 'Var', (212, 216))	('HPV', 'Species', '10566', (264, 267))	('neck tumors', 'Disease', 'MESH:D006258', (75, 86))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('missense/truncating mutations', 'Var', (124, 153))	('neck tumors', 'Disease', (75, 86))	('FAT1', 'Gene', '2195', (0, 4))	('head and neck tumors', 'Phenotype', 'HP:0012288', (66, 86))	('FAT1', 'Gene', (0, 4))	('HPV', 'Species', '10566', (212, 215))
344269	29034103	KEAP1 complexes with the E3 ligase CUL3 (inactivated in 6 % of HPV- cases) to polyubiquitinate NFE2L2; thus, disruption of canonical KEAP1-CUL3 function promotes NFE2L2 activity.	('NFE2L2', 'Gene', '4780', (95, 101))	('CUL3', 'Gene', (139, 143))	('NFE2L2', 'Gene', (162, 168))	('KEAP1', 'Gene', (0, 5))	('disruption', 'Var', (109, 119))	('HPV', 'Species', '10566', (63, 66))	('NFE2L2', 'Gene', (95, 101))	('CUL3', 'Gene', '8452', (139, 143))	('activity', 'MPA', (169, 177))	('KEAP1', 'Gene', (133, 138))	('KEAP1', 'Gene', '9817', (133, 138))	('KEAP1', 'Gene', '9817', (0, 5))	('NFE2L2', 'Gene', '4780', (162, 168))	('promotes', 'PosReg', (153, 161))	('polyubiquitinate', 'MPA', (78, 94))	('CUL3', 'Gene', '8452', (35, 39))	('CUL3', 'Gene', (35, 39))
344272	29034103	Secondary analysis of the TCGA dataset indeed revealed that DNA level alterations of any member of the KEAP1/CUL3/RBX1 complex correlated with significantly reduced survival (median survival of ~35 months versus ~72 months).	('alterations', 'Var', (70, 81))	('CUL3', 'Gene', (109, 113))	('KEAP1', 'Gene', '9817', (103, 108))	('CUL3', 'Gene', '8452', (109, 113))	('KEAP1', 'Gene', (103, 108))	('rat', 'Species', '10116', (74, 77))	('RBX1', 'Gene', '9978', (114, 118))	('survival', 'MPA', (165, 173))	('RBX1', 'Gene', (114, 118))	('reduced', 'NegReg', (157, 164))
344276	29034103	BIRC2 is more commonly altered in HPV- HNSCC (7 % of cases versus 3 % of cases in HPV+ HNSCC) and, as would have been predicated based on functionality, CASP8 was also frequently detected as inactivated through mutations or homozygous deletion (11 % of HPV- cases; Fig.	('HPV- HNSCC', 'Disease', (34, 44))	('BIRC2', 'Gene', '329', (0, 5))	('BIRC2', 'Gene', (0, 5))	('mutations', 'Var', (211, 220))	('inactivated', 'NegReg', (191, 202))	('altered', 'Reg', (23, 30))	('HPV', 'Species', '10566', (253, 256))	('CASP8', 'Gene', (153, 158))	('CASP8', 'Gene', '841', (153, 158))	('HPV', 'Species', '10566', (82, 85))	('HPV', 'Species', '10566', (34, 37))
344279	29034103	Interestingly, a recent study found that YAP1 amplification strongly correlated with resistance to cetuximab in vitro, which may reflect YAP1 associated upregulation of the EGFR ligand amphiregulin; further investigations are needed to fully uncover the precise mechanism of this type of resistance.	('YAP1', 'Gene', '10413', (137, 141))	('correlated', 'Reg', (69, 79))	('cetuximab', 'Chemical', 'MESH:D000068818', (99, 108))	('YAP1', 'Gene', (41, 45))	('YAP1', 'Gene', '10413', (41, 45))	('amplification', 'Var', (46, 59))	('upregulation', 'PosReg', (153, 165))	('amphiregulin', 'Gene', '374', (185, 197))	('EGFR', 'Gene', '1956', (173, 177))	('resistance to cetuximab', 'MPA', (85, 108))	('EGFR', 'Gene', (173, 177))	('YAP1', 'Gene', (137, 141))	('amphiregulin', 'Gene', (185, 197))
344297	29034103	As E6 and E7 function through cell cycle dysregulation by eliminating RB1 and TP53, very few alterations in additional cell cycle regulators occur in HPV+ disease: inactivation of CDKN2A, or TP53, or overexpression of CDK6 or CCND1, occur seldom in HPV+ HNSCC.	('CDK6', 'Gene', (218, 222))	('rat', 'Species', '10116', (97, 100))	('CDKN2A', 'Gene', '1029', (180, 186))	('TP53', 'Gene', '7157', (191, 195))	('HPV+ HNSCC', 'Disease', (249, 259))	('HPV+ disease', 'Disease', (150, 162))	('RB1', 'Gene', (70, 73))	('inactivation', 'Var', (164, 176))	('cell cycle dysregulation', 'Phenotype', 'HP:0011018', (30, 54))	('TP53', 'Gene', '7157', (78, 82))	('HPV', 'Species', '10566', (249, 252))	('overexpression', 'PosReg', (200, 214))	('TP53', 'Gene', (191, 195))	('RB1', 'Gene', '5925', (70, 73))	('HPV', 'Species', '10566', (150, 153))	('CDKN2A', 'Gene', (180, 186))	('CCND1', 'Gene', '595', (226, 231))	('CDK6', 'Gene', '1021', (218, 222))	('CCND1', 'Gene', (226, 231))	('TP53', 'Gene', (78, 82))
344299	29034103	1b); it is the only cell cycle regulator identifier by the TCGA study as being predominantly altered in HPV+ cases (19 % activated via amplification of chromosome 20q11, seen in only in 2 % of HPV- HNSCC; Fig.	('HPV+', 'Disease', (104, 108))	('HPV', 'Species', '10566', (104, 107))	('amplification', 'Var', (135, 148))	('altered', 'Reg', (93, 100))	('HPV', 'Species', '10566', (193, 196))	('activated', 'PosReg', (121, 130))
344300	29034103	Also associated with HPV+ disease is the RTK FGFR3, which is activated in 11 % of cases through either mutation or a gene fusion event, and the aforementioned TNF receptor associated factor TRAF3, inactivated in 22 % of cases (versus 1 % in HPV- disease).	('associated', 'Reg', (5, 15))	('HPV', 'Species', '10566', (241, 244))	('HPV', 'Species', '10566', (21, 24))	('HPV- disease', 'Disease', 'MESH:D030361', (241, 253))	('TRAF3', 'Gene', (190, 195))	('FGFR3', 'Gene', '2261', (45, 50))	('HPV+ disease', 'Disease', (21, 33))	('gene fusion', 'Var', (117, 128))	('TRAF3', 'Gene', '7187', (190, 195))	('HPV- disease', 'Disease', (241, 253))	('mutation', 'Var', (103, 111))	('FGFR3', 'Gene', (45, 50))
344302	29034103	A FGFR3-TACC3 fusion was first described in glioblastoma and subsequently detected in nasopharyngeal carcinoma and other HNSCCs.	('glioblastoma', 'Disease', (44, 56))	('FGFR3', 'Gene', (2, 7))	('nasopharyngeal carcinoma', 'Disease', 'MESH:D000077274', (86, 110))	('glioblastoma', 'Disease', 'MESH:D005909', (44, 56))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (86, 110))	('nasopharyngeal carcinoma', 'Disease', (86, 110))	('glioblastoma', 'Phenotype', 'HP:0012174', (44, 56))	('fusion', 'Var', (14, 20))	('TACC3', 'Gene', '10460', (8, 13))	('FGFR3', 'Gene', '2261', (2, 7))	('TACC3', 'Gene', (8, 13))
344311	29034103	Earlier work indicated that HPV- tumors had significantly higher heterogeneity than HPV+ tumors (though substantial even for HPV+ cases), which would be predicated based on the frequency of and genomic instability associated with TP53 mutations, increased age and continuous tobacco use.	('HPV- tumors', 'Disease', 'MESH:D030361', (28, 39))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('HPV', 'Species', '10566', (28, 31))	('TP53', 'Gene', (230, 234))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('HPV- tumors', 'Disease', (28, 39))	('mutations', 'Var', (235, 244))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tobacco', 'Species', '4097', (275, 282))	('HPV', 'Species', '10566', (125, 128))	('heterogeneity', 'MPA', (65, 78))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('higher', 'PosReg', (58, 64))	('HPV', 'Species', '10566', (84, 87))	('HPV+ tumors', 'Disease', (84, 95))	('TP53', 'Gene', '7157', (230, 234))	('HPV+ tumors', 'Disease', 'MESH:D030361', (84, 95))
344313	29034103	For example, disruptive TP53 mutations are strongly associated with higher intra-tumor heterogeneity as calculated by MATH (i.e., high MATH scores), and both TP53 mutational status and high MATH scores, based on univariate analysis, indicated reduced survival.	('TP53', 'Gene', '7157', (158, 162))	('TP53', 'Gene', (158, 162))	('intra-tumor', 'Disease', 'MESH:D009369', (75, 86))	('disruptive', 'Var', (13, 23))	('TP53', 'Gene', (24, 28))	('mutations', 'Var', (29, 38))	('higher', 'PosReg', (68, 74))	('intra-tumor', 'Disease', (75, 86))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('reduced', 'NegReg', (243, 250))	('survival', 'MPA', (251, 259))	('TP53', 'Gene', '7157', (24, 28))
344316	29034103	used exome sequencing data and single-nucleotide polymorphism arrays to calculate the confidence interval of the cancer cell fraction (CCF; proportion of cancer cells harboring a given mutation) for a given mutation.	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('cancer', 'Disease', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('cancer', 'Disease', (113, 119))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('mutation', 'Var', (207, 215))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
344317	29034103	In HNSCC, the majority of driver mutations were clonal, and CDKN2A and TP53 were identified as almost exclusively clonal.	('CDKN2A', 'Gene', (60, 66))	('mutations', 'Var', (33, 42))	('CDKN2A', 'Gene', '1029', (60, 66))	('TP53', 'Gene', '7157', (71, 75))	('TP53', 'Gene', (71, 75))
344318	29034103	Based on the proportion of mutations, three mutational signatures (previously defined) were identified for HNSCC: 1) a signature with C > T transitions at CpG sites associated with spontaneous deamination of methylated cytosines that strongly correlated with patient age at diagnosis and was most prevalently linked to "early" mutations; 2) a signature indicative of up-regulation of APOBEC cytosine deaminases, seen in both "early" and "late" mutations, although with significant prominence in "late" mutations; and 3) a signature associated with smoking induced mutations, seen predominantly with "early" mutations.	('methylated', 'MPA', (208, 218))	('associated', 'Reg', (165, 175))	('linked', 'Reg', (309, 315))	('correlated', 'Reg', (243, 253))	('cytosine', 'Chemical', 'MESH:D003596', (391, 399))	('cytosine', 'Chemical', 'MESH:D003596', (219, 227))	('up-regulation', 'PosReg', (367, 380))	('spontaneous deamination', 'MPA', (181, 204))	('HNSCC', 'Gene', (107, 112))	('C > T transitions', 'Var', (134, 151))	('patient', 'Species', '9606', (259, 266))	('CpG', 'Gene', (155, 158))
344320	29034103	Furthermore, the same study suggested that APOEC-mediated mutagenesis significantly contributes to helical domain E545K and E542K gain of function mutations in PIK3CA, one of the most frequently altered genes in HNSCC (32 out of 58 PIK3CA mutations in the TCGA cohort are E545K/E542K mutations).	('PIK3CA', 'Gene', '5290', (232, 238))	('PIK3CA', 'Gene', '5290', (160, 166))	('E545K/E542K', 'Var', (272, 283))	('E542K', 'Var', (124, 129))	('helical domain', 'MPA', (99, 113))	('E545K', 'Mutation', 'rs104886003', (272, 277))	('gain of function', 'PosReg', (130, 146))	('E542K', 'Mutation', 'rs121913273', (278, 283))	('E542K', 'Mutation', 'rs121913273', (124, 129))	('E545K', 'Mutation', 'rs104886003', (114, 119))	('E545K', 'Var', (114, 119))	('PIK3CA', 'Gene', (232, 238))	('PIK3CA', 'Gene', (160, 166))
344322	29034103	Recent analysis of TCGA data suggested that 15 % (44 out of 291 cases; incompletely congruent with the published TCGA dataset) of HNSCC cases have rare germline truncations, including truncations in several genes important in the Fanconi Anemia Pathway, specifically FANCA and FANCM, which are involved in DNA repair.	('FANCM', 'Gene', (277, 282))	('FANCA', 'Gene', '2175', (267, 272))	('Fanconi Anemia', 'Disease', 'MESH:D005199', (230, 244))	('truncations', 'Var', (184, 195))	('FANCA', 'Gene', (267, 272))	('FANCM', 'Gene', '57697', (277, 282))	('HNSCC', 'Gene', (130, 135))	('Fanconi Anemia', 'Phenotype', 'HP:0001994', (230, 244))	('Anemia', 'Phenotype', 'HP:0001903', (238, 244))	('Fanconi Anemia', 'Disease', (230, 244))
344323	29034103	FANCM mutations significantly correlated with increased somatic mutational frequency in the complete HNSCC cohort (mean age was 60.9 +/- 12.4 years; based on personal correspondence with authors), whereas, FANCA had a similar correlation with the frequency of somatic mutations, but specific in cases defined as younger age (mean age was 46.3 +/- 7.0 years) of onset (no indication regarding HPV status).	('FANCA', 'Gene', (206, 211))	('FANCM', 'Gene', (0, 5))	('somatic mutational frequency', 'MPA', (56, 84))	('increased', 'PosReg', (46, 55))	('HPV', 'Species', '10566', (392, 395))	('FANCM', 'Gene', '57697', (0, 5))	('FANCA', 'Gene', '2175', (206, 211))	('mutations', 'Var', (6, 15))
344326	29034103	MYH9 and MYH10 were mutated in 4 and 5 % of cases, respectively within the TCGA cohort of 279 patients.	('patients', 'Species', '9606', (94, 102))	('MYH9', 'Gene', (0, 4))	('MYH10', 'Gene', '4628', (9, 14))	('MYH10', 'Gene', (9, 14))	('mutated', 'Var', (20, 27))
344328	29034103	Success of future clinical efforts, particularly for targeted therapeutics, will likely heavily depend on consideration of heterogeneity and cancer evolution, guided by studies of spatio-temporal differences in genomic alterations, including presence or absence of germline mutations.	('clinical', 'Species', '191496', (18, 26))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('cancer', 'Disease', (141, 147))	('rat', 'Species', '10116', (113, 116))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('rat', 'Species', '10116', (223, 226))	('germline mutations', 'Var', (265, 283))
344343	29034103	Furthermore, therapeutic targeting of aberrant cell cycle activity may partially circumvent the challenge presented by heterogeneity, given that clonal status analysis of the TCGA HNSCC cohort indicated that genes associated with cyclin-dependent kinases have 0 % of mutations arise in subclonal populations, which suggests that cell cycle alterations arise early during tumor development and are present in most if not all tumor cells.	('rat', 'Species', '10116', (344, 347))	('tumor', 'Disease', 'MESH:D009369', (424, 429))	('tumor', 'Disease', (371, 376))	('tumor', 'Phenotype', 'HP:0002664', (424, 429))	('mutations', 'Var', (267, 276))	('tumor', 'Disease', (424, 429))	('tumor', 'Disease', 'MESH:D009369', (371, 376))	('cell cycle alterations', 'Phenotype', 'HP:0011018', (329, 351))	('tumor', 'Phenotype', 'HP:0002664', (371, 376))	('aberrant cell cycle', 'Phenotype', 'HP:0011018', (38, 57))
344346	29034103	Additional promising pre-clinical work has explored Second Mitochondria-derived Activator of Caspases (SMAC)-mimetics, antagonists of inhibitors of apoptosis, which seem particularly effective against HNSCC models with FADD/BIRC2 alterations; particularly meaningful considering the aforementioned high incident of FADD/BIRC2 alterations in HNSCC (Table 1).	('FADD', 'Gene', (315, 319))	('FADD', 'Gene', '8772', (315, 319))	('SMAC', 'Gene', (103, 107))	('clinical', 'Species', '191496', (25, 33))	('BIRC2', 'Gene', '329', (224, 229))	('FADD', 'Gene', (219, 223))	('BIRC2', 'Gene', '329', (320, 325))	('FADD', 'Gene', '8772', (219, 223))	('HNSCC', 'Disease', (201, 206))	('rat', 'Species', '10116', (234, 237))	('SMAC', 'Gene', '56616', (103, 107))	('rat', 'Species', '10116', (330, 333))	('BIRC2', 'Gene', (224, 229))	('alterations', 'Var', (230, 241))	('BIRC2', 'Gene', (320, 325))
344350	29034103	Furthermore, HNSCC appears to be an immunosuppressive disease commonly associated with lymphopenia and in a few cases (7 % of HPV- and 11 % of HPV+ HNSCC in the TCGA cohort) presenting with specific mutations in HLA alleles and the antigen processing machinery to reduce tumor immunodetection.	('lymphopenia', 'Disease', (87, 98))	('HPV', 'Species', '10566', (143, 146))	('immunosuppressive disease', 'Disease', 'MESH:D004194', (36, 61))	('tumor', 'Phenotype', 'HP:0002664', (271, 276))	('tumor', 'Disease', 'MESH:D009369', (271, 276))	('lymphopenia', 'Phenotype', 'HP:0001888', (87, 98))	('tumor', 'Disease', (271, 276))	('lymphopenia', 'Disease', 'MESH:D008231', (87, 98))	('immunosuppressive disease', 'Disease', (36, 61))	('HLA', 'Gene', (212, 215))	('mutations', 'Var', (199, 208))	('HNSCC', 'Disease', (13, 18))	('associated', 'Reg', (71, 81))	('HPV', 'Species', '10566', (126, 129))
344353	29034103	Regarding HNSCC, several phase III studies are currently exploring the utility of checkpoint inhibitors; specifically, the humanized monoclonal PD-1 specific antibody pembrolizumab [NCT02564263, NCT02358031, NCT02252042], recently approved for the treatment of melanoma and lung cancer (two cancer types with high mutational burden) and tremelimumab (fully human antibody against CTLA-4) with or without durvalumab (Fc optimized monoclonal antibody against the PD1 ligand 1; NCT02551159).	('NCT02358031', 'Var', (195, 206))	('melanoma and lung cancer', 'Disease', 'MESH:D008175', (261, 285))	('lung cancer', 'Phenotype', 'HP:0100526', (274, 285))	('cancer', 'Phenotype', 'HP:0002664', (291, 297))	('cancer', 'Disease', (291, 297))	('human', 'Species', '9606', (123, 128))	('cancer', 'Disease', 'MESH:D009369', (291, 297))	('human', 'Species', '9606', (357, 362))	('cancer', 'Phenotype', 'HP:0002664', (279, 285))	('NCT02252042]', 'Var', (208, 220))	('[NCT02564263', 'Var', (181, 193))	('cancer', 'Disease', (279, 285))	('cancer', 'Disease', 'MESH:D009369', (279, 285))	('melanoma', 'Phenotype', 'HP:0002861', (261, 269))
344355	29034103	DNA methylation is important in the regulation of gene expression, and aberrant methylation has been described for essentially all cancer types and as a critical aspect of cancer genomics.	('cancer', 'Disease', (131, 137))	('aberrant methylation', 'Var', (71, 91))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('methylation', 'Var', (80, 91))	('cancer', 'Disease', (172, 178))	('cancer', 'Disease', 'MESH:D009369', (131, 137))
344362	29034103	Interestingly, prominent differential methylation of three members of the zinc finger gene family, ZNF14, ZNF160 and ZNF420, has been identified as suitable to detect HNSCC with 100 % specificity in primary tissue and saliva samples; subsequently, the three ZNF methylation signature was validated using the 273 TCGA cohort.	('ZNF160', 'Gene', '90338', (106, 112))	('ZNF160', 'Gene', (106, 112))	('ZNF420', 'Gene', '147923', (117, 123))	('methylation', 'Var', (38, 49))	('detect', 'Reg', (160, 166))	('HNSCC', 'Disease', (167, 172))	('ZNF14', 'Gene', (99, 104))	('ZNF420', 'Gene', (117, 123))	('ZNF14', 'Gene', '7561', (99, 104))
344372	29034103	For example, consistent identification of tumors with highly immunogenic alterations would significantly help guide therapeutic decision-making.	('rat', 'Species', '10116', (77, 80))	('help', 'Reg', (105, 109))	('tumors', 'Disease', (42, 48))	('tumors', 'Disease', 'MESH:D009369', (42, 48))	('alterations', 'Var', (73, 84))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
344377	27311963	OncodriveFML: a general framework to identify coding and non-coding regions with cancer driver mutations Distinguishing the driver mutations from somatic mutations in a tumor genome is one of the major challenges of cancer research.	('cancer', 'Disease', 'MESH:D009369', (216, 222))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('cancer', 'Disease', (81, 87))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('tumor', 'Disease', (169, 174))	('mutations', 'Var', (95, 104))	('cancer', 'Disease', (216, 222))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))
344378	27311963	Here we present OncodriveFML, a method designed to analyze the pattern of somatic mutations across tumors in both coding and non-coding genomic regions to identify signals of positive selection, and therefore, their involvement in tumorigenesis.	('tumor', 'Disease', (99, 104))	('tumor', 'Disease', 'MESH:D009369', (231, 236))	('tumors', 'Disease', 'MESH:D009369', (99, 105))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('tumor', 'Disease', (231, 236))	('mutations', 'Var', (82, 91))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('involvement', 'Reg', (216, 227))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))	('tumors', 'Disease', (99, 105))
344379	27311963	We describe the method and illustrate its usefulness to identify protein-coding genes, promoters, untranslated regions, intronic splice regions, and lncRNAs-containing driver mutations in several malignancies.	('malignancies', 'Disease', 'MESH:D009369', (196, 208))	('mutations', 'Var', (175, 184))	('malignancies', 'Disease', (196, 208))
344382	27311963	These abnormal mutational patterns are caused by positive selection acting on the mutations in driver genes during the course of tumorigenesis and tumor evolution.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('mutations', 'Var', (82, 91))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('tumor', 'Disease', (129, 134))
344383	27311963	A mutational frequency across a cohort of tumors that is significantly higher than the background mutation rate is the most intuitive and exploited signal of positive selection, implemented for example by computational approaches such as MuSiC and MutSig.	('tumors', 'Disease', (42, 48))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('mutational', 'Var', (2, 12))	('tumors', 'Disease', 'MESH:D009369', (42, 48))	('MuSiC', 'CellLine', 'CVCL:3165', (238, 243))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
344385	27311963	We proved that the top-ranking genes in their deviation of the average impact score of mutations observed from the expected average impact score of the same number of mutations in the given cohort:functional mutation (FM) bias:were bona fide cancer drivers.	('cancer', 'Phenotype', 'HP:0002664', (242, 248))	('cancer', 'Disease', (242, 248))	('mutations', 'Var', (87, 96))	('cancer', 'Disease', 'MESH:D009369', (242, 248))
344390	27311963	Here we propose a novel approach, OncodriveFML, to estimate the accumulated functional impact (FI) bias of tumor somatic mutations in genomic regions of interest, both coding and non-coding, based on a local simulation of the mutational processes affecting it.	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('mutations', 'Var', (121, 130))	('tumor', 'Disease', (107, 112))	('functional', 'MPA', (76, 86))	('tumor', 'Disease', 'MESH:D009369', (107, 112))
344397	27311963	The rationale behind OncodriveFML is that the observation of somatic mutations on a genomic element (coding gene, promoter, UTR, lncRNA, etc) across tumors, whose average impact score is significantly greater than expected for said element constitutes a signal that these mutations have undergone positive selection during tumorigenesis.	('mutations', 'Var', (69, 78))	('tumor', 'Phenotype', 'HP:0002664', (323, 328))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('tumor', 'Disease', (323, 328))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('tumors', 'Disease', 'MESH:D009369', (149, 155))	('tumors', 'Disease', (149, 155))	('tumor', 'Disease', (149, 154))	('tumors', 'Phenotype', 'HP:0002664', (149, 155))	('tumor', 'Disease', 'MESH:D009369', (323, 328))
344400	27311963	To accurately model mutational processes in the tumor type of interest, the sampling is done following the probability of mutation of different tri-nucleotides, which can either be computed from the mutations observed in each sample, in cohort under analysis as a whole, or pre-computed from previously analyzed tumor cohorts of the same or similar type.	('tumor', 'Disease', (48, 53))	('tri-nucleotides', 'Chemical', '-', (144, 159))	('tumor', 'Disease', 'MESH:D009369', (312, 317))	('mutation', 'Var', (122, 130))	('tumor', 'Phenotype', 'HP:0002664', (312, 317))	('tumor', 'Disease', (312, 317))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
344406	27311963	We next applied the OncodriveFML FM bias test to randomized datasets of mutations, built by reshuffling the mutations observed within each genome, following the rates of tri-nucleotides and the constraints of number of mutations per sample and per region.	('mutations', 'Var', (72, 81))	('tri-nucleotides', 'Chemical', '-', (170, 185))	('mutations', 'Var', (108, 117))
344408	27311963	Therefore, we next tested its performance in the identification of putative driver promoter, 5' UTR, splice intronic, and 3' UTR regions of coding genes containing mutations across 22 tumor cohorts with whole-genome data sequenced by TCGA or other projects (datasets WG-505 and WG-608, respectively, in Additional file 1), as well as two pan-cancer cohorts resulting from pooling the mutations detected in all cohorts of each dataset (Figs.	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('cancer', 'Disease', 'MESH:D009369', (342, 348))	('tested', 'Reg', (19, 25))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('cancer', 'Disease', (342, 348))	('tumor', 'Disease', (184, 189))	('cancer', 'Phenotype', 'HP:0002664', (342, 348))	('mutations', 'Var', (164, 173))
344413	27311963	Activating mutations in TERT promoter have been found as drivers in multiple types of cancer.	('Activating mutations', 'Var', (0, 20))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('TERT', 'Gene', (24, 28))	('TERT', 'Gene', '7015', (24, 28))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('cancer', 'Disease', (86, 92))
344416	27311963	3d), a subunit of the RNA polymerase, which contains mutations very close to the transcription start site (TSS) in melanoma samples.	('melanoma', 'Disease', (115, 123))	('melanoma', 'Disease', 'MESH:D008545', (115, 123))	('melanoma', 'Phenotype', 'HP:0002861', (115, 123))	('mutations', 'Var', (53, 62))
344423	27311963	These mutations were recently reported as significantly redundant by, with 15 % of bladder tumor samples bearing mutations using whole-exome data.	('bladder tumor', 'Phenotype', 'HP:0009725', (83, 96))	('bladder tumor', 'Disease', (83, 96))	('mutations', 'Var', (113, 122))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('bladder tumor', 'Disease', 'MESH:D001749', (83, 96))
344425	27311963	TP53 contains 16 mutations within the first 50 bps of its introns, seven of which appear in breast cancer samples, while the others are distributed across the cohorts of other tumor types (including GBM, CRC, LUSC, SKCM, LUAD) (Fig.	('breast cancer', 'Phenotype', 'HP:0003002', (92, 105))	('appear', 'Reg', (82, 88))	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('breast cancer', 'Disease', (92, 105))	('CRC', 'Disease', (204, 207))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('tumor', 'Disease', (176, 181))	('SKCM', 'Disease', (215, 219))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('mutations', 'Var', (17, 26))	('tumor', 'Disease', 'MESH:D009369', (176, 181))	('breast cancer', 'Disease', 'MESH:D001943', (92, 105))
344427	27311963	Most of the mutations (4 out of 6) observed in the pan-cancer cohort of the WG-505 dataset falling within the first 50 bps of its introns indeed correspond to lung adenocarcinoma samples and all are in close proximity to the intron-exon boundary (Fig.	('lung adenocarcinoma', 'Disease', (159, 178))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (159, 178))	('carcinoma', 'Phenotype', 'HP:0030731', (169, 178))	('mutations', 'Var', (12, 21))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('falling', 'Phenotype', 'HP:0002527', (91, 98))	('correspond to', 'Reg', (145, 158))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (159, 178))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('cancer', 'Disease', (55, 61))
344428	27311963	In the pan-cancer cohort of the WG-505 dataset, OncodriveFML identified BORA and CHAF1B as putative driver genes from the mutations in their 3' UTR regions (Fig.	('CHAF1B', 'Gene', (81, 87))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('CHAF1B', 'Gene', '8208', (81, 87))	('cancer', 'Disease', 'MESH:D009369', (11, 17))	('mutations', 'Var', (122, 131))	('cancer', 'Disease', (11, 17))	('BORA', 'Gene', (72, 76))
344430	27311963	On the other hand, in the pan-cancer cohort of the WG-608 dataset, where it also appears as significantly FM biased, mutations appear in BRCA and STAD samples (Fig.	('mutations', 'Var', (117, 126))	('appear', 'Reg', (127, 133))	('BRCA', 'Disease', (137, 141))	('STAD', 'Disease', (146, 150))	('cancer', 'Disease', (30, 36))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
344445	27311963	Furthermore, due to its unique local background model of the FI of mutations it is able to detect signals of positive selection in tumorigenesis when only the sequence of a small portion of the genome is available, opening the opportunity to exploit data obtained from the interrogation of gene panels.	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumor', 'Disease', (131, 136))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('mutations', 'Var', (67, 76))
344458	27311963	It then calculates the mean of the FI scores of all the observed mutations in the element across tumors.	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('tumors', 'Disease', (97, 103))	('tumors', 'Disease', 'MESH:D009369', (97, 103))	('mutations', 'Var', (65, 74))
344461	27311963	The matrices are computed by counting all the observed mutations in all the tumors.	('mutations', 'Var', (55, 64))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumors', 'Disease', (76, 82))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('tumors', 'Disease', 'MESH:D009369', (76, 82))
344462	27311963	In the present study, we adjusted the p values of regions mutated in at least two samples in individual tumor types and five samples in the pan-cancer dataset.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('tumor', 'Disease', (104, 109))	('cancer', 'Disease', (144, 150))	('mutated', 'Var', (58, 65))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
344472	27311963	CADD, combined annotation dependent depletion; CGC, Cancer Gene Census; COSMIC, Catalog Of Somatic Mutations In Cancer; cSCC, cutaneous squamous cell carcinoma; FI, functional impact; FM bias, functional mutations bias; GP-234, dataset of a gene panel sequence of 234 tumor samples; TCGA, The Cancer Genome Atlas; WE-4482, dataset of whole-exome sequence of 4482 tumor samples; WG-505, dataset of whole-genome sequence of 505 tumor samples; WG-608, dataset of whole-genome sequence of 608 tumor samples	('tumor', 'Disease', 'MESH:D009369', (489, 494))	('tumor', 'Disease', (426, 431))	('Mutations', 'Var', (99, 108))	('tumor', 'Phenotype', 'HP:0002664', (363, 368))	('tumor', 'Disease', 'MESH:D009369', (426, 431))	('tumor', 'Phenotype', 'HP:0002664', (268, 273))	('Cancer', 'Phenotype', 'HP:0002664', (112, 118))	('tumor', 'Phenotype', 'HP:0002664', (489, 494))	('carcinoma', 'Phenotype', 'HP:0030731', (150, 159))	('tumor', 'Phenotype', 'HP:0002664', (426, 431))	('cutaneous squamous cell carcinoma', 'Disease', (126, 159))	('tumor', 'Disease', (363, 368))	('Cancer', 'Phenotype', 'HP:0002664', (293, 299))	('cutaneous squamous cell carcinoma', 'Disease', 'MESH:D002294', (126, 159))	('tumor', 'Disease', 'MESH:D009369', (363, 368))	('tumor', 'Disease', (268, 273))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (136, 159))	('tumor', 'Disease', (489, 494))	('Cancer', 'Phenotype', 'HP:0002664', (52, 58))	('tumor', 'Disease', 'MESH:D009369', (268, 273))
344547	32438606	Instead, mismatched nucleotides in the lncRNA binding site lead to sequestration of the miRNA by the lncRNA.	('sequestration of the miRNA', 'MPA', (67, 93))	('lead to', 'Reg', (59, 66))	('mismatched nucleotides', 'Var', (9, 31))	('rat', 'Species', '10116', (74, 77))
344565	32438606	For example, HOTAIR can repress a limited number of genes through H3K27me3 without the involvement of the PRC2 complex.	('HOTAIR', 'Gene', '100124700', (13, 19))	('HOTAIR', 'Gene', (13, 19))	('H3K27me3', 'Var', (66, 74))
344588	32438606	H19 is upregulated in the quadriceps of the low fat-free mass index (FFMI) COPD patients when compared to normal FFMI.	('H19', 'Gene', (0, 3))	('patients', 'Species', '9606', (80, 88))	('COPD', 'Disease', 'MESH:D029424', (75, 79))	('H19', 'Gene', '283120', (0, 3))	('COPD', 'Disease', (75, 79))	('upregulated', 'PosReg', (7, 18))	('low fat-free mass index', 'Var', (44, 67))
344600	32438606	suggested that H19 demethylation may precede the methylations that silence tumor suppressor genes such as p16-CDKN2A, MGMT, DAPK, E-cadherin (CDH1), and CDH13.	('CDKN2A', 'Gene', '1029', (110, 116))	('CDH1', 'Gene', (142, 146))	('MGMT', 'Gene', (118, 122))	('DAPK', 'Gene', '1612', (124, 128))	('tumor suppressor', 'Gene', '7248', (75, 91))	('CDH13', 'Gene', (153, 158))	('p16', 'Gene', (106, 109))	('E-cadherin', 'Gene', (130, 140))	('E-cadherin', 'Gene', '999', (130, 140))	('H19', 'Gene', (15, 18))	('p16', 'Gene', '1029', (106, 109))	('MGMT', 'Gene', '4255', (118, 122))	('H19', 'Gene', '283120', (15, 18))	('CDH1', 'Gene', '999', (153, 157))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('CDKN2A', 'Gene', (110, 116))	('demethylation', 'Var', (19, 32))	('tumor suppressor', 'Gene', (75, 91))	('CDH1', 'Gene', '999', (142, 146))	('CDH13', 'Gene', '1012', (153, 158))	('CDH1', 'Gene', (153, 157))	('DAPK', 'Gene', (124, 128))
344635	32438606	Regulators of MEG3: MEG3 promoter methylation was reported in 96% of NSCLC tumor tissues, which mainly contributes to its downregulation.	('NSCLC tumor', 'Disease', 'MESH:D009369', (69, 80))	('MEG3', 'Gene', '55384', (14, 18))	('methylation', 'Var', (34, 45))	('downregulation', 'NegReg', (122, 136))	('NSCLC tumor', 'Disease', (69, 80))	('MEG3', 'Gene', (20, 24))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('MEG3', 'Gene', (14, 18))	('MEG3', 'Gene', '55384', (20, 24))
344641	32438606	This PRC2 recruitment will eventually repress the expression of CDH1, ZEB family (ZEB1 and ZEB2), and hsa-miR-200 family ( MIR200A, MIR200B, and MIR200C ), which will lead to a decreased EMT.	('MIR200C', 'Gene', (145, 152))	(' MIR200A', 'Var', (122, 130))	('MIR200B', 'Gene', '406984', (132, 139))	('ZEB2', 'Gene', '9839', (91, 95))	('MIR200B', 'Gene', (132, 139))	('ZEB2', 'Gene', (91, 95))	('EMT', 'CPA', (187, 190))	('ZEB1', 'Gene', '6935', (82, 86))	('hsa', 'Gene', '213', (102, 105))	('ZEB1', 'Gene', (82, 86))	('hsa', 'Gene', (102, 105))	('decreased', 'NegReg', (177, 186))	('MIR200C', 'Gene', '406985', (145, 152))	('CDH1', 'Gene', (64, 68))	('CDH1', 'Gene', '999', (64, 68))	('decreased EMT', 'Phenotype', 'HP:0032198', (177, 190))
344649	32438606	Besides, MEG3 genotype rs4081134 SNP (AA) was associated with a lung cancer risk in Chinese patients.	('lung cancer', 'Disease', (64, 75))	('MEG3', 'Gene', (9, 13))	('lung cancer', 'Phenotype', 'HP:0100526', (64, 75))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('patients', 'Species', '9606', (92, 100))	('rs4081134', 'Mutation', 'rs4081134', (23, 32))	('MEG3', 'Gene', '55384', (9, 13))	('lung cancer', 'Disease', 'MESH:D008175', (64, 75))	('associated', 'Reg', (46, 56))	('rs4081134 SNP', 'Var', (23, 36))
344658	32438606	Downregulated MEG3 can regulate cell proliferation, EMT, and apoptosis in NSCLC tumor tissues from patients with an advanced pathological stage, as well as in cell lines.	('Downregulated', 'Var', (0, 13))	('apoptosis', 'CPA', (61, 70))	('MEG3', 'Gene', '55384', (14, 18))	('regulate', 'Reg', (23, 31))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('EMT', 'CPA', (52, 55))	('rat', 'Species', '10116', (44, 47))	('patients', 'Species', '9606', (99, 107))	('NSCLC tumor', 'Disease', 'MESH:D009369', (74, 85))	('NSCLC tumor', 'Disease', (74, 85))	('MEG3', 'Gene', (14, 18))	('cell proliferation', 'CPA', (32, 50))
344662	32438606	Subsequently, the low MEG3 expression observed in NSCLC patients with an advanced pathological stage may be due to a deletion of the MEG3-DMR locus or could be due to the deletion of a transcription factor binding MEG3 promoter.	('patients', 'Species', '9606', (56, 64))	('DMR', 'Gene', (138, 141))	('MEG3', 'Gene', (214, 218))	('MEG3', 'Gene', (133, 137))	('MEG3', 'Gene', (22, 26))	('deletion', 'Var', (171, 179))	('expression', 'MPA', (27, 37))	('MEG3', 'Gene', '55384', (133, 137))	('NSCLC', 'Disease', (50, 55))	('MEG3', 'Gene', '55384', (214, 218))	('MEG3', 'Gene', '55384', (22, 26))	('low', 'NegReg', (18, 21))	('NSCLC', 'Disease', 'MESH:D002289', (50, 55))	('DMR', 'Gene', '91833', (138, 141))	('deletion', 'Var', (117, 125))
344701	32438606	Regulators of FENDRR: Two studies described FENDRR as hypermethylated through a presumable involvement of EZH2.	('FENDRR', 'Gene', (44, 50))	('EZH2', 'Gene', (106, 110))	('EZH2', 'Gene', '2146', (106, 110))	('hypermethylated', 'Var', (54, 69))
344727	32438606	Conversely, in SCLCs, TUG1 may silence LIMK2 and BAX expression by interacting with EZH2.	('TUG1', 'Var', (22, 26))	('interacting', 'Interaction', (67, 78))	('SCLC', 'Disease', (15, 19))	('LIMK2', 'Gene', '3985', (39, 44))	('SCLC', 'Disease', 'MESH:D018288', (15, 19))	('silence', 'NegReg', (31, 38))	('BAX', 'Gene', (49, 52))	('BAX', 'Gene', '581', (49, 52))	('LIMK2', 'Gene', (39, 44))	('expression', 'MPA', (53, 63))	('EZH2', 'Gene', '2146', (84, 88))	('EZH2', 'Gene', (84, 88))
344728	32438606	TUG1 recruits the PRC2: In NSCLC tumor tissues, TUG1 can regulate CELF1 through PRC2 binding, and may also recruit EZH2, which will then trimethylates H3K27 and repress HOXB7.	('trimethylates', 'Var', (137, 150))	('H3K27', 'Protein', (151, 156))	('repress', 'NegReg', (161, 168))	('NSCLC tumor', 'Disease', (27, 38))	('CELF1', 'Gene', '10658', (66, 71))	('HOXB7', 'Gene', '3217', (169, 174))	('recruit', 'PosReg', (107, 114))	('PRC2', 'Protein', (80, 84))	('CELF1', 'Gene', (66, 71))	('TUG1', 'Gene', (48, 52))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('EZH2', 'Gene', '2146', (115, 119))	('HOXB7', 'Gene', (169, 174))	('EZH2', 'Gene', (115, 119))	('NSCLC tumor', 'Disease', 'MESH:D009369', (27, 38))	('binding', 'Interaction', (85, 92))
344779	32438606	Since the alteration of the DNA repair mechanism is part of the hallmark of cancers, it would be interesting to seek for CDKN2B-AS1 in the extracellular vesicles of early-stage lung tumors.	('CDKN2B-AS1', 'Gene', (121, 131))	('cancers', 'Phenotype', 'HP:0002664', (76, 83))	('tumors', 'Phenotype', 'HP:0002664', (182, 188))	('lung tumors', 'Phenotype', 'HP:0100526', (177, 188))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('CDKN2B-AS1', 'Gene', '100048912', (121, 131))	('hallmark of cancers', 'Disease', (64, 83))	('lung tumors', 'Disease', 'MESH:D008175', (177, 188))	('hallmark of cancers', 'Disease', 'MESH:D009369', (64, 83))	('alteration', 'Var', (10, 20))	('rat', 'Species', '10116', (14, 17))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))	('lung tumors', 'Disease', (177, 188))
344791	32438606	Interestingly, a specific negative regulation loop involves HOTAIR and TP53 in NSCLC tumor tissues.	('NSCLC tumor', 'Disease', (79, 90))	('TP53', 'Var', (71, 75))	('HOTAIR', 'Gene', (60, 66))	('HOTAIR', 'Gene', '100124700', (60, 66))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('negative regulation', 'NegReg', (26, 45))	('NSCLC tumor', 'Disease', 'MESH:D009369', (79, 90))
344794	32438606	HOTAIR regulated genes: In SCLC cell lines (H69 and H446), HOTAIR can activate the NF-kappaB signaling pathway through the methylation of HOXA1.	('HOTAIR', 'Gene', (59, 65))	('H446', 'CellLine', 'CVCL:1562', (52, 56))	('HOTAIR', 'Gene', '100124700', (0, 6))	('HOTAIR', 'Gene', '100124700', (59, 65))	('HOXA1', 'Gene', '3198', (138, 143))	('NF-kappaB', 'Gene', '4790', (83, 92))	('methylation', 'Var', (123, 134))	('H69', 'CellLine', 'CVCL:8121', (44, 47))	('activate', 'PosReg', (70, 78))	('SCLC', 'Disease', (27, 31))	('NF-kappaB', 'Gene', (83, 92))	('HOTAIR', 'Gene', (0, 6))	('SCLC', 'Disease', 'MESH:D018288', (27, 31))	('HOXA1', 'Gene', (138, 143))
344846	32438606	Besides, in NSCLC tumor tissues and cell lines (A549, H1299, H1975, HCC827), GAS5 can deregulate the expression of phospho-EGFR, phospho-MAPK1, phospho-AKT1, and IGF1R.	('EGFR', 'Gene', (123, 127))	('IGF1R', 'Gene', '3480', (162, 167))	('EGFR', 'Gene', '1956', (123, 127))	('NSCLC tumor', 'Disease', 'MESH:D009369', (12, 23))	('MAPK1', 'Gene', (137, 142))	('GAS5', 'Var', (77, 81))	('A549', 'CellLine', 'CVCL:0023', (48, 52))	('H1299', 'CellLine', 'CVCL:0060', (54, 59))	('NSCLC tumor', 'Disease', (12, 23))	('deregulate', 'Reg', (86, 96))	('AKT1', 'Gene', '207', (152, 156))	('H1975', 'CellLine', 'CVCL:1511', (61, 66))	('AKT1', 'Gene', (152, 156))	('expression', 'MPA', (101, 111))	('IGF1R', 'Gene', (162, 167))	('MAPK1', 'Gene', '5594', (137, 142))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
344870	32438606	LINC00861 and the uncharacterized LOC101928100 RNA gene were co-expressed with RORA, while the authors observed an upregulation of hsa-miR-218-5p.	('RORA', 'Gene', '6095', (79, 83))	('LOC101928100', 'Var', (34, 46))	('upregulation', 'PosReg', (115, 127))	('hsa-miR-218', 'Gene', '407001', (131, 142))	('LINC00861', 'Gene', '100130231', (0, 9))	('hsa-miR-218', 'Gene', (131, 142))	('LINC00861', 'Gene', (0, 9))	('RORA', 'Gene', (79, 83))
344881	32438606	demonstrated that the transfer of extracellular Vesicle-Associated-RNAs could induce drug resistance in ALK-Translocated lung Adenocarcinoma.	('induce', 'Reg', (78, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('lung Adenocarcinoma', 'Phenotype', 'HP:0030078', (121, 140))	('lung Adenocarcinoma', 'Disease', 'MESH:D000077192', (121, 140))	('ALK', 'Gene', '238', (104, 107))	('transfer', 'Var', (22, 30))	('drug resistance', 'MPA', (85, 100))	('lung Adenocarcinoma', 'Disease', (121, 140))	('extracellular', 'Protein', (34, 47))	('rat', 'Species', '10116', (7, 10))	('ALK', 'Gene', (104, 107))	('drug resistance', 'Phenotype', 'HP:0020174', (85, 100))
344887	32438606	Erlotinib is a tyrosine kinase inhibitor that is effective in patients with or without EGFR mutations but appears to be more effective in patients with EGFR mutations.	('EGFR', 'Gene', '1956', (87, 91))	('EGFR', 'Gene', '1956', (152, 156))	('EGFR', 'Gene', (87, 91))	('mutations', 'Var', (92, 101))	('Erlotinib', 'Chemical', 'MESH:D000069347', (0, 9))	('EGFR', 'Gene', (152, 156))	('patients', 'Species', '9606', (62, 70))	('patients', 'Species', '9606', (138, 146))
344914	32438606	Genome instability and mutation: MALAT1 and CDKN2B-AS1 may be key players of the "Genome instability and mutation" hallmark since they can decrease the expression levels of PARP1.	('mutation', 'Var', (105, 113))	('CDKN2B-AS1', 'Gene', '100048912', (44, 54))	('PARP1', 'Gene', '142', (173, 178))	('expression levels', 'MPA', (152, 169))	('MALAT1', 'Gene', '378938', (33, 39))	('PARP1', 'Gene', (173, 178))	('CDKN2B-AS1', 'Gene', (44, 54))	('MALAT1', 'Gene', (33, 39))	('decrease', 'NegReg', (139, 147))
344917	32438606	However, RIOX2 may demethylate H19 before the DNA-repair gene MGMT and the cyclin-dependent kinase inhibitor p16-CDKN2A are methylated.	('MGMT', 'Gene', (62, 66))	('H19', 'Gene', '283120', (31, 34))	('p16', 'Gene', (109, 112))	('MGMT', 'Gene', '4255', (62, 66))	('H19', 'Gene', (31, 34))	('CDKN2A', 'Gene', (113, 119))	('p16', 'Gene', '1029', (109, 112))	('CDKN2A', 'Gene', '1029', (113, 119))	('demethylate', 'Var', (19, 30))
344954	32438606	First, these lncRNAs may trigger important hallmarks of cancers, such as "Genome instability and mutation" for CDKN2B-AS1, "Activating invasion and metastasis" for FENDRR, "Resisting cell death" for MEG3 and CDKN2B-AS1, and "Sustaining and proliferative signaling" for TUG1.	('Resisting', 'NegReg', (173, 182))	('hallmarks of cancers', 'Disease', (43, 63))	('CDKN2B-AS1', 'Gene', (111, 121))	('Activating', 'PosReg', (124, 134))	('mutation', 'Var', (97, 105))	('hes', 'Gene', '3280', (8, 11))	('hallmarks of cancers', 'Disease', 'MESH:D009369', (43, 63))	('CDKN2B-AS1', 'Gene', (208, 218))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('hes', 'Gene', (8, 11))	('rat', 'Species', '10116', (247, 250))	('MEG3', 'Gene', (199, 203))	('CDKN2B-AS1', 'Gene', '100048912', (208, 218))	('CDKN2B-AS1', 'Gene', '100048912', (111, 121))	('cancers', 'Phenotype', 'HP:0002664', (56, 63))	('cell death', 'CPA', (183, 193))	('MEG3', 'Gene', '55384', (199, 203))
345094	31877723	If the results from further investigations from in vivo and in vitro studies support our findings, the combination of the appropriate strategy with targeting MAGEA9 might be expected as a high efficacy of the chemo-immunotherapeutic approach.	('MAGEA9', 'Gene', '4108', (158, 164))	('MAGEA9', 'Gene', (158, 164))	('targeting', 'Var', (148, 157))
345133	31877723	It was also further demonstrated that high levels of serum NO were associated with advanced-stage lung cancer and poor survival rate of patients.	('serum NO', 'MPA', (53, 61))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('lung cancer', 'Phenotype', 'HP:0100526', (98, 109))	('advanced-stage lung cancer', 'Disease', (83, 109))	('high', 'Var', (38, 42))	('patients', 'Species', '9606', (136, 144))	('associated', 'Reg', (67, 77))	('advanced-stage lung cancer', 'Disease', 'MESH:D008175', (83, 109))
345156	31877723	It has been reported that siRNA-mediated knockdown of MZB1 significantly increased proliferation, invasion and migration of GC cell lines.	('increased', 'PosReg', (73, 82))	('GC', 'Disease', 'MESH:D013274', (124, 126))	('proliferation', 'CPA', (83, 96))	('invasion', 'CPA', (98, 106))	('GC', 'Phenotype', 'HP:0012126', (124, 126))	('MZB1', 'Gene', '51237', (54, 58))	('MZB1', 'Gene', (54, 58))	('knockdown', 'Var', (41, 50))
345164	31877723	Interestingly, it was shown that re-expression of PAX5 in lung cells inhibited beta-catenin signalling pathway, which plays important role not only in proliferation, differentiation, and migration but also in regulating immune cell infiltration of the tumour microenvironment.	('men', 'Species', '9606', (271, 274))	('PAX5', 'Gene', (50, 54))	('re-expression', 'Var', (33, 46))	('regulating', 'Reg', (209, 219))	('proliferation', 'CPA', (151, 164))	('beta-catenin', 'Gene', '1499', (79, 91))	('tumour', 'Disease', (252, 258))	('migration', 'CPA', (187, 196))	('immune cell infiltration', 'CPA', (220, 244))	('differentiation', 'CPA', (166, 181))	('inhibited', 'NegReg', (69, 78))	('PAX5', 'Gene', '5079', (50, 54))	('tumour', 'Phenotype', 'HP:0002664', (252, 258))	('beta-catenin', 'Gene', (79, 91))	('tumour', 'Disease', 'MESH:D009369', (252, 258))
345203	31877723	Taken together, our RNA-seq data has generated a wealth of information for potentially new biomarkers, networks, and pathways dysregulated in lung ADC and SCC tissues which can be further explored to unravel the molecular mechanisms regulating the development of each subtype of NSCLC.	('SCC', 'Phenotype', 'HP:0002860', (155, 158))	('NSCLC', 'Disease', (279, 284))	('lung ADC', 'Disease', 'MESH:C538231', (142, 150))	('NSCLC', 'Disease', 'MESH:D002289', (279, 284))	('SCLC', 'Phenotype', 'HP:0030357', (280, 284))	('lung ADC', 'Disease', (142, 150))	('SCC', 'Disease', (155, 158))	('dysregulated', 'Var', (126, 138))	('men', 'Species', '9606', (255, 258))	('NSCLC', 'Phenotype', 'HP:0030358', (279, 284))	('SCC', 'Disease', 'MESH:D002294', (155, 158))
345216	28952053	TDP-43 regulates cancer-associated microRNAs Aberrant regulation of miRNA genes contributes to pathogenesis of a wide range of human diseases, including cancer.	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('TDP-43', 'Gene', (0, 6))	('miR', 'Gene', '220972', (68, 71))	('human', 'Species', '9606', (127, 132))	('miR', 'Gene', (68, 71))	('cancer', 'Disease', (153, 159))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('Aberrant', 'Var', (45, 53))	('regulation', 'MPA', (54, 64))	('contributes', 'Reg', (80, 91))	('cancer', 'Disease', (17, 23))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('TDP-43', 'Gene', '23435', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
345219	28952053	TDP-43 knockdown affected the expression of a number of miRNAs.	('TDP-43', 'Gene', (0, 6))	('expression', 'MPA', (30, 40))	('affected', 'Reg', (17, 25))	('miR', 'Gene', '220972', (56, 59))	('miR', 'Gene', (56, 59))	('knockdown', 'Var', (7, 16))
345231	28952053	Specifically, aberrant expression of miRNA is found in different types of cancer, and multiple miRNAs have been shown to contribute to cancer development and progression (Kong et al.,;Parpart and Wang,).	('miR', 'Gene', '220972', (95, 98))	('cancer', 'Disease', (135, 141))	('miR', 'Gene', (95, 98))	('miR', 'Gene', (37, 40))	('progression', 'CPA', (158, 169))	('miR', 'Gene', '220972', (37, 40))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('aberrant', 'Var', (14, 22))	('cancer', 'Disease', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('contribute', 'Reg', (121, 131))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('cancer', 'Disease', 'MESH:D009369', (135, 141))	('expression', 'MPA', (23, 33))
345250	28952053	Taken together, our study has revealed complex gene networks that may be regulated by TDP-43 in human cancers and suggests that TDP-43 may modulate the expression of a subset of miRNAs associated with human cancers.	('TDP-43', 'Gene', (86, 92))	('cancers', 'Phenotype', 'HP:0002664', (207, 214))	('human cancers', 'Disease', (96, 109))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('miR', 'Gene', '220972', (178, 181))	('miR', 'Gene', (178, 181))	('human cancers', 'Disease', (201, 214))	('modulate', 'Reg', (139, 147))	('expression', 'MPA', (152, 162))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('human cancers', 'Disease', 'MESH:D009369', (96, 109))	('regulated', 'Reg', (73, 82))	('TDP-43', 'Var', (128, 134))	('human cancers', 'Disease', 'MESH:D009369', (201, 214))
345255	28952053	The annotations of reads from TDP-43 knockdown and control SH-SY5Y cell lines are shown in Fig.	('TDP-43', 'Gene', (30, 36))	('SH-SY5Y', 'CellLine', 'CVCL:0019', (59, 66))	('knockdown', 'Var', (37, 46))
345259	28952053	In the SH-SY5Y cell line, TDP-43 knockdown resulted in 98 differentially expressed miRNAs (P-value < 0.001), of which 68 miRNAs were down-regulated.	('down-regulated', 'NegReg', (133, 147))	('knockdown', 'Var', (33, 42))	('SH-SY5Y', 'CellLine', 'CVCL:0019', (7, 14))	('TDP-43', 'Gene', (26, 32))	('miR', 'Gene', '220972', (83, 86))	('miR', 'Gene', (83, 86))	('miR', 'Gene', '220972', (121, 124))	('miR', 'Gene', (121, 124))
345260	28952053	Of these 98 miRNAs, 2 miRNAs were up-regulated and 14 down-regulated after TDP-43 knockdown in the SNB-19 and HT22 cell lines.	('miR', 'Gene', (12, 15))	('miR', 'Gene', '220972', (22, 25))	('up-regulated', 'PosReg', (34, 46))	('knockdown', 'Var', (82, 91))	('TDP-43', 'Gene', (75, 81))	('miR', 'Gene', (22, 25))	('miR', 'Gene', '220972', (12, 15))	('HT22', 'CellLine', 'CVCL:0321', (110, 114))	('down-regulated', 'NegReg', (54, 68))
345266	28952053	Applying the chi-square test to the expression levels of the 4 types of isomiRs based on mature miRNA sequences from miRBase version 18 (Kozomara and Griffiths-Jones,), we identified 9, 9 and 26 miRNAsin the SH-SY5Y, SNB19 and HT22 cells, respectively, that had significantly changed isomiR patterns after TDP-43 knockdown, in comparison to the control cells (Table S3; see MATERIALS AND METHODS).	('TDP-43', 'Gene', (306, 312))	('SH-SY5Y', 'CellLine', 'CVCL:0019', (208, 215))	('miR', 'Gene', (75, 78))	('miR', 'Gene', '220972', (75, 78))	('miR', 'Gene', '220972', (287, 290))	('miR', 'Gene', (287, 290))	('miR', 'Gene', '220972', (195, 198))	('miR', 'Gene', (195, 198))	('changed', 'Reg', (276, 283))	('miR', 'Gene', '220972', (96, 99))	('miR', 'Gene', (96, 99))	('miR', 'Gene', '220972', (117, 120))	('miR', 'Gene', (117, 120))	('knockdown', 'Var', (313, 322))	('HT22', 'CellLine', 'CVCL:0321', (227, 231))
345268	28952053	Reduced expression levels of isomiR-3p after TDP-43 knockdown were frequently accompanied by increased expression of isomiR-3e, as observed for hsa-miR-199a-5p, hsa-miR-301a-3p, and mmu-miR-199a-5p (Fig.	('miR', 'Gene', (32, 35))	('miR', 'Gene', '220972', (186, 189))	('miR', 'Gene', (186, 189))	('miR', 'Gene', '220972', (120, 123))	('increased', 'PosReg', (93, 102))	('miR', 'Gene', (120, 123))	('expression', 'MPA', (103, 113))	('Reduced', 'NegReg', (0, 7))	('miR', 'Gene', '220972', (165, 168))	('miR', 'Gene', (165, 168))	('miR', 'Gene', '220972', (148, 151))	('miR', 'Gene', '220972', (32, 35))	('expression levels', 'MPA', (8, 25))	('knockdown', 'Var', (52, 61))	('TDP-43', 'Gene', (45, 51))	('miR', 'Gene', (148, 151))
345269	28952053	In contrast, the expression levels of isomiR-5p and isomiR-53p are less frequently altered after TDP-43 knockdown.	('expression levels', 'MPA', (17, 34))	('altered', 'Reg', (83, 90))	('miR', 'Gene', '220972', (41, 44))	('miR', 'Gene', (41, 44))	('miR', 'Gene', '220972', (55, 58))	('miR', 'Gene', (55, 58))	('knockdown', 'Var', (104, 113))
345275	28952053	For example, in the SH-SY5Ycell line, 12 precursors showed increased and 12 showed decreased 5' arm/3' arm reads count ratio after TDP-43 knockdown.	('knockdown', 'Var', (138, 147))	('SH-SY5Ycell', 'CellLine', 'CVCL:0019', (20, 31))	('TDP-43', 'Gene', (131, 137))	('decreased', 'NegReg', (83, 92))	("5' arm/3' arm reads count ratio", 'MPA', (93, 124))	('increased', 'PosReg', (59, 68))
345277	28952053	In the SH-SY5Y control sample, the number of reads deriving from the 3' arm of pre-mir-152 was nearly twice the number of reads deriving from the 5' arm, whereas after TDP-43 knockdown the number of reads from the 5' arm was about 12% higher than from the 3' arm.	('mir', 'Gene', (83, 86))	('higher', 'PosReg', (235, 241))	('SH-SY5Y', 'CellLine', 'CVCL:0019', (7, 14))	('mir', 'Gene', '220972', (83, 86))	('knockdown', 'Var', (175, 184))
345278	28952053	Reads derived from the 5' arm of pre-mir-152 after TDP-43 knockdown were of 3 different isoforms (Fig.	('mir', 'Gene', (37, 40))	('mir', 'Gene', '220972', (37, 40))	('knockdown', 'Var', (58, 67))	('TDP-43', 'Gene', (51, 57))
345279	28952053	The ratios of five pre-miRNAs (pre-let-7g, pre-let-7i, pre-mir-101, pre-mir-125a, and pre-mir-185) increased in at least two cell lines after TDP-43 knockdown, whereas the ratios of five other pre-miRNAs (pre-mir-106b, pre-mir-188, pre-mir-18a, pre-mir-33a, and pre-mir-93) decreased in at least two cell lines after TDP-43 knockdown (Fig.	('miR', 'Gene', (197, 200))	('let-7g', 'Gene', '406890', (35, 41))	('miR', 'Gene', (23, 26))	('knockdown', 'Var', (324, 333))	('mir', 'Gene', (266, 269))	('let-7g', 'Gene', (35, 41))	('mir', 'Gene', (209, 212))	('mir', 'Gene', (59, 62))	('mir', 'Gene', (90, 93))	('let-7i', 'Gene', (47, 53))	('mir', 'Gene', (249, 252))	('mir', 'Gene', '220972', (223, 226))	('mir', 'Gene', '220972', (72, 75))	('increased', 'PosReg', (99, 108))	('mir', 'Gene', '220972', (236, 239))	('mir', 'Gene', '220972', (266, 269))	('mir', 'Gene', (223, 226))	('miR', 'Gene', '220972', (197, 200))	('mir', 'Gene', '220972', (209, 212))	('mir', 'Gene', (72, 75))	('miR', 'Gene', '220972', (23, 26))	('mir', 'Gene', (236, 239))	('mir', 'Gene', '220972', (59, 62))	('mir', 'Gene', '220972', (90, 93))	('let-7i', 'Gene', '406891', (47, 53))	('mir', 'Gene', '220972', (249, 252))
345285	28952053	Most of these novel miRNA candidates were only detected after TDP-43 knockdown, suggesting that TDP-43 may inhibit the expression of these novel miRNA candidates.	('inhibit', 'NegReg', (107, 114))	('expression', 'MPA', (119, 129))	('miR', 'Gene', '220972', (20, 23))	('miR', 'Gene', (20, 23))	('miR', 'Gene', '220972', (145, 148))	('miR', 'Gene', (145, 148))	('TDP-43', 'Var', (96, 102))
345290	28952053	1B), we assayed the expression of miR-27a-3p and four other miRNAs in SH-SY-5Y cells by qRT-PCR, and found that the expression levels of all five miRNAs decreased significantly after knockdown of TDP-43 (Fig.	('miR', 'Gene', '220972', (60, 63))	('miR', 'Gene', (60, 63))	('knockdown', 'Var', (183, 192))	('SH-SY-5Y', 'CellLine', 'CVCL:0019', (70, 78))	('miR', 'Gene', '220972', (34, 37))	('miR', 'Gene', '220972', (146, 149))	('miR', 'Gene', (34, 37))	('decreased', 'NegReg', (153, 162))	('TDP-43', 'Gene', (196, 202))	('miR', 'Gene', (146, 149))	('expression levels', 'MPA', (116, 133))	('27a', 'Species', '1412829', (38, 41))
345329	28952053	To test this hypothesis, we performed TDP-43 knockdown on H1299 lung cancer cells and measured cell migration using the transwell migration assay.	('lung cancer', 'Phenotype', 'HP:0100526', (64, 75))	('H1299 lung cancer', 'Disease', 'MESH:D008175', (58, 75))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('knockdown', 'Var', (45, 54))	('TDP-43', 'Gene', (38, 44))	('H1299 lung cancer', 'Disease', (58, 75))	('cell migration', 'CPA', (95, 109))
345332	28952053	Co-transfection with other miRNAs did not rescue the reduction in cell migration caused by TDP-43 knockdown (Fig.	('cell migration', 'CPA', (66, 80))	('knockdown', 'Var', (98, 107))	('miR', 'Gene', '220972', (27, 30))	('miR', 'Gene', (27, 30))	('TDP-43', 'Gene', (91, 97))
345354	28952053	Consistently, after knockdown of miR-500a-3p, LIF and PAPPA mRNA levels were up-regulated in H1299 cells (Fig.	('H1299', 'CellLine', 'CVCL:0060', (93, 98))	('miR-500a', 'Gene', (33, 41))	('PAPPA', 'Gene', '5069', (54, 59))	('LIF', 'Gene', '3976', (46, 49))	('PAPPA', 'Gene', (54, 59))	('knockdown', 'Var', (20, 29))	('up-regulated', 'PosReg', (77, 89))	('LIF', 'Gene', (46, 49))	('miR-500a', 'Gene', '574502', (33, 41))
345355	28952053	To determine whether miR-500a-3p interacts with the 3'UTR regions of LIF and PAPPA mRNAs, we co-transfected miR-500a-3p mimetic or control with luciferase reporter constructs for LIF or PAPPA containing the respective wild-type 3'UTR or the mutant 3'UTR containing mutated binding site for miR-500a-3p into H1299 cells.	('binding', 'Interaction', (273, 280))	('miR-500a', 'Gene', (108, 116))	('miR-500a', 'Gene', '574502', (290, 298))	('PAPPA', 'Gene', '5069', (186, 191))	('mutant', 'Var', (241, 247))	('LIF', 'Gene', '3976', (179, 182))	('H1299', 'CellLine', 'CVCL:0060', (307, 312))	('LIF', 'Gene', '3976', (69, 72))	('miR-500a', 'Gene', '574502', (21, 29))	('LIF', 'Gene', (179, 182))	('LIF', 'Gene', (69, 72))	('PAPPA', 'Gene', (186, 191))	('miR-500a', 'Gene', (290, 298))	('PAPPA', 'Gene', '5069', (77, 82))	('miR-500a', 'Gene', '574502', (108, 116))	('PAPPA', 'Gene', (77, 82))	('miR-500a', 'Gene', (21, 29))	('mutated', 'Var', (265, 272))
345356	28952053	Mutating the miR-500a-3p binding site in the LIF 3'UTR reversed effect of miR-500a-3p (Figs.	('Mutating', 'Var', (0, 8))	('miR-500a', 'Gene', '574502', (13, 21))	('LIF', 'Gene', (45, 48))	('LIF', 'Gene', '3976', (45, 48))	('miR-500a', 'Gene', (13, 21))	('miR-500a', 'Gene', (74, 82))	('miR-500a', 'Gene', '574502', (74, 82))
345360	28952053	Dysregulation of miRNAs is associated with a variety of human diseases, such as cancers and neurological disorders (Calin and Croce,; Maciotta et al.,; Nelson et al.,;Abu-Elneel et al,;Jonas and Izaurralde; Bracken et al,;Adams et al,).	('neurological disorders', 'Disease', 'MESH:D009422', (92, 114))	('Croce', 'Disease', (126, 131))	('cancers', 'Disease', 'MESH:D009369', (80, 87))	('Dysregulation', 'Var', (0, 13))	('miR', 'Gene', '220972', (17, 20))	('miR', 'Gene', (17, 20))	('cancers', 'Disease', (80, 87))	('associated', 'Reg', (27, 37))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('human', 'Species', '9606', (56, 61))	('Adams', 'Disease', (222, 227))	('neurological disorders', 'Disease', (92, 114))	('Bracken', 'Disease', (207, 214))	('Jonas', 'Disease', (185, 190))	('Abu-Elneel', 'Disease', (167, 177))	('Izaurralde', 'Disease', (195, 205))	('cancers', 'Phenotype', 'HP:0002664', (80, 87))
345368	28952053	To take another example, it was reported that in Drosophila, TDP-43 bound to pri-miR-9a to maintain its stability and the expression level of the mature sequence, and that TDP-43 conferred robustness to neuronal specification through miR-9a (Li et al.,).	('expression', 'MPA', (122, 132))	('pri', 'Gene', '47191', (77, 80))	('miR-9a', 'Gene', (81, 87))	('miR-9a', 'Gene', '12797939', (81, 87))	('stability', 'MPA', (104, 113))	('miR-9a', 'Gene', (234, 240))	('TDP-43', 'Var', (172, 178))	('TDP-43', 'Gene', (61, 67))	('pri', 'Gene', (77, 80))	('miR-9a', 'Gene', '12797939', (234, 240))	('Drosophila', 'Species', '7227', (49, 59))
345369	28952053	Consistent with these results, our data show that both miR-9-5p and miR-9-3p were significantly down-regulated after TDP-43 knockdown (Table S2).	('knockdown', 'Var', (124, 133))	('miR-9-3p', 'Gene', (68, 76))	('TDP-43', 'Gene', (117, 123))	('miR-9-5p', 'Gene', (55, 63))	('down-regulated', 'NegReg', (96, 110))	('miR-9-5p', 'Gene', '407052', (55, 63))	('miR-9-3p', 'Gene', '407051', (68, 76))
345373	28952053	Our high-throughput sequencing data showed that the expression levels of a substantial number of miRNAs were altered in at least one of the three cell lines after TDP-43 knockdown.	('knockdown', 'Var', (170, 179))	('TDP-43', 'Gene', (163, 169))	('expression levels', 'MPA', (52, 69))	('altered', 'Reg', (109, 116))	('miR', 'Gene', '220972', (97, 100))	('miR', 'Gene', (97, 100))
345374	28952053	Many of the miRNAs affected by TDP-43 knockdown were down-regulated, but only 13 of the affected miRNAs have previously been reported to be affected by TDP-43 expression level changes (Buratti et al.,; Kawahara and Mieda-Sato,,Li et al.,).	('TDP-43', 'Gene', (31, 37))	('TDP-43', 'Gene', (152, 158))	('expression', 'MPA', (159, 169))	('miR', 'Gene', '220972', (12, 15))	('miR', 'Gene', '220972', (97, 100))	('knockdown', 'Var', (38, 47))	('miR', 'Gene', (97, 100))	('down-regulated', 'NegReg', (53, 67))	('miR', 'Gene', (12, 15))
345381	28952053	Marked differences in isomiR distributions were seen after TDP-43 knockdown.	('TDP-43', 'Gene', (59, 65))	('miR', 'Gene', '220972', (25, 28))	('differences', 'Reg', (7, 18))	('miR', 'Gene', (25, 28))	('knockdown', 'Var', (66, 75))
345382	28952053	The expression levels of most miRNAs with altered isomiRs patterns were also significantly changed by TDP-43 knockdown, indicating a role of TDP-43 in miRNA editing, modification and/or turnover.	('expression levels', 'MPA', (4, 21))	('miR', 'Gene', '220972', (30, 33))	('miR', 'Gene', (30, 33))	('miR', 'Gene', (53, 56))	('miR', 'Gene', '220972', (53, 56))	('miR', 'Gene', '220972', (151, 154))	('miR', 'Gene', (151, 154))	('changed', 'Reg', (91, 98))	('knockdown', 'Var', (109, 118))	('TDP-43', 'Gene', (102, 108))
345399	28952053	Prima facie, the results seem mixed because two genes were shown to inhibit cell migration (LCP2 (Baker et al.,) and ADRB2 (Yu et al.,)), one showed mixed results with respect to cell migration (ITGA9; Mostovich et al.,), and another was reported to promote cell migration (CRK (Sriram and Birge,)).	('CRK', 'Gene', (274, 277))	('cell migration', 'CPA', (258, 272))	('ITGA9', 'Gene', '3680', (195, 200))	('promote', 'PosReg', (250, 257))	('ITGA9', 'Gene', (195, 200))	('cell migration', 'CPA', (76, 90))	('inhibit', 'NegReg', (68, 75))	('LCP2', 'Gene', (92, 96))	('ADRB2', 'Gene', '154', (117, 122))	('genes', 'Var', (48, 53))	('LCP2', 'Gene', '3937', (92, 96))	('CRK', 'Gene', '1398', (274, 277))	('ADRB2', 'Gene', (117, 122))	('cell migration', 'CPA', (179, 193))
345414	28952053	In the case of miR-500a-3p, TDP-43 binds to the mature miR-500a-3p sequence, and miR-500a-3p expression is significantly down-regulated by TDP-43 knockdown.	('knockdown', 'Var', (146, 155))	('miR-500a', 'Gene', (55, 63))	('miR-500a', 'Gene', '574502', (81, 89))	('TDP-43', 'Gene', (139, 145))	('miR-500a', 'Gene', (15, 23))	('binds', 'Interaction', (35, 40))	('miR-500a', 'Gene', '574502', (55, 63))	('down-regulated', 'NegReg', (121, 135))	('expression', 'MPA', (93, 103))	('miR-500a', 'Gene', (81, 89))	('miR-500a', 'Gene', '574502', (15, 23))
345468	28952053	The number of reads mapping to miRNAs and their isomiRs were used to estimate their expression levels in the 3 pairs of libraries (SNB-19_siCtrl VS SNB-19_siTDP, SY-5Y_siCtrl VS SY-5Y_siTDP and HT22_siCtrl VS HT22_siTDP).	('TDP', 'Disease', (216, 219))	('HT22_siCtrl', 'Var', (194, 205))	('TDP', 'Disease', 'MESH:D016171', (157, 160))	('HT22', 'CellLine', 'CVCL:0321', (194, 198))	('TDP', 'Disease', 'MESH:D016171', (216, 219))	('TDP', 'Disease', (186, 189))	('SNB-19_siCtrl', 'Var', (131, 144))	('miR', 'Gene', '220972', (31, 34))	('miR', 'Gene', (31, 34))	('miR', 'Gene', (51, 54))	('miR', 'Gene', '220972', (51, 54))	('HT22', 'CellLine', 'CVCL:0321', (209, 213))	('SY-5Y', 'CellLine', 'CVCL:0019', (178, 183))	('expression', 'MPA', (84, 94))	('TDP', 'Disease', 'MESH:D016171', (186, 189))	('SY-5Y', 'CellLine', 'CVCL:0019', (162, 167))	('TDP', 'Disease', (157, 160))
345471	28952053	The Chi-squared test was employed to calculate the statistical significance of changes in isomiR expression patterns after TDP-43 knockdown.	('changes', 'Reg', (79, 86))	('knockdown', 'Var', (130, 139))	('TDP-43', 'Gene', (123, 129))	('miR', 'Gene', '220972', (93, 96))	('miR', 'Gene', (93, 96))
345472	28952053	We applied filter criteria to select miRNAs with isomiR pattern changes with high confidence: (1) total expression of at least 1000 counts in at least one condition; (2) the ratio of at least one isomiR variant to the total reads needed to change by at least 5% between conditions.	('miR', 'Gene', '220972', (37, 40))	('miR', 'Gene', (37, 40))	('variant', 'Var', (203, 210))	('miR', 'Gene', '220972', (199, 202))	('miR', 'Gene', (199, 202))	('miR', 'Gene', '220972', (52, 55))	('miR', 'Gene', (52, 55))
345520	29383178	We found that patients with scores of 2-3 had significantly poorer local control rates than patients with scores of 0-1 (33.3% versus 86.8%, p=0.003).	('poorer', 'NegReg', (60, 66))	('scores', 'Var', (28, 34))	('patients', 'Species', '9606', (92, 100))	('local control rates', 'CPA', (67, 86))	('patients', 'Species', '9606', (14, 22))
345544	29383178	The primary tumor sites consisted of 31 (53.5%) oropharynx and 27 (46.5%) hypopharynx, and all were in advanced T categories with 14 (24.1%) T3, 38 (65.6%) T4a and 6 (10.3%) T4b.	('oropharynx', 'Disease', (48, 58))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('T4a', 'Var', (156, 159))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('tumor', 'Disease', (12, 17))
345561	29383178	Patients with scores of 0-1 had significantly better 2-year local control rates than patients with scores of 2-3 (86.8% versus 33.3%, p=0.003).	('patients', 'Species', '9606', (85, 93))	('local control', 'CPA', (60, 73))	('scores', 'Var', (14, 20))	('Patients', 'Species', '9606', (0, 8))	('better', 'PosReg', (46, 52))
345562	29383178	Multivariate Cox proportional hazard analysis demonstrated a poorer local control rate in patients with a score of 1-2 than those with a score of 0 (hazard ratio [HR] = 5.220 and 21.494; p = 0.140 and 0.006, respectively), while patients with a score of 3 showed the poorest local control rate (HR = 314.834; p < 0.001) (Table 4).	('patients', 'Species', '9606', (229, 237))	('score', 'Var', (106, 111))	('patients', 'Species', '9606', (90, 98))	('poorer', 'NegReg', (61, 67))	('local control', 'CPA', (68, 81))
345575	29383178	in vivo 1H MR spectroscopy studies of HNSCC with 1.5T MR scanner, King et al reported that both the pretreatment choline and change in choline early during a course of treatment did not predict clinical outcome, while the presence of choline in a post-treatment mass, instead of a percentage change in choline ratios, may serve as a marker of residual cancer.	('choline', 'Chemical', 'MESH:D002794', (135, 142))	('cancer', 'Disease', 'MESH:D009369', (352, 358))	('choline', 'Chemical', 'MESH:D002794', (302, 309))	('cancer', 'Disease', (352, 358))	('choline', 'Chemical', 'MESH:D002794', (234, 241))	('presence', 'Var', (222, 230))	('cancer', 'Phenotype', 'HP:0002664', (352, 358))	('1H', 'Chemical', '-', (8, 10))	('choline', 'Chemical', 'MESH:D002794', (113, 120))	('HNSCC', 'Phenotype', 'HP:0012288', (38, 43))
345594	29383178	However, some other studies showed that MTV and TLG, instead of SUVmax, were adverse prognostic factors for local failure.	('MTV', 'Var', (40, 43))	('local failure', 'Disease', (108, 121))	('local failure', 'Disease', 'MESH:D012594', (108, 121))	('MTV', 'Chemical', '-', (40, 43))	('TLG', 'Chemical', '-', (48, 51))
345664	29321960	Recent studies have confirmed the correlation between lung cancer and non-coding RNAs, among which microRNAs (miRNAs) account for a large proportion.	('lung cancer', 'Disease', (54, 65))	('non-coding', 'Var', (70, 80))	('lung cancer', 'Phenotype', 'HP:0100526', (54, 65))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('lung cancer', 'Disease', 'MESH:D008175', (54, 65))	('miR', 'Gene', '220972', (110, 113))	('miR', 'Gene', (110, 113))
345671	29321960	Aberrant regulation of miR-193a-3p has also been found in the development of other types of cancer, such as prostate cancer, breast cancer, head and neck squamous cell carcinomas, and colorectal cancer 12, 13, 14, 15.	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('colorectal cancer', 'Disease', 'MESH:D015179', (184, 201))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('colorectal cancer', 'Disease', (184, 201))	('breast cancer', 'Phenotype', 'HP:0003002', (125, 138))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (168, 177))	('carcinomas', 'Phenotype', 'HP:0030731', (168, 178))	('head and neck squamous cell carcinomas', 'Disease', 'MESH:D000077195', (140, 178))	('Aberrant', 'Var', (0, 8))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (154, 178))	('miR-193a', 'Gene', '406968', (23, 31))	('miR-193a', 'Gene', (23, 31))	('breast cancer', 'Disease', 'MESH:D001943', (125, 138))	('breast cancer', 'Disease', (125, 138))	('cancer', 'Disease', (117, 123))	('found', 'Reg', (49, 54))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', (195, 201))	('colorectal cancer', 'Phenotype', 'HP:0003003', (184, 201))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (154, 177))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('cancer', 'Disease', (132, 138))	('men', 'Species', '9606', (69, 72))	('prostate cancer', 'Disease', 'MESH:D011471', (108, 123))	('prostate cancer', 'Phenotype', 'HP:0012125', (108, 123))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('prostate cancer', 'Disease', (108, 123))	('head and neck squamous cell carcinomas', 'Phenotype', 'HP:0012288', (140, 178))
345714	29321960	The data for GSE14936 (USA), GSE16025 (USA), GSE15008 (China), GSE25508 (Finland), GSE19945 (Japan), GSE47525 (Netherlands), GSE48414 (Norway), GSE51853 (Japan), GSE63805 (USA), GSE72526 (Switzerland), GSE74190 (China) and GSE77380 (Japan) were from NSCLC tissues.	('GSE47525', 'Var', (101, 109))	('GSE15008', 'Var', (45, 53))	('NSCLC', 'Disease', 'MESH:D002289', (250, 255))	('GSE72526', 'Var', (178, 186))	('GSE48414', 'Var', (125, 133))	('GSE51853', 'Var', (144, 152))	('NSCLC', 'Phenotype', 'HP:0030358', (250, 255))	('GSE16025', 'Var', (29, 37))	('GSE63805', 'Var', (162, 170))	('GSE14936', 'Var', (13, 21))	('GSE77380', 'Var', (223, 231))	('GSE25508', 'Var', (63, 71))	('GSE19945', 'Var', (83, 91))	('NSCLC', 'Disease', (250, 255))	('GSE74190', 'Var', (202, 210))
345741	29321960	The methylation of the mir-193a gene has an indirect effect on the expression level of the target gene 25, 26, 27.	('mir-193a', 'Gene', (23, 31))	('expression level', 'MPA', (67, 83))	('effect', 'Reg', (53, 59))	('methylation', 'Var', (4, 15))	('mir-193a', 'Gene', '406968', (23, 31))
345743	29321960	Conversely, miR-193a gene methylation silencing could reduce miR-193a expression in some diseases, for example acute myeloid leukemia and NSCLC 27, 28.	('myeloid leukemia', 'Phenotype', 'HP:0012324', (117, 133))	('miR-193a', 'Gene', (12, 20))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (111, 133))	('NSCLC', 'Disease', (138, 143))	('miR-193a', 'Gene', '406968', (12, 20))	('methylation silencing', 'Var', (26, 47))	('reduce', 'NegReg', (54, 60))	('NSCLC', 'Disease', 'MESH:D002289', (138, 143))	('miR-193a', 'Gene', '406968', (61, 69))	('expression', 'MPA', (70, 80))	('miR-193a', 'Gene', (61, 69))	('leukemia', 'Phenotype', 'HP:0001909', (125, 133))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (111, 133))	('NSCLC', 'Phenotype', 'HP:0030358', (138, 143))	('acute myeloid leukemia', 'Disease', (111, 133))
345782	29321960	Overexpression of CHEK1 in lung cancers was related to poor overall survival 36.	('lung cancers', 'Disease', (27, 39))	('cancers', 'Phenotype', 'HP:0002664', (32, 39))	('CHEK1', 'Gene', '1111', (18, 23))	('overall', 'MPA', (60, 67))	('lung cancer', 'Phenotype', 'HP:0100526', (27, 38))	('CHEK1', 'Gene', (18, 23))	('lung cancers', 'Disease', 'MESH:D008175', (27, 39))	('lung cancers', 'Phenotype', 'HP:0100526', (27, 39))	('Overexpression', 'Var', (0, 14))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('poor', 'NegReg', (55, 59))
345899	31616594	In a large clinical staging series (using the 6th edition TNM staging system), survival rates for patients with clinical T1 disease were significantly higher than those with T2 disease (HR 1.48, P < 0.0001).	('TNM', 'Gene', '10178', (58, 61))	('T2 disease', 'Disease', (174, 184))	('patients', 'Species', '9606', (98, 106))	('TNM', 'Gene', (58, 61))	('higher', 'PosReg', (151, 157))	('T1 disease', 'Var', (121, 131))	('survival', 'MPA', (79, 87))	('T2 disease', 'Disease', 'MESH:C535434', (174, 184))
345940	31616594	In addition, selected 917 patients who underwent surgery for retrospective analysis, and found that the smaller the tumor, the higher the proportion of N0M0, indicating that the smaller the tumor size, the earlier the staging.	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('smaller', 'NegReg', (178, 185))	('earlier', 'Reg', (206, 213))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('patients', 'Species', '9606', (26, 34))	('tumor', 'Disease', (190, 195))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('N0M0', 'Var', (152, 156))	('tumor', 'Disease', (116, 121))	('staging', 'MPA', (218, 225))
345941	31616594	A study involving 868 NSCLC patients showed that the survival rate of patients with a tumor size <=3 cm was significantly higher than that of patients with a tumor size of 3-7 cm (including upper limit).	('patients', 'Species', '9606', (70, 78))	('tumor', 'Disease', (158, 163))	('survival', 'CPA', (53, 61))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('NSCLC', 'Phenotype', 'HP:0030358', (22, 27))	('tumor', 'Disease', (86, 91))	('higher', 'PosReg', (122, 128))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('NSCLC', 'Disease', (22, 27))	('patients', 'Species', '9606', (142, 150))	('patients', 'Species', '9606', (28, 36))	('NSCLC', 'Disease', 'MESH:D002289', (22, 27))	('<=3 cm', 'Var', (97, 103))
345957	31616594	Secondly, the abnormality of epigenetics would lead to intratumoral heterogeneity, which could also be the cause of the above results.	('lead to', 'Reg', (47, 54))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('abnormality', 'Var', (14, 25))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Disease', (60, 65))	('epigenetics', 'Var', (29, 40))
345987	31423239	In GEO, the optimal Affymetrix IDs were 212239_at (PIK3R1), 212486_s_at (FYN), 201110_s_at (THBS1), 215235_at (SPTAN1) and 48580_at (SPP1).	('FYN', 'Gene', (73, 76))	('SPP1', 'Gene', '6696', (133, 137))	('THBS1', 'Gene', '7057', (92, 97))	('FYN', 'Gene', '2534', (73, 76))	('SPP1', 'Gene', (133, 137))	('201110_s_at', 'Var', (79, 90))	('PIK3R1', 'Gene', '5295', (51, 57))	('212486_s_at', 'Var', (60, 71))	('215235_at', 'Var', (100, 109))	('SPTAN1', 'Gene', (111, 117))	('PIK3R1', 'Gene', (51, 57))	('SPTAN1', 'Gene', '6709', (111, 117))	('48580_at', 'Var', (123, 131))	('THBS1', 'Gene', (92, 97))	('212239_at', 'Var', (40, 49))
346027	31423239	Mutations in PIK3R1 are implicated in cases of breast cancer.	('PIK3R1', 'Gene', '5295', (13, 19))	('PIK3R1', 'Gene', (13, 19))	('breast cancer', 'Disease', (47, 60))	('breast cancer', 'Phenotype', 'HP:0003002', (47, 60))	('Mutations', 'Var', (0, 9))	('implicated', 'Reg', (24, 34))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('breast cancer', 'Disease', 'MESH:D001943', (47, 60))
346031	31423239	In the present study, FYN was expressed at a low level in high metastatic cancer cells, while the database analysis indicated that high FYN expression was associated with an improved OS time.	('FYN', 'Gene', (22, 25))	('expression', 'MPA', (140, 150))	('FYN', 'Gene', '2534', (22, 25))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('FYN', 'Gene', (136, 139))	('cancer', 'Disease', (74, 80))	('FYN', 'Gene', '2534', (136, 139))	('improved', 'PosReg', (174, 182))	('high', 'Var', (131, 135))
346040	31423239	Recent studies have reported that a dysregulation of SPTAN1 effects cellular behavior and promotes tumor progression.	('dysregulation', 'Var', (36, 49))	('tumor', 'Disease', (99, 104))	('cellular behavior', 'CPA', (68, 85))	('effects', 'Reg', (60, 67))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('SPTAN1', 'Gene', '6709', (53, 59))	('promotes', 'PosReg', (90, 98))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('SPTAN1', 'Gene', (53, 59))
346041	31423239	A study reported that SPTAN1 had recurrent mutations in 27 lung adenocarcinomas of individuals that had never smoked, and these mutations were highly associated with pathway dysregulation and patient survival.	('associated', 'Reg', (150, 160))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))	('patient', 'Species', '9606', (192, 199))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (59, 79))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (59, 79))	('mutations', 'Var', (128, 137))	('lung adenocarcinomas', 'Disease', (59, 79))	('pathway dysregulation', 'MPA', (166, 187))	('mutations', 'Var', (43, 52))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (59, 78))	('SPTAN1', 'Gene', (22, 28))	('SPTAN1', 'Gene', '6709', (22, 28))
346047	31423239	The expression of SPP1 is higher in epithelial ovarian cancer tissues compared with that in normal ovarian tissues, and silencing SPP1 decreased the cell proliferation, migration, and invasion; these effects may be dependent on the integrin beta1/FAK/AKT signaling pathway.	('expression', 'MPA', (4, 14))	('AKT', 'Gene', (251, 254))	('integrin beta1', 'Gene', (232, 246))	('FAK', 'Gene', (247, 250))	('decreased', 'NegReg', (135, 144))	('invasion', 'CPA', (184, 192))	('SPP1', 'Gene', (130, 134))	('epithelial ovarian cancer', 'Disease', (36, 61))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('FAK', 'Gene', '5747', (247, 250))	('SPP1', 'Gene', (18, 22))	('AKT', 'Gene', '207', (251, 254))	('cell proliferation', 'CPA', (149, 167))	('SPP1', 'Gene', '6696', (130, 134))	('epithelial ovarian cancer', 'Disease', 'MESH:D000077216', (36, 61))	('higher', 'PosReg', (26, 32))	('integrin beta1', 'Gene', '3688', (232, 246))	('SPP1', 'Gene', '6696', (18, 22))	('silencing', 'Var', (120, 129))	('ovarian cancer', 'Phenotype', 'HP:0100615', (47, 61))
346049	31423239	A recent study revealed that OPN-a, a splicing variant, increased A549 cell adherent abilities to bone tissues by interacting with the cell surface receptor alphavbeta3 integrin.	('interacting', 'Interaction', (114, 125))	('increased', 'PosReg', (56, 65))	('A549', 'CellLine', 'CVCL:0023', (66, 70))	('variant', 'Var', (47, 54))	('OPN', 'Gene', '6696', (29, 32))	('A549 cell adherent abilities to bone tissues', 'CPA', (66, 110))	('OPN', 'Gene', (29, 32))
346174	27358048	Genomic alterations underlie a pan-cancer metabolic shift associated with tumour hypoxia Altered metabolism is a hallmark of cancer.	('hallmark of cancer', 'Disease', 'MESH:D009369', (113, 131))	('tumour hypoxia', 'Disease', 'MESH:D000860', (74, 88))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('metabolism', 'MPA', (97, 107))	('alterations', 'Var', (8, 19))	('tumour hypoxia', 'Disease', (74, 88))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('tumour', 'Phenotype', 'HP:0002664', (74, 80))	('hallmark of cancer', 'Disease', (113, 131))	('cancer', 'Disease', (125, 131))	('Genomic', 'Var', (0, 7))	('underlie', 'Reg', (20, 28))	('cancer', 'Disease', (35, 41))
346177	27358048	A systematic pan-cancer analysis of 6538 tumour/normal samples covering ten major cancer types identified a core metabolic signature of 44 genes that exhibit high frequency somatic copy number gains/amplifications (>20 % cases) associated with increased mRNA expression (rho > 0.3, q < 10-3).	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('gains/amplifications', 'PosReg', (193, 213))	('tumour', 'Phenotype', 'HP:0002664', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('tumour', 'Disease', 'MESH:D009369', (41, 47))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('copy number', 'Var', (181, 192))	('cancer', 'Disease', (17, 23))	('mRNA expression', 'MPA', (254, 269))	('tumour', 'Disease', (41, 47))	('increased', 'PosReg', (244, 253))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
346192	27358048	Here, we hypothesise that metabolic requirements in the hypoxic tumour microenvironment are driving selection of genomic alterations leading to genetic heterogeneity as well as transcriptional deregulation.	('alterations', 'Var', (121, 132))	('hypoxic tumour', 'Disease', 'MESH:D009369', (56, 70))	('hypoxic tumour', 'Disease', (56, 70))	('leading to', 'Reg', (133, 143))	('genetic heterogeneity', 'MPA', (144, 165))	('tumour', 'Phenotype', 'HP:0002664', (64, 70))
346196	27358048	Specifically, we asked whether (1) somatically acquired mutations are independent drivers of metabolic shift, (2) over-expression of metabolic genes is induced by somatically acquired copy-number alterations, (3) metabolic genes are associated with previously reported cancer drivers and (4) metabolic genes are associated with tumour hypoxia and (5) are prognostic.	('associated', 'Reg', (312, 322))	('mutations', 'Var', (56, 65))	('tumour hypoxia', 'Disease', 'MESH:D000860', (328, 342))	('tumour', 'Phenotype', 'HP:0002664', (328, 334))	('tumour hypoxia', 'Disease', (328, 342))	('cancer', 'Phenotype', 'HP:0002664', (269, 275))	('metabolic shift', 'MPA', (93, 108))	('metabolic genes', 'Gene', (213, 228))	('metabolic genes', 'Gene', (133, 148))	('associated', 'Interaction', (233, 243))	('metabolic genes', 'Gene', (292, 307))	('cancer', 'Disease', (269, 275))	('cancer', 'Disease', 'MESH:D009369', (269, 275))
346200	27358048	We found no difference in the mean frequency of somatic copy number alterations (SCNAs) across all cancers between the 2752 metabolic genes and other genes (P = 0.85, two-sided proportion test) and a slight but not significant decrease in the mean frequency of somatic mutations (P = 0.06, two-sided proportion test).	('cancers', 'Disease', 'MESH:D009369', (99, 106))	('copy number alterations', 'Var', (56, 79))	('cancers', 'Phenotype', 'HP:0002664', (99, 106))	('cancers', 'Disease', (99, 106))	('decrease', 'NegReg', (227, 235))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
346204	27358048	Specifically, tumour hypoxia was correlated with the extent of SCNAs in metabolic genes in up to seven of the ten cancer types (P < 0.05, one-sided Wilcoxon test; Additional file 1: Figure S1b, c) and with the extent of somatic mutations in three of the ten cancer types (Additional file 1: Figure S1d).	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('thr', 'Chemical', 'MESH:D013912', (241, 244))	('cancer', 'Phenotype', 'HP:0002664', (258, 264))	('SCNAs', 'Var', (63, 68))	('cancer', 'Disease', 'MESH:D009369', (258, 264))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('tumour', 'Phenotype', 'HP:0002664', (14, 20))	('metabolic genes', 'Gene', (72, 87))	('cancer', 'Disease', (258, 264))	('tumour hypoxia', 'Disease', 'MESH:D000860', (14, 28))	('tumour hypoxia', 'Disease', (14, 28))	('cancer', 'Disease', (114, 120))
346208	27358048	Given the variety of cancer types and experimental systems considered, the above results taken together suggest that genomic alterations in metabolic pathways, and particularly in SCNAs, act as a conserved selective pressure in hypoxic tumours.	('cancer', 'Disease', 'MESH:D009369', (21, 27))	('tumours', 'Phenotype', 'HP:0002664', (236, 243))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('hypoxic tumours', 'Disease', 'MESH:D009369', (228, 243))	('SCNAs', 'Disease', (180, 185))	('hypoxic tumours', 'Disease', (228, 243))	('alterations', 'Var', (125, 136))	('cancer', 'Disease', (21, 27))	('metabolic pathways', 'Pathway', (140, 158))	('tumour', 'Phenotype', 'HP:0002664', (236, 242))
346216	27358048	The list also contained TYMS, a well-known chemotherapeutic target, and another five genes (GAPDH, PYCR1, TPI1, TSTA3 and TTYH3) for which inhibition of expression has been previously shown to reduce cell viability in in vitro and in vivo functional genomics screens.	('reduce', 'NegReg', (193, 199))	('TSTA3', 'Gene', '7264', (112, 117))	('TTYH3', 'Gene', (122, 127))	('TYMS', 'Gene', (24, 28))	('PYCR1', 'Gene', (99, 104))	('TTYH3', 'Gene', '80727', (122, 127))	('inhibition of', 'Var', (139, 152))	('TPI1', 'Gene', (106, 110))	('PYCR1', 'Gene', '5831', (99, 104))	('cell viability', 'CPA', (200, 214))	('TYMS', 'Gene', '7298', (24, 28))	('TSTA3', 'Gene', (112, 117))	('TPI1', 'Gene', '7167', (106, 110))	('GAPDH', 'Gene', '2597', (92, 97))	('expression', 'MPA', (153, 163))	('GAPDH', 'Gene', (92, 97))
346221	27358048	The association between hypoxia and these 44 genes was also reflected in a significantly elevated fraction of copy number gains for these genes in patients with higher hypoxia in four of the ten cancer types (Additional file 1: Figure S5b; P < 0.05, one-sided Wilcoxon test).	('cancer', 'Disease', (195, 201))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('hypoxia', 'Disease', (168, 175))	('hypoxia', 'Disease', 'MESH:D000860', (168, 175))	('patients', 'Species', '9606', (147, 155))	('hypoxia', 'Disease', 'MESH:D000860', (24, 31))	('elevated', 'PosReg', (89, 97))	('S5b', 'Gene', '5711', (235, 238))	('gains', 'PosReg', (122, 127))	('hypoxia', 'Disease', (24, 31))	('copy number', 'Var', (110, 121))	('S5b', 'Gene', (235, 238))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
346224	27358048	These results support the hypothesis that a core group of metabolic genes are preferentially selected through genomic gains/amplifications, with rare exceptions such as IDH1/2 .	('gains/amplifications', 'PosReg', (118, 138))	('IDH1/2', 'Gene', (169, 175))	('thr', 'Chemical', 'MESH:D013912', (102, 105))	('IDH1/2', 'Gene', '3417;3418', (169, 175))	('genomic', 'Var', (110, 117))
346235	27358048	Next, correlation analysis was performed between mRNA profiles of the core metabolic signature and mRNA profiles of (1) cancer-type specific candidate drivers mutated in at least 5 % of the cohort and (2) a merged global high-confidence cancer gene consensus list (Additional file 1 and Additional file 2: Table S11).	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('mutated', 'Var', (159, 166))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (237, 243))	('core metabolic signature', 'MPA', (70, 94))	('cancer', 'Disease', (237, 243))
346265	27358048	Since we observed a modest increase in SQLE mRNA abundance in the TP53 mutant group in breast cancer (Additional file 1 and Additional file 2: Table S12), we further interrogated this association with TP53 mutation status in the TCGA breast cancer cohort (where all data modalities were available) and found that SQLE's prognostic ability was decreased when adjusting for TP53 mutation status (P = 0.03 to 0.18) (Additional file 1: Figure S8).	('SQLE', 'Gene', '6713', (39, 43))	('TP53', 'Gene', '7157', (66, 70))	('SQLE', 'Gene', (39, 43))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('breast cancer', 'Disease', 'MESH:D001943', (87, 100))	('breast cancer', 'Disease', (87, 100))	('TP53', 'Gene', '7157', (372, 376))	('breast cancer', 'Phenotype', 'HP:0003002', (234, 247))	('SQLE', 'Gene', '6713', (313, 317))	('mutant', 'Var', (71, 77))	('TP53', 'Gene', (201, 205))	('SQLE', 'Gene', (313, 317))	('increase', 'PosReg', (27, 35))	('breast cancer', 'Disease', 'MESH:D001943', (234, 247))	('TP53', 'Gene', (66, 70))	('breast cancer', 'Disease', (234, 247))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('TP53', 'Gene', '7157', (201, 205))	('TP53', 'Gene', (372, 376))	('breast cancer', 'Phenotype', 'HP:0003002', (87, 100))
346277	27358048	We further verified SQLE copy number gains and mRNA correlation in both breast and colorectal cancer cell lines (Fig.	('colorectal cancer', 'Phenotype', 'HP:0003003', (83, 100))	('copy number gains', 'Var', (25, 42))	('breast and colorectal cancer', 'Disease', 'MESH:D015179', (72, 100))	('SQLE', 'Gene', '6713', (20, 24))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('SQLE', 'Gene', (20, 24))	('mRNA correlation', 'MPA', (47, 63))
346287	27358048	This suggests other mechanisms such as epigenetic regulation, as shown previously, may also play a role in increasing SQLE expression in tumours.	('SQLE', 'Gene', (118, 122))	('epigenetic regulation', 'Var', (39, 60))	('tumours', 'Phenotype', 'HP:0002664', (137, 144))	('tumours', 'Disease', 'MESH:D009369', (137, 144))	('increasing', 'PosReg', (107, 117))	('tumours', 'Disease', (137, 144))	('SQLE', 'Gene', '6713', (118, 122))	('tumour', 'Phenotype', 'HP:0002664', (137, 143))
346295	27358048	Equivalent knockdown analyses on TSTA3 and PYCRL, two of the other four top candidate metabolism genes, followed by cell viability and clonogenic assays indicated a smaller yet significant effect for PYCRL knockdown; in particular, PYCRL knockdown reduced the number of colonies in HCC1806 and DLD-1 cells only under hypoxia (P < 0.05; Additional file 1: Figure S11e-p).	('TSTA3', 'Gene', '7264', (33, 38))	('knockdown', 'Var', (238, 247))	('TSTA3', 'Gene', (33, 38))	('reduced', 'NegReg', (248, 255))	('PYCRL', 'Gene', (200, 205))	('hypoxia', 'Disease', 'MESH:D000860', (317, 324))	('PYCRL', 'Gene', (232, 237))	('PYCRL', 'Gene', (43, 48))	('PYCRL', 'Gene', '65263', (200, 205))	('PYCRL', 'Gene', '65263', (232, 237))	('hypoxia', 'Disease', (317, 324))	('HCC1806', 'CellLine', 'CVCL:1258', (282, 289))	('PYCRL', 'Gene', '65263', (43, 48))
346305	27358048	Our results suggest that these genomic alterations form a core part of the metabolic reprogramming that is conserved across different cancer types.	('metabolic reprogramming', 'CPA', (75, 98))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('alterations', 'Var', (39, 50))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
346311	27358048	Importantly, we show that both copy number amplification and expression of the identified metabolic driver genes are significantly associated with tumour hypoxia, suggesting a mechanism of metabolic reprogramming via adaptation within a hypoxic tumour microenvironment.	('hypoxic tumour', 'Disease', 'MESH:D009369', (237, 251))	('copy number amplification', 'Var', (31, 56))	('tumour', 'Phenotype', 'HP:0002664', (147, 153))	('hypoxic tumour', 'Disease', (237, 251))	('associated', 'Reg', (131, 141))	('tumour hypoxia', 'Disease', 'MESH:D000860', (147, 161))	('tumour hypoxia', 'Disease', (147, 161))	('tumour', 'Phenotype', 'HP:0002664', (245, 251))	('metabolic reprogramming', 'CPA', (189, 212))	('expression', 'MPA', (61, 71))
346314	27358048	Importantly, high SQLE expression in hypoxic tumours was significantly associated with poor survival.	('high', 'Var', (13, 17))	('tumour', 'Phenotype', 'HP:0002664', (45, 51))	('hypoxic tumours', 'Disease', 'MESH:D009369', (37, 52))	('hypoxic tumours', 'Disease', (37, 52))	('tumours', 'Phenotype', 'HP:0002664', (45, 52))	('SQLE', 'Gene', '6713', (18, 22))	('SQLE', 'Gene', (18, 22))	('poor', 'NegReg', (87, 91))	('associated', 'Reg', (71, 81))	('expression', 'MPA', (23, 33))
346318	27358048	A recent study has also demonstrated that over-expression of SQLE promotes cell proliferation and migration and acts as a positive regulator of ERK signalling in hepatocellular carcinoma cells.	('SQLE', 'Gene', '6713', (61, 65))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (162, 186))	('SQLE', 'Gene', (61, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (177, 186))	('hepatocellular carcinoma', 'Disease', (162, 186))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (162, 186))	('promotes', 'PosReg', (66, 74))	('over-expression', 'Var', (42, 57))	('cell proliferation', 'CPA', (75, 93))
346319	27358048	A second study, published while this manuscript was in revision, independently confirmed SQLE as bona fide oncogene by amplification, further supporting our findings.	('SQLE', 'Gene', (89, 93))	('amplification', 'Var', (119, 132))	('SQLE', 'Gene', '6713', (89, 93))
346385	27358048	These were 2q11.1 (TEKT4) and 14q11.2 (POTEG).	('TEKT4', 'Gene', '150483', (19, 24))	('POTEG', 'Gene', '404785', (39, 44))	('14q11.2', 'Var', (30, 37))	('POTEG', 'Gene', (39, 44))	('TEKT4', 'Gene', (19, 24))
346397	33335425	Silencing LINC01426 inhibited proliferation, migration, and invasion of NSCLC cells and facilitated cell apoptosis in vitro.	('si', 'Chemical', 'MESH:D012825', (111, 113))	('migration', 'CPA', (45, 54))	('NSCLC', 'Disease', (72, 77))	('facilitated', 'PosReg', (88, 99))	('NSCLC', 'Disease', 'MESH:D002289', (72, 77))	('LINC01426', 'Gene', '100506385', (10, 19))	('LINC01426', 'Gene', (10, 19))	('inhibited', 'NegReg', (20, 29))	('si', 'Chemical', 'MESH:D012825', (64, 66))	('cell apoptosis', 'CPA', (100, 114))	('Silencing', 'Var', (0, 9))	('NSCLC', 'Phenotype', 'HP:0030358', (72, 77))	('proliferation', 'CPA', (30, 43))
346400	33335425	Furthermore, the ETS proto-oncogene 1 (ETS1) was identified as a direct target of miR-519d-5p and LINC01426 could indirectly upregulate ETS1 expression by sponging miR-519d-5p.	('LINC01426', 'Gene', (98, 107))	('ETS1', 'Gene', (136, 140))	('ETS1', 'Gene', '2113', (136, 140))	('ETS proto-oncogene 1', 'Gene', '2113', (17, 37))	('LINC01426', 'Gene', '100506385', (98, 107))	('ETS proto-oncogene 1', 'Gene', (17, 37))	('miR-519d-5p', 'Chemical', '-', (164, 175))	('miR-519d-5p', 'Chemical', '-', (82, 93))	('expression', 'MPA', (141, 151))	('miR-519d-5p', 'Var', (164, 175))	('si', 'Chemical', 'MESH:D012825', (147, 149))	('miR-519d-5p', 'Var', (82, 93))	('upregulate', 'PosReg', (125, 135))	('ETS1', 'Gene', '2113', (39, 43))	('ETS1', 'Gene', (39, 43))
346401	33335425	Moreover, the cancer-inhibiting activities of LINC01426 knockdown in NSCLC cells were partially offset by miR-519d-5p inhibition.	('cancer', 'Disease', (14, 20))	('NSCLC', 'Disease', (69, 74))	('LINC01426', 'Gene', '100506385', (46, 55))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('LINC01426', 'Gene', (46, 55))	('NSCLC', 'Disease', 'MESH:D002289', (69, 74))	('miR-519d-5p', 'Chemical', '-', (106, 117))	('cancer', 'Disease', 'MESH:D009369', (14, 20))	('NSCLC', 'Phenotype', 'HP:0030358', (69, 74))	('knockdown', 'Var', (56, 65))
346443	33335425	Quantitative PCR was then performed to detect miR-519d-5p expression using a Mir-X miRNA qRT-PCR TB Green  Kit (Takara).	('si', 'Chemical', 'MESH:D012825', (70, 72))	('Kit', 'Gene', (107, 110))	('miR-519d-5p', 'Chemical', '-', (46, 57))	('miR-519d-5p expression', 'Var', (46, 68))	('Kit', 'Gene', '3815', (107, 110))	('si', 'Chemical', 'MESH:D012825', (64, 66))
346470	33335425	The putative targets of miR-519d-5p were predicted using the miRDB (http://mirdb.org/) and TargetScan (http://www.targetscan.org/) programs.	('miRDB', 'Gene', (61, 66))	('miR-519d-5p', 'Var', (24, 35))	('miR-519d-5p', 'Chemical', '-', (24, 35))	('si', 'Chemical', 'MESH:D012825', (52, 54))
346485	33335425	The correlations among LINC01426, miR-519d-5p, and ETS1 expression in the NSCLC tissues were evaluated using Pearson's correlation analysis.	('LINC01426', 'Gene', (23, 32))	('NSCLC', 'Phenotype', 'HP:0030358', (74, 79))	('si', 'Chemical', 'MESH:D012825', (136, 138))	('ETS1', 'Gene', '2113', (51, 55))	('ETS1', 'Gene', (51, 55))	('si', 'Chemical', 'MESH:D012825', (104, 106))	('miR-519d-5p', 'Chemical', '-', (34, 45))	('NSCLC', 'Disease', (74, 79))	('miR-519d-5p', 'Var', (34, 45))	('NSCLC', 'Disease', 'MESH:D002289', (74, 79))	('si', 'Chemical', 'MESH:D012825', (62, 64))	('LINC01426', 'Gene', '100506385', (23, 32))
346500	33335425	Using CCK-8 assay, our results revealed that LINC01426 depletion inhibited the proliferation of H460 and A549 cells (Figure 2B).	('A549', 'Chemical', '-', (105, 109))	('proliferation', 'CPA', (79, 92))	('si', 'Chemical', 'MESH:D012825', (1, 3))	('LINC01426', 'Gene', '100506385', (45, 54))	('inhibited', 'NegReg', (65, 74))	('LINC01426', 'Gene', (45, 54))	('depletion', 'Var', (55, 64))	('CCK-8', 'Chemical', '-', (6, 11))
346501	33335425	Additionally, LINC01426 silencing increased apoptosis in H460 and A549 cells (Figure 2C).	('apoptosis', 'CPA', (44, 53))	('LINC01426', 'Gene', '100506385', (14, 23))	('si', 'Chemical', 'MESH:D012825', (50, 52))	('LINC01426', 'Gene', (14, 23))	('A549', 'Chemical', '-', (66, 70))	('increased', 'PosReg', (34, 43))	('si', 'Chemical', 'MESH:D012825', (24, 26))	('silencing', 'Var', (24, 33))
346502	33335425	Furthermore, si-LINC01426 transfection resulted in reduced migration (Figure 2D) and invasion (Figure 2E) of H460 and A549 cells.	('LINC01426', 'Gene', '100506385', (16, 25))	('transfection', 'Var', (26, 38))	('LINC01426', 'Gene', (16, 25))	('reduced', 'NegReg', (51, 58))	('invasion', 'CPA', (85, 93))	('si', 'Chemical', 'MESH:D012825', (89, 91))	('si', 'Chemical', 'MESH:D012825', (13, 15))	('migration', 'CPA', (59, 68))	('A549', 'Chemical', '-', (118, 122))
346508	33335425	Among these candidates, miR-519d-5p, miR-873-3p, miR-377-5p, and miR-548c-3p were selected for experimental verification because they played critical functions in various human cancers.	('miR-519d-5p', 'Var', (24, 35))	('miR-873-3p', 'Var', (37, 47))	('played', 'Reg', (134, 140))	('cancers', 'Disease', 'MESH:D009369', (177, 184))	('5p', 'Chemical', '-', (33, 35))	('cancers', 'Phenotype', 'HP:0002664', (177, 184))	('5p', 'Chemical', '-', (57, 59))	('cancers', 'Disease', (177, 184))	('miR-377', 'Gene', '494326', (49, 56))	('miR-548c-3p', 'Var', (65, 76))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('miR-519d-5p', 'Chemical', '-', (24, 35))	('human', 'Species', '9606', (171, 176))	('miR-377', 'Gene', (49, 56))
346510	33335425	It was found that miR-519d-5p expression was significantly increased in LINC01426 deficient-H460 and -A549 cells (Figure 3D).	('miR-519d-5p', 'Chemical', '-', (18, 29))	('miR-519d-5p', 'Var', (18, 29))	('A549', 'Chemical', '-', (102, 106))	('si', 'Chemical', 'MESH:D012825', (36, 38))	('LINC01426', 'Gene', '100506385', (72, 81))	('LINC01426', 'Gene', (72, 81))	('increased', 'PosReg', (59, 68))	('si', 'Chemical', 'MESH:D012825', (45, 47))
346511	33335425	By contrast, the expression of other three miRNAs remained unchanged following si-LINC01426 transfection.	('LINC01426', 'Gene', '100506385', (82, 91))	('si', 'Chemical', 'MESH:D012825', (79, 81))	('transfection', 'Var', (92, 104))	('LINC01426', 'Gene', (82, 91))	('expression', 'MPA', (17, 27))	('si', 'Chemical', 'MESH:D012825', (23, 25))
346512	33335425	In addition, miR-519d-5p expression was reduced in NSCLC tissues compared with that in the adjacent normal tissues (Figure 3E).	('NSCLC', 'Disease', (51, 56))	('miR-519d-5p', 'Chemical', '-', (13, 24))	('NSCLC', 'Disease', 'MESH:D002289', (51, 56))	('reduced', 'NegReg', (40, 47))	('miR-519d-5p', 'Var', (13, 24))	('si', 'Chemical', 'MESH:D012825', (31, 33))	('NSCLC', 'Phenotype', 'HP:0030358', (51, 56))
346514	33335425	Figure 3G depicts the binding sequence of miR-519d-5p within the sequence of LINC01426.	('LINC01426', 'Gene', '100506385', (77, 86))	('miR-519d-5p', 'Var', (42, 53))	('LINC01426', 'Gene', (77, 86))	('miR-519d-5p', 'Chemical', '-', (42, 53))
346515	33335425	To further validate this prediction, the luciferase reporter assay was conducted to address the binding interaction between LINC01426 and miR-519d-5p in NSCLC cells.	('miR-519d-5p', 'Chemical', '-', (138, 149))	('NSCLC', 'Phenotype', 'HP:0030358', (153, 158))	('miR-519d-5p', 'Var', (138, 149))	('binding', 'Interaction', (96, 103))	('NSCLC', 'Disease', (153, 158))	('LINC01426', 'Gene', '100506385', (124, 133))	('NSCLC', 'Disease', 'MESH:D002289', (153, 158))	('LINC01426', 'Gene', (124, 133))
346517	33335425	In miR-519d-5p mimic-transfected H460 and A549 cells, miR-519d-5p showed marked overexpression (Figure 3H).	('overexpression', 'PosReg', (80, 94))	('si', 'Chemical', 'MESH:D012825', (90, 92))	('miR-519d-5p', 'Chemical', '-', (54, 65))	('A549', 'Chemical', '-', (42, 46))	('miR-519d-5p', 'Chemical', '-', (3, 14))	('miR-519d-5p', 'Var', (54, 65))
346518	33335425	The luciferase activity of LINC01426-wt was lower in response to miR-519d-5p upregulation, whereas the activity of LINC01426-mut showed no significant change following miR-519d-5p mimic cotransfection (Figure 3I).	('lower', 'NegReg', (44, 49))	('si', 'Chemical', 'MESH:D012825', (139, 141))	('activity', 'MPA', (15, 23))	('LINC01426', 'Gene', '100506385', (27, 36))	('LINC01426', 'Gene', (27, 36))	('miR-519d-5p', 'Chemical', '-', (168, 179))	('LINC01426', 'Gene', '100506385', (115, 124))	('upregulation', 'PosReg', (77, 89))	('LINC01426', 'Gene', (115, 124))	('miR-519d-5p', 'Chemical', '-', (65, 76))	('luciferase', 'Enzyme', (4, 14))	('miR-519d-5p', 'Var', (65, 76))
346519	33335425	RIP assay further confirmed this result considering that LINC01426 and miR-519d-5p were immunoprecipitated by anti-Ago2 antibody (Figure 3J), indicating the coexistence of LINC01426 and miR-519d-5p in the same RNA-induced silencing complex.	('LINC01426', 'Gene', '100506385', (57, 66))	('miR-519d-5p', 'Chemical', '-', (186, 197))	('LINC01426', 'Gene', (57, 66))	('miR-519d-5p', 'Chemical', '-', (71, 82))	('miR-519d-5p', 'Var', (186, 197))	('si', 'Chemical', 'MESH:D012825', (43, 45))	('Ago2', 'Gene', '27161', (115, 119))	('si', 'Chemical', 'MESH:D012825', (222, 224))	('LINC01426', 'Gene', '100506385', (172, 181))	('LINC01426', 'Gene', (172, 181))	('Ago2', 'Gene', (115, 119))
346522	33335425	Results of the luciferase reporter assay revealed that miR-519d-5p overexpression significantly inhibited the luciferase activity of ETS1-wt in H460 and A549 cells, whereas the inhibitory effect was abrogated when the binding sequences were mutated (Figure 4B).	('miR-519d-5p', 'Var', (55, 66))	('ETS1', 'Gene', (133, 137))	('luciferase', 'Enzyme', (110, 120))	('ETS1', 'Gene', '2113', (133, 137))	('activity', 'MPA', (121, 129))	('overexpression', 'PosReg', (67, 81))	('si', 'Chemical', 'MESH:D012825', (77, 79))	('si', 'Chemical', 'MESH:D012825', (82, 84))	('inhibited', 'NegReg', (96, 105))	('A549', 'Chemical', '-', (153, 157))	('miR-519d-5p', 'Chemical', '-', (55, 66))
346523	33335425	Moreover, miR-519d-5p upregulation negatively affected ETS1 mRNA (Figure 4C) and protein (Figure 4D) expression in H460 and A549 cells.	('miR-519d-5p', 'Var', (10, 21))	('negatively', 'NegReg', (35, 45))	('ETS1', 'Gene', '2113', (55, 59))	('ETS1', 'Gene', (55, 59))	('A549', 'Chemical', '-', (124, 128))	('upregulation', 'PosReg', (22, 34))	('miR-519d-5p', 'Chemical', '-', (10, 21))	('si', 'Chemical', 'MESH:D012825', (107, 109))
346525	33335425	Importantly, an inverse correlation was observed between the levels of miR-519d-5p and ETS1 in the 58 NSCLC tissues (Figure 4F; r = -0.6239, P < 0.0001).	('NSCLC', 'Disease', 'MESH:D002289', (102, 107))	('miR-519d-5p', 'Chemical', '-', (71, 82))	('ETS1', 'Gene', '2113', (87, 91))	('ETS1', 'Gene', (87, 91))	('miR-519d-5p', 'Var', (71, 82))	('NSCLC', 'Phenotype', 'HP:0030358', (102, 107))	('NSCLC', 'Disease', (102, 107))
346526	33335425	In summary, miR-519d-5p directly targets ETS1 and inhibits NSCLC progression.	('NSCLC', 'Disease', 'MESH:D002289', (59, 64))	('miR-519d-5p', 'Var', (12, 23))	('ETS1', 'Gene', '2113', (41, 45))	('ETS1', 'Gene', (41, 45))	('NSCLC', 'Phenotype', 'HP:0030358', (59, 64))	('si', 'Chemical', 'MESH:D012825', (72, 74))	('inhibits', 'NegReg', (50, 58))	('NSCLC', 'Disease', (59, 64))	('miR-519d-5p', 'Chemical', '-', (12, 23))
346527	33335425	LINC01426 was verified as an miR-519d-5p sponge and miR-519d-5p directly targeted ETS1 in NSCLC cells.	('ETS1', 'Gene', '2113', (82, 86))	('ETS1', 'Gene', (82, 86))	('miR-519d-5p', 'Var', (52, 63))	('LINC01426', 'Gene', '100506385', (0, 9))	('miR-519d-5p', 'Chemical', '-', (29, 40))	('LINC01426', 'Gene', (0, 9))	('NSCLC', 'Disease', (90, 95))	('targeted', 'Reg', (73, 81))	('NSCLC', 'Disease', 'MESH:D002289', (90, 95))	('miR-519d-5p', 'Chemical', '-', (52, 63))	('NSCLC', 'Phenotype', 'HP:0030358', (90, 95))
346530	33335425	The results revealed that ETS1 expression was significantly inhibited in H460 and A549 cells when LINC01426 was silenced (Figure 5A and B).	('ETS1', 'Gene', (26, 30))	('silenced', 'Var', (112, 120))	('LINC01426', 'Gene', (98, 107))	('A549', 'Chemical', '-', (82, 86))	('si', 'Chemical', 'MESH:D012825', (37, 39))	('si', 'Chemical', 'MESH:D012825', (46, 48))	('si', 'Chemical', 'MESH:D012825', (112, 114))	('inhibited', 'NegReg', (60, 69))	('expression', 'MPA', (31, 41))	('LINC01426', 'Gene', '100506385', (98, 107))	('ETS1', 'Gene', '2113', (26, 30))
346533	33335425	Subsequently, rescue experiments were performed by knocking down miR-519d-5p expression in LNC01426-depleted H460 and A549 cells.	('knocking', 'Var', (51, 59))	('miR-519d-5p', 'Gene', (65, 76))	('LNC01426', 'Chemical', '-', (91, 99))	('miR-519d-5p', 'Chemical', '-', (65, 76))	('si', 'Chemical', 'MESH:D012825', (83, 85))	('A549', 'Chemical', '-', (118, 122))
346535	33335425	Furthermore, although the migratory (Figure 5I) and invasive (Figure 5J) capacities of H460 and A549 cells were decreased by LINC01426 downregulation, they were restored following miR-519d-5p inhibition.	('miR-519d-5p', 'Chemical', '-', (180, 191))	('invasive', 'CPA', (52, 60))	('miR-519d-5p', 'Var', (180, 191))	('si', 'Chemical', 'MESH:D012825', (56, 58))	('migratory', 'CPA', (26, 35))	('A549', 'Chemical', '-', (96, 100))	('LINC01426', 'Gene', '100506385', (125, 134))	('decreased', 'NegReg', (112, 121))	('LINC01426', 'Gene', (125, 134))	('downregulation', 'NegReg', (135, 149))
346543	33335425	A significant body of evidence has indicated that lncRNAs are aberrantly expressed in NSCLC, which results in cancer progression, unlimited growth, and metastasis.	('si', 'Chemical', 'MESH:D012825', (159, 161))	('cancer', 'Disease', (110, 116))	('si', 'Chemical', 'MESH:D012825', (2, 4))	('NSCLC', 'Disease', (86, 91))	('metastasis', 'CPA', (152, 162))	('lncRNAs', 'Gene', (50, 57))	('NSCLC', 'Disease', 'MESH:D002289', (86, 91))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('unlimited growth', 'CPA', (130, 146))	('results in', 'Reg', (99, 109))	('NSCLC', 'Phenotype', 'HP:0030358', (86, 91))	('aberrantly', 'Var', (62, 72))	('si', 'Chemical', 'MESH:D012825', (124, 126))	('cancer', 'Disease', 'MESH:D009369', (110, 116))
346554	33335425	Functional experiments showed that LINC01426 knockdown markedly inhibited the proliferation, migration, and invasion of NSCLC cells and facilitated cell apoptosis in vitro.	('si', 'Chemical', 'MESH:D012825', (159, 161))	('NSCLC', 'Disease', 'MESH:D002289', (120, 125))	('migration', 'CPA', (93, 102))	('inhibited', 'NegReg', (64, 73))	('facilitated', 'PosReg', (136, 147))	('si', 'Chemical', 'MESH:D012825', (112, 114))	('NSCLC', 'Phenotype', 'HP:0030358', (120, 125))	('LINC01426', 'Gene', '100506385', (35, 44))	('LINC01426', 'Gene', (35, 44))	('NSCLC', 'Disease', (120, 125))	('knockdown', 'Var', (45, 54))	('cell apoptosis', 'CPA', (148, 162))
346561	33335425	Bioinformatics analysis was performed and the findings validated the relationship between miR-519d-5p and LINC01426 by revealing that miR-519d-5p was significantly overexpressed in response to LINC01426 depletion.	('LINC01426', 'Gene', (193, 202))	('overexpressed', 'PosReg', (164, 177))	('LINC01426', 'Gene', '100506385', (106, 115))	('LINC01426', 'Gene', (106, 115))	('miR-519d-5p', 'Chemical', '-', (134, 145))	('si', 'Chemical', 'MESH:D012825', (150, 152))	('miR-519d-5p', 'Var', (134, 145))	('si', 'Chemical', 'MESH:D012825', (20, 22))	('miR-519d-5p', 'Chemical', '-', (90, 101))	('LINC01426', 'Gene', '100506385', (193, 202))
346563	33335425	In addition, the luciferase reporter and RIP assays revealed that LINC01426 showed the ability to directly bind to miR-519d-5p and act as a molecular sponge for miR-519d-5p in NSCLC cells.	('bind', 'Interaction', (107, 111))	('miR-519d-5p', 'Chemical', '-', (115, 126))	('NSCLC', 'Disease', (176, 181))	('miR-519d-5p', 'Var', (115, 126))	('LINC01426', 'Gene', '100506385', (66, 75))	('NSCLC', 'Disease', 'MESH:D002289', (176, 181))	('LINC01426', 'Gene', (66, 75))	('ability', 'MPA', (87, 94))	('miR-519d-5p', 'Chemical', '-', (161, 172))	('NSCLC', 'Phenotype', 'HP:0030358', (176, 181))
346564	33335425	Further, mechanistic experiments revealed that ETS1 is a direct target gene of miR-519d-5p in NSCLC cells.	('NSCLC', 'Phenotype', 'HP:0030358', (94, 99))	('ETS1', 'Gene', '2113', (47, 51))	('ETS1', 'Gene', (47, 51))	('NSCLC', 'Disease', (94, 99))	('NSCLC', 'Disease', 'MESH:D002289', (94, 99))	('miR-519d-5p', 'Chemical', '-', (79, 90))	('miR-519d-5p', 'Var', (79, 90))
346569	33335425	ETS1, a member of the ETS family of transcription factors, was shown to be the downstream target of miR-519d-5p.	('miR-519d-5p', 'Var', (100, 111))	('ETS1', 'Gene', '2113', (0, 4))	('ETS1', 'Gene', (0, 4))	('miR-519d-5p', 'Chemical', '-', (100, 111))
346572	33335425	MiR-519d-5p functions as a molecular bridge between LINC01426 and ETS1, and the regulatory effect of LINC01426 on ETS1 expression is eliminated by miR-519d-5p.	('expression', 'MPA', (119, 129))	('MiR-519d', 'Gene', (0, 8))	('MiR-519d', 'Gene', '574480', (0, 8))	('5p', 'Chemical', '-', (156, 158))	('5p', 'Chemical', '-', (9, 11))	('LINC01426', 'Gene', '100506385', (52, 61))	('ETS1', 'Gene', (66, 70))	('ETS1', 'Gene', '2113', (66, 70))	('LINC01426', 'Gene', (52, 61))	('LINC01426', 'Gene', '100506385', (101, 110))	('LINC01426', 'Gene', (101, 110))	('ETS1', 'Gene', (114, 118))	('ETS1', 'Gene', '2113', (114, 118))	('miR-519d-5p', 'Chemical', '-', (147, 158))	('miR-519d-5p', 'Var', (147, 158))	('si', 'Chemical', 'MESH:D012825', (125, 127))
346578	33335425	LINC01426 knockdown suppressed the tumorigenicity of NSCLC cells in vitro and in vivo.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('NSCLC', 'Phenotype', 'HP:0030358', (53, 58))	('LINC01426', 'Gene', '100506385', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('LINC01426', 'Gene', (0, 9))	('suppressed', 'NegReg', (20, 30))	('tumor', 'Disease', (35, 40))	('NSCLC', 'Disease', (53, 58))	('knockdown', 'Var', (10, 19))	('NSCLC', 'Disease', 'MESH:D002289', (53, 58))
346583	31981897	Here, we report that c-Src can interact with and phosphorylate AGO2, a core component of RISC complex, at tyr 393, tyr 529 and tyr749.	('interact', 'Interaction', (31, 39))	('tyr 393', 'Var', (106, 113))	('AGO2', 'Gene', (63, 67))	('phosphorylate', 'MPA', (49, 62))	('tyr 529', 'Var', (115, 122))	('tyr749', 'Var', (127, 133))	('c-Src', 'Gene', (21, 26))	('c-Src', 'Gene', '6714', (21, 26))
346584	31981897	Mechanistically, it is confirmed that c-Src phosphorylation of AGO2 at tyr393 reduces its binding to DICER, thereby suppressing the maturation of long-loop pre-miR-192.	('DICER', 'Gene', '23405', (101, 106))	('tyr393', 'Var', (71, 77))	('maturation', 'MPA', (132, 142))	('DICER', 'Gene', (101, 106))	('suppressing', 'NegReg', (116, 127))	('binding', 'Interaction', (90, 97))	('AGO2', 'Gene', (63, 67))	('c-Src', 'Gene', (38, 43))	('c-Src', 'Gene', '6714', (38, 43))	('reduces', 'NegReg', (78, 85))	('miR-192', 'Gene', (160, 167))	('miR-192', 'Gene', '406967', (160, 167))
346598	31981897	Recently, acetylation of AGO2 by P300/CBP was found to increase its recruitment of pre-miR-19b-1 to enhance miR-19b maturation.	('increase', 'PosReg', (55, 63))	('miR-19b', 'Gene', (108, 115))	('miR-19b', 'Gene', (87, 94))	('miR-19b-1', 'Gene', '406980', (87, 96))	('enhance', 'PosReg', (100, 107))	('miR-19b-1', 'Gene', (87, 96))	('miR-19b', 'Gene', '406980', (108, 115))	('recruitment', 'MPA', (68, 79))	('miR-19b', 'Gene', '406980', (87, 94))	('P300/CBP', 'Var', (33, 41))	('acetylation', 'MPA', (10, 21))
346599	31981897	identified that epidermal growth factor receptor (EGFR) could phosphorylate AGO2 at Tyr393, and thus attenuate its affinity toward DICER and impede the maturation of long-loop miRNA in response to hypoxic stress.	('DICER', 'Gene', '23405', (131, 136))	('affinity toward', 'Interaction', (115, 130))	('impede', 'NegReg', (141, 147))	('AGO2', 'Protein', (76, 80))	('epidermal growth factor receptor', 'Gene', '1956', (16, 48))	('hypoxic stress', 'Disease', 'MESH:D054549', (197, 211))	('maturation', 'MPA', (152, 162))	('DICER', 'Gene', (131, 136))	('miR', 'Gene', '220972', (176, 179))	('EGFR', 'Gene', '1956', (50, 54))	('attenuate', 'NegReg', (101, 110))	('hypoxic stress', 'Disease', (197, 211))	('epidermal growth factor receptor', 'Gene', (16, 48))	('EGFR', 'Gene', (50, 54))	('Tyr', 'Chemical', 'MESH:C042696', (84, 87))	('Tyr393', 'Var', (84, 90))	('miR', 'Gene', (176, 179))
346601	31981897	In this study, we identify that c-Src kinase could interact with AGO2 directly, and phosphorylate AGO2 at Tyr393, Tyr529 and Tyr749 residues.	('c-Src kinase', 'Gene', '1445', (32, 44))	('Tyr529', 'Chemical', 'MESH:C087958', (114, 120))	('Tyr529', 'Var', (114, 120))	('interact', 'Interaction', (51, 59))	('Tyr', 'Chemical', 'MESH:C042696', (106, 109))	('Tyr393', 'Var', (106, 112))	('Tyr749 residues', 'Var', (125, 140))	('c-Src kinase', 'Gene', (32, 44))	('Tyr', 'Chemical', 'MESH:C042696', (125, 128))	('Tyr', 'Chemical', 'MESH:C042696', (114, 117))
346613	31981897	Domain-deletion of HA-c-Src, Myc-AGO2 and point mutations of Myc-AGO2 were generated by using the KOD-plus-mutagenesis Kit (TOYOBO).	('Myc', 'Gene', '4609', (61, 64))	('Myc', 'Gene', (61, 64))	('c-Src', 'Gene', (22, 27))	('point mutations', 'Var', (42, 57))	('c-Src', 'Gene', '6714', (22, 27))	('Domain-deletion', 'Var', (0, 15))	('Myc', 'Gene', '4609', (29, 32))	('Myc', 'Gene', (29, 32))
346614	31981897	The Flag-tagged full-length or tyrosine -mutated AGO2 was cloned into the lentiviral expression vector CD513B for establishing stable cell lines with the packaging plasmids pMD2G and pCMV-dR8.	('AGO2', 'Gene', (49, 53))	('tyrosine -mutated', 'Var', (31, 48))	('tyrosine', 'Chemical', 'None', (31, 39))
346651	31981897	This interaction was confirmed with reciprocal co-IP assays by transient transfected with Flag-c-Src and HA-AGO2 in HEK293T cells (Fig.	('HA-AGO2', 'Var', (105, 112))	('c-Src', 'Gene', (95, 100))	('c-Src', 'Gene', '6714', (95, 100))	('HEK293T', 'CellLine', 'CVCL:0063', (116, 123))
346664	31981897	Based on https://www.genecards.org and published literatures, three tyrosine residues in AGO2 protein have been reported as phosphorylation sites, including tyr749 firstly identified with mass spectrometry in 2009, and tyr393/tyr529 identified with mass spectrometry in 2011.	('tyrosine', 'Chemical', 'None', (68, 76))	('AGO2', 'Gene', (89, 93))	('tyr393/tyr529', 'Var', (219, 232))	('tyr529', 'Chemical', 'MESH:C087958', (226, 232))	('tyr749', 'Var', (157, 163))
346666	31981897	Tyr   phe (Y   F) mutational analysis showed that each of the single point mutation (Y393F, Y529F, Y749F) has dramatically attenuated the c-Src-induced AGO2 phosphorylation (Fig.	('c-Src', 'Gene', '6714', (138, 143))	('Tyr', 'Chemical', 'MESH:C042696', (0, 3))	('Y749F', 'Mutation', 'p.Y749F', (99, 104))	('Y529F', 'Mutation', 'p.Y529F', (92, 97))	('Y393F', 'Var', (85, 90))	('Y749F', 'Var', (99, 104))	('Y393F', 'Mutation', 'p.Y393F', (85, 90))	('c-Src', 'Gene', (138, 143))	('Y529F', 'Var', (92, 97))	('attenuated', 'NegReg', (123, 133))
346667	31981897	Notably, tri-mutation AGO2 had hardly any phosphorylation modification by c-Src (Fig.	('c-Src', 'Gene', (74, 79))	('phosphorylation modification', 'MPA', (42, 70))	('tri-mutation', 'Var', (9, 21))	('c-Src', 'Gene', '6714', (74, 79))
346669	31981897	Collectively, we conducted that AGO2 could be phosphorylated at tyr393, tyr529, and tyr749 by c-Src kinase.	('c-Src kinase', 'Gene', '1445', (94, 106))	('tyr529', 'Chemical', 'MESH:C087958', (72, 78))	('tyr393', 'Var', (64, 70))	('tyr749', 'Var', (84, 90))	('c-Src kinase', 'Gene', (94, 106))	('tyr529', 'Var', (72, 78))
346673	31981897	2F, the degree of total tyrosine phosphorylation (upper lane 2) or pY393 (middle lane 2) of AGO2 by c-Src kinase was much stronger than those by EGFR (upper and middle lane 3).	('c-Src kinase', 'Gene', (100, 112))	('tyrosine phosphorylation', 'MPA', (24, 48))	('EGFR', 'Gene', '1956', (145, 149))	('stronger', 'PosReg', (122, 130))	('EGFR', 'Gene', (145, 149))	('c-Src kinase', 'Gene', '1445', (100, 112))	('pY393', 'Var', (67, 72))	('tyrosine', 'Chemical', 'None', (24, 32))
346677	31981897	It's reported that EGFR-induced AGO2 phosphorylation at tyr393 specifically suppresses the maturation of pre-miRNAs with long-loop structures under hypoxia.	('miR', 'Gene', '220972', (109, 112))	('miR', 'Gene', (109, 112))	('maturation', 'MPA', (91, 101))	('hypoxia', 'Disease', 'MESH:D000860', (148, 155))	('EGFR', 'Gene', '1956', (19, 23))	('tyr393', 'Var', (56, 62))	('EGFR', 'Gene', (19, 23))	('suppresses', 'NegReg', (76, 86))	('hypoxia', 'Disease', (148, 155))
346686	31981897	S2C, lane 2) was significantly increased when transfection with AGO2, whereas inhibited when co-transfection with c-Src (Fig.	('c-Src', 'Gene', (114, 119))	('c-Src', 'Gene', '6714', (114, 119))	('increased', 'PosReg', (31, 40))	('S2C', 'Chemical', 'MESH:D013455', (0, 3))	('AGO2', 'Var', (64, 68))	('transfection', 'Var', (46, 58))
346692	31981897	Next, we try to verify which tyrosine residue in AGO2 is responsible for inhibiton of miRNA maturation.	('tyrosine residue', 'Var', (29, 45))	('tyrosine', 'Chemical', 'None', (29, 37))	('inhibiton', 'NegReg', (73, 82))	('miR', 'Gene', '220972', (86, 89))	('miR', 'Gene', (86, 89))
346693	31981897	3D), we characterized that AGO2Y393F, but not AGO2Y529F or AGO2Y749F can recover the c-Src inhibition on miR-192 maturation.	('miR-192', 'Gene', '406967', (105, 112))	('AGO2Y393F', 'Var', (27, 36))	('Y749F', 'Mutation', 'p.Y749F', (63, 68))	('c-Src', 'Gene', (85, 90))	('c-Src', 'Gene', '6714', (85, 90))	('recover', 'PosReg', (73, 80))	('miR-192', 'Gene', (105, 112))
346698	31981897	To explore whether phosphorylation of AGO2 has a biological significance in tumors, we generated stable A549 lung cancer cell lines by polyclonal lentiviral infections with vector, AGO2 WT, AGO2Y393F, AGO2Y529F, or AGO2Y749F.	('lung cancer', 'Disease', (109, 120))	('lung cancer', 'Phenotype', 'HP:0100526', (109, 120))	('Y749F', 'Mutation', 'p.Y749F', (219, 224))	('A549', 'CellLine', 'CVCL:0023', (104, 108))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('AGO2Y529F', 'Var', (201, 210))	('tumors', 'Disease', (76, 82))	('Y529F', 'Mutation', 'p.Y529F', (205, 210))	('lung cancer', 'Disease', 'MESH:D008175', (109, 120))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('AGO2Y393F', 'Var', (190, 199))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('AGO2Y749F', 'Var', (215, 224))
346702	31981897	Interestingly, over-expressed AGO2 WT in A549 cell significantly increased the size and weight of tumor compared with both vector control and three AGO2 mutants (**P < 0.01 between AGO2 WT and vector, AGO2Y393F, AGO2Y529F, *P < 0.05 between AGO2 WT and AGO2Y749F).	('increased', 'PosReg', (65, 74))	('A549', 'CellLine', 'CVCL:0023', (41, 45))	('tumor', 'Disease', (98, 103))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('AGO2Y393F', 'Var', (201, 210))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('over-expressed', 'PosReg', (15, 29))	('AGO2Y529F', 'Var', (212, 221))	('AGO2', 'Var', (30, 34))
346703	31981897	However, compared with vector, AGO2Y749F or AGO2Y529F also significantly increased the size and weight of tumor (*P < 0.05), and AGO2Y393F had a slight increasing effect with no statistical difference.	('increased', 'PosReg', (73, 82))	('AGO2Y749F', 'Var', (31, 40))	('AGO2Y393F', 'Var', (129, 138))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('Y529F', 'Mutation', 'p.Y529F', (48, 53))	('AGO2Y529F', 'Var', (44, 53))	('tumor', 'Disease', (106, 111))	('Y749F', 'Mutation', 'p.Y749F', (35, 40))
346704	31981897	These data suggest that phosphorylation of AGO2 promotes tumorigenesis, and each phosphorylation at the three tyrosine residues is essential to this oncogenic function.	('AGO2', 'Gene', (43, 47))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('promotes', 'PosReg', (48, 56))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tyrosine', 'Chemical', 'None', (110, 118))	('tumor', 'Disease', (57, 62))	('phosphorylation', 'Var', (24, 39))
346712	31981897	Furthermore, colony formation assay on DU145 stable cell lines showed cells transfected with AGO2 shRNA could reduce the numbers of colonies, but this suppression could be rescued fully by re-expression of AGO2 WT rather than AGO2Y393F.	('DU145', 'CellLine', 'CVCL:0105', (39, 44))	('AGO2 shRNA', 'Var', (93, 103))	('reduce', 'NegReg', (110, 116))
346732	31981897	Second, only one tyrosine residue Y393 in AGO2 is confirmed to be phosphorylated by EGFR.	('Y393', 'Var', (34, 38))	('EGFR', 'Gene', (84, 88))	('EGFR', 'Gene', '1956', (84, 88))	('tyrosine', 'Chemical', 'None', (17, 25))
346733	31981897	However, not only tyr393, but also tyr529 and tyr749, have been identified as phosphorylation sites for c-Src kinase (Fig.	('tyr529', 'Chemical', 'MESH:C087958', (35, 41))	('c-Src kinase', 'Gene', (104, 116))	('tyr749', 'Var', (46, 52))	('c-Src kinase', 'Gene', '1445', (104, 116))	('tyr529', 'Var', (35, 41))	('tyr393', 'Var', (18, 24))
346734	31981897	Functionally, Y393 phosphorylation by c-Src under nomoxia is identical to that by EGFR under hypoxia, which can reduce the binding of DICER to AGO2 and inhibits pre-miR-192 maturation.	('binding', 'Interaction', (123, 130))	('EGFR', 'Gene', (82, 86))	('reduce', 'NegReg', (112, 118))	('miR-192', 'Gene', '406967', (165, 172))	('miR-192', 'Gene', (165, 172))	('inhibits', 'NegReg', (152, 160))	('AGO2', 'Protein', (143, 147))	('DICER', 'Gene', '23405', (134, 139))	('c-Src', 'Gene', (38, 43))	('DICER', 'Gene', (134, 139))	('hypoxia', 'Disease', 'MESH:D000860', (93, 100))	('c-Src', 'Gene', '6714', (38, 43))	('EGFR', 'Gene', '1956', (82, 86))	('hypoxia', 'Disease', (93, 100))	('Y393', 'Var', (14, 18))
346735	31981897	did not observe any significant changes among parental, vector, AGO2 WT and AGO2Y393F stable cell lines (HeLa and MDA-MB-231) in cell proliferation (under normoxia or hypoxia) or anchorage-independent growth (Ref., Fig.	('HeLa', 'CellLine', 'CVCL:0030', (105, 109))	('anchorage-independent growth', 'CPA', (179, 207))	('hypoxia', 'Disease', (167, 174))	('hypoxia', 'Disease', 'MESH:D000860', (167, 174))	('AGO2Y393F', 'Var', (76, 85))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (114, 124))
346740	31981897	It is evidenced that EGFR can be phosphorylated on multiple sites by c-Src, most notably tyr845, which is required for EGF-induced cell proliferation and cell survival.	('EGFR', 'Gene', '1956', (21, 25))	('c-Src', 'Gene', '6714', (69, 74))	('EGFR', 'Gene', (21, 25))	('tyr845', 'Var', (89, 95))	('c-Src', 'Gene', (69, 74))
346745	31981897	Results showed that only pY393 AGO2 inhibits processing maturation of long-loop miRNAs, whereas pY529 AGO2 or pY749 AGO2 does not function through this mechanism.	('miR', 'Gene', '220972', (80, 83))	('pY393 AGO2', 'Var', (25, 35))	('miR', 'Gene', (80, 83))	('inhibits', 'NegReg', (36, 44))
346746	31981897	It has been reported pY529 could prevent AGO2 binding to 5' phosphate of the small RNA.	('pY529', 'Var', (21, 26))	('prevent', 'NegReg', (33, 40))	('AGO2', 'Protein', (41, 45))	('phosphate', 'Chemical', 'MESH:D010710', (60, 69))
346753	31981897	AGO2 interacts with c-Src and is phosphorylated at its tyr393, tyr529 and tyr749 sites by c-Src kinase, which phosphorylation could be blocked by treatment with saracatinib, the c-Src kinase inhibitor.	('c-Src', 'Gene', (90, 95))	('c-Src kinase', 'Gene', (178, 190))	('tyr529', 'Chemical', 'MESH:C087958', (63, 69))	('c-Src', 'Gene', '6714', (90, 95))	('interacts', 'Interaction', (5, 14))	('c-Src', 'Gene', '6714', (178, 183))	('c-Src kinase', 'Gene', (90, 102))	('c-Src kinase', 'Gene', '1445', (178, 190))	('tyr749', 'Var', (74, 80))	('c-Src', 'Gene', (20, 25))	('c-Src', 'Gene', '6714', (20, 25))	('c-Src', 'Gene', (178, 183))	('saracatinib', 'Chemical', 'MESH:C515233', (161, 172))	('tyr529', 'Var', (63, 69))	('c-Src kinase', 'Gene', '1445', (90, 102))
346758	30924596	Here, we conducted an epigenome-wide interaction analysis between DNA methylation and smoking cessation on NSCLC survival.	('NSCLC', 'Disease', 'MESH:D002289', (107, 112))	('methylation', 'Var', (70, 81))	('NSCLC', 'Disease', (107, 112))
346759	30924596	We used a two-stage study design to identify DNA methylation-smoking cessation interactions that affect overall survival for early-stage NSCLC.	('interactions', 'Var', (79, 91))	('NSCLC', 'Disease', 'MESH:D002289', (137, 142))	('affect', 'Reg', (97, 103))	('NSCLC', 'Disease', (137, 142))
346763	30924596	We identified one CpG probe (cg02268510SIPA 1L3) that significantly and exclusively modified the effect of smoking cessation on survival in LUAD patients [hazard ratio (HR)interaction = 1.12; 95% confidence interval (CI): 1.07-1.16; P = 4.30 x 10-7].	('patients', 'Species', '9606', (145, 153))	('LUAD', 'Disease', 'None', (140, 144))	('cg02268510SIPA', 'Var', (29, 43))	('modified', 'Reg', (84, 92))	('LUAD', 'Disease', (140, 144))
346764	30924596	Further, the effect of smoking cessation on early-stage LUAD survival varied across patients with different methylation levels of cg02268510SIPA 1L3.	('patients', 'Species', '9606', (84, 92))	('LUAD', 'Disease', 'None', (56, 60))	('LUAD', 'Disease', (56, 60))	('cg02268510SIPA', 'Var', (130, 144))	('early-stage', 'Disease', (44, 55))
346765	30924596	Smoking cessation only benefited LUAD patients with low methylation (HR  = 0.53; 95% CI: 0.34-0.82; P = 4.61 x 10-3) rather than medium or high methylation (HR  = 1.21; 95% CI: 0.86-1.70; P = 0.266) of cg02268510SIPA 1L3.	('methylation', 'MPA', (56, 67))	('LUAD', 'Disease', 'None', (33, 37))	('LUAD', 'Disease', (33, 37))	('patients', 'Species', '9606', (38, 46))	('cg02268510SIPA', 'Var', (202, 216))	('low', 'NegReg', (52, 55))
346766	30924596	In summary, smoking cessation benefited survival of LUAD patients with low methylation at cg02268510SIPA 1L3.	('low', 'NegReg', (71, 74))	('cg02268510SIPA', 'Var', (90, 104))	('LUAD', 'Disease', 'None', (52, 56))	('LUAD', 'Disease', (52, 56))	('patients', 'Species', '9606', (57, 65))	('benefited', 'PosReg', (30, 39))	('methylation', 'MPA', (75, 86))	('survival', 'CPA', (40, 48))
346771	30924596	Furthermore, as a potential mechanistic link between cigarette smoking and disease, DNA methylation changes can result from various environmental exposures and may explain part of the association between smoking and cancer recurrence or mortality (Lee and Pausova, 2013; Shui et al., 2016).	('result', 'Reg', (112, 118))	('methylation', 'Var', (88, 99))	('cancer', 'Disease', 'MESH:D009369', (216, 222))	('explain', 'Reg', (164, 171))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('cancer', 'Disease', (216, 222))	('changes', 'Reg', (100, 107))	('smoking', 'Disease', (204, 211))	('association', 'Interaction', (184, 195))	('DNA', 'Gene', (84, 87))
346773	30924596	In this study, we hypothesized that epigenetic and smoking cessation interactions may affect NSCLC survival.	('affect', 'Reg', (86, 92))	('NSCLC', 'Disease', (93, 98))	('NSCLC', 'Disease', 'MESH:D002289', (93, 98))	('epigenetic', 'Var', (36, 46))	('interactions', 'Interaction', (69, 81))
346801	30924596	This site, cg02268510, is located in signal-induced proliferation-associated 1-like 3 (SIPA1L3).	('signal-induced proliferation-associated 1-like 3', 'Gene', '23094', (37, 85))	('SIPA1L3', 'Gene', '23094', (87, 94))	('SIPA1L3', 'Gene', (87, 94))	('cg02268510', 'Chemical', '-', (11, 21))	('cg02268510', 'Var', (11, 21))	('signal-induced proliferation-associated 1-like 3', 'Gene', (37, 85))
346802	30924596	Further histology-stratified analysis showed that cg02268510SIPA1L3 is a LUAD-specific CpG probe that interacts with smoking cessation to affect patient survival in the discovery phase (HRinteraction = 1.10; 95% CI: 1.05-1.16; P = 2.95 x 10-5), the validation phase (HRinteraction = 1.17; 95% CI: 1.02-1.35; P = 0.0255), and the combined data (HRinteraction = 1.12; 95% CI: 1.07-1.16; P = 4.30 x 10-7).	('affect', 'Reg', (138, 144))	('LUAD', 'Disease', 'None', (73, 77))	('LUAD', 'Disease', (73, 77))	('cg02268510SIPA1L3', 'Var', (50, 67))	('patient', 'Species', '9606', (145, 152))	('patient survival', 'CPA', (145, 161))
346803	30924596	2A, with decreased methylation level of cg02268510SIPA1L3, there was an elevated benefit effect size of smoking cessation on LUAD survival.	('LUAD', 'Disease', 'None', (125, 129))	('LUAD', 'Disease', (125, 129))	('smoking', 'Disease', (104, 111))	('decreased', 'NegReg', (9, 18))	('methylation level', 'MPA', (19, 36))	('cg02268510SIPA1L3', 'Var', (40, 57))
346804	30924596	After including tumor purity as an additional covariate in sensitivity analysis, DNA methylation at cg02268510SIPA1L3 retained a significant interaction with smoking cessation on LUAD survival (HRinteraction  = 1.18; 95% CI: 1.02-1.36; P = 0.024).	('cg02268510SIPA1L3', 'Var', (100, 117))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('tumor', 'Disease', (16, 21))	('LUAD', 'Disease', 'None', (179, 183))	('LUAD', 'Disease', (179, 183))
346808	30924596	Smoking cessation only benefited LUAD patients with low methylation of cg02268510SIPA1L3 (HRlow  = 0.53; 95% CI: 0.34-0.82; P = 4.61 x 10-3).	('methylation', 'MPA', (56, 67))	('cg02268510SIPA1L3', 'Var', (71, 88))	('LUAD', 'Disease', 'None', (33, 37))	('LUAD', 'Disease', (33, 37))	('patients', 'Species', '9606', (38, 46))	('low', 'NegReg', (52, 55))
346809	30924596	However, there was no significant association between smoking cessation and survival in LUAD patients with medium-high methylation of cg02268510SIPA1L3 (HRmedium  = 1.12; 95% CI: 0.67-1.87; P = 0.665; HRhigh  = 1.29; 95% CI: 0.80-2.07; P = 0.293; HRmedium-high  = 1.21; 95% CI: 0.86-1.70; P = 0.266).	('LUAD', 'Disease', 'None', (88, 92))	('LUAD', 'Disease', (88, 92))	('patients', 'Species', '9606', (93, 101))	('cg02268510SIPA1L3', 'Var', (134, 151))
346810	30924596	These results also indicated that LUAD patients who did not quit smoking (current smokers) had the poorest prognosis if their methylation of cg02268510SIPA1L3 was in a low level.	('LUAD', 'Disease', 'None', (34, 38))	('methylation', 'MPA', (126, 137))	('LUAD', 'Disease', (34, 38))	('patients', 'Species', '9606', (39, 47))	('cg02268510SIPA1L3', 'Var', (141, 158))
346811	30924596	The results also indicated that smoking cessation was quite urgent for LUAD patients with low methylation of cg02268510SIPA1L3.	('patients', 'Species', '9606', (76, 84))	('low', 'NegReg', (90, 93))	('methylation', 'MPA', (94, 105))	('cg02268510SIPA1L3', 'Var', (109, 126))	('LUAD', 'Disease', 'None', (71, 75))	('LUAD', 'Disease', (71, 75))
346818	30924596	To our knowledge, this is the first study with a large sample size to investigate interactions between DNA methylation and smoking behavior on lung cancer survival, and it provides new evidence to account for the missing heritability of complex diseases (Trerotola et al., 2015).	('interactions', 'Interaction', (82, 94))	('lung cancer', 'Disease', (143, 154))	('lung cancer', 'Phenotype', 'HP:0100526', (143, 154))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('DNA', 'Gene', (103, 106))	('lung cancer', 'Disease', 'MESH:D008175', (143, 154))	('methylation', 'Var', (107, 118))
346819	30924596	Our results show that the effect of smoking cessation on early-stage LUAD patient survival varies with methylation level of cg02268510SIPA1L3.	('cg02268510SIPA1L3', 'Var', (124, 141))	('patient', 'Species', '9606', (74, 81))	('LUAD', 'Disease', 'None', (69, 73))	('LUAD', 'Disease', (69, 73))	('methylation', 'MPA', (103, 114))
346820	30924596	Smoking cessation only benefits LUAD patients with low methylation, rather than medium or high methylation, of cg02268510SIPA1L3.	('patients', 'Species', '9606', (37, 45))	('cg02268510SIPA1L3', 'Var', (111, 128))	('methylation', 'MPA', (55, 66))	('LUAD', 'Disease', 'None', (32, 36))	('low', 'NegReg', (51, 54))	('LUAD', 'Disease', (32, 36))
346821	30924596	We found that in LUAD patients with low methylation of cg02268510SIPA1L3, current smokers with more accumulative exposure had worse survival than former smokers.	('low', 'NegReg', (36, 39))	('worse', 'NegReg', (126, 131))	('cg02268510SIPA1L3', 'Var', (55, 72))	('survival', 'MPA', (132, 140))	('patients', 'Species', '9606', (22, 30))	('methylation', 'MPA', (40, 51))	('LUAD', 'Disease', 'None', (17, 21))	('LUAD', 'Disease', (17, 21))
346823	30924596	Our results indicated that smoking cessation was urgent especially for LUAD patients with low methylation of cg02268510SIPA1L3.	('patients', 'Species', '9606', (76, 84))	('low', 'NegReg', (90, 93))	('methylation', 'MPA', (94, 105))	('cg02268510SIPA1L3', 'Var', (109, 126))	('LUAD', 'Disease', 'None', (71, 75))	('LUAD', 'Disease', (71, 75))
346829	30924596	Additionally, overexpression of RAP1 may desensitize NSCLC cells to cisplatin, a first-line drug to treat NSCLC (Besse et al., 2014).	('cisplatin', 'Chemical', 'MESH:D002945', (68, 77))	('RAP1', 'Gene', '27342', (32, 36))	('RAP1', 'Gene', (32, 36))	('NSCLC', 'Disease', 'MESH:D002289', (106, 111))	('overexpression', 'Var', (14, 28))	('desensitize', 'NegReg', (41, 52))	('NSCLC', 'Disease', (53, 58))	('NSCLC', 'Disease', 'MESH:D002289', (53, 58))	('NSCLC', 'Disease', (106, 111))
346830	30924596	Our results suggest that low methylation at cg02268510SIPA1L3 might promote SIPA1L3 expression, further leading to Rap1 activation and resulting in poor prognosis (Fig.	('methylation', 'Var', (29, 40))	('Rap1', 'Gene', (115, 119))	('leading to', 'Reg', (104, 114))	('promote', 'PosReg', (68, 75))	('SIPA1L3', 'Gene', '23094', (54, 61))	('low methylation', 'Var', (25, 40))	('activation', 'PosReg', (120, 130))	('Rap1', 'Gene', '5906', (115, 119))	('SIPA1L3', 'Gene', (76, 83))	('SIPA1L3', 'Gene', '23094', (76, 83))	('expression', 'MPA', (84, 94))	('SIPA1L3', 'Gene', (54, 61))
346835	30924596	Therefore, for current smokers, nicotine in tobacco stimulates activation of NF-kappaB, induces inflammatory responses, and is relevant to poor patient prognosis (Fig.	('inflammatory responses', 'CPA', (96, 118))	('induces', 'Reg', (88, 95))	('nicotine', 'Chemical', 'MESH:D009538', (32, 40))	('tobacco', 'Species', '4097', (44, 51))	('NF-kappaB', 'Gene', (77, 86))	('patient', 'Species', '9606', (144, 151))	('activation', 'MPA', (63, 73))	('nicotine', 'Var', (32, 40))	('NF-kappaB', 'Gene', '4790', (77, 86))
346840	30924596	In terms of cg02268510SIPA1L3 and smoking cessation interaction, keeping smoking was associated with poor prognosis only in LUAD patients with low methylation, rather than medium or high methylation, possibly because high activation of both Rap1 and NF-kappaB may only occur in patients with low methylation.	('patients', 'Species', '9606', (129, 137))	('low methylation', 'Var', (143, 158))	('NF-kappaB', 'Gene', (250, 259))	('LUAD', 'Disease', 'None', (124, 128))	('LUAD', 'Disease', (124, 128))	('Rap1', 'Gene', '5906', (241, 245))	('cg02268510SIPA1L3', 'Var', (12, 29))	('Rap1', 'Gene', (241, 245))	('patients', 'Species', '9606', (278, 286))	('NF-kappaB', 'Gene', '4790', (250, 259))
346841	30924596	5, low methylation and keeping smoking resulted in the worst prognosis, which might be due to the positive feedback in Rap1 and NF-kappaB.	('NF-kappaB', 'Gene', (128, 137))	('methylation', 'MPA', (7, 18))	('Rap1', 'Gene', (119, 123))	('low', 'Var', (3, 6))	('Rap1', 'Gene', '5906', (119, 123))	('NF-kappaB', 'Gene', '4790', (128, 137))
346842	30924596	But, high methylation of cg02268510SIPA1L3 resulted in low SIPA1L3 expression that was hard to active Rap1 and NF-kappaB, and then might weaken the harmful effect of smoking, which also indicated an antagonistic effect.	('SIPA1L3', 'Gene', (59, 66))	('smoking', 'CPA', (166, 173))	('Rap1', 'Gene', (102, 106))	('SIPA1L3', 'Gene', (35, 42))	('SIPA1L3', 'Gene', '23094', (59, 66))	('SIPA1L3', 'Gene', '23094', (35, 42))	('harmful', 'MPA', (148, 155))	('weaken', 'NegReg', (137, 143))	('NF-kappaB', 'Gene', '4790', (111, 120))	('low', 'NegReg', (55, 58))	('methylation', 'Var', (10, 21))	('expression', 'MPA', (67, 77))	('NF-kappaB', 'Gene', (111, 120))	('Rap1', 'Gene', '5906', (102, 106))
346846	30924596	Moreover, a previous study has found that activation of Rap1 serves to attenuate ROS production (Remans et al., 2004) and there is a potential interrelationship between Rap1, ROS, and NF-kappaB activation (Moon et al., 2011).	('ROS production', 'MPA', (81, 95))	('ROS', 'Chemical', 'MESH:D017382', (175, 178))	('activation', 'Var', (42, 52))	('Rap1', 'Gene', '5906', (56, 60))	('Rap1', 'Gene', '5906', (169, 173))	('NF-kappaB', 'Gene', '4790', (184, 193))	('attenuate', 'NegReg', (71, 80))	('Rap1', 'Gene', (56, 60))	('ROS', 'Chemical', 'MESH:D017382', (81, 84))	('Rap1', 'Gene', (169, 173))	('NF-kappaB', 'Gene', (184, 193))
346847	30924596	But further functional studies are warranted to elucidate the mechanism of cg02268510SIPA1L3 and smoking cessation interaction on LUAD survival.	('LUAD', 'Disease', 'None', (130, 134))	('LUAD', 'Disease', (130, 134))	('cg02268510SIPA1L3', 'Var', (75, 92))
346851	30924596	Patients with high GADD45G expression had a better prognosis in our study.	('GADD45G', 'Gene', '10912', (19, 26))	('high', 'Var', (14, 18))	('GADD45G', 'Gene', (19, 26))	('Patients', 'Species', '9606', (0, 8))
346860	30924596	Though there is a lack of explicit evidence of relevance between these genes and smoking, what we found may inspire functional studies of these potential genes and further help to complete a picture of the mechanism pathway of cg02268510SIPA1L3 and smoking cessation interaction on LUAD survival.	('cg02268510SIPA1L3', 'Var', (227, 244))	('LUAD', 'Disease', 'None', (282, 286))	('LUAD', 'Disease', (282, 286))
346864	30924596	This epigenome-wide DNA methylation-smoking cessation interaction analysis of early-stage NSCLC identified one LUAD-specific CpG probe, cg02268510SIPA1L3 , which could significantly modify effects of smoking cessation on lung cancer survival.	('lung cancer', 'Disease', 'MESH:D008175', (221, 232))	('NSCLC', 'Disease', (90, 95))	('LUAD', 'Disease', 'None', (111, 115))	('LUAD', 'Disease', (111, 115))	('NSCLC', 'Disease', 'MESH:D002289', (90, 95))	('modify', 'Reg', (182, 188))	('lung cancer', 'Phenotype', 'HP:0100526', (221, 232))	('cg02268510SIPA1L3', 'Var', (136, 153))	('lung cancer', 'Disease', (221, 232))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
346865	30924596	Smoking cessation benefited survival of LUAD patients with low methylation at cg02268510SIPA1L3.	('low methylation', 'Var', (59, 74))	('survival', 'CPA', (28, 36))	('LUAD', 'Disease', 'None', (40, 44))	('LUAD', 'Disease', (40, 44))	('patients', 'Species', '9606', (45, 53))	('cg02268510SIPA1L3', 'Var', (78, 95))	('benefited', 'PosReg', (18, 27))
346870	33718149	BNCT utilizes boronated agents to preferentially deliver boron-10 to tumors, which, after undergoing irradiation with neutrons, yields litihium-7 and an alpha particle.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('boron-10', 'Var', (57, 65))	('litihium-7', 'MPA', (135, 145))	('boronated', 'Chemical', '-', (14, 23))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('boron-10', 'Chemical', 'MESH:C000615219', (57, 65))	('tumors', 'Disease', (69, 75))	('tumors', 'Disease', 'MESH:D009369', (69, 75))	('litihium-7', 'Chemical', '-', (135, 145))
347120	32300588	In particular, SLK was more likely to be cancer-related due to its high missense mutation rate and associated with cell adhesion.	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('missense mutation', 'Var', (72, 89))	('SLK', 'Gene', '9748', (15, 18))	('SLK', 'Gene', (15, 18))	('cell adhesion', 'CPA', (115, 128))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('associated', 'Reg', (99, 109))
347131	32300588	developed a prognostic 3-miRNA classifier (miR-106b-5p, miR-148a-3p, and miR-338-3p) in early-stage mycosis fungoides.	('miR-338-3p', 'Var', (73, 83))	('miR-148a-3p', 'Var', (56, 67))	('miR-106b', 'Gene', '406900', (43, 51))	('early-stage mycosis fungoides', 'Disease', (88, 117))	('miR-106b', 'Gene', (43, 51))
347163	32300588	Univariate Cox proportional hazards regression model was used to identify candidate survival-related genes from each omics data through the formula: where the explanatory variable X was the omics data (DM, GE, copy number variation, or miRNA expression) of a gene, and the response variable t was the survival time.	('Cox', 'Gene', '1351', (11, 14))	('Cox', 'Gene', (11, 14))	('DM', 'Disease', 'MESH:D009223', (202, 204))	('copy number variation', 'Var', (210, 231))	('survival-related', 'Gene', (84, 100))	('survival-related', 'Gene', '54897', (84, 100))
347221	32300588	We found that SLK had an unconservative exon region, which containing four missense variants (Figure 7A).	('missense', 'Var', (75, 83))	('SLK', 'Gene', '9748', (14, 17))	('SLK', 'Gene', (14, 17))
347222	32300588	In order to further verify the close relationship of SLK and cancer, we checked the mutation of SLK in the COSMIC database, and found that missense substitution occurred in 36.93% of the samples (Figure 7B).	('missense substitution', 'Var', (139, 160))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('cancer', 'Disease', (61, 67))	('SLK', 'Gene', '9748', (53, 56))	('SLK', 'Gene', (53, 56))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('SLK', 'Gene', '9748', (96, 99))	('occurred', 'Reg', (161, 169))	('SLK', 'Gene', (96, 99))
347232	32300588	Based on the COSMIC database, we found extensive mutations occurred in EPRS, and 70% of them were missense mutation.	('EPRS', 'Gene', (71, 75))	('missense mutation', 'Var', (98, 115))	('EPRS', 'Gene', '2058', (71, 75))	('mutations', 'Var', (49, 58))
347239	32300588	These locations were the peak regions of copy number alternation, suggesting a relationship between these genes and cancer.	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('relationship', 'Reg', (79, 91))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('copy number', 'Var', (41, 52))
347264	32300588	Cell adhesion plays an important role in the maintenance of tissue structure, whose abnormality results in tumor invasion and metastasis.	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('metastasis', 'CPA', (126, 136))	('results in', 'Reg', (96, 106))	('abnormality', 'Var', (84, 95))
347285	31956415	Next-generation sequencing (NGS) analysis showed EGFR T790M and genomic alterations in PTEN, PDGFR, and HRAS.	('EGFR', 'Gene', '1956', (49, 53))	('PTEN', 'Gene', (87, 91))	('PTEN', 'Gene', '5728', (87, 91))	('EGFR', 'Gene', (49, 53))	('T790M', 'Mutation', 'rs121434569', (54, 59))	('HRAS', 'Gene', (104, 108))	('T790M', 'Var', (54, 59))	('PDGFR', 'Gene', (93, 98))	('HRAS', 'Gene', '3265', (104, 108))	('PDGFR', 'Gene', '5159', (93, 98))
347286	31956415	The second case was a 72-year-old man who was an ex-smoker with stage IV lung adenocarcinoma harbouring EGFR exon 21 L858R.	('lung adenocarcinoma', 'Disease', (73, 92))	('EGFR', 'Gene', (104, 108))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (73, 92))	('L858R', 'Var', (117, 122))	('man', 'Species', '9606', (34, 37))	('L858R', 'Mutation', 'rs121434568', (117, 122))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (73, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))	('EGFR', 'Gene', '1956', (104, 108))
347288	31956415	NGS analysis showed EGFR T790M and genomic alterations in PTEN, SMARCB1, TP53, and KIT.	('T790M', 'Var', (25, 30))	('PTEN', 'Gene', '5728', (58, 62))	('TP53', 'Gene', '7157', (73, 77))	('EGFR', 'Gene', (20, 24))	('KIT', 'Gene', (83, 86))	('TP53', 'Gene', (73, 77))	('SMARCB1', 'Gene', '6598', (64, 71))	('SMARCB1', 'Gene', (64, 71))	('T790M', 'Mutation', 'rs121434569', (25, 30))	('EGFR', 'Gene', '1956', (20, 24))	('KIT', 'Gene', '3815', (83, 86))	('PTEN', 'Gene', (58, 62))
347289	31956415	Both patients had PTEN genomic alterations and the PI3K/AKT/mTOR (mammalian target of rapamycin) pathway might play an important role in squamous cell transformation.	('AKT', 'Gene', '207', (56, 59))	('PTEN', 'Gene', (18, 22))	('squamous cell transformation', 'Disease', (137, 165))	('patients', 'Species', '9606', (5, 13))	('PTEN', 'Gene', '5728', (18, 22))	('genomic', 'Var', (23, 30))	('AKT', 'Gene', (56, 59))	('mTOR', 'Gene', '2475', (60, 64))	('mTOR', 'Gene', (60, 64))	('mammalian target of rapamycin', 'Gene', '2475', (66, 95))	('mammalian target of rapamycin', 'Gene', (66, 95))
347292	31956415	Chemotherapy-naive patients with epidermal growth factor receptor (EGFR) mutations show a high response rate of 60-70% to first- and second-generation EGFR-tyrosine kinase inhibitors (TKIs) 1.	('tyrosine', 'Chemical', 'None', (156, 164))	('epidermal growth factor receptor', 'Gene', '1956', (33, 65))	('EGFR', 'Gene', '1956', (151, 155))	('EGFR', 'Gene', (151, 155))	('patients', 'Species', '9606', (19, 27))	('EGFR', 'Gene', '1956', (67, 71))	('EGFR', 'Gene', (67, 71))	('mutations', 'Var', (73, 82))	('epidermal growth factor receptor', 'Gene', (33, 65))
347294	31956415	The most common mechanism of resistance to first- and second-generation EGFR-TKIs is the T790M mutation, accounting for 60% of patients 2, 3.	('EGFR', 'Gene', '1956', (72, 76))	('T790M', 'Mutation', 'rs121434569', (89, 94))	('EGFR', 'Gene', (72, 76))	('patients', 'Species', '9606', (127, 135))	('T790M', 'Var', (89, 94))
347295	31956415	EGFR and mesenchymal-epithelial transition proto-oncogene amplifications and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha gene (PIK3CA) mutations have also been reported as molecular resistance mechanisms 2.	('mutations', 'Var', (162, 171))	('PIK3CA', 'Gene', (154, 160))	('EGFR', 'Gene', (0, 4))	('phosphatidylinositol-4,5-bisphosphate', 'Chemical', 'MESH:C106336', (77, 114))	('PIK3CA', 'Gene', '5290', (154, 160))	('EGFR', 'Gene', '1956', (0, 4))
347307	31956415	Next-generation sequencing (NGS) analysis of the specimen with Ion AmpliSeq Cancer Hotspot Panel version 2 (Thermo Fisher Scientific, USA) showed EGFR c.2369C>T (p.T790M), PTEN c.963 del (p.N323Mfs*21), c.964_964 delA (p.N323Mfs*21), c.968 del (p.N323Mfs*21), PDGFRA c.2472C>T (p.V824V), and HRAS c.81T>C (p.H27H).	('HRAS', 'Gene', '3265', (292, 296))	('p.N323Mfs*21', 'Mutation', 'rs121913291', (245, 257))	('c.2369C>T', 'Var', (151, 160))	('p.N323Mfs*21', 'Mutation', 'rs121913291', (188, 200))	('Ion AmpliSeq Cancer', 'Disease', 'MESH:D009369', (63, 82))	('p.V824V', 'Mutation', 'rs2228230', (278, 285))	('Ion AmpliSeq Cancer', 'Disease', (63, 82))	('c.81T>C', 'Mutation', 'rs12628', (297, 304))	('EGFR', 'Gene', (146, 150))	('HRAS', 'Gene', (292, 296))	('p.H27H', 'Mutation', 'rs12628', (306, 312))	('PDGFRA', 'Gene', (260, 266))	('PDGFRA', 'Gene', '5156', (260, 266))	('PTEN', 'Gene', (172, 176))	('c.968 del', 'Mutation', 'rs121913291', (234, 243))	('c.2369C>T', 'Mutation', 'rs121434569', (151, 160))	('c.968 del (p.N323Mfs*21', 'Var', (234, 257))	('p.N323Mfs*21', 'Mutation', 'rs121913291', (219, 231))	('p.T790M', 'SUBSTITUTION', 'None', (162, 169))	('PTEN', 'Gene', '5728', (172, 176))	('EGFR', 'Gene', '1956', (146, 150))	('c.963 del', 'Mutation', 'c.963del', (177, 186))	('p.T790M', 'Var', (162, 169))	('c.2472C>T', 'Mutation', 'rs2228230', (267, 276))	('c.964_964 delA', 'Var', (203, 217))	('c.964_964 delA', 'Mutation', 'c.964_964delA', (203, 217))	('Cancer', 'Phenotype', 'HP:0002664', (76, 82))
347316	31956415	2A-2C) harbouring EGFR exon 21 L858R without T790M mutation.	('EGFR', 'Gene', '1956', (18, 22))	('L858R', 'Var', (31, 36))	('EGFR', 'Gene', (18, 22))	('L858R', 'Mutation', 'rs121434568', (31, 36))	('T790M', 'Mutation', 'rs121434569', (45, 50))
347319	31956415	NGS analysis of the specimen using Ion AmpliSeq Cancer Hotspot Panel showed EGFR c.2573T>G (p.L858R), c.2369C>T (p.T790M), PTEN c.963 del (p.N323Mfs*21), c.964_964 delA (p.N323Mfs*21), c.968 del (p.N323Mfs*21), SMARCB1 c.1119-41G>A (unknown), TP53 c.892G>T (p.E298*), and KIT c.1621A>C (p.M541L).	('p.M541L', 'Mutation', 'rs3822214', (287, 294))	('p.L858R', 'Var', (92, 99))	('SMARCB1', 'Gene', '6598', (211, 218))	('p.N323Mfs*21', 'Mutation', 'rs121913291', (196, 208))	('SMARCB1', 'Gene', (211, 218))	('c.964_964 delA', 'Mutation', 'c.964_964delA', (154, 168))	('c.1119-41G>A', 'Mutation', 'rs5030613', (219, 231))	('EGFR', 'Gene', (76, 80))	('PTEN', 'Gene', (123, 127))	('TP53', 'Gene', (243, 247))	('c.2369C>T', 'Mutation', 'rs121434569', (102, 111))	('p.N323Mfs*21', 'Var', (170, 182))	('Cancer', 'Phenotype', 'HP:0002664', (48, 54))	('c.964_964 delA (p.N323Mfs*21', 'Var', (154, 182))	('PTEN', 'Gene', '5728', (123, 127))	('p.N323Mfs*21', 'Mutation', 'rs121913291', (170, 182))	('KIT', 'Gene', (272, 275))	('p.N323Mfs*21', 'Mutation', 'rs121913291', (139, 151))	('c.1119-41G>A', 'Var', (219, 231))	('Ion AmpliSeq Cancer', 'Disease', 'MESH:D009369', (35, 54))	('p.T790M', 'SUBSTITUTION', 'None', (113, 120))	('c.968 del', 'Mutation', 'rs121913291', (185, 194))	('EGFR', 'Gene', '1956', (76, 80))	('c.892G>T', 'Var', (248, 256))	('p.E298*', 'Mutation', 'rs201744589', (258, 265))	('c.968 del (p.N323Mfs*21', 'Var', (185, 208))	('Ion AmpliSeq Cancer', 'Disease', (35, 54))	('TP53', 'Gene', '7157', (243, 247))	('c.892G>T', 'Mutation', 'rs201744589', (248, 256))	('c.963 del', 'Mutation', 'c.963del', (128, 137))	('p.T790M', 'Var', (113, 120))	('c.1621A>C', 'Mutation', 'rs3822214', (276, 285))	('c.2573T>G', 'Var', (81, 90))	('c.2369C>T', 'Var', (102, 111))	('KIT', 'Gene', '3815', (272, 275))	('p.L858R', 'SUBSTITUTION', 'None', (92, 99))	('c.2573T>G', 'Mutation', 'rs121434568', (81, 90))
347327	31956415	12 performed a pooled analysis of 17 patients and showed that most of these patients were smokers and harboured original EGFR mutations.	('patients', 'Species', '9606', (76, 84))	('EGFR', 'Gene', '1956', (121, 125))	('patients', 'Species', '9606', (37, 45))	('EGFR', 'Gene', (121, 125))	('mutations', 'Var', (126, 135))
347328	31956415	In addition to squamous cell transformation, they observed coexisting EGFR T790M mutation in approximately half of the patients.	('T790M', 'Mutation', 'rs121434569', (75, 80))	('EGFR', 'Gene', '1956', (70, 74))	('patients', 'Species', '9606', (119, 127))	('T790M', 'Var', (75, 80))	('EGFR', 'Gene', (70, 74))	('squamous', 'Disease', (15, 23))
347329	31956415	In our two patients, osimertinib was administered because of the coexisting EGFR T790M mutation in specimens after erlotinib therapy.	('T790M', 'Mutation', 'rs121434569', (81, 86))	('erlotinib', 'Chemical', 'MESH:C400278', (115, 124))	('EGFR', 'Gene', '1956', (76, 80))	('T790M', 'Var', (81, 86))	('EGFR', 'Gene', (76, 80))	('osimertinib', 'Chemical', 'None', (21, 32))	('patients', 'Species', '9606', (11, 19))
347330	31956415	However, we achieved control of the lung cancer with squamous cell transformation and EGFR T790M by osimertinib for only three months in both patients.	('lung cancer', 'Disease', (36, 47))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('T790M', 'Mutation', 'rs121434569', (91, 96))	('EGFR', 'Gene', '1956', (86, 90))	('lung cancer', 'Disease', 'MESH:D008175', (36, 47))	('squamous cell transformation', 'CPA', (53, 81))	('T790M', 'Var', (91, 96))	('EGFR', 'Gene', (86, 90))	('lung cancer', 'Phenotype', 'HP:0100526', (36, 47))	('osimertinib', 'Chemical', 'None', (100, 111))	('patients', 'Species', '9606', (142, 150))
347331	31956415	AURA3 was a phase 3 study comparing osimertinib and platinum-pemetrexed in patients with EGFR T790M-positive non-small cell lung cancer after erlotinib therapy or gefitinib therapy.	('T790M', 'Mutation', 'rs121434569', (94, 99))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (109, 135))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('platinum', 'Chemical', 'MESH:D010984', (52, 60))	('EGFR', 'Gene', (89, 93))	('osimertinib', 'Chemical', 'None', (36, 47))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (109, 135))	('erlotinib', 'Chemical', 'MESH:C400278', (142, 151))	('patients', 'Species', '9606', (75, 83))	('gefitinib', 'Chemical', 'MESH:C419708', (163, 172))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (113, 135))	('non-small cell lung cancer', 'Disease', (109, 135))	('T790M-positive', 'Var', (94, 108))	('lung cancer', 'Phenotype', 'HP:0100526', (124, 135))	('EGFR', 'Gene', '1956', (89, 93))
347334	31956415	This was better than the PFS of three months in our patients with squamous cell transformation and EGFR T790M mutation.	('EGFR', 'Gene', (99, 103))	('T790M', 'Var', (104, 109))	('EGFR', 'Gene', '1956', (99, 103))	('T790M', 'Mutation', 'rs121434569', (104, 109))	('patients', 'Species', '9606', (52, 60))
347335	31956415	Thus, the prognosis of lung cancer patients with squamous cell transformation and EGFR T790M mutation appears to be worse than that of patients with only EGFR T790M mutation.	('EGFR', 'Gene', (154, 158))	('EGFR', 'Gene', (82, 86))	('squamous cell transformation', 'CPA', (49, 77))	('lung cancer', 'Disease', (23, 34))	('patients', 'Species', '9606', (135, 143))	('lung cancer', 'Phenotype', 'HP:0100526', (23, 34))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('T790M mutation', 'Var', (87, 101))	('lung cancer', 'Disease', 'MESH:D008175', (23, 34))	('T790M', 'Mutation', 'rs121434569', (87, 92))	('patients', 'Species', '9606', (35, 43))	('EGFR', 'Gene', '1956', (82, 86))	('T790M', 'Mutation', 'rs121434569', (159, 164))	('EGFR', 'Gene', '1956', (154, 158))
347337	31956415	In a study of surgically resected specimens, PTEN mutations were more often identified in ex-smokers and in squamous cell carcinomas than in adenocarcinomas 14.	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (108, 131))	('identified', 'Reg', (76, 86))	('mutations', 'Var', (50, 59))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (108, 132))	('adenocarcinomas', 'Disease', 'MESH:D000230', (141, 156))	('carcinomas', 'Phenotype', 'HP:0030731', (146, 156))	('adenocarcinomas', 'Disease', (141, 156))	('squamous cell carcinomas', 'Disease', (108, 132))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (108, 132))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('carcinomas', 'Phenotype', 'HP:0030731', (122, 132))	('PTEN', 'Gene', (45, 49))	('PTEN', 'Gene', '5728', (45, 49))
347340	31956415	15 hypothesized that the PI3K/AKT/mTOR pathway was activated by EGFR-TKIs and loss of PTEN, which facilitates cell proliferation and resulted in squamous cell transformation.	('mTOR', 'Gene', '2475', (34, 38))	('facilitates', 'PosReg', (98, 109))	('PTEN', 'Gene', (86, 90))	('squamous cell transformation', 'CPA', (145, 173))	('PTEN', 'Gene', '5728', (86, 90))	('resulted in', 'Reg', (133, 144))	('AKT', 'Gene', '207', (30, 33))	('cell proliferation', 'CPA', (110, 128))	('loss', 'Var', (78, 82))	('EGFR', 'Gene', (64, 68))	('AKT', 'Gene', (30, 33))	('EGFR', 'Gene', '1956', (64, 68))	('activated', 'PosReg', (51, 60))	('mTOR', 'Gene', (34, 38))
347346	31956415	In summary, we encountered two cases of EGFR mutation in lung adenocarcinoma with pathological transformation to squamous cell carcinoma.	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (57, 76))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (57, 76))	('lung adenocarcinoma', 'Disease', (57, 76))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (113, 136))	('EGFR', 'Gene', '1956', (40, 44))	('mutation', 'Var', (45, 53))	('EGFR', 'Gene', (40, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (113, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('squamous cell carcinoma', 'Disease', (113, 136))
347360	31190998	Patients with high CD8+ or Foxp3+ cell infiltration had better clinical outcomes.	('Foxp3+', 'Var', (27, 33))	('CD8', 'Gene', (19, 22))	('CD8', 'Gene', '925', (19, 22))	('Patients', 'Species', '9606', (0, 8))
347376	31190998	High p16 expression has been found to be associated with better prognosis of head and neck cancer, especially in oropharyngeal squamous cell carcinoma (OPSCC).	('neck cancer', 'Disease', (86, 97))	('head and neck cancer', 'Phenotype', 'HP:0012288', (77, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('p16', 'Gene', (5, 8))	('High', 'Var', (0, 4))	('OPSCC', 'Phenotype', 'HP:0012182', (152, 157))	('oropharyngeal squamous cell carcinoma', 'Phenotype', 'HP:0012182', (113, 150))	('expression', 'MPA', (9, 19))	('p16', 'Gene', '1029', (5, 8))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (127, 150))	('squamous cell carcinoma', 'Disease', (127, 150))	('neck cancer', 'Disease', 'MESH:D006258', (86, 97))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (127, 150))
347388	31190998	The primary antibodies used were as follows: anti-PD-L1 (rabbit mAb, 13684, CST, Danvers, MA,, USA, 1:200), anti-Foxp3 (rabbit mAb, 98377, CST, Danvers, MA, USA, 1:200), anti-CD8 (rabbit mAb, ab93278, Abcam, Cambridge, UK, 1:500), and anti-p16 (rabbit mAb, ab108349, Abcam, Cambridge, UK, 1:100).	('p16', 'Gene', '1029', (240, 243))	('rabbit', 'Species', '9986', (180, 186))	('CD8', 'Gene', (175, 178))	('anti-Foxp3', 'Var', (108, 118))	('PD-L1', 'Gene', (50, 55))	('rabbit', 'Species', '9986', (57, 63))	('rabbit', 'Species', '9986', (245, 251))	('CD8', 'Gene', '925', (175, 178))	('p16', 'Gene', (240, 243))	('PD-L1', 'Gene', '29126', (50, 55))	('rabbit', 'Species', '9986', (120, 126))
347407	31190998	The membranous PD-L1 staining on tumor cells was scored using the following cutoff values: >1% staining, found in 48 patients (50%); >5% staining, found in 29 (30.2%); and >50% staining, found in 16 (16.7%) patients.	('patients', 'Species', '9606', (207, 215))	('>1%', 'Var', (91, 94))	('PD-L1', 'Gene', (15, 20))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('PD-L1', 'Gene', '29126', (15, 20))	('>5%', 'Var', (133, 136))	('tumor', 'Disease', (33, 38))	('patients', 'Species', '9606', (117, 125))
347437	31190998	Other studies have demonstrated an association between high PD-L1 expression and lymph node metastasis in head and neck cancers.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('head and neck cancer', 'Phenotype', 'HP:0012288', (106, 126))	('head and neck cancers', 'Phenotype', 'HP:0012288', (106, 127))	('PD-L1', 'Gene', (60, 65))	('cancers', 'Phenotype', 'HP:0002664', (120, 127))	('expression', 'MPA', (66, 76))	('neck cancers', 'Disease', (115, 127))	('lymph node metastasis', 'CPA', (81, 102))	('high', 'Var', (55, 59))	('PD-L1', 'Gene', '29126', (60, 65))	('neck cancers', 'Disease', 'MESH:D006258', (115, 127))
347439	31190998	High PD-L1 expression contributes to the process of immune evasion, and it has been found be an indicator of poor survival in many different types of malignancies.	('contributes', 'Reg', (22, 33))	('High', 'Var', (0, 4))	('PD-L1', 'Gene', (5, 10))	('malignancies', 'Disease', (150, 162))	('PD-L1', 'Gene', '29126', (5, 10))	('immune evasion', 'MPA', (52, 66))	('malignancies', 'Disease', 'MESH:D009369', (150, 162))
347442	31190998	In the present study, the PD-L1 positive cohort tended to have better DFS rates (p=0.233).	('PD-L1', 'Gene', (26, 31))	('better', 'PosReg', (63, 69))	('PD-L1', 'Gene', '29126', (26, 31))	('positive', 'Var', (32, 40))	('DFS rates', 'CPA', (70, 79))
347443	31190998	All patients in our study received radiotherapy, and some studies have found that high PD-L1 expression is associated with radiosensitivity.	('PD-L1', 'Gene', '29126', (87, 92))	('high', 'Var', (82, 86))	('associated', 'Reg', (107, 117))	('expression', 'MPA', (93, 103))	('patients', 'Species', '9606', (4, 12))	('PD-L1', 'Gene', (87, 92))	('radiosensitivity', 'Disease', (123, 139))
347447	31190998	CD8+ cytotoxic T-cells and Foxp3+ regulatory T-cells (Tregs) are the most important subsets of TILs.	('Foxp3+', 'Var', (27, 33))	('CD8', 'Gene', '925', (0, 3))	('CD8', 'Gene', (0, 3))
347451	31190998	The meta-analysis found that high Foxp3+ Treg infiltration predicted worse survival rates in the majority of solid tumors, but better outcomes in colorectal, head and neck, and esophageal cancers.	('high', 'Var', (29, 33))	('solid tumors', 'Disease', (109, 121))	('esophageal cancers', 'Disease', 'MESH:D004938', (177, 195))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('colorectal', 'Disease', (146, 156))	('worse', 'NegReg', (69, 74))	('solid tumors', 'Disease', 'MESH:D009369', (109, 121))	('cancers', 'Phenotype', 'HP:0002664', (188, 195))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('survival', 'MPA', (75, 83))	('esophageal cancers', 'Disease', (177, 195))	('Foxp3+', 'Protein', (34, 40))
347455	31190998	Thus, the positive correlation between CD8+ and Foxp3+ cells suggested that deletion of Foxp3+ regulatory T-cells could be an effective immunotherapy strategy for SNSCC.	('deletion', 'Var', (76, 84))	('CD8', 'Gene', (39, 42))	('CD8', 'Gene', '925', (39, 42))	('Foxp3+', 'Gene', (88, 94))	('SNSCC', 'Phenotype', 'HP:0012182', (163, 168))	('SNSCC', 'Disease', (163, 168))
347460	31190998	Chen et al found that p16 positive was associated with high PD-L1 expression in nonoropharyngeal HNSCC.	('HNSCC', 'Phenotype', 'HP:0012288', (97, 102))	('p16', 'Gene', '1029', (22, 25))	('PD-L1', 'Gene', (60, 65))	('expression', 'MPA', (66, 76))	('nonoropharyngeal HNSCC', 'Disease', (80, 102))	('high', 'Var', (55, 59))	('PD-L1', 'Gene', '29126', (60, 65))	('p16', 'Gene', (22, 25))
347479	31190998	In particular, high CD8 infiltration is a favorable independent prognostic indicator of SNSCC.	('high', 'Var', (15, 19))	('SNSCC', 'Phenotype', 'HP:0012182', (88, 93))	('CD8', 'Gene', (20, 23))	('CD8', 'Gene', '925', (20, 23))	('SNSCC', 'Disease', (88, 93))
347493	31032351	These two series, GSE59652 and GSE89657, included 7 HNSCC tissues and 7 normal tissues, and 6 HNSCC tissues and 6 normal tissues, respectively.	('GSE59652', 'Var', (18, 26))	('HNSCC', 'Phenotype', 'HP:0012288', (52, 57))	('HNSCC', 'Phenotype', 'HP:0012288', (94, 99))	('6 HNSCC', 'CellLine', 'CVCL:L181', (92, 99))	('GSE89657', 'Var', (31, 39))
347503	31032351	As a result, HOXA13, HOXA11, and HOXA10 were shown to significantly correlate with HOTTIP (r=0.719,0.484 and 0.507, respectively; P<0.05).	('HOXA13', 'Gene', (13, 19))	('HOXA11', 'Gene', (21, 27))	('HOXA13', 'Gene', '3209', (13, 19))	('correlate', 'Reg', (68, 77))	('HOTTIP', 'Disease', (83, 89))	('HOXA10', 'Var', (33, 39))	('HOXA11', 'Gene', '3207', (21, 27))
347509	31032351	Aberrant expression of HOTTIP has been validated in various malignancies, including hepatocellular carcinoma, colorectal cancer, and gastric cancer.	('Aberrant expression', 'Var', (0, 19))	('gastric cancer', 'Phenotype', 'HP:0012126', (133, 147))	('colorectal cancer', 'Disease', 'MESH:D015179', (110, 127))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (84, 108))	('colorectal cancer', 'Phenotype', 'HP:0003003', (110, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('hepatocellular carcinoma', 'Disease', (84, 108))	('gastric cancer', 'Disease', (133, 147))	('gastric cancer', 'Disease', 'MESH:D013274', (133, 147))	('colorectal cancer', 'Disease', (110, 127))	('HOTTIP', 'Gene', (23, 29))
347564	29926751	IHC evaluation with P53, Ki-67, and P16 staining showed that all of the USCC were positive for P53 and Ki-67, and P16 were positive in four cases of HPV associated USCC and negative in 14 cases of HPV independent USCC (Table 1).	('positive', 'Reg', (123, 131))	('SCC', 'Gene', (165, 168))	('positive', 'Reg', (82, 90))	('Ki-67', 'Var', (103, 108))	('P53', 'Gene', '7157', (95, 98))	('SCC', 'Gene', '6317', (73, 76))	('P16', 'Gene', '1029', (36, 39))	('SCC', 'Gene', (73, 76))	('P53', 'Gene', (20, 23))	('P16', 'Gene', '1029', (114, 117))	('P16', 'Gene', (36, 39))	('SCC', 'Gene', '6317', (214, 217))	('HPV', 'Species', '10566', (149, 152))	('HPV', 'Species', '10566', (197, 200))	('P16', 'Gene', (114, 117))	('SCC', 'Gene', '6317', (165, 168))	('HPV', 'Disease', (149, 152))	('P53', 'Gene', '7157', (20, 23))	('SCC', 'Gene', (214, 217))	('P53', 'Gene', (95, 98))
347601	29926751	A retrospective series found no evidence of local recurrence, even with <5-mm resection margins (median follow-up: 17-37 months), in men with pT1-3 N0-2 anterior UC treated with well-defined penis-preserving surgery and additional iliac/inguinal lymphadenectomy for clinically suspected lymph node disease.	('lymph node disease', 'Phenotype', 'HP:0002733', (287, 305))	('pT1-3', 'Var', (142, 147))	('lymph node disease', 'Disease', 'MESH:D000072717', (287, 305))	('men', 'Species', '9606', (133, 136))	('lymph node disease', 'Disease', (287, 305))
347625	28780673	This suggests a role of gene expression regulators in the shared genetic etiology between AD and cancer, and that some shared variants modulate disease risk concordantly while others have effects in opposite directions.	('modulate', 'Reg', (135, 143))	('variants', 'Var', (126, 134))	('cancer', 'Disease', (97, 103))	('cancer', 'Disease', 'MESH:D009369', (97, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('disease', 'Disease', (144, 151))	('AD', 'Disease', 'MESH:D000544', (90, 92))	('AD', 'Disease', (90, 92))
347657	28780673	These annotations included repressed region, introns, transcribed region, super enhancers, DNase I hypersensitivity sites (DHSs), and histone marks H3K27ac, H3K4me1, and H3K4me3.	('H3K4me3', 'Var', (170, 177))	('DHSs', 'Disease', (123, 127))	('H3K27ac', 'Var', (148, 155))	('hypersensitivity', 'Disease', (99, 115))	('hypersensitivity', 'Disease', 'MESH:D004342', (99, 115))	('DHSs', 'Disease', 'None', (123, 127))	('H3K4me1', 'Var', (157, 164))
347663	28780673	To search for SNPs of a possible CP effect on AD and one or more cancer types, we also conducted individual SNP meta-analysis using Cross-Phenotype Meta-Analysis (CPMA) to explore if there is any SNP associated with some of the cancer types in addition to its correlation with AD.	('SNP', 'Var', (196, 199))	('AD', 'Disease', 'MESH:D000544', (46, 48))	('cancer', 'Disease', (228, 234))	('AD', 'Disease', (46, 48))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('AD', 'Disease', 'MESH:D000544', (277, 279))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('AD', 'Disease', (277, 279))	('associated', 'Reg', (200, 210))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (228, 234))
347668	28780673	This implied that the two traits:AD and breast cancer, or AD and lung cancer:may share some common genetic background across the genome and the shared gene variants modulate the diseases risk in the same direction.	('AD', 'Disease', 'MESH:D000544', (33, 35))	('breast cancer', 'Disease', 'MESH:D001943', (40, 53))	('AD', 'Disease', (33, 35))	('lung cancer', 'Disease', 'MESH:D008175', (65, 76))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('breast cancer', 'Disease', (40, 53))	('breast cancer', 'Phenotype', 'HP:0003002', (40, 53))	('lung cancer', 'Disease', (65, 76))	('variants', 'Var', (156, 164))	('lung cancer', 'Phenotype', 'HP:0100526', (65, 76))	('AD', 'Disease', 'MESH:D000544', (58, 60))	('modulate', 'Reg', (165, 173))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('AD', 'Disease', (58, 60))
347677	28780673	Effect sizes of genetic variants in the repressed and the H3K4me3 annotations were negatively correlated between AD and breast cancer, lung cancer or the "any cancer" category, whereas positive genetic correlations were observed in the other six annotations.	('breast cancer', 'Disease', (120, 133))	('breast cancer', 'Disease', 'MESH:D001943', (120, 133))	('AD', 'Disease', 'MESH:D000544', (113, 115))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('lung cancer', 'Disease', (135, 146))	('cancer', 'Disease', (159, 165))	('negatively', 'NegReg', (83, 93))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('correlated', 'Interaction', (94, 104))	('cancer', 'Disease', (127, 133))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('variants', 'Var', (24, 32))	('cancer', 'Disease', (140, 146))	('lung cancer', 'Disease', 'MESH:D008175', (135, 146))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('lung cancer', 'Phenotype', 'HP:0100526', (135, 146))	('breast cancer', 'Phenotype', 'HP:0003002', (120, 133))	('AD', 'Disease', (113, 115))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('H3K4me3', 'Protein', (58, 65))
347679	28780673	Examining across all functional categories, three regions that represent active enhancer marks on the genome, including super enhancers, H3K27ac, and H3K4me1, all showed stronger and positive AD-cancer genetic correlations.	('H3K27ac', 'Var', (137, 144))	('AD-cancer', 'Disease', 'MESH:D000544', (192, 201))	('H3K4me1', 'Var', (150, 157))	('AD-cancer', 'Disease', (192, 201))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
347686	28780673	While for lung cancer there were two candidate SNPs that survived the correction: rs56117933 at chr15:78,832,349 (unadjusted SNP-lung cancer p-value = 4.1*10-20, corrected p-value = 6.7*10-17; AD z-score = -3.34, lung cancer z-score = 9.19), in close proximity to the PSMA4 gene encoding for proteasome subunit alpha 4, whose polymorphisms have been related to lung cancer susceptibility from published GWAS, and rs11249708 at chr5: 179821728 (unadjusted SNP-lung cancer p-value = 1.5*10-5, corrected p-value = 0.025; AD z-score = -3.43, lung cancer z-score = 4.33), for which no previous genome-wise associations have been reported.	('AD', 'Disease', 'MESH:D000544', (193, 195))	('SNP-lung cancer', 'Disease', (455, 470))	('lung cancer', 'Disease', 'MESH:D008175', (361, 372))	('lung cancer', 'Disease', (213, 224))	('cancer', 'Phenotype', 'HP:0002664', (464, 470))	('AD', 'Disease', 'MESH:D000544', (518, 520))	('lung cancer', 'Disease', 'MESH:D008175', (129, 140))	('cancer', 'Phenotype', 'HP:0002664', (366, 372))	('lung cancer', 'Disease', 'MESH:D008175', (10, 21))	('rs11249708', 'Mutation', 'rs11249708', (413, 423))	('lung cancer', 'Phenotype', 'HP:0100526', (361, 372))	('lung cancer', 'Disease', (538, 549))	('lung cancer', 'Phenotype', 'HP:0100526', (129, 140))	('rs56117933', 'Mutation', 'rs56117933', (82, 92))	('SNP-lung cancer', 'Disease', 'MESH:D008175', (455, 470))	('lung cancer', 'Phenotype', 'HP:0100526', (10, 21))	('lung cancer', 'Disease', 'MESH:D008175', (213, 224))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('SNP-lung cancer', 'Disease', (125, 140))	('lung cancer', 'Phenotype', 'HP:0100526', (213, 224))	('PSMA4', 'Gene', '5685', (268, 273))	('proteasome subunit alpha 4', 'Gene', (292, 318))	('rs11249708', 'Var', (413, 423))	('lung cancer', 'Disease', 'MESH:D008175', (459, 470))	('lung cancer', 'Disease', 'MESH:D008175', (538, 549))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('lung cancer', 'Disease', (361, 372))	('SNP-lung cancer', 'Disease', 'MESH:D008175', (125, 140))	('lung cancer', 'Phenotype', 'HP:0100526', (459, 470))	('rs56117933', 'Var', (82, 92))	('AD', 'Disease', (193, 195))	('AD', 'Disease', (518, 520))	('lung cancer', 'Disease', (10, 21))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('PSMA4', 'Gene', (268, 273))	('proteasome subunit alpha 4', 'Gene', '5685', (292, 318))
347688	28780673	This top SNP rs56117933 (CPMA p-value < 2.2*10-16; AD z-score = -3.34, breast cancer z-score = -0.59, lung cancer z-score = 9.19) was the same as discovered just previously, which had a highly significant association with lung cancer (p-value = 4.1*10-20) but a much larger p-value with breast cancer (>0.05).	('breast cancer', 'Phenotype', 'HP:0003002', (71, 84))	('breast cancer', 'Disease', 'MESH:D001943', (71, 84))	('breast cancer', 'Disease', (71, 84))	('lung cancer', 'Disease', (222, 233))	('rs56117933', 'Var', (13, 23))	('lung cancer', 'Disease', (102, 113))	('cancer', 'Phenotype', 'HP:0002664', (294, 300))	('lung cancer', 'Disease', 'MESH:D008175', (102, 113))	('lung cancer', 'Disease', 'MESH:D008175', (222, 233))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('AD', 'Disease', (51, 53))	('breast cancer', 'Phenotype', 'HP:0003002', (287, 300))	('lung cancer', 'Phenotype', 'HP:0100526', (102, 113))	('rs56117933', 'Mutation', 'rs56117933', (13, 23))	('lung cancer', 'Phenotype', 'HP:0100526', (222, 233))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('AD', 'Disease', 'MESH:D000544', (51, 53))	('breast cancer', 'Disease', 'MESH:D001943', (287, 300))	('breast cancer', 'Disease', (287, 300))
347692	28780673	For example, SNP rs17466060 appeared to increase AD risk (z-score = 4.60) but decrease the risk of both breast cancer (z-score = -2.39) and lung cancer (z-score = -3.45).	('AD', 'Disease', (49, 51))	('lung cancer', 'Disease', (140, 151))	('lung cancer', 'Phenotype', 'HP:0100526', (140, 151))	('decrease', 'NegReg', (78, 86))	('rs17466060', 'Mutation', 'rs17466060', (17, 27))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('increase', 'PosReg', (40, 48))	('breast cancer', 'Disease', 'MESH:D001943', (104, 117))	('SNP rs17466060', 'Var', (13, 27))	('breast cancer', 'Disease', (104, 117))	('lung cancer', 'Disease', 'MESH:D008175', (140, 151))	('breast cancer', 'Phenotype', 'HP:0003002', (104, 117))	('AD', 'Disease', 'MESH:D000544', (49, 51))
347693	28780673	No significant eQTLs were found for the 11 SNPs in the most relevant tissues (brain or tumor) from the GTEx project, nor did they correspond to genetic variants on the previously reported candidate genes encoding p53, Pin1, or those involving in the Wnt pathway.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('Pin1', 'Gene', '5300', (218, 222))	('tumor', 'Disease', (87, 92))	('variants', 'Var', (152, 160))	('Wnt', 'Pathway', (250, 253))	('p53', 'Gene', (213, 216))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('p53', 'Gene', '7157', (213, 216))	('Pin1', 'Gene', (218, 222))
347733	33363036	A comparable prevalence of FGFR1 amplifications was identified between KSCC and NKSCC (11.4 versus 26.9%, p = 0.007).	('FGFR1', 'Gene', (27, 32))	('KSCC', 'Chemical', '-', (71, 75))	('amplifications', 'Var', (33, 47))	('KSCC', 'Chemical', '-', (81, 85))	('NKSCC', 'Disease', (80, 85))	('FGFR1', 'Gene', '2260', (27, 32))	('KSCC', 'Disease', (71, 75))
347734	33363036	Compared with NKSCC, IGF1R amplifications were more frequent in BSCC (0 versus 15.4%, p = 0.019).	('BSCC', 'Disease', (64, 68))	('KSCC', 'Chemical', '-', (15, 19))	('amplifications', 'Var', (27, 41))	('BSCC', 'Phenotype', 'HP:0002671', (64, 68))	('IGF1R', 'Gene', (21, 26))	('frequent', 'Reg', (52, 60))	('IGF1R', 'Gene', '3480', (21, 26))
347735	33363036	We found cases with TP53 alterations had less EGFR alterations in KSCC (P = 0.013, OR = 0.158).	('alterations', 'Var', (25, 36))	('KSCC', 'Chemical', '-', (66, 70))	('TP53', 'Gene', (20, 24))	('EGFR', 'Gene', '1956', (46, 50))	('KSCC', 'Disease', (66, 70))	('EGFR', 'Gene', (46, 50))	('less', 'NegReg', (41, 45))	('TP53', 'Gene', '7157', (20, 24))
347736	33363036	We found that STK 11 alterations and TOP2A alterations were significantly associated with higher risk of recurrence in patients with LUSC.	('TOP2A', 'Gene', '7153', (37, 42))	('patients', 'Species', '9606', (119, 127))	('STK 11', 'Gene', '6794', (14, 20))	('STK 11', 'Gene', (14, 20))	('alterations', 'Var', (43, 54))	('LUSC', 'Disease', (133, 137))	('TOP2A', 'Gene', (37, 42))	('LUSC', 'Phenotype', 'HP:0030359', (133, 137))	('alterations', 'Var', (21, 32))	('associated', 'Reg', (74, 84))
347740	33363036	With the emergence and progress of molecular targeted therapies, the objective response rates (ORRs) and progression-free survival (PFS) of NSCLC patients treated with gene-directed therapies have been improved compared with traditional cytotoxic chemotherapy.	('improved', 'PosReg', (202, 210))	('NSCLC', 'Disease', 'MESH:D002289', (140, 145))	('gene-directed therapies', 'Var', (168, 191))	('NSCLC', 'Phenotype', 'HP:0030358', (140, 145))	('objective response rates', 'CPA', (69, 93))	('progression-free survival', 'CPA', (105, 130))	('patients', 'Species', '9606', (146, 154))	('NSCLC', 'Disease', (140, 145))
347760	33363036	The comprehensive genetic spectra of patients with LUSC showed that the overwhelming majority of them (99.5%) harbored genetic abnormalities including somatic mutations or copy number alterations (CNAs).	('LUSC', 'Phenotype', 'HP:0030359', (51, 55))	('genetic abnormalities', 'Disease', (119, 140))	('patients', 'Species', '9606', (37, 45))	('copy number alterations', 'Var', (172, 195))	('harbored', 'Reg', (110, 118))	('genetic abnormalities', 'Disease', 'MESH:D030342', (119, 140))
347761	33363036	91% of patients harbored TP53 alterations, among which all BSCC patients harbored TP53 alterations.	('TP53', 'Gene', (82, 86))	('harbored', 'Reg', (16, 24))	('TP53', 'Gene', (25, 29))	('patients', 'Species', '9606', (64, 72))	('alterations', 'Var', (87, 98))	('alterations', 'Var', (30, 41))	('harbored', 'Reg', (73, 81))	('TP53', 'Gene', '7157', (82, 86))	('TP53', 'Gene', '7157', (25, 29))	('patients', 'Species', '9606', (7, 15))	('BSCC', 'Phenotype', 'HP:0002671', (59, 63))
347762	33363036	Second to TP53, 36% of patients harbored PIK3CA alterations and 26% harbored CDKN2A alterations ( Figure 1 ).	('TP53', 'Gene', (10, 14))	('alterations', 'Var', (48, 59))	('CDKN2A', 'Gene', (77, 83))	('patients', 'Species', '9606', (23, 31))	('PIK3CA', 'Gene', (41, 47))	('alterations', 'Reg', (84, 95))	('CDKN2A', 'Gene', '1029', (77, 83))	('PIK3CA', 'Gene', '5290', (41, 47))	('harbored', 'Reg', (32, 40))	('TP53', 'Gene', '7157', (10, 14))
347763	33363036	FGFR alterations were more common in patients diagnosed with stage II, compared with stage I and stage III/IV (5.4% in stage II, 0% in stage I, 0% in III/IV, p = 0.038).	('FGFR', 'Gene', (0, 4))	('alterations', 'Var', (5, 16))	('patients', 'Species', '9606', (37, 45))	('common', 'Reg', (27, 33))
347765	33363036	Contrast to non-smoker, TP53 mutations were more frequent in smoker (77.5 vs 95.1%, p = 0.001).	('TP53', 'Gene', (24, 28))	('mutations', 'Var', (29, 38))	('TP53', 'Gene', '7157', (24, 28))
347766	33363036	AXL mutations occurred more frequently in younger patients than older patients (6.0 vs 0.6%, p = 0.046).	('occurred', 'Reg', (14, 22))	('patients', 'Species', '9606', (70, 78))	('patients', 'Species', '9606', (50, 58))	('AXL', 'Gene', '558', (0, 3))	('mutations', 'Var', (4, 13))	('AXL', 'Gene', (0, 3))
347771	33363036	All the subtypes presented similarly high proportions of mutations, including TP53 (93.9% in KSCC, 88.5% in NKSCC, 100% in BSCC, p = 0.25), CDKN2A (28.1% in KSCC, 25.6% in NKSCC, 30.8% in BSCC, p = 0.88), and NOTCH1 (15.8% in KSCC, 15.4% in NKSCC, 30.8% in BSCC, p = 0.40).	('BSCC', 'Phenotype', 'HP:0002671', (123, 127))	('KSCC', 'Chemical', '-', (93, 97))	('CDKN2A', 'Gene', (140, 146))	('KSCC', 'Chemical', '-', (242, 246))	('NOTCH1', 'Gene', '4851', (209, 215))	('NOTCH1', 'Gene', (209, 215))	('mutations', 'Var', (57, 66))	('KSCC', 'Chemical', '-', (109, 113))	('KSCC', 'Chemical', '-', (173, 177))	('KSCC', 'Disease', (93, 97))	('TP53', 'Gene', '7157', (78, 82))	('TP53', 'Gene', (78, 82))	('KSCC', 'Chemical', '-', (226, 230))	('KSCC', 'Chemical', '-', (157, 161))	('CDKN2A', 'Gene', '1029', (140, 146))	('BSCC', 'Phenotype', 'HP:0002671', (188, 192))	('BSCC', 'Phenotype', 'HP:0002671', (257, 261))
347772	33363036	However, compared with BSCC (0%), PIK3CA mutations occurred more frequently in KSCC (16.7%) and NKSCC (16.7%) (p = 0.36).	('mutations', 'Var', (41, 50))	('PIK3CA', 'Gene', (34, 40))	('KSCC', 'Chemical', '-', (97, 101))	('KSCC', 'Disease', (79, 83))	('NKSCC', 'Disease', (96, 101))	('PIK3CA', 'Gene', '5290', (34, 40))	('BSCC', 'Phenotype', 'HP:0002671', (23, 27))	('occurred', 'Reg', (51, 59))	('KSCC', 'Chemical', '-', (79, 83))
347775	33363036	PIK3CA amplifications were most prevalent in LUSC (24%), followed by FGFR1 amplifications (17%).	('LUSC', 'Phenotype', 'HP:0030359', (45, 49))	('amplifications', 'Var', (7, 21))	('PIK3CA', 'Gene', (0, 6))	('prevalent', 'Reg', (32, 41))	('FGFR1', 'Gene', (69, 74))	('PIK3CA', 'Gene', '5290', (0, 6))	('FGFR1', 'Gene', '2260', (69, 74))	('LUSC', 'Disease', (45, 49))
347777	33363036	As shown in  Supplemental Tables 2 - 5 , the differences of CNAs in LUSC pathologic subtypes were statistically significant as followed: FGFR1 amplifications (p = 0.015), IGF1R amplifications (p = 0.011).	('amplifications', 'Var', (143, 157))	('IGF1R', 'Gene', (171, 176))	('FGFR1', 'Gene', (137, 142))	('LUSC', 'Disease', (68, 72))	('LUSC', 'Phenotype', 'HP:0030359', (68, 72))	('IGF1R', 'Gene', '3480', (171, 176))	('FGFR1', 'Gene', '2260', (137, 142))	('amplifications', 'Var', (177, 191))
347778	33363036	A comparable prevalence of FGFR1 amplifications was identified between KSCC and NKSCC (11.4 vs 26.9%, p = 0.007).	('FGFR1', 'Gene', (27, 32))	('KSCC', 'Chemical', '-', (71, 75))	('amplifications', 'Var', (33, 47))	('KSCC', 'Chemical', '-', (81, 85))	('NKSCC', 'Disease', (80, 85))	('FGFR1', 'Gene', '2260', (27, 32))	('KSCC', 'Disease', (71, 75))
347779	33363036	Compared with NKSCC, IGF1R amplifications were more frequent in BSCC (0 vs 15.4%, p = 0.019).	('BSCC', 'Disease', (64, 68))	('KSCC', 'Chemical', '-', (15, 19))	('amplifications', 'Var', (27, 41))	('BSCC', 'Phenotype', 'HP:0002671', (64, 68))	('IGF1R', 'Gene', (21, 26))	('frequent', 'Reg', (52, 60))	('IGF1R', 'Gene', '3480', (21, 26))
347781	33363036	Compared with KSCC, incidence of RAS signaling pathway mutations in NKSCC was more frequent (14.9 vs 26.0% p = 0.087) ( Supplemental Figure 3A ).	('KSCC', 'Chemical', '-', (69, 73))	('RAS signaling pathway', 'Pathway', (33, 54))	('KSCC', 'Chemical', '-', (14, 18))	('mutations', 'Var', (55, 64))
347784	33363036	Results showed that PIK3CA alterations strongly correlated with aberrations of PTCH1/FGFR1/CDKN2A; KRAS and FGFR1/CDKN2A/JAK1/KIT co-alterations were frequently observed in LUSC ( Figure 4A ).	('CDKN2A', 'Gene', (91, 97))	('PTCH1', 'Gene', (79, 84))	('PIK3CA', 'Gene', (20, 26))	('FGFR1', 'Gene', '2260', (85, 90))	('KRAS', 'Gene', '3845', (99, 103))	('CDKN2A', 'Gene', (114, 120))	('alterations', 'Var', (27, 38))	('FGFR1', 'Gene', '2260', (108, 113))	('CDKN2A', 'Gene', '1029', (91, 97))	('LUSC', 'Disease', (173, 177))	('KIT', 'Gene', '3815', (126, 129))	('KRAS', 'Gene', (99, 103))	('correlated', 'Reg', (48, 58))	('JAK1', 'Gene', '3716', (121, 125))	('CDKN2A', 'Gene', '1029', (114, 120))	('FGFR1', 'Gene', (85, 90))	('PIK3CA', 'Gene', '5290', (20, 26))	('LUSC', 'Phenotype', 'HP:0030359', (173, 177))	('PTCH1', 'Gene', '5727', (79, 84))	('FGFR1', 'Gene', (108, 113))	('aberrations', 'MPA', (64, 75))	('KIT', 'Gene', (126, 129))	('JAK1', 'Gene', (121, 125))
347788	33363036	As for Cluster 3, FGFR1 amplifications and EGFR and BRCA2 mutations were more frequent.	('BRCA2', 'Gene', (52, 57))	('mutations', 'Var', (58, 67))	('amplifications', 'Var', (24, 38))	('frequent', 'Reg', (78, 86))	('BRCA2', 'Gene', '675', (52, 57))	('FGFR1', 'Gene', (18, 23))	('EGFR', 'Gene', '1956', (43, 47))	('FGFR1', 'Gene', '2260', (18, 23))	('EGFR', 'Gene', (43, 47))
347789	33363036	Almost all the cases in Cluster 4 harbored TP53 mutations and less gene amplifications.	('TP53', 'Gene', '7157', (43, 47))	('TP53', 'Gene', (43, 47))	('harbored', 'Reg', (34, 42))	('mutations', 'Var', (48, 57))
347791	33363036	For signaling pathway, mutations of TP53 cell cycle, Receptor tyrosine kinase pathway and JAK-STAT signaling pathway were more frequent in our cohort (p = 0.014, p = 0.002, p = 0.018, respectively) ( Figure 5B ).	('Receptor tyrosine kinase', 'Gene', (53, 77))	('Receptor tyrosine kinase', 'Gene', '5979', (53, 77))	('TP53', 'Gene', '7157', (36, 40))	('mutations', 'Var', (23, 32))	('TP53', 'Gene', (36, 40))	('JAK', 'Gene', (90, 93))	('signaling pathway', 'Pathway', (4, 21))	('JAK', 'Gene', '3716;3717', (90, 93))
347795	33363036	Univariable analysis revealed that pathological stage (p = 0.011), STK11 alterations (p < 0.001), and TOP2A alterations (p = 0.001) were in connection with a risk of recurrence in the patients with LUSC.	('TOP2A', 'Gene', (102, 107))	('alterations', 'Var', (108, 119))	('patients', 'Species', '9606', (184, 192))	('alterations', 'Var', (73, 84))	('STK11', 'Gene', '6794', (67, 72))	('recurrence', 'Disease', (166, 176))	('LUSC', 'Disease', (198, 202))	('LUSC', 'Phenotype', 'HP:0030359', (198, 202))	('TOP2A', 'Gene', '7153', (102, 107))	('STK11', 'Gene', (67, 72))
347796	33363036	IDH1 alterations (p = 0.028) and TOP2A alterations (p = 0.003) were in connection with a higher risk of recurrence in the patients with KSCC; higher pathological stage (p = 0.01), BRCA2 alterations (p = 0.098) and TOP2A alterations (p = 0.073) were in connection with a higher risk of recurrence in the patients with NKSCC.	('alterations', 'Var', (220, 231))	('patients', 'Species', '9606', (303, 311))	('KSCC', 'Disease', (136, 140))	('IDH1', 'Gene', '3417', (0, 4))	('BRCA2', 'Gene', '675', (180, 185))	('TOP2A', 'Gene', '7153', (214, 219))	('TOP2A', 'Gene', '7153', (33, 38))	('KSCC', 'Chemical', '-', (318, 322))	('NKSCC', 'Disease', (317, 322))	('alterations', 'Var', (39, 50))	('alterations', 'Var', (5, 16))	('TOP2A', 'Gene', (214, 219))	('TOP2A', 'Gene', (33, 38))	('patients', 'Species', '9606', (122, 130))	('IDH1', 'Gene', (0, 4))	('KSCC', 'Chemical', '-', (136, 140))	('BRCA2', 'Gene', (180, 185))
347797	33363036	Further multivariable analysis showed that higher pathological stage (HR, 1.635; p = 0.015), STK11 alterations (HR, 13.266; p < 0.001), and TOP2A alterations (HR, 4.759; p = 0.004) were relevant to higher risk of recurrence in the patients with LUSC.	('patients', 'Species', '9606', (231, 239))	('alterations', 'Var', (146, 157))	('LUSC', 'Phenotype', 'HP:0030359', (245, 249))	('STK11', 'Gene', (93, 98))	('STK11', 'Gene', '6794', (93, 98))	('alterations', 'Var', (99, 110))	('LUSC', 'Disease', (245, 249))	('TOP2A', 'Gene', '7153', (140, 145))	('TOP2A', 'Gene', (140, 145))
347798	33363036	TOP2A alterations were relevant to higher risk of recurrence in the patients with KSCC (HR, 6.490; p = 0.003), while no statistic differences of correlation occurred in the patients with NKSCC.	('alterations', 'Var', (6, 17))	('KSCC', 'Disease', (82, 86))	('TOP2A', 'Gene', (0, 5))	('patients', 'Species', '9606', (173, 181))	('patients', 'Species', '9606', (68, 76))	('KSCC', 'Chemical', '-', (188, 192))	('TOP2A', 'Gene', '7153', (0, 5))	('KSCC', 'Chemical', '-', (82, 86))
347799	33363036	The 1-year DFS of STK11 alterations and STK11 wild subgroups were 25.0 and 78.0% (p < 0.001,  Figure 6B ).	('STK11', 'Gene', (40, 45))	('alterations', 'Var', (24, 35))	('STK11', 'Gene', '6794', (40, 45))	('STK11', 'Gene', (18, 23))	('STK11', 'Gene', '6794', (18, 23))
347800	33363036	The 1-year DFS of BRCA2 alterations and BRCA2 wild subgroups were 0 and 26.1% (p = 0.011,  Figure 6C ).	('BRCA2', 'Gene', '675', (18, 23))	('alterations', 'Var', (24, 35))	('BRCA2', 'Gene', (40, 45))	('BRCA2', 'Gene', (18, 23))	('BRCA2', 'Gene', '675', (40, 45))
347807	33363036	We found that FGFR alterations were more common in patients diagnosed with stage II, compared with other stages.	('stage II', 'Disease', (75, 83))	('FGFR', 'Gene', (14, 18))	('alterations', 'Var', (19, 30))	('patients', 'Species', '9606', (51, 59))	('common', 'Reg', (41, 47))
347808	33363036	In this study, we found generally congruent mutation frequencies of different subtypes in TOP 20 genes including TP53 (93.9% in KSCC, 88.5% in NKSCC, 100% in BSCC), CDKN2A (28.1% in KSCC, 25.6% in NKSCC, 30.8% in BSCC), and NOTCH1 (15.8% in KSCC, 15.4% in NKSCC, 30.8% in BSCC), however, BSCC represented relatively lower frequency of PIK3CA mutations compared to the other two subtypes (16.7% in KSCC, 16.7% in NKSCC, 0% in BSCC).	('KSCC', 'Chemical', '-', (397, 401))	('PIK3CA', 'Gene', '5290', (335, 341))	('KSCC', 'Chemical', '-', (198, 202))	('mutations', 'Var', (342, 351))	('NOTCH1', 'Gene', '4851', (224, 230))	('CDKN2A', 'Gene', '1029', (165, 171))	('BSCC', 'Phenotype', 'HP:0002671', (158, 162))	('KSCC', 'Chemical', '-', (182, 186))	('BSCC', 'Phenotype', 'HP:0002671', (213, 217))	('BSCC', 'Phenotype', 'HP:0002671', (425, 429))	('TP53', 'Gene', (113, 117))	('KSCC', 'Chemical', '-', (257, 261))	('PIK3CA', 'Gene', (335, 341))	('BSCC', 'Phenotype', 'HP:0002671', (288, 292))	('BSCC', 'Phenotype', 'HP:0002671', (272, 276))	('KSCC', 'Chemical', '-', (128, 132))	('KSCC', 'Chemical', '-', (413, 417))	('KSCC', 'Chemical', '-', (241, 245))	('CDKN2A', 'Gene', (165, 171))	('lower', 'NegReg', (316, 321))	('TP53', 'Gene', '7157', (113, 117))	('NOTCH1', 'Gene', (224, 230))	('KSCC', 'Chemical', '-', (144, 148))
347812	33363036	As reported by a recent study, TP53 mutations were detected in almost all LUSC patients (90%) and CDKN2A mutations accounted for 19.4% of LUSC patients.	('detected', 'Reg', (51, 59))	('LUSC', 'Phenotype', 'HP:0030359', (138, 142))	('TP53', 'Gene', '7157', (31, 35))	('TP53', 'Gene', (31, 35))	('mutations', 'Var', (36, 45))	('patients', 'Species', '9606', (143, 151))	('LUSC', 'Phenotype', 'HP:0030359', (74, 78))	('CDKN2A', 'Gene', (98, 104))	('LUSC', 'Disease', (74, 78))	('patients', 'Species', '9606', (79, 87))	('CDKN2A', 'Gene', '1029', (98, 104))
347818	33363036	Another study including TCGA cohorts proposed that losses of CDKN2A increased the susceptibility to resistance of IFNgamma and immunotherapy by concomitant losses of JAK2 in LUSC.	('JAK2', 'Gene', (166, 170))	('IFNgamma', 'Gene', '3458', (114, 122))	('susceptibility', 'MPA', (82, 96))	('losses', 'NegReg', (156, 162))	('losses', 'Var', (51, 57))	('CDKN2A', 'Gene', (61, 67))	('CDKN2A', 'Gene', '1029', (61, 67))	('immunotherapy', 'CPA', (127, 140))	('JAK2', 'Gene', '3717', (166, 170))	('LUSC', 'Phenotype', 'HP:0030359', (174, 178))	('increased', 'PosReg', (68, 77))	('IFNgamma', 'Gene', (114, 122))
347821	33363036	As for CNAs, our findings demonstrated that FGFR1 amplifications occurred more frequently in NKSCC than KSCC with statistic difference and compared with NKSCC, IGF1R amplifications were more frequent in BSCC.	('frequent', 'Reg', (191, 199))	('KSCC', 'Chemical', '-', (104, 108))	('BSCC', 'Phenotype', 'HP:0002671', (203, 207))	('FGFR1', 'Gene', (44, 49))	('IGF1R', 'Gene', (160, 165))	('KSCC', 'Chemical', '-', (94, 98))	('FGFR1', 'Gene', '2260', (44, 49))	('NKSCC', 'Disease', (93, 98))	('IGF1R', 'Gene', '3480', (160, 165))	('BSCC', 'Disease', (203, 207))	('amplifications', 'Var', (50, 64))	('KSCC', 'Chemical', '-', (154, 158))
347822	33363036	identified that FGFR1 amplifications were found in 16% of LUSC patients and FGFR1 amplifications status had no correlation with age, sex, staging, histologic subtype, smoking history.	('LUSC', 'Disease', (58, 62))	('LUSC', 'Phenotype', 'HP:0030359', (58, 62))	('FGFR1', 'Gene', '2260', (16, 21))	('found', 'Reg', (42, 47))	('amplifications', 'Var', (22, 36))	('patients', 'Species', '9606', (63, 71))	('FGFR1', 'Gene', (76, 81))	('FGFR1', 'Gene', '2260', (76, 81))	('FGFR1', 'Gene', (16, 21))
347824	33363036	Incidence of RAS signaling pathway mutations was more frequent in NKSCC compared with KSCC.	('frequent', 'Reg', (54, 62))	('RAS signaling pathway', 'Pathway', (13, 34))	('KSCC', 'Chemical', '-', (86, 90))	('KSCC', 'Chemical', '-', (67, 71))	('NKSCC', 'Disease', (66, 71))	('mutations', 'Var', (35, 44))
347826	33363036	Exclusivity and co-occurrence of mutations revealed that cases with TP53 alterations had less EGFR alterations in KSCC (P= 0.013, OR= 0.158), while not in NKSCC.	('EGFR', 'Gene', '1956', (94, 98))	('alterations', 'Var', (73, 84))	('KSCC', 'Chemical', '-', (156, 160))	('TP53', 'Gene', '7157', (68, 72))	('EGFR', 'Gene', (94, 98))	('KSCC', 'Chemical', '-', (114, 118))	('KSCC', 'Disease', (114, 118))	('less', 'NegReg', (89, 93))	('TP53', 'Gene', (68, 72))
347830	33363036	recently reported that among LUSC patients, TP53 and PIK3CA mutations were more common in TCGA cohorts.	('common', 'Reg', (80, 86))	('PIK3CA', 'Gene', '5290', (53, 59))	('LUSC', 'Phenotype', 'HP:0030359', (29, 33))	('TP53', 'Gene', '7157', (44, 48))	('patients', 'Species', '9606', (34, 42))	('mutations', 'Var', (60, 69))	('TCGA', 'Disease', (90, 94))	('PIK3CA', 'Gene', (53, 59))	('TP53', 'Gene', (44, 48))
347831	33363036	Another study comparing the Korean cohorts with TCGA cohorts found that both cohorts displayed a similarly high frequency of mutations of TP53 and NOTCH1, but CDKN2A mutations were observed more frequently in TCGA cohorts.	('mutations', 'Var', (125, 134))	('CDKN2A', 'Gene', '1029', (159, 165))	('TP53', 'Gene', '7157', (138, 142))	('TP53', 'Gene', (138, 142))	('NOTCH1', 'Gene', '4851', (147, 153))	('NOTCH1', 'Gene', (147, 153))	('CDKN2A', 'Gene', (159, 165))
347832	33363036	Multivariable analysis displayed that higher pathological stage, STK11 alterations and TOP2A alterations were relevant to a higher risk of recurrence in the patients with LUSC.	('alterations', 'Var', (93, 104))	('TOP2A', 'Gene', (87, 92))	('STK11', 'Gene', (65, 70))	('patients', 'Species', '9606', (157, 165))	('alterations', 'Var', (71, 82))	('STK11', 'Gene', '6794', (65, 70))	('LUSC', 'Phenotype', 'HP:0030359', (171, 175))	('LUSC', 'Disease', (171, 175))	('TOP2A', 'Gene', '7153', (87, 92))
347833	33363036	Further analysis demonstrated that TOP2A alterations were related to a higher risk of recurrence in the patients with KSCC, neither in NKSCC nor in BSCC.	('BSCC', 'Phenotype', 'HP:0002671', (148, 152))	('TOP2A', 'Gene', '7153', (35, 40))	('KSCC', 'Chemical', '-', (118, 122))	('TOP2A', 'Gene', (35, 40))	('KSCC', 'Chemical', '-', (136, 140))	('KSCC', 'Disease', (118, 122))	('patients', 'Species', '9606', (104, 112))	('alterations', 'Var', (41, 52))
347836	33363036	A recent study reported a trend toward a reduced PFS in LUAD patients harboring STK11 mutations.	('STK11', 'Gene', '6794', (80, 85))	('mutations', 'Var', (86, 95))	('reduced', 'NegReg', (41, 48))	('patients', 'Species', '9606', (61, 69))	('PFS', 'MPA', (49, 52))	('LUAD', 'Phenotype', 'HP:0030078', (56, 60))	('STK11', 'Gene', (80, 85))
347837	33363036	Worse OS and PFS outcomes were also observed in NSCLC patients with STK11 mutations receiving immunotherapy or chemotherapy.	('NSCLC', 'Disease', (48, 53))	('STK11', 'Gene', (68, 73))	('patients', 'Species', '9606', (54, 62))	('NSCLC', 'Disease', 'MESH:D002289', (48, 53))	('mutations', 'Var', (74, 83))	('STK11', 'Gene', '6794', (68, 73))	('NSCLC', 'Phenotype', 'HP:0030358', (48, 53))
347838	33363036	found co-mutations of STK11 with TP53 was associated with a better prognosis.	('STK11', 'Gene', '6794', (22, 27))	('TP53', 'Gene', '7157', (33, 37))	('co-mutations', 'Var', (6, 18))	('TP53', 'Gene', (33, 37))	('STK11', 'Gene', (22, 27))
347841	33363036	A study reported patients with gains of 11q13.1 had a poor survival.	('gains', 'Var', (31, 36))	('patients', 'Species', '9606', (17, 25))	('11q13.1', 'Gene', (40, 47))
347847	33038763	Pan-cancer analysis of somatic mutations in miRNA genes miRNAs are considered important players in oncogenesis, serving either as oncomiRs or suppressormiRs.	('miR', 'Gene', '220972', (44, 47))	('miR', 'Gene', (44, 47))	('mutations', 'Var', (31, 40))	('miR', 'Gene', '220972', (134, 137))	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('miR', 'Gene', (134, 137))	('miR', 'Gene', '220972', (152, 155))	('miR', 'Gene', '220972', (56, 59))	('oncomiRs', 'Disease', (130, 138))	('miR', 'Gene', (56, 59))	('cancer', 'Disease', 'MESH:D009369', (4, 10))	('miR', 'Gene', (152, 155))	('cancer', 'Disease', (4, 10))	('oncomiRs', 'Disease', 'None', (130, 138))
347848	33038763	Although the accumulation of somatic alterations is an intrinsic aspect of cancer development and many important cancer-driving mutations have been identified in protein-coding genes, the area of functional somatic mutations in miRNA genes is heavily understudied.	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('mutations', 'Var', (128, 137))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('cancer', 'Disease', (75, 81))	('cancer', 'Disease', (113, 119))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('miR', 'Gene', '220972', (228, 231))	('miR', 'Gene', (228, 231))
347851	33038763	Nonrandom occurrence of the identified mutations was confirmed by a strong association of overmutated miRNA genes with KEGG pathways, most of which were related to specific cancer types or cancer-related processes.	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('KEGG pathways', 'Pathway', (119, 132))	('miR', 'Gene', '220972', (102, 105))	('miR', 'Gene', (102, 105))	('cancer', 'Disease', (173, 179))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('mutations', 'Var', (39, 48))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('association', 'Interaction', (75, 86))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('overmutated', 'Var', (90, 101))	('related', 'Reg', (153, 160))	('cancer', 'Disease', (189, 195))
347852	33038763	Additionally, we showed that mutations in some of the overmutated genes correlate with miRNA expression, cancer staging, and patient survival.	('cancer', 'Disease', (105, 111))	('mutations', 'Var', (29, 38))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('patient survival', 'CPA', (125, 141))	('correlate', 'Reg', (72, 81))	('miR', 'Gene', '220972', (87, 90))	('miR', 'Gene', (87, 90))	('patient', 'Species', '9606', (125, 132))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))
347854	33038763	It may help to understand the consequences of mutations in miRNA genes and the identification of miRNA functional mutations.	('mutations', 'Var', (46, 55))	('miR', 'Gene', '220972', (59, 62))	('miR', 'Gene', (59, 62))	('miR', 'Gene', '220972', (97, 100))	('miR', 'Gene', (97, 100))
347856	33038763	Cancer genome analyses supported by data generated in large projects such as The Cancer Genome Atlas (TCGA) have led to the identification of hundreds of cancer-driving genes and thousands of cancer-driving mutations in protein-coding regions, which encompass barely 2% of the genome.	('Cancer', 'Phenotype', 'HP:0002664', (81, 87))	('Cancer', 'Disease', (81, 87))	('Cancer', 'Disease', 'MESH:D009369', (81, 87))	('cancer', 'Disease', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('Cancer', 'Disease', (0, 6))	('mutations', 'Var', (207, 216))	('cancer', 'Disease', (192, 198))	('cancer', 'Disease', 'MESH:D009369', (192, 198))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))
347857	33038763	Some of these genes/mutations, serve as important biomarkers for cancer-targeted therapies.	('cancer', 'Disease', (65, 71))	('genes/mutations', 'Var', (14, 29))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))
347859	33038763	With the use of sequencing datasets generated within the large cancer-genome projects, mostly TCGA, we identified and characterized >10,000 miRNA gene mutations in 33 types of cancers.	('cancers', 'Disease', (176, 183))	('cancers', 'Disease', 'MESH:D009369', (176, 183))	('cancers', 'Phenotype', 'HP:0002664', (176, 183))	('miR', 'Gene', '220972', (140, 143))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('miR', 'Gene', (140, 143))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('cancer', 'Disease', (176, 182))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('mutations', 'Var', (151, 160))	('cancer', 'Disease', (63, 69))
347860	33038763	Among the identified variants were mutations in well-known oncomiRs and miRNA suppressors, including let-7, miR-21, and miR-205.	('variants', 'Var', (21, 29))	('oncomiRs', 'Disease', (59, 67))	('oncomiRs', 'Disease', 'None', (59, 67))	('miR', 'Gene', '220972', (120, 123))	('miR', 'Gene', (120, 123))	('miR-205', 'Gene', (120, 127))	('miR-21', 'Gene', (108, 114))	('miR', 'Gene', '220972', (63, 66))	('miR', 'Gene', '220972', (108, 111))	('miR', 'Gene', (63, 66))	('miR', 'Gene', (108, 111))	('miR-205', 'Gene', '406988', (120, 127))	('miR', 'Gene', '220972', (72, 75))	('miR-21', 'Gene', '406991', (108, 114))	('miR', 'Gene', (72, 75))	('let-7', 'Gene', (101, 106))	('mutations', 'Var', (35, 44))
347861	33038763	We identified and characterized dozens of significantly overmutated miRNA genes and hotspot nucleotide positions that are recurrently mutated in particular cancer types or the overall Pan-Cancer dataset and showed that some of these mutations affect miRNA expression, cancer staging, and patient survival as well as occur more frequently in miRNA genes playing role in cancer.	('miR', 'Gene', '220972', (250, 253))	('patient', 'Species', '9606', (288, 295))	('miR', 'Gene', '220972', (68, 71))	('overmutated', 'PosReg', (56, 67))	('patient survival', 'CPA', (288, 304))	('cancer', 'Disease', 'MESH:D009369', (268, 274))	('cancer', 'Disease', 'MESH:D009369', (369, 375))	('miR', 'Gene', (250, 253))	('Pan-Cancer', 'Disease', 'MESH:D009369', (184, 194))	('miR', 'Gene', (68, 71))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('affect', 'Reg', (243, 249))	('mutations', 'Var', (233, 242))	('miR', 'Gene', '220972', (341, 344))	('cancer', 'Disease', (268, 274))	('cancer', 'Disease', (369, 375))	('cancer', 'Disease', (156, 162))	('Cancer', 'Phenotype', 'HP:0002664', (188, 194))	('cancer', 'Phenotype', 'HP:0002664', (268, 274))	('cancer', 'Phenotype', 'HP:0002664', (369, 375))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('miR', 'Gene', (341, 344))	('Pan-Cancer', 'Disease', (184, 194))
347862	33038763	This is the first comprehensive analysis of somatic mutations in miRNA genes in cancer.	('mutations', 'Var', (52, 61))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('miR', 'Gene', '220972', (65, 68))	('miR', 'Gene', (65, 68))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('cancer', 'Disease', (80, 86))
347863	33038763	It may serve as the first step in the identification of driver mutations in miRNA genes and may help in understanding the role of particular miRNAs in cancer.	('mutations', 'Var', (63, 72))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('miR', 'Gene', '220972', (141, 144))	('cancer', 'Disease', (151, 157))	('miR', 'Gene', (141, 144))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('miR', 'Gene', '220972', (76, 79))	('miR', 'Gene', (76, 79))
347864	33038763	After further functional validation, some of the mutations may be utilized as cancer biomarkers.	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('mutations', 'Var', (49, 58))
347865	33038763	Alt-text: Unlabelled box Cancer encompasses a broad spectrum of heterogeneous diseases whose development (i.e., initiation, promotion, and progression) is associated with the accumulation of numerous genetic alterations in the cancer genome, which is the hallmark of all cancers.	('genetic alterations', 'Var', (200, 219))	('cancer', 'Phenotype', 'HP:0002664', (271, 277))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('associated', 'Reg', (155, 165))	('Cancer', 'Phenotype', 'HP:0002664', (25, 31))	('Cancer', 'Disease', (25, 31))	('cancer', 'Disease', 'MESH:D009369', (227, 233))	('cancers', 'Disease', (271, 278))	('cancer', 'Disease', 'MESH:D009369', (271, 277))	('cancer', 'Disease', (227, 233))	('cancers', 'Disease', 'MESH:D009369', (271, 278))	('Cancer', 'Disease', 'MESH:D009369', (25, 31))	('cancers', 'Phenotype', 'HP:0002664', (271, 278))	('cancer', 'Disease', (271, 277))
347866	33038763	As a result of clonal selection of the fastest dividing cells, functional (driver) mutations often recur in genes playing an important role in cancer development (driver genes) and therefore may serve as indicators of such genes.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('mutations', 'Var', (83, 92))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))
347869	33038763	As the overwhelming majority of the cancer genome studies have focused on protein-coding genes, the most identified cancer-driver mutations are in protein-coding sequences, which encompass barely 2% of the genome.	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('cancer', 'Disease', (36, 42))	('mutations', 'Var', (130, 139))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))
347870	33038763	The spectacular exception are TERT promoter mutations, which occur most frequently in melanoma, brain, and bladder cancers but have also been identified in other cancers.	('bladder cancers', 'Disease', (107, 122))	('cancers', 'Disease', 'MESH:D009369', (162, 169))	('cancers', 'Disease', 'MESH:D009369', (115, 122))	('melanoma', 'Disease', (86, 94))	('melanoma', 'Disease', 'MESH:D008545', (86, 94))	('TERT', 'Gene', (30, 34))	('cancers', 'Disease', (115, 122))	('cancers', 'Disease', (162, 169))	('melanoma', 'Phenotype', 'HP:0002861', (86, 94))	('cancers', 'Phenotype', 'HP:0002664', (115, 122))	('bladder cancers', 'Phenotype', 'HP:0009725', (107, 122))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('TERT', 'Gene', '7015', (30, 34))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('mutations', 'Var', (44, 53))	('bladder cancers', 'Disease', 'MESH:D001749', (107, 122))	('brain', 'Disease', (96, 101))	('cancers', 'Phenotype', 'HP:0002664', (162, 169))
347875	33038763	It was also shown that miRNA genes frequently show copy number alterations (either amplification or deletion) in cancer.	('copy', 'MPA', (51, 55))	('miR', 'Gene', '220972', (23, 26))	('miR', 'Gene', (23, 26))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('amplification', 'MPA', (83, 96))	('cancer', 'Disease', (113, 119))	('deletion', 'Var', (100, 108))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
347878	33038763	Considering subsequent steps of miRNA biogenesis and the mechanism of miRNA posttranscriptional gene regulation, mutations may be expected to affect different attributes of miRNA genes.	('miR', 'Gene', (32, 35))	('affect', 'Reg', (142, 148))	('mutations', 'Var', (113, 122))	('miR', 'Gene', '220972', (32, 35))	('miR', 'Gene', '220972', (70, 73))	('miR', 'Gene', (70, 73))	('miR', 'Gene', '220972', (173, 176))	('miR', 'Gene', (173, 176))
347879	33038763	In addition to the most obvious consequences of mutations in seed sequences that affect the pivotal function of miRNAs, i.e., the ability to recognize and downregulate their specific targets, mutations in any part of the miRNA precursor may affect the effectiveness or precision of miRNA biogenesis by altering/destabilizing the hairpin structure of the miRNA precursor, by altering DROSHA or DICER1 cleavage sites, or by altering protein-interacting or other regulatory sequences/structure motifs.	('DICER1', 'Gene', '23405', (393, 399))	('miR', 'Gene', '220972', (282, 285))	('miR', 'Gene', (354, 357))	('protein-interacting', 'Protein', (431, 450))	('mutations', 'Var', (192, 201))	('mutations', 'Var', (48, 57))	('DICER1', 'Gene', (393, 399))	('hairpin structure', 'MPA', (329, 346))	('miR', 'Gene', (282, 285))	('DROSHA', 'Gene', '29102', (383, 389))	('DROSHA', 'Gene', (383, 389))	('altering/destabilizing', 'Reg', (302, 324))	('affect', 'Reg', (241, 247))	('altering', 'Reg', (422, 430))	('effectiveness', 'MPA', (252, 265))	('miR', 'Gene', '220972', (112, 115))	('altering/destabilizing', 'NegReg', (302, 324))	('miR', 'Gene', '220972', (221, 224))	('miR', 'Gene', (112, 115))	('altering', 'Reg', (374, 382))	('precision', 'CPA', (269, 278))	('regulatory sequences/structure', 'MPA', (460, 490))	('miR', 'Gene', '220972', (354, 357))	('miR', 'Gene', (221, 224))
347880	33038763	Additionally, mutations destabilizing one of the miRNA duplex ends may alter 5p/3p miRNA preference.	('alter', 'Reg', (71, 76))	('miR', 'Gene', '220972', (49, 52))	('miR', 'Gene', '220972', (83, 86))	('miR', 'Gene', (49, 52))	('miR', 'Gene', (83, 86))	('mutations', 'Var', (14, 23))
347881	33038763	Despite the scarcity of identified miRNA gene mutations, the individual examples of SNPs, germline or somatic mutations provide proof, at least for some of the scenarios listed above.	('miR', 'Gene', '220972', (35, 38))	('miR', 'Gene', (35, 38))	('mutations', 'Var', (46, 55))	('SNPs', 'Disease', (84, 88))
347882	33038763	Examples include (i) the mutation in the seed sequence of miR-204-5p, affecting target recognition, that causes inherited retinal dystrophy; (ii) the mutation in the passenger strand of hsa-miR-96 that destabilizes the structure of the miRNA precursor, affects its processing, and decreases the miR-96-5p level, eventually resulting in the same phenotypic effect as mutations in the seed sequence of the guide strand, i.e., nonsyndromic inherited hearing loss; (iii) the G>C substitution (SNP rs138166791) in the penultimate position of the 3p passenger strand of hsa-miR-890 that significantly lowers the cleavage efficiency by DROSHA and consequently decreases the levels of both mature miR-890-5p and passenger miR-890-3p; (iv) the G>C substitution (SNP rs2910164) located in the 3p passenger strand of hsa-miR-146a that is associated with an increased risk of papillary thyroid carcinoma, where it was shown that the C allele of the SNP alters the structure of the precursor, decreases expression of the mature miRNA and activates the passenger strand, which becomes the second mature miRNA modulating many genes involved in the regulation of apoptosis; (v) interesting example is a mutation in the seed sequence of miR-184-3p, causing familial keratoconus, whose effect is not the disruption of miR-184-3p target recognition but the inability to mask overlapping targets for miR-205 in INPPL1 and ITGB4 ; (vi) mutations in hsa-miR-30c-1 and hsa-miR-17 that affect the precursor structure and thereby increase the levels of mature miRNAs, downregulating BRCA1 in familial breast cancer cases without BRCA1/2 mutations; and finally, (vii) two different somatic mutations in the seed sequence of miR-142-3p, found in acute myeloid leukemia (AML) samples, that were shown to decrease miR-142-5p and reverse the miR-5p/3p ratio (in favor of miR-3p) (more details and references on mutations in hsa-miR-142 in the subsequent sections).	('mutations', 'Var', (1415, 1424))	('miR', 'Gene', (236, 239))	('miR', 'Gene', (1300, 1303))	('miR-890', 'Gene', (714, 721))	('miR', 'Gene', (1785, 1788))	('miR', 'Gene', (1380, 1383))	('miR', 'Gene', '220972', (58, 61))	('miR', 'Gene', (568, 571))	('retinal dystrophy', 'Phenotype', 'HP:0000556', (122, 139))	('nonsyndromic inherited hearing loss', 'Disease', 'MESH:C537845', (424, 459))	('carcinoma', 'Phenotype', 'HP:0030731', (882, 891))	('miR', 'Gene', (1432, 1435))	('miR-96', 'Gene', (190, 196))	('miR', 'Gene', '220972', (1898, 1901))	('miR', 'Gene', '220972', (1015, 1018))	('familial breast cancer', 'Disease', 'MESH:D001943', (1567, 1589))	('acute myeloid leukemia', 'Disease', (1719, 1741))	('familial breast cancer', 'Disease', (1567, 1589))	('miR', 'Gene', '220972', (714, 717))	('hsa-miR-96', 'Gene', '407053', (186, 196))	('miR', 'Gene', '220972', (190, 193))	('miR', 'Gene', (295, 298))	('hearing loss', 'Phenotype', 'HP:0000365', (447, 459))	('miR', 'Gene', (1841, 1844))	('AML', 'Disease', (1743, 1746))	('hsa-miR-142', 'Gene', '406934', (1894, 1905))	('miR', 'Gene', (1698, 1701))	('miR', 'Gene', (689, 692))	('miR-890', 'Gene', (689, 696))	('INPPL1', 'Gene', (1391, 1397))	('hsa-miR-30c-1', 'Gene', (1428, 1441))	('miR', 'Gene', '220972', (1812, 1815))	('miR-890', 'Gene', (568, 575))	('increase', 'PosReg', (1505, 1513))	('miR-96', 'Gene', '407053', (295, 301))	('miR', 'Gene', (1535, 1538))	('papillary thyroid carcinoma', 'Phenotype', 'HP:0002895', (864, 891))	('hsa-miR-146a', 'Gene', '406938', (806, 818))	('BRCA1', 'Gene', '672', (1604, 1609))	('ITGB4', 'Gene', (1402, 1407))	('miR', 'Gene', '220972', (810, 813))	('papillary thyroid carcinoma', 'Disease', 'MESH:D000077273', (864, 891))	('DROSHA', 'Gene', '29102', (629, 635))	('miR', 'Gene', (1089, 1092))	('DROSHA', 'Gene', (629, 635))	('miR-205', 'Gene', (1380, 1387))	('inherited retinal dystrophy', 'Disease', 'MESH:D058499', (112, 139))	('leukemia', 'Phenotype', 'HP:0001909', (1733, 1741))	('miR', 'Gene', '220972', (236, 239))	('miR', 'Gene', '220972', (1300, 1303))	('cancer', 'Phenotype', 'HP:0002664', (1583, 1589))	('AML', 'Disease', 'MESH:D015470', (1743, 1746))	('miR', 'Gene', '220972', (1785, 1788))	('hsa-miR-30c-1', 'Gene', '407031', (1428, 1441))	('miR', 'Gene', '220972', (1380, 1383))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (1719, 1741))	('miR', 'Gene', '220972', (568, 571))	('miR', 'Gene', '220972', (1432, 1435))	('BRCA1', 'Gene', '672', (1558, 1563))	('miR-96', 'Gene', (295, 301))	('decrease', 'NegReg', (1776, 1784))	('miR', 'Gene', (1220, 1223))	('miR', 'Gene', (1450, 1453))	('ITGB4', 'Gene', '3691', (1402, 1407))	('rs2910164', 'Mutation', 'rs2910164', (757, 766))	('miR', 'Gene', (58, 61))	('downregulating', 'NegReg', (1543, 1557))	('inherited retinal dystrophy', 'Disease', (112, 139))	('papillary thyroid carcinoma', 'Disease', (864, 891))	('miR', 'Gene', '220972', (295, 298))	('hsa-miR-17', 'Gene', (1446, 1456))	('miR-890', 'Gene', '100126303', (714, 721))	('mutations', 'Var', (1664, 1673))	('miR', 'Gene', (1898, 1901))	('BRCA1', 'Gene', (1604, 1609))	('keratoconus', 'Phenotype', 'HP:0000563', (1249, 1260))	('miR', 'Gene', '220972', (1841, 1844))	('hsa-miR-17', 'Gene', '406952', (1446, 1456))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (1725, 1741))	('rs138166791', 'Mutation', 'rs138166791', (493, 504))	('miR', 'Gene', '220972', (1698, 1701))	('miR', 'Gene', '220972', (689, 692))	('miR', 'Gene', (1015, 1018))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (874, 891))	('miR', 'Gene', (714, 717))	('miR', 'Gene', (190, 193))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (1719, 1741))	('hsa-miR-96', 'Gene', (186, 196))	('miR', 'Gene', '220972', (1535, 1538))	('BRCA1', 'Gene', (1558, 1563))	('miR-205', 'Gene', '406988', (1380, 1387))	('hsa-miR-890', 'Gene', '100126303', (564, 575))	('miR', 'Gene', '220972', (1089, 1092))	('nonsyndromic inherited hearing loss', 'Disease', (424, 459))	('breast cancer', 'Phenotype', 'HP:0003002', (1576, 1589))	('miR-96', 'Gene', '407053', (190, 196))	('miR', 'Gene', (1812, 1815))	('miR-890', 'Gene', '100126303', (689, 696))	('hsa-miR-890', 'Gene', (564, 575))	('hsa-miR-142', 'Gene', (1894, 1905))	('miR', 'Gene', (810, 813))	('miR-890', 'Gene', '100126303', (568, 575))	('hsa-miR-146a', 'Gene', (806, 818))	('INPPL1', 'Gene', '3636', (1391, 1397))	('miR', 'Gene', '220972', (1220, 1223))	('miR', 'Gene', '220972', (1450, 1453))
347884	33038763	The SNP occurring in miRNA genes and other non-coding RNA sequences are collected in curated databases (e.g., MSDD and lincSNP 2.0), whose use may facilitate identification of functionally relevant SNP or mutations.	('miR', 'Gene', '220972', (21, 24))	('mutations', 'Var', (205, 214))	('miR', 'Gene', (21, 24))
347885	33038763	In our recent analysis of somatic mutations in lung cancers, we confirmed that seed mutations affect the vast majority of the predicted targets and showed that mutations in miRNA genes often alter the predicted structure of miRNA precursors.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('mutations', 'Var', (160, 169))	('alter', 'Reg', (191, 196))	('affect', 'Reg', (94, 100))	('lung cancers', 'Disease', 'MESH:D008175', (47, 59))	('lung cancers', 'Phenotype', 'HP:0100526', (47, 59))	('mutations', 'Var', (84, 93))	('miR', 'Gene', '220972', (224, 227))	('miR', 'Gene', (224, 227))	('lung cancers', 'Disease', (47, 59))	('miR', 'Gene', '220972', (173, 176))	('miR', 'Gene', (173, 176))	('cancers', 'Phenotype', 'HP:0002664', (52, 59))
347886	33038763	miRNAs in cancers were also considered in the context of somatic mutations found in mRNAs that affect mRNA-miRNA and competing endogenous RNA (ceRNA)-miRNA interactions.	('miR', 'Gene', '220972', (150, 153))	('miR', 'Gene', (150, 153))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('mRNAs', 'Gene', (84, 89))	('miR', 'Gene', '220972', (0, 3))	('miR', 'Gene', (0, 3))	('affect', 'Reg', (95, 101))	('cancers', 'Phenotype', 'HP:0002664', (10, 17))	('miR', 'Gene', '220972', (107, 110))	('cancers', 'Disease', 'MESH:D009369', (10, 17))	('miR', 'Gene', (107, 110))	('cancers', 'Disease', (10, 17))	('mutations', 'Var', (65, 74))
347887	33038763	As we consider sequence variations in mRNAs that may affect miRNA function, the same should apply to the sequence variations in the miRNA genes themselves.	('mRNAs', 'Gene', (38, 43))	('miR', 'Gene', '220972', (60, 63))	('variations', 'Var', (24, 34))	('miR', 'Gene', (60, 63))	('affect', 'Reg', (53, 59))	('miR', 'Gene', '220972', (132, 135))	('miR', 'Gene', (132, 135))
347888	33038763	The more general effect of sequence variants, including cancer somatic mutations on RNA structure, was recently demonstrated with the use of high-throughput combined experimental and computational approaches, that have led to the identification of many RNA structure motifs (termed riboSNitches) whose functionalities were affected by the variants detected in both coding and non-coding sequences.	('variants', 'Var', (339, 347))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('mutations', 'Var', (71, 80))	('RNA', 'MPA', (253, 256))	('affected', 'Reg', (323, 331))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))
347893	33038763	As a result, we identified thousands of mutations in all subregions of miRNA genes and identified many Pan-Cancer or cancer-specific overmutated miRNA genes.	('miR', 'Gene', (71, 74))	('overmutated', 'PosReg', (133, 144))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('mutations', 'Var', (40, 49))	('Cancer', 'Phenotype', 'HP:0002664', (107, 113))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('Pan-Cancer', 'Disease', (103, 113))	('miR', 'Gene', '220972', (145, 148))	('miR', 'Gene', (145, 148))	('Pan-Cancer', 'Disease', 'MESH:D009369', (103, 113))	('cancer', 'Disease', (117, 123))	('miR', 'Gene', '220972', (71, 74))
347894	33038763	We showed that mutations in some of the overmutated genes correlate with miRNA expression, cancer staging, and patient survival.	('cancer', 'Disease', (91, 97))	('mutations', 'Var', (15, 24))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('patient survival', 'CPA', (111, 127))	('correlate', 'Reg', (58, 67))	('miR', 'Gene', '220972', (73, 76))	('miR', 'Gene', (73, 76))	('patient', 'Species', '9606', (111, 118))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))
347895	33038763	Although the functionality of individual mutations or groups of mutations needs to be verified in independent functional studies, the strong association of the overmutated miRNA genes with cancer-related pathways indicates that miRNA gene mutations are not only random events and that at least some of them play a role in cancer.	('play', 'Reg', (307, 311))	('cancer', 'Disease', 'MESH:D009369', (322, 328))	('role', 'Reg', (314, 318))	('cancer', 'Disease', (322, 328))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('miR', 'Gene', '220972', (172, 175))	('mutations', 'Var', (239, 248))	('miR', 'Gene', (172, 175))	('cancer', 'Phenotype', 'HP:0002664', (322, 328))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('miR', 'Gene', '220972', (228, 231))	('miR', 'Gene', (228, 231))	('cancer', 'Disease', (189, 195))
347905	33038763	To avoid duplicating mutations detected in multiple sequencing experiments in the same cancer patient (e.g., due to the presence of two cancer samples sequenced from a single cancer patient), we combined files summing reads associated with particular mutations.	('cancer', 'Disease', (87, 93))	('mutations', 'Var', (251, 260))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('cancer', 'Disease', (175, 181))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('patient', 'Species', '9606', (182, 189))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cancer', 'Disease', (136, 142))	('patient', 'Species', '9606', (94, 101))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
347906	33038763	To further increase the reliability of the identified mutations, we removed mutations that did not fulfil the following criteria: (i) at least two mutation-supporting reads in a tumour sample (if no mutation-supporting read was detected in the corresponding normal sample); (ii) at least 5 x higher frequency of mutation-supporting reads in the tumour sample than in the corresponding normal sample; (iii) somatic score parameter (SSC) >30 (for VarScan2 and SomaticSniper); and (iv) base quality (BQ) parameter for mutation-supporting reads in the tumour sample >20 (for MuSE and MuTect2).	('tumour', 'Disease', (345, 351))	('tumour', 'Phenotype', 'HP:0002664', (548, 554))	('mutations', 'Var', (76, 85))	('tumour', 'Phenotype', 'HP:0002664', (178, 184))	('mutations', 'Var', (54, 63))	('tumour', 'Disease', 'MESH:D009369', (548, 554))	('tumour', 'Disease', 'MESH:D009369', (178, 184))	('tumour', 'Phenotype', 'HP:0002664', (345, 351))	('tumour', 'Disease', (548, 554))	('tumour', 'Disease', (178, 184))	('tumour', 'Disease', 'MESH:D009369', (345, 351))	('higher', 'PosReg', (292, 298))
347907	33038763	Additionally, we checked if any of the analyzed miRNA genes are localized within DAC blacklisted regions wgEncodeDacMapabilityConsensusExcludable.bed.gz from Genome Browser for hg19) and found 7 miRNA genes at least partially overlapping with the blacklisted region (hsa-mir-12136, hsa-mir-4485, hsa-mir-9901, hsa-mir-3648-2, hsa-mir-10396a, hsa-mir-4477a-1, hsa-mir-4477b-1).	('hsa-mir-4477b', 'Gene', '100616194', (359, 372))	('hsa-mir-4485', 'Gene', (282, 294))	('hsa-mir-4477a', 'Gene', (342, 355))	('hsa-mir-12136', 'Var', (267, 280))	('hsa-mir-4477a', 'Gene', '100616184', (342, 355))	('miR', 'Gene', '220972', (195, 198))	('hsa-mir-3648-2', 'Gene', (310, 324))	('miR', 'Gene', (195, 198))	('hsa-mir-4477b', 'Gene', (359, 372))	('hsa-mir-3648-2', 'Gene', '103504731', (310, 324))	('miR', 'Gene', '220972', (48, 51))	('miR', 'Gene', (48, 51))	('hsa-mir-4485', 'Gene', '100616263', (282, 294))
347909	33038763	Due to the used statistical approach, both ordinary binomial analysis and functionally-weighted analysis (see below) induced threshold of a minimal number of mutations assigned to relevant miRNA genes and only genes with at least 3 mutations (ordinary binomial) or 4 weighted points (functionally-weighted) were considered as overmutated.	('mutations', 'Var', (158, 167))	('miR', 'Gene', '220972', (189, 192))	('miR', 'Gene', (189, 192))
347912	33038763	The level of miRNA expression was classified to the following categories based on average reads_per_million_miRNA_mapped (RPM) values calculated for particular cancer types: <1 RPM, not expressed; 1-20 RPM, low level (low); 21-100 RPM medium level (medium); >101 RPM high level (high).	('21-100', 'Var', (224, 230))	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('miR', 'Gene', '220972', (13, 16))	('miR', 'Gene', (13, 16))	('cancer', 'Disease', (160, 166))	('miR', 'Gene', '220972', (108, 111))	('miR', 'Gene', (108, 111))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))
347915	33038763	OncordriveFML was run using CADD score (hg38, version 1.6) against the mutations in Pan-Cancer and individual cancer types.	('Cancer', 'Phenotype', 'HP:0002664', (88, 94))	('Pan-Cancer', 'Disease', (84, 94))	('cancer', 'Disease', (110, 116))	('Pan-Cancer', 'Disease', 'MESH:D009369', (84, 94))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('mutations', 'Var', (71, 80))	('hg38', 'Gene', (40, 44))	('hg38', 'Gene', '8549', (40, 44))	('cancer', 'Disease', 'MESH:D009369', (110, 116))
347919	33038763	For extraction/analysis of the mutations, we used a pipeline similar to that described above for the TCGA mutations, with minor modifications resulting from differences in input files (the code is available in the github repository on icgc_hg19 branch https://github.com/martynaut/pancancer_mirnome/tree/icgc_hg19).	('TCGA', 'Gene', (101, 105))	('cancer', 'Disease', 'MESH:D009369', (284, 290))	('cancer', 'Disease', (284, 290))	('mutations', 'Var', (106, 115))	('cancer', 'Phenotype', 'HP:0002664', (284, 290))
347922	33038763	To further evaluate the reliability of the identified hotspot miRNA genes, we recalculated the mutation enrichment significance, weighting the mutation occurrences by the following factors: 2 x, mutations in seeds (guide strand only); 1.5 x, mutations in miRNAs (miRNA duplex), mutations affecting the functional motifs (identified by miRNAmotif) or +/-1 positions of DROSHA/DICER1 cleavage sites; and 1 x, other mutations.	('mutations', 'Var', (278, 287))	('miR', 'Gene', '220972', (335, 338))	('miR', 'Gene', '220972', (263, 266))	('miR', 'Gene', (335, 338))	('miR', 'Gene', (263, 266))	('DICER1', 'Gene', (375, 381))	('affecting', 'Reg', (288, 297))	('miR', 'Gene', '220972', (62, 65))	('miR', 'Gene', (62, 65))	('miR', 'Gene', '220972', (255, 258))	('miR', 'Gene', (255, 258))	('functional', 'MPA', (302, 312))	('mutations', 'Var', (242, 251))	('DICER1', 'Gene', '23405', (375, 381))	('DROSHA', 'Gene', '29102', (368, 374))	('DROSHA', 'Gene', (368, 374))
347929	33038763	In total, we found 10,588 mutations in miRNA genes; however, as the number of miRNome mutations in hypermutated samples (samples with >10,000 mutations in the whole exome) was highly correlated with the general mutation burden in these samples (Fig.	('mutations', 'Var', (86, 95))	('miR', 'Gene', '220972', (39, 42))	('miR', 'Gene', (39, 42))	('correlated', 'Reg', (183, 193))	('miR', 'Gene', '220972', (78, 81))	('miR', 'Gene', (78, 81))	('mutation burden', 'MPA', (211, 226))
347930	33038763	The remaining 7,110 mutations (Supplementary Table S2), including 6,312 substitutions, 198 insertions, and 600 deletions, were found in 1179 distinct miRNA genes.	('miR', 'Gene', '220972', (150, 153))	('insertions', 'Var', (91, 101))	('miR', 'Gene', (150, 153))	('substitutions', 'Var', (72, 85))
347931	33038763	At the Pan-Cancer level, 3,370/10,255 (33%) samples had at least one miRNome mutation.	('mutation', 'Var', (77, 85))	('Cancer', 'Phenotype', 'HP:0002664', (11, 17))	('Pan-Cancer', 'Disease', (7, 17))	('miR', 'Gene', '220972', (69, 72))	('miR', 'Gene', (69, 72))	('Pan-Cancer', 'Disease', 'MESH:D009369', (7, 17))
347933	33038763	It should be noted, however, that the occurrence of mutations in miRNome is consistent with the general burden of mutations in particular cancer types (Fig.	('mutations', 'Var', (52, 61))	('cancer', 'Disease', (138, 144))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('miR', 'Gene', '220972', (65, 68))	('miR', 'Gene', (65, 68))	('cancer', 'Disease', 'MESH:D009369', (138, 144))
347935	33038763	It is also noteworthy that some cancers, including COAD, STAD, and UCEC, have substantially heightened numbers of indel mutations (Table 1), which is consistent with known cancerous mechanisms, including DNA repair defects, associated with those cancers.	('cancers', 'Phenotype', 'HP:0002664', (246, 253))	('cancers', 'Disease', 'MESH:D009369', (32, 39))	('COAD', 'Disease', (51, 55))	('cancers', 'Phenotype', 'HP:0002664', (32, 39))	('cancerous', 'Disease', 'MESH:D009369', (172, 181))	('cancers', 'Disease', (246, 253))	('cancers', 'Disease', (32, 39))	('cancers', 'Disease', 'MESH:D009369', (246, 253))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('indel mutations', 'Var', (114, 129))	('UCEC', 'Disease', (67, 71))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('heightened', 'PosReg', (92, 102))	('COAD', 'Disease', 'MESH:D029424', (51, 55))	('cancerous', 'Disease', (172, 181))	('STAD', 'Disease', (57, 61))
347936	33038763	For a closer examination of the localization of sequence variants in subregions of miRNA precursors, we superimposed the identified variants on the consensus miRNA precursor structure and categorized them according to localization in the miRNA gene subregions (Fig.	('miR', 'Gene', '220972', (158, 161))	('miR', 'Gene', (158, 161))	('variants', 'Var', (132, 140))	('miR', 'Gene', '220972', (83, 86))	('miR', 'Gene', (83, 86))	('miR', 'Gene', '220972', (238, 241))	('miR', 'Gene', (238, 241))
347942	33038763	The most frequently mutated miRNA genes are presented in Fig.	('miR', 'Gene', '220972', (28, 31))	('mutated', 'Var', (20, 27))	('miR', 'Gene', (28, 31))
347944	33038763	As mutations may not be randomly distributed in the genome and to consider the enrichment of functional variants, we next performed functionally weighted analysis, increasing the value of mutations located in most likely functional sequences including seed regions, DROSHA/DICER1 cleavage sites, miRNA duplexes, and protein binding motifs (see Materials and Methods section).	('DROSHA', 'Gene', (266, 272))	('DICER1', 'Gene', '23405', (273, 279))	('protein', 'Protein', (316, 323))	('DICER1', 'Gene', (273, 279))	('miR', 'Gene', '220972', (296, 299))	('increasing', 'PosReg', (164, 174))	('miR', 'Gene', (296, 299))	('mutations', 'Var', (188, 197))	('DROSHA', 'Gene', '29102', (266, 272))
347947	33038763	Two main types of overmutated miRNA genes can be distinguished based on mutation occurrence in various cancer types: one shows a somewhat sample-number dependent distribution of mutations across various cancer types (e.g., hsa-miR-1324, hsa-miR-6891, hsa-miR-3675), and the other shows an overrepresentation of mutations in one or two cancer types (e.g., hsa-miR-1303 for STAD, hsa-miR-890 for LUAD, hsa-miR-519e for OV).	('miR', 'Gene', (30, 33))	('hsa-miR-1324', 'Gene', (223, 235))	('hsa-miR-890', 'Gene', '100126303', (378, 389))	('LUAD', 'Disease', (394, 398))	('hsa-miR-519e', 'Gene', '574463', (400, 412))	('miR', 'Gene', '220972', (241, 244))	('cancer', 'Disease', (335, 341))	('mutations', 'Var', (311, 320))	('cancer', 'Disease', 'MESH:D009369', (203, 209))	('miR', 'Gene', '220972', (227, 230))	('cancer', 'Disease', (103, 109))	('cancer', 'Phenotype', 'HP:0002664', (335, 341))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('hsa-miR-6891', 'Gene', (237, 249))	('miR', 'Gene', '220972', (255, 258))	('miR', 'Gene', (241, 244))	('miR', 'Gene', (227, 230))	('miR', 'Gene', '220972', (359, 362))	('miR', 'Gene', '220972', (382, 385))	('hsa-miR-3675', 'Gene', (251, 263))	('hsa-miR-890', 'Gene', (378, 389))	('miR', 'Gene', (255, 258))	('hsa-miR-6891', 'Gene', '102465537', (237, 249))	('cancer', 'Disease', 'MESH:D009369', (335, 341))	('cancer', 'Disease', (203, 209))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('miR', 'Gene', (359, 362))	('miR', 'Gene', (382, 385))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('miR', 'Gene', '220972', (30, 33))	('miR', 'Gene', '220972', (404, 407))	('hsa-miR-1324', 'Gene', '100302212', (223, 235))	('hsa-miR-1303', 'Gene', (355, 367))	('hsa-miR-519e', 'Gene', (400, 412))	('hsa-miR-1303', 'Gene', '100302284', (355, 367))	('hsa-miR-3675', 'Gene', '100500876', (251, 263))	('mutations', 'Var', (178, 187))	('miR', 'Gene', (404, 407))
347948	33038763	As some mutations were unevenly distributed across cancer types, we also performed mutation enrichment analysis for individual cancers.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('cancers', 'Disease', (127, 134))	('mutations', 'Var', (8, 17))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('cancers', 'Disease', 'MESH:D009369', (127, 134))	('cancers', 'Phenotype', 'HP:0002664', (127, 134))	('cancer', 'Disease', (127, 133))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))
347950	33038763	These lists included 8 and 12 cancer-specific overmutated genes, respectively, i.e., genes enriched in mutations in one or more cancers but not in Pan-Cancer.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('cancers', 'Disease', 'MESH:D009369', (128, 135))	('mutations', 'Var', (103, 112))	('cancers', 'Phenotype', 'HP:0002664', (128, 135))	('cancers', 'Disease', (128, 135))	('overmutated', 'PosReg', (46, 57))	('cancer', 'Disease', (30, 36))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('Cancer', 'Phenotype', 'HP:0002664', (151, 157))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('Pan-Cancer', 'Disease', (147, 157))	('Pan-Cancer', 'Disease', 'MESH:D009369', (147, 157))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('cancer', 'Disease', (128, 134))
347951	33038763	Among the most striking examples of the cancer-specific overmutated genes are (i) hsa-miR-3613 with 7 mutations in UCEC but also with 1 mutation in CHOL and 1 in ESCA, (ii) hsa-miR-135a-2 with 8 mutations in SKCM and 2 in UCEC, and (iii) hsa-miR-664b with 6 mutations in LUAD and 1 or 2 in UCEC, STAD, SKCM, and CESC.	('overmutated', 'PosReg', (56, 67))	('hsa-miR-664b', 'Gene', '100847052', (238, 250))	('hsa-miR-3613', 'Gene', '100500908', (82, 94))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('cancer', 'Disease', (40, 46))	('CHOL', 'CellLine', 'None', (148, 152))	('hsa-miR-664b', 'Gene', (238, 250))	('hsa-miR-135a-2', 'Gene', (173, 187))	('mutations', 'Var', (102, 111))	('mutations', 'Var', (195, 204))	('hsa-miR-135a-2', 'Gene', '406926', (173, 187))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('hsa-miR-3613', 'Gene', (82, 94))
347956	33038763	3b and Supplementary Table S4, we visualized the occurrence of mutations in overmutated genes as a percentage of patients in the individual cancers and Pan-Cancer.	('mutations', 'Var', (63, 72))	('Cancer', 'Phenotype', 'HP:0002664', (156, 162))	('Pan-Cancer', 'Disease', 'MESH:D009369', (152, 162))	('patients', 'Species', '9606', (113, 121))	('cancers', 'Phenotype', 'HP:0002664', (140, 147))	('cancers', 'Disease', (140, 147))	('cancers', 'Disease', 'MESH:D009369', (140, 147))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('Pan-Cancer', 'Disease', (152, 162))
347957	33038763	3b, the highest frequency of mutations belonged to hsa-miR-142 in DLBC, but other overmutated genes often exceeded a frequency of 2% or even 5% in individual cancers, e.g., hsa-miR-1303 in STAD (6%) and hsa-miR-3132 in CHOL (4,5%).	('hsa-miR-1303', 'Gene', '100302284', (173, 185))	('hsa-miR-142', 'Gene', (51, 62))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('DLBC', 'Disease', (66, 70))	('STAD', 'Disease', (189, 193))	('mutations', 'Var', (29, 38))	('cancers', 'Phenotype', 'HP:0002664', (158, 165))	('CHOL', 'Disease', (219, 223))	('CHOL', 'CellLine', 'None', (219, 223))	('cancers', 'Disease', (158, 165))	('hsa-miR-142', 'Gene', '406934', (51, 62))	('cancers', 'Disease', 'MESH:D009369', (158, 165))	('hsa-miR-1303', 'Gene', (173, 185))	('hsa-miR-3132', 'Gene', (203, 215))	('hsa-miR-3132', 'Gene', '100423039', (203, 215))
347958	33038763	For reasons explained in the next section, we do not comment here on mutations in hsa-miR-1324.	('mutations', 'Var', (69, 78))	('hsa-miR-1324', 'Gene', (82, 94))	('hsa-miR-1324', 'Gene', '100302212', (82, 94))
347963	33038763	We also confirmed the recurrence of mutations in hsa-miR-21 as previously identified with the Annotative Database of miRNA Elements (ADmiRe).	('miR', 'Gene', (135, 138))	('miR', 'Gene', '220972', (53, 56))	('miR', 'Gene', (53, 56))	('hsa-miR-21', 'Gene', '406991', (49, 59))	('mutations', 'Var', (36, 45))	('miR', 'Gene', '220972', (117, 120))	('hsa-miR-21', 'Gene', (49, 59))	('miR', 'Gene', (117, 120))	('miR', 'Gene', '220972', (135, 138))
347964	33038763	As some miRNA coded in a cluster are not only simultaneously expressed but also are functionally related, e.g., may target different genes in the same pathway, we compared enrichment of the mutations in 155 clusters of miRNA genes defined as a group of miRNAs with genomic inter-miRNA distance <10,000 bp (Supplementary Table S5).	('miR', 'Gene', '220972', (253, 256))	('miR', 'Gene', (253, 256))	('mutations', 'Var', (190, 199))	('miR', 'Gene', '220972', (279, 282))	('miR', 'Gene', (279, 282))	('miR', 'Gene', '220972', (219, 222))	('miR', 'Gene', (219, 222))	('miR', 'Gene', '220972', (8, 11))	('miR', 'Gene', (8, 11))
347965	33038763	As shown in Supplementary Table S6, mutations are enriched (at adjusted p < 0.01, binomial distribution test) in 4 of the miRNA clusters in Pan-Cancer and up to 3 clusters in individual cancer types.	('Cancer', 'Phenotype', 'HP:0002664', (144, 150))	('Pan-Cancer', 'Disease', (140, 150))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('miR', 'Gene', '220972', (122, 125))	('mutations', 'Var', (36, 45))	('miR', 'Gene', (122, 125))	('Pan-Cancer', 'Disease', 'MESH:D009369', (140, 150))	('cancer', 'Disease', (186, 192))	('cancer', 'Disease', 'MESH:D009369', (186, 192))
347972	33038763	The list and characteristics of hotspot mutations along with the expression level of corresponding miRNAs are shown in Table 4 and Supplementary Table S7.	('mutations', 'Var', (40, 49))	('miR', 'Gene', '220972', (99, 102))	('miR', 'Gene', (99, 102))
347973	33038763	The two most frequently recurring point mutations were found in hsa-miR-1324 (chr3:75630855T>C[+] and chr3:375630794C>G[+], Fig.	('chr3:375630794C>G', 'SUBSTITUTION', 'None', (102, 119))	('chr3:75630855T>C', 'Var', (78, 94))	('chr3:375630794C>G', 'Var', (102, 119))	('hsa-miR-1324', 'Gene', '100302212', (64, 76))	('hsa-miR-1324', 'Gene', (64, 76))	('chr3:75630855T>C', 'SUBSTITUTION', 'None', (78, 94))
347974	33038763	Other interesting hotspot mutations include hsa-miR-142 (chr17:58331260A>G[-] in the seed sequence of miR-142-3p) found in DLBC (3 mutations) and hsa-miR-519e (chr19:53679964G>A/T[+] and chr19:53679965G>A[+]) found in Pan-Cancer and OV.	('hsa-miR-142', 'Gene', '406934', (44, 55))	('miR', 'Gene', (102, 105))	('Pan-Cancer', 'Disease', 'MESH:D009369', (218, 228))	('chr19:53679965G>A', 'Var', (187, 204))	('chr19:53679964G>A', 'Var', (160, 177))	('chr17:58331260A>G', 'Var', (57, 74))	('miR', 'Gene', '220972', (150, 153))	('Cancer', 'Phenotype', 'HP:0002664', (222, 228))	('chr19:53679964G>A', 'SUBSTITUTION', 'None', (160, 177))	('chr19:53679965G>A', 'SUBSTITUTION', 'None', (187, 204))	('miR', 'Gene', '220972', (48, 51))	('miR', 'Gene', (150, 153))	('Pan-Cancer', 'Disease', (218, 228))	('miR', 'Gene', '220972', (102, 105))	('hsa-miR-519e', 'Gene', (146, 158))	('hsa-miR-142', 'Gene', (44, 55))	('chr17:58331260A>G', 'SUBSTITUTION', 'None', (57, 74))	('miR', 'Gene', (48, 51))	('hsa-miR-519e', 'Gene', '574463', (146, 158))
347975	33038763	Please note that mutation occurring in a miRNA gene encoded on the minus chromosome strand in the sequence of a miRNA precursor occurs in reverse/complementary orientation; therefore, to avoid, confusion, a [+] or [-] sign indicates the orientation of the affected gene.	('confusion', 'Phenotype', 'HP:0001289', (194, 203))	('miR', 'Gene', '220972', (112, 115))	('miR', 'Gene', (112, 115))	('mutation', 'Var', (17, 25))	('miR', 'Gene', '220972', (41, 44))	('miR', 'Gene', (41, 44))
347977	33038763	Additionally, in our sequencing analysis performed within the framework of other projects, we found also one mutation in the seed region of hsa-miR-142 (chr17:58331263C>T[-]) in the Raji Burkitt lymphoma cell line (out of 5 Burkitt's lymphoma cell lines tested) (Fig.	('Burkitt lymphoma', 'Disease', (187, 203))	('Burkitt lymphoma', 'Phenotype', 'HP:0030080', (187, 203))	('hsa-miR-142', 'Gene', '406934', (140, 151))	('Raji', 'CellLine', 'CVCL:0511', (182, 186))	('Burkitt lymphoma', 'Disease', 'MESH:D002051', (187, 203))	("Burkitt's lymphoma", 'Disease', 'MESH:D002051', (224, 242))	('lymphoma', 'Phenotype', 'HP:0002665', (234, 242))	('chr17:58331263C>T', 'Var', (153, 170))	('lymphoma', 'Phenotype', 'HP:0002665', (195, 203))	('hsa-miR-142', 'Gene', (140, 151))	("Burkitt's lymphoma", 'Disease', (224, 242))	('chr17:58331263C>T', 'SUBSTITUTION', 'None', (153, 170))
347978	33038763	The occurrence of hsa-miR-142 mutations in haematological cancers may be consistent with the high abundance of miR-142-3p in mature hematologic cells and with the observation that loss of the miRNA impairs the development and function of different hematologic lineages.	('miR', 'Gene', '220972', (22, 25))	('hsa-miR-142', 'Gene', (18, 29))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('impairs', 'NegReg', (198, 205))	('miR', 'Gene', (111, 114))	('miR', 'Gene', (192, 195))	('miR', 'Gene', '220972', (192, 195))	('cancers', 'Phenotype', 'HP:0002664', (58, 65))	('loss', 'Var', (180, 184))	('mutations', 'Var', (30, 39))	('haematological cancers', 'Disease', (43, 65))	('hsa-miR-142', 'Gene', '406934', (18, 29))	('miR', 'Gene', '220972', (111, 114))	('miR', 'Gene', (22, 25))	('haematological cancers', 'Disease', 'MESH:D009369', (43, 65))
347980	33038763	In this study, we found 16 mutations in hsa-miR-142.	('mutations', 'Var', (27, 36))	('hsa-miR-142', 'Gene', '406934', (40, 51))	('hsa-miR-142', 'Gene', (40, 51))
347981	33038763	Consistent with previous studies, we identified the highest number of mutations in DLBC (10 mutations, including 3 in one sample) and LAML (2 mutations), but we also found 4 mutations in solid tumours, i.e., in UCEC, BLCA, GBM, and BRCA, in which the hsa-miR-142 have not been found before.	('tumours', 'Disease', 'MESH:D009369', (193, 200))	('mutations', 'Var', (70, 79))	('AML', 'Disease', 'MESH:D015470', (135, 138))	('UCEC', 'Disease', (211, 215))	('GBM', 'Disease', (223, 226))	('tumours', 'Disease', (193, 200))	('hsa-miR-142', 'Gene', '406934', (251, 262))	('AML', 'Disease', (135, 138))	('mutations', 'Var', (92, 101))	('tumour', 'Phenotype', 'HP:0002664', (193, 199))	('BRCA', 'Gene', '672', (232, 236))	('BLCA', 'Disease', (217, 221))	('hsa-miR-142', 'Gene', (251, 262))	('BRCA', 'Gene', (232, 236))	('tumours', 'Phenotype', 'HP:0002664', (193, 200))	('DLBC', 'Gene', (83, 87))
347982	33038763	Five of the mutations in DLBC are located in the seed sequence of miR-142-3p, three in the 7th nucleotide (significantly recurring position chr17:58331260A>G[-]) and two in the 6th nucleotide (chr17:58331261C>G/T[-]) of the seed.	('chr17:58331260A>G', 'Var', (140, 157))	('mutations', 'Var', (12, 21))	('miR', 'Gene', (66, 69))	('chr17:58331261C>G', 'Var', (193, 210))	('miR', 'Gene', '220972', (66, 69))	('DLBC', 'Gene', (25, 29))	('chr17:58331260A>G', 'SUBSTITUTION', 'None', (140, 157))	('chr17:58331261C>G', 'SUBSTITUTION', 'None', (193, 210))
347983	33038763	Additionally, one mutation (chr17:58331264T>C[-]) was detected in the 3rd seed nucleotide in LAML.	('AML', 'Disease', 'MESH:D015470', (94, 97))	('chr17:58331264T>C', 'SUBSTITUTION', 'None', (28, 45))	('AML', 'Disease', (94, 97))	('chr17:58331264T>C', 'Var', (28, 45))
347984	33038763	To better understand the distribution of mutations in hsa-miR-142, we combined the mutations detected in our study with the mutations detected previously (Fig.	('mutations', 'Var', (41, 50))	('hsa-miR-142', 'Gene', '406934', (54, 65))	('hsa-miR-142', 'Gene', (54, 65))
347985	33038763	The distribution of mutations shows pronounced clustering of the mutations in the miR-142-3p seed region, with chr17:58331260A[-] being the most frequently mutated nucleotide, substituted with either G[-] (n=8) or T[-] (n=1).	('mutations', 'Var', (65, 74))	('chr17:58331260A[-]', 'Var', (111, 129))	('miR', 'Gene', '220972', (82, 85))	('miR', 'Gene', (82, 85))
347986	33038763	This result may suggest that the miRNA hairpin precursor is quite a fragile structure, and therefore, almost any mutation may be deleterious for the gene, either by disturbing the structure of the precursor or by disruption of the seed sequence.	('miR', 'Gene', '220972', (33, 36))	('mutation', 'Var', (113, 121))	('miR', 'Gene', (33, 36))	('disturbing', 'Reg', (165, 175))	('structure', 'MPA', (180, 189))	('disruption', 'Reg', (213, 223))
347987	33038763	A recent functional study of two seed mutations, i.e., chr17:58331264T>C[-] and chr17:58331261C>G[-], showed that even though the mutations are located in miR-142-3p, they result in a decrease in both miR-142-3p and miR-142-5p levels and reverse the miR-5p:3p ratio (in favour of miR-3p).	('miR', 'Gene', (280, 283))	('chr17:58331264T>C', 'Var', (55, 72))	('miR', 'Gene', (250, 253))	('decrease', 'NegReg', (184, 192))	('miR', 'Gene', '220972', (250, 253))	('miR', 'Gene', '220972', (216, 219))	('chr17:58331261C>G', 'Var', (80, 97))	('miR', 'Gene', (216, 219))	('chr17:58331264T>C', 'SUBSTITUTION', 'None', (55, 72))	('reverse', 'NegReg', (238, 245))	('miR', 'Gene', '220972', (155, 158))	('miR', 'Gene', (155, 158))	('miR', 'Gene', '220972', (201, 204))	('miR', 'Gene', (201, 204))	('chr17:58331261C>G', 'SUBSTITUTION', 'None', (80, 97))	('miR', 'Gene', '220972', (280, 283))
347988	33038763	The functional consequences of the mutations are (i) aberration of hematopoietic differentiation, enhancing the myeloid and suppressing the lymphoid potential of hematopoietic progenitors, and (ii) inefficient repression of ASH1L, resulting in increased levels of HOXA9 and A10 (positively regulated by ASH1L) and ultimately leukemic transformation.	('leukemic transformation', 'Disease', 'MESH:D002472', (325, 348))	('HOXA9', 'Gene', '3205', (264, 269))	('A10', 'Gene', '28870', (274, 277))	('lymphoid potential of hematopoietic progenitors', 'CPA', (140, 187))	('myeloid', 'CPA', (112, 119))	('suppressing', 'NegReg', (124, 135))	('leukemic transformation', 'Disease', (325, 348))	('A10', 'Gene', (274, 277))	('hematopoietic differentiation', 'CPA', (67, 96))	('ASH1L', 'Gene', (224, 229))	('ASH1L', 'Gene', (303, 308))	('ASH1L', 'Gene', '55870', (224, 229))	('enhancing', 'PosReg', (98, 107))	('ASH1L', 'Gene', '55870', (303, 308))	('HOXA9', 'Gene', (264, 269))	('inefficient repression', 'NegReg', (198, 220))	('levels', 'MPA', (254, 260))	('increased', 'PosReg', (244, 253))	('mutations', 'Var', (35, 44))
347993	33038763	We found that hsa-miR-205 was overmutated in Pan-Cancer (in total, 15 mutations) with mutations in SKCM (5 mutations), CESC (3), LUSC (2), BLCA (2), COAD, ESCA, and THYM.	('mutations', 'Var', (86, 95))	('Pan-Cancer', 'Disease', 'MESH:D009369', (45, 55))	('COAD', 'Disease', 'MESH:D029424', (149, 153))	('SKCM', 'Gene', (99, 103))	('overmutated', 'PosReg', (30, 41))	('COAD', 'Disease', (149, 153))	('ESCA', 'Disease', (155, 159))	('Pan-Cancer', 'Disease', (45, 55))	('THYM', 'Disease', (165, 169))	('CESC', 'Disease', (119, 123))	('hsa-miR-205', 'Gene', '406988', (14, 25))	('Cancer', 'Phenotype', 'HP:0002664', (49, 55))	('hsa-miR-205', 'Gene', (14, 25))
347995	33038763	Five of the mutations are located in a single hotspot position (chr1:209432167C>T[+]) that is the first position of the seed sequence of miR-205-5p (guide miRNA).	('miR', 'Gene', '220972', (137, 140))	('mutations', 'Var', (12, 21))	('miR', 'Gene', (137, 140))	('chr1:209432167C>T', 'Var', (64, 81))	('miR-205', 'Gene', (137, 144))	('miR', 'Gene', '220972', (155, 158))	('miR-205', 'Gene', '406988', (137, 144))	('miR', 'Gene', (155, 158))	('chr1:209432167C>T', 'SUBSTITUTION', 'None', (64, 81))
347996	33038763	As we have shown before, the mutation may substantially affect target recognition, disrupting 250/288 (87%) predicted miR-205-5p targets and creating 471 new targets.	('affect', 'Reg', (56, 62))	('mutation', 'Var', (29, 37))	('miR-205', 'Gene', '406988', (118, 125))	('target recognition', 'MPA', (63, 81))	('disrupting', 'NegReg', (83, 93))	('miR-205', 'Gene', (118, 125))
347998	33038763	On the other hand, the recurrence of a specific mutation may suggest its gain-of-function character, such as the creation of a new seed/miRNA targeting the gene, whose downregulation may be beneficial for cancer.	('cancer', 'Disease', 'MESH:D009369', (205, 211))	('cancer', 'Disease', (205, 211))	('miR', 'Gene', '220972', (136, 139))	('miR', 'Gene', (136, 139))	('mutation', 'Var', (48, 56))	('gain-of-function', 'PosReg', (73, 89))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))
347999	33038763	The other hsa-miR-205 mutations are dispersed alongside the miRNA duplex, hairpin loop, and flanking sequences.	('miR', 'Gene', '220972', (60, 63))	('miR', 'Gene', (60, 63))	('hsa-miR-205', 'Gene', '406988', (10, 21))	('miR', 'Gene', '220972', (14, 17))	('mutations', 'Var', (22, 31))	('miR', 'Gene', (14, 17))	('hsa-miR-205', 'Gene', (10, 21))
348000	33038763	The mutations may affect the structure of the miRNA precursor and consequently its processing and effective miRNA biogenesis.	('miR', 'Gene', (46, 49))	('affect', 'Reg', (18, 24))	('miR', 'Gene', '220972', (108, 111))	('miR', 'Gene', (108, 111))	('mutations', 'Var', (4, 13))	('processing', 'MPA', (83, 93))	('structure', 'MPA', (29, 38))	('miR', 'Gene', '220972', (46, 49))
348001	33038763	An example of a mutation seriously affecting the structure is chr1:209432226G>A[+] transition, which disrupts the structure in the DROSHA cleavage site (Fig.	('chr1:209432226G>A', 'Var', (62, 79))	('chr1:209432226G>A', 'SUBSTITUTION', 'None', (62, 79))	('disrupts', 'NegReg', (101, 109))	('structure', 'MPA', (49, 58))	('DROSHA', 'Gene', '29102', (131, 137))	('DROSHA', 'Gene', (131, 137))
348005	33038763	We found that hsa-let-7d was overmutated in Pan-Cancer (in total 23 mutations) and UCEC (16 mutations) but was also recurrently mutated in STAD (3) and COAD (2).	('COAD', 'Disease', 'MESH:D029424', (152, 156))	('Pan-Cancer', 'Disease', (44, 54))	('hsa-let-7d', 'Gene', '406886', (14, 24))	('UCEC', 'Disease', (83, 87))	('overmutated', 'PosReg', (29, 40))	('Pan-Cancer', 'Disease', 'MESH:D009369', (44, 54))	('Cancer', 'Phenotype', 'HP:0002664', (48, 54))	('COAD', 'Disease', (152, 156))	('hsa-let-7d', 'Gene', (14, 24))	('mutations', 'Var', (68, 77))
348006	33038763	All the mutations are indels of the poly-A10 tract (chr9:94178817[+] delA (20), delAA (1), and insA (2)) located in a 5p flanking sequence of the let-7d precursor (Fig.	('A10', 'Gene', (41, 44))	('let-7d', 'Gene', (146, 152))	('let-7d', 'Gene', '406886', (146, 152))	('mutations', 'Var', (8, 17))	('delAA', 'Mutation', 'c.delAA', (80, 85))	('delAA', 'Var', (80, 85))	('A10', 'Gene', '28870', (41, 44))
348007	33038763	Although the mutation does not directly affect the sequence of mature let-7d, it may still affect miRNA processing.	('mutation', 'Var', (13, 21))	('miR', 'Gene', '220972', (98, 101))	('miR', 'Gene', (98, 101))	('affect', 'Reg', (91, 97))	('let-7d', 'Gene', (70, 76))	('let-7d', 'Gene', '406886', (70, 76))
348008	33038763	It should be noted, however, that indels in the polynucleotide tract, such as those observed in hsa-let-7d, may result from microsatellite instability (MSI).	('hsa-let-7d', 'Gene', '406886', (96, 106))	('result from', 'Reg', (112, 123))	('indels', 'Var', (34, 40))	('microsatellite instability', 'Disease', 'MESH:D053842', (124, 150))	('hsa-let-7d', 'Gene', (96, 106))	('polynucleotide', 'Chemical', 'MESH:D011119', (48, 62))	('microsatellite instability', 'Disease', (124, 150))
348009	33038763	This is consistent with the overrepresentation of the hsa-let-7d indels in cancers such as UCEC, STAD, and COAD, in which MSI is especially frequent.	('hsa-let-7d', 'Gene', (54, 64))	('cancers', 'Disease', 'MESH:D009369', (75, 82))	('cancers', 'Phenotype', 'HP:0002664', (75, 82))	('cancers', 'Disease', (75, 82))	('STAD', 'Disease', (97, 101))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('UCEC', 'Disease', (91, 95))	('COAD', 'Disease', (107, 111))	('hsa-let-7d', 'Gene', '406886', (54, 64))	('indels', 'Var', (65, 71))	('COAD', 'Disease', 'MESH:D029424', (107, 111))
348010	33038763	Hsa-miR-411 is overmutated in Pan-Cancer (19 mutations) and GBM (5 mutations) and is also recurrently mutated in SKCM (3) and ESCA (2).	('mutations', 'Var', (45, 54))	('ESCA', 'Disease', (126, 130))	('Pan-Cancer', 'Disease', (30, 40))	('Cancer', 'Phenotype', 'HP:0002664', (34, 40))	('overmutated', 'PosReg', (15, 26))	('SKCM', 'Disease', (113, 117))	('Pan-Cancer', 'Disease', 'MESH:D009369', (30, 40))	('Hsa-miR-411', 'Gene', (0, 11))	('Hsa-miR-411', 'Gene', '693121', (0, 11))
348012	33038763	All mutations in hsa-miR-411 are substitutions and are generally dispersed over the gene without clustering in any specific region or hotspot (Fig.	('mutations', 'Var', (4, 13))	('hsa-miR-411', 'Gene', '693121', (17, 28))	('hsa-miR-411', 'Gene', (17, 28))
348017	33038763	The majority of the mutations are located in two subsequent hotspot positions, i.e., the 12th and 13th nucleotides (chr19:53679964G>A/T[+] and chr19:53679965G>A[+]) of the miR-519e-5p (passenger) strand (Fig.	('chr19:53679964G>A', 'SUBSTITUTION', 'None', (116, 133))	('chr19:53679964G>A', 'Var', (116, 133))	('miR', 'Gene', '220972', (172, 175))	('miR', 'Gene', (172, 175))	('chr19:53679965G>A', 'SUBSTITUTION', 'None', (143, 160))	('chr19:53679965G>A', 'Var', (143, 160))
348023	33038763	Hsa-miR-664b is a highly validated (miRBase) and moderately conserved miRNA gene that substantially overlaps with the SNORA36A H/ACA box small nuclear RNA (snoRNA; snoRNABase) playing a role in the pseudouridylation of rRNAs and snRNAs; therefore, all mutations may also affect the function of snoRNA.	('snoRNA', 'Gene', (294, 300))	('miR', 'Gene', '220972', (4, 7))	('snoRNA', 'Gene', '6079', (164, 170))	('miR', 'Gene', (70, 73))	('miR', 'Gene', (36, 39))	('Hsa-miR-664b', 'Gene', '100847052', (0, 12))	('Hsa-miR-664b', 'Gene', (0, 12))	('snoRNA', 'Gene', '6079', (156, 162))	('miR', 'Gene', (4, 7))	('snoRNA', 'Gene', (164, 170))	('snoRNA', 'Gene', (156, 162))	('mutations', 'Var', (252, 261))	('affect', 'Reg', (271, 277))	('SNORA36A', 'Gene', (118, 126))	('snoRNA', 'Gene', '6079', (294, 300))	('function', 'MPA', (282, 290))	('miR', 'Gene', '220972', (70, 73))	('SNORA36A', 'Gene', '677817', (118, 126))	('miR', 'Gene', '220972', (36, 39))
348028	33038763	Additionally, it was overmutated in SKCM with 7 mutations, 3 of which were located at a single position (chr14:101060649C>T[+]) in the DROSHA cleavage site (Fig.	('DROSHA', 'Gene', '29102', (135, 141))	('chr14:101060649C>T', 'SUBSTITUTION', 'None', (105, 123))	('DROSHA', 'Gene', (135, 141))	('chr14:101060649C>T', 'Var', (105, 123))
348030	33038763	Other mutated cancers include LUSC (2 mutations), HNC (2 mutations) and OV, UCEC, LUAD, and GBM (with single mutations).	('cancers', 'Disease', (14, 21))	('UCEC', 'Disease', (76, 80))	('cancers', 'Phenotype', 'HP:0002664', (14, 21))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('mutations', 'Var', (57, 66))	('LUAD', 'Disease', (82, 86))	('GBM', 'Disease', (92, 95))	('cancers', 'Disease', 'MESH:D009369', (14, 21))	('LUSC', 'Disease', (30, 34))
348036	33038763	Most of the mutations occur in two positions in the 5' arm of the precursor, one of which is a hotspot mutation (chr2:113583038A>C[-]) significantly recurrent in LIHC and PAN-Cancer, localized within the passenger miRNA strand (Fig.	('LIHC', 'Disease', (162, 166))	('PAN-Cancer', 'Disease', 'MESH:D009369', (171, 181))	('miR', 'Gene', '220972', (214, 217))	('Cancer', 'Phenotype', 'HP:0002664', (175, 181))	('miR', 'Gene', (214, 217))	('PAN-Cancer', 'Disease', (171, 181))	('chr2:113583038A>C', 'SUBSTITUTION', 'None', (113, 130))	('chr2:113583038A>C', 'Var', (113, 130))
348038	33038763	The expression of hsa-miR-1302-3 was not observed in any of the TCGA cancer types, which argue against the functionality of the mutations, although, we cannot rule out that, in certain situations, some mutations may activate the expression or biogenesis of low- or not-expressed miRNAs.	('miR', 'Gene', '220972', (22, 25))	('activate', 'PosReg', (216, 224))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('miR', 'Gene', '220972', (279, 282))	('miR', 'Gene', (22, 25))	('miR', 'Gene', (279, 282))	('hsa-miR-1302-3', 'Gene', '100302128', (18, 32))	('expression', 'MPA', (229, 239))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Disease', (69, 75))	('hsa-miR-1302-3', 'Gene', (18, 32))	('biogenesis', 'MPA', (243, 253))	('mutations', 'Var', (202, 211))
348039	33038763	Finally, hsa-miR-1324 is the most commonly mutated gene, with a total of 166 mutations in Pan-Cancer, greatly exceeding the other highly mutated genes.	('Pan-Cancer', 'Disease', 'MESH:D009369', (90, 100))	('hsa-miR-1324', 'Gene', (9, 21))	('hsa-miR-1324', 'Gene', '100302212', (9, 21))	('mutations', 'Var', (77, 86))	('Cancer', 'Phenotype', 'HP:0002664', (94, 100))	('Pan-Cancer', 'Disease', (90, 100))
348040	33038763	The vast majority of the mutations (n = 146) were located in just two positions (i.e., chr3:75630855T>C[+] and chr3:375630794C>G[+]), which are also the two most highly mutated hotspots (Supplementary Fig.	('chr3:375630794C>G', 'Var', (111, 128))	('chr3:75630855T>C', 'Var', (87, 103))	('chr3:375630794C>G', 'SUBSTITUTION', 'None', (111, 128))	('chr3:75630855T>C', 'SUBSTITUTION', 'None', (87, 103))
348041	33038763	We observed similar high frequency and a similar pattern of mutations in hsa-miR-1324 in a relatively small panel of diffuse large B-cell lymphoma and Hodgkin lymphoma cell lines sequenced in our laboratory with the conventional Sanger sequencing method (data not shown).	('Hodgkin lymphoma', 'Disease', (151, 167))	('hsa-miR-1324', 'Gene', (73, 85))	('B-cell lymphoma', 'Disease', (131, 146))	('B-cell lymphoma', 'Disease', 'MESH:D016393', (131, 146))	('hsa-miR-1324', 'Gene', '100302212', (73, 85))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (131, 146))	('Hodgkin lymphoma', 'Disease', 'MESH:D006689', (151, 167))	('Hodgkin lymphoma', 'Phenotype', 'HP:0012189', (151, 167))	('lymphoma', 'Phenotype', 'HP:0002665', (159, 167))	('mutations', 'Var', (60, 69))	('lymphoma', 'Phenotype', 'HP:0002665', (138, 146))
348043	33038763	The detailed comparison of the hsa-miR-1324 sequence with its paralog counterparts revealed that the substitutions differentiating paralogs correspond (position and type of substitution) with the identified mutations.	('mutations', 'Var', (207, 216))	('hsa-miR-1324', 'Gene', '100302212', (31, 43))	('hsa-miR-1324', 'Gene', (31, 43))
348044	33038763	This indicates that the hsa-miR-1324 mutations are most likely artefacts of the sequencing procedures and/or computational analyses (e.g., mapping).	('hsa-miR-1324', 'Gene', (24, 36))	('mutations', 'Var', (37, 46))	('hsa-miR-1324', 'Gene', '100302212', (24, 36))
348046	33038763	In summary, based on the above facts, we concluded that the hsa-miR-1324 alterations are not credible somatic mutations, and therefore, we did not pursue further analysis of miR-1324.	('miR-1324', 'Gene', '100302212', (64, 72))	('miR-1324', 'Gene', '100302212', (174, 182))	('alterations', 'Var', (73, 84))	('miR-1324', 'Gene', (64, 72))	('miR-1324', 'Gene', (174, 182))	('hsa-miR-1324', 'Gene', (60, 72))	('hsa-miR-1324', 'Gene', '100302212', (60, 72))
348047	33038763	To check whether mutations may affect miRNA expression, we compared the levels of miRNAs in samples with mutations vs. samples without mutations in genes either overmutated or with hotspot mutations in a particular cancer type or Pan-Cancer.	('affect', 'Reg', (31, 37))	('cancer type or Pan-Cancer', 'Disease', 'MESH:D009369', (215, 240))	('miR', 'Gene', '220972', (82, 85))	('levels', 'MPA', (72, 78))	('miR', 'Gene', (82, 85))	('miR', 'Gene', '220972', (38, 41))	('mutations', 'Var', (105, 114))	('miR', 'Gene', (38, 41))	('Cancer', 'Phenotype', 'HP:0002664', (234, 240))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('mutations', 'Var', (17, 26))	('cancer type or Pan-Cancer', 'Disease', (215, 240))	('compared', 'Reg', (59, 67))
348052	33038763	Additionally, we found 2 miRNAs whose levels were downregulated by particular hotspot mutations (Fig.	('mutations', 'Var', (86, 95))	('miR', 'Gene', '220972', (25, 28))	('miR', 'Gene', (25, 28))	('downregulated', 'NegReg', (50, 63))	('levels', 'MPA', (38, 44))
348053	33038763	No miRNA was upregulated by the mutations.	('miR', 'Gene', (3, 6))	('mutations', 'Var', (32, 41))	('upregulated', 'PosReg', (13, 24))	('miR', 'Gene', '220972', (3, 6))
348054	33038763	The striking excess of downregulated miRNAs is consistent with the notion that most mutations are loss-of-function mutations for particular miRNA genes.	('downregulated', 'NegReg', (23, 36))	('miR', 'Gene', '220972', (37, 40))	('miR', 'Gene', (37, 40))	('loss-of-function', 'NegReg', (98, 114))	('miR', 'Gene', '220972', (140, 143))	('miR', 'Gene', (140, 143))	('mutations', 'Var', (84, 93))
348055	33038763	It should be noted, however, that due to a low number of mutations, especially in the hotspots, the analysis is of relatively low statistical power, and most results are only nominally significant (Mann-Whitney or t-test, p<0.05; Supplementary Table S9), resulting in a relatively low number of miRNAs associated with the mutations in their genes.	('miR', 'Gene', (295, 298))	('mutations', 'Var', (57, 66))	('mutations', 'Var', (322, 331))	('miR', 'Gene', '220972', (295, 298))
348057	33038763	As shown in Supplementary Table S10 only mutations in groups of miRNA genes coding for miR-509-3p show borderline significant association with a decrease of the miRNA level.	('mutations', 'Var', (41, 50))	('miR', 'Gene', '220972', (64, 67))	('miR', 'Gene', (64, 67))	('miR', 'Gene', '220972', (161, 164))	('miR', 'Gene', (161, 164))	('miR', 'Gene', '220972', (87, 90))	('miR', 'Gene', (87, 90))	('decrease', 'NegReg', (145, 153))	('miR-509-3p', 'Gene', '100847022', (87, 97))	('miR-509-3p', 'Gene', (87, 97))
348059	33038763	Changes in miRNA expression, processing, and target specificity may influence various cancer-related processes, including cell proliferation, metastasis, progression, and/or drug resistance.	('drug resistance', 'CPA', (174, 189))	('drug resistance', 'Phenotype', 'HP:0020174', (174, 189))	('progression', 'CPA', (154, 165))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('influence', 'Reg', (68, 77))	('metastasis', 'CPA', (142, 152))	('miR', 'Gene', '220972', (11, 14))	('miR', 'Gene', (11, 14))	('Changes', 'Var', (0, 7))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('cell proliferation', 'CPA', (122, 140))	('cancer', 'Disease', (86, 92))
348060	33038763	These changes may result in disease progression and treatment outcomes affecting patient survival.	('changes', 'Var', (6, 13))	('result in', 'Reg', (18, 27))	('disease progression', 'CPA', (28, 47))	('patient', 'Species', '9606', (81, 88))
348063	33038763	As survival metrics, including PFI, differ substantially between cancers, Pan-Cancer comparisons of survival in patients with mutations vs. patients without mutations may be affected by the fact that mutations are not equally distributed between cancer types.	('cancer', 'Disease', 'MESH:D009369', (246, 252))	('cancers', 'Disease', (65, 72))	('cancer', 'Disease', (246, 252))	('Cancer', 'Phenotype', 'HP:0002664', (78, 84))	('Pan-Cancer', 'Disease', (74, 84))	('patients', 'Species', '9606', (112, 120))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))	('patients', 'Species', '9606', (140, 148))	('Pan-Cancer', 'Disease', 'MESH:D009369', (74, 84))	('mutations', 'Var', (126, 135))	('cancers', 'Disease', 'MESH:D009369', (65, 72))	('cancers', 'Phenotype', 'HP:0002664', (65, 72))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))
348064	33038763	We found 22 significant associations between mutations in the overmutated miRNA genes or hotspot positions and the PFI of cancer patients (either specific cancers or PAN-Cancer) (Supplementary Table S11).	('miR', 'Gene', (74, 77))	('PAN-Cancer', 'Disease', 'MESH:D009369', (166, 176))	('mutations', 'Var', (45, 54))	('Cancer', 'Phenotype', 'HP:0002664', (170, 176))	('miR', 'Gene', '220972', (74, 77))	('patients', 'Species', '9606', (129, 137))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('PFI', 'Disease', (115, 118))	('cancers', 'Phenotype', 'HP:0002664', (155, 162))	('cancers', 'Disease', (155, 162))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('cancers', 'Disease', 'MESH:D009369', (155, 162))	('overmutated', 'PosReg', (62, 73))	('cancer', 'Disease', (155, 161))	('cancer', 'Disease', 'MESH:D009369', (155, 161))	('PAN-Cancer', 'Disease', (166, 176))
348065	33038763	The associations were linked with mutations in 12 distinct miRNA genes (Fig.	('miR', 'Gene', (59, 62))	('mutations', 'Var', (34, 43))	('associations', 'Interaction', (4, 16))	('miR', 'Gene', '220972', (59, 62))
348066	33038763	Interesting examples may be (i) hsa-miR-1244-2, in which hotspot mutations chr5:118974595C>T[+] are associated with decreased PFI in both OV and Pan-Cancer and total mutations decrease PFI in Pan-Cancer; (ii) hsa-miR-519e, in which total mutations are associated with decreased PFI in OV and hotspot mutations (chr19:53679964G>A/T[+], chr19:53679965G>A[+]) decrease PFI in OV and Pan-Cancer; and (iii) hsa-miR-602, in which hotspot mutations (chr9:137838508GC>G[+]) decrease PFI in COAD and total mutations decrease PFI in Pan-Cancer and UCEC (Fig.	('Cancer', 'Phenotype', 'HP:0002664', (527, 533))	('decrease', 'NegReg', (507, 515))	('Cancer', 'Phenotype', 'HP:0002664', (384, 390))	('Pan-Cancer', 'Disease', (192, 202))	('hsa-miR-519e', 'Gene', '574463', (209, 221))	('hsa-miR-1244-2', 'Gene', '100422885', (32, 46))	('hsa-miR-602', 'Gene', '693187', (402, 413))	('Pan-Cancer', 'Disease', 'MESH:D009369', (145, 155))	('decrease', 'NegReg', (466, 474))	('PFI', 'MPA', (475, 478))	('hsa-miR-602', 'Gene', (402, 413))	('Pan-Cancer', 'Disease', (380, 390))	('chr19:53679964G>A', 'Var', (311, 328))	('hsa-miR-1244-2', 'Gene', (32, 46))	('COAD', 'Disease', 'MESH:D029424', (482, 486))	('Pan-Cancer', 'Disease', 'MESH:D009369', (192, 202))	('chr5:118974595C>T', 'Var', (75, 92))	('chr19:53679965G>A', 'Var', (335, 352))	('Pan-Cancer', 'Disease', (523, 533))	('chr9:137838508GC>G', 'Var', (443, 461))	('chr19:53679964G>A', 'SUBSTITUTION', 'None', (311, 328))	('Pan-Cancer', 'Disease', 'MESH:D009369', (380, 390))	('Cancer', 'Phenotype', 'HP:0002664', (149, 155))	('COAD', 'Disease', (482, 486))	('chr9:137838508GC>G', 'SUBSTITUTION', 'None', (443, 461))	('Pan-Cancer', 'Disease', 'MESH:D009369', (523, 533))	('Cancer', 'Phenotype', 'HP:0002664', (196, 202))	('chr19:53679965G>A', 'SUBSTITUTION', 'None', (335, 352))	('chr5:118974595C>T', 'SUBSTITUTION', 'None', (75, 92))	('Pan-Cancer', 'Disease', (145, 155))	('hsa-miR-519e', 'Gene', (209, 221))
348067	33038763	Additionally, we observed that mutations in hsa-miR-411 that was overmutated only in ordinary binomial analysis in GBM were associated with a decrease in PFI in GBM (log-rank test, p < 0.001, data not shown).	('hsa-miR-411', 'Gene', (44, 55))	('mutations', 'Var', (31, 40))	('decrease', 'NegReg', (142, 150))	('hsa-miR-411', 'Gene', '693121', (44, 55))	('PFI', 'Disease', (154, 157))
348068	33038763	5c, mutations of particular miRNA genes associated with PFI are also frequently associated with other measures of survival (DFI, OS, DSS), which were analyzed as appropriate for particular cancers.	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('PFI', 'Disease', (56, 59))	('cancers', 'Phenotype', 'HP:0002664', (189, 196))	('associated', 'Reg', (80, 90))	('miR', 'Gene', '220972', (28, 31))	('miR', 'Gene', (28, 31))	('mutations', 'Var', (4, 13))	('cancers', 'Disease', 'MESH:D009369', (189, 196))	('DSS', 'Chemical', '-', (133, 136))	('cancers', 'Disease', (189, 196))
348069	33038763	A profound excess mutations associated with decreased survival may suggest a predominant tumour suppressor role of miRNAs, which is also consistent with the global decrease in miRNA levels observed in many cancers.	('mutations', 'Var', (18, 27))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('tumour', 'Phenotype', 'HP:0002664', (89, 95))	('tumour', 'Disease', 'MESH:D009369', (89, 95))	('tumour', 'Disease', (89, 95))	('survival', 'CPA', (54, 62))	('miR', 'Gene', (176, 179))	('cancers', 'Disease', 'MESH:D009369', (206, 213))	('cancers', 'Phenotype', 'HP:0002664', (206, 213))	('cancers', 'Disease', (206, 213))	('miR', 'Gene', '220972', (176, 179))	('miR', 'Gene', '220972', (115, 118))	('decreased', 'NegReg', (44, 53))	('miR', 'Gene', (115, 118))
348071	33038763	The analysis showed 25 statistically significant associations of mutations, predominantly with lower cancer stages (Cochran-Mantel-Haenszel test for Pan-Cancer and Fisher exact test for specific cancers, p < 0.05, Supplementary Table S12, Fig.	('Pan-Cancer', 'Disease', 'MESH:D009369', (149, 159))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('cancer', 'Disease', (101, 107))	('cancer', 'Disease', (195, 201))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('mutations', 'Var', (65, 74))	('cancers', 'Disease', 'MESH:D009369', (195, 202))	('cancers', 'Phenotype', 'HP:0002664', (195, 202))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('cancers', 'Disease', (195, 202))	('Cancer', 'Phenotype', 'HP:0002664', (153, 159))	('Pan-Cancer', 'Disease', (149, 159))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
348073	33038763	However, due to the low number of identified mutations in particular miRNA genes or hotspots, the abovementioned associations with survival and cancer stages are of very low statistical power (not corrected for multiple comparisons) and therefore must be interpreted cautiously and cannot be generalized without further experimental validation.	('mutations', 'Var', (45, 54))	('low', 'NegReg', (170, 173))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('cancer', 'Disease', (144, 150))	('miR', 'Gene', '220972', (69, 72))	('miR', 'Gene', (69, 72))	('associations', 'Interaction', (113, 125))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
348077	33038763	Although currently there is no software dedicated specifically to finding cancer driver miRNA genes and none of the currently available tools for non-coding regions take into account miRNA-specific characteristics (described above), we used OncodriveFML that predict potential cancer drivers based on CADD score of mutations deleteriousness that in non-coding regions is generally low.	('miR', 'Gene', (88, 91))	('cancer', 'Disease', (277, 283))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Disease', 'MESH:D009369', (277, 283))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('cancer', 'Disease', (74, 80))	('mutations', 'Var', (315, 324))	('miR', 'Gene', '220972', (183, 186))	('miR', 'Gene', (183, 186))	('cancer', 'Phenotype', 'HP:0002664', (277, 283))	('miR', 'Gene', '220972', (88, 91))
348080	33038763	In total, we extracted 1523 mutations (Supplementary Table S15) in 856 miRNA genes (from 1914 analyzed for hg19).	('miR', 'Gene', (71, 74))	('mutations', 'Var', (28, 37))	('miR', 'Gene', '220972', (71, 74))
348081	33038763	Although the number of identified mutations was too small to perform formal mutation-enrichment analysis, especially in individual cancers, the identified mutations were significantly enriched in the miRNA genes identified as overmutated in the TCGA Pan-Cancer cohort (at least one mutation identified in 66% of overmutated miRNA genes vs. 43% of all other tested genes; Fisher exact test, p < 0.0001).	('miR', 'Gene', '220972', (200, 203))	('cancers', 'Disease', 'MESH:D009369', (131, 138))	('miR', 'Gene', (200, 203))	('cancers', 'Phenotype', 'HP:0002664', (131, 138))	('mutations', 'Var', (155, 164))	('Pan-Cancer', 'Disease', (250, 260))	('cancers', 'Disease', (131, 138))	('Cancer', 'Phenotype', 'HP:0002664', (254, 260))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('Pan-Cancer', 'Disease', 'MESH:D009369', (250, 260))	('overmutated', 'PosReg', (312, 323))	('miR', 'Gene', (324, 327))	('miR', 'Gene', '220972', (324, 327))	('overmutated', 'PosReg', (226, 237))
348082	33038763	Among the recurrently mutated genes were hsa-miR-142 with 19 mutations in B-cell non-Hodgkin lymphoma (Lymph-BNHL, n = 16) and chronic lymphocytic leukaemia (Lymph-CLL, n = 3) samples, hsa-miR-205 and hsa-miR-496 (Fig.	('non-Hodgkin lymphoma', 'Phenotype', 'HP:0012539', (81, 101))	('hsa-miR-205', 'Gene', (185, 196))	('chronic lymphocytic leukaemia', 'Disease', 'MESH:D007945', (127, 156))	('Hodgkin lymphoma', 'Disease', (85, 101))	('mutations', 'Var', (61, 70))	('hsa-miR-496', 'Gene', (201, 212))	('hsa-miR-496', 'Gene', '574454', (201, 212))	('hsa-miR-142', 'Gene', '406934', (41, 52))	('Hodgkin lymphoma', 'Disease', 'MESH:D006689', (85, 101))	('Hodgkin lymphoma', 'Phenotype', 'HP:0012189', (85, 101))	('hsa-miR-205', 'Gene', '406988', (185, 196))	('lymphoma', 'Phenotype', 'HP:0002665', (93, 101))	('chronic lymphocytic leukaemia', 'Disease', (127, 156))	('hsa-miR-142', 'Gene', (41, 52))
348085	33038763	In this study, we identified 7110 mutations in miRNA genes across 33 cancer types based on data available in the TCGA repository.	('miR', 'Gene', '220972', (47, 50))	('miR', 'Gene', (47, 50))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('mutations', 'Var', (34, 43))	('cancer', 'Disease', (69, 75))
348086	33038763	Most of the mutations were substitutions (~89%), with indels overrepresented within a couple of analyzed cancer types (COAD, STAD, and UCEC).	('COAD', 'Disease', (119, 123))	('mutations', 'Var', (12, 21))	('cancer', 'Disease', (105, 111))	('STAD', 'Disease', (125, 129))	('COAD', 'Disease', 'MESH:D029424', (119, 123))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('overrepresented', 'PosReg', (61, 76))
348087	33038763	Overall, approximately 33% of Pan-Cancer samples have at least one mutation in miRNA genes, with percentages substantially differing among cancer types, similar to what is observed for mutations in other genomic regions.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('mutation', 'Var', (67, 75))	('Pan-Cancer', 'Disease', (30, 40))	('Cancer', 'Phenotype', 'HP:0002664', (34, 40))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('Pan-Cancer', 'Disease', 'MESH:D009369', (30, 40))	('miR', 'Gene', '220972', (79, 82))	('miR', 'Gene', (79, 82))	('cancer', 'Disease', (139, 145))
348088	33038763	The mutations were in general evenly distributed across miRNA gene functional subregions.	('mutations', 'Var', (4, 13))	('miR', 'Gene', '220972', (56, 59))	('miR', 'Gene', (56, 59))
348089	33038763	This could be attributed to the fact that the majority of detected sequence variants are spontaneous mutations randomly accumulating in the cancer genome.	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('variants', 'Var', (76, 84))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))
348090	33038763	Among the identified mutations, we found ones located in miRNA genes playing an important and well-recognized role in cancer (e.g., hsa-let-7 family, hsa-miR-205, and hsa-miR-142) as well as miRNAs that were not yet investigated broadly in relation to cancer.	('cancer', 'Disease', 'MESH:D009369', (252, 258))	('miR', 'Gene', '220972', (154, 157))	('miR', 'Gene', '220972', (171, 174))	('hsa-miR-205', 'Gene', (150, 161))	('miR', 'Gene', (154, 157))	('hsa-miR-205', 'Gene', '406988', (150, 161))	('miR', 'Gene', (171, 174))	('hsa-miR-142', 'Gene', (167, 178))	('miR', 'Gene', '220972', (191, 194))	('cancer', 'Disease', (118, 124))	('hsa-miR-142', 'Gene', '406934', (167, 178))	('miR', 'Gene', '220972', (57, 60))	('cancer', 'Disease', (252, 258))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('hsa-let-7 family', 'Gene', (132, 148))	('mutations', 'Var', (21, 30))	('miR', 'Gene', (191, 194))	('miR', 'Gene', (57, 60))	('cancer', 'Disease', 'MESH:D009369', (118, 124))
348092	33038763	In particular, we found multiple mutations in hsa-miR-142, hsa-miR-205, hsa-let-7d, hsa-miR-411, hsa-miR-519e, hsa-miR-664b, hsa-miR-585, hsa-miR-496, and hsa-miR-1302-3.	('hsa-miR-519e', 'Gene', (97, 109))	('hsa-miR-1302-3', 'Gene', '100302128', (155, 169))	('mutations', 'Var', (33, 42))	('hsa-miR-664b', 'Gene', (111, 123))	('hsa-miR-1302-3', 'Gene', (155, 169))	('hsa-miR-411', 'Gene', '693121', (84, 95))	('hsa-miR-411', 'Gene', (84, 95))	('hsa-miR-519e', 'Gene', '574463', (97, 109))	('hsa-miR-585', 'Gene', (125, 136))	('hsa-miR-496', 'Gene', (138, 149))	('hsa-miR-664b', 'Gene', '100847052', (111, 123))	('hsa-let-7d', 'Gene', '406886', (72, 82))	('hsa-miR-142', 'Gene', (46, 57))	('hsa-let-7d', 'Gene', (72, 82))	('hsa-miR-142', 'Gene', '406934', (46, 57))	('hsa-miR-205', 'Gene', (59, 70))	('hsa-miR-496', 'Gene', '574454', (138, 149))	('hsa-miR-585', 'Gene', '693170', (125, 136))	('hsa-miR-205', 'Gene', '406988', (59, 70))
348093	33038763	Although the frequency of mutations in overmutated miRNA genes is lower than in commonly mutated drivers such as TP53, CDKN2A, or KRAS, it is comparable to the cancer-specific frequencies of mutations in many other protein-coding driver genes that are generally much longer than miRNA genes, e.g., MET (7%), RB1 (4%), and RIT1 (2%) in LUAD, HRAS (4%), PTEN, RB1, NF1 (<1%) in PTC or DRD5 (3%), and BRAF (2%) in GBM.	('DRD5', 'Gene', (383, 387))	('RIT1', 'Gene', (322, 326))	('RB1', 'Gene', '5925', (358, 361))	('mutations', 'Var', (26, 35))	('miR', 'Gene', '220972', (51, 54))	('DRD5', 'Gene', '1816', (383, 387))	('NF1', 'Gene', '4763', (363, 366))	('BRAF', 'Gene', (398, 402))	('RB1', 'Gene', (308, 311))	('BRAF', 'Gene', '673', (398, 402))	('MET', 'Gene', '79811', (298, 301))	('KRAS', 'Gene', '3845', (130, 134))	('cancer', 'Disease', (160, 166))	('NF1', 'Gene', (363, 366))	('lower', 'NegReg', (66, 71))	('miR', 'Gene', '220972', (279, 282))	('KRAS', 'Gene', (130, 134))	('miR', 'Gene', (51, 54))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('TP53', 'Gene', (113, 117))	('RB1', 'Gene', '5925', (308, 311))	('RIT1', 'Gene', '6016', (322, 326))	('CDKN2A', 'Gene', (119, 125))	('PTEN', 'Gene', (352, 356))	('miR', 'Gene', (279, 282))	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('RB1', 'Gene', (358, 361))	('HRAS', 'Gene', '3265', (341, 345))	('MET', 'Gene', (298, 301))	('TP53', 'Gene', '7157', (113, 117))	('HRAS', 'Gene', (341, 345))	('PTEN', 'Gene', '5728', (352, 356))	('CDKN2A', 'Gene', '1029', (119, 125))
348095	33038763	The mutations were identified predominantly in STAD and UCEC cancers known to be associated with MSI.	('cancers', 'Phenotype', 'HP:0002664', (61, 68))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('UCEC cancers', 'Disease', 'MESH:D009369', (56, 68))	('identified', 'Reg', (19, 29))	('STAD', 'Disease', (47, 51))	('mutations', 'Var', (4, 13))	('UCEC cancers', 'Disease', (56, 68))
348096	33038763	It was previously suggested that simple repeats in human miRNA genes are relatively rare and preserved from mutations due to MSI.	('human', 'Species', '9606', (51, 56))	('miR', 'Gene', '220972', (57, 60))	('miR', 'Gene', (57, 60))	('mutations', 'Var', (108, 117))
348098	33038763	In our study, we identified indels associated with MSI in numerous miRNA genes (e.g., hsa-miR-320c-1, hsa-miR-320b-2, and hsa-miR-1249), including previously observed ones.	('hsa-miR-1249', 'Gene', (122, 134))	('hsa-miR-320c-1', 'Gene', '100302135', (86, 100))	('hsa-miR-320b-2', 'Gene', (102, 116))	('associated', 'Reg', (35, 45))	('miR', 'Gene', (106, 109))	('miR', 'Gene', (126, 129))	('hsa-miR-1249', 'Gene', '100302149', (122, 134))	('miR', 'Gene', '220972', (106, 109))	('miR', 'Gene', '220972', (126, 129))	('indels', 'Var', (28, 34))	('hsa-miR-320b-2', 'Gene', '100313769', (102, 116))	('miR', 'Gene', '220972', (90, 93))	('miR', 'Gene', (90, 93))	('miR', 'Gene', '220972', (67, 70))	('miR', 'Gene', (67, 70))	('MSI', 'Var', (51, 54))	('hsa-miR-320c-1', 'Gene', (86, 100))
348099	33038763	Many MSI-associated mutations are recurrently mutated hotspots; for example, hsa-let-7d (chr9:94178817delAA[+]) in UCEC, COAD, and Pan-Cancer (Fig.	('UCEC', 'Disease', (115, 119))	('Pan-Cancer', 'Disease', 'MESH:D009369', (131, 141))	('chr9:94178817delAA', 'DELETION', 'None', (89, 107))	('hsa-let-7d', 'Gene', (77, 87))	('COAD', 'Disease', (121, 125))	('MSI-associated', 'Gene', (5, 19))	('COAD', 'Disease', 'MESH:D029424', (121, 125))	('hsa-let-7d', 'Gene', '406886', (77, 87))	('Cancer', 'Phenotype', 'HP:0002664', (135, 141))	('chr9:94178817delAA', 'Var', (89, 107))	('Pan-Cancer', 'Disease', (131, 141))	('mutations', 'Var', (20, 29))
348100	33038763	4c), hsa-miR-1303 (chr5:154685821TTA>T[+]) in STAD, UCEC, and Pan-Cancer and hsa-miR-567 (chr3:112112876TA/TAAA>T[+]) in UCEC and Pan-Cancer.	('Pan-Cancer', 'Disease', 'MESH:D009369', (62, 72))	('chr5:154685821TTA>T', 'SUBSTITUTION', 'None', (19, 38))	('chr5:154685821TTA>T', 'Var', (19, 38))	('Pan-Cancer', 'Disease', (130, 140))	('Cancer', 'Phenotype', 'HP:0002664', (134, 140))	('hsa-miR-567', 'Gene', '693152', (77, 88))	('Pan-Cancer', 'Disease', 'MESH:D009369', (130, 140))	('STAD', 'Disease', (46, 50))	('Cancer', 'Phenotype', 'HP:0002664', (66, 72))	('chr3:112112876TA/TAAA', 'Var', (90, 111))	('hsa-miR-1303', 'Gene', (5, 17))	('Pan-Cancer', 'Disease', (62, 72))	('hsa-miR-567', 'Gene', (77, 88))	('UCEC', 'Disease', (121, 125))	('UCEC', 'Disease', (52, 56))	('hsa-miR-1303', 'Gene', '100302284', (5, 17))
348101	33038763	This result shows that the idea of the involvement of MSI in mutations within miRNA genes should be revisited, especially as those mutations may also be functional.	('miR', 'Gene', '220972', (78, 81))	('miR', 'Gene', (78, 81))	('mutations', 'Var', (61, 70))
348102	33038763	As mentioned earlier, depending on localization within the miRNA gene, mutations can have multiple effects on miRNA functionality, including changes in targets (mutations within seeds) or processing (mutations that change structure or are located in the DROSHA/DICER1 cleavage site), resulting in changed miRNA levels and/or strand balance.	('DICER1', 'Gene', (261, 267))	('mutations', 'Var', (200, 209))	('changed', 'Reg', (297, 304))	('miR', 'Gene', '220972', (59, 62))	('changes', 'Reg', (141, 148))	('miR', 'Gene', (305, 308))	('miR', 'Gene', (59, 62))	('mutations', 'Var', (71, 80))	('strand balance', 'MPA', (325, 339))	('DROSHA', 'Gene', '29102', (254, 260))	('DROSHA', 'Gene', (254, 260))	('miR', 'Gene', '220972', (110, 113))	('targets', 'MPA', (152, 159))	('DICER1', 'Gene', '23405', (261, 267))	('processing', 'MPA', (188, 198))	('miR', 'Gene', (110, 113))	('change', 'Reg', (215, 221))	('structure', 'MPA', (222, 231))	('miR', 'Gene', '220972', (305, 308))
348103	33038763	In our study, we detected 536 mutations and 7 recurrently mutated hotspots in seed sequences of different miRNAs, including miRNAs with defined roles in cancer.	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('cancer', 'Disease', (153, 159))	('miR', 'Gene', (106, 109))	('miR', 'Gene', '220972', (106, 109))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('mutations', 'Var', (30, 39))	('miR', 'Gene', '220972', (124, 127))	('miR', 'Gene', (124, 127))
348104	33038763	As shown before, in our previous study, such mutations affect the vast majority of predicted miRNA targets.	('miR', 'Gene', (93, 96))	('mutations', 'Var', (45, 54))	('affect', 'Reg', (55, 61))	('miR', 'Gene', '220972', (93, 96))
348105	33038763	An example of a seed hotspot mutation is chr1:209432167C>T[+] in miR-205-5p, which affects most of the predicted miRNA targets.	('miR', 'Gene', '220972', (113, 116))	('miR', 'Gene', (113, 116))	('miR', 'Gene', '220972', (65, 68))	('miR', 'Gene', (65, 68))	('chr1:209432167C>T', 'SUBSTITUTION', 'None', (41, 58))	('miR-205', 'Gene', (65, 72))	('chr1:209432167C>T', 'Var', (41, 58))	('miR-205', 'Gene', '406988', (65, 72))
348106	33038763	Additionally, due to mutation occurrence in the seed region, mutated miRNAs may gain the ability to recognize and downregulate new targets (Supplementary Fig.	('recognize', 'MPA', (100, 109))	('ability', 'MPA', (89, 96))	('gain', 'PosReg', (80, 84))	('miR', 'Gene', '220972', (69, 72))	('miR', 'Gene', (69, 72))	('downregulate', 'NegReg', (114, 126))	('mutated', 'Var', (61, 68))
348108	33038763	Although probably not all of the observed miRNA aberrations play any relevant functional role in cancer, a vast excess of downregulated miRNAs confirms that mutations in miRNA genes have mostly destructive effects on the structure or stability of the miRNA precursors, making them less optimal substrates for the miRNA biogenesis process.	('effects', 'Reg', (206, 213))	('stability', 'MPA', (234, 243))	('cancer', 'Disease', (97, 103))	('miR', 'Gene', '220972', (313, 316))	('miR', 'Gene', (251, 254))	('miR', 'Gene', '220972', (136, 139))	('miR', 'Gene', (136, 139))	('miR', 'Gene', '220972', (251, 254))	('mutations', 'Var', (157, 166))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('structure', 'MPA', (221, 230))	('miR', 'Gene', '220972', (42, 45))	('miR', 'Gene', (42, 45))	('miR', 'Gene', (313, 316))	('miR', 'Gene', '220972', (170, 173))	('miR', 'Gene', (170, 173))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
348110	33038763	Subsequent analyses of available clinical data, including patient survival and cancer stage, showed that mutations in 12 miRNA genes were associated with different metrics of patient survival (predominantly with decreases in survival), and mutations in 18 miRNA genes were associated with cancer stage.	('miR', 'Gene', '220972', (256, 259))	('miR', 'Gene', (256, 259))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('cancer', 'Disease', (79, 85))	('patient', 'Species', '9606', (58, 65))	('patient', 'Species', '9606', (175, 182))	('cancer', 'Phenotype', 'HP:0002664', (289, 295))	('associated', 'Reg', (138, 148))	('mutations', 'Var', (105, 114))	('miR', 'Gene', '220972', (121, 124))	('cancer', 'Disease', 'MESH:D009369', (289, 295))	('miR', 'Gene', (121, 124))	('associated', 'Reg', (273, 283))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('decreases', 'NegReg', (212, 221))	('cancer', 'Disease', (289, 295))
348111	33038763	This observation further confirms the potential functionality of the miRNA gene mutations acting directly (e.g., a mutation in seed), by changes in miRNA levels, or by other secondary effects.	('mutations', 'Var', (80, 89))	('changes', 'Reg', (137, 144))	('miR', 'Gene', '220972', (69, 72))	('miR', 'Gene', (69, 72))	('miR', 'Gene', '220972', (148, 151))	('miR', 'Gene', (148, 151))
348112	33038763	Although we tested only the effects of overmutated miRNA genes, we cannot exclude the possibility that some of the individual mutations also affect miRNA biogenesis/function and/or cancer.	('affect', 'Reg', (141, 147))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('miR', 'Gene', '220972', (51, 54))	('miR', 'Gene', (51, 54))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('mutations', 'Var', (126, 135))	('cancer', 'Disease', (181, 187))	('miR', 'Gene', '220972', (148, 151))	('miR', 'Gene', (148, 151))
348115	33038763	On the other hand, globally, the nonrandom character of the identified mutations was confirmed by a strong association of overmutated miRNA genes with KEGG pathways, of which the vast majority were specific to particular cancers or cancer-related processes.	('cancer', 'Disease', 'MESH:D009369', (232, 238))	('cancer', 'Disease', 'MESH:D009369', (221, 227))	('cancers', 'Disease', 'MESH:D009369', (221, 228))	('cancers', 'Phenotype', 'HP:0002664', (221, 228))	('KEGG pathways', 'Pathway', (151, 164))	('cancer', 'Disease', (232, 238))	('cancers', 'Disease', (221, 228))	('miR', 'Gene', (134, 137))	('cancer', 'Disease', (221, 227))	('miR', 'Gene', '220972', (134, 137))	('overmutated', 'Var', (122, 133))	('mutations', 'Var', (71, 80))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('association', 'Interaction', (107, 118))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))
348116	33038763	Many approaches have been developed to discover and evaluate cancer-driver mutations in protein-coding sequences, e.g., MutSig2CV, HotSpot 3D, CLUMPS, and PARADIGM-SHIFT, and numerous cancer-driving mutations and genes have been identified by taking advantage of these tools.	('cancer', 'Disease', (184, 190))	('CLUMPS', 'Disease', (143, 149))	('CLUMPS', 'Disease', 'MESH:C563527', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('cancer', 'Disease', (61, 67))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('mutations', 'Var', (75, 84))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('cancer', 'Disease', 'MESH:D009369', (184, 190))
348117	33038763	These factors allow estimation of the excess of deleterious functionally relevant mutations over neutral variants, which is one of the most important components of models identifying signals of cancer-driven selection.	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('mutations', 'Var', (82, 91))	('cancer', 'Disease', (194, 200))	('cancer', 'Disease', 'MESH:D009369', (194, 200))
348122	33038763	To overcome this limitation, in addition to evaluating the excess of the mutation in particular genes, we also weighted the mutations based on our proposed functionally related factors, with higher scores for mutations within the seed sequence, mature miRNAs, DROSHA/DICER1 cleavage sites, and disrupting protein binding motifs.	('miR', 'Gene', (252, 255))	('higher', 'PosReg', (191, 197))	('DROSHA', 'Gene', '29102', (260, 266))	('DROSHA', 'Gene', (260, 266))	('DICER1', 'Gene', (267, 273))	('mutations', 'Var', (209, 218))	('DICER1', 'Gene', '23405', (267, 273))	('protein', 'Protein', (305, 312))	('miR', 'Gene', '220972', (252, 255))	('disrupting', 'Reg', (294, 304))
348126	33038763	This underlines the need for the development of a tool dedicated to the identification of cancer-driver mutations in miRNA genes.	('mutations', 'Var', (104, 113))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('miR', 'Gene', '220972', (117, 120))	('miR', 'Gene', (117, 120))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))
348127	33038763	As there is no list of previously defined miRNA driver genes, we could not formally validate our approach; however, among the top-scored overmutated miRNA genes, we identified hsa-miR-142, which is the only miRNA gene in which mutations were identified in several hematologic neoplasms in several studies, and their cancer relevance was functionally confirmed.	('mutations', 'Var', (227, 236))	('hsa-miR-142', 'Gene', (176, 187))	('hematologic neoplasms', 'Disease', (264, 285))	('hematologic neoplasms', 'Disease', 'MESH:D019337', (264, 285))	('hsa-miR-142', 'Gene', '406934', (176, 187))	('cancer', 'Phenotype', 'HP:0002664', (316, 322))	('miR', 'Gene', '220972', (149, 152))	('miR', 'Gene', (149, 152))	('miR', 'Gene', '220972', (42, 45))	('cancer', 'Disease', 'MESH:D009369', (316, 322))	('miR', 'Gene', (42, 45))	('miR', 'Gene', '220972', (180, 183))	('hematologic neoplasms', 'Phenotype', 'HP:0004377', (264, 285))	('miR', 'Gene', (180, 183))	('cancer', 'Disease', (316, 322))	('miR', 'Gene', '220972', (207, 210))	('neoplasms', 'Phenotype', 'HP:0002664', (276, 285))	('miR', 'Gene', (207, 210))
348128	33038763	Our analysis confirmed the recurrence of hsa-miR-142 mutations in hematologic neoplasms, i.e., LAML, DLBC, and also the newly identified mutation in the Burkitt lymphoma Raji cell line, but also showed mutations in several solid tumours, i.e., UCEC, BLCA, GBM, and BRCA.	('Burkitt lymphoma', 'Disease', 'MESH:D002051', (153, 169))	('lymphoma', 'Phenotype', 'HP:0002665', (161, 169))	('GBM', 'Disease', (256, 259))	('AML', 'Disease', 'MESH:D015470', (96, 99))	('UCEC', 'Disease', (244, 248))	('mutations', 'Reg', (202, 211))	('hsa-miR-142', 'Gene', (41, 52))	('AML', 'Disease', (96, 99))	('hematologic neoplasms', 'Disease', 'MESH:D019337', (66, 87))	('hsa-miR-142', 'Gene', '406934', (41, 52))	('hematologic neoplasms', 'Phenotype', 'HP:0004377', (66, 87))	('Burkitt lymphoma', 'Phenotype', 'HP:0030080', (153, 169))	('BLCA', 'Disease', (250, 254))	('tumours', 'Disease', (229, 236))	('BRCA', 'Gene', '672', (265, 269))	('mutations', 'Var', (53, 62))	('tumours', 'Phenotype', 'HP:0002664', (229, 236))	('neoplasms', 'Phenotype', 'HP:0002664', (78, 87))	('hematologic neoplasms', 'Disease', (66, 87))	('tumours', 'Disease', 'MESH:D009369', (229, 236))	('Raji', 'CellLine', 'CVCL:0511', (170, 174))	('BRCA', 'Gene', (265, 269))	('tumour', 'Phenotype', 'HP:0002664', (229, 235))	('Burkitt lymphoma', 'Disease', (153, 169))
348129	33038763	This result showed that mutations may occur in any part of the gene, not only in the seed sequence, which indicates their loss-of-function character, acting most likely by destabilizing the precursor structure and impairing miRNA biogenesis.	('precursor structure', 'MPA', (190, 209))	('impairing', 'NegReg', (214, 223))	('miR', 'Gene', '220972', (224, 227))	('miR', 'Gene', (224, 227))	('mutations', 'Var', (24, 33))	('destabilizing', 'NegReg', (172, 185))
348130	33038763	This observation may also have the more general intriguing implication that miRNA precursors are overall quite fragile structures that may be affected by almost any mutation within the hairpin-coding sequence.	('miR', 'Gene', (76, 79))	('affected', 'Reg', (142, 150))	('mutation', 'Var', (165, 173))	('miR', 'Gene', '220972', (76, 79))
348131	33038763	Such hypotheses may be tested by the functional analysis of a higher number of randomly selected mutations in different miRNA genes.	('miR', 'Gene', '220972', (120, 123))	('mutations', 'Var', (97, 106))	('miR', 'Gene', (120, 123))
348132	33038763	First, further functional analyses of the identified recurring mutations are needed to verify their role in particular cancers.	('mutations', 'Var', (63, 72))	('cancers', 'Disease', 'MESH:D009369', (119, 126))	('cancers', 'Phenotype', 'HP:0002664', (119, 126))	('cancers', 'Disease', (119, 126))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
348137	33038763	Finally, the analyses of mutations involved in cancers would also benefit from a better understanding of the structure of miRNA genes, including more complete information about the full sequence of miRNA transcriptional units (full pri-miRNA sequences) and their regulatory elements and better functional validation/annotation of the known miRNA genes, as proposed, e.g., in the miRGeneDB database.	('miR', 'Gene', '220972', (236, 239))	('miR', 'Gene', (236, 239))	('mutations', 'Var', (25, 34))	('miR', 'Gene', (198, 201))	('miR', 'Gene', '220972', (198, 201))	('miR', 'Gene', '220972', (122, 125))	('cancers', 'Disease', 'MESH:D009369', (47, 54))	('miR', 'Gene', (122, 125))	('miR', 'Gene', '220972', (340, 343))	('miR', 'Gene', (340, 343))	('cancers', 'Disease', (47, 54))	('cancers', 'Phenotype', 'HP:0002664', (47, 54))	('miR', 'Gene', '220972', (379, 382))	('miR', 'Gene', (379, 382))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))
348139	33038763	As a result, we detected thousands of different mutations located in different functionally relevant parts of miRNA genes, and many miRNA genes were overmutated either in Pan-Cancer or in specific cancer types.	('overmutated', 'PosReg', (149, 160))	('cancer', 'Disease', 'MESH:D009369', (197, 203))	('Cancer', 'Phenotype', 'HP:0002664', (175, 181))	('Pan-Cancer', 'Disease', (171, 181))	('cancer', 'Disease', (197, 203))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('Pan-Cancer', 'Disease', 'MESH:D009369', (171, 181))	('miR', 'Gene', '220972', (132, 135))	('miR', 'Gene', '220972', (110, 113))	('miR', 'Gene', (132, 135))	('miR', 'Gene', (110, 113))	('mutations', 'Var', (48, 57))
348140	33038763	The frequency of the mutations in some of the overmutated miRNA genes corresponds to that observed in some validated protein-coding driver genes.	('miR', 'Gene', '220972', (58, 61))	('miR', 'Gene', (58, 61))	('mutations', 'Var', (21, 30))
348212	32631330	In this study, the shape features Compactness2, Spherical Disproportion and Spherical are the quantification of tumor roundness, and there is a certain correlation between these three features in definition.	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumor roundness', 'Disease', 'MESH:D058405', (112, 127))	('tumor roundness', 'Disease', (112, 127))	('Compactness2', 'Var', (34, 46))
348213	32631330	In this study, the ROC curves of these three features(F16, F18, F19) coincide, which also confirms this fact.	('F19', 'Var', (64, 67))	('F18', 'Gene', '10046', (59, 62))	('F16', 'Var', (54, 57))	('F18', 'Gene', (59, 62))
348250	31718009	The reactions catalyzed by complex Cp*Ru(PPh3)2Cl were also accompanied by Ru(II)-mediated C9-epimerization resulting in cinchona products 11c,d and 12c,d (Scheme 3) in low-to-mediocre yields (31-60%: Table 3).	('Ru(PPh3)2Cl', 'Chemical', '-', (38, 49))	('C9-epimerization', 'Var', (91, 107))	('12c', 'Chemical', '-', (149, 152))	('Ru(II)', 'Chemical', '-', (75, 81))	('Cp*Ru(PPh3)2Cl', 'Var', (35, 49))
348254	31718009	Accordingly, the approximate endo orientation of the hydroxyl group in this compound is confirmed by the signals of the proximal quinuclidine protons H5alpha-, H6alpha- and H7alpha downfield-shifted by 0.2-0.7 ppm relative to those of epiquinines types 6, 7 and 11 discernible in narrow regions of their 1H-NMR spectra.	('H7alpha', 'Var', (173, 180))	('downfield-shifted', 'NegReg', (181, 198))	('H5alpha-', 'Var', (150, 158))	('H6alpha-', 'Var', (160, 168))	('epiquinines', 'Chemical', '-', (235, 246))	('quinuclidine', 'Chemical', 'MESH:D011812', (129, 141))	('1H', 'Chemical', '-', (304, 306))
348255	31718009	Again, due to the anisotropic effect of the proximal hydroxyl group, in the 1H-NMR spectra of quinidines 9*c and 9*d, the signals of H2A and H7beta protons are downfield-shifted by ca.	('quinidines', 'Chemical', 'MESH:D011802', (94, 104))	('H7beta', 'Protein', (141, 147))	('1H', 'Chemical', '-', (76, 78))	('9*d', 'Var', (113, 116))	('downfield-shifted', 'NegReg', (160, 177))	('9*c', 'Var', (105, 108))	('H2A', 'MPA', (133, 136))
348257	31718009	Accordingly, in 12c, characteristic NOE's were detected between proton pairs H9/H7beta and H9/H2A.	('12c', 'Chemical', '-', (16, 19))	('H9/H7beta', 'Var', (77, 86))	('H9/H2A', 'Var', (91, 97))
348263	31718009	The data listed in Table 4 indicate that hybrids with 1,4-disubstituted triazole linker (types 6, 7, 9 and 10) produced significant cell-line dependent cytotoxicity characterised by IC50 values in the low micromolar range, irrespective of the C8- and C9-configurations of the cinchona fragment.	('1,4-disubstituted triazole', 'Chemical', '-', (54, 80))	('IC50', 'MPA', (182, 186))	('cytotoxicity', 'Disease', 'MESH:D064420', (152, 164))	('hybrids', 'Var', (41, 48))	('cytotoxicity', 'Disease', (152, 164))
348270	31718009	This view gains support from the optimized structure of 12c (Figure 2) featuring the following interatomic distances from the triazole-CH: 2.780 A (to H9); 2.449 A (to H2A); 2.518 A (to H7beta).	('12c', 'Chemical', '-', (56, 59))	('2.780 A', 'Var', (139, 146))	('2.449 A', 'Var', (156, 163))	('triazole', 'Chemical', 'MESH:D014230', (126, 134))
348291	31718009	for C18H18N3O4 [MH]+, requires m/z: 340.12973, found m/z: 340.12927.	('C18H18N3O4 [', 'Var', (4, 16))	('C18H18N3O4', 'Chemical', '-', (4, 14))	('m/z: 340.12927', 'Var', (53, 67))
348415	31718009	Besides the structure-activity relationships (SAR) set up on the basis of the IC50 values, the results of comparative cell-cycle analyses in PANC-1 cells that disclosed extensive inhibitory effects of the most potent hybrid in subG1, S and G2/M phases, might also be utilized in rational structure-refinement in the development of more potent antiproliferative agents with enhanced activity, selectivity and established mechanism of action.	('PANC-1', 'CellLine', 'CVCL:0480', (141, 147))	('enhanced', 'PosReg', (373, 381))	('activity', 'MPA', (382, 390))	('SAR', 'Species', '2698737', (46, 49))	('hybrid', 'Var', (217, 223))
348436	31228354	Plasma samples were then aliquotted and stored at -80 C. Eight lung cancer cell lines were used for tumor-associated antigens for immunoblot analysis: H460 (large cell), H23 (lung adenocarcinoma), H522 (lung adenocarcinoma), H1299 (lung carcinoma), A549 (lung carcinoma), H520 (lung squamous cell carcinoma), H2882 (lung squamous cell carcinoma), and H2170 (lung squamous cell carcinoma).	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (175, 194))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (358, 386))	('tumor', 'Disease', (100, 105))	('H522', 'CellLine', 'CVCL:1567', (197, 201))	('lung cancer', 'Disease', (63, 74))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (175, 194))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('H522', 'Var', (197, 201))	('lung adenocarcinoma', 'Disease', (203, 222))	('H520', 'CellLine', 'CVCL:1566', (272, 276))	('H2882', 'Var', (309, 314))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (316, 344))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (278, 306))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (283, 306))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (358, 386))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (363, 386))	('lung squamous cell carcinoma', 'Disease', (358, 386))	('H2170', 'Var', (351, 356))	('carcinoma', 'Phenotype', 'HP:0030731', (213, 222))	('A549', 'Var', (249, 253))	('H520', 'Var', (272, 276))	('carcinoma', 'Phenotype', 'HP:0030731', (237, 246))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('lung cancer', 'Disease', 'MESH:D008175', (63, 74))	('H1299', 'CellLine', 'CVCL:0060', (225, 230))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (203, 222))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (321, 344))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (316, 344))	('lung squamous cell carcinoma', 'Disease', (316, 344))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (278, 306))	('lung squamous cell carcinoma', 'Disease', (278, 306))	('lung cancer', 'Phenotype', 'HP:0100526', (63, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (260, 269))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (203, 222))	('lung adenocarcinoma', 'Disease', (175, 194))	('H1299', 'Var', (225, 230))	('H460', 'CellLine', 'CVCL:0459', (151, 155))	('carcinoma', 'Phenotype', 'HP:0030731', (297, 306))	('A549', 'CellLine', 'CVCL:0023', (249, 253))	('H2882', 'CellLine', 'CVCL:5158', (309, 314))	('carcinoma', 'Phenotype', 'HP:0030731', (185, 194))
348509	31186696	CX3CL1 and its receptor are involved in a number of inflammatory processes, including allergic asthma, rheumatoid arthritis, Crohn's disease and atherosclerosis.	('rheumatoid arthritis', 'Phenotype', 'HP:0001370', (103, 123))	('asthma', 'Phenotype', 'HP:0002099', (95, 101))	("Crohn's disease", 'Phenotype', 'HP:0100280', (125, 140))	('atherosclerosis', 'Disease', (145, 160))	("Crohn's disease", 'Disease', 'MESH:D003424', (125, 140))	('rheumatoid arthritis', 'Disease', (103, 123))	("Crohn's disease", 'Disease', (125, 140))	('rheumatoid arthritis', 'Disease', 'MESH:D001172', (103, 123))	('CX3CL1', 'Var', (0, 6))	('allergic asthma', 'Disease', 'MESH:D004342', (86, 101))	('involved', 'Reg', (28, 36))	('arthritis', 'Phenotype', 'HP:0001369', (114, 123))	('allergic asthma', 'Disease', (86, 101))	('atherosclerosis', 'Disease', 'MESH:D050197', (145, 160))	('atherosclerosis', 'Phenotype', 'HP:0002621', (145, 160))
348510	31186696	These previous studies demonstrated that CX3CL1 may be expressed in different tissues and may contribute to a number of inflammatory diseases by promoting the accumulation of CX3CR1-positive immune cells at inflammation sites.	('inflammation', 'Disease', 'MESH:D007249', (207, 219))	('inflammation', 'Disease', (207, 219))	('CX3CL1', 'Var', (41, 47))	('promoting', 'PosReg', (145, 154))	('accumulation', 'MPA', (159, 171))	('inflammatory diseases', 'Disease', (120, 141))	('CX3CR1', 'Gene', '1524', (175, 181))	('CX3CR1', 'Gene', (175, 181))	('contribute', 'Reg', (94, 104))
348511	31186696	However, under pathogenic conditions with abnormal local and systemic immune responses, CX3CL1 may additionally induce potent antitumour and tissue-protective effects.	('tumour', 'Disease', 'MESH:D009369', (130, 136))	('tissue-protective effects', 'CPA', (141, 166))	('tumour', 'Disease', (130, 136))	('CX3CL1', 'Var', (88, 94))	('tumour', 'Phenotype', 'HP:0002664', (130, 136))
348513	31186696	In epithelial ovarian cancer cells, CX3CL1 promoted cancer cell proliferation by binding to CX3CR1 and subsequently activating protein kinase B.	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('activating', 'PosReg', (116, 126))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('epithelial ovarian cancer', 'Phenotype', 'HP:0025318', (3, 28))	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('promoted', 'PosReg', (43, 51))	('ovarian cancer', 'Phenotype', 'HP:0100615', (14, 28))	('cancer', 'Disease', (22, 28))	('protein kinase B', 'Gene', (127, 143))	('CX3CR1', 'Gene', '1524', (92, 98))	('epithelial ovarian cancer', 'Disease', 'MESH:D000077216', (3, 28))	('protein kinase B', 'Gene', '2185', (127, 143))	('epithelial ovarian cancer', 'Disease', (3, 28))	('CX3CL1', 'Var', (36, 42))	('binding', 'Interaction', (81, 88))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('cancer', 'Disease', (52, 58))	('CX3CR1', 'Gene', (92, 98))
348514	31186696	Furthermore, ovarian carcinoma cells migrated towards CX3CL1, and silencing of CX3CR1 reduced their migration.	('reduced', 'NegReg', (86, 93))	('silencing', 'Var', (66, 75))	('migration', 'CPA', (100, 109))	('CX3CR1', 'Gene', '1524', (79, 85))	('CX3CR1', 'Gene', (79, 85))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (13, 30))	('migrated', 'CPA', (37, 45))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (13, 30))	('ovarian carcinoma', 'Disease', (13, 30))	('carcinoma', 'Phenotype', 'HP:0030731', (21, 30))
348516	31186696	However, CX3CL1 has a range of effects in breast cancer.	('effects', 'Reg', (31, 38))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('breast cancer', 'Disease', 'MESH:D001943', (42, 55))	('breast cancer', 'Phenotype', 'HP:0003002', (42, 55))	('breast cancer', 'Disease', (42, 55))	('CX3CL1', 'Var', (9, 15))
348521	31186696	In total, six datasets downloaded from the GEO database [GSE30219, GSE37745, GSE42127, GSE50081, GSE68465 and GSE14814 ] and two TCGA datasets: lung adenocarcinoma [LUAD, ] and lung squamous cell carcinoma [LUSC, ] were included in the present study.	('LUAD', 'Phenotype', 'HP:0030078', (165, 169))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (144, 163))	('LUSC', 'Phenotype', 'HP:0030359', (207, 211))	('GSE37745', 'Var', (67, 75))	('[GSE30219', 'Var', (56, 65))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (144, 163))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (177, 205))	('GSE42127', 'Var', (77, 85))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (177, 205))	('carcinoma', 'Phenotype', 'HP:0030731', (196, 205))	('carcinoma', 'Phenotype', 'HP:0030731', (154, 163))	('GSE14814 ]', 'Var', (110, 120))	('lung adenocarcinoma', 'Disease', (144, 163))	('GSE50081', 'Var', (87, 95))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (182, 205))	('lung squamous cell carcinoma', 'Disease', (177, 205))
348529	31186696	In patients with LUSC, univariate Cox model analysis of the GSE14814 dataset revealed that CX3CL1 mRNA expression exhibited a significant protective effect on prognosis (HR<1, P<0.05).	('CX3CL1 mRNA expression', 'Var', (91, 113))	('prognosis', 'CPA', (159, 168))	('Cox', 'Gene', '1351', (34, 37))	('Cox', 'Gene', (34, 37))	('patients', 'Species', '9606', (3, 11))	('LUSC', 'Phenotype', 'HP:0030359', (17, 21))
348531	31186696	In six out of seven datasets, high expression of CX3CL1 was associated with a decreased risk of mortality in patients with LUAD (Fig.	('mortality', 'MPA', (96, 105))	('high expression', 'Var', (30, 45))	('patients', 'Species', '9606', (109, 117))	('CX3CL1', 'Gene', (49, 55))	('decreased', 'NegReg', (78, 87))	('LUAD', 'Phenotype', 'HP:0030078', (123, 127))	('LUAD', 'Disease', (123, 127))
348532	31186696	Amongst patients with LUSC, two datasets demonstrated that CX3CL1 was associated with a decreased risk of mortality, whereas, in four datasets, CX3CL1 was associated with an increased risk of mortality (Fig.	('CX3CL1', 'Var', (144, 150))	('CX3CL1', 'Var', (59, 65))	('mortality', 'MPA', (106, 115))	('decreased', 'NegReg', (88, 97))	('LUSC', 'Phenotype', 'HP:0030359', (22, 26))	('patients', 'Species', '9606', (8, 16))
348533	31186696	These findings indicated that CX3CL1 may be a candidate prognostic indicator for patients with LUAD but not for patients with LUSC.	('LUAD', 'Phenotype', 'HP:0030078', (95, 99))	('patients', 'Species', '9606', (81, 89))	('patients', 'Species', '9606', (112, 120))	('LUSC', 'Phenotype', 'HP:0030359', (126, 130))	('LUAD', 'Disease', (95, 99))	('CX3CL1', 'Var', (30, 36))
348538	31186696	Membrane-bound CX3CL1 serves as a molecule that promotes adhesion of leukocytes to endothelial cells, whereas, soluble CX3CL1 serves as a potent chemoattractant of T-cells and monocytes, causing them to move towards sites of inflammation.	('CX3CL1', 'Var', (119, 125))	('soluble CX3CL1', 'Var', (111, 125))	('inflammation', 'Disease', 'MESH:D007249', (225, 237))	('inflammation', 'Disease', (225, 237))	('promotes', 'PosReg', (48, 56))	('adhesion', 'MPA', (57, 65))	('move', 'PosReg', (203, 207))
348539	31186696	CX3CL1 is able to attract immune effector cells to the tumour location site and exert an antitumour immune effect.	('tumour', 'Disease', (55, 61))	('tumour', 'Disease', (93, 99))	('CX3CL1', 'Var', (0, 6))	('tumour', 'Phenotype', 'HP:0002664', (55, 61))	('tumour', 'Disease', 'MESH:D009369', (55, 61))	('attract', 'PosReg', (18, 25))	('tumour', 'Phenotype', 'HP:0002664', (93, 99))	('tumour', 'Disease', 'MESH:D009369', (93, 99))
348541	31186696	CX3CL1 may additionally promote the adhesion of CX3CR1-positive tumour cells to target organs, causing the migration of tumour cells, thus promoting tumourigenesis.	('tumour', 'Phenotype', 'HP:0002664', (120, 126))	('tumour', 'Phenotype', 'HP:0002664', (64, 70))	('tumour', 'Disease', 'MESH:D009369', (64, 70))	('tumour', 'Disease', 'MESH:D009369', (120, 126))	('CX3CL1', 'Var', (0, 6))	('CX3CR1', 'Gene', (48, 54))	('adhesion', 'CPA', (36, 44))	('tumour', 'Disease', (64, 70))	('tumour', 'Disease', (120, 126))	('tumour', 'Phenotype', 'HP:0002664', (149, 155))	('promoting', 'PosReg', (139, 148))	('causing', 'PosReg', (95, 102))	('promote', 'PosReg', (24, 31))	('tumour', 'Disease', 'MESH:D009369', (149, 155))	('tumour', 'Disease', (149, 155))	('CX3CR1', 'Gene', '1524', (48, 54))
348547	31186696	Therefore, high expression of CX3CR1 in pancreatic ductal adenocarcinoma (PDAC) may be one of the mechanisms that promote the spread of pancreatic cancer cells along the peripheral nerves, which results in a risk of early recurrence in patients with PDAC.	('pancreatic cancer', 'Disease', 'MESH:D010190', (136, 153))	('spread', 'CPA', (126, 132))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('pancreatic ductal adenocarcinoma', 'Disease', (40, 72))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (40, 72))	('patients', 'Species', '9606', (236, 244))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (136, 153))	('CX3CR1', 'Gene', '1524', (30, 36))	('high', 'Var', (11, 15))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))	('pancreatic cancer', 'Disease', (136, 153))	('CX3CR1', 'Gene', (30, 36))	('promote', 'PosReg', (114, 121))
348552	31186696	Similarly, previous studies on the mechanism of CX3CL1 in glioma and neuroblastoma demonstrated its negative regulatory function in these tumours.	('neuroblastoma', 'Phenotype', 'HP:0003006', (69, 82))	('CX3CL1', 'Var', (48, 54))	('negative', 'NegReg', (100, 108))	('glioma', 'Disease', 'MESH:D005910', (58, 64))	('glioma', 'Phenotype', 'HP:0009733', (58, 64))	('tumour', 'Phenotype', 'HP:0002664', (138, 144))	('tumours', 'Phenotype', 'HP:0002664', (138, 145))	('neuroblastoma', 'Disease', 'MESH:D009447', (69, 82))	('glioma', 'Disease', (58, 64))	('neuroblastoma', 'Disease', (69, 82))	('tumours', 'Disease', 'MESH:D009369', (138, 145))	('tumours', 'Disease', (138, 145))
348553	31186696	However, CX3CL1 additionally has tumour-suppressive activity.	('tumour', 'Disease', 'MESH:D009369', (33, 39))	('CX3CL1', 'Var', (9, 15))	('tumour', 'Phenotype', 'HP:0002664', (33, 39))	('tumour', 'Disease', (33, 39))
348556	31186696	Xin et al transduced CX3CL1 into mouse mesenchymal stem cells (MSCs) ex vivo using an adenoviral vector with the Arg-Gly-Asp-4C peptide in the fibre knob.	('Xin', 'Gene', '165904', (0, 3))	('Xin', 'Gene', (0, 3))	('mouse', 'Species', '10090', (33, 38))	('Arg', 'Chemical', 'MESH:D001120', (113, 116))	('Gly', 'Chemical', 'MESH:D005998', (117, 120))	('Arg-Gly-Asp-4C', 'Var', (113, 127))
348559	31186696	Hyakudomi et al suggested that patients with gastric adenocarcinoma with increased levels of CX3CL1 expression had elevated levels of cluster of differentiation 8 T-cells and NK cells, which may induce innate and adaptive immunity, and are correlated with a more favourable prognosis.	('increased', 'PosReg', (73, 82))	('induce', 'PosReg', (195, 201))	('elevated', 'PosReg', (115, 123))	('levels', 'MPA', (124, 130))	('gastric adenocarcinoma', 'Disease', 'MESH:D013274', (45, 67))	('patients', 'Species', '9606', (31, 39))	('CX3CL1', 'Var', (93, 99))	('gastric adenocarcinoma', 'Disease', (45, 67))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))
348561	31186696	Intra- and extrahepatic recurrence rates were significantly reduced in tumours with high expression of CX3CL1 and CX3CR1.	('high expression', 'Var', (84, 99))	('tumours', 'Disease', 'MESH:D009369', (71, 78))	('CX3CR1', 'Gene', '1524', (114, 120))	('CX3CL1', 'Var', (103, 109))	('tumours', 'Disease', (71, 78))	('CX3CR1', 'Gene', (114, 120))	('reduced', 'NegReg', (60, 67))	('tumour', 'Phenotype', 'HP:0002664', (71, 77))	('tumours', 'Phenotype', 'HP:0002664', (71, 78))
348568	31186696	CX3CL1 may promote the adhesion of CX3CR1-positive tumour cells to target organs, causing migration of tumour cells.	('CX3CR1', 'Gene', '1524', (35, 41))	('tumour', 'Phenotype', 'HP:0002664', (103, 109))	('CX3CL1', 'Var', (0, 6))	('tumour', 'Phenotype', 'HP:0002664', (51, 57))	('CX3CR1', 'Gene', (35, 41))	('tumour', 'Disease', 'MESH:D009369', (103, 109))	('promote', 'PosReg', (11, 18))	('adhesion', 'CPA', (23, 31))	('tumour', 'Disease', 'MESH:D009369', (51, 57))	('causing', 'Reg', (82, 89))	('tumour', 'Disease', (103, 109))	('tumour', 'Disease', (51, 57))
348669	25909284	This study characterized the therapeutic efficacy and action mechanism of a novel natural macrolide compound F806 in human ESCC xenograft models and cell lines.	('human', 'Species', '9606', (117, 122))	('ESCC', 'Disease', (123, 127))	('F806', 'Var', (109, 113))	('macrolide', 'Chemical', 'MESH:D018942', (90, 99))	('F806', 'Chemical', '-', (109, 113))
348670	25909284	F806 inhibited growth of ESCC, most importantly, it displayed fewer undesirable side effects on normal tissues in two human ESCC xenograft models.	('F806', 'Chemical', '-', (0, 4))	('F806', 'Var', (0, 4))	('inhibited', 'NegReg', (5, 14))	('ESCC', 'Disease', (25, 29))	('growth', 'CPA', (15, 21))	('human', 'Species', '9606', (118, 123))
348671	25909284	F806 inhibited proliferation of six ESCC cells lines, with the half maximal inhibitory concentration (IC50) ranging from 9.31 to 16.43 muM.	('F806', 'Chemical', '-', (0, 4))	('rat', 'Species', '10116', (94, 97))	('F806', 'Var', (0, 4))	('inhibited', 'NegReg', (5, 14))	('rat', 'Species', '10116', (22, 25))	('proliferation', 'CPA', (15, 28))
348672	25909284	Furthermore, F806 induced apoptosis of ESCC cells, contributing to its growth-inhibitory effect.	('F806', 'Var', (13, 17))	('apoptosis', 'CPA', (26, 35))	('growth-inhibitory', 'CPA', (71, 88))	('F806', 'Chemical', '-', (13, 17))
348673	25909284	Also, F806 inhibited cell adhesion resulting in anoikis.	('F806', 'Var', (6, 10))	('cell adhesion', 'CPA', (21, 34))	('F806', 'Chemical', '-', (6, 10))	('anoikis', 'CPA', (48, 55))	('inhibited', 'NegReg', (11, 20))
348674	25909284	Mechanistic studies revealed that F806 inhibited the activation of beta1 integrin in part by binding to a novel site Arg610 of beta1 integrin, suppressed focal adhesion formation, decreased cell adhesion to extracellular matrix and eventually triggered apoptosis.	('focal adhesion formation', 'CPA', (154, 178))	('F806', 'Chemical', '-', (34, 38))	('inhibited', 'NegReg', (39, 48))	('beta1 integrin', 'Gene', (127, 141))	('suppressed', 'NegReg', (143, 153))	('beta1 integrin', 'Gene', '3688', (67, 81))	('triggered', 'Reg', (243, 252))	('binding', 'Interaction', (93, 100))	('decreased', 'NegReg', (180, 189))	('decreased cell adhesion', 'Phenotype', 'HP:0008352', (180, 203))	('beta1 integrin', 'Gene', '3688', (127, 141))	('Arg610', 'Var', (117, 123))	('activation', 'MPA', (53, 63))	('beta1 integrin', 'Gene', (67, 81))	('Arg610', 'Chemical', '-', (117, 123))	('F806', 'Var', (34, 38))	('cell adhesion to extracellular matrix', 'CPA', (190, 227))
348675	25909284	We concluded that F806 would potentially be a well-tolerated anticancer drug by targeting beta1 integrin, resulting in anoikis in ESCC cells.	('rat', 'Species', '10116', (55, 58))	('beta1 integrin', 'Gene', '3688', (90, 104))	('F806', 'Var', (18, 22))	('resulting in', 'Reg', (106, 118))	('F806', 'Chemical', '-', (18, 22))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('anoikis', 'Disease', (119, 126))	('beta1 integrin', 'Gene', (90, 104))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))
348687	25909284	Our previous study has been reported that F806 exhibited potent activity against human cancer cells.	('cancer', 'Disease', (87, 93))	('F806', 'Var', (42, 46))	('F806', 'Chemical', '-', (42, 46))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('activity', 'MPA', (64, 72))	('human', 'Species', '9606', (81, 86))	('cancer', 'Disease', 'MESH:D009369', (87, 93))
348688	25909284	In the current study, we investigated the anti-cancer effect of F806 in ESCC cells in vivo and in vitro, and the biological activity of F806 against ESCC cells by blocking beta1 integrin activation.	('F806', 'Chemical', '-', (136, 140))	('F806', 'Chemical', '-', (64, 68))	('beta1 integrin', 'Gene', (172, 186))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('cancer', 'Disease', (47, 53))	('blocking', 'NegReg', (163, 171))	('activation', 'MPA', (187, 197))	('F806', 'Var', (64, 68))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('F806', 'Var', (136, 140))	('beta1 integrin', 'Gene', '3688', (172, 186))
348689	25909284	To assess the antitumor potential of F806 in xenograft models, EC109 and KYSE510 esophageal squamous cell carcinoma (ESCC) cells were inoculated subcutaneously into nude mice.	('esophageal squamous cell carcinoma', 'Disease', (81, 115))	('tumor', 'Disease', (18, 23))	('nude mice', 'Species', '10090', (165, 174))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (92, 115))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (81, 115))	('F806', 'Var', (37, 41))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('KYSE510', 'CellLine', 'CVCL:1354', (73, 80))	('F806', 'Chemical', '-', (37, 41))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
348691	25909284	The data showed that tumors from both of F806-treated groups grew more slowly than the control group (Figure 1A and 1B).	('F806-treated', 'Var', (41, 53))	('F806', 'Chemical', '-', (41, 45))	('slowly', 'NegReg', (71, 77))	('tumors', 'Disease', (21, 27))	('tumors', 'Disease', 'MESH:D009369', (21, 27))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('grew', 'CPA', (61, 65))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
348693	25909284	However, a significant (P < 0.05) antitumor effect of F806 was displayed in EC109 and KYSE510 xenograft models beginning at day 8/9 after the start of treatment.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('F806', 'Var', (54, 58))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('F806', 'Chemical', '-', (54, 58))	('KYSE510', 'CellLine', 'CVCL:1354', (86, 93))
348694	25909284	At the end of treatment, 4 mg/kg or 8 mg/kg F806 reduced tumor growth by 55.0% (P = 0.015) or 47.2% (P = 0.035) in EC109 cells, and 62.2% (P = 0.003) or 75.9% (P = 0.000) in KYSE510 cells, as compared to the control group.	('reduced', 'NegReg', (49, 56))	('F806', 'Chemical', '-', (44, 48))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('KYSE510', 'CellLine', 'CVCL:1354', (174, 181))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('F806', 'Var', (44, 48))	('tumor', 'Disease', (57, 62))
348698	25909284	No effect on complete blood count including white blood, red blood, hemoglobin and blood platelet count, was observed between F806-treated and control mice (Supplementary Table 4).	('F806', 'Chemical', '-', (126, 130))	('mice', 'Species', '10090', (151, 155))	('red blood', 'MPA', (57, 66))	('blood platelet count', 'MPA', (83, 103))	('hemoglobin', 'MPA', (68, 78))	('F806-treated', 'Var', (126, 138))
348699	25909284	In addition, no histological abnormality was shown in lungs, brains, liver, heart and kidneys of mice between F806-treated and control groups at the end of drug treatment (Figure 1C).	('F806-treated', 'Var', (110, 122))	('F806', 'Chemical', '-', (110, 114))	('kidney', 'Disease', 'MESH:D007674', (86, 92))	('mice', 'Species', '10090', (97, 101))	('kidney', 'Disease', (86, 92))	('histological abnormality', 'Phenotype', 'HP:0002664', (16, 40))
348700	25909284	Together, these data suggest that F806 effectively inhibits tumor growth in the absence of drug-induced adverse effects.	('F806', 'Chemical', '-', (34, 38))	('inhibits', 'NegReg', (51, 59))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Disease', (60, 65))	('F806', 'Var', (34, 38))
348702	25909284	Meanwhile, as a positive control, the growth of MTLn3 rat mammary adenocarcinoma cell was inhibited by F806 with 72 hr IC50 value of 9.60 muM, which is consistent with a previous report.	('F806', 'Var', (103, 107))	('F806', 'Chemical', '-', (103, 107))	('rat', 'Species', '10116', (54, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('adenocarcinoma', 'Disease', (66, 80))	('adenocarcinoma', 'Disease', 'MESH:D000230', (66, 80))	('inhibited', 'NegReg', (90, 99))	('growth', 'CPA', (38, 44))
348703	25909284	Shown in cell viability assays on ESCC cells, rounding and detachment of cultured cells increased in a dose- (0-40 muM) and time-dependent (0-72 h) manner after treatment with F806 (the morphology features of EC109 cells as shown in Supplementary Figure 2).	('F806', 'Var', (176, 180))	('F806', 'Chemical', '-', (176, 180))	('increased', 'PosReg', (88, 97))	('detachment', 'CPA', (59, 69))	('rounding', 'CPA', (46, 54))
348705	25909284	Notably F806 demonstrated potent growth-inhibitory effects against ESCC cells.	('ESCC cells', 'Disease', (67, 77))	('F806', 'Var', (8, 12))	('rat', 'Species', '10116', (20, 23))	('F806', 'Chemical', '-', (8, 12))	('growth-inhibitory effects', 'CPA', (33, 58))
348706	25909284	We next examined whether the growth-inhibitory effect of F806 was due to apoptosis.	('growth-inhibitory', 'MPA', (29, 46))	('F806', 'Var', (57, 61))	('F806', 'Chemical', '-', (57, 61))
348707	25909284	Transmission electron microscopy revealed condensation and margination of nuclear chromatin surrounding in the nucleus of EC109 cells treated with F806 for 24 hr, which is strongly suggestive of apoptotic cell death (Figure 2B).	('condensation', 'CPA', (42, 54))	('margination', 'CPA', (59, 70))	('F806', 'Var', (147, 151))	('F806', 'Chemical', '-', (147, 151))
348708	25909284	An apoptotic phenotype was further supported by DNA laddering, a specific marker for cell apoptosis (Figure 2C) in F806-treated EC109 cells.	('F806', 'Chemical', '-', (115, 119))	('F806-treated', 'Var', (115, 127))	('DNA laddering', 'CPA', (48, 61))
348709	25909284	On the other hand, cell cycle analysis presented the presence of a sub-G1 DNA peak in F806-treated EC109 cells (Figure 2D).	('sub-G1 DNA peak', 'MPA', (67, 82))	('F806', 'Chemical', '-', (86, 90))	('F806-treated', 'Var', (86, 98))
348710	25909284	Furthermore, the apoptosis precursor (ADP-ribose) polymerase (PARP) was cleaved, along with the reduction of PARP and the increase of cleaved PARP in F806-treated ESCC cells (Figure 2E).	('F806', 'Chemical', '-', (150, 154))	('reduction', 'NegReg', (96, 105))	('cleaved', 'MPA', (134, 141))	('PARP', 'MPA', (109, 113))	('F806-treated', 'Var', (150, 162))	('increase', 'PosReg', (122, 130))	('PARP', 'Protein', (142, 146))
348711	25909284	To further confirm the F806-induced apoptosis in ESCC cells, tumor sections from xenograft models were stained for nuclear apoptosis using the DeadEnd Fluorometric TUNEL reagent staining (Figure 2F).	('tumor', 'Disease', (61, 66))	('F806-induced', 'Var', (23, 35))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('F806', 'Chemical', '-', (23, 27))
348713	25909284	Thus, F806 would induce apoptosis, contributing to growth inhibition and cell death in ESCC cells.	('induce', 'Reg', (17, 23))	('growth inhibition', 'CPA', (51, 68))	('F806', 'Var', (6, 10))	('F806', 'Chemical', '-', (6, 10))	('apoptosis', 'CPA', (24, 33))	('cell death', 'CPA', (73, 83))
348714	25909284	Interestingly, we noted that ESCC cells began to round up and detach after 24 hr of F806-treatment, however, visible inhibition of growth was not observed until 48 hr after treatment.	('detach', 'CPA', (62, 68))	('round up', 'CPA', (49, 57))	('F806-treatment', 'Var', (84, 98))	('F806', 'Chemical', '-', (84, 88))
348715	25909284	These results clued that F806 inhibited cell adhesion, resulting in the induction of apoptosis in a process named 'anoikis'.	('F806', 'Chemical', '-', (25, 29))	('inhibited', 'NegReg', (30, 39))	('induction', 'Reg', (72, 81))	('apoptosis', 'CPA', (85, 94))	('F806', 'Var', (25, 29))	('cell adhesion', 'CPA', (40, 53))
348716	25909284	When EC109 and KYSE510 cells were cultured in poly-HEMA plates in presence of F806, a significant induction of anoikis in a dose-dependent manner was found (Figure 3A).	('poly-HEMA', 'Chemical', 'MESH:D011102', (46, 55))	('KYSE510', 'CellLine', 'CVCL:1354', (15, 22))	('anoikis', 'CPA', (111, 118))	('F806', 'Var', (78, 82))	('F806', 'Chemical', '-', (78, 82))	('induction', 'Reg', (98, 107))
348718	25909284	As shown in Figure 3B, F806 significantly inhibited cell adhesion, while there was no selectivity on fibronectin (FN), collagen (COL) or laminin (LAM).	('cell adhesion', 'CPA', (52, 65))	('fibronectin', 'Gene', (101, 112))	('inhibited', 'NegReg', (42, 51))	('F806', 'Var', (23, 27))	('fibronectin', 'Gene', '2335', (101, 112))	('FN', 'Gene', '2335', (114, 116))	('F806', 'Chemical', '-', (23, 27))
348719	25909284	Furthermore, when EC109 and KYSE510 cells were kept in FN or COL-coated plates for 30 min and treated with F806 for another 24 h (Figure 3C), or kept for 24 h prior to 30 min of F806 stimulation (Figure 3D), cell adhesion was still significantly inhibited.	('F806', 'Chemical', '-', (178, 182))	('inhibited', 'NegReg', (246, 255))	('F806', 'Var', (107, 111))	('F806', 'Chemical', '-', (107, 111))	('FN', 'Gene', '2335', (55, 57))	('cell adhesion', 'CPA', (208, 221))	('KYSE510', 'CellLine', 'CVCL:1354', (28, 35))
348720	25909284	These data indicated that F806 clearly inhibited cell adhesion, indicating anoikis.	('inhibited', 'NegReg', (39, 48))	('cell adhesion', 'CPA', (49, 62))	('anoikis', 'CPA', (75, 82))	('F806', 'Var', (26, 30))	('F806', 'Chemical', '-', (26, 30))
348721	25909284	The results of anoikis led us to the hypothesis that adhesion complex formation might be inhibited in ESCC cells by F806.	('ESCC', 'Disease', (102, 106))	('inhibited', 'NegReg', (89, 98))	('F806', 'Var', (116, 120))	('adhesion complex formation', 'MPA', (53, 79))	('F806', 'Chemical', '-', (116, 120))
348723	25909284	After cells on FN, COL or LAM-coated coverslips treated with F806 for 24 hr, focal adhesion were clearly observed in the basal layer of cells and the cell shapes remained normal in the control group, however, focal adhesion formation were obviously inhibited in F806-treated group (Figure 4A and 4B, left panel).	('inhibited', 'NegReg', (249, 258))	('F806-treated', 'Var', (262, 274))	('F806', 'Chemical', '-', (61, 65))	('FN', 'Gene', '2335', (15, 17))	('F806', 'Chemical', '-', (262, 266))	('focal adhesion formation', 'CPA', (209, 233))	('focal adhesion', 'CPA', (77, 91))	('F806', 'Var', (61, 65))
348725	25909284	Additionally, the effect of F806 on expression of Paxillin and Kindlin-2 were evaluated by Western blot.	('F806', 'Var', (28, 32))	('Paxillin', 'Gene', (50, 58))	('F806', 'Chemical', '-', (28, 32))	('Kindlin-2', 'Gene', (63, 72))	('Paxillin', 'Gene', '5829', (50, 58))	('Kindlin-2', 'Gene', '10979', (63, 72))
348726	25909284	As shown in Figure 4A and 4B, right panel, compared to the control, no difference on expression of Paxillin and Kindlin-2 were found in F806-treated cells.	('F806', 'Chemical', '-', (136, 140))	('Paxillin', 'Gene', '5829', (99, 107))	('Paxillin', 'Gene', (99, 107))	('Kindlin-2', 'Gene', (112, 121))	('Kindlin-2', 'Gene', '10979', (112, 121))	('F806-treated', 'Var', (136, 148))
348727	25909284	Therefore, F806 inhibited focal adhesion formation of ESCC cells and consequently inhibited cells to attach to ECM.	('focal adhesion formation', 'CPA', (26, 50))	('inhibited', 'NegReg', (16, 25))	('inhibited', 'NegReg', (82, 91))	('F806', 'Var', (11, 15))	('F806', 'Chemical', '-', (11, 15))	('cells to attach to ECM', 'CPA', (92, 114))
348728	25909284	We next investigated the potential mechanism of F806 involved in the inhibition of cell adhesion.	('cell adhesion', 'CPA', (83, 96))	('F806', 'Chemical', '-', (48, 52))	('F806', 'Var', (48, 52))
348730	25909284	Western blot analysis revealed that no apparent effect on the total protein level of beta1 integrin, beta4 integrin and alpha5 integrin was observed; nevertheless, F806 inhibited beta1 integrin activation in KYSE510 and EC109 cells by immunoprecipitation (Figure 5A).	('F806', 'Var', (164, 168))	('beta1 integrin', 'Gene', (179, 193))	('F806', 'Chemical', '-', (164, 168))	('beta4', 'Gene', '10381', (101, 106))	('KYSE510', 'CellLine', 'CVCL:1354', (208, 215))	('beta4', 'Gene', (101, 106))	('beta1 integrin', 'Gene', '3688', (85, 99))	('beta1 integrin', 'Gene', '3688', (179, 193))	('activation', 'MPA', (194, 204))	('inhibited', 'NegReg', (169, 178))	('beta1 integrin', 'Gene', (85, 99))
348733	25909284	Decreases in levels of activated FAK (p-FAK), AKT (p-AKT) and ERK1/2 (p-ERK1/2) were observed in F806-treated ESCC cells (Figure 5C).	('p-AKT', 'Gene', (51, 56))	('FAK', 'Gene', '5747', (33, 36))	('AKT', 'Gene', '207', (46, 49))	('FAK', 'Gene', (40, 43))	('F806-treated', 'Var', (97, 109))	('FAK', 'Gene', '5747', (40, 43))	('FAK', 'Gene', (33, 36))	('ERK1/2', 'MPA', (62, 68))	('F806', 'Chemical', '-', (97, 101))	('AKT', 'Gene', '207', (53, 56))	('AKT', 'Gene', (46, 49))	('levels', 'MPA', (13, 19))	('AKT', 'Gene', (53, 56))	('Decreases', 'NegReg', (0, 9))	('p-AKT', 'Gene', '207', (51, 56))
348734	25909284	To determine whether F806 inhibited the activation of beta1 integrin, resulting in inhibition of cell adhesion and inducing anoikis, the blockade of the activation of beta1 integrin using specific antibody JB1A and down-regulation of beta1 integrin by siRNA were examined to mimic the effect of F806.	('F806', 'Var', (21, 25))	('F806', 'Chemical', '-', (295, 299))	('inhibition', 'NegReg', (83, 93))	('F806', 'Chemical', '-', (21, 25))	('inhibited', 'NegReg', (26, 35))	('anoikis', 'CPA', (124, 131))	('beta1 integrin', 'Gene', '3688', (167, 181))	('beta1 integrin', 'Gene', (234, 248))	('cell adhesion', 'CPA', (97, 110))	('beta1 integrin', 'Gene', '3688', (54, 68))	('inducing', 'Reg', (115, 123))	('beta1 integrin', 'Gene', (167, 181))	('beta1 integrin', 'Gene', (54, 68))	('beta1 integrin', 'Gene', '3688', (234, 248))
348735	25909284	As shown in Figure 5D, the blockade of the activation of beta1 integrin inhibited cell adhesion in KYSE510 cells; however, F806 was more effective and the combination of anti-beta1 integrin with F806 caused the most suppression of cell adhesion.	('beta1 integrin', 'Gene', (175, 189))	('F806', 'Chemical', '-', (195, 199))	('F806', 'Var', (123, 127))	('KYSE510', 'CellLine', 'CVCL:1354', (99, 106))	('beta1 integrin', 'Gene', '3688', (57, 71))	('F806', 'Chemical', '-', (123, 127))	('beta1 integrin', 'Gene', '3688', (175, 189))	('beta1 integrin', 'Gene', (57, 71))	('cell adhesion', 'CPA', (231, 244))	('inhibited', 'NegReg', (72, 81))	('cell adhesion', 'CPA', (82, 95))	('F806', 'Var', (195, 199))	('suppression', 'NegReg', (216, 227))
348736	25909284	Furthermore, knockdown of beta1 integrin by siRNA certainly decreased the number of cell adhesion; nevertheless, F806 still was more effective.	('decreased', 'NegReg', (60, 69))	('beta1 integrin', 'Gene', '3688', (26, 40))	('F806', 'Chemical', '-', (113, 117))	('knockdown', 'Var', (13, 22))	('beta1 integrin', 'Gene', (26, 40))	('number of cell adhesion', 'CPA', (74, 97))
348737	25909284	Importantly, after the knockdown of beta1 integrin, mounting inhibition ratio of cell adhesion was found in F806-treated KYSE510 cells (Figure 5E).	('rat', 'Species', '10116', (72, 75))	('KYSE510', 'CellLine', 'CVCL:1354', (121, 128))	('inhibition', 'NegReg', (61, 71))	('knockdown', 'Var', (23, 32))	('beta1 integrin', 'Gene', '3688', (36, 50))	('F806', 'Chemical', '-', (108, 112))	('beta1 integrin', 'Gene', (36, 50))	('cell adhesion', 'CPA', (81, 94))
348738	25909284	Collectively, it can be concluded that F806 would inhibit the activation of beta1 integrin, leading to inhibition of focal adhesion formation and cell adhesion, finally triggering apoptosis.	('beta1 integrin', 'Gene', '3688', (76, 90))	('inhibit', 'NegReg', (50, 57))	('cell adhesion', 'CPA', (146, 159))	('activation', 'MPA', (62, 72))	('beta1 integrin', 'Gene', (76, 90))	('focal adhesion formation', 'CPA', (117, 141))	('F806', 'Var', (39, 43))	('F806', 'Chemical', '-', (39, 43))	('triggering', 'Reg', (169, 179))	('inhibition', 'NegReg', (103, 113))
348740	25909284	Anticancer activity of F806 was evaluated in two human ESCC xenograft models and in six ESCC cell lines.	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('human', 'Species', '9606', (49, 54))	('cancer', 'Disease', 'MESH:D009369', (4, 10))	('F806', 'Var', (23, 27))	('cancer', 'Disease', (4, 10))	('F806', 'Chemical', '-', (23, 27))
348741	25909284	Our data showed principle mechanisms for how F806 inhibited the growth in ESCC cells: F806 decreased the activation of beta1 integrin, prevented cancer cells away from the ECM, and eventually initiated apoptosis (Figure 6).	('cancer', 'Disease', (145, 151))	('F806', 'Chemical', '-', (45, 49))	('F806', 'Var', (86, 90))	('initiated', 'Reg', (192, 201))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('F806', 'Chemical', '-', (86, 90))	('beta1 integrin', 'Gene', '3688', (119, 133))	('apoptosis', 'CPA', (202, 211))	('prevented', 'NegReg', (135, 144))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('F806', 'Var', (45, 49))	('decreased', 'NegReg', (91, 100))	('activation', 'MPA', (105, 115))	('beta1 integrin', 'Gene', (119, 133))
348744	25909284	In the present study, F806 displays promising antitumor activity in ESCC cells and showed very low toxicity to the non-cancerous cells.	('toxicity', 'Disease', 'MESH:D064420', (99, 107))	('toxicity', 'Disease', (99, 107))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('cancer', 'Disease', (119, 125))	('F806', 'Var', (22, 26))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('F806', 'Chemical', '-', (22, 26))	('tumor', 'Disease', (50, 55))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
348745	25909284	Notably, F806 reduced the volume of ESCC xenografts at a 4 mg/kg/d dose by intraperitoneal administration, which is far below the reported minimal dose of 50 mg/kg.	('reduced', 'NegReg', (14, 21))	('volume', 'CPA', (26, 32))	('rat', 'Species', '10116', (99, 102))	('F806', 'Var', (9, 13))	('F806', 'Chemical', '-', (9, 13))	('ESCC', 'Disease', (36, 40))
348747	25909284	Indeed, F806 exhibited good safety during the treatment in ESCC xenografts: no abnormality in body weight, daily diet, liver and renal function, hematological indices, and histological characteristics in the lungs, brain, heart, kidney and liver tissue, were observed (Figure 1C, Supplementary Tables 3 and 4).	('kidney', 'Disease', (229, 235))	('abnormality in body weight', 'Phenotype', 'HP:0004323', (79, 105))	('F806', 'Var', (8, 12))	('kidney', 'Disease', 'MESH:D007674', (229, 235))	('F806', 'Chemical', '-', (8, 12))
348749	25909284	Our previous study reported that F806, could bind to the N-terminal of Hsp90 and inhibit Hsp90/Cdc37 interaction, resulting in the disassociation of Hsp90/Cdc37/client complexes and the degradation of Hsp90 client proteins in breast cancer cells.	('Hsp90', 'Gene', '3320', (89, 94))	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('Cdc37', 'Gene', (95, 100))	('Cdc37', 'Gene', '11140', (155, 160))	('Hsp90', 'Gene', (201, 206))	('Hsp90', 'Gene', (89, 94))	('disassociation', 'MPA', (131, 145))	('Hsp90', 'Gene', '3320', (71, 76))	('breast cancer', 'Phenotype', 'HP:0003002', (226, 239))	('interaction', 'Interaction', (101, 112))	('Hsp90', 'Gene', '3320', (149, 154))	('F806', 'Chemical', '-', (33, 37))	('Cdc37', 'Gene', (155, 160))	('Hsp90', 'Gene', (71, 76))	('breast cancer', 'Disease', 'MESH:D001943', (226, 239))	('breast cancer', 'Disease', (226, 239))	('degradation', 'MPA', (186, 197))	('Hsp90', 'Gene', (149, 154))	('bind', 'Interaction', (45, 49))	('Cdc37', 'Gene', '11140', (95, 100))	('inhibit', 'NegReg', (81, 88))	('F806', 'Var', (33, 37))	('Hsp90', 'Gene', '3320', (201, 206))
348750	25909284	Here our observations suggested that another novel anti-cancer mechanism of F806 would exist in ESCC cells.	('F806', 'Var', (76, 80))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('F806', 'Chemical', '-', (76, 80))	('ESCC', 'Disease', (96, 100))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))
348752	25909284	Indeed, anoikis induction contributed to the potent antitumor effects of F806, as evidenced by inhibition of cell adhesion to the ECM components including FN, COL and LAM.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('F806', 'Var', (73, 77))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('F806', 'Chemical', '-', (73, 77))	('tumor', 'Disease', (56, 61))	('inhibition', 'NegReg', (95, 105))	('FN', 'Gene', '2335', (155, 157))	('anoikis induction', 'CPA', (8, 25))	('cell adhesion', 'CPA', (109, 122))
348753	25909284	These results strongly supported the notion that F806 attenuated cell adhesion, contributing to the inhibition of cell growth, i.e., anoikis.	('cell adhesion', 'CPA', (65, 78))	('cell growth', 'CPA', (114, 125))	('F806', 'Var', (49, 53))	('F806', 'Chemical', '-', (49, 53))	('anoikis', 'Disease', (133, 140))	('attenuated', 'NegReg', (54, 64))	('inhibition', 'NegReg', (100, 110))
348755	25909284	In our present study, no apparent effect on the protein level of beta1 integrin, beta4 integrin and alpha5 integrin was observed; nevertheless, the activation of beta1 integrin was inhibited by F806 both in vitro and in vivo.	('beta1 integrin', 'Gene', '3688', (162, 176))	('beta1 integrin', 'Gene', '3688', (65, 79))	('activation', 'PosReg', (148, 158))	('beta1 integrin', 'Gene', (162, 176))	('beta1 integrin', 'Gene', (65, 79))	('inhibited', 'NegReg', (181, 190))	('beta4', 'Gene', '10381', (81, 86))	('F806', 'Var', (194, 198))	('F806', 'Chemical', '-', (194, 198))	('beta4', 'Gene', (81, 86))
348757	25909284	Therefore, the inactivation of beta1 integrin would in part inhibit the affinity of integrins for their ligands, resulting in anoikis.	('affinity', 'Interaction', (72, 80))	('beta1 integrin', 'Gene', '3688', (31, 45))	('inhibit', 'NegReg', (60, 67))	('beta1 integrin', 'Gene', (31, 45))	('integrins', 'Protein', (84, 93))	('anoikis', 'Disease', (126, 133))	('inactivation', 'Var', (15, 27))
348759	25909284	These roles of beta1 integrin prompt us to identify it as a potential target of F806 in ESCC cells.	('ESCC', 'Disease', (88, 92))	('beta1 integrin', 'Gene', '3688', (15, 29))	('F806', 'Var', (80, 84))	('F806', 'Chemical', '-', (80, 84))	('beta1 integrin', 'Gene', (15, 29))
348760	25909284	The decrease in the downstream signal molecules (such as p-FAK, p-AKT and p-ERK1/2) of integrin signaling confirmed the suppression of beta1 integrin activation by F806 in ESCC cells.	('F806', 'Var', (164, 168))	('beta1 integrin', 'Gene', '3688', (135, 149))	('F806', 'Chemical', '-', (164, 168))	('decrease', 'NegReg', (4, 12))	('p-AKT', 'Gene', '207', (64, 69))	('p-AKT', 'Gene', (64, 69))	('beta1 integrin', 'Gene', (135, 149))	('FAK', 'Gene', '5747', (59, 62))	('integrin signaling', 'MPA', (87, 105))	('FAK', 'Gene', (59, 62))	('suppression', 'NegReg', (120, 131))
348761	25909284	The specific blockade of beta1 integrin antibody was performed to determine whether the inhibition of beta1 integrin activation by F806 resulted in suppression of cell adhesion and inducing anoikis.	('inducing', 'Reg', (181, 189))	('beta1 integrin', 'Gene', (25, 39))	('beta1 integrin', 'Gene', '3688', (25, 39))	('suppression', 'NegReg', (148, 159))	('F806', 'Var', (131, 135))	('beta1 integrin', 'Gene', '3688', (102, 116))	('cell adhesion', 'CPA', (163, 176))	('F806', 'Chemical', '-', (131, 135))	('anoikis', 'CPA', (190, 197))	('activation', 'PosReg', (117, 127))	('beta1 integrin', 'Gene', (102, 116))
348762	25909284	It was showed that F806 revealed greater inhibitory effect on cell adhesion in ESCC cells, in contrast to specific anti-beta1 integrin JB1A.	('cell adhesion', 'CPA', (62, 75))	('inhibitory effect', 'NegReg', (41, 58))	('beta1 integrin', 'Gene', '3688', (120, 134))	('F806', 'Chemical', '-', (19, 23))	('F806', 'Var', (19, 23))	('beta1 integrin', 'Gene', (120, 134))
348763	25909284	Nevertheless, the combination of F806 with JB1A could cause the most suppression of cell adhesion in ESCC cells (Figure 5D).	('JB1A', 'Gene', (43, 47))	('suppression', 'NegReg', (69, 80))	('F806', 'Var', (33, 37))	('F806', 'Chemical', '-', (33, 37))	('cell adhesion in', 'CPA', (84, 100))	('combination', 'Interaction', (18, 29))
348764	25909284	The potential synergistic effect of F806 and JB1A on the inhibition of cell adhesion hinted different binding site between F806 and JB1A.	('binding', 'Interaction', (102, 109))	('inhibition', 'NegReg', (57, 67))	('F806', 'Var', (36, 40))	('F806', 'Chemical', '-', (36, 40))	('F806', 'Var', (123, 127))	('cell adhesion', 'CPA', (71, 84))	('F806', 'Chemical', '-', (123, 127))
348766	25909284	Based on these observations, docking computation model was performed to predict possible F806-binding site of beta1 integrin.	('F806', 'Chemical', '-', (89, 93))	('F806-binding', 'Var', (89, 101))	('beta1 integrin', 'Gene', '3688', (110, 124))	('beta1 integrin', 'Gene', (110, 124))
348767	25909284	Indeed, it was presented that F806 would interact with Arg610 site of beta1 integrin by pi bond (pi bond) (Supplementary Figure 3).	('beta1 integrin', 'Gene', '3688', (70, 84))	('F806', 'Chemical', '-', (30, 34))	('Arg610', 'Chemical', '-', (55, 61))	('interact', 'Reg', (41, 49))	('beta1 integrin', 'Gene', (70, 84))	('pi bond', 'MPA', (88, 95))	('F806', 'Var', (30, 34))	('Arg610', 'Var', (55, 61))
348768	25909284	However, detailed investigation might be necessary to clarify the mechanism of the interaction between F806 and Arg610 site of beta1 integrin.	('F806', 'Var', (103, 107))	('beta1 integrin', 'Gene', (127, 141))	('F806', 'Chemical', '-', (103, 107))	('Arg610 site', 'Var', (112, 123))	('Arg610', 'Chemical', '-', (112, 118))	('beta1 integrin', 'Gene', '3688', (127, 141))
348769	25909284	Our study also showed that the knockdown of beta1 integrin indeed decreased cell adhesion in KYSE510 cells, while F806 still was more effective than si-beta1 integrin.	('beta1 integrin', 'Gene', (44, 58))	('beta1 integrin', 'Gene', '3688', (152, 166))	('decreased', 'NegReg', (66, 75))	('F806', 'Var', (114, 118))	('beta1 integrin', 'Gene', (152, 166))	('beta1 integrin', 'Gene', '3688', (44, 58))	('decreased cell adhesion', 'Phenotype', 'HP:0008352', (66, 89))	('F806', 'Chemical', '-', (114, 118))	('cell adhesion in KYSE510 cells', 'CPA', (76, 106))	('KYSE510', 'CellLine', 'CVCL:1354', (93, 100))	('knockdown', 'Var', (31, 40))
348770	25909284	Intriguingly, after the remarkable knockdown of beta1 integrin, mounting inhibition ratio of cell adhesion was found in F806-treated KYSE510 cells (Figure 5E).	('knockdown', 'Var', (35, 44))	('F806', 'Chemical', '-', (120, 124))	('inhibition', 'NegReg', (73, 83))	('beta1 integrin', 'Gene', (48, 62))	('rat', 'Species', '10116', (84, 87))	('cell adhesion', 'CPA', (93, 106))	('KYSE510', 'CellLine', 'CVCL:1354', (133, 140))	('beta1 integrin', 'Gene', '3688', (48, 62))
348771	25909284	Obviously, after the loss of the target molecule beta1 integrin by si-RNA, F806 still could suppress KYSE510 cells binding to ECM.	('F806', 'Chemical', '-', (75, 79))	('KYSE510', 'CellLine', 'CVCL:1354', (101, 108))	('beta1 integrin', 'Gene', (49, 63))	('suppress', 'NegReg', (92, 100))	('beta1 integrin', 'Gene', '3688', (49, 63))	('KYSE510 cells binding', 'CPA', (101, 122))	('F806', 'Var', (75, 79))	('si-RNA', 'Gene', (67, 73))
348772	25909284	It hinted that beta1 integrin would not be the only potential target of F806 in ESCC cells.	('F806', 'Var', (72, 76))	('beta1 integrin', 'Gene', '3688', (15, 29))	('F806', 'Chemical', '-', (72, 76))	('beta1 integrin', 'Gene', (15, 29))	('ESCC', 'Disease', (80, 84))
348774	25909284	Therefore, F806 might also direct or indirect against other integrin subunit and further investigations would be warranted to verify the detailed mechanism.	('F806', 'Var', (11, 15))	('integrin subunit', 'Protein', (60, 76))	('F806', 'Chemical', '-', (11, 15))
348775	25909284	Mounting experimental evidence supports that drug resistance of a targeted therapeutic agent can be acquired, because inhibition of one key pathway in a tumor may not completely turn off other parallel signaling pathways, allowing some cancer cells to survive and propagate.	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('cancer', 'Disease', 'MESH:D009369', (236, 242))	('cancer', 'Disease', (236, 242))	('drug resistance', 'Phenotype', 'HP:0020174', (45, 60))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('inhibition', 'Var', (118, 128))
348778	25909284	Furthermore, targeting beta1 integrin inhibits tumor growth in bevacizumab-resistant glioblastoma.	('beta1 integrin', 'Gene', '3688', (23, 37))	('inhibits', 'NegReg', (38, 46))	('glioblastoma', 'Disease', (85, 97))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('glioblastoma', 'Disease', 'MESH:D005909', (85, 97))	('targeting', 'Var', (13, 22))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('beta1 integrin', 'Gene', (23, 37))	('glioblastoma', 'Phenotype', 'HP:0012174', (85, 97))	('bevacizumab', 'Chemical', 'MESH:D000068258', (63, 74))	('tumor', 'Disease', (47, 52))
348779	25909284	In this study, it was clearly demonstrated that F806 could induce apoptosis and inhibit cell growth via blocking the activation of beta1 integrin.	('F806', 'Var', (48, 52))	('blocking', 'NegReg', (104, 112))	('inhibit', 'NegReg', (80, 87))	('F806', 'Chemical', '-', (48, 52))	('rat', 'Species', '10116', (37, 40))	('activation', 'MPA', (117, 127))	('beta1 integrin', 'Gene', (131, 145))	('cell growth', 'CPA', (88, 99))	('apoptosis', 'CPA', (66, 75))	('beta1 integrin', 'Gene', '3688', (131, 145))
348781	25909284	In summary, our data indicate that the novel drug F806 revealed promising antitumor activity in ESCC models and showed very low toxicity to the non-cancerous cells.	('cancer', 'Disease', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('F806', 'Var', (50, 54))	('toxicity', 'Disease', 'MESH:D064420', (128, 136))	('toxicity', 'Disease', (128, 136))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('F806', 'Chemical', '-', (50, 54))	('ESCC', 'Disease', (96, 100))	('tumor', 'Disease', (78, 83))
348782	25909284	In addition, this study highlights the inhibition of beta1 integrin activation as a potential mechanism of F806, contributing to the suppression of focal adhesion formation, the prevention of further tumor growth and survival from the ECM, and the eventual initiation of apoptosis (i.e., anoikis) in ESCC cells.	('prevention', 'NegReg', (178, 188))	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('focal adhesion', 'Protein', (148, 162))	('F806', 'Var', (107, 111))	('inhibition', 'NegReg', (39, 49))	('beta1 integrin', 'Gene', '3688', (53, 67))	('tumor', 'Disease', (200, 205))	('survival', 'CPA', (217, 225))	('F806', 'Chemical', '-', (107, 111))	('suppression', 'NegReg', (133, 144))	('apoptosis', 'CPA', (271, 280))	('beta1 integrin', 'Gene', (53, 67))
348783	25909284	Therefore, F806 merits further evaluation and precise delineation as a therapeutic agent against human ESCC.	('ESCC', 'Disease', (103, 107))	('F806', 'Var', (11, 15))	('human', 'Species', '9606', (97, 102))	('F806', 'Chemical', '-', (11, 15))
348790	25909284	Mice were inoculated subcutaneously with 1.0 x 106 EC109 or 1.0 x 106 KYSE510 human esophageal squamous cell carcinoma (ESCC) cells on the right flank.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (95, 118))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (84, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('KYSE510', 'CellLine', 'CVCL:1354', (70, 77))	('EC109', 'Var', (51, 56))	('Mice', 'Species', '10090', (0, 4))	('human', 'Species', '9606', (78, 83))	('esophageal squamous cell carcinoma', 'Disease', (84, 118))
348804	25909284	Inhibition of growth was expressed as an inhibition ratio (%) = (1 - OD490Treated/OD490Control) x 100 or a growth ratio (%) = OD490Treated/OD490Control x 100.	('rat', 'Species', '10116', (52, 55))	('rat', 'Species', '10116', (114, 117))	('OD490Treated/OD490Control', 'Var', (126, 151))	('growth', 'MPA', (107, 113))	('growth', 'MPA', (14, 20))	('inhibition', 'NegReg', (41, 51))
348838	29545906	Downregulation of LC3A was related to DNA methylation in lung cancer cell lines, while in primary lung tumor samples, protein expression of LC3A was not significantly correlated with DNA methylation, and the methylation status of LC3A was not related to clinicopathological features.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('LC3A', 'Gene', (140, 144))	('LC3A', 'Gene', (230, 234))	('lung tumor', 'Disease', 'MESH:D008175', (98, 108))	('Downregulation', 'NegReg', (0, 14))	('LC3A', 'Gene', '84557', (140, 144))	('lung tumor', 'Disease', (98, 108))	('LC3A', 'Gene', '84557', (230, 234))	('LC3A', 'Gene', (18, 22))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('LC3A', 'Gene', '84557', (18, 22))	('lung cancer', 'Disease', 'MESH:D008175', (57, 68))	('methylation', 'Var', (42, 53))	('lung tumor', 'Phenotype', 'HP:0100526', (98, 108))	('lung cancer', 'Disease', (57, 68))	('lung cancer', 'Phenotype', 'HP:0100526', (57, 68))
348839	29545906	Taken together, our results suggest that autophagy-associated proteins such as LC3A, LC3B, and Beclin-1 might be potential biomarkers for subclassification, differentiation, and local metastasis in primary lung tumor, and epigenetic mechanism is partially responsible for gene silencing of LC3A in lung cancer cell lines.	('LC3A', 'Gene', '84557', (290, 294))	('LC3B', 'Gene', (85, 89))	('lung tumor', 'Phenotype', 'HP:0100526', (206, 216))	('lung cancer', 'Disease', (298, 309))	('lung cancer', 'Phenotype', 'HP:0100526', (298, 309))	('LC3A', 'Gene', (79, 83))	('LC3A', 'Gene', '84557', (79, 83))	('LC3B', 'Gene', '81631', (85, 89))	('cancer', 'Phenotype', 'HP:0002664', (303, 309))	('gene silencing', 'Var', (272, 286))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('lung tumor', 'Disease', (206, 216))	('lung cancer', 'Disease', 'MESH:D008175', (298, 309))	('lung tumor', 'Disease', 'MESH:D008175', (206, 216))	('LC3A', 'Gene', (290, 294))
348851	29545906	Accumulating evidence reveals that dysregulation of autophagy-associated proteins may lead to development of different tumors.	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('autophagy-associated proteins', 'Protein', (52, 81))	('tumors', 'Disease', (119, 125))	('tumors', 'Disease', 'MESH:D009369', (119, 125))	('men', 'Species', '9606', (101, 104))	('lead to', 'Reg', (86, 93))	('dysregulation', 'Var', (35, 48))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))
348853	29545906	It has been believed that epigenetically mediated aberrant gene silencing is closely related to pathogenesis of cancers including lung cancer.	('lung cancer', 'Phenotype', 'HP:0100526', (130, 141))	('related', 'Reg', (85, 92))	('cancers', 'Phenotype', 'HP:0002664', (112, 119))	('cancers', 'Disease', 'MESH:D009369', (112, 119))	('lung cancer', 'Disease', 'MESH:D008175', (130, 141))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('cancers', 'Disease', (112, 119))	('epigenetically mediated aberrant gene silencing', 'Var', (26, 73))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('lung cancer', 'Disease', (130, 141))
348854	29545906	DNA methylation of autophagy genes plays an important role in cancer development.	('autophagy genes', 'Gene', (19, 34))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('men', 'Species', '9606', (76, 79))	('methylation', 'Var', (4, 15))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))
348855	29545906	In glioblastoma, the most aggressive type of brain cancer, methylation of an upstream autophagy inducer ULK2 was found to be essential for astrocyte transformation and tumor growth.	('glioblastoma', 'Phenotype', 'HP:0012174', (3, 15))	('tumor', 'Disease', (168, 173))	('ULK2', 'Gene', (104, 108))	('ULK2', 'Gene', '9706', (104, 108))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('astrocyte transformation', 'CPA', (139, 163))	('glioblastoma', 'Disease', (3, 15))	('glioblastoma', 'Disease', 'MESH:D005909', (3, 15))	('methylation', 'Var', (59, 70))	('aggressive type of brain cancer', 'Disease', 'MESH:D001932', (26, 57))	('brain cancer', 'Phenotype', 'HP:0030692', (45, 57))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('aggressive type of brain cancer', 'Disease', (26, 57))	('essential', 'Reg', (125, 134))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
348860	29545906	Five non-small-cell lung cancer (NSCLC) cell lines including H322, H1650, H1975, H2170, and H226 as well as one small cell lung cancer (SCLC) cell line COLO677 were purchased from the American Type Culture Collection (ATCC, Rockville, USA).	('non-small-cell lung cancer', 'Disease', (5, 31))	('NSCLC', 'Phenotype', 'HP:0030358', (33, 38))	('H1650', 'CellLine', 'CVCL:1483', (67, 72))	('lung cancer', 'Phenotype', 'HP:0100526', (123, 134))	('lung cancer', 'Phenotype', 'HP:0100526', (20, 31))	('SCLC', 'Disease', 'MESH:D018288', (136, 140))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('H1975', 'Var', (74, 79))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (112, 134))	('H1975', 'CellLine', 'CVCL:1511', (74, 79))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('SCLC', 'Disease', (34, 38))	('SCLC', 'Phenotype', 'HP:0030357', (34, 38))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (5, 31))	('H2170', 'Var', (81, 86))	('H226', 'CellLine', 'CVCL:J621', (92, 96))	('SCLC', 'Disease', (136, 140))	('H2170', 'CellLine', 'CVCL:1535', (81, 86))	('SCLC', 'Phenotype', 'HP:0030357', (136, 140))	('NSCLC', 'Disease', 'MESH:D002289', (33, 38))	('small cell lung cancer', 'Disease', 'MESH:D055752', (112, 134))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (9, 31))	('NSCLC', 'Disease', (33, 38))	('SCLC', 'Disease', 'MESH:D018288', (34, 38))	('non-small-cell lung cancer', 'Disease', 'MESH:D002289', (5, 31))	('small cell lung cancer', 'Disease', (112, 134))
348880	29545906	Compared to normal bronchial epithelial cells (HBEC), the expression of LC3A was downregulated in lung cancer cell lines H226, COLO677, H322, and H1975 at mRNA level, while in the cell lines H2170 and H1650, the expression of LC3A was higher than in HBEC (Figure 1(a)).	('LC3A', 'Gene', (226, 230))	('H1650', 'CellLine', 'CVCL:1483', (201, 206))	('downregulated', 'NegReg', (81, 94))	('LC3A', 'Gene', '84557', (226, 230))	('lung cancer', 'Disease', (98, 109))	('expression', 'MPA', (58, 68))	('H1975', 'Var', (146, 151))	('expression', 'MPA', (212, 222))	('H1975', 'CellLine', 'CVCL:1511', (146, 151))	('H2170', 'CellLine', 'CVCL:1535', (191, 196))	('lung cancer', 'Phenotype', 'HP:0100526', (98, 109))	('LC3A', 'Gene', (72, 76))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('LC3A', 'Gene', '84557', (72, 76))	('lung cancer', 'Disease', 'MESH:D008175', (98, 109))	('H226', 'CellLine', 'CVCL:J621', (121, 125))
348885	29545906	By contrast, only a slight upregulation of LC3A was observed in H1975 (Figure 1(b)).	('LC3A', 'Gene', (43, 47))	('H1975', 'Var', (64, 69))	('LC3A', 'Gene', '84557', (43, 47))	('H1975', 'CellLine', 'CVCL:1511', (64, 69))
348892	29545906	COLO677 exhibits no LC3A expression and is highly methylated in exon 4 and partially methylated in promoter region.	('expression', 'MPA', (25, 35))	('COLO677', 'Var', (0, 7))	('LC3A', 'Gene', (20, 24))	('LC3A', 'Gene', '84557', (20, 24))
348896	29545906	The methylation status was not significantly associated with clinicopathological parameters including tumor subtype, stage, and grading (Supplementary Data 3).	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('methylation', 'Var', (4, 15))	('men', 'Species', '9606', (143, 146))	('tumor', 'Disease', (102, 107))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))
348909	29545906	It turned out that the p62 expression was significantly associated with the expression of Beclin-1 and LC3B (Table 4; p < 0.01).	('p62', 'Var', (23, 26))	('LC3B', 'Gene', (103, 107))	('associated', 'Reg', (56, 66))	('Beclin-1', 'Gene', (90, 98))	('LC3B', 'Gene', '81631', (103, 107))
348914	29545906	Here, we demonstrated the epigenetic regulation and clinical influence of autophagy-related proteins on human lung cancer.	('lung cancer', 'Disease', 'MESH:D008175', (110, 121))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('lung cancer', 'Disease', (110, 121))	('epigenetic regulation', 'Var', (26, 47))	('lung cancer', 'Phenotype', 'HP:0100526', (110, 121))	('human', 'Species', '9606', (104, 109))
348916	29545906	LC3A, not LC3B, was found to be frequently downregulated in various cancer cell lines, and gene silencing of LC3A could be explained by DNA methylation in esophageal squamous cell carcinoma and lung cancer.	('downregulated', 'NegReg', (43, 56))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('lung cancer', 'Disease', 'MESH:D008175', (194, 205))	('cancer', 'Disease', (199, 205))	('lung cancer', 'Phenotype', 'HP:0100526', (194, 205))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('LC3B', 'Gene', (10, 14))	('methylation', 'Var', (140, 151))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (155, 189))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (166, 189))	('LC3A', 'Gene', '84557', (0, 4))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('LC3B', 'Gene', '81631', (10, 14))	('LC3A', 'Gene', '84557', (109, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (180, 189))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('lung cancer', 'Disease', (194, 205))	('silencing', 'NegReg', (96, 105))	('LC3A', 'Gene', (0, 4))	('esophageal squamous cell carcinoma', 'Disease', (155, 189))	('cancer', 'Disease', (68, 74))	('LC3A', 'Gene', (109, 113))
348917	29545906	In line with this, we found decreased expression of LC3A in 4 out of 6 lung cancer cell lines compared to normal human bronchial epithelial cells (HBEC), which correlated to DNA methylation of LC3A in promoter region and exon 4.	('decreased', 'NegReg', (28, 37))	('expression', 'MPA', (38, 48))	('lung cancer', 'Disease', 'MESH:D008175', (71, 82))	('methylation', 'Var', (178, 189))	('LC3A', 'Gene', (52, 56))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('LC3A', 'Gene', '84557', (52, 56))	('LC3A', 'Gene', (193, 197))	('LC3A', 'Gene', '84557', (193, 197))	('decreased expression of LC3A', 'Phenotype', 'HP:0032429', (28, 56))	('lung cancer', 'Disease', (71, 82))	('human', 'Species', '9606', (113, 118))	('lung cancer', 'Phenotype', 'HP:0100526', (71, 82))
348922	29545906	In skin cancer including cutaneous squamous cell carcinoma and malignant melanoma, SLS-staining of LC3A was associated with tumor hypoxia and aggressiveness.	('LC3A', 'Gene', '84557', (99, 103))	('skin cancer', 'Disease', (3, 14))	('tumor hypoxia', 'Disease', (124, 137))	('malignant melanoma', 'Disease', (63, 81))	('cutaneous squamous cell carcinoma', 'Disease', (25, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('skin cancer', 'Phenotype', 'HP:0008069', (3, 14))	('cutaneous squamous cell carcinoma', 'Disease', 'MESH:D002294', (25, 58))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('LC3A', 'Gene', (99, 103))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('tumor hypoxia', 'Disease', 'MESH:D000860', (124, 137))	('malignant melanoma', 'Phenotype', 'HP:0002861', (63, 81))	('skin cancer', 'Disease', 'MESH:D012878', (3, 14))	('associated', 'Reg', (108, 118))	('SLS-staining', 'Var', (83, 95))	('malignant melanoma', 'Disease', 'MESH:D008545', (63, 81))	('aggressiveness', 'Disease', (142, 156))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (35, 58))	('aggressiveness', 'Phenotype', 'HP:0000718', (142, 156))	('cutaneous squamous cell carcinoma', 'Phenotype', 'HP:0006739', (25, 58))	('aggressiveness', 'Disease', 'MESH:D001523', (142, 156))
348925	29545906	Overexpression of LC3B correlates with malignant progression and aggressive behavior and predicts a poor clinical outcome in hepatocellular carcinoma, glioblastoma, and pancreatic ductal adenocarcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (192, 201))	('pancreatic ductal adenocarcinoma', 'Disease', (169, 201))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (169, 201))	('malignant progression', 'CPA', (39, 60))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (125, 149))	('LC3B', 'Gene', (18, 22))	('glioblastoma', 'Disease', (151, 163))	('hepatocellular carcinoma', 'Disease', (125, 149))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (125, 149))	('glioblastoma', 'Disease', 'MESH:D005909', (151, 163))	('Overexpression', 'Var', (0, 14))	('aggressive behavior', 'Disease', 'MESH:D001523', (65, 84))	('glioblastoma', 'Phenotype', 'HP:0012174', (151, 163))	('aggressive behavior', 'Disease', (65, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))	('aggressive behavior', 'Phenotype', 'HP:0000718', (65, 84))	('LC3B', 'Gene', '81631', (18, 22))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (169, 201))
348955	24966803	Positive staining for the proliferation markers Ki67 and PCNA (proliferating cell nuclear antigen) was detected in 56.9% and 60.2% of ESCC specimens, respectively, and was strongly correlated with the nestin phenotype.	('proliferating cell nuclear antigen', 'Gene', (63, 97))	('detected', 'Reg', (103, 111))	('PCNA', 'Gene', (57, 61))	('nestin', 'Gene', (201, 207))	('ESCC', 'Disease', (134, 138))	('PCNA', 'Gene', '5111', (57, 61))	('proliferating cell nuclear antigen', 'Gene', '5111', (63, 97))	('Ki67', 'Var', (48, 52))	('correlated', 'Reg', (181, 191))	('nestin', 'Gene', '10763', (201, 207))
348969	24966803	Subsequent studies have revealed that nestin knockdown inhibits cell proliferation and G1/S arrest in human non-small cell lung cancer cells, possibly via downregulation of AKT-GSK3beta-cyclin D signaling.	('lung cancer', 'Phenotype', 'HP:0100526', (123, 134))	('inhibits', 'NegReg', (55, 63))	('AKT', 'Gene', (173, 176))	('S arrest', 'Disease', (90, 98))	('knockdown', 'Var', (45, 54))	('GSK3beta', 'Gene', (177, 185))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (112, 134))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (108, 134))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('downregulation', 'NegReg', (155, 169))	('S arrest', 'Disease', 'MESH:D006323', (90, 98))	('human', 'Species', '9606', (102, 107))	('AKT', 'Gene', '207', (173, 176))	('cell proliferation', 'CPA', (64, 82))	('lung cancer', 'Disease', (123, 134))	('nestin', 'Gene', '10763', (38, 44))	('lung cancer', 'Disease', 'MESH:D008175', (123, 134))	('GSK3beta', 'Gene', '2932', (177, 185))	('nestin', 'Gene', (38, 44))
349007	24966803	As shown in Figure 5 (A and B) and Table 1, a subsequent Pearson's correlation analysis revealed a significant relationship between the nestin phenotype and Ki67 and PCNA optical density (Ki67: r = 0.223, P = 0.036; PCNA: r = 0.328, P = 0.003).	('PCNA', 'Gene', '5111', (166, 170))	('nestin', 'Gene', '10763', (136, 142))	('Ki67', 'Var', (157, 161))	('PCNA', 'Gene', (216, 220))	('nestin', 'Gene', (136, 142))	('PCNA', 'Gene', '5111', (216, 220))	('PCNA', 'Gene', (166, 170))
349030	24966803	Moreover, a quantitative analysis revealed that Ki67 and PCNA expression were positively correlated with nestin expression.	('correlated', 'Interaction', (89, 99))	('PCNA', 'Gene', (57, 61))	('nestin', 'Gene', '10763', (105, 111))	('nestin', 'Gene', (105, 111))	('PCNA', 'Gene', '5111', (57, 61))	('Ki67', 'Var', (48, 52))	('expression', 'MPA', (112, 122))
349054	24966803	Targeted regulation of nestin may thus have therapeutic applications in the treatment of human esophageal cancer.	('human', 'Species', '9606', (89, 94))	('esophageal cancer', 'Disease', 'MESH:D004938', (95, 112))	('nestin', 'Gene', '10763', (23, 29))	('nestin', 'Gene', (23, 29))	('Targeted regulation', 'Var', (0, 19))	('esophageal cancer', 'Disease', (95, 112))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
349069	32390763	TUG1 expression was elevated in cisplatin-resistant TSCC tissues and cells compared with that in sensitive group and its knockdown inhibited cisplatin resistance to SCC25/CDDP and CAL27/CDDP cells.	('knockdown', 'Var', (121, 130))	('expression', 'MPA', (5, 15))	('TSCC', 'Phenotype', 'HP:0030413', (52, 56))	('TUG1', 'Gene', (0, 4))	('cisplatin', 'Chemical', 'MESH:D002945', (141, 150))	('CDDP', 'Chemical', 'MESH:D002945', (186, 190))	('TSCC', 'Chemical', '-', (52, 56))	('elevated', 'PosReg', (20, 28))	('cisplatin', 'Chemical', 'MESH:D002945', (32, 41))	('cisplatin resistance', 'MPA', (141, 161))	('inhibited', 'NegReg', (131, 140))	('TUG1', 'Gene', '55000', (0, 4))	('CDDP', 'Chemical', 'MESH:D002945', (171, 175))
349073	32390763	The level of CXCR4 protein was decreased by inhibition of TUG1 and recuperated by miR-133b knockdown.	('TUG1', 'Gene', '55000', (58, 62))	('miR-133b', 'Gene', (82, 90))	('TUG1', 'Gene', (58, 62))	('decreased', 'NegReg', (31, 40))	('knockdown', 'Var', (91, 100))	('CXCR4', 'Gene', '7852', (13, 18))	('inhibition', 'NegReg', (44, 54))	('CXCR4', 'Gene', (13, 18))	('miR-133b', 'Gene', '442890', (82, 90))
349074	32390763	Besides, interference of TUG1 attenuated tumor growth by regulating miR-133b and CXCR4 in vivo.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('interference', 'Var', (9, 21))	('miR-133b', 'Gene', (68, 76))	('regulating', 'Reg', (57, 67))	('CXCR4', 'Gene', '7852', (81, 86))	('TUG1', 'Gene', (25, 29))	('TUG1', 'Gene', '55000', (25, 29))	('CXCR4', 'Gene', (81, 86))	('miR-133b', 'Gene', '442890', (68, 76))	('attenuated tumor', 'Disease', (30, 46))	('attenuated tumor', 'Disease', 'MESH:C538265', (30, 46))
349083	32390763	reporte that lncRNA urothelial cancer-associated 1 knockdown promotes cisplatin sensitivity to TSCC cells by regulating phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) pathway.	('phosphatidylinositol', 'MPA', (120, 140))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('cisplatin', 'Chemical', 'MESH:D002945', (70, 79))	('regulating', 'Reg', (109, 119))	('promotes', 'PosReg', (61, 69))	('urothelial cancer', 'Disease', (20, 37))	('TSCC', 'Chemical', '-', (95, 99))	('Akt', 'Gene', '207', (175, 178))	('urothelial cancer', 'Disease', 'MESH:D014523', (20, 37))	('cisplatin sensitivity', 'MPA', (70, 91))	('Akt', 'Gene', (175, 178))	('TSCC', 'Phenotype', 'HP:0030413', (95, 99))	('knockdown', 'Var', (51, 60))
349118	32390763	In brief, after 48 h of transfection, cells were lysed in RIP buffer containing magnetic beads conjugated with Ago2 or IgG antibody.	('Ago2', 'Gene', '27161', (111, 115))	('IgG antibody', 'Protein', (119, 131))	('IgG antibody', 'Phenotype', 'HP:0003237', (119, 131))	('Ago2', 'Gene', (111, 115))	('transfection', 'Var', (24, 36))
349133	32390763	In order to investigate the biological function of TUG1 on cisplatin resistance, SCC25/CDDP and CAL27/CDDP cells were transfected with si-TUG1 or si-NC.	('TUG1', 'Gene', (51, 55))	('TUG1', 'Gene', (138, 142))	('CDDP', 'Chemical', 'MESH:D002945', (87, 91))	('si-NC', 'Var', (146, 151))	('TUG1', 'Gene', '55000', (138, 142))	('cisplatin', 'Chemical', 'MESH:D002945', (59, 68))	('TUG1', 'Gene', '55000', (51, 55))	('CDDP', 'Chemical', 'MESH:D002945', (102, 106))
349135	32390763	After treatment of different concentrations of cisplatin for 48 h, the IC50 of cisplatin was remarkably decreased by knockdown of TUG1 in the two cisplatin-resistant cell lines (Fig.	('cisplatin', 'Chemical', 'MESH:D002945', (79, 88))	('cisplatin', 'Chemical', 'MESH:D002945', (146, 155))	('decreased', 'NegReg', (104, 113))	('cisplatin', 'Chemical', 'MESH:D002945', (47, 56))	('TUG1', 'Gene', '55000', (130, 134))	('IC50 of cisplatin', 'MPA', (71, 88))	('knockdown', 'Var', (117, 126))	('TUG1', 'Gene', (130, 134))
349136	32390763	Moreover, interference of TUG1 notably suppressed the viability of SCC25/CDDP and CAL27/CDDP cells (Fig.	('CDDP', 'Chemical', 'MESH:D002945', (73, 77))	('TUG1', 'Gene', '55000', (26, 30))	('viability', 'CPA', (54, 63))	('interference', 'Var', (10, 22))	('CDDP', 'Chemical', 'MESH:D002945', (88, 92))	('TUG1', 'Gene', (26, 30))	('suppressed', 'NegReg', (39, 49))
349137	32390763	Additionally, the data of transwell invasion assay revealed that silence of TUG1 significantly reduced the invasive ability of SCC25/CDDP and CAL27/CDDP cells (Fig.	('silence', 'Var', (65, 72))	('TUG1', 'Gene', '55000', (76, 80))	('CDDP', 'Chemical', 'MESH:D002945', (148, 152))	('invasive ability of SCC25/CDDP', 'CPA', (107, 137))	('TUG1', 'Gene', (76, 80))	('reduced', 'NegReg', (95, 102))	('CDDP', 'Chemical', 'MESH:D002945', (133, 137))
349138	32390763	Besides, the results of flow cytometry showed that transfection of si-TUG1 remarkably promoted the resistant cell apoptosis (Fig.	('TUG1', 'Gene', '55000', (70, 74))	('TUG1', 'Gene', (70, 74))	('resistant cell apoptosis', 'CPA', (99, 123))	('transfection', 'Var', (51, 63))	('promoted', 'PosReg', (86, 94))
349147	32390763	3f, g, up-regulation of TUG1 induced by transfection of TUG1 overexpression vector led to obvious loss of miR-133b abundance, while its knockdown increased miR-133b level.	('up-regulation', 'PosReg', (7, 20))	('TUG1', 'Gene', (24, 28))	('TUG1', 'Gene', '55000', (56, 60))	('miR-133b', 'Gene', (106, 114))	('abundance', 'MPA', (115, 124))	('increased', 'PosReg', (146, 155))	('TUG1', 'Gene', (56, 60))	('miR-133b', 'Gene', '442890', (156, 164))	('knockdown', 'Var', (136, 145))	('loss', 'NegReg', (98, 102))	('miR-133b', 'Gene', (156, 164))	('TUG1', 'Gene', '55000', (24, 28))	('miR-133b', 'Gene', '442890', (106, 114))
349155	32390763	5e, that the abundance of CXCR4 was evidently inhibited by overexpression of miR-133b and up-regulated by knockdown of miR-133b.	('miR-133b', 'Gene', (77, 85))	('CXCR4', 'Gene', '7852', (26, 31))	('up-regulated', 'PosReg', (90, 102))	('knockdown', 'Var', (106, 115))	('CXCR4', 'Gene', (26, 31))	('overexpression', 'PosReg', (59, 73))	('miR-133b', 'Gene', '442890', (77, 85))	('miR-133b', 'Gene', '442890', (119, 127))	('inhibited', 'NegReg', (46, 55))	('miR-133b', 'Gene', (119, 127))
349156	32390763	To explore whether CXCR4 is involved in miR-133b-mediated cisplatin resistance, two resistant cell lines were transfected with si-NC, ssi-CXCR4, si-CXCR4 + in-miR-NC or in-miR-133b.	('miR', 'Gene', '220972', (40, 43))	('CXCR4', 'Gene', (148, 153))	('miR', 'Gene', (40, 43))	('miR-133b', 'Gene', '442890', (172, 180))	('cisplatin', 'Chemical', 'MESH:D002945', (58, 67))	('CXCR4', 'Gene', (19, 24))	('CXCR4', 'Gene', '7852', (19, 24))	('miR-133b', 'Gene', (172, 180))	('si-NC', 'Var', (127, 132))	('miR', 'Gene', '220972', (172, 175))	('miR', 'Gene', (172, 175))	('miR-133b', 'Gene', '442890', (40, 48))	('CXCR4', 'Gene', '7852', (138, 143))	('miR', 'Gene', '220972', (159, 162))	('miR', 'Gene', (159, 162))	('CXCR4', 'Gene', '7852', (148, 153))	('CXCR4', 'Gene', (138, 143))	('miR-133b', 'Gene', (40, 48))
349157	32390763	In addition, loss-of-function experiments demonstrated that silencing CXCR4 impeded cisplatin resistance, uncovered by inhibition of IC50 of cisplatin, cell viability and invasion as well as increase of apoptosis in SCC25/CDDP and CAL27/CDDP cells (Fig.	('loss-of-function', 'NegReg', (13, 29))	('increase', 'PosReg', (191, 199))	('CDDP', 'Chemical', 'MESH:D002945', (237, 241))	('cisplatin', 'Chemical', 'MESH:D002945', (141, 150))	('invasion', 'CPA', (171, 179))	('inhibition', 'NegReg', (119, 129))	('apoptosis', 'CPA', (203, 212))	('CXCR4', 'Gene', '7852', (70, 75))	('cisplatin', 'Chemical', 'MESH:D002945', (84, 93))	('cell viability', 'CPA', (152, 166))	('silencing', 'Var', (60, 69))	('CDDP', 'Chemical', 'MESH:D002945', (222, 226))	('cisplatin resistance', 'MPA', (84, 104))	('CXCR4', 'Gene', (70, 75))	('impeded', 'NegReg', (76, 83))
349158	32390763	However, knockdown of miR-133b attenuated the suppressive role of CXCR4 silence.	('CXCR4', 'Gene', (66, 71))	('knockdown', 'Var', (9, 18))	('attenuated', 'NegReg', (31, 41))	('CXCR4', 'Gene', '7852', (66, 71))	('miR-133b', 'Gene', '442890', (22, 30))	('miR-133b', 'Gene', (22, 30))
349166	32390763	Additionally, the abundance of CXCR4 was significantly reduced at mRNA and protein levels in xenograft tissues induced by CAL27/CDDP cells with transfection of sh-TUG1 (Fig.	('reduced', 'NegReg', (55, 62))	('CDDP', 'Chemical', 'MESH:D002945', (128, 132))	('transfection', 'Var', (144, 156))	('sh-TUG1', 'Gene', '55000', (160, 167))	('sh-TUG1', 'Gene', (160, 167))	('CXCR4', 'Gene', '7852', (31, 36))	('CXCR4', 'Gene', (31, 36))
349176	32390763	Subsequently, loss-of-function experiments revealed that TUG1 knockdown inhibited IC50 of cisplatin, cell viability and invasion and increased apoptosis, indicating the suppressive role of TUG1 knockdown in cisplatin resistance in TSCC.	('TSCC', 'Chemical', '-', (231, 235))	('TUG1', 'Gene', (189, 193))	('cisplatin', 'Chemical', 'MESH:D002945', (90, 99))	('loss-of-function', 'NegReg', (14, 30))	('invasion', 'CPA', (120, 128))	('TUG1', 'Gene', '55000', (57, 61))	('apoptosis', 'CPA', (143, 152))	('cell viability', 'CPA', (101, 115))	('cisplatin', 'Chemical', 'MESH:D002945', (207, 216))	('TSCC', 'Phenotype', 'HP:0030413', (231, 235))	('inhibited', 'NegReg', (72, 81))	('increased', 'PosReg', (133, 142))	('IC50 of cisplatin', 'MPA', (82, 99))	('TUG1', 'Gene', '55000', (189, 193))	('TUG1', 'Gene', (57, 61))	('knockdown', 'Var', (62, 71))
349189	32390763	Similarly, this paper also exhibited high expression of CXCR4 in resistant cells and showed that its silence suppressed cisplatin resistance of TSCC, which was also consistent with that in other cancers.	('suppressed', 'NegReg', (109, 119))	('cisplatin resistance', 'MPA', (120, 140))	('expression', 'MPA', (42, 52))	('TSCC', 'Chemical', '-', (144, 148))	('silence', 'Var', (101, 108))	('cancers', 'Disease', 'MESH:D009369', (195, 202))	('cancers', 'Phenotype', 'HP:0002664', (195, 202))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('CXCR4', 'Gene', '7852', (56, 61))	('cancers', 'Disease', (195, 202))	('cisplatin', 'Chemical', 'MESH:D002945', (120, 129))	('CXCR4', 'Gene', (56, 61))	('TSCC', 'Phenotype', 'HP:0030413', (144, 148))
349190	32390763	Moreover, deficiency of miR-133b attenuated the effect of CXCR4 interference, suggesting the importance of CXCR4 for miR-133b-mediated resistance in TSCC.	('CXCR4', 'Gene', (107, 112))	('miR-133b', 'Gene', '442890', (24, 32))	('miR-133b', 'Gene', '442890', (117, 125))	('miR-133b', 'Gene', (24, 32))	('CXCR4', 'Gene', '7852', (58, 63))	('attenuated', 'NegReg', (33, 43))	('TSCC', 'Phenotype', 'HP:0030413', (149, 153))	('miR-133b', 'Gene', (117, 125))	('CXCR4', 'Gene', '7852', (107, 112))	('deficiency', 'Var', (10, 20))	('CXCR4', 'Gene', (58, 63))	('TSCC', 'Chemical', '-', (149, 153))
349191	32390763	Besides, CXCR4 protein level was decreased by TUG1 knockdown and rescued by depletion of miR-133b, which supported that TUG1 might act as a ceRNA of miR-133b to regulate CXCR4 expression in TSCC cells.	('TUG1', 'Gene', (120, 124))	('miR-133b', 'Gene', '442890', (89, 97))	('CXCR4', 'Gene', (170, 175))	('CXCR4', 'Gene', (9, 14))	('miR-133b', 'Gene', (89, 97))	('TUG1', 'Gene', '55000', (46, 50))	('TSCC', 'Phenotype', 'HP:0030413', (190, 194))	('miR-133b', 'Gene', '442890', (149, 157))	('CXCR4', 'Gene', '7852', (170, 175))	('miR-133b', 'Gene', (149, 157))	('TUG1', 'Gene', (46, 50))	('decreased', 'NegReg', (33, 42))	('TUG1', 'Gene', '55000', (120, 124))	('CXCR4', 'Gene', '7852', (9, 14))	('TSCC', 'Chemical', '-', (190, 194))	('knockdown', 'Var', (51, 60))
349195	32390763	Our results revealed that TUG1 knockdown inhibited cisplatin resistance in TSCC, possibly via regulating CXCR4 by sponging miR-133b.	('miR-133b', 'Gene', (123, 131))	('CXCR4', 'Gene', '7852', (105, 110))	('TSCC', 'Chemical', '-', (75, 79))	('cisplatin', 'Chemical', 'MESH:D002945', (51, 60))	('CXCR4', 'Gene', (105, 110))	('cisplatin resistance', 'MPA', (51, 71))	('TUG1', 'Gene', '55000', (26, 30))	('miR-133b', 'Gene', '442890', (123, 131))	('inhibited', 'NegReg', (41, 50))	('TSCC', 'Phenotype', 'HP:0030413', (75, 79))	('TUG1', 'Gene', (26, 30))	('knockdown', 'Var', (31, 40))
349199	31434729	Transcriptional Response of Ovine Lung to Infection with Jaagsiekte Sheep Retrovirus Ovine pulmonary adenocarcinoma is a chronic respiratory disease of sheep caused by jaagsiekte sheep retrovirus (JSRV).	('jaagsiekte', 'Var', (168, 178))	('Ovine pulmonary adenocarcinoma', 'Disease', (85, 115))	('sheep', 'Species', '9940', (152, 157))	('pulmonary adenocarcinoma', 'Phenotype', 'HP:0030078', (91, 115))	('JSRV', 'Species', '11746', (197, 201))	('Sheep Retrovirus', 'Disease', 'MESH:D012192', (68, 84))	('jaagsiekte sheep retrovirus', 'Species', '11746', (168, 195))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('respiratory disease', 'Phenotype', 'HP:0011947', (129, 148))	('respiratory disease', 'Disease', (129, 148))	('sheep', 'Species', '9940', (179, 184))	('Ovine pulmonary adenocarcinoma', 'Disease', 'MESH:D011648', (85, 115))	('respiratory disease', 'Disease', 'MESH:D012131', (129, 148))	('Sheep Retrovirus', 'Disease', (68, 84))
349223	31434729	JSRV Env expression activates a number of signaling pathways that control cellular proliferation, including phosphatidylinositol 3-kinase (PI3K)-Akt and mitogen-activated protein kinase (MAPK)-extracellular signal-regulated kinase 1/2 (ERK1/2).	('Akt', 'Gene', (145, 148))	('expression', 'Var', (9, 19))	('cellular proliferation', 'CPA', (74, 96))	('Env', 'Gene', (5, 8))	('JSRV Env', 'Gene', (0, 8))	('signaling pathways', 'Pathway', (42, 60))	('phosphatidylinositol', 'Chemical', 'MESH:D010716', (108, 128))	('Akt', 'Gene', '207', (145, 148))	('JSRV', 'Species', '11746', (0, 4))	('activates', 'PosReg', (20, 29))
349249	31434729	These results revealed key signaling networks in cancer, including neovascularization, cell viability, and tumor growth, to be activated in JSRV-infected tissue compared to mock-infected tissue (Fig.	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('cell viability', 'CPA', (87, 101))	('tumor', 'Disease', (107, 112))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('JSRV-infected', 'Var', (140, 153))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('neovascularization', 'CPA', (67, 85))	('JSRV', 'Species', '11746', (140, 144))	('activated', 'PosReg', (127, 136))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('cancer', 'Disease', (49, 55))
349282	31434729	Markers of T lymphocytes were either not significantly changed (CD3 [gamma, delta, and epsilon chains] and CD4) or downregulated (CD8, alpha and beta chains).	('CD8', 'Gene', (130, 133))	('CD4', 'Gene', (107, 110))	('CD8', 'Gene', '925', (130, 133))	('CD4', 'Gene', '920', (107, 110))	('CD3', 'Var', (64, 67))	('downregulated', 'NegReg', (115, 128))
349294	31434729	Consistent with the greater abundance of macrophages in OPA-affected lung, RNA-Seq identified the increased expression of several myeloid cell chemoattractants (e.g., CCL2, CSF2, S100A8, S100A9, and CXCL8) in JSRV-infected tissues.	('CXCL8', 'Gene', '3576', (199, 204))	('CXCL8', 'Gene', (199, 204))	('CSF2', 'Gene', (173, 177))	('S100A8', 'Var', (179, 185))	('S100A9', 'Var', (187, 193))	('CCL2', 'Gene', '6347', (167, 171))	('JSRV', 'Species', '11746', (209, 213))	('increased', 'PosReg', (98, 107))	('expression', 'MPA', (108, 118))	('CSF2', 'Gene', '1437', (173, 177))	('CCL2', 'Gene', (167, 171))
349316	31434729	Several studies have shown that Env expression leads to activation of the PI3K/Akt and MAPK/ERK1/2 signaling pathways, while additional pathways, including EGFR and Wnt signaling, may also play a role.	('EGFR', 'Gene', '1956', (156, 160))	('MAPK/ERK1/2 signaling pathways', 'Pathway', (87, 117))	('expression', 'Var', (36, 46))	('EGFR', 'Gene', (156, 160))	('Akt', 'Gene', '207', (79, 82))	('Akt', 'Gene', (79, 82))	('activation', 'PosReg', (56, 66))	('Env', 'Gene', (32, 35))
349331	31434729	The absence of a significant adaptive immune response to JSRV in sheep is commonly attributed to enJSRV expression in the fetal thymus during immune development, which is proposed to lead to immune tolerance through the deletion of T lymphocytes that recognize the closely related JSRV proteins.	('immune tolerance', 'CPA', (191, 207))	('enJSRV', 'Gene', (97, 103))	('JSRV', 'Species', '11746', (99, 103))	('JSRV', 'Species', '11746', (57, 61))	('deletion', 'Var', (220, 228))	('JSRV', 'Species', '11746', (281, 285))	('lead to', 'Reg', (183, 190))	('sheep', 'Species', '9940', (65, 70))
349477	32871048	For example, lncRNA GHET1 predicts unfavorable prognosis of hepatocellular carcinoma patients and boosts proliferation via silencing of KLF2.	('lncRNA GHET1', 'Gene', '102723099', (13, 25))	('hepatocellular carcinoma', 'Disease', (60, 84))	('KLF2', 'Gene', (136, 140))	('boosts', 'PosReg', (98, 104))	('patients', 'Species', '9606', (85, 93))	('proliferation', 'CPA', (105, 118))	('KLF2', 'Gene', '10365', (136, 140))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (60, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('lncRNA GHET1', 'Gene', (13, 25))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (60, 84))	('silencing', 'Var', (123, 132))	('unfavorable prognosis', 'MPA', (35, 56))
349478	32871048	6  HOXA11-AS enhances proliferative HCC cells through epigenetic silencing of DUSP5.	('proliferative HCC cells', 'CPA', (22, 45))	('HOXA11-AS', 'Gene', (3, 12))	('DUSP5', 'Gene', (78, 83))	('HOXA11-AS', 'Gene', '221883', (3, 12))	('enhances', 'PosReg', (13, 21))	('DUSP5', 'Gene', '1847', (78, 83))	('epigenetic silencing', 'Var', (54, 74))
349520	32871048	Cell lysates were incubated with protein A/G beads coated with the antibodies against TAF15 and control IgG at 4 C for 3 hours.	('TAF15', 'Gene', (86, 91))	('TAF15', 'Gene', '8148', (86, 91))	('antibodies', 'Var', (67, 77))
349527	32871048	Before functional assays, we silenced PITPNA-AS1 in NCI-H520 and SK-MES-1 cells with highest PITPNA-AS1 expression to investigate the role of PITPNA-AS1 in LUSC (Figure 1C).	('PITPNA-AS1', 'Gene', '100306951', (93, 103))	('PITPNA-AS1', 'Gene', '100306951', (142, 152))	('PITPNA-AS1', 'Gene', (93, 103))	('NCI-H520', 'CellLine', 'CVCL:1566', (52, 60))	('PITPNA-AS1', 'Gene', (142, 152))	('LUSC', 'Phenotype', 'HP:0030359', (156, 160))	('PITPNA-AS1', 'Gene', '100306951', (38, 48))	('expression', 'MPA', (104, 114))	('silenced', 'Var', (29, 37))	('PITPNA-AS1', 'Gene', (38, 48))	('SK-MES-1', 'CellLine', 'CVCL:0630', (65, 73))
349528	32871048	EdU staining illustrated that silencing of PITPNA-AS1 lead to reduced EdU-stained cells (Figure 1D).	('PITPNA-AS1', 'Gene', '100306951', (43, 53))	('EdU-stained cells', 'CPA', (70, 87))	('EdU', 'Chemical', '-', (70, 73))	('PITPNA-AS1', 'Gene', (43, 53))	('silencing', 'Var', (30, 39))	('EdU', 'Chemical', '-', (0, 3))	('reduced', 'NegReg', (62, 69))
349529	32871048	Colony-forming assay demonstrated that decreased colony-forming numbers of two cells under transfection of sh-PITPNA-AS1#1/2 (Figure 1E).	('colony-forming numbers of two cells', 'CPA', (49, 84))	('transfection', 'Var', (91, 103))	('sh-PITPNA-AS1', 'Gene', (107, 120))	('sh-PITPNA-AS1', 'Chemical', '-', (107, 120))	('decreased', 'NegReg', (39, 48))
349530	32871048	These two experiments exhibited that cell proliferation was inhibited when PITPNA-AS1 was knocked down.	('PITPNA-AS1', 'Gene', '100306951', (75, 85))	('inhibited', 'NegReg', (60, 69))	('PITPNA-AS1', 'Gene', (75, 85))	('knocked down', 'Var', (90, 102))	('cell proliferation', 'CPA', (37, 55))
349531	32871048	The apoptosis rate was higher in sh-PITPNA-AS1#1/2 group than those in sh-NC group (Figure 1F-G).	('apoptosis rate', 'CPA', (4, 18))	('sh-PITPNA-AS1', 'Chemical', '-', (33, 46))	('sh-PITPNA-AS1', 'Var', (33, 46))	('higher', 'PosReg', (23, 29))
349532	32871048	In transwell migration assay, migrated cells were lowered after treated with sh-PITPNA-AS1#1/2 (Figure 1H).	('sh-PITPNA-AS1', 'Chemical', '-', (77, 90))	('lowered', 'NegReg', (50, 57))	('sh-PITPNA-AS1', 'Var', (77, 90))
349541	32871048	Luciferase reporter assay demonstrated that HMGB3 promoter activity was unaffected by the knockdown of PITPNA-AS1 (Figure 2G).	('activity', 'MPA', (59, 67))	('knockdown', 'Var', (90, 99))	('HMGB3', 'Gene', '3149', (44, 49))	('HMGB3', 'Gene', (44, 49))	('PITPNA-AS1', 'Gene', '100306951', (103, 113))	('PITPNA-AS1', 'Gene', (103, 113))
349547	32871048	Among these RBPs, TAF15 is selected for investigation as TAF15 silencing distinctly decreased HMGB3 level (Figure 3B-D).	('TAF15', 'Gene', '8148', (18, 23))	('TAF15', 'Gene', (57, 62))	('HMGB3', 'Gene', (94, 99))	('RBP', 'Gene', '5725', (12, 15))	('TAF15', 'Gene', (18, 23))	('HMGB3', 'Gene', '3149', (94, 99))	('TAF15', 'Gene', '8148', (57, 62))	('RBP', 'Gene', (12, 15))	('decreased', 'NegReg', (84, 93))	('silencing', 'Var', (63, 72))
349550	32871048	We discovered that HMGB3 mRNA half-life was distinctly shortened through silencing of TAF15 (Figure 3F).	('silencing', 'Var', (73, 82))	('TAF15', 'Gene', '8148', (86, 91))	('HMGB3', 'Gene', '3149', (19, 24))	('mRNA half-life', 'MPA', (25, 39))	('HMGB3', 'Gene', (19, 24))	('TAF15', 'Gene', (86, 91))	('shortened', 'NegReg', (55, 64))
349557	32871048	Also, we found out that there was no expression change of TAF15 or PITPNA-AS1 in response to knockdown of PITPNA-AS1 or TAF15 in two LUSC cells (Figure 4C-D).	('knockdown', 'Var', (93, 102))	('TAF15', 'Gene', (120, 125))	('PITPNA-AS1', 'Gene', '100306951', (67, 77))	('PITPNA-AS1', 'Gene', (67, 77))	('TAF15', 'Gene', (58, 63))	('PITPNA-AS1', 'Gene', '100306951', (106, 116))	('LUSC', 'Phenotype', 'HP:0030359', (133, 137))	('TAF15', 'Gene', '8148', (120, 125))	('PITPNA-AS1', 'Gene', (106, 116))	('expression', 'MPA', (37, 47))	('TAF15', 'Gene', '8148', (58, 63))
349559	32871048	In EBC-1 cells, TAF15 and PITPNA-AS1 were separately up-regulated after transfections (Figure S1A-B).	('PITPNA-AS1', 'Gene', '100306951', (26, 36))	('TAF15', 'Gene', '8148', (16, 21))	('transfections', 'Var', (72, 85))	('PITPNA-AS1', 'Gene', (26, 36))	('up-regulated', 'PosReg', (53, 65))	('TAF15', 'Gene', (16, 21))
349567	32871048	For rescue assays, HMGB3 was up-regulated via transfecting pc-HMGB3 into NCI-H520 cells (Figure 5A).	('HMGB3', 'Gene', (62, 67))	('NCI-H520', 'CellLine', 'CVCL:1566', (73, 81))	('HMGB3', 'Gene', (19, 24))	('HMGB3', 'Gene', '3149', (62, 67))	('pc', 'Gene', '5091', (59, 61))	('up-regulated', 'PosReg', (29, 41))	('transfecting', 'Var', (46, 58))	('HMGB3', 'Gene', '3149', (19, 24))
349571	32871048	TUNEL staining disclosed that cell apoptosis was accelerated by silenced PITPNA-AS1, which was abolished by up-regulated HMGB3 (Figure 5D).	('PITPNA-AS1', 'Gene', '100306951', (73, 83))	('HMGB3', 'Gene', (121, 126))	('PITPNA-AS1', 'Gene', (73, 83))	('cell apoptosis', 'CPA', (30, 44))	('HMGB3', 'Gene', '3149', (121, 126))	('silenced', 'Var', (64, 72))	('accelerated', 'PosReg', (49, 60))
349598	31253192	MicroRNA-486-3p functions as a tumor suppressor in oral cancer by targeting DDR1 Discoidin domain receptor-1 (DDR1) tyrosine kinase is highly expressed in a variety of human cancers and involved in various steps of tumorigenesis.	('DDR1', 'Gene', (76, 80))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('human', 'Species', '9606', (168, 173))	('DDR1', 'Gene', '780', (76, 80))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('cancers', 'Phenotype', 'HP:0002664', (174, 181))	('oral cancer', 'Disease', 'MESH:D009062', (51, 62))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('cancers', 'Disease', (174, 181))	('oral cancer', 'Disease', (51, 62))	('tyrosine', 'Chemical', 'MESH:D014443', (116, 124))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('DDR1', 'Gene', (110, 114))	('tumor', 'Disease', (215, 220))	('DDR1', 'Gene', '780', (110, 114))	('tumor', 'Disease', 'MESH:D009369', (215, 220))	('tumor', 'Disease', (31, 36))	('cancers', 'Disease', 'MESH:D009369', (174, 181))	('MicroRNA-486-3p', 'Var', (0, 15))	('involved', 'Reg', (186, 194))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
349605	31253192	Overexpression of miR-486-3p led to growth inhibition and apoptosis induction with a similar function by knockdown of DDR1.	('apoptosis induction', 'CPA', (58, 77))	('miR-486', 'Gene', '619554', (18, 25))	('DDR1', 'Gene', '780', (118, 122))	('growth inhibition', 'CPA', (36, 53))	('knockdown', 'Var', (105, 114))	('DDR1', 'Gene', (118, 122))	('miR-486', 'Gene', (18, 25))
349606	31253192	Aberrant methylation of ANK1 promoter was a highly prevalent in OSCC and contributes to oral carcinogenesis by epigenetic silencing of ANK1 and miR-486-3p.	('prevalent', 'Reg', (51, 60))	('ANK1', 'Gene', '286', (135, 139))	('oral carcinogenesis', 'Disease', (88, 107))	('ANK1', 'Gene', (135, 139))	('OSCC', 'Disease', (64, 68))	('epigenetic silencing', 'Var', (111, 131))	('oral carcinogenesis', 'Disease', 'MESH:D063646', (88, 107))	('Aberrant methylation', 'Var', (0, 20))	('contributes', 'Reg', (73, 84))	('miR-486', 'Gene', (144, 151))	('miR-486', 'Gene', '619554', (144, 151))	('ANK1', 'Gene', '286', (24, 28))	('ANK1', 'Gene', (24, 28))
349607	31253192	We found that miR-486-3p can be transcriptionally co-regulated with its host gene ANK1 through epigenetic repression.	('miR-486', 'Gene', '619554', (14, 21))	('epigenetic repression', 'Var', (95, 116))	('ANK1', 'Gene', '286', (82, 86))	('ANK1', 'Gene', (82, 86))	('miR-486', 'Gene', (14, 21))
349623	31253192	Aberrant expression and activation of DDR1 have been reported in several human cancers, such aslung cancer, breast cancer, brain cancer, oral cancer and liver cancer.	('aslung cancer', 'Disease', 'MESH:D009369', (93, 106))	('brain cancer', 'Phenotype', 'HP:0030692', (123, 135))	('brain cancer', 'Disease', 'MESH:D001932', (123, 135))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('aslung cancer', 'Disease', (93, 106))	('human', 'Species', '9606', (73, 78))	('liver cancer', 'Disease', 'MESH:D006528', (153, 165))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('activation', 'PosReg', (24, 34))	('breast cancer', 'Phenotype', 'HP:0003002', (108, 121))	('oral cancer', 'Disease', 'MESH:D009062', (137, 148))	('Aberrant expression', 'Var', (0, 19))	('cancers', 'Disease', (79, 86))	('lung cancer', 'Phenotype', 'HP:0100526', (95, 106))	('oral cancer', 'Disease', (137, 148))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('liver cancer', 'Phenotype', 'HP:0002896', (153, 165))	('brain cancer', 'Disease', (123, 135))	('breast cancer', 'Disease', 'MESH:D001943', (108, 121))	('breast cancer', 'Disease', (108, 121))	('DDR1', 'Gene', (38, 42))	('liver cancer', 'Disease', (153, 165))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('DDR1', 'Gene', '780', (38, 42))	('cancers', 'Disease', 'MESH:D009369', (79, 86))
349624	31253192	Like many other receptor tyrosine kinases, the dysregulated DDR1 display crucial roles in tumor initiation and progression, such as survival, proliferation, adhesion, migration, metastasis, epithelial-mesenchymal transition (EMT) and drug resistance.	('proliferation', 'CPA', (142, 155))	('DDR1', 'Gene', '780', (60, 64))	('adhesion', 'CPA', (157, 165))	('tumor initiation', 'Disease', 'MESH:D009369', (90, 106))	('drug resistance', 'Phenotype', 'HP:0020174', (234, 249))	('roles', 'Reg', (81, 86))	('tumor initiation', 'Disease', (90, 106))	('he', 'Chemical', 'MESH:D006371', (12, 14))	('he', 'Chemical', 'MESH:D006371', (44, 46))	('survival', 'CPA', (132, 140))	('he', 'Chemical', 'MESH:D006371', (194, 196))	('metastasis', 'CPA', (178, 188))	('epithelial-mesenchymal transition', 'CPA', (190, 223))	('tyrosine', 'Chemical', 'MESH:D014443', (25, 33))	('drug resistance', 'CPA', (234, 249))	('he', 'Chemical', 'MESH:D006371', (159, 161))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('DDR1', 'Gene', (60, 64))	('migration', 'CPA', (167, 176))	('dysregulated', 'Var', (47, 59))
349627	31253192	Accumulating evidence suggests that miRNAs can act as either oncogenes or tumor suppressors by affecting proliferative signaling, apoptosis, immortality, angiogenesis, invasion and metastasis.	('affecting', 'Reg', (95, 104))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('apoptosis', 'CPA', (130, 139))	('miRNAs', 'Var', (36, 42))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('he', 'Chemical', 'MESH:D006371', (57, 59))	('tumor', 'Disease', (74, 79))	('immortality', 'CPA', (141, 152))	('angiogenesis', 'CPA', (154, 166))	('metastasis', 'CPA', (181, 191))	('proliferative signaling', 'MPA', (105, 128))	('invasion', 'CPA', (168, 176))
349628	31253192	Specifically, miR-199a-5p has been reported to target DDR1 in hepatocellular carcinoma, acute myeloid leukemia, colorectal cancer and cutaneous squamous cell carcinoma.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (62, 86))	('target', 'Reg', (47, 53))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (88, 110))	('colorectal cancer', 'Disease', 'MESH:D015179', (112, 129))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (88, 110))	('leukemia', 'Phenotype', 'HP:0001909', (102, 110))	('colorectal cancer', 'Disease', (112, 129))	('hepatocellular carcinoma', 'Disease', (62, 86))	('cutaneous squamous cell carcinoma', 'Phenotype', 'HP:0006739', (134, 167))	('carcinoma', 'Phenotype', 'HP:0030731', (158, 167))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (94, 110))	('miR-199a-5p', 'Var', (14, 25))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('DDR1', 'Gene', (54, 58))	('cutaneous squamous cell carcinoma', 'Disease', (134, 167))	('colorectal cancer', 'Phenotype', 'HP:0003003', (112, 129))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (62, 86))	('cutaneous squamous cell carcinoma', 'Disease', 'MESH:D002294', (134, 167))	('acute myeloid leukemia', 'Disease', (88, 110))	('DDR1', 'Gene', '780', (54, 58))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (144, 167))
349629	31253192	Moreover, decreased expression of miR-199a-5p contributes to increased cell migration, invasion and tumorigenic capabilities through upregulating DDR1 expression.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('DDR1', 'Gene', (146, 150))	('decreased', 'NegReg', (10, 19))	('expression', 'MPA', (20, 30))	('tumor', 'Disease', (100, 105))	('expression', 'MPA', (151, 161))	('DDR1', 'Gene', '780', (146, 150))	('increased', 'PosReg', (61, 70))	('invasion', 'CPA', (87, 95))	('cell migration', 'CPA', (71, 85))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('upregulating', 'PosReg', (133, 145))	('miR-199a-5p', 'Var', (34, 45))
349633	31253192	In this study, we found that miR-483-5p is revealed as an upstream regulator of DDR1 which confers the cell proliferation and anti-apoptosis in OSCC.	('he', 'Chemical', 'MESH:D006371', (100, 102))	('DDR1', 'Gene', '780', (80, 84))	('DDR1', 'Gene', (80, 84))	('cell proliferation', 'CPA', (103, 121))	('confers', 'PosReg', (91, 98))	('miR-483-5p', 'Var', (29, 39))	('anti-apoptosis', 'CPA', (126, 140))	('OSCC', 'Disease', (144, 148))
349636	31253192	Moreover, miR-486-3p can be transcriptionally co-regulated with its host gene ANK1 through epigenetic mechanism.	('miR-486', 'Gene', '619554', (10, 17))	('epigenetic', 'Var', (91, 101))	('ANK1', 'Gene', '286', (78, 82))	('ANK1', 'Gene', (78, 82))	('miR-486', 'Gene', (10, 17))
349638	31253192	Together, our study indicates that betel quid chewing may induce aberrant methylation in OSCC interrupts the inhibitory effect of miR-486-3p on DDR1 expression which consequently promotes the oncogenic activity.	('miR-486', 'Gene', (130, 137))	('he', 'Chemical', 'MESH:D006371', (189, 191))	('aberrant', 'Var', (65, 73))	('promotes', 'PosReg', (179, 187))	('miR-486', 'Gene', '619554', (130, 137))	('inhibitory effect', 'MPA', (109, 126))	('he', 'Chemical', 'MESH:D006371', (5, 7))	('expression', 'MPA', (149, 159))	('he', 'Chemical', 'MESH:D006371', (47, 49))	('he', 'Chemical', 'MESH:D006371', (106, 108))	('methylation', 'MPA', (74, 85))	('oncogenic activity', 'CPA', (192, 210))	('DDR1', 'Gene', '780', (144, 148))	('DDR1', 'Gene', (144, 148))
349648	31253192	OSCC tissue array (#OR601a, #OR2081, #HN811 and #BC34011, Biomax Inc., Rockville, MD) were deparaffnized using xylene and then rehydratedthrough an ethanol series.	('#OR2081', 'Var', (28, 35))	('ethanol', 'Chemical', 'MESH:D000431', (148, 155))	('#BC34011', 'Var', (48, 56))	('raf', 'Gene', '22882', (95, 98))	('raf', 'Gene', (95, 98))	('he', 'Chemical', 'MESH:D006371', (123, 125))	('#OR601a', 'Var', (19, 26))	('xylene', 'Chemical', 'MESH:D014992', (111, 117))
349656	31253192	Cells were treated with 5-Aza-dC (5 muM, A3656, Sigma), arecoline (100 muM, MERCK) or lentiviral infected with shRNA vectors as described in Additional file 1: Table S2.	('muM', 'Gene', (71, 74))	('A3656', 'Var', (41, 46))	('muM', 'Gene', '56925', (36, 39))	('arecoline', 'Chemical', 'MESH:D001115', (56, 65))	('muM', 'Gene', '56925', (71, 74))	('5-Aza-dC', 'Chemical', 'MESH:D000077209', (24, 32))	('muM', 'Gene', (36, 39))
349666	31253192	The entire 3'-UTR of DDR1 fragment, containing target sequences of miR-337-3p and miR-486-3p, were PCR-amplified and cloned into the pmirGLO firefly luciferase-expressing vector (Promega, WI, USA) according to the manufacturer's instructions.	('miR-486', 'Gene', (82, 89))	('he', 'Chemical', 'MESH:D006371', (130, 132))	('he', 'Chemical', 'MESH:D006371', (211, 213))	('miR-486', 'Gene', '619554', (82, 89))	('he', 'Chemical', 'MESH:D006371', (1, 3))	('DDR1', 'Gene', '780', (21, 25))	('DDR1', 'Gene', (21, 25))	('miR-337-3p', 'Var', (67, 77))
349668	31253192	For luciferase reporter assay, luciferase reporter vectors together with miRNA-mimics (PM-337-3p or PM-486-3p) and negative control (NC) were transfected into HEK293,OEC-M1 and TW2.6 cells using Lipofectamine RNAiMAX Transfection Reagent (Thermo Fisher).	('PM-486-3p', 'Var', (100, 109))	('he', 'Chemical', 'MESH:D006371', (249, 251))	('he', 'Chemical', 'MESH:D006371', (64, 66))	('HEK293', 'CellLine', 'CVCL:0045', (159, 165))	('Lipofectamine', 'Chemical', 'MESH:C086724', (195, 208))	('PM-337-3p', 'Var', (87, 96))	('he', 'Chemical', 'MESH:D006371', (240, 242))
349694	31253192	Further clinical analysis showed that high expression of DDR1 was statistically associated with lymph node metastasis, perineural invasion and lymphangiogenesis (p < 0.05) (Table S4).	('he', 'Chemical', 'MESH:D006371', (4, 6))	('clinical', 'Species', '191496', (8, 16))	('DDR1', 'Gene', '780', (57, 61))	('high expression', 'Var', (38, 53))	('lymphangiogenesis', 'CPA', (143, 160))	('associated', 'Reg', (80, 90))	('perineural invasion', 'CPA', (119, 138))	('DDR1', 'Gene', (57, 61))	('lymph node metastasis', 'CPA', (96, 117))
349699	31253192	Furthermore, Kaplan-Meier analysis revealed that DDR1 expression was correlated with poor overall survival in oral cancer patients (n = 75) in our cohort (p = 0.0249; Fig.	('he', 'Chemical', 'MESH:D006371', (4, 6))	('DDR1', 'Gene', (49, 53))	('expression', 'Var', (54, 64))	('oral cancer', 'Disease', 'MESH:D009062', (110, 121))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('poor', 'NegReg', (85, 89))	('patients', 'Species', '9606', (122, 130))	('oral cancer', 'Disease', (110, 121))	('DDR1', 'Gene', '780', (49, 53))	('overall survival', 'MPA', (90, 106))
349704	31253192	We used two different shRNA sequences (shDDR1-A1 and shDDR1-D1) to knockdown DDR1 expression (Fig.	('DDR1', 'Gene', '780', (55, 59))	('DDR1', 'Gene', (55, 59))	('expression', 'MPA', (82, 92))	('knockdown', 'Var', (67, 76))	('DDR1', 'Gene', '780', (77, 81))	('DDR1', 'Gene', (77, 81))	('DDR1', 'Gene', '780', (41, 45))	('DDR1', 'Gene', (41, 45))
349705	31253192	2b and c, DDR1 knockdown suppressed colony formation and cell proliferation compared with control cells in both OSCC cell lines (P < 0.0001).	('knockdown', 'Var', (15, 24))	('colony formation', 'CPA', (36, 52))	('suppressed', 'NegReg', (25, 35))	('DDR1', 'Gene', '780', (10, 14))	('cell proliferation', 'CPA', (57, 75))	('DDR1', 'Gene', (10, 14))
349706	31253192	In addition, knockdown of DDR1 significantly decreased Bcl-2 protein level and induced caspase-3activation and PARP cleavage in OSCC cells (Fig.	('Bcl-2', 'Gene', (55, 60))	('Bcl-2', 'Gene', '596', (55, 60))	('caspase-3', 'Gene', '836', (87, 96))	('decreased', 'NegReg', (45, 54))	('DDR1', 'Gene', '780', (26, 30))	('PARP', 'Gene', '1302', (111, 115))	('PARP', 'Gene', (111, 115))	('DDR1', 'Gene', (26, 30))	('induced', 'Reg', (79, 86))	('knockdown', 'Var', (13, 22))	('caspase-3', 'Gene', (87, 96))
349710	31253192	Based on the computational algorithm, we found miR-337-3p and miR-486-3p were downregulated in OSCC tissues compared with their matched adjacent non-cancerous tissues and were selected for the further study (Fig.	('he', 'Chemical', 'MESH:D006371', (10, 12))	('miR-337-3p', 'Var', (47, 57))	('he', 'Chemical', 'MESH:D006371', (190, 192))	('he', 'Chemical', 'MESH:D006371', (132, 134))	('non-cancerous', 'Disease', 'MESH:D009369', (145, 158))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('he', 'Chemical', 'MESH:D006371', (197, 199))	('miR-486', 'Gene', (62, 69))	('OSCC', 'Disease', (95, 99))	('he', 'Chemical', 'MESH:D006371', (123, 125))	('non-cancerous', 'Disease', (145, 158))	('miR-486', 'Gene', '619554', (62, 69))	('downregulated', 'NegReg', (78, 91))
349711	31253192	To determine whether miR-337-3p and miR-486-3p directly target DDR1 3'-UTR, a luciferase reporter assay was performed in HEK293 cells.	('miR-486', 'Gene', (36, 43))	('he', 'Chemical', 'MESH:D006371', (14, 16))	('DDR1', 'Gene', '780', (63, 67))	('miR-337-3p', 'Var', (21, 31))	('miR-486', 'Gene', '619554', (36, 43))	('HEK293', 'CellLine', 'CVCL:0045', (121, 127))	('he', 'Chemical', 'MESH:D006371', (17, 19))	('DDR1', 'Gene', (63, 67))
349716	31253192	The data showed that DDR1 protein level was dramatically down-regulated by the transfection of miR-486-3p mimics (PM-486-3p) in OEC-M1 and TW2.6 (Fig.	('down-regulated', 'NegReg', (57, 71))	('miR-486', 'Gene', (95, 102))	('he', 'Chemical', 'MESH:D006371', (76, 78))	('PM-486-3p', 'Var', (114, 123))	('miR-486', 'Gene', '619554', (95, 102))	('he', 'Chemical', 'MESH:D006371', (1, 3))	('DDR1', 'Gene', '780', (21, 25))	('DDR1', 'Gene', (21, 25))
349719	31253192	These data suggested that DDR1 as a direct target of miR-486-3p and repression of miR-486-3p in OSCC cells directly increased expression of DDR1.	('expression', 'MPA', (126, 136))	('miR-486', 'Gene', (53, 60))	('miR-486', 'Gene', (82, 89))	('miR-486', 'Gene', '619554', (53, 60))	('DDR1', 'Gene', '780', (26, 30))	('miR-486', 'Gene', '619554', (82, 89))	('he', 'Chemical', 'MESH:D006371', (1, 3))	('DDR1', 'Gene', (26, 30))	('repression', 'Var', (68, 78))	('increased', 'PosReg', (116, 125))	('DDR1', 'Gene', '780', (140, 144))	('DDR1', 'Gene', (140, 144))
349733	31253192	Simultaneously, we foundthatthe expression of miR-486-3p significantly increasedwhile DDR1 expression were downregulated after 5-Aza-dC treatment, suggesting a hypermethylation mediated lossof miR-486-3p in OEC-M1 and TW2.6 (Fig.	('DDR1', 'Gene', '780', (86, 90))	('miR-486', 'Gene', (193, 200))	('expression', 'MPA', (91, 101))	('lossof', 'NegReg', (186, 192))	('miR-486', 'Gene', (46, 53))	('DDR1', 'Gene', (86, 90))	('he', 'Chemical', 'MESH:D006371', (29, 31))	('miR-486', 'Gene', '619554', (193, 200))	('miR-486', 'Gene', '619554', (46, 53))	('5-Aza-dC', 'Chemical', 'MESH:D000077209', (127, 135))	('hypermethylation', 'Var', (160, 176))	('downregulated', 'NegReg', (107, 120))	('expression', 'MPA', (32, 42))	('increasedwhile', 'PosReg', (71, 85))
349735	31253192	Collectively, these data indicate that ANK1 promoter hypermethylationis associated with miR-486-3p repression and in turn induces DDR1 expression in OSCC cells.	('miR-486', 'Gene', (88, 95))	('induces', 'Reg', (122, 129))	('ANK1', 'Gene', '286', (39, 43))	('DDR1', 'Gene', '780', (130, 134))	('miR-486', 'Gene', '619554', (88, 95))	('expression', 'MPA', (135, 145))	('ANK1', 'Gene', (39, 43))	('hypermethylationis', 'Var', (53, 71))	('DDR1', 'Gene', (130, 134))	('he', 'Chemical', 'MESH:D006371', (15, 17))
349741	31253192	Furthermore, arecoline treatment increased the cellular proliferation in OKF4/hTERT cells, while knockdown of DDR1 expression blocked arecoline-induced cellular proliferation (Additional file 2: Figure S2).	('he', 'Chemical', 'MESH:D006371', (4, 6))	('DDR1', 'Gene', (110, 114))	('knockdown', 'Var', (97, 106))	('arecoline', 'Chemical', 'MESH:D001115', (134, 143))	('arecoline', 'Chemical', 'MESH:D001115', (13, 22))	('cellular proliferation', 'CPA', (47, 69))	('hTERT', 'Gene', '7015', (78, 83))	('blocked', 'NegReg', (126, 133))	('he', 'Chemical', 'MESH:D006371', (44, 46))	('hTERT', 'Gene', (78, 83))	('DDR1', 'Gene', '780', (110, 114))
349758	31253192	High DDR1 expression can promote survival signaling through activation of Bcl-xl, Notch1 and Ras/raf/MAPK pathway.	('raf', 'Gene', '22882', (97, 100))	('High', 'Var', (0, 4))	('Notch1', 'Gene', '4851', (82, 88))	('DDR1', 'Gene', '780', (5, 9))	('raf', 'Gene', (97, 100))	('Bcl-xl', 'Gene', (74, 80))	('activation', 'PosReg', (60, 70))	('promote', 'PosReg', (25, 32))	('DDR1', 'Gene', (5, 9))	('survival signaling', 'CPA', (33, 51))	('Bcl-xl', 'Gene', '598', (74, 80))	('Notch1', 'Gene', (82, 88))
349763	31253192	Interestingly, several reports have shown that loss of miR-199a was found to causethe elevated expression of DDR1in hepatocellular carcinoma, leukemia, colorectal cancer, cutaneous squamous cell carcinoma, breast cancer and ovarian cancer, suggesting that miR-199a has a critical role in DDR1 regulation.	('elevated', 'PosReg', (86, 94))	('cutaneous squamous cell carcinoma', 'Disease', 'MESH:D002294', (171, 204))	('colorectal cancer', 'Disease', 'MESH:D015179', (152, 169))	('miR-199a', 'Gene', (55, 63))	('leukemia', 'Phenotype', 'HP:0001909', (142, 150))	('DDR1', 'Gene', (288, 292))	('he', 'Chemical', 'MESH:D006371', (116, 118))	('breast cancer', 'Phenotype', 'HP:0003002', (206, 219))	('loss', 'Var', (47, 51))	('colorectal cancer', 'Disease', (152, 169))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (116, 140))	('DDR1', 'Gene', '780', (288, 292))	('breast cancer', 'Disease', 'MESH:D001943', (206, 219))	('leukemia', 'Disease', 'MESH:D007938', (142, 150))	('breast cancer', 'Disease', (206, 219))	('leukemia', 'Disease', (142, 150))	('ovarian cancer', 'Disease', 'MESH:D010051', (224, 238))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (181, 204))	('expression', 'MPA', (95, 105))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (116, 140))	('cutaneous squamous cell carcinoma', 'Phenotype', 'HP:0006739', (171, 204))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('he', 'Chemical', 'MESH:D006371', (83, 85))	('colorectal cancer', 'Phenotype', 'HP:0003003', (152, 169))	('DDR1', 'Gene', (109, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (195, 204))	('ovarian cancer', 'Disease', (224, 238))	('hepatocellular carcinoma', 'Disease', (116, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('DDR1', 'Gene', '780', (109, 113))	('ovarian cancer', 'Phenotype', 'HP:0100615', (224, 238))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('cutaneous squamous cell carcinoma', 'Disease', (171, 204))
349774	31253192	Taken together, our results providea new mechanism thata low level of miR486-3p is supportive for OSCC tumorigenesis by way of DDR1 upregulation, and the clinical relevance strongly implies that this mechanism is important in OSCC.	('he', 'Chemical', 'MESH:D006371', (151, 153))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('upregulation', 'PosReg', (132, 144))	('tumor', 'Disease', (103, 108))	('OSCC', 'Disease', (98, 102))	('DDR1', 'Gene', '780', (127, 131))	('miR486-3p', 'Var', (70, 79))	('DDR1', 'Gene', (127, 131))	('clinical', 'Species', '191496', (154, 162))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('he', 'Chemical', 'MESH:D006371', (11, 13))
349776	31253192	Down regulation of miR-486-3p following ANK1 knockdown has also been reported.	('miR-486', 'Gene', (19, 26))	('ANK1', 'Gene', '286', (40, 44))	('miR-486', 'Gene', '619554', (19, 26))	('ANK1', 'Gene', (40, 44))	('Down regulation', 'NegReg', (0, 15))	('knockdown', 'Var', (45, 54))
349780	31253192	Interestingly, aberrant promoter methylation has been reported tobe involved in oral cancer associated with betel quid chewing.	('involved', 'Reg', (68, 76))	('promoter', 'MPA', (24, 32))	('oral cancer', 'Disease', 'MESH:D009062', (80, 91))	('he', 'Chemical', 'MESH:D006371', (120, 122))	('oral cancer', 'Disease', (80, 91))	('aberrant', 'Var', (15, 23))	('associated', 'Reg', (92, 102))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
349783	31253192	also showed that aberrant ANK1 methylation is highly associated with patients' smoking history in lung cancer.	('aberrant', 'Var', (17, 25))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('lung cancer', 'Disease', (98, 109))	('lung cancer', 'Phenotype', 'HP:0100526', (98, 109))	('methylation', 'Var', (31, 42))	('associated', 'Reg', (53, 63))	('ANK1', 'Gene', '286', (26, 30))	('ANK1', 'Gene', (26, 30))	('patients', 'Species', '9606', (69, 77))	('lung cancer', 'Disease', 'MESH:D008175', (98, 109))
349786	31253192	Thus, abnormal repression of miR486-3p in oral cancer provides a growth advantage by enhancing the tumor promoting activities of DDR1.	('growth advantage', 'CPA', (65, 81))	('tumor', 'Disease', (99, 104))	('he', 'Chemical', 'MESH:D006371', (96, 98))	('enhancing', 'PosReg', (85, 94))	('abnormal', 'Var', (6, 14))	('DDR1', 'Gene', '780', (129, 133))	('DDR1', 'Gene', (129, 133))	('miR486-3p', 'Var', (29, 38))	('oral cancer', 'Disease', 'MESH:D009062', (42, 53))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('oral cancer', 'Disease', (42, 53))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('repression', 'NegReg', (15, 25))
349792	31253192	Aberrant methylation ofANK1 promoter is a highly prevalent in OSCC and contributes to oral carcinogenesis by epigenetic silencing of ANK1 and miR-486-3p (Fig.7).	('miR-486', 'Gene', '619554', (142, 149))	('prevalent', 'Reg', (49, 58))	('ANK1', 'Gene', (23, 27))	('contributes to', 'Reg', (71, 85))	('ANK1', 'Gene', (133, 137))	('Aberrant methylation', 'Var', (0, 20))	('ANK1', 'Gene', '286', (23, 27))	('epigenetic silencing', 'Var', (109, 129))	('oral carcinogenesis', 'Disease', 'MESH:D063646', (86, 105))	('ANK1', 'Gene', '286', (133, 137))	('oral carcinogenesis', 'Disease', (86, 105))	('OSCC', 'Disease', (62, 66))	('miR-486', 'Gene', (142, 149))
349816	28443091	Current therapeutic regimens combine surgery, radiotherapy and chemotherapy with 5-year survival rates of 30-65 and 5-58% for the tumor stages T1-T4 and N0-N3, respectively.	('T1-T4', 'Var', (143, 148))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('N0-N3', 'Var', (153, 158))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumor', 'Disease', (130, 135))
349854	28443091	After saturation with BSA blocking solution (Candor, Germany), the plates were incubated with soluble MICA*04 or recombinant Fc-fusion proteins of human MICB, ULBP1/2/3 (1599-MB-050, 1380-UL-050, 1298-UL-050, 1517-UL-050; R&D Systems, USA) as standards.	('human', 'Species', '9606', (147, 152))	('1599-MB-050', 'Var', (170, 181))	('MICB', 'Gene', '4277', (153, 157))	('ULBP1/2/3', 'Gene', (159, 168))	('MICA', 'Gene', (102, 106))	('MICA', 'Gene', '100507436', (102, 106))	('ULBP1/2/3', 'Gene', '80329;80328;79465', (159, 168))	('MICB', 'Gene', (153, 157))
349902	28443091	Nevertheless, the sole depletion of sNKG2DLs was sufficient to restore NK cell cytotoxicity, assuming shedding of ligands as a key mechanism of NKG2D-dependent tumor immune escape in HNSCC.	('cytotoxicity', 'Disease', 'MESH:D064420', (79, 91))	('NKG2D', 'Gene', (144, 149))	('depletion', 'Var', (23, 32))	('NKG2D-dependent tumor', 'Disease', 'MESH:D019966', (144, 165))	('HNSCC', 'Phenotype', 'HP:0012288', (183, 188))	('cytotoxicity', 'Disease', (79, 91))	('NKG2D', 'Gene', '22914', (37, 42))	('restore', 'PosReg', (63, 70))	('NKG2D-dependent tumor', 'Disease', (144, 165))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('NKG2D', 'Gene', '22914', (144, 149))	('NKG2D', 'Gene', (37, 42))
349915	28443091	In contrast, under inhibitory conditions (in the presence of sMICA or CAL27 SN), NK cell cytotoxicity, shown as tumor spheroid volume reduction (Figure S5C in Supplementary Material), was inhibited.	('CAL27 SN', 'Var', (70, 78))	('AL', 'Chemical', 'MESH:D000535', (71, 73))	('sMICA', 'Chemical', '-', (61, 66))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('und', 'Gene', (13, 16))	('cytotoxicity', 'Disease', (89, 101))	('inhibited', 'NegReg', (188, 197))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('und', 'Gene', '7373', (13, 16))	('tumor', 'Disease', (112, 117))	('cytotoxicity', 'Disease', 'MESH:D064420', (89, 101))
349938	28443091	The antibody showed a depletion efficacy of 89-97% of sMICA allelic variants frequently found in the Caucasian population independent of the donor immune status (Figures 6A,B).	('variants', 'Var', (68, 76))	('donor', 'Species', '9606', (141, 146))	('und', 'Gene', '7373', (90, 93))	('sMICA', 'Gene', (54, 59))	('sMICA', 'Chemical', '-', (54, 59))	('depletion', 'MPA', (22, 31))	('und', 'Gene', (90, 93))
349978	28443091	Importantly, we could show that specific depletion of sNKG2DLs could completely restore NKG2D-dependent killing of monolayer cell cultures and 3D tumor spheroids, demonstrating that NK cell dysfunction is predominantly governed by shed NKG2DLs.	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('NKG2D', 'Gene', '22914', (55, 60))	('tumor', 'Disease', (146, 151))	('NKG2D', 'Gene', (55, 60))	('NKG2D', 'Gene', '22914', (88, 93))	('NKG2D', 'Gene', '22914', (236, 241))	('depletion', 'Var', (41, 50))	('tumor', 'Disease', 'MESH:D009369', (146, 151))	('NKG2D', 'Gene', (88, 93))	('NKG2D', 'Gene', (236, 241))
349980	28443091	A marginal increase in NK cell cytotoxicity after sNKG2DL depletion, which was not significant, could also be observed in three more samples.	('cytotoxicity', 'Disease', 'MESH:D064420', (31, 43))	('increase', 'PosReg', (11, 19))	('NKG2D', 'Gene', '22914', (51, 56))	('NKG2D', 'Gene', (51, 56))	('cytotoxicity', 'Disease', (31, 43))	('depletion', 'Var', (58, 67))
350005	28443091	In our in vitro cytotoxicity assays, we could show that depletion of sNKG2DLs efficiently restored NK cell functions.	('NKG2D', 'Gene', '22914', (70, 75))	('NK cell functions', 'CPA', (99, 116))	('cytotoxicity', 'Disease', 'MESH:D064420', (16, 28))	('NKG2D', 'Gene', (70, 75))	('restored', 'PosReg', (90, 98))	('depletion', 'Var', (56, 65))	('cytotoxicity', 'Disease', (16, 28))
350150	29996673	TU-ECS-1, a new human uterine carcinosarcoma cell line, was recently established to exhibit mutations of the tumor protein p53 gene (TP53) and KRAS and represents a novel targeted therapy.	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (22, 44))	('carcinosarcoma', 'Disease', (30, 44))	('TU-ECS-1', 'CellLine', 'CVCL:Z893', (0, 8))	('mutations', 'Var', (92, 101))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('sarcoma', 'Phenotype', 'HP:0100242', (37, 44))	('p53', 'Gene', '7157', (123, 126))	('p53', 'Gene', (123, 126))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('KRAS', 'Gene', (143, 147))	('human', 'Species', '9606', (16, 21))	('TP53', 'Gene', '7157', (133, 137))	('KRAS', 'Gene', '3845', (143, 147))	('TP53', 'Gene', (133, 137))	('carcinosarcoma', 'Disease', 'MESH:D002296', (30, 44))	('tumor', 'Disease', (109, 114))
350152	29996673	Pathogenic mutations were also detected in TP53 and PIK3CA.	('mutations', 'Var', (11, 20))	('TP53', 'Gene', '7157', (43, 47))	('Pathogenic', 'Reg', (0, 10))	('PIK3CA', 'Gene', (52, 58))	('PIK3CA', 'Gene', '5290', (52, 58))	('TP53', 'Gene', (43, 47))
350163	29996673	We also review its clinical manifestations, pathogenesis, clinicopathology, immunohistochemistry, diagnosis, prognostic factors, and therapeutic approaches; identify the presence of PI3K, HIF-1alpha, HK-II, and GLUT-1 within the carcinosarcoma; and discuss the role of 18F-FDG PET/CT in diagnosing carcinosarcoma.	('HK-II', 'Gene', (200, 205))	('GLUT-1 within the carcinosarcoma', 'Disease', 'MESH:D001929', (211, 243))	('carcinosarcoma', 'Disease', (229, 243))	('PI3K', 'Var', (182, 186))	('HIF-1alpha', 'Gene', '3091', (188, 198))	('carcinosarcoma', 'Disease', (298, 312))	('man', 'Species', '9606', (28, 31))	('GLUT-1 within the carcinosarcoma', 'Disease', (211, 243))	('FDG', 'Chemical', 'MESH:D019788', (273, 276))	('sarcoma', 'Phenotype', 'HP:0100242', (305, 312))	('sarcoma', 'Phenotype', 'HP:0100242', (236, 243))	('carcinosarcoma', 'Disease', 'MESH:D002296', (229, 243))	('HIF-1alpha', 'Gene', (188, 198))	('carcinosarcoma', 'Disease', 'MESH:D002296', (298, 312))	('HK-II', 'Gene', '3099', (200, 205))
350228	29996673	We previously confirmed that inhibition of GLUT-1 inhibited proliferation and enhanced the radiosensitivity of Hep-2 cells.	('GLUT-1', 'Gene', '6513', (43, 49))	('GLUT-1', 'Gene', (43, 49))	('Hep-2', 'CellLine', 'CVCL:1906', (111, 116))	('radiosensitivity', 'CPA', (91, 107))	('proliferation', 'CPA', (60, 73))	('inhibition', 'Var', (29, 39))	('inhibited', 'NegReg', (50, 59))	('enhanced', 'PosReg', (78, 86))
350262	29996673	Targeting of PI3K, HIF-1alpha, HK-II, and GLUT-1 may be effective in the treatment of hypopharyngeal carcinosarcoma.	('PI3K', 'Var', (13, 17))	('HIF-1alpha', 'Gene', '3091', (19, 29))	('sarcoma', 'Phenotype', 'HP:0100242', (108, 115))	('men', 'Species', '9606', (78, 81))	('HK-II', 'Gene', '3099', (31, 36))	('hypopharyngeal carcinosarcoma', 'Disease', 'MESH:D002296', (86, 115))	('hypopharyngeal carcinosarcoma', 'Disease', (86, 115))	('HK-II', 'Gene', (31, 36))	('HIF-1alpha', 'Gene', (19, 29))	('hypopharyngeal carcinosarcoma', 'Phenotype', 'HP:0012182', (86, 115))	('GLUT-1', 'Gene', (42, 48))	('GLUT-1', 'Gene', '6513', (42, 48))
350270	28526815	PARD3 overexpression promoted apoptosis, impaired proliferation, and inhibited cell migration and invasion in Eca109 cells, while PARD3 silencing promoted proliferation and increased migration and invasion.	('PARD3', 'Gene', (0, 5))	('invasion', 'CPA', (197, 205))	('cell migration', 'CPA', (79, 93))	('apoptosis', 'CPA', (30, 39))	('migration', 'CPA', (183, 192))	('proliferation', 'CPA', (155, 168))	('PARD3', 'Gene', '56288', (130, 135))	('PARD3', 'Gene', '56288', (0, 5))	('promoted', 'PosReg', (21, 29))	('increased', 'PosReg', (173, 182))	('impaired', 'NegReg', (41, 49))	('inhibited', 'NegReg', (69, 78))	('PARD3', 'Gene', (130, 135))	('silencing', 'Var', (136, 145))	('promoted', 'PosReg', (146, 154))
350272	28526815	Overexpression of PARD3 could be a promising new therapeutic intervention against ESCC.	('ESCC', 'Disease', (82, 86))	('PARD3', 'Gene', '56288', (18, 23))	('PARD3', 'Gene', (18, 23))	('Overexpression', 'Var', (0, 14))
350317	28526815	On the other hand, PARD3 silencing did not significantly affect apoptosis (2.7+-0.4% compared with 2.2+-0.5% in controls; P>0.05, Table 4, Figure 3).	('silencing', 'Var', (25, 34))	('PARD3', 'Gene', '56288', (19, 24))	('apoptosis', 'CPA', (64, 73))	('PARD3', 'Gene', (19, 24))
350320	28526815	On the other hand, PARD3 overexpression significantly reduced cell migration compared to control cells (P<0.05, Figure 4B).	('cell migration', 'CPA', (62, 76))	('overexpression', 'Var', (25, 39))	('reduced', 'NegReg', (54, 61))	('PARD3', 'Gene', '56288', (19, 24))	('PARD3', 'Gene', (19, 24))
350321	28526815	PARD3 silencing resulted in a significant promotion of Eca109 cell invasion (P<0.01, Figure 4C), while PARD3 overexpression significantly decreased cell invasion by approximately 50% compared to the control cells (P<0.05, Figure 4D).	('PARD3', 'Gene', (0, 5))	('promotion', 'PosReg', (42, 51))	('PARD3', 'Gene', (103, 108))	('PARD3', 'Gene', '56288', (103, 108))	('decreased', 'NegReg', (138, 147))	('cell invasion', 'CPA', (148, 161))	('PARD3', 'Gene', '56288', (0, 5))	('silencing', 'Var', (6, 15))	('Eca109 cell invasion', 'CPA', (55, 75))
350328	28526815	observed that PARD3 deletions were limited to 2 distinct types of cancer: (1) squamous carcinomas including the esophagus, lung, and head and neck, and (2) glioblastoma, as supported by other studies.	('PARD3', 'Gene', '56288', (14, 19))	('squamous carcinomas', 'Disease', 'MESH:D002294', (78, 97))	('glioblastoma', 'Phenotype', 'HP:0012174', (156, 168))	('PARD3', 'Gene', (14, 19))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('deletions', 'Var', (20, 29))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))	('carcinomas', 'Phenotype', 'HP:0030731', (87, 97))	('lung', 'Disease', (123, 127))	('squamous carcinomas', 'Disease', (78, 97))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('esophagus', 'Disease', (112, 121))	('glioblastoma', 'Disease', (156, 168))	('cancer', 'Disease', (66, 72))	('glioblastoma', 'Disease', 'MESH:D005909', (156, 168))
350329	28526815	Recurrent tumor-specific inactivating alterations of PARD3 were observed in 8% of lung squamous cell cancer (LSCC).	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('lung squamous cell cancer', 'Disease', (82, 107))	('LSCC', 'Phenotype', 'HP:0030359', (109, 113))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (87, 107))	('tumor', 'Disease', (10, 15))	('observed', 'Reg', (64, 72))	('PARD3', 'Gene', (53, 58))	('PARD3', 'Gene', '56288', (53, 58))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('lung squamous cell cancer', 'Disease', 'MESH:D002294', (82, 107))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('inactivating alterations', 'Var', (25, 49))	('lung squamous cell cancer', 'Phenotype', 'HP:0030359', (82, 107))
350334	28526815	These findings are in accordance with those of Rothenberg et al., who reported that shRNA-mediated knockdown of PARD3 in some cancer cells with a disrupted wild type endogenous gene reduced the localization of ZO-1.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('ZO-1', 'Gene', '7082', (210, 214))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('ZO-1', 'Gene', (210, 214))	('localization', 'MPA', (194, 206))	('knockdown', 'Var', (99, 108))	('PARD3', 'Gene', (112, 117))	('PARD3', 'Gene', '56288', (112, 117))	('reduced', 'NegReg', (182, 189))
350335	28526815	Loss of PARD3 in mammary epithelial cells promotes proliferation.	('proliferation', 'CPA', (51, 64))	('promotes', 'PosReg', (42, 50))	('PARD3', 'Gene', '56288', (8, 13))	('PARD3', 'Gene', (8, 13))	('Loss', 'Var', (0, 4))
350357	26870599	BCC aetiology includes factors like sun exposure, genetic modifications, skin colour, precancerous lesions.	('genetic modifications', 'Var', (50, 71))	('BCC', 'Disease', (0, 3))	('precancerous lesions', 'Disease', 'MESH:D011230', (86, 106))	('precancerous lesions', 'Disease', (86, 106))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
350379	33391406	After silencing GINS2 in A549 cells, we performed MTT assays, flow cytometry assays, colony formation assays, cell cycle analyses and RNA sequence analysis to elucidate the effect of GINS2 on lung cancer.	('MTT', 'Chemical', 'MESH:C070243', (50, 53))	('GINS2', 'Gene', (16, 21))	('lung cancer', 'Disease', (192, 203))	('A549', 'CellLine', 'CVCL:0023', (25, 29))	('lung cancer', 'Phenotype', 'HP:0100526', (192, 203))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('lung cancer', 'Disease', 'MESH:D008175', (192, 203))	('silencing', 'Var', (6, 15))
350382	33391406	Subsequently, knockdown of GINS2 inhibited cell proliferation, colony formation, cell cycle arrest and apoptosis in A549 cells.	('colony formation', 'CPA', (63, 79))	('A549', 'CellLine', 'CVCL:0023', (116, 120))	('apoptosis', 'CPA', (103, 112))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (81, 98))	('arrest', 'Disease', 'MESH:D006323', (92, 98))	('knockdown', 'Var', (14, 23))	('GINS2', 'Gene', (27, 32))	('arrest', 'Disease', (92, 98))	('cell proliferation', 'CPA', (43, 61))	('inhibited', 'NegReg', (33, 42))
350384	33391406	The analysis of nude mouse tumors showed that the tumor volume and weight of shGINS2 mice were significantly smaller than those of the control mice.	('smaller', 'NegReg', (109, 116))	('mice', 'Species', '10090', (85, 89))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumor', 'Disease', (27, 32))	('mouse', 'Species', '10090', (21, 26))	('tumors', 'Disease', (27, 33))	('tumors', 'Disease', 'MESH:D009369', (27, 33))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('shGINS2', 'Var', (77, 84))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('tumor', 'Disease', (50, 55))	('mice', 'Species', '10090', (143, 147))
350385	33391406	To reveal the mechanism of GINS2 in lung cancer, we collected A549 cells with GINS2 knockdown to examine the downstream gene expression changes.	('lung cancer', 'Disease', (36, 47))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('A549', 'CellLine', 'CVCL:0023', (62, 66))	('GINS2', 'Gene', (78, 83))	('knockdown', 'Var', (84, 93))	('lung cancer', 'Disease', 'MESH:D008175', (36, 47))	('lung cancer', 'Phenotype', 'HP:0100526', (36, 47))
350386	33391406	The results showed that STAT1 and STAT2 mRNA and protein expression were significantly upregulated after GINS2 knockdown in A549 cells.	('STAT1', 'Gene', (24, 29))	('GINS2', 'Gene', (105, 110))	('knockdown', 'Var', (111, 120))	('A549', 'CellLine', 'CVCL:0023', (124, 128))	('STAT1', 'Gene', '6772', (24, 29))	('upregulated', 'PosReg', (87, 98))
350387	33391406	Our results suggest that GINS2 inhibits the proliferation of lung cancer cells by inhibiting the STAT signaling pathway, which may be a potential biomarker for the diagnosis or prognosis of lung cancer.	('lung cancer', 'Disease', (61, 72))	('lung cancer', 'Phenotype', 'HP:0100526', (61, 72))	('inhibiting', 'NegReg', (82, 92))	('inhibits', 'NegReg', (31, 39))	('STAT signaling pathway', 'Pathway', (97, 119))	('GINS2', 'Var', (25, 30))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('lung cancer', 'Disease', 'MESH:D008175', (190, 201))	('lung cancer', 'Disease', 'MESH:D008175', (61, 72))	('lung cancer', 'Disease', (190, 201))	('lung cancer', 'Phenotype', 'HP:0100526', (190, 201))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('proliferation', 'CPA', (44, 57))
350396	33391406	In the previous study, Chi et al discovered that knockdown of GINS2 inhibits proliferation and promotes apoptosis through the p53/growth arrest and DNA damage 45A pathway in NSCLC.	('knockdown', 'Var', (49, 58))	('p53', 'Gene', '7157', (126, 129))	('NSCLC', 'Disease', 'MESH:D002289', (174, 179))	('DNA damage 45A pathway', 'Pathway', (148, 170))	('growth arrest', 'Disease', 'MESH:D006323', (130, 143))	('growth arrest', 'Disease', (130, 143))	('NSCLC', 'Phenotype', 'HP:0030358', (174, 179))	('GINS2', 'Gene', (62, 67))	('growth arrest', 'Phenotype', 'HP:0001510', (130, 143))	('apoptosis', 'CPA', (104, 113))	('p53', 'Gene', (126, 129))	('inhibits', 'NegReg', (68, 76))	('promotes', 'PosReg', (95, 103))	('proliferation', 'CPA', (77, 90))	('NSCLC', 'Disease', (174, 179))
350397	33391406	Additionally, another research group performed the experiment to demonstrate that GINS2 facilitates epithelial-to-mesenchymal transition in NSCLC cancer through modulating phosphoinositide-3-kinase/protein kinase B and mitogen-activated protein kinase/extracellular signal-regulated kinase pathway.	('NSCLC cancer', 'Disease', 'MESH:D009369', (140, 152))	('epithelial-to-mesenchymal transition', 'CPA', (100, 136))	('modulating', 'Reg', (161, 171))	('GINS2', 'Var', (82, 87))	('protein kinase B', 'Gene', (198, 214))	('NSCLC', 'Phenotype', 'HP:0030358', (140, 145))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('NSCLC cancer', 'Disease', (140, 152))	('facilitates', 'PosReg', (88, 99))	('protein kinase B', 'Gene', '2185', (198, 214))
350401	33391406	All cells were maintained in Dulbecco's modified Eagle's medium (DMEM) high glucose containing 10% fetal bovine serum (FBS), penicillin (100 U/mL) and streptomycin (100 mg/mL).	('100 U/mL', 'Var', (137, 145))	('FBS', 'Disease', 'MESH:D005198', (119, 122))	('DMEM', 'Chemical', '-', (65, 69))	('glucose', 'Chemical', 'MESH:D005947', (76, 83))	("Dulbecco's modified Eagle's medium", 'Chemical', '-', (29, 63))	('FBS', 'Disease', (119, 122))	('high glucose', 'Phenotype', 'HP:0003074', (71, 83))	('penicillin', 'Chemical', 'MESH:D010406', (125, 135))	('streptomycin', 'Chemical', 'MESH:D013307', (151, 163))
350419	33391406	A549 cells were seeded in six-well plates at 105 cells/well, and the medium was changed every two days and cultured in 5% CO2, 37 C. We transfected the lentivirus shGFP and shGINS2 into A549 cells and observed the status of the cells.	('A549', 'CellLine', 'CVCL:0023', (0, 4))	('CO2', 'Chemical', 'MESH:D002245', (122, 125))	('shGFP', 'Gene', (163, 168))	('A549', 'CellLine', 'CVCL:0023', (186, 190))	('transfected', 'Var', (136, 147))	('shGINS2', 'Gene', (173, 180))
350446	33391406	As shown in Figure 4G, after silencing GINS2 in A549 cells, the viable cell number increased significantly compared with that in the shCtrl group on days 4 and 5.	('increased', 'PosReg', (83, 92))	('GINS2', 'Gene', (39, 44))	('viable cell number', 'CPA', (64, 82))	('silencing', 'Var', (29, 38))	('A549', 'CellLine', 'CVCL:0023', (48, 52))
350447	33391406	Furthermore, after transfection with shGINS2 for 5 days, the percentages of A549 lung cancer cells in G2/M-phase and S-phase were significantly decreased, while the percentage of cells in G1-phase was dramatically increased (Figure 5B).	('lung cancer', 'Disease', (81, 92))	('transfection', 'Var', (19, 31))	('lung cancer', 'Phenotype', 'HP:0100526', (81, 92))	('decreased', 'NegReg', (144, 153))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('A549', 'CellLine', 'CVCL:0023', (76, 80))	('increased', 'PosReg', (214, 223))	('lung cancer', 'Disease', 'MESH:D008175', (81, 92))	('S-phase', 'CPA', (117, 124))	('shGINS2', 'Var', (37, 44))
350456	33391406	Meanwhile, the weight of the tumors was significantly decreased in the shGINS2 group compared to the shCtrl group (Figure 7C).	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('tumors', 'Disease', 'MESH:D009369', (29, 35))	('shGINS2', 'Var', (71, 78))	('decreased', 'NegReg', (54, 63))	('tumors', 'Disease', (29, 35))
350457	33391406	In our study, we found that knockdown of GINS2 in A549 cells inhibited cell proliferation and migration.	('GINS2', 'Gene', (41, 46))	('A549', 'CellLine', 'CVCL:0023', (50, 54))	('inhibited', 'NegReg', (61, 70))	('knockdown', 'Var', (28, 37))
350459	33391406	We found 697 differentially expressed genes after knockdown GINS2 in A549 cells, and the results are shown as a volcano plot (Figure 8A).	('A549', 'CellLine', 'CVCL:0023', (69, 73))	('knockdown', 'Var', (50, 59))	('GINS2', 'Gene', (60, 65))
350460	33391406	Additionally, we performed Western blotting to measure protein expression in A549 cells after GINS2 knockdown.	('knockdown', 'Var', (100, 109))	('A549', 'CellLine', 'CVCL:0023', (77, 81))	('GINS2', 'Gene', (94, 99))
350461	33391406	BMPR2, IFIT1, IRF1 and IFITM1 protein expression was not changed in the GINS2 knockdown group compared to the control group (Figure 9A, B and C).	('BMPR2', 'Gene', (0, 5))	('BMPR2', 'Gene', '659', (0, 5))	('IFIT1', 'Gene', (7, 12))	('knockdown', 'Var', (78, 87))	('IFIT1', 'Gene', '3434', (7, 12))	('IRF1', 'Gene', (14, 18))	('IRF1', 'Gene', '3659', (14, 18))	('GINS2', 'Gene', (72, 77))	('IFITM1', 'Gene', (23, 29))	('IFITM1', 'Gene', '8519', (23, 29))
350462	33391406	STAT1, STAT2 and TNFAIP3 protein expression were all upregulated after GINS2 knockdown (Figure 9B, C and D).	('STAT1', 'Gene', '6772', (0, 5))	('STAT2', 'MPA', (7, 12))	('protein', 'Protein', (25, 32))	('GINS2', 'Gene', (71, 76))	('knockdown', 'Var', (77, 86))	('TNFAIP3', 'Gene', '7128', (17, 24))	('expression', 'MPA', (33, 43))	('TNFAIP3', 'Gene', (17, 24))	('upregulated', 'PosReg', (53, 64))	('STAT1', 'Gene', (0, 5))
350465	33391406	In addition, functional studies revealed that GINS2 promoted cell migration and proliferation and that STAT1 and STAT2 protein expression was elevated with GINS2 knockdown.	('STAT1', 'Gene', (103, 108))	('GINS2', 'Gene', (156, 161))	('proliferation', 'CPA', (80, 93))	('STAT1', 'Gene', '6772', (103, 108))	('cell migration', 'CPA', (61, 75))	('elevated', 'PosReg', (142, 150))	('promoted', 'PosReg', (52, 60))	('knockdown', 'Var', (162, 171))
350467	33391406	Moreover, RNA sequence analysis demonstrated that silencing GINS2 upregulated STAT1 and STAT2 protein expression in A549 cells.	('STAT2 protein expression', 'MPA', (88, 112))	('GINS2', 'Gene', (60, 65))	('upregulated', 'PosReg', (66, 77))	('silencing', 'Var', (50, 59))	('STAT1', 'Gene', (78, 83))	('STAT1', 'Gene', '6772', (78, 83))	('A549', 'CellLine', 'CVCL:0023', (116, 120))
350480	33391406	Tumorigenesis assays showed that the volume, size and weight of tumors in the shGINS2 group were significantly decreased compared to those in the control group, demonstrating that GINS2 knockdown inhibited tumor proliferation and growth in vivo.	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('tumors', 'Disease', (64, 70))	('shGINS2', 'Gene', (78, 85))	('tumor', 'Disease', (64, 69))	('knockdown', 'Var', (186, 195))	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('tumor', 'Disease', (206, 211))	('decreased', 'NegReg', (111, 120))	('inhibited', 'NegReg', (196, 205))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('GINS2', 'Gene', (180, 185))	('tumor', 'Disease', 'MESH:D009369', (206, 211))	('volume', 'CPA', (37, 43))
350481	33391406	To reveal the molecular mechanisms of GINS2 in NSCLC, we performed RNA sequencing to identify differentially expressed genes after GINS2 knockdown in A549 cells.	('A549', 'CellLine', 'CVCL:0023', (150, 154))	('NSCLC', 'Phenotype', 'HP:0030358', (47, 52))	('knockdown', 'Var', (137, 146))	('NSCLC', 'Disease', (47, 52))	('GINS2', 'Gene', (131, 136))	('NSCLC', 'Disease', 'MESH:D002289', (47, 52))
350482	33391406	Analysis of the cell signaling pathway showed that silencing GINS2 promoted STAT1 and STAT2 mRNA expression.	('silencing', 'Var', (51, 60))	('promoted', 'PosReg', (67, 75))	('GINS2', 'Gene', (61, 66))	('STAT1', 'Gene', (76, 81))	('STAT2 mRNA expression', 'MPA', (86, 107))	('STAT1', 'Gene', '6772', (76, 81))
350485	33391406	In another study, STAT2 knockout mice formed larger tumors than wild-type mice, indicating that STAT2 reduces tumor growth in a syngeneic tumor transplantation model.	('reduces', 'NegReg', (102, 109))	('mice', 'Species', '10090', (74, 78))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('tumor', 'Disease', (138, 143))	('tumor', 'Disease', (52, 57))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumors', 'Disease', (52, 58))	('tumor', 'Disease', (110, 115))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('mice', 'Species', '10090', (33, 37))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('STAT2', 'Var', (96, 101))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
350486	33391406	In addition to detecting gene expression, we found that GINS2 knockdown increased STAT1 and STAT2 protein expression and inhibited tumor migration and proliferation, which was consistent with a previous study.	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('increased', 'PosReg', (72, 81))	('STAT2', 'Gene', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumor', 'Disease', (131, 136))	('STAT1', 'Gene', (82, 87))	('inhibited', 'NegReg', (121, 130))	('GINS2', 'Gene', (56, 61))	('STAT1', 'Gene', '6772', (82, 87))	('knockdown', 'Var', (62, 71))
350488	33391406	Our results showed that GINS2 knockdown increased TNFAIP3 protein expression, suggesting that TNFAIP3 may be involved in the effects of GINS2 on NSCLC proliferation and migration.	('TNFAIP3', 'Gene', (94, 101))	('TNFAIP3', 'Gene', '7128', (50, 57))	('NSCLC', 'Disease', (145, 150))	('migration', 'CPA', (169, 178))	('protein expression', 'MPA', (58, 76))	('NSCLC', 'Phenotype', 'HP:0030358', (145, 150))	('NSCLC', 'Disease', 'MESH:D002289', (145, 150))	('GINS2', 'Gene', (24, 29))	('TNFAIP3', 'Gene', (50, 57))	('increased', 'PosReg', (40, 49))	('knockdown', 'Var', (30, 39))	('TNFAIP3', 'Gene', '7128', (94, 101))	('involved', 'Reg', (109, 117))
350489	33391406	Taken together, based on previous studies, we determined the clinical significance of GINS2 in NSCLC and demonstrated that GINS2 knockout significantly impaired the proliferation and tumorigenicity of A549 cells.	('impaired', 'NegReg', (152, 160))	('NSCLC', 'Disease', 'MESH:D002289', (95, 100))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('knockout', 'Var', (129, 137))	('A549', 'CellLine', 'CVCL:0023', (201, 205))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('NSCLC', 'Phenotype', 'HP:0030358', (95, 100))	('GINS2', 'Gene', (123, 128))	('tumor', 'Disease', (183, 188))	('proliferation', 'CPA', (165, 178))	('NSCLC', 'Disease', (95, 100))
350490	33391406	Furthermore, GINS2 inhibits the proliferation of NSCLC by inhibiting the STAT signaling pathway, which may be a potential biomarker for the diagnosis or prognosis of lung cancer.	('NSCLC', 'Disease', (49, 54))	('lung cancer', 'Disease', 'MESH:D008175', (166, 177))	('NSCLC', 'Disease', 'MESH:D002289', (49, 54))	('inhibiting', 'NegReg', (58, 68))	('GINS2', 'Var', (13, 18))	('STAT signaling pathway', 'Pathway', (73, 95))	('proliferation', 'CPA', (32, 45))	('lung cancer', 'Disease', (166, 177))	('inhibits', 'NegReg', (19, 27))	('lung cancer', 'Phenotype', 'HP:0100526', (166, 177))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('NSCLC', 'Phenotype', 'HP:0030358', (49, 54))
350545	28932050	showed the deregulation of paxillin gene involving in the metastasis and progression of different malignancies with colorectal cancer.	('colorectal cancer', 'Phenotype', 'HP:0003003', (116, 133))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('malignancies', 'Disease', (98, 110))	('colorectal cancer', 'Disease', (116, 133))	('deregulation', 'Var', (11, 23))	('colorectal cancer', 'Disease', 'MESH:D015179', (116, 133))	('involving in', 'Reg', (41, 53))	('paxillin', 'Gene', '5829', (27, 35))	('malignancies', 'Disease', 'MESH:D009369', (98, 110))	('metastasis', 'CPA', (58, 68))	('paxillin', 'Gene', (27, 35))
350558	24932237	SLC23A2-05 (rs4987219) and KRAS-LCS6 (rs61764370) polymorphisms in patients with squamous cell carcinoma of the head and neck Cancer is a genetic disease that is highly influenced by environmental factors.	('KRAS-LCS6', 'Gene', (27, 36))	('KRAS-LCS6', 'Gene', '3845', (27, 36))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (81, 104))	('SLC23A2', 'Gene', (0, 7))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('squamous cell carcinoma', 'Disease', (81, 104))	('patients', 'Species', '9606', (67, 75))	('carcinoma of the head and neck', 'Phenotype', 'HP:0012288', (95, 125))	('Cancer', 'Phenotype', 'HP:0002664', (126, 132))	('rs61764370', 'Mutation', 'rs61764370', (38, 48))	('SLC23A2', 'Gene', '9962', (0, 7))	('rs4987219', 'Var', (12, 21))	('head and neck Cancer', 'Phenotype', 'HP:0012288', (112, 132))	('rs61764370) polymorphisms', 'Var', (38, 63))	('genetic disease', 'Disease', (138, 153))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (81, 104))	('genetic disease', 'Disease', 'MESH:D030342', (138, 153))	('rs4987219', 'Mutation', 'rs4987219', (12, 21))	('polymorphisms', 'Var', (50, 63))
350559	24932237	To determine the risk factors of squamous cell carcinoma of the head and neck, two polymorphisms, solute carrier family 23 member 2 (SLC23A2-05 [rs4987219]) and v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS)-LCS6 (rs61764370), and environmental factors, including smoking and alcohol consumption, were studied in a population.	('sarcoma', 'Disease', 'MESH:D012509', (183, 190))	('rat', 'Species', '10116', (179, 182))	('rs61764370', 'Var', (227, 237))	('sarcoma', 'Disease', (183, 190))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (33, 56))	('carcinoma of the head and neck', 'Phenotype', 'HP:0012288', (47, 77))	('sarcoma', 'Phenotype', 'HP:0100242', (183, 190))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (33, 56))	('carcinoma', 'Phenotype', 'HP:0030731', (47, 56))	('squamous cell carcinoma', 'Disease', (33, 56))	('rs4987219', 'Mutation', 'rs4987219', (145, 154))	('rs61764370', 'Mutation', 'rs61764370', (227, 237))	('alcohol', 'Chemical', 'MESH:D000438', (289, 296))
350564	24932237	The results of the present study demonstrate that the SLC23A2-05 and KRAS-LCS6 polymorphisms are not a risk factor for squamous cell carcinoma of the head and neck.	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (119, 142))	('SLC23A2-05', 'Gene', (54, 64))	('carcinoma of the head and neck', 'Phenotype', 'HP:0012288', (133, 163))	('rat', 'Species', '10116', (40, 43))	('polymorphisms', 'Var', (79, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('KRAS-LCS6', 'Gene', (69, 78))	('KRAS-LCS6', 'Gene', '3845', (69, 78))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (119, 142))	('squamous cell carcinoma', 'Disease', (119, 142))
350570	24932237	The v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS)-LCS6 (G>T) polymorphism is located in the KRAS2 gene (region 12p12.1, 6 exons; exon 5 has an alternative splicing site and results in the B isoform, KRASB) and appears to reduce the lifespan of head and neck cancer patients.	('reduce', 'NegReg', (235, 241))	('results in', 'Reg', (187, 197))	('cancer', 'Phenotype', 'HP:0002664', (272, 278))	('head and neck cancer', 'Phenotype', 'HP:0012288', (258, 278))	('KRAS2', 'Gene', (106, 111))	('B isoform', 'MPA', (202, 211))	('p12', 'Gene', (127, 130))	('rat', 'Species', '10116', (22, 25))	('sarcoma', 'Disease', 'MESH:D012509', (26, 33))	('p12', 'Gene', '56655', (127, 130))	('lifespan', 'CPA', (246, 254))	('sarcoma', 'Disease', (26, 33))	('neck cancer', 'Disease', 'MESH:D006258', (267, 278))	('neck cancer', 'Disease', (267, 278))	('patients', 'Species', '9606', (279, 287))	('sarcoma', 'Phenotype', 'HP:0100242', (26, 33))	('KRAS2', 'Gene', '24525', (106, 111))	('polymorphism', 'Var', (75, 87))
350575	24932237	In small cell lung cancer, smokers aged >40 years with the KRAS let-7 (KRAS-LCS6) variant possessed an increased risk of disease.	('KRAS-LCS6', 'Gene', (71, 80))	('KRAS let-7', 'Gene', (59, 69))	('KRAS-LCS6', 'Gene', '3845', (71, 80))	('small cell lung cancer', 'Disease', (3, 25))	('lung cancer', 'Phenotype', 'HP:0100526', (14, 25))	('variant', 'Var', (82, 89))	('small cell lung cancer', 'Disease', 'MESH:D055752', (3, 25))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (3, 25))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))
350576	24932237	Furthermore, the KRAS-LCS6 variant allele is associated with a high KRAS expression and decreased levels of let-7.	('levels of let-7', 'MPA', (98, 113))	('KRAS-LCS6', 'Gene', (17, 26))	('KRAS', 'Protein', (68, 72))	('KRAS-LCS6', 'Gene', '3845', (17, 26))	('decreased', 'NegReg', (88, 97))	('variant', 'Var', (27, 34))	('high', 'PosReg', (63, 67))
350580	24932237	In addition, the low level of let-7a-2 is associated with a poor survival rate of patients with lung adenocarcinoma.	('lung adenocarcinoma', 'Disease', (96, 115))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (96, 115))	('low level', 'Var', (17, 26))	('patients', 'Species', '9606', (82, 90))	('poor', 'NegReg', (60, 64))	('rat', 'Species', '10116', (74, 77))	('let-7a-2', 'Gene', '406882', (30, 38))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (96, 115))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('let-7a-2', 'Gene', (30, 38))
350583	24932237	The SLC23A2-05 polymorphism has been associated with squamous cell carcinoma of the head and neck.	('carcinoma of the head and neck', 'Phenotype', 'HP:0012288', (67, 97))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (53, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('squamous cell carcinoma', 'Disease', (53, 76))	('SLC23A2-05', 'Gene', (4, 14))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (53, 76))	('associated', 'Reg', (37, 47))	('polymorphism', 'Var', (15, 27))
350584	24932237	However, the association between the SLC23A2-05 variation and positive HPV, as a risk factor for squamous cell carcinoma of the head and neck, is ambiguous.	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (97, 120))	('SLC23A2-05', 'Gene', (37, 47))	('variation', 'Var', (48, 57))	('squamous cell carcinoma', 'Disease', (97, 120))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (97, 120))	('carcinoma of the head and neck', 'Phenotype', 'HP:0012288', (111, 141))
350613	24932237	In the case group for the SLC23A2-05 polymorphism, 35 (21.21%) patients exhibited the CC genotype, 84 (50.91%) CG and 46 (27.88%) GG.	('exhibited', 'Reg', (72, 81))	('polymorphism', 'Var', (37, 49))	('SLC23A2-05', 'Gene', (26, 36))	('CG', 'Chemical', 'MESH:C028505', (111, 113))	('patients', 'Species', '9606', (63, 71))
350624	24932237	In the present study, squamous cell carcinoma of the head and neck was analyzed considering two polymorphisms, SLC23A2-05 (rs4987219) and KRAS-LCS6 (rs61764370), and environmental factors (smoking habit and alcohol consumption).	('alcohol', 'Chemical', 'MESH:D000438', (207, 214))	('rs4987219', 'Mutation', 'rs4987219', (123, 132))	('rs4987219', 'Var', (123, 132))	('carcinoma of the head and neck', 'Phenotype', 'HP:0012288', (36, 66))	('rs61764370', 'Var', (149, 159))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (22, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (36, 45))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (22, 45))	('KRAS-LCS6', 'Gene', (138, 147))	('KRAS-LCS6', 'Gene', '3845', (138, 147))	('squamous cell carcinoma', 'Disease', (22, 45))	('rs61764370', 'Mutation', 'rs61764370', (149, 159))
350625	24932237	For the KRAS-LCS6 polymorphism, the case and control groups were in Hardy-Weinberg equilibrium.	('polymorphism', 'Var', (18, 30))	('KRAS-LCS6', 'Gene', (8, 17))	('KRAS-LCS6', 'Gene', '3845', (8, 17))
350626	24932237	In the literature, there is a hypothesis that the activation of the KRAS pathway may occur in squamous cell carcinomas by the action of the KRAS-LCS6 normal variant, which may therefore be associated with the susceptibility and clinical outcome of cancer.	('cancer', 'Disease', (248, 254))	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (94, 117))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (94, 118))	('KRAS pathway', 'Pathway', (68, 80))	('KRAS-LCS6', 'Gene', (140, 149))	('associated', 'Reg', (189, 199))	('activation', 'PosReg', (50, 60))	('KRAS-LCS6', 'Gene', '3845', (140, 149))	('variant', 'Var', (157, 164))	('cancer', 'Phenotype', 'HP:0002664', (248, 254))	('squamous cell carcinomas', 'Disease', (94, 118))	('carcinomas', 'Phenotype', 'HP:0030731', (108, 118))	('rat', 'Species', '10116', (11, 14))	('cancer', 'Disease', 'MESH:D009369', (248, 254))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (94, 118))
350627	24932237	The present study did not show an association with the overall risk of squamous cell carcinoma of the head and neck, however, cases with the G allele showed a reduction in survival: Hazard ratio (HR), 1.6 and 95% confidence interval; CI, 1.0-2.5.	('reduction', 'NegReg', (159, 168))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (71, 94))	('carcinoma of the head and neck', 'Phenotype', 'HP:0012288', (85, 115))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (71, 94))	('G allele', 'Var', (141, 149))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('squamous cell carcinoma', 'Disease', (71, 94))	('rat', 'Species', '10116', (189, 192))	('survival', 'MPA', (172, 180))
350633	24932237	In the present study, the SLC23A2-05 polymorphism in the case and control groups demonstrated the same allele frequency.	('rat', 'Species', '10116', (88, 91))	('SLC23A2-05', 'Gene', (26, 36))	('polymorphism', 'Var', (37, 49))
350636	24932237	A study by Chen et al evaluated 319 patients with squamous cell carcinoma of the head and neck, and 495 control subjects in association with HPV16 status, citrus consumption and the single nucleotide polymorphism (SNP) panel (SNP500Cancer).	('Cancer', 'Phenotype', 'HP:0002664', (232, 238))	('patients', 'Species', '9606', (36, 44))	('single nucleotide polymorphism', 'Var', (182, 212))	('HPV16', 'Species', '333760', (141, 146))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (50, 73))	('carcinoma of the head and neck', 'Phenotype', 'HP:0012288', (64, 94))	('status', 'Var', (147, 153))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (50, 73))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))	('squamous cell carcinoma', 'Disease', (50, 73))	('HPV16', 'Gene', (141, 146))
350637	24932237	The SLC23A2-05 polymorphism plus HPV16 infection were considered to be a risk factor for cancer.	('infection', 'Disease', 'MESH:D007239', (39, 48))	('HPV16', 'Gene', (33, 38))	('HPV16', 'Species', '333760', (33, 38))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('cancer', 'Disease', (89, 95))	('SLC23A2-05', 'Gene', (4, 14))	('polymorphism', 'Var', (15, 27))	('infection', 'Disease', (39, 48))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
350638	24932237	Among G allele patients with the SLC23A2-05 polymorphism, the cancer risk in association with HPV16 was 5.0 (95% CI, 3.2-7.8).	('HPV16', 'Gene', (94, 99))	('patients', 'Species', '9606', (15, 23))	('SLC23A2-05', 'Gene', (33, 43))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('cancer', 'Disease', (62, 68))	('polymorphism', 'Var', (44, 56))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('HPV16', 'Species', '333760', (94, 99))
350640	24932237	In determining if the genotype modifies the interaction between citrus consumption, HPV16 and cancer risk, there was an increased risk of cancer found in individuals with one G allele to SLC23A2-5 polymorphism, HPV16 seropositive and high citrus consumption (OR, 7.4; 95% CI, 3.6-15.1).	('HPV16', 'Species', '333760', (211, 216))	('cancer', 'Disease', (138, 144))	('HPV16', 'Gene', (211, 216))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('polymorphism', 'Var', (197, 209))	('SLC23A2-5', 'Gene', (187, 196))	('cancer', 'Disease', 'MESH:D009369', (138, 144))	('HPV16', 'Species', '333760', (84, 89))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
350650	24932237	Potentially, the observation of these polymorphisms in a localized tumor may provide a significant tool for the detection of cancer.	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('polymorphisms', 'Var', (38, 51))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Disease', (67, 72))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))
350659	29525205	Ye et al comprehensively analyzed alterations of clock genes and circadian rhythms across multiple human cancers, and revealed strong interactions between clock genes and clinically actionable genes, which highlights the clinical utility of circadian timing in cancer chronotherapy.	('cancer', 'Disease', 'MESH:D009369', (261, 267))	('cancers', 'Phenotype', 'HP:0002664', (105, 112))	('interactions', 'Interaction', (134, 146))	('cancer', 'Disease', (105, 111))	('cancers', 'Disease', (105, 112))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('cancers', 'Disease', 'MESH:D009369', (105, 112))	('cancer', 'Phenotype', 'HP:0002664', (261, 267))	('clock', 'Gene', (49, 54))	('clock', 'Gene', (155, 160))	('clock', 'Gene', '9575', (155, 160))	('cancer', 'Disease', (261, 267))	('clock', 'Gene', '9575', (49, 54))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('alterations', 'Var', (34, 45))	('human', 'Species', '9606', (99, 104))
350661	29525205	Disruption of the circadian rhythm is associated with cancer development and poor prognosis.	('associated', 'Reg', (38, 48))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('circadian rhythm', 'MPA', (18, 34))	('cancer', 'Disease', (54, 60))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('Disruption', 'Var', (0, 10))
350672	29525205	Dysregulation of clock genes promotes tumorigenesis through mechanisms that include the cell cycle, DNA damage and metabolism.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('Dysregulation', 'Var', (0, 13))	('clock', 'Gene', '9575', (17, 22))	('clock', 'Gene', (17, 22))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('promotes', 'PosReg', (29, 37))
350675	29525205	CRY2 deficiency elevates c-MYC and enhances cancer transformation susceptibility.	('CRY2', 'Gene', (0, 4))	('deficiency', 'Var', (5, 15))	('c-MYC', 'Gene', (25, 30))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('c-MYC', 'Gene', '4609', (25, 30))	('CRY2', 'Gene', '1408', (0, 4))	('enhances', 'PosReg', (35, 43))	('elevates', 'PosReg', (16, 24))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
350679	29525205	Composite knockdown of paralog clock genes may cause more serious consequences than single knockdown.	('knockdown', 'Var', (10, 19))	('Composite knockdown', 'Var', (0, 19))	('clock', 'Gene', '9575', (31, 36))	('clock', 'Gene', (31, 36))
350680	29525205	For example, composite PER1/2 double or PER1/2/3 triple knockdown caused complete arrhythmicity.	('PER1/2/3', 'Gene', '5187;8864;8863', (40, 48))	('arrhythmicity', 'Disease', 'MESH:D001145', (82, 95))	('PER1/2', 'Gene', '5187;8864', (23, 29))	('PER1/2', 'Gene', '5187;8864', (40, 46))	('caused', 'Reg', (66, 72))	('arrhythmicity', 'Disease', (82, 95))	('PER1/2/3', 'Gene', (40, 48))	('PER1/2', 'Gene', (23, 29))	('PER1/2', 'Gene', (40, 46))	('knockdown', 'Var', (56, 65))
350681	29525205	Similarly, knockdown of Cry1 or Cry2 displayed shorter or longer clock rhythm of locomotor activity, respectively, while Cry1/2 double knockdown caused arrhythmicity.	('shorter', 'NegReg', (47, 54))	('Cry1', 'Gene', (24, 28))	('caused', 'Reg', (145, 151))	('clock', 'Gene', (65, 70))	('Cry2', 'Gene', (32, 36))	('clock', 'Gene', '9575', (65, 70))	('Cry1', 'Gene', '1407', (24, 28))	('Cry1', 'Gene', (121, 125))	('arrhythmicity', 'Disease', 'MESH:D001145', (152, 165))	('Cry1', 'Gene', '1407', (121, 125))	('Cry2', 'Gene', '1408', (32, 36))	('arrhythmicity', 'Disease', (152, 165))	('knockdown', 'Var', (11, 20))	('locomotor activity', 'MPA', (81, 99))
350682	29525205	Despite the arrhythmicity caused by double or triple knockdown, the interactive effects of these paralog genes in cancer remain to be ascertained.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('triple knockdown', 'Var', (46, 62))	('arrhythmicity', 'Disease', (12, 25))	('arrhythmicity', 'Disease', 'MESH:D001145', (12, 25))	('double', 'Var', (36, 42))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('cancer', 'Disease', (114, 120))
350708	29525205	For example, CRY2, PER1, PER2, PER3, RORA and RORC are highly associated with inhibition of apoptosis and cell cycle, and activation of PI3K/AKT and RAS/MAPK signaling pathways.	('CRY2', 'Gene', (13, 17))	('PER2', 'Gene', '8864', (25, 29))	('cell cycle', 'CPA', (106, 116))	('ROR', 'Gene', '6095', (46, 49))	('PER3', 'Gene', '8863', (31, 35))	('ROR', 'Gene', (46, 49))	('RORA', 'Gene', (37, 41))	('AKT', 'Gene', (141, 144))	('ROR', 'Gene', '6095', (37, 40))	('inhibition', 'NegReg', (78, 88))	('activation', 'PosReg', (122, 132))	('PER1', 'Var', (19, 23))	('ROR', 'Gene', (37, 40))	('PER3', 'Gene', (31, 35))	('RORA', 'Gene', '6095', (37, 41))	('CRY2', 'Gene', '1408', (13, 17))	('AKT', 'Gene', '207', (141, 144))	('PER2', 'Gene', (25, 29))
350714	29525205	Despite the arrhythmicity caused by double or triple knockdown, the interactive effects of these paralog genes in cancer remains unclear.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('triple knockdown', 'Var', (46, 62))	('arrhythmicity', 'Disease', (12, 25))	('arrhythmicity', 'Disease', 'MESH:D001145', (12, 25))	('double', 'Var', (36, 42))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('cancer', 'Disease', (114, 120))
350718	29525205	On the other hand, we observed that alterations of CRY1 and CRY2 in combination led to fewer alterations of signaling pathways than CRY2 alterations alone (Figure S2B), suggesting that CRY2 may play a dominant role in cancer.	('fewer', 'NegReg', (87, 92))	('cancer', 'Disease', 'MESH:D009369', (218, 224))	('CRY2', 'Gene', '1408', (185, 189))	('CRY2', 'Gene', (185, 189))	('cancer', 'Disease', (218, 224))	('alterations', 'Reg', (93, 104))	('CRY2', 'Gene', (132, 136))	('alterations', 'Var', (36, 47))	('CRY2', 'Gene', '1408', (60, 64))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('CRY1', 'Gene', (51, 55))	('CRY2', 'Gene', (60, 64))	('signaling pathways', 'Pathway', (108, 126))	('CRY1', 'Gene', '1407', (51, 55))	('CRY2', 'Gene', '1408', (132, 136))
350722	29525205	However, mutations of core clock genes were associated with patients' overall survival.	('associated', 'Reg', (44, 54))	('mutations', 'Var', (9, 18))	('patients', 'Species', '9606', (60, 68))	('clock', 'Gene', (27, 32))	('clock', 'Gene', '9575', (27, 32))
350723	29525205	For example, breast cancer patients with mutations in core clock genes had worse overall survival than those without mutations (log-rank test P = 0.05; Figure 3C).	('mutations', 'Var', (41, 50))	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('clock', 'Gene', (59, 64))	('breast cancer', 'Disease', 'MESH:D001943', (13, 26))	('breast cancer', 'Phenotype', 'HP:0003002', (13, 26))	('breast cancer', 'Disease', (13, 26))	('clock', 'Gene', '9575', (59, 64))	('patients', 'Species', '9606', (27, 35))	('overall', 'MPA', (81, 88))	('worse', 'NegReg', (75, 80))
350724	29525205	We observed the highest mutation rate for core circadian genes in PER1/2/3 (Figure 3B), which are associated with worse survival (P = 5.9 x 10-5; Figure 3D).	('mutation', 'Var', (24, 32))	('associated', 'Reg', (98, 108))	('PER1/2/3 (Figure 3B', 'Gene', '5187', (66, 85))	('circadian genes', 'Gene', (47, 62))
350725	29525205	These results suggest that genetic alterations of clock genes play functional roles in cancer.	('cancer', 'Disease', (87, 93))	('clock', 'Gene', (50, 55))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('roles', 'Reg', (78, 83))	('clock', 'Gene', '9575', (50, 55))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('genetic alterations', 'Var', (27, 46))
350728	29525205	For example, we observed hypermethylation in HLF, but hypomethylation in ARNTL2 (Figure S3B).	('HLF', 'Gene', (45, 48))	('hypermethylation', 'Var', (25, 41))	('hypomethylation', 'NegReg', (54, 69))	('HLF', 'Gene', '3131', (45, 48))	('ARNTL2', 'Gene', '56938', (73, 79))	('ARNTL2', 'Gene', (73, 79))
350729	29525205	In particular, ARNTL2 showed hypomethylation in three cancer types, which is consistent with upregulation of gene expression.	('ARNTL2', 'Gene', '56938', (15, 21))	('ARNTL2', 'Gene', (15, 21))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('cancer', 'Disease', (54, 60))	('hypomethylation', 'Var', (29, 44))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
350746	29525205	This suggests that disrupted and reprogrammed circadian rhythm in cancer cells may contribute to cancer development.	('cancer', 'Disease', (97, 103))	('cancer', 'Disease', (66, 72))	('disrupted', 'Var', (19, 28))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('contribute', 'Reg', (83, 93))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
350751	29525205	For example, patients with low expression level of CRY2 showed significantly worse survival in LIHC (log-rank test P = 1.9 x 10-4), KIRP (P = 4.5 x 10-4) and KIRC (P = 1.4 x 10-5; Figures 5B and S5A).	('CRY2', 'Gene', (51, 55))	('patients', 'Species', '9606', (13, 21))	('LIHC', 'Disease', (95, 99))	('low expression level', 'Var', (27, 47))	('LIHC', 'Disease', 'None', (95, 99))	('CRY2', 'Gene', '1408', (51, 55))	('worse', 'NegReg', (77, 82))
350774	29525205	To further investigate the interactions between clock genes and clinically actionable genes, we reanalyzed data from a time series expression study on a CRY2 knockdown in MEF cells.	('CRY2', 'Gene', '1408', (153, 157))	('MEF', 'Gene', '2000', (171, 174))	('MEF', 'Gene', (171, 174))	('clock', 'Gene', '9575', (48, 53))	('clock', 'Gene', (48, 53))	('knockdown', 'Var', (158, 167))	('CRY2', 'Gene', (153, 157))
350775	29525205	There were decreased expression levels of clinically actionable genes that are positively correlated to CRY2, such as AKT3, EPHA3 and PIK3R1, as well as increased expression levels of clinically actionable genes that are negatively correlated to CRY2, such as JAK3, BRCA1 and CDK4, across the majority of time points in the CRY2 knockdown versus control (Figure 6B).	('CDK4', 'Gene', '1019', (276, 280))	('decreased', 'NegReg', (11, 20))	('AKT3', 'Gene', '10000', (118, 122))	('BRCA1', 'Gene', '672', (266, 271))	('CRY2', 'Gene', '1408', (104, 108))	('PIK3R1', 'Gene', '5295', (134, 140))	('BRCA1', 'Gene', (266, 271))	('CRY2', 'Gene', (104, 108))	('AKT3', 'Gene', (118, 122))	('knockdown', 'Var', (329, 338))	('EPHA3', 'Gene', (124, 129))	('expression levels', 'MPA', (21, 38))	('CRY2', 'Gene', '1408', (246, 250))	('increased', 'PosReg', (153, 162))	('EPHA3', 'Gene', '2042', (124, 129))	('expression levels', 'MPA', (163, 180))	('CRY2', 'Gene', (246, 250))	('JAK3', 'Gene', (260, 264))	('PIK3R1', 'Gene', (134, 140))	('CDK4', 'Gene', (276, 280))	('CRY2', 'Gene', '1408', (324, 328))	('CRY2', 'Gene', (324, 328))	('JAK3', 'Gene', '3718', (260, 264))
350795	29525205	For example, ATM, the target of CP466722, is negatively correlated with clock genes, including PPARG (R = -0.29) and CRY1 (R = -0.28), and positively correlated with CREB1 (R = 0.28).	('negatively', 'NegReg', (45, 55))	('CREB1', 'Gene', (166, 171))	('correlated', 'Interaction', (56, 66))	('CRY1', 'Gene', '1407', (117, 121))	('ATM', 'Gene', (13, 16))	('clock', 'Gene', '9575', (72, 77))	('clock', 'Gene', (72, 77))	('CP466722', 'Var', (32, 40))	('PPARG', 'Gene', (95, 100))	('PPARG', 'Gene', '5468', (95, 100))	('CRY1', 'Gene', (117, 121))	('correlated', 'Interaction', (150, 160))	('ATM', 'Gene', '472', (13, 16))	('CREB1', 'Gene', '1385', (166, 171))
350815	29525205	Despite the relatively low mutation frequency of clock genes, combinations of mutations in multiple colck genes may provide prognostic value.	('mutations', 'Var', (78, 87))	('combinations', 'Var', (62, 74))	('clock', 'Gene', (49, 54))	('colck', 'Gene', (100, 105))	('clock', 'Gene', '9575', (49, 54))
350816	29525205	For example, higher frequency mutation rate of core clock genes, especially PER1/2/3, will lead to worse survival in BRCA.	('PER1/2/3', 'Gene', (76, 84))	('BRCA', 'Gene', (117, 121))	('BRCA', 'Gene', '672', (117, 121))	('clock', 'Gene', '9575', (52, 57))	('clock', 'Gene', (52, 57))	('PER1/2/3', 'Gene', '5187;8864;8863', (76, 84))	('mutation rate', 'Var', (30, 43))
350858	29525205	We performed Spearman's correlation analysis for the promoter DNA methylation and clock gene expression and retained the minimum Spearman correlation coefficient.	('clock', 'Gene', '9575', (82, 87))	('promoter', 'Var', (53, 61))	('clock', 'Gene', (82, 87))
350862	29525205	ChIP-seq data for clock genes were downloaded from Gene Expression Omnibus (GEO, https://www.ncbi.nlm.nih.gov/geo/; GSE39860, GSE69100 and GSE34019) (; Koike et al., 2012b).	('clock', 'Gene', (18, 23))	('GSE69100', 'Var', (126, 134))	('clock', 'Gene', '9575', (18, 23))	('GSE34019', 'Var', (139, 147))	('GSE39860', 'Var', (116, 124))
350878	29384143	Then, lung squamous cell carcinoma and adenocarcinoma cell lines were transfected with lentivirus-mediated RNA interference vector to knockdown the expression of Cbl-b.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (11, 34))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (6, 34))	('knockdown', 'Var', (134, 143))	('Cbl-b', 'Gene', (162, 167))	('carcinoma', 'Phenotype', 'HP:0030731', (44, 53))	('expression', 'MPA', (148, 158))	('carcinoma', 'Phenotype', 'HP:0030731', (25, 34))	('lung squamous cell carcinoma and adenocarcinoma', 'Disease', 'MESH:D002294', (6, 53))
350880	29384143	Finally, Western blot analysis was performed to measure the expressions of PI3K, p-PI3K, AKT, p-AKT, ERK1/2, p-ERK1/2, GSK3beta, p-GSK3beta, mTOR, and p-mTOR protein in lung adenocarcinoma and squamous cell carcinoma cells.	('mTOR', 'Gene', '2475', (141, 145))	('GSK3beta', 'Gene', (131, 139))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (193, 216))	('PI3K', 'Var', (75, 79))	('lung adenocarcinoma', 'Disease', (169, 188))	('mTOR', 'Gene', (153, 157))	('carcinoma', 'Phenotype', 'HP:0030731', (207, 216))	('GSK3beta', 'Gene', (119, 127))	('squamous cell carcinoma', 'Disease', (193, 216))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (169, 188))	('mTOR', 'Gene', '2475', (153, 157))	('GSK3beta', 'Gene', '2932', (131, 139))	('p-ERK', 'Gene', '9451', (109, 114))	('AKT', 'Gene', (89, 92))	('p-ERK', 'Gene', (109, 114))	('carcinoma', 'Phenotype', 'HP:0030731', (179, 188))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (169, 188))	('mTOR', 'Gene', (141, 145))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (193, 216))	('p-PI3K', 'Var', (81, 87))	('ERK1/2', 'Gene', (101, 107))	('p-AKT', 'Var', (94, 99))	('GSK3beta', 'Gene', '2932', (119, 127))
350882	29384143	After transfection, the expression of Cbl-b was inhibited in A549, H1975, and SW900 cells.	('Cbl-b', 'Gene', (38, 43))	('expression', 'MPA', (24, 34))	('transfection', 'Var', (6, 18))	('SW900', 'CellLine', 'CVCL:1731', (78, 83))	('inhibited', 'NegReg', (48, 57))	('H1975', 'CellLine', 'CVCL:1511', (67, 72))	('A549', 'CellLine', 'CVCL:0023', (61, 65))
350894	29384143	These genes can modulate the host immune system, enhancing T cell immunity, reducing T cell exhaustion, and enhancing local anti-tumor immune effects, and are part of a promising treatment model that changed the treatment guidelines for advanced NSCLC.	('NSCLC', 'Disease', 'MESH:D002289', (246, 251))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('modulate', 'Reg', (16, 24))	('genes', 'Var', (6, 11))	('T cell exhaustion', 'Phenotype', 'HP:0005435', (85, 102))	('NSCLC', 'Disease', (246, 251))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('reducing', 'NegReg', (76, 84))	('enhancing', 'PosReg', (49, 58))	('enhancing', 'PosReg', (108, 117))	('tumor', 'Disease', (129, 134))	('T cell immunity', 'CPA', (59, 74))	('T cell exhaustion', 'CPA', (85, 102))
350896	29384143	Recent studies have shown that knockdown of Cbl-b strengthens the immune activation of CD8+ T cells against tumor cells, downregulates phosphorylated-Foxo3a in Treg cells, and inhibits cancer metastasis via natural killer cells.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('Cbl-b', 'Gene', (44, 49))	('strengthens', 'PosReg', (50, 61))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('immune activation', 'MPA', (66, 83))	('inhibits', 'NegReg', (176, 184))	('downregulates', 'NegReg', (121, 134))	('tumor', 'Disease', (108, 113))	('phosphorylated-Foxo3a', 'MPA', (135, 156))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('CD8', 'Gene', (87, 90))	('CD8', 'Gene', '925', (87, 90))	('cancer', 'Disease', (185, 191))	('knockdown', 'Var', (31, 40))
350899	29384143	has proved that knockdown of Cbl-b also strengthens TRAIL-induced apoptosis, EGFR translocation into lipid rafts, and EGFR pathway activation induced by TRAIL.	('activation', 'PosReg', (131, 141))	('TRAIL', 'Gene', '8743', (52, 57))	('strengthens', 'PosReg', (40, 51))	('knockdown', 'Var', (16, 25))	('TRAIL', 'Gene', '8743', (153, 158))	('EGFR', 'Gene', '1956', (118, 122))	('TRAIL', 'Gene', (52, 57))	('EGFR', 'Gene', (118, 122))	('EGFR', 'Gene', '1956', (77, 81))	('lipid', 'Chemical', 'MESH:D008055', (101, 106))	('Cbl-b', 'Gene', (29, 34))	('TRAIL', 'Gene', (153, 158))	('EGFR', 'Gene', (77, 81))
350903	29384143	The knockdown TGF-beta1 gene impaired the tumorigenic ability of HCC.	('TGF-beta1', 'Gene', '7040', (14, 23))	('tumor', 'Disease', (42, 47))	('TGF-beta1', 'Gene', (14, 23))	('impaired', 'NegReg', (29, 37))	('HCC', 'Disease', (65, 68))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('knockdown', 'Var', (4, 13))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
350909	29384143	Then, the cells were infected with viruses for 72 h. There were 8 groups: A549-negative control (NC), A549-knockdown (KD), H1975-NC, H1975-KD, H1299-NC, H1299-KD, SW900-NC, and SW900-KD.	('H1299-KD', 'Var', (153, 161))	('SW900-KD', 'Var', (177, 185))	('SW900-NC', 'Var', (163, 171))	('SW900', 'CellLine', 'CVCL:1731', (163, 168))	('H1975-KD', 'Var', (133, 141))	('H1299-NC', 'Var', (143, 151))	('A549', 'CellLine', 'CVCL:0023', (102, 106))	('H1299', 'CellLine', 'CVCL:0060', (153, 158))	('SW900', 'CellLine', 'CVCL:1731', (177, 182))	('H1975', 'CellLine', 'CVCL:1511', (133, 138))	('H1299-NC', 'CellLine', 'CVCL:0060', (143, 151))	('A549-knockdown', 'Var', (102, 116))	('H1975-NC', 'Var', (123, 131))	('A549', 'CellLine', 'CVCL:0023', (74, 78))	('H1975', 'CellLine', 'CVCL:1511', (123, 128))	('H1299', 'CellLine', 'CVCL:0060', (143, 148))
350916	29384143	In patients (age >=65 years) with squamous carcinoma, the prognosis of the Cbl-b high-expression group was significantly worse than in the Cbl-b low-expression group (Figure 1E, 1F).	('squamous carcinoma', 'Disease', 'MESH:D002294', (34, 52))	('squamous carcinoma', 'Disease', (34, 52))	('high-expression', 'Var', (81, 96))	('worse', 'NegReg', (121, 126))	('carcinoma', 'Phenotype', 'HP:0030731', (43, 52))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (34, 52))	('patients', 'Species', '9606', (3, 11))	('Cbl-b', 'Gene', (75, 80))
350919	29384143	As shown in Figure 2, the expression of Cbl-b protein in the A549-KD group was markedly downregulated and the expression of Cbl-b protein in H1975-KD and SW900-KD groups was slightly downregulated, compared with their negative control (A549-NC, H1975-NC, or SW900-NC, respectively) groups.	('expression', 'MPA', (26, 36))	('Cbl-b protein', 'Gene', (40, 53))	('H1975-KD', 'Var', (141, 149))	('H1975', 'CellLine', 'CVCL:1511', (141, 146))	('A549-NC', 'CellLine', 'CVCL:0023', (236, 243))	('SW900', 'CellLine', 'CVCL:1731', (258, 263))	('A549', 'CellLine', 'CVCL:0023', (236, 240))	('H1975', 'CellLine', 'CVCL:1511', (245, 250))	('SW900-KD', 'Var', (154, 162))	('expression', 'MPA', (110, 120))	('A549-KD', 'Var', (61, 68))	('SW900', 'CellLine', 'CVCL:1731', (154, 159))	('downregulated', 'NegReg', (88, 101))	('downregulated', 'NegReg', (183, 196))	('A549', 'CellLine', 'CVCL:0023', (61, 65))
350920	29384143	There was no significant difference in the expression of Cbl-b protein between H1299-KD and H1299-NC groups.	('H1299-NC', 'Var', (92, 100))	('H1299-NC', 'CellLine', 'CVCL:0060', (92, 100))	('H1299', 'CellLine', 'CVCL:0060', (92, 97))	('H1299-KD', 'Var', (79, 87))	('Cbl-b protein', 'Gene', (57, 70))	('H1299', 'CellLine', 'CVCL:0060', (79, 84))
350925	29384143	There were 75+-1 migrating cells in the H1975-NC group and 133+-9 in the H1975-KD group.	('H1975-NC', 'Var', (40, 48))	('H1975', 'CellLine', 'CVCL:1511', (73, 78))	('H1975-KD', 'Var', (73, 81))	('H1975', 'CellLine', 'CVCL:1511', (40, 45))
350927	29384143	However, there were 22+-1 migrating cells in both the SW900-NC and SW900-KD groups.	('SW900-KD', 'Var', (67, 75))	('SW900', 'CellLine', 'CVCL:1731', (67, 72))	('SW900', 'CellLine', 'CVCL:1731', (54, 59))	('SW900-NC', 'Var', (54, 62))
350928	29384143	There was no significant difference in cell migration between SW900-NC and SW900-KD groups.	('SW900', 'CellLine', 'CVCL:1731', (62, 67))	('SW900-NC', 'Var', (62, 70))	('SW900-KD', 'Var', (75, 83))	('SW900', 'CellLine', 'CVCL:1731', (75, 80))	('cell migration', 'CPA', (39, 53))
350933	29384143	There were 23+-2 invading cells in the H1975-NC group and 75+-3 in the H1975-KD group.	('H1975', 'CellLine', 'CVCL:1511', (71, 76))	('H1975-NC', 'Var', (39, 47))	('H1975', 'CellLine', 'CVCL:1511', (39, 44))	('H1975-KD', 'Var', (71, 79))
350939	29384143	As shown in Figure 5, compared with the A549-NC group, the expression levels of PI3K, p-AKT, and GSK3beta protein in the A549-KD group were downregulated, but the expression levels of p-PI3K, p-ERK1/2, mTOR, and p-GSK3beta protein were upregulated.	('p-ERK', 'Gene', (192, 197))	('upregulated', 'PosReg', (236, 247))	('expression levels', 'MPA', (59, 76))	('downregulated', 'NegReg', (140, 153))	('A549-KD', 'Var', (121, 128))	('GSK3beta', 'Gene', '2932', (97, 105))	('GSK3beta', 'Gene', (214, 222))	('A549-NC', 'CellLine', 'CVCL:0023', (40, 47))	('A549', 'CellLine', 'CVCL:0023', (121, 125))	('expression levels', 'MPA', (163, 180))	('A549', 'CellLine', 'CVCL:0023', (40, 44))	('mTOR', 'Gene', '2475', (202, 206))	('GSK3beta', 'Gene', '2932', (214, 222))	('mTOR', 'Gene', (202, 206))	('p-ERK', 'Gene', '9451', (192, 197))	('GSK3beta', 'Gene', (97, 105))
350940	29384143	There was no significant difference in the expression levels of AKT, ERK1/2, and p-mTOR protein between the A549-NC and A549-KD groups.	('mTOR', 'Gene', (83, 87))	('ERK1/2', 'Protein', (69, 75))	('A549-NC', 'Var', (108, 115))	('A549', 'CellLine', 'CVCL:0023', (108, 112))	('AKT', 'Protein', (64, 67))	('A549-KD', 'Var', (120, 127))	('A549-NC', 'CellLine', 'CVCL:0023', (108, 115))	('mTOR', 'Gene', '2475', (83, 87))	('A549', 'CellLine', 'CVCL:0023', (120, 124))
350941	29384143	Compared with the SW900-NC group, the expression levels of PI3K and GSK3beta protein in the SW900-KD group were downregulated, but the expression levels of p-PI3K, p-AKT, p-ERK1/2, mTOR, p-mTOR, and p-GSK3beta protein were upregulated.	('GSK3beta', 'Gene', (201, 209))	('expression levels', 'MPA', (135, 152))	('downregulated', 'NegReg', (112, 125))	('expression levels', 'MPA', (38, 55))	('SW900', 'CellLine', 'CVCL:1731', (18, 23))	('GSK3beta', 'Gene', '2932', (68, 76))	('p-PI3K', 'Var', (156, 162))	('upregulated', 'PosReg', (223, 234))	('SW900-KD', 'Var', (92, 100))	('GSK3beta', 'Gene', '2932', (201, 209))	('p-ERK', 'Gene', '9451', (171, 176))	('p-AKT', 'Pathway', (164, 169))	('mTOR', 'Gene', (189, 193))	('p-ERK', 'Gene', (171, 176))	('mTOR', 'Gene', (181, 185))	('GSK3beta', 'Gene', (68, 76))	('SW900', 'CellLine', 'CVCL:1731', (92, 97))	('mTOR', 'Gene', '2475', (181, 185))	('mTOR', 'Gene', '2475', (189, 193))
350942	29384143	There was no significant difference in the expression levels of AKT and ERK1/2 protein between the SW900-NC and SW900-KD groups.	('ERK1/2', 'Gene', (72, 78))	('SW900-KD', 'Var', (112, 120))	('SW900', 'CellLine', 'CVCL:1731', (112, 117))	('AKT', 'Protein', (64, 67))	('SW900-NC', 'Var', (99, 107))	('SW900', 'CellLine', 'CVCL:1731', (99, 104))
350945	29384143	The results showed that the prognostic significance of Cbl-b mRNA low expression in lung adenocarcinoma and squamous cell carcinoma was different, suggesting that the biological functions of Cbl-b in lung adenocarcinoma and squamous cell carcinoma are different.	('carcinoma', 'Phenotype', 'HP:0030731', (210, 219))	('squamous cell carcinoma', 'Disease', (108, 131))	('lung adenocarcinoma', 'Disease', (84, 103))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (224, 247))	('lung adenocarcinoma', 'Disease', (200, 219))	('carcinoma', 'Phenotype', 'HP:0030731', (238, 247))	('mRNA', 'Var', (61, 65))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (84, 103))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (84, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (108, 131))	('squamous cell carcinoma', 'Disease', (224, 247))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (200, 219))	('Cbl-b', 'Gene', (55, 60))	('expression', 'MPA', (70, 80))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (200, 219))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (108, 131))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (224, 247))
350947	29384143	The results of Western blot analysis showed that the expression levels of Cbl-b protein were markedly downregulated in the A549-KD group, and were slightly downregulated in the H1975-KD and SW900-KD groups.	('Cbl-b', 'Gene', (74, 79))	('downregulated', 'NegReg', (102, 115))	('A549', 'CellLine', 'CVCL:0023', (123, 127))	('H1975-KD', 'Var', (177, 185))	('SW900', 'CellLine', 'CVCL:1731', (190, 195))	('H1975', 'CellLine', 'CVCL:1511', (177, 182))	('protein', 'Protein', (80, 87))	('expression levels', 'MPA', (53, 70))	('downregulated', 'NegReg', (156, 169))	('A549-KD', 'Var', (123, 130))
350948	29384143	Compared with the negative groups, the migration and invasion ability of A549-KD and H1975-KD groups were enhanced, while the invasion ability in the SW900-KD group was weakened.	('A549-KD', 'Var', (73, 80))	('enhanced', 'PosReg', (106, 114))	('A549', 'CellLine', 'CVCL:0023', (73, 77))	('migration', 'CPA', (39, 48))	('H1975-KD', 'Var', (85, 93))	('SW900', 'CellLine', 'CVCL:1731', (150, 155))	('H1975', 'CellLine', 'CVCL:1511', (85, 90))	('invasion ability', 'CPA', (53, 69))
350954	29384143	Gastric cancer patients with low Cbl-b expression were more likely to have tumor invasion and lymph node metastasis, and upregulation of Cbl-b inhibited cell migration in vitro and in vivo through inhibition of the EGFR-ERK/AKT-miR-200c-ZEB1 axis.	('patients', 'Species', '9606', (15, 23))	('upregulation', 'PosReg', (121, 133))	('low', 'Var', (29, 32))	('miR-200c-ZEB1', 'Gene', '406985;6935', (228, 241))	('Cbl-b', 'Gene', (33, 38))	('tumor', 'Disease', (75, 80))	('cancer', 'Disease', (8, 14))	('inhibition', 'NegReg', (197, 207))	('Cbl-b', 'Gene', (137, 142))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('cell migration', 'CPA', (153, 167))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('EGFR', 'Gene', (215, 219))	('Gastric cancer', 'Phenotype', 'HP:0012126', (0, 14))	('expression', 'MPA', (39, 49))	('lymph node metastasis', 'CPA', (94, 115))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('cancer', 'Disease', 'MESH:D009369', (8, 14))	('miR-200c-ZEB1', 'Gene', (228, 241))	('inhibited', 'NegReg', (143, 152))	('EGFR', 'Gene', '1956', (215, 219))
350955	29384143	Another study also indicated that silencing Cbl-b expression in breast cancer cells enhanced the risk of lung metastasis in nude mice, and also found that Cbl-b can reduce RANK protein expression and inhibited RANKL-induced breast cancer cells migration through negative regulation of the Src-AKT/ERK pathway.	('Cbl-b', 'Gene', (44, 49))	('lung metastasis', 'Disease', (105, 120))	('negative regulation', 'NegReg', (262, 281))	('Src', 'Gene', '20779', (289, 292))	('RANKL', 'Gene', (210, 215))	('RANK protein', 'Protein', (172, 184))	('reduce', 'NegReg', (165, 171))	('RANKL', 'Gene', '21943', (210, 215))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('inhibited', 'NegReg', (200, 209))	('breast cancer', 'Phenotype', 'HP:0003002', (224, 237))	('Src', 'Gene', (289, 292))	('enhanced', 'PosReg', (84, 92))	('silencing', 'Var', (34, 43))	('nude mice', 'Species', '10090', (124, 133))	('breast cancer', 'Phenotype', 'HP:0003002', (64, 77))	('breast cancer', 'Disease', 'MESH:D001943', (224, 237))	('lung metastasis', 'Disease', 'MESH:D009362', (105, 120))	('breast cancer', 'Disease', (224, 237))	('Cbl-b', 'Var', (155, 160))	('breast cancer', 'Disease', 'MESH:D001943', (64, 77))	('breast cancer', 'Disease', (64, 77))
350956	29384143	In the present study, we found that Cbl-b shRNA promoted cell migration and invasion of A549 and mediated the PI3K-ERK1/2 pathways, which may help to further elucidate of the downstream signaling pathway.	('PI3K-ERK1/2', 'Gene', (110, 121))	('Cbl-b shRNA', 'Var', (36, 47))	('A549', 'CellLine', 'CVCL:0023', (88, 92))	('PI3K-ERK1/2', 'Gene', '5293;5595;5594', (110, 121))	('promoted', 'PosReg', (48, 56))	('cell migration', 'CPA', (57, 71))	('mediated', 'Reg', (97, 105))	('invasion of A549', 'CPA', (76, 92))
350960	29384143	studied the efficacy of co-treatment with the dual PI3K/mTOR inhibitor BEZ235 and histone deacetylase inhibitor Trichostatin A in NSCLC cells, which was found to inhibit cell proliferation, migration, and invasion, and promote cell apoptosis via downregulating the expression of p-AKT and GSK-3beta.	('invasion', 'CPA', (205, 213))	('NSCLC', 'Disease', 'MESH:D002289', (130, 135))	('p-AKT', 'Pathway', (279, 284))	('inhibit', 'NegReg', (162, 169))	('mTOR', 'Gene', (56, 60))	('migration', 'CPA', (190, 199))	('mTOR', 'Gene', '2475', (56, 60))	('GSK-3beta', 'Gene', '2932', (289, 298))	('GSK-3beta', 'Gene', (289, 298))	('promote', 'PosReg', (219, 226))	('expression', 'MPA', (265, 275))	('cell proliferation', 'CPA', (170, 188))	('Trichostatin A', 'Chemical', 'MESH:C012589', (112, 126))	('cell apoptosis', 'CPA', (227, 241))	('downregulating', 'NegReg', (246, 260))	('BEZ235', 'Var', (71, 77))	('BEZ235', 'Chemical', 'MESH:C531198', (71, 77))	('NSCLC', 'Disease', (130, 135))
350967	29384143	In prostate cancer cells, knockdown of CPAN2 level suppressed cell migration and invasion ability by reducing MMP-2 and MMP-9 activation, and also repressed the protein expression of p-AKT and p-mTOR.	('prostate cancer', 'Phenotype', 'HP:0012125', (3, 18))	('CPAN2', 'Gene', (39, 44))	('MMP-2', 'Gene', '4313', (110, 115))	('prostate cancer', 'Disease', (3, 18))	('mTOR', 'Gene', '2475', (195, 199))	('p-AKT', 'Pathway', (183, 188))	('invasion ability', 'CPA', (81, 97))	('MMP-2', 'Gene', (110, 115))	('protein expression', 'MPA', (161, 179))	('knockdown', 'Var', (26, 35))	('reducing', 'NegReg', (101, 109))	('MMP-9', 'Gene', '4318', (120, 125))	('MMP-9', 'Gene', (120, 125))	('repressed', 'NegReg', (147, 156))	('cell migration', 'CPA', (62, 76))	('mTOR', 'Gene', (195, 199))	('suppressed', 'NegReg', (51, 61))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('prostate cancer', 'Disease', 'MESH:D011471', (3, 18))
350968	29384143	Cbl/Cbl-b double knockout in mammary epithelial organoids leads to activation of AKT-mTOR signaling.	('activation', 'PosReg', (67, 77))	('mTOR', 'Gene', '2475', (85, 89))	('mTOR', 'Gene', (85, 89))	('Cbl/Cbl-b', 'Gene', (0, 9))	('double knockout', 'Var', (10, 25))
350972	29384143	In the present study, lentiviral-mediated RNAi promoted the invasion and metastasis of A549 cells, and upregulated the expression of p-ERK and mTOR, which may agree with the conclusions reported by Chandrani et al.	('expression', 'MPA', (119, 129))	('metastasis of A549 cells', 'CPA', (73, 97))	('invasion', 'CPA', (60, 68))	('A549', 'CellLine', 'CVCL:0023', (87, 91))	('lentiviral-mediated RNAi', 'Var', (22, 46))	('promoted', 'PosReg', (47, 55))	('p-ERK', 'Gene', '9451', (133, 138))	('mTOR', 'Gene', '2475', (143, 147))	('p-ERK', 'Gene', (133, 138))	('mTOR', 'Gene', (143, 147))	('upregulated', 'PosReg', (103, 114))
350976	29384143	discovered that LMO4 overexpression promoted the migration of A549 cells and markedly upregulated the expression of p-PI3K and p-AKT; AKT inhibitor LY294002 could reverse the enhancement of migration of p-AKT and upregulation of p-PI3K expression induced by LMO4.	('LMO4', 'Gene', (16, 20))	('enhancement', 'PosReg', (175, 186))	('LY294002', 'Chemical', 'MESH:C085911', (148, 156))	('A549', 'CellLine', 'CVCL:0023', (62, 66))	('migration', 'CPA', (190, 199))	('expression', 'MPA', (102, 112))	('migration', 'CPA', (49, 58))	('LY294002', 'Var', (148, 156))	('LMO4', 'Gene', '8543', (258, 262))	('p-PI3K', 'Protein', (229, 235))	('p-AKT', 'Pathway', (203, 208))	('LMO4', 'Gene', (258, 262))	('upregulated', 'PosReg', (86, 97))	('upregulation', 'PosReg', (213, 225))	('LMO4', 'Gene', '8543', (16, 20))	('expression', 'MPA', (236, 246))	('promoted', 'PosReg', (36, 44))
350978	29384143	GSK3beta, as a tumor-suppressor gene in skin cancer and breast cancer, is involved in the transfer of cancer cells, and it can play an critical role in EMT by regulating Wnt and Snail pathways, and inhibition of GSK3beta can promote the development of EMT.	('skin cancer', 'Disease', 'MESH:D012878', (40, 51))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('breast cancer', 'Disease', 'MESH:D001943', (56, 69))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('breast cancer', 'Disease', (56, 69))	('GSK3beta', 'Gene', '2932', (212, 220))	('Snail', 'Gene', (178, 183))	('EMT', 'Gene', (152, 155))	('EMT', 'Gene', '3702', (152, 155))	('GSK3beta', 'Gene', (0, 8))	('cancer', 'Disease', (63, 69))	('inhibition', 'Var', (198, 208))	('skin cancer', 'Disease', (40, 51))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('cancer', 'Disease', (102, 108))	('tumor', 'Disease', (15, 20))	('GSK3beta', 'Gene', (212, 220))	('EMT', 'Gene', (252, 255))	('EMT', 'Gene', '3702', (252, 255))	('cancer', 'Disease', (45, 51))	('skin cancer', 'Phenotype', 'HP:0008069', (40, 51))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('Snail', 'Gene', '6615', (178, 183))	('regulating', 'Reg', (159, 169))	('breast cancer', 'Phenotype', 'HP:0003002', (56, 69))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('promote', 'PosReg', (225, 232))	('GSK3beta', 'Gene', '2932', (0, 8))
350979	29384143	GSK3beta, as an oncogene, is highly expressed in ovarian cancer, colorectal cancer, and pancreatic cancer, and inhibition of GSK3beta activity can inhibit cell proliferation and survival.	('colorectal cancer', 'Disease', (65, 82))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (88, 105))	('ovarian cancer', 'Disease', 'MESH:D010051', (49, 63))	('GSK3beta', 'Gene', '2932', (125, 133))	('inhibition', 'Var', (111, 121))	('GSK3beta', 'Gene', (0, 8))	('colorectal cancer', 'Phenotype', 'HP:0003003', (65, 82))	('inhibit', 'NegReg', (147, 154))	('pancreatic cancer', 'Disease', 'MESH:D010190', (88, 105))	('ovarian cancer', 'Disease', (49, 63))	('GSK3beta', 'Gene', (125, 133))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('ovarian cancer', 'Phenotype', 'HP:0100615', (49, 63))	('cell proliferation', 'CPA', (155, 173))	('pancreatic cancer', 'Disease', (88, 105))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('colorectal cancer', 'Disease', 'MESH:D015179', (65, 82))	('GSK3beta', 'Gene', '2932', (0, 8))
350990	26937435	Blood flow (BF) and blood volume (BV) decreased and Mean Transit Time (MTT) increased significantly (p < 0.05) at 66 Gy among responders to CRT as compared to non-responders.	('Blood flow', 'MPA', (0, 10))	('decreased', 'NegReg', (38, 47))	('CRT', 'Gene', (140, 143))	('increased', 'PosReg', (76, 85))	('Mean Transit Time', 'MPA', (52, 69))	('MTT', 'Chemical', '-', (71, 74))	('responders', 'Var', (126, 136))
350991	26937435	Patients with high BF (>106 ml/100 g/min) at baseline were five times more likely (p = 0.004) to respond to treatment as compared to those with low BF.	('Patients', 'Species', '9606', (0, 8))	('respond to treatment', 'MPA', (97, 117))	('>106 ml/100 g/min', 'Var', (23, 40))	('men', 'Species', '9606', (113, 116))
350992	26937435	Other perfusion parameters were not significantly predictive of outcome (p > 0.05) Combination of high BF (>106 ml/100 g/min) and low (<=47 ml/100 g/min) permeability surface (PS) was 100% predictive of response to CRT irrespective of the stage of tumor.	('tumor', 'Disease', (248, 253))	('>106 ml/100', 'Var', (107, 118))	('tumor', 'Disease', 'MESH:D009369', (248, 253))	('PS', 'Chemical', '-', (176, 178))	('tumor', 'Phenotype', 'HP:0002664', (248, 253))
350993	26937435	A combination of high BF and low PS was found to be 100% predictive of complete response irrespective of the stage of the tumor.	('PS', 'Chemical', '-', (33, 35))	('low PS', 'Var', (29, 35))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('high BF', 'Var', (17, 24))	('tumor', 'Disease', (122, 127))
351029	26937435	Prognostically, patients with high BF were five times more likely to respond to chemoradiation as compared to patients with low BF (Table 4) and the difference was statistically significant (p = 0.004).	('more', 'PosReg', (54, 58))	('high BF', 'Var', (30, 37))	('patients', 'Species', '9606', (16, 24))	('respond to chemoradiation', 'MPA', (69, 94))	('patients', 'Species', '9606', (110, 118))
351034	26937435	On bivariate analysis, patients with high blood flow were found to be five times more likely to respond as compared to the patients with low BF at baseline.	('respond', 'MPA', (96, 103))	('patients', 'Species', '9606', (23, 31))	('patients', 'Species', '9606', (123, 131))	('high blood flow', 'Var', (37, 52))
351041	26937435	Defective endothelium causes vascular hyperpermeability which results in raised intratumoral interstitial pressure.	('tumor', 'Disease', (85, 90))	('raised', 'PosReg', (73, 79))	('vascular hyperpermeability', 'Disease', (29, 55))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('Defective', 'Var', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('causes', 'Reg', (22, 28))
351062	26937435	divided perfusion parameters of a tumor into four different patterns of vascularization - high BF and high PS as matched vascularization, high BF and low PS as high interstitial pressure, low BF and high PS as mismatched vascularization and low BF and low PS as necrosis.	('high BF', 'Var', (138, 145))	('tumor', 'Disease', (34, 39))	('necrosis', 'Disease', (262, 270))	('low BF', 'Var', (188, 194))	('PS', 'Chemical', '-', (256, 258))	('PS', 'Chemical', '-', (154, 156))	('necrosis', 'Disease', 'MESH:D009336', (262, 270))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('PS', 'Chemical', '-', (107, 109))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('PS', 'Chemical', '-', (204, 206))
351087	26273408	The combined effect of gene mutations in the base excision repair (BER) pathway may cause a defect in the repair of DNA damage and, thus, contribute to lung carcinogenesis.	('lung carcinogenesis', 'Disease', 'MESH:D063646', (152, 171))	('gene mutations', 'Var', (23, 37))	('repair of DNA damage', 'MPA', (106, 126))	('lung carcinogenesis', 'Disease', (152, 171))	('N', 'Chemical', 'MESH:D009584', (117, 118))	('cause', 'Reg', (84, 89))	('defect', 'NegReg', (92, 98))	('BER', 'Gene', (67, 70))	('contribute to', 'Reg', (138, 151))
351088	26273408	The aberration of Janus kinase-signal transducer and activator of transcription (JAK-STAT) regulating cell growth, differentiation, and metabolism pathways also leads to carcinogenic potential in NSCLC cells.	('leads to', 'Reg', (161, 169))	('NSCLC', 'Disease', (196, 201))	('NSCLC', 'Disease', 'MESH:D002289', (196, 201))	('aberration', 'Var', (4, 14))	('NSCLC', 'Phenotype', 'HP:0030358', (196, 201))	('SCLC', 'Phenotype', 'HP:0030357', (197, 201))	('carcinogenic', 'Disease', 'MESH:D063646', (170, 182))	('carcinogenic', 'Disease', (170, 182))
351136	26273408	The involved mutant genes in the BER pathway may be associated with an increasing susceptibility to develop lung cancer.	('lung cancer', 'Disease', 'MESH:D008175', (108, 119))	('mutant genes', 'Var', (13, 25))	('BER pathway', 'Pathway', (33, 44))	('associated', 'Reg', (52, 62))	('lung cancer', 'Disease', (108, 119))	('lung cancer', 'Phenotype', 'HP:0100526', (108, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
351141	26273408	An aberrantly activated JAK-STAT3 signaling pathway is involved in the oncogenesis of NSCLC.	('STAT3', 'Gene', (28, 33))	('NSCLC', 'Disease', (86, 91))	('SCLC', 'Phenotype', 'HP:0030357', (87, 91))	('involved', 'Reg', (55, 63))	('NSCLC', 'Disease', 'MESH:D002289', (86, 91))	('STAT3', 'Gene', '6774', (28, 33))	('aberrantly', 'Var', (3, 13))	('NSCLC', 'Phenotype', 'HP:0030358', (86, 91))
351169	31113936	XPO1 inhibitor KPT-330 synergizes with Bcl-xL inhibitor to induce cancer cell apoptosis by perturbing rRNA processing and Mcl-1 protein synthesis XPO1 (exportin1) mediates nuclear export of proteins and RNAs and is frequently overexpressed in cancers.	('exportin1', 'Gene', '7514', (152, 161))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('XPO1', 'Gene', (0, 4))	('induce', 'PosReg', (59, 65))	('XPO1', 'Gene', '7514', (146, 150))	('KPT-330', 'Var', (15, 22))	('rRNA processing', 'MPA', (102, 117))	('cancer', 'Disease', 'MESH:D009369', (243, 249))	('cancers', 'Disease', 'MESH:D009369', (243, 250))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('Mcl-1', 'Gene', '4170', (122, 127))	('RNAs', 'MPA', (203, 207))	('Bcl-xL', 'Gene', (39, 45))	('perturbing', 'NegReg', (91, 101))	('XPO1', 'Gene', '7514', (0, 4))	('nuclear export of proteins', 'MPA', (172, 198))	('XPO1', 'Gene', (146, 150))	('Bcl-xL', 'Gene', '598', (39, 45))	('exportin1', 'Gene', (152, 161))	('Mcl-1', 'Gene', (122, 127))	('KPT-330', 'Chemical', 'MESH:C585161', (15, 22))	('cancers', 'Phenotype', 'HP:0002664', (243, 250))	('cancer', 'Disease', (243, 249))	('cancers', 'Disease', (243, 250))	('cancer', 'Phenotype', 'HP:0002664', (243, 249))	('cancer', 'Disease', (66, 72))
351175	31113936	Reconstitution of XPO1 by expressing degradation-resistant C528S mutant retained rRNA amount, Mcl-1 expression, and Bcl-xL inhibitor resistance upon KPT-330 treatment.	('KPT-330', 'Chemical', 'MESH:C585161', (149, 156))	('Bcl-xL', 'Gene', (116, 122))	('rRNA amount', 'MPA', (81, 92))	('Mcl-1', 'Gene', '4170', (94, 99))	('XPO1', 'Gene', (18, 22))	('XPO1', 'Gene', '7514', (18, 22))	('C528S', 'Mutation', 'p.C528S', (59, 64))	('C528S', 'Var', (59, 64))	('Mcl-1', 'Gene', (94, 99))	('Bcl-xL', 'Gene', '598', (116, 122))
351179	31113936	XPO1 is frequently amplified or mutated in several hematological and solid tumors.	('solid tumors', 'Disease', 'MESH:D009369', (69, 81))	('XPO1', 'Gene', '7514', (0, 4))	('mutated', 'Var', (32, 39))	('XPO1', 'Gene', (0, 4))	('solid tumors', 'Disease', (69, 81))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('hematological', 'Disease', (51, 64))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))
351181	31113936	SINE compounds degrade XPO1 protein by specific binding to its C528 residue in the cargo-binding groove.	('degrade', 'NegReg', (15, 22))	('XPO1', 'Gene', '7514', (23, 27))	('XPO1', 'Gene', (23, 27))	('binding', 'Interaction', (48, 55))	('SINE', 'Disease', (0, 4))	('C528', 'Var', (63, 67))	('SINE', 'Disease', 'None', (0, 4))
351188	31113936	However, the Bcl-xL-selective inhibitors A-1155463 and A-1331862 demonstrated tolerability and efficacy in preclinical solid tumor models.	('Bcl-xL', 'Gene', '598', (13, 19))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('solid tumor', 'Disease', (119, 130))	('Bcl-xL', 'Gene', (13, 19))	('A-1155463', 'Var', (41, 50))	('solid tumor', 'Disease', 'MESH:D009369', (119, 130))	('A-1331862', 'Var', (55, 64))	('A-1155463', 'Chemical', 'MESH:C000603579', (41, 50))
351191	31113936	Furthermore, it was demonstrated that SINE compounds including KPT-185, KPT-276, and KPT-330 downregulated Mcl-1 protein, but the underlying mechanism and function of Mcl-1 upon SINE treatment are unclear.	('KPT', 'Chemical', '-', (63, 66))	('KPT-185', 'Var', (63, 70))	('Mcl-1', 'Gene', '4170', (107, 112))	('Mcl-1', 'Gene', (107, 112))	('Mcl-1', 'Gene', (167, 172))	('KPT-276', 'Var', (72, 79))	('KPT', 'Chemical', '-', (72, 75))	('KPT-330', 'Chemical', 'MESH:C585161', (85, 92))	('SINE', 'Disease', (38, 42))	('downregulated', 'NegReg', (93, 106))	('SINE', 'Disease', (178, 182))	('KPT-330', 'Var', (85, 92))	('KPT', 'Chemical', '-', (85, 88))	('Mcl-1', 'Gene', '4170', (167, 172))	('SINE', 'Disease', 'None', (38, 42))	('SINE', 'Disease', 'None', (178, 182))
351201	31113936	Therefore, Mcl-1 downregulation by XPO1 inhibitor was insufficient to induce apoptosis in cancer cells but likely made cancer cells more susceptible to inhibitors targeting of Bcl-2 and/or Bcl-xL.	('insufficient', 'Disease', (54, 66))	('Bcl-2', 'Gene', (176, 181))	('Mcl-1', 'Gene', '4170', (11, 16))	('Bcl-2', 'Gene', '596', (176, 181))	('Bcl-xL', 'Gene', '598', (189, 195))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('cancer', 'Disease', (119, 125))	('downregulation', 'NegReg', (17, 31))	('Bcl-xL', 'Gene', (189, 195))	('Mcl-1', 'Gene', (11, 16))	('XPO1', 'Gene', '7514', (35, 39))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('XPO1', 'Gene', (35, 39))	('cancer', 'Disease', (90, 96))	('insufficient', 'Disease', 'MESH:D000309', (54, 66))	('inhibitor', 'Var', (40, 49))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
351205	31113936	In glioblastoma, NSCLC, and cervical cancer cells, KPT-330 plus A-1331852 had a strong synergistic effect on viability inhibition, as evaluated by their combination index (Figs.	('NSCLC', 'Disease', (17, 22))	('NSCLC', 'Disease', 'MESH:D002289', (17, 22))	('A-1331852', 'Chemical', 'MESH:C000603580', (64, 73))	('glioblastoma', 'Disease', (3, 15))	('glioblastoma', 'Disease', 'MESH:D005909', (3, 15))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('NSCLC', 'Phenotype', 'HP:0030358', (17, 22))	('KPT-330', 'Chemical', 'MESH:C585161', (51, 58))	('cervical cancer', 'Disease', 'MESH:D002583', (28, 43))	('glioblastoma', 'Phenotype', 'HP:0012174', (3, 15))	('A-1331852', 'Var', (64, 73))	('viability inhibition', 'CPA', (109, 129))	('cervical cancer', 'Disease', (28, 43))
351207	31113936	Although KPT-330 treatment counteracted the effect of Mcl-1 overexpression, a slight increase of Mcl-1 level partially reversed KPT-330/A-1331852-triggered apoptosis in U251 and H1299 cells (Fig.	('Mcl-1', 'Gene', (54, 59))	('KPT-330', 'Chemical', 'MESH:C585161', (9, 16))	('KPT-330', 'Chemical', 'MESH:C585161', (128, 135))	('A-1331852', 'Chemical', 'MESH:C000603580', (136, 145))	('Mcl-1', 'Gene', '4170', (97, 102))	('Mcl-1', 'Gene', '4170', (54, 59))	('H1299', 'CellLine', 'CVCL:0060', (178, 183))	('Mcl-1', 'Gene', (97, 102))	('KPT-330/A-1331852-triggered', 'Var', (128, 155))	('apoptosis', 'CPA', (156, 165))
351210	31113936	A-1331852 prevented Bax and Bim from Bcl-xL binding.	('Bax', 'Gene', '581', (20, 23))	('prevented', 'NegReg', (10, 19))	('A-1331852', 'Chemical', 'MESH:C000603580', (0, 9))	('A-1331852', 'Var', (0, 9))	('Bim', 'Gene', (28, 31))	('Bax', 'Gene', (20, 23))	('Bim', 'Gene', '10018', (28, 31))	('binding', 'Interaction', (44, 51))	('Bcl-xL', 'Gene', '598', (37, 43))	('Bcl-xL', 'Gene', (37, 43))
351213	31113936	Simultaneous knockdown of Bax and Bak reversed KPT-330/A-1331852-triggered apoptosis and MOMP in U251 cells (Fig.	('KPT-330/A-1331852-triggered', 'Var', (47, 74))	('Bax', 'Gene', (26, 29))	('apoptosis', 'CPA', (75, 84))	('KPT-330', 'Chemical', 'MESH:C585161', (47, 54))	('Bak', 'Gene', (34, 37))	('Bax', 'Gene', '581', (26, 29))	('A-1331852', 'Chemical', 'MESH:C000603580', (55, 64))	('Bak', 'Gene', '578', (34, 37))
351214	31113936	Noxa knockdown slightly reduced KPT-330/A-1331852-triggered apoptosis while Bim knockdown upregulated Noxa (at least in U251 cells) and increased such apoptosis (Fig.	('knockdown', 'Var', (80, 89))	('Bim', 'Gene', '10018', (76, 79))	('A-1331852', 'Chemical', 'MESH:C000603580', (40, 49))	('reduced', 'NegReg', (24, 31))	('Noxa', 'Gene', '5366', (102, 106))	('KPT-330', 'Chemical', 'MESH:C585161', (32, 39))	('upregulated', 'PosReg', (90, 101))	('Noxa', 'Gene', '5366', (0, 4))	('Noxa', 'Gene', (102, 106))	('apoptosis', 'CPA', (60, 69))	('Bim', 'Gene', (76, 79))	('Noxa', 'Gene', (0, 4))	('increased', 'PosReg', (136, 145))	('KPT-330/A-1331852-triggered', 'Var', (32, 59))
351225	31113936	Unexpectedly, the OPP incorporation assay demonstrated a reduced nascent synthesized protein content upon KPT-330 treatment (Fig.	('KPT-330', 'Gene', (106, 113))	('OPP', 'Chemical', 'MESH:C570448', (18, 21))	('nascent synthesized protein content', 'MPA', (65, 100))	('KPT-330', 'Chemical', 'MESH:C585161', (106, 113))	('reduced', 'NegReg', (57, 64))	('treatment', 'Var', (114, 123))
351232	31113936	Consistently, KPT-330 inactivated mTOR and Mnk1 signaling as revealed by downregulation of total mTOR and Mnk1 and phosphorylation of mTOR, p70S6K, 4E-BP1, Mnk1, and eIF4E (Fig.	('KPT-330', 'Chemical', 'MESH:C585161', (14, 21))	('Mnk1', 'Gene', '8569', (43, 47))	('Mnk1', 'Gene', '8569', (106, 110))	('p70S6K', 'Gene', '6198', (140, 146))	('mTOR', 'Gene', (34, 38))	('mTOR', 'Gene', (97, 101))	('4E-BP1', 'Gene', '1978', (148, 154))	('mTOR', 'Gene', '2475', (34, 38))	('Mnk1', 'Gene', (156, 160))	('KPT-330', 'Var', (14, 21))	('mTOR', 'Gene', '2475', (97, 101))	('eIF4E', 'Gene', (166, 171))	('p70S6K', 'Gene', (140, 146))	('eIF4E', 'Gene', '1977', (166, 171))	('mTOR', 'Gene', (134, 138))	('inactivated', 'NegReg', (22, 33))	('Mnk1', 'Gene', '8569', (156, 160))	('Mnk1', 'Gene', (43, 47))	('4E-BP1', 'Gene', (148, 154))	('Mnk1', 'Gene', (106, 110))	('phosphorylation', 'MPA', (115, 130))	('downregulation', 'NegReg', (73, 87))	('mTOR', 'Gene', '2475', (134, 138))
351243	31113936	To further clarify whether KPT-330 disrupts nucleolar rRNA synthesis or processing, the nucleoli of U87, U251, and H1299 cells treated with KPT-330 or Act D were purified and the nucleolar RNAs were extracted.	('H1299', 'CellLine', 'CVCL:0060', (115, 120))	('KPT-330', 'Gene', (140, 147))	('disrupts', 'NegReg', (35, 43))	('nucleolar rRNA synthesis', 'MPA', (44, 68))	('KPT-330', 'Chemical', 'MESH:C585161', (140, 147))	('KPT-330', 'Chemical', 'MESH:C585161', (27, 34))	('processing', 'MPA', (72, 82))	('KPT-330', 'Var', (27, 34))
351246	31113936	Expressing a degradation-resistant form of XPO1 (C528S) partially reversed KPT-330-induced defects of rRNA processing (Fig.	('C528S', 'Mutation', 'p.C528S', (49, 54))	('C528S', 'Var', (49, 54))	('XPO1', 'Gene', '7514', (43, 47))	('XPO1', 'Gene', (43, 47))	('KPT-330-induced', 'Gene', (75, 90))	('KPT-330', 'Chemical', 'MESH:C585161', (75, 82))	('rRNA processing', 'MPA', (102, 117))
351250	31113936	To verify that XPO1 degradation upon KPT-330 contributes to Mcl-1 reduction and cancer cell apoptosis following KPT-330 and A-1331852 treatment, we reconstituted XPO1 expression by overexpressing wild-type XPO1, degradation-resistant mutant C528S, or recurrent hotspot mutant E571K or R749Q in U251 and H1299 cells.	('H1299', 'CellLine', 'CVCL:0060', (303, 308))	('KPT-330', 'Chemical', 'MESH:C585161', (37, 44))	('XPO1', 'Gene', (206, 210))	('XPO1', 'Gene', '7514', (162, 166))	('XPO1', 'Gene', (15, 19))	('cancer', 'Disease', (80, 86))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('Mcl-1', 'Gene', '4170', (60, 65))	('C528S', 'Mutation', 'p.C528S', (241, 246))	('A-1331852', 'Chemical', 'MESH:C000603580', (124, 133))	('reduction', 'NegReg', (66, 75))	('R749Q', 'Var', (285, 290))	('XPO1', 'Gene', '7514', (206, 210))	('KPT-330', 'Chemical', 'MESH:C585161', (112, 119))	('XPO1', 'Gene', (162, 166))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('XPO1', 'Gene', '7514', (15, 19))	('E571K', 'Mutation', 'rs1057520009', (276, 281))	('Mcl-1', 'Gene', (60, 65))	('R749Q', 'Mutation', 'p.R749Q', (285, 290))	('E571K', 'Var', (276, 281))
351251	31113936	C528S mutant restored protein levels of XPO1 and Mcl-1 in cells treated with medium (1 muM) or high dose (10 muM) of KPT-330, while wild-type, E571K, and R749Q variants had weak effects (Fig.	('restored', 'PosReg', (13, 21))	('muM', 'Gene', (109, 112))	('muM', 'Gene', '56925', (87, 90))	('Mcl-1', 'Gene', '4170', (49, 54))	('KPT-330', 'Gene', (117, 124))	('C528S', 'Mutation', 'p.C528S', (0, 5))	('R749Q', 'Var', (154, 159))	('E571K', 'Var', (143, 148))	('muM', 'Gene', (87, 90))	('E571K', 'Mutation', 'rs1057520009', (143, 148))	('R749Q', 'Mutation', 'p.R749Q', (154, 159))	('C528S', 'Var', (0, 5))	('Mcl-1', 'Gene', (49, 54))	('muM', 'Gene', '56925', (109, 112))	('XPO1', 'Gene', '7514', (40, 44))	('XPO1', 'Gene', (40, 44))	('KPT-330', 'Chemical', 'MESH:C585161', (117, 124))
351252	31113936	C528S mutant also restored rRNA and Mcl-1 mRNA in KPT-330-treated U251 cells (Fig.	('Mcl-1', 'Gene', (36, 41))	('KPT-330', 'Chemical', 'MESH:C585161', (50, 57))	('restored', 'PosReg', (18, 26))	('C528S', 'Mutation', 'p.C528S', (0, 5))	('C528S', 'Var', (0, 5))	('Mcl-1', 'Gene', '4170', (36, 41))
351253	31113936	Accordingly, U251 and H1299 cells expressing C528S mutant but not cells expressing other XPO1 variants were resistant to KPT-330/A-13331852-induced viability reduction and apoptosis (Fig.	('KPT-330', 'Chemical', 'MESH:C585161', (121, 128))	('C528S', 'Var', (45, 50))	('XPO1', 'Gene', '7514', (89, 93))	('H1299', 'CellLine', 'CVCL:0060', (22, 27))	('XPO1', 'Gene', (89, 93))	('apoptosis', 'CPA', (172, 181))	('viability reduction', 'Disease', (148, 167))	('C528S', 'Mutation', 'p.C528S', (45, 50))	('viability reduction', 'Disease', 'MESH:D015431', (148, 167))
351254	31113936	However, C528S mutant failed to rescue KPT-330/A-13331852-induced apoptosis in Mcl-1-deficient U251 cells (Fig.	('Mcl-1', 'Gene', '4170', (79, 84))	('C528S', 'Mutation', 'p.C528S', (9, 14))	('C528S', 'Var', (9, 14))	('KPT-330', 'Chemical', 'MESH:C585161', (39, 46))	('Mcl-1', 'Gene', (79, 84))	('KPT-330/A-13331852-induced', 'Var', (39, 65))
351255	31113936	Unexpectedly, C528S augmented apoptosis in A-1331852-treated Mcl-1-deficient cells (Fig.	('A-1331852', 'Chemical', 'MESH:C000603580', (43, 52))	('augmented', 'PosReg', (20, 29))	('Mcl-1', 'Gene', (61, 66))	('apoptosis', 'CPA', (30, 39))	('C528S', 'Mutation', 'p.C528S', (14, 19))	('Mcl-1', 'Gene', '4170', (61, 66))	('C528S', 'Var', (14, 19))
351256	31113936	Bim was not involved in this effect since C528S did not enhanced Bim expression and Bim knockdown failed to abolish elevated apoptosis (Supplementary Fig.	('Bim', 'Gene', (84, 87))	('Bim', 'Gene', '10018', (84, 87))	('Bim', 'Gene', (0, 3))	('knockdown', 'Var', (88, 97))	('Bim', 'Gene', (65, 68))	('Bim', 'Gene', '10018', (0, 3))	('Bim', 'Gene', '10018', (65, 68))	('C528S', 'Mutation', 'p.C528S', (42, 47))	('C528S', 'Var', (42, 47))
351258	31113936	Finally, to evaluate the anticancer activity of KPT-330/A-1331852 combination in vivo, we inoculated NOD-SCID mice with H1299 cells and treated them with KPT-330 (10 mg/kg, p.o., Monday, Wednesday, and Friday) and/or A-1331852 (25 mg/kg, p.o., every day) or vehicle for 10 days when tumor volume reached ~50 mm3.	('KPT-330', 'Chemical', 'MESH:C585161', (48, 55))	('cancer', 'Disease', (29, 35))	('tumor', 'Disease', 'MESH:D009369', (283, 288))	('tumor', 'Phenotype', 'HP:0002664', (283, 288))	('mice', 'Species', '10090', (110, 114))	('KPT-330', 'Chemical', 'MESH:C585161', (154, 161))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('A-1331852', 'Chemical', 'MESH:C000603580', (217, 226))	('A-1331852', 'Chemical', 'MESH:C000603580', (56, 65))	('tumor', 'Disease', (283, 288))	('KPT-330', 'Var', (154, 161))	('H1299', 'CellLine', 'CVCL:0060', (120, 125))	('cancer', 'Disease', 'MESH:D009369', (29, 35))
351259	31113936	Exposure to KPT-330 or A-1331852 alone resulted in inhibition of tumor growth throughout the treatment and lower tumor weight in the end, while cotreatment with two drugs further suppressed tumor growth (Fig.	('tumor', 'Disease', (113, 118))	('inhibition', 'NegReg', (51, 61))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('tumor', 'Disease', (65, 70))	('KPT-330', 'Chemical', 'MESH:C585161', (12, 19))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('lower', 'NegReg', (107, 112))	('A-1331852', 'Var', (23, 32))	('tumor', 'Disease', (190, 195))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('KPT-330', 'Gene', (12, 19))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('A-1331852', 'Chemical', 'MESH:C000603580', (23, 32))
351262	31113936	Despite not downregulating XPO1 level post treatment, KPT-330 generally maintained lower Mcl-1 level and, when combined with A-1331852, induced apoptosis in terms of caspase-3 cleavage (Fig.	('caspase-3', 'Gene', (166, 175))	('lower Mcl', 'Phenotype', 'HP:0025066', (83, 92))	('Mcl-1', 'Gene', (89, 94))	('induced', 'Reg', (136, 143))	('KPT-330', 'Chemical', 'MESH:C585161', (54, 61))	('XPO1', 'Gene', '7514', (27, 31))	('XPO1', 'Gene', (27, 31))	('lower', 'NegReg', (83, 88))	('KPT-330', 'Var', (54, 61))	('caspase-3', 'Gene', '836', (166, 175))	('A-1331852', 'Chemical', 'MESH:C000603580', (125, 134))	('Mcl-1', 'Gene', '4170', (89, 94))
351263	31113936	These results suggest that KPT-330/A-1331852 exerts anticancer effect in NSCLC xenografts and is tolerant in mice.	('KPT-330/A-1331852', 'Var', (27, 44))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('NSCLC', 'Disease', (73, 78))	('A-1331852', 'Chemical', 'MESH:C000603580', (35, 44))	('KPT-330', 'Chemical', 'MESH:C585161', (27, 34))	('mice', 'Species', '10090', (109, 113))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('NSCLC', 'Phenotype', 'HP:0030358', (73, 78))	('NSCLC', 'Disease', 'MESH:D002289', (73, 78))
351271	31113936	Simultaneous inhibition of another apoptosis gatekeeper Bcl-xL using A-1331852 minimizes the sequestration of Bax and Bak and potently triggers MOMP and apoptosis.	('triggers', 'Reg', (135, 143))	('Bak', 'Gene', (118, 121))	('Bak', 'Gene', '578', (118, 121))	('A-1331852', 'Var', (69, 78))	('Bcl-xL', 'Gene', '598', (56, 62))	('MOMP', 'CPA', (144, 148))	('Bax', 'Gene', '581', (110, 113))	('A-1331852', 'Chemical', 'MESH:C000603580', (69, 78))	('Bcl-xL', 'Gene', (56, 62))	('inhibition', 'NegReg', (13, 23))	('Bax', 'Gene', (110, 113))	('apoptosis', 'CPA', (153, 162))	('gatekeeper', 'Species', '111938', (45, 55))	('minimizes', 'NegReg', (79, 88))
351272	31113936	Synergistic effect of KPT-330/A-1331852 cotreatment is strong in cancer cells relatively more resistant to KPT-330 (U87, U118, U251, A549, and HeLa) and is moderate in KPT-330-sensitive cells (A172 and H1299) (Fig.	('H1299', 'CellLine', 'CVCL:0060', (202, 207))	('KPT-330', 'Chemical', 'MESH:C585161', (107, 114))	('KPT-330', 'Var', (107, 114))	('A-1331852', 'Chemical', 'MESH:C000603580', (30, 39))	('KPT-330', 'Chemical', 'MESH:C585161', (22, 29))	('resistant', 'NegReg', (94, 103))	('HeLa', 'CellLine', 'CVCL:0030', (143, 147))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('more', 'PosReg', (89, 93))	('KPT-330', 'Chemical', 'MESH:C585161', (168, 175))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('A549', 'CellLine', 'CVCL:0023', (133, 137))
351273	31113936	Reconstituting XPO1 in cells by expressing the KPT-330-unbound C528S mutant restores the expression of rRNA and Mcl-1 and resistance to cotreatment of KPT-330 and A-1331852, while cells expressing recurrent hotspot mutant E571K and R749Q are as vulnerable to the cotreatment as those with wild-type XPO1 (Fig.	('Mcl-1', 'Gene', (112, 117))	('E571K', 'Var', (222, 227))	('R749Q', 'Var', (232, 237))	('rRNA', 'MPA', (103, 107))	('C528S', 'Var', (63, 68))	('XPO1', 'Gene', (15, 19))	('restores', 'PosReg', (76, 84))	('expression', 'MPA', (89, 99))	('R749Q', 'Mutation', 'p.R749Q', (232, 237))	('XPO1', 'Gene', (299, 303))	('resistance', 'MPA', (122, 132))	('A-1331852', 'Chemical', 'MESH:C000603580', (163, 172))	('C528S', 'Mutation', 'p.C528S', (63, 68))	('Mcl-1', 'Gene', '4170', (112, 117))	('KPT-330', 'Chemical', 'MESH:C585161', (151, 158))	('XPO1', 'Gene', '7514', (15, 19))	('KPT-330-unbound', 'Gene', (47, 62))	('E571K', 'Mutation', 'rs1057520009', (222, 227))	('XPO1', 'Gene', '7514', (299, 303))	('KPT-330', 'Chemical', 'MESH:C585161', (47, 54))
351276	31113936	Coincide with the previous report that XPO1 inactivation dampened mTOR signaling, we showed that KPT-330 inhibited mTORC1/4E-BP1 axis and Mnk1/eIF4E axis to diminish cap-dependent translation initiation activity, but dephosphorylation of 4E-BP1 and eIF4E lagged behind and was dispensable for Mcl-1 downregulation.	('mTORC1', 'Gene', (115, 121))	('dampened', 'NegReg', (57, 65))	('eIF4E', 'Gene', (249, 254))	('mTOR', 'Gene', (115, 119))	('Mcl-1', 'Gene', '4170', (293, 298))	('mTORC1', 'Gene', '382056', (115, 121))	('inactivation', 'Var', (44, 56))	('XPO1', 'Gene', (39, 43))	('mTOR', 'Gene', (66, 70))	('eIF4E', 'Gene', '1977', (249, 254))	('mTOR', 'Gene', '2475', (115, 119))	('4E-BP1', 'Gene', (238, 244))	('cap', 'Chemical', '-', (166, 169))	('Mcl-1', 'Gene', (293, 298))	('4E-BP1', 'Gene', '1978', (122, 128))	('KPT-330', 'Chemical', 'MESH:C585161', (97, 104))	('mTOR', 'Gene', '2475', (66, 70))	('inhibited', 'NegReg', (105, 114))	('cap-dependent translation initiation activity', 'MPA', (166, 211))	('Mnk1', 'Gene', (138, 142))	('eIF4E', 'Gene', (143, 148))	('XPO1', 'Gene', '7514', (39, 43))	('eIF4E', 'Gene', '1977', (143, 148))	('4E-BP1', 'Gene', (122, 128))	('KPT-330', 'Gene', (97, 104))	('Mnk1', 'Gene', '8569', (138, 142))	('diminish', 'NegReg', (157, 165))	('4E-BP1', 'Gene', '1978', (238, 244))
351279	31113936	An iTRAQ analysis showed that SINE compound KPT-185 downregulated a series of ribosome proteins by ~10-27%, while a recent study demonstrated that KPT-330 crippled nuclear export of 5S and 18S rRNA, ribosome assembly, and protein synthesis in glioblastoma cells.	('glioblastoma', 'Disease', (243, 255))	('glioblastoma', 'Disease', 'MESH:D005909', (243, 255))	('protein synthesis', 'CPA', (222, 239))	('glioblastoma', 'Phenotype', 'HP:0012174', (243, 255))	('downregulated', 'NegReg', (52, 65))	('KPT-185', 'Var', (44, 51))	('KPT', 'Chemical', '-', (44, 47))	('KPT-330', 'Chemical', 'MESH:C585161', (147, 154))	('SINE', 'Disease', (30, 34))	('SINE', 'Disease', 'None', (30, 34))	('KPT-330', 'Var', (147, 154))	('ribosome assembly', 'MPA', (199, 216))	('KPT', 'Chemical', '-', (147, 150))	('crippled', 'NegReg', (155, 163))
351281	31113936	Consist with a previous study revealing that XPO1 inhibition using LMB disrupts rRNA synthesis and processing, we found KPT-330 caused decreased pre-rRNAs while increased 28S levels in the nucleolus of U87 and H1299 cells, which further reduced total expression of mature rRNAs in glioblastoma cells.	('processing', 'MPA', (99, 109))	('KPT-330', 'Var', (120, 127))	('mature rRNAs', 'MPA', (265, 277))	('disrupts', 'NegReg', (71, 79))	('inhibition', 'Var', (50, 60))	('glioblastoma', 'Disease', 'MESH:D005909', (281, 293))	('XPO1', 'Gene', (45, 49))	('decreased', 'NegReg', (135, 144))	('increased', 'PosReg', (161, 170))	('28S levels', 'MPA', (171, 181))	('reduced', 'NegReg', (237, 244))	('rRNA synthesis', 'MPA', (80, 94))	('glioblastoma', 'Disease', (281, 293))	('KPT-330', 'Chemical', 'MESH:C585161', (120, 127))	('glioblastoma', 'Phenotype', 'HP:0012174', (281, 293))	('H1299', 'CellLine', 'CVCL:0060', (210, 215))	('expression', 'MPA', (251, 261))	('XPO1', 'Gene', '7514', (45, 49))	('LMB', 'Chemical', 'MESH:C038753', (67, 70))	('pre-rRNAs', 'MPA', (145, 154))
351282	31113936	Despite enhanced 28S levels in the nucleolar, KPT-330 resulted in reduced nuclear 28S of glioblastoma cells, suggesting that KPT-330 suppressed nucleolar/nuclear export.	('reduced', 'NegReg', (66, 73))	('KPT-330', 'Chemical', 'MESH:C585161', (125, 132))	('suppressed', 'NegReg', (133, 143))	('nuclear 28S', 'MPA', (74, 85))	('glioblastoma', 'Disease', (89, 101))	('KPT-330', 'Chemical', 'MESH:C585161', (46, 53))	('KPT-330', 'Var', (125, 132))	('KPT-330', 'Var', (46, 53))	('enhanced', 'PosReg', (8, 16))	('nucleolar/nuclear export', 'MPA', (144, 168))	('glioblastoma', 'Disease', 'MESH:D005909', (89, 101))	('glioblastoma', 'Phenotype', 'HP:0012174', (89, 101))
351283	31113936	Furthermore, KPT-330-mitigated RNA synthesis ability may reflect the fact but more likely reflects the difficulty of rRNA processing as 45S pre-rRNA is unstable if not processed and reduction of mature rRNAs impairs nascent RNA accumulation.	('KPT-330-mitigated', 'Var', (13, 30))	('impairs', 'NegReg', (208, 215))	('nascent RNA accumulation', 'MPA', (216, 240))	('KPT-330', 'Chemical', 'MESH:C585161', (13, 20))	('RNA synthesis', 'MPA', (31, 44))	('reduction', 'NegReg', (182, 191))
351289	31113936	Lung cancer samples with XPO1 alteration tend to express higher level of NMD3 (Supplementary Fig.	('cancer', 'Disease', 'MESH:D009369', (5, 11))	('alteration', 'Var', (30, 40))	('higher', 'PosReg', (57, 63))	('NMD3', 'Gene', '51068', (73, 77))	('cancer', 'Disease', (5, 11))	('XPO1', 'Gene', '7514', (25, 29))	('Lung cancer', 'Phenotype', 'HP:0100526', (0, 11))	('XPO1', 'Gene', (25, 29))	('NMD3', 'Gene', (73, 77))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))
351293	31113936	Although mTORC1 controls ribosome biogenesis, including rRNA transcription and processing, it is not the case here given that protein synthesis was attenuated 1 h after KPT-330 treatment and mTORC1 substrate 4E-BP1 was dephosphorylated 24 h after treatment (Fig.	('treatment', 'Var', (177, 186))	('mTORC1', 'Gene', (9, 15))	('mTORC1', 'Gene', (191, 197))	('KPT-330', 'Chemical', 'MESH:C585161', (169, 176))	('4E-BP1', 'Gene', (208, 214))	('rRNA transcription', 'MPA', (56, 74))	('KPT-330', 'Gene', (169, 176))	('processing', 'MPA', (79, 89))	('attenuated', 'NegReg', (148, 158))	('mTORC1', 'Gene', '382056', (9, 15))	('mTORC1', 'Gene', '382056', (191, 197))	('protein synthesis', 'MPA', (126, 143))	('4E-BP1', 'Gene', '1978', (208, 214))	('controls', 'Reg', (16, 24))	('ribosome biogenesis', 'MPA', (25, 44))
351305	31113936	Moreover, A-1331852 proves effective against solid tumors alone or in combination with other drugs in preclinical animal models and less toxic than Bcl-2 inhibitor or Bcl-2/Bcl-xL inhibitor to granulocytes like neutrophils.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('Bcl-2', 'Gene', (148, 153))	('Bcl-2', 'Gene', '596', (148, 153))	('solid tumors', 'Disease', (45, 57))	('A-1331852', 'Chemical', 'MESH:C000603580', (10, 19))	('Bcl-xL', 'Gene', '598', (173, 179))	('Bcl-2', 'Gene', (167, 172))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('Bcl-2', 'Gene', '596', (167, 172))	('solid tumors', 'Disease', 'MESH:D009369', (45, 57))	('Bcl-xL', 'Gene', (173, 179))	('A-1331852', 'Var', (10, 19))
351308	31113936	Based on this mechanism, we develop a potential therapeutic strategy combining KPT-330 and A-1331852 against solid tumors.	('solid tumors', 'Disease', (109, 121))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('A-1331852', 'Chemical', 'MESH:C000603580', (91, 100))	('solid tumors', 'Disease', 'MESH:D009369', (109, 121))	('KPT-330', 'Gene', (79, 86))	('A-1331852', 'Var', (91, 100))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('KPT-330', 'Chemical', 'MESH:C585161', (79, 86))
351309	31113936	Such treatment is effective regardless the clinical relevant mutation status (E571K and R749Q) of XPO1.	('XPO1', 'Gene', '7514', (98, 102))	('E571K', 'Mutation', 'rs1057520009', (78, 83))	('XPO1', 'Gene', (98, 102))	('E571K', 'Var', (78, 83))	('R749Q', 'Mutation', 'p.R749Q', (88, 93))	('R749Q', 'Var', (88, 93))
351312	31113936	U87, U251, and H1299 were purchased in April 7, 2017 (purchase order, 85676), U118 and A172 were purchased in July 13, 2018 (purchase order, 115354), and HeLa was purchased in August 14, 2018 (purchase order, 117111) from cell bank of Chinese Academy of Sciences (Shanghai, China), where they were authenticated by means of STR profiling.	('H1299', 'Var', (15, 20))	('HeLa', 'CellLine', 'CVCL:0030', (154, 158))	('U251', 'Var', (5, 9))	('H1299', 'CellLine', 'CVCL:0060', (15, 20))
351315	31113936	Primary antibodies used in this study are listed as follows: antibodies against alpha-tubulin (HRP-conjugated) (HRP-66031) (ProteinTech Group, Wuhan, China), 4E-BP1 (9644), Bcl-xL (2764), Bak (12105) (for total Bak immunoprecipitation), Bax (5023) (for total Bax immunoprecipitation), Bim (2933), caspase-3 (9662), eIF4E (2067), eIF4G (2469), ERK (4695), GbetaL (3274), Mcl-1 (5453), MeCP2 (3456), Mnk1 (2195), mTOR (2983), Noxa (14766), p38 (8690), p-4E-BP1 (T37/46) (2855), p70S6K (2708), PARP (9532), p-Akt (S473) (4060), p-eIF4E (S209) (9741), p-ERK (T202/Y204) (4370), p-Mnk (T197/202) (2111), p-mTOR (S2448) (2972), p-p38 (T180/Y182) (4511), p-p70S6K (T389) (T389), Raptor (2280) (Cell Signaling Technology, Beverly, USA), Bax (6A7) (for active Bax immunoprecipitation) (556467) (BD Biosciences, San Jose, USA), Bak, NT (for active Bak immunoprecipitation) (06-536) (Merck Millipore, Darmstadt, Germany), LRPPRC (BS70542), XPO1 (BS70045) (Bioworld Technology, Nanjing, China), and GAPDH (KC-5G5) (Kangchen, Shanghai, China).	('p38', 'Gene', '1432', (438, 441))	('MeCP2', 'Gene', '4204', (384, 389))	('Bak', 'Gene', '578', (211, 214))	('eIF4E', 'Gene', (527, 532))	('p-ERK', 'Gene', (548, 553))	('Mcl-1', 'Gene', '4170', (370, 375))	('eIF4E', 'Gene', '1977', (527, 532))	('Bax', 'Gene', (237, 240))	('ERK', 'Gene', (343, 346))	('GAPDH', 'Gene', (987, 992))	('4E-BP1', 'Gene', (158, 164))	('Bax', 'Gene', (729, 732))	('Noxa', 'Gene', '5366', (424, 428))	('Bax', 'Gene', '581', (729, 732))	('GbetaL', 'Gene', (355, 361))	('mTOR', 'Gene', (411, 415))	('556467', 'Var', (777, 783))	('Bcl-xL', 'Gene', (173, 179))	('p70S6K', 'Gene', '6198', (650, 656))	('Bax', 'Gene', (259, 262))	('PARP', 'Gene', '1302', (491, 495))	('Bcl-xL', 'Gene', '598', (173, 179))	('Bak', 'Gene', '578', (188, 191))	('Bax', 'Gene', '581', (259, 262))	('LRPPRC', 'Gene', (911, 917))	('mTOR', 'Gene', '2475', (411, 415))	('ERK', 'Gene', '5594', (343, 346))	('eIF4E', 'Gene', '1977', (315, 320))	('p70S6K', 'Gene', (650, 656))	('Bak', 'Gene', '578', (838, 841))	('p70S6K', 'Gene', (476, 482))	('p38', 'Gene', '1432', (624, 627))	('MeCP2', 'Gene', (384, 389))	('Mnk1', 'Gene', '8569', (398, 402))	('Bak', 'Gene', (188, 191))	('Mnk', 'Gene', (398, 401))	('Akt', 'Gene', '207', (506, 509))	('Mcl-1', 'Gene', (370, 375))	('Bax', 'Gene', '581', (237, 240))	('p38', 'Gene', (438, 441))	('Bak', 'Gene', (838, 841))	('caspase-3', 'Gene', (297, 306))	('Mnk', 'Gene', '538', (398, 401))	('Bim', 'Gene', '10018', (285, 288))	('XPO1', 'Gene', (929, 933))	('4E-BP1', 'Gene', '1978', (158, 164))	('PARP', 'Gene', (491, 495))	('p-ERK', 'Gene', '9451', (548, 553))	('LRPPRC', 'Gene', '10128', (911, 917))	('4E-BP1', 'Gene', (452, 458))	('XPO1', 'Gene', '7514', (929, 933))	('mTOR', 'Gene', (601, 605))	('caspase-3', 'Gene', '836', (297, 306))	('Noxa', 'Gene', (424, 428))	('eIF4G', 'Gene', '1981', (329, 334))	('Bax', 'Gene', (751, 754))	('mTOR', 'Gene', '2475', (601, 605))	('Bax', 'Gene', '581', (751, 754))	('Bak', 'Gene', (818, 821))	('Raptor', 'Gene', (672, 678))	('GbetaL', 'Gene', '64223', (355, 361))	('Bim', 'Gene', (285, 288))	('GAPDH', 'Gene', '2597', (987, 992))	('Mnk1', 'Gene', (398, 402))	('Mnk', 'Gene', (576, 579))	('ERK', 'Gene', (550, 553))	('Akt', 'Gene', (506, 509))	('alpha-tubulin', 'Gene', (80, 93))	('eIF4G', 'Gene', (329, 334))	('Raptor', 'Gene', '57521', (672, 678))	('Bak', 'Gene', (211, 214))	('Bak', 'Gene', '578', (818, 821))	('Mnk', 'Gene', '538', (576, 579))	('p70S6K', 'Gene', '6198', (476, 482))	('alpha-tubulin', 'Gene', '10376', (80, 93))	('eIF4E', 'Gene', (315, 320))	('ERK', 'Gene', '5594', (550, 553))	('p38', 'Gene', (624, 627))	('4E-BP1', 'Gene', '1978', (452, 458))
351319	31113936	Coding DNA of human non-degradable Mcl-1 (T92A) mutant was inserted into pLOV-EF1a-eGFP, and coding DNAs of human eIF4E, XPO1 and XPO1 mutants C528S, E571K and R749Q were inserted into pCDH-CMV-MCS-EF1-copGFP.	('EF1a', 'Gene', '1917', (78, 82))	('T92A', 'Gene', (42, 46))	('E571K', 'Var', (150, 155))	('Mcl-1', 'Gene', (35, 40))	('XPO1', 'Gene', '7514', (130, 134))	('eIF4E', 'Gene', (114, 119))	('XPO1', 'Gene', '7514', (121, 125))	('eIF4E', 'Gene', '1977', (114, 119))	('R749Q', 'Var', (160, 165))	('C528S', 'Var', (143, 148))	('human', 'Species', '9606', (14, 19))	('Mcl-1', 'Gene', '4170', (35, 40))	('R749Q', 'Mutation', 'p.R749Q', (160, 165))	('T92A', 'Mutation', 'c.92T>A', (42, 46))	('XPO1', 'Gene', (130, 134))	('E571K', 'Mutation', 'rs1057520009', (150, 155))	('EF1a', 'Gene', (78, 82))	('human', 'Species', '9606', (108, 113))	('XPO1', 'Gene', (121, 125))	('C528S', 'Mutation', 'p.C528S', (143, 148))
351338	31113936	When average tumor volume reached ~50 mm3, mice were randomized into four groups (n = 5 per arm) and treated with KPT-330 (10 mg/kg, Monday, Wednesday, and Friday of every week) and/or A-1331852 (25 mg/kg, daily) by oral gavage.	('mice', 'Species', '10090', (43, 47))	('tumor', 'Disease', (13, 18))	('KPT-330', 'Chemical', 'MESH:C585161', (114, 121))	('A-1331852', 'Chemical', 'MESH:C000603580', (185, 194))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('KPT-330', 'Gene', (114, 121))	('A-1331852', 'Var', (185, 194))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
351345	28852126	Our results showed low FSTL1 immunoexpression was significantly correlated with poor prognosis while patients with low BMP4 or low Smad4 immunoexpression showed a trend toward poor prognosis.	('patients', 'Species', '9606', (101, 109))	('Smad4', 'Gene', (131, 136))	('low', 'Var', (19, 22))	('Smad4', 'Gene', '4089', (131, 136))	('FSTL1', 'Gene', (23, 28))
351346	28852126	When stratified by different histological types, low FSTL1, BMP4, and Smad4 expression retained their trends in predicting poor prognosis in lung adenocarcinoma (LUAD) but not in lung squamous cell carcinoma (SCC).	('lung adenocarcinoma', 'Disease', (141, 160))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (184, 207))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (179, 207))	('Smad4', 'Gene', (70, 75))	('Smad4', 'Gene', '4089', (70, 75))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (179, 207))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (141, 160))	('carcinoma', 'Phenotype', 'HP:0030731', (198, 207))	('LUAD', 'Phenotype', 'HP:0030078', (162, 166))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (141, 160))	('SCC', 'Phenotype', 'HP:0002860', (209, 212))	('lung squamous cell carcinoma', 'Disease', (179, 207))	('carcinoma', 'Phenotype', 'HP:0030731', (151, 160))	('low', 'Var', (49, 52))	('FSTL1', 'Gene', (53, 58))	('BMP4', 'Gene', (60, 64))
351348	28852126	To determine smoking effect on FSTL1, normal cell BEAS2B and lung cancer cell lines was treated with nicotine and the results showed nicotine increased the proliferation of these cells.	('lung cancer', 'Disease', (61, 72))	('lung cancer', 'Phenotype', 'HP:0100526', (61, 72))	('nicotine', 'Chemical', 'MESH:D009538', (101, 109))	('increased', 'PosReg', (142, 151))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('nicotine', 'Chemical', 'MESH:D009538', (133, 141))	('proliferation', 'CPA', (156, 169))	('BEAS2B', 'CellLine', 'CVCL:0168', (50, 56))	('lung cancer', 'Disease', 'MESH:D008175', (61, 72))	('nicotine increased', 'Phenotype', 'HP:0410206', (133, 151))	('nicotine', 'Var', (133, 141))
351355	28852126	For adenocarcinoma, the dominant histological subtype of lung cancer, increased understanding of molecular pathogenesis such as EGFR mutation, KRAS mutation and ALK fusion leads to the success of targeted therapy.	('adenocarcinoma', 'Disease', 'MESH:D000230', (4, 18))	('mutation', 'Var', (133, 141))	('carcinoma', 'Phenotype', 'HP:0030731', (9, 18))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('EGFR', 'Gene', '1956', (128, 132))	('ALK', 'Gene', (161, 164))	('EGFR', 'Gene', (128, 132))	('adenocarcinoma', 'Disease', (4, 18))	('lung cancer', 'Disease', 'MESH:D008175', (57, 68))	('KRAS', 'Gene', (143, 147))	('KRAS', 'Gene', '3845', (143, 147))	('lung cancer', 'Disease', (57, 68))	('ALK', 'Gene', '238', (161, 164))	('lung cancer', 'Phenotype', 'HP:0100526', (57, 68))
351371	28852126	Moreover, frequent decrease of FSTL1-BMP4-p-Smad1/5/8-Smad4 pathway observed in smokers and in ALK-fusion or KRAS mutant adenocarcinoma patients may facilitate the understanding of the molecular pathogenesis of lung adenocarcinoma.	('lung adenocarcinoma', 'Disease', (211, 230))	('mutant', 'Var', (114, 120))	('adenocarcinoma', 'Disease', 'MESH:D000230', (216, 230))	('Smad4', 'Gene', (54, 59))	('carcinoma', 'Phenotype', 'HP:0030731', (221, 230))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (211, 230))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (211, 230))	('decrease', 'NegReg', (19, 27))	('adenocarcinoma', 'Disease', (121, 135))	('ALK', 'Gene', '238', (95, 98))	('KRAS', 'Gene', '3845', (109, 113))	('Smad4', 'Gene', '4089', (54, 59))	('ALK', 'Gene', (95, 98))	('facilitate', 'PosReg', (149, 159))	('KRAS', 'Gene', (109, 113))	('adenocarcinoma', 'Disease', (216, 230))	('patients', 'Species', '9606', (136, 144))	('adenocarcinoma', 'Disease', 'MESH:D000230', (121, 135))
351405	28852126	Low FSTL1 IHC expression retained its prognostic significance in lung adenocarcinoma (P = 0.018) (Fig.	('FSTL1', 'Gene', (4, 9))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (65, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (65, 84))	('lung adenocarcinoma', 'Disease', (65, 84))	('Low', 'Var', (0, 3))
351406	28852126	Patients with low BMP4 or low Smad4 IHC expression tend to have worse survival compared to those with high BMP4 or high Smad4.	('worse', 'NegReg', (64, 69))	('survival', 'MPA', (70, 78))	('low', 'Var', (26, 29))	('Patients', 'Species', '9606', (0, 8))	('low', 'Var', (14, 17))	('Smad4', 'Gene', (30, 35))	('Smad4', 'Gene', '4089', (30, 35))	('Smad4', 'Gene', (120, 125))	('Smad4', 'Gene', '4089', (120, 125))
351413	28852126	In multivariate analysis, only low FSTL1 expression (hazard ratio [HR] = 2.55; 95% confidence interval [CI] = 1.04-6.24; P = 0.041) and lymph node metastasis (HR = 2.62; 95% CI = 1.26-5.46; P = 0.010) remained independently prognostic.	('lymph node metastasis', 'Disease', (136, 157))	('expression', 'MPA', (41, 51))	('FSTL1', 'Gene', (35, 40))	('low', 'Var', (31, 34))	('lymph node metastasis', 'Disease', 'MESH:D009362', (136, 157))
351415	28852126	The results indicated that there were significant positive correlations among FSTL1, BMP4, Smad4, and p-Smad1/5/8 IHC expression in adenocarcinoma (Table 2).	('adenocarcinoma', 'Disease', 'MESH:D000230', (132, 146))	('BMP4', 'Gene', (85, 89))	('p-Smad1/5/8', 'Var', (102, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('Smad4', 'Gene', (91, 96))	('Smad4', 'Gene', '4089', (91, 96))	('adenocarcinoma', 'Disease', (132, 146))	('FSTL1', 'Gene', (78, 83))
351422	28852126	In public dataset GSE31210, low FSTL1 RNA level was associated with lung adenocarcinoma patients with ALK-fusion or KRAS mutation compared to those with EGFR mutation or EGFR/KRAS/ALK triple-negative tumors (Fig.	('ALK', 'Gene', (102, 105))	('ALK', 'Gene', '238', (180, 183))	('EGFR', 'Gene', (170, 174))	('KRAS', 'Gene', (116, 120))	('tumors', 'Disease', 'MESH:D009369', (200, 206))	('lung adenocarcinoma', 'Disease', (68, 87))	('ALK', 'Gene', (180, 183))	('GSE', 'Gene', '317782', (18, 21))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('mutation', 'Var', (121, 129))	('EGFR', 'Gene', (153, 157))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (68, 87))	('KRAS', 'Gene', '3845', (175, 179))	('GSE', 'Gene', (18, 21))	('EGFR', 'Gene', '1956', (170, 174))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (68, 87))	('tumors', 'Phenotype', 'HP:0002664', (200, 206))	('KRAS', 'Gene', (175, 179))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('patients', 'Species', '9606', (88, 96))	('EGFR', 'Gene', '1956', (153, 157))	('tumors', 'Disease', (200, 206))	('ALK', 'Gene', '238', (102, 105))	('low', 'NegReg', (28, 31))	('KRAS', 'Gene', '3845', (116, 120))
351427	28852126	Subcutaneous tumorigenicity testing showed that knockdown of FSTL1 in CL1-0 cells promoted the tumor growth (Fig.	('tumor', 'Disease', (13, 18))	('promoted', 'PosReg', (82, 90))	('CL1', 'Gene', '9201', (70, 73))	('CL1', 'Gene', (70, 73))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('FSTL1', 'Gene', (61, 66))	('tumor', 'Disease', (95, 100))	('knockdown', 'Var', (48, 57))
351437	28852126	Meanwhile, extracellular FSTL1 protein levels were decreased by nicotine treatment and this downregulation was diminished by PD98059 (Supplementary Figure 3C).	('PD98059', 'Chemical', 'MESH:C093973', (125, 132))	('nicotine', 'Chemical', 'MESH:D009538', (64, 72))	('decreased', 'NegReg', (51, 60))	('PD98059', 'Var', (125, 132))	('extracellular FSTL1 protein levels', 'MPA', (11, 45))
351438	28852126	Furthermore, in cell proliferation assay, PD98059 treatment abolished nicotine-induced proliferation in a dose-dependent manner (Supplementary Figure 3D).	('nicotine-induced', 'MPA', (70, 86))	('nicotine', 'Chemical', 'MESH:D009538', (70, 78))	('abolished', 'NegReg', (60, 69))	('PD98059', 'Var', (42, 49))	('PD98059', 'Chemical', 'MESH:C093973', (42, 49))
351444	28852126	Considering that type II pneumocytes are generally regarded as the origin of lung adenocarcinoma, it is reasonable that FSTL1-BMP4-Smad pathway dysregulation could result in strong prognostic impacts on lung adenocarcinoma patients.	('lung adenocarcinoma', 'Disease', (203, 222))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (203, 222))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (203, 222))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (77, 96))	('dysregulation', 'Var', (144, 157))	('lung adenocarcinoma', 'Disease', (77, 96))	('impacts', 'Reg', (192, 199))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (77, 96))	('patients', 'Species', '9606', (223, 231))	('carcinoma', 'Phenotype', 'HP:0030731', (213, 222))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))
351454	28852126	Although loss of FSTL1 expression was shown to be a predictive marker of poor prognosis for lung adenocarcinoma in our study, it was reported to have contradictive roles in different kinds of tumor.	('tumor', 'Disease', (192, 197))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (92, 111))	('FSTL1', 'Gene', (17, 22))	('loss', 'Var', (9, 13))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('lung adenocarcinoma', 'Disease', (92, 111))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (92, 111))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))
351455	28852126	FSTL1 expression inhibits cell growth and invasion of lung cancer cells, and the invasion ability could be blocked by FSTL1 antibody treatment.	('inhibits', 'NegReg', (17, 25))	('lung cancer', 'Disease', (54, 65))	('FSTL1', 'Gene', (0, 5))	('lung cancer', 'Phenotype', 'HP:0100526', (54, 65))	('invasion ability', 'CPA', (81, 97))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('lung cancer', 'Disease', 'MESH:D008175', (54, 65))	('expression', 'Var', (6, 16))
351466	28852126	Besides, among molecular subtypes of lung adenocarcinoma, significant decrease of FSTL1 expression in KRAS mutation or ALK mutation tumor shown in our study also suggests that FSTL1 has variable influence on different molecular subtypes of lung adenocarcinoma and points out the direction of FSTL1 as a target for personalized therapeutic approach.	('mutation', 'Var', (123, 131))	('lung adenocarcinoma', 'Disease', (37, 56))	('tumor', 'Disease', (132, 137))	('decrease', 'NegReg', (70, 78))	('mutation', 'Var', (107, 115))	('expression', 'MPA', (88, 98))	('FSTL1', 'Gene', (82, 87))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('carcinoma', 'Phenotype', 'HP:0030731', (47, 56))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (37, 56))	('lung adenocarcinoma', 'Disease', (240, 259))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (37, 56))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('influence', 'Reg', (195, 204))	('ALK', 'Gene', '238', (119, 122))	('KRAS', 'Gene', '3845', (102, 106))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (240, 259))	('ALK', 'Gene', (119, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (250, 259))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (240, 259))	('KRAS', 'Gene', (102, 106))
351503	30607347	In 1 case, there was a high rate of positive p53 immunoexpression (indicative of mutations in the TP53 gene, where tumors with more than 10% positively stained p53 cells are highly suggestive of malignant features), which was found in more than 90% of basal and suprabasal cells, whereas it was minimally expressed with no mutations in another case and showed negative results for expression in 2 other cases.	('p53', 'Gene', (45, 48))	('p53', 'Gene', '7157', (45, 48))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('p53', 'Gene', (160, 163))	('tumors', 'Disease', (115, 121))	('p53', 'Gene', '7157', (160, 163))	('tumors', 'Disease', 'MESH:D009369', (115, 121))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('mutations', 'Var', (81, 90))	('TP53', 'Gene', '7157', (98, 102))	('TP53', 'Gene', (98, 102))
351526	30607347	The presence of mutated forms of p53 was found to be associated with malignant features; yet, studies on its association with oral CC are lacking, since only 4 studies reported findings on p53 expression.	('oral CC', 'Disease', (126, 133))	('p53', 'Gene', '7157', (189, 192))	('malignant features', 'CPA', (69, 87))	('mutated', 'Var', (16, 23))	('p53', 'Gene', (33, 36))	('p53', 'Gene', '7157', (33, 36))	('associated', 'Reg', (53, 63))	('presence', 'Var', (4, 12))	('p53', 'Gene', (189, 192))
351548	27684953	We used a stable isotope dimethyl labeling based quantitative proteomic method to identify differentially expressed proteins in NSCLC cell lines after ANXA5 transfection.	('NSCLC', 'Phenotype', 'HP:0030358', (128, 133))	('ANXA5', 'Gene', '308', (151, 156))	('ANXA5', 'Gene', (151, 156))	('transfection', 'Var', (157, 169))	('NSCLC', 'Disease', (128, 133))	('NSCLC', 'Disease', 'MESH:D002289', (128, 133))
351549	27684953	Out of 314 proteins, we identified 26 and 44 proteins that were down- and up-regulated upon ANXA5 modulation, respectively.	('down-', 'NegReg', (64, 69))	('proteins', 'Protein', (45, 53))	('up-regulated', 'PosReg', (74, 86))	('ANXA5', 'Gene', '308', (92, 97))	('ANXA5', 'Gene', (92, 97))	('modulation', 'Var', (98, 108))
351551	27684953	Multiple central nodes, namely HSPA5, FN1, PDIA6, ENO1, ALDOA, JUP and KRT6A appeared to occupy regulatory nodes in the protein-protein networks upon ANXA5 modulation.	('KRT6A', 'Gene', '3853', (71, 76))	('JUP', 'Gene', (63, 66))	('HSPA5', 'Gene', '3309', (31, 36))	('ENO1', 'Gene', (50, 54))	('PDIA6', 'Gene', '10130', (43, 48))	('ENO1', 'Gene', '2023', (50, 54))	('ALDOA', 'Gene', '226', (56, 61))	('HSPA5', 'Gene', (31, 36))	('KRT6A', 'Gene', (71, 76))	('modulation', 'Var', (156, 166))	('FN1', 'Gene', '2335', (38, 41))	('FN1', 'Gene', (38, 41))	('PDIA6', 'Gene', (43, 48))	('JUP', 'Gene', '3728', (63, 66))	('ALDOA', 'Gene', (56, 61))	('ANXA5', 'Gene', (150, 155))	('ANXA5', 'Gene', '308', (150, 155))
351561	27684953	ANXA5 also has been reported to inhibit diffuse large B-cell lymphoma cell invasion and chemo-resistance, and the expression of ANXA5 may induce mitochondrial apoptosis in prostate cancer cells.	('expression', 'Var', (114, 124))	('prostate cancer', 'Disease', 'MESH:D011471', (172, 187))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('inhibit', 'NegReg', (32, 39))	('prostate cancer', 'Phenotype', 'HP:0012125', (172, 187))	('chemo-resistance', 'CPA', (88, 104))	('lymphoma', 'Phenotype', 'HP:0002665', (61, 69))	('induce', 'Reg', (138, 144))	('mitochondrial apoptosis', 'CPA', (145, 168))	('diffuse large B-cell lymphoma cell invasion', 'CPA', (40, 83))	('ANXA5', 'Gene', (128, 133))	('prostate cancer', 'Disease', (172, 187))	('ANXA5', 'Gene', '308', (128, 133))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (54, 69))	('ANXA5', 'Gene', '308', (0, 5))	('ANXA5', 'Gene', (0, 5))
351575	27684953	The tested cells were divided into three groups: pCDNA3.1-NCI-H520-ANXA5 transfected cells, pCDNA3.1-NCI-H520-NC and NCI-H520.	('pCDNA3.1-NCI-H520-NC', 'Var', (92, 112))	('NCI-H520-NC', 'CellLine', 'CVCL:1566', (101, 112))	('ANXA5', 'Gene', '308', (67, 72))	('ANXA5', 'Gene', (67, 72))
351590	27684953	Peptides were searched using the following parameters: fully tryptic cleavage constraints; up to two internal cleavage sites allowed for tryptic digestion; carbamidomethylation as a fixed modification; oxidation of methionine and protein N-terminal acetylation as variable modifications; dimethyl (+ 28.0313 Da) and dimethyl (+ 32.0564) N-termini and K set as light/heavy labels for quantification.	('dimethyl (+ 28.0313 Da', 'Var', (288, 310))	('methionine', 'Chemical', 'MESH:D008715', (215, 225))	('dimethyl (+ 32.0564) N-termini', 'Var', (316, 346))
351599	27684953	Besides, ANXA5 was altered in 3 (1.7%, all 178 cases) from TCGA in LUSC, in which two of them are missense mutations and the another one is truncating mutation.	('missense mutations', 'Var', (98, 116))	('ANXA5', 'Gene', '308', (9, 14))	('ANXA5', 'Gene', (9, 14))	('LUSC', 'Phenotype', 'HP:0030359', (67, 71))	('TCGA', 'Gene', (59, 63))	('altered', 'Reg', (19, 26))
351601	27684953	For copy number alterations, there are 70 shallow deletions (39.3%), 101 diploids (56.7%) and 7 gains (3.9%) in 178 LUSC patients from TCGA.	('gains', 'PosReg', (96, 101))	('patients', 'Species', '9606', (121, 129))	('LUSC', 'Phenotype', 'HP:0030359', (116, 120))	('copy number alterations', 'Var', (4, 27))
351612	27684953	The computational network analysis was applied to capture the complex and dynamic nature of the changes in the H520 cell upon ANXA5 modulation.	('modulation', 'Var', (132, 142))	('ANXA5', 'Gene', '308', (126, 131))	('ANXA5', 'Gene', (126, 131))
351618	27684953	This study was undertaken to identify the alterations in the lung squamous carcinoma cell proteome caused by ANXA5 transfection.	('lung squamous carcinoma', 'Disease', 'MESH:D002294', (61, 84))	('lung squamous carcinoma', 'Phenotype', 'HP:0030359', (61, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('lung squamous carcinoma', 'Disease', (61, 84))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (66, 84))	('transfection', 'Var', (115, 127))	('ANXA5', 'Gene', '308', (109, 114))	('ANXA5', 'Gene', (109, 114))
351636	27684953	Overexpression of ENO1 is associated with tumor progression and invasion.	('ENO1', 'Gene', (18, 22))	('ENO1', 'Gene', '2023', (18, 22))	('tumor', 'Disease', (42, 47))	('invasion', 'CPA', (64, 72))	('Overexpression', 'Var', (0, 14))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('associated', 'Reg', (26, 36))
351657	33863364	NFKBIA amplification and IkappaBalpha overexpression identify a unique cancer subtype associated with specific expression profile and metabolic signatures.	('NFKBIA', 'Gene', (0, 6))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('NFKBIA', 'Gene', '4792', (0, 6))	('cancer', 'Disease', (71, 77))	('overexpression', 'PosReg', (38, 52))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('amplification', 'Var', (7, 20))
351664	33863364	If not eliminated, ROS increase the oxidative damage to mitochondrial proteins and feed their own further production as in a vicious circle, which ultimately lead to the apoptosis induction.	('ROS increase', 'Phenotype', 'HP:0025464', (19, 31))	('lead to', 'Reg', (158, 165))	('oxidative damage', 'MPA', (36, 52))	('increase', 'PosReg', (23, 31))	('ROS', 'Var', (19, 22))	('apoptosis', 'CPA', (170, 179))	('ROS', 'Chemical', 'MESH:D017382', (19, 22))
351669	33863364	Here, we unravel a novel NFKBIA amplification in lung cancer and demonstrate a strong link between IkappaBalpha overexpression, low-ROS levels and chemoresistance.	('tween', 'Chemical', 'MESH:D011136', (93, 98))	('NFKBIA', 'Gene', (25, 31))	('lung cancer', 'Disease', 'MESH:D008175', (49, 60))	('NFKBIA', 'Gene', '4792', (25, 31))	('overexpression', 'PosReg', (112, 126))	('amplification', 'Var', (32, 45))	('lung cancer', 'Disease', (49, 60))	('IkappaBalpha', 'Protein', (99, 111))	('lung cancer', 'Phenotype', 'HP:0100526', (49, 60))	('ROS', 'Chemical', 'MESH:D017382', (132, 135))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('chemoresistance', 'CPA', (147, 162))	('low-ROS levels', 'MPA', (128, 142))
351676	33863364	The following plasmid were obtained from Addgene: RelA cFlag pcDNA3 plasmid, pCMV-VSV-G, pCMV-dR8.2 dvpr, p1242-3x-KB-L. IkappaBalpha was cloned into myc-tagged pRK5 plasmid.	('RelA', 'Gene', '5970', (50, 54))	('myc', 'Gene', '4609', (150, 153))	('myc', 'Gene', (150, 153))	('p1242-3x-KB-L.', 'Var', (106, 120))	('RelA', 'Gene', (50, 54))
351681	33863364	ZINC639309 (MolPort-002-836-946) was purchased from MolPort and Psammaplin-A (SC-258049) was purchased from Santa Cruz.	('ZINC639309', 'Chemical', '-', (0, 10))	('Psammaplin-A', 'Gene', (64, 76))	('ZINC639309', 'Var', (0, 10))	('Psammaplin-A', 'Gene', '354', (64, 76))
351684	33863364	Virus containing supernatants were collected 48 h after co-transfection of pCMV-VSV-G, pCMV-dR8.2 dvpr and the shRNA vector into HEK293T cells, and then added to the target cells.	('pCMV-VSV-G', 'Var', (75, 85))	('pCMV-dR8.2', 'Var', (87, 97))	('HEK293T', 'CellLine', 'CVCL:0063', (129, 136))
351727	33863364	Using the Pancan12 TCGA data set, which includes 32 studies and 10,967 cancers of different histotypes (Table S1), we measured NFKBIA (the gene coding for IkappaBalpha) copy number variations, revealing several cases of amplification in cancer.	('NFKBIA', 'Gene', (127, 133))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('cancers', 'Disease', 'MESH:D009369', (71, 78))	('cancers', 'Phenotype', 'HP:0002664', (71, 78))	('copy number variations', 'Var', (169, 191))	('NFKBIA', 'Gene', '4792', (127, 133))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('cancers', 'Disease', (71, 78))	('cancer', 'Disease', (71, 77))	('cancer', 'Disease', 'MESH:D009369', (237, 243))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('cancer', 'Disease', (237, 243))
351738	33863364	1f), which suggested a potential interference of NFKBIA copy gains on the global transcriptional profile of target cells.	('copy gains', 'Var', (56, 66))	('NFKBIA', 'Gene', '4792', (49, 55))	('NFKBIA', 'Gene', (49, 55))	('global transcriptional profile', 'MPA', (74, 104))
351743	33863364	Interestingly, this analysis showed a profile very similar to the one previously identified in primary samples, with NFKBIA predominantly amplified in lung cancer, deleted in kidney and variously expressed in breast, large intestine and hematological tumors (Fig.	('NFKBIA', 'Gene', (117, 123))	('breast', 'Disease', (209, 215))	('deleted', 'Var', (164, 171))	('NFKBIA', 'Gene', '4792', (117, 123))	('tumors', 'Phenotype', 'HP:0002664', (251, 257))	('lung cancer', 'Phenotype', 'HP:0100526', (151, 162))	('hematological tumors', 'Disease', 'MESH:D019337', (237, 257))	('lung cancer', 'Disease', 'MESH:D008175', (151, 162))	('lung cancer', 'Disease', (151, 162))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('amplified', 'Reg', (138, 147))	('tumor', 'Phenotype', 'HP:0002664', (251, 256))	('hematological tumors', 'Disease', (237, 257))
351744	33863364	To corroborate these observations, we also assessed IkappaBalpha protein expression by western immunoblot in various lung cancer cell lines, where IkappaBalpha appeared over-expressed when compared to normal lung cell line, as shown in Fig.	('lung cancer', 'Disease', (117, 128))	('lung cancer', 'Phenotype', 'HP:0100526', (117, 128))	('IkappaBalpha', 'Var', (147, 159))	('over-expressed', 'PosReg', (169, 183))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('lung cancer', 'Disease', 'MESH:D008175', (117, 128))
351763	33863364	Interestingly, IkappaBalpha down-modulated cells showed a significant reduction in lactate production compared to controls (Fig.	('reduction', 'NegReg', (70, 79))	('IkappaBalpha', 'Var', (15, 27))	('down-modulated', 'NegReg', (28, 42))	('lactate', 'Chemical', 'MESH:D019344', (83, 90))	('lactate production', 'MPA', (83, 101))
351777	33863364	The metabolic changes induced by IkappaBalpha-silencing: ETC hyperactivity (Fig.	('IkappaBalpha-silencing', 'Var', (33, 55))	('metabolic changes', 'MPA', (4, 21))	('hyperactivity', 'Disease', 'MESH:D006948', (61, 74))	('hyperactivity', 'Disease', (61, 74))	('hyperactivity', 'Phenotype', 'HP:0000752', (61, 74))
351780	33863364	3d and e) were at least in part rescued by p65 knock-down.	('knock-down', 'Var', (47, 57))	('p65', 'Gene', (43, 46))	('p65', 'Gene', '5970', (43, 46))
351788	33863364	Finally, on the basis of ADME-Tox considerations, two compounds for each task were identified and submitted to the in vitro tests: ZINC639309 and ZINC3005818 for task 1; ZINC1250968 and ZINC26500814 (also known as Psammaplin-A, PSA) (Fig.	('ZINC639309', 'Chemical', '-', (131, 141))	('ZINC26500814', 'Chemical', '-', (186, 198))	('ZINC26500814', 'Var', (186, 198))	('Psammaplin-A', 'Gene', '354', (214, 226))	('ZINC1250968', 'Chemical', '-', (170, 181))	('Tox', 'Gene', (30, 33))	('ZINC3005818', 'Chemical', '-', (146, 157))	('ZINC3005818', 'Var', (146, 157))	('Tox', 'Gene', '9760', (30, 33))	('Psammaplin-A', 'Gene', (214, 226))	('ZINC639309', 'Var', (131, 141))	('ZINC1250968', 'Var', (170, 181))
351789	33863364	Further validation for ZINC639309 as an IkappaBalpha/p65 dimerization inhibitor in vitro and in vivo was obtained (Fig.	('p65', 'Gene', (53, 56))	('ZINC639309', 'Var', (23, 33))	('p65', 'Gene', '5970', (53, 56))	('ZINC639309', 'Chemical', '-', (23, 33))
351790	33863364	Despite the effectiveness shown by the ZINC639309 due its high IC50 we have focused our further validations on the second compound: Psammaplin-A.	('ZINC639309', 'Var', (39, 49))	('IC50', 'MPA', (63, 67))	('ZINC639309', 'Chemical', '-', (39, 49))	('Psammaplin-A', 'Gene', '354', (132, 144))	('Psammaplin-A', 'Gene', (132, 144))
351828	33863364	6a) and we found that IkappaBalpha silencing affects cisplatin induced apoptosis (Fig.	('IkappaBalpha', 'Protein', (22, 34))	('cisplatin', 'Chemical', 'MESH:D002945', (53, 62))	('silencing', 'Var', (35, 44))	('cisplatin induced', 'MPA', (53, 70))
351833	33863364	S11B), did not cause body weight loss >=20% (Fig.	('S11B', 'Var', (0, 4))	('weight loss', 'Phenotype', 'HP:0001824', (26, 37))	('S11B', 'SUBSTITUTION', 'None', (0, 4))	('weight loss', 'Disease', 'MESH:D015431', (26, 37))	('weight loss', 'Disease', (26, 37))
351834	33863364	S11C) and inhibited tumor growth even in the presence of suboptimal cisplatin concentrations.	('cisplatin', 'Chemical', 'MESH:D002945', (68, 77))	('S11C', 'SUBSTITUTION', 'None', (0, 4))	('inhibited', 'NegReg', (10, 19))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('S11C', 'Var', (0, 4))	('tumor', 'Disease', (20, 25))
351841	33863364	Here, we have demonstrated that variations in IkappaBalpha levels are associated with metabolic reprogramming in lung cancer cells: high IkappaBalpha expression identifies a group of cancers with low levels of ROS and low mitochondrial oxidative metabolism, while low IkappaBalpha expression drives metabolic switch characterized by increased fatty acid oxidation, OXPHOS, mitochondrial respiration and expression of ETC components and higher levels of ROS.	('low', 'NegReg', (218, 221))	('higher', 'PosReg', (436, 442))	('lung cancer', 'Disease', 'MESH:D008175', (113, 124))	('cancers', 'Phenotype', 'HP:0002664', (183, 190))	('cancers', 'Disease', (183, 190))	('lung cancer', 'Phenotype', 'HP:0100526', (113, 124))	('ROS', 'Chemical', 'MESH:D017382', (453, 456))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('fatty acid', 'Chemical', 'MESH:D005227', (343, 353))	('high', 'Var', (132, 136))	('mitochondrial oxidative metabolism', 'MPA', (222, 256))	('OXPHOS', 'MPA', (365, 371))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('low', 'NegReg', (196, 199))	('expression', 'MPA', (403, 413))	('ROS', 'MPA', (210, 213))	('cancers', 'Disease', 'MESH:D009369', (183, 190))	('mitochondrial respiration', 'MPA', (373, 398))	('levels', 'MPA', (200, 206))	('lung cancer', 'Disease', (113, 124))	('ROS', 'Chemical', 'MESH:D017382', (210, 213))	('high IkappaBalpha', 'Phenotype', 'HP:0003261', (132, 149))	('fatty acid oxidation', 'MPA', (343, 363))	('increased', 'PosReg', (333, 342))
351862	28202506	Recurrent patterns of DNA copy number alterations in tumors reflect metabolic selection pressures Copy number alteration (CNA) profiling of human tumors has revealed recurrent patterns of DNA amplifications and deletions across diverse cancer types.	('deletions', 'Var', (211, 220))	('human', 'Species', '9606', (140, 145))	('cancer', 'Disease', 'MESH:D009369', (236, 242))	('tumors', 'Phenotype', 'HP:0002664', (146, 152))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('amplifications', 'Var', (192, 206))	('cancer', 'Disease', (236, 242))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('tumors', 'Disease', 'MESH:D009369', (146, 152))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('tumors', 'Disease', (146, 152))	('tumors', 'Disease', (53, 59))
351865	28202506	The primary CNA signature is enriched for p53 mutations and is associated with glycolysis through coordinate amplification of glycolytic genes and other cancer-linked metabolic enzymes.	('p53', 'Gene', (42, 45))	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('mutations', 'Var', (46, 55))	('cancer', 'Disease', (153, 159))	('glycolytic genes', 'Gene', (126, 142))	('associated', 'Reg', (63, 73))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('glycolysis', 'MPA', (79, 89))	('amplification', 'PosReg', (109, 122))
351869	28202506	Modern cancer classification relies on molecular characterization, including examination of genomic DNA mutations and copy number alterations (CNAs; Stuart & Sellers, 2009).	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('copy number alterations', 'Var', (118, 141))	('cancer', 'Disease', (7, 13))	('cancer', 'Disease', 'MESH:D009369', (7, 13))
351870	28202506	Although individual oncogenes and tumor suppressor genes are preferential targets of DNA amplifications and deletions, respectively, the recurrent CNA patterns in tumors cannot be fully explained by canonical cancer genes (Beroukhim et al, 2010; Muller et al, 2012; Davoli et al, 2013).	('tumor', 'Disease', (34, 39))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('cancer', 'Disease', 'MESH:D009369', (209, 215))	('tumors', 'Disease', (163, 169))	('cancer', 'Disease', (209, 215))	('tumor', 'Disease', (163, 168))	('tumors', 'Disease', 'MESH:D009369', (163, 169))	('deletions', 'Var', (108, 117))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('tumors', 'Phenotype', 'HP:0002664', (163, 169))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
351872	28202506	Reports that the cumulative phenotypic effects of many small gene dosage alterations across the genome can impact the resulting tumor copy number landscape (Solimini et al, 2012; Davoli et al, 2013) illustrate a need to consider more subtle and combinatorial effects to explain the remaining selective forces underlying recurrent CNA patterns observed in human cancers.	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('cancers', 'Disease', (361, 368))	('small gene dosage alterations', 'Var', (55, 84))	('cancers', 'Disease', 'MESH:D009369', (361, 368))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('cancer', 'Phenotype', 'HP:0002664', (361, 367))	('human', 'Species', '9606', (355, 360))	('impact', 'Reg', (107, 113))	('tumor', 'Disease', (128, 133))	('cancers', 'Phenotype', 'HP:0002664', (361, 368))
351878	28202506	Using an integrative analysis of CNA data from human tumors, mouse models of cancer, cancer cell lines, and a murine experimental immortalization system, here we show that the loci of metabolic genes impact the recurrent CNA changes observed in genomically unstable tumors.	('unstable tumors', 'Disease', (257, 272))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('impact', 'Reg', (200, 206))	('murine', 'Species', '10090', (110, 116))	('metabolic genes', 'Gene', (184, 199))	('CNA changes', 'MPA', (221, 232))	('unstable tumors', 'Disease', 'MESH:D000789', (257, 272))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('mouse', 'Species', '10090', (61, 66))	('tumors', 'Phenotype', 'HP:0002664', (266, 272))	('human', 'Species', '9606', (47, 52))	('tumors', 'Disease', (53, 59))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', (85, 91))	('tumor', 'Phenotype', 'HP:0002664', (266, 271))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('tumors', 'Disease', (266, 272))	('loci', 'Var', (176, 180))	('tumors', 'Disease', 'MESH:D009369', (266, 272))
351879	28202506	Our bioinformatic and experimental results support a tumorigenesis model in which copy number changes in metabolic genes contribute to an enhanced glycolytic and proliferative state (see Fig EV1 for a schematic of our overall approach).	('metabolic genes', 'Gene', (105, 120))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('EV1', 'Gene', '11322', (191, 194))	('copy number changes', 'Var', (82, 101))	('enhanced', 'PosReg', (138, 146))	('EV1', 'Gene', (191, 194))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('glycolytic and', 'MPA', (147, 161))	('tumor', 'Disease', (53, 58))
351884	28202506	In BRCA, signature A tumors were enriched for the basal subtype, p53 point mutations, high numbers of genomic breakpoints, and thus subchromosomal alterations (Figs 1B and D, and EV2D; P < 0.001, P < 0.001, P = 2 x 10-4, respectively).	('p53', 'Gene', (65, 68))	('BRCA', 'Gene', (3, 7))	('BRCA', 'Gene', '672', (3, 7))	('EV2', 'Gene', '147138', (179, 182))	('EV2', 'Gene', (179, 182))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('subchromosomal alterations', 'Var', (132, 158))	('point mutations', 'Var', (69, 84))	('A tumors', 'Disease', (19, 27))	('A tumors', 'Disease', 'MESH:D009369', (19, 27))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
351885	28202506	Signature B BRCA tumors, in contrast, were enriched for luminal type tumors (P < 0.001) and exhibited amplifications of the oncogenes MYC and MDM2 and deletion of the tumor suppressor CDKN2A (Fig 1B).	('MYC', 'Gene', '4609', (134, 137))	('deletion', 'Var', (151, 159))	('CDKN2A', 'Gene', (184, 190))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('tumor', 'Disease', (167, 172))	('tumor', 'Disease', (17, 22))	('CDKN2A', 'Gene', '1029', (184, 190))	('BRCA tumors', 'Disease', (12, 23))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('luminal type tumors', 'Disease', (56, 75))	('BRCA tumors', 'Disease', 'MESH:D009369', (12, 23))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('luminal type tumors', 'Disease', 'MESH:D009369', (56, 75))	('MDM2', 'Gene', (142, 146))	('MYC', 'Gene', (134, 137))	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('tumor', 'Disease', (69, 74))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('MDM2', 'Gene', '4193', (142, 146))	('amplifications', 'MPA', (102, 116))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
351886	28202506	Amplification of MDM2 and loss of CDKN2A were generally mutually exclusive in signature B tumors (Fig EV2E), reflecting alternate mechanisms for disabling the p53/ARF axis (Sherr & Weber, 2000).	('Amplification', 'Var', (0, 13))	('EV2', 'Gene', '147138', (102, 105))	('B tumors', 'Disease', 'MESH:D006509', (88, 96))	('EV2', 'Gene', (102, 105))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('MDM2', 'Gene', '4193', (17, 21))	('disabling', 'NegReg', (145, 154))	('ARF axis', 'Disease', (163, 171))	('MDM2', 'Gene', (17, 21))	('CDKN2A', 'Gene', (34, 40))	('CDKN2A', 'Gene', '1029', (34, 40))	('loss', 'NegReg', (26, 30))	('ARF axis', 'Disease', 'MESH:C566610', (163, 171))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('B tumors', 'Disease', (88, 96))
351888	28202506	Overall, signature A tumors demonstrated enrichment of p53 mutations, more genomic breakpoints (BRCA, LU, and UCEC), and a higher degree of copy number alterations (LU, OV, and UCEC) than signature B tumors (Appendix Fig S2A and B, P-values indicated in figure).	('BRCA', 'Gene', '672', (96, 100))	('copy', 'MPA', (140, 144))	('p53', 'Gene', (55, 58))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('BRCA', 'Gene', (96, 100))	('B tumors', 'Disease', 'MESH:D006509', (198, 206))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('tumors', 'Phenotype', 'HP:0002664', (200, 206))	('OV', 'Phenotype', 'HP:0012887', (169, 171))	('genomic breakpoints', 'CPA', (75, 94))	('mutations', 'Var', (59, 68))	('A tumors', 'Disease', (19, 27))	('B tumors', 'Disease', (198, 206))	('A tumors', 'Disease', 'MESH:D009369', (19, 27))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
351891	28202506	Unlike signature A tumors, the signature B CNA patterns were quite distinct between tumor types, although some commonalities were observed including point mutations in oncogenes such as KRAS (LU and UCEC) and amplification of MYC (BRCA, LU, and OV).	('OV', 'Phenotype', 'HP:0012887', (245, 247))	('MYC', 'Gene', (226, 229))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('A tumors', 'Disease', 'MESH:D009369', (17, 25))	('KRAS', 'Gene', (186, 190))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('BRCA', 'Gene', (231, 235))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('MYC', 'Gene', '4609', (226, 229))	('tumor', 'Disease', (84, 89))	('KRAS', 'Gene', '3845', (186, 190))	('BRCA', 'Gene', '672', (231, 235))	('tumor', 'Disease', (19, 24))	('amplification', 'Var', (209, 222))	('point mutations', 'Var', (149, 164))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('A tumors', 'Disease', (17, 25))
351895	28202506	Using CNA-based gene set enrichment analysis over all metabolic pathways defined by KEGG (Kanehisa et al, 2014), we found that the conserved profile of core signature A tumors (i.e., OV, BRCA, UCEC, LU) (Fig 1C) was significantly enriched for DNA amplifications of core glycolysis pathway genes (Fig 1E and F, and Table EV1; P = 0.024).	('UCEC', 'Disease', (193, 197))	('A tumors', 'Disease', 'MESH:D009369', (167, 175))	('EV1', 'Gene', '11322', (320, 323))	('amplifications', 'Var', (247, 261))	('EV1', 'Gene', (320, 323))	('BRCA', 'Gene', '672', (187, 191))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('OV', 'Phenotype', 'HP:0012887', (183, 185))	('tumors', 'Phenotype', 'HP:0002664', (169, 175))	('BRCA', 'Gene', (187, 191))	('DNA amplifications', 'Var', (243, 261))	('A tumors', 'Disease', (167, 175))
351896	28202506	For example, BRCA signature A tumors exhibited DNA amplification of most genes from the glycolytic pathway, as well as amplification of lactate dehydrogenase B, deletion of pyruvate dehydrogenase subunits A and B, and amplification of the glycolysis-regulating metabolic enzyme TIGAR (human gene C12orf5; Fig 1G).	('TIGAR', 'Gene', (278, 283))	('pyruvate dehydrogenase', 'Gene', '54704', (173, 195))	('pyruvate dehydrogenase', 'Gene', (173, 195))	('BRCA', 'Gene', (13, 17))	('glycolytic', 'Enzyme', (88, 98))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('A tumors', 'Disease', 'MESH:D009369', (28, 36))	('amplification', 'Var', (218, 231))	('lactate dehydrogenase B', 'Gene', '3945', (136, 159))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('TIGAR', 'Gene', '57103', (278, 283))	('lactate dehydrogenase B', 'Gene', (136, 159))	('human', 'Species', '9606', (285, 290))	('amplification', 'PosReg', (51, 64))	('genes', 'Gene', (73, 78))	('A tumors', 'Disease', (28, 36))	('C12orf5', 'Gene', '57103', (296, 303))	('deletion', 'Var', (161, 169))	('C12orf5', 'Gene', (296, 303))	('amplification', 'Var', (119, 132))	('BRCA', 'Gene', '672', (13, 17))
351899	28202506	Thus, PCA identified a shared signature from breast, lung, ovarian, and uterine carcinomas that was enriched for p53 mutations, higher numbers of genomic breakpoints, and CNA of genes from the core glycolysis pathway.	('mutations', 'Var', (117, 126))	('breast', 'Disease', (45, 51))	('core glycolysis pathway', 'Pathway', (193, 216))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('ovarian', 'Disease', (59, 66))	('uterine carcinomas', 'Phenotype', 'HP:0010784', (72, 90))	('carcinomas', 'Phenotype', 'HP:0030731', (80, 90))	('carcinomas', 'Disease', (80, 90))	('carcinomas', 'Disease', 'MESH:D002277', (80, 90))	('lung', 'Disease', (53, 57))	('p53', 'Gene', (113, 116))
351900	28202506	While canonical oncogenes and tumor suppressor genes drive some recurrent DNA copy number alterations, many recurrent CNA regions cannot be fully explained by the presence of known cancer genes (Beroukhim et al, 2010; Muller et al, 2012; Davoli et al, 2013).	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('DNA', 'Gene', (74, 77))	('cancer', 'Disease', (181, 187))	('tumor', 'Disease', (30, 35))	('copy number alterations', 'Var', (78, 101))
351946	28202506	Returning to the result of the CNA-defined signature A being associated with increased FDG uptake in human primary tumors in vivo, we next asked which sets of metabolic gene loci copy number levels were most predictive of glycolytic phenotypes.	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('FDG', 'Chemical', 'MESH:D019788', (87, 90))	('human', 'Species', '9606', (101, 106))	('tumors', 'Disease', (115, 121))	('tumors', 'Disease', 'MESH:D009369', (115, 121))	('copy number', 'Var', (179, 190))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('increased', 'PosReg', (77, 86))
351950	28202506	Averaging results across these two test cases revealed that genes from the glycolysis and pentose phosphate pathway were most predictive of these metabolic phenotypes (Fig 3C and Table EV4; P = 0.01).	('genes', 'Var', (60, 65))	('glycolysis', 'Enzyme', (75, 85))	('pentose phosphate', 'Chemical', 'MESH:D010428', (90, 107))
351952	28202506	Thus, consistent with the gene expression-based predictions above, the glycolysis and pentose phosphate pathway DNA copy number alterations from signature A are predictive of glycolytic phenotypes of primary human breast tumors and cancer cell lines.	('DNA', 'Gene', (112, 115))	('cancer', 'Disease', 'MESH:D009369', (232, 238))	('breast tumors', 'Disease', 'MESH:D001943', (214, 227))	('glycolysis', 'Enzyme', (71, 81))	('cancer', 'Disease', (232, 238))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('breast tumors', 'Disease', (214, 227))	('predictive', 'Reg', (161, 171))	('pentose phosphate', 'Chemical', 'MESH:D010428', (86, 103))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('glycolytic', 'MPA', (175, 185))	('tumors', 'Phenotype', 'HP:0002664', (221, 227))	('human', 'Species', '9606', (208, 213))	('breast tumors', 'Phenotype', 'HP:0100013', (214, 227))	('copy number alterations', 'Var', (116, 139))
351962	28202506	In contrast, the MEF-derived signature B was characterized by amplification of Mdm2 or deletion of Cdkn2a (Ink4a/Arf) and fewer overall copy number alterations.	('amplification', 'PosReg', (62, 75))	('Cdkn2a', 'Gene', (99, 105))	('Mdm2', 'Gene', (79, 83))	('Ink4a/Arf', 'Gene', (107, 116))	('deletion', 'Var', (87, 95))	('Ink4a/Arf', 'Gene', '1029', (107, 116))
351964	28202506	As in human BRCA (Fig EV2E), amplification of Mdm2 and loss of Cdkn2a were generally mutually exclusive in signature B MEFs (Appendix Fig S6D), reflecting alternate mechanisms for disabling the p53/ARF axis (Sherr & Weber, 2000).	('Mdm2', 'Gene', (46, 50))	('human', 'Species', '9606', (6, 11))	('loss', 'NegReg', (55, 59))	('signature B', 'Disease', (107, 118))	('amplification', 'Var', (29, 42))	('MEFs', 'CellLine', 'CVCL:9115', (119, 123))	('ARF axis', 'Disease', (198, 206))	('BRCA', 'Gene', '672', (12, 16))	('ARF axis', 'Disease', 'MESH:C566610', (198, 206))	('EV2', 'Gene', '147138', (22, 25))	('BRCA', 'Gene', (12, 16))	('EV2', 'Gene', (22, 25))	('Cdkn2a', 'Gene', (63, 69))
351967	28202506	Comparison of the p53-/- MEF CNA patterns to wild-type MEFs by PCA demonstrated that the CNA patterns of p53-/- MEFs resemble the wild-type MEF signature A pattern, with no signature B-like sublines observed (Appendix Fig S7).	('MEFs', 'CellLine', 'CVCL:9115', (55, 59))	('p53-/- MEFs', 'Var', (105, 116))	('CNA', 'MPA', (89, 92))	('MEFs', 'CellLine', 'CVCL:9115', (112, 116))
351968	28202506	p53-/- MEFs do not undergo senescence (Olive et al, 2004), and consistent with this, we observed that they tended to have less strong copy number alterations.	('less', 'NegReg', (122, 126))	('p53-/- MEFs', 'Var', (0, 11))	('Olive', 'Species', '4146', (39, 44))	('MEFs', 'CellLine', 'CVCL:9115', (7, 11))
351969	28202506	In summary, strong p53 functional loss (p53 mutation or genetic loss) tends to lead to the CNA signature A pattern, which is associated with a higher degree of copy number alterations (higher integrated CNA score and more breakpoints) and Hk2 amplification, while weaker or less complete p53 functional loss (e.g., mediated by Mdm2 amplification or Cdkn2a loss) is associated with an alternative signature (signature B).	('CNA signature', 'Disease', (91, 104))	('mutation', 'Var', (44, 52))	('functional loss', 'NegReg', (23, 38))	('amplification', 'Var', (243, 256))	('Hk2', 'Gene', (239, 242))	('p53', 'Gene', (288, 291))	('Cdkn2a', 'Gene', (349, 355))	('lead', 'Reg', (79, 83))	('p53', 'Gene', (19, 22))	('functional loss', 'NegReg', (292, 307))	('copy', 'MPA', (160, 164))	('genetic loss', 'Disease', 'MESH:D030342', (56, 68))	('genetic loss', 'Disease', (56, 68))	('Mdm2', 'Gene', (327, 331))	('loss', 'NegReg', (356, 360))
351970	28202506	Next we sought to understand how CNA signatures revealed by CGH relate to numerical and structural aneuploidy (i.e., whole chromosomal and subchromosomal gains or losses, respectively).	('subchromosomal', 'Var', (139, 153))	('aneuploidy', 'Disease', 'MESH:D000782', (99, 109))	('losses', 'NegReg', (163, 169))	('aneuploidy', 'Disease', (99, 109))
351984	28202506	Furthermore, p53-/- cells did not undergo senescence (Olive et al, 2004) and exhibited less strong copy number alterations than wild-type signature A MEFs (Appendix Fig S7B; P = 9 x 10-4).	('Olive', 'Species', '4146', (54, 59))	('MEFs', 'CellLine', 'CVCL:9115', (150, 154))	('copy number alterations', 'MPA', (99, 122))	('p53-/-', 'Var', (13, 19))
351990	28202506	In cross-species pathway enrichment analysis, MEF CNA signatures added a similar amount of enrichment signal to human tumor signatures as do the non-MEF mouse model signatures, and when combined together, the enrichment was even stronger (e.g., glycolysis and core glycolysis pathways, Fig 4F).	('enrichment', 'MPA', (91, 101))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('core glycolysis pathways', 'Pathway', (260, 284))	('mouse', 'Species', '10090', (153, 158))	('tumor', 'Disease', (118, 123))	('MEF', 'Var', (46, 49))	('human', 'Species', '9606', (112, 117))
352006	28202506	We found that three glycolytic genes (LDHB, TPI1, and GAPDH) and one oncogene (KRAS) exhibited strong DNA-RNA correlation (r > 0.66), three glycolytic genes (HK2, ENO2, and PGAM2) and three oncogenes (MYC, CHD4, and TRRAP) exhibited moderate correlation (0.2 < r < 0.5), and only one glycolytic gene (GCK) and one oncogene (GATA2) exhibited weak DNA-RNA correlation (r < 0.2) (Appendix Fig S10A and B).	('PGAM2', 'Gene', '5224', (173, 178))	('S10A', 'SUBSTITUTION', 'None', (390, 394))	('TPI1', 'Gene', (44, 48))	('TRRAP', 'Gene', '8295', (216, 221))	('GCK', 'Gene', '2645', (301, 304))	('MYC', 'Gene', (201, 204))	('S10A', 'Var', (390, 394))	('PGAM2', 'Gene', (173, 178))	('HK2', 'Gene', (158, 161))	('HK2', 'Gene', '3099', (158, 161))	('MYC', 'Gene', '4609', (201, 204))	('LDHB', 'Gene', (38, 42))	('KRAS', 'Gene', '3845', (79, 83))	('LDHB', 'Gene', '3945', (38, 42))	('GAPDH', 'Gene', '2597', (54, 59))	('ENO2', 'Gene', '2026', (163, 167))	('CHD4', 'Gene', (206, 210))	('KRAS', 'Gene', (79, 83))	('GCK', 'Gene', (301, 304))	('ENO2', 'Gene', (163, 167))	('CHD4', 'Gene', '1108', (206, 210))	('TRRAP', 'Gene', (216, 221))	('TPI1', 'Gene', '7167', (44, 48))	('GAPDH', 'Gene', (54, 59))
352007	28202506	This analysis indicates that gene copy number alterations at the DNA level generally lead to increased RNA expression in signature A tumors in BRCA, LU, and OV tumors, with a similar degree of correlation observed for both glycolysis genes and oncogenes.	('RNA', 'Gene', (103, 106))	('gene copy number alterations', 'Var', (29, 57))	('BRCA', 'Gene', (143, 147))	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('OV tumors', 'Disease', 'MESH:D009369', (157, 166))	('OV', 'Phenotype', 'HP:0012887', (157, 159))	('increased', 'PosReg', (93, 102))	('A tumors', 'Disease', (131, 139))	('expression', 'MPA', (107, 117))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('OV tumors', 'Disease', (157, 166))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('A tumors', 'Disease', 'MESH:D009369', (131, 139))	('BRCA', 'Gene', '672', (143, 147))
352012	28202506	Taken together, these results support a model in which the selection pressures shared during immortalization and tumorigenesis result in cross-species conservation of the glycolysis gene loci copy number alterations (Fig 4E and F, and Table EV2).	('tumor', 'Disease', (113, 118))	('copy number alterations', 'Var', (192, 215))	('EV2', 'Gene', (241, 244))	('EV2', 'Gene', '147138', (241, 244))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))
352013	28202506	To test this hypothesis, we transduced pre-senescent MEFs with either wild-type HK2 or HK1, kinase-dead HK2 (D209A/D657A) (McCoy et al, 2014), or wild-type ENO2 and allowed the cells to senesce and immortalize in the presence of these exogenously expressed proteins (Appendix Fig S11).	('HK2', 'Gene', (80, 83))	('HK2', 'Gene', '3099', (80, 83))	('HK2', 'Gene', '3099', (104, 107))	('MEFs', 'CellLine', 'CVCL:9115', (53, 57))	('transduced', 'Reg', (28, 38))	('D657A', 'SUBSTITUTION', 'None', (115, 120))	('D209A', 'Var', (109, 114))	('immortalize', 'CPA', (198, 209))	('D209A', 'SUBSTITUTION', 'None', (109, 114))	('HK1', 'Gene', '3098', (87, 90))	('D657A', 'Var', (115, 120))	('HK2', 'Gene', (104, 107))	('HK1', 'Gene', (87, 90))	('ENO2', 'Gene', '2026', (156, 160))	('ENO2', 'Gene', (156, 160))
352017	28202506	In this analysis, we found that cells expressing exogenous hexokinase demonstrated significantly reduced Hk2:Chr6 max ratios (P = 3 x 10-3) (Fig 5A and C).	('hexokinase', 'Gene', (59, 69))	('exogenous', 'Var', (49, 58))	('hexokinase', 'Gene', '3098', (59, 69))	('reduced', 'NegReg', (97, 104))	('Hk2:Chr6 max ratios', 'MPA', (105, 124))
352018	28202506	Additionally, a MEF subline expressing exogenous ENO2 exhibited deletion rather than amplification of the Eno2 locus on chr.	('ENO2', 'Gene', '2026', (49, 53))	('exhibited', 'Reg', (54, 63))	('deletion', 'Var', (64, 72))	('ENO2', 'Gene', (49, 53))
352027	28202506	As noted above, the evolving MEF CNA signature pattern was enriched for DNA amplifications of genes in the core glycolysis and glycolysis-associated pathways (Table EV2), particularly due to amplification of chromosome 6, which contains multiple metabolic gene loci including Hk2 and Eno2 (Fig 4A and E, and Appendix Fig S6B).	('Eno2', 'Gene', (284, 288))	('amplification', 'Var', (191, 204))	('Hk2', 'Gene', (276, 279))	('EV2', 'Gene', '147138', (165, 168))	('EV2', 'Gene', (165, 168))	('glycolysis-associated pathways', 'Pathway', (127, 157))
352040	28202506	Chromosomal instability and high glycolysis characterize some of the most aggressive tumors, and the complexity and plasticity of the genomes in aggressive tumors can hinder molecularly targeted therapies (Nakamura et al, 2011; McGranahan et al, 2012; Shi et al, 2012).	('aggressive tumors', 'Disease', 'MESH:D001523', (74, 91))	('high glycolysis', 'MPA', (28, 43))	('aggressive tumors', 'Disease', (145, 162))	('aggressive tumors', 'Disease', (74, 91))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('Chromosomal', 'Var', (0, 11))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('Chromosomal instability', 'Phenotype', 'HP:0040012', (0, 23))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('hinder', 'NegReg', (167, 173))	('aggressive tumors', 'Disease', 'MESH:D001523', (145, 162))
352043	28202506	We found that CNAs in core glycolysis enzymes (e.g., HK2) and other cancer-linked metabolic enzymes such as TIGAR are coordinately enriched in tumors with distinct CNA signatures.	('CNAs', 'Var', (14, 18))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('HK2', 'Gene', (53, 56))	('tumors', 'Disease', (143, 149))	('TIGAR', 'Gene', (108, 113))	('tumors', 'Disease', 'MESH:D009369', (143, 149))	('HK2', 'Gene', '3099', (53, 56))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('cancer', 'Disease', (68, 74))	('TIGAR', 'Gene', '57103', (108, 113))
352048	28202506	Combined with the observation that metabolic genes can facilitate cellular immortalization (Kondoh et al, 2005; Kondoh, 2009; Kaplon et al, 2013), our results implicate tumor metabolism as an additional fitness measure linked to how genomic instability can enable tumorigenesis.	('enable', 'PosReg', (257, 263))	('tumor', 'Phenotype', 'HP:0002664', (264, 269))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('tumor', 'Disease', (264, 269))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('genomic instability', 'Var', (233, 252))	('tumor', 'Disease', (169, 174))	('tumor', 'Disease', 'MESH:D009369', (264, 269))
352050	28202506	Paradoxically, chromosomal instability can act either as an oncogene or as a tumor suppressor depending on the context (Weaver et al, 2007).	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('chromosomal instability', 'Var', (15, 38))	('tumor', 'Disease', (77, 82))	('chromosomal instability', 'Phenotype', 'HP:0040012', (15, 38))
352056	28202506	Numerous stimuli, including RAS mutations, matrix detachment, altered metabolism, and hypoxia, induce the accumulation of intracellular ROS (Lee et al, 1999; Schafer et al, 2009; Weinberg et al, 2010; Anastasiou et al, 2011).	('ROS', 'Chemical', 'MESH:D017382', (136, 139))	('accumulation', 'PosReg', (106, 118))	('RAS', 'Gene', (28, 31))	('mutations', 'Var', (32, 41))	('hypoxia', 'Disease', (86, 93))	('hypoxia', 'Disease', 'MESH:D000860', (86, 93))	('intracellular ROS', 'MPA', (122, 139))
352062	28202506	RNA knockdown-based analyses have also been used to support a more systems-level model in which the selection for amplification and deletion of a particular DNA region is based on the cumulative effects of many positive and negative fitness gains from multiple genes within that genomic region (Solimini et al, 2012; Cai et al, 2016).	('deletion', 'Var', (132, 140))	('fitness gains', 'Disease', 'MESH:D015430', (233, 246))	('negative', 'NegReg', (224, 232))	('fitness gains', 'Disease', (233, 246))
352066	28202506	The coordinated alterations of metabolic genes at the DNA level adds an additional mechanism, namely conserved sets of CNA changes, by which glycolysis is dysregulated to promote tumorigenesis.	('alterations', 'Reg', (16, 27))	('promote', 'PosReg', (171, 178))	('changes', 'Var', (123, 130))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('glycolysis', 'MPA', (141, 151))	('tumor', 'Disease', (179, 184))
352069	28202506	Across multiple tumor types, loss of p53 function through p53 mutation is associated with the high breakpoint signature A pattern.	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('function', 'MPA', (41, 49))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('loss', 'NegReg', (29, 33))	('p53', 'Protein', (37, 40))	('mutation', 'Var', (62, 70))	('tumor', 'Disease', (16, 21))	('p53', 'Gene', (58, 61))	('high breakpoint signature A', 'MPA', (94, 121))
352070	28202506	In contrast, loss of the p53/ARF axis via other mechanisms (MDM2 amplification or CDKN2A deletion) in BRCA human tumors is associated with a different CNA signature (signature B) that in general has fewer breakpoints.	('MDM2', 'Gene', '4193', (60, 64))	('BRCA', 'Gene', (102, 106))	('MDM2', 'Gene', (60, 64))	('tumors', 'Disease', (113, 119))	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('human', 'Species', '9606', (107, 112))	('CDKN2A', 'Gene', (82, 88))	('ARF axis', 'Disease', (29, 37))	('deletion', 'Var', (89, 97))	('CDKN2A', 'Gene', '1029', (82, 88))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('loss', 'NegReg', (13, 17))	('CNA signature', 'MPA', (151, 164))	('ARF axis', 'Disease', 'MESH:C566610', (29, 37))	('BRCA', 'Gene', '672', (102, 106))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
352071	28202506	Notably, the two mouse signatures and their associated phenotype strengths were defined by the initiating loss of tumor suppression event, namely Trp53 mutation versus either Mdm2 amplification or Cdkn2a loss.	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('mouse', 'Species', '10090', (17, 22))	('Trp53', 'Gene', (146, 151))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('loss', 'NegReg', (204, 208))	('tumor', 'Disease', (114, 119))	('Trp53', 'Gene', '22059', (146, 151))	('loss', 'NegReg', (106, 110))	('mutation', 'Var', (152, 160))
352072	28202506	Thus, while the consequences of TP53 mutation and "MDM2 amplification/CDKN2A loss" are considered functionally similar and therefore mutually exclusive (Wade et al, 2013), our findings indicate they are not fully equivalent in terms of genomic instability and subsequent metabolic evolution.	('mutation', 'Var', (37, 45))	('TP53', 'Gene', '7157', (32, 36))	('MDM2', 'Gene', '4193', (51, 55))	('MDM2', 'Gene', (51, 55))	('TP53', 'Gene', (32, 36))	('loss', 'NegReg', (77, 81))	('CDKN2A', 'Gene', (70, 76))	('CDKN2A', 'Gene', '1029', (70, 76))
352073	28202506	The tolerance of more highly disrupted and rearranged genomes upon p53 mutation appears to allow more flexibility in the evolution of aneuploid cancer genomes, thereby resulting in stronger glycolysis and somewhat enhanced proliferation.	('glycolysis', 'MPA', (190, 200))	('proliferation', 'CPA', (223, 236))	('aneuploid cancer', 'Disease', (134, 150))	('mutation', 'Var', (71, 79))	('aneuploid cancer', 'Disease', 'MESH:D000782', (134, 150))	('p53', 'Gene', (67, 70))	('stronger', 'PosReg', (181, 189))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('enhanced', 'PosReg', (214, 222))
352077	28202506	The most copy number aberrant tumors tend to have fewer point mutations in canonical oncogenes (e.g., KRAS, Fig EV2A and C) and less canonical oncogene amplification (e.g., MYC, Fig 1B).	('tumors', 'Disease', (30, 36))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('MYC', 'Gene', '4609', (173, 176))	('point mutations', 'MPA', (56, 71))	('MYC', 'Gene', (173, 176))	('fewer', 'NegReg', (50, 55))	('copy number aberrant', 'Var', (9, 29))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('EV2A and C', 'Gene', '2121', (112, 122))	('KRAS', 'Gene', (102, 106))	('KRAS', 'Gene', '3845', (102, 106))
352078	28202506	Hence, genomic instability and subsequent coordinate alterations in multiple genes within a functional pathway may provide an alternate, more complex, pathway to acquisition of aggressive tumor phenotypes:with tumor evolution and selection guiding the trajectory (Ciriello et al, 2013).	('tumor', 'Disease', (188, 193))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('aggressive tumor', 'Disease', (177, 193))	('tumor', 'Disease', (210, 215))	('genomic instability', 'Var', (7, 26))	('alterations', 'Var', (53, 64))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('aggressive tumor', 'Disease', 'MESH:D001523', (177, 193))	('tumor', 'Disease', 'MESH:D009369', (210, 215))
352079	28202506	In that KRAS mutation and MYC amplification can drive glycolysis (Ying et al, 2012; Dang, 2013), the findings that signature A tumors are de-enriched in these events relative to signature B tumors and enriched for glycolysis gene loci CNA amplifications support that tumor cells can meet their metabolic demands through distinct mechanisms, or combinations thereof.	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('tumor', 'Disease', 'MESH:D009369', (267, 272))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('A tumors', 'Disease', 'MESH:D009369', (125, 133))	('MYC', 'Gene', (26, 29))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('drive', 'Reg', (48, 53))	('glycolysis', 'MPA', (54, 64))	('tumor', 'Phenotype', 'HP:0002664', (267, 272))	('B tumors', 'Disease', (188, 196))	('MYC', 'Gene', '4609', (26, 29))	('A tumors', 'Disease', (125, 133))	('B tumors', 'Disease', 'MESH:D006509', (188, 196))	('KRAS', 'Gene', '3845', (8, 12))	('tumor', 'Disease', (190, 195))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('tumor', 'Disease', (127, 132))	('mutation', 'Var', (13, 21))	('KRAS', 'Gene', (8, 12))	('tumor', 'Disease', (267, 272))	('tumors', 'Phenotype', 'HP:0002664', (190, 196))	('tumor', 'Disease', 'MESH:D009369', (127, 132))
352080	28202506	Future models of the most aggressive cases of cancer will need to incorporate aspects of spontaneous genomic instability (mediated by distinct instability mechanisms) and resulting copy number alterations.	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('cancer', 'Disease', (46, 52))	('copy number alterations', 'Var', (181, 204))	('spontaneous genomic instability', 'MPA', (89, 120))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))
352083	28202506	p53fl/fl MEFs were obtained at day E14.5 from p53fl/fl (FVB.129P2-Trp53tm1Brn/Nci) crossed with C57BL/6-129/SV mice.	('129/SV', 'Species', '10090', (104, 110))	('MEFs', 'CellLine', 'CVCL:9115', (9, 13))	('Trp53', 'Gene', (66, 71))	('mice', 'Species', '10090', (111, 115))	('Trp53', 'Gene', '22059', (66, 71))	('p53fl/fl', 'Var', (46, 54))
352087	28202506	Overexpression of HK1, HK2, kinase-dead HK2 (D209A/D657A), or ENO2 glycolysis enzymes and the MYC oncogene or the control protein RFP in CD1 MEFs was accomplished by transduction of non-immortalized cells with pDS-FB-neo retrovirus, followed by selection in 600 mug/ml G418.	('RFP', 'Gene', (130, 133))	('MYC', 'Gene', (94, 97))	('D657A', 'SUBSTITUTION', 'None', (51, 56))	('ENO2', 'Gene', '2026', (62, 66))	('HK2, kinase-dead HK2', 'Gene', '3099', (23, 43))	('HK1', 'Gene', '3098', (18, 21))	('RFP', 'Gene', '2358', (130, 133))	('HK1', 'Gene', (18, 21))	('MEFs', 'CellLine', 'CVCL:9115', (141, 145))	('D657A', 'Var', (51, 56))	('G418', 'Chemical', 'MESH:C010680', (269, 273))	('ENO2', 'Gene', (62, 66))	('MYC', 'Gene', '4609', (94, 97))	('D209A', 'Var', (45, 50))	('D209A', 'SUBSTITUTION', 'None', (45, 50))
352088	28202506	Deletion of p53 in p53fl/fl MEFs was induced by infection of non-immortalized cells with either retroviral Cre-GFP or Cre-ERT2 plus treatment with 1 muM 4-OHT.	('4-OHT', 'Chemical', 'MESH:C032278', (153, 158))	('ERT2', 'Gene', '5595', (122, 126))	('p53', 'Gene', (12, 15))	('MEFs', 'CellLine', 'CVCL:9115', (28, 32))	('ERT2', 'Gene', (122, 126))	('Deletion', 'Var', (0, 8))
352096	28202506	Molecular subtypes tested were as follows: BRCA: basal, luminal, claudin-low, and HER2-enriched (The Cancer Genome Atlas Research Network, 2012b); LUAD: bronchioid, magnoid, and squamoid (The Cancer Genome Atlas Research Network, 2014); LUSC: basal, classical, primitive, and secretory (The Cancer Genome Atlas Research Network, 2012a); OV: proliferative, immunoreactive, differentiated, and mesenchymal (The Cancer Genome Atlas Research Network, 2011); and UCEC: POLE ultramutated, microsatellite instability hypermutated, copy number low, and copy number high (The Cancer Genome Atlas Research Network, 2013).	('AD', 'Disease', (149, 151))	('low', 'NegReg', (536, 539))	('copy number high', 'Var', (545, 561))	('LUSC', 'Phenotype', 'HP:0030359', (237, 241))	('Cancer', 'Phenotype', 'HP:0002664', (291, 297))	('copy number', 'Var', (524, 535))	('OV', 'Phenotype', 'HP:0012887', (337, 339))	('Cancer', 'Phenotype', 'HP:0002664', (192, 198))	('HER2', 'Gene', (82, 86))	('Cancer', 'Phenotype', 'HP:0002664', (567, 573))	('BRCA', 'Gene', '672', (43, 47))	('HER2', 'Gene', '2064', (82, 86))	('Cancer', 'Phenotype', 'HP:0002664', (409, 415))	('Cancer', 'Phenotype', 'HP:0002664', (101, 107))	('BRCA', 'Gene', (43, 47))	('AD', 'Disease', 'MESH:D000544', (149, 151))
352101	28202506	The signed absolute minimum consistency score (SAMCS) was defined as non-zero when all CNA summary signatures have the same sign across all tumor types, and the score is derived from the absolute value-based minimum summary metric and then re-signed positive for amplification or negative for deletion.	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('amplification', 'Var', (263, 276))	('tumor', 'Disease', (140, 145))
352102	28202506	Consistent amplifications or deletions were combined into a "consistent region", when absolute SAMCS values greater than 0.05 spanned at least 1 Mbp.	('deletions', 'Var', (29, 38))	('Mbp', 'Gene', (145, 148))	('Mbp', 'Gene', '4155', (145, 148))
352149	28202506	The genetically engineered mouse models with characterized CNA were obtained from public datasets: mammary (breast) tumors (Brca, 57 samples, GSE30710; 62 samples, GSE43997; 44 samples, GSE27101) (Drost et al, 2011; Herschkowitz et al, 2012); melanoma (Skcm, 30 samples, GSE58265) (Viros et al, 2014); glioblastoma/high-grade astrocytoma (Gbm, 72 samples, GSE22927) (Chow et al, 2011); and prostate tumors (Prad, 18 samples GSE35247; 55 samples, GSE61382) (Ding et al, 2012; Wanjala et al, 2015).	('glioblastoma', 'Phenotype', 'HP:0012174', (302, 314))	('GSE35247; 55', 'Var', (424, 436))	('melanoma', 'Disease', 'MESH:D008545', (243, 251))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))	('prostate tumors', 'Disease', (390, 405))	('breast) tumors', 'Disease', 'MESH:D001943', (108, 122))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('prostate tumors', 'Disease', 'MESH:D011471', (390, 405))	('astrocytoma', 'Phenotype', 'HP:0009592', (326, 337))	('Brca', 'Gene', '672', (124, 128))	('melanoma', 'Phenotype', 'HP:0002861', (243, 251))	('melanoma', 'Disease', (243, 251))	('tumors', 'Phenotype', 'HP:0002664', (399, 405))	('glioblastoma', 'Disease', 'MESH:D005909', (302, 314))	('Brca', 'Gene', (124, 128))	('mouse', 'Species', '10090', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (399, 404))	('glioblastoma', 'Disease', (302, 314))	('astrocytoma', 'Disease', 'MESH:D001254', (326, 337))	('astrocytoma', 'Disease', (326, 337))
352235	27057838	Nodal yield <18 has been associated with reduced OS, disease-specific survival (DSS), and DFS.	('disease-specific survival', 'CPA', (53, 78))	('reduced', 'NegReg', (41, 48))	('DFS', 'CPA', (90, 93))	('OS', 'Chemical', '-', (49, 51))	('<18', 'Var', (12, 15))	('DSS', 'Chemical', '-', (80, 83))
352237	27057838	In the present study, patients with LND >= 0.06 had significantly worse OS and DSS.	('OS', 'Chemical', '-', (72, 74))	('patients', 'Species', '9606', (22, 30))	('worse', 'NegReg', (66, 71))	('DSS', 'Chemical', '-', (79, 82))	('LND >= 0.06', 'Var', (36, 47))	('DSS', 'CPA', (79, 82))
352270	33474827	7  In addition, TEP RNA profiles have been reported to precisely pinpoint the primary origin of pan-cancer, as well as predict the oncogenic status of many tumors including MET or HER2 positivity and the existence of KRAS, EGFR, or PIK3CA mutations.	('PIK3CA', 'Gene', '5290', (232, 238))	('EGFR', 'Gene', '1956', (223, 227))	('HER2', 'Gene', (180, 184))	('TEP', 'Chemical', '-', (16, 19))	('mutations', 'Var', (239, 248))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('KRAS', 'Gene', '3845', (217, 221))	('MET', 'Gene', (173, 176))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('PIK3CA', 'Gene', (232, 238))	('KRAS', 'Gene', (217, 221))	('positivity', 'Var', (185, 195))	('HER2', 'Gene', '2064', (180, 184))	('EGFR', 'Gene', (223, 227))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('cancer', 'Disease', (100, 106))	('tumors', 'Disease', (156, 162))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('MET', 'Gene', '79811', (173, 176))	('tumors', 'Disease', 'MESH:D009369', (156, 162))
352311	33474827	To explore the potential of TEP SNORD55 as a circulating diagnostic marker for NSCLC, a ROC curve was plotted as shown in Figure 3a, and excellent separation between the groups of patients and controls was observed.	('NSCLC', 'Disease', 'MESH:D002289', (79, 84))	('SNORD55', 'Gene', '26811', (32, 39))	('TEP', 'Var', (28, 31))	('SNORD55', 'Gene', (32, 39))	('NSCLC', 'Disease', (79, 84))	('NSCLC', 'Phenotype', 'HP:0030358', (79, 84))	('patients', 'Species', '9606', (180, 188))	('TEP', 'Chemical', '-', (28, 31))
352314	33474827	As shown in Figure 3b, the AUC of SNORD55 was 0.784 with 91.2% sensitivity and 49.7% specificity.	('SNORD55', 'Gene', (34, 41))	('SNORD55', 'Gene', '26811', (34, 41))	('0.784', 'Var', (46, 51))
352369	29707153	Finally, the kallikreins can activate one another, and cross-activation of kallikreins may be related to malignancies.	('malignancies', 'Disease', (105, 117))	('kallikrein', 'Gene', (75, 85))	('kallikrein', 'Gene', (13, 23))	('kallikrein', 'Gene', '9622', (75, 85))	('kallikrein', 'Gene', '9622', (13, 23))	('cross-activation', 'Var', (55, 71))	('malignancies', 'Disease', 'MESH:D009369', (105, 117))	('activate', 'PosReg', (29, 37))	('related', 'Reg', (94, 101))
352443	29707153	Thyroid hormones regulate kallikrein levels, and the dysfunction of thyroid hormones during thyroid carcinoma may lead to the dramatic changes in the kallikreins' expression.	('changes', 'Reg', (135, 142))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (92, 109))	('kallikrein', 'Gene', (26, 36))	('kallikrein', 'Gene', '9622', (150, 160))	('dysfunction of thyroid hormones', 'Phenotype', 'HP:0002930', (53, 84))	('kallikrein', 'Gene', (150, 160))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (92, 109))	('kallikrein', 'Gene', '9622', (26, 36))	('expression', 'MPA', (163, 173))	('thyroid carcinoma', 'Disease', (92, 109))	('dysfunction', 'Var', (53, 64))	('lead to', 'Reg', (114, 121))
352450	29707153	Increased KLK8 has been associated with a favorable clinical outcome in lung adenocarcinoma by suppressing tumor invasiveness through inhibition of integrin signaling and cell adhesion; however we could not confirm this finding in our study.	('lung adenocarcinoma', 'Disease', (72, 91))	('tumor invasiveness', 'Disease', (107, 125))	('suppressing', 'NegReg', (95, 106))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (72, 91))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('Increased', 'Var', (0, 9))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('inhibition', 'NegReg', (134, 144))	('tumor invasiveness', 'Disease', 'MESH:D009369', (107, 125))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (72, 91))	('KLK8', 'Gene', '11202', (10, 14))	('integrin signaling', 'MPA', (148, 166))	('KLK8', 'Gene', (10, 14))	('cell adhesion', 'CPA', (171, 184))
352557	33324549	The results showed that only CSS was significantly better in LSCC group than LCNEC group (HR, 0.563; 95% CI, 0.392-0.807; P = 0.002), while OS was not (HR, 0.893; 95% CI, 0.750-1.064; P = 0.204) (Figures 4A, B).	('LCNEC', 'Chemical', '-', (77, 82))	('CSS', 'MPA', (29, 32))	('better', 'PosReg', (51, 57))	('LSCC', 'Var', (61, 65))	('LSCC', 'Chemical', '-', (61, 65))
352596	30463956	Additionally, we defined germline variants associated with the abundance of immune cells that infiltrated the tumor.	('variants', 'Var', (34, 42))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('associated', 'Reg', (43, 53))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
352601	30463956	Herein, we systematically determined the association of common germline genetic variants with gene expression and immune cell infiltration of the tumor.	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('association', 'Interaction', (41, 52))	('tumor', 'Disease', (146, 151))	('variants', 'Var', (80, 88))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
352607	30463956	To thrive, tumor cells acquire characteristics of sustained proliferation, genome instability, and mutation.	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('tumor', 'Disease', (11, 16))	('genome instability', 'CPA', (75, 93))	('mutation', 'Var', (99, 107))	('sustained proliferation', 'CPA', (50, 73))	('tumor', 'Disease', 'MESH:D009369', (11, 16))
352615	30463956	To formally test whether similar underlying genetic variants are determinants of gene expression in cancer, we applied a similar approach, establishing the set of common hereditable factors that are associated with cancer-immune phenotypes.	('associated', 'Reg', (199, 209))	('cancer', 'Disease', (215, 221))	('cancer', 'Disease', 'MESH:D009369', (215, 221))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('variants', 'Var', (52, 60))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))
352634	30463956	Interestingly, several cancer types, including THCA, prostate adenocarcinoma (PRAD), brain lower grade glioma, and acute myeloid leukemia, had a higher number of eGenes than other cancer types when sample size differences were adjusted (SI Appendix, Fig.	('THCA', 'Phenotype', 'HP:0002890', (47, 51))	('cancer', 'Disease', 'MESH:D009369', (23, 29))	('SI Appendix', 'Disease', 'MESH:D001063', (237, 248))	('glioma', 'Disease', (103, 109))	('acute myeloid leukemia', 'Disease', (115, 137))	('cancer', 'Disease', (180, 186))	('SI Appendix', 'Disease', (237, 248))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('glioma', 'Disease', 'MESH:D005910', (103, 109))	('cancer', 'Disease', (23, 29))	('prostate adenocarcinoma', 'Disease', (53, 76))	('eGenes', 'Var', (162, 168))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('leukemia', 'Phenotype', 'HP:0001909', (129, 137))	('THCA', 'Disease', (47, 51))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (115, 137))	('glioma', 'Phenotype', 'HP:0009733', (103, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('prostate adenocarcinoma', 'Disease', 'MESH:D011471', (53, 76))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (115, 137))	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (121, 137))
352649	30463956	We asked if copy number alteration, a common anomaly in cancer, could be one of the unexplained confounding factors.	('anomaly', 'Disease', (45, 52))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('copy number alteration', 'Var', (12, 34))	('anomaly', 'Disease', 'MESH:D000014', (45, 52))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))
352650	30463956	Indeed, we found in many cancer types that select PEER factors correlated with copy number (SI Appendix, Fig.	('correlated', 'Reg', (63, 73))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('SI Appendix', 'Disease', 'MESH:D001063', (92, 103))	('cancer', 'Disease', 'MESH:D009369', (25, 31))	('cancer', 'Disease', (25, 31))	('copy number', 'Var', (79, 90))	('SI Appendix', 'Disease', (92, 103))
352655	30463956	The impact of copy number on SETD4 expression is illustrated by the boxplot showing a positive correlation between SETD4 copy number and SETD4 mRNA expression levels (Fig.	('SETD4', 'Gene', '54093', (115, 120))	('SETD4', 'Gene', (115, 120))	('SETD4', 'Gene', '54093', (29, 34))	('SETD4', 'Gene', (29, 34))	('mRNA expression levels', 'MPA', (143, 165))	('copy number', 'Var', (121, 132))	('SETD4', 'Gene', '54093', (137, 142))	('SETD4', 'Gene', (137, 142))
352664	30463956	We focused on eQTL-eGene pairs for which associated genetic variants most strongly contribute to heterogeneity in tumor gene expression.	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumor', 'Disease', (114, 119))	('heterogeneity', 'MPA', (97, 110))	('variants', 'Var', (60, 68))	('contribute', 'Reg', (83, 93))
352668	30463956	For the top eQTL, rs2927608, the effect sizes (beta) on ERAP2 gene expression ranged from 1.02 in lung squamous cell carcinoma (LUSC) to 0.98 in skin cutaneous melanoma (SKCM) (Fig.	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (98, 126))	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (103, 126))	('melanoma', 'Phenotype', 'HP:0002861', (160, 168))	('lung squamous cell carcinoma', 'Disease', (98, 126))	('rs2927608', 'Mutation', 'rs2927608', (18, 27))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (145, 168))	('ERAP2', 'Gene', (56, 61))	('skin cutaneous melanoma', 'Disease', (145, 168))	('rs2927608', 'Var', (18, 27))	('ERAP2', 'Gene', '64167', (56, 61))	('expression', 'MPA', (67, 77))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (150, 168))
352669	30463956	For example, in BLCA, the genotype of rs2927608 was associated with expression levels of ERAP2 (beta = 1.19, P = 6.69 x 10-36) (Fig.	('rs2927608', 'Mutation', 'rs2927608', (38, 47))	('ERAP2', 'Gene', (89, 94))	('ERAP2', 'Gene', '64167', (89, 94))	('rs2927608', 'Var', (38, 47))	('expression levels', 'MPA', (68, 85))
352671	30463956	Interestingly, the haplotype associated with low ERAP2 expression, tagged by the rs2927608-G allele, contains an SNP that has been previously reported to alter a splice donor site, and thus to result in intronic read-through and the introduction of a stop codon, which, in turn, leads to nonsense-mediated decay (NMD) of the ERAP2 mRNA (haplotype B in SI Appendix, Fig.	('SI Appendix', 'Disease', 'MESH:D001063', (352, 363))	('leads to', 'Reg', (279, 287))	('alter', 'Reg', (154, 159))	('intronic read-through', 'MPA', (203, 224))	('SI Appendix', 'Disease', (352, 363))	('rs2927608-G', 'Var', (81, 92))	('SNP', 'Var', (113, 116))	('rs2927608', 'Mutation', 'rs2927608', (81, 90))	('donor', 'Species', '9606', (169, 174))	('ERAP2', 'Gene', (49, 54))	('ERAP2', 'Gene', (325, 330))	('nonsense-mediated decay', 'MPA', (288, 311))	('result in', 'Reg', (193, 202))	('expression', 'MPA', (55, 65))	('low', 'NegReg', (45, 48))	('ERAP2', 'Gene', '64167', (49, 54))	('stop', 'MPA', (251, 255))	('mRNA', 'MPA', (331, 335))	('ERAP2', 'Gene', '64167', (325, 330))	('splice donor site', 'MPA', (162, 179))
352673	30463956	The most significant eQTL for ICOSLG, rs7278940, mapped to a haplotype with a known GWAS hit for celiac disease.	('rs7278940', 'Mutation', 'rs7278940', (38, 47))	('celiac disease', 'Phenotype', 'HP:0002608', (97, 111))	('ICOSLG', 'Disease', (30, 36))	('rs7278940', 'Var', (38, 47))	('celiac disease', 'Disease', (97, 111))
352674	30463956	The rs7278940 eQTL showed an effect size on ICOSLG gene expression that ranged from 0.85 in stomach adenocarcinoma (STAD) to 1.2 in LUSC (SI Appendix, Fig.	('SI Appendix', 'Disease', 'MESH:D001063', (138, 149))	('ICOSLG gene', 'Gene', (44, 55))	('stomach adenocarcinoma', 'Disease', 'MESH:D013274', (92, 114))	('SI Appendix', 'Disease', (138, 149))	('stomach adenocarcinoma', 'Disease', (92, 114))	('rs7278940', 'Var', (4, 13))	('expression', 'MPA', (56, 66))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('rs7278940', 'Mutation', 'rs7278940', (4, 13))
352681	30463956	Additionally, activating ICOS has been shown to enhance tumor immunity in mice, and agonist antibodies are being developed for cancer immunotherapy in humans.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Disease', (56, 61))	('activating', 'Var', (14, 24))	('ICOS', 'Protein', (25, 29))	('enhance', 'PosReg', (48, 55))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('cancer', 'Disease', (127, 133))	('mice', 'Species', '10090', (74, 78))	('humans', 'Species', '9606', (151, 157))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
352686	30463956	Consistent with mouse studies, patients with low ERAP2 expression had better overall survival relative to those with higher ERAP2 expression (P = 0.03) (Fig.	('ERAP2', 'Gene', '64167', (124, 129))	('ERAP2', 'Gene', (49, 54))	('better', 'PosReg', (70, 76))	('overall survival', 'MPA', (77, 93))	('ERAP2', 'Gene', (124, 129))	('ERAP2', 'Gene', '64167', (49, 54))	('mouse', 'Species', '10090', (16, 21))	('patients', 'Species', '9606', (31, 39))	('low', 'Var', (45, 48))
352691	30463956	These data suggest that ERAP2 is an independent prognostic predictor of survival in patients with luminal subtype bladder cancer receiving anti-PD-L1 therapy, and, in fact, low ERAP2 expression can be used along with the IFN-gamma response to establish a further improved prognostic biomarker signature.	('low', 'Var', (173, 176))	('ERAP2', 'Gene', '64167', (177, 182))	('patients', 'Species', '9606', (84, 92))	('ERAP2', 'Gene', (24, 29))	('luminal subtype bladder cancer', 'Disease', (98, 128))	('IFN-gamma', 'Gene', (221, 230))	('IFN-gamma', 'Gene', '3458', (221, 230))	('ERAP2', 'Gene', '64167', (24, 29))	('luminal subtype bladder cancer', 'Disease', 'MESH:D001749', (98, 128))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('bladder cancer', 'Phenotype', 'HP:0009725', (114, 128))	('ERAP2', 'Gene', (177, 182))
352709	30463956	For example, the gsQTL rs35051459 was associated with the NKT cell gene signature in HNSC (beta = 0.44, P = 1.79 x 10-10) (Fig.	('associated', 'Reg', (38, 48))	('gsQTL', 'Gene', (17, 22))	('NKT cell gene signature', 'Gene', (58, 81))	('rs35051459', 'Var', (23, 33))	('rs35051459', 'Mutation', 'rs35051459', (23, 33))	('HNSC', 'Disease', (85, 89))
352712	30463956	Interestingly, expression of SEMA4D has been shown to influence the infiltration and distribution of leukocytes in the tumor microenvironment, and the inhibition of SEMA4D promoted immune infiltration into the tumor.	('SEMA4D', 'Gene', '10507', (165, 171))	('tumor', 'Disease', (119, 124))	('expression', 'Var', (15, 25))	('SEMA4D', 'Gene', (165, 171))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('infiltration', 'MPA', (68, 80))	('SEMA4D', 'Gene', '10507', (29, 35))	('tumor', 'Disease', (210, 215))	('SEMA4D', 'Gene', (29, 35))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('promoted', 'PosReg', (172, 180))	('inhibition', 'Var', (151, 161))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('tumor', 'Disease', 'MESH:D009369', (210, 215))	('distribution', 'MPA', (85, 97))	('influence', 'Reg', (54, 63))
352713	30463956	In agreement, the rs35051459 genotype associated with lower SEMA4D expression was associated with a higher NKT cell gene signature (Fig.	('SEMA4D', 'Gene', (60, 66))	('rs35051459', 'Mutation', 'rs35051459', (18, 28))	('rs35051459', 'Var', (18, 28))	('higher', 'PosReg', (100, 106))	('expression', 'MPA', (67, 77))	('NKT', 'MPA', (107, 110))	('SEMA4D', 'Gene', '10507', (60, 66))	('lower', 'NegReg', (54, 59))
352714	30463956	As a second example in STAD, the association between the gsQTL rs9308067 and the monocyte gene signature (beta = -0.95, P = 6.25 x 10-9) was partially mediated through the MARCH1 gene (Fig.	('MARCH1', 'Gene', (172, 178))	('MARCH1', 'Gene', '55016', (172, 178))	('rs9308067', 'Mutation', 'rs9308067', (63, 72))	('rs9308067', 'Var', (63, 72))	('gsQTL', 'Gene', (57, 62))	('monocyte gene signature', 'MPA', (81, 104))	('association', 'Interaction', (33, 44))
352716	30463956	For example, the gsQTL rs12063638 was associated with the cDC gene signature in STAD (beta = 0.44, P = 1.79 x 10-10) (Dataset S1).	('associated', 'Reg', (38, 48))	('gsQTL', 'Gene', (17, 22))	('rs12063638', 'Var', (23, 33))	('rs12063638', 'Mutation', 'rs12063638', (23, 33))	('STAD', 'Disease', (80, 84))	('cDC gene signature', 'Gene', (58, 76))
352717	30463956	Although rs12063638 has not been shown to be an eQTL, it is located downstream of the gene that encodes for glycoprotein podoplanin (PDPN) (Fig.	('rs12063638', 'Mutation', 'rs12063638', (9, 19))	('podoplanin', 'Gene', '10630', (121, 131))	('podoplanin', 'Gene', (121, 131))	('rs12063638', 'Var', (9, 19))	('PDPN', 'Gene', '10630', (133, 137))	('PDPN', 'Gene', (133, 137))
352718	30463956	We also highlight the gsQTL rs73016119, which was associated with the plasma cell gene signature in PAAD (beta = 1.39, P = 3.39 x 10-9).	('associated', 'Reg', (50, 60))	('PAAD', 'Phenotype', 'HP:0006725', (100, 104))	('rs73016119', 'Var', (28, 38))	('rs73016119', 'Mutation', 'rs73016119', (28, 38))
352719	30463956	Notably, rs73016119 is in LD with rs561722 (R2 = 0.74), which has been shown through GWASs to be associated with ulcerative colitis (Fig.	('rs73016119', 'Mutation', 'rs73016119', (9, 19))	('ulcerative colitis', 'Disease', (113, 131))	('rs561722', 'Var', (34, 42))	('rs561722', 'Mutation', 'rs561722', (34, 42))	('ulcerative colitis', 'Phenotype', 'HP:0100279', (113, 131))	('colitis', 'Phenotype', 'HP:0002583', (124, 131))	('associated', 'Reg', (97, 107))	('rs73016119', 'Var', (9, 19))	('ulcerative colitis', 'Disease', 'MESH:D003093', (113, 131))
352721	30463956	Together, the presence of gsQTLs for immune gene signatures suggests that germline genetic variants may influence the abundance, infiltration, and composition of immune cells in tumors.	('tumors', 'Disease', (178, 184))	('tumors', 'Disease', 'MESH:D009369', (178, 184))	('composition', 'CPA', (147, 158))	('tumors', 'Phenotype', 'HP:0002664', (178, 184))	('infiltration', 'CPA', (129, 141))	('abundance', 'MPA', (118, 127))	('variants', 'Var', (91, 99))	('influence', 'Reg', (104, 113))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))
352726	30463956	This allowed us to assign with confidence the impact of germline variants on the heterogeneous genes in patient tumors.	('germline variants', 'Var', (56, 73))	('tumors', 'Disease', (112, 118))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('patient', 'Species', '9606', (104, 111))	('tumors', 'Disease', 'MESH:D009369', (112, 118))	('heterogeneous genes', 'MPA', (81, 100))
352733	30463956	As discussed, haplotype B is known to generate an RNA transcript that is susceptible to NMD, providing a likely explanation for the low level of ERAP2 expression that is associated with the rs2927608-G allele.	('rs2927608-G', 'Var', (190, 201))	('expression', 'MPA', (151, 161))	('rs2927608', 'Mutation', 'rs2927608', (190, 199))	('ERAP2', 'Gene', (145, 150))	('ERAP2', 'Gene', '64167', (145, 150))
352734	30463956	The other major ERAP2 haplotype, tagged by the rs2927608-A allele, contains multiple risk alleles for autoimmune and inflammatory diseases, as identified in prior GWASs (SI Appendix, Fig.	('ERAP2', 'Gene', '64167', (16, 21))	('SI Appendix', 'Disease', 'MESH:D001063', (170, 181))	('SI Appendix', 'Disease', (170, 181))	('rs2927608', 'Mutation', 'rs2927608', (47, 56))	('rs2927608-A', 'Var', (47, 58))	('ERAP2', 'Gene', (16, 21))
352739	30463956	While seemingly paradoxical, ERAAP deficiency does not necessarily reduce the number of epitopes presented; instead, it alters the peptide repertoire, which may confer enhanced T cell responses in some individuals or mouse models.	('mouse', 'Species', '10090', (217, 222))	('peptide repertoire', 'MPA', (131, 149))	('alters', 'Reg', (120, 126))	('enhanced', 'PosReg', (168, 176))	('ERAAP', 'Gene', (29, 34))	('deficiency', 'Var', (35, 45))	('T cell responses', 'CPA', (177, 193))
352744	30463956	Further studies will be necessary to evaluate whether the prognostic effect of low ERAP2 expression can be generalized to other cancer types or other clinical trial datasets.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('expression', 'MPA', (89, 99))	('ERAP2', 'Gene', (83, 88))	('ERAP2', 'Gene', '64167', (83, 88))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('low', 'Var', (79, 82))	('cancer', 'Disease', (128, 134))
352746	30463956	Studies of autoimmune diseases, including ankylosing spondylitis and birdshot chorioretinitis, have already demonstrated strong interactions between ERAP2 polymorphisms and HLA haplotypes.	('chorioretinitis', 'Disease', (78, 93))	('autoimmune diseases', 'Disease', 'MESH:D001327', (11, 30))	('chorioretinitis', 'Disease', 'MESH:C566236', (78, 93))	('autoimmune diseases', 'Disease', (11, 30))	('autoimmune diseases', 'Phenotype', 'HP:0002960', (11, 30))	('ankylosing spondylitis', 'Disease', 'MESH:D013167', (42, 64))	('interactions', 'Interaction', (128, 140))	('chorioretinitis', 'Phenotype', 'HP:0012424', (78, 93))	('ERAP2', 'Gene', (149, 154))	('ERAP2', 'Gene', '64167', (149, 154))	('polymorphisms', 'Var', (155, 168))	('ankylosing spondylitis', 'Disease', (42, 64))
352747	30463956	While we did not observe stratification in our sample of patients with bladder cancer receiving anti-PD-L1, the strong underlying role for germline genetics may be an important consideration for active clinical development programs that are attempting to extend preclinical observations from mice.	('anti-PD-L1', 'Var', (96, 106))	('bladder cancer', 'Disease', 'MESH:D001749', (71, 85))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('patients', 'Species', '9606', (57, 65))	('bladder cancer', 'Disease', (71, 85))	('mice', 'Species', '10090', (292, 296))	('bladder cancer', 'Phenotype', 'HP:0009725', (71, 85))
352796	27455841	250 ng isolated cell line DNA and 250 ng sex-mismatched normal reference DNA (Promega) were labeled with Cy3 and Cy5, respectively, using the CGH labeling kit for oligo arrays (Enzo) following the Enzo's protocol.	('CGH', 'Gene', '3342', (142, 145))	('Cy5', 'Var', (113, 116))	('Cy3', 'Chemical', '-', (105, 108))	('Cy5', 'Chemical', 'MESH:C085321', (113, 116))	('Cy3', 'Var', (105, 108))	('CGH', 'Gene', (142, 145))
352806	27455841	The following Taqman  Assays were used (Life Technologies): AKT3 (Hs00987350_m1), GADD45A (Hs01077132_m1), MAL (Hs00360838_m1), HOPX (Hs04188695_m1), HYAL3 (Hs00185910_m1), TUBGCP3 (Hs00902139_m1), RGS16 (Hs00892674_m1), TNFAIP3 (Hs00234713_m1).	('Hs00185910_m1', 'Var', (157, 170))	('Hs00892674_m1', 'Var', (205, 218))	('RGS16', 'Gene', '6004', (198, 203))	('Hs04188695_m1', 'Var', (134, 147))	('AKT3', 'Gene', '10000', (60, 64))	('TUBGCP3', 'Gene', '10426', (173, 180))	('Hs01077132_m1', 'Var', (91, 104))	('AKT3', 'Gene', (60, 64))	('Hs00360838_m1', 'Var', (112, 125))	('Hs00902139_m1', 'Var', (182, 195))	('HYAL3', 'Gene', '8372', (150, 155))	('Hs00987350_m1', 'Var', (66, 79))	('TNFAIP3', 'Gene', '7128', (221, 228))	('GADD45A', 'Gene', (82, 89))	('TNFAIP3', 'Gene', (221, 228))	('TUBGCP3', 'Gene', (173, 180))	('GADD45A', 'Gene', '1647', (82, 89))	('Hs00234713_m1', 'Var', (230, 243))	('RGS16', 'Gene', (198, 203))	('HYAL3', 'Gene', (150, 155))
352807	27455841	ACTB (Hs01060665_g1) and GAPDH (Hs99999905_m1) served as endogenous reference genes.	('Hs99999905_m1', 'Var', (32, 45))	('ACTB', 'Gene', '60', (0, 4))	('ACTB', 'Gene', (0, 4))	('Hs01060665_g1', 'Var', (6, 19))
352819	27455841	Array CGH analysis identified 173 regions with aberrant copy number status from which 78, 111 and 132 regions were affected by DNA gains or DNA losses in the CAL-33 parental cells, SP, or RP subclones, respectively (Fig.	('copy number status', 'Var', (56, 74))	('SP', 'Chemical', 'MESH:C000604007', (181, 183))	('gains', 'PosReg', (131, 136))	('DNA', 'Gene', (127, 130))	('CAL', 'Gene', '54751', (158, 161))	('affected', 'Reg', (115, 123))	('losses', 'NegReg', (144, 150))	('CGH', 'Gene', '3342', (6, 9))	('CGH', 'Gene', (6, 9))	('CAL', 'Gene', (158, 161))
352820	27455841	68 copy number alterations (for SP) and 85 copy number alterations (for RP) were different from the parental CAL-33 cell line.	('copy number alterations', 'Var', (3, 26))	('SP', 'Chemical', 'MESH:C000604007', (32, 34))	('CAL', 'Gene', (109, 112))	('copy', 'MPA', (43, 47))	('CAL', 'Gene', '54751', (109, 112))
352821	27455841	In addition, recurrent CAL-33-specific alterations on chromosomes 3, 7, 18, X and Y were observed showing the authenticity of the newly generated cell lines.	('CAL', 'Gene', '54751', (23, 26))	('CAL', 'Gene', (23, 26))	('alterations', 'Var', (39, 50))
352823	27455841	This might be due to the observation that under exponential growth conditions, the percentage of mitotic cells in both subclones was decreased (2.1 % for subclone SP, 1.5 % for subclone RP, and 2.9 % for the parental cells), but fails to explain the differences in radiosensitivity (Additional file 3: Figure S1, B).	('mitotic cells', 'CPA', (97, 110))	('subclone SP', 'Var', (154, 165))	('decreased', 'NegReg', (133, 142))	('SP', 'Chemical', 'MESH:C000604007', (163, 165))
352832	27455841	For subclone SP, we identified 18 genes with DNA gains being up-regulated and 31 genes with DNA losses being down-regulated, whereas for subclone RP, 44 up-regulated genes showed copy number gains and 5 genes with copy number losses were down-regulated (Table 2).	('gains', 'PosReg', (191, 196))	('copy number', 'Var', (179, 190))	('down-regulated', 'NegReg', (238, 252))	('SP', 'Chemical', 'MESH:C000604007', (13, 15))	('up-regulated', 'PosReg', (61, 73))
352835	27455841	recently showed that high expression of TIAM1 is associated with poor clinical outcome in patients with HNSCC.	('HNSCC', 'Disease', (104, 109))	('TIAM1', 'Gene', (40, 45))	('HNSCC', 'Phenotype', 'HP:0012288', (104, 109))	('TIAM1', 'Gene', '7074', (40, 45))	('high', 'Var', (21, 25))	('patients', 'Species', '9606', (90, 98))
352854	27455841	Furthermore, ERVs may lead to genome instability, and contribute to tumor initiation and progression.	('tumor initiation', 'Disease', (68, 84))	('lead to', 'Reg', (22, 29))	('genome', 'CPA', (30, 36))	('ERVs', 'Var', (13, 17))	('progression', 'CPA', (89, 100))	('contribute', 'Reg', (54, 64))	('tumor initiation', 'Disease', 'MESH:D009369', (68, 84))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))
352876	25644061	Recently, a strong link between microRNA dysregulation and human cancers has been established.	('microRNA', 'Var', (32, 40))	('human', 'Species', '9606', (59, 64))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('cancers', 'Phenotype', 'HP:0002664', (65, 72))	('cancers', 'Disease', 'MESH:D009369', (65, 72))	('cancers', 'Disease', (65, 72))
352883	25644061	Though implicated in carcinogenesis, it is not clear how miRNAs promote tumorigenesis and metastasis or what networks regulate miRNAs expression.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('promote', 'PosReg', (64, 71))	('miRNAs', 'Var', (57, 63))	('tumor', 'Disease', (72, 77))	('metastasis', 'CPA', (90, 100))	('carcinogenesis', 'Disease', 'MESH:D063646', (21, 35))	('carcinogenesis', 'Disease', (21, 35))	('tumor', 'Disease', 'MESH:D009369', (72, 77))
352887	25644061	Overexpression of miR-31 has been linked to disease progression in colorectal cancer, head-and-neck squamous cell carcinoma (HNSCC) and lung cancer.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (100, 123))	('lung cancer', 'Phenotype', 'HP:0100526', (136, 147))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (95, 123))	('head-and-neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (86, 123))	('HNSCC', 'Phenotype', 'HP:0012288', (125, 130))	('linked to', 'Reg', (34, 43))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('colorectal cancer', 'Disease', 'MESH:D015179', (67, 84))	('miR-31', 'Gene', (18, 24))	('lung cancer', 'Disease', 'MESH:D008175', (136, 147))	('lung cancer', 'Disease', (136, 147))	('Overexpression', 'Var', (0, 14))	('colorectal cancer', 'Phenotype', 'HP:0003003', (67, 84))	('neck squamous cell carcinoma', 'Disease', (95, 123))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('colorectal cancer', 'Disease', (67, 84))
352901	25644061	The histone methyltransferase EZH2 (enhancer of zeste homolog 2) epigenetically regulates genes involved in cell fate determination.	('EZH2', 'Gene', (30, 34))	('enhancer of zeste homolog 2', 'Gene', '2146', (36, 63))	('epigenetically', 'Var', (65, 79))	('regulates', 'Reg', (80, 89))	('genes', 'Gene', (90, 95))	('enhancer of zeste homolog 2', 'Gene', (36, 63))
352906	25644061	Genetic and epigenetic loss of miR-31 is associated with EZH2 overexpression in melanoma, suggesting that miR-31 directly or indirectly regulates EZH2 expression.	('EZH2', 'Gene', (57, 61))	('epigenetic loss', 'Var', (12, 27))	('associated', 'Reg', (41, 51))	('miR-31', 'Gene', (31, 37))	('regulates', 'Reg', (136, 145))	('melanoma', 'Disease', 'MESH:D008545', (80, 88))	('melanoma', 'Phenotype', 'HP:0002861', (80, 88))	('melanoma', 'Disease', (80, 88))	('expression', 'MPA', (151, 161))	('overexpression', 'PosReg', (62, 76))
352913	25644061	Comparing esophageal squamous cell carcinoma cell lines, TE11 is less motile than TE8 and displays an epithelial phenotype (Figure 1A).	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (10, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (35, 44))	('esophageal squamous cell carcinoma', 'Disease', (10, 44))	('TE11', 'Var', (57, 61))	('less', 'NegReg', (65, 69))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (21, 44))
352914	25644061	The esophageal adenocarcinoma cell lines OE33 and FLO1 differ in that FLO1 is more mesenchymal and therefore more motile than the OE33 (Figure 1B).	('more', 'PosReg', (78, 82))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (4, 29))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (4, 29))	('esophageal adenocarcinoma', 'Disease', (4, 29))	('carcinoma', 'Phenotype', 'HP:0030731', (20, 29))	('motile', 'CPA', (114, 120))	('FLO1', 'Var', (70, 74))	('more', 'PosReg', (109, 113))
352915	25644061	After miR-200a and 200b, which are known for their roles in EMT, miR-31 was the most downregulated miRNA in invasive FLO1 cells compared to their less invasive OE33 counterparts by qPCR screen (Figure 1C).	('miRNA', 'MPA', (99, 104))	('downregulated', 'NegReg', (85, 98))	('miR-31', 'Var', (65, 71))	('miR-200a', 'Gene', (6, 14))	('miR-200a', 'Gene', '406983', (6, 14))
352919	25644061	In FLO1 cells, however, miR-31 suppressed proliferation and colony formation (Figure 2D, E, respectively), indicating miR-31 regulates esophageal carcinoma cell growth in some cell lines.	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('proliferation', 'CPA', (42, 55))	('miR-31', 'Var', (118, 124))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (135, 155))	('colony formation', 'CPA', (60, 76))	('miR-31', 'Var', (24, 30))	('suppressed', 'NegReg', (31, 41))	('regulates', 'Reg', (125, 134))	('esophageal carcinoma', 'Disease', (135, 155))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (135, 155))
352935	25644061	SOX4 knockdown (Figure 5A) using shRNA led to significant upregulation of miR-31 in TE8 and FLO1 cells, while miR-191 and miR-423-5p, used as controls, did not show any significant change (Figure 5B and C).	('miR-423', 'Gene', '494335', (122, 129))	('miR-191', 'Gene', '406966', (110, 117))	('knockdown', 'Var', (5, 14))	('miR-191', 'Gene', (110, 117))	('miR-31', 'Gene', (74, 80))	('miR-423', 'Gene', (122, 129))	('SOX4', 'Gene', (0, 4))	('upregulation', 'PosReg', (58, 70))
352936	25644061	We next investigated if loss of SOX4 functionally mimics overexpression of miR-31 in esophageal cancer cells.	('loss', 'Var', (24, 28))	('esophageal cancer', 'Disease', 'MESH:D004938', (85, 102))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('miR-31', 'Gene', (75, 81))	('esophageal cancer', 'Disease', (85, 102))
352941	25644061	HDAC3 and H3K27me3 were equally enriched at the MYT1 promoter, which was used as a positive control as EZH2 has been shown to bind and regulate MYT1 promoter activity.	('regulate', 'Reg', (135, 143))	('MYT1', 'Gene', '4661', (48, 52))	('MYT1', 'Gene', (144, 148))	('MYT1', 'Gene', (48, 52))	('bind', 'Interaction', (126, 130))	('H3K27me3', 'Var', (10, 18))	('MYT1', 'Gene', '4661', (144, 148))
352961	25644061	A number of studies argue that epithelial-mesenchymal transition (EMT) plays a crucial role in cancer metastasis and progression, and loss of miR-200 family members drives EMT in multiple cancers.	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('cancer metastasis', 'Disease', 'MESH:D009362', (95, 112))	('multiple cancers', 'Disease', 'MESH:D009369', (179, 195))	('drives', 'PosReg', (165, 171))	('cancers', 'Phenotype', 'HP:0002664', (188, 195))	('epithelial-mesenchymal transition', 'CPA', (31, 64))	('miR-200', 'Gene', (142, 149))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('cancer metastasis', 'Disease', (95, 112))	('multiple cancers', 'Disease', (179, 195))	('loss', 'Var', (134, 138))	('EMT', 'CPA', (172, 175))
352967	25644061	Therefore, we propose a key role for Polycomb/EZH2, HDAC and DNMT for survival and metastasis of esophageal cancers.	('metastasis of esophageal cancers', 'Disease', (83, 115))	('HDAC', 'Gene', (52, 56))	('HDAC', 'Gene', '9734', (52, 56))	('metastasis of esophageal cancers', 'Disease', 'MESH:D009362', (83, 115))	('DNMT', 'Gene', '1786', (61, 65))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('Polycomb/EZH2', 'Var', (37, 50))	('DNMT', 'Gene', (61, 65))	('cancers', 'Phenotype', 'HP:0002664', (108, 115))
352971	25644061	Additional studies will aim to identify a subset of patients with concomitant high SOX4, EZH2 and HDAC3 and low miR-31 to demonstrate the mechanistic and clinical correlation between these pathways.	('high', 'Var', (78, 82))	('EZH2', 'Gene', (89, 93))	('low', 'NegReg', (108, 111))	('HDAC3', 'Gene', (98, 103))	('SOX4', 'Gene', (83, 87))	('miR-31', 'Gene', (112, 118))	('patients', 'Species', '9606', (52, 60))
352993	25644061	Equal volumes of chromatin were immunoprecipitated with anti-HDAC3, anti-SOX4, anti-EZH2, anti-trimethyl-Histone H3 Lys27 or normal IgG as a negative control (Millipore).	('anti-EZH2', 'Var', (79, 88))	('anti-trimethyl-Histone H3 Lys27', 'Var', (90, 121))	('trimethyl-Histone', 'Chemical', '-', (95, 112))	('anti-SOX4', 'Var', (68, 77))	('IgG', 'Gene', '16059', (132, 135))	('IgG', 'Gene', (132, 135))	('anti-HDAC3', 'Var', (56, 66))	('Lys27', 'Chemical', '-', (116, 121))
353078	32509574	According to the 8th TNM staging by American Joint Committee on Cancer (AJCC), M1a was defined as intrathoracic metastases including contralateral lung nodules, pleural metastases and pericardial effusion, and M1b or M1c were defined as single or multiple extrathoracic metastases.	('TNM', 'Gene', '10178', (21, 24))	('pericardial effusion', 'Disease', 'MESH:D010490', (184, 204))	('Cancer', 'Disease', (64, 70))	('metastases', 'Disease', 'MESH:D009362', (270, 280))	('metastases', 'Disease', (169, 179))	('pericardial effusion', 'Phenotype', 'HP:0001698', (184, 204))	('Cancer', 'Disease', 'MESH:D009369', (64, 70))	('Cancer', 'Phenotype', 'HP:0002664', (64, 70))	('TNM', 'Gene', (21, 24))	('metastases', 'Disease', (270, 280))	('metastases', 'Disease', (112, 122))	('pericardial effusion', 'Disease', (184, 204))	('pleural metastases', 'Disease', 'MESH:D009362', (161, 179))	('metastases', 'Disease', 'MESH:D009362', (169, 179))	('M1a', 'Var', (79, 82))	('metastases', 'Disease', 'MESH:D009362', (112, 122))	('pleural metastases', 'Disease', (161, 179))	('contralateral lung nodules', 'Disease', (133, 159))
353136	30867647	Most importantly, MYC overexpression significantly coincided with mutations in PHACTR3 and E2F4 genes, in group of all patients and in squamous cell carcinoma subtype.	('mutations', 'Var', (66, 75))	('E2F4', 'Gene', '1874', (91, 95))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (135, 158))	('overexpression', 'PosReg', (22, 36))	('carcinoma', 'Phenotype', 'HP:0030731', (149, 158))	('squamous cell carcinoma subtype', 'Disease', 'MESH:D002294', (135, 166))	('MYC', 'Gene', (18, 21))	('patients', 'Species', '9606', (119, 127))	('squamous cell carcinoma subtype', 'Disease', (135, 166))	('PHACTR3', 'Gene', (79, 86))	('E2F4', 'Gene', (91, 95))	('PHACTR3', 'Gene', '116154', (79, 86))	('MYC', 'Gene', '4609', (18, 21))	('coincided', 'Reg', (51, 60))
353137	30867647	Moreover, patients with jointly overexpressed MYC and altered PHACTR3 or E2F4 showed trend of shorter survival.	('E2F4', 'Gene', (73, 77))	('PHACTR3', 'Gene', (62, 69))	('shorter', 'NegReg', (94, 101))	('E2F4', 'Gene', '1874', (73, 77))	('PHACTR3', 'Gene', '116154', (62, 69))	('MYC', 'Gene', (46, 49))	('altered', 'Var', (54, 61))	('patients', 'Species', '9606', (10, 18))	('survival', 'MPA', (102, 110))	('overexpressed', 'PosReg', (32, 45))	('MYC', 'Gene', '4609', (46, 49))
353138	30867647	Overall, MYC is frequently overexpressed in NSCLC and it is associated with mutated PHACTR3 gene, as well as mutated E2F4 gene.	('NSCLC', 'Disease', 'MESH:D002289', (44, 49))	('PHACTR3', 'Gene', '116154', (84, 91))	('MYC', 'Gene', '4609', (9, 12))	('E2F4', 'Gene', (117, 121))	('overexpressed', 'PosReg', (27, 40))	('mutated', 'Var', (76, 83))	('NSCLC', 'Phenotype', 'HP:0030358', (44, 49))	('MYC', 'Gene', (9, 12))	('mutated', 'Var', (109, 116))	('associated', 'Reg', (60, 70))	('E2F4', 'Gene', '1874', (117, 121))	('NSCLC', 'Disease', (44, 49))	('PHACTR3', 'Gene', (84, 91))
353174	30867647	Five out of six tested primers (p53 A, MDR A, E5A p53, GAPDH A, and GAPDH S) produced informative sequence alterations differentiating normal from tumor tissue.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('sequence alterations', 'MPA', (98, 118))	('E5A', 'Var', (46, 49))	('differentiating', 'Reg', (119, 134))	('GAPDH S', 'Gene', (68, 75))	('p53', 'Gene', (32, 35))	('GAPDH', 'Gene', (55, 60))	('p53', 'Gene', '7157', (32, 35))	('p53', 'Gene', (50, 53))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('p53', 'Gene', '7157', (50, 53))	('GAPDH S', 'Gene', '26330', (68, 75))
353191	30867647	We further examined MYC expression in relation to the presence of alterations in PHACTR3 and E2F4.	('E2F4', 'Gene', (93, 97))	('MYC', 'Gene', (20, 23))	('PHACTR3', 'Gene', (81, 88))	('PHACTR3', 'Gene', '116154', (81, 88))	('MYC', 'Gene', '4609', (20, 23))	('examined', 'Reg', (11, 19))	('E2F4', 'Gene', '1874', (93, 97))	('alterations', 'Var', (66, 77))
353193	30867647	Patients with altered PHACTR3 gene had more frequently increased MYC gene expression (Table III; p=0.015).	('PHACTR3', 'Gene', '116154', (22, 29))	('PHACTR3', 'Gene', (22, 29))	('altered', 'Var', (14, 21))	('MYC', 'Gene', (65, 68))	('increased', 'PosReg', (55, 64))	('Patients', 'Species', '9606', (0, 8))	('MYC', 'Gene', '4609', (65, 68))
353194	30867647	Among six patients with altered PHACTR3 gene, 5 (83.3%) had increased MYC mRNA level, while in 1 patient (16.7%) MYC was not overexpressed.	('MYC', 'Gene', '4609', (70, 73))	('altered', 'Var', (24, 31))	('MYC', 'Gene', '4609', (113, 116))	('patient', 'Species', '9606', (10, 17))	('MYC', 'Gene', (70, 73))	('patient', 'Species', '9606', (97, 104))	('patients', 'Species', '9606', (10, 18))	('MYC', 'Gene', (113, 116))	('PHACTR3', 'Gene', (32, 39))	('increased', 'PosReg', (60, 69))	('PHACTR3', 'Gene', '116154', (32, 39))
353197	30867647	MYC overexpression in the presence of E2F4 gene alterations showed the same pattern of conjunction as with the incidence of altered PHACTR3 gene (Table III).	('MYC', 'Gene', (0, 3))	('alterations', 'Var', (48, 59))	('E2F4', 'Gene', '1874', (38, 42))	('MYC', 'Gene', '4609', (0, 3))	('PHACTR3', 'Gene', (132, 139))	('E2F4', 'Gene', (38, 42))	('PHACTR3', 'Gene', '116154', (132, 139))
353198	30867647	Namely, 83.3% of patients with abnormal E2F4 had overexpressed MYC compared to 16.7% of patients that did not show overexpression of this oncogene (p=0.015).	('abnormal', 'Var', (31, 39))	('MYC', 'Gene', (63, 66))	('E2F4', 'Gene', (40, 44))	('patients', 'Species', '9606', (88, 96))	('overexpressed', 'PosReg', (49, 62))	('patients', 'Species', '9606', (17, 25))	('MYC', 'Gene', '4609', (63, 66))	('E2F4', 'Gene', '1874', (40, 44))
353200	30867647	Kaplan-Meier survival curves were analyzed to evaluate the effect of MYC gene overexpression in the presence of aforementioned gene alterations on NSCLC patients' survival.	('NSCLC', 'Disease', (147, 152))	('patients', 'Species', '9606', (153, 161))	('MYC', 'Gene', (69, 72))	('NSCLC', 'Disease', 'MESH:D002289', (147, 152))	('alterations', 'Var', (132, 143))	('overexpression', 'PosReg', (78, 92))	('NSCLC', 'Phenotype', 'HP:0030358', (147, 152))	('MYC', 'Gene', '4609', (69, 72))
353203	30867647	The median survival time was 1 month for patients with overexpressed MYC and altered PHACTR3 or E2F4 compared to 7.5 months for those with overexpressed MYC only (Figure 2B and C; p=0.138).	('PHACTR3', 'Gene', '116154', (85, 92))	('MYC', 'Gene', (69, 72))	('PHACTR3', 'Gene', (85, 92))	('MYC', 'Gene', '4609', (153, 156))	('MYC', 'Gene', '4609', (69, 72))	('E2F4', 'Gene', '1874', (96, 100))	('to 7', 'Species', '1214577', (110, 114))	('patients', 'Species', '9606', (41, 49))	('MYC', 'Gene', (153, 156))	('altered', 'Var', (77, 84))	('E2F4', 'Gene', (96, 100))
353205	30867647	Deregulation of its expression is critical for the pathogenesis of various cancer types, including lung cancer.	('lung cancer', 'Disease', (99, 110))	('expression', 'MPA', (20, 30))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('Deregulation', 'Var', (0, 12))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('cancer', 'Disease', (75, 81))	('lung cancer', 'Disease', 'MESH:D008175', (99, 110))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('lung cancer', 'Phenotype', 'HP:0100526', (99, 110))
353215	30867647	Moreover, these alterations significantly coincide with MYC overexpression in squamous cell carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('alterations', 'Var', (16, 27))	('MYC', 'Gene', (56, 59))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (78, 101))	('squamous cell carcinoma', 'Disease', (78, 101))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (78, 101))	('MYC', 'Gene', '4609', (56, 59))
353221	30867647	Considering interrelationship between MYC overexpression and mutational status of E2F4 the observed positive association is not surprising.	('E2F4', 'Gene', '1874', (82, 86))	('MYC', 'Gene', (38, 41))	('E2F4', 'Gene', (82, 86))	('mutational status', 'Var', (61, 78))	('MYC', 'Gene', '4609', (38, 41))
353229	30867647	Considering our previous results this joint effect of MYC and altered genes could be mainly attributed to the significant negative effects of altered PHACTR3 and E2F4 genes on NSCLC patients' survival.	('PHACTR3', 'Gene', (150, 157))	('MYC', 'Gene', '4609', (54, 57))	('PHACTR3', 'Gene', '116154', (150, 157))	('negative', 'NegReg', (122, 130))	('NSCLC', 'Disease', (176, 181))	('altered', 'Var', (142, 149))	('NSCLC', 'Disease', 'MESH:D002289', (176, 181))	('E2F4', 'Gene', '1874', (162, 166))	('patients', 'Species', '9606', (182, 190))	('MYC', 'Gene', (54, 57))	('NSCLC', 'Phenotype', 'HP:0030358', (176, 181))	('E2F4', 'Gene', (162, 166))
353232	30867647	Most importantly, we identified positive associations between MYC overexpression and aforementioned gene alterations not previously considered in NSCLC nor other cancer types, therefore opening a novel research perspective in studying c-Myc role in carcinogenesis.	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('carcinogenesis', 'Disease', (249, 263))	('MYC', 'Gene', (62, 65))	('cancer', 'Disease', (162, 168))	('NSCLC', 'Disease', (146, 151))	('c-Myc', 'Gene', '4609', (235, 240))	('alterations', 'Var', (105, 116))	('MYC', 'Gene', '4609', (62, 65))	('NSCLC', 'Disease', 'MESH:D002289', (146, 151))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('c-Myc', 'Gene', (235, 240))	('NSCLC', 'Phenotype', 'HP:0030358', (146, 151))	('overexpression', 'PosReg', (66, 80))	('carcinogenesis', 'Disease', 'MESH:D063646', (249, 263))
353246	28977982	Dysregulated expression of miRNA-100 is correlated with cancer diagnosis and prognosis.	('miRNA-100', 'Gene', (27, 36))	('expression', 'MPA', (13, 23))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('miRNA-100', 'Chemical', '-', (27, 36))	('correlated', 'Reg', (40, 50))	('Dysregulated', 'Var', (0, 12))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))
353272	28977982	MiRNA-100 could suppress the related proteins of the IGF/mTOR signaling cascade in different cancers.	('cancers', 'Disease', (93, 100))	('MiRNA-100', 'Chemical', '-', (0, 9))	('cancers', 'Phenotype', 'HP:0002664', (93, 100))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('suppress', 'NegReg', (16, 24))	('proteins', 'Protein', (37, 45))	('mTOR', 'Gene', (57, 61))	('MiRNA-100', 'Var', (0, 9))	('mTOR', 'Gene', '2475', (57, 61))	('cancers', 'Disease', 'MESH:D009369', (93, 100))
353274	28977982	And, miRNA-100 can also exert as a tumor suppressor in many cancers by targeting polo-like kinase 1 (PLK1).	('targeting', 'Reg', (71, 80))	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('cancers', 'Phenotype', 'HP:0002664', (60, 67))	('PLK1', 'Gene', (101, 105))	('polo-like kinase 1', 'Gene', '5347', (81, 99))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('cancers', 'Disease', (60, 67))	('polo-like kinase 1', 'Gene', (81, 99))	('cancers', 'Disease', 'MESH:D009369', (60, 67))	('tumor', 'Disease', (35, 40))	('PLK1', 'Gene', '5347', (101, 105))	('miRNA-100', 'Chemical', '-', (5, 14))	('miRNA-100', 'Var', (5, 14))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
353275	28977982	MiRNA-100 was found to significantly inhibit the expression of PLK1 and other proteins, which has a vital effect on cell growth, apoptosis, development and drug resistance.	('MiRNA-100', 'Chemical', '-', (0, 9))	('PLK1', 'Gene', '5347', (63, 67))	('inhibit', 'NegReg', (37, 44))	('expression', 'MPA', (49, 59))	('drug resistance', 'Phenotype', 'HP:0020174', (156, 171))	('MiRNA-100', 'Var', (0, 9))	('proteins', 'Protein', (78, 86))	('PLK1', 'Gene', (63, 67))
353276	28977982	In addition, several studies reported that miR-100 regulated apoptosis in gastric tumor cells and breast cancer cells, and they declared miR-100 antagonism triggers apoptosis by inhibiting ubiquitination-mediated p53 degradation.	('breast cancer', 'Disease', 'MESH:D001943', (98, 111))	('gastric tumor', 'Disease', (74, 87))	('apoptosis', 'CPA', (61, 70))	('breast cancer', 'Phenotype', 'HP:0003002', (98, 111))	('breast cancer', 'Disease', (98, 111))	('inhibiting', 'NegReg', (178, 188))	('apoptosis', 'CPA', (165, 174))	('miR-100', 'Gene', '406892', (137, 144))	('miR-100', 'Gene', '406892', (43, 50))	('gastric tumor', 'Disease', 'MESH:D013274', (74, 87))	('gastric tumor', 'Phenotype', 'HP:0006753', (74, 87))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('p53', 'Gene', (213, 216))	('p53', 'Gene', '7157', (213, 216))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('miR-100', 'Gene', (43, 50))	('antagonism', 'Var', (145, 155))	('miR-100', 'Gene', (137, 144))
353284	28977982	Some studies on EOC, SCCC and NSCLC found miR-100 was significantly decreased in cancer tissues in comparison to healthy people, which appeared that low miR-100 was a poor prognostic biomarker by targeting PLK1 in patients and some researches in HCC, CRC and ESCC hold the similar view.	('SCC', 'Gene', (21, 24))	('decreased', 'NegReg', (68, 77))	('people', 'Species', '9606', (121, 127))	('patients', 'Species', '9606', (214, 222))	('miR-100', 'Gene', (153, 160))	('cancer', 'Disease', (81, 87))	('targeting', 'Reg', (196, 205))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('NSCLC', 'Disease', 'MESH:D002289', (30, 35))	('miR-100', 'Gene', (42, 49))	('PLK1', 'Gene', (206, 210))	('NSCLC', 'Disease', (30, 35))	('miR-100', 'Gene', '406892', (153, 160))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('miR-100', 'Gene', '406892', (42, 49))	('low', 'Var', (149, 152))	('PLK1', 'Gene', '5347', (206, 210))	('SCC', 'Gene', '6317', (260, 263))	('SCC', 'Gene', '6317', (21, 24))	('SCC', 'Gene', (260, 263))
353305	28977982	We collect HRs and their 95% CIs preferentially from multivariate or univariate analyses in the original article, and HR>1 means higher expression of miRNA-100 in tumor tissues that may have a poorer prognosis in cancer patients.	('HR>1', 'Var', (118, 122))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('expression', 'MPA', (136, 146))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('miRNA-100', 'Protein', (150, 159))	('higher', 'PosReg', (129, 135))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('cancer', 'Disease', 'MESH:D009369', (213, 219))	('patients', 'Species', '9606', (220, 228))	('tumor', 'Disease', (163, 168))	('cancer', 'Disease', (213, 219))	('miRNA-100', 'Chemical', '-', (150, 159))
353331	32328125	For instance, AIM2 improved proliferation of non-small-cell lung cancer (NSCLC) cells via inflammasome-dependent pathway.	('inflammasome-dependent pathway', 'Pathway', (90, 120))	('lung cancer', 'Disease', (60, 71))	('lung cancer', 'Phenotype', 'HP:0100526', (60, 71))	('proliferation', 'CPA', (28, 41))	('AIM2', 'Var', (14, 18))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (49, 71))	('lung cancer', 'Disease', 'MESH:D008175', (60, 71))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('NSCLC', 'Disease', (73, 78))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (45, 71))	('NSCLC', 'Disease', 'MESH:D002289', (73, 78))	('improved', 'PosReg', (19, 27))	('NSCLC', 'Phenotype', 'HP:0030358', (73, 78))
353341	31786674	This increased risk of death observed for alcohol consumers was more evident in patients with normal p53 expression, GLUT-1 positive or CD-8 positive tumors.	('tumors', 'Disease', (150, 156))	('GLUT-1', 'Gene', (117, 123))	('tumors', 'Disease', 'MESH:D009369', (150, 156))	('death', 'Disease', (23, 28))	('patients', 'Species', '9606', (80, 88))	('GLUT-1', 'Gene', '6513', (117, 123))	('tumors', 'Phenotype', 'HP:0002664', (150, 156))	('p53', 'Gene', (101, 104))	('p53', 'Gene', '7157', (101, 104))	('CD-8', 'Gene', (136, 140))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('normal', 'Var', (94, 100))	('death', 'Disease', 'MESH:D003643', (23, 28))	('expression', 'MPA', (105, 115))	('CD-8', 'Gene', '925', (136, 140))	('alcohol', 'Chemical', 'MESH:D000431', (42, 49))
353344	31786674	However, in some biomarker-selected subgroups, ever-alcohol consumption was associated with a worsened survival in comparison with never drinkers.	('survival', 'MPA', (103, 111))	('alcohol', 'Chemical', 'MESH:D000431', (52, 59))	('worsened', 'NegReg', (94, 102))	('ever-alcohol consumption', 'Var', (47, 71))	('ever-alcohol consumption', 'Phenotype', 'HP:0030955', (47, 71))
353366	31786674	In esophageal squamous cell carcinoma, heavy smokers have been shown to have a two-times higher odds of P53 mutation than non-smokers, and in lung cancer, frequent alcohol drinkers had a 4.6-fold increased odds of having a P53 mutation.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (14, 37))	('alcohol drinkers', 'Phenotype', 'HP:0030955', (164, 180))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('lung cancer', 'Disease', 'MESH:D008175', (142, 153))	('carcinoma', 'Phenotype', 'HP:0030731', (28, 37))	('alcohol drinker', 'Phenotype', 'HP:0030955', (164, 179))	('esophageal squamous cell carcinoma', 'Disease', (3, 37))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:C562729', (3, 37))	('lung cancer', 'Disease', (142, 153))	('P53', 'Gene', (104, 107))	('lung cancer', 'Phenotype', 'HP:0100526', (142, 153))	('mutation', 'Var', (108, 116))	('alcohol', 'Chemical', 'MESH:D000431', (164, 171))	('P53', 'Gene', (223, 226))	('P53', 'Gene', '7157', (223, 226))	('P53', 'Gene', '7157', (104, 107))
353375	31786674	Relevant ethical approvals were obtained from the Northern Ireland Biobank (NIB12-0032 and NIB12-0062) and the Office for Research Ethics Committees Northern Ireland (ORECNI, 13/NI/0149).	('NIB12-0032', 'Var', (76, 86))	('NIB12-0032', 'Chemical', 'MESH:C102275', (76, 86))	('NIB12-0062', 'Chemical', 'MESH:C102275', (91, 101))	('NIB12-0062', 'Var', (91, 101))
353376	31786674	The staining and study of the biomarker CD8 was performed under the accelerator grant from Cancer Research UK (C11512/A20256 to PWH/MS-T).	('C11512', 'Chemical', 'MESH:D002244', (111, 117))	('Cancer', 'Phenotype', 'HP:0002664', (91, 97))	('CD8', 'Gene', '925', (40, 43))	('C11512/A20256', 'Var', (111, 124))	('CD8', 'Gene', (40, 43))
353423	31786674	The previously observed increased risk of death for alcohol consumers was more evident in patients within the normal tertile of p53 expression (HR 11.8 95% CI 1.55-89.7), GLUT-1-positive (HR 2.40 95% CI 1.31-4.41), CD 8-positive (HR 2.77 95% CI 1.26-6.09), and HER 2-positive tumors (HR 7.00 95% CI 0.85-57.6), although the latter did not reach statistical significance.	('tumors', 'Phenotype', 'HP:0002664', (276, 282))	('CD 8-positive', 'Var', (215, 228))	('alcohol', 'Chemical', 'MESH:D000431', (52, 59))	('p53', 'Gene', (128, 131))	('p53', 'Gene', '7157', (128, 131))	('tumor', 'Phenotype', 'HP:0002664', (276, 281))	('tumors', 'Disease', 'MESH:D009369', (276, 282))	('death', 'Disease', 'MESH:D003643', (42, 47))	('death', 'Disease', (42, 47))	('GLUT-1', 'Gene', '6513', (171, 177))	('HER 2', 'Gene', (261, 266))	('GLUT-1', 'Gene', (171, 177))	('patients', 'Species', '9606', (90, 98))	('tumors', 'Disease', (276, 282))	('HER 2', 'Gene', '2064', (261, 266))
353447	31786674	To date, there has only been one study (performed on the same cohort of patients as this study) which has investigated the role of GLUT1 as a biomarker in esophageal adenocarcinoma, and positive expression was associated with a poorer prognosis.	('esophageal adenocarcinoma', 'Disease', 'MESH:D004941', (155, 180))	('positive expression', 'Var', (186, 205))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (155, 180))	('carcinoma', 'Phenotype', 'HP:0030731', (171, 180))	('GLUT1', 'Gene', (131, 136))	('GLUT1', 'Gene', '6513', (131, 136))	('esophageal adenocarcinoma', 'Disease', (155, 180))	('patients', 'Species', '9606', (72, 80))
353449	31786674	The poorer outcomes in ever drinkers with CD8 positive, or normal p53, tumor expression indicate that further mechanistic studies are warranted to verify the biological plausibility of a potential underlying interaction with alcohol intake in relation to prognosis.	('p53', 'Gene', '7157', (66, 69))	('alcohol', 'Chemical', 'MESH:D000431', (225, 232))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('CD8', 'Gene', (42, 45))	('normal', 'Var', (59, 65))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('CD8', 'Gene', '925', (42, 45))	('tumor', 'Disease', (71, 76))	('p53', 'Gene', (66, 69))
353459	30442178	The rationale behind such molecular reclassifications is that genetic alterations underlying cancer pathology predict response to therapy and may therefore offer a more precise view on cancer than histology.	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('predict', 'Reg', (110, 117))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('genetic alterations', 'Var', (62, 81))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('cancer', 'Disease', (185, 191))	('response to therapy', 'MPA', (118, 137))
353460	30442178	The use of individual actionable mutations to select cancers for treatment across histotypes is already being tested in the so-called basket trials with variable success rates.	('cancers', 'Phenotype', 'HP:0002664', (53, 60))	('cancers', 'Disease', (53, 60))	('cancers', 'Disease', 'MESH:D009369', (53, 60))	('mutations', 'Var', (33, 42))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))
353462	30442178	To determine effects of oncogenic mutations on protein profiles, we used the energy distance, which compares the Euclidean distances of protein profiles in tumors with an oncogenic mutation (inner distance) to that in tumors without the mutation (outer distance) and performed Monte Carlo simulations for the significance analysis.	('tumors', 'Disease', (156, 162))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('mutation', 'Var', (181, 189))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('tumors', 'Phenotype', 'HP:0002664', (218, 224))	('tumors', 'Disease', 'MESH:D009369', (156, 162))	('tumors', 'Disease', (218, 224))	('tumors', 'Disease', 'MESH:D009369', (218, 224))
353468	30442178	Next-generation sequencing has facilitated comprehensive mutational profiling of all major cancers and has led to the discovery of oncogenic driver mutations, many of which can be targeted therapeutically.	('mutations', 'Var', (148, 157))	('cancers', 'Phenotype', 'HP:0002664', (91, 98))	('cancers', 'Disease', 'MESH:D009369', (91, 98))	('cancers', 'Disease', (91, 98))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))
353470	30442178	However, sequencing data has shown that actionable mutations, albeit with different frequencies, occur across cancers, which has raised the question about histotype-independent therapies and novel ways of tumor classifications no longer relying on histology but on genetic profiles.	('cancers', 'Disease', (110, 117))	('mutations', 'Var', (51, 60))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumor', 'Disease', (205, 210))	('cancers', 'Phenotype', 'HP:0002664', (110, 117))	('cancers', 'Disease', 'MESH:D009369', (110, 117))
353473	30442178	That targeted therapies against the same single molecular alteration can be effective across cancers, as shown, for instance, by the efficacy of anti-Her2 therapy in both gastric and breast cancers or the clinical benefit from inhibition of mutated cKIT in gastrointestinal stromal tumors (GIST) and melanoma or mastocytosis.	('gastric and breast cancers', 'Disease', 'MESH:D013274', (171, 197))	('melanoma or mastocytosis', 'Disease', (300, 324))	('cancers', 'Disease', 'MESH:D009369', (190, 197))	('Her2', 'Gene', '2064', (150, 154))	('cancers', 'Disease', 'MESH:D009369', (93, 100))	('gastrointestinal stromal tumors', 'Disease', (257, 288))	('GIST', 'Phenotype', 'HP:0100723', (290, 294))	('tumors', 'Phenotype', 'HP:0002664', (282, 288))	('Her2', 'Gene', (150, 154))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('mutated', 'Var', (241, 248))	('melanoma', 'Phenotype', 'HP:0002861', (300, 308))	('cancers', 'Phenotype', 'HP:0002664', (190, 197))	('cKIT', 'Gene', '3815', (249, 253))	('tumor', 'Phenotype', 'HP:0002664', (282, 287))	('cancers', 'Disease', (190, 197))	('cancers', 'Phenotype', 'HP:0002664', (93, 100))	('cancers', 'Disease', (93, 100))	('melanoma or mastocytosis', 'Disease', 'MESH:D008415', (300, 324))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (257, 288))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (257, 288))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('breast cancers', 'Phenotype', 'HP:0003002', (183, 197))	('inhibition', 'Var', (227, 237))	('mastocytosis', 'Phenotype', 'HP:0100495', (312, 324))	('cKIT', 'Gene', (249, 253))	('breast cancer', 'Phenotype', 'HP:0003002', (183, 196))
353474	30442178	However, the fact that inhibition of BRAF mutated at V600 is effective in melanoma but not in colorectal cancer is a prominent example against the general transferability of knowledge on a single actionable mutation from one histological tumor type to another.	('tumor', 'Disease', 'MESH:D009369', (238, 243))	('colorectal cancer', 'Disease', 'MESH:D015179', (94, 111))	('BRAF', 'Gene', '673', (37, 41))	('tumor', 'Phenotype', 'HP:0002664', (238, 243))	('rectal cancer', 'Phenotype', 'HP:0100743', (98, 111))	('BRAF', 'Gene', (37, 41))	('mutated at V600', 'Var', (42, 57))	('melanoma', 'Disease', 'MESH:D008545', (74, 82))	('melanoma', 'Disease', (74, 82))	('melanoma', 'Phenotype', 'HP:0002861', (74, 82))	('colorectal cancer', 'Phenotype', 'HP:0003003', (94, 111))	('tumor', 'Disease', (238, 243))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('colorectal cancer', 'Disease', (94, 111))	('ran', 'Gene', (156, 159))	('ran', 'Gene', '5901', (156, 159))
353476	30442178	Using mutational profiles or just single genetic aberrations, as is the case in the current basket trials, is unlikely to cover the full scope of (tissue-specific) molecular effects including epigenetic mechanisms and downstream regulation such as post-translational modifications.	('ran', 'Gene', '5901', (254, 257))	('ran', 'Gene', (254, 257))	('mutational profiles', 'Var', (6, 25))
353491	30442178	To address the question of how mutational differences between two classes affect protein expressions in more than one histotype in the same way, we performed a cross-cancer effect analysis.	('mutational', 'Var', (31, 41))	('affect', 'Reg', (74, 80))	('protein expressions', 'MPA', (81, 100))	('cross-cancer', 'Disease', (160, 172))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('cross-cancer', 'Disease', 'MESH:C537866', (160, 172))
353506	30442178	At this point, it is unclear whether the reason for this inconsistency between genetic and protein profiles is the differential translation of genetic profiles into protein levels in different cancer types, or organ- and tissue-specific protein base levels that are modulated by mutations:or a combination of both.	('ran', 'Gene', (129, 132))	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('mutations', 'Var', (279, 288))	('ran', 'Gene', '5901', (129, 132))	('cancer', 'Disease', (193, 199))	('modulated', 'Reg', (266, 275))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))
353520	30442178	In the proposal by Ciriello et al., tumors are classified by the presence of somatic mutations and copy number alterations in cancer-related pathways.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('copy number alterations', 'Var', (99, 122))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumors', 'Disease', (36, 42))	('tumors', 'Disease', 'MESH:D009369', (36, 42))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))
353532	30442178	The least pronounced but still significant class discriminability is achieved for classes C12 and C5 in breast cancer (sdis = - 0.31, p = 4.4e-3; srand = - 8.0e-5).	('ran', 'Gene', (147, 150))	('sdis', 'Chemical', '-', (119, 123))	('ran', 'Gene', '5901', (147, 150))	('C12', 'Var', (90, 93))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('breast cancer', 'Disease', 'MESH:D001943', (104, 117))	('breast cancer', 'Disease', (104, 117))	('breast cancer', 'Phenotype', 'HP:0003002', (104, 117))
353551	30442178	With CES = 2%, the overall classification effectivity score of this classification is the lowest among all tested classifications indicating that global comparisons based on somatic mutations only are not effective in classifying tumors in a meaningful way if the available protein profiles are considered relevant.	('CES', 'Chemical', '-', (5, 8))	('tumors', 'Disease', 'MESH:D009369', (230, 236))	('tumors', 'Disease', (230, 236))	('tumors', 'Phenotype', 'HP:0002664', (230, 236))	('CES', 'Var', (5, 8))	('lowest', 'NegReg', (90, 96))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))
353554	30442178	For this classification, class discriminability sdis is highest between class toLGG (cases that are most similar to low-grade glioma cases by their mutation profile) and class toPRAD for low-grade glioma (LGG) (sdis = - 3.26; p = 0.0; srand = - 6.1e-5; characteristic protein profiles increased in toLGG: p70S6K_pT389; increased in ToPRAD: YAP_pS127, HER2_pY1248, HER2, EGFR_pY1068, EGFR_pY1173, Src_pY416, and Cyclin_D1).	('glioma', 'Phenotype', 'HP:0009733', (126, 132))	('EGFR', 'Gene', (370, 374))	('HER2', 'Gene', '2064', (351, 355))	('increased', 'PosReg', (285, 294))	('sdis', 'Chemical', '-', (48, 52))	('glioma', 'Phenotype', 'HP:0009733', (197, 203))	('p70S6K', 'Gene', '6198', (305, 311))	('Cyclin_D1', 'Gene', (411, 420))	('EGFR', 'Gene', (383, 387))	('sdis', 'Chemical', '-', (211, 215))	('EGFR', 'Gene', '1956', (370, 374))	('HER2', 'Gene', '2064', (364, 368))	('HER2', 'Gene', (351, 355))	('glioma', 'Disease', (126, 132))	('ran', 'Gene', (236, 239))	('ran', 'Gene', '5901', (236, 239))	('increased', 'PosReg', (319, 328))	('glioma', 'Disease', 'MESH:D005910', (126, 132))	('p70S6K', 'Gene', (305, 311))	('EGFR', 'Gene', '1956', (383, 387))	('glioma', 'Disease', (197, 203))	('Src_pY416', 'Var', (396, 405))	('HER2', 'Gene', (364, 368))	('Cyclin_D1', 'Gene', '595', (411, 420))	('glioma', 'Disease', 'MESH:D005910', (197, 203))
353577	30442178	Using the same approach as above, we are systematically evaluating all major actionable somatic mutations and copy number alterations against which drugs are approved for clinical use or which are currently tested in clinical trials with respect to their effects on proteins across cancers.	('cancers', 'Disease', (282, 289))	('cancer', 'Phenotype', 'HP:0002664', (282, 288))	('copy number alterations', 'Var', (110, 133))	('cancers', 'Phenotype', 'HP:0002664', (282, 289))	('cancers', 'Disease', 'MESH:D009369', (282, 289))	('mutations', 'Var', (96, 105))
353582	30442178	Overall, our analysis showed for all analyzed 12 actionable genes (OncoKB evidence levels 1-3) that the mutational status is associated with significant differences in protein profiles in histotypes for which the respective targeted drugs are approved or currently being clinically tested and showed additional mutation-associated protein profiles in 9 histological tumor types.	('tumor', 'Disease', (366, 371))	('mutational', 'Var', (104, 114))	('associated', 'Reg', (125, 135))	('protein profiles', 'MPA', (168, 184))	('tumor', 'Phenotype', 'HP:0002664', (366, 371))	('tumor', 'Disease', 'MESH:D009369', (366, 371))	('differences', 'Reg', (153, 164))
353584	30442178	Only KRAS/NRAS mutations in colorectal cancer do not result in discriminable protein profiles comparing wild-type and mutated cases, whereas an effect can be observed for thyroid cancer and melanoma.	('result', 'Reg', (53, 59))	('NRAS', 'Gene', '4893', (10, 14))	('colorectal cancer', 'Phenotype', 'HP:0003003', (28, 45))	('melanoma', 'Phenotype', 'HP:0002861', (190, 198))	('melanoma', 'Disease', (190, 198))	('rectal cancer', 'Phenotype', 'HP:0100743', (32, 45))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('mutations', 'Var', (15, 24))	('colorectal cancer', 'Disease', (28, 45))	('KRAS', 'Gene', (5, 9))	('melanoma', 'Disease', 'MESH:D008545', (190, 198))	('KRAS', 'Gene', '3845', (5, 9))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('thyroid cancer', 'Disease', (171, 185))	('thyroid cancer', 'Phenotype', 'HP:0002890', (171, 185))	('NRAS', 'Gene', (10, 14))	('colorectal cancer', 'Disease', 'MESH:D015179', (28, 45))	('thyroid cancer', 'Disease', 'MESH:D013964', (171, 185))
353587	30442178	Our results demonstrate that in addition to confirming known druggable genes in the available cell line data, protein profile discriminability in between presence or absence of oncogenic mutations is predictive of drug response in cell line data across cancers (p = 0.048, Table 2).	('cancers', 'Phenotype', 'HP:0002664', (253, 260))	('cancers', 'Disease', (253, 260))	('cancers', 'Disease', 'MESH:D009369', (253, 260))	('mutations', 'Var', (187, 196))	('protein', 'MPA', (110, 117))	('cancer', 'Phenotype', 'HP:0002664', (253, 259))
353588	30442178	BRAF mutations are actionable in melanomas (OncoKB level 1).	('melanomas', 'Disease', 'MESH:D008545', (33, 42))	('melanoma', 'Phenotype', 'HP:0002861', (33, 41))	('melanomas', 'Phenotype', 'HP:0002861', (33, 42))	('mutations', 'Var', (5, 14))	('BRAF', 'Gene', '673', (0, 4))	('BRAF', 'Gene', (0, 4))	('melanomas', 'Disease', (33, 42))
353589	30442178	Mutations of BRAF are frequent enough in our data for melanoma (46% cases with mutation) and thyroid carcinoma (not yet reported by OncoKB, 56% cases with mutation) for further analysis.	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (93, 110))	('thyroid carcinoma', 'Disease', (93, 110))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('BRAF', 'Gene', '673', (13, 17))	('melanoma', 'Disease', 'MESH:D008545', (54, 62))	('melanoma', 'Phenotype', 'HP:0002861', (54, 62))	('melanoma', 'Disease', (54, 62))	('BRAF', 'Gene', (13, 17))	('Mutations', 'Var', (0, 9))	('mutation', 'Var', (79, 87))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (93, 110))
353590	30442178	The actionable mutations create discriminable groups of cases for thyroid carcinoma (sdis = - 2.07; p = 0.0; srand = - 1.0e-4) and melanoma (sdis = - 0.10; p = 4.7e-3; srand = - 1.1e-4).	('melanoma', 'Phenotype', 'HP:0002861', (131, 139))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (66, 83))	('melanoma', 'Disease', (131, 139))	('thyroid carcinoma', 'Disease', (66, 83))	('sdis', 'Chemical', '-', (85, 89))	('melanoma', 'Disease', 'MESH:D008545', (131, 139))	('mutations', 'Var', (15, 24))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('ran', 'Gene', (110, 113))	('ran', 'Gene', '5901', (110, 113))	('sdis', 'Chemical', '-', (141, 145))	('ran', 'Gene', (169, 172))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (66, 83))	('ran', 'Gene', '5901', (169, 172))
353594	30442178	CDK4 amplification is actionable for differentiated sarcomas (OncoKB level 2).	('sarcomas', 'Disease', 'MESH:D012509', (52, 60))	('amplification', 'Var', (5, 18))	('sarcomas', 'Phenotype', 'HP:0100242', (52, 60))	('sarcoma', 'Phenotype', 'HP:0100242', (52, 59))	('sarcomas', 'Disease', (52, 60))	('CDK4', 'Gene', (0, 4))	('CDK4', 'Gene', '1019', (0, 4))
353596	30442178	For sarcoma, 36% of the cases show CDK4 amplification and protein profiles are discriminable (sdis = - 0.34; p = 0.0; srand = - 6.0e-5) with E-Cadherin, Caveolin-1, Akt_pS473, Cyclin_B1, ER-alpha, Akt_pT308, YAP_pS127, S6_pS240_S244, and Cyclin_E1 decreased and HSP70, Syk, Lck, Src_pY416, and Src_pY527 increased in CDK4 amplified cases.	('CDK4', 'Gene', '1019', (317, 321))	('Cyclin_B1', 'Gene', (176, 185))	('decreased', 'NegReg', (248, 257))	('Lck', 'Gene', (274, 277))	('ER-alpha', 'Gene', (187, 195))	('E-Cadherin', 'Gene', '999', (141, 151))	('ER-alpha', 'Gene', '2099', (187, 195))	('increased', 'PosReg', (304, 313))	('sdis', 'Chemical', '-', (94, 98))	('Cyclin_B1', 'Gene', '891', (176, 185))	('Syk', 'Gene', '6850', (269, 272))	('sarcoma', 'Disease', 'MESH:D012509', (4, 11))	('CDK4', 'Gene', (35, 39))	('HSP70', 'Gene', (262, 267))	('ran', 'Gene', (119, 122))	('sarcoma', 'Disease', (4, 11))	('ran', 'Gene', '5901', (119, 122))	('Syk', 'Gene', (269, 272))	('Cyclin_E1', 'Gene', '898', (238, 247))	('E-Cadherin', 'Gene', (141, 151))	('Caveolin-1', 'Gene', (153, 163))	('CDK4', 'Gene', (317, 321))	('CDK4', 'Gene', '1019', (35, 39))	('sarcoma', 'Phenotype', 'HP:0100242', (4, 11))	('Src_pY416', 'Var', (279, 288))	('Caveolin-1', 'Gene', '857', (153, 163))	('Src_pY527', 'Var', (294, 303))	('Cyclin_E1', 'Gene', (238, 247))	('HSP70', 'Gene', '3308', (262, 267))	('Lck', 'Gene', '3932', (274, 277))
353598	30442178	EGFR mutations are actionable in non-small cell lung cancer (OncoKB level 1).	('EGFR', 'Gene', (0, 4))	('non-small cell lung cancer', 'Disease', (33, 59))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (37, 59))	('mutations', 'Var', (5, 14))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('lung cancer', 'Phenotype', 'HP:0100526', (48, 59))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (33, 59))	('EGFR', 'Gene', '1956', (0, 4))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (33, 59))
353600	30442178	Lung adenocarcinoma (LUAD) cases with actionable mutation of EGFR are discriminable from those without by protein profile (sdis = - 0.44; p = 5.9e-4; srand = 3.1e-5).	('sdis', 'Chemical', '-', (123, 127))	('LUAD', 'Phenotype', 'HP:0030078', (21, 25))	('ran', 'Gene', (151, 154))	('ran', 'Gene', '5901', (151, 154))	('mutation', 'Var', (49, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (10, 19))	('Lung adenocarcinoma', 'Phenotype', 'HP:0030078', (0, 19))	('Lung adenocarcinoma', 'Disease', (0, 19))	('Lung adenocarcinoma', 'Disease', 'MESH:D000077192', (0, 19))	('EGFR', 'Gene', '1956', (61, 65))	('EGFR', 'Gene', (61, 65))
353601	30442178	EGFR_pY1068 levels are increased for cases with the respective mutations, and Claudin-7 levels are decreased among those cases.	('mutations', 'Var', (63, 72))	('decreased', 'NegReg', (99, 108))	('EGFR', 'Gene', (0, 4))	('Claudin-7', 'Gene', '1366', (78, 87))	('increased', 'PosReg', (23, 32))	('EGFR', 'Gene', '1956', (0, 4))	('Claudin-7', 'Gene', (78, 87))
353602	30442178	ERBB2/HER2 amplification is actionable in breast cancer and gastric cancer (level 1 evidence, FDA-approved).	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('ERBB2', 'Gene', '2064', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('ERBB2', 'Gene', (0, 5))	('gastric cancer', 'Disease', (60, 74))	('breast cancer', 'Disease', 'MESH:D001943', (42, 55))	('breast cancer', 'Phenotype', 'HP:0003002', (42, 55))	('gastric cancer', 'Disease', 'MESH:D013274', (60, 74))	('breast cancer', 'Disease', (42, 55))	('HER2', 'Gene', (6, 10))	('HER2', 'Gene', '2064', (6, 10))	('gastric cancer', 'Phenotype', 'HP:0012126', (60, 74))	('amplification', 'Var', (11, 24))
353612	30442178	Two histological tumor types in which ERBB2 amplification has a similar impact on proteins are breast (BRCA) and gastric (STAD) cancers (p = 2.3e-3).	('cancers', 'Phenotype', 'HP:0002664', (128, 135))	('tumor', 'Disease', (17, 22))	('BRCA', 'Gene', '672', (103, 107))	('BRCA', 'Gene', (103, 107))	('gastric (STAD) cancers', 'Disease', 'MESH:D013274', (113, 135))	('amplification', 'Var', (44, 57))	('ERBB2', 'Gene', (38, 43))	('proteins', 'MPA', (82, 90))	('ERBB2', 'Gene', '2064', (38, 43))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('impact', 'Reg', (72, 78))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
353617	30442178	For FGFR1 amplification, clinical evidence (OncoKB level 3) exists on its actionability in lung squamous cell carcinomas.	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('FGFR1', 'Gene', (4, 9))	('carcinomas', 'Phenotype', 'HP:0030731', (110, 120))	('lung squamous cell carcinomas', 'Disease', (91, 120))	('FGFR1', 'Gene', '2260', (4, 9))	('amplification', 'Var', (10, 23))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (96, 120))	('lung squamous cell carcinomas', 'Disease', 'MESH:D002294', (91, 120))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (96, 119))
353618	30442178	Our analysis shows that besides lung squamous cell carcinoma, protein expression of amplified cases is discriminable from non-amplified cases in renal clear cell carcinoma, testicular germ cell tumors, lung adenocarcinoma, endometrial carcinoma, breast cancer, and thymoma (all currently not reported by OncoKB).	('endometrial carcinoma', 'Disease', 'MESH:D016889', (223, 244))	('breast cancer', 'Phenotype', 'HP:0003002', (246, 259))	('renal clear cell carcinoma', 'Disease', 'MESH:C538614', (145, 171))	('renal clear cell carcinoma', 'Disease', (145, 171))	('thymoma', 'Disease', (265, 272))	('thymoma', 'Phenotype', 'HP:0100522', (265, 272))	('breast cancer', 'Disease', 'MESH:D001943', (246, 259))	('breast cancer', 'Disease', (246, 259))	('lung adenocarcinoma', 'Disease', (202, 221))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (37, 60))	('carcinoma', 'Phenotype', 'HP:0030731', (212, 221))	('tumors', 'Phenotype', 'HP:0002664', (194, 200))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (32, 60))	('lung squamous cell carcinoma', 'Disease', (32, 60))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (202, 221))	('endometrial carcinoma', 'Disease', (223, 244))	('carcinoma', 'Phenotype', 'HP:0030731', (235, 244))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (202, 221))	('tumors', 'Disease', (194, 200))	('cancer', 'Phenotype', 'HP:0002664', (253, 259))	('carcinoma', 'Phenotype', 'HP:0030731', (162, 171))	('protein expression', 'MPA', (62, 80))	('thymoma', 'Disease', 'MESH:D013945', (265, 272))	('testicular', 'Disease', (173, 183))	('amplified', 'Var', (84, 93))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (223, 244))	('tumors', 'Disease', 'MESH:D009369', (194, 200))	('carcinoma', 'Phenotype', 'HP:0030731', (51, 60))
353621	30442178	A cross-cancer effect is found between breast cancer and lung adenocarcinoma with HER2, HER2_pY1248, and EGFR_pY1068 levels decrease and 4E-BP1 levels increase associated with FGFR1 amplification for both histological tumor types.	('breast cancer', 'Phenotype', 'HP:0003002', (39, 52))	('A cross-cancer', 'Disease', 'MESH:C537866', (0, 14))	('HER2', 'Gene', '2064', (88, 92))	('4E-BP1', 'Gene', (137, 143))	('EGFR', 'Gene', (105, 109))	('decrease', 'NegReg', (124, 132))	('breast cancer', 'Disease', 'MESH:D001943', (39, 52))	('tumor', 'Disease', (218, 223))	('breast cancer', 'Disease', (39, 52))	('levels', 'MPA', (117, 123))	('A cross-cancer', 'Disease', (0, 14))	('tumor', 'Disease', 'MESH:D009369', (218, 223))	('lung adenocarcinoma', 'Disease', (57, 76))	('HER2', 'Gene', (82, 86))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('FGFR1', 'Gene', '2260', (176, 181))	('amplification', 'Var', (182, 195))	('HER2', 'Gene', (88, 92))	('EGFR', 'Gene', '1956', (105, 109))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (57, 76))	('4E-BP1', 'Gene', '1978', (137, 143))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (57, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('FGFR1', 'Gene', (176, 181))	('HER2', 'Gene', '2064', (82, 86))	('levels', 'MPA', (144, 150))	('increase', 'PosReg', (151, 159))
353622	30442178	Certain FGFR3 mutations are actionable in bladder cancer (OncoKB level 3).	('bladder cancer', 'Phenotype', 'HP:0009725', (42, 56))	('FGFR3', 'Gene', '2261', (8, 13))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('actionable', 'Reg', (28, 38))	('bladder cancer', 'Disease', 'MESH:D001749', (42, 56))	('bladder cancer', 'Disease', (42, 56))	('mutations', 'Var', (14, 23))	('FGFR3', 'Gene', (8, 13))
353623	30442178	Targetable FGFR3 mutations are only frequent enough in urothelial and bladder carcinoma for our analysis.	('frequent', 'Reg', (36, 44))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (70, 87))	('FGFR3', 'Gene', '2261', (11, 16))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('bladder carcinoma', 'Disease', 'MESH:D001749', (70, 87))	('FGFR3', 'Gene', (11, 16))	('bladder carcinoma', 'Disease', (70, 87))	('urothelial', 'Disease', (55, 65))	('mutations', 'Var', (17, 26))
353624	30442178	The protein profiles of cases with at least one of these mutations are discriminable from the profiles of those without (sdis = - 0.76; p = 2.7e-3; srand = - 1.3e-5).	('ran', 'Gene', '5901', (149, 152))	('mutations', 'Var', (57, 66))	('sdis', 'Chemical', '-', (121, 125))	('ran', 'Gene', (149, 152))
353625	30442178	E-Cadherin, beta-Catenin, HER2, Ku80, PTEN, IRS1, and 53BP1 are increased among cases having one or more specific FGF3 mutation.	('53BP1', 'Gene', (54, 59))	('53BP1', 'Gene', '7158', (54, 59))	('FGF3', 'Gene', (114, 118))	('mutation', 'Var', (119, 127))	('PTEN', 'Gene', '5728', (38, 42))	('beta-Catenin', 'Gene', '1499', (12, 24))	('Ku80', 'Gene', '7520', (32, 36))	('Ku80', 'Gene', (32, 36))	('HER2', 'Gene', (26, 30))	('E-Cadherin', 'Gene', (0, 10))	('IRS1', 'Gene', '3667', (44, 48))	('HER2', 'Gene', '2064', (26, 30))	('IRS1', 'Gene', (44, 48))	('FGF3', 'Gene', '2248', (114, 118))	('increased', 'PosReg', (64, 73))	('E-Cadherin', 'Gene', '999', (0, 10))	('PTEN', 'Gene', (38, 42))	('beta-Catenin', 'Gene', (12, 24))
353626	30442178	IDH1 mutations are actionable in acute myeloid leukemia, cholangiocarcinoma, and glioma (OncoKB level 3).	('leukemia', 'Phenotype', 'HP:0001909', (47, 55))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (57, 75))	('carcinoma', 'Phenotype', 'HP:0030731', (66, 75))	('glioma', 'Phenotype', 'HP:0009733', (81, 87))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (57, 75))	('acute myeloid leukemia', 'Disease', (33, 55))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (39, 55))	('mutations', 'Var', (5, 14))	('glioma', 'Disease', (81, 87))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (33, 55))	('glioma', 'Disease', 'MESH:D005910', (81, 87))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (33, 55))	('IDH1', 'Gene', (0, 4))	('cholangiocarcinoma', 'Disease', (57, 75))	('IDH1', 'Gene', '3417', (0, 4))
353627	30442178	Specific IDH1 mutations lead to discriminable protein profiles for low-grade glioma (sdis = - 0.47; p = 0.0; srand = - 3.1e-6) and glioblastoma (sdis = - 1.59; p = 5.0e-4; srand = - 1.0e-5).	('glioma', 'Disease', 'MESH:D005910', (77, 83))	('IDH1', 'Gene', (9, 13))	('glioblastoma', 'Phenotype', 'HP:0012174', (131, 143))	('sdis', 'Chemical', '-', (85, 89))	('IDH1', 'Gene', '3417', (9, 13))	('ran', 'Gene', (110, 113))	('ran', 'Gene', '5901', (110, 113))	('glioma', 'Disease', (77, 83))	('ran', 'Gene', (173, 176))	('protein profiles', 'MPA', (46, 62))	('ran', 'Gene', '5901', (173, 176))	('sdis', 'Chemical', '-', (145, 149))	('mutations', 'Var', (14, 23))	('glioblastoma', 'Disease', (131, 143))	('glioma', 'Phenotype', 'HP:0009733', (77, 83))	('glioblastoma', 'Disease', 'MESH:D005909', (131, 143))
353629	30442178	For glioblastoma IGFBP2, EGFR_pY1068, HER2_pY1248, Caveolin-1, Akt_pT308, Fibronectin, Collagen_VI, and EGFR_pY1173 are decreased in the group of mutated cases.	('decreased', 'NegReg', (120, 129))	('Fibronectin', 'Gene', (74, 85))	('HER2', 'Gene', (38, 42))	('EGFR', 'Gene', (25, 29))	('mutated', 'Var', (146, 153))	('EGFR', 'Gene', (104, 108))	('Caveolin-1', 'Gene', '857', (51, 61))	('EGFR', 'Gene', '1956', (104, 108))	('glioblastoma', 'Disease', (4, 16))	('glioblastoma', 'Disease', 'MESH:D005909', (4, 16))	('Caveolin-1', 'Gene', (51, 61))	('glioblastoma', 'Phenotype', 'HP:0012174', (4, 16))	('IGFBP2', 'Gene', '3485', (17, 23))	('IGFBP2', 'Gene', (17, 23))	('EGFR', 'Gene', '1956', (25, 29))	('HER2', 'Gene', '2064', (38, 42))	('Fibronectin', 'Gene', '2335', (74, 85))
353630	30442178	Therefore, IGFBP2, EGFR_pY1068, HER2_pY1248, and EGFR_pY1173 are affected in the same way by IDH1 mutations in low-grade glioma and glioblastoma, and we report a cross-cancer effect for those groups.	('HER2', 'Gene', '2064', (32, 36))	('EGFR', 'Gene', (19, 23))	('glioblastoma', 'Disease', (132, 144))	('glioma', 'Disease', (121, 127))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('glioblastoma', 'Phenotype', 'HP:0012174', (132, 144))	('EGFR', 'Gene', (49, 53))	('glioma', 'Disease', 'MESH:D005910', (121, 127))	('cross-cancer', 'Disease', 'MESH:C537866', (162, 174))	('IDH1', 'Gene', (93, 97))	('HER2', 'Gene', (32, 36))	('EGFR', 'Gene', '1956', (19, 23))	('glioma', 'Phenotype', 'HP:0009733', (121, 127))	('cross-cancer', 'Disease', (162, 174))	('IGFBP2', 'Gene', '3485', (11, 17))	('EGFR', 'Gene', '1956', (49, 53))	('IDH1', 'Gene', '3417', (93, 97))	('mutations', 'Var', (98, 107))	('affected', 'Reg', (65, 73))	('glioblastoma', 'Disease', 'MESH:D005909', (132, 144))	('IGFBP2', 'Gene', (11, 17))
353631	30442178	KIT mutations are actionable in gastrointestinal stromal tumors (OncoKB level 1).	('gastrointestinal stromal tumors', 'Disease', (32, 63))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('mutations', 'Var', (4, 13))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (32, 63))	('KIT', 'Gene', (0, 3))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (32, 63))
353632	30442178	For the tested KIT mutations, only testicular germ cell tumors (TGCT) had enough mutated cases sufficient for our analysis.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('KIT', 'Gene', (15, 18))	('mutations', 'Var', (19, 28))	('tumors', 'Disease', (56, 62))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))
353633	30442178	The protein profiles of the mutated and wild-type cases are discriminable (sdis = - 0.90; p = 4.5e-3; srand = - 2.6e-4) with decreased E-Cadherin and Fibronectin expression in wildtype cases and increased c-Kit, STAT5-alpha, and Syk expression levels.	('Fibronectin', 'Gene', '2335', (150, 161))	('mutated', 'Var', (28, 35))	('c-Kit', 'Gene', (205, 210))	('Fibronectin', 'Gene', (150, 161))	('sdis', 'Chemical', '-', (75, 79))	('expression levels', 'MPA', (233, 250))	('c-Kit', 'Gene', '3815', (205, 210))	('Syk', 'Gene', '6850', (229, 232))	('decreased', 'NegReg', (125, 134))	('E-Cadherin', 'Gene', '999', (135, 145))	('STAT5-alpha', 'Gene', '6776', (212, 223))	('ran', 'Gene', (103, 106))	('expression', 'MPA', (162, 172))	('ran', 'Gene', '5901', (103, 106))	('STAT5-alpha', 'Gene', (212, 223))	('Syk', 'Gene', (229, 232))	('increased', 'PosReg', (195, 204))	('E-Cadherin', 'Gene', (135, 145))
353635	30442178	KRAS/NRAS mutations are therapeutically relevant for melanomas, colorectal cancer, and thyroid cancer (OncoKB level 3).	('melanomas', 'Disease', (53, 62))	('KRAS', 'Gene', '3845', (0, 4))	('colorectal cancer', 'Disease', (64, 81))	('NRAS', 'Gene', (5, 9))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('thyroid cancer', 'Disease', 'MESH:D013964', (87, 101))	('melanoma', 'Phenotype', 'HP:0002861', (53, 61))	('melanomas', 'Phenotype', 'HP:0002861', (53, 62))	('colorectal cancer', 'Disease', 'MESH:D015179', (64, 81))	('NRAS', 'Gene', '4893', (5, 9))	('melanomas', 'Disease', 'MESH:D008545', (53, 62))	('rectal cancer', 'Phenotype', 'HP:0100743', (68, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('mutations', 'Var', (10, 19))	('KRAS', 'Gene', (0, 4))	('colorectal cancer', 'Phenotype', 'HP:0003003', (64, 81))	('thyroid cancer', 'Phenotype', 'HP:0002890', (87, 101))	('thyroid cancer', 'Disease', (87, 101))
353636	30442178	Specific KRAS/NRAS mutations are correlated with differences in protein profiles for melanomas and thyroid cancer and also for testicular germ cell tumors, endometrial carcinoma, and lung adenocarcinoma (in conformity with OncoKB level 4 data).	('melanomas', 'Disease', (85, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (193, 202))	('thyroid cancer', 'Disease', (99, 113))	('differences', 'Reg', (49, 60))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (156, 177))	('carcinoma', 'Phenotype', 'HP:0030731', (168, 177))	('NRAS', 'Gene', '4893', (14, 18))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (156, 177))	('KRAS', 'Gene', '3845', (9, 13))	('melanomas', 'Phenotype', 'HP:0002861', (85, 94))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('thyroid cancer', 'Disease', 'MESH:D013964', (99, 113))	('protein profiles', 'MPA', (64, 80))	('lung adenocarcinoma', 'Disease', (183, 202))	('KRAS', 'Gene', (9, 13))	('thyroid cancer', 'Phenotype', 'HP:0002890', (99, 113))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('tumors', 'Disease', (148, 154))	('NRAS', 'Gene', (14, 18))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (183, 202))	('mutations', 'Var', (19, 28))	('melanomas', 'Disease', 'MESH:D008545', (85, 94))	('tumors', 'Disease', 'MESH:D009369', (148, 154))	('endometrial carcinoma', 'Disease', (156, 177))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (183, 202))
353639	30442178	For melanoma (sdis = - 0.16; p = 1.0e-3; and = 5.2e-6) E-Cadherin, Caveolin-1, and c-Kit expression levels are decreased for mutated cases, and MAPK_pT202_Y204 is increased.	('E-Cadherin', 'Gene', '999', (55, 65))	('mutated', 'Var', (125, 132))	('MAPK_pT202_Y204', 'Var', (144, 159))	('decreased', 'NegReg', (111, 120))	('E-Cadherin', 'Gene', (55, 65))	('sdis', 'Chemical', '-', (14, 18))	('Caveolin-1', 'Gene', '857', (67, 77))	('c-Kit', 'Gene', (83, 88))	('c-Kit', 'Gene', '3815', (83, 88))	('expression levels', 'MPA', (89, 106))	('melanoma', 'Phenotype', 'HP:0002861', (4, 12))	('melanoma', 'Disease', (4, 12))	('Caveolin-1', 'Gene', (67, 77))	('melanoma', 'Disease', 'MESH:D008545', (4, 12))
353640	30442178	For thyroid carcinoma (sdis = - 1.53; p = 0.0; srand = - 3.0e-4), the level of Fibronectin is decreased in mutated cases.	('sdis', 'Chemical', '-', (23, 27))	('carcinoma', 'Phenotype', 'HP:0030731', (12, 21))	('mutated', 'Var', (107, 114))	('ran', 'Gene', (48, 51))	('ran', 'Gene', '5901', (48, 51))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (4, 21))	('decreased', 'NegReg', (94, 103))	('Fibronectin', 'Gene', '2335', (79, 90))	('Fibronectin', 'Gene', (79, 90))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (4, 21))	('thyroid carcinoma', 'Disease', (4, 21))
353641	30442178	For lung adenocarcinoma and endometrial carcinoma, we observed a cross-cancer effect for KRAS/NRAS-mutated cases as ATM levels are decreased, and MAPK_pT202_Y204, Claudin-7, S6_pS235_S236, and MEK1_pS217_S221 are increased in both histological tumor types consistently.	('S6_pS235_S236', 'Var', (174, 187))	('endometrial carcinoma', 'Disease', (28, 49))	('Claudin-7', 'Gene', '1366', (163, 172))	('lung adenocarcinoma', 'Disease', (4, 23))	('tumor', 'Phenotype', 'HP:0002664', (244, 249))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (28, 49))	('NRAS', 'Gene', '4893', (94, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (40, 49))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('MEK', 'Gene', '5609', (193, 196))	('ATM', 'Gene', '472', (116, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (14, 23))	('KRAS', 'Gene', '3845', (89, 93))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (28, 49))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (4, 23))	('cross-cancer', 'Disease', 'MESH:C537866', (65, 77))	('MEK', 'Gene', (193, 196))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (4, 23))	('MAPK_pT202_Y204', 'Var', (146, 161))	('KRAS', 'Gene', (89, 93))	('NRAS', 'Gene', (94, 98))	('tumor', 'Disease', (244, 249))	('cross-cancer', 'Disease', (65, 77))	('decreased', 'NegReg', (131, 140))	('ATM', 'Gene', (116, 119))	('Claudin-7', 'Gene', (163, 172))	('tumor', 'Disease', 'MESH:D009369', (244, 249))	('increased', 'PosReg', (213, 222))
353642	30442178	MDM2 amplification is actionable in liposarcoma (OncoKB level 3).	('liposarcoma', 'Disease', (36, 47))	('amplification', 'Var', (5, 18))	('liposarcoma', 'Phenotype', 'HP:0012034', (36, 47))	('liposarcoma', 'Disease', 'MESH:D008080', (36, 47))	('MDM2', 'Gene', '4193', (0, 4))	('MDM2', 'Gene', (0, 4))	('sarcoma', 'Phenotype', 'HP:0100242', (40, 47))
353643	30442178	Besides sarcoma, the protein profiles of cases with MDM2 amplification are discriminable from those with normal copy numbers for renal clear cell carcinoma, lung adenocarcinoma, thyroid carcinoma, breast cancer, ovarian carcinoma, and low-grade glioma (all currently not reported by OncoKB).	('carcinoma', 'Phenotype', 'HP:0030731', (167, 176))	('sarcoma', 'Phenotype', 'HP:0100242', (8, 15))	('MDM2', 'Gene', (52, 56))	('renal clear cell carcinoma', 'Disease', 'MESH:C538614', (129, 155))	('glioma', 'Phenotype', 'HP:0009733', (245, 251))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (157, 176))	('renal clear cell carcinoma', 'Disease', (129, 155))	('breast cancer', 'Phenotype', 'HP:0003002', (197, 210))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (157, 176))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (178, 195))	('MDM2', 'Gene', '4193', (52, 56))	('carcinoma', 'Phenotype', 'HP:0030731', (220, 229))	('breast cancer', 'Disease', 'MESH:D001943', (197, 210))	('thyroid carcinoma', 'Disease', (178, 195))	('breast cancer', 'Disease', (197, 210))	('amplification', 'Var', (57, 70))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (212, 229))	('ovarian carcinoma', 'Disease', (212, 229))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (178, 195))	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('sarcoma', 'Disease', 'MESH:D012509', (8, 15))	('carcinoma', 'Phenotype', 'HP:0030731', (186, 195))	('glioma', 'Disease', (245, 251))	('sarcoma', 'Disease', (8, 15))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (212, 229))	('lung adenocarcinoma', 'Disease', (157, 176))	('glioma', 'Disease', 'MESH:D005910', (245, 251))
353644	30442178	Protein levels of sarcoma cases with MDM2 amplifications are discriminable from those without, with a dissimilarity score of sdis = - 0.41 (p = 0.0; srand = - 8.9e-5).	('ran', 'Gene', '5901', (150, 153))	('sarcoma', 'Disease', 'MESH:D012509', (18, 25))	('sarcoma', 'Disease', (18, 25))	('Protein levels', 'MPA', (0, 14))	('MDM2', 'Gene', '4193', (37, 41))	('sarcoma', 'Phenotype', 'HP:0100242', (18, 25))	('MDM2', 'Gene', (37, 41))	('amplifications', 'Var', (42, 56))	('sdis', 'Chemical', '-', (125, 129))	('ran', 'Gene', (150, 153))
353645	30442178	Amplified cases show decreased levels of E-Cadherin, Akt_pS473, Akt_pT308, ER-alpha, Caveolin-1, S6_pS240_S244, S6_pS235_S236, and Cyclin_B1 and increased levels of HSP70, Syk, and Lck.	('Lck', 'Gene', (181, 184))	('Akt_pT308', 'Gene', (64, 73))	('HSP70', 'Gene', '3308', (165, 170))	('Cyclin_B1', 'Gene', '891', (131, 140))	('Caveolin-1', 'Gene', (85, 95))	('E-Cadherin', 'Gene', (41, 51))	('Caveolin-1', 'Gene', '857', (85, 95))	('S6_pS240_S244', 'Var', (97, 110))	('levels', 'MPA', (155, 161))	('ER-alpha', 'Gene', (75, 83))	('increased', 'PosReg', (145, 154))	('ER-alpha', 'Gene', '2099', (75, 83))	('Syk', 'Gene', '6850', (172, 175))	('HSP70', 'Gene', (165, 170))	('S6_pS235_S236', 'Var', (112, 125))	('Syk', 'Gene', (172, 175))	('decreased', 'NegReg', (21, 30))	('Cyclin_B1', 'Gene', (131, 140))	('Lck', 'Gene', '3932', (181, 184))	('Akt_pS473', 'Protein', (53, 62))	('E-Cadherin', 'Gene', '999', (41, 51))
353648	30442178	In addition to these histotypes, we found 11 other histological tumor types (renal clear cell carcinoma, low-grade glioma, renal papillary cell carcinoma, colon carcinoma, thyroid carcinoma, thymoma, sarcoma, lung adenocarcinoma, testicular germ cell tumors, prostate adenocarcinoma, glioblastoma, breast and ovarian carcinoma) where MET amplification is associated with a significant change in protein expression.	('tumor', 'Disease', (251, 256))	('glioma', 'Disease', (115, 121))	('breast and ovarian carcinoma', 'Disease', 'MESH:D001943', (298, 326))	('glioblastoma', 'Phenotype', 'HP:0012174', (284, 296))	('protein expression', 'MPA', (395, 413))	('sarcoma', 'Phenotype', 'HP:0100242', (200, 207))	('MET amplification', 'Var', (334, 351))	('glioma', 'Disease', 'MESH:D005910', (115, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('tumor', 'Disease', 'MESH:D009369', (251, 256))	('lung adenocarcinoma', 'Disease', (209, 228))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (172, 189))	('thymoma', 'Disease', 'MESH:D013945', (191, 198))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('thyroid carcinoma', 'Disease', (172, 189))	('renal papillary cell carcinoma', 'Disease', (123, 153))	('tumors', 'Phenotype', 'HP:0002664', (251, 257))	('glioma', 'Phenotype', 'HP:0009733', (115, 121))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (209, 228))	('thymoma', 'Disease', (191, 198))	('tumor', 'Phenotype', 'HP:0002664', (251, 256))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (172, 189))	('thymoma', 'Phenotype', 'HP:0100522', (191, 198))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (209, 228))	('carcinoma', 'Phenotype', 'HP:0030731', (180, 189))	('prostate adenocarcinoma', 'Disease', (259, 282))	('tumors', 'Disease', (251, 257))	('colon carcinoma', 'Disease', (155, 170))	('change', 'Reg', (385, 391))	('renal clear cell carcinoma', 'Disease', 'MESH:C538614', (77, 103))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (309, 326))	('renal clear cell carcinoma', 'Disease', (77, 103))	('renal papillary cell carcinoma', 'Disease', 'MESH:C538614', (123, 153))	('carcinoma', 'Phenotype', 'HP:0030731', (219, 228))	('tumor', 'Disease', (64, 69))	('glioblastoma', 'Disease', 'MESH:D005909', (284, 296))	('sarcoma', 'Disease', 'MESH:D012509', (200, 207))	('tumors', 'Disease', 'MESH:D009369', (251, 257))	('colon carcinoma', 'Disease', 'MESH:D015179', (155, 170))	('sarcoma', 'Disease', (200, 207))	('prostate adenocarcinoma', 'Disease', 'MESH:D011471', (259, 282))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (161, 170))	('glioblastoma', 'Disease', (284, 296))
353651	30442178	MET amplification is present in renal clear cell carcinoma cases, and protein profiles of amplified and non-amplified cases can be discriminated (sdis = - 0.18; p = 0.0; srand = - 2.0e-5; Src_pY527, Bcl-2, beta-Catenin, PTEN, MAPK_pT202_Y204 are decreased in amplified cases and ACC1, Cyclin_B1, ASNS, ACC_pS79, and Transglutaminase are increased).	('Cyclin_B1', 'Gene', '891', (285, 294))	('ran', 'Gene', (171, 174))	('ran', 'Gene', '5901', (171, 174))	('beta-Catenin', 'Gene', '1499', (206, 218))	('ASNS', 'Gene', (296, 300))	('Src_pY527', 'Var', (188, 197))	('PTEN', 'Gene', '5728', (220, 224))	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('increased', 'PosReg', (337, 346))	('ACC_pS79', 'MPA', (302, 310))	('ACC1', 'Gene', (279, 283))	('renal clear cell carcinoma', 'Disease', 'MESH:C538614', (32, 58))	('beta-Catenin', 'Gene', (206, 218))	('MAPK_pT202_Y204', 'Gene', (226, 241))	('renal clear cell carcinoma', 'Disease', (32, 58))	('decreased', 'NegReg', (246, 255))	('ACC1', 'Gene', '597', (279, 283))	('Cyclin_B1', 'Gene', (285, 294))	('ran', 'Gene', (317, 320))	('ran', 'Gene', '5901', (317, 320))	('sdis', 'Chemical', '-', (146, 150))	('Bcl-2', 'Gene', (199, 204))	('ASNS', 'Gene', '440', (296, 300))	('PTEN', 'Gene', (220, 224))	('Bcl-2', 'Gene', '596', (199, 204))
353653	30442178	PIK3CA activating mutations are actionable for breast cancer (OncoKB evidence level 3).	('breast cancer', 'Disease', (47, 60))	('activating', 'PosReg', (7, 17))	('breast cancer', 'Phenotype', 'HP:0003002', (47, 60))	('PIK3CA', 'Gene', (0, 6))	('PIK3CA', 'Gene', '5290', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('breast cancer', 'Disease', 'MESH:D001943', (47, 60))	('mutations', 'Var', (18, 27))
353655	30442178	OncoKB level 4 data lists all available histological tumor types as possibly actionable for PIK3CA activating mutations.	('mutations', 'Var', (110, 119))	('PIK3CA', 'Gene', '5290', (92, 98))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Disease', (53, 58))	('PIK3CA', 'Gene', (92, 98))
353657	30442178	Breast cancer cases with PIK3CA-activating mutations are discriminable from those without (sdis = - 0.52; p = 0.0; srand = 6.2e-6) with specific proteins (increased levels) PR, ER-alpha, MAPK_pT202_Y204, Fibronectin, AR, and GATA3 in mutated cases and Cyclin_B1, Cyclin_E1, ASNS, and HER2 being decreased.	('ran', 'Gene', (116, 119))	('ran', 'Gene', '5901', (116, 119))	('Breast cancer', 'Phenotype', 'HP:0003002', (0, 13))	('Cyclin_B1', 'Gene', '891', (252, 261))	('PIK3CA', 'Gene', '5290', (25, 31))	('increased', 'PosReg', (155, 164))	('HER2', 'Gene', '2064', (284, 288))	('Cyclin_E1', 'Gene', '898', (263, 272))	('ASNS', 'Gene', '440', (274, 278))	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('mutated', 'Var', (234, 241))	('GATA3', 'Gene', '2625', (225, 230))	('PIK3CA', 'Gene', (25, 31))	('Cyclin_E1', 'Gene', (263, 272))	('Fibronectin', 'Gene', '2335', (204, 215))	('Cyclin_B1', 'Gene', (252, 261))	('sdis', 'Chemical', '-', (91, 95))	('ASNS', 'Gene', (274, 278))	('HER2', 'Gene', (284, 288))	('GATA3', 'Gene', (225, 230))	('ER-alpha', 'Gene', (177, 185))	('Breast cancer', 'Disease', 'MESH:D001943', (0, 13))	('mutations', 'Var', (43, 52))	('ER-alpha', 'Gene', '2099', (177, 185))	('Breast cancer', 'Disease', (0, 13))	('Fibronectin', 'Gene', (204, 215))
353661	30442178	However, many open questions remain because apart from mutations with unknown functional effects, it is often not possible even for oncogenic mutations with established clinical relevance in one cancer type to transfer knowledge of actionability to another cancer type.	('mutations', 'Var', (142, 151))	('cancer', 'Phenotype', 'HP:0002664', (257, 263))	('cancer', 'Disease', (195, 201))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('cancer', 'Disease', 'MESH:D009369', (257, 263))	('ran', 'Gene', (211, 214))	('ran', 'Gene', '5901', (211, 214))	('cancer', 'Disease', (257, 263))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
353667	30442178	This indicates that identical genetic alterations are not translated into protein profiles in the same way in different histotypes.	('ran', 'Gene', '5901', (59, 62))	('ran', 'Gene', (59, 62))	('genetic alterations', 'Var', (30, 49))
353672	30442178	This includes ERBB2/HER2 amplification in endometrial carcinoma, renal papillary carcinoma, testicular germ cell tumors, urothelial carcinoma, renal clear cell carcinoma, colon carcinoma, ovarian carcinoma, thymoma, thyroid carcinoma, cervical carcinoma, and head and neck squamous cell carcinoma.	('colon carcinoma', 'Disease', 'MESH:D015179', (171, 186))	('tumors', 'Disease', (113, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (160, 169))	('carcinoma', 'Phenotype', 'HP:0030731', (177, 186))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('HER2', 'Gene', (20, 24))	('thymoma', 'Disease', 'MESH:D013945', (207, 214))	('renal papillary carcinoma', 'Disease', (65, 90))	('cervical carcinoma', 'Disease', (235, 253))	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (54, 63))	('endometrial carcinoma', 'Disease', (42, 63))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (216, 233))	('ERBB2', 'Gene', (14, 19))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (121, 141))	('thyroid carcinoma', 'Disease', (216, 233))	('thymoma', 'Disease', (207, 214))	('renal clear cell carcinoma', 'Disease', 'MESH:C538614', (143, 169))	('cervical carcinoma', 'Disease', 'MESH:D002575', (235, 253))	('renal clear cell carcinoma', 'Disease', (143, 169))	('thymoma', 'Phenotype', 'HP:0100522', (207, 214))	('neck squamous cell carcinoma', 'Disease', (268, 296))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (188, 205))	('ERBB2', 'Gene', '2064', (14, 19))	('ovarian carcinoma', 'Disease', (188, 205))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (42, 63))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (268, 296))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (216, 233))	('HER2', 'Gene', '2064', (20, 24))	('amplification', 'Var', (25, 38))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))	('renal papillary carcinoma', 'Disease', 'MESH:D007681', (65, 90))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (42, 63))	('colon carcinoma', 'Disease', (171, 186))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (188, 205))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (273, 296))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('urothelial carcinoma', 'Disease', (121, 141))
353676	30442178	Interestingly, actionable genes with copy number alterations showed effects on protein expression for more histotypes than those with simple somatic mutations (10.2 affected tumor types on average for amplifications vs. 2.14 for simple somatic mutations).	('tumor', 'Disease', (174, 179))	('protein expression', 'MPA', (79, 97))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('effects', 'Reg', (68, 75))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('copy number alterations', 'Var', (37, 60))
353680	30442178	With respect to the actionable gene analysis, our approach may underestimate the number of potentially druggable genes, but the fact that it readily identifies many well-established actionable gene, cancer combinations, such as, for instance, HER2 amplification in breast and gastric cancer, indicates its validity.	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('cancer', 'Disease', 'MESH:D009369', (284, 290))	('cancer', 'Disease', (284, 290))	('HER2', 'Gene', (243, 247))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('cancer', 'Phenotype', 'HP:0002664', (284, 290))	('HER2', 'Gene', '2064', (243, 247))	('cancer', 'Disease', (199, 205))	('gastric cancer', 'Phenotype', 'HP:0012126', (276, 290))	('breast and gastric cancer', 'Disease', 'MESH:D013274', (265, 290))	('amplification', 'Var', (248, 261))
353687	30442178	By evaluating protein-level effects of genetic aberrations, our approach facilitates the identification of functionally relevant mutations and may therefore contribute to predicting actionable mutations across cancers and to guide basket trial design.	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('mutations', 'Var', (129, 138))	('facilitates', 'PosReg', (73, 84))	('cancers', 'Disease', 'MESH:D009369', (210, 217))	('cancers', 'Phenotype', 'HP:0002664', (210, 217))	('cancers', 'Disease', (210, 217))
353755	33712045	However, OSCC patients with high IGFBP3 expression had improved survival compared with those with low expression.	('improved', 'PosReg', (55, 63))	('OSCC', 'Disease', (9, 13))	('survival', 'MPA', (64, 72))	('IGFBP3', 'Gene', (33, 39))	('high', 'Var', (28, 32))	('patients', 'Species', '9606', (14, 22))
353759	33712045	Ectopic IGFBP3 expression enhanced IR-induced cell-killing in vitro.	('IR', 'Gene', '3643', (35, 37))	('IGFBP3', 'Gene', (8, 14))	('enhanced', 'PosReg', (26, 34))	('Ectopic', 'Var', (0, 7))
353761	33712045	Combined with IR, ectopic IGFBP3 expression induced mitochondria-dependent apoptosis, which was apparent through mitochondrial destruction and increased ROS production.	('increased', 'PosReg', (143, 152))	('induced', 'Reg', (44, 51))	('mitochondria-dependent', 'MPA', (52, 74))	('IR', 'Gene', '3643', (14, 16))	('ROS production', 'MPA', (153, 167))	('IGFBP3', 'Gene', (26, 32))	('ROS', 'Chemical', 'MESH:D017382', (153, 156))	('increased ROS production', 'Phenotype', 'HP:0025464', (143, 167))	('ectopic', 'Var', (18, 25))
353763	33712045	IGFBP3-mediated ROS production was reduced by the NF-kappaB inhibitor BMS-345541, while exogenous IL-6 rescued the NF-kappaB-inhibited, IGFBP3-mediated ROS production.	('reduced', 'NegReg', (35, 42))	('IL-6', 'Gene', (98, 102))	('IL-6', 'Gene', '3569', (98, 102))	('IGFBP3-mediated', 'Gene', (0, 15))	('NF-kappaB', 'Gene', '4790', (115, 124))	('BMS-345541', 'Var', (70, 80))	('ROS', 'Chemical', 'MESH:D017382', (152, 155))	('ROS', 'Chemical', 'MESH:D017382', (16, 19))	('NF-kappaB', 'Gene', '4790', (50, 59))	('NF-kappaB', 'Gene', (115, 124))	('ROS production', 'MPA', (16, 30))	('NF-kappaB', 'Gene', (50, 59))
353778	33712045	Abnormal expression or malfunction of IGFBP3 is associated with cancer development and progression.	('Abnormal expression', 'Var', (0, 19))	('IGFBP3', 'Gene', (38, 44))	('malfunction', 'MPA', (23, 34))	('associated', 'Reg', (48, 58))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('progression', 'CPA', (87, 98))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
353783	33712045	Ectopic IGFBP3 expression in p53-independent human breast cancer cells appeared to enhance radiosensitivity, with apoptosis induced through Bax and Bcl-2 after irradiation.	('Bax', 'Gene', '581', (140, 143))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('Bcl-2', 'Gene', (148, 153))	('enhance radiosensitivity', 'Phenotype', 'HP:0010997', (83, 107))	('Bcl-2', 'Gene', '596', (148, 153))	('IGFBP3', 'Gene', (8, 14))	('enhance', 'PosReg', (83, 90))	('p53', 'Gene', (29, 32))	('human', 'Species', '9606', (45, 50))	('Ectopic', 'Var', (0, 7))	('Bax', 'Gene', (140, 143))	('radiosensitivity', 'CPA', (91, 107))	('p53', 'Gene', '7157', (29, 32))	('breast cancer', 'Disease', 'MESH:D001943', (51, 64))	('breast cancer', 'Phenotype', 'HP:0003002', (51, 64))	('breast cancer', 'Disease', (51, 64))	('apoptosis', 'CPA', (114, 123))
353784	33712045	Esophageal squamous cell carcinoma cells with IGFBP3 knockdown had enhanced relative radioresistance.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (11, 34))	('squamous cell carcinoma', 'Disease', (11, 34))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (11, 34))	('knockdown', 'Var', (53, 62))	('IGFBP3', 'Gene', (46, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (25, 34))	('enhanced', 'PosReg', (67, 75))
353791	33712045	Different from the previous study, we found that OSCC patients with high levels of IGFBP3 had improved survival compared to those with low levels of IGFBP3.	('patients', 'Species', '9606', (54, 62))	('IGFBP3', 'Gene', (83, 89))	('improved', 'PosReg', (94, 102))	('survival', 'CPA', (103, 111))	('high levels', 'Var', (68, 79))	('OSCC', 'Disease', (49, 53))
353792	33712045	Ectopic IGFBP3 expression enhanced IR-induced cell-killing in vivo and in vitro.	('IR', 'Gene', '3643', (35, 37))	('IGFBP3', 'Gene', (8, 14))	('enhanced', 'PosReg', (26, 34))	('Ectopic', 'Var', (0, 7))
353794	33712045	IGFBP3-mediated ROS production was disrupted by IKK inhibition, while exogenous IL-6 rescued the NF-kappaB-inhibited, IGFBP3-mediated ROS production.	('IL-6', 'Gene', (80, 84))	('ROS', 'Chemical', 'MESH:D017382', (134, 137))	('IL-6', 'Gene', '3569', (80, 84))	('ROS', 'MPA', (16, 19))	('inhibition', 'Var', (52, 62))	('NF-kappaB', 'Gene', '4790', (97, 106))	('ROS', 'Chemical', 'MESH:D017382', (16, 19))	('NF-kappaB', 'Gene', (97, 106))
353810	33712045	The following primary antibodies were used: anti-Ki-67 (1:500, NCL-Ki-67p, Novacastra Laboratories, Newcastle upon Tyne, UK), anti-NF-kappaB (1:500, sc-8008, Santa Cruz, Dallas, TX, USA) and anti-IL-6 (1:100, GTX110527, GeneTex).	('Ki-67', 'Gene', '17345', (67, 72))	('Ki-67', 'Gene', (49, 54))	('1:500', 'Var', (142, 147))	('IL-6', 'Gene', (196, 200))	('NF-kappaB', 'Gene', '4790', (131, 140))	('IL-6', 'Gene', '3569', (196, 200))	('Ki-67', 'Gene', '17345', (49, 54))	('Ki-67', 'Gene', (67, 72))	('NF-kappaB', 'Gene', (131, 140))
353844	33712045	Furthermore, when patients were stratified using IGFBP3 expression level as a threshold, Kaplan-Meier survival analysis showed that OSCC patients with low levels of IGFBP3 had a reduced survival rate compared to those with high IGFBP3 levels (p = 0.0336, Figure S1A).	('IGFBP3', 'Gene', (165, 171))	('OSCC', 'Disease', (132, 136))	('survival', 'MPA', (186, 194))	('patients', 'Species', '9606', (137, 145))	('low', 'Var', (151, 154))	('patients', 'Species', '9606', (18, 26))	('reduced', 'NegReg', (178, 185))
353848	33712045	OEC-M1 cells with ectopic IGFBP3 expression demonstrated a reduced survival after cisplatin plus 10 Gy IR combination treatment compared with corresponding controls (Figure S1C).	('survival', 'CPA', (67, 75))	('reduced', 'NegReg', (59, 66))	('IR', 'Gene', '3643', (103, 105))	('IGFBP3', 'Gene', (26, 32))	('cisplatin', 'Chemical', 'MESH:D002945', (82, 91))	('ectopic', 'Var', (18, 25))
353851	33712045	However, TW2.6 cells with ectopic IGFBP3 expression demonstrated worse survival after combination treatment with cisplatin and 10 Gy IR compared with corresponding controls (Figure S1E).	('TW2.6', 'CellLine', 'CVCL:Y014', (9, 14))	('ectopic', 'Var', (26, 33))	('worse', 'NegReg', (65, 70))	('IR', 'Gene', '3643', (133, 135))	('S1E', 'Mutation', 'p.S1E', (181, 184))	('cisplatin', 'Chemical', 'MESH:D002945', (113, 122))	('survival', 'MPA', (71, 79))	('IGFBP3', 'Gene', (34, 40))
353852	33712045	These data indicate that high IGFBP3 expression enhances sensitivity to IR and may contribute to better outcomes after treatment of OSCC with conventional therapies.	('OSCC', 'Disease', (132, 136))	('high', 'Var', (25, 29))	('IR', 'Gene', '3643', (72, 74))	('better', 'PosReg', (97, 103))	('outcomes', 'MPA', (104, 112))	('enhances', 'PosReg', (48, 56))	('IGFBP3', 'Gene', (30, 36))	('contribute', 'Reg', (83, 93))
353854	33712045	LN1-1 cells with IGFBP3 knockdown showed improved survival and colony formation after IR treatment (Fig.	('LN1-1', 'CellLine', 'CVCL:L211', (0, 5))	('IGFBP3', 'Gene', (17, 23))	('survival', 'CPA', (50, 58))	('improved', 'PosReg', (41, 49))	('IR', 'Gene', '3643', (86, 88))	('knockdown', 'Var', (24, 33))	('colony formation', 'CPA', (63, 79))
353856	33712045	After 4 weeks, the mean weight of non-irradiated tumors from mice receiving OEC-M1 cells with ectopic IGFBP3 expression (n = 8; 0.19 +- 0.02 g) was significantly greater than that of the irradiated tumors (n = 7; 0.09 +- 0.007 g, p = 0.0007; Fig.	('mice', 'Species', '10090', (61, 65))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('expression', 'Var', (109, 119))	('greater', 'PosReg', (162, 169))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('tumors', 'Disease', (49, 55))	('tumors', 'Disease', 'MESH:D009369', (49, 55))	('tumors', 'Disease', (198, 204))	('tumors', 'Disease', 'MESH:D009369', (198, 204))	('tumors', 'Phenotype', 'HP:0002664', (198, 204))	('IGFBP3', 'Gene', (102, 108))
353859	33712045	Our results show that ectopic expression of IGFBP3 decreases tumor growth upon IR, suggesting a role for IGFBP3 in modulating tumor cell radiosensitivity in vivo.	('decreases tumor', 'Disease', 'MESH:D002303', (51, 66))	('ectopic expression', 'Var', (22, 40))	('modulating', 'Reg', (115, 125))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('cell radiosensitivity', 'Phenotype', 'HP:0010997', (132, 153))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('IR', 'Gene', '3643', (79, 81))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('decreases tumor', 'Disease', (51, 66))	('IGFBP3', 'Gene', (44, 50))	('tumor', 'Disease', (61, 66))	('tumor', 'Disease', (126, 131))
353861	33712045	At 72 h after IR, we observed similar weight and volume of orthotopic tumors in mice receiving OEC-M1 cells with ectopic IGFBP3 expression compared with vector controls (Fig.	('IGFBP3', 'Gene', (121, 127))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('ectopic', 'Var', (113, 120))	('tumors', 'Disease', (70, 76))	('tumors', 'Disease', 'MESH:D009369', (70, 76))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('IR', 'Gene', '3643', (14, 16))	('mice', 'Species', '10090', (80, 84))
353863	33712045	Immunostaining of tumor sections by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay demonstrated a higher trend of apoptotic cells in IGFBP3-expressing tumor cells (n = 75; 5.08 +- 0.8278% per filed) compared to controls (n = 75; 3.173 +- 0.56% per field; p = 0.0584; Fig.	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('tumor', 'Disease', (18, 23))	('dUTP', 'Chemical', 'MESH:C027078', (74, 78))	('apoptotic cells', 'CPA', (142, 157))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('IGFBP3-expressing', 'Var', (161, 178))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('tumor', 'Disease', (179, 184))
353865	33712045	Our in vivo data indicate that ectopic IGFBP3 expression increases tumor cell apoptosis and inhibits tumor cell proliferation at 72 h after exposure to IR.	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('increases', 'PosReg', (57, 66))	('IGFBP3', 'Gene', (39, 45))	('ectopic', 'Var', (31, 38))	('tumor', 'Disease', (67, 72))	('inhibits', 'NegReg', (92, 100))	('IR', 'Gene', '3643', (152, 154))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
353866	33712045	At 6, 24, 48 and 72 h after exposure to 10 Gy IR, ectopic IGFBP3 expression gradually reduced the proportion of cells in G0/G1 and increased G2/M phases of the cell cycle in comparison with control cells (Fig.	('reduced', 'NegReg', (86, 93))	('IR', 'Gene', '3643', (46, 48))	('ectopic', 'Var', (50, 57))	('increased', 'PosReg', (131, 140))	('G2/M phases of the cell cycle', 'CPA', (141, 170))	('IGFBP3', 'Gene', (58, 64))
353867	33712045	An assay for apoptosis via double staining with Annexin V and PI showed that ectopic IGFBP3 expression resulted in a higher proportion of apoptotic cells compared with control cells at 48 and 72 h after exposure to 10 Gy IR (Fig.	('ectopic', 'Var', (77, 84))	('Annexin V', 'Gene', '308', (48, 57))	('Annexin V', 'Gene', (48, 57))	('apoptotic cells', 'CPA', (138, 153))	('IGFBP3', 'Gene', (85, 91))	('IR', 'Gene', '3643', (221, 223))
353868	33712045	The proportion of PI-/Annexin V+ and PI+/Annexin V+ cells in OEC-M1 cells with ectopic IGFBP3 expression reached 42.16%, compared with 12.61% in OEC-M1 cells with vector control expression at 72 h (p = 0.00152; Fig.	('Annexin V', 'Gene', '308', (41, 50))	('IGFBP3', 'Gene', (87, 93))	('Annexin V', 'Gene', (41, 50))	('ectopic', 'Var', (79, 86))	('Annexin V', 'Gene', '308', (22, 31))	('Annexin V', 'Gene', (22, 31))
353870	33712045	At 72 h post-irradiation, the ratios of cytochrome c/alpha-tubulin and cleaved caspase-3/alpha-tubulin in irradiated OEC-M1 cells with ectopic IGFBP3 expression were higher (1.35 and 0.85, respectively; Fig.	('alpha-tubulin', 'Gene', (89, 102))	('higher', 'PosReg', (166, 172))	('IGFBP3', 'Gene', (143, 149))	('ectopic', 'Var', (135, 142))	('alpha-tubulin', 'Gene', '10376', (89, 102))	('caspase-3', 'Gene', '836', (79, 88))	('cytochrome c', 'Gene', (40, 52))	('alpha-tubulin', 'Gene', (53, 66))	('cytochrome c', 'Gene', '54205', (40, 52))	('caspase-3', 'Gene', (79, 88))	('alpha-tubulin', 'Gene', '10376', (53, 66))	('ratios', 'MPA', (30, 36))
353871	33712045	3c), indicating that ectopic IGFBP3 expression increases mitochondria-associated apoptosis upon IR exposure.	('mitochondria-associated apoptosis', 'MPA', (57, 90))	('IR', 'Gene', '3643', (96, 98))	('ectopic', 'Var', (21, 28))	('IGFBP3', 'Gene', (29, 35))	('increases', 'PosReg', (47, 56))
353874	33712045	We used the gamma-H2AX assay to investigate whether ectopic IGFBP3 expression affects IR-induced apoptosis by directly inducing DNA damage.	('gamma-H2AX', 'Gene', (12, 22))	('DNA damage', 'MPA', (128, 138))	('affects', 'Reg', (78, 85))	('IGFBP3', 'Gene', (60, 66))	('IR', 'Gene', '3643', (86, 88))	('ectopic', 'Var', (52, 59))	('gamma-H2AX', 'Gene', '15270', (12, 22))	('inducing', 'Reg', (119, 127))
353877	33712045	We also determined whether ectopic IGFBP3 expression promotes radiosensitivity through regulation of cellular ROS levels.	('promotes', 'PosReg', (53, 61))	('radiosensitivity', 'CPA', (62, 78))	('IGFBP3', 'Gene', (35, 41))	('ROS', 'Chemical', 'MESH:D017382', (110, 113))	('ectopic', 'Var', (27, 34))	('cellular ROS levels', 'MPA', (101, 120))
353878	33712045	A higher level of ROS production was detected in OEC-M1 cells with ectopic IGFBP3 expression compared with control cells at 2, 4, and 6 h after exposure to 10 Gy IR (Figures S3A, 4a, S3B).	('ectopic', 'Var', (67, 74))	('higher', 'PosReg', (2, 8))	('IR', 'Gene', '3643', (162, 164))	('ROS', 'Chemical', 'MESH:D017382', (18, 21))	('ROS production', 'MPA', (18, 32))	('IGFBP3', 'Gene', (75, 81))
353880	33712045	IR-induced ROS production in LN1-1 cells was suppressed by IGFBP3 knockdown (Fig.	('ROS', 'Chemical', 'MESH:D017382', (11, 14))	('IGFBP3', 'Gene', (59, 65))	('IR', 'Gene', '3643', (0, 2))	('suppressed', 'NegReg', (45, 55))	('ROS production', 'MPA', (11, 25))	('LN1-1', 'CellLine', 'CVCL:L211', (29, 34))	('knockdown', 'Var', (66, 75))
353881	33712045	4b), while ROS generation in TW2.6 cells was enhanced by ectopic IGFBP3 expression (Fig.	('TW2.6', 'CellLine', 'CVCL:Y014', (29, 34))	('ROS', 'Chemical', 'MESH:D017382', (11, 14))	('IGFBP3', 'Gene', (65, 71))	('ectopic', 'Var', (57, 64))	('enhanced', 'PosReg', (45, 53))	('ROS generation', 'MPA', (11, 25))
353884	33712045	At 6 h after irradiation, ectopic IGFBP3 expression increased the mitochondrial ROS level by 3.5 folds in OEC-M1 cells compared to controls (p = 0.0012; Fig.	('ectopic', 'Var', (26, 33))	('increased', 'PosReg', (52, 61))	('mitochondrial ROS level', 'MPA', (66, 89))	('ROS', 'Chemical', 'MESH:D017382', (80, 83))	('IGFBP3', 'Gene', (34, 40))
353885	33712045	In assessment of mitochondrial membrane potential (MMP), we found a significantly disruption of MMP in IGFBP3 expressing OEC-M1 and control cells after exposure to 10 Gy IR compared to corresponding non-irradiated cells (p = 0.067; Fig.	('IR', 'Gene', '3643', (170, 172))	('MMP', 'MPA', (96, 99))	('IGFBP3', 'Gene', (103, 109))	('OEC-M1', 'Var', (121, 127))	('disruption', 'NegReg', (82, 92))
353894	33712045	By Ingenuity Pathway Analysis (IPA), the canonical pathway analysis showed that "IL-6 signaling" was inhibited by IGFBP3 knockdown (z score = - 2.887; Fig.	('knockdown', 'Var', (121, 130))	('IGFBP3', 'Gene', (114, 120))	('IL-6', 'Gene', (81, 85))	('IL-6', 'Gene', '3569', (81, 85))	('inhibited', 'NegReg', (101, 110))
353896	33712045	To confirm the relationship between IGFBP3 expression and NF-kappaB signaling as indicated by GSEA and IPA, quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to evaluate the expression of IL6, IL1A and IL1B and demonstrated down-regulation of these genes by IGFBP3 knockdown in LN1-1 cells (Fig.	('IL6', 'Gene', '3569', (218, 221))	('down-regulation', 'NegReg', (254, 269))	('IL6', 'Gene', (218, 221))	('GSEA', 'Chemical', '-', (94, 98))	('IL1A', 'Gene', (223, 227))	('NF-kappaB', 'Gene', '4790', (58, 67))	('knockdown', 'Var', (295, 304))	('IL1A', 'Gene', '3552', (223, 227))	('IGFBP3', 'Gene', (288, 294))	('NF-kappaB', 'Gene', (58, 67))	('IL1B', 'Gene', (232, 236))	('IL1B', 'Gene', '3553', (232, 236))	('LN1-1', 'CellLine', 'CVCL:L211', (308, 313))
353897	33712045	Inversely, ectopic IGFBP3 expression in OEC-M1 and TW2.6 cells was associated with increased expression of IL6, IL1A and IL1B (Fig.	('increased', 'PosReg', (83, 92))	('IL1B', 'Gene', '3553', (121, 125))	('IL1B', 'Gene', (121, 125))	('IL1A', 'Gene', '3552', (112, 116))	('IL6', 'Gene', '3569', (107, 110))	('ectopic', 'Var', (11, 18))	('expression', 'MPA', (93, 103))	('IL6', 'Gene', (107, 110))	('IGFBP3', 'Gene', (19, 25))	('TW2.6', 'CellLine', 'CVCL:Y014', (51, 56))	('IL1A', 'Gene', (112, 116))
353898	33712045	Analysis via the Bio-Plex assay also demonstrated effects of IGFBP3 on NF-kappaB signaling by showing upregulated expression of IL-1beta, IL-6 and IL-8 protein in ectopic IGFBP3 expressing OEC-M1 and TW2.6 cells, and down-regulation of these proteins in IGFBP3 knockdown LN1-1 cells (Figure S6).	('IL-6', 'Gene', '3569', (138, 142))	('IL-1beta', 'Gene', (128, 136))	('IL-8', 'Gene', '3576', (147, 151))	('NF-kappaB', 'Gene', (71, 80))	('LN1-1', 'CellLine', 'CVCL:L211', (271, 276))	('upregulated', 'PosReg', (102, 113))	('NF-kappaB', 'Gene', '4790', (71, 80))	('IGFBP3', 'Gene', (171, 177))	('TW2.6', 'CellLine', 'CVCL:Y014', (200, 205))	('IL-1beta', 'Gene', '3552', (128, 136))	('IL-8', 'Gene', (147, 151))	('expression', 'MPA', (114, 124))	('down-regulation', 'NegReg', (217, 232))	('IL-6', 'Gene', (138, 142))	('ectopic', 'Var', (163, 170))
353901	33712045	The western blot analysis showed that ectopic IGFBP3 expression elevated the phosphorylation status of nuclear factor of IkappaBalpha and p65-NF-kappaB (Fig.	('IkappaBalpha', 'Gene', '4792', (121, 133))	('p65', 'Gene', '5970', (138, 141))	('elevated', 'PosReg', (64, 72))	('IkappaBalpha', 'Gene', (121, 133))	('p65', 'Gene', (138, 141))	('NF-kappaB', 'Gene', '4790', (142, 151))	('ectopic', 'Var', (38, 45))	('NF-kappaB', 'Gene', (142, 151))	('phosphorylation status', 'MPA', (77, 99))	('IGFBP3', 'Gene', (46, 52))
353902	33712045	In contrast, treatment of IkappaB kinase (IKK) inhibitor, BMS-345541 suppressed the phosphorylation of IkappaBalpha and p65-NF-kappaB in a dose-dependent manner in IGFBP3 expressing OEC-M1 cells (Fig.	('IkappaBalpha', 'Gene', '4792', (103, 115))	('IkappaBalpha', 'Gene', (103, 115))	('p65', 'Gene', '5970', (120, 123))	('BMS-345541', 'Var', (58, 68))	('p65', 'Gene', (120, 123))	('suppressed', 'NegReg', (69, 79))	('NF-kappaB', 'Gene', '4790', (124, 133))	('NF-kappaB', 'Gene', (124, 133))	('phosphorylation', 'MPA', (84, 99))
353903	33712045	These data strongly suggested that ectopic IGFBP3 expression constitutively elevated canonical NF-kappaB activity in OEC-M1 cells.	('NF-kappaB', 'Gene', '4790', (95, 104))	('elevated', 'PosReg', (76, 84))	('NF-kappaB', 'Gene', (95, 104))	('ectopic', 'Var', (35, 42))	('IGFBP3', 'Gene', (43, 49))
353904	33712045	Both ectopic IGFBP3 expression and IR treatment elevated NF-kappaB activity in 293T ells (Fig.	('ectopic', 'Var', (5, 12))	('293T', 'CellLine', 'CVCL:0063', (79, 83))	('NF-kappaB', 'Gene', (57, 66))	('IR', 'Gene', '3643', (35, 37))	('NF-kappaB', 'Gene', '4790', (57, 66))	('activity', 'MPA', (67, 75))	('elevated', 'PosReg', (48, 56))	('IGFBP3', 'Gene', (13, 19))
353905	33712045	Similarly, the levels of IL-1beta, IL-6 and IL-8 in OSCC cells were enhanced by ectopic IGFBP3 expression and IR exposure (Figure S6).	('IL-8', 'Gene', '3576', (44, 48))	('enhanced', 'PosReg', (68, 76))	('IL-6', 'Gene', (35, 39))	('IL-1beta', 'Gene', '3552', (25, 33))	('IL-8', 'Gene', (44, 48))	('IL-6', 'Gene', '3569', (35, 39))	('levels', 'MPA', (15, 21))	('IGFBP3', 'Gene', (88, 94))	('IL-1beta', 'Gene', (25, 33))	('IR', 'Gene', '3643', (110, 112))	('ectopic', 'Var', (80, 87))
353906	33712045	These data indicate that both ectopic IGFBP3 expression and IR enhance NF-kappaB signaling and increase downstream inflammatory cytokine production.	('downstream inflammatory cytokine production', 'MPA', (104, 147))	('IR', 'Gene', '3643', (60, 62))	('IGFBP3', 'Gene', (38, 44))	('ectopic', 'Var', (30, 37))	('NF-kappaB', 'Gene', (71, 80))	('increase', 'PosReg', (95, 103))	('enhance', 'PosReg', (63, 70))	('NF-kappaB', 'Gene', '4790', (71, 80))
353908	33712045	Similarly, the level of phosphorylated NF-kappaB was increased by ectopic IGFBP3 expression and irradiation, while NAC administration suppressed the phosphorylation of p65-NF-kappaB (Fig.	('NF-kappaB', 'Gene', '4790', (39, 48))	('suppressed', 'NegReg', (134, 144))	('NF-kappaB', 'Gene', (39, 48))	('NAC', 'Chemical', 'MESH:D000111', (115, 118))	('p65', 'Gene', (168, 171))	('NF-kappaB', 'Gene', '4790', (172, 181))	('NF-kappaB', 'Gene', (172, 181))	('expression', 'Var', (81, 91))	('ectopic', 'Var', (66, 73))	('increased', 'PosReg', (53, 62))	('phosphorylation', 'MPA', (149, 164))	('level of phosphorylated', 'MPA', (15, 38))	('p65', 'Gene', '5970', (168, 171))	('IGFBP3', 'Gene', (74, 80))
353910	33712045	ROS production in IGFBP3 expressing OEC-M1 cells upon IR was inhibited by BMS-345541 in a dose-dependent manner (Fig.	('IR', 'Gene', '3643', (54, 56))	('ROS production', 'MPA', (0, 14))	('inhibited', 'NegReg', (61, 70))	('BMS-345541', 'Var', (74, 84))	('ROS', 'Chemical', 'MESH:D017382', (0, 3))	('IGFBP3', 'Gene', (18, 24))
353911	33712045	The levels of IL6 expression in irradiated IGFBP3 expressing OEC-M1 and TW2.6 cells were abolished by BMS-345541 (Figs.	('levels', 'MPA', (4, 10))	('IL6', 'Gene', '3569', (14, 17))	('BMS-345541', 'Var', (102, 112))	('TW2.6', 'CellLine', 'CVCL:Y014', (72, 77))	('expression', 'MPA', (18, 28))	('IL6', 'Gene', (14, 17))	('IGFBP3', 'Gene', (43, 49))	('abolished', 'NegReg', (89, 98))
353913	33712045	Treatment with exogenous IL-6 had no impact on ROS production in BMS-345541-treated OSCC cells without irradiation, however, IL-6 restored ROS production in BMS-345541-treated IGFBP3-expressing OEC-M1 cells upon IR (Fig.	('IL-6', 'Gene', '3569', (125, 129))	('IGFBP3-expressing', 'Gene', (176, 193))	('IR', 'Gene', '3643', (212, 214))	('BMS-345541-treated', 'Var', (157, 175))	('IL-6', 'Gene', (25, 29))	('ROS production', 'MPA', (139, 153))	('ROS', 'Chemical', 'MESH:D017382', (139, 142))	('IL-6', 'Gene', '3569', (25, 29))	('IL-6', 'Gene', (125, 129))	('ROS', 'Chemical', 'MESH:D017382', (47, 50))
353915	33712045	These data demonstrate that ectopic IGFBP3 expression enhances ROS production via activation of NF-kappaB signaling and downstream cytokine expression.	('enhances', 'PosReg', (54, 62))	('ROS', 'Chemical', 'MESH:D017382', (63, 66))	('NF-kappaB', 'Gene', '4790', (96, 105))	('activation', 'PosReg', (82, 92))	('IGFBP3', 'Gene', (36, 42))	('ectopic', 'Var', (28, 35))	('ROS production', 'MPA', (63, 77))	('NF-kappaB', 'Gene', (96, 105))
353919	33712045	Our in vivo data indicated that ectopic IGFBP3 expression increased the levels of nuclear NF-kappaB and IL-6 upon IR.	('increased', 'PosReg', (58, 67))	('NF-kappaB', 'Gene', '4790', (90, 99))	('IGFBP3', 'Gene', (40, 46))	('IR', 'Gene', '3643', (114, 116))	('NF-kappaB', 'Gene', (90, 99))	('IL-6', 'Gene', (104, 108))	('ectopic', 'Var', (32, 39))	('IL-6', 'Gene', '3569', (104, 108))
353921	33712045	We found that OSCC patients with high IGFBP3 levels had better prognostic outcomes compared with patients with low levels of IGFBP3 (Figure S1A).	('high', 'Var', (33, 37))	('IGFBP3', 'Gene', (38, 44))	('patients', 'Species', '9606', (19, 27))	('better', 'PosReg', (56, 62))	('OSCC', 'Disease', (14, 18))	('patients', 'Species', '9606', (97, 105))
353923	33712045	reported that a high IGFBP3 level was associated with favorable radiotherapy response and good prognosis among patients with esophageal squamous cell carcinoma.	('IGFBP3', 'Gene', (21, 27))	('high', 'Var', (16, 20))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (125, 159))	('carcinoma', 'Phenotype', 'HP:0030731', (150, 159))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (136, 159))	('esophageal squamous cell carcinoma', 'Disease', (125, 159))	('radiotherapy response', 'CPA', (64, 85))	('patients', 'Species', '9606', (111, 119))
353924	33712045	Our results indicate that ectopic IGFBP3 expression leads to decreased OEC-M1 and TW2.6 cell survival when treated with IR alone or in combination with cisplatin (Figs.	('ectopic', 'Var', (26, 33))	('IR', 'Gene', '3643', (120, 122))	('TW2.6', 'CellLine', 'CVCL:Y014', (82, 87))	('cisplatin', 'Chemical', 'MESH:D002945', (152, 161))	('TW2.6 cell survival', 'CPA', (82, 101))	('decreased', 'NegReg', (61, 70))	('OEC-M1', 'CPA', (71, 77))	('IGFBP3', 'Gene', (34, 40))
353932	33712045	In contrast, our data demonstrated a G2/M accumulation caused by ectopic IGFBP3 expression upon irradiation in p53-mutated OEC-M1 cells (Fig.	('G2/M accumulation', 'MPA', (37, 54))	('p53', 'Gene', (111, 114))	('p53', 'Gene', '7157', (111, 114))	('IGFBP3', 'Gene', (73, 79))	('ectopic', 'Var', (65, 72))
353933	33712045	Ectopic IGFBP3 expression significantly increased the percentage of apoptosis detected by Annexin V/PI staining in irradiated cells in vitro (Fig.	('IGFBP3', 'Gene', (8, 14))	('Annexin V', 'Gene', '308', (90, 99))	('Annexin V', 'Gene', (90, 99))	('Ectopic', 'Var', (0, 7))	('increased', 'PosReg', (40, 49))
353936	33712045	However, we found that ectopic IGFBP3 expression enhanced IR-induced gamma-H2AX via ROS production, indicating IGFBP3 served as an indirect player in IR-mediated DNA damage (Figure S2C).	('gamma-H2AX', 'Gene', (69, 79))	('IR', 'Gene', '3643', (150, 152))	('IGFBP3', 'Gene', (31, 37))	('enhanced', 'PosReg', (49, 57))	('ectopic', 'Var', (23, 30))	('gamma-H2AX', 'Gene', '15270', (69, 79))	('IR', 'Gene', '3643', (58, 60))	('ROS production', 'MPA', (84, 98))	('ROS', 'Chemical', 'MESH:D017382', (84, 87))
353951	33712045	Our data demonstrate that IGFBP3-mediated NF-kappaB activation could be inhibited by removal of ROS, suggesting ROS induces NF-kappaB activation (Figs.	('ROS', 'Chemical', 'MESH:D017382', (112, 115))	('ROS', 'Chemical', 'MESH:D017382', (96, 99))	('NF-kappaB', 'Gene', '4790', (42, 51))	('activation', 'PosReg', (134, 144))	('NF-kappaB', 'Gene', '4790', (124, 133))	('NF-kappaB', 'Gene', (42, 51))	('NF-kappaB', 'Gene', (124, 133))	('ROS', 'Var', (112, 115))
353956	33712045	Similarly, our results suggest that blockage of NF-kappaB activation diminishes ROS production, an effect that is reversible by treatment with exogenous IL-6 (Fig.	('IL-6', 'Gene', (153, 157))	('diminishes', 'NegReg', (69, 79))	('IL-6', 'Gene', '3569', (153, 157))	('blockage', 'Var', (36, 44))	('NF-kappaB', 'Gene', '4790', (48, 57))	('ROS production', 'MPA', (80, 94))	('ROS', 'Chemical', 'MESH:D017382', (80, 83))	('NF-kappaB', 'Gene', (48, 57))
353963	33712045	We found that ectopic IGFBP3 expression enhanced IR-induced cell-killing in vivo and in vitro.	('enhanced', 'PosReg', (40, 48))	('IGFBP3', 'Gene', (22, 28))	('ectopic', 'Var', (14, 21))	('IR', 'Gene', '3643', (49, 51))
353964	33712045	More specifically, ectopic IGFBP3 expression increased IR-induced apoptosis as indicated by elevated ROS production.	('IGFBP3', 'Gene', (27, 33))	('ectopic', 'Var', (19, 26))	('increased', 'PosReg', (45, 54))	('IR', 'Gene', '3643', (55, 57))	('elevated', 'PosReg', (92, 100))	('ROS', 'Chemical', 'MESH:D017382', (101, 104))	('ROS production', 'MPA', (101, 115))
353977	32051379	By comparing the mutational panel of each tumor, we are now able to determine whether or not multiple tumors have the same origin.	('tumor', 'Disease', (42, 47))	('tumors', 'Disease', 'MESH:D009369', (102, 108))	('tumors', 'Disease', (102, 108))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('mutational', 'Var', (17, 27))	('tumor', 'Disease', (102, 107))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))
353996	32051379	TP53 R342*, POLD1 Q53H, IL7R D122H, and COL22A1 S440L were detected as somatic mutations from the skin lesion, while TP53 A138P, CTLA4 A66S, ZFHX3 N1043D, and KMT2D G4593E were detected as somatic mutations from the lung lesion.	('TP53', 'Gene', (117, 121))	('POLD1', 'Gene', (12, 17))	('D122H', 'SUBSTITUTION', 'None', (29, 34))	('Q53H', 'Mutation', 'p.Q53H', (18, 22))	('COL22A1', 'Gene', '169044', (40, 47))	('A138P', 'Mutation', 'rs28934875', (122, 127))	('skin lesion', 'Disease', 'MESH:D012871', (98, 109))	('KMT2D', 'Gene', (159, 164))	('R342*', 'SUBSTITUTION', 'None', (5, 10))	('TP53', 'Gene', '7157', (0, 4))	('S440L', 'Var', (48, 53))	('N1043D', 'Mutation', 'p.N1043D', (147, 153))	('ZFHX3', 'Gene', '463', (141, 146))	('CTLA4', 'Gene', '1493', (129, 134))	('ZFHX3', 'Gene', (141, 146))	('R342*', 'Var', (5, 10))	('IL7R', 'Gene', '3575', (24, 28))	('TP53', 'Gene', '7157', (117, 121))	('IL7R', 'Gene', (24, 28))	('COL22A1', 'Gene', (40, 47))	('POLD1', 'Gene', '5424', (12, 17))	('A66S', 'Var', (135, 139))	('CTLA4', 'Gene', (129, 134))	('KMT2D', 'Gene', '8085', (159, 164))	('skin lesion', 'Disease', (98, 109))	('A66S', 'Mutation', 'p.A66S', (135, 139))	('TP53', 'Gene', (0, 4))	('S440L', 'Mutation', 'rs1174446571', (48, 53))	('D122H', 'Var', (29, 34))	('G4593E', 'Mutation', 'rs1425274289', (165, 171))
353998	32051379	A germline mutation of BRCA2 (R2318*) was also detected from the patient.	('R2318*', 'SUBSTITUTION', 'None', (30, 36))	('BRCA2', 'Gene', (23, 28))	('R2318*', 'Var', (30, 36))	('patient', 'Species', '9606', (65, 72))	('BRCA2', 'Gene', '675', (23, 28))
354000	32051379	TP53 R342*, the mutation detected in the skin lesion, is a mutation within the tetramerization motif of tumor protein p53.	('R342*', 'SUBSTITUTION', 'None', (5, 10))	('skin lesion', 'Disease', 'MESH:D012871', (41, 52))	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('skin lesion', 'Disease', (41, 52))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('p53', 'Gene', (118, 121))	('tumor', 'Disease', (104, 109))	('p53', 'Gene', '7157', (118, 121))	('R342*', 'Var', (5, 10))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
354003	32051379	Considering the mutation site and high variant allele frequency of TP53 gene mutation in each lesion, these mutations are likely driver mutations.	('mutation', 'Var', (77, 85))	('TP53', 'Gene', '7157', (67, 71))	('TP53', 'Gene', (67, 71))
354014	32051379	Histopathological markers are reported to aid in identifying the origin of metastatic lung SCC with a history of extrapulmonary SCC, including p16 staining for pulmonary SCC versus cervical SCC; the combination of CK19, MMP3, ZNF830, and PI3 for pulmonary SCC versus head and neck SCC; and the combination of TTF-1, napsin A, and p16 staining for pulmonary SCC versus esophagus and anorectal SCC.	('pulmonary SCC versus head', 'Disease', (246, 271))	('napsin A', 'Gene', (316, 324))	('CK19', 'Gene', (214, 218))	('SCC', 'Phenotype', 'HP:0002860', (128, 131))	('SCC', 'Gene', (91, 94))	('CK19', 'Gene', '3880', (214, 218))	('pulmonary SCC versus esophagus', 'Disease', 'MESH:D004938', (347, 377))	('PI3', 'Gene', '5266', (238, 241))	('SCC', 'Gene', '6317', (392, 395))	('SCC', 'Gene', '6317', (170, 173))	('MMP3', 'Gene', '4314', (220, 224))	('SCC', 'Gene', '6317', (256, 259))	('SCC', 'Gene', '6317', (91, 94))	('SCC', 'Gene', '6317', (281, 284))	('ZNF830', 'Gene', (226, 232))	('SCC', 'Gene', (392, 395))	('SCC', 'Gene', (170, 173))	('SCC', 'Gene', '6317', (128, 131))	('SCC', 'Gene', (256, 259))	('SCC', 'Phenotype', 'HP:0002860', (190, 193))	('SCC', 'Gene', (281, 284))	('TTF-1', 'Gene', '7270', (309, 314))	('PI3', 'Gene', (238, 241))	('SCC', 'Gene', '6317', (357, 360))	('SCC', 'Gene', (128, 131))	('pulmonary SCC versus head', 'Disease', 'MESH:D006086', (246, 271))	('p16', 'Gene', (143, 146))	('napsin A', 'Gene', '9476', (316, 324))	('ZNF830', 'Gene', '91603', (226, 232))	('pulmonary SCC versus cervical SCC', 'Disease', 'MESH:D002575', (160, 193))	('p16', 'Gene', '1029', (143, 146))	('SCC', 'Gene', '6317', (190, 193))	('SCC', 'Phenotype', 'HP:0002860', (91, 94))	('SCC', 'Gene', (357, 360))	('combination', 'Var', (199, 210))	('p16', 'Gene', (330, 333))	('SCC', 'Gene', (190, 193))	('MMP3', 'Gene', (220, 224))	('SCC', 'Phenotype', 'HP:0002860', (256, 259))	('SCC', 'Phenotype', 'HP:0002860', (170, 173))	('pulmonary SCC versus esophagus', 'Disease', (347, 377))	('p16', 'Gene', '1029', (330, 333))	('pulmonary SCC versus cervical SCC', 'Disease', (160, 193))	('TTF-1', 'Gene', (309, 314))
354017	32051379	Strong and diffuse expression or the complete absence of p53 expression may indicate a TP53 gene mutation.	('absence', 'NegReg', (46, 53))	('p53', 'Gene', '7157', (57, 60))	('TP53', 'Gene', '7157', (87, 91))	('TP53', 'Gene', (87, 91))	('p53', 'Gene', (57, 60))	('mutation', 'Var', (97, 105))	('expression', 'MPA', (61, 71))
354021	32051379	NGS and the comparison of trunk mutations in each lesion can be used to determine whether a tumor is primary or metastatic with high specificity.	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('mutations', 'Var', (32, 41))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Disease', (92, 97))
354029	32051379	Nevertheless, caution must be practiced when comparing driver mutations in multiple lesions, as subclonal driver mutations may also occur later during tumor progression as low-allele-frequency mutations.	('mutations', 'Var', (113, 122))	('tumor', 'Disease', (151, 156))	('tumor', 'Disease', 'MESH:D009369', (151, 156))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))
354030	32051379	In the present case, if the lung lesion had been recurrence of skin cancer, then TP53 R342*, the probable driver mutation of skin cancer would have been detected in the lung lesion as well.	('skin cancer', 'Disease', 'MESH:D012878', (125, 136))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('recurrence of skin', 'Phenotype', 'HP:0001581', (49, 67))	('skin cancer', 'Disease', (63, 74))	('skin cancer', 'Phenotype', 'HP:0008069', (125, 136))	('skin cancer', 'Phenotype', 'HP:0008069', (63, 74))	('R342*', 'SUBSTITUTION', 'None', (86, 91))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('R342*', 'Var', (86, 91))	('skin cancer', 'Disease', (125, 136))	('skin cancer', 'Disease', 'MESH:D012878', (63, 74))	('TP53', 'Gene', '7157', (81, 85))	('TP53', 'Gene', (81, 85))
354033	32051379	The comparison of driver mutations is important for the evaluation of a tumor's origin; the detection of the driver mutations in each tumor by clinical sequencing is therefore effective and useful.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Disease', (72, 77))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('mutations', 'Var', (116, 125))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('tumor', 'Disease', (134, 139))
354129	25440877	We identified 911 candidate somatic mutations in 725 genes among the 32 tumors; 609 out of 911 candidate somatic mutations were further confirmed by Sanger sequencing or by 454 sequencing.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('tumors', 'Disease', (72, 78))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('mutations', 'Var', (36, 45))
354130	25440877	The range of confirmed mutations per tumor was 2 to 78, with a mean and SD of 19 +- 16.5 mutations per tumor.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('tumor', 'Disease', (103, 108))	('mutations', 'Var', (23, 32))	('tumor', 'Disease', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
354132	25440877	Of note, NOTCH1, with alterations present in 15% of patients in the combined discovery and prevalence set, has not been reported be mutated at a significant frequency in other solid tumor types.	('tumor', 'Disease', (182, 187))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))	('alterations', 'Var', (22, 33))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('patients', 'Species', '9606', (52, 60))	('NOTCH1', 'Gene', (9, 15))
354137	25440877	is that point mutations affecting NOTCH1 occurred in 11% of the HNSCC tumors.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('HNSCC tumors', 'Disease', (64, 76))	('SCC', 'Phenotype', 'HP:0002860', (66, 69))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('NOTCH1', 'Gene', (34, 40))	('HNSCC tumors', 'Disease', 'MESH:D000077195', (64, 76))	('occurred', 'Reg', (41, 49))	('HNSCC', 'Phenotype', 'HP:0012288', (64, 69))	('point mutations', 'Var', (8, 23))
354138	25440877	In addition to NOTCH1, they found non-synonymous point mutations in NOTCH2 or NOTCH3 in 11% of the samples.	('NOTCH2', 'Gene', (68, 74))	('NOTCH3', 'Gene', (78, 84))	('NOTCH3', 'Gene', '4854', (78, 84))	('NOTCH2', 'Gene', '4853', (68, 74))	('non-synonymous point mutations', 'Var', (34, 64))
354139	25440877	They also reported that the mutation rate of HPV-positive tumors was approximately half that of HPV-negative tumors (mean = 2.28 mutations per megabase compared with 4.83 mutations per megabase); among patients who reported a smoking history, tumors with the highest fraction of G -> T transversion showed a trendency toward increased overall mutation rates, which are indicative of smoking-induced mutations, and may represent a robust readout of functional tobacco exposure.	('tobacco', 'Species', '4097', (459, 466))	('tumors', 'Disease', 'MESH:D009369', (243, 249))	('HPV', 'Species', '10566', (45, 48))	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('HPV-positive tumors', 'Disease', 'MESH:D030361', (45, 64))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('patients', 'Species', '9606', (202, 210))	('mutation rates', 'MPA', (343, 357))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumors', 'Disease', (109, 115))	('G -> T transversion', 'Var', (279, 298))	('HPV', 'Species', '10566', (96, 99))	('tumors', 'Phenotype', 'HP:0002664', (243, 249))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumors', 'Disease', 'MESH:D009369', (109, 115))	('tumors', 'Disease', (243, 249))	('tumors', 'Disease', (58, 64))	('increased', 'PosReg', (325, 334))	('HPV-positive tumors', 'Disease', (45, 64))
354143	25440877	Among these, PIK3CA was mutated in approximately 21% of all samples.	('mutated', 'Var', (24, 31))	('PIK3CA', 'Gene', '5290', (13, 19))	('PIK3CA', 'Gene', (13, 19))
354144	25440877	Of note, the study revealed 40% to 50% of HPV positive samples had alterations in PIK3CA that were linked with very low rates of EGFR alterations.	('HPV', 'Species', '10566', (42, 45))	('PIK3CA', 'Gene', (82, 88))	('alterations', 'Var', (67, 78))	('HPV', 'Gene', (42, 45))	('PIK3CA', 'Gene', '5290', (82, 88))	('EGFR', 'Gene', '1956', (129, 133))	('EGFR', 'Gene', (129, 133))
354148	25440877	They consistently found mutations of TP53, NOTCH1, CDKN2A, PIK3CA, HRAS, FAT1, and CASP8.	('CDKN2A', 'Gene', '1029', (51, 57))	('FAT1', 'Gene', '2195', (73, 77))	('TP53', 'Gene', (37, 41))	('NOTCH1', 'Gene', (43, 49))	('HRAS', 'Gene', '3265', (67, 71))	('CASP8', 'Gene', (83, 88))	('PIK3CA', 'Gene', (59, 65))	('mutations', 'Var', (24, 33))	('CASP8', 'Gene', '841', (83, 88))	('found', 'Reg', (18, 23))	('CDKN2A', 'Gene', (51, 57))	('PIK3CA', 'Gene', '5290', (59, 65))	('HRAS', 'Gene', (67, 71))	('FAT1', 'Gene', (73, 77))
354151	25440877	We detected mutations in the previously reported genes, such as TP53, NOTCH1, PIK3CA, CDKN2A, and FGFR3, and in two genes, CEBPA and FES, which have not been previously reported in HNSCC.	('PIK3CA', 'Gene', (78, 84))	('CDKN2A', 'Gene', '1029', (86, 92))	('FGFR3', 'Gene', (98, 103))	('HNSCC', 'Phenotype', 'HP:0012288', (181, 186))	('mutations', 'Var', (12, 21))	('PIK3CA', 'Gene', '5290', (78, 84))	('SCC', 'Gene', (183, 186))	('SCC', 'Phenotype', 'HP:0002860', (183, 186))	('TP53', 'Gene', (64, 68))	('CEBPA', 'Gene', (123, 128))	('NOTCH1', 'Gene', (70, 76))	('SCC', 'Gene', '6317', (183, 186))	('FGFR3', 'Gene', '2261', (98, 103))	('CEBPA', 'Gene', '1050', (123, 128))	('CDKN2A', 'Gene', (86, 92))
354152	25440877	We also found that HNSCC patients with tobacco smoking had 3.2-fold more mutations than HNSCC patients without tobacco smoking, whereas HPV-negative patients had 4-fold more TP53 mutations than HPV-positive patients.	('SCC', 'Gene', (21, 24))	('patients', 'Species', '9606', (207, 215))	('patients', 'Species', '9606', (149, 157))	('tobacco', 'Species', '4097', (39, 46))	('patients', 'Species', '9606', (94, 102))	('TP53', 'Gene', (174, 178))	('SCC', 'Phenotype', 'HP:0002860', (21, 24))	('SCC', 'Gene', '6317', (21, 24))	('SCC', 'Gene', (90, 93))	('SCC', 'Phenotype', 'HP:0002860', (90, 93))	('HNSCC', 'Phenotype', 'HP:0012288', (88, 93))	('patients', 'Species', '9606', (25, 33))	('HNSCC', 'Phenotype', 'HP:0012288', (19, 24))	('HPV', 'Species', '10566', (194, 197))	('SCC', 'Gene', '6317', (90, 93))	('tobacco', 'Species', '4097', (111, 118))	('HPV', 'Species', '10566', (136, 139))	('mutations', 'Var', (73, 82))
354157	25440877	In contrast, in a clinical and genomic and metagenomic characterization of oral tongue SCC in patients, we found that non-smokers were younger than smokers, were more likely female, and that non-smokers had fewer TP53 mutations than smokers.	('patients', 'Species', '9606', (94, 102))	('TP53', 'Gene', (213, 217))	('mutations', 'Var', (218, 227))	('SCC', 'Gene', (87, 90))	('SCC', 'Phenotype', 'HP:0002860', (87, 90))	('fewer', 'NegReg', (207, 212))	('SCC', 'Gene', '6317', (87, 90))
354159	25440877	Compared to cancers from non-smokers, a greater proportion of mutations in cancers from smokers were either A:T -> G:C or A:T -> T:A substitutions.	('cancers', 'Disease', 'MESH:D009369', (12, 19))	('cancers', 'Phenotype', 'HP:0002664', (12, 19))	('cancers', 'Disease', 'MESH:D009369', (75, 82))	('cancers', 'Disease', (12, 19))	('cancers', 'Phenotype', 'HP:0002664', (75, 82))	('cancers', 'Disease', (75, 82))	('A:T -> T', 'Var', (122, 130))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('mutations', 'Var', (62, 71))	('A:T -> G:C', 'Var', (108, 118))
354160	25440877	Conversely, compared to cancers from smokers, a greater proportion of mutations in cancers from non-smokers were C:G -> G:C transversions.	('cancers', 'Disease', 'MESH:D009369', (83, 90))	('cancers', 'Phenotype', 'HP:0002664', (83, 90))	('mutations', 'Var', (70, 79))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('cancers', 'Phenotype', 'HP:0002664', (24, 31))	('cancers', 'Disease', 'MESH:D009369', (24, 31))	('C:G -> G:C transversions', 'Var', (113, 137))	('cancers', 'Disease', (24, 31))	('cancers', 'Disease', (83, 90))
354163	25440877	To understand the genetic alterations in HPV-positive versus HPV-negative HNSCC, Lechner and colleagues performed targeted next-generation sequencing on 182 genes often mutated in oropharyngeal HNSCC tumors.	('SCC', 'Gene', (196, 199))	('HPV', 'Species', '10566', (41, 44))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('mutated', 'Var', (169, 176))	('SCC', 'Phenotype', 'HP:0002860', (196, 199))	('SCC', 'Gene', '6317', (196, 199))	('HNSCC', 'Phenotype', 'HP:0012288', (194, 199))	('SCC', 'Gene', (76, 79))	('tumors', 'Phenotype', 'HP:0002664', (200, 206))	('HNSCC', 'Phenotype', 'HP:0012288', (74, 79))	('oropharyngeal HNSCC tumors', 'Disease', 'MESH:D000077195', (180, 206))	('oropharyngeal HNSCC tumors', 'Disease', (180, 206))	('SCC', 'Phenotype', 'HP:0002860', (76, 79))	('SCC', 'Gene', '6317', (76, 79))	('HPV', 'Species', '10566', (61, 64))
354165	25440877	TP53 mutations were detected in all the HPV-negative samples, whereas PIK3CA mutations or amplification and PTEN inactivation by gene copy number loss or mutations were seen more frequently in HPV-positive oropharyngeal tumors.	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('TP53', 'Gene', (0, 4))	('PTEN', 'Gene', (108, 112))	('tumors', 'Phenotype', 'HP:0002664', (220, 226))	('PTEN', 'Gene', '5728', (108, 112))	('oropharyngeal tumors', 'Phenotype', 'HP:0100638', (206, 226))	('HPV', 'Species', '10566', (193, 196))	('number loss', 'Disease', (139, 150))	('mutations', 'Var', (5, 14))	('HPV-positive oropharyngeal tumors', 'Disease', 'MESH:D030361', (193, 226))	('PIK3CA', 'Gene', (70, 76))	('number loss', 'Disease', 'MESH:D016388', (139, 150))	('mutations', 'Var', (77, 86))	('HPV', 'Species', '10566', (40, 43))	('HPV-positive oropharyngeal tumors', 'Disease', (193, 226))	('mutations', 'Var', (154, 163))	('PIK3CA', 'Gene', '5290', (70, 76))
354166	25440877	In concordance, Braakhuis and colleagues showed that TP53 mutations are common in oral SCC of young adult patients in which infection with biologically active HPV is rare.	('mutations', 'Var', (58, 67))	('HPV', 'Species', '10566', (159, 162))	('common', 'Reg', (72, 78))	('SCC', 'Gene', (87, 90))	('SCC', 'Phenotype', 'HP:0002860', (87, 90))	('infection', 'Disease', (124, 133))	('patients', 'Species', '9606', (106, 114))	('SCC', 'Gene', '6317', (87, 90))	('infection', 'Disease', 'MESH:D007239', (124, 133))	('TP53', 'Gene', (53, 57))
354168	25440877	reported a high frequency of activating PIK3CA mutations in HPV-positive oropharyngeal cancer.	('HPV-positive oropharyngeal cancer', 'Disease', 'MESH:D009959', (60, 93))	('PIK3CA', 'Gene', (40, 46))	('PIK3CA', 'Gene', '5290', (40, 46))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('mutations', 'Var', (47, 56))	('HPV-positive oropharyngeal cancer', 'Disease', (60, 93))	('activating', 'PosReg', (29, 39))
354169	25440877	also found that PIK3CA mutations were more frequent in HPV-positive oropharyngeal SCCs.	('SCC', 'Phenotype', 'HP:0002860', (82, 85))	('SCC', 'Gene', '6317', (82, 85))	('PIK3CA', 'Gene', '5290', (16, 22))	('HPV', 'Species', '10566', (55, 58))	('frequent', 'Reg', (43, 51))	('mutations', 'Var', (23, 32))	('PIK3CA', 'Gene', (16, 22))	('SCC', 'Gene', (82, 85))
354172	25440877	As revealed by massive parallel sequencing, the genetic alterations in HNSCC are mainly in a handful of molecular pathways and/or biological processes including TP53 pathways (TP53); mitogenic pathways (RAS/PI3K/mTOR pathway, PIK3CA, HRAS); cell cycle (CDKN2A); NOTCH pathways (NOTCH1, NOTCH2, NOTCH3); and cell communication and death (FAT1, CASP8).	('NOTCH', 'Gene', (278, 283))	('NOTCH3', 'Gene', (294, 300))	('NOTCH', 'Gene', (262, 267))	('CASP8', 'Gene', '841', (343, 348))	('cell cycle', 'CPA', (241, 251))	('SCC', 'Phenotype', 'HP:0002860', (73, 76))	('mitogenic pathways', 'Pathway', (183, 201))	('CDKN2A', 'Gene', '1029', (253, 259))	('death', 'Disease', 'MESH:D003643', (330, 335))	('NOTCH', 'Gene', (294, 299))	('PI3', 'Gene', '5266', (207, 210))	('HRAS', 'Gene', '3265', (234, 238))	('genetic alterations', 'Var', (48, 67))	('FAT1', 'Gene', (337, 341))	('HRAS', 'Gene', (234, 238))	('CASP8', 'Gene', (343, 348))	('PIK3CA', 'Gene', (226, 232))	('NOTCH2', 'Gene', '4853', (286, 292))	('SCC', 'Gene', '6317', (73, 76))	('PI3', 'Gene', (207, 210))	('SCC', 'Gene', (73, 76))	('TP53 pathways', 'Pathway', (161, 174))	('HNSCC', 'Phenotype', 'HP:0012288', (71, 76))	('mTOR', 'Gene', (212, 216))	('death', 'Disease', (330, 335))	('NOTCH', 'Gene', '31293', (278, 283))	('NOTCH', 'Gene', '31293', (262, 267))	('FAT1', 'Gene', '2195', (337, 341))	('NOTCH', 'Gene', '31293', (286, 291))	('alterations', 'Var', (56, 67))	('NOTCH3', 'Gene', '4854', (294, 300))	('CDKN2A', 'Gene', (253, 259))	('cell communication', 'CPA', (307, 325))	('NOTCH2', 'Gene', (286, 292))	('NOTCH', 'Gene', '31293', (294, 299))	('PIK3CA', 'Gene', '5290', (226, 232))	('mTOR', 'Gene', '2475', (212, 216))	('NOTCH', 'Gene', (286, 291))
354173	25440877	Below, we will draw attention to therapeutic implications related to the mutations in TP53, PIK3CA, and NOTCH1, and their corresponding pathways.	('TP53', 'Gene', (86, 90))	('NOTCH1', 'Gene', (104, 110))	('mutations', 'Var', (73, 82))	('PIK3CA, a', 'Gene', '5290;133584', (92, 101))
354174	25440877	TP53 is the most commonly mutated gene, with loss-of-function mutations frequently detected in HNSCC and in many other tumors.	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('TP53', 'Gene', (0, 4))	('tumors', 'Disease', (119, 125))	('tumors', 'Disease', 'MESH:D009369', (119, 125))	('loss-of-function', 'NegReg', (45, 61))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('SCC', 'Gene', (97, 100))	('SCC', 'Phenotype', 'HP:0002860', (97, 100))	('SCC', 'Gene', '6317', (97, 100))	('HNSCC', 'Phenotype', 'HP:0012288', (95, 100))	('mutations', 'Var', (62, 71))
354175	25440877	More than half of all HNSCCs have mutations in TP53, and nearly all of these cancers show defects in the p53 pathway.	('defects', 'NegReg', (90, 97))	('cancers', 'Disease', 'MESH:D009369', (77, 84))	('cancers', 'Phenotype', 'HP:0002664', (77, 84))	('SCC', 'Gene', (24, 27))	('TP53', 'Gene', (47, 51))	('cancers', 'Disease', (77, 84))	('SCC', 'Phenotype', 'HP:0002860', (24, 27))	('p53', 'Gene', (105, 108))	('SCC', 'Gene', '6317', (24, 27))	('p53', 'Gene', '7157', (105, 108))	('HNSCC', 'Phenotype', 'HP:0012288', (22, 27))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('mutations', 'Var', (34, 43))
354179	25440877	In a prospective, multicenter trial with 560 patients registered, we demonstrated that TP53 mutations generally, and disruptive mutations of TP53 (resulting in amino acid substitution predicted to disrupt DNA binding) particularly, are significantly associated with short survival in HNSCC.	('mutations', 'Var', (128, 137))	('TP53', 'Gene', (87, 91))	('TP53', 'Gene', (141, 145))	('mutations', 'Var', (92, 101))	('SCC', 'Gene', (286, 289))	('SCC', 'Phenotype', 'HP:0002860', (286, 289))	('HNSCC', 'Phenotype', 'HP:0012288', (284, 289))	('patients', 'Species', '9606', (45, 53))	('SCC', 'Gene', '6317', (286, 289))	('short survival', 'MPA', (266, 280))	('associated with', 'Reg', (250, 265))
354180	25440877	Studies from TCGA also reported the correlation of TP53 mutations with generally unfavorable indicators, for example in tumor stage and elapsed time to death in HNSCC.	('mutations', 'Var', (56, 65))	('TP53', 'Gene', (51, 55))	('SCC', 'Gene', (163, 166))	('HNSCC', 'Phenotype', 'HP:0012288', (161, 166))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('SCC', 'Phenotype', 'HP:0002860', (163, 166))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('death', 'Disease', 'MESH:D003643', (152, 157))	('SCC', 'Gene', '6317', (163, 166))	('death', 'Disease', (152, 157))	('tumor', 'Disease', (120, 125))	('correlation', 'Interaction', (36, 47))
354181	25440877	reported that TP53 mutation increased the risk of not responding to cisplatin and 5-FU by 2.7 times, implying that p53 status may be a useful indicator of response to neo-adjuvant chemotherapy in HNSCC.	('SCC', 'Phenotype', 'HP:0002860', (198, 201))	('5-FU', 'Chemical', 'MESH:D005472', (82, 86))	('SCC', 'Gene', '6317', (198, 201))	('HNSCC', 'Phenotype', 'HP:0012288', (196, 201))	('TP53', 'Gene', (14, 18))	('mutation', 'Var', (19, 27))	('p53', 'Gene', (115, 118))	('p53', 'Gene', '7157', (115, 118))	('SCC', 'Gene', (198, 201))	('cisplatin', 'Chemical', 'MESH:D002945', (68, 77))
354182	25440877	reported a significant association between nonfunctional TP53 mutations and a low probability of pathological complete response in patients with oral cavity SCC and receiving nonadjuvant cisplatin and fluorouracil chemotherapy in a prospective randomized trial.	('SCC', 'Gene', (157, 160))	('patients', 'Species', '9606', (131, 139))	('SCC', 'Phenotype', 'HP:0002860', (157, 160))	('fluorouracil', 'Chemical', 'MESH:D005472', (201, 213))	('SCC', 'Gene', '6317', (157, 160))	('nonfunctional', 'Var', (43, 56))	('cisplatin', 'Chemical', 'MESH:D002945', (187, 196))	('TP53', 'Gene', (57, 61))	('mutations', 'Var', (62, 71))
354184	25440877	The reasons why p53 mutation may lead to refractoriness to chemotherapy remain to be investigated.	('lead to', 'Reg', (33, 40))	('p53', 'Gene', (16, 19))	('mutation', 'Var', (20, 28))	('p53', 'Gene', '7157', (16, 19))
354185	25440877	As proposed by Perrone and colleagues, the observed relationship between nonfunctional TP53 mutations and a low response rate is in line with the current paradigm suggesting that DNA-damaging agents operate mainly by triggering cells to undergo apoptosis, which is impaired by an inefficient p53-dependent apoptotic pathway in oral SCCs.	('SCC', 'Phenotype', 'HP:0002860', (332, 335))	('p53', 'Gene', '7157', (292, 295))	('SCC', 'Gene', '6317', (332, 335))	('undergo', 'Reg', (237, 244))	('TP53', 'Gene', (87, 91))	('triggering', 'Reg', (217, 227))	('SCC', 'Gene', (332, 335))	('mutations', 'Var', (92, 101))	('apoptosis', 'CPA', (245, 254))	('p53', 'Gene', (292, 295))
354186	25440877	As a consequence, drugs that functino by means of p53-independent apoptosis, such as spindle-damaging agents (taxanes), may be effective in oral SCCs carrying nonfunctional TP53 mutations.	('taxanes', 'Chemical', 'MESH:D043823', (110, 117))	('SCC', 'Gene', (145, 148))	('SCC', 'Phenotype', 'HP:0002860', (145, 148))	('p53', 'Gene', (50, 53))	('p53', 'Gene', '7157', (50, 53))	('SCC', 'Gene', '6317', (145, 148))	('TP53', 'Gene', (173, 177))	('mutations', 'Var', (178, 187))
354187	25440877	Another possibility may be related to increased MAP4 expression, which occurs when p53 is mutated and transcriptionally inactive and enhance microtubule polymerization, taxane binding, and drug sensibility.	('enhance', 'PosReg', (133, 140))	('p53', 'Gene', (83, 86))	('mutated', 'Var', (90, 97))	('p53', 'Gene', '7157', (83, 86))	('taxane', 'CPA', (169, 175))	('MAP4', 'Gene', (48, 52))	('taxane', 'Chemical', 'MESH:C080625', (169, 175))	('MAP4', 'Gene', '4134', (48, 52))	('drug sensibility', 'CPA', (189, 205))	('microtubule polymerization', 'MPA', (141, 167))	('expression', 'MPA', (53, 63))	('increased', 'PosReg', (38, 47))
354188	25440877	Perturbations in p53 signaling pathways are believed to be required for the development of most cancers.	('cancers', 'Phenotype', 'HP:0002664', (96, 103))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('p53', 'Gene', (17, 20))	('cancers', 'Disease', 'MESH:D009369', (96, 103))	('Perturbations', 'Var', (0, 13))	('cancers', 'Disease', (96, 103))	('p53', 'Gene', '7157', (17, 20))
354189	25440877	There is evidence to suggest that restoration or reactivation of p53 function will have significant therapeutic benefit.	('function', 'MPA', (69, 77))	('p53', 'Gene', (65, 68))	('p53', 'Gene', '7157', (65, 68))	('reactivation', 'Var', (49, 61))
354198	25440877	In HNSCCs, PI3KCA is mutated at the frequencies of 6-21% and ~90% of PIK3CA mutations found in the helical/kinase domains.	('SCC', 'Gene', '6317', (5, 8))	('HNSCC', 'Phenotype', 'HP:0012288', (3, 8))	('mutations', 'Var', (76, 85))	('PI3', 'Gene', '5266', (11, 14))	('PIK3CA', 'Gene', (69, 75))	('SCC', 'Gene', (5, 8))	('PIK3CA', 'Gene', '5290', (69, 75))	('PI3', 'Gene', (11, 14))	('SCC', 'Phenotype', 'HP:0002860', (5, 8))
354199	25440877	In addition to PIK3CA mutations, PIK3CA copy number increases were found in ~9% of HNSCC tumors.	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('PIK3CA', 'Gene', '5290', (33, 39))	('copy number', 'Var', (40, 51))	('HNSCC', 'Phenotype', 'HP:0012288', (83, 88))	('increases', 'PosReg', (52, 61))	('PIK3CA', 'Gene', '5290', (15, 21))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('HNSCC tumors', 'Disease', (83, 95))	('PIK3CA', 'Gene', (33, 39))	('SCC', 'Phenotype', 'HP:0002860', (85, 88))	('HNSCC tumors', 'Disease', 'MESH:D000077195', (83, 95))	('PIK3CA', 'Gene', (15, 21))
354202	25440877	In addition to PIK3CA mutation, they found mutations in PIK3AP1, PIK3C2A, PIK3C2B, PIK3CB, PIK3CD, PIK3CG, PIK3IP1, PIK3R1, PIK3R2, PIK3R3, PIK3R4, PIK3R5, PIK3R6, AKT1, AKT2, AKT3, mTOR, PTEN, PDK1, TSC1/2, and RICTOR, all in the PI3K pathway.	('PIK3CG', 'Gene', '5294', (99, 105))	('PIK3R5', 'Gene', (148, 154))	('PIK3R6', 'Gene', (156, 162))	('mTOR', 'Gene', '2475', (182, 186))	('AKT2', 'Gene', '208', (170, 174))	('PIK3C2A', 'Gene', '5286', (65, 72))	('PTEN', 'Gene', '5728', (188, 192))	('PIK3R4', 'Gene', '30849', (140, 146))	('PIK3IP1', 'Gene', '113791', (107, 114))	('PI3', 'Gene', '5266', (231, 234))	('AKT1', 'Gene', '207', (164, 168))	('PIK3CD', 'Gene', '5293', (91, 97))	('AKT2', 'Gene', (170, 174))	('PIK3AP1', 'Gene', '118788', (56, 63))	('PIK3R3', 'Gene', '8503', (132, 138))	('PIK3R1', 'Gene', '5295', (116, 122))	('PIK3IP1', 'Gene', (107, 114))	('TSC1', 'Gene', (200, 204))	('PIK3R4', 'Gene', (140, 146))	('PDK1', 'Gene', (194, 198))	('PIK3C2B', 'Gene', (74, 81))	('PIK3CD', 'Gene', (91, 97))	('PI3', 'Gene', (231, 234))	('PIK3CA', 'Gene', '5290', (15, 21))	('PIK3R2', 'Gene', (124, 130))	('PIK3R5', 'Gene', '23533', (148, 154))	('AKT1', 'Gene', (164, 168))	('PIK3CA', 'Gene', (15, 21))	('AKT3', 'Gene', '10000', (176, 180))	('PIK3AP1', 'Gene', (56, 63))	('PIK3CB', 'Gene', (83, 89))	('PIK3CB', 'Gene', '5291', (83, 89))	('TSC1', 'Gene', '7248', (200, 204))	('PIK3R3', 'Gene', (132, 138))	('RICTOR', 'Gene', '253260', (212, 218))	('mTOR', 'Gene', (182, 186))	('AKT3', 'Gene', (176, 180))	('PIK3C2B', 'Gene', '5287', (74, 81))	('PTEN', 'Gene', (188, 192))	('PIK3R2', 'Gene', '5296', (124, 130))	('mutations', 'Var', (43, 52))	('RICTOR', 'Gene', (212, 218))	('PIK3C2A', 'Gene', (65, 72))	('PIK3R6', 'Gene', '146850', (156, 162))	('PIK3CG', 'Gene', (99, 105))	('PDK1', 'Gene', '5163', (194, 198))	('PIK3R1', 'Gene', (116, 122))
354203	25440877	reported that PI3K pathway-mutated HNSCC tumors showed an increased rate of cancer gene mutations; and, of interest, all tumors with concurrent mutations of multiple PI3K pathway genes were advanced (Stage IV).	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('PI3', 'Gene', (14, 17))	('mutations', 'Var', (88, 97))	('tumors', 'Disease', (41, 47))	('HNSCC tumors', 'Disease', (35, 47))	('tumors', 'Disease', 'MESH:D009369', (121, 127))	('mutations', 'Var', (144, 153))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('HNSCC', 'Phenotype', 'HP:0012288', (35, 40))	('tumors', 'Disease', 'MESH:D009369', (41, 47))	('PI3', 'Gene', '5266', (166, 169))	('advanced', 'PosReg', (190, 198))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('PI3', 'Gene', '5266', (14, 17))	('SCC', 'Phenotype', 'HP:0002860', (37, 40))	('cancer', 'Disease', (76, 82))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('PI3', 'Gene', (166, 169))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('tumors', 'Disease', (121, 127))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('HNSCC tumors', 'Disease', 'MESH:D000077195', (35, 47))
354204	25440877	With respect to therapeutic implications, expression of the PIK3CA mutants was found to confer growth advantage compared with overexpression of wild-type PIK3CA.	('PIK3CA', 'Gene', (154, 160))	('PIK3CA', 'Gene', (60, 66))	('PIK3CA', 'Gene', '5290', (60, 66))	('growth advantage', 'CPA', (95, 111))	('PIK3CA', 'Gene', '5290', (154, 160))	('mutants', 'Var', (67, 74))
354205	25440877	Furthermore, patient-derived tumor grafts with PIK3CA mutations were exquisitely sensitive to an mTOR/PI3K inhibitor (bez-235), in contrast to PIK3CA-wildtype tumor grafts, suggesting that activating mutations of the PI3K pathway have the potential to serve as biomarkers for treatment selection in HNSCC.	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('mutations', 'Var', (200, 209))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('PI3', 'Gene', '5266', (217, 220))	('SCC', 'Phenotype', 'HP:0002860', (301, 304))	('PIK3CA', 'Gene', '5290', (47, 53))	('mTOR', 'Gene', (97, 101))	('mutations', 'Var', (54, 63))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('PIK3CA', 'Gene', '5290', (143, 149))	('SCC', 'Gene', '6317', (301, 304))	('PI3', 'Gene', (217, 220))	('PI3', 'Gene', '5266', (102, 105))	('mTOR', 'Gene', '2475', (97, 101))	('patient', 'Species', '9606', (13, 20))	('bez-235', 'Chemical', 'MESH:C531198', (118, 125))	('activating', 'PosReg', (189, 199))	('SCC', 'Gene', (301, 304))	('tumor', 'Disease', (159, 164))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('PIK3CA', 'Gene', (47, 53))	('HNSCC', 'Phenotype', 'HP:0012288', (299, 304))	('PIK3CA', 'Gene', (143, 149))	('PI3', 'Gene', (102, 105))	('tumor', 'Disease', (29, 34))
354206	25440877	In support of this, xenografts developed from an HNSCC cell line with a PIK3CA mutation (H1047R) were more sensitive to the combination of bez-235 plus cetuximab compared with cetuximab alone.	('combination', 'Interaction', (124, 135))	('H1047R', 'Mutation', 'rs121913279', (89, 95))	('cetuximab', 'Chemical', 'MESH:D000068818', (176, 185))	('HNSCC', 'Phenotype', 'HP:0012288', (49, 54))	('SCC', 'Gene', (51, 54))	('cetuximab', 'Chemical', 'MESH:D000068818', (152, 161))	('more', 'PosReg', (102, 106))	('bez-235', 'Chemical', 'MESH:C531198', (139, 146))	('PIK3CA', 'Gene', (72, 78))	('SCC', 'Phenotype', 'HP:0002860', (51, 54))	('SCC', 'Gene', '6317', (51, 54))	('H1047R', 'Var', (89, 95))	('PIK3CA', 'Gene', '5290', (72, 78))	('sensitive', 'MPA', (107, 116))
354207	25440877	Moreover, pharmacologic profiling of antitumor agents in HNSCC cell lines suggested that PIK3CA mutation may serve as a predictive biomarker for the drugs targeting the EGFR/PI3K pathway.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('SCC', 'Gene', (59, 62))	('tumor', 'Disease', (41, 46))	('PIK3CA', 'Gene', (89, 95))	('PI3', 'Gene', '5266', (174, 177))	('EGFR', 'Gene', '1956', (169, 173))	('mutation', 'Var', (96, 104))	('PIK3CA', 'Gene', '5290', (89, 95))	('SCC', 'Gene', '6317', (59, 62))	('SCC', 'Phenotype', 'HP:0002860', (59, 62))	('PI3', 'Gene', (174, 177))	('EGFR', 'Gene', (169, 173))	('HNSCC', 'Phenotype', 'HP:0012288', (57, 62))	('tumor', 'Disease', 'MESH:D009369', (41, 46))
354208	25440877	In Sewall's study investigating the significance of PIK3CA mutations in HPV-associated oropharyngeal SCCs, the authors reported that mutant PIK3CA tumors had a distinct protein expression profile within HPV-positive oropharyngeal SCCs, and PIK3CA mutations in HPV-positive cells were associated with activation of the mTOR, but not AKT, signaling pathway; and HPV-positive cells expressing mutant PIK3CA were more sensitive to PIK3CA/mTOR inhibition versus AKT inhibition, implying that inhibitors for mTOR may have activity against HPV-positive PIK3CA mutant oropharyngeal cancers.	('cancers', 'Disease', (574, 581))	('PIK3CA', 'Gene', (140, 146))	('mTOR', 'Gene', '2475', (434, 438))	('cancer', 'Phenotype', 'HP:0002664', (574, 580))	('PIK3CA', 'Gene', (52, 58))	('tumors', 'Disease', 'MESH:D009369', (147, 153))	('SCC', 'Gene', (101, 104))	('PIK3CA', 'Gene', '5290', (240, 246))	('mutations', 'Var', (247, 256))	('PIK3CA', 'Gene', '5290', (397, 403))	('HPV', 'Species', '10566', (203, 206))	('mTOR', 'Gene', (502, 506))	('activity', 'MPA', (516, 524))	('SCC', 'Phenotype', 'HP:0002860', (230, 233))	('mTOR', 'Gene', (318, 322))	('mutant', 'Var', (390, 396))	('PIK3CA', 'Gene', '5290', (546, 552))	('HPV', 'Species', '10566', (360, 363))	('cancers', 'Disease', 'MESH:D009369', (574, 581))	('tumors', 'Phenotype', 'HP:0002664', (147, 153))	('mTOR', 'Gene', '2475', (502, 506))	('PIK3CA', 'Gene', '5290', (427, 433))	('SCC', 'Gene', '6317', (230, 233))	('HPV', 'Species', '10566', (533, 536))	('mTOR', 'Gene', '2475', (318, 322))	('PIK3CA', 'Gene', '5290', (140, 146))	('PIK3CA', 'Gene', (240, 246))	('SCC', 'Phenotype', 'HP:0002860', (101, 104))	('mutations', 'Var', (59, 68))	('PIK3CA', 'Gene', '5290', (52, 58))	('PIK3CA', 'Gene', (397, 403))	('mutant', 'Var', (133, 139))	('activation', 'PosReg', (300, 310))	('SCC', 'Gene', (230, 233))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumors', 'Disease', (147, 153))	('mutant', 'Var', (553, 559))	('PIK3CA', 'Gene', (546, 552))	('mTOR', 'Gene', (434, 438))	('HPV', 'Species', '10566', (72, 75))	('HPV', 'Species', '10566', (260, 263))	('cancers', 'Phenotype', 'HP:0002664', (574, 581))	('protein', 'MPA', (169, 176))	('SCC', 'Gene', '6317', (101, 104))	('PIK3CA', 'Gene', (427, 433))
354212	25440877	reported that the combination of erlotinib and temsirolimus was poorly tolerated, and low prevalence of PTEN expression and 8% incidence of PIK3CA mutations indicate biological relevance of this pathway in recurrent and/or metastatic HNSCC.	('SCC', 'Gene', '6317', (236, 239))	('mutations', 'Var', (147, 156))	('HNSCC', 'Phenotype', 'HP:0012288', (234, 239))	('PIK3CA', 'Gene', (140, 146))	('SCC', 'Phenotype', 'HP:0002860', (236, 239))	('erlotinib', 'Chemical', 'MESH:D000069347', (33, 42))	('PIK3CA', 'Gene', '5290', (140, 146))	('SCC', 'Gene', (236, 239))	('temsirolimus', 'Chemical', 'MESH:C401859', (47, 59))	('PTEN', 'Gene', (104, 108))	('PTEN', 'Gene', '5728', (104, 108))
354220	25440877	NOTCH1 mutations have found in 10-15% of the HNSCC tumors, making NOTCH1 one of the most frequently mutated genes in this tumor type.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('SCC', 'Phenotype', 'HP:0002860', (47, 50))	('HNSCC', 'Phenotype', 'HP:0012288', (45, 50))	('tumor', 'Disease', (51, 56))	('HNSCC tumors', 'Disease', (45, 57))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('NOTCH1', 'Gene', (0, 6))	('HNSCC tumors', 'Disease', 'MESH:D000077195', (45, 57))	('tumor', 'Disease', (122, 127))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('mutations', 'Var', (7, 16))
354221	25440877	Among the 28 NOTCH1 mutations identified in our sequencing study, ~25% of nonsense mutations and ~15% of indel mutations were detected in HNSCC; inactivation of both alleles probably occurred in at least 9 of the 21 patients with NOTCH1 mutations.	('HNSCC', 'Phenotype', 'HP:0012288', (138, 143))	('SCC', 'Phenotype', 'HP:0002860', (140, 143))	('SCC', 'Gene', '6317', (140, 143))	('NOTCH1', 'Gene', (13, 19))	('patients', 'Species', '9606', (216, 224))	('NOTCH1', 'Gene', (230, 236))	('mutations', 'Var', (20, 29))	('SCC', 'Gene', (140, 143))
354223	25440877	Several studies support this notion: (1) in cutaneous and lung SCC, loss-of-function NOTCH1 mutations lie within the terminal region; (2) ablation of NOTCH1 results in epidermal and corneal hyperplasia followed by the development of skin tumors and facilitates chemical-induced skin carcinogenesis; and (3) impaired Notch signaling promotes de novo cutaneous squamous cell carcinoma in mice.	('cutaneous squamous cell carcinoma', 'Phenotype', 'HP:0006739', (349, 382))	('loss-of-function', 'NegReg', (68, 84))	('promotes', 'PosReg', (332, 340))	('corneal hyperplasia', 'Disease', 'MESH:D006965', (182, 201))	('corneal hyperplasia', 'Disease', (182, 201))	('tumor', 'Phenotype', 'HP:0002664', (238, 243))	('NOTCH1', 'Gene', (150, 156))	('mice', 'Species', '10090', (386, 390))	('ablation', 'Var', (138, 146))	('SCC', 'Phenotype', 'HP:0002860', (63, 66))	('NOTCH1', 'Gene', (85, 91))	('impaired', 'Var', (307, 315))	('skin tumors', 'Disease', (233, 244))	('cutaneous squamous cell carcinoma', 'Disease', (349, 382))	('corneal hyperplasia', 'Phenotype', 'HP:0000485', (182, 201))	('facilitates', 'PosReg', (249, 260))	('Notch', 'Gene', '31293', (316, 321))	('carcinoma', 'Phenotype', 'HP:0030731', (373, 382))	('cutaneous squamous cell carcinoma', 'Disease', 'MESH:D002294', (349, 382))	('mutations', 'Var', (92, 101))	('SCC', 'Gene', '6317', (63, 66))	('skin carcinogenesis', 'Disease', 'MESH:D063646', (278, 297))	('skin tumors', 'Disease', 'MESH:D012878', (233, 244))	('SCC', 'Gene', (63, 66))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (359, 382))	('skin carcinogenesis', 'Disease', (278, 297))	('Notch', 'Gene', (316, 321))	('tumors', 'Phenotype', 'HP:0002664', (238, 244))	('skin tumors', 'Phenotype', 'HP:0008069', (233, 244))
354224	25440877	In addition, in oral squamous cell carcinoma cell lines that have missense or truncating NOTCH1 mutations, expression of the cleaved/activated form of NOTCH1 or full-length wild-type NOTCH1 inhibits cell proliferation both in vitro and in vivo .	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (21, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (35, 44))	('oral squamous cell carcinoma', 'Disease', (16, 44))	('cell proliferation', 'CPA', (199, 217))	('missense', 'Var', (66, 74))	('NOTCH1', 'Gene', (89, 95))	('inhibits', 'NegReg', (190, 198))	('truncating', 'MPA', (78, 88))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (16, 44))	('NOTCH1', 'Gene', (151, 157))	('mutations', 'Var', (96, 105))
354226	25440877	In T cell acute lymphoblastic leukemia/lymphoma, NOTCH signaling has previously been implicated as pro-tumorigenic owning to activating mutations and translocations in the genes for NOTCH receptors or their regulators.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('leukemia', 'Phenotype', 'HP:0001909', (30, 38))	('lymphoma', 'Phenotype', 'HP:0002665', (39, 47))	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (10, 38))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (16, 38))	('tumor', 'Disease', (103, 108))	('lymphoblastic leukemia/lymphoma', 'Disease', 'MESH:D054198', (16, 47))	('acute lymphoblastic leukemia', 'Disease', (10, 38))	('activating', 'PosReg', (125, 135))	('translocations', 'Var', (150, 164))	('lymphoblastic leukemia/lymphoma', 'Disease', (16, 47))	('acute lymphoblastic leukemia', 'Disease', 'MESH:D054198', (10, 38))	('mutations', 'Var', (136, 145))	('NOTCH', 'Gene', '31293', (49, 54))	('NOTCH', 'Gene', '31293', (182, 187))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('NOTCH', 'Gene', (182, 187))	('NOTCH', 'Gene', (49, 54))
354232	25440877	Notably, we performed exomic sequencing on 37 HNSCC tumors from the cohort and a total of 5 novel inactivating NOTCH1 mutations were identified in 4 of the 37 tumors analyzed, none of the mutation was associated with HES1 or HEY1 activation.	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('tumors', 'Disease', (159, 165))	('HES1', 'Gene', '3280', (217, 221))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('SCC', 'Phenotype', 'HP:0002860', (48, 51))	('tumors', 'Disease', 'MESH:D009369', (159, 165))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('HNSCC tumors', 'Disease', 'MESH:D000077195', (46, 58))	('HNSCC', 'Phenotype', 'HP:0012288', (46, 51))	('mutations', 'Var', (118, 127))	('tumors', 'Disease', (52, 58))	('HEY1', 'Gene', (225, 229))	('HEY1', 'Gene', '23462', (225, 229))	('HNSCC tumors', 'Disease', (46, 58))	('inactivating', 'NegReg', (98, 110))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('tumors', 'Phenotype', 'HP:0002664', (159, 165))	('HES1', 'Gene', (217, 221))	('NOTCH1', 'Gene', (111, 117))
354234	25440877	Our data demonstrate a bimodal pattern of NOTCH pathway alterations in HNSCC, with a smaller subset exhibiting inactivating NOTCH1-specific mutations, and a larger subset exhibiting other NOTCH pathway alterations, including increased expression or gene copy number of either the receptor or ligands, as well as downstream pathway activation.	('expression', 'MPA', (235, 245))	('NOTCH', 'Gene', (124, 129))	('NOTCH', 'Gene', '31293', (124, 129))	('activation', 'PosReg', (331, 341))	('alterations', 'Reg', (56, 67))	('increased', 'PosReg', (225, 234))	('SCC', 'Gene', (73, 76))	('SCC', 'Phenotype', 'HP:0002860', (73, 76))	('NOTCH', 'Gene', (42, 47))	('NOTCH', 'Gene', '31293', (188, 193))	('NOTCH', 'Gene', '31293', (42, 47))	('NOTCH', 'Gene', (188, 193))	('SCC', 'Gene', '6317', (73, 76))	('mutations', 'Var', (140, 149))	('gene copy number', 'Var', (249, 265))	('HNSCC', 'Phenotype', 'HP:0012288', (71, 76))
354236	25440877	Consistent with our study, Pickering and colleagues have discovered changes in gene copy number and expression for other NOTCH pathway genes, including increased copy number changes in NOTCH receptor ligands JAG1 and JAG2 and in MUMB that were associated with elevated mRNA levels.	('mRNA levels', 'MPA', (269, 280))	('NOTCH', 'Gene', (121, 126))	('copy number changes', 'Var', (162, 181))	('increased', 'PosReg', (152, 161))	('changes', 'Reg', (68, 75))	('JAG2', 'Gene', '3714', (217, 221))	('expression', 'MPA', (100, 110))	('elevated', 'PosReg', (260, 268))	('JAG1', 'Gene', '182', (208, 212))	('NOTCH', 'Gene', '31293', (185, 190))	('JAG2', 'Gene', (217, 221))	('NOTCH', 'Gene', (185, 190))	('NOTCH', 'Gene', '31293', (121, 126))	('MUMB', 'Gene', (229, 233))	('JAG1', 'Gene', (208, 212))
354237	25440877	analyzed the NOTCH1 mutations in Chinese oral squamous cell carcinoma (OSCC); they detected 42 somatic NOTCH1 mutations, including 7 nonsense mutations and 11 mutations with the heterodimerization domain commonly harboring potential activating mutations in acute lymphoblastic leukemia in 22 of the 51 Chinese OSCC tumors.	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (41, 69))	('OSCC tumors', 'Disease', 'MESH:D009369', (310, 321))	('oral squamous cell carcinoma', 'Disease', (41, 69))	('tumors', 'Phenotype', 'HP:0002664', (315, 321))	('SCC', 'Gene', '6317', (311, 314))	('leukemia', 'Phenotype', 'HP:0001909', (277, 285))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (46, 69))	('acute lymphoblastic leukemia', 'Disease', (257, 285))	('acute lymphoblastic leukemia', 'Disease', 'MESH:D054198', (257, 285))	('SCC', 'Phenotype', 'HP:0002860', (72, 75))	('SCC', 'Gene', (311, 314))	('tumor', 'Phenotype', 'HP:0002664', (315, 320))	('mutations', 'Var', (110, 119))	('OSCC tumors', 'Disease', (310, 321))	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (257, 285))	('SCC', 'Gene', '6317', (72, 75))	('mutations', 'Var', (20, 29))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (263, 285))	('activating', 'PosReg', (233, 243))	('SCC', 'Gene', (72, 75))	('carcinoma', 'Phenotype', 'HP:0030731', (60, 69))	('NOTCH1', 'Gene', (103, 109))	('SCC', 'Phenotype', 'HP:0002860', (311, 314))
354238	25440877	Patients whose tumors have NOTCH1 mutation had significantly shorter overall and disease-free survival compared with those patients whose tumors had no NOTCH1 mutations.	('shorter', 'NegReg', (61, 68))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('mutation', 'Var', (34, 42))	('tumors', 'Disease', 'MESH:D009369', (15, 21))	('patients', 'Species', '9606', (123, 131))	('Patients', 'Species', '9606', (0, 8))	('tumors', 'Disease', (138, 144))	('tumors', 'Disease', 'MESH:D009369', (138, 144))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('NOTCH1', 'Gene', (27, 33))	('tumors', 'Disease', (15, 21))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
354239	25440877	To date, the available potential therapeutic interventions in NOTCH signaling pathway include MK-0752 and RO4929097, two potent inhibitors of gamma-secretase, an enzyme required for NOTCH pathway activation.	('RO4929097', 'Chemical', 'MESH:C545185', (106, 115))	('MK-0752', 'Chemical', 'MESH:C554093', (94, 101))	('RO4929097', 'Var', (106, 115))	('NOTCH', 'Gene', '31293', (182, 187))	('MK-0752', 'Var', (94, 101))	('NOTCH', 'Gene', (62, 67))	('NOTCH', 'Gene', '31293', (62, 67))	('NOTCH', 'Gene', (182, 187))
354240	25440877	In a phase I pharmacologic and pharmacodynamic study of MK-0752 in adult patients with advanced solid tumors, MK-0752 demonstrated good tolerability and evidence of NOTCH pathway inhibition using a once-per-week dosing schedule.	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('solid tumors', 'Disease', (96, 108))	('patients', 'Species', '9606', (73, 81))	('inhibition', 'NegReg', (179, 189))	('NOTCH', 'Gene', (165, 170))	('NOTCH', 'Gene', '31293', (165, 170))	('solid tumors', 'Disease', 'MESH:D009369', (96, 108))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('MK-0752', 'Chemical', 'MESH:C554093', (110, 117))	('MK-0752', 'Chemical', 'MESH:C554093', (56, 63))	('MK-0752', 'Var', (110, 117))
354242	25440877	In phase I study of RO4929097 in patients with refractory metastatic or locally advanced solid tumors, RO4929097 was well tolerated when administered by using both intermittent and continuous dosing schedules.	('RO4929097', 'Var', (103, 112))	('patients', 'Species', '9606', (33, 41))	('solid tumors', 'Disease', (89, 101))	('RO4929097', 'Chemical', 'MESH:C545185', (20, 29))	('solid tumors', 'Disease', 'MESH:D009369', (89, 101))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('RO4929097', 'Chemical', 'MESH:C545185', (103, 112))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))
354243	25440877	Currently clinical trials with RO4929097 and MK-0752 are ongoing in a variety of tumor types, including breast cancer, sarcoma, melanoma, pancreatic cancer, non-small cell lung cancer, prostate cancer, and T cell acute lymphoblastic leukemia/lymphoma and results are awaits with interest.	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (213, 241))	('lymphoblastic leukemia/lymphoma', 'Disease', (219, 250))	('breast cancer', 'Disease', 'MESH:D001943', (104, 117))	('breast cancer', 'Disease', (104, 117))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (161, 183))	('MK-0752', 'Var', (45, 52))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('sarcoma', 'Phenotype', 'HP:0100242', (119, 126))	('prostate cancer', 'Disease', 'MESH:D011471', (185, 200))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (157, 183))	('pancreatic cancer', 'Disease', 'MESH:D010190', (138, 155))	('prostate cancer', 'Phenotype', 'HP:0012125', (185, 200))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('prostate cancer', 'Disease', (185, 200))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (219, 241))	('RO4929097', 'Chemical', 'MESH:C545185', (31, 40))	('tumor', 'Disease', (81, 86))	('melanoma', 'Disease', 'MESH:D008545', (128, 136))	('melanoma', 'Disease', (128, 136))	('pancreatic cancer', 'Disease', (138, 155))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('non-small cell lung cancer', 'Disease', (157, 183))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('MK-0752', 'Chemical', 'MESH:C554093', (45, 52))	('lymphoblastic leukemia/lymphoma', 'Disease', 'MESH:D054198', (219, 250))	('lymphoma', 'Phenotype', 'HP:0002665', (242, 250))	('acute lymphoblastic leukemia', 'Disease', (213, 241))	('leukemia', 'Phenotype', 'HP:0001909', (233, 241))	('acute lymphoblastic leukemia', 'Disease', 'MESH:D054198', (213, 241))	('sarcoma', 'Disease', 'MESH:D012509', (119, 126))	('lung cancer', 'Phenotype', 'HP:0100526', (172, 183))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('sarcoma', 'Disease', (119, 126))	('breast cancer', 'Phenotype', 'HP:0003002', (104, 117))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (138, 155))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (157, 183))	('melanoma', 'Phenotype', 'HP:0002861', (128, 136))	('RO4929097', 'Var', (31, 40))
354250	25440877	found that HPV integration affects the host genome by amplification of oncogenes and disruption of tumor suppressors, as well as by driving inter- and intra-chromosomal rearrangements.	('tumor', 'Disease', (99, 104))	('HPV', 'Species', '10566', (11, 14))	('HPV', 'Gene', (11, 14))	('driving', 'Reg', (132, 139))	('integration', 'Var', (15, 26))	('oncogenes', 'Protein', (71, 80))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('disruption', 'NegReg', (85, 95))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('amplification', 'PosReg', (54, 67))	('inter- and', 'CPA', (140, 150))
354253	25440877	In HNSCC, inactivating mutations in tumor suppressor genes were identified in a majority of tumors, whereas the activating mutations in oncogenes were mutated at a relatively low rate.	('identified', 'Reg', (64, 74))	('inactivating mutations', 'Var', (10, 32))	('SCC', 'Gene', '6317', (5, 8))	('tumors', 'Disease', 'MESH:D009369', (92, 98))	('HNSCC', 'Phenotype', 'HP:0012288', (3, 8))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('SCC', 'Gene', (5, 8))	('tumor', 'Disease', (92, 97))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))	('tumors', 'Disease', (92, 98))	('tumor', 'Disease', (36, 41))	('SCC', 'Phenotype', 'HP:0002860', (5, 8))
354256	25440877	As mutations generated from genomic sequencing represent only one aspect of HNSCC tumorigenesis, a comprehensive molecular characterization of HNSCC, with integration of genetic, epigenetic, transcriptional data, will yield more precise insight into HNSCC tumor biology.	('HNSCC', 'Phenotype', 'HP:0012288', (76, 81))	('HNSCC', 'Phenotype', 'HP:0012288', (250, 255))	('SCC', 'Gene', '6317', (145, 148))	('HNSCC tumor', 'Disease', (76, 87))	('HNSCC tumor', 'Disease', (250, 261))	('SCC', 'Gene', (145, 148))	('SCC', 'Phenotype', 'HP:0002860', (252, 255))	('SCC', 'Phenotype', 'HP:0002860', (78, 81))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('HNSCC tumor', 'Disease', 'MESH:D000077195', (76, 87))	('HNSCC', 'Phenotype', 'HP:0012288', (143, 148))	('SCC', 'Gene', '6317', (252, 255))	('SCC', 'Gene', '6317', (78, 81))	('HNSCC tumor', 'Disease', 'MESH:D000077195', (250, 261))	('SCC', 'Phenotype', 'HP:0002860', (145, 148))	('SCC', 'Gene', (252, 255))	('tumor', 'Phenotype', 'HP:0002664', (256, 261))	('mutations', 'Var', (3, 12))	('SCC', 'Gene', (78, 81))
354257	25440877	As an example, a recent analysis of the five tiers of TCGA data from 378 HNSCC tumors, including somatic mutations, chromosomal aberrations, mRNA expression, microRNA expression and clinical variables, Gross and colleagues reported that TP53 mutation is frequently accompanied by loss of chromosome 3p, and that the combination of these events is associated with a surprising decrease in survival time (1.9 years versus >5 years for TP53 alone).	('HNSCC tumors', 'Disease', 'MESH:D000077195', (73, 85))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (116, 139))	('loss', 'NegReg', (280, 284))	('HNSCC', 'Phenotype', 'HP:0012288', (73, 78))	('TP53', 'Gene', (237, 241))	('chromosome 3p', 'Protein', (288, 301))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('HNSCC tumors', 'Disease', (73, 85))	('SCC', 'Phenotype', 'HP:0002860', (75, 78))	('decrease', 'NegReg', (376, 384))	('survival', 'MPA', (388, 396))	('mutation', 'Var', (242, 250))
354265	25386559	We found that let-7i-3p and miR-154-5p were significantly downregulated in the sera of smokers and lung-cancer patients, so the serum levels of let-7i-3p and miR-154-5p are associated with smoking and smoking-related lung cancer.	('lung-cancer', 'Disease', 'MESH:D008175', (99, 110))	('miR-154', 'Gene', (158, 165))	('lung cancer', 'Disease', (217, 228))	('miR-154', 'Gene', '406946', (158, 165))	('lung cancer', 'Phenotype', 'HP:0100526', (217, 228))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('let-7i-3p', 'Var', (144, 153))	('miR-154', 'Gene', '406946', (28, 35))	('smoking', 'Disease', (189, 196))	('downregulated', 'NegReg', (58, 71))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('miR-154', 'Gene', (28, 35))	('associated', 'Reg', (173, 183))	('let-7i-3p', 'Chemical', '-', (144, 153))	('let-7i-3p', 'Chemical', '-', (14, 23))	('lung cancer', 'Disease', 'MESH:D008175', (217, 228))	('lung-cancer', 'Disease', (99, 110))	('patients', 'Species', '9606', (111, 119))
354266	25386559	The areas under receiver operating characteristic curves for let-7i-3p and miR-154-5p were approximately 0.892 and 0.957, respectively.	('miR-154', 'Gene', (75, 82))	('let-7i-3p', 'Var', (61, 70))	('let-7i-3p', 'Chemical', '-', (61, 70))	('miR-154', 'Gene', '406946', (75, 82))	('rat', 'Species', '10116', (28, 31))
354267	25386559	In conclusion, our results indicate that changes in serum miRNAs are associated with cigarette smoking and lung cancer and that let-7i-3p and miR-154-5p are potential biomarkers of smoking-related lung cancer.	('let-7i-3p', 'Var', (128, 137))	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('lung cancer', 'Disease', 'MESH:D008175', (107, 118))	('miR', 'Gene', '220972', (58, 61))	('lung cancer', 'Phenotype', 'HP:0100526', (107, 118))	('lung cancer', 'Disease', (197, 208))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('miR-154', 'Gene', (142, 149))	('cigarette smoking', 'Disease', (85, 102))	('miR', 'Gene', (58, 61))	('lung cancer', 'Disease', 'MESH:D008175', (197, 208))	('associated', 'Reg', (69, 79))	('miR', 'Gene', '220972', (142, 145))	('lung cancer', 'Disease', (107, 118))	('lung cancer', 'Phenotype', 'HP:0100526', (197, 208))	('let-7i-3p', 'Chemical', '-', (128, 137))	('changes', 'Reg', (41, 48))	('miR', 'Gene', (142, 145))	('miR-154', 'Gene', '406946', (142, 149))
354274	25386559	MicroRNAs (miRNAs) are a class of short, highly conserved noncoding RNAs of 18-25 nucleotides that regulate gene expression by incompletely base-pairing with a complementary sequence in the 3'-untranslated region (UTR) of the target mRNA.	('regulate', 'Reg', (99, 107))	('miR', 'Gene', '220972', (11, 14))	('miR', 'Gene', (11, 14))	('gene expression', 'MPA', (108, 123))	('incompletely base-pairing', 'Var', (127, 152))	('base-pairing', 'Var', (140, 152))
354340	25386559	Of these eight miRNAs, four (miR-7-5p, miR-502-3p, miR-200c-5p, and miR-1301) were upregulated and four (miR-129-2-3p, let-7i-3p, miR-196a-3p, and miR-154-5p) were downregulated in smokers and lung-cancer patients compared with the nonsmoking control serum samples, according to the results of the microarray analysis.	('miR', 'Gene', (39, 42))	('miR', 'Gene', '220972', (29, 32))	('miR', 'Gene', '220972', (68, 71))	('patients', 'Species', '9606', (205, 213))	('let-7i-3p', 'Var', (119, 128))	('miR', 'Gene', '220972', (147, 150))	('miR', 'Gene', '220972', (51, 54))	('miR-502', 'Gene', '574504', (39, 46))	('miR-1301', 'Gene', '100302246', (68, 76))	('miR', 'Gene', '220972', (105, 108))	('miR', 'Gene', (29, 32))	('miR', 'Gene', (68, 71))	('miR-154', 'Gene', '406946', (147, 154))	('miR-7-5p', 'Gene', '407045', (29, 37))	('miR', 'Gene', '220972', (130, 133))	('miR', 'Gene', (147, 150))	('miR', 'Gene', (51, 54))	('lung-cancer', 'Disease', (193, 204))	('upregulated', 'PosReg', (83, 94))	('lung-cancer', 'Disease', 'MESH:D008175', (193, 204))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('miR', 'Gene', (105, 108))	('miR-154', 'Gene', (147, 154))	('miR', 'Gene', (130, 133))	('miR-1301', 'Gene', (68, 76))	('miR', 'Gene', '220972', (15, 18))	('miR', 'Gene', '220972', (39, 42))	('miR-7-5p', 'Gene', (29, 37))	('miR-502', 'Gene', (39, 46))	('downregulated', 'NegReg', (164, 177))	('let-7i-3p', 'Chemical', '-', (119, 128))	('miR', 'Gene', (15, 18))
354342	25386559	As shown in Figure 3, the levels of serums let-7i-3p (Kruskal-Wallis test, P < 0.05) and miR-154-5p (Kruskal-Wallis test, P < 0.05) were significantly downregulated in smokers and lung-cancer patients compared with those in the nonsmoking control serum samples.	('miR-154', 'Gene', '406946', (89, 96))	('let-7i-3p', 'Var', (43, 52))	('miR-154', 'Gene', (89, 96))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('let-7i-3p', 'Chemical', '-', (43, 52))	('downregulated', 'NegReg', (151, 164))	('patients', 'Species', '9606', (192, 200))	('lung-cancer', 'Disease', (180, 191))	('lung-cancer', 'Disease', 'MESH:D008175', (180, 191))
354344	25386559	To confirm that serums let-7i-3p and miR-154-5p are associated with smoking and lung cancer, we quantified the levels of let-7i-3p and miR-154-5p in larger samples with qRT-PCR.	('let-7i-3p', 'Var', (23, 32))	('miR-154', 'Gene', (37, 44))	('lung cancer', 'Disease', 'MESH:D008175', (80, 91))	('miR-154', 'Gene', '406946', (37, 44))	('smoking', 'Disease', (68, 75))	('let-7i-3p', 'Chemical', '-', (23, 32))	('associated', 'Reg', (52, 62))	('lung cancer', 'Disease', (80, 91))	('lung cancer', 'Phenotype', 'HP:0100526', (80, 91))	('let-7i-3p', 'Chemical', '-', (121, 130))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('miR-154', 'Gene', (135, 142))	('miR-154', 'Gene', '406946', (135, 142))
354346	25386559	As shown in Figures 4(a) and 4(b), compared with the nonsmoking control serum samples, the serum levels of both let-7i-3p and miR-154-5p were significantly downregulated in the smokers (Kruskal-Wallis test, P < 0.001) and lung-cancer patients (Kruskal-Wallis test, P < 0.001).	('lung-cancer', 'Disease', (222, 233))	('let-7i-3p', 'Var', (112, 121))	('miR-154', 'Gene', (126, 133))	('let-7i-3p', 'Chemical', '-', (112, 121))	('miR-154', 'Gene', '406946', (126, 133))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('serum levels', 'MPA', (91, 103))	('patients', 'Species', '9606', (234, 242))	('downregulated', 'NegReg', (156, 169))	('lung-cancer', 'Disease', 'MESH:D008175', (222, 233))
354348	25386559	To explore the relationships between these two miRNAs (let-7i-3p and miR-154-5p), the pathological type of lung cancer, and smoking, we compared the levels of let-7i-3p and miR-154-5p in 84 serum samples from lung-cancer patients, according to their pathological types and smoking characteristics.	('let-7i-3p', 'Chemical', '-', (55, 64))	('patients', 'Species', '9606', (221, 229))	('lung cancer', 'Disease', 'MESH:D008175', (107, 118))	('miR', 'Gene', (47, 50))	('miR-154', 'Gene', (173, 180))	('miR', 'Gene', (69, 72))	('miR-154', 'Gene', '406946', (69, 76))	('lung cancer', 'Phenotype', 'HP:0100526', (107, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('lung-cancer', 'Disease', 'MESH:D008175', (209, 220))	('lung-cancer', 'Disease', (209, 220))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('miR-154', 'Gene', (69, 76))	('lung cancer', 'Disease', (107, 118))	('miR', 'Gene', '220972', (173, 176))	('let-7i-3p', 'Chemical', '-', (159, 168))	('miR', 'Gene', '220972', (47, 50))	('miR', 'Gene', '220972', (69, 72))	('miR-154', 'Gene', '406946', (173, 180))	('let-7i-3p', 'Var', (159, 168))	('miR', 'Gene', (173, 176))
354353	25386559	As shown in Figures 4(c) and 4(d), the expression levels of serums let-7i-3p (Kruskal-Wallis test, P < 0.001) and miR-154-5p (Kruskal-Wallis test, P < 0.001) were significantly downregulated in the samples of patients with squamous cell carcinoma and adenocarcinoma compared with the nonsmoking controls.	('let-7i-3p', 'Var', (67, 76))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (223, 246))	('let-7i-3p', 'Chemical', '-', (67, 76))	('adenocarcinoma', 'Disease', (251, 265))	('carcinoma', 'Phenotype', 'HP:0030731', (256, 265))	('adenocarcinoma', 'Disease', 'MESH:D000230', (251, 265))	('patients', 'Species', '9606', (209, 217))	('miR-154', 'Gene', '406946', (114, 121))	('expression levels', 'MPA', (39, 56))	('miR-154', 'Gene', (114, 121))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (223, 246))	('downregulated', 'NegReg', (177, 190))	('carcinoma', 'Phenotype', 'HP:0030731', (237, 246))	('squamous cell carcinoma', 'Disease', (223, 246))
354358	25386559	When the lung-cancer patients were classified into the smoking group (TS) and the nonsmoking group (TN) and compared with the nonsmoking control group, let-7i-3p (Kruskal-Wallis test, P < 0.001) and miR-154-5p (Kruskal-Wallis test, P < 0.001) were both significantly downregulated in the TS group and TN group.	('miR-154', 'Gene', '406946', (199, 206))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('miR-154', 'Gene', (199, 206))	('patients', 'Species', '9606', (21, 29))	('lung-cancer', 'Disease', 'MESH:D008175', (9, 20))	('let-7i-3p', 'Chemical', '-', (152, 161))	('let-7i-3p', 'Var', (152, 161))	('lung-cancer', 'Disease', (9, 20))	('downregulated', 'NegReg', (267, 280))
354360	25386559	These results indicate that the downregulation of serums let-7i-3p and miR-154-5p was associated with smoking and lung cancer.	('downregulation', 'NegReg', (32, 46))	('lung cancer', 'Disease', 'MESH:D008175', (114, 125))	('let-7i-3p', 'Chemical', '-', (57, 66))	('smoking', 'Disease', (102, 109))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('lung cancer', 'Disease', (114, 125))	('lung cancer', 'Phenotype', 'HP:0100526', (114, 125))	('serums let-7i-3p', 'Var', (50, 66))	('miR-154', 'Gene', (71, 78))	('miR-154', 'Gene', '406946', (71, 78))
354361	25386559	A ROC curve analysis was performed to evaluate the sensitivity and specificity of let-7i-3p and miR-154-5p as biomarkers of smoking-related lung cancer.	('lung cancer', 'Disease', (140, 151))	('let-7i-3p', 'Var', (82, 91))	('lung cancer', 'Phenotype', 'HP:0100526', (140, 151))	('let-7i-3p', 'Chemical', '-', (82, 91))	('miR-154', 'Gene', '406946', (96, 103))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('miR-154', 'Gene', (96, 103))	('lung cancer', 'Disease', 'MESH:D008175', (140, 151))
354370	25386559	After systematically analyzing the predicted target genes, we identified the 52 most promising potential target genes for let-7i-3p and the seven most promising potential target genes for miR-154-5p.	('miR-154', 'Gene', (188, 195))	('let-7i-3p', 'Var', (122, 131))	('miR-154', 'Gene', '406946', (188, 195))	('let-7i-3p', 'Chemical', '-', (122, 131))
354371	25386559	As shown in Table 3, the main target genes of let-7i-3p and miR-154-5p included ACTB, ATP2A2, BDNF, BTG3, ROS, ATG7, and CUL2.	('ACTB', 'Gene', (80, 84))	('CUL2', 'Gene', (121, 125))	('BTG3', 'Gene', '10950', (100, 104))	('ATG7', 'Gene', (111, 115))	('BDNF', 'Gene', (94, 98))	('ATG7', 'Gene', '10533', (111, 115))	('ACTB', 'Gene', '60', (80, 84))	('CUL2', 'Gene', '8453', (121, 125))	('let-7i-3p', 'Chemical', '-', (46, 55))	('ATP2A2', 'Gene', '488', (86, 92))	('BDNF', 'Gene', '627', (94, 98))	('ATP2A2', 'Gene', (86, 92))	('miR-154', 'Gene', '406946', (60, 67))	('BTG3', 'Gene', (100, 104))	('let-7i-3p', 'Var', (46, 55))	('ROS', 'Chemical', '-', (106, 109))	('miR-154', 'Gene', (60, 67))
354374	25386559	Collectively, these predictions and analyses imply that let-7i-3p and miR-154-5p potentially function during cigarette-smoking-induced lung carcinogenesis.	('function', 'Reg', (93, 101))	('miR-154', 'Gene', (70, 77))	('miR-154', 'Gene', '406946', (70, 77))	('lung carcinogenesis', 'Disease', (135, 154))	('let-7i-3p', 'Var', (56, 65))	('let-7i-3p', 'Chemical', '-', (56, 65))	('lung carcinogenesis', 'Disease', 'MESH:D063646', (135, 154))
354385	25386559	These previous studies provide evidence that miRNA dysregulation is an important mechanism in cigarette-smoke-induced lung carcinogenesis.	('miR', 'Gene', '220972', (45, 48))	('miR', 'Gene', (45, 48))	('lung carcinogenesis', 'Disease', (118, 137))	('dysregulation', 'Var', (51, 64))	('lung carcinogenesis', 'Disease', 'MESH:D063646', (118, 137))
354388	25386559	A correlation analysis showed a negative correlation between the smoking index and the serum levels of let-7i-3p and miR-154-5p and that an increasing trend in the smoking index is associated with lower relative expression of let-7i-3p and miR-154-5p.	('lower', 'NegReg', (197, 202))	('let-7i-3p', 'Var', (226, 235))	('serum levels', 'MPA', (87, 99))	('miR-154', 'Gene', (240, 247))	('miR-154', 'Gene', '406946', (240, 247))	('let-7i-3p', 'Chemical', '-', (226, 235))	('let-7i-3p', 'Var', (103, 112))	('miR-154', 'Gene', (117, 124))	('let-7i-3p', 'Chemical', '-', (103, 112))	('miR-154', 'Gene', '406946', (117, 124))	('negative', 'NegReg', (32, 40))
354398	25386559	In the present study, a ROC curve analysis showed that the AUCs for serums let-7i-3p and miR-154-5p were 0.892 and 0.957, respectively.	('miR-154', 'Gene', '406946', (89, 96))	('let-7i-3p', 'Chemical', '-', (75, 84))	('let-7i-3p', 'Var', (75, 84))	('miR-154', 'Gene', (89, 96))
354400	25386559	The downregulated expression of serums let-7i-3p and miR-154-5p was also related to the histological subtype of the lung cancer and the smoking history of the patient.	('lung cancer', 'Disease', (116, 127))	('lung cancer', 'Phenotype', 'HP:0100526', (116, 127))	('downregulated', 'NegReg', (4, 17))	('let-7i-3p', 'Chemical', '-', (39, 48))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('expression', 'MPA', (18, 28))	('serums let-7i-3p', 'Var', (32, 48))	('lung cancer', 'Disease', 'MESH:D008175', (116, 127))	('patient', 'Species', '9606', (159, 166))	('miR-154', 'Gene', (53, 60))	('miR-154', 'Gene', '406946', (53, 60))
354404	25386559	In this study, the levels of let-7i-3p and miR-154-5p were significantly downregulated in the sera of smokers and lung-cancer patients.	('miR-154', 'Gene', (43, 50))	('let-7i-3p', 'Chemical', '-', (29, 38))	('miR-154', 'Gene', '406946', (43, 50))	('lung-cancer', 'Disease', (114, 125))	('lung-cancer', 'Disease', 'MESH:D008175', (114, 125))	('downregulated', 'NegReg', (73, 86))	('patients', 'Species', '9606', (126, 134))	('let-7i-3p', 'Var', (29, 38))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
354406	25386559	let-7i-3p is a member of the let-7 family, which regulates many important lung-cancer-associated oncogenes and inhibits the growth of lung-cancer cell lines in vitro and in vivo.	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('growth', 'CPA', (124, 130))	('inhibits', 'NegReg', (111, 119))	('lung-cancer', 'Disease', 'MESH:D008175', (134, 145))	('let-7i-3p', 'Var', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('let-7i-3p', 'Chemical', '-', (0, 9))	('regulates', 'Reg', (49, 58))	('lung-cancer', 'Disease', 'MESH:D008175', (74, 85))	('lung-cancer', 'Disease', (74, 85))	('oncogenes', 'Gene', (97, 106))	('lung-cancer', 'Disease', (134, 145))
354408	25386559	Therefore, we predicted the potential target genes of let-7i-3p and miR-154-5p and their involvement in various cellular pathways.	('miR-154', 'Gene', (68, 75))	('let-7i-3p', 'Chemical', '-', (54, 63))	('miR-154', 'Gene', '406946', (68, 75))	('involvement', 'Reg', (89, 100))	('let-7i-3p', 'Var', (54, 63))
354411	25386559	We speculate that let-7i-3p and miR-154-5p are associated with the development or progression of cigarette-smoke-induced lung cancer.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('lung cancer', 'Disease', 'MESH:D008175', (121, 132))	('lung cancer', 'Disease', (121, 132))	('lung cancer', 'Phenotype', 'HP:0100526', (121, 132))	('let-7i-3p', 'Var', (18, 27))	('miR-154', 'Gene', '406946', (32, 39))	('let-7i-3p', 'Chemical', '-', (18, 27))	('associated', 'Reg', (47, 57))	('miR-154', 'Gene', (32, 39))
354412	25386559	However, further studies are required to clarify the functions of let-7i-3p and miR-154-5p in cigarette-smoke-induced lung carcinogenesis.	('let-7i-3p', 'Chemical', '-', (66, 75))	('lung carcinogenesis', 'Disease', (118, 137))	('let-7i-3p', 'Var', (66, 75))	('miR-154', 'Gene', '406946', (80, 87))	('lung carcinogenesis', 'Disease', 'MESH:D063646', (118, 137))	('miR-154', 'Gene', (80, 87))
354416	25386559	Serums let-7i-3p and miR-154-5p, which correlated negatively with the smoking index, may be potential biomarkers of exposure to cigarette smoke and cigarette-smoke-induced lung cancer.	('miR-154', 'Gene', (21, 28))	('lung cancer', 'Disease', (172, 183))	('miR-154', 'Gene', '406946', (21, 28))	('lung cancer', 'Phenotype', 'HP:0100526', (172, 183))	('let-7i-3p', 'Var', (7, 16))	('let-7i-3p', 'Chemical', '-', (7, 16))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('lung cancer', 'Disease', 'MESH:D008175', (172, 183))
354417	25386559	The downregulated expression of serums let-7i-3p and miR-154-5p is probably related to the pathological type of the cancer and the smoking history of the patient.	('patient', 'Species', '9606', (154, 161))	('downregulated', 'NegReg', (4, 17))	('let-7i-3p', 'Chemical', '-', (39, 48))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('expression', 'MPA', (18, 28))	('serums let-7i-3p', 'Var', (32, 48))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('miR-154', 'Gene', (53, 60))	('miR-154', 'Gene', '406946', (53, 60))
354418	25386559	Target gene prediction and pathway analysis of let-7i-3p and miR-154-5p suggested that these miRNAs are involved in regulating the occurrence, development, and metastasis of NSCLC through multiple target genes and signaling pathways.	('regulating', 'Reg', (116, 126))	('let-7i-3p', 'Var', (47, 56))	('miR-154', 'Gene', (61, 68))	('miR-154', 'Gene', '406946', (61, 68))	('miR', 'Gene', (61, 64))	('let-7i-3p', 'Chemical', '-', (47, 56))	('miR', 'Gene', '220972', (61, 64))	('development', 'CPA', (143, 154))	('NSCLC', 'Disease', 'MESH:D002289', (174, 179))	('metastasis', 'CPA', (160, 170))	('involved', 'Reg', (104, 112))	('NSCLC', 'Phenotype', 'HP:0030358', (174, 179))	('miR', 'Gene', '220972', (93, 96))	('miR', 'Gene', (93, 96))	('occurrence', 'CPA', (131, 141))	('NSCLC', 'Disease', (174, 179))
354419	25386559	These findings suggest that let-7i-3p and miR-154-5p are associated with the development or progression of cigarette-smoke-induced lung cancer.	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('lung cancer', 'Disease', 'MESH:D008175', (131, 142))	('let-7i-3p', 'Var', (28, 37))	('miR-154', 'Gene', (42, 49))	('miR-154', 'Gene', '406946', (42, 49))	('let-7i-3p', 'Chemical', '-', (28, 37))	('lung cancer', 'Disease', (131, 142))	('lung cancer', 'Phenotype', 'HP:0100526', (131, 142))	('associated', 'Reg', (57, 67))
354445	31967271	We included cases of malignant neoplasm of bronchus and lung, according to the International Statistical Classification of Diseases and Related Health Problems, 10th edition (ICD-10 code C34), with the following morphologies, according to the International Classification of Diseases for Oncology, 3rd edition: adenocarcinoma (codes 8140, 8144, 8211, 8230, 8250, 8251, 8252, 8253, 8254, 8255, 8260, 8265, 8256, 8257, 8310, 8323, 8333, 8480, 8481, and 8551); squamous cell carcinoma (codes 8070, 8071, 8072, 8074, and 8083), small cell carcinoma (codes 8041 and 8045); and non-small cell carcinoma or undifferentiated carcinoma (code 8012).	('adenocarcinoma', 'Disease', 'MESH:D000230', (311, 325))	('malignant neoplasm of bronchus', 'Disease', (21, 51))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (458, 481))	('codes 8070', 'Var', (483, 493))	('small cell carcinoma', 'Disease', (524, 544))	('codes 8041', 'Var', (546, 556))	('carcinoma', 'Phenotype', 'HP:0030731', (617, 626))	('small cell carcinoma', 'Disease', 'MESH:D018288', (524, 544))	('carcinoma', 'Phenotype', 'HP:0030731', (587, 596))	('carcinoma', 'Phenotype', 'HP:0030731', (316, 325))	('small cell carcinoma', 'Phenotype', 'HP:0030357', (576, 596))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (458, 481))	('codes 8140', 'Var', (327, 337))	('malignant neoplasm of bronchus', 'Disease', 'MESH:D009369', (21, 51))	('adenocarcinoma', 'Disease', (311, 325))	('non-small cell carcinoma or undifferentiated carcinoma', 'Disease', 'MESH:D018288', (572, 626))	('neoplasm', 'Phenotype', 'HP:0002664', (31, 39))	('Oncology', 'Phenotype', 'HP:0002664', (288, 296))	('carcinoma', 'Phenotype', 'HP:0030731', (472, 481))	('squamous cell carcinoma', 'Disease', (458, 481))	('carcinoma', 'Phenotype', 'HP:0030731', (535, 544))	('small cell carcinoma', 'Disease', (576, 596))	('small cell carcinoma', 'Disease', 'MESH:D018288', (576, 596))	('non-small cell carcinoma', 'Phenotype', 'HP:0030358', (572, 596))	('small cell carcinoma', 'Phenotype', 'HP:0030357', (524, 544))
354544	32819300	These suggested that the DEGs were most likely associated with tumor proliferation and metastasis.	('tumor', 'Disease', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('metastasis', 'CPA', (87, 97))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('DEGs', 'Var', (25, 29))	('associated', 'Reg', (47, 57))
354555	32819300	Based on the 10-gene signature-based model, patients in GSE72094 (including 442 patients with LUAD) and GSE31210 (including 226 patients with LUAD) datasets were given a score using multivariate Cox regression analysis.	('patients', 'Species', '9606', (80, 88))	('patients', 'Species', '9606', (44, 52))	('LUAD', 'Phenotype', 'HP:0030078', (142, 146))	('GSE72094', 'Var', (56, 64))	('LUAD', 'Phenotype', 'HP:0030078', (94, 98))	('GSE31210', 'Var', (104, 112))	('patients', 'Species', '9606', (128, 136))
354557	32819300	It indicated that the 10-gene risk assessment model had a good predictive ability for the prognosis of LUAD patients in the two independent datasets GSE72094 and GSE31210.	('LUAD', 'Phenotype', 'HP:0030078', (103, 107))	('LUAD', 'Disease', (103, 107))	('GSE72094', 'Var', (149, 157))	('patients', 'Species', '9606', (108, 116))	('GSE31210', 'Var', (162, 170))
354558	32819300	6c and g. We further plotted a scatter diagram showing the survival of patients with different risk scores, and the result showed that with the increase of the score, the number of death event increased gradually, which was supported by the previous research (Fig.	('patients', 'Species', '9606', (71, 79))	('score', 'Var', (160, 165))	('death', 'Disease', 'MESH:D003643', (181, 186))	('death', 'Disease', (181, 186))
354587	32184305	Our hypothesis is that combining chemoradiation with a WEE1 inhibitor will affect the biological response to DNA damage caused by cisplatin and radiation, thereby enhancing clinical outcomes, without increased toxicity.	('clinical outcomes', 'MPA', (173, 190))	('WEE1', 'Gene', (55, 59))	('inhibitor', 'Var', (60, 69))	('toxicity', 'Disease', 'MESH:D064420', (210, 218))	('toxicity', 'Disease', (210, 218))	('affect', 'Reg', (75, 81))	('enhancing', 'PosReg', (163, 172))	('cisplatin', 'Chemical', 'MESH:D002945', (130, 139))	('WEE1', 'Gene', '7465', (55, 59))
354608	32184305	Cancer development is a multistep process where deregulation of the DDR contributes to phenotypes such as sustained cell proliferation and resistance to cell death.	('DDR', 'Gene', (68, 71))	('sustained cell proliferation', 'CPA', (106, 134))	('deregulation', 'Var', (48, 60))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('contributes', 'Reg', (72, 83))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('resistance to cell death', 'CPA', (139, 163))
354612	32184305	Manipulation of the DDR pathway, therefore, represents a rational means by which the therapeutic index of POCRT might be improved.	('POCRT', 'Chemical', '-', (106, 111))	('DDR pathway', 'Pathway', (20, 31))	('Manipulation', 'Var', (0, 12))
354614	32184305	TP53 mutations, which are seen in 60%-70% of HNSCC cases, are sufficient to impair the function of this checkpoint and thereby create a critical reliance on the later G2/M checkpoint.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('create', 'Reg', (127, 133))	('HNSCC', 'Disease', (45, 50))	('impair', 'NegReg', (76, 82))	('mutations', 'Var', (5, 14))	('function', 'MPA', (87, 95))
354615	32184305	In addition, p53 function can be inactivated by various mechanisms, including somatic and germline mutations as well as polymorphisms.	('function', 'MPA', (17, 25))	('p53', 'Gene', (13, 16))	('polymorphisms', 'Var', (120, 133))	('p53', 'Gene', '7157', (13, 16))	('inactivated', 'NegReg', (33, 44))
354620	32184305	However, inhibition of WEE1 leads to high CDK1 activity, allowing cells to progress through the G2/M checkpoint without the opportunity to repair damaged DNA, leading to potentially catastrophic levels of unrepaired DNA damage induction of cell death.	('WEE1', 'Gene', '7465', (23, 27))	('WEE1', 'Gene', (23, 27))	('CDK1', 'Gene', '983', (42, 46))	('CDK1', 'Gene', (42, 46))	('activity', 'MPA', (47, 55))	('inhibition', 'Var', (9, 19))
354630	32184305	WEE1 has also been implicated in maintaining genomic stability through stabilisation of replication forks:downregulation reduces replication fork speed during S-phase, generating potentially lethal dsDNA breaks.	('downregulation', 'Var', (106, 120))	('replication fork speed', 'MPA', (129, 151))	('reduces', 'NegReg', (121, 128))	('dsDNA breaks', 'Disease', (198, 210))	('WEE1', 'Gene', '7465', (0, 4))	('WEE1', 'Gene', (0, 4))
354631	32184305	By impacting both cell cycle progression and DNA damage repair, WEE1 inhibition may potentiate cell death in response to chemotherapy and IR.	('cell cycle progression', 'CPA', (18, 40))	('cell death', 'CPA', (95, 105))	('DNA damage repair', 'MPA', (45, 62))	('impacting', 'Reg', (3, 12))	('WEE1', 'Gene', (64, 68))	('WEE1', 'Gene', '7465', (64, 68))	('potentiate', 'PosReg', (84, 94))	('inhibition', 'Var', (69, 79))
354633	32184305	AZD1775 is being tested in many clinical settings including in combination with docetaxel and cisplatin in HNSCC (NCT02508246), with radiotherapy in childhood pontine glioma (NCT01922076), with temozolomide and radiotherapy in glioblastoma (NCT01849146), and with cisplatin and radiotherapy in cervical cancer (NCT01958658).	('NCT01849146', 'Var', (241, 252))	('cisplatin', 'Chemical', 'MESH:D002945', (264, 273))	('AZD1775', 'Chemical', 'MESH:C549567', (0, 7))	('NCT02508246', 'Var', (114, 125))	('cisplatin', 'Chemical', 'MESH:D002945', (94, 103))	('cervical cancer', 'Disease', (294, 309))	('docetaxel', 'Chemical', 'MESH:D000077143', (80, 89))	('cervical cancer', 'Disease', 'MESH:D002583', (294, 309))	('cancer', 'Phenotype', 'HP:0002664', (303, 309))	('glioma', 'Phenotype', 'HP:0009733', (167, 173))	('glioblastoma', 'Disease', (227, 239))	('glioblastoma', 'Disease', 'MESH:D005909', (227, 239))	('temozolomide', 'Chemical', 'MESH:D000077204', (194, 206))	('pontine glioma', 'Disease', 'MESH:D005910', (159, 173))	('glioblastoma', 'Phenotype', 'HP:0012174', (227, 239))	('pontine glioma', 'Disease', (159, 173))	('NCT01922076', 'Var', (175, 186))
354634	32184305	In summary, the available mechanistic data lend strong support to combining AZD1775 with cisplatin and with POCRT in the clinic.	('AZD1775', 'Var', (76, 83))	('AZD1775', 'Chemical', 'MESH:C549567', (76, 83))	('cisplatin', 'Chemical', 'MESH:D002945', (89, 98))	('POCRT', 'Chemical', '-', (108, 113))	('combining', 'Interaction', (66, 75))
354635	32184305	Given that the predictive effect of TP53 mutation on such combinations has yet to be clinically validated, this study does not prospectively stratify patients based on any such clinical or biological characteristic.	('mutation', 'Var', (41, 49))	('patients', 'Species', '9606', (150, 158))	('TP53', 'Gene', '7157', (36, 40))	('TP53', 'Gene', (36, 40))
354638	32184305	In an earlier study, TP53 mutation conferred increased resistance to preoperative cisplatin-based chemotherapy in oral cancer.	('TP53', 'Gene', (21, 25))	('increased', 'PosReg', (45, 54))	('mutation', 'Var', (26, 34))	('oral cancer', 'Disease', 'MESH:D009062', (114, 125))	('cisplatin', 'Chemical', 'MESH:D002945', (82, 91))	('oral cancer', 'Disease', (114, 125))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('TP53', 'Gene', '7157', (21, 25))
354640	32184305	If this is a promising combination, the long-term aim is to test AZD1775 in the neoadjuvant setting to downstage the disease through treatment with cisplatin and AZD1775 in the preoperative setting, which may decrease the extent of surgery, and may also reduce the need for PORT/POCRT by reducing the involved margin rate.	('downstage', 'NegReg', (103, 112))	('AZD1775', 'Var', (65, 72))	('cisplatin', 'Chemical', 'MESH:D002945', (148, 157))	('AZD1775', 'Var', (162, 169))	('decrease', 'NegReg', (209, 217))	('reduce', 'NegReg', (254, 260))	('AZD1775', 'Chemical', 'MESH:C549567', (65, 72))	('AZD1775', 'Chemical', 'MESH:C549567', (162, 169))	('POCRT', 'Chemical', '-', (279, 284))	('PORT/POCRT', 'Disease', (274, 284))	('reducing', 'NegReg', (288, 296))
354647	32184305	The MTDs of AZD1775 for both groups are expected to differ given the additional toxicities of radiotherapy in group B.	('toxicities', 'Disease', 'MESH:D064420', (80, 90))	('toxicities', 'Disease', (80, 90))	('AZD1775', 'Var', (12, 19))	('AZD1775', 'Chemical', 'MESH:C549567', (12, 19))
354663	32184305	Total bilirubin <=1.5 ULN (except for patients with known Gilbert's syndrome).	('bilirubin', 'Chemical', 'MESH:D001663', (6, 15))	('<=1.5', 'Var', (16, 21))	("Gilbert's syndrome", 'Disease', (58, 76))	('Total bilirubin', 'MPA', (0, 15))	('patients', 'Species', '9606', (38, 46))	("Gilbert's syndrome", 'Disease', 'MESH:D005878', (58, 76))
354688	32184305	Mean resting corrected QTc interval using the Fridericia's formula34 >450 ms (male) and >470 ms (female) (as calculated per institutional standards) obtained from three ECGs 2-5 min apart at study entry, or congenital long QT syndrome.	('congenital long QT syndrome', 'Disease', (207, 234))	('QTc interval', 'MPA', (23, 35))	('congenital long QT syndrome', 'Disease', 'MESH:D008133', (207, 234))	('>470 ms', 'Var', (88, 95))	('long QT syndrome', 'Phenotype', 'HP:0001657', (218, 234))
354756	32184305	Circulatory levels of AZD1775 and changes over time will be reported.	('AZD1775', 'Var', (22, 29))	('AZD1775', 'Chemical', 'MESH:C549567', (22, 29))	('Circulatory levels', 'MPA', (0, 18))
354794	28949956	To determine the phenotype of macrophages, the following antibodies were used: anti-hCD163-APC, anti-hCD206-Alexa Fluor 488, anti-hHLA-DR-eFluor 450, anti-hCD86-PE, and anti-hCD80-PE-Cy5.	('Cy5', 'Chemical', 'MESH:C085321', (183, 186))	('hCD86', 'Gene', (155, 160))	('CD163', 'Gene', '9332', (85, 90))	('Alexa Fluor 488', 'Chemical', '-', (108, 123))	('CD163', 'Gene', (85, 90))	('hCD86', 'Gene', '942', (155, 160))	('hCD80', 'Gene', (174, 179))	('anti-hHLA-DR-eFluor', 'Var', (125, 144))	('CD206', 'Gene', (102, 107))	('hCD80', 'Gene', '941', (174, 179))	('CD206', 'Gene', '4360', (102, 107))
354795	28949956	To determine the frequency of the three distinct Treg subsets, the following antibodies were used: anti-hCD4-FITC, anti-hCD25-APC, and anti-hCD45RA-eFluor 450 for surface staining; anti-hFoxp3-APC for intracellular staining.	('anti-hCD4-FITC', 'Var', (99, 113))	('anti-hCD45RA-eFluor', 'Var', (135, 154))	('hCD25', 'Gene', '3559', (120, 125))	('Foxp3', 'Gene', '50943', (187, 192))	('hCD25', 'Gene', (120, 125))	('Foxp3', 'Gene', (187, 192))	('hCD4-FITC', 'Chemical', '-', (104, 113))
354833	28949956	Our results showed that neutralising IL-10 partially attenuated the typical increase in aTreg cell frequency resulting from co-culture of MphiSNU899 with CD4+CD25- T cells, whereas blocking TGF-beta1 had no significant effect (Figure 3D and E).	('IL-10', 'Gene', (37, 42))	('MphiSNU899', 'Var', (138, 148))	('increase', 'PosReg', (76, 84))	('aTreg cell frequency', 'CPA', (88, 108))	('TGF-beta1', 'Gene', '7040', (190, 199))	('CD25', 'Gene', (158, 162))	('TGF-beta1', 'Gene', (190, 199))	('attenuated', 'NegReg', (53, 63))	('IL-10', 'Gene', '3586', (37, 42))	('CD25', 'Gene', '3559', (158, 162))	('neutralising', 'Var', (24, 36))
354840	28949956	Unsurprisingly, neutralising IL-10 was sufficient to reverse the upregulation of CD163 and the down-regulation of HLA-DR (data not shown), whereas neutralising IL-4/IL-13 had no effect (Figure 4D).	('IL-4', 'Gene', '3565', (160, 164))	('IL-10', 'Gene', (29, 34))	('IL-13', 'Gene', '3596', (165, 170))	('neutralising', 'Var', (16, 28))	('CD163', 'Gene', (81, 86))	('HLA-DR', 'Gene', (114, 120))	('down-regulation', 'NegReg', (95, 110))	('IL-10', 'Gene', '3586', (29, 34))	('upregulation', 'PosReg', (65, 77))	('CD163', 'Gene', '9332', (81, 86))	('IL-4', 'Gene', (160, 164))	('IL-13', 'Gene', (165, 170))
354856	28949956	Immunohistochemical staining and flow cytometric analysis showed that the frequencies of CD3+, CD4+, and CD8+ T cells and Th1 cells were significantly higher in tumour tissues of the combined treatment group than in those of the other groups (Figure 6G and H and Figure 5Ac, Bc-d, C and D).	('CD8', 'Gene', (105, 108))	('CD8', 'Gene', '925', (105, 108))	('CD4+', 'Var', (95, 99))	('Th1', 'Gene', (122, 125))	('tumour', 'Phenotype', 'HP:0002664', (161, 167))	('tumour', 'Disease', 'MESH:D009369', (161, 167))	('higher', 'PosReg', (151, 157))	('tumour', 'Disease', (161, 167))	('Th1', 'Gene', '51497', (122, 125))	('Bc-d, C and D', 'Gene', '285440', (275, 288))	('CD3+', 'CPA', (89, 93))
354895	28949956	The efficiency is derived from deregulation of antitumour immunity because the proportions of CD4+ and CD8+ T cells and Th1 cells were increased significantly.	('Th1', 'Gene', (120, 123))	('CD8', 'Gene', '925', (103, 106))	('tumour', 'Phenotype', 'HP:0002664', (51, 57))	('increased', 'PosReg', (135, 144))	('Th1', 'Gene', '51497', (120, 123))	('CD8', 'Gene', (103, 106))	('CD4+', 'Var', (94, 98))	('tumour', 'Disease', 'MESH:D009369', (51, 57))	('tumour', 'Disease', (51, 57))
354897	28949956	Various options can be provided for the specific therapeutic program, including blocking tumour trafficking of macrophages/Treg cells using CSF1R/CCR4 antagonists, respectively, ligation of GITR to down-regulate Foxp3 expression and reduce production of IL-10 by Treg cells, and re-educating M2 macrophages to an M1 phenotype using Toll-like receptor 3 ligands or STING agonists.	('CSF1R', 'Gene', '1436', (140, 145))	('GITR', 'Gene', (190, 194))	('tumour', 'Phenotype', 'HP:0002664', (89, 95))	('IL-10', 'Gene', '3586', (254, 259))	('tumour', 'Disease', 'MESH:D009369', (89, 95))	('Toll-like receptor 3', 'Gene', (332, 352))	('tumour', 'Disease', (89, 95))	('ligation', 'Var', (178, 186))	('reduce', 'NegReg', (233, 239))	('CSF1R', 'Gene', (140, 145))	('production', 'MPA', (240, 250))	('GITR', 'Gene', '8784', (190, 194))	('IL-10', 'Gene', (254, 259))	('Toll-like receptor 3', 'Gene', '7098', (332, 352))	('expression', 'MPA', (218, 228))	('down-regulate', 'NegReg', (198, 211))	('Foxp3', 'Gene', '50943', (212, 217))	('Foxp3', 'Gene', (212, 217))
354904	24526064	Enhancer of zeste homolog 2 (EZH2), catalytic core subunit of PRC2, epigenetically silences several tumor suppressor genes by catalyzing the trimethylation of histone H3 at lysine 27, which serves as a docking site for DNA methyltransferases and histone deacetylases.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('Enhancer of zeste homolog 2', 'Gene', '2146', (0, 27))	('tumor', 'Disease', (100, 105))	('silences', 'NegReg', (83, 91))	('epigenetically', 'Var', (68, 82))	('lysine', 'Chemical', 'MESH:D008239', (173, 179))	('H3', 'Chemical', 'MESH:C012616', (167, 169))	('histone H3', 'Protein', (159, 169))	('Enhancer of zeste homolog 2', 'Gene', (0, 27))	('EZH2', 'Gene', (29, 33))	('EZH2', 'Gene', '2146', (29, 33))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('trimethylation', 'MPA', (141, 155))
354906	24526064	The regulatory circuit and molecular cues causing EZH2 deregulation vary in different cancer types.	('deregulation', 'Var', (55, 67))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('EZH2', 'Gene', '2146', (50, 54))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('EZH2', 'Gene', (50, 54))	('cancer', 'Disease', (86, 92))
354915	24526064	Trimethylation at H3K27 (H3K27me3) is a distinct histone modification catalyzed by histone methyltransferase enhancer of zeste homolog 2 (EZH2), catalytic component of PRC2, involved in the regulation of homeotic (Hox) gene expression and in the early steps of X-chromosome inactivation in women.	('histone methyltransferase', 'Gene', (83, 108))	('EZH2', 'Gene', '2146', (138, 142))	('women', 'Species', '9606', (290, 295))	('enhancer of zeste homolog 2', 'Gene', '2146', (109, 136))	('EZH2', 'Gene', (138, 142))	('Trimethylation', 'Var', (0, 14))	('histone methyltransferase', 'Gene', '56979', (83, 108))	('H3K27', 'Protein', (18, 23))	('enhancer of zeste homolog 2', 'Gene', (109, 136))
354923	24526064	EZH2 is the catalytic core of the PRC2 complex which catalyzes H3K27me3 repressive chromatin mark.	('H3K27me3', 'Var', (63, 71))	('EZH2', 'Gene', (0, 4))	('EZH2', 'Gene', '2146', (0, 4))
354932	24526064	Mutation of any of these residues in the active site of EZH2 abolishes its HMTase activity.	('abolishes', 'NegReg', (61, 70))	('Mutation', 'Var', (0, 8))	('EZH2', 'Gene', '2146', (56, 60))	('EZH2', 'Gene', (56, 60))	('HMTase', 'Enzyme', (75, 81))
354933	24526064	Focusing on highly evolutionarily conserved Tyr641 of EZH2, Yap et al.	('EZH2', 'Gene', (54, 58))	('Yap', 'Gene', '55249', (60, 63))	('Tyr641', 'Var', (44, 50))	('Tyr641', 'Chemical', '-', (44, 50))	('EZH2', 'Gene', '2146', (54, 58))	('Yap', 'Gene', (60, 63))
354934	24526064	demonstrated that EZH2 Y641 mutant protein-containing PRC2 complexes display enhanced H3K27me3 activity on di-methylated peptides (and not on unmethylated histone peptides) as compared to wild-type containing PRC2 complexes which ultimately shifts the steady state of H3K27 in favor of trimethylation in vivo.	('enhanced', 'PosReg', (77, 85))	('EZH2', 'Gene', '2146', (18, 22))	('activity', 'MPA', (95, 103))	('EZH2', 'Gene', (18, 22))	('H3K27me3', 'Enzyme', (86, 94))	('PRC2', 'Gene', (54, 58))	('Y641 mutant', 'Var', (23, 34))
354935	24526064	The presence of wild-type EZH2-PRC2 complex was found to be mandatory for Y641 EZH2 mutant to act so that previously methylated histone substrates remain available for trimethylation.	('EZH2', 'Gene', '2146', (26, 30))	('EZH2', 'Gene', (26, 30))	('EZH2', 'Gene', (79, 83))	('EZH2', 'Gene', '2146', (79, 83))	('trimethylation', 'MPA', (168, 182))	('Y641', 'Var', (74, 78))
354937	24526064	For example, phosphorylation of EZH2 by Akt1 at serine 21 reduces H3K27me3 activity whereas phosphorylation at threonine 345 by CDK1 and CDK2 is required for maintenance of H3K27me3 repressive marks at target gene promoters.	('reduces', 'NegReg', (58, 65))	('serine', 'Var', (48, 54))	('CDK1', 'Gene', (128, 132))	('threonine', 'Chemical', 'MESH:D013912', (111, 120))	('serine', 'Chemical', 'MESH:D012694', (48, 54))	('CDK2', 'Gene', '1017', (137, 141))	('EZH2', 'Gene', '2146', (32, 36))	('Akt1', 'Gene', (40, 44))	('H3K27me3', 'Protein', (66, 74))	('CDK1', 'Gene', '983', (128, 132))	('EZH2', 'Gene', (32, 36))	('CDK2', 'Gene', (137, 141))	('Akt1', 'Gene', '207', (40, 44))
354941	24526064	demonstrated that EZH2 conditional knockout allele containing embryonic stem cells (EZH2-/- ESCs) sustain H3K27me3 at some developmental genes and display H3K27me1, despite global loss of di- and tri- methylation on H3K27, indicating the presence of another HMTase catalyzing methylation on H3K27.	('H3K27me1', 'Var', (155, 163))	('loss', 'NegReg', (180, 184))	('ESCs', 'CellLine', 'CVCL:9108', (92, 96))	('EZH2', 'Gene', '2146', (18, 22))	('EZH2', 'Gene', (18, 22))	('H3K27me3', 'Var', (106, 114))	('EZH2', 'Gene', '2146', (84, 88))	('men', 'Species', '9606', (130, 133))	('EZH2', 'Gene', (84, 88))
354947	24526064	Lysine residue in the histone tail may be present in the unmethylated form or covalently modified by HMTases into mono, -di and -tri methylated lysine (H3K27me1, H3K27me2 and H3K27me3), with each form functionally different from the other.	('H3K27me2', 'Var', (162, 170))	('H3K27me1', 'Var', (152, 160))	('H3K27me3', 'Var', (175, 183))	('Lysine', 'Chemical', 'MESH:D008239', (0, 6))	('lysine', 'Chemical', 'MESH:D008239', (144, 150))
354948	24526064	Methylation of histone H3 Lysine-27 by the SET domain of EZH2 (as part of PRC2 complex) has been reported to be a processive event where H3K27me3 results from mono-methylation of H3K27me2.	('EZH2', 'Gene', (57, 61))	('H3K27me2', 'Protein', (179, 187))	('Lysine', 'Chemical', 'MESH:D008239', (26, 32))	('Methylation', 'MPA', (0, 11))	('mono-methylation', 'MPA', (159, 175))	('H3K27me3', 'Var', (137, 145))	('H3', 'Chemical', 'MESH:C012616', (23, 25))	('H3', 'Chemical', 'MESH:C012616', (137, 139))	('H3', 'Chemical', 'MESH:C012616', (179, 181))	('EZH2', 'Gene', '2146', (57, 61))
354949	24526064	Di- and tri-methylated forms of Histone H3 Lysine 27 are associated with facultative heterochromatin region whereas mono-methylated form is associated with stably silent constitutive heterochromatin.	('Di-', 'Var', (0, 3))	('facultative heterochromatin region', 'Disease', (73, 107))	('tri-methylated', 'Var', (8, 22))	('Lysine', 'Chemical', 'MESH:D008239', (43, 49))	('H3', 'Chemical', 'MESH:C012616', (40, 42))	('associated', 'Reg', (57, 67))	('Histone H3', 'Protein', (32, 42))
354950	24526064	In embryonic stem (ES) cells, 50% of the H3 histone was reported to be dimethylated, 15% trimethylated and 15% monomethylated which add up to a total of 80% methylated histone H3.	('trimethylated', 'Var', (89, 102))	('methylated', 'MPA', (157, 167))	('H3 histone', 'Protein', (41, 51))	('H3', 'Chemical', 'MESH:C012616', (41, 43))	('dimethylated', 'Var', (71, 83))	('H3', 'Chemical', 'MESH:C012616', (176, 178))
354951	24526064	H3K27me3 is a stable repressive chromatin mark catalyzed by PRC2 complexes containing either EZH1 or EZH2.	('EZH1', 'Gene', (93, 97))	('EZH2', 'Gene', (101, 105))	('EZH2', 'Gene', '2146', (101, 105))	('H3K27me3', 'Var', (0, 8))	('EZH1', 'Gene', '2145', (93, 97))
354952	24526064	In plants, two mono-methyltransferases namely Arabidopsis trithorax related protein 5 (ATXR5) and ATXR6 that are not orthologous to E(z) are involved in generating H3K27me1 mark but in mammals the appearance of H3K27me1 is still controversial.	('ATXR5', 'Gene', '830839', (87, 92))	('H3K27me1', 'Var', (164, 172))	('ATXR6', 'Gene', '832503', (98, 103))	('ATXR6', 'Gene', (98, 103))	('ATXR5', 'Gene', (87, 92))	('Arabidopsis', 'Species', '3702', (46, 57))
354953	24526064	Some reports speculate that in mammals H3K27me1 might be catalyzed by an enzymatic activity distinct from PRC2 and its presence in actively transcribed genes may result from H3K27me2/3 demethylation by the demethylases UTX or JMJD3.	('UTX', 'Gene', '7403', (219, 222))	('H3K27me2/3', 'Var', (174, 184))	('JMJD3', 'Gene', (226, 231))	('H3K27me1', 'Var', (39, 47))	('result from', 'Reg', (162, 173))	('JMJD3', 'Gene', '23135', (226, 231))	('UTX', 'Gene', (219, 222))
354954	24526064	In contrast, few reports suggest that in Drosophila, generation of H3K27me1 mark is dependent on E(z) while in mammals PRC2 complex containing either EZH1 or EZH2 function redundantly control the global H3K27me1 levels.	('EZH2', 'Gene', '2146', (158, 162))	('EZH1', 'Gene', (150, 154))	('EZH2', 'Gene', (158, 162))	('EZH1', 'Gene', '2145', (150, 154))	('global H3K27me1 levels', 'MPA', (196, 218))	('H3K27me1', 'Var', (67, 75))	('Drosophila', 'Species', '7227', (41, 51))
354967	24526064	In castration resistant prostate cancer (CRPC), methylation of androgen receptor (AR) or AR-associated proteins has emerged as a potential mechanism for EZH2-mediated transcriptional induction.	('EZH2', 'Gene', '2146', (153, 157))	('prostate cancer', 'Disease', 'MESH:D011471', (24, 39))	('androgen receptor', 'Gene', '367', (63, 80))	('prostate cancer', 'Phenotype', 'HP:0012125', (24, 39))	('AR', 'Gene', '367', (89, 91))	('AR', 'Gene', '367', (82, 84))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('EZH2', 'Gene', (153, 157))	('transcriptional', 'MPA', (167, 182))	('methylation', 'Var', (48, 59))	('androgen receptor', 'Gene', (63, 80))	('prostate cancer', 'Disease', (24, 39))
354969	24526064	Furthermore, it was demonstrated that depletion of EZH2 causes a decrease in AR-associated lysine methylation at lysine 630 and 632 but the AR levels remain unchanged.	('EZH2', 'Gene', '2146', (51, 55))	('EZH2', 'Gene', (51, 55))	('AR', 'Gene', '367', (77, 79))	('depletion', 'Var', (38, 47))	('lysine', 'Chemical', 'MESH:D008239', (91, 97))	('AR', 'Gene', '367', (140, 142))	('decrease', 'NegReg', (65, 73))	('lysine', 'Chemical', 'MESH:D008239', (113, 119))
354972	24526064	Also, in NKTL cell lines, ectopic expression of EZH2 mutant lacking histone methyltransferase activity was found to confer growth advantage and prevent growth inhibition upon endogenous EZH2 depletion.	('NKTL', 'Gene', '57410', (9, 13))	('NKTL', 'Gene', (9, 13))	('EZH2', 'Gene', '2146', (48, 52))	('prevent', 'NegReg', (144, 151))	('activity', 'MPA', (94, 102))	('growth advantage', 'CPA', (123, 139))	('EZH2', 'Gene', (48, 52))	('histone methyltransferase', 'Gene', '56979', (68, 93))	('EZH2', 'Gene', (186, 190))	('mutant', 'Var', (53, 59))	('histone methyltransferase', 'Gene', (68, 93))	('EZH2', 'Gene', '2146', (186, 190))	('lacking', 'NegReg', (60, 67))	('growth inhibition', 'CPA', (152, 169))
354982	24526064	proposed a dominant role of CpG DNA methylation in gene silencing and maintenance of heritable repressive states of target gene promoters by demonstrating that EZH2 depletion neither affected the methylation status nor induced the hyper-methylated genes such as p16INK4a in U2OS cells.	('p16INK4a', 'Gene', '1029', (262, 270))	('methylation status', 'MPA', (196, 214))	('hyper-methylated', 'MPA', (231, 247))	('depletion', 'Var', (165, 174))	('induced', 'Reg', (219, 226))	('repressive states', 'Phenotype', 'HP:0000716', (95, 112))	('EZH2', 'Gene', '2146', (160, 164))	('affected', 'Reg', (183, 191))	('U2OS', 'CellLine', 'CVCL:0042', (274, 278))	('repressive state', 'Phenotype', 'HP:0000716', (95, 111))	('p16INK4a', 'Gene', (262, 270))	('EZH2', 'Gene', (160, 164))
354984	24526064	Subsequent findings provided more inputs to the EZH2-DNA methylation link by comparing gene profiles of EZH2 target genes in normal versus cancer cells and revealed that EZH2 targets which display H3K27Me3 in normal cells are correlated to the aberrantly hyper-methylated corresponding genes in cancer cells.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('EZH2', 'Gene', '2146', (104, 108))	('cancer', 'Disease', 'MESH:D009369', (295, 301))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('EZH2', 'Gene', (104, 108))	('cancer', 'Disease', (295, 301))	('EZH2', 'Gene', '2146', (48, 52))	('EZH2', 'Gene', '2146', (170, 174))	('EZH2', 'Gene', (48, 52))	('H3K27Me3', 'Var', (197, 205))	('EZH2', 'Gene', (170, 174))	('cancer', 'Phenotype', 'HP:0002664', (295, 301))	('cancer', 'Disease', (139, 145))
354985	24526064	This suggests that genes which acquire EZH2 catalyzed H3K27me3 marks are susceptible to subsequent DNA methylation and silencing during cellular transformation.	('H3K27me3', 'Var', (54, 62))	('silencing', 'NegReg', (119, 128))	('EZH2', 'Gene', (39, 43))	('EZH2', 'Gene', '2146', (39, 43))
354990	24526064	Also, HDACs may alter the chromatin configuration by modulating local histone code favorable to polycomb mediated silencing by deacetylation of other histone lysines such as H3-K9, H3-K14 or H4-K8.	('alter', 'Reg', (16, 21))	('deacetylation', 'MPA', (127, 140))	('chromatin configuration', 'MPA', (26, 49))	('polycomb', 'Gene', (96, 104))	('H3-K14', 'Var', (181, 187))	('H4-K8', 'Var', (191, 196))	('H3', 'Chemical', 'MESH:C012616', (174, 176))	('polycomb', 'Gene', '40358', (96, 104))	('lysines', 'Chemical', 'MESH:D008239', (158, 165))	('modulating', 'Reg', (53, 63))	('H3', 'Chemical', 'MESH:C012616', (181, 183))	('H3-K9', 'Var', (174, 179))	('local', 'MPA', (64, 69))
354991	24526064	Additionally, H3K4me3 and H3K36me2, which mark actively transcribing genes, have been shown to antagonize EZH2-mediated H3K27me3 silencing.	('EZH2', 'Gene', (106, 110))	('H3K27me3', 'Protein', (120, 128))	('H3K36me2', 'Var', (26, 34))	('H3', 'Chemical', 'MESH:C012616', (26, 28))	('antagonize', 'NegReg', (95, 105))	('H3', 'Chemical', 'MESH:C012616', (120, 122))	('H3K4me3', 'Var', (14, 21))	('H3', 'Chemical', 'MESH:C012616', (14, 16))	('EZH2', 'Gene', '2146', (106, 110))
354993	24526064	Accumulated evidences reveal that EZH2 deregulation and over-expression is frequently observed in a variety of cancer types including solid tumors and haematological malignancies.	('haematological malignancies', 'Disease', (151, 178))	('haematological malignancies', 'Disease', 'MESH:D019337', (151, 178))	('observed', 'Reg', (86, 94))	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('EZH2', 'Gene', '2146', (34, 38))	('solid tumors', 'Disease', (134, 146))	('deregulation', 'Var', (39, 51))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('EZH2', 'Gene', (34, 38))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('over-expression', 'PosReg', (56, 71))	('solid tumors', 'Disease', 'MESH:D009369', (134, 146))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))
354996	24526064	The causes and consequences of EZH2 deregulation in different cancer types are discussed.	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('EZH2', 'Gene', '2146', (31, 35))	('EZH2', 'Gene', (31, 35))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('deregulation', 'Var', (36, 48))
354998	24526064	It is well established that deregulated epigenetic factors coupled to genetic mutations contribute to their pathogenesis by causing abnormal silencing of critical tumor suppressor genes (TSGs).	('epigenetic factors', 'Protein', (40, 58))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('silencing', 'MPA', (141, 150))	('tumor', 'Disease', (163, 168))	('deregulated', 'Var', (28, 39))
355001	24526064	In patients with p15INK4b methylation, EZH2 levels were found to be high as compared to patients without methylation.	('methylation', 'Var', (26, 37))	('p15INK4b', 'Gene', '1030', (17, 25))	('patients', 'Species', '9606', (88, 96))	('high', 'PosReg', (68, 72))	('patients', 'Species', '9606', (3, 11))	('p15INK4b', 'Gene', (17, 25))	('EZH2', 'Gene', (39, 43))	('EZH2', 'Gene', '2146', (39, 43))
355004	24526064	So it was concluded that the p15INK4b locus was enriched by bivalent histone marks H3K27me3/H3K4me3 in AML cells without DNA methylation.	('p15INK4b', 'Gene', (29, 37))	('AML', 'Disease', (103, 106))	('H3', 'Chemical', 'MESH:C012616', (92, 94))	('H3K27me3/H3K4me3', 'Var', (83, 99))	('p15INK4b', 'Gene', '1030', (29, 37))	('AML', 'Disease', 'MESH:D015470', (103, 106))	('H3', 'Chemical', 'MESH:C012616', (83, 85))
355005	24526064	They further reported that epigenetic therapies could restore the loss of H3K4me3 and reactivate p15INK4b expression but the H3K27me3 mark is retained which ultimately causes the return of p15INK4b locus to a bivalent state.	('H3', 'Chemical', 'MESH:C012616', (125, 127))	('loss', 'NegReg', (66, 70))	('return', 'MPA', (179, 185))	('H3K4me3', 'Protein', (74, 81))	('p15INK4b', 'Gene', '1030', (189, 197))	('causes', 'Reg', (168, 174))	('reactivate', 'MPA', (86, 96))	('H3', 'Chemical', 'MESH:C012616', (74, 76))	('p15INK4b', 'Gene', '1030', (97, 105))	('p15INK4b', 'Gene', (189, 197))	('epigenetic therapies', 'Var', (27, 47))	('p15INK4b', 'Gene', (97, 105))
355009	24526064	Mutations in EZH2 gene have been described in myelodysplasia-MPNs (10-13%), myelofibrosis (13%), and various subtypes of MDS.	('EZH2', 'Gene', (13, 17))	('EZH2', 'Gene', '2146', (13, 17))	('myelofibrosis', 'Disease', 'MESH:D055728', (76, 89))	('MDS', 'Disease', (121, 124))	('MDS', 'Disease', 'MESH:D009190', (121, 124))	('myelodysplasia-MPNs', 'Disease', (46, 65))	('described', 'Reg', (33, 42))	('myelofibrosis', 'Phenotype', 'HP:0011974', (76, 89))	('Mutations', 'Var', (0, 9))	('myelodysplasia-MPNs', 'Disease', 'MESH:D009190', (46, 65))	('myelodysplasia', 'Phenotype', 'HP:0002863', (46, 60))	('myelofibrosis', 'Disease', (76, 89))
355010	24526064	In myeloid neoplasms, EZH2 mutations were found to be inactivating /hypomorphic and distributed throughout the gene which includes missense, nonsense and premature stop codons.	('mutations', 'Var', (27, 36))	('EZH2', 'Gene', (22, 26))	('neoplasms', 'Phenotype', 'HP:0002664', (11, 20))	('myeloid neoplasms', 'Disease', (3, 20))	('neoplasm', 'Phenotype', 'HP:0002664', (11, 19))	('myeloid neoplasms', 'Phenotype', 'HP:0012324', (3, 20))	('myeloid neoplasm', 'Phenotype', 'HP:0012324', (3, 19))	('missense', 'Var', (131, 139))	('hypo', 'Disease', (68, 72))	('myeloid neoplasms', 'Disease', 'MESH:D007951', (3, 20))	('EZH2', 'Gene', '2146', (22, 26))	('hypo', 'Disease', 'MESH:D052456', (68, 72))
355011	24526064	Histone methyltransferase activity was predicted to be lost in all EZH2 missense and nonsense mutants as the SET domain responsible for catalyzing H3K27 trimethylation was located in the C-terminal domain of the EZH2 protein.	('EZH2', 'Gene', (212, 216))	('EZH2', 'Gene', '2146', (212, 216))	('Histone methyltransferase', 'Gene', (0, 25))	('mutants', 'Var', (94, 101))	('lost', 'NegReg', (55, 59))	('nonsense mutants', 'Var', (85, 101))	('missense', 'Var', (72, 80))	('Histone methyltransferase', 'Gene', '56979', (0, 25))	('activity', 'MPA', (26, 34))	('EZH2', 'Gene', (67, 71))	('EZH2', 'Gene', '2146', (67, 71))
355012	24526064	Assessment of mutational status in 469 cases of myeloid malignancy revealed that EZH2 mutations were present in 8% cases while EED/SUZ12 mutations were reported in 3.3% cases.	('mutations', 'Var', (86, 95))	('EZH2', 'Gene', (81, 85))	('EZH2', 'Gene', '2146', (81, 85))	('EED', 'Gene', '8726', (127, 130))	('EED', 'Gene', (127, 130))	('myeloid malignancy', 'Disease', 'MESH:D009369', (48, 66))	('SUZ12', 'Gene', '23512', (131, 136))	('SUZ12', 'Gene', (131, 136))	('myeloid malignancy', 'Disease', (48, 66))	('men', 'Species', '9606', (6, 9))
355013	24526064	In addition to EZH2 mutation, decreased EZH2 expression was found be associated with hemizygous deletion (-7/del7q) involving EZH2 locus (78% of cases), diploid chromosome 7 (41% of cases) and spliceosomal U2AF1/SRSF2 mutations (63% of cases).	('U2AF1', 'Gene', (206, 211))	('U2AF1', 'Gene', '7307', (206, 211))	('EZH2', 'Gene', '2146', (126, 130))	('EZH2', 'Gene', '2146', (40, 44))	('SRSF2', 'Gene', (212, 217))	('mutations', 'Var', (218, 227))	('EZH2', 'Gene', (126, 130))	('EZH2', 'Gene', (40, 44))	('expression', 'MPA', (45, 55))	('SRSF2', 'Gene', '6427', (212, 217))	('EZH2', 'Gene', (15, 19))	('EZH2', 'Gene', '2146', (15, 19))	('hemizygous deletion', 'Disease', (85, 104))	('decreased', 'NegReg', (30, 39))
355014	24526064	EZH2 mutation was associated reduced H3K27me3ethylation and de-repression of EZH2 target genes which may contribute to leukemogenesis.	('EZH2', 'Gene', (77, 81))	('EZH2', 'Gene', '2146', (0, 4))	('de-repression', 'NegReg', (60, 73))	('contribute', 'Reg', (105, 115))	('EZH2', 'Gene', (0, 4))	('H3K27me3ethylation', 'Protein', (37, 55))	('reduced', 'NegReg', (29, 36))	('leukemogenesis', 'Disease', (119, 133))	('EZH2', 'Gene', '2146', (77, 81))	('mutation', 'Var', (5, 13))
355016	24526064	Unlike myeloid neoplasm, in follicular lymphomas and diffused B-cell lymphomas, a heterozygous missense somatic mutation at tyrosine 641 (Y641) in the EZH2-SET domain causes a gain-of-function leading to increased H3K27me3.	('B-cell lymphomas', 'Phenotype', 'HP:0012191', (62, 78))	('lymphomas', 'Phenotype', 'HP:0002665', (69, 78))	('increased', 'PosReg', (204, 213))	('tyrosine', 'Chemical', 'MESH:D014443', (124, 132))	('EZH2', 'Gene', '2146', (151, 155))	('Y641', 'Var', (138, 142))	('EZH2', 'Gene', (151, 155))	('lymphoma', 'Phenotype', 'HP:0002665', (39, 47))	('lymphoma', 'Phenotype', 'HP:0002665', (69, 77))	('cell lymphoma', 'Phenotype', 'HP:0012191', (64, 77))	('gain-of-function', 'PosReg', (176, 192))	('B-cell lymphomas', 'Disease', 'MESH:D016393', (62, 78))	('B-cell lymphomas', 'Disease', (62, 78))	('follicular lymphomas', 'Disease', (28, 48))	('myeloid neoplasm', 'Phenotype', 'HP:0012324', (7, 23))	('follicular lymphomas', 'Disease', 'MESH:D008224', (28, 48))	('neoplasm', 'Phenotype', 'HP:0002664', (15, 23))	('myeloid neoplasm', 'Disease', (7, 23))	('myeloid neoplasm', 'Disease', 'MESH:D007951', (7, 23))	('lymphomas', 'Phenotype', 'HP:0002665', (39, 48))	('H3K27me3', 'Protein', (214, 222))
355017	24526064	The complex role of EZH2 in tumorigenesis is reflected by the fact that both activating and inactivating mutations in the EZH2 gene contribute to oncogenesis and malignancy.	('EZH2', 'Gene', (122, 126))	('contribute', 'Reg', (132, 142))	('tumor', 'Disease', (28, 33))	('EZH2', 'Gene', '2146', (20, 24))	('EZH2', 'Gene', '2146', (122, 126))	('malignancy', 'Disease', 'MESH:D009369', (162, 172))	('EZH2', 'Gene', (20, 24))	('malignancy', 'Disease', (162, 172))	('oncogenesis', 'CPA', (146, 157))	('inactivating mutations', 'Var', (92, 114))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('activating', 'PosReg', (77, 87))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
355019	24526064	Like other cancer types, interplay between genetic and epigenetic factors have been demonstrated to play a major role in the pathogenesis and progression of prostate cancer.	('prostate cancer', 'Disease', 'MESH:D011471', (157, 172))	('cancer', 'Disease', (166, 172))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('prostate cancer', 'Phenotype', 'HP:0012125', (157, 172))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('cancer', 'Disease', 'MESH:D009369', (11, 17))	('prostate cancer', 'Disease', (157, 172))	('interplay', 'Interaction', (25, 34))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('cancer', 'Disease', (11, 17))	('epigenetic factors', 'Var', (55, 73))
355020	24526064	Epigenetic alterations such as aberrant DNA methylation (hypo or hypermethylation), changes in chromatin remodeling patterns due to dysfunction in histone modifying enzymes and miRNA deregulation has been reported to be the major players in prostate carcinogenesis [reviewed in ].	('prostate carcinogenesis', 'Disease', 'MESH:D063646', (241, 264))	('changes', 'Reg', (84, 91))	('aberrant DNA', 'Var', (31, 43))	('dysfunction', 'Var', (132, 143))	('prostate carcinogenesis', 'Disease', (241, 264))	('hypo', 'Disease', (57, 61))	('miR', 'Gene', '220972', (177, 180))	('miR', 'Gene', (177, 180))	('hypo', 'Disease', 'MESH:D052456', (57, 61))
355027	24526064	Also, unlike androgen dependent growth of LNCaP cells, EZH2 silencing has been demonstrated to have a more profound effect in androgen independent growth both in vitro (abl cells) and in vivo (mouse xenograft CRPC model using CWR22Rv1 cells).	('EZH2', 'Gene', '2146', (55, 59))	('EZH2', 'Gene', (55, 59))	('LNCaP', 'CellLine', 'CVCL:0395', (42, 47))	('silencing', 'Var', (60, 69))	('CWR22Rv1', 'CellLine', 'CVCL:1045', (226, 234))	('mouse', 'Species', '10090', (193, 198))	('androgen independent growth', 'CPA', (126, 153))
355033	24526064	reported that EZH2 and AR physically interact in androgen-independent abl cells and the interaction was lost in EZH2 deletion mutants either in Domain I (N-terminal protein-protein interaction domain) or in the C-terminal SET domain emphasizing the importance of these two domains for the interaction.	('EZH2', 'Gene', (112, 116))	('EZH2', 'Gene', (14, 18))	('lost', 'NegReg', (104, 108))	('EZH2', 'Gene', '2146', (14, 18))	('AR', 'Gene', '367', (23, 25))	('interaction', 'Interaction', (88, 99))	('deletion mutants', 'Var', (117, 133))	('mutants', 'Var', (126, 133))	('EZH2', 'Gene', '2146', (112, 116))
355034	24526064	They have also shown that the AR mRNA or protein levels did not change upon EZH2 depletion but there was decrease in AR- associated lysine methylation.	('lysine', 'Chemical', 'MESH:D008239', (132, 138))	('depletion', 'Var', (81, 90))	('AR', 'Gene', '367', (30, 32))	('EZH2', 'Gene', '2146', (76, 80))	('EZH2', 'Gene', (76, 80))	('AR', 'Gene', '367', (117, 119))	('decrease', 'NegReg', (105, 113))
355038	24526064	In prostate cancer, various molecular mechanisms have been proposed to be responsible for EZH2 over-expression which includes EZH2 gene amplification, miR-101 deletion, and transcriptional regulation by MYC and ETS gene family members [reviewed in ].	('prostate cancer', 'Phenotype', 'HP:0012125', (3, 18))	('EZH2', 'Gene', '2146', (126, 130))	('MYC', 'Gene', (203, 206))	('deletion', 'Var', (159, 167))	('miR', 'Gene', '220972', (151, 154))	('miR', 'Gene', (151, 154))	('EZH2', 'Gene', (126, 130))	('prostate cancer', 'Disease', (3, 18))	('EZH2', 'Gene', '2146', (90, 94))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('over-expression', 'PosReg', (95, 110))	('amplification', 'Var', (136, 149))	('MYC', 'Gene', '4609', (203, 206))	('EZH2', 'Gene', (90, 94))	('prostate cancer', 'Disease', 'MESH:D011471', (3, 18))
355043	24526064	proposed that miR-101 negatively regulates EZH2 expression and somatic loss of one or both miR-101 genomic loci elevates EZH2 levels causing deregulation of various epigenetic pathways in prostate cancer.	('EZH2', 'Gene', (43, 47))	('miR', 'Gene', (91, 94))	('miR', 'Gene', '220972', (91, 94))	('deregulation', 'MPA', (141, 153))	('epigenetic pathways', 'Pathway', (165, 184))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('expression', 'MPA', (48, 58))	('EZH2', 'Gene', '2146', (121, 125))	('prostate cancer', 'Disease', (188, 203))	('EZH2', 'Gene', '2146', (43, 47))	('EZH2', 'Gene', (121, 125))	('miR', 'Gene', '220972', (14, 17))	('miR', 'Gene', (14, 17))	('loss', 'Var', (71, 75))	('prostate cancer', 'Disease', 'MESH:D011471', (188, 203))	('prostate cancer', 'Phenotype', 'HP:0012125', (188, 203))	('elevates', 'PosReg', (112, 120))
355065	24526064	Upregulation of EZH2 levels caused H3K27me3 mediated aberrant silencing of various essential tumor suppressor genes such as FOXC1, CDKN1C (p57KIP2), RUNX3, RKIP, CIITA, IL-6 and IL-8 [For a review see ref ].	('CDKN1C', 'Gene', (131, 137))	('IL-8', 'Gene', (178, 182))	('CIITA', 'Gene', (162, 167))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('RUNX3', 'Gene', (149, 154))	('p57KIP2', 'Gene', (139, 146))	('EZH2', 'Gene', '2146', (16, 20))	('EZH2', 'Gene', (16, 20))	('FOXC1', 'Gene', (124, 129))	('CDKN1C', 'Gene', '1028', (131, 137))	('IL-8', 'Gene', '3576', (178, 182))	('RKIP', 'Gene', (156, 160))	('IL-6', 'Gene', '3569', (169, 173))	('p57KIP2', 'Gene', '1028', (139, 146))	('H3K27me3', 'Var', (35, 43))	('Upregulation', 'PosReg', (0, 12))	('IL-6', 'Gene', (169, 173))	('RKIP', 'Gene', '5037', (156, 160))	('tumor', 'Disease', (93, 98))	('RUNX3', 'Gene', '864', (149, 154))	('CIITA', 'Gene', '4261', (162, 167))	('FOXC1', 'Gene', '2296', (124, 129))	('silencing', 'NegReg', (62, 71))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
355068	24526064	It is well established that defects in pRB-E2F pathway is a mandatory event in the pathogenesis of almost all human malignancies.	('defects', 'Var', (28, 35))	('malignancies', 'Disease', 'MESH:D009369', (116, 128))	('malignancies', 'Disease', (116, 128))	('human', 'Species', '9606', (110, 115))	('pRB', 'Gene', '5925', (39, 42))	('pRB', 'Gene', (39, 42))
355071	24526064	The study further confirmed that although the abrogation of EZH2 or EED expression could significantly decrease positive regulators of cell proliferation such as cyclinD1 (CCND1), cyclinE1 (CCNE1), cyclinA2 (CCNA2) and cyclinB1 (CCNB1), there was no increase in the expression of negative regulators of cell cycle viz.	('cyclinB1', 'Gene', '891', (219, 227))	('cyclin', 'Gene', (162, 168))	('abrogation', 'Var', (46, 56))	('EED', 'Gene', (68, 71))	('cyclin', 'Gene', '5111', (180, 186))	('CCNE1', 'Gene', '898', (190, 195))	('CCNA2', 'Gene', '890', (208, 213))	('cyclinA2', 'Gene', (198, 206))	('cyclin', 'Gene', (198, 204))	('CCNB1', 'Gene', '891', (229, 234))	('cyclin', 'Gene', '5111', (219, 225))	('cyclinE1', 'Gene', (180, 188))	('cyclin', 'Gene', (180, 186))	('EED', 'Gene', '8726', (68, 71))	('cyclinA2', 'Gene', '890', (198, 206))	('cyclin', 'Gene', (219, 225))	('EZH2', 'Gene', '2146', (60, 64))	('cyclin', 'Gene', '5111', (162, 168))	('EZH2', 'Gene', (60, 64))	('cyclinB1', 'Gene', (219, 227))	('CCNB1', 'Gene', (229, 234))	('CCNA2', 'Gene', (208, 213))	('cyclinE1', 'Gene', '898', (180, 188))	('positive regulators of', 'MPA', (112, 134))	('decrease', 'NegReg', (103, 111))	('CCNE1', 'Gene', (190, 195))	('cyclin', 'Gene', '5111', (198, 204))
355076	24526064	Treatment with MEK inhibitor, U0126 decreased EZH2 levels in triple-negative breast cancer type MDA-MB-231 cells and ERBB2-overexpressing SKBr3 cells.	('breast cancer', 'Disease', (77, 90))	('men', 'Species', '9606', (5, 8))	('breast cancer', 'Phenotype', 'HP:0003002', (77, 90))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (96, 106))	('U0126', 'Chemical', 'MESH:C113580', (30, 35))	('U0126', 'Var', (30, 35))	('SKBr3', 'CellLine', 'CVCL:0033', (138, 143))	('ERBB2', 'Gene', (117, 122))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('EZH2', 'Gene', '2146', (46, 50))	('ERBB2', 'Gene', '2064', (117, 122))	('MEK', 'Gene', (15, 18))	('MEK', 'Gene', '5609', (15, 18))	('EZH2', 'Gene', (46, 50))	('breast cancer', 'Disease', 'MESH:D001943', (77, 90))	('decreased', 'NegReg', (36, 45))
355077	24526064	Also siRNA mediated knockdown of Elk-1, caused a significant decrease in EZH2 mRNA expression that was similar to the decrease caused by U0126 treatment.	('U0126', 'Chemical', 'MESH:C113580', (137, 142))	('decrease', 'NegReg', (61, 69))	('mRNA expression', 'MPA', (78, 93))	('EZH2', 'Gene', '2146', (73, 77))	('men', 'Species', '9606', (148, 151))	('EZH2', 'Gene', (73, 77))	('Elk-1', 'Gene', '2002', (33, 38))	('knockdown', 'Var', (20, 29))	('Elk-1', 'Gene', (33, 38))
355079	24526064	In conclusion the study suggests that MEK/ERK pathway activated via KRAS mutation, EGFR amplification and ERBB2 amplification in triple-negative and ERBB2-overexpressing cells causes EZH2 over-expression.	('ERBB2', 'Gene', '2064', (106, 111))	('EGFR', 'Gene', (83, 87))	('EZH2', 'Gene', (183, 187))	('MEK', 'Gene', '5609', (38, 41))	('EZH2', 'Gene', '2146', (183, 187))	('KRAS', 'Gene', (68, 72))	('ERK', 'Gene', '5594', (42, 45))	('MEK', 'Gene', (38, 41))	('mutation', 'Var', (73, 81))	('ERBB2', 'Gene', (149, 154))	('ERK', 'Gene', (42, 45))	('EGFR', 'Gene', '1956', (83, 87))	('over-expression', 'MPA', (188, 203))	('amplification', 'Var', (88, 101))	('amplification', 'Var', (112, 125))	('ERBB2', 'Gene', '2064', (149, 154))	('activated', 'PosReg', (54, 63))	('ERBB2', 'Gene', (106, 111))	('causes', 'Reg', (176, 182))	('KRAS', 'Gene', '3845', (68, 72))
355086	24526064	Recent evidences indicate that post-translational modifications also play a crucial role in regulating EZH2 levels in breast cancer cells.	('regulating', 'Reg', (92, 102))	('EZH2', 'Gene', '2146', (103, 107))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('EZH2', 'Gene', (103, 107))	('post-translational modifications', 'Var', (31, 63))	('breast cancer', 'Disease', 'MESH:D001943', (118, 131))	('breast cancer', 'Disease', (118, 131))	('breast cancer', 'Phenotype', 'HP:0003002', (118, 131))
355097	24526064	Like other cancer types, accumulation of several genetic and epigenetic aberrations has been implicated in the initiation and progression of lung cancer.	('implicated', 'Reg', (93, 103))	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('epigenetic aberrations', 'Var', (61, 83))	('lung cancer', 'Disease', (141, 152))	('genetic', 'Var', (49, 56))	('cancer', 'Disease', 'MESH:D009369', (11, 17))	('lung cancer', 'Phenotype', 'HP:0100526', (141, 152))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('cancer', 'Disease', (11, 17))	('lung cancer', 'Disease', 'MESH:D008175', (141, 152))
355101	24526064	Generation of 'stem-cell like' hypermethylator profile in SCLC tumors due to aberrant methylation of PRC2 target genes was found to be associated with elevated EZH2 levels.	('SCLC tumors', 'Disease', (58, 69))	("'stem-cell like'", 'PosReg', (14, 30))	('SCLC tumors', 'Disease', 'MESH:D018288', (58, 69))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('PRC2', 'Gene', (101, 105))	('methylation', 'Var', (86, 97))	('aberrant methylation', 'Var', (77, 97))	('EZH2', 'Gene', '2146', (160, 164))	('elevated', 'PosReg', (151, 159))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('EZH2', 'Gene', (160, 164))
355102	24526064	Additionally, the finding that lentivirus-mediated knockdown of EZH2 in two SCLC cell lines caused a significant decrease in growth as compared to empty vector controls, emphasized the pro-proliferative and oncogenic role of EZH2 in SCLC.	('SCLC', 'Gene', (233, 237))	('decrease', 'NegReg', (113, 121))	('SCLC', 'Gene', '7864', (233, 237))	('SCLC', 'Gene', '7864', (76, 80))	('SCLC', 'Gene', (76, 80))	('EZH2', 'Gene', '2146', (225, 229))	('growth', 'MPA', (125, 131))	('EZH2', 'Gene', (225, 229))	('EZH2', 'Gene', (64, 68))	('EZH2', 'Gene', '2146', (64, 68))	('knockdown', 'Var', (51, 60))
355105	24526064	highlighted the implication of EZH2 in cell death and cell cycle regulation by demonstrating that shRNA-mediated knockdown of EZH2 in SCLC cells induced apoptosis by elevating pro-apoptotic factors Puma and Bad, increased p21 protein levels and decreased fraction of cells in S or G2/M cell cycle phases.	('SCLC', 'Gene', (134, 138))	('Bad', 'MPA', (207, 210))	('EZH2', 'Gene', '2146', (126, 130))	('fraction of cells in S or G2/M cell cycle phases', 'CPA', (255, 303))	('elevating', 'PosReg', (166, 175))	('EZH2', 'Gene', '2146', (31, 35))	('EZH2', 'Gene', (126, 130))	('EZH2', 'Gene', (31, 35))	('decreased', 'NegReg', (245, 254))	('p21', 'Gene', '1026', (222, 225))	('knockdown', 'Var', (113, 122))	('induced', 'Reg', (145, 152))	('Puma', 'MPA', (198, 202))	('increased', 'PosReg', (212, 221))	('SCLC', 'Gene', '7864', (134, 138))	('p21', 'Gene', (222, 225))	('apoptosis', 'CPA', (153, 162))
355118	24526064	Additionally, ectopic expression of EZH2 was shown to rescue miR-138 induced growth inhibition, cell cycle arrest and apoptosis in the lung cancer cells.	('apoptosis', 'CPA', (118, 127))	('arrest', 'Disease', 'MESH:D006323', (107, 113))	('miR', 'Gene', '220972', (61, 64))	('growth inhibition', 'CPA', (77, 94))	('miR', 'Gene', (61, 64))	('arrest', 'Disease', (107, 113))	('lung cancer', 'Disease', (135, 146))	('lung cancer', 'Disease', 'MESH:D008175', (135, 146))	('EZH2', 'Gene', '2146', (36, 40))	('rescue', 'PosReg', (54, 60))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('ectopic expression', 'Var', (14, 32))	('EZH2', 'Gene', (36, 40))	('lung cancer', 'Phenotype', 'HP:0100526', (135, 146))
355131	24526064	Interestingly, some studies have highlighted over-expression of E2F transcription factors including E2F3 and deregulation of pRB-E2F pathway, which directly regulate EZH2 expression, as one of the fundamental factors driving human bladder tumorigenesis.	('E2F3', 'Gene', (100, 104))	('E2F3', 'Gene', '1871', (100, 104))	('men', 'Species', '9606', (202, 205))	('tumor', 'Disease', 'MESH:D009369', (239, 244))	('over-expression', 'PosReg', (45, 60))	('pRB', 'Gene', '5925', (125, 128))	('tumor', 'Phenotype', 'HP:0002664', (239, 244))	('human', 'Species', '9606', (225, 230))	('EZH2', 'Gene', (166, 170))	('EZH2', 'Gene', '2146', (166, 170))	('tumor', 'Disease', (239, 244))	('pRB', 'Gene', (125, 128))	('deregulation', 'Var', (109, 121))
355132	24526064	Collectively, these findings suggest that aberration in pRB-E2F pathway may cause elevated EZH2 levels at successive stages of bladder carcinogenesis.	('EZH2', 'Gene', (91, 95))	('EZH2', 'Gene', '2146', (91, 95))	('pRB', 'Gene', '5925', (56, 59))	('aberration', 'Var', (42, 52))	('bladder carcinogenesis', 'Disease', 'MESH:D063646', (127, 149))	('elevated', 'PosReg', (82, 90))	('pRB', 'Gene', (56, 59))	('bladder carcinogenesis', 'Disease', (127, 149))
355134	24526064	This raises an interesting question of whether alterations in p53 may lead to increased EZH2 expression in bladder cancer.	('bladder cancer', 'Disease', 'MESH:D001749', (107, 121))	('bladder cancer', 'Disease', (107, 121))	('EZH2', 'Gene', (88, 92))	('EZH2', 'Gene', '2146', (88, 92))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('bladder cancer', 'Phenotype', 'HP:0009725', (107, 121))	('increased', 'PosReg', (78, 87))	('expression', 'MPA', (93, 103))	('alterations', 'Var', (47, 58))	('p53', 'Gene', (62, 65))	('p53', 'Gene', '7157', (62, 65))
355135	24526064	showed that in squamous cell carcinoma of the esophagus (SCCE), elevated EZH2 expression was associated with p53 alteration and activated p53 reduced EZH2 mRNA levels in SCCE cell lines.	('p53', 'Gene', (138, 141))	('EZH2', 'Gene', '2146', (73, 77))	('EZH2', 'Gene', (73, 77))	('SCC', 'Gene', '6317', (170, 173))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (15, 38))	('SCC', 'Gene', (170, 173))	('p53', 'Gene', '7157', (109, 112))	('squamous cell carcinoma of the esophagus', 'Disease', (15, 55))	('EZH2', 'Gene', '2146', (150, 154))	('SCC', 'Gene', '6317', (57, 60))	('carcinoma', 'Phenotype', 'HP:0030731', (29, 38))	('elevated', 'PosReg', (64, 72))	('EZH2', 'Gene', (150, 154))	('reduced', 'NegReg', (142, 149))	('alteration', 'Var', (113, 123))	('p53', 'Gene', (109, 112))	('SCC', 'Gene', (57, 60))	('expression', 'MPA', (78, 88))	('p53', 'Gene', '7157', (138, 141))	('squamous cell carcinoma of the esophagus', 'Disease', 'MESH:D002294', (15, 55))
355141	24526064	Interestingly, knockdown of EZH2 expression in both in vitro and in vivo xenograft models resulted in decreased H3K27me3 levels, induced apoptosis, suppressed growth and invasion of human EOC cells.	('apoptosis', 'CPA', (137, 146))	('knockdown', 'Var', (15, 24))	('human', 'Species', '9606', (182, 187))	('induced', 'Reg', (129, 136))	('EZH2', 'Gene', '2146', (28, 32))	('EZH2', 'Gene', (28, 32))	('H3K27me3 levels', 'MPA', (112, 127))	('suppressed', 'NegReg', (148, 158))	('decreased', 'NegReg', (102, 111))
355144	24526064	EZH2 knockdown was shown to reduce expression of TGF-beta1 and increase E-cadherin expression either at the transcript or protein levels.	('increase', 'PosReg', (63, 71))	('EZH2', 'Gene', '2146', (0, 4))	('knockdown', 'Var', (5, 14))	('EZH2', 'Gene', (0, 4))	('TGF-beta1', 'Gene', '7040', (49, 58))	('expression', 'MPA', (35, 45))	('TGF-beta1', 'Gene', (49, 58))	('reduce', 'NegReg', (28, 34))	('expression', 'MPA', (83, 93))	('E-cadherin', 'Gene', (72, 82))	('E-cadherin', 'Gene', '999', (72, 82))
355147	24526064	SiRNA mediated knockdown of EZH2 resulted in re-sensitization of A2780 cells to cisplatin and also decreased H3K27me3 levels.	('decreased', 'NegReg', (99, 108))	('re-sensitization', 'MPA', (45, 61))	('knockdown', 'Var', (15, 24))	('EZH2', 'Gene', '2146', (28, 32))	('H3K27me3 levels', 'MPA', (109, 124))	('cisplatin', 'Chemical', 'MESH:D002945', (80, 89))	('EZH2', 'Gene', (28, 32))	('A2780', 'CellLine', 'CVCL:0134', (65, 70))
355148	24526064	reported EZH2 over-expression in ovarian tumor derived side population (SP) cells, which are stem cell like cells enriched by chemotherapy and demonstrated that siRNA knockdown of EZH2 caused loss of SP and reduced anchorage-independent growth in ovarian tumor models.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Phenotype', 'HP:0002664', (255, 260))	('SP', 'Chemical', '-', (200, 202))	('over-expression', 'PosReg', (14, 29))	('EZH2', 'Gene', (9, 13))	('EZH2', 'Gene', '2146', (9, 13))	('SP', 'Chemical', '-', (72, 74))	('ovarian tumor', 'Disease', (33, 46))	('reduced', 'NegReg', (207, 214))	('ovarian tumor', 'Disease', 'MESH:D010051', (33, 46))	('ovarian tumor', 'Disease', (247, 260))	('loss', 'NegReg', (192, 196))	('ovarian tumor', 'Disease', 'MESH:D010051', (247, 260))	('knockdown', 'Var', (167, 176))	('EZH2', 'Gene', (180, 184))	('EZH2', 'Gene', '2146', (180, 184))	('anchorage-independent growth', 'CPA', (215, 243))	('ovarian tumor', 'Phenotype', 'HP:0100615', (33, 46))	('ovarian tumor', 'Phenotype', 'HP:0100615', (247, 260))
355153	24526064	Furthermore, NY-YA knockdown down-regulated EZH2 expression as well as H3K27me3 levels, induced apoptosis and reduced both in vitro and in vivo growth of human EOC cells.	('human', 'Species', '9606', (154, 159))	('NY-YA', 'Gene', (13, 18))	('induced', 'Reg', (88, 95))	('reduced', 'NegReg', (110, 117))	('H3K27me3 levels', 'MPA', (71, 86))	('knockdown', 'Var', (19, 28))	('expression', 'MPA', (49, 59))	('apoptosis', 'CPA', (96, 105))	('down-regulated', 'NegReg', (29, 43))	('EZH2', 'Gene', (44, 48))	('EZH2', 'Gene', '2146', (44, 48))
355154	24526064	Consequently ectopic EZH2 expression rescued NF-YA induced apoptosis in EOC cells.	('EZH2', 'Gene', (21, 25))	('EZH2', 'Gene', '2146', (21, 25))	('ectopic', 'Var', (13, 20))	('NF-YA', 'Gene', '4800', (45, 50))	('apoptosis', 'CPA', (59, 68))	('NF-YA', 'Gene', (45, 50))
355162	24526064	Melanoma is a type of cancer that develops in the melanocytes in the skin represent genetically and epigenetically complex group of malignancy characterized by deregulation of multiple tumor suppressor and oncogenic pathways, including BRAF, NRAS, PTEN, and CDKN2A.	('type of cancer', 'Disease', 'MESH:D009369', (14, 28))	('Melanoma', 'Disease', 'MESH:D008545', (0, 8))	('NRAS', 'Gene', (242, 246))	('CDKN2A', 'Gene', '1029', (258, 264))	('tumor', 'Disease', (185, 190))	('Melanoma', 'Disease', (0, 8))	('malignancy', 'Disease', 'MESH:D009369', (132, 142))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('PTEN', 'Gene', (248, 252))	('Melanoma', 'Phenotype', 'HP:0002861', (0, 8))	('BRAF', 'Gene', '673', (236, 240))	('type of cancer', 'Disease', (14, 28))	('BRAF', 'Gene', (236, 240))	('NRAS', 'Gene', '4893', (242, 246))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('malignancy', 'Disease', (132, 142))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('PTEN', 'Gene', '5728', (248, 252))	('oncogenic pathways', 'Pathway', (206, 224))	('CDKN2A', 'Gene', (258, 264))	('deregulation', 'Var', (160, 172))
355166	24526064	A key oncogenic event reported in majority of melanoma cases is the BRAFT1799A mutation that results in the constitutively activated BRAFV600E kinase.	('constitutively activated BRAFV600E kinase', 'MPA', (108, 149))	('results in', 'Reg', (93, 103))	('melanoma', 'Disease', 'MESH:D008545', (46, 54))	('BRAFT1799A mutation', 'Var', (68, 87))	('melanoma', 'Phenotype', 'HP:0002861', (46, 54))	('melanoma', 'Disease', (46, 54))	('BRAFT1799A', 'Mutation', 'rs113488022', (68, 78))	('BRAFV600E', 'Mutation', 'rs113488022', (133, 142))
355167	24526064	The epigenetic mechanism of action of BRAFV600E, which is well known to play an important role in melanoma progression, was recently studied as one of the potential mechanisms for BRAFV600E-mediated gene hypermethylation via upregulation of DNMT1 and EZH2 in melanoma cells.	('DNMT1', 'Gene', '1786', (241, 246))	('BRAFV600E', 'Mutation', 'rs113488022', (38, 47))	('EZH2', 'Gene', '2146', (251, 255))	('BRAFV600E', 'Gene', (38, 47))	('upregulation', 'PosReg', (225, 237))	('BRAFV600E', 'Mutation', 'rs113488022', (180, 189))	('EZH2', 'Gene', (251, 255))	('melanoma', 'Disease', (259, 267))	('melanoma', 'Disease', 'MESH:D008545', (259, 267))	('melanoma', 'Phenotype', 'HP:0002861', (259, 267))	('hypermethylation', 'Var', (204, 220))	('melanoma', 'Disease', 'MESH:D008545', (98, 106))	('melanoma', 'Phenotype', 'HP:0002861', (98, 106))	('melanoma', 'Disease', (98, 106))	('BRAFV600E-mediated', 'Var', (180, 198))	('DNMT1', 'Gene', (241, 246))	('gene', 'MPA', (199, 203))
355170	24526064	In contrast, EZH2 depletion, results in p21 activation and senescence induction in human melanoma cells.	('EZH2', 'Gene', (13, 17))	('senescence', 'CPA', (59, 69))	('EZH2', 'Gene', '2146', (13, 17))	('activation', 'PosReg', (44, 54))	('human', 'Species', '9606', (83, 88))	('p21', 'Gene', '1026', (40, 43))	('depletion', 'Var', (18, 27))	('induction', 'PosReg', (70, 79))	('melanoma', 'Phenotype', 'HP:0002861', (89, 97))	('melanoma', 'Disease', (89, 97))	('p21', 'Gene', (40, 43))	('melanoma', 'Disease', 'MESH:D008545', (89, 97))
355177	24526064	Another critical tumor suppressor gene Rap1GAP, which is down-regulated in multiple aggressive tumors including melanoma, pancreatic and thyroid cancer was demonstrated to be epigenetically silenced by promoter hypermethylation in melanoma cells; whereas EZH2 mediated Rap1GAP transcriptional repression by H3K27 trimethylation was reported in squamous cell carcinoma of head and neck.	('down-regulated', 'NegReg', (57, 71))	('Rap1GAP', 'Gene', (269, 276))	('EZH2', 'Gene', (255, 259))	('EZH2', 'Gene', '2146', (255, 259))	('melanoma', 'Phenotype', 'HP:0002861', (231, 239))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (344, 367))	('silenced', 'NegReg', (190, 198))	('melanoma', 'Disease', (231, 239))	('pancreatic', 'Disease', 'MESH:D010195', (122, 132))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('aggressive tumors', 'Disease', (84, 101))	('melanoma', 'Phenotype', 'HP:0002861', (112, 120))	('melanoma', 'Disease', (112, 120))	('Rap1GAP', 'Gene', (39, 46))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('aggressive tumors', 'Disease', 'MESH:D001523', (84, 101))	('carcinoma', 'Phenotype', 'HP:0030731', (358, 367))	('squamous cell carcinoma', 'Disease', (344, 367))	('pancreatic', 'Disease', (122, 132))	('thyroid cancer', 'Disease', (137, 151))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('tumor', 'Disease', (17, 22))	('melanoma', 'Disease', 'MESH:D008545', (231, 239))	('Rap1GAP', 'Gene', '5909', (269, 276))	('melanoma', 'Disease', 'MESH:D008545', (112, 120))	('promoter hypermethylation', 'Var', (202, 227))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('Rap1GAP', 'Gene', '5909', (39, 46))	('tumor', 'Disease', (95, 100))	('thyroid cancer', 'Disease', 'MESH:D013964', (137, 151))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (344, 367))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('thyroid cancer', 'Phenotype', 'HP:0002890', (137, 151))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))
355184	24526064	In limited number of studies, epigenetic mechanism of gene silencing by EZH2 has been linked to CSC-associated features such as invasion and chemoresistance.	('chemoresistance', 'CPA', (141, 156))	('linked', 'Reg', (86, 92))	('epigenetic', 'Var', (30, 40))	('gene', 'MPA', (54, 58))	('EZH2', 'Gene', '2146', (72, 76))	('CSC-associated', 'Disease', (96, 110))	('EZH2', 'Gene', (72, 76))	('invasion', 'CPA', (128, 136))
355198	24526064	Although DZNep has exhibited some promising results in in vitro and in vivo studies, there are concerns regarding its specificity as a potential therapeutic compound as it may also affect other SAM-dependent processes.	('SAM-dependent processes', 'CPA', (194, 217))	('DZNep', 'Chemical', '-', (9, 14))	('DZNep', 'Var', (9, 14))	('affect', 'Reg', (181, 187))
355201	24526064	EPZ005687 displayed considerable specificity and selectivity when tested on tyrosine 641 or alanine 677 mutation harboring lymphoma cells.	('lymphoma', 'Disease', (123, 131))	('tyrosine', 'Chemical', 'MESH:D014443', (76, 84))	('alanine 677', 'Var', (92, 103))	('lymphoma', 'Disease', 'MESH:D008223', (123, 131))	('EPZ005687', 'Var', (0, 9))	('lymphoma', 'Phenotype', 'HP:0002665', (123, 131))	('tyrosine 641', 'Var', (76, 88))	('alanine', 'Chemical', 'MESH:D000409', (92, 99))
355203	24526064	They also showed El1 mediated selective inhibition of EZH2 caused reduced proliferation, cell cycle arrest and apoptosis in DLBCL cells Y641 mutation and other EZH2 over-expressing cancer cell lines.	('EZH2', 'Gene', (54, 58))	('reduced', 'NegReg', (66, 73))	('El1', 'Gene', (17, 20))	('arrest', 'Disease', 'MESH:D006323', (100, 106))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('Y641 mutation', 'Var', (136, 149))	('arrest', 'Disease', (100, 106))	('inhibition', 'NegReg', (40, 50))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('EZH2', 'Gene', '2146', (160, 164))	('El1', 'Gene', '2035', (17, 20))	('proliferation', 'CPA', (74, 87))	('EZH2', 'Gene', '2146', (54, 58))	('cancer', 'Disease', (181, 187))	('EZH2', 'Gene', (160, 164))	('apoptosis', 'CPA', (111, 120))
355213	24526064	Since EZH2 play key roles in normal functioning of the cells by establishing the repressive state of genes that function as developmental regulators and maintain stem cell pluripotency, alternative inhibition strategies are needed which focus on the regulatory network causing EZH2 deregulation in a specific cancer type.	('EZH2', 'Gene', (277, 281))	('pluripotency', 'Disease', (172, 184))	('EZH2', 'Gene', '2146', (6, 10))	('repressive state', 'Phenotype', 'HP:0000716', (81, 97))	('EZH2', 'Gene', (6, 10))	('pluripotency', 'Disease', 'None', (172, 184))	('deregulation', 'Var', (282, 294))	('men', 'Species', '9606', (131, 134))	('cancer', 'Phenotype', 'HP:0002664', (309, 315))	('cancer', 'Disease', 'MESH:D009369', (309, 315))	('EZH2', 'Gene', '2146', (277, 281))	('cancer', 'Disease', (309, 315))
355215	24526064	For example, a recent study proposed that inhibition of CDK1/2 mediated threonine 350 phosphorylation of EZH2 may emerge as an alternative therapeutic option to diminish EZH2 activity in cancer cells without affecting the global EZH2 mediated gene silencing.	('cancer', 'Disease', 'MESH:D009369', (187, 193))	('CDK1/2', 'Gene', (56, 62))	('CDK1/2', 'Gene', '51755;983;1017', (56, 62))	('cancer', 'Disease', (187, 193))	('threonine', 'Chemical', 'MESH:D013912', (72, 81))	('inhibition', 'Var', (42, 52))	('EZH2', 'Gene', '2146', (170, 174))	('diminish', 'NegReg', (161, 169))	('threonine 350 phosphorylation', 'MPA', (72, 101))	('EZH2', 'Gene', '2146', (105, 109))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('EZH2', 'Gene', (170, 174))	('EZH2', 'Gene', (229, 233))	('EZH2', 'Gene', '2146', (229, 233))	('EZH2', 'Gene', (105, 109))	('activity', 'MPA', (175, 183))
355218	24526064	Traditionally, the oncogenic role of EZH2 depends on its ability to act as a 'transcriptional repressor' which causes H3K27me3 based silencing of critical tumor suppressor genes and contribute to tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('tumor', 'Disease', (196, 201))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('tumor', 'Disease', (155, 160))	('silencing', 'NegReg', (133, 142))	('contribute to', 'Reg', (182, 195))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('EZH2', 'Gene', '2146', (37, 41))	('H3K27me3', 'Var', (118, 126))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('EZH2', 'Gene', (37, 41))
355225	24526064	Notably, administration of EZH2 inhibitors by a cancer cell or tumor specific delivery mechanism may also reduce the unwanted side-effects and toxicity to the normal or stem cells.	('tumor', 'Disease', (63, 68))	('inhibitors', 'Var', (32, 42))	('toxicity', 'Disease', 'MESH:D064420', (143, 151))	('toxicity', 'Disease', (143, 151))	('EZH2', 'Gene', (27, 31))	('EZH2', 'Gene', '2146', (27, 31))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('reduce', 'NegReg', (106, 112))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
355284	31684858	We found that copy number alterations underpinning transcriptional dysregulation of JAK-STAT pathway genes differ within and between cancer types.	('cancer type', 'Disease', (133, 144))	('JAK-STAT pathway genes', 'Gene', (84, 106))	('cancer type', 'Disease', 'MESH:D009369', (133, 144))	('copy number', 'Var', (14, 25))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
355286	31684858	High JAK-STAT scores were associated with increased mortality rates in brain and renal cancers, but not in lung and endometrial cancers where hyperactive JAK-STAT signaling is a positive prognostic factor.	('cancers', 'Phenotype', 'HP:0002664', (128, 135))	('renal cancer', 'Phenotype', 'HP:0009726', (81, 93))	('lung and endometrial cancers', 'Disease', 'MESH:D016889', (107, 135))	('High', 'Var', (0, 4))	('brain', 'Disease', (71, 76))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('renal cancers', 'Disease', 'MESH:D007680', (81, 94))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('JAK-STAT', 'Gene', (5, 13))	('renal cancers', 'Disease', (81, 94))	('cancers', 'Phenotype', 'HP:0002664', (87, 94))
355287	31684858	Patients with aberrant JAK-STAT signaling demonstrated pan-cancer molecular features associated with misexpression of genes in other oncogenic pathways (Wnt, MAPK, TGF-beta, PPAR and VEGF).	('VEGF', 'Gene', (183, 187))	('PPAR', 'Gene', (174, 178))	('TGF-beta', 'Gene', '7040', (164, 172))	('TGF-beta', 'Gene', (164, 172))	('MAPK', 'Gene', (158, 162))	('misexpression', 'Var', (101, 114))	('PPAR', 'Gene', '5465', (174, 178))	('VEGF', 'Gene', '7422', (183, 187))	('aberrant', 'Var', (14, 22))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('Patients', 'Species', '9606', (0, 8))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))
355290	31684858	Providing a pan-cancer perspective of clinically-relevant JAK-STAT alterations, this study could serve as a framework for future research investigating anti-tumor immunity using combination therapy involving JAK-STAT and immune checkpoint inhibitors.	('tumor', 'Disease', (157, 162))	('cancer', 'Disease', 'MESH:D009369', (16, 22))	('cancer', 'Disease', (16, 22))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('alterations', 'Var', (67, 78))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))
355318	31684858	Lung squamous cell carcinoma (LUSC) and papillary renal cell carcinoma (KIRP) had the highest and lowest fraction of samples with deleted JAK-STAT pathway genes respectively (Additional file 2).	('papillary renal cell carcinoma', 'Phenotype', 'HP:0006766', (40, 70))	('JAK-STAT pathway', 'Pathway', (138, 154))	('papillary renal cell carcinoma', 'Disease', (40, 70))	('carcinoma', 'Phenotype', 'HP:0030731', (19, 28))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (50, 70))	('Lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (0, 28))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (5, 28))	('squamous cell carcinoma', 'Disease', (5, 28))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (5, 28))	('deleted', 'Var', (130, 137))	('papillary renal cell carcinoma', 'Disease', 'MESH:D002292', (40, 70))
355321	31684858	We identified 71 and 49 genes that were recurrently deleted and amplified respectively in at least 20% of samples within each cancer type and at least 7 cancer types (Additional file 2).	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('cancer type', 'Disease', (126, 137))	('deleted', 'Var', (52, 59))	('cancer type', 'Disease', (153, 164))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('cancer type', 'Disease', 'MESH:D009369', (126, 137))	('cancer type', 'Disease', 'MESH:D009369', (153, 164))
355322	31684858	Esophageal carcinoma (ESCA) had 70 genes that were recurrently deleted while only four recurrently deleted genes were found in papillary renal cell carcinoma (KIRP).	('Esophageal carcinoma', 'Disease', (0, 20))	('papillary renal cell carcinoma', 'Disease', 'MESH:D002292', (127, 157))	('Esophageal carcinoma', 'Disease', 'MESH:D004938', (0, 20))	('papillary renal cell carcinoma', 'Phenotype', 'HP:0006766', (127, 157))	('Esophageal carcinoma', 'Phenotype', 'HP:0011459', (0, 20))	('papillary renal cell carcinoma', 'Disease', (127, 157))	('deleted', 'Var', (63, 70))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (137, 157))	('carcinoma', 'Phenotype', 'HP:0030731', (11, 20))	('carcinoma', 'Phenotype', 'HP:0030731', (148, 157))
355338	31684858	Kaplan-Meier analyses and log-rank tests revealed that patients with high scores (4th quartile) had higher death risks in glioma (P < 0.0001), pan-kidney (consisting of chromophobe renal cell, clear cell renal cell and papillary renal cell cancers; P < 0.0001) and clear cell renal cell (P < 0.0001) cohorts (Fig.	('papillary renal cell cancers', 'Disease', (219, 247))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('pan-kidney', 'Disease', (143, 153))	('glioma', 'Phenotype', 'HP:0009733', (122, 128))	('glioma', 'Disease', (122, 128))	('chromophobe renal cell', 'Disease', 'MESH:D002292', (169, 191))	('clear cell renal cell', 'Disease', (265, 286))	('high scores', 'Var', (69, 80))	('cancers', 'Phenotype', 'HP:0002664', (240, 247))	('patients', 'Species', '9606', (55, 63))	('chromophobe renal cell', 'Disease', (169, 191))	('renal cell cancer', 'Phenotype', 'HP:0005584', (229, 246))	('glioma', 'Disease', 'MESH:D005910', (122, 128))	('papillary renal cell cancers', 'Disease', 'MESH:D002292', (219, 247))
355339	31684858	In contrast, high expression of signature genes was linked to improved survival rates in lung (P = 0.025) and endometrial (P = 0.032) cancers (Fig.	('endometrial', 'Disease', (110, 121))	('lung', 'Disease', (89, 93))	('survival', 'CPA', (71, 79))	('improved', 'PosReg', (62, 70))	('high', 'Var', (13, 17))	('cancers', 'Disease', 'MESH:D009369', (134, 141))	('cancers', 'Phenotype', 'HP:0002664', (134, 141))	('cancers', 'Disease', (134, 141))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
355343	31684858	Lastly, multidimensional scaling analyses of signature genes in the five cohorts revealed significant differences between tumor and non-tumor samples, implying that dysregulated JAK-STAT signaling may serve as a diagnostic marker for early detection in pre-cancerous lesions (Fig.	('dysregulated', 'Var', (165, 177))	('cancer', 'Phenotype', 'HP:0002664', (257, 263))	('cancerous lesions', 'Disease', (257, 274))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('non-tumor', 'Disease', (132, 141))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('non-tumor', 'Disease', 'MESH:C580335', (132, 141))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('tumor', 'Disease', (136, 141))	('tumor', 'Disease', (122, 127))	('cancerous lesions', 'Disease', 'MESH:D009369', (257, 274))
355346	31684858	High JAK-STAT scores were associated with decreased survival rates in glioma patients.	('survival rates', 'CPA', (52, 66))	('glioma', 'Disease', (70, 76))	('decreased', 'NegReg', (42, 51))	('High', 'Var', (0, 4))	('glioma', 'Disease', 'MESH:D005910', (70, 76))	('glioma', 'Phenotype', 'HP:0009733', (70, 76))	('patients', 'Species', '9606', (77, 85))
355351	31684858	3), we reasoned that patients from diverse cancer types might harbor similar transcriptional defects caused by aberrant activation of JAK-STAT.	('cancer type', 'Disease', (43, 54))	('JAK-STAT', 'Gene', (134, 142))	('cancer type', 'Disease', 'MESH:D009369', (43, 54))	('activation', 'PosReg', (120, 130))	('patients', 'Species', '9606', (21, 29))	('aberrant', 'Var', (111, 119))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))
355359	31684858	For instance, except for THBS1 and THBS2, a vast majority of TGF-beta DEGs exhibited somatic gains (Fig.	('DEGs', 'Var', (70, 74))	('DEGs', 'Chemical', 'MESH:C062694', (70, 74))	('THBS1', 'Gene', (25, 30))	('somatic gains', 'CPA', (85, 98))	('THBS2', 'Gene', (35, 40))	('TGF-beta', 'Gene', '7040', (61, 69))	('THBS1', 'Gene', '7057', (25, 30))	('TGF-beta', 'Gene', (61, 69))	('THBS2', 'Gene', '7058', (35, 40))
355363	31684858	IRF8 was among one of the most enriched TFs implicated in the regulation of transcriptional outputs of patients with dysregulated JAK-STAT signaling (Fig.	('patients', 'Species', '9606', (103, 111))	('JAK-STAT signaling', 'MPA', (130, 148))	('IRF8', 'Gene', (0, 4))	('dysregulated', 'Var', (117, 129))
355366	31684858	To evaluate the combined relationship between JAK-STAT signaling and IRF8 expression, patients were categorized into four groups based on median IRF8 and JAK-STAT scores: 1) high-high, 2) low-low, 3) high IRF8 and low 28-gene score and 4) low IRF8 and high 28-gene score.	('low', 'NegReg', (239, 242))	('low', 'NegReg', (214, 217))	('low-low', 'Var', (188, 195))	('28-gene score', 'MPA', (218, 231))	('high', 'Var', (200, 204))	('patients', 'Species', '9606', (86, 94))
355369	31684858	Our results support a model in which IRF8 influences the behavior of tumors with aberrant JAK-STAT signaling.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('aberrant', 'Var', (81, 89))	('influences', 'Reg', (42, 52))	('behavior', 'CPA', (57, 65))	('IRF8', 'Gene', (37, 41))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('tumors', 'Disease', (69, 75))	('tumors', 'Disease', 'MESH:D009369', (69, 75))	('JAK-STAT signaling', 'MPA', (90, 108))
355375	31684858	Tumor-promoting and tumor-suppressing roles of JAK-STAT signaling is very much cell type-dependent (Fig.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('JAK-STAT', 'Var', (47, 55))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('Tumor-promoting', 'CPA', (0, 15))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('tumor', 'Disease', (20, 25))
355379	31684858	In contrast, phosphorylated STAT5 promotes cellular differentiation and inhibits invasive properties in breast cancer cells (Sultan et al.,; Sultan et al.,).	('invasive properties', 'CPA', (81, 100))	('STAT5', 'Gene', (28, 33))	('promotes', 'PosReg', (34, 42))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('phosphorylated', 'Var', (13, 27))	('breast cancer', 'Disease', 'MESH:D001943', (104, 117))	('inhibits', 'NegReg', (72, 80))	('breast cancer', 'Disease', (104, 117))	('STAT5', 'Gene', '6776', (28, 33))	('breast cancer', 'Phenotype', 'HP:0003002', (104, 117))	('cellular differentiation', 'CPA', (43, 67))
355381	31684858	Similarly, in rectal cancers, patients with tumors positive for phosphorylated STAT3 had improved survival outcomes (Monnien et al.,).	('improved', 'PosReg', (89, 97))	('rectal cancers', 'Disease', (14, 28))	('tumors', 'Disease', (44, 50))	('tumors', 'Disease', 'MESH:D009369', (44, 50))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('phosphorylated', 'Var', (64, 78))	('survival outcomes', 'CPA', (98, 115))	('cancers', 'Phenotype', 'HP:0002664', (21, 28))	('patients', 'Species', '9606', (30, 38))	('STAT3', 'Gene', '6774', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('rectal cancers', 'Disease', 'MESH:D012004', (14, 28))	('STAT3', 'Gene', (79, 84))
355382	31684858	In contrast, high levels of phosphorylated STAT3 is associated with reduced survival rates in glioblastoma (Birner et al.,) and renal cancer (Horiguchi et al.,), which independently corroborates our findings on the tumor-promoting effects of JAK-STAT signaling in these cancer types (Figs.	('phosphorylated', 'Var', (28, 42))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('glioblastoma', 'Disease', (94, 106))	('glioblastoma', 'Phenotype', 'HP:0012174', (94, 106))	('cancer', 'Phenotype', 'HP:0002664', (270, 276))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('cancer type', 'Disease', (270, 281))	('high levels', 'Var', (13, 24))	('survival rates', 'CPA', (76, 90))	('cancer type', 'Disease', 'MESH:D009369', (270, 281))	('renal cancer', 'Disease', (128, 140))	('renal cancer', 'Phenotype', 'HP:0009726', (128, 140))	('STAT3', 'Gene', (43, 48))	('tumor', 'Disease', (215, 220))	('tumor', 'Disease', 'MESH:D009369', (215, 220))	('STAT3', 'Gene', '6774', (43, 48))	('reduced', 'NegReg', (68, 75))	('renal cancer', 'Disease', 'MESH:D007680', (128, 140))	('glioblastoma', 'Disease', 'MESH:D005909', (94, 106))
355387	31684858	Patients with aberrant JAK-STAT signaling exhibited interactions with other major oncogenic pathways, including MAPK, Wnt, TGF-beta, PPAR and VEGF (Fig.	('JAK-STAT', 'Var', (23, 31))	('VEGF', 'Gene', (142, 146))	('PPAR', 'Gene', '5465', (133, 137))	('MAPK', 'Disease', (112, 116))	('PPAR', 'Gene', (133, 137))	('interactions', 'Interaction', (52, 64))	('oncogenic pathways', 'Pathway', (82, 100))	('TGF-beta', 'Gene', '7040', (123, 131))	('Patients', 'Species', '9606', (0, 8))	('VEGF', 'Gene', '7422', (142, 146))	('aberrant JAK-STAT', 'Var', (14, 31))	('TGF-beta', 'Gene', (123, 131))
355388	31684858	We demonstrated that hyperactivation of JAK-STAT signaling promotes the loss of anti-tumor immunity in glioma and renal cancer patients (Fig.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('tumor', 'Disease', (85, 90))	('loss', 'NegReg', (72, 76))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('renal cancer', 'Disease', (114, 126))	('JAK-STAT signaling', 'MPA', (40, 58))	('glioma', 'Disease', 'MESH:D005910', (103, 109))	('glioma', 'Phenotype', 'HP:0009733', (103, 109))	('renal cancer', 'Phenotype', 'HP:0009726', (114, 126))	('patients', 'Species', '9606', (127, 135))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('renal cancer', 'Disease', 'MESH:D007680', (114, 126))	('hyperactivation', 'Var', (21, 36))	('glioma', 'Disease', (103, 109))
355390	31684858	Furthermore, hyperactivation of STAT3 is linked to abnormal differentiation of dendritic cells in colon cancer cells (Nefedova et al.,).	('linked', 'Reg', (41, 47))	('STAT3', 'Gene', '6774', (32, 37))	('colon cancer', 'Disease', 'MESH:D015179', (98, 110))	('colon cancer', 'Phenotype', 'HP:0003003', (98, 110))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('STAT3', 'Gene', (32, 37))	('hyperactivation', 'Var', (13, 28))	('colon cancer', 'Disease', (98, 110))
355395	31684858	Promoter hypermethylation and gene silencing of IRF8 abrogates cellular response to interferon stimulation and overexpression of IRF8 in nasopharyngeal, esophageal and colon cancer cell lines could inhibit clonogenicity (Lee et al.,).	('colon cancer', 'Disease', (168, 180))	('gene silencing', 'Var', (30, 44))	('IRF8', 'Gene', (129, 133))	('inhibit', 'NegReg', (198, 205))	('clonogenicity', 'CPA', (206, 219))	('abrogates', 'NegReg', (53, 62))	('colon cancer', 'Phenotype', 'HP:0003003', (168, 180))	('colon cancer', 'Disease', 'MESH:D015179', (168, 180))	('cellular response to interferon stimulation', 'MPA', (63, 106))	('overexpression', 'PosReg', (111, 125))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('IRF8', 'Gene', (48, 52))	('Promoter hypermethylation', 'Var', (0, 25))
355398	31684858	Importantly, loss of IRF8 may further suppress tumor immunity in patients with hyperactive JAK-STAT signaling.	('tumor', 'Disease', (47, 52))	('JAK-STAT signaling', 'MPA', (91, 109))	('hyperactive', 'PosReg', (79, 90))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('patients', 'Species', '9606', (65, 73))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('IRF8', 'Gene', (21, 25))	('loss', 'Var', (13, 17))	('suppress', 'NegReg', (38, 46))
355407	29959060	For squamous cell carcinomas, lower prescription doses were associated with worse in-field control (12Gyx4 or 10Gyx5 vs. 18Gy or 20Gyx3: HR=3.530, p=0.0447, confirmed by propensity score matching) and was independent of GTV (HR=1.014 per mL, 95% CI 1.005-1.022, p=0.0012).	('lower', 'NegReg', (30, 35))	('carcinoma', 'Phenotype', 'HP:0030731', (18, 27))	('10Gyx5', 'Var', (110, 116))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (4, 28))	('squamous cell carcinomas', 'Disease', (4, 28))	('carcinomas', 'Phenotype', 'HP:0030731', (18, 28))	('worse', 'NegReg', (76, 81))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (4, 28))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (4, 27))
355409	29959060	We suggest lower prescription doses (i.e., 12Gyx4 or 10Gx5) should be avoided for squamous cell carcinomas if normal tissue tolerances are met.	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('carcinomas', 'Phenotype', 'HP:0030731', (96, 106))	('squamous cell carcinomas', 'Disease', (82, 106))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (82, 106))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (82, 105))	('12Gyx4', 'Var', (43, 49))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (82, 106))
355457	29959060	Within the subset of patients prescribed 12Gy x4 or 10Gy x5, in-field control was higher for adenocarcinomas than for squamous cell carcinomas (HR 0.351, 95% CI 0.129-0.953, p=0.04), with 3-year in-field control of 88.9% and 78.5%, respectively (p=0.0317).	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (118, 142))	('12Gy x4', 'Var', (41, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (118, 141))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('higher', 'PosReg', (82, 88))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (118, 142))	('patients', 'Species', '9606', (21, 29))	('carcinomas', 'Phenotype', 'HP:0030731', (132, 142))	('adenocarcinomas', 'Disease', 'MESH:D000230', (93, 108))	('carcinomas', 'Phenotype', 'HP:0030731', (98, 108))	('adenocarcinomas', 'Disease', (93, 108))	('squamous cell carcinomas', 'Disease', (118, 142))	('10Gy x5', 'Var', (52, 59))
355459	29959060	When analyzed by histology (adenocarcinoma vs. squamous cell carcinoma), infield control did not differ by dose grouping (12Gy x4 or 10Gy x5 vs. 18Gy or 20Gy x3) for adenocarcinomas but was significantly worse for squamous cell carcinomas receiving 12Gy x4 or 10Gy x5 (HR 3.96, 95% CI 1.20-13.03, p=0.0238).	('carcinoma', 'Phenotype', 'HP:0030731', (33, 42))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (214, 238))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (214, 237))	('adenocarcinoma', 'Disease', 'MESH:D000230', (166, 180))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (214, 238))	('adenocarcinoma', 'Disease', (28, 42))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (47, 70))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (214, 237))	('squamous cell carcinomas', 'Disease', (214, 238))	('carcinoma', 'Phenotype', 'HP:0030731', (228, 237))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('adenocarcinoma', 'Disease', 'MESH:D000230', (28, 42))	('carcinoma', 'Phenotype', 'HP:0030731', (171, 180))	('carcinomas', 'Phenotype', 'HP:0030731', (228, 238))	('carcinomas', 'Phenotype', 'HP:0030731', (171, 181))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (47, 70))	('adenocarcinomas', 'Disease', 'MESH:D000230', (166, 181))	('adenocarcinomas', 'Disease', (166, 181))	('adenocarcinoma', 'Disease', (166, 180))	('12Gy x4', 'Var', (249, 256))	('squamous cell carcinoma', 'Disease', (47, 70))
355460	29959060	When analyzed by the dose groupings, in-field control did not differ by histology for 18Gy or 20Gy x3 but was significantly worse for squamous cell carcinomas when treating to 12Gy x4 or 10Gy x5 (HR 2.80, 95% CI 1.03-7.60, p=0.043).	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (134, 158))	('squamous cell carcinomas', 'Disease', (134, 158))	('12Gy x4', 'Var', (176, 183))	('carcinomas', 'Phenotype', 'HP:0030731', (148, 158))	('worse', 'NegReg', (124, 129))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (134, 158))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (134, 157))	('10Gy x5', 'Var', (187, 194))	('carcinoma', 'Phenotype', 'HP:0030731', (148, 157))
355462	29959060	Within the adenocarcinoma cohort, there were no differences in in-field control according to dose using the above radiation dose groupings (cutoff 110Gy, p=0.12; 10Gy x5 and 12Gy x4 vs. 18Gy or 20Gy x3, p=0.31).	('carcinoma', 'Phenotype', 'HP:0030731', (16, 25))	('adenocarcinoma cohort', 'Disease', 'MESH:D000230', (11, 32))	('adenocarcinoma cohort', 'Disease', (11, 32))	('10Gy x5', 'Var', (162, 169))	('12Gy x4', 'Var', (174, 181))
355469	29959060	reported on both patients treated for metastatic and primary NSCLC with SABR and identified that the dose to isocenter (i.e., maximum dose) to achieve 90% tumor control probability was 160Gy and 176Gy, respectively.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('NSCLC', 'Phenotype', 'HP:0030358', (61, 66))	('tumor', 'Disease', (155, 160))	('patients', 'Species', '9606', (17, 25))	('NSCLC', 'Disease', (61, 66))	('160Gy', 'Var', (185, 190))	('NSCLC', 'Disease', 'MESH:D002289', (61, 66))
355470	29959060	reported in 2016 on 1092 patients with 1200 T1-T2N0M0 lesions treated with 12.5Gy x4 or 7Gy x10 fractions for those at higher risk of normal tissue toxicity.	('toxicity', 'Disease', (148, 156))	('patients', 'Species', '9606', (25, 33))	('T1-T2N0M0', 'Var', (44, 53))	('toxicity', 'Disease', 'MESH:D064420', (148, 156))
355471	29959060	reported in 2017 on 747 patients with 765 T1-T2N0M0 lung tumors treated with SABR and found that prescription dose cutoffs of both 105Gy and 110Gy were predictive for OS (and only 110Gy was predictive for local failure).	('lung tumors', 'Disease', 'MESH:D008175', (52, 63))	('105Gy', 'Var', (131, 136))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('patients', 'Species', '9606', (24, 32))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('lung tumors', 'Disease', (52, 63))	('T1-T2N0M0', 'Var', (42, 51))	('110Gy', 'Var', (141, 146))	('lung tumors', 'Phenotype', 'HP:0100526', (52, 63))
355474	29959060	reported in 2017 on T1-T3N0M0 lung tumors treated with SABR and suggested that squamous histologic subtype was associated with local failure, with 3-year cumulative incidence of local failure of 18.9% vs. 4.1% in squamous cell and adenocarcinoma lesions, respectively.	('adenocarcinoma lesions', 'Disease', 'MESH:D002292', (231, 253))	('lung tumors', 'Disease', (30, 41))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('lung tumors', 'Phenotype', 'HP:0100526', (30, 41))	('carcinoma', 'Phenotype', 'HP:0030731', (236, 245))	('squamous cell', 'Disease', (213, 226))	('adenocarcinoma lesions', 'Disease', (231, 253))	('lung tumors', 'Disease', 'MESH:D008175', (30, 41))	('T1-T3N0M0', 'Var', (20, 29))
355475	29959060	reported in 2017 on a smaller cohort with biopsy-proven T1-T3N0M0 lung tumors treated with SABR and similarly found histologic subtype to be associated with local failure.	('lung tumors', 'Disease', 'MESH:D008175', (66, 77))	('T1-T3N0M0', 'Var', (56, 65))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('lung tumors', 'Disease', (66, 77))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('lung tumors', 'Phenotype', 'HP:0100526', (66, 77))
355479	29959060	<110Gy), whereas such results were not observed for adenocarcinomas.	('carcinoma', 'Phenotype', 'HP:0030731', (57, 66))	('adenocarcinomas', 'Disease', 'MESH:D000230', (52, 67))	('carcinomas', 'Phenotype', 'HP:0030731', (57, 67))	('adenocarcinomas', 'Disease', (52, 67))	('<110Gy', 'Var', (0, 6))
355484	29959060	Our findings also suggest that patients with squamous cell carcinoma have higher failure rates at prescription doses <110Gy independent of GTV and may need higher doses to achieve acceptable local control outcomes.	('squamous cell carcinoma', 'Disease', (45, 68))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (45, 68))	('patients', 'Species', '9606', (31, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (59, 68))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (45, 68))	('<110Gy', 'Var', (117, 123))	('failure', 'MPA', (81, 88))
355488	30693177	Here, the function and molecular mechanism of circNOL10 in lung cancer development are investigated using in vitro and in vivo studies, and it is shown that circNOL10 significantly inhibits the development of lung cancer and that circNOL10 expression is co-regulated by methylation of its parental gene Pre-NOL10 and by splicing factor epithelial splicing regulatory protein 1 (ESRP1).	('circNOL10', 'Chemical', '-', (157, 166))	('NOL10', 'Gene', (50, 55))	('lung cancer', 'Disease', 'MESH:D008175', (59, 70))	('methylation', 'Var', (270, 281))	('lung cancer', 'Phenotype', 'HP:0100526', (209, 220))	('lung cancer', 'Phenotype', 'HP:0100526', (59, 70))	('inhibits', 'NegReg', (181, 189))	('NOL10', 'Gene', '79954', (234, 239))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('expression', 'MPA', (240, 250))	('NOL10', 'Gene', '79954', (307, 312))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('NOL10', 'Gene', '79954', (161, 166))	('ESRP1', 'Gene', (378, 383))	('lung cancer', 'Disease', (209, 220))	('NOL10', 'Gene', (234, 239))	('lung cancer', 'Disease', (59, 70))	('NOL10', 'Gene', (307, 312))	('NOL10', 'Gene', '79954', (50, 55))	('NOL10', 'Gene', (161, 166))	('ESRP1', 'Gene', '54845', (378, 383))	('circNOL10', 'Chemical', '-', (230, 239))	('expression', 'Species', '29278', (240, 250))	('lung cancer', 'Disease', 'MESH:D008175', (209, 220))	('circNOL10', 'Chemical', '-', (46, 55))
355495	30693177	Increasing evidence suggests the existence of a close association between epigenetics and lung cancer.	('lung cancer', 'Disease', 'MESH:D008175', (90, 101))	('lung cancer', 'Disease', (90, 101))	('lung cancer', 'Phenotype', 'HP:0100526', (90, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('epigenetics', 'Var', (74, 85))
355501	30693177	Furthermore, Pre-NOL10 methylation and the splicing factor epithelial splicing regulatory protein 1 (ESRP1) worked together to downregulate circNOL10 expression in lung cancer, associated with significant inhibition of lung cancer development.	('NOL10', 'Gene', (144, 149))	('NOL10', 'Gene', (17, 22))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('inhibition of lung cancer', 'Disease', 'MESH:D008175', (205, 230))	('lung cancer', 'Disease', (164, 175))	('methylation', 'Var', (23, 34))	('circNOL10', 'Chemical', '-', (140, 149))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('ESRP1', 'Gene', (101, 106))	('expression', 'MPA', (150, 160))	('inhibition of lung cancer', 'Disease', (205, 230))	('ESRP1', 'Gene', '54845', (101, 106))	('lung cancer', 'Disease', 'MESH:D008175', (219, 230))	('lung cancer', 'Disease', 'MESH:D008175', (164, 175))	('lung cancer', 'Phenotype', 'HP:0100526', (219, 230))	('lung cancer', 'Phenotype', 'HP:0100526', (164, 175))	('NOL10', 'Gene', '79954', (144, 149))	('NOL10', 'Gene', '79954', (17, 22))	('downregulate', 'NegReg', (127, 139))	('expression', 'Species', '29278', (150, 160))
355506	30693177	This alteration in mitochondrial function triggered multiple signaling pathways and ultimately inhibited cell proliferation and cell cycle progression and promoted apoptosis of lung cancer cells, thereby significantly inhibiting lung cancer progression.	('signaling pathways', 'Pathway', (61, 79))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('triggered', 'Reg', (42, 51))	('alteration', 'Var', (5, 15))	('lung cancer', 'Disease', 'MESH:D008175', (177, 188))	('mitochondrial', 'MPA', (19, 32))	('cell cycle progression', 'CPA', (128, 150))	('inhibited', 'NegReg', (95, 104))	('lung cancer', 'Disease', 'MESH:D008175', (229, 240))	('apoptosis', 'CPA', (164, 173))	('lung cancer', 'Phenotype', 'HP:0100526', (229, 240))	('promoted', 'PosReg', (155, 163))	('lung cancer', 'Disease', (177, 188))	('lung cancer', 'Phenotype', 'HP:0100526', (177, 188))	('lung cancer', 'Disease', (229, 240))	('cell proliferation', 'CPA', (105, 123))	('inhibiting', 'NegReg', (218, 228))
355522	30693177	Compared with transfection with a scrambled sequence, transfection of H460 cells and A549 cells with circNOL10 siRNA1 or siRNA2 significantly increased cell viability, proliferation, invasion ability, migration, and adhesion, as well as the proportion of cells in S and G2/M phases, and significantly decreased the proportion of cells undergoing apoptosis and in G0/G1 phase.	('proliferation', 'CPA', (168, 181))	('G2/M phases', 'CPA', (270, 281))	('A549', 'CellLine', 'CVCL:0023', (85, 89))	('increased', 'PosReg', (142, 151))	('migration', 'CPA', (201, 210))	('transfection', 'Var', (54, 66))	('invasion ability', 'CPA', (183, 199))	('circNOL10', 'Chemical', '-', (101, 110))	('cell viability', 'CPA', (152, 166))	('G0/G1 phase', 'CPA', (363, 374))	('decreased', 'NegReg', (301, 310))	('adhesion', 'CPA', (216, 224))
355530	30693177	The fluorescence intensities at different time points were significantly lower in the circNOL10 OE-ST group compared with the control vec-ST group, while tumors also appeared later in the circNOL10 OE-ST compared with the vec-ST group.	('tumors', 'Disease', (154, 160))	('circNOL10', 'Var', (188, 197))	('tumors', 'Disease', 'MESH:D009369', (154, 160))	('circNOL10', 'Chemical', '-', (188, 197))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('fluorescence intensities', 'MPA', (4, 28))	('lower', 'NegReg', (73, 78))	('circNOL10', 'Chemical', '-', (86, 95))	('circNOL10 OE-ST', 'Var', (86, 101))
355531	30693177	The tumors were solid, and tumors in the circNOL10 OE-ST group were significantly smaller than those in the vec-ST group.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('smaller', 'NegReg', (82, 89))	('tumors', 'Disease', (4, 10))	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('tumors', 'Disease', (27, 33))	('tumors', 'Disease', 'MESH:D009369', (27, 33))	('circNOL10', 'Chemical', '-', (41, 50))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('circNOL10 OE-ST', 'Var', (41, 56))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))
355533	30693177	The fluorescence intensities and tumor growth rates at different time points were significantly lower in the circNOL10 OE-ST compared with the vec-ST group, as shown with in vivo imaging (Figure 2F).	('circNOL10', 'Chemical', '-', (109, 118))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('circNOL10 OE-ST', 'Var', (109, 124))	('lower', 'NegReg', (96, 101))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('fluorescence intensities', 'MPA', (4, 28))	('tumor', 'Disease', (33, 38))
355534	30693177	Hematoxylin and eosin (HE) staining of the subcutaneous tumors showed that the nuclear: cytoplasmic ratio and nuclear atypia were both reduced in the circNOL10 OE-ST compared with the control group, suggesting that circNOL10 overexpression reduced the degree of malignancy (Figure 2G).	('circNOL10', 'Var', (150, 159))	('subcutaneous tumors', 'Disease', (43, 62))	('circNOL10', 'Chemical', '-', (150, 159))	('reduced', 'NegReg', (240, 247))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('nuclear: cytoplasmic ratio', 'CPA', (79, 105))	('circNOL10', 'Chemical', '-', (215, 224))	('nuclear atypia', 'CPA', (110, 124))	('malignancy', 'Disease', (262, 272))	('subcutaneous tumors', 'Phenotype', 'HP:0001482', (43, 62))	('subcutaneous tumors', 'Disease', 'MESH:D013352', (43, 62))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('reduced', 'NegReg', (135, 142))	('HE', 'Chemical', '-', (23, 25))	('Hematoxylin and eosin', 'Chemical', '-', (0, 21))	('expression', 'Species', '29278', (229, 239))	('malignancy', 'Disease', 'MESH:D009369', (262, 272))
355535	30693177	HE staining also revealed fewer lung-tumor foci in the circNOL10 OE-ST compared with the vec-ST group, and a lower degree of malignancy (Figure 2H).	('lung-tumor', 'Disease', 'MESH:D008175', (32, 42))	('lung-tumor', 'Disease', (32, 42))	('malignancy', 'Disease', 'MESH:D009369', (125, 135))	('malignancy', 'Disease', (125, 135))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('fewer', 'NegReg', (26, 31))	('circNOL10', 'Chemical', '-', (55, 64))	('HE', 'Chemical', '-', (0, 2))	('circNOL10 OE-ST', 'Var', (55, 70))
355537	30693177	Expression levels of the proapoptotic protein Bax and caspase-9 were significantly increased in the circNOL10 OE-ST group compared with the vec-ST group, while levels of the apoptosis-inhibitory protein Bcl-2 were significantly decreased.	('Bcl-2', 'Gene', '596', (203, 208))	('Bax', 'Gene', (46, 49))	('increased', 'PosReg', (83, 92))	('caspase-9', 'Gene', (54, 63))	('Expression levels', 'MPA', (0, 17))	('Expression', 'Species', '29278', (0, 10))	('circNOL10 OE-ST', 'Var', (100, 115))	('levels of the apoptosis-inhibitory', 'MPA', (160, 194))	('caspase-9', 'Gene', '842', (54, 63))	('decreased', 'NegReg', (228, 237))	('Bax', 'Gene', '581', (46, 49))	('circNOL10', 'Chemical', '-', (100, 109))	('Bcl-2', 'Gene', (203, 208))
355538	30693177	Furthermore, expression of the invasion-inhibitory marker E-cadherin and the tumor suppressor phosphatase and tensin homolog deleted on chromosome 10 (PTEN) were significantly increased, while the proliferation marker proliferating cell nuclear antigen (PCNA) was significantly decreased by circNOL10 overexpression (Figure 2I,J).	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('invasion-inhibitory', 'CPA', (31, 50))	('circNOL10', 'Chemical', '-', (291, 300))	('expression', 'Species', '29278', (13, 23))	('decreased', 'NegReg', (278, 287))	('PCNA', 'Gene', (254, 258))	('E-cadherin', 'Gene', (58, 68))	('E-cadherin', 'Gene', '999', (58, 68))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('proliferation', 'CPA', (197, 210))	('expression', 'Species', '29278', (305, 315))	('increased', 'PosReg', (176, 185))	('PCNA', 'Gene', '5111', (254, 258))	('PTEN', 'Gene', (151, 155))	('expression', 'MPA', (13, 23))	('overexpression', 'PosReg', (301, 315))	('tumor', 'Disease', (77, 82))	('circNOL10', 'Var', (291, 300))	('PTEN', 'Gene', '5728', (151, 155))
355555	30693177	circNOL10 and NOL10 mRNA levels were both significantly downregulated by silencing ESRP1 (Figure 3J,K).	('silencing', 'Var', (73, 82))	('NOL10', 'Gene', (4, 9))	('circNOL10', 'Chemical', '-', (0, 9))	('NOL10', 'Gene', '79954', (4, 9))	('NOL10', 'Gene', (14, 19))	('ESRP1', 'Gene', '54845', (83, 88))	('NOL10', 'Gene', '79954', (14, 19))	('ESRP1', 'Gene', (83, 88))	('downregulated', 'NegReg', (56, 69))
355559	30693177	RNA methylation is known to be a switch regulating RNA structure, and hypermethylation opens nucleic acid bonds and thus affects the formation of circRNAs rather than linear mRNAs.22 We therefore supposed that hypermethylation of Pre-NOL10 in H460 and A549 cells inhibited the formation of circNOL10.	('inhibited', 'NegReg', (263, 272))	('NOL10', 'Gene', '79954', (294, 299))	('NOL10', 'Gene', (294, 299))	('hypermethylation', 'Var', (210, 226))	('circNOL10', 'Chemical', '-', (290, 299))	('NOL10', 'Gene', (234, 239))	('NOL10', 'Gene', '79954', (234, 239))	('A549', 'CellLine', 'CVCL:0023', (252, 256))
355570	30693177	Compared with cells transfected with scrambled sequences, relative fluorescence intensity was significantly increased in SCML1-silenced cells, and was significantly decreased by SCML1 overexpression (Figure 4I).	('decreased', 'NegReg', (165, 174))	('expression', 'Species', '29278', (188, 198))	('SCML1', 'Gene', '6322', (178, 183))	('relative fluorescence intensity', 'MPA', (58, 89))	('SCML1', 'Gene', (121, 126))	('increased', 'PosReg', (108, 117))	('SCML1', 'Gene', '6322', (121, 126))	('overexpression', 'Var', (184, 198))	('SCML1', 'Gene', (178, 183))
355574	30693177	A shifted band was detected in the SCML1 and circNOL10 EMSA probe group, but not in the circNOL10 or nonmutant probe groups (Figure 4J).	('SCML1', 'Gene', (35, 40))	('SCML1', 'Gene', '6322', (35, 40))	('circNOL10', 'Var', (45, 54))	('circNOL10', 'Chemical', '-', (45, 54))	('circNOL10', 'Chemical', '-', (88, 97))
355578	30693177	Analysis of SCML1 functional domains (http://smart.embl-heidelberg.de) showed amino acids 255-324 of SCML1 included a sterile alpha motif (SAM) domain, located in the binding regions predicted by catRAPID (Figure 4K).	('SCML1', 'Gene', (101, 106))	('amino acids 255-324', 'Var', (78, 97))	('SCML1', 'Gene', (12, 17))	('SCML1', 'Gene', '6322', (101, 106))	('SCML1', 'Gene', '6322', (12, 17))	('included', 'Reg', (107, 115))
355584	30693177	SCML1 expression was increased by overexpression of circNOL10, and decreased by circNOL10 silencing (Figure 4O,P).	('expression', 'Species', '29278', (38, 48))	('increased', 'PosReg', (21, 30))	('silencing', 'NegReg', (90, 99))	('expression', 'Species', '29278', (6, 16))	('expression', 'MPA', (6, 16))	('overexpression', 'PosReg', (34, 48))	('circNOL10', 'Chemical', '-', (52, 61))	('circNOL10', 'Var', (80, 89))	('circNOL10', 'Chemical', '-', (80, 89))	('SCML1', 'Gene', (0, 5))	('decreased', 'NegReg', (67, 76))	('SCML1', 'Gene', '6322', (0, 5))
355588	30693177	We then silenced or overexpressed circNOL10 in H460 cells and performed SCML1 co-immunoprecipitation assays in BEAS-2B cells (Figure S3F, Supporting Information).	('SCML1', 'Gene', (72, 77))	('SCML1', 'Gene', '6322', (72, 77))	('circNOL10', 'Chemical', '-', (34, 43))	('circNOL10', 'Gene', (34, 43))	('silenced', 'Var', (8, 16))	('BEAS-2B', 'CellLine', 'CVCL:0168', (111, 118))	('overexpressed', 'PosReg', (20, 33))
355591	30693177	Ubiquitin expression was significantly decreased by circNOL10 overexpression and increased by silencing circNOL10 (Figure 4S-U).	('silencing', 'Var', (94, 103))	('Ubiquitin expression', 'MPA', (0, 20))	('expression', 'Species', '29278', (66, 76))	('circNOL10', 'Chemical', '-', (52, 61))	('expression', 'Species', '29278', (10, 20))	('circNOL10', 'Chemical', '-', (104, 113))	('decreased', 'NegReg', (39, 48))	('increased', 'PosReg', (81, 90))	('circNOL10', 'Gene', (104, 113))
355608	30693177	Silencing SCML1 resulted in a significant decrease in HN2 and HN8 expression levels, while SCML1 overexpression had the opposite effects (Figure 5Q).	('SCML1', 'Gene', '6322', (10, 15))	('HN2', 'Gene', (54, 57))	('HN8', 'Gene', (62, 65))	('expression levels', 'MPA', (66, 83))	('expression', 'Species', '29278', (66, 76))	('HN8', 'Gene', '100463486', (62, 65))	('SCML1', 'Gene', (91, 96))	('decrease', 'NegReg', (42, 50))	('expression', 'Species', '29278', (101, 111))	('HN2', 'Gene', '100462981', (54, 57))	('Silencing', 'Var', (0, 9))	('SCML1', 'Gene', (10, 15))	('SCML1', 'Gene', '6322', (91, 96))
355609	30693177	HN2 and HN8 expression levels were also reduced by silencing circNOL10 and increased by circNOL10 overexpression (Figure 5R).	('silencing', 'Var', (51, 60))	('HN2', 'Gene', '100462981', (0, 3))	('expression', 'Species', '29278', (102, 112))	('circNOL10', 'Chemical', '-', (61, 70))	('circNOL10', 'Gene', (61, 70))	('expression levels', 'MPA', (12, 29))	('HN2', 'Gene', (0, 3))	('reduced', 'NegReg', (40, 47))	('expression', 'Species', '29278', (12, 22))	('HN8', 'Gene', '100463486', (8, 11))	('HN8', 'Gene', (8, 11))	('increased', 'PosReg', (75, 84))	('circNOL10', 'Chemical', '-', (88, 97))
355614	30693177	We therefore explored the effects of HN and circNOL10 on mitochondrial function in lung cancer cells (H460 and A549 cells) by overexpressing HN2 and HN8 alone, silencing circNOL10 alone, and silencing circNOL10 combined with overexpressing HN2 and HN8, respectively.	('lung cancer', 'Disease', 'MESH:D008175', (83, 94))	('HN2', 'Gene', '100462981', (141, 144))	('silencing', 'Var', (191, 200))	('lung cancer', 'Phenotype', 'HP:0100526', (83, 94))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('HN2', 'Gene', (240, 243))	('A549', 'CellLine', 'CVCL:0023', (111, 115))	('circNOL10', 'Chemical', '-', (201, 210))	('HN8', 'Gene', (248, 251))	('circNOL10', 'Chemical', '-', (170, 179))	('HN2', 'Gene', (141, 144))	('circNOL10', 'Chemical', '-', (44, 53))	('HN8', 'Gene', (149, 152))	('lung cancer', 'Disease', (83, 94))	('HN8', 'Gene', '100463486', (248, 251))	('silencing', 'Var', (160, 169))	('HN2', 'Gene', '100462981', (240, 243))	('HN8', 'Gene', '100463486', (149, 152))	('circNOL10', 'Gene', (170, 179))
355616	30693177	Silencing circNOL10 alone caused a significant decrease in ROS and significant increases in MMP and total ATP levels, while overexpressing HN2 and HN8 alone had the opposite effects.	('HN2', 'Gene', (139, 142))	('increases', 'PosReg', (79, 88))	('ROS', 'Chemical', 'MESH:D017382', (59, 62))	('circNOL10', 'Chemical', '-', (10, 19))	('HN8', 'Gene', '100463486', (147, 150))	('HN8', 'Gene', (147, 150))	('decrease', 'NegReg', (47, 55))	('ATP', 'Chemical', 'MESH:D000255', (106, 109))	('circNOL10', 'Gene', (10, 19))	('HN2', 'Gene', '100462981', (139, 142))	('Silencing', 'Var', (0, 9))	('ROS', 'MPA', (59, 62))
355617	30693177	Silencing circNOL10 combined with overexpressing HN2 and HN8 induced a more significant increase in ROS and decreases in MMP and total ATP level compared with overexpressing HN2 and HN8 alone.	('HN2', 'Gene', '100462981', (174, 177))	('HN8', 'Gene', (57, 60))	('HN8', 'Gene', '100463486', (182, 185))	('circNOL10', 'Chemical', '-', (10, 19))	('HN8', 'Gene', (182, 185))	('HN8', 'Gene', '100463486', (57, 60))	('HN2', 'Gene', '100462981', (49, 52))	('ROS', 'Chemical', 'MESH:D017382', (100, 103))	('HN2', 'Gene', (174, 177))	('increase', 'PosReg', (88, 96))	('decreases', 'NegReg', (108, 117))	('circNOL10', 'Gene', (10, 19))	('HN2', 'Gene', (49, 52))	('Silencing', 'Var', (0, 9))	('ATP', 'Chemical', 'MESH:D000255', (135, 138))	('ROS', 'MPA', (100, 103))
355618	30693177	These results suggest that the HN family (HN2 and HN8) and circNOL10 can both modulate mitochondrial function in lung cancer cells, and circNOL10 may affect mitochondrial function by regulating the HN polypeptide family.	('circNOL10', 'Var', (136, 145))	('HN8', 'Gene', (50, 53))	('circNOL10', 'Chemical', '-', (136, 145))	('lung cancer', 'Disease', (113, 124))	('lung cancer', 'Phenotype', 'HP:0100526', (113, 124))	('mitochondrial function', 'MPA', (157, 179))	('HN2', 'Gene', '100462981', (42, 45))	('circNOL10', 'Chemical', '-', (59, 68))	('modulate', 'Reg', (78, 86))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('HN polypeptide', 'Enzyme', (198, 212))	('mitochondrial function', 'MPA', (87, 109))	('lung cancer', 'Disease', 'MESH:D008175', (113, 124))	('HN2', 'Gene', (42, 45))	('affect', 'Reg', (150, 156))	('HN8', 'Gene', '100463486', (50, 53))	('regulating', 'Reg', (183, 193))
355619	30693177	ROS are produced by aerobic metabolism, and can affect tumor cell apoptosis, proliferation, and cell cycle.30, 31 A decrease in MMP is a marker of the early stage of apoptosis,32 while changes in ATP levels are associated with abnormal tumor cell behaviors, including cell viability and apoptosis.33, 34 We therefore investigated the effects of the HN polypeptide family (HN2, HN8) and circNOL10 on the biological processes and behaviors of H460 and A549 lung cancer cells overexpressing HN2 and HN8 alone, with silencing of circNOL10 alone, or with silencing of circNOL10 combined with overexpressing HN2 and HN8, respectively.	('HN8', 'Gene', (496, 499))	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('investigated', 'Reg', (317, 329))	('HN8', 'Gene', (377, 380))	('circNOL10', 'Chemical', '-', (563, 572))	('HN2', 'Gene', '100462981', (372, 375))	('ATP', 'Chemical', 'MESH:D000255', (196, 199))	('tumor', 'Disease', 'MESH:D009369', (236, 241))	('HN2', 'Gene', '100462981', (602, 605))	('circNOL10', 'Chemical', '-', (386, 395))	('lung cancer', 'Phenotype', 'HP:0100526', (455, 466))	('HN8', 'Gene', '100463486', (496, 499))	('ROS', 'Chemical', 'MESH:D017382', (0, 3))	('HN8', 'Gene', '100463486', (377, 380))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('abnormal tumor', 'Disease', 'MESH:D009369', (227, 241))	('tumor', 'Phenotype', 'HP:0002664', (236, 241))	('HN2', 'Gene', (372, 375))	('HN2', 'Gene', (602, 605))	('silencing', 'Var', (512, 521))	('cancer', 'Phenotype', 'HP:0002664', (460, 466))	('A549 lung cancer', 'Disease', 'MESH:D008175', (450, 466))	('HN8', 'Gene', '100463486', (610, 613))	('HN2', 'Gene', '100462981', (488, 491))	('circNOL10', 'Gene', (563, 572))	('A549 lung cancer', 'Disease', (450, 466))	('abnormal tumor', 'Phenotype', 'HP:0002664', (227, 241))	('HN8', 'Gene', (610, 613))	('circNOL10', 'Chemical', '-', (525, 534))	('silencing', 'Var', (550, 559))	('tumor', 'Disease', (55, 60))	('HN2', 'Gene', (488, 491))	('abnormal tumor', 'Disease', (227, 241))	('tumor', 'Disease', (236, 241))
355621	30693177	Silencing circNOL10 alone significantly increased cell viability and proliferation, decreased apoptosis, shortened G0/G1, and prolonged S phase and G2/M phase, while overexpressing HN2 and HN8 alone had the opposite effects.	('S phase', 'CPA', (136, 143))	('shortened', 'NegReg', (105, 114))	('prolonged', 'PosReg', (126, 135))	('circNOL10', 'Chemical', '-', (10, 19))	('HN2', 'Gene', '100462981', (181, 184))	('Silencing', 'Var', (0, 9))	('HN8', 'Gene', (189, 192))	('G2/M phase', 'CPA', (148, 158))	('HN8', 'Gene', '100463486', (189, 192))	('circNOL10', 'Gene', (10, 19))	('increased', 'PosReg', (40, 49))	('HN2', 'Gene', (181, 184))	('cell viability', 'CPA', (50, 64))	('decreased', 'NegReg', (84, 93))	('apoptosis', 'CPA', (94, 103))	('G0/G1', 'CPA', (115, 120))
355622	30693177	Compared with silencing circNOL10 alone, silencing circNOL10 combined with overexpressing HN2 and HN8 significantly decreased cell viability and proliferation, increased cell apoptosis, prolonged G0/G1 phase, and shortened S and G2/M phases.	('cell viability', 'CPA', (126, 140))	('silencing', 'Var', (41, 50))	('HN8', 'Gene', '100463486', (98, 101))	('HN8', 'Gene', (98, 101))	('increased', 'PosReg', (160, 169))	('shortened', 'NegReg', (213, 222))	('circNOL10', 'Chemical', '-', (24, 33))	('HN2', 'Gene', '100462981', (90, 93))	('proliferation', 'CPA', (145, 158))	('circNOL10', 'Chemical', '-', (51, 60))	('circNOL10', 'Gene', (51, 60))	('prolonged', 'PosReg', (186, 195))	('G0/G1 phase', 'CPA', (196, 207))	('HN2', 'Gene', (90, 93))	('decreased', 'NegReg', (116, 125))	('cell apoptosis', 'CPA', (170, 184))
355623	30693177	Compared with overexpressing HN2 and HN8 alone, the combined treatment had the opposite effects to those observed with silencing circNOL10 alone.	('HN8', 'Gene', '100463486', (37, 40))	('circNOL10', 'Chemical', '-', (129, 138))	('HN8', 'Gene', (37, 40))	('HN2', 'Gene', (29, 32))	('silencing', 'Var', (119, 128))	('HN2', 'Gene', '100462981', (29, 32))
355628	30693177	We examined these 16 biomarkers in H460 and A549 cells with western blotting after silencing circNOL10 alone, overexpressing HN2 and HN8 alone, or silencing circNOL10 combined with overexpressing HN2 and HN8 (group 1: Figure  7 A-D; group 2: Figure 7E-J).	('circNOL10', 'Chemical', '-', (157, 166))	('HN8', 'Gene', '100463486', (204, 207))	('HN8', 'Gene', '100463486', (133, 136))	('HN8', 'Gene', (133, 136))	('silencing', 'Var', (83, 92))	('HN2', 'Gene', '100462981', (196, 199))	('circNOL10', 'Gene', (157, 166))	('HN2', 'Gene', '100462981', (125, 128))	('HN2', 'Gene', (196, 199))	('circNOL10', 'Chemical', '-', (93, 102))	('A549', 'CellLine', 'CVCL:0023', (44, 48))	('HN8', 'Gene', (204, 207))	('HN2', 'Gene', (125, 128))	('silencing', 'Var', (147, 156))
355629	30693177	Silencing circNOL10 alone decreased expression levels of ten biomarkers (POLE, MLH3, MSH2, p53, P-p53, CKEK2, P-CHEK2, P-CDC25A, Rb, and P-E2F1) and increased six (LIG4, CDC25A, CCND1, CDK2, P-Rb, and E2F1), while overexpressing HN2 and HN8 had the opposite effects.	('CDC25A', 'Gene', '993', (170, 176))	('CCND1', 'Gene', '595', (178, 183))	('E2F1', 'Gene', '1869', (201, 205))	('biomarkers', 'MPA', (61, 71))	('increased', 'PosReg', (149, 158))	('E2F1', 'Gene', '1869', (139, 143))	('LIG4', 'Gene', (164, 168))	('circNOL10', 'Gene', (10, 19))	('p53', 'Gene', (98, 101))	('CDK2', 'Gene', '1017', (185, 189))	('CDC25A', 'Gene', (121, 127))	('HN2', 'Gene', '100462981', (229, 232))	('CCND1', 'Gene', (178, 183))	('decreased', 'NegReg', (26, 35))	('Silencing', 'Var', (0, 9))	('CDC25A', 'Gene', (170, 176))	('CDK2', 'Gene', (185, 189))	('P-Rb', 'Gene', '5925', (191, 195))	('MLH3', 'Gene', '27030', (79, 83))	('MLH3', 'Gene', (79, 83))	('LIG4', 'Gene', '3981', (164, 168))	('P-CHEK2', 'Disease', 'MESH:C000656865', (110, 117))	('expression', 'Species', '29278', (36, 46))	('MSH2', 'Gene', (85, 89))	('HN2', 'Gene', (229, 232))	('HN8', 'Gene', (237, 240))	('circNOL10', 'Chemical', '-', (10, 19))	('P-Rb', 'Gene', (191, 195))	('p53', 'Gene', '7157', (91, 94))	('P-CHEK2', 'Disease', (110, 117))	('expression levels', 'MPA', (36, 53))	('E2F1', 'Gene', (201, 205))	('MSH2', 'Gene', '4436', (85, 89))	('E2F1', 'Gene', (139, 143))	('HN8', 'Gene', '100463486', (237, 240))	('p53', 'Gene', (91, 94))	('CDC25A', 'Gene', '993', (121, 127))	('p53', 'Gene', '7157', (98, 101))
355630	30693177	Combined treatment increased the ten biomarkers and decreased the six compared with silencing circNOL10 alone, and had the opposite effects compared with overexpressing HN2 and HN8 alone.	('decreased', 'NegReg', (52, 61))	('silencing', 'Var', (84, 93))	('HN2', 'Gene', '100462981', (169, 172))	('increased', 'PosReg', (19, 28))	('six', 'MPA', (66, 69))	('HN8', 'Gene', (177, 180))	('circNOL10', 'Chemical', '-', (94, 103))	('circNOL10', 'Gene', (94, 103))	('HN2', 'Gene', (169, 172))	('HN8', 'Gene', '100463486', (177, 180))	('ten biomarkers', 'MPA', (33, 47))
355646	30693177	High ubiquitination of proteins in the cell can promote their degradation, and increased protein expression is sometimes due to inhibition of ubiquitination.23, 24 The current study showed that circNOL10 enhanced SCML1 expression by inhibiting ubiquitination of the transcription factor SCML1.	('SCML1', 'Gene', '6322', (213, 218))	('expression', 'Species', '29278', (219, 229))	('SCML1', 'Gene', '6322', (287, 292))	('expression', 'MPA', (219, 229))	('SCML1', 'Gene', (213, 218))	('inhibiting', 'NegReg', (233, 243))	('SCML1', 'Gene', (287, 292))	('ubiquitination', 'MPA', (244, 258))	('expression', 'Species', '29278', (97, 107))	('circNOL10', 'Var', (194, 203))	('enhanced', 'PosReg', (204, 212))	('circNOL10', 'Chemical', '-', (194, 203))
355650	30693177	The mitochondria are responsible for cellular energy metabolism, and abnormalities in mitochondrial function also contribute to tumor development.29, 30 We detected biomarkers of mitochondrial function and key molecules involved in proliferation, apoptosis, and cell cycle signaling pathways, and showed that circNOL10 inhibited cell proliferation and cell cycle progression, and promoted apoptosis in lung cancer cells.	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('circNOL10', 'Var', (309, 318))	('cell proliferation', 'CPA', (329, 347))	('lung cancer', 'Disease', (402, 413))	('circNOL10', 'Chemical', '-', (309, 318))	('lung cancer', 'Phenotype', 'HP:0100526', (402, 413))	('promoted', 'PosReg', (380, 388))	('inhibited', 'NegReg', (319, 328))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('cancer', 'Phenotype', 'HP:0002664', (407, 413))	('cell cycle progression', 'CPA', (352, 374))	('tumor', 'Disease', (128, 133))	('abnormalities in mitochondrial function', 'Phenotype', 'HP:0003287', (69, 108))	('lung cancer', 'Disease', 'MESH:D008175', (402, 413))	('apoptosis', 'CPA', (389, 398))
355654	30693177	Furthermore, we showed that circNOL10 inhibited lung cancer by enhancing transcriptional regulation of the HN polypeptide family by SCML1.	('lung cancer', 'Disease', 'MESH:D008175', (48, 59))	('circNOL10', 'Var', (28, 37))	('enhancing', 'PosReg', (63, 72))	('circNOL10', 'Chemical', '-', (28, 37))	('SCML1', 'Gene', (132, 137))	('inhibited', 'NegReg', (38, 47))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('SCML1', 'Gene', '6322', (132, 137))	('lung cancer', 'Disease', (48, 59))	('lung cancer', 'Phenotype', 'HP:0100526', (48, 59))	('transcriptional regulation', 'MPA', (73, 99))
355657	30693177	circNOL10 downregulation in lung cancer cells was co-regulated by Pre-NOL10 methylation and the splicing factor ESRP1.	('NOL10', 'Gene', (4, 9))	('circNOL10', 'Chemical', '-', (0, 9))	('lung cancer', 'Disease', 'MESH:D008175', (28, 39))	('NOL10', 'Gene', '79954', (4, 9))	('NOL10', 'Gene', '79954', (70, 75))	('NOL10', 'Gene', (70, 75))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('lung cancer', 'Disease', (28, 39))	('methylation', 'Var', (76, 87))	('downregulation', 'NegReg', (10, 24))	('ESRP1', 'Gene', '54845', (112, 117))	('lung cancer', 'Phenotype', 'HP:0100526', (28, 39))	('ESRP1', 'Gene', (112, 117))
355709	25527865	Detection of ALK protein expression in lung squamous cell carcinomas by immunohistochemistry The echinoderm microtubule-associated protein-like 4 (EML4) gene and the anaplastic lymphoma kinase (ALK) gene rearrangements occur in approximately 5% of lung adenocarcimomas (ACA), leading to ALK overexpression and predicting response to targeted therapy.	('lung squamous cell carcinomas', 'Disease', 'MESH:D002294', (39, 68))	('anaplastic lymphoma', 'Disease', (166, 185))	('ALK', 'Gene', (13, 16))	('overexpression', 'PosReg', (291, 305))	('lung adenocarcimomas', 'Disease', (248, 268))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (44, 68))	('EML4', 'Gene', (147, 151))	('lymphoma', 'Phenotype', 'HP:0002665', (177, 185))	('lung squamous cell carcinomas', 'Disease', (39, 68))	('echinoderm microtubule-associated protein-like 4', 'Gene', '27436', (97, 145))	('ALK', 'Gene', '238', (194, 197))	('EML4', 'Gene', '27436', (147, 151))	('rearrangements', 'Var', (204, 218))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (39, 67))	('ALK', 'Gene', (194, 197))	('echinoderm microtubule-associated protein-like 4', 'Gene', (97, 145))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (44, 67))	('anaplastic lymphoma', 'Disease', 'MESH:D017728', (166, 185))	('ALK', 'Gene', '238', (287, 290))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (166, 185))	('lung adenocarcimomas', 'Disease', 'MESH:D008171', (248, 268))	('ALK', 'Gene', (287, 290))	('ALK', 'Gene', '238', (13, 16))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))	('carcinomas', 'Phenotype', 'HP:0030731', (58, 68))
355717	25527865	Although the frequency of EML4-ALK rearrangements is lower in lung SqCC than that in lung adenocarcinomas, their presence may provide additional treatment options in lung SqCC.	('ALK', 'Gene', '238', (31, 34))	('SqCC', 'Phenotype', 'HP:0002860', (67, 71))	('lung SqCC', 'Disease', (166, 175))	('SqCC', 'Phenotype', 'HP:0002860', (171, 175))	('EML4', 'Gene', (26, 30))	('rearrangements', 'Var', (35, 49))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (85, 104))	('EML4', 'Gene', '27436', (26, 30))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (85, 105))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('ALK', 'Gene', (31, 34))	('presence', 'Var', (113, 121))	('carcinomas', 'Phenotype', 'HP:0030731', (95, 105))	('lung adenocarcinomas', 'Disease', (85, 105))	('lung SqCC', 'Disease', (62, 71))	('lower', 'NegReg', (53, 58))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (85, 105))
355728	25527865	Specifically, the discovery of the biologic and therapeutic importance of acquired genetic alterations in 2 genes that encode pharmacologically targetable tyrosine kinases involved in growth factor receptor signaling, epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK), has changed the way these cancers are diagnosed and treated.	('epidermal growth factor receptor', 'Gene', (218, 250))	('changed', 'Reg', (300, 307))	('genetic alterations', 'Var', (83, 102))	('anaplastic lymphoma', 'Disease', (262, 281))	('ALK', 'Gene', (290, 293))	('epidermal growth factor receptor', 'Gene', '1956', (218, 250))	('rat', 'Species', '10116', (95, 98))	('cancers', 'Disease', 'MESH:D009369', (322, 329))	('cancers', 'Phenotype', 'HP:0002664', (322, 329))	('lymphoma', 'Phenotype', 'HP:0002665', (273, 281))	('cancers', 'Disease', (322, 329))	('anaplastic lymphoma', 'Disease', 'MESH:D017728', (262, 281))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (262, 281))	('ALK', 'Gene', '238', (290, 293))	('cancer', 'Phenotype', 'HP:0002664', (322, 328))	('EGFR', 'Gene', '1956', (252, 256))	('EGFR', 'Gene', (252, 256))
355729	25527865	It is well known that mutations of the epidermal growth factor receptor (EGFR) gene are present in some patients with lung adenocarcinoma, with the implication that patients with this genotype were super responders to EGFR-tyrosine kinase inhibitors (TKIs), including gefitinib and erlotinib.	('erlotinib', 'Chemical', 'MESH:D000069347', (282, 291))	('EGFR', 'Gene', '1956', (73, 77))	('epidermal growth factor receptor', 'Gene', '1956', (39, 71))	('gefitinib', 'Chemical', 'MESH:D000077156', (268, 277))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('lung adenocarcinoma', 'Disease', (118, 137))	('EGFR', 'Gene', (73, 77))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (118, 137))	('EGFR', 'Gene', '1956', (218, 222))	('mutations', 'Var', (22, 31))	('patients', 'Species', '9606', (165, 173))	('EGFR', 'Gene', (218, 222))	('patients', 'Species', '9606', (104, 112))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (118, 137))	('epidermal growth factor receptor', 'Gene', (39, 71))
355730	25527865	In patients with a somatic EGFR mutation, frontline treatment with an EGFR inhibitor, gefitinib, results in improved response rate and superior progression-free survival.	('response', 'MPA', (117, 125))	('EGFR', 'Gene', '1956', (27, 31))	('EGFR', 'Gene', (27, 31))	('progression-free survival', 'CPA', (144, 169))	('superior', 'PosReg', (135, 143))	('EGFR', 'Gene', '1956', (70, 74))	('improved', 'PosReg', (108, 116))	('gefitinib', 'Chemical', 'MESH:D000077156', (86, 95))	('EGFR', 'Gene', (70, 74))	('patients', 'Species', '9606', (3, 11))	('rat', 'Species', '10116', (126, 129))	('mutation', 'Var', (32, 40))
355731	25527865	This benefit is limited to patients with EGFR mutation, as patients without the mutation have better overall response rates and progression-free survival with combination chemotherapy.	('EGFR', 'Gene', (41, 45))	('rat', 'Species', '10116', (118, 121))	('patients', 'Species', '9606', (27, 35))	('patients', 'Species', '9606', (59, 67))	('better', 'PosReg', (94, 100))	('EGFR', 'Gene', '1956', (41, 45))	('mutation', 'Var', (46, 54))
355734	25527865	In addition to anaplastic large-cell lymphoma, ALK fusion genes have also been described in half of the inflammatory myofibroblastic tumors and rare ALK-positive diffuse large B-cell lymphomas.	('ALK', 'Gene', (47, 50))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('lymphoma', 'Disease', (37, 45))	('lymphoma', 'Phenotype', 'HP:0002665', (183, 191))	('anaplastic large-cell lymphoma', 'Phenotype', 'HP:0012193', (15, 45))	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('lymphoma', 'Disease', 'MESH:D008223', (37, 45))	('lymphomas', 'Disease', (183, 192))	('fusion genes', 'Var', (51, 63))	('B-cell lymphomas', 'Phenotype', 'HP:0012191', (176, 192))	('cell lymphoma', 'Phenotype', 'HP:0012191', (178, 191))	('tumors', 'Disease', (133, 139))	('lymphoma', 'Disease', (183, 191))	('lymphoma', 'Disease', 'MESH:D008223', (183, 191))	('described', 'Reg', (79, 88))	('tumors', 'Disease', 'MESH:D009369', (133, 139))	('lymphoma', 'Phenotype', 'HP:0002665', (37, 45))	('ALK', 'Gene', '238', (149, 152))	('lymphomas', 'Disease', 'MESH:D008223', (183, 192))	('myofibroblastic tumors', 'Phenotype', 'HP:0020135', (117, 139))	('ALK', 'Gene', (149, 152))	('lymphomas', 'Phenotype', 'HP:0002665', (183, 192))	('cell lymphoma', 'Phenotype', 'HP:0012191', (32, 45))	('ALK', 'Gene', '238', (47, 50))
355735	25527865	Recently, by screening a retroviral complementary DNA expression library generated from a NSCLC patient tumor sample, a rearrangements in the anaplastic lymphoma kinase gene (ALK) and echinoderm microtubule-associated protein-like 4 (EML4) have been identified as a result of a small inversion within the short arm of chromosome 2 between the N -terminal half of EML4 and the intracellular kinase domain of ALK.	('rearrangements', 'Var', (120, 134))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('EML4', 'Gene', (363, 367))	('anaplastic lymphoma kinase gene', 'Gene', '238', (142, 173))	('EML4', 'Gene', '27436', (363, 367))	('patient', 'Species', '9606', (96, 103))	('echinoderm microtubule-associated protein-like 4', 'Gene', '27436', (184, 232))	('anaplastic lymphoma kinase gene', 'Gene', (142, 173))	('lymphoma', 'Phenotype', 'HP:0002665', (153, 161))	('rat', 'Species', '10116', (77, 80))	('EML4', 'Gene', (234, 238))	('short arm', 'Phenotype', 'HP:0009824', (305, 314))	('ALK', 'Gene', '238', (407, 410))	('EML4', 'Gene', '27436', (234, 238))	('echinoderm microtubule-associated protein-like 4', 'Gene', (184, 232))	('ALK', 'Gene', (407, 410))	('tumor', 'Disease', (104, 109))	('NSCLC', 'Disease', 'MESH:D002289', (90, 95))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('ALK', 'Gene', '238', (175, 178))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (142, 161))	('ALK', 'Gene', (175, 178))	('NSCLC', 'Disease', (90, 95))	('NSCLC', 'Phenotype', 'HP:0030358', (90, 95))
355736	25527865	EML4-ALK rearrangement has been demonstrated to be a potent oncogenic drive and a promising therapeutic target in NSCLC.	('NSCLC', 'Phenotype', 'HP:0030358', (114, 119))	('ALK', 'Gene', (5, 8))	('EML4', 'Gene', (0, 4))	('NSCLC', 'Disease', (114, 119))	('rat', 'Species', '10116', (39, 42))	('ALK', 'Gene', '238', (5, 8))	('EML4', 'Gene', '27436', (0, 4))	('NSCLC', 'Disease', 'MESH:D002289', (114, 119))	('rearrangement', 'Var', (9, 22))	('oncogenic', 'CPA', (60, 69))
355739	25527865	ALK rearrangement-positive patients treated with a novel ALK inhibitor, crizotinib, showed an overall response rate of 57%, with 72% having a PFS of 6 months or greater.	('rat', 'Species', '10116', (111, 114))	('ALK', 'Gene', (57, 60))	('patients', 'Species', '9606', (27, 35))	('ALK', 'Gene', (0, 3))	('crizotinib', 'Chemical', 'MESH:D000077547', (72, 82))	('ALK', 'Gene', '238', (57, 60))	('rearrangement-positive', 'Var', (4, 26))	('ALK', 'Gene', '238', (0, 3))
355742	25527865	Notably, the vast majority of ALK gene rearrangements were observed in lung adenocarcinoma specimens.	('ALK', 'Gene', (30, 33))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (71, 90))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (71, 90))	('lung adenocarcinoma', 'Disease', (71, 90))	('ALK', 'Gene', '238', (30, 33))	('rearrangements', 'Var', (39, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('observed', 'Reg', (59, 67))
355743	25527865	The incidence of ALK gene rearrangements in lung SqCC has not been well documented except few cases were reported.	('ALK', 'Gene', '238', (17, 20))	('SqCC', 'Phenotype', 'HP:0002860', (49, 53))	('ALK', 'Gene', (17, 20))	('lung SqCC', 'Disease', (44, 53))	('rearrangements', 'Var', (26, 40))
355781	25527865	Although strong staining seems to be 100% specific for the presence of rearrangement by FISH, weak-to-intermediate staining has been reported in FISH-negative tumors.	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('tumors', 'Phenotype', 'HP:0002664', (159, 165))	('tumors', 'Disease', (159, 165))	('tumors', 'Disease', 'MESH:D009369', (159, 165))	('rearrangement', 'Var', (71, 84))
355787	25527865	ALK rearrangements have been reported to occur at frequencies that range from 0.4 to 15% in NSCLC.	('rearrangements', 'Var', (4, 18))	('NSCLC', 'Phenotype', 'HP:0030358', (92, 97))	('ALK', 'Gene', (0, 3))	('NSCLC', 'Disease', (92, 97))	('NSCLC', 'Disease', 'MESH:D002289', (92, 97))	('ALK', 'Gene', '238', (0, 3))
355797	25527865	Although the frequency of these mutations is lower in lung SqCC than that in lung adenocarcinomas, their presence may provide additional treatment options in this group.	('lung SqCC', 'Disease', (54, 63))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (77, 96))	('SqCC', 'Phenotype', 'HP:0002860', (59, 63))	('carcinomas', 'Phenotype', 'HP:0030731', (87, 97))	('lung adenocarcinomas', 'Disease', (77, 97))	('mutations', 'Var', (32, 41))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (77, 97))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (77, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))
355844	33277966	Mutation analysis revealed that many prognosis-related lipid metabolism genes had missense mutations (Figure 3).	('lipid', 'Chemical', 'MESH:D008055', (55, 60))	('missense mutations', 'Var', (82, 100))	('prognosis-related lipid metabolism genes', 'Gene', (37, 77))
355860	33277966	Multiple studies have shown that aberrant lipid metabolism influences HNSCC tumorigenesis.	('lipid', 'Chemical', 'MESH:D008055', (42, 47))	('HNSCC', 'Phenotype', 'HP:0012288', (70, 75))	('influences', 'Reg', (59, 69))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('HNSCC tumor', 'Disease', 'MESH:D000077195', (70, 81))	('aberrant', 'Var', (33, 41))	('HNSCC tumor', 'Disease', (70, 81))
355890	33277966	45  Together, these findings indicate that abnormal lipid metabolism may affect the number and function of tumor immune cells.	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('affect', 'Reg', (73, 79))	('lipid', 'Chemical', 'MESH:D008055', (52, 57))	('lipid metabolism', 'MPA', (52, 68))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('abnormal', 'Var', (43, 51))
355897	33277966	In summary, we conducted a comprehensive analysis of HNSCC mutations, the regulatory mechanisms of lipid metabolism-related genes, the relationship between these genes and clinical prognosis and immune infiltration, and determined the genes' prognostic value.	('HNSCC', 'Phenotype', 'HP:0012288', (53, 58))	('lipid', 'Chemical', 'MESH:D008055', (99, 104))	('HNSCC', 'Gene', (53, 58))	('mutations', 'Var', (59, 68))
355900	28906590	 FGF19 genetic amplification as a potential therapeutic target in lung squamous cell carcinomas Although FGF 19 gene aberrations are associated with carcinogenesis and progression in human cancers, the roles of FGF 19 genetic amplification and expression in Chinese patients with lung squamous cell carcinoma (LSCC) and FGF 19 amplification as a potential therapeutic target for LSCC are not well understood.	('FGF 19', 'Gene', '9965', (320, 326))	('carcinogenesis', 'Disease', (149, 163))	('lung squamous cell carcinomas', 'Disease', (66, 95))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (71, 94))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (66, 94))	('FGF 19', 'Gene', '9965', (105, 111))	('carcinogenesis', 'Disease', 'MESH:D063646', (149, 163))	('FGF 19', 'Gene', (211, 217))	('cancers', 'Disease', 'MESH:D009369', (189, 196))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (280, 308))	('lung squamous cell carcinoma', 'Disease', (280, 308))	('aberrations', 'Var', (117, 128))	('patients', 'Species', '9606', (266, 274))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (285, 308))	('FGF 19', 'Gene', (320, 326))	('human', 'Species', '9606', (183, 188))	('FGF 19', 'Gene', (105, 111))	('associated', 'Reg', (133, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (299, 308))	('FGF19', 'Gene', '9965', (1, 6))	('lung squamous cell carcinomas', 'Disease', 'MESH:D002294', (66, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('FGF19', 'Gene', (1, 6))	('cancers', 'Phenotype', 'HP:0002664', (189, 196))	('carcinomas', 'Phenotype', 'HP:0030731', (85, 95))	('cancers', 'Disease', (189, 196))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (71, 95))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (66, 94))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('FGF 19', 'Gene', '9965', (211, 217))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (280, 308))
355901	28906590	Fluorescence in situ hybridization analysis and quantitative real-time-PCR was used to detect FGF 19 genetic amplification and FGF 19 messenger RNA expression in LSCC tumor and paired adjacent samples.	('messenger RNA expression', 'MPA', (134, 158))	('FGF 19', 'Gene', (127, 133))	('FGF 19', 'Gene', '9965', (94, 100))	('genetic amplification', 'Var', (101, 122))	('FGF 19', 'Gene', (94, 100))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('LSCC', 'Disease', (162, 166))	('tumor', 'Disease', (167, 172))	('FGF 19', 'Gene', '9965', (127, 133))
355904	28906590	Small interfering RNA knockdown of FGF 19 led to the significant inhibition of cell growth and induced apoptosis in LSCC cells carrying the amplified FGF 19 gene, but these effects was not observed in non-amplified LSCC cells.	('inhibition', 'NegReg', (65, 75))	('FGF 19', 'Gene', '9965', (35, 41))	('FGF 19', 'Gene', (35, 41))	('knockdown', 'Var', (22, 31))	('FGF 19', 'Gene', '9965', (150, 156))	('apoptosis', 'CPA', (103, 112))	('FGF 19', 'Gene', (150, 156))	('cell growth', 'CPA', (79, 90))
355905	28906590	Interfering FGF 19 expression with short hairpin RNA also resulted in tumor growth inhibition and induced apoptosis in LSCC xenografts with amplified FGF 19 in tumor cells.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('LSCC', 'Disease', (119, 123))	('induced', 'Reg', (98, 105))	('tumor', 'Disease', (70, 75))	('apoptosis', 'CPA', (106, 115))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('FGF 19', 'Gene', '9965', (12, 18))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('FGF 19', 'Gene', '9965', (150, 156))	('FGF 19', 'Gene', (12, 18))	('FGF 19', 'Gene', (150, 156))	('tumor', 'Disease', (160, 165))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('amplified', 'Var', (140, 149))
355907	28906590	Intervention of FGF 19 activation could be a potential therapeutic strategy for LSCC patients with FGF 19 amplification.	('FGF 19', 'Gene', '9965', (16, 22))	('patients', 'Species', '9606', (85, 93))	('amplification', 'Var', (106, 119))	('FGF 19', 'Gene', (16, 22))	('FGF 19', 'Gene', '9965', (99, 105))	('FGF 19', 'Gene', (99, 105))	('LSCC', 'Disease', (80, 84))
355911	28906590	A number of candidates have been identified as potential clinical targets for cancer treatment, including amplification of SOX2, PDGFR2, FGFR1 and deletion of CDKN2A, and recurrent mutations in TP53, KLHL19, NRF2, CDC4, GPRC1H, MUC16, RUNX1T1, BAI3, LKB1, and HER4 genes.8, 9, 10, 11 However, no effective targeted agents have emerged based on these related targets/pathways.	('CDC4', 'Gene', (214, 218))	('GPRC1H', 'Gene', '2918', (220, 226))	('BAI3', 'Gene', '577', (244, 248))	('LKB1', 'Gene', '6794', (250, 254))	('PDGFR2', 'Gene', (129, 135))	('HER4', 'Gene', (260, 264))	('MUC16', 'Gene', (228, 233))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('FGFR1', 'Gene', (137, 142))	('KLHL19', 'Gene', (200, 206))	('RUNX1T1', 'Gene', '862', (235, 242))	('CDC4', 'Gene', '55294', (214, 218))	('NRF2', 'Gene', '4780', (208, 212))	('TP53', 'Gene', (194, 198))	('LKB1', 'Gene', (250, 254))	('CDKN2A', 'Gene', (159, 165))	('GPRC1H', 'Gene', (220, 226))	('PDGFR2', 'Gene', '5156', (129, 135))	('RUNX1T1', 'Gene', (235, 242))	('HER4', 'Gene', '2066', (260, 264))	('cancer', 'Disease', (78, 84))	('deletion', 'Var', (147, 155))	('KLHL19', 'Gene', '9817', (200, 206))	('NRF2', 'Gene', (208, 212))	('FGFR1', 'Gene', '2260', (137, 142))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('MUC16', 'Gene', '94025', (228, 233))	('BAI3', 'Gene', (244, 248))	('CDKN2A', 'Gene', '1029', (159, 165))	('TP53', 'Gene', '7157', (194, 198))	('SOX2', 'Gene', '6657', (123, 127))	('SOX2', 'Gene', (123, 127))
355913	28906590	15 A previous study suggested that the FGF19-FGFR4 signaling axis may be a crucial player, contributing to the development of a certain type of hepatocellular carcinoma (HCC), drawing great attention to therapeutic intervention of the FGF19/FGFR4 autocrine loop in this disease setting.16, 17 Small interfering RNA (siRNA)-mediated silencing of FGF19 was also reported to decrease AKT phosphorylation, inhibit cancer cell growth, and sensitize doxorubicin treatment in both FGFR4 and FGF19 positive breast cancer cells.	('FGFR4', 'Gene', '2264', (241, 246))	('AKT', 'Gene', (381, 384))	('FGFR4', 'Gene', (45, 50))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (144, 168))	('silencing', 'Var', (332, 341))	('breast cancer', 'Phenotype', 'HP:0003002', (499, 512))	('cancer', 'Disease', 'MESH:D009369', (506, 512))	('FGFR4', 'Gene', (241, 246))	('carcinoma', 'Phenotype', 'HP:0030731', (159, 168))	('hepatocellular carcinoma', 'Disease', (144, 168))	('cancer', 'Disease', 'MESH:D009369', (410, 416))	('inhibit', 'NegReg', (402, 409))	('breast cancer', 'Disease', 'MESH:D001943', (499, 512))	('FGF19', 'Gene', (345, 350))	('breast cancer', 'Disease', (499, 512))	('AKT', 'Gene', '207', (381, 384))	('FGFR4', 'Gene', '2264', (474, 479))	('FGFR4', 'Gene', (474, 479))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (144, 168))	('cancer', 'Disease', (506, 512))	('FGFR4', 'Gene', '2264', (45, 50))	('sensitize', 'Reg', (434, 443))	('cancer', 'Disease', (410, 416))	('cancer', 'Phenotype', 'HP:0002664', (506, 512))	('decrease', 'NegReg', (372, 380))	('cancer', 'Phenotype', 'HP:0002664', (410, 416))	('doxorubicin treatment', 'MPA', (444, 465))
355926	28906590	Quantitative real-time-PCR was performed using FGF19 TaqMan assay Hs00192780_m1 and glyceraldehyde 3-phosphate dehydrogenase (GAPDH) TaqMan assay Hs99999905_m1 (Invitrogen, Carlsbad, CA, USA) on an ABI 7500 instrument (Applied Biosystems).	('Hs00192780_m1', 'Var', (66, 79))	('GAPDH', 'Gene', (126, 131))	('glyceraldehyde 3-phosphate dehydrogenase', 'Gene', '2597', (84, 124))	('glyceraldehyde 3-phosphate dehydrogenase', 'Gene', (84, 124))	('Hs99999905_m1', 'Var', (146, 159))	('GAPDH', 'Gene', '2597', (126, 131))
355929	28906590	Western blot analysis was conducted using 20 mug of cell lysates in radioimmunoprecipitation assay buffer and the proteins were examined with monoclonal antibodies directed against FGF19 (83 348), p-FRS2 (3961), AKT (11 962), p-AKT (9271), ERK (4695), p-ERK (12 638), cleaved-Caspase 3 (CC3; 9661) and anti-GAPDH (5174, Cell Signaling Technology, Danvers, MA, USA), and FRS2 (ab10425), FGFR4 (ab5841), and p-FGFR4 (ab192589, Abcam, Cambridge, UK).	('AKT', 'Gene', (228, 231))	('GAPDH', 'Gene', (307, 312))	('FGFR4', 'Gene', (386, 391))	('ERK', 'Gene', '5594', (240, 243))	('FGFR4', 'Gene', (408, 413))	('AKT', 'Gene', (212, 215))	('CC3', 'Chemical', '-', (287, 290))	('FRS2', 'Gene', '10818', (370, 374))	('ERK', 'Gene', '5594', (254, 257))	('FRS2', 'Gene', (199, 203))	('ERK', 'Gene', (240, 243))	('AKT', 'Gene', '207', (228, 231))	('ab10425', 'Var', (376, 383))	('AKT', 'Gene', '207', (212, 215))	('p-ERK', 'Gene', '9451', (252, 257))	('p-ERK', 'Gene', (252, 257))	('ERK', 'Gene', (254, 257))	('GAPDH', 'Gene', '2597', (307, 312))	('FGFR4', 'Gene', '2264', (386, 391))	('FRS2', 'Gene', '10818', (199, 203))	('FGFR4', 'Gene', '2264', (408, 413))	('FRS2', 'Gene', (370, 374))
355952	28906590	Importantly, we also observed that all 15 tumor tissues with amplified FGF19 genes had upregulated FGF19 mRNA expression.	('tumor', 'Disease', (42, 47))	('FGF19 genes', 'Gene', (71, 82))	('FGF19', 'Gene', (99, 104))	('mRNA expression', 'MPA', (105, 120))	('amplified', 'Var', (61, 70))	('upregulated', 'PosReg', (87, 98))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
355953	28906590	To test the potential role of FGF19 on LSCC cell growth, we determined that EPLC-272H lung squamous cancer cells carry FGF19 amplification (Fig 2a).	('amplification', 'Var', (125, 138))	('EPLC-272H lung squamous cancer', 'Disease', (76, 106))	('FGF19', 'Gene', (119, 124))	('lung squamous cancer', 'Phenotype', 'HP:0030359', (86, 106))	('squamous cancer', 'Phenotype', 'HP:0002860', (91, 106))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('EPLC-272H lung squamous cancer', 'Disease', 'MESH:D008175', (76, 106))
355956	28906590	CC3 expression indicated that the cell apoptotic level was also elevated in EPLC-272H with siRNA.	('elevated', 'PosReg', (64, 72))	('CC3', 'Chemical', '-', (0, 3))	('CC3', 'Gene', (0, 3))	('expression', 'MPA', (4, 14))	('cell apoptotic level', 'CPA', (34, 54))	('EPLC-272H', 'Var', (76, 85))	('EPLC-272H', 'CellLine', 'CVCL:1197', (76, 85))
355958	28906590	We next determined the effects of FGF19 knockdown on the downstream signaling pathways in EPLC-272H cells.	('FGF19', 'Gene', (34, 39))	('knockdown', 'Var', (40, 49))	('EPLC-272H', 'CellLine', 'CVCL:1197', (90, 99))
355960	28906590	As expected, we found that phosphorylation levels of FRS2, FGFR4, AKT, and ERK1/2 were significantly reduced in cells with FGF19 knockdown compared to control cells that were not treated with siRNA (Fig 4).	('FGFR4', 'Gene', (59, 64))	('AKT', 'Gene', (66, 69))	('FRS2', 'Gene', '10818', (53, 57))	('FGF19', 'Gene', (123, 128))	('knockdown', 'Var', (129, 138))	('ERK1/2', 'Gene', '5595;5594', (75, 81))	('reduced', 'NegReg', (101, 108))	('phosphorylation levels', 'MPA', (27, 49))	('FRS2', 'Gene', (53, 57))	('ERK1/2', 'Gene', (75, 81))	('AKT', 'Gene', '207', (66, 69))	('FGFR4', 'Gene', '2264', (59, 64))
355963	28906590	FGF19 expression can be modulated by shRNA in EPLC-272H cells and an in vitro proliferation assay showed that shRNA knockdown of FGF19 expression significantly reduced the proliferation of EPLC-272H cells (Fig 5).	('proliferation', 'CPA', (172, 185))	('EPLC-272H', 'CellLine', 'CVCL:1197', (46, 55))	('FGF19', 'Gene', (0, 5))	('knockdown', 'Var', (116, 125))	('reduced', 'NegReg', (160, 167))	('EPLC-272H', 'CellLine', 'CVCL:1197', (189, 198))	('FGF19', 'Gene', (129, 134))
355971	28906590	The AKT phosphorylation level was obviously suppressed in the group with FGF19 knockdown, compared to the control group.	('suppressed', 'NegReg', (44, 54))	('AKT', 'Gene', (4, 7))	('FGF19', 'Gene', (73, 78))	('AKT', 'Gene', '207', (4, 7))	('knockdown', 'Var', (79, 88))
355973	28906590	These data show that silencing of FGF19 expression inhibits tumor growth and increases apoptosis in EPLC-272H cells in vivo.	('EPLC-272H', 'CellLine', 'CVCL:1197', (100, 109))	('inhibits', 'NegReg', (51, 59))	('FGF19', 'Gene', (34, 39))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('apoptosis', 'CPA', (87, 96))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('increases', 'PosReg', (77, 86))	('tumor', 'Disease', (60, 65))	('silencing', 'Var', (21, 30))
355977	28906590	Of note, we found that all tumor samples from LSCC patients carrying FGF19 amplifications also expressed high levels of FGF19 mRNA, which indicated that FGF19 amplification and upregulation of FGF19 expression may correlate closely in human LSCC.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('FGF19', 'Gene', (153, 158))	('tumor', 'Disease', (27, 32))	('FGF19 mRNA', 'MPA', (120, 130))	('upregulation', 'PosReg', (177, 189))	('FGF19', 'Gene', (69, 74))	('LSCC', 'Disease', (241, 245))	('patients', 'Species', '9606', (51, 59))	('human', 'Species', '9606', (235, 240))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('amplifications', 'Var', (75, 89))	('FGF19', 'Gene', (193, 198))
355978	28906590	This finding is consistent with a previous study, which showed that amplification regions containing FGF19, FGF3, FGF4, and CCND1 were found five-times more often in smoking LSCC than in non-smoking LSCC patients.24  With siRNA intervention of the FGF19 gene, downregulation of FGF19 expression could significantly inhibit tumor cell growth and enhance apoptosis in LSCC cells with gene copy number amplification and a high expression of FGF19.	('CCND1', 'Gene', (124, 129))	('FGF4', 'Gene', '2249', (114, 118))	('patients', 'Species', '9606', (204, 212))	('tumor', 'Phenotype', 'HP:0002664', (323, 328))	('downregulation', 'NegReg', (260, 274))	('inhibit', 'NegReg', (315, 322))	('apoptosis', 'CPA', (353, 362))	('FGF19', 'Gene', (248, 253))	('gene copy number amplification', 'Var', (382, 412))	('enhance', 'PosReg', (345, 352))	('FGF3', 'Gene', (108, 112))	('expression', 'MPA', (284, 294))	('FGF19', 'Gene', (438, 443))	('FGF4', 'Gene', (114, 118))	('FGF3', 'Gene', '2248', (108, 112))	('tumor', 'Disease', (323, 328))	('FGF19', 'Gene', (278, 283))	('CCND1', 'Gene', '595', (124, 129))	('expression', 'MPA', (424, 434))	('tumor', 'Disease', 'MESH:D009369', (323, 328))
355979	28906590	FGF19 knockdown by inducible shRNA further demonstrated the tumor growth inhibitory effect in xenografts in vivo.	('FGF19', 'Gene', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('knockdown', 'Var', (6, 15))	('tumor', 'Disease', (60, 65))
355982	28906590	reported that hyperactivated FGF signaling can promote tumor angiogenesis and predicts a poor clinical outcome in prostate patients with overexpressed FRS2.23  In this study, we also investigated the phosphorylation level of downstream proteins.	('FRS2', 'Gene', (151, 155))	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('FGF', 'Gene', (29, 32))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('promote', 'PosReg', (47, 54))	('patients', 'Species', '9606', (123, 131))	('tumor', 'Disease', (55, 60))	('FRS2', 'Gene', '10818', (151, 155))	('prostate', 'Disease', 'MESH:D011472', (114, 122))	('FGF', 'Gene', '2248;2249;9965;14170', (29, 32))	('prostate', 'Disease', (114, 122))	('hyperactivated', 'Var', (14, 28))
355983	28906590	The results showed obvious inhibition of p-FGFR4, FRS2, AKT, and ERK in LSCC cells with FGF19 knockdown interference, which indicated the potential therapeutic effect of targeting FGF19 may mainly depend on the downstream pathway of FGFR4/FRS2alpha-ERK1/2 signaling.	('FGFR4', 'Gene', '2264', (233, 238))	('ERK', 'Gene', '5594', (249, 252))	('AKT', 'Gene', (56, 59))	('FRS2', 'Gene', (50, 54))	('FGF19', 'Gene', (180, 185))	('ERK1/2', 'Gene', (249, 255))	('FGFR4', 'Gene', (43, 48))	('ERK', 'Gene', '5594', (65, 68))	('ERK1/2', 'Gene', '5595;5594', (249, 255))	('FGFR4', 'Gene', (233, 238))	('ERK', 'Gene', (249, 252))	('FRS2', 'Gene', (239, 243))	('FRS2', 'Gene', '10818', (50, 54))	('ERK', 'Gene', (65, 68))	('AKT', 'Gene', '207', (56, 59))	('FRS2alpha', 'Gene', '10818', (239, 248))	('knockdown interference', 'Var', (94, 116))	('interference', 'Var', (104, 116))	('inhibition', 'NegReg', (27, 37))	('FGF19', 'Gene', (88, 93))	('FRS2', 'Gene', '10818', (239, 243))	('FRS2alpha', 'Gene', (239, 248))	('FGFR4', 'Gene', '2264', (43, 48))
355984	28906590	This study showed that FGF19 amplification is a genetic event in Chinese LSCC patients, with a frequency of 37.5%.	('LSCC', 'Disease', (73, 77))	('patients', 'Species', '9606', (78, 86))	('FGF19', 'Gene', (23, 28))	('amplification', 'Var', (29, 42))
355985	28906590	These preclinical data strongly support the potential role of FGF19 as a therapeutic target and the development of molecular inhibitors targeting FGF19 amplification in LSCC patients.	('patients', 'Species', '9606', (174, 182))	('LSCC', 'Disease', (169, 173))	('FGF19', 'Gene', (146, 151))	('amplification', 'Var', (152, 165))
356022	28787442	After ruling out significant batch effects (S1 Fig), we discovered that the greatest component driving gene expression variation (PC1) accounted for significantly more variation (34% of total) than other components (Fig 1B).	('variation', 'MPA', (168, 177))	('PC1', 'Gene', '3868', (130, 133))	('variation', 'Var', (119, 128))	('gene expression', 'MPA', (103, 118))	('PC1', 'Gene', (130, 133))
356030	28787442	Other notable genes relatively upregulated in SCCs were keratins KRT14 and KRT17; DSC3, a member of the desmocollin family (a component of intercellular desmosomes); FAT2, an atypical cadherin found to be induced by DeltaNp63alpha (isoform of TP63) and promote invasion in LUSC; EGFR, a key growth factor receptor in many cancers; CCNA1, which encodes for cyclin A1, a cell cycle regulator; and WNT3A, a member of the Wnt family of signaling proteins, which also may have a role in SCCs.	('WNT3A', 'Gene', '89780', (395, 400))	('Wnt', 'Gene', (418, 421))	('DSC3', 'Gene', '1825', (82, 86))	('CCNA1', 'Gene', '8900', (331, 336))	('SCCs', 'Phenotype', 'HP:0002860', (46, 50))	('EGFR', 'Gene', (279, 283))	('cancers', 'Disease', 'MESH:D009369', (322, 329))	('KRT17', 'Gene', '3872', (75, 80))	('Wnt', 'Gene', '89780', (418, 421))	('KRT14', 'Gene', '3861', (65, 70))	('WNT3A', 'Gene', (395, 400))	('DSC3', 'Gene', (82, 86))	('SCCs', 'Phenotype', 'HP:0002860', (482, 486))	('KRT14', 'Gene', (65, 70))	('promote', 'PosReg', (253, 260))	('cyclin A1', 'Gene', '8900', (356, 365))	('TP63', 'Gene', (243, 247))	('invasion', 'CPA', (261, 269))	('FAT2', 'Gene', '2196', (166, 170))	('cancer', 'Phenotype', 'HP:0002664', (322, 328))	('KRT17', 'Gene', (75, 80))	('SCC', 'Gene', '6317', (482, 485))	('cyclin A1', 'Gene', (356, 365))	('SCC', 'Gene', '6317', (46, 49))	('EGFR', 'Gene', '1956', (279, 283))	('TP63', 'Gene', '8626', (243, 247))	('cancers', 'Phenotype', 'HP:0002664', (322, 329))	('CCNA1', 'Gene', (331, 336))	('upregulated', 'PosReg', (31, 42))	('SCC', 'Gene', (482, 485))	('cancers', 'Disease', (322, 329))	('SCC', 'Gene', (46, 49))	('DeltaNp63alpha', 'Var', (216, 230))	('FAT2', 'Gene', (166, 170))
356037	28787442	Genes that were downregulated and hypermethylated in ADCs were squamous markers such as DSC3 and KRT5, as well as transcription factors such as FOXE1 and TP73, whose isoforms have demonstrated both tumor suppressor and oncogenic properties.	('ADC', 'Gene', '113451', (53, 56))	('KRT5', 'Gene', '3852', (97, 101))	('oncogenic properties', 'CPA', (219, 239))	('FOXE1', 'Gene', (144, 149))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('DSC3', 'Gene', '1825', (88, 92))	('FOXE1', 'Gene', '2304', (144, 149))	('ADC', 'Gene', (53, 56))	('hypermethylated', 'Var', (34, 49))	('TP73', 'Gene', (154, 158))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('KRT5', 'Gene', (97, 101))	('DSC3', 'Gene', (88, 92))	('tumor', 'Disease', (198, 203))	('TP73', 'Gene', '7161', (154, 158))	('downregulated', 'NegReg', (16, 29))
356041	28787442	By contrast, genes that were upregulated and hypomethylated included mucins like MUC1; SERPINA1, a serine protease inhibitor that acts in the liver and lung; HNF1B, a transcription factor that regulates in renal and pancreatic development; and ME3, a mitochondrial malic enzyme whose deletion was shown recently to confer lethality in SMAD4-deleted pancreatic adenocarcinoma.	('SERPINA1', 'Gene', (87, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (365, 374))	('deletion', 'Var', (284, 292))	('upregulated', 'PosReg', (29, 40))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (349, 374))	('pancreatic adenocarcinoma', 'Disease', (349, 374))	('SMAD4', 'Gene', (335, 340))	('MUC1', 'Gene', (81, 85))	('SERPINA1', 'Gene', '5265', (87, 95))	('HNF1B', 'Gene', '6928', (158, 163))	('MUC1', 'Gene', '4582', (81, 85))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D010190', (349, 374))	('ME3', 'Gene', (244, 247))	('HNF1B', 'Gene', (158, 163))	('SMAD4', 'Gene', '4089', (335, 340))	('ME3', 'Gene', '10873', (244, 247))
356064	28787442	Furthermore, aberrant Wnt signaling and non-canonical Wnt/PCP signaling, which normally regulates cell shape via the cytoskeleton, have been hypothesized to have a unique role in SCCs, and may represent a functional distinction between SCCs and ADCs.	('SCC', 'Gene', '6317', (236, 239))	('SCCs', 'Phenotype', 'HP:0002860', (236, 240))	('Wnt', 'Gene', (22, 25))	('SCCs', 'Phenotype', 'HP:0002860', (179, 183))	('SCC', 'Gene', (179, 182))	('Wnt', 'Gene', (54, 57))	('Wnt', 'Gene', '89780', (22, 25))	('Wnt', 'Gene', '89780', (54, 57))	('ADC', 'Gene', (245, 248))	('SCC', 'Gene', '6317', (179, 182))	('SCC', 'Gene', (236, 239))	('ADC', 'Gene', '113451', (245, 248))	('role', 'Reg', (171, 175))	('aberrant', 'Var', (13, 21))
356065	28787442	Notably upregulated in ADCs relative to SCCs was STK11 (or LKB1), loss of which has been previously shown to induce adeno-to-squamous differentiation of lung tumors in mice; GATA4 and GATA6, important for cell differentiation and commonly amplified in EAC and gastric cancers; and NKX2-1, a commonly used marker for lung adenocarcinomas.	('tumors', 'Phenotype', 'HP:0002664', (158, 164))	('lung tumors', 'Phenotype', 'HP:0100526', (153, 164))	('LKB1', 'Gene', '20869', (59, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (326, 335))	('carcinomas', 'Phenotype', 'HP:0030731', (326, 336))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (316, 335))	('NKX2-1', 'Gene', (281, 287))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('lung tumors', 'Disease', (153, 164))	('GATA6', 'Gene', (184, 189))	('GATA4', 'Gene', '14463', (174, 179))	('LKB1', 'Gene', (59, 63))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (316, 336))	('lung adenocarcinomas', 'Disease', (316, 336))	('ADC', 'Gene', '113451', (23, 26))	('SCC', 'Gene', '6317', (40, 43))	('EAC', 'Disease', (252, 255))	('ADC', 'Gene', (23, 26))	('STK11', 'Gene', (49, 54))	('adeno-to-squamous differentiation', 'CPA', (116, 149))	('SCC', 'Gene', (40, 43))	('upregulated', 'PosReg', (8, 19))	('induce', 'Reg', (109, 115))	('cancers', 'Phenotype', 'HP:0002664', (268, 275))	('GATA4', 'Gene', (174, 179))	('gastric cancers', 'Disease', (260, 275))	('gastric cancers', 'Disease', 'MESH:D013274', (260, 275))	('gastric cancers', 'Phenotype', 'HP:0012126', (260, 275))	('loss', 'Var', (66, 70))	('NKX2-1', 'Gene', '21869', (281, 287))	('mice', 'Species', '10090', (168, 172))	('cancer', 'Phenotype', 'HP:0002664', (268, 274))	('lung tumors', 'Disease', 'MESH:D008175', (153, 164))	('SCCs', 'Phenotype', 'HP:0002860', (40, 44))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (316, 336))
356093	28787442	In fact, one study utilized an inverse agonist SR9243 to inhibit LXR activity, suppressing tumor growth in several colon, prostate, lung and pancreatic adenocarcinoma cell lines.	('activity', 'MPA', (69, 77))	('LXR', 'Enzyme', (65, 68))	('inhibit', 'NegReg', (57, 64))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D010190', (141, 166))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (141, 166))	('suppressing', 'NegReg', (79, 90))	('pancreatic adenocarcinoma', 'Disease', (141, 166))	('SR9243', 'Var', (47, 53))	('SR9243', 'Chemical', 'MESH:C000602007', (47, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (157, 166))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('colon', 'Disease', (115, 120))	('tumor', 'Disease', (91, 96))
356110	28787442	Another finding with potential therapeutic relevance is TP73 methylation and low expression in ADCs.	('low', 'NegReg', (77, 80))	('methylation', 'Var', (61, 72))	('TP73', 'Gene', '7161', (56, 60))	('TP73', 'Gene', (56, 60))	('ADC', 'Gene', (95, 98))	('ADC', 'Gene', '113451', (95, 98))	('expression', 'MPA', (81, 91))
356111	28787442	TP73 is a known tumor suppressor, and its methylation could contribute to reduced apoptosis in response to chemo- or radiotherapy relative to SCCs.	('TP73', 'Gene', '7161', (0, 4))	('TP73', 'Gene', (0, 4))	('apoptosis', 'CPA', (82, 91))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('SCC', 'Gene', (142, 145))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('SCCs', 'Phenotype', 'HP:0002860', (142, 146))	('SCC', 'Gene', '6317', (142, 145))	('tumor', 'Disease', (16, 21))	('methylation', 'Var', (42, 53))	('reduced', 'NegReg', (74, 81))
356115	28787442	These findings are consistent with other reports: while loss of STK11 has been associated with lung, skin, and head and neck SCCs, inherited loss of STK11, as in Peutz-Jeghers syndrome, has been associated with endometrial adenocarcinoma and a rare variant of endocervical carcinoma, minimal deviation adenocarcinoma of the endocervix.	('associated', 'Reg', (79, 89))	('loss', 'Var', (56, 60))	('SCC', 'Gene', (125, 128))	('Peutz-Jeghers syndrome', 'Disease', 'MESH:D010580', (162, 184))	('adenocarcinoma', 'Disease', 'MESH:D000230', (223, 237))	('endometrial adenocarcinoma', 'Phenotype', 'HP:0012114', (211, 237))	('adenocarcinoma', 'Disease', 'MESH:D000230', (302, 316))	('endometrial adenocarcinoma', 'Disease', (211, 237))	('endocervical carcinoma', 'Disease', (260, 282))	('loss', 'Var', (141, 145))	('SCCs', 'Phenotype', 'HP:0002860', (125, 129))	('endocervical carcinoma', 'Disease', 'MESH:D002277', (260, 282))	('endometrial adenocarcinoma', 'Disease', 'MESH:D016889', (211, 237))	('lung', 'Disease', (95, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (307, 316))	('associated', 'Reg', (195, 205))	('skin', 'Disease', (101, 105))	('carcinoma', 'Phenotype', 'HP:0030731', (228, 237))	('Peutz-Jeghers syndrome', 'Disease', (162, 184))	('STK11', 'Gene', (64, 69))	('adenocarcinoma', 'Disease', (223, 237))	('adenocarcinoma', 'Disease', (302, 316))	('carcinoma', 'Phenotype', 'HP:0030731', (273, 282))	('SCC', 'Gene', '6317', (125, 128))	('STK11', 'Gene', (149, 154))
356172	25819073	Together, BioMuta and BioXpress provide a detailed view of the expression and mutations of genes in cancer and therefore can be used for pan-cancer studies like the one performed by our group recently and described in this manuscript.	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('mutations', 'Var', (78, 87))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('cancer', 'Disease', (141, 147))
356244	25819073	Third, alterations in the ubiquitin system have direct or indirect roles in the genesis of various tumors due to defects in the ubiquitin-dependent proteolysis of critical house-keeping genes or cell-cycle elements:p53 is a good example.	('tumors', 'Disease', 'MESH:D009369', (99, 105))	('ubiquitin-dependent proteolysis', 'MPA', (128, 159))	('defects', 'NegReg', (113, 120))	('p53', 'Gene', (215, 218))	('p53', 'Gene', '7157', (215, 218))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))	('alterations', 'Var', (7, 18))	('tumors', 'Disease', (99, 105))
356259	25819073	MT1H is under-expressed in adenoid cystic carcinoma of salivary gland, prostate and liver cancer due to hypermethylation of its promoter.	('hypermethylation', 'Var', (104, 120))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('MT1H', 'Gene', (0, 4))	('carcinoma', 'Phenotype', 'HP:0030731', (42, 51))	('liver cancer', 'Phenotype', 'HP:0002896', (84, 96))	('liver cancer', 'Disease', 'MESH:D006528', (84, 96))	('carcinoma of salivary', 'Phenotype', 'HP:0100684', (42, 63))	('liver cancer', 'Disease', (84, 96))	('MT1H', 'Gene', '4496', (0, 4))	('adenoid cystic carcinoma of salivary gland, prostate', 'Disease', 'MESH:D003528', (27, 79))
356268	25819073	Some potential new features include the following: addition of cancer subtypes; linking BioXpress to BioMuta to obtain comprehensive view of expression as it may relate to mutation; integration of clinical annotations; inclusion of additional graphical elements and more.	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('clinical', 'Species', '191496', (197, 205))	('mutation', 'Var', (172, 180))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('cancer', 'Disease', (63, 69))
356269	25819073	Our preliminary results show that there is a correlation between mutation density of a gene and its expression in certain types of cancer.	('cancer', 'Disease', (131, 137))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('expression', 'MPA', (100, 110))	('mutation density', 'Var', (65, 81))	('cancer', 'Disease', 'MESH:D009369', (131, 137))
356314	33460401	In the TME, inflammatory cells secrete chemokines and cytokines to promote the growth and metastasis of tumor cells, genetic mutations, and angiogenesis.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumor', 'Disease', (104, 109))	('angiogenesis', 'CPA', (140, 152))	('genetic mutations', 'Var', (117, 134))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('promote', 'PosReg', (67, 74))
356346	33460401	The radar chart analysis showed that the targets we screened were closely related to carcinoma (D002277), neoplasm metastasis (D009362), lung neoplasms (D008175), inflammation (D007249) and so on, and these targets simultaneously targeted two or more diseases.	('D009362', 'Var', (127, 134))	('inflammation', 'Disease', (163, 175))	('carcinoma', 'Disease', (85, 94))	('neoplasm metastasis', 'Disease', (106, 125))	('targeted', 'Reg', (230, 238))	('neoplasm', 'Phenotype', 'HP:0002664', (106, 114))	('carcinoma', 'Disease', 'MESH:D009369', (85, 94))	('neoplasm', 'Phenotype', 'HP:0002664', (142, 150))	('lung neoplasms', 'Disease', (137, 151))	('D008175', 'Var', (153, 160))	('D007249', 'Var', (177, 184))	('lung neoplasms', 'Disease', 'MESH:D008175', (137, 151))	('D002277', 'Var', (96, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('neoplasms', 'Phenotype', 'HP:0002664', (142, 151))	('inflammation', 'Disease', 'MESH:D007249', (163, 175))	('neoplasm metastasis', 'Disease', 'MESH:D009362', (106, 125))	('lung neoplasms', 'Phenotype', 'HP:0100526', (137, 151))
356353	33460401	Leukocyte fraction correlated with CNR2, PI3KCG, TLR2, PTGS1, ALOX5 and so on.	('CNR2', 'Gene', (35, 39))	('PI3KCG', 'Var', (41, 47))	('ALOX5', 'Gene', '240', (62, 67))	('ALOX5', 'Gene', (62, 67))	('Leukocyte fraction', 'CPA', (0, 18))	('TLR2', 'Gene', '7097', (49, 53))	('CNR2', 'Gene', '1269', (35, 39))	('PTGS1', 'Gene', '5742', (55, 60))	('PTGS1', 'Gene', (55, 60))	('TLR2', 'Gene', (49, 53))
356354	33460401	Among them, inactivation of CNR2 or activation of ALOX5 has been reported to enhance leukocyte migration.	('CNR2', 'Gene', (28, 32))	('CNR2', 'Gene', '1269', (28, 32))	('inactivation', 'Var', (12, 24))	('ALOX5', 'Gene', '240', (50, 55))	('enhance', 'PosReg', (77, 84))	('leukocyte migration', 'CPA', (85, 104))	('ALOX5', 'Gene', (50, 55))
356424	33460401	Note that, for internal signal, we also observed that ICT reduced the levels of Bcl-2 and CDK2 while increased Bax expression (Figure 8D).	('increased', 'PosReg', (101, 110))	('CDK2', 'MPA', (90, 94))	('ICT', 'Var', (54, 57))	('levels of Bcl-2', 'MPA', (70, 85))	('ICT', 'Chemical', 'MESH:C499403', (54, 57))	('Bax expression', 'MPA', (111, 125))	('reduced', 'NegReg', (58, 65))
356443	33460401	Applying the systems pharmacology, we successfully revealed the ICT enhanced the infiltration of CD8+ T cells in TME via multiple pathways, which shown the accuracy and reliability of systems pharmacology.	('enhanced', 'PosReg', (68, 76))	('infiltration', 'CPA', (81, 93))	('ICT', 'Var', (64, 67))	('CD8', 'Gene', (97, 100))	('ICT', 'Chemical', 'MESH:C499403', (64, 67))	('CD8', 'Gene', '925', (97, 100))
356445	33460401	In addition, we consider that Epimedium and ICT might sensitize the cancers to anti-PD-1/PD-L1 or anti-CTLA4 via increasing the infiltration of CD8+ T cells, since immune checkpoint blockade therapies often fail in the patients with poor T cell infiltration.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('sensitize', 'Reg', (54, 63))	('increasing', 'PosReg', (113, 123))	('cancers', 'Phenotype', 'HP:0002664', (68, 75))	('CD8', 'Gene', (144, 147))	('cancers', 'Disease', (68, 75))	('PD-L1', 'Gene', (89, 94))	('ICT', 'Chemical', 'MESH:C499403', (44, 47))	('cancers', 'Disease', 'MESH:D009369', (68, 75))	('CD8', 'Gene', '925', (144, 147))	('anti-CTLA4', 'Var', (98, 108))	('patients', 'Species', '9606', (219, 227))	('PD-L1', 'Gene', '29126', (89, 94))	('Epimedium', 'Species', '253618', (30, 39))	('infiltration', 'MPA', (128, 140))
356501	33460401	The membrane was washed three times with TBST buffer and blocked with 5% skim milk for 2 h. After washing three times, the membrane incubated with primary antibodies against Bcl-2, Bax, CDK2, eNOS, PKC, p38, p-p38, iNOS, COX2, TNF-alpha, and GAPDH at 4  C overnight.	('TBST buffer', 'Chemical', '-', (41, 52))	('p-p38', 'Var', (208, 213))	('CDK2', 'Gene', (186, 190))	('PKC', 'Gene', (198, 201))	('Bcl-2', 'Gene', (174, 179))	('PKC', 'Gene', '112476', (198, 201))
356507	33460401	Annexin V+/PI- and V+/PI+ cells were considered as apoptotic cells.	('Annexin V', 'Gene', '308', (0, 9))	('V+/PI+', 'Var', (19, 25))	('Annexin V', 'Gene', (0, 9))
356514	32143717	For instance, (P) RR was recently demonstrated to induce the oncogenesis of pancreatic, colorectal and brain cancers via the Wnt signaling, while promote the endometrial cancer and glioblastoma through the RAS.	('oncogenesis', 'CPA', (61, 72))	('endometrial cancer', 'Disease', 'MESH:D016889', (158, 176))	('endometrial cancer', 'Phenotype', 'HP:0012114', (158, 176))	('pancreatic', 'Disease', (76, 86))	('glioblastoma', 'Phenotype', 'HP:0012174', (181, 193))	('cancers', 'Phenotype', 'HP:0002664', (109, 116))	('colorectal and brain cancers', 'Disease', 'MESH:D015179', (88, 116))	('glioblastoma', 'Disease', (181, 193))	('glioblastoma', 'Disease', 'MESH:D005909', (181, 193))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('P) RR', 'Var', (15, 20))	('endometrial cancer', 'Disease', (158, 176))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('promote', 'PosReg', (146, 153))	('induce', 'PosReg', (50, 56))
356531	32143717	The first link between (P) RR and the Wnt/beta-catenin pathway was clarified by Cruciat et al., who indicated that (P) RR is an important component of the Wnt receptor complex and acts as an adaptor between LRP6 and the V-ATPase independent of the RAS, thus facilitating the binding of Wnts to the Wnt receptor complex.	('ATPase', 'Gene', (222, 228))	('beta-catenin', 'Gene', (42, 54))	('beta-catenin', 'Gene', '1499', (42, 54))	('binding', 'Interaction', (275, 282))	('LRP6', 'Gene', '4040', (207, 211))	('ATPase', 'Gene', '1769', (222, 228))	('LRP6', 'Gene', (207, 211))	('facilitating', 'PosReg', (258, 270))	('P) RR', 'Var', (116, 121))
356532	32143717	Based on this evidence, further studies convincingly revealed that (P) RR promotes pancreatic, brain and colorectal cancers through the Wnt/beta-catenin pathway.	('promotes', 'PosReg', (74, 82))	('P) RR', 'Var', (68, 73))	('beta-catenin', 'Gene', '1499', (140, 152))	('colorectal cancers', 'Disease', (105, 123))	('pancreatic', 'Disease', (83, 93))	('brain', 'Disease', (95, 100))	('cancers', 'Phenotype', 'HP:0002664', (116, 123))	('colorectal cancer', 'Phenotype', 'HP:0003003', (105, 122))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('colorectal cancers', 'Disease', 'MESH:D015179', (105, 123))	('beta-catenin', 'Gene', (140, 152))
356533	32143717	Interestingly, research also suggests that (P) RR not only serves as a membrane adaptor protein but also exists in the cytoplasm and positively affects the protein expression level of Wnt2 in glioma cells as well as that of Wnt3 and total LRP6 in CRC cells.	('CRC', 'Phenotype', 'HP:0003003', (247, 250))	('Wnt3', 'Gene', (224, 228))	('Wnt2', 'Gene', (184, 188))	('glioma', 'Disease', 'MESH:D005910', (192, 198))	('glioma', 'Phenotype', 'HP:0009733', (192, 198))	('Wnt2', 'Gene', '7472', (184, 188))	('protein expression level', 'MPA', (156, 180))	('affects', 'Reg', (144, 151))	('LRP6', 'Gene', '4040', (239, 243))	('Wnt3', 'Gene', '7473', (224, 228))	('glioma', 'Disease', (192, 198))	('LRP6', 'Gene', (239, 243))	('P) RR', 'Var', (44, 49))
356540	32143717	Therefore, (P) RR may promote cancer initiation and progression via the RAS (Fig.	('promote', 'PosReg', (22, 29))	('cancer initiation', 'Disease', 'MESH:D009369', (30, 47))	('cancer initiation', 'Disease', (30, 47))	('progression', 'CPA', (52, 63))	('P) RR', 'Var', (12, 17))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
356543	32143717	Additionally, (P) RR induces reactive oxygen species (ROS) formation, which is independent of Ang II, thus further contributing to MAPK/ERK and PI3K/AKT/mTOR signal transduction.	('reactive oxygen species', 'Chemical', 'MESH:D017382', (29, 52))	('contributing', 'PosReg', (115, 127))	('mTOR', 'Gene', (153, 157))	('AKT', 'Gene', (149, 152))	('mTOR', 'Gene', '2475', (153, 157))	('ERK', 'Gene', '5594', (136, 139))	('P) RR', 'Var', (15, 20))	('ERK', 'Gene', (136, 139))	('ROS', 'Chemical', 'MESH:D017382', (54, 57))	('AKT', 'Gene', '207', (149, 152))
356544	32143717	investigated the function of (P) RR in the biological activities of the human pancreatic cancer cell lines Panc-1 and ASPC and found that (P) RR exerts a cancer-promoting effect by enhancing activity in the MAPK/ERK and PI3K/AKT/mTOR signaling pathways.	('AKT', 'Gene', '207', (225, 228))	('activity', 'MPA', (191, 199))	('cancer', 'Disease', (89, 95))	('pancreatic cancer', 'Disease', (78, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('enhancing', 'PosReg', (181, 190))	('human', 'Species', '9606', (72, 77))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('Panc-1', 'CellLine', 'CVCL:0480', (107, 113))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (78, 95))	('mTOR', 'Gene', (229, 233))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('ERK', 'Gene', '5594', (212, 215))	('AKT', 'Gene', (225, 228))	('P) RR', 'Var', (139, 144))	('cancer', 'Disease', (154, 160))	('mTOR', 'Gene', '2475', (229, 233))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('ERK', 'Gene', (212, 215))	('pancreatic cancer', 'Disease', 'MESH:D010190', (78, 95))
356557	32143717	Furthermore, (P) RR was revealed to be essential for Wnt/beta-catenin-mediated proliferation of PDAC cells, while (P) RR silencing decreased Wnt signaling activity and cell proliferation, as well as induced the apoptosis of PDAC cells via caspase-3 activation.	('apoptosis', 'CPA', (211, 220))	('silencing', 'Var', (121, 130))	('PDAC', 'Chemical', '-', (96, 100))	('PDAC', 'Chemical', '-', (224, 228))	('cell proliferation', 'CPA', (168, 186))	('caspase-3', 'Gene', (239, 248))	('decreased', 'NegReg', (131, 140))	('activation', 'PosReg', (249, 259))	('induced', 'Reg', (199, 206))	('caspase-3', 'Gene', '836', (239, 248))	('Wnt signaling activity', 'MPA', (141, 163))	('PDAC', 'Phenotype', 'HP:0006725', (224, 228))	('PDAC', 'Phenotype', 'HP:0006725', (96, 100))	('beta-catenin', 'Gene', (57, 69))	('P) RR', 'Gene', (115, 120))	('beta-catenin', 'Gene', '1499', (57, 69))
356565	32143717	At the cellular level, (P) RR promoted the proliferation of human glioma cells through the Wnt/beta-catenin pathway and inhibited cell apoptosis by attenuating caspase-3 activation.	('glioma', 'Disease', (66, 72))	('attenuating', 'NegReg', (148, 159))	('caspase-3', 'Gene', (160, 169))	('cell apoptosis', 'CPA', (130, 144))	('P) RR', 'Var', (24, 29))	('inhibited', 'NegReg', (120, 129))	('glioma', 'Phenotype', 'HP:0009733', (66, 72))	('beta-catenin', 'Gene', (95, 107))	('promoted', 'PosReg', (30, 38))	('caspase-3', 'Gene', '836', (160, 169))	('glioma', 'Disease', 'MESH:D005910', (66, 72))	('proliferation', 'CPA', (43, 56))	('activation', 'MPA', (170, 180))	('beta-catenin', 'Gene', '1499', (95, 107))	('human', 'Species', '9606', (60, 65))
356567	32143717	also reported a high expression level of (P) RR in human glioblastoma (GBM) (WHO grade IV), the most malignant type of glioma, and indicated that attenuation of renin activity in glioblastoma cells could decrease cell proliferation and induce apoptosis.	('glioma', 'Phenotype', 'HP:0009733', (119, 125))	('renin', 'Gene', '5972', (161, 166))	('glioblastoma', 'Disease', 'MESH:D005909', (179, 191))	('human', 'Species', '9606', (51, 56))	('decrease', 'NegReg', (204, 212))	('malignant type of glioma', 'Disease', (101, 125))	('apoptosis', 'CPA', (243, 252))	('glioblastoma', 'Disease', (179, 191))	('glioblastoma', 'Phenotype', 'HP:0012174', (179, 191))	('malignant type of glioma', 'Disease', 'MESH:D005910', (101, 125))	('expression level', 'MPA', (21, 37))	('glioblastoma', 'Disease', 'MESH:D005909', (57, 69))	('cell proliferation', 'CPA', (213, 231))	('induce', 'Reg', (236, 242))	('attenuation', 'Var', (146, 157))	('GBM', 'Phenotype', 'HP:0012174', (71, 74))	('glioblastoma', 'Disease', (57, 69))	('glioblastoma', 'Phenotype', 'HP:0012174', (57, 69))	('renin', 'Gene', (161, 166))
356571	32143717	More than 80% of colorectal tumors harbor loss-of-function mutations in APC, and approximately 5% harbor activating mutation in beta-catenin, which result in constitutive aberrant activation of the Wnt/beta-catenin pathway and thus promote carcinogenesis.	('beta-catenin', 'Gene', (202, 214))	('promote', 'PosReg', (232, 239))	('colorectal tumors', 'Disease', (17, 34))	('colorectal tumors', 'Disease', 'MESH:D015179', (17, 34))	('beta-catenin', 'Gene', '1499', (202, 214))	('carcinogenesis', 'Disease', (240, 254))	('mutation', 'Var', (116, 124))	('beta-catenin', 'Gene', (128, 140))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('beta-catenin', 'Gene', '1499', (128, 140))	('loss-of-function', 'NegReg', (42, 58))	('carcinogenesis', 'Disease', 'MESH:D063646', (240, 254))	('mutations', 'Var', (59, 68))	('APC', 'Disease', 'MESH:D011125', (72, 75))	('activating', 'PosReg', (105, 115))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('activation', 'PosReg', (180, 190))	('APC', 'Disease', (72, 75))
356572	32143717	found that Wnt3 knockdown noticeably reduced the activity of the Wnt/beta-catenin pathway and proliferation of CRC cells independent of APC or beta-catenin mutations.	('proliferation of CRC cells', 'CPA', (94, 120))	('activity', 'MPA', (49, 57))	('beta-catenin', 'Gene', '1499', (143, 155))	('Wnt3', 'Gene', (11, 15))	('beta-catenin', 'Gene', (69, 81))	('APC', 'Disease', 'MESH:D011125', (136, 139))	('beta-catenin', 'Gene', '1499', (69, 81))	('knockdown', 'Var', (16, 25))	('CRC', 'Phenotype', 'HP:0003003', (111, 114))	('APC', 'Disease', (136, 139))	('reduced', 'NegReg', (37, 44))	('beta-catenin', 'Gene', (143, 155))	('Wnt3', 'Gene', '7473', (11, 15))
356573	32143717	The above findings suggest that Wnts can further stimulate a mutated Wnt/beta-catenin pathway with constitutively hyperactivated signaling activity.	('beta-catenin', 'Gene', '1499', (73, 85))	('beta-catenin', 'Gene', (73, 85))	('mutated', 'Var', (61, 68))	('stimulate', 'PosReg', (49, 58))
356574	32143717	More recently, we have published the data that demonstrated, for the first time, that (P) RR promotes CRC through the Wnt/beta-catenin pathway despite constitutive activating mutations in APC or beta-catenin.	('CRC', 'Phenotype', 'HP:0003003', (102, 105))	('APC', 'Disease', 'MESH:D011125', (188, 191))	('beta-catenin', 'Gene', '1499', (122, 134))	('APC', 'Disease', (188, 191))	('activating', 'PosReg', (164, 174))	('beta-catenin', 'Gene', '1499', (195, 207))	('CRC', 'CPA', (102, 105))	('mutations', 'Var', (175, 184))	('promotes', 'PosReg', (93, 101))	('beta-catenin', 'Gene', (122, 134))	('beta-catenin', 'Gene', (195, 207))
356580	32143717	The results showed that (P) RR expression increases throughout the colorectal adenoma:adenocarcinoma process, moreover, (P) RR protein in both primary tumor and distant metastases is associated with worse prognosis including 5- and 10-year survival of CRC patients.	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('P) RR protein', 'Var', (121, 134))	('metastases', 'Disease', (169, 179))	('colorectal adenoma:adenocarcinoma process', 'Disease', (67, 108))	('tumor', 'Disease', (151, 156))	('patients', 'Species', '9606', (256, 264))	('metastases', 'Disease', 'MESH:D009362', (169, 179))	('CRC', 'Phenotype', 'HP:0003003', (252, 255))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('colorectal adenoma:adenocarcinoma process', 'Disease', 'MESH:D015179', (67, 108))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
356582	32143717	However, approximately 30-50% of CRCs carry a KRAS mutation, which automatically activates the downstream pathway and results in resistance to EGFR-targeted therapy.	('EGFR', 'Gene', (143, 147))	('results in', 'Reg', (118, 128))	('downstream pathway', 'Pathway', (95, 113))	('KRAS', 'Gene', (46, 50))	('KRAS', 'Gene', '3845', (46, 50))	('resistance', 'MPA', (129, 139))	('mutation', 'Var', (51, 59))	('activates', 'PosReg', (81, 90))	('EGFR', 'Gene', '1956', (143, 147))	('CRCs', 'Disease', (33, 37))	('CRC', 'Phenotype', 'HP:0003003', (33, 36))
356584	32143717	found that (P) RR silencing markedly inhibited the proliferation and induced the apoptosis of CRC cell lines carrying both activating mutations in Wnt signaling components and KRAS mutations DLD-1 (with APC and KRAS mutations) and HCT116 (with beta-catenin and KRAS mutations) by weakening Wnt signaling activity.	('KRAS', 'Gene', (261, 265))	('inhibited', 'NegReg', (37, 46))	('KRAS', 'Gene', (211, 215))	('KRAS', 'Gene', '3845', (176, 180))	('mutations', 'Var', (181, 190))	('mutations', 'Var', (134, 143))	('HCT116', 'Gene', (231, 237))	('silencing', 'NegReg', (18, 27))	('beta-catenin', 'Gene', (244, 256))	('HCT116', 'CellLine', 'CVCL:0291', (231, 237))	('KRAS', 'Gene', (176, 180))	('DLD-1', 'Gene', (191, 196))	('beta-catenin', 'Gene', '1499', (244, 256))	('APC', 'Disease', 'MESH:D011125', (203, 206))	('APC', 'Disease', (203, 206))	('induced', 'Reg', (69, 76))	('Wnt signaling', 'Pathway', (290, 303))	('weakening', 'NegReg', (280, 289))	('KRAS', 'Gene', '3845', (261, 265))	('apoptosis', 'CPA', (81, 90))	('proliferation', 'CPA', (51, 64))	('CRC', 'Phenotype', 'HP:0003003', (94, 97))	('KRAS', 'Gene', '3845', (211, 215))
356585	32143717	These findings suggest that (P) RR has great potential as a novel biomarker and therapeutic target for CRC despite spontaneously activating mutations in the Wnt/beta-catenin and/or RAS-ERK pathways.	('beta-catenin', 'Gene', '1499', (161, 173))	('CRC', 'Phenotype', 'HP:0003003', (103, 106))	('ERK', 'Gene', '5594', (185, 188))	('mutations', 'Var', (140, 149))	('beta-catenin', 'Gene', (161, 173))	('ERK', 'Gene', (185, 188))	('CRC', 'Disease', (103, 106))	('activating', 'PosReg', (129, 139))
356587	32143717	(P) RR silencing inhibited the proliferation of both MCF-7 (estrogen receptor (ER)alpha-positive) and SK-BR-3 (ERalpha-negative) breast cancer cells.	('breast cancer', 'Disease', (129, 142))	('breast cancer', 'Phenotype', 'HP:0003002', (129, 142))	('breast cancer', 'Disease', 'MESH:D001943', (129, 142))	('proliferation', 'CPA', (31, 44))	('ER', 'Gene', '2099', (79, 81))	('ER', 'Gene', '2099', (111, 113))	('inhibited', 'NegReg', (17, 26))	('estrogen receptor', 'Gene', (60, 77))	('SK-BR-3', 'CellLine', 'CVCL:0033', (102, 109))	('MCF-7', 'CellLine', 'CVCL:0031', (53, 58))	('estrogen receptor', 'Gene', '2099', (60, 77))	('MCF-7', 'Gene', (53, 58))	('silencing', 'Var', (7, 16))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
356590	32143717	The above data suggest that (P) RR may stimulate the proliferation of breast carcinoma cells, possibly via ERK1/2 phosphorylation and/or the association with the V-ATPase.	('ERK1/2', 'Gene', (107, 113))	('breast carcinoma', 'Phenotype', 'HP:0003002', (70, 86))	('stimulate', 'PosReg', (39, 48))	('ATPase', 'Gene', (164, 170))	('association', 'Interaction', (141, 152))	('ERK1/2', 'Gene', '5595;5594', (107, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('proliferation', 'CPA', (53, 66))	('P) RR', 'Var', (29, 34))	('breast carcinoma', 'Disease', (70, 86))	('breast carcinoma', 'Disease', 'MESH:D001943', (70, 86))	('ATPase', 'Gene', '1769', (164, 170))
356601	32143717	These data suggest that (P) RR possibly contributes to endometrial cancer by enhancing activity in the RAS.	('endometrial cancer', 'Disease', (55, 73))	('activity', 'MPA', (87, 95))	('P) RR', 'Var', (25, 30))	('endometrial cancer', 'Phenotype', 'HP:0012114', (55, 73))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('RAS', 'Protein', (103, 106))	('endometrial cancer', 'Disease', 'MESH:D016889', (55, 73))	('contributes', 'Reg', (40, 51))	('enhancing', 'PosReg', (77, 86))
356636	30981944	Clinical sequencing of tumor DNA has received the greatest attention with an emphasis on detection of hotspot single nucleotide variants (SNVs), small insertions and deletions (INDELs), and copy number variants (CNVs) that confer sensitivity to targeted therapies.	('single nucleotide variants', 'Var', (110, 136))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('copy number variants', 'Var', (190, 210))	('tumor', 'Disease', (23, 28))	('deletions', 'Var', (166, 175))
356638	30981944	Tumors with innate or acquired resistance mutations are responsive to second- or third-generation inhibitors afatinib and osimertinib.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('osimertinib', 'Chemical', 'MESH:C000603933', (122, 133))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('afatinib', 'Chemical', 'MESH:D000077716', (109, 117))	('mutations', 'Var', (42, 51))
356640	30981944	Gene fusions have emerged as an important class of markers for precision medicine in solid tumors.	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('Gene fusions', 'Var', (0, 12))	('solid tumors', 'Disease', (85, 97))	('solid tumors', 'Disease', 'MESH:D009369', (85, 97))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))
356641	30981944	Transforming rearrangements of the anaplastic lymphoma kinase (ALK) gene are present in 3%-6% of lung adenocarcinomas (LUADs), and these tumors are responsive to crizotinib.	('lung adenocarcinomas', 'Disease', (97, 117))	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('lymphoma', 'Phenotype', 'HP:0002665', (46, 54))	('rearrangements', 'Var', (13, 27))	('tumors', 'Disease', (137, 143))	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('ALK', 'Gene', '238', (63, 66))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (97, 117))	('carcinomas', 'Phenotype', 'HP:0030731', (107, 117))	('anaplastic lymphoma kinase', 'Gene', '238', (35, 61))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (97, 117))	('LUADs', 'Phenotype', 'HP:0030078', (119, 124))	('ALK', 'Gene', (63, 66))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (35, 54))	('anaplastic lymphoma kinase', 'Gene', (35, 61))	('crizotinib', 'Chemical', 'MESH:D000077547', (162, 172))
356642	30981944	Rearrangements of ROS1 and RET have also been found in LUADs at a prevalence of 1%-3% and are responsive to crizotinib and multikinase inhibitors cabozantinib and vandetanib, respectively.	('crizotinib', 'Chemical', 'MESH:D000077547', (108, 118))	('Rearrangements', 'Var', (0, 14))	('responsive', 'Reg', (94, 104))	('cabozantinib', 'Chemical', 'MESH:C558660', (146, 158))	('RET', 'Gene', (27, 30))	('ROS1', 'Gene', (18, 22))	('LUADs', 'Disease', (55, 60))	('ROS1', 'Gene', '6098', (18, 22))	('vandetanib', 'Chemical', 'MESH:C452423', (163, 173))	('LUADs', 'Phenotype', 'HP:0030078', (55, 60))	('found', 'Reg', (46, 51))	('RET', 'Gene', '5979', (27, 30))
356643	30981944	In addition to ALK, RET, and ROS1, fusions involving NTRK1, FGFR1/2/3, and NRG1 genes have been reported in NSCLC among other cancers and represent emerging therapeutic targets.	('ALK', 'Gene', (15, 18))	('ROS1', 'Gene', '6098', (29, 33))	('NRG1', 'Gene', (75, 79))	('RET', 'Gene', (20, 23))	('NRG1', 'Gene', '3084', (75, 79))	('cancers', 'Disease', 'MESH:D009369', (126, 133))	('reported', 'Reg', (96, 104))	('FGFR1/2/3', 'Gene', '2260;2263;2261', (60, 69))	('NSCLC', 'Disease', 'MESH:D002289', (108, 113))	('ROS1', 'Gene', (29, 33))	('fusions', 'Var', (35, 42))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('NSCLC', 'Disease', (108, 113))	('cancers', 'Phenotype', 'HP:0002664', (126, 133))	('cancers', 'Disease', (126, 133))	('NSCLC', 'Phenotype', 'HP:0030358', (108, 113))	('RET', 'Gene', '5979', (20, 23))	('NTRK1', 'Gene', '4914', (53, 58))	('FGFR1/2/3', 'Gene', (60, 69))	('ALK', 'Gene', '238', (15, 18))	('NTRK1', 'Gene', (53, 58))
356644	30981944	In addition, targeted RNA-Seq is capable of detecting additional classes of clinically relevant RNA variation including aberrant splice variants such as the exon 14 skipped isoform of MET, which leads to a constitutively activated form of cMET that confers sensitivity to crizotinib.	('sensitivity', 'MPA', (257, 268))	('variation', 'Var', (100, 109))	('cMET', 'Gene', '4233', (239, 243))	('crizotinib', 'Chemical', 'MESH:D000077547', (272, 282))	('cMET', 'Gene', (239, 243))	('constitutively activated', 'MPA', (206, 230))	('MET', 'Gene', (184, 187))
356659	30981944	The RNA pool enables detection of MET exon 14 skipping and quantification of 23 other mRNA targets of published prognostic and theranostic value, including markers relevant to immune checkpoint inhibitor response such as PD-L1, PD-L2, IFNG, and CTLA4.	('IFNG', 'Gene', '3458', (235, 239))	('MET exon 14 skipping', 'Var', (34, 54))	('PD-L2', 'Gene', (228, 233))	('PD-L2', 'Gene', '80380', (228, 233))	('PD-L1', 'Gene', '29126', (221, 226))	('IFNG', 'Gene', (235, 239))	('CTLA4', 'Gene', '1493', (245, 250))	('CTLA4', 'Gene', (245, 250))	('PD-L1', 'Gene', (221, 226))
356676	30981944	Consistent with other studies such as TCGA, fusions in ALK, RET and ROS1 were restricted to the LUAD subtype.	('ROS1', 'Gene', '6098', (68, 72))	('ALK', 'Gene', '238', (55, 58))	('RET', 'Gene', (60, 63))	('fusions', 'Var', (44, 51))	('RET', 'Gene', '5979', (60, 63))	('ALK', 'Gene', (55, 58))	('ROS1', 'Gene', (68, 72))
356682	30981944	However, the third sample (AD62), which had a RET imbalance, was also positive for EGFR and TP53 mutations.	('mutations', 'Var', (97, 106))	('EGFR', 'Gene', '1956', (83, 87))	('EGFR', 'Gene', (83, 87))	('imbalance', 'Phenotype', 'HP:0002172', (50, 59))	('RET', 'Gene', '5979', (46, 49))	('positive', 'Reg', (70, 78))	('TP53', 'Gene', '7157', (92, 96))	('TP53', 'Gene', (92, 96))	('RET', 'Gene', (46, 49))
356683	30981944	For example, mutations in KRAS, EGFR, and STK11 were present in LUADs whereas PIK3CA and FGFR3 were detected in LUSC.	('PIK3CA', 'Gene', (78, 84))	('LUSC', 'Phenotype', 'HP:0030359', (112, 116))	('FGFR3', 'Gene', (89, 94))	('STK11', 'Gene', (42, 47))	('EGFR', 'Gene', '1956', (32, 36))	('PIK3CA', 'Gene', '5290', (78, 84))	('LUADs', 'Phenotype', 'HP:0030078', (64, 69))	('present', 'Reg', (53, 60))	('EGFR', 'Gene', (32, 36))	('KRAS', 'Gene', (26, 30))	('STK11', 'Gene', '6794', (42, 47))	('mutations', 'Var', (13, 22))	('KRAS', 'Gene', '3845', (26, 30))	('FGFR3', 'Gene', '2261', (89, 94))
356684	30981944	TP53 mutations were detected in both subtypes.	('detected', 'Reg', (20, 28))	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))
356685	30981944	Also consistent with other NSCLC cohorts, KRAS and EGFR mutations in LUAD specimens were mutually exclusive events.	('KRAS', 'Gene', (42, 46))	('mutations', 'Var', (56, 65))	('KRAS', 'Gene', '3845', (42, 46))	('NSCLC', 'Disease', (27, 32))	('EGFR', 'Gene', (51, 55))	('NSCLC', 'Disease', 'MESH:D002289', (27, 32))	('NSCLC', 'Phenotype', 'HP:0030358', (27, 32))	('EGFR', 'Gene', '1956', (51, 55))
356686	30981944	When examining the spectrum of KRAS mutations in the LUAD specimens, codon 12 was the most frequently mutated (74% of all 62 KRAS mutations), a result that is consonant with other studies such as the TCGA LUAD cohort where codon 12 represented 96% of KRAS mutations.	('KRAS', 'Gene', '3845', (251, 255))	('KRAS', 'Gene', (31, 35))	('KRAS', 'Gene', (125, 129))	('KRAS', 'Gene', '3845', (125, 129))	('KRAS', 'Gene', '3845', (31, 35))	('mutations', 'Var', (36, 45))	('codon 12', 'Gene', (69, 77))	('KRAS', 'Gene', (251, 255))
356687	30981944	Mutations in other codons of KRAS were largely represented by codons 13 (18%) and 61 (5%).	('Mutations', 'Var', (0, 9))	('KRAS', 'Gene', (29, 33))	('KRAS', 'Gene', '3845', (29, 33))
356688	30981944	Two unexpected KRAS mutations were detected in LUSC.	('KRAS', 'Gene', (15, 19))	('KRAS', 'Gene', '3845', (15, 19))	('mutations', 'Var', (20, 29))	('LUSC', 'Phenotype', 'HP:0030359', (47, 51))
356689	30981944	One specimen, SQ28 (KRAS p.G13D) was identified as a poorly differentiated NSCLC with LUAD features (TTF1+, p40-) and the other, SQCC5, presented with a noncanonical KRAS variant p.N26I at 20% variant allele frequency.	('KRAS', 'Gene', '3845', (20, 24))	('p40-', 'Var', (108, 112))	('TTF1', 'Gene', '7270', (101, 105))	('NSCLC', 'Phenotype', 'HP:0030358', (75, 80))	('KRAS', 'Gene', (166, 170))	('p.G13D', 'Mutation', 'rs112445441', (25, 31))	('p.N26I', 'Var', (179, 185))	('KRAS', 'Gene', '3845', (166, 170))	('NSCLC', 'Disease', (75, 80))	('TTF1', 'Gene', (101, 105))	('p.N26I', 'Mutation', 'p.N26I', (179, 185))	('NSCLC', 'Disease', 'MESH:D002289', (75, 80))	('KRAS', 'Gene', (20, 24))
356691	30981944	While ALK fusions are generally thought to be mutually exclusive with other oncogenic mutations such as KRAS and EGFR, these have been previously reported to co-occur in rare instances.	('ALK', 'Gene', '238', (6, 9))	('KRAS', 'Gene', '3845', (104, 108))	('ALK', 'Gene', (6, 9))	('EGFR', 'Gene', '1956', (113, 117))	('EGFR', 'Gene', (113, 117))	('KRAS', 'Gene', (104, 108))	('fusions', 'Var', (10, 17))
356695	30981944	While CDKN2A is on average expressed at higher levels in LUSCs relative to LUADs, the gene is also reported as recurrently downregulated in LUSCs via epigenetic silencing and whole gene deletions.	('higher', 'PosReg', (40, 46))	('downregulated', 'NegReg', (123, 136))	('LUADs', 'Phenotype', 'HP:0030078', (75, 80))	('LUSC', 'Phenotype', 'HP:0030359', (57, 61))	('CDKN2A', 'Gene', (6, 12))	('LUSC', 'Phenotype', 'HP:0030359', (140, 144))	('epigenetic silencing', 'Var', (150, 170))	('CDKN2A', 'Gene', '1029', (6, 12))
356703	30981944	Evidence of FGFR1 amplification in the LUSC subtype was further supported by targeted RNA-Seq evidence of concomitant overexpression of FGFR1 (SCC: 0.56; P < 3.5e-6; Figure 5B).	('FGFR1', 'Gene', (12, 17))	('overexpression', 'PosReg', (118, 132))	('FGFR1', 'Gene', (136, 141))	('FGFR1', 'Gene', '2260', (12, 17))	('FGFR1', 'Gene', '2260', (136, 141))	('LUSC', 'Phenotype', 'HP:0030359', (39, 43))	('amplification', 'Var', (18, 31))
356704	30981944	Only one discordant variant was identified, MET p.T1010I, detected at 59% VAF in our assay but not reported by FoundationOne.	('p.T1010I', 'Var', (48, 56))	('p.T1010I', 'Mutation', 'p.T1010I', (48, 56))	('VAF', 'Chemical', '-', (74, 77))	('VAF', 'CPA', (74, 77))
356706	30981944	We applied this workflow to the analysis of a cohort of FFPE NSCLC specimens, demonstrating its utility to accurately detect SNVs, INDELs, CNVs, gene fusions, and gene expression signatures consistent with previously published molecular analyses of NSCLC.	('SNVs', 'Var', (125, 129))	('NSCLC', 'Phenotype', 'HP:0030358', (249, 254))	('INDELs', 'Var', (131, 137))	('NSCLC', 'Phenotype', 'HP:0030358', (61, 66))	('gene', 'MPA', (163, 167))	('gene fusions', 'Var', (145, 157))	('CNVs', 'Var', (139, 143))	('NSCLC', 'Disease', (249, 254))	('NSCLC', 'Disease', (61, 66))	('NSCLC', 'Disease', 'MESH:D002289', (249, 254))	('NSCLC', 'Disease', 'MESH:D002289', (61, 66))
356714	30981944	We identified DNA mutations that were able to lend further insights to ambiguous histopathologies and an RNA expression signature that distinguished adenocarcinomas from squamous cell carcinomas.	('carcinoma', 'Phenotype', 'HP:0030731', (184, 193))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (170, 194))	('carcinomas', 'Phenotype', 'HP:0030731', (154, 164))	('adenocarcinomas', 'Disease', 'MESH:D000230', (149, 164))	('carcinomas', 'Phenotype', 'HP:0030731', (184, 194))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (170, 193))	('adenocarcinomas', 'Disease', (149, 164))	('carcinoma', 'Phenotype', 'HP:0030731', (154, 163))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (170, 194))	('squamous cell carcinomas', 'Disease', (170, 194))	('mutations', 'Var', (18, 27))
356716	30981944	The co-occurrence of these two events is rare but not unprecedented, and the low VAF of KRAS p.G12D in this specimen (6.9%) is suggestive of a subclonal or potentially distinct population of tumor cells.	('low', 'NegReg', (77, 80))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('p.G12D', 'Var', (93, 99))	('VAF', 'Chemical', '-', (81, 84))	('VAF', 'MPA', (81, 84))	('p.G12D', 'Mutation', 'rs121913529', (93, 99))	('KRAS', 'Gene', (88, 92))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('tumor', 'Disease', (191, 196))	('KRAS', 'Gene', '3845', (88, 92))
356717	30981944	Mutations in KRAS have been established as a mechanism of innate and acquired crizotinib resistance, which further highlights the clinical research value of integrative profiling of DNA and RNA to identify and further characterize resistance mechanisms.	('mechanism', 'Reg', (45, 54))	('crizotinib resistance', 'MPA', (78, 99))	('crizotinib', 'Chemical', 'MESH:D000077547', (78, 88))	('Mutations', 'Var', (0, 9))	('KRAS', 'Gene', (13, 17))	('KRAS', 'Gene', '3845', (13, 17))
356720	30981944	Finally, our incorporation of preanalytical QC measurements to inform bioinformatics variant detection and interpretation enables the suppression of false-positive variant calls and flags samples at risk of false-negative calls, thus enabling accurate analysis of poorer-quality specimens.	('flags', 'Species', '34205', (182, 187))	('suppression', 'NegReg', (134, 145))	('variant', 'Var', (164, 171))
356724	30981944	Functional pathway analysis will enable the resolution of cryptic and latent oncogenic driver mutations and shed light onto the "dark matter" that underlies cancer.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('mutations', 'Var', (94, 103))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('cryptic', 'Gene', '55997', (58, 65))	('cancer', 'Disease', (157, 163))	('cryptic', 'Gene', (58, 65))
356746	30837448	It has been suggested that the p53 and RAS pathways play a pivotal role in malignant transformation, It has been demonstrated that UV radiation is directly absorbed by DNA resulting in DNA damage causing both genetic and epigenetic changes in keratinocytes and dermal cells.	('p53', 'Gene', '7157', (31, 34))	('p53', 'Gene', (31, 34))	('epigenetic', 'Var', (221, 231))	('genetic', 'MPA', (209, 216))
356747	30837448	UVB radiation from cumulative sun exposure induces mutations inactivating TP53 in almost 60% of cases.	('induces', 'Reg', (43, 50))	('TP53', 'Gene', '7157', (74, 78))	('TP53', 'Gene', (74, 78))	('mutations inactivating', 'Var', (51, 73))
356748	30837448	RAS mutation is found in almost 3% to 30% of sporadic SCCs and 14% in patient treated with BRAF inhibitors.	('RAS', 'Gene', (0, 3))	('SCC', 'Gene', '6317', (54, 57))	('BRAF', 'Gene', '673', (91, 95))	('patient', 'Species', '9606', (70, 77))	('found', 'Reg', (16, 21))	('mutation', 'Var', (4, 12))	('BRAF', 'Gene', (91, 95))	('SCC', 'Gene', (54, 57))	('SCC', 'Phenotype', 'HP:0002860', (54, 57))
356753	30837448	The mutation or hypermethylation of CDH2A was described in 35 primary and metastatic tumors.	('primary and', 'Disease', (62, 73))	('tumors', 'Disease', 'MESH:D009369', (85, 91))	('described', 'Reg', (46, 55))	('mutation', 'Var', (4, 12))	('hypermethylation', 'Var', (16, 32))	('CDH2A', 'Gene', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('tumors', 'Disease', (85, 91))
356761	30837448	The association of single nucleotide polymorphisms (SNP) of the class II human leukocyte antigen with tumor development was reported.	('association', 'Interaction', (4, 15))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('human', 'Species', '9606', (73, 78))	('single nucleotide polymorphisms', 'Var', (19, 50))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))
356779	30837448	The tissue was positive for programmed death ligand-1 (PDL1) by 30% and negative for EGFR mutation.	('EGFR', 'Gene', (85, 89))	('EGFR', 'Gene', '1956', (85, 89))	('PDL1', 'Gene', '29126', (55, 59))	('programmed death ligand-1', 'Gene', '29126', (28, 53))	('PDL1', 'Gene', (55, 59))	('programmed death ligand-1', 'Gene', (28, 53))	('mutation', 'Var', (90, 98))	('positive', 'Reg', (15, 23))
356820	29593943	In addition, we observed that the mutational event signatures might play a more important role in predicting immunotherapy response in squamous cell carcinoma and two subgroups of adenocarcinomas.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (135, 158))	('carcinoma', 'Phenotype', 'HP:0030731', (149, 158))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (135, 158))	('squamous cell carcinoma', 'Disease', (135, 158))	('adenocarcinomas', 'Disease', 'MESH:D000230', (180, 195))	('mutational', 'Var', (34, 44))	('adenocarcinomas', 'Disease', (180, 195))	('carcinoma', 'Phenotype', 'HP:0030731', (185, 194))
356831	29593943	Additionally, mutation burden combined with high expression of PD-L1 expression is also a potential predictor of response in NSCLS.	('mutation burden', 'Var', (14, 29))	('PD-L1', 'Gene', (63, 68))	('NSCLS', 'Disease', (125, 130))	('PD-L1', 'Gene', '29126', (63, 68))
356843	29593943	Through correlating all the derived immune, genomic and clinical metrics, we address several questions: how cytolytic activity in lung cancer correlate with mutation load; do the patient stratification analyses based on cytolytic activity and tumor mutational signatures reflect different mechanisms of immune evasion; and whether we can develop a new set of immunogenecity scores, which serve as a more accurate predictor of response to immune checkpoint inhibitor therapy with lung cancers.	('lung cancer', 'Phenotype', 'HP:0100526', (130, 141))	('lung cancer', 'Phenotype', 'HP:0100526', (479, 490))	('cancer', 'Phenotype', 'HP:0002664', (484, 490))	('lung cancers', 'Disease', 'MESH:D008175', (479, 491))	('lung cancers', 'Phenotype', 'HP:0100526', (479, 491))	('patient', 'Species', '9606', (179, 186))	('mutation', 'Var', (157, 165))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('lung cancer', 'Disease', 'MESH:D008175', (130, 141))	('tumor', 'Disease', 'MESH:D009369', (243, 248))	('lung cancer', 'Disease', 'MESH:D008175', (479, 490))	('lung cancers', 'Disease', (479, 491))	('cancers', 'Phenotype', 'HP:0002664', (484, 491))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))	('lung cancer', 'Disease', (130, 141))	('tumor', 'Disease', (243, 248))
356874	29593943	The mutations of few LUSC patients are even dominated by unexpected signatures such as signature 7 (associated with ultraviolet light exposure) and signature 15 (more likely to be associated with small cell lung cancer).	('small cell lung cancer', 'Phenotype', 'HP:0030357', (196, 218))	('associated', 'Reg', (180, 190))	('small cell lung cancer', 'Disease', (196, 218))	('associated', 'Reg', (100, 110))	('patients', 'Species', '9606', (26, 34))	('signature 15', 'Var', (148, 160))	('LUSC', 'Phenotype', 'HP:0030359', (21, 25))	('lung cancer', 'Phenotype', 'HP:0100526', (207, 218))	('small cell lung cancer', 'Disease', 'MESH:D055752', (196, 218))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))
356877	29593943	Furthermore, we also observe that the TCR clonality score derived from RNA-seq is much higher in cytolytic high groups.	('TCR', 'Gene', '6962', (38, 41))	('cytolytic high', 'Var', (97, 111))	('TCR', 'Gene', (38, 41))	('higher', 'PosReg', (87, 93))
356901	29593943	We observed that the CYT values are strongly associated with higher total immune infiltration scores, T cell infiltration scores and TCR clonality scores.	('TCR', 'Gene', '6962', (133, 136))	('higher', 'PosReg', (61, 67))	('TCR', 'Gene', (133, 136))	('CYT values', 'Var', (21, 31))	('immune infiltration scores', 'CPA', (74, 100))	('T cell infiltration scores', 'CPA', (102, 128))
356902	29593943	However, we did find that the immunologically hot and mutation-high patients tend to have higher immune scores compared to other patient groups in LUSC.	('patient', 'Species', '9606', (68, 75))	('immune scores', 'MPA', (97, 110))	('mutation-high', 'Var', (54, 67))	('patients', 'Species', '9606', (68, 76))	('higher', 'PosReg', (90, 96))	('LUSC', 'Phenotype', 'HP:0030359', (147, 151))	('patient', 'Species', '9606', (129, 136))
356906	29593943	S5, we also found that tumors with high CYT exhibited increase expression of immune checkpoint genes such as CD274 (PDL1), TIGIT, HAVCR2 (TIM3) and CTLA4.	('CD274', 'Gene', '29126', (109, 114))	('immune checkpoint genes', 'Gene', (77, 100))	('increase', 'PosReg', (54, 62))	('CTLA4', 'Gene', '1493', (148, 153))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))	('TIGIT', 'Gene', (123, 128))	('TIM3', 'Gene', (138, 142))	('PDL1', 'Gene', (116, 120))	('TIM3', 'Gene', '84868', (138, 142))	('HAVCR2', 'Gene', (130, 136))	('CD274', 'Gene', (109, 114))	('CTLA4', 'Gene', (148, 153))	('PDL1', 'Gene', '29126', (116, 120))	('tumors', 'Disease', (23, 29))	('expression', 'MPA', (63, 73))	('TIGIT', 'Gene', '201633', (123, 128))	('tumors', 'Disease', 'MESH:D009369', (23, 29))	('HAVCR2', 'Gene', '84868', (130, 136))	('high', 'Var', (35, 39))
356909	29593943	Just like the UV signature in melanoma, both mutational and immune profiles of tumors are greatly influenced by mutational signature related to smoking.	('influenced', 'Reg', (98, 108))	('mutational', 'Var', (112, 122))	('tumors', 'Disease', (79, 85))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('melanoma', 'Disease', 'MESH:D008545', (30, 38))	('melanoma', 'Phenotype', 'HP:0002861', (30, 38))	('melanoma', 'Disease', (30, 38))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
356922	27474168	We demonstrated that DHM can markedly induce apoptotic cell death and autophagy in HNSCC cells.	('HNSCC', 'Phenotype', 'HP:0012288', (83, 88))	('autophagy', 'CPA', (70, 79))	('induce', 'PosReg', (38, 44))	('DHM', 'Var', (21, 24))	('apoptotic cell death', 'CPA', (45, 65))	('DHM', 'Chemical', 'MESH:C472036', (21, 24))	('HNSC', 'CellLine', 'CVCL:F234', (83, 87))
356923	27474168	Pharmacological or genetic inhibition of autophagy further sensitized the HNSCC cells to DHM-induced apoptosis.	('autophagy', 'CPA', (41, 50))	('HNSC', 'CellLine', 'CVCL:F234', (74, 78))	('sensitized', 'Reg', (59, 69))	('HNSCC', 'Phenotype', 'HP:0012288', (74, 79))	('inhibition', 'Var', (27, 37))	('DHM', 'Chemical', 'MESH:C472036', (89, 92))	('genetic inhibition', 'Var', (19, 37))
356925	27474168	Importantly, DHM triggered reactive oxygen species (ROS) generation in the HNSCC cells and the levels of ROS decreased with N-acetyl-cysteine (NAC), a ROS scavenger.	('decreased', 'NegReg', (109, 118))	('N-acetyl-cysteine', 'Chemical', 'MESH:D000111', (124, 141))	('ROS', 'Chemical', 'MESH:D017382', (151, 154))	('DHM', 'Var', (13, 16))	('DHM', 'Chemical', 'MESH:C472036', (13, 16))	('ROS', 'Chemical', 'MESH:D017382', (52, 55))	('HNSC', 'CellLine', 'CVCL:F234', (75, 79))	('levels', 'MPA', (95, 101))	('NAC', 'Chemical', 'MESH:D000111', (143, 146))	('HNSCC', 'Phenotype', 'HP:0012288', (75, 80))	('ROS', 'Chemical', 'MESH:D017382', (105, 108))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (27, 50))	('N-acetyl-cysteine', 'Var', (124, 141))
356926	27474168	Moreover, NAC abrogated the effects of DHM on STAT3-dependent autophagy.	('NAC', 'Var', (10, 13))	('STAT3-dependent', 'MPA', (46, 61))	('DHM', 'Chemical', 'MESH:C472036', (39, 42))	('NAC', 'Chemical', 'MESH:D000111', (10, 13))	('abrogated', 'NegReg', (14, 23))
356927	27474168	Overall, the following critical issues were observed: first, DHM increased the p-STAT3-dependent autophagy by generating ROS-signaling pathways in head and neck squamous cell carcinoma.	('increased', 'PosReg', (65, 74))	('generating', 'PosReg', (110, 120))	('p-STAT3-dependent', 'MPA', (79, 96))	('DHM', 'Var', (61, 64))	('ROS', 'Chemical', 'MESH:D017382', (121, 124))	('ROS-signaling', 'MPA', (121, 134))	('DHM', 'Chemical', 'MESH:C472036', (61, 64))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (147, 184))	('carcinoma', 'Phenotype', 'HP:0030731', (175, 184))	('neck squamous cell carcinoma', 'Disease', (156, 184))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (161, 184))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (156, 184))
356935	27474168	Specifically, one study has revealed that DHM causes cell cycle arrest in human hepatoma cells.	('arrest', 'Disease', (64, 70))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (53, 70))	('arrest', 'Disease', 'MESH:D006323', (64, 70))	('hepatoma', 'Disease', (80, 88))	('hepatoma', 'Disease', 'MESH:D006528', (80, 88))	('DHM', 'Var', (42, 45))	('human', 'Species', '9606', (74, 79))	('DHM', 'Chemical', 'MESH:C472036', (42, 45))
356943	27474168	In the present study, we report that DHM induces obvious apoptosis in HNSCC cells.	('HNSC', 'CellLine', 'CVCL:F234', (70, 74))	('apoptosis', 'CPA', (57, 66))	('DHM', 'Var', (37, 40))	('HNSCC', 'Phenotype', 'HP:0012288', (70, 75))	('DHM', 'Chemical', 'MESH:C472036', (37, 40))
356944	27474168	Meanwhile, apoptosis is not the sole consequence of DHM deprivation, as DHM treatment rapidly activates an autophagic process.	('DHM', 'Chemical', 'MESH:C472036', (52, 55))	('DHM', 'Chemical', 'MESH:C472036', (72, 75))	('activates', 'PosReg', (94, 103))	('autophagic process', 'CPA', (107, 125))	('DHM', 'Var', (72, 75))
356946	27474168	Pharmacological or genetic inhibition of STAT3-dependent autophagy sensitized DHM-induced apoptosis in HNSCC.	('HNSCC', 'Phenotype', 'HP:0012288', (103, 108))	('inhibition', 'Var', (27, 37))	('DHM', 'Chemical', 'MESH:C472036', (78, 81))	('sensitized', 'Reg', (67, 77))	('HNSC', 'CellLine', 'CVCL:F234', (103, 107))
356947	27474168	These findings indicate that autophagy provides a cytoprotective mechanism in HNSCC cells treated by DHM, and inhibition of autophagy may improve the therapeutic efficacy of DHM in HNSCC treatment.	('cytoprotective mechanism', 'CPA', (50, 74))	('DHM', 'Chemical', 'MESH:C472036', (101, 104))	('therapeutic efficacy', 'CPA', (150, 170))	('autophagy', 'CPA', (124, 133))	('HNSC', 'CellLine', 'CVCL:F234', (78, 82))	('autophagy', 'CPA', (29, 38))	('improve', 'PosReg', (138, 145))	('HNSC', 'CellLine', 'CVCL:F234', (181, 185))	('HNSCC', 'Phenotype', 'HP:0012288', (78, 83))	('DHM', 'Chemical', 'MESH:C472036', (174, 177))	('inhibition', 'Var', (110, 120))	('HNSCC', 'Phenotype', 'HP:0012288', (181, 186))
356949	27474168	As shown in Figure 1A, cells were treated with different concentrations of DHM for 24 h or 50 muM DHM for 6, 12, and 24 h. We found that DHM induced cell apoptosis in a dose- and time-dependent manner.	('muM', 'Gene', '56925', (94, 97))	('DHM', 'Chemical', 'MESH:C472036', (75, 78))	('DHM', 'Var', (137, 140))	('DHM', 'Chemical', 'MESH:C472036', (98, 101))	('DHM', 'Chemical', 'MESH:C472036', (137, 140))	('muM', 'Gene', (94, 97))	('cell apoptosis', 'CPA', (149, 163))
356960	27474168	Moreover, induction of autophagy was identified by two established measurements of autophagy, that is, enhancement of Beclin-1, a component of class III phosphatidylinositol 3-kinase complex essential for autophagosome formation, and degradation of p62, a protein-facilitating autophagic degradation of ubiquitinated protein aggregation (Figure 2B and 2C).	('p62', 'Gene', (249, 252))	('enhancement', 'PosReg', (103, 114))	('ubiquitinated protein aggregation', 'Disease', 'MESH:D066263', (303, 336))	('degradation', 'Var', (234, 245))	('Beclin-1', 'Gene', (118, 126))	('autophagy', 'CPA', (23, 32))	('p62', 'Gene', '23636', (249, 252))	('ubiquitinated protein aggregation', 'Disease', (303, 336))	('Beclin-1', 'Gene', '8678', (118, 126))
356962	27474168	Considering that manipulation of autophagy may improve the efficacy of anticancer therapeutics, we were eager to determine whether the DHM-elicited autophagy in HNSCC favored cell survival or cell death.	('cell survival', 'CPA', (175, 188))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('DHM', 'Chemical', 'MESH:C472036', (135, 138))	('cancer', 'Disease', (75, 81))	('HNSC', 'CellLine', 'CVCL:F234', (161, 165))	('manipulation', 'Var', (17, 29))	('efficacy', 'MPA', (59, 67))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('HNSCC', 'Phenotype', 'HP:0012288', (161, 166))	('favored', 'PosReg', (167, 174))
356963	27474168	Beclin1 is an essential protein for autophagy activation; thus, beclin1 deficiency can significantly interrupt autophagy.	('Beclin1', 'Gene', (0, 7))	('beclin1', 'Gene', (64, 71))	('autophagy', 'CPA', (111, 120))	('deficiency', 'Var', (72, 82))	('beclin1', 'Gene', '8678', (64, 71))	('interrupt', 'NegReg', (101, 110))	('Beclin1', 'Gene', '8678', (0, 7))
356968	27474168	In agreement with the data derived from pharmacological inhibitors, knockdown of Beclin-1 by siRNA enhanced the cleaved PARP, as assayed by Western blot analysis (Figure 3C), indicating that autophagy is cytoprotective for DHM-induced apoptotic cell death.	('PARP', 'Gene', (120, 124))	('enhanced', 'PosReg', (99, 107))	('Beclin-1', 'Gene', (81, 89))	('Beclin-1', 'Gene', '8678', (81, 89))	('autophagy', 'CPA', (191, 200))	('knockdown', 'Var', (68, 77))	('siRNA', 'Gene', (93, 98))	('PARP', 'Gene', '1302', (120, 124))	('DHM', 'Chemical', 'MESH:C472036', (223, 226))
356971	27474168	These results reveal that inhibition of DHM-induced autophagy sensitized the HNSCC cells to DHM-induced apoptotic cell death.	('autophagy', 'CPA', (52, 61))	('inhibition', 'Var', (26, 36))	('DHM', 'Chemical', 'MESH:C472036', (40, 43))	('HNSC', 'CellLine', 'CVCL:F234', (77, 81))	('DHM', 'Chemical', 'MESH:C472036', (92, 95))	('HNSCC', 'Phenotype', 'HP:0012288', (77, 82))
356976	27474168	To further confirm the exact role of STAT3 signaling, we characterized the effects of DHM in cells in which STAT3 was decreased with NSC74859, an inhibitor of the dimerization and phosphorylation of STAT3.	('DHM', 'Chemical', 'MESH:C472036', (86, 89))	('STAT3', 'MPA', (108, 113))	('decreased', 'NegReg', (118, 127))	('NSC74859', 'Var', (133, 141))
356979	27474168	Moreover, Cl-PARP levels increased when p-STAT3T705 was suppressed (Figure 4C).	('PARP', 'Gene', (13, 17))	('PARP', 'Gene', '1302', (13, 17))	('increased', 'PosReg', (25, 34))	('p-STAT3T705', 'Var', (40, 51))
356980	27474168	These results suggested that DHM induced autophagy through activating STAT3 pathways in HNSCC cells.	('STAT3 pathways', 'Pathway', (70, 84))	('DHM', 'Var', (29, 32))	('autophagy', 'CPA', (41, 50))	('HNSC', 'CellLine', 'CVCL:F234', (88, 92))	('activating', 'PosReg', (59, 69))	('DHM', 'Chemical', 'MESH:C472036', (29, 32))	('HNSCC', 'Phenotype', 'HP:0012288', (88, 93))
356994	27474168	found that DHM induces cell apoptosis through a p53-related pathway in AGS human gastric cancer cells.	('cell apoptosis', 'CPA', (23, 37))	('p53', 'Gene', (48, 51))	('AGS', 'Disease', (71, 74))	('p53', 'Gene', '7157', (48, 51))	('AGS', 'Disease', 'MESH:C535607', (71, 74))	('DHM', 'Var', (11, 14))	('gastric cancer', 'Disease', 'MESH:D013274', (81, 95))	('gastric cancer', 'Disease', (81, 95))	('DHM', 'Chemical', 'MESH:C472036', (11, 14))	('human', 'Species', '9606', (75, 80))	('gastric cancer', 'Phenotype', 'HP:0012126', (81, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
356995	27474168	used a carbon tetrachloride-induced acute liver injury model to demonstrate that DHM alleviated the injury through a JNK-dependent mechanism.	('DHM', 'Var', (81, 84))	('acute liver injury', 'Disease', 'MESH:D056486', (36, 54))	('JNK', 'Gene', '5599', (117, 120))	('DHM', 'Chemical', 'MESH:C472036', (81, 84))	('acute liver injury', 'Disease', (36, 54))	('carbon tetrachloride', 'Chemical', 'MESH:D002251', (7, 27))	('alleviated', 'NegReg', (85, 95))	('JNK', 'Gene', (117, 120))
356996	27474168	showed that DHM enhanced the chemosensitivity of nedaplatin through regulation of the p53/Bcl-2 pathway in hepatocellular carcinoma cells.	('chemosensitivity', 'MPA', (29, 45))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (107, 131))	('p53', 'Gene', '7157', (86, 89))	('DHM', 'Chemical', 'MESH:C472036', (12, 15))	('Bcl-2', 'Gene', (90, 95))	('hepatocellular carcinoma', 'Disease', (107, 131))	('Bcl-2', 'Gene', '596', (90, 95))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (107, 131))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('DHM', 'Var', (12, 15))	('enhanced', 'PosReg', (16, 24))	('p53', 'Gene', (86, 89))
357000	27474168	We also propose a novel mechanism in which DHM increased the p-STAT3-dependent autophagy by generating ROS-signaling pathways in head and neck squamous cell carcinoma (Figure 6).	('DHM', 'Var', (43, 46))	('ROS', 'Chemical', 'MESH:D017382', (103, 106))	('neck squamous cell carcinoma', 'Disease', (138, 166))	('ROS-signaling', 'MPA', (103, 116))	('DHM', 'Chemical', 'MESH:C472036', (43, 46))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (129, 166))	('increased', 'PosReg', (47, 56))	('carcinoma', 'Phenotype', 'HP:0030731', (157, 166))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (143, 166))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (138, 166))	('p-STAT3-dependent', 'MPA', (61, 78))
357008	27474168	To further illustrate the role of STAT3 signaling in DHM-induced autophagy, STAT3 was blocked by NSC74859 (also known as S3I-201), an inhibitor of the dimerization and phosphorylation of STAT3; we found that blocking p-STAT3 could suppress DHM-induced autophagy.	('DHM', 'Chemical', 'MESH:C472036', (240, 243))	('p-STAT3', 'Protein', (217, 224))	('suppress', 'NegReg', (231, 239))	('DHM-induced', 'Disease', (240, 251))	('DHM', 'Chemical', 'MESH:C472036', (53, 56))	('blocking', 'Var', (208, 216))
357017	27474168	Thus, we report that DHM induces obvious apoptosis in HNSCC cells.	('HNSC', 'CellLine', 'CVCL:F234', (54, 58))	('DHM', 'Var', (21, 24))	('DHM', 'Chemical', 'MESH:C472036', (21, 24))	('apoptosis', 'CPA', (41, 50))	('HNSCC', 'Phenotype', 'HP:0012288', (54, 59))
357020	27474168	Pharmacological or genetic inhibition of STAT3-dependent autophagy sensitizes DHM-induced apoptosis in HNSCC.	('HNSCC', 'Phenotype', 'HP:0012288', (103, 108))	('HNSCC', 'Disease', (103, 108))	('sensitizes', 'Reg', (67, 77))	('inhibition', 'Var', (27, 37))	('DHM', 'Chemical', 'MESH:C472036', (78, 81))	('HNSC', 'CellLine', 'CVCL:F234', (103, 107))
357051	27892457	Amplification of USP13 drives ovarian cancer metabolism Dysregulated energetic metabolism has been recently identified as a hallmark of cancer.	('cancer', 'Disease', (38, 44))	('drives', 'PosReg', (23, 29))	('Amplification', 'Var', (0, 13))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('ovarian cancer', 'Disease', 'MESH:D010051', (30, 44))	('USP13', 'Gene', '8975', (17, 22))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('ovarian cancer', 'Disease', (30, 44))	('USP13', 'Gene', (17, 22))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('cancer', 'Disease', (136, 142))	('Dysregulated energetic metabolism', 'MPA', (56, 89))	('ovarian cancer', 'Phenotype', 'HP:0100615', (30, 44))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
357052	27892457	Although mutations in metabolic enzymes hardwire metabolism to tumourigenesis, they are relatively infrequent in ovarian cancer.	('ovarian cancer', 'Phenotype', 'HP:0100615', (113, 127))	('metabolism', 'MPA', (49, 59))	('ovarian cancer', 'Disease', 'MESH:D010051', (113, 127))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('hardwire', 'Reg', (40, 48))	('mutations', 'Var', (9, 18))	('tumour', 'Phenotype', 'HP:0002664', (63, 69))	('ovarian cancer', 'Disease', (113, 127))	('tumour', 'Disease', 'MESH:D009369', (63, 69))	('tumour', 'Disease', (63, 69))
357055	27892457	USP13 specifically deubiquitinates and thus upregulates ATP citrate lyase and oxoglutarate dehydrogenase, two key enzymes that determine mitochondrial respiration, glutaminolysis and fatty acid synthesis.	('ATP citrate lyase', 'Gene', (56, 73))	('fatty acid', 'Chemical', 'MESH:D005227', (183, 193))	('oxoglutarate dehydrogenase', 'Gene', '4967', (78, 104))	('oxoglutarate dehydrogenase', 'Gene', (78, 104))	('upregulates', 'PosReg', (44, 55))	('USP13', 'Var', (0, 5))	('ATP citrate lyase', 'Gene', '47', (56, 73))	('deubiquitinates', 'MPA', (19, 34))
357057	27892457	Inhibiting USP13 remarkably suppresses ovarian tumour progression and sensitizes tumour cells to the treatment of PI3K/AKT inhibitor.	('tumour', 'Disease', 'MESH:D009369', (47, 53))	('tumour', 'Disease', 'MESH:D009369', (81, 87))	('Inhibiting', 'Var', (0, 10))	('ovarian tumour', 'Disease', (39, 53))	('AKT', 'Gene', '207', (119, 122))	('USP13', 'Gene', (11, 16))	('tumour', 'Disease', (47, 53))	('tumour', 'Disease', (81, 87))	('suppresses', 'NegReg', (28, 38))	('ovarian tumour', 'Phenotype', 'HP:0100615', (39, 53))	('AKT', 'Gene', (119, 122))	('ovarian tumour', 'Disease', 'MESH:D010051', (39, 53))	('tumour', 'Phenotype', 'HP:0002664', (47, 53))	('tumour', 'Phenotype', 'HP:0002664', (81, 87))
357083	27892457	Inhibition of OGDH leads to buildup of lactic acid and suppresses cell growth.	('lactic acid', 'Chemical', 'MESH:D019344', (39, 50))	('buildup', 'MPA', (28, 35))	('lactic acid', 'MPA', (39, 50))	('OGDH', 'Gene', (14, 18))	('Inhibition', 'Var', (0, 10))	('cell growth', 'CPA', (66, 77))	('suppresses', 'NegReg', (55, 65))
357087	27892457	Genomic analyses reveal that HGSC is driven primarily by gene copy-number changes rather than recurrent gene point mutations, among which genomic alteration of the PI3K/AKT pathway is most common and associated with poor clinical outcomes.	('AKT', 'Gene', (169, 172))	('gene copy-number changes', 'Var', (57, 81))	('HGSC', 'Disease', (29, 33))	('AKT', 'Gene', '207', (169, 172))
357089	27892457	We identified genomic amplification of USP13 in HGSC and the association of USP13 overexpression with aggressive OVCA progression.	('genomic amplification', 'Var', (14, 35))	('OVCA', 'Phenotype', 'HP:0100615', (113, 117))	('expression', 'Species', '29278', (86, 96))	('HGSC', 'Disease', (48, 52))	('overexpression', 'PosReg', (82, 96))	('USP13', 'Gene', (76, 81))	('USP13', 'Gene', (39, 44))	('aggressive OVCA progression', 'Disease', (102, 129))	('association', 'Interaction', (61, 72))
357091	27892457	Inhibition of USP13 simultaneously suppresses glutamate anaplerosis to refill the TCA cycle and the generation of acetyl-CoA, a vital building block for de novo biosynthesis of fatty acids, leading to the marked supersession of OVCA cell proliferation and tumourigenic potential.	('generation', 'MPA', (100, 110))	('tumour', 'Disease', 'MESH:D009369', (256, 262))	('TCA', 'Chemical', 'MESH:D014233', (82, 85))	('tumour', 'Disease', (256, 262))	('OVCA', 'Phenotype', 'HP:0100615', (228, 232))	('tumour', 'Phenotype', 'HP:0002664', (256, 262))	('USP13', 'Gene', (14, 19))	('fatty acids', 'Chemical', 'MESH:D005227', (177, 188))	('Inhibition', 'Var', (0, 10))	('glutamate', 'Chemical', 'MESH:D018698', (46, 55))	('OVCA cell proliferation', 'CPA', (228, 251))	('glutamate anaplerosis', 'MPA', (46, 67))	('acetyl-CoA', 'Chemical', 'MESH:D000105', (114, 124))	('suppresses', 'NegReg', (35, 45))
357096	27892457	Copy number of USP13 is also significantly correlated with its messenger RNA expression (R=0.306, P=0.0002, unpaired t-test) (Fig.	('messenger RNA expression', 'MPA', (63, 87))	('correlated', 'Reg', (43, 53))	('Copy number', 'Var', (0, 11))	('expression', 'Species', '29278', (77, 87))	('USP13', 'Gene', (15, 20))
357102	27892457	Consequently, high expression of USP13 is significantly associated with poor survival of patients with OVCA (Fig.	('associated', 'Reg', (56, 66))	('patients', 'Species', '9606', (89, 97))	('high expression', 'Var', (14, 29))	('OVCA', 'Disease', (103, 107))	('OVCA', 'Phenotype', 'HP:0100615', (103, 107))	('USP13', 'Gene', (33, 38))	('expression', 'Species', '29278', (19, 29))	('poor', 'NegReg', (72, 76))
357108	27892457	The results suggest that OVCA cells are probably addicted to the USP13 amplification or overexpression.	('overexpression', 'PosReg', (88, 102))	('USP13', 'Gene', (65, 70))	('amplification', 'Var', (71, 84))	('OVCA', 'Disease', (25, 29))	('OVCA', 'Phenotype', 'HP:0100615', (25, 29))	('expression', 'Species', '29278', (92, 102))
357110	27892457	Depletion of USP13 resulted in profound decrease in tumour weight and number of tumour nodules in both CAOV3- and HeyA8-derived ovarian tumour xenografts (Fig.	('decrease', 'NegReg', (40, 48))	('ovarian tumour', 'Disease', (128, 142))	('tumour weight', 'Disease', (52, 65))	('tumour', 'Phenotype', 'HP:0002664', (52, 58))	('USP13', 'Gene', (13, 18))	('ovarian tumour', 'Phenotype', 'HP:0100615', (128, 142))	('tumour weight', 'Disease', 'MESH:D015431', (52, 65))	('Depletion', 'Var', (0, 9))	('tumour', 'Phenotype', 'HP:0002664', (80, 86))	('tumour nodules', 'Disease', 'MESH:D016606', (80, 94))	('ovarian tumour', 'Disease', 'MESH:D010051', (128, 142))	('tumour', 'Phenotype', 'HP:0002664', (136, 142))	('tumour nodules', 'Disease', (80, 94))
357112	27892457	Since USP13 and PIK3CA are often co-amplified, we asked whether the USP13 amplification influences the sensitivity of OVCA cells to the inhibition of PI3K/AKT.	('AKT', 'Gene', (155, 158))	('PIK3CA', 'Gene', '5290', (16, 22))	('OVCA', 'Phenotype', 'HP:0100615', (118, 122))	('amplification', 'Var', (74, 87))	('USP13', 'Gene', (68, 73))	('influences', 'Reg', (88, 98))	('sensitivity', 'MPA', (103, 114))	('AKT', 'Gene', '207', (155, 158))	('PIK3CA', 'Gene', (16, 22))
357114	27892457	By contrast, SKOV3 and IGROV1 cells expressing low levels of USP13 and PIK3CA were very sensitive to the treatment of MK-2206- and USP13-KD had minimal effect on cell survival.	('PIK3CA', 'Gene', '5290', (71, 77))	('USP13-KD', 'Var', (131, 139))	('MK-2206', 'Chemical', 'MESH:C548887', (118, 125))	('MK-2206-', 'Var', (118, 126))	('SKOV3', 'CellLine', 'CVCL:0532', (13, 18))	('PIK3CA', 'Gene', (71, 77))
357115	27892457	The results suggest that inhibition of USP13 may enhance the effects of PI3K/AKT inhibitors on killing OVCA cells.	('effects', 'MPA', (61, 68))	('AKT', 'Gene', '207', (77, 80))	('enhance', 'PosReg', (49, 56))	('inhibition', 'Var', (25, 35))	('OVCA', 'Phenotype', 'HP:0100615', (103, 107))	('AKT', 'Gene', (77, 80))	('USP13', 'Gene', (39, 44))
357117	27892457	USP13-KD significantly reduced the levels of ACLY and OGDH, while overexpression of USP13 had the opposite effect (Fig.	('reduced', 'NegReg', (23, 30))	('expression', 'Species', '29278', (70, 80))	('USP13-KD', 'Var', (0, 8))	('ACLY', 'MPA', (45, 49))	('OGDH', 'MPA', (54, 58))
357118	27892457	Cys345 of USP13 is a critical residue for its deubiquitination activity, and mutating it to alanine abolishes this activity.	('Cys345', 'Var', (0, 6))	('USP13', 'Gene', (10, 15))	('mutating', 'Var', (77, 85))	('deubiquitination activity', 'MPA', (46, 71))	('Cys345', 'Chemical', '-', (0, 6))	('alanine', 'Chemical', 'MESH:D000409', (92, 99))	('abolishes', 'NegReg', (100, 109))
357119	27892457	We found that the C345A mutant of USP13 was unable to increase the steady-state levels of ACLY and OGDH in contrast to the wild-type USP13 (Fig.	('USP13', 'Gene', (34, 39))	('C345A', 'Mutation', 'c.345C>A', (18, 23))	('OGDH', 'MPA', (99, 103))	('C345A', 'Var', (18, 23))
357129	27892457	Ubiquitin has seven lysine residues as points of ubiquitination, in which K48-linked polyubiquitin chains target proteins for degradation, whereas K63-linked chains are associated with regulatory functions.	('K48-linked', 'Var', (74, 84))	('target', 'Reg', (106, 112))	('proteins', 'MPA', (113, 121))	('lysine', 'Chemical', 'MESH:D008239', (20, 26))	('degradation', 'MPA', (126, 137))
357130	27892457	To determine what type of ubiquitination USP13 acts on, we transfected HEK293T cells with K48R or K63R mutant form of ubiquitin.	('HEK293T', 'CellLine', 'CVCL:0063', (71, 78))	('K63R', 'Var', (98, 102))	('K48R', 'SUBSTITUTION', 'None', (90, 94))	('K63R', 'Mutation', 'p.K63R', (98, 102))	('ubiquitin', 'Protein', (118, 127))	('K48R', 'Var', (90, 94))
357131	27892457	Overexpression of USP13 inhibited wild-type and K63R mutant forms of ubiquitin-associated ubiquitination of ACLY, but had no effect on the K48R ubiquitin-associated ubiquitination (Fig.	('K48R', 'Var', (139, 143))	('expression', 'Species', '29278', (4, 14))	('USP13', 'Gene', (18, 23))	('inhibited', 'NegReg', (24, 33))	('K48R', 'SUBSTITUTION', 'None', (139, 143))	('K63R', 'Var', (48, 52))	('K63R', 'Mutation', 'p.K63R', (48, 52))	('ubiquitin-associated ubiquitination', 'MPA', (69, 104))
357132	27892457	The C345A mutant of USP13 failed to reduce the ubiquitination of ACLY (Fig.	('C345A', 'Mutation', 'c.345C>A', (4, 9))	('reduce', 'NegReg', (36, 42))	('C345A', 'Var', (4, 9))	('USP13', 'Gene', (20, 25))	('ubiquitination of ACLY', 'MPA', (47, 69))
357133	27892457	Increasing amounts of USP13 proteins resulted in decreasing ubiquitination levels of ACLY, while the C345A mutation abolished the activity of USP13 (Fig.	('ubiquitination levels', 'MPA', (60, 81))	('C345A', 'Mutation', 'c.345C>A', (101, 106))	('decreasing', 'NegReg', (49, 59))	('C345A', 'Var', (101, 106))	('abolished', 'NegReg', (116, 125))	('activity', 'MPA', (130, 138))
357144	27892457	USP13-KD reduced the percentages of M5 glutamate, M4 fumarate, M4 aspartate, M3 pyruvate, M3 lactate and M3 alanine in HeyA8 and CAOV3 cells (Fig.	('M3 pyruvate', 'MPA', (77, 88))	('glutamate', 'Chemical', 'MESH:D018698', (39, 48))	('M3 alanine', 'MPA', (105, 115))	('alanine', 'Chemical', 'MESH:D000409', (108, 115))	('M3 lactate', 'MPA', (90, 100))	('USP13-KD', 'Var', (0, 8))	('reduced', 'NegReg', (9, 16))	('pyruvate', 'Chemical', 'MESH:D019289', (80, 88))	('aspartate', 'Chemical', 'MESH:D001224', (66, 75))	('M4 fumarate', 'MPA', (50, 61))	('M4 fumarate', 'Chemical', '-', (50, 61))	('M4 aspartate', 'MPA', (63, 75))	('M5 glutamate', 'MPA', (36, 48))	('lactate', 'Chemical', 'MESH:D019344', (93, 100))
357146	27892457	Furthermore, we found that USP13-KD decreased the level of M4 TCA cycle metabolites, which are directly derived from [U-13C5] glutamine, indicating a reduced flux of glutamine into TCA cycle (Supplementary Fig.	('[U-13C5] glutamine', 'Chemical', '-', (117, 135))	('glutamine', 'Chemical', 'MESH:D005973', (166, 175))	('TCA', 'Chemical', 'MESH:D014233', (62, 65))	('level of M4 TCA cycle metabolites', 'MPA', (50, 83))	('TCA', 'Chemical', 'MESH:D014233', (181, 184))	('USP13-KD', 'Var', (27, 35))	('reduced', 'NegReg', (150, 157))	('glutamine', 'Chemical', 'MESH:D005973', (126, 135))	('flux', 'MPA', (158, 162))	('decreased', 'NegReg', (36, 45))
357148	27892457	Marked reduction of basal oxygen consumption rate (OCR) levels was observed in the USP13-KD cells, indicating the influence of USP13 on respiration (Fig.	('USP13', 'Var', (127, 132))	('oxygen', 'Chemical', 'MESH:D010100', (26, 32))	('USP13-KD', 'Var', (83, 91))	('reduction', 'NegReg', (7, 16))
357149	27892457	Significant reduction of ATP-linked OCR, maximal OCR and mitochondrial respiratory control ratio were seen in the USP13-KD cells.	('ATP-linked OCR', 'MPA', (25, 39))	('reduction', 'NegReg', (12, 21))	('ATP', 'Chemical', 'MESH:D000255', (25, 28))	('mitochondrial respiratory control ratio', 'MPA', (57, 96))	('USP13-KD', 'Var', (114, 122))	('maximal OCR', 'MPA', (41, 52))
357150	27892457	In support of the involvement of USP13 in bioenergetics, USP13-KD inhibited ATP production in cells (Fig.	('inhibited', 'NegReg', (66, 75))	('ATP', 'Chemical', 'MESH:D000255', (76, 79))	('ATP production', 'MPA', (76, 90))	('USP13-KD', 'Var', (57, 65))
357151	27892457	Under glutamine depletion conditions, USP13-KD CAOV3 cells are less dependent on glutamine for respiration (basal OCR) compared with control CAOV3 cells (Fig.	('dependent', 'MPA', (68, 77))	('USP13-KD', 'Var', (38, 46))	('glutamine', 'Chemical', 'MESH:D005973', (81, 90))	('glutamine', 'Chemical', 'MESH:D005973', (6, 15))	('less', 'NegReg', (63, 67))
357152	27892457	To investigate the effect of USP13 KD on glucose metabolism, we measured glycolytic capacity of OVCA cells when USP13 was knocked down and found that USP13 depletion significantly enhances lactate secretion in CAOV3 and HeyA8 cells, but it does not have a consistent effect on glucose uptake for CAOV3 and HeyA8 (Supplementary Fig.	('enhances', 'PosReg', (180, 188))	('USP13', 'Gene', (112, 117))	('USP13', 'Gene', (150, 155))	('lactate secretion', 'MPA', (189, 206))	('glucose', 'Chemical', 'MESH:D005947', (277, 284))	('OVCA', 'Phenotype', 'HP:0100615', (96, 100))	('knocked', 'Var', (122, 129))	('glucose', 'Chemical', 'MESH:D005947', (41, 48))	('lactate', 'Chemical', 'MESH:D019344', (189, 196))	('depletion', 'Var', (156, 165))
357155	27892457	We found that in both CAOV3 and HeyA8 cell lines, USP13-KD decreases the relative levels of M2 fumarate, malate and citrate, which are derived directly from [U-13C6] glucose (Fig.	('USP13-KD', 'Var', (50, 58))	('decreases', 'NegReg', (59, 68))	('M2 fumarate', 'MPA', (92, 103))	('malate', 'MPA', (105, 111))	('M2 fumarate', 'Chemical', '-', (92, 103))	('malate', 'Chemical', 'MESH:C030298', (105, 111))	('[U-13C6] glucose', 'Chemical', '-', (157, 173))	('citrate', 'Chemical', 'MESH:D019343', (116, 123))	('citrate', 'MPA', (116, 123))
357156	27892457	Therefore, USP13-KD also decreases glucose oxidation into TCA cycle metabolites.	('glucose', 'Chemical', 'MESH:D005947', (35, 42))	('TCA', 'Chemical', 'MESH:D014233', (58, 61))	('decreases', 'NegReg', (25, 34))	('decreases glucose oxidation', 'Phenotype', 'HP:0040270', (25, 52))	('glucose oxidation into TCA cycle metabolites', 'MPA', (35, 79))	('USP13-KD', 'Var', (11, 19))
357158	27892457	Interestingly, we found that OGDH KD and OGDH/ACLY double KD have profound effects on reducing both glutamine oxidation and glucose oxidation (Fig.	('glutamine', 'Chemical', 'MESH:D005973', (100, 109))	('glucose', 'Chemical', 'MESH:D005947', (124, 131))	('OGDH KD', 'Var', (29, 36))	('glutamine oxidation', 'MPA', (100, 119))	('reducing', 'NegReg', (86, 94))	('glucose oxidation', 'MPA', (124, 141))
357169	27892457	In line with our hypothesis, we found that USP13-KD significantly decreased M5 citrate, M3 fumarate and M3 malate pools in CAOV3 cells (Fig.	('fumarate', 'Chemical', 'MESH:D005650', (91, 99))	('citrate', 'Chemical', 'MESH:D019343', (79, 86))	('M5 citrate', 'MPA', (76, 86))	('USP13-KD', 'Var', (43, 51))	('decreased', 'NegReg', (66, 75))	('M3 malate pools', 'MPA', (104, 119))	('malate', 'Chemical', 'MESH:C030298', (107, 113))
357175	27892457	The palmitate isotopologue distribution shows that USP13-KD will also decrease glucose's contribution to de novo lipid synthesis in CAOV3 and HeyA8 (Supplementary Fig.	('lipid', 'Chemical', 'MESH:D008055', (113, 118))	('palmitate', 'Chemical', 'MESH:D010168', (4, 13))	('contribution', 'MPA', (89, 101))	('glucose', 'MPA', (79, 86))	('USP13-KD', 'Var', (51, 59))	('decrease', 'NegReg', (70, 78))	('glucose', 'Chemical', 'MESH:D005947', (79, 86))
357178	27892457	USP13-KD also significantly decreased ACLY activity, while USP13 overexpression enhanced ACLY activity in the ACLY activity assay (Supplementary Fig.	('ACLY activity assay', 'MPA', (110, 129))	('ACLY activity', 'MPA', (38, 51))	('decreased', 'NegReg', (28, 37))	('USP13', 'Gene', (59, 64))	('expression', 'Species', '29278', (69, 79))	('USP13-KD', 'Var', (0, 8))	('overexpression enhanced', 'PosReg', (65, 88))	('ACLY activity', 'MPA', (89, 102))
357179	27892457	We observed that lipid synthesis from both glucose and glutamine was significantly reduced when USP13 was knocked down (Fig.	('glutamine', 'Chemical', 'MESH:D005973', (55, 64))	('lipid', 'Chemical', 'MESH:D008055', (17, 22))	('reduced', 'NegReg', (83, 90))	('knocked down', 'Var', (106, 118))	('USP13', 'Gene', (96, 101))	('glucose', 'Chemical', 'MESH:D005947', (43, 50))	('lipid synthesis from', 'MPA', (17, 37))
357180	27892457	To further clarify the effects of OGDH and ACLY on de novo fatty acids synthesis in OVCA, we used [U-13C5] glutamine or [U-13C6] glucose to culture cancer cells for 72 h. Our results show that both OGDH KD and ACLY KD decrease the conversion of glutamine and glucose in palmitate (Fig.	('cancer', 'Disease', (148, 154))	('fatty acids', 'Chemical', 'MESH:D005227', (59, 70))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('palmitate', 'Chemical', 'MESH:D010168', (270, 279))	('glutamine', 'Chemical', 'MESH:D005973', (107, 116))	('OVCA', 'Phenotype', 'HP:0100615', (84, 88))	('glutamine', 'Chemical', 'MESH:D005973', (245, 254))	('decrease', 'NegReg', (218, 226))	('OGDH', 'Var', (198, 202))	('[U-13C6] glucose', 'Chemical', '-', (120, 136))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('glucose', 'Chemical', 'MESH:D005947', (259, 266))	('glucose', 'Chemical', 'MESH:D005947', (129, 136))	('[U-13C5] glutamine', 'Chemical', '-', (98, 116))
357181	27892457	Isotopomer spectral analysis indicates that OGDH KD and ACLY KD decreases the fraction of de novo synthesized palmitate in total cellular palmitate pool as well as the percentage contribution from glutamine reductive carboxylation and glucose oxidation (Fig.	('OGDH KD', 'Var', (44, 51))	('glutamine reductive carboxylation', 'MPA', (197, 230))	('glucose oxidation', 'MPA', (235, 252))	('glutamine', 'Chemical', 'MESH:D005973', (197, 206))	('palmitate', 'Chemical', 'MESH:D010168', (138, 147))	('glucose', 'Chemical', 'MESH:D005947', (235, 242))	('palmitate', 'Chemical', 'MESH:D010168', (110, 119))	('fraction of de novo synthesized palmitate', 'MPA', (78, 119))	('decreases', 'NegReg', (64, 73))
357185	27892457	These data suggest that USP13-KD induces mitochondrial dysfunction and lipogenic dysfunction by reducing OGDH and ACLY activity, thereby reducing glutamine's reductive carboxylation and glucose's oxidation for lipid synthesis (Fig.	('glucose', 'MPA', (186, 193))	('reducing', 'NegReg', (137, 145))	('glutamine', 'Chemical', 'MESH:D005973', (146, 155))	('mitochondrial dysfunction', 'Disease', (41, 66))	('lipogenic dysfunction', 'Disease', (71, 92))	('glucose', 'Chemical', 'MESH:D005947', (186, 193))	('ACLY activity', 'MPA', (114, 127))	('reducing', 'NegReg', (96, 104))	('glutamine', 'MPA', (146, 155))	('lipid', 'Chemical', 'MESH:D008055', (210, 215))	('reductive carboxylation', 'MPA', (158, 181))	('oxidation for lipid synthesis', 'MPA', (196, 225))	('USP13-KD', 'Var', (24, 32))	('mitochondrial dysfunction', 'Disease', 'MESH:D028361', (41, 66))	('induces', 'Reg', (33, 40))	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (41, 66))	('OGDH', 'MPA', (105, 109))
357186	27892457	Targeting USP13 may result in synthetically lethal metabolic targets, which not only block nutrient's entry into TCA, but also reduce de novo lipogenesis.	('de novo lipogenesis', 'MPA', (134, 153))	('USP13', 'Gene', (10, 15))	('reduce', 'NegReg', (127, 133))	('Targeting', 'Var', (0, 9))	('TCA', 'Chemical', 'MESH:D014233', (113, 116))	('block', 'NegReg', (85, 90))
357191	27892457	Examination of end-point tumour burden in Dox-treated or -untreated groups (n=10 per group) demonstrated that depletion of USP13 resulted in profound decreases in tumour weight (78.5% reduction, P<0.001) and number of nodules (68.7% reduction, P<0.001; Fig.	('reduction', 'NegReg', (184, 193))	('Dox', 'Chemical', 'MESH:D004318', (42, 45))	('tumour burden', 'Disease', (25, 38))	('USP13', 'Gene', (123, 128))	('tumour', 'Phenotype', 'HP:0002664', (25, 31))	('tumour burden', 'Disease', 'MESH:D009369', (25, 38))	('tumour', 'Phenotype', 'HP:0002664', (163, 169))	('tumour weight', 'Disease', 'MESH:D015431', (163, 176))	('tumour weight', 'Disease', (163, 176))	('reduction', 'NegReg', (233, 242))	('depletion', 'Var', (110, 119))	('decreases', 'NegReg', (150, 159))
357198	27892457	To further determine the essential role of ACLY and OGDH in USP13-induced ovarian tumourigenesis, the expression of ACLY and OGDH was restored by exogenous overexpression in OVCA cells with USP13-KD (Supplementary Fig.	('tumour', 'Phenotype', 'HP:0002664', (82, 88))	('expression', 'Species', '29278', (102, 112))	('USP13-KD', 'Var', (190, 198))	('expression', 'MPA', (102, 112))	('ovarian tumourigenesis', 'Disease', (74, 96))	('OVCA', 'Phenotype', 'HP:0100615', (174, 178))	('OGDH', 'Gene', (125, 129))	('expression', 'Species', '29278', (160, 170))	('ovarian tumour', 'Phenotype', 'HP:0100615', (74, 88))	('ovarian tumourigenesis', 'Disease', 'MESH:D010049', (74, 96))
357201	27892457	Next, we determined whether inhibition of USP13 sensitizes ovarian tumours to the treatment of the pan-AKT inhibitor MK-2206 in vivo.	('AKT', 'Gene', '207', (103, 106))	('ovarian tumour', 'Phenotype', 'HP:0100615', (59, 73))	('MK-2206', 'Chemical', 'MESH:C548887', (117, 124))	('ovarian tumours', 'Disease', (59, 74))	('AKT', 'Gene', (103, 106))	('inhibition', 'Var', (28, 38))	('USP13', 'Gene', (42, 47))	('tumour', 'Phenotype', 'HP:0002664', (67, 73))	('sensitizes', 'Reg', (48, 58))	('tumours', 'Phenotype', 'HP:0002664', (67, 74))	('ovarian tumours', 'Disease', 'MESH:D010051', (59, 74))
357204	27892457	In comparison with vehicle control, MK-2206 treatment modestly inhibited tumour growth, but tumours were significantly smaller in the mice co-treated with MK-2206 and Dox (Fig.	('tumours', 'Phenotype', 'HP:0002664', (92, 99))	('MK-2206', 'Var', (155, 162))	('smaller', 'NegReg', (119, 126))	('mice', 'Species', '10090', (134, 138))	('MK-2206', 'Chemical', 'MESH:C548887', (155, 162))	('tumours', 'Disease', 'MESH:D009369', (92, 99))	('tumours', 'Disease', (92, 99))	('tumour growth', 'Disease', (73, 86))	('tumour', 'Phenotype', 'HP:0002664', (73, 79))	('MK-2206', 'Chemical', 'MESH:C548887', (36, 43))	('inhibited', 'NegReg', (63, 72))	('tumour growth', 'Disease', 'MESH:D006130', (73, 86))	('tumour', 'Phenotype', 'HP:0002664', (92, 98))	('Dox', 'Chemical', 'MESH:D004318', (167, 170))
357208	27892457	Treatment of MK-2206 significantly inhibited the activity of AKT (indicated by pAKT levels; Fig.	('MK-2206', 'Chemical', 'MESH:C548887', (13, 20))	('activity', 'MPA', (49, 57))	('AKT', 'Gene', '207', (80, 83))	('AKT', 'Gene', '207', (61, 64))	('AKT', 'Gene', (80, 83))	('inhibited', 'NegReg', (35, 44))	('AKT', 'Gene', (61, 64))	('MK-2206', 'Var', (13, 20))
357210	27892457	However, the tumours co-treated with Dox and MK-2206 had a markedly lower percentage of Ki-67-positive cells compared with the untreated or MK-2206-treated tumours.	('MK-2206', 'Var', (45, 52))	('tumour', 'Phenotype', 'HP:0002664', (13, 19))	('MK-2206', 'Chemical', 'MESH:C548887', (45, 52))	('lower', 'NegReg', (68, 73))	('tumours', 'Phenotype', 'HP:0002664', (13, 20))	('tumours', 'Disease', 'MESH:D009369', (156, 163))	('tumours', 'Disease', (156, 163))	('Ki-67-positive', 'Protein', (88, 102))	('tumour', 'Phenotype', 'HP:0002664', (156, 162))	('tumours', 'Disease', 'MESH:D009369', (13, 20))	('tumours', 'Disease', (13, 20))	('Dox', 'Chemical', 'MESH:D004318', (37, 40))	('tumours', 'Phenotype', 'HP:0002664', (156, 163))	('MK-2206', 'Chemical', 'MESH:C548887', (140, 147))
357214	27892457	In this study, we identified frequent copy-number gain of the USP13 gene in OVCA and found two USP13 deubiquitination targets that determine glutaminolysis, glucose oxidation, mitochondrial respiration and lipid synthesis.	('glutaminolysis', 'MPA', (141, 155))	('lipid', 'Chemical', 'MESH:D008055', (206, 211))	('glucose oxidation', 'MPA', (157, 174))	('mitochondrial respiration', 'MPA', (176, 201))	('USP13', 'Gene', (62, 67))	('gain', 'PosReg', (50, 54))	('OVCA', 'Phenotype', 'HP:0100615', (76, 80))	('lipid synthesis', 'MPA', (206, 221))	('glucose', 'Chemical', 'MESH:D005947', (157, 164))	('copy-number', 'Var', (38, 49))	('OVCA', 'Disease', (76, 80))
357215	27892457	Our findings suggest that USP13 amplification is likely an important driver in ovarian tumour progression.	('ovarian tumour', 'Phenotype', 'HP:0100615', (79, 93))	('USP13', 'Gene', (26, 31))	('ovarian tumour', 'Disease', 'MESH:D010051', (79, 93))	('amplification', 'Var', (32, 45))	('tumour', 'Phenotype', 'HP:0002664', (87, 93))	('ovarian tumour', 'Disease', (79, 93))
357216	27892457	Amplification of USP13 allows OVCA cells to rely on glutamine anaplerosis to replenish the TCA cycle with metabolic intermediates, and USP13 knocked down represses mitochondrial function.	('TCA', 'Chemical', 'MESH:D014233', (91, 94))	('mitochondrial function', 'MPA', (164, 186))	('USP13', 'Gene', (17, 22))	('OVCA', 'Phenotype', 'HP:0100615', (30, 34))	('knocked down', 'Var', (141, 153))	('USP13', 'Gene', (135, 140))	('TCA cycle with metabolic intermediates', 'MPA', (91, 129))	('represses', 'NegReg', (154, 163))	('glutamine', 'Chemical', 'MESH:D005973', (52, 61))
357219	27892457	Our study provides a potential therapeutic strategy in which targeting USP13 blocks biosynthesis of metabolic intermediates and lipids thereby simultaneously inducing energy stress and cell death.	('blocks', 'NegReg', (77, 83))	('inducing', 'Reg', (158, 166))	('targeting', 'Var', (61, 70))	('cell death', 'CPA', (185, 195))	('lipids', 'Chemical', 'MESH:D008055', (128, 134))	('energy stress', 'MPA', (167, 180))	('USP13', 'Gene', (71, 76))
357224	27892457	However, USP13 also appears to stabilize PTEN, at least in breast cancer, implicating its tumour suppressive role.	('tumour', 'Disease', 'MESH:D009369', (90, 96))	('breast cancer', 'Disease', 'MESH:D001943', (59, 72))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('breast cancer', 'Disease', (59, 72))	('tumour', 'Phenotype', 'HP:0002664', (90, 96))	('breast cancer', 'Phenotype', 'HP:0003002', (59, 72))	('USP13', 'Var', (9, 14))	('PTEN', 'Gene', (41, 45))	('stabilize', 'NegReg', (31, 40))	('tumour', 'Disease', (90, 96))	('PTEN', 'Gene', '5728', (41, 45))
357231	27892457	We found that inhibiting USP13 sensitized OVCA cells to the treatment of AKT inhibitor, suggesting a synergistic role of USP13 in the PI3K/AKT-induced tumourigenesis.	('tumour', 'Phenotype', 'HP:0002664', (151, 157))	('AKT', 'Gene', '207', (139, 142))	('AKT', 'Gene', (73, 76))	('inhibiting', 'Var', (14, 24))	('USP13', 'Gene', (121, 126))	('tumour', 'Disease', 'MESH:D009369', (151, 157))	('AKT', 'Gene', (139, 142))	('USP13', 'Gene', (25, 30))	('tumour', 'Disease', (151, 157))	('OVCA', 'Phenotype', 'HP:0100615', (42, 46))	('AKT', 'Gene', '207', (73, 76))
357232	27892457	Amplification of USP13 may be a part of the mechanism for intrinsic resistance of PI3K/AKT inhibitors in the treatment of OVCA.	('Amplification', 'Var', (0, 13))	('AKT', 'Gene', (87, 90))	('USP13', 'Gene', (17, 22))	('OVCA', 'Disease', (122, 126))	('OVCA', 'Phenotype', 'HP:0100615', (122, 126))	('AKT', 'Gene', '207', (87, 90))
357273	27892457	In brief, cells were incubated with 13C-labelled tracer (for example, U-13C6-glucose and U-13C5-glutamine) for 72 h to produce 13C-labelled fatty acids.	('13C', 'Chemical', '-', (127, 130))	('labelled fatty acids', 'Chemical', '-', (131, 151))	('U-13C5-glutamine', 'Chemical', '-', (89, 105))	('13C', 'Chemical', '-', (72, 75))	('13C', 'Chemical', '-', (91, 94))	('13C', 'Chemical', '-', (36, 39))	('U-13C5-glutamine', 'Var', (89, 105))	('U-13C6-glucose', 'Var', (70, 84))	('U-13C6-glucose', 'Chemical', '-', (70, 84))
357292	27892457	To determine the effect of USP13, ACLY or OGDH KD on ovarian tumour growth, OVCA cells (1 x 106) stably expressing control or USP13, ACLY or OGDH shRNA in 100 mul HBSS Hank's solution were injected intraperitoneally into mice after they were anaesthetized.	('tumour growth', 'Disease', (61, 74))	('tumour growth', 'Disease', 'MESH:D006130', (61, 74))	('HBSS', 'Chemical', '-', (163, 167))	("Hank's solution", 'Chemical', '-', (168, 183))	('mice', 'Species', '10090', (221, 225))	('ovarian tumour', 'Phenotype', 'HP:0100615', (53, 67))	('OGDH KD on ovarian tumour', 'Disease', (42, 67))	('OGDH KD on ovarian tumour', 'Disease', 'MESH:C537017', (42, 67))	('USP13', 'Var', (126, 131))	('tumour', 'Phenotype', 'HP:0002664', (61, 67))	('OVCA', 'Phenotype', 'HP:0100615', (76, 80))
357297	27892457	To determine whether USP13-KD sensitizes ovarian tumour cells to the treatment of MK-2206, CAOV3 cells (1 x 106) stably expressing Dox-inducible USP13 shRNA were injected intraperitoneally into female NOD/SCID mice.	('NOD', 'Gene', '1822', (201, 204))	('ovarian tumour', 'Phenotype', 'HP:0100615', (41, 55))	('USP13-KD sensitizes ovarian tumour', 'Disease', (21, 55))	('mice', 'Species', '10090', (210, 214))	('NOD', 'Gene', (201, 204))	('USP13-KD sensitizes ovarian tumour', 'Disease', 'MESH:C537017', (21, 55))	('tumour', 'Phenotype', 'HP:0002664', (49, 55))	('Dox', 'Chemical', 'MESH:D004318', (131, 134))	('MK-2206', 'Chemical', 'MESH:C548887', (82, 89))	('SCID', 'Disease', 'MESH:D053632', (205, 209))	('USP13 shRNA', 'Var', (145, 156))	('SCID', 'Disease', (205, 209))
357302	27892457	Amplification of USP13 drives ovarian cancer metabolism.	('drives', 'PosReg', (23, 29))	('Amplification', 'Var', (0, 13))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('ovarian cancer', 'Disease', 'MESH:D010051', (30, 44))	('ovarian cancer', 'Disease', (30, 44))	('USP13', 'Gene', (17, 22))	('ovarian cancer', 'Phenotype', 'HP:0100615', (30, 44))
357312	32947897	Several studies have demonstrated the association of non-coding RNAs in regulating various cancer hallmarks, including the radioresistance processes in cells.	('cancer hallmarks', 'Disease', 'MESH:D009369', (91, 107))	('association', 'Interaction', (38, 49))	('non-coding RNAs', 'Var', (53, 68))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('cancer hallmarks', 'Disease', (91, 107))	('radioresistance processes in', 'CPA', (123, 151))
357314	32947897	Furthermore, recent studies have reported the association of long non-coding RNAs (lncRNAs) with altered patients' responses towards radiation therapy due to their active involvement in DNA damage response (DDR), apoptosis, and cell cycle arrest.	('DNA', 'MPA', (186, 189))	('patients', 'Species', '9606', (105, 113))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (228, 245))	('responses towards radiation therapy', 'MPA', (115, 150))	('long non-coding RNAs', 'Var', (61, 81))	('apoptosis', 'CPA', (213, 222))	('involvement', 'Reg', (171, 182))	('association', 'Interaction', (46, 57))	('arrest', 'Disease', 'MESH:D006323', (239, 245))	('arrest', 'Disease', (239, 245))
357319	32947897	Furthermore, dysregulated DNM3OS is implicated in several cancers, including gastric cancer, ovarian cancer, and esophageal squamous cell carcinoma.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('DNM3OS', 'Gene', (26, 32))	('implicated', 'Reg', (36, 46))	('ovarian cancer', 'Disease', (93, 107))	('gastric cancer', 'Disease', (77, 91))	('esophageal squamous cell carcinoma', 'Disease', (113, 147))	('cancers', 'Disease', 'MESH:D009369', (58, 65))	('ovarian cancer', 'Phenotype', 'HP:0100615', (93, 107))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (124, 147))	('gastric cancer', 'Disease', 'MESH:D013274', (77, 91))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (113, 147))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('cancers', 'Phenotype', 'HP:0002664', (58, 65))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('gastric cancer', 'Phenotype', 'HP:0012126', (77, 91))	('ovarian cancer', 'Disease', 'MESH:D010051', (93, 107))	('cancers', 'Disease', (58, 65))	('dysregulated', 'Var', (13, 25))
357322	32947897	Additionally, the elevated expression of DNM3OS was also observed in several esophageal cancer cell lines viz.	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('expression', 'MPA', (27, 37))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('DNM3OS', 'Var', (41, 47))	('elevated', 'PosReg', (18, 26))
357328	32947897	Moreover, the tumor inhibition rate was higher for the DNM3OS knockout mice group, compared to the control group mice (76.59% vs. 47.03%).	('mice', 'Species', '10090', (71, 75))	('tumor', 'Disease', (14, 19))	('higher', 'PosReg', (40, 46))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('mice', 'Species', '10090', (113, 117))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('DNM3OS', 'Var', (55, 61))
357332	32947897	Furthermore, to elucidate the underlying pathways responsible for DNM3OS deregulation, a molecule called "crenolanib" identified with kinase inhibitor signaling.	('crenolanib', 'Chemical', 'MESH:C577197', (106, 116))	('deregulation', 'Var', (73, 85))	('DNM3OS', 'Gene', (66, 72))
357340	32947897	The above findings suggest that the DNM3OS in association with CAFs induced radioresistance via targeting PDGFbeta and FOXO1 genes in ESCC, which indicate the importance of DNM3OS in ESCC as a target molecule.	('FOXO1', 'Gene', '2308', (119, 124))	('induced', 'Reg', (68, 75))	('DNM3OS', 'Var', (36, 42))	('FOXO1', 'Gene', (119, 124))	('radioresistance', 'CPA', (76, 91))	('PDGFbeta', 'Gene', (106, 114))	('PDGFbeta', 'Gene', '5154', (106, 114))
357342	32947897	Several studies have reported the association of dysregulated LINC00473 in head and neck squamous cell carcinoma (HNSCC) and ESCC, enhancing tumor progression inhibiting radiation response.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('ESCC', 'Disease', (125, 129))	('dysregulated', 'Var', (49, 61))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (84, 112))	('LINC00473', 'Gene', '90632', (62, 71))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumor', 'Disease', (141, 146))	('enhancing', 'PosReg', (131, 140))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (89, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('radiation response', 'CPA', (170, 188))	('LINC00473', 'Gene', (62, 71))	('neck squamous cell carcinoma', 'Disease', (84, 112))
357345	32947897	Similar results were validated in the ESCC cell lines (TE-1, EC9706, Eca109, and KYSE-450), where TE-1 (~6.20-fold) and EC9706 (~6.80-fold) ESCC cell line demonstrated a higher expression level of LINC00473 compared to normal esophageal epithelial cell line Het-1A (Table 1).	('TE', 'Chemical', 'MESH:D013691', (98, 100))	('EC9706', 'CellLine', 'CVCL:E307', (61, 67))	('EC9706', 'CellLine', 'CVCL:E307', (120, 126))	('higher', 'PosReg', (170, 176))	('LINC00473', 'Gene', '90632', (197, 206))	('KYSE', 'Chemical', '-', (81, 85))	('LINC00473', 'Gene', (197, 206))	('TE', 'Chemical', 'MESH:D013691', (55, 57))	('expression level', 'MPA', (177, 193))	('EC9706', 'Var', (120, 126))
357348	32947897	Moreover, the shRNA-mediated knockdown of LINC00473 paired with an accumulated dose of irradiation caused a lower survival fraction in the ESCC cell lines (TE-1 and EC9706) as assessed using the colony survival assay (Table 1).	('knockdown', 'Var', (29, 38))	('EC9706', 'CellLine', 'CVCL:E307', (165, 171))	('lower', 'NegReg', (108, 113))	('LINC00473', 'Gene', '90632', (42, 51))	('TE', 'Chemical', 'MESH:D013691', (156, 158))	('LINC00473', 'Gene', (42, 51))	('survival fraction', 'CPA', (114, 131))
357354	32947897	Validating the role of LINC00473 in association with miR-374a-5p and miR-497-5p in ESCC radioresistance, these researchers observed enhanced cell viability, colony survival, PARP, and CdC25A protein expression levels in miR-374a-5p and miR-497-5p knockdown in ESCC cell.	('PARP', 'Gene', (174, 178))	('miR-374a', 'Gene', '442919', (53, 61))	('ESCC', 'Disease', (83, 87))	('miR-497', 'Gene', (236, 243))	('miR-497', 'Gene', '574456', (236, 243))	('CdC25A', 'Gene', (184, 190))	('radioresistance', 'CPA', (88, 103))	('CdC25A', 'Gene', '993', (184, 190))	('colony survival', 'CPA', (157, 172))	('miR-374a', 'Gene', (220, 228))	('miR-497', 'Gene', (69, 76))	('miR-497', 'Gene', '574456', (69, 76))	('miR-374a', 'Gene', (53, 61))	('cell viability', 'CPA', (141, 155))	('enhanced', 'PosReg', (132, 140))	('knockdown', 'Var', (247, 256))	('LINC00473', 'Gene', '90632', (23, 32))	('LINC00473', 'Gene', (23, 32))	('PARP', 'Gene', '142', (174, 178))	('miR-374a', 'Gene', '442919', (220, 228))
357357	32947897	Additionally, SPIN1 overexpression promoted proliferation and colony formation in vitro, and induced tumor formation and reduced apoptosis in nude mice through PI3K/AKT signaling pathways in ovarian cancer.	('colony formation', 'CPA', (62, 78))	('AKT', 'Gene', (165, 168))	('overexpression', 'Var', (20, 34))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('apoptosis', 'CPA', (129, 138))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('ovarian cancer', 'Disease', (191, 205))	('reduced', 'NegReg', (121, 128))	('tumor', 'Disease', (101, 106))	('induced', 'PosReg', (93, 100))	('SPIN1', 'Gene', (14, 19))	('promoted', 'PosReg', (35, 43))	('ovarian cancer', 'Phenotype', 'HP:0100615', (191, 205))	('AKT', 'Gene', '11651', (165, 168))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('nude mice', 'Species', '10090', (142, 151))	('ovarian cancer', 'Disease', 'MESH:D010051', (191, 205))	('proliferation', 'CPA', (44, 57))
357362	32947897	Further, its inactivation leads to chromosomal instability in diploid human cell lines.	('leads to', 'Reg', (26, 34))	('inactivation', 'Var', (13, 25))	('chromosomal instability', 'Phenotype', 'HP:0040012', (35, 58))	('human', 'Species', '9606', (70, 75))	('chromosomal instability', 'MPA', (35, 58))
357373	32947897	Moreover, an upregulated expression of POU6F2-AS2 in irradiated ESCC cell lines KYSE-140~5-fold) KYSE-510 (~6.1-fold), KYSE-30 (~2-fold), and KYSE-70 (~1-fold), compared to the control cells (Table 1).	('KYSE-140~5-fold', 'Var', (80, 95))	('POU6F2', 'Gene', '11281', (39, 45))	('KYSE', 'Chemical', '-', (119, 123))	('POU6F2', 'Gene', (39, 45))	('KYSE-510', 'Var', (97, 105))	('expression', 'MPA', (25, 35))	('AS2', 'Chemical', 'MESH:C021591', (46, 49))	('upregulated', 'PosReg', (13, 24))	('KYSE', 'Chemical', '-', (142, 146))	('KYSE', 'Chemical', '-', (80, 84))	('KYSE', 'Chemical', '-', (97, 101))
357377	32947897	Moreover, knockdown of POU6F2-AS2 inhibited the recruitment of Ybx1 to the promoters of cyclin B1 (CCNB1) and p53 gene as well as to the DNA damage sites, thereby, confirming a close relationship between POU6F2-AS2 and DNA repair pathways (Figure 2, Table 1).	('POU6F2', 'Gene', '11281', (204, 210))	('POU6F2', 'Gene', (204, 210))	('p53', 'Gene', (110, 113))	('recruitment', 'MPA', (48, 59))	('Ybx1', 'Gene', '4904', (63, 67))	('p53', 'Gene', '7157', (110, 113))	('inhibited', 'NegReg', (34, 43))	('AS2', 'Chemical', 'MESH:C021591', (211, 214))	('POU6F2', 'Gene', '11281', (23, 29))	('POU6F2', 'Gene', (23, 29))	('CCNB1', 'Gene', (99, 104))	('AS2', 'Chemical', 'MESH:C021591', (30, 33))	('cyclin B1', 'Gene', '891', (88, 97))	('cyclin B1', 'Gene', (88, 97))	('CCNB1', 'Gene', '891', (99, 104))	('knockdown', 'Var', (10, 19))	('Ybx1', 'Gene', (63, 67))
357381	32947897	For instance, several of its single nucleotide polymorphisms (SNPs) associated with both obsessive-compulsive disorders of Tourette's syndrome.	('associated', 'Reg', (68, 78))	('obsessive-compulsive disorders', 'Phenotype', 'HP:0000722', (89, 119))	("obsessive-compulsive disorders of Tourette's syndrome", 'Disease', 'MESH:D009771', (89, 142))	('single nucleotide polymorphisms', 'Var', (29, 60))
357384	32947897	Further analyses suggested that ESCC patients belonging to the FAM-high expression group (n = 13,  Ct = 8.437) exhibited an inadequate short term response to radiotherapy and had a lower survival time, contrary to the FAM-low expression group (n = 22,  Ct = 6.155), whereas, neither of the groups correlated with either T or N stage of tumor stage.	('ESCC', 'Disease', (32, 36))	('inadequate', 'NegReg', (124, 134))	('patients', 'Species', '9606', (37, 45))	('lower', 'NegReg', (181, 186))	('tumor', 'Disease', 'MESH:D009369', (336, 341))	('FAM-high expression', 'Var', (63, 82))	('tumor', 'Phenotype', 'HP:0002664', (336, 341))	('tumor', 'Disease', (336, 341))	('survival time', 'CPA', (187, 200))
357385	32947897	Furthermore, siRNA-mediated knockdown of FAM201A exhibited decreased proliferation in ESCC cell lines Eca109 and Eca109R.	('FAM201A', 'Gene', (41, 48))	('proliferation', 'CPA', (69, 82))	('FAM201A', 'Gene', '158228', (41, 48))	('decreased', 'NegReg', (59, 68))	('knockdown', 'Var', (28, 37))	('ESCC', 'Disease', (86, 90))
357390	32947897	by luciferase reporter assays, observed that FAM201A mutants suppressed the expression of miR-101 in Eca109 cells, suggesting a negative correlation between FAM201A and miR-101.	('suppressed', 'NegReg', (61, 71))	('FAM201A', 'Gene', (45, 52))	('FAM201A', 'Gene', '158228', (157, 164))	('miR-101', 'Chemical', '-', (90, 97))	('miR-101', 'Chemical', '-', (169, 176))	('FAM201A', 'Gene', '158228', (45, 52))	('negative', 'NegReg', (128, 136))	('mutants', 'Var', (53, 60))	('miR-101', 'Gene', (90, 97))	('expression', 'MPA', (76, 86))	('FAM201A', 'Gene', (157, 164))
357396	32947897	by qRT-PCR observed a downregulated expression of MALAT1 in ESCC cells (EC9706 and KYSE-150) treated with ionizing radiation of 5 Gy for 8 h. Additionally, the overexpression of MALAT1 in irradiated EC9706 and KYSE-150 cells reduced the apoptotic rate leading to enhanced cell viability, suggesting the role of MALAT1 in reducing the radiosensitivity of ESCC cells.	('apoptotic rate', 'CPA', (237, 251))	('overexpression', 'PosReg', (160, 174))	('MALAT1', 'Gene', (178, 184))	('EC9706', 'CellLine', 'CVCL:E307', (199, 205))	('cell viability', 'CPA', (272, 286))	('EC9706', 'CellLine', 'CVCL:E307', (72, 78))	('reduced', 'NegReg', (225, 232))	('KYSE', 'Chemical', '-', (210, 214))	('KYSE', 'Chemical', '-', (83, 87))	('EC9706', 'Var', (199, 205))	('enhanced', 'PosReg', (263, 271))
357406	32947897	by qRT-PCR, examined the expression of LOC285194 in 142 ESCC tissues and observed that the expression of LOC285194 was significantly reduced (~1.10-fold) (Table 1) compared to adjacent healthy tissues.	('expression', 'MPA', (91, 101))	('LOC285194', 'Var', (105, 114))	('LOC285194', 'Chemical', '-', (39, 48))	('LOC285194', 'Chemical', '-', (105, 114))	('reduced', 'NegReg', (133, 140))	('LOC285194', 'Var', (39, 48))
357408	32947897	They observed downregulated levels of LOC285194 in KYSE-30 (~2.0-fold), KYSE-510 (~1.7-fold), KYSE-109 (~2.0-fold) cells lines compared to a standard esophageal epithelial cell line, Het-1A (Table 1).	('LOC285194', 'Var', (38, 47))	('downregulated', 'NegReg', (14, 27))	('KYSE', 'Chemical', '-', (51, 55))	('LOC285194', 'Chemical', '-', (38, 47))	('KYSE', 'Chemical', '-', (94, 98))	('KYSE', 'Chemical', '-', (72, 76))
357412	32947897	The above results indicate that LOC285194 could be used as a biomarker for screening and treating ESCC patients before esophagectomy.	('LOC285194', 'Var', (32, 41))	('LOC285194', 'Chemical', '-', (32, 41))	('patients', 'Species', '9606', (103, 111))	('ESCC', 'Disease', (98, 102))
357413	32947897	Furthermore, to study the prognostic significance of LOC285194 expression, Kaplan-Meier analysis was performed, which revealed that low expression of LOC285194 was associated with wretched disease-free survival (DFS) and overall survival (OS).	('low', 'NegReg', (132, 135))	('LOC285194', 'Var', (150, 159))	('associated', 'Reg', (164, 174))	('LOC285194', 'Chemical', '-', (150, 159))	('overall survival', 'CPA', (221, 237))	('LOC285194', 'Chemical', '-', (53, 62))	('wretched', 'Disease', (180, 188))
357414	32947897	Meanwhile, multivariate analysis revealed that low expression of LOC285194 and distant metastases were independent factors that affected DFS and OS.	('metastases', 'Disease', (87, 97))	('DFS', 'Disease', (137, 140))	('low', 'NegReg', (47, 50))	('LOC285194', 'Var', (65, 74))	('metastases', 'Disease', 'MESH:D009362', (87, 97))	('expression', 'MPA', (51, 61))	('LOC285194', 'Chemical', '-', (65, 74))	('affected', 'Reg', (128, 136))
357416	32947897	Therefore, these results suggest that the downregulated expression of LOC285194 signifies a higher risk of disease recurrence and treatment failure.	('LOC285194', 'Chemical', '-', (70, 79))	('downregulated', 'NegReg', (42, 55))	('disease recurrence', 'CPA', (107, 125))	('treatment failure', 'CPA', (130, 147))	('expression', 'MPA', (56, 66))	('LOC285194', 'Var', (70, 79))
357427	32947897	A similar upregulation of about ~2.2-15-fold was found in the cell lines KYSE-30, KYSE-70, KYSE-150, KYSE-450, KYSE-510, and KYSE-10 as compared to the healthy esophageal mucosa cell Het-1A (Table 1).	('KYSE', 'Chemical', '-', (111, 115))	('KYSE-30', 'Var', (73, 80))	('KYSE', 'Chemical', '-', (82, 86))	('KYSE', 'Chemical', '-', (91, 95))	('KYSE-510', 'Var', (111, 119))	('KYSE-150', 'Var', (91, 99))	('KYSE', 'Chemical', '-', (73, 77))	('KYSE-70', 'Var', (82, 89))	('KYSE', 'Chemical', '-', (125, 129))	('KYSE', 'Chemical', '-', (101, 105))	('upregulation', 'PosReg', (10, 22))	('KYSE-450', 'Var', (101, 109))
357436	32947897	Interestingly, reduced tumor volume, tumor growth, and tumor weight observed in response to TUG1 knockdown in the KYSE-30 xenografts compared to the controls after irradiation of 2 Gy.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('knockdown', 'Var', (97, 106))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('tumor', 'Disease', (23, 28))	('tumor', 'Disease', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('reduced', 'NegReg', (15, 22))	('tumor', 'Disease', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('TUG1', 'Gene', (92, 96))	('KYSE', 'Chemical', '-', (114, 118))
357438	32947897	The authors further indicated by Luciferase reporter assays that miR-144-3p was indeed a downstream target of TUG1, where these two transcripts were inversely correlated as established by Pearson's correlation coefficient.	('TUG1', 'Gene', (110, 114))	('miR-144-3p', 'Var', (65, 75))	('miR-144-3p', 'Chemical', '-', (65, 75))
357439	32947897	miR-144-3p acts as a tumor suppressor in ESCC, and depletion of miR-144-3p restored the effects of TUG1 suppression on radiotherapy, consequently validating its role as a regulator of radiation (Figure 3, Table 1).	('effects', 'MPA', (88, 95))	('restored', 'PosReg', (75, 83))	('depletion', 'MPA', (51, 60))	('suppression', 'NegReg', (104, 115))	('TUG1', 'Gene', (99, 103))	('miR-144-3p', 'Chemical', '-', (0, 10))	('tumor', 'Disease', (21, 26))	('ESCC', 'Disease', (41, 45))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('miR-144-3p', 'Var', (64, 74))	('miR-144-3p', 'Chemical', '-', (64, 74))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
357444	32947897	Consistent with these findings, knockdown of MET decreased EGFR and phosphorylated-Akt (p-Akt) protein levels, possibly inhibiting cell proliferation.	('inhibiting', 'NegReg', (120, 130))	('Akt', 'Gene', (90, 93))	('EGFR', 'Gene', (59, 63))	('Akt', 'Gene', (83, 86))	('MET', 'Gene', '79811', (45, 48))	('MET', 'Gene', (45, 48))	('knockdown', 'Var', (32, 41))	('decreased', 'NegReg', (49, 58))	('cell proliferation', 'CPA', (131, 149))	('Akt', 'Gene', '207', (83, 86))	('EGFR', 'Gene', '1950', (59, 63))	('Akt', 'Gene', '207', (90, 93))
357449	32947897	The lncRNAs DNM3OS, LINC00473, LINC00657, POU6F2-AS2 found to be involved in radioresistance, while FAM201A, MALAT1, LOC285194, AFAP1-AS1, TUG1 lncRNAs linked to radiosensitivity in ESCC.	('radioresistance', 'CPA', (77, 92))	('FAM201A', 'Gene', (100, 107))	('AFAP1', 'Gene', (128, 133))	('AFAP1', 'Gene', '60312', (128, 133))	('AS2', 'Chemical', 'MESH:C021591', (49, 52))	('LINC00657', 'Gene', '647979', (31, 40))	('FAM201A', 'Gene', '158228', (100, 107))	('LINC00473', 'Gene', '90632', (20, 29))	('LOC285194', 'Var', (117, 126))	('involved', 'Reg', (65, 73))	('AS1', 'Gene', '5729', (134, 137))	('ESCC', 'Disease', (182, 186))	('AS1', 'Gene', (134, 137))	('POU6F2', 'Gene', '11281', (42, 48))	('LOC285194', 'Chemical', '-', (117, 126))	('POU6F2', 'Gene', (42, 48))	('LINC00473', 'Gene', (20, 29))	('LINC00657', 'Gene', (31, 40))
357452	32947897	The reviewed literature data indicate the potential efficacy of DNM3OS and POU6F2-AS2 as targets to improve the outcome of radiotherapy.	('POU6F2', 'Gene', '11281', (75, 81))	('DNM3OS', 'Var', (64, 70))	('POU6F2', 'Gene', (75, 81))	('AS2', 'Chemical', 'MESH:C021591', (82, 85))
357458	32947897	However, several factors, such as familial mutation, epigenetic changes, and other comorbid pathological conditions, increase the resistance in a large cohort of patients, which is alarming and needs more in-depth analysis for improving interventions.	('epigenetic changes', 'Var', (53, 71))	('patients', 'Species', '9606', (162, 170))	('increase', 'PosReg', (117, 125))	('resistance', 'MPA', (130, 140))	('familial mutation', 'Var', (34, 51))
357459	32947897	We have also proposed that modifying the lncRNA signature can influence the sensitivity of refractory patients.	('patients', 'Species', '9606', (102, 110))	('sensitivity', 'MPA', (76, 87))	('modifying', 'Var', (27, 36))	('influence', 'Reg', (62, 71))	('lncRNA signature', 'MPA', (41, 57))
357471	31998650	Although FUNDC1 showed a protective effect on pan-cancer, a high expression level of FUNDC1 was detrimental to the survival of LIHC patients.	('FUNDC1', 'Gene', (9, 15))	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('high', 'Var', (60, 64))	('FUNDC1', 'Gene', (85, 91))	('FUNDC1', 'Gene', '139341', (9, 15))	('LIHC', 'Disease', (127, 131))	('detrimental', 'NegReg', (96, 107))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('LIHC', 'Disease', 'MESH:D006528', (127, 131))	('FUNDC1', 'Gene', '139341', (85, 91))	('patients', 'Species', '9606', (132, 140))
357489	31998650	For example, cytotoxic T lymphocyte associated antigen 4 (CTLA4), programmed death-1 (PD-1), and programmed death ligand-1 (PD-L1) inhibitors were found to have promising antitumor effects on malignant melanoma and non-small-cell lung carcinoma.	('melanoma', 'Disease', 'MESH:D008545', (202, 210))	('programmed death ligand-1', 'Gene', (97, 122))	('malignant melanoma', 'Phenotype', 'HP:0002861', (192, 210))	('non-small-cell lung carcinoma', 'Disease', (215, 244))	('programmed death-1', 'Gene', '5133', (66, 84))	('programmed death-1', 'Gene', (66, 84))	('non-small-cell lung carcinoma', 'Disease', 'MESH:D002289', (215, 244))	('cytotoxic T lymphocyte associated antigen 4', 'Gene', (13, 56))	('programmed death ligand-1', 'Gene', '29126', (97, 122))	('tumor', 'Disease', (175, 180))	('CTLA4', 'Gene', '1493', (58, 63))	('cytotoxic T lymphocyte associated antigen 4', 'Gene', '1493', (13, 56))	('carcinoma', 'Phenotype', 'HP:0030731', (235, 244))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('melanoma', 'Disease', (202, 210))	('inhibitors', 'Var', (131, 141))	('PD-L1', 'Gene', (124, 129))	('PD-L1', 'Gene', '29126', (124, 129))	('CTLA4', 'Gene', (58, 63))	('small-cell lung carcinoma', 'Phenotype', 'HP:0030357', (219, 244))	('PD-1', 'Gene', (86, 90))	('PD-1', 'Gene', '5133', (86, 90))	('non-small-cell lung carcinoma', 'Phenotype', 'HP:0030358', (215, 244))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))
357530	31998650	The findings for lung cancer were partly different from those using PrognoScan, as a high expression of FUNDC1 only benefited LUSC (OS: HR = 0.64, 95 % CI from 0.48 to 0.85 logrank P = 0.0017; RFS: HR = 0.55, 95% CI from 0.33 to 0.91, logrank P = 0.019) (Figures 2C,D) and not LUAD (OS: HR = 0.8, 95% CI from 0.6 to 1.08, logrank P = 0.15; RFS: HR = 1.41, 95% CI from 0.91 to 2.19, logrank P = 0.13) (Figures 3M,N).	('LUSC', 'Disease', (126, 130))	('FUNDC1', 'Gene', (104, 110))	('lung cancer', 'Disease', (17, 28))	('benefited', 'PosReg', (116, 125))	('lung cancer', 'Phenotype', 'HP:0100526', (17, 28))	('FUNDC1', 'Gene', '139341', (104, 110))	('LUSC', 'Phenotype', 'HP:0030359', (126, 130))	('high', 'Var', (85, 89))	('lung cancer', 'Disease', 'MESH:D008175', (17, 28))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('LUAD', 'Disease', (277, 281))	('LUAD', 'Disease', 'MESH:C538231', (277, 281))	('LUAD', 'Phenotype', 'HP:0030078', (277, 281))	('LUSC', 'Disease', 'MESH:D002294', (126, 130))
357546	31998650	For progression-free survival (PFS), FUNDC1 expression was significantly hazardous to LIHC patients without hepatitis virus infection (n = 167, HR = 2.1, 95% CI from 1.3 to 3.38, P = 0.0019) but became protective to LIHC patients at stage 2 (n = 84, HR = 0.52, 95% CI from 0.28 to 0.98, P = 0.039) and grade 3 (n = 119, HR = 0.6, 95% CI from 0.36 to 0.98, P = 0.041) (Figure 4).	('LIHC', 'Disease', (86, 90))	('patients', 'Species', '9606', (221, 229))	('hepatitis virus infection', 'Disease', (108, 133))	('patients', 'Species', '9606', (91, 99))	('LIHC', 'Disease', 'MESH:D006528', (86, 90))	('hepatitis', 'Phenotype', 'HP:0012115', (108, 117))	('FUNDC1', 'Gene', (37, 43))	('expression', 'Var', (44, 54))	('FUNDC1', 'Gene', '139341', (37, 43))	('LIHC', 'Disease', (216, 220))	('LIHC', 'Disease', 'MESH:D006528', (216, 220))	('hepatitis virus infection', 'Disease', 'MESH:D006525', (108, 133))
357570	31998650	Mitochondria are essential for human immunity, and aberrant mitochondrial activity affects immune responses.	('aberrant', 'Var', (51, 59))	('mitochondrial activity', 'MPA', (60, 82))	('human', 'Species', '9606', (31, 36))	('immune responses', 'CPA', (91, 107))	('affects', 'Reg', (83, 90))
357571	31998650	For example, some studies have demonstrated that viruses (e.g., HBV in LIHC) can manipulate mitophagy, which enables viruses to promote persistent infection and attenuate the innate immune responses.	('attenuate', 'NegReg', (161, 170))	('innate immune responses', 'CPA', (175, 198))	('mitophagy', 'CPA', (92, 101))	('manipulate', 'Reg', (81, 91))	('infection', 'Disease', (147, 156))	('LIHC', 'Disease', (71, 75))	('infection', 'Disease', 'MESH:D007239', (147, 156))	('persistent infection', 'Phenotype', 'HP:0031035', (136, 156))	('viruses', 'Var', (117, 124))	('LIHC', 'Disease', 'MESH:D006528', (71, 75))	('promote', 'PosReg', (128, 135))
357574	31998650	FUNDC1-mediated mitophagy is negatively regulated by the phosphorylation of FUNDC1, as the phosphorylation of Tyr 18 in the FUNDC1 LC3-interacting region motif can weaken the binding affinity of FUNDC1 to LC3.	('FUNDC1', 'Gene', (76, 82))	('Tyr 18', 'Var', (110, 116))	('FUNDC1', 'Gene', (124, 130))	('mitophagy', 'CPA', (16, 25))	('phosphorylation', 'Var', (91, 106))	('FUNDC1', 'Gene', '139341', (0, 6))	('FUNDC1', 'Gene', '139341', (76, 82))	('FUNDC1', 'Gene', '139341', (124, 130))	('weaken', 'NegReg', (164, 170))	('Tyr', 'Chemical', 'MESH:C042696', (110, 113))	('binding affinity', 'Interaction', (175, 191))	('FUNDC1', 'Gene', (195, 201))	('FUNDC1', 'Gene', '139341', (195, 201))	('FUNDC1', 'Gene', (0, 6))	('LC3', 'Protein', (205, 208))
357582	31998650	Thus, it is reasonable to surmise that FUNDC1 expression may influence patient survival through tumor cell proliferation.	('expression', 'Var', (46, 56))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('influence', 'Reg', (61, 70))	('tumor', 'Disease', (96, 101))	('FUNDC1', 'Gene', (39, 45))	('FUNDC1', 'Gene', '139341', (39, 45))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('patient', 'Species', '9606', (71, 78))	('patient survival', 'CPA', (71, 87))
357586	31998650	One previous study has demonstrated that FUNDC1-mediated mitophagy can suppress hepatocarcinogenesis.	('FUNDC1', 'Gene', (41, 47))	('FUNDC1', 'Gene', '139341', (41, 47))	('hepatocarcinogenesis', 'Disease', 'MESH:D063646', (80, 100))	('mitophagy', 'Var', (57, 66))	('suppress', 'NegReg', (71, 79))	('hepatocarcinogenesis', 'Disease', (80, 100))
357587	31998650	This study found that the specific knockout of FUNDC1 in hepatocytes promotes the initiation and progression of chemical carcinogen diethylnitrosamine-induced HCC.	('diethylnitrosamine', 'Chemical', 'MESH:D004052', (132, 150))	('progression', 'CPA', (97, 108))	('promotes', 'PosReg', (69, 77))	('FUNDC1', 'Gene', (47, 53))	('knockout', 'Var', (35, 43))	('FUNDC1', 'Gene', '139341', (47, 53))
357588	31998650	The study also found that FUNDC1 transgenic hepatocytes protect against the development of HCC.	('transgenic', 'Var', (33, 43))	('FUNDC1', 'Gene', (26, 32))	('HCC', 'Disease', (91, 94))	('FUNDC1', 'Gene', '139341', (26, 32))
357611	31998650	In 8 datasets in PrognoScan, high FUNDC1 expression levels could be used as an independent risk factor for a poor prognosis in brain, breast, colorectal, and skin cancers (Figure 2).	('high', 'Var', (29, 33))	('cancers', 'Phenotype', 'HP:0002664', (163, 170))	('colorectal', 'Disease', (142, 152))	('expression', 'MPA', (41, 51))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('skin cancers', 'Disease', (158, 170))	('skin cancers', 'Phenotype', 'HP:0008069', (158, 170))	('brain', 'Disease', (127, 132))	('FUNDC1', 'Gene', (34, 40))	('skin cancers', 'Disease', 'MESH:D012878', (158, 170))	('breast', 'Disease', (134, 140))	('FUNDC1', 'Gene', '139341', (34, 40))
357612	31998650	In addition, a high level of FUNDC1 expression was shown to be related to a poor prognosis in LIHC with micro-vascular invasion but a favorable prognosis in LIHC with AJCC T2 (Figure 4).	('high', 'Var', (15, 19))	('LIHC', 'Disease', (94, 98))	('FUNDC1', 'Gene', (29, 35))	('LIHC', 'Disease', 'MESH:D006528', (94, 98))	('LIHC', 'Disease', (157, 161))	('FUNDC1', 'Gene', '139341', (29, 35))	('LIHC', 'Disease', 'MESH:D006528', (157, 161))	('expression', 'MPA', (36, 46))
357614	31998650	Another major finding from this study is that FUNDC1 expression correlates with diverse immune infiltration levels in cancers, especially in LIHC and LUSC.	('LIHC', 'Disease', (141, 145))	('cancers', 'Disease', (118, 125))	('cancers', 'Phenotype', 'HP:0002664', (118, 125))	('cancers', 'Disease', 'MESH:D009369', (118, 125))	('correlates with', 'Reg', (64, 79))	('expression', 'Var', (53, 63))	('immune infiltration levels', 'MPA', (88, 114))	('FUNDC1', 'Gene', (46, 52))	('LIHC', 'Disease', 'MESH:D006528', (141, 145))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('FUNDC1', 'Gene', '139341', (46, 52))	('LUSC', 'Disease', 'MESH:D002294', (150, 154))	('LUSC', 'Disease', (150, 154))	('LUSC', 'Phenotype', 'HP:0030359', (150, 154))
357638	31998650	These interactions between tumor cells and infiltrating immune cells help explain the findings from this study indicating that TAMs have a positive correlation with FUNDC1 expression in LIHC and that the high expression of FUNDC1 is associated with a worse LIHC patient prognosis.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('FUNDC1', 'Gene', '139341', (223, 229))	('FUNDC1', 'Gene', '139341', (165, 171))	('LIHC', 'Disease', (186, 190))	('tumor', 'Disease', (27, 32))	('FUNDC1', 'Gene', (165, 171))	('associated with', 'Reg', (233, 248))	('LIHC', 'Disease', 'MESH:D006528', (186, 190))	('TAM', 'Gene', '8205', (127, 130))	('expression', 'MPA', (172, 182))	('FUNDC1', 'Gene', (223, 229))	('patient', 'Species', '9606', (262, 269))	('LIHC', 'Disease', (257, 261))	('LIHC', 'Disease', 'MESH:D006528', (257, 261))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('TAM', 'Gene', (127, 130))	('high expression', 'Var', (204, 219))
357756	27880766	SOX2 and PI3K Cooperate to Induce and Stabilize a Squamous-Committed Stem Cell Injury State during Lung Squamous Cell Carcinoma Pathogenesis Although cancers are considered stem cell diseases, mechanisms involving stem cell alterations are poorly understood.	('SOX2', 'Gene', '6657', (0, 4))	('SOX2', 'Gene', (0, 4))	('Lung Squamous Cell Carcinoma', 'Disease', 'MESH:D002294', (99, 127))	('cancers', 'Phenotype', 'HP:0002664', (150, 157))	('rat', 'Species', '10116', (228, 231))	('cancers', 'Disease', (150, 157))	('Squamous-Committed', 'MPA', (50, 68))	('cancers', 'Disease', 'MESH:D009369', (150, 157))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (104, 127))	('rat', 'Species', '10116', (19, 22))	('Lung Squamous Cell Carcinoma', 'Phenotype', 'HP:0030359', (99, 127))	('Induce', 'PosReg', (27, 33))	('PI3K', 'Var', (9, 13))	('Carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('Lung Squamous Cell Carcinoma', 'Disease', (99, 127))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
357761	27880766	We used primary human tracheobronchial basal cells to investigate how copy number gains in SOX2 and PIK3CA at 3q26-28, which co-occur in dysplasia and are observed in 94% of SQCCs, may promote progression.	('SQCC', 'Phenotype', 'HP:0002860', (174, 178))	('human', 'Species', '9606', (16, 21))	('PIK3CA', 'Gene', (100, 106))	('copy number gains', 'Var', (70, 87))	('dysplasia', 'Disease', (137, 146))	('promote', 'PosReg', (185, 192))	('dysplasia', 'Disease', 'MESH:D004476', (137, 146))	('PIK3CA', 'Gene', '5290', (100, 106))	('SOX2', 'Gene', (91, 95))	('progression', 'CPA', (193, 204))
357764	27880766	By contrast, during regeneration of mucociliary epithelia, PI3K signaling is low and basal cells transiently enter a SOX2LoSOX9Hi state, with SOX9 promoting proliferation and preventing squamous differentiation.	('squamous differentiation', 'CPA', (186, 210))	('SOX9', 'Var', (142, 146))	('promoting', 'PosReg', (147, 156))	('mucociliary epithelia', 'Disease', (36, 57))	('P', 'Chemical', 'MESH:D010758', (59, 60))	('rat', 'Species', '10116', (26, 29))	('preventing', 'NegReg', (175, 185))	('rat', 'Species', '10116', (164, 167))	('mucociliary epithelia', 'Disease', 'None', (36, 57))
357765	27880766	Frequent coamplification of SOX2 and PIK3CA in dysplasia may, thus, promote progression by locking basal cells in a SOX2HiSOX9Lo state with active PI3K signaling, which sustains the squamous injury response while precluding normal mucociliary differentiation.	('SOX2HiSOX9', 'Gene', '6662', (116, 126))	('PIK3CA', 'Gene', '5290', (37, 43))	('SOX2', 'Gene', (28, 32))	('promote', 'PosReg', (68, 75))	('SOX2HiSOX9', 'Gene', (116, 126))	('P', 'Chemical', 'MESH:D010758', (147, 148))	('progression', 'Disease', (76, 87))	('dysplasia', 'Disease', (47, 56))	('squamous injury', 'Disease', (182, 197))	('dysplasia', 'Disease', 'MESH:D004476', (47, 56))	('squamous injury', 'Disease', 'MESH:D002294', (182, 197))	('P', 'Chemical', 'MESH:D010758', (37, 38))	('coamplification', 'Var', (9, 24))	('PIK3CA', 'Gene', (37, 43))
357767	27880766	We propose that early pathogenesis of most SQCCs involves stabilization of the squamous injury state in stem cells through copy number gains at 3q, with the pro-proliferative activity of SOX9 possibly being exploited in a subset of SQCCs in later stages.	('SQCC', 'Phenotype', 'HP:0002860', (232, 236))	('SQCC', 'Phenotype', 'HP:0002860', (43, 47))	('squamous injury', 'Disease', 'MESH:D002294', (79, 94))	('copy number gains', 'Var', (123, 140))	('SQCCs', 'Disease', (43, 48))	('rat', 'Species', '10116', (168, 171))	('squamous injury', 'Disease', (79, 94))
357776	27880766	Ninety-four percent of SQCCs have copy number gains in chromosome 3 that affect SOX2 and PIK3CA, a catalytic PI3K subunit.	('P', 'Chemical', 'MESH:D010758', (109, 110))	('SQCC', 'Phenotype', 'HP:0002860', (23, 27))	('copy number gains', 'Var', (34, 51))	('P', 'Chemical', 'MESH:D010758', (89, 90))	('affect', 'Reg', (73, 79))	('SOX2', 'Gene', (80, 84))	('PIK3CA', 'Gene', (89, 95))	('PIK3CA', 'Gene', '5290', (89, 95))
357789	27880766	Although low grade dysplasias regress at a high rate, high grade dysplasia and carcinoma in situ mark a different phase of progression, as these later stages have more genetic alterations, lower rates of regression, and higher rates of progression to SQCC.	('dysplasia', 'Disease', (19, 28))	('dysplasias regress', 'Disease', (19, 37))	('dysplasia', 'Disease', 'MESH:D004476', (19, 28))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('genetic alterations', 'Var', (168, 187))	('rat', 'Species', '10116', (48, 51))	('dysplasia', 'Disease', (65, 74))	('SQCC', 'Disease', (251, 255))	('dysplasia', 'Disease', 'MESH:D004476', (65, 74))	('carcinoma', 'Disease', (79, 88))	('dysplasias regress', 'Disease', 'MESH:C537770', (19, 37))	('rat', 'Species', '10116', (180, 183))	('regression', 'MPA', (204, 214))	('rat', 'Species', '10116', (195, 198))	('carcinoma', 'Disease', 'MESH:D002277', (79, 88))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (79, 96))	('rat', 'Species', '10116', (227, 230))	('SQCC', 'Phenotype', 'HP:0002860', (251, 255))	('lower', 'NegReg', (189, 194))
357791	27880766	One of the earliest genetic events is SOX2 amplification, which is common in high grade dysplasias and is associated with greater progression to SQCC.	('SOX2', 'Gene', (38, 42))	('dysplasias', 'Disease', (88, 98))	('associated', 'Reg', (106, 116))	('amplification', 'Var', (43, 56))	('common', 'Reg', (67, 73))	('dysplasias', 'Disease', 'MESH:D004476', (88, 98))	('SQCC', 'Disease', (145, 149))	('SQCC', 'Phenotype', 'HP:0002860', (145, 149))
357792	27880766	Ultimately, SOX2 copy number gains are found in 94% of SQCCs (54% amplification/40% lower copy number gain only, provisional TCGA (The Cancer Genome Atlas) data, www.cbioportal.org).	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (135, 154))	('SQCC', 'Phenotype', 'HP:0002860', (55, 59))	('copy number gains', 'Var', (17, 34))	('SOX2', 'Gene', (12, 16))	('Cancer', 'Phenotype', 'HP:0002664', (135, 141))	('Cancer Genome Atlas', 'Disease', (135, 154))
357795	27880766	In all cases, which included functionally distinct drivers such as Sox2 overexpression, Pten loss, and Kras mutation, Lkb1 inactivation was necessary for SQCC generation, and in one model, SQCC was generated in distal airways through transdifferentiation of adenocarcinoma (ADC).	('Kras', 'Gene', '3845', (103, 107))	('rat', 'Species', '10116', (163, 166))	('Lkb1', 'Gene', (118, 122))	('Pten', 'Gene', '5728', (88, 92))	('Pten', 'Gene', (88, 92))	('SQCC', 'Phenotype', 'HP:0002860', (154, 158))	('carcinoma', 'Phenotype', 'HP:0030731', (263, 272))	('adenocarcinoma', 'Disease', (258, 272))	('Sox2', 'Gene', '6657', (67, 71))	('loss', 'Var', (93, 97))	('SQCC', 'Phenotype', 'HP:0002860', (189, 193))	('Sox2', 'Gene', (67, 71))	('adenocarcinoma', 'Disease', 'MESH:D000230', (258, 272))	('mutation', 'Var', (108, 116))	('Kras', 'Gene', (103, 107))	('rat', 'Species', '10116', (202, 205))	('Lkb1', 'Gene', '6794', (118, 122))
357796	27880766	However, in human lung cancer, LKB1 DNA alterations are infrequent in SQCCs and more common in ADCs (3% of SQCCs and 19% of ADCs, provisional TCGA data, www.cbioportal.org), and SQCCs generally do not arise in distal airways.	('lung cancer', 'Disease', 'MESH:D008175', (18, 29))	('SQCC', 'Phenotype', 'HP:0002860', (178, 182))	('SQCC', 'Phenotype', 'HP:0002860', (107, 111))	('alterations', 'Var', (40, 51))	('LKB1', 'Gene', (31, 35))	('rat', 'Species', '10116', (44, 47))	('lung cancer', 'Phenotype', 'HP:0100526', (18, 29))	('SQCC', 'Phenotype', 'HP:0002860', (70, 74))	('human', 'Species', '9606', (12, 17))	('lung cancer', 'Disease', (18, 29))	('LKB1', 'Gene', '6794', (31, 35))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('SQCCs', 'Disease', (70, 75))
357803	27880766	This mechanism potentially explains selection of SOX2 and PIK3CA coamplification during SQCC pathogenesis and how it may promote progression of high-grade dysplasias by altering the behavior of stem cells.	('dysplasias', 'Disease', 'MESH:D004476', (155, 165))	('PIK3CA', 'Gene', (58, 64))	('coamplification', 'Var', (65, 80))	('PIK3CA', 'Gene', '5290', (58, 64))	('SQCC', 'Disease', (88, 92))	('altering', 'Reg', (169, 177))	('promote', 'PosReg', (121, 128))	('dysplasias', 'Disease', (155, 165))	('SQCC', 'Phenotype', 'HP:0002860', (88, 92))	('behavior of stem cells', 'CPA', (182, 204))
357808	27880766	Notably, SQCCs do not spontaneously arise in healthy epithelia, but do arise after years of smoking, and SOX2 amplification is commonly detected in dysplasia, in which it is associated with a higher rate of progression to SQCC.	('SQCC', 'Disease', (222, 226))	('healthy epithelia', 'Disease', 'MESH:D000067329', (45, 62))	('dysplasia', 'Disease', (148, 157))	('amplification', 'Var', (110, 123))	('healthy epithelia', 'Disease', (45, 62))	('dysplasia', 'Disease', 'MESH:D004476', (148, 157))	('SOX2', 'Gene', (105, 109))	('SQCC', 'Phenotype', 'HP:0002860', (9, 13))	('rat', 'Species', '10116', (199, 202))	('SQCC', 'Phenotype', 'HP:0002860', (222, 226))	('detected', 'Reg', (136, 144))
357817	27880766	Thus, SOX2 amplification could prevent regression of dysplasias by preventing generation of a SOX2Lo state that might be necessary for normal mucociliary differentiation.	('dysplasias', 'Disease', (53, 63))	('preventing', 'NegReg', (67, 77))	('dysplasias', 'Disease', 'MESH:D004476', (53, 63))	('SOX2Lo state', 'MPA', (94, 106))	('rat', 'Species', '10116', (82, 85))	('generation', 'MPA', (78, 88))	('amplification', 'Var', (11, 24))	('SOX2', 'Gene', (6, 10))
357836	27880766	In control ALI cultures, P-S6 was high during the proliferative SOX2Lo phase but declined at initial confluence, before SOX2 levels normally rise and mucociliary differentiation occurs (Figs 4B, 1C and 1D for SOX2 expression).	('SOX2 levels', 'MPA', (120, 131))	('P-S6', 'Var', (25, 29))	('P', 'Chemical', 'MESH:D010758', (25, 26))	('rat', 'Species', '10116', (57, 60))	('mucociliary differentiation', 'CPA', (150, 177))	('S6', 'Chemical', 'MESH:C012008', (27, 29))
357837	27880766	Nuclear accumulation of phospho-Thr308-AKT, which is PI3K-dependent, tracked with P-S6 and provided additional evidence that PI3K signaling is more active in proliferating rather than quiescing basal cells (Fig 4B).	('P', 'Chemical', 'MESH:D010758', (82, 83))	('S6', 'Chemical', 'MESH:C012008', (84, 86))	('AKT', 'Gene', '207', (39, 42))	('P', 'Chemical', 'MESH:D010758', (125, 126))	('rat', 'Species', '10116', (172, 175))	('rat', 'Species', '10116', (165, 168))	('P', 'Chemical', 'MESH:D010758', (53, 54))	('AKT', 'Gene', (39, 42))	('Thr308', 'Chemical', '-', (32, 38))	('P-S6', 'Var', (82, 86))	('Nuclear accumulation', 'MPA', (0, 20))
357843	27880766	To determine if PI3K signaling is necessary for the squamous response to SOX2, we treated proliferating basal cell cultures on plastic with pan-class I/II/III and class I-specific PI3K inhibitors LY294002 and BKM120, respectively, concurrently with Lenti-SOX2 infection.	('Lenti-SOX2 infection', 'Disease', 'MESH:C565948', (249, 269))	('rat', 'Species', '10116', (97, 100))	('P', 'Chemical', 'MESH:D010758', (16, 17))	('BKM120', 'Chemical', 'MESH:C571178', (209, 215))	('LY294002', 'Chemical', 'MESH:C085911', (196, 204))	('P', 'Chemical', 'MESH:D010758', (180, 181))	('PI3K', 'Var', (180, 184))	('Lenti-SOX2 infection', 'Disease', (249, 269))	('LY294002', 'Var', (196, 204))	('BKM120', 'Var', (209, 215))
357845	27880766	Notably, in some experiments, the class I (p110alpha, beta, delta, gamma)-specific drug, BKM120, enhanced MUC16 expression.	('BKM120', 'Chemical', 'MESH:C571178', (89, 95))	('MUC16', 'Protein', (106, 111))	('p110alpha', 'Gene', '5290', (43, 52))	('enhanced', 'PosReg', (97, 105))	('p110alpha', 'Gene', (43, 52))	('BKM120', 'Var', (89, 95))
357851	27880766	Consistent with the in vitro data, when basal cells were seeded with BKM120, even though PI3K signaling was only partially inhibited, IVL expression was suppressed (Fig 6C).	('P', 'Chemical', 'MESH:D010758', (89, 90))	('BKM120', 'Var', (69, 75))	('IVL expression', 'MPA', (134, 148))	('BKM120', 'Chemical', 'MESH:C571178', (69, 75))	('suppressed', 'NegReg', (153, 163))
357859	27880766	In the absence of Lenti-SOX2, BKM120 treatment was sufficient to increase SOX9 expression (S5B Fig), suggesting that PI3K signaling might act parallel to SOX2 in repressing SOX9 expression.	('increase', 'PosReg', (65, 73))	('S5B', 'Gene', (91, 94))	('BKM120', 'Chemical', 'MESH:C571178', (30, 36))	('expression', 'MPA', (79, 89))	('BKM120 treatment', 'Var', (30, 46))	('P', 'Chemical', 'MESH:D010758', (117, 118))	('SOX9', 'Gene', (74, 78))	('S5B', 'Gene', '5711', (91, 94))
357877	27880766	The amount of squamous marker induction was also generally weaker than observed for Lenti-SOX2, supporting the concept that SOX9 is an early determinant of columnar versus squamous lineage commitment, rather than a strong inducer of differentiation.	('rat', 'Species', '10116', (201, 204))	('SOX9', 'Var', (124, 128))	('columnar', 'CPA', (156, 164))
357878	27880766	Similarly, in ALI cultures, coinfection of Lenti-SOX9 with Lenti-SOX2 inhibited histologic squamous metaplasia, but not MUC16 differentiation (Fig 10D).	('squamous metaplasia', 'Phenotype', 'HP:0002860', (91, 110))	('squamous metaplasia', 'Disease', 'MESH:D008679', (91, 110))	('Lenti-SOX9', 'Var', (43, 53))	('inhibited', 'NegReg', (70, 79))	('squamous metaplasia', 'Disease', (91, 110))
357879	27880766	Thus, SOX9 repression is part of the mechanism through which SOX2 and PI3K promote squamous metaplasia from stem cells.	('squamous metaplasia', 'Phenotype', 'HP:0002860', (83, 102))	('promote', 'PosReg', (75, 82))	('PI3K', 'Var', (70, 74))	('P', 'Chemical', 'MESH:D010758', (70, 71))	('SOX2', 'Gene', (61, 65))	('squamous metaplasia', 'Disease', (83, 102))	('squamous metaplasia', 'Disease', 'MESH:D008679', (83, 102))
357880	27880766	To further investigate if the mechanism regulating squamous differentiation in stem cells might contribute to progression through early stages of SQCC pathogenesis, we characterized SOX2, SOX9, and P-S6 expression during preneoplasia (Fig 11).	('S6', 'Chemical', 'MESH:C012008', (200, 202))	('preneoplasia', 'Disease', 'None', (221, 233))	('SQCC', 'Disease', (146, 150))	('SQCC', 'Phenotype', 'HP:0002860', (146, 150))	('preneoplasia', 'Disease', (221, 233))	('P-S6', 'Var', (198, 202))	('P', 'Chemical', 'MESH:D010758', (198, 199))	('SOX9', 'Gene', (188, 192))	('SOX2', 'Gene', (182, 186))
357888	27880766	By contrast, in high-grade dysplasia, expression of SOX2, SOX9, and P-S6 was uniform.	('dysplasia', 'Disease', (27, 36))	('dysplasia', 'Disease', 'MESH:D004476', (27, 36))	('SOX2', 'Gene', (52, 56))	('P', 'Chemical', 'MESH:D010758', (68, 69))	('SOX9', 'Gene', (58, 62))	('P-S6', 'Var', (68, 72))	('S6', 'Chemical', 'MESH:C012008', (70, 72))
357895	27880766	Given that SOX2 and SOX9 H-scores were not that different between basal and suprabasal layers, for P-S6, we only scored the fraction of tumor cells that stained positive.	('P', 'Chemical', 'MESH:D010758', (99, 100))	('S6', 'Chemical', 'MESH:C012008', (101, 103))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('tumor', 'Disease', (136, 141))	('P-S6', 'Var', (99, 103))
357896	27880766	In 92% of SQCCs, some P-S6 staining was detectable, and 91% of SQCCs that expressed SOX2 also expressed P-S6, although in many cases, few tumor cells expressed P-S6 (S9A and S9B Fig).	('S6', 'Chemical', 'MESH:C012008', (24, 26))	('P-S6', 'Var', (104, 108))	('P', 'Chemical', 'MESH:D010758', (160, 161))	('S6', 'Chemical', 'MESH:C012008', (162, 164))	('tumor', 'Disease', (138, 143))	('SQCC', 'Phenotype', 'HP:0002860', (63, 67))	('SQCC', 'Phenotype', 'HP:0002860', (10, 14))	('P-S6', 'Var', (160, 164))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('P', 'Chemical', 'MESH:D010758', (104, 105))	('S6', 'Chemical', 'MESH:C012008', (106, 108))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('P', 'Chemical', 'MESH:D010758', (22, 23))
357899	27880766	Consistent with our IHC data, in most SQCCs, SOX9 was expressed at much lower levels than SOX2, and there was a weak negative correlation between their expression (S10A and S10B Fig, Table 1).	('S10A', 'Var', (164, 168))	('SOX9', 'Gene', (45, 49))	('SQCC', 'Phenotype', 'HP:0002860', (38, 42))	('S10B', 'Var', (173, 177))	('negative', 'NegReg', (117, 125))	('S10A', 'SUBSTITUTION', 'None', (164, 168))	('S10B', 'SUBSTITUTION', 'None', (173, 177))	('expression', 'MPA', (152, 162))
357901	27880766	In support of this possibility, the upper quartile of cases, which, on average, had 4-fold higher SOX9 expression than the remaining 75% of cases, were associated with fewer high copy number SOX2 gains (amplification) (S10C Fig).	('gains', 'PosReg', (196, 201))	('SOX9', 'Gene', (98, 102))	('higher', 'PosReg', (91, 97))	('SOX2', 'Protein', (191, 195))	('expression', 'MPA', (103, 113))	('high copy number', 'Var', (174, 190))	('fewer', 'NegReg', (168, 173))	('S10C', 'Mutation', 'p.S10C', (219, 223))
357902	27880766	Furthermore, when using publicly available data from nine SQCC cohorts and stratifying by approximately the upper quartile, there was a tendency for high SOX9 expression to be associated with a lower probability of survival (Fig 12A).	('high', 'Var', (149, 153))	('rat', 'Species', '10116', (77, 80))	('SQCC', 'Phenotype', 'HP:0002860', (58, 62))	('SOX9', 'Protein', (154, 158))	('survival', 'MPA', (215, 223))	('expression', 'MPA', (159, 169))	('lower', 'NegReg', (194, 199))
357903	27880766	This association was significant when restricting analysis to patients with stage I disease and a smoking history (Fig 12B), suggesting that SOX9 might promote more aggressive behavior in early stage SQCCs.	('SOX9', 'Var', (141, 145))	('aggressive behavior', 'Phenotype', 'HP:0000718', (165, 184))	('early stage SQCCs', 'Disease', (188, 205))	('stage I disease', 'Disease', (76, 91))	('aggressive behavior', 'CPA', (165, 184))	('SQCC', 'Phenotype', 'HP:0002860', (200, 204))	('patients', 'Species', '9606', (62, 70))	('promote', 'PosReg', (152, 159))	('stage I disease', 'Disease', 'MESH:D058625', (76, 91))
357909	27880766	Here, we show that SOX2 and PI3K cooperate to induce the squamous injury response in basal cells.	('squamous injury', 'Disease', (57, 72))	('PI3K', 'Var', (28, 32))	('squamous injury', 'Disease', 'MESH:D002294', (57, 72))	('P', 'Chemical', 'MESH:D010758', (28, 29))	('induce', 'PosReg', (46, 52))	('rat', 'Species', '10116', (38, 41))
357911	27880766	SOX2 can induce a specific type of mucinous differentiation marked by MUC16, or it can drive basal cells into a hyperplastic state that differentiates into squamous epithelia.	('MUC16', 'Gene', (70, 75))	('squamous epithelia', 'Phenotype', 'HP:0002860', (156, 174))	('squamous epithelia', 'Disease', 'MESH:D002294', (156, 174))	('drive', 'PosReg', (87, 92))	('squamous epithelia', 'Disease', (156, 174))	('SOX2', 'Var', (0, 4))	('mucinous', 'MPA', (35, 43))
357913	27880766	In embryonic stem (ES) cells, AKT directly regulates SOX2 through phosphorylation at Thr116, which increases SOX2 stability and, thus, generally promotes its activity.	('Thr116', 'Var', (85, 91))	('regulates', 'Reg', (43, 52))	('activity', 'MPA', (158, 166))	('Thr116', 'Chemical', '-', (85, 91))	('SOX2 stability', 'MPA', (109, 123))	('AKT', 'Gene', '207', (30, 33))	('phosphorylation', 'MPA', (66, 81))	('SOX2', 'Protein', (53, 57))	('AKT', 'Gene', (30, 33))	('increases', 'PosReg', (99, 108))	('promotes', 'PosReg', (145, 153))
357914	27880766	However, upon PI3K inhibition in basal cells, SOX2 protein expression is not reduced, and one differentiating activity of SOX2 (squamous) is much more affected than the other (mucinous).	('inhibition', 'Var', (19, 29))	('affected', 'Reg', (151, 159))	('P', 'Chemical', 'MESH:D010758', (14, 15))	('differentiating activity', 'MPA', (94, 118))	('SOX2 protein', 'Protein', (46, 58))	('PI3K inhibition', 'Var', (14, 29))
357925	27880766	Because functional PI3K activity may be below our detection limits in some cells, and because it is not certain where the stem cells in the metaplasia reside (e.g., center: low P-S6 versus edges: high P-S6, Fig 11), the significance of the P-S6 heterogeneity is not clear.	('P', 'Chemical', 'MESH:D010758', (240, 241))	('S6', 'Chemical', 'MESH:C012008', (242, 244))	('S6', 'Chemical', 'MESH:C012008', (179, 181))	('low P-S6', 'Var', (173, 181))	('P-S6', 'Var', (201, 205))	('PI3K', 'Enzyme', (19, 23))	('metaplasia', 'Disease', (140, 150))	('metaplasia', 'Disease', 'MESH:D008679', (140, 150))	('S6', 'Chemical', 'MESH:C012008', (203, 205))	('P-S6', 'Var', (177, 181))	('P', 'Chemical', 'MESH:D010758', (201, 202))	('P', 'Chemical', 'MESH:D010758', (177, 178))	('P', 'Chemical', 'MESH:D010758', (19, 20))
357936	27880766	Such 3q-amplified dysplasias would be more prone to progression due to the sustained hyperproliferative squamous-committed stem cell state and the inability to regress to quiescent mucociliary differentiated epithelia.	('3q-amplified', 'Var', (5, 17))	('rat', 'Species', '10116', (97, 100))	('dysplasias', 'Disease', (18, 28))	('dysplasias', 'Disease', 'MESH:D004476', (18, 28))
357937	27880766	As such, we would predict that 3q amplification would be a biomarker for non-regressing dysplasias.	('dysplasias', 'Disease', 'MESH:D004476', (88, 98))	('dysplasias', 'Disease', (88, 98))	('3q amplification', 'Var', (31, 47))
357947	27880766	We would also suggest that even dysplasias with 3q amplification might respond to anti-PI3K therapy.	('dysplasias', 'Disease', (32, 42))	('P', 'Chemical', 'MESH:D010758', (87, 88))	('dysplasias', 'Disease', 'MESH:D004476', (32, 42))	('3q amplification', 'Var', (48, 64))	('respond', 'Reg', (71, 78))
357948	27880766	We and others have found that PI3K signaling is high in dysplasia, and our stem cell data suggest that 3q amplification is initially selected to maintain a waning squamous injury response, which together, support 3q-amplified dysplastic cells being dependent on PI3K signaling.	('squamous injury', 'Disease', (163, 178))	('P', 'Chemical', 'MESH:D010758', (30, 31))	('dysplastic', 'Disease', 'MESH:D004416', (226, 236))	('squamous injury', 'Disease', 'MESH:D002294', (163, 178))	('dysplastic', 'Disease', (226, 236))	('dysplasia', 'Disease', 'MESH:D004476', (56, 65))	('P', 'Chemical', 'MESH:D010758', (262, 263))	('3q amplification', 'Var', (103, 119))	('dysplasia', 'Disease', (56, 65))
357952	27880766	Accordingly, PI3K may be a vulnerability in invasive carcinoma.	('PI3K', 'Var', (13, 17))	('P', 'Chemical', 'MESH:D010758', (13, 14))	('invasive carcinoma', 'Disease', 'MESH:D009361', (44, 62))	('carcinoma', 'Phenotype', 'HP:0030731', (53, 62))	('invasive carcinoma', 'Disease', (44, 62))
357954	27880766	This could reflect a problem with the therapeutic index, in which case co-targeting additional components of the squamous injury response mechanism might improve PI3K inhibitor effectiveness.	('co-targeting', 'Var', (71, 83))	('effectiveness', 'MPA', (177, 190))	('improve', 'PosReg', (154, 161))	('squamous injury', 'Disease', (113, 128))	('squamous injury', 'Disease', 'MESH:D002294', (113, 128))	('P', 'Chemical', 'MESH:D010758', (162, 163))
357957	27880766	On the other hand, in 20% of cases, P-S6 was expressed in at least 70% or more of tumor cells.	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('P-S6', 'Var', (36, 40))	('S6', 'Chemical', 'MESH:C012008', (38, 40))	('tumor', 'Disease', (82, 87))	('P', 'Chemical', 'MESH:D010758', (36, 37))
357962	27880766	Thus, during later stages of pathogenesis, in a subset of SQCCs, genetic or epigenetic alterations may be selected that promote this natural, SOX9Hi non-squamous-committed stem cell state.	('SQCC', 'Phenotype', 'HP:0002860', (58, 62))	('promote', 'PosReg', (120, 127))	('epigenetic alterations', 'Var', (76, 98))	('rat', 'Species', '10116', (91, 94))
357963	27880766	For example, our gene set enrichment analysis found similarity between SOX9Hi SQCCs and certain breast cancers (especially triple negative) and neural crest-derived tumors, whose genesis and malignant properties are affected by SOX9.	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('breast cancers', 'Phenotype', 'HP:0003002', (96, 110))	('tumors', 'Disease', (165, 171))	('SQCCs', 'Disease', (78, 83))	('breast cancers', 'Disease', 'MESH:D001943', (96, 110))	('tumors', 'Disease', 'MESH:D009369', (165, 171))	('breast cancers', 'Disease', (96, 110))	('tumors', 'Phenotype', 'HP:0002664', (165, 171))	('breast cancer', 'Phenotype', 'HP:0003002', (96, 109))	('cancers', 'Phenotype', 'HP:0002664', (103, 110))	('SOX9Hi', 'Var', (71, 77))	('SQCC', 'Phenotype', 'HP:0002860', (78, 82))
357972	27880766	These decisions may analogously be driven by SOX2 and SOX9, with injury-induced changes in their expression causing metaplasia.	('changes', 'Var', (80, 87))	('causing', 'Reg', (108, 115))	('metaplasia', 'Disease', 'MESH:D008679', (116, 126))	('metaplasia', 'Disease', (116, 126))	('expression', 'MPA', (97, 107))
357974	27880766	In some cases, such as in the lung and cervix, gains at 3q may be used to stabilize a more proliferative squamous metaplastic injury state in stem cells that do not normally exclusively generate a squamous epithelium.	('gains', 'Var', (47, 52))	('rat', 'Species', '10116', (190, 193))	('rat', 'Species', '10116', (98, 101))	('squamous metaplastic injury', 'Disease', (105, 132))	('squamous metaplastic injury', 'Disease', 'MESH:D002294', (105, 132))
357975	27880766	However, in other cases such as in the esophagus, where stem cells are already squamous-committed and quite proliferative, there is evidence that coamplification of SOX2 and PIK3CA stabilize a non-metaplastic injury state that increases squamous stem cell self-renewal.	('squamous stem cell self-renewal', 'CPA', (237, 268))	('PIK3CA', 'Gene', (174, 180))	('rat', 'Species', '10116', (115, 118))	('increases', 'PosReg', (227, 236))	('PIK3CA', 'Gene', '5290', (174, 180))	('coamplification', 'Var', (146, 161))	('SOX2', 'Gene', (165, 169))
358004	27880766	Mutations called by both GATK and Strelka were validated using targeted exome capture with the Agilent SureSelect Custom 2Mbp kit and the same pipeline.	('Mutations', 'Var', (0, 9))	('Mbp', 'Gene', (122, 125))	('Mbp', 'Gene', '4155', (122, 125))
358005	27880766	High confidence variants in PDXs included only mutations called by both exome and targeted sequence analysis or called in only exome sequence analysis but also found in the COSMIC database v70.	('variants', 'Var', (16, 24))	('P', 'Chemical', 'MESH:D010758', (28, 29))	('PDXs', 'Gene', (28, 32))
358020	27880766	Primary antibodies for immunohistochemistry were alpha-Ki-67 (#MIB-1, Dako, 1:150), alpha-HMWCK (#34BE12, Dako, 1:100), alpha- SOX9 (#AB5535, Millipore, 1:1,200), and alpha-SOX2 (#AF2018, R&D Systems, 1:2,000).	('P', 'Chemical', 'MESH:D010758', (0, 1))	('#34BE12', 'Var', (97, 104))	('MIB-1', 'Gene', (63, 68))	('MIB-1', 'Gene', '57534', (63, 68))	('#AB5535', 'Var', (133, 140))
358032	27880766	The FLAG-tagged SOX2 cDNA was then amplified using primers CMVFLAG14-1 (5'-5'-TCCAG AGA TCT AGA GCT CGT TTA GTG AAC CGT CAG-3') and CMVFLAG14-2 (5'-ATAGTA GAT CTG GGG AGG GGT CAC AGG GAT GCC-3') and cloned into the Gateway entry vector, pCR8/GW/TOPO.	('P', 'Chemical', 'MESH:D010758', (247, 248))	('CMVFLAG14-2', 'Var', (132, 143))	('CMVFLAG14-1', 'Gene', (59, 70))
358045	27880766	Genes significantly changed by SOX2/DMSO or SOX2/BKM120 were identified by comparing the replicates of each condition with the control vector/DMSO replicates using a one-way ANOVA test and a Benjamini-Hochberg-corrected p < 0.05 cutoff and a post-hoc Tukey's HSD test.	('HSD', 'Disease', (259, 262))	('DMSO', 'Chemical', 'MESH:D004121', (36, 40))	('SOX2/BKM120', 'Var', (44, 55))	('HSD', 'Disease', 'OMIM:143095', (259, 262))	('BKM120', 'Chemical', 'MESH:C571178', (49, 55))	('DMSO', 'Chemical', 'MESH:D004121', (142, 146))
358051	27880766	Eight cohort datasets can be downloaded from GEO (http://www.ncbi.nlm.nih.gov/geo/) with the accession numbers GSE14814, GSE19188, GSE29013, GSE30219, GSE3141, GSE37745, GSE4573, and GSE50081.	('GSE19188', 'Var', (121, 129))	('GSE3141', 'Chemical', '-', (151, 158))	('GSE50081', 'Var', (183, 191))	('GSE37745', 'Var', (160, 168))	('GSE4573', 'Var', (170, 177))	('GSE4573', 'Chemical', '-', (170, 177))	('GSE14814', 'Var', (111, 119))	('GSE29013', 'Var', (131, 139))	('GSE3141', 'Var', (151, 158))	('GSE30219', 'Var', (141, 149))
358085	32005248	In the past few years, long non-coding RNAs (lncRNAs), defined as transcripts longer than 200 nt lacking protein-coding capacity, have been reported to have complex biological functions and involved in tumorigenesis and metastasis.	('tumor', 'Disease', (202, 207))	('long non-coding RNAs', 'Var', (23, 43))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('involved', 'Reg', (190, 198))	('metastasis', 'CPA', (220, 230))
358098	32005248	Briefly, 2 mug of total RNAs from the training cohort were reverse transcribed using random primers and Cy5-dUTP or Cy3-dUTP with GoScript  Reverse Transcription system (Promega) in a total reaction volume of 20 mul.	('Cy3-dUTP', 'Chemical', 'MESH:C088941', (116, 124))	('RNAs', 'Protein', (24, 28))	('Cy5-dUTP', 'Var', (104, 112))	('Cy3-dUTP', 'Var', (116, 124))	('Cy5-dUTP', 'Chemical', 'MESH:C088942', (104, 112))
358116	32005248	To validate lncRNA expression levels detected by the microarray analysis, we randomly selected two upregulated lncRNAs (ASLNC11164 and BQ376030) and two downregulated lncRNAs (XLOC_001061 and RP11-473M20.9) in ESCC tissues and detected them by quantitative RT-PCR in 40 pairs of ESCC and noncancerous esophagus tissues randomly chosen from the training cohort.	('RP11', 'Gene', '26121', (192, 196))	('ESCC', 'Disease', 'MESH:C562729', (210, 214))	('XLOC_001061', 'Var', (176, 187))	('upregulated', 'PosReg', (99, 110))	('ESCC', 'Disease', 'MESH:C562729', (279, 283))	('cancer', 'Disease', (291, 297))	('BQ376030', 'Var', (135, 143))	('cancer', 'Disease', 'MESH:D009369', (291, 297))	('ESCC', 'Disease', (279, 283))	('RP11', 'Gene', (192, 196))	('ESCC', 'Disease', (210, 214))	('BQ376030', 'Chemical', 'MESH:C025612', (135, 143))	('cancer', 'Phenotype', 'HP:0002664', (291, 297))	('ASLNC11164', 'Chemical', 'None', (120, 130))	('ASLNC11164', 'Var', (120, 130))
358120	32005248	The formula consists of a linear combination of the expression level of 7 lncRNAs weighted by Cox regression coefficient: Risk score = (0.155 x expression value of BQ376030 + 0.112 x expression value of ASLNC11164 + 0.125 x expression value of BF894811 + 0.155 x expression value of RP11-473M20.9 - 0.182 x expression value of XLOC_007869 - 0.15 x XLOC_006476 - 0.172 x expression value of CK327190).	('CK327190', 'Var', (390, 398))	('BF894811 + 0.155 x', 'Var', (244, 262))	('0.155', 'Var', (136, 141))	('ASLNC11164', 'Chemical', 'None', (203, 213))	('Cox', 'Gene', '1351', (94, 97))	('BQ376030', 'Chemical', 'MESH:C025612', (164, 172))	('BQ376030 + 0.112', 'Var', (164, 180))	('RP11', 'Gene', (283, 287))	('XLOC_007869', 'Chemical', 'None', (327, 338))	('Cox', 'Gene', (94, 97))	('RP11', 'Gene', '26121', (283, 287))	('XLOC_007869 - 0.15', 'Var', (327, 345))	('ASLNC11164 + 0.125 x', 'Var', (203, 223))	('BF894811', 'Chemical', 'MESH:C088437', (244, 252))
358127	32005248	Then we constructed a new risk score formula with the same method used in the training cohort: Risk score = (0.028 x expression value of BQ376030 + 0.053 x expression value of ASLNC11164 + 0.049 x expression value of BF894811 + 0.031 x expression value of RP11-473M20.9 - 0.058 x expression value of XLOC_007869 - 0.116 x XLOC_006476 - 0.061 x expression value of CK327190).	('BF894811', 'Chemical', 'MESH:C088437', (217, 225))	('BF894811 + 0.031 x', 'Var', (217, 235))	('XLOC_007869', 'Chemical', 'None', (300, 311))	('BQ376030 + 0.053', 'Var', (137, 153))	('ASLNC11164', 'Chemical', 'None', (176, 186))	('CK327190', 'Var', (364, 372))	('ASLNC11164 + 0.049 x', 'Var', (176, 196))	('RP11', 'Gene', (256, 260))	('RP11', 'Gene', '26121', (256, 260))	('XLOC_007869 - 0.116 x XLOC_006476 - 0.061', 'Var', (300, 341))	('BQ376030', 'Chemical', 'MESH:C025612', (137, 145))
358165	32005248	Recently, non-coding RNA (including microRNA [miRNA], long non-coding RNA and others) has been found to play critical roles in physiological and pathological processes of organisms, and involved in disease processes including that of cancer.	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('non-coding', 'Var', (10, 20))	('cancer', 'Disease', 'MESH:D009369', (234, 240))	('play', 'Reg', (104, 108))	('cancer', 'Disease', (234, 240))	('involved', 'Reg', (186, 194))
358177	31110442	Detection and comparison of microsatellite marker D9S1747 with clinical stages and grades of oral squamous cell carcinoma One of the main characteristics of oral squamous cell carcinoma (OSCC) is genetic alteration in specific target regions.	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (157, 185))	('oral squamous cell carcinoma', 'Disease', (93, 121))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (162, 185))	('oral squamous cell carcinoma', 'Disease', (157, 185))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (93, 121))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (98, 121))	('D9S1747', 'Var', (50, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (176, 185))
358178	31110442	Allelic imbalance in tumor suppressor genes is the key event in OSCC which is associated with loss of heterozygosity mostly on chromosome 9p21 locus which includes p16 marker.	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('tumor', 'Disease', (21, 26))	('p16', 'Gene', (164, 167))	('imbalance', 'Phenotype', 'HP:0002172', (8, 17))	('OSCC', 'Disease', (64, 68))	('Allelic imbalance', 'Var', (0, 17))	('p21', 'Gene', (139, 142))	('p16', 'Gene', '1029', (164, 167))	('p21', 'Gene', '644914', (139, 142))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
358180	31110442	To redefine more clearly the role of D9S1747 (p16 microsatellite marker) and its expression in OSCC, the study was designed with the aim to check the detection of D9S1747 in OSCC and to compare the same with histopathological grades and tumor node metastasis staging.	('D9S1747', 'Var', (37, 44))	('tumor', 'Disease', (237, 242))	('p16', 'Gene', '1029', (46, 49))	('D9S1747', 'Var', (163, 170))	('OSCC', 'Disease', (95, 99))	('OSCC', 'Disease', (174, 178))	('tumor', 'Disease', 'MESH:D009369', (237, 242))	('p16', 'Gene', (46, 49))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))
358182	31110442	DNA was extracted from the tissue sections and subjected for polymerase chain reaction to detect p16 microsatellite marker D9S1747.	('D9S1747', 'Var', (123, 130))	('p16', 'Gene', '1029', (97, 100))	('p16', 'Gene', (97, 100))
358185	31110442	p16 microsatellite marker positivity was found in 77.8%, 22.2% and 0% for well-differentiated, moderately differentiated and poorly differentiated OSCC cases, respectively.	('poorly differentiated OSCC', 'Disease', (125, 151))	('found', 'Reg', (41, 46))	('well-differentiated', 'Disease', (74, 93))	('p16', 'Gene', (0, 3))	('p16', 'Gene', '1029', (0, 3))	('microsatellite marker positivity', 'Var', (4, 36))	('moderately differentiated', 'Disease', (95, 120))
358186	31110442	Cancer is a genetic disease which results due to a variety of genetic alteration which induces normal cells to transform into malignancy.	('results', 'Reg', (34, 41))	('malignancy', 'Disease', (126, 136))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('genetic alteration', 'Var', (62, 80))	('Cancer', 'Disease', (0, 6))	('induces', 'Reg', (87, 94))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('genetic disease', 'Disease', (12, 27))	('malignancy', 'Disease', 'MESH:D009369', (126, 136))	('genetic disease', 'Disease', 'MESH:D030342', (12, 27))	('transform', 'CPA', (111, 120))
358188	31110442	Among such genetic alterations, gene deletion, gene amplification or rearrangements, leading to either mutation or overexpression of oncogenes, activation of protooncogenes along with mitotic recombination of nondisjunction events which might cause loss of tumor suppressor genes (TSGs) appears to be main events.	('TSG', 'Gene', '57045', (281, 284))	('tumor', 'Disease', (257, 262))	('tumor', 'Phenotype', 'HP:0002664', (257, 262))	('rearrangements', 'Var', (69, 83))	('alterations', 'Var', (19, 30))	('tumor', 'Disease', 'MESH:D009369', (257, 262))	('TSG', 'Gene', (281, 284))	('gene deletion', 'Var', (32, 45))	('overexpression', 'PosReg', (115, 129))
358189	31110442	The key event in tumorigenesis of OSCC is inactivation of TSG.	('TSG', 'Gene', '57045', (58, 61))	('tumor', 'Disease', (17, 22))	('inactivation', 'Var', (42, 54))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('TSG', 'Gene', (58, 61))	('OSCC', 'Disease', (34, 38))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
358195	31110442	In head and neck cancers, p16 protein is often inactivated by any one or a combination of homozygous deletions, promoter methylations or point mutations.	('p16', 'Gene', (26, 29))	('inactivated', 'NegReg', (47, 58))	('point mutations', 'Var', (137, 152))	('cancers', 'Phenotype', 'HP:0002664', (17, 24))	('neck cancers', 'Disease', (12, 24))	('promoter methylations', 'Var', (112, 133))	('p16', 'Gene', '1029', (26, 29))	('head and neck cancers', 'Phenotype', 'HP:0012288', (3, 24))	('deletions', 'Var', (101, 110))	('neck cancers', 'Disease', 'MESH:D006258', (12, 24))	('head and neck cancer', 'Phenotype', 'HP:0012288', (3, 23))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
358198	31110442	The LOH markers 9p21 (D9s1747, RPS6 and D9s162) and 17 p13 (T53) were assessed along with the immunostaining result of the corresponding matched mutant P53, P14, P15 and P16 proteins in surgical margins of OSCC.	('P53', 'Gene', '7157', (152, 155))	('P14', 'Gene', '1029', (157, 160))	('P14', 'Gene', (157, 160))	('p13', 'Gene', (55, 58))	('D9s1747', 'Var', (22, 29))	('P15', 'Gene', (162, 165))	('P15', 'Gene', '1030', (162, 165))	('P16', 'Gene', (170, 173))	('P16', 'Gene', '1029', (170, 173))	('p21', 'Gene', '644914', (17, 20))	('RPS6', 'Gene', '6194', (31, 35))	('RPS6', 'Gene', (31, 35))	('p13', 'Gene', '440926', (55, 58))	('P53', 'Gene', (152, 155))	('p21', 'Gene', (17, 20))	('D9s162', 'Var', (40, 46))
358208	31110442	For PCR analysis, p16 microsatellite marker DS91747 with the sequence of forward 5'-ATTCAACG AGTGG GATGAAG-3' and reverse 5'-TCCAGGTTGCTGCAAATGCC-3' was selected.	('p16', 'Gene', (18, 21))	('p16', 'Gene', '1029', (18, 21))	('DS91747', 'Var', (44, 51))
358211	31110442	Cross-tabulations were done to show association of p16 microsatellite marker D9S1747 between OSCC cases along with clinical staging and histopathological grading.	('p16', 'Gene', '1029', (51, 54))	('OSCC', 'Disease', (93, 97))	('p16', 'Gene', (51, 54))	('association', 'Interaction', (36, 47))	('D9S1747', 'Var', (77, 84))
358213	31110442	p16 microsatellite marker D9S1747 was positive for 27 (67.5%) cases of OSCC and 13 (32.5%) cases were negative for OSCC.	('positive', 'Reg', (38, 46))	('p16', 'Gene', (0, 3))	('OSCC', 'Disease', (71, 75))	('p16', 'Gene', '1029', (0, 3))	('D9S1747', 'Var', (26, 33))
358214	31110442	In normal cases, only 2 (20%) cases showed positivity for p16 microsatellite marker D9S1747 and 8 (80%) cases were negative [Table 1].	('p16', 'Gene', '1029', (58, 61))	('p16', 'Gene', (58, 61))	('D9S1747', 'Var', (84, 91))
358217	31110442	On histopathological grade showed 21 (77.8%) cases showed positivity for p16 in WDSCC followed by 22.2% cases for MDSCC where as PDSCC did not show any positivity [Table 3].	('positivity', 'Var', (58, 68))	('p16', 'Gene', (73, 76))	('p16', 'Gene', '1029', (73, 76))
358219	31110442	Failure to correct inaccurate repetition producing insertion or deletion of repeated DNA microsatellite sequences results in MSI.	('results in', 'Reg', (114, 124))	('deletion', 'Var', (64, 72))	('MSI', 'Disease', 'None', (125, 128))	('insertion', 'Var', (51, 60))	('MSI', 'Disease', (125, 128))
358224	31110442	The aim of this study was to detect one of the p16 microsatellite markers D9S1747 on locus 9p21 in various stages and grades of OSCC and compare to normal oral mucosa.	('OSCC', 'Disease', (128, 132))	('p21', 'Gene', '644914', (92, 95))	('D9S1747', 'Var', (74, 81))	('p16', 'Gene', (47, 50))	('p16', 'Gene', '1029', (47, 50))	('p21', 'Gene', (92, 95))
358225	31110442	Several studies have been conducted on OSCC for changes in p16 using microsatellite markers on different chromosomes, methylation and immunohistochemistry.	('p16', 'Gene', '1029', (59, 62))	('p16', 'Gene', (59, 62))	('changes', 'Var', (48, 55))
358226	31110442	It was observed that these markers that have provided evidence up to 87% of oral cancers show inactivation of p16 and in that homozygous deletion is the most common mechanism of inactivation.	('p16', 'Gene', '1029', (110, 113))	('oral cancers', 'Disease', 'MESH:D009062', (76, 88))	('cancers', 'Phenotype', 'HP:0002664', (81, 88))	('oral cancers', 'Disease', (76, 88))	('inactivation', 'NegReg', (94, 106))	('homozygous', 'Var', (126, 136))	('p16', 'Gene', (110, 113))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))
358227	31110442	In the present study, we observed high p16 microsatellite marker D9S1747 positivity in OSCC than normal cases [Figure 1].	('D9S1747', 'Var', (65, 72))	('OSCC', 'Disease', (87, 91))	('p16', 'Gene', (39, 42))	('p16', 'Gene', '1029', (39, 42))
358228	31110442	LOH in 9p region has been reported in several human cancers.	('reported', 'Reg', (26, 34))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('cancers', 'Disease', (52, 59))	('LOH', 'Var', (0, 3))	('human', 'Species', '9606', (46, 51))	('cancers', 'Phenotype', 'HP:0002664', (52, 59))	('cancers', 'Disease', 'MESH:D009369', (52, 59))
358229	31110442	In head and neck cancer, LOH was studied in different chromosomal loci by el-Naggar et al., and they showed high incidence of LOH in 9p, 8p, 3p, 9q and 11q loci.	('neck cancer', 'Disease', 'MESH:D006258', (12, 23))	('LOH', 'Var', (126, 129))	('neck cancer', 'Disease', (12, 23))	('head and neck cancer', 'Phenotype', 'HP:0012288', (3, 23))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
358232	31110442	in their analysis on young adults; OSCC patients' highest frequency of alteration of microsatellite marker found was D9S168 on locus 9p23-22.	('patients', 'Species', '9606', (40, 48))	('alteration', 'MPA', (71, 81))	('D9S168', 'Var', (117, 123))
358233	31110442	However, in one of the cases, it was found that MSI with the marker similar to our D9S1747 was present in tumor but not in matched normal tissue.	('MSI', 'Disease', 'None', (48, 51))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('MSI', 'Disease', (48, 51))	('D9S1747', 'Var', (83, 90))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Disease', (106, 111))
358234	31110442	conducted molecular analysis of TP53, D9S1747, D9S162 and RPS6 in OSCC.	('D9S162', 'Var', (47, 53))	('D9S1747', 'Var', (38, 45))	('TP53', 'Gene', '7157', (32, 36))	('RPS6', 'Gene', (58, 62))	('TP53', 'Gene', (32, 36))	('D9S162', 'CellLine', 'CVCL:J920', (47, 53))	('RPS6', 'Gene', '6194', (58, 62))	('OSCC', 'Disease', (66, 70))
358237	31110442	Microsatellite marker D9S1747 LOH was commonly detected near p16 in superficial as well as deeper parts.	('p16', 'Gene', '1029', (61, 64))	('D9S1747 LOH', 'Var', (22, 33))	('p16', 'Gene', (61, 64))
358238	31110442	In the present study, 32.5% of the OSCC samples were negative for p16 microsatellite marker D9S1747.	('D9S1747', 'Var', (92, 99))	('OSCC', 'Disease', (35, 39))	('p16', 'Gene', (66, 69))	('negative', 'NegReg', (53, 61))	('p16', 'Gene', '1029', (66, 69))
358243	31110442	The correlation of p16 microsatellite marker D9S1747 with TNM staging in the present study, we found 44.4%, 51.9% and 3.7% positivity in Stage 1, Stage 2 and Stage 4 OSCC cases, respectively.	('TNM', 'Gene', '10178', (58, 61))	('p16', 'Gene', (19, 22))	('Stage 1', 'Disease', (137, 144))	('Stage 2', 'Disease', (146, 153))	('D9S1747', 'Var', (45, 52))	('TNM', 'Gene', (58, 61))	('p16', 'Gene', '1029', (19, 22))
358245	31110442	analyzed allelic imbalance and clinicopathological features on the key chromosomal loci such as 3p24-26, 3p13 and 9p21.	('imbalance', 'Phenotype', 'HP:0002172', (17, 26))	('p13', 'Gene', (106, 109))	('p13', 'Gene', '440926', (106, 109))	('p21', 'Gene', (115, 118))	('p21', 'Gene', '644914', (115, 118))	('3p24-26', 'Var', (96, 103))
358247	31110442	They found the hazard ratios for survival analysis showed poor prognosis with hazard ratios of 3.93, 2.60 and 2.48 for 3p24-26, 3p13 and 9p21, respectively.	('p13', 'Gene', '440926', (129, 132))	('p21', 'Gene', (138, 141))	('p21', 'Gene', '644914', (138, 141))	('3p24-26', 'Var', (119, 126))	('p13', 'Gene', (129, 132))
358248	31110442	Also found that allelic imbalance was a better prognostic marker than TNM staging.	('TNM', 'Gene', '10178', (70, 73))	('allelic imbalance', 'Var', (16, 33))	('TNM', 'Gene', (70, 73))	('imbalance', 'Phenotype', 'HP:0002172', (24, 33))
358249	31110442	Allelic imbalance at each of these regions has shown 25 times increase in cases in morbidity rate relative to patient showed LOH at these loci.	('morbidity rate', 'MPA', (83, 97))	('imbalance', 'Phenotype', 'HP:0002172', (8, 17))	('Allelic imbalance', 'Var', (0, 17))	('patient', 'Species', '9606', (110, 117))	('increase', 'PosReg', (62, 70))
358252	31110442	found that the LOH and MI frequency at 9p21 was significantly associated with WHO grading (P < 0.01) and lymph node metastasis.	('associated', 'Reg', (62, 72))	('lymph node metastasis', 'CPA', (105, 126))	('WHO grading', 'CPA', (78, 89))	('p21', 'Gene', (40, 43))	('LOH', 'Var', (15, 18))	('p21', 'Gene', '644914', (40, 43))
358255	31110442	Genetic alterations of the p16 gene lead to its inactivation, resulting in deregulation of cell proliferation and tumorigenesis.	('Genetic alterations', 'Var', (0, 19))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('inactivation', 'MPA', (48, 60))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('deregulation', 'MPA', (75, 87))	('tumor', 'Disease', (114, 119))	('p16', 'Gene', (27, 30))	('cell proliferation', 'CPA', (91, 109))	('p16', 'Gene', '1029', (27, 30))
358256	31110442	Our results indicate that the detection of p16 microsatellite marker D9S1747 is the most common genetic change delineated in OSCC and its detection decreases as the grade increases suggesting that it is an early event in OSCC.	('p16', 'Gene', (43, 46))	('decreases', 'NegReg', (148, 157))	('detection', 'MPA', (138, 147))	('D9S1747', 'Var', (69, 76))	('p16', 'Gene', '1029', (43, 46))
358258	31110442	In the present study, the p16 microsatellite positivity was higher in Stage II specimen.	('p16', 'Gene', (26, 29))	('higher', 'PosReg', (60, 66))	('p16', 'Gene', '1029', (26, 29))	('microsatellite', 'Var', (30, 44))	('Stage II', 'Disease', (70, 78))
358262	31044156	Resistance to paclitaxel is associated with a variant of the gene BCL2 in multiple tumor types Paclitaxel, the most commonly used form of chemotherapy, is utilized in curative protocols in different types of cancer.	('Paclitaxel', 'Chemical', 'MESH:D017239', (95, 105))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('BCL2', 'Gene', '596', (66, 70))	('cancer', 'Disease', (208, 214))	('variant', 'Var', (46, 53))	('paclitaxel', 'Chemical', 'MESH:D017239', (14, 24))	('associated', 'Reg', (28, 38))	('tumor', 'Disease', (83, 88))	('BCL2', 'Gene', (66, 70))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('cancer', 'Disease', 'MESH:D009369', (208, 214))
358264	31044156	Since paclitaxel is known to target BCL2 and TUBB1, we used pan-cancer genomic data from hundreds of patients to show that a single-nucleotide variant in the BCL2 sequence can predict a patient's response to paclitaxel.	('patients', 'Species', '9606', (101, 109))	('paclitaxel', 'Chemical', 'MESH:D017239', (6, 16))	('paclitaxel', 'Chemical', 'MESH:D017239', (208, 218))	('predict', 'Reg', (176, 183))	('BCL2', 'Gene', (158, 162))	('BCL2', 'Gene', '596', (36, 40))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('TUBB1', 'Gene', (45, 50))	('single-nucleotide variant', 'Var', (125, 150))	('BCL2', 'Gene', (36, 40))	('patient', 'Species', '9606', (101, 108))	('response to paclitaxel', 'MPA', (196, 218))	('patient', 'Species', '9606', (186, 193))	('BCL2', 'Gene', '596', (158, 162))	('TUBB1', 'Gene', '81027', (45, 50))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
358265	31044156	Here, we show a connection between this BCL2 genomic variant, its transcript structure, and protein abundance.	('variant', 'Var', (53, 60))	('BCL2', 'Gene', (40, 44))	('BCL2', 'Gene', '596', (40, 44))
358268	31044156	We also show that tumor and normal cells with the variant express higher levels of BCL2 protein, a phenomenon that we validated in an independent cohort of patients.	('patients', 'Species', '9606', (156, 164))	('BCL2', 'Gene', '596', (83, 87))	('tumor', 'Disease', (18, 23))	('variant', 'Var', (50, 57))	('BCL2', 'Gene', (83, 87))	('higher', 'PosReg', (66, 72))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
358269	31044156	Our results indicate BCL2 sequence variations as determinants of chemotherapy resistance.	('BCL2', 'Gene', (21, 25))	('BCL2', 'Gene', '596', (21, 25))	('variations', 'Var', (35, 45))
358275	31044156	The recent increase in genome-wide association studies has revealed a substantial contribution of synonymous SNPs to human disease risk and other complex traits.	('synonymous SNPs', 'Var', (98, 113))	('human disease', 'Disease', (117, 130))	('human', 'Species', '9606', (117, 122))
358276	31044156	showed that a synonymous polymorphism in TTP affects translation efficiency and response to Herceptin treatment in breast cancer.	('synonymous polymorphism', 'Var', (14, 37))	('translation efficiency', 'MPA', (53, 75))	('response', 'MPA', (80, 88))	('TTP', 'Gene', '7538', (41, 44))	('breast cancer', 'Disease', 'MESH:D001943', (115, 128))	('Herceptin', 'Chemical', 'MESH:D000068878', (92, 101))	('affects', 'Reg', (45, 52))	('breast cancer', 'Disease', (115, 128))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('breast cancer', 'Phenotype', 'HP:0003002', (115, 128))	('TTP', 'Gene', (41, 44))
358283	31044156	In the work presented here, we used pan-cancer genomic data from hundreds of patients to show that a single-nucleotide variant in the BCL2 sequence can predict a patient's response to paclitaxel, a widely used chemotherapy.	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('BCL2', 'Gene', (134, 138))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('paclitaxel', 'Chemical', 'MESH:D017239', (184, 194))	('predict', 'Reg', (152, 159))	('cancer', 'Disease', (40, 46))	('patients', 'Species', '9606', (77, 85))	('patient', 'Species', '9606', (162, 169))	('single-nucleotide variant', 'Var', (101, 126))	('patient', 'Species', '9606', (77, 84))	('BCL2', 'Gene', '596', (134, 138))	('response to paclitaxel', 'MPA', (172, 194))
358284	31044156	Furthermore, we highlight a connection between this BCL2 genomic variant, its transcript structure, and protein abundance.	('BCL2', 'Gene', (52, 56))	('BCL2', 'Gene', '596', (52, 56))	('variant', 'Var', (65, 72))
358285	31044156	Finally, our results indicate BCL2 sequence variations as determinants of chemotherapy resistance.	('variations', 'Var', (44, 54))	('BCL2', 'Gene', (30, 34))	('BCL2', 'Gene', '596', (30, 34))
358292	31044156	However, one variation, the transition from a C to a T at location 21 of BCL2 (+ 21 T > C, Fig.	('21 T > C', 'SUBSTITUTION', 'None', (81, 89))	('BCL2', 'Gene', '596', (73, 77))	('BCL2', 'Gene', (73, 77))	('21 T > C', 'Var', (81, 89))
358295	31044156	The variation status matched patient resistance to paclitaxel in a manner that was able to retrospectively predict whether the patient received single or multiple lines of treatment.	('patient', 'Species', '9606', (29, 36))	('paclitaxel', 'Chemical', 'MESH:D017239', (51, 61))	('matched', 'Reg', (21, 28))	('patient', 'Species', '9606', (127, 134))	('variation', 'Var', (4, 13))
358297	31044156	In total, 73% of patients had a T at location 21 and did not respond to Taxol-platinum first-line therapy and eventually received multiple lines of treatment (Fig.	('received', 'Reg', (121, 129))	('patients', 'Species', '9606', (17, 25))	('Taxol-platinum', 'Chemical', '-', (72, 86))	('T at', 'Var', (32, 36))
358300	31044156	We therefore hypothesized that the BCL2 variant is a determinant of paclitaxel resistance and that the phenomenon is not specific to a type of cancer.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('type of cancer', 'Disease', 'MESH:D009369', (135, 149))	('BCL2', 'Gene', '596', (35, 39))	('variant', 'Var', (40, 47))	('determinant', 'Reg', (53, 64))	('paclitaxel resistance', 'MPA', (68, 89))	('BCL2', 'Gene', (35, 39))	('type of cancer', 'Disease', (135, 149))	('paclitaxel', 'Chemical', 'MESH:D017239', (68, 78))
358303	31044156	In addition, to further test drug efficacy in association with the presence of the mutation, we performed Kaplan-Meier survival analysis to establish the connection between the presence of the SNP and overall survival in response to paclitaxel-platinum treatment in ovarian cancer patients.	('paclitaxel', 'Chemical', 'MESH:D017239', (233, 243))	('platinum', 'Chemical', 'MESH:D010984', (244, 252))	('ovarian cancer', 'Disease', 'MESH:D010051', (266, 280))	('ovarian cancer', 'Disease', (266, 280))	('patients', 'Species', '9606', (281, 289))	('SNP', 'Gene', (193, 196))	('presence', 'Var', (177, 185))	('ovarian cancer', 'Phenotype', 'HP:0100615', (266, 280))	('cancer', 'Phenotype', 'HP:0002664', (274, 280))
358305	31044156	This observation strengthens our hypothesis that the BCL2 polymorphism determines the response to paclitaxel.	('determines', 'Reg', (71, 81))	('polymorphism', 'Var', (58, 70))	('paclitaxel', 'Chemical', 'MESH:D017239', (98, 108))	('BCL2', 'Gene', '596', (53, 57))	('response to paclitaxel', 'MPA', (86, 108))	('BCL2', 'Gene', (53, 57))
358306	31044156	Here, we used RNA-folding prediction software to assess structural changes that could result from the C > T change in BCL2.	('C > T change', 'Var', (102, 114))	('BCL2', 'Gene', (118, 122))	('BCL2', 'Gene', '596', (118, 122))
358307	31044156	Specifically, we used the tools RNAsnp and RNAplfold to test the effect of the T at position 21 by comparison with adjacent variations (+ 21 T > C vs. + 23 C > T).	('21 T > C', 'SUBSTITUTION', 'None', (138, 146))	('23 C > T', 'SUBSTITUTION', 'None', (153, 161))	('23 C > T', 'Var', (153, 161))	('21 T > C', 'Var', (138, 146))
358309	31044156	Ovarian carcinoma HeyA8 cells were transfected with GFP or one of three GFP-BCL2 variants: reference (+21 T), T > C (+21 C) or random (+23 C > T).	('+21 T', 'Var', (102, 107))	('BCL2', 'Gene', '596', (76, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (8, 17))	('Ovarian carcinoma', 'Phenotype', 'HP:0025318', (0, 17))	('Ovarian carcinoma', 'Disease', (0, 17))	('BCL2', 'Gene', (76, 80))	('+23 C > T', 'Mutation', 'rs771312293', (135, 144))	('Ovarian carcinoma', 'Disease', 'MESH:D010051', (0, 17))	('T > C (+21 C', 'Var', (110, 122))
358311	31044156	At 48 h post transfection, we recovered the total RNA and used qRT-PCR to quantify BCL2 expression levels in all three variants (normalized for GFP as a control for the quality of transfection).	('BCL2', 'Gene', (83, 87))	('variants', 'Var', (119, 127))	('BCL2', 'Gene', '596', (83, 87))
358315	31044156	4b, the transcript of the form of BCL2 that includes the T > C modification with GFP-BCL2 was significantly more stable.	('BCL2', 'Gene', '596', (34, 38))	('BCL2', 'Gene', (85, 89))	('BCL2', 'Gene', (34, 38))	('stable', 'MPA', (113, 119))	('more', 'PosReg', (108, 112))	('T > C', 'Var', (57, 62))	('BCL2', 'Gene', '596', (85, 89))
358316	31044156	These findings led us to hypothesize that the + 21 T > C substitution leads, through a more stable transcript, to an increase in BCL2 protein levels.	('BCL2', 'Gene', (129, 133))	('increase', 'PosReg', (117, 125))	('21 T > C', 'SUBSTITUTION', 'None', (48, 56))	('more', 'PosReg', (87, 91))	('BCL2', 'Gene', '596', (129, 133))	('21 T > C', 'Var', (48, 56))
358318	31044156	First, we overexpressed the control GFP-empty vector or one of the three BCL2-GFP variants described above.	('variants', 'Var', (82, 90))	('BCL2', 'Gene', (73, 77))	('BCL2', 'Gene', '596', (73, 77))
358319	31044156	The BCL2 protein levels in cells with a C instead of a T at location 21 of BCL2 were fourfold (p-value < 1.1e-006) higher than those with the reference sequence.	('BCL2', 'Gene', '596', (4, 8))	('BCL2', 'Gene', (75, 79))	('BCL2', 'Gene', (4, 8))	('C instead', 'Var', (40, 49))	('BCL2', 'Gene', '596', (75, 79))	('higher', 'PosReg', (115, 121))
358328	31044156	Variation at location 21 of BCL2 may regulate the transcriptional activity of the gene in other cell types.	('regulate', 'Reg', (37, 45))	('BCL2', 'Gene', '596', (28, 32))	('BCL2', 'Gene', (28, 32))	('transcriptional activity', 'MPA', (50, 74))	('Variation', 'Var', (0, 9))
358332	31044156	To directly quantify the effect of the variant on the in vitro sensitivity to paclitaxel, the GFP-empty vector control or one of three GFP-BCL2 variants (reference, variant, or random) were overexpressed, and the cells were treated with paclitaxel.	('variants', 'Var', (144, 152))	('BCL2', 'Gene', '596', (139, 143))	('variant', 'Var', (165, 172))	('BCL2', 'Gene', (139, 143))	('paclitaxel', 'Chemical', 'MESH:D017239', (237, 247))	('paclitaxel', 'Chemical', 'MESH:D017239', (78, 88))
358335	31044156	Cells transfected with either reference or random variation BCL2 showed reduced cell death (increased rates of cell viability), which is also expected, as the levels of BCL2 were elevated compared with the intrinsic response.	('reduced', 'NegReg', (72, 79))	('BCL2', 'Gene', '596', (169, 173))	('rates', 'CPA', (102, 107))	('increased', 'PosReg', (92, 101))	('random variation', 'Var', (43, 59))	('elevated', 'PosReg', (179, 187))	('cell death', 'CPA', (80, 90))	('BCL2', 'Gene', '596', (60, 64))	('BCL2', 'Gene', (60, 64))	('BCL2', 'Gene', (169, 173))
358336	31044156	However, cell viability was significantly improved (p-value < 0.05) in cells that were transfected to provide a BCL2 transcript with a 21 T > C. Another approach to control the expression of the BCL2 transcript is through an increase in copy number.	('BCL2', 'Gene', (112, 116))	('BCL2', 'Gene', (195, 199))	('improved', 'PosReg', (42, 50))	('increase', 'PosReg', (225, 233))	('21 T > C', 'Mutation', 'rs369581368', (135, 143))	('copy number', 'Var', (237, 248))	('cell viability', 'CPA', (9, 23))	('BCL2', 'Gene', '596', (112, 116))	('BCL2', 'Gene', '596', (195, 199))
358341	31044156	5g, an increase in BCL2 copy number led to a decrease in relative cell death in response to paclitaxel.	('increase', 'PosReg', (7, 15))	('response to paclitaxel', 'MPA', (80, 102))	('relative cell death', 'CPA', (57, 76))	('BCL2', 'Gene', '596', (19, 23))	('paclitaxel', 'Chemical', 'MESH:D017239', (92, 102))	('decrease', 'NegReg', (45, 53))	('copy number', 'Var', (24, 35))	('BCL2', 'Gene', (19, 23))
358342	31044156	We cotransfected cells with the reference and variant forms of BCL2 and treated them with paclitaxel and/or carboplatin.	('BCL2', 'Gene', '596', (63, 67))	('variant', 'Var', (46, 53))	('paclitaxel', 'Chemical', 'MESH:D017239', (90, 100))	('BCL2', 'Gene', (63, 67))	('carboplatin', 'Chemical', 'MESH:D016190', (108, 119))
358346	31044156	These findings further support our notion that the variant form of the gene leads to higher BCL2 expression, which leads to paclitaxel resistance.	('paclitaxel resistance', 'MPA', (124, 145))	('leads to', 'Reg', (115, 123))	('higher', 'PosReg', (85, 91))	('paclitaxel', 'Chemical', 'MESH:D017239', (124, 134))	('BCL2', 'Gene', '596', (92, 96))	('variant', 'Var', (51, 58))	('expression', 'MPA', (97, 107))	('BCL2', 'Gene', (92, 96))
358348	31044156	HEK293T cells were grown on coverslips in a 24-well plate and transfected with the different forms of BCL2, followed by an immunofluorescence assay.	('BCL2', 'Gene', (102, 106))	('HEK293T', 'CellLine', 'CVCL:0063', (0, 7))	('transfected', 'Var', (62, 73))	('BCL2', 'Gene', '596', (102, 106))
358349	31044156	Staining of both reference and variant BCL2-GFP demonstrated similar cell localization patterns, whereas the empty vector was localized perfectly in the cell nucleus, thereby ruling out relocalization as a relevant mechanism.	('BCL2', 'Gene', '596', (39, 43))	('variant', 'Var', (31, 38))	('BCL2', 'Gene', (39, 43))
358350	31044156	The Broad Institute established a resource to identify drug-targetable dependencies that specific genomic alterations impart on human cancers.	('cancers', 'Disease', 'MESH:D009369', (134, 141))	('cancers', 'Phenotype', 'HP:0002664', (134, 141))	('cancers', 'Disease', (134, 141))	('human', 'Species', '9606', (128, 133))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('alterations', 'Var', (106, 117))
358352	31044156	To test our results in a high-throughput manner, we utilized the CTD2 database, where we examined the area under the curve (AUC) of 39 different ovarian cancer cell lines and 406 different compounds (targeted and cytotoxic) to learn about any associations between the rs1801018 variant and response to different treatments.	('ovarian cancer', 'Disease', (145, 159))	('rs1801018', 'Mutation', 'rs1801018', (268, 277))	('rs1801018', 'Var', (268, 277))	('ovarian cancer', 'Phenotype', 'HP:0100615', (145, 159))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('ovarian cancer', 'Disease', 'MESH:D010051', (145, 159))	('associations', 'Interaction', (243, 255))
358353	31044156	Figure 6a shows the distribution of different BCL2 states (wild-type, heterozygous, and variant) across paclitaxel AUC levels.	('BCL2', 'Gene', '596', (46, 50))	('variant', 'Var', (88, 95))	('paclitaxel', 'Chemical', 'MESH:D017239', (104, 114))	('BCL2', 'Gene', (46, 50))
358354	31044156	Low paclitaxel AUC levels (sensitivity) are enriched with cell lines with wild-type BCL2, while high paclitaxel AUC levels (resistance) are enriched with the variant form (q-value = 0.067).	('BCL2', 'Gene', (84, 88))	('paclitaxel', 'Chemical', 'MESH:D017239', (4, 14))	('variant', 'Var', (158, 165))	('high paclitaxel AUC levels', 'MPA', (96, 122))	('BCL2', 'Gene', '596', (84, 88))	('paclitaxel', 'Chemical', 'MESH:D017239', (101, 111))
358355	31044156	This qq-plot shows that of the 406 different treatments tested, paclitaxel was the only one with a significant value in association with the variant.	('variant', 'Var', (141, 148))	('association', 'Interaction', (120, 131))	('paclitaxel', 'Chemical', 'MESH:D017239', (64, 74))
358359	31044156	The results of this analysis show that a single variant in the BCL2 gene is significantly associated with resistance to paclitaxel in multiple tumor types.	('BCL2', 'Gene', '596', (63, 67))	('tumor', 'Disease', (143, 148))	('paclitaxel', 'Chemical', 'MESH:D017239', (120, 130))	('associated with', 'Reg', (90, 105))	('BCL2', 'Gene', (63, 67))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('resistance to paclitaxel', 'MPA', (106, 130))	('single variant', 'Var', (41, 55))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
358360	31044156	We found that the secondary structures of BCL2 variants were dramatically different in conformation.	('secondary structures', 'MPA', (18, 38))	('variants', 'Var', (47, 55))	('BCL2', 'Gene', '596', (42, 46))	('BCL2', 'Gene', (42, 46))	('different', 'Reg', (74, 83))
358363	31044156	Finally, to observe the effect on protein levels, we showed that the rs1801018 variant produces increased BCL2 protein levels.	('increased', 'PosReg', (96, 105))	('rs1801018', 'Mutation', 'rs1801018', (69, 78))	('BCL2', 'Gene', (106, 110))	('rs1801018', 'Var', (69, 78))	('BCL2', 'Gene', '596', (106, 110))
358369	31044156	(PMID: 17185560) found that a synonymous SNP in the MDR1 gene alters protein conformation.	('synonymous SNP', 'Var', (30, 44))	('alters', 'Reg', (62, 68))	('MDR1', 'Gene', (52, 56))	('protein conformation', 'MPA', (69, 89))	('MDR1', 'Gene', '5243', (52, 56))
358370	31044156	It is possible that Taxol resistance in the presence of the rs1801018 SNP is not only due to changes in RNA but also to changes in protein conformation.	('rs1801018', 'Var', (60, 69))	('Taxol resistance', 'MPA', (20, 36))	('protein conformation', 'MPA', (131, 151))	('RNA', 'MPA', (104, 107))	('Taxol', 'Chemical', 'MESH:D017239', (20, 25))	('changes', 'Reg', (120, 127))	('changes', 'Reg', (93, 100))	('rs1801018', 'Mutation', 'rs1801018', (60, 69))
358378	31044156	The personalization of treatment and the identification of new drugs that target mutant Bcl2 are needed.	('Bcl2', 'Gene', (88, 92))	('Bcl2', 'Gene', '596', (88, 92))	('mutant', 'Var', (81, 87))
358384	31044156	GFP-BCL2 variants were obtained by introducing point mutations at the following locations: + 21 T > C, + 23 C > T using appropriate primers set and the QuickChange II Site-Directed Mutagenesis Kit (Agilent Technologies) on the GFP-BCL2 variant template, purchased from Addgene (plasmid cat# 3336).	('BCL2', 'Gene', '596', (4, 8))	('23 C > T', 'SUBSTITUTION', 'None', (105, 113))	('21 T > C', 'SUBSTITUTION', 'None', (93, 101))	('BCL2', 'Gene', (4, 8))	('BCL2', 'Gene', '596', (231, 235))	('23 C > T', 'Var', (105, 113))	('21 T > C', 'Var', (93, 101))	('BCL2', 'Gene', (231, 235))
358385	31044156	HeyA8 cells were seeded into 10 -cm plates and transfected with GFP-empty vector, GFP-BCL2 reference, variant or a random.	('BCL2', 'Gene', (86, 90))	('BCL2', 'Gene', '596', (86, 90))	('variant', 'Var', (102, 109))
358390	31044156	Heya8 cells transfected with GFP or one of three GFP-BCL2 variants (reference, + 21 T > C or random + 23 C > T) were treated 24 h post transfection with Actinomycin D (1 microg/ml, sigma) for 30 min at 37  C. Cells were treated at the following time points: 0, 2 h, 4 h, and 7 h post incubation period.	('23 C > T', 'Var', (102, 110))	('21 T > C', 'Var', (81, 89))	('variants', 'Var', (58, 66))	('Actinomycin D', 'Chemical', 'MESH:D003609', (153, 166))	('23 C > T', 'SUBSTITUTION', 'None', (102, 110))	('BCL2', 'Gene', '596', (53, 57))	('Heya8', 'CellLine', 'CVCL:T367', (0, 5))	('21 T > C', 'SUBSTITUTION', 'None', (81, 89))	('BCL2', 'Gene', (53, 57))
358402	31044156	GFP-empty vector or one of three types of GFP-BCL2 variants were measured for their sensitivity to Paclitaxel.	('Paclitaxel', 'Chemical', 'MESH:D017239', (99, 109))	('variants', 'Var', (51, 59))	('sensitivity to Paclitaxel', 'MPA', (84, 109))	('BCL2', 'Gene', '596', (46, 50))	('BCL2', 'Gene', (46, 50))
358404	31044156	The RNA structure of the reference, variant, and random BCL2 was predicted using the RNA-folding prediction tool Mfold at http://www.bioinfo.rpi.edu/applications/mfold.	('variant', 'Var', (36, 43))	('BCL2', 'Gene', (56, 60))	('BCL2', 'Gene', '596', (56, 60))
358405	31044156	Heya8 cells were transfected with reference BCL2-GFP, variant BCL2-GFP.	('BCL2', 'Gene', '596', (62, 66))	('variant', 'Var', (54, 61))	('BCL2', 'Gene', (62, 66))	('BCL2', 'Gene', '596', (44, 48))	('Heya8', 'CellLine', 'CVCL:T367', (0, 5))	('BCL2', 'Gene', (44, 48))
358411	31044156	HEK293T cells were grown on coverslips in a 24-well plate and transfected with reference BCL2-GFP, variant BCL2-GFP (+ 21 T- > C) or GFP-empty vector.	('BCL2', 'Gene', '596', (107, 111))	('BCL2', 'Gene', (89, 93))	('variant', 'Var', (99, 106))	('+ 21 T- > C', 'Mutation', 'rs369581368', (117, 128))	('HEK293T', 'CellLine', 'CVCL:0063', (0, 7))	('BCL2', 'Gene', (107, 111))	('BCL2', 'Gene', '596', (89, 93))
358414	32722287	Pan-Cancer Analysis of the Genomic Alterations and Mutations of the Matrisome The extracellular matrix (ECM) is a master regulator of all cellular functions and a major component of the tumor microenvironment.	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('tumor', 'Disease', (186, 191))	('Cancer', 'Phenotype', 'HP:0002664', (4, 10))	('Cancer', 'Disease', (4, 10))	('Cancer', 'Disease', 'MESH:D009369', (4, 10))	('Mutations', 'Var', (51, 60))
358416	32722287	Here, mining The Cancer Genome Atlas (TCGA) data, we found that copy number alterations and mutations are frequent in matrisome genes, even more so than in the rest of the genome.	('Cancer', 'Disease', (17, 23))	('matrisome genes', 'Gene', (118, 133))	('Cancer', 'Disease', 'MESH:D009369', (17, 23))	('mutations', 'Var', (92, 101))	('Cancer', 'Phenotype', 'HP:0002664', (17, 23))	('copy number alterations', 'Var', (64, 87))
358419	32722287	In recent years, The Cancer Genome Atlas (TCGA) has provided researchers with an unmatched set of genomics, epigenomics, transcriptomics, and clinical data, enabling disruptive discoveries of driver mutations and oncogenic signaling pathways, probing the immune landscape of tumors pathways, or correlating genomic alterations to response to anti-cancer therapies.	('oncogenic signaling pathways', 'Pathway', (213, 241))	('tumor', 'Phenotype', 'HP:0002664', (275, 280))	('cancer', 'Phenotype', 'HP:0002664', (347, 353))	('tumors', 'Disease', (275, 281))	('Cancer', 'Disease', (21, 27))	('tumors', 'Phenotype', 'HP:0002664', (275, 281))	('Cancer', 'Disease', 'MESH:D009369', (21, 27))	('tumors', 'Disease', 'MESH:D009369', (275, 281))	('Cancer', 'Phenotype', 'HP:0002664', (21, 27))	('cancer', 'Disease', (347, 353))	('cancer', 'Disease', 'MESH:D009369', (347, 353))	('mutations', 'Var', (199, 208))	('probing', 'Reg', (243, 250))
358425	32722287	Used to annotate proteomics data of murine or human tumors, it has revealed that compositional and quantitative alterations of the matrisome contribute to tumor progression.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('murine', 'Species', '10090', (36, 42))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('tumor', 'Disease', (52, 57))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('tumors', 'Disease', (52, 58))	('tumor', 'Disease', (155, 160))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('human', 'Species', '9606', (46, 51))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('alterations', 'Var', (112, 123))	('contribute', 'Reg', (141, 151))	('compositional', 'MPA', (81, 94))
358430	32722287	However, while mutations in ECM genes have been linked to a plethora of diseases and syndromes, no study has focused on determining the presence and extent of genomic alterations and mutations in ECM genes in cancers, a crucial piece of information to further understanding of the tumor microenvironment (TME).	('plethora', 'Phenotype', 'HP:0001050', (60, 68))	('mutations', 'Var', (15, 24))	('ECM genes', 'Gene', (28, 37))	('cancers', 'Disease', 'MESH:D009369', (209, 216))	('tumor', 'Disease', 'MESH:D009369', (281, 286))	('cancers', 'Phenotype', 'HP:0002664', (209, 216))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))	('cancers', 'Disease', (209, 216))	('tumor', 'Phenotype', 'HP:0002664', (281, 286))	('tumor', 'Disease', (281, 286))	('linked', 'Reg', (48, 54))
358432	32722287	For our analysis, we retrieved data on 1014 of the 1027 human matrisome genes for 6740 patients and surveyed the nature and potential consequences of 4433 copy number alterations (CNAs) and 4497 mutations affecting matrisome genes (Table 2).	('matrisome genes', 'Gene', (62, 77))	('4497', 'Var', (190, 194))	('human', 'Species', '9606', (56, 61))	('copy number alterations', 'Var', (155, 178))	('patients', 'Species', '9606', (87, 95))
358434	32722287	We further identified common core matrisome and matrisome-associated genes altered across multiple cancer types, and within these genes, we identified sequences encoding protein domains that accumulate more frequent mutations, which hints at the potential functional consequences these mutations could have on the multi-faceted roles of the ECM in cancer initiation and progression.	('cancer', 'Disease', 'MESH:D009369', (348, 354))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('cancer', 'Disease', (99, 105))	('cancer', 'Phenotype', 'HP:0002664', (348, 354))	('mutations', 'Var', (216, 225))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('cancer', 'Disease', (348, 354))
358435	32722287	Last, we report the identification of matrisome genes whose mutational burden correlates with overall survival, demonstrating the potential prognostic value of analyzing genomic features of the matrisome to predict cancer patient outcome.	('matrisome genes', 'Gene', (38, 53))	('correlates', 'Reg', (78, 88))	('mutational burden', 'Var', (60, 77))	('cancer', 'Disease', (215, 221))	('overall survival', 'MPA', (94, 110))	('cancer', 'Disease', 'MESH:D009369', (215, 221))	('patient', 'Species', '9606', (222, 229))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))
358439	32722287	Further breakdown of the data per matrisome gene category (Figure S2) shows the same general outlook: matrisome genes seem particularly tolerant of copy number alterations, with minor tumor-specific differences in the amount and type of CNAs within the matrisome categories.	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('matrisome genes', 'Gene', (102, 117))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('tumor', 'Disease', (184, 189))	('copy number alterations', 'Var', (148, 171))
358443	32722287	This suggests that either or both a lower selective pressure on these mutations by, for example, immune cells and/or a higher fitness as local mutators that act as a buffer to the preservation of the global genomic information might act on matrisome sequences at the genomic level.	('fitness', 'Disease', 'MESH:D012640', (126, 133))	('mutations', 'Var', (70, 79))	('fitness', 'Disease', (126, 133))
358445	32722287	Of note, for three cancer types, cutaneous melanoma, stomach adenocarcinoma, and endometrial carcinoma, we found a subset of mutations in matrisome genes found in more than five patients (Table S2C).	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('mutations', 'Var', (125, 134))	('carcinoma', 'Phenotype', 'HP:0030731', (66, 75))	('endometrial carcinoma', 'Disease', (81, 102))	('cancer', 'Disease', 'MESH:D009369', (19, 25))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (81, 102))	('cancer', 'Disease', (19, 25))	('stomach adenocarcinoma', 'Disease', (53, 75))	('patients', 'Species', '9606', (178, 186))	('melanoma', 'Phenotype', 'HP:0002861', (43, 51))	('matrisome genes', 'Gene', (138, 153))	('cutaneous melanoma', 'Disease', (33, 51))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (33, 51))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (33, 51))	('stomach adenocarcinoma', 'Disease', 'MESH:D000230', (53, 75))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (81, 102))
358446	32722287	In light of our findings on CNAs, we can speculate that the selective pressure on these mutations might be counteracted and dispersed by the high number of matrisome gene paralogs, which might further point to a role for matrisome gene mutations as local mutators or interactors rather than cancer drivers.	('cancer', 'Disease', (291, 297))	('cancer', 'Disease', 'MESH:D009369', (291, 297))	('mutations', 'Var', (88, 97))	('mutations', 'Var', (236, 245))	('cancer', 'Phenotype', 'HP:0002664', (291, 297))
358447	32722287	While most of the mutations identified were specific to only one patient or to a few patients within a single tumor type (Table S2), we could nonetheless identify potential "hotspot" mutations, defined as occurring in at least five patients per tumor type, and in at least two different tumor types, for six genes (Figure S4).	('patient', 'Species', '9606', (85, 92))	('tumor', 'Disease', 'MESH:D009369', (110, 115))	('patients', 'Species', '9606', (232, 240))	('tumor', 'Disease', 'MESH:D009369', (245, 250))	('tumor', 'Disease', 'MESH:D009369', (287, 292))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('patients', 'Species', '9606', (85, 93))	('tumor', 'Disease', (287, 292))	('patient', 'Species', '9606', (65, 72))	('tumor', 'Phenotype', 'HP:0002664', (287, 292))	('tumor', 'Disease', (245, 250))	('patient', 'Species', '9606', (232, 239))	('mutations', 'Var', (18, 27))
358449	32722287	We further interrogated the molecular nature of the mutations and found that for all matrisome gene categories and for most cancer types, these were in majority (>~70%) transitions, i.e., the interchange of a purine for another (A/G) or of a pyrimidine for another (C/T) (Figure S5).	('mutations', 'Var', (52, 61))	('cancer', 'Disease', (124, 130))	('interchange', 'Var', (192, 203))	('matrisome gene', 'Gene', (85, 99))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('purine', 'MPA', (209, 215))	('purine', 'Chemical', 'MESH:C030985', (209, 215))	('pyrimidine', 'Chemical', 'MESH:C030986', (242, 252))	('cancer', 'Disease', 'MESH:D009369', (124, 130))
358451	32722287	Interestingly, for the former, the frequency of transversions, the replacement of a purine by a pyrimidine and a hallmark of the carcinogenic effects of smoking on genes, and the frequency of transitions were similar, and this was consistent across all matrisome gene categories (Figure S5).	('carcinogenic', 'Disease', 'MESH:D063646', (129, 141))	('purine', 'Chemical', 'MESH:C030985', (84, 90))	('replacement', 'MPA', (67, 78))	('carcinogenic', 'Disease', (129, 141))	('pyrimidine', 'Chemical', 'MESH:C030986', (96, 106))	('transversions', 'Var', (48, 61))
358453	32722287	When looking at the type of mutations affecting matrisome genes, we found that the majority of mutations across all cancer types were missense mutations (~50%), followed by silent mutations (~25%) (Figure 3C).	('missense mutations', 'Var', (134, 152))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('mutations', 'Var', (95, 104))
358455	32722287	In addition, when looking specifically at the frequency of mutation types per matrisome gene categories and cancer types, we observed that matrisome genes and particularly secreted factors presented frequent mutations affecting splicing sites in cervical squamous cell carcinomas and endocervical adenocarcinomas (CESC), esophageal carcinomas (ESCA), and uterine carcinosarcoma (UCS) (Figure S6).	('esophageal carcinomas', 'Phenotype', 'HP:0011459', (321, 342))	('UCS', 'Phenotype', 'HP:0002891', (379, 382))	('esophageal carcinomas', 'Disease', 'MESH:D004938', (321, 342))	('mutations', 'Var', (208, 217))	('carcinosarcoma', 'Disease', (363, 377))	('esophageal carcinomas', 'Disease', (321, 342))	('cancer', 'Disease', 'MESH:D009369', (108, 114))	('carcinosarcoma', 'Disease', 'MESH:D002296', (363, 377))	('carcinomas', 'Phenotype', 'HP:0030731', (302, 312))	('carcinoma', 'Phenotype', 'HP:0030731', (302, 311))	('splicing sites', 'MPA', (228, 242))	('carcinoma', 'Phenotype', 'HP:0030731', (332, 341))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (355, 377))	('matrisome genes', 'Gene', (139, 154))	('carcinoma', 'Phenotype', 'HP:0030731', (269, 278))	('carcinomas', 'Phenotype', 'HP:0030731', (269, 279))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (255, 279))	('ESCA', 'Phenotype', 'HP:0011459', (344, 348))	('carcinomas', 'Phenotype', 'HP:0030731', (332, 342))	('cancer', 'Disease', (108, 114))	('cervical squamous cell carcinomas and endocervical adenocarcinomas', 'Disease', 'MESH:D002294', (246, 312))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))
358456	32722287	This is of particular relevance, since there exist multiple examples of alternative splicing of ECM genes (e.g., fibronectin, tenascin) or growth factors resulting in the production of isoforms only reported to be expressed in pathological conditions such as wound healing and cancers, and these splice variants have been proposed to serve as biomarkers or anchors to selectively target drugs or biological agents to tumors.	('tenascin', 'Gene', (126, 134))	('tenascin', 'Gene', '3371', (126, 134))	('fibronectin', 'Gene', '2335', (113, 124))	('cancers', 'Phenotype', 'HP:0002664', (277, 284))	('tumor', 'Phenotype', 'HP:0002664', (417, 422))	('cancers', 'Disease', (277, 284))	('ECM genes', 'Gene', (96, 105))	('cancers', 'Disease', 'MESH:D009369', (277, 284))	('tumors', 'Disease', 'MESH:D009369', (417, 423))	('tumors', 'Phenotype', 'HP:0002664', (417, 423))	('tumors', 'Disease', (417, 423))	('cancer', 'Phenotype', 'HP:0002664', (277, 283))	('fibronectin', 'Gene', (113, 124))	('alternative splicing', 'Var', (72, 92))
358461	32722287	This is, for example, the case of mucin 16 (MUC16) or filaggrin (FLG), which are mutated in all 14 tumors analyzed, or of hemicentin 1 (HMCN1), mucin 5 B (MUC5B) or reelin (RELN) mutated in 12/14 tumors.	('MUC16', 'Gene', '94025', (44, 49))	('tumors', 'Phenotype', 'HP:0002664', (196, 202))	('mucin 16', 'Gene', (34, 42))	('MUC16', 'Gene', (44, 49))	('hemicentin 1', 'Gene', '83872', (122, 134))	('RELN', 'Gene', '5649', (173, 177))	('reelin', 'Gene', '5649', (165, 171))	('MUC5B', 'Gene', '727897', (155, 160))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('mutated', 'Var', (179, 186))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))	('mucin 5 B', 'Gene', (144, 153))	('HMCN1', 'Gene', (136, 141))	('filaggrin', 'Gene', '2312', (54, 63))	('tumors', 'Disease', (196, 202))	('FLG', 'Gene', (65, 68))	('mutated', 'Var', (81, 88))	('hemicentin 1', 'Gene', (122, 134))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('MUC5B', 'Gene', (155, 160))	('tumors', 'Disease', (99, 105))	('reelin', 'Gene', (165, 171))	('tumors', 'Disease', 'MESH:D009369', (196, 202))	('filaggrin', 'Gene', (54, 63))	('mucin 16', 'Gene', '94025', (34, 42))	('FLG', 'Gene', '2312', (65, 68))	('RELN', 'Gene', (173, 177))	('mucin 5 B', 'Gene', '727897', (144, 153))	('HMCN1', 'Gene', '83872', (136, 141))	('tumors', 'Disease', 'MESH:D009369', (99, 105))
358463	32722287	Interestingly, we observed again a differential distribution in the accumulation of mutations between core matrisome and matrisome-associated genes, with the latter (which includes the mucins) being more frequently represented at top position across all cancers considered.	('cancer', 'Phenotype', 'HP:0002664', (254, 260))	('mucin', 'Gene', '100508689', (185, 190))	('matrisome-associated genes', 'Gene', (121, 147))	('mucin', 'Gene', (185, 190))	('mutations', 'Var', (84, 93))	('cancers', 'Phenotype', 'HP:0002664', (254, 261))	('cancers', 'Disease', (254, 261))	('cancers', 'Disease', 'MESH:D009369', (254, 261))
358467	32722287	Similarly, especially considering the impact on patient survival (see Figure 7), our data suggest that mutations within the mucin genes, especially MUC16 and MUC5B, are worth further assessment for their potential prognostic use, again expanding on observations from previous reports.	('mutations', 'Var', (103, 112))	('MUC16', 'Gene', (148, 153))	('MUC5B', 'Gene', '727897', (158, 163))	('mucin', 'Gene', '100508689', (124, 129))	('MUC5B', 'Gene', (158, 163))	('patient', 'Species', '9606', (48, 55))	('MUC16', 'Gene', '94025', (148, 153))	('mucin', 'Gene', (124, 129))
358469	32722287	Figure 7 depicts the prognostic value of two core matrisome genes, COL6A1 and LAMB3, and of two matrisome-associated genes, MUC5B and MUC16, whose mutational burden significantly correlated either negatively (Table 3A and Table 4A) or positively (Table 3B and Table 4B) with overall survival in at least two cancer types: colorectal cancer and melanoma for COL6A1, lung adenocarcinoma and stomach adenocarcinoma for LAMB3, melanoma and uterine corpus endometrial carcinoma for MUC16, and lung adenocarcinoma and uterine corpus endometrial carcinoma for MUC5B.	('stomach adenocarcinoma', 'Disease', (389, 411))	('carcinoma', 'Phenotype', 'HP:0030731', (375, 384))	('LAMB3', 'Gene', (416, 421))	('cancer', 'Disease', 'MESH:D009369', (308, 314))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (451, 472))	('MUC5B', 'Gene', '727897', (553, 558))	('colorectal cancer', 'Phenotype', 'HP:0003003', (322, 339))	('mutational', 'Var', (147, 157))	('melanoma', 'Disease', 'MESH:D008545', (344, 352))	('lung adenocarcinoma', 'Disease', (488, 507))	('endometrial carcinoma', 'Disease', (527, 548))	('cancer', 'Disease', (333, 339))	('MUC16', 'Gene', '94025', (477, 482))	('carcinoma', 'Phenotype', 'HP:0030731', (539, 548))	('MUC5B', 'Gene', (553, 558))	('LAMB3', 'Gene', '3914', (416, 421))	('MUC5B', 'Gene', '727897', (124, 129))	('LAMB3', 'Gene', (78, 83))	('cancer', 'Phenotype', 'HP:0002664', (333, 339))	('carcinoma', 'Phenotype', 'HP:0030731', (498, 507))	('MUC16', 'Gene', '94025', (134, 139))	('melanoma', 'Disease', 'MESH:D008545', (423, 431))	('COL6A1', 'Gene', '1291', (357, 363))	('COL6A1', 'Gene', (357, 363))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (488, 507))	('lung adenocarcinoma', 'Disease', (365, 384))	('colorectal cancer', 'Disease', 'MESH:D015179', (322, 339))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (527, 548))	('endometrial carcinoma', 'Disease', (451, 472))	('cancer', 'Disease', (308, 314))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (488, 507))	('MUC5B', 'Gene', (124, 129))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (365, 384))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (527, 548))	('cancer', 'Phenotype', 'HP:0002664', (308, 314))	('MUC16', 'Gene', (477, 482))	('melanoma', 'Phenotype', 'HP:0002861', (344, 352))	('carcinoma', 'Phenotype', 'HP:0030731', (402, 411))	('colorectal cancer', 'Disease', (322, 339))	('melanoma', 'Disease', (344, 352))	('LAMB3', 'Gene', '3914', (78, 83))	('cancer', 'Disease', 'MESH:D009369', (333, 339))	('stomach adenocarcinoma', 'Disease', 'MESH:D000230', (389, 411))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (365, 384))	('MUC16', 'Gene', (134, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (463, 472))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (451, 472))	('COL6A1', 'Gene', '1291', (67, 73))	('COL6A1', 'Gene', (67, 73))	('melanoma', 'Phenotype', 'HP:0002861', (423, 431))	('melanoma', 'Disease', (423, 431))
358471	32722287	The same holds true for matrisome protein domains (Table S5B), though, from both the gene-centric and the domain-centric analyses, we observed that mutations in the tumor matrisome are much more likely to associate with increased overall survival (overall survival, approximately 61% of genes and 81% of domains reported in Table S5), supporting the idea that mutations in the tumor matrisome disrupt the organization of the tumor microenvironment and disadvantage neoplastic cells taking away structural cues they require for extensive growth, spreading, and metastasis.	('increased', 'PosReg', (220, 229))	('tumor', 'Disease', (425, 430))	('overall survival', 'CPA', (230, 246))	('mutations', 'Var', (148, 157))	('S5B', 'Gene', '5711', (57, 60))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('tumor', 'Disease', (377, 382))	('S5B', 'Gene', (57, 60))	('disrupt', 'NegReg', (393, 400))	('organization of', 'CPA', (405, 420))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('tumor', 'Disease', 'MESH:D009369', (425, 430))	('mutations', 'Var', (360, 369))	('tumor', 'Disease', 'MESH:D009369', (377, 382))	('tumor', 'Phenotype', 'HP:0002664', (425, 430))	('tumor', 'Phenotype', 'HP:0002664', (377, 382))	('tumor', 'Disease', (165, 170))
358472	32722287	This observation may provide another explanation for the low recurrence of matrisome mutations found across tumors, though the lack of time coordinates within the TCGA data and their bulk rather than single cell structure prevented us from testing this further (see Section 4).	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('mutations', 'Var', (85, 94))	('tumors', 'Disease', 'MESH:D009369', (108, 114))	('tumors', 'Disease', (108, 114))	('matrisome', 'Gene', (75, 84))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))
358474	32722287	We focused on the four genes, COL6A1, LAMB3, MUC5B, and MUC16, for which we showed that mutational burden had a prognostic value for patient survival (Figure 7) and interrogated a large collection of samples from patients and cells from 178 cohorts available via the cBioPortal (see Section 3).	('COL6A1', 'Gene', (30, 36))	('LAMB3', 'Gene', (38, 43))	('patient', 'Species', '9606', (213, 220))	('patient', 'Species', '9606', (133, 140))	('mutational', 'Var', (88, 98))	('LAMB3', 'Gene', '3914', (38, 43))	('MUC16', 'Gene', '94025', (56, 61))	('COL6A1', 'Gene', '1291', (30, 36))	('MUC5B', 'Gene', '727897', (45, 50))	('patients', 'Species', '9606', (213, 221))	('MUC5B', 'Gene', (45, 50))	('MUC16', 'Gene', (56, 61))
358475	32722287	We also observed an overall low occurrence and recurrence of CNAs and mutations for each of these genes (see the peak of the density plots around the 0 value in Figure S8A) and a higher number of studies with cases affected by CNAs or mutations for MUC5B and MUC16, than for COL6A1 and LAMB3 (Table S6A-D).	('affected', 'Reg', (215, 223))	('MUC5B', 'Gene', (249, 254))	('mutations', 'Var', (70, 79))	('MUC16', 'Gene', (259, 264))	('LAMB3', 'Gene', (286, 291))	('mutations', 'Var', (235, 244))	('COL6A1', 'Gene', '1291', (275, 281))	('COL6A1', 'Gene', (275, 281))	('CNAs', 'Gene', (227, 231))	('MUC16', 'Gene', '94025', (259, 264))	('LAMB3', 'Gene', '3914', (286, 291))	('MUC5B', 'Gene', '727897', (249, 254))
358477	32722287	Interestingly, we observed significant associations with survival for both MUC5B and MUC16 and a borderline association for COL6A1, which is similar to what we observed in the pan-cancer TCGA cohort (Figure 7), with MUC5B mutations associating with better survival and COL6A1 and MUC16 associating with poorer survival (Figure S8B).	('MUC16', 'Gene', '94025', (85, 90))	('MUC5B', 'Gene', '727897', (75, 80))	('MUC16', 'Gene', '94025', (280, 285))	('MUC5B', 'Gene', (75, 80))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('MUC5B', 'Gene', '727897', (216, 221))	('MUC16', 'Gene', (280, 285))	('MUC5B', 'Gene', (216, 221))	('COL6A1', 'Gene', '1291', (124, 130))	('COL6A1', 'Gene', (124, 130))	('COL6A1', 'Gene', (269, 275))	('COL6A1', 'Gene', '1291', (269, 275))	('mutations', 'Var', (222, 231))	('MUC16', 'Gene', (85, 90))	('associations', 'Interaction', (39, 51))	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('cancer', 'Disease', (180, 186))	('better', 'PosReg', (249, 255))
358486	32722287	The prevalence of mutations in COL6A1, LAMB3, MUC5B, and MUC16 across 178 studies was evaluated via cBioPortal .	('LAMB3', 'Gene', '3914', (39, 44))	('MUC16', 'Gene', '94025', (57, 62))	('MUC16', 'Gene', (57, 62))	('COL6A1', 'Gene', (31, 37))	('COL6A1', 'Gene', '1291', (31, 37))	('MUC5B', 'Gene', '727897', (46, 51))	('LAMB3', 'Gene', (39, 44))	('MUC5B', 'Gene', (46, 51))	('mutations', 'Var', (18, 27))
358490	32722287	Hotspots mutations were defined as those occurring at least five times per tumor type in at least two different tumor types.	('mutations', 'Var', (9, 18))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', (112, 117))	('tumor', 'Disease', (75, 80))
358493	32722287	This first survey of the genomic and mutational landscape of the cancer matrisome has uncovered the interesting, and yet perhaps unexpected, extent and consequences of copy number and mutational alterations of matrisome genes in a panel of 14 solid tumor types.	('tumor', 'Disease', 'MESH:D009369', (249, 254))	('matrisome genes', 'Gene', (210, 225))	('tumor', 'Phenotype', 'HP:0002664', (249, 254))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('tumor', 'Disease', (249, 254))	('copy number', 'Var', (168, 179))	('mutational alterations', 'Var', (184, 206))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))
358496	32722287	Further acknowledging that the number of CNAs and mutations in the cancer genome and the sample composition in terms of tumor/TME fractions are not linearly nor directly associated, the estimates we report for their interactions probably exceed their true extent.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('cancer', 'Disease', (67, 73))	('mutations', 'Var', (50, 59))	('interactions', 'Interaction', (216, 228))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('tumor', 'Disease', (120, 125))
358500	32722287	One possibility is that mutations in matrisome genes, and more specifically located in sequences encoding protein domains, can affect protein/protein (e.g., ECM protein/ECM protein, ECM/growth factor, ECM/enzyme, ECM protein/ECM receptor) interactions and subsequently alter biochemical and mechanical signaling, leading to dysregulation of cellular phenotypes and eventually to cancer progression.	('cancer', 'Disease', (379, 385))	('cancer', 'Disease', 'MESH:D009369', (379, 385))	('leading to', 'Reg', (313, 323))	('dysregulation', 'MPA', (324, 337))	('protein/protein', 'Protein', (134, 149))	('cellular phenotypes', 'MPA', (341, 360))	('cancer', 'Phenotype', 'HP:0002664', (379, 385))	('mutations', 'Var', (24, 33))	('alter', 'Reg', (269, 274))	('matrisome genes', 'Gene', (37, 52))	('affect', 'Reg', (127, 133))	('interactions', 'Interaction', (239, 251))
358501	32722287	Additionally, with recent reports highlighting the impact of the ECM on immune cells within the tumor microenvironment, mutations in matrisome genes could also result in the generation of neo-antigens and thus rewire the immune response.	('immune response', 'CPA', (221, 236))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('neo-antigens', 'MPA', (188, 200))	('result in', 'Reg', (160, 169))	('rewire', 'Reg', (210, 216))	('tumor', 'Disease', (96, 101))	('mutations', 'Var', (120, 129))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('matrisome genes', 'Gene', (133, 148))
358502	32722287	We believe that our results are a starting point to the more extensive mapping of clinically relevant matrisome gene alterations and can be used to prioritize further investigations that may lead to significant translational applications to improve cancer patient care.	('alterations', 'Var', (117, 128))	('cancer', 'Disease', 'MESH:D009369', (249, 255))	('matrisome gene', 'Gene', (102, 116))	('cancer', 'Disease', (249, 255))	('cancer', 'Phenotype', 'HP:0002664', (249, 255))	('patient', 'Species', '9606', (256, 263))
358504	32722287	Frequency of CNAs and mutations in the matrisome genes COL6A1 (A), LAMB3 (B), MUC5B (C), MUC16 (D) in 180 different patient cohorts, representing 47500 cases available via cBioPortal, Table S7.	('MUC5B', 'Gene', '727897', (78, 83))	('MUC16', 'Gene', '94025', (89, 94))	('MUC5B', 'Gene', (78, 83))	('LAMB3', 'Gene', '3914', (67, 72))	('patient', 'Species', '9606', (116, 123))	('COL6A1', 'Gene', '1291', (55, 61))	('COL6A1', 'Gene', (55, 61))	('mutations', 'Var', (22, 31))	('MUC16', 'Gene', (89, 94))	('LAMB3', 'Gene', (67, 72))	('CNAs', 'Disease', (13, 17))
358505	32722287	Correlation of tumor purity with occurrence of CNAs and mutations in matrisome genes.	('mutations', 'Var', (56, 65))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('matrisome genes', 'Gene', (69, 84))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumor', 'Disease', (15, 20))	('CNAs', 'Disease', (47, 51))
358547	31338557	Purified NK cells from normal healthy donors were treated with IL-15 (10 ng/ml) or ALT-803 (10 ng/ml) overnight in RPMI-1640 media supplemented with 10% HAB serum at 37 C. As previously described for immobilized antibody experiments, wells of a 96-well flat-bottom plate were coated with 100 mug/ml cetuximab or 100 mug/ml polyclonal human IgG overnight at 37 C. Eighteen hours later, cetuximab- or IgG-coated 51Cr-labeled tumor cells were incubated with NK cells at various effetor:target (E:T) ratios (50 to1; 25 to 1; 12.5 to 1; and 6.25 to 1).	('tumor', 'Phenotype', 'HP:0002664', (423, 428))	('ALT', 'Gene', '76282', (83, 86))	('cetuximab', 'Chemical', 'MESH:D000068818', (385, 394))	('IL-15', 'Gene', (63, 68))	('50 to1', 'Var', (504, 510))	('tumor', 'Disease', (423, 428))	('human', 'Species', '9606', (334, 339))	('RPMI-1640 media', 'Chemical', '-', (115, 130))	('ALT', 'Gene', (83, 86))	('IL-15', 'Gene', '3600', (63, 68))	('tumor', 'Disease', 'MESH:D009369', (423, 428))	('cetuximab', 'Chemical', 'MESH:D000068818', (299, 308))
358660	33375464	Head and Neck Squamous Cell Carcinoma: Epigenetic Landscape Head and neck squamous carcinoma (HNSCC) constitutes the sixth most prevalent cancer worldwide.	('Head and Neck Squamous Cell Carcinoma', 'Phenotype', 'HP:0012288', (0, 37))	('cancer', 'Disease', (138, 144))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (74, 92))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (14, 37))	('HNSCC', 'Phenotype', 'HP:0012288', (94, 99))	('Carcinoma', 'Phenotype', 'HP:0030731', (28, 37))	('Neck Squamous Cell Carcinoma', 'Disease', 'MESH:D000077195', (9, 37))	('Epigenetic Landscape', 'Var', (39, 59))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('neck squamous carcinoma', 'Disease', 'MESH:D000077195', (69, 92))	('Head and neck squamous carcinoma', 'Phenotype', 'HP:0012288', (60, 92))	('neck squamous carcinoma', 'Disease', (69, 92))	('Neck Squamous Cell Carcinoma', 'Disease', (9, 37))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))	('cancer', 'Disease', 'MESH:D009369', (138, 144))
358661	33375464	In addition to the genetic mutations, changes in HNSCC are also characterized by the accumulation of epigenetic alterations such as DNA methylation, histone modifications, non-coding RNA activity and RNA methylation.	('DNA methylation', 'MPA', (132, 147))	('epigenetic alterations', 'MPA', (101, 123))	('HNSCC', 'Phenotype', 'HP:0012288', (49, 54))	('R', 'Chemical', 'MESH:D001120', (183, 184))	('accumulation', 'PosReg', (85, 97))	('histone modifications', 'MPA', (149, 170))	('methyl', 'Chemical', '-', (204, 210))	('RNA', 'MPA', (200, 203))	('methyl', 'Chemical', '-', (136, 142))	('changes', 'Var', (38, 45))	('non-coding RNA activity', 'MPA', (172, 195))	('HNSCC', 'Gene', (49, 54))	('R', 'Chemical', 'MESH:D001120', (200, 201))
358663	33375464	In this review, we focus on the current knowledge regarding epigenetic modifications observed in HNSCC and its predictive value for cancer development.	('epigenetic modifications', 'Var', (60, 84))	('cancer', 'Disease', (132, 138))	('HNSCC', 'Phenotype', 'HP:0012288', (97, 102))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('HNSCC', 'Gene', (97, 102))
358675	33375464	Similarly, a higher rate of cancer recurrence and metastases is associated with mutations in NOTCH1-4 genes in HNSCC.	('NOTCH1-4', 'Gene', (93, 101))	('HNSCC', 'Phenotype', 'HP:0012288', (111, 116))	('mutations', 'Var', (80, 89))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('HNSCC', 'Disease', (111, 116))	('metastases', 'Disease', (50, 60))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('metastases', 'Disease', 'MESH:D009362', (50, 60))	('cancer', 'Disease', (28, 34))
358680	33375464	It is crucial to bear in mind the fact that, carcinogenesis of HNSCC is driven not only by the accumulation of genetic alterations, but also by the changes in the epigenetic landscape.	('carcinogenesis of HNSCC', 'Disease', (45, 68))	('carcinogenesis of HNSCC', 'Disease', 'MESH:D000077195', (45, 68))	('HNSCC', 'Phenotype', 'HP:0012288', (63, 68))	('epigenetic landscape', 'MPA', (163, 183))	('genetic', 'Var', (111, 118))	('changes', 'Reg', (148, 155))
358682	33375464	Since these modifications regulate the expression of target genes (tumor suppressor genes (TSGs) and oncogenes), they have become a focus of attention in cancer studies, also in terms of personalized therapy strategies.	('oncogenes', 'Gene', (101, 110))	('expression', 'MPA', (39, 49))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('regulate', 'Reg', (26, 34))	('cancer', 'Disease', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('focus of attention', 'Phenotype', 'HP:0000736', (132, 150))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('modifications', 'Var', (12, 25))	('tumor', 'Disease', (67, 72))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))
358684	33375464	In this review, we discuss the current literature associated with the impact of epigenetic modification on the progression of head and neck squamous cell carcinoma.	('neck squamous cell carcinoma', 'Disease', (135, 163))	('epigenetic modification', 'Var', (80, 103))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (140, 163))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (126, 163))	('carcinoma', 'Phenotype', 'HP:0030731', (154, 163))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (135, 163))
358685	33375464	DNA methylation is one of the best investigated DNA modifications which modulates the expression of genes without affecting their nucleotide sequence.	('methyl', 'Chemical', '-', (4, 10))	('modulates', 'Reg', (72, 81))	('expression of genes', 'MPA', (86, 105))	('methylation', 'Var', (4, 15))
358688	33375464	The presence of DNA methylation in promoters causes transcriptional repression by preventing the binding of transcription factors and by influencing interactions between enhancers and promoters.	('influencing', 'Reg', (137, 148))	('transcription', 'Protein', (108, 121))	('DNA', 'Var', (16, 19))	('binding', 'Interaction', (97, 104))	('methylation', 'Var', (20, 31))	('preventing', 'NegReg', (82, 92))	('transcriptional repression', 'MPA', (52, 78))	('methyl', 'Chemical', '-', (20, 26))	('interactions', 'Interaction', (149, 161))
358691	33375464	On the other hand, non-CpG methylation is tissue-specific and functions as a transcriptional repressor by blocking transcription factors binding sites.	('binding', 'Interaction', (137, 144))	('methyl', 'Chemical', '-', (27, 33))	('methylation', 'Var', (27, 38))	('non-CpG methylation', 'Var', (19, 38))	('transcription factors', 'MPA', (115, 136))	('blocking', 'NegReg', (106, 114))
358704	33375464	One of the cancer hallmarks is a global DNA hypomethylation and specific local hypermethylation of CpG islands.	('hypermethylation', 'Var', (79, 95))	('DNA hypomethylation', 'MPA', (40, 59))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('methyl', 'Chemical', '-', (84, 90))	('CpG', 'Protein', (99, 102))	('cancer', 'Disease', 'MESH:D009369', (11, 17))	('cancer', 'Disease', (11, 17))	('methyl', 'Chemical', '-', (48, 54))
358705	33375464	Hypomethylation in cancerous tissues appears predominantly on multiple repeats elements (e.g., SAT2) and retrotransposons (e.g., LINE-1 and ALU) sequences leading to genomic instability and activation of oncogenes.	('methyl', 'Chemical', '-', (4, 10))	('activation', 'PosReg', (190, 200))	('SAT2', 'Gene', '112483', (95, 99))	('oncogenes', 'CPA', (204, 213))	('cancerous', 'Disease', (19, 28))	('Hypomethylation', 'Var', (0, 15))	('LINE-1', 'CellLine', 'CVCL:B526', (129, 135))	('genomic instability', 'CPA', (166, 185))	('SAT2', 'Gene', (95, 99))	('cancerous', 'Disease', 'MESH:D009369', (19, 28))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('leading to', 'Reg', (155, 165))
358706	33375464	Local hypermethylation of DNA is usually associated with CpG islands in promoters of tumor suppressor genes where their expression is downregulated.	('tumor', 'Disease', (85, 90))	('CpG islands', 'Var', (57, 68))	('expression', 'MPA', (120, 130))	('associated', 'Reg', (41, 51))	('Local hypermethylation', 'Var', (0, 22))	('methyl', 'Chemical', '-', (11, 17))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('DNA', 'Gene', (26, 29))
358713	33375464	Additionally, there are differences in DNA methylation profiles between HPV(+) and HPV(-) HNSCC as shown on the whole-genome sequencing data.	('DNA methylation profiles', 'MPA', (39, 63))	('HPV', 'Species', '10566', (83, 86))	('HNSCC', 'Phenotype', 'HP:0012288', (90, 95))	('methyl', 'Chemical', '-', (43, 49))	('HPV', 'Var', (83, 86))	('differences', 'Reg', (24, 35))	('HPV', 'Species', '10566', (72, 75))
358714	33375464	The HPV(+) tumors tend to be more globally methylated than HPV(-).	('HPV', 'Species', '10566', (4, 7))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('HPV', 'Species', '10566', (59, 62))	('tumors', 'Phenotype', 'HP:0002664', (11, 17))	('globally methylated', 'MPA', (34, 53))	('methyl', 'Chemical', '-', (43, 49))	('tumors', 'Disease', 'MESH:D009369', (11, 17))	('tumors', 'Disease', (11, 17))	('HPV(+', 'Var', (4, 9))
358724	33375464	In response to hypoxia, H3K2 is acetylated and activates the epithelial mesenchymal transition (EMT) correlated genes, including GLI1 and SMO genes, thus increasing the metastatic potential of the tumor.	('hypoxia', 'Disease', (15, 22))	('hypoxia', 'Disease', 'MESH:D000860', (15, 22))	('increasing', 'PosReg', (154, 164))	('SMO', 'Gene', '6608', (138, 141))	('SMO', 'Gene', (138, 141))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('GLI1', 'Gene', '2735', (129, 133))	('activates', 'PosReg', (47, 56))	('H3K2', 'Var', (24, 28))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('GLI1', 'Gene', (129, 133))	('tumor', 'Disease', (197, 202))
358726	33375464	Furthermore, in oral squamous carcinoma (OSCC), acetylation of H3K27 increased the expression of long non-coding RNA (lncRNA) PLAC2, which induced Wnt/beta-catenin signaling cascade and affected tumor growth and metastases.	('induced', 'Reg', (139, 146))	('tumor', 'Disease', (195, 200))	('increased', 'PosReg', (69, 78))	('PLAC2', 'Gene', '257000', (126, 131))	('expression', 'MPA', (83, 93))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (21, 39))	('beta-catenin', 'Gene', (151, 163))	('beta-catenin', 'Gene', '1499', (151, 163))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('acetylation', 'Var', (48, 59))	('oral squamous carcinoma', 'Disease', (16, 39))	('PLAC2', 'Gene', (126, 131))	('R', 'Chemical', 'MESH:D001120', (121, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (30, 39))	('affected', 'Reg', (186, 194))	('oral squamous carcinoma', 'Disease', 'MESH:D002294', (16, 39))	('metastases', 'Disease', 'MESH:D009362', (212, 222))	('R', 'Chemical', 'MESH:D001120', (113, 114))	('H3K27', 'Protein', (63, 68))	('metastases', 'Disease', (212, 222))
358731	33375464	Moreover, inhibition of HDAC leads to decreased number of cancer stem cells (CSC) and reduces the clonogenic sphere formation.	('HDAC', 'Gene', '9734', (24, 28))	('decreased', 'NegReg', (38, 47))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('reduces', 'NegReg', (86, 93))	('cancer', 'Disease', (58, 64))	('clonogenic sphere formation', 'CPA', (98, 125))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('inhibition', 'Var', (10, 20))	('HDAC', 'Gene', (24, 28))
358733	33375464	Histone methylation in a lysine (Lys or K) or arginine (Arg or R) residue constitutes another posttranslational modification which plays a vital role in gene regulation.	('Lys', 'Var', (33, 36))	('Histone', 'Var', (0, 7))	('Arg', 'Chemical', 'MESH:D001120', (56, 59))	('methyl', 'Chemical', '-', (8, 14))	('R', 'Chemical', 'MESH:D001120', (63, 64))	('Lys', 'Chemical', 'MESH:D008239', (33, 36))	('arginine', 'Chemical', 'MESH:D001120', (46, 54))	('lysine', 'Chemical', 'MESH:D008239', (25, 31))
358734	33375464	According to the literature, lysine residues in histone can be mono-, di-, or tri-methylated.	('lysine', 'Chemical', 'MESH:D008239', (29, 35))	('tri-methylated', 'Var', (78, 92))	('lysine residues', 'Var', (29, 44))	('methyl', 'Chemical', '-', (82, 88))	('histone', 'Protein', (48, 55))
358735	33375464	Di- and tri-methylation at H3K4, H3K36 and H3K79 are typically gene-activating, whereas H3K9 and H3K27 methylations are generally gene-repressive.	('Di-', 'Var', (0, 3))	('tri-methylation', 'Var', (8, 23))	('methyl', 'Chemical', '-', (103, 109))	('H3K4', 'Protein', (27, 31))	('methyl', 'Chemical', '-', (12, 18))	('H3K79', 'Var', (43, 48))	('H3K36', 'Var', (33, 38))
358736	33375464	Moreover, H3K4me3 marks promoters, as well as H3K36 and H3K79 methylation occurs primarily over gene bodies.	('H3K79', 'Protein', (56, 61))	('H3K4me3', 'Var', (10, 17))	('H3K36', 'Protein', (46, 51))	('methyl', 'Chemical', '-', (62, 68))
358742	33375464	Furthermore, aberrant methylation of H3K9 carried out by G9a has been observed in HNSCC cells, and may be involved in the lymph node-related metastases and TGF-beta-induced EMT.	('H3K9', 'Protein', (37, 41))	('involved', 'Reg', (106, 114))	('metastases', 'Disease', (141, 151))	('metastases', 'Disease', 'MESH:D009362', (141, 151))	('TGF-beta', 'Gene', (156, 164))	('methyl', 'Chemical', '-', (22, 28))	('G9a', 'Gene', (57, 60))	('G9a', 'Gene', '10919', (57, 60))	('methylation', 'MPA', (22, 33))	('HNSCC', 'Phenotype', 'HP:0012288', (82, 87))	('TGF-beta', 'Gene', '7039', (156, 164))	('observed', 'Reg', (70, 78))	('aberrant', 'Var', (13, 21))
358744	33375464	In addition, an elevated level of histone methylation mark at H3K27me3 in HPV(+) HNSCC may, in turn, increase the tumorigenic potential and constitute a HNSCC diagnostic biomarker.	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('H3K27me3', 'Var', (62, 70))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('elevated', 'PosReg', (16, 24))	('increase', 'PosReg', (101, 109))	('HNSCC', 'Phenotype', 'HP:0012288', (153, 158))	('tumor', 'Disease', (114, 119))	('HPV', 'Species', '10566', (74, 77))	('HNSCC', 'Phenotype', 'HP:0012288', (81, 86))	('histone methylation mark', 'MPA', (34, 58))	('methyl', 'Chemical', '-', (42, 48))
358746	33375464	Small ncRNAs include small nuclear RNA (snoRNA), PIWI-interacting RNA (piRNA), small interfering RNA (siRNA) and microRNA (miRNA).	('R', 'Chemical', 'MESH:D001120', (125, 126))	('R', 'Chemical', 'MESH:D001120', (73, 74))	('R', 'Chemical', 'MESH:D001120', (43, 44))	('R', 'Chemical', 'MESH:D001120', (118, 119))	('PIWI', 'Gene', (49, 53))	('snoRNA', 'Gene', (40, 46))	('small interfering', 'Var', (79, 96))	('snoRNA', 'Gene', '6079', (40, 46))	('R', 'Chemical', 'MESH:D001120', (66, 67))	('R', 'Chemical', 'MESH:D001120', (97, 98))	('R', 'Chemical', 'MESH:D001120', (104, 105))	('PIWI', 'Gene', '9271', (49, 53))	('R', 'Chemical', 'MESH:D001120', (35, 36))	('R', 'Chemical', 'MESH:D001120', (8, 9))
358750	33375464	miRNAs may act as tumor suppressors or as oncogenes (oncomiRs), and play a crucial role in angiogenesis, cell proliferation and apoptosis.	('R', 'Chemical', 'MESH:D001120', (2, 3))	('angiogenesis', 'CPA', (91, 103))	('tumor', 'Disease', (18, 23))	('R', 'Chemical', 'MESH:D001120', (59, 60))	('cell proliferation', 'CPA', (105, 123))	('miRNAs', 'Var', (0, 6))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('apoptosis', 'CPA', (128, 137))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
358751	33375464	Besides, there are several miRNAs influencing gene instability, immune evasion, tumor metastases and chemo- and radioresistance in tumorigenesis.	('tumor metastases', 'Disease', 'MESH:D009362', (80, 96))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('R', 'Chemical', 'MESH:D001120', (29, 30))	('immune evasion', 'MPA', (64, 78))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumor', 'Disease', (80, 85))	('tumor', 'Disease', (131, 136))	('gene', 'Var', (46, 50))	('tumor metastases', 'Disease', (80, 96))
358771	33375464	The ADAMTS9-AS2 knockdown experiments in TSCC cell lines reduced the cell migration and invasion together with an inhibition of cell growth presented in vitro and in vivo models.	('cell growth', 'CPA', (128, 139))	('inhibition', 'NegReg', (114, 124))	('invasion', 'CPA', (88, 96))	('cell migration', 'CPA', (69, 83))	('knockdown', 'Var', (16, 25))	('ADAMTS9', 'Gene', '56999', (4, 11))	('reduced', 'NegReg', (57, 64))	('ADAMTS9', 'Gene', (4, 11))
358773	33375464	On the other hand, in the case of laryngeal squamous cell cancer (LSCC), high expression of lncRNA MIR31HG is associated with HIF1A and p21 action which leads to an increased cancer cells proliferation.	('p21', 'Gene', (136, 139))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (44, 64))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('HIF1A', 'Gene', (126, 131))	('HIF1A', 'Gene', '3091', (126, 131))	('R', 'Chemical', 'MESH:D001120', (95, 96))	('p21', 'Gene', '644914', (136, 139))	('squamous cell cancer', 'Disease', 'MESH:D002294', (44, 64))	('cancer', 'Disease', (175, 181))	('lncRNA MIR31HG', 'Var', (92, 106))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('squamous cell cancer', 'Disease', (44, 64))	('associated', 'Reg', (110, 120))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('cancer', 'Disease', (58, 64))	('increased', 'PosReg', (165, 174))	('R', 'Chemical', 'MESH:D001120', (101, 102))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
358783	33375464	Additionally, m6A RNA methylation affects tumor initiation and progression by various mechanisms.	('m6A', 'Gene', (14, 17))	('tumor', 'Disease', (42, 47))	('affects', 'Reg', (34, 41))	('m6A', 'Gene', '56339', (14, 17))	('methyl', 'Chemical', '-', (22, 28))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('R', 'Chemical', 'MESH:D001120', (18, 19))	('progression', 'CPA', (63, 74))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('methylation', 'Var', (22, 33))
358792	33375464	Variations in RNA methylation process contribute to tumor growth, progression, invasion and migration of cancer cells in acute myeloid leukemia, glioblastoma, lung cancer, breast cancer, liver cancer, bladder cancer or pancreatic cancer.	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (121, 143))	('bladder cancer', 'Disease', 'MESH:D001749', (201, 215))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('tumor', 'Disease', (52, 57))	('cancer', 'Disease', (193, 199))	('cancer', 'Disease', (105, 111))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (127, 143))	('bladder cancer', 'Disease', (201, 215))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (121, 143))	('liver cancer', 'Phenotype', 'HP:0002896', (187, 199))	('Variations', 'Var', (0, 10))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('liver cancer', 'Disease', (187, 199))	('R', 'Chemical', 'MESH:D001120', (14, 15))	('leukemia', 'Phenotype', 'HP:0001909', (135, 143))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('bladder cancer', 'Phenotype', 'HP:0009725', (201, 215))	('pancreatic cancer', 'Disease', 'MESH:D010190', (219, 236))	('lung cancer', 'Disease', 'MESH:D008175', (159, 170))	('cancer', 'Disease', 'MESH:D009369', (209, 215))	('migration', 'CPA', (92, 101))	('breast cancer', 'Phenotype', 'HP:0003002', (172, 185))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('cancer', 'Disease', (230, 236))	('lung cancer', 'Phenotype', 'HP:0100526', (159, 170))	('glioblastoma', 'Disease', 'MESH:D005909', (145, 157))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('pancreatic cancer', 'Disease', (219, 236))	('breast cancer', 'Disease', 'MESH:D001943', (172, 185))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('breast cancer', 'Disease', (172, 185))	('cancer', 'Disease', (164, 170))	('glioblastoma', 'Disease', (145, 157))	('acute myeloid leukemia', 'Disease', (121, 143))	('invasion', 'CPA', (79, 87))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('glioblastoma', 'Phenotype', 'HP:0012174', (145, 157))	('methyl', 'Chemical', '-', (18, 24))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (219, 236))	('contribute', 'Reg', (38, 48))	('liver cancer', 'Disease', 'MESH:D006528', (187, 199))	('progression', 'CPA', (66, 77))	('cancer', 'Disease', (209, 215))	('lung cancer', 'Disease', (159, 170))	('cancer', 'Disease', 'MESH:D009369', (230, 236))	('cancer', 'Disease', (179, 185))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
358796	33375464	The ZNF750 overexpression experiments show cell growth inhibition in NPC in vitro and in vivo models, and indicate the importance of m6A RNA methylation in gene expression regulation.	('ZNF750', 'Gene', '79755', (4, 10))	('methyl', 'Chemical', '-', (141, 147))	('overexpression', 'Var', (11, 25))	('NPC', 'Disease', (69, 72))	('ZNF750', 'Gene', (4, 10))	('R', 'Chemical', 'MESH:D001120', (137, 138))	('cell growth', 'CPA', (43, 54))	('m6A', 'Gene', (133, 136))	('m6A', 'Gene', '56339', (133, 136))	('NPC', 'Phenotype', 'HP:0100630', (69, 72))
358804	33375464	In in vitro experiments LNCAROD silencing inhibits cell proliferation, mobility, and tumorigenicity, whereas overexpression of LNCAROD in vivo demonstrated opposite results.	('tumor', 'Disease', (85, 90))	('R', 'Chemical', 'MESH:D001120', (131, 132))	('inhibits', 'NegReg', (42, 50))	('LNCAROD', 'Gene', (24, 31))	('silencing', 'Var', (32, 41))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('R', 'Chemical', 'MESH:D001120', (28, 29))	('cell proliferation', 'CPA', (51, 69))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('mobility', 'CPA', (71, 79))
358806	33375464	Currently, epigenetic modifications gain more interest in the HNSCC carcinogenesis.	('HNSCC carcinogenesis', 'Disease', (62, 82))	('epigenetic modifications', 'Var', (11, 35))	('HNSCC carcinogenesis', 'Disease', 'MESH:D000077195', (62, 82))	('HNSCC', 'Phenotype', 'HP:0012288', (62, 67))
358808	33375464	Consequently, the detailed characteristics of the epigenetic changes in HNSCC will ultimately deliver novel, critical prognostic and predictive factors, thus providing the necessary information regarding the treatment and anti-cancer therapies.	('HNSCC', 'Phenotype', 'HP:0012288', (72, 77))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('cancer', 'Disease', (227, 233))	('cancer', 'Disease', 'MESH:D009369', (227, 233))	('HNSCC', 'Gene', (72, 77))	('epigenetic changes', 'Var', (50, 68))
358821	32047565	The pro-metastatic effect of MFAP5 can be reversed by MK2206, an AKT phosphorylation inhibitor.	('MFAP5', 'Gene', (29, 34))	('pro-metastatic', 'CPA', (4, 18))	('MK2206', 'Chemical', 'MESH:C548887', (54, 60))	('MK2206', 'Var', (54, 60))
358832	32047565	demonstrated that knockdown MFAP5 can markedly reduce the cell proliferation, migration and invasion depend on ROS production in cervical cancer.	('knockdown', 'Var', (18, 27))	('cancer', 'Disease', (138, 144))	('reduce', 'NegReg', (47, 53))	('invasion', 'CPA', (92, 100))	('cell proliferation', 'CPA', (58, 76))	('ROS production', 'MPA', (111, 125))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('migration', 'CPA', (78, 87))	('MFAP5', 'Gene', (28, 33))	('cancer', 'Disease', 'MESH:D009369', (138, 144))
358843	32047565	Overexpression of MFAP5 significantly correlated with advanced clinical stage, metastasis and poor prognosis of HNSCC patients.	('metastasis', 'CPA', (79, 89))	('advanced clinical stage', 'CPA', (54, 77))	('HNSCC', 'Disease', 'MESH:C535575', (112, 117))	('HNSCC', 'Disease', (112, 117))	('Overexpression', 'Var', (0, 14))	('HNSCC', 'Phenotype', 'HP:0012288', (112, 117))	('MFAP5', 'Gene', (18, 23))	('correlated', 'Reg', (38, 48))	('patients', 'Species', '9606', (118, 126))
358844	32047565	Our findings not only suggested that hypoxia environment could stimulate tumor cell to secret MFAP5 but also proved that MFAP5 promotes EMT program in HNSCC.	('HNSCC', 'Disease', 'MESH:C535575', (151, 156))	('MFAP5', 'Gene', (94, 99))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('HNSCC', 'Phenotype', 'HP:0012288', (151, 156))	('HNSCC', 'Disease', (151, 156))	('promotes', 'PosReg', (127, 135))	('EMT program', 'CPA', (136, 147))	('hypoxia', 'Disease', (37, 44))	('hypoxia', 'Disease', 'MESH:D000860', (37, 44))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('secret', 'MPA', (87, 93))	('stimulate', 'PosReg', (63, 72))	('tumor', 'Disease', (73, 78))	('MFAP5', 'Var', (121, 126))
358861	32047565	A wet transfer (Bio-Rad, USA) were then performed to transfer the protein onto polyvinylidene fluoride (PVDF) membranes and blocked with non-fat milk for 1 h. The membranes were incubated with primary antibody MFAP5 (HPA010553,Sigma,Germany), MMP9 (D6O3H, Cell signaling technology, USA), MMP2 (D4M2N Cell signaling technology, USA), vimentin (D21H3, Cell signaling technology, USA), Sanil (C15D3, Cell signaling technology, USA), AKT (11E7, Cell signaling technology, USA), p-AKT (D9E, Cell signaling technology, USA), HIF-1alpha (D1S7W, Cell signaling technology, USA), alpha-tubulin (11224, Proteintech, USA), beta-actin (20536 Proteintech, USA) at 1:1000 dilution overnight and then with anti-rabbit HRP-linked IgG secondary antibody(7074, Cell signaling technology, USA) at 1:2000 dilution for 1 hour.	('20536 Proteintech', 'Var', (625, 642))	('beta-actin', 'Gene', (613, 623))	('PVDF', 'Chemical', 'MESH:C024865', (104, 108))	('beta-actin', 'Gene', '11461', (613, 623))	('Sanil', 'Chemical', 'None', (384, 389))	('alpha-tubulin', 'Protein', (572, 585))	('D6O3H', 'Chemical', 'MESH:D014867', (249, 254))	('HPA010553', 'Chemical', 'MESH:C047158', (217, 226))	('polyvinylidene fluoride', 'Chemical', 'MESH:C024865', (79, 102))
358878	32047565	Lung of Cal27-MFAP5 group had a higher amount of tumor node metastasis.	('Cal27-MFAP5', 'Var', (8, 19))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Disease', (49, 54))
358885	32047565	Western blot showed that it could markedly reduce the expression of p-AKT (P<0.01, Figure 5A) in MFAP5 transfected cells, the level of MMP2, MMP9, vimentin and snail was declined along with it (P<0.01, Figure 5A).	('expression', 'MPA', (54, 64))	('declined', 'NegReg', (170, 178))	('reduce', 'NegReg', (43, 49))	('MFAP5', 'Gene', (97, 102))	('MMP9', 'MPA', (141, 145))	('level', 'MPA', (126, 131))	('vimentin', 'MPA', (147, 155))	('MMP2', 'MPA', (135, 139))	('p-AKT', 'Protein', (68, 73))	('transfected', 'Var', (103, 114))	('snail', 'Gene', (160, 165))	('snail', 'Gene', '6615', (160, 165))
358886	32047565	Cell invasion and migration ability which enhanced by MFAP5 were also inhibited by MK2206 (P<0.01, Figure 5B, 5C, 5D).	('MK2206', 'Chemical', 'MESH:C548887', (83, 89))	('enhanced', 'PosReg', (42, 50))	('migration ability', 'CPA', (18, 35))	('MFAP5', 'Gene', (54, 59))	('Cell invasion', 'CPA', (0, 13))	('inhibited', 'NegReg', (70, 79))	('MK2206', 'Var', (83, 89))
358903	32047565	As the indicator and product of hypoxia environment, the expression of HIF-1alpha increase the extravasation of cancer cell and recruitment of circulating tumor cell.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('expression', 'Var', (57, 67))	('tumor', 'Disease', (155, 160))	('hypoxia', 'Disease', 'MESH:D000860', (32, 39))	('increase', 'PosReg', (82, 90))	('HIF-1alpha', 'Gene', (71, 81))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('hypoxia', 'Disease', (32, 39))
358914	32047565	However, in this study, further exploration showed that AKT enhances the malignant biological behavior of tumor by increases the expression of snail, which is a promotor of EMT progress.	('expression', 'MPA', (129, 139))	('enhances', 'PosReg', (60, 68))	('snail', 'Gene', '6615', (143, 148))	('increases', 'PosReg', (115, 124))	('AKT', 'Var', (56, 59))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Disease', (106, 111))	('snail', 'Gene', (143, 148))
358933	31819639	Compared with that in nontransfected controls, cell proliferation, adhesion, and migration, as well as vimentin protein expression and levels of phosphorylated JAK2/STAT3, were significantly decreased (P<0.05) in A549 lung adenocarcinoma cells transfected with STIP1 shRNA, whereas E-cadherin protein expression and rates of apoptosis were significantly increased in these cells (P< 0.05).	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (218, 237))	('lung adenocarcinoma', 'Disease', (218, 237))	('STAT3', 'Gene', (165, 170))	('E-cadherin', 'Gene', (282, 292))	('JAK2', 'Gene', (160, 164))	('expression', 'MPA', (120, 130))	('JAK2', 'Gene', '16452', (160, 164))	('decreased', 'NegReg', (191, 200))	('E-cadherin', 'Gene', '12550', (282, 292))	('STIP1', 'Var', (261, 266))	('cell proliferation', 'CPA', (47, 65))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (218, 237))	('vimentin', 'Gene', (103, 111))	('A549', 'CellLine', 'CVCL:0023', (213, 217))	('carcinoma', 'Phenotype', 'HP:0030731', (228, 237))	('adhesion', 'CPA', (67, 75))	('vimentin', 'Gene', '22352', (103, 111))	('STAT3', 'Gene', '20848', (165, 170))	('migration', 'CPA', (81, 90))
358944	31819639	In colorectal cancer, this pathway influences tumor cell activity by regulating the expression of BCL2, E-cadherin, and VEGF, among others, while in ovarian cancer, activated STAT3 can promote the occurrence of EMT through the JAK2/STAT3/Snail signaling pathway.	('JAK2', 'Gene', '16452', (227, 231))	('ovarian cancer', 'Disease', (149, 163))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('colorectal cancer', 'Disease', (3, 20))	('promote', 'PosReg', (185, 192))	('ovarian cancer', 'Phenotype', 'HP:0100615', (149, 163))	('BCL2', 'Gene', '12043', (98, 102))	('EMT', 'CPA', (211, 214))	('regulating', 'Reg', (69, 79))	('BCL2', 'Gene', (98, 102))	('STAT3', 'Gene', '20848', (232, 237))	('colorectal cancer', 'Phenotype', 'HP:0003003', (3, 20))	('tumor', 'Disease', (46, 51))	('STAT3', 'Gene', '20848', (175, 180))	('VEGF', 'Gene', (120, 124))	('ovarian cancer', 'Disease', 'MESH:D010051', (149, 163))	('expression', 'MPA', (84, 94))	('E-cadherin', 'Gene', (104, 114))	('tumor', 'Disease', 'MESH:D009369', (46, 51))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('activated', 'Var', (165, 174))	('VEGF', 'Gene', '22339', (120, 124))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('STAT3', 'Gene', (232, 237))	('influences', 'Reg', (35, 45))	('STAT3', 'Gene', (175, 180))	('colorectal cancer', 'Disease', 'MESH:D015179', (3, 20))	('JAK2', 'Gene', (227, 231))	('E-cadherin', 'Gene', '12550', (104, 114))
358945	31819639	Furthermore, albumin can induce cell proliferation and transdifferentiation of renal tubular epithelial cells by activating the JAK2/STAT3 signaling pathway.	('JAK2', 'Gene', (128, 132))	('activating', 'PosReg', (113, 123))	('JAK2', 'Gene', '16452', (128, 132))	('induce', 'PosReg', (25, 31))	('STAT3', 'Gene', '20848', (133, 138))	('transdifferentiation', 'CPA', (55, 75))	('STAT3', 'Gene', (133, 138))	('albumin', 'Var', (13, 20))	('cell proliferation', 'CPA', (32, 50))
358994	31819639	The results showed that STIP1 mRNA and protein expression levels were significantly higher in A549 cells than those in HBE cells (P< 0.05) (Figure 2D and E).	('HBE', 'CellLine', 'CVCL:3285', (119, 122))	('STIP1', 'Gene', (24, 29))	('A549', 'CellLine', 'CVCL:0023', (94, 98))	('A549', 'Var', (94, 98))	('higher', 'PosReg', (84, 90))
359002	31819639	We found that the relative value for the migratory ability of lung adenocarcinoma cells transfected with STIP1 shRNA was distinctly lower than that of the nontransfected controls (P< 0.05, Figure 3D).	('STIP1 shRNA', 'Var', (105, 116))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('migratory ability', 'CPA', (41, 58))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (62, 81))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (62, 81))	('lower', 'NegReg', (132, 137))	('lung adenocarcinoma', 'Disease', (62, 81))
359004	31819639	The results indicated that the migratory ability of lung adenocarcinoma cells transfected with STIP1 shRNA was considerably lower than that of nontransfected cells (P< 0.05, Figure 3E).	('lung adenocarcinoma', 'Disease', (52, 71))	('STIP1', 'Var', (95, 100))	('lower', 'NegReg', (124, 129))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (52, 71))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (52, 71))	('migratory ability', 'CPA', (31, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (62, 71))
359011	31819639	However, the levels of phosphorylated JAK2 (p-JAK2) and STAT3 (p-STAT3) in transfection group were significantly lower in the STIP1 shRNA-transfected group than in the control, nontransfected group (P<0.05, Figure 4A).	('STAT3', 'Gene', '20848', (56, 61))	('JAK2', 'Gene', (46, 50))	('lower', 'NegReg', (113, 118))	('STAT3', 'Gene', (56, 61))	('JAK2', 'Gene', '16452', (46, 50))	('transfection', 'Var', (75, 87))	('STAT3', 'Gene', '20848', (65, 70))	('JAK2', 'Gene', (38, 42))	('JAK2', 'Gene', '16452', (38, 42))	('STAT3', 'Gene', (65, 70))
359016	31819639	Tumor volume in nude mice injected with STIP1 shRNA-transfected A549 cells was significantly lower than that of nude mice injected with nontransfected A549 cells(P< 0.05, Figure 5A and B), indicating that STIP1 shRNA markedly suppressed the growth of lung adenocarcinoma.	('A549', 'CellLine', 'CVCL:0023', (151, 155))	('Tumor volume', 'CPA', (0, 12))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('carcinoma', 'Phenotype', 'HP:0030731', (261, 270))	('growth', 'CPA', (241, 247))	('STIP1', 'Var', (205, 210))	('nude mice', 'Species', '10090', (16, 25))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (251, 270))	('suppressed', 'NegReg', (226, 236))	('nude mice', 'Species', '10090', (112, 121))	('lower', 'NegReg', (93, 98))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (251, 270))	('A549', 'CellLine', 'CVCL:0023', (64, 68))	('lung adenocarcinoma', 'Disease', (251, 270))
359022	31819639	Moreover, E-cadherin expression in the tumors of nude mice injected with STIP1 shRNA-transfected A549 cells was significantly higher (P<0.05, Figure 5F) than that of nude mice injected with nontransfected A549 cells.	('nude mice', 'Species', '10090', (166, 175))	('nude mice', 'Species', '10090', (49, 58))	('STIP1', 'Var', (73, 78))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('higher', 'PosReg', (126, 132))	('expression', 'MPA', (21, 31))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('A549', 'CellLine', 'CVCL:0023', (205, 209))	('A549', 'CellLine', 'CVCL:0023', (97, 101))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('E-cadherin', 'Gene', '12550', (10, 20))	('tumors', 'Disease', (39, 45))	('E-cadherin', 'Gene', (10, 20))
359055	30631355	A number of PLK1 inhibitors have been explored in laboratory or clinical studies such as BI2536, volasertib, GSK461364, rigosertib, poloxin, poloxin-2, and RO3280.	('BI2536', 'Var', (89, 95))	('BI2536', 'Chemical', 'MESH:C518477', (89, 95))	('PLK1', 'Gene', (12, 16))	('GSK461364', 'Var', (109, 118))	('GSK461364', 'Chemical', 'MESH:C561573', (109, 118))
359059	30631355	For example, a recent study demonstrated that the combination of cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors with immunotherapy could promote antitumor immunity.	('antitumor immunity', 'CPA', (151, 169))	('combination', 'Interaction', (50, 61))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('CDK4/6', 'Gene', (99, 105))	('cyclin-dependent kinases 4 and 6', 'Gene', '1019;1021', (65, 97))	('promote', 'PosReg', (143, 150))	('inhibitors', 'Var', (107, 117))	('CDK4/6', 'Gene', '1019;1021', (99, 105))
359072	30631355	In comparisons of TP53 mutation rates between the cancers with higher PLK1 expression levels (upper third) and the cancers with lower PLK1 expression levels (lower third), we used the Fisher's exact test.	('cancers', 'Phenotype', 'HP:0002664', (115, 122))	('TP53', 'Gene', '7157', (18, 22))	('mutation', 'Var', (23, 31))	('cancers', 'Phenotype', 'HP:0002664', (50, 57))	('TP53', 'Gene', (18, 22))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('higher', 'PosReg', (63, 69))	('expression levels', 'MPA', (75, 92))	('PLK1', 'Protein', (70, 74))
359081	30631355	Hence, the higher TP53 mutation rates in the cancers with higher PLK1 expression levels may also be partly responsible for the depressed tumor immunity in these cancers (Figure 8(a)) since a prior study has demonstrated that wildtype p53 could promote tumor immunity.	('PLK1', 'Gene', (65, 69))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('higher', 'PosReg', (11, 17))	('mutation', 'Var', (23, 31))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('expression levels', 'MPA', (70, 87))	('TP53', 'Gene', (18, 22))	('tumor immunity', 'CPA', (252, 266))	('cancers', 'Phenotype', 'HP:0002664', (161, 168))	('tumor', 'Phenotype', 'HP:0002664', (252, 257))	('cancers', 'Phenotype', 'HP:0002664', (45, 52))	('promote', 'PosReg', (244, 251))	('higher', 'PosReg', (58, 64))	('depressed tumor', 'Disease', 'MESH:D000275', (127, 142))	('depressed tumor', 'Disease', (127, 142))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
359108	29097801	Recently, EFHD2 enhances cell migration velocity by activating the Rho family of small GTPases in mouse B16F10 melanoma cells, suggesting the potential role of EFHD2 in cancer metastasis.	('small GTPases', 'Protein', (81, 94))	('melanoma', 'Disease', 'MESH:D008545', (111, 119))	('melanoma', 'Phenotype', 'HP:0002861', (111, 119))	('melanoma', 'Disease', (111, 119))	('B16F10', 'CellLine', 'CVCL:0159', (104, 110))	('enhances', 'PosReg', (16, 24))	('activating', 'PosReg', (52, 62))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('cancer metastasis', 'Disease', (169, 186))	('cell migration velocity', 'CPA', (25, 48))	('EFHD2', 'Var', (10, 15))	('Rho', 'Protein', (67, 70))	('mouse', 'Species', '10090', (98, 103))	('cancer metastasis', 'Disease', 'MESH:D009362', (169, 186))
359114	29097801	CAV1 mRNA and protein levels were downregulated during cell transformation by oncogenes, such as Ha-Ras, v-Abl, Myc, and Neu, suggesting a negatively regulatory role of CAV1 in tumor development.	('Myc', 'Gene', '4609', (112, 115))	('Myc', 'Gene', (112, 115))	('downregulated', 'NegReg', (34, 47))	('Ha-Ras', 'Var', (97, 103))	('cell transformation', 'CPA', (55, 74))	('v-Abl', 'Gene', (105, 110))	('CAV1', 'Gene', '857', (0, 4))	('CAV1', 'Gene', (0, 4))	('CAV1', 'Gene', '857', (169, 173))	('v-Abl', 'Gene', '25', (105, 110))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('tumor', 'Disease', (177, 182))	('Neu', 'Gene', (121, 124))	('CAV1', 'Gene', (169, 173))	('Neu', 'Gene', '2064', (121, 124))
359128	29097801	Several demographic, clinical and biochemical variables, such as age, gender, pathologic stage, tumor location, differentiation, smoking status, EGFR mutation, and EFHD2 expression were evaluated for the consideration of recurrence (Table 1).	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('EGFR', 'Gene', '1956', (145, 149))	('mutation', 'Var', (150, 158))	('tumor', 'Disease', (96, 101))	('EGFR', 'Gene', (145, 149))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('clinical', 'Species', '191496', (21, 29))
359136	29097801	The primary antibodies used in this study included EFHD2 (ab106667; abcam), E-cadherin (#5296; Cell Signaling), vimentin (#3932; Cell Signaling), CAV1 (#3238; Cell Signaling), and beta-actin (ab8226; abcam).	('CAV1', 'Gene', '857', (146, 150))	('EFHD2', 'Gene', (51, 56))	('#3932', 'Var', (122, 127))	('beta-actin', 'Gene', (180, 190))	('#5296', 'Var', (88, 93))	('vimentin', 'Gene', '7431', (112, 120))	('CAV1', 'Gene', (146, 150))	('beta-actin', 'Gene', '728378', (180, 190))	('#3238', 'Var', (152, 157))	('vimentin', 'Gene', (112, 120))	('E-cadherin', 'Gene', (76, 86))	('E-cadherin', 'Gene', '999', (76, 86))
359157	29097801	F4 and H1299 expressed increased endogenous levels of EFHD2 and exhibited an increased invasive ability compared with A549, CL1-0, and H2981.	('invasive ability', 'CPA', (87, 103))	('CL1', 'Gene', '9201', (124, 127))	('CL1', 'Gene', (124, 127))	('EFHD2', 'Gene', (54, 59))	('A549', 'CellLine', 'CVCL:0023', (118, 122))	('increased', 'PosReg', (23, 32))	('endogenous levels', 'MPA', (33, 50))	('increased', 'PosReg', (77, 86))	('H1299', 'Var', (7, 12))	('H2981', 'CellLine', 'CVCL:D346', (135, 140))	('H1299', 'CellLine', 'CVCL:0060', (7, 12))
359162	29097801	The percentages of cell expressing EFHD2 in cancer stage I, II, and IIIa were 36.8%, 37.5%, and 28.6%, respectively, in lung squamous cell carcinoma and 41.2%, 68.8%, and 50.0%, respectively, in lung adenocarcinoma (Supplemental Fig.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (125, 148))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (120, 148))	('lung squamous cell carcinoma', 'Disease', (120, 148))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (195, 214))	('carcinoma', 'Phenotype', 'HP:0030731', (139, 148))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('carcinoma', 'Phenotype', 'HP:0030731', (205, 214))	('lung adenocarcinoma', 'Disease', (195, 214))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (195, 214))	('EFHD2', 'Var', (35, 40))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
359170	29097801	Log-rank tests revealed the disease-free survival rates were significantly different between patients who express EFHD2 and patients who do not express EFHD2 (P < 0.001) (Fig.	('disease-free survival rates', 'CPA', (28, 55))	('patients', 'Species', '9606', (93, 101))	('patients', 'Species', '9606', (124, 132))	('different', 'Reg', (75, 84))	('EFHD2', 'Var', (114, 119))
359171	29097801	In addition, the demographic, clinical and biochemical variables of patients were also evaluated for the consideration of recurrence, including age, gender, pathologic stage, tumor location, differentiation, smoking status, and EGFR mutation (Table 1).	('tumor', 'Disease', (175, 180))	('EGFR', 'Gene', '1956', (228, 232))	('mutation', 'Var', (233, 241))	('patients', 'Species', '9606', (68, 76))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('EGFR', 'Gene', (228, 232))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('clinical', 'Species', '191496', (30, 38))
359175	29097801	1C) and shRNA to knockdown EFHD2 in H1299 cells (high endogenous EFHD2 levels; Fig.	('EFHD2', 'Gene', (27, 32))	('H1299', 'CellLine', 'CVCL:0060', (36, 41))	('knockdown', 'Var', (17, 26))
359178	29097801	The images demonstrated that EFHD2 increased invadopodia-like protrusive structures and the formation of invadopodia, which can be visualized by colocalization of cortactin and F-actin (Fig.	('increased', 'PosReg', (35, 44))	('cortactin', 'Gene', (163, 172))	('EFHD2', 'Var', (29, 34))	('cortactin', 'Gene', '2017', (163, 172))	('invadopodia-like protrusive structures', 'CPA', (45, 83))
359181	29097801	Western blot assay indicated that EFHD2 knockdown decreased the expression of the mesenchymal cell marker vimentin in H1299 and H2981 cells (Fig.	('vimentin', 'Gene', (106, 114))	('expression', 'MPA', (64, 74))	('H1299', 'CellLine', 'CVCL:0060', (118, 123))	('knockdown', 'Var', (40, 49))	('decreased', 'NegReg', (50, 59))	('vimentin', 'Gene', '7431', (106, 114))	('H2981', 'CellLine', 'CVCL:D346', (128, 133))	('EFHD2', 'Gene', (34, 39))
359183	29097801	In addition, EFHD2 increased the expression levels of EMT-related transcriptional factors Snail, Twist1, ZEB1 and ZEB2 in A549 cells (Fig.	('Twist1', 'Gene', '7291', (97, 103))	('ZEB2', 'Gene', (114, 118))	('ZEB1', 'Gene', (105, 109))	('ZEB1', 'Gene', '6935', (105, 109))	('EFHD2', 'Var', (13, 18))	('Twist1', 'Gene', (97, 103))	('increased', 'PosReg', (19, 28))	('Snail', 'Gene', (90, 95))	('expression levels', 'MPA', (33, 50))	('ZEB2', 'Gene', '9839', (114, 118))	('Snail', 'Gene', '6615', (90, 95))	('A549', 'CellLine', 'CVCL:0023', (122, 126))
359189	29097801	To confirm whether EFHD2 regulates the EMT through inhibition of CAV1, we performed CAV1 knockdown in parental A549 and CAV1 rescue in EFHD2-overexpressing A549 cells.	('CAV1', 'Gene', (84, 88))	('CAV1', 'Gene', '857', (65, 69))	('CAV1', 'Gene', (120, 124))	('CAV1', 'Gene', '857', (84, 88))	('A549', 'CellLine', 'CVCL:0023', (111, 115))	('A549', 'CellLine', 'CVCL:0023', (156, 160))	('EMT', 'CPA', (39, 42))	('CAV1', 'Gene', (65, 69))	('knockdown', 'Var', (89, 98))	('CAV1', 'Gene', '857', (120, 124))
359190	29097801	Direct CAV1 knockdown increased the expression of the mesenchymal cell marker vimentin and decreases the expression of the epithelial cell marker E-cadherin (Fig.	('E-cadherin', 'Gene', (146, 156))	('E-cadherin', 'Gene', '999', (146, 156))	('knockdown', 'Var', (12, 21))	('CAV1', 'Gene', (7, 11))	('increased', 'PosReg', (22, 31))	('vimentin', 'Gene', '7431', (78, 86))	('vimentin', 'Gene', (78, 86))	('decreases', 'NegReg', (91, 100))	('expression', 'MPA', (105, 115))	('expression', 'MPA', (36, 46))	('CAV1', 'Gene', '857', (7, 11))
359191	29097801	In rescue experiments, the re-expression of CAV1 partly abolished EFHD2-induced EMT in A549 cells (Fig.	('CAV1', 'Gene', (44, 48))	('A549', 'CellLine', 'CVCL:0023', (87, 91))	('EFHD2-induced', 'Gene', (66, 79))	('abolished', 'NegReg', (56, 65))	('EMT', 'CPA', (80, 83))	('CAV1', 'Gene', '857', (44, 48))	('re-expression', 'Var', (27, 40))
359192	29097801	In addition, CAV1 knockdown enhanced the expression of EMT-related transcriptional factors Twist1, ZEB1 and ZEB2 (Fig.	('knockdown', 'Var', (18, 27))	('Twist1', 'Gene', '7291', (91, 97))	('expression', 'MPA', (41, 51))	('CAV1', 'Gene', (13, 17))	('enhanced', 'PosReg', (28, 36))	('ZEB1', 'Gene', (99, 103))	('Twist1', 'Gene', (91, 97))	('ZEB2', 'Gene', '9839', (108, 112))	('ZEB1', 'Gene', '6935', (99, 103))	('CAV1', 'Gene', '857', (13, 17))	('ZEB2', 'Gene', (108, 112))
359198	29097801	Several molecular markers, such as gene mutation/deletion, DNA modification, miRNA, and alterations in protein or mRNA expression levels, are used to predict the recurrence potential in early-stage NSCLC.	('mRNA expression levels', 'MPA', (114, 136))	('miRNA', 'MPA', (77, 82))	('NSCLC', 'Phenotype', 'HP:0030358', (198, 203))	('gene mutation/deletion', 'Var', (35, 57))	('DNA modification', 'MPA', (59, 75))	('NSCLC', 'Disease', (198, 203))	('NSCLC', 'Disease', 'MESH:D002289', (198, 203))	('protein', 'MPA', (103, 110))
359216	29097801	The finding of EFHD2 was based on our originally risky hypothesis; thus, we assessed whether the hypothesis was applicable to other types of tumor cells.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumor', 'Disease', (141, 146))	('EFHD2', 'Var', (15, 20))
359222	29097801	Consequently, although EFHD2 is capable of inducing the expression of multiple EMT-related transcriptional factors, such as Snail, Twist1, ZEB1 and ZEB2, and whether EFHD2 directly regulates these factors remains unknown.	('ZEB1', 'Gene', '6935', (139, 143))	('EFHD2', 'Var', (23, 28))	('Snail', 'Gene', '6615', (124, 129))	('ZEB1', 'Gene', (139, 143))	('Twist1', 'Gene', (131, 137))	('expression', 'MPA', (56, 66))	('ZEB2', 'Gene', '9839', (148, 152))	('inducing', 'PosReg', (43, 51))	('Snail', 'Gene', (124, 129))	('Twist1', 'Gene', '7291', (131, 137))	('ZEB2', 'Gene', (148, 152))
359225	29097801	EFHD2 increased the expression of early endosome antigen 1 (EEA1) in lung tumor cells (Supplementary Fig.	('increased', 'PosReg', (6, 15))	('expression', 'MPA', (20, 30))	('lung tumor', 'Phenotype', 'HP:0100526', (69, 79))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('early endosome antigen 1', 'Gene', '8411', (34, 58))	('EEA1', 'Gene', '8411', (60, 64))	('EFHD2', 'Var', (0, 5))	('early endosome antigen 1', 'Gene', (34, 58))	('lung tumor', 'Disease', (69, 79))	('EEA1', 'Gene', (60, 64))	('lung tumor', 'Disease', 'MESH:D008175', (69, 79))
359226	29097801	This phenomenon is consistent with the previous finding that CAV1 knockdown increased endocytosis, which is involved in the regulation of cell migration and cancer metastasis.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('cancer metastasis', 'Disease', 'MESH:D009362', (157, 174))	('increased', 'PosReg', (76, 85))	('CAV1', 'Gene', '857', (61, 65))	('CAV1', 'Gene', (61, 65))	('knockdown', 'Var', (66, 75))	('cancer metastasis', 'Disease', (157, 174))	('endocytosis', 'MPA', (86, 97))
359242	28521453	Our results suggest nicotine may promote tongue squamous carcinoma cells progression by activating the Wnt/beta-catenin and Wnt/PCP signaling pathways and may play a significant role in the progression and metastasis of smoking-related TSCC.	('play', 'Reg', (159, 163))	('tongue squamous carcinoma', 'Phenotype', 'HP:0030413', (41, 66))	('nicotine', 'Var', (20, 28))	('promote', 'PosReg', (33, 40))	('beta-catenin', 'Gene', (107, 119))	('tongue squamous carcinoma', 'Disease', 'MESH:D002294', (41, 66))	('carcinoma', 'Phenotype', 'HP:0030731', (57, 66))	('tongue squamous carcinoma', 'Disease', (41, 66))	('beta-catenin', 'Gene', '1499', (107, 119))	('activating', 'PosReg', (88, 98))	('nicotine', 'Chemical', 'MESH:D009538', (20, 28))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (48, 66))	('Wnt/PCP signaling pathways', 'Pathway', (124, 150))
359248	28521453	Specifically, it is been shown that nicotine stimulation can induce proliferation, angiogenesis and EMT in non-small cell lung cancer cells and esophageal squamous cell cancer.	('nicotine stimulation', 'Var', (36, 56))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (111, 133))	('induce', 'PosReg', (61, 67))	('non-small cell lung cancer', 'Disease', (107, 133))	('proliferation', 'CPA', (68, 81))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (155, 175))	('nicotine', 'Chemical', 'MESH:D009538', (36, 44))	('lung cancer', 'Phenotype', 'HP:0100526', (122, 133))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('esophageal squamous cell cancer', 'Disease', (144, 175))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (107, 133))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (107, 133))	('angiogenesis', 'CPA', (83, 95))	('esophageal squamous cell cancer', 'Disease', 'MESH:D002294', (144, 175))	('EMT', 'CPA', (100, 103))
359250	28521453	In these recent studies, nicotine has been found to contribute to the progression and metastasis of tumor cells or normal cells by activation of several signaling pathways.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('nicotine', 'Var', (25, 33))	('metastasis of tumor', 'Disease', 'MESH:D009362', (86, 105))	('nicotine', 'Chemical', 'MESH:D009538', (25, 33))	('progression', 'CPA', (70, 81))	('contribute', 'Reg', (52, 62))	('metastasis of tumor', 'Disease', (86, 105))
359261	28521453	Rabbit monoclonal phospho-Akt (Ser473) and phospho-GSK-3beta antibodies were from Cell Signaling Technologies (Beverly, MA, USA; cat.	('Akt', 'Gene', '207', (26, 29))	('GSK-3beta', 'Gene', '2932', (51, 60))	('GSK-3beta', 'Gene', (51, 60))	('Akt', 'Gene', (26, 29))	('Ser473', 'Var', (31, 37))	('Ser473', 'Chemical', '-', (31, 37))	('Rabbit', 'Species', '9986', (0, 6))
359308	28521453	For example, at 12 h 32.2+-2.43% of the wound was healed in the 10 microM nicotine group, but only 19.67+-2.08% was healed in the control group in Cal27 cells (P<0.001).	('nicotine', 'Var', (74, 82))	('nicotine', 'Chemical', 'MESH:D009538', (74, 82))	('10 microM nicotine', 'Var', (64, 82))
359315	28521453	Additionally, we found that Wnt/beta-catenin signaling activity was substantially higher in Cal27 cells treated with nicotine compared to the control group, as determined using the TCF-dependent TOPflash reporter (Fig.	('TCF', 'Gene', (181, 184))	('nicotine', 'Chemical', 'MESH:D009538', (117, 125))	('TCF', 'Gene', '3172', (181, 184))	('TOPflash', 'Disease', (195, 203))	('beta-catenin', 'Gene', (32, 44))	('higher', 'PosReg', (82, 88))	('TOPflash', 'Disease', 'None', (195, 203))	('nicotine', 'Var', (117, 125))	('beta-catenin', 'Gene', '1499', (32, 44))
359319	28521453	Previous studies showed that nicotine can promote proliferation and invasion in several cancers via the Wnt/beta-catenin pathway.	('beta-catenin', 'Gene', (108, 120))	('nicotine', 'Chemical', 'MESH:D009538', (29, 37))	('cancers', 'Disease', 'MESH:D009369', (88, 95))	('invasion', 'CPA', (68, 76))	('proliferation', 'CPA', (50, 63))	('beta-catenin', 'Gene', '1499', (108, 120))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('cancers', 'Disease', (88, 95))	('nicotine', 'Var', (29, 37))	('promote', 'PosReg', (42, 49))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))
359336	28521453	In our study, we have found that nicotine can reduce the expression level of E-cadherin and activate Wnt/beta-catenin pathway in vitro.	('reduce', 'NegReg', (46, 52))	('E-cadherin', 'Gene', (77, 87))	('beta-catenin', 'Gene', (105, 117))	('E-cadherin', 'Gene', '999', (77, 87))	('nicotine', 'Chemical', 'MESH:D009538', (33, 41))	('expression level', 'MPA', (57, 73))	('beta-catenin', 'Gene', '1499', (105, 117))	('nicotine', 'Var', (33, 41))	('activate', 'PosReg', (92, 100))
359343	28521453	We found that aberrant expression of beta-catenin is more common in patients with a smoking history.	('common', 'Reg', (58, 64))	('patients', 'Species', '9606', (68, 76))	('beta-catenin', 'Gene', (37, 49))	('aberrant expression', 'Var', (14, 33))	('beta-catenin', 'Gene', '1499', (37, 49))
359345	28521453	Overexpression of Wnt5a has recently been linked to melanoma, osteosarcoma, renal cell carcinoma, prostate cancer, breast cancer and TSCC.	('Wnt5a', 'Gene', (18, 23))	('osteosarcoma', 'Disease', (62, 74))	('osteosarcoma', 'Disease', 'MESH:D012516', (62, 74))	('Overexpression', 'Var', (0, 14))	('prostate cancer', 'Disease', 'MESH:D011471', (98, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))	('renal cell carcinoma', 'Disease', (76, 96))	('prostate cancer', 'Phenotype', 'HP:0012125', (98, 113))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (76, 96))	('melanoma', 'Disease', 'MESH:D008545', (52, 60))	('prostate cancer', 'Disease', (98, 113))	('TSCC', 'Disease', (133, 137))	('breast cancer', 'Phenotype', 'HP:0003002', (115, 128))	('osteosarcoma', 'Phenotype', 'HP:0002669', (62, 74))	('breast cancer', 'Disease', 'MESH:D001943', (115, 128))	('breast cancer', 'Disease', (115, 128))	('melanoma', 'Phenotype', 'HP:0002861', (52, 60))	('melanoma', 'Disease', (52, 60))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (76, 96))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('Wnt5a', 'Gene', '7474', (18, 23))	('linked', 'Reg', (42, 48))
359349	28521453	In addition our results indicate that aberrant expressions of Ror2 and Wnt5a are more common in patients with a smoking history, which are consistent with previous reports.	('Wnt5a', 'Gene', (71, 76))	('smoking', 'Disease', (112, 119))	('common', 'Reg', (86, 92))	('Wnt5a', 'Gene', '7474', (71, 76))	('Ror2', 'Gene', '4920', (62, 66))	('aberrant expressions', 'Var', (38, 58))	('patients', 'Species', '9606', (96, 104))	('Ror2', 'Gene', (62, 66))
359354	28521453	These molecular changes may be a common mechanism that induces poor prognosis in other smoking-related cancers.	('changes', 'Var', (16, 23))	('cancers', 'Disease', 'MESH:D009369', (103, 110))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('cancers', 'Phenotype', 'HP:0002664', (103, 110))	('cancers', 'Disease', (103, 110))
359382	33950913	Abnormal serum tumor markers refer to serum squamous cell carcinoma antigens in patients with squamous cell carcinoma >=1.5 mug/L, serum carbohydrate antigens 125 in patients with adenocarcinoma >=35U/mL, and/or carbohydrate antigens 19-9 >=37 U/mL, serum neuron-specific enolase of patients with neuroendocrine cancer >=12.5 mug/L.	('patients', 'Species', '9606', (80, 88))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('neuron-specific enolase', 'Gene', '2026', (256, 279))	('Abnormal serum tumor', 'Disease', 'MESH:D012713', (0, 20))	('adenocarcinoma', 'Disease', (180, 194))	('squamous cell carcinoma', 'Disease', (44, 67))	('cancer', 'Phenotype', 'HP:0002664', (312, 318))	('>=1.5', 'Var', (118, 123))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (94, 117))	('patients', 'Species', '9606', (283, 291))	('patients', 'Species', '9606', (166, 174))	('adenocarcinoma', 'Disease', 'MESH:D000230', (180, 194))	('carbohydrate', 'Chemical', 'MESH:D002241', (212, 224))	('Abnormal serum tumor', 'Disease', (0, 20))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (94, 117))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (44, 67))	('neuroendocrine cancer', 'Disease', 'MESH:D009369', (297, 318))	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('neuroendocrine cancer', 'Phenotype', 'HP:0100634', (297, 318))	('neuroendocrine cancer', 'Disease', (297, 318))	('squamous cell carcinoma', 'Disease', (94, 117))	('carcinoma', 'Phenotype', 'HP:0030731', (185, 194))	('neuron-specific enolase', 'Gene', (256, 279))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (44, 67))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))	('carbohydrate', 'Chemical', 'MESH:D002241', (137, 149))
359404	33950913	In this work, we also found that the risk of lung metastasis in patients with PLNM is 3.456 times (95% CI = 2.268-8.691) higher than that in patients without PLNM.	('PLNM', 'Var', (78, 82))	('patients', 'Species', '9606', (64, 72))	('higher', 'PosReg', (121, 127))	('lung metastasis', 'CPA', (45, 60))	('patients', 'Species', '9606', (141, 149))
359421	32463532	Circular RNA_0001742 has potential to predict advanced tumor stage and poor survival profiles in tongue squamous cell carcinoma management Circular RNA_0001742 (circ_0001742) has been reported to be upregulated in tongue squamous cell carcinoma (TSCC) tissues/cells and regulate TSCC cell proliferation, migration, and invasion.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (104, 127))	('tongue squamous cell carcinoma', 'Disease', (214, 244))	('tongue squamous cell carcinoma', 'Phenotype', 'HP:0030413', (97, 127))	('TSCC', 'Phenotype', 'HP:0030413', (279, 283))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (221, 244))	('Circular RNA_0001742', 'Var', (139, 159))	('tongue squamous cell carcinoma', 'Phenotype', 'HP:0030413', (214, 244))	('tongue squamous cell carcinoma', 'Disease', 'MESH:D002294', (97, 127))	('migration', 'CPA', (304, 313))	('carcinoma', 'Phenotype', 'HP:0030731', (235, 244))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('invasion', 'CPA', (319, 327))	('TSCC', 'Phenotype', 'HP:0030413', (246, 250))	('regulate', 'Reg', (270, 278))	('tongue squamous cell carcinoma', 'Disease', (97, 127))	('tongue squamous cell carcinoma', 'Disease', 'MESH:D002294', (214, 244))	('tumor', 'Disease', (55, 60))	('upregulated', 'PosReg', (199, 210))
359425	32463532	Circ_0001742 expression was increased in TSCC tumor tissue compared with adjacent tissue, and it presented good value in discriminating tumor tissue from adjacent tissue (area under the curve (AUC): 0.870, 95% CI: 0.831-0.910).	('increased', 'PosReg', (28, 37))	('TSCC tumor', 'Disease', 'MESH:D009369', (41, 51))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('expression', 'MPA', (13, 23))	('Circ_0001742', 'Var', (0, 12))	('tumor', 'Disease', (46, 51))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('TSCC', 'Phenotype', 'HP:0030413', (41, 45))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('TSCC tumor', 'Disease', (41, 51))	('tumor', 'Disease', (136, 141))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
359426	32463532	Tumor high circ_0001742 expression was associated with higher T stage, N stage, and TNM stage, but not age, gender, or pathological grade.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('TNM', 'Gene', (84, 87))	('T stage', 'CPA', (62, 69))	('high circ_0001742 expression', 'Var', (6, 34))	('N stage', 'CPA', (71, 78))	('TNM', 'Gene', '10178', (84, 87))	('higher', 'PosReg', (55, 61))
359427	32463532	Furthermore, OS was reduced in tumor circ_0001742 high patients compared with tumor circ_0001742 low patients; moreover, OS was the shortest in tumor circ_0001742 high+++ patients, followed by tumor circ_0001742 high++ patients and tumor circ_0001742 high+ patients, and the longest in tumor circ_0001742 low patients.	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('patients', 'Species', '9606', (101, 109))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('patients', 'Species', '9606', (171, 179))	('patients', 'Species', '9606', (257, 265))	('patients', 'Species', '9606', (219, 227))	('tumor', 'Disease', (232, 237))	('tumor', 'Disease', (193, 198))	('tumor', 'Disease', (144, 149))	('tumor', 'Disease', (286, 291))	('tumor', 'Disease', 'MESH:D009369', (232, 237))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('high+++', 'Var', (163, 170))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('tumor', 'Disease', (78, 83))	('tumor', 'Disease', 'MESH:D009369', (286, 291))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Disease', (31, 36))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('patients', 'Species', '9606', (55, 63))	('patients', 'Species', '9606', (309, 317))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
359429	32463532	Circ_0001742 serves as a potential biomarker for advanced tumor stage and poor survival in TSCC patients.	('TSCC', 'Disease', (91, 95))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('Circ_0001742', 'Var', (0, 12))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('patients', 'Species', '9606', (96, 104))	('TSCC', 'Phenotype', 'HP:0030413', (91, 95))
359435	32463532	11  Another study exhibits that circ_0001742 is upregulated in TSCC tissues as well as cells, and its knockdown inhibits cell proliferation, migration, and invasion via regulating microRNA (miR)-431/ATF3 axis in TSCC cells.	('migration', 'CPA', (141, 150))	('circ_0001742', 'Var', (32, 44))	('TSCC', 'Phenotype', 'HP:0030413', (63, 67))	('TSCC', 'Disease', (63, 67))	('ATF3', 'Gene', '467', (199, 203))	('knockdown', 'Var', (102, 111))	('cell proliferation', 'CPA', (121, 139))	('microRNA (miR)-431', 'Gene', (180, 198))	('upregulated', 'PosReg', (48, 59))	('microRNA (miR)-431', 'Gene', '574038', (180, 198))	('inhibits', 'NegReg', (112, 120))	('TSCC', 'Phenotype', 'HP:0030413', (212, 216))	('invasion', 'CPA', (156, 164))	('ATF3', 'Gene', (199, 203))	('regulating', 'Reg', (169, 179))
359447	32463532	Then, qPCR was performed using QuantiNova SYBR Green PCR Kit (Qiagen) to quantify circ_0001742 and GAPDH Ct value.	('circ_0001742', 'Var', (82, 94))	('GAPDH', 'Gene', (99, 104))	('GAPDH', 'Gene', '2597', (99, 104))
359449	32463532	The detailed description of circ_0001742 expression normalization was as follows: (1) qPCR was performed in triplicate, and the average of circ_0001742 Ct and GAPDH Ct in every sample were determined, respectively.	('GAPDH', 'Gene', '2597', (159, 164))	('GAPDH', 'Gene', (159, 164))	('circ_0001742', 'Var', (139, 151))
359456	32463532	The ability of circ_0001742 in discriminating tumor tissue from adjacent tissue was displayed by receiver operating characteristic (ROC) curve and area under the curve (AUC) with 95% confidence interval (CI).	('circ_0001742', 'Var', (15, 27))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Disease', (46, 51))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
359457	32463532	Comparison of clinicopathological features between tumor circ_0001742 high group and tumor circ_0001742 low group was determined by the chi-square test or Wilcoxon rank-sum test.	('tumor', 'Disease', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor', 'Disease', (51, 56))	('circ_0001742', 'Var', (57, 69))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
359466	32463532	Circ_0001742 expression was increased in TSCC tumor tissue (2.624 [1.972-3.574]) compared with adjacent tissue (0.997 (0.717-1.748)) (P < .001) (Figure 1A).	('increased', 'PosReg', (28, 37))	('TSCC tumor', 'Disease', 'MESH:D009369', (41, 51))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('expression', 'MPA', (13, 23))	('Circ_0001742', 'Var', (0, 12))	('TSCC tumor', 'Disease', (41, 51))	('TSCC', 'Phenotype', 'HP:0030413', (41, 45))
359467	32463532	ROC curve analysis exhibited that circ_0001742 presented good value in discriminating tumor tissue from adjacent tissue (AUC: 0.870, 95% CI: 0.831-0.910) (Figure 1B).	('tumor', 'Disease', (86, 91))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('circ_0001742', 'Var', (34, 46))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))
359469	32463532	Tumor high circ_0001742 expression was associated with higher T stage (P = .023) (Figure 2D), N stage (P < .001) (Figure 2E), and TNM stage (P < .001) (Figure 2F); however, there was no correlation of tumor circ_0001742 expression with age (P = .618) (Figure 2A), gender (P = .854) (Figure 2B), or pathological grade (P = .467) (Figure 2C) in TSCC patients.	('patients', 'Species', '9606', (348, 356))	('TNM', 'Gene', '10178', (130, 133))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('N stage', 'CPA', (94, 101))	('T stage', 'CPA', (62, 69))	('TNM', 'Gene', (130, 133))	('high circ_0001742 expression', 'Var', (6, 34))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('TSCC', 'Phenotype', 'HP:0030413', (343, 347))	('TSCC', 'Disease', (343, 347))	('tumor', 'Disease', (201, 206))	('higher', 'PosReg', (55, 61))
359470	32463532	OS was reduced in patients with tumor circ_0001742 high expression compared with those with tumor circ_0001742 low expression (P = .010) (Figure 3A).	('reduced', 'NegReg', (7, 14))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('patients', 'Species', '9606', (18, 26))	('tumor', 'Disease', (92, 97))	('tumor', 'Disease', (32, 37))	('circ_0001742 high expression', 'Var', (38, 66))
359472	32463532	OS was the shortest in patients with tumor circ_0001742 high+++ expression, followed by patients with tumor circ_0001742 high++ expression and those with tumor circ_0001742 high+ expression, and the longest in patients with tumor circ_0001742 low expression (P = .005) (Figure 3B).	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('tumor', 'Disease', 'MESH:D009369', (224, 229))	('patients', 'Species', '9606', (23, 31))	('patients', 'Species', '9606', (88, 96))	('tumor', 'Disease', (224, 229))	('circ_0001742 high+++ expression', 'Var', (43, 74))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('tumor', 'Disease', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('patients', 'Species', '9606', (210, 218))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('shortest', 'NegReg', (11, 19))	('tumor', 'Disease', (102, 107))	('tumor', 'Disease', (154, 159))
359475	32463532	In the present study, we found that (a) circ_0001742 expression was increased in TSCC tumor tissue compared with adjacent tissue and presented good value in discriminating tumor tissue from adjacent tissue.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('TSCC tumor', 'Disease', 'MESH:D009369', (81, 91))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('circ_0001742', 'Var', (40, 52))	('tumor', 'Disease', (86, 91))	('tumor', 'Disease', (172, 177))	('TSCC tumor', 'Disease', (81, 91))	('expression', 'MPA', (53, 63))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('increased', 'PosReg', (68, 77))	('TSCC', 'Phenotype', 'HP:0030413', (81, 85))
359476	32463532	(b2) Tumor high circ_0001742 expression was associated with higher T stage, N stage, and TNM stage in TSCC patients.	('higher', 'PosReg', (60, 66))	('TNM', 'Gene', (89, 92))	('high circ_0001742 expression', 'Var', (11, 39))	('N stage', 'CPA', (76, 83))	('Tumor', 'Phenotype', 'HP:0002664', (5, 10))	('TSCC', 'Phenotype', 'HP:0030413', (102, 106))	('patients', 'Species', '9606', (107, 115))	('TNM', 'Gene', '10178', (89, 92))	('T stage', 'CPA', (67, 74))
359480	32463532	16 ,  17  For example, cirRNA TP63 is upregulated in lung squamous cell carcinoma tissue compared with paired non-cancerous tissue, and mechanically, it facilitates cell cycle progression via downregulating miR-873 targeted FOXM1 in lung squamous cell carcinoma.	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (53, 81))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (233, 261))	('lung squamous cell carcinoma', 'Disease', (53, 81))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (238, 261))	('miR-873', 'Gene', '100126316', (207, 214))	('lung squamous cell carcinoma', 'Disease', (233, 261))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('cirRNA', 'Var', (23, 29))	('FOXM1', 'Gene', '2305', (224, 229))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('cell cycle progression', 'CPA', (165, 187))	('facilitates', 'PosReg', (153, 164))	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('carcinoma', 'Phenotype', 'HP:0030731', (252, 261))	('TP63', 'Gene', (30, 34))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (53, 81))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (58, 81))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (233, 261))	('miR-873', 'Gene', (207, 214))	('FOXM1', 'Gene', (224, 229))	('downregulating', 'NegReg', (192, 206))	('upregulated', 'PosReg', (38, 49))	('TP63', 'Gene', '8626', (30, 34))	('cancer', 'Disease', (114, 120))
359482	32463532	11  Meanwhile, several studies reveal tumorigenic implication of circ_0001742 in the TSCC development.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('circ_0001742', 'Var', (65, 77))	('TSCC', 'Phenotype', 'HP:0030413', (85, 89))	('TSCC', 'Disease', (85, 89))
359483	32463532	12 ,  19  Silencing circ_0001742 is reported to inhibit cell proliferation, invasion and epithelial-mesenchymal transition (EMT) processes of TSCC cells via targeting miR-634/RAB1A pathway.	('miR-634', 'Gene', (167, 174))	('RAB1A', 'Gene', '5861', (175, 180))	('epithelial-mesenchymal transition', 'CPA', (89, 122))	('targeting', 'Reg', (157, 166))	('RAB1A', 'Gene', (175, 180))	('miR-634', 'Gene', '693219', (167, 174))	('TSCC', 'Phenotype', 'HP:0030413', (142, 146))	('Silencing circ_0001742', 'Var', (10, 32))	('cell proliferation', 'CPA', (56, 74))	('circ_0001742', 'Var', (20, 32))	('invasion', 'CPA', (76, 84))	('inhibit', 'NegReg', (48, 55))
359484	32463532	19  Based on the previous evidence, we proposed that circ_0001742 might be associated with clinicopathological features and survival in TSCC patients.	('circ_0001742', 'Var', (53, 65))	('TSCC', 'Disease', (136, 140))	('TSCC', 'Phenotype', 'HP:0030413', (136, 140))	('associated', 'Reg', (75, 85))	('patients', 'Species', '9606', (141, 149))
359485	32463532	We enrolled 146 TSCC patients underwent surgical treatment, and collected their fresh-frozen tumor tissue and adjacent tissue excised from surgery for detection of circ_0001742 expression.	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('circ_0001742 expression', 'Var', (164, 187))	('tumor', 'Disease', (93, 98))	('patients', 'Species', '9606', (21, 29))	('TSCC', 'Phenotype', 'HP:0030413', (16, 20))	('TSCC', 'Disease', (16, 20))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
359488	32463532	The possible reasons might include that (a) given the existing study that EMT was an essential biological process which was implicated in tumor invasion and metastasis, and considering the prior evidence that circ_0001742 enhances the EMT progress of TSCC cells, therefore, tumor high circ_0001742 expression was associated with advanced tumor stage in TSCC patients.	('TSCC', 'Phenotype', 'HP:0030413', (353, 357))	('tumor', 'Disease', (138, 143))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('tumor', 'Disease', 'MESH:D009369', (274, 279))	('tumor', 'Disease', (338, 343))	('tumor', 'Phenotype', 'HP:0002664', (338, 343))	('EMT progress', 'CPA', (235, 247))	('enhances', 'PosReg', (222, 230))	('associated', 'Reg', (313, 323))	('circ_0001742', 'Var', (209, 221))	('tumor', 'Phenotype', 'HP:0002664', (274, 279))	('tumor', 'Disease', (274, 279))	('TSCC', 'Disease', (353, 357))	('TSCC', 'Phenotype', 'HP:0030413', (251, 255))	('patients', 'Species', '9606', (358, 366))	('tumor', 'Disease', 'MESH:D009369', (338, 343))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
359489	32463532	Hence, TSCC patients with high circ_0001742 expression presented increased tumor stage.	('increased', 'PosReg', (65, 74))	('patients', 'Species', '9606', (12, 20))	('TSCC', 'Phenotype', 'HP:0030413', (7, 11))	('TSCC', 'Disease', (7, 11))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('high circ_0001742 expression', 'Var', (26, 54))	('tumor', 'Disease', (75, 80))
359490	32463532	12  (c) According to the prior study, circ_0001742 might exhibit pro-tumor activities via serving as the sponge of miR-634, and miR-634 exerts anti-tumor function via targeting Rab1A and DHX33; therefore, circ_0001742 was positively correlated with advanced T, N, and TNM stages.	('Rab1A', 'Gene', (177, 182))	('Rab1A', 'Gene', '5861', (177, 182))	('TNM', 'Gene', '10178', (268, 271))	('miR-634', 'Gene', (115, 122))	('correlated', 'Reg', (233, 243))	('TNM', 'Gene', (268, 271))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('circ_0001742', 'Var', (205, 217))	('DHX33', 'Gene', '56919', (187, 192))	('miR-634', 'Gene', (128, 135))	('circ_0001742', 'Var', (38, 50))	('miR-634', 'Gene', '693219', (115, 122))	('targeting', 'Reg', (167, 176))	('DHX33', 'Gene', (187, 192))	('miR-634', 'Gene', '693219', (128, 135))	('tumor', 'Disease', (69, 74))	('tumor', 'Disease', (148, 153))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('tumor', 'Disease', 'MESH:D009369', (148, 153))
359493	32463532	The possible reasons might include that (a) considering the previous founding that higher tumor circ_0001742 expression was associated with increased T stage and N stage, and the observation that higher T stage and N stage were independent predictive factors for reduced OS in TSCC patients, high tumor circ_0001742 expression might be correlated with poor prognosis via interacting with T and N stages.	('T stage', 'CPA', (150, 157))	('expression', 'MPA', (109, 119))	('reduced OS', 'Disease', (263, 273))	('tumor', 'Disease', (90, 95))	('N stage', 'CPA', (162, 169))	('tumor', 'Disease', 'MESH:D009369', (297, 302))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('patients', 'Species', '9606', (282, 290))	('TSCC', 'Phenotype', 'HP:0030413', (277, 281))	('tumor', 'Phenotype', 'HP:0002664', (297, 302))	('circ_0001742', 'Gene', (96, 108))	('high', 'Var', (292, 296))	('tumor', 'Disease', (297, 302))	('TSCC', 'Disease', (277, 281))	('increased', 'PosReg', (140, 149))	('higher', 'PosReg', (83, 89))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
359498	32463532	(e) The underlying molecular mechanism of circ_0001742 in regulating TSCC tumor progression was not involved in the present study, which needed further cellular experiments to validate.	('TSCC', 'Phenotype', 'HP:0030413', (69, 73))	('TSCC tumor', 'Disease', 'MESH:D009369', (69, 79))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('circ_0001742', 'Var', (42, 54))	('TSCC tumor', 'Disease', (69, 79))
359499	32463532	In conclusion, circ_0001742 is upregulated, associates with advanced TNM stage, and predicts unfavorable OS independently in TSCC patients, providing evidence that circ_0001742 has potential to be a biomarker, which could bring benefit to the follow-up surveillance and the survival prognosis in TSCC management.	('TNM', 'Gene', '10178', (69, 72))	('circ_0001742', 'Var', (15, 27))	('TSCC', 'Phenotype', 'HP:0030413', (296, 300))	('TSCC', 'Phenotype', 'HP:0030413', (125, 129))	('TSCC', 'Disease', (125, 129))	('upregulated', 'PosReg', (31, 42))	('patients', 'Species', '9606', (130, 138))	('TNM', 'Gene', (69, 72))	('circ_0001742', 'Var', (164, 176))	('advanced', 'CPA', (60, 68))
359507	31993222	Treatment of tumor-bearing mice with F-PLP/pBIM significantly inhibited tumor growth in vivo by inducing tumor cell and macrophage apoptosis, reducing tumor proliferation, and inhibiting tumor angiogenesis.	('tumor', 'Disease', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Disease', (187, 192))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('mice', 'Species', '10090', (27, 31))	('reducing', 'NegReg', (142, 150))	('inhibiting', 'NegReg', (176, 186))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('tumor', 'Disease', (105, 110))	('inducing', 'NegReg', (96, 104))	('tumor', 'Disease', (72, 77))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('tumor', 'Disease', (151, 156))	('F-PLP/pBIM', 'Var', (37, 47))	('inhibited', 'NegReg', (62, 71))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('men', 'Species', '9606', (5, 8))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
359533	31993222	Gene therapy against lung cancer has been reported to have potential efficacy and has been a worldwide research field over the last two decades.	('lung cancer', 'Disease', (21, 32))	('lung cancer', 'Phenotype', 'HP:0100526', (21, 32))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('Gene therapy', 'Var', (0, 12))	('lung cancer', 'Disease', 'MESH:D008175', (21, 32))
359581	31993222	Fresh surgical specimens from lung cancer patients and tumor tissue specimens from mice were digested into single-cell suspensions and stained with CD45, F4/80, CD206, CD11c, FRbeta, FRalpha, CD11b, Gr-1, CD19, CD3, CD4, CD8, CD44 or the corresponding isotypes.	('CD3', 'Gene', '28134', (211, 214))	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('CD11b', 'Gene', '16409', (192, 197))	('CD44', 'Var', (226, 230))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('CD19', 'Gene', '12478', (205, 209))	('CD11c', 'Gene', (168, 173))	('CD206', 'Gene', (161, 166))	('F4/80', 'Gene', '13733', (154, 159))	('CD8', 'Gene', '925', (221, 224))	('CD11b', 'Gene', (192, 197))	('lung cancer', 'Disease', (30, 41))	('FRalpha', 'Var', (183, 190))	('men', 'Species', '9606', (73, 76))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('mice', 'Species', '10090', (83, 87))	('CD11c', 'Gene', '16411', (168, 173))	('Gr-1', 'Gene', '546644', (199, 203))	('Gr-1', 'Gene', (199, 203))	('F4/80', 'Gene', (154, 159))	('CD45', 'Gene', '19264', (148, 152))	('CD19', 'Gene', (205, 209))	('lung cancer', 'Disease', 'MESH:D008175', (30, 41))	('patients', 'Species', '9606', (42, 50))	('CD8', 'Gene', (221, 224))	('lung cancer', 'Phenotype', 'HP:0100526', (30, 41))	('CD4', 'Gene', (216, 219))	('CD45', 'Gene', (148, 152))	('tumor', 'Disease', (55, 60))	('CD3', 'Gene', (211, 214))	('CD206', 'Gene', '17533', (161, 166))	('men', 'Species', '9606', (20, 23))
359592	31993222	Immunofluorescence analysis was performed on tumor sections to detect changes in macrophages after treatment in vivo with an F4/80 antibody (1:100, cat# 70076, Cell Signaling Technology, USA) and a cleaved-caspase 3 antibody (1:100, cat# 9662, Cell Signaling Technology, USA).	('1:100', 'Var', (141, 146))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('men', 'Species', '9606', (104, 107))	('F4/80', 'Gene', '13733', (125, 130))	('tumor', 'Disease', (45, 50))	('F4/80', 'Gene', (125, 130))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
359601	31993222	Thirteen lung adenocarcinoma patients suffered EGFR gene mutations, and fifteen lung adenocarcinoma patients had ALK gene mutations.	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (9, 28))	('patients', 'Species', '9606', (29, 37))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (9, 28))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('ALK', 'Gene', (113, 116))	('lung adenocarcinoma', 'Disease', (80, 99))	('lung adenocarcinoma', 'Disease', (9, 28))	('carcinoma', 'Phenotype', 'HP:0030731', (19, 28))	('mutations', 'Var', (57, 66))	('patients', 'Species', '9606', (100, 108))	('EGFR', 'Gene', '1956', (47, 51))	('ALK', 'Gene', '238', (113, 116))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (80, 99))	('suffered', 'Reg', (38, 46))	('EGFR', 'Gene', (47, 51))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (80, 99))
359622	31993222	To investigate whether the FR could be used as an independent prognostic predictor in NSCLC, as shown in Table 2, we converted the risk factors associated with lung cancer prognosis into two-category variables for stratified analysis, including sex (male/female), age (<60 years old/>=60 years old), pathological grade (I-II grades/III grade), tumor size (<=5 cm/>5 cm), T stage (T1-T2/T3-T4), N stage (N0/N1-N3), AJCC stage (I-II/III-IV), adenocarcinoma EGFR gene status (wild type/mutant type), and ALK gene status (wild type/mutant type).	('NSCLC', 'Disease', 'MESH:D002289', (86, 91))	('EGFR', 'Gene', (455, 459))	('NSCLC', 'Disease', (86, 91))	('tumor', 'Disease', (344, 349))	('lung cancer', 'Disease', 'MESH:D008175', (160, 171))	('carcinoma', 'Phenotype', 'HP:0030731', (445, 454))	('ALK', 'Gene', '238', (501, 504))	('lung cancer', 'Phenotype', 'HP:0100526', (160, 171))	('tumor', 'Disease', 'MESH:D009369', (344, 349))	('N0/N1-N3', 'Var', (403, 411))	('EGFR', 'Gene', '1956', (455, 459))	('AJCC', 'Disease', (414, 418))	('ALK', 'Gene', (501, 504))	('adenocarcinoma', 'Disease', (440, 454))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('tumor', 'Phenotype', 'HP:0002664', (344, 349))	('N1-N3', 'Chemical', 'MESH:D009584', (406, 411))	('adenocarcinoma', 'Disease', 'MESH:D000230', (440, 454))	('lung cancer', 'Disease', (160, 171))
359624	31993222	When distinguishing FR subtypes, lung cancer patients with high FRbeta expression had a poor prognosis.	('lung cancer', 'Phenotype', 'HP:0100526', (33, 44))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('lung cancer', 'Disease', 'MESH:D008175', (33, 44))	('high', 'Var', (59, 63))	('patients', 'Species', '9606', (45, 53))	('FRbeta', 'Protein', (64, 70))	('lung cancer', 'Disease', (33, 44))
359625	31993222	The median survival time of lung cancer patients with high FRalpha expression was 49 months, while the median survival time of lung cancer patients with low FRalpha expression was 59 months.	('high FRalpha expression', 'Var', (54, 77))	('lung cancer', 'Disease', (127, 138))	('patients', 'Species', '9606', (139, 147))	('lung cancer', 'Disease', 'MESH:D008175', (28, 39))	('lung cancer', 'Phenotype', 'HP:0100526', (127, 138))	('patients', 'Species', '9606', (40, 48))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('lung cancer', 'Disease', (28, 39))	('lung cancer', 'Disease', 'MESH:D008175', (127, 138))	('lung cancer', 'Phenotype', 'HP:0100526', (28, 39))
359628	31993222	The median survival time of lung cancer patients with high FRbeta expression was 33.5 months, and the median survival time of patients with low FRbeta expression was 81 months (Fig.	('lung cancer', 'Disease', 'MESH:D008175', (28, 39))	('high', 'Var', (54, 58))	('patients', 'Species', '9606', (40, 48))	('FRbeta', 'Protein', (59, 65))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('lung cancer', 'Disease', (28, 39))	('patients', 'Species', '9606', (126, 134))	('lung cancer', 'Phenotype', 'HP:0100526', (28, 39))
359632	31993222	2d, in lung adenocarcinoma, there was no significant difference in the overall survival between patients with high FRalpha expression and those with low FRalpha expression (p = 0.1168, HR = 0.6773, 95% CI 0.4186-1.096).	('FRalpha', 'Protein', (115, 122))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (7, 26))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (7, 26))	('high', 'Var', (110, 114))	('patients', 'Species', '9606', (96, 104))	('carcinoma', 'Phenotype', 'HP:0030731', (17, 26))	('lung adenocarcinoma', 'Disease', (7, 26))
359634	31993222	The median survival of patients with low FRalpha expression was 46 months.	('FRalpha expression', 'Protein', (41, 59))	('low', 'Var', (37, 40))	('patients', 'Species', '9606', (23, 31))
359635	31993222	2e, in lung squamous cell carcinoma, there was no significant difference in the overall survival between patients with high FRalpha expression and those with low FRalpha expression (p = 0.580, HR = 1.224, 95% CI 0.6076-2.4657).	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (7, 35))	('patients', 'Species', '9606', (105, 113))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (12, 35))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (7, 35))	('lung squamous cell carcinoma', 'Disease', (7, 35))	('high FRalpha', 'Var', (119, 131))	('carcinoma', 'Phenotype', 'HP:0030731', (26, 35))
359636	31993222	The median survival time of patients with high FRalpha expression in lung squamous cell carcinoma was 76 months, and the median survival of patients with low FRalpha expression was 81 months.	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (69, 97))	('high FRalpha expression', 'Var', (42, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (74, 97))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (69, 97))	('lung squamous cell carcinoma', 'Disease', (69, 97))	('patients', 'Species', '9606', (140, 148))	('patients', 'Species', '9606', (28, 36))
359642	31993222	2f, a significant difference existed in the overall survival between patients with high FRbeta expression and those with low FRbeta expression in interstitial TAMs in lung adenocarcinoma (p = 0.0077, HR = 0.5325, 95% CI 0.3296-0.8604).	('TAM', 'Chemical', 'MESH:C419191', (159, 162))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (167, 186))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (167, 186))	('carcinoma', 'Phenotype', 'HP:0030731', (177, 186))	('FRbeta', 'Protein', (88, 94))	('lung adenocarcinoma', 'Disease', (167, 186))	('high', 'Var', (83, 87))	('patients', 'Species', '9606', (69, 77))
359643	31993222	The median survival time of lung adenocarcinoma patients with high FRbeta expression was 29 months, and the median survival time of patients with low FRbeta expression was 54 months.	('lung adenocarcinoma', 'Disease', (28, 47))	('carcinoma', 'Phenotype', 'HP:0030731', (38, 47))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (28, 47))	('FRbeta', 'Protein', (67, 73))	('high', 'Var', (62, 66))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (28, 47))	('patients', 'Species', '9606', (48, 56))	('patients', 'Species', '9606', (132, 140))
359644	31993222	2g, in lung squamous cell carcinoma, the difference in overall survival between patients with high FRbeta expression in stromal TAMs and patients with low FRbeta expression was statistically significant (p < 0.0001, HR = 0.2672, 95% CI 0.1364-0.5234).	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (7, 35))	('patients', 'Species', '9606', (80, 88))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (12, 35))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (7, 35))	('lung squamous cell carcinoma', 'Disease', (7, 35))	('patients', 'Species', '9606', (137, 145))	('TAM', 'Chemical', 'MESH:C419191', (128, 131))	('carcinoma', 'Phenotype', 'HP:0030731', (26, 35))	('FRbeta', 'Gene', (99, 105))	('high', 'Var', (94, 98))
359645	31993222	The median survival time of lung squamous cell carcinoma patients with high FRbeta expression was 46 months, and the median survival time of patients with low FRbeta expression was not reached.	('FRbeta', 'Gene', (76, 82))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (28, 56))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (33, 56))	('high', 'Var', (71, 75))	('patients', 'Species', '9606', (57, 65))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (28, 56))	('carcinoma', 'Phenotype', 'HP:0030731', (47, 56))	('lung squamous cell carcinoma', 'Disease', (28, 56))	('patients', 'Species', '9606', (141, 149))
359646	31993222	We found that high FRbeta expression was an independent predictor of lung adenocarcinoma prognosis (p = 0.003, 95% CI 1.491-6.536) and an independent predictor of lung squamous cell carcinoma prognosis (p = 0.002, 95% CI 1.793-12.465).	('expression', 'MPA', (26, 36))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (163, 191))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (69, 88))	('lung adenocarcinoma', 'Disease', (69, 88))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (163, 191))	('high', 'Var', (14, 18))	('lung squamous cell carcinoma', 'Disease', (163, 191))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('FRbeta', 'Protein', (19, 25))	('carcinoma', 'Phenotype', 'HP:0030731', (182, 191))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (168, 191))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (69, 88))
359651	31993222	Moreover, there were many fewer necrotic cells in the F-PLP group than in the LP group in vitro and in vivo, as shown in Fig.	('necrotic', 'Disease', (32, 40))	('necrotic', 'Disease', 'MESH:D009336', (32, 40))	('fewer', 'NegReg', (26, 31))	('F-PLP', 'Var', (54, 59))
359652	31993222	4b, c. Much less pulmonary inflammation was induced by F-PLP than by LP, as shown in Fig.	('pulmonary inflammation', 'Disease', (17, 39))	('F-PLP', 'Var', (55, 60))	('pulmonary inflammation', 'Disease', 'MESH:D011014', (17, 39))	('less', 'NegReg', (12, 16))
359655	31993222	Our previous study demonstrated that cationic liposome-induced necrotic cells could result in mtDNA release and cause subsequent inflammatory responses.	('cause', 'Reg', (112, 117))	('necrotic', 'Disease', (63, 71))	('result in', 'Reg', (84, 93))	('cationic liposome-induced', 'Var', (37, 62))	('necrotic', 'Disease', 'MESH:D009336', (63, 71))	('inflammatory responses', 'CPA', (129, 151))	('mtDNA release', 'MPA', (94, 107))
359663	31993222	administration of F-PLP/pBIM resulted in less tumor growth, as represented by both the weight of the lungs and the total number of tumor nodules, than that seen in the control treatment.	('F-PLP/pBIM', 'Var', (18, 28))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumor', 'Disease', (46, 51))	('tumor', 'Disease', (131, 136))	('less', 'NegReg', (41, 45))	('men', 'Species', '9606', (181, 184))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
359670	31993222	8a, tumor cell proliferation in the F-PLP/pBIM group was significantly lower than that in the other groups.	('tumor', 'Disease', (4, 9))	('F-PLP/pBIM', 'Var', (36, 46))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('lower', 'NegReg', (71, 76))
359671	31993222	There were many fewer Ki67-positive cells upon microscopic observation in the F-PLP/pBIM group than in the PLP/pBIM (p < 0.05) and control (p < 0.001) groups, as shown in Fig.	('fewer', 'NegReg', (16, 21))	('F-PLP/pBIM', 'Var', (78, 88))	('Ki67', 'Gene', (22, 26))	('Ki67', 'Gene', '17345', (22, 26))
359674	31993222	8d, tumor cell apoptosis in the F-PLP/pBIM group was much higher than that in the PLP/pBIM (p < 0.05) and control (p < 0.001) groups.	('tumor', 'Disease', (4, 9))	('F-PLP/pBIM', 'Var', (32, 42))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('higher', 'PosReg', (58, 64))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))
359677	31993222	The number of MDSCs in the tumor microenvironment of the F-PLP/pBIM treatment group were significantly reduced compared with that in the control group and the PLP/pBIM group.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('men', 'Species', '9606', (45, 48))	('men', 'Species', '9606', (73, 76))	('tumor', 'Disease', (27, 32))	('reduced', 'NegReg', (103, 110))	('F-PLP/pBIM', 'Var', (57, 67))	('tumor', 'Disease', 'MESH:D009369', (27, 32))
359681	31993222	The CD3+ CD8+ CD44+ memory T cell numbers in the F-PLP/pBIM group were significantly increased compared with those in the control group and the PLP/pBIM group.	('CD8', 'Gene', '925', (9, 12))	('F-PLP/pBIM', 'Var', (49, 59))	('CD3', 'Gene', (4, 7))	('CD3', 'Gene', '28134', (4, 7))	('increased', 'PosReg', (85, 94))	('CD8', 'Gene', (9, 12))
359682	31993222	The CD3+ CD8+ CD44+ memory T cell numbers, CD4+ CD69+ activated T cell numbers and CD8+ CD69+ activated T cell numbers in spleens in the F-PLP/pBIM group were significantly increased compared with the respective numbers in the control group and the PLP/pBIM group.	('CD8', 'Gene', '925', (9, 12))	('CD69', 'Gene', (88, 92))	('CD4+', 'Var', (43, 47))	('CD3', 'Gene', (4, 7))	('CD69', 'Gene', '969', (48, 52))	('CD3', 'Gene', '28134', (4, 7))	('CD69', 'Gene', (48, 52))	('increased', 'PosReg', (173, 182))	('CD8', 'Gene', (83, 86))	('CD69', 'Gene', '969', (88, 92))	('CD8', 'Gene', '925', (83, 86))	('F-PLP/pBIM', 'Var', (137, 147))	('CD8', 'Gene', (9, 12))
359695	31993222	The F-PLP used in our study blocks some of the positive charges because of the folate modification, so the toxicity is greatly reduced.	('folate', 'Chemical', 'MESH:D005492', (79, 85))	('blocks', 'NegReg', (28, 34))	('positive charges', 'MPA', (47, 63))	('toxicity', 'Disease', 'MESH:D064420', (107, 115))	('toxicity', 'Disease', (107, 115))	('reduced', 'NegReg', (127, 134))	('modification', 'Var', (86, 98))	('folate', 'MPA', (79, 85))
359698	31993222	Moreover, high expression of interstitial FRbeta was associated with poor prognosis in lung adenocarcinoma and lung squamous cell carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('lung adenocarcinoma', 'Disease', (87, 106))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (87, 106))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (111, 139))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (111, 139))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (116, 139))	('high', 'Var', (10, 14))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('lung squamous cell carcinoma', 'Disease', (111, 139))	('interstitial', 'Protein', (29, 41))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (87, 106))
359705	31993222	There was no significant difference in the overall survival between patients with high and low FRalpha expression.	('patients', 'Species', '9606', (68, 76))	('low', 'NegReg', (91, 94))	('FRalpha expression', 'Protein', (95, 113))	('high', 'Var', (82, 86))
359706	31993222	However, the prognosis of patients with high FRbeta expression was much worse than that of patients with low FRbeta expression.	('high', 'Var', (40, 44))	('FRbeta', 'Protein', (45, 51))	('patients', 'Species', '9606', (91, 99))	('patients', 'Species', '9606', (26, 34))
359713	31993222	In vivo antitumor experiments showed that F-PLP/pBIM significantly inhibited lung cancer growth.	('lung cancer', 'Phenotype', 'HP:0100526', (77, 88))	('men', 'Species', '9606', (24, 27))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('inhibited', 'NegReg', (67, 76))	('F-PLP/pBIM', 'Var', (42, 52))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('lung cancer', 'Disease', 'MESH:D008175', (77, 88))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('tumor', 'Disease', (12, 17))	('lung cancer', 'Disease', (77, 88))
359718	31993222	We found that F-PLP/pBIM also significantly inhibited the growth of subcutaneous tumors.	('subcutaneous tumors', 'Disease', (68, 87))	('F-PLP/pBIM', 'Var', (14, 24))	('inhibited', 'NegReg', (44, 53))	('subcutaneous tumors', 'Phenotype', 'HP:0001482', (68, 87))	('subcutaneous tumors', 'Disease', 'MESH:D013352', (68, 87))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))
359727	31993222	This finding is supported by our current data indicating that F-PLP/pBIM significantly suppresses tumor proliferation, as determined by Ki67 expression analysis.	('F-PLP/pBIM', 'Var', (62, 72))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('Ki67', 'Gene', (136, 140))	('tumor', 'Disease', (98, 103))	('Ki67', 'Gene', '17345', (136, 140))	('suppresses', 'NegReg', (87, 97))
359728	31993222	We also demonstrated that the induction of apoptosis in the F-PLP/pBIM group was much greater than that in other groups by TUNEL staining, and the percentage of apoptosis of folate-targeted cells was greater than that of nontargeted cells.	('folate', 'Chemical', 'MESH:D005492', (174, 180))	('apoptosis', 'CPA', (43, 52))	('F-PLP/pBIM', 'Var', (60, 70))
359733	31993222	However, the number of TAMs was significantly lower in the F-PLP/pBIM group than in the other groups.	('F-PLP/pBIM', 'Var', (59, 69))	('lower', 'NegReg', (46, 51))	('TAM', 'Chemical', 'MESH:C419191', (23, 26))
359746	31993222	In vivo antitumor experiments demonstrated that F-PLP/pBIM significantly inhibited lung cancer growth and reduced both the number of tumor nodules and tumor weight.	('men', 'Species', '9606', (24, 27))	('lung cancer', 'Disease', 'MESH:D008175', (83, 94))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('tumor', 'Disease', (151, 156))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('lung cancer', 'Disease', (83, 94))	('inhibited', 'NegReg', (73, 82))	('lung cancer', 'Phenotype', 'HP:0100526', (83, 94))	('tumor', 'Disease', (133, 138))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('tumor', 'Disease', (12, 17))	('F-PLP/pBIM', 'Var', (48, 58))	('reduced', 'NegReg', (106, 113))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
359755	28528867	A Pan-Cancer Proteogenomic Atlas of PI3K/AKT/mTOR Pathway Alterations Molecular alterations involving PI3K/AKT/mTOR pathway (including mutation, copy number, protein, or RNA) were examined across 11219 human cancers representing 32 major types.	('Pan-Cancer', 'Disease', (2, 12))	('PI3K/AKT', 'Gene', (102, 110))	('human', 'Species', '9606', (202, 207))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('AKT', 'Gene', '207', (41, 44))	('PI3K/AKT', 'Gene', '5295;207', (102, 110))	('PI3K/AKT', 'Gene', (36, 44))	('cancers', 'Phenotype', 'HP:0002664', (208, 215))	('cancers', 'Disease', (208, 215))	('PI3K/AKT', 'Gene', '5295;207', (36, 44))	('AKT', 'Gene', (107, 110))	('mTOR', 'Gene', (111, 115))	('Pan-Cancer', 'Disease', 'MESH:C537931', (2, 12))	('AKT', 'Gene', (41, 44))	('mTOR', 'Gene', (45, 49))	('mTOR', 'Gene', '2475', (111, 115))	('cancers', 'Disease', 'MESH:D009369', (208, 215))	('Cancer', 'Phenotype', 'HP:0002664', (6, 12))	('copy number', 'Var', (145, 156))	('mTOR', 'Gene', '2475', (45, 49))	('AKT', 'Gene', '207', (107, 110))
359757	28528867	In addition to mutation, structural variations and partial copy losses involving PTEN and STK11 showed evidence for having functional relevance.	('structural variations', 'Var', (25, 46))	('STK11', 'Gene', (90, 95))	('PTEN', 'Gene', (81, 85))	('partial copy losses', 'Var', (51, 70))	('STK11', 'Gene', '6794', (90, 95))
359758	28528867	A substantial fraction of cancers showed high mTOR pathway activity without an associated canonical genetic or genomic alteration, including cancers harboring IDH1 or VHL mutations, suggesting multiple mechanisms for pathway activation.	('activity', 'MPA', (59, 67))	('cancers', 'Disease', 'MESH:D009369', (141, 148))	('cancers', 'Phenotype', 'HP:0002664', (26, 33))	('IDH1', 'Gene', (159, 163))	('VHL', 'Disease', (167, 170))	('VHL', 'Disease', 'MESH:D006623', (167, 170))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('cancers', 'Disease', 'MESH:D009369', (26, 33))	('IDH1', 'Gene', '3417', (159, 163))	('cancers', 'Disease', (26, 33))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('cancers', 'Phenotype', 'HP:0002664', (141, 148))	('mTOR pathway', 'Pathway', (46, 58))	('mutations', 'Var', (171, 180))	('cancers', 'Disease', (141, 148))
359766	28528867	AKT is phosphorylated at Thr308 by PDK1 and at Ser473 by mTOR complex 2 (mTORC2), which increases its kinase activity.	('mTORC2', 'Gene', '74343', (73, 79))	('mTORC2', 'Gene', (73, 79))	('Thr308', 'Chemical', '-', (25, 31))	('Ser473', 'Chemical', '-', (47, 53))	('AKT', 'Pathway', (0, 3))	('increases', 'PosReg', (88, 97))	('kinase activity', 'MPA', (102, 117))	('PDK1', 'Gene', '5163', (35, 39))	('Thr308', 'Var', (25, 31))	('PDK1', 'Gene', (35, 39))
359774	28528867	PIK3R1 and less commonly PIK3R2, which encode the p85alpha and p85beta regulatory subunits of PI3K, are commonly mutated, resulting in reduced ability to inhibit PI3K p110a.	('p85beta', 'Gene', (63, 70))	('PI3', 'Gene', (94, 97))	('PI3', 'Gene', (162, 165))	('PIK3R2', 'Gene', (25, 31))	('PIK3R2', 'Gene', '5296', (25, 31))	('p110a', 'Gene', (167, 172))	('ability', 'MPA', (143, 150))	('inhibit', 'NegReg', (154, 161))	('PIK3R1', 'Gene', (0, 6))	('p85alpha', 'Gene', '5295', (50, 58))	('p85beta', 'Gene', '5296', (63, 70))	('p110a', 'Gene', '5290', (167, 172))	('PI3', 'Gene', '5266', (94, 97))	('reduced', 'NegReg', (135, 142))	('mutated', 'Var', (113, 120))	('PI3', 'Gene', '5266', (162, 165))	('p85alpha', 'Gene', (50, 58))
359776	28528867	AKT1 is occasionally activated by mutation at a single site, E17K.	('E17K', 'Var', (61, 65))	('AKT1', 'Gene', '207', (0, 4))	('AKT1', 'Gene', (0, 4))	('activated', 'PosReg', (21, 30))	('E17K', 'Mutation', 'rs121434592', (61, 65))
359777	28528867	Inactivating mutations in both TSC1 and TSC2 have been identified in cancer at low frequency, as well as activating mutations in MTOR .	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('MTOR', 'Gene', (129, 133))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('Inactivating mutations', 'Var', (0, 22))	('TSC2', 'Gene', '7249', (40, 44))	('MTOR', 'Gene', '2475', (129, 133))	('TSC1', 'Gene', '7248', (31, 35))	('TSC2', 'Gene', (40, 44))	('TSC1', 'Gene', (31, 35))	('cancer', 'Disease', (69, 75))
359778	28528867	RHEB mutations are rare but focal at Y35, suggesting a driver effect.	('RHEB', 'Gene', '6009', (0, 4))	('Y35', 'Var', (37, 40))	('RHEB', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))
359798	28528867	With the notable exception of AKT3, copy number alterations of PI3K/AKT/mTOR pathway member genes were highly correlated with their mRNA expression (Figure S2A).	('mRNA expression', 'MPA', (132, 147))	('AKT3', 'Gene', '10000', (30, 34))	('correlated', 'Reg', (110, 120))	('AKT3', 'Gene', (30, 34))	('PI3K/AKT', 'Gene', (63, 71))	('copy number alterations', 'Var', (36, 59))	('PI3K/AKT', 'Gene', '5295;207', (63, 71))
359801	28528867	Out of 1363 cases with WGS data available (1218 by low-pass sequencing), 63 cases (~5%) harbored a rearrangement within pathway suppressor genes PTEN (39 cases), INPP4B (14), STK11 (5), TSC1 (2), TSC2 (2), PIK3R1 (2), or PPP2R1A (2)(Figure 2C).	('PTEN', 'Gene', (145, 149))	('TSC1', 'Gene', (186, 190))	('rearrangement', 'Var', (99, 112))	('STK11', 'Gene', (175, 180))	('PIK3R1', 'Gene', (206, 212))	('PPP2R1A', 'Gene', (221, 228))	('INPP4B', 'Gene', '8821', (162, 168))	('STK11', 'Gene', '6794', (175, 180))	('PPP2R1A', 'Gene', '5518', (221, 228))	('INPP4B', 'Gene', (162, 168))	('TSC1', 'Gene', '7248', (186, 190))	('TSC2', 'Gene', '7249', (196, 200))	('TSC2', 'Gene', (196, 200))
359802	28528867	By structural variation (SV), copy loss (partial or total), or mutation, PTEN was found altered in 40% of cancers with both RPPA and WGS data, with PTEN protein expression most impacted in tumors with SV, homozygous loss, or nonsense/indel/frameshift mutations (Figure 2D).	('copy loss', 'Var', (30, 39))	('PTEN', 'Gene', (148, 152))	('cancers', 'Phenotype', 'HP:0002664', (106, 113))	('cancers', 'Disease', (106, 113))	('altered', 'Reg', (88, 95))	('impacted', 'Reg', (177, 185))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('expression', 'MPA', (161, 171))	('tumors', 'Phenotype', 'HP:0002664', (189, 195))	('SV', 'Disease', 'None', (201, 203))	('PTEN', 'Gene', (73, 77))	('SV', 'Disease', 'None', (25, 27))	('tumors', 'Disease', (189, 195))	('mutation', 'Var', (63, 71))	('homozygous loss', 'Var', (205, 220))	('cancers', 'Disease', 'MESH:D009369', (106, 113))	('nonsense/indel/frameshift mutations', 'Var', (225, 260))	('protein', 'Protein', (153, 160))	('tumors', 'Disease', 'MESH:D009369', (189, 195))
359804	28528867	Furthermore, high-level and low-level copy number loss for several pathway genes were strongly correlated with reduced mRNA levels (Figure S2B), and 20 cases harbored candidate gene fusions involving PIK3CA, AKT1, AKT2, AKT3, or MTOR (Figure S2C and Table S3).	('AKT3', 'Gene', '10000', (220, 224))	('MTOR', 'Gene', (229, 233))	('harbored', 'Reg', (158, 166))	('loss', 'NegReg', (50, 54))	('AKT2', 'Gene', (214, 218))	('reduced', 'NegReg', (111, 118))	('copy number', 'Var', (38, 49))	('AKT1', 'Gene', '207', (208, 212))	('PIK3CA', 'Gene', (200, 206))	('AKT2', 'Gene', '208', (214, 218))	('MTOR', 'Gene', '2475', (229, 233))	('mRNA levels', 'MPA', (119, 130))	('fusions', 'Interaction', (182, 189))	('AKT1', 'Gene', (208, 212))	('AKT3', 'Gene', (220, 224))
359805	28528867	A large proportion of mutations identified in driver genes that activate PI3K/AKT/mTOR are of low occurrence, highlighting the need to functionally annotate the long tail of infrequent mutations present in heterogeneous cancers .	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('PI3K/AKT', 'Gene', '5295;207', (73, 81))	('cancers', 'Phenotype', 'HP:0002664', (220, 227))	('mutations', 'Var', (22, 31))	('long tail', 'Phenotype', 'HP:0002831', (161, 170))	('cancers', 'Disease', (220, 227))	('cancers', 'Disease', 'MESH:D009369', (220, 227))	('PI3K/AKT', 'Gene', (73, 81))
359806	28528867	For example, PIK3CA is the gene most commonly activated by mutation in the cancer genome, with mutations being most frequent at positions E542, E545, and H1047 (Figure 3A); on the other hand, 13% of PIK3CA mutations observed occurred in a single case and showed no significant pattern of occurrence.	('mutations', 'Var', (206, 215))	('E545', 'Var', (144, 148))	('PIK3CA', 'Gene', (199, 205))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('cancer', 'Disease', (75, 81))	('H1047', 'Var', (154, 159))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('E542', 'Var', (138, 142))
359807	28528867	Somatic copy alteration represents another potential mechanism for altering gene function, where for example, amplification of PIK3CA impacts p110alpha protein expression (Figure 3B).	('p110alpha', 'Gene', (142, 151))	('impacts', 'Reg', (134, 141))	('amplification', 'Var', (110, 123))	('PIK3CA', 'Gene', (127, 133))	('p110alpha', 'Gene', '5290', (142, 151))
359808	28528867	Previous pan-cancer sequence analyses  have identified recurrent mutational hotspots, where such hotspots would presumably have greater impact on protein function.	('cancer', 'Disease', (13, 19))	('cancer', 'Disease', 'MESH:D009369', (13, 19))	('mutational', 'Var', (65, 75))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))
359809	28528867	In the case of PIK3CA, 73% of somatic, nonsilent mutation variants identified in TCGA pan-cancer cohort involved a hotspot residue as identified by Chang et al., while 13% of PIK3R1 mutations and 7% of MTOR mutations involved a hotspot residue (Figure 3C).	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('variants', 'Var', (58, 66))	('hotspot', 'MPA', (115, 122))	('involved', 'Reg', (217, 225))	('mutations', 'Var', (207, 216))	('involved', 'Reg', (104, 112))	('MTOR', 'Gene', (202, 206))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('cancer', 'Disease', (90, 96))	('MTOR', 'Gene', '2475', (202, 206))	('mutations', 'Var', (182, 191))	('PIK3R1', 'Gene', (175, 181))
359811	28528867	For each of the genes considered (AKT1, MTOR, PIK3CA, PIK3R1, PTEN), tumors harboring mutations that were predicted to have functional effects had elevated phospho-AKT levels on average, as compared to tumors that did not harbor an alteration; in addition, tumors with mutations not predicted to be functional showed either a lesser effect or no significant effect on phospho-AKT.	('tumors', 'Disease', 'MESH:D009369', (257, 263))	('tumors', 'Disease', 'MESH:D009369', (202, 208))	('elevated', 'PosReg', (147, 155))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('MTOR', 'Gene', (40, 44))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('MTOR', 'Gene', '2475', (40, 44))	('mutations', 'Var', (86, 95))	('AKT1', 'Gene', '207', (34, 38))	('tumors', 'Phenotype', 'HP:0002664', (202, 208))	('phospho-AKT levels', 'MPA', (156, 174))	('tumors', 'Phenotype', 'HP:0002664', (257, 263))	('tumors', 'Disease', (69, 75))	('tumor', 'Phenotype', 'HP:0002664', (257, 262))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('AKT1', 'Gene', (34, 38))	('tumors', 'Disease', (257, 263))	('tumors', 'Disease', (202, 208))	('tumors', 'Disease', 'MESH:D009369', (69, 75))
359813	28528867	Using MCF10A and Ba/F3 cells, 69 different nonsilent PIK3CA mutation variants were functionally assessed in vitro for their activating potential (Figures 4A and S4 and Table S5).	('MCF10A', 'CellLine', 'CVCL:0598', (6, 12))	('variants', 'Var', (69, 77))	('activating potential', 'MPA', (124, 144))	('mutation variants', 'Var', (60, 77))	('PIK3CA', 'Gene', (53, 59))
359814	28528867	When the results of the functional studies were aligned with data from TCGA, a significant trend was observed for both PIK3CA and PIK3R1, whereby variants that were associated with functionality in vitro had a higher frequency of occurrence in human tumors (Figure 4C), suggesting that natural selection favored tumor development for those variants with greater functional effects.	('human', 'Species', '9606', (244, 249))	('PIK3CA', 'Gene', (119, 125))	('tumor', 'Disease', 'MESH:D009369', (312, 317))	('tumors', 'Disease', (250, 256))	('tumor', 'Disease', 'MESH:D009369', (250, 255))	('tumor', 'Phenotype', 'HP:0002664', (312, 317))	('tumors', 'Phenotype', 'HP:0002664', (250, 256))	('variants', 'Var', (146, 154))	('tumor', 'Phenotype', 'HP:0002664', (250, 255))	('favored', 'PosReg', (304, 311))	('tumor', 'Disease', (312, 317))	('tumors', 'Disease', 'MESH:D009369', (250, 256))	('higher', 'PosReg', (210, 216))	('tumor', 'Disease', (250, 255))	('PIK3R1', 'Gene', (130, 136))
359815	28528867	Most variants showing some functionality also had higher phospho-AKT on average, as compared to tumors with the corresponding wild-type gene (Figures 4A and 4B), though variants associated with higher phospho-AKT were not necessarily associated with higher phospho-TSC2 (downstream in the pathway from AKT).	('higher', 'PosReg', (194, 200))	('higher', 'PosReg', (50, 56))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('phospho-AKT', 'MPA', (201, 212))	('tumors', 'Disease', (96, 102))	('phospho-AKT', 'MPA', (57, 68))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('TSC2', 'Gene', '7249', (265, 269))	('TSC2', 'Gene', (265, 269))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('variants', 'Var', (5, 13))	('variants', 'Var', (169, 177))
359818	28528867	MTOR, RPTOR) resulted in gene signature patterns inversely correlated to those of our PI3K/AKT/mTOR signature, while knockdown of pathway suppressors (e.g.	('PI3K/AKT', 'Gene', (86, 94))	('RPTOR', 'Gene', (6, 11))	('PI3K/AKT', 'Gene', '5295;207', (86, 94))	('RPTOR', 'Gene', '57521', (6, 11))	('MTOR', 'Gene', (0, 4))	('knockdown', 'Var', (117, 126))	('MTOR', 'Gene', '2475', (0, 4))
359820	28528867	Notably, knockdown of MYC and KRAS also suppressed the PI3K/AKT/mTOR signature; furthermore, when scoring TCGA pan-cancer mRNA profiles for pre-defined signatures of PI3K/AKT/mTOR, MYC, and k-ras, cancers scoring high for PI3K/AKT/mTOR also tended to score high for MYC and k-ras (Figures 5C, S5A, and S5B), suggesting that multiple oncogenic signaling pathways may converge on similar sets of transcriptional targets.	('MYC', 'Gene', '4609', (22, 25))	('cancer', 'Disease', 'MESH:D009369', (197, 203))	('cancers', 'Disease', 'MESH:D009369', (197, 204))	('PI3K/AKT', 'Gene', '5295;207', (55, 63))	('PI3K/AKT', 'Gene', (222, 230))	('PI3K/AKT', 'Gene', '5295;207', (166, 174))	('k-ras', 'Gene', (190, 195))	('MYC', 'Gene', '4609', (181, 184))	('KRAS', 'Gene', (30, 34))	('PI3K/AKT', 'Gene', '5295;207', (222, 230))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('suppressed', 'NegReg', (40, 50))	('MYC', 'Gene', '4609', (266, 269))	('S5B', 'Gene', (302, 305))	('KRAS', 'Gene', '3845', (30, 34))	('k-ras', 'Gene', '3845', (274, 279))	('knockdown', 'Var', (9, 18))	('cancers', 'Phenotype', 'HP:0002664', (197, 204))	('cancer', 'Disease', (197, 203))	('cancers', 'Disease', (197, 204))	('MYC', 'Gene', (22, 25))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('k-ras', 'Gene', (274, 279))	('high', 'Reg', (257, 261))	('MYC', 'Gene', (181, 184))	('cancer', 'Disease', (115, 121))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('S5B', 'Gene', '5711', (302, 305))	('k-ras', 'Gene', '3845', (190, 195))	('MYC', 'Gene', (266, 269))	('PI3K/AKT', 'Gene', (55, 63))	('PI3K/AKT', 'Gene', (166, 174))
359834	28528867	Features significantly associated with worse patient outcome, independent of cancer type, included STK11 mutation, STK11 copy loss, PTEN copy loss, PIK3CA amplification, and higher phospho-4EBP1 expression.	('4EBP1', 'Gene', (189, 194))	('amplification', 'Var', (155, 168))	('mutation', 'Var', (105, 113))	('STK11', 'Gene', (99, 104))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('PTEN copy loss', 'Disease', (132, 146))	('higher', 'PosReg', (174, 180))	('patient', 'Species', '9606', (45, 52))	('STK11', 'Gene', (115, 120))	('PTEN copy loss', 'Disease', 'MESH:D006223', (132, 146))	('STK11', 'Gene', '6794', (99, 104))	('PIK3CA', 'Gene', (148, 154))	('4EBP1', 'Gene', '1978', (189, 194))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('copy', 'Var', (121, 125))	('STK11', 'Gene', '6794', (115, 120))
359835	28528867	Focusing on PTEN and STK11 copy alterations, these features were found significant within several individual cancer types, with the aggregated patterns across cancer types denoting pan-cancer significance (Figure 6B).	('cancer', 'Disease', (159, 165))	('significant', 'Reg', (71, 82))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('cancer', 'Disease', (109, 115))	('STK11', 'Gene', (21, 26))	('PTEN', 'Gene', (12, 16))	('copy alterations', 'Var', (27, 43))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('STK11', 'Gene', '6794', (21, 26))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('cancer', 'Disease', (185, 191))
359836	28528867	Interestingly, for both PTEN and STK11, low level deletion (approximating partial copy loss) but not high level deletion (approximating total loss) was associated with significantly worse outcome compared to wild-type (Figures 6C and 6D); loss of one copy combined with somatic mutation of the other copy was associated with the poorest outcome.	('loss', 'Var', (239, 243))	('STK11', 'Gene', (33, 38))	('PTEN', 'Gene', (24, 28))	('STK11', 'Gene', '6794', (33, 38))
359837	28528867	For both PTEN and STK11, neither high-level deletion nor mutation without copy loss could be associated with worse outcome, where in this instance, survival differences by tumor type were a likely confounder (e.g.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('PTEN', 'Gene', (9, 13))	('tumor', 'Disease', (172, 177))	('deletion', 'Var', (44, 52))	('STK11', 'Gene', (18, 23))	('STK11', 'Gene', '6794', (18, 23))	('tumor', 'Disease', 'MESH:D009369', (172, 177))
359838	28528867	65% of the PTEN mutation with no copy alteration group were UCEC:or uterine corpus endometrial carcinoma:cases).	('PTEN', 'Gene', (11, 15))	('mutation', 'Var', (16, 24))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (83, 104))	('endometrial carcinoma', 'Disease', (83, 104))	('UCEC', 'Disease', (60, 64))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (83, 104))
359840	28528867	We then sought to examine the effects on pathway activation of some key genomic events in the tumors in which they occurred (including mutations represented in Figure 2A and copy alterations involving PIK3CA, PTEN, and STK11).	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('mutations', 'Var', (135, 144))	('copy alterations', 'Var', (174, 190))	('STK11', 'Gene', (219, 224))	('tumors', 'Disease', (94, 100))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('PIK3CA', 'Gene', (201, 207))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('STK11', 'Gene', '6794', (219, 224))	('PTEN', 'Gene', (209, 213))
359841	28528867	Of the 7099 tumor cases examined (with both mutation and protein data), 4468 (63%) harbored at least one nonsilent somatic mutation or copy alteration involving PI3K/AKT/mTOR pathway (Figures 7A and S6A).	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('PI3K/AKT', 'Gene', (161, 169))	('tumor', 'Disease', (12, 17))	('PI3K/AKT', 'Gene', '5295;207', (161, 169))	('copy alteration', 'Var', (135, 150))
359843	28528867	In comparison to a set of tumors that did not show pathway alteration at the DNA or protein level (an "unaligned" set, n=1058), mutation or copy alteration of individual PI3K/AKT/mTOR pathway members in general could be associated with higher PI3K/AKT or mTOR signaling as measured by protein arrays (Figures 7B and S6B).	('PI3K/AKT', 'Gene', (170, 178))	('copy alteration', 'Var', (140, 155))	('higher', 'PosReg', (236, 242))	('mTOR signaling', 'Pathway', (255, 269))	('PI3K/AKT', 'Gene', (243, 251))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('PI3K/AKT', 'Gene', '5295;207', (170, 178))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('PI3K/AKT', 'Gene', '5295;207', (243, 251))	('mutation', 'Var', (128, 136))	('tumors', 'Disease', (26, 32))
359844	28528867	Notably, STK11 alteration or low phospho-AMPK was strongly associated with high mTOR signaling but not with high PI3K/AKT signaling, consistent with the LKB1/AMPK pathway acting on mTOR independently of PI3K/AKT (Figure 2A).	('PI3K/AKT', 'Gene', '5295;207', (113, 121))	('PI3K/AKT', 'Gene', '5295;207', (203, 211))	('STK11', 'Gene', '6794', (9, 14))	('low', 'Var', (29, 32))	('PI3K/AKT', 'Gene', (113, 121))	('AMPK', 'Gene', '5562', (158, 162))	('associated', 'Reg', (59, 69))	('PI3K/AKT', 'Gene', (203, 211))	('AMPK', 'Gene', '5562', (41, 45))	('LKB1', 'Gene', (153, 157))	('AMPK', 'Gene', (41, 45))	('AMPK', 'Gene', (158, 162))	('high mTOR signaling', 'MPA', (75, 94))	('STK11', 'Gene', (9, 14))	('LKB1', 'Gene', '6794', (153, 157))	('alteration', 'Var', (15, 25))
359845	28528867	Mutations associated with Receptor Tyrosine Kinase (RTK) signaling were not strongly associated with PI3K/AKT/mTOR activation (Figures 7A and 7B), indicative of decoupling between PI3K/AKT/mTOR and RTK.	('PI3K/AKT', 'Gene', (101, 109))	('RTK', 'Gene', '5979', (198, 201))	('RTK', 'Gene', (52, 55))	('Receptor Tyrosine Kinase', 'Gene', (26, 50))	('PI3K/AKT', 'Gene', '5295;207', (180, 188))	('PI3K/AKT', 'Gene', '5295;207', (101, 109))	('Mutations', 'Var', (0, 9))	('RTK', 'Gene', '5979', (52, 55))	('RTK', 'Gene', (198, 201))	('Receptor Tyrosine Kinase', 'Gene', '5979', (26, 50))	('PI3K/AKT', 'Gene', (180, 188))
359846	28528867	Low-level as well as high-level copy losses of PTEN and STK11 could be associated with greater mTOR signaling.	('greater', 'PosReg', (87, 94))	('STK11', 'Gene', (56, 61))	('PTEN', 'Gene', (47, 51))	('mTOR signaling', 'MPA', (95, 109))	('STK11', 'Gene', '6794', (56, 61))	('copy losses', 'Var', (32, 43))
359847	28528867	PI3K/AKT/mTOR pathway activity, when measured at the protein level, was explained by known mutations or copy alteration in most but not all of the cases examined, suggesting additional, unexplained or underappreciated mechanisms of pathway activation.	('PI3K/AKT', 'Gene', '5295;207', (0, 8))	('copy alteration', 'Var', (104, 119))	('mutations', 'Var', (91, 100))	('PI3K/AKT', 'Gene', (0, 8))	('activity', 'MPA', (22, 30))
359848	28528867	Focusing on the "High P-AKT" tumor group (n=764), with high phospho-AKT but lacking a DNA alteration classically associated with PI3K/AKT activation, these tumors were highly enriched for specific cancer types including LGG, PRAD, KIRC, and PCPG (Figure 7C), as well as for IDH1 mutations (associated primarily with LGG, i.e.	('cancer', 'Disease', 'MESH:D009369', (197, 203))	('PRAD', 'Disease', (225, 229))	('P-AKT" tumor', 'Disease', (22, 34))	('mutations', 'Var', (279, 288))	('P-AKT" tumor', 'Disease', 'MESH:C000656865', (22, 34))	('LGG', 'Disease', (316, 319))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('KIRC', 'Disease', (231, 235))	('LGG', 'Disease', (220, 223))	('PI3K/AKT', 'Gene', (129, 137))	('cancer', 'Disease', (197, 203))	('IDH1', 'Gene', (274, 278))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('PI3K/AKT', 'Gene', '5295;207', (129, 137))	('tumors', 'Disease', (156, 162))	('PCPG', 'Disease', (241, 245))	('IDH1', 'Gene', '3417', (274, 278))	('tumors', 'Disease', 'MESH:D009369', (156, 162))
359849	28528867	gliomas) and VHL mutations (associated with renal cancers).	('renal cancers', 'Disease', (44, 57))	('VHL', 'Disease', (13, 16))	('VHL', 'Disease', 'MESH:D006623', (13, 16))	('cancers', 'Phenotype', 'HP:0002664', (50, 57))	('associated', 'Reg', (28, 38))	('glioma', 'Phenotype', 'HP:0009733', (0, 6))	('renal cancers', 'Disease', 'MESH:D007680', (44, 57))	('gliomas', 'Disease', (0, 7))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('gliomas', 'Disease', 'MESH:D005910', (0, 7))	('mutations', 'Var', (17, 26))	('gliomas', 'Phenotype', 'HP:0009733', (0, 7))
359851	28528867	These mutations and proteins would suggest a model (Figure 7E), whereby mutant IDH1 may lead to high phospho-ERK, and SRC can activate PI3K  and where activated mTOR signaling may activate transcription targets of hypoxia via HIF-1alpha (particularly in the absence of VHL), including NDRG1 and growth factors that may lead to a further increase ERK and PI3K signaling.	('NDRG1', 'Gene', (285, 290))	('PI3', 'Gene', (354, 357))	('activate', 'PosReg', (126, 134))	('hypoxia via HIF-1alpha', 'Disease', (214, 236))	('VHL', 'Disease', 'MESH:D006623', (269, 272))	('activate', 'PosReg', (180, 188))	('IDH1', 'Gene', (79, 83))	('ERK', 'Gene', (346, 349))	('SRC', 'Gene', '6714', (118, 121))	('mutant', 'Var', (72, 78))	('PI3', 'Gene', '5266', (135, 138))	('IDH1', 'Gene', '3417', (79, 83))	('increase', 'PosReg', (337, 345))	('SRC', 'Gene', (118, 121))	('ERK', 'Gene', '5594', (109, 112))	('VHL', 'Disease', (269, 272))	('PI3', 'Gene', '5266', (354, 357))	('NDRG1', 'Gene', '10397', (285, 290))	('hypoxia via HIF-1alpha', 'Disease', 'MESH:D000860', (214, 236))	('PI3', 'Gene', (135, 138))	('ERK', 'Gene', '5594', (346, 349))	('ERK', 'Gene', (109, 112))
359852	28528867	Notably, VHL was recently found to directly suppress AKT activity, and generation of 2-hydroxyglutarate (2HG) by mutated IDH1/2 was also recently found to lead to the activation of mTOR; our data here would highlight the importance of both of the above relationships in the setting of human cancer.	('mTOR', 'Pathway', (181, 185))	('cancer', 'Disease', (291, 297))	('cancer', 'Disease', 'MESH:D009369', (291, 297))	('AKT', 'Pathway', (53, 56))	('IDH1/2', 'Gene', '3417;3418', (121, 127))	('activation', 'PosReg', (167, 177))	('human', 'Species', '9606', (285, 290))	('suppress', 'NegReg', (44, 52))	('mutated', 'Var', (113, 120))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (85, 103))	('IDH1/2', 'Gene', (121, 127))	('VHL', 'Disease', 'MESH:D006623', (9, 12))	('VHL', 'Disease', (9, 12))	('cancer', 'Phenotype', 'HP:0002664', (291, 297))
359857	28528867	Most of the correlations observed in our study fit well with our understanding of PI3K/AKT/mTOR signaling, in particular the genetic or genomic alteration of specific genes having an impact on phospho-protein expression of key downstream intermediates.	('PI3K/AKT', 'Gene', (82, 90))	('alteration', 'Var', (144, 154))	('PI3K/AKT', 'Gene', '5295;207', (82, 90))	('phospho-protein expression', 'MPA', (193, 219))	('impact', 'Reg', (183, 189))
359859	28528867	Where gene mutation often inactivates one allele, loss of one allele by copy alteration, which is common across multiple cancer types for both PTEN and STK11, would presumably have the same impact on loss of gene function.	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('loss', 'NegReg', (50, 54))	('copy alteration', 'Var', (72, 87))	('inactivates', 'NegReg', (26, 37))	('STK11', 'Gene', (152, 157))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('mutation', 'Var', (11, 19))	('cancer', 'Disease', (121, 127))	('STK11', 'Gene', '6794', (152, 157))
359860	28528867	IDH1 and VHL mutations would also be implicated here with PI3K/AKT/mTOR, where such alterations were associated with particularly high AKT/mTOR signaling, and which genes might be put forth for consideration as part of the "canon" of what would be recognized to constitute the core standard model of PI3K/AKT/mTOR pathway.	('IDH1', 'Gene', '3417', (0, 4))	('PI3K/AKT', 'Gene', '5295;207', (300, 308))	('PI3K/AKT', 'Gene', (58, 66))	('implicated', 'Reg', (37, 47))	('PI3K/AKT', 'Gene', '5295;207', (58, 66))	('high', 'PosReg', (130, 134))	('associated', 'Reg', (101, 111))	('AKT/mTOR signaling', 'MPA', (135, 153))	('IDH1', 'Gene', (0, 4))	('mutations', 'Var', (13, 22))	('VHL', 'Disease', 'MESH:D006623', (9, 12))	('VHL', 'Disease', (9, 12))	('PI3K/AKT', 'Gene', (300, 308))
359869	28528867	Results of this study include a comprehensive and annotated catalog of PI3K/AKT/mTOR-associated variants across over 10,000 tumors, which may serve as an additional resource for assessing variants in the clinical setting.	('000 tumors', 'Disease', 'MESH:D009369', (120, 130))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('variants', 'Var', (96, 104))	('PI3K/AKT', 'Gene', (71, 79))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('000 tumors', 'Disease', (120, 130))	('PI3K/AKT', 'Gene', '5295;207', (71, 79))
359872	28528867	PIK3CA mutation, has been shown to increase response rates in clinical trials testing inhibitors to PI3K/AKT/mTOR pathway, though non-responders are still common.	('PI3K/AKT', 'Gene', '5295;207', (100, 108))	('increase', 'PosReg', (35, 43))	('response', 'MPA', (44, 52))	('PIK3CA', 'Gene', (0, 6))	('PI3K/AKT', 'Gene', (100, 108))	('mutation', 'Var', (7, 15))
359888	28528867	Pan-cancer RPPA profiles were scored for a PI3K/AKT pathway signature, defined as the sum of normalized phosphoprotein levels of AKT (both S473 and T308 RPPA features), GSK3 (S9 and S21/S9 features), PRAS40, and phospho-TSC2.	('TSC2', 'Gene', '7249', (220, 224))	('S9', 'Var', (175, 177))	('PRAS40', 'Gene', '84335', (200, 206))	('Pan-cancer', 'Disease', (0, 10))	('TSC2', 'Gene', (220, 224))	('PI3K/AKT', 'Gene', (43, 51))	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('AKT', 'Pathway', (129, 132))	('T308 RPPA', 'Var', (148, 157))	('Pan-cancer', 'Disease', 'MESH:C537931', (0, 10))	('PI3K/AKT', 'Gene', '5295;207', (43, 51))	('PRAS40', 'Gene', (200, 206))	('S21/S9 features', 'Var', (182, 197))
359889	28528867	RPPA profiles were also scored for an mTOR pathway signature, defined as the sum of phosphoprotein levels of mTOR, 4EBP1 (S65, T37/T46, and T70 RPPA features), P70S6K, and S6 (S235/S236 and S240/S244 features).	('4EBP1', 'Gene', '1978', (115, 120))	('S240/S244 features', 'Var', (190, 208))	('P70S6K', 'Gene', (160, 166))	('4EBP1', 'Gene', (115, 120))	('mTOR', 'Gene', (109, 113))	('S65', 'Var', (122, 125))	('S235/S236', 'Var', (176, 185))	('T70 RPPA', 'Var', (140, 148))	('T37/T46', 'Var', (127, 134))	('P70S6K', 'Gene', '6198', (160, 166))
359897	28528867	Manual review of variants involving AKT1/2/3, MTOR, PIK3CA, PTEN, RHEB, TSC1/2 was also carried out by domain experts in the analysis group.	('MTOR', 'Gene', (46, 50))	('TSC1/2', 'Gene', (72, 78))	('variants', 'Var', (17, 25))	('AKT1/2/3', 'Gene', (36, 44))	('PIK3CA', 'Gene', (52, 58))	('MTOR', 'Gene', '2475', (46, 50))	('RHEB', 'Gene', (66, 70))	('PTEN', 'Gene', (60, 64))	('RHEB', 'Gene', '6009', (66, 70))	('AKT1/2/3', 'Gene', '207;208;10000', (36, 44))	('TSC1/2', 'Gene', '7248;7249', (72, 78))
359898	28528867	Mutations that were predicted as potentially functional by any of the above:as well as mutations in tumor suppressor genes (e.g.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Disease', (100, 105))	('Mutations', 'Var', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('mutations', 'Var', (87, 96))
359899	28528867	The effects of mutations on the function of PIK3CA and PIK3R1 were assessed in Ba/F3 and MCF10A by survival assay as previously described  with lentiviral vector pHAGE used in the cloning.	('PIK3CA', 'Gene', (44, 50))	('PIK3R1', 'Gene', (55, 61))	('mutations', 'Var', (15, 24))	('MCF10A', 'CellLine', 'CVCL:0598', (89, 95))
359900	28528867	In Ba/F3, the PIK3CA mutations were assigned as "Strong activating (SA)" if the mutations have an activity higher than M1043I (known moderate driver); as "Moderate activating (MA)" if the mutations have a similar or lower activity than M1043I; as "No difference from WT (NDFW)" if the mutations have a similar activity with WT; or as "Inactivating (INA)" if the mutations have an activity similar to negative controls (GFP/mCherry/Luciferase).	('M1043I', 'Mutation', 'rs121913283', (236, 242))	('lower', 'NegReg', (216, 221))	('mutations', 'Var', (80, 89))	('M1043I', 'Mutation', 'rs121913283', (119, 125))	('higher', 'PosReg', (107, 113))	('PIK3CA', 'Gene', (14, 20))	('activity', 'MPA', (222, 230))	('activity', 'MPA', (98, 106))	('mutations', 'Var', (21, 30))
359901	28528867	The PIK3R1 mutations were assigned as "SA" if the mutations have a relative level of activation higher than that of PIK3CA M1043I comparing to negative controls; as "MA" if the mutations have a relative level of activation between PIK3CA M1043I and WT; as "Weak activating (WA)" if the mutations have a relative level of activation between PIK3CA WT and negative controls; or as "NDFW" if the mutations have a similar activity with WT.	('mutations', 'Var', (11, 20))	('activating', 'MPA', (262, 272))	('PIK3R1', 'Gene', (4, 10))	('M1043I', 'Mutation', 'rs121913283', (123, 129))	('activation higher', 'PosReg', (85, 102))	('M1043I', 'Mutation', 'rs121913283', (238, 244))	('PIK3CA M1043I', 'Var', (231, 244))
359902	28528867	In MCF10A, the PIK3CA mutations were assigned as "SA" and "NDFW" by the same mean as in Ba/F3 model.	('MCF10A', 'CellLine', 'CVCL:0598', (3, 9))	('mutations', 'Var', (22, 31))	('PIK3CA', 'Gene', (15, 21))
359903	28528867	The mutations were assigned as "MA" and "WA" if the mutations have an activity above and lower than 50% of that of M1043I, respectively.	('mutations', 'Var', (52, 61))	('M1043I', 'Mutation', 'rs121913283', (115, 121))	('lower', 'NegReg', (89, 94))	('activity', 'MPA', (70, 78))
359906	28528867	An "other gene mutation" class of Figures 7A and 7B involved nonsilent mutations for other genes represented in Figure 2A (AKTS1, DEPDC5, DEPTOR, MAPKAP1, MLST8, NPRL2, NPRL3, PDK1, PRR5, RHEB, RICTOR, RPTOR, PIK3C2B).	('RICTOR', 'Gene', (194, 200))	('MAPKAP1', 'Gene', '79109', (146, 153))	('DEPTOR', 'Gene', '64798', (138, 144))	('RPTOR', 'Gene', (202, 207))	('MLST8', 'Gene', '64223', (155, 160))	('PDK1', 'Gene', '5163', (176, 180))	('MLST8', 'Gene', (155, 160))	('NPRL3', 'Gene', (169, 174))	('RHEB', 'Gene', '6009', (188, 192))	('PIK3C2B', 'Gene', (209, 216))	('DEPDC5', 'Gene', '9681', (130, 136))	('PRR5', 'Gene', (182, 186))	('mutations', 'Var', (71, 80))	('DEPDC5', 'Gene', (130, 136))	('MAPKAP1', 'Gene', (146, 153))	('DEPTOR', 'Gene', (138, 144))	('PRR5', 'Gene', '55615', (182, 186))	('NPRL2', 'Gene', '10641', (162, 167))	('PIK3C2B', 'Gene', '5287', (209, 216))	('RPTOR', 'Gene', '57521', (202, 207))	('PDK1', 'Gene', (176, 180))	('RICTOR', 'Gene', '253260', (194, 200))	('NPRL3', 'Gene', '8131', (169, 174))	('NPRL2', 'Gene', (162, 167))	('RHEB', 'Gene', (188, 192))
359907	28528867	The RTK group represented cases with hotspot mutations in KRAS, BRAF, EGFR, or ERBB2, that were not also included in the other PI3K/AKT/mTOR-related groups.	('KRAS', 'Gene', (58, 62))	('mutations', 'Var', (45, 54))	('BRAF', 'Gene', '673', (64, 68))	('KRAS', 'Gene', '3845', (58, 62))	('EGFR', 'Gene', '1956', (70, 74))	('BRAF', 'Gene', (64, 68))	('RTK', 'Gene', '5979', (4, 7))	('ERBB2', 'Gene', (79, 84))	('ERBB2', 'Gene', '2064', (79, 84))	('PI3K/AKT', 'Gene', (127, 135))	('EGFR', 'Gene', (70, 74))	('PI3K/AKT', 'Gene', '5295;207', (127, 135))	('RTK', 'Gene', (4, 7))
359909	28528867	When defining proteins that were highly expressed specifically within the High P-AKT group (Figure 7D), RPPA features were selected that were over- or under-expressed in the High P-AKT compared to unaligned cases (p<0.05, t-test on log-transformed data) for at least four of the seven cancer types, and differentially expressed in High P-AKT compared to unaligned and to PI3K/AKT/mTOR or RTK-altered cases across all cancer cases (p<0.01 for each).	('over-', 'PosReg', (142, 147))	('cancer', 'Disease', (417, 423))	('RTK', 'Gene', '5979', (388, 391))	('High', 'Var', (174, 178))	('under-expressed', 'NegReg', (151, 166))	('cancer', 'Phenotype', 'HP:0002664', (285, 291))	('PI3K/AKT', 'Gene', (371, 379))	('cancer', 'Phenotype', 'HP:0002664', (417, 423))	('High P-AKT', 'Var', (331, 341))	('RTK', 'Gene', (388, 391))	('cancer', 'Disease', (285, 291))	('cancer', 'Disease', 'MESH:D009369', (285, 291))	('PI3K/AKT', 'Gene', '5295;207', (371, 379))	('cancer', 'Disease', 'MESH:D009369', (417, 423))
359919	28528867	Multiplatform-based survey of PI3K/AKT/mTOR across over 10,000 human cancers Distinct classes of somatic alteration associated with greater pathway activation Functional interrogation of specific mutations in PIK3CA and PIK3R1 Support for inclusion of IDH1 and VHL mutations within the canonical pathway model	('cancers', 'Disease', 'MESH:D009369', (69, 76))	('human', 'Species', '9606', (63, 68))	('PIK3CA', 'Gene', (209, 215))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('PIK3R1', 'Gene', (220, 226))	('IDH1', 'Gene', (252, 256))	('VHL', 'Disease', 'MESH:D006623', (261, 264))	('mutations', 'Var', (196, 205))	('VHL', 'Disease', (261, 264))	('PI3K/AKT', 'Gene', (30, 38))	('IDH1', 'Gene', '3417', (252, 256))	('cancers', 'Phenotype', 'HP:0002664', (69, 76))	('PI3K/AKT', 'Gene', '5295;207', (30, 38))	('cancers', 'Disease', (69, 76))
359926	33219256	We identified the age-associated mutations in ALK, ERBB2, KMT2D, RBM10, NRAS, NF1, PIK3CA, MET, PBRM1, LRP2, and CDKN2B; smoking-associated mutations in CDKN2A, FAT1, FGFR1, NFE2L2, CCNE1, CCND1, SMARCA4, KEAP1, KMT2C, and STK11; tumor stage-associated mutations in ARFRP1, AURKA, and CBFB; and sex-associated mutations in EGFR.	('age', 'Gene', '5973', (18, 21))	('FGFR1', 'Gene', (167, 172))	('SMARCA4', 'Gene', '6597', (196, 203))	('NRAS', 'Gene', '4893', (72, 76))	('NFE2L2', 'Gene', (174, 180))	('PIK3CA', 'Gene', '5290', (83, 89))	('mutations', 'Var', (33, 42))	('AURKA', 'Gene', '6790', (274, 279))	('MET', 'Gene', '79811', (91, 94))	('NF1', 'Gene', '4763', (78, 81))	('CCNE1', 'Gene', (182, 187))	('PBRM1', 'Gene', '55193', (96, 101))	('CDKN2B', 'Gene', '1030', (113, 119))	('ERBB2', 'Gene', '2064', (51, 56))	('AURKA', 'Gene', (274, 279))	('LRP2', 'Gene', '4036', (103, 107))	('CBFB', 'Gene', '865', (285, 289))	('CDKN2A', 'Gene', (153, 159))	('mutations', 'Var', (310, 319))	('RBM10', 'Gene', (65, 70))	('ARFRP1', 'Gene', '10139', (266, 272))	('EGFR', 'Gene', '1956', (323, 327))	('mutations', 'Var', (253, 262))	('CCNE1', 'Gene', '898', (182, 187))	('NF1', 'Gene', (78, 81))	('PIK3CA', 'Gene', (83, 89))	('PBRM1', 'Gene', (96, 101))	('KMT2D', 'Gene', '8085', (58, 63))	('FAT1', 'Gene', (161, 165))	('RBM10', 'Gene', '8241', (65, 70))	('tumor', 'Disease', (230, 235))	('NRAS', 'Gene', (72, 76))	('CCND1', 'Gene', '595', (189, 194))	('SMARCA4', 'Gene', (196, 203))	('ERBB2', 'Gene', (51, 56))	('STK11', 'Gene', (223, 228))	('CDKN2A', 'Gene', '1029', (153, 159))	('FGFR1', 'Gene', '2260', (167, 172))	('KMT2C', 'Gene', '58508', (212, 217))	('LRP2', 'Gene', (103, 107))	('age', 'Gene', (18, 21))	('KMT2C', 'Gene', (212, 217))	('CCND1', 'Gene', (189, 194))	('age', 'Gene', '5973', (238, 241))	('KEAP1', 'Gene', '9817', (205, 210))	('mutations', 'Var', (140, 149))	('age', 'Gene', (238, 241))	('tumor', 'Disease', 'MESH:D009369', (230, 235))	('MET', 'Gene', (91, 94))	('KEAP1', 'Gene', (205, 210))	('NFE2L2', 'Gene', '4780', (174, 180))	('CBFB', 'Gene', (285, 289))	('ALK', 'Gene', '238', (46, 49))	('FAT1', 'Gene', '2195', (161, 165))	('CDKN2B', 'Gene', (113, 119))	('EGFR', 'Gene', (323, 327))	('STK11', 'Gene', '6794', (223, 228))	('KMT2D', 'Gene', (58, 63))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))	('ALK', 'Gene', (46, 49))	('ARFRP1', 'Gene', (266, 272))
359928	33219256	TMB-associated mutations included CDKN2A, LRP1B, LRP2, TP53, and EGFR.	('EGFR', 'Gene', '1956', (65, 69))	('EGFR', 'Gene', (65, 69))	('TP53', 'Gene', '7157', (55, 59))	('TP53', 'Gene', (55, 59))	('TMB', 'Chemical', '-', (0, 3))	('mutations', 'Var', (15, 24))	('LRP1B', 'Gene', (42, 47))	('CDKN2A', 'Gene', (34, 40))	('CDKN2A', 'Gene', '1029', (34, 40))	('LRP2', 'Gene', (49, 53))	('TMB-associated', 'Disease', (0, 14))	('LRP2', 'Gene', '4036', (49, 53))	('LRP1B', 'Gene', '53353', (42, 47))
359929	33219256	EGFR amplification was commonly detected in patients with acquired lcotinib/gefitinib resistance.	('EGFR', 'Gene', (0, 4))	('lcotinib/gefitinib', 'MPA', (67, 85))	('patients', 'Species', '9606', (44, 52))	('amplification', 'Var', (5, 18))	('detected', 'Reg', (32, 40))	('gefitinib', 'Chemical', 'MESH:D000077156', (76, 85))	('lcotinib', 'Chemical', '-', (67, 75))	('EGFR', 'Gene', '1956', (0, 4))
359930	33219256	DNMT3A and NOTCH4 mutations may be associated with the benefit of icotinib/gefitinib treatment.	('gefitinib', 'Chemical', 'MESH:D000077156', (75, 84))	('NOTCH4', 'Gene', '4855', (11, 17))	('men', 'Species', '9606', (90, 93))	('DNMT3A', 'Gene', (0, 6))	('DNMT3A', 'Gene', '1788', (0, 6))	('icotinib', 'Chemical', 'MESH:C531470', (66, 74))	('NOTCH4', 'Gene', (11, 17))	('mutations', 'Var', (18, 27))
359941	33219256	Several genomic alterations that could be relevant in the clinical management of patients, such as RET, ALK, and NTRK1 fusions, and EGFR and KRAS mutations, were identified and used for the exploration of targeted drugs.	('mutations', 'Var', (146, 155))	('RET', 'Gene', (99, 102))	('KRAS', 'Gene', (141, 145))	('EGFR', 'Gene', '1956', (132, 136))	('KRAS', 'Gene', '3845', (141, 145))	('ALK', 'Gene', '238', (104, 107))	('patients', 'Species', '9606', (81, 89))	('EGFR', 'Gene', (132, 136))	('NTRK1', 'Gene', '4914', (113, 118))	('fusions', 'Var', (119, 126))	('ALK', 'Gene', (104, 107))	('RET', 'Gene', '5979', (99, 102))	('NTRK1', 'Gene', (113, 118))
359942	33219256	At present, targeted treatment of EGFR mutant tumors with EGFR tyrosine kinase inhibitors (TKIs) has been used as the standard clinical treatment.	('EGFR', 'Gene', '1956', (58, 62))	('men', 'Species', '9606', (141, 144))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('EGFR', 'Gene', (34, 38))	('EGFR', 'Gene', (58, 62))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('men', 'Species', '9606', (26, 29))	('mutant', 'Var', (39, 45))	('tumors', 'Disease', (46, 52))	('EGFR', 'Gene', '1956', (34, 38))	('tumors', 'Disease', 'MESH:D009369', (46, 52))
359944	33219256	Acquired EGFR T790M mutation is one reason for resistance to first- and second-generation EGFR-TKIs.	('EGFR', 'Gene', '1956', (90, 94))	('EGFR', 'Gene', '1956', (9, 13))	('EGFR', 'Gene', (9, 13))	('EGFR', 'Gene', (90, 94))	('T790M', 'Mutation', 'rs121434569', (14, 19))	('T790M', 'Var', (14, 19))
359945	33219256	Osimertinib, a targeted drug to treat NSCLC patients with certain mutations demonstrated improved efficacy for EGFR T790M mutation.	('improved', 'PosReg', (89, 97))	('NSCLC', 'Disease', (38, 43))	('patients', 'Species', '9606', (44, 52))	('NSCLC', 'Disease', 'MESH:D002289', (38, 43))	('EGFR', 'Gene', '1956', (111, 115))	('T790M', 'Mutation', 'rs121434569', (116, 121))	('efficacy', 'MPA', (98, 106))	('EGFR', 'Gene', (111, 115))	('T790M', 'Var', (116, 121))	('NSCLC', 'Phenotype', 'HP:0030358', (38, 43))
359976	33219256	Among these mutations, 1301 (68.5%) were substitution/indels, 487 (21.9%) were gene amplifications, 313 (14.1%) were truncations, 96 (4.3%) were fusions/rearrangements, and 28 (1.3%) were gene homozygous deletions (Fig.	('mutations', 'Var', (12, 21))	('substitution/indels', 'Var', (41, 60))	('men', 'Species', '9606', (162, 165))
359977	33219256	The most common mutated genes were EGFR (55%, 203/371), TP53 (62%, 228/371), and KRAS (11%, 41/371).	('KRAS', 'Gene', '3845', (81, 85))	('TP53', 'Gene', '7157', (56, 60))	('EGFR', 'Gene', '1956', (35, 39))	('mutated', 'Var', (16, 23))	('EGFR', 'Gene', (35, 39))	('TP53', 'Gene', (56, 60))	('KRAS', 'Gene', (81, 85))
359980	33219256	In 203 lung cancer tissue samples, we detected a total of 313 EGFR GAs: 253 Substitution/Indels (including 250 Substitutions/Shortindels and 3 LongIndels, with 5 SNVs were belonging to germline mutation), 58 gene amplifications, and 2 fusions.	('EGFR', 'Gene', '1956', (62, 66))	('Substitutions/Shortindels', 'Var', (111, 136))	('lung cancer', 'Disease', (7, 18))	('lung cancer', 'Phenotype', 'HP:0100526', (7, 18))	('EGFR', 'Gene', (62, 66))	('Substitution/Indels', 'Var', (76, 95))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('lung cancer', 'Disease', 'MESH:D008175', (7, 18))
359982	33219256	Our results showed that mutations in KMT2C, APC, CDKN2A, RB1, and EGFR co-occurred with TP53 mutations, while mutations in MDM2 and KRAS were mutually exclusive with TP53 mutations.	('co-occurred', 'Reg', (71, 82))	('KRAS', 'Gene', (132, 136))	('MDM2', 'Gene', (123, 127))	('TP53', 'Gene', '7157', (88, 92))	('mutations', 'Var', (24, 33))	('RB1', 'Gene', '5925', (57, 60))	('MDM2', 'Gene', '4193', (123, 127))	('EGFR', 'Gene', (66, 70))	('TP53', 'Gene', '7157', (166, 170))	('CDKN2A', 'Gene', (49, 55))	('APC', 'Disease', 'MESH:D011125', (44, 47))	('APC', 'Disease', (44, 47))	('mutations', 'Var', (93, 102))	('TP53', 'Gene', (88, 92))	('CDKN2A', 'Gene', '1029', (49, 55))	('KMT2C', 'Gene', '58508', (37, 42))	('KMT2C', 'Gene', (37, 42))	('EGFR', 'Gene', '1956', (66, 70))	('KRAS', 'Gene', '3845', (132, 136))	('TP53', 'Gene', (166, 170))	('RB1', 'Gene', (57, 60))
359983	33219256	In addition, the mutations in BCL2L11, CTNNB1, RBM10, and RB1 co-occurred with EGFR mutations, while mutations in STK11, KEAP, LRP1B, ALK, and KRAS were mutually exclusive with EGFR mutations.	('EGFR', 'Gene', '1956', (79, 83))	('LRP1B', 'Gene', (127, 132))	('co-occurred', 'Reg', (62, 73))	('ALK', 'Gene', (134, 137))	('BCL2L11', 'Gene', (30, 37))	('mutations', 'Var', (17, 26))	('CTNNB1', 'Gene', '1499', (39, 45))	('STK11', 'Gene', (114, 119))	('LRP1B', 'Gene', '53353', (127, 132))	('RB1', 'Gene', (58, 61))	('KRAS', 'Gene', '3845', (143, 147))	('EGFR', 'Gene', (177, 181))	('EGFR', 'Gene', (79, 83))	('mutations', 'Var', (84, 93))	('KRAS', 'Gene', (143, 147))	('RBM10', 'Gene', (47, 52))	('STK11', 'Gene', '6794', (114, 119))	('CTNNB1', 'Gene', (39, 45))	('RB1', 'Gene', '5925', (58, 61))	('BCL2L11', 'Gene', '10018', (30, 37))	('EGFR', 'Gene', '1956', (177, 181))	('RBM10', 'Gene', '8241', (47, 52))	('ALK', 'Gene', '238', (134, 137))
359984	33219256	Notably, both TP53 and EGFR mutations co-occurred with RB1 mutations, and mutually exclusive with KRAS mutations (Fig.	('TP53', 'Gene', '7157', (14, 18))	('KRAS', 'Gene', '3845', (98, 102))	('TP53', 'Gene', (14, 18))	('RB1', 'Gene', (55, 58))	('co-occurred', 'Reg', (38, 49))	('RB1', 'Gene', '5925', (55, 58))	('EGFR', 'Gene', '1956', (23, 27))	('KRAS', 'Gene', (98, 102))	('mutations', 'Var', (59, 68))	('EGFR', 'Gene', (23, 27))	('mutations', 'Var', (28, 37))
359987	33219256	The most common mutations in LUAD and LUSC were EGFR, TP53, and KRAS, and TP53, PIK3CA, CDKN2A, EGFR, CCND1, NFE2L2, FAM1358, and FGFR1, respectively (Fig.	('NFE2L2', 'Gene', '4780', (109, 115))	('EGFR', 'Gene', '1956', (48, 52))	('PIK3CA', 'Gene', '5290', (80, 86))	('CDKN2A', 'Gene', (88, 94))	('EGFR', 'Gene', (96, 100))	('NFE2L2', 'Gene', (109, 115))	('FGFR1', 'Gene', '2260', (130, 135))	('mutations', 'Var', (16, 25))	('TP53', 'Gene', '7157', (54, 58))	('KRAS', 'Gene', '3845', (64, 68))	('TP53', 'Gene', (74, 78))	('CCND1', 'Gene', '595', (102, 107))	('LUSC', 'Phenotype', 'HP:0030359', (38, 42))	('CDKN2A', 'Gene', '1029', (88, 94))	('EGFR', 'Gene', (48, 52))	('KRAS', 'Gene', (64, 68))	('LUSC', 'Chemical', '-', (38, 42))	('CCND1', 'Gene', (102, 107))	('PIK3CA', 'Gene', (80, 86))	('LUAD', 'Phenotype', 'HP:0030078', (29, 33))	('EGFR', 'Gene', '1956', (96, 100))	('FGFR1', 'Gene', (130, 135))	('TP53', 'Gene', '7157', (74, 78))	('TP53', 'Gene', (54, 58))
359988	33219256	In LUAD, the main mutation type of PIK3CA was SNV; in LUSC, it was mainly gene amplification.	('LUSC', 'Chemical', '-', (54, 58))	('LUAD', 'Phenotype', 'HP:0030078', (3, 7))	('LUSC', 'Phenotype', 'HP:0030359', (54, 58))	('PIK3CA', 'Gene', (35, 41))	('PIK3CA', 'Gene', '5290', (35, 41))	('gene amplification', 'Var', (74, 92))
359989	33219256	ALK fusion; RBM10 truncation; MET, TERT, NKX2-1, SDHA, CDK4, and MDM2 amplifications, and CDKN2A deletion were mainly identified in LUAD (Fig.	('CDK4', 'Gene', '1019', (55, 59))	('truncation', 'Var', (18, 28))	('SDHA', 'Gene', (49, 53))	('RBM10', 'Gene', (12, 17))	('CDKN2A', 'Gene', (90, 96))	('SDHA', 'Gene', '6389', (49, 53))	('NKX2-1', 'Gene', '7080', (41, 47))	('RBM10', 'Gene', '8241', (12, 17))	('MDM2', 'Gene', (65, 69))	('MET', 'Gene', (30, 33))	('CDKN2A', 'Gene', '1029', (90, 96))	('NKX2-1', 'Gene', (41, 47))	('LUAD', 'Phenotype', 'HP:0030078', (132, 136))	('identified', 'Reg', (118, 128))	('MDM2', 'Gene', '4193', (65, 69))	('TERT', 'Gene', (35, 39))	('CDK4', 'Gene', (55, 59))	('TERT', 'Gene', '7015', (35, 39))	('ALK', 'Gene', '238', (0, 3))	('LUAD', 'Disease', (132, 136))	('ALK', 'Gene', (0, 3))	('MET', 'Gene', '79811', (30, 33))	('deletion', 'Var', (97, 105))
359990	33219256	CCND1, FGFR1, and FGF3/4/13, and SOX2 amplifications were mainly identified in LUSC (Fig.	('LUSC', 'Phenotype', 'HP:0030359', (79, 83))	('amplifications', 'Var', (38, 52))	('LUSC', 'Disease', (79, 83))	('identified', 'Reg', (65, 75))	('SOX2', 'Gene', '6657', (33, 37))	('LUSC', 'Chemical', '-', (79, 83))	('SOX2', 'Gene', (33, 37))	('FGFR1', 'Gene', (7, 12))	('CCND1', 'Gene', (0, 5))	('FGF3/4/13', 'Gene', '2248', (18, 27))	('FGFR1', 'Gene', '2260', (7, 12))	('CCND1', 'Gene', '595', (0, 5))	('FGF3/4/13', 'Gene', (18, 27))
359993	33219256	The results showed that patients with mutations in ALK, ERBB2, or KMT2D were younger than those without these mutations, while patients with mutations in RBM10, NRAS, NF1, PIK3CA, MET, PBRM1, LRP2, NFE2L2, or CDKN2B were older than those without these mutations.	('NFE2L2', 'Gene', (198, 204))	('PBRM1', 'Gene', (185, 190))	('PIK3CA', 'Gene', (172, 178))	('NF1', 'Gene', (167, 170))	('MET', 'Gene', '79811', (180, 183))	('NRAS', 'Gene', (161, 165))	('ERBB2', 'Gene', (56, 61))	('RBM10', 'Gene', (154, 159))	('ALK', 'Gene', '238', (51, 54))	('LRP2', 'Gene', (192, 196))	('ALK', 'Gene', (51, 54))	('ERBB2', 'Gene', '2064', (56, 61))	('RBM10', 'Gene', '8241', (154, 159))	('mutations', 'Var', (38, 47))	('KMT2D', 'Gene', '8085', (66, 71))	('mutations', 'Var', (141, 150))	('PIK3CA', 'Gene', '5290', (172, 178))	('NFE2L2', 'Gene', '4780', (198, 204))	('CDKN2B', 'Gene', (209, 215))	('MET', 'Gene', (180, 183))	('NRAS', 'Gene', '4893', (161, 165))	('LRP2', 'Gene', '4036', (192, 196))	('patients', 'Species', '9606', (127, 135))	('PBRM1', 'Gene', '55193', (185, 190))	('NF1', 'Gene', '4763', (167, 170))	('patients', 'Species', '9606', (24, 32))	('CDKN2B', 'Gene', '1030', (209, 215))	('KMT2D', 'Gene', (66, 71))
359994	33219256	Statistical analysis showed that the mutation of these genes was significantly associated with the patient age (Fig.	('patient', 'Species', '9606', (99, 106))	('associated', 'Reg', (79, 89))	('mutation', 'Var', (37, 45))	('age', 'Gene', (107, 110))	('age', 'Gene', '5973', (107, 110))
359996	33219256	The most common mutated genes in smokers included TP53, EGFR, KRAS, CDKN2A, LRP1B, ALK, BCL2L11, KEAP1, KMT2C, PIK3CA, and STK11.	('KRAS', 'Gene', (62, 66))	('KEAP1', 'Gene', '9817', (97, 102))	('EGFR', 'Gene', '1956', (56, 60))	('CDKN2A', 'Gene', (68, 74))	('KEAP1', 'Gene', (97, 102))	('PIK3CA', 'Gene', '5290', (111, 117))	('ALK', 'Gene', '238', (83, 86))	('STK11', 'Gene', (123, 128))	('CDKN2A', 'Gene', '1029', (68, 74))	('LRP1B', 'Gene', (76, 81))	('TP53', 'Gene', (50, 54))	('ALK', 'Gene', (83, 86))	('KMT2C', 'Gene', '58508', (104, 109))	('KMT2C', 'Gene', (104, 109))	('PIK3CA', 'Gene', (111, 117))	('EGFR', 'Gene', (56, 60))	('BCL2L11', 'Gene', '10018', (88, 95))	('STK11', 'Gene', '6794', (123, 128))	('LRP1B', 'Gene', '53353', (76, 81))	('KRAS', 'Gene', '3845', (62, 66))	('TP53', 'Gene', '7157', (50, 54))	('mutated', 'Var', (16, 23))	('BCL2L11', 'Gene', (88, 95))
359997	33219256	The most common mutated genes in non-smokers were EGFR, TP53, RB1, SDHA, RBM10, and TERT (Table S2).	('TERT', 'Gene', (84, 88))	('TERT', 'Gene', '7015', (84, 88))	('RB1', 'Gene', '5925', (62, 65))	('TP53', 'Gene', '7157', (56, 60))	('RBM10', 'Gene', '8241', (73, 78))	('SDHA', 'Gene', '6389', (67, 71))	('mutated', 'Var', (16, 23))	('EGFR', 'Gene', '1956', (50, 54))	('RBM10', 'Gene', (73, 78))	('TP53', 'Gene', (56, 60))	('EGFR', 'Gene', (50, 54))	('SDHA', 'Gene', (67, 71))	('RB1', 'Gene', (62, 65))
359998	33219256	TP53 and EGFR mutations frequently occurred in both smokers and nonsmokers.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('EGFR', 'Gene', '1956', (9, 13))	('EGFR', 'Gene', (9, 13))	('mutations', 'Var', (14, 23))	('occurred', 'Reg', (35, 43))
359999	33219256	Based on statistical analysis, the frequency of EGFR mutations was significantly higher in nonsmoking than smoking patients (Fig.	('patients', 'Species', '9606', (115, 123))	('EGFR', 'Gene', '1956', (48, 52))	('higher', 'PosReg', (81, 87))	('EGFR', 'Gene', (48, 52))	('mutations', 'Var', (53, 62))
360002	33219256	Statistical analysis showed that TP53 and RB1 mutation frequencies were significantly higher in cases with tumor stages III and IV than in those with tumor stages I and II, while the mutation frequencies of TAF1, LRP1B, SDHA, CBFB, BRIP1, and SMAD4 were significantly higher in cases with tumor stages I and II than in those with tumor stages III and IV (Fig.	('SMAD4', 'Gene', '4089', (243, 248))	('tumor', 'Disease', (107, 112))	('LRP1B', 'Gene', (213, 218))	('tumor', 'Disease', (330, 335))	('TP53', 'Gene', '7157', (33, 37))	('RB1', 'Gene', '5925', (42, 45))	('age', 'Gene', (338, 341))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('age', 'Gene', '5973', (158, 161))	('higher', 'PosReg', (86, 92))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('age', 'Gene', (297, 300))	('tumor', 'Disease', 'MESH:D009369', (330, 335))	('CBFB', 'Gene', (226, 230))	('tumor', 'Disease', (289, 294))	('BRIP1', 'Gene', (232, 237))	('LRP1B', 'Gene', '53353', (213, 218))	('age', 'Gene', (115, 118))	('higher', 'PosReg', (268, 274))	('age', 'Gene', '5973', (338, 341))	('tumor', 'Disease', 'MESH:D009369', (289, 294))	('TAF1', 'Gene', (207, 211))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('SDHA', 'Gene', (220, 224))	('age', 'Gene', '5973', (297, 300))	('tumor', 'Phenotype', 'HP:0002664', (330, 335))	('SMAD4', 'Gene', (243, 248))	('TP53', 'Gene', (33, 37))	('CBFB', 'Gene', '865', (226, 230))	('mutation', 'Var', (46, 54))	('tumor', 'Disease', (150, 155))	('SDHA', 'Gene', '6389', (220, 224))	('RB1', 'Gene', (42, 45))	('age', 'Gene', '5973', (115, 118))	('age', 'Gene', (158, 161))	('tumor', 'Phenotype', 'HP:0002664', (289, 294))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('BRIP1', 'Gene', '83990', (232, 237))	('TAF1', 'Gene', '6872', (207, 211))
360003	33219256	The statistical analysis results showed that EGFR mutation was significantly associated with sex (Fig.	('EGFR', 'Gene', (45, 49))	('sex', 'Disease', (93, 96))	('EGFR', 'Gene', '1956', (45, 49))	('mutation', 'Var', (50, 58))	('associated', 'Reg', (77, 87))
360011	33219256	In this cohort, we also found that the median TMB was higher in males than in females (7 mutations/Mb vs 4.3 mutations/Mb).	('TMB', 'MPA', (46, 49))	('TMB', 'Chemical', '-', (46, 49))	('mutations/Mb', 'Var', (89, 101))
360016	33219256	Statistical analysis showed that mutations in CDKN2A, LRP1B, LRP2, TP53, and EGFR were significantly associated with TMB.	('TMB', 'Disease', (117, 120))	('LRP1B', 'Gene', (54, 59))	('CDKN2A', 'Gene', (46, 52))	('LRP2', 'Gene', (61, 65))	('mutations', 'Var', (33, 42))	('CDKN2A', 'Gene', '1029', (46, 52))	('LRP2', 'Gene', '4036', (61, 65))	('LRP1B', 'Gene', '53353', (54, 59))	('TMB', 'Chemical', '-', (117, 120))	('EGFR', 'Gene', '1956', (77, 81))	('TP53', 'Gene', '7157', (67, 71))	('associated', 'Reg', (101, 111))	('TP53', 'Gene', (67, 71))	('EGFR', 'Gene', (77, 81))
360017	33219256	Among these five genes, mutations in CDKN2A, LRP1B, LRP2, and TP53 were associated with high TMB, while EGFR mutations were associated with low TMB (Fig.	('high TMB', 'MPA', (88, 96))	('LRP2', 'Gene', '4036', (52, 56))	('LRP1B', 'Gene', '53353', (45, 50))	('TP53', 'Gene', '7157', (62, 66))	('CDKN2A', 'Gene', (37, 43))	('EGFR', 'Gene', (104, 108))	('TMB', 'Chemical', '-', (144, 147))	('TP53', 'Gene', (62, 66))	('associated', 'Reg', (72, 82))	('CDKN2A', 'Gene', '1029', (37, 43))	('TMB', 'Chemical', '-', (93, 96))	('LRP1B', 'Gene', (45, 50))	('LRP2', 'Gene', (52, 56))	('mutations', 'Var', (24, 33))	('EGFR', 'Gene', '1956', (104, 108))
360018	33219256	In this cohort, 203 patients were harbored EGFR mutations, with 77 patients receiving EGFR-TKIs treatment.	('patients', 'Species', '9606', (67, 75))	('EGFR', 'Gene', '1956', (86, 90))	('men', 'Species', '9606', (101, 104))	('EGFR', 'Gene', (86, 90))	('EGFR', 'Gene', '1956', (43, 47))	('patients', 'Species', '9606', (20, 28))	('EGFR', 'Gene', (43, 47))	('mutations', 'Var', (48, 57))
360021	33219256	A total of 55 EGFR alterations were detected in these 29 patients, including 8 L858R, 16 T790M, 19 19del, and 12 EGFR amplifications.	('EGFR', 'Gene', '1956', (14, 18))	('EGFR', 'Gene', (14, 18))	('L858R', 'Var', (79, 84))	('patients', 'Species', '9606', (57, 65))	('T790M', 'Mutation', 'rs121434569', (89, 94))	('L858R', 'Mutation', 'rs121434568', (79, 84))	('T790M', 'Var', (89, 94))	('EGFR', 'Gene', '1956', (113, 117))	('EGFR', 'Gene', (113, 117))	('19del', 'Mutation', 'c.19del', (99, 104))
360023	33219256	The patients who did not have this mutation included 2 patients with L858R mutation (one of them harbored ERBB2 amplification), 2 patients with EGFR amplification, 4 patients with 19del mutation (one of them harbored ERBB2 amplification), and 2 patients with both 19del mutation and EGFR amplification.	('19del', 'Mutation', 'c.19del', (264, 269))	('EGFR', 'Gene', (144, 148))	('19del', 'Mutation', 'c.19del', (180, 185))	('patients', 'Species', '9606', (245, 253))	('ERBB2', 'Gene', '2064', (106, 111))	('L858R', 'Var', (69, 74))	('ERBB2', 'Gene', (106, 111))	('ERBB2', 'Gene', '2064', (217, 222))	('patients', 'Species', '9606', (130, 138))	('ERBB2', 'Gene', (217, 222))	('EGFR', 'Gene', '1956', (283, 287))	('L858R', 'Mutation', 'rs121434568', (69, 74))	('patients', 'Species', '9606', (4, 12))	('patients', 'Species', '9606', (55, 63))	('EGFR', 'Gene', '1956', (144, 148))	('EGFR', 'Gene', (283, 287))	('patients', 'Species', '9606', (166, 174))
360025	33219256	In addition to the T790M mutation, we found that the proportion of EGFR amplification in patients with drug resistance was higher than that in patients with drug sensitivity (40% vs 0%).	('T790M', 'Mutation', 'rs121434569', (19, 24))	('amplification', 'Var', (72, 85))	('drug', 'MPA', (103, 107))	('higher', 'PosReg', (123, 129))	('T790M', 'Var', (19, 24))	('patients', 'Species', '9606', (143, 151))	('drug resistance', 'Phenotype', 'HP:0020174', (103, 118))	('patients', 'Species', '9606', (89, 97))	('drug sensitivity', 'Phenotype', 'HP:0020174', (157, 173))	('EGFR', 'Gene', '1956', (67, 71))	('EGFR', 'Gene', (67, 71))
360027	33219256	We found that DNMT3A and NOTCH4 mutations were lower in the lcotinib/gefitinib-resistant patients than those in the drug-sensitive patients (0% vs 28.6%, P = 0.052, for both) (Fig.	('patients', 'Species', '9606', (131, 139))	('lower', 'NegReg', (47, 52))	('gefitinib', 'Chemical', 'MESH:D000077156', (69, 78))	('lcotinib/gefitinib-resistant', 'MPA', (60, 88))	('mutations', 'Var', (32, 41))	('patients', 'Species', '9606', (89, 97))	('lcotinib', 'Chemical', '-', (60, 68))	('NOTCH4', 'Gene', (25, 31))	('DNMT3A', 'Gene', (14, 20))	('DNMT3A', 'Gene', '1788', (14, 20))	('NOTCH4', 'Gene', '4855', (25, 31))
360045	33219256	reported that mutations in PIK3CA, FGFR1, CCND1, and CDKN2 mainly occurred in LUAD, while TP53 mutations occurred in nearly 90% of LUSC patients.	('CDKN2', 'Gene', (53, 58))	('CDKN2', 'Gene', '1029', (53, 58))	('occurred', 'Reg', (66, 74))	('CCND1', 'Gene', '595', (42, 47))	('LUAD', 'Phenotype', 'HP:0030078', (78, 82))	('TP53', 'Gene', '7157', (90, 94))	('LUSC', 'Phenotype', 'HP:0030359', (131, 135))	('PIK3CA', 'Gene', (27, 33))	('patients', 'Species', '9606', (136, 144))	('TP53', 'Gene', (90, 94))	('LUAD', 'Disease', (78, 82))	('FGFR1', 'Gene', (35, 40))	('PIK3CA', 'Gene', '5290', (27, 33))	('LUSC', 'Chemical', '-', (131, 135))	('CCND1', 'Gene', (42, 47))	('mutations', 'Var', (14, 23))	('FGFR1', 'Gene', '2260', (35, 40))
360046	33219256	Although we identified TP53 mutations in 87% of LUSC patients, there was no significant difference in TP53 mutational frequency between both types of cancer.	('TP53', 'Gene', (102, 106))	('patients', 'Species', '9606', (53, 61))	('LUSC', 'Phenotype', 'HP:0030359', (48, 52))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('cancer', 'Disease', (150, 156))	('TP53', 'Gene', '7157', (102, 106))	('LUSC', 'Chemical', '-', (48, 52))	('TP53', 'Gene', '7157', (23, 27))	('TP53', 'Gene', (23, 27))	('mutations', 'Var', (28, 37))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
360047	33219256	In lung cancer, EGFR mutations are frequently co-mutated with TP53 and RB1, while KRAS mutations are frequently co-mutated with STK11, KEAP1 and RBM10.	('STK11', 'Gene', '6794', (128, 133))	('lung cancer', 'Phenotype', 'HP:0100526', (3, 14))	('TP53', 'Gene', (62, 66))	('EGFR', 'Gene', '1956', (16, 20))	('RB1', 'Gene', '5925', (71, 74))	('KRAS', 'Gene', '3845', (82, 86))	('RBM10', 'Gene', (145, 150))	('KEAP1', 'Gene', '9817', (135, 140))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('KEAP1', 'Gene', (135, 140))	('KRAS', 'Gene', (82, 86))	('TP53', 'Gene', '7157', (62, 66))	('lung cancer', 'Disease', (3, 14))	('RBM10', 'Gene', '8241', (145, 150))	('STK11', 'Gene', (128, 133))	('EGFR', 'Gene', (16, 20))	('mutations', 'Var', (21, 30))	('RB1', 'Gene', (71, 74))	('lung cancer', 'Disease', 'MESH:D008175', (3, 14))
360048	33219256	Similarly, we found co-mutations of EGFR, TP53, and RB1, and the mutually exclusive mutations of EGFR with STK11, KEAP1, ALK and KRAS in this study.	('TP53', 'Gene', '7157', (42, 46))	('RB1', 'Gene', (52, 55))	('EGFR', 'Gene', '1956', (97, 101))	('ALK', 'Gene', '238', (121, 124))	('TP53', 'Gene', (42, 46))	('STK11', 'Gene', (107, 112))	('EGFR', 'Gene', '1956', (36, 40))	('KRAS', 'Gene', (129, 133))	('EGFR', 'Gene', (97, 101))	('mutations', 'Var', (84, 93))	('RB1', 'Gene', '5925', (52, 55))	('KRAS', 'Gene', '3845', (129, 133))	('KEAP1', 'Gene', '9817', (114, 119))	('STK11', 'Gene', '6794', (107, 112))	('EGFR', 'Gene', (36, 40))	('KEAP1', 'Gene', (114, 119))	('ALK', 'Gene', (121, 124))
360049	33219256	Concurrent KRAS mutations may lead to resistance to osimertinib and MEK inhibitor combined treatment.	('KRAS', 'Gene', (11, 15))	('lead to', 'Reg', (30, 37))	('men', 'Species', '9606', (96, 99))	('osimertinib', 'Chemical', 'MESH:C000596361', (52, 63))	('MEK', 'Gene', '5609', (68, 71))	('KRAS', 'Gene', '3845', (11, 15))	('mutations', 'Var', (16, 25))	('resistance', 'MPA', (38, 48))	('MEK', 'Gene', (68, 71))
360050	33219256	Mutual exclusive mutations of EGFR and KRAS may imply the potential opportunity to benefit from TKI-inhibitor therapy.	('EGFR', 'Gene', (30, 34))	('KRAS', 'Gene', (39, 43))	('KRAS', 'Gene', '3845', (39, 43))	('EGFR', 'Gene', '1956', (30, 34))	('mutations', 'Var', (17, 26))
360052	33219256	The inactivation of TP53 and RB1 is the molecular characterization of SCLC.	('SCLC', 'Disease', 'MESH:D018288', (70, 74))	('inactivation', 'Var', (4, 16))	('TP53', 'Gene', (20, 24))	('RB1', 'Gene', (29, 32))	('RB1', 'Gene', '5925', (29, 32))	('TP53', 'Gene', '7157', (20, 24))	('SCLC', 'Disease', (70, 74))
360053	33219256	In this study, 8 out of 11 SCLC patients harbored a co-mutation of TP53 and RB1.	('patients', 'Species', '9606', (32, 40))	('RB1', 'Gene', (76, 79))	('harbored', 'Reg', (41, 49))	('co-mutation', 'Var', (52, 63))	('SCLC', 'Disease', (27, 31))	('TP53', 'Gene', '7157', (67, 71))	('TP53', 'Gene', (67, 71))	('RB1', 'Gene', '5925', (76, 79))	('SCLC', 'Disease', 'MESH:D018288', (27, 31))
360057	33219256	A previous reports suggested that the NFE2L2 mutation may be a biomarker for the special treatment of LUSC.	('LUSC', 'Chemical', '-', (102, 106))	('NFE2L2', 'Gene', '4780', (38, 44))	('men', 'Species', '9606', (94, 97))	('mutation', 'Var', (45, 53))	('NFE2L2', 'Gene', (38, 44))	('LUSC', 'Phenotype', 'HP:0030359', (102, 106))	('LUSC', 'Disease', (102, 106))
360058	33219256	Another study reported that the KMT2D mutation correlates with poor prognosis in NSCLC.	('KMT2D', 'Gene', '8085', (32, 37))	('KMT2D', 'Gene', (32, 37))	('NSCLC', 'Phenotype', 'HP:0030358', (81, 86))	('mutation', 'Var', (38, 46))	('NSCLC', 'Disease', (81, 86))	('NSCLC', 'Disease', 'MESH:D002289', (81, 86))
360059	33219256	In this way, the high frequency of KMT2D mutations indicated a poor prognosis of LUSC.	('mutations', 'Var', (41, 50))	('LUSC', 'Chemical', '-', (81, 85))	('KMT2D', 'Gene', (35, 40))	('LUSC', 'Phenotype', 'HP:0030359', (81, 85))	('KMT2D', 'Gene', '8085', (35, 40))	('LUSC', 'Disease', (81, 85))
360063	33219256	focused on the GAs of young lung cancer patients and identified that mutations in EGFR, ALK, and ERBB2 trend to occur in younger NSCLC patients.	('mutations', 'Var', (69, 78))	('EGFR', 'Gene', (82, 86))	('ALK', 'Gene', (88, 91))	('patients', 'Species', '9606', (135, 143))	('NSCLC', 'Phenotype', 'HP:0030358', (129, 134))	('lung cancer', 'Disease', 'MESH:D008175', (28, 39))	('patients', 'Species', '9606', (40, 48))	('NSCLC', 'Disease', (129, 134))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('lung cancer', 'Disease', (28, 39))	('ALK', 'Gene', '238', (88, 91))	('NSCLC', 'Disease', 'MESH:D002289', (129, 134))	('ERBB2', 'Gene', (97, 102))	('EGFR', 'Gene', '1956', (82, 86))	('ERBB2', 'Gene', '2064', (97, 102))	('lung cancer', 'Phenotype', 'HP:0100526', (28, 39))	('occur', 'Reg', (112, 117))
360065	33219256	reported that mutations in EGFR and TP53 were associated with age in Chinese NSCLC patients.	('NSCLC', 'Disease', 'MESH:D002289', (77, 82))	('EGFR', 'Gene', '1956', (27, 31))	('EGFR', 'Gene', (27, 31))	('TP53', 'Gene', (36, 40))	('age', 'Gene', '5973', (62, 65))	('age', 'Gene', (62, 65))	('NSCLC', 'Phenotype', 'HP:0030358', (77, 82))	('TP53', 'Gene', '7157', (36, 40))	('associated', 'Reg', (46, 56))	('patients', 'Species', '9606', (83, 91))	('NSCLC', 'Disease', (77, 82))	('mutations', 'Var', (14, 23))
360066	33219256	In contrast to this study, we did not detect an association between age and TP53 and EGFR mutations.	('EGFR', 'Gene', (85, 89))	('mutations', 'Var', (90, 99))	('age', 'Gene', (68, 71))	('TP53', 'Gene', '7157', (76, 80))	('TP53', 'Gene', (76, 80))	('age', 'Gene', '5973', (68, 71))	('EGFR', 'Gene', '1956', (85, 89))
360067	33219256	However, we detected the correlation between age and ALK and ERBB2 mutations, similar to the results of Sacher et al., which showed the reliability of our analysis.	('ERBB2', 'Gene', (61, 66))	('ALK', 'Gene', (53, 56))	('ERBB2', 'Gene', '2064', (61, 66))	('mutations', 'Var', (67, 76))	('age', 'Gene', (45, 48))	('ALK', 'Gene', '238', (53, 56))	('age', 'Gene', '5973', (45, 48))
360068	33219256	Furthermore, we identified associations between younger patients and NRAS and KMT2D mutations, and elderly patients and RBM10, NF1, PIK3CA, MET, PBRM1, LRP2, and CDKN2B mutations.	('associations', 'Interaction', (27, 39))	('patients', 'Species', '9606', (56, 64))	('mutations', 'Var', (169, 178))	('LRP2', 'Gene', '4036', (152, 156))	('CDKN2B', 'Gene', '1030', (162, 168))	('NF1', 'Gene', (127, 130))	('PIK3CA', 'Gene', (132, 138))	('PBRM1', 'Gene', (145, 150))	('NRAS', 'Gene', '4893', (69, 73))	('MET', 'Gene', '79811', (140, 143))	('KMT2D', 'Gene', (78, 83))	('patients', 'Species', '9606', (107, 115))	('LRP2', 'Gene', (152, 156))	('RBM10', 'Gene', (120, 125))	('mutations', 'Var', (84, 93))	('RBM10', 'Gene', '8241', (120, 125))	('NRAS', 'Gene', (69, 73))	('PIK3CA', 'Gene', '5290', (132, 138))	('KMT2D', 'Gene', '8085', (78, 83))	('MET', 'Gene', (140, 143))	('CDKN2B', 'Gene', (162, 168))	('NF1', 'Gene', '4763', (127, 130))	('PBRM1', 'Gene', '55193', (145, 150))
360071	33219256	Mutations in EGFR, ROS1, and ALK mainly occur in nonsmoking patients, while mutations in KRAS, TP53, BRAF, JAK2, and JAK3 mainly occur in smoking patients.	('ALK', 'Gene', '238', (29, 32))	('EGFR', 'Gene', '1956', (13, 17))	('ROS1', 'Gene', '6098', (19, 23))	('ALK', 'Gene', (29, 32))	('patients', 'Species', '9606', (60, 68))	('Mutations', 'Var', (0, 9))	('BRAF', 'Gene', '673', (101, 105))	('patients', 'Species', '9606', (146, 154))	('TP53', 'Gene', '7157', (95, 99))	('occur', 'Reg', (40, 45))	('KRAS', 'Gene', '3845', (89, 93))	('BRAF', 'Gene', (101, 105))	('JAK3', 'Gene', (117, 121))	('JAK2', 'Gene', '3717', (107, 111))	('ROS1', 'Gene', (19, 23))	('KRAS', 'Gene', (89, 93))	('EGFR', 'Gene', (13, 17))	('JAK3', 'Gene', '3718', (117, 121))	('JAK2', 'Gene', (107, 111))	('TP53', 'Gene', (95, 99))
360072	33219256	However, only EGFR mutations were found to be associated with nonsmoking.	('EGFR', 'Gene', '1956', (14, 18))	('EGFR', 'Gene', (14, 18))	('mutations', 'Var', (19, 28))	('associated', 'Reg', (46, 56))	('nonsmoking', 'Disease', (62, 72))
360073	33219256	Although the mutational frequencies of KRAS and TP53 were also higher in smoking than those in nonsmoking patients in this study, the statistical analysis showed no significant difference (17.1% vs. 7.3%, P = 0.052; and 62.9% vs. 52.7%, P = 0.22, respectively).	('TP53', 'Gene', '7157', (48, 52))	('TP53', 'Gene', (48, 52))	('patients', 'Species', '9606', (106, 114))	('KRAS', 'Gene', (39, 43))	('mutational', 'Var', (13, 23))	('KRAS', 'Gene', '3845', (39, 43))	('higher', 'PosReg', (63, 69))
360077	33219256	Similar to previous studies, we found that the mutational frequency of EGFR was significantly higher in female patients than that in male patients.	('higher', 'Reg', (94, 100))	('EGFR', 'Gene', '1956', (71, 75))	('mutational', 'Var', (47, 57))	('EGFR', 'Gene', (71, 75))	('patients', 'Species', '9606', (138, 146))	('patients', 'Species', '9606', (111, 119))
360080	33219256	Our results showed a correlation between TP53 and RB1 mutations and tumor stages III-IV.	('tumor', 'Disease', (68, 73))	('TP53', 'Gene', '7157', (41, 45))	('TP53', 'Gene', (41, 45))	('age', 'Gene', '5973', (76, 79))	('mutations', 'Var', (54, 63))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('RB1', 'Gene', (50, 53))	('age', 'Gene', (76, 79))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('RB1', 'Gene', '5925', (50, 53))	('correlation', 'Reg', (21, 32))
360082	33219256	TP53 is the most common mutated gene in human cancers, and both TP53 and RB1 mutations are reported to be associated with poor prognosis of lung cancer patients.	('lung cancer', 'Disease', (140, 151))	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('cancers', 'Disease', 'MESH:D009369', (46, 53))	('human', 'Species', '9606', (40, 45))	('lung cancer', 'Phenotype', 'HP:0100526', (140, 151))	('associated', 'Reg', (106, 116))	('RB1', 'Gene', (73, 76))	('cancers', 'Disease', (46, 53))	('cancers', 'Phenotype', 'HP:0002664', (46, 53))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('RB1', 'Gene', '5925', (73, 76))	('mutations', 'Var', (77, 86))	('lung cancer', 'Disease', 'MESH:D008175', (140, 151))	('TP53', 'Gene', '7157', (64, 68))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('TP53', 'Gene', (64, 68))	('patients', 'Species', '9606', (152, 160))
360083	33219256	Our results indicate that these mutations may predict the prognosis of Chinese lung cancer patients.	('lung cancer', 'Disease', 'MESH:D008175', (79, 90))	('patients', 'Species', '9606', (91, 99))	('lung cancer', 'Disease', (79, 90))	('lung cancer', 'Phenotype', 'HP:0100526', (79, 90))	('predict', 'Reg', (46, 53))	('mutations', 'Var', (32, 41))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))
360084	33219256	Moreover, we showed a significant association between early tumor stage and mutations in TAF1, LRP1B, SDHA, CBFB, BRIP1, and SMAD4.	('LRP1B', 'Gene', (95, 100))	('CBFB', 'Gene', (108, 112))	('TAF1', 'Gene', '6872', (89, 93))	('tumor', 'Disease', (60, 65))	('SMAD4', 'Gene', (125, 130))	('age', 'Gene', (68, 71))	('BRIP1', 'Gene', (114, 119))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('LRP1B', 'Gene', '53353', (95, 100))	('SDHA', 'Gene', (102, 106))	('CBFB', 'Gene', '865', (108, 112))	('significant association', 'Reg', (22, 45))	('SMAD4', 'Gene', '4089', (125, 130))	('SDHA', 'Gene', '6389', (102, 106))	('age', 'Gene', '5973', (68, 71))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('TAF1', 'Gene', (89, 93))	('mutations', 'Var', (76, 85))	('BRIP1', 'Gene', '83990', (114, 119))
360085	33219256	reported that LRP1B mutation was associated with better survival in NSCLC patients treated with immunotherapy.	('NSCLC', 'Disease', 'MESH:D002289', (68, 73))	('survival', 'MPA', (56, 64))	('patients', 'Species', '9606', (74, 82))	('mutation', 'Var', (20, 28))	('LRP1B', 'Gene', (14, 19))	('NSCLC', 'Phenotype', 'HP:0030358', (68, 73))	('better', 'PosReg', (49, 55))	('LRP1B', 'Gene', '53353', (14, 19))	('NSCLC', 'Disease', (68, 73))
360087	33219256	In this study, we first reported the correlation between SDHA mutation and tumor stage, indicating its potential predictive value.	('correlation', 'Interaction', (37, 48))	('age', 'Gene', '5973', (83, 86))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('SDHA', 'Gene', '6389', (57, 61))	('mutation', 'Var', (62, 70))	('age', 'Gene', (83, 86))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('SDHA', 'Gene', (57, 61))	('tumor', 'Disease', (75, 80))
360088	33219256	Although the correlation between TAF1, BRIP1, and CBFB mutations and prognosis has been reported, only have been reported in lung cancer.	('lung cancer', 'Disease', 'MESH:D008175', (125, 136))	('mutations', 'Var', (55, 64))	('TAF1', 'Gene', (33, 37))	('TAF1', 'Gene', '6872', (33, 37))	('CBFB', 'Gene', '865', (50, 54))	('BRIP1', 'Gene', (39, 44))	('CBFB', 'Gene', (50, 54))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('BRIP1', 'Gene', '83990', (39, 44))	('lung cancer', 'Disease', (125, 136))	('lung cancer', 'Phenotype', 'HP:0100526', (125, 136))
360095	33219256	In NSCLC patients with TMB-H, non-smokers had a significantly better prognosis compared with smokers.	('patients', 'Species', '9606', (9, 17))	('NSCLC', 'Disease', (3, 8))	('NSCLC', 'Disease', 'MESH:D002289', (3, 8))	('TMB-H', 'Chemical', '-', (23, 28))	('TMB-H', 'Var', (23, 28))	('NSCLC', 'Phenotype', 'HP:0030358', (3, 8))
360102	33219256	However, statistical analysis showed the significant association between TMB and mutations in EGFR, TP53, LRP1B, LRP2, and CDKN2A, suggesting potential biomarkers for the prognosis of Chinese lung cancer patients.	('TP53', 'Gene', (100, 104))	('CDKN2A', 'Gene', (123, 129))	('mutations', 'Var', (81, 90))	('significant association', 'Reg', (41, 64))	('lung cancer', 'Disease', 'MESH:D008175', (192, 203))	('patients', 'Species', '9606', (204, 212))	('LRP2', 'Gene', (113, 117))	('TMB', 'Disease', (73, 76))	('EGFR', 'Gene', '1956', (94, 98))	('lung cancer', 'Phenotype', 'HP:0100526', (192, 203))	('CDKN2A', 'Gene', '1029', (123, 129))	('TP53', 'Gene', '7157', (100, 104))	('LRP1B', 'Gene', (106, 111))	('TMB', 'Chemical', '-', (73, 76))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('lung cancer', 'Disease', (192, 203))	('LRP2', 'Gene', '4036', (113, 117))	('EGFR', 'Gene', (94, 98))	('LRP1B', 'Gene', '53353', (106, 111))
360103	33219256	Particularly, TP53 mutation status may be a useful biomarker for predicting the response to immunotherapy in different cancer types.	('TP53', 'Gene', '7157', (14, 18))	('TP53', 'Gene', (14, 18))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('cancer', 'Disease', (119, 125))	('mutation status', 'Var', (19, 34))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
360104	33219256	reported that high TMB is associated with poor prognosis in NSCLC.	('NSCLC', 'Phenotype', 'HP:0030358', (60, 65))	('high', 'Var', (14, 18))	('TMB', 'MPA', (19, 22))	('NSCLC', 'Disease', (60, 65))	('TMB', 'Chemical', '-', (19, 22))	('NSCLC', 'Disease', 'MESH:D002289', (60, 65))
360106	33219256	The clinical course of EGFR mutant lung cancer is significantly heterogeneous, and acquisition of EGFR T790M mutation is the most frequent reason for first- and second-generation EGFR-TKIs.	('EGFR', 'Gene', (98, 102))	('T790M', 'Var', (103, 108))	('EGFR', 'Gene', (179, 183))	('mutant', 'Var', (28, 34))	('lung cancer', 'Disease', 'MESH:D008175', (35, 46))	('lung cancer', 'Disease', (35, 46))	('EGFR', 'Gene', '1956', (23, 27))	('lung cancer', 'Phenotype', 'HP:0100526', (35, 46))	('T790M', 'Mutation', 'rs121434569', (103, 108))	('EGFR', 'Gene', '1956', (98, 102))	('EGFR', 'Gene', (23, 27))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('EGFR', 'Gene', '1956', (179, 183))
360108	33219256	Besides 19del and L858R, EGFR amplification is also frequently occurs in lung cancer.	('lung cancer', 'Disease', 'MESH:D008175', (73, 84))	('EGFR', 'Gene', (25, 29))	('L858R', 'Var', (18, 23))	('19del', 'Mutation', 'c.19del', (8, 13))	('amplification', 'Var', (30, 43))	('occurs', 'Reg', (63, 69))	('L858R', 'Mutation', 'rs121434568', (18, 23))	('lung cancer', 'Disease', (73, 84))	('lung cancer', 'Phenotype', 'HP:0100526', (73, 84))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('EGFR', 'Gene', '1956', (25, 29))
360110	33219256	EGFR amplification was also reported to be associated with better OS, PFS, CR, and PR in LUAD patients treated with erlotinib.	('EGFR', 'Gene', (0, 4))	('patients', 'Species', '9606', (94, 102))	('amplification', 'Var', (5, 18))	('PFS', 'Disease', (70, 73))	('better OS', 'Disease', (59, 68))	('erlotinib', 'Chemical', 'MESH:D000069347', (116, 125))	('EGFR', 'Gene', '1956', (0, 4))	('LUAD', 'Phenotype', 'HP:0030078', (89, 93))
360112	33219256	In addition to the T790M mutation or ERBB2 amplification, we found a higher proportion of EGFR amplification in EGFR-TKI-resistant patients than that in EGFR-TKI-sensitive patients.	('EGFR', 'Gene', (112, 116))	('ERBB2', 'Gene', (37, 42))	('patients', 'Species', '9606', (131, 139))	('ERBB2', 'Gene', '2064', (37, 42))	('T790M', 'Mutation', 'rs121434569', (19, 24))	('EGFR', 'Gene', '1956', (90, 94))	('T790M', 'Var', (19, 24))	('EGFR', 'Gene', '1956', (153, 157))	('amplification', 'Var', (95, 108))	('EGFR', 'Gene', (90, 94))	('patients', 'Species', '9606', (172, 180))	('EGFR', 'Gene', '1956', (112, 116))	('EGFR', 'Gene', (153, 157))
360113	33219256	It is important to consider whether EGFR amplification is associated with the rapid development of lcotinib/gefitinib resistance.	('associated', 'Reg', (58, 68))	('gefitinib', 'Chemical', 'MESH:D000077156', (108, 117))	('men', 'Species', '9606', (91, 94))	('EGFR', 'Gene', '1956', (36, 40))	('amplification', 'Var', (41, 54))	('EGFR', 'Gene', (36, 40))	('lcotinib', 'Chemical', '-', (99, 107))	('lcotinib/gefitinib resistance', 'MPA', (99, 128))
360114	33219256	However, 6 patients with 19del or L858R mutations also rapidly developed EGFR-TKIs resistance.	('19del', 'Mutation', 'c.19del', (25, 30))	('developed', 'PosReg', (63, 72))	('EGFR', 'Gene', '1956', (73, 77))	('L858R', 'Var', (34, 39))	('EGFR', 'Gene', (73, 77))	('L858R', 'Mutation', 'rs121434568', (34, 39))	('patients', 'Species', '9606', (11, 19))
360118	33219256	Mutations in DNMT3a and NOTCH4 have been reported to be associated with better prognosis in patients with LUAD and NSCLC, respectively.	('LUAD', 'Phenotype', 'HP:0030078', (106, 110))	('DNMT3a', 'Gene', (13, 19))	('NSCLC', 'Disease', (115, 120))	('patients', 'Species', '9606', (92, 100))	('DNMT3a', 'Gene', '1788', (13, 19))	('associated', 'Reg', (56, 66))	('NOTCH4', 'Gene', (24, 30))	('Mutations', 'Var', (0, 9))	('NSCLC', 'Disease', 'MESH:D002289', (115, 120))	('NOTCH4', 'Gene', '4855', (24, 30))	('LUAD', 'Disease', (106, 110))	('NSCLC', 'Phenotype', 'HP:0030358', (115, 120))
360120	33219256	It is suggested that DNMT3a and NOTCH4 mutations may be potential biomarkers to predict sensitivity to EGFR-TKIs.	('EGFR', 'Gene', '1956', (103, 107))	('NOTCH4', 'Gene', (32, 38))	('EGFR', 'Gene', (103, 107))	('DNMT3a', 'Gene', (21, 27))	('NOTCH4', 'Gene', '4855', (32, 38))	('mutations', 'Var', (39, 48))	('DNMT3a', 'Gene', '1788', (21, 27))
360122	33219256	Furthermore, we detected that certain gene mutations were associated with age, smoking status, tumor stage, and TMB value.	('age', 'Gene', '5973', (103, 106))	('TMB value', 'Disease', (112, 121))	('associated', 'Reg', (58, 68))	('age', 'Gene', '5973', (74, 77))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('mutations', 'Var', (43, 52))	('age', 'Gene', (103, 106))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('TMB', 'Chemical', '-', (112, 115))	('tumor', 'Disease', (95, 100))	('age', 'Gene', (74, 77))
360123	33219256	We also suggested a series of biomarkers for potential therapy and prognosis, and indicated that EGFR amplification, DNMT3a mutation, and NOTCH4 mutation may be used to predict EGFR-TKI resistance.	('NOTCH4', 'Gene', (138, 144))	('NOTCH4', 'Gene', '4855', (138, 144))	('predict', 'Reg', (169, 176))	('EGFR', 'Gene', '1956', (97, 101))	('amplification', 'Var', (102, 115))	('DNMT3a', 'Gene', (117, 123))	('EGFR', 'Gene', (97, 101))	('EGFR', 'Gene', '1956', (177, 181))	('mutation', 'Var', (124, 132))	('DNMT3a', 'Gene', '1788', (117, 123))	('EGFR', 'Gene', (177, 181))	('mutation', 'Var', (145, 153))
360125	33219256	collected patient consents and samples and analyzed data; X.L., W.L., X.S., S.Y.	('W.L.', 'Var', (64, 68))	('X.S.', 'Var', (70, 74))	('patient', 'Species', '9606', (10, 17))
360140	32266223	Aberrant expression of miRNAs has been identified in many types of cancer.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('Aberrant', 'Var', (0, 8))	('cancer', 'Disease', (67, 73))	('miRNAs', 'Protein', (23, 29))	('expression', 'MPA', (9, 19))	('identified', 'Reg', (39, 49))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))
360144	32266223	Identified co-expression miRNA-mRNA pairs in the current study can be applied as targets for clinical co-detection of ependymoma.	('miRNA-mRNA', 'Var', (25, 35))	('ependymoma', 'Disease', 'MESH:D004806', (118, 128))	('ependymoma', 'Phenotype', 'HP:0002888', (118, 128))	('ependymoma', 'Disease', (118, 128))
360161	32266223	Beside the KEGG and GO functional annotations, we enriched the modules with reported multi-omics ependymoma signatures: the 51 gene expression signatures of ependymoma survival from Supplementary Table 6 of, and the validated 632 amplification and deletion genes of ependymoma from Supplementary Tables 5a,b of.	('ependymoma', 'Phenotype', 'HP:0002888', (97, 107))	('ependymoma', 'Disease', (157, 167))	('ependymoma', 'Phenotype', 'HP:0002888', (266, 276))	('ependymoma', 'Disease', 'MESH:D004806', (97, 107))	('ependymoma', 'Disease', (97, 107))	('ependymoma', 'Disease', 'MESH:D004806', (266, 276))	('ependymoma', 'Disease', (266, 276))	('ependymoma', 'Phenotype', 'HP:0002888', (157, 167))	('deletion', 'Var', (248, 256))	('ependymoma', 'Disease', 'MESH:D004806', (157, 167))
360164	32266223	For the 728 genes with validated deletion in ependymoma, they were marginally significantly mapped onto the light cyan module with a hypergeometric test FDR of 0.0770 and there were 18 overlapped genes.	('ependymoma', 'Disease', 'MESH:D004806', (45, 55))	('deletion', 'Var', (33, 41))	('ependymoma', 'Disease', (45, 55))	('ependymoma', 'Phenotype', 'HP:0002888', (45, 55))
360165	32266223	It can be seen that the modules were associated with ependymoma survival and DNA copy number alterations (CNAs).	('copy number', 'Var', (81, 92))	('ependymoma', 'Phenotype', 'HP:0002888', (53, 63))	('ependymoma', 'Disease', (53, 63))	('ependymoma', 'Disease', 'MESH:D004806', (53, 63))	('associated', 'Reg', (37, 47))	('DNA', 'Gene', (77, 80))
360206	32266223	Dysregulation of WNT signaling was associated with various solid tumors, including glioblastoma.	('WNT signaling', 'Pathway', (17, 30))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('Dysregulation', 'Var', (0, 13))	('associated', 'Reg', (35, 45))	('tumors', 'Disease', (65, 71))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('glioblastoma', 'Disease', (83, 95))	('glioblastoma', 'Disease', 'MESH:D005909', (83, 95))	('glioblastoma', 'Phenotype', 'HP:0012174', (83, 95))
360217	31788048	Tumours were categorized based on programmed cell death-ligand 1 (PD-L1) immunoreactivity and copy number alterations in the PD-L1 gene, as determined by fluorescence in situ hybridization.	('Tumours', 'Phenotype', 'HP:0002664', (0, 7))	('PD-L1', 'Gene', '29126', (66, 71))	('PD-L1', 'Gene', '29126', (125, 130))	('programmed cell death-ligand 1', 'Gene', '29126', (34, 64))	('copy number alterations', 'Var', (94, 117))	('programmed cell death-ligand 1', 'Gene', (34, 64))	('PD-L1', 'Gene', (66, 71))	('PD-L1', 'Gene', (125, 130))
360219	31788048	Furthermore, ART-treated patients with PD-L1 immunonegativity exhibited an improved recurrence-free survival (RFS) compared with patients that did not receive ART and HIV-negative individuals with PD-L1 immunopositivity (P=0.041 vs. P=0.030).	('improved', 'PosReg', (75, 83))	('PD-L1', 'Gene', (39, 44))	('recurrence-free survival', 'CPA', (84, 108))	('PD-L1', 'Gene', (197, 202))	('patients', 'Species', '9606', (129, 137))	('ART', 'Gene', (159, 162))	('PD-L1', 'Gene', '29126', (39, 44))	('HIV', 'Disease', (167, 170))	('patients', 'Species', '9606', (25, 33))	('ART', 'Gene', '9048', (159, 162))	('PD-L1', 'Gene', '29126', (197, 202))	('ART', 'Gene', '9048', (13, 16))	('HIV', 'Disease', 'MESH:D015658', (167, 170))	('ART', 'Gene', (13, 16))	('immunonegativity', 'Var', (45, 61))
360224	31788048	However, only PD-L1 polysomy was determined to be a predictor of poor LRR (HR, 2.50; 95% CI, 1.11-5.63; P=0.027).	('PD-L1', 'Gene', '29126', (14, 19))	('LRR', 'Disease', (70, 73))	('poor LRR', 'Disease', (65, 73))	('PD-L1', 'Gene', (14, 19))	('polysomy', 'Var', (20, 28))
360237	31788048	Interestingly, amplification of chromosome 9p24.1 has recently been demonstrated as an essential mechanism for increased PD-L1 protein expression in nodular sclerosing classical Hodgkin lymphoma and primary mediastinal large B-cell lymphoma.	('PD-L1', 'Gene', (121, 126))	('Hodgkin lymphoma', 'Disease', (178, 194))	('PD-L1', 'Gene', '29126', (121, 126))	('increased', 'PosReg', (111, 120))	('primary mediastinal large B-cell lymphoma', 'Disease', (199, 240))	('amplification', 'Var', (15, 28))	('lymphoma', 'Phenotype', 'HP:0002665', (232, 240))	('p24.1', 'Gene', '29102', (44, 49))	('Hodgkin lymphoma', 'Disease', 'MESH:D006689', (178, 194))	('Hodgkin lymphoma', 'Phenotype', 'HP:0012189', (178, 194))	('p24.1', 'Gene', (44, 49))	('expression', 'MPA', (135, 145))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (225, 240))	('increased PD', 'Phenotype', 'HP:0008151', (111, 123))	('lymphoma', 'Phenotype', 'HP:0002665', (186, 194))
360278	31788048	No significant correlation was observed between the NRTI+NNRTI group and the NRTI+PI group with regard to patient age [40.69 (10.14) vs. 41.43 (5.97) years; P=0.441], higher CD4 counts (75.0 vs. 71.4%; P=1.000), undetectable viral loads (81.2 vs. 85.7%; P=1.000), FIGO stage 1B2-IIB disease (81.3 vs. 85.7%; P=1.000), tumour size >=4 cm (75.0 vs. 42.9%; P=0.182), the presence of parametrial invasion (75.0 vs. 71.4%; P=1.000), histologic subtype of squamous cell carcinoma (68.8 vs. 85.7%; P=0.621), or the presence of metastatic nodes (37.3%; P=0.366).	('tumour', 'Disease', (318, 324))	('undetectable', 'Var', (212, 224))	('CD4', 'Gene', '920', (174, 177))	('FIGO stage 1B2-IIB disease', 'Disease', (264, 290))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (450, 473))	('squamous cell carcinoma', 'Disease', (450, 473))	('patient', 'Species', '9606', (106, 113))	('tumour', 'Phenotype', 'HP:0002664', (318, 324))	('parametrial invasion', 'CPA', (380, 400))	('carcinoma', 'Phenotype', 'HP:0030731', (464, 473))	('CD4', 'Gene', (174, 177))	('tumour', 'Disease', 'MESH:D009369', (318, 324))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (450, 473))
360289	31788048	Gene copy number gain was restricted to tumour cells and was not present in the inflammatory cell component.	('Gene copy number', 'Var', (0, 16))	('tumour', 'Disease', 'MESH:D009369', (40, 46))	('tumour', 'Disease', (40, 46))	('tumour', 'Phenotype', 'HP:0002664', (40, 46))	('gain', 'PosReg', (17, 21))
360291	31788048	3 shows the proportion of PD-L1 copy number alterations in each patient group.	('patient', 'Species', '9606', (64, 71))	('copy number alterations', 'Var', (32, 55))	('PD-L1', 'Gene', (26, 31))	('PD-L1', 'Gene', '29126', (26, 31))
360292	31788048	There was no significant difference in PD-L1 amplification, polysomy, or disomy (64.6 vs. 55.3%, 27.1 vs. 38.2% and 8.3 vs. 6.5%, respectively; P=0.387) between the HIV-positive cohort and the HIV-negative cohort.	('HIV', 'Disease', 'MESH:D015658', (165, 168))	('PD-L1', 'Gene', (39, 44))	('HIV', 'Disease', (193, 196))	('HIV', 'Disease', 'MESH:D015658', (193, 196))	('disomy', 'Disease', (73, 79))	('disomy', 'Disease', 'MESH:D024182', (73, 79))	('PD-L1', 'Gene', '29126', (39, 44))	('polysomy', 'Var', (60, 68))	('HIV', 'Disease', (165, 168))
360293	31788048	Among the HIV-positive cohort, ART-exposed patients had a lower prevalence of amplification (0 vs. 28.6%; P=0.019) and polysomy (8.7 vs. 52.4%; P=0.002) and a higher prevalence of disomy (91.3 vs. 40%; P<0.001) than their ART-untreated counterparts.	('amplification', 'MPA', (78, 91))	('ART', 'Gene', (31, 34))	('disomy', 'Disease', (180, 186))	('disomy', 'Disease', 'MESH:D024182', (180, 186))	('lower', 'NegReg', (58, 63))	('patients', 'Species', '9606', (43, 51))	('HIV', 'Disease', 'MESH:D015658', (10, 13))	('ART', 'Gene', '9048', (222, 225))	('polysomy', 'Var', (119, 127))	('ART', 'Gene', (222, 225))	('HIV', 'Disease', (10, 13))	('ART', 'Gene', '9048', (31, 34))
360296	31788048	Tumours with PD-L1 gene amplification and polysomy displayed membranous PD-L1 immunostaining (scores 1+ to 3+) by immunohistochemistry in 11/12 (92%) and 46/60 (76%) cases, respectively.	('polysomy', 'Var', (42, 50))	('Tumours', 'Phenotype', 'HP:0002664', (0, 7))	('PD-L1', 'Gene', '29126', (72, 77))	('gene amplification', 'Var', (19, 37))	('PD-L1', 'Gene', (13, 18))	('PD-L1', 'Gene', (72, 77))	('PD-L1', 'Gene', '29126', (13, 18))
360298	31788048	Likewise, the proportion of PD-L1 immunopositive tumours with PD-L1 polysomy were significantly higher than those of tumours with disomy (76.7 vs. 52.5%; P=0.002).	('tumours', 'Disease', (49, 56))	('tumours', 'Disease', (117, 124))	('PD-L1', 'Gene', '29126', (28, 33))	('PD-L1', 'Gene', '29126', (62, 67))	('tumour', 'Phenotype', 'HP:0002664', (117, 123))	('tumour', 'Phenotype', 'HP:0002664', (49, 55))	('tumours', 'Disease', 'MESH:D009369', (117, 124))	('tumours', 'Phenotype', 'HP:0002664', (49, 56))	('tumours', 'Disease', 'MESH:D009369', (49, 56))	('tumours with disomy', 'Disease', 'MESH:D024182', (117, 136))	('PD-L1', 'Gene', (28, 33))	('polysomy', 'Var', (68, 76))	('tumours with disomy', 'Disease', (117, 136))	('higher', 'PosReg', (96, 102))	('tumours', 'Phenotype', 'HP:0002664', (117, 124))	('PD-L1', 'Gene', (62, 67))
360299	31788048	Furthermore, 7/12 carcinoma cases with strong membranous PD-L1 immunostaining (score 3+) showed PD-L1 amplification, 11/60 showed a polysomy, and 6/99 cases displayed a disomy.	('carcinoma', 'Disease', 'MESH:D002277', (18, 27))	('carcinoma', 'Phenotype', 'HP:0030731', (18, 27))	('PD-L1', 'Gene', '29126', (96, 101))	('amplification', 'MPA', (102, 115))	('carcinoma', 'Disease', (18, 27))	('polysomy', 'Var', (132, 140))	('disomy', 'Disease', (169, 175))	('PD-L1', 'Gene', (57, 62))	('disomy', 'Disease', 'MESH:D024182', (169, 175))	('PD-L1', 'Gene', '29126', (57, 62))	('PD-L1', 'Gene', (96, 101))
360302	31788048	For the entire cohort, FIGO stage (HR, 2.87; 95% CI, 1.76-4.69; P<0.001 vs. HR, 14.73; 95% CI, 6.18-35.09; P<0.001), tumour size (HR, 2.30; 95% CI, 1.17-4.52; P=0.016 vs. HR, 6.79; 95% CI, 1.64-28.08; P=0.008), nodal status (HR, 1.98; 95% CI, 1.20-3.27; P=0.007 vs. HR, 2.19; 95% CI, 1.19-4.03; P=0.012), PD-L1 amplification (HR, 8.37; 95% CI, 3.67-19.12; P<0.001 vs. HR, 7.46; 95% CI, 3.15-17.69; P<0.001) and polysomy (HR, 2.39; 95% CI, 1.44-3.99; P=0.001 vs. HR, 2.08; 95% CI, 1.07-4.05; P=0.031) were univariately associated with RFS and CSS.	('associated', 'Reg', (518, 528))	('tumour', 'Phenotype', 'HP:0002664', (117, 123))	('CSS', 'Disease', (542, 545))	('PD-L1', 'Gene', (305, 310))	('tumour', 'Disease', 'MESH:D009369', (117, 123))	('PD-L1', 'Gene', '29126', (305, 310))	('tumour', 'Disease', (117, 123))	('RFS', 'Disease', (534, 537))	('polysomy', 'Var', (411, 419))
360323	31788048	Interactions between extrinsic stimuli and the IFN-gamma receptor could lead to the expression and activation of various downstream signalling pathways, including nuclear factor-kappa light chain enhancer of activated B cells (NF-kappaB), mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase (PI3K), mammalian target of rapamycin (mTOR) and Janus kinase/signal transducer and activator of transcription (JAK/STAT), which promote cell cycle progression and the activation of transcription factors.	('mammalian target of rapamycin', 'Gene', (314, 343))	('activator of transcription', 'Gene', (390, 416))	('promote', 'PosReg', (435, 442))	('mammalian target of rapamycin', 'Gene', '2475', (314, 343))	('mTOR', 'Gene', (345, 349))	('mTOR', 'Gene', '2475', (345, 349))	('Interactions', 'Var', (0, 12))	('NF-kappaB', 'Gene', '4790', (227, 236))	('activation', 'PosReg', (99, 109))	('IFN-gamma', 'Gene', '3458', (47, 56))	('IFN-gamma', 'Gene', (47, 56))	('phosphoinositide 3-kinase', 'Gene', '5290', (280, 305))	('phosphoinositide 3-kinase', 'Gene', (280, 305))	('NF-kappaB', 'Gene', (227, 236))	('cell cycle progression', 'CPA', (443, 465))
360335	31788048	In contrast, PD-L1 expression can be continuously activated via gene amplification events involving a gene locus on chromosome 9p24.1.	('expression', 'MPA', (19, 29))	('p24.1', 'Gene', '29102', (128, 133))	('activated', 'PosReg', (50, 59))	('p24.1', 'Gene', (128, 133))	('PD-L1', 'Gene', (13, 18))	('gene amplification', 'Var', (64, 82))	('PD-L1', 'Gene', '29126', (13, 18))
360339	31788048	Amplification of the chromosomal region 9p24.1 has recently been demonstrated as an essential mechanism for increased PD-L1 protein expression in nodular sclerosing classical Hodgkin lymphoma and primary mediastinal large B-cell lymphoma and has also been identified in colorectal carcinoma, triple-negative breast cancer, glioblastoma and gastric adenocarcinoma, and cervical and vulvar carcinoma.	('Hodgkin lymphoma', 'Disease', (175, 191))	('p24.1', 'Gene', (41, 46))	('breast cancer', 'Phenotype', 'HP:0003002', (308, 321))	('glioblastoma', 'Disease', (323, 335))	('breast cancer', 'Disease', 'MESH:D001943', (308, 321))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (222, 237))	('primary mediastinal large B-cell lymphoma', 'Disease', (196, 237))	('glioblastoma', 'Phenotype', 'HP:0012174', (323, 335))	('lymphoma', 'Phenotype', 'HP:0002665', (183, 191))	('breast cancer', 'Disease', (308, 321))	('gastric adenocarcinoma', 'Disease', 'MESH:D013274', (340, 362))	('increased', 'PosReg', (108, 117))	('Hodgkin lymphoma', 'Phenotype', 'HP:0012189', (175, 191))	('Hodgkin lymphoma', 'Disease', 'MESH:D006689', (175, 191))	('carcinoma', 'Phenotype', 'HP:0030731', (388, 397))	('lymphoma', 'Phenotype', 'HP:0002665', (229, 237))	('vulvar carcinoma', 'Disease', 'MESH:D014846', (381, 397))	('PD-L1', 'Gene', (118, 123))	('protein', 'Protein', (124, 131))	('increased PD', 'Phenotype', 'HP:0008151', (108, 120))	('PD-L1', 'Gene', '29126', (118, 123))	('cancer', 'Phenotype', 'HP:0002664', (315, 321))	('Amplification', 'Var', (0, 13))	('gastric adenocarcinoma', 'Disease', (340, 362))	('colorectal carcinoma', 'Disease', (270, 290))	('p24.1', 'Gene', '29102', (41, 46))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (270, 290))	('carcinoma', 'Phenotype', 'HP:0030731', (281, 290))	('glioblastoma', 'Disease', 'MESH:D005909', (323, 335))	('vulvar carcinoma', 'Disease', (381, 397))	('expression', 'MPA', (132, 142))	('carcinoma', 'Phenotype', 'HP:0030731', (353, 362))
360340	31788048	In the present study, our results demonstrated that PD-L1 copy number gains (amplification and polysomy) can be observed in a subset of cervical cancer patients using FISH analysis (35.4% for HIV-positive patients and 44.7% for HIV-negative patients).	('HIV', 'Disease', (228, 231))	('patients', 'Species', '9606', (205, 213))	('PD-L1', 'Gene', '29126', (52, 57))	('cervical cancer', 'Disease', (136, 151))	('cervical cancer', 'Disease', 'MESH:D002583', (136, 151))	('HIV', 'Disease', 'MESH:D015658', (228, 231))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('copy number', 'Var', (58, 69))	('HIV', 'Disease', (192, 195))	('patients', 'Species', '9606', (152, 160))	('HIV', 'Disease', 'MESH:D015658', (192, 195))	('PD-L1', 'Gene', (52, 57))	('patients', 'Species', '9606', (241, 249))	('gains', 'PosReg', (70, 75))
360342	31788048	More importantly, we found that ART was correlated with PD-L1 copy number status in addition to protein expression.	('PD-L1', 'Gene', '29126', (56, 61))	('ART', 'Gene', '9048', (32, 35))	('correlated', 'Reg', (40, 50))	('ART', 'Gene', (32, 35))	('copy number status', 'Var', (62, 80))	('PD-L1', 'Gene', (56, 61))
360343	31788048	In the present study, we demonstrated a novel genetic association between PD-L1 copy number gain and ART in cervical carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('PD-L1', 'Gene', (74, 79))	('cervical carcinoma', 'Disease', 'MESH:D002583', (108, 126))	('ART', 'Gene', '9048', (101, 104))	('ART', 'Gene', (101, 104))	('PD-L1', 'Gene', '29126', (74, 79))	('copy number', 'Var', (80, 91))	('gain', 'PosReg', (92, 96))	('cervical carcinoma', 'Disease', (108, 126))
360349	31788048	Considering survival outcomes, we found that both copy number gains in the PD-L1 gene and PD-L1 overexpression indicated poor prognosis in univariate analysis.	('PD-L1', 'Gene', (75, 80))	('PD-L1', 'Gene', '29126', (90, 95))	('PD-L1', 'Gene', '29126', (75, 80))	('copy number gains', 'Var', (50, 67))	('PD-L1', 'Gene', (90, 95))
360350	31788048	However, PD-L1 copy number gains were superior to PD-L1 overexpression and could act as independent and strong predictors of survival outcomes in cervical carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (155, 164))	('PD-L1', 'Gene', (50, 55))	('PD-L1', 'Gene', '29126', (9, 14))	('cervical carcinoma', 'Disease', 'MESH:D002583', (146, 164))	('copy number gains', 'Var', (15, 32))	('PD-L1', 'Gene', '29126', (50, 55))	('PD-L1', 'Gene', (9, 14))	('cervical carcinoma', 'Disease', (146, 164))
360351	31788048	Our results may identify a new subgroup of cervical cancer with a disease-specific genetic alteration.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('genetic alteration', 'Var', (83, 101))	('cervical cancer', 'Disease', (43, 58))	('cervical cancer', 'Disease', 'MESH:D002583', (43, 58))
360352	31788048	Further studies are required to evaluate the impact of PD-L1 copy number gain on pathogenesis, disease progression and prognosis in this newly identified subgroup of cervical cancer patients.	('cervical cancer', 'Disease', (166, 181))	('cervical cancer', 'Disease', 'MESH:D002583', (166, 181))	('copy number', 'Var', (61, 72))	('PD-L1', 'Gene', '29126', (55, 60))	('gain', 'PosReg', (73, 77))	('patients', 'Species', '9606', (182, 190))	('PD-L1', 'Gene', (55, 60))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
360374	31632065	Patients who drive gene mutations can choose molecular-targeted therapy, which has achieved significant effects on mutations of epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK) and ROS1 translocation/rearrangement, while these mutations are accounting for only 5-15% of NSCLC.	('ALK', 'Gene', (197, 200))	('effects', 'Reg', (104, 111))	('EGFR', 'Gene', (162, 166))	('ROS1', 'Gene', (206, 210))	('NSCLC', 'Phenotype', 'HP:0030358', (295, 300))	('mutations', 'Var', (24, 33))	('SCLC', 'Disease', 'MESH:D055752', (296, 300))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (169, 188))	('Patients', 'Species', '9606', (0, 8))	('anaplastic lymphoma kinase', 'Gene', '238', (169, 195))	('SCLC', 'Disease', (296, 300))	('anaplastic lymphoma kinase', 'Gene', (169, 195))	('EGFR', 'Gene', '1956', (162, 166))	('SCLC', 'Phenotype', 'HP:0030357', (296, 300))	('ROS1', 'Gene', '6098', (206, 210))	('lymphoma', 'Phenotype', 'HP:0002665', (180, 188))	('mutations', 'Var', (115, 124))	('ALK', 'Gene', '238', (197, 200))	('epidermal growth factor receptor', 'Gene', (128, 160))	('epidermal growth factor receptor', 'Gene', '1956', (128, 160))
360380	31632065	Recent studies have shown that inhibition of proteasome activity can prevent the degradation of IFIT2, promote the aggregation of IFIT2 in the cell centrosome and then induce cell apoptosis.	('induce', 'Reg', (168, 174))	('aggregation', 'MPA', (115, 126))	('IFIT2', 'Gene', '3433', (96, 101))	('cell apoptosis', 'CPA', (175, 189))	('IFIT2', 'Gene', (130, 135))	('degradation', 'MPA', (81, 92))	('prevent', 'NegReg', (69, 76))	('inhibition', 'Var', (31, 41))	('promote', 'PosReg', (103, 110))	('IFIT2', 'Gene', '3433', (130, 135))	('IFIT2', 'Gene', (96, 101))
360424	31632065	In lung adenocarcinoma, when we selected H-score=170 as the cut-off, the patients with H-score>=170 were defined as high expression group, while the patients with H-score<170 were defined as low expression group.	('patients', 'Species', '9606', (149, 157))	('carcinoma', 'Phenotype', 'HP:0030731', (13, 22))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (3, 22))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (3, 22))	('H-score>=170', 'Var', (87, 99))	('patients', 'Species', '9606', (73, 81))	('lung adenocarcinoma', 'Disease', (3, 22))
360431	31632065	In lung squamous cell carcinoma, the survival analysis showed that the OS of patients with low IFIT2 expression was significantly poorer compared with those with high IFIT2 expression (HR =2.907, 95% CI: 1.118-7.559, P = 0.029, Figure 2D).	('low', 'Var', (91, 94))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (8, 31))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (3, 31))	('lung squamous cell carcinoma', 'Disease', (3, 31))	('IFIT2', 'Gene', (167, 172))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('patients', 'Species', '9606', (77, 85))	('IFIT2', 'Gene', (95, 100))	('IFIT2', 'Gene', '3433', (167, 172))	('expression', 'MPA', (101, 111))	('poorer', 'NegReg', (130, 136))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (3, 31))	('IFIT2', 'Gene', '3433', (95, 100))
360432	31632065	Multi-factor Cox model analysis indicated that lymph node metastasis (HR = 3.390, 95% CI: 1.029-11.175, P = 0.045) and low IFIT2 expression (HR = 3.762, 95% CI: 1.236-11.451, P = 0.020) were independent prognostic factors of lung squamous cell carcinoma (Table 4).	('lung squamous cell carcinoma', 'Disease', (225, 253))	('expression', 'MPA', (129, 139))	('Cox', 'Gene', (13, 16))	('IFIT2', 'Gene', '3433', (123, 128))	('low', 'Var', (119, 122))	('lymph node metastasis', 'CPA', (47, 68))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (225, 253))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (225, 253))	('carcinoma', 'Phenotype', 'HP:0030731', (244, 253))	('IFIT2', 'Gene', (123, 128))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (230, 253))	('Cox', 'Gene', '1351', (13, 16))
360438	31632065	All these data suggested that depletion of IFIT2 could significantly promote the proliferation of human NSCLC cells.	('SCLC', 'Disease', 'MESH:D055752', (105, 109))	('SCLC', 'Disease', (105, 109))	('depletion', 'Var', (30, 39))	('IFIT2', 'Gene', (43, 48))	('SCLC', 'Phenotype', 'HP:0030357', (105, 109))	('promote', 'PosReg', (69, 76))	('IFIT2', 'Gene', '3433', (43, 48))	('human', 'Species', '9606', (98, 103))	('NSCLC', 'Phenotype', 'HP:0030358', (104, 109))
360441	31632065	These results suggested that depletion of IFIT2 could significantly enhance the migration ability of A549, H1975 and SK-MES-1 cells.	('depletion', 'Var', (29, 38))	('IFIT2', 'Gene', '3433', (42, 47))	('migration ability', 'CPA', (80, 97))	('IFIT2', 'Gene', (42, 47))	('enhance', 'PosReg', (68, 75))
360442	31632065	Transwell invasion assay was conducted to study the invasive ability of human lung cancer cell lines A549, H1975 and SK-MES-1 upon IFIT2 depletion.	('lung cancer', 'Disease', (78, 89))	('IFIT2', 'Gene', (131, 136))	('lung cancer', 'Phenotype', 'HP:0100526', (78, 89))	('depletion', 'Var', (137, 146))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('IFIT2', 'Gene', '3433', (131, 136))	('human', 'Species', '9606', (72, 77))	('lung cancer', 'Disease', 'MESH:D008175', (78, 89))
360461	31632065	Studies have shown that IFIT2 depletion can lead to up-regulation of TNFalpha, which promotes angiogenesis and metastasis of oral squamous cell carcinoma.	('up-regulation', 'PosReg', (52, 65))	('angiogenesis', 'CPA', (94, 106))	('IFIT2', 'Gene', '3433', (24, 29))	('metastasis of oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (111, 153))	('TNFalpha', 'Gene', (69, 77))	('depletion', 'Var', (30, 39))	('promotes', 'PosReg', (85, 93))	('TNFalpha', 'Gene', '7124', (69, 77))	('metastasis of oral squamous cell carcinoma', 'Disease', (111, 153))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (130, 153))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('IFIT2', 'Gene', (24, 29))
360462	31632065	Studies on the mechanism of IFIT2 in OSCC indicate that IFIT2 deficiency can activate atypical protein kinase C (aPKC) pathway, induce epithelial-mesenchymal transition (EMT), cell migration and invasion, and participate in the progression of OSCC tumors.	('activate', 'PosReg', (77, 85))	('IFIT2', 'Gene', (56, 61))	('OSCC tumors', 'Disease', 'MESH:D009369', (243, 254))	('IFIT2', 'Gene', '3433', (28, 33))	('cell migration', 'CPA', (176, 190))	('IFIT2', 'Gene', '3433', (56, 61))	('epithelial-mesenchymal transition', 'Pathway', (135, 168))	('deficiency', 'Var', (62, 72))	('invasion', 'CPA', (195, 203))	('tumors', 'Phenotype', 'HP:0002664', (248, 254))	('participate', 'Reg', (209, 220))	('induce', 'PosReg', (128, 134))	('tumor', 'Phenotype', 'HP:0002664', (248, 253))	('OSCC tumors', 'Disease', (243, 254))	('IFIT2', 'Gene', (28, 33))
360470	31632065	Our results showed that after depletion of IFIT2 in these cells, the cellular abilities of viability, migration and invasion were significantly inhibited.	('depletion', 'Var', (30, 39))	('invasion', 'CPA', (116, 124))	('inhibited', 'NegReg', (144, 153))	('IFIT2', 'Gene', (43, 48))	('IFIT2', 'Gene', '3433', (43, 48))	('cellular abilities of viability', 'CPA', (69, 100))
360477	30899002	Here we demonstrate that Rb and mTORC1 contribute to Gln-addiction upon the dysregulation of the Fbxo4-cyclin D1 axis, which leads to the reprogramming of cellular metabolism.	('contribute', 'Reg', (39, 49))	('mTORC1', 'Gene', (32, 38))	('cellular metabolism', 'MPA', (155, 174))	('Gln', 'Chemical', 'MESH:D005973', (53, 56))	('leads to', 'Reg', (125, 133))	('dysregulation', 'Var', (76, 89))	('reprogramming', 'MPA', (138, 151))	('mTORC1', 'Gene', '382056', (32, 38))	('Gln-addiction', 'Disease', (53, 66))
360480	30899002	Our findings reveal a molecular basis for cancer therapy through targeting glutaminolysis and mitochondrial respiration in ESCC with dysregulated Fbxo4-cyclin D1 axis as well as cancers resistant to CDK4/6 inhibitors.	('SCC', 'Gene', '6317', (124, 127))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('cancers', 'Disease', 'MESH:D009369', (178, 185))	('SCC', 'Gene', (124, 127))	('cancers', 'Phenotype', 'HP:0002664', (178, 185))	('cancers', 'Disease', (178, 185))	('cancer', 'Disease', (42, 48))	('glutaminolysis', 'MPA', (75, 89))	('cancer', 'Disease', (178, 184))	('mitochondrial respiration', 'MPA', (94, 119))	('dysregulated', 'Var', (133, 145))	('targeting', 'Reg', (65, 74))	('Fbxo4-cyclin D1 axis', 'MPA', (146, 166))	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('cancer', 'Disease', 'MESH:D009369', (42, 48))
360482	30899002	Here, the authors show that the dysregulation of Fbxo4-cyclin D1 leads to mitochondrial dysfunction and glutamine addiction rendering these tumors susceptible to metabolic inhibitors even when resistant to CDK4/6 inhibitors.	('glutamine', 'Chemical', 'MESH:D005973', (104, 113))	('tumors', 'Disease', (140, 146))	('dysregulation', 'Var', (32, 45))	('glutamine addiction', 'MPA', (104, 123))	('tumors', 'Disease', 'MESH:D009369', (140, 146))	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('leads to', 'Reg', (65, 73))	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (74, 99))	('Fbxo4-cyclin D1', 'Gene', (49, 64))	('mitochondrial dysfunction', 'Disease', 'MESH:D028361', (74, 99))	('mitochondrial dysfunction', 'Disease', (74, 99))
360485	30899002	Genome-wide screening has revealed numerous genetic alterations in ESCC, including inactivating mutations of TP53, Retinoblastoma protein (Rb) and CDKN2A, or activating mutations of NFE2L2, NOTCH1/2, MLL2, and EP300, or amplification of cyclin D1.	('EP300', 'Gene', '328572', (210, 215))	('inactivating mutations', 'Var', (83, 105))	('MLL2', 'Gene', (200, 204))	('SCC', 'Gene', '6317', (68, 71))	('TP53', 'Gene', '22059', (109, 113))	('NFE2L2', 'Gene', (182, 188))	('CDKN2A', 'Gene', '12578', (147, 153))	('CDKN2A', 'Gene', (147, 153))	('SCC', 'Gene', (68, 71))	('Rb', 'Gene', (139, 141))	('activating', 'PosReg', (158, 168))	('Retinoblastoma', 'Phenotype', 'HP:0009919', (115, 129))	('cyclin', 'Gene', (237, 243))	('Retinoblastoma protein', 'Disease', 'MESH:D012175', (115, 137))	('EP300', 'Gene', (210, 215))	('NFE2L2', 'Gene', '18024', (182, 188))	('NOTCH1/2', 'Gene', '18128;18129', (190, 198))	('NOTCH1/2', 'Gene', (190, 198))	('Retinoblastoma protein', 'Disease', (115, 137))	('MLL2', 'Gene', '75410', (200, 204))	('amplification', 'Var', (220, 233))	('TP53', 'Gene', (109, 113))
360486	30899002	Cyclin D1-CDK4/6 promotes G1 cell cycle progression through phosphorylation-dependent inactivation of Rb, the master gatekeeper of cell division.	('phosphorylation-dependent', 'Var', (60, 85))	('promotes', 'PosReg', (17, 25))	('G1 cell cycle progression', 'CPA', (26, 51))	('inactivation', 'Var', (86, 98))	('gatekeeper', 'Species', '111938', (117, 127))
360488	30899002	Overexpression of cyclin D1, due to gene amplification and inactivation of its degradation machinery, (for example, loss of the Fbxo4 E3 ubiquitin ligase or mutations in the cyclin D1 degron), directly contributes to the development and progression of ESCC, supporting a model wherein targeting cyclin D1-CDK4/6 could be effective for ESCC patients.	('SCC', 'Gene', '6317', (253, 256))	('SCC', 'Gene', (336, 339))	('degradation', 'MPA', (79, 90))	('inactivation', 'NegReg', (59, 71))	('SCC', 'Gene', '6317', (336, 339))	('Fbxo4', 'Gene', (128, 133))	('mutations', 'Var', (157, 166))	('patients', 'Species', '9606', (340, 348))	('cyclin D1 degron', 'Gene', (174, 190))	('SCC', 'Gene', (253, 256))	('loss', 'NegReg', (116, 120))	('contributes to', 'Reg', (202, 216))
360494	30899002	Knockdown or chemical suppression of GLS1 typically induces apoptosis, suppresses cell proliferation and tumor growth.	('GLS1', 'Gene', (37, 41))	('suppresses', 'NegReg', (71, 81))	('cell proliferation', 'CPA', (82, 100))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('apoptosis', 'CPA', (60, 69))	('GLS1', 'Gene', '2744', (37, 41))	('suppression', 'NegReg', (22, 33))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('induces', 'Reg', (52, 59))	('tumor', 'Disease', (105, 110))	('chemical', 'Var', (13, 21))
360499	30899002	We demonstrate that cyclin D1 overexpression, either as a consequence of direct mutation, or loss of its regulatory E3 ubiquitin ligase Fbxo4, results in Gln-addiction.	('cyclin D1', 'Protein', (20, 29))	('loss', 'NegReg', (93, 97))	('overexpression', 'PosReg', (30, 44))	('Gln-addiction', 'MPA', (154, 167))	('Gln', 'Chemical', 'MESH:D005973', (154, 157))	('Fbxo4', 'Gene', (136, 141))	('results in', 'Reg', (143, 153))	('mutation', 'Var', (80, 88))
360500	30899002	The dysregulation of Fbxo4-cyclin D1 axis leads to mitochondrial dysfunction and Gln-addiction.	('Gln-addiction', 'Disease', (81, 94))	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (51, 76))	('mitochondrial dysfunction', 'Disease', 'MESH:D028361', (51, 76))	('leads to', 'Reg', (42, 50))	('mitochondrial dysfunction', 'Disease', (51, 76))	('dysregulation', 'Var', (4, 17))	('Gln', 'Chemical', 'MESH:D005973', (81, 84))
360502	30899002	Gln-addiction has been associated with overexpression of c-Myc; however, its role has not been evaluated in cells harboring Fbxo4 mutation or cyclin D1 overexpression, which frequently occurs in human ESCC.	('SCC', 'Gene', (202, 205))	('human', 'Species', '9606', (195, 200))	('overexpression', 'MPA', (39, 53))	('Gln-addiction', 'Disease', (0, 13))	('mutation', 'Var', (130, 138))	('SCC', 'Gene', '6317', (202, 205))	('Fbxo4', 'Gene', (124, 129))	('c-Myc', 'Gene', '4609', (57, 62))	('c-Myc', 'Gene', (57, 62))	('Gln', 'Chemical', 'MESH:D005973', (0, 3))
360505	30899002	Gln-depletion triggered increased cleavage of both PARP and caspase-3, suggesting increased apoptosis of Fbxo4-/- versus +/+ MEFs (Fig.	('Gln', 'Chemical', 'MESH:D005973', (0, 3))	('caspase-3', 'Gene', '12367', (60, 69))	('apoptosis', 'CPA', (92, 101))	('MEFs', 'CellLine', 'CVCL:9115', (125, 129))	('Gln-depletion', 'Var', (0, 13))	('PARP', 'Gene', (51, 55))	('cleavage', 'MPA', (34, 42))	('PARP', 'Gene', '11545', (51, 55))	('caspase-3', 'Gene', (60, 69))	('increased', 'PosReg', (82, 91))	('Fbxo4-/-', 'Var', (105, 113))	('increased', 'PosReg', (24, 33))
360506	30899002	Elevated Gln uptake was apparent in Fbxo4-/- MEFs (Supplementary Fig.	('Gln uptake', 'MPA', (9, 19))	('Gln', 'Chemical', 'MESH:D005973', (9, 12))	('MEFs', 'CellLine', 'CVCL:9115', (45, 49))	('Elevated', 'PosReg', (0, 8))	('Fbxo4-/- MEFs', 'Var', (36, 49))
360510	30899002	To determine whether the sensitivity to Gln-depletion reflected Fbxo4 E3 ligase function, WT Fbxo4 or Fbxo4 DeltaN, DeltaF, DeltaC2, and DeltaC3 were transduced into Fbxo4-/- MEFs.	('DeltaC2', 'Var', (124, 131))	('DeltaF', 'Var', (116, 122))	('DeltaC2', 'DELETION', 'None', (124, 131))	('MEFs', 'CellLine', 'CVCL:9115', (175, 179))	('DeltaC3', 'Var', (137, 144))	('DeltaC3', 'DELETION', 'None', (137, 144))	('DeltaN', 'Var', (108, 114))	('Gln', 'Chemical', 'MESH:D005973', (40, 43))	('Fbxo4', 'Gene', (102, 107))
360519	30899002	Fbxo4 and cyclin D1 double knockout MEFs exhibited lower apoptosis triggered by Gln-depletion relative to Fbxo4 single knockout MEFs (Fig.	('apoptosis triggered by Gln-depletion', 'MPA', (57, 93))	('Gln', 'Chemical', 'MESH:D005973', (80, 83))	('lower', 'NegReg', (51, 56))	('cyclin D1', 'Gene', (10, 19))	('MEFs', 'CellLine', 'CVCL:9115', (128, 132))	('double knockout', 'Var', (20, 35))	('Fbxo4', 'Gene', (0, 5))	('MEFs', 'CellLine', 'CVCL:9115', (36, 40))
360520	30899002	In addition, ectopic expression of WT cyclin D1, or a stabilized Fbxo4-resistant cyclin D1 mutant, D1T286A, greatly sensitized cells to Gln restriction (Fig.	('sensitized', 'Reg', (116, 126))	('D1T286A', 'Var', (99, 106))	('T286A', 'Mutation', 'c.286T>A', (101, 106))	('Gln restriction', 'MPA', (136, 151))	('Gln', 'Chemical', 'MESH:D005973', (136, 139))
360522	30899002	Furthermore, Gln uptake was also increased by ectopic cyclin D1 (Supplementary Fig.	('ectopic', 'Var', (46, 53))	('cyclin D1', 'Protein', (54, 63))	('increased', 'PosReg', (33, 42))	('Gln', 'Chemical', 'MESH:D005973', (13, 16))	('Gln uptake', 'MPA', (13, 23))
360525	30899002	Loss of function mutation of Fbxo4 leads to cyclin D1 accumulation, contributing to the development of human ESCC; moreover, Fbxo4 loss results in susceptibility to upper gastrointestinal tumors in transgenic mice.	('tumors', 'Phenotype', 'HP:0002664', (188, 194))	('human', 'Species', '9606', (103, 108))	('Fbxo4', 'Gene', (125, 130))	('mutation', 'Var', (17, 25))	('loss', 'NegReg', (131, 135))	('cyclin D1 accumulation', 'MPA', (44, 66))	('SCC', 'Gene', (110, 113))	('gastrointestinal tumors', 'Phenotype', 'HP:0007378', (171, 194))	('Loss of function', 'NegReg', (0, 16))	('transgenic mice', 'Species', '10090', (198, 213))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('Fbxo4', 'Gene', (29, 34))	('upper gastrointestinal tumors', 'Disease', (165, 194))	('SCC', 'Gene', '6317', (110, 113))	('upper gastrointestinal tumors', 'Disease', 'MESH:D004067', (165, 194))
360530	30899002	Furthermore, SurvExpress survival analysis indicated the dysregulation of Gln metabolism genes correlates with poor prognosis of human esophageal cancer as well as Head and Neck SCC (Fig.	('dysregulation', 'Var', (57, 70))	('SCC', 'Gene', '6317', (178, 181))	('Gln metabolism genes', 'Gene', (74, 94))	('esophageal cancer', 'Disease', (135, 152))	('esophageal cancer', 'Disease', 'MESH:D004938', (135, 152))	('Gln', 'Chemical', 'MESH:D005973', (74, 77))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('human', 'Species', '9606', (129, 134))	('SCC', 'Gene', (178, 181))
360531	30899002	To corroborate the above genome-wide findings, five representative ESCC cells were chosen to investigate Gln-dependency: TE7 (WT Fbxo4, cyclin D1P287A), TE8 (WT Fbxo4, WT cyclin D1, Akt hyperactivation), TE10 (Fbxo4 S8R, WT cyclin D1), TE15 (WT Fbxo4, WT cyclin D1), and TE1 (Rb deficient).	('TE1', 'Gene', (236, 239))	('TE1', 'Gene', '57816', (271, 274))	('TE1', 'Gene', (204, 207))	('SCC', 'Gene', '6317', (68, 71))	('WT Fbxo4', 'Var', (242, 250))	('Gln', 'Chemical', 'MESH:D005973', (105, 108))	('Akt', 'Gene', '11651', (182, 185))	('TE1', 'Gene', (271, 274))	('TE1', 'Gene', '57816', (236, 239))	('TE1', 'Gene', '57816', (204, 207))	('Akt', 'Gene', (182, 185))	('SCC', 'Gene', (68, 71))
360532	30899002	Gln restriction triggered more PARP cleavage and apoptosis in TE7 and TE10 than in TE15 cells (Fig.	('Gln', 'Chemical', 'MESH:D005973', (0, 3))	('TE1', 'Gene', '57816', (83, 86))	('TE1', 'Gene', '57816', (70, 73))	('PARP', 'Gene', (31, 35))	('PARP', 'Gene', '11545', (31, 35))	('Gln restriction', 'Var', (0, 15))	('TE1', 'Gene', (83, 86))	('TE1', 'Gene', (70, 73))	('apoptosis', 'CPA', (49, 58))
360533	30899002	2d, h), consistent with the notion that dysregulation of Fbxo4-cyclin D1 promotes Gln-dependency.	('Gln-dependency', 'Disease', (82, 96))	('Fbxo4-cyclin', 'Gene', (57, 69))	('dysregulation', 'Var', (40, 53))	('promotes', 'PosReg', (73, 81))	('Gln', 'Chemical', 'MESH:D005973', (82, 85))
360534	30899002	Importantly, c-Myc knockdown did not reduce Gln-addiction in TE7 or TE10 cells (Supplementary Fig.	('c-Myc', 'Gene', (13, 18))	('knockdown', 'Var', (19, 28))	('Gln-addiction', 'MPA', (44, 57))	('TE1', 'Gene', (68, 71))	('Gln', 'Chemical', 'MESH:D005973', (44, 47))	('c-Myc', 'Gene', '4609', (13, 18))	('TE1', 'Gene', '57816', (68, 71))
360537	30899002	Furthermore, WT Fbxo4 not only reduced cyclin D1 levels but also compromised apoptosis triggered by Gln restriction in TE10 cells (Fig.	('cyclin D1 levels', 'MPA', (39, 55))	('Gln', 'Chemical', 'MESH:D005973', (100, 103))	('reduced', 'NegReg', (31, 38))	('apoptosis', 'CPA', (77, 86))	('TE1', 'Gene', (119, 122))	('compromised', 'NegReg', (65, 76))	('Gln restriction', 'Var', (100, 115))	('TE1', 'Gene', '57816', (119, 122))
360538	30899002	To test whether cyclin D1 is sufficient to drive cellular Gln-dependency, cyclin D1 or D1T286A (a stable oncogenic D1 mutant analogous to D1P287A), were ectopically expressed in TE15 cells.	('TE1', 'Gene', '57816', (178, 181))	('TE1', 'Gene', (178, 181))	('cyclin D1', 'Gene', (74, 83))	('D1T286A', 'Var', (87, 94))	('Gln', 'Chemical', 'MESH:D005973', (58, 61))	('T286A', 'Mutation', 'c.286T>A', (89, 94))
360539	30899002	D1T286A expression drove apoptosis of TE15 cells cultured in Gln-free medium (Fig.	('D1T286A expression', 'Var', (0, 18))	('TE1', 'Gene', '57816', (38, 41))	('T286A', 'Mutation', 'c.286T>A', (2, 7))	('Gln', 'Chemical', 'MESH:D005973', (61, 64))	('apoptosis', 'CPA', (25, 34))	('TE1', 'Gene', (38, 41))
360541	30899002	Likewise, Rb knockdown promoted Gln-addiction in TE15 cells that mimics the findings in TE1 cells (Supplementary Fig.	('TE1', 'Gene', (88, 91))	('promoted', 'PosReg', (23, 31))	('Gln-addiction', 'MPA', (32, 45))	('TE1', 'Gene', '57816', (49, 52))	('Gln', 'Chemical', 'MESH:D005973', (32, 35))	('TE1', 'Gene', '57816', (88, 91))	('TE1', 'Gene', (49, 52))	('knockdown', 'Var', (13, 22))
360549	30899002	In addition, dysregulation of Fbxo4-cyclin D1 also promoted more mTORC1 activation in TE7 and TE10 cells compared to TE15 cells; furthermore, increased basal mTORC1 activation was also detected in TE7 and TE10 cells (Fig.	('TE1', 'Gene', (205, 208))	('mTORC1', 'Gene', (65, 71))	('mTORC1', 'Gene', '382056', (158, 164))	('dysregulation', 'Var', (13, 26))	('activation', 'MPA', (72, 82))	('Fbxo4-cyclin', 'Var', (30, 42))	('TE1', 'Gene', '57816', (117, 120))	('TE1', 'Gene', '57816', (94, 97))	('mTORC1', 'Gene', (158, 164))	('TE1', 'Gene', '57816', (205, 208))	('promoted', 'PosReg', (51, 59))	('mTORC1', 'Gene', '382056', (65, 71))	('TE1', 'Gene', (94, 97))	('TE1', 'Gene', (117, 120))
360553	30899002	Consistent with mTORC1 inhibition, both rapamycin and Rad001, partially suppressed cell apoptosis as determined by reduced cleavage of both PARP and caspases-3 (Fig.	('cleavage', 'MPA', (123, 131))	('caspases-3', 'Protein', (149, 159))	('PARP', 'Gene', (140, 144))	('reduced', 'NegReg', (115, 122))	('Rad001', 'Var', (54, 60))	('mTORC1', 'Gene', (16, 22))	('inhibition', 'NegReg', (23, 33))	('PARP', 'Gene', '11545', (140, 144))	('suppressed', 'NegReg', (72, 82))	('cell apoptosis', 'CPA', (83, 97))	('mTORC1', 'Gene', '382056', (16, 22))
360554	30899002	In addition, Raptor knockdown also compromised cell apoptosis (Fig.	('cell apoptosis', 'CPA', (47, 61))	('Raptor', 'Gene', (13, 19))	('compromised', 'NegReg', (35, 46))	('Raptor', 'Gene', '74370', (13, 19))	('knockdown', 'Var', (20, 29))
360559	30899002	Likewise, overexpression of cyclin D1 or D1T286A, either of which increases CDK4/6 catalytic activity, reduced the ATP/ADP ratio with oncogenic D1T286A having a more profound effect (Fig.	('CDK4/6', 'Protein', (76, 82))	('T286A', 'Mutation', 'c.286T>A', (146, 151))	('increases', 'PosReg', (66, 75))	('reduced', 'NegReg', (103, 110))	('ATP/ADP ratio', 'MPA', (115, 128))	('catalytic activity', 'MPA', (83, 101))	('ADP', 'Chemical', 'MESH:D000244', (119, 122))	('D1T286A', 'Var', (144, 151))	('T286A', 'Mutation', 'c.286T>A', (43, 48))	('ATP', 'Chemical', 'MESH:D000255', (115, 118))
360560	30899002	In addition, TE10 cells with mutant Fbxo4 exhibited a decreased ATP/ADP ratio, as did TE7 cells harboring D1P287A, a mutant refractory to Fbxo4-mediated degradation (Fig.	('ATP', 'Chemical', 'MESH:D000255', (64, 67))	('mutant', 'Var', (29, 35))	('TE1', 'Gene', (13, 16))	('ATP/ADP ratio', 'MPA', (64, 77))	('decreased', 'NegReg', (54, 63))	('Fbxo4', 'Gene', (36, 41))	('ADP', 'Chemical', 'MESH:D000244', (68, 71))	('TE1', 'Gene', '57816', (13, 16))
360561	30899002	Moreover, activation of the AMPK pathway was also observed upon Gln-depletion (Fig.	('Gln-depletion', 'Var', (64, 77))	('AMPK pathway', 'Pathway', (28, 40))	('activation', 'PosReg', (10, 20))	('Gln', 'Chemical', 'MESH:D005973', (64, 67))
360562	30899002	4d), supporting reduced ATP/ADP ratio in Fbxo4-/- MEFs.	('ADP', 'Chemical', 'MESH:D000244', (28, 31))	('reduced', 'NegReg', (16, 23))	('ATP', 'Chemical', 'MESH:D000255', (24, 27))	('Fbxo4-/- MEFs', 'Var', (41, 54))	('ATP/ADP ratio', 'MPA', (24, 37))	('MEFs', 'CellLine', 'CVCL:9115', (50, 54))
360566	30899002	Fbxo4 -/- MEFs exhibited reduced oxygen consumption relative to +/+ counterparts (Fig.	('oxygen consumption', 'MPA', (33, 51))	('reduced', 'NegReg', (25, 32))	('Fbxo4 -/- MEFs', 'Var', (0, 14))	('MEFs', 'CellLine', 'CVCL:9115', (10, 14))	('oxygen', 'Chemical', 'MESH:D010100', (33, 39))
360567	30899002	Fbxo4-/- MEFs exhibited a lower mitochondrial potential than +/+ counterparts (Fig.	('MEFs', 'CellLine', 'CVCL:9115', (9, 13))	('lower mitochondrial potential', 'Phenotype', 'HP:0040013', (26, 55))	('mitochondrial potential', 'MPA', (32, 55))	('Fbxo4-/- MEFs', 'Var', (0, 13))	('lower', 'NegReg', (26, 31))
360569	30899002	Moreover, ectopic cyclin D1 also compromised mitochondrial membrane potential in NIH3T3 cells (Supplementary Fig.	('cyclin D1', 'Protein', (18, 27))	('mitochondrial membrane potential', 'MPA', (45, 77))	('ectopic', 'Var', (10, 17))	('compromised', 'NegReg', (33, 44))	('NIH3T3', 'CellLine', 'CVCL:0594', (81, 87))
360570	30899002	Gln-addiction and defective mitochondrial respiration suggests the therapeutic potential of targeting both glutaminolysis and mitochondrial respiration in tumors with dysregulated Fbxo4-cyclin D1 axis.	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('mitochondrial respiration', 'MPA', (28, 53))	('tumors', 'Phenotype', 'HP:0002664', (155, 161))	('defective', 'Var', (18, 27))	('tumors', 'Disease', (155, 161))	('tumors', 'Disease', 'MESH:D009369', (155, 161))	('mitochondrial', 'MPA', (126, 139))	('Gln', 'Chemical', 'MESH:D005973', (0, 3))
360572	30899002	Phenformin induced more apoptosis in Fbxo4-/- MEFs challenged by Gln-depletion or GLS1 inhibition (Fig.	('Gln-depletion', 'MPA', (65, 78))	('GLS1', 'Gene', (82, 86))	('Phenformin', 'Chemical', 'MESH:D010629', (0, 10))	('apoptosis', 'CPA', (24, 33))	('GLS1', 'Gene', '2744', (82, 86))	('MEFs', 'CellLine', 'CVCL:9115', (46, 50))	('Fbxo4-/-', 'Var', (37, 45))	('Gln', 'Chemical', 'MESH:D005973', (65, 68))
360574	30899002	Consistently, combined treatment induced more cell apoptosis in NIH3T3 and TE15 cells with ectopic cyclin D1 expression and in TE7 or TE10 cells harboring dysregulated Fbxo4-cyclin D1 (Fig.	('TE1', 'Gene', '57816', (134, 137))	('TE1', 'Gene', (75, 78))	('dysregulated', 'Var', (155, 167))	('ectopic', 'Var', (91, 98))	('cell apoptosis', 'CPA', (46, 60))	('TE1', 'Gene', (134, 137))	('TE1', 'Gene', '57816', (75, 78))	('cyclin D1', 'Gene', (99, 108))	('NIH3T3', 'CellLine', 'CVCL:0594', (64, 70))
360575	30899002	Taken together, these data provide a molecular basis for treating tumors with dysregulated Fbxo4-cyclin D1.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('treating tumors', 'Disease', (57, 72))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('treating tumors', 'Disease', 'MESH:D019553', (57, 72))	('dysregulated', 'Var', (78, 90))	('Fbxo4-cyclin D1', 'Gene', (91, 106))
360577	30899002	For single treatment, the EC50 for either CB-839 or metformin was uniformly lower in TE7 and TE10 cells relative to TE15 cells (Table 1 and Supplementary Fig.	('EC50', 'MPA', (26, 30))	('CB-839', 'Chemical', 'MESH:C000593334', (42, 48))	('TE7', 'Var', (85, 88))	('TE1', 'Gene', (116, 119))	('TE1', 'Gene', '57816', (93, 96))	('lower', 'NegReg', (76, 81))	('metformin', 'Chemical', 'MESH:D008687', (52, 61))	('metformin', 'Gene', (52, 61))	('CB-839', 'Gene', (42, 48))	('TE1', 'Gene', '57816', (116, 119))	('TE1', 'Gene', (93, 96))
360579	30899002	The combined treatment exhibited synergism at low concentration, with a stronger impact on TE7 and TE10 cells; the EC50s of CB-839 were 0.75 and 0.92 muM, respectively, compared to 1.77 muM for TE15 cells.	('TE1', 'Gene', (194, 197))	('50s', 'Species', '1214577', (117, 120))	('CB-839', 'Var', (124, 130))	('TE1', 'Gene', (99, 102))	('CB-839', 'Chemical', 'MESH:C000593334', (124, 130))	('TE1', 'Gene', '57816', (194, 197))	('TE1', 'Gene', '57816', (99, 102))
360581	30899002	The analyses demonstrated that cells with elevated cyclin D1 were more sensitive to combined treatment, 5 muM CB-839 and 0.5 mM metformin exhibited better suppressing effects in TE7 and TE10 than that in TE15 cells, while similar effects were also revealed in NIH3T3 cells (Supplementary Fig.	('NIH3T3', 'CellLine', 'CVCL:0594', (260, 266))	('TE1', 'Gene', (186, 189))	('cyclin', 'Gene', (51, 57))	('metformin', 'Chemical', 'MESH:D008687', (128, 137))	('TE1', 'Gene', (204, 207))	('CB-839', 'Var', (110, 116))	('TE1', 'Gene', '57816', (186, 189))	('suppressing', 'NegReg', (155, 166))	('CB-839', 'Chemical', 'MESH:C000593334', (110, 116))	('TE7', 'Var', (178, 181))	('TE1', 'Gene', '57816', (204, 207))	('elevated', 'PosReg', (42, 50))
360582	30899002	In addition, combined treatment also effectively suppressed colony formation of NIH3T3 cells with ectopic cyclin D1 expression (Supplementary Fig.	('NIH3T3', 'CellLine', 'CVCL:0594', (80, 86))	('suppressed', 'NegReg', (49, 59))	('ectopic', 'Var', (98, 105))	('colony formation', 'CPA', (60, 76))
360583	30899002	To assess the efficacy of combined treatment in vivo, two cell lines: TE7 (mutant cyclin D1P287A) and TE15 (WT cyclin D1) were chosen.	('TE1', 'Gene', '57816', (102, 105))	('TE1', 'Gene', (102, 105))	('mutant', 'Var', (75, 81))	('cyclin', 'Gene', (82, 88))
360591	30899002	In addition, pathological analyses revealed stronger impacts on cell proliferation (Ki-67 index) and apoptosis (cleaved caspase-3 staining) in TE7 xenografts than that in TE15 tumors (Fig.	('TE1', 'Gene', '57816', (171, 174))	('Ki-67', 'Gene', '17345', (84, 89))	('impacts', 'Reg', (53, 60))	('cell proliferation', 'CPA', (64, 82))	('caspase-3', 'Gene', '12367', (120, 129))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('tumors', 'Disease', (176, 182))	('TE7', 'Var', (143, 146))	('caspase-3', 'Gene', (120, 129))	('TE1', 'Gene', (171, 174))	('tumors', 'Disease', 'MESH:D009369', (176, 182))	('Ki-67', 'Gene', (84, 89))	('tumors', 'Phenotype', 'HP:0002664', (176, 182))	('apoptosis', 'CPA', (101, 110))
360594	30899002	Moreover, investigation of genome-wide datasets revealed the reprogramming of Gln metabolism genes upon either palbociclib treatment or CDK4/6 knockdown (Fig.	('Gln metabolism genes', 'Gene', (78, 98))	('palbociclib', 'Chemical', 'MESH:C500026', (111, 122))	('CDK4/6', 'Gene', (136, 142))	('Gln', 'Chemical', 'MESH:D005973', (78, 81))	('knockdown', 'Var', (143, 152))
360597	30899002	Phenotypically, both TE7PDR and TE10PDR cells demonstrated loss of Rb, and upregulation of GLS1 that was independent of c-Myc expression (Fig.	('c-Myc', 'Gene', (120, 125))	('GLS1', 'Gene', (91, 95))	('TE7PDR', 'Var', (21, 27))	('upregulation', 'PosReg', (75, 87))	('TE1', 'Gene', '57816', (32, 35))	('GLS1', 'Gene', '2744', (91, 95))	('c-Myc', 'Gene', '4609', (120, 125))	('loss', 'NegReg', (59, 63))	('TE1', 'Gene', (32, 35))
360598	30899002	PDR cells also exhibited increased Gln uptake relative to parental counterparts (Fig.	('Gln', 'Chemical', 'MESH:D005973', (35, 38))	('PDR', 'Var', (0, 3))	('Gln uptake', 'MPA', (35, 45))	('increased', 'PosReg', (25, 34))
360599	30899002	In accordance with these characteristics, both TE7PDR and TE10PDR cells were more sensitive to Gln-depletion (Supplementary Fig.	('TE1', 'Gene', (58, 61))	('Gln', 'Chemical', 'MESH:D005973', (95, 98))	('sensitive to Gln-depletion', 'MPA', (82, 108))	('TE7PDR', 'Var', (47, 53))	('TE1', 'Gene', '57816', (58, 61))
360600	30899002	19a), or GLS1 knockdown (Fig.	('GLS1', 'Gene', '2744', (9, 13))	('GLS1', 'Gene', (9, 13))	('knockdown', 'Var', (14, 23))
360603	30899002	In addition, both TE7PDR and TE10PDR cells showed lower EC50s comparing to their parental counterparts (Table 1 and Supplementary Fig.	('50s', 'Species', '1214577', (58, 61))	('lower', 'NegReg', (50, 55))	('TE1', 'Gene', (29, 32))	('TE7PDR', 'Var', (18, 24))	('TE1', 'Gene', '57816', (29, 32))	('EC50s', 'MPA', (56, 61))
360607	30899002	TE7PDR cells formed squamous cell carcinoma xenografts that responded better to combined treatment than their parental counterparts (Figs.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (20, 43))	('squamous cell carcinoma', 'Disease', (20, 43))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (20, 43))	('carcinoma', 'Phenotype', 'HP:0030731', (34, 43))	('TE7PDR cells', 'Var', (0, 12))
360612	30899002	The current investigation reveals the importance of dysregulation of the Fbxo4-cyclin D1 axis, a frequent occurrence in numerous cancers, in regulating Gln-addiction independent of the known signaling pathways (Fig.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('cancers', 'Phenotype', 'HP:0002664', (129, 136))	('numerous cancers', 'Disease', 'MESH:D009369', (120, 136))	('Gln', 'Chemical', 'MESH:D005973', (152, 155))	('dysregulation', 'Var', (52, 65))	('numerous cancers', 'Disease', (120, 136))	('Gln-addiction', 'MPA', (152, 165))
360616	30899002	Indeed, we find that cells with dysregulated Fbxo4-cyclin D1 exhibit increased Gln uptake.	('increased', 'PosReg', (69, 78))	('Fbxo4-cyclin D1', 'Gene', (45, 60))	('dysregulated', 'Var', (32, 44))	('Gln uptake', 'MPA', (79, 89))	('Gln', 'Chemical', 'MESH:D005973', (79, 82))
360623	30899002	Loss of Fbxo4 triggers radio-resistant DNA synthesis, and sensitizes cells to chemotherapeutic intervention; moreover, ectopic phospho-dead cyclin D1 (T286A) expression causes DNA re-replication, Cdt1 stabilization, DNA damage, and finally cell apoptosis.	('T286A', 'Mutation', 'c.286T>A', (151, 156))	('Cdt1', 'Gene', (196, 200))	('DNA damage', 'CPA', (216, 226))	('ectopic', 'Var', (119, 126))	('stabilization', 'PosReg', (201, 214))	('Fbxo4', 'Gene', (8, 13))	('T286A', 'Var', (151, 156))	('cell apoptosis', 'CPA', (240, 254))	('Loss', 'Var', (0, 4))	('DNA re-replication', 'CPA', (176, 194))	('Cdt1', 'Gene', '67177', (196, 200))
360625	30899002	Importantly, taking advantage of this genetic predisposition, targeting both GLS1 and OXPHOS effectively induces apoptosis, suppresses cell proliferation in cell culture, and inhibits the growth of tumor xenografts, demonstrating promising therapeutic efficacy.	('suppresses', 'NegReg', (124, 134))	('GLS1', 'Gene', (77, 81))	('induces', 'Reg', (105, 112))	('apoptosis', 'CPA', (113, 122))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('GLS1', 'Gene', '2744', (77, 81))	('OXPHOS', 'Gene', (86, 92))	('cell proliferation in cell culture', 'CPA', (135, 169))	('targeting', 'Var', (62, 71))	('tumor', 'Disease', (198, 203))	('inhibits', 'NegReg', (175, 183))
360629	30899002	Indeed, several CDK4/6 specific inhibitors have been developed, including PD-0332991 (palbociclib), LY2835219 (abemaciclib), and LEE011 (ribociclib), which are being intensively investigated in human tumors in pre-clinical studies and clinical trials.	('CDK4/6', 'Gene', (16, 22))	('palbociclib', 'Chemical', 'MESH:C500026', (86, 97))	('PD-0332991', 'Chemical', 'MESH:C500026', (74, 84))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('tumors', 'Phenotype', 'HP:0002664', (200, 206))	('LY2835219', 'Var', (100, 109))	('human', 'Species', '9606', (194, 199))	('tumors', 'Disease', (200, 206))	('LY2835219', 'Chemical', 'MESH:C000590451', (100, 109))	('tumors', 'Disease', 'MESH:D009369', (200, 206))	('PD-0332991', 'Var', (74, 84))	('LEE011', 'Var', (129, 135))
360631	30899002	We noted that loss of Rb engenders resistance to CDK4/6 inhibitors, but it enhances the sensitivity of tumor cells to combined treatment with CB-839 and metformin.	('metformin', 'Chemical', 'MESH:D008687', (153, 162))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('loss', 'Var', (14, 18))	('tumor', 'Disease', (103, 108))	('enhances', 'PosReg', (75, 83))	('combined treatment', 'Interaction', (118, 136))	('CB-839', 'Chemical', 'MESH:C000593334', (142, 148))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('sensitivity', 'MPA', (88, 99))	('resistance', 'MPA', (35, 45))
360632	30899002	It is worth noting that one recent study highlighted CDK4/6 knockdown reprograms metabolism in tumor cells, leading to Gln-addiction, which relies on c-Myc upregulation.	('Gln-addiction', 'Disease', (119, 132))	('CDK4/6', 'Gene', (53, 59))	('tumor', 'Disease', (95, 100))	('reprograms', 'Reg', (70, 80))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('c-Myc', 'Gene', '4609', (150, 155))	('metabolism', 'MPA', (81, 91))	('knockdown', 'Var', (60, 69))	('Gln', 'Chemical', 'MESH:D005973', (119, 122))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('c-Myc', 'Gene', (150, 155))	('leading to', 'Reg', (108, 118))
360639	30899002	Under glucose-depleted conditions, hyperactivation of mTORC1 drives AMPK activation, promotes energy consumption and reduces ATP/ADP ratio, leading to apoptosis.	('hyperactivation', 'Var', (35, 50))	('AMPK activation', 'MPA', (68, 83))	('energy consumption', 'MPA', (94, 112))	('ATP/ADP ratio', 'MPA', (125, 138))	('promotes', 'PosReg', (85, 93))	('reduces', 'NegReg', (117, 124))	('leading to', 'Reg', (140, 150))	('mTORC1', 'Gene', (54, 60))	('ATP', 'Chemical', 'MESH:D000255', (125, 128))	('ADP', 'Chemical', 'MESH:D000244', (129, 132))	('apoptosis', 'CPA', (151, 160))	('glucose', 'Chemical', 'MESH:D005947', (6, 13))	('mTORC1', 'Gene', '382056', (54, 60))
360640	30899002	Consistently, our data suggest activation of mTORC1, resulting from cyclin D1 dysregulation, might drive Gln-addiction through enhancing energy consumption.	('dysregulation', 'Var', (78, 91))	('drive', 'PosReg', (99, 104))	('enhancing', 'PosReg', (127, 136))	('mTORC1', 'Gene', '382056', (45, 51))	('Gln', 'Chemical', 'MESH:D005973', (105, 108))	('energy consumption', 'MPA', (137, 155))	('Gln-addiction', 'Disease', (105, 118))	('mTORC1', 'Gene', (45, 51))	('activation', 'PosReg', (31, 41))	('cyclin D1', 'Protein', (68, 77))
360641	30899002	Recent work revealed that the mTORC1 inhibitor, MLN128, suppresses glucose metabolism, and shifts the metabolism of tumor cells to glutaminolysis in a c-Jun-dependent manner, with an elusive role of c-Myc in this process.	('c-Jun', 'Gene', (151, 156))	('MLN128', 'Var', (48, 54))	('c-Myc', 'Gene', (199, 204))	('mTORC1', 'Gene', '382056', (30, 36))	('c-Myc', 'Gene', '4609', (199, 204))	('MLN128', 'Chemical', '-', (48, 54))	('glucose', 'Chemical', 'MESH:D005947', (67, 74))	('mTORC1', 'Gene', (30, 36))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('c-Jun', 'Gene', '16476', (151, 156))	('glucose metabolism', 'MPA', (67, 85))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('shifts', 'Reg', (91, 97))	('metabolism', 'MPA', (102, 112))	('suppresses', 'NegReg', (56, 66))	('tumor', 'Disease', (116, 121))
360642	30899002	Consistently, combined MLN128 plus CB-839 successfully overcame the metabolic reprogramming and reduced tumor burden in vivo.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('overcame', 'NegReg', (55, 63))	('CB-839', 'Gene', (35, 41))	('metabolic reprogramming', 'CPA', (68, 91))	('tumor', 'Disease', (104, 109))	('MLN128', 'Chemical', '-', (23, 29))	('CB-839', 'Chemical', 'MESH:C000593334', (35, 41))	('MLN128', 'Var', (23, 29))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('reduced', 'NegReg', (96, 103))
360643	30899002	Instead of using MLN128, metformin was combined with CB-839 and administrated in our study.	('CB-839', 'Gene', (53, 59))	('MLN128', 'Chemical', '-', (17, 23))	('MLN128', 'Var', (17, 23))	('metformin', 'Chemical', 'MESH:D008687', (25, 34))	('CB-839', 'Chemical', 'MESH:C000593334', (53, 59))
360645	30899002	In addition, metformin can activate AMPK and suppress mTORC1; taking these biological functions into account, the observed therapeutic effects in our study are totally consistent with those observed with MLN128 and CB-839.	('suppress', 'NegReg', (45, 53))	('MLN128', 'Chemical', '-', (204, 210))	('MLN128', 'Var', (204, 210))	('activate', 'PosReg', (27, 35))	('AMPK', 'MPA', (36, 40))	('mTORC1', 'Gene', (54, 60))	('metformin', 'Chemical', 'MESH:D008687', (13, 22))	('CB-839', 'Chemical', 'MESH:C000593334', (215, 221))	('mTORC1', 'Gene', '382056', (54, 60))
360650	30899002	Importantly, the disruption of both glutaminolysis and mitochondrial respiration provides a promising way to treat human ESCC and to overcome palbociclib resistance.	('SCC', 'Gene', (122, 125))	('glutaminolysis', 'Protein', (36, 50))	('palbociclib', 'Chemical', 'MESH:C500026', (142, 153))	('mitochondrial respiration', 'MPA', (55, 80))	('SCC', 'Gene', '6317', (122, 125))	('human', 'Species', '9606', (115, 120))	('disruption', 'Var', (17, 27))
360657	30899002	All cells were authenticated by short tandem repeat analysis for highly polymorphic microsatellites FES/FPS, vWA31, D22S417, D10S526, and D5S592 as performed by the Cell Culture Core to validate the identity of cells by comparing the earliest stocks with those grown more than 8-12 passages.	('D10S526', 'Var', (125, 132))	('D22S417', 'Var', (116, 123))	('FES/FPS', 'Gene', (100, 107))	('stocks', 'Species', '3724', (243, 249))	('D5S592', 'Var', (138, 144))
360665	30899002	For retrovirus production, pMX-puro empty vector, and vectors with Flag-tagged Fbxo4 WT, DeltaN, DeltaF, DeltaC2, and DeltaC3, and pBabe control as well as cyclin D1 WT and T286A were co-transfected with either QPsi or Psi2 vectors; for lentivirus production, lentiviral vectors were co-transfected with pMDLg/pRRE, CMV-VSVG, and RSV-Rev vectors.	('DeltaC3', 'DELETION', 'None', (118, 125))	('T286A', 'Mutation', 'c.286T>A', (173, 178))	('DeltaC2', 'Var', (105, 112))	('DeltaC2', 'DELETION', 'None', (105, 112))	('DeltaC3', 'Var', (118, 125))
360666	30899002	The pLKO.1 shRNA constructs were purchased from Addgene: Rb shRNA#19 (25640), Rb shRNA#63 (25641), Raptor shRNA (1857) and Rictor shRNA (1853), and Dharmacon (GE Healthcare Life Sciences): TRC GLS1 and c-Myc shRNAs.	('Raptor', 'Gene', (99, 105))	('GLS1', 'Gene', '2744', (193, 197))	('Raptor', 'Gene', '74370', (99, 105))	('c-Myc', 'Gene', (202, 207))	('c-Myc', 'Gene', '4609', (202, 207))	('25640', 'Var', (70, 75))	('25641', 'Var', (91, 96))	('GLS1', 'Gene', (193, 197))	('Rictor shRNA', 'Phenotype', 'HP:0040212', (123, 135))
360690	30899002	TE7 (5 x 106), TE15 (5 x 106) and TE7PDR (5 x 106) cells were subcutaneously injected into the flank regions.	('TE1', 'Gene', (15, 18))	('TE1', 'Gene', '57816', (15, 18))	('TE7PDR', 'Var', (34, 40))
360702	30728854	The role of Tannerella forsythia and Porphyromonas gingivalis in pathogenesis of esophageal cancer Tannerella forsythia and Porphyromonas gingivalis are anaerobic, Gram-negative bacterial species which have been implicated in periodontal diseases as a part of red complex of periodontal pathogens.	('esophageal cancer', 'Disease', 'MESH:D004938', (81, 98))	('Porphyromonas gingivalis', 'Species', '837', (37, 61))	('periodontal disease', 'Disease', 'MESH:D010510', (226, 245))	('periodontal disease', 'Disease', (226, 245))	('Tannerella', 'Var', (99, 109))	('periodontal diseases', 'Phenotype', 'HP:0000704', (226, 246))	('periodontal disease', 'Phenotype', 'HP:0000704', (226, 245))	('Tannerella forsythia', 'Species', '28112', (12, 32))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('Porphyromonas gingivalis', 'Species', '837', (124, 148))	('esophageal cancer', 'Disease', (81, 98))	('Tannerella forsythia', 'Species', '28112', (99, 119))
360705	30728854	Moreover, the presence of oral P. gingivalis and T. forsythia has been found to be associated with an increased risk of esophageal cancer.	('presence', 'Var', (14, 22))	('esophageal cancer', 'Disease', 'MESH:D004938', (120, 137))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('P. gingivalis', 'Species', '837', (31, 44))	('associated', 'Reg', (83, 93))	('T. forsythia', 'Species', '28112', (49, 61))	('esophageal cancer', 'Disease', (120, 137))
360746	30728854	In addition, LPS causes the inhibition of alkaline phosphatase, alpha1 collagen and osteocalcin differentiation and mineralization in stem cells of the periodontal ligament, which are involved in the regeneration of periodontal tissues.	('LPS', 'Var', (13, 16))	('osteocalcin differentiation', 'CPA', (84, 111))	('alkaline phosphatase', 'Enzyme', (42, 62))	('alpha1 collagen', 'Protein', (64, 79))	('inhibition', 'NegReg', (28, 38))	('men', 'Species', '9606', (168, 171))	('mineralization', 'CPA', (116, 130))
360757	30728854	Development of T. forsythia along with other periodontal pathogens in the oral cavity may cause gingivitis and lead to periodontal disease.	('periodontal disease', 'Disease', (119, 138))	('T. forsythia', 'Var', (15, 27))	('gingivitis', 'Disease', 'MESH:D005891', (96, 106))	('periodontal disease', 'Disease', 'MESH:D010510', (119, 138))	('T. forsythia', 'Species', '28112', (15, 27))	('gingivitis', 'Disease', (96, 106))	('periodontal disease', 'Phenotype', 'HP:0000704', (119, 138))	('gingivitis', 'Phenotype', 'HP:0000230', (96, 106))	('cause', 'Reg', (90, 95))	('men', 'Species', '9606', (7, 10))	('lead to', 'Reg', (111, 118))
360764	30728854	Fusobacterium nucleatum or P. gingivalis, enhanced the formation of abscesses in rabbits and mice.	('abscesses', 'Phenotype', 'HP:0025615', (68, 77))	('P. gingivalis', 'Var', (27, 40))	('enhanced', 'PosReg', (42, 50))	('formation of abscesses', 'CPA', (55, 77))	('rabbits', 'Species', '9986', (81, 88))	('P. gingivalis', 'Species', '837', (27, 40))	('mice', 'Species', '10090', (93, 97))	('Fusobacterium nucleatum', 'Species', '851', (0, 23))
360783	30728854	T. forsythia has also been shown to increase number of P. gingivalis by its ability to reduce fumarate to succinate (precursor of lipid and phospholipid synthesis).	('lipid', 'Chemical', 'MESH:D008055', (130, 135))	('fumarate to succinate', 'MPA', (94, 115))	('fumarate', 'Chemical', 'MESH:D005650', (94, 102))	('lipid', 'Chemical', 'MESH:D008055', (147, 152))	('phospholipid', 'Chemical', 'MESH:D010743', (140, 152))	('T. forsythia', 'Species', '28112', (0, 12))	('P. gingivalis', 'Species', '837', (55, 68))	('P. gingivalis', 'Var', (55, 68))	('succinate', 'Chemical', 'MESH:D019802', (106, 115))	('reduce', 'NegReg', (87, 93))
360794	30728854	The accumulation of genetic changes initiates the process of carcinogenesis, which causes histological changes in epithelial cells.	('genetic changes', 'Var', (20, 35))	('carcinogenesis', 'Disease', (61, 75))	('carcinogenesis', 'Disease', 'MESH:D063646', (61, 75))
360803	30728854	Free radicals cause DNA damage, and the resulting mutations initiate the cancer process.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('mutations', 'Var', (50, 59))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('initiate', 'Reg', (60, 68))	('DNA damage', 'MPA', (20, 30))
360813	30728854	The results of the study indicate the relationship between T. forsythia and adenocarcinoma, while the presence of more P. gingivalis is associated with a higher risk of esophageal squamous cell carcinoma.	('adenocarcinoma', 'Disease', 'MESH:D000230', (76, 90))	('P. gingivalis', 'Species', '837', (119, 132))	('P. gingivalis', 'Var', (119, 132))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (180, 203))	('carcinoma', 'Phenotype', 'HP:0030731', (194, 203))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (169, 203))	('T. forsythia', 'Species', '28112', (59, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('presence', 'Var', (102, 110))	('adenocarcinoma', 'Disease', (76, 90))	('esophageal squamous cell carcinoma', 'Disease', (169, 203))
360820	30728854	Various forms of periodontal disease caused by P. gingivalis and T. forsythia indicate the systemic inflammatory response in the body.	('P. gingivalis', 'Species', '837', (47, 60))	('P. gingivalis', 'Var', (47, 60))	('periodontal disease', 'Disease', (17, 36))	('periodontal disease', 'Disease', 'MESH:D010510', (17, 36))	('T. forsythia', 'Disease', (65, 77))	('caused', 'Reg', (37, 43))	('T. forsythia', 'Species', '28112', (65, 77))	('periodontal disease', 'Phenotype', 'HP:0000704', (17, 36))
360821	30728854	The long-term presence of P. gingivalis in the mouth can infect epithelial cells in the mouth, disrupt the cell cycle and immune responses of the host, as well as cell apoptosis.	('infect', 'Reg', (57, 63))	('P. gingivalis', 'Species', '837', (26, 39))	('immune responses', 'CPA', (122, 138))	('cell cycle', 'CPA', (107, 117))	('cell apoptosis', 'CPA', (163, 177))	('disrupt', 'NegReg', (95, 102))	('P. gingivalis', 'Var', (26, 39))
360823	30728854	Due to the high probability of infection of the esophagus from the oral niche, it is possible that infection with P. gingivalis may be associated with the development of esophageal squamous cell carcinoma.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (181, 204))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (170, 204))	('men', 'Species', '9606', (162, 165))	('infection', 'Var', (99, 108))	('P. gingivalis', 'Gene', (114, 127))	('associated with', 'Reg', (135, 150))	('esophageal squamous cell carcinoma', 'Disease', (170, 204))	('P. gingivalis', 'Species', '837', (114, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (195, 204))
360841	30728854	Inflammatory cytokines produced by the inflammation induced by P. gingivalis and T. forsythia may affect the regulation of the Notch pathway.	('T. forsythia', 'Species', '28112', (81, 93))	('P. gingivalis', 'Species', '837', (63, 76))	('P. gingivalis', 'Var', (63, 76))	('inflammation', 'Disease', 'MESH:D007249', (39, 51))	('inflammation', 'Disease', (39, 51))	('regulation', 'MPA', (109, 119))	('affect', 'Reg', (98, 104))	('Notch pathway', 'Pathway', (127, 140))
360852	30728854	MMP9 inactivating chemokines produced by cancer cells inhibits the inflow of neutrophils to the place of inflammation and, consequently, the development of esophageal cancer.	('MMP9', 'Gene', (0, 4))	('inflammation', 'Disease', 'MESH:D007249', (105, 117))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('inflammation', 'Disease', (105, 117))	('cancer', 'Disease', (167, 173))	('inactivating', 'Var', (5, 17))	('esophageal cancer', 'Disease', (156, 173))	('men', 'Species', '9606', (148, 151))	('esophageal cancer', 'Disease', 'MESH:D004938', (156, 173))	('inhibits', 'NegReg', (54, 62))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))
360871	30728854	Overexpression of GLUT-1 and GLUT-4 transporters has been observed in many types of tumors and correlates with the increase in tumor invasiveness.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('GLUT-4 transporters', 'Protein', (29, 48))	('tumor invasiveness', 'Disease', 'MESH:D009369', (127, 145))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('GLUT-1', 'Protein', (18, 24))	('increase', 'PosReg', (115, 123))	('Overexpression', 'Var', (0, 14))	('tumors', 'Disease', (84, 90))	('tumors', 'Disease', 'MESH:D009369', (84, 90))	('tumor invasiveness', 'Disease', (127, 145))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('observed', 'Reg', (58, 66))
360872	30728854	It has been suggested that inhibition of these proteins reduces the rate of glucose uptake, induces cell cycle arrest, and consequently, the arrest of tumor cell proliferation in vitro and in vivo.	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('induces', 'Reg', (92, 99))	('cell cycle arrest', 'CPA', (100, 117))	('glucose', 'Chemical', 'MESH:D005947', (76, 83))	('reduces', 'NegReg', (56, 63))	('arrest of tumor', 'Disease', (141, 156))	('inhibition', 'Var', (27, 37))	('arrest of tumor', 'Disease', 'MESH:D006323', (141, 156))	('rate', 'MPA', (68, 72))
360886	30728854	Detection of P. gingivalis and T. forsythia in pre-cancer lesions may become an important element of cancer diagnostics and become a prognostic indicator of esophageal cancer.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('cancer lesions', 'Disease', 'MESH:D009062', (51, 65))	('P. gingivalis', 'Var', (13, 26))	('esophageal cancer', 'Disease', 'MESH:D004938', (157, 174))	('cancer lesions', 'Disease', (51, 65))	('cancer', 'Disease', (101, 107))	('men', 'Species', '9606', (93, 96))	('P. gingivalis', 'Species', '837', (13, 26))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('T. forsythia', 'Species', '28112', (31, 43))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('cancer', 'Disease', (168, 174))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('esophageal cancer', 'Disease', (157, 174))
360895	29382705	Here we report the discovery of the azaindole compounds BDP8900 and BDP9066 as potent and selective MRCK inhibitors that reduce substrate phosphorylation, leading to morphological changes in cancer cells along with inhibition of their motility and invasive character.	('substrate phosphorylation', 'MPA', (128, 153))	('cancer', 'Disease', (191, 197))	('cancer', 'Disease', 'MESH:D009369', (191, 197))	('invasive character', 'CPA', (248, 266))	('MRCK', 'Gene', (100, 104))	('azaindole', 'Chemical', '-', (36, 45))	('BDP9066', 'Var', (68, 75))	('rat', 'Species', '10116', (133, 136))	('BDP8900', 'Var', (56, 63))	('BDP8900', 'Chemical', '-', (56, 63))	('reduce', 'NegReg', (121, 127))	('motility', 'CPA', (235, 243))	('BDP9066', 'Chemical', '-', (68, 75))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('morphological changes', 'CPA', (166, 187))	('leading to', 'Reg', (155, 165))	('MRCK', 'Gene', '8476', (100, 104))
360896	29382705	In over 750 human cancer cell lines tested, BDP8900 and BDP9066 displayed consistent anti-proliferative effects with greatest activity in hematological cancer cells.	('rat', 'Species', '10116', (97, 100))	('cancer', 'Disease', (152, 158))	('hematological cancer', 'Disease', (138, 158))	('cancer', 'Disease', 'MESH:D009369', (18, 24))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('BDP9066', 'Chemical', '-', (56, 63))	('BDP8900', 'Chemical', '-', (44, 51))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('anti-proliferative effects', 'MPA', (85, 111))	('hematological cancer', 'Phenotype', 'HP:0004377', (138, 158))	('human', 'Species', '9606', (12, 17))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('BDP8900', 'Var', (44, 51))	('cancer', 'Disease', (18, 24))	('hematological cancer', 'Disease', 'MESH:D009369', (138, 158))	('BDP9066', 'Var', (56, 63))
360903	29382705	In non-muscle cells, a key event in promoting actin-myosin contractility is the phosphorylation of class 2 regulatory myosin light chains (MLC2) on Thr18 and Ser19 residues, which activates myosin ATP activity to drive the interaction of myosin heavy and light chain complexes with filamentous actin (F-actin).	('interaction', 'Interaction', (223, 234))	('myosin', 'Gene', (238, 244))	('Ser19', 'Var', (158, 163))	('myosin', 'Gene', '79784', (238, 244))	('myosin', 'Gene', (52, 58))	('Thr18', 'Var', (148, 153))	('MLC2', 'Gene', (139, 143))	('MLC2', 'Gene', '10398', (139, 143))	('myosin', 'Gene', '79784', (52, 58))	('Ser19', 'Chemical', '-', (158, 163))	('myosin', 'Gene', (190, 196))	('myosin', 'Gene', (118, 124))	('promoting', 'PosReg', (36, 45))	('Thr18', 'Chemical', '-', (148, 153))	('ATP', 'Chemical', 'MESH:D000255', (197, 200))	('myosin', 'Gene', '79784', (190, 196))	('myosin', 'Gene', '79784', (118, 124))
360907	29382705	The roles of MRCK signaling in normal cell function and contributions to cancer are less well characterized than for ROCK, largely due to two historical factors: ROCK kinases were identified before the MRCK kinases, and because of the discovery in 1997 of the relatively potent and selective small molecule ROCK inhibitor Y27632, which has enabled two decades of research on ROCK biology.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('Y27632', 'Var', (322, 328))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('MRCK', 'Gene', '8476', (202, 206))	('MRCK', 'Gene', '8476', (13, 17))	('Y27632', 'Chemical', 'MESH:C108830', (322, 328))	('MRCK', 'Gene', (202, 206))	('MRCK', 'Gene', (13, 17))
360914	29382705	In addition, MRCK knockdown or inhibition alone was sufficient to reduce 3D invasion by squamous cell carcinoma (SCC) cells.	('knockdown', 'Var', (18, 27))	('SCC', 'Gene', '6317', (113, 116))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (88, 111))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (88, 111))	('3D invasion', 'CPA', (73, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('MRCK', 'Gene', '8476', (13, 17))	('reduce', 'NegReg', (66, 72))	('SCC', 'Gene', (113, 116))	('squamous cell carcinoma', 'Disease', (88, 111))	('MRCK', 'Gene', (13, 17))
360918	29382705	Structure-guided fragment elaboration led to the novel MRCK inhibitors BDP8900 and BDP9066, which are considerably more potent and selective than the previously described BDP5290, or the mixed ROCK-MRCK inhibitor DJ4 or PKC-MRCK inhibitor chelerythrine.	('BDP8900', 'Chemical', '-', (71, 78))	('MRCK', 'Gene', (224, 228))	('BDP5290', 'Chemical', 'MESH:C000602147', (171, 178))	('MRCK', 'Gene', (55, 59))	('BDP9066', 'Chemical', '-', (83, 90))	('DJ4', 'Gene', '10049', (213, 216))	('DJ4', 'Gene', (213, 216))	('MRCK', 'Gene', '8476', (55, 59))	('MRCK', 'Gene', '8476', (198, 202))	('chelerythrine', 'Chemical', 'MESH:C016299', (239, 252))	('rat', 'Species', '10116', (31, 34))	('MRCK', 'Gene', (198, 202))	('BDP8900', 'Var', (71, 78))	('MRCK', 'Gene', '8476', (224, 228))	('BDP9066', 'Var', (83, 90))	('S', 'Chemical', 'MESH:D013455', (0, 1))
360919	29382705	Screening of more than 750 human cancer cell lines, from more than 40 different cancer types, for anti-proliferative effects of BDP8900 and BDP9066 identified hematological cancers as the most sensitive malignancy type.	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('cancer', 'Disease', (33, 39))	('human', 'Species', '9606', (27, 32))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('hematological cancer', 'Phenotype', 'HP:0004377', (159, 179))	('cancer', 'Disease', (80, 86))	('rat', 'Species', '10116', (110, 113))	('malignancy', 'Disease', 'MESH:D009369', (203, 213))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('BDP9066', 'Var', (140, 147))	('hematological cancers', 'Disease', (159, 180))	('cancers', 'Phenotype', 'HP:0002664', (173, 180))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('cancer', 'Disease', (173, 179))	('malignancy', 'Disease', (203, 213))	('hematological cancers', 'Disease', 'MESH:D009369', (159, 180))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('BDP8900', 'Chemical', '-', (128, 135))	('BDP9066', 'Chemical', '-', (140, 147))	('S', 'Chemical', 'MESH:D013455', (0, 1))	('anti-proliferative effects', 'MPA', (98, 124))	('BDP8900', 'Var', (128, 135))
360920	29382705	Mass spectrometry led to the discovery and validation of MRCKalpha S1003 autophosphorylation as a pharmacodynamic biomarker that enabled evaluation of on-target drug action in tissues, as well as a biomarker of MRCKalpha activity in skin tumors.	('MRCKalpha', 'Gene', '8476', (211, 220))	('skin tumors', 'Disease', 'MESH:D012878', (233, 244))	('tumor', 'Phenotype', 'HP:0002664', (238, 243))	('S', 'Chemical', 'MESH:D013455', (67, 68))	('skin tumors', 'Phenotype', 'HP:0008069', (233, 244))	('tumors', 'Phenotype', 'HP:0002664', (238, 244))	('skin tumors', 'Disease', (233, 244))	('MRCKalpha', 'Gene', (57, 66))	('MRCKalpha', 'Gene', (211, 220))	('S1003', 'Var', (67, 72))	('MRCKalpha', 'Gene', '8476', (57, 66))
360921	29382705	BDP9066 treatment of SCC cells induced changes in cell morphology, motility and invasion, while topical treatment of mice in a two-stage chemical carcinogenesis model of SCC significantly reduced papilloma growth and MRCKalpha S1003 autophosphorylation.	('SCC', 'Gene', (21, 24))	('mice', 'Species', '10090', (117, 121))	('BDP9066', 'Chemical', '-', (0, 7))	('SCC', 'Gene', '6317', (170, 173))	('S', 'Chemical', 'MESH:D013455', (21, 22))	('S', 'Chemical', 'MESH:D013455', (227, 228))	('MRCKalpha', 'Gene', '8476', (217, 226))	('changes', 'Reg', (39, 46))	('S', 'Chemical', 'MESH:D013455', (170, 171))	('SCC', 'Gene', (170, 173))	('papilloma', 'Phenotype', 'HP:0012740', (196, 205))	('papilloma growth', 'Disease', 'MESH:D010212', (196, 212))	('reduced', 'NegReg', (188, 195))	('invasion', 'CPA', (80, 88))	('MRCKalpha', 'Gene', (217, 226))	('SCC', 'Gene', '6317', (21, 24))	('motility', 'CPA', (67, 75))	('papilloma growth', 'Disease', (196, 212))	('BDP9066', 'Var', (0, 7))	('cell morphology', 'CPA', (50, 65))
360922	29382705	These results demonstrate that the potent and selective inhibitors BDP8900 and BDP9066 are valuable chemical biology tools to identify MRCK biological functions and roles in cancer, and that MRCK inhibition has in vivo therapeutic effects on skin cancer in mice.	('BDP9066', 'Var', (79, 86))	('MRCK', 'Gene', '8476', (135, 139))	('cancer', 'Disease', (247, 253))	('MRCK', 'Gene', (191, 195))	('skin cancer', 'Phenotype', 'HP:0008069', (242, 253))	('BDP8900', 'Chemical', '-', (67, 74))	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('BDP9066', 'Chemical', '-', (79, 86))	('mice', 'Species', '10090', (257, 261))	('cancer', 'Disease', (174, 180))	('MRCK', 'Gene', (135, 139))	('rat', 'Species', '10116', (21, 24))	('BDP8900', 'Var', (67, 74))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('inhibition', 'NegReg', (196, 206))	('skin cancer', 'Disease', 'MESH:D012878', (242, 253))	('cancer', 'Disease', 'MESH:D009369', (247, 253))	('MRCK', 'Gene', '8476', (191, 195))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('skin cancer', 'Disease', (242, 253))
360927	29382705	MRCKalpha and MRCKbeta kinases assays by out-sourced supplier were carried out in 50 mM HEPES pH 7.5, 0.01% (v/v) BRIJ-35, 10 mM MgCl2, 1 mM EGTA and 2 microM Ser/Thr 13 peptide substrate, with 1 hour incubation before addition of development reagent and quantification by fluorescence resonance energy transfer (FRET).	('MgCl2', 'Chemical', 'MESH:D015636', (129, 134))	('EGTA', 'Chemical', 'MESH:D004533', (141, 145))	('MRCKalpha', 'Gene', '8476', (0, 9))	('HEPES', 'Chemical', 'MESH:D006531', (88, 93))	('MRCKalpha', 'Gene', (0, 9))	('rat', 'Species', '10116', (183, 186))	('Ser/Thr 13', 'SUBSTITUTION', 'None', (159, 169))	('Ser/Thr 13', 'Var', (159, 169))
360928	29382705	Kinase selectivity profiling was performed by Invitrogen with indicated concentrations of BDP8900 or BDP9066.	('BDP9066', 'Var', (101, 108))	('BDP9066', 'Chemical', '-', (101, 108))	('BDP8900', 'Var', (90, 97))	('BDP8900', 'Chemical', '-', (90, 97))	('rat', 'Species', '10116', (79, 82))
360929	29382705	MDA MB 231 D3H2LN Luc cells (Caliper LifeScience, obtained 2006), MDA MB 231 D3H2LN Luc TetOn MRCKbeta, ROCK1 and ROCK2 inducible cell lines, human cancer-associated fibroblasts (obtained 2008) and SCC12 human squamous cell carcinoma cells (gift of Erik Sahai, Crick Institute, London UK; obtained 2006) were cultured as described.	('SCC12', 'CellLine', 'CVCL:4026', (198, 203))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (210, 233))	('MDA MB 231 D3H2LN', 'CellLine', 'CVCL:D257', (66, 83))	('MDA MB 231 D3H2LN', 'Var', (66, 83))	('ROCK1', 'Gene', '6093', (104, 109))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('ROCK2', 'Gene', '9475', (114, 119))	('MDA MB 231 D3H2LN', 'CellLine', 'CVCL:D257', (0, 17))	('squamous cell carcinoma', 'Disease', (210, 233))	('human', 'Species', '9606', (142, 147))	('human', 'Species', '9606', (204, 209))	('ROCK2', 'Gene', (114, 119))	('ROCK1', 'Gene', (104, 109))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (210, 233))	('S', 'Chemical', 'MESH:D013455', (254, 255))	('cancer', 'Disease', (148, 154))	('S', 'Chemical', 'MESH:D013455', (41, 42))	('S', 'Chemical', 'MESH:D013455', (198, 199))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('carcinoma', 'Phenotype', 'HP:0030731', (224, 233))
360934	29382705	The following antibodies were used: rabbit anti-MRCKalpha pS1003 antibody raised by Eurogentec using the peptide AcNH-KGCPG-S(PO3H2)-TGFPP-CONH2, rabbit anti-pMLC2 Thr18/Ser19 (#3674; Cell Signaling Technology), mouse anti-MRCL3/MRLC2/MYL9 (sc-28329; Santa Cruz Biotechnology), mouse anti alpha-tubulin (T9026; Sigma), rabbit anti-ERK2 (Chris Marshall, Institute of Cancer Research, London UK), mouse anti-MRCKalpha (H00008476-M01; Abnova), mouse anti-MRCKbeta (H00009578-M03; Abnova), mouse anti-MRCKalphabeta (MANDM1 6G8; Glenn Morris, Centre for Inherited Neuromuscular Disease, Oswestry UK), mouse anti-ROCK1 (BD-611136; BD Biosciences), mouse anti-ROCK2 (BD-61062; BD Biosciences), mouse anti-Cas9 (C15200229; Diagenode), mouse anti-FLAG (F4042; Sigma).	('TGFPP-CONH2', 'Chemical', '-', (133, 144))	('mouse', 'Species', '10090', (278, 283))	('MRCKalpha', 'Gene', (48, 57))	('rabbit', 'Species', '9986', (36, 42))	('MRLC2', 'Gene', '103910', (229, 234))	('mouse', 'Species', '10090', (596, 601))	('S', 'Chemical', 'MESH:D013455', (751, 752))	('MRCL3', 'Gene', '10627', (223, 228))	('MYL9', 'Gene', (235, 239))	('ROCK2', 'Gene', '9475', (653, 658))	('S', 'Chemical', 'MESH:D013455', (251, 252))	('Inherited Neuromuscular Disease', 'Disease', 'None', (549, 580))	('mouse', 'Species', '10090', (212, 217))	('S', 'Chemical', 'MESH:D013455', (59, 60))	('mouse', 'Species', '10090', (395, 400))	('Ser19', 'Chemical', '-', (170, 175))	('Cancer', 'Phenotype', 'HP:0002664', (366, 372))	('S', 'Chemical', 'MESH:D013455', (124, 125))	('mouse', 'Species', '10090', (642, 647))	('rabbit', 'Species', '9986', (146, 152))	('S', 'Chemical', 'MESH:D013455', (170, 171))	('Inherited Neuromuscular Disease', 'Disease', (549, 580))	('PO3H2', 'Chemical', '-', (126, 131))	('C15200229;', 'Var', (704, 714))	('ROCK1', 'Gene', (607, 612))	('MRCKalpha', 'Gene', '8476', (406, 415))	('rabbit', 'Species', '9986', (319, 325))	('mouse', 'Species', '10090', (727, 732))	('H00008476-M01; Abnova', 'Disease', 'None', (417, 438))	('MRCKalpha', 'Gene', (497, 506))	('MRLC2', 'Gene', (229, 234))	('MYL9', 'Gene', '10398', (235, 239))	('mouse', 'Species', '10090', (687, 692))	('MRCKalpha', 'Gene', '8476', (48, 57))	('Thr18', 'Chemical', '-', (164, 169))	('ROCK2', 'Gene', (653, 658))	('S', 'Chemical', 'MESH:D013455', (311, 312))	('AcNH-KGCPG-S', 'Chemical', '-', (113, 125))	('H00008476-M01; Abnova', 'Disease', (417, 438))	('MRCKalphabeta', 'Disease', 'None', (497, 510))	('mouse', 'Species', '10090', (441, 446))	('H00009578-M03; Abnova', 'Disease', (462, 483))	('ERK2', 'Gene', '5594', (331, 335))	('MRCKalphabeta', 'Disease', (497, 510))	('MLC2', 'Gene', (159, 163))	('MLC2', 'Gene', '10398', (159, 163))	('H00009578-M03; Abnova', 'Disease', 'None', (462, 483))	('ROCK1', 'Gene', '6093', (607, 612))	('MRCL3', 'Gene', (223, 228))	('MRCKalpha', 'Gene', (406, 415))	('ERK2', 'Gene', (331, 335))	('mouse', 'Species', '10090', (486, 491))	('S', 'Chemical', 'MESH:D013455', (189, 190))	('MRCKalpha', 'Gene', '8476', (497, 506))
360935	29382705	Secondary antibodies used were: goat anti-mouse IgG Dylight 800 (35521; Thermo Scientific), goat anti-rabbit IgG AlexaFluor 680 (A12076; Invitrogen), goat anti-rabbit IgG IR Dye 800 CW (926-32211; LI-COR Biosciences), goat anti-mouse IgG IR Dye 680 (926-68020; LI-COR Biosciences).	('S', 'Chemical', 'MESH:D013455', (79, 80))	('goat', 'Species', '9925', (218, 222))	('mouse', 'Species', '10090', (42, 47))	('926-68020', 'Var', (250, 259))	('goat', 'Species', '9925', (92, 96))	('rabbit', 'Species', '9986', (160, 166))	('926-32211', 'Var', (186, 195))	('mouse', 'Species', '10090', (228, 233))	('goat', 'Species', '9925', (150, 154))	('AlexaFluor', 'Chemical', '-', (113, 123))	('rabbit', 'Species', '9986', (102, 108))	('goat', 'Species', '9925', (32, 36))	('S', 'Chemical', 'MESH:D013455', (0, 1))
360955	29382705	After 24 hours of culture, medium was replaced with medium supplemented with either DMSO vehicle or 0.4 muM BDP9066.	('DMSO', 'Chemical', 'MESH:D004121', (84, 88))	('BDP9066', 'Chemical', '-', (108, 115))	('muM', 'Gene', '56925', (104, 107))	('muM', 'Gene', (104, 107))	('BDP9066', 'Var', (108, 115))
360959	29382705	The pEF-FLAG-MRCKalpha-S1003A was generated by site directed mutagenesis of pEF-FLAG-MRCKalpha using Quickchange II XL (Agilent Technologies) following manufacturer recommendations.	('MRCKalpha', 'Gene', (85, 94))	('MRCKalpha', 'Gene', '8476', (13, 22))	('MRCKalpha', 'Gene', '8476', (85, 94))	('MRCKalpha', 'Gene', (13, 22))	('mutagenesis', 'Var', (61, 72))	('rat', 'Species', '10116', (38, 41))	('S1003A', 'Mutation', 'p.S1003A', (23, 29))
360960	29382705	Primers used were: S1003A forward: aaaaaggatgtcctggtgcaactggctttccacct, S1003A reverse: aggtggaaagccagttgcaccaggacatccttttt.	('S1003A', 'Mutation', 'p.S1003A', (72, 78))	('S1003A', 'Var', (19, 25))	('S1003A', 'Mutation', 'p.S1003A', (19, 25))	('S1003A', 'Var', (72, 78))
360961	29382705	The pEF-FLAG-MRCKalphaDeltaC plasmid was created using sited directed mutagenesis of pEF-FLAG-MRCKalpha by inserting a stop codon after nucleotide 4860 corresponding to amino acid 1620.	('MRCKalpha', 'Gene', '8476', (13, 22))	('MRCKalpha', 'Gene', (13, 22))	('mutagenesis', 'Var', (70, 81))	('MRCKalpha', 'Gene', (94, 103))	('MRCKalpha', 'Gene', '8476', (94, 103))
360981	29382705	After 48 hours, medium was replaced with medium supplemented with either DMSO, 3 muM BDP5290 or 1 muM BDP9066.	('muM', 'Gene', (98, 101))	('BDP5290', 'Chemical', 'MESH:C000602147', (85, 92))	('BDP9066', 'Chemical', '-', (102, 109))	('muM', 'Gene', '56925', (81, 84))	('DMSO', 'Chemical', 'MESH:D004121', (73, 77))	('BDP5290', 'Var', (85, 92))	('muM', 'Gene', '56925', (98, 101))	('muM', 'Gene', (81, 84))
360985	29382705	After 24 hours, cells were treated with 1 microg/ml doxycycline for 18 hours to induce kinase domain expression and then tested with BDP8900 or BDP9066 at the concentrations indicated for 60 minutes.	('BDP9066', 'Chemical', '-', (144, 151))	('doxycycline', 'Chemical', 'MESH:D004318', (52, 63))	('BDP8900', 'Chemical', '-', (133, 140))	('rat', 'Species', '10116', (166, 169))	('kinase domain expression', 'MPA', (87, 111))	('BDP9066', 'Var', (144, 151))
360988	29382705	Full length MRCKalpha isoform b and full length MRCKalpha isoform b K106M were expressed in HEK293 cells and immunoprecipitated with FLAG antibody in triplicate experiments.	('K106M', 'Var', (68, 73))	('K106M', 'Mutation', 'p.K106M', (68, 73))	('MRCKalpha', 'Gene', '8476', (48, 57))	('MRCKalpha', 'Gene', (48, 57))	('MRCKalpha', 'Gene', '8476', (12, 21))	('MRCKalpha', 'Gene', (12, 21))	('HEK293', 'CellLine', 'CVCL:0045', (92, 98))
360994	29382705	MGF files were searched using Mascot (Matrix Science, version 2.4.1), querying the UniProt Homo sapiens database (09/07/2016; 92,939 entries) plus an in-house database containing common proteomic contaminants and the MRCKalpha K106M sequence.	('S', 'Chemical', 'MESH:D013455', (45, 46))	('MRCKalpha', 'Gene', '8476', (217, 226))	('K106M', 'Var', (227, 232))	('MRCKalpha', 'Gene', (217, 226))	('Homo sapiens', 'Species', '9606', (91, 103))	('K106M', 'Mutation', 'p.K106M', (227, 232))	('MGF', 'Gene', '6776', (0, 3))	('MGF', 'Gene', (0, 3))
361000	29382705	The peak areas of phosphopeptide 999-1009 that were measured in the 3 replicate experiments were normalized to "Global Standard" areas derived from the unmodified MRCKalpha tryptic peptides 310-315, 1113-1122 and 1268-1286.	('peptides', 'Chemical', 'MESH:D010455', (181, 189))	('310-315', 'Var', (190, 197))	('MRCKalpha', 'Gene', '8476', (163, 172))	('S', 'Chemical', 'MESH:D013455', (119, 120))	('MRCKalpha', 'Gene', (163, 172))	('1113-1122', 'Var', (199, 208))
361001	29382705	For treatments with phosphatase and in vitro autophosphorylation, full length MRCKalpha or mutants bound to anti-FLAG beads were resuspended in 100 muL of phosphatase buffer with lambda protein phosphatase (P0753; New England Biolabs) following manufacturer's instructions and incubated with constant agitation at 30 C for 1 hour.	('bound', 'Interaction', (99, 104))	('agitation', 'Phenotype', 'HP:0000713', (301, 310))	('agitation', 'Disease', 'MESH:D011595', (301, 310))	('mutants', 'Var', (91, 98))	('MRCKalpha', 'Gene', (78, 87))	('agitation', 'Disease', (301, 310))	('MRCKalpha', 'Gene', '8476', (78, 87))
361008	29382705	Immunoprecipitated full length MRCKalpha and MRCKalpha K106M bound to anti-FLAG beads were resuspended in kinase buffer supplemented with gamma[32P]-labelled ATP with constant agitation at 30 C for 1 hour.	('32P', 'Chemical', 'MESH:C000615311', (144, 147))	('agitation', 'Disease', 'MESH:D011595', (176, 185))	('agitation', 'Disease', (176, 185))	('ATP', 'Chemical', 'MESH:D000255', (158, 161))	('MRCKalpha', 'Gene', (31, 40))	('MRCKalpha', 'Gene', (45, 54))	('MRCKalpha', 'Gene', '8476', (31, 40))	('MRCKalpha', 'Gene', '8476', (45, 54))	('K106M', 'Var', (55, 60))	('K106M', 'Mutation', 'p.K106M', (55, 60))	('agitation', 'Phenotype', 'HP:0000713', (176, 185))	('bound', 'Interaction', (61, 66))
361019	29382705	The Translational Cancer Genomics team at the Wellcome Trust Sanger Institute screened 757 cancer cell lines with BDP8900 and BDP9066.	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('BDP8900', 'Var', (114, 121))	('BDP9066', 'Var', (126, 133))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('S', 'Chemical', 'MESH:D013455', (61, 62))	('Cancer', 'Phenotype', 'HP:0002664', (18, 24))	('BDP8900', 'Chemical', '-', (114, 121))	('BDP9066', 'Chemical', '-', (126, 133))
361047	29382705	A focused fragment library was screened using an MRCKbeta biochemical assay, and structure-guided elaboration of a ligand-efficient 7-azaindole-3-carbonitrile fragment hit (Figure 1A), prioritizing the identification of MRCK-selective inhibitors, led to the discovery of BDP8900 and BDP9066 (Figure 1A).	('MRCK', 'Gene', (220, 224))	('7-azaindole-3-carbonitrile', 'Chemical', '-', (132, 158))	('rat', 'Species', '10116', (103, 106))	('MRCK', 'Gene', (49, 53))	('BDP8900', 'Var', (271, 278))	('BDP9066', 'Var', (283, 290))	('BDP9066', 'Chemical', '-', (283, 290))	('BDP8900', 'Chemical', '-', (271, 278))	('MRCK', 'Gene', '8476', (220, 224))	('MRCK', 'Gene', '8476', (49, 53))
361048	29382705	Synthesis routes and methods for BDP8900 and BDP9066 will be described in a subsequent manuscript (in preparation).	('BDP9066', 'Chemical', '-', (45, 52))	('rat', 'Species', '10116', (107, 110))	('BDP9066', 'Var', (45, 52))	('BDP8900', 'Var', (33, 40))	('S', 'Chemical', 'MESH:D013455', (0, 1))	('BDP8900', 'Chemical', '-', (33, 40))
361051	29382705	Inhibition of myosin light chain phosphorylation (pMLC2) in MDA MB 231 human breast cancer cells, engineered to express tetracycline-inducible MRCKbeta, ROCK1, or ROCK2 kinase domains, by BDP8900 was >562 times more selective for MRCKbeta relative to ROCK1 or ROCK2 (Figure 1D), and by BDP9066 was >100 times more selective for MRCKbeta relative to ROCK1 or ROCK2 (Figure 1E).	('ROCK2', 'Gene', '9475', (163, 168))	('BDP8900', 'Chemical', '-', (188, 195))	('ROCK1', 'Gene', (251, 256))	('myosin', 'Gene', (14, 20))	('BDP8900', 'Var', (188, 195))	('breast cancer', 'Phenotype', 'HP:0003002', (77, 90))	('MLC2', 'Gene', (51, 55))	('ROCK1', 'Gene', '6093', (349, 354))	('BDP9066', 'Chemical', '-', (286, 293))	('ROCK2', 'Gene', (260, 265))	('MLC2', 'Gene', '10398', (51, 55))	('breast cancer', 'Disease', 'MESH:D001943', (77, 90))	('ROCK2', 'Gene', (163, 168))	('human', 'Species', '9606', (71, 76))	('tetracycline', 'Chemical', 'MESH:D013752', (120, 132))	('ROCK1', 'Gene', (153, 158))	('breast cancer', 'Disease', (77, 90))	('ROCK2', 'Gene', '9475', (358, 363))	('MDA MB 231', 'CellLine', 'CVCL:0062', (60, 70))	('ROCK1', 'Gene', '6093', (251, 256))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('more', 'PosReg', (211, 215))	('myosin', 'Gene', '79784', (14, 20))	('ROCK2', 'Gene', '9475', (260, 265))	('ROCK1', 'Gene', (349, 354))	('ROCK2', 'Gene', (358, 363))	('ROCK1', 'Gene', '6093', (153, 158))
361052	29382705	To extend selectivity profiling, a larger panel of 115 kinases was screened with 1 microM BDP8900 or BDP9066 either for inhibition of kinase activity at the apparent Km for ATP of each kinase, or for competitive inhibition of binding to the ATP site (Supplemental Table 3).	('binding', 'Interaction', (226, 233))	('BDP9066', 'Var', (101, 108))	('ATP', 'Chemical', 'MESH:D000255', (241, 244))	('BDP9066', 'Chemical', '-', (101, 108))	('BDP8900', 'Var', (90, 97))	('kinase activity', 'MPA', (134, 149))	('inhibition', 'NegReg', (120, 130))	('BDP8900', 'Chemical', '-', (90, 97))	('ATP', 'Chemical', 'MESH:D000255', (173, 176))	('S', 'Chemical', 'MESH:D013455', (251, 252))
361054	29382705	The majority of kinases were unaffected by BDP8900 or BDP9066 (indicated by green circles with labels, with >75% inhibition (red circles) of the AGC kinases PKCgamma and DMPK by BDP8900 (Supplemental Figure 1A, Figures 2A and 2B), and ROCK1, ROCK2, CDK2/Cyclin A, CDK9/(Cyclin K or Cyclin T1), PKCalpha, TSSK1 (STK22D) and DMPK by BDP9066 (Supplemental Figure 1B, Figures 2A and 2B).	('Cyclin K', 'Gene', '8812', (270, 278))	('CDK2', 'Gene', '1017', (249, 253))	('ROCK1', 'Gene', (235, 240))	('DMPK', 'Gene', '1760', (323, 327))	('ROCK2', 'Gene', '9475', (242, 247))	('Cyclin K', 'Gene', (270, 278))	('STK22D', 'Gene', '81629', (311, 317))	('CDK2', 'Gene', (249, 253))	('TSSK1', 'Gene', (304, 309))	('BDP9066', 'Var', (331, 338))	('BDP8900', 'Chemical', '-', (178, 185))	('S', 'Chemical', 'MESH:D013455', (306, 307))	('DMPK', 'Gene', '1760', (170, 174))	('S', 'Chemical', 'MESH:D013455', (187, 188))	('BDP9066', 'Chemical', '-', (54, 61))	('S', 'Chemical', 'MESH:D013455', (305, 306))	('PKCgamma', 'Gene', (157, 165))	('Cyclin T1', 'Gene', (282, 291))	('PKCgamma', 'Gene', '5582', (157, 165))	('CDK9', 'Gene', (264, 268))	('Cyclin A', 'Gene', (254, 262))	('ROCK2', 'Gene', (242, 247))	('BDP8900', 'Var', (178, 185))	('ROCK1', 'Gene', '6093', (235, 240))	('DMPK', 'Gene', (323, 327))	('BDP8900', 'Chemical', '-', (43, 50))	('AGC kinases', 'Enzyme', (145, 156))	('PKCalpha', 'Gene', '5578', (294, 302))	('BDP9066', 'Chemical', '-', (331, 338))	('S', 'Chemical', 'MESH:D013455', (311, 312))	('BDP8900', 'Var', (43, 50))	('STK22D', 'Gene', (311, 317))	('CDK9', 'Gene', '1025', (264, 268))	('DMPK', 'Gene', (170, 174))	('Cyclin A', 'Gene', '890', (254, 262))	('inhibition', 'NegReg', (113, 123))	('PKCalpha', 'Gene', (294, 302))	('Cyclin T1', 'Gene', '904', (282, 291))	('S', 'Chemical', 'MESH:D013455', (340, 341))	('TSSK1', 'Gene', '23752', (304, 309))
361055	29382705	To more precisely characterize the selectivity of BDP8900 and BDP9066, dose-response assays were performed against kinases identified by the screen as comparatively sensitive (Figure 2B, red dots).	('BDP8900', 'Chemical', '-', (50, 57))	('rat', 'Species', '10116', (156, 159))	('BDP8900', 'Var', (50, 57))	('BDP9066', 'Var', (62, 69))	('BDP9066', 'Chemical', '-', (62, 69))
361056	29382705	Under the assay conditions, BDP8900 and BDP9066 were markedly selective against all kinases tested (Figures 2C and 2D).	('BDP8900', 'Var', (28, 35))	('BDP8900', 'Chemical', '-', (28, 35))	('BDP9066', 'Chemical', '-', (40, 47))	('BDP9066', 'Var', (40, 47))
361057	29382705	Using ATP Km values and the Cheng-Prusoff equation, calculated Ki values from this screen revealed minimum fold-selectivity for MRCKbeta that was 43 times greater for BDP8900 (Supplemental Table 4) and 27 times greater for BDP9066 against all kinases tested (Supplemental Table 5).	('BDP8900', 'Var', (167, 174))	('BDP9066', 'Chemical', '-', (223, 230))	('S', 'Chemical', 'MESH:D013455', (176, 177))	('BDP8900', 'Chemical', '-', (167, 174))	('greater', 'PosReg', (155, 162))	('S', 'Chemical', 'MESH:D013455', (259, 260))	('ATP', 'Chemical', 'MESH:D000255', (6, 9))	('BDP9066', 'Var', (223, 230))
361060	29382705	Given the >1.0 Hill slopes (~1.9) for the MRCKbeta inhibition curves for BDP8900 (Figure 2C) and for BDP9066 (Figure 2D), and the lower apparent potencies of both MRCK inhibitors in this assay format relative to the potencies observed assay using optimized conditions established in-house (Figures 1B and 1C), the selectivities of BDP8900 and BDP9066 were likely underestimated.	('lower', 'NegReg', (130, 135))	('inhibition', 'NegReg', (51, 61))	('potencies', 'MPA', (145, 154))	('MRCK', 'Gene', '8476', (42, 46))	('MRCK', 'Gene', (42, 46))	('MRCK', 'Gene', '8476', (163, 167))	('BDP8900', 'Var', (73, 80))	('BDP9066', 'Chemical', '-', (101, 108))	('MRCK', 'Gene', (163, 167))	('BDP8900', 'Chemical', '-', (73, 80))	('BDP9066', 'Chemical', '-', (343, 350))	('BDP8900', 'Chemical', '-', (331, 338))
361061	29382705	Plotting the natural log Ki values determined in-house (Figure 2F, red dots) against out-sourced values (Figure 2F, black dots) indicated that the differences between in-house and outsourced Ki values for ROCK1 inhibition were only 4.4-fold for BDP8900 and 2.9-fold for BDP9066, but for MRCKbeta differed by 41-fold for BDP8900 and 59-fold for BDP9066, consistent with on-target compound potencies being undervalued due to insufficient sensitivity of the out-sourced assays.	('BDP8900', 'Chemical', '-', (245, 252))	('ROCK1', 'Gene', '6093', (205, 210))	('ROCK1', 'Gene', (205, 210))	('BDP8900', 'Var', (320, 327))	('BDP9066', 'Chemical', '-', (344, 351))	('BDP9066', 'Chemical', '-', (270, 277))	('BDP8900', 'Chemical', '-', (320, 327))
361063	29382705	When compared against MRCKbeta Ki values determined in-house (Figure 2F, red dots), the affinity of BDP8900 was more than 2083 times greater, and of BDP9066 was more than 1635 times greater, relative to all other kinases tested for inhibition of activity (Figure 2F, black dots), and 33-fold higher than the DMPK Kd determined for BDP8900 and 42-fold higher than for BDP9066 (Figure 2F, purple dot).	('greater', 'PosReg', (133, 140))	('BDP9066', 'Var', (149, 156))	('greater', 'PosReg', (182, 189))	('affinity', 'MPA', (88, 96))	('BDP9066', 'Chemical', '-', (149, 156))	('BDP8900', 'Var', (100, 107))	('DMPK', 'Gene', '1760', (308, 312))	('DMPK', 'Gene', (308, 312))	('activity', 'MPA', (246, 254))	('BDP8900', 'Chemical', '-', (100, 107))	('higher', 'PosReg', (292, 298))	('BDP8900', 'Chemical', '-', (331, 338))	('BDP9066', 'Chemical', '-', (367, 374))
361064	29382705	Taken together, these results reveal that BDP8900 and BDP9066 are potent and highly selective inhibitors of MRCK with robust on-target actions in vitro and in whole cells.	('MRCK', 'Gene', '8476', (108, 112))	('BDP9066', 'Var', (54, 61))	('BDP8900', 'Var', (42, 49))	('MRCK', 'Gene', (108, 112))	('BDP9066', 'Chemical', '-', (54, 61))	('BDP8900', 'Chemical', '-', (42, 49))
361065	29382705	To investigate the binding mode of these azaindole compounds, crystal structures of MRCKbeta in complex with BDP8900 and BDP9066 were determined to 1.68A and 2.00A resolutions, respectively (Supplemental Table 1).	('BDP9066', 'Var', (121, 128))	('BDP8900', 'Chemical', '-', (109, 116))	('BDP8900', 'Var', (109, 116))	('BDP9066', 'Chemical', '-', (121, 128))	('S', 'Chemical', 'MESH:D013455', (191, 192))	('azaindole', 'Chemical', '-', (41, 50))	('MRCKbeta', 'Gene', (84, 92))
361072	29382705	BDP8900 and BDP9066 adopt highly similar poses in the ATP-binding site (Figures 3A and 3B): the all-atom coordinate RMSD for the two ligands after superposition of the two complex structures on the protein residues highlighted in Figure 3A was 0.105A for 21 comparable atoms (i.e.	('ATP', 'Chemical', 'MESH:D000255', (54, 57))	('BDP9066', 'Var', (12, 19))	('BDP9066', 'Chemical', '-', (12, 19))	('BDP8900', 'Chemical', '-', (0, 7))	('RMSD', 'Disease', 'None', (116, 120))	('RMSD', 'Disease', (116, 120))
361075	29382705	Both ligands preserved the two 'pocket waters' seen in the BDP5290 complex and satisfy the hydrogen bonding potential of the outer (left in Figures 3A and 3B) water by accepting an H-bond to the thiazole (BDP8900) or pyrimidine (BDP9066) nitrogen.	('H-bond', 'MPA', (181, 187))	('BDP5290', 'Var', (59, 66))	('hydrogen', 'Chemical', 'MESH:D006859', (91, 99))	('water', 'Chemical', 'MESH:D014867', (39, 44))	('hydrogen bonding potential', 'MPA', (91, 117))	('BDP9066', 'Var', (229, 236))	("'pocket waters'", 'MPA', (31, 46))	('BDP5290', 'Chemical', 'MESH:C000602147', (59, 66))	('thiazole', 'Chemical', 'MESH:D013844', (195, 203))	('pyrimidine', 'Chemical', 'MESH:C030986', (217, 227))	('BDP9066', 'Chemical', '-', (229, 236))	('BDP8900', 'Var', (205, 212))	('nitrogen', 'Chemical', 'MESH:D009584', (238, 246))	('water', 'Chemical', 'MESH:D014867', (159, 164))	('BDP8900', 'Chemical', '-', (205, 212))
361076	29382705	In addition, the second pyrimidine nitrogen of BDP9066 accepts a hydrogen bond of relatively poor geometry from Lys105.	('Lys105', 'Chemical', '-', (112, 118))	('hydrogen bond', 'MPA', (65, 78))	('pyrimidine', 'Chemical', 'MESH:C030986', (24, 34))	('BDP9066', 'Var', (47, 54))	('hydrogen', 'Chemical', 'MESH:D006859', (65, 73))	('nitrogen', 'Chemical', 'MESH:D009584', (35, 43))	('BDP9066', 'Chemical', '-', (47, 54))
361077	29382705	The spiro moiety of the azaindole ligands provides a 'plug' for the ATP-binding site opening, interacting with residues around the glycine-rich loop (Ile82, Gly83, Arg84, Val90), the catalytic loop (Asp204, Asn205, Leu207) as well as Phe370 (Figure 3C).	('Asn205', 'Var', (207, 213))	('Asp204', 'Chemical', '-', (199, 205))	('Phe370', 'Chemical', '-', (234, 240))	('ATP', 'Chemical', 'MESH:D000255', (68, 71))	('Arg84', 'Var', (164, 169))	('Gly83', 'Var', (157, 162))	('azaindole', 'Chemical', '-', (24, 33))	('Val90', 'Chemical', '-', (171, 176))	('Ile82', 'Chemical', '-', (150, 155))	('glycine', 'Chemical', 'MESH:D005998', (131, 138))	('Arg84', 'Chemical', '-', (164, 169))	('Leu207', 'Var', (215, 221))	('Leu207', 'Chemical', '-', (215, 221))	('Gly83', 'Chemical', '-', (157, 162))	('interacting', 'Interaction', (94, 105))	('Asn205', 'Chemical', '-', (207, 213))	('Ile82', 'Var', (150, 155))	('Asp204', 'Var', (199, 205))
361080	29382705	The other water was more exposed to bulk solvent and accordingly appears less well bound and less consistent in its interactions, which can involve Asp204 and (via additional ordered waters) Arg84, Asn205 and Asp218.	('Asn205', 'Var', (198, 204))	('Arg84', 'Chemical', '-', (191, 196))	('interactions', 'Interaction', (116, 128))	('water', 'Chemical', 'MESH:D014867', (183, 188))	('Asp218', 'Chemical', '-', (209, 215))	('Asp204', 'Var', (148, 154))	('Asp204', 'Chemical', '-', (148, 154))	('water', 'Chemical', 'MESH:D014867', (10, 15))	('Asp218', 'Var', (209, 215))	('Arg84', 'Var', (191, 196))	('Asn205', 'Chemical', '-', (198, 204))
361084	29382705	The diazaspiro[5.5]undecane substituent of the azaindole compounds provided an approximate replacement for the piperidine of BDP5290, though it appears that the shift in location and nitrogen position of the terminal piperidine moiety allowed BDP8900/9066 to form more extensive interactions with the protein, which may contribute to the higher affinity of these compounds for MRCKbeta.	('piperidine', 'Chemical', 'MESH:C032727', (111, 121))	('affinity', 'Interaction', (345, 353))	('BDP8900', 'Chemical', '-', (243, 250))	('diazaspiro[5.5]undecane', 'Chemical', '-', (4, 27))	('interactions', 'Interaction', (279, 291))	('BDP8900/9066', 'Var', (243, 255))	('piperidine', 'Chemical', 'MESH:C032727', (217, 227))	('protein', 'Protein', (301, 308))	('BDP5290', 'Chemical', 'MESH:C000602147', (125, 132))	('nitrogen', 'Chemical', 'MESH:D009584', (183, 191))	('azaindole', 'Chemical', '-', (47, 56))
361085	29382705	Another notable difference between the two series is that, unlike the 2-pyridylpyrazole of BDP5290, the smaller azaindole of BDP8900/9066 did not displace the Phe370 side chain on binding (Figure 3D), avoiding energetic penalties associated with this conformational change and preserving a more compact ATP-binding site conformation for the spiro moiety to interact with, which could contribute to the improved affinity of the azaindoles compared to BDP5290.	('BDP8900/9066', 'Var', (125, 137))	('compact ATP-binding site conformation', 'MPA', (295, 332))	('azaindole', 'Chemical', '-', (112, 121))	('more', 'PosReg', (290, 294))	('2-pyridylpyrazole', 'Chemical', '-', (70, 87))	('improved', 'PosReg', (402, 410))	('Phe370', 'Chemical', '-', (159, 165))	('BDP5290', 'Chemical', 'MESH:C000602147', (450, 457))	('azaindoles', 'Chemical', '-', (427, 437))	('affinity', 'MPA', (411, 419))	('ATP', 'Chemical', 'MESH:D000255', (303, 306))	('energetic penalties', 'MPA', (210, 229))	('BDP8900', 'Chemical', '-', (125, 132))	('azaindole', 'Chemical', '-', (427, 436))	('BDP5290', 'Chemical', 'MESH:C000602147', (91, 98))
361086	29382705	We previously proposed the ligand interaction with the pocket waters as a determinant of selectivity for MRCK over ROCK, and this appears to hold true when comparing BDP8900 and BDP9066.	('MRCK', 'Gene', '8476', (105, 109))	('MRCK', 'Gene', (105, 109))	('BDP9066', 'Var', (178, 185))	('BDP8900', 'Var', (166, 173))	('BDP8900', 'Chemical', '-', (166, 173))	('water', 'Chemical', 'MESH:D014867', (62, 67))	('BDP9066', 'Chemical', '-', (178, 185))
361087	29382705	The hydrogen bonding geometry between the thiazole of BDP8900 and the outer pocket water is closer to ideal than that seen for the pyrimidine of BDP9066, and correspondingly the former compound exhibit greater selectivity.	('BDP9066', 'Chemical', '-', (145, 152))	('BDP8900', 'Chemical', '-', (54, 61))	('hydrogen bonding geometry', 'MPA', (4, 29))	('selectivity', 'MPA', (210, 221))	('thiazole', 'Chemical', 'MESH:D013844', (42, 50))	('hydrogen', 'Chemical', 'MESH:D006859', (4, 12))	('water', 'Chemical', 'MESH:D014867', (83, 88))	('pyrimidine', 'Chemical', 'MESH:C030986', (131, 141))	('BDP8900', 'Var', (54, 61))
361088	29382705	To identify cancer cell lines with significant sensitivity to the anti-proliferative effects of MRCK inhibitors as single agents, 757 cancer cell lines were screened using a 7-point dose range up to 10 microM of either BDP8900 or BDP9066, and viability monitored after 72 hours as described in.	('BDP8900', 'Var', (219, 226))	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('MRCK', 'Gene', (96, 100))	('cancer', 'Disease', (12, 18))	('BDP8900', 'Chemical', '-', (219, 226))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('rat', 'Species', '10116', (78, 81))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('BDP9066', 'Var', (230, 237))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('MRCK', 'Gene', '8476', (96, 100))	('BDP9066', 'Chemical', '-', (230, 237))
361092	29382705	Similarly, 8 cancer types were significantly sensitive and 4 were significantly resistant to BDP9066 relative to all cancer cells (Figure 4B).	('BDP9066', 'Var', (93, 100))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('BDP9066', 'Chemical', '-', (93, 100))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('resistant', 'NegReg', (80, 89))	('cancer', 'Disease', (13, 19))	('cancer', 'Disease', 'MESH:D009369', (13, 19))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('cancer', 'Disease', (117, 123))	('S', 'Chemical', 'MESH:D013455', (0, 1))
361093	29382705	When the mean EC50 values of BDP8900 and BDP9066 for each cancer type were plotted, Deming regression analysis revealed a strong correlation (p<0.001) and a line slope that approached 1.0, with common sensitive cancer types (green dots) and resistant cancer types (red dots) relative to all cancers (blue dots) indicated (Figure 4C).	('BDP9066', 'Chemical', '-', (41, 48))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('cancer', 'Disease', 'MESH:D009369', (291, 297))	('cancer', 'Disease', 'MESH:D009369', (251, 257))	('BDP8900', 'Chemical', '-', (29, 36))	('cancer', 'Disease', 'MESH:D009369', (211, 217))	('cancers', 'Disease', 'MESH:D009369', (291, 298))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('BDP8900', 'Var', (29, 36))	('Deming regression', 'Phenotype', 'HP:0002376', (84, 101))	('cancer', 'Disease', (291, 297))	('BDP9066', 'Var', (41, 48))	('cancer', 'Disease', (251, 257))	('cancer', 'Phenotype', 'HP:0002664', (291, 297))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('cancers', 'Phenotype', 'HP:0002664', (291, 298))	('cancer', 'Disease', (211, 217))	('cancers', 'Disease', (291, 298))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('cancer', 'Disease', (58, 64))
361094	29382705	Plotting the EC50 values of BDP8900 and BDP9066 for each cell line also revealed a strong correlation (p<0.0001) by Deming regression and a line slope that approached 1.0 (Supplemental Figure 2).	('Deming regression', 'Phenotype', 'HP:0002376', (116, 133))	('S', 'Chemical', 'MESH:D013455', (172, 173))	('BDP9066', 'Var', (40, 47))	('BDP8900', 'Var', (28, 35))	('BDP9066', 'Chemical', '-', (40, 47))	('BDP8900', 'Chemical', '-', (28, 35))
361096	29382705	Interestingly, all 8 cancer types sensitive to both BDP8900 and BDP9066 were hematological cancers, with 2 additional blood cancers being significantly sensitive to one compound and others clustering, albeit not reaching statistical significance, to the sensitive end of the rankings.	('blood cancers', 'Disease', (118, 131))	('BDP9066', 'Chemical', '-', (64, 71))	('cancer', 'Disease', 'MESH:D009369', (21, 27))	('blood cancers', 'Disease', 'MESH:D009369', (118, 131))	('cancer', 'Disease', 'MESH:D009369', (124, 130))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('sensitive', 'Reg', (152, 161))	('BDP8900', 'Chemical', '-', (52, 59))	('BDP8900', 'Var', (52, 59))	('cancer', 'Disease', (21, 27))	('cancers', 'Phenotype', 'HP:0002664', (124, 131))	('hematological cancers', 'Disease', (77, 98))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('cancer', 'Disease', (124, 130))	('cancers', 'Phenotype', 'HP:0002664', (91, 98))	('hematological cancer', 'Phenotype', 'HP:0004377', (77, 97))	('cancer', 'Disease', (91, 97))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('BDP9066', 'Var', (64, 71))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('hematological cancers', 'Disease', 'MESH:D009369', (77, 98))	('blood cancers', 'Phenotype', 'HP:0001909', (118, 131))
361099	29382705	When wild-type MRCKalpha, or a kinase-dead version with a K106M mutation that prevents ATP binding, were expressed and immunoprecipitated from HEK293 cells (Figure 5A, left panel), in vitro kinase assays with [gamma-32P] ATP revealed considerable 32P labelling of wild-type MRCKalpha, but not MRCKalpha K106M (Figure 5A, right panel).	('MRCKalpha', 'Gene', (274, 283))	('32P labelling', 'MPA', (247, 260))	('MRCKalpha', 'Gene', '8476', (274, 283))	('[gamma-32P', 'Chemical', '-', (209, 219))	('K106M', 'Var', (58, 63))	('K106M', 'Mutation', 'p.K106M', (58, 63))	('HEK293', 'CellLine', 'CVCL:0045', (143, 149))	('MRCKalpha', 'Gene', '8476', (293, 302))	('K106M', 'Var', (303, 308))	('MRCKalpha', 'Gene', (15, 24))	('ATP', 'Chemical', 'MESH:D000255', (87, 90))	('K106M', 'Mutation', 'p.K106M', (303, 308))	('MRCKalpha', 'Gene', '8476', (15, 24))	('MRCKalpha', 'Gene', (293, 302))	('ATP', 'Chemical', 'MESH:D000255', (221, 224))	('32P', 'Chemical', 'MESH:C000615311', (216, 219))	('32P', 'Chemical', 'MESH:C000615311', (247, 250))
361100	29382705	To identify autophosphorylation sites, wild-type MRCKalpha and MRCKalpha K106M were expressed and immunoprecipitated from HEK293 cells (Figure 5B, left panel), and phosphorylations measured by mass spectrometry (Figure 5B, right panel).	('HEK293', 'CellLine', 'CVCL:0045', (122, 128))	('MRCKalpha', 'Gene', (63, 72))	('MRCKalpha', 'Gene', '8476', (63, 72))	('MRCKalpha', 'Gene', (49, 58))	('MRCKalpha', 'Gene', '8476', (49, 58))	('K106M', 'Var', (73, 78))	('K106M', 'Mutation', 'p.K106M', (73, 78))
361101	29382705	A total of 22 phosphorylations were identified on MRCKalpha (Supplemental Table 7), of which 8 were not detected in MRCKalpha K106M, including S1003 (Figure 5B, y7 m/z peaks in right panel; Supplemental Table 8), consistent with these phosphorylations being autocatalyzed.	('MRCKalpha', 'Gene', '8476', (116, 125))	('S', 'Chemical', 'MESH:D013455', (143, 144))	('MRCKalpha', 'Gene', (116, 125))	('K106M', 'Var', (126, 131))	('S', 'Chemical', 'MESH:D013455', (61, 62))	('K106M', 'Mutation', 'p.K106M', (126, 131))	('S1003', 'Var', (143, 148))	('S', 'Chemical', 'MESH:D013455', (190, 191))	('MRCKalpha', 'Gene', '8476', (50, 59))	('MRCKalpha', 'Gene', (50, 59))	('phosphorylations', 'MPA', (14, 30))
361106	29382705	Detection of immunoprecipitated FLAG-tagged MRCKalpha by western blotting was blocked by pre-incubation of the antibody with phosphopeptide P, but not peptide U (Figure 5D).	('MRCKalpha', 'Gene', '8476', (44, 53))	('MRCKalpha', 'Gene', (44, 53))	('FLAG-tagged', 'Var', (32, 43))
361108	29382705	Immunoreactivity with the pS1003 antibody was detected on immunoprecipitated FLAG-tagged MRCKalpha, but not kinase-dead K106M or non-phosphorylatable S1003A mutants, consistent with this site being autophosphorylated (Figure 5F).	('K106M', 'Var', (120, 125))	('S', 'Chemical', 'MESH:D013455', (27, 28))	('S1003A', 'Mutation', 'p.S1003A', (150, 156))	('MRCKalpha', 'Gene', (89, 98))	('MRCKalpha', 'Gene', '8476', (89, 98))	('K106M', 'Mutation', 'p.K106M', (120, 125))	('S1003A', 'Var', (150, 156))	('S', 'Chemical', 'MESH:D013455', (150, 151))
361111	29382705	To determine the mechanism of MRCKalpha S1003 autophosphorylation, a FLAG-tagged MRCKalpha mutant lacking the last 100 amino acids (MRCKalphaDeltaC), or the kinase-dead K106M mutant, were expressed and purified from HEK293 cells.	('MRCKalpha', 'Gene', '8476', (30, 39))	('MRCKalpha', 'Gene', (30, 39))	('MRCKalpha', 'Gene', '8476', (81, 90))	('lacking', 'NegReg', (98, 105))	('K106M', 'Mutation', 'p.K106M', (169, 174))	('S', 'Chemical', 'MESH:D013455', (40, 41))	('HEK293', 'CellLine', 'CVCL:0045', (216, 222))	('MRCKalpha', 'Gene', (132, 141))	('K106M', 'Var', (169, 174))	('mutant', 'Var', (91, 97))	('MRCKalpha', 'Gene', '8476', (132, 141))	('MRCKalpha', 'Gene', (81, 90))
361113	29382705	While the faster-migrating MRCKalphaDeltaC was able to autophosphorylate S1003 in cis when alone or with K106M, there was no evidence of trans phosphorylation of the larger K106M mutant by active MRCKalphaDeltaC (Figure 5I).	('MRCKalpha', 'Gene', (196, 205))	('MRCKalpha', 'Gene', '8476', (196, 205))	('S', 'Chemical', 'MESH:D013455', (73, 74))	('MRCKalpha', 'Gene', '8476', (27, 36))	('MRCKalpha', 'Gene', (27, 36))	('rat', 'Species', '10116', (20, 23))	('K106M', 'Mutation', 'p.K106M', (173, 178))	('K106M', 'Var', (173, 178))	('K106M', 'Var', (105, 110))	('K106M', 'Mutation', 'p.K106M', (105, 110))
361114	29382705	Therefore, MRCKalpha utilizes an intra-molecular mechanism for S1003 autophosphorylation.	('MRCKalpha', 'Gene', (11, 20))	('MRCKalpha', 'Gene', '8476', (11, 20))	('S', 'Chemical', 'MESH:D013455', (63, 64))	('S1003', 'Var', (63, 68))
361115	29382705	When dephosphorylated MRCKalpha (Figure 5J, upper panel) was allowed to phosphorylate itself and recombinant MLC2 in the same in vitro reaction, both autophosphorylation (Figure 5J, lower left panel) and MLC2 phosphorylation (Figure 5J, lower right panel) were blocked by BDP9066, supporting the relationship between MRCKalpha S1003 autophosphorylation and kinase activity.	('MRCKalpha', 'Gene', '8476', (22, 31))	('BDP9066', 'Chemical', '-', (272, 279))	('S', 'Chemical', 'MESH:D013455', (327, 328))	('MRCKalpha', 'Gene', (317, 326))	('MRCKalpha', 'Gene', '8476', (317, 326))	('MLC2', 'Gene', '10398', (109, 113))	('MLC2', 'Gene', (204, 208))	('MLC2', 'Gene', '10398', (204, 208))	('MLC2', 'Gene', (109, 113))	('BDP9066', 'Var', (272, 279))	('MRCKalpha', 'Gene', (22, 31))
361116	29382705	To characterize whether S1003 autophosphorylation is required for substrate phosphorylation, FLAG-tagged MRCKalpha, kinase-dead K106M and non-phosphorylatable S1003A mutants were immunoprecipitated from HEK293 cells and assayed for MLC2 phosphorylating activity in vitro.	('MRCKalpha', 'Gene', '8476', (105, 114))	('MRCKalpha', 'Gene', (105, 114))	('rat', 'Species', '10116', (71, 74))	('HEK293', 'CellLine', 'CVCL:0045', (203, 209))	('MLC2', 'Gene', '10398', (232, 236))	('S', 'Chemical', 'MESH:D013455', (159, 160))	('S1003A', 'Mutation', 'p.S1003A', (159, 165))	('MLC2', 'Gene', (232, 236))	('K106M', 'Var', (128, 133))	('S', 'Chemical', 'MESH:D013455', (24, 25))	('K106M', 'Mutation', 'p.K106M', (128, 133))	('S1003A', 'Var', (159, 165))
361117	29382705	While kinase-dead K106M was significantly less active than wild-type MRCKalpha or the S1003A mutant, there was no significant difference in activity between wild-type MRCKalpha or the S1003A mutant (Figure 5K).	('MRCKalpha', 'Gene', '8476', (167, 176))	('MRCKalpha', 'Gene', (69, 78))	('K106M', 'Var', (18, 23))	('MRCKalpha', 'Gene', '8476', (69, 78))	('S1003A', 'Mutation', 'p.S1003A', (86, 92))	('K106M', 'Mutation', 'p.K106M', (18, 23))	('S1003A', 'Var', (86, 92))	('S1003A', 'Mutation', 'p.S1003A', (184, 190))	('active', 'MPA', (47, 53))	('less', 'NegReg', (42, 46))	('MRCKalpha', 'Gene', (167, 176))	('S1003A', 'Var', (184, 190))
361125	29382705	MRCKalpha, MRCKalpha pS1003 and MRCKbeta immunoreactivity were examined in GM mouse SCC models expressing epidermis-targeted activated Hras alone, or in combination with epidermis-targeted transgenic c-Fos and conditional epidermal deletion of Pten, which give rise to stable papillomas that may stochastically convert to malignancy via additional events such as p53 loss.	('SCC', 'Gene', '6317', (84, 87))	('papilloma', 'Phenotype', 'HP:0012740', (276, 285))	('MRCKalpha', 'Gene', (0, 9))	('S', 'Chemical', 'MESH:D013455', (84, 85))	('deletion', 'Var', (232, 240))	('S', 'Chemical', 'MESH:D013455', (22, 23))	('amine', 'Chemical', 'MESH:D000588', (65, 70))	('malignancy', 'Disease', 'MESH:D009369', (322, 332))	('mouse', 'Species', '10090', (78, 83))	('SCC', 'Gene', (84, 87))	('MRCKalpha', 'Gene', '8476', (11, 20))	('loss', 'NegReg', (367, 371))	('malignancy', 'Disease', (322, 332))	('MRCKalpha', 'Gene', '8476', (0, 9))	('papillomas', 'Disease', 'MESH:D010212', (276, 286))	('p53', 'Gene', (363, 366))	('papillomas', 'Phenotype', 'HP:0012740', (276, 286))	('GM', 'Chemical', '-', (75, 77))	('p53', 'Gene', '22060', (363, 366))	('MRCKalpha', 'Gene', (11, 20))	('papillomas', 'Disease', (276, 286))	('Pten', 'Gene', (244, 248))	('transgenic', 'Species', '10090', (189, 199))
361132	29382705	Furthermore, the MRCK inhibitor BDP5290 also reduced MLC phosphorylation and inhibited SCC12 organotypic invasion.	('SCC12 organotypic invasion', 'CPA', (87, 113))	('reduced', 'NegReg', (45, 52))	('inhibited', 'NegReg', (77, 86))	('BDP5290', 'Var', (32, 39))	('MLC', 'Gene', (53, 56))	('MLC', 'Gene', '23209', (53, 56))	('MRCK', 'Gene', '8476', (17, 21))	('BDP5290', 'Chemical', 'MESH:C000602147', (32, 39))	('MRCK', 'Gene', (17, 21))	('SCC12', 'CellLine', 'CVCL:4026', (87, 92))
361133	29382705	To investigate the effect of BDP9066 on pMLC2 in SCC12 cells, which express MRCK but no detectable DMPK (Supplemental Figure 5), varying BDP9066 concentrations incubated with cells for 2 hours led to dose-dependent inhibition of MLC2 phosphorylation (Figure 6A, left) with an EC50 = 64 nM (Figure 6A, right), corresponding to a 5-fold increase in cellular potency relative to BDP5290.	('rat', 'Species', '10116', (152, 155))	('inhibition', 'NegReg', (215, 225))	('DMPK', 'Gene', '1760', (99, 103))	('MLC2', 'Gene', (41, 45))	('MLC2', 'Gene', '10398', (41, 45))	('MRCK', 'Gene', '8476', (76, 80))	('BDP9066', 'Chemical', '-', (29, 36))	('BDP9066', 'Var', (137, 144))	('BDP5290', 'Chemical', 'MESH:C000602147', (376, 383))	('S', 'Chemical', 'MESH:D013455', (105, 106))	('DMPK', 'Gene', (99, 103))	('S', 'Chemical', 'MESH:D013455', (49, 50))	('MRCK', 'Gene', (76, 80))	('MLC2', 'Gene', (229, 233))	('cellular potency', 'MPA', (347, 363))	('MLC2', 'Gene', '10398', (229, 233))	('BDP9066', 'Chemical', '-', (137, 144))	('increase', 'PosReg', (335, 343))	('SCC12', 'CellLine', 'CVCL:4026', (49, 54))
361135	29382705	These results indicate that BDP9066 is relatively non-toxic at concentrations that profoundly inhibit substrate phosphorylation.	('BDP9066', 'Chemical', '-', (28, 35))	('rat', 'Species', '10116', (70, 73))	('substrate phosphorylation', 'MPA', (102, 127))	('BDP9066', 'Var', (28, 35))	('inhibit', 'NegReg', (94, 101))	('rat', 'Species', '10116', (107, 110))
361136	29382705	Treatment of SCC12 cells with non-toxic 0.5 muM BDP9066 led to changes in cell morphology, with reduced proportions of regularly (rounded, few protrusions) shaped cells (Figure 6C, green cells), and increased irregularly (greater spreading, increased protrusions) shaped cells (Figure 6C, blue cells) as determined by high content imaging.	('BDP9066', 'Var', (48, 55))	('cell morphology', 'CPA', (74, 89))	('greater', 'PosReg', (222, 229))	('increased', 'PosReg', (241, 250))	('muM', 'Gene', (44, 47))	('BDP9066', 'Chemical', '-', (48, 55))	('SCC12', 'CellLine', 'CVCL:4026', (13, 18))	('muM', 'Gene', '56925', (44, 47))	('changes', 'Reg', (63, 70))	('increased', 'PosReg', (199, 208))	('reduced', 'NegReg', (96, 103))
361141	29382705	Consistent with our previous observations using the MRCK inhibitor BDP5290, BDP9066 similarly reduced the bundling of filamentous actin at cortical and cytoplasmic regions (Figure 6F).	('MRCK', 'Gene', '8476', (52, 56))	('BDP9066', 'Var', (76, 83))	('reduced', 'NegReg', (94, 101))	('bundling', 'MPA', (106, 114))	('BDP9066', 'Chemical', '-', (76, 83))	('MRCK', 'Gene', (52, 56))	('BDP5290', 'Chemical', 'MESH:C000602147', (67, 74))
361143	29382705	Scatterplots of cell paths showed marked reduction of cell motility induced by BDP9066 (Figure 6G).	('BDP9066', 'Var', (79, 86))	('BDP9066', 'Chemical', '-', (79, 86))	('cell motility', 'CPA', (54, 67))	('S', 'Chemical', 'MESH:D013455', (0, 1))	('reduction', 'NegReg', (41, 50))
361144	29382705	The effect of non-toxic 0.4 muM BDP9066 was tested on organotypic invasion, in which the movement of SCC12 cells was measured from the surface downwards into a dense 3D rat tail collagen matrix that had been conditioned by cancer-associated fibroblasts for 7 days prior to their removal (Figure 6I).	('rat', 'Species', '10116', (169, 172))	('SCC12', 'CellLine', 'CVCL:4026', (101, 106))	('muM', 'Gene', '56925', (28, 31))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('BDP9066', 'Var', (32, 39))	('BDP9066', 'Chemical', '-', (32, 39))	('muM', 'Gene', (28, 31))	('cancer', 'Disease', 'MESH:D009369', (223, 229))	('cancer', 'Disease', (223, 229))	('rat tail', 'Phenotype', 'HP:0002825', (169, 177))
361145	29382705	A significant 50% decrease in the percentage of invading cells was observed for cells treated with 0.4 muM BDP9066 relative to DMSO vehicle (Figure 6J).	('BDP9066', 'Var', (107, 114))	('BDP9066', 'Chemical', '-', (107, 114))	('muM', 'Gene', '56925', (103, 106))	('DMSO', 'Chemical', 'MESH:D004121', (127, 131))	('decrease', 'NegReg', (18, 26))	('muM', 'Gene', (103, 106))
361146	29382705	Taken together, the results indicate that in SCC12 cells BDP9066 potently inhibits MRCK at sub-micromolar levels, leading to inhibition of MLC phosphorylation, changes in cell morphology, and reduced cell motility and 3D collagen invasion, without significantly affecting cell viability.	('changes', 'Reg', (160, 167))	('MRCK', 'Gene', '8476', (83, 87))	('MRCK', 'Gene', (83, 87))	('cell morphology', 'CPA', (171, 186))	('MLC', 'Gene', (139, 142))	('BDP9066', 'Var', (57, 64))	('MLC', 'Gene', '23209', (139, 142))	('inhibits', 'NegReg', (74, 82))	('cell motility', 'CPA', (200, 213))	('3D collagen invasion', 'CPA', (218, 238))	('BDP9066', 'Chemical', '-', (57, 64))	('SCC12', 'CellLine', 'CVCL:4026', (45, 50))	('reduced', 'NegReg', (192, 199))	('inhibition', 'NegReg', (125, 135))
361147	29382705	These findings are consistent with the previously reported inhibitory effects of MRCKalpha + MRCKbeta knockdown by siRNA, and the MRCK inhibitor BDP5290 on SCC12 organotypic invasion.	('MRCK', 'Gene', '8476', (93, 97))	('MRCKalpha', 'Gene', '8476', (81, 90))	('MRCK', 'Gene', (130, 134))	('MRCK', 'Gene', (93, 97))	('SCC12', 'CellLine', 'CVCL:4026', (156, 161))	('knockdown', 'Var', (102, 111))	('BDP5290', 'Chemical', 'MESH:C000602147', (145, 152))	('MRCK', 'Gene', '8476', (81, 85))	('SCC12 organotypic invasion', 'CPA', (156, 182))	('MRCK', 'Gene', '8476', (130, 134))	('MRCK', 'Gene', (81, 85))	('MRCKalpha', 'Gene', (81, 90))
361148	29382705	Having established that BDP9066 affects SCC tumor cell motility and invasion at sub-micromolar concentrations and viability at 1 microM in vitro (Figure 6), and that MRCKalpha, MRCKalpha pS1003 and MRCKbeta levels were elevated in GM and chemically-induced mouse models of skin cancer (Figure 5L), BDP9066 was evaluated for in vivo pharmacological proof-of-concept as an SCC chemotherapeutic agent.	('BDP9066', 'Gene', (24, 31))	('invasion', 'CPA', (68, 76))	('MRCKbeta levels', 'MPA', (198, 213))	('MRCKalpha', 'Gene', (166, 175))	('elevated', 'PosReg', (219, 227))	('S', 'Chemical', 'MESH:D013455', (188, 189))	('tumor', 'Disease', (44, 49))	('BDP9066', 'Chemical', '-', (24, 31))	('S', 'Chemical', 'MESH:D013455', (371, 372))	('GM', 'Chemical', '-', (231, 233))	('cancer', 'Phenotype', 'HP:0002664', (278, 284))	('skin cancer', 'Disease', (273, 284))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('BDP9066', 'Var', (298, 305))	('rat', 'Species', '10116', (102, 105))	('MRCKalpha', 'Gene', '8476', (177, 186))	('skin cancer', 'Phenotype', 'HP:0008069', (273, 284))	('SCC', 'Gene', '6317', (40, 43))	('MRCKalpha', 'Gene', '8476', (166, 175))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('BDP9066', 'Chemical', '-', (298, 305))	('SCC', 'Gene', (40, 43))	('affects', 'Reg', (32, 39))	('mouse', 'Species', '10090', (257, 262))	('SCC', 'Gene', '6317', (371, 374))	('skin cancer', 'Disease', 'MESH:D012878', (273, 284))	('S', 'Chemical', 'MESH:D013455', (40, 41))	('MRCKalpha', 'Gene', (177, 186))	('SCC', 'Gene', (371, 374))
361154	29382705	In either dosing regimen, over 16 muM BDP9066 was detected in skin 24 hours after final dosing (Figure 7D, left panel), while the low levels detected in blood were undetectable after 24 hours (Figure 7D, right panel).	('muM', 'Gene', '56925', (34, 37))	('muM', 'Gene', (34, 37))	('BDP9066', 'Var', (38, 45))	('BDP9066', 'Chemical', '-', (38, 45))
361155	29382705	These results indicated that it was possible to achieve sustainable BDP9066 levels in mouse skin by repeated topical application, which were sufficient to induce phenotypic responses in squamous cell carcinoma cells in vitro, without significant compound accumulation following sequential administration.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (186, 209))	('rat', 'Species', '10116', (297, 300))	('carcinoma', 'Phenotype', 'HP:0030731', (200, 209))	('squamous cell carcinoma', 'Disease', (186, 209))	('mouse', 'Species', '10090', (86, 91))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (186, 209))	('BDP9066', 'Var', (68, 75))	('BDP9066', 'Chemical', '-', (68, 75))
361159	29382705	At study end, skin papillomas in the BDP9066 treated group appeared visually smaller than in the DMSO treated group (Figure 7F).	('papilloma', 'Phenotype', 'HP:0012740', (19, 28))	('papillomas', 'Phenotype', 'HP:0012740', (19, 29))	('skin papillomas', 'Disease', (14, 29))	('BDP9066', 'Var', (37, 44))	('BDP9066', 'Chemical', '-', (37, 44))	('skin papillomas', 'Disease', 'MESH:D010212', (14, 29))	('DMSO', 'Chemical', 'MESH:D004121', (97, 101))	('smaller', 'NegReg', (77, 84))
361160	29382705	Although total papilloma numbers per mouse were not different between the DMSO and BDP9066 treatment groups (Figure 7G), both the total tumor volume (Figure 7H, left panel) and average papilloma volume (Figure 7H, right panel) per mouse were significantly reduced in the BDP9066 treatment group.	('papilloma', 'Disease', 'MESH:D010212', (185, 194))	('papilloma', 'Phenotype', 'HP:0012740', (15, 24))	('total tumor', 'Disease', (130, 141))	('BDP9066', 'Chemical', '-', (83, 90))	('DMSO', 'Chemical', 'MESH:D004121', (74, 78))	('papilloma', 'Disease', (15, 24))	('mouse', 'Species', '10090', (231, 236))	('papilloma', 'Phenotype', 'HP:0012740', (185, 194))	('mouse', 'Species', '10090', (37, 42))	('papilloma', 'Disease', 'MESH:D010212', (15, 24))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('reduced', 'NegReg', (256, 263))	('total tumor', 'Disease', 'MESH:D009369', (130, 141))	('BDP9066', 'Var', (271, 278))	('papilloma', 'Disease', (185, 194))	('BDP9066', 'Chemical', '-', (271, 278))
361161	29382705	Topical BDP9066 application resulted in undetectable compound in blood, and >1 microM mean BDP9066 concentration in skin at experimental endpoint (Figure 7I), which was associated with significant decreases in MRCKalpha pS1003 immunohistochemistry staining (Figure 7J) and reduced histoscores both in the treated skin area (Figure 7K, left panel) and in papillomas (Figure 7K, right panel).	('papillomas', 'Disease', 'MESH:D010212', (354, 364))	('papilloma', 'Phenotype', 'HP:0012740', (354, 363))	('BDP9066', 'Var', (8, 15))	('undetectable', 'NegReg', (40, 52))	('BDP9066', 'Gene', (91, 98))	('papillomas', 'Disease', (354, 364))	('MRCKalpha', 'Gene', (210, 219))	('BDP9066', 'Chemical', '-', (8, 15))	('S', 'Chemical', 'MESH:D013455', (221, 222))	('papillomas', 'Phenotype', 'HP:0012740', (354, 364))	('MRCKalpha', 'Gene', '8476', (210, 219))	('BDP9066', 'Chemical', '-', (91, 98))	('histoscores', 'CPA', (281, 292))	('decreases', 'NegReg', (197, 206))	('rat', 'Species', '10116', (106, 109))	('reduced', 'NegReg', (273, 280))
361163	29382705	The small molecule inhibitors BDP8900 and BDP9066 are the most potent and selective MRCK inhibitors discovered to date.	('BDP9066', 'Chemical', '-', (42, 49))	('MRCK', 'Gene', '8476', (84, 88))	('MRCK', 'Gene', (84, 88))	('BDP9066', 'Var', (42, 49))	('BDP8900', 'Var', (30, 37))	('BDP8900', 'Chemical', '-', (30, 37))
361168	29382705	Furthermore, topical application of BDP9066 to mice undergoing a DMBA/TPA chemical carcinogenesis protocol resulted in the therapeutic effect of significantly reduced papilloma volumes associated with micromolar compound levels in skin and reduced MRCKalpha S1003 autophosphorylation (Figure 7).	('S', 'Chemical', 'MESH:D013455', (258, 259))	('reduced', 'NegReg', (240, 247))	('papilloma', 'Phenotype', 'HP:0012740', (167, 176))	('reduced', 'NegReg', (159, 166))	('BDP9066', 'Var', (36, 43))	('MRCKalpha', 'Gene', (248, 257))	('BDP9066', 'Chemical', '-', (36, 43))	('MRCKalpha', 'Gene', '8476', (248, 257))	('papilloma', 'Disease', (167, 176))	('papilloma', 'Disease', 'MESH:D010212', (167, 176))	('micromolar compound levels', 'MPA', (201, 227))	('DMBA/TPA', 'Chemical', '-', (65, 73))	('mice', 'Species', '10090', (47, 51))
361175	29382705	The highly potent and selective inhibitors BDP8900 and BDP9066 will enable studies focused on discovery of MRCK actions and roles in cancer.	('MRCK', 'Gene', '8476', (107, 111))	('BDP9066', 'Chemical', '-', (55, 62))	('MRCK', 'Gene', (107, 111))	('BDP8900', 'Chemical', '-', (43, 50))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('cancer', 'Disease', (133, 139))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('BDP9066', 'Var', (55, 62))	('BDP8900', 'Var', (43, 50))
361181	29382705	Indications consistent with a role of MRCKalpha or MRCKbeta in cancer include elevated expression and gene copy number variations.	('MRCKalpha', 'Gene', '8476', (38, 47))	('MRCKalpha', 'Gene', (38, 47))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('elevated', 'PosReg', (78, 86))	('expression', 'MPA', (87, 97))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('cancer', 'Disease', (63, 69))	('gene copy number variations', 'Var', (102, 129))
361184	29382705	Increased MRCK activity might be trigged from upstream signals via CDC42, which could be activated through elevated expression, loss of inhibitory GTPase-activating proteins (GAPs), increased expression or activating mutation of guanine-nucleotide exchange factors (GEFs), or aberrant activity of regulators further upstream, such as receptor tyrosine kinases.	('activity', 'MPA', (285, 293))	('receptor tyrosine kinases', 'Enzyme', (334, 359))	('expression', 'MPA', (116, 126))	('MRCK', 'Gene', (10, 14))	('loss', 'NegReg', (128, 132))	('increased', 'PosReg', (182, 191))	('activating', 'PosReg', (206, 216))	('expression', 'MPA', (192, 202))	('MRCK', 'Gene', '8476', (10, 14))	('activated', 'PosReg', (89, 98))	('tyrosine', 'Chemical', 'MESH:D014443', (343, 351))	('aberrant', 'Var', (276, 284))	('CDC42', 'Gene', '998', (67, 72))	('elevated', 'PosReg', (107, 115))	('CDC42', 'Gene', (67, 72))
361187	29382705	A total of 8 phosphorylation sites were identified in wild-type MRCKalpha, but not the kinase dead K106M mutant, consistent with their being autophosphorylation events (Figure 5, Supplemental Tables 7 and 8).	('MRCKalpha', 'Gene', '8476', (64, 73))	('K106M', 'Var', (99, 104))	('MRCKalpha', 'Gene', (64, 73))	('K106M', 'Mutation', 'p.K106M', (99, 104))	('phosphorylation', 'MPA', (13, 28))	('S', 'Chemical', 'MESH:D013455', (179, 180))
361193	29382705	A role for MRCK in squamous cell carcinoma was previously indicated by microarray expression analysis of normal human skin versus epidermal SCC (Figure 5K) and by a GM mouse model of epidermal SCC induced by oncogenic Hras expression combined with Notch1 inhibition.	('MRCK', 'Gene', (11, 15))	('MRCK', 'Gene', '8476', (11, 15))	('mouse', 'Species', '10090', (168, 173))	('SCC', 'Gene', '6317', (140, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (33, 42))	('Hras', 'Protein', (218, 222))	('Notch1', 'Gene', (248, 254))	('GM', 'Chemical', '-', (165, 167))	('Notch1', 'Gene', '18128', (248, 254))	('SCC', 'Gene', (193, 196))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (19, 42))	('human', 'Species', '9606', (112, 117))	('squamous cell carcinoma', 'Disease', (19, 42))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (19, 42))	('oncogenic', 'Var', (208, 217))	('SCC', 'Gene', '6317', (193, 196))	('SCC', 'Gene', (140, 143))
361195	29382705	Furthermore, BDP9066 topical application significantly decreased phosphorylated MRCKalpha S1003 staining and tumor volumes (Figure 7), consistent with antibody staining for MRCK autophosphorylation being both an indicator of an association between MRCK activity with cancer, and a predictor of therapeutic response to inhibitor treatment.	('cancer', 'Disease', 'MESH:D009369', (267, 273))	('MRCK', 'Gene', (248, 252))	('MRCK', 'Gene', '8476', (80, 84))	('MRCKalpha', 'Gene', (80, 89))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('BDP9066', 'Var', (13, 20))	('association', 'Interaction', (228, 239))	('MRCK', 'Gene', (80, 84))	('MRCK', 'Gene', '8476', (173, 177))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('BDP9066', 'Chemical', '-', (13, 20))	('cancer', 'Disease', (267, 273))	('S', 'Chemical', 'MESH:D013455', (90, 91))	('decreased', 'NegReg', (55, 64))	('cancer', 'Phenotype', 'HP:0002664', (267, 273))	('MRCK', 'Gene', (173, 177))	('MRCKalpha', 'Gene', '8476', (80, 89))	('MRCK', 'Gene', '8476', (248, 252))	('tumor', 'Disease', (109, 114))
361201	24224046	Patients with mutations had worse overall survival compared to those with absence of mutations; and patients who harbored DNA binding domain (DBD) and L2/L3/LSH mutations showed a worse survival probability compared to those patients with wild type TP53.	('overall', 'MPA', (34, 41))	('mutations', 'Var', (14, 23))	('patients', 'Species', '9606', (225, 233))	('binding', 'Interaction', (126, 133))	('worse', 'NegReg', (28, 33))	('Patients', 'Species', '9606', (0, 8))	('patients', 'Species', '9606', (100, 108))	('mutations', 'Var', (161, 170))	('LSH', 'Gene', (157, 160))	('LSH', 'Gene', '3070', (157, 160))
361202	24224046	Hotspot oncogenic mutations which are frequently present in common solid tumors are exceedingly rare in OSCC.	('solid tumors', 'Disease', (67, 79))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('solid tumors', 'Disease', 'MESH:D009369', (67, 79))	('OSCC', 'Disease', (104, 108))	('mutations', 'Var', (18, 27))
361206	24224046	Cancer occurs due to the progressive accumulation of abnormalities in cellular DNA which, in turn, provide a selective growth advantage to cancer cells and facilitate metastatic dissemination.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('cellular DNA', 'Protein', (70, 82))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('abnormalities', 'Var', (53, 66))	('growth advantage', 'CPA', (119, 135))	('facilitate', 'PosReg', (156, 166))	('Cancer', 'Disease', (0, 6))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('metastatic dissemination', 'CPA', (167, 191))	('cancer', 'Disease', (139, 145))
361210	24224046	By contrast, very little is known about the spectrum of gene mutations in OSCC of Asian origin where the disease is most prevalent and where the practice of betel quid chewing, with or without smoking has been demonstrated to be associated with the increase risk to oral cancer in about 50% of the patients.	('oral cancer', 'Disease', (266, 277))	('cancer', 'Phenotype', 'HP:0002664', (271, 277))	('patients', 'Species', '9606', (298, 306))	('mutations', 'Var', (61, 70))	('oral cancer', 'Disease', 'MESH:D009062', (266, 277))	('associated', 'Reg', (229, 239))
361211	24224046	Mutations in genes that play fundamental roles in driving cancer development have defined treatment protocols in a diverse group of tumor types, but information regarding oral squamous cell carcinoma is limited.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (176, 199))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('carcinoma', 'Phenotype', 'HP:0030731', (190, 199))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (171, 199))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('oral squamous cell carcinoma', 'Disease', (171, 199))	('Mutations', 'Var', (0, 9))	('tumor', 'Disease', (132, 137))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('cancer', 'Disease', (58, 64))
361212	24224046	We demonstrate lower levels of TP53 mutations but similar mutational frequencies in HRAS and PIK3CA in Asian OSCC compared to Caucasian OSCC.	('PIK3CA', 'Gene', '5290', (93, 99))	('Asian OSCC', 'Disease', (103, 113))	('TP53', 'Gene', (31, 35))	('mutations', 'Var', (36, 45))	('HRAS', 'Gene', '3265', (84, 88))	('HRAS', 'Gene', (84, 88))	('lower', 'NegReg', (15, 20))	('PIK3CA', 'Gene', (93, 99))
361213	24224046	Most notably, we show that mutations in the 19 oncogenes are exceedingly low compared to other solid cancers including lung cancer where the etiological factors are similar to that of OSCC.	('mutations', 'Var', (27, 36))	('cancers', 'Phenotype', 'HP:0002664', (101, 108))	('lung cancer', 'Disease', (119, 130))	('lung cancer', 'Phenotype', 'HP:0100526', (119, 130))	('solid cancers', 'Disease', (95, 108))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('solid cancers', 'Disease', 'MESH:D009369', (95, 108))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('lung cancer', 'Disease', 'MESH:D008175', (119, 130))
361214	24224046	The findings suggest that mutations other than those commonly seen in solid cancers may play an important role in driving OSCC and argue strongly for further comprehensive analysis of gene mutations in this tumor type.	('cancers', 'Phenotype', 'HP:0002664', (76, 83))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('mutations', 'Var', (26, 35))	('OSCC', 'Disease', (122, 126))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('solid cancers', 'Disease', (70, 83))	('tumor', 'Disease', (207, 212))	('driving OSCC', 'Disease', (114, 126))	('solid cancers', 'Disease', 'MESH:D009369', (70, 83))
361222	24224046	The OncoCarta  Panel v1.0 assay (Sequenom, San Diego, CA, USA) was used for the detection of somatic mutations because it is a rapid and cost effective method of identifying key cancer driving mutations also known as "actionable mutations" across a large number of samples.	('mutations', 'Var', (193, 202))	('cancer', 'Disease', (178, 184))	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))
361223	24224046	Two key advantages of using the Sequenom platform, which detects mutations based on the mass of the sequence, are 1) it has the ability to simultaneously profile multiple mutations in several genes in an large number of samples through multiplexing and 2) it can provide a 3-fold increase in mutation detection limit (as low as 5-10% of the mutant allele) compared to sequencing.	('are 1', 'Gene', '6293', (110, 115))	('increase', 'PosReg', (280, 288))	('mutation', 'MPA', (292, 300))	('are 1', 'Gene', (110, 115))	('mutations', 'Var', (65, 74))
361226	24224046	The TP53 mutations found in this study were compared to those reported in the IARC version R15 (http://www-p53.iarc.fr/).	('p53', 'Gene', (107, 110))	('mutations', 'Var', (9, 18))	('p53', 'Gene', '7157', (107, 110))	('TP53', 'Gene', (4, 8))
361227	24224046	Mutations were classified into five groups: DNA binding domain (DBD), L2/L3/LSH hotspot, disruptive and truncating, and based on functional consequences, as described by others.	('LSH', 'Gene', (76, 79))	('Mutations', 'Var', (0, 9))	('LSH', 'Gene', '3070', (76, 79))	('binding', 'Interaction', (48, 55))
361230	24224046	Mutations in the PIK3CA gene were detected in 7/123 (5.7%) specimens.	('detected', 'Reg', (34, 42))	('PIK3CA', 'Gene', (17, 23))	('Mutations', 'Var', (0, 9))	('PIK3CA', 'Gene', '5290', (17, 23))
361231	24224046	Mutations at H1047R, E545K, Q546R, E542K, and M1043I were found in six OSCC tissues and one cell line, and the mutated allele frequency ranged from 17-50% (Table 2).	('E542K', 'Var', (35, 40))	('E545K', 'Mutation', 'rs104886003', (21, 26))	('M1043I', 'Var', (46, 52))	('E542K', 'Mutation', 'rs121913273', (35, 40))	('H1047R', 'Var', (13, 19))	('E545K', 'Var', (21, 26))	('Q546R', 'Mutation', 'rs397517201', (28, 33))	('Q546R', 'Var', (28, 33))	('H1047R', 'Mutation', 'rs121913279', (13, 19))	('M1043I', 'Mutation', 'rs121913283', (46, 52))
361234	24224046	Mutations at G12S and G12D were detected in three OSCC tissues, with mutation allele frequencies of 23-82%; no mutations were detected in the cell lines (Table 2).	('G12D', 'Mutation', 'rs121913529', (22, 26))	('G12D', 'Var', (22, 26))	('G12S', 'Var', (13, 17))	('G12S', 'Mutation', 'rs104894229', (13, 17))
361235	24224046	Most of the mutations occurred within the DBD (81.8%), 63.6% occurred in L2/L3/LSH domain, 24.2% were hotspot mutations and 48.5% and 27.3% were disruptive and truncating mutations, respectively.	('mutations', 'Var', (12, 21))	('occurred', 'Reg', (61, 69))	('LSH', 'Gene', '3070', (79, 82))	('LSH', 'Gene', (79, 82))
361236	24224046	Notably, the missense mutation M237K and designated hotspot mutations R175H, R248Q and R273C were found in more than one OSCC specimen (Table 3).	('R175H', 'Mutation', 'rs28934578', (70, 75))	('M237K', 'Var', (31, 36))	('R248Q', 'Mutation', 'rs11540652', (77, 82))	('R175H', 'Var', (70, 75))	('R273C', 'Mutation', 'rs121913343', (87, 92))	('M237K', 'Mutation', 'rs765848205', (31, 36))	('R248Q', 'Var', (77, 82))	('R273C', 'Var', (87, 92))
361237	24224046	One of the patients who had mutations in both PIK3CA and HRAS, also carried a TP53mutation (06-0005-10; Table 3).	('patients', 'Species', '9606', (11, 19))	('PIK3CA', 'Gene', '5290', (46, 52))	('TP53mutation', 'Var', (78, 90))	('HRAS', 'Gene', '3265', (57, 61))	('carried', 'Reg', (68, 75))	('HRAS', 'Gene', (57, 61))	('mutations', 'Var', (28, 37))	('PIK3CA', 'Gene', (46, 52))
361241	24224046	Truncating mutations were significantly enriched in OSCC patients with no risk habits (23.8%) compared to 4.6% in patients with at least one risk factor (p =0.019).	('patients', 'Species', '9606', (114, 122))	('Truncating mutations', 'Var', (0, 20))	('patients', 'Species', '9606', (57, 65))	('OSCC', 'Disease', (52, 56))
361242	24224046	In addition, patients who harbored DBD and L2/L3/LSH mutations showed a worse survival probability compared to patients who had wild type TP53 (Figure 1b, 1c, 1d) but the Cox-Regression analysis showed that TP53 mutations were not a significant independent factor in modulating survival (Table 4).	('LSH', 'Gene', (49, 52))	('Cox', 'Gene', (171, 174))	('LSH', 'Gene', '3070', (49, 52))	('Cox', 'Gene', '1351', (171, 174))	('patients', 'Species', '9606', (13, 21))	('mutations', 'Var', (53, 62))	('DBD', 'Var', (35, 38))	('patients', 'Species', '9606', (111, 119))
361243	24224046	The comprehensive profiling of cancer mutations in tumor samples has led to the detection of key perturbations that promote tumorigenesis in many types of cancers.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('tumor', 'Disease', (51, 56))	('tumor', 'Disease', (124, 129))	('promote', 'PosReg', (116, 123))	('cancer', 'Disease', 'MESH:D009369', (155, 161))	('cancers', 'Phenotype', 'HP:0002664', (155, 162))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('cancers', 'Disease', 'MESH:D009369', (155, 162))	('mutations', 'Var', (38, 47))	('cancer', 'Disease', (31, 37))	('cancer', 'Disease', (155, 161))	('cancers', 'Disease', (155, 162))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
361245	24224046	High-throughput analysis of key cancer driving mutations using mass-spectrometry remains a cost effective and efficient way of analyzing multiple mutations across a large number of samples, particularly when these are known and could influence clinical management of patients.	('clinical', 'Species', '191496', (244, 252))	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('patients', 'Species', '9606', (267, 275))	('cancer', 'Disease', (32, 38))	('mutations', 'Var', (47, 56))	('influence', 'Reg', (234, 243))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))
361246	24224046	In this study, we examined the spectrum of oncogenic mutations across ABL1, AKT1, AKT2, BRAF, CDK4, EGFR, ERBB2, FGFR1, FGFR3, FLT3, HRAS, JAK2, KIT, KRAS, MET, NRAS, PDGFRA, PIK3CA and RET in a broad spectrum of tissues and cell lines derived from Asian OSCC.	('CDK4', 'Gene', (94, 98))	('JAK2', 'Gene', (139, 143))	('BRAF', 'Gene', (88, 92))	('ERBB2', 'Gene', '2064', (106, 111))	('FGFR1', 'Gene', (113, 118))	('BRAF', 'Gene', '673', (88, 92))	('PIK3CA', 'Gene', '5290', (175, 181))	('NRAS', 'Gene', (161, 165))	('AKT2', 'Gene', '208', (82, 86))	('RET', 'Gene', (186, 189))	('EGFR', 'Gene', '1956', (100, 104))	('CDK4', 'Gene', '1019', (94, 98))	('AKT2', 'Gene', (82, 86))	('AKT1', 'Gene', '207', (76, 80))	('PIK3CA', 'Gene', (175, 181))	('ABL1', 'Gene', (70, 74))	('mutations', 'Var', (53, 62))	('FGFR1', 'Gene', '2260', (113, 118))	('AKT1', 'Gene', (76, 80))	('PDGFRA', 'Gene', '5156', (167, 173))	('PDGFRA', 'Gene', (167, 173))	('FLT3', 'Gene', (127, 131))	('NRAS', 'Gene', '4893', (161, 165))	('JAK2', 'Gene', '3717', (139, 143))	('KRAS', 'Gene', '3845', (150, 154))	('ABL1', 'Gene', '25', (70, 74))	('FGFR3', 'Gene', (120, 125))	('EGFR', 'Gene', (100, 104))	('ERBB2', 'Gene', (106, 111))	('FLT3', 'Gene', '2322', (127, 131))	('RET', 'Gene', '5979', (186, 189))	('HRAS', 'Gene', '3265', (133, 137))	('FGFR3', 'Gene', '2261', (120, 125))	('KRAS', 'Gene', (150, 154))	('HRAS', 'Gene', (133, 137))
361249	24224046	Notably, only 6.5% of OSCC patients harbored at least one PIK3CA and HRAS mutation, whereas, these oncogenic mutations occur in 30-70% of solid tumours, including colorectal, ovarian, endometrial, lung, melanoma and breast cancer (Table S8 in File S1).	('HRAS', 'Gene', '3265', (69, 73))	('HRAS', 'Gene', (69, 73))	('melanoma and breast cancer', 'Disease', 'MESH:D001943', (203, 229))	('colorectal', 'Disease', 'MESH:D015179', (163, 173))	('mutation', 'Var', (74, 82))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('endometrial', 'Disease', (184, 195))	('PIK3CA', 'Gene', (58, 64))	('patients', 'Species', '9606', (27, 35))	('occur', 'Reg', (119, 124))	('solid tumours', 'Disease', (138, 151))	('tumour', 'Phenotype', 'HP:0002664', (144, 150))	('breast cancer', 'Phenotype', 'HP:0003002', (216, 229))	('tumours', 'Phenotype', 'HP:0002664', (144, 151))	('OSCC', 'Disease', (22, 26))	('melanoma', 'Phenotype', 'HP:0002861', (203, 211))	('lung', 'Disease', (197, 201))	('ovarian', 'Disease', (175, 182))	('colorectal', 'Disease', (163, 173))	('ovarian', 'Disease', 'MESH:D010051', (175, 182))	('PIK3CA', 'Gene', '5290', (58, 64))	('solid tumours', 'Disease', 'MESH:D009369', (138, 151))
361250	24224046	Further, mutations in 5 of 19 genes identified by the OncoCarta  Panel v1.0 assay are typically seen in many of these cancers.	('seen', 'Reg', (96, 100))	('cancers', 'Disease', (118, 125))	('cancers', 'Disease', 'MESH:D009369', (118, 125))	('mutations', 'Var', (9, 18))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('cancers', 'Phenotype', 'HP:0002664', (118, 125))
361251	24224046	With respect to lung cancer, for example, which shares similar risk factors to OSCC, mutations of PIK3CA, HRAS, NRAS, KRAS, BRAF, EGFR, ERBB2, PDFGRA and RET are seen in some 30% of patients.	('RET', 'Gene', (154, 157))	('KRAS', 'Gene', (118, 122))	('ERBB2', 'Gene', (136, 141))	('PIK3CA', 'Gene', '5290', (98, 104))	('patients', 'Species', '9606', (182, 190))	('EGFR', 'Gene', (130, 134))	('ERBB2', 'Gene', '2064', (136, 141))	('lung cancer', 'Disease', 'MESH:D008175', (16, 27))	('NRAS', 'Gene', (112, 116))	('HRAS', 'Gene', '3265', (106, 110))	('lung cancer', 'Phenotype', 'HP:0100526', (16, 27))	('BRAF', 'Gene', '673', (124, 128))	('BRAF', 'Gene', (124, 128))	('HRAS', 'Gene', (106, 110))	('PIK3CA', 'Gene', (98, 104))	('mutations', 'Var', (85, 94))	('RET', 'Gene', '5979', (154, 157))	('EGFR', 'Gene', '1956', (130, 134))	('PDFGRA', 'Gene', (143, 149))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('KRAS', 'Gene', '3845', (118, 122))	('NRAS', 'Gene', '4893', (112, 116))	('lung cancer', 'Disease', (16, 27))
361253	24224046	The results suggest that mutations within this spectrum of oncogenes appear not to be a characteristic of OSCC and, most probably, are unrelated to risk factors such as tobacco, alcohol and betel quid chewing that are historically associated with OSCC.	('mutations', 'Var', (25, 34))	('alcohol', 'Chemical', 'MESH:D000438', (178, 185))	('OSCC', 'Disease', (106, 110))	('tobacco', 'Species', '4097', (169, 176))
361254	24224046	Deregulation of HRAS is known to activate two major signaling pathways, namely, PI3K/AKT and MAPK.	('MAPK', 'Pathway', (93, 97))	('Deregulation', 'Var', (0, 12))	('AKT', 'Gene', '207', (85, 88))	('HRAS', 'Gene', '3265', (16, 20))	('AKT', 'Gene', (85, 88))	('HRAS', 'Gene', (16, 20))	('activate', 'PosReg', (33, 41))
361255	24224046	In this study, only some 3% of samples contained HRAS mutations, findings that were surprising in view of the fact that studies in India have reported higher HRAS mutation frequencies whereas those relating to Caucasian patients with OSCC range from 4-8%.	('HRAS', 'Gene', (49, 53))	('HRAS', 'Gene', (158, 162))	('mutations', 'Var', (54, 63))	('higher', 'PosReg', (151, 157))	('patients', 'Species', '9606', (220, 228))	('HRAS', 'Gene', '3265', (158, 162))	('HRAS', 'Gene', '3265', (49, 53))
361257	24224046	Other up- or down-stream proteins within the RAS pathway such as activation or over-expression of EGFR, and/or loss of PTEN can result in the activation of the RAS signaling pathway, and may be a reason for the lack of RAS mutations in the present study.	('EGFR', 'Gene', (98, 102))	('loss', 'NegReg', (111, 115))	('activation', 'PosReg', (142, 152))	('RAS', 'Gene', (219, 222))	('up-', 'PosReg', (6, 9))	('activation', 'PosReg', (65, 75))	('over-expression', 'PosReg', (79, 94))	('down-stream', 'NegReg', (13, 24))	('PTEN', 'Gene', (119, 123))	('PTEN', 'Gene', '5728', (119, 123))	('EGFR', 'Gene', '1956', (98, 102))	('RAS signaling pathway', 'Pathway', (160, 181))	('mutations', 'Var', (223, 232))	('proteins', 'Protein', (25, 33))
361258	24224046	PIK3CA mutations occur frequently in many cancers including colorectal, breast, brain, gastric, ovarian and lung and 75% of these occur in exons 9 and 20.	('cancers', 'Disease', (42, 49))	('brain', 'Disease', (80, 85))	('cancers', 'Disease', 'MESH:D009369', (42, 49))	('colorectal', 'Disease', 'MESH:D015179', (60, 70))	('breast', 'Disease', (72, 78))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('colorectal', 'Disease', (60, 70))	('PIK3CA', 'Gene', (0, 6))	('gastric', 'Disease', (87, 94))	('PIK3CA', 'Gene', '5290', (0, 6))	('cancers', 'Phenotype', 'HP:0002664', (42, 49))	('ovarian and lung', 'Disease', 'MESH:D010051', (96, 112))	('mutations', 'Var', (7, 16))
361259	24224046	Hotspot mutations at these sites (E545K, E542K and H1047R) increase kinase activity and induce transformation, tumour cell proliferation, invasion and metastasis resulting in over activated PI3K pathway as shown in in vitro and in vivo models.	('metastasis', 'CPA', (151, 161))	('E542K', 'Var', (41, 46))	('E545K', 'Mutation', 'rs104886003', (34, 39))	('E545K', 'Var', (34, 39))	('PI3K pathway', 'Pathway', (190, 202))	('tumour', 'Phenotype', 'HP:0002664', (111, 117))	('over activated', 'PosReg', (175, 189))	('E542K', 'Mutation', 'rs121913273', (41, 46))	('H1047R', 'Mutation', 'rs121913279', (51, 57))	('kinase activity', 'MPA', (68, 83))	('transformation', 'CPA', (95, 109))	('induce', 'Reg', (88, 94))	('tumour', 'Disease', 'MESH:D009369', (111, 117))	('invasion', 'CPA', (138, 146))	('tumour', 'Disease', (111, 117))	('H1047R', 'Var', (51, 57))	('increase', 'PosReg', (59, 67))
361260	24224046	In the present study, hotspot PIK3CA mutations were found in 5.7% of OSCC specimens, findings that confirm previous observations in both Asian and Caucasian populations.	('found', 'Reg', (52, 57))	('PIK3CA', 'Gene', (30, 36))	('mutations', 'Var', (37, 46))	('PIK3CA', 'Gene', '5290', (30, 36))
361261	24224046	Importantly, the fact that oncogenic mutations occur in a small subset of OSCC patients suggests that they may benefit from targeted therapy as opposed to the conventional treatment modalities.	('mutations', 'Var', (37, 46))	('OSCC', 'Disease', (74, 78))	('patients', 'Species', '9606', (79, 87))
361263	24224046	PIK3CA mutations, for example, have been demonstrated to modulate response to mTOR- and EGFR-targeted therapy.	('mTOR-', 'Gene', (78, 83))	('modulate', 'Reg', (57, 65))	('PIK3CA', 'Gene', (0, 6))	('EGFR', 'Gene', '1956', (88, 92))	('PIK3CA', 'Gene', '5290', (0, 6))	('mTOR-', 'Gene', '21977', (78, 83))	('EGFR', 'Gene', (88, 92))	('response', 'MPA', (66, 74))	('mutations', 'Var', (7, 16))
361264	24224046	New generation of drugs targeting PI3K are currently being tested clinically (NCT01690871, NCT01219699, and NCT01501604) on patients with and without PIK3CA mutations, and results from these trials should provide further information on the role of these mutations in modulating drug response.	('PIK3CA', 'Gene', (150, 156))	('NCT01219699', 'Var', (91, 102))	('NCT01501604', 'Var', (108, 119))	('clinical', 'Species', '191496', (66, 74))	('PIK3CA', 'Gene', '5290', (150, 156))	('mutations', 'Var', (157, 166))	('patients', 'Species', '9606', (124, 132))	('NCT01690871', 'Var', (78, 89))
361267	24224046	Interestingly, a recent in vitro study has shown that cells containing coexistence PIK3CA and RAS mutations were resistant to PI3K inhibitors suggesting that coexistence of these mutations may be a predictive biomarker for resistance to PI3K inhibitors.	('RAS', 'Gene', (94, 97))	('mutations', 'Var', (98, 107))	('PIK3CA', 'Gene', (83, 89))	('resistant', 'MPA', (113, 122))	('PIK3CA', 'Gene', '5290', (83, 89))
361268	24224046	It is very apparent that the TP53 mutational frequency of OSCC patients from Asia (17-21%) differs dramatically from those reported from the West (53-80%).	('patients', 'Species', '9606', (63, 71))	('TP53', 'Gene', (29, 33))	('mutational', 'Var', (34, 44))	('OSCC', 'Disease', (58, 62))
361269	24224046	For example, mutant TP53 have been shown to interfere with mechanisms that maintain genome integrity including DNA damage response pathways resulting in genomic instability which is a major driver of cancer development and a hallmark of cancer.	('mutant', 'Var', (13, 19))	('DNA damage response pathways', 'Pathway', (111, 139))	('TP53', 'Gene', (20, 24))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('interfere', 'NegReg', (44, 53))	('hallmark of cancer', 'Disease', (225, 243))	('genome integrity', 'MPA', (84, 100))	('cancer', 'Disease', 'MESH:D009369', (237, 243))	('cancer', 'Disease', 'MESH:D009369', (200, 206))	('hallmark of cancer', 'Disease', 'MESH:D009369', (225, 243))	('cancer', 'Disease', (237, 243))	('genomic instability', 'MPA', (153, 172))	('cancer', 'Disease', (200, 206))
361270	24224046	The results are consistent with previous observations where TP53 mutations facilitate the establishment of human myeloid cell lines and enhance tumor implantation in vivo.	('tumor', 'Disease', (144, 149))	('human', 'Species', '9606', (107, 112))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('establishment of human myeloid cell lines', 'CPA', (90, 131))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('facilitate', 'PosReg', (75, 85))	('enhance', 'PosReg', (136, 143))	('TP53', 'Gene', (60, 64))	('mutations', 'Var', (65, 74))
361271	24224046	Interestingly, the diversity of TP53 point mutations makes this gene informative for the identification of tumor- and exposure-specific mutation patterns.	('point mutations', 'Var', (37, 52))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('TP53', 'Gene', (32, 36))	('tumor', 'Disease', 'MESH:D009369', (107, 112))
361272	24224046	Similarly, G:C to A:T transitions have been reported as the most predominant TP53 mutation in OSCC in Taiwan where risk habits include the use of betel quid and tobacco.	('tobacco', 'Species', '4097', (161, 168))	('TP53', 'Gene', (77, 81))	('T transitions', 'Var', (20, 33))	('OSCC', 'Disease', (94, 98))
361273	24224046	However, truncating mutations in the present study were found more frequently in OSCC patients with absence of risk habits suggesting that inactivation of TP53 may be important in the pathogenesis of OSCC.	('truncating mutations', 'Var', (9, 29))	('OSCC', 'Disease', (200, 204))	('TP53', 'Gene', (155, 159))	('OSCC', 'Disease', (81, 85))	('important', 'Reg', (167, 176))	('inactivation', 'Var', (139, 151))	('patients', 'Species', '9606', (86, 94))
361274	24224046	Notably, one OSCC patient in this study has three concurrent mutations in PIK3CA, HRAS and TP53.	('HRAS', 'Gene', (82, 86))	('TP53', 'Gene', (91, 95))	('PIK3CA', 'Gene', '5290', (74, 80))	('mutations', 'Var', (61, 70))	('patient', 'Species', '9606', (18, 25))	('HRAS', 'Gene', '3265', (82, 86))	('PIK3CA', 'Gene', (74, 80))
361277	24224046	We demonstrate that HRAS and PIK3CA mutations in Asian OSCC are uncommon but comparable to that seen in the West.	('PIK3CA', 'Gene', '5290', (29, 35))	('HRAS', 'Gene', (20, 24))	('Asian OSCC', 'Disease', (49, 59))	('mutations', 'Var', (36, 45))	('PIK3CA', 'Gene', (29, 35))	('HRAS', 'Gene', '3265', (20, 24))
361285	33219226	Aberrant activation of NRF2 in cancer cells contributes to tumorigenicity and therapeutic resistance.	('activation', 'PosReg', (9, 19))	('tumor', 'Disease', (59, 64))	('Aberrant', 'Var', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('therapeutic resistance', 'CPA', (78, 100))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('NRF2', 'Gene', (23, 27))	('cancer', 'Disease', (31, 37))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('contributes', 'Reg', (44, 55))
361294	33219226	Several causes have been described for the aberrant accumulation of NRF2 in cancer cells, including somatic mutations in KEAP1 or NRF2 genes, sequestration of KEAP1 by p62/SQSTM1 and electrophilic attack of KEAP1 thiols by fumarate.	('KEAP1', 'Gene', '9817', (121, 126))	('accumulation', 'PosReg', (52, 64))	('KEAP1', 'Gene', (121, 126))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('sequestration', 'MPA', (142, 155))	('KEAP1', 'Gene', '9817', (159, 164))	('KEAP1', 'Gene', '9817', (207, 212))	('KEAP1', 'Gene', (159, 164))	('SQSTM1', 'Gene', (172, 178))	('NRF2', 'Gene', (130, 134))	('KEAP1', 'Gene', (207, 212))	('cancer', 'Disease', (76, 82))	('SQSTM1', 'Gene', '8878', (172, 178))	('electrophilic attack', 'MPA', (183, 203))	('p62', 'Gene', '8878', (168, 171))	('p62', 'Gene', (168, 171))	('mutations', 'Var', (108, 117))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('thiols', 'Chemical', 'MESH:D013438', (213, 219))
361300	33219226	Resistance may arise through genetic and/or epigenetic changes that are induced in cancer cells during treatment.	('arise', 'Reg', (15, 20))	('epigenetic changes', 'Var', (44, 62))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('cancer', 'Disease', (83, 89))
361303	33219226	Thus, the self-renewal capacity of TICs is not easily separated from their proliferative and survival abilities, which are strongly enhanced by NRF2, and chemo-resistant populations expressing high levels of NRF2 are often regarded as TICs.	('TICs', 'Disease', (235, 239))	('TICs', 'Disease', 'MESH:D020323', (235, 239))	('proliferative', 'CPA', (75, 88))	('survival', 'CPA', (93, 101))	('NRF2', 'Var', (144, 148))	('enhanced', 'PosReg', (132, 140))	('self-renewal', 'CPA', (10, 22))	('TICs', 'Phenotype', 'HP:0100033', (35, 39))	('TICs', 'Phenotype', 'HP:0100033', (235, 239))	('TICs', 'Disease', (35, 39))	('TICs', 'Disease', 'MESH:D020323', (35, 39))
361306	33219226	We conduct an unbiased approach by investigating NRF2-dependent transcriptome in NSCLC cell lines with KEAP1 mutations (NRF2-activated NSCLCs) and in those with an intact KEAP1-NRF2 system (NRF2-normal NSCLCs).	('NSCLC', 'Phenotype', 'HP:0030358', (81, 86))	('NSCLC', 'Disease', (135, 140))	('NSCLCs', 'Phenotype', 'HP:0030358', (135, 141))	('NSCLC', 'Phenotype', 'HP:0030358', (135, 140))	('KEAP1', 'Gene', '9817', (103, 108))	('NSCLCs', 'Disease', 'MESH:D002289', (202, 208))	('NSCLCs', 'Disease', (135, 141))	('KEAP1', 'Gene', (103, 108))	('NSCLC', 'Disease', 'MESH:D002289', (202, 207))	('NSCLCs', 'Disease', 'MESH:D002289', (135, 141))	('mutations', 'Var', (109, 118))	('KEAP1', 'Gene', '9817', (171, 176))	('NSCLC', 'Disease', 'MESH:D002289', (81, 86))	('KEAP1', 'Gene', (171, 176))	('NSCLC', 'Disease', (202, 207))	('NSCLCs', 'Phenotype', 'HP:0030358', (202, 208))	('NSCLC', 'Disease', 'MESH:D002289', (135, 140))	('NSCLC', 'Disease', (81, 86))	('NSCLC', 'Phenotype', 'HP:0030358', (202, 207))	('NSCLCs', 'Disease', (202, 208))
361308	33219226	CEBPB accumulation in NRF2-activated NSCLCs is found to be one of the prerequisites for the establishment of the unique enhancers, in which NOTCH3 enhancer is critical for the promotion of tumor-initiating activity.	('enhancer', 'PosReg', (147, 155))	('tumor', 'Disease', (189, 194))	('NSCLC', 'Phenotype', 'HP:0030358', (37, 42))	('NOTCH3', 'Var', (140, 146))	('NSCLCs', 'Phenotype', 'HP:0030358', (37, 43))	('NSCLCs', 'Disease', (37, 43))	('CEBPB', 'Gene', '1051', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('CEBPB', 'Gene', (0, 5))	('NSCLCs', 'Disease', 'MESH:D002289', (37, 43))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))
361331	33219226	In both LUAD and LUSC, NOTCH3 expression was elevated in the cases with high NRF2 activity (Fig.	('NRF2', 'Protein', (77, 81))	('NOTCH3', 'Gene', (23, 29))	('LUAD', 'Phenotype', 'HP:0030078', (8, 12))	('activity', 'MPA', (82, 90))	('elevated', 'PosReg', (45, 53))	('expression', 'Species', '29278', (30, 40))	('high', 'Var', (72, 76))
361332	33219226	KEAP1 mutation, a major cause of increased NRF2 activity in LUAD, was uniquely enriched in LUAD cases showing high NRF2 activity with elevated NOTCH3 expression compared with other mutations (Supplementary Fig.	('expression', 'MPA', (150, 160))	('activity', 'MPA', (48, 56))	('KEAP1', 'Gene', (0, 5))	('mutation', 'Var', (6, 14))	('NOTCH3', 'Gene', (143, 149))	('increased', 'PosReg', (33, 42))	('elevated', 'PosReg', (134, 142))	('LUAD', 'Phenotype', 'HP:0030078', (60, 64))	('LUAD', 'Phenotype', 'HP:0030078', (91, 95))	('activity', 'MPA', (120, 128))	('KEAP1', 'Gene', '9817', (0, 5))	('expression', 'Species', '29278', (150, 160))
361335	33219226	Most of the NRF2-positive cases, which are regarded as NRF2-activated cancers, were NOTCH3-positive (Fig.	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('NOTCH3-positive', 'Var', (84, 99))	('cancers', 'Phenotype', 'HP:0002664', (70, 77))	('cancers', 'Disease', 'MESH:D009369', (70, 77))	('cancers', 'Disease', (70, 77))	('NRF2-positive', 'Gene', (12, 25))
361338	33219226	3b), suggesting that the combination of NRF2 and NOTCH3 makes cancers malignant and that NOTCH3 contributes to cancer malignancy when it is co-expressed with NRF2 target genes in NRF2-activated NSCLCs.	('NSCLC', 'Phenotype', 'HP:0030358', (194, 199))	('cancers malignant', 'Disease', (62, 79))	('NRF2', 'Var', (40, 44))	('NOTCH3', 'Var', (89, 95))	('cancers malignant', 'Disease', 'MESH:D009369', (62, 79))	('combination', 'Var', (25, 36))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('NSCLCs', 'Disease', (194, 200))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('contributes', 'Reg', (96, 107))	('cancer malignancy', 'Disease', 'MESH:D009369', (111, 128))	('NSCLCs', 'Disease', 'MESH:D002289', (194, 200))	('NOTCH3', 'Var', (49, 55))	('cancers', 'Phenotype', 'HP:0002664', (62, 69))	('NSCLCs', 'Phenotype', 'HP:0030358', (194, 200))	('cancer malignancy', 'Disease', (111, 128))
361339	33219226	Although NOTCH3 has been reported to be associated with a poor prognosis of NSCLC, it appears to be the NRF2-NOTCH3 axis rather than NOTCH3 itself that contributes to the malignancy of NSCLCs.	('malignancy of NSCLCs', 'Disease', (171, 191))	('malignancy of NSCLCs', 'Disease', 'MESH:D009369', (171, 191))	('NSCLC', 'Disease', 'MESH:D002289', (185, 190))	('NSCLC', 'Disease', (76, 81))	('NSCLCs', 'Phenotype', 'HP:0030358', (185, 191))	('NSCLC', 'Disease', 'MESH:D002289', (76, 81))	('NSCLC', 'Phenotype', 'HP:0030358', (185, 190))	('NOTCH3', 'Var', (9, 15))	('NSCLC', 'Phenotype', 'HP:0030358', (76, 81))	('NSCLC', 'Disease', (185, 190))
361344	33219226	The H3K27ac deposition was decreased by NRF2 knockdown in NRF2-activated NSCLC cell lines (Fig.	('H3K27ac', 'Chemical', '-', (4, 11))	('decreased', 'NegReg', (27, 36))	('NSCLC', 'Disease', (73, 78))	('NRF2', 'Gene', (40, 44))	('NSCLC', 'Disease', 'MESH:D002289', (73, 78))	('H3K27ac', 'Protein', (4, 11))	('NSCLC', 'Phenotype', 'HP:0030358', (73, 78))	('knockdown', 'Var', (45, 54))
361349	33219226	NRF2 binding and H3K27ac deposition were abrogated in the mutated region in DeltaN3U H460 cells (Fig.	('abrogated', 'NegReg', (41, 50))	('H3K27ac', 'Chemical', '-', (17, 24))	('U H460', 'CellLine', 'CVCL:0459', (83, 89))	('NRF2', 'Protein', (0, 4))	('H3K27ac', 'Protein', (17, 24))	('mutated', 'Var', (58, 65))	('deposition', 'MPA', (25, 35))	('binding', 'Interaction', (5, 12))
361357	33219226	NRF2 knockdown decreased NOTCH3 as well as NQO1, a canonical NRF2 target gene, in NRF2-activated NSCLC cells (Fig.	('NRF2', 'Gene', (0, 4))	('NSCLC', 'Disease', (97, 102))	('NQO1', 'Gene', (43, 47))	('knockdown', 'Var', (5, 14))	('NOTCH3', 'Gene', (25, 31))	('NQO1', 'Gene', '1728', (43, 47))	('decreased', 'NegReg', (15, 24))	('NSCLC', 'Disease', 'MESH:D002289', (97, 102))	('NSCLC', 'Phenotype', 'HP:0030358', (97, 102))
361362	33219226	Although a reciprocal relationship between NRF2 and the NOTCH pathway was previously reported, NOTCH3 knockdown did not affect the expression levels of NRF2 or NQO1 in NRF2-activated NSCLC cells (Fig.	('NSCLC', 'Phenotype', 'HP:0030358', (183, 188))	('NOTCH', 'Gene', (56, 61))	('NQO1', 'Gene', (160, 164))	('NQO1', 'Gene', '1728', (160, 164))	('NOTCH', 'Gene', '4851;18128;4853;4854;18131', (95, 100))	('expression', 'Species', '29278', (131, 141))	('NSCLC', 'Disease', (183, 188))	('knockdown', 'Var', (102, 111))	('expression', 'MPA', (131, 141))	('NSCLC', 'Disease', 'MESH:D002289', (183, 188))	('NOTCH', 'Gene', '4851;18128;4853;4854;18131', (56, 61))	('NOTCH', 'Gene', (95, 100))
361365	33219226	In good agreement with this selective response of NOTCH3 to NRF2 activation, the NOTCH3 enhancer formation indicated by H3K27ac deposition was clearly detected in NRF2-activated NSCLCs but not in NRF2-normal NSCLCs (Fig.	('H3K27ac', 'Chemical', '-', (120, 127))	('NSCLC', 'Phenotype', 'HP:0030358', (208, 213))	('NRF2-activated', 'Var', (163, 177))	('NSCLCs', 'Disease', (208, 214))	('NSCLCs', 'Disease', 'MESH:D002289', (178, 184))	('NSCLCs', 'Phenotype', 'HP:0030358', (178, 184))	('NSCLC', 'Phenotype', 'HP:0030358', (178, 183))	('NSCLCs', 'Disease', 'MESH:D002289', (208, 214))	('NSCLCs', 'Phenotype', 'HP:0030358', (208, 214))	('NSCLCs', 'Disease', (178, 184))	('enhancer formation', 'PosReg', (88, 106))	('NOTCH3', 'Gene', (81, 87))
361370	33219226	We conducted ChIP-seq analysis of H3K27ac in A549 cells with or without NRF2 knockdown and aligned the results with ENCODE NRF2 ChIP-seq data.	('H3K27ac', 'Chemical', '-', (34, 41))	('H3K27ac', 'Protein', (34, 41))	('knockdown', 'Var', (77, 86))	('NRF2', 'Gene', (72, 76))
361371	33219226	NRF2 binding peaks were accompanied by H3K27ac deposition, which was reduced by NRF2 knockdown (Supplementary Fig.	('reduced', 'NegReg', (69, 76))	('H3K27ac', 'Protein', (39, 46))	('NRF2', 'Protein', (0, 4))	('NRF2', 'Gene', (80, 84))	('knockdown', 'Var', (85, 94))	('H3K27ac', 'Chemical', '-', (39, 46))	('binding', 'Interaction', (5, 12))
361383	33219226	We also compared the H3K27ac depositions in A549 and HCC4006 as representatives of NRF2-activated and NRF2-normal NSCLC cells, respectively.	('NSCLC', 'Phenotype', 'HP:0030358', (114, 119))	('H3K27ac', 'Var', (21, 28))	('NSCLC', 'Disease', (114, 119))	('HCC4006', 'CellLine', 'CVCL:1269', (53, 60))	('NSCLC', 'Disease', 'MESH:D002289', (114, 119))	('H3K27ac', 'Chemical', '-', (21, 28))
361384	33219226	H3K27ac depositions in the NRF2-activated NSCLC-specific NRF2 target loci were decreased by NRF2 knockdown in A549 cells but were not changed by DEM treatment in HCC4006 (Fig.	('NSCLC', 'Disease', (42, 47))	('knockdown', 'Var', (97, 106))	('decreased', 'NegReg', (79, 88))	('NSCLC', 'Disease', 'MESH:D002289', (42, 47))	('depositions', 'MPA', (8, 19))	('DEM', 'Chemical', 'MESH:C014476', (145, 148))	('HCC4006', 'CellLine', 'CVCL:1269', (162, 169))	('H3K27ac', 'Protein', (0, 7))	('NRF2', 'Gene', (92, 96))	('NSCLC', 'Phenotype', 'HP:0030358', (42, 47))	('H3K27ac', 'Chemical', '-', (0, 7))
361385	33219226	H3K27ac depositions in the canonical NRF2 target gene loci were decreased by NRF2 knockdown in A549 cells and increased by DEM treatment in HCC4006 cells (Fig.	('H3K27ac', 'Var', (0, 7))	('HCC4006', 'CellLine', 'CVCL:1269', (140, 147))	('increased', 'PosReg', (110, 119))	('depositions', 'MPA', (8, 19))	('knockdown', 'Var', (82, 91))	('H3K27ac', 'Chemical', '-', (0, 7))	('NRF2', 'Gene', (77, 81))	('DEM', 'Chemical', 'MESH:C014476', (123, 126))	('decreased', 'NegReg', (64, 73))
361393	33219226	CEBPB colocalized with NRF2 in the active chromatin marked by H3K27ac deposition but not in the region without H3K27ac deposition (Fig.	('H3K27ac', 'Chemical', '-', (62, 69))	('CEBPB', 'Gene', (0, 5))	('H3K27ac', 'Chemical', '-', (111, 118))	('H3K27ac deposition', 'Var', (62, 80))	('NRF2', 'Gene', (23, 27))	('CEBPB', 'Gene', '1051', (0, 5))	('deposition', 'Var', (70, 80))
361399	33219226	Three out of six NRF2-dependent enhancers unique to NRF2-activated NSCLCs, those in FAM20B, ZC3H12A, and C5AR1 loci, exhibited reduced H3K27ac deposition by CEBPB knockdown (Fig.	('enhancers', 'PosReg', (32, 41))	('ZC3H12A', 'Gene', '80149', (92, 99))	('H3K27ac', 'Protein', (135, 142))	('knockdown', 'Var', (163, 172))	('NRF2-dependent', 'Gene', (17, 31))	('FAM20B', 'Gene', '9917', (84, 90))	('NSCLC', 'Phenotype', 'HP:0030358', (67, 72))	('NSCLCs', 'Disease', (67, 73))	('C5AR1', 'Gene', (105, 110))	('CEBPB', 'Gene', (157, 162))	('FAM20B', 'Gene', (84, 90))	('ZC3H12A', 'Gene', (92, 99))	('NSCLCs', 'Disease', 'MESH:D002289', (67, 73))	('CEBPB', 'Gene', '1051', (157, 162))	('reduced', 'NegReg', (127, 134))	('H3K27ac', 'Chemical', '-', (135, 142))	('C5AR1', 'Gene', '728', (105, 110))	('NSCLCs', 'Phenotype', 'HP:0030358', (67, 73))
361411	33219226	At the NOTCH3 enhancer region, FOSL2 knockdown decreased H3K27ac deposition but did not affect NRF2 binding (Supplementary Fig.	('FOSL2', 'Gene', (31, 36))	('knockdown', 'Var', (37, 46))	('H3K27ac', 'Protein', (57, 64))	('FOSL2', 'Gene', '2355', (31, 36))	('H3K27ac', 'Chemical', '-', (57, 64))	('decreased', 'NegReg', (47, 56))
361412	33219226	10b, c), and NRF2 knockdown did not alter FOSL2 binding (Supplementary Fig.	('knockdown', 'Var', (18, 27))	('binding', 'Interaction', (48, 55))	('FOSL2', 'Gene', '2355', (42, 47))	('FOSL2', 'Gene', (42, 47))	('NRF2', 'Gene', (13, 17))
361414	33219226	In contrast, CEBPB knockdown decreased both H3K27ac deposition and NRF2 binding (Fig.	('H3K27ac', 'Protein', (44, 51))	('knockdown', 'Var', (19, 28))	('binding', 'Interaction', (72, 79))	('decreased', 'NegReg', (29, 38))	('H3K27ac', 'Chemical', '-', (44, 51))	('CEBPB', 'Gene', (13, 18))	('CEBPB', 'Gene', '1051', (13, 18))	('NRF2', 'Protein', (67, 71))
361415	33219226	8d, e), and NRF2 knockdown decreased CEBPB binding (Fig.	('decreased', 'NegReg', (27, 36))	('CEBPB', 'Gene', (37, 42))	('CEBPB', 'Gene', '1051', (37, 42))	('knockdown', 'Var', (17, 26))	('NRF2', 'Gene', (12, 16))
361417	33219226	We further verified the necessity of NRF2 for CEBPB binding to the NOTCH3 enhancer by utilizing DeltaN3U A549 cells, which harbor deletions in NRF2 binding sites (Fig.	('deletions', 'Var', (130, 139))	('CEBPB', 'Gene', (46, 51))	('CEBPB', 'Gene', '1051', (46, 51))	('U A549', 'CellLine', 'CVCL:0023', (103, 109))	('NRF2', 'Gene', (143, 147))
361430	33219226	The tumor growth of NOTCH3 enhancer-disrupted cells, DeltaN3U H460, DeltaN3U A549, and DeltaN3U H2023, was decreased compared with that of their parental cells (Fig.	('tumor', 'Disease', (4, 9))	('H2023', 'CellLine', 'CVCL:1515', (96, 101))	('DeltaN3U A549', 'Var', (68, 81))	('U A549', 'CellLine', 'CVCL:0023', (75, 81))	('NOTCH3', 'Var', (20, 26))	('U H460', 'CellLine', 'CVCL:0459', (60, 66))	('decreased', 'NegReg', (107, 116))	('DeltaN3U H460', 'Var', (53, 66))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('enhancer-disrupted', 'PosReg', (27, 45))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('DeltaN3U H2023', 'Var', (87, 101))
361434	33219226	After the secondary transplantation, both clones of DeltaN3U H460 cells generated a reduced number of tumors compared with parental H460 cells, supporting the notion that the NRF2-NOTCH3 axis contributes to the improved maintenance of tumor-initiating activity.	('H460', 'CellLine', 'CVCL:0459', (61, 65))	('tumors', 'Disease', (102, 108))	('tumors', 'Disease', 'MESH:D009369', (102, 108))	('tumor', 'Disease', 'MESH:D009369', (235, 240))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('DeltaN3U', 'Var', (52, 60))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('H460', 'CellLine', 'CVCL:0459', (132, 136))	('reduced', 'NegReg', (84, 91))	('tumor', 'Disease', (235, 240))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('U H460', 'CellLine', 'CVCL:0459', (59, 65))
361436	33219226	The tumorigenesis of DeltaN3U H460 cells was suppressed by CDDP more effectively than that of parental cells (Fig.	('tumor', 'Disease', (4, 9))	('CDDP', 'Chemical', 'MESH:D002945', (59, 63))	('suppressed', 'NegReg', (45, 55))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('U H460', 'CellLine', 'CVCL:0459', (28, 34))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('DeltaN3U', 'Var', (21, 29))
361439	33219226	The significant anti-tumorigenic effect caused by the disruption of a single enhancer, i.e., disruption of the NOTCH3 enhancer, stresses that enhancer dysregulation plays a critical role in the biological characteristics of cancers.	('tumor', 'Disease', (21, 26))	('cancers', 'Phenotype', 'HP:0002664', (224, 231))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('disruption', 'Var', (54, 64))	('stress', 'Disease', 'MESH:D000079225', (128, 134))	('NOTCH3 enhancer', 'Gene', (111, 126))	('stress', 'Disease', (128, 134))	('cancers', 'Disease', 'MESH:D009369', (224, 231))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('cancers', 'Disease', (224, 231))	('disruption', 'Var', (93, 103))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
361443	33219226	Based on studies demonstrating that sole overexpression of NRF2 in normal cells does not cause carcinogenesis, it is clear that constitutive activation of NRF2 by KEAP1 or NRF2 mutations, which are often encountered in NRF2-activated cancers, is not by itself cancer driver.	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('cancer', 'Phenotype', 'HP:0002664', (260, 266))	('NRF2', 'Gene', (172, 176))	('cancer', 'Disease', 'MESH:D009369', (260, 266))	('mutations', 'Var', (177, 186))	('cancer', 'Disease', (234, 240))	('NRF2', 'Gene', (155, 159))	('cancer', 'Disease', (260, 266))	('KEAP1', 'Gene', '9817', (163, 168))	('expression', 'Species', '29278', (45, 55))	('cancer', 'Disease', 'MESH:D009369', (234, 240))	('cancers', 'Phenotype', 'HP:0002664', (234, 241))	('KEAP1', 'Gene', (163, 168))	('cancers', 'Disease', (234, 241))	('cancers', 'Disease', 'MESH:D009369', (234, 241))	('activation', 'PosReg', (141, 151))
361449	33219226	Our clinical study demonstrated that NRF2-NOTCH3 double-positive patients tended to have a significantly poorer prognosis compared with the others.	('patients', 'Species', '9606', (65, 73))	('double-positive', 'Var', (49, 64))	('NRF2-NOTCH3', 'Gene', (37, 48))
361450	33219226	These results suggest that not only NOTCH3 but other NRF2 canonical targets such as cytoprotective genes would also contribute to the poorer prognosis in NRF2-activated NSCLC.	('NSCLC', 'Phenotype', 'HP:0030358', (169, 174))	('NSCLC', 'Disease', (169, 174))	('NSCLC', 'Disease', 'MESH:D002289', (169, 174))	('NRF2-activated', 'Gene', (154, 168))	('NOTCH3', 'Var', (36, 42))
361454	33219226	However, considering the critical protective functions of NRF2, systemic administration of NRF2 inhibitors may cause deleterious effects in cancer-bearing hosts.	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('inhibitors', 'Var', (96, 106))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('NRF2', 'Gene', (91, 95))	('cause', 'Reg', (111, 116))
361458	33219226	NOTCH3 inhibition is expected to efficiently reduce the recurrence of NRF2-activated cancers by suppressing tumor-initiating activities without having adverse effects on cancer-bearing hosts.	('NRF2-activated', 'Gene', (70, 84))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('cancer', 'Disease', (170, 176))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('NOTCH3', 'Gene', (0, 6))	('cancers', 'Disease', 'MESH:D009369', (85, 92))	('cancers', 'Phenotype', 'HP:0002664', (85, 92))	('tumor', 'Disease', (108, 113))	('cancer', 'Disease', (85, 91))	('inhibition', 'Var', (7, 17))	('suppressing', 'NegReg', (96, 107))	('cancers', 'Disease', (85, 92))	('reduce', 'NegReg', (45, 51))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
361476	33219226	The antibodies used are as follows: anti-NRF2 (sc-13032X, Santa Cruz; 1:1,000-1:500), anti-KEAP1 (#111; 1:200), anti-NOTCH3 (ab23426, Abcam; 1:2,000), anti-CEBPB antibody (sc-150 X, Santa Cruz; 1:1,000), anti-Tubulin (T9026, Sigma; 1:5,000-1:2,000) and anti-Lamin B (sc-6217, Santa Cruz; 1:2,000).	('KEAP1', 'Gene', (91, 96))	('sc-13032X', 'Var', (47, 56))	('T9026', 'Var', (218, 223))	('sc-150', 'Var', (172, 178))	('ab23426', 'Var', (125, 132))	('CEBPB', 'Gene', (156, 161))	('KEAP1', 'Gene', '9817', (91, 96))	('CEBPB', 'Gene', '1051', (156, 161))
361479	33219226	ON-TARGETplus SMARTpool siRNAs were purchased for F2RL2 (L-005491), FAM20B (L-021203), GPI (L-004900), GSTP1 (L-011179), HGD (L-009823), HJURP (L-015443), HMGA1 (L-004597), HPDL (L-014985), NRG4 (L-015692), PFN2 (L-011750), SRPK1 (L-003982) and VRK1 (L-004683) from Dharmacon.	('HJURP', 'Gene', (137, 142))	('NRG4', 'Gene', (190, 194))	('PFN2', 'Gene', '5217', (207, 211))	('HPDL', 'Gene', '84842', (173, 177))	('L-005491', 'Var', (57, 65))	('F2RL2', 'Gene', (50, 55))	('FAM20B', 'Gene', '9917', (68, 74))	('L-015692', 'Var', (196, 204))	('HGD', 'Gene', '3081', (121, 124))	('GPI', 'Gene', '2821', (87, 90))	('F2RL2', 'Gene', '2151', (50, 55))	('L-015443', 'Var', (144, 152))	('L-004597', 'Var', (162, 170))	('GSTP1', 'Gene', '2950', (103, 108))	('SRPK1', 'Gene', '6732', (224, 229))	('L-011179', 'Var', (110, 118))	('FAM20B', 'Gene', (68, 74))	('HGD', 'Gene', (121, 124))	('VRK1', 'Gene', '7443', (245, 249))	('GSTP1', 'Gene', (103, 108))	('L-011750', 'Var', (213, 221))	('NRG4', 'Gene', '145957', (190, 194))	('HMGA1', 'Gene', '3159', (155, 160))	('HJURP', 'Gene', '55355', (137, 142))	('L-021203', 'Var', (76, 84))	('L-004900', 'Var', (92, 100))	('HPDL', 'Gene', (173, 177))	('PFN2', 'Gene', (207, 211))	('L-014985', 'Var', (179, 187))	('SRPK1', 'Gene', (224, 229))	('L-003982', 'Var', (231, 239))	('L-009823', 'Var', (126, 134))	('VRK1', 'Gene', (245, 249))	('L-004683', 'Var', (251, 259))	('GPI', 'Gene', (87, 90))	('HMGA1', 'Gene', (155, 160))
361480	33219226	CEBPB siRNAs (SASI_Hs01_00236022 and SASI_Hs01_00236027), FOSL2 siRNAs (SASI_Hs01_00057657 and SASI_Hs02_00339278), MYC siRNA (SASI_Hs01_00222676) and MZF1 siRNA (SASI_Hs01_00096728) were purchased from Sigma-Aldrich.	('MZF1', 'Gene', (151, 155))	('SASI_Hs01_00222676', 'Var', (127, 145))	('FOSL2', 'Gene', (58, 63))	('MYC', 'Gene', '4609', (116, 119))	('FOSL2', 'Gene', '2355', (58, 63))	('SASI_Hs01_00057657', 'Var', (72, 90))	('MZF1', 'Gene', '7593', (151, 155))	('SASI_Hs01_00236022', 'Var', (14, 32))	('CEBPB', 'Gene', (0, 5))	('CEBPB', 'Gene', '1051', (0, 5))	('MYC', 'Gene', (116, 119))
361486	33219226	HSS107128 and HSS107130) using the RNeasy Mini Kit (Qiagen).	('Kit', 'Gene', (47, 50))	('Kit', 'Gene', '3815', (47, 50))	('HSS107130', 'Var', (14, 23))
361487	33219226	Total RNA was extracted from ABC1 and HCC4006 cells 16 hrs after treatment with 100 muM DEM or vehicle (DMSO).	('ABC1', 'Gene', '19', (29, 33))	('HCC4006', 'CellLine', 'CVCL:1269', (38, 45))	('ABC1', 'Gene', (29, 33))	('DMSO', 'Chemical', 'MESH:D004121', (104, 108))	('DEM', 'Chemical', 'MESH:C014476', (88, 91))	('100 muM DEM', 'Var', (80, 91))
361493	33219226	To identify NRF2 downstream effectors, significantly decreased genes by NRF2 knockdown were selected for A549, H460, and H2023 cells, and significantly increased genes by DEM treatment were selected for ABC1 and HCC4006 cells.	('ABC1', 'Gene', (203, 207))	('DEM', 'Chemical', 'MESH:C014476', (171, 174))	('HCC4006', 'CellLine', 'CVCL:1269', (212, 219))	('H2023', 'CellLine', 'CVCL:1515', (121, 126))	('increased', 'PosReg', (152, 161))	('knockdown', 'Var', (77, 86))	('NRF2', 'Gene', (72, 76))	('H460', 'CellLine', 'CVCL:0459', (111, 115))	('ABC1', 'Gene', '19', (203, 207))	('decreased', 'NegReg', (53, 62))
361510	33219226	Chromatin immunoprecipitation (ChIP) was performed using anti-H3K27ac antibody (MABI0309, MAB Institute), anti-NRF2 antibody (#12721, Cell Signaling Technology), anti-FOSL2 antibody (#19967S, Cell Signaling Technology), anti-CEBPB antibody (sc-150 X, Santa Cruz) and rabbit IgG (#55944, Cappel/MP Biomedicals).	('H3K27ac', 'Chemical', '-', (62, 69))	('anti-H3K27ac', 'Var', (57, 69))	('CEBPB', 'Gene', (225, 230))	('FOSL2', 'Gene', '2355', (167, 172))	('CEBPB', 'Gene', '1051', (225, 230))	('FOSL2', 'Gene', (167, 172))
361517	33219226	ChIP-seq data from the ENCODE project (ENCSR584GHV for NRF2, ENCSR541WQI for MAFK, ENCSR000BUB for CEBPB and the other transcription factors in A549 cells) were obtained as raw sequencing files and analyzed using the same procedure described above.	('MAFK', 'Gene', (77, 81))	('NRF2', 'Gene', (55, 59))	('ENCSR584GHV', 'Var', (39, 50))	('MAFK', 'Gene', '7975', (77, 81))	('CEBPB', 'Gene', (99, 104))	('CEBPB', 'Gene', '1051', (99, 104))	('ENCSR541WQI', 'Var', (61, 72))
361528	33219226	The inducible NRF2 shRNA lentiviral vector (SMARTvector Inducible Lentiviral shRNA; V3SH11252, V3IHSMCG_6358637 and V3IHSMCG_6804335) and control vector (SMARTvector Inducible Non-targeting mCMV-TurboGFP; VSC11651) were purchased from Dharmacon.	('V3SH11252', 'Var', (84, 93))	('V3IHSMCG_6358637', 'Var', (95, 111))	('mCMV', 'Species', '10366', (190, 194))
361536	33219226	Adenoviruses harboring expression vectors for human KEAP1 (ADV-212864) and GFP (SL100708) was purchased from Vector BIOLABS and SignaGen Laboratories, respectively.	('expression vectors', 'Species', '29278', (23, 41))	('KEAP1', 'Gene', '9817', (52, 57))	('ADV-212864', 'Var', (59, 69))	('human', 'Species', '9606', (46, 51))	('KEAP1', 'Gene', (52, 57))	('SL100708', 'Var', (80, 88))
361550	33219226	In the case of the inducible NRF2-knockdown H460 cells, 1 x 104 cells were injected and the resulting tumors were analyzed after 21 days.	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('tumors', 'Disease', 'MESH:D009369', (102, 108))	('tumors', 'Disease', (102, 108))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('NRF2-knockdown', 'Var', (29, 43))	('H460', 'CellLine', 'CVCL:0459', (44, 48))
361552	33219226	In the case of the NOTCH3 enhancer-disrupted (DeltaN3E) H460 cells, 1 x 103 and 1 x 104 cells were injected and the resulting tumors were dissected and weighed after 21 days and 15 days, respectively.	('enhancer-disrupted', 'PosReg', (26, 44))	('tumors', 'Disease', (126, 132))	('NOTCH3', 'Var', (19, 25))	('tumors', 'Disease', 'MESH:D009369', (126, 132))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('H460', 'CellLine', 'CVCL:0459', (56, 60))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))
361553	33219226	In the case of DeltaN3E A549 and H2023 cells, 1 x 105 (A549) and 3 x 105 (H2023) cells were injected and both of the resulting tumors were dissected and weighed after 35 days.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumors', 'Disease', (127, 133))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('H2023', 'CellLine', 'CVCL:1515', (33, 38))	('tumors', 'Disease', 'MESH:D009369', (127, 133))	('H2023', 'CellLine', 'CVCL:1515', (74, 79))	('DeltaN3E A549', 'Var', (15, 28))
361554	33219226	In the case of DeltaN3E H460 cells with LacZ expression and those with N3ICD expression, 1 x 104 cells were injected and the resulting tumors were analyzed after 18 days.	('DeltaN3E', 'Var', (15, 23))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('H460', 'CellLine', 'CVCL:0459', (24, 28))	('expression', 'Species', '29278', (45, 55))	('tumors', 'Disease', (135, 141))	('tumors', 'Disease', 'MESH:D009369', (135, 141))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))	('expression', 'Species', '29278', (77, 87))
361565	33219226	The eluate was analyzed by immunoblot analysis with anti-NRF2 antibody (sc-13032X, Santa Cruz; 1:1,000), anti-FOSL2 antibody (#19967S, Cell Signaling Technology; 1:1,000), and anti-CEBPB antibody (sc-150 X, Santa Cruz; 1:1,000).	('CEBPB', 'Gene', '1051', (181, 186))	('FOSL2', 'Gene', '2355', (110, 115))	('FOSL2', 'Gene', (110, 115))	('CEBPB', 'Gene', (181, 186))	('sc-13032X', 'Var', (72, 81))
361584	31433481	After multivariable adjustment, surgical resection was associated with superior overall survival compared with EBRT/TA or systemic therapy alone (hazard ratio [HR] for EBRT/TA, 0.62; 95% CI, 0.57-0.67; P < .001; HR for systemic therapy alone, 0.59; 95% CI, 0.55-0.64; P < .001).	('overall survival', 'MPA', (80, 96))	('surgical', 'Var', (32, 40))	('superior', 'PosReg', (71, 79))	('EBRT', 'Chemical', '-', (168, 172))	('men', 'Species', '9606', (26, 29))	('EBRT', 'Chemical', '-', (111, 115))
361587	31433481	In stage IV NSCLC, surgical resection or EBRT/TA of the primary tumor site may provide survival benefits in addition to systemic therapy alone in selected patients.	('tumor', 'Disease', (64, 69))	('NSCLC', 'Phenotype', 'HP:0030358', (12, 17))	('survival benefits', 'CPA', (87, 104))	('EBRT/TA', 'Var', (41, 48))	('EBRT', 'Chemical', '-', (41, 45))	('NSCLC', 'Disease', (12, 17))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('patients', 'Species', '9606', (155, 163))	('NSCLC', 'Disease', 'MESH:D002289', (12, 17))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
361638	31433481	Surgical resection was more common in patients with N0 to N1 category disease (506 of 835 [60.6%]), in cases of local tumor spread to the same lobe (116 of 835 [13.9%]) or a different lobe (164 of 835 [19.6%]), and in cases of limited systemic metastases (495 of 835 patients with >=1 metastatic site reported [59.3%]) and M1a status (572 of 835 [68.5%]).	('Surgical resection', 'CPA', (0, 18))	('N0 to N1 category', 'Var', (52, 69))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('patients', 'Species', '9606', (267, 275))	('metastases', 'Disease', 'MESH:D009362', (244, 254))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumor', 'Disease', (118, 123))	('patients', 'Species', '9606', (38, 46))	('metastases', 'Disease', (244, 254))
361639	31433481	Systemic therapy plus EBRT/TA and systemic therapy alone were more commonly used in patients with limited local spread but multiple systemic metastases (6686 of 9539 patients receiving EBRT/TA [70.1%] and 16 993 of 24 513 receiving systemic therapy [81.6%] with >=2 metastatic sites reported).	('patients', 'Species', '9606', (84, 92))	('EBRT', 'Chemical', '-', (22, 26))	('EBRT/TA', 'Var', (185, 192))	('metastases', 'Disease', 'MESH:D009362', (141, 151))	('EBRT', 'Chemical', '-', (185, 189))	('patients', 'Species', '9606', (166, 174))	('metastases', 'Disease', (141, 151))
361652	31433481	To further quantify the potential benefit of EBRT/TA in selected patients with stage IV NSCLC, a subgroup analysis from the matched cohort was conducted in patients with squamous cell carcinoma, T1 to T2 category disease, N0 to N1 category disease, and oligometastases.	('patients', 'Species', '9606', (156, 164))	('carcinoma', 'Phenotype', 'HP:0030731', (184, 193))	('metastases', 'Disease', 'MESH:D009362', (258, 268))	('NSCLC', 'Phenotype', 'HP:0030358', (88, 93))	('T1 to T2 category', 'Var', (195, 212))	('NSCLC', 'Disease', 'MESH:D002289', (88, 93))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (170, 193))	('EBRT', 'Chemical', '-', (45, 49))	('squamous cell carcinoma', 'Disease', (170, 193))	('NSCLC', 'Disease', (88, 93))	('patients', 'Species', '9606', (65, 73))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (170, 193))	('metastases', 'Disease', (258, 268))	('N0 to N1', 'Var', (222, 230))
361653	31433481	As shown in Figure 4, patients treated with EBRT/TA had a survival benefit compared with those receiving systemic therapy alone (HR, 0.68; 95% CI, 0.57-0.80; P < .001).	('EBRT/TA', 'Var', (44, 51))	('EBRT', 'Chemical', '-', (44, 48))	('patients', 'Species', '9606', (22, 30))	('survival benefit', 'CPA', (58, 74))
361655	31433481	In contrast, patients with adenocarcinoma, T3 to T4 category disease, N2 to N3 category disease, and 2 or more distant metastatic sites had an inferior overall survival after EBRT/TA compared with patients undergoing systemic therapy alone (Figure 4) (HR, 1.39; 95% CI, 1.22-1.59; P < .001), with overall survival rates at 1 year of 41.4% vs 25.3%; at 2 years of 19.5% vs 10.6%; and at 3 years of 9.4% vs 7.4%.	('patients', 'Species', '9606', (197, 205))	('overall survival', 'MPA', (152, 168))	('patients', 'Species', '9606', (13, 21))	('carcinoma', 'Phenotype', 'HP:0030731', (32, 41))	('inferior', 'NegReg', (143, 151))	('EBRT', 'Chemical', '-', (175, 179))	('adenocarcinoma', 'Disease', (27, 41))	('adenocarcinoma', 'Disease', 'MESH:D000230', (27, 41))	('T3 to T4', 'Var', (43, 51))	('N2 to N3', 'Var', (70, 78))
361660	31433481	Further, a survival benefit was evident for EBRT/TA compared with systemic therapy alone, although its clinical relevance remains unclear given the limited effect size.	('EBRT/TA', 'Var', (44, 51))	('EBRT', 'Chemical', '-', (44, 48))	('survival benefit', 'CPA', (11, 27))
361661	31433481	Nevertheless, subgroup analyses indicate that the survival benefit of EBRT/TA varied by patient and cancer-specific variables; in optimally selected patients presenting with squamous cell carcinoma and limited nodal disease as well as oligometastases, EBRT/TA yielded a clinically relevant overall survival benefit vs systemic therapy alone.	('patient', 'Species', '9606', (88, 95))	('nodal disease', 'Disease', 'MESH:D013611', (210, 223))	('cancer', 'Disease', (100, 106))	('metastases', 'Disease', (240, 250))	('nodal disease', 'Disease', (210, 223))	('EBRT', 'Chemical', '-', (252, 256))	('patients', 'Species', '9606', (149, 157))	('metastases', 'Disease', 'MESH:D009362', (240, 250))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (174, 197))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('patient', 'Species', '9606', (149, 156))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (174, 197))	('EBRT/TA', 'Var', (252, 259))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (188, 197))	('squamous cell carcinoma', 'Disease', (174, 197))	('EBRT', 'Chemical', '-', (70, 74))
361667	31433481	Addressing the primary tumor with surgical resection, EBRT, or TA may therefore contribute to observed increases in overall survival.	('increases', 'PosReg', (103, 112))	('EBRT', 'Chemical', '-', (54, 58))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('overall survival', 'MPA', (116, 132))	('EBRT', 'Var', (54, 58))	('tumor', 'Disease', (23, 28))
361701	31433481	This study found that in stage IV NSCLC, surgical resection or EBRT/TA of the primary tumor site in addition to systemic therapy may confer additional survival benefit compared with systemic therapy alone in select patients.	('patients', 'Species', '9606', (215, 223))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('NSCLC', 'Disease', (34, 39))	('tumor', 'Disease', (86, 91))	('NSCLC', 'Disease', 'MESH:D002289', (34, 39))	('EBRT/TA', 'Var', (63, 70))	('NSCLC', 'Phenotype', 'HP:0030358', (34, 39))	('EBRT', 'Chemical', '-', (63, 67))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('survival benefit', 'CPA', (151, 167))
361708	30300578	The frequencies of TP53 mutations and amplification of CCNE1 were increased in AAs in the cancer types showing higher levels of chromosomal instability.	('increased', 'PosReg', (66, 75))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('AAs', 'Disease', (79, 82))	('cancer', 'Disease', (90, 96))	('TP53', 'Gene', '7157', (19, 23))	('chromosomal instability', 'Phenotype', 'HP:0040012', (128, 151))	('TP53', 'Gene', (19, 23))	('CCNE1', 'Gene', '898', (55, 60))	('CCNE1', 'Gene', (55, 60))	('mutations', 'Var', (24, 33))	('amplification', 'Var', (38, 51))	('cancer', 'Disease', 'MESH:D009369', (90, 96))
361709	30300578	We observed lower frequencies of genomic alterations affecting genes in the PI3K pathway in AA patients across cancers.	('cancers', 'Disease', 'MESH:D009369', (111, 118))	('cancers', 'Phenotype', 'HP:0002664', (111, 118))	('cancers', 'Disease', (111, 118))	('patients', 'Species', '9606', (95, 103))	('PI3K pathway', 'Pathway', (76, 88))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('genomic alterations', 'Var', (33, 52))
361734	30300578	As expected, a large percentage of the TCGA specimens showed genetic diversity (Figures 1D and S2).	('men', 'Species', '9606', (49, 52))	('genetic diversity', 'Var', (61, 78))	('exp', 'Gene', '4154', (3, 6))	('exp', 'Gene', (3, 6))
361741	30300578	The average proportions of East Asian and Native American ancestry were 0.945 (SD =0.047) and 0.224 (SD = 0.024) in EAA and NA patients, respectively.	('EAA', 'Disease', (116, 119))	('patients', 'Species', '9606', (127, 135))	('0.224', 'Var', (94, 99))
361771	30300578	For example, the recurrent focal amplification residing within the 19q12 region had a significantly higher amplification frequency in AA patients across four cancer types (BRCA, GBM, LUSC, and UCEC) compared with EA patients (raw p value = 9.37 x 10-4, corrected p value = 0.072).	('GBM', 'Disease', (178, 181))	('BRCA', 'Gene', '672', (172, 176))	('focal amplification', 'Var', (27, 46))	('LUSC', 'Disease', (183, 187))	('BRCA', 'Gene', (172, 176))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('patients', 'Species', '9606', (137, 145))	('amplification', 'MPA', (107, 120))	('cancer', 'Disease', (158, 164))	('patients', 'Species', '9606', (216, 224))	('higher', 'PosReg', (100, 106))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
361787	30300578	At a pan-cancer level, we found that TP53 mutations were significantly enriched in AA patients compared with EA patients (raw p value =1.02 x 10-3, corrected p value = 3.05 x 10-2, Figure 6A).	('cancer', 'Disease', (9, 15))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('patients', 'Species', '9606', (112, 120))	('TP53', 'Gene', '7157', (37, 41))	('TP53', 'Gene', (37, 41))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('mutations', 'Var', (42, 51))	('patients', 'Species', '9606', (86, 94))
361792	30300578	AA patients had significantly higher TP53 mutation frequency in BRCA.	('higher', 'PosReg', (30, 36))	('BRCA', 'Gene', '672', (64, 68))	('mutation', 'Var', (42, 50))	('patients', 'Species', '9606', (3, 11))	('BRCA', 'Gene', (64, 68))	('TP53', 'Gene', '7157', (37, 41))	('TP53', 'Gene', (37, 41))
361793	30300578	COAD fell just below the threshold of significance but also demonstrated the trend of TP53 mutation enrichment in AAs (odds ratio [OR] =1.82, p = 0.043).	('mutation', 'Var', (91, 99))	('TP53', 'Gene', '7157', (86, 90))	('TP53', 'Gene', (86, 90))	('AAs', 'Disease', (114, 117))	('men', 'Species', '9606', (106, 109))
361794	30300578	Significant enrichment of PIK3CA mutations in EA patients was observed in BRCA.	('men', 'Species', '9606', (18, 21))	('PIK3CA', 'Gene', '5290', (26, 32))	('mutations', 'Var', (33, 42))	('BRCA', 'Gene', '672', (74, 78))	('patients', 'Species', '9606', (49, 57))	('BRCA', 'Gene', (74, 78))	('PIK3CA', 'Gene', (26, 32))
361795	30300578	HNSC fell just below the significance threshold, but also followed the trend of fewer PIK3CA mutations in AAs (OR = 0.29, p = 0.048).	('PIK3CA', 'Gene', '5290', (86, 92))	('fewer', 'NegReg', (80, 85))	('mutations', 'Var', (93, 102))	('PIK3CA', 'Gene', (86, 92))
361797	30300578	Across the ten cancer types analyzed, we observed that, compared with EA, AA patients showed a significantly higher level of chromosomal instability in BRCA, UCEC, and HNSC, which was associated with increased frequencies of TP53 mutations as well as CCNE1 amplification (Figure 7A).	('higher level of chromosomal instability', 'Phenotype', 'HP:0040012', (109, 148))	('cancer', 'Disease', (15, 21))	('cancer', 'Disease', 'MESH:D009369', (15, 21))	('increased', 'PosReg', (200, 209))	('CCNE1', 'Gene', '898', (251, 256))	('TP53', 'Gene', '7157', (225, 229))	('chromosomal instability', 'Phenotype', 'HP:0040012', (125, 148))	('BRCA', 'Gene', '672', (152, 156))	('UCEC', 'Disease', (158, 162))	('mutations', 'Var', (230, 239))	('patients', 'Species', '9606', (77, 85))	('CCNE1', 'Gene', (251, 256))	('TP53', 'Gene', (225, 229))	('BRCA', 'Gene', (152, 156))	('chromosomal instability', 'MPA', (125, 148))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))
361812	30300578	Interestingly, the frequencies of TP53 mutations and amplification of CCNE1 were significantly higher in AA patients in the cancer types that show higher levels of chromosomal instability.	('cancer', 'Disease', (124, 130))	('TP53', 'Gene', (34, 38))	('chromosomal instability', 'Phenotype', 'HP:0040012', (164, 187))	('amplification', 'Var', (53, 66))	('mutations', 'Var', (39, 48))	('higher', 'Reg', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('CCNE1', 'Gene', '898', (70, 75))	('CCNE1', 'Gene', (70, 75))	('patients', 'Species', '9606', (108, 116))	('TP53', 'Gene', '7157', (34, 38))	('cancer', 'Disease', 'MESH:D009369', (124, 130))
361815	30300578	As a transcription factor, both loss-of-function and gain-of-function mutations in the TP53 gene will have large effects on the transcriptome, such as the expression of ER and ER-regulated/associated genes in breast cancer.	('exp', 'Gene', '4154', (155, 158))	('mutations', 'Var', (70, 79))	('TP53', 'Gene', '7157', (87, 91))	('breast cancer', 'Disease', 'MESH:D001943', (209, 222))	('gain-of-function', 'PosReg', (53, 69))	('ER-regulated/associated genes', 'Gene', (176, 205))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('breast cancer', 'Disease', (209, 222))	('TP53', 'Gene', (87, 91))	('breast cancer', 'Phenotype', 'HP:0003002', (209, 222))	('exp', 'Gene', (155, 158))	('transcriptome', 'MPA', (128, 141))	('loss-of-function', 'NegReg', (32, 48))
361816	30300578	TP53 mutant breast tumors are enriched for the triple-negative (basal-like) transcriptional pheno-type, providing a potential explanation for higher prevalence of the basal-like subtype (PAM50) in AA patients with breast cancer.	('breast cancer', 'Phenotype', 'HP:0003002', (214, 227))	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('patients', 'Species', '9606', (200, 208))	('exp', 'Gene', '4154', (126, 129))	('exp', 'Gene', (126, 129))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('breast tumors', 'Disease', (12, 25))	('breast tumors', 'Disease', 'MESH:D061325', (12, 25))	('mutant', 'Var', (5, 11))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('breast cancer', 'Disease', 'MESH:D001943', (214, 227))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('breast cancer', 'Disease', (214, 227))	('higher', 'PosReg', (142, 148))	('breast tumors', 'Phenotype', 'HP:0100013', (12, 25))
361817	30300578	In addition, we found that genomic alterations of the genes in the PI3K pathway were less frequent in AA patients compared with EA across most cancer types.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('genomic alterations', 'Var', (27, 46))	('patients', 'Species', '9606', (105, 113))	('less', 'NegReg', (85, 89))	('PI3K pathway', 'Pathway', (67, 79))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))
361819	30300578	For example, recent studies on breast cancer from the TCGA cohort demonstrated that AAs had more TP53 mutations and fewer PIK3CA mutations.	('PIK3CA', 'Gene', (122, 128))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('TP53', 'Gene', '7157', (97, 101))	('PIK3CA', 'Gene', '5290', (122, 128))	('breast cancer', 'Disease', 'MESH:D001943', (31, 44))	('TP53', 'Gene', (97, 101))	('breast cancer', 'Disease', (31, 44))	('mutations', 'Var', (102, 111))	('breast cancer', 'Phenotype', 'HP:0003002', (31, 44))	('fewer', 'NegReg', (116, 121))
361824	30300578	The correlation between chromosomal instability and the amplification of CCNE1 further supports the idea that it may play biological roles in cancer disparities.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('play', 'Reg', (117, 121))	('chromosomal instability', 'Phenotype', 'HP:0040012', (24, 47))	('chromosomal', 'Disease', (24, 35))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('CCNE1', 'Gene', '898', (73, 78))	('CCNE1', 'Gene', (73, 78))	('amplification', 'Var', (56, 69))	('cancer', 'Disease', (142, 148))
361826	30300578	Genomic instability, epigenetic regulation and PI3K were the major molecular pathways implicated by the 39 genes found to be altered (either through SCNA or mutation) with significantly different frequency between AA and EA patients at a pan-cancer level.	('cancer', 'Disease', (242, 248))	('cancer', 'Disease', 'MESH:D009369', (242, 248))	('altered', 'Reg', (125, 132))	('mutation', 'Var', (157, 165))	('epigenetic regulation', 'MPA', (21, 42))	('Genomic instability', 'MPA', (0, 19))	('patients', 'Species', '9606', (224, 232))	('cancer', 'Phenotype', 'HP:0002664', (242, 248))	('PI3K', 'Var', (47, 51))
361846	30300578	The PI3-kinase score was defined as the sum of normalized protein levels of selected proteins involved in the PI3-kinase pathway, including AKT (S473 and T308 features), GSK3 (S9 and S21/S9 features), PRAS40, and phospho-TSC2.	('AKT', 'Gene', (140, 143))	('PRAS40', 'Gene', (201, 207))	('T308 features', 'Var', (154, 167))	('S473', 'Var', (145, 149))	('S21', 'Gene', (183, 186))	('TSC2', 'Gene', '7249', (221, 225))	('phospho', 'Chemical', 'MESH:C033601', (213, 220))	('TSC2', 'Gene', (221, 225))	('PI3-kinase pathway', 'Pathway', (110, 128))	('S21', 'Gene', '6227', (183, 186))	('AKT', 'Gene', '207', (140, 143))	('PRAS40', 'Gene', '84335', (201, 207))
361888	30300578	Neoplasm histologic grade was also treated as an ordinal categorical variable (G1/low grade, 3.2%; G2/intermediate grade, 11.9%; G3.G4/high grade, 13.1%).	('Neoplasm', 'Disease', (0, 8))	('Neoplasm', 'Phenotype', 'HP:0002664', (0, 8))	('Neoplasm', 'Disease', 'MESH:D009369', (0, 8))	('G3.G4/high', 'Var', (129, 139))
361910	30300578	At the cancer-specific level, in order to control the overall level of genomic disruption when comparing the alteration frequencies for each SCNA event between AA and EA patients, we performed a controlled permutation test in which both the fractions of the genome affected by each of the amplifications and deletions in each sample (column-wise) and the alteration frequency of each recurrent focal SCNA (row-wise) were maintained in the permuted data.	('patients', 'Species', '9606', (170, 178))	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('deletions', 'Var', (308, 317))	('cancer', 'Disease', (7, 13))	('cancer', 'Disease', 'MESH:D009369', (7, 13))
361944	30300578	Signature 6, associated with defective DNA mismatch repair, was enriched in COAD and UCEC, two cancer types where the hypermutator phenotype has been reported.	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('cancer', 'Disease', (95, 101))	('UCEC', 'Disease', (85, 89))	('COAD', 'Disease', (76, 80))	('defective', 'Var', (29, 38))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))
361949	30300578	Additionally, signatures 2 and 13 exhibited predominantly C > T and C > G mutations at TpC sites and were associated with the activity of the APOBEC cytidine deaminases.	('APOBEC cytidine deaminases', 'Enzyme', (142, 168))	('associated', 'Reg', (106, 116))	('cytidine', 'Chemical', 'MESH:D003562', (149, 157))	('C > G mutations', 'Var', (68, 83))	('activity', 'MPA', (126, 134))	('C > T', 'Var', (58, 63))
361974	30300578	The genetic ancestry of TCGA patients was estimated at global and local levels The Cancer Genetic Ancestry Atlas, a publicly accessible resource, was developed The frequencies of TP53 mutations and CCNE1 amplification were higher among AAs The frequencies of the alterations in the PI3K pathway were lower among AAs The TCGA patient cohort is ethnically diverse, therefore providing a unique resource to understand the genomic basis ofcancer disparities across multiple cancer types.	('CCNE1', 'Gene', '898', (198, 203))	('CCNE1', 'Gene', (198, 203))	('patients', 'Species', '9606', (29, 37))	('patient', 'Species', '9606', (29, 36))	('PI3K pathway', 'Pathway', (282, 294))	('patient', 'Species', '9606', (325, 332))	('cancer', 'Phenotype', 'HP:0002664', (435, 441))	('mutations', 'Var', (184, 193))	('cancer', 'Phenotype', 'HP:0002664', (470, 476))	('Cancer', 'Phenotype', 'HP:0002664', (83, 89))	('ofcancer disparities across multiple cancer', 'Disease', 'MESH:D009369', (433, 476))	('ofcancer disparities across multiple cancer', 'Disease', (433, 476))	('TP53', 'Gene', '7157', (179, 183))	('TP53', 'Gene', (179, 183))
361984	29770330	In the particular area of cancer therapy, the first combination was granted in January 2014 by FDA to treat melanoma with BRAF V600E or V600K mutations.	('melanoma', 'Disease', 'MESH:D008545', (108, 116))	('cancer', 'Disease', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('BRAF', 'Gene', '673', (122, 126))	('BRAF', 'Gene', (122, 126))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('V600K', 'Var', (136, 141))	('V600E', 'Mutation', 'rs113488022', (127, 132))	('melanoma', 'Phenotype', 'HP:0002861', (108, 116))	('melanoma', 'Disease', (108, 116))	('V600K', 'Mutation', 'rs121913227', (136, 141))
361991	29770330	Six microarray datasets (GSE9476, GSE33615, GSE22529, GSE26049, GSE19429, and GSE47552) were selected from the GEO database (https://www.ncbi.nlm.nih.gov/geo/), including 9 blood cell and bone marrow related malignancies and diseases (Table S2).	('GSE47552', 'Var', (78, 86))	('GSE9476', 'Var', (25, 32))	('GSE19429', 'Var', (64, 72))	('GSE26049', 'Var', (54, 62))	('GSE22529', 'Var', (44, 52))	('GSE9476', 'Chemical', '-', (25, 32))	('GSE33615', 'Var', (34, 42))	('malignancies and diseases', 'Disease', 'MESH:D009369', (208, 233))
361996	29770330	These drug combinations were also closely related to chronic adult T-cell leukemia, which may be due to their similar pathophysiologic characteristics.	('chronic adult T-cell leukemia', 'Disease', (53, 82))	('chronic adult T-cell leukemia', 'Disease', 'MESH:D015459', (53, 82))	('combinations', 'Var', (11, 23))	('related', 'Reg', (42, 49))	('leukemia', 'Phenotype', 'HP:0001909', (74, 82))
362093	26829042	In MS/MS mode, both peaks of the compound in leaf juice and the pheophorbide A standard produced four major fragment ions with matching m/z values: (m/z 565.2727, 533.2461, 505.2212 and 460.2235 for compound in LJ) and (m/z 565.2706, 533.2534, 505.2272 and 460.2249 for standard) (Fig 6G and 6H).	('505.2272', 'Var', (244, 252))	('533.2461', 'Var', (163, 171))	('m/z 565.2706', 'Var', (220, 232))	('leaf juice', 'Chemical', '-', (45, 55))	('pheophorbide A', 'Chemical', '-', (64, 78))	('505.2212', 'Var', (173, 181))	('533.2534', 'Var', (234, 242))	('460.2235', 'Var', (186, 194))	('m/z 565.2727', 'Var', (149, 161))
362094	26829042	The fragmentation pattern of the pheophorbide A molecule to produce those major fragments (m/z 565, 533, 505 and 460) in positive ionization mode was proposed in S2 Fig.	('m/z 565', 'Var', (91, 98))	('505', 'Var', (105, 108))	('ionization', 'Disease', 'MESH:D004194', (130, 140))	('pheophorbide A', 'Chemical', '-', (33, 47))	('ionization', 'Disease', (130, 140))	('533', 'Var', (100, 103))
362140	33855685	In a prospective trial of HNSCC patients undergoing chemoradiation, HIF1alpha expression correlated with an increase in intratumoral FMISO uptake during the first 2 weeks of chemoradiation, and high levels of HIF1alpha and CAIX were associated with a delayed resolution of the FMISO uptake between weeks 2 and 5.	('CAIX', 'Gene', '768', (223, 227))	('high', 'Var', (194, 198))	('increase', 'PosReg', (108, 116))	('HIF1alpha', 'Gene', (68, 77))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('patients', 'Species', '9606', (32, 40))	('HIF1alpha', 'Gene', (209, 218))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('HIF1alpha', 'Gene', '3091', (209, 218))	('HIF1alpha', 'Gene', '3091', (68, 77))	('tumor', 'Disease', (125, 130))	('CAIX', 'Gene', (223, 227))	('HNSCC', 'Phenotype', 'HP:0012288', (26, 31))	('FMISO', 'Chemical', 'MESH:C031843', (133, 138))	('FMISO', 'Chemical', 'MESH:C031843', (277, 282))
362145	33855685	This is exacerbated in tumors with low hypoxic fractions due to partial-volume effect.	('partial-volume', 'Var', (64, 78))	('tumors', 'Disease', (23, 29))	('low hypoxic fractions', 'Disease', (35, 56))	('tumors', 'Disease', 'MESH:D009369', (23, 29))	('exacerbated', 'PosReg', (8, 19))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('low hypoxic fractions', 'Disease', 'MESH:D009800', (35, 56))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))
362187	33855685	The strength of the correlation between the FDG and FMISO distributions was defined according to the following criteria: R < 0.5 indicates a weak correlation, 0.5 <= R < 0.7 indicates a moderate correlation, and R >= 0.7 a strong correlation.	('R <', 'Var', (121, 124))	('FMISO', 'Chemical', 'MESH:C031843', (52, 57))	('0.5 <= R <', 'Var', (159, 169))	('FDG', 'Chemical', '-', (44, 47))
362231	33855685	Restricting the analysis to the HVs defined by a T/B > 1.2 resulted in a decrease in the correlation coefficient values so that only 39% of the primary tumors and 22% of the LNs resulted in R values > 0.7.	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('tumors', 'Disease', 'MESH:D009369', (152, 158))	('tumors', 'Disease', (152, 158))	('decrease', 'NegReg', (73, 81))	('T/B', 'Var', (49, 52))	('correlation coefficient values', 'MPA', (89, 119))	('tumors', 'Phenotype', 'HP:0002664', (152, 158))
362284	29113230	Squamous cell transformation and EGFR T790M mutation as acquired resistance mechanisms in a patient with lung adenocarcinoma treated with a tyrosine kinase inhibitor: A case report The present case report describes the infrequent coexistence of squamous cell transformation and the epidermal growth factor receptor (EGFR) T790M mutation as resistance mechanisms to first line treatment with tyrosine kinase inhibitors.	('patient', 'Species', '9606', (92, 99))	('EGFR', 'Gene', (33, 37))	('T790M', 'Mutation', 'rs121434569', (322, 327))	('squamous cell', 'Disease', (245, 258))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (105, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('T790M', 'Var', (322, 327))	('EGFR', 'Gene', '1956', (316, 320))	('EGFR', 'Gene', (316, 320))	('lung adenocarcinoma', 'Disease', (105, 124))	('EGFR', 'Gene', '1956', (33, 37))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (105, 124))	('T790M', 'Mutation', 'rs121434569', (38, 43))	('epidermal growth factor receptor', 'Gene', (282, 314))	('T790M', 'Var', (38, 43))	('epidermal growth factor receptor', 'Gene', '1956', (282, 314))
362286	29113230	The tumor was positive for the EGFR exon 19 deletion, therefore the patient was treated with afatinib (40 mg/day, orally) and radiotherapy for bone lesions.	('tumor', 'Disease', (4, 9))	('bone lesions', 'Disease', 'MESH:D001847', (143, 155))	('EGFR', 'Gene', '1956', (31, 35))	('patient', 'Species', '9606', (68, 75))	('deletion', 'Var', (44, 52))	('EGFR', 'Gene', (31, 35))	('positive', 'Reg', (14, 22))	('afatinib', 'Chemical', 'MESH:D000077716', (93, 101))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('bone lesions', 'Disease', (143, 155))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))
362288	29113230	Cytological examination of the pleural effusion confirmed an adenocarcinoma positive for the EGFR exon 19 deletion and the T790M mutation within exon 20, while a biopsy from the upper left bronchus revealed a keratinizing squamous cell carcinoma positive for the EGFR exon 19 deletion.	('carcinoma', 'Phenotype', 'HP:0030731', (66, 75))	('pleural effusion', 'Disease', 'MESH:D010996', (31, 47))	('EGFR', 'Gene', '1956', (93, 97))	('pleural effusion', 'Phenotype', 'HP:0002202', (31, 47))	('pleural effusion', 'Disease', (31, 47))	('adenocarcinoma', 'Disease', 'MESH:D000230', (61, 75))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (222, 245))	('EGFR', 'Gene', (263, 267))	('EGFR', 'Gene', (93, 97))	('T790M', 'Mutation', 'rs121434569', (123, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (236, 245))	('EGFR', 'Gene', '1956', (263, 267))	('deletion', 'Var', (106, 114))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (222, 245))	('positive', 'Reg', (76, 84))	('squamous cell carcinoma', 'Disease', (222, 245))	('T790M', 'Var', (123, 128))	('adenocarcinoma', 'Disease', (61, 75))
362289	29113230	In addition, the EGFR mutations were concomitantly detected in circulating cell-free tumour DNA.	('tumour', 'Disease', 'MESH:D009369', (85, 91))	('tumour', 'Disease', (85, 91))	('mutations', 'Var', (22, 31))	('EGFR', 'Gene', '1956', (17, 21))	('tumour', 'Phenotype', 'HP:0002664', (85, 91))	('EGFR', 'Gene', (17, 21))
362290	29113230	Due to the presence of the T790M mutation, the patient underwent osimertinib therapy (80 mg/day, orally), which resulted in a partial tumour regression at the 2-month follow-up, whereas the squamous lesions were treated with radiotherapy.	('squamous lesions', 'Disease', (190, 206))	('patient', 'Species', '9606', (47, 54))	('tumour', 'Disease', 'MESH:D009369', (134, 140))	('osimertinib', 'Chemical', 'MESH:C000603933', (65, 76))	('tumour', 'Disease', (134, 140))	('T790M', 'Mutation', 'rs121434569', (27, 32))	('squamous lesions', 'Disease', 'MESH:D002294', (190, 206))	('T790M', 'Var', (27, 32))	('tumour', 'Phenotype', 'HP:0002664', (134, 140))
362291	29113230	The adenocarcinoma and squamous carcinoma components may share the same origin, according to the presence of the EGFR exon 19 deletion in both lesions.	('squamous carcinoma', 'Disease', (23, 41))	('carcinoma', 'Phenotype', 'HP:0030731', (9, 18))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (23, 41))	('carcinoma', 'Phenotype', 'HP:0030731', (32, 41))	('adenocarcinoma', 'Disease', (4, 18))	('EGFR', 'Gene', '1956', (113, 117))	('deletion', 'Var', (126, 134))	('EGFR', 'Gene', (113, 117))	('adenocarcinoma', 'Disease', 'MESH:D000230', (4, 18))	('squamous carcinoma', 'Disease', 'MESH:D002294', (23, 41))
362292	29113230	A significant proportion (15-20%) of patients with lung adenocarcinoma harbor epidermal growth factor receptor (EGFR) activating mutations and can benefit from first-line treatment with tyrosine kinase inhibitors (TKI), including gefitinib or erlotinib (first generation TKI) and afatinib (second generation TKI).	('EGFR', 'Gene', (112, 116))	('lung adenocarcinoma', 'Disease', (51, 70))	('epidermal growth factor receptor', 'Gene', '1956', (78, 110))	('patients', 'Species', '9606', (37, 45))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (51, 70))	('mutations', 'Var', (129, 138))	('erlotinib', 'Chemical', 'MESH:D000069347', (243, 252))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('EGFR', 'Gene', '1956', (112, 116))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (51, 70))	('afatinib', 'Chemical', 'MESH:D000077716', (280, 288))	('activating', 'PosReg', (118, 128))	('epidermal growth factor receptor', 'Gene', (78, 110))	('gefitinib', 'Chemical', 'MESH:D000077156', (230, 239))	('benefit', 'PosReg', (147, 154))
362294	29113230	The most common resistance mechanism, detectable in ~50% of TKI resistant tumors, is the emergence of a secondary T790M mutation in exon 20 of EGFR.	('EGFR', 'Gene', (143, 147))	('T790M', 'Mutation', 'rs121434569', (114, 119))	('T790M', 'Var', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumors', 'Disease', (74, 80))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('EGFR', 'Gene', '1956', (143, 147))	('tumors', 'Disease', 'MESH:D009369', (74, 80))
362295	29113230	Other well-known resistance mechanisms, in patients with non-small cell lung cancer treated with EGFR-TKI, include the amplification of MET proto-oncogene tyrosine kinase receptor (MET) (20%), the development of small cell lung cancer transformation (14%) and the presence of acquired phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PI3KCA) mutations (5%).	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (57, 83))	('mutations', 'Var', (365, 374))	('lung cancer', 'Phenotype', 'HP:0100526', (223, 234))	('small cell lung cancer', 'Disease', 'MESH:D055752', (61, 83))	('EGFR', 'Gene', (97, 101))	('non-small cell lung cancer', 'Disease', (57, 83))	('lung cancer', 'Phenotype', 'HP:0100526', (72, 83))	('small cell lung cancer', 'Disease', 'MESH:D055752', (212, 234))	('small cell lung cancer', 'Disease', (212, 234))	('phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha', 'Gene', '5290', (285, 355))	('patients', 'Species', '9606', (43, 51))	('MET', 'Gene', (181, 184))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (57, 83))	('PI3KCA', 'Gene', (357, 363))	('EGFR', 'Gene', '1956', (97, 101))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (61, 83))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (212, 234))
362299	29113230	For instance, in cases of T790M-mediated resistance, the use of a third-generation TKI, which irreversibly and selectively blocks T790M mutant clones, has been demonstrated to increase the potency of EGFR-TK inhibition.	('increase', 'PosReg', (176, 184))	('blocks', 'NegReg', (123, 129))	('T790M', 'Mutation', 'rs121434569', (26, 31))	('T790M', 'Mutation', 'rs121434569', (130, 135))	('EGFR', 'Gene', '1956', (200, 204))	('EGFR', 'Gene', (200, 204))	('T790M', 'Var', (130, 135))	('potency', 'MPA', (189, 196))	('T790M-mediated', 'Var', (26, 40))
362302	29113230	In addition, temporal changes to EGFR activating and resistance mutations in plasma DNA are directly linked to treatment efficacy.	('resistance mutations', 'Var', (53, 73))	('activating', 'PosReg', (38, 48))	('EGFR', 'Gene', '1956', (33, 37))	('EGFR', 'Gene', (33, 37))
362307	29113230	A few weeks later the patient underwent magnetic resonance imaging of the vertebral column, which revealed a number of osteoblastic bone lesions (S1-3; D2-3 and D7-10 laminas).	('patient', 'Species', '9606', (22, 29))	('osteoblastic bone lesions', 'Disease', (119, 144))	('D2-3', 'Var', (152, 156))	('S1-3; D2-3', 'Var', (146, 156))	('osteoblastic bone lesions', 'Disease', 'MESH:D001847', (119, 144))	('D7-10', 'Var', (161, 166))
362315	29113230	All FISH tests were negative: ALK, 4% of neoplastic rearranged cells (cut-off 15%); ROS1, 0% of neoplastic rearranged cells (cut-off 15%); RET, 5% of neoplastic rearranged cells (cut-off 15%); and MET, MET/CEP7=1,1 (cut-off >=2).	('ROS1', 'Gene', '6098', (84, 88))	('RET', 'Gene', (139, 142))	('ALK', 'Gene', (30, 33))	('MET', 'Var', (197, 200))	('ALK', 'Gene', '238', (30, 33))	('RET', 'Gene', '5979', (139, 142))	('ROS1', 'Gene', (84, 88))
362317	29113230	The PE demonstrated a deletion in EGFR exon 19 (ex19del).	('EGFR', 'Gene', (34, 38))	('deletion', 'Var', (22, 30))	('ex19del', 'Var', (48, 55))	('EGFR', 'Gene', '1956', (34, 38))	('PE', 'Phenotype', 'HP:0001698', (4, 6))
362324	29113230	At subsequent medical examinations, after 5, 7 and 9 months of treatment, the patient was stable and no EGFR mutations were detected on ctDNA from plasma collected at each visit (Fig.	('patient', 'Species', '9606', (78, 85))	('EGFR', 'Gene', '1956', (104, 108))	('mutations', 'Var', (109, 118))	('EGFR', 'Gene', (104, 108))
362331	29113230	Cytological samples from pleural effusion were positive for EGFR ex19del and T790M; both mutations were concomitantly detected in ctDNA (Fig.	('pleural effusion', 'Disease', 'MESH:D010996', (25, 41))	('T790M', 'Mutation', 'rs121434569', (77, 82))	('pleural effusion', 'Phenotype', 'HP:0002202', (25, 41))	('pleural effusion', 'Disease', (25, 41))	('detected', 'Reg', (118, 126))	('ctDNA', 'Disease', (130, 135))	('T790M', 'Var', (77, 82))	('EGFR', 'Gene', '1956', (60, 64))	('EGFR', 'Gene', (60, 64))
362337	29113230	Again, all FISH tests gave negative results: ALK, 0% of neoplastic rearranged cells; ROS1, 0% of neoplastic rearranged cells; RET, 0% of neoplastic rearranged cells; and MET, MET/CEP7=1 in the adenocarcinoma.	('ALK', 'Gene', '238', (45, 48))	('ROS1', 'Gene', (85, 89))	('adenocarcinoma', 'Disease', 'MESH:D000230', (193, 207))	('ROS1', 'Gene', '6098', (85, 89))	('carcinoma', 'Phenotype', 'HP:0030731', (198, 207))	('RET', 'Gene', (126, 129))	('MET', 'Var', (170, 173))	('ALK', 'Gene', (45, 48))	('adenocarcinoma', 'Disease', (193, 207))	('RET', 'Gene', '5979', (126, 129))
362338	29113230	In the squamous cell carcinoma: ALK, 2% of neoplastic rearranged cells; ROS1, 0% of neoplastic rearranged cells; RET, 0% of neoplastic rearranged cells; and MET, MET/CEP7=1.	('RET', 'Gene', '5979', (113, 116))	('ALK', 'Gene', (32, 35))	('squamous cell carcinoma', 'Disease', (7, 30))	('RET', 'Gene', (113, 116))	('ALK', 'Gene', '238', (32, 35))	('ROS1', 'Gene', (72, 76))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (7, 30))	('ROS1', 'Gene', '6098', (72, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (21, 30))	('MET', 'Var', (157, 160))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (7, 30))
362344	29113230	Patients with EGFR mutant lung adenocarcinoma treated with TKI typically develop resistance within 1 year of treatment.	('EGFR', 'Gene', '1956', (14, 18))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (26, 45))	('EGFR', 'Gene', (14, 18))	('resistance', 'MPA', (81, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (36, 45))	('Patients', 'Species', '9606', (0, 8))	('lung adenocarcinoma', 'Disease', (26, 45))	('mutant', 'Var', (19, 25))	('develop', 'Reg', (73, 80))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (26, 45))
362346	29113230	The present report describes the case of a patient with lung adenocarcinoma treated with afatinib who developed the T790M mutation and squamous cell transformation.	('carcinoma', 'Phenotype', 'HP:0030731', (66, 75))	('patient', 'Species', '9606', (43, 50))	('afatinib', 'Chemical', 'MESH:D000077716', (89, 97))	('lung adenocarcinoma', 'Disease', (56, 75))	('T790M', 'Mutation', 'rs121434569', (116, 121))	('squamous cell transformation', 'CPA', (135, 163))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (56, 75))	('T790M', 'Var', (116, 121))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (56, 75))
362347	29113230	To date, only a few cases of squamous cell transformation, with and without concomitant T790M, have been reported in response to erlotinib and gefitinib, and no similar cases have been reported in response to afatinib.	('squamous cell', 'Disease', (29, 42))	('gefitinib', 'Chemical', 'MESH:D000077156', (143, 152))	('T790M', 'Mutation', 'rs121434569', (88, 93))	('afatinib', 'Chemical', 'MESH:D000077716', (209, 217))	('T790M', 'Var', (88, 93))	('erlotinib', 'Chemical', 'MESH:D000069347', (129, 138))
362348	29113230	Longo et al recently reported a case of lung cell adenocarcinoma positive for the EGFR exon 21 L858R mutation, who, following TKI treatment, developed squamous cell carcinoma change together with an EGFR exon 20 S768I secondary mutation.	('L858R mutation', 'Var', (95, 109))	('EGFR', 'Gene', (82, 86))	('squamous cell carcinoma change', 'Disease', (151, 181))	('EGFR', 'Gene', (199, 203))	('developed', 'PosReg', (141, 150))	('L858R', 'Mutation', 'rs121434568', (95, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (55, 64))	('S768I', 'Var', (212, 217))	('lung cell adenocarcinoma', 'Disease', (40, 64))	('positive', 'Reg', (65, 73))	('lung cell adenocarcinoma', 'Disease', 'MESH:D000077192', (40, 64))	('S768I', 'Mutation', 'rs121913465', (212, 217))	('carcinoma', 'Phenotype', 'HP:0030731', (165, 174))	('EGFR', 'Gene', '1956', (82, 86))	('mutation', 'Var', (101, 109))	('squamous cell carcinoma change', 'Disease', 'MESH:D002294', (151, 181))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (151, 174))	('EGFR', 'Gene', '1956', (199, 203))
362351	29113230	However, lung adenocarcinoma exhibits a different molecular landscape compared with squamous cell carcinoma, for instance EGFR mutations are present in 10-40% of cases of adenocarcinoma, but rarely in squamous cell carcinoma.	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (9, 28))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (201, 224))	('squamous cell carcinoma', 'Disease', (84, 107))	('EGFR', 'Gene', (122, 126))	('adenocarcinoma', 'Disease', (171, 185))	('carcinoma', 'Phenotype', 'HP:0030731', (215, 224))	('squamous cell carcinoma', 'Disease', (201, 224))	('adenocarcinoma', 'Disease', (14, 28))	('mutations', 'Var', (127, 136))	('adenocarcinoma', 'Disease', 'MESH:D000230', (171, 185))	('lung adenocarcinoma', 'Disease', (9, 28))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (84, 107))	('EGFR', 'Gene', '1956', (122, 126))	('adenocarcinoma', 'Disease', 'MESH:D000230', (14, 28))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (201, 224))	('carcinoma', 'Phenotype', 'HP:0030731', (19, 28))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (9, 28))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (84, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (176, 185))
362353	29113230	Furthermore, all the tumour lesions were extensively characterized from a molecular point of view and the only difference was the presence of the T790M mutation, which was detected only in the post-TKI adenocarcinoma specimen.	('T790M', 'Var', (146, 151))	('tumour lesions', 'Disease', 'MESH:D009062', (21, 35))	('tumour', 'Phenotype', 'HP:0002664', (21, 27))	('tumour lesions', 'Disease', (21, 35))	('carcinoma', 'Phenotype', 'HP:0030731', (207, 216))	('adenocarcinoma', 'Disease', (202, 216))	('adenocarcinoma', 'Disease', 'MESH:D000230', (202, 216))	('T790M', 'Mutation', 'rs121434569', (146, 151))
362356	29113230	In the present context, a single tumour biopsy, limited by the presence of geographic heterogeneity, may be inadequate to detect all cancer gene mutations, explaining the lack of a direct correlation between molecular alteration and clinical efficacy of treatment.	('tumour', 'Disease', (33, 39))	('mutations', 'Var', (145, 154))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('cancer', 'Disease', (133, 139))	('tumour', 'Phenotype', 'HP:0002664', (33, 39))	('tumour', 'Disease', 'MESH:D009369', (33, 39))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
362358	29113230	In the present case report, as soon as the patient experienced clinical progression, activating and resistance mutations became detectable on ctDNA, supporting its value in agreement with previously published data.	('activating', 'MPA', (85, 95))	('resistance mutations', 'Var', (100, 120))	('patient', 'Species', '9606', (43, 50))
362509	33361747	For example, high expression of FGF19 may promote breast cancer progression by activating Akt signaling in cells, resulting in a discouraging prognosis for individuals with the disease.	('Akt', 'Gene', (90, 93))	('activating', 'PosReg', (79, 89))	('high expression', 'Var', (13, 28))	('breast cancer', 'Phenotype', 'HP:0003002', (50, 63))	('breast cancer', 'Disease', 'MESH:D001943', (50, 63))	('promote', 'PosReg', (42, 49))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('breast cancer', 'Disease', (50, 63))	('FGF19', 'Gene', '9965', (32, 37))	('Akt', 'Gene', '207', (90, 93))	('FGF19', 'Gene', (32, 37))
362531	33361747	Supplementary Figure 1 shows the expression of DEGs and IRDEGs in LSCC.	('DEGs', 'Var', (47, 51))	('men', 'Species', '9606', (6, 9))	('IRDEGs', 'Var', (56, 62))
362578	33361747	In terms of prognosis, not only was the OS rate in the high-risk score group significantly lower than in low-risk score group, but the risk curve showed that there were significantly fewer deaths in patients with lower risk scores.	('lower', 'NegReg', (91, 96))	('deaths', 'Disease', 'MESH:D003643', (189, 195))	('deaths', 'Disease', (189, 195))	('OS rate', 'MPA', (40, 47))	('fewer', 'NegReg', (183, 188))	('high-risk', 'Var', (55, 64))	('patients', 'Species', '9606', (199, 207))
362581	33361747	Among them, BTC is considered to promote the development of head and neck squamous cell carcinoma (HNSCC) and has been shown to be a prognostic risk factor in patients with the disease; this was confirmed by our research.	('HNSCC', 'Disease', 'MESH:D000077195', (99, 104))	('promote', 'PosReg', (33, 40))	('men', 'Species', '9606', (52, 55))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (60, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('neck squamous cell carcinoma', 'Disease', (69, 97))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (74, 97))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (69, 97))	('patients', 'Species', '9606', (159, 167))	('HNSCC', 'Disease', (99, 104))	('BTC', 'Var', (12, 15))
362678	31850229	They were LINC00377, LINC00536, LINC01224, LINC00668, LINC01234, LINC02037, and LINC01456 and the cluster dendrogram for these lncRNA is shown in Figure 2.	('LINC00536', 'Gene', (21, 30))	('LINC01234', 'Gene', (54, 63))	('LINC01456', 'Gene', '105373144', (80, 89))	('LINC01224', 'Gene', '104472717', (32, 41))	('LINC01224', 'Gene', (32, 41))	('LINC00536', 'Gene', '100859921', (21, 30))	('LINC00668', 'Gene', '400643', (43, 52))	('LINC00377', 'Gene', '103724386', (10, 19))	('LINC01234', 'Gene', '100506465', (54, 63))	('LINC01456', 'Gene', (80, 89))	('LINC02037', 'Var', (65, 74))	('LINC00377', 'Gene', (10, 19))	('LINC00668', 'Gene', (43, 52))
362680	31850229	Of these seven lncRNAs obtained by Cox-regression analysis, five (LINC00536, LINC00668, LINC01234, LINC02037, and LINC01456) showed positive coefficients, suggesting that these lncRNAs have a higher risk and their expression corresponds to the shorter OS in BRCA patients.	('BRCA', 'Phenotype', 'HP:0003002', (258, 262))	('BRCA', 'Gene', '672', (258, 262))	('LINC01234', 'Gene', (88, 97))	('patients', 'Species', '9606', (263, 271))	('BRCA', 'Gene', (258, 262))	('LINC00536', 'Gene', (66, 75))	('LINC02037', 'Var', (99, 108))	('Cox', 'Gene', '1351', (35, 38))	('LINC01456', 'Gene', '105373144', (114, 123))	('LINC00536', 'Gene', '100859921', (66, 75))	('LINC00668', 'Gene', '400643', (77, 86))	('Cox', 'Gene', (35, 38))	('LINC01456', 'Gene', (114, 123))	('LINC00668', 'Gene', (77, 86))	('LINC01234', 'Gene', '100506465', (88, 97))
362704	31850229	Finally, BRCA prognostic risk prediction model was constructed using seven lncRNAs (LINC00377, LINC00536, LINC01224, LINC00668, LINC01234, LINC02037, and LINC01456).	('LINC02037', 'Var', (139, 148))	('LINC01234', 'Gene', (128, 137))	('LINC01456', 'Gene', (154, 163))	('LINC00377', 'Gene', '103724386', (84, 93))	('LINC00536', 'Gene', '100859921', (95, 104))	('LINC01234', 'Gene', '100506465', (128, 137))	('LINC00377', 'Gene', (84, 93))	('BRCA', 'Phenotype', 'HP:0003002', (9, 13))	('BRCA', 'Gene', '672', (9, 13))	('LINC00668', 'Gene', (117, 126))	('LINC01224', 'Gene', '104472717', (106, 115))	('LINC01224', 'Gene', (106, 115))	('BRCA', 'Gene', (9, 13))	('LINC01456', 'Gene', '105373144', (154, 163))	('LINC00536', 'Gene', (95, 104))	('LINC00668', 'Gene', '400643', (117, 126))
362708	31850229	showed that in laryngeal squamous cell carcinoma, the expression levels of LINC00668 were associated with age, pathological differentiation degree, T stage, clinical stage, and cervical lymph node metastasis, and using a series of bioinformatics tools and in vitro experiments, proved that knockdown of LINC00668 can inhibit the proliferation, migration, and invasion ability of laryngeal squamous cell carcinoma cells.	('expression', 'MPA', (54, 64))	('LINC00668', 'Gene', (75, 84))	('squamous cell carcinoma', 'Disease', (25, 48))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (389, 412))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (25, 48))	('squamous cell carcinoma', 'Disease', (389, 412))	('migration', 'CPA', (344, 353))	('cervical lymph node metastasis', 'Phenotype', 'HP:0025289', (177, 207))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (389, 412))	('LINC00668', 'Gene', (303, 312))	('carcinoma', 'Phenotype', 'HP:0030731', (403, 412))	('associated', 'Reg', (90, 100))	('knockdown', 'Var', (290, 299))	('LINC00668', 'Gene', '400643', (75, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (39, 48))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (25, 48))	('inhibit', 'NegReg', (317, 324))	('LINC00668', 'Gene', '400643', (303, 312))
362710	31850229	found that knockdown of LINC00668 significantly inhibited the proliferation of gastric cancer cells in vitro and in vivo, and the significant increase in expression was associated with gastric cancer outcomes and prognosis.	('gastric cancer', 'Phenotype', 'HP:0012126', (185, 199))	('gastric cancer', 'Disease', 'MESH:D013274', (79, 93))	('increase', 'PosReg', (142, 150))	('LINC00668', 'Gene', (24, 33))	('gastric cancer', 'Phenotype', 'HP:0012126', (79, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('associated', 'Reg', (169, 179))	('gastric cancer', 'Disease', (185, 199))	('inhibited', 'NegReg', (48, 57))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('LINC00668', 'Gene', '400643', (24, 33))	('gastric cancer', 'Disease', 'MESH:D013274', (185, 199))	('gastric cancer', 'Disease', (79, 93))	('knockdown', 'Var', (11, 20))	('expression', 'MPA', (154, 164))
362716	31850229	Furthermore, knockdown of LINC01234 induced apoptosis, arrested growth, and inhibited tumorigenesis in mouse xenografts.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('induced', 'Reg', (36, 43))	('LINC01234', 'Gene', '100506465', (26, 35))	('arrested growth', 'Phenotype', 'HP:0001510', (55, 70))	('tumor', 'Disease', (86, 91))	('apoptosis', 'CPA', (44, 53))	('mouse', 'Species', '10090', (103, 108))	('LINC01234', 'Gene', (26, 35))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('arrested', 'NegReg', (55, 63))	('knockdown', 'Var', (13, 22))	('growth', 'CPA', (64, 70))	('inhibited', 'NegReg', (76, 85))
362718	31850229	ZMYND10, a candidate tumor suppressor gene, is frequently downregulated in nasopharyngeal carcinoma and many other tumors like gastric cancer, due to hypermethylation of the promoter.	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('tumor', 'Disease', (21, 26))	('tumor', 'Disease', (115, 120))	('carcinoma', 'Disease', (90, 99))	('downregulated', 'NegReg', (58, 71))	('gastric cancer', 'Disease', (127, 141))	('hypermethylation', 'Var', (150, 166))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (75, 99))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('ZMYND10', 'Gene', '51364', (0, 7))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('gastric cancer', 'Disease', 'MESH:D013274', (127, 141))	('carcinoma', 'Disease', 'MESH:D009369', (90, 99))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumors', 'Disease', (115, 121))	('gastric cancer', 'Phenotype', 'HP:0012126', (127, 141))	('tumors', 'Disease', 'MESH:D009369', (115, 121))	('ZMYND10', 'Gene', (0, 7))
362722	31850229	So far, no studies have reported any association between LINC00377, LINC00536, LINC01224, and LINC02037, and cancer.	('LINC02037', 'Var', (94, 103))	('LINC00377', 'Gene', '103724386', (57, 66))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('LINC00536', 'Gene', '100859921', (68, 77))	('LINC00377', 'Gene', (57, 66))	('cancer', 'Disease', (109, 115))	('LINC01224', 'Gene', '104472717', (79, 88))	('LINC01224', 'Gene', (79, 88))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('LINC00536', 'Gene', (68, 77))
362731	31850229	showed that LINC01224 is associated with the expression of RIPPLY3, LINC02037 is associated with the expression of CEACAM7, and CEACAM7 is found to be a potential prognostic biomarker for colorectal cancer.	('LINC01224', 'Gene', '104472717', (12, 21))	('colorectal cancer', 'Disease', (188, 205))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('LINC01224', 'Gene', (12, 21))	('associated', 'Reg', (25, 35))	('RIPPLY3', 'Gene', (59, 66))	('CEACAM7', 'Gene', '1087', (128, 135))	('CEACAM7', 'Gene', '1087', (115, 122))	('colorectal cancer', 'Disease', 'MESH:D015179', (188, 205))	('LINC02037', 'Var', (68, 77))	('CEACAM7', 'Gene', (128, 135))	('CEACAM7', 'Gene', (115, 122))	('colorectal cancer', 'Phenotype', 'HP:0003003', (188, 205))	('RIPPLY3', 'Gene', '53820', (59, 66))	('associated', 'Reg', (81, 91))
362776	31348244	1ug total RNA was used to be transformed into single-strand DNA labeled with Cy3-dCTP or Cy5-dCTP (GE Healthcare, Piscataway, NJ) through various steps (The procedure was depicted in Fig.	('Cy5-dCTP', 'Chemical', 'MESH:C544355', (89, 97))	('Cy3-dCTP', 'Var', (77, 85))	('Cy5-dCTP', 'Var', (89, 97))
362833	31348244	We found that high expression of LINC01614 was significantly associated with poor OS.	('LINC01614', 'Gene', (33, 42))	('high', 'Var', (14, 18))	('poor OS', 'Disease', (77, 84))	('associated', 'Reg', (61, 71))	('LINC01614', 'Gene', '105373869', (33, 42))
362843	31348244	And the release of non-coding RNAs into the blood is thought to be associated with apoptosis and necrosis of tumor cells from the tumor microenvironment and is also the result of secretion.	('release', 'MPA', (8, 15))	('necrosis of tumor', 'Disease', (97, 114))	('non-coding RNAs', 'Var', (19, 34))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('associated', 'Reg', (67, 77))	('apoptosis', 'CPA', (83, 92))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('necrosis of tumor', 'Disease', 'MESH:D009336', (97, 114))	('tumor', 'Disease', (130, 135))	('tumor', 'Disease', (109, 114))
362939	32334459	These carcinogenic changes may lead to decreased lactate to pyruvate conversion resulting in anomaly in the regeneration of nicotinamide adenine dinucleotide (NAD+) which may interfere with glycolysis part of carbohydrate metabolism (Kavyashree et al., 2016; Joshi and Golgire, 2014).	('carbohydrate', 'Chemical', 'MESH:D002241', (209, 221))	('glycolysis', 'MPA', (190, 200))	('lactate to pyruvate conversion', 'MPA', (49, 79))	('nicotinamide adenine dinucleotide', 'Chemical', 'MESH:D009243', (124, 157))	('changes', 'Var', (19, 26))	('anomaly', 'Disease', (93, 100))	('interfere', 'NegReg', (175, 184))	('NAD+', 'Chemical', 'MESH:D009243', (159, 163))	('regeneration of nicotinamide adenine dinucleotide', 'MPA', (108, 157))	('anomaly', 'Disease', 'MESH:D000014', (93, 100))	('decreased', 'NegReg', (39, 48))	('lactate', 'Chemical', 'MESH:D019344', (49, 56))	('pyruvate', 'Chemical', 'MESH:D019289', (60, 68))
363001	32334459	The study revealed that occurrence of squamous cell carcinoma was high in those cases in which the level of serum and salivary ALP 500 and 50 IU/L respectively and further reveled LR>1, sensitivity 83%, specificity 79% in serum ALP and LR>1 and sensitivity 80%, specificity 73% in salivary ALP with significant p value of less than 0.01.	('carcinoma', 'Phenotype', 'HP:0030731', (52, 61))	('ALP', 'Gene', '250', (127, 130))	('ALP', 'Gene', (228, 231))	('ALP', 'Gene', (290, 293))	('ALP', 'Gene', (127, 130))	('ALP', 'Gene', '250', (228, 231))	('LR>1', 'Var', (180, 184))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (38, 61))	('ALP', 'Gene', '250', (290, 293))	('squamous cell carcinoma', 'Disease', (38, 61))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (38, 61))
363022	32334459	Aminian et al., (2011) retrospectively examined serum ALP in esophageal carcinoma and found that mean ALP was higher in patients with LNM (141 U/L) than with negative node involvement (116 U/L), with a mean difference of (25 U/L).	('esophageal carcinoma', 'Disease', (61, 81))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (61, 81))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (61, 81))	('ALP', 'Gene', (54, 57))	('ALP', 'Gene', (102, 105))	('ALP', 'Gene', '250', (54, 57))	('LNM (141 U/L', 'Var', (134, 146))	('patients', 'Species', '9606', (120, 128))	('higher', 'PosReg', (110, 116))	('ALP', 'Gene', '250', (102, 105))
363052	31504061	Loss-of-function mutations in the genes encoding SWI/SNF subunits have been reported in more than 20% of human cancers.	('cancers', 'Disease', 'MESH:D009369', (111, 118))	('Loss-of-function', 'NegReg', (0, 16))	('cancers', 'Phenotype', 'HP:0002664', (111, 118))	('cancers', 'Disease', (111, 118))	('SWI/SNF', 'Gene', (49, 56))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('human', 'Species', '9606', (105, 110))	('mutations', 'Var', (17, 26))
363063	31504061	Loss-of-function mutations in the genes encoding SWI/SNF subunits are reported in more than 20% of human cancers, and the critical tumor suppressive role of the SWI/SNF complex has been widely acknowledged.	('Loss-of-function', 'NegReg', (0, 16))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('cancers', 'Phenotype', 'HP:0002664', (105, 112))	('SWI/SNF', 'Gene', (49, 56))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('cancers', 'Disease', (105, 112))	('cancers', 'Disease', 'MESH:D009369', (105, 112))	('tumor', 'Disease', (131, 136))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('mutations', 'Var', (17, 26))	('human', 'Species', '9606', (99, 104))
363066	31504061	These results suggested that not all of the genes encoding the subunits of the SWI/SNF complex have loss-of-function mutations in cancer.	('mutations', 'Var', (117, 126))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('cancer', 'Disease', (130, 136))	('loss-of-function', 'NegReg', (100, 116))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))
363078	31504061	Moreover, to make the result more convincing, three additional gene expression datasets (GSE120235, GSE129437 and GSE79284) for BRD9 KD based on 4 different tumor cell lines (G401, MV4-11, HL-60, RN2) were also download, and the following analysis were also performed next.	('tumor', 'Disease', (157, 162))	('SE', 'Disease', 'None', (90, 92))	('KD', 'Disease', 'MESH:C537017', (133, 135))	('SE', 'Disease', 'None', (115, 117))	('SE', 'Disease', 'None', (101, 103))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('RN2', 'CellLine', 'CVCL:4293', (196, 199))	('HL-60', 'CellLine', 'CVCL:0002', (189, 194))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('BRD9', 'Var', (128, 132))	('G401', 'CellLine', 'CVCL:0270', (175, 179))
363085	31504061	The relationship between the mRNA expression level and copy number variation of ACTL6A or BRD9 was described by boxplots using TIMER (http://cistrome.dfci.harvard.edu/TIMER/).	('BRD9', 'Gene', (90, 94))	('ACTL6A', 'Gene', '86', (80, 86))	('copy number variation', 'Var', (55, 76))	('mRNA expression level', 'MPA', (29, 50))	('ACTL6A', 'Gene', (80, 86))
363092	31504061	As shown in Fig 2, SWI/SNF complex genes tended to have point mutations in some cancers, such as melanoma (26.97%), clear cell renal cell carcinoma (ccRCC) (26.77%) and stomach cancer (24.06%).	('melanoma', 'Phenotype', 'HP:0002861', (97, 105))	('melanoma', 'Disease', (97, 105))	('cancers', 'Disease', 'MESH:D009369', (80, 87))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (116, 147))	('stomach cancer', 'Disease', (169, 183))	('cancers', 'Phenotype', 'HP:0002664', (80, 87))	('melanoma', 'Disease', 'MESH:D008545', (97, 105))	('cancers', 'Disease', (80, 87))	('clear cell renal cell carcinoma', 'Disease', (116, 147))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (127, 147))	('ccRCC', 'Phenotype', 'HP:0006770', (149, 154))	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('SWI/SNF complex genes', 'Gene', (19, 40))	('stomach cancer', 'Disease', 'MESH:D013274', (169, 183))	('stomach cancer', 'Phenotype', 'HP:0012126', (169, 183))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (116, 147))	('point mutations', 'Var', (56, 71))
363093	31504061	However, there are a variety of cancer types in which the genetic alterations of the SWI/SNF complex tended to have copy number variations, particularly amplifications, such as in lung squamous cell carcinoma (61.06%), ovarian cancer (58.71%), sarcoma (47.89%), esophageal cancer (40.32%), cervical cancer (35.48%), head and neck cancer (32.45%), breast cancer (32.13%), bladder cancer (33.41%), lung adenocarcinoma (31.39%), stomach cancer (29.70%), uterine cancer (26.28%), glioma (23.87%), liver cancer (23.08%) and prostate cancer (22.58%) (Fig 2A).	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (185, 208))	('cancer', 'Disease', 'MESH:D009369', (459, 465))	('stomach cancer', 'Disease', (426, 440))	('carcinoma', 'Phenotype', 'HP:0030731', (406, 415))	('copy number variations', 'Var', (116, 138))	('prostate cancer', 'Disease', 'MESH:D011471', (519, 534))	('breast cancer', 'Phenotype', 'HP:0003002', (347, 360))	('prostate cancer', 'Phenotype', 'HP:0012125', (519, 534))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (396, 415))	('cancer', 'Disease', 'MESH:D009369', (330, 336))	('cancer', 'Disease', 'MESH:D009369', (227, 233))	('ovarian cancer', 'Disease', (219, 233))	('sarcoma', 'Disease', 'MESH:D012509', (244, 251))	('cancer', 'Disease', 'MESH:D009369', (434, 440))	('cancer', 'Disease', 'MESH:D009369', (299, 305))	('cancer', 'Disease', 'MESH:D009369', (354, 360))	('alterations', 'Var', (66, 77))	('carcinoma', 'Phenotype', 'HP:0030731', (199, 208))	('prostate cancer', 'Disease', (519, 534))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (396, 415))	('sarcoma', 'Disease', (244, 251))	('cancer', 'Disease', 'MESH:D009369', (273, 279))	('cancer', 'Disease', (32, 38))	('glioma', 'Phenotype', 'HP:0009733', (476, 482))	('ovarian cancer', 'Phenotype', 'HP:0100615', (219, 233))	('breast cancer', 'Disease', 'MESH:D001943', (347, 360))	('cancer', 'Disease', 'MESH:D009369', (528, 534))	('variations', 'Var', (128, 138))	('breast cancer', 'Disease', (347, 360))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('liver cancer', 'Disease', 'MESH:D006528', (493, 505))	('stomach cancer', 'Disease', 'MESH:D013274', (426, 440))	('stomach cancer', 'Phenotype', 'HP:0012126', (426, 440))	('cancer', 'Disease', (379, 385))	('cancer', 'Disease', (499, 505))	('cancer', 'Disease', (434, 440))	('cervical cancer', 'Disease', 'MESH:D002583', (290, 305))	('sarcoma', 'Phenotype', 'HP:0100242', (244, 251))	('cancer', 'Disease', (459, 465))	('cervical cancer', 'Disease', (290, 305))	('glioma', 'Disease', (476, 482))	('uterine cancer', 'Phenotype', 'HP:0010784', (451, 465))	('bladder cancer', 'Disease', 'MESH:D001749', (371, 385))	('esophageal cancer', 'Disease', 'MESH:D004938', (262, 279))	('liver cancer', 'Phenotype', 'HP:0002896', (493, 505))	('cancer', 'Disease', (227, 233))	('glioma', 'Disease', 'MESH:D005910', (476, 482))	('bladder cancer', 'Disease', (371, 385))	('cancer', 'Disease', (299, 305))	('cancer', 'Disease', (330, 336))	('cancer', 'Disease', (354, 360))	('liver cancer', 'Disease', (493, 505))	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('cancer', 'Disease', (273, 279))	('head and neck cancer', 'Phenotype', 'HP:0012288', (316, 336))	('esophageal cancer', 'Disease', (262, 279))	('cancer', 'Phenotype', 'HP:0002664', (330, 336))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('lung adenocarcinoma', 'Disease', (396, 415))	('ovarian cancer', 'Disease', 'MESH:D010051', (219, 233))	('bladder cancer', 'Phenotype', 'HP:0009725', (371, 385))	('cancer', 'Phenotype', 'HP:0002664', (299, 305))	('cancer', 'Disease', (528, 534))	('neck cancer', 'Disease', 'MESH:D006258', (325, 336))	('neck cancer', 'Disease', (325, 336))	('cancer', 'Phenotype', 'HP:0002664', (273, 279))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (180, 208))	('SWI/SNF', 'Gene', (85, 92))	('cancer', 'Disease', 'MESH:D009369', (379, 385))	('cancer', 'Disease', 'MESH:D009369', (499, 505))	('lung squamous cell carcinoma', 'Disease', (180, 208))
363094	31504061	These results suggested that the amplification of distinct genes was the main alteration type in most cancers, and the subunits of SWI/SNF complexes may play an essential oncogenic role in cancers.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('play', 'Reg', (153, 157))	('amplification', 'Var', (33, 46))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('cancers', 'Phenotype', 'HP:0002664', (189, 196))	('cancers', 'Disease', 'MESH:D009369', (102, 109))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))	('cancers', 'Disease', (102, 109))	('cancers', 'Disease', 'MESH:D009369', (189, 196))	('cancers', 'Disease', (189, 196))
363095	31504061	Different types of genetic alterations occurred more frequently in some subunits within the SWI/SNF complex in some cancers.	('occurred', 'Reg', (39, 47))	('genetic alterations', 'Var', (19, 38))	('cancers', 'Disease', 'MESH:D009369', (116, 123))	('cancers', 'Phenotype', 'HP:0002664', (116, 123))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cancers', 'Disease', (116, 123))	('SWI/SNF', 'Gene', (92, 99))
363102	31504061	These results demonstrated that the different mutations of each subunit played distinct roles in different cancer types.	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('cancer', 'Disease', (107, 113))	('mutations', 'Var', (46, 55))	('cancer', 'Disease', 'MESH:D009369', (107, 113))
363103	31504061	In addition, the amplification of ACTL6A and BRD9 commonly occurred in multiple cancers and may play crucial roles in tumor formation.	('play', 'Reg', (96, 100))	('ACTL6A', 'Gene', '86', (34, 40))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('multiple cancers', 'Disease', 'MESH:D009369', (71, 87))	('roles', 'Reg', (109, 114))	('multiple cancers', 'Disease', (71, 87))	('tumor', 'Disease', (118, 123))	('ACTL6A', 'Gene', (34, 40))	('amplification', 'Var', (17, 30))	('occurred', 'Reg', (59, 67))	('BRD9', 'Gene', (45, 49))	('cancers', 'Phenotype', 'HP:0002664', (80, 87))
363104	31504061	To determine whether the increased copy number of ACTL6A and BRD9 led to an increase in their expression levels, we acquired two pan-cancer boxplots (Fig 3) regarding the difference of these two genes expression between normal and tumor tissues from Tumor IMmune Estimation Resource (Timer).	('tumor', 'Disease', 'MESH:D009369', (231, 236))	('increase', 'PosReg', (76, 84))	('increased', 'PosReg', (25, 34))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('ACTL6A', 'Gene', (50, 56))	('expression levels', 'MPA', (94, 111))	('tumor', 'Disease', (231, 236))	('cancer', 'Disease', (133, 139))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('Tumor', 'Phenotype', 'HP:0002664', (250, 255))	('BRD9', 'Gene', (61, 65))	('copy number', 'Var', (35, 46))	('ACTL6A', 'Gene', '86', (50, 56))
363108	31504061	However, according to the chi-square test, we still can not make a conclusion that the protein levels are increased with the amplification of the copy number of ACTL6A or BRD9 due to the limited sample size and qualitative data (p value > 0.05).	('amplification', 'Var', (125, 138))	('ACTL6A', 'Gene', '86', (161, 167))	('copy number', 'Var', (146, 157))	('ACTL6A', 'Gene', (161, 167))	('increased', 'PosReg', (106, 115))	('protein levels', 'MPA', (87, 101))	('BRD9', 'Gene', (171, 175))
363111	31504061	Regarding ACTL6A, we found that ACTL6A expression might significantly affect the survival time of patients with pancreatic cancer (HR, 1.88; 95% CI, 1.21 to 2.94), brain lower grade glioma (HR, 1.85; 95% CI, 1.13 to 3.01), lung adenocarcinoma (HR, 1.59; 95% CI, 1.04 to 2.43), and sarcoma (HR, 1.61; 95% CI, 1.06 to 2.46) (Fig 4A).	('affect', 'Reg', (70, 76))	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('glioma', 'Phenotype', 'HP:0009733', (182, 188))	('ACTL6A', 'Gene', (10, 16))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (112, 129))	('ACTL6A', 'Gene', (32, 38))	('ACTL6A', 'Gene', '86', (10, 16))	('ACTL6A', 'Gene', '86', (32, 38))	('lung adenocarcinoma', 'Disease', (223, 242))	('patients', 'Species', '9606', (98, 106))	('sarcoma', 'Disease', 'MESH:D012509', (281, 288))	('glioma', 'Disease', (182, 188))	('sarcoma', 'Disease', (281, 288))	('pancreatic cancer', 'Disease', 'MESH:D010190', (112, 129))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (223, 242))	('survival time', 'CPA', (81, 94))	('expression', 'Var', (39, 49))	('glioma', 'Disease', 'MESH:D005910', (182, 188))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (223, 242))	('pancreatic cancer', 'Disease', (112, 129))	('carcinoma', 'Phenotype', 'HP:0030731', (233, 242))	('sarcoma', 'Phenotype', 'HP:0100242', (281, 288))
363113	31504061	To study how the cancer cells were affected by the genetic alteration of BRD9 or ACTL6A, we performed KEGG analysis and GSEA analysis.	('BRD9', 'Gene', (73, 77))	('ACTL6A', 'Gene', (81, 87))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('cancer', 'Disease', (17, 23))	('GSEA', 'Chemical', '-', (120, 124))	('genetic alteration', 'Var', (51, 69))	('ACTL6A', 'Gene', '86', (81, 87))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
363116	31504061	These results indicated that the amplification of both BRD9 and ACTL6A affect these essential biological pathways in human cancers.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('ACTL6A', 'Gene', '86', (64, 70))	('BRD9', 'Gene', (55, 59))	('human', 'Species', '9606', (117, 122))	('amplification', 'Var', (33, 46))	('essential biological pathways', 'Pathway', (84, 113))	('affect', 'Reg', (71, 77))	('cancers', 'Disease', 'MESH:D009369', (123, 130))	('cancers', 'Phenotype', 'HP:0002664', (123, 130))	('ACTL6A', 'Gene', (64, 70))	('cancers', 'Disease', (123, 130))
363123	31504061	Moreover, the results of KEGG analyses for additional 3 datasets for BRD9 knockdown were associated to oxidoreductase activity in hl60 cell line, ribosome biogenesis in RN2 cell line, and also related to the translation in G401 cell line.	('BRD9', 'Gene', (69, 73))	('associated', 'Reg', (89, 99))	('RN2', 'CellLine', 'CVCL:4293', (169, 172))	('ribosome biogenesis', 'MPA', (146, 165))	('oxidoreductase activity', 'MPA', (103, 126))	('knockdown', 'Var', (74, 83))	('G401', 'CellLine', 'CVCL:0270', (223, 227))
363124	31504061	Within the 3 cancer types (ovarian cancer, esophageal cancer and lung adenocarcinoma) that were commonly mutated in BRD9 and ACTL6A, a significant comutation relationship (p<0.001, log odds ratio = 1.051) was also shown in BRD9 and ACTL6A (Fig 7), which suggested that they may drive the oncogenic process together by affecting the same pathways.	('ACTL6A', 'Gene', (232, 238))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('oncogenic process', 'CPA', (288, 305))	('cancer', 'Disease', 'MESH:D009369', (13, 19))	('ovarian cancer', 'Disease', 'MESH:D010051', (27, 41))	('ACTL6A', 'Gene', '86', (232, 238))	('esophageal cancer', 'Disease', 'MESH:D004938', (43, 60))	('drive', 'Reg', (278, 283))	('esophageal cancer', 'Disease', (43, 60))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('ACTL6A', 'Gene', (125, 131))	('ovarian cancer', 'Disease', (27, 41))	('lung adenocarcinoma', 'Disease', (65, 84))	('ovarian cancer', 'Phenotype', 'HP:0100615', (27, 41))	('cancer', 'Disease', (54, 60))	('cancer', 'Disease', (13, 19))	('ACTL6A', 'Gene', '86', (125, 131))	('mutated', 'Var', (105, 112))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('affecting', 'Reg', (318, 327))	('BRD9', 'Gene', (223, 227))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (65, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (65, 84))	('cancer', 'Disease', (35, 41))
363126	31504061	This result suggests that the amplification of ACTL6A and TP63 could be a common oncogenic mechanism across human cancers.	('cancers', 'Disease', 'MESH:D009369', (114, 121))	('cancers', 'Phenotype', 'HP:0002664', (114, 121))	('cancers', 'Disease', (114, 121))	('ACTL6A', 'Gene', (47, 53))	('amplification', 'Var', (30, 43))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('human', 'Species', '9606', (108, 113))	('TP63', 'Gene', '8626', (58, 62))	('ACTL6A', 'Gene', '86', (47, 53))	('TP63', 'Gene', (58, 62))
363139	31504061	These results suggest that the amplification of BRD9 and ACTL6A could be a universal mechanism in human cancer and may play critical roles in tumor formation.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('BRD9', 'Gene', (48, 52))	('roles', 'Reg', (133, 138))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('ACTL6A', 'Gene', (57, 63))	('tumor', 'Disease', (142, 147))	('play', 'Reg', (119, 123))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('human', 'Species', '9606', (98, 103))	('ACTL6A', 'Gene', '86', (57, 63))	('cancer', 'Disease', (104, 110))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('amplification', 'Var', (31, 44))
363145	31504061	Some studies have illustrated that overexpressed ACTL6A promotes epithelial-mesenchymal transition (EMT) and invasion in multiple cancers, such as osteosarcoma, hepatocellular carcinoma, and glioma.	('hepatocellular carcinoma', 'Disease', (161, 185))	('overexpressed', 'Var', (35, 48))	('multiple cancers', 'Disease', 'MESH:D009369', (121, 137))	('sarcoma', 'Phenotype', 'HP:0100242', (152, 159))	('ACTL6A', 'Gene', (49, 55))	('osteosarcoma', 'Disease', (147, 159))	('epithelial-mesenchymal transition', 'CPA', (65, 98))	('osteosarcoma', 'Disease', 'MESH:D012516', (147, 159))	('ACTL6A', 'Gene', '86', (49, 55))	('promotes', 'PosReg', (56, 64))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (161, 185))	('multiple cancers', 'Disease', (121, 137))	('glioma', 'Disease', (191, 197))	('glioma', 'Disease', 'MESH:D005910', (191, 197))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (161, 185))	('invasion', 'CPA', (109, 117))	('osteosarcoma', 'Phenotype', 'HP:0002669', (147, 159))	('cancers', 'Phenotype', 'HP:0002664', (130, 137))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('glioma', 'Phenotype', 'HP:0009733', (191, 197))	('carcinoma', 'Phenotype', 'HP:0030731', (176, 185))
363150	31504061	Thus, we hypothesized that the aberrant overexpression of ACTL6A might reactivate some signaling pathways that occur during embryonic development and drive the oncogenic process.	('aberrant', 'Var', (31, 39))	('drive', 'PosReg', (150, 155))	('oncogenic process', 'CPA', (160, 177))	('overexpression', 'PosReg', (40, 54))	('reactivate', 'Reg', (71, 81))	('ACTL6A', 'Gene', '86', (58, 64))	('signaling pathways', 'Pathway', (87, 105))	('ACTL6A', 'Gene', (58, 64))
363155	31504061	For BRD9, we indicated remarkable copy number amplifications across multiple human cancers.	('cancers', 'Disease', 'MESH:D009369', (83, 90))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('BRD9', 'Gene', (4, 8))	('copy number amplifications', 'Var', (34, 60))	('cancers', 'Phenotype', 'HP:0002664', (83, 90))	('cancers', 'Disease', (83, 90))	('human', 'Species', '9606', (77, 82))
363156	31504061	The amplification of BRD9 may play a significant role in cancer.	('role', 'Reg', (49, 53))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('cancer', 'Disease', (57, 63))	('play', 'Reg', (30, 34))	('amplification', 'Var', (4, 17))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('BRD9', 'Gene', (21, 25))
363169	31504061	Increasing small-molecule inhibitors of bromodomain-containing protein, such as GSK2801 and BI9564, have been discovered in the past decade.	('BI9564', 'Var', (92, 98))	('BI9564', 'Chemical', 'MESH:C000619421', (92, 98))	('GSK2801', 'Gene', (80, 87))	('bromodomain-containing protein', 'Protein', (40, 70))
363172	31504061	Another study demonstrated that the inhibition of BRD9 acted in a synthetic lethal manner in cBAF-deficient cancer, and the inhibitor of BRD9 effectively decreased the proliferation of cancer cells in synovial sarcoma and malignant rhabdoid tumors.	('decreased', 'NegReg', (154, 163))	('proliferation', 'CPA', (168, 181))	('synovial sarcoma', 'Disease', 'MESH:D013584', (201, 217))	('cancer', 'Disease', (185, 191))	('cancer', 'Disease', 'MESH:D009369', (108, 114))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (201, 217))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('BRD9', 'Gene', (50, 54))	('malignant rhabdoid tumors', 'Disease', 'MESH:D018335', (222, 247))	('BRD9', 'Gene', (137, 141))	('cBAF-deficient cancer', 'Disease', (93, 114))	('inhibition', 'NegReg', (36, 46))	('tumors', 'Phenotype', 'HP:0002664', (241, 247))	('inhibitor', 'Var', (124, 133))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('cancer', 'Disease', (108, 114))	('malignant rhabdoid tumors', 'Disease', (222, 247))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))	('sarcoma', 'Phenotype', 'HP:0100242', (210, 217))	('cBAF-deficient cancer', 'Disease', 'MESH:D009369', (93, 114))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('synovial sarcoma', 'Disease', (201, 217))
363210	31262974	Synthetic miRNA mimics (Pre-193b-3p, Pre-193b-5p) and miRNA antisense inhibitors (Anti-193b-3p and Anti-193b-5p) were purchased from Ambion (U.S.A.).	('miR', 'Gene', '220972', (54, 57))	('miR', 'Gene', (54, 57))	('Anti-193b-5p', 'Var', (99, 111))	('Anti-193b-3p', 'Var', (82, 94))	('miR', 'Gene', '220972', (10, 13))	('miR', 'Gene', (10, 13))
363220	31262974	The expression levels of miR-193b-3p (MIMAT0002819) and miR-193b-5p (MIMAT0004767) were assessed using specific TaqMan primers (Applied Biosystems, U.S.A.).	('MIMAT0004767', 'Var', (69, 81))	('miR-193b', 'Gene', '574455', (56, 64))	('miR-193b', 'Gene', (56, 64))	('MIMAT0002819', 'Var', (38, 50))	('miR-193b', 'Gene', '574455', (25, 33))	('miR-193b', 'Gene', (25, 33))
363221	31262974	For reporter assay, we constructed dual luciferase vectors (pmirGLO dual-luciferase vector, Promega E1330) containing wild-type (WT) or mutated (MT) miR-193b-3p and miR-193b-5p binding sites (miRNA recognition element, MRE) in the 3'UTR of the target genes.	('miR-193b', 'Gene', (165, 173))	('miR-193b', 'Gene', '574455', (149, 157))	('miR-193b', 'Gene', '574455', (165, 173))	('miR', 'Gene', '220972', (192, 195))	('mir', 'Gene', '220972', (61, 64))	('miR', 'Gene', (192, 195))	('miR-193b', 'Gene', (149, 157))	('mir', 'Gene', (61, 64))	('miR', 'Gene', '220972', (165, 168))	('miR', 'Gene', (165, 168))	('miR', 'Gene', (149, 152))	('miR', 'Gene', '220972', (149, 152))	('mutated', 'Var', (136, 143))	('binding', 'Interaction', (177, 184))
363222	31262974	Mutated reporter vectors were constructed by substituting four or five nucleotides in the seed region, abolishing the interaction between miRNA and target mRNAs.	('abolishing', 'NegReg', (103, 113))	('interaction', 'Interaction', (118, 129))	('miR', 'Gene', '220972', (138, 141))	('miR', 'Gene', (138, 141))	('substituting', 'Var', (45, 57))
363223	31262974	Briefly, cells transfected with Con-miR or Pre-miR (Pre-193b-3p or Pre-193b-5p) were seeded into 24-well plates.	('miR', 'Gene', '220972', (47, 50))	('miR', 'Gene', (47, 50))	('Pre-193b-5p', 'Var', (67, 78))	('miR', 'Gene', '220972', (36, 39))	('Pre-193b-3p', 'Var', (52, 63))	('miR', 'Gene', (36, 39))
363235	31262974	To search differentially expressed miRNAs between PC14PE6 and PC14PE6/LvBr4 cells, we performed GeneChip miRNA 3.0 microarray (Thermo fisher Scientific, U.S.A.) and identified 25 miRNAs that were down-regulated in PC14PE6/LvBr4 cells (Supplementary Figure S1A).	('miR', 'Gene', (105, 108))	('PC14PE6', 'CellLine', 'CVCL:9W70', (214, 221))	('PC14PE6/LvBr4', 'CellLine', 'CVCL:9W70', (214, 227))	('down-regulated', 'NegReg', (196, 210))	('PC14PE6', 'CellLine', 'CVCL:9W70', (62, 69))	('miR', 'Gene', '220972', (179, 182))	('miR', 'Gene', (179, 182))	('miR', 'Gene', '220972', (35, 38))	('miR', 'Gene', (35, 38))	('PC14PE6/LvBr4', 'CellLine', 'CVCL:9W70', (62, 75))	('PC14PE6/LvBr4', 'Var', (214, 227))	('PC14PE6', 'CellLine', 'CVCL:9W70', (50, 57))	('miR', 'Gene', '220972', (105, 108))
363266	31262974	Similarly, the mRNA level of common target genes was higher in PC14PE6/LvBr4 cells than in parental PC14PE6 cells (Figure 3C).	('mRNA level of common', 'MPA', (15, 35))	('higher', 'PosReg', (53, 59))	('PC14PE6/LvBr4', 'Var', (63, 76))	('PC14PE6', 'CellLine', 'CVCL:9W70', (100, 107))	('PC14PE6', 'CellLine', 'CVCL:9W70', (63, 70))	('PC14PE6/LvBr4', 'CellLine', 'CVCL:9W70', (63, 76))
363287	31262974	Conversely, suppression of target genes by miR-193b-3p and -5p was abolished by the disruption of the direct binding between miR-193b and the 3'UTR of the target mRNAs by point mutations in the seed sequence.	('miR-193b', 'Gene', '574455', (125, 133))	('miR-193b', 'Gene', (125, 133))	('point mutations', 'Var', (171, 186))	('miR-193b', 'Gene', '574455', (43, 51))	('miR-193b', 'Gene', (43, 51))	('abolished', 'NegReg', (67, 76))	('binding', 'Interaction', (109, 116))
363299	31262974	Accumulating reports have demonstrated that aberrant expression of miRNAs is closely involved in cancer progression.	('cancer', 'Disease', (97, 103))	('cancer', 'Disease', 'MESH:D009369', (97, 103))	('involved', 'Reg', (85, 93))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('miR', 'Gene', '220972', (67, 70))	('miR', 'Gene', (67, 70))	('aberrant expression', 'Var', (44, 63))
363345	31262974	Moreover, knockdown of the HEG1 gene dramatically decreased the survival and proliferation of mesothelioma cells.	('HEG1', 'Gene', (27, 31))	('mesothelioma', 'Disease', 'MESH:D008654', (94, 106))	('survival', 'CPA', (64, 72))	('decreased', 'NegReg', (50, 59))	('mesothelioma', 'Disease', (94, 106))	('knockdown', 'Var', (10, 19))	('HEG1', 'Gene', '57493', (27, 31))
363372	30356371	Dysplasia is the occurrence of irregular/immature cells in the epithelium, cells that have changed morphology (polymorphic cells with big irregular nuclei, containing an increased number of nucleoli), and aberrations in the laminar structure of the epithelium (chaotic, irregular arrangement of cells, change in the polarity of basilar cells, and the presence of incorrect mitoses above the basal layer).	('aberrations', 'Var', (205, 216))	('change', 'Reg', (302, 308))	('men', 'Species', '9606', (287, 290))	('laminar structure', 'CPA', (224, 241))	('polarity', 'CPA', (316, 324))	('Dysplasia', 'Disease', (0, 9))	('Dysplasia', 'Disease', 'MESH:D004476', (0, 9))
363393	30356371	In 1979 Merriman confirmed the importance of therapy with retinoids in inhibition of carcinogenesis and:what is more:demonstrated that discontinuation of such treatment causes further progress of neoplasia.	('neoplasia', 'Phenotype', 'HP:0002664', (196, 205))	('carcinogenesis', 'Disease', 'MESH:D063646', (85, 99))	('neoplasia', 'Disease', 'MESH:D009369', (196, 205))	('carcinogenesis', 'Disease', (85, 99))	('retinoids', 'Chemical', 'MESH:D012176', (58, 67))	('neoplasia', 'Disease', (196, 205))	('men', 'Species', '9606', (164, 167))	('discontinuation', 'Var', (135, 150))
363410	30356371	After 3.5 years, no differences were observed as to the number of recurrences of primary cancer; still a lower amount of SPTs was noted in the group receiving isotretinoin (4%), in comparison with the group receiving placebo (24%).	('lower', 'NegReg', (105, 110))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('isotretinoin', 'Chemical', 'MESH:D015474', (159, 171))	('cancer', 'Disease', (89, 95))	('SPTs', 'Chemical', '-', (121, 125))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('isotretinoin', 'Var', (159, 171))
363451	30356371	5-year overall survival was 45.6% among patients receiving radiotherapy and cetuximab, whereas only 36.4% in the group treated with radiotherapy alone.	('cetuximab', 'Var', (76, 85))	('patients', 'Species', '9606', (40, 48))	('radiotherapy', 'Var', (59, 71))	('cetuximab', 'Chemical', 'MESH:D000068818', (76, 85))
363454	30356371	However, the median overall survival was still short, 10.1 months in the cetuximab group compared to 7.4 months in patients receiving chemotherapy alone.	('overall', 'MPA', (20, 27))	('patients', 'Species', '9606', (115, 123))	('to 7', 'Species', '1214577', (98, 102))	('cetuximab', 'Chemical', 'MESH:D000068818', (73, 82))	('cetuximab', 'Var', (73, 82))
363461	30356371	The patients that qualified for participating in the study belonged to a high risk group, as regards development of squamous cell carcinoma, due to advanced dysplasia, confirmed loss of heterozygosity (LOH), a potential risk marker of premalignancies turning malignant, in one of typical locations for head and neck cancerogenesis, or due to the history of head and neck carcinoma.	('loss of heterozygosity', 'Var', (178, 200))	('cancer', 'Phenotype', 'HP:0002664', (316, 322))	('neck carcinoma', 'Disease', 'MESH:D006258', (366, 380))	('men', 'Species', '9606', (108, 111))	('head and neck cancer', 'Phenotype', 'HP:0012288', (302, 322))	('neck carcinoma', 'Disease', (366, 380))	('malignancies', 'Disease', 'MESH:D009369', (238, 250))	('neck cancer', 'Disease', 'MESH:D006258', (311, 322))	('neck cancer', 'Disease', (311, 322))	('dysplasia', 'Disease', (157, 166))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (116, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (371, 380))	('squamous cell carcinoma', 'Disease', (116, 139))	('patients', 'Species', '9606', (4, 12))	('dysplasia', 'Disease', 'MESH:D004476', (157, 166))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (116, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('malignancies', 'Disease', (238, 250))
363479	30356371	Excessive activity of its proteins is connected with amplification or mutation of genes encoding the serine/threonine protein kinase Akt, phosphoinositide 3-kinase (PI3K), as well as deletion or mutation of the phosphatase and tensin (PTEN) gene.	('activity', 'MPA', (10, 18))	('Akt', 'Gene', '207', (133, 136))	('PTEN', 'Gene', (235, 239))	('mutation', 'Var', (195, 203))	('Akt', 'Gene', (133, 136))	('PTEN', 'Gene', '5728', (235, 239))	('mutation', 'Var', (70, 78))	('deletion', 'Var', (183, 191))
363491	30356371	This was caused by ethical reasons, resulting from the report that emerged at that time, concerning increased incidence of lung cancer during supplementation with beta-carotene.	('lung cancer', 'Disease', (123, 134))	('lung cancer', 'Phenotype', 'HP:0100526', (123, 134))	('men', 'Species', '9606', (148, 151))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('lung cancer', 'Disease', 'MESH:D008175', (123, 134))	('supplementation', 'Var', (142, 157))	('beta-carotene', 'Chemical', 'MESH:D019207', (163, 176))
363496	30356371	What is more, deficiency of folic acid contributes to problems with DNA methylation and difficulties with control and expression of proto oncogenes.	('problems', 'Reg', (54, 62))	('control', 'MPA', (106, 113))	('folic acid', 'Chemical', 'MESH:D005492', (28, 38))	('DNA methylation', 'MPA', (68, 83))	('deficiency', 'Var', (14, 24))	('folic', 'Protein', (28, 33))
363533	30356371	EGCG reduces the generation of metalloproteinase MMP-2 and -9 in cancer cells, which influences reduction of tumour invasiveness.	('tumour invasiveness', 'Disease', 'MESH:D009361', (109, 128))	('reduces', 'NegReg', (5, 12))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('EGCG', 'Chemical', 'MESH:C045651', (0, 4))	('EGCG', 'Var', (0, 4))	('cancer', 'Disease', (65, 71))	('tumour invasiveness', 'Disease', (109, 128))	('reduction', 'NegReg', (96, 105))	('tumour', 'Phenotype', 'HP:0002664', (109, 115))
363540	30356371	EGCG also inhibited the ETM process in human CSCs.	('ETM process', 'CPA', (24, 35))	('inhibited', 'NegReg', (10, 19))	('EGCG', 'Chemical', 'MESH:C045651', (0, 4))	('EGCG', 'Var', (0, 4))	('human', 'Species', '9606', (39, 44))
363543	30356371	The research with the use of HN4 cell lines of head and neck carcinoma demonstrated that pleiotropic activity of genistein causes induction of apoptosis and inhibition of cancer cell growth, by stopping the cell cycle in the G2/M phase.	('stopping', 'NegReg', (194, 202))	('neck carcinoma', 'Disease', 'MESH:D006258', (56, 70))	('pleiotropic activity', 'Var', (89, 109))	('genistein', 'Chemical', 'MESH:D019833', (113, 122))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('cancer', 'Disease', (171, 177))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('apoptosis', 'CPA', (143, 152))	('inhibition', 'NegReg', (157, 167))	('HN4', 'CellLine', 'CVCL:5515', (29, 32))	('neck carcinoma', 'Disease', (56, 70))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('cell cycle', 'CPA', (207, 217))
363595	30356371	Yet another interesting attempt at chemoprevention of HNSCC was the development of modified adenovirus ONYX-15, which replicates selectively only in cells with mutated gene p53, destroying them.	('p53', 'Gene', (173, 176))	('mutated', 'Var', (160, 167))	('p53', 'Gene', '7157', (173, 176))	('men', 'Species', '9606', (75, 78))	('HNSCC', 'Phenotype', 'HP:0012288', (54, 59))	('destroying', 'NegReg', (178, 188))
363596	30356371	As mutations of gene p53 occur in some 40-50% cases of HNSCC and in some 45% of dysplastic lesions, the idea was born to apply adenovirus ONYX-15 in patients with dysplasia of the oral cavity.	('patients', 'Species', '9606', (149, 157))	('HNSCC', 'Phenotype', 'HP:0012288', (55, 60))	('dysplasia', 'Disease', (163, 172))	('HNSCC', 'Disease', (55, 60))	('p53', 'Gene', '7157', (21, 24))	('dysplasia', 'Disease', 'MESH:D004476', (163, 172))	('dysplastic lesions', 'Disease', 'MESH:D021782', (80, 98))	('occur', 'Reg', (25, 30))	('p53', 'Gene', (21, 24))	('mutations', 'Var', (3, 12))	('dysplastic lesions', 'Disease', (80, 98))
363636	30356371	As a result of those activities, isotretinoin causes reduced secretion of the oily secretion (meibum).	('reduced', 'NegReg', (53, 60))	('isotretinoin', 'Var', (33, 45))	('isotretinoin', 'Chemical', 'MESH:D015474', (33, 45))
363637	30356371	Isotretinoin leads to atrophy of Meibonian glands.	('Isotretinoin', 'Chemical', 'MESH:D015474', (0, 12))	('atrophy', 'Disease', 'MESH:D001284', (22, 29))	('Isotretinoin', 'Var', (0, 12))	('atrophy', 'Disease', (22, 29))	('Meibonian glands', 'Disease', (33, 49))
363638	30356371	Although the amount of tears produced is not reduced, the deficiency of lipids leads to disturbances in the lacrimal film, symptoms of dry eye syndrome, clinical manifestations of inflammation of eyelid margins, as well as disturbances of the eye surface.	('dry eye syndrome', 'Disease', 'MESH:D015352', (135, 151))	('inflammation', 'Disease', 'MESH:D007249', (180, 192))	('lipids', 'Protein', (72, 78))	('lipids', 'Chemical', 'MESH:D008055', (72, 78))	('inflammation of eyelid', 'Phenotype', 'HP:0000498', (180, 202))	('leads to', 'Reg', (79, 87))	('deficiency', 'Var', (58, 68))	('inflammation', 'Disease', (180, 192))	('dry eye', 'Phenotype', 'HP:0001097', (135, 142))	('tears', 'Phenotype', 'HP:0009926', (23, 28))	('disturbances', 'MPA', (88, 100))	('tear', 'Phenotype', 'HP:0009926', (23, 27))	('dry eye syndrome', 'Disease', (135, 151))
363648	30356371	A disturbance of that process results in reducing the retinol level in blood plasma and its bioavailability in the retina.	('retinol', 'Chemical', 'MESH:D014801', (54, 61))	('bioavailability in the retina', 'MPA', (92, 121))	('reducing', 'NegReg', (41, 49))	('disturbance', 'Var', (2, 13))	('retinol level in blood plasma', 'MPA', (54, 83))
363665	30356371	Erlotinib caused dermatological problems, diarrhea, fatigue, and mucositis.	('caused', 'Reg', (10, 16))	('fatigue', 'Disease', 'MESH:D005221', (52, 59))	('mucositis', 'Disease', 'MESH:D052016', (65, 74))	('diarrhea', 'Phenotype', 'HP:0002014', (42, 50))	('Erlotinib', 'Var', (0, 9))	('diarrhea', 'Disease', (42, 50))	('fatigue', 'Disease', (52, 59))	('diarrhea', 'Disease', 'MESH:D003967', (42, 50))	('dermatological problems', 'Disease', (17, 40))	('fatigue', 'Phenotype', 'HP:0012378', (52, 59))	('mucositis', 'Disease', (65, 74))	('Erlotinib', 'Chemical', 'MESH:D000069347', (0, 9))
363701	28927388	Many studies have found that the dysregulation of miRNAs correlates with diseases, including lung cancer.	('dysregulation', 'Var', (33, 46))	('miR', 'Gene', '220972', (50, 53))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('miR', 'Gene', (50, 53))	('lung cancer', 'Disease', 'MESH:D008175', (93, 104))	('lung cancer', 'Disease', (93, 104))	('lung cancer', 'Phenotype', 'HP:0100526', (93, 104))
363703	28927388	However, the clinicopathological significance and related mechanisms of dysregulated miRNAs in NSCLC remain largely unclear.	('NSCLC', 'Disease', 'MESH:D002289', (95, 100))	('miR', 'Gene', '220972', (85, 88))	('miR', 'Gene', (85, 88))	('dysregulated', 'Var', (72, 84))	('NSCLC', 'Phenotype', 'HP:0030358', (95, 100))	('NSCLC', 'Disease', (95, 100))
363748	28927388	The AUC values were 0.859, 0.876 and 0.769 in NSCLC, LUAD and LUSC, respectively (Fig.	('0.769', 'Var', (37, 42))	('LUSC', 'Disease', (62, 66))	('NSCLC', 'Disease', (46, 51))	('NSCLC', 'Phenotype', 'HP:0030358', (46, 51))	('NSCLC', 'Disease', 'MESH:D002289', (46, 51))	('LUAD', 'Disease', (53, 57))	('AUC', 'MPA', (4, 7))	('LUAD', 'Phenotype', 'HP:0030078', (53, 57))	('0.876', 'Var', (27, 32))
363761	28927388	In tumor tissues of NSCLC patients, the relative expression of miR-542-5p in patients with high EGFR protein expression was significantly lower than that of patients with low EGFR protein expression (0.739 +- 0.407 vs 3.049 +- 1.194, t = 7.753, p < 0.001).	('NSCLC', 'Disease', 'MESH:D002289', (20, 25))	('EGFR', 'Gene', (175, 179))	('tumor', 'Disease', (3, 8))	('EGFR', 'Gene', (96, 100))	('high', 'Var', (91, 95))	('lower', 'NegReg', (138, 143))	('expression', 'MPA', (49, 59))	('patients', 'Species', '9606', (26, 34))	('patients', 'Species', '9606', (157, 165))	('patients', 'Species', '9606', (77, 85))	('miR-542', 'Gene', '664617', (63, 70))	('NSCLC', 'Phenotype', 'HP:0030358', (20, 25))	('tumor', 'Disease', 'MESH:D009369', (3, 8))	('miR-542', 'Gene', (63, 70))	('EGFR', 'Gene', '1956', (175, 179))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))	('NSCLC', 'Disease', (20, 25))	('EGFR', 'Gene', '1956', (96, 100))
363763	28927388	While in the groups of LUAD and LUSC, the expression of miR-542-5p in patients with high EGFR protein expression was significantly lower than that of patients with low EGFR protein expression (0.836 +- 0.373 vs 3.180 +- 0.952, t = 10.098, p < 0.001, LUAD; 0.436 +- 0.345 vs 2.888 +- 1.448; t = 6.543, p < 0.001, LUSC).	('miR-542', 'Gene', (56, 63))	('patients', 'Species', '9606', (70, 78))	('EGFR', 'Gene', '1956', (89, 93))	('high', 'Var', (84, 88))	('EGFR', 'Gene', (89, 93))	('EGFR', 'Gene', (168, 172))	('expression', 'MPA', (102, 112))	('EGFR', 'Gene', '1956', (168, 172))	('expression', 'MPA', (42, 52))	('patients', 'Species', '9606', (150, 158))	('lower', 'NegReg', (131, 136))	('LUAD', 'Phenotype', 'HP:0030078', (250, 254))	('LUAD', 'Phenotype', 'HP:0030078', (23, 27))	('miR-542', 'Gene', '664617', (56, 63))
363782	28927388	Many dysregulated miRNAs have been shown to relate to tumorigenesis or development in numerous cancers.	('development', 'CPA', (71, 82))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('cancers', 'Phenotype', 'HP:0002664', (95, 102))	('relate', 'Reg', (44, 50))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('dysregulated', 'Var', (5, 17))	('miR', 'Gene', '220972', (18, 21))	('miR', 'Gene', (18, 21))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('numerous cancers', 'Disease', 'MESH:D009369', (86, 102))	('tumor', 'Disease', (54, 59))	('numerous cancers', 'Disease', (86, 102))
363802	28927388	found that Hippo/YAP signaling was inhibited after knockdown of ERK1/2.	('ERK1/2', 'Gene', '5595;5594', (64, 70))	('YAP', 'Gene', '10413', (17, 20))	('inhibited', 'NegReg', (35, 44))	('ERK1/2', 'Gene', (64, 70))	('YAP', 'Gene', (17, 20))	('knockdown', 'Var', (51, 60))
363822	28118606	Moreover, PROS1 knockdown reduced anchorage-independent growth in-vitro, reduced tumor xenograft growth in nude mice and altered their differentiation profile.	('PROS1', 'Gene', (10, 15))	('reduced', 'NegReg', (73, 80))	('knockdown', 'Var', (16, 25))	('altered', 'Reg', (121, 128))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('anchorage-independent growth', 'CPA', (34, 62))	('reduced', 'NegReg', (26, 33))	('differentiation profile', 'CPA', (135, 158))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Disease', (81, 86))	('nude mice', 'Species', '10090', (107, 116))
363823	28118606	The anti-proliferative effect of the AXL inhibitor R428 was significantly reduced following PROS1 inhibition, indicating the functional significance of PROS1-mediated regulation of AXL in OSCC.	('R428', 'Chemical', '-', (51, 55))	('inhibition', 'Var', (98, 108))	('SCC', 'Gene', (189, 192))	('rat', 'Species', '10116', (16, 19))	('SCC', 'Gene', '6317', (189, 192))	('anti-proliferative effect', 'CPA', (4, 29))	('PROS1', 'Gene', (92, 97))	('reduced', 'NegReg', (74, 81))
363835	28118606	Inhibition of PROS1 expression suppressed tumor cell proliferation, migration and anchorage-independent growth in-vitro.	('PROS1', 'Gene', (14, 19))	('tumor', 'Disease', (42, 47))	('rat', 'Species', '10116', (71, 74))	('anchorage-independent growth', 'CPA', (82, 110))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('rat', 'Species', '10116', (60, 63))	('Inhibition', 'Var', (0, 10))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('suppressed', 'NegReg', (31, 41))	('migration', 'CPA', (68, 77))
363839	28118606	In keeping with PROS1-regulated AXL expression, sensitivity to the small molecule AXL inhibitor R428 was lost following PROS1 knockdown.	('R428', 'Chemical', '-', (96, 100))	('sensitivity to the', 'MPA', (48, 66))	('PROS1', 'Gene', (120, 125))	('knockdown', 'Var', (126, 135))	('lost', 'NegReg', (105, 109))
363856	28118606	Decreased cell viability was observed for both sh1 and sh2 knockdown constructs in SCC-1 and SCC-25 cells (Figure 2A, 2B).	('SCC', 'Gene', (83, 86))	('Decreased', 'NegReg', (0, 9))	('sh1', 'Gene', (47, 50))	('SCC', 'Gene', (93, 96))	('cell viability', 'CPA', (10, 24))	('sh2', 'Gene', (55, 58))	('SCC', 'Gene', '6317', (83, 86))	('SCC', 'Gene', '6317', (93, 96))	('knockdown', 'Var', (59, 68))
363859	28118606	Similarly, PROS1 knockdown in SCC-25 cells reduced the proliferative index by 43% (P = 0.003) and by 53% (P < 0.0001), indicating an inhibitory effect on the proliferation (Figure 2E, 2F).	('SCC', 'Gene', '6317', (30, 33))	('PROS1', 'Gene', (11, 16))	('rat', 'Species', '10116', (165, 168))	('proliferative index', 'CPA', (55, 74))	('SCC', 'Gene', (30, 33))	('knockdown', 'Var', (17, 26))	('rat', 'Species', '10116', (62, 65))	('reduced', 'NegReg', (43, 50))
363861	28118606	As for sh-treated cell lines, we found that si-mediated targeting of PROS1 reduced cell growth by 31% (P=0.007) and inhibited BrdU incorporation rates by 42% (P=0.01) (Supplementary Figure 2C, 2D).	('rat', 'Species', '10116', (138, 141))	('PROS1', 'Gene', (69, 74))	('BrdU incorporation rates', 'CPA', (126, 150))	('BrdU', 'Chemical', 'MESH:D001973', (126, 130))	('inhibited', 'NegReg', (116, 125))	('reduced', 'NegReg', (75, 82))	('si-mediated targeting', 'Var', (44, 65))	('rat', 'Species', '10116', (145, 148))	('cell growth', 'CPA', (83, 94))
363878	28118606	Together, our results indicate that inhibition of PROS1 decreases the migratory capacity of OSCC cells.	('inhibition', 'Var', (36, 46))	('decreases', 'NegReg', (56, 65))	('SCC', 'Gene', (93, 96))	('PROS1', 'Gene', (50, 55))	('SCC', 'Gene', '6317', (93, 96))	('rat', 'Species', '10116', (73, 76))
363879	28118606	We next evaluated the effect of PROS1 knockdown on anchorage-independent growth in SCC-25 cell lines using the soft agar assay.	('agar', 'Chemical', 'MESH:D000362', (116, 120))	('SCC', 'Gene', (83, 86))	('PROS1', 'Gene', (32, 37))	('SCC', 'Gene', '6317', (83, 86))	('knockdown', 'Var', (38, 47))
363882	28118606	To determine whether PROS1 inhibition could also constrain OSCC tumorigenic potential in-vivo, SCC1 cells were injected subcutaneously into the flanks of immune-deficient nude mice.	('OSCC tumor', 'Disease', (59, 69))	('OSCC tumor', 'Disease', 'MESH:D009369', (59, 69))	('inhibition', 'Var', (27, 37))	('nude mice', 'Species', '10090', (171, 180))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
363894	28118606	We verified PROS1 expression in shEV tumors, as well as conservation of PROS1 knockdown in shPS1 and shPS2 tumors during in-vivo growth by immunohistochemistry of tumor sections at the endpoint.	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('shPS2', 'Gene', (101, 106))	('tumor', 'Disease', (107, 112))	('shEV', 'Species', '63421', (32, 36))	('PROS1', 'Gene', (72, 77))	('tumor', 'Disease', (163, 168))	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumors', 'Disease', (37, 43))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumors', 'Disease', (107, 113))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('tumors', 'Disease', 'MESH:D009369', (37, 43))	('knockdown', 'Var', (78, 87))	('shPS1', 'Gene', (91, 96))	('tumor', 'Disease', (37, 42))	('tumors', 'Disease', 'MESH:D009369', (107, 113))	('shPS1', 'Gene', '140885', (91, 96))
363897	28118606	The marked reduction in cytokeratin levels following PROS1 knockdown supports the pathological assessment, and together with reduced tumor growth in-vivo indicate decreased malignancy of OSCC tumors following PROS1 knockdown.	('reduction', 'NegReg', (11, 20))	('tumor', 'Disease', (192, 197))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumors', 'Phenotype', 'HP:0002664', (192, 198))	('cytokeratin levels', 'MPA', (24, 42))	('malignancy of OSCC tumors', 'Disease', (173, 198))	('malignancy of OSCC tumors', 'Disease', 'MESH:D018198', (173, 198))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('PROS1', 'Gene', (53, 58))	('rat', 'Species', '10116', (30, 33))	('knockdown', 'Var', (215, 224))	('tumor', 'Disease', (133, 138))	('decreased', 'NegReg', (163, 172))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('knockdown', 'Var', (59, 68))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('PROS1', 'Gene', (209, 214))
363901	28118606	The lower proliferation rates in tumors inhibited for PROS1 expression also showed more numerous apoptotic foci, and contained more apoptotic cells positive for DNA fragmentation, as measured by the TUNEL (Terminal deoxynucleotidyltransferase -mediated dUTP Nick End Labeling) reaction (P=0.024 for shPS1; P=0.001 for shPS2; Supplementary Figure 4B, 4C).	('shPS1', 'Gene', (299, 304))	('lower', 'NegReg', (4, 9))	('Terminal deoxynucleotidyltransferase', 'Gene', (206, 242))	('expression', 'Var', (60, 70))	('dUTP', 'Chemical', 'MESH:C027078', (253, 257))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('Terminal deoxynucleotidyltransferase', 'Gene', '1791', (206, 242))	('shPS1', 'Gene', '140885', (299, 304))	('tumors', 'Disease', 'MESH:D009369', (33, 39))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('rat', 'Species', '10116', (17, 20))	('PROS1', 'Gene', (54, 59))	('rat', 'Species', '10116', (24, 27))	('tumors', 'Disease', (33, 39))	('apoptotic foci', 'CPA', (97, 111))
363902	28118606	Taken together, we conclude that PROS1 knockdown increases apoptotic cell death in tumors, which is also reflected by fewer cycling Ki-67-positive cells.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('knockdown', 'Var', (39, 48))	('tumors', 'Disease', (83, 89))	('PROS1', 'Gene', (33, 38))	('increases', 'PosReg', (49, 58))	('fewer', 'NegReg', (118, 123))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('apoptotic cell death', 'CPA', (59, 79))	('tumors', 'Disease', 'MESH:D009369', (83, 89))
363908	28118606	Reintroducing PROS1 into the culture resulted in re-induction of AXL mRNA and protein levels, as assessed by RT-qPCR (P=0.001 for sh-EV; P=0.01 for shPS1) and western blot, respectively (Figure 5G-5I).	('shPS1', 'Gene', (148, 153))	('shPS1', 'Gene', '140885', (148, 153))	('Reintroducing', 'Var', (0, 13))
363909	28118606	PROS1 knockdown did not affect the expression of Tyro3, Mertk or Gas6 (Supplementary Figure 5A-5C) indicating AXL as the only TAM signaling component affected by PROS1-kd.	('Gas6', 'Gene', (65, 69))	('Gas6', 'Gene', '2621', (65, 69))	('Tyro3', 'Gene', '7301', (49, 54))	('TAM', 'Chemical', '-', (126, 129))	('Mertk', 'Gene', '10461', (56, 61))	('Tyro3', 'Gene', (49, 54))	('knockdown', 'Var', (6, 15))	('Mertk', 'Gene', (56, 61))	('PROS1', 'Gene', (0, 5))
363911	28118606	R428 was previously shown to effectively block AXL phosphorylation and AXL-mediated cellular events, including cell migration, proliferation and angiogenesis in a variety of cancer cells, including Head and Neck Squamous Cell Carcinoma (HNSCC).	('rat', 'Species', '10116', (119, 122))	('angiogenesis', 'CPA', (145, 157))	('proliferation', 'CPA', (127, 140))	('R428', 'Chemical', '-', (0, 4))	('Carcinoma', 'Phenotype', 'HP:0030731', (226, 235))	('cancer', 'Disease', (174, 180))	('Head and Neck Squamous Cell Carcinoma', 'Phenotype', 'HP:0012288', (198, 235))	('Neck Squamous Cell Carcinoma', 'Disease', (207, 235))	('rat', 'Species', '10116', (134, 137))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('SCC', 'Gene', '6317', (239, 242))	('cell migration', 'CPA', (111, 125))	('SCC', 'Gene', (239, 242))	('AXL', 'Protein', (47, 50))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (212, 235))	('block', 'NegReg', (41, 46))	('R428', 'Var', (0, 4))	('AXL-mediated', 'MPA', (71, 83))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('Neck Squamous Cell Carcinoma', 'Disease', 'MESH:D000077195', (207, 235))
363915	28118606	These results indicate that OSCC cells have lost the AXL-mediated cell growth following PROS1 knockdown, and that this knockdown has functional significance.	('AXL-mediated cell growth', 'MPA', (53, 77))	('lost', 'NegReg', (44, 48))	('knockdown', 'Var', (94, 103))	('SCC', 'Gene', '6317', (29, 32))	('PROS1', 'Gene', (88, 93))	('SCC', 'Gene', (29, 32))
363918	28118606	We hypothesized that if PROS1 induction of cell growth is AXL-dependent and if PROS1 positively upregulates AXL expression (Figure 5G-5I) then PROS1 addition may attenuate the toxic effect of R428.	('toxic effect', 'MPA', (176, 188))	('attenuate', 'NegReg', (162, 171))	('PROS1', 'Var', (79, 84))	('AXL expression', 'MPA', (108, 122))	('upregulates', 'PosReg', (96, 107))	('R428', 'Chemical', '-', (192, 196))
363931	28118606	Finally, to assess whether the decreased migratory capacity following PROS1 inhibition (Figure 3) is also mediated through AXL, we assessed wound healing closure of SCC1-shPS1 cells in the presence of PROS1 or R428.	('inhibition', 'NegReg', (76, 86))	('R428', 'Chemical', '-', (210, 214))	('shPS1', 'Gene', (170, 175))	('decreased', 'NegReg', (31, 40))	('R428', 'Var', (210, 214))	('rat', 'Species', '10116', (44, 47))	('migratory capacity', 'CPA', (41, 59))	('shPS1', 'Gene', '140885', (170, 175))
363932	28118606	In keeping with our previous results, inhibition of PROS1 attenuated closure of the scratch area (P<0.0001) (Figure 6D 1-2').	('PROS1', 'Protein', (52, 57))	('attenuated', 'NegReg', (58, 68))	('closure of the scratch area', 'CPA', (69, 96))	('inhibition', 'Var', (38, 48))	('rat', 'Species', '10116', (86, 89))
363934	28118606	This is further stressed by the fact that addition of R428 eliminated the rescue effect of PROS1 (P = 0.157, Figure 6D 3-5').	('R428', 'Var', (54, 58))	('R428', 'Chemical', '-', (54, 58))	('eliminated', 'NegReg', (59, 69))	('rescue effect', 'MPA', (74, 87))
363935	28118606	Taken together, these results indicate that targeting PROS1 has a major impact on AXL expression and AXL-related cellular proliferation and migration.	('AXL expression', 'MPA', (82, 96))	('rat', 'Species', '10116', (129, 132))	('targeting', 'Var', (44, 53))	('rat', 'Species', '10116', (143, 146))	('PROS1', 'Gene', (54, 59))	('impact', 'Reg', (72, 78))	('migration', 'CPA', (140, 149))
363938	28118606	PROS1 stimulates proliferation and migration of OSCC cell lines and inhibition of PROS1 expression decreased proliferation, migration and anchorage-independent growth.	('proliferation', 'CPA', (17, 30))	('decreased', 'NegReg', (99, 108))	('migration', 'CPA', (35, 44))	('SCC', 'Gene', (49, 52))	('migration', 'CPA', (124, 133))	('inhibition', 'Var', (68, 78))	('PROS1', 'Gene', (82, 87))	('SCC', 'Gene', '6317', (49, 52))	('rat', 'Species', '10116', (116, 119))	('rat', 'Species', '10116', (127, 130))	('proliferation', 'CPA', (109, 122))	('anchorage-independent growth', 'CPA', (138, 166))	('rat', 'Species', '10116', (38, 41))	('rat', 'Species', '10116', (24, 27))
363939	28118606	Furthermore, knockdown of PROS1 reduced tumor growth in a xenograft transplantation model.	('PROS1 reduced tumor', 'Disease', (26, 45))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('knockdown', 'Var', (13, 22))	('PROS1 reduced tumor', 'Disease', 'MESH:D015354', (26, 45))
363959	28118606	It is tempting to speculate that PROS1-driven AXL expression may lead to functional receptor heterodimerization with EGFR, as was shown for HNSCC and esophageal squamous cell carcinoma.	('heterodimerization', 'Interaction', (93, 111))	('esophageal squamous cell carcinoma', 'Disease', (150, 184))	('SCC', 'Gene', (142, 145))	('EGFR', 'Gene', (117, 121))	('EGFR', 'Gene', '1956', (117, 121))	('expression', 'Var', (50, 60))	('receptor', 'Protein', (84, 92))	('lead to', 'Reg', (65, 72))	('SCC', 'Gene', '6317', (142, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (175, 184))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (161, 184))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (150, 184))
363960	28118606	Our results show that knockdown of PROS1 reduced AXL protein levels in the OSCC lines tested (Figure 5B, 5C), and that stimulation of these cells with PROS1 rescued AXL expression (Figure 5G-5I).	('reduced', 'NegReg', (41, 48))	('PROS1', 'Gene', (35, 40))	('SCC', 'Gene', (76, 79))	('AXL expression', 'MPA', (165, 179))	('AXL protein levels', 'MPA', (49, 67))	('knockdown', 'Var', (22, 31))	('SCC', 'Gene', '6317', (76, 79))
363961	28118606	Axl expression is also negatively regulated by the microRNAs (miR) miR-34 and miR-199a/b, with an inverse correlation between AXL protein levels and miR-34a expression found in a panel of cancer cell lines.	('miR-34', 'Gene', (149, 155))	('AXL protein levels', 'MPA', (126, 144))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('miR-34a', 'Gene', '407040', (149, 156))	('Axl', 'Gene', '558', (0, 3))	('miR-34', 'Gene', '407040', (149, 155))	('miR-199a/b', 'Var', (78, 88))	('miR-34', 'Gene', (67, 73))	('miR-34a', 'Gene', (149, 156))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('miR-34', 'Gene', '407040', (67, 73))	('Axl', 'Gene', (0, 3))	('cancer', 'Disease', (188, 194))	('negatively', 'NegReg', (23, 33))
363967	28118606	Taken together, the normal expression of PROS1 in the epidermal basal layer, its high expression in the basal cell layer of OSCC xenograft tumors and its proliferative effect on OSCC cells (Figure 1C, 1D and Figure 2C-2I) suggest a role for PROS1 in the regulation of epithelial cell proliferation, and that dysregulated PROS1 expression may contribute to OSCC etiology.	('contribute', 'Reg', (342, 352))	('SCC', 'Gene', (179, 182))	('PROS1', 'Gene', (41, 46))	('SCC', 'Gene', '6317', (357, 360))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('OSCC xenograft tumors', 'Disease', (124, 145))	('SCC', 'Gene', (125, 128))	('SCC', 'Gene', '6317', (179, 182))	('rat', 'Species', '10116', (291, 294))	('SCC', 'Gene', '6317', (125, 128))	('rat', 'Species', '10116', (161, 164))	('dysregulated', 'Var', (308, 320))	('PROS1', 'Gene', (321, 326))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('OSCC xenograft tumors', 'Disease', 'MESH:D009369', (124, 145))	('SCC', 'Gene', (357, 360))
363968	28118606	Accordingly, compared to control-treated cells, PROS1 knockdown cells appeared histologically more differentiated (Supplementary Figure 3A, 3B), and correlated with a reduction in cytokeratin markers CK5/6, CK8/18 and CK19 (Figure 4) associated with increased dysplasia and tumor aggressiveness.	('PROS1', 'Gene', (48, 53))	('CK5/6', 'Gene', '3852', (200, 205))	('knockdown', 'Var', (54, 63))	('rat', 'Species', '10116', (186, 189))	('aggressiveness', 'Phenotype', 'HP:0000718', (280, 294))	('CK5/6', 'Gene', (200, 205))	('reduction', 'NegReg', (167, 176))	('CK19', 'Gene', (218, 222))	('increased dysplasia and tumor aggressiveness', 'Disease', 'MESH:D009369', (250, 294))	('tumor', 'Phenotype', 'HP:0002664', (274, 279))	('CK19', 'Gene', '3880', (218, 222))	('CK8/18', 'Gene', (207, 213))	('CK8/18', 'Gene', '3856;3875', (207, 213))	('more', 'PosReg', (94, 98))
363975	28118606	SCC cell lines were transiently transfected with PROS1 siRNA (siPROS1; ON-TARGETplus, SMARTpool # L-004833; Dharmacon) or with non-targeting siRNA (siNT ON-TARGETplus, SMARTpool #D-001810; Dharmacon) using DharmaFECT transfection reagent according to the manufacturer's instructions.	('SCC', 'Gene', (0, 3))	('SMARTpool # L-004833', 'Var', (86, 106))	('SCC', 'Gene', '6317', (0, 3))
363976	28118606	Stable PROS1 knockdown (KD) was achieved in SCC1 and SCC25 cell lines using a pLKO.1 based lenriviral system (Open Biosystems).	('SCC', 'Gene', '6317', (44, 47))	('SCC', 'Gene', '6317', (53, 56))	('KD', 'Disease', 'MESH:C537017', (24, 26))	('SCC', 'Gene', (44, 47))	('SCC', 'Gene', (53, 56))	('knockdown', 'Var', (13, 22))	('PROS1', 'Gene', (7, 12))
364037	27385983	NSCLC patients with high RelB expression had significantly shorter overall survival than those with low RelB expression (P < 0.001).	('NSCLC', 'Disease', 'MESH:D002289', (0, 5))	('RelB', 'Gene', (25, 29))	('RelB', 'Gene', '5971', (25, 29))	('RelB', 'Gene', (104, 108))	('RelB', 'Gene', '5971', (104, 108))	('overall survival', 'MPA', (67, 83))	('shorter', 'NegReg', (59, 66))	('NSCLC', 'Phenotype', 'HP:0030358', (0, 5))	('high', 'Var', (20, 24))	('patients', 'Species', '9606', (6, 14))	('NSCLC', 'Disease', (0, 5))
364038	27385983	Our results indicate that high RelB expression is an independent prognostic factor for patients with NSCLC (P < 0.001).	('high', 'Var', (26, 30))	('NSCLC', 'Disease', (101, 106))	('RelB', 'Gene', (31, 35))	('RelB', 'Gene', '5971', (31, 35))	('NSCLC', 'Disease', 'MESH:D002289', (101, 106))	('patients', 'Species', '9606', (87, 95))	('expression', 'MPA', (36, 46))	('NSCLC', 'Phenotype', 'HP:0030358', (101, 106))
364048	27385983	In addition, the NSCLC patients with high RelB expression had significantly shorter overall survival (OS) than those with low RelB expression.	('RelB', 'Gene', (126, 130))	('NSCLC', 'Disease', (17, 22))	('RelB', 'Gene', (42, 46))	('high', 'Var', (37, 41))	('RelB', 'Gene', '5971', (126, 130))	('patients', 'Species', '9606', (23, 31))	('NSCLC', 'Disease', 'MESH:D002289', (17, 22))	('RelB', 'Gene', '5971', (42, 46))	('expression', 'Var', (47, 57))	('overall survival', 'MPA', (84, 100))	('NSCLC', 'Phenotype', 'HP:0030358', (17, 22))	('shorter', 'NegReg', (76, 83))
364049	27385983	High RelB expression could be considered an independent prognostic factor for lower OS in patients with NSCLC.	('lower OS', 'Disease', (78, 86))	('High', 'Var', (0, 4))	('NSCLC', 'Disease', (104, 109))	('RelB', 'Gene', '5971', (5, 9))	('expression', 'MPA', (10, 20))	('NSCLC', 'Disease', 'MESH:D002289', (104, 109))	('RelB', 'Gene', (5, 9))	('patients', 'Species', '9606', (90, 98))	('NSCLC', 'Phenotype', 'HP:0030358', (104, 109))
364093	27385983	Patients with high RelB expression had significantly shorter OS than those with low RelB expression (chi2 = 32.993, P < 0.001; Fig 2).	('RelB', 'Gene', '5971', (19, 23))	('high', 'Var', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('RelB', 'Gene', '5971', (84, 88))	('shorter', 'NegReg', (53, 60))	('RelB', 'Gene', (19, 23))	('RelB', 'Gene', (84, 88))
364100	27385983	Importantly, high RelB expression could be considered an independent prognostic factor for lower OS in patients with NSCLC.	('NSCLC', 'Disease', (117, 122))	('RelB', 'Gene', (18, 22))	('high', 'Var', (13, 17))	('NSCLC', 'Disease', 'MESH:D002289', (117, 122))	('RelB', 'Gene', '5971', (18, 22))	('patients', 'Species', '9606', (103, 111))	('NSCLC', 'Phenotype', 'HP:0030358', (117, 122))	('lower OS', 'Disease', (91, 99))	('expression', 'MPA', (23, 33))
364111	27385983	Moreover, according to multivariate analyses, the high expression of RelB protein was a significant predictor of poor prognosis in NSCLC patients (HR 6.983, P < 0.001).	('NSCLC', 'Disease', (131, 136))	('RelB', 'Gene', '5971', (69, 73))	('RelB', 'Gene', (69, 73))	('patients', 'Species', '9606', (137, 145))	('NSCLC', 'Disease', 'MESH:D002289', (131, 136))	('NSCLC', 'Phenotype', 'HP:0030358', (131, 136))	('high', 'Var', (50, 54))
364112	27385983	In conclusion, based on IHC assay combined with clinicopathological characteristic analyses, our study indicated a strong clinical and prognostic significance of high RelB expression in NSCLC patients.	('NSCLC', 'Phenotype', 'HP:0030358', (186, 191))	('RelB', 'Gene', '5971', (167, 171))	('patients', 'Species', '9606', (192, 200))	('NSCLC', 'Disease', (186, 191))	('NSCLC', 'Disease', 'MESH:D002289', (186, 191))	('high', 'Var', (162, 166))	('RelB', 'Gene', (167, 171))
364195	24376802	Figure 7C  shows that A431 spheroid-derived cells are enriched for expression of Ezh2, H3K27me3, Bmi-1 and Sox2.	('Sox2', 'Gene', '6657', (107, 111))	('Ezh2', 'Gene', (81, 85))	('Sox2', 'Gene', (107, 111))	('Ezh2', 'Gene', '2146', (81, 85))	('A431', 'CellLine', 'CVCL:0037', (22, 26))	('Bmi-1', 'Gene', '648', (97, 102))	('H3K27me3', 'Var', (87, 95))	('Bmi-1', 'Gene', (97, 102))
364231	24376802	H3K27me3 formation is a chromatin mark that is associated with silencing of tumor suppressor gene expression.	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('silencing', 'NegReg', (63, 72))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('H3K27me3 formation', 'Var', (0, 18))
364262	24376802	DMEM (11960-077), sodium pyruvate, (11360-070), L-Glutamine (25030-164), penicillin-streptomycin solution (15140-122), 0.25% trypsin-EDTA (25200-056) were purchased from Gibco (Grand Island, NY).	('penicillin', 'Chemical', 'MESH:D010406', (73, 83))	('DMEM', 'Chemical', '-', (0, 4))	('11360-070', 'Var', (36, 45))	('L-Glutamine', 'Chemical', 'MESH:D005973', (48, 59))	('sodium pyruvate', 'Chemical', '-', (18, 33))	('11960-077', 'Var', (6, 15))	('streptomycin', 'Chemical', 'MESH:D013307', (84, 96))	('EDTA', 'Chemical', 'MESH:D004492', (133, 137))	('15140-122', 'Var', (107, 116))	('25030-164', 'Var', (61, 70))
364263	24376802	Antibodies for Ezh2 (612667) and Oct4 (611203) were obtained from BD transduction laboratories (San Jose, CA).	('612667', 'Var', (21, 27))	('Oct4', 'Gene', '5460', (33, 37))	('611203', 'Var', (39, 45))	('Oct4', 'Gene', (33, 37))	('rat', 'Species', '10116', (86, 89))	('Ezh2', 'Gene', (15, 19))	('Ezh2', 'Gene', '2146', (15, 19))
364264	24376802	Antibodies of Sox2 (ab15830-100), CD200 (ab23552), Bmi-1 (ab14389) and ALDH1 (ab23375) were obtained from Abcam.	('Sox2', 'Gene', (14, 18))	('CD200', 'Gene', (34, 39))	('ab15830-100', 'Var', (20, 31))	('Sox2', 'Gene', '6657', (14, 18))	('ALDH1', 'Gene', '216', (71, 76))	('ALDH1', 'Gene', (71, 76))	('Bmi-1', 'Gene', '648', (51, 56))	('CD200', 'Gene', '4345', (34, 39))	('Bmi-1', 'Gene', (51, 56))	('ab23375', 'Var', (78, 85))
364266	24376802	Anti-mouse IgM magnetic microbeads (#130-047-301) and anti-CD71 (transferrin receptor) (#130-046-201) magnetic microbeads were obtained from Miltenyi Biotech (Cambridge, MA).	('#130-046-201', 'Var', (88, 100))	('CD71', 'Gene', (59, 63))	('transferrin receptor', 'Gene', (65, 85))	('transferrin receptor', 'Gene', '7037', (65, 85))	('CD71', 'Gene', '7037', (59, 63))	('mouse', 'Species', '10090', (5, 10))	('#130-047-301', 'Var', (36, 48))
364267	24376802	Alexa Fluor 594 goat anti-rat IgG (A11007), Alexa Fluor 488 goat anti-mouse IgG (A21121) and Alexa Fluor 594 goat anti-rabbit IgG (A11012) secondary antibodies were obtained from Invitrogen and used at 1:500 dilution.	('goat', 'Species', '9925', (109, 113))	('goat', 'Species', '9925', (60, 64))	('goat', 'Species', '9925', (16, 20))	('Alexa Fluor 594', 'Chemical', '-', (93, 108))	('mouse', 'Species', '10090', (70, 75))	('rat', 'Species', '10116', (26, 29))	('Alexa Fluor 488', 'Chemical', '-', (44, 59))	('rabbit', 'Species', '9986', (119, 125))	('A11012', 'Var', (131, 137))	('Alexa Fluor 594', 'Chemical', '-', (0, 15))	('A11007', 'Var', (35, 41))
364355	31885738	Recent studies have indicated that HMGA2 and LINC00858 function as ceRNA to promote lung cancer progression and MTAT rs1061451 was a protective factor of non-small-cell lung cancer (NSCLC).	('promote', 'PosReg', (76, 83))	('non-small-cell lung cancer', 'Disease', (154, 180))	('lung cancer', 'Phenotype', 'HP:0100526', (84, 95))	('non-small-cell lung cancer', 'Disease', 'MESH:D002289', (154, 180))	('NSCLC', 'Disease', 'MESH:D002289', (182, 187))	('HMGA2', 'Gene', '8091', (35, 40))	('lung cancer', 'Phenotype', 'HP:0100526', (169, 180))	('rs1061451', 'Mutation', 'rs1061451', (117, 126))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('NSCLC', 'Disease', (182, 187))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (158, 180))	('NSCLC', 'Phenotype', 'HP:0030358', (182, 187))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('lung cancer', 'Disease', (84, 95))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (154, 180))	('HMGA2', 'Gene', (35, 40))	('LINC00858', 'Gene', (45, 54))	('MTAT rs1061451', 'Var', (112, 126))	('LINC00858', 'Gene', '170425', (45, 54))
364357	31885738	miR-574-5p, miR-874, and miR-361-3p dysregulation was associated with metastasis of non-small-cell lung cancer (NSCLC).	('metastasis', 'CPA', (70, 80))	('miR-874', 'Gene', (12, 19))	('miR-361-3p', 'Gene', (25, 35))	('miR-874', 'Gene', '100126343', (12, 19))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('NSCLC', 'Phenotype', 'HP:0030358', (112, 117))	('miR-574-5p', 'Var', (0, 10))	('non-small-cell lung cancer', 'Disease', (84, 110))	('miR-361-3p', 'Gene', '100500908', (25, 35))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (84, 110))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (88, 110))	('associated', 'Reg', (54, 64))	('lung cancer', 'Phenotype', 'HP:0100526', (99, 110))
364369	31885738	Abnormally expressed lncRNAs can play an important role in tumor suppressor or oncogenes, in tumorigenesis and development of lung cancer, breast cancer, and prostate cancer.	('play', 'Reg', (33, 37))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('tumorigenesis', 'CPA', (93, 106))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('lung cancer', 'Disease', (126, 137))	('breast cancer', 'Phenotype', 'HP:0003002', (139, 152))	('oncogenes', 'Gene', (79, 88))	('prostate cancer', 'Disease', 'MESH:D011471', (158, 173))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('role', 'Reg', (51, 55))	('prostate cancer', 'Phenotype', 'HP:0012125', (158, 173))	('prostate cancer', 'Disease', (158, 173))	('breast cancer', 'Disease', 'MESH:D001943', (139, 152))	('breast cancer', 'Disease', (139, 152))	('Abnormally expressed', 'Var', (0, 20))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('lncRNAs', 'Protein', (21, 28))	('lung cancer', 'Phenotype', 'HP:0100526', (126, 137))	('tumor suppressor', 'CPA', (59, 75))
364372	31885738	It has been reported that dysregulated miRNAs play various roles in initiation, progression, invasiveness, and metastasis of tumors.	('invasiveness', 'CPA', (93, 105))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('metastasis of tumors', 'Disease', 'MESH:D009362', (111, 131))	('progression', 'CPA', (80, 91))	('dysregulated', 'Var', (26, 38))	('metastasis of tumors', 'Disease', (111, 131))	('miRNAs', 'Protein', (39, 45))
364373	31885738	More importantly, comparative analysis of the two groups of ceRNA network showed only three unique DEmiRNAs (hsa-miR-140, hsa-miR-193b, and hsa-miR-182) in the smoking group.	('hsa-miR-182', 'Var', (140, 151))	('hsa-miR-140', 'Gene', '406932', (109, 120))	('hsa-miR-140', 'Gene', (109, 120))	('hsa-miR-193b', 'Gene', (122, 134))	('hsa-miR-193b', 'Gene', '574455', (122, 134))
364388	29712937	GCR also generates non-targeted effects in cells not directly traversed by radiation tracks (bystander effects), which may account for as much as half of the cancer risk at doses relevant to human exposure.	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('cancer', 'Disease', (158, 164))	('non-targeted effects', 'MPA', (19, 39))	('human', 'Species', '9606', (191, 196))	('GCR', 'Var', (0, 3))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
364395	29712937	In contrast, exposure to protons and high-LET species (28Si, 56Fe, 48Ti-ion) are often, though not always, associated with increases in global and/or repetitive element methylation although this too exhibits significant dose, time (acute vs. latent) and tissue/cell type dependence.	('global', 'MPA', (136, 142))	('56Fe', 'Chemical', '-', (61, 65))	('28Si', 'Var', (55, 59))	('28Si', 'Chemical', '-', (55, 59))	('increases', 'PosReg', (123, 132))
364416	29712937	We examined the distribution of CpG sites significantly associated with 56Fe ion, 28Si ion, or X ray dose relative to genetic features, including the distribution in and around CpG islands and genes (Fig.	('28Si', 'Chemical', '-', (82, 86))	('56Fe', 'Var', (72, 76))	('56Fe', 'Chemical', '-', (72, 76))	('associated', 'Reg', (56, 66))
364441	29712937	While there is no way to directly relate our nucleotide level analysis with these broader scale observations, it is intriguing to speculate that a persistence of radiation-induced lesions in heterochromatin might underlie the differences in tumor-promoting activities between high-LET and low-LET irradiation or even that between different HZE ions.	('lesions', 'Var', (180, 187))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))	('tumor', 'Disease', 'MESH:D009369', (241, 246))	('tumor', 'Disease', (241, 246))
364456	29712937	We find here that the CpG sites affected by 56Fe were enriched in these regions, making it interesting to speculate that the increased methylation observed might reflect irradiation-induced impairment of 5mC turnover.	('56Fe', 'Chemical', '-', (44, 48))	('increased', 'PosReg', (125, 134))	('5mC', 'Chemical', '-', (204, 207))	('methylation', 'MPA', (135, 146))	('56Fe', 'Var', (44, 48))
364461	29712937	Interestingly, a gene expression signature specifically associated with fractionated 56Fe ion -promoted lung tumorigenesis and derived 70 days after the initial insult in mouse lung could accurately predict overall survival among patients with lung or breast cancer.	('breast cancer', 'Disease', (252, 265))	('breast cancer', 'Phenotype', 'HP:0003002', (252, 265))	('predict', 'Reg', (199, 206))	('lung', 'Disease', (244, 248))	('56Fe', 'Chemical', '-', (85, 89))	('patients', 'Species', '9606', (230, 238))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('cancer', 'Phenotype', 'HP:0002664', (259, 265))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('mouse', 'Species', '10090', (171, 176))	('breast cancer', 'Disease', 'MESH:D001943', (252, 265))	('fractionated', 'Var', (72, 84))	('tumor', 'Disease', (109, 114))
364465	29712937	While hypermethylation of normally unmethylated CpG island containing promoters is a well-described mechanism for the inactivation of tumor suppressor genes in cancer, recent studies underscore the contribution of altered methylation at enhancer elements as an important contributor to the aberrant gene expression programs that define human cancers.	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('cancer', 'Disease', 'MESH:D009369', (342, 348))	('cancer', 'Phenotype', 'HP:0002664', (342, 348))	('cancer', 'Disease', (160, 166))	('cancer', 'Disease', (342, 348))	('inactivation', 'NegReg', (118, 130))	('cancers', 'Phenotype', 'HP:0002664', (342, 349))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('cancers', 'Disease', (342, 349))	('cancers', 'Disease', 'MESH:D009369', (342, 349))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('altered', 'Var', (214, 221))	('methylation', 'MPA', (222, 233))	('tumor', 'Disease', (134, 139))	('human', 'Species', '9606', (336, 341))
364480	29712937	ENCODE ChIP-seq data sets derived from A549 lung cancer cells (H3K27Ac, ENCSR000AUI; H3K4me3 ENCSR000ASH; DNaseI, ENCSR136DNA) were downloaded as mapped bam files from the ENCODE project website (https://www.encodeproject.org).	('lung cancer', 'Phenotype', 'HP:0100526', (44, 55))	('H3K4me3', 'Var', (85, 92))	('A549 lung cancer', 'Disease', (39, 55))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('A549 lung cancer', 'Disease', 'MESH:D008175', (39, 55))
364493	25766659	Meanwhile, ethanol may also disturb fatty-acid metabolism in these cells.	('fatty-acid metabolism', 'MPA', (36, 57))	('ethanol', 'Var', (11, 18))	('fatty-acid', 'Chemical', 'MESH:D005227', (36, 46))	('disturb fatty-acid metabolism', 'Phenotype', 'HP:0004359', (28, 57))	('disturb', 'Reg', (28, 35))	('ethanol', 'Chemical', 'MESH:D000431', (11, 18))
364494	25766659	(3) Disturbance of signaling pathways in squamous epithelial cells: due to its physico-chemical properties, ethanol changes cell membrane fluidity and shape, and may thus impact multiple signaling pathways.	('ethanol', 'Chemical', 'MESH:D000431', (108, 115))	('impact', 'Reg', (171, 177))	('cell membrane fluidity', 'MPA', (124, 146))	('changes', 'Reg', (116, 123))	('ethanol', 'Var', (108, 115))
364506	25766659	Genetic polymorphisms of ethanol-metabolizing genes, such as acetaldehyde dehydrogenase (ALDH) and alcohol dehydrogenases (ADH), are associated with OESCC.	('hydrogen', 'Chemical', 'MESH:D006859', (109, 117))	('SCC', 'Phenotype', 'HP:0002860', (151, 154))	('ALDH', 'Gene', '11670', (89, 93))	('SCC', 'Gene', '6317', (151, 154))	('associated', 'Reg', (133, 143))	('acetaldehyde dehydrogenase', 'Gene', (61, 87))	('alcohol', 'Chemical', 'MESH:D000438', (99, 106))	('acetaldehyde dehydrogenase', 'Gene', '11670', (61, 87))	('ALDH', 'Gene', (89, 93))	('hydrogen', 'Chemical', 'MESH:D006859', (76, 84))	('polymorphisms', 'Var', (8, 21))	('ethanol', 'Chemical', 'MESH:D000431', (25, 32))	('SCC', 'Gene', (151, 154))
364543	25766659	Alcohol drinking has been shown to cause iron overload in the liver.	('Alcohol drinking', 'Var', (0, 16))	('iron', 'Chemical', 'MESH:D007501', (41, 45))	('iron overload', 'MPA', (41, 54))	('Alcohol', 'Chemical', 'MESH:D000438', (0, 7))	('Alcohol drinking', 'Phenotype', 'HP:0030955', (0, 16))	('cause', 'Reg', (35, 40))
364546	25766659	Mechanistically, iron overload may initiate and promote carcinogenesis through oxidative damage and modification of the immune reaction.	('iron overload', 'Var', (17, 30))	('immune reaction', 'CPA', (120, 135))	('modification', 'Reg', (100, 112))	('carcinogenesis', 'Disease', 'MESH:D063646', (56, 70))	('iron', 'Chemical', 'MESH:D007501', (17, 21))	('oxidative damage', 'CPA', (79, 95))	('promote', 'PosReg', (48, 55))	('carcinogenesis', 'Disease', (56, 70))
364550	25766659	Inhibition of methyl group transfer regulates expression of genes involved in carcinogenesis.	('carcinogenesis', 'Disease', 'MESH:D063646', (78, 92))	('regulates', 'Reg', (36, 45))	('carcinogenesis', 'Disease', (78, 92))	('Inhibition', 'Var', (0, 10))	('expression of genes', 'MPA', (46, 65))
364551	25766659	DNA hypomethylation of oncogenes (e.g., c-Ha-ras, c-Ki-ras and c-fos) is associated with an increased incidence of liver cancer in rats.	('c-Ki-ras', 'Gene', '24525', (50, 58))	('hypomethylation', 'Var', (4, 19))	('rats', 'Species', '10116', (131, 135))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('c-fos', 'Gene', (63, 68))	('liver cancer', 'Phenotype', 'HP:0002896', (115, 127))	('liver cancer', 'Disease', 'MESH:D006528', (115, 127))	('liver cancer', 'Disease', (115, 127))	('c-fos', 'Gene', '314322', (63, 68))	('c-Ha-ras', 'Var', (40, 48))	('c-Ki-ras', 'Gene', (50, 58))
364552	25766659	These data suggest that ethanol may contribute to OESCC through aberrant gene methylation.	('ethanol', 'Chemical', 'MESH:D000431', (24, 31))	('SCC', 'Gene', (52, 55))	('SCC', 'Phenotype', 'HP:0002860', (52, 55))	('SCC', 'Gene', '6317', (52, 55))	('aberrant gene methylation', 'Var', (64, 89))
364553	25766659	In addition, aberrant gene methylation may impact signaling pathways through critical pathway genes, such as Notch4 of the Notch signaling pathway, PTEN of the phospoinositide 3-kinase (PI3K)/Akt pathway, and Wnt inhibitory factor 1 (WIF1) of the Wnt signaling pathway.	('signaling pathways', 'Pathway', (50, 68))	('PTEN', 'Gene', (148, 152))	('PTEN', 'Gene', '19211', (148, 152))	('impact', 'Reg', (43, 49))	('WIF1', 'Gene', (234, 238))	('Wnt inhibitory factor 1', 'Gene', '24117', (209, 232))	('Notch4', 'Gene', (109, 115))	('Wnt inhibitory factor 1', 'Gene', (209, 232))	('WIF1', 'Gene', '24117', (234, 238))	('Notch signaling pathway', 'Pathway', (123, 146))	('PI3', 'Gene', (186, 189))	('methylation', 'Var', (27, 38))	('phospoinositide 3-kinase', 'Gene', (160, 184))	('phospoinositide 3-kinase', 'Gene', '18708', (160, 184))	('gene', 'Protein', (22, 26))	('Notch4', 'Gene', '18132', (109, 115))	('PI3', 'Gene', '20702', (186, 189))	('aberrant', 'Var', (13, 21))
364556	25766659	Oral epithelium expresses chi and sigma type ADH with high Km values (ADH3 and ADH4), and a negligible amount of ALDH.	('sigma type ADH', 'Disease', 'MESH:D007177', (34, 48))	('ADH3', 'Gene', (70, 74))	('ALDH', 'Gene', (113, 117))	('ADH3', 'Gene', '11529', (70, 74))	('ADH4', 'Gene', (79, 83))	('ADH4', 'Gene', '26876', (79, 83))	('chi', 'Var', (26, 29))	('sigma type ADH', 'Disease', (34, 48))	('ALDH', 'Gene', '11670', (113, 117))
364565	25766659	As the most abundant DNA adduct, N2-ethylidene-2'-deoxyguanosine (N2-EtidG), impairs the DNA repair system and apoptosis.	('impairs', 'NegReg', (77, 84))	("N2-ethylidene-2'-deoxyguanosine", 'Chemical', 'MESH:C525837', (33, 64))	('DNA', 'MPA', (89, 92))	('N2-EtidG', 'Chemical', 'MESH:C525837', (66, 74))	("N2-ethylidene-2'-deoxyguanosine", 'Var', (33, 64))	('apoptosis', 'CPA', (111, 120))
364568	25766659	In animals, lack of ALDH2 leads to an increased level of N2-EtidG in the mouse upper aerodigestive tract after ethanol treatment.	('lack', 'Var', (12, 16))	('level of N2-EtidG', 'MPA', (48, 65))	('ethanol', 'Chemical', 'MESH:D000431', (111, 118))	('ALDH2', 'Gene', (20, 25))	('mouse', 'Species', '10090', (73, 78))	('N2-EtidG', 'Chemical', 'MESH:C525837', (57, 65))	('increased', 'PosReg', (38, 47))
364575	25766659	Furthermore, ethanol can induce hyperacetylation of proteins such as histone H3, p53 and SREBP-1c, perturbing hepatic function.	('p53', 'Gene', '22060', (81, 84))	('hepatic function', 'MPA', (110, 126))	('ethanol', 'Chemical', 'MESH:D000431', (13, 20))	('perturbing', 'NegReg', (99, 109))	('proteins', 'Protein', (52, 60))	('ethanol', 'Var', (13, 20))	('hyperacetylation', 'MPA', (32, 48))	('p53', 'Gene', (81, 84))	('histone H3', 'Protein', (69, 79))	('SREBP-1c', 'Gene', '20787', (89, 97))	('SREBP-1c', 'Gene', (89, 97))	('perturbing hepatic function', 'Phenotype', 'HP:0001410', (99, 126))
364582	25766659	Activation of Nrf2 prevents ethanol-induced oxidative stress, lipid accumulation and accelerated acetaldehyde metabolism.	('acetaldehyde metabolism', 'Phenotype', 'HP:0003533', (97, 120))	('oxidative stress', 'Phenotype', 'HP:0025464', (44, 60))	('lipid accumulation', 'MPA', (62, 80))	('Nrf2', 'Gene', '18024', (14, 18))	('rat', 'Species', '10116', (91, 94))	('accelerated', 'PosReg', (85, 96))	('prevents', 'NegReg', (19, 27))	('lipid', 'Chemical', 'MESH:D008055', (62, 67))	('Nrf2', 'Gene', (14, 18))	('oxidative stress', 'MPA', (44, 60))	('Activation', 'Var', (0, 10))	('acetaldehyde', 'Chemical', 'MESH:D000079', (97, 109))	('acetaldehyde metabolism', 'MPA', (97, 120))	('ethanol', 'Chemical', 'MESH:D000431', (28, 35))
364588	25766659	Elovl6 deficient mice became obese and developed hepatosteatosis when fed a high-fat diet.	('obese', 'Disease', 'MESH:D009765', (29, 34))	('mice', 'Species', '10090', (17, 21))	('obese', 'Disease', (29, 34))	('Elovl6', 'Gene', (0, 6))	('hepatosteatosis', 'Disease', (49, 64))	('deficient', 'Var', (7, 16))	('hepatosteatosis', 'Disease', 'None', (49, 64))	('developed', 'Reg', (39, 48))
364609	25766659	In the oral cavity, Notch1 is highly activated in oral epithelium differentiation, and disrupted Notch1 interferes with normal palate development.	('Notch1', 'Gene', '18128', (20, 26))	('normal palate development', 'CPA', (120, 145))	('interferes', 'NegReg', (104, 114))	('Notch1', 'Gene', (97, 103))	('Notch1', 'Gene', '18128', (97, 103))	('Notch1', 'Gene', (20, 26))	('disrupted', 'Var', (87, 96))
364610	25766659	Exome sequencing has shown in multiple studies that loss-of-function Notch mutations are frequently seen in OESCC.	('SCC', 'Gene', (110, 113))	('SCC', 'Phenotype', 'HP:0002860', (110, 113))	('loss-of-function', 'NegReg', (52, 68))	('Notch', 'Gene', (69, 74))	('mutations', 'Var', (75, 84))	('SCC', 'Gene', '6317', (110, 113))
364642	25766659	In head and neck SCC, loss of type 2 TGFbeta receptor or Smad4 not only abrogates TGFbeta-mediated tumor suppression, but also causes a compensatory increase in TGFbeta ligand expression that promotes inflammation and angiogenesis.	('abrogates', 'NegReg', (72, 81))	('tumor', 'Disease', (99, 104))	('inflammation', 'Disease', 'MESH:D007249', (201, 213))	('SCC', 'Phenotype', 'HP:0002860', (17, 20))	('increase', 'PosReg', (149, 157))	('inflammation', 'Disease', (201, 213))	('promotes', 'PosReg', (192, 200))	('Smad4', 'Gene', '17128', (57, 62))	('angiogenesis', 'CPA', (218, 230))	('TGFbeta', 'Protein', (161, 168))	('SCC', 'Gene', '6317', (17, 20))	('expression', 'MPA', (176, 186))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('Smad4', 'Gene', (57, 62))	('TGFbeta-mediated', 'Gene', (82, 98))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('loss', 'Var', (22, 26))	('SCC', 'Gene', (17, 20))
364646	25766659	In the oro-esophagus, NFkappaB alleles are associated with oral carcinogenesis.	('associated with', 'Reg', (43, 58))	('NFkappaB', 'Gene', (22, 30))	('alleles', 'Var', (31, 38))	('NFkappaB', 'Gene', '18033', (22, 30))	('oral carcinogenesis', 'Disease', 'MESH:D063646', (59, 78))	('oral carcinogenesis', 'Disease', (59, 78))
364674	25766659	Knockdown of Notch1 enhances the activation of Wnt target genes, whereas chemical inhibition of gamma-secretase or expression of a Notch1 mutant inhibits Wnt signaling.	('Wnt signaling', 'MPA', (154, 167))	('Notch1', 'Gene', '18128', (13, 19))	('mutant', 'Var', (138, 144))	('Notch1', 'Gene', (131, 137))	('Notch1', 'Gene', '18128', (131, 137))	('enhances', 'PosReg', (20, 28))	('inhibits', 'NegReg', (145, 153))	('activation', 'MPA', (33, 43))	('Wnt target', 'Gene', (47, 57))	('Notch1', 'Gene', (13, 19))
364677	25766659	Nrf2 disruption impedes liver regeneration which can be rescued by reestablishment of Notch1 signaling.	('liver regeneration', 'CPA', (24, 42))	('Nrf2', 'Gene', '18024', (0, 4))	('Notch1', 'Gene', (86, 92))	('rat', 'Species', '10116', (36, 39))	('disruption', 'Var', (5, 15))	('Notch1', 'Gene', '18128', (86, 92))	('Nrf2', 'Gene', (0, 4))	('impedes', 'NegReg', (16, 23))
364694	25766659	Genomics techniques such as NextGen sequencing, CGH array and SNP array are used for detection of DNA alterations, RNA-Seq and microarray for detection of mRNA differential expression, and methylation array for detection of alterations in gene methylation.	('alterations', 'Var', (102, 113))	('rat', 'Species', '10116', (228, 231))	('DNA', 'MPA', (98, 101))	('rat', 'Species', '10116', (106, 109))	('mRNA differential expression', 'MPA', (155, 183))
364706	32860308	We found that knockdown of Spt16 led to obvious decreases of both Rb and MCM7, and further activated the DNA damage response (DDR) pathway.	('DDR', 'Chemical', '-', (126, 129))	('decreases', 'NegReg', (48, 57))	('MCM7', 'Gene', (73, 77))	('Rb', 'Chemical', 'MESH:D012413', (66, 68))	('activated', 'PosReg', (91, 100))	('Spt16', 'Gene', (27, 32))	('knockdown', 'Var', (14, 23))	('MCM7', 'Gene', '4176', (73, 77))
364708	32860308	Furthermore, we found that CBL0137, the functional inhibitor of FACT, showed similar effects as loss of Spt16.	('CBL0137', 'Chemical', 'MESH:C000600493', (27, 34))	('loss', 'NegReg', (96, 100))	('CBL0137', 'Var', (27, 34))	('Spt16', 'Gene', (104, 109))
364720	32860308	For instance, knockdown of Spt16 decreased the expression of the genes that were not influenced by loss of SSRP1.	('expression of the genes', 'MPA', (47, 70))	('SSRP1', 'Gene', '6749', (107, 112))	('Spt16', 'Gene', (27, 32))	('knockdown', 'Var', (14, 23))	('decreased', 'NegReg', (33, 42))	('SSRP1', 'Gene', (107, 112))
364727	32860308	10  In breast cancer, knockdown of Spt16 suppressed cell viability, and higher Spt16-expressing cancer cells were more prone to Spt16 depletion-induced cell death compared with lower Spt16-expressing cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('suppressed', 'NegReg', (41, 51))	('knockdown', 'Var', (22, 31))	('breast cancer', 'Phenotype', 'HP:0003002', (7, 20))	('cancer', 'Disease', 'MESH:D009369', (14, 20))	('cancer', 'Disease', (96, 102))	('breast cancer', 'Disease', 'MESH:D001943', (7, 20))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('death', 'Disease', (157, 162))	('breast cancer', 'Disease', (7, 20))	('cancer', 'Disease', 'MESH:D009369', (200, 206))	('Spt16', 'Gene', (35, 40))	('Spt16-expressing', 'Gene', (79, 95))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Disease', (14, 20))	('death', 'Disease', 'MESH:D003643', (157, 162))	('cell viability', 'CPA', (52, 66))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('cancer', 'Disease', (200, 206))
364734	32860308	BEAS-2B was cultured in High Glucose DMEM (#SH30022.01, Hyclone) supplemented with 10% FBS (#SH30084.03, Hyclone).	('#SH30022.01', 'Var', (43, 54))	('High Glucose', 'Phenotype', 'HP:0003074', (24, 36))	('BEAS-2B', 'Chemical', '-', (0, 7))	('High Glucose DMEM', 'Disease', 'MESH:D044882', (24, 41))	('High Glucose DMEM', 'Disease', (24, 41))	('#SH30084.03', 'Var', (92, 103))
364738	32860308	Cells were infected in the presence of 5 mug/mL polybrene according to the manufacturer's instructions.	('polybrene', 'Chemical', 'MESH:D006583', (48, 57))	('polybrene', 'Var', (48, 57))	('infected', 'Disease', 'MESH:D007239', (11, 19))	('mL', 'Gene', '21832', (45, 47))	('infected', 'Disease', (11, 19))
364753	32860308	Antibodies against p-ATR (2853), p-ATM (5883), p-BRCA1 (9009), p-CHK2 (Thr1079, 8654), N-cadherin (13116), E-cadherin (3195), ZO-1 (13663), vimentin (5741), Snail (3879), Bcl-2 (4223), cleaved caspase 7 (8438), and cyclin D1 (55506) were purchased from Cell Signaling Technology.	('caspase 7', 'Gene', '840', (193, 202))	('CHK2', 'Gene', (65, 69))	('Bcl-2', 'Gene', (171, 176))	('E-cadherin', 'Gene', (107, 117))	('E-cadherin', 'Gene', '999', (107, 117))	('Snail', 'Gene', '6615', (157, 162))	('cyclin D1', 'Gene', (215, 224))	('ATR', 'Gene', (21, 24))	('Bcl-2', 'Gene', '596', (171, 176))	('13116', 'Var', (99, 104))	('ZO-1', 'Gene', '7082', (126, 130))	('CHK2', 'Gene', '11200', (65, 69))	('ATM', 'Gene', '472', (35, 38))	('BRCA1', 'Gene', '672', (49, 54))	('cyclin D1', 'Gene', '595', (215, 224))	('ZO-1', 'Gene', (126, 130))	('BRCA1', 'Gene', (49, 54))	('caspase 7', 'Gene', (193, 202))	('Snail', 'Gene', (157, 162))	('ATR', 'Gene', '545', (21, 24))	('N-cadherin', 'Gene', (87, 97))	('ATM', 'Gene', (35, 38))	('vimentin', 'Gene', '7431', (140, 148))	('N-cadherin', 'Gene', '1000', (87, 97))	('vimentin', 'Gene', (140, 148))
364754	32860308	Antibodies against p-Rb (sc-377539), cyclin E (sc-377100), MCM7 (sc-9966), and Rb (sc-102) were purchased from Santa Cruz Biotechnology.	('MCM7', 'Gene', (59, 63))	('sc-377100', 'Var', (47, 56))	('sc-377539', 'Var', (25, 34))	('Rb', 'Chemical', 'MESH:D012413', (21, 23))	('p-Rb', 'Gene', (19, 23))	('Rb', 'Chemical', 'MESH:D012413', (79, 81))	('p-Rb', 'Gene', '5925', (19, 23))	('MCM7', 'Gene', '4176', (59, 63))
364786	32860308	Consistently, we found that loss of Spt16 also led to an impaired xenograft tumor growth (Figure 2D).	('loss', 'Var', (28, 32))	('Spt16', 'Gene', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('impaired xenograft tumor', 'Disease', 'MESH:D060825', (57, 81))	('impaired xenograft tumor', 'Disease', (57, 81))
364787	32860308	Together, these data suggested that knockdown of Spt16 inhibits lung cancer cell growth both in vitro and in vivo.	('lung cancer', 'Disease', (64, 75))	('lung cancer', 'Phenotype', 'HP:0100526', (64, 75))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('inhibits', 'NegReg', (55, 63))	('knockdown', 'Var', (36, 45))	('lung cancer', 'Disease', 'MESH:D008175', (64, 75))	('Spt16', 'Gene', (49, 54))
364789	32860308	Our data suggested that knockdown of Spt16 expression led to an accumulation of cells in the G0/G1-phase and a decrease of cells in the S-phase in both A549 and NCI-H1299 cells (Figure 3A).	('A549', 'CellLine', 'CVCL:0023', (152, 156))	('cells in the G0/G1-phase', 'CPA', (80, 104))	('NCI-H1299', 'CellLine', 'CVCL:0060', (161, 170))	('cells in the', 'CPA', (123, 135))	('decrease', 'NegReg', (111, 119))	('knockdown', 'Var', (24, 33))	('Spt16', 'Gene', (37, 42))	('accumulation', 'PosReg', (64, 76))
364792	32860308	The levels of a series of cell cycle regulators that are essential for G1/S transition are impaired after Spt16 depletion, including phosphorylated Rb (p-Rb), cyclin D1, and cyclin E1 (Figure 3C).	('cyclin D1', 'Gene', (159, 168))	('cyclin E1', 'Gene', '898', (174, 183))	('impaired', 'NegReg', (91, 99))	('Spt16', 'Gene', (106, 111))	('depletion', 'Var', (112, 121))	('Rb (p-Rb', 'Gene', '5925', (148, 156))	('cyclin E1', 'Gene', (174, 183))	('levels of a series of', 'MPA', (4, 25))	('cyclin D1', 'Gene', '595', (159, 168))
364794	32860308	Thus, the above data indicated that Spt16 depletion impairs cell cycle progression and promotes apoptosis in human lung cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('human', 'Species', '9606', (109, 114))	('lung cancer', 'Disease', (115, 126))	('Spt16', 'Gene', (36, 41))	('lung cancer', 'Disease', 'MESH:D008175', (115, 126))	('promotes', 'PosReg', (87, 95))	('apoptosis', 'CPA', (96, 105))	('impairs', 'NegReg', (52, 59))	('depletion', 'Var', (42, 51))	('cell cycle progression', 'CPA', (60, 82))	('lung cancer', 'Phenotype', 'HP:0100526', (115, 126))
364795	32860308	We found that knockdown of Spt16 resulted in significant decreases in the protein levels of both Rb and MCM7 in A549, NCI-H1299, and NCI-H460 lung cancer cells (Figure 4A).	('A549', 'CellLine', 'CVCL:0023', (112, 116))	('MCM7', 'Gene', '4176', (104, 108))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('NCI-H460 lung cancer', 'Disease', (133, 153))	('NCI-H1299', 'CellLine', 'CVCL:0060', (118, 127))	('MCM7', 'Gene', (104, 108))	('Spt16', 'Gene', (27, 32))	('lung cancer', 'Phenotype', 'HP:0100526', (142, 153))	('knockdown', 'Var', (14, 23))	('decreases', 'NegReg', (57, 66))	('NCI-H460 lung cancer', 'Disease', 'MESH:D008175', (133, 153))	('protein levels', 'MPA', (74, 88))	('Rb', 'Chemical', 'MESH:D012413', (97, 99))
364797	32860308	Our previous work demonstrated that co-depletion of MCM7 and Rb caused severe DNA damage and further activated DDR.	('MCM7', 'Gene', '4176', (52, 56))	('co-depletion', 'Var', (36, 48))	('Rb', 'Chemical', 'MESH:D012413', (61, 63))	('DNA', 'CPA', (78, 81))	('DDR', 'MPA', (111, 114))	('MCM7', 'Gene', (52, 56))	('DDR', 'Chemical', '-', (111, 114))	('activated', 'PosReg', (101, 110))
364799	32860308	In parallel with the changes of Rb and MCM7 after Spt16 depletion, our data confirmed that loss of Spt16 activated DDR (Figure 4C).	('Rb', 'Chemical', 'MESH:D012413', (32, 34))	('activated', 'PosReg', (105, 114))	('Spt16', 'Gene', (99, 104))	('MCM7', 'Gene', '4176', (39, 43))	('DDR', 'MPA', (115, 118))	('DDR', 'Chemical', '-', (115, 118))	('loss', 'Var', (91, 95))	('MCM7', 'Gene', (39, 43))
364808	32860308	Taken together, these data revealed that knockdown of Spt16 activates DDR likely by downregulating the expression of both Rb and MCM7.	('DDR likely', 'Disease', (70, 80))	('Spt16', 'Gene', (54, 59))	('Rb', 'Chemical', 'MESH:D012413', (122, 124))	('expression', 'MPA', (103, 113))	('MCM7', 'Gene', '4176', (129, 133))	('DDR', 'Chemical', '-', (70, 73))	('downregulating', 'NegReg', (84, 98))	('activates', 'PosReg', (60, 69))	('MCM7', 'Gene', (129, 133))	('knockdown', 'Var', (41, 50))
364811	32860308	Wound healing and transwell assays were performed, and the loss of Spt16 significantly impaired the migration and invasion rates of both A549 and NCI-H1299 cells (Figure 5A-C).	('impaired', 'NegReg', (87, 95))	('invasion rates', 'CPA', (114, 128))	('Spt16', 'Gene', (67, 72))	('migration', 'CPA', (100, 109))	('A549', 'CellLine', 'CVCL:0023', (137, 141))	('NCI-H1299', 'CellLine', 'CVCL:0060', (146, 155))	('loss', 'Var', (59, 63))
364814	32860308	Moreover, the levels of the EMT transcription factor, Snail, were also suppressed after Spt16 depletion (Figure 5D).	('Snail', 'Gene', (54, 59))	('Snail', 'Gene', '6615', (54, 59))	('suppressed', 'NegReg', (71, 81))	('levels of', 'MPA', (14, 23))	('depletion', 'Var', (94, 103))	('Spt16', 'Gene', (88, 93))
364817	32860308	Together, these results suggested that knockdown of Spt16 inhibits EMT, invasion, and metastasis of lung cancer cells both in vitro and in vivo.	('knockdown', 'Var', (39, 48))	('inhibits', 'NegReg', (58, 66))	('metastasis of lung cancer', 'Disease', (86, 111))	('EMT', 'CPA', (67, 70))	('lung cancer', 'Phenotype', 'HP:0100526', (100, 111))	('Spt16', 'Gene', (52, 57))	('metastasis of lung cancer', 'Disease', 'MESH:D008175', (86, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('invasion', 'CPA', (72, 80))
364819	32860308	Gain of copy numbers is the most frequent mechanism of oncogene overexpression in cancer cells.	('copy numbers', 'Var', (8, 20))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('Gain', 'PosReg', (0, 4))	('overexpression', 'PosReg', (64, 78))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))
364820	32860308	However, according to the data from cBioPortal (https://www.cbioportal.org/), the incidence of gene amplification in the Spt16 locus is quite low (<2%) in both lung adenocarcinoma and lung squamous cell carcinoma (Figure 6A).	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (189, 212))	('carcinoma', 'Phenotype', 'HP:0030731', (170, 179))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (160, 179))	('lung adenocarcinoma', 'Disease', (160, 179))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (184, 212))	('low', 'NegReg', (142, 145))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (160, 179))	('Spt16', 'Gene', (121, 126))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (184, 212))	('lung squamous cell carcinoma', 'Disease', (184, 212))	('carcinoma', 'Phenotype', 'HP:0030731', (203, 212))	('gene amplification', 'Var', (95, 113))
364825	32860308	The wild-type or mutated 3'-UTR of Spt16 were cloned into a luciferase reporter construct, and dual luciferase reporter assays were performed to determine the direct regulation of miR-1227-5p on the 3'-UTR of Spt16 (Figure 6F).	('miR-1227', 'Gene', '100302283', (180, 188))	('miR-1227', 'Gene', (180, 188))	('Spt16', 'Gene', (209, 214))	('Spt16', 'Gene', (35, 40))	('mutated', 'Var', (17, 24))
364831	32860308	FACS analyses showed that treatment with CBL0137 also resulted in an obvious increase in cell apoptosis in A549 and NCI-H1299 lung cancer cells, which is similar to the effects of Spt16 depletion on cell apoptosis (Figure S2C).	('CBL0137', 'Var', (41, 48))	('cell apoptosis', 'CPA', (89, 103))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('A549', 'CellLine', 'CVCL:0023', (107, 111))	('NCI-H1299 lung cancer', 'Disease', 'MESH:D008175', (116, 137))	('lung cancer', 'Phenotype', 'HP:0100526', (126, 137))	('CBL0137', 'Chemical', 'MESH:C000600493', (41, 48))	('NCI-H1299 lung cancer', 'Disease', (116, 137))	('increase', 'PosReg', (77, 85))
364832	32860308	Finally, decreases in the protein levels of MCM7 and Rb (Figure S2D) and an activation of DDR (Figure S2E and F) were also detected in lung cancer cells treated with CBL0137.	('CBL0137', 'Chemical', 'MESH:C000600493', (166, 173))	('lung cancer', 'Phenotype', 'HP:0100526', (135, 146))	('DDR', 'MPA', (90, 93))	('protein levels', 'MPA', (26, 40))	('MCM7', 'Gene', '4176', (44, 48))	('decreases', 'NegReg', (9, 18))	('CBL0137', 'Var', (166, 173))	('DDR', 'Chemical', '-', (90, 93))	('lung cancer', 'Disease', 'MESH:D008175', (135, 146))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('activation', 'PosReg', (76, 86))	('lung cancer', 'Disease', (135, 146))	('MCM7', 'Gene', (44, 48))	('Rb', 'Chemical', 'MESH:D012413', (53, 55))
364835	32860308	Our results indicated that both CBL0137 and miR-1227-5p mimic inhibited cell growth and promoted apoptosis in A549 lung cancer cells.	('cell growth', 'CPA', (72, 83))	('promoted', 'PosReg', (88, 96))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('A549', 'CellLine', 'CVCL:0023', (110, 114))	('miR-1227', 'Gene', '100302283', (44, 52))	('lung cancer', 'Disease', 'MESH:D008175', (115, 126))	('CBL0137', 'Var', (32, 39))	('miR-1227', 'Gene', (44, 52))	('inhibited', 'NegReg', (62, 71))	('lung cancer', 'Phenotype', 'HP:0100526', (115, 126))	('lung cancer', 'Disease', (115, 126))	('apoptosis', 'CPA', (97, 106))	('CBL0137', 'Chemical', 'MESH:C000600493', (32, 39))
364836	32860308	However, no obvious differences were observed between CBL0137, miR-1227-5p single treatment and the combinational treatment (Figure S3).	('CBL0137', 'Chemical', 'MESH:C000600493', (54, 61))	('miR-1227', 'Gene', (63, 71))	('miR-1227', 'Gene', '100302283', (63, 71))	('CBL0137', 'Var', (54, 61))
364842	32860308	Cyclin D1, cyclin E1, and p-Rb are well-known cell cycle regulators, we found that the levels of these regulators were downregulated after Spt16 depletion.	('cyclin E1', 'Gene', (11, 20))	('levels', 'MPA', (87, 93))	('downregulated', 'NegReg', (119, 132))	('Cyclin D1', 'Gene', '595', (0, 9))	('cyclin E1', 'Gene', '898', (11, 20))	('p-Rb', 'Gene', (26, 30))	('Cyclin D1', 'Gene', (0, 9))	('p-Rb', 'Gene', '5925', (26, 30))	('Spt16', 'Gene', (139, 144))	('depletion', 'Var', (145, 154))
364846	32860308	21 ,  22  Here, consistent with the effects of cleaved caspase-7 and Bcl-2, we found that loss of Spt16 significantly increased the levels of the cleaved caspase-7, while the levels of Bcl-2 were downregulated (Figure 3E), supporting the observation that cell apoptosis was increased after Spt16 depletion (Figure 3D).	('increased', 'PosReg', (274, 283))	('Spt16', 'Gene', (98, 103))	('caspase-7', 'Gene', (154, 163))	('Bcl-2', 'Gene', (69, 74))	('Bcl-2', 'Gene', '596', (69, 74))	('levels', 'MPA', (132, 138))	('caspase-7', 'Gene', '840', (154, 163))	('loss', 'Var', (90, 94))	('downregulated', 'NegReg', (196, 209))	('increased', 'PosReg', (118, 127))	('caspase-7', 'Gene', (55, 64))	('cell apoptosis', 'CPA', (255, 269))	('caspase-7', 'Gene', '840', (55, 64))	('Bcl-2', 'Gene', (185, 190))	('Bcl-2', 'Gene', '596', (185, 190))
364847	32860308	We demonstrated that depletion of Spt16 led to DDR activation likely due to the decreases in the protein levels of both MCM7 and Rb (Figure 4).	('MCM7', 'Gene', (120, 124))	('Rb', 'Chemical', 'MESH:D012413', (129, 131))	('protein levels', 'MPA', (97, 111))	('decreases', 'NegReg', (80, 89))	('Spt16', 'Gene', (34, 39))	('depletion', 'Var', (21, 30))	('MCM7', 'Gene', '4176', (120, 124))	('activation', 'PosReg', (51, 61))	('DDR', 'MPA', (47, 50))	('DDR', 'Chemical', '-', (47, 50))
364853	32860308	Moreover, double depletion of Rb and MCM7 caused more severe DNA damage and DDR activation than individual depletion of Rb or MCM7.	('DNA damage', 'CPA', (61, 71))	('MCM7', 'Gene', (37, 41))	('Rb', 'Chemical', 'MESH:D012413', (30, 32))	('Rb', 'Chemical', 'MESH:D012413', (120, 122))	('MCM7', 'Gene', (126, 130))	('double depletion', 'Var', (10, 26))	('DDR', 'Chemical', '-', (76, 79))	('MCM7', 'Gene', '4176', (37, 41))	('DDR', 'CPA', (76, 79))	('MCM7', 'Gene', '4176', (126, 130))	('activation', 'PosReg', (80, 90))
364856	32860308	Thus, the activation of DDR after Spt16 depletion may also contribute to the observed cell growth inhibition of Spt16-depleted lung cancer cells.	('lung cancer', 'Disease', (127, 138))	('depletion', 'Var', (40, 49))	('lung cancer', 'Phenotype', 'HP:0100526', (127, 138))	('DDR', 'Chemical', '-', (24, 27))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('DDR', 'Gene', (24, 27))	('Spt16', 'Gene', (34, 39))	('cell growth inhibition', 'CPA', (86, 108))	('lung cancer', 'Disease', 'MESH:D008175', (127, 138))	('activation', 'PosReg', (10, 20))
364864	32860308	We found that treatment with CBL0137 showed similar effects on lung cancer cells as the effects of Spt16 depletion (Figure S2), supporting the function of Spt16 in lung cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('lung cancer', 'Disease', 'MESH:D008175', (63, 74))	('CBL0137', 'Chemical', 'MESH:C000600493', (29, 36))	('lung cancer', 'Disease', (164, 175))	('lung cancer', 'Phenotype', 'HP:0100526', (164, 175))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('lung cancer', 'Disease', (63, 74))	('lung cancer', 'Phenotype', 'HP:0100526', (63, 74))	('CBL0137', 'Var', (29, 36))	('lung cancer', 'Disease', 'MESH:D008175', (164, 175))
364865	32860308	Furthermore, our results showed that CBL0137 significantly inhibited lung cancer proliferation and induced apoptosis, suggesting that CBL0137 may be used as a novel drug candidate for lung cancer therapy.	('lung cancer', 'Disease', (184, 195))	('lung cancer', 'Disease', 'MESH:D008175', (69, 80))	('induced', 'Reg', (99, 106))	('CBL0137', 'Chemical', 'MESH:C000600493', (134, 141))	('CBL0137', 'Chemical', 'MESH:C000600493', (37, 44))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('inhibited', 'NegReg', (59, 68))	('lung cancer', 'Disease', 'MESH:D008175', (184, 195))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('lung cancer', 'Disease', (69, 80))	('lung cancer', 'Phenotype', 'HP:0100526', (69, 80))	('apoptosis', 'CPA', (107, 116))	('lung cancer', 'Phenotype', 'HP:0100526', (184, 195))	('CBL0137', 'Var', (37, 44))
364883	30555465	In most cancer types [e.g., acute myeloid leukemia (AML), adrenocortical carcinoma (ACC), breast cancer, Ewing sarcoma, hepatocellular carcinoma, melanoma, non-small cell lung cancer (NSCLC), prostate cancer, and squamous cell carcinoma of the skin] chemerin is downregulated, likely via hypermethylation of RARRES2 (Table 1).	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (58, 82))	('RARRES2', 'Gene', (308, 315))	('NSCLC', 'Phenotype', 'HP:0030358', (184, 189))	('AML', 'Phenotype', 'HP:0004808', (52, 55))	('cancer', 'Disease', (201, 207))	('AML', 'Disease', (52, 55))	('lung cancer', 'Phenotype', 'HP:0100526', (171, 182))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('non-small cell lung cancer', 'Disease', (156, 182))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('RARRES2', 'Gene', '5919', (308, 315))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (213, 236))	('Ewing sarcoma', 'Disease', (105, 118))	('prostate cancer', 'Disease', 'MESH:D011471', (192, 207))	('prostate cancer', 'Phenotype', 'HP:0012125', (192, 207))	('hepatocellular carcinoma', 'Disease', (120, 144))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (58, 82))	('cancer', 'Disease', (8, 14))	('cancer', 'Disease', (97, 103))	('melanoma', 'Disease', 'MESH:D008545', (146, 154))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('downregulated', 'NegReg', (262, 275))	('adrenocortical carcinoma', 'Disease', (58, 82))	('prostate cancer', 'Disease', (192, 207))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('sarcoma', 'Phenotype', 'HP:0100242', (111, 118))	('acute myeloid leukemia', 'Disease', (28, 50))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (156, 182))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('squamous cell carcinoma of the skin', 'Phenotype', 'HP:0006739', (213, 248))	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (160, 182))	('NSCLC', 'Disease', 'MESH:D002289', (184, 189))	('breast cancer', 'Phenotype', 'HP:0003002', (90, 103))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (120, 144))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (28, 50))	('cancer', 'Disease', 'MESH:D009369', (8, 14))	('cancer', 'Disease', 'MESH:D009369', (97, 103))	('melanoma', 'Disease', (146, 154))	('melanoma', 'Phenotype', 'HP:0002861', (146, 154))	('carcinoma', 'Phenotype', 'HP:0030731', (227, 236))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (105, 118))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (156, 182))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (105, 118))	('ACC', 'Phenotype', 'HP:0006744', (84, 87))	('breast cancer', 'Disease', 'MESH:D001943', (90, 103))	('leukemia', 'Phenotype', 'HP:0001909', (42, 50))	('squamous cell carcinoma of the skin', 'Disease', (213, 248))	('NSCLC', 'Disease', (184, 189))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (28, 50))	('hypermethylation', 'Var', (288, 304))	('breast cancer', 'Disease', (90, 103))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (34, 50))	('squamous cell carcinoma of the skin', 'Disease', 'MESH:D002294', (213, 248))	('cancer', 'Disease', (176, 182))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (120, 144))	('AML', 'Disease', 'MESH:D015470', (52, 55))
364892	30555465	Moreover, multivariate analysis on parameters such as age, various gene mutations, chemerin expression, karyotypic classifications, and white blood cell count verified that chemerin was independently able to prognosticate AML patients, while univariate analysis of chemerin expression levels showed that high chemerin expression was associated with positive prognosis.	('mutations', 'Var', (72, 81))	('AML', 'Disease', 'MESH:D015470', (222, 225))	('AML', 'Phenotype', 'HP:0004808', (222, 225))	('patients', 'Species', '9606', (226, 234))	('AML', 'Disease', (222, 225))
364899	30555465	Chemerin's role as a chemoattractant, in recruiting immune cells to sites of inflammation, has already been well documented; for instance, chemerin has been shown to suppress neoplasia by eliciting natural killer cells to the tumor site in melanoma.	('eliciting', 'PosReg', (188, 197))	('neoplasia', 'Phenotype', 'HP:0002664', (175, 184))	('chemerin', 'Var', (139, 147))	('suppress', 'NegReg', (166, 174))	('melanoma', 'Disease', 'MESH:D008545', (240, 248))	('Chemerin', 'Gene', (0, 8))	('tumor', 'Disease', 'MESH:D009369', (226, 231))	('neoplasia', 'Disease', (175, 184))	('inflammation', 'Disease', 'MESH:D007249', (77, 89))	('melanoma', 'Phenotype', 'HP:0002861', (240, 248))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('inflammation', 'Disease', (77, 89))	('melanoma', 'Disease', (240, 248))	('Chemerin', 'Gene', '5919', (0, 8))	('neoplasia', 'Disease', 'MESH:D009369', (175, 184))	('tumor', 'Disease', (226, 231))
364905	30555465	Specifically, the silenced RARRES2 gene in ACC tumors was characterized by hypermethylation at five CpG sites.	('tumors', 'Disease', (47, 53))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('hypermethylation', 'Var', (75, 91))	('RARRES2', 'Gene', (27, 34))	('ACC', 'Phenotype', 'HP:0006744', (43, 46))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))	('RARRES2', 'Gene', '5919', (27, 34))
364908	30555465	Thus, hypermethylation of RARRES2 is likely a common method of gene silencing in tumors where chemerin is downregulated].	('RARRES2', 'Gene', (26, 33))	('tumors', 'Disease', (81, 87))	('hypermethylation', 'Var', (6, 22))	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('RARRES2', 'Gene', '5919', (26, 33))	('silencing', 'NegReg', (68, 77))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))
364911	30555465	The phosphorylated sites were identified as Ser33, Ser37, and Thr41.	('Thr41', 'Var', (62, 67))	('Ser33', 'Chemical', '-', (44, 49))	('Ser33', 'Var', (44, 49))	('Ser37', 'Chemical', '-', (51, 56))	('Ser37', 'Var', (51, 56))	('Thr41', 'Chemical', '-', (62, 67))
364918	30555465	beta-catenin (CTNNB1), a proto-oncogene, is frequently mutated in ACC, resulting in constitutive activation of the Wnt/beta-catenin pathway.	('Wnt/beta-catenin pathway', 'Pathway', (115, 139))	('activation', 'PosReg', (97, 107))	('CTNNB1', 'Gene', '1499', (14, 20))	('mutated', 'Var', (55, 62))	('CTNNB1', 'Gene', (14, 20))	('ACC', 'Phenotype', 'HP:0006744', (66, 69))
364921	30555465	Aberrant activation of the Wnt/beta-catenin pathway is common in many other cancer types, such as breast cancer, lung cancer, hepatocellular carcinoma, and squamous cell carcinoma.	('cancer', 'Disease', (105, 111))	('squamous cell carcinoma', 'Disease', (156, 179))	('lung cancer', 'Disease', 'MESH:D008175', (113, 124))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (126, 150))	('activation', 'PosReg', (9, 19))	('Aberrant', 'Var', (0, 8))	('lung cancer', 'Phenotype', 'HP:0100526', (113, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('cancer', 'Disease', (118, 124))	('hepatocellular carcinoma', 'Disease', (126, 150))	('breast cancer', 'Phenotype', 'HP:0003002', (98, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (156, 179))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('cancer', 'Disease', (76, 82))	('breast cancer', 'Disease', 'MESH:D001943', (98, 111))	('lung cancer', 'Disease', (113, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (170, 179))	('breast cancer', 'Disease', (98, 111))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (156, 179))	('Wnt/beta-catenin pathway', 'Pathway', (27, 51))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (126, 150))
364959	30555465	VEGF, IL-6, and MMP-7 have all been associated with enhanced tumor invasiveness in gastric cancer, while high expression of VEGF and IL-6 have been shown to stimulate metastasis of malignant cells and indicate poor clinical outcomes in gastric cancer patients, suggesting a potential impact of chemerin in this setting.	('gastric cancer', 'Phenotype', 'HP:0012126', (83, 97))	('IL-6', 'Gene', (133, 137))	('IL-6', 'Gene', (6, 10))	('patients', 'Species', '9606', (251, 259))	('high expression', 'Var', (105, 120))	('tumor invasiveness', 'Disease', 'MESH:D009369', (61, 79))	('metastasis of malignant cells', 'CPA', (167, 196))	('gastric cancer', 'Disease', (236, 250))	('stimulate', 'PosReg', (157, 166))	('gastric cancer', 'Disease', (83, 97))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('MMP-7', 'Gene', (16, 21))	('VEGF', 'Gene', '7422', (0, 4))	('gastric cancer', 'Disease', 'MESH:D013274', (236, 250))	('tumor invasiveness', 'Disease', (61, 79))	('gastric cancer', 'Disease', 'MESH:D013274', (83, 97))	('VEGF', 'Gene', (0, 4))	('MMP-7', 'Gene', '4316', (16, 21))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('enhanced', 'PosReg', (52, 60))	('VEGF', 'Gene', '7422', (124, 128))	('gastric cancer', 'Phenotype', 'HP:0012126', (236, 250))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('VEGF', 'Gene', (124, 128))
364970	30555465	First, one study found that chem158 K, a bioactive isoform of chemerin, was elevated in the cerebrospinal fluid of patients with malignant glioblastoma.	('patients', 'Species', '9606', (115, 123))	('elevated', 'PosReg', (76, 84))	('glioblastoma', 'Phenotype', 'HP:0012174', (139, 151))	('malignant glioblastoma', 'Disease', 'MESH:D005909', (129, 151))	('malignant glioblastoma', 'Disease', (129, 151))	('chem158 K', 'Var', (28, 37))
364973	30555465	Experimental results determined that the addition of chem157S, another bioactive isoform of chemerin, to U-87 MG cells resulted in a transient, dose-dependent increase of intracellular calcium, indicating that chemerin could instigate intracellular signaling in U-87 MG cells.	('intracellular calcium', 'MPA', (171, 192))	('U-87 MG', 'CellLine', 'CVCL:0022', (105, 112))	('instigate', 'Reg', (225, 234))	('chem157S', 'Var', (53, 61))	('increase of intracellular calcium', 'Phenotype', 'HP:0003575', (159, 192))	('U-87 MG', 'CellLine', 'CVCL:0022', (262, 269))	('calcium', 'Chemical', 'MESH:D002118', (185, 192))	('increase', 'PosReg', (159, 167))
364994	30555465	Chemerin knockdown, in turn, resulted in increased migratory ability and invasiveness.	('invasiveness', 'CPA', (73, 85))	('increased', 'PosReg', (41, 50))	('knockdown', 'Var', (9, 18))	('Chemerin', 'Gene', (0, 8))	('migratory ability', 'CPA', (51, 68))	('Chemerin', 'Gene', '5919', (0, 8))
365017	30555465	Additionally, high expression of chemerin was shown to be associated with better outcomes for patients in two clinical studies, demonstrating chemerin's potential for therapeutic intervention in melanoma.	('patients', 'Species', '9606', (94, 102))	('high expression', 'Var', (14, 29))	('melanoma', 'Phenotype', 'HP:0002861', (195, 203))	('melanoma', 'Disease', (195, 203))	('melanoma', 'Disease', 'MESH:D008545', (195, 203))
365041	30555465	Thus, the results of both in vitro and in vivo experiments indicated that targeting chemerin/CMKLR1 could potentially elicit antitumor effects in clinical settings.	('chemerin/CMKLR1', 'Gene', (84, 99))	('tumor', 'Disease', (129, 134))	('targeting', 'Var', (74, 83))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('elicit', 'Reg', (118, 124))
365064	30555465	In syngeneic C57BL6 mice implanted with prochemerin-expressing LLC grafts, tumor formation was impeded by prochemerin expression.	('prochemerin', 'Var', (106, 117))	('impeded', 'NegReg', (95, 102))	('mice', 'Species', '10090', (20, 24))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', (75, 80))
365099	30555465	In some cases, cancers may silence RARRES2 via hypermethylation to evade immune surveillance.	('cancers', 'Disease', 'MESH:D009369', (15, 22))	('cancers', 'Phenotype', 'HP:0002664', (15, 22))	('RARRES2', 'Gene', (35, 42))	('silence', 'NegReg', (27, 34))	('cancers', 'Disease', (15, 22))	('RARRES2', 'Gene', '5919', (35, 42))	('hypermethylation', 'Var', (47, 63))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))
365102	30555465	Importantly, for cases in which silencing of RARRES2 has been reported, the restoration and/or forced overexpression of chemerin in the microtumor environment may incite compelling antitumor effects, indicating new avenues of research for chemerin in cancer.	('tumor', 'Disease', (185, 190))	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('incite', 'NegReg', (163, 169))	('RARRES2', 'Gene', (45, 52))	('overexpression', 'PosReg', (102, 116))	('tumor', 'Disease', (141, 146))	('silencing', 'Var', (32, 41))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('cancer', 'Disease', 'MESH:D009369', (251, 257))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('cancer', 'Disease', (251, 257))	('RARRES2', 'Gene', '5919', (45, 52))
365131	29473860	Two potential pathways that may relate NMSC risk to overall cancer risk are DNA repair and inflammatory and/or immune response pathways, which have been hypothesized to be linked to carcinogenesis in general, making it plausible to speculate that impaired immunity results in an increased risk for multiple cancers, including NMSC.	('cancer', 'Disease', (307, 313))	('cancer', 'Disease', 'MESH:D009369', (307, 313))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('impaired', 'Var', (247, 255))	('cancer', 'Phenotype', 'HP:0002664', (307, 313))	('carcinogenesis', 'Disease', 'MESH:D063646', (182, 196))	('cancer', 'Disease', (60, 66))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('multiple cancers', 'Disease', (298, 314))	('carcinogenesis', 'Disease', (182, 196))	('NMSC', 'Disease', (326, 330))	('cancers', 'Phenotype', 'HP:0002664', (307, 314))	('multiple cancers', 'Disease', 'MESH:D009369', (298, 314))
365132	29473860	In the gastroenterological setting, NMSC might have an increased risk with inflammatory bowel disease and gastrointestinal tumours.	('inflammatory bowel disease', 'Disease', (75, 101))	('gastrointestinal tumours', 'Disease', 'MESH:D004067', (106, 130))	('tumours', 'Phenotype', 'HP:0002664', (123, 130))	('NMSC', 'Var', (36, 40))	('gastrointestinal tumours', 'Disease', (106, 130))	('inflammatory bowel disease', 'Phenotype', 'HP:0002037', (75, 101))	('inflammatory bowel disease', 'Disease', 'MESH:D015212', (75, 101))	('tumour', 'Phenotype', 'HP:0002664', (123, 129))
365227	29473860	In the association between BCC and gastrointestinal cancer, the high CEA serum levels positively shows a 90% negative predictive value (48% positive value, 84% sensitivity, and 63% specificity).	('CEA', 'Gene', (69, 72))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('high', 'Var', (64, 68))	('CEA', 'Gene', '5670', (69, 72))	('association', 'Interaction', (7, 18))	('gastrointestinal cancer', 'Disease', 'MESH:D004067', (35, 58))	('BCC', 'Phenotype', 'HP:0002671', (27, 30))	('gastrointestinal cancer', 'Disease', (35, 58))	('high CEA serum', 'Phenotype', 'HP:0031029', (64, 78))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (35, 58))
365253	27446567	The multivariate analysis identified squamous cell carcinoma, high SUVmax and lymphatic invasion as significant and independent factors for high HIF-1alpha expression.	('HIF-1alpha', 'Gene', (145, 155))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (37, 60))	('high', 'Var', (140, 144))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (37, 60))	('squamous cell carcinoma', 'Disease', (37, 60))	('HIF-1alpha', 'Gene', '3091', (145, 155))	('expression', 'MPA', (156, 166))	('lymphatic invasion', 'CPA', (78, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (51, 60))
365256	27446567	Oxygen is essential for aerobic organisms and a lack of oxygen results in considerable stresses to these organisms.	('lack', 'Var', (48, 52))	('Oxygen', 'Chemical', 'MESH:D010100', (0, 6))	('stresses', 'MPA', (87, 95))	('oxygen', 'Chemical', 'MESH:D010100', (56, 62))
365307	27446567	The multivariate logistic regression analysis identified squamous cell carcinoma (P=0.0009), lymphatic invasion (P=0.0350), and high SUVmax (P=0.0471) as significant and independent factors for high HIF-1alpha expression in patients with lung cancer.	('high', 'Var', (194, 198))	('lung cancer', 'Disease', 'MESH:D008175', (238, 249))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (57, 80))	('HIF-1alpha', 'Gene', '3091', (199, 209))	('expression', 'MPA', (210, 220))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (57, 80))	('squamous cell carcinoma', 'Disease', (57, 80))	('lung cancer', 'Disease', (238, 249))	('patients', 'Species', '9606', (224, 232))	('lung cancer', 'Phenotype', 'HP:0100526', (238, 249))	('cancer', 'Phenotype', 'HP:0002664', (243, 249))	('HIF-1alpha', 'Gene', (199, 209))
365316	27446567	The Ki-67 proliferation index also had significant associations with high-survivin tumors and high-c-Myc tumors: The Ki-67-positive rates for high- and low-survivin tumors were 58.1+-28.8 and 29.7+-30.8%, respectively (P<0.01), while the Ki-67-positive rates for high- and low-c-Myc tumors were 47.0+-31.1 and 30.1+-32.3%, respectively (P<0.01).	('tumors', 'Disease', (105, 111))	('associations', 'Interaction', (51, 63))	('survivin', 'Gene', '11799', (74, 82))	('tumors', 'Disease', 'MESH:D009369', (83, 89))	('c-Myc', 'Gene', '4609', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('tumors', 'Phenotype', 'HP:0002664', (283, 289))	('tumors', 'Disease', 'MESH:D009369', (105, 111))	('tumors', 'Phenotype', 'HP:0002664', (165, 171))	('high-', 'Var', (142, 147))	('tumor', 'Phenotype', 'HP:0002664', (283, 288))	('tumors', 'Disease', (283, 289))	('c-Myc', 'Gene', (277, 282))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumors', 'Disease', (165, 171))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('c-Myc', 'Gene', '4609', (277, 282))	('survivin', 'Gene', (156, 164))	('tumors', 'Disease', 'MESH:D009369', (283, 289))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('survivin', 'Gene', '11799', (156, 164))	('tumors', 'Disease', 'MESH:D009369', (165, 171))	('tumors', 'Disease', (83, 89))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('survivin', 'Gene', (74, 82))	('c-Myc', 'Gene', (99, 104))
365336	27446567	Subgroups of patients in which high HIF-1alpha expression is expected may represent good candidates for these therapies, including patients of squamous cell carcinoma with positive lymphatic invasion, low tumor differentiation, a low GGO ratio and a high SUVmax.	('patients', 'Species', '9606', (131, 139))	('squamous cell carcinoma', 'Disease', (143, 166))	('low tumor', 'Disease', 'MESH:D009800', (201, 210))	('GGO ratio', 'MPA', (234, 243))	('HIF-1alpha', 'Gene', '3091', (36, 46))	('patients', 'Species', '9606', (13, 21))	('low tumor', 'Disease', (201, 210))	('HIF-1alpha', 'Gene', (36, 46))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('carcinoma', 'Phenotype', 'HP:0030731', (157, 166))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (143, 166))	('high', 'Var', (31, 35))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (143, 166))	('SUVmax', 'MPA', (255, 261))
365342	26411585	Mx1 gene mutations in the coding region for MxA have been discovered in many types of cancer, suggesting potential biological associations between mutations in MxA protein and corresponding cancers.	('mutations', 'Var', (147, 156))	('MxA', 'Gene', (44, 47))	('cancers', 'Disease', 'MESH:D009369', (190, 197))	('mutations', 'Var', (9, 18))	('cancer', 'Disease', (190, 196))	('sc', 'Species', '4932', (60, 62))	('MxA', 'Gene', '4599', (44, 47))	('discovered', 'Reg', (58, 68))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('gg', 'Species', '9031', (96, 98))	('cancer', 'Disease', (86, 92))	('MxA', 'Gene', (160, 163))	('cancers', 'Phenotype', 'HP:0002664', (190, 197))	('cancers', 'Disease', (190, 197))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('associations', 'Interaction', (126, 138))	('cancer', 'Disease', 'MESH:D009369', (190, 196))	('MxA', 'Gene', '4599', (160, 163))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('Mx1', 'Gene', (0, 3))
365343	26411585	In this study, we performed a systematic analysis based on the crystal structures of MxA and elucidated how these mutations specifically affect the structure and therefore the function of MxA protein.	('MxA', 'Gene', (188, 191))	('MxA', 'Gene', (85, 88))	('mutations', 'Var', (114, 123))	('function', 'MPA', (176, 184))	('structure', 'MPA', (148, 157))	('MxA', 'Gene', '4599', (85, 88))	('protein', 'Protein', (192, 199))	('MxA', 'Gene', '4599', (188, 191))	('affect', 'Reg', (137, 143))
365344	26411585	Cancer-associated Mx1 mutations were collected and screened from the COSMIC database.	('Mx1', 'Gene', (18, 21))	('ce', 'Species', '6239', (3, 5))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('mutations', 'Var', (22, 31))	('sc', 'Species', '4932', (51, 53))
365345	26411585	Twenty-two unique mutations that cause single amino acid alterations in the MxA protein were chosen for the analysis.	('MxA', 'Gene', (76, 79))	('MxA', 'Gene', '4599', (76, 79))	('mutations', 'Var', (18, 27))
365348	26411585	Through individual structural analysis, we found that some mutations severely affect the stability and function of MxA either by disrupting the intra-/inter-molecular interactions supported by the original residues or by incurring unfavorable configuration alterations, whereas other mutations lead to gentle or no interference to the protein stability and function because of positions or polarity features.	('intra-/inter-molecular interactions supported', 'MPA', (144, 189))	('ce', 'Species', '6239', (325, 327))	('disrupting', 'NegReg', (129, 139))	('function', 'MPA', (357, 365))	('unfavorable', 'MPA', (231, 242))	('MxA', 'Gene', '4599', (115, 118))	('function', 'MPA', (103, 111))	('configuration alterations', 'MPA', (243, 268))	('affect', 'Reg', (78, 84))	('incurring', 'Reg', (221, 230))	('mutations', 'Var', (59, 68))	('protein', 'Protein', (335, 342))	('stability', 'MPA', (89, 98))	('MxA', 'Gene', (115, 118))
365349	26411585	The potential clinical value of the mutations that lead to drastic influence on MxA protein is also assessed.	('ce', 'Species', '6239', (74, 76))	('dr', 'Species', '7955', (59, 61))	('mutations', 'Var', (36, 45))	('MxA', 'Gene', '4599', (80, 83))	('MxA', 'Gene', (80, 83))
365350	26411585	Among all of the reported tumor-associated single-point mutations, seven of them notably affect the structure and function of MxA and therefore deserve more attention with respect to potential clinical applications.	('MxA', 'Gene', (126, 129))	('single-point mutations', 'Var', (43, 65))	('affect', 'Reg', (89, 95))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('structure', 'MPA', (100, 109))	('function', 'MPA', (114, 122))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('MxA', 'Gene', '4599', (126, 129))
365351	26411585	Our research provides an example for systematic analysis and consequence evaluation of single-point mutations on a given cancer-related protein.	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('ce', 'Species', '6239', (70, 72))	('ce', 'Species', '6239', (124, 126))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('cancer', 'Disease', (121, 127))	('single-point mutations', 'Var', (87, 109))
365359	26411585	It has been reported that the deletion of Mx1 gene, as a consequence of certain gene fusion events, is closely related to prostate cancer with a high aggressive tendency.	('Mx1', 'Gene', (42, 45))	('related', 'Reg', (111, 118))	('prostate cancer', 'Disease', 'MESH:D011471', (122, 137))	('aggressive tendency', 'Phenotype', 'HP:0000718', (150, 169))	('prostate cancer', 'Phenotype', 'HP:0012125', (122, 137))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('prostate cancer', 'Disease', (122, 137))	('deletion', 'Var', (30, 38))	('ce', 'Species', '6239', (66, 68))	('ce', 'Species', '6239', (72, 74))	('gg', 'Species', '9031', (151, 153))	('ce', 'Species', '6239', (134, 136))
365361	26411585	Prostate cancer cells in which the Mx1 gene is knocked out have been shown to be much less sensitive to docetaxel compared with MxA-positive cells.	('Prostate cancer', 'Phenotype', 'HP:0012125', (0, 15))	('MxA', 'Gene', '4599', (128, 131))	('Mx1', 'Gene', (35, 38))	('ce', 'Species', '6239', (12, 14))	('Prostate cancer', 'Disease', (0, 15))	('docetaxel', 'Chemical', 'MESH:D000077143', (104, 113))	('ce', 'Species', '6239', (106, 108))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('MxA', 'Gene', (128, 131))	('knocked out', 'Var', (47, 58))	('ce', 'Species', '6239', (141, 143))	('sensitive to docetaxel', 'MPA', (91, 113))	('Prostate cancer', 'Disease', 'MESH:D011471', (0, 15))	('ce', 'Species', '6239', (16, 18))	('less', 'NegReg', (86, 90))
365371	26411585	According to these comprehensive data sets, Mx1 mutations have been discovered in a number of common cancer types, including colorectal cancer, head and neck squamous cell carcinoma, follicular lymphoma, cutaneous squamous cell carcinoma, mantle cell lymphoma, embryonal rhabdomyosarcoma, renal cell carcinoma, prostate cancer, lung adenocarcinoma, melanoma, medulloblastoma, and ovarian carcinoma.	('embryonal rhabdomyosarcoma', 'Phenotype', 'HP:0006743', (261, 287))	('lymphoma', 'Phenotype', 'HP:0002665', (194, 202))	('cancer', 'Phenotype', 'HP:0002664', (320, 326))	('melanoma', 'Phenotype', 'HP:0002861', (349, 357))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (214, 237))	('melanoma', 'Disease', (349, 357))	('colorectal cancer', 'Phenotype', 'HP:0003003', (125, 142))	('follicular lymphoma', 'Disease', (183, 202))	('cancer', 'Disease', (136, 142))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (158, 181))	('prostate cancer', 'Disease', 'MESH:D011471', (311, 326))	('prostate cancer', 'Phenotype', 'HP:0012125', (311, 326))	('mutations', 'Var', (48, 57))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('renal cell carcinoma', 'Disease', (289, 309))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (289, 309))	('prostate cancer', 'Disease', (311, 326))	('discovered', 'Reg', (68, 78))	('Mx1', 'Gene', (44, 47))	('lung adenocarcinoma', 'Disease', (328, 347))	('cancer', 'Disease', 'MESH:D009369', (320, 326))	('carcinoma', 'Phenotype', 'HP:0030731', (388, 397))	('cutaneous squamous cell carcinoma', 'Phenotype', 'HP:0006739', (204, 237))	('mantle cell lymphoma', 'Disease', 'MESH:D020522', (239, 259))	('embryonal rhabdomyosarcoma', 'Disease', 'MESH:D018233', (261, 287))	('carcinoma', 'Phenotype', 'HP:0030731', (300, 309))	('mantle cell lymphoma', 'Disease', (239, 259))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (271, 287))	('colorectal cancer', 'Disease', 'MESH:D015179', (125, 142))	('carcinoma', 'Phenotype', 'HP:0030731', (228, 237))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (380, 397))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('melanoma', 'Disease', 'MESH:D008545', (349, 357))	('medulloblastoma', 'Disease', 'MESH:D008527', (359, 374))	('lymphoma', 'Phenotype', 'HP:0002665', (251, 259))	('medulloblastoma', 'Phenotype', 'HP:0002885', (359, 374))	('colorectal cancer', 'Disease', (125, 142))	('ovarian carcinoma', 'Disease', (380, 397))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (328, 347))	('embryonal rhabdomyosarcoma', 'Disease', (261, 287))	('carcinoma', 'Phenotype', 'HP:0030731', (172, 181))	('medulloblastoma', 'Disease', (359, 374))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (144, 181))	('carcinoma', 'Phenotype', 'HP:0030731', (338, 347))	('cancer', 'Disease', (101, 107))	('cutaneous squamous cell carcinoma', 'Disease', (204, 237))	('mm', 'Species', '10090', (96, 98))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (289, 309))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (328, 347))	('neck squamous cell carcinoma', 'Disease', (153, 181))	('follicular lymphoma', 'Disease', 'MESH:D008224', (183, 202))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (153, 181))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (380, 397))	('cutaneous squamous cell carcinoma', 'Disease', 'MESH:D002294', (204, 237))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('cell lymphoma', 'Phenotype', 'HP:0012191', (246, 259))	('sc', 'Species', '4932', (70, 72))	('cancer', 'Disease', (320, 326))
365372	26411585	Given the potential importance of MxA in tumorigenesis and metastasis as well as in the treatment and prognosis of different cancers, additional efforts are needed to investigate the biological associations between Mx1 mutations, especially the mutations that lead to the malfunction of its encoded protein MxA, and corresponding cancers.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('ce', 'Species', '6239', (128, 130))	('cancers', 'Disease', 'MESH:D009369', (330, 337))	('cancers', 'Disease', 'MESH:D009369', (125, 132))	('MxA', 'Gene', '4599', (307, 310))	('ce', 'Species', '6239', (333, 335))	('MxA', 'Gene', (34, 37))	('malfunction', 'MPA', (272, 283))	('tumor', 'Disease', (41, 46))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('cancers', 'Phenotype', 'HP:0002664', (330, 337))	('mutations', 'Var', (219, 228))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('cancers', 'Disease', (330, 337))	('MxA', 'Gene', '4599', (34, 37))	('cancers', 'Phenotype', 'HP:0002664', (125, 132))	('cancers', 'Disease', (125, 132))	('cancer', 'Phenotype', 'HP:0002664', (330, 336))	('Mx1', 'Gene', (215, 218))	('ce', 'Species', '6239', (28, 30))	('MxA', 'Gene', (307, 310))
365373	26411585	Mutations in coding regions can result in different consequences to the translated polypeptides, of which single amino acid alterations take up a considerable portion.	('translated polypeptides', 'MPA', (72, 95))	('Mutations', 'Var', (0, 9))	('ce', 'Species', '6239', (61, 63))
365374	26411585	These single-point mutations may give rise to various consequences to the function of MxA which, however, are difficult to be predicted and evaluated from the analysis of primary structure.	('give rise to', 'Reg', (33, 45))	('consequences', 'Reg', (54, 66))	('MxA', 'Gene', (86, 89))	('ce', 'Species', '6239', (63, 65))	('single-point mutations', 'Var', (6, 28))	('function', 'MPA', (74, 82))	('MxA', 'Gene', '4599', (86, 89))
365375	26411585	In this study, we exploit the crystal structures of MxA and illustrate how these mutations specifically affect the structure and thus the function of MxA protein.	('affect', 'Reg', (104, 110))	('MxA', 'Gene', (150, 153))	('MxA', 'Gene', '4599', (52, 55))	('function', 'MPA', (138, 146))	('MxA', 'Gene', '4599', (150, 153))	('structure', 'MPA', (115, 124))	('mutations', 'Var', (81, 90))	('MxA', 'Gene', (52, 55))	('protein', 'Protein', (154, 161))
365376	26411585	Information on cancer-related mutations in human Mx1 gene was collected from the Catalogue of Somatic Mutations in Cancer (COSMIC) database.	('cancer', 'Disease', (15, 21))	('cancer', 'Disease', 'MESH:D009369', (15, 21))	('human', 'Species', '9606', (43, 48))	('mutations', 'Var', (30, 39))	('ce', 'Species', '6239', (18, 20))	('Cancer', 'Phenotype', 'HP:0002664', (115, 121))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('ce', 'Species', '6239', (118, 120))	('Mx1', 'Gene', (49, 52))
365377	26411585	All mutations were manually screened and only the mutations that cause single amino acid alterations in MxA were chosen for subsequent analysis.	('MxA', 'Gene', '4599', (104, 107))	('sc', 'Species', '4932', (28, 30))	('MxA', 'Gene', (104, 107))	('single amino acid alterations', 'Var', (71, 100))
365378	26411585	Amino acid sequences of Homo sapiens (hs) MxA (UniProt code P20591) and MxB (P20592), Mus musculus (mm) Mx1 (P09922) and Mx2 (Q9WVP9), Gallus gallus (gg) Mx protein (Q90597), Danio rerio (dr) MxA protein (Q8JH68), Homo sapiens dynamin1 (Q05193), dynamin2 (P50570), and dynamin3 (Q9UQ16), Drosophila melanogaster (dm) dynamin (P27619), Caenorhabditis elegans (ce) dynamin (Q9U9I9), and Saccharomyces cerevisiae (sc) dynamin-related protein DNM1 (P54861) were aligned using Clustal W and manually adjusted for non-conserved loop regions.	('MxB', 'Gene', (72, 75))	('DNM1', 'Gene', (439, 443))	('Saccharomyces cerevisiae', 'Species', '4932', (385, 409))	('Drosophila melanogaster', 'Species', '7227', (288, 311))	('ce', 'Species', '6239', (17, 19))	('sc', 'Species', '4932', (411, 413))	('Mx2', 'Gene', (121, 124))	('P54861', 'Var', (445, 451))	('Mus musculus', 'Species', '10090', (86, 98))	('Danio rerio', 'Species', '7955', (175, 186))	('Mx2', 'Gene', '17858', (121, 124))	('dynamin2', 'Gene', (246, 254))	('Gallus gallus', 'Species', '9031', (135, 148))	('MxA', 'Gene', (192, 195))	('sc', 'Species', '4932', (92, 94))	('MxA', 'Gene', (42, 45))	('dynamin3', 'Gene', (269, 277))	('mm', 'Species', '10090', (100, 102))	('hs', 'Species', '9606', (38, 40))	('Caenorhabditis elegans', 'Species', '6239', (335, 357))	('P50570', 'Var', (256, 262))	('Homo sapiens', 'Species', '9606', (24, 36))	('dynamin1', 'Gene', '1759', (227, 235))	('MxB', 'Gene', '4600', (72, 75))	('gg', 'Species', '9031', (150, 152))	('U9I9', 'CellLine', 'CVCL:3725', (374, 378))	('P27619', 'Var', (326, 332))	('ce', 'Species', '6239', (395, 397))	('Homo sapiens', 'Species', '9606', (214, 226))	('MxA', 'Gene', '4599', (192, 195))	('dr', 'Species', '7955', (188, 190))	('dm', 'Species', '7227', (313, 315))	('dynamin1', 'Gene', (227, 235))	('MxA', 'Gene', '4599', (42, 45))	('dynamin3', 'Gene', '26052', (269, 277))	('DNM1', 'Gene', '1759', (439, 443))	('ce', 'Species', '6239', (359, 361))	('ce', 'Species', '6239', (399, 401))	('dynamin2', 'Gene', '1785', (246, 254))
365381	26411585	For mutations within the G domain, the crystal structure of apo Stalkless MxA (1.9 A resolution) was applied as reference with the exception of L95P and P96S on Switch I.	('MxA', 'Gene', (74, 77))	('L95P', 'Mutation', 'p.L95P', (144, 148))	('ce', 'Species', '6239', (119, 121))	('ce', 'Species', '6239', (133, 135))	('P96S', 'Mutation', 'p.P96S', (153, 157))	('MxA', 'Gene', '4599', (74, 77))	('mutations', 'Var', (4, 13))	('P96S', 'Var', (153, 157))	('L95P', 'Var', (144, 148))
365382	26411585	For these two mutations, the GMPPCP-bound Stalkless MxA structure (3.3 A) was taken as reference because only when a GTP analogue is bound to the G domain can Switch I be ordered and fully observable.	('GMPPCP', 'Chemical', 'MESH:C004805', (29, 35))	('MxA', 'Gene', '4599', (52, 55))	('GTP', 'Chemical', 'MESH:D006160', (117, 120))	('ce', 'Species', '6239', (94, 96))	('MxA', 'Gene', (52, 55))	('mutations', 'Var', (14, 23))
365383	26411585	For mutations in the stalk region, the MxA Stalk structure (2.4 A) was used for structural analysis.	('mutations', 'Var', (4, 13))	('MxA', 'Gene', '4599', (39, 42))	('MxA', 'Gene', (39, 42))
365384	26411585	For mutations in BSE and Hinge 1, the full-length MxA structure (3.5 A) was the only choice because other published structural models do not contain these residues.	('BSE', 'Gene', (17, 20))	('MxA', 'Gene', (50, 53))	('ce', 'Species', '6239', (89, 91))	('MxA', 'Gene', '4599', (50, 53))	('mutations', 'Var', (4, 13))
365387	26411585	Structural models of selected cancer-associated single-point mutants were calculated by the SWISS-MODEL server.	('single-point', 'Var', (48, 60))	('cancer', 'Disease', (30, 36))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
365388	26411585	In the amino acid sequence input files for each MxA mutant, the original residue was substituted by the post-mutation residue.	('MxA', 'Gene', (48, 51))	('ce', 'Species', '6239', (24, 26))	('MxA', 'Gene', '4599', (48, 51))	('mutant', 'Var', (52, 58))
365389	26411585	Mutated MxA sequences were then individually uploaded to the SWISS-MODEL server for model calculation.	('ce', 'Species', '6239', (18, 20))	('Mutated', 'Var', (0, 7))	('MxA', 'Gene', (8, 11))	('MxA', 'Gene', '4599', (8, 11))
365394	26411585	In the COSMIC database, 122 tumor-related mutations were identified in the human Mx1 gene from whole-genome, whole-exome, and transcriptome sequencing data of human cancers.	('tumor', 'Disease', (28, 33))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('human cancers', 'Disease', (159, 172))	('sc', 'Species', '4932', (130, 132))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('Mx1', 'Gene', (81, 84))	('human', 'Species', '9606', (159, 164))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('cancers', 'Phenotype', 'HP:0002664', (165, 172))	('human', 'Species', '9606', (75, 80))	('mutations', 'Var', (42, 51))	('human cancers', 'Disease', 'MESH:D009369', (159, 172))
365395	26411585	All 122 mutations reside in coding regions of the MxA protein.	('MxA', 'Gene', '4599', (50, 53))	('MxA', 'Gene', (50, 53))	('mutations', 'Var', (8, 17))
365396	26411585	For these genetic aberrances, frameshift mutations and termination codon mutations were excluded, as they lead to obvious truncation of the polypeptide chain and therefore the obliteration of MxA structure and function.	('MxA', 'Gene', (192, 195))	('truncation', 'MPA', (122, 132))	('ce', 'Species', '6239', (25, 27))	('frameshift mutations', 'Var', (30, 50))	('obliteration', 'NegReg', (176, 188))	('MxA', 'Gene', '4599', (192, 195))
365398	26411585	Consequently, 22 unique cancer-related single amino acid mutations in MxA protein were selected and subjected to subsequent analysis.	('single amino acid mutations', 'Var', (39, 66))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('MxA', 'Gene', '4599', (70, 73))	('cancer', 'Disease', (24, 30))	('cancer', 'Disease', 'MESH:D009369', (24, 30))	('MxA', 'Gene', (70, 73))	('protein', 'Protein', (74, 81))
365399	26411585	These 22 MxA mutations, summarized in Table 1, were found across 12 types of human cancer, of which colorectal cancer accounted for half of the mutations, followed by cutaneous squamous cell carcinoma (3 mutations) and mantle cell lymphoma (2 mutations).	('cutaneous squamous cell carcinoma', 'Phenotype', 'HP:0006739', (167, 200))	('mantle cell lymphoma', 'Disease', 'MESH:D020522', (219, 239))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('mantle cell lymphoma', 'Disease', (219, 239))	('cancer', 'Disease', (111, 117))	('mutations', 'Var', (144, 153))	('cell lymphoma', 'Phenotype', 'HP:0012191', (226, 239))	('lymphoma', 'Phenotype', 'HP:0002665', (231, 239))	('colorectal cancer', 'Phenotype', 'HP:0003003', (100, 117))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('carcinoma', 'Phenotype', 'HP:0030731', (191, 200))	('cutaneous squamous cell carcinoma', 'Disease', (167, 200))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('MxA', 'Gene', (9, 12))	('cutaneous squamous cell carcinoma', 'Disease', 'MESH:D002294', (167, 200))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('mutations', 'Var', (13, 22))	('mm', 'Species', '10090', (26, 28))	('human', 'Species', '9606', (77, 82))	('colorectal cancer', 'Disease', 'MESH:D015179', (100, 117))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (177, 200))	('MxA', 'Gene', '4599', (9, 12))	('colorectal cancer', 'Disease', (100, 117))	('cancer', 'Disease', (83, 89))
365401	26411585	Two mutations, namely T651M and R655C, both appeared twice.	('R655C', 'Var', (32, 37))	('R655C', 'Mutation', 'rs867613553', (32, 37))	('T651M', 'Mutation', 'rs758038928', (22, 27))	('T651M', 'Var', (22, 27))	('ce', 'Species', '6239', (56, 58))
365402	26411585	T651M was found in colorectal cancer and head and neck squamous cell carcinoma, whereas R655C was discovered in two separate sequencing projects for colorectal cancer.	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (50, 78))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (55, 78))	('R655C', 'Mutation', 'rs867613553', (88, 93))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('colorectal cancer', 'Disease', 'MESH:D015179', (149, 166))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (41, 78))	('colorectal cancer', 'Disease', 'MESH:D015179', (19, 36))	('T651M', 'Mutation', 'rs758038928', (0, 5))	('colorectal cancer', 'Phenotype', 'HP:0003003', (149, 166))	('colorectal cancer', 'Phenotype', 'HP:0003003', (19, 36))	('T651M', 'Var', (0, 5))	('neck squamous cell carcinoma', 'Disease', (50, 78))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('sc', 'Species', '4932', (100, 102))	('found', 'Reg', (10, 15))	('colorectal cancer', 'Disease', (149, 166))	('colorectal cancer', 'Disease', (19, 36))
365403	26411585	Overall, MxA single-point mutations are widely spread in different human cancers, and MxA mutates more frequently in colorectal cancer according to current data.	('colorectal cancer', 'Disease', 'MESH:D015179', (117, 134))	('human cancers', 'Disease', 'MESH:D009369', (67, 80))	('colorectal cancer', 'Phenotype', 'HP:0003003', (117, 134))	('MxA', 'Gene', '4599', (9, 12))	('human cancers', 'Disease', (67, 80))	('MxA', 'Gene', (86, 89))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('colorectal cancer', 'Disease', (117, 134))	('single-point mutations', 'Var', (13, 35))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('mutates', 'Var', (90, 97))	('MxA', 'Gene', '4599', (86, 89))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('MxA', 'Gene', (9, 12))
365408	26411585	We took advantage of these structures to perform an in-depth analysis of the 22 cancer-related mutations and their possible structural and functional outcomes on the protein.	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancer', 'Disease', (80, 86))	('mutations', 'Var', (95, 104))
365409	26411585	First, we mapped the mutated residues on MxA molecule and found that these 22 mutations are scattered throughout all regions (Fig.	('sc', 'Species', '4932', (92, 94))	('MxA', 'Gene', '4599', (41, 44))	('MxA', 'Gene', (41, 44))	('mutations', 'Var', (78, 87))
365412	26411585	Cutaneous squamous cell carcinoma-associated single-point mutations L95P and P96S sit within Switch I, a key component of the active site which harbors guanine nucleotides and exists in all known GTPases.	('L95P', 'Mutation', 'p.L95P', (68, 72))	('P96S', 'Mutation', 'p.P96S', (77, 81))	('GTP', 'Chemical', 'MESH:D006160', (196, 199))	('carcinoma', 'Phenotype', 'HP:0030731', (24, 33))	('guanine nucleotides', 'Chemical', 'MESH:D006150', (152, 171))	('L95P', 'Var', (68, 72))	('Cutaneous squamous cell carcinoma', 'Disease', 'MESH:D002294', (0, 33))	('Cutaneous squamous cell carcinoma', 'Disease', (0, 33))	('P96S', 'Var', (77, 81))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (10, 33))
365413	26411585	L95 is deeply buried in a comprehensive hydrophobic pocket composed of L87, V93, L107, L109, I143, and L164 (Fig.	('L87', 'Var', (71, 74))	('dr', 'Species', '7955', (42, 44))	('V93', 'Var', (76, 79))	('L107', 'Var', (81, 85))	('L164', 'Var', (103, 107))	('I143', 'Var', (93, 97))	('L109', 'Var', (87, 91))
365414	26411585	Its mutation to proline is less favored in this hydrophobic network and thereby affecting the stability of the whole domain.	('mutation', 'Var', (4, 12))	('dr', 'Species', '7955', (50, 52))	('affecting', 'Reg', (80, 89))	('stability of', 'MPA', (94, 106))	('proline', 'Chemical', 'MESH:D011392', (16, 23))
365415	26411585	Besides, as proline and glycine are chemically different from other amino acids in psi and phi dihedral angles about the peptide bond, L95P mutation may lead Switch I to a different bending direction, and this will hinder the binding of nucleotides (Fig.	('lead', 'Reg', (153, 157))	('binding', 'Interaction', (226, 233))	('glycine', 'Chemical', 'MESH:D005998', (24, 31))	('proline', 'Chemical', 'MESH:D011392', (12, 19))	('L95P', 'Mutation', 'p.L95P', (135, 139))	('dr', 'Species', '7955', (99, 101))	('L95P mutation', 'Var', (135, 148))	('hinder', 'NegReg', (215, 221))
365416	26411585	Similarly, P96S mutation tends to generate more freedom for Switch I to swing, which is also unfavorable for nucleotide binding and hydrolysis (Fig.	('P96S', 'Var', (11, 15))	('P96S', 'Mutation', 'p.P96S', (11, 15))	('freedom', 'MPA', (48, 55))	('swing', 'MPA', (72, 77))	('Switch I', 'MPA', (60, 68))	('dr', 'Species', '7955', (134, 136))
365417	26411585	S134L mutation occurs between the extra beta-strand 1 (betaE1G) and extra alpha-helix (alphaEG) of MxA (Fig.	('S134L', 'Var', (0, 5))	('S134L', 'Mutation', 'rs375569357', (0, 5))	('MxA', 'Gene', '4599', (99, 102))	('MxA', 'Gene', (99, 102))
365418	26411585	As the polar S134 is located on the surface of the molecule, and its side chain also protrudes outward, its mutation to hydrophobic leucine would not influence the global folding of the G domain, but just slightly change the surface entropy of the molecule.	('ce', 'Species', '6239', (157, 159))	('ce', 'Species', '6239', (230, 232))	('ce', 'Species', '6239', (41, 43))	('leucine', 'Chemical', 'MESH:D007930', (132, 139))	('dr', 'Species', '7955', (122, 124))	('mutation', 'Var', (108, 116))	('surface entropy of the molecule', 'MPA', (225, 256))	('change', 'Reg', (214, 220))
365420	26411585	Analogous to P96S, P218S may change the original trajectory of the following loop and therefore affect the folding of the protein.	('P218S', 'Var', (19, 24))	('affect', 'Reg', (96, 102))	('folding of the', 'MPA', (107, 121))	('P96S', 'Var', (13, 17))	('original trajectory of the following loop', 'MPA', (40, 81))	('P96S', 'Mutation', 'p.P96S', (13, 17))	('P218S', 'Mutation', 'p.P218S', (19, 24))	('change', 'Reg', (29, 35))
365421	26411585	V263 is surrounded by several other hydrophobic residues, including I223, L246, V264, and V268 (Fig.	('V268', 'CellLine', 'CVCL:1689', (90, 94))	('L246', 'Var', (74, 78))	('dr', 'Species', '7955', (38, 40))	('V263', 'Chemical', '-', (0, 4))	('V263', 'Var', (0, 4))	('V264', 'Var', (80, 84))	('I223', 'Var', (68, 72))	('V268', 'Var', (90, 94))	('V264', 'CellLine', 'CVCL:8629', (80, 84))
365423	26411585	As methionine is also a nonpolar residue, V263M mutation makes no alteration of the hydrophobic property of this area.	('hydrophobic', 'MPA', (84, 95))	('dr', 'Species', '7955', (86, 88))	('methionine', 'Chemical', 'MESH:D008715', (3, 13))	('V263M', 'Mutation', 'rs1286178707', (42, 47))	('V263M mutation', 'Var', (42, 56))
365425	26411585	Therefore, V263M mutation would cause very limited influence to the folding and stability of the protein.	('V263M mutation', 'Var', (11, 25))	('stability', 'MPA', (80, 89))	('ce', 'Species', '6239', (58, 60))	('folding', 'MPA', (68, 75))	('V263M', 'Mutation', 'rs1286178707', (11, 16))
365428	26411585	In this situation, its mutation to a polar serine residue will neither break any intra-molecular associations nor drastically change the surface polarity of MxA.	('change', 'Reg', (126, 132))	('mutation', 'Var', (23, 31))	('dr', 'Species', '7955', (114, 116))	('MxA', 'Gene', (157, 160))	('surface polarity', 'MPA', (137, 153))	('ce', 'Species', '6239', (142, 144))	('MxA', 'Gene', '4599', (157, 160))	('serine', 'Chemical', 'MESH:D012694', (43, 49))	('break', 'Reg', (71, 76))
365429	26411585	Although R310S causes the loss of some positive charge, this mutation would not negatively affect the function of the protein.	('R310S', 'Mutation', 'p.R310S', (9, 14))	('positive charge', 'MPA', (39, 54))	('R310S', 'Var', (9, 14))	('loss', 'NegReg', (26, 30))
365431	26411585	It forms a hydrogen bond with the oxygen of K273 and additionally a weak salt bridge with E330 which also sits in alpha5G (Fig.	('hydrogen bond', 'MPA', (11, 24))	('E330', 'Chemical', 'MESH:D019343', (90, 94))	('oxygen', 'Chemical', 'MESH:D010100', (34, 40))	('E330', 'Var', (90, 94))	('K273', 'Chemical', '-', (44, 48))	('hydrogen', 'Chemical', 'MESH:D006859', (11, 19))	('K273', 'Var', (44, 48))	('salt bridge', 'MPA', (73, 84))
365432	26411585	The K326 N mutation may not substantially affect these two interactions, as asparagine also has a polar side chain that can form hydrogen bonds with K273 and E330.	('K326 N', 'Var', (4, 10))	('asparagine', 'Chemical', 'MESH:D001216', (76, 86))	('hydrogen', 'Chemical', 'MESH:D006859', (129, 137))	('K273', 'Chemical', '-', (149, 153))	('K326 N', 'Mutation', 'p.K326N', (4, 10))	('hydrogen bonds', 'MPA', (129, 143))	('E330', 'Var', (158, 162))	('K273', 'Var', (149, 153))	('E330', 'Chemical', 'MESH:D019343', (158, 162))
365436	26411585	Five tumor-associated single-point mutations were found in BSE and, more precisely, the alpha-helix 3 of BSE (alpha3B), which is also close to the end of the protein (Fig.	('single-point', 'Var', (22, 34))	('BSE', 'Gene', (59, 62))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('tumor', 'Disease', (5, 10))
365438	26411585	L643 is hydrophobically linked to L357, but its mutation to nonpolar valine would not substantially disrupt this interaction, and thus does not adversely affect the structure of the protein.	('valine', 'Chemical', 'MESH:D014633', (69, 75))	('structure', 'MPA', (165, 174))	('dr', 'Species', '7955', (10, 12))	('L643', 'Var', (0, 4))	('affect', 'Reg', (154, 160))	('L357', 'Var', (34, 38))
365439	26411585	Therefore, their mutations, except for mutating to glycine or proline, will lead to negligible interference in the folding of the protein.	('ce', 'Species', '6239', (105, 107))	('ce', 'Species', '6239', (30, 32))	('glycine', 'Chemical', 'MESH:D005998', (51, 58))	('proline', 'Chemical', 'MESH:D011392', (62, 69))	('folding of the protein', 'MPA', (115, 137))	('mutations', 'Var', (17, 26))
365440	26411585	However, since arginine and threonine are both strong polar residues, whereas methionine and tryptophan possess bulky hydrophobic side chains, and cysteine is a weak-polar residue prone to various post-translational modifications, the R649W, T651M, and R655C mutations bear the possibility to interrupt the association between the protein and other protein partners or incur unexpected modifications.	('R655C', 'Var', (253, 258))	('arginine', 'Chemical', 'MESH:D001120', (15, 23))	('threonine', 'Chemical', 'MESH:D013912', (28, 37))	('T651M', 'Var', (242, 247))	('R649W', 'Mutation', 'rs375998659', (235, 240))	('T651M', 'Mutation', 'rs758038928', (242, 247))	('R655C', 'Mutation', 'rs867613553', (253, 258))	('modifications', 'Reg', (386, 399))	('methionine', 'Chemical', 'MESH:D008715', (78, 88))	('tryptophan', 'Chemical', 'MESH:D014364', (93, 103))	('protein', 'Protein', (331, 338))	('association', 'Interaction', (307, 318))	('dr', 'Species', '7955', (120, 122))	('ce', 'Species', '6239', (12, 14))	('cysteine', 'Chemical', 'MESH:D003545', (147, 155))	('interrupt', 'NegReg', (293, 302))	('R649W', 'Var', (235, 240))
365441	26411585	R654 participates in BSE-Stalk interaction between parallel MxA monomers via a charged interaction with D478 on the other molecule (Fig.	('MxA', 'Gene', (60, 63))	('R654', 'Var', (0, 4))	('participates', 'Reg', (5, 17))	('interaction', 'Interaction', (87, 98))	('D478', 'Chemical', '-', (104, 108))	('D478', 'Var', (104, 108))	('MxA', 'Gene', '4599', (60, 63))
365442	26411585	Disruption of this salt bridge by a D478A mutation results in abnormal GTPase activity and weakened oligomerization and antiviral abilities.	('weakened', 'NegReg', (91, 99))	('GTPase', 'Protein', (71, 77))	('D478A', 'Var', (36, 41))	('antiviral abilities', 'CPA', (120, 139))	('D478A', 'Mutation', 'p.D478A', (36, 41))	('oligomerization', 'MPA', (100, 115))	('activity', 'MPA', (78, 86))	('GTP', 'Chemical', 'MESH:D006160', (71, 74))
365443	26411585	Not surprisingly, the colorectal cancer-associated R654Q mutation, which abolishes the D478-R654 salt bridge, should have a similar effect.	('colorectal cancer', 'Disease', (22, 39))	('D478-R654 salt bridge', 'MPA', (87, 108))	('R654Q', 'Var', (51, 56))	('colorectal cancer', 'Disease', 'MESH:D015179', (22, 39))	('abolishes', 'NegReg', (73, 82))	('R654Q', 'Mutation', 'rs562050037', (51, 56))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('D478', 'Chemical', '-', (87, 91))	('colorectal cancer', 'Phenotype', 'HP:0003003', (22, 39))
365446	26411585	Destruction of this salt bridge by mutating either E632 or R640 to alanine leads to tremendous change of GTPase activity, and almost completely abolishes the oligomerization ability and antiviral effect of MxA.	('change', 'Reg', (95, 101))	('antiviral', 'MPA', (186, 195))	('E632', 'Var', (51, 55))	('oligomerization ability', 'MPA', (158, 181))	('GTPase', 'Protein', (105, 111))	('R640', 'Var', (59, 63))	('MxA', 'Gene', (206, 209))	('alanine', 'Chemical', 'MESH:D000409', (67, 74))	('abolishes', 'NegReg', (144, 153))	('activity', 'MPA', (112, 120))	('GTP', 'Chemical', 'MESH:D006160', (105, 108))	('MxA', 'Gene', '4599', (206, 209))
365447	26411585	Therefore, it can be well expected that the melanoma-related mutant E632K, which also disrupts the E632-R640 interaction, would be detrimental to the integrity of Hinge 1, and thus the global stability of MxA molecule.	('E632K', 'Mutation', 'rs746945696', (68, 73))	('integrity', 'MPA', (150, 159))	('detrimental', 'NegReg', (131, 142))	('melanoma', 'Phenotype', 'HP:0002861', (44, 52))	('melanoma', 'Disease', (44, 52))	('melanoma', 'Disease', 'MESH:D008545', (44, 52))	('MxA', 'Gene', '4599', (205, 208))	('disrupts', 'NegReg', (86, 94))	('global', 'MPA', (185, 191))	('MxA', 'Gene', (205, 208))	('E632K', 'Var', (68, 73))	('E632-R640 interaction', 'MPA', (99, 120))
365450	26411585	Therefore, it was necessary to first determine the mutations residing in these interfaces, namely G392V and V449G.	('ce', 'Species', '6239', (20, 22))	('G392V', 'Var', (98, 103))	('G392V', 'Mutation', 'p.G392V', (98, 103))	('ce', 'Species', '6239', (86, 88))	('V449G', 'Mutation', 'p.V449G', (108, 113))	('V449G', 'Var', (108, 113))
365452	26411585	The G392D mutation in MxA was demonstrated to disrupt the oligomerization of the protein.	('oligomerization of the protein', 'MPA', (58, 88))	('MxA', 'Gene', '4599', (22, 25))	('G392D', 'Var', (4, 9))	('G392D', 'Mutation', 'p.G392D', (4, 9))	('disrupt', 'NegReg', (46, 53))	('MxA', 'Gene', (22, 25))
365453	26411585	Moreover, its counterpart mutation (G385) in yeast dynamin leads to the breakdown of tetramer into stable dimers.	('leads to', 'Reg', (59, 67))	('G385', 'Var', (36, 40))	('yeast', 'Species', '4932', (45, 50))	('yeast dynamin', 'Protein', (45, 58))	('breakdown of tetramer into stable dimers', 'MPA', (72, 112))
365454	26411585	It is therefore not astonishing that the G392V mutation found in renal cell carcinoma deprives the oligomerization capability of MxA and thus its biological activity.	('G392V', 'Mutation', 'p.G392V', (41, 46))	('G392V', 'Var', (41, 46))	('renal cell carcinoma deprives', 'Disease', (65, 94))	('MxA', 'Gene', (129, 132))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('biological activity', 'MPA', (146, 165))	('renal cell carcinoma deprives', 'Disease', 'MESH:C538614', (65, 94))	('MxA', 'Gene', '4599', (129, 132))	('oligomerization capability', 'MPA', (99, 125))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (65, 85))
365455	26411585	In addition, the V449 residue was found to be the interaction partner of G392 on the parallel monomer in the MxA oligomer (Fig.	('MxA', 'Gene', (109, 112))	('V449', 'Var', (17, 21))	('G392', 'Var', (73, 77))	('interaction', 'Interaction', (50, 61))	('MxA', 'Gene', '4599', (109, 112))
365456	26411585	Its mutation to glycine tends to affect the integrity of interface 3, as well as the conformation of the subsequent Loop 2 on the stalk (L2S).	('integrity', 'MPA', (44, 53))	('ce', 'Species', '6239', (64, 66))	('affect', 'Reg', (33, 39))	('mutation', 'Var', (4, 12))	('glycine', 'Chemical', 'MESH:D005998', (16, 23))	('conformation', 'MPA', (85, 97))
365457	26411585	Altogether, these two mutations (G392V and V449G) are likely to impair the physiological function of MxA.	('V449G', 'Mutation', 'p.V449G', (43, 48))	('G392V', 'Var', (33, 38))	('V449G', 'Var', (43, 48))	('G392V', 'Mutation', 'p.G392V', (33, 38))	('MxA', 'Gene', '4599', (101, 104))	('physiological function', 'MPA', (75, 97))	('impair', 'NegReg', (64, 70))	('MxA', 'Gene', (101, 104))
365459	26411585	N491 is a surface-located residue situated on the alpha-helix 2 of Stalk (alpha2S), forming a hydrogen bond with D385 on the parallel alpha-helix 1N-terminal part (alpha1NS) (Fig.	('ce', 'Species', '6239', (15, 17))	('D385', 'Var', (113, 117))	('N491', 'Var', (0, 4))	('D385', 'Chemical', '-', (113, 117))	('forming', 'Reg', (84, 91))	('hydrogen', 'Chemical', 'MESH:D006859', (94, 102))
365460	26411585	Its mutation to positively charged arginine may strengthen this interaction, as a salt bridge can be thus introduced.	('ce', 'Species', '6239', (113, 115))	('arginine', 'Chemical', 'MESH:D001120', (35, 43))	('mutation', 'Var', (4, 12))	('strengthen', 'PosReg', (48, 58))	('interaction', 'Interaction', (64, 75))
365461	26411585	Therefore, this single-point mutation would play an insignificant role in tumorigenesis or in the development of colorectal cancer.	('colorectal cancer', 'Disease', (113, 130))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('colorectal cancer', 'Disease', 'MESH:D015179', (113, 130))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('tumor', 'Disease', (74, 79))	('single-point mutation', 'Var', (16, 37))	('colorectal cancer', 'Phenotype', 'HP:0003003', (113, 130))
365462	26411585	Another colorectal cancer-related mutation site, R522, is also a solvent-exposed residue on alpha3S.	('R522', 'Var', (49, 53))	('colorectal cancer', 'Disease', 'MESH:D015179', (8, 25))	('colorectal cancer', 'Phenotype', 'HP:0003003', (8, 25))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('colorectal cancer', 'Disease', (8, 25))
365463	26411585	This residue, together with three neighboring negatively charged glutamates (E466 and E467 on alpha2S, and E518 on alpha3S), constitutes a vast network of charged interactions endorsed by the salt bridges, in which R522 is at the center, to provide positive charge (Fig.	('E467', 'Chemical', '-', (86, 90))	('E466', 'Chemical', 'MESH:D002266', (77, 81))	('glutamates', 'Chemical', 'MESH:D005971', (65, 75))	('R522', 'Var', (215, 219))	('ce', 'Species', '6239', (230, 232))	('E466', 'Var', (77, 81))	('E467', 'Var', (86, 90))	('E518', 'Var', (107, 111))
365464	26411585	It is imaginable that its mutation to weak polar cysteine causes the absence of the pivotal positive charge and lead to interference of electrostatic balance on the protein surface.	('cysteine', 'Chemical', 'MESH:D003545', (49, 57))	('ce', 'Species', '6239', (74, 76))	('ce', 'Species', '6239', (130, 132))	('mutation', 'Var', (26, 34))	('pivotal positive charge', 'MPA', (84, 107))	('ce', 'Species', '6239', (178, 180))	('electrostatic balance on the protein surface', 'MPA', (136, 180))	('ce', 'Species', '6239', (155, 157))	('absence', 'NegReg', (69, 76))	('interference', 'MPA', (120, 132))
365466	26411585	It is part of a local hydrophobic core that includes L498 on alpha3S, M616 on alpha4S, and L629 on alpha5S.	('M616', 'Var', (70, 74))	('dr', 'Species', '7955', (24, 26))	('L498', 'Var', (53, 57))	('L629', 'Var', (91, 95))
365468	26411585	As a result, this ovarian carcinoma-associated mutation L619I will lead to hardly detectable structural and functional aberrance to MxA.	('L619I', 'Mutation', 'p.L619I', (56, 61))	('ce', 'Species', '6239', (126, 128))	('MxA', 'Gene', '4599', (132, 135))	('L619I', 'Var', (56, 61))	('carcinoma', 'Phenotype', 'HP:0030731', (26, 35))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (18, 35))	('MxA', 'Gene', (132, 135))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (18, 35))	('ovarian carcinoma', 'Disease', (18, 35))
365471	26411585	Given the similar properties of threonine and serine, the T27S mutant would not chemically differ from wild-type MxA, but it is unpredictable whether this mutation would affect the protein's interaction with viral structures.	('MxA', 'Gene', (113, 116))	('T27S', 'Var', (58, 62))	('affect', 'Reg', (170, 176))	('interaction', 'Interaction', (191, 202))	('T27S', 'Mutation', 'p.T27S', (58, 62))	('MxA', 'Gene', '4599', (113, 116))	('threonine', 'Chemical', 'MESH:D013912', (32, 41))	('serine', 'Chemical', 'MESH:D012694', (46, 52))
365473	26411585	However, currently only several residues in the middle of L4, but not Y538, G540, or S572, were proven to be functionally important for MxA.	('S572', 'Var', (85, 89))	('Y538', 'Var', (70, 74))	('MxA', 'Gene', (136, 139))	('G540', 'Var', (76, 80))	('MxA', 'Gene', '4599', (136, 139))
365474	26411585	Therefore, it is difficult to predict the influence of these three mutations on MxA function, although they are not likely to disrupt the flexible conformation of L4.	('MxA', 'Gene', '4599', (80, 83))	('MxA', 'Gene', (80, 83))	('ce', 'Species', '6239', (49, 51))	('mutations', 'Var', (67, 76))
365481	26411585	Therefore, mutations either from or to proline may mislead the peptide chain to inappropriate directions and/or give rise to unexpected kinks in secondary structure elements.	('proline', 'Chemical', 'MESH:D011392', (39, 46))	('give rise to', 'Reg', (112, 124))	('mutations', 'Var', (11, 20))	('mislead', 'Reg', (51, 58))	('peptide chain', 'MPA', (63, 76))	('kinks in secondary structure elements', 'MPA', (136, 173))
365482	26411585	In contrast, glycine is the most limber residue, and thus mutations that involve this amino acid may alter the flexibility of the peptide chain at particular positions.	('alter', 'Reg', (101, 106))	('mutations', 'Var', (58, 67))	('glycine', 'Chemical', 'MESH:D005998', (13, 20))	('flexibility of the peptide chain', 'MPA', (111, 143))
365484	26411585	To provide a more intuitionistic view of how these mutations may affect the structure of MxA, we performed modeling of several mutants selected from all four groups, and compared the output models to the original crystal structures.	('affect', 'Reg', (65, 71))	('mutations', 'Var', (51, 60))	('MxA', 'Gene', (89, 92))	('structure', 'MPA', (76, 85))	('MxA', 'Gene', '4599', (89, 92))
365486	26411585	The seven drastic MxA mutations found in this study (L95P, P96S, G392V, V449G, P218S, R522C, and E632K) are likely to play important roles in tumorigenesis and development of corresponding human cancers, and therefore evolve to effective tumor-related biomarkers, although more biochemical and cellular assays are needed for their potential clinical applications.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('P96S', 'Var', (59, 63))	('tumor', 'Phenotype', 'HP:0002664', (238, 243))	('V449G', 'Var', (72, 77))	('L95P', 'Mutation', 'p.L95P', (53, 57))	('ce', 'Species', '6239', (294, 296))	('dr', 'Species', '7955', (10, 12))	('P96S', 'Mutation', 'p.P96S', (59, 63))	('P218S', 'Var', (79, 84))	('MxA', 'Gene', (18, 21))	('L95P', 'Var', (53, 57))	('P218S', 'Mutation', 'p.P218S', (79, 84))	('human cancers', 'Disease', (189, 202))	('R522C', 'Var', (86, 91))	('E632K', 'Var', (97, 102))	('roles', 'Reg', (133, 138))	('ce', 'Species', '6239', (198, 200))	('tumor', 'Disease', (142, 147))	('play', 'Reg', (118, 122))	('E632K', 'Mutation', 'rs746945696', (97, 102))	('V449G', 'Mutation', 'p.V449G', (72, 77))	('tumor', 'Disease', (238, 243))	('human cancers', 'Disease', 'MESH:D009369', (189, 202))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('G392V', 'Mutation', 'p.G392V', (65, 70))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('R522C', 'Mutation', 'rs149039781', (86, 91))	('MxA', 'Gene', '4599', (18, 21))	('tumor', 'Disease', 'MESH:D009369', (238, 243))	('cancers', 'Phenotype', 'HP:0002664', (195, 202))	('G392V', 'Var', (65, 70))
365487	26411585	Moreover, it is noteworthy that all three cutaneous squamous cell carcinoma-related mutations (L95P, P96S, and P218S) lead to remarkable disruption of the protein structure, suggesting a strong association between this cancer type and MxA.	('L95P', 'Mutation', 'p.L95P', (95, 99))	('protein structure', 'MPA', (155, 172))	('carcinoma', 'Phenotype', 'HP:0030731', (66, 75))	('MxA', 'Gene', (235, 238))	('cancer', 'Disease', 'MESH:D009369', (219, 225))	('gg', 'Species', '9031', (176, 178))	('P96S', 'Mutation', 'p.P96S', (101, 105))	('L95P', 'Var', (95, 99))	('cutaneous squamous cell carcinoma', 'Disease', (42, 75))	('cutaneous squamous cell carcinoma', 'Disease', 'MESH:D002294', (42, 75))	('MxA', 'Gene', '4599', (235, 238))	('P218S', 'Var', (111, 116))	('disruption', 'NegReg', (137, 147))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (52, 75))	('P218S', 'Mutation', 'p.P218S', (111, 116))	('cancer', 'Disease', (219, 225))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('cutaneous squamous cell carcinoma', 'Phenotype', 'HP:0006739', (42, 75))	('P96S', 'Var', (101, 105))
365488	26411585	Finally, our systematic approaches of structure-based analysis for single-point mutations in MxA protein are widely applicable to the evaluation of outcomes of mutations in different types of cancer for those proteins with available structural information.	('MxA', 'Gene', '4599', (93, 96))	('single-point mutations', 'Var', (67, 89))	('cancer', 'Disease', (192, 198))	('cancer', 'Disease', 'MESH:D009369', (192, 198))	('protein', 'Protein', (97, 104))	('MxA', 'Gene', (93, 96))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))
365489	26411585	In this study, by analyzing 22 unique tumor-associated mutations in the human MxA protein by structural methods, we found that 7 out of 22 mutations have a high propensity to affect tumorigenesis and the development of corresponding cancers.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('tumor', 'Disease', (182, 187))	('mutations', 'Var', (55, 64))	('mutations', 'Var', (139, 148))	('MxA', 'Gene', (78, 81))	('human', 'Species', '9606', (72, 77))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('cancers', 'Disease', 'MESH:D009369', (233, 240))	('cancers', 'Phenotype', 'HP:0002664', (233, 240))	('cancers', 'Disease', (233, 240))	('development', 'CPA', (204, 215))	('MxA', 'Gene', '4599', (78, 81))	('affect', 'Reg', (175, 181))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
365490	26411585	In addition, our research provides a good example for thorough analysis and consequence evaluation of single-point mutations on a given cancer-related protein.	('ce', 'Species', '6239', (85, 87))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('single-point mutations', 'Var', (102, 124))	('cancer', 'Disease', (136, 142))	('ce', 'Species', '6239', (139, 141))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
365501	33159015	A large amount of genetic alterations have been proved to be "drivers" in the progression of NSCLC, including mesenchymal-epidermal transition (EMT)-related genes and mutations in epidermal growth factor receptor (EGFR).	('NSCLC', 'Disease', (93, 98))	('si', 'Chemical', 'MESH:D012825', (136, 138))	('NSCLC', 'Disease', 'MESH:D002289', (93, 98))	('mutations', 'Var', (167, 176))	('EGFR', 'Gene', '1956', (214, 218))	('si', 'Chemical', 'MESH:D012825', (85, 87))	('epidermal growth factor receptor', 'Gene', (180, 212))	('EGFR', 'Gene', (214, 218))	('NSCLC', 'Phenotype', 'HP:0030358', (93, 98))	('epidermal growth factor receptor', 'Gene', '1956', (180, 212))
365505	33159015	For instance, lncRNA HUMT hypomethylation facilities the lymphangiogenesis and metastasis of triple-negative breast carcinoma cell via activating FOXK1 transcription.	('breast carcinoma', 'Disease', 'MESH:D001943', (109, 125))	('FOXK1', 'Gene', '221937', (146, 151))	('si', 'Chemical', 'MESH:D012825', (71, 73))	('facilities', 'PosReg', (42, 52))	('breast carcinoma', 'Phenotype', 'HP:0003002', (109, 125))	('FOXK1', 'Gene', (146, 151))	('lymphangiogenesis', 'CPA', (57, 74))	('activating', 'PosReg', (135, 145))	('transcription', 'MPA', (152, 165))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('hypomethylation', 'Var', (26, 41))	('metastasis', 'CPA', (79, 89))	('breast carcinoma', 'Disease', (109, 125))	('si', 'Chemical', 'MESH:D012825', (86, 88))
365519	33159015	We further demonstrated that low level of linc00968 was associated with the metastasis and poor survival of patients with LUAD.	('metastasis', 'CPA', (76, 86))	('linc00968', 'Gene', '100507632', (42, 51))	('associated', 'Reg', (56, 66))	('poor', 'NegReg', (91, 95))	('low level', 'Var', (29, 38))	('LUAD', 'Phenotype', 'HP:0030078', (122, 126))	('patients', 'Species', '9606', (108, 116))	('linc00968', 'Gene', (42, 51))	('si', 'Chemical', 'MESH:D012825', (83, 85))
365521	33159015	Initially, microarray analysis of expression profiles GEO: GSE19804 and GSE18842 displayed that linc00968 was significantly downregulated in NSCLC (Figure 1A-1C).	('GSE18842', 'Var', (72, 80))	('si', 'Chemical', 'MESH:D012825', (110, 112))	('linc00968', 'Gene', '100507632', (96, 105))	('si', 'Chemical', 'MESH:D012825', (27, 29))	('NSCLC', 'Disease', (141, 146))	('si', 'Chemical', 'MESH:D012825', (40, 42))	('downregulated', 'NegReg', (124, 137))	('NSCLC', 'Disease', 'MESH:D002289', (141, 146))	('NSCLC', 'Phenotype', 'HP:0030358', (141, 146))	('linc00968', 'Gene', (96, 105))
365523	33159015	Using the Kaplan-Meier survival plot (http://kmplot.com/analysis/index.php?p=service&cancer=lung), we revealed that LUAD patients who had high level of linc00968 exhibited better overall survival (OS).	('linc00968', 'Gene', '100507632', (152, 161))	('better', 'MPA', (172, 178))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('si', 'Chemical', 'MESH:D012825', (61, 63))	('exhibited', 'PosReg', (162, 171))	('cancer', 'Disease', (85, 91))	('si', 'Chemical', 'MESH:D012825', (1, 3))	('had high', 'Var', (134, 142))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('patients', 'Species', '9606', (121, 129))	('LUAD', 'Phenotype', 'HP:0030078', (116, 120))	('linc00968', 'Gene', (152, 161))
365529	33159015	The dysregulated expression of linc00968 was negatively related to the lymph node metastasis (LNM) and clinical stage.	('linc00968', 'Gene', '100507632', (31, 40))	('linc00968', 'Gene', (31, 40))	('negatively', 'NegReg', (45, 55))	('expression', 'MPA', (17, 27))	('si', 'Chemical', 'MESH:D012825', (23, 25))	('si', 'Chemical', 'MESH:D012825', (89, 91))	('dysregulated', 'Var', (4, 16))
365537	33159015	Similarly, linc00968 impaired the migration abilities of A549 and H1975 cell, whereas silencing of linc00968 reinforced the mobility of HCC827 cell (Figure 2D).	('HCC827', 'CellLine', 'CVCL:2063', (136, 142))	('linc00968', 'Gene', '100507632', (11, 20))	('linc00968', 'Gene', (11, 20))	('silencing', 'Var', (86, 95))	('H1975', 'CellLine', 'CVCL:1511', (66, 71))	('linc00968', 'Gene', '100507632', (99, 108))	('linc00968', 'Gene', (99, 108))	('impaired', 'NegReg', (21, 29))	('migration abilities', 'CPA', (34, 53))	('mobility', 'MPA', (124, 132))	('A549', 'CellLine', 'CVCL:0023', (57, 61))	('reinforced', 'PosReg', (109, 119))	('si', 'Chemical', 'MESH:D012825', (86, 88))
365540	33159015	Nevertheless, si-linc00968 transfection caused opposite results in the expressions of EMT-related markers in HCC827 cell (Figure 2F).	('si', 'Chemical', 'MESH:D012825', (14, 16))	('HCC827', 'CellLine', 'CVCL:2063', (109, 115))	('si', 'Chemical', 'MESH:D012825', (77, 79))	('transfection', 'Var', (27, 39))	('linc00968', 'Gene', '100507632', (17, 26))	('expressions', 'MPA', (71, 82))	('si', 'Chemical', 'MESH:D012825', (51, 53))	('linc00968', 'Gene', (17, 26))
365544	33159015	Among them, miR-9-5p (Figure 3C) has been proved to be involved in regulating the progression of caners.	('si', 'Chemical', 'MESH:D012825', (89, 91))	('involved', 'Reg', (55, 63))	('progression of caners', 'CPA', (82, 103))	('miR-9-5p', 'Var', (12, 20))
365546	33159015	As shown in Figure 3D, the Ago2 protein was distinctly immunoprecipitated from A549 or H1975 cell extracts, and both miR-9-5p and linc00968 were remarkedly enriched in anti-Ago2 group when compared with the anti-IgG group.	('H1975', 'CellLine', 'CVCL:1511', (87, 92))	('Ago2', 'Gene', (27, 31))	('A549', 'CellLine', 'CVCL:0023', (79, 83))	('Ago2', 'Gene', '27161', (173, 177))	('linc00968', 'Gene', '100507632', (130, 139))	('linc00968', 'Gene', (130, 139))	('miR-9-5p', 'Var', (117, 125))	('Ago2', 'Gene', '27161', (27, 31))	('Ago2', 'Gene', (173, 177))
365547	33159015	Luciferase reporter gene assay suggested that transfected of miR-9-5p decreased the luciferase activity of linc00968-wt but had no suppressive impact on linc00968-mut (Figure 3E).	('si', 'Chemical', 'MESH:D012825', (138, 140))	('linc00968', 'Gene', '100507632', (107, 116))	('linc00968', 'Gene', (107, 116))	('luciferase', 'Enzyme', (84, 94))	('miR-9-5p', 'Var', (61, 69))	('linc00968', 'Gene', (153, 162))	('decreased', 'NegReg', (70, 79))	('linc00968', 'Gene', '100507632', (153, 162))	('activity', 'MPA', (95, 103))
365548	33159015	Moreover, linc00968 silencing raised the levels of miR-9-5p in A549 and H1975 cell (Figure 3F).	('H1975', 'CellLine', 'CVCL:1511', (72, 77))	('A549', 'CellLine', 'CVCL:0023', (63, 67))	('levels of miR-9-5p', 'MPA', (41, 59))	('raised', 'PosReg', (30, 36))	('si', 'Chemical', 'MESH:D012825', (20, 22))	('linc00968', 'Gene', (10, 19))	('silencing', 'Var', (20, 29))	('linc00968', 'Gene', '100507632', (10, 19))
365552	33159015	Consistently, miR-9-5p was also overexpressed in LUAD tissues compared to in para-carcinoma tissues (Figure 4A).	('LUAD', 'Phenotype', 'HP:0030078', (49, 53))	('LUAD', 'Disease', (49, 53))	('para-carcinoma', 'Disease', 'MESH:D002277', (77, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('para-carcinoma', 'Disease', (77, 91))	('miR-9-5p', 'Var', (14, 22))	('si', 'Chemical', 'MESH:D012825', (3, 5))	('overexpressed', 'PosReg', (32, 45))
365554	33159015	Importantly, an inversely relationship between miR-9-5p and linc00968 in LUAD tissues was observed (Figure 4D).	('miR-9-5p', 'Var', (47, 55))	('linc00968', 'Gene', (60, 69))	('LUAD', 'Phenotype', 'HP:0030078', (73, 77))	('linc00968', 'Gene', '100507632', (60, 69))
365555	33159015	In TCGA, miR-9-5p was significantly upregulated in LUAD and negatively associated with linc00968 expression (Figure 4E, 4F).	('LUAD', 'Phenotype', 'HP:0030078', (51, 55))	('upregulated', 'PosReg', (36, 47))	('linc00968', 'Gene', '100507632', (87, 96))	('LUAD', 'Disease', (51, 55))	('linc00968', 'Gene', (87, 96))	('si', 'Chemical', 'MESH:D012825', (22, 24))	('negatively', 'NegReg', (60, 70))	('miR-9-5p', 'Var', (9, 17))	('si', 'Chemical', 'MESH:D012825', (103, 105))	('expression', 'MPA', (97, 107))
365561	33159015	Among the targets of miR-9-5p, we focused on CPEB3, whose mRNA level was significantly decreased by miR-9-5p in LUAD cell (data not shown).	('mRNA level', 'MPA', (58, 68))	('si', 'Chemical', 'MESH:D012825', (73, 75))	('CPEB3', 'Gene', (45, 50))	('decreased', 'NegReg', (87, 96))	('miR-9-5p', 'Var', (100, 108))	('LUAD', 'Phenotype', 'HP:0030078', (112, 116))
365568	33159015	Finally, miR-9-5p reduced the expressions of CPEB3, which was reversed by transfection with linc00968 overexpression plasmid (Figure 5G).	('CPEB3', 'Gene', (45, 50))	('expressions', 'MPA', (30, 41))	('si', 'Chemical', 'MESH:D012825', (36, 38))	('reduced', 'NegReg', (18, 25))	('si', 'Chemical', 'MESH:D012825', (112, 114))	('linc00968', 'Gene', (92, 101))	('linc00968', 'Gene', '100507632', (92, 101))	('miR-9-5p', 'Var', (9, 17))
365569	33159015	On the contrary, anti-miR-9-5p elevated the level of CPEB3, which was reversed after si-linc00968 transfection (Figure 5H).	('level', 'MPA', (44, 49))	('anti-miR-9-5p', 'Var', (17, 30))	('linc00968', 'Gene', (88, 97))	('CPEB3', 'Gene', (53, 58))	('si', 'Chemical', 'MESH:D012825', (85, 87))	('linc00968', 'Gene', '100507632', (88, 97))	('elevated', 'PosReg', (31, 39))
365572	33159015	We found that after transfected miR-9-5p mimics into linc00968 overexpressing cell, the proliferation, colony formation and invasive capacities were obviously rescued compared with those of LUAD cell transfected with linc00968 alone (Figure 6A-6D).	('linc00968', 'Gene', '100507632', (217, 226))	('si', 'Chemical', 'MESH:D012825', (73, 75))	('proliferation', 'CPA', (88, 101))	('si', 'Chemical', 'MESH:D012825', (128, 130))	('linc00968', 'Gene', '100507632', (53, 62))	('LUAD', 'Phenotype', 'HP:0030078', (190, 194))	('linc00968', 'Gene', (53, 62))	('miR-9-5p mimics', 'Var', (32, 47))	('invasive capacities', 'CPA', (124, 143))	('rescued', 'PosReg', (159, 166))	('linc00968', 'Gene', (217, 226))	('colony formation', 'CPA', (103, 119))
365578	33159015	On the contrary, knocked-down of CPEB3 abolished the enhancive effect of linc00968 on the expression level of E-cadherin (Figure 7E).	('linc00968', 'Gene', '100507632', (73, 82))	('enhancive effect', 'MPA', (53, 69))	('E-cadherin', 'Gene', '999', (110, 120))	('knocked-down', 'Var', (17, 29))	('CPEB3', 'Gene', (33, 38))	('abolished', 'NegReg', (39, 48))	('si', 'Chemical', 'MESH:D012825', (96, 98))	('linc00968', 'Gene', (73, 82))	('E-cadherin', 'Gene', (110, 120))	('expression level', 'MPA', (90, 106))
365579	33159015	Taken together, CPEB3 silencing rescues LUAD cell proliferation, migration, and invasion that were inhibited by linc00968.	('invasion', 'CPA', (80, 88))	('migration', 'CPA', (65, 74))	('si', 'Chemical', 'MESH:D012825', (84, 86))	('LUAD cell proliferation', 'CPA', (40, 63))	('CPEB3', 'Gene', (16, 21))	('si', 'Chemical', 'MESH:D012825', (22, 24))	('linc00968', 'Gene', (112, 121))	('silencing', 'Var', (22, 31))	('linc00968', 'Gene', '100507632', (112, 121))	('LUAD', 'Phenotype', 'HP:0030078', (40, 44))	('rescues', 'PosReg', (32, 39))
365585	33159015	Our results revealed that the number of lung metastatic foci was reduced in mice injected with linc00968 overexpressed A549 cell compared with the vector group (Figure 8D).	('reduced', 'NegReg', (65, 72))	('overexpressed', 'Var', (105, 118))	('mice', 'Species', '10090', (76, 80))	('lung metastatic foci', 'CPA', (40, 60))	('linc00968', 'Gene', '100507632', (95, 104))	('linc00968', 'Gene', (95, 104))	('A549', 'CellLine', 'CVCL:0023', (119, 123))
365586	33159015	In TCGA, CPEB3 is significantly downregulated in LUAD and patients who had high CPEB3 expression exhibited better OS compared with patients with low CPEB3 expression (Figure 8E, 8F).	('patients', 'Species', '9606', (131, 139))	('downregulated', 'NegReg', (32, 45))	('si', 'Chemical', 'MESH:D012825', (18, 20))	('LUAD', 'Phenotype', 'HP:0030078', (49, 53))	('CPEB3', 'Gene', (80, 85))	('LUAD', 'Disease', (49, 53))	('high', 'Var', (75, 79))	('expression', 'MPA', (86, 96))	('si', 'Chemical', 'MESH:D012825', (92, 94))	('patients', 'Species', '9606', (58, 66))	('si', 'Chemical', 'MESH:D012825', (161, 163))
365587	33159015	Finally, an inversely relationship between miR-9-5p and CPEB3 whereas a positively relationship between CPEB3 and linc00968 in LUAD tissues were found (Figure 8G).	('CPEB3', 'Gene', (56, 61))	('miR-9-5p', 'Var', (43, 51))	('linc00968', 'Gene', (114, 123))	('linc00968', 'Gene', '100507632', (114, 123))	('si', 'Chemical', 'MESH:D012825', (74, 76))	('LUAD', 'Phenotype', 'HP:0030078', (127, 131))
365593	33159015	For instance, lncRNA SNHG7 is downregulated in LUAD tissues and altered SNHG7 expression induces the changes in LUAD cell proliferation and migration.	('SNHG7', 'Gene', '84973', (72, 77))	('SNHG7', 'Gene', (21, 26))	('expression', 'MPA', (78, 88))	('SNHG7', 'Gene', (72, 77))	('induces', 'Reg', (89, 96))	('si', 'Chemical', 'MESH:D012825', (84, 86))	('LUAD cell proliferation', 'CPA', (112, 135))	('LUAD', 'Phenotype', 'HP:0030078', (47, 51))	('LUAD', 'Phenotype', 'HP:0030078', (112, 116))	('altered', 'Var', (64, 71))	('SNHG7', 'Gene', '84973', (21, 26))	('migration', 'CPA', (140, 149))	('changes', 'Reg', (101, 108))
365595	33159015	Recently, increasing studies elucidate that aberrantly expressed linc00968 play vital roles in the tumorigenesis of cancers through involving to diverse biological behaviors.	('tumor', 'Disease', (99, 104))	('involving', 'Reg', (132, 141))	('si', 'Chemical', 'MESH:D012825', (16, 18))	('si', 'Chemical', 'MESH:D012825', (109, 111))	('aberrantly expressed', 'Var', (44, 64))	('cancers', 'Disease', 'MESH:D009369', (116, 123))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('cancers', 'Phenotype', 'HP:0002664', (116, 123))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cancers', 'Disease', (116, 123))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('linc00968', 'Gene', '100507632', (65, 74))	('linc00968', 'Gene', (65, 74))
365604	33159015	Then, we measured the expressions of EMT-related markers (N-cadherin and E-cadherin) in LUAD cell and found that linc00968 silencing decreased the expression of E-cadherin and raised the expression of N-cadherin.	('si', 'Chemical', 'MESH:D012825', (28, 30))	('si', 'Chemical', 'MESH:D012825', (153, 155))	('si', 'Chemical', 'MESH:D012825', (193, 195))	('expression', 'MPA', (147, 157))	('LUAD', 'Phenotype', 'HP:0030078', (88, 92))	('linc00968', 'Gene', '100507632', (113, 122))	('N-cadherin', 'Gene', (58, 68))	('N-cadherin', 'Gene', '1000', (58, 68))	('N-cadherin', 'Gene', (201, 211))	('decreased', 'NegReg', (133, 142))	('N-cadherin', 'Gene', '1000', (201, 211))	('linc00968', 'Gene', (113, 122))	('E-cadherin', 'Gene', (161, 171))	('E-cadherin', 'Gene', '999', (161, 171))	('silencing', 'Var', (123, 132))	('raised', 'PosReg', (176, 182))	('E-cadherin', 'Gene', (73, 83))	('E-cadherin', 'Gene', '999', (73, 83))	('si', 'Chemical', 'MESH:D012825', (123, 125))	('expression', 'MPA', (187, 197))
365610	33159015	MiRNAs bind to the 3'-UTR of their target mRNAs and cause the repression of translation or the degradation of genes.	('MiRNAs', 'Var', (0, 6))	('repression', 'MPA', (62, 72))	('si', 'Chemical', 'MESH:D012825', (68, 70))	('cause', 'Reg', (52, 57))	('degradation of genes', 'MPA', (95, 115))	('translation', 'MPA', (76, 87))
365612	33159015	Moreover, the level miR-9-5p was negatively associated with CPEB3 level in LUAD samples, and we further demonstrated that miR-9-5p transfection decreased the expression of CPEB3 in LUAD cells in vitro.	('decreased', 'NegReg', (144, 153))	('LUAD', 'Phenotype', 'HP:0030078', (181, 185))	('expression', 'MPA', (158, 168))	('LUAD', 'Phenotype', 'HP:0030078', (75, 79))	('CPEB3 level', 'MPA', (60, 71))	('negatively', 'NegReg', (33, 43))	('si', 'Chemical', 'MESH:D012825', (164, 166))	('transfection', 'Var', (131, 143))	('CPEB3', 'Gene', (172, 177))	('miR-9-5p transfection', 'Var', (122, 143))
365615	33159015	However, CPEB3 knockdown reversed the suppressive influences of linc00968 on the growth and invasiveness of LUAD cell, which certificated the existence of linc00968/miR-9-5p/CPEB3 axis in LUAD.	('linc00968', 'Gene', '100507632', (155, 164))	('knockdown', 'Var', (15, 24))	('CPEB3', 'Gene', (9, 14))	('LUAD', 'Phenotype', 'HP:0030078', (108, 112))	('invasiveness of LUAD cell', 'CPA', (92, 117))	('LUAD', 'Phenotype', 'HP:0030078', (188, 192))	('linc00968', 'Gene', (64, 73))	('linc00968', 'Gene', '100507632', (64, 73))	('si', 'Chemical', 'MESH:D012825', (45, 47))	('growth', 'CPA', (81, 87))	('si', 'Chemical', 'MESH:D012825', (96, 98))	('linc00968', 'Gene', (155, 164))
365620	33159015	Another potential limitation is that we have not attempted to detect the colocalization of linc00968 and miR-9-5p by RNA-FISH in LUAD cells.	('miR-9-5p', 'Var', (105, 113))	('linc00968', 'Gene', (91, 100))	('linc00968', 'Gene', '100507632', (91, 100))	('LUAD', 'Phenotype', 'HP:0030078', (129, 133))
365662	32296577	Results: We reported that silencing of 11 UPGs resulted in enhanced proliferation of NSCLC cells, and four UPGs (UBL3, TRIM22, UBE2G2, and MARCH1) were significantly downregulated in tumor samples compared to that in normal lung tissues and their expression levels were positively associated with overall survival (OS) of NSCLC patients.	('SCLC', 'Phenotype', 'HP:0030357', (323, 327))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('SCLC', 'Phenotype', 'HP:0030357', (86, 90))	('NSCLC', 'Disease', 'MESH:D002289', (322, 327))	('NSCLC', 'Disease', 'MESH:D002289', (85, 90))	('expression', 'MPA', (247, 257))	('TRIM22', 'Gene', '10346', (119, 125))	('NSCLC', 'Disease', (322, 327))	('MARCH1', 'Gene', '55016', (139, 145))	('downregulated', 'NegReg', (166, 179))	('NSCLC', 'Disease', (85, 90))	('NSCLC', 'Phenotype', 'HP:0030358', (322, 327))	('patients', 'Species', '9606', (328, 336))	('NSCLC', 'Phenotype', 'HP:0030358', (85, 90))	('MARCH1', 'Gene', (139, 145))	('tumor', 'Disease', (183, 188))	('associated', 'Reg', (281, 291))	('proliferation', 'CPA', (68, 81))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('enhanced', 'PosReg', (59, 67))	('overall', 'MPA', (297, 304))	('TRIM22', 'Gene', (119, 125))	('silencing', 'Var', (26, 35))	('UBE2G2', 'Gene', '7327', (127, 133))	('UBE2G2', 'Gene', (127, 133))
365664	32296577	Silencing UBL3 accelerated cell proliferation and ectopic expression of UBL3 suppressed NSCLC in vitro and in vivo.	('suppressed', 'NegReg', (77, 87))	('SCLC', 'Phenotype', 'HP:0030357', (89, 93))	('UBL3', 'Gene', (10, 14))	('NSCLC', 'Phenotype', 'HP:0030358', (88, 93))	('accelerated', 'PosReg', (15, 26))	('cell proliferation', 'CPA', (27, 45))	('UBL3', 'Gene', (72, 76))	('NSCLC', 'Disease', (88, 93))	('NSCLC', 'Disease', 'MESH:D002289', (88, 93))	('Silencing', 'Var', (0, 9))
365670	32296577	Abnormalities in oncogenes and tumor suppressors act as drivers to initiate the onset and progression of NSCLCs.	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('Abnormalities', 'Var', (0, 13))	('NSCLC', 'Phenotype', 'HP:0030358', (105, 110))	('tumor', 'Disease', (31, 36))	('NSCLCs', 'Disease', (105, 111))	('SCLC', 'Phenotype', 'HP:0030357', (106, 110))	('NSCLCs', 'Disease', 'MESH:D002289', (105, 111))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
365684	32296577	Human siGENOME SMARTpool siRNA libraries, containing 696 UPGs (Catalog numbers G-004705-05, G-005615-05, G-005625-05, G-005635-05), were purchased from Thermo Scientific Dharmacon (Lafayette, CO, USA).	('Human', 'Species', '9606', (0, 5))	('G-004705-05', 'Var', (79, 90))	('G-005615-05', 'Var', (92, 103))	('G-005635-05', 'Var', (118, 129))	('G-005625-05', 'Var', (105, 116))
365686	32296577	The Z-score of a gene reflects its requirement for cell proliferation, and a Z-score of <= -2 indicates that the gene is required for cell proliferation; silencing of the gene significantly inhibits cell proliferation.	('cell proliferation', 'CPA', (199, 217))	('inhibits', 'NegReg', (190, 198))	('silencing', 'Var', (154, 163))	('men', 'Species', '9606', (42, 45))
365687	32296577	However, a Z score of >= 2 indicates that the gene inhibits lung cancer cell proliferation and that inhibition of the gene significantly promotes cell proliferation.	('lung cancer', 'Disease', (60, 71))	('promotes', 'PosReg', (137, 145))	('lung cancer', 'Phenotype', 'HP:0100526', (60, 71))	('inhibits', 'NegReg', (51, 59))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('lung cancer', 'Disease', 'MESH:D008175', (60, 71))	('inhibition', 'Var', (100, 110))	('cell proliferation', 'CPA', (146, 164))
365706	32296577	The Oncomine cancer microarray database (www.oncomine.org), including the Hou Lung, Selamat Lung, Su Lung, StearmanLung, Landi Lung, Okayama Lung, Lee lung, Kuner Lung, and Zhu Lung datasets, with the accession codes GSE19188, GSE32867, GSE7670, GSE2514, GSE10072, GSE31210, GSE8894, GSE10245, and GSE14814, respectively, were used.	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('GSE14814', 'Var', (298, 306))	('GSE8894', 'Var', (275, 282))	('GSE10245', 'Var', (284, 292))	('GSE2514', 'Var', (246, 253))	('cancer', 'Disease', (13, 19))	('cancer', 'Disease', 'MESH:D009369', (13, 19))	('GSE10072', 'Var', (255, 263))	('GSE7670', 'Var', (237, 244))	('GSE31210', 'Var', (265, 273))	('Oncomine', 'Chemical', '-', (4, 12))	('GSE32867', 'Var', (227, 235))	('GSE19188', 'Var', (217, 225))
365715	32296577	These included UBL3, USP26, UBL4, UBE2G2, FBXO42, RNF10, TRIM6, LOC51136, RNF113A, MARCH1, and TRIM22.	('UBL4', 'Gene', (28, 32))	('LOC51136', 'Var', (64, 72))	('USP26', 'Gene', (21, 26))	('TRIM22', 'Gene', '10346', (95, 101))	('TRIM6', 'Gene', (57, 62))	('RNF113A', 'Gene', '7737', (74, 81))	('UBE2G2', 'Gene', (34, 40))	('UBE2G2', 'Gene', '7327', (34, 40))	('FBXO42', 'Gene', '54455', (42, 48))	('FBXO42', 'Gene', (42, 48))	('USP26', 'Gene', '83844', (21, 26))	('TRIM6', 'Gene', '117854', (57, 62))	('MARCH1', 'Gene', '55016', (83, 89))	('UBL4', 'Gene', '8266', (28, 32))	('MARCH1', 'Gene', (83, 89))	('RNF113A', 'Gene', (74, 81))	('TRIM22', 'Gene', (95, 101))	('RNF10', 'Gene', (50, 55))	('RNF10', 'Gene', '9921', (50, 55))
365718	32296577	We found that the expression of four genes, UBL3, TRIM22, UBE2G2, and MARCH1, was positively associated with the OS of the patients, and the median OS of patients with high levels of these genes was significantly longer than that of patients with low levels of these genes (Figure 1D-G).	('TRIM22', 'Gene', '10346', (50, 56))	('MARCH1', 'Gene', (70, 76))	('patients', 'Species', '9606', (154, 162))	('TRIM22', 'Gene', (50, 56))	('associated', 'Reg', (93, 103))	('patients', 'Species', '9606', (123, 131))	('MARCH1', 'Gene', '55016', (70, 76))	('high', 'Var', (168, 172))	('expression', 'MPA', (18, 28))	('UBL3', 'Gene', (44, 48))	('patients', 'Species', '9606', (233, 241))	('UBE2G2', 'Gene', (58, 64))	('UBE2G2', 'Gene', '7327', (58, 64))
365725	32296577	In addition, the UBL3 copy number loss was found in 632 (62.1%) of 1,017 TCGA patients (Figure 2L).	('UBL3', 'Gene', (17, 21))	('copy number loss', 'Var', (22, 38))	('found', 'Reg', (43, 48))	('patients', 'Species', '9606', (78, 86))
365735	32296577	Among patients with stage III NSCLCs (Figure 3F, right panel), those with higher UBL3 had slightly but not statistically significantly shorter OS than those with lower expression of UBL3.	('NSCLCs', 'Disease', 'MESH:D002289', (30, 36))	('SCLC', 'Phenotype', 'HP:0030357', (31, 35))	('higher UBL3', 'Var', (74, 85))	('UBL3', 'Var', (81, 85))	('NSCLC', 'Phenotype', 'HP:0030358', (30, 35))	('NSCLCs', 'Disease', (30, 36))	('patients', 'Species', '9606', (6, 14))	('shorter', 'NegReg', (135, 142))
365741	32296577	We found that silencing UBL3 accelerated cell proliferation, with Z-scores of 4.22 and 3.42 in A549 and H1975 cells, respectively (Figure 1A and Supplementary Figure S1).	('men', 'Species', '9606', (151, 154))	('silencing', 'Var', (14, 23))	('accelerated', 'PosReg', (29, 40))	('cell proliferation', 'CPA', (41, 59))	('H1975', 'CellLine', 'CVCL:1511', (104, 109))	('UBL3', 'Gene', (24, 28))	('A549', 'CellLine', 'CVCL:0023', (95, 99))
365742	32296577	We verified the effects of siRNA against UBL3 (siUBL3) on lung cancer cells, and found that siUBL3 treatment resulted in a reduction of UBL3 protein expression and increased viability of A549 and H1975 cells (Figure 4A).	('siUBL3', 'Var', (92, 98))	('H1975', 'CellLine', 'CVCL:1511', (196, 201))	('protein', 'Protein', (141, 148))	('viability', 'CPA', (174, 183))	('men', 'Species', '9606', (104, 107))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('lung cancer', 'Disease', (58, 69))	('A549', 'CellLine', 'CVCL:0023', (187, 191))	('lung cancer', 'Phenotype', 'HP:0100526', (58, 69))	('reduction', 'NegReg', (123, 132))	('UBL3', 'Gene', (136, 140))	('lung cancer', 'Disease', 'MESH:D008175', (58, 69))	('increased', 'PosReg', (164, 173))
365743	32296577	We further showed that knockdown of UBL3 promoted the colony-forming activity of A549 cells (Figure 4E).	('colony-forming activity of A549 cells', 'CPA', (54, 91))	('knockdown', 'Var', (23, 32))	('UBL3', 'Gene', (36, 40))	('promoted', 'PosReg', (41, 49))	('A549', 'CellLine', 'CVCL:0023', (81, 85))
365744	32296577	Silencing UBL3 in H1975 cells led to cell cycle arrest at the S phase (Figure 4F), downregulation of p27, Cyclin D1, and upregulation of Cyclin E (Figure 4G), indicating that UBL3 played a role in the control of the replication checkpoint.	('arrest', 'Disease', 'MESH:D006323', (48, 54))	('UBL3', 'Gene', (10, 14))	('upregulation', 'PosReg', (121, 133))	('arrest', 'Disease', (48, 54))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (37, 54))	('Cyclin D1', 'Gene', '595', (106, 115))	('p27', 'Gene', '10671', (101, 104))	('downregulation', 'NegReg', (83, 97))	('Cyclin D1', 'Gene', (106, 115))	('Cyclin E', 'MPA', (137, 145))	('Silencing', 'Var', (0, 9))	('p27', 'Gene', (101, 104))	('H1975', 'CellLine', 'CVCL:1511', (18, 23))
365762	32296577	An in-frame fusion of MAP3K8-UBL3 was reported as a distinct genetic driver in a unique subgroup of spitzoid neoplasms.	('fusion', 'Var', (12, 18))	('spitzoid neoplasms', 'Disease', 'MESH:D009369', (100, 118))	('MAP3K8', 'Gene', '1326', (22, 28))	('neoplasms', 'Phenotype', 'HP:0002664', (109, 118))	('spitzoid neoplasms', 'Disease', (100, 118))	('MAP3K8', 'Gene', (22, 28))
365768	32296577	We investigated the function of UBL3 in NSCLC cells and demonstrated that silencing of UBL3 promoted, whereas overexpression of UBL3 suppressed, NSCLC cell proliferation in vitro and in vivo (Figure 4 and Figure 5).	('SCLC', 'Phenotype', 'HP:0030357', (41, 45))	('UBL3', 'Gene', (87, 91))	('NSCLC', 'Disease', (145, 150))	('promoted', 'PosReg', (92, 100))	('NSCLC', 'Phenotype', 'HP:0030358', (40, 45))	('SCLC', 'Phenotype', 'HP:0030357', (146, 150))	('NSCLC', 'Disease', 'MESH:D002289', (145, 150))	('silencing', 'Var', (74, 83))	('NSCLC', 'Disease', (40, 45))	('NSCLC', 'Phenotype', 'HP:0030358', (145, 150))	('NSCLC', 'Disease', 'MESH:D002289', (40, 45))
365772	32296577	Tobacco smoke causes genomic mutations in cancers; promotes cell proliferation; inhibits programmed cell death; facilitates angiogenesis, invasion and metastasis; and enhances tumor-promoting inflammation.	('cell proliferation', 'CPA', (60, 78))	('death', 'Disease', (105, 110))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('inhibits', 'NegReg', (80, 88))	('Tobacco', 'Species', '4097', (0, 7))	('cancers', 'Phenotype', 'HP:0002664', (42, 49))	('cancers', 'Disease', (42, 49))	('tumor', 'Disease', (176, 181))	('enhances', 'PosReg', (167, 175))	('promotes', 'PosReg', (51, 59))	('inflammation', 'Disease', 'MESH:D007249', (192, 204))	('tumor', 'Disease', 'MESH:D009369', (176, 181))	('death', 'Disease', 'MESH:D003643', (105, 110))	('mutations', 'Var', (29, 38))	('inflammation', 'Disease', (192, 204))	('angiogenesis', 'CPA', (124, 136))	('cancers', 'Disease', 'MESH:D009369', (42, 49))	('facilitates', 'PosReg', (112, 123))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('genomic mutations', 'Var', (21, 38))
365773	32296577	We found that the expression of UBL3 was significantly higher in non-smoking than in smoking patients and that non-smoking patients with NSCLC with high levels of UBL3 had much more favorable prognosis than those who smoked (Figure 3).	('NSCLC', 'Disease', (137, 142))	('patients', 'Species', '9606', (93, 101))	('NSCLC', 'Disease', 'MESH:D002289', (137, 142))	('SCLC', 'Phenotype', 'HP:0030357', (138, 142))	('patients', 'Species', '9606', (123, 131))	('NSCLC', 'Phenotype', 'HP:0030358', (137, 142))	('high levels', 'Var', (148, 159))	('UBL3', 'Gene', (32, 36))	('expression', 'MPA', (18, 28))	('higher', 'PosReg', (55, 61))
365798	29238985	The substrate-product ratio HK:XA has been shown to increase in B6 deficient individuals and reduced to normal levels after supplementation with B6.	('HK', 'Chemical', 'MESH:C005045', (28, 30))	('deficient', 'Var', (67, 76))	('increase', 'PosReg', (52, 60))	('reduced', 'NegReg', (93, 100))	('substrate-product ratio', 'MPA', (4, 27))	('men', 'Species', '9606', (130, 133))	('HK:XA', 'Enzyme', (28, 33))
365825	29238985	Overall, high levels of HK:XA (4th vs. 1st quartile) were associated with a 25% increased risk for lung cancer (Figure 2).	('lung cancer', 'Disease', (99, 110))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('HK', 'Chemical', 'MESH:C005045', (24, 26))	('lung cancer', 'Disease', 'MESH:D008175', (99, 110))	('high levels', 'Var', (9, 20))	('lung cancer', 'Phenotype', 'HP:0100526', (99, 110))
365829	29238985	When those cohorts (The Women's Health Intiative, The New York University Women's Health Study, Women's Health Study and Nurses Health Study) were excluded, the association of HK:XA with risk of lung cancer in the USA was similar, 1.41 (1.15, 1.46), to that seen in Europe.	('HK', 'Chemical', 'MESH:C005045', (176, 178))	('Women', 'Species', '9606', (24, 29))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('Women', 'Species', '9606', (96, 101))	('lung cancer', 'Disease', (195, 206))	('lung cancer', 'Phenotype', 'HP:0100526', (195, 206))	('HK:XA', 'Var', (176, 181))	('Women', 'Species', '9606', (74, 79))	('lung cancer', 'Disease', 'MESH:D008175', (195, 206))
365836	29238985	In analysis according to histology of lung cancer in the overall population, HK:XA was related to an increased risk for squamous cell carcinoma OR (95%CI) 1.42 (1.10, 1.82) for 3rd vs. 1st tertile, but not with other histological types (data not shown).	('HK:XA', 'Var', (77, 82))	('lung cancer', 'Disease', (38, 49))	('lung cancer', 'Phenotype', 'HP:0100526', (38, 49))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (120, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (120, 143))	('lung cancer', 'Disease', 'MESH:D008175', (38, 49))	('HK', 'Chemical', 'MESH:C005045', (77, 79))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('squamous cell carcinoma', 'Disease', (120, 143))
365873	29238985	PLP pyridoxal 5'-phosphate HK:XA 3-hydroxykynurenine:xanthurenic acid CI confidence interval EPIC European Prospective Investigation into Cancer and Nutrition ATBC Alpha-Tocopherol, Beta-Carotene Cancer Prevention OR odds ratio LC3 Lung Cancer Cohort Consortium Low vitamin B6 status, assessed by circulating pyridoxal 5'-phosphate (PLP), has been associated with increased risk of lung cancer.	('ATBC', 'Chemical', '-', (159, 163))	('PLP', 'Gene', '57026', (333, 336))	('Cancer', 'Disease', (196, 202))	("pyridoxal 5'-phosphate", 'Chemical', 'MESH:D011732', (4, 26))	('PLP', 'Gene', '57026', (0, 3))	('xanthurenic acid', 'Chemical', 'MESH:C028330', (53, 69))	('Beta-Carotene', 'Chemical', 'MESH:D019207', (182, 195))	('LC3', 'Gene', (228, 231))	('Cancer', 'Disease', 'MESH:D009369', (237, 243))	('Cancer', 'Phenotype', 'HP:0002664', (138, 144))	('Low vitamin B6 status', 'Phenotype', 'HP:0008326', (262, 283))	('vitamin B6', 'Chemical', 'MESH:D025101', (266, 276))	('lung cancer', 'Disease', 'MESH:D008175', (382, 393))	('Cancer', 'Disease', 'MESH:D009369', (196, 202))	('Cancer', 'Disease', (138, 144))	('3-hydroxykynurenine', 'Chemical', 'MESH:C005045', (33, 52))	('lung cancer', 'Phenotype', 'HP:0100526', (382, 393))	('Low', 'Var', (262, 265))	('Alpha-Tocopherol', 'Chemical', 'MESH:D024502', (164, 180))	("pyridoxal 5'-phosphate", 'Chemical', 'MESH:D011732', (309, 331))	('Cancer', 'Phenotype', 'HP:0002664', (237, 243))	('LC3', 'Gene', '84557', (228, 231))	('PLP', 'Gene', (333, 336))	('Cancer', 'Disease', 'MESH:D009369', (138, 144))	('HK', 'Chemical', 'MESH:C005045', (27, 29))	('PLP', 'Gene', (0, 3))	('cancer', 'Phenotype', 'HP:0002664', (387, 393))	('Lung Cancer', 'Phenotype', 'HP:0100526', (232, 243))	('Cancer', 'Phenotype', 'HP:0002664', (196, 202))	('Cancer', 'Disease', (237, 243))	('lung cancer', 'Disease', (382, 393))
365881	27764818	Lung SCC patients with high 14-3-3zeta expression have significantly shorter OS and DFS compared to patients with low 14-3-3zeta expression.	('SCC', 'Gene', '6317', (5, 8))	('patients', 'Species', '9606', (9, 17))	('high 14-3-3zeta expression', 'Var', (23, 49))	('shorter', 'NegReg', (69, 76))	('patients', 'Species', '9606', (100, 108))	('OS', 'Chemical', '-', (77, 79))	('SCC', 'Gene', (5, 8))	('DFS', 'CPA', (84, 87))	('SCC', 'Phenotype', 'HP:0002860', (5, 8))
365882	27764818	Additionally, 14-3-3zeta knockdown inhibited cell proliferation, migratory and invasive properties of human lung SCC cells.	('SCC', 'Gene', '6317', (113, 116))	('cell proliferation', 'CPA', (45, 63))	('inhibited', 'NegReg', (35, 44))	('SCC', 'Gene', (113, 116))	('SCC', 'Phenotype', 'HP:0002860', (113, 116))	('knockdown', 'Var', (25, 34))	('human', 'Species', '9606', (102, 107))
365922	27764818	It also confirmed that both protein and RNA level, 14-3-3zeta was highly expressed in positive lymph node patients than in the negative lymph node patients (Figures 2B and 2C).	('patients', 'Species', '9606', (147, 155))	('highly', 'PosReg', (66, 72))	('patients', 'Species', '9606', (106, 114))	('positive', 'Var', (86, 94))	('RNA level', 'MPA', (40, 49))	('expressed', 'MPA', (73, 82))
365929	27764818	Kaplan-Meier curve analysis showed that the highexpression of 14-3-3zeta had a shorter overall survival (OS) than those with low 14-3-3zeta expression, and had a worse disease-free survival (DFS) (Figure 3A, p=0.000 and p=0.002, respectively).	('14-3-3zeta', 'Var', (62, 72))	('shorter', 'NegReg', (79, 86))	('disease-free survival', 'CPA', (168, 189))	('worse', 'NegReg', (162, 167))	('OS', 'Chemical', '-', (105, 107))	('highexpression', 'Var', (44, 58))	('overall survival', 'MPA', (87, 103))
365930	27764818	Furthermore, patients with high TGFbetaR1 expression had a shorter OS and DFS than those with low TGFbetaR1 expression (Figure 3B, p=0.017 and 0.048, respectively).	('DFS', 'MPA', (74, 77))	('TGFbeta', 'Gene', (98, 105))	('TGFbeta', 'Gene', '7040', (32, 39))	('shorter', 'NegReg', (59, 66))	('patients', 'Species', '9606', (13, 21))	('high', 'Var', (27, 31))	('OS', 'Chemical', '-', (67, 69))	('expression', 'Var', (42, 52))	('TGFbeta', 'Gene', '7040', (98, 105))	('TGFbeta', 'Gene', (32, 39))
365936	27764818	Lung SCC patients with high expression of both 14-3-3zeta and TGFbetaR1 have significantly shorter OS compared to patients with low 14-3-3zeta and TGFbetaR1 expression (p=0.045, Figure 3D).	('SCC', 'Gene', '6317', (5, 8))	('patients', 'Species', '9606', (9, 17))	('OS', 'Chemical', '-', (99, 101))	('high expression', 'Var', (23, 38))	('TGFbeta', 'Gene', (147, 154))	('TGFbeta', 'Gene', (62, 69))	('SCC', 'Gene', (5, 8))	('TGFbeta', 'Gene', '7040', (147, 154))	('patients', 'Species', '9606', (114, 122))	('14-3-3zeta', 'Var', (47, 57))	('TGFbeta', 'Gene', '7040', (62, 69))	('SCC', 'Phenotype', 'HP:0002860', (5, 8))	('shorter', 'NegReg', (91, 98))
365942	27764818	In addition, colony formation analysis showed that the colony-forming efficiency of sh14-3-3zeta were significantly lower than that of cells with sh-control (p<0.05, Figure 4E).	('lower', 'NegReg', (116, 121))	('sh14-3-3zeta', 'Chemical', '-', (84, 96))	('colony-forming efficiency', 'CPA', (55, 80))	('sh14-3-3zeta', 'Var', (84, 96))
365943	27764818	To investigate the potential role of 14-3-3zeta in tumor metastasis, using a wound healing assay, it showed that cells transfected with sh14-3-3zeta resulted in a slower closing of scratch wounds compared with that of control group (Figure 5A).	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('sh14-3-3zeta', 'Chemical', '-', (136, 148))	('tumor metastasis', 'Disease', 'MESH:D009362', (51, 67))	('slower closing', 'NegReg', (163, 177))	('tumor metastasis', 'Disease', (51, 67))	('sh14-3-3zeta', 'Var', (136, 148))
365944	27764818	Transwell assay showed that 14-3-3zeta knockdown suppresses migration and invasion ability in lung SCC cells compared to the control (Figure 5B).	('SCC', 'Gene', '6317', (99, 102))	('suppresses', 'NegReg', (49, 59))	('knockdown', 'Var', (39, 48))	('lung', 'Disease', (94, 98))	('invasion ability in', 'CPA', (74, 93))	('migration', 'CPA', (60, 69))	('14-3-3zeta', 'Protein', (28, 38))	('SCC', 'Gene', (99, 102))	('SCC', 'Phenotype', 'HP:0002860', (99, 102))
365950	27764818	Furthermore, the knockdown of 14-3-3zeta inhibited the expression of TGFbetaR1 (Figure 5C).	('TGFbeta', 'Gene', '7040', (69, 76))	('expression', 'MPA', (55, 65))	('inhibited', 'NegReg', (41, 50))	('knockdown', 'Var', (17, 26))	('TGFbeta', 'Gene', (69, 76))
365951	27764818	Through knockdown TGFbetaR1 in lung SCC cells, cells were decreased proliferation, migratory and invasive capability and inhibited EMT markers than control.	('EMT markers', 'CPA', (131, 142))	('proliferation', 'CPA', (68, 81))	('invasive capability', 'CPA', (97, 116))	('TGFbeta', 'Gene', '7040', (18, 25))	('knockdown', 'Var', (8, 17))	('decreased', 'NegReg', (58, 67))	('SCC', 'Gene', (36, 39))	('SCC', 'Phenotype', 'HP:0002860', (36, 39))	('inhibited', 'NegReg', (121, 130))	('SCC', 'Gene', '6317', (36, 39))	('migratory', 'CPA', (83, 92))	('TGFbeta', 'Gene', (18, 25))
365952	27764818	Through transfection of TGFbetaR1 in TGFbetaR1-knockdown cells, cells were increased proliferation, migratory, invasive capability and EMT markers expression than control (Figures 6A-6E).	('migratory', 'CPA', (100, 109))	('invasive capability', 'CPA', (111, 130))	('EMT markers expression', 'CPA', (135, 157))	('TGFbeta', 'Gene', '7040', (24, 31))	('TGFbeta', 'Gene', (37, 44))	('TGFbeta', 'Gene', '7040', (37, 44))	('TGFbeta', 'Gene', (24, 31))	('increased', 'PosReg', (75, 84))	('transfection', 'Var', (8, 20))	('proliferation', 'CPA', (85, 98))
365954	27764818	To further verify if 14-3-3zeta silencing inhibits tumor proliferation in vivo, NCI-H520/sh-control or NCI-H520/sh14-3-3zeta#1 stable clones were established and injected into the ventral region of nude mice.	('sh14-3-3zeta', 'Chemical', '-', (112, 124))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('inhibits', 'NegReg', (42, 50))	('nude mice', 'Species', '10090', (198, 207))	('tumor', 'Disease', (51, 56))	('silencing', 'Var', (32, 41))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
365956	27764818	The numbers of lung metastasis nodules were significantly reduced in sh14-3-3zeta group compared to control group (Figure 7B).	('lung metastasis nodules', 'CPA', (15, 38))	('sh14-3-3zeta', 'Var', (69, 81))	('reduced', 'NegReg', (58, 65))	('sh14-3-3zeta', 'Chemical', '-', (69, 81))
365977	27764818	Lung SCC patients with high expression of both 14-3-3zeta and TGFbetaR1 have significantly shorter OS compared to patients with low 14-3-3zeta and TGFbetaR1 expression.	('SCC', 'Gene', '6317', (5, 8))	('patients', 'Species', '9606', (9, 17))	('OS', 'Chemical', '-', (99, 101))	('high expression', 'Var', (23, 38))	('TGFbeta', 'Gene', (147, 154))	('TGFbeta', 'Gene', (62, 69))	('SCC', 'Gene', (5, 8))	('TGFbeta', 'Gene', '7040', (147, 154))	('patients', 'Species', '9606', (114, 122))	('14-3-3zeta', 'Var', (47, 57))	('TGFbeta', 'Gene', '7040', (62, 69))	('SCC', 'Phenotype', 'HP:0002860', (5, 8))	('shorter', 'NegReg', (91, 98))
365981	27764818	14-3-3zeta dysregulates BH3-only protein and leads to a lower level of Bax activation resulting in apoptosis suppression.	('dysregulates', 'Var', (11, 23))	('Bax', 'Gene', (71, 74))	('apoptosis suppression', 'CPA', (99, 120))	('lower', 'NegReg', (56, 61))	('Bax', 'Gene', '581', (71, 74))	('BH3-only protein', 'Protein', (24, 40))
366013	27764818	For tumor metastasis analysis, nude mice were inoculated with 1x 106 H520/sh control or H520/sh14-3-3zeta cells via tail vein injection.	('tumor metastasis', 'Disease', 'MESH:D009362', (4, 20))	('sh14-3-3zeta', 'Chemical', '-', (93, 105))	('tumor metastasis', 'Disease', (4, 20))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('H520/sh14-3-3zeta', 'Var', (88, 105))	('nude mice', 'Species', '10090', (31, 40))
366061	27903974	There are many chip-seq datasets specific to the A549 cell line in the ENCODE database, including Pol II, H3K4Me2, H3K4Me3, and H3K27ac chip-seq data.	('A549', 'CellLine', 'CVCL:0023', (49, 53))	('H3K4Me3', 'Var', (115, 122))	('H3K27ac', 'Var', (128, 135))	('H3K4Me2', 'Var', (106, 113))
366089	27903974	Cytochrome P450 was associated with cancer development, and polymorphisms are lung cancer risk factors.	('lung cancer', 'Disease', (78, 89))	('polymorphisms', 'Var', (60, 73))	('associated', 'Reg', (20, 30))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('lung cancer', 'Phenotype', 'HP:0100526', (78, 89))	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('cancer', 'Disease', (36, 42))	('Cytochrome P450', 'Gene', '4051', (0, 15))	('lung cancer', 'Disease', 'MESH:D008175', (78, 89))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('Cytochrome P450', 'Gene', (0, 15))	('cancer', 'Disease', (83, 89))
366091	27903974	The remaining pathways in LUAD included mitotic prometaphase, APC-C-mediated degradation of cell cycle proteins, M phase, mitotic prometaphase, mitotic M-M/G1 phases, DNA replication, PLK1 signaling events, and cyclin A/B1 associated events during G2/M transition.	('A/B1', 'SUBSTITUTION', 'None', (218, 222))	('PLK1', 'Gene', (184, 188))	('PLK1', 'Gene', '5347', (184, 188))	('A/B1', 'Var', (218, 222))	('cell', 'Protein', (92, 96))	('LUAD', 'Phenotype', 'HP:0030078', (26, 30))
366094	27903974	IGF2BP2-AS1 and DGCR5 upregulation and amplification predicted better LUSC prognosis, possibly functioning as tumor suppressors.	('IGF2BP2-AS1', 'Gene', (0, 11))	('LUSC', 'Phenotype', 'HP:0030359', (70, 74))	('amplification', 'Var', (39, 52))	('DGCR5', 'Gene', (16, 21))	('LUSC', 'Disease', (70, 74))	('tumor', 'Disease', (110, 115))	('IGF2BP2-AS1', 'Gene', '646600;10644;5729', (0, 11))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('better', 'PosReg', (63, 69))	('upregulation', 'PosReg', (22, 34))	('DGCR5', 'Gene', '26220', (16, 21))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
366119	27903974	Dimethylation of histone H3 at lysine 4 (H3K4Me2) helped predict promoters and enhancers, and H3K27ac helped identify active enhancers.	('promoters', 'MPA', (65, 74))	('H3K27ac', 'Var', (94, 101))	('enhancers', 'PosReg', (79, 88))	('lysine', 'Chemical', 'MESH:D008239', (31, 37))
366136	27903974	We choose the GSE33213 series for the Pol II chip-seq data and the GSE29611 series for the H3K4me2, H3K4me3 and H3K27ac chip-seq data in the A549 cell line.	('H3K27ac', 'Var', (112, 119))	('H3K4me3', 'Var', (100, 107))	('A549', 'CellLine', 'CVCL:0023', (141, 145))
366154	27220886	Moreover, shRNA-mediated knockdown of RHAMM reduced the migratory ability of two lung adenocarcinoma cell lines, H1975 and H3255.	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (81, 100))	('RHAMM', 'Gene', '3161', (38, 43))	('RHAMM', 'Gene', (38, 43))	('H3255', 'CellLine', 'CVCL:6831', (123, 128))	('lung adenocarcinoma', 'Disease', (81, 100))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (81, 100))	('reduced', 'NegReg', (44, 51))	('migratory ability of two', 'CPA', (56, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('H1975', 'CellLine', 'CVCL:1511', (113, 118))	('knockdown', 'Var', (25, 34))
366160	27220886	Some Food and Drug Administration (FDA) approved drugs for stage IV lung adenocarcinoma target molecular alterations including mutations in epidermal growth factor receptor (EGFR) and rearrangements of anaplastic lymphoma kinase (ALK).	('epidermal growth factor receptor', 'Gene', (140, 172))	('EGFR', 'Gene', (174, 178))	('epidermal growth factor receptor', 'Gene', '1956', (140, 172))	('IV lung adenocarcinoma', 'Disease', 'MESH:D000077192', (65, 87))	('anaplastic lymphoma kinase', 'Gene', '238', (202, 228))	('IV lung adenocarcinoma', 'Disease', (65, 87))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (68, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('ALK', 'Gene', (230, 233))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (202, 221))	('rearrangements', 'Var', (184, 198))	('lymphoma', 'Phenotype', 'HP:0002665', (213, 221))	('anaplastic lymphoma kinase', 'Gene', (202, 228))	('mutations', 'Var', (127, 136))	('ALK', 'Gene', '238', (230, 233))	('EGFR', 'Gene', '1956', (174, 178))
366172	27220886	In this study, we aimed to determine the expression and the prognostic value of RHAMM for primary NSCLC and metastatic tumors, and the expression levels of RHAMM variants in NSCLC.	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('NSCLC', 'Disease', 'MESH:D002289', (174, 179))	('tumors', 'Disease', (119, 125))	('tumors', 'Disease', 'MESH:D009369', (119, 125))	('NSCLC', 'Disease', (98, 103))	('RHAMM', 'Gene', '3161', (80, 85))	('variants', 'Var', (162, 170))	('RHAMM', 'Gene', '3161', (156, 161))	('NSCLC', 'Disease', (174, 179))	('RHAMM', 'Gene', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('NSCLC', 'Disease', 'MESH:D002289', (98, 103))	('RHAMM', 'Gene', (156, 161))
366199	27220886	RHAMMv3 (NM_012485, also known as RHAMMB) lacks exon 4, a 45-nucleotide sequence.RHAMMv4 (NM_001142557) misses 3 consecutive internal coding exons compared to transcript variant 1, which results in translation initiation from an alternate AUG start site and a shorter isoform with an unique N terminus compared to the other 3 variants.	('RHAMM', 'Gene', (0, 5))	('RHAMM', 'Gene', '3161', (34, 39))	('RHAMM', 'Gene', (34, 39))	('isoform', 'MPA', (268, 275))	('misses', 'NegReg', (104, 110))	('translation initiation', 'MPA', (198, 220))	('NM_001142557', 'Var', (90, 102))	('RHAMM', 'Gene', '3161', (0, 5))	('RHAMM', 'Gene', '3161', (81, 86))	('RHAMM', 'Gene', (81, 86))
366200	27220886	We analyzed the transcript levels of the 4 RHAMM variants in the 58 normal lung tissues and 470 lung adenocarcinomas from the cohorts in the TCGA dataset.	('carcinomas', 'Phenotype', 'HP:0030731', (106, 116))	('RHAMM', 'Gene', (43, 48))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (96, 116))	('variants', 'Var', (49, 57))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (96, 115))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('RHAMM', 'Gene', '3161', (43, 48))	('lung adenocarcinomas', 'Disease', (96, 116))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (96, 116))
366201	27220886	Transcript levels of all 4 RHAMM variants were significantly higher in tumors compared to normal tissues, and RHAMMv3 (RHAMMB) was the most prominent transcript (Figure 3B).	('RHAMM', 'Gene', '3161', (119, 124))	('RHAMM', 'Gene', (119, 124))	('RHAMM', 'Gene', '3161', (27, 32))	('higher', 'PosReg', (61, 67))	('RHAMM', 'Gene', '3161', (110, 115))	('RHAMM', 'Gene', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('Transcript levels', 'MPA', (0, 17))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('RHAMM', 'Gene', (110, 115))	('tumors', 'Disease', (71, 77))	('variants', 'Var', (33, 41))	('tumors', 'Disease', 'MESH:D009369', (71, 77))
366203	27220886	To independently validate the expression of RHAMM variants in lung adenocarcinoma, we performed real-time quantitative PCR using isoform specific primers for 2 lung adenocarcinoma and paired normal tissues, 4 lung adenocarcinoma cell lines (H1975, HCC827, H3255, and PC9), and a control lung bronchial epithelial cell line (HBEC3-KT).	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (62, 81))	('RHAMM', 'Gene', (44, 49))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (160, 179))	('variants', 'Var', (50, 58))	('lung adenocarcinoma', 'Disease', (209, 228))	('PC9', 'Gene', '255738', (267, 270))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (62, 81))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('HCC827', 'CellLine', 'CVCL:2063', (248, 254))	('PC9', 'Gene', (267, 270))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (209, 228))	('HBEC3', 'CellLine', 'CVCL:X491', (324, 329))	('H1975', 'CellLine', 'CVCL:1511', (241, 246))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (209, 228))	('lung adenocarcinoma', 'Disease', (160, 179))	('carcinoma', 'Phenotype', 'HP:0030731', (219, 228))	('lung adenocarcinoma', 'Disease', (62, 81))	('carcinoma', 'Phenotype', 'HP:0030731', (170, 179))	('H3255', 'CellLine', 'CVCL:6831', (256, 261))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (160, 179))	('RHAMM', 'Gene', '3161', (44, 49))
366204	27220886	In agreement with TCGA results, we confirmed that the upregulation of RHAMM variants in tumors and cancer cell lines (Figure 4A-4D).	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('RHAMM', 'Gene', '3161', (70, 75))	('upregulation', 'PosReg', (54, 66))	('cancer', 'Disease', (99, 105))	('variants', 'Var', (76, 84))	('RHAMM', 'Gene', (70, 75))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('tumors', 'Disease', (88, 94))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
366206	27220886	The predicted RHAMM sizes without post-translational modification are very close to each other (v1: 84.2 kDa, v2: 84.1 kDa, v3: 82.3 kDa, and v4: 74.5 kDa) and it is unknown whether any of RHAMM variants have post-translational modification in lung cells.	('RHAMM', 'Gene', '3161', (189, 194))	('variants', 'Var', (195, 203))	('RHAMM', 'Gene', '3161', (14, 19))	('RHAMM', 'Gene', (189, 194))	('RHAMM', 'Gene', (14, 19))
366208	27220886	Since this shRNA targets a common sequence of RHAMM variants, expression of all RHAMM variants was expected to be reduced.	('reduced', 'NegReg', (114, 121))	('expression', 'MPA', (62, 72))	('RHAMM', 'Gene', '3161', (46, 51))	('variants', 'Var', (52, 60))	('RHAMM', 'Gene', '3161', (80, 85))	('RHAMM', 'Gene', (46, 51))	('RHAMM', 'Gene', (80, 85))
366210	27220886	We found that knockdown of RHAMM significantly inhibited the migration ability of human lung adenocarcinoma cell lines, H1975 (Figure 5B) and H3255 (Figure 5C).	('inhibited', 'NegReg', (47, 56))	('RHAMM', 'Gene', '3161', (27, 32))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (88, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (88, 107))	('RHAMM', 'Gene', (27, 32))	('lung adenocarcinoma', 'Disease', (88, 107))	('knockdown', 'Var', (14, 23))	('H3255', 'CellLine', 'CVCL:6831', (142, 147))	('H1975', 'CellLine', 'CVCL:1511', (120, 125))	('human', 'Species', '9606', (82, 87))
366220	27220886	We further demonstrate that shRNA knockdown of RHAMM inhibits tumor cell migration in two lung adenocarcinoma cell lines (Figure 5B and 5C).	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('lung adenocarcinoma', 'Disease', (90, 109))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (90, 109))	('tumor', 'Disease', (62, 67))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (90, 109))	('knockdown', 'Var', (34, 43))	('inhibits', 'NegReg', (53, 61))	('RHAMM', 'Gene', '3161', (47, 52))	('RHAMM', 'Gene', (47, 52))
366225	27220886	Although there was an increasing trend of RHAMM positivity in primary tumors with regional nodal metastases, it did not reach statistical significance and beckons study in larger cohorts of patients.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('RHAMM', 'Gene', '3161', (42, 47))	('metastases', 'Disease', (97, 107))	('primary tumors', 'Disease', (62, 76))	('patients', 'Species', '9606', (190, 198))	('positivity', 'Var', (48, 58))	('RHAMM', 'Gene', (42, 47))	('primary tumors', 'Disease', 'MESH:D009369', (62, 76))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('metastases', 'Disease', 'MESH:D009362', (97, 107))
366227	27220886	Similarly, activating mutations in EGFR are common in lung adenocarcinomas, but they are typically not present in squamous cell carcinomas.	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (54, 73))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (114, 137))	('lung adenocarcinomas', 'Disease', (54, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (114, 138))	('EGFR', 'Gene', '1956', (35, 39))	('carcinomas', 'Phenotype', 'HP:0030731', (128, 138))	('EGFR', 'Gene', (35, 39))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (54, 74))	('squamous cell carcinomas', 'Disease', (114, 138))	('activating mutations', 'Var', (11, 31))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (54, 74))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (114, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))	('carcinomas', 'Phenotype', 'HP:0030731', (64, 74))
366229	27220886	It is possible that aberrant RHAMMB-EGFR signaling affects the survival of lung adenocarcinoma patients, but not that of squamous cell carcinoma patients.	('patients', 'Species', '9606', (145, 153))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (75, 94))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (121, 144))	('patients', 'Species', '9606', (95, 103))	('squamous cell carcinoma', 'Disease', (121, 144))	('aberrant', 'Var', (20, 28))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('EGFR', 'Gene', '1956', (36, 40))	('lung adenocarcinoma', 'Disease', (75, 94))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (75, 94))	('RHAMM', 'Gene', '3161', (29, 34))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('EGFR', 'Gene', (36, 40))	('affects', 'Reg', (51, 58))	('RHAMM', 'Gene', (29, 34))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (121, 144))	('survival', 'MPA', (63, 71))
366236	27220886	Here, we showed that knockdown of RHAMM inhibited the migration ability of human lung adenocarcinoma cell lines, H1975 and H3255.	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (81, 100))	('RHAMM', 'Gene', '3161', (34, 39))	('human', 'Species', '9606', (75, 80))	('inhibited', 'NegReg', (40, 49))	('RHAMM', 'Gene', (34, 39))	('H3255', 'CellLine', 'CVCL:6831', (123, 128))	('lung adenocarcinoma', 'Disease', (81, 100))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (81, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('H1975', 'CellLine', 'CVCL:1511', (113, 118))	('knockdown', 'Var', (21, 30))
366245	27220886	Catalogue number: ab108339) or a Ki67 antibody (Dako, Carpinteria, CA.	('Ki67', 'Chemical', '-', (33, 37))	('Carpinteria', 'Disease', (54, 65))	('Ki67', 'Var', (33, 37))
366284	27716309	While telomere shortening represents a mitotic clock and has been associated with increased cancer risk, these associations have, however, been largely inconsistent and only obtained in surrogate tissues such as blood.	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('telomere shortening', 'Var', (6, 25))	('associated', 'Reg', (66, 76))	('telomere shortening', 'Phenotype', 'HP:0031413', (6, 25))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
366285	27716309	A recently identified mutational clock-like signature may also approximate a mitotic clock but has not yet been applied to cancer risk prediction.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('mitotic clock', 'MPA', (77, 90))	('approximate', 'MPA', (63, 74))	('mutational', 'Var', (22, 32))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('cancer', 'Disease', (123, 129))
366287	27716309	Indeed, clonal genetic and copy number variation mosaicism has already been associated with the future risk of hematological cancers, and DNAm variability in normal cervical cells has been shown to predict the prospective risk of cervical cancer.	('cancers', 'Phenotype', 'HP:0002664', (125, 132))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('hematological cancers', 'Disease', 'MESH:D009369', (111, 132))	('associated', 'Reg', (76, 86))	('copy number variation mosaicism', 'Var', (27, 58))	('cervical cancer', 'Disease', (230, 245))	('hematological cancers', 'Disease', (111, 132))	('cervical cancer', 'Disease', 'MESH:D002583', (230, 245))	('clonal genetic', 'Var', (8, 22))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))
366295	27716309	To this end, we analyzed Illumina 450 k data from a cohort of healthy individuals spanning a wide age range of over 70 years, obtained from purified cells sorted using FACS and representing three different blood cell subtypes (CD4+ T cells, CD14+/CD16- monocytes, and CD19+ B cells) and encompassing 151 independent samples ("Methods").	('CD16', 'Gene', '2214', (247, 251))	('CD4+ T', 'Var', (227, 233))	('CD14', 'Gene', (241, 245))	('CD16', 'Gene', (247, 251))	('CD19', 'Gene', (268, 272))	('CD14', 'Gene', '929', (241, 245))	('CD19', 'Gene', '930', (268, 272))
366331	27716309	That the pcgtAge score could discriminate normal tissue containing such field defects from the normal tissue of age-matched cancer-free women (AUC of 0.66, 95 % CI 0.55-0.77) suggests that epiTOC may serve to assess the risk of neoplastic transformation of normal tissue.	('cancer', 'Disease', (124, 130))	('women', 'Species', '9606', (136, 141))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('defects', 'Var', (78, 85))	('cancer', 'Disease', 'MESH:D009369', (124, 130))
366344	27716309	Importantly, our work has further exposed a subtle difference between promoter CpGs that undergo age-associated hypermethylation from those that undergo hypomethylation, with the analogous model based on age-hypomethylated sites not correlating with the mitotic index in cancer tissue and correspondingly not exhibiting a consistent acceleration in cancer.	('cancer', 'Phenotype', 'HP:0002664', (349, 355))	('cancer', 'Phenotype', 'HP:0002664', (271, 277))	('cancer', 'Disease', (349, 355))	('cancer', 'Disease', 'MESH:D009369', (349, 355))	('cancer', 'Disease', 'MESH:D009369', (271, 277))	('hypermethylation', 'Var', (112, 128))	('cancer', 'Disease', (271, 277))
366345	27716309	In fact, whereas the model based on hypomethylation also correlated with the number of stem cell divisions per stem cell in normal tissues, as well as with exposure to smoking in normal buccal tissue, it is intriguing that no consistent associations were found in cancer or preinvasive cancer lesions.	('cancer lesions', 'Disease', 'MESH:D009062', (286, 300))	('cancer', 'Disease', 'MESH:D009369', (264, 270))	('cancer lesions', 'Disease', (286, 300))	('cancer', 'Phenotype', 'HP:0002664', (286, 292))	('cancer', 'Phenotype', 'HP:0002664', (264, 270))	('correlated', 'Reg', (57, 67))	('stem cell divisions per stem cell', 'CPA', (87, 120))	('hypomethylation', 'Var', (36, 51))	('cancer', 'Disease', 'MESH:D009369', (286, 292))	('cancer', 'Disease', (286, 292))	('cancer', 'Disease', (264, 270))
366347	27716309	It will be important for future studies to try to understand this deep and subtle asymmetry between age-associated hyper- and hypomethylation in relation to the changes seen in cancer.	('cancer', 'Disease', (177, 183))	('cancer', 'Disease', 'MESH:D009369', (177, 183))	('hypomethylation', 'Var', (126, 141))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))
366364	27716309	Both models together are highly consistent with an overarching "phase transition" model of oncogenesis, in which epigenetic clonal mosaicism is maximal before cancer emerges.	('cancer', 'Disease', (159, 165))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('epigenetic clonal', 'Var', (113, 130))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))
366371	27716309	3 above is independent of the sample s; hence, one can write for the cancer risk: and so, if pcgtAge(s1,x) > pcgtAge(s2,x), then the cancer risk (CR) of sample s1 is also greater than that of s2: CR(s1,x) > CR(s2,x).	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('CR', 'Chemical', '-', (146, 148))	('pcgtAge(s1,x', 'Var', (93, 105))	('cancer', 'Disease', (133, 139))	('CR', 'Chemical', '-', (207, 209))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Disease', (69, 75))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('CR', 'Chemical', '-', (196, 198))
366413	30065837	In human subjects, mutations in HNF-1B caused severe pancreatic agenesis or hypoplasia, maturity-onset diabetes of the young (MODY) type 5, multicystic renal dysplasia, and hepatobiliary tract and Mullerian tract abnormalities.	('renal dysplasia', 'Phenotype', 'HP:0000110', (152, 167))	('HNF-1B', 'Gene', (32, 38))	('multicystic renal dysplasia', 'Disease', (140, 167))	('human', 'Species', '9606', (3, 8))	('multicystic renal dysplasia', 'Disease', 'MESH:D021782', (140, 167))	('HNF-1B', 'Gene', '6928', (32, 38))	('pancreatic agenesis or hypoplasia', 'Disease', 'MESH:C564908', (53, 86))	('diabetes', 'Disease', (103, 111))	('mutations', 'Var', (19, 28))	('maturity-onset diabetes of the young', 'Phenotype', 'HP:0004904', (88, 124))	('pancreatic agenesis or hypoplasia', 'Disease', (53, 86))	('diabetes', 'Disease', 'MESH:D003920', (103, 111))	('multicystic renal dysplasia', 'Phenotype', 'HP:0000003', (140, 167))	('caused', 'Reg', (39, 45))	('agenesis or hypoplasia', 'Phenotype', 'HP:0009115', (64, 86))	('pancreatic agenesis or hypoplasia', 'Phenotype', 'HP:0100800', (53, 86))	('pancreatic agenesis', 'Phenotype', 'HP:0100801', (53, 72))	('hepatobiliary tract and Mullerian tract abnormalities', 'Disease', 'MESH:D014552', (173, 226))
366470	30065837	KRAS mutation is a frequent molecular abnormality that is identified in up to 90% of PDACs.	('PDAC', 'Chemical', '-', (85, 89))	('KRAS', 'Gene', (0, 4))	('mutation', 'Var', (5, 13))	('KRAS', 'Gene', '3845', (0, 4))
366471	30065837	Interestingly, a recent study showed that mutated KRAS can induce abnormal regulations of pancreatic transcription factors including HNF-1B, which in turn causes abnormal cell growth and proliferation that leads to pancreatic cancer.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (215, 232))	('mutated', 'Var', (42, 49))	('pancreatic', 'Disease', (90, 100))	('leads to', 'Reg', (206, 214))	('pancreatic', 'Disease', 'MESH:D010195', (215, 225))	('HNF-1B', 'Gene', (133, 139))	('KRAS', 'Gene', (50, 54))	('pancreatic', 'Disease', (215, 225))	('pancreatic cancer', 'Disease', (215, 232))	('KRAS', 'Gene', '3845', (50, 54))	('proliferation', 'CPA', (187, 200))	('HNF-1B', 'Gene', '6928', (133, 139))	('cell growth', 'CPA', (171, 182))	('causes', 'Reg', (155, 161))	('pancreatic cancer', 'Disease', 'MESH:D010190', (215, 232))	('regulations', 'MPA', (75, 86))	('pancreatic', 'Disease', 'MESH:D010195', (90, 100))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
366477	30065837	Interestingly, silencing of HNF-1B expression secondary to promoter methylation appears to promote disease progression via epithelial-to-mesenchymal transition in both prostate and ovarian cancers.	('promote', 'PosReg', (91, 98))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('silencing', 'Var', (15, 24))	('prostate and ovarian cancers', 'Disease', 'MESH:D010051', (168, 196))	('HNF-1B', 'Gene', (28, 34))	('disease progression', 'CPA', (99, 118))	('ovarian cancers', 'Phenotype', 'HP:0100615', (181, 196))	('cancers', 'Phenotype', 'HP:0002664', (189, 196))	('HNF-1B', 'Gene', '6928', (28, 34))	('epithelial-to-mesenchymal transition', 'CPA', (123, 159))
366567	26944083	It is now understood that the majority of human genes produce multiple functional products, or isoforms, primarily through alternative transcription and splicing.	('splicing', 'Var', (153, 161))	('human', 'Species', '9606', (42, 47))	('alternative transcription', 'Var', (123, 148))
366603	26944083	RNA-seq removes the need for prior knowledge of targeted sequences and offers single-nucleotide resolution, thereby enabling accurate identification of novel isoforms, RNA editing events, allele-specific expression, sequence variants and somatic mutations, all of which have been implicated in cancer development.	('cancer', 'Disease', (294, 300))	('cancer', 'Disease', 'MESH:D009369', (294, 300))	('cancer', 'Phenotype', 'HP:0002664', (294, 300))	('sequence variants', 'Var', (216, 233))
366625	33167355	TSPAN1 depletion in parental and CDDP-resistant HNSCC cells reduced cell proliferation, induced apoptosis, decreased autophagy, sensitized to chemotherapeutic agents and inhibited several signaling cascades, with phospho-SRC inhibition being a major common target.	('SRC', 'Gene', '6714', (221, 224))	('HNSCC', 'Phenotype', 'HP:0012288', (48, 53))	('SRC', 'Gene', (221, 224))	('autophagy', 'CPA', (117, 126))	('induced', 'Reg', (88, 95))	('cell proliferation', 'CPA', (68, 86))	('decreased', 'NegReg', (107, 116))	('N', 'Chemical', 'MESH:D009584', (4, 5))	('apoptosis', 'CPA', (96, 105))	('reduced', 'NegReg', (60, 67))	('depletion', 'Var', (7, 16))	('CDDP', 'Chemical', 'MESH:D002945', (33, 37))	('N', 'Chemical', 'MESH:D009584', (49, 50))	('TSPAN1', 'Gene', (0, 6))	('inhibited', 'NegReg', (170, 179))
366626	33167355	Moreover, TSPAN1 depletion in vivo decreased the size and proliferation of parental and CDDP-resistant tumors and reduced metastatic spreading.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('CDDP-resistant tumors', 'Disease', 'MESH:D060467', (88, 109))	('metastatic spreading', 'CPA', (122, 142))	('CDDP-resistant tumors', 'Disease', (88, 109))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('reduced', 'NegReg', (114, 121))	('decreased', 'NegReg', (35, 44))	('depletion', 'Var', (17, 26))	('size', 'CPA', (49, 53))	('TSPAN1', 'Gene', (10, 16))
366656	33167355	To determine their respective IC50, JHU029, JHU029-R, HTB-43, HTB-43-R, CCL-138 and CCL-138-R, cell lines were seeded at 15 x 103 cells per well into 96-well plates, and the primary cell lines derived from patients at 10 x 103 cells per well.	('JHU029', 'Var', (36, 42))	('CCL-138-R', 'Chemical', '-', (84, 93))	('JHU029-R', 'Var', (44, 52))	('CCL-138', 'Chemical', '-', (84, 91))	('patients', 'Species', '9606', (206, 214))	('CCL-138', 'Chemical', '-', (72, 79))
366679	33167355	TMT-10plex on lysine and N-termini were set as quantification modifications, oxidation of methionine and acetylation of N-termini were set as dynamic modifications, whereas carbamidomethylation of cysteine was set as static modifications.	('lysine', 'Chemical', 'MESH:D008239', (14, 20))	('acetylation', 'MPA', (105, 116))	('N', 'Chemical', 'MESH:D009584', (120, 121))	('TMT-10plex', 'Var', (0, 10))	('cysteine', 'Chemical', 'MESH:D003545', (197, 205))	('N', 'Chemical', 'MESH:D009584', (25, 26))	('oxidation of methionine', 'MPA', (77, 100))	('methionine', 'Chemical', 'MESH:D008715', (90, 100))
366689	33167355	The expression of TSPAN1 (Hs00371661_m1) was analyzed by qRT-PCR using the expression of IPO8 (Hs00183533_m1) as an endogenous gene and TaqMan  Universal Master Mix II (Applied Biosystems, CA, USA; Thermo Fisher Scientific).	('Hs00371661_m1', 'Var', (26, 39))	('IPO8', 'Gene', (89, 93))	('IPO8', 'Gene', '10526', (89, 93))	('Hs00183533_m1', 'Var', (95, 108))
366693	33167355	A total of 16 mice were included in the study, four mice for each of the following experimental groups: JHU029 NC, JHU029 siTSPAN1, JHU029-R NC, JHU029-R siTSPAN1.	('N', 'Chemical', 'MESH:D009584', (128, 129))	('mice', 'Species', '10090', (14, 18))	('N', 'Chemical', 'MESH:D009584', (160, 161))	('JHU029 siTSPAN1', 'Var', (115, 130))	('mice', 'Species', '10090', (52, 56))	('JHU029-R NC', 'Var', (132, 143))	('JHU029-R siTSPAN1', 'Var', (145, 162))	('N', 'Chemical', 'MESH:D009584', (111, 112))	('JHU029 NC', 'Var', (104, 113))	('N', 'Chemical', 'MESH:D009584', (141, 142))
366710	33167355	Staining was done at room temperature on an automatic staining workstation (Dako Autostainer Plus), using the Dako EnVision Flex + Visualization System (Dako Autostainer, Denmark) with the following antibodies: anti-TSPAN1 monoclonal antibody Clone HPA011909 (Sigma:Aldrich Quimica SL, Madrid, Spain) at 1:50 dilution, anti-E-Cadherin (BD Biosciences #610181, San Jose, CA, USA) at 1:4000 dilution and active SRC monoclonal antibody Clone 28 (Thermo Fisher Scientific #AHO0051) at 1:300 dilution.	('Aldrich', 'Disease', (266, 273))	('E-Cadherin', 'Gene', '999', (324, 334))	('HPA011909', 'Var', (249, 258))	('Aldrich', 'Disease', 'MESH:D014923', (266, 273))	('SRC', 'Gene', '6714', (409, 412))	('SRC', 'Gene', (409, 412))	('E-Cadherin', 'Gene', (324, 334))
366729	33167355	In order to verify the proteomic results, TSPAN1 expression was analyzed by Western blot in the aforementioned HNSCC cell lines confirming that TSPAN1 was upregulated in CCL-138-R, JHU029-R and HTB-43-R cells compared to their respective control cells (Figure 1C, Figure S8).	('N', 'Chemical', 'MESH:D009584', (148, 149))	('CCL-138-R', 'Chemical', '-', (170, 179))	('N', 'Chemical', 'MESH:D009584', (46, 47))	('HNSCC', 'Phenotype', 'HP:0012288', (111, 116))	('N', 'Chemical', 'MESH:D009584', (112, 113))	('JHU029-R', 'Var', (181, 189))	('TSPAN1', 'Gene', (144, 150))	('upregulated', 'PosReg', (155, 166))
366732	33167355	Transduced parental JHU029, HTB-43 and CCL-138 cells and their respective CDDP-resistant variants with siTSPAN1 robustly decreased TSPAN1 mRNA levels by ~90% in all cell lines (Figure 1D).	('siTSPAN1', 'Gene', (103, 111))	('variants', 'Var', (89, 97))	('N', 'Chemical', 'MESH:D009584', (109, 110))	('CCL-138', 'Chemical', '-', (39, 46))	('decreased', 'NegReg', (121, 130))	('N', 'Chemical', 'MESH:D009584', (140, 141))	('CDDP', 'Chemical', 'MESH:D002945', (74, 78))	('TSPAN1 mRNA levels', 'MPA', (131, 149))	('N', 'Chemical', 'MESH:D009584', (135, 136))
366733	33167355	Consistently, colony formation capacity was also significantly reduced upon TSPAN1 depletion in CDDP-resistant and parental HNSCC cells (Figure 1F).	('CDDP', 'Chemical', 'MESH:D002945', (96, 100))	('reduced', 'NegReg', (63, 70))	('HNSCC', 'Phenotype', 'HP:0012288', (124, 129))	('depletion', 'Var', (83, 92))	('N', 'Chemical', 'MESH:D009584', (125, 126))	('TSPAN1', 'Gene', (76, 82))	('colony formation capacity', 'CPA', (14, 39))	('N', 'Chemical', 'MESH:D009584', (80, 81))
366736	33167355	Sensitization to CDDP was observed by TSPAN1 depletion in all cell lines, with a higher effect in the respective resistant variants, and HTB-43-R cells showing the highest sensitization (Figure 2A,B).	('CDDP', 'Chemical', 'MESH:D002945', (17, 21))	('depletion', 'NegReg', (45, 54))	('variants', 'Var', (123, 131))	('TSPAN1', 'Gene', (38, 44))
366748	33167355	Evidence of apoptosis induction upon TSPAN1 inhibition emerged from PARP cleavage analysis by Western blot (Figure 3A and Figure S8).	('PARP', 'Gene', (68, 72))	('inhibition', 'Var', (44, 54))	('TSPAN1', 'Gene', (37, 43))	('PARP', 'Gene', '142', (68, 72))	('apoptosis', 'CPA', (12, 21))
366749	33167355	The active form of PARP, cleaved PARP1 -indicative of apoptosis activation-, was found to increase in all TSPAN1-depleted cell lines.	('cleaved', 'Var', (25, 32))	('increase', 'PosReg', (90, 98))	('PARP', 'Gene', (33, 37))	('PARP1', 'Gene', (33, 38))	('PARP', 'Gene', '142', (19, 23))	('PARP1', 'Gene', '142', (33, 38))	('PARP', 'Gene', '142', (33, 37))	('PARP', 'Gene', (19, 23))
366753	33167355	These results show that TSPAN1 depletion induces apoptosis in HNSCC cells.	('HNSCC', 'Phenotype', 'HP:0012288', (62, 67))	('TSPAN1', 'Gene', (24, 30))	('N', 'Chemical', 'MESH:D009584', (63, 64))	('induces', 'Reg', (41, 48))	('N', 'Chemical', 'MESH:D009584', (28, 29))	('depletion', 'Var', (31, 40))	('apoptosis', 'CPA', (49, 58))
366757	33167355	In fact, p-SRC levels (an indicator of SRC activation) consistently decreased in all six cell lines tested: JHU029, JHU029-R, HTB-43, HTB-43-R, CCL-138, CCL-138-R upon TSPAN1 depletion (Figure 4A).	('CCL-138-R', 'Chemical', '-', (153, 162))	('decreased', 'NegReg', (68, 77))	('CCL-138', 'Chemical', '-', (153, 160))	('SRC', 'Gene', '6714', (39, 42))	('CCL-138', 'Var', (144, 151))	('SRC', 'Gene', (39, 42))	('HTB-43-R', 'Var', (134, 142))	('SRC', 'Gene', '6714', (11, 14))	('SRC', 'Gene', (11, 14))	('CCL-138', 'Chemical', '-', (144, 151))	('CCL-138-R', 'Var', (153, 162))
366768	33167355	p-ERK1/2 also decreased at varying levelsin CCL-138, CCL-138-R, JHU029, JHU029-R, HTB-43 and HTB-43-R cells (Figure 4A).	('CCL-138', 'Chemical', '-', (53, 60))	('decreased', 'NegReg', (14, 23))	('CCL-138-R', 'Chemical', '-', (53, 62))	('CCL-138', 'Chemical', '-', (44, 51))	('ERK1/2', 'Gene', (2, 8))	('JHU029-R', 'Var', (72, 80))	('ERK1/2', 'Gene', '5595;5594', (2, 8))	('CCL-138', 'Var', (44, 51))	('CCL-138-R', 'Var', (53, 62))
366774	33167355	Notably, tumors formed by the resistant JHU029-R cells, despite being smaller in size, showed EMT features, characteristic of fusocellular morphology (Figure 5F, arrows).	('EMT features', 'CPA', (94, 106))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('N', 'Chemical', 'MESH:D009584', (0, 1))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('tumors', 'Disease', (9, 15))	('tumors', 'Disease', 'MESH:D009369', (9, 15))	('JHU029-R', 'Var', (40, 48))
366776	33167355	At the endpoint of the experiment, we found that tumors from the group JHU029-R siTSPAN1 generally showed lower TSPAN1 expression than the corresponding control group (JHU029-R NC) (Figure S5C), beyond some variability in TSPAN1 levels among the tumors from each experimental group.	('expression', 'MPA', (119, 129))	('lower', 'NegReg', (106, 111))	('tumors', 'Disease', 'MESH:D009369', (246, 252))	('N', 'Chemical', 'MESH:D009584', (177, 178))	('N', 'Chemical', 'MESH:D009584', (116, 117))	('N', 'Chemical', 'MESH:D009584', (226, 227))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('TSPAN1', 'Protein', (112, 118))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('tumors', 'Disease', (49, 55))	('tumors', 'Disease', 'MESH:D009369', (49, 55))	('tumors', 'Phenotype', 'HP:0002664', (246, 252))	('N', 'Chemical', 'MESH:D009584', (86, 87))	('JHU029-R siTSPAN1', 'Var', (71, 88))	('tumors', 'Disease', (246, 252))
366780	33167355	Overall, TSPAN1 inhibition renders smaller tumors with reduced metastatic potential.	('reduced', 'NegReg', (55, 62))	('TSPAN1', 'Protein', (9, 15))	('smaller', 'NegReg', (35, 42))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumors', 'Disease', (43, 49))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('tumors', 'Disease', 'MESH:D009369', (43, 49))	('metastatic potential', 'CPA', (63, 83))	('inhibition', 'Var', (16, 26))
366802	33167355	Importantly, TSPAN1 depletion was found to sensitize resistant cells to the action of distinct therapeutic drugs (i.e., CDDP and dasatinib), and this sensitization was more pronounced in biopsy-derived primary cell lines from laryngeal and pharyngeal tumors in comparison to established HNSCC cell lines.	('pharyngeal tumors', 'Phenotype', 'HP:0100638', (240, 257))	('tumors', 'Disease', (251, 257))	('tumors', 'Disease', 'MESH:D009369', (251, 257))	('sensitize', 'Reg', (43, 52))	('N', 'Chemical', 'MESH:D009584', (288, 289))	('tumors', 'Phenotype', 'HP:0002664', (251, 257))	('TSPAN1', 'Gene', (13, 19))	('action', 'MPA', (76, 82))	('depletion', 'Var', (20, 29))	('N', 'Chemical', 'MESH:D009584', (17, 18))	('HNSCC', 'Phenotype', 'HP:0012288', (287, 292))	('laryngeal', 'Disease', (226, 235))	('dasatinib', 'Chemical', 'MESH:D000069439', (129, 138))	('tumor', 'Phenotype', 'HP:0002664', (251, 256))	('CDDP', 'Chemical', 'MESH:D002945', (120, 124))
366804	33167355	Upon TSPAN1 inhibition, a decrease in p-SRC activation occurs as a common feature in all HNSCC cell lines tested, which was accompanied by a decrease in p-AKT and p-ERK1/2 levels.	('ERK1/2', 'Gene', (165, 171))	('inhibition', 'Var', (12, 22))	('AKT', 'Gene', (155, 158))	('SRC', 'Gene', '6714', (40, 43))	('decrease', 'NegReg', (26, 34))	('ERK1/2', 'Gene', '5595;5594', (165, 171))	('SRC', 'Gene', (40, 43))	('TSPAN1', 'Gene', (5, 11))	('activation', 'PosReg', (44, 54))	('AKT', 'Gene', '207', (155, 158))	('HNSCC', 'Phenotype', 'HP:0012288', (89, 94))	('N', 'Chemical', 'MESH:D009584', (9, 10))	('N', 'Chemical', 'MESH:D009584', (90, 91))	('decrease', 'NegReg', (141, 149))
366806	33167355	Moreover, Vimentin was reduced in both parental JHU029 and resistant JHU029-R cells upon TSPAN1 depletion, suggestive of a link between TSPAN1 and the EMT process.	('Vimentin', 'Gene', '7431', (10, 18))	('depletion', 'Var', (96, 105))	('TSPAN1', 'Gene', (89, 95))	('reduced', 'NegReg', (23, 30))	('Vimentin', 'Gene', (10, 18))
366809	33167355	However, the effects of TSPAN1 depletion extend beyond solely regulating p-SRC activation to also effectively target the levels of p-AKT, p-ERK1/2 and autophagy pathway.	('SRC', 'Gene', '6714', (75, 78))	('SRC', 'Gene', (75, 78))	('AKT', 'Gene', (133, 136))	('autophagy pathway', 'CPA', (151, 168))	('AKT', 'Gene', '207', (133, 136))	('TSPAN1', 'Gene', (24, 30))	('depletion', 'Var', (31, 40))	('ERK1/2', 'Gene', '5595;5594', (140, 146))	('ERK1/2', 'Gene', (140, 146))
366814	33167355	In the xenografted mice, we found that tumors formed by resistant JHU029-R cells were smaller in size but developed more metastasis than those formed by parental JHU029 cells.	('metastasis', 'CPA', (121, 131))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('JHU029-R', 'Var', (66, 74))	('developed', 'PosReg', (106, 115))	('tumors', 'Disease', (39, 45))	('mice', 'Species', '10090', (19, 23))
366818	33167355	In this line of evidence, tumors formed by slowly growing resistant cells JHU029-R showed a fusocellular pattern compared to parental JHU029 cells.	('JHU029-R', 'Var', (74, 82))	('tumors', 'Disease', (26, 32))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('fusocellular pattern', 'CPA', (92, 112))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumors', 'Disease', 'MESH:D009369', (26, 32))
366820	33167355	Moreover, in tumors formed by resistant JHU029-R cells, TSPAN1 inhibition was able to revert the fusocellular pattern to an epithelial morphology and reduce metastasis capacity of these resistant HNSCC cells.	('fusocellular pattern', 'MPA', (97, 117))	('HNSCC', 'Phenotype', 'HP:0012288', (196, 201))	('N', 'Chemical', 'MESH:D009584', (197, 198))	('tumors', 'Disease', (13, 19))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('N', 'Chemical', 'MESH:D009584', (60, 61))	('reduce', 'NegReg', (150, 156))	('metastasis capacity', 'CPA', (157, 176))	('inhibition', 'Var', (63, 73))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('TSPAN1', 'Gene', (56, 62))	('revert', 'NegReg', (86, 92))
366836	33167355	The fact that inhibition of TSPAN1 is able to sensitize resistant cells to different chemotherapeutic agents, has an important added value to be considered a potential novel target for cancer therapy.	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('TSPAN1', 'Gene', (28, 34))	('inhibition', 'Var', (14, 24))	('cancer', 'Disease', (185, 191))
366843	33167355	An ANOVA test was performed to determine proteins significantly dysregulated between CCL-138, CCL-138-R and CCL-138 CSCs, Table S3.	('CCL-138-R', 'Chemical', '-', (94, 103))	('dysregulated', 'Reg', (64, 76))	('CCL-138', 'Var', (108, 115))	('CCL-138', 'Chemical', '-', (85, 92))	('N', 'Chemical', 'MESH:D009584', (4, 5))	('CCL-138', 'Chemical', '-', (108, 115))	('CCL-138-R', 'Var', (94, 103))	('proteins', 'Protein', (41, 49))	('CCL-138', 'Chemical', '-', (94, 101))	('CCL-138', 'Var', (85, 92))
366844	33167355	ANOVA test to determine proteins significantly dysregulated between CCL-138, CCL-138-R and CCL-138 CSCs, Table S4.	('proteins', 'Protein', (24, 32))	('CCL-138', 'Var', (68, 75))	('CCL-138', 'Chemical', '-', (77, 84))	('CCL-138', 'Chemical', '-', (91, 98))	('dysregulated', 'Reg', (47, 59))	('CCL-138-R', 'Chemical', '-', (77, 86))	('CCL-138', 'Chemical', '-', (68, 75))	('CCL-138', 'Var', (91, 98))	('N', 'Chemical', 'MESH:D009584', (1, 2))
366900	32082689	Such mutations in the fragile histidine triad gene have been suggested in the pathogenesis of lung cancer following pulmonary TB.	('lung cancer', 'Disease', 'MESH:D008175', (94, 105))	('pulmonary TB', 'Phenotype', 'HP:0032262', (116, 128))	('mutations', 'Var', (5, 14))	('lung cancer', 'Disease', (94, 105))	('histidine', 'Chemical', 'MESH:D006639', (30, 39))	('lung cancer', 'Phenotype', 'HP:0100526', (94, 105))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('pulmonary TB', 'Disease', 'MESH:D014397', (116, 128))	('pulmonary TB', 'Disease', (116, 128))
366924	31067633	In the ubiquitination system, different proteins are involved and their dysregulation can lead to various human diseases, including cancers.	('cancers', 'Phenotype', 'HP:0002664', (132, 139))	('cancers', 'Disease', (132, 139))	('human', 'Species', '9606', (106, 111))	('cancers', 'Disease', 'MESH:D009369', (132, 139))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('human diseases', 'Disease', (106, 120))	('proteins', 'Protein', (40, 48))	('lead to', 'Reg', (90, 97))	('dysregulation', 'Var', (72, 85))	('ubiquitin', 'Gene', (7, 16))	('ubiquitin', 'Gene', '108708852', (7, 16))
366937	31067633	Various cellular processes are regulated by the ubiquitin system; therefore, it is expected its dysregulation results in human diseases, including cancers.	('ubiquitin', 'Gene', (48, 57))	('ubiquitin', 'Gene', '108708852', (48, 57))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('human', 'Species', '9606', (121, 126))	('cancers', 'Disease', 'MESH:D009369', (147, 154))	('cancers', 'Phenotype', 'HP:0002664', (147, 154))	('dysregulation', 'Var', (96, 109))	('cancers', 'Disease', (147, 154))	('results in', 'Reg', (110, 120))
366955	31067633	In PRAD tumors, the increase was statistically more significant for Gleason score 8, followed by Gleason score 9 and Gleason score 7 (Table 1 and Figure S2 panel 1F).	('Gleason', 'Var', (68, 75))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('tumors', 'Phenotype', 'HP:0002664', (8, 14))	('PRAD tumors', 'Disease', (3, 14))	('PRAD tumors', 'Disease', 'MESH:D009369', (3, 14))
366956	31067633	The more statistically significant molecular signature was observed for erythroblast transformation-specific (ETS) transcription factor ERG (ERG) fusion, speckle type BTB/POZ protein (SPOP) mutation, and ETS translocation variant 1 (ETV1) fusion (Table 1 and Figure S2 panel 1G).	('mutation', 'Var', (190, 198))	('ERG', 'Gene', '2078', (136, 139))	('fusion', 'Var', (146, 152))	('speckle type BTB/POZ protein', 'Gene', (154, 182))	('ERG', 'Gene', (136, 139))	('ETV1', 'Gene', (233, 237))	('ETS translocation variant 1', 'Gene', '2115', (204, 231))	('ERG', 'Gene', '2078', (141, 144))	('ERG', 'Gene', (141, 144))	('SPOP', 'Gene', '8405', (184, 188))	('SPOP', 'Gene', (184, 188))	('ETV1', 'Gene', '2115', (233, 237))	('speckle type BTB/POZ protein', 'Gene', '8405', (154, 182))	('ETS translocation variant 1', 'Gene', (204, 231))
367019	31067633	Therefore, it is likely that aberrant UBE2C overexpression, leading to changes in ubiquitination, might be involved in uncontrolled cell proliferation, which is one of the main features of cancers.	('changes', 'Reg', (71, 78))	('UBE2C', 'Gene', '11065', (38, 43))	('UBE2C', 'Gene', (38, 43))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('overexpression', 'PosReg', (44, 58))	('ubiquitin', 'Gene', (82, 91))	('involved', 'Reg', (107, 115))	('ubiquitin', 'Gene', '108708852', (82, 91))	('cancers', 'Phenotype', 'HP:0002664', (189, 196))	('aberrant', 'Var', (29, 37))	('uncontrolled cell proliferation', 'CPA', (119, 150))	('cancers', 'Disease', 'MESH:D009369', (189, 196))	('cancers', 'Disease', (189, 196))
367099	27843256	Paracrine effects of TGF-beta include the stimulation of angiogenesis, escape from immuno-surveillance and recruitment of myofibroblasts, while the autocrine effects of TGF-beta in cancer cells with a functional TGF-beta receptor complex may be caused by a convergence between TGF-beta signaling and beta-catenin or activating Ras mutations.	('mutations', 'Var', (331, 340))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('beta-catenin', 'Gene', (300, 312))	('angiogenesis', 'CPA', (57, 69))	('TGF-beta', 'Gene', '7040', (169, 177))	('Ras', 'Gene', (327, 330))	('TGF-beta', 'Gene', '7040', (21, 29))	('stimulation', 'PosReg', (42, 53))	('TGF-beta', 'Gene', (169, 177))	('TGF-beta', 'Gene', '7040', (277, 285))	('beta-catenin', 'Gene', '1499', (300, 312))	('TGF-beta', 'Gene', (21, 29))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('TGF-beta', 'Gene', '7040', (212, 220))	('cancer', 'Disease', (181, 187))	('TGF-beta', 'Gene', (212, 220))	('TGF-beta', 'Gene', (277, 285))
367215	33757566	Furthermore, the high expression of SPRY4-IT1 was significantly correlated with tumor differentiation (P = 0.029), T classification (P = 0.013), lymph node metastasis(P = 0.022) and pathological stage (P = 0.001).	('lymph node metastasis', 'CPA', (145, 166))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('SPRY4-IT1', 'Gene', (36, 45))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('SPRY4-IT1', 'Gene', '100642175;81848;79441', (36, 45))	('high', 'Var', (17, 21))	('T classification', 'CPA', (115, 131))	('tumor', 'Disease', (80, 85))	('correlated', 'Reg', (64, 74))
367230	33757566	With the deepening research of lncRNA function, the study revealed that there are a large number of abnormal expression of lncRNAs in esophageal cancer, which play an important role in the development and progression of esophageal carcinoma.	('cancer', 'Disease', (145, 151))	('abnormal', 'Var', (100, 108))	('expression', 'MPA', (109, 119))	('esophageal carcinoma', 'Disease', (220, 240))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (220, 240))	('carcinoma', 'Phenotype', 'HP:0030731', (231, 240))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (220, 240))	('lncRNAs', 'Gene', (123, 130))	('cancer', 'Disease', 'MESH:D009369', (145, 151))
367252	33757566	The abdominal and cervical surgery: 1) Place the patients in the supine position and separate legs, expose the small bend in the stomach; cut off the left gastric artery, and lymph nodes along the left gastric artery hepatic artery and the celiac axis were dissected.	('gastric artery hepatic artery', 'Disease', 'MESH:D007022', (202, 231))	('gastric artery hepatic artery', 'Disease', (202, 231))	('patients', 'Species', '9606', (49, 57))	('cut', 'Var', (138, 141))
367253	33757566	2) The stomach was mobilized with reserve of the right gastroepiploic artery, meanwhile, dissect the perigastric LNs, separate the esophageal hiatus and mobilize the abdominal esophagus.	('dissect', 'Var', (89, 96))	('gastroepiploic artery', 'Disease', (55, 76))	('gastroepiploic artery', 'Disease', 'MESH:D007022', (55, 76))
367254	33757566	3) Make an 5 cm incision in the anterior border of the sternocleidomastoid muscle of the left cervix, separate the sternocleidomastoid, dissect the LNs in the left lower cervical esophagus [included left cervical paraesophageal (101) and supraclavicular (104)] and cut off the cervical esophagus at the level of thoracic inlet.	('dissect', 'Var', (136, 143))	('sternocleidomastoid', 'Disease', (115, 134))	('sternocleidomastoid muscle', 'Disease', 'MESH:C535977', (55, 81))	('sternocleidomastoid', 'Disease', 'MESH:C535977', (55, 74))	('sternocleidomastoid', 'Disease', 'MESH:C535977', (115, 134))	('sternocleidomastoid muscle', 'Phenotype', 'HP:0012036', (55, 81))	('sternocleidomastoid', 'Disease', (55, 74))	('sternocleidomastoid muscle', 'Disease', (55, 81))
367274	33757566	Among 32 patients with high expression of SPRY4-IT1 harboring lymph-node metastasis, 19 patients (59.4%) had cervical and superior mediastinal lymph-node metastasis and 13 patients (40.6%) only had others' site lymph-node metastasis that didn't include cervical and superior mediastinum.	('patients', 'Species', '9606', (9, 17))	('high expression', 'Var', (23, 38))	('mediastinal lymph-node metastasis', 'Phenotype', 'HP:0100721', (131, 164))	('patients', 'Species', '9606', (88, 96))	('SPRY4-IT1', 'Gene', '100642175;81848;79441', (42, 51))	('SPRY4-IT1', 'Gene', (42, 51))	('patients', 'Species', '9606', (172, 180))
367275	33757566	Among 20 patients with low expression of SPRY4-IT1 existing lymph-node metastasis,6 patients (30%) had cervical and superior mediastinal lymph-node metastasis and 14 patients (70%) only had others' site lymph-node metastasis excluded cervical and superior mediastinum.	('patients', 'Species', '9606', (9, 17))	('mediastinal lymph-node metastasis', 'Phenotype', 'HP:0100721', (125, 158))	('patients', 'Species', '9606', (84, 92))	('SPRY4-IT1', 'Gene', '100642175;81848;79441', (41, 50))	('SPRY4-IT1', 'Gene', (41, 50))	('low expression', 'Var', (23, 37))	('patients', 'Species', '9606', (166, 174))
367280	33757566	Among 47 patients with the high expression of SPRY4-IT1, 38 patients (80.9%) had lymph-node recurrence.	('SPRY4-IT1', 'Gene', '100642175;81848;79441', (46, 55))	('patients', 'Species', '9606', (9, 17))	('patients', 'Species', '9606', (60, 68))	('lymph-node recurrence', 'CPA', (81, 102))	('high expression', 'Var', (27, 42))	('SPRY4-IT1', 'Gene', (46, 55))
367310	33757566	This reflected that the high expression of SPRY4-IT1 is associated with a higher risk of cervical and superior mediastinal lymph-node metastasis and that this could be mitigated by radical three-field lymph node dissection surgery.	('SPRY4-IT1', 'Gene', (43, 52))	('mediastinal lymph-node metastasis', 'Phenotype', 'HP:0100721', (111, 144))	('SPRY4-IT1', 'Gene', '100642175;81848;79441', (43, 52))	('cervical', 'Disease', (89, 97))	('high', 'Var', (24, 28))
367312	33757566	But no significant differences were observed in the ESCC patients with 3FLND.Thus, patients with high SPRY4-IT1 expression might benefit from 3FLND esophagectomy.	('SPRY4-IT1', 'Gene', '100642175;81848;79441', (102, 111))	('SPRY4-IT1', 'Gene', (102, 111))	('patients', 'Species', '9606', (57, 65))	('patients', 'Species', '9606', (83, 91))	('benefit', 'PosReg', (129, 136))	('high', 'Var', (97, 101))	('esophagectomy', 'Disease', (148, 161))	('expression', 'MPA', (112, 122))
367320	33363204	The Family with sequence similarity 83 (FAM83) of poorly characterized proteins are defined by the presence of the conserved DUF1669 domain of unknown function at their N-termini, most of which significantly elevated levels of expression in multiple cancers.	('DUF1669', 'Chemical', '-', (125, 132))	('multiple cancers', 'Disease', (241, 257))	('elevated', 'PosReg', (208, 216))	('cancers', 'Phenotype', 'HP:0002664', (250, 257))	('expression', 'MPA', (227, 237))	('multiple cancers', 'Disease', 'MESH:D009369', (241, 257))	('DUF1669', 'Var', (125, 132))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))	('levels', 'MPA', (217, 223))
367323	33363204	The transcriptional levels of FAM83A/B/C/D/F/G/H were up-regulated in patients with NSCLC.	('patients', 'Species', '9606', (70, 78))	('NSCLC', 'Disease', (84, 89))	('up-regulated', 'PosReg', (54, 66))	('FAM83A/B/C/D/F/G/H', 'Var', (30, 48))	('transcriptional levels', 'MPA', (4, 26))	('NSCLC', 'Disease', 'MESH:D002289', (84, 89))
367324	33363204	A noticeable correlation was found between the over-expressions of FAM83A/B/D/F/H and clinical cancer stages in NSCLC patients.	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('cancer', 'Disease', (95, 101))	('over-expressions', 'PosReg', (47, 63))	('FAM83A/B/D/F/H', 'Var', (67, 81))	('NSCLC', 'Disease', (112, 117))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('patients', 'Species', '9606', (118, 126))	('NSCLC', 'Disease', 'MESH:D002289', (112, 117))
367325	33363204	Besides, higher mRNA expressions of FAM83A/B/C/D/F/H were discovered to be expressively associated with overall survival (OS) in lung cancer patients, furthermore, FAM83A, FAM83C, and FAM83H in OS group achieved 0.9475/1, 0.971897/1, and 0.9454545/0.8974359 specificity/sensitivity in distinguishing short survivors from long survivors, respectively.	('FAM83A/B/C/D/F/H', 'Var', (36, 52))	('lung cancer', 'Disease', (129, 140))	('lung cancer', 'Phenotype', 'HP:0100526', (129, 140))	('FAM83C', 'Gene', (172, 178))	('FAM83A', 'Var', (164, 170))	('FAM83H', 'Gene', (184, 190))	('mRNA expressions', 'MPA', (16, 32))	('lung cancer', 'Disease', 'MESH:D008175', (129, 140))	('FAM83H', 'Gene', '286077', (184, 190))	('FAM83C', 'Gene', '128876', (172, 178))	('associated', 'Reg', (88, 98))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('patients', 'Species', '9606', (141, 149))	('overall', 'Disease', (104, 111))	('higher', 'PosReg', (9, 15))
367326	33363204	Moreover, a high mutation rate of FAM83 family (51%) was also observed in lung adenocarcinoma (LUAD) patients, and genetic alteration in the FAM83 family was associated with shorter OS and disease-free survival (DFS) in LUAD patients.	('patients', 'Species', '9606', (101, 109))	('FAM83', 'Gene', (141, 146))	('patients', 'Species', '9606', (225, 233))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (74, 93))	('mutation', 'Var', (17, 25))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('FAM83 family', 'Gene', (34, 46))	('disease-free survival', 'CPA', (189, 210))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (74, 93))	('lung adenocarcinoma', 'Disease', (74, 93))	('genetic alteration', 'Var', (115, 133))	('observed', 'Reg', (62, 70))	('shorter', 'NegReg', (174, 181))
367334	33363204	demonstrated that FAM83A accelerated NSCLC cell migration and invasion through the activation of epithelial-mesenchymal transition (EMT) via PI3K/ATK/Snail signaling.	('NSCLC', 'Disease', 'MESH:D002289', (37, 42))	('Snail', 'Gene', '6615', (150, 155))	('Snail', 'Gene', (150, 155))	('invasion', 'CPA', (62, 70))	('epithelial-mesenchymal transition', 'CPA', (97, 130))	('NSCLC', 'Disease', (37, 42))	('FAM83A', 'Var', (18, 24))	('accelerated', 'PosReg', (25, 36))	('activation', 'PosReg', (83, 93))
367341	33363204	In this present study, bioinformatics was performed initially to address this problem by analyzing the expression, prognosis, and mutations of different FAM83 family members and their relations with individual cancer stages in NSCLC patients.	('NSCLC', 'Disease', (227, 232))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('NSCLC', 'Disease', 'MESH:D002289', (227, 232))	('FAM83', 'Gene', (153, 158))	('relations', 'Reg', (184, 193))	('mutations', 'Var', (130, 139))	('cancer', 'Disease', 'MESH:D009369', (210, 216))	('patients', 'Species', '9606', (233, 241))	('cancer', 'Disease', (210, 216))
367353	33363204	Genetic mutations in FAM83 family and their association with OS and disease free survival (DFS) of lung cancer patients were displayed as Kaplan-Meier plots, and the log-rank test was performed to identify the significance of the diversity between the survival curves, and when a p-value is <0.05, the difference was considered statically significant.	('lung cancer', 'Disease', (99, 110))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('mutations', 'Var', (8, 17))	('lung cancer', 'Disease', 'MESH:D008175', (99, 110))	('lung cancer', 'Phenotype', 'HP:0100526', (99, 110))	('FAM83', 'Gene', (21, 26))	('association', 'Interaction', (44, 55))	('patients', 'Species', '9606', (111, 119))
367358	33363204	The results in Figure 1B showed that the mRNA expression levels of FAM83A/C/D/E/F/H were remarkably up-regulated in lung cancer tissues in multiple datasets.	('up-regulated', 'PosReg', (100, 112))	('lung cancer', 'Disease', (116, 127))	('lung cancer', 'Phenotype', 'HP:0100526', (116, 127))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('FAM83A/C/D/E/F/H', 'Var', (67, 83))	('mRNA expression levels', 'MPA', (41, 63))	('lung cancer', 'Disease', 'MESH:D008175', (116, 127))
367368	33363204	Besides, we also contrast the relative expression levels of FAM83 family in LUAD and LUSC tissues and determined that among all the factors we evaluated, FAM83A was the highest expression in LUAD and FAM83H was the highest in LUSC (Figure 3).	('FAM83A', 'Var', (154, 160))	('FAM83H', 'Gene', (200, 206))	('FAM83H', 'Gene', '286077', (200, 206))
367369	33363204	Taken together, our results showed that transcriptional expressions of FAM83A/B/C/D/F/G/H were over-expressed in patients with NSCLC.	('NSCLC', 'Disease', (127, 132))	('NSCLC', 'Disease', 'MESH:D002289', (127, 132))	('patients', 'Species', '9606', (113, 121))	('FAM83A/B/C/D/F/G/H', 'Var', (71, 89))	('transcriptional', 'MPA', (40, 55))	('over-expressed', 'PosReg', (95, 109))
367373	33363204	In short, the results above suggested that mRNA expressions of FAM83A/B/D/F/H were obviously related to patients' individual cancer stages, and patients who were in more advanced cancer stages were inclined to express higher mRNA expression of FAM83A/B/D/F/H.	('mRNA expression', 'MPA', (225, 240))	('higher', 'PosReg', (218, 224))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('FAM83A/B/D/F/H', 'Var', (244, 258))	('FAM83A/B/D/F/H', 'Var', (63, 77))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('patients', 'Species', '9606', (144, 152))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('cancer', 'Disease', (125, 131))	('related', 'Reg', (93, 100))	('mRNA expressions', 'MPA', (43, 59))	('cancer', 'Disease', (179, 185))	('patients', 'Species', '9606', (104, 112))
367377	33363204	There was no significant correlation in lung cancer between FP and either FAM83D or FAM83H, whereas high FAM83A/B/C/E/F mRNA expression led to a reduced FP.	('reduced', 'NegReg', (145, 152))	('high FAM83A/B/C/E/F', 'Var', (100, 119))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('FAM83D', 'Gene', (74, 80))	('reduced FP', 'Phenotype', 'HP:0032341', (145, 155))	('FAM83H', 'Gene', (84, 90))	('lung cancer', 'Disease', 'MESH:D008175', (40, 51))	('FAM83D', 'Gene', '81610', (74, 80))	('FAM83H', 'Gene', '286077', (84, 90))	('lung cancer', 'Disease', (40, 51))	('lung cancer', 'Phenotype', 'HP:0100526', (40, 51))
367378	33363204	In addition, increased FAM83A/D/F/H mRNA expression levels were associated with PPS.	('PPS', 'Disease', (80, 83))	('PPS', 'Chemical', '-', (80, 83))	('increased', 'PosReg', (13, 22))	('FAM83A/D/F/H', 'Var', (23, 35))
367383	33363204	As shown in Supplementary Table 3, we described FAM83 family prognostic potential: FAM83A in OS group and PPS group achieved a 0.9475/1 and 0.952381/0.7586207 specificity/sensitivity in distinguishing short survivors from long survivors, accordingly.	('FAM83A', 'Var', (83, 89))	('0.952381/0.7586207', 'Var', (140, 158))	('PPS', 'Chemical', '-', (106, 109))
367386	33363204	FAM83D in PPS group achieved a 0.8333333/0.9661017 specificity/sensitivity.	('0.8333333/0.9661017', 'Var', (31, 50))	('FAM83D', 'Gene', '81610', (0, 6))	('PPS', 'Chemical', '-', (10, 13))	('FAM83D', 'Gene', (0, 6))
367387	33363204	FAM83E in FP group achieved a 0.3424658/0.9504717 specificity/sensitivity in discriminating short survivors from long survivors.	('FAM83E', 'Gene', '54854', (0, 6))	('FAM83E', 'Gene', (0, 6))	('0.3424658/0.9504717', 'Var', (30, 49))
367390	33363204	Epigenetic alteration plays a vital role in early malignancies.	('malignancies', 'Disease', 'MESH:D009369', (50, 62))	('Epigenetic alteration', 'Var', (0, 21))	('malignancies', 'Disease', (50, 62))
367392	33363204	FAM83H, FAM83A, FAM83D, and FAM83B were the top four genes with genetic alterations, and their mutation rates were 23, 16, 14, and 10%, respectively.	('FAM83D', 'Gene', (16, 22))	('FAM83H', 'Gene', (0, 6))	('FAM83D', 'Gene', '81610', (16, 22))	('FAM83B', 'Gene', (28, 34))	('FAM83B', 'Gene', '222584', (28, 34))	('FAM83H', 'Gene', '286077', (0, 6))	('FAM83A', 'Var', (8, 14))
367395	33363204	Results from the Kaplan-Meier plot and log-rank test uncovered that genetic alteration in FAM83 family was related to shorter OS (Figure 6C, p = 1.135E-3) and DFS (Figure 6D, p = 0.0381) of lung cancer patients.	('shorter OS', 'Disease', (118, 128))	('FAM83', 'Gene', (90, 95))	('genetic alteration', 'Var', (68, 86))	('lung cancer', 'Disease', 'MESH:D008175', (190, 201))	('patients', 'Species', '9606', (202, 210))	('DFS', 'MPA', (159, 162))	('lung cancer', 'Disease', (190, 201))	('lung cancer', 'Phenotype', 'HP:0100526', (190, 201))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
367396	33363204	These discovery observed that the change of FAM83 family gene may also crucially affect the prognosis of lung cancer patients.	('lung cancer', 'Phenotype', 'HP:0100526', (105, 116))	('change', 'Var', (34, 40))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('lung cancer', 'Disease', 'MESH:D008175', (105, 116))	('affect', 'Reg', (81, 87))	('FAM83 family gene', 'Gene', (44, 61))	('patients', 'Species', '9606', (117, 125))	('lung cancer', 'Disease', (105, 116))
367399	33363204	As shown in Figures 7B-E, we found that BP such as GO:0007062 (sister chromatid cohesion), GO:0030198 (extracellular matrix organization), GO:0007067 (mitotic nuclear division), GO:0051301 (cell division), and GO:0008283 (cell proliferation) were remarkably regulated by the FAM83 family mutations in NSCLC (Figure 7B).	('GO:0007067', 'Var', (139, 149))	('FAM83', 'Gene', (275, 280))	('GO:0008283', 'Var', (210, 220))	('GO:0051301', 'Var', (178, 188))	('GO:0030198', 'Var', (91, 101))	('NSCLC', 'Disease', (301, 306))	('regulated', 'Reg', (258, 267))	('mutations', 'Var', (288, 297))	('NSCLC', 'Disease', 'MESH:D002289', (301, 306))	('cell proliferation', 'CPA', (222, 240))
367400	33363204	Furthermore, FAM83 family mutations also prominently affected the MF, such as GO:0005515 (protein binding), GO:0005524 (ATP binding), GO:0019901 (protein kinase binding), and GO:0098641 (cadherin binding involved in cell-cell adhesion).	('GO:0005515', 'Var', (78, 88))	('GO:0098641', 'Var', (175, 185))	('affected', 'Reg', (53, 61))	('ATP', 'Chemical', 'MESH:D000255', (120, 123))	('GO:0019901', 'Var', (134, 144))	('FAM83 family', 'Gene', (13, 25))	('mutations', 'Var', (26, 35))	('GO:0005524', 'Var', (108, 118))
367402	33363204	While all eight FAM83 members share the highly conserved DUF1669, they also possess unique C-terminus of variable length and otherwise lack any significant homology beyond the DUF1669, explaining the reason of poor enrichment function.	('DUF1669', 'Chemical', '-', (57, 64))	('FAM83', 'Gene', (16, 21))	('lack', 'NegReg', (135, 139))	('DUF1669', 'Var', (57, 64))	('DUF1669', 'Chemical', '-', (176, 183))	('C-terminus', 'MPA', (91, 101))	('homology', 'MPA', (156, 164))
367406	33363204	FAM83A has been reported to play a role in promoting cancer and reducing drug sensitivity in a variety of cancer.	('reducing', 'NegReg', (64, 72))	('drug sensitivity', 'MPA', (73, 89))	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('drug sensitivity', 'Phenotype', 'HP:0020174', (73, 89))	('FAM83A', 'Var', (0, 6))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('cancer', 'Disease', (106, 112))	('promoting', 'PosReg', (43, 52))	('reducing drug sensitivity', 'Phenotype', 'HP:0020173', (64, 89))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
367407	33363204	indicated that FAM83A was overexpressed in human and murine pancreatic cancers and protected from cell death in pancreatic cancer cells by activating essential MEK/ERK survival signaling.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('death', 'Disease', (103, 108))	('pancreatic cancer', 'Disease', 'MESH:D010190', (60, 77))	('FAM83A', 'Var', (15, 21))	('ERK', 'Gene', '26413', (164, 167))	('cancers', 'Phenotype', 'HP:0002664', (71, 78))	('murine', 'Species', '10090', (53, 59))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (112, 129))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('overexpressed', 'PosReg', (26, 39))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (60, 78))	('MEK', 'Gene', '17242', (160, 163))	('pancreatic cancers', 'Disease', (60, 78))	('activating', 'Reg', (139, 149))	('death', 'Disease', 'MESH:D003643', (103, 108))	('MEK', 'Gene', (160, 163))	('pancreatic cancer', 'Disease', 'MESH:D010190', (112, 129))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (60, 77))	('pancreatic cancers', 'Disease', 'MESH:D010190', (60, 78))	('pancreatic cancer', 'Disease', (112, 129))	('ERK', 'Gene', (164, 167))	('human', 'Species', '9606', (43, 48))
367408	33363204	Similarly, a study on breast cancer found that overexpression of FAM83A also enhanced cell proliferation and invasiveness, while increasing resistance to tyrosine kinase inhibitors (TKIs).	('invasiveness', 'Disease', (109, 121))	('enhanced', 'PosReg', (77, 85))	('breast cancer', 'Disease', (22, 35))	('increasing', 'PosReg', (129, 139))	('breast cancer', 'Phenotype', 'HP:0003002', (22, 35))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('FAM83A', 'Var', (65, 71))	('cell proliferation', 'CPA', (86, 104))	('invasiveness', 'Disease', 'MESH:D009361', (109, 121))	('resistance to tyrosine kinase inhibitors', 'MPA', (140, 180))	('breast cancer', 'Disease', 'MESH:D001943', (22, 35))
367410	33363204	In the past few years, the expression of FAM83A was found to be noticeably over-expressed in lung cancer, moreover, FAM83A was related to an advanced TNM stage and poor prognosis, and regulated the Wnt and Hippo signaling pathways and EMT process to accelerate lung cancer cells' proliferation and invasion.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('EMT process', 'CPA', (235, 246))	('lung cancer', 'Disease', 'MESH:D008175', (93, 104))	('invasion', 'CPA', (298, 306))	('lung cancer', 'Phenotype', 'HP:0100526', (93, 104))	('lung cancer', 'Disease', (261, 272))	('regulated', 'Reg', (184, 193))	('lung cancer', 'Phenotype', 'HP:0100526', (261, 272))	('related', 'Reg', (127, 134))	('TNM stage', 'CPA', (150, 159))	('cancer', 'Phenotype', 'HP:0002664', (266, 272))	('lung cancer', 'Disease', (93, 104))	('FAM83A', 'Gene', (41, 47))	('over-expressed', 'PosReg', (75, 89))	('lung cancer', 'Disease', 'MESH:D008175', (261, 272))	('FAM83A', 'Var', (116, 122))	('accelerate', 'PosReg', (250, 260))
367412	33363204	What was more, higher mRNA expression of FAM83A led to a reduced OS, FP, and PPS of lung cancer patients, which were similar to the findings of studies.	('mRNA expression', 'MPA', (22, 37))	('PPS of lung cancer', 'Disease', 'MESH:D008175', (77, 95))	('lung cancer', 'Phenotype', 'HP:0100526', (84, 95))	('higher', 'PosReg', (15, 21))	('FAM83A', 'Var', (41, 47))	('patients', 'Species', '9606', (96, 104))	('PPS of lung cancer', 'Disease', (77, 95))	('reduced', 'NegReg', (57, 64))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
367423	33363204	Reduced OS and FP with high FAM83B expression, indicating that FAM83B may be a prognosis signature and potential oncogene of NSCLC.	('high', 'Var', (23, 27))	('NSCLC', 'Disease', (125, 130))	('FAM83B', 'Gene', (28, 34))	('Reduced', 'NegReg', (0, 7))	('FAM83B', 'Gene', '222584', (28, 34))	('FAM83B', 'Gene', '222584', (63, 69))	('NSCLC', 'Disease', 'MESH:D002289', (125, 130))	('FAM83B', 'Gene', (63, 69))
367458	33363204	Additionally, our results also revealed that overexpression of FAM83A/B/D/F/H was memorably related to clinical cancer stages in NSCLC patients.	('patients', 'Species', '9606', (135, 143))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('related', 'Reg', (92, 99))	('FAM83A/B/D/F/H', 'Var', (63, 77))	('NSCLC', 'Disease', (129, 134))	('NSCLC', 'Disease', 'MESH:D002289', (129, 134))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('overexpression', 'PosReg', (45, 59))
367459	33363204	Besides, higher mRNA expressions of FAM83A/B/C/D/F/H were found to be notably associated with OS in lung cancer patients, furthermore, FAM83A, FAM83C, and FAM83H in OS group achieved a 0.9475/1, 0.971897/1, and 0.9454545/0.8974359 specificity/sensitivity in distinguishing short survivors from long survivors, respectively.	('FAM83A/B/C/D/F/H', 'Var', (36, 52))	('associated', 'Reg', (78, 88))	('FAM83C', 'Gene', (143, 149))	('FAM83H', 'Gene', (155, 161))	('patients', 'Species', '9606', (112, 120))	('mRNA expressions', 'MPA', (16, 32))	('lung cancer', 'Phenotype', 'HP:0100526', (100, 111))	('FAM83H', 'Gene', '286077', (155, 161))	('lung cancer', 'Disease', (100, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('FAM83A', 'Var', (135, 141))	('FAM83C', 'Gene', '128876', (143, 149))	('lung cancer', 'Disease', 'MESH:D008175', (100, 111))	('higher', 'PosReg', (9, 15))
367460	33363204	Moreover, a high mutation rate of FAM83 family (51%) was also discovered in LUAD patients, and genetic alteration in FAM83 family was associated with a shorter OS and DFS in LUAD patients.	('FAM83', 'Gene', (117, 122))	('genetic alteration', 'Var', (95, 113))	('shorter OS', 'Disease', (152, 162))	('DFS', 'MPA', (167, 170))	('patients', 'Species', '9606', (81, 89))	('FAM83 family', 'Gene', (34, 46))	('patients', 'Species', '9606', (179, 187))
367464	30816543	miR-146a-5p targets TCSF and influences cell growth and apoptosis to repress NSCLC progression Several studies have indicated that microRNAs (miRs) mediate multiple pathways associated with tumorigenesis and progression.	('NSCLC', 'Disease', 'MESH:D002289', (77, 82))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('microRNAs', 'Var', (131, 140))	('TCSF', 'Gene', '682', (20, 24))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('repress', 'NegReg', (69, 76))	('NSCLC', 'Phenotype', 'HP:0030358', (77, 82))	('miR', 'Gene', '220972', (0, 3))	('miR', 'Gene', (0, 3))	('NSCLC', 'Disease', (77, 82))	('tumor', 'Disease', (190, 195))	('influences', 'Reg', (29, 39))	('miR', 'Gene', '220972', (142, 145))	('TCSF', 'Gene', (20, 24))	('miR', 'Gene', (142, 145))	('apoptosis', 'CPA', (56, 65))	('mediate', 'Reg', (148, 155))	('cell', 'CPA', (40, 44))
367479	30816543	EGFR mutations are easily identified in female patients who do not smoke, and the anaplastic lymphoma kinase receptor tyrosine kinase (ALK) fusion gene is also common in patients with lung cancer.	('patients', 'Species', '9606', (170, 178))	('ALK', 'Gene', (135, 138))	('EGFR', 'Gene', (0, 4))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (82, 101))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('lung cancer', 'Disease', 'MESH:D008175', (184, 195))	('patients', 'Species', '9606', (47, 55))	('mutations', 'Var', (5, 14))	('lymphoma', 'Disease', (93, 101))	('ALK', 'Gene', '238', (135, 138))	('common', 'Reg', (160, 166))	('lymphoma', 'Disease', 'MESH:D008223', (93, 101))	('lung cancer', 'Disease', (184, 195))	('lymphoma', 'Phenotype', 'HP:0002665', (93, 101))	('EGFR', 'Gene', '1956', (0, 4))	('lung cancer', 'Phenotype', 'HP:0100526', (184, 195))
367480	30816543	Fortunately, there are targeted medicines for these patients, including Gefitinib, Erlotinib and Icotinib for patients with the EGFR mutation, and Crizotinib for patients with the ALK fusion gene.	('Icotinib', 'Chemical', 'MESH:C531470', (97, 105))	('patients', 'Species', '9606', (162, 170))	('mutation', 'Var', (133, 141))	('Crizotinib', 'Chemical', 'MESH:D000077547', (147, 157))	('EGFR', 'Gene', '1956', (128, 132))	('Erlotinib', 'Chemical', 'MESH:D000069347', (83, 92))	('EGFR', 'Gene', (128, 132))	('ALK', 'Gene', '238', (180, 183))	('Gefitinib', 'Chemical', 'MESH:D000077156', (72, 81))	('ALK', 'Gene', (180, 183))	('patients', 'Species', '9606', (110, 118))	('patients', 'Species', '9606', (52, 60))
367481	30816543	According to a report including 741 patients with Chinese lung adenocarcinoma, patients with EGFR mutation account for ~50.2% of the population.	('EGFR', 'Gene', '1956', (93, 97))	('mutation', 'Var', (98, 106))	('patients', 'Species', '9606', (36, 44))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (58, 77))	('EGFR', 'Gene', (93, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (68, 77))	('patients', 'Species', '9606', (79, 87))	('lung adenocarcinoma', 'Disease', (58, 77))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (58, 77))
367506	30816543	As reported recently, TCSF silencing could suppress the progression of malignant melanoma.	('silencing', 'Var', (27, 36))	('malignant melanoma', 'Disease', (71, 89))	('TCSF', 'Gene', (22, 26))	('suppress', 'NegReg', (43, 51))	('malignant melanoma', 'Phenotype', 'HP:0002861', (71, 89))	('malignant melanoma', 'Disease', 'MESH:D008545', (71, 89))	('TCSF', 'Gene', '682', (22, 26))
367536	30816543	The pGL3 reporter vector was applied to construct the TCSF wild type (TCSF-wt) plasmid and TCSF mutant type (TCSF-mut) plasmid.	('TCSF', 'Gene', (70, 74))	('TCSF', 'Gene', '682', (91, 95))	('mutant', 'Var', (96, 102))	('TCSF', 'Gene', (109, 113))	('TCSF', 'Gene', (54, 58))	('pGL3', 'Gene', '6391', (4, 8))	('TCSF', 'Gene', (91, 95))	('TCSF', 'Gene', '682', (70, 74))	('TCSF', 'Gene', '682', (54, 58))	('TCSF', 'Gene', '682', (109, 113))	('pGL3', 'Gene', (4, 8))
367546	30816543	The primer sequences were as follows: TCSF, sense 5'-CCATGCTGGTCTGCAAGTCAG-3' and antisense 5'-CCGTTCATGAGGGCCTTGTC-3'; and GAPDH, sense 5'-CTATAAATTGAGCCCGCAGC-3' and antisense 5'-GACCAAATCCGTTGACTCCG-3'.	("antisense 5'-GACCAAATCCGTTGACTCCG-3", 'Var', (168, 203))	('TCSF', 'Gene', '682', (38, 42))	('GAPDH', 'Gene', '2597', (124, 129))	('GAPDH', 'Gene', (124, 129))	('TCSF', 'Gene', (38, 42))
367593	30816543	For the combined TCSF siRNA and miR-146a-5p inhibitor transfection group, the cell proliferation was not significantly different when compared with the scrambled siRNA control group (Fig.	('TCSF', 'Gene', '682', (17, 21))	('miR-146a', 'Gene', '406938', (32, 40))	('TCSF', 'Gene', (17, 21))	('miR-146a', 'Gene', (32, 40))	('transfection', 'Var', (54, 66))
367595	30816543	As for the Hoechst 33342 and PI apoptosis assay, a significant increase was observed in the TCSF siRNA only, TCSF siRNA and miR-146a-5p mimic, and the TCSF siRNA and the miR-146a-5p inhibitor transfection groups on day 5 (P<0.05), but not on day 10, when compared with the scrambled siRNA control group (Fig.	('TCSF', 'Gene', '682', (92, 96))	('increase', 'PosReg', (63, 71))	('miR-146a', 'Gene', '406938', (124, 132))	('TCSF', 'Gene', (92, 96))	('TCSF', 'Gene', (109, 113))	('transfection', 'Var', (192, 204))	('miR-146a', 'Gene', '406938', (170, 178))	('TCSF', 'Gene', '682', (151, 155))	('Hoechst 33342', 'Chemical', 'MESH:C017807', (11, 24))	('miR-146a', 'Gene', (124, 132))	('miR-146a', 'Gene', (170, 178))	('TCSF', 'Gene', (151, 155))	('TCSF', 'Gene', '682', (109, 113))
367624	30816543	As is reported by Zhang et al, in hepatocellular carcinoma (HCC) miR-146a inhibited the invasion and metastasis of HCC cells by targeting HAb18G to downregulate NF-kappaB p65 and repress VEGF expression via the upregulation of adenomatosis polyposis coli tumor suppressor through multiple pathways.	('adenomatosis polyposis coli tumor', 'Disease', (227, 260))	('VEGF', 'Gene', (187, 191))	('tumor', 'Phenotype', 'HP:0002664', (255, 260))	('hepatocellular carcinoma', 'Disease', (34, 58))	('p65', 'Gene', (171, 174))	('downregulate', 'NegReg', (148, 160))	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('inhibited', 'NegReg', (74, 83))	('p65', 'Gene', '6857', (171, 174))	('repress', 'NegReg', (179, 186))	('expression', 'MPA', (192, 202))	('targeting', 'Var', (128, 137))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (34, 58))	('adenomatosis polyposis coli tumor', 'Disease', 'MESH:D011125', (227, 260))	('upregulation', 'PosReg', (211, 223))	('HCC', 'Phenotype', 'HP:0001402', (60, 63))	('HAb18G', 'Gene', (138, 144))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (34, 58))	('HCC', 'Phenotype', 'HP:0001402', (115, 118))	('miR-146a', 'Gene', (65, 73))	('VEGF', 'Gene', '7422', (187, 191))	('miR-146a', 'Gene', '406938', (65, 73))
367694	27511987	Of the two studies assessing SHS in childhood, one suggested that SHS increased the risk of lung cancer, while the other study showed the opposite result.	('lung cancer', 'Disease', (92, 103))	('lung cancer', 'Phenotype', 'HP:0100526', (92, 103))	('SHS', 'Var', (66, 69))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('lung cancer', 'Disease', 'MESH:D008175', (92, 103))
367713	25114896	Unique Pattern of Component Gene Disruption in the NRF2 Inhibitor KEAP1/CUL3/RBX1 E3-Ubiquitin Ligase Complex in Serous Ovarian Cancer The NFE2-related factor 2 (NRF2) pathway is critical to initiate responses to oxidative stress; however, constitutive activation occurs in different cancer types, including serous ovarian carcinomas (OVCA).	('E3-Ubiquitin Ligase', 'Gene', (82, 101))	('ovarian carcinomas', 'Phenotype', 'HP:0025318', (315, 333))	('cancer', 'Disease', 'MESH:D009369', (284, 290))	('KEAP1', 'Gene', '9817', (66, 71))	('KEAP1', 'Gene', (66, 71))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (315, 332))	('CUL3', 'Gene', '8452', (72, 76))	('serous ovarian carcinomas', 'Phenotype', 'HP:0012887', (308, 333))	('Serous Ovarian Cancer', 'Disease', (113, 134))	('NRF2', 'Gene', (51, 55))	('RBX1', 'Gene', (77, 81))	('NRF2', 'Gene', (162, 166))	('NFE2-related factor 2', 'Gene', (139, 160))	('oxidative stress', 'Phenotype', 'HP:0025464', (213, 229))	('Cancer', 'Phenotype', 'HP:0002664', (128, 134))	('OVCA', 'Phenotype', 'HP:0025318', (335, 339))	('carcinoma', 'Phenotype', 'HP:0030731', (323, 332))	('cancer', 'Disease', (284, 290))	('Serous Ovarian Cancer', 'Disease', 'MESH:D010051', (113, 134))	('serous ovarian carcinomas', 'Disease', (308, 333))	('cancer', 'Phenotype', 'HP:0002664', (284, 290))	('CUL3', 'Gene', (72, 76))	('E3-Ubiquitin Ligase', 'Gene', '79594', (82, 101))	('serous ovarian carcinomas', 'Disease', 'MESH:D010051', (308, 333))	('Disruption', 'Var', (33, 43))	('carcinomas', 'Phenotype', 'HP:0030731', (323, 333))	('Ovarian Cancer', 'Phenotype', 'HP:0100615', (120, 134))	('NFE2-related factor 2', 'Gene', '4780', (139, 160))	('RBX1', 'Gene', '9978', (77, 81))	('NRF2', 'Gene', '4780', (51, 55))	('NRF2', 'Gene', '4780', (162, 166))
367718	25114896	These alterations were associated with reduced mRNA expression of complex components, and NRF2 target gene expression was positively enriched in 90% of samples harboring altered complex components.	('alterations', 'Var', (6, 17))	('NRF2', 'Gene', '4780', (90, 94))	('NRF2', 'Gene', (90, 94))	('mRNA expression of complex components', 'MPA', (47, 84))	('reduced', 'NegReg', (39, 46))
367719	25114896	We conclude that a remarkably high frequency of DNA and mRNA alterations affects components of the KEAP1/CUL3/RBX1 complex, through a unique pattern of genetic mechanisms.	('RBX1', 'Gene', '9978', (110, 114))	('KEAP1', 'Gene', (99, 104))	('CUL3', 'Gene', (105, 109))	('mRNA', 'Gene', (56, 60))	('alterations', 'Var', (61, 72))	('RBX1', 'Gene', (110, 114))	('affects', 'Reg', (73, 80))	('KEAP1', 'Gene', '9817', (99, 104))	('CUL3', 'Gene', '8452', (105, 109))
367731	25114896	Gain-of-function mutations in NFE2L2 and inactivating KEAP1 mutations are the most frequent NRF2 activation mechanisms observed in breast, gallbladder, and lung tumors, among other cancer types.	('lung tumors', 'Disease', (156, 167))	('Gain-of-function', 'PosReg', (0, 16))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('NRF2', 'Gene', (92, 96))	('inactivating', 'Var', (41, 53))	('mutations', 'Var', (17, 26))	('NFE2L2', 'Gene', (30, 36))	('breast', 'Disease', (131, 137))	('gallbladder', 'Disease', (139, 150))	('activation', 'PosReg', (97, 107))	('lung tumors', 'Disease', 'MESH:D008175', (156, 167))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('KEAP1', 'Gene', '9817', (54, 59))	('cancer', 'Disease', (181, 187))	('KEAP1', 'Gene', (54, 59))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('tumors', 'Phenotype', 'HP:0002664', (161, 167))	('lung tumors', 'Phenotype', 'HP:0100526', (156, 167))	('NRF2', 'Gene', '4780', (92, 96))	('mutations', 'Var', (60, 69))	('NFE2L2', 'Gene', '4780', (30, 36))
367732	25114896	Notably, multiple inactivating genetic mechanisms affecting components of the KEAP1/CUL3/RBX1 inhibitory complex are also known to occur, and the disruption of even a single complex component has been shown to compromise its function and stimulate substrate accumulation in lung tumors.	('RBX1', 'Gene', '9978', (89, 93))	('KEAP1', 'Gene', (78, 83))	('CUL3', 'Gene', (84, 88))	('stimulate', 'PosReg', (238, 247))	('tumor', 'Phenotype', 'HP:0002664', (279, 284))	('lung tumors', 'Phenotype', 'HP:0100526', (274, 285))	('substrate accumulation', 'MPA', (248, 270))	('lung tumors', 'Disease', (274, 285))	('tumors', 'Phenotype', 'HP:0002664', (279, 285))	('RBX1', 'Gene', (89, 93))	('compromise', 'NegReg', (210, 220))	('function', 'MPA', (225, 233))	('KEAP1', 'Gene', '9817', (78, 83))	('lung tumors', 'Disease', 'MESH:D008175', (274, 285))	('disruption', 'Var', (146, 156))	('CUL3', 'Gene', '8452', (84, 88))
367734	25114896	A previous study identified heterozygous missense KEAP1 mutations in 5 of 27 (19%) ovarian carcinomas, although frequencies differ across subtypes (29% and 8% in clear cell and serous tumors, resp.).	('KEAP1', 'Gene', (50, 55))	('mutations', 'Var', (56, 65))	('serous tumors', 'Disease', 'MESH:D018284', (177, 190))	('ovarian carcinomas', 'Disease', (83, 101))	('ovarian carcinomas', 'Phenotype', 'HP:0025318', (83, 101))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('serous tumors', 'Disease', (177, 190))	('tumors', 'Phenotype', 'HP:0002664', (184, 190))	('KEAP1', 'Gene', '9817', (50, 55))	('ovarian carcinomas', 'Disease', 'MESH:D010051', (83, 101))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (83, 100))	('carcinomas', 'Phenotype', 'HP:0030731', (91, 101))
367736	25114896	We hypothesized that DNA-level disruptions affecting the master NRF2 inhibitory complex may account for this discrepancy.	('NRF2', 'Gene', (64, 68))	('NRF2', 'Gene', '4780', (64, 68))	('disruptions', 'Var', (31, 42))
367743	25114896	For enrichment analysis, we used 3 published gene sets (SINGH_NFE2L2_TARGETS, BIOCARTA_ARENRF2_PATHWAY, and V$NRF2_Q4) that contain genes either altered upon inactivation of NRF2 or genes that contain the NRF2 recognition motif (NTGCTGAGTCAKN) in the vicinity of its transcription start site [+-2 kb].	('NRF2', 'Gene', '4780', (205, 209))	('inactivation', 'Var', (158, 170))	('NRF2', 'Gene', (110, 114))	('altered', 'Reg', (145, 152))	('NRF2', 'Gene', '4780', (90, 94))	('NFE2L2', 'Gene', '4780', (62, 68))	('SINGH', 'Disease', 'MESH:C537341', (56, 61))	('NRF2', 'Gene', (90, 94))	('NRF2', 'Gene', (205, 209))	('NFE2L2', 'Gene', (62, 68))	('NRF2', 'Gene', '4780', (174, 178))	('SINGH', 'Disease', (56, 61))	('NRF2', 'Gene', '4780', (110, 114))	('NRF2', 'Gene', (174, 178))
367746	25114896	First we investigated the frequency of DNA-level alterations (i.e., sequence mutations, copy-number loss, and hypermethylation) affecting each component gene of the CUL3/KEAP1/RBX1 E3-ubiquitin ligase complex.	('hypermethylation', 'Var', (110, 126))	('E3-ubiquitin ligase', 'Gene', '79594', (181, 200))	('CUL3', 'Gene', '8452', (165, 169))	('RBX1', 'Gene', '9978', (176, 180))	('CUL3', 'Gene', (165, 169))	('KEAP1', 'Gene', '9817', (170, 175))	('E3-ubiquitin ligase', 'Gene', (181, 200))	('copy-number', 'Var', (88, 99))	('RBX1', 'Gene', (176, 180))	('KEAP1', 'Gene', (170, 175))	('loss', 'NegReg', (100, 104))
367748	25114896	Deletion of CUL3, KEAP1, and RBX1 was detected in 26.0%, 32.7%, and 81.5% of samples, respectively (Table 1).	('CUL3', 'Gene', '8452', (12, 16))	('RBX1', 'Gene', (29, 33))	('CUL3', 'Gene', (12, 16))	('RBX1', 'Gene', '9978', (29, 33))	('KEAP1', 'Gene', (18, 23))	('KEAP1', 'Gene', '9817', (18, 23))	('Deletion', 'Var', (0, 8))
367749	25114896	Remarkably, when CNL and hypermethylation were considered concurrently, 90.5% of the OVCA cases examined sustained one or more alterations affecting any of the three components of the CUL3/KEAP1/RBX1 E3-ubiquitin ligase complex (Figure 3).	('RBX1', 'Gene', '9978', (195, 199))	('KEAP1', 'Gene', '9817', (189, 194))	('OVCA', 'Phenotype', 'HP:0025318', (85, 89))	('RBX1', 'Gene', (195, 199))	('OVCA', 'Disease', (85, 89))	('KEAP1', 'Gene', (189, 194))	('E3-ubiquitin ligase', 'Gene', '79594', (200, 219))	('alterations', 'Var', (127, 138))	('CUL3', 'Gene', '8452', (184, 188))	('E3-ubiquitin ligase', 'Gene', (200, 219))	('CUL3', 'Gene', (184, 188))	('affecting', 'Reg', (139, 148))
367750	25114896	We next evaluated the impact of DNA-level alterations on mRNA expression of CUL3, KEAP1, and RBX1, by comparing mRNA levels in samples with and without inactivating DNA-level alterations affecting any of the complex component genes for samples with available expression data for these genes (n = 37) (Figure 5).	('KEAP1', 'Gene', (82, 87))	('RBX1', 'Gene', '9978', (93, 97))	('KEAP1', 'Gene', '9817', (82, 87))	('CUL3', 'Gene', '8452', (76, 80))	('RBX1', 'Gene', (93, 97))	('CUL3', 'Gene', (76, 80))	('alterations', 'Var', (175, 186))
367751	25114896	For the CUL3, KEAP1, and RBX1 genes, mRNA levels were lower among samples harboring inactivating DNA-level alterations compared to those lacking these alterations (P value <0.01, Mann Whitney test), the vast majority of which were copy-number loss (Table 1).	('CUL3', 'Gene', (8, 12))	('RBX1', 'Gene', '9978', (25, 29))	('KEAP1', 'Gene', '9817', (14, 19))	('alterations', 'Var', (107, 118))	('KEAP1', 'Gene', (14, 19))	('RBX1', 'Gene', (25, 29))	('mRNA levels', 'MPA', (37, 48))	('copy-number loss', 'Var', (231, 247))	('CUL3', 'Gene', '8452', (8, 12))	('lower', 'NegReg', (54, 59))
367752	25114896	We assessed activation of NRF2 target genes in each sample harboring DNA-level disruption affecting any component of the KEAP1/CUL3/RBX1 E3-ubiquitin ligase complex (N = 502) using single-sample gene set enrichment analysis (ssGSEA).	('E3-ubiquitin ligase', 'Gene', '79594', (137, 156))	('CUL3', 'Gene', '8452', (127, 131))	('RBX1', 'Gene', '9978', (132, 136))	('CUL3', 'Gene', (127, 131))	('KEAP1', 'Gene', '9817', (121, 126))	('E3-ubiquitin ligase', 'Gene', (137, 156))	('disruption', 'Var', (79, 89))	('NRF2', 'Gene', '4780', (26, 30))	('KEAP1', 'Gene', (121, 126))	('NRF2', 'Gene', (26, 30))	('affecting', 'Reg', (90, 99))	('RBX1', 'Gene', (132, 136))
367754	25114896	Results for three different datasets from the Molecular Signatures Database revealed that 90.2% of samples harboring DNA-level alterations in complex components exhibited a positive enrichment for NRF2 target genes (Figure 6(b)).	('NRF2', 'Gene', '4780', (197, 201))	('NRF2', 'Gene', (197, 201))	('alterations', 'Var', (127, 138))
367760	25114896	However, the frequency of alterations affecting RBX1 in OVCA was the highest of any complex component gene in any of the tumor types analyzed, with CNL of RBX1 observed in 81.5% of 568 cases (Figure 7(c)).	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('RBX1', 'Gene', '9978', (48, 52))	('RBX1', 'Gene', '9978', (155, 159))	('OVCA', 'Phenotype', 'HP:0025318', (56, 60))	('tumor', 'Disease', (121, 126))	('alterations', 'Var', (26, 37))	('highest', 'Reg', (69, 76))	('RBX1', 'Gene', (48, 52))	('RBX1', 'Gene', (155, 159))	('OVCA', 'Disease', (56, 60))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
367762	25114896	However, the low reported frequency of inactivating KEAP1 mutations does not account for the reportedly high frequency of NRF2 protein activation in ovarian cancer.	('mutations', 'Var', (58, 67))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('activation', 'PosReg', (135, 145))	('ovarian cancer', 'Disease', (149, 163))	('KEAP1', 'Gene', '9817', (52, 57))	('NRF2', 'Gene', '4780', (122, 126))	('KEAP1', 'Gene', (52, 57))	('ovarian cancer', 'Phenotype', 'HP:0100615', (149, 163))	('ovarian cancer', 'Disease', 'MESH:D010051', (149, 163))	('NRF2', 'Gene', (122, 126))	('protein', 'Protein', (127, 134))
367763	25114896	In this study, we provide evidence that inactivating genetic alterations affect multiple components of the CUL3/KEAP1/RBX1 E3-ubiquitin ligase NRF2 inhibitory complex in a remarkably high number of OVCA cases.	('KEAP1', 'Gene', (112, 117))	('RBX1', 'Gene', (118, 122))	('OVCA', 'Disease', (198, 202))	('E3-ubiquitin ligase', 'Gene', '79594', (123, 142))	('inactivating genetic alterations', 'Var', (40, 72))	('affect', 'Reg', (73, 79))	('E3-ubiquitin ligase', 'Gene', (123, 142))	('RBX1', 'Gene', '9978', (118, 122))	('OVCA', 'Phenotype', 'HP:0025318', (198, 202))	('CUL3', 'Gene', '8452', (107, 111))	('NRF2', 'Gene', '4780', (143, 147))	('CUL3', 'Gene', (107, 111))	('KEAP1', 'Gene', '9817', (112, 117))	('NRF2', 'Gene', (143, 147))
367766	25114896	DNA-level inactivating alterations affecting gene components of the CUL3/KEAP1/RBX1 E3-ubiquitin ligase NRF2 inhibitory complex resulting in reduction of mRNA expression levels has been previously shown in thyroid, head and neck, and non-small cell lung tumors.	('CUL3', 'Gene', (68, 72))	('E3-ubiquitin ligase', 'Gene', (84, 103))	('lung tumors', 'Phenotype', 'HP:0100526', (249, 260))	('non-small cell lung tumors', 'Disease', (234, 260))	('NRF2', 'Gene', '4780', (104, 108))	('thyroid', 'Disease', (206, 213))	('small cell lung tumors', 'Phenotype', 'HP:0030357', (238, 260))	('KEAP1', 'Gene', '9817', (73, 78))	('KEAP1', 'Gene', (73, 78))	('CUL3', 'Gene', '8452', (68, 72))	('RBX1', 'Gene', '9978', (79, 83))	('non-small cell lung tumors', 'Phenotype', 'HP:0030358', (234, 260))	('NRF2', 'Gene', (104, 108))	('E3-ubiquitin ligase', 'Gene', '79594', (84, 103))	('inactivating alterations', 'Var', (10, 34))	('tumors', 'Phenotype', 'HP:0002664', (254, 260))	('mRNA expression levels', 'MPA', (154, 176))	('non-small cell lung tumors', 'Disease', 'MESH:D002289', (234, 260))	('RBX1', 'Gene', (79, 83))	('tumor', 'Phenotype', 'HP:0002664', (254, 259))	('reduction', 'NegReg', (141, 150))
367767	25114896	Concordant with our findings, we also observed a positive enrichment of NRF2 target genes in ~90% of OVCA samples harboring alteration in any of the individual complex component genes.	('NRF2', 'Gene', '4780', (72, 76))	('OVCA', 'Phenotype', 'HP:0025318', (101, 105))	('NRF2', 'Gene', (72, 76))	('alteration', 'Var', (124, 134))	('OVCA', 'Disease', (101, 105))
367772	25114896	Analysis of the frequency of KEAP1/CUL3/RBX1 E3-ubiquitin ligase complex component gene disruption in a broad spectrum of cancer types revealed that component gene alteration is a common phenomenon in cancer, albeit at varying frequencies, suggesting this NRF2 inhibitory complex is important to many cancer types (Figure 7(a)).	('cancer', 'Disease', (201, 207))	('alteration', 'Var', (164, 174))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('disruption', 'NegReg', (88, 98))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('cancer', 'Disease', (301, 307))	('RBX1', 'Gene', '9978', (40, 44))	('NRF2', 'Gene', '4780', (256, 260))	('cancer', 'Phenotype', 'HP:0002664', (301, 307))	('CUL3', 'Gene', (35, 39))	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('E3-ubiquitin ligase', 'Gene', '79594', (45, 64))	('KEAP1', 'Gene', '9817', (29, 34))	('NRF2', 'Gene', (256, 260))	('KEAP1', 'Gene', (29, 34))	('RBX1', 'Gene', (40, 44))	('cancer', 'Disease', 'MESH:D009369', (301, 307))	('cancer', 'Disease', (122, 128))	('E3-ubiquitin ligase', 'Gene', (45, 64))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('CUL3', 'Gene', '8452', (35, 39))
367774	25114896	Given that NRF2 inhibitory complex alterations are known to drive NRF2 pathway activation, we speculate that the alterations we have identified may contribute to the high frequency of aberrant NRF2 activation reported in ovarian cancer.	('NRF2', 'Gene', '4780', (66, 70))	('alterations', 'Var', (35, 46))	('NRF2', 'Gene', (66, 70))	('activation', 'PosReg', (198, 208))	('NRF2', 'Gene', (11, 15))	('ovarian cancer', 'Disease', (221, 235))	('NRF2', 'Gene', '4780', (193, 197))	('NRF2', 'Gene', (193, 197))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('ovarian cancer', 'Phenotype', 'HP:0100615', (221, 235))	('ovarian cancer', 'Disease', 'MESH:D010051', (221, 235))	('NRF2', 'Gene', '4780', (11, 15))
367779	25114896	Taken together, these results demonstrate that the frequencies and patterns of alteration affecting KEAP1/CUL3/RBX1 E3-ubiquitin ligase complex components are tumor-type and tissue specific and that, in OVCA, copy-number loss affecting RBX1 is the most prominent mechanism likely contributing to the increased NRF2 activation observed in ovarian cancer.	('OVCA', 'Phenotype', 'HP:0025318', (203, 207))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('increased', 'PosReg', (300, 309))	('copy-number loss', 'Var', (209, 225))	('ovarian cancer', 'Disease', (338, 352))	('CUL3', 'Gene', (106, 110))	('RBX1', 'Gene', (236, 240))	('ovarian cancer', 'Phenotype', 'HP:0100615', (338, 352))	('RBX1', 'Gene', (111, 115))	('E3-ubiquitin ligase', 'Gene', '79594', (116, 135))	('NRF2', 'Gene', '4780', (310, 314))	('RBX1', 'Gene', '9978', (111, 115))	('tumor', 'Disease', (159, 164))	('cancer', 'Phenotype', 'HP:0002664', (346, 352))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('CUL3', 'Gene', '8452', (106, 110))	('KEAP1', 'Gene', '9817', (100, 105))	('E3-ubiquitin ligase', 'Gene', (116, 135))	('activation', 'PosReg', (315, 325))	('NRF2', 'Gene', (310, 314))	('KEAP1', 'Gene', (100, 105))	('OVCA', 'Disease', (203, 207))	('ovarian cancer', 'Disease', 'MESH:D010051', (338, 352))	('RBX1', 'Gene', '9978', (236, 240))
367780	25114896	Given the extensive role of CUL3/KEAP1/RBX1 complex component proteins in other cellular pathways and functions, biological consequences of disruption to these genes certainly extend beyond the NRF2 pathway.	('RBX1', 'Gene', (39, 43))	('disruption', 'Var', (140, 150))	('NRF2', 'Gene', '4780', (194, 198))	('KEAP1', 'Gene', '9817', (33, 38))	('CUL3', 'Gene', '8452', (28, 32))	('RBX1', 'Gene', '9978', (39, 43))	('NRF2', 'Gene', (194, 198))	('CUL3', 'Gene', (28, 32))	('KEAP1', 'Gene', (33, 38))
367781	25114896	For example, somatic disruption of KEAP1/CUL3 E3-ubiquitin ligase complex components also promote activation of NF-kappaB in lung cancer, by compromising degradation of the NF-kappaB activator, IKBKB; given the extensive functions of NF-kappaB, this may have broad implications to a multitude of biological systems of particular relevance to cancer.	('KEAP1', 'Gene', '9817', (35, 40))	('activation', 'PosReg', (98, 108))	('cancer', 'Disease', (342, 348))	('NF-kappaB', 'Gene', (112, 121))	('KEAP1', 'Gene', (35, 40))	('cancer', 'Phenotype', 'HP:0002664', (342, 348))	('NF-kappaB', 'Gene', '4790', (112, 121))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('disruption', 'Var', (21, 31))	('CUL3', 'Gene', (41, 45))	('degradation', 'MPA', (154, 165))	('IKBKB', 'Gene', (194, 199))	('E3-ubiquitin ligase', 'Gene', '79594', (46, 65))	('lung cancer', 'Disease', (125, 136))	('compromising', 'NegReg', (141, 153))	('IKBKB', 'Gene', '3551', (194, 199))	('cancer', 'Disease', 'MESH:D009369', (342, 348))	('NF-kappaB', 'Gene', (173, 182))	('NF-kappaB', 'Gene', (234, 243))	('NF-kappaB', 'Gene', '4790', (173, 182))	('E3-ubiquitin ligase', 'Gene', (46, 65))	('lung cancer', 'Disease', 'MESH:D008175', (125, 136))	('NF-kappaB', 'Gene', '4790', (234, 243))	('CUL3', 'Gene', '8452', (41, 45))	('cancer', 'Disease', (130, 136))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('lung cancer', 'Phenotype', 'HP:0100526', (125, 136))
367782	25114896	Moreover, KEAP1 interacts with other "ETGE" containing proteins that may be affected by KEAP1 disruption.	('KEAP1', 'Gene', '9817', (10, 15))	('interacts', 'Interaction', (16, 25))	('KEAP1', 'Gene', (10, 15))	('KEAP1', 'Gene', '9817', (88, 93))	('disruption', 'Var', (94, 104))	('affected', 'Reg', (76, 84))	('KEAP1', 'Gene', (88, 93))
367784	25114896	Thus, it is plausible that DNA-level inactivation of KEAP1 may result in activation of DPP3 and subsequently pose an alternative pathway for NRF2 target gene activation.	('activation', 'PosReg', (73, 83))	('NRF2', 'Gene', '4780', (141, 145))	('DPP3', 'Gene', (87, 91))	('DPP3', 'Gene', '10072', (87, 91))	('NRF2', 'Gene', (141, 145))	('KEAP1', 'Gene', '9817', (53, 58))	('activation', 'PosReg', (158, 168))	('KEAP1', 'Gene', (53, 58))	('inactivation', 'Var', (37, 49))
367787	25114896	Taken together, the potential implications of DNA-level alterations affecting components of the CUL3/KEAP1/RBX1 protein complex are broad and, cumulatively, may have profound implications in tumor biology.	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('alterations', 'Var', (56, 67))	('RBX1', 'Gene', '9978', (107, 111))	('KEAP1', 'Gene', '9817', (101, 106))	('CUL3', 'Gene', '8452', (96, 100))	('CUL3', 'Gene', (96, 100))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('tumor', 'Disease', (191, 196))	('KEAP1', 'Gene', (101, 106))	('implications', 'Reg', (175, 187))	('RBX1', 'Gene', (107, 111))
367791	25114896	To assess the possibility that alteration to these components may be contributing to NRF2 activation in ovarian tumors, we evaluated DNA-level alterations affecting the genes involved in this BTRC/SKP1/CUL1 complex.	('NRF2', 'Gene', (85, 89))	('ovarian tumor', 'Phenotype', 'HP:0100615', (104, 117))	('activation', 'PosReg', (90, 100))	('CUL1', 'Gene', '8454', (202, 206))	('ovarian tumors', 'Phenotype', 'HP:0100615', (104, 118))	('BTRC', 'Gene', '8945', (192, 196))	('ovarian tumors', 'Disease', 'MESH:D010051', (104, 118))	('SKP1', 'Gene', '6500', (197, 201))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('affecting', 'Reg', (155, 164))	('NRF2', 'Gene', '4780', (85, 89))	('BTRC', 'Gene', (192, 196))	('SKP1', 'Gene', (197, 201))	('CUL1', 'Gene', (202, 206))	('alterations', 'Var', (143, 154))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('ovarian tumors', 'Disease', (104, 118))
367793	25114896	A significant effect on gene expression was also observed when samples with any alterations affecting BTRC, GSK3A, or SKP1 were compared against those cases without alterations affecting these complex components (see supplementary Figure 1 in Supplementary Material available online at http://dx.doi.org/10.1155/2014/159459).	('SKP1', 'Gene', '6500', (118, 122))	('GSK3A', 'Gene', (108, 113))	('alterations', 'Var', (80, 91))	('BTRC', 'Gene', '8945', (102, 106))	('gene expression', 'MPA', (24, 39))	('BTRC', 'Gene', (102, 106))	('SKP1', 'Gene', (118, 122))	('GSK3A', 'Gene', '2931', (108, 113))
367796	25114896	In conclusion, we have identified an extremely high frequency of genetic disruption affecting the KEAP1/CUL3/RBX1 E3-ubiquitin ligase complex in serous ovarian tumors, occurring predominantly through copy-number loss of RBX1.	('KEAP1', 'Gene', (98, 103))	('RBX1', 'Gene', (109, 113))	('ovarian tumors', 'Phenotype', 'HP:0100615', (152, 166))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('RBX1', 'Gene', (220, 224))	('E3-ubiquitin ligase', 'Gene', (114, 133))	('copy-number loss', 'Var', (200, 216))	('genetic disruption', 'Disease', 'MESH:D030342', (65, 83))	('serous ovarian tumors', 'Phenotype', 'HP:0012887', (145, 166))	('CUL3', 'Gene', (104, 108))	('RBX1', 'Gene', '9978', (109, 113))	('serous ovarian tumor', 'Phenotype', 'HP:0012887', (145, 165))	('RBX1', 'Gene', '9978', (220, 224))	('ovarian tumor', 'Phenotype', 'HP:0100615', (152, 165))	('serous ovarian tumors', 'Disease', (145, 166))	('genetic disruption', 'Disease', (65, 83))	('CUL3', 'Gene', '8452', (104, 108))	('E3-ubiquitin ligase', 'Gene', '79594', (114, 133))	('KEAP1', 'Gene', '9817', (98, 103))	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('serous ovarian tumors', 'Disease', 'MESH:D010051', (145, 166))
367797	25114896	Disruption was associated with NRF2 pathway activation in the same individual tumors harboring complex alterations.	('tumors', 'Disease', (78, 84))	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('NRF2', 'Gene', (31, 35))	('activation', 'PosReg', (44, 54))	('Disruption', 'Var', (0, 10))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('NRF2', 'Gene', '4780', (31, 35))
367845	31931698	When applying medepir pipeline on real heterogeneous dataset, we selected 456 tumor samples of DNAm 450 K for LUAD and 370 tumor samples of DNAm 450 K for LUSC.	('tumor', 'Disease', (123, 128))	('DNAm 450 K', 'Var', (95, 105))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Disease', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
367916	31623639	In RTOG 94-05 and previous retrospective studies, RT was delivered by 2DRT or Co60 radiation which was now-outdated technique and may bring about risk of radiation toxicity in lung and heart.	('bring about', 'Reg', (134, 145))	('toxicity', 'Disease', 'MESH:D064420', (164, 172))	('toxicity', 'Disease', (164, 172))	('Co60', 'Chemical', 'MESH:C069837', (78, 82))	('Co60 radiation', 'Var', (78, 92))
367942	31443700	Retrospective correlation with sociodemographic and clinicopathological patient details identified two subgroups of opposing molecular signature (+q6 and -q6) that correlated to two recognised high-risk HNSCC populations in the UK.	('patient', 'Species', '9606', (72, 79))	('HNSCC', 'Phenotype', 'HP:0012288', (203, 208))	('+q6', 'Var', (146, 149))	('correlated', 'Reg', (164, 174))
367949	31443700	As with many cancers HNSCC occurs as a result of abnormal genetic alterations such as point mutations, amplifications, rearrangements and deletions of genes, paving the way for tumour progression.	('tumour', 'Disease', 'MESH:D009369', (177, 183))	('HNSCC', 'Disease', (21, 26))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('HNSCC', 'Phenotype', 'HP:0012288', (21, 26))	('tumour', 'Disease', (177, 183))	('amplifications', 'Var', (103, 117))	('cancers', 'Disease', (13, 20))	('genes', 'Gene', (151, 156))	('cancers', 'Disease', 'MESH:D009369', (13, 20))	('point mutations', 'Var', (86, 101))	('cancers', 'Phenotype', 'HP:0002664', (13, 20))	('deletions of', 'Var', (138, 150))	('tumour', 'Phenotype', 'HP:0002664', (177, 183))	('rearrangements', 'Var', (119, 133))
367950	31443700	Whereas, other epithelial origin cancers such as breast and lung already have reliable diagnostic markers (mutant HER2 and EGFR, respectively) which are routinely used by oncologists to personalise treatments and improve outcomes for individual patients.	('EGFR', 'Gene', (123, 127))	('mutant', 'Var', (107, 113))	('patients', 'Species', '9606', (245, 253))	('HER2', 'Gene', (114, 118))	('cancers', 'Phenotype', 'HP:0002664', (33, 40))	('cancers', 'Disease', (33, 40))	('HER2', 'Gene', '2064', (114, 118))	('breast', 'Disease', (49, 55))	('cancers', 'Disease', 'MESH:D009369', (33, 40))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('EGFR', 'Gene', '1956', (123, 127))	('lung', 'Disease', (60, 64))
367954	31443700	Genomic changes such as hypermethylation of RAS association domain family protein 1a (RASSF1A), a tumour suppressor gene, has been associated with a high risk of developing HNSCC.	('hypermethylation', 'Var', (24, 40))	('tumour', 'Phenotype', 'HP:0002664', (98, 104))	('RASSF1A', 'Gene', (86, 93))	('tumour', 'Disease', 'MESH:D009369', (98, 104))	('HNSCC', 'Disease', (173, 178))	('associated', 'Reg', (131, 141))	('tumour', 'Disease', (98, 104))	('RASSF1A', 'Gene', '11186', (86, 93))	('HNSCC', 'Phenotype', 'HP:0012288', (173, 178))
367985	31443700	We found that poor prognosis was associated with high expressions of PLAU1 and FN1 on ovarian, lung and gastric cancers.	('high expressions', 'Var', (49, 65))	('ovarian', 'Disease', (86, 93))	('cancers', 'Phenotype', 'HP:0002664', (112, 119))	('gastric cancer', 'Phenotype', 'HP:0012126', (104, 118))	('FN1', 'Gene', '2335', (79, 82))	('PLAU', 'Gene', (69, 73))	('gastric cancers', 'Phenotype', 'HP:0012126', (104, 119))	('FN1', 'Gene', (79, 82))	('PLAU', 'Gene', '5328', (69, 73))	('gastric cancers', 'Disease', (104, 119))	('gastric cancers', 'Disease', 'MESH:D013274', (104, 119))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('lung', 'Disease', (95, 99))
367986	31443700	Similarly, high expression of CDCA5 were associated with poor prognosis of breast, lung and liver cancers.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('liver cancers', 'Phenotype', 'HP:0002896', (92, 105))	('associated', 'Reg', (41, 51))	('lung and liver cancers', 'Disease', 'MESH:D006528', (83, 105))	('cancers', 'Phenotype', 'HP:0002664', (98, 105))	('CDCA5', 'Gene', '113130', (30, 35))	('high', 'Var', (11, 15))	('liver cancer', 'Phenotype', 'HP:0002896', (92, 104))	('breast', 'Disease', (75, 81))	('CDCA5', 'Gene', (30, 35))
368030	31443700	CDCA5 was found to be upregulated in 4 OSCC cell lines and its knockdown led to tumour cell growth inhibition in vitro and in vivo.	('tumour', 'Disease', (80, 86))	('upregulated', 'PosReg', (22, 33))	('CDCA5', 'Gene', (0, 5))	('CDCA5', 'Gene', '113130', (0, 5))	('tumour', 'Phenotype', 'HP:0002664', (80, 86))	('tumour', 'Disease', 'MESH:D009369', (80, 86))	('knockdown', 'Var', (63, 72))
368036	31443700	CRNN expression is reported to be downregulated in HNSCC through loss of heterozygosity and microsatellite instability.	('loss', 'NegReg', (65, 69))	('expression', 'MPA', (5, 15))	('HNSCC', 'Disease', (51, 56))	('downregulated', 'NegReg', (34, 47))	('HNSCC', 'Phenotype', 'HP:0012288', (51, 56))	('CRNN', 'Gene', '49860', (0, 4))	('microsatellite instability', 'Var', (92, 118))	('CRNN', 'Gene', (0, 4))
368044	31443700	It has been found that in 50% of lung cancers NADPH oxidase DUOX1 and DUOX2 go under epigenetic silencing via hypermethylation of CpG-rich promoter regions.	('lung cancer', 'Phenotype', 'HP:0100526', (33, 44))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('lung cancers', 'Disease', 'MESH:D008175', (33, 45))	('lung cancers', 'Phenotype', 'HP:0100526', (33, 45))	('hypermethylation', 'Var', (110, 126))	('epigenetic', 'MPA', (85, 95))	('DUOX1', 'Gene', '53905', (60, 65))	('cancers', 'Phenotype', 'HP:0002664', (38, 45))	('DUOX2', 'Gene', '50506', (70, 75))	('DUOX1', 'Gene', (60, 65))	('lung cancers', 'Disease', (33, 45))	('DUOX2', 'Gene', (70, 75))
368065	30987362	Integrating all the results, we highlighted 4 miRNAs (mmu-miR-215-5p, mmu-miR-204-5p, mmu-miR-708-3p and mmu-miR-1298-5p) as the key for AZD6244 treatment, mmu-miR-23a-3p as key for XL-147 treatment, and mmu-miR-125a-5p and mmu-miR-16-5p as key for Budesonide treatment.	('Budesonide', 'Chemical', 'MESH:D019819', (249, 259))	('miR-125a-5p', 'Chemical', '-', (208, 219))	('-204-5p', 'Chemical', '-', (77, 84))	('miR-16-5p', 'Chemical', '-', (228, 237))	('mmu-miR-1298-5p', 'Var', (105, 120))	('5p', 'Chemical', '-', (118, 120))	('miR-23a', 'Gene', (160, 167))	('XL-147', 'Chemical', 'MESH:C581157', (182, 188))	('miR-23a', 'Gene', '387216', (160, 167))	('5p', 'Chemical', '-', (235, 237))	('mmu-miR-204-5p', 'Var', (70, 84))	('5p', 'Chemical', '-', (82, 84))	('5p', 'Chemical', '-', (217, 219))	('AZD6244', 'Chemical', 'MESH:C517975', (137, 144))	('mmu-miR-708-3p', 'Gene', '102465657', (86, 100))	('5p', 'Chemical', '-', (66, 68))	('mmu-miR-708-3p', 'Gene', (86, 100))
368083	30987362	We treated the mice with three known CPAs (a MEK inhibitor AZD6244, a PI3K inhibitor XL-147 and a glucocorticoid Budesonide).	('AZD6244', 'Chemical', 'MESH:C517975', (59, 66))	('Budesonide', 'Chemical', 'MESH:D019819', (113, 123))	('XL-147', 'Chemical', 'MESH:C581157', (85, 91))	('MEK', 'Gene', (45, 48))	('AZD6244', 'Var', (59, 66))	('CPA', 'Chemical', '-', (37, 40))	('mice', 'Species', '10090', (15, 19))	('MEK', 'Gene', '17242', (45, 48))
368086	30987362	The five most abundant miRNAs included mmu-miR-128-3p, mmu-miR-148a-3p, mmu-miR-99a-5p, mmu-let-7i-5p and mmu-let-7b-5p (log2 transformed read counts were 18.0, 17.2, 16.1, 15.3 and 15.1, respectively, and Table S1).	('5p', 'Chemical', '-', (117, 119))	('5p', 'Chemical', '-', (84, 86))	('mmu-let-7i-5p', 'Var', (88, 101))	('mmu-miR-148a-3p', 'Var', (55, 70))	('5p', 'Chemical', '-', (99, 101))	('mmu-miR-128-3p', 'Var', (39, 53))	('mmu-miR-99a-5p', 'Var', (72, 86))	('mmu-let-7b-5p', 'Var', (106, 119))
368087	30987362	Based on the high stringent p-values after adjustment by a false-discovery-rate (FDR) based multiple-test correction (FDR < 0.05), eight exosomal miRNAs were differentially expressed after AZD6244 treatment of which four exosomal miRNAs were down-regulated and four exosomal miRNAs were up-regulated (Table 2).	('AZD6244', 'Var', (189, 196))	('down-regulated', 'NegReg', (242, 256))	('up-regulated', 'PosReg', (287, 299))	('AZD6244', 'Chemical', 'MESH:C517975', (189, 196))
368099	30987362	Meanwhile, MEs of red module were up-regulated in all AZD6244 treated mice, suggesting that miRNAs in the red module might be involved in the biological function that was specific to AZD6244 treatment.	('MEs', 'Chemical', '-', (11, 14))	('MEs', 'MPA', (11, 14))	('AZD6244', 'Chemical', 'MESH:C517975', (183, 190))	('up-regulated', 'PosReg', (34, 46))	('involved', 'Reg', (126, 134))	('AZD6244', 'Var', (54, 61))	('AZD6244', 'Chemical', 'MESH:C517975', (54, 61))	('mice', 'Species', '10090', (70, 74))
368100	30987362	Similarly, the pink module was only up-regulated in the mice of XL-147 treatment.	('XL-147', 'Chemical', 'MESH:C581157', (64, 70))	('XL-147', 'Var', (64, 70))	('up-regulated', 'PosReg', (36, 48))	('pink module', 'Gene', (15, 26))	('mice', 'Species', '10090', (56, 60))
368106	30987362	As a result, we detected that 4 DE exosomal miRNAs (mmu-miR-215-5p, mmu-miR-204-5p, mmu-miR-708-3p and mmu-miR-1298-5p) distinguished the AZD6244 treatment group.	('-204-5p', 'Chemical', '-', (75, 82))	('mmu-miR-204-5p', 'Var', (68, 82))	('AZD6244', 'Chemical', 'MESH:C517975', (138, 145))	('mmu-miR-1298-5p', 'Var', (103, 118))	('mmu-miR-708-3p', 'Gene', '102465657', (84, 98))	('mmu-miR-708-3p', 'Gene', (84, 98))	('5p', 'Chemical', '-', (80, 82))	('5p', 'Chemical', '-', (116, 118))	('5p', 'Chemical', '-', (64, 66))
368108	30987362	Meanwhile, two DE exosomal miRNAs (mmu-miR-125a-5p and mmu-miR-16-5p) in turquoise module were considered as predictors for Budesonide treatment.	('mmu-miR-16-5p', 'Var', (55, 68))	('mmu-miR-125a-5p', 'Var', (35, 50))	('miR-16-5p', 'Chemical', '-', (59, 68))	('miR-125a-5p', 'Chemical', '-', (39, 50))	('Budesonide', 'Chemical', 'MESH:D019819', (124, 134))
368110	30987362	The predicted target genes of four key exosomal miRNAs for AZD6244 treatment were mostly enriched in Estrogen signaling pathway (mmu04915) (Table 3).	('AZD6244', 'Chemical', 'MESH:C517975', (59, 66))	('Estrogen signaling pathway', 'Pathway', (101, 127))	('AZD6244', 'Var', (59, 66))
368117	30987362	The sequences of five key mature miRNAs (mmu-miR-204-5p, mmu-miR-708-3p, mmu-miR-23a-3p, mmu-miR-125a-5p and mmu-miR-16-5p) were same between mouse and human beings.	('mmu-miR-708-3p', 'Gene', '102465657', (57, 71))	('miR-16-5p', 'Chemical', '-', (113, 122))	('mmu-miR-708-3p', 'Gene', (57, 71))	('mmu-miR-204-5p', 'Var', (41, 55))	('mouse', 'Species', '10090', (142, 147))	('miR-23a', 'Gene', (77, 84))	('miR-23a', 'Gene', '387216', (77, 84))	('human', 'Species', '9606', (152, 157))	('-204-5p', 'Chemical', '-', (48, 55))	('miR-125a-5p', 'Chemical', '-', (93, 104))
368118	30987362	For mmu-miR-215-5p and mmu-miR-1298-5p, only one nucleic acid was mismatched between the homologs in mouse and human beings.	('5p', 'Chemical', '-', (16, 18))	('5p', 'Chemical', '-', (36, 38))	('mmu-miR-1298-5p', 'Var', (23, 38))	('mouse', 'Species', '10090', (101, 106))	('human', 'Species', '9606', (111, 116))	('mmu-miR-215-5p', 'Var', (4, 18))
368120	30987362	In differential expression analysis, 16 miRNAs (raw p-value < 0.05) were shared between DE miRNA lists of AZD6244 and XL-147 treatment and most of these miRNAs (15 of 16 miRNAs) were up-regulated after agents' treatment.	('XL-147', 'Chemical', 'MESH:C581157', (118, 124))	('AZD6244', 'Chemical', 'MESH:C517975', (106, 113))	('AZD6244', 'Var', (106, 113))	('up-regulated', 'PosReg', (183, 195))
368121	30987362	Interestingly, a study has shown that MAPK/ERK (inhibited by AZD6244) and PI3K (inhibited by XL-147) signaling pathways had cross-talk with each other.	('MAPK/ERK', 'Pathway', (38, 46))	('PI3K', 'Pathway', (74, 78))	('AZD6244', 'Var', (61, 68))	('AZD6244', 'Chemical', 'MESH:C517975', (61, 68))	('XL-147', 'Chemical', 'MESH:C581157', (93, 99))	('cross-talk', 'Reg', (124, 134))
368128	30987362	In cluster analysis, yellow module was up-regulated in each mouse after treated with AZD6244 or XL-147 and contained eight of 16 shared DE miRNAs between AZD6244 and XL-147 treatment.	('yellow module', 'Gene', (21, 34))	('AZD6244', 'Var', (85, 92))	('XL-147', 'Chemical', 'MESH:C581157', (96, 102))	('AZD6244', 'Chemical', 'MESH:C517975', (154, 161))	('up-regulated', 'PosReg', (39, 51))	('AZD6244', 'Chemical', 'MESH:C517975', (85, 92))	('XL-147', 'Chemical', 'MESH:C581157', (166, 172))	('mouse', 'Species', '10090', (60, 65))
368130	30987362	We found that 4 DE exosomal miRNAs (mmu-miR-215-5p, mmu-miR-204-5p, mmu-miR-708-3p and mmu-miR-1298-5p) in red module were selected to be the predictors for AZD6244 treatment.	('mmu-miR-215-5p', 'Var', (36, 50))	('mmu-miR-204-5p', 'Var', (52, 66))	('5p', 'Chemical', '-', (64, 66))	('mmu-miR-708-3p', 'Gene', '102465657', (68, 82))	('mmu-miR-708-3p', 'Gene', (68, 82))	('-204-5p', 'Chemical', '-', (59, 66))	('5p', 'Chemical', '-', (48, 50))	('AZD6244', 'Chemical', 'MESH:C517975', (157, 164))	('5p', 'Chemical', '-', (100, 102))	('mmu-miR-1298-5p', 'Var', (87, 102))
368133	30987362	found that in cancers of respiratory system miR-204-5p level was significantly decreased in lung cancer tissues compared with normal tissues (both p < 0.05) via a comprehensive exploration based on RNA-seq high-throughput data and bioinformatics.	('lung cancer', 'Disease', (92, 103))	('cancers', 'Disease', (14, 21))	('lung cancer', 'Phenotype', 'HP:0100526', (92, 103))	('cancers', 'Phenotype', 'HP:0002664', (14, 21))	('decreased', 'NegReg', (79, 88))	('cancers of respiratory system', 'Phenotype', 'HP:0100606', (14, 43))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('-204-5p', 'Chemical', '-', (47, 54))	('miR-204-5p', 'Var', (44, 54))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('lung cancer', 'Disease', 'MESH:D008175', (92, 103))	('cancers', 'Disease', 'MESH:D009369', (14, 21))
368134	30987362	miR-204 might also inhibit STAT3 and favor the MAPK signaling pathway in cutaneous squamous cell carcinoma progression; miR-708-3p was found to inhibit breast cancer cell epithelial-to-mesenchymal transition (EMT) by directly binding to ZEB1 which was also the downstream gene of MAPK/ERK pathway; miR-1298 was also found to inhibit mutant KRAS-driven tumor growth.	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('miR-708-3p', 'Gene', (120, 130))	('inhibit', 'NegReg', (325, 332))	('inhibit', 'NegReg', (144, 151))	('KRAS', 'Gene', '16653', (340, 344))	('miR-1298', 'Var', (298, 306))	('ZEB1', 'Gene', (237, 241))	('cutaneous squamous cell carcinoma', 'Disease', (73, 106))	('binding', 'Interaction', (226, 233))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('cutaneous squamous cell carcinoma', 'Disease', 'MESH:D002294', (73, 106))	('tumor', 'Disease', (352, 357))	('STAT3', 'Gene', '20848', (27, 32))	('miR-708-3p', 'Gene', '102465657', (120, 130))	('mutant', 'Var', (333, 339))	('tumor', 'Disease', 'MESH:D009369', (352, 357))	('breast cancer', 'Phenotype', 'HP:0003002', (152, 165))	('STAT3', 'Gene', (27, 32))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (83, 106))	('ZEB1', 'Gene', '21417', (237, 241))	('tumor', 'Phenotype', 'HP:0002664', (352, 357))	('cutaneous squamous cell carcinoma', 'Phenotype', 'HP:0006739', (73, 106))	('breast cancer', 'Disease', 'MESH:D001943', (152, 165))	('breast cancer', 'Disease', (152, 165))	('KRAS', 'Gene', (340, 344))
368137	30987362	AZD6244 was a CPA and the four exosomal miRNAs which were tumor suppressors were up-regulated after treatment.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('CPA', 'Chemical', '-', (14, 17))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('up-regulated', 'PosReg', (81, 93))	('AZD6244', 'Var', (0, 7))	('AZD6244', 'Chemical', 'MESH:C517975', (0, 7))
368139	30987362	The previous studies showed that miR-125a-5p and miR-16-5p would induce apoptosis via activating p53.	('miR-16-5p', 'Var', (49, 58))	('miR-125a-5p', 'Var', (33, 44))	('p53', 'Gene', (97, 100))	('miR-125a-5p', 'Chemical', '-', (33, 44))	('activating', 'PosReg', (86, 96))	('induce', 'PosReg', (65, 71))	('p53', 'Gene', '22060', (97, 100))	('apoptosis', 'CPA', (72, 81))	('miR-16-5p', 'Chemical', '-', (49, 58))
368156	30987362	showed that AZD6244 could inhibit the MEK pathway in CT26 mouse syngeneic model and Hung Huynh et al.	('MEK', 'Gene', '17242', (38, 41))	('mouse', 'Species', '10090', (58, 63))	('AZD6244', 'Var', (12, 19))	('AZD6244', 'Chemical', 'MESH:C517975', (12, 19))	('MEK', 'Gene', (38, 41))	('inhibit', 'NegReg', (26, 33))	('CT26', 'CellLine', 'CVCL:7254', (53, 57))
368158	30987362	treated tumor lysates from KitV558Delta/+ mice with XL147 for 4 h and found decreased PI3K signaling with reduced pAKT, pS6, and p4EBP1.	('AKT', 'Gene', '11651', (115, 118))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('KitV558Delta/+', 'Var', (27, 41))	('mice', 'Species', '10090', (42, 46))	('decreased', 'NegReg', (76, 85))	('AKT', 'Gene', (115, 118))	('PI3K signaling', 'MPA', (86, 100))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('pS6', 'MPA', (120, 123))	('tumor', 'Disease', (8, 13))	('reduced', 'NegReg', (106, 113))
368165	30987362	By further feature selection, we highlighted mmu-miR-215-5p, mmu-miR-204-5p, mmu-miR-708-3p and mmu-miR-1298-5p as the key exosomal miRNAs for AZD6244 treatment, mmu-miR-23a-3p as key for XL-147 treatment and mmu-miR-125a-5p and mmu-miR-16-5p as key for Budesonide treatment.	('5p', 'Chemical', '-', (73, 75))	('5p', 'Chemical', '-', (240, 242))	('miR-23a', 'Gene', (166, 173))	('miR-23a', 'Gene', '387216', (166, 173))	('mmu-miR-708-3p', 'Gene', '102465657', (77, 91))	('5p', 'Chemical', '-', (57, 59))	('mmu-miR-708-3p', 'Gene', (77, 91))	('5p', 'Chemical', '-', (222, 224))	('-204-5p', 'Chemical', '-', (68, 75))	('5p', 'Chemical', '-', (109, 111))	('XL-147', 'Chemical', 'MESH:C581157', (188, 194))	('miR-16-5p', 'Chemical', '-', (233, 242))	('Budesonide', 'Chemical', 'MESH:D019819', (254, 264))	('miR-125a-5p', 'Chemical', '-', (213, 224))	('mmu-miR-1298-5p', 'Var', (96, 111))	('AZD6244', 'Chemical', 'MESH:C517975', (143, 150))
368204	30987362	Using comprehensive analysis methods, we highlighted four miRNAs (mmu-miR-215-5p, mmu-miR-204-5p, mmu-miR-708-3p and mmu-miR-1298-5p) as the key for AZD6244 treatment, mmu-miR-23a-3p as key for XL-147 treatment, and mmu-miR-125a-5p and mmu-miR-16-5p as key for Budesonide treatment.	('mmu-miR-204-5p', 'Var', (82, 96))	('-204-5p', 'Chemical', '-', (89, 96))	('miR-16-5p', 'Chemical', '-', (240, 249))	('mmu-miR-708-3p', 'Gene', '102465657', (98, 112))	('AZD6244', 'Chemical', 'MESH:C517975', (149, 156))	('mmu-miR-708-3p', 'Gene', (98, 112))	('5p', 'Chemical', '-', (229, 231))	('5p', 'Chemical', '-', (130, 132))	('5p', 'Chemical', '-', (78, 80))	('Budesonide', 'Chemical', 'MESH:D019819', (261, 271))	('miR-125a-5p', 'Chemical', '-', (220, 231))	('5p', 'Chemical', '-', (247, 249))	('mmu-miR-1298-5p', 'Var', (117, 132))	('miR-23a', 'Gene', '387216', (172, 179))	('miR-23a', 'Gene', (172, 179))	('XL-147', 'Chemical', 'MESH:C581157', (194, 200))	('5p', 'Chemical', '-', (94, 96))
368216	30347759	Of note, ZFPM1/FOG1 mutations occurred in 50% of adrenocortical carcinoma patients and were localized in a hotspot region.	('ZFPM1/FOG1', 'Gene', (9, 19))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (49, 73))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (49, 73))	('patients', 'Species', '9606', (74, 82))	('adrenocortical carcinoma', 'Disease', (49, 73))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))	('occurred', 'Reg', (30, 38))	('mutations', 'Var', (20, 29))
368226	30347759	The imbalance in favor of the PR-minus is found in many human malignancies and it can be due to inactivating mutations or silencing of the complete form and/or to increased expression of the PR-minus form.	('inactivating mutations', 'Var', (96, 118))	('increased', 'PosReg', (163, 172))	('human', 'Species', '9606', (56, 61))	('malignancies', 'Disease', 'MESH:D009369', (62, 74))	('expression', 'MPA', (173, 183))	('silencing', 'Var', (122, 131))	('malignancies', 'Disease', (62, 74))	('imbalance', 'Phenotype', 'HP:0002172', (4, 13))
368231	30347759	For instance, frameshift mutations of microsatellite repeats within the PRDM2 coding region are frequent events in various cancers.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('frameshift mutations', 'Var', (14, 34))	('cancers', 'Disease', 'MESH:D009369', (123, 130))	('cancers', 'Phenotype', 'HP:0002664', (123, 130))	('PRDM2', 'Gene', (72, 77))	('cancers', 'Disease', (123, 130))	('PRDM2', 'Gene', '7799', (72, 77))	('microsatellite repeats', 'Var', (38, 60))
368232	30347759	A recent study has described a frameshift mutation in the C-terminal region of PRDM2, affecting the (A)9 repeat within exon 8, as a microsatellite indel driver hotspot and as a driver mutation in microsatellite instability (MSI) colorectal cancer.	('colorectal cancer', 'Disease', (229, 246))	('frameshift mutation', 'Var', (31, 50))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('colorectal cancer', 'Disease', 'MESH:D015179', (229, 246))	('MSI', 'Disease', 'None', (224, 227))	('colorectal cancer', 'Phenotype', 'HP:0003003', (229, 246))	('PRDM2', 'Gene', (79, 84))	('PRDM2', 'Gene', '7799', (79, 84))	('MSI', 'Disease', (224, 227))	('affecting', 'Reg', (86, 95))	('microsatellite instability', 'Disease', (196, 222))
368233	30347759	Notably, a similar frameshift mutation was found to occur in a mononucleotide repeat (A7) of PRDM3/MECOM gene in this cancer type.	('cancer', 'Disease', (118, 124))	('PRDM3', 'Gene', (93, 98))	('occur', 'Reg', (52, 57))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('MECOM', 'Gene', (99, 104))	('PRDM3', 'Gene', '2122', (93, 98))	('frameshift', 'Var', (19, 29))	('mononucleotide', 'Chemical', '-', (63, 77))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('MECOM', 'Gene', '2122', (99, 104))
368239	30347759	This evidence suggests that PRDMs are involved in human cancer through modulation of several processes, such as epigenetic modifications, genetic reprogramming, inflammation, and metabolic homeostasis.	('epigenetic modifications', 'Var', (112, 136))	('modulation', 'Reg', (71, 81))	('involved', 'Reg', (38, 46))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('metabolic homeostasis', 'CPA', (179, 200))	('genetic reprogramming', 'CPA', (138, 159))	('human', 'Species', '9606', (50, 55))	('inflammation', 'Disease', 'MESH:D007249', (161, 173))	('inflammation', 'Disease', (161, 173))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))
368240	30347759	To date, both mutations and altered expression have been reported for some PRDMs in specific cancer entities.	('PRDMs', 'Disease', (75, 80))	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('reported', 'Reg', (57, 65))	('mutations', 'Var', (14, 23))	('expression', 'MPA', (36, 46))
368246	30347759	Silent or synonymous mutations were 1531 (26.7% of total mutations) and ranged between 11% (PRDM6) and 41% (PRDM8) of the total mutations for each gene (Figure 1).	('PRDM6', 'Gene', '93166', (92, 97))	('PRDM6', 'Gene', (92, 97))	('PRDM8', 'Gene', '56978', (108, 113))	('PRDM8', 'Gene', (108, 113))	('Silent or synonymous mutations', 'Var', (0, 30))
368248	30347759	Non-sense mutations were more recurrent in PRDM5 (23), PRDM9 (60), and ZFPM2/FOG2 (34), whereas splice sites disrupting mutations were more frequently detected in PRDM3/MECOM (13), PRDM9 (19), PRDM10 (14) and PRDM12 (13) (Figure 1).	('MECOM', 'Gene', (169, 174))	('PRDM9', 'Gene', (55, 60))	('PRDM9', 'Gene', '56979', (55, 60))	('PRDM5', 'Gene', '11107', (43, 48))	('PRDM10', 'Gene', '56980', (193, 199))	('MECOM', 'Gene', '2122', (169, 174))	('ZFPM2', 'Gene', '23414', (71, 76))	('ZFPM2', 'Gene', (71, 76))	('PRDM12', 'Gene', '59335', (209, 215))	('FOG2', 'Gene', '23414', (77, 81))	('FOG2', 'Gene', (77, 81))	('PRDM5', 'Gene', (43, 48))	('PRDM3', 'Gene', (163, 168))	('PRDM3', 'Gene', '2122', (163, 168))	('PRDM12', 'Gene', (209, 215))	('Non-sense mutations', 'Var', (0, 19))	('PRDM10', 'Gene', (193, 199))	('PRDM9', 'Gene', (181, 186))	('PRDM9', 'Gene', '56979', (181, 186))
368252	30347759	In detail, PRDM8 and PRDM15 were mutated at low rates in most of the analyzed cancer types except PAAD where they were both frequently mutated (16.0% and 11.2%, respectively).	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('mutated', 'Var', (33, 40))	('PRDM8', 'Gene', (11, 16))	('PRDM8', 'Gene', '56978', (11, 16))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('PRDM15', 'Gene', '63977', (21, 27))	('PRDM15', 'Gene', (21, 27))
368258	30347759	Through this approach, we evaluated the percentage of samples with at least one mutated PRDM gene in each tumor type ranging from 1.02% (2/196) in LAML samples to 55.43% (51/92) in ACC samples.	('PRDM', 'Gene', (88, 92))	('mutated', 'Var', (80, 87))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Disease', (106, 111))
368260	30347759	Specifically, we found 11/18 (61%) multi-hit mutations in COAD, 10/11 (90%) in READ, and 23/47 (48%) in ACC (see Supplementary file S1).	('COAD', 'Disease', 'MESH:D029424', (58, 62))	('mutations', 'Var', (45, 54))	('COAD', 'Disease', (58, 62))
368261	30347759	Missense mutations with a SIFT score ranging in the interval 0.0-0.05 and/or with a PolyPhen score in the interval 0.5-1 were considered as deleterious or probably damaging, respectively.	('SIFT', 'Disease', (26, 30))	('SIFT', 'Disease', 'None', (26, 30))	('Missense mutations', 'Var', (0, 18))
368264	30347759	Interestingly, a random sampling weighted on the size of the annotated protein domains demonstrated that somatic deleterious mutations were significantly enriched in the PR domain of PRDM1, PRDM5, PRDM6, PRDM8, PRDM9, PRDM12 and PRDM13 (p < 0.005).	('PRDM13', 'Gene', '59336', (229, 235))	('PRDM12', 'Gene', '59335', (218, 224))	('PRDM8', 'Gene', (204, 209))	('PRDM13', 'Gene', (229, 235))	('PRDM1', 'Gene', '639', (229, 234))	('PRDM1', 'Gene', '639', (183, 188))	('PRDM9', 'Gene', (211, 216))	('PRDM6', 'Gene', '93166', (197, 202))	('PRDM9', 'Gene', '56979', (211, 216))	('PRDM1', 'Gene', (229, 234))	('PRDM1', 'Gene', (183, 188))	('mutations', 'Var', (125, 134))	('PRDM5', 'Gene', '11107', (190, 195))	('PRDM6', 'Gene', (197, 202))	('PRDM12', 'Gene', (218, 224))	('PRDM5', 'Gene', (190, 195))	('PRDM1', 'Gene', '639', (218, 223))	('PRDM8', 'Gene', '56978', (204, 209))	('PRDM1', 'Gene', (218, 223))
368265	30347759	Another important aspect of cancer genetic studies is the presence of possible recurrent and hotspot mutations.	('cancer', 'Disease', (28, 34))	('mutations', 'Var', (101, 110))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))
368266	30347759	Figure 3 illustrates mutations in PRDM genes recurring in more than three tumor types.	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('PRDM genes', 'Gene', (34, 44))	('tumor', 'Disease', (74, 79))	('mutations', 'Var', (21, 30))
368267	30347759	Interestingly, the frameshift mutation T/- K678X, despite affecting PRDM3/MECOM in a region not containing known domains, was recurrent in different tumor types; similarly, also the missense mutation G/A S237L occurred in a region without known domains but in many tumors.	('G/A S237L', 'Var', (200, 209))	('MECOM', 'Gene', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (265, 270))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('tumor', 'Disease', (265, 270))	('PRDM3', 'Gene', '2122', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('affecting', 'Reg', (58, 67))	('tumors', 'Disease', (265, 271))	('S237L', 'Mutation', 'rs748747672', (204, 209))	('MECOM', 'Gene', '2122', (74, 79))	('K678X', 'Mutation', 'p.K678X', (43, 48))	('tumor', 'Disease', (149, 154))	('tumors', 'Disease', 'MESH:D009369', (265, 271))	('tumors', 'Phenotype', 'HP:0002664', (265, 271))	('T/- K678X', 'Var', (39, 48))	('tumor', 'Disease', 'MESH:D009369', (265, 270))	('PRDM3', 'Gene', (68, 73))
368268	30347759	Otherwise, missense mutations affecting a Zn-finger domain and occurring in different tumors were observed for PRDM9, PRDM14, and PRDM16.	('PRDM16', 'Gene', '63976', (130, 136))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('Zn-finger domain', 'MPA', (42, 58))	('PRDM9', 'Gene', (111, 116))	('affecting', 'Reg', (30, 39))	('PRDM9', 'Gene', '56979', (111, 116))	('tumors', 'Disease', (86, 92))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('missense mutations', 'Var', (11, 29))	('PRDM16', 'Gene', (130, 136))	('PRDM14', 'Gene', (118, 124))	('PRDM14', 'Gene', '63978', (118, 124))
368269	30347759	Likewise, PRDM12 was frequently mutated in a splice donor site in a region coding for the PR domain whereas in different tumor types, ZFPM2/FOG2 was affected by the missense mutation C/T R734C in a region without known domains.	('donor', 'Species', '9606', (52, 57))	('ZFPM2', 'Gene', '23414', (134, 139))	('R734C', 'Mutation', 'rs781567366', (187, 192))	('ZFPM2', 'Gene', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumor', 'Disease', (121, 126))	('PRDM12', 'Gene', '59335', (10, 16))	('PRDM12', 'Gene', (10, 16))	('FOG2', 'Gene', '23414', (140, 144))	('FOG2', 'Gene', (140, 144))	('C/T R734C', 'Var', (183, 192))	('affected', 'Reg', (149, 157))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
368270	30347759	In addition, PRDM2 and PRDM15 revealed an in-frame deletion in various cancers and PRDM11 a frameshift mutation.	('cancers', 'Disease', 'MESH:D009369', (71, 78))	('cancers', 'Phenotype', 'HP:0002664', (71, 78))	('in-frame deletion', 'Var', (42, 59))	('cancers', 'Disease', (71, 78))	('PRDM11', 'Gene', '56981', (83, 89))	('PRDM2', 'Gene', (13, 18))	('PRDM2', 'Gene', '7799', (13, 18))	('frameshift mutation', 'Var', (92, 111))	('PRDM15', 'Gene', '63977', (23, 29))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('PRDM15', 'Gene', (23, 29))	('PRDM11', 'Gene', (83, 89))
368271	30347759	Interestingly, all these mutations were particularly recurrent in ACC patients.	('patients', 'Species', '9606', (70, 78))	('mutations', 'Var', (25, 34))	('ACC', 'Disease', (66, 69))
368272	30347759	Otherwise, the frameshift mutations E444X and P445X led to premature stop codons at the residues 669 and 796, respectively; both of the mutated proteins shared only the first 443 residues with the canonical protein whereas they changed in the 444-669 and 444-796 regions and missed respectively 337 and 210 residues at the C-terminal, which contains the last five zinc fingers of ZFPM1/FOG1.	('P445X', 'Var', (46, 51))	('E444X', 'Mutation', 'p.E444X', (36, 41))	('ZFPM1/FOG1', 'Gene', (380, 390))	('P445X', 'Mutation', 'p.P445X', (46, 51))	('E444X', 'Var', (36, 41))
368274	30347759	This method is based on the feature that cancer gene mutations frequently cluster in particular positions of the protein.	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('mutations', 'Var', (53, 62))	('cluster', 'Reg', (74, 81))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (41, 47))
368275	30347759	Based on the scores of this analysis, ZFPM1/FOG1 can be considered as a cancer driver for ACC (Figure 4f) and PRDM8 for PAAD (Figure S2).	('ACC', 'Disease', (90, 93))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('ZFPM1/FOG1', 'Var', (38, 48))	('PAAD', 'Disease', (120, 124))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('PRDM8', 'Gene', (110, 115))	('PRDM8', 'Gene', '56978', (110, 115))	('cancer', 'Disease', (72, 78))
368300	30347759	Remarkably, VEP analysis indicated that the percentage of total deleterious mutations across the tumor samples was high for most genes.	('tumor', 'Disease', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('mutations', 'Var', (76, 85))
368301	30347759	More interestingly, a random sampling weighted on the size of the annotated protein domains demonstrated that deleterious mutations were significantly enriched in the PR domain of PRDM1, PRDM5, PRDM6, PRDM8, PRDM9, PRDM12 and PRDM13.	('PRDM5', 'Gene', '11107', (187, 192))	('PRDM12', 'Gene', (215, 221))	('PRDM5', 'Gene', (187, 192))	('PRDM1', 'Gene', '639', (215, 220))	('PRDM1', 'Gene', (215, 220))	('PRDM8', 'Gene', '56978', (201, 206))	('PRDM13', 'Gene', '59336', (226, 232))	('PRDM1', 'Gene', '639', (180, 185))	('PRDM9', 'Gene', (208, 213))	('PRDM6', 'Gene', '93166', (194, 199))	('PRDM13', 'Gene', (226, 232))	('PRDM1', 'Gene', (180, 185))	('PRDM9', 'Gene', '56979', (208, 213))	('PRDM1', 'Gene', '639', (226, 231))	('PRDM8', 'Gene', (201, 206))	('PRDM12', 'Gene', '59335', (215, 221))	('PRDM1', 'Gene', (226, 231))	('PRDM6', 'Gene', (194, 199))	('mutations', 'Var', (122, 131))
368302	30347759	Frequent mutations disrupting the PR domain in tumor samples would be a mechanism for removing the tumor suppressor function of the PR-plus isoform in favor of the oncogenic PR-minus form.	('tumor', 'Disease', (99, 104))	('removing', 'NegReg', (86, 94))	('mutations', 'Var', (9, 18))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumor', 'Disease', (47, 52))
368303	30347759	A big challenge in cancer biology studies is distinguishing between mutations conferring a selective growth advantage to cancer cells (drivers) and those randomly accumulating and without significant effects on the oncogenic process (passengers).	('cancer', 'Disease', 'MESH:D009369', (19, 25))	('growth advantage', 'CPA', (101, 117))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('cancer', 'Disease', (19, 25))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('mutations', 'Var', (68, 77))	('cancer', 'Disease', (121, 127))
368304	30347759	Moreover, recent studies have highlighted the existence of "mini-driver" genes with weaker tumor-promoting effects, thus expanding the previous driver-passenger dichotomy to a continuous model.	('genes', 'Var', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor', 'Disease', (91, 96))	('tumor', 'Disease', 'MESH:D009369', (91, 96))
368307	30347759	Notably, these hotspot mutations recurred also in other malignancies, such as COAD, KIRP, READ, STAD, and UCS, supporting an important role of this gene in carcinogenesis.	('carcinogenesis', 'Disease', 'MESH:D063646', (156, 170))	('STAD', 'Disease', (96, 100))	('READ', 'Disease', (90, 94))	('carcinogenesis', 'Disease', (156, 170))	('KIRP', 'Disease', (84, 88))	('malignancies', 'Disease', 'MESH:D009369', (56, 68))	('UCS', 'Disease', (106, 109))	('COAD', 'Disease', 'MESH:D029424', (78, 82))	('mutations', 'Var', (23, 32))	('malignancies', 'Disease', (56, 68))	('COAD', 'Disease', (78, 82))
368315	30347759	Additionally, a recent study identified a driver PRDM2 mutation in MSI colorectal cancer.	('colorectal cancer', 'Phenotype', 'HP:0003003', (71, 88))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('MSI colorectal cancer', 'Disease', 'MESH:D015179', (67, 88))	('MSI colorectal cancer', 'Disease', (67, 88))	('PRDM2', 'Gene', '7799', (49, 54))	('mutation', 'Var', (55, 63))	('PRDM2', 'Gene', (49, 54))
368322	30347759	Moreover, it would be interesting to investigate whether these mutations contribute to cancer progression and metastasis, as well as whether they correlate with prognosis and/or with drug response and resistance.	('mutations', 'Var', (63, 72))	('contribute', 'Reg', (73, 83))	('cancer', 'Disease', (87, 93))	('metastasis', 'CPA', (110, 120))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('correlate', 'Reg', (146, 155))	('cancer', 'Disease', 'MESH:D009369', (87, 93))
368325	30347759	To assess whether one or more PRDM proteins could be considered as cancer driver genes based on the positional clustering of the variants in the selected human cancers, we used a re-implementation of the software OncodriveCLUST within the maftools package.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('human', 'Species', '9606', (154, 159))	('cancers', 'Disease', 'MESH:D009369', (160, 167))	('cancer', 'Disease', (67, 73))	('cancers', 'Phenotype', 'HP:0002664', (160, 167))	('cancers', 'Disease', (160, 167))	('cancer', 'Disease', (160, 166))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('variants', 'Var', (129, 137))
368326	30347759	Three-dimensional (3D) modeling of the human canonical and mutant ZFPM1/FOG1 proteins was carried out using I-TASSER.	('ZFPM1/FOG1', 'Gene', (66, 76))	('mutant', 'Var', (59, 65))	('human', 'Species', '9606', (39, 44))
368408	29854832	In addition, poly(I:C) induced higher levels of proinflammatory cytokine secretion (IFN-I, IL-6, and CXCL-10), MHC I expression of tumor cells, and monocyte activation in vitro, impairing tumor growth in vitro and in vivo even when TLR signalling was hampered on host cells.	('tumor', 'Disease', (188, 193))	('impairing tumor', 'Disease', 'MESH:D015417', (178, 193))	('poly(I:C', 'Var', (13, 21))	('IFN', 'Gene', (84, 87))	('tumor', 'Disease', (131, 136))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('higher', 'PosReg', (31, 37))	('levels', 'MPA', (38, 44))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('IL-6', 'Gene', '3569', (91, 95))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('impairing tumor', 'Disease', (178, 193))	('IL-6', 'Gene', (91, 95))	('CXCL-10', 'Gene', '3627', (101, 108))	('IFN', 'Gene', '3439', (84, 87))	('poly(I:C', 'Chemical', 'MESH:D011070', (13, 21))	('CXCL-10', 'Gene', (101, 108))	('MHC I', 'Gene', (111, 116))
368415	29854832	Other studies have also been or are currently being conducted with other TLRs: ISA201 (HESPECTA, a second generation vaccine based on ISA101), which uses a synthetic TLR2 agonist (Amplivant) with two HPV16 E6 peptides (NCT02821494); EMD 1201081 (IMO2055, TLR9 agonist) + cetuximab (NCT01040832), which did not demonstrate additional clinical efficacy than using cetuximab alone but it was well tolerated by patients; EMD 1201081 + fluorouracil + cisplatin + cetuximab (NCT01360827); and entolimod (CBLB502), a TLR5 agonist which is being tested in combination with cisplatin and radiation (NCT01728480) due to the previously shown effects on radiation: it induced an increase in its therapeutic effect and a reduction of its toxicity in vivo when administered 1 h after exposure to radiation.	('TLR5', 'Gene', (510, 514))	('increase', 'PosReg', (667, 675))	('fluorouracil', 'Chemical', 'MESH:D005472', (431, 443))	('cetuximab', 'Chemical', 'MESH:D000068818', (271, 280))	('therapeutic effect', 'MPA', (683, 701))	('cisplatin', 'Chemical', 'MESH:D002945', (565, 574))	('TLR9', 'Gene', (255, 259))	('TLR5', 'Gene', '7100', (510, 514))	('TLR9', 'Gene', '54106', (255, 259))	('cetuximab', 'Chemical', 'MESH:D000068818', (458, 467))	('HPV16', 'Species', '333760', (200, 205))	('reduction', 'NegReg', (708, 717))	('toxicity', 'Disease', 'MESH:D064420', (725, 733))	('cetuximab', 'Chemical', 'MESH:D000068818', (362, 371))	('NCT01728480', 'Var', (590, 601))	('TLR2', 'Gene', '7097', (166, 170))	('TLR2', 'Gene', (166, 170))	('patients', 'Species', '9606', (407, 415))	('toxicity', 'Disease', (725, 733))	('cisplatin', 'Chemical', 'MESH:D002945', (446, 455))
368419	29854832	It is known that Th1 cytokines are potent activators of cellular-mediated immunity response that may precede HPV clearance, while Th2 cytokines impair the immune response, leading to an inefficient virus elimination and to chronic infection.	('Th1', 'Gene', (17, 20))	('impair', 'NegReg', (144, 150))	('cellular-mediated', 'CPA', (56, 73))	('chronic infection', 'Disease', 'MESH:D006505', (223, 240))	('chronic infection', 'Phenotype', 'HP:0031035', (223, 240))	('Th2 cytokines', 'Var', (130, 143))	('chronic infection', 'Disease', (223, 240))	('virus elimination', 'CPA', (198, 215))	('Th1', 'Gene', '51497', (17, 20))	('immune response', 'CPA', (155, 170))	('HPV', 'Species', '10566', (109, 112))	('inefficient', 'NegReg', (186, 197))
368432	29854832	This promising strategy, which combines the gene sequences of E6 + E7 antigens (VGX-3100) and the IL-12 (INO-9012), has been tested for treatment of both cervical invasive (NCT02172911) and head and neck (NCT02163057) HPV-related cancers in clinical phase I/II trials with good results about safety and CD8+ T cell immunogenicity.	('NCT02163057', 'Var', (205, 216))	('IL-1', 'Gene', '3553', (98, 102))	('cervical invasive', 'Disease', (154, 171))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('HPV', 'Species', '10566', (218, 221))	('NCT02172911', 'Var', (173, 184))	('cancers', 'Disease', 'MESH:D009369', (230, 237))	('cancers', 'Phenotype', 'HP:0002664', (230, 237))	('CD8', 'Gene', (303, 306))	('cancers', 'Disease', (230, 237))	('CD8', 'Gene', '925', (303, 306))	('IL-1', 'Gene', (98, 102))
368455	29854832	Alteration of this interferon was reported in hrHPV cell infection status, and it was suggested that it may support immune surveillance against HPV infection and cervical carcinogenesis.	('HPV infection', 'Disease', 'MESH:D030361', (144, 157))	('HPV', 'Species', '10566', (144, 147))	('carcinogenesis', 'Disease', 'MESH:D063646', (171, 185))	('HPV', 'Species', '10566', (48, 51))	('HPV infection', 'Disease', (144, 157))	('carcinogenesis', 'Disease', (171, 185))	('Alteration', 'Var', (0, 10))	('infection', 'Disease', (148, 157))	('infection', 'Disease', 'MESH:D007239', (148, 157))	('infection', 'Disease', (57, 66))	('infection', 'Disease', 'MESH:D007239', (57, 66))	('support', 'PosReg', (108, 115))
368488	29854832	Interestingly, the expression of IL-1alpha has been associated with higher risk of distant metastasis in HNSCC, the major cause of death in this type of cancer.	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('cancer', 'Disease', (153, 159))	('expression', 'Var', (19, 29))	('associated', 'Reg', (52, 62))	('IL-1alpha', 'Gene', (33, 42))	('HNSCC', 'Phenotype', 'HP:0012288', (105, 110))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('HNSCC', 'Disease', (105, 110))	('IL-1alpha', 'Gene', '3552', (33, 42))	('distant metastasis', 'CPA', (83, 101))
368551	29854832	Checkpoint inhibitor monoclonal antibodies combined with other immune approaches have already been evaluated for cervical and HNSCC treatment: anti-PD-1 such as pembrolizumab (which is in ongoing studies for HNSCC treatment: NCT02255097 and NCT02252042) and nivolumab (NCT02105636 and NCT02488759); anti-PD-L1 such as durvalumab (NCT02207530); anti-CTLA4 such as ipilimumab and tremelimumab; anti-LAG-3 such as BMS-986016 (NCT01968109); and anti-TIM-3 (NCT02817633).	('LAG-3', 'Gene', '3902', (397, 402))	('NCT02207530', 'Var', (330, 341))	('BMS-986016', 'CellLine', 'CVCL:D133', (411, 421))	('CTLA4', 'Gene', (349, 354))	('NCT02817633', 'Var', (453, 464))	('HNSCC', 'Phenotype', 'HP:0012288', (208, 213))	('NCT02105636', 'Var', (269, 280))	('LAG-3', 'Gene', (397, 402))	('TIM-3', 'Gene', '84868', (446, 451))	('durvalumab', 'Chemical', 'MESH:C000613593', (318, 328))	('tremelimumab', 'Chemical', 'MESH:C520704', (378, 390))	('nivolumab', 'Chemical', 'MESH:D000077594', (258, 267))	('NCT02488759', 'Var', (285, 296))	('HNSCC', 'Phenotype', 'HP:0012288', (126, 131))	('TIM-3', 'Gene', (446, 451))	('PD-L1', 'Gene', (304, 309))	('PD-L1', 'Gene', '29126', (304, 309))	('PD-1', 'Gene', (148, 152))	('PD-1', 'Gene', '5133', (148, 152))	('CTLA4', 'Gene', '1493', (349, 354))	('NCT01968109', 'Var', (423, 434))
368553	29854832	On the other hand, the combination with TLR agonists is new for HPV-related cancers; there are only two studies, NCT02643303 and NCT02124850, which are currently recruiting patients for testing the poly(I:C) with tremelimumab and durvalumab and the combination of VTX-2337 plus cetuximab or VTX-2337 plus cetuximab plus nivolumab, respectively.	('cetuximab', 'Chemical', 'MESH:D000068818', (278, 287))	('cancers', 'Disease', 'MESH:D009369', (76, 83))	('VTX-2337', 'Chemical', 'MESH:C573973', (291, 299))	('cancers', 'Phenotype', 'HP:0002664', (76, 83))	('patients', 'Species', '9606', (173, 181))	('cancers', 'Disease', (76, 83))	('VTX-2337', 'Chemical', 'MESH:C573973', (264, 272))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('tremelimumab', 'Chemical', 'MESH:C520704', (213, 225))	('cetuximab', 'Chemical', 'MESH:D000068818', (305, 314))	('durvalumab', 'Chemical', 'MESH:C000613593', (230, 240))	('nivolumab', 'Chemical', 'MESH:D000077594', (320, 329))	('poly(I:C', 'Chemical', 'MESH:D011070', (198, 206))	('poly', 'Var', (198, 202))	('HPV', 'Species', '10566', (64, 67))
368554	29854832	Regarding the evaluation of the combination of checkpoint inhibitors with cytokines in HPV-related cancers, no current study is reported at least to the best of our knowledge; and only three studies were reported for other HPV-unrelated solid tumors (NCT02614456, NCT02174172, and NCT02947165).	('tumors', 'Phenotype', 'HP:0002664', (243, 249))	('cancers', 'Disease', 'MESH:D009369', (99, 106))	('HPV', 'Species', '10566', (223, 226))	('solid tumors', 'Disease', (237, 249))	('HPV', 'Species', '10566', (87, 90))	('cancers', 'Phenotype', 'HP:0002664', (99, 106))	('NCT02174172', 'Var', (264, 275))	('cancers', 'Disease', (99, 106))	('NCT02614456', 'Var', (251, 262))	('NCT02947165', 'Var', (281, 292))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('solid tumors', 'Disease', 'MESH:D009369', (237, 249))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))
368565	29285292	CA19-9 was associated with subcarinal and paracardial LNM (P=0.000, P=0.038).	('CA19-9', 'Var', (0, 6))	('CA19-9', 'Chemical', 'MESH:C086528', (0, 6))	('associated', 'Reg', (11, 21))
368578	29285292	CA199 and CA724 are elevated in a variety of cancers, especially gastrointestinal cancer.	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (65, 88))	('CA724', 'Var', (10, 15))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('especially gastrointestinal cancer', 'Disease', 'MESH:D004067', (54, 88))	('especially gastrointestinal cancer', 'Disease', (54, 88))	('CA199', 'Var', (0, 5))	('elevated', 'PosReg', (20, 28))	('cancers', 'Disease', 'MESH:D009369', (45, 52))	('cancers', 'Phenotype', 'HP:0002664', (45, 52))	('cancers', 'Disease', (45, 52))	('CA199', 'Chemical', 'MESH:C086528', (0, 5))
368579	29285292	(2) SCC-Ag, Cyrfra21-1, CEA and CA19-9, which showed a significant correlation with LNM, were selected to evaluate the relationship with lymph node metastatic number and stations.	('CEA', 'Gene', (24, 27))	('SCC', 'Gene', (4, 7))	('CEA', 'Gene', '1084', (24, 27))	('Cyrfra21-1', 'Var', (12, 22))	('SCC', 'Gene', '6317', (4, 7))	('CA19-9', 'Chemical', 'MESH:C086528', (32, 38))
368582	29285292	The median and interquartile range of SCC-Ag, Cyfra21-1, CEA, CA19-9 and CA72-4 were 0.7 ug/L (0.4-1.3 ug/L), 2.36 ug/L(1.69-3.26 ug/L), 2.19 ug/L(1.49- 3.11 ug/L), 8.66 U/ml (5.06-15.92 U/ml) and 1.30 U/ml (0.92-2.44 U/ml).	('Cyfra21-1', 'Var', (46, 55))	('SCC', 'Gene', (38, 41))	('CEA', 'Gene', (57, 60))	('SCC', 'Gene', '6317', (38, 41))	('CEA', 'Gene', '1084', (57, 60))	('CA19-9', 'Chemical', 'MESH:C086528', (62, 68))
368584	29285292	The positive rate of serum SCC-Ag, Cyfra21-1, CEA and CA19-9 were associated with LNM in the Chi-square test (Table 2; all P<0.05).	('SCC', 'Gene', (27, 30))	('CA19-9', 'Gene', (54, 60))	('CEA', 'Gene', (46, 49))	('associated', 'Reg', (66, 76))	('SCC', 'Gene', '6317', (27, 30))	('CEA', 'Gene', '1084', (46, 49))	('CA19-9', 'Chemical', 'MESH:C086528', (54, 60))	('LNM', 'Disease', (82, 85))	('Cyfra21-1', 'Var', (35, 44))
368585	29285292	Same statistically significant results were found when assessing the relation between the biomarkers level and LNM using the Mann-Whitney-U test (SCC-Ag, P=0.000; Cyfra21-1, P=0.049; CEA, P=0.032; CA19-9, P= 0.024; CA72-2, P=0.361).	('Cyfra21-1', 'Var', (163, 172))	('CEA', 'Gene', (183, 186))	('CEA', 'Gene', '1084', (183, 186))	('LNM', 'Disease', (111, 114))	('SCC', 'Gene', (146, 149))	('CA19-9', 'Chemical', 'MESH:C086528', (197, 203))	('SCC', 'Gene', '6317', (146, 149))
368586	29285292	On the multivariate analysis, SCC-Ag and CA19-9 were independent risk factors for LNM (Table 2; P<0.05).	('SCC', 'Gene', '6317', (30, 33))	('CA19-9', 'Chemical', 'MESH:C086528', (41, 47))	('CA19-9', 'Var', (41, 47))	('SCC', 'Gene', (30, 33))	('LNM', 'Disease', (82, 85))
368592	29285292	Patients with pN0-1stage were considered earlier and less extensive LNM, while patients with pN2-3 stage were considered more extensive LNM.	('pN2', 'Gene', (93, 96))	('Patients', 'Species', '9606', (0, 8))	('pN2', 'Gene', '351', (93, 96))	('patients', 'Species', '9606', (79, 87))	('pN0-1stage', 'Var', (14, 24))
368593	29285292	High positive rate of preoperative serum CEA and CA199 were associated with more extensive LNM (P=0.039, P=0.000, respectively).	('CA199', 'Var', (49, 54))	('CA199', 'Chemical', 'MESH:C086528', (49, 54))	('extensive LNM', 'Disease', (81, 94))	('CEA', 'Gene', (41, 44))	('CEA', 'Gene', '1084', (41, 44))	('serum', 'Protein', (35, 40))
368601	29285292	The positive rate of serum CA19-9 was associated with subcarinal and paracardial LNM (P=0.000, P=0.038) (Table 6).	('CA19-9', 'Chemical', 'MESH:C086528', (27, 33))	('associated', 'Reg', (38, 48))	('CA19-9', 'Protein', (27, 33))	('serum', 'Var', (21, 26))
368614	29285292	In our study, the positive rate of SCC-Ag and Cyfra21-1 were 18.1% and 24.3%.	('SCC', 'Gene', (35, 38))	('Cyfra21-1', 'Var', (46, 55))	('SCC', 'Gene', '6317', (35, 38))
368621	29285292	Although Cyfra21-1, CEA and CA19-9 were associated with LNM in ESCC, they do not serve as precise predictors for early stage LNM.	('Cyfra21-1', 'Var', (9, 18))	('CEA', 'Gene', '1084', (20, 23))	('LNM', 'Disease', (56, 59))	('SCC', 'Gene', '6317', (64, 67))	('CA19-9', 'Chemical', 'MESH:C086528', (28, 34))	('CA19-9', 'Var', (28, 34))	('associated with', 'Reg', (40, 55))	('CEA', 'Gene', (20, 23))	('SCC', 'Gene', (64, 67))
368632	29285292	In abdominal lymph node stations, CA19-9 was correlated with paracardial LNM.	('CA19-9', 'Chemical', 'MESH:C086528', (34, 40))	('CA19-9', 'Var', (34, 40))	('paracardial LNM', 'Disease', (61, 76))	('correlated', 'Reg', (45, 55))
368640	29285292	CA19-9 is also called sialylated Lewis Antigen which is speculated to play roles in the extravasation of cancer cells from blood and the promotion of metastatic spread to distant organs.	('CA19-9', 'Chemical', 'MESH:C086528', (0, 6))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('metastatic spread to distant organs', 'CPA', (150, 185))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('CA19-9', 'Var', (0, 6))	('promotion', 'PosReg', (137, 146))	('extravasation', 'MPA', (88, 101))
368644	29285292	first reported CA19-9 with a new cutoff value was associated with LNM and hematogenic metastasis.	('CA19-9', 'Var', (15, 21))	('hematogenic metastasis', 'Disease', (74, 96))	('hematogenic metastasis', 'Disease', 'MESH:D009362', (74, 96))	('CA19-9', 'Chemical', 'MESH:C086528', (15, 21))	('associated', 'Reg', (50, 60))	('LNM', 'Disease', (66, 69))
368645	29285292	Our study reveals that elevated CEA and CA19-9 are associated with advanced stage of LNM.	('advanced stage of LNM', 'Disease', (67, 88))	('CA19-9', 'Var', (40, 46))	('elevated', 'PosReg', (23, 31))	('CEA', 'Gene', (32, 35))	('associated', 'Reg', (51, 61))	('CEA', 'Gene', '1084', (32, 35))	('CA19-9', 'Chemical', 'MESH:C086528', (40, 46))	('elevated CEA', 'Phenotype', 'HP:0031029', (23, 35))
368647	29285292	In conclusion, this study demonstrates the correlation between LNM and the positive rate of preoperative serum SCC-Ag, Cyfra21-1, CEA and CA19-9.	('CA19-9', 'Chemical', 'MESH:C086528', (138, 144))	('Cyfra21-1', 'Var', (119, 128))	('SCC', 'Gene', (111, 114))	('CA19-9', 'Var', (138, 144))	('CEA', 'Gene', (130, 133))	('SCC', 'Gene', '6317', (111, 114))	('CEA', 'Gene', '1084', (130, 133))
368655	29285292	The normal upper limit was 1.5 ug/L, 3.3 ug/L, 5 ug/L, 39 U/ml and 6 U/ml for SCC-Ag, Cyfra21-1, CEA, CA19-9 and CA72-4 respectively.	('CEA', 'Gene', (97, 100))	('SCC', 'Gene', '6317', (78, 81))	('CEA', 'Gene', '1084', (97, 100))	('SCC', 'Gene', (78, 81))	('CA19-9', 'Chemical', 'MESH:C086528', (102, 108))	('Cyfra21-1', 'Var', (86, 95))
368672	27530686	Alterations in the FGFR kinase genes are very common in lung squamous cell cancer, while KRAS and EGFR mutations are most commonly activated oncogenes in lung adenocarcinoma.	('EGFR', 'Gene', (98, 102))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (61, 81))	('lung squamous cell cancer', 'Disease', 'MESH:D002294', (56, 81))	('Alterations', 'Var', (0, 11))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (154, 173))	('FGFR kinase', 'Gene', (19, 30))	('lung squamous cell cancer', 'Phenotype', 'HP:0030359', (56, 81))	('common', 'Reg', (46, 52))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (154, 173))	('EGFR', 'Gene', '1956', (98, 102))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('lung adenocarcinoma', 'Disease', (154, 173))	('KRAS', 'Gene', (89, 93))	('lung squamous cell cancer', 'Disease', (56, 81))	('KRAS', 'Gene', '3845', (89, 93))
368682	27530686	Copy number alteration is probably most frequent genetic events during the course of tumor development.	('tumor', 'Disease', (85, 90))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('Copy number alteration', 'Var', (0, 22))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))
368692	27530686	For example, it can provide list of genes whose copy number alteration, methylation, mRNA expression, and mutations are significantly correlated with tumor stages, survival of patients, sex, ages, or ethnic groups.	('patients', 'Species', '9606', (176, 184))	('copy number alteration', 'Var', (48, 70))	('mRNA expression', 'MPA', (85, 100))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('correlated', 'Reg', (134, 144))	('methylation', 'Var', (72, 83))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('mutations', 'Var', (106, 115))	('tumor', 'Disease', (150, 155))
368700	27530686	For example, genetic alterations of peroxiredoxin family in all cancer types can be assessed through cBioPortal (Fig.	('genetic alterations', 'Var', (13, 32))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
368717	31645905	Biomarkers have been developed to predict patients' responsivity to immunotherapy treatments, such as genome-wide mutational load, PD-L1 protein expression in infiltrating immune cells, the number of cytotoxic T cells in a tumor microenvironment, or MSI status.	('men', 'Species', '9606', (241, 244))	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('tumor', 'Disease', (223, 228))	('men', 'Species', '9606', (87, 90))	('PD-L1', 'Gene', '29126', (131, 136))	('MSI', 'Gene', '5928', (250, 253))	('MSI', 'Gene', (250, 253))	('mutational load', 'Var', (114, 129))	('tumor', 'Disease', 'MESH:D009369', (223, 228))	('patients', 'Species', '9606', (42, 50))	('protein', 'Protein', (137, 144))	('PD-L1', 'Gene', (131, 136))
368757	31645905	In head and neck squamous cell carcinoma (HNSC, P = 0.0044, adjusted) and skin cutaneous melanoma (SKCM, P = 0.0044, adjusted), patients with T3/4 had significantly lower immune response than those with T1/2, while kidney renal clear cell carcinoma (KIRC, P = 0.0044, adjusted) showed the opposite trend.	('kidney renal clear cell carcinoma', 'Disease', 'MESH:D002292', (215, 248))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (79, 97))	('skin cutaneous melanoma', 'Disease', (74, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (239, 248))	('melanoma', 'Phenotype', 'HP:0002861', (89, 97))	('KIRC', 'Disease', (250, 254))	('SKCM', 'Disease', 'MESH:C562393', (99, 103))	('kidney renal clear cell carcinoma', 'Disease', (215, 248))	('HNSC', 'Phenotype', 'HP:0012288', (42, 46))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (3, 40))	('carcinoma', 'Phenotype', 'HP:0030731', (31, 40))	('KIRC', 'Disease', 'MESH:D002292', (250, 254))	('immune response', 'MPA', (171, 186))	('neck squamous cell carcinoma', 'Disease', 'MESH:C535575', (12, 40))	('neck squamous cell carcinoma', 'Disease', (12, 40))	('T3/4', 'Var', (142, 146))	('patients', 'Species', '9606', (128, 136))	('lower', 'NegReg', (165, 170))	('lower immune response', 'Phenotype', 'HP:0002721', (165, 186))	('SKCM', 'Disease', (99, 103))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (74, 97))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (17, 40))
368775	31645905	It appears that the hypermutated (HM) colon adenocarcinoma (COAD) patients had the significantly highest immune response among the three different molecular subtypes (CIN, GS, HM) (P = 1.04 x 10-06, Figure 8C).	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('immune response', 'MPA', (105, 120))	('hypermutated', 'Var', (20, 32))	('COAD', 'Disease', 'MESH:D015179', (60, 64))	('HM) colon adenocarcinoma', 'Disease', 'MESH:D015179', (34, 58))	('COAD', 'Disease', (60, 64))	('CIN', 'Phenotype', 'HP:0040012', (167, 170))	('highest', 'PosReg', (97, 104))	('patients', 'Species', '9606', (66, 74))
368792	31645905	Our results further demonstrated that the hypermutated (HM) subtype in colon adenocarcinoma (COAD) had a significantly higher immune response than either the chromosomal instability (CIN) or genome stable (GS) subtypes, making such patients potential candidates for immunotherapeutic treatments.	('COAD', 'Disease', 'MESH:D015179', (93, 97))	('chromosomal instability', 'Phenotype', 'HP:0040012', (158, 181))	('CIN', 'Phenotype', 'HP:0040012', (183, 186))	('patients', 'Species', '9606', (232, 240))	('immune', 'MPA', (126, 132))	('men', 'Species', '9606', (289, 292))	('colon adenocarcinoma', 'Disease', (71, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('higher', 'PosReg', (119, 125))	('colon adenocarcinoma', 'Disease', 'MESH:D015179', (71, 91))	('COAD', 'Disease', (93, 97))	('hypermutated', 'Var', (42, 54))
368819	31645905	For the same reason, the molecular subtypes investigated in detail in this study included: Basal/Her2/LumA/LumB in breast invasive carcinoma (BRCA) patients, CIN/GS/HM-indel/HM-SNV or /EBV in gastrointestinal cancer patients, IDH mutation status in glioma patients, and POLE/MSI/CN_Low/CN_High in uterine corpus endometrial carcinoma (UCEC) patients.	('patients', 'Species', '9606', (341, 349))	('IDH', 'Gene', '3417', (226, 229))	('gastrointestinal cancer', 'Disease', 'MESH:D005770', (192, 215))	('breast invasive carcinoma', 'Phenotype', 'HP:0003002', (115, 140))	('gastrointestinal cancer', 'Disease', (192, 215))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (192, 215))	('CIN', 'Phenotype', 'HP:0040012', (158, 161))	('patients', 'Species', '9606', (148, 156))	('LumA', 'Gene', '79188', (102, 106))	('breast invasive carcinoma (BRCA', 'Gene', (115, 146))	('glioma', 'Disease', (249, 255))	('breast invasive carcinoma (BRCA)', 'Gene', '672', (115, 147))	('MSI', 'Gene', (275, 278))	('MSI', 'Gene', '5928', (275, 278))	('glioma', 'Disease', 'MESH:D005910', (249, 255))	('BRCA', 'Phenotype', 'HP:0003002', (142, 146))	('carcinoma', 'Phenotype', 'HP:0030731', (324, 333))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (312, 333))	('corpus endometrial carcinoma', 'Disease', (305, 333))	('patients', 'Species', '9606', (216, 224))	('corpus endometrial carcinoma', 'Disease', 'MESH:D016889', (305, 333))	('LumA', 'Gene', (102, 106))	('IDH', 'Gene', (226, 229))	('glioma', 'Phenotype', 'HP:0009733', (249, 255))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('Her2', 'Gene', '2064', (97, 101))	('patients', 'Species', '9606', (256, 264))	('CIN/GS/HM-indel/HM-SNV', 'Var', (158, 180))	('Her2', 'Gene', (97, 101))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
368822	31645905	The Normal subtype in breast invasive carcinoma (BRCA) and IDH mutant group in glioblastoma multiforme (GBM) typically had a small number of patients, and as such were excluded from downstream analyses.	('BRCA', 'Phenotype', 'HP:0003002', (49, 53))	('breast invasive carcinoma (BRCA)', 'Gene', '672', (22, 54))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (79, 102))	('IDH', 'Gene', (59, 62))	('breast invasive carcinoma', 'Phenotype', 'HP:0003002', (22, 47))	('mutant', 'Var', (63, 69))	('GBM', 'Disease', (104, 107))	('IDH', 'Gene', '3417', (59, 62))	('carcinoma', 'Phenotype', 'HP:0030731', (38, 47))	('GBM', 'Disease', 'MESH:D005909', (104, 107))	('breast invasive carcinoma (BRCA', 'Gene', (22, 53))	('glioblastoma multiforme', 'Disease', (79, 102))	('glioblastoma', 'Phenotype', 'HP:0012174', (79, 91))	('patients', 'Species', '9606', (141, 149))
368826	31645905	CIN Chromosomal instability GS genome stable HM hypermutated MSI microsatellite instability EBV Epstein-Barr virus SNV single-nucleotide variant HPV human papillomavirus	('single-nucleotide variant', 'Var', (119, 144))	('Epstein-Barr virus', 'Disease', 'MESH:D020031', (96, 114))	('HPV', 'Species', '10566', (145, 148))	('MSI', 'Gene', '5928', (61, 64))	('MSI', 'Gene', (61, 64))	('human papillomavirus', 'Species', '10566', (149, 169))	('Epstein-Barr virus', 'Disease', (96, 114))	('Chromosomal instability', 'Phenotype', 'HP:0040012', (4, 27))	('CIN', 'Phenotype', 'HP:0040012', (0, 3))
368832	31578148	Using specific antibodies against PGK1 S203 and PDHK1 T338 phosphorylation, we performed immunohistochemistry with tissue microarray assay in additional 818 cancer cases with 619 paired normal tissues from five cancer types.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('PDHK1', 'Gene', '5163', (48, 53))	('cancer', 'Disease', 'MESH:D009369', (211, 217))	('cancer', 'Disease', (211, 217))	('S203', 'Var', (39, 43))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('cancer', 'Disease', (157, 163))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('PGK1', 'Gene', (34, 38))	('PDHK1', 'Gene', (48, 53))	('PGK1', 'Gene', '5230', (34, 38))
368833	31578148	The PGK1 mRNA level was significantly elevated with hypomethylation in promotor regions and associated with advanced TNM stage in 15 and four cancer types, respectively.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('TNM', 'Gene', '10178', (117, 120))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('mRNA level', 'MPA', (9, 19))	('N', 'Chemical', 'MESH:D009584', (11, 12))	('N', 'Chemical', 'MESH:D009584', (118, 119))	('hypomethylation', 'Var', (52, 67))	('elevated', 'PosReg', (38, 46))	('PGK1', 'Gene', '5230', (4, 8))	('associated', 'Reg', (92, 102))	('PGK1', 'Gene', (4, 8))	('TNM', 'Gene', (117, 120))	('cancer', 'Disease', (142, 148))
368835	31578148	Positively correlated PGK1 S203 and PDHK1 T338 phosphorylation levels were significantly associated with short overall survival (OS) in cancers of the breast, liver, lung, stomach, and esophagus and with advanced TNM stage in breast and esophageal cancers.	('short', 'NegReg', (105, 110))	('associated', 'Reg', (89, 99))	('cancers', 'Phenotype', 'HP:0002664', (136, 143))	('PDHK1', 'Gene', (36, 41))	('cancers', 'Phenotype', 'HP:0002664', (248, 255))	('cancers of the breast', 'Phenotype', 'HP:0100013', (136, 157))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('cancer', 'Phenotype', 'HP:0002664', (248, 254))	('lung', 'Disease', (166, 170))	('cancers of the breast', 'Disease', (136, 157))	('S203', 'Var', (27, 31))	('PDHK1', 'Gene', '5163', (36, 41))	('cancers of the breast', 'Disease', 'MESH:D001943', (136, 157))	('PGK1', 'Gene', '5230', (22, 26))	('breast and esophageal cancers', 'Disease', 'MESH:D001943', (226, 255))	('TNM', 'Gene', '10178', (213, 216))	('phosphorylation levels', 'MPA', (47, 69))	('TNM', 'Gene', (213, 216))	('PGK1', 'Gene', (22, 26))	('T338', 'Var', (42, 46))	('liver', 'Disease', (159, 164))	('esophagus', 'Disease', (185, 194))	('stomach', 'Disease', (172, 179))
368836	31578148	PGK1 pS203 and PDHK1 pT338 were also independent predictors of short OS in liver, lung, and stomach cancer.	('lung', 'Disease', (82, 86))	('liver', 'Disease', (75, 80))	('pS203', 'Var', (5, 10))	('short OS', 'Disease', (63, 71))	('stomach cancer', 'Disease', 'MESH:D013274', (92, 106))	('PDHK1', 'Gene', (15, 20))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('PDHK1', 'Gene', '5163', (15, 20))	('stomach cancer', 'Phenotype', 'HP:0012126', (92, 106))	('stomach cancer', 'Disease', (92, 106))	('PGK1', 'Gene', (0, 4))	('PGK1', 'Gene', '5230', (0, 4))
368846	31578148	In response to receptor tyrosine kinase activation, the expression of K-Ras G12V and B-Raf V600E, hypoxia, pyruvate metabolism in mitochondria is suppressed.	('G12V', 'Mutation', 'p.G12V', (76, 80))	('hypoxia', 'Disease', (98, 105))	('V600E', 'Mutation', 'p.V600E', (91, 96))	('B-Raf V600E', 'Var', (85, 96))	('hypoxia', 'Disease', 'MESH:D000860', (98, 105))	('activation', 'PosReg', (40, 50))	('pyruvate', 'Chemical', 'MESH:D011773', (107, 115))	('pyruvate metabolism in mitochondria', 'MPA', (107, 142))	('V600E', 'Var', (91, 96))	('K-Ras G12V', 'Var', (70, 80))	('tyrosine', 'Chemical', 'None', (24, 32))	('suppressed', 'NegReg', (146, 156))
368850	31578148	In addition, PGK1 S203 and PDHK1 T338 phosphorylation levels were found to be positively correlated with each other, and both were correlated with PDH S293 inactivating phosphorylation levels and poor prognosis in patients with glioblastoma (GBM).	('correlated', 'Interaction', (89, 99))	('correlated', 'Reg', (131, 141))	('glioblastoma', 'Disease', 'MESH:D005909', (228, 240))	('PDHK1', 'Gene', '5163', (27, 32))	('patients', 'Species', '9606', (214, 222))	('PDH', 'Gene', '54704', (27, 30))	('PDH', 'Gene', '54704', (147, 150))	('GBM', 'Phenotype', 'HP:0012174', (242, 245))	('PDHK1', 'Gene', (27, 32))	('glioblastoma', 'Disease', (228, 240))	('glioblastoma', 'Phenotype', 'HP:0012174', (228, 240))	('PGK1', 'Gene', '5230', (13, 17))	('inactivating', 'NegReg', (156, 168))	('PDH', 'Gene', (27, 30))	('PDH', 'Gene', (147, 150))	('PGK1', 'Gene', (13, 17))	('S203', 'Var', (18, 22))	('GBM', 'Disease', (242, 245))	('phosphorylation levels', 'MPA', (38, 60))	('GBM', 'Disease', 'MESH:D005909', (242, 245))
368853	31578148	We also analyzed the clinical relevance of PGK1 S203 and PDHK1 T338 phosphorylation levels by conducting immunohistochemical experiments in an additional 818 independent cancer cases (including 619 with paired normal tissues).	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('cancer', 'Disease', (170, 176))	('PGK1', 'Gene', (43, 47))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('PDHK1', 'Gene', (57, 62))	('PGK1', 'Gene', '5230', (43, 47))	('PDHK1', 'Gene', '5163', (57, 62))	('clinical', 'Species', '191496', (21, 29))	('S203', 'Var', (48, 52))
368864	31578148	Rabbit polyclonal antibodies recognizing phospho-PGK1 S203 and phospho-PDHK1 T338 were obtained from Signalway Antibody (College Park, MD, USA).	('PGK1', 'Gene', '5230', (49, 53))	('S203', 'Var', (54, 58))	('PDHK1', 'Gene', (71, 76))	('PDHK1', 'Gene', '5163', (71, 76))	('PGK1', 'Gene', (49, 53))	('Rabbit', 'Species', '9986', (0, 6))
368892	31578148	DNA methylation regulates gene expression and is implicated in tumor progression and therapeutic response.	('tumor', 'Disease', (63, 68))	('regulates', 'Reg', (16, 25))	('gene expression', 'MPA', (26, 41))	('methylation', 'Var', (4, 15))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('N', 'Chemical', 'MESH:D009584', (1, 2))	('implicated', 'Reg', (49, 59))
368900	31578148	3b; Additional file 1: Table S4), suggesting promoter hypomethylation as a mechanism promoting PGK1 expression.	('promoter hypomethylation', 'Var', (45, 69))	('expression', 'MPA', (100, 110))	('PGK1', 'Gene', (95, 99))	('PGK1', 'Gene', '5230', (95, 99))	('promoting', 'PosReg', (85, 94))
368902	31578148	We next analyzed the association between PGK1 promoter hypomethylation and the survival of patients with STAD, BLCA, ESCA, LIHC, and BRCA, and found that only in BRCA, hypomethylation of cg13203541 was associated with short OS (HR = 0.551, 95% CI 0.361-0.841, P = 0.005; Additional file 1: Table S5; Fig.	('BRCA', 'Phenotype', 'HP:0003002', (162, 166))	('BRCA', 'Disease', (133, 137))	('ESCA', 'Phenotype', 'HP:0011459', (117, 121))	('BLCA', 'Disease', 'MESH:D001749', (111, 115))	('LIHC', 'Disease', 'MESH:D006528', (123, 127))	('BRCA', 'Disease', 'MESH:D001943', (133, 137))	('PGK1', 'Gene', (41, 45))	('STAD', 'Disease', (105, 109))	('cg13203541', 'Var', (187, 197))	('patients', 'Species', '9606', (91, 99))	('BRCA', 'Disease', (162, 166))	('short OS', 'Disease', (218, 226))	('BRCA', 'Disease', 'MESH:D001943', (162, 166))	('hypomethylation', 'Var', (168, 183))	('ESCA', 'Disease', (117, 121))	('BRCA', 'Phenotype', 'HP:0003002', (133, 137))	('STAD', 'Disease', 'MESH:D013274', (105, 109))	('ESCA', 'Disease', 'MESH:D004938', (117, 121))	('associated', 'Reg', (202, 212))	('LIHC', 'Disease', (123, 127))	('BLCA', 'Disease', (111, 115))	('PGK1', 'Gene', '5230', (41, 45))
368903	31578148	A multivariate Cox regression model showed that cg13203541 methylation was an independent predictor of prolonged OS in BRCA (HR = 0.599, 95% CI 0.382-0.939, P = 0.026; Additional file 1: Table S5).	('cg13203541 methylation', 'Var', (48, 70))	('BRCA', 'Disease', (119, 123))	('BRCA', 'Phenotype', 'HP:0003002', (119, 123))	('BRCA', 'Disease', 'MESH:D001943', (119, 123))
368908	31578148	We found that in all five cancer types, PGK1 pS203 and PDHK1 pT338 levels were higher in most tumor tissues than in their matched normal tissues (Additional file 1: Fig.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('pT338 levels', 'MPA', (61, 73))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('cancer', 'Disease', (26, 32))	('PDHK1', 'Gene', (55, 60))	('PGK1', 'Gene', (40, 44))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('PGK1', 'Gene', '5230', (40, 44))	('PDHK1', 'Gene', '5163', (55, 60))	('tumor', 'Disease', (94, 99))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('higher', 'PosReg', (79, 85))	('pS203', 'Var', (45, 50))
368911	31578148	Kaplan-Meier analysis showed that higher levels of both PGK1 pS203 and PDHK1 pT338 were associated with shorter OS in patients with these five cancer types (all P < 0.05) (Fig.	('shorter OS', 'Disease', (104, 114))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('PGK1', 'Gene', '5230', (56, 60))	('PGK1', 'Gene', (56, 60))	('higher', 'PosReg', (34, 40))	('pS203', 'Var', (61, 66))	('PDHK1', 'Gene', (71, 76))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('PDHK1', 'Gene', '5163', (71, 76))	('patients', 'Species', '9606', (118, 126))
368912	31578148	An independent variable t test showed that both PGK1 pS203 and PDHK1 pT338 were associated with advanced TNM stage in patients with BRCA and ESCA (all P < 0.05) (Table 1).	('TNM', 'Gene', (105, 108))	('PGK1', 'Gene', (48, 52))	('PDHK1', 'Gene', '5163', (63, 68))	('BRCA', 'Disease', 'MESH:D001943', (132, 136))	('pS203', 'Var', (53, 58))	('PGK1', 'Gene', '5230', (48, 52))	('BRCA', 'Phenotype', 'HP:0003002', (132, 136))	('patients', 'Species', '9606', (118, 126))	('ESCA', 'Phenotype', 'HP:0011459', (141, 145))	('associated', 'Reg', (80, 90))	('ESCA', 'Disease', (141, 145))	('TNM', 'Gene', '10178', (105, 108))	('PDHK1', 'Gene', (63, 68))	('BRCA', 'Disease', (132, 136))	('ESCA', 'Disease', 'MESH:D004938', (141, 145))
368915	31578148	Additional analyses of a cohort of 818 cases revealed that the phosphorylation levels of PGK1 S203 and PDHK1 T338 were independent prognostic biomarkers for LIHC, LUAD, and STAD.	('PDHK1', 'Gene', (103, 108))	('T338', 'Var', (109, 113))	('PGK1', 'Gene', (89, 93))	('PDHK1', 'Gene', '5163', (103, 108))	('LUAD', 'Phenotype', 'HP:0030078', (163, 167))	('LIHC', 'Disease', (157, 161))	('LUAD', 'Disease', (163, 167))	('STAD', 'Disease', 'MESH:D013274', (173, 177))	('LUAD', 'Disease', 'MESH:C538231', (163, 167))	('phosphorylation levels', 'MPA', (63, 85))	('STAD', 'Disease', (173, 177))	('LIHC', 'Disease', 'MESH:D006528', (157, 161))	('PGK1', 'Gene', '5230', (89, 93))	('S203', 'Var', (94, 98))
368916	31578148	All these findings suggest that PGK1 gene modification and PGK1-mitochondrial function were significantly associated with clinical behaviors of cancer patients.	('clinical behaviors', 'Disease', (122, 140))	('associated', 'Reg', (106, 116))	('PGK1', 'Gene', (32, 36))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('PGK1', 'Gene', '5230', (32, 36))	('patients', 'Species', '9606', (151, 159))	('cancer', 'Disease', (144, 150))	('gene modification', 'Var', (37, 54))	('PGK1', 'Gene', (59, 63))	('clinical', 'Species', '191496', (122, 130))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('PGK1', 'Gene', '5230', (59, 63))
368926	31578148	Therefore, in the present study, we analyzed the DNA methylation data for 14 cancer types from TCGA datasets and identified hypomethylation of the PGK1 promoter (cg13203541) as an independent prognostic biomarker in BRCA patients (Additional file 1: Table S5).	('patients', 'Species', '9606', (221, 229))	('N', 'Chemical', 'MESH:D009584', (50, 51))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('hypomethylation', 'Var', (124, 139))	('BRCA', 'Disease', (216, 220))	('cg13203541', 'Var', (162, 172))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('PGK1', 'Gene', (147, 151))	('BRCA', 'Phenotype', 'HP:0003002', (216, 220))	('BRCA', 'Disease', 'MESH:D001943', (216, 220))	('PGK1', 'Gene', '5230', (147, 151))
368927	31578148	We also detected mitochondrial PGK1-dependent PDHK1 T338 phosphorylation in additional cases of five cancer types and demonstrated that mitochondrial function of PGK1 significantly affected the clinical behaviors of patients with these cancers.	('PGK1', 'Gene', (162, 166))	('cancer', 'Disease', 'MESH:D009369', (236, 242))	('cancers', 'Disease', 'MESH:D009369', (236, 243))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('mitochondrial function', 'MPA', (136, 158))	('PDHK1', 'Gene', '5163', (46, 51))	('affected', 'Reg', (181, 189))	('PGK1', 'Gene', '5230', (31, 35))	('PDHK1', 'Gene', (46, 51))	('cancers', 'Phenotype', 'HP:0002664', (236, 243))	('cancer', 'Disease', (236, 242))	('cancers', 'Disease', (236, 243))	('patients', 'Species', '9606', (216, 224))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('T338', 'Var', (52, 56))	('PGK1', 'Gene', (31, 35))	('PGK1', 'Gene', '5230', (162, 166))	('cancer', 'Disease', (101, 107))	('clinical behaviors', 'CPA', (194, 212))	('clinical', 'Species', '191496', (194, 202))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('phosphorylation', 'MPA', (57, 72))
368929	31578148	One important example is isocitrate dehydrogenase 1 (IDH1) mutation, which has important clinical significance and was found in GBM and myeloid malignancies, such as acute myelocytic leukaemia (AML) and myelodysplastic syndromes (MDS).	('AML', 'Disease', 'MESH:D015470', (194, 197))	('myeloid malignancies', 'Disease', (136, 156))	('acute myelocytic leukaemia', 'Disease', 'MESH:D015470', (166, 192))	('isocitrate', 'Chemical', 'MESH:D007523', (25, 35))	('AML', 'Disease', (194, 197))	('mutation', 'Var', (59, 67))	('AML', 'Phenotype', 'HP:0004808', (194, 197))	('acute myelocytic leukaemia', 'Phenotype', 'HP:0004808', (166, 192))	('MDS', 'Phenotype', 'HP:0002863', (230, 233))	('clinical', 'Species', '191496', (89, 97))	('GBM', 'Disease', (128, 131))	('myelodysplastic syndromes', 'Phenotype', 'HP:0002863', (203, 228))	('myeloid malignancies', 'Disease', 'OMIM:601308', (136, 156))	('GBM', 'Disease', 'MESH:D005909', (128, 131))	('myelodysplastic syndromes', 'Disease', (203, 228))	('MDS', 'Disease', 'MESH:D009190', (230, 233))	('IDH1', 'Gene', (53, 57))	('found', 'Reg', (119, 124))	('acute myelocytic leukaemia', 'Disease', (166, 192))	('myelodysplastic syndromes', 'Disease', 'MESH:D009190', (203, 228))	('MDS', 'Disease', (230, 233))	('GBM', 'Phenotype', 'HP:0012174', (128, 131))	('IDH1', 'Gene', '3417', (53, 57))	('myelocytic leukaemia', 'Phenotype', 'HP:0012324', (172, 192))
368930	31578148	A clinical study suggested that IDH1 mutation was an independent, favorable prognostic marker in grade 2-4 glioma.	('mutation', 'Var', (37, 45))	('IDH1', 'Gene', (32, 36))	('glioma', 'Disease', 'MESH:D005910', (107, 113))	('IDH1', 'Gene', '3417', (32, 36))	('glioma', 'Phenotype', 'HP:0009733', (107, 113))	('clinical', 'Species', '191496', (2, 10))	('glioma', 'Disease', (107, 113))
368943	31578148	This study was funded by The National Key R&D Program of China (2017YFC1308702, 2017YFC1311000, 2018YFC1312100), the Beijing Municipal Science & Technology Commission (Z181100006218032, Z181100001918002), the CAMS Initiative for Innovative Medicine (2017-I2M-1-005, 2017-I2M-2-003, 2019-I2M-2-002), Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences (2017PT32001, 2017PT32017).	('Z181100006218032', 'Chemical', 'MESH:C017788', (168, 184))	('Technology Commission', 'Var', (145, 166))	('N', 'Chemical', 'MESH:D009584', (29, 30))	('N', 'Chemical', 'MESH:D009584', (299, 300))	('Innovative', 'Var', (229, 239))
368954	29954406	In this review, we summarized the tissue distribution, expression, and roles of IGF2BP1 in embryogenesis and tumorigenesis, and focused on modulation of the interconnectivity between IGF2BP1 and its targeted mRNAs or non-coding RNAs (ncRNAs).	('IGF2BP1', 'Gene', (80, 87))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('ncRNA', 'Gene', (234, 239))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('ncRNA', 'Gene', '220202', (234, 239))	('IGF2BP1', 'Var', (183, 190))	('tumor', 'Disease', (109, 114))
368977	29954406	Similarly, knockdown of this gene may lead to 60% of perinatal death and significantly smaller body with hypoplastic tissues among almost all organs in mice.	('hypoplastic', 'Disease', 'MESH:D000741', (105, 116))	('hypoplastic', 'Disease', (105, 116))	('smaller', 'NegReg', (87, 94))	('mice', 'Species', '10090', (152, 156))	('lead to', 'Reg', (38, 45))	('knockdown', 'Var', (11, 20))
368978	29954406	The SNP rs9674544 in IGF2BP1 was identified to be significantly associated with primary tooth development in infancy.	('associated with', 'Reg', (64, 79))	('primary tooth development', 'CPA', (80, 105))	('SNP rs9674544', 'Var', (4, 17))	('IGF2BP1', 'Gene', (21, 28))	('rs9674544', 'Mutation', 'rs9674544', (8, 17))
368982	29954406	One study showed that downregulation of IGF2BP1 expression in the dorsal neural tube was both necessary and sufficient for the delamination and emigration of CNC, whereas inhibition of its expression enhanced CNC delamination and induced epithelial dissociation.	('emigration', 'CPA', (144, 154))	('downregulation', 'NegReg', (22, 36))	('inhibition', 'Var', (171, 181))	('rat', 'Species', '10116', (148, 151))	('IGF2BP1', 'Gene', (40, 47))	('epithelial dissociation', 'Disease', (238, 261))	('induced', 'Reg', (230, 237))	('epithelial dissociation', 'Disease', 'MESH:D004213', (238, 261))	('enhanced', 'PosReg', (200, 208))	('delamination', 'CPA', (127, 139))	('CNC delamination', 'CPA', (209, 225))
368984	29954406	In another study on the role of IGF2BP1 in amphibian neural crest migration, the reduced IGF2BP1 expression by antisense morpholino oligonucleotides (AMO), throughout the entire embryo, was showed to increase CNC migration, suggesting the reduction in CNC migration originally observed in the AMO-injected Xenopus embryos is a result of a global, non-cell autonomous reduction in IGF2BP1 expression.	('antisense', 'Var', (111, 120))	('reduction', 'NegReg', (239, 248))	('expression', 'MPA', (388, 398))	('IGF2BP1', 'Gene', (380, 387))	('increase', 'PosReg', (200, 208))	('CNC migration', 'CPA', (252, 265))	('IGF2BP1', 'Gene', (89, 96))	('reduction', 'NegReg', (367, 376))	('expression', 'Var', (97, 107))	('rat', 'Species', '10116', (259, 262))	('Xenopus', 'Species', '8355', (306, 313))	('CNC migration', 'CPA', (209, 222))	('reduced', 'NegReg', (81, 88))	('rat', 'Species', '10116', (216, 219))	('rat', 'Species', '10116', (69, 72))	('morpholino oligonucleotides', 'Chemical', 'MESH:D060172', (121, 148))
368985	29954406	Those findings reveal the essential roles of IGF2BP1 in regulating cell growth and differentiation during development of organisms and suggest that aberrant expression of this gene could cause dysplasia of tissues and organs by dysregulating the expression levels of its targets such as ACTB mRNA and ITGA6 mRNA.	('ITGA6', 'Gene', '3655', (301, 306))	('ITGA6', 'Gene', (301, 306))	('cell growth', 'CPA', (67, 78))	('aberrant expression', 'Var', (148, 167))	('dysplasia', 'Disease', (193, 202))	('ACTB', 'Gene', '60', (287, 291))	('ACTB', 'Gene', (287, 291))	('IGF2BP1', 'Gene', (45, 52))	('dysplasia', 'Disease', 'MESH:D004476', (193, 202))	('expression levels', 'MPA', (246, 263))	('cause', 'Reg', (187, 192))	('dysregulating', 'Reg', (228, 241))
369003	29954406	MiR-491-5p, which may suppress the growth and metastasis of multiple types of tumors by targeting some cancer-related genes, was observed to be downregulated in NSCLC tissues and cell lines.	('NSCLC', 'Disease', 'MESH:D002289', (161, 166))	('tumors', 'Disease', (78, 84))	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('downregulated', 'NegReg', (144, 157))	('NSCLC', 'Phenotype', 'HP:0030358', (161, 166))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('suppress', 'NegReg', (22, 30))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('NSCLC', 'Disease', (161, 166))	('MiR-491-5p', 'Var', (0, 10))
369004	29954406	In a mouse model, upregulation of miR-491-5p was observed to enhance the tumor cell cycle arrest at the G1/G0 stage and promote tumor cell apoptosis, as well as repress tumor cell proliferation, migration, and invasion, and growth by inhibiting IGF2BP1.	('upregulation', 'PosReg', (18, 30))	('IGF2BP1', 'Gene', (245, 252))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('invasion', 'CPA', (210, 218))	('growth', 'CPA', (224, 230))	('promote', 'PosReg', (120, 127))	('inhibiting', 'NegReg', (234, 244))	('rat', 'Species', '10116', (198, 201))	('tumor', 'Disease', (169, 174))	('mouse', 'Species', '10090', (5, 10))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (79, 96))	('migration', 'CPA', (195, 204))	('enhance', 'PosReg', (61, 68))	('rat', 'Species', '10116', (187, 190))	('repress', 'NegReg', (161, 168))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('tumor', 'Disease', (73, 78))	('tumor', 'Disease', (128, 133))	('miR-491-5p', 'Var', (34, 44))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))
369012	29954406	Nevertheless, knockdown of HCG11 was showed to lead to IGF2BP1 suppression and inhibition of cell viability and proliferation, cell migration and invasion, and colony formation ability of HepG2 cells, as well as induce cell apoptosis and cell cycle arrest at G1 stage, which is similar to the effects of IGF2BP1 suppression by shRNA.	('cell migration', 'CPA', (127, 141))	('HCG11', 'Gene', '493812', (27, 32))	('suppression', 'NegReg', (63, 74))	('rat', 'Species', '10116', (135, 138))	('induce', 'PosReg', (212, 218))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (238, 255))	('rat', 'Species', '10116', (119, 122))	('cell apoptosis', 'CPA', (219, 233))	('invasion', 'CPA', (146, 154))	('HCG11', 'Gene', (27, 32))	('HepG2', 'CellLine', 'CVCL:0027', (188, 193))	('cell cycle arrest at G1 stage', 'CPA', (238, 267))	('inhibition', 'NegReg', (79, 89))	('IGF2BP1', 'Gene', (55, 62))	('knockdown', 'Var', (14, 23))	('colony formation ability', 'CPA', (160, 184))
369014	29954406	Interestingly, IGF2BP1 served as a trans-acting factor to inhibit HULC expression by recruiting CNOT1 and bringing HULC into close proximity to the CCR4-NOT deadenylase complex.	('HULC', 'Gene', (115, 119))	('recruiting', 'PosReg', (85, 95))	('IGF2BP1', 'Var', (15, 22))	('CNOT1', 'Gene', '23019', (96, 101))	('bringing', 'Reg', (106, 114))	('HULC', 'Gene', '728655', (66, 70))	('CNOT1', 'Gene', (96, 101))	('inhibit', 'NegReg', (58, 65))	('HULC', 'Gene', '728655', (115, 119))	('HULC', 'Gene', (66, 70))	('CC', 'Phenotype', 'HP:0002664', (148, 150))
369016	29954406	Presently, some miRNAs including miR-625, miR-98-5p, miR-9, miR-1275, and miRNA-196b were showed to be frequently downregulated in HCC samples, and their upregulation may hinder HCC development.	('HCC', 'Disease', (131, 134))	('miR-9', 'Var', (53, 58))	('miR-625', 'Gene', '693210', (33, 40))	('HCC', 'Phenotype', 'HP:0001402', (131, 134))	('miR-1275', 'Gene', (60, 68))	('HCC development', 'CPA', (178, 193))	('miRNA-196b', 'Gene', '442920', (74, 84))	('miR-1275', 'Gene', '100302123', (60, 68))	('miR-98', 'Gene', '407054', (42, 48))	('CC', 'Phenotype', 'HP:0002664', (179, 181))	('HCC', 'Phenotype', 'HP:0001402', (178, 181))	('miRNA-196b', 'Gene', (74, 84))	('upregulation', 'PosReg', (154, 166))	('CC', 'Phenotype', 'HP:0002664', (132, 134))	('downregulated', 'NegReg', (114, 127))	('miR-625', 'Gene', (33, 40))	('miR-98', 'Gene', (42, 48))	('hinder', 'NegReg', (171, 177))
369019	29954406	Another potential prognostic marker for HCC, miR-9, was observed to promote HCC cell proliferation and migration by hypermethylation-mediated downregulation of it and inhibit HCC development via suppressing AKT and ERK phosphorylation that are well known for their oncogenic properties after targeting IGF2BP1.	('HCC', 'Phenotype', 'HP:0001402', (40, 43))	('inhibit', 'NegReg', (167, 174))	('HCC', 'Phenotype', 'HP:0001402', (175, 178))	('downregulation', 'NegReg', (142, 156))	('AKT', 'Gene', '207', (207, 210))	('ERK', 'Gene', '5594', (215, 218))	('HCC development', 'CPA', (175, 190))	('HCC cell proliferation', 'CPA', (76, 98))	('suppressing', 'NegReg', (195, 206))	('CC', 'Phenotype', 'HP:0002664', (176, 178))	('hypermethylation-mediated', 'Var', (116, 141))	('ERK', 'Gene', (215, 218))	('rat', 'Species', '10116', (92, 95))	('CC', 'Phenotype', 'HP:0002664', (41, 43))	('IGF2BP1', 'Gene', (302, 309))	('miR-9', 'Var', (45, 50))	('migration', 'CPA', (103, 112))	('promote', 'PosReg', (68, 75))	('HCC', 'Phenotype', 'HP:0001402', (76, 79))	('AKT', 'Gene', (207, 210))	('rat', 'Species', '10116', (106, 109))	('CC', 'Phenotype', 'HP:0002664', (77, 79))
369023	29954406	However, the suppression of invasion and metastasis by IGF2BP1 was seen in breast carcinoma cells of human and rat.	('suppression', 'NegReg', (13, 24))	('rat', 'Species', '10116', (111, 114))	('breast carcinoma', 'Disease', 'MESH:D001943', (75, 91))	('breast carcinoma', 'Disease', (75, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('human', 'Species', '9606', (101, 106))	('breast carcinoma', 'Phenotype', 'HP:0003002', (75, 91))	('invasion', 'CPA', (28, 36))	('IGF2BP1', 'Var', (55, 62))
369025	29954406	The high promoter methylation and significant downregulation of IGF2BP1 was observed in all metastatic cell lines including MTLn3, MDA435, MDA231, and 4T1 but slightly in non-metastatic cell lines including MTC in T47D, and the promoter demethylation of IGF2BP1 induced its endogenous expression in metastatic MTLn3 cells, indicating epigenetic modifications could act a role in silencing the IGF2BP1 in metastatic breast tumor cells.	('breast tumor', 'Disease', (415, 427))	('downregulation', 'NegReg', (46, 60))	('silencing', 'NegReg', (379, 388))	('MDA231', 'CellLine', 'CVCL:0062', (139, 145))	('tumor', 'Phenotype', 'HP:0002664', (422, 427))	('IGF2BP1', 'Gene', (64, 71))	('breast tumor', 'Phenotype', 'HP:0100013', (415, 427))	('T47D', 'CellLine', 'CVCL:0553', (214, 218))	('promoter methylation', 'MPA', (9, 29))	('IGF2BP1', 'Gene', (254, 261))	('MDA435', 'CellLine', 'CVCL:0417', (131, 137))	('breast tumor', 'Disease', 'MESH:D001943', (415, 427))	('promoter demethylation', 'Var', (228, 250))	('IGF2BP1', 'Gene', (393, 400))	('endogenous expression', 'MPA', (274, 295))
369027	29954406	Repression of IGF2BP1 expression may reduce the accumulation of E-cadherin, a crucial cell adhesion protein, at cell-cell contacts, as well as impair the dynamics of focal adhesions, subsequently converting the polarized adherent phenotype into an unpolarized morphological one with invasive behavior.	('reduce', 'NegReg', (37, 43))	('dynamics', 'MPA', (154, 162))	('impair', 'NegReg', (143, 149))	('polarized', 'CPA', (211, 220))	('E-cadherin', 'Gene', (64, 74))	('converting', 'Reg', (196, 206))	('accumulation', 'MPA', (48, 60))	('Repression', 'Var', (0, 10))	('E-cadherin', 'Gene', '999', (64, 74))	('IGF2BP1', 'Gene', (14, 21))
369029	29954406	Taken together, it seems possible to draw a conclusion from these in vitro and in vivo studies that methylation events of IGF2BP1 are becoming more frequent with the higher breast cancer grade, and this leads to more silence and downregulation events of IGF2BP1, resulting in dysregulated effects on IGF2BP1-target mRNAs.	('breast cancer', 'Phenotype', 'HP:0003002', (173, 186))	('downregulation', 'NegReg', (229, 243))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('IGF2BP1', 'Gene', (122, 129))	('methylation', 'Var', (100, 111))	('IGF2BP1', 'Gene', (254, 261))	('silence', 'MPA', (217, 224))	('dysregulated effects', 'MPA', (276, 296))	('breast cancer', 'Disease', 'MESH:D001943', (173, 186))	('breast cancer', 'Disease', (173, 186))
369055	29954406	Enhanced GHET1 expression can contribute to gastric carcinoma cell proliferation and tumor growth in vitro and in vivo by physically associating with IGF2BP1 and increasing the physical interaction of IGF2BP1 with c-Myc mRNA, consequently enhancing c-Myc mRNA stability and expression.	('expression', 'MPA', (274, 284))	('tumor', 'Disease', (85, 90))	('contribute', 'Reg', (30, 40))	('c-Myc', 'Gene', '4609', (249, 254))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('GHET1', 'Gene', '102723099', (9, 14))	('GHET1', 'Gene', (9, 14))	('c-Myc', 'Gene', (214, 219))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('increasing', 'PosReg', (162, 172))	('IGF2BP1', 'Var', (201, 208))	('c-Myc', 'Gene', '4609', (214, 219))	('carcinoma', 'Phenotype', 'HP:0030731', (52, 61))	('gastric carcinoma', 'Disease', 'MESH:D013274', (44, 61))	('gastric carcinoma', 'Disease', (44, 61))	('rat', 'Species', '10116', (74, 77))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (44, 61))	('c-Myc', 'Gene', (249, 254))	('physical', 'MPA', (177, 185))	('enhancing', 'PosReg', (239, 248))
369056	29954406	Although the study of IGF2BP1 in osteosarcoma (OS) is little, the observation of the restoration of miR-150 expression in OS cells could suppress the proliferation, migration and invasion, and growth of tumor cell and induce apoptosis by targeting it was reported.	('tumor', 'Disease', (203, 208))	('invasion', 'CPA', (179, 187))	('OS', 'Phenotype', 'HP:0002669', (47, 49))	('suppress', 'NegReg', (137, 145))	('miR-150', 'Gene', (100, 107))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('osteosarcoma', 'Phenotype', 'HP:0002669', (33, 45))	('proliferation', 'CPA', (150, 163))	('OS', 'Phenotype', 'HP:0002669', (122, 124))	('rat', 'Species', '10116', (157, 160))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('apoptosis', 'CPA', (225, 234))	('osteosarcoma', 'Disease', (33, 45))	('osteosarcoma', 'Disease', 'MESH:D012516', (33, 45))	('miR-150', 'Gene', '406942', (100, 107))	('rat', 'Species', '10116', (90, 93))	('rat', 'Species', '10116', (168, 171))	('restoration', 'Var', (85, 96))	('induce', 'PosReg', (218, 224))
369060	29954406	Decreasing levels of cIAP1 in RMS cell lines upon IGF2BP1 knockdown sensitize RMS cells to tumor necrosis factor-alpha (TNFalpha)-mediated cell death, similar to the result by Smac mimetic compound (SMC) treatment.	('Smac', 'Gene', (176, 180))	('TNFalpha', 'Gene', (120, 128))	('RMS', 'Phenotype', 'HP:0002859', (78, 81))	('IGF2BP1', 'Gene', (50, 57))	('Decreasing', 'NegReg', (0, 10))	('TNFalpha', 'Gene', '7124', (120, 128))	('tumor necrosis factor-alpha', 'Gene', '7124', (91, 118))	('sensitize', 'Reg', (68, 77))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor necrosis factor-alpha', 'Gene', (91, 118))	('Smac', 'Gene', '56616', (176, 180))	('RMS', 'Phenotype', 'HP:0002859', (30, 33))	('knockdown', 'Var', (58, 67))	('levels', 'MPA', (11, 17))
369061	29954406	Moreover, targeting cIAP1 by SMC suppresses the formation and growth of RMS xenograft tumors in mice.	('cIAP1', 'Gene', (20, 25))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('suppresses', 'NegReg', (33, 43))	('mice', 'Species', '10090', (96, 100))	('RMS xenograft tumors', 'Disease', (72, 92))	('formation', 'CPA', (48, 57))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('targeting', 'Var', (10, 19))	('RMS', 'Phenotype', 'HP:0002859', (72, 75))	('RMS xenograft tumors', 'Disease', 'MESH:D009369', (72, 92))
369069	29954406	Those findings show that methylation of IGF2BP1 involves tumor development and regulates its expression and thus modulates the downstream biological pathway.	('modulates', 'Reg', (113, 122))	('involves', 'Reg', (48, 56))	('IGF2BP1', 'Gene', (40, 47))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('regulates', 'Reg', (79, 88))	('methylation', 'Var', (25, 36))	('expression', 'MPA', (93, 103))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Disease', (57, 62))
369079	29954406	In metastatic melanoma, IGF2BP1 expression was observed to confer a resistance to chemotherapeutic agents, whereas its inhibition or knockdown enhanced the effects of chemotherapy and reduced tumorigenic characteristics.	('melanoma', 'Disease', (14, 22))	('tumor', 'Disease', (192, 197))	('enhanced', 'PosReg', (143, 151))	('effects of chemotherapy', 'MPA', (156, 179))	('knockdown', 'Var', (133, 142))	('inhibition', 'NegReg', (119, 129))	('reduced', 'NegReg', (184, 191))	('resistance to chemotherapeutic agents', 'MPA', (68, 105))	('IGF2BP1', 'Gene', (24, 31))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('melanoma', 'Disease', 'MESH:D008545', (14, 22))	('melanoma', 'Phenotype', 'HP:0002861', (14, 22))
369080	29954406	Moreover, IGF2BP1 knockdown was found to reduce levels of c-MYC, which contributes to the suppression of NF-kB activity and of anchorage-independent growth of melanoma cells and proliferation, as well as induces apoptosis.	('melanoma', 'Disease', (159, 167))	('knockdown', 'Var', (18, 27))	('suppression', 'NegReg', (90, 101))	('levels', 'MPA', (48, 54))	('anchorage-independent growth', 'CPA', (127, 155))	('activity', 'MPA', (111, 119))	('apoptosis', 'CPA', (212, 221))	('NF-kB', 'Protein', (105, 110))	('reduce', 'NegReg', (41, 47))	('c-MYC', 'Gene', '4609', (58, 63))	('rat', 'Species', '10116', (185, 188))	('melanoma', 'Phenotype', 'HP:0002861', (159, 167))	('IGF2BP1', 'Gene', (10, 17))	('induces', 'Reg', (204, 211))	('melanoma', 'Disease', 'MESH:D008545', (159, 167))	('c-MYC', 'Gene', (58, 63))
369087	29954406	Additionally, the loss of IGF2BP1 was indicated to increase tumor cell proliferation related to increased IGF-II protein levels in K562 leukemia cells and promote PARP- and caspase-3 mediated apoptosis in colorectal cancer cells.	('leukemia', 'Phenotype', 'HP:0001909', (136, 144))	('increased IGF-', 'Phenotype', 'HP:0030269', (96, 110))	('PARP', 'Gene', '1302', (163, 167))	('tumor', 'Disease', (60, 65))	('IGF-II', 'Gene', '3481', (106, 112))	('leukemia', 'Disease', (136, 144))	('colorectal cancer', 'Disease', 'MESH:D015179', (205, 222))	('leukemia', 'Disease', 'MESH:D007938', (136, 144))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('rat', 'Species', '10116', (78, 81))	('caspase-3', 'Gene', '836', (173, 182))	('colorectal cancer', 'Disease', (205, 222))	('PARP', 'Gene', (163, 167))	('increase', 'PosReg', (51, 59))	('IGF-II', 'Gene', (106, 112))	('IGF2BP1', 'Gene', (26, 33))	('caspase-3', 'Gene', (173, 182))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('promote', 'PosReg', (155, 162))	('K562', 'CellLine', 'CVCL:0004', (131, 135))	('increased', 'PosReg', (96, 105))	('loss', 'Var', (18, 22))	('colorectal cancer', 'Phenotype', 'HP:0003003', (205, 222))	('protein levels', 'MPA', (113, 127))
369092	29954406	In choriocarcinoma cell lines, the depletion of ribosomal protein S6 kinase (RSK2) or protein phosphatase methylesterase 1 (PPME1) inhibits cell migration and invasion, which is similar to that after knockdown of IGF2BP1 that controls RSK2 and PPME expression, whereas it did not influence cellular proliferation and morphology, indicating that IGF2BP1 promotes choriocarcinoma cell migration and invasion partly via the effect of RSK2 and PPME1.	('RSK2', 'Gene', (77, 81))	('carcinoma', 'Phenotype', 'HP:0030731', (9, 18))	('PPME1', 'Gene', '51400', (124, 129))	('choriocarcinoma', 'Phenotype', 'HP:0100768', (362, 377))	('choriocarcinoma', 'Phenotype', 'HP:0100768', (3, 18))	('promotes', 'PosReg', (353, 361))	('RSK2', 'Gene', '6197', (235, 239))	('RSK2', 'Gene', '6197', (77, 81))	('PPME1', 'Gene', '51400', (440, 445))	('IGF2BP1', 'Var', (345, 352))	('RSK2', 'Gene', (431, 435))	('rat', 'Species', '10116', (148, 151))	('rat', 'Species', '10116', (386, 389))	('PPME1', 'Gene', (124, 129))	('inhibits', 'NegReg', (131, 139))	('protein phosphatase methylesterase 1', 'Gene', '51400', (86, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (368, 377))	('rat', 'Species', '10116', (306, 309))	('choriocarcinoma', 'Disease', 'MESH:D002822', (362, 377))	('invasion', 'CPA', (397, 405))	('PPME1', 'Gene', (440, 445))	('RSK2', 'Gene', '6197', (431, 435))	('choriocarcinoma', 'Disease', (362, 377))	('choriocarcinoma', 'Disease', 'MESH:D002822', (3, 18))	('protein phosphatase methylesterase 1', 'Gene', (86, 122))	('RSK2', 'Gene', (235, 239))	('choriocarcinoma', 'Disease', (3, 18))	('cell migration', 'CPA', (140, 154))
369094	29954406	Almost all of the reported miRNAs including miR-491-5p, miR-625, miR-98-5p, miR-9, miR-196b, miR-1275, miR-708, let-7 miRNA family, miR-150, miR-506, miR-873, miR-140-5p, and miR-124-3p are downregulated in corresponding cancer samples, whereas all of the three lncRNAs including HCG11, GHET1, and THOR are highly expressed in corresponding solid tumors.	('cancer', 'Disease', 'MESH:D009369', (221, 227))	('miR-196b', 'Gene', '442920', (83, 91))	('tumors', 'Phenotype', 'HP:0002664', (347, 353))	('miR-124-3p', 'Gene', '406909', (175, 185))	('miR-873', 'Gene', '100126316', (150, 157))	('miR-98', 'Gene', '407054', (65, 71))	('miR-1275', 'Gene', (93, 101))	('miR-150', 'Gene', (132, 139))	('tumor', 'Phenotype', 'HP:0002664', (347, 352))	('HCG11', 'Gene', (280, 285))	('solid tumors', 'Disease', 'MESH:D009369', (341, 353))	('miR-140', 'Gene', (159, 166))	('GHET1', 'Gene', '102723099', (287, 292))	('miR-625', 'Gene', (56, 63))	('GHET1', 'Gene', (287, 292))	('downregulated', 'NegReg', (190, 203))	('miR-140', 'Gene', '406932', (159, 166))	('miR-124-3p', 'Gene', (175, 185))	('miR-506', 'Gene', '574511', (141, 148))	('ncRNA', 'Gene', (263, 268))	('miR-196b', 'Gene', (83, 91))	('miR-708', 'Gene', (103, 110))	('cancer', 'Disease', (221, 227))	('ncRNA', 'Gene', '220202', (263, 268))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('miR-491-5p', 'Var', (44, 54))	('miR-9', 'Var', (76, 81))	('miR-625', 'Gene', '693210', (56, 63))	('miR-98', 'Gene', (65, 71))	('miR-873', 'Gene', (150, 157))	('miR-150', 'Gene', '406942', (132, 139))	('miR-1275', 'Gene', '100302123', (93, 101))	('HCG11', 'Gene', '493812', (280, 285))	('solid tumors', 'Disease', (341, 353))	('miR-708', 'Gene', '100126333', (103, 110))	('miR-506', 'Gene', (141, 148))
369099	29954406	Nearly the levels of all those targets are reduced in both MM603 and H1299 cells with THOR knock down similar to that with IGF2BP1 knockdown, whereas elevates with overexpression of THOR in SKMEL5 and H1437 cells.	('elevates', 'PosReg', (150, 158))	('SKMEL5', 'CellLine', 'CVCL:0527', (190, 196))	('H1437', 'CellLine', 'CVCL:1472', (201, 206))	('H1299', 'CellLine', 'CVCL:0060', (69, 74))	('THOR', 'Gene', (86, 90))	('knock down', 'Var', (91, 101))	('reduced', 'NegReg', (43, 50))	('MM603', 'CellLine', 'CVCL:2612', (59, 64))	('levels', 'MPA', (11, 17))
369100	29954406	Taken together, those findings show that lncRNAs HCG11, GHET1, and THOR dysregulate the expression of IGF2BP1-downstream targets by modulating IGF2BP1.	('GHET1', 'Gene', '102723099', (56, 61))	('dysregulate', 'Var', (72, 83))	('GHET1', 'Gene', (56, 61))	('IGF2BP1-downstream', 'Gene', (102, 120))	('HCG11', 'Gene', '493812', (49, 54))	('IGF2BP1', 'Gene', (143, 150))	('ncRNA', 'Gene', (42, 47))	('modulating', 'Reg', (132, 142))	('HCG11', 'Gene', (49, 54))	('expression', 'MPA', (88, 98))	('ncRNA', 'Gene', '220202', (42, 47))
369106	29954406	Additionally, IGF2BP1 prevents CD44 and PTEN mRNA turnover, consequently enhances CD44 expression, and induces the formation of invadopodia and therefore may promote tumor cell migration and invasiveness.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('rat', 'Species', '10116', (180, 183))	('PTEN', 'Gene', (40, 44))	('prevents', 'NegReg', (22, 30))	('promote', 'PosReg', (158, 165))	('invasiveness', 'CPA', (191, 203))	('CD44', 'Gene', '960', (82, 86))	('tumor', 'Disease', (166, 171))	('PTEN', 'Gene', '5728', (40, 44))	('induces', 'Reg', (103, 110))	('CD44', 'Gene', (82, 86))	('expression', 'MPA', (87, 97))	('CD44', 'Gene', '960', (31, 35))	('IGF2BP1', 'Var', (14, 21))	('CD44', 'Gene', (31, 35))	('formation of invadopodia', 'MPA', (115, 139))	('enhances', 'PosReg', (73, 81))
369122	29954406	Moreover, it also selectively reduces the levels of other cancer-related IGF2BP1 mRNA targets including CALM1, CDC34, COL5A, and BTRC, similar to the effect by RNAi knockdown of IGF2BP1 both in IGROV-1 and SK-MEL2 cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('BTRC', 'Gene', '8945', (129, 133))	('cancer', 'Disease', (214, 220))	('SK-MEL2 cancer', 'Disease', (206, 220))	('IGF2BP1', 'Gene', (178, 185))	('SK-MEL2 cancer', 'Disease', 'MESH:D009369', (206, 220))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('CDC34', 'Gene', (111, 116))	('CDC34', 'Gene', '997', (111, 116))	('IGF2BP1', 'Gene', (73, 80))	('reduces', 'NegReg', (30, 37))	('cancer', 'Disease', 'MESH:D009369', (214, 220))	('levels', 'MPA', (42, 48))	('COL5A', 'MPA', (118, 123))	('CALM1', 'Gene', '801', (104, 109))	('BTRC', 'Gene', (129, 133))	('knockdown', 'Var', (165, 174))	('CALM1', 'Gene', (104, 109))	('cancer', 'Disease', (58, 64))
369128	29954406	At least in breast cancer, it is confirmed that IGF2BP1 inhibits tumor cell growth and invasion.	('breast cancer', 'Disease', (12, 25))	('breast cancer', 'Disease', 'MESH:D001943', (12, 25))	('breast cancer', 'Phenotype', 'HP:0003002', (12, 25))	('tumor', 'Disease', (65, 70))	('inhibits', 'NegReg', (56, 64))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('IGF2BP1', 'Var', (48, 55))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
369137	29954406	Though currently available inhibitors of ncRNA-IGF2BP1-mRNA target-axes are limited, an inhibitor of IGF2BP1 binding to targeted mRNAs, BTYNB, has showed therapeutic potential by inhibiting cell proliferation of IGF2BP1-positive cancer cells.	('IGF2BP1', 'Gene', (101, 108))	('rat', 'Species', '10116', (202, 205))	('ncRNA', 'Gene', '220202', (41, 46))	('inhibiting', 'NegReg', (179, 189))	('cancer', 'Disease', (229, 235))	('cancer', 'Disease', 'MESH:D009369', (229, 235))	('inhibitor', 'Var', (88, 97))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('cell proliferation', 'CPA', (190, 208))	('BTYNB', 'Chemical', '-', (136, 141))	('ncRNA', 'Gene', (41, 46))	('binding', 'Interaction', (109, 116))
369191	28684728	In general, CK5/6 and p63 are markers of squamous cell carcinoma, whereas SP-A and TTF-1 are markers of adenocarcinoma.	('p63', 'Gene', '8626', (22, 25))	('squamous cell carcinoma', 'Disease', (41, 64))	('TTF', 'Gene', '399', (83, 86))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (41, 64))	('carcinoma', 'Phenotype', 'HP:0030731', (55, 64))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('p63', 'Gene', (22, 25))	('TTF', 'Gene', (83, 86))	('adenocarcinoma', 'Disease', (104, 118))	('CK5/6', 'Var', (12, 17))	('SP-A', 'Gene', (74, 78))	('adenocarcinoma', 'Disease', 'MESH:D000230', (104, 118))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (41, 64))
369201	28684728	In a study by Ro et al., a tumor size of >5 cm, a clinical stage of >I, metastasis, associated genetic mutation (K-Ras or p53 mutation), and lymph node involvement significantly shortened patient survival.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('metastasis', 'CPA', (72, 82))	('shortened', 'NegReg', (178, 187))	('patient', 'Species', '9606', (188, 195))	('tumor', 'Disease', (27, 32))	('men', 'Species', '9606', (159, 162))	('p53', 'Gene', '7157', (122, 125))	('K-Ras', 'Var', (113, 118))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('patient survival', 'CPA', (188, 204))	('p53', 'Gene', (122, 125))
369226	32351986	have demonstrated that FOXD1 is overexpressed in human NSCLC, and patients with high FOXD1 expression have a much shorter survival time than patients with low FOXD1 expression.	('survival time', 'CPA', (122, 135))	('expression', 'Var', (91, 101))	('shorter', 'NegReg', (114, 121))	('FOXD1', 'Gene', (85, 90))	('high', 'Var', (80, 84))	('patients', 'Species', '9606', (141, 149))	('patients', 'Species', '9606', (66, 74))
369242	32351986	To identify the binding probability of miR-30a-5p with FOXD1 3'-UTR, the 3'-UTR of FOXD1 was cloned to psiCHECK luciferase reporter vector (Sangon Co., LTD., Shanghai, China) to construct wild-type (wt) and mutant-type (mut) FOXD1 HEK293T cells were seeded in 48-well plates and cultured for 24 h before transfection.	('FOXD1', 'Gene', (225, 230))	('HEK293T', 'CellLine', 'CVCL:0063', (231, 238))	('psiCHECK', 'Disease', 'None', (103, 111))	('mutant-type', 'Var', (207, 218))	('psiCHECK', 'Disease', (103, 111))
369243	32351986	miR-30a-5p has been found regulating tumor development by inhibiting oncogenes in various tumors, and it can enhance the sensitivity of NSCLC to paclitaxel by targeting BCL-2 expression.	('expression', 'MPA', (175, 185))	('paclitaxel', 'Chemical', 'MESH:D017239', (145, 155))	('sensitivity of NSCLC to paclitaxel', 'MPA', (121, 155))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('inhibiting', 'NegReg', (58, 68))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('miR-30a-5p', 'Var', (0, 10))	('tumor development', 'CPA', (37, 54))	('oncogenes', 'Gene', (69, 78))	('BCL-2', 'Protein', (169, 174))	('enhance', 'PosReg', (109, 116))	('targeting', 'Reg', (159, 168))
369306	28208216	As illustrated in Figure 1(a) and (b), CCN1, CCN2 and CCN3 expression increased in the MSC treated with TSCCA or CAL27 CM compared with the control MSC.	('TSCC', 'Phenotype', 'HP:0030413', (104, 108))	('MSC', 'Gene', (148, 151))	('CCN1', 'Gene', (39, 43))	('CAL27 CM', 'Var', (113, 121))	('MSC', 'Gene', (87, 90))	('increased', 'PosReg', (70, 79))	('CCN2', 'Gene', (45, 49))	('CCN3', 'Gene', (54, 58))	('CCN1', 'Gene', '3491', (39, 43))	('CCN3', 'Gene', '4856', (54, 58))	('expression', 'MPA', (59, 69))	('CAL27', 'CellLine', 'CVCL:1107', (113, 118))	('TSCCA', 'Chemical', '-', (104, 109))	('MSC', 'Gene', '9242', (148, 151))	('MSC', 'Gene', '9242', (87, 90))
369326	28208216	Then, to determine whether CCN2 secreted by MSC is involved in TSCC cell proliferation, we explored the effect of CCN2 knockdown in MSC on TSCC cell proliferation.	('TSCC', 'Phenotype', 'HP:0030413', (63, 67))	('MSC', 'Gene', (132, 135))	('MSC', 'Gene', '9242', (44, 47))	('TSCC', 'Phenotype', 'HP:0030413', (139, 143))	('MSC', 'Gene', (44, 47))	('knockdown', 'Var', (119, 128))	('CCN2', 'Gene', (114, 118))	('MSC', 'Gene', '9242', (132, 135))
369334	28208216	However, the invasion-stimulating effect was decreased by knockdown of CCN2 in MSC (Fig.	('invasion-stimulating effect', 'CPA', (13, 40))	('decreased', 'NegReg', (45, 54))	('CCN2', 'Gene', (71, 75))	('MSC', 'Gene', '9242', (79, 82))	('knockdown', 'Var', (58, 67))	('MSC', 'Gene', (79, 82))
369335	28208216	CCN2 knockdown increased the mRNA level of epithelial markers, including E-Cadherin, in TSCCA and CAL27 cells, whereas the mRNA levels of mesenchymal markers, including N-cadherin, Vimentin and Twist, MMP2 and MMP9, were significantly reduced (Fig.	('E-Cadherin', 'Gene', '999', (73, 83))	('knockdown', 'Var', (5, 14))	('MMP2', 'Gene', (201, 205))	('mRNA level of epithelial markers', 'MPA', (29, 61))	('Twist', 'Gene', (194, 199))	('CCN2', 'Gene', (0, 4))	('Vimentin', 'Gene', '7431', (181, 189))	('TSCC', 'Phenotype', 'HP:0030413', (88, 92))	('N-cadherin', 'Gene', (169, 179))	('E-Cadherin', 'Gene', (73, 83))	('N-cadherin', 'Gene', '1000', (169, 179))	('Vimentin', 'Gene', (181, 189))	('MMP2', 'Gene', '4313', (201, 205))	('MMP9', 'Gene', '4318', (210, 214))	('MMP9', 'Gene', (210, 214))	('Twist', 'Gene', '7291', (194, 199))	('increased', 'PosReg', (15, 24))	('CAL27', 'CellLine', 'CVCL:1107', (98, 103))	('reduced', 'NegReg', (235, 242))	('mRNA levels', 'MPA', (123, 134))	('TSCCA', 'Chemical', '-', (88, 93))
369342	28208216	These results indicated that exogenous CCN2 might play a positive role in EMT progression in TSCCA and CAL27 cells, and aid migration and invasion.	('CAL27', 'CellLine', 'CVCL:1107', (103, 108))	('EMT progression', 'CPA', (74, 89))	('positive', 'PosReg', (57, 65))	('TSCC', 'Phenotype', 'HP:0030413', (93, 97))	('exogenous', 'Var', (29, 38))	('TSCCA', 'Chemical', '-', (93, 98))	('aid', 'PosReg', (120, 123))	('invasion', 'CPA', (138, 146))	('CCN2', 'Gene', (39, 43))	('TSCCA', 'Disease', (93, 98))
369350	28208216	All these results indicated that MSC proliferation was not changed by knockdown of CCN2.	('MSC', 'Gene', '9242', (33, 36))	('knockdown', 'Var', (70, 79))	('CCN2', 'Gene', (83, 87))	('MSC', 'Gene', (33, 36))
369353	28208216	We further identified the silencing effects of CCN2 on the proliferation, migration and invasion of TSCC cells by knocking down CCN2 in MSC, and the results confirmed that CCN2 knockdown in MSC similarly reduced the proliferation, migration and invasion of TSCC cells.	('TSCC', 'Phenotype', 'HP:0030413', (100, 104))	('proliferation', 'CPA', (59, 72))	('invasion', 'CPA', (245, 253))	('MSC', 'Gene', '9242', (190, 193))	('invasion', 'CPA', (88, 96))	('MSC', 'Gene', (190, 193))	('migration', 'CPA', (231, 240))	('MSC', 'Gene', '9242', (136, 139))	('CCN2', 'Gene', (172, 176))	('CCN2', 'Gene', (128, 132))	('knockdown', 'Var', (177, 186))	('reduced', 'NegReg', (204, 211))	('knocking down', 'Var', (114, 127))	('migration', 'CPA', (74, 83))	('MSC', 'Gene', (136, 139))	('TSCC', 'Phenotype', 'HP:0030413', (257, 261))	('proliferation', 'CPA', (216, 229))
369381	24454720	 XRCC3 C18067T Polymorphism Contributes a Decreased Risk to Both Basal Cell Carcinoma and Squamous Cell Carcinoma: Evidence from a Meta-Analysis The X-ray repair cross-complementing group 3 (XRCC3) in homologous recombination repair (HRR) pathway plays a very important role in DNA double-strand break repair (DSBR).	('Basal Cell Carcinoma and Squamous Cell Carcinoma', 'Disease', 'MESH:D002294', (65, 113))	('XRCC3', 'Gene', '7517', (1, 6))	('XRCC3', 'Gene', (191, 196))	('C18067T', 'SUBSTITUTION', 'None', (7, 14))	('DSBR', 'Chemical', '-', (310, 314))	('XRCC3', 'Gene', '7517', (191, 196))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (90, 113))	('X-ray repair cross-complementing group 3', 'Gene', '7517', (149, 189))	('Decreased', 'NegReg', (42, 51))	('C18067T', 'Var', (7, 14))	('Carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('Carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('Basal Cell Carcinoma', 'Phenotype', 'HP:0002671', (65, 85))	('Polymorphism', 'Var', (15, 27))	('X-ray repair cross-complementing group 3', 'Gene', (149, 189))	('XRCC3', 'Gene', (1, 6))
369382	24454720	Variations in the XRCC3 gene might lead to altered protein structure or function which may change DSBR efficiency and result in cancer.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('result in', 'Reg', (118, 127))	('protein structure', 'MPA', (51, 68))	('cancer', 'Disease', (128, 134))	('XRCC3', 'Gene', (18, 23))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('Variations', 'Var', (0, 10))	('DSBR efficiency', 'CPA', (98, 113))	('function', 'MPA', (72, 80))	('XRCC3', 'Gene', '7517', (18, 23))	('lead', 'Reg', (35, 39))	('DSBR', 'Chemical', '-', (98, 102))	('altered', 'Reg', (43, 50))	('change', 'Reg', (91, 97))
369383	24454720	The XRCC3 C18067T polymorphism has been reported to be associated with skin cancer susceptibility, yet the results of these previous results have been inconsistent or controversial.	('skin cancer', 'Disease', 'MESH:D012878', (71, 82))	('associated', 'Reg', (55, 65))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('XRCC3', 'Gene', (4, 9))	('XRCC3', 'Gene', '7517', (4, 9))	('skin cancer', 'Phenotype', 'HP:0008069', (71, 82))	('C18067T', 'Mutation', 'rs861539', (10, 17))	('C18067T', 'Var', (10, 17))	('skin cancer', 'Disease', (71, 82))
369384	24454720	The association between the XRCC3 C18067T polymorphism and skin cancer risk was assessed by odds ratios (ORs) together with their 95% confidence intervals (CIs).	('skin cancer', 'Phenotype', 'HP:0008069', (59, 70))	('skin cancer', 'Disease', (59, 70))	('XRCC3', 'Gene', (28, 33))	('XRCC3', 'Gene', '7517', (28, 33))	('skin cancer', 'Disease', 'MESH:D012878', (59, 70))	('C18067T', 'Mutation', 'rs861539', (34, 41))	('C18067T', 'Var', (34, 41))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
369385	24454720	Overall, no significant association was observed between XRCC3 C18067T polymorphism and skin cancer risk in any genetic model.	('skin cancer', 'Disease', (88, 99))	('XRCC3', 'Gene', '7517', (57, 62))	('XRCC3', 'Gene', (57, 62))	('skin cancer', 'Disease', 'MESH:D012878', (88, 99))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('C18067T', 'Mutation', 'rs861539', (63, 70))	('C18067T', 'Var', (63, 70))	('skin cancer', 'Phenotype', 'HP:0008069', (88, 99))
369386	24454720	Stratified analyses according to tumor type, significant association was found in the relationship between XRCC3 C18067T polymorphism and nonmelanoma skin cancer risk (homozygote comparison TT versus CC: OR = 0.74, 95%CI = 0.61-0.90, P = 0.003; recessive model TT versus TC/CC: OR = 0.81, 95%CI = 0.68-0.95, P = 0.01).	('melanoma', 'Phenotype', 'HP:0002861', (141, 149))	('nonmelanoma skin cancer', 'Disease', (138, 161))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('nonmelanoma skin cancer', 'Disease', 'MESH:D012878', (138, 161))	('polymorphism', 'Var', (121, 133))	('C18067T', 'Mutation', 'rs861539', (113, 120))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('TC', 'Chemical', 'MESH:D013667', (271, 273))	('XRCC3', 'Gene', (107, 112))	('tumor', 'Disease', (33, 38))	('skin cancer', 'Phenotype', 'HP:0008069', (150, 161))	('XRCC3', 'Gene', '7517', (107, 112))	('C18067T polymorphism', 'Var', (113, 133))
369387	24454720	Furthermore, significant association was also observed in XRCC3 C18067T polymorphism with both basal cell carcinoma risk (homozygote comparison TT versus CC: OR = 0.70, 95%CI = 0.53-0.92, P = 0.011; recessive model TT versus.	('C18067T', 'Mutation', 'rs861539', (64, 71))	('C18067T', 'Var', (64, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('XRCC3', 'Gene', (58, 63))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (95, 115))	('basal cell carcinoma', 'Disease', 'MESH:D002280', (95, 115))	('basal cell carcinoma', 'Disease', (95, 115))	('XRCC3', 'Gene', '7517', (58, 63))
369389	24454720	The present meta-analysis demonstrates that XRCC3 C18067T polymorphism was not associated with risk of cutaneous melanoma but contributed a decreased risk to both basal cell carcinoma and squamous cell carcinoma.	('decreased', 'NegReg', (140, 149))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (163, 183))	('basal cell carcinoma', 'Disease', 'MESH:D002280', (163, 183))	('cutaneous melanoma', 'Disease', (103, 121))	('basal cell carcinoma', 'Disease', (163, 183))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (103, 121))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (103, 121))	('C18067T', 'Mutation', 'rs861539', (50, 57))	('C18067T', 'Var', (50, 57))	('XRCC3', 'Gene', (44, 49))	('XRCC3', 'Gene', '7517', (44, 49))	('melanoma', 'Phenotype', 'HP:0002861', (113, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (202, 211))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (188, 211))	('carcinoma', 'Phenotype', 'HP:0030731', (174, 183))	('squamous cell carcinoma', 'Disease', (188, 211))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (188, 211))
369397	24454720	Therefore, the DNA repair systems play an important role in maintaining the integrity of the genome and protecting against mutations that can lead to cancer, including skin cancer.	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('cancer', 'Disease', (173, 179))	('skin cancer', 'Phenotype', 'HP:0008069', (168, 179))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('skin cancer', 'Disease', (168, 179))	('skin cancer', 'Disease', 'MESH:D012878', (168, 179))	('cancer', 'Disease', (150, 156))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('mutations', 'Var', (123, 132))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
369401	24454720	The XRCC3 gene is located in human chromosomes 14q32.3 and various polymorphisms in this gene have been identified with susceptibility to cancers such as Thr241Met (C18067T, rs861539), 5-UTR (A4541G rs1799794) and IVERSUS 5-14 (A17893G, rs1799796).	('rs1799794', 'DBSNP_MENTION', 'None', (199, 208))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('rs1799794', 'Var', (199, 208))	('XRCC3', 'Gene', '7517', (4, 9))	('C18067T', 'Mutation', 'rs861539', (165, 172))	('rs861539', 'Mutation', 'rs861539', (174, 182))	('rs1799796', 'Mutation', 'rs1799796', (237, 246))	('rs861539', 'Var', (174, 182))	('A4541G', 'Var', (192, 198))	('A4541G', 'SUBSTITUTION', 'None', (192, 198))	('cancers', 'Disease', 'MESH:D009369', (138, 145))	('susceptibility', 'Reg', (120, 134))	('A17893G', 'Mutation', 'rs1799796', (228, 235))	('XRCC3', 'Gene', (4, 9))	('human', 'Species', '9606', (29, 34))	('C18067T', 'Var', (165, 172))	('A17893G', 'Var', (228, 235))	('rs1799796', 'Var', (237, 246))	('Thr241Met', 'Var', (154, 163))	('cancers', 'Phenotype', 'HP:0002664', (138, 145))	('cancers', 'Disease', (138, 145))	('Thr241Met', 'SUBSTITUTION', 'None', (154, 163))
369402	24454720	In the past decade, the majority of molecular epidemiologic studies investigated XRCC3 C18067T polymorphism on skin cancer susceptibility.	('skin cancer', 'Disease', 'MESH:D012878', (111, 122))	('XRCC3', 'Gene', (81, 86))	('XRCC3', 'Gene', '7517', (81, 86))	('skin cancer', 'Phenotype', 'HP:0008069', (111, 122))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('skin cancer', 'Disease', (111, 122))	('C18067T', 'Mutation', 'rs861539', (87, 94))	('C18067T', 'Var', (87, 94))
369403	24454720	To derive a more precise estimation of the relationship between XRCC3 C18067T polymorphism and skin cancer risk, we conducted a meta-analysis of all available case-control studies relating the XRCC3 C18067T polymorphism to the risk of developing skin cancer.	('skin cancer', 'Disease', (95, 106))	('skin cancer', 'Disease', (246, 257))	('XRCC3', 'Gene', (193, 198))	('skin cancer', 'Disease', 'MESH:D012878', (246, 257))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('skin cancer', 'Disease', 'MESH:D012878', (95, 106))	('XRCC3', 'Gene', '7517', (193, 198))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('XRCC3', 'Gene', (64, 69))	('C18067T', 'Mutation', 'rs861539', (199, 206))	('C18067T', 'Var', (199, 206))	('XRCC3', 'Gene', '7517', (64, 69))	('C18067T', 'Mutation', 'rs861539', (70, 77))	('skin cancer', 'Phenotype', 'HP:0008069', (95, 106))	('skin cancer', 'Phenotype', 'HP:0008069', (246, 257))
369404	24454720	We performed a comprehensive literature search in PubMed, EMBASE and Chinese Biomedical Literature Database (CBM) using the terms as follows: "X-ray repair cross-complementing group 3 or XRCC3 or DSBR" in combination with "polymorphism or variant or mutation" and in combination with "Skin cancer" updated on July 2013 for all publications on the association between XRCC3 C18067T polymorphism and skin cancer risk.	('C18067T polymorphism', 'Var', (373, 393))	('XRCC3', 'Gene', (187, 192))	('Skin cancer', 'Disease', 'MESH:D012878', (285, 296))	('XRCC3', 'Gene', '7517', (187, 192))	('skin cancer', 'Phenotype', 'HP:0008069', (398, 409))	('association', 'Interaction', (347, 358))	('X-ray repair cross-complementing group 3', 'Gene', '7517', (143, 183))	('X-ray repair cross-complementing group 3', 'Gene', (143, 183))	('skin cancer', 'Disease', (398, 409))	('C18067T', 'Mutation', 'rs861539', (373, 380))	('cancer', 'Phenotype', 'HP:0002664', (403, 409))	('XRCC3', 'Gene', (367, 372))	('XRCC3', 'Gene', '7517', (367, 372))	('Skin cancer', 'Disease', (285, 296))	('skin cancer', 'Disease', 'MESH:D012878', (398, 409))	('cancer', 'Phenotype', 'HP:0002664', (290, 296))	('DSBR', 'Chemical', '-', (196, 200))	('Skin cancer', 'Phenotype', 'HP:0008069', (285, 296))
369405	24454720	The following inclusion criteria were used for the paper selection: (a) a case-control study; (b) information on the relationship between XRCC3 C18067T polymorphisms and skin cancer risk; (c) the papers had to provide the size of the samples, distribution of alleles, genotypes or other information that can help us infer the results; (d) Of the studies with overlapping data published by the same investigators, we chose the most recent or complete study was included.	('skin cancer', 'Disease', (170, 181))	('XRCC3', 'Gene', (138, 143))	('skin cancer', 'Disease', 'MESH:D012878', (170, 181))	('C18067T polymorphisms', 'Var', (144, 165))	('C18067T', 'Mutation', 'rs861539', (144, 151))	('XRCC3', 'Gene', '7517', (138, 143))	('skin cancer', 'Phenotype', 'HP:0008069', (170, 181))	('polymorphisms', 'Var', (152, 165))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
369408	24454720	After screening the titles and abstracts, 10 studies were excluded because they were not relevant to the role of XRCC3 C18067T polymorphism on skin cancer risk.	('skin cancer', 'Phenotype', 'HP:0008069', (143, 154))	('skin cancer', 'Disease', (143, 154))	('XRCC3', 'Gene', (113, 118))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('C18067T', 'Mutation', 'rs861539', (119, 126))	('C18067T', 'Var', (119, 126))	('skin cancer', 'Disease', 'MESH:D012878', (143, 154))	('XRCC3', 'Gene', '7517', (113, 118))
369411	24454720	All the genotype distributions of control population were consistent with HWE for XRCC3 C18067T polymorphism.	('XRCC3', 'Gene', '7517', (82, 87))	('XRCC3', 'Gene', (82, 87))	('C18067T', 'Mutation', 'rs861539', (88, 95))	('C18067T', 'Var', (88, 95))
369412	24454720	Forest plot of skin cancer risk associated with XRCC3 C18067T polymorphism is shown under homozygote comparison (TT versus CC) in Figure 2 and receive model (TT versus TC/CC) in Figure 3.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('skin cancer', 'Disease', (15, 26))	('skin cancer', 'Disease', 'MESH:D012878', (15, 26))	('C18067T', 'Mutation', 'rs861539', (54, 61))	('C18067T', 'Var', (54, 61))	('TC', 'Chemical', 'MESH:D013667', (168, 170))	('XRCC3', 'Gene', (48, 53))	('XRCC3', 'Gene', '7517', (48, 53))	('skin cancer', 'Phenotype', 'HP:0008069', (15, 26))
369413	24454720	The meta-analysis showed insignificant association between skin cancer and XRCC3 C18067T polymorphism in the overall population.	('XRCC3', 'Gene', (75, 80))	('skin cancer', 'Phenotype', 'HP:0008069', (59, 70))	('C18067T', 'Mutation', 'rs861539', (81, 88))	('C18067T', 'Var', (81, 88))	('skin cancer', 'Disease', (59, 70))	('XRCC3', 'Gene', '7517', (75, 80))	('skin cancer', 'Disease', 'MESH:D012878', (59, 70))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
369414	24454720	In the stratified analysis by tumor type, the present meta-analysis showed that the C18067T polymorphism was associated with decreased nomelanoma risk (homozygote comparison TT versus.	('decreased nomelanoma', 'Disease', (125, 145))	('C18067T', 'Mutation', 'rs861539', (84, 91))	('C18067T', 'Var', (84, 91))	('decreased nomelanoma', 'Disease', 'MESH:D012021', (125, 145))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('melanoma', 'Phenotype', 'HP:0002861', (137, 145))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('tumor', 'Disease', (30, 35))
369416	24454720	Further subgroup analysis by subtype of nonmelanoma, we found that the XRCC3 C18067T polymorphism contributed decreased risk to not only basal cell carcinoma (homozygote comparison TT versus.	('nonmelanoma', 'Disease', (40, 51))	('XRCC3', 'Gene', (71, 76))	('C18067T', 'Mutation', 'rs861539', (77, 84))	('C18067T', 'Var', (77, 84))	('XRCC3', 'Gene', '7517', (71, 76))	('melanoma', 'Phenotype', 'HP:0002861', (43, 51))	('decreased', 'NegReg', (110, 119))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (137, 157))	('basal cell carcinoma', 'Disease', 'MESH:D002280', (137, 157))	('basal cell carcinoma', 'Disease', (137, 157))	('nonmelanoma', 'Disease', 'None', (40, 51))	('carcinoma', 'Phenotype', 'HP:0030731', (148, 157))
369425	24454720	The significance of the summary ORs for XRCC3 C18067T polymorphism in different comparison models in subgroup analyses were not influenced by omitting the two studies.	('XRCC3', 'Gene', (40, 45))	('XRCC3', 'Gene', '7517', (40, 45))	('C18067T', 'Mutation', 'rs861539', (46, 53))	('C18067T', 'Var', (46, 53))
369426	24454720	Funnel plot of skin cancer risk associated with XRCC3 C18067T polymorphism is shown in Figure 8.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('skin cancer', 'Disease', (15, 26))	('skin cancer', 'Disease', 'MESH:D012878', (15, 26))	('C18067T', 'Mutation', 'rs861539', (54, 61))	('C18067T', 'Var', (54, 61))	('XRCC3', 'Gene', (48, 53))	('XRCC3', 'Gene', '7517', (48, 53))	('skin cancer', 'Phenotype', 'HP:0008069', (15, 26))
369435	24454720	Matullo et al have demonstrated that the XRCC3 C18067T polymorphism was associated with DNA repair capacity, which made it well-founded to hypothesize that XRCC3 C18067T polymorphism may be associated with cancer risk.	('DNA repair capacity', 'MPA', (88, 107))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('XRCC3', 'Gene', (156, 161))	('XRCC3', 'Gene', '7517', (156, 161))	('associated', 'Reg', (72, 82))	('C18067T', 'Mutation', 'rs861539', (47, 54))	('C18067T', 'Var', (47, 54))	('associated', 'Reg', (190, 200))	('XRCC3', 'Gene', (41, 46))	('cancer', 'Disease', (206, 212))	('cancer', 'Disease', 'MESH:D009369', (206, 212))	('XRCC3', 'Gene', '7517', (41, 46))	('C18067T', 'Mutation', 'rs861539', (162, 169))	('C18067T', 'Var', (162, 169))
369436	24454720	Up to now, a lot of studies have been conducted to investigate the relationship between XRCC3 C18067T polymorphism and skin cancer risk.	('XRCC3', 'Gene', (88, 93))	('skin cancer', 'Phenotype', 'HP:0008069', (119, 130))	('XRCC3', 'Gene', '7517', (88, 93))	('skin cancer', 'Disease', (119, 130))	('skin cancer', 'Disease', 'MESH:D012878', (119, 130))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('C18067T', 'Mutation', 'rs861539', (94, 101))	('C18067T', 'Var', (94, 101))
369437	24454720	Unfortunately, so far there has not yet a report which comprehensively and specially evaluates all of the previous literature to get a precious estimate of this association between XRCC3 C18067T polymorphism and skin cancer risk.	('C18067T', 'Mutation', 'rs861539', (187, 194))	('C18067T', 'Var', (187, 194))	('skin cancer', 'Phenotype', 'HP:0008069', (212, 223))	('skin cancer', 'Disease', (212, 223))	('XRCC3', 'Gene', (181, 186))	('skin cancer', 'Disease', 'MESH:D012878', (212, 223))	('XRCC3', 'Gene', '7517', (181, 186))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))
369439	24454720	To the best of our knowledge, no meta-analysis specially evaluating on the association between the XRCC3 C18067T polymorphism and skin cancer risk has been performed, and the present meta-analysis is the first study on such an association.	('skin cancer', 'Disease', (130, 141))	('skin cancer', 'Disease', 'MESH:D012878', (130, 141))	('C18067T', 'Mutation', 'rs861539', (105, 112))	('C18067T', 'Var', (105, 112))	('XRCC3', 'Gene', (99, 104))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('XRCC3', 'Gene', '7517', (99, 104))	('skin cancer', 'Phenotype', 'HP:0008069', (130, 141))
369440	24454720	So far, plenty of studies have evaluated the XRCC3 C18067T polymorphism with cancers risk, including colorectal, bladder, lung, breast, pancreatic cancer and so on.	('pancreatic cancer', 'Disease', 'MESH:D010190', (136, 153))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('cancers', 'Disease', 'MESH:D009369', (77, 84))	('cancers', 'Phenotype', 'HP:0002664', (77, 84))	('XRCC3', 'Gene', '7517', (45, 50))	('cancers', 'Disease', (77, 84))	('colorectal', 'Disease', (101, 111))	('bladder', 'Disease', (113, 120))	('breast', 'Disease', (128, 134))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (136, 153))	('lung', 'Disease', (122, 126))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('C18067T', 'Mutation', 'rs861539', (51, 58))	('C18067T', 'Var', (51, 58))	('XRCC3', 'Gene', (45, 50))	('pancreatic cancer', 'Disease', (136, 153))
369441	24454720	And a few meta-analyses have been conducted on XRCC3 C18067T polymorphism and cancers risk, including colorectal cancer, lung cancer, bladder cancer, and breast cancer.	('lung cancer', 'Disease', 'MESH:D008175', (121, 132))	('C18067T', 'Mutation', 'rs861539', (53, 60))	('cancers', 'Disease', 'MESH:D009369', (78, 85))	('lung cancer', 'Phenotype', 'HP:0100526', (121, 132))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('XRCC3', 'Gene', (47, 52))	('bladder cancer', 'Disease', 'MESH:D001749', (134, 148))	('bladder cancer', 'Disease', (134, 148))	('colorectal cancer', 'Disease', 'MESH:D015179', (102, 119))	('bladder cancer', 'Phenotype', 'HP:0009725', (134, 148))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('colorectal cancer', 'Disease', (102, 119))	('C18067T', 'Var', (53, 60))	('breast cancer', 'Phenotype', 'HP:0003002', (154, 167))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('cancers', 'Phenotype', 'HP:0002664', (78, 85))	('lung cancer', 'Disease', (121, 132))	('cancers', 'Disease', (78, 85))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('breast cancer', 'Disease', 'MESH:D001943', (154, 167))	('breast cancer', 'Disease', (154, 167))	('XRCC3', 'Gene', '7517', (47, 52))	('colorectal cancer', 'Phenotype', 'HP:0003003', (102, 119))
369442	24454720	Our study was carried out to investigate the association between XRCC3 C18067T polymorphism and skin cancer risk.	('C18067T', 'Mutation', 'rs861539', (71, 78))	('C18067T', 'Var', (71, 78))	('skin cancer', 'Phenotype', 'HP:0008069', (96, 107))	('skin cancer', 'Disease', (96, 107))	('XRCC3', 'Gene', (65, 70))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('XRCC3', 'Gene', '7517', (65, 70))	('skin cancer', 'Disease', 'MESH:D012878', (96, 107))
369443	24454720	Different results derived from previous meta-analysis which focused on relationship between XRCC3 Thr241Met polymorphism with cancers risk.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('Thr241Met', 'Var', (98, 107))	('XRCC3', 'Gene', '7517', (92, 97))	('XRCC3', 'Gene', (92, 97))	('cancers', 'Phenotype', 'HP:0002664', (126, 133))	('cancers', 'Disease', (126, 133))	('cancers', 'Disease', 'MESH:D009369', (126, 133))	('Thr241Met', 'SUBSTITUTION', 'None', (98, 107))
369444	24454720	This phenomenon indicates that the XRCC3 C18067T polymorphism exerts different effect on various types of cancers.	('cancers', 'Phenotype', 'HP:0002664', (106, 113))	('cancers', 'Disease', (106, 113))	('C18067T', 'Mutation', 'rs861539', (41, 48))	('cancers', 'Disease', 'MESH:D009369', (106, 113))	('C18067T', 'Var', (41, 48))	('XRCC3', 'Gene', (35, 40))	('XRCC3', 'Gene', '7517', (35, 40))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
369445	24454720	So that it is necessary to get a better understanding of XRCC3 C18067T polymorphism on skin cancer risk, especially when inclusive and controversial findings still exists.	('skin cancer', 'Disease', (87, 98))	('XRCC3', 'Gene', '7517', (57, 62))	('XRCC3', 'Gene', (57, 62))	('skin cancer', 'Phenotype', 'HP:0008069', (87, 98))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('C18067T', 'Mutation', 'rs861539', (63, 70))	('C18067T', 'Var', (63, 70))	('skin cancer', 'Disease', 'MESH:D012878', (87, 98))
369446	24454720	The present meta-analysis was carried out by critically reviewing 15 individual case-control studies on XRCC3 C18067T polymorphism and skin cancer risk.	('XRCC3', 'Gene', (104, 109))	('skin cancer', 'Disease', 'MESH:D012878', (135, 146))	('C18067T polymorphism', 'Var', (110, 130))	('skin cancer', 'Phenotype', 'HP:0008069', (135, 146))	('XRCC3', 'Gene', '7517', (104, 109))	('C18067T', 'Mutation', 'rs861539', (110, 117))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('skin cancer', 'Disease', (135, 146))
369447	24454720	Our meta-analysis showed XRCC3 C18067T polymorphism was not associated with risk of skin cancer.	('skin cancer', 'Disease', (84, 95))	('skin cancer', 'Phenotype', 'HP:0008069', (84, 95))	('skin cancer', 'Disease', 'MESH:D012878', (84, 95))	('XRCC3', 'Gene', '7517', (25, 30))	('C18067T', 'Mutation', 'rs861539', (31, 38))	('C18067T', 'Var', (31, 38))	('XRCC3', 'Gene', (25, 30))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
369448	24454720	Subgroup analysis based on tumor type indicated that XRCC3 C18067T polymorphism was not associated with risk of cutaneous melanomas but with decreased risk of nonmelanoma skin cancer.	('XRCC3', 'Gene', '7517', (53, 58))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('cutaneous melanomas', 'Disease', (112, 131))	('nonmelanoma skin cancer', 'Disease', (159, 182))	('tumor', 'Disease', (27, 32))	('skin cancer', 'Phenotype', 'HP:0008069', (171, 182))	('C18067T', 'Mutation', 'rs861539', (59, 66))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('XRCC3', 'Gene', (53, 58))	('decreased', 'NegReg', (141, 150))	('melanomas', 'Phenotype', 'HP:0002861', (122, 131))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('melanoma', 'Phenotype', 'HP:0002861', (162, 170))	('nonmelanoma skin cancer', 'Disease', 'MESH:D012878', (159, 182))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (112, 131))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (112, 131))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (112, 130))	('melanoma', 'Phenotype', 'HP:0002861', (122, 130))	('C18067T', 'Var', (59, 66))
369450	24454720	As a result, we found that XRCC3 C18067T polymorphism was associated with decreased risk of both basal cell carcinoma and squamous cell carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('C18067T', 'Mutation', 'rs861539', (33, 40))	('C18067T', 'Var', (33, 40))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (97, 117))	('basal cell carcinoma', 'Disease', 'MESH:D002280', (97, 117))	('basal cell carcinoma', 'Disease', (97, 117))	('XRCC3', 'Gene', (27, 32))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (122, 145))	('decreased', 'NegReg', (74, 83))	('squamous cell carcinoma', 'Disease', (122, 145))	('XRCC3', 'Gene', '7517', (27, 32))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (122, 145))
369451	24454720	Its conclusion showed no significant association between XRCC3 C18067T polymorphism and cutaneous melanomas, which was consistent with our pooled conclusion.	('cutaneous melanomas', 'Disease', (88, 107))	('XRCC3', 'Gene', '7517', (57, 62))	('XRCC3', 'Gene', (57, 62))	('melanomas', 'Phenotype', 'HP:0002861', (98, 107))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (88, 106))	('melanoma', 'Phenotype', 'HP:0002861', (98, 106))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (88, 107))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (88, 107))	('C18067T', 'Mutation', 'rs861539', (63, 70))	('C18067T', 'Var', (63, 70))
369452	24454720	It seems that selection bias may occur if the genotype distribution of XRCC3 C18067T polymorphism among control populations disobeyed the law of HWE.	('C18067T', 'Var', (77, 84))	('XRCC3', 'Gene', '7517', (71, 76))	('XRCC3', 'Gene', (71, 76))	('C18067T', 'Mutation', 'rs861539', (77, 84))
369456	24454720	Although comprehensive analysis was conducted to show the association between XRCC3 C18067T polymorphism and risk of skin cancer, there are still some limitations should be pointed out.	('C18067T', 'Mutation', 'rs861539', (84, 91))	('C18067T', 'Var', (84, 91))	('association', 'Interaction', (58, 69))	('XRCC3', 'Gene', '7517', (78, 83))	('XRCC3', 'Gene', (78, 83))	('skin cancer', 'Phenotype', 'HP:0008069', (117, 128))	('skin cancer', 'Disease', (117, 128))	('skin cancer', 'Disease', 'MESH:D012878', (117, 128))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))
369457	24454720	In spite of the shortages above, our meta-analysis had also several advantages as follows: First, a meta-analysis of the association of XRCC3 C18067T polymorphism on skin cancer risk is statistically more powerful than any other single study.	('skin cancer', 'Disease', 'MESH:D012878', (166, 177))	('association', 'Interaction', (121, 132))	('XRCC3', 'Gene', (136, 141))	('XRCC3', 'Gene', '7517', (136, 141))	('skin cancer', 'Phenotype', 'HP:0008069', (166, 177))	('C18067T', 'Var', (142, 149))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('C18067T', 'Mutation', 'rs861539', (142, 149))	('skin cancer', 'Disease', (166, 177))
369458	24454720	In summary, this meta-analysis systematically analyzed the association between XRCC3 C18067T polymorphism and the risk of skin cancer.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('skin cancer', 'Phenotype', 'HP:0008069', (122, 133))	('skin cancer', 'Disease', (122, 133))	('C18067T', 'Mutation', 'rs861539', (85, 92))	('C18067T', 'Var', (85, 92))	('XRCC3', 'Gene', (79, 84))	('skin cancer', 'Disease', 'MESH:D012878', (122, 133))	('XRCC3', 'Gene', '7517', (79, 84))
369459	24454720	The pooled results suggest that the XRCC3 C18067T polymorphism was not associated with risk of cutaneous melanoma but contributed a decreased risk to nonmelanoma skin cancer including basal cell carcinoma and squamous cell carcinoma.	('melanoma', 'Phenotype', 'HP:0002861', (153, 161))	('basal cell carcinoma', 'Disease', (184, 204))	('C18067T', 'Var', (42, 49))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('squamous cell carcinoma', 'Disease', (209, 232))	('cutaneous melanoma', 'Disease', (95, 113))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (95, 113))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (95, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (223, 232))	('XRCC3', 'Gene', '7517', (36, 41))	('nonmelanoma skin cancer', 'Disease', (150, 173))	('skin cancer', 'Phenotype', 'HP:0008069', (162, 173))	('basal cell carcinoma', 'Disease', 'MESH:D002280', (184, 204))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (209, 232))	('C18067T', 'Mutation', 'rs861539', (42, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (195, 204))	('XRCC3', 'Gene', (36, 41))	('melanoma', 'Phenotype', 'HP:0002861', (105, 113))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (184, 204))	('decreased', 'NegReg', (132, 141))	('nonmelanoma skin cancer', 'Disease', 'MESH:D012878', (150, 173))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (209, 232))
369462	33026449	In this randomized clinical trial that included 127 patients 70 years or older with esophageal squamous cell carcinoma, patients treated with icotinib plus radiotherapy had a median overall survival of 24.0 months, whereas those treated with radiotherapy alone had a median overall survival of 16.3 months.	('esophageal squamous cell carcinoma', 'Disease', (84, 118))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (95, 118))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (84, 118))	('icotinib', 'Var', (142, 150))	('icotinib', 'Chemical', 'MESH:C531470', (142, 150))	('patients', 'Species', '9606', (120, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('patients', 'Species', '9606', (52, 60))
369468	33026449	Patients aged 70 years or older with clinical stage T2 to T4, N0/1, M0/1a unresectable (because of comorbidities, T4 disease, unresectable lymph node, or refused surgery) ESCC were randomized 1:1 to receive RT plus icotinib or RT alone.	('M0/1a', 'Var', (68, 73))	('icotinib', 'Chemical', 'MESH:C531470', (215, 223))	('age', 'Gene', '5973', (9, 12))	('age', 'Gene', (48, 51))	('Patients', 'Species', '9606', (0, 8))	('age', 'Gene', (9, 12))	('age', 'Gene', '5973', (48, 51))
369592	33026449	The response rate was higher (17.6% vs 0%, P = .34) for patients with high EGFR-expressing tumors.	('tumors', 'Disease', (91, 97))	('tumors', 'Disease', 'MESH:D009369', (91, 97))	('patients', 'Species', '9606', (56, 64))	('higher', 'PosReg', (22, 28))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('EGFR', 'Gene', '1956', (75, 79))	('response', 'MPA', (4, 12))	('high', 'Var', (70, 74))	('EGFR', 'Gene', (75, 79))
369594	33026449	Another study suggested that EGFR amplification appears to identify a subgroup of patients with esophageal cancer who may benefit from gefitinib.	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('patients', 'Species', '9606', (82, 90))	('esophageal cancer', 'Disease', (96, 113))	('gefitinib', 'Chemical', 'MESH:D000077156', (135, 144))	('EGFR', 'Gene', '1956', (29, 33))	('esophageal cancer', 'Disease', 'MESH:D004938', (96, 113))	('EGFR', 'Gene', (29, 33))	('amplification', 'Var', (34, 47))
369606	30816443	A recent study demonstrated that ZNF692 is overexpressed in lung adenocarcinoma (LUAD) tissues and that ZNF692 knockdown inhibited LUAD cell proliferation, migration, and invasion both in vitro and in vivo.	('LUAD', 'Phenotype', 'HP:0030078', (81, 85))	('knockdown', 'Var', (111, 120))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (60, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('ZNF692', 'Gene', (33, 39))	('invasion', 'CPA', (171, 179))	('migration', 'CPA', (156, 165))	('LUAD', 'Phenotype', 'HP:0030078', (131, 135))	('lung adenocarcinoma', 'Disease', (60, 79))	('ZNF692', 'Gene', '55657', (104, 110))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (60, 79))	('inhibited', 'NegReg', (121, 130))	('LUAD cell proliferation', 'CPA', (131, 154))	('ZNF692', 'Gene', (104, 110))	('ZNF692', 'Gene', '55657', (33, 39))
369608	30816443	The present study revealed that ZNF692 was upregulated in COAD tissues and cells and that high ZNF692 expression was significantly correlated with lymph node metastasis, distant metastasis and tumor stage in COAD patients.	('distant metastasis', 'CPA', (170, 188))	('ZNF692', 'Gene', '55657', (32, 38))	('correlated', 'Reg', (131, 141))	('upregulated', 'PosReg', (43, 54))	('ZNF692', 'Gene', (32, 38))	('ZNF692', 'Gene', '55657', (95, 101))	('expression', 'MPA', (102, 112))	('ZNF692', 'Gene', (95, 101))	('COAD', 'Disease', 'MESH:D029424', (208, 212))	('tumor', 'Disease', (193, 198))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('high', 'Var', (90, 94))	('COAD', 'Disease', (58, 62))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('COAD', 'Disease', 'MESH:D029424', (58, 62))	('patients', 'Species', '9606', (213, 221))	('lymph node metastasis', 'CPA', (147, 168))	('COAD', 'Disease', (208, 212))
369627	30816443	High ZNF692 expression was correlated with lymph node metastasis, distant metastasis and tumor stage in patients with COAD.	('ZNF692', 'Gene', '55657', (5, 11))	('High', 'Var', (0, 4))	('ZNF692', 'Gene', (5, 11))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('COAD', 'Disease', 'MESH:D029424', (118, 122))	('expression', 'MPA', (12, 22))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('lymph node metastasis', 'CPA', (43, 64))	('distant metastasis', 'CPA', (66, 84))	('COAD', 'Disease', (118, 122))	('correlated', 'Reg', (27, 37))	('patients', 'Species', '9606', (104, 112))	('tumor', 'Disease', (89, 94))
369628	30816443	In addition, ZNF692 knockdown attenuated cell proliferation, migration and invasion in vitro and in vivo; conversely, ZNF692 upregulation produced the opposite effects.	('upregulation', 'PosReg', (125, 137))	('invasion', 'CPA', (75, 83))	('ZNF692', 'Gene', '55657', (13, 19))	('cell proliferation', 'CPA', (41, 59))	('ZNF692', 'Gene', (13, 19))	('migration', 'CPA', (61, 70))	('knockdown', 'Var', (20, 29))	('ZNF692', 'Gene', '55657', (118, 124))	('attenuated', 'NegReg', (30, 40))	('ZNF692', 'Gene', (118, 124))
369629	30816443	Flow cytometric analysis revealed that ZNF692 knockdown induced G1-phase cell cycle arrest in COAD cells, whereas ZNF692 overexpression promoted G1/S phase transition.	('ZNF692', 'Gene', (114, 120))	('knockdown', 'Var', (46, 55))	('ZNF692', 'Gene', (39, 45))	('G1-phase cell cycle arrest', 'CPA', (64, 90))	('promoted', 'PosReg', (136, 144))	('G1/S phase transition', 'CPA', (145, 166))	('COAD', 'Disease', (94, 98))	('ZNF692', 'Gene', '55657', (114, 120))	('COAD', 'Disease', 'MESH:D029424', (94, 98))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (73, 90))	('ZNF692', 'Gene', '55657', (39, 45))
369631	30816443	The PI3K/AKT inhibitor LY294002 markedly reversed ZNF692-induced cyclin D1 and MMP-9 expression.	('expression', 'MPA', (85, 95))	('cyclin D1', 'Gene', (65, 74))	('MMP-9', 'Gene', (79, 84))	('AKT', 'Gene', '207', (9, 12))	('MMP-9', 'Gene', '4318', (79, 84))	('ZNF692', 'Gene', (50, 56))	('LY294002', 'Chemical', 'MESH:C085911', (23, 31))	('AKT', 'Gene', (9, 12))	('LY294002', 'Var', (23, 31))	('cyclin D1', 'Gene', '595', (65, 74))	('ZNF692', 'Gene', '55657', (50, 56))
369717	30816443	The results of these assays demonstrated that ZNF692 knockdown cells displayed reduced viability and colony formation efficiency (P<0.01; Fig.	('ZNF692', 'Gene', '55657', (46, 52))	('ZNF692', 'Gene', (46, 52))	('reduced', 'NegReg', (79, 86))	('knockdown', 'Var', (53, 62))	('viability', 'CPA', (87, 96))	('colony formation efficiency', 'CPA', (101, 128))
369719	30816443	2G, ZNF692 silencing resulted in G1 arrest in COAD cells (P<0.05).	('silencing', 'Var', (11, 20))	('COAD', 'Disease', 'MESH:D029424', (46, 50))	('COAD', 'Disease', (46, 50))	('ZNF692', 'Gene', '55657', (4, 10))	('ZNF692', 'Gene', (4, 10))	('G1 arrest', 'CPA', (33, 42))
369721	30816443	The results demonstrated that ZNF692 knockdown decreased the migration of DLD-1 (P<0.05) and LoVo cells (P<0.01) compared with the control group (Fig.	('ZNF692', 'Gene', '55657', (30, 36))	('LoVo', 'CellLine', 'CVCL:0399', (93, 97))	('knockdown', 'Var', (37, 46))	('ZNF692', 'Gene', (30, 36))	('migration', 'CPA', (61, 70))	('decreased', 'NegReg', (47, 56))
369723	30816443	Having confirmed the inhibitory effects of ZNF692 knockdown in COAD cells, HCT116 cells, which exhibit low levels of ZNF692 (Fig.	('HCT116', 'CellLine', 'CVCL:0291', (75, 81))	('ZNF692', 'Gene', '55657', (43, 49))	('ZNF692', 'Gene', (43, 49))	('COAD', 'Disease', (63, 67))	('knockdown', 'Var', (50, 59))	('ZNF692', 'Gene', '55657', (117, 123))	('ZNF692', 'Gene', (117, 123))	('COAD', 'Disease', 'MESH:D029424', (63, 67))
369732	30816443	Quantification of the tumor weights and volumes also demonstrated that the Lv-NC group tumors were significantly larger compared with the sh-ZNF692 #1 group (P<0.01; Fig.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('tumor', 'Disease', (87, 92))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('Lv-NC', 'Var', (75, 80))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('larger', 'PosReg', (113, 119))	('tumor', 'Disease', (22, 27))	('tumors', 'Disease', (87, 93))	('ZNF692', 'Gene', (141, 147))	('ZNF692', 'Gene', '55657', (141, 147))	('tumors', 'Disease', 'MESH:D009369', (87, 93))
369735	30816443	According to IHC analysis, ZNF692 knockdown significantly decreased the expression of the cell proliferation marker Ki-67 (Fig.	('ZNF692', 'Gene', (27, 33))	('decreased', 'NegReg', (58, 67))	('cell proliferation', 'CPA', (90, 108))	('expression', 'MPA', (72, 82))	('ZNF692', 'Gene', '55657', (27, 33))	('knockdown', 'Var', (34, 43))	('Ki-67', 'Protein', (116, 121))
369737	30816443	6A-D, ZNF692 knockdown decreased AKT phosphorylation in DLD-1 (P<0.05) and LoVo (P<0.01) cells, but the opposite results were obtained when ZNF692 was upregulated in HCT116 cells (P<0.01).	('ZNF692', 'Gene', '55657', (140, 146))	('HCT116', 'CellLine', 'CVCL:0291', (166, 172))	('AKT', 'Gene', '207', (33, 36))	('ZNF692', 'Gene', (140, 146))	('ZNF692', 'Gene', '55657', (6, 12))	('knockdown', 'Var', (13, 22))	('ZNF692', 'Gene', (6, 12))	('LoVo', 'CellLine', 'CVCL:0399', (75, 79))	('AKT', 'Gene', (33, 36))	('decreased', 'NegReg', (23, 32))
369743	30816443	6E, cyclin D1 and MMP-9 expression induced by ectopic ZNF692 expression was significantly reversed following treatment of HCT116 cells with LY294002 (20 microM).	('HCT116', 'CellLine', 'CVCL:0291', (122, 128))	('MMP-9', 'Gene', '4318', (18, 23))	('ectopic', 'Var', (46, 53))	('ZNF692', 'Gene', '55657', (54, 60))	('MMP-9', 'Gene', (18, 23))	('ZNF692', 'Gene', (54, 60))	('expression', 'Var', (61, 71))	('LY294002', 'Chemical', 'MESH:C085911', (140, 148))	('cyclin D1', 'Gene', '595', (4, 13))	('cyclin D1', 'Gene', (4, 13))
369765	30816443	The current western blot results indicated that ZNF692 silencing significantly increased the expression of p27Kip1.	('increased', 'PosReg', (79, 88))	('silencing', 'Var', (55, 64))	('ZNF692', 'Gene', '55657', (48, 54))	('p27Kip1', 'Gene', '1027', (107, 114))	('expression', 'MPA', (93, 103))	('ZNF692', 'Gene', (48, 54))	('p27Kip1', 'Gene', (107, 114))
369769	30816443	PI3K transduces various signals, such as growth factors and cytokines, from the extracellular matrix (ECM) into the intracellular environment, which in turn results in the phosphorylation of AKT.	('PI3K', 'Var', (0, 4))	('AKT', 'Gene', '207', (191, 194))	('phosphorylation', 'MPA', (172, 187))	('AKT', 'Gene', (191, 194))	('results in', 'Reg', (157, 167))
369775	30816443	This hypothesis was also supported by the addition of LY294002, which dramatically reversed the ZNF692-induced cyclin D1 expression.	('cyclin D1', 'Gene', (111, 120))	('LY294002', 'Chemical', 'MESH:C085911', (54, 62))	('expression', 'MPA', (121, 131))	('ZNF692', 'Gene', '55657', (96, 102))	('LY294002', 'Var', (54, 62))	('ZNF692', 'Gene', (96, 102))	('cyclin D1', 'Gene', '595', (111, 120))
369784	30816443	To decipher the molecular mechanism through which ZNF692 contributes to cell migration and invasion, the MMP-9 protein expression levels were analyzed by western blotting, in the presence or absence of LY294002.	('LY294002', 'Var', (202, 210))	('contributes', 'Reg', (57, 68))	('ZNF692', 'Gene', (50, 56))	('invasion', 'CPA', (91, 99))	('cell migration', 'CPA', (72, 86))	('LY294002', 'Chemical', 'MESH:C085911', (202, 210))	('MMP-9', 'Gene', '4318', (105, 110))	('MMP-9', 'Gene', (105, 110))	('ZNF692', 'Gene', '55657', (50, 56))
369788	30816443	In summary, the present findings revealed that ZNF692 expression is significantly upregulated in COAD tissues and cell lines and that high ZNF692 expression is significantly associated with lymph node metastasis, distant metastasis and tumor stage.	('expression', 'MPA', (54, 64))	('ZNF692', 'Gene', (139, 145))	('COAD', 'Disease', 'MESH:D029424', (97, 101))	('associated with', 'Reg', (174, 189))	('ZNF692', 'Gene', '55657', (47, 53))	('ZNF692', 'Gene', (47, 53))	('lymph node metastasis', 'CPA', (190, 211))	('high', 'Var', (134, 138))	('upregulated', 'PosReg', (82, 93))	('tumor', 'Disease', 'MESH:D009369', (236, 241))	('COAD', 'Disease', (97, 101))	('tumor', 'Phenotype', 'HP:0002664', (236, 241))	('distant metastasis', 'CPA', (213, 231))	('ZNF692', 'Gene', '55657', (139, 145))	('expression', 'MPA', (146, 156))	('tumor', 'Disease', (236, 241))
369801	30375717	Interestingly, high expression of NCS1 predicted a significantly poorer prognosis in patients with LUSQ (overall survival, P = 0.013; disease-free survival, P = 0.048).	('high expression', 'Var', (15, 30))	('NCS1', 'Gene', (34, 38))	('LUSQ', 'Phenotype', 'HP:0030359', (99, 103))	('poorer', 'NegReg', (65, 71))	('LUSQ', 'Chemical', '-', (99, 103))	('LUSQ', 'Disease', (99, 103))	('patients', 'Species', '9606', (85, 93))
369803	30375717	Overexpression of NCS1 was detected in LUSQ clinical specimens, and its aberrant expression enhanced malignant transformation of LUSQ cells.	('LUSQ', 'Chemical', '-', (39, 43))	('LUSQ', 'Phenotype', 'HP:0030359', (39, 43))	('LUSQ', 'Chemical', '-', (129, 133))	('NCS1', 'Gene', (18, 22))	('malignant transformation of LUSQ cells', 'CPA', (101, 139))	('aberrant expression', 'Var', (72, 91))	('LUSQ', 'Phenotype', 'HP:0030359', (129, 133))	('men', 'Species', '9606', (58, 61))	('enhanced', 'PosReg', (92, 100))
369852	30375717	The TCGA database analysis showed that high NCS1 expression significantly predicted a poor prognosis in patients with LUSQ (5-year OS, P = 0.013; 5-year DFS, P = 0.048; Figure 4A).	('LUSQ', 'Phenotype', 'HP:0030359', (118, 122))	('high', 'Var', (39, 43))	('LUSQ', 'Disease', (118, 122))	('OS', 'Chemical', '-', (131, 133))	('expression', 'MPA', (49, 59))	('patients', 'Species', '9606', (104, 112))	('NCS1', 'Gene', (44, 48))	('LUSQ', 'Chemical', '-', (118, 122))
369861	30375717	We examined the effects of NCS1 knockdown in EBC-1 and SK-MES-1 cells using 2 types of si-NCS1 oligos: si-NCS1-1 and si-NCS1-2.	('si-NCS1-2', 'Var', (117, 126))	('si-NCS1-1', 'Var', (103, 112))	('SK-MES-1', 'CellLine', 'CVCL:0630', (55, 63))
369862	30375717	Cancer cell proliferation, migration, and invasive abilities were markedly inhibited by si-NCS1 transfection compared with those in mock or control EBC-1 and SK-MES-1 cells (Figure 6C-E).	('migration', 'CPA', (27, 36))	('inhibited', 'NegReg', (75, 84))	('transfection', 'Var', (96, 108))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('invasive abilities', 'CPA', (42, 60))	('SK-MES-1', 'CellLine', 'CVCL:0630', (158, 166))	('si-NCS1', 'Gene', (88, 95))
369865	30375717	Multivariate analysis showed that NCS1 expression was an independent predictive factor for OS (hazard ratio = 1.508, P = 0.007; Figure 8).	('OS', 'Chemical', '-', (91, 93))	('NCS1', 'Gene', (34, 38))	('expression', 'Var', (39, 49))
369869	30375717	In an analysis of previous studies of the functional significance of the miR-144 duplex, the antitumor function of miR-144-3p was reported in several type of cancers.36, 37, 38, 39, 40, 41 For example, expression of miR-144-3p suppressed cancer cell proliferation in glioblastoma and hepatocellular carcinoma through targeting c-MET and SGK3, respectively.36, 37 In laryngeal squamous cell carcinoma, miR-144-3p inhibited the cancer cell epithelial-mesenchymal transition phenotype through targeting ETS-1.38 These data indicated that miR-144-3p was a pivotal tumor suppressor, and that downregulation of miR-144-3p enhanced cancer cell aggressiveness.	('c-MET', 'Gene', (327, 332))	('laryngeal squamous cell carcinoma', 'Disease', (366, 399))	('carcinoma', 'Phenotype', 'HP:0030731', (390, 399))	('tumor', 'Disease', (560, 565))	('glioblastoma', 'Disease', 'MESH:D005909', (267, 279))	('miR-144', 'Gene', '406936', (216, 223))	('cancer', 'Disease', 'MESH:D009369', (426, 432))	('miR-144', 'Gene', '406936', (73, 80))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (284, 308))	('cancer', 'Disease', 'MESH:D009369', (625, 631))	('tumor', 'Disease', 'MESH:D009369', (560, 565))	('miR-144', 'Gene', (535, 542))	('glioblastoma', 'Disease', (267, 279))	('miR-144', 'Gene', (401, 408))	('cancer', 'Disease', (238, 244))	('aggressiveness', 'Phenotype', 'HP:0000718', (637, 651))	('glioblastoma', 'Phenotype', 'HP:0012174', (267, 279))	('cancer cell aggressiveness', 'Disease', 'MESH:C538614', (625, 651))	('ETS-1', 'Gene', (500, 505))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('SGK3', 'Gene', (337, 341))	('tumor', 'Disease', (97, 102))	('cancer', 'Disease', (158, 164))	('cancers', 'Disease', (158, 165))	('miR-144', 'Gene', (605, 612))	('hepatocellular carcinoma', 'Disease', (284, 308))	('laryngeal squamous cell carcinoma', 'Disease', 'MESH:D002294', (366, 399))	('SGK3', 'Gene', '23678', (337, 341))	('miR-144', 'Gene', (115, 122))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('carcinoma', 'Phenotype', 'HP:0030731', (299, 308))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('downregulation', 'Var', (587, 601))	('miR-144', 'Gene', (216, 223))	('tumor', 'Phenotype', 'HP:0002664', (560, 565))	('cancer', 'Disease', (426, 432))	('enhanced', 'PosReg', (616, 624))	('miR-144', 'Gene', (73, 80))	('cancer', 'Disease', (625, 631))	('miR-144', 'Gene', '406936', (535, 542))	('cancer', 'Disease', 'MESH:D009369', (238, 244))	('cancer cell aggressiveness', 'Disease', (625, 651))	('cancer', 'Phenotype', 'HP:0002664', (426, 432))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (376, 399))	('cancer', 'Phenotype', 'HP:0002664', (625, 631))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('miR-144', 'Gene', '406936', (401, 408))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (284, 308))	('cancers', 'Disease', 'MESH:D009369', (158, 165))	('miR-144', 'Gene', '406936', (605, 612))	('ETS-1', 'Gene', '2113', (500, 505))	('c-MET', 'Gene', '4233', (327, 332))	('miR-144', 'Gene', '406936', (115, 122))
369873	30375717	MARCKS is a major substrate of protein kinase C.42 Recent studies have shown that MARCKS plays a pivotal role in cancer development and progression.42 Moreover, in lung cancer, aberrant MARCKS expression was detected in clinical specimens, and MARCKS expression was implicated in this disease.43, 44  Among the 3 targets, we focused on NCS1 because its aberrant expression significantly predicted poor prognosis in patients.	('cancer', 'Disease', (169, 175))	('cancer', 'Disease', (113, 119))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('MARCKS', 'Gene', (244, 250))	('MARCKS', 'Gene', (186, 192))	('lung cancer', 'Disease', (164, 175))	('MARCKS', 'Gene', '4082', (0, 6))	('poor prognosis', 'CPA', (397, 411))	('men', 'Species', '9606', (127, 130))	('cancer', 'Disease', 'MESH:D009369', (169, 175))	('NCS1', 'Gene', (336, 340))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('MARCKS', 'Gene', '4082', (244, 250))	('MARCKS', 'Gene', '4082', (186, 192))	('MARCKS', 'Gene', (82, 88))	('patients', 'Species', '9606', (415, 423))	('lung cancer', 'Disease', 'MESH:D008175', (164, 175))	('aberrant', 'Var', (353, 361))	('lung cancer', 'Phenotype', 'HP:0100526', (164, 175))	('MARCKS', 'Gene', (0, 6))	('MARCKS', 'Gene', '4082', (82, 88))	('men', 'Species', '9606', (234, 237))
369874	30375717	The NCS1 protein is a member of the NCS family, which harbors a functional Ca2+ binding domain and N-terminally myristoylated site.45, 46 Previous studies have reported that NCS1 is a multifunctional protein involved in exocytosis, neurite outgrowth, neuroprotection, axonal regeneration, and nuclear Ca2+ regulation.45, 46 Furthermore, NCS1 interacts with various proteins to control their functions.45, 46 For example, NCS1 interacts with D2R and inhibits D2R-mediated signaling pathways.47 Interestingly, activation of D2R-mediated signaling suppresses lung cancer aggressiveness.48 Moreover, aberrant expression of NCS1 could interfere with D2R-mediated signaling and might be involved in LUSQ cell progression.	('D2R-mediated signaling', 'MPA', (645, 667))	('LUSQ cell', 'Disease', (693, 702))	('LUSQ', 'Chemical', '-', (693, 697))	('LUSQ', 'Phenotype', 'HP:0030359', (693, 697))	('aggressiveness', 'Phenotype', 'HP:0000718', (568, 582))	('lung cancer', 'Phenotype', 'HP:0100526', (556, 567))	('NCS1', 'Gene', (619, 623))	('aberrant', 'Var', (596, 604))	('lung cancer aggressiveness', 'Disease', 'MESH:D008175', (556, 582))	('cancer', 'Phenotype', 'HP:0002664', (561, 567))	('involved', 'Reg', (681, 689))	('axonal regeneration', 'Phenotype', 'HP:0003450', (268, 287))	('interfere', 'NegReg', (630, 639))	('lung cancer aggressiveness', 'Disease', (556, 582))
369875	30375717	Our functional assays showed that inhibition of NCS1 by siRNA suppressed cancer cell migration and invasion in LUSQ cells.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('inhibition', 'Var', (34, 44))	('NCS1', 'Gene', (48, 52))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('suppressed', 'NegReg', (62, 72))	('LUSQ', 'Phenotype', 'HP:0030359', (111, 115))	('invasion in LUSQ cells', 'CPA', (99, 121))	('LUSQ', 'Chemical', '-', (111, 115))
369876	30375717	Moreover, in multivariate Cox proportional hazards regression analysis, expression of NCS1 predicted poor prognosis in patients with LUSQ.	('LUSQ', 'Phenotype', 'HP:0030359', (133, 137))	('LUSQ', 'Chemical', '-', (133, 137))	('LUSQ', 'Disease', (133, 137))	('patients', 'Species', '9606', (119, 127))	('NCS1', 'Gene', (86, 90))	('expression', 'Var', (72, 82))	('Cox', 'Gene', '1351', (26, 29))	('Cox', 'Gene', (26, 29))
369877	30375717	Another study showed that overexpression of NCS1 promoted cell invasion and migration in breast cancer cells and that NCS1 overexpression was associated with poor prognosis in these patients.49 These findings indicate that aberrantly expressed NCS1 is involved in cancer cell aggressiveness.	('involved', 'Reg', (252, 260))	('breast cancer', 'Disease', 'MESH:D001943', (89, 102))	('NCS1', 'Gene', (244, 248))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('aggressiveness', 'Phenotype', 'HP:0000718', (276, 290))	('cancer', 'Phenotype', 'HP:0002664', (264, 270))	('breast cancer', 'Disease', (89, 102))	('cancer cell aggressiveness', 'Disease', (264, 290))	('breast cancer', 'Phenotype', 'HP:0003002', (89, 102))	('cancer cell aggressiveness', 'Disease', 'MESH:C538614', (264, 290))	('patients', 'Species', '9606', (182, 190))	('aberrantly expressed', 'Var', (223, 243))
369882	30375717	Aberrantly expressed NCS1 enhanced LUSQ cell aggressiveness.	('NCS1', 'Gene', (21, 25))	('enhanced', 'PosReg', (26, 34))	('Aberrantly expressed', 'Var', (0, 20))	('aggressiveness', 'Phenotype', 'HP:0000718', (45, 59))	('aggressiveness', 'Disease', 'MESH:D001523', (45, 59))	('aggressiveness', 'Disease', (45, 59))	('LUSQ', 'Chemical', '-', (35, 39))	('LUSQ', 'Phenotype', 'HP:0030359', (35, 39))
369928	29890622	They found a high risk of loco-regional recurrence and distant metastasis associated with the presence of DTCs.	('DTCs', 'Chemical', '-', (106, 110))	('loco-regional recurrence', 'CPA', (26, 50))	('presence', 'Var', (94, 102))	('DTCs', 'Gene', (106, 110))	('distant metastasis', 'CPA', (55, 73))
369977	29890622	Nowadays, cfDNA is being studied extensively since it is easy to analyze compared with other biomarkers and contains specific tumour- and metastasis-related alterations, such as single-nucleotide mutations, methylation changes, and copy-number variations.	('tumour', 'Phenotype', 'HP:0002664', (126, 132))	('single-nucleotide mutations', 'Var', (178, 205))	('copy-number variations', 'Var', (232, 254))	('tumour', 'Disease', 'MESH:D009369', (126, 132))	('tumour', 'Disease', (126, 132))	('methylation changes', 'Var', (207, 226))
369979	29890622	These technologies allow high-throughput and relatively low-cost analyses to identify ctDNA alterations across wide genomic regions and have the advantage of not requiring prior knowledge of the genetic alterations of the tumour.	('tumour', 'Disease', 'MESH:D009369', (222, 228))	('tumour', 'Disease', (222, 228))	('alterations', 'Var', (92, 103))	('tumour', 'Phenotype', 'HP:0002664', (222, 228))	('ctDNA', 'Gene', (86, 91))
369982	29890622	reported the detection of ctDNA mutations in head and neck cancers, of which 41 were oral cavity cancers, using two different approaches.	('cancers', 'Disease', 'MESH:D009369', (97, 104))	('cancers', 'Phenotype', 'HP:0002664', (97, 104))	('cancers', 'Disease', (97, 104))	('head and neck cancer', 'Phenotype', 'HP:0012288', (45, 65))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('ctDNA', 'Gene', (26, 31))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('mutations', 'Var', (32, 41))	('head and neck cancers', 'Phenotype', 'HP:0012288', (45, 66))	('cancers', 'Disease', 'MESH:D009369', (59, 66))	('neck cancers', 'Disease', (54, 66))	('cancers', 'Phenotype', 'HP:0002664', (59, 66))	('head and neck cancer', 'Disease', 'MESH:D006258', (45, 65))	('cancers', 'Disease', (59, 66))	('neck cancers', 'Disease', 'MESH:D006258', (54, 66))
369983	29890622	In the first approach, the presence of ctDNA mutations in five genes (TP53, NOTCH1, CDKN2A, CASP8 and PTEN), previously identified in tumour samples, were examined in plasma, finding a total of 18 mutations in 42% of the patients, including those in the early stages.	('CASP8', 'Gene', '841', (92, 97))	('patients', 'Species', '9606', (221, 229))	('mutations', 'Var', (45, 54))	('CDKN2A', 'Gene', (84, 90))	('CDKN2A', 'Gene', '1029', (84, 90))	('TP53', 'Gene', '7157', (70, 74))	('tumour', 'Disease', 'MESH:D009369', (134, 140))	('mutations', 'Var', (197, 206))	('ctDNA', 'Gene', (39, 44))	('tumour', 'Disease', (134, 140))	('TP53', 'Gene', (70, 74))	('NOTCH1', 'Gene', '4851', (76, 82))	('PTEN', 'Gene', (102, 106))	('NOTCH1', 'Gene', (76, 82))	('PTEN', 'Gene', '5728', (102, 106))	('CASP8', 'Gene', (92, 97))	('tumour', 'Phenotype', 'HP:0002664', (134, 140))
369984	29890622	In the second approach, they analyzed TP53 mutation by sequencing tumour tissue, plasma, and oral rinses, showing TP53 mutations in 36%, 3%, and 26% of patients, respectively.	('TP53', 'Gene', (38, 42))	('tumour', 'Phenotype', 'HP:0002664', (66, 72))	('TP53', 'Gene', '7157', (114, 118))	('tumour', 'Disease', 'MESH:D009369', (66, 72))	('TP53', 'Gene', (114, 118))	('tumour', 'Disease', (66, 72))	('mutations', 'Var', (119, 128))	('patients', 'Species', '9606', (152, 160))	('TP53', 'Gene', '7157', (38, 42))
369987	29890622	analyzed the cfDNA levels of 200 head and neck squamous cell carcinomas by examining HPV16/18, KRAS, and EGFR mutations via q-PCR.	('neck squamous cell carcinomas', 'Disease', (42, 71))	('mutations', 'Var', (110, 119))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (47, 71))	('HPV16', 'Species', '333760', (85, 90))	('EGFR', 'Gene', '1956', (105, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('carcinomas', 'Phenotype', 'HP:0030731', (61, 71))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (47, 70))	('neck squamous cell carcinomas', 'Disease', 'MESH:D000077195', (42, 71))	('EGFR', 'Gene', (105, 109))	('HPV16/18', 'Gene', (85, 93))
369990	29890622	From all patients, 14% showed positivity for HPV, most of whom were HPV16-positive (96.4%), while somatic EGFR and KRAS mutations were not detected.	('patients', 'Species', '9606', (9, 17))	('positivity', 'Var', (30, 40))	('HPV16-positive', 'Gene', (68, 82))	('HPV', 'Species', '10566', (45, 48))	('HPV16', 'Species', '333760', (68, 73))	('HPV', 'Disease', (45, 48))	('EGFR', 'Gene', '1956', (106, 110))	('HPV', 'Species', '10566', (68, 71))	('EGFR', 'Gene', (106, 110))
369997	29890622	analyzed nine microsatellite markers (D5s178, D9S104, IFNA, D11S910, D11S1356, D13S273, TP53, D18S46 and D22S274) in the tissue and serum of OSCC patients at three different time points (preoperatively, postoperatively, and four weeks after surgery).	('D13S273', 'Var', (79, 86))	('IFNA', 'Gene', '3438', (54, 58))	('D9S104', 'Var', (46, 52))	('D5s178', 'Var', (38, 44))	('IFNA', 'Gene', (54, 58))	('D22S274', 'Var', (105, 112))	('TP53', 'Gene', '7157', (88, 92))	('OSCC', 'Chemical', '-', (141, 145))	('D11S910', 'Var', (60, 67))	('D11S1356', 'Var', (69, 77))	('TP53', 'Gene', (88, 92))	('patients', 'Species', '9606', (146, 154))	('D18S46', 'Var', (94, 100))
370001	29890622	analyzed a panel of nine microsatellite markers (D2S1327, D2S206, D3S1007, D3S1079, D3S966, D21S36, D21S11, D21S1254 and D21S369) in blood and tumour tissue samples before and one month after surgery.	('D21S36', 'Var', (92, 98))	('D2S1327', 'Var', (49, 56))	('tumour', 'Phenotype', 'HP:0002664', (143, 149))	('D3S966', 'Var', (84, 90))	('D2S206', 'Var', (58, 64))	('tumour', 'Disease', 'MESH:D009369', (143, 149))	('D3S1007', 'Var', (66, 73))	('D21S11', 'Var', (100, 106))	('D3S1079', 'Var', (75, 82))	('D21S369', 'Var', (121, 128))	('tumour', 'Disease', (143, 149))	('D21S1254', 'Var', (108, 116))
370002	29890622	The presence of an allelic imbalance in tumour DNA was observed in the serum of 90% of patients.	('tumour', 'Disease', 'MESH:D009369', (40, 46))	('imbalance', 'Phenotype', 'HP:0002172', (27, 36))	('tumour', 'Disease', (40, 46))	('tumour', 'Phenotype', 'HP:0002664', (40, 46))	('patients', 'Species', '9606', (87, 95))	('allelic imbalance', 'Var', (19, 36))
370003	29890622	Based on these results, microsatellite analysis could help to assess risk of recurrence, metastasis, and death in OSCC.	('death', 'Disease', 'MESH:D003643', (105, 110))	('OSCC', 'Disease', (114, 118))	('death', 'Disease', (105, 110))	('OSCC', 'Chemical', '-', (114, 118))	('metastasis', 'CPA', (89, 99))	('microsatellite', 'Var', (24, 38))
370004	29890622	analyzed eight microsatellite markers (D2S123, D13S308E, D5S1501, D1S3721, D12S1052, D17S974, D17S1294 and D13S800) in 91 stage I to IV head and neck tumours (51% from oral origin).	('D17S1294', 'Var', (94, 102))	('D13S308E', 'Var', (47, 55))	('tumours', 'Phenotype', 'HP:0002664', (150, 157))	('D13S800', 'Var', (107, 114))	('S974', 'CellLine', 'CVCL:U295', (88, 92))	('D2S123', 'Var', (39, 45))	('D17S974', 'Var', (85, 92))	('D5S1501', 'Var', (57, 64))	('D12S1052', 'Var', (75, 83))	('head and neck tumours', 'Disease', 'MESH:D006258', (136, 157))	('tumour', 'Phenotype', 'HP:0002664', (150, 156))	('D1S3721', 'Var', (66, 73))
370005	29890622	Fifty-eight patients presented microsatellite alterations in the tumour, mainly at D17S974 and D13S800.	('D17S974', 'Var', (83, 90))	('patients', 'Species', '9606', (12, 20))	('D13S800', 'Var', (95, 102))	('microsatellite alterations', 'Var', (31, 57))	('tumour', 'Phenotype', 'HP:0002664', (65, 71))	('tumour', 'Disease', 'MESH:D009369', (65, 71))	('S974', 'CellLine', 'CVCL:U295', (86, 90))	('tumour', 'Disease', (65, 71))
370011	29890622	Both biomarkers have been validated in a large prospective cohort of 649 head and neck cancer patients as valuable biomarkers for tumour diagnosis, showing 59% of patients as methylation-positive at 96% specificity.	('tumour', 'Disease', 'MESH:D009369', (130, 136))	('patients', 'Species', '9606', (163, 171))	('methylation-positive', 'Var', (175, 195))	('patients', 'Species', '9606', (94, 102))	('head and neck cancer', 'Phenotype', 'HP:0012288', (73, 93))	('tumour', 'Disease', (130, 136))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('tumour', 'Phenotype', 'HP:0002664', (130, 136))	('head and neck cancer', 'Disease', 'MESH:D006258', (73, 93))
370013	29890622	Secondly, due to tumour heterogeneity and evolution, multiplexed assays are need to analyze several mutations simultaneously and to solve the limitation of the low levels of cfDNA present in some patients.	('mutations', 'Var', (100, 109))	('tumour', 'Phenotype', 'HP:0002664', (17, 23))	('tumour', 'Disease', 'MESH:D009369', (17, 23))	('patients', 'Species', '9606', (196, 204))	('tumour', 'Disease', (17, 23))
370042	29890622	Of them, nine were upregulated (miR-19a, miR-512-3p, miR-27b, miR-20a, miR-28-3p, miR-200c, miR-151-3p, hsa-miR-223, miR-20b), whereas seven were downregulated (miR-22, miR-516-3p, miR-370, miR-139-5p, let-7e, miR-145-3p, miR-30c) in tumour tissue compared to matched benign tissue.	('miR-145-3p', 'Var', (210, 220))	('miR-27b', 'Gene', (53, 60))	('let-7e', 'Gene', (202, 208))	('miR-22', 'Gene', '407004', (108, 114))	('miR-22', 'Gene', (108, 114))	('let-7e', 'Gene', '406887', (202, 208))	('miR-370', 'Gene', (181, 188))	('miR-27b', 'Gene', '407019', (53, 60))	('miR-20b', 'Gene', (117, 124))	('miR-30c', 'Gene', '407031', (222, 229))	('miR-28-3p', 'Var', (71, 80))	('tumour', 'Phenotype', 'HP:0002664', (234, 240))	('tumour', 'Disease', 'MESH:D009369', (234, 240))	('miR-370', 'Gene', '442915', (181, 188))	('miR-200c', 'Gene', '406985', (82, 90))	('miR-516-3p', 'Var', (169, 179))	('tumour', 'Disease', (234, 240))	('upregulated', 'PosReg', (19, 30))	('miR-22', 'Gene', '407004', (161, 167))	('miR-22', 'Gene', (161, 167))	('miR-20a', 'Gene', (62, 69))	('miR-223', 'Gene', (108, 115))	('miR-200c', 'Gene', (82, 90))	('miR-20a', 'Gene', '406982', (62, 69))	('miR-19a', 'Gene', (32, 39))	('miR-20b', 'Gene', '574032', (117, 124))	('miR-19a', 'Gene', '406979', (32, 39))	('miR-30c', 'Gene', (222, 229))	('miR-151-3p', 'Var', (92, 102))	('miR-512-3p', 'Var', (41, 51))	('downregulated', 'NegReg', (146, 159))	('miR-139-5p', 'Var', (190, 200))	('miR-223', 'Gene', '407008', (108, 115))
370052	29890622	In a study performed by Spafford et al., a total of 44 head and neck squamous cell carcinoma patients (13 of which were located in the oral cavity) and 43 healthy subjects were analyzed to find tumour-specific microsatellite alterations in the DNA from exfoliated salivary oral cells.	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (64, 92))	('tumour', 'Disease', (194, 200))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (69, 92))	('microsatellite alterations', 'Var', (210, 236))	('tumour', 'Phenotype', 'HP:0002664', (194, 200))	('tumour', 'Disease', 'MESH:D009369', (194, 200))	('head', 'Disease', (55, 59))	('patients', 'Species', '9606', (93, 101))	('neck squamous cell carcinoma', 'Disease', (64, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))
370053	29890622	A panel of 23 microsatellite markers were studied (D9S753, D20S77, UT5307, D9S242, CSFIR-6, D11S488, ACTBP2, D8S321, UT5320, D9S171, D9S162, D20S82, D20S85, Li7686, FGA, D9SIFNA, D11S654, D3S1560, D3S1286, D3S1289, D17S695, D17S654, and D17S656).	('D11S654', 'Var', (179, 186))	('D9S242', 'Var', (75, 81))	('IFNA', 'Gene', '3438', (173, 177))	('D17S656', 'Var', (237, 244))	('D17S695', 'Var', (215, 222))	('D20S77', 'Var', (59, 65))	('ACTBP2', 'Gene', (101, 107))	('FGA', 'Gene', '2243', (165, 168))	('D3S1286', 'Var', (197, 204))	('D20S85', 'Var', (149, 155))	('FGA', 'Gene', (165, 168))	('ACTBP2', 'Gene', '62', (101, 107))	('D8S321', 'Var', (109, 115))	('D9S162', 'Var', (133, 139))	('IFNA', 'Gene', (173, 177))	('D11S488', 'Var', (92, 99))	('D3S1560', 'Var', (188, 195))	('D9S171', 'Var', (125, 131))	('D20S82', 'Var', (141, 147))	('D3S1289', 'Var', (206, 213))	('D17S654', 'Var', (224, 231))	('D9S753', 'Var', (51, 57))
370055	29890622	In another study using tissue and saliva from 23 oral and pharyngeal cancer patients, a panel of eight microsatellite markers (D3S1289, D3S1300, D8S320, D8S321, D9S242, D11S488, and D20S82) was chosen because they show a high incidence of microsatellite abnormalities in head and neck cancers.	('D8S320', 'Var', (145, 151))	('head and neck cancers', 'Phenotype', 'HP:0012288', (271, 292))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('microsatellite abnormalities in head and neck cancers', 'Disease', 'MESH:D006258', (239, 292))	('D9S242', 'Var', (161, 167))	('cancer', 'Disease', (285, 291))	('cancers', 'Phenotype', 'HP:0002664', (285, 292))	('D3S1300', 'Var', (136, 143))	('patients', 'Species', '9606', (76, 84))	('head and neck cancer', 'Phenotype', 'HP:0012288', (271, 291))	('cancer', 'Phenotype', 'HP:0002664', (285, 291))	('pharyngeal cancer', 'Phenotype', 'HP:0100638', (58, 75))	('cancer', 'Disease', (69, 75))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('D20S82', 'Var', (182, 188))	('D11S488', 'Var', (169, 176))	('D3S1289', 'Var', (127, 134))	('D8S321', 'Var', (153, 159))	('cancer', 'Disease', 'MESH:D009369', (285, 291))	('abnormalities in head', 'Phenotype', 'HP:0000234', (254, 275))
370070	29890622	Of them, eight candidate exosomal miRNAs were assessed in human saliva samples, finding increased levels of miR-486-5p, miR-486-3p, and miR10b-5p in the saliva of head and neck squamous cell carcinoma patients when compared with healthy individuals.	('miR10b-5p', 'Var', (136, 145))	('neck squamous cell carcinoma', 'Disease', (172, 200))	('miR-486-5p', 'Var', (108, 118))	('patients', 'Species', '9606', (201, 209))	('human', 'Species', '9606', (58, 63))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (177, 200))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (172, 200))	('carcinoma', 'Phenotype', 'HP:0030731', (191, 200))	('increased', 'PosReg', (88, 97))	('miR-486-3p', 'Var', (120, 130))
370081	28182650	The overall and cancer-specific survival of patients who exhibited low TPM1 levels were inferior to those of patients who had high TPM1 levels.	('low', 'Var', (67, 70))	('inferior', 'NegReg', (88, 96))	('cancer', 'Disease', 'MESH:D009369', (16, 22))	('patients', 'Species', '9606', (44, 52))	('patients', 'Species', '9606', (109, 117))	('cancer', 'Disease', (16, 22))	('overall', 'CPA', (4, 11))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('TPM1', 'MPA', (71, 75))
370094	28182650	Previous studies have demonstrated that modification of microfilament structure was associated with cellular tumorigenicity and anchorage-independent growth.	('modification', 'Var', (40, 52))	('microfilament structure', 'Protein', (56, 79))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('associated', 'Reg', (84, 94))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('anchorage-independent growth', 'CPA', (128, 156))	('tumor', 'Disease', (109, 114))
370099	28182650	Moreover, it was verified that TPM1 plays an essential role by inhibiting migration in colorectal carcinoma, breast cancer, gliomagenesis and renal carcinoma, but none of these cancers were mentioned in Jinsong Li's study.	('renal carcinoma', 'Phenotype', 'HP:0005584', (142, 157))	('breast cancer', 'Disease', (109, 122))	('cancers', 'Disease', 'MESH:D009369', (177, 184))	('cancers', 'Phenotype', 'HP:0002664', (177, 184))	('breast cancer', 'Phenotype', 'HP:0003002', (109, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (148, 157))	('cancers', 'Disease', (177, 184))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (87, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('migration', 'CPA', (74, 83))	('inhibiting', 'NegReg', (63, 73))	('gliomagenesis and renal carcinoma', 'Disease', 'MESH:C538614', (124, 157))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('TPM1', 'Var', (31, 35))	('colorectal carcinoma', 'Disease', (87, 107))	('breast cancer', 'Disease', 'MESH:D001943', (109, 122))
370101	28182650	However, in this study, the researcher transfected TPM1-siRNA in tongue squamous cell carcinoma cell lines, which decreased the expression of TPM1, and the results indicated that there was no influence on cell survival or cell growth.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (72, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('tongue squamous cell carcinoma', 'Disease', (65, 95))	('TPM1-siRNA', 'Var', (51, 61))	('decreased', 'NegReg', (114, 123))	('tongue squamous cell carcinoma', 'Phenotype', 'HP:0030413', (65, 95))	('expression', 'MPA', (128, 138))	('TPM1', 'Gene', (142, 146))	('tongue squamous cell carcinoma', 'Disease', 'MESH:D002294', (65, 95))
370134	28182650	Cells that exhibited Annexin V+ and PI- staining were regarded to be in the early stage of apoptosis, while cells that exhibited Annexin V+ and PI-/+ were regarded to be in the late stage of apoptosis.	('Annexin V', 'Gene', '308', (21, 30))	('Annexin V', 'Gene', (21, 30))	('PI-/+', 'Var', (144, 149))	('PI- staining', 'Var', (36, 48))	('Annexin V', 'Gene', '308', (129, 138))	('Annexin V', 'Gene', (129, 138))
370139	28182650	Overall survival and OSCC cancer-specific survival of the OSCC patients were associated with TPM1 expression.	('expression', 'Var', (98, 108))	('cancer', 'Disease', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('patients', 'Species', '9606', (63, 71))	('TPM1', 'Gene', (93, 97))	('associated', 'Reg', (77, 87))
370145	28182650	The survival curves show that a high-level of TPM1 significantly improved five-year overall survival (59.5% vs. 31.1%; hazard ratio, 0.45; 95% confidence interval [CI], 0.25 to 0.77; p<0.01) and five-year cancer-specific survival (61.9% vs. 26.7%; hazard ratio, 0.44; 95% CI, 0.24 to 0.77; p<0.01) in OSCC patients, compared with those with low-expression of TPM1 (Fig 1C).	('TPM1', 'Gene', (46, 50))	('cancer', 'Disease', 'MESH:D009369', (205, 211))	('improved', 'PosReg', (65, 73))	('cancer', 'Disease', (205, 211))	('OSCC', 'Disease', (301, 305))	('overall survival', 'CPA', (84, 100))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('high-level', 'Var', (32, 42))	('patients', 'Species', '9606', (306, 314))
370150	28182650	There were no significant differences in sex (p>0.05), histological grade (p>0.05), recurrence (p>0.05), tumor class (p>0.05) and distant metastasis (no statistical data) between patients who exhibited high or low TPM1 levels.	('distant metastasis', 'CPA', (130, 148))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('high', 'Var', (202, 206))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('patients', 'Species', '9606', (179, 187))	('tumor', 'Disease', (105, 110))	('TPM1', 'MPA', (214, 218))
370156	28182650	After transfection, the SCC25 cell proliferation of the TPM1 group was reduced at 24 h (p<0.05), 48 h (p>0.05) and 72 h (p>0.05), in contrast to the negative control.	('transfection', 'Var', (6, 18))	('SCC25 cell proliferation', 'CPA', (24, 48))	('SCC25', 'CellLine', 'CVCL:1682', (24, 29))	('reduced', 'NegReg', (71, 78))	('TPM1', 'Var', (56, 60))
370160	28182650	Twenty-four hours after SCC15 and SCC25 cells were transfected with TPM1, the rates of early-stage apoptosis (Annexin V+/PI-) were 0.845%+-0.075% and 4.339%+-0.379%, respectively, which significantly exceeded those of the negative controls (0.368%+-0.049% and 3.238%+-0.221% in SCC15 and SCC25 cells, respectively) (p<0.01 and p<0.05, Fig 2C).	('TPM1', 'Gene', (68, 72))	('transfected', 'Var', (51, 62))	('SCC25', 'CellLine', 'CVCL:1682', (288, 293))	('Annexin V', 'Gene', '308', (110, 119))	('Annexin V', 'Gene', (110, 119))	('SCC25', 'CellLine', 'CVCL:1682', (34, 39))
370163	28182650	The invasiveness of SCC15 and SCC25 cells transfected with TPM1 was obviously reduced (p<0.01 and p<0.05, respectively, Fig 2D).	('transfected', 'Var', (42, 53))	('SCC25', 'CellLine', 'CVCL:1682', (30, 35))	('TPM1', 'Gene', (59, 63))	('reduced', 'NegReg', (78, 85))	('invasiveness', 'CPA', (4, 16))
370164	28182650	The number of invasive cells in SCC25-con and SCC25-TPM1 groups was 698+-51 and 543+-42, respectively.	('SCC25-TPM1', 'Var', (46, 56))	('SCC25', 'CellLine', 'CVCL:1682', (32, 37))	('invasive cells', 'CPA', (14, 28))	('SCC25', 'CellLine', 'CVCL:1682', (46, 51))
370172	28182650	The occurrence rates of lymphatic metastasis in patients who exhibited a low TPM1 level were higher than in patients with a high TPM1 level.	('higher', 'PosReg', (93, 99))	('TPM1', 'Gene', (77, 81))	('patients', 'Species', '9606', (108, 116))	('patients', 'Species', '9606', (48, 56))	('low', 'Var', (73, 76))	('lymphatic metastasis', 'CPA', (24, 44))
370257	33379285	In addition, miRNAs can also suppress the expression of wild-type tumor suppressor genes.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('suppress', 'NegReg', (29, 37))	('tumor', 'Disease', (66, 71))	('exp', 'Gene', (42, 45))	('miRNAs', 'Var', (13, 19))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('exp', 'Gene', '4154', (42, 45))
370282	33379285	Both genes take parts in purine (hsa00230, p = 6.47 x 10-10) and pyrimidine metabolism (hsa00240, p = 5.20 x 10-8) and NTC3A has a role in nicotinate and nicotinamide metabolism (hsa00760) and other metabolic pathways (hsa01100) as well.	('metabolic', 'MPA', (199, 208))	('hsa00230', 'Var', (33, 41))	('take parts', 'Reg', (11, 21))	('NTC3A', 'Gene', (119, 124))	('nicotinamide', 'Chemical', 'MESH:D009536', (154, 166))	('hsa01100', 'Var', (219, 227))	('role', 'Reg', (131, 135))	('hsa00240', 'Var', (88, 96))	('purine', 'Chemical', 'MESH:C030985', (25, 31))	('hsa00760', 'Var', (179, 187))	('pyrimidine', 'Chemical', 'MESH:C030986', (65, 75))	('nicotinate', 'Chemical', 'MESH:D009525', (139, 149))	('purine', 'MPA', (25, 31))
370283	33379285	The underexpressed miRNAs (hsa-mir-5586, hsa-mir-642a, hsa-mir-101, hsa-mir-632) have nine common predicted target genes in four KEGG pathways.	('hsa-mir-101', 'Var', (55, 66))	('exp', 'Gene', '4154', (9, 12))	('hsa-mir-642a', 'Gene', (41, 53))	('hsa-mir-632', 'Gene', '693217', (68, 79))	('hsa-mir-632', 'Gene', (68, 79))	('hsa-mir-5586', 'Gene', (27, 39))	('hsa-mir-5586', 'Gene', '100847088', (27, 39))	('KEGG pathways', 'Pathway', (129, 142))	('exp', 'Gene', (9, 12))	('hsa-mir-642a', 'Gene', '693227', (41, 53))
370294	33379285	We have found 4 significant miRNAs (hsa-miR-16, hsa-miR-145, hsa-miR-199b) which have been previously reported as HPV core miRNAs in HNSC and CESC clinical samples.	('hsa-miR-199b', 'Gene', '406978', (61, 73))	('HNSC', 'Phenotype', 'HP:0012288', (133, 137))	('hsa-miR-145', 'Gene', '406937', (48, 59))	('hsa-miR-199b', 'Gene', (61, 73))	('hsa-miR-145', 'Gene', (48, 59))	('hsa-miR-16', 'Var', (36, 46))
370320	33379285	Interestingly, the most significant pathway related to genes targeted by the four miRNAs with lower expression (hsa-mir-5586, hsa-mir-642a, hsa-mir-101, hsa-mir-632) was the circadian entrainment pathway with six potential target genes.	('hsa-mir-642a', 'Gene', (126, 138))	('hsa-mir-632', 'Gene', (153, 164))	('hsa-mir-5586', 'Gene', (112, 124))	('exp', 'Gene', (100, 103))	('hsa-mir-101', 'Var', (140, 151))	('lower', 'NegReg', (94, 99))	('hsa-mir-5586', 'Gene', '100847088', (112, 124))	('exp', 'Gene', '4154', (100, 103))	('hsa-mir-642a', 'Gene', '693227', (126, 138))	('hsa-mir-632', 'Gene', '693217', (153, 164))
370345	30690883	We found that WTIP expression was significantly reduced in both NSCLC cell lines and clinical specimens compared to that in normal controls; this reduction was largely attributed to promoter hypermethylation.	('NSCLC', 'Disease', 'MESH:D002289', (64, 69))	('reduced', 'NegReg', (48, 55))	('NSCLC', 'Phenotype', 'HP:0030358', (64, 69))	('WTIP', 'Protein', (14, 18))	('promoter hypermethylation', 'Var', (182, 207))	('clinical', 'Species', '191496', (85, 93))	('NSCLC', 'Disease', (64, 69))
370352	30690883	Carcinogenesis is a complex multistep process characterized by the progressive accumulation of genetic and epigenetic alterations, which ultimately lead to uncontrolled cell proliferation and tumor formation.	('Carcinogenesis', 'Disease', (0, 14))	('genetic', 'Var', (95, 102))	('tumor', 'Disease', (192, 197))	('uncontrolled', 'MPA', (156, 168))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('epigenetic alterations', 'Var', (107, 129))	('lead to', 'Reg', (148, 155))
370391	30690883	Antibodies against AKT (4691), phospho-AKT (2965), GSK-3beta (12456), phospho-GSK-3beta (9323), FOXO1 (2880), phospho-FOXO1 (9461), p27 (3686), p21 (2947), Rb (9309), and phospho-Rb (8516) were purchased from Cell Signaling Technology.	('AKT', 'Gene', '207', (19, 22))	('FOXO1', 'Gene', (96, 101))	('AKT', 'Gene', (39, 42))	('FOXO1', 'Gene', '2308', (118, 123))	('GSK-3beta', 'Gene', '2932', (51, 60))	('p21', 'Gene', (144, 147))	('p27', 'Gene', '3429', (132, 135))	('p27', 'Gene', (132, 135))	('FOXO1', 'Gene', (118, 123))	('GSK-3beta', 'Gene', (51, 60))	('AKT', 'Gene', '207', (39, 42))	('2880', 'Var', (103, 107))	('GSK-3beta', 'Gene', '2932', (78, 87))	('AKT', 'Gene', (19, 22))	('p21', 'Gene', '1026', (144, 147))	('9461', 'Var', (125, 129))	('FOXO1', 'Gene', '2308', (96, 101))	('GSK-3beta', 'Gene', (78, 87))	('2965', 'Var', (44, 48))
370392	30690883	Anti-cyclin D1 (TA801655) was purchased from ORIGENE (Rockville, MD, USA).	('TA801655', 'Var', (16, 24))	('cyclin D1', 'Gene', (5, 14))	('cyclin D1', 'Gene', '595', (5, 14))
370393	30690883	WTIP (SAB1411722) and alpha-tubulin (T9026) antibodies were obtained from Sigma-Aldrich.	('alpha-tubulin', 'Gene', '10376', (22, 35))	('alpha-tubulin', 'Gene', (22, 35))	('T9026', 'Var', (37, 42))	('T9026', 'CellLine', 'CVCL:3174', (37, 42))
370421	30690883	To investigate whether WTIP downregulation results from the DNA methylation of this promoter region, we treated the cells with the DNA methyltransferase inhibitor 5-Aza-dC for 72 h and found that inhibiting DNA methylation significantly promoted WTIP expression, especially in cells with endogenously low levels of WTIP, such as H1299 and PC-9 cells.	('5-Aza-dC', 'Chemical', 'MESH:D000077209', (163, 171))	('PC-9', 'Gene', (339, 343))	('inhibiting', 'Var', (196, 206))	('WTIP', 'Gene', (246, 250))	('expression', 'MPA', (251, 261))	('H1299', 'CellLine', 'CVCL:0060', (329, 334))	('promoted', 'PosReg', (237, 245))	('PC-9', 'Gene', '255738', (339, 343))
370425	30690883	In contrast, the majority of CpG islands in BEAS-2B cells were not methylated (Fig.	('BEAS-2B', 'CellLine', 'CVCL:0168', (44, 51))	('methylated', 'Var', (67, 77))	('not', 'NegReg', (63, 66))
370445	30690883	The BrdU incorporation assay and cell cycle analysis by flow cytometry demonstrated that knockdown of WTIP released A549-WTIP and H460-WTIP cells from G1/S phase arrest, as indicated by the increase in the overall percentage of BrdU-positive cells and percentage of cells in the S fraction and a decrease in the percentage of cells in the G0/G1 fraction (Fig.	('H460', 'CellLine', 'CVCL:0459', (130, 134))	('BrdU', 'Chemical', 'MESH:D001973', (4, 8))	('increase', 'PosReg', (190, 198))	('WTIP', 'Gene', (102, 106))	('decrease', 'NegReg', (296, 304))	('knockdown', 'Var', (89, 98))	('A549', 'CellLine', 'CVCL:0023', (116, 120))	('BrdU', 'Chemical', 'MESH:D001973', (228, 232))
370446	30690883	The expression of p21Cip1 and p27Kip1 was impaired, while the expression levels of cyclin D1 and phosphorylated Rb were enhanced by silencing WTIP expression (Fig.	('enhanced', 'PosReg', (120, 128))	('p27Kip1', 'Gene', (30, 37))	('silencing', 'Var', (132, 141))	('p21Cip1', 'Gene', (18, 25))	('WTIP expression', 'Gene', (142, 157))	('expression levels', 'MPA', (62, 79))	('expression', 'MPA', (4, 14))	('p21Cip1', 'Gene', '1026', (18, 25))	('p27Kip1', 'Gene', '1027', (30, 37))	('cyclin D1 and phosphorylated Rb', 'Gene', '595', (83, 114))	('impaired', 'NegReg', (42, 50))
370452	30690883	After 42 days, the sizes and weights of tumors from the A549-WTIP cells were substantially lower than those from the control cells (Fig.	('lower', 'NegReg', (91, 96))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('A549', 'CellLine', 'CVCL:0023', (56, 60))	('A549-WTIP cells', 'Var', (56, 71))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumors', 'Disease', (40, 46))	('tumors', 'Disease', 'MESH:D009369', (40, 46))
370459	30690883	AKT-mediated phosphorylation of FOXO1 leads to the nuclear export and subsequent degradation of FOXO1 via the proteasome, which consequently inactivates the transcriptional activity of the protein (Aoki et al., 2004; Tang et al., 1999).	('AKT', 'Gene', (0, 3))	('FOXO1', 'Gene', (32, 37))	('transcriptional activity', 'MPA', (157, 181))	('nuclear export', 'MPA', (51, 65))	('leads to', 'Reg', (38, 46))	('FOXO1', 'Gene', '2308', (32, 37))	('phosphorylation', 'Var', (13, 28))	('FOXO1', 'Gene', '2308', (96, 101))	('degradation', 'MPA', (81, 92))	('AKT', 'Gene', '207', (0, 3))	('FOXO1', 'Gene', (96, 101))	('inactivates', 'NegReg', (141, 152))
370460	30690883	Western blotting assays showed that ectopic expression of WTIP decreased the expression of phospho-AKT (Thr308) and phospho-FOXO1 (Ser256) and increased the total expression level of FOXO1.	('FOXO1', 'Gene', (183, 188))	('Thr308', 'Var', (104, 110))	('expression', 'MPA', (77, 87))	('increased', 'PosReg', (143, 152))	('decreased', 'NegReg', (63, 72))	('Ser256', 'Chemical', '-', (131, 137))	('AKT', 'Gene', '207', (99, 102))	('Thr308', 'Chemical', '-', (104, 110))	('total expression level', 'MPA', (157, 179))	('WTIP', 'Gene', (58, 62))	('FOXO1', 'Gene', '2308', (124, 129))	('AKT', 'Gene', (99, 102))	('FOXO1', 'Gene', (124, 129))	('FOXO1', 'Gene', '2308', (183, 188))
370472	30690883	Both genetic and epigenetic alterations of tumor suppressor and tumor-related genes are involved in the pathogenesis of cancer.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('tumor', 'Disease', (64, 69))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Disease', (43, 48))	('epigenetic alterations', 'Var', (17, 39))	('involved', 'Reg', (88, 96))
370480	30690883	Accordingly, we speculate that both epigenetic and genetic alterations lead to WTIP downregulation in NSCLC.	('NSCLC', 'Disease', 'MESH:D002289', (102, 107))	('downregulation', 'NegReg', (84, 98))	('NSCLC', 'Phenotype', 'HP:0030358', (102, 107))	('epigenetic', 'Var', (36, 46))	('NSCLC', 'Disease', (102, 107))	('genetic alterations', 'Var', (51, 70))
370511	30513627	Mutations in Kirsten rat sarcoma viral oncogene homolog (KRAS) were detected in 75% of IMAs, but in only 11.6% of conventional adenocarcinomas.	('sarcoma', 'Disease', (25, 32))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('adenocarcinomas', 'Disease', 'MESH:D000230', (127, 142))	('sarcoma', 'Phenotype', 'HP:0100242', (25, 32))	('adenocarcinomas', 'Disease', (127, 142))	('IMAs', 'Disease', (87, 91))	('IMA', 'Chemical', '-', (87, 90))	('KRAS', 'Gene', (57, 61))	('Mutations', 'Var', (0, 9))	('rat', 'Species', '10116', (21, 24))	('carcinomas', 'Phenotype', 'HP:0030731', (132, 142))	('detected', 'Reg', (68, 76))	('sarcoma', 'Disease', 'MESH:D012509', (25, 32))
370512	30513627	On the other hand, the frequency of mutations in epidermal growth factor receptor (EGFR) and tumor protein p53 (TP53) genes was 5% and 10%, respectively, in the former, but 48.8% and 34.9%, respectively, in the latter.	('EGFR', 'Gene', '1956', (83, 87))	('tumor', 'Disease', 'MESH:D009369', (93, 98))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('epidermal growth factor receptor', 'Gene', (49, 81))	('p53', 'Gene', (107, 110))	('EGFR', 'Gene', (83, 87))	('p53', 'Gene', '7157', (107, 110))	('tumor', 'Disease', (93, 98))	('mutations', 'Var', (36, 45))	('TP53', 'Gene', '7157', (112, 116))	('epidermal growth factor receptor', 'Gene', '1956', (49, 81))	('TP53', 'Gene', (112, 116))
370523	30513627	IMAs are strongly correlated with mutations in Kirsten rat sarcoma viral oncogene homolog (KRAS), which are present in 28-87% of cases.	('correlated', 'Reg', (18, 28))	('sarcoma', 'Disease', (59, 66))	('IMAs', 'Disease', (0, 4))	('IMA', 'Chemical', '-', (0, 3))	('sarcoma', 'Phenotype', 'HP:0100242', (59, 66))	('sarcoma', 'Disease', 'MESH:D012509', (59, 66))	('KRAS', 'Gene', (91, 95))	('rat', 'Species', '10116', (55, 58))	('mutations', 'Var', (34, 43))
370532	30513627	Remarkably, KRAS mutations were detected in 75% of IMAs (15/20), but only in 11.6% of NMAs (5/43), a statistically significant difference in frequency (Figure 1B).	('NMA', 'Chemical', '-', (86, 89))	('IMAs', 'Disease', (51, 55))	('IMA', 'Chemical', '-', (51, 54))	('detected', 'Reg', (32, 40))	('KRAS', 'Gene', (12, 16))	('mutations', 'Var', (17, 26))
370533	30513627	The frequency of mutations in epidermal growth factor receptor (EGFR) and tumor protein p53 (TP53) were 5% (1/20) and 10% (2/20), respectively, in IMA patients, which are significantly lower rates than the corresponding frequencies of 48.8% (21/43) and 34.9% (15/43) in patients with conventional lung adenocarcinoma (p < 0.05, Figure 1B).	('rat', 'Species', '10116', (191, 194))	('TP53', 'Gene', (93, 97))	('lung adenocarcinoma', 'Disease', (297, 316))	('p53', 'Gene', '7157', (88, 91))	('tumor', 'Disease', (74, 79))	('mutations', 'Var', (17, 26))	('epidermal growth factor receptor', 'Gene', (30, 62))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('epidermal growth factor receptor', 'Gene', '1956', (30, 62))	('p53', 'Gene', (88, 91))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (297, 316))	('EGFR', 'Gene', (64, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (307, 316))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (297, 316))	('TP53', 'Gene', '7157', (93, 97))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('IMA', 'Chemical', '-', (147, 150))	('patients', 'Species', '9606', (270, 278))	('patients', 'Species', '9606', (151, 159))	('EGFR', 'Gene', '1956', (64, 68))
370535	30513627	Mutations obtained by targeted sequencing of specimens from patients with IMA (n = 12), NMA (n = 43), squamous cell carcinoma (n = 13), and other tumors (n = 10) were clustered based on similarity by in silico unsupervised hierarchical clustering (Figure 2A).	('squamous cell carcinoma', 'Disease', (102, 125))	('IMA', 'Disease', (74, 77))	('tumors', 'Phenotype', 'HP:0002664', (146, 152))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('patients', 'Species', '9606', (60, 68))	('tumors', 'Disease', 'MESH:D009369', (146, 152))	('men', 'Species', '9606', (50, 53))	('Mutations', 'Var', (0, 9))	('NMA', 'Chemical', '-', (88, 91))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (102, 125))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('IMA', 'Chemical', '-', (74, 77))	('tumors', 'Disease', (146, 152))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (102, 125))	('NMA', 'Disease', (88, 91))
370561	30513627	EGFR mutations were affected significantly more frequently in B7-H3 negative adenocarcinomas than in B7-H3 positive adenocarcinomas, while KRAS mutations were affected significantly more frequently in B7-H3 positive adenocarcinomas than in B7-H3 negative adenocarcinomas (Figure 5, *, p < 0.05).	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('carcinomas', 'Phenotype', 'HP:0030731', (121, 131))	('B7-H3', 'Gene', (240, 245))	('carcinomas', 'Phenotype', 'HP:0030731', (82, 92))	('B7-H3', 'Gene', '80381', (62, 67))	('adenocarcinomas', 'Disease', 'MESH:D000230', (116, 131))	('B7-H3', 'Gene', (201, 206))	('adenocarcinomas', 'Disease', (116, 131))	('B7-H3', 'Gene', '80381', (101, 106))	('negative', 'NegReg', (68, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (221, 230))	('EGFR', 'Gene', (0, 4))	('adenocarcinomas', 'Disease', 'MESH:D000230', (216, 231))	('adenocarcinomas', 'Disease', 'MESH:D000230', (255, 270))	('adenocarcinomas', 'Disease', (255, 270))	('affected', 'Reg', (20, 28))	('mutations', 'Var', (5, 14))	('adenocarcinomas', 'Disease', (216, 231))	('carcinoma', 'Phenotype', 'HP:0030731', (260, 269))	('carcinomas', 'Phenotype', 'HP:0030731', (221, 231))	('carcinomas', 'Phenotype', 'HP:0030731', (260, 270))	('B7-H3', 'Gene', (62, 67))	('B7-H3', 'Gene', (101, 106))	('B7-H3', 'Gene', '80381', (240, 245))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('B7-H3', 'Gene', '80381', (201, 206))	('affected', 'Reg', (159, 167))	('adenocarcinomas', 'Disease', 'MESH:D000230', (77, 92))	('EGFR', 'Gene', '1956', (0, 4))	('adenocarcinomas', 'Disease', (77, 92))
370564	30513627	KRAS mutations were the most frequent drivers, while EGFR mutations were rare, in line with previous studies.	('EGFR', 'Gene', (53, 57))	('KRAS', 'Gene', (0, 4))	('EGFR', 'Gene', '1956', (53, 57))	('mutations', 'Var', (5, 14))
370565	30513627	TP53 mutations were similarly rare in IMA, and were detected in only 2 of 20 IMA cases examined, but in approximately 35% of NMA cases.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('IMA', 'Chemical', '-', (38, 41))	('mutations', 'Var', (5, 14))	('NMA', 'Chemical', '-', (125, 128))	('IMA', 'Disease', (38, 41))	('IMA', 'Chemical', '-', (77, 80))	('IMA', 'Disease', (77, 80))
370577	30513627	Thus, hierarchical clustering based on gene mutations is novel, meaningful, and functional classification of lung tumors.	('lung tumors', 'Phenotype', 'HP:0100526', (109, 120))	('lung tumors', 'Disease', (109, 120))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('mutations', 'Var', (44, 53))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('lung tumors', 'Disease', 'MESH:D008175', (109, 120))
370582	30513627	recently reported that a combination of MEK and FGFR inhibitors is effective against lung cancers with KRAS mutations.	('MEK', 'Gene', '5609', (40, 43))	('KRAS', 'Gene', (103, 107))	('lung cancer', 'Phenotype', 'HP:0100526', (85, 96))	('mutations', 'Var', (108, 117))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('lung cancers', 'Disease', 'MESH:D008175', (85, 97))	('FGFR', 'Gene', (48, 52))	('lung cancers', 'Phenotype', 'HP:0100526', (85, 97))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('MEK', 'Gene', (40, 43))	('lung cancers', 'Disease', (85, 97))
370587	30513627	In addition, several studies observed frequent NKX2-1 mutations in IMA, and proposed NKX2-1 as a lineage-specific tumor suppressor in the lung.	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('mutations', 'Var', (54, 63))	('tumor', 'Disease', (114, 119))	('IMA', 'Chemical', '-', (67, 70))	('NKX2-1', 'Gene', (47, 53))	('IMA', 'Disease', (67, 70))
370588	30513627	Similarly, mice with KRAS mutations and NKX2-1 deletion develop lung tumors that resemble human mucinous lung adenocarcinomas.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (105, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('lung tumors', 'Disease', (64, 75))	('carcinomas', 'Phenotype', 'HP:0030731', (115, 125))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('lung tumors', 'Phenotype', 'HP:0100526', (64, 75))	('develop', 'PosReg', (56, 63))	('mutations', 'Var', (26, 35))	('deletion', 'Var', (47, 55))	('human', 'Species', '9606', (90, 95))	('mice', 'Species', '10090', (11, 15))	('NKX2-1', 'Gene', (40, 46))	('mucinous lung adenocarcinomas', 'Disease', (96, 125))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (105, 125))	('KRAS', 'Gene', (21, 25))	('mucinous lung adenocarcinomas', 'Disease', 'MESH:D002288', (96, 125))	('lung tumors', 'Disease', 'MESH:D008175', (64, 75))
370596	30513627	Our data also showed that B7-H3-positive adenocarcinomas harbor EGFR mutations significantly less frequently, suggesting a non-redundant biological role of the two targets: EGFR and B7-H3.	('mutations', 'Var', (69, 78))	('B7-H3', 'Gene', (182, 187))	('adenocarcinomas', 'Disease', 'MESH:D000230', (41, 56))	('carcinoma', 'Phenotype', 'HP:0030731', (46, 55))	('adenocarcinomas', 'Disease', (41, 56))	('B7-H3', 'Gene', (26, 31))	('carcinomas', 'Phenotype', 'HP:0030731', (46, 56))	('EGFR', 'Gene', '1956', (173, 177))	('B7-H3', 'Gene', '80381', (26, 31))	('EGFR', 'Gene', '1956', (64, 68))	('EGFR', 'Gene', (64, 68))	('EGFR', 'Gene', (173, 177))	('B7-H3', 'Gene', '80381', (182, 187))
370597	30513627	It was also revealed that B7-H3-expressing cancers harbor KRAS mutations significantly more frequently, which may make a breakthrough in the treatment of KRAS mutant lung cancers.	('KRAS', 'Gene', (58, 62))	('mutations', 'Var', (63, 72))	('cancers', 'Phenotype', 'HP:0002664', (43, 50))	('B7-H3', 'Gene', (26, 31))	('lung cancers', 'Disease', (166, 178))	('men', 'Species', '9606', (146, 149))	('cancers', 'Disease', (43, 50))	('cancers', 'Disease', 'MESH:D009369', (171, 178))	('cancers', 'Disease', 'MESH:D009369', (43, 50))	('B7-H3', 'Gene', '80381', (26, 31))	('cancers', 'Phenotype', 'HP:0002664', (171, 178))	('cancers', 'Disease', (171, 178))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('lung cancer', 'Phenotype', 'HP:0100526', (166, 177))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('lung cancers', 'Disease', 'MESH:D008175', (166, 178))	('lung cancers', 'Phenotype', 'HP:0100526', (166, 178))
370601	30513627	reported that B7-H3 expression was elevated in meningiomas harboring gene mutations affecting the AKT pathway.	('meningiomas', 'Phenotype', 'HP:0002858', (47, 58))	('expression', 'MPA', (20, 30))	('gene mutations', 'Var', (69, 83))	('AKT', 'Gene', '207', (98, 101))	('meningiomas', 'Disease', (47, 58))	('B7-H3', 'Gene', (14, 19))	('meningiomas', 'Disease', 'MESH:D008577', (47, 58))	('elevated', 'PosReg', (35, 43))	('AKT', 'Gene', (98, 101))	('B7-H3', 'Gene', '80381', (14, 19))
370603	30513627	i.e., KRAS mutation may be the key trigger of B7-H3 expression in lung cancer.	('B7-H3', 'Gene', '80381', (46, 51))	('lung cancer', 'Disease', (66, 77))	('KRAS mutation', 'Var', (6, 19))	('lung cancer', 'Phenotype', 'HP:0100526', (66, 77))	('trigger', 'Reg', (35, 42))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('lung cancer', 'Disease', 'MESH:D008175', (66, 77))	('B7-H3', 'Gene', (46, 51))
370604	30513627	In fact, the cases in cluster C, which are mainly related to KRAS mutations, expressed B7-H3 most frequently.	('mutations', 'Var', (66, 75))	('B7-H3', 'Gene', '80381', (87, 92))	('B7-H3', 'Gene', (87, 92))
370607	30513627	To summarize our data and previous reports, IMA usually harbors both KRAS and NKX2-1 mutations, both of which are oncogenic.	('KRAS', 'Gene', (69, 73))	('NKX2-1', 'Gene', (78, 84))	('mutations', 'Var', (85, 94))	('IMA', 'Chemical', '-', (44, 47))
370608	30513627	It is estimated that NKX2-1 mutation leads to loss of TTF-1 and PD-L1 expressions, while KRAS mutation tends to upregulate B7-H3 expression:presumably by disrupting the AKT pathway.	('NKX2-1', 'Gene', (21, 27))	('disrupting', 'NegReg', (154, 164))	('loss', 'NegReg', (46, 50))	('upregulate', 'PosReg', (112, 122))	('AKT', 'Gene', (169, 172))	('B7-H3', 'Gene', (123, 128))	('PD-L1', 'Gene', (64, 69))	('mutation', 'Var', (28, 36))	('expressions', 'MPA', (70, 81))	('TTF-1', 'Gene', (54, 59))	('KRAS', 'Gene', (89, 93))	('B7-H3', 'Gene', '80381', (123, 128))	('AKT', 'Gene', '207', (169, 172))
370615	30513627	Similarly, B7-H3 blockade increased CD8+ T cell proliferation and activity in mouse models of pancreatic cancer.	('activity', 'MPA', (66, 74))	('blockade', 'Var', (17, 25))	('pancreatic cancer', 'Disease', (94, 111))	('CD8+ T cell proliferation', 'CPA', (36, 61))	('pancreatic cancer', 'Disease', 'MESH:D010190', (94, 111))	('increased', 'PosReg', (26, 35))	('B7-H3', 'Gene', (11, 16))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('mouse', 'Species', '10090', (78, 83))	('rat', 'Species', '10116', (55, 58))	('B7-H3', 'Gene', '80381', (11, 16))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (94, 111))
370629	30513627	Single nucleotide variants, insertions, and deletions were then annotated by tumor-normal pair analysis against lymphocytes from peripheral blood, using Ion Reporter Server System (Thermo Fisher Scientific).	('deletions', 'Var', (44, 53))	('insertions', 'Var', (28, 38))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Disease', (77, 82))
370639	30513627	The following are available online at , Figure S1: Immunostaining for VTCN-1 in IMA, NMA, and squamous cell carcinoma, Table S1: Clinical characteristics of the patients, Table S2: Mutations in IMA specimens, Table S3: Pathways affected in IMA and NMA by mutations with allele fractions >=20%, Table S4: Sequencing targets.	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('affected', 'Reg', (228, 236))	('men', 'Species', '9606', (203, 206))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (94, 117))	('IMA', 'Chemical', '-', (240, 243))	('squamous cell carcinoma', 'Disease', (94, 117))	('VTCN-1', 'Gene', (70, 76))	('NMA', 'Chemical', '-', (248, 251))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (94, 117))	('IMA', 'Disease', (240, 243))	('Mutations', 'Var', (181, 190))	('patients', 'Species', '9606', (161, 169))	('IMA', 'Chemical', '-', (80, 83))	('VTCN-1', 'Gene', '79679', (70, 76))	('NMA', 'Disease', (248, 251))	('IMA', 'Chemical', '-', (194, 197))	('NMA', 'Chemical', '-', (85, 88))	('mutations', 'Var', (255, 264))
370665	30425004	The miR-5p and miR-3p represent 5' mature miRNA and 3' mature miRNA, respectively, as shown in Fig.	('miR-5p', 'Var', (4, 10))	('miR-5p', 'Chemical', '-', (4, 10))	('miR-3p', 'Var', (15, 21))
370671	30425004	Moreover, some cancer-related studies have integrated miR-5p and miR-3p together.	('cancer', 'Disease', (15, 21))	('cancer', 'Disease', 'MESH:D009369', (15, 21))	('miR-5p', 'Var', (54, 60))	('miR-5p', 'Chemical', '-', (54, 60))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))
370672	30425004	For example, miR-193a-5p and miR-193a-3p were found significantly increased in breast cancer and revealed that strand expression preference may be a means of modulating miRNA function.	('miR-193a-3p', 'Var', (29, 40))	('modulating', 'Reg', (158, 168))	('increased', 'PosReg', (66, 75))	('breast cancer', 'Disease', 'MESH:D001943', (79, 92))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('breast cancer', 'Disease', (79, 92))	('breast cancer', 'Phenotype', 'HP:0003002', (79, 92))	('miR-193a-5p', 'Var', (13, 24))	('miRNA function', 'MPA', (169, 183))
370674	30425004	miR-5p and miR-3p have been found that co-express and cross-target in colon cancer cells.	('miR-5p', 'Chemical', '-', (0, 6))	('colon cancer', 'Disease', (70, 82))	('miR-3p', 'Var', (11, 17))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('colon cancer', 'Phenotype', 'HP:0003003', (70, 82))	('colon cancer', 'Disease', 'MESH:D015179', (70, 82))	('miR-5p', 'Gene', (0, 6))
370675	30425004	Moreover, dysregulation of miR-5p/miR-3p specific miRNAs were found in gastric cancer in a TCGA data set.	('gastric cancer', 'Disease', (71, 85))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('gastric cancer', 'Disease', 'MESH:D013274', (71, 85))	('miR-5p/miR-3p', 'Var', (27, 40))	('gastric cancer', 'Phenotype', 'HP:0012126', (71, 85))	('miR-5p', 'Chemical', '-', (27, 33))
370692	30425004	The ratio was adopted as a measure of the arm selection, where 1 >= ratio > 0.5 indicates miR-5p dominant expression, and 0.5 > ratio >=0 indicates miR-3p dominant expression.	('miR-5p', 'Var', (90, 96))	('miR-5p', 'Chemical', '-', (90, 96))	('0.5 > ratio >', 'Var', (122, 135))
370694	30425004	We then defined an arm switching event between normal and tumour samples by finding a transformation between miR-5p and miR-3p dominant expression.	('miR-3p', 'Var', (120, 126))	('tumour', 'Phenotype', 'HP:0002664', (58, 64))	('tumour', 'Disease', 'MESH:D009369', (58, 64))	('miR-5p', 'Var', (109, 115))	('tumour', 'Disease', (58, 64))	('miR-5p', 'Chemical', '-', (109, 115))
370706	30425004	While most arm-switching events were consistent in arm preference (miR-5p to miR-3p or vice versa) in tumour tissues, hsa-mir-106b and hsa-mir-130b showed different arm preference depending upon the tumour (miR-5p dominant in some, miR-3p in others).	('tumour', 'Phenotype', 'HP:0002664', (199, 205))	('tumour', 'Phenotype', 'HP:0002664', (102, 108))	('miR-5p', 'Var', (207, 213))	('hsa-mir-130b', 'Gene', '406920', (135, 147))	('hsa-mir-130b', 'Gene', (135, 147))	('tumour', 'Disease', 'MESH:D009369', (199, 205))	('tumour', 'Disease', 'MESH:D009369', (102, 108))	('miR-5p', 'Chemical', '-', (67, 73))	('miR-5p', 'Chemical', '-', (207, 213))	('tumour', 'Disease', (199, 205))	('tumour', 'Disease', (102, 108))	('hsa-mir-106b', 'Gene', '406900', (118, 130))	('hsa-mir-106b', 'Gene', (118, 130))
370708	30425004	In order to explore the arm switching effect of the 51 pre-miRNAs, we performed GO and KEGG enrichment analysis for miR-3p and miR-5p arms, respectively.	('miR-5p', 'Var', (127, 133))	('miR-5p', 'Chemical', '-', (127, 133))	('miR-3p', 'Var', (116, 122))
370714	30425004	As a tumour promoter, miR-29-3p mediates epithelial-mesenchymal transition (EMT) and promotes metastasis in breast cancer and colon cancer.	('tumour', 'Disease', 'MESH:D009369', (5, 11))	('metastasis', 'CPA', (94, 104))	('epithelial-mesenchymal transition', 'CPA', (41, 74))	('miR-29-3p', 'Var', (22, 31))	('promotes', 'PosReg', (85, 93))	('tumour', 'Disease', (5, 11))	('mediates', 'Reg', (32, 40))	('colon cancer', 'Disease', 'MESH:D015179', (126, 138))	('colon cancer', 'Phenotype', 'HP:0003003', (126, 138))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('tumour', 'Phenotype', 'HP:0002664', (5, 11))	('breast cancer', 'Disease', 'MESH:D001943', (108, 121))	('breast cancer', 'Phenotype', 'HP:0003002', (108, 121))	('colon cancer', 'Disease', (126, 138))	('breast cancer', 'Disease', (108, 121))
370721	30425004	In most miRNAs, we could observe three patterns: miR-5p preference, miR-3p preference, and not expressed in tumours compared to others.	('tumours', 'Disease', (108, 115))	('miR-5p', 'Var', (49, 55))	('miR-5p', 'Chemical', '-', (49, 55))	('miR-3p', 'MPA', (68, 74))	('tumour', 'Phenotype', 'HP:0002664', (108, 114))	('tumours', 'Phenotype', 'HP:0002664', (108, 115))	('tumours', 'Disease', 'MESH:D009369', (108, 115))
370725	30425004	Some of the miRNAs were associated with increased survival in more than one cancer.	('miRNAs', 'Var', (12, 18))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('increased', 'PosReg', (40, 49))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))
370741	30425004	They were serum miRNAs: miR-369-5p, miR-30e-5p, and miR-423-3p and plasma miRNAs: miR-671-3p, miR-483-3p, and miR-744-5p.	('miR-483', 'Gene', (94, 101))	('miR-30e', 'Gene', '407034', (36, 43))	('miR-483', 'Gene', '619552', (94, 101))	('miR-744', 'Gene', '100126313', (110, 117))	('miR-369-5p', 'Var', (24, 34))	('miR-30e', 'Gene', (36, 43))	('miR-423-3p', 'Var', (52, 62))	('miR-671-3p', 'Var', (82, 92))	('miR-744', 'Gene', (110, 117))
370756	28978023	Here, we investigated 11 mucin expressing cancers for DNA mutations, mRNA expression, copy number, methylation, and the impacts these genomic features may have on patient survival by utilizing The Cancer Genome Atlas dataset.	('cancers', 'Disease', (42, 49))	('mutations', 'Var', (58, 67))	('Cancer', 'Disease', (197, 203))	('Cancer', 'Phenotype', 'HP:0002664', (197, 203))	('mucin', 'Gene', '100508689', (25, 30))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('Cancer', 'Disease', 'MESH:D009369', (197, 203))	('mucin', 'Gene', (25, 30))	('patient', 'Species', '9606', (163, 170))	('cancers', 'Phenotype', 'HP:0002664', (42, 49))	('cancers', 'Disease', 'MESH:D009369', (42, 49))
370757	28978023	We demonstrate that mucin DNA mutations have a significant rate, pattern, and impact on cancer patient survival depending on the tissue of origin.	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('patient', 'Species', '9606', (95, 102))	('mucin', 'Gene', (20, 25))	('impact', 'Reg', (78, 84))	('mutations', 'Var', (30, 39))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('mucin', 'Gene', '100508689', (20, 25))
370758	28978023	This includes a frequent T112P mutation in MUC1 that is seen in half of the pancreatic MUC1 mutations, as well as being present in other cancers.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('T112P', 'Mutation', 'rs753286956', (25, 30))	('pancreatic', 'Disease', (76, 86))	('MUC1', 'Gene', (43, 47))	('mutations', 'Var', (92, 101))	('cancers', 'Disease', 'MESH:D009369', (137, 144))	('T112P', 'Var', (25, 30))	('MUC1', 'Gene', '4582', (43, 47))	('cancers', 'Phenotype', 'HP:0002664', (137, 144))	('cancers', 'Disease', (137, 144))	('MUC1', 'Gene', (87, 91))	('MUC1', 'Gene', '4582', (87, 91))	('pancreatic', 'Disease', 'MESH:D010195', (76, 86))
370764	28978023	Thus, our study presents a comprehensive analysis of genomic alterations in mucins and their corresponding roles in cancer progression.	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('mucin', 'Gene', '100508689', (76, 81))	('genomic alterations', 'Var', (53, 72))	('roles', 'Reg', (107, 112))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('mucin', 'Gene', (76, 81))
370797	28978023	Hence, we undertook a pan-mucin genomic study across multiple cancers to investigate potential new avenues and to discover new alterations that may impact the mucin functions in cancers.	('impact', 'Reg', (148, 154))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('mucin', 'Gene', (26, 31))	('mucin', 'Gene', '100508689', (159, 164))	('cancers', 'Disease', 'MESH:D009369', (178, 185))	('cancers', 'Phenotype', 'HP:0002664', (178, 185))	('cancers', 'Disease', (178, 185))	('multiple cancers', 'Disease', (53, 69))	('cancers', 'Disease', 'MESH:D009369', (62, 69))	('alterations', 'Var', (127, 138))	('cancers', 'Phenotype', 'HP:0002664', (62, 69))	('mucin', 'Gene', (159, 164))	('mucin', 'Gene', '100508689', (26, 31))	('cancers', 'Disease', (62, 69))	('multiple cancers', 'Disease', 'MESH:D009369', (53, 69))
370801	28978023	The rate of mutations varies from mucin to mucin depending on the histological cohort (Figures 1A, 1B, and Supplementary Dataset 1).	('mucin', 'Gene', (43, 48))	('mutations', 'Var', (12, 21))	('mucin', 'Gene', (34, 39))	('mucin', 'Gene', '100508689', (43, 48))	('mucin', 'Gene', '100508689', (34, 39))
370802	28978023	Kidney papillary cell carcinoma (KIRP) shows the largest relative mutation rate for MUC2, while no other histological subtypes appear to favor MUC2 mutations to a similar degree (Figure 1C).	('MUC2', 'Gene', (143, 147))	('Kidney papillary cell carcinoma', 'Disease', (0, 31))	('MUC2', 'Gene', '4583', (143, 147))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('mutation', 'Var', (66, 74))	('MUC2', 'Gene', (84, 88))	('MUC2', 'Gene', '4583', (84, 88))	('Kidney papillary cell carcinoma', 'Disease', 'MESH:C538614', (0, 31))
370804	28978023	Like KIRP, kidney clear cell carcinoma (KIRC) trends with lower rate of mucin mutations, except for MUC4, which shows a cluster of in-frame deletions for KIRC (Figure 1D).	('kidney clear cell carcinoma', 'Disease', (11, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (29, 38))	('MUC4', 'Gene', (100, 104))	('mucin', 'Gene', '100508689', (72, 77))	('mutations', 'Var', (78, 87))	('mucin', 'Gene', (72, 77))	('MUC4', 'Gene', '4585', (100, 104))	('kidney clear cell carcinoma', 'Disease', 'MESH:C538614', (11, 38))
370805	28978023	Uterine corpus endometrioid endometrial adenocarcinoma (UEC) appears to acquire more mutations in multiple mucins, including MUC5B and MUC17, which becomes very prominent in stage III (Figures 1A, 1B, and Supplementary Dataset 1).	('carcinoma', 'Phenotype', 'HP:0030731', (45, 54))	('endometrial adenocarcinoma', 'Phenotype', 'HP:0012114', (28, 54))	('mucin', 'Gene', '100508689', (107, 112))	('mutations', 'Var', (85, 94))	('endometrioid endometrial adenocarcinoma', 'Disease', 'MESH:D016889', (15, 54))	('MUC5B', 'Gene', '727897', (125, 130))	('endometrioid endometrial adenocarcinoma', 'Disease', (15, 54))	('mucin', 'Gene', (107, 112))	('MUC5B', 'Gene', (125, 130))	('MUC17', 'Gene', '140453', (135, 140))	('MUC17', 'Gene', (135, 140))
370806	28978023	UEC tumors also have mutations in other mucins, such as MUC4 and MUC16, however, the mutation rates are much lower (Figure 1D and 1E).	('MUC4', 'Gene', '4585', (56, 60))	('MUC16', 'Gene', '94025', (65, 70))	('mucin', 'Gene', (40, 45))	('UEC', 'Disease', (0, 3))	('tumors', 'Disease', (4, 10))	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('MUC4', 'Gene', (56, 60))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('mucin', 'Gene', '100508689', (40, 45))	('MUC16', 'Gene', (65, 70))	('mutations', 'Var', (21, 30))
370809	28978023	Lung squamous cell carcinoma (LUSC) and lung adenocarcinoma (LUAD) share MUC16 and MUC17 mutations at a similar rate between the histological subtypes.	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (40, 59))	('MUC16', 'Gene', (73, 78))	('carcinoma', 'Phenotype', 'HP:0030731', (19, 28))	('carcinoma', 'Phenotype', 'HP:0030731', (50, 59))	('MUC17', 'Gene', '140453', (83, 88))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (5, 28))	('Lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (0, 28))	('MUC16', 'Gene', '94025', (73, 78))	('lung adenocarcinoma', 'Disease', (40, 59))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (5, 28))	('mutations', 'Var', (89, 98))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (40, 59))	('squamous cell carcinoma', 'Disease', (5, 28))	('MUC17', 'Gene', (83, 88))	('LUSC', 'Phenotype', 'HP:0030359', (30, 34))	('LUAD', 'Phenotype', 'HP:0030078', (61, 65))
370810	28978023	Lastly, despite many cancers observed not to harbor mutations in MUC12 and MUC19, breast cancer appears to have a unique profile.	('mutations', 'Var', (52, 61))	('breast cancer', 'Disease', (82, 95))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('breast cancer', 'Phenotype', 'HP:0003002', (82, 95))	('MUC12', 'Gene', (65, 70))	('cancers', 'Disease', 'MESH:D009369', (21, 28))	('MUC19', 'Gene', '283463', (75, 80))	('cancers', 'Phenotype', 'HP:0002664', (21, 28))	('cancers', 'Disease', (21, 28))	('breast cancer', 'Disease', 'MESH:D001943', (82, 95))	('MUC12', 'Gene', '10071', (65, 70))	('MUC19', 'Gene', (75, 80))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
370811	28978023	Furthermore, location specific mutations may indicate a significant role of the residue or protein domain(s) in cancer pathogenesis.	('mutations', 'Var', (31, 40))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('protein', 'Protein', (91, 98))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))
370813	28978023	A total of five tissues were observed with MUC1 mutations (Supplementary Table 2).	('mutations', 'Var', (48, 57))	('MUC1', 'Gene', (43, 47))	('MUC1', 'Gene', '4582', (43, 47))
370814	28978023	Non-papillary bladder cancer, pancreatic ductal adenocarcinomas (PDAC), and stomach intestinal adenocarcinoma not otherwise specified (SIA NOS) were the only tissues that were observed to have MUC1 mutation(s) at stage II cancer (Figures 2A and Supplementary Table 2).	('II cancer', 'Disease', 'MESH:D009369', (219, 228))	('Non-papillary bladder cancer', 'Disease', (0, 28))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('II cancer', 'Disease', (219, 228))	('PDAC', 'Chemical', '-', (65, 69))	('MUC1', 'Gene', (193, 197))	('MUC1', 'Gene', '4582', (193, 197))	('pancreatic ductal adenocarcinomas', 'Disease', 'MESH:D021441', (30, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (53, 62))	('pancreatic ductal adenocarcinomas', 'Disease', (30, 63))	('carcinomas', 'Phenotype', 'HP:0030731', (53, 63))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('stomach intestinal adenocarcinoma', 'Disease', 'MESH:D013274', (76, 109))	('mutation', 'Var', (198, 206))	('stomach intestinal adenocarcinoma', 'Disease', (76, 109))	('SIA', 'Disease', (135, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('SIA', 'Disease', 'None', (135, 138))	('bladder cancer', 'Phenotype', 'HP:0009725', (14, 28))	('Non-papillary bladder cancer', 'Disease', 'MESH:D001749', (0, 28))
370815	28978023	Half of stage II PDAC MUC1 mutations are T112P.	('mutations', 'Var', (27, 36))	('T112P', 'Mutation', 'rs753286956', (41, 46))	('MUC1', 'Gene', (22, 26))	('MUC1', 'Gene', '4582', (22, 26))	('T112P', 'Var', (41, 46))	('PDAC', 'Chemical', '-', (17, 21))
370816	28978023	Altogether, 5/8 of stage II MUC1 mutations are T112P and 31.25% of MUC1 mutations observed in all stages were T112P.	('MUC1', 'Gene', '4582', (28, 32))	('T112P', 'Var', (47, 52))	('T112P', 'Mutation', 'rs753286956', (110, 115))	('MUC1', 'Gene', (67, 71))	('MUC1', 'Gene', '4582', (67, 71))	('mutations', 'Var', (33, 42))	('T112P', 'Mutation', 'rs753286956', (47, 52))	('T112P', 'Var', (110, 115))	('MUC1', 'Gene', (28, 32))
370817	28978023	MUC2 mutations increase with the increasing disease stage in KIRP, appearing in 9.5% of stage I KIRP (n = 95) and up to 50% of stage IV KIRP cancers (n = 10).	('MUC2', 'Gene', (0, 4))	('MUC2', 'Gene', '4583', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('mutations', 'Var', (5, 14))	('cancers', 'Phenotype', 'HP:0002664', (141, 148))	('cancers', 'Disease', 'MESH:D009369', (141, 148))	('cancers', 'Disease', (141, 148))	('stage I KIRP', 'Disease', (88, 100))
370818	28978023	MUC2 shows a large cluster of mutations with a Gaussian distribution across tissues with the mode at T1538 (Figure 2B).	('mutations', 'Var', (30, 39))	('T1538', 'Var', (101, 106))	('MUC2', 'Gene', (0, 4))	('MUC2', 'Gene', '4583', (0, 4))
370819	28978023	Many of the multiple mutations appear to target threonine and appear to include multiple silent mutations, perhaps suggesting a role of the region in regulating transcription, mRNA stability, or non-coding RNAs.	('threonine', 'MPA', (48, 57))	('transcription', 'MPA', (161, 174))	('threonine', 'Chemical', 'MESH:D013912', (48, 57))	('mRNA stability', 'MPA', (176, 190))	('target', 'Reg', (41, 47))	('mutations', 'Var', (21, 30))
370820	28978023	Amino acid changes observed in more than one patient in the cluster spanning from residues 1353-1652 target the threonine codon in over 85% of the cases.	('Amino acid changes', 'Var', (0, 18))	('target', 'Reg', (101, 107))	('threonine codon', 'MPA', (112, 127))	('patient', 'Species', '9606', (45, 52))	('threonine', 'Chemical', 'MESH:D013912', (112, 121))
370821	28978023	Within this dense cluster, three non-damaging T1488P mutations are observed in KIRP, while three T1568M mutations are observed once in KIRP, rectal adenocarcinoma (READ), and uterine endometrioid endometrial adenocarcinoma (UEC).	('EA', 'Chemical', '-', (165, 167))	('T1488P', 'Var', (46, 52))	('endometrial adenocarcinoma', 'Phenotype', 'HP:0012114', (196, 222))	('carcinoma', 'Phenotype', 'HP:0030731', (153, 162))	('T1488P', 'Mutation', 'rs149562922', (46, 52))	('rectal adenocarcinoma', 'Disease', (141, 162))	('rectal adenocarcinoma', 'Disease', 'MESH:D012004', (141, 162))	('endometrioid endometrial adenocarcinoma', 'Disease', 'MESH:D016889', (183, 222))	('endometrioid endometrial adenocarcinoma', 'Disease', (183, 222))	('carcinoma', 'Phenotype', 'HP:0030731', (213, 222))	('T1568M', 'Mutation', 'rs78684063', (97, 103))
370822	28978023	UEC has a large percent of the MUC3A mutations with 11 out of the 35 of the mutations in MUC3A, of which, over a third of the UEC mutations occur at S207, with two in-frame insertions and one non-synonymous mutation (Supplementary Table 2 and Supplementary Dataset 2).	('MUC3A', 'Gene', '4584', (31, 36))	('UEC', 'Gene', (126, 129))	('MUC3A', 'Gene', (89, 94))	('mutations', 'Var', (130, 139))	('MUC3A', 'Gene', '4584', (89, 94))	('MUC3A', 'Gene', (31, 36))
370825	28978023	Furthermore, compared to silent mutations, non-damaging MUC4 mutations are drastically increased in KIRC, resulting in amino acid changing mutations to be 19.8% in stage I (n = 197), 35.0% in stage II (n = 40), 32.2% in stage III (n = 112), and 44.1% in stage IV (n = 68).	('MUC4', 'Gene', '4585', (56, 60))	('mutations', 'Var', (139, 148))	('mutations', 'Var', (61, 70))	('MUC4', 'Gene', (56, 60))	('amino acid changing', 'MPA', (119, 138))
370826	28978023	UEC also has an increased rate of non-damaging mutations for MUC4 that increase with the increasing stages, ultimately resulting in 41.4% single nucleotide variation (SNVs) mutations in stage III (n = 29) (Figure 1D).	('MUC4', 'Gene', (61, 65))	('single nucleotide variation', 'Var', (138, 165))	('mutations', 'Var', (47, 56))	('mutations', 'Var', (173, 182))	('MUC4', 'Gene', '4585', (61, 65))	('resulting in', 'Reg', (119, 131))
370827	28978023	This dataset reveals all 10 H4205Q MUC4 mutations occur as 10 G < C; half of which are from KIRC, three from bladder cancer, and two from LUAD (Figure 2C and Supplementary Table 2).	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('MUC4', 'Gene', '4585', (35, 39))	('LUAD', 'Phenotype', 'HP:0030078', (138, 142))	('bladder cancer', 'Disease', 'MESH:D001749', (109, 123))	('MUC4', 'Gene', (35, 39))	('H4205Q', 'Mutation', 'rs369326402', (28, 34))	('bladder cancer', 'Disease', (109, 123))	('H4205Q', 'Var', (28, 34))	('bladder cancer', 'Phenotype', 'HP:0009725', (109, 123))
370828	28978023	In KIRC, high rates of in-frame deletions occur compared to other tissues for MUC4 (Figure 2C).	('MUC4', 'Gene', '4585', (78, 82))	('deletions', 'Var', (32, 41))	('MUC4', 'Gene', (78, 82))
370831	28978023	Lastly, multiple positions in MUC4 had at least two mutations at the same position, which overall suggests a role of mutations in MUC4, especially in KIRC.	('MUC4', 'Gene', (30, 34))	('mutations', 'Var', (117, 126))	('role', 'Reg', (109, 113))	('MUC4', 'Gene', '4585', (130, 134))	('MUC4', 'Gene', '4585', (30, 34))	('MUC4', 'Gene', (130, 134))
370834	28978023	MUC6 has a relatively high mutation rate in stage II PDAC, where 9.6% (n = 114) of the mutations caused amino acid changes, while no silent mutations were discovered.	('MUC6', 'Gene', '4588', (0, 4))	('caused', 'Reg', (97, 103))	('MUC6', 'Gene', (0, 4))	('amino', 'MPA', (104, 109))	('PDAC', 'Chemical', '-', (53, 57))	('mutations', 'Var', (87, 96))
370835	28978023	Furthermore, breast invasive carcinoma (BRCA) harbors three frameshift insertions at L2241, while KIRC has two at P1570.	('L2241', 'Var', (85, 90))	('carcinoma', 'Phenotype', 'HP:0030731', (29, 38))	('breast invasive carcinoma (BRCA', 'Gene', (13, 44))	('BRCA', 'Phenotype', 'HP:0003002', (40, 44))	('breast invasive carcinoma (BRCA)', 'Gene', '672', (13, 45))	('breast invasive carcinoma', 'Phenotype', 'HP:0003002', (13, 38))
370837	28978023	Three of the seven non-damaging UEC stage I (n = 149) mutations were found to be S336L in MUC7.	('S336L', 'Var', (81, 86))	('S336L', 'Mutation', 'p.S336L', (81, 86))	('UEC stage I', 'Gene', (32, 43))	('MUC7', 'Gene', '4589', (90, 94))	('MUC7', 'Gene', (90, 94))
370839	28978023	A wide range of mutations in MUC12 have been found to associate with many BRCA histological subtypes as well as UEC.	('UEC', 'Disease', (112, 115))	('MUC12', 'Gene', (29, 34))	('MUC12', 'Gene', '10071', (29, 34))	('associate', 'Reg', (54, 63))	('mutations', 'Var', (16, 25))	('BRCA', 'Phenotype', 'HP:0003002', (74, 78))	('BRCA', 'Gene', '672', (74, 78))	('BRCA', 'Gene', (74, 78))
370840	28978023	Most striking is estrogen-receptor and progesterone-receptor-positive BRCA - stage II (n = 279) with 12.2% patient tumors having amino acid altering mutations.	('estrogen-receptor', 'Gene', (17, 34))	('BRCA', 'Phenotype', 'HP:0003002', (70, 74))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('BRCA', 'Gene', '672', (70, 74))	('tumors', 'Disease', (115, 121))	('tumors', 'Disease', 'MESH:D009369', (115, 121))	('patient', 'Species', '9606', (107, 114))	('BRCA', 'Gene', (70, 74))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('progesterone-receptor', 'Gene', '5241', (39, 60))	('amino acid altering mutations', 'Var', (129, 158))	('progesterone-receptor', 'Gene', (39, 60))	('estrogen-receptor', 'Gene', '2099', (17, 34))
370841	28978023	Most strikingly, multiple mutations appear to target arginine (R) in BRCA, where it is converted into either cysteine (C) or histidine (H).	('histidine', 'Chemical', 'MESH:D006639', (125, 134))	('BRCA', 'Phenotype', 'HP:0003002', (69, 73))	('target', 'Reg', (46, 52))	('BRCA', 'Gene', '672', (69, 73))	('arginine', 'Chemical', 'MESH:D001120', (53, 61))	('cysteine', 'MPA', (109, 117))	('arginine', 'MPA', (53, 61))	('BRCA', 'Gene', (69, 73))	('mutations', 'Var', (26, 35))	('cysteine', 'Chemical', 'MESH:D003545', (109, 117))
370843	28978023	Another event is seen at R2777 in BRCA, in which two mutations result in histidine and one becomes cysteine.	('BRCA', 'Gene', '672', (34, 38))	('BRCA', 'Gene', (34, 38))	('result in', 'Reg', (63, 72))	('R2777', 'Var', (25, 30))	('histidine', 'MPA', (73, 82))	('cysteine', 'Chemical', 'MESH:D003545', (99, 107))	('histidine', 'Chemical', 'MESH:D006639', (73, 82))	('BRCA', 'Phenotype', 'HP:0003002', (34, 38))
370844	28978023	Lastly, three A1933 frame shift insertions and three P4621T mutations and were observed in BRCA.	('BRCA', 'Gene', (91, 95))	('P4621T mutations', 'Var', (53, 69))	('A1933 frame shift', 'Var', (14, 31))	('BRCA', 'Phenotype', 'HP:0003002', (91, 95))	('P4621T', 'Mutation', 'p.P4621T', (53, 59))	('BRCA', 'Gene', '672', (91, 95))
370846	28978023	MUC16 is a very large transmembrane protein whose mutation rate is relatively high in colon adenocarcinoma (COAD) and colon mucinous adenocarcinoma (COMA) cancers, LUAD, bladder urothelial carcinoma (BLCA), PDAC, and UEC (Figure 1E).	('COMA', 'Phenotype', 'HP:0001259', (149, 153))	('LUAD', 'Disease', (164, 168))	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('colon mucinous adenocarcinoma (COMA) cancers', 'Disease', 'MESH:C537423', (118, 162))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (170, 198))	('BLCA', 'Chemical', '-', (200, 204))	('mutation', 'Var', (50, 58))	('PDAC', 'Disease', (207, 211))	('COAD', 'Disease', 'MESH:D029424', (108, 112))	('colon adenocarcinoma', 'Disease', (86, 106))	('MUC16', 'Gene', '94025', (0, 5))	('UEC', 'Disease', (217, 220))	('high', 'Reg', (78, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (189, 198))	('COAD', 'Disease', (108, 112))	('PDAC', 'Chemical', '-', (207, 211))	('cancers', 'Phenotype', 'HP:0002664', (155, 162))	('MUC16', 'Gene', (0, 5))	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('colon adenocarcinoma', 'Disease', 'MESH:D003110', (86, 106))	('LUAD', 'Phenotype', 'HP:0030078', (164, 168))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('bladder urothelial carcinoma', 'Disease', (170, 198))
370847	28978023	Non-damaging nonsynonymous mutations occur in 62.5% of stage II COAD, which is 3.3-fold higher than silent mutations.	('nonsynonymous mutations', 'Var', (13, 36))	('COAD', 'Disease', (64, 68))	('COAD', 'Disease', 'MESH:D029424', (64, 68))
370850	28978023	LUAD shows a trend of increased nonsense mutations in MUC16.	('MUC16', 'Gene', '94025', (54, 59))	('nonsense mutations', 'Var', (32, 50))	('MUC16', 'Gene', (54, 59))	('LUAD', 'Phenotype', 'HP:0030078', (0, 4))
370851	28978023	In the case of PDAC, 43.0% of specimens have amino acid altering mutations, with 14.9% of these mutations resulting in frameshifts or deletions.	('deletions', 'Var', (134, 143))	('amino acid altering mutations', 'Var', (45, 74))	('frameshifts', 'MPA', (119, 130))	('PDAC', 'Chemical', '-', (15, 19))	('resulting', 'Reg', (106, 115))
370853	28978023	In other cancers, R8606 has four amino acid changing mutations (Supplementary Table 2).	('cancers', 'Disease', 'MESH:D009369', (9, 16))	('cancers', 'Phenotype', 'HP:0002664', (9, 16))	('cancers', 'Disease', (9, 16))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('R8606', 'Var', (18, 23))
370854	28978023	MUC20 mutations do not appear to be common, only three A515 frameshift deletions standout (Supplementary Table 2 and Supplementary Figure 1).	('A515 frameshift deletions', 'Var', (55, 80))	('MUC20', 'Gene', (0, 5))	('MUC20', 'Gene', '200958', (0, 5))
370855	28978023	MUC13 also has a very low mutation profile with three R324W SNVs and two S185 amino acid altering mutations predicted to be damaging.	('S185 amino acid altering', 'Var', (73, 97))	('R324W', 'Mutation', 'p.R324W', (54, 59))	('MUC13', 'Gene', '56667', (0, 5))	('R324W', 'Var', (54, 59))	('MUC13', 'Gene', (0, 5))
370857	28978023	Since half of the MUC1 mutations in stage II PDAC specimens had mutations at T112P in MUC1 (Figure 2A), we examined the mutational impact on survival in the cohort.	('MUC1', 'Gene', (86, 90))	('PDAC', 'Chemical', '-', (45, 49))	('MUC1', 'Gene', '4582', (86, 90))	('mutations', 'Var', (23, 32))	('mutations at T112P', 'Var', (64, 82))	('T112P', 'Mutation', 'rs753286956', (77, 82))	('MUC1', 'Gene', (18, 22))	('MUC1', 'Gene', '4582', (18, 22))
370860	28978023	Despite high occurrences, these mutations appear to improve survival of the patient in stage III KIRC (Figure 3B).	('survival', 'MPA', (60, 68))	('mutations', 'Var', (32, 41))	('improve', 'PosReg', (52, 59))	('patient', 'Species', '9606', (76, 83))
370861	28978023	Further examination of the impact of MUC4 mutations on patient survival highlights that not all mutations in a gene are potentially beneficial to the patient.	('patient', 'Species', '9606', (150, 157))	('MUC4', 'Gene', '4585', (37, 41))	('patient', 'Species', '9606', (55, 62))	('mutations', 'Var', (42, 51))	('MUC4', 'Gene', (37, 41))	('mutations', 'Var', (96, 105))
370862	28978023	A nearly significant (p = 0.0795) in-frame mutation at 4045 is associated with increased aggressive behavior of the tumor, while all other mutations appeared to have improved survival compared to patients without MUC4 mutations in KIRC stage I patients (Figure 3C).	('in-frame mutation at 4045', 'Var', (34, 59))	('increased', 'PosReg', (79, 88))	('survival', 'CPA', (175, 183))	('aggressive behavior', 'Disease', (89, 108))	('MUC4', 'Gene', (213, 217))	('aggressive behavior', 'Disease', 'MESH:D001523', (89, 108))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('patients', 'Species', '9606', (196, 204))	('improved', 'PosReg', (166, 174))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('aggressive behavior', 'Phenotype', 'HP:0000718', (89, 108))	('patients', 'Species', '9606', (244, 252))	('MUC4', 'Gene', '4585', (213, 217))	('tumor', 'Disease', (116, 121))
370892	28978023	Here we report frequent copy number gains in MUC1 and the locus 3q29 containing MUC4 and MUC20 (Figure 6A and 6B).	('MUC1', 'Gene', '4582', (45, 49))	('copy number gains', 'Var', (24, 41))	('MUC4', 'Gene', '4585', (80, 84))	('MUC4', 'Gene', (80, 84))	('MUC1', 'Gene', (45, 49))	('MUC20', 'Gene', (89, 94))	('MUC20', 'Gene', '200958', (89, 94))
370893	28978023	MUC1 copy gain state predominates for several cohorts of BRCA, stages I and II of ovarian serous cystadenocarcinoma (OSC), and stage II UEC.	('copy', 'Var', (5, 9))	('ovarian serous cystadenocarcinoma', 'Phenotype', 'HP:0012887', (82, 115))	('II of ovarian serous cystadenocarcinoma', 'Disease', 'MESH:D018284', (76, 115))	('II of ovarian serous cystadenocarcinoma', 'Disease', (76, 115))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('OSC', 'Phenotype', 'HP:0012887', (117, 120))	('BRCA', 'Phenotype', 'HP:0003002', (57, 61))	('BRCA', 'Gene', '672', (57, 61))	('MUC1', 'Gene', (0, 4))	('MUC1', 'Gene', '4582', (0, 4))	('BRCA', 'Gene', (57, 61))
370896	28978023	After adjusting for multiple hypothesis testing within each histology, only MUC1 in KIRP was found to significantly impact patient survival for both univariate (HR = 20.1; q = 5.8E-6) and multivariate (HR = 12.9; q = 0.01), indicating a possible negative role of MUC1 copy number increase in patient survival (Supplementary Table 5).	('MUC1', 'Gene', (76, 80))	('MUC1', 'Gene', '4582', (76, 80))	('impact', 'Reg', (116, 122))	('patient', 'Species', '9606', (123, 130))	('MUC1', 'Gene', (263, 267))	('increase', 'PosReg', (280, 288))	('MUC1', 'Gene', '4582', (263, 267))	('patient', 'Species', '9606', (292, 299))	('copy number', 'Var', (268, 279))	('patient survival', 'CPA', (123, 139))	('negative', 'NegReg', (246, 254))
370910	28978023	The MUC15 promoter methylation has strong impact on patient survival with LUAD; it was discovered to have a significant (q = 0.0001) astounding HR of 64.1 when corrected by a multiple regression analysis and a univariate HR of 30.2 (q = 0.0017) (Supplementary Table 6).	('methylation', 'Var', (19, 30))	('MUC15', 'Gene', (4, 9))	('impact', 'Reg', (42, 48))	('patient', 'Species', '9606', (52, 59))	('LUAD', 'Phenotype', 'HP:0030078', (74, 78))	('MUC15', 'Gene', '143662', (4, 9))
370913	28978023	To further understand the genomic significance of mucins, 37 histological subtypes across 12 cancers were examined for mutations, mRNA, copy number, methylation profile, de novo expression and silencing, and the impact on survival.	('cancers', 'Disease', (93, 100))	('mucin', 'Gene', (50, 55))	('cancers', 'Phenotype', 'HP:0002664', (93, 100))	('expression', 'MPA', (178, 188))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('mRNA', 'MPA', (130, 134))	('mucin', 'Gene', '100508689', (50, 55))	('silencing', 'MPA', (193, 202))	('mutations', 'Var', (119, 128))	('cancers', 'Disease', 'MESH:D009369', (93, 100))
370918	28978023	MUC1 is overexpressed in more than 90% of breast carcinomas and we hereby report that copy number might play a significant role in this tissue, as copy gain was frequently seen in breast cancer (Figure 6A and 6B).	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('carcinomas', 'Phenotype', 'HP:0030731', (49, 59))	('breast carcinomas', 'Disease', 'MESH:D001943', (42, 59))	('breast cancer', 'Phenotype', 'HP:0003002', (180, 193))	('breast carcinomas', 'Disease', (42, 59))	('breast cancer', 'Disease', 'MESH:D001943', (180, 193))	('copy', 'Var', (147, 151))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('breast cancer', 'Disease', (180, 193))	('breast carcinomas', 'Phenotype', 'HP:0003002', (42, 59))	('MUC1', 'Gene', (0, 4))	('MUC1', 'Gene', '4582', (0, 4))
370919	28978023	These observations are further supported by a significant correlation of MUC1 mRNA in breast cancer with copy number (q = 3.65E-09) (Supplementary Table 7), but not with methylation (Supplementary Table 8), after correcting for multiple hypotheses.	('MUC1', 'Gene', (73, 77))	('MUC1', 'Gene', '4582', (73, 77))	('correlation', 'Interaction', (58, 69))	('copy number', 'Var', (105, 116))	('mRNA', 'Var', (78, 82))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('breast cancer', 'Disease', 'MESH:D001943', (86, 99))	('breast cancer', 'Phenotype', 'HP:0003002', (86, 99))	('breast cancer', 'Disease', (86, 99))
370920	28978023	Furthermore, we report that only a few cancer subtypes carry MUC1 mutations, where extracellular region point mutation T112P was commonly seen and responsible for 50% of the MUC1 mutations observed in PDAC (Figure 1 and Supplementary Table 2).	('mutations', 'Var', (66, 75))	('cancer', 'Disease', (39, 45))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('MUC1', 'Gene', (61, 65))	('PDAC', 'Chemical', '-', (201, 205))	('MUC1', 'Gene', '4582', (61, 65))	('MUC1', 'Gene', (174, 178))	('MUC1', 'Gene', '4582', (174, 178))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('mutations', 'Var', (179, 188))	('T112P', 'Mutation', 'rs753286956', (119, 124))
370922	28978023	However, the only cohort with enough mutations to test survival was in stage II PDAC, in which the corresponding patients were too newly enrolled to obtain any meaningful statistics for survival comparisons (Figure 3A).	('mutations', 'Var', (37, 46))	('patients', 'Species', '9606', (113, 121))	('PDAC', 'Disease', (80, 84))	('PDAC', 'Chemical', '-', (80, 84))
370927	28978023	Furthermore, MUC2 is seen to have a Gaussian distribution of mutations around T1538 (Figure 2B), many of which are threonine, a key component for glycosylation.	('MUC2', 'Gene', (13, 17))	('T1538', 'Gene', (78, 83))	('threonine', 'Chemical', 'MESH:D013912', (115, 124))	('mutations', 'Var', (61, 70))	('MUC2', 'Gene', '4583', (13, 17))
370931	28978023	If there is truly low abundance of mRNA, it is rather unclear why mutations in MUC2 appear to cluster together in KIRP.	('mutations', 'Var', (66, 75))	('MUC2', 'Gene', '4583', (79, 83))	('MUC2', 'Gene', (79, 83))
370940	28978023	Copy number alterations may contribute significantly to MUC4 expression, as the genomic segment containing MUC4 and MUC20 demonstrates copy gains in over 50% of the specimens in all stages of LUSC, later stages of OSC, and in USEC.	('copy', 'Var', (135, 139))	('MUC4', 'Gene', '4585', (56, 60))	('MUC4', 'Gene', '4585', (107, 111))	('MUC4', 'Gene', (56, 60))	('MUC4', 'Gene', (107, 111))	('MUC20', 'Gene', (116, 121))	('LUSC', 'Phenotype', 'HP:0030359', (192, 196))	('MUC20', 'Gene', '200958', (116, 121))	('OSC', 'Phenotype', 'HP:0012887', (214, 217))
370941	28978023	Positive significant correlations between mRNA and copy number were seen in breast and pancreatic cancer histological subtypes (r = 0.14 and r = 0.38, respectively) (Supplementary Table 7).	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('breast and pancreatic cancer', 'Disease', 'MESH:D010190', (76, 104))	('copy number', 'Var', (51, 62))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (87, 104))	('mRNA', 'MPA', (42, 46))
370942	28978023	Here we also shed light on the significance of mutations in MUC4, especially in KIRC.	('MUC4', 'Gene', (60, 64))	('MUC4', 'Gene', '4585', (60, 64))	('mutations', 'Var', (47, 56))
370943	28978023	Although MUC4 is a rather large gene, repeated mutations and matching in-frame deletions in the same position where seen, especially H4205Q, which we believe should be further investigated.	('H4205Q', 'Mutation', 'rs369326402', (133, 139))	('MUC4', 'Gene', '4585', (9, 13))	('H4205Q', 'Var', (133, 139))	('MUC4', 'Gene', (9, 13))
370961	28978023	This study reveals demethylations of mucin CpG are very frequent in cancer (Figure 7).	('demethylations', 'Var', (19, 33))	('mucin', 'Gene', (37, 42))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('mucin', 'Gene', '100508689', (37, 42))	('cancer', 'Disease', (68, 74))	('frequent', 'Reg', (56, 64))
370964	28978023	Lastly, MUC15 and MUC20 methylation also appears to be of interest beyond renal carcinomas (Figure 7).	('renal carcinomas', 'Disease', 'MESH:C538614', (74, 90))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('MUC15', 'Gene', (8, 13))	('MUC20', 'Gene', '200958', (18, 23))	('carcinomas', 'Phenotype', 'HP:0030731', (80, 90))	('renal carcinoma', 'Phenotype', 'HP:0005584', (74, 89))	('methylation', 'Var', (24, 35))	('renal carcinomas', 'Disease', (74, 90))	('MUC15', 'Gene', '143662', (8, 13))	('renal carcinomas', 'Phenotype', 'HP:0005584', (74, 90))	('MUC20', 'Gene', (18, 23))
370968	28978023	Lastly, despite not being of kidney origin, LUAD MUC15 methylation was associated with a multiple regression HR of 64.1 (q = 0.0001) and a univariate HR of 30.2 (q = 0.0017) (Supplementary Table 6).	('LUAD', 'Gene', (44, 48))	('MUC15', 'Gene', '143662', (49, 54))	('methylation', 'Var', (55, 66))	('LUAD', 'Phenotype', 'HP:0030078', (44, 48))	('MUC15', 'Gene', (49, 54))
370970	28978023	Furthermore, within KIRP, MUC1 copy number had a large impact on survival for both univariate (HR = 20.1; q = 5.8E-6) and multivariate (HR = 12.9; q = 0.01) analyses (Supplementary Table 5).	('MUC1', 'Gene', (26, 30))	('MUC1', 'Gene', '4582', (26, 30))	('copy number', 'Var', (31, 42))	('impact', 'Reg', (55, 61))	('survival', 'MPA', (65, 73))
370972	28978023	Many significantly aberrant mRNA expression levels were observed in conjunction with histological subtypes favoring certain mucin mutations as well as location specific mutations.	('aberrant', 'Reg', (19, 27))	('mucin', 'Gene', '100508689', (124, 129))	('mutations', 'Var', (130, 139))	('mRNA expression levels', 'MPA', (28, 50))	('mucin', 'Gene', (124, 129))
371000	28978023	Both the univariate and multivariate Cox-proportional hazard regressions were used to evaluate the associations between the copy number, methylation, log2 scaled mRNA expression levels with the survival of each patient.	('mRNA expression levels', 'MPA', (162, 184))	('methylation', 'Var', (137, 148))	('log2', 'MPA', (150, 154))	('associations', 'Interaction', (99, 111))	('copy number', 'Var', (124, 135))	('patient', 'Species', '9606', (211, 218))	('Cox', 'Gene', '1351', (37, 40))	('Cox', 'Gene', (37, 40))
371004	26372664	Radon Exposure, IL-6 Promoter Variants, and Lung Squamous Cell Carcinoma in Former Uranium Miners High radon exposure is a risk factor for squamous cell carcinoma, a major lung cancer histology observed in former uranium miners.	('IL-6', 'Gene', (16, 20))	('squamous cell carcinoma', 'Disease', (139, 162))	('carcinoma', 'Phenotype', 'HP:0030731', (153, 162))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('Squamous Cell Carcinoma', 'Disease', 'MESH:D002294', (49, 72))	('miners', 'Species', '265634', (221, 227))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (49, 72))	('lung cancer', 'Disease', (172, 183))	('Squamous Cell Carcinoma', 'Disease', (49, 72))	('Variants', 'Var', (30, 38))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (139, 162))	('uranium', 'Chemical', 'MESH:D014501', (213, 220))	('Uranium', 'Chemical', 'MESH:D014501', (83, 90))	('Lung Squamous Cell Carcinoma', 'Phenotype', 'HP:0030359', (44, 72))	('lung cancer', 'Disease', 'MESH:D008175', (172, 183))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (139, 162))	('lung cancer', 'Phenotype', 'HP:0100526', (172, 183))	('Carcinoma', 'Phenotype', 'HP:0030731', (63, 72))	('IL-6', 'Gene', '3569', (16, 20))
371007	26372664	We assessed whether single nucleotide polymorphisms (SNPs) in the IL6 promoter are associated with lung cancer in former uranium miners with high occupational exposure to radon gas.	('lung cancer', 'Disease', (99, 110))	('uranium', 'Chemical', 'MESH:D014501', (121, 128))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('IL6', 'Gene', '3569', (66, 69))	('IL6', 'Gene', (66, 69))	('miners', 'Species', '265634', (129, 135))	('lung cancer', 'Disease', 'MESH:D008175', (99, 110))	('associated', 'Reg', (83, 93))	('single nucleotide polymorphisms', 'Var', (20, 51))	('lung cancer', 'Phenotype', 'HP:0100526', (99, 110))
371010	26372664	We found that rs1800797 was associated with squamous cell carcinoma in miners and with a shorter time between the midpoint of the period of substantial exposure and diagnosis among the cases.	('miners', 'Species', '265634', (71, 77))	('associated with', 'Reg', (28, 43))	('rs1800797', 'Var', (14, 23))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (44, 67))	('rs1800797', 'Mutation', 'rs1800797', (14, 23))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (44, 67))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))	('squamous cell carcinoma', 'Disease', (44, 67))
371011	26372664	Furthermore, rs1800797 was also associated with lung cancer among never smokers in the GENEVA dataset.	('lung cancer', 'Disease', 'MESH:D008175', (48, 59))	('rs1800797', 'Var', (13, 22))	('rs1800797', 'Mutation', 'rs1800797', (13, 22))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('lung cancer', 'Disease', (48, 59))	('associated with', 'Reg', (32, 47))	('lung cancer', 'Phenotype', 'HP:0100526', (48, 59))
371014	26372664	An IL6 promoter variant was associated with lung cancer in uranium miners and never smokers in two external study populations.	('lung cancer', 'Phenotype', 'HP:0100526', (44, 55))	('IL6', 'Gene', '3569', (3, 6))	('variant', 'Var', (16, 23))	('IL6', 'Gene', (3, 6))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('associated with', 'Reg', (28, 43))	('lung cancer', 'Disease', 'MESH:D008175', (44, 55))	('uranium', 'Chemical', 'MESH:D014501', (59, 66))	('miners', 'Species', '265634', (67, 73))	('lung cancer', 'Disease', (44, 55))
371017	26372664	Radon exposure, IL-6 promoter variants, and lung squamous cell carcinoma in former uranium miners.	('uranium', 'Chemical', 'MESH:D014501', (83, 90))	('variants', 'Var', (30, 38))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (49, 72))	('lung squamous cell carcinoma', 'Disease', (44, 72))	('miners', 'Species', '265634', (91, 97))	('IL-6', 'Gene', (16, 20))	('IL-6', 'Gene', '3569', (16, 20))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (44, 72))
371026	26372664	Increased induction of IL6 promoter activity by norepinephrine, lipopolysaccharide, and IL-1 in an in vitro plasmid construct carrying the G allele of rs1800795 has been identified.	('IL6', 'Gene', (23, 26))	('lipopolysaccharide', 'Chemical', 'MESH:D008070', (64, 82))	('norepinephrine', 'Chemical', 'MESH:D009638', (48, 62))	('IL-1', 'Gene', (88, 92))	('IL6', 'Gene', '3569', (23, 26))	('rs1800795', 'Mutation', 'rs1800795', (151, 160))	('rs1800795', 'Var', (151, 160))
371027	26372664	Gel shift assays confirmed the exclusive binding of GATA1 to the sequence containing the rs1800795 G allele following norepinephrine induction.	('rs1800795 G', 'Var', (89, 100))	('norepinephrine', 'Chemical', 'MESH:D009638', (118, 132))	('GATA1', 'Gene', (52, 57))	('binding', 'Interaction', (41, 48))	('rs1800795', 'Mutation', 'rs1800795', (89, 98))
371028	26372664	However, results from population studies assessing the association between rs1800795 and plasma levels of IL-6 as an indicator for systematic inflammation were inconsistent.	('inflammation', 'Disease', (142, 154))	('IL-6', 'Gene', (106, 110))	('rs1800795', 'Mutation', 'rs1800795', (75, 84))	('rs1800795', 'Var', (75, 84))	('IL-6', 'Gene', '3569', (106, 110))	('inflammation', 'Disease', 'MESH:D007249', (142, 154))
371046	26372664	This study was selected to assess whether the association with lung cancer that was observed for rs1800797 in miners can be generalized to populations with residential radon exposure because of the large sample size and available smoking history data.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('lung cancer', 'Disease', 'MESH:D008175', (63, 74))	('lung cancer', 'Disease', (63, 74))	('lung cancer', 'Phenotype', 'HP:0100526', (63, 74))	('rs1800797', 'Var', (97, 106))	('rs1800797', 'Mutation', 'rs1800797', (97, 106))	('miners', 'Species', '265634', (110, 116))
371052	26372664	Four SNPs (rs12700386, rs2069827, rs1800797, and rs2069840) in promoters not in high linkage disequilibrium (LD) (r 2 < 0.22) were suggested to affect the binding of transcription factors as indicated by the fact that MATCHTM predicted a transcriptional factor binding site with one allele but not with the other or the difference in the matrix similarity scores or core similarity scores between the two alleles was >= 0.2, and thus were selected for genotyping using the TaqMan genotyping assay (Life Technologies).	('rs2069827', 'Var', (23, 32))	('rs2069827', 'Mutation', 'rs2069827', (23, 32))	('transcriptional factor', 'MPA', (238, 260))	('binding', 'Interaction', (155, 162))	('rs1800797', 'Var', (34, 43))	('rs12700386', 'Mutation', 'rs12700386', (11, 21))	('rs1800797', 'Mutation', 'rs1800797', (34, 43))	('rs2069840', 'Mutation', 'rs2069840', (49, 58))	('rs12700386', 'Var', (11, 21))	('affect', 'Reg', (144, 150))	('rs2069840', 'Var', (49, 58))
371059	26372664	Twenty-one alleles of the IL6 promoter (690 bps, chr7:22732707-22733396) that contained 9 rs1800797 A alleles and 12 rs1800797 G alleles were successfully amplified using primers listed in Supplemental Material, Table S2, from 13 human BEC cultures that were heterozygous for rs1800797 and were directionally cloned into the pGL2-basic luciferase reporter vector (Promega) upstream of the luciferase coding sequence using MluI and BglII cloning sites according to the manufacturer's instructions.	('rs1800797', 'Mutation', 'rs1800797', (276, 285))	('IL6', 'Gene', (26, 29))	('rs1800797 G', 'Var', (117, 128))	('pGL2', 'Gene', (325, 329))	('IL6', 'Gene', '3569', (26, 29))	('chr7:22732707-22733396', 'STRUCTURAL_ABNORMALITY', 'None', (49, 71))	('pGL2', 'Gene', '54949', (325, 329))	('human', 'Species', '9606', (230, 235))	('rs1800797 A', 'Var', (90, 101))	('rs1800797', 'Mutation', 'rs1800797', (117, 126))	('rs1800797', 'Mutation', 'rs1800797', (90, 99))	('rs1800797', 'Var', (276, 285))
371060	26372664	Bidirectional Sanger sequencing was performed to confirm the haplotype alleles that contained four SNPs: rs1800797, rs1800796, rs36215814, and rs1800795.	('rs36215814', 'Mutation', 'rs36215814', (127, 137))	('rs1800797', 'Var', (105, 114))	('rs1800797', 'Mutation', 'rs1800797', (105, 114))	('rs1800796', 'Mutation', 'rs1800796', (116, 125))	('rs36215814', 'Var', (127, 137))	('rs1800796', 'Var', (116, 125))	('rs1800795', 'Mutation', 'rs1800795', (143, 152))	('rs1800795', 'Var', (143, 152))
371061	26372664	pGL2 constructs generated using the method described above that contained two common haplotype alleles (A-G-A8T12-C and G-G-A10T11-G) of the IL6 promoter were sequence verified for transfection experiments.	('IL6', 'Gene', '3569', (141, 144))	('IL6', 'Gene', (141, 144))	('pGL2', 'Gene', (0, 4))	('G-G-A10T11-G', 'Var', (120, 132))	('pGL2', 'Gene', '54949', (0, 4))	('A-G-A8T12-C', 'Var', (104, 115))
371062	26372664	Transfection was performed in a human embryonic kidney cell line and a human lung fibroblast line (HEK293 and HFL1, respectively; both obtained directly from the American Type Culture Collection) using TransIT-2020 transfection reagent (Mirus Bio LLC) and in a normal human bronchial epithelial cell line (HBEC2) immortalized by insertion of the telomerase catalytic subunit and cyclin-dependent kinase 4 (obtained from Shay and Minna, Southwestern Medical Center, Dallas, TX) using a Neon electroporation system (Life Technologies).	('HFL1', 'Gene', (110, 114))	('HEK293', 'CellLine', 'CVCL:0045', (99, 105))	('insertion', 'Var', (329, 338))	('embryonic kidney', 'Disease', (38, 54))	('human', 'Species', '9606', (268, 273))	('HBEC2', 'CellLine', 'CVCL:X490', (306, 311))	('embryonic kidney', 'Disease', 'MESH:D007674', (38, 54))	('human', 'Species', '9606', (32, 37))	('HFL1', 'Gene', '3078', (110, 114))	('human', 'Species', '9606', (71, 76))
371064	26372664	The constructs carrying two major haplotype alleles (A-G-A8T12-C and G-G-A10T11-G) in the IL6 promoter generated 5-30 times higher reporter activity relative to the promoterless construct in the three cell lines tested (not shown), suggesting that IL6 has a robust promoter.	('reporter activity', 'MPA', (131, 148))	('A-G-A8T12-C', 'Var', (53, 64))	('IL6', 'Gene', '3569', (248, 251))	('IL6', 'Gene', '3569', (90, 93))	('IL6', 'Gene', (248, 251))	('IL6', 'Gene', (90, 93))	('higher', 'PosReg', (124, 130))	('G-G-A10T11-G', 'Var', (69, 81))
371068	26372664	Thus, owing to the lack of lung fibroblasts with varied genotypes, the effect of IL6 variants on IL-6 induction by lung carcinogen treatment was assessed in skin fibroblasts that were wild homozygous (GG, n = 3) and heterozygous (AG, n = 3) for rs1800797.	('rs1800797', 'Mutation', 'rs1800797', (245, 254))	('IL6', 'Gene', (81, 84))	('variants', 'Var', (85, 93))	('IL-6', 'Gene', '3569', (97, 101))	('IL6', 'Gene', '3569', (81, 84))	('IL-6', 'Gene', (97, 101))
371077	26372664	The least-square means of MIL for miners with GG, GA, and AA genotypes of rs1800797 were calculated using a generalized linear model with adjustment for underground mining history and smoking history surveyed at cancer diagnosis.	('rs1800797', 'Var', (74, 83))	('rs1800797', 'Mutation', 'rs1800797', (74, 83))	('miners', 'Species', '265634', (34, 40))	('cancer', 'Disease', (212, 218))	('cancer', 'Disease', 'MESH:D009369', (212, 218))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))
371078	26372664	Cox proportional hazard models were used for 162 cases to estimate associations between IL6 variants and the time to cancer diagnosis.	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('associations', 'Interaction', (67, 79))	('cancer', 'Disease', (117, 123))	('IL6', 'Gene', '3569', (88, 91))	('variants', 'Var', (92, 100))	('IL6', 'Gene', (88, 91))
371080	26372664	A generalized linear model was used to assess the association between rs1800797 and IL6 expression in 85 primary human BECs and between subsequent lung cancer diagnosis and IL6 expression in a subset of primary human BECs with adjustment for rs1800797 genotype coded as 0, 1, and 2 for GG, GA, and AA, respectively (n = 78).	('IL6', 'Gene', (84, 87))	('rs1800797', 'Var', (242, 251))	('rs1800797', 'Mutation', 'rs1800797', (242, 251))	('IL6', 'Gene', '3569', (84, 87))	('lung cancer', 'Disease', (147, 158))	('lung cancer', 'Phenotype', 'HP:0100526', (147, 158))	('human', 'Species', '9606', (113, 118))	('IL6', 'Gene', '3569', (173, 176))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('rs1800797', 'Var', (70, 79))	('human', 'Species', '9606', (211, 216))	('rs1800797', 'Mutation', 'rs1800797', (70, 79))	('IL6', 'Gene', (173, 176))	('lung cancer', 'Disease', 'MESH:D008175', (147, 158))
371081	26372664	A likehood ratio test implemented in Merlin was applied to test the association between rs1800797 and steady-state IL6 expression (GI_10834983-S) in 79 Epstein-Barr virus (EBV)-transformed lymphoblastoid cell lines from CEU families (Utah residents with ancestry from northern and western Europe) in the HapMap project.	('rs1800797', 'Var', (88, 97))	('rs1800797', 'Mutation', 'rs1800797', (88, 97))	('IL6', 'Gene', '3569', (115, 118))	('EBV', 'Species', '10376', (172, 175))	('IL6', 'Gene', (115, 118))
371088	26372664	Miners with cumulative radon exposure levels >= 0.895 kWLM had a statistically significant greater risk for squamous cell carcinoma than miners with < 0.895 kWLM (OR = 1.51, 95% CI: 1.05, 2.18, p = 0.026 with adjustment for rs1800797 genotype, pack-years, and age at sputum collection), consistent with radon progeny exposure as a risk factor for squamous cell carcinoma in miners.	('carcinoma', 'Phenotype', 'HP:0030731', (361, 370))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (347, 370))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (108, 131))	('squamous cell carcinoma', 'Disease', (347, 370))	('miners', 'Species', '265634', (137, 143))	('miners', 'Species', '265634', (374, 380))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (108, 131))	('rs1800797', 'Mutation', 'rs1800797', (224, 233))	('squamous cell carcinoma', 'Disease', (108, 131))	('>= 0.895 kWLM', 'Var', (45, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('Miners', 'Species', '265634', (0, 6))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (347, 370))
371089	26372664	The variant allele A of rs1800797 was a statistically significant risk factor for squamous cell carcinoma in former uranium miners (OR = 1.36, 95% CI: 1.05, 1.75, p = 0.018; Table 2).	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('squamous cell carcinoma', 'Disease', (82, 105))	('rs1800797', 'Var', (24, 33))	('rs1800797', 'Mutation', 'rs1800797', (24, 33))	('uranium', 'Chemical', 'MESH:D014501', (116, 123))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (82, 105))	('miners', 'Species', '265634', (124, 130))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (82, 105))
371093	26372664	The least-square means of MIL calculated using a generalized linear model with adjustment for underground mining history and smoking history surveyed at cancer diagnosis were 20.7 (standard error, 0.68), 19.5 (0.50), and 18.0 (0.73) for miners with GG, GA, and AA genotypes of rs1800797, respectively (p = 0.0075).	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('cancer', 'Disease', (153, 159))	('rs1800797', 'Var', (277, 286))	('rs1800797', 'Mutation', 'rs1800797', (277, 286))	('miners', 'Species', '265634', (237, 243))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))
371094	26372664	Consistent with being a risk allele for squamous cell carcinoma, each copy of the A allele of rs1800797 was associated with a hazard ratio (HR) of 1.57 (95% CI: 1.22, 2.01, p = 0.00037) for latency (Table 2).	('carcinoma', 'Phenotype', 'HP:0030731', (54, 63))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (40, 63))	('squamous cell carcinoma', 'Disease', (40, 63))	('latency', 'Disease', (190, 197))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (40, 63))	('rs1800797', 'Var', (94, 103))	('rs1800797', 'Mutation', 'rs1800797', (94, 103))
371095	26372664	Association between rs1800797 and risk for lung cancer in the GENEVA dataset.	('lung cancer', 'Disease', (43, 54))	('lung cancer', 'Phenotype', 'HP:0100526', (43, 54))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('rs1800797', 'Var', (20, 29))	('rs1800797', 'Mutation', 'rs1800797', (20, 29))	('lung cancer', 'Disease', 'MESH:D008175', (43, 54))	('Association', 'Interaction', (0, 11))
371096	26372664	The GWAS of 2,522 lung cancer cases and 2,725 controls identified an increased risk for lung cancer associated with the rs1800797 A allele (OR = 1.10, 95% CI: 1.01, 1.20, p = 0.04; Table 3).	('lung cancer', 'Disease', 'MESH:D008175', (18, 29))	('lung cancer', 'Disease', (88, 99))	('rs1800797', 'Mutation', 'rs1800797', (120, 129))	('lung cancer', 'Disease', 'MESH:D008175', (88, 99))	('rs1800797 A', 'Var', (120, 131))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('lung cancer', 'Phenotype', 'HP:0100526', (18, 29))	('lung cancer', 'Disease', (18, 29))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('lung cancer', 'Phenotype', 'HP:0100526', (88, 99))
371097	26372664	Associations between rs1800797 and lung cancer varied significantly by smoking status, with OR = 1.41 (95% CI: 1.05, 1.91) for each A allele in never smokers (interaction p-value = 0.05 for the difference from current smokers); OR = 1.08 (95% CI: 0.95, 1.24) for each A allele in former smokers (interaction p-value = 0.03 for the difference from current smokers); and OR 1.06 (95% CI: 0.92, 1.22) in current smokers (Table 3).	('lung cancer', 'Disease', 'MESH:D008175', (35, 46))	('Associations', 'Interaction', (0, 12))	('rs1800797', 'Var', (21, 30))	('lung cancer', 'Disease', (35, 46))	('lung cancer', 'Phenotype', 'HP:0100526', (35, 46))	('rs1800797', 'Mutation', 'rs1800797', (21, 30))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))
371098	26372664	Associations with each rs1800797 A allele also varied by histologic subtype, with a significant positive association with adenocarcinoma (OR = 1.16; 95% CI:1.04, 1.31; p = 0.009) compared with squamous cell carcinoma (OR = 1.08; 95% CI: 0.93, 1.25; p = 0.3) (Table 3).	('adenocarcinoma', 'Disease', (122, 136))	('rs1800797 A', 'Var', (23, 34))	('adenocarcinoma', 'Disease', 'MESH:D000230', (122, 136))	('rs1800797', 'Mutation', 'rs1800797', (23, 32))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (193, 216))	('carcinoma', 'Phenotype', 'HP:0030731', (207, 216))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (193, 216))	('squamous cell carcinoma', 'Disease', (193, 216))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))
371099	26372664	Association between rs1800797 and IL6 expression.	('IL6', 'Gene', '3569', (34, 37))	('expression', 'MPA', (38, 48))	('rs1800797', 'Var', (20, 29))	('IL6', 'Gene', (34, 37))	('rs1800797', 'Mutation', 'rs1800797', (20, 29))	('Association', 'Interaction', (0, 11))
371100	26372664	The risk allele of rs1800797 was associated with increased IL6 expression in an allelic dose-dependent manner assessed in 85 primary human BECs from current and former smokers (p = 0.009) and 79 lymphoblastic cell lines from the HapMap CEU population (p = 0.034) (Table 4).	('rs1800797', 'Mutation', 'rs1800797', (19, 28))	('increased', 'PosReg', (49, 58))	('IL6', 'Gene', '3569', (59, 62))	('expression', 'MPA', (63, 73))	('IL6', 'Gene', (59, 62))	('human', 'Species', '9606', (133, 138))	('rs1800797', 'Var', (19, 28))
371102	26372664	Haplotype alleles in the IL6 promoter.	('IL6', 'Gene', '3569', (25, 28))	('Haplotype alleles', 'Var', (0, 17))	('IL6', 'Gene', (25, 28))
371103	26372664	AGC and GGG are two major haplotype alleles in the IL6 promoter that contain rs1800797, rs1800796, and rs1800795 and have cumulative allele frequency > 0.95 in European populations from the 1000 Genomes Project.	('rs1800795', 'Var', (103, 112))	('rs1800796', 'Mutation', 'rs1800796', (88, 97))	('rs1800797', 'Var', (77, 86))	('rs1800797', 'Mutation', 'rs1800797', (77, 86))	('IL6', 'Gene', '3569', (51, 54))	('IL6', 'Gene', (51, 54))	('rs1800796', 'Var', (88, 97))	('rs1800795', 'Mutation', 'rs1800795', (103, 112))
371104	26372664	However, the phasing status is unclear between rs36215814 as an AnTn polymorphism located between rs1800796 and rs1800795 and the other three SNPs.	('rs1800796', 'Mutation', 'rs1800796', (98, 107))	('rs36215814', 'Var', (47, 57))	('rs1800795', 'Mutation', 'rs1800795', (112, 121))	('rs1800796', 'Var', (98, 107))	('rs1800795', 'Var', (112, 121))	('rs36215814', 'Mutation', 'rs36215814', (47, 57))
371105	26372664	Cloned sequencing of 21 IL6 promoter alleles amplified from 13 self-identified non-Hispanic white study participants who were heterozygous for rs1800797 identified eight different compositions of the AnTn polymorphism with A8T12 enriched in the AGC allele and A10T11 enriched in the GGG allele (see Supplemental Material, Table S2).	('IL6', 'Gene', '3569', (24, 27))	('IL6', 'Gene', (24, 27))	('A10T11', 'Var', (260, 266))	('A8T12', 'Var', (223, 228))	('participants', 'Species', '9606', (104, 116))	('rs1800797', 'Mutation', 'rs1800797', (143, 152))	('AnTn', 'Gene', (200, 204))
371107	26372664	The reporter assay showed that haplotype allele A-G-A8T12-C carrying the risk allele of rs1800797 had 45-92% increased promoter activity compared with G-G-A10T11-G in HFL1, HEK293, and HBEC2 cell lines (p-values < 0.00062; Figure 2).	('HBEC2', 'CellLine', 'CVCL:X490', (185, 190))	('rs1800797', 'Var', (88, 97))	('rs1800797', 'Mutation', 'rs1800797', (88, 97))	('HFL1', 'Gene', (167, 171))	('HFL1', 'Gene', '3078', (167, 171))	('promoter activity', 'MPA', (119, 136))	('HEK293', 'CellLine', 'CVCL:0045', (173, 179))	('increased', 'PosReg', (109, 118))
371109	26372664	Six skin fibroblast lines (three GGs and three AGs for rs1800797 as described in "Methods") were used to assess whether the rs1800797 genotype could modify IL-6 secretion as the response to DNA damage indicative of radon or tobacco carcinogen exposure.	('modify', 'Reg', (149, 155))	('IL-6', 'Gene', '3569', (156, 160))	('rs1800797', 'Mutation', 'rs1800797', (55, 64))	('response to DNA damage', 'MPA', (178, 200))	('tobacco', 'Species', '4097', (224, 231))	('rs1800797', 'Var', (124, 133))	('rs1800797', 'Mutation', 'rs1800797', (124, 133))	('IL-6', 'Gene', (156, 160))
371112	26372664	The effects of the rs1800797 genotype (coded as 0 for GG and 1 for AG) and the dose of carcinogen (concentration in medium) on IL-6 secretion in human skin fibroblast lines (n = 6) were assessed using generalized linear models.	('rs1800797', 'Mutation', 'rs1800797', (19, 28))	('human', 'Species', '9606', (145, 150))	('IL-6', 'Gene', (127, 131))	('IL-6', 'Gene', '3569', (127, 131))	('rs1800797', 'Var', (19, 28))
371113	26372664	A dose-dependent induction of IL-6 secretion was seen in skin fibroblasts treated with H2O2 and BPDE (p-values < 0.0001; Figure 1).	('H2O2', 'Chemical', 'MESH:D006861', (87, 91))	('H2O2', 'Var', (87, 91))	('BPDE', 'Chemical', 'MESH:D015123', (96, 100))	('IL-6', 'Gene', (30, 34))	('IL-6', 'Gene', '3569', (30, 34))
371117	26372664	In this study, we comprehensively evaluated the association between four IL6 promoter variants predicted by in silico analyses to affect binding of transcription factors and lung squamous cell carcinoma in former uranium miners with high levels of radon exposure.	('binding', 'Interaction', (137, 144))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (174, 202))	('lung squamous cell carcinoma', 'Disease', (174, 202))	('IL6', 'Gene', '3569', (73, 76))	('transcription factors', 'Protein', (148, 169))	('carcinoma', 'Phenotype', 'HP:0030731', (193, 202))	('variants', 'Var', (86, 94))	('affect', 'Reg', (130, 136))	('uranium', 'Chemical', 'MESH:D014501', (213, 220))	('IL6', 'Gene', (73, 76))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (179, 202))	('miners', 'Species', '265634', (221, 227))
371118	26372664	We found that rs1800797 was significantly associated with increased odds for squamous cell carcinoma and shortened latency for development of squamous cell carcinoma.	('shortened', 'NegReg', (105, 114))	('carcinoma', 'Phenotype', 'HP:0030731', (156, 165))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (142, 165))	('squamous cell carcinoma', 'Disease', (142, 165))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (77, 100))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (142, 165))	('rs1800797', 'Var', (14, 23))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (77, 100))	('rs1800797', 'Mutation', 'rs1800797', (14, 23))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('squamous cell carcinoma', 'Disease', (77, 100))
371119	26372664	In particular, rs1800797 was associated with increased basal expression and induced secretion of IL-6 by fibroblasts in response to DNA damage in vitro, supporting a role for IL-6 in the association between rs1800797 and squamous cell carcinoma in the former uranium miners.	('rs1800797', 'Var', (15, 24))	('rs1800797', 'Mutation', 'rs1800797', (207, 216))	('rs1800797', 'Mutation', 'rs1800797', (15, 24))	('miners', 'Species', '265634', (267, 273))	('increased', 'PosReg', (45, 54))	('IL-6', 'Gene', '3569', (97, 101))	('response to DNA damage', 'MPA', (120, 142))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (221, 244))	('carcinoma', 'Phenotype', 'HP:0030731', (235, 244))	('uranium', 'Chemical', 'MESH:D014501', (259, 266))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (221, 244))	('IL-6', 'Gene', (175, 179))	('association', 'Interaction', (187, 198))	('squamous cell carcinoma', 'Disease', (221, 244))	('IL-6', 'Gene', '3569', (175, 179))	('basal expression', 'MPA', (55, 71))	('IL-6', 'Gene', (97, 101))	('rs1800797', 'Var', (207, 216))
371120	26372664	The association between rs1800797 and squamous cell carcinoma in the former uranium miners was somewhat consistent with the association between rs1800797 and all lung cancers among never smokers in the GENEVA GWAS of Lung Cancer and Smoking study population, although the association was stronger for adenocarcinoma than for squamous cell carcinoma when evaluated by case subtype.	('adenocarcinoma', 'Disease', (301, 315))	('lung cancers', 'Disease', (162, 174))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (325, 348))	('lung cancer', 'Phenotype', 'HP:0100526', (162, 173))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (38, 61))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('miners', 'Species', '265634', (84, 90))	('lung cancers', 'Phenotype', 'HP:0100526', (162, 174))	('adenocarcinoma', 'Disease', 'MESH:D000230', (301, 315))	('uranium', 'Chemical', 'MESH:D014501', (76, 83))	('cancers', 'Phenotype', 'HP:0002664', (167, 174))	('rs1800797', 'Var', (24, 33))	('rs1800797', 'Var', (144, 153))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (325, 348))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (38, 61))	('Cancer', 'Phenotype', 'HP:0002664', (222, 228))	('GWAS of Lung Cancer', 'Disease', 'MESH:D008175', (209, 228))	('GWAS of Lung Cancer', 'Disease', (209, 228))	('Lung Cancer', 'Phenotype', 'HP:0100526', (217, 228))	('squamous cell carcinoma', 'Disease', (325, 348))	('squamous cell carcinoma', 'Disease', (38, 61))	('carcinoma', 'Phenotype', 'HP:0030731', (339, 348))	('carcinoma', 'Phenotype', 'HP:0030731', (52, 61))	('carcinoma', 'Phenotype', 'HP:0030731', (306, 315))	('rs1800797', 'Mutation', 'rs1800797', (24, 33))	('rs1800797', 'Mutation', 'rs1800797', (144, 153))	('lung cancers', 'Disease', 'MESH:D008175', (162, 174))
371122	26372664	This finding reinforces the importance of considering the levels of environmental exposures when studying the association between IL6 promoter variants and environmental disease phenotype.	('IL6', 'Gene', '3569', (130, 133))	('IL6', 'Gene', (130, 133))	('variants', 'Var', (143, 151))
371123	26372664	In addition, a stratified analysis by tumor histology identified a significant association between rs1800797 and lung adenocarcinoma, a result consistent with the finding that > 73% of lung cancer patients who were never smokers were diagnosed with adenocarcinoma in the GENEVA dataset.	('patients', 'Species', '9606', (197, 205))	('rs1800797', 'Var', (99, 108))	('carcinoma', 'Phenotype', 'HP:0030731', (254, 263))	('adenocarcinoma', 'Disease', (118, 132))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('lung cancer', 'Disease', 'MESH:D008175', (185, 196))	('lung cancer', 'Phenotype', 'HP:0100526', (185, 196))	('lung adenocarcinoma', 'Disease', (113, 132))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('adenocarcinoma', 'Disease', (249, 263))	('adenocarcinoma', 'Disease', 'MESH:D000230', (118, 132))	('rs1800797', 'Mutation', 'rs1800797', (99, 108))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (113, 132))	('tumor', 'Disease', (38, 43))	('adenocarcinoma', 'Disease', 'MESH:D000230', (249, 263))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (113, 132))	('lung cancer', 'Disease', (185, 196))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))
371124	26372664	The association between the IL6 promoter variants and increased risk for lung cancer was strongly supported by functional studies.	('lung cancer', 'Disease', 'MESH:D008175', (73, 84))	('variants', 'Var', (41, 49))	('IL6', 'Gene', '3569', (28, 31))	('lung cancer', 'Disease', (73, 84))	('IL6', 'Gene', (28, 31))	('lung cancer', 'Phenotype', 'HP:0100526', (73, 84))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))
371125	26372664	We found that rs1800797 was significantly associated with increased IL6 mRNA expression in primary HBECs, lymphoblastic cells, and fibroblasts, which may at least partially stem from the increased gene transcription assessed using the luciferase reporter assay.	('IL6', 'Gene', '3569', (68, 71))	('IL6', 'Gene', (68, 71))	('increased', 'PosReg', (58, 67))	('rs1800797', 'Var', (14, 23))	('rs1800797', 'Mutation', 'rs1800797', (14, 23))	('mRNA expression', 'MPA', (72, 87))
371126	26372664	Our cloning strategy recapitulated the physical linear allelic combination for the four common SNPs at this 690-bp promoter region for the two common haplotype alleles studied (A-G-A8T12-C and G-G-A10T11-G) and allows for the detection of potential combined function of the four individual SNPs on gene transcription, a key factor in detecting the difference in basal expression of IL6.	('G-G-A10T11-G', 'Var', (193, 205))	('A-G-A8T12-C', 'Var', (177, 188))	('gene transcription', 'MPA', (298, 316))	('IL6', 'Gene', '3569', (382, 385))	('IL6', 'Gene', (382, 385))
371127	26372664	Other studies that compared luciferase activities for two promoter constructs that differed by only one base (rs1800795, G/C) with one allele not naturally existing did not see an increase in basal transcription associated with the rs1800795 C allele.	('rs1800795', 'Mutation', 'rs1800795', (232, 241))	('basal transcription', 'MPA', (192, 211))	('rs1800795 C', 'Var', (232, 243))	('rs1800795', 'Mutation', 'rs1800795', (110, 119))
371131	26372664	In the present study, we observed a strong induction of IL-6 secretion in fibroblasts with exposure to H2O2 and BPDE.	('IL-6', 'Gene', (56, 60))	('H2O2', 'Chemical', 'MESH:D006861', (103, 107))	('H2O2', 'Var', (103, 107))	('BPDE', 'Chemical', 'MESH:D015123', (112, 116))	('IL-6', 'Gene', '3569', (56, 60))
371133	26372664	Of great importance, assessment of the effects of the rs1800797 genotype on the slopes for IL-6 induction by H2O2 or BPDE treatments identified greater induction of IL-6 secretion in rs1800797 AG lines than in GG lines.	('rs1800797', 'Mutation', 'rs1800797', (54, 63))	('BPDE', 'Chemical', 'MESH:D015123', (117, 121))	('H2O2', 'Chemical', 'MESH:D006861', (109, 113))	('IL-6', 'Gene', (91, 95))	('rs1800797 AG', 'Var', (183, 195))	('IL-6', 'Gene', '3569', (91, 95))	('IL-6', 'Gene', (165, 169))	('IL-6', 'Gene', '3569', (165, 169))	('rs1800797', 'Mutation', 'rs1800797', (183, 192))
371134	26372664	Thus, the elevated levels of basal and carcinogen-induced IL-6 secretion observed in fibroblasts carrying IL-6 variants could lead to a microenvironment that may favor clonal expansion and progression of lung premalignant field defects.	('IL-6', 'Gene', '3569', (106, 110))	('IL-6', 'Gene', '3569', (58, 62))	('lung premalignant field defects', 'Disease', 'MESH:D005128', (204, 235))	('lung premalignant field defects', 'Disease', (204, 235))	('favor', 'PosReg', (162, 167))	('IL-6', 'Gene', (106, 110))	('variants', 'Var', (111, 119))	('levels', 'MPA', (19, 25))	('lead to', 'Reg', (126, 133))	('clonal expansion', 'CPA', (168, 184))	('IL-6', 'Gene', (58, 62))	('elevated', 'PosReg', (10, 18))
371141	26372664	Our findings suggest that sequence variants in the IL6 promoter modulate gene transcription and responses to environmental carcinogens by lung fibroblasts.	('sequence variants', 'Var', (26, 43))	('IL6', 'Gene', '3569', (51, 54))	('modulate', 'Reg', (64, 72))	('IL6', 'Gene', (51, 54))	('gene transcription', 'MPA', (73, 91))	('responses to environmental carcinogens', 'MPA', (96, 134))
371142	26372664	In particular, in vitro evidence that the rs1800797 variant modulated IL6 expression supports a role for IL-6 in pathogenic mechanisms associated with squamous cell lung cancer in uranium miners and with lung cancer in never smokers.	('uranium', 'Chemical', 'MESH:D014501', (180, 187))	('rs1800797', 'Var', (42, 51))	('modulated', 'Reg', (60, 69))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('lung cancer', 'Disease', (204, 215))	('expression', 'MPA', (74, 84))	('squamous cell lung cancer', 'Disease', (151, 176))	('miners', 'Species', '265634', (188, 194))	('IL-6', 'Gene', '3569', (105, 109))	('lung cancer', 'Disease', 'MESH:D008175', (204, 215))	('IL-6', 'Gene', (105, 109))	('squamous cell lung cancer', 'Disease', 'MESH:D002294', (151, 176))	('IL6', 'Gene', '3569', (70, 73))	('rs1800797', 'Mutation', 'rs1800797', (42, 51))	('lung cancer', 'Phenotype', 'HP:0100526', (204, 215))	('lung cancer', 'Disease', 'MESH:D008175', (165, 176))	('lung cancer', 'Phenotype', 'HP:0100526', (165, 176))	('IL6', 'Gene', (70, 73))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
371288	29318765	Although some potentially targetable markers have been identified,1, 2 including DDR2 mutation, and PIK3CA, FGFR1, and MET amplification, none has been validated in SCC for particular targeted drugs.	('FGFR1', 'Gene', '2260', (108, 113))	('SCC', 'Gene', (165, 168))	('DDR2', 'Gene', '4921', (81, 85))	('SCC', 'Phenotype', 'HP:0002860', (165, 168))	('PIK3CA', 'Gene', (100, 106))	('SCC', 'Gene', '6317', (165, 168))	('DDR2', 'Gene', (81, 85))	('mutation', 'Var', (86, 94))	('FGFR1', 'Gene', (108, 113))	('PIK3CA', 'Gene', '5290', (100, 106))
371325	29318765	The World Health Organization defines BMI groups as: underweight (BMI < 18.5 kg/m2), normal weight (BMI 18.5 to < 25 kg/m2), overweight (BMI 25 to < 30 kg/m2), and obese (BMI >= 30 kg/m2).17 Our study showed that higher BMI predicts longer PFS and OS.	('BMI', 'Var', (220, 223))	('OS', 'Chemical', '-', (248, 250))	('obese', 'Disease', 'MESH:D009765', (164, 169))	('PFS', 'CPA', (240, 243))	('obese', 'Disease', (164, 169))	('overweight', 'Phenotype', 'HP:0025502', (125, 135))
371328	29318765	found that clearance of doxorubicin was significantly reduced in individuals with a proportion of body fat exceeding 30%, even with a body surface area based dose adjustment.22 Similarly, a high BMI might also affect the clearance of gemcitabine and cisplatin.	('affect', 'Reg', (210, 216))	('gemcitabine', 'Chemical', 'MESH:C056507', (234, 245))	('doxorubicin', 'Chemical', 'MESH:D004317', (24, 35))	('cisplatin', 'Chemical', 'MESH:D002945', (250, 259))	('clearance', 'MPA', (221, 230))	('high', 'Var', (190, 194))
371329	29318765	Thirdly, fatty acids (which are rich in patients with high BMI), can act as peroxisome proliferator-activated receptor ligands, which have been shown to increase the efficacy of platinum-based chemotherapy.23 Fourthly, patients with high BMI are more likely to receive metabolic drugs, such as metformin.	('receive', 'Reg', (261, 268))	('more', 'PosReg', (246, 250))	('patients', 'Species', '9606', (40, 48))	('metabolic drugs', 'MPA', (269, 284))	('metformin', 'Disease', (294, 303))	('metformin', 'Chemical', 'MESH:D008687', (294, 303))	('fatty acids', 'Chemical', 'MESH:D005227', (9, 20))	('patients', 'Species', '9606', (219, 227))	('platinum', 'Chemical', 'MESH:D010984', (178, 186))	('high BMI', 'Var', (233, 241))
371330	29318765	These drugs induce apoptosis in LKB1-deficient NSCLC.24 As inactivation of LKB1 has been found in 19% of lung SCC,25 and is also important for SCC transformation,26 patients with a high BMI have a reasonable likelihood of receiving metabolic drugs and to have an LKB1-deficient tumor.	('tumor', 'Phenotype', 'HP:0002664', (278, 283))	('lung SCC', 'Disease', (105, 113))	('LKB1', 'Gene', '6794', (75, 79))	('LKB1-deficient tumor', 'Disease', (263, 283))	('patients', 'Species', '9606', (165, 173))	('LKB1', 'Gene', '6794', (263, 267))	('LKB1-deficient tumor', 'Disease', 'MESH:D009369', (263, 283))	('LKB1', 'Gene', '6794', (32, 36))	('SCC', 'Phenotype', 'HP:0002860', (143, 146))	('inactivation', 'Var', (59, 71))	('NSCLC', 'Phenotype', 'HP:0030358', (47, 52))	('SCC', 'Phenotype', 'HP:0002860', (110, 113))	('LKB1', 'Gene', (75, 79))	('SCC', 'Gene', '6317', (143, 146))	('LKB1-deficient NSCLC', 'Disease', (32, 52))	('lung SCC', 'Disease', 'MESH:D008171', (105, 113))	('LKB1', 'Gene', (32, 36))	('metabolic drugs', 'MPA', (232, 247))	('SCC', 'Gene', '6317', (110, 113))	('LKB1', 'Gene', (263, 267))	('SCC', 'Gene', (143, 146))	('LKB1-deficient NSCLC', 'Disease', 'MESH:D002289', (32, 52))	('SCC', 'Gene', (110, 113))
371331	29318765	In our study, patients with a high BMI and aged < 54.5 experienced longer PFS, which indicates that advanced age might be a negative predictive factor of chemotherapy.	('high', 'Var', (30, 34))	('patients', 'Species', '9606', (14, 22))	('longer', 'PosReg', (67, 73))	('PFS', 'MPA', (74, 77))
371339	29113315	Positive PD-L1 status for the SP142 clone related with improved overall survival in oropharyngeal squamous cell carcinoma.	('improved', 'PosReg', (55, 63))	('oropharyngeal squamous cell carcinoma', 'Disease', 'MESH:D002294', (84, 121))	('PD-L1', 'Gene', '29126', (9, 14))	('overall survival', 'MPA', (64, 80))	('SP142', 'Chemical', '-', (30, 35))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (98, 121))	('oropharyngeal squamous cell carcinoma', 'Disease', (84, 121))	('SP142', 'Var', (30, 35))	('PD-L1', 'Gene', (9, 14))	('oropharyngeal squamous cell carcinoma', 'Phenotype', 'HP:0012182', (84, 121))
371345	29113315	PD-L1 positivity for SP142, but not for 22C3, also tends to have a positive effect on survival in oropharyngeal squamous cell carcinoma.	('SP142', 'Var', (21, 26))	('positive', 'PosReg', (67, 75))	('oropharyngeal squamous cell carcinoma', 'Phenotype', 'HP:0012182', (98, 135))	('positivity', 'Var', (6, 16))	('oropharyngeal squamous cell carcinoma', 'Disease', 'MESH:D002294', (98, 135))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (112, 135))	('PD-L1', 'Gene', (0, 5))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('PD-L1', 'Gene', '29126', (0, 5))	('SP142', 'Chemical', '-', (21, 26))	('oropharyngeal squamous cell carcinoma', 'Disease', (98, 135))
371370	29113315	PD-L1 positivity defined as >= 5% PD-L1 expression on TCs resulted in 23% (22/94) and 34% (33/97) PD-L1+ tumor specimens for the SP142 and 22C3 clone, respectively (Table 1).	('TCs', 'Chemical', '-', (54, 57))	('PD-L1', 'Gene', (98, 103))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('SP142', 'Chemical', '-', (129, 134))	('PD-L1', 'Gene', (0, 5))	('PD-L1', 'Gene', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('SP142', 'Var', (129, 134))	('PD-L1', 'Gene', '29126', (98, 103))	('PD-L1', 'Gene', '29126', (0, 5))	('tumor', 'Disease', (105, 110))	('PD-L1', 'Gene', '29126', (34, 39))
371373	29113315	A positive link was found between HPV status and PD-L1 positivity on TCs for the SP142 clone (P < 0.0001) and 22C3 clone (P = 0.0649).	('PD-L1', 'Gene', '29126', (49, 54))	('positivity', 'Var', (55, 65))	('SP142', 'Chemical', '-', (81, 86))	('PD-L1', 'Gene', (49, 54))	('HPV', 'Species', '10566', (34, 37))	('TCs', 'Chemical', '-', (69, 72))
371374	29113315	Next, positive SP142 PD-L1 expression was associated with poorly differentiated/basaloid tumors (15/29 versus 7/65; P = 0.0001) whereas positive 22C3 PD-L1 expression on TCs was most common in elder patients (8/12 versus 25/85; P = 0.0234) and in poorly differentiated/basaloid tumors (17/31 versus 16/66; P = 0.0111).	('tumor', 'Phenotype', 'HP:0002664', (278, 283))	('basaloid tumors', 'Disease', 'MESH:C565284', (269, 284))	('basaloid tumors', 'Disease', (80, 95))	('positive SP142', 'Var', (6, 20))	('SP142', 'Chemical', '-', (15, 20))	('PD-L1', 'Gene', (150, 155))	('PD-L1', 'Gene', '29126', (150, 155))	('basaloid tumors', 'Disease', (269, 284))	('TCs', 'Chemical', '-', (170, 173))	('PD-L1', 'Gene', (21, 26))	('basaloid tumors', 'Phenotype', 'HP:0002671', (80, 95))	('PD-L1', 'Gene', '29126', (21, 26))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('tumors', 'Phenotype', 'HP:0002664', (278, 284))	('associated', 'Reg', (42, 52))	('basaloid tumors', 'Phenotype', 'HP:0002671', (269, 284))	('SP142', 'Var', (15, 20))	('basaloid tumors', 'Disease', 'MESH:C565284', (80, 95))	('patients', 'Species', '9606', (199, 207))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))
371376	29113315	Notably, PD-L1 positivity on TCs was linked with the immune environment, as this parameter was associated with increased TIL count (P < 0.0001 and P = 0.0009), CD3+ T cell count (P = 0.0009 and P = 0.0044), CD8+ T cell count (P < 0.0001 and P = 0.0001) and FoxP3+ T cell count (P = 0.0004 and P = 0.0094) for the SP142 and 22C3 clone, respectively.	('SP142', 'Var', (313, 318))	('CD8', 'Gene', '925', (207, 210))	('increased', 'PosReg', (111, 120))	('CD3+', 'MPA', (160, 164))	('TIL', 'MPA', (121, 124))	('FoxP3', 'Gene', '50943', (257, 262))	('TCs', 'Chemical', '-', (29, 32))	('PD-L1', 'Gene', '29126', (9, 14))	('FoxP3', 'Gene', (257, 262))	('positivity', 'Var', (15, 25))	('PD-L1', 'Gene', (9, 14))	('SP142', 'Chemical', '-', (313, 318))	('CD8', 'Gene', (207, 210))
371377	29113315	Positive PD-L1 expression using the SP142 clone resulted in a more favorable outcome with median overall survival (OS) of 9.8 years versus 4.1 years for SP142 PD-L1 negativity (hazard ratio [HR] = 0.51 [0.31-0.99], P = 0.0466; Figure 1A) whereas 22C3 PD-L1 expression on TCs showed no significant association with OS (4.0 years versus 4.4 years; HR = 0.99 [0.58-1.72], P = 0.9846; Figure 1B).	('PD-L1', 'Gene', '29126', (251, 256))	('SP142', 'Chemical', '-', (153, 158))	('PD-L1', 'Gene', '29126', (159, 164))	('PD-L1', 'Gene', '29126', (9, 14))	('SP142', 'Var', (153, 158))	('SP142', 'Chemical', '-', (36, 41))	('TCs', 'Chemical', '-', (271, 274))	('PD-L1', 'Gene', (251, 256))	('SP142', 'Var', (36, 41))	('PD-L1', 'Gene', (159, 164))	('PD-L1', 'Gene', (9, 14))
371386	29113315	Patients with 'at least one variable positive' had a more favorable outcome for the SP142 PD-L1 expression (median OS 9.8 years versus 4.0 years; HR = 0.40 [0.24-0.78], P = 0.0048; Figure 2C) but not for the 22C3 PD-L1 expression (median OS 5.5 years versus 4.1 years; HR = 0.66 [0.38-1.15], P = 0.1415; Figure 2D).	('SP142', 'Chemical', '-', (84, 89))	('PD-L1', 'Gene', '29126', (90, 95))	('SP142', 'Var', (84, 89))	('Patients', 'Species', '9606', (0, 8))	('PD-L1', 'Gene', (213, 218))	('PD-L1', 'Gene', '29126', (213, 218))	('PD-L1', 'Gene', (90, 95))
371390	29113315	In our study, positive PD-L1 expression on TCs using the SP142 clone was noticed in 23% of specimens whereas 34% of specimens were PD-L1+ according to the 22C3 clone (>= 5 % cut-off).	('PD-L1', 'Gene', (23, 28))	('PD-L1', 'Gene', '29126', (131, 136))	('SP142', 'Chemical', '-', (57, 62))	('TCs', 'Chemical', '-', (43, 46))	('PD-L1', 'Gene', '29126', (23, 28))	('SP142', 'Var', (57, 62))	('PD-L1', 'Gene', (131, 136))
371419	29113315	Furthermore, PD-L1 expression on TCs, assessed by the SP142 clone, also tends to have a positive effect on patient outcome in OSCC.	('positive', 'PosReg', (88, 96))	('expression', 'Var', (19, 29))	('TCs', 'Chemical', '-', (33, 36))	('SP142', 'Chemical', '-', (54, 59))	('PD-L1', 'Gene', (13, 18))	('OSCC', 'Disease', (126, 130))	('patient', 'Species', '9606', (107, 114))	('PD-L1', 'Gene', '29126', (13, 18))
371494	28435394	The other possible methods in which mast cells promote tumours is by their mitogenic ability, deletion of tumour suppressor genes, and activation of certain oncogenes via the c-kit locus.	('tumour', 'Disease', (55, 61))	('tumours', 'Disease', (55, 62))	('activation', 'PosReg', (135, 145))	('deletion', 'Var', (94, 102))	('c-kit', 'Gene', (175, 180))	('c-kit', 'Gene', '3815', (175, 180))	('tumour', 'Phenotype', 'HP:0002664', (106, 112))	('tumour', 'Disease', 'MESH:D009369', (106, 112))	('promote', 'PosReg', (47, 54))	('oncogenes', 'Gene', (157, 166))	('tumour', 'Phenotype', 'HP:0002664', (55, 61))	('mitogenic ability', 'CPA', (75, 92))	('tumour', 'Disease', 'MESH:D009369', (55, 61))	('tumour', 'Disease', (106, 112))	('tumours', 'Phenotype', 'HP:0002664', (55, 62))	('tumours', 'Disease', 'MESH:D009369', (55, 62))
371553	33007980	Following overexpression of Drosophila miR-31, we found a significant decrease in the size of the imaginal wing discs and downregulation of a subset of putative targets, including wntless (wls), an important regulator of the Wnt signaling pathway.	('wntless', 'Gene', (180, 187))	('Wnt', 'Gene', (225, 228))	('Drosophila miR-31', 'Var', (28, 45))	('Wnt', 'Gene', '22408;89780;7474;7480', (225, 228))	('downregulation', 'NegReg', (122, 136))	('Drosophila', 'Species', '7227', (28, 38))	('size of the imaginal wing discs', 'CPA', (86, 117))	('wntless', 'Gene', '39259', (180, 187))	('overexpression', 'PosReg', (10, 24))	('decrease', 'NegReg', (70, 78))
371557	33007980	A perturbation of Wnt signaling and its role in segment polarity was first demonstrated in Drosophila mutants of a wingless allele (wg1), and subsequent gene cloning of its sequence revealed a significant degree of homology to human and murine INT-1.	('mutants', 'Var', (102, 109))	('Wnt', 'Gene', '22408;89780;7474;7480', (18, 21))	('Drosophila', 'Species', '7227', (91, 101))	('human', 'Species', '9606', (227, 232))	('murine', 'Species', '10090', (237, 243))	('INT-1', 'Gene', '22408', (244, 249))	('Wnt', 'Gene', (18, 21))	('INT-1', 'Gene', (244, 249))
371560	33007980	In addition to its endogenous activity during development, abnormal regulation of Wnt signaling has been implicated in a number of human diseases, including cancer.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('abnormal', 'Var', (59, 67))	('implicated', 'Reg', (105, 115))	('Wnt', 'Gene', '22408;89780;7474;7480', (82, 85))	('Wnt', 'Gene', (82, 85))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('human', 'Species', '9606', (131, 136))	('cancer', 'Disease', (157, 163))
371564	33007980	In addition, dysregulation of non-canonical Wnt signaling may also contribute to tumorigenesis and cancer progression via metabolic and inflammatory reprogramming in a subset of cancer.	('Wnt', 'Gene', (44, 47))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('Wnt', 'Gene', '22408;89780;7474;7480', (44, 47))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('dysregulation', 'Var', (13, 26))	('cancer', 'Disease', (99, 105))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('cancer', 'Disease', (178, 184))	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Disease', (81, 86))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('non-canonical', 'Protein', (30, 43))	('contribute', 'Reg', (67, 77))
371565	33007980	Recent reports suggest that malignant tumors occurring in the oral cavity may also be influenced by these Wnt signaling pathways, as demonstrated by the dysregulation of the soluble frizzled receptor protein family, a representative Wnt receptor, in oral squamous cell carcinoma (OSCC) cells.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('dysregulation', 'Var', (153, 166))	('oral squamous cell carcinoma', 'Disease', (250, 278))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (269, 278))	('OSCC', 'CellLine', 'CVCL:L894', (280, 284))	('Wnt', 'Gene', (233, 236))	('malignant tumors', 'Disease', (28, 44))	('tumors occurring in the oral cavity', 'Phenotype', 'HP:0100649', (38, 73))	('Wnt', 'Gene', (106, 109))	('Wnt', 'Gene', '22408;89780;7474;7480', (233, 236))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (250, 278))	('malignant tumors', 'Disease', 'MESH:D009369', (28, 44))	('Wnt', 'Gene', '22408;89780;7474;7480', (106, 109))	('influenced', 'Reg', (86, 96))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (255, 278))
371586	33007980	Importantly, the level of wntless (wls) mRNA, one of its putative targets and an important regulator of Wnt signaling pathway, was significantly downregulated in Drosophila following overexpression of miR-31.	('Wnt', 'Gene', '22408;89780;7474;7480', (104, 107))	('miR-31', 'Var', (201, 207))	('wntless', 'Gene', (26, 33))	('wntless', 'Gene', '39259', (26, 33))	('Drosophila', 'Species', '7227', (162, 172))	('downregulated', 'NegReg', (145, 158))	('Wnt', 'Gene', (104, 107))	('overexpression', 'PosReg', (183, 197))
371609	33007980	Among the suggested targets (Table S1), those with significant homology to human counterparts as well as relevant function to growth control were then selected and screened for changes in its transcript levels following overexpression of miR-31.	('changes', 'Reg', (177, 184))	('miR-31', 'Var', (238, 244))	('transcript levels', 'MPA', (192, 209))	('human', 'Species', '9606', (75, 80))	('overexpression', 'PosReg', (220, 234))
371610	33007980	Such candidates screened included Drosophila wntless (wls), of which 3'-UTR was presumably targeted by both miR-31a and miR-31b (positions 120-126 and 379-385, as conserved and poorly conserved sites, respectively) (Figure 3A,B).	('positions 120-126', 'Var', (129, 146))	('Drosophila', 'Species', '7227', (34, 44))	('miR-31b', 'Gene', '12797955', (120, 127))	('miR-31a', 'Gene', '12798333', (108, 115))	('miR-31b', 'Gene', (120, 127))	('wntless', 'Gene', (45, 52))	('wntless', 'Gene', '39259', (45, 52))	('miR-31a', 'Gene', (108, 115))
371613	33007980	Our data derived from Drosophila strongly suggest miR-31-dependent regulation of wls important for the Wnt signaling pathway.	('wls', 'Gene', (81, 84))	('Drosophila', 'Species', '7227', (22, 32))	('regulation', 'MPA', (67, 77))	('miR-31-dependent', 'Var', (50, 66))	('Wnt', 'Gene', '22408;89780;7474;7480', (103, 106))	('Wnt', 'Gene', (103, 106))
371619	33007980	Despite the lack of complete seed match (Figure S3A), the luciferase activity of the OSCC cells transfected with a candidate construct was significantly reduced following transfection of miR-31 (Figure S3B).	('activity', 'MPA', (69, 77))	('miR-31', 'Var', (187, 193))	('reduced', 'NegReg', (153, 160))	('luciferase', 'Enzyme', (58, 68))	('OSCC', 'CellLine', 'CVCL:L894', (85, 89))
371624	33007980	In line with these results, an independent OSCC cell line, OSC20 cells, following a transfection of miR-31 mimic displayed a prominent reduction in both WLS transcripts and protein products (Figure 4D,E).	('reduction', 'NegReg', (135, 144))	('miR-31', 'Gene', (100, 106))	('OSCC', 'CellLine', 'CVCL:L894', (43, 47))	('protein products', 'MPA', (173, 189))	('transfection', 'Var', (84, 96))	('OSC20', 'CellLine', 'CVCL:3087', (59, 64))
371626	33007980	Consistent with those transfected with miR-31, the OSCC cell lines stably expressing miR-31 also exhibited significant downregulation of the WLS transcripts and protein products (Figure 4F,G; Figure S4), further confirming the miR-31-dependent regulation of human WLS that had not been preferentially projected by the majority of prediction platforms.	('human', 'Species', '9606', (258, 263))	('downregulation', 'NegReg', (119, 133))	('miR-31', 'Var', (85, 91))	('WLS', 'Protein', (141, 144))	('OSCC', 'CellLine', 'CVCL:L894', (51, 55))
371632	33007980	When the miR-31 mimic was transiently expressed in SAS and OSC20 cells, we found a noticeable decrease in the levels of cyclin D1 (CCND1) and c-MYC mRNAs (Figure 5A), two of the most common targets of the canonical Wnt signaling pathway that have been implicated in oral carcinogenesis.	('CCND1', 'Gene', (131, 136))	('Wnt', 'Gene', '22408;89780;7474;7480', (215, 218))	('c-MYC', 'Gene', (142, 147))	('miR-31', 'Var', (9, 15))	('Wnt', 'Gene', (215, 218))	('levels', 'MPA', (110, 116))	('CCND1', 'Gene', '595', (131, 136))	('cyclin D1', 'Gene', '595', (120, 129))	('OSC20', 'CellLine', 'CVCL:3087', (59, 64))	('carcinogenesis', 'Disease', 'MESH:D063646', (271, 285))	('cyclin D1', 'Gene', (120, 129))	('c-MYC', 'Gene', '4609', (142, 147))	('carcinogenesis', 'Disease', (271, 285))	('decrease', 'NegReg', (94, 102))
371633	33007980	Such transcriptional regulation of CCND1 and c-MYC by miR-31 was further translated into a reduced amount of their protein products, as shown in the Western blot analysis (Figure 5B).	('amount of', 'MPA', (99, 108))	('transcriptional regulation', 'MPA', (5, 31))	('c-MYC', 'Gene', (45, 50))	('protein products', 'MPA', (115, 131))	('miR-31', 'Var', (54, 60))	('CCND1', 'Gene', '595', (35, 40))	('c-MYC', 'Gene', '4609', (45, 50))	('reduced', 'NegReg', (91, 98))	('CCND1', 'Gene', (35, 40))
371634	33007980	In line with these results, stable expression of miR-31 in OSCC cells led to consistent decreases in both CCND1 and c-MYC transcripts as well as their protein products (Figure 5C,D).	('protein products', 'MPA', (151, 167))	('miR-31', 'Var', (49, 55))	('c-MYC', 'Gene', '4609', (116, 121))	('decreases', 'NegReg', (88, 97))	('CCND1', 'Gene', (106, 111))	('c-MYC', 'Gene', (116, 121))	('OSCC', 'CellLine', 'CVCL:L894', (59, 63))	('CCND1', 'Gene', '595', (106, 111))
371637	33007980	Indeed, we found a slight shift in the ratio of OSCC cells in the G0/G1 phase over those in the M/G2 phase following stable expression of miR-31 in a subset of SAS cells (Figure 5E), with a similar trend in the pooled data detected, albeit a lack of statistical difference (Figure 5F).	('OSCC', 'CellLine', 'CVCL:L894', (48, 52))	('shift', 'Reg', (26, 31))	('miR-31', 'Gene', (138, 144))	('M/G2', 'Var', (96, 100))	('M/G2', 'SUBSTITUTION', 'None', (96, 100))
371641	33007980	Meanwhile, dysfunction of microRNAs (miRNAs), one of the most abundant short non-coding RNAs, has been considered critical in development of a number of pathologic conditions, including various malignancies.	('miR', 'Gene', '220972', (37, 40))	('malignancies', 'Disease', (194, 206))	('miR', 'Gene', (37, 40))	('dysfunction', 'Var', (11, 22))	('malignancies', 'Disease', 'MESH:D009369', (194, 206))
371664	33007980	WLS is an important regulator of Wnt signaling, a well-known pathway of which dysregulation has been linked to tumorigenesis and progression of various types of malignant tumors.	('dysregulation', 'Var', (78, 91))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('Wnt', 'Gene', '22408;89780;7474;7480', (33, 36))	('Wnt', 'Gene', (33, 36))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('malignant tumors', 'Disease', (161, 177))	('malignant tumors', 'Disease', 'MESH:D009369', (161, 177))	('tumor', 'Disease', (111, 116))	('linked', 'Reg', (101, 107))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', (171, 176))	('tumors', 'Phenotype', 'HP:0002664', (171, 177))
371673	33007980	Further systematic analyses are thus required to explore the possibility of miR-31-dependent control of cell cycle regulators beyond the canonical Wnt signaling pathway.	('Wnt', 'Gene', (147, 150))	('miR-31-dependent', 'Var', (76, 92))	('Wnt', 'Gene', '22408;89780;7474;7480', (147, 150))
371678	33007980	All fly stocks used in our study were acquired from the Bloomington Drosophila Stock Center (Bloomington, IN, USA), including w*; PBac{UAS-mir-31a.S}VK00037/CyO, w1118; P{UAS-LUC-mir-31a.T}attp2, w1118; P{UAS-LUC-mir-31b.T}attP2, w*; P{GawB}459.2 and y1w*; P{GawB}ushMD751.	('stocks', 'Species', '3724', (8, 14))	('mir-31a', 'Gene', (179, 186))	('CyO', 'Gene', (157, 160))	('Drosophila', 'Species', '7227', (68, 78))	('mir-31a', 'Gene', '12798333', (139, 146))	('CyO', 'Gene', '34350', (157, 160))	('mir-31b', 'Gene', (213, 220))	('mir-31b', 'Gene', '12797955', (213, 220))	('mir-31a', 'Gene', (139, 146))	('y1w*; P{GawB', 'Var', (251, 263))	('mir-31a', 'Gene', '12798333', (179, 186))
371683	33007980	Cells expressing the ectopic miR-31 were positively selected by an application of puromycin at the concentration of 2 mug/mL (Invitrogen, ThermoFisher Scientific).	('miR-31', 'Var', (29, 35))	('puromycin', 'Chemical', 'MESH:D011691', (82, 91))	('ectopic miR-31', 'Var', (21, 35))
371727	29679068	So far, a number of groups have reported specific subsets of circulating miRNAs in blood that were linked to tumour location, clinical properties, and genetic phenotypes, including certain EGFR mutations and ALK fusion positivity.	('EGFR', 'Gene', '1956', (189, 193))	('ALK', 'Gene', (208, 211))	('miR', 'Gene', (73, 76))	('EGFR', 'Gene', (189, 193))	('mutations', 'Var', (194, 203))	('ALK', 'Gene', '238', (208, 211))	('miR', 'Gene', '220972', (73, 76))	('tumour location', 'Disease', 'MESH:D009369', (109, 124))	('tumour location', 'Disease', (109, 124))	('linked', 'Reg', (99, 105))	('tumour', 'Phenotype', 'HP:0002664', (109, 115))
371890	32477468	Genetic disruption of TLR and adaptor molecule of TLR pathway found to be associated with tumor development and progression in mice.	('mice', 'Species', '10090', (127, 131))	('L', 'Chemical', 'MESH:D007930', (23, 24))	('progression', 'CPA', (112, 123))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('Genetic disruption', 'Var', (0, 18))	('TLR', 'Gene', (50, 53))	('TLR', 'Gene', (22, 25))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('L', 'Chemical', 'MESH:D007930', (51, 52))	('associated', 'Reg', (74, 84))
371897	32477468	With that also TLR in the epithelial and inflammatory cells induces persistent innate immunity response, expression of pro-inflammatory cytokines and the generation of ROS take place.	('L', 'Chemical', 'MESH:D007930', (16, 17))	('induces', 'Reg', (60, 67))	('ROS', 'Chemical', 'MESH:D017382', (168, 171))	('innate immunity response', 'CPA', (79, 103))	('expression of pro-inflammatory cytokines', 'MPA', (105, 145))	('TLR', 'Var', (15, 18))
371900	32477468	But the modulation of inflammatory processes by TLRs is a key factor in tumor development and progression of tumor cells as well as found to be both tumor promoting anti-tumor response Genetic disruptions of TLRs and adaptor molecules of TLRs pathways has also been observed in previous studies that has shown association with tumor development and progression in mice.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('disruptions', 'Var', (193, 204))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('L', 'Chemical', 'MESH:D007930', (239, 240))	('mice', 'Species', '10090', (364, 368))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumor', 'Disease', (170, 175))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('tumor', 'Disease', (327, 332))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumor', 'Disease', 'MESH:D009369', (327, 332))	('tumor', 'Disease', (72, 77))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('L', 'Chemical', 'MESH:D007930', (209, 210))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('tumor', 'Phenotype', 'HP:0002664', (327, 332))	('TLRs', 'Gene', (208, 212))	('tumor', 'Disease', (149, 154))	('L', 'Chemical', 'MESH:D007930', (49, 50))	('tumor', 'Disease', (109, 114))
371907	32477468	TLR-4 has also shown pro tumorigenic effects with mice deficient in TLR4 at reduced risk of developing gastrointestinal; and hepatocellular cancer.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('hepatocellular cancer', 'Disease', (125, 146))	('hepatocellular cancer', 'Phenotype', 'HP:0001402', (125, 146))	('TLR-4', 'Gene', '21898', (0, 5))	('tumor', 'Disease', (25, 30))	('hepatocellular cancer', 'Disease', 'MESH:D006528', (125, 146))	('TLR-4', 'Gene', (0, 5))	('mice', 'Species', '10090', (50, 54))	('gastrointestinal', 'Disease', (103, 119))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('TLR4', 'Gene', (68, 72))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('deficient', 'Var', (55, 64))
371932	32477468	Nuclear TLR2 expression is affiliated with large tumor and occurred more often in primary tumor than metastasis or even in recurrent tumor.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('TLR2', 'Gene', '7097', (8, 12))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('TLR2', 'Gene', (8, 12))	('tumor', 'Disease', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('Nuclear', 'Var', (0, 7))	('tumor', 'Disease', (133, 138))	('occurred', 'Reg', (59, 67))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
371936	32477468	Significant increase in oral cancer risk was observed in mutated TLR3 genotype, where heterozygous and mutated TLR3 genotype and has worse survival in a group of patients with stage III tumor.	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('cancer', 'Disease', (29, 35))	('mutated', 'Var', (103, 110))	('TLR3', 'Gene', (65, 69))	('patients', 'Species', '9606', (162, 170))	('increase in oral cancer', 'Phenotype', 'HP:0100649', (12, 35))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('TLR3', 'Gene', '7098', (65, 69))	('increase', 'PosReg', (12, 20))	('TLR3', 'Gene', (111, 115))	('tumor', 'Disease', (186, 191))	('TLR3', 'Gene', '7098', (111, 115))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('mutated', 'Var', (57, 64))	('cancer', 'Disease', 'MESH:D009369', (29, 35))
371948	32477468	Even in early stages, high TLR5 expression was found to associated with lower tumor grade.	('TLR5', 'Gene', '7100', (27, 31))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('high', 'Var', (22, 26))	('lower', 'NegReg', (72, 77))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('TLR5', 'Gene', (27, 31))	('tumor', 'Disease', (78, 83))	('expression', 'MPA', (32, 42))
371952	32477468	Low tumor stages, no lymph node metastasis and better prognosis were observed with high expression of TLR7 in stroma fibroblast like cells.	('Low tumor', 'Disease', (0, 9))	('TLR7', 'Gene', (102, 106))	('high expression', 'Var', (83, 98))	('Low tumor', 'Disease', 'MESH:D009800', (0, 9))	('TLR7', 'Gene', '51284', (102, 106))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))
371964	32477468	With the treatment of poly I:C, cell growth is found to be inhibited in a dose dependent manner.	('cell growth', 'CPA', (32, 43))	('poly I:C', 'Var', (22, 30))	('inhibited', 'NegReg', (59, 68))	('poly I', 'Chemical', 'MESH:D011069', (22, 28))
371976	32477468	As far as the progression was concerned mutant TLR3 genotype found to be significantly increase in oral cancer, where as it has act as ligand and induce apoptosis of OSCC by interferon-beta production and activation of caspase 3 and 9.	('interferon-beta', 'Gene', '3456', (174, 189))	('increase', 'PosReg', (87, 95))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('activation', 'PosReg', (205, 215))	('TLR3', 'Gene', '7098', (47, 51))	('increase in oral cancer', 'Phenotype', 'HP:0100649', (87, 110))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('caspase 3 and 9', 'Gene', '836;842', (219, 234))	('mutant', 'Var', (40, 46))	('induce', 'PosReg', (146, 152))	('TLR3', 'Gene', (47, 51))	('interferon-beta', 'Gene', (174, 189))	('apoptosis', 'CPA', (153, 162))
371985	32477468	Relationship between TLRs and OSCC found to be linked with genetic disruption of TLR & adopter molecule that promote tumor development and progression, where as progression of OSCC found to be mainly associated with the TLR2, TLR3, TLR4, TLR5, TLR7 and TLR9.	('that', 'PosReg', (104, 108))	('TLR3', 'Gene', '7098', (226, 230))	('L', 'Chemical', 'MESH:D007930', (239, 240))	('mainly', 'Reg', (193, 199))	('TLR3', 'Gene', (226, 230))	('L', 'Chemical', 'MESH:D007930', (245, 246))	('L', 'Chemical', 'MESH:D007930', (22, 23))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('and', 'CPA', (135, 138))	('L', 'Chemical', 'MESH:D007930', (227, 228))	('TLR5', 'Gene', (238, 242))	('TLR9', 'Gene', (253, 257))	('L', 'Chemical', 'MESH:D007930', (82, 83))	('L', 'Chemical', 'MESH:D007930', (233, 234))	('TLR7', 'Gene', (244, 248))	('TLR5', 'Gene', '7100', (238, 242))	('TLR9', 'Gene', '54106', (253, 257))	('TLR7', 'Gene', '51284', (244, 248))	('genetic disruption', 'Var', (59, 77))	('and', 'Gene', (249, 252))	('tumor', 'Disease', (117, 122))	('the', 'Gene', (216, 219))	('TLR2', 'Gene', '7097', (220, 224))	('L', 'Chemical', 'MESH:D007930', (254, 255))	('TLR &', 'Gene', (81, 86))	('TLR2', 'Gene', (220, 224))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('L', 'Chemical', 'MESH:D007930', (221, 222))
372003	26425122	The aberrant expression of Snail is related to poor patient survival in breast, ovarian, hepatocellular, and colorectal carcinomas.	('colorectal carcinomas', 'Disease', (109, 130))	('hepatocellular', 'Disease', (89, 103))	('breast', 'Disease', (72, 78))	('colorectal carcinomas', 'Disease', 'MESH:D015179', (109, 130))	('aberrant expression', 'Var', (4, 23))	('Snail', 'Gene', (27, 32))	('ovarian', 'Disease', (80, 87))	('Snail', 'Gene', '6615', (27, 32))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('patient', 'Species', '9606', (52, 59))	('carcinomas', 'Phenotype', 'HP:0030731', (120, 130))
372053	26425122	Finally, salinomycin, an antibiotic, reduced significantly vimentin level and induced increase in E-cadherin expression in CD133+ colorectal cancer cell lines HT29 and SW480 resulting in decreased malignant traits.	('colorectal cancer', 'Phenotype', 'HP:0003003', (130, 147))	('increase', 'PosReg', (86, 94))	('colorectal cancer', 'Disease', (130, 147))	('expression', 'MPA', (109, 119))	('HT29', 'CellLine', 'CVCL:0320', (159, 163))	('salinomycin', 'Chemical', 'MESH:C010327', (9, 20))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('E-cadherin', 'Protein', (98, 108))	('colorectal cancer', 'Disease', 'MESH:D015179', (130, 147))	('salinomycin', 'Var', (9, 20))	('reduced', 'NegReg', (37, 44))	('decreased', 'NegReg', (187, 196))	('vimentin level', 'MPA', (59, 73))	('malignant traits', 'CPA', (197, 213))
372060	26425122	have shown using many different pancreatic cell lines that silencing Zeb-1 not only restored the expression of epithelial marker genes, but also increased cellular sensitivity to therapeutic reagents.	('cellular sensitivity to therapeutic reagents', 'MPA', (155, 199))	('pancreatic', 'Disease', 'MESH:D010195', (32, 42))	('expression of epithelial marker genes', 'MPA', (97, 134))	('Zeb-1', 'Gene', (69, 74))	('pancreatic', 'Disease', (32, 42))	('increased', 'PosReg', (145, 154))	('Zeb-1', 'Gene', '6935', (69, 74))	('silencing', 'Var', (59, 68))	('restored', 'PosReg', (84, 92))
372061	26425122	In a lung carcinoma cell line, the knockdown of Snail or Twist-1 is able to restore the cell chemosensitivity to cisplatin.	('knockdown', 'Var', (35, 44))	('cell chemosensitivity to cisplatin', 'MPA', (88, 122))	('Twist-1', 'Gene', (57, 64))	('lung carcinoma', 'Disease', 'MESH:D008175', (5, 19))	('Snail', 'Gene', '6615', (48, 53))	('Snail', 'Gene', (48, 53))	('lung carcinoma', 'Disease', (5, 19))	('restore', 'PosReg', (76, 83))	('cisplatin', 'Chemical', 'MESH:D002945', (113, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (10, 19))
372066	26425122	However, a clinical trial is currently investigating the molecular mechanism and clinical significance of the interplay between Twist-1 and other EMT regulators through microRNA-29 family in head and neck squamous cell carcinoma (NCT01927354).	('microRNA-29', 'Gene', (169, 180))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (205, 228))	('neck squamous cell carcinoma', 'Disease', (200, 228))	('carcinoma', 'Phenotype', 'HP:0030731', (219, 228))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (200, 228))	('NCT01927354', 'Var', (230, 241))	('Twist-1', 'Gene', (128, 135))	('microRNA-29', 'Gene', '407021', (169, 180))
372069	26425122	Inhibitors of ALK5, MEK, and SRC are able to block EMT in response to EGF, HGF, and IGF-1.	('EMT', 'CPA', (51, 54))	('IGF-1', 'Gene', '3479', (84, 89))	('IGF-1', 'Gene', (84, 89))	('HGF', 'Gene', '3082', (75, 78))	('SRC', 'Gene', '6714', (29, 32))	('MEK', 'Gene', (20, 23))	('SRC', 'Gene', (29, 32))	('block', 'NegReg', (45, 50))	('MEK', 'Gene', '5609', (20, 23))	('Inhibitors', 'Var', (0, 10))	('ALK5', 'Gene', (14, 18))	('HGF', 'Gene', (75, 78))
372073	26425122	SD-093 and LY-580276, two competitive inhibitors for the ATP-binding site of TGFbetaRI kinase, disrupt EMT and tumor cell migration in many cancers.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('EMT', 'CPA', (103, 106))	('ATP', 'Chemical', 'MESH:D000255', (57, 60))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('cancers', 'Phenotype', 'HP:0002664', (140, 147))	('tumor', 'Disease', (111, 116))	('TGFbetaRI', 'Gene', (77, 86))	('SD-093', 'Chemical', '-', (0, 6))	('LY-580276', 'Chemical', '-', (11, 20))	('cancers', 'Disease', (140, 147))	('cancers', 'Disease', 'MESH:D009369', (140, 147))	('LY-580276', 'Var', (11, 20))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('disrupt', 'NegReg', (95, 102))
372074	26425122	EW-7203, EW-7195, and EW-7197, specific TGFbeta/ALK5 inhibitors available as orally administered drugs, have been shown to inhibit EMT in both TGFbeta treated breast cancer cells and 4T1 orthotropic xenograft mice.	('mice', 'Species', '10090', (209, 213))	('TGFbeta/ALK5', 'Gene', (40, 52))	('EW-7197', 'Var', (22, 29))	('EMT', 'CPA', (131, 134))	('breast cancer', 'Phenotype', 'HP:0003002', (159, 172))	('inhibit', 'NegReg', (123, 130))	('EW-7195', 'Var', (9, 16))	('breast cancer', 'Disease', 'MESH:D001943', (159, 172))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('breast cancer', 'Disease', (159, 172))	('4T1', 'CellLine', 'CVCL:0125', (183, 186))
372076	26425122	In 2008, already, the LY2157299, a clinical selective TGFbeta1 receptor inhibitor, was undergoing a still unpublished phase I trial for colon, prostate, and adrenocortical or breast cancer and malignant melanoma patients.	('LY2157299', 'Var', (22, 31))	('TGFbeta1', 'Gene', '7040', (54, 62))	('adrenocortical or breast cancer', 'Disease', (157, 188))	('TGFbeta1', 'Gene', (54, 62))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('breast cancer', 'Phenotype', 'HP:0003002', (175, 188))	('colon', 'Disease', (136, 141))	('adrenocortical or breast cancer', 'Disease', 'MESH:D000306', (157, 188))	('patients', 'Species', '9606', (212, 220))	('colon', 'Disease', 'MESH:D015179', (136, 141))	('prostate', 'Disease', (143, 151))	('melanoma', 'Phenotype', 'HP:0002861', (203, 211))	('malignant melanoma', 'Phenotype', 'HP:0002861', (193, 211))	('LY2157299', 'Chemical', 'MESH:C557799', (22, 31))	('malignant melanoma', 'Disease', 'MESH:D008545', (193, 211))	('malignant melanoma', 'Disease', (193, 211))
372077	26425122	That same year, another preclinical trial using human xenografts Calu6 (non-small-cell lung cancer) and MX1 (breast cancer) implanted subcutaneously in nude mice demonstrated that LY2157299 is able to reduce the tumor growth.	('nude mice', 'Species', '10090', (152, 161))	('reduce', 'NegReg', (201, 207))	('breast cancer', 'Disease', (109, 122))	('lung cancer', 'Disease', 'MESH:D008175', (87, 98))	('breast cancer', 'Phenotype', 'HP:0003002', (109, 122))	('human', 'Species', '9606', (48, 53))	('tumor', 'Disease', 'MESH:D009369', (212, 217))	('LY2157299', 'Var', (180, 189))	('LY2157299', 'Chemical', 'MESH:C557799', (180, 189))	('MX1', 'Gene', (104, 107))	('lung cancer', 'Disease', (87, 98))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('lung cancer', 'Phenotype', 'HP:0100526', (87, 98))	('MX1', 'Gene', '4599', (104, 107))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('tumor', 'Disease', (212, 217))	('breast cancer', 'Disease', 'MESH:D001943', (109, 122))
372078	26425122	LY2157299 is now known to display antitumor effects in patients with glioblastoma and hepatocellular carcinoma.	('LY2157299', 'Var', (0, 9))	('tumor', 'Disease', (38, 43))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (86, 110))	('LY2157299', 'Chemical', 'MESH:C557799', (0, 9))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (86, 110))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('hepatocellular carcinoma', 'Disease', (86, 110))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('glioblastoma', 'Disease', (69, 81))	('glioblastoma', 'Disease', 'MESH:D005909', (69, 81))	('patients', 'Species', '9606', (55, 63))	('glioblastoma', 'Phenotype', 'HP:0012174', (69, 81))
372079	26425122	LY2157299 is currently tested in four clinical trials, in patients recruiting state: Phase Ib/II in stages II-IV pancreatic cancer of LY2157299 combined with gemcitabine versus gemcitabine plus placebo (NCT01373164); Phase II in HCC patients with disease progression on sorafenib or who are not eligible to receive sorafenib (NCT01246986); Phase Ib/IIa study combining LY2157299 with standard temozolomide based radiochemotherapy in patients with newly diagnosed malignant glioma (NCT01220271); and Phase II Study of LY2157299 monotherapy or LY2157299 plus Lomustine therapy compared to Lomustine monotherapy in patients with recurrent glioblastoma (NCT01582269).	('pancreatic cancer', 'Phenotype', 'HP:0002894', (113, 130))	('LY2157299', 'Chemical', 'MESH:C557799', (369, 378))	('LY2157299', 'Chemical', 'MESH:C557799', (542, 551))	('LY2157299', 'Var', (517, 526))	('HCC', 'Disease', (229, 232))	('patients', 'Species', '9606', (433, 441))	('LY2157299', 'Chemical', 'MESH:C557799', (517, 526))	('II-IV pancreatic cancer', 'Disease', 'MESH:D010190', (107, 130))	('glioma', 'Phenotype', 'HP:0009733', (473, 479))	('LY2157299', 'Chemical', 'MESH:C557799', (0, 9))	('glioblastoma', 'Disease', 'MESH:D005909', (636, 648))	('II-IV pancreatic cancer', 'Disease', (107, 130))	('malignant glioma', 'Disease', 'MESH:D005910', (463, 479))	('malignant glioma', 'Disease', (463, 479))	('patients', 'Species', '9606', (233, 241))	('patients', 'Species', '9606', (58, 66))	('LY2157299', 'Chemical', 'MESH:C557799', (134, 143))	('patients', 'Species', '9606', (612, 620))	('glioblastoma', 'Disease', (636, 648))	('HCC', 'Disease', 'MESH:D006528', (229, 232))	('glioblastoma', 'Phenotype', 'HP:0012174', (636, 648))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('LY2157299', 'Var', (542, 551))
372088	26425122	In fact, GC-1008 is currently tested in two clinical studies: fresolimumab and radiotherapy in metastatic breast cancer (NCT01401062) and safety and imaging study of GC1008 in glioma (NCT01472731).	('GC1008', 'Chemical', 'MESH:C560928', (166, 172))	('glioma', 'Disease', (176, 182))	('NCT01472731', 'Var', (184, 195))	('breast cancer', 'Disease', (106, 119))	('breast cancer', 'Phenotype', 'HP:0003002', (106, 119))	('glioma', 'Disease', 'MESH:D005910', (176, 182))	('GC1008', 'Gene', (166, 172))	('fresolimumab', 'Chemical', 'MESH:C560928', (62, 74))	('glioma', 'Phenotype', 'HP:0009733', (176, 182))	('NCT01401062', 'Var', (121, 132))	('GC-1008', 'Chemical', 'MESH:C560928', (9, 16))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('breast cancer', 'Disease', 'MESH:D001943', (106, 119))
372180	34046188	Some suggests metformin reduces progression of SCC and may illicit antitumorigenic immune response.	('SCC', 'Phenotype', 'HP:0002860', (47, 50))	('reduces', 'NegReg', (24, 31))	('SCC', 'Gene', '6317', (47, 50))	('metformin', 'Var', (14, 23))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('illicit', 'Reg', (59, 66))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('progression', 'CPA', (32, 43))	('metformin', 'Chemical', 'MESH:D008687', (14, 23))	('tumor', 'Disease', (71, 76))	('SCC', 'Gene', (47, 50))
372199	31741753	In lung cancer patients with high PD-L1 expression, blocking or reducing its expression can inhibit tumor growth.	('high', 'Var', (29, 33))	('reducing', 'NegReg', (64, 72))	('expression', 'MPA', (77, 87))	('expression', 'MPA', (40, 50))	('patients', 'Species', '9606', (15, 23))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('lung cancer', 'Disease', (3, 14))	('tumor', 'Disease', (100, 105))	('lung cancer', 'Phenotype', 'HP:0100526', (3, 14))	('PD-L1', 'Gene', (34, 39))	('inhibit', 'NegReg', (92, 99))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('lung cancer', 'Disease', 'MESH:D008175', (3, 14))	('tumor', 'Disease', 'MESH:D009369', (100, 105))
372216	31741753	SDH5 has been reported to contribute to the development of several kinds of cancers and is mutated in paraganglioma and gastrointestinal stromal tumors.	('paraganglioma', 'Phenotype', 'HP:0002668', (102, 115))	('cancers', 'Disease', 'MESH:D009369', (76, 83))	('cancers', 'Phenotype', 'HP:0002664', (76, 83))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (120, 151))	('contribute', 'Reg', (26, 36))	('cancers', 'Disease', (76, 83))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('SDH5', 'Gene', (0, 4))	('mutated', 'Var', (91, 98))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('paraganglioma and gastrointestinal stromal tumors', 'Disease', 'MESH:C564650', (102, 151))	('SDH5', 'Gene', '54949', (0, 4))
372217	31741753	Previously, we demonstrated that the loss of SDH5 could augment the expression of ZEB1, induce EMT and lead to lung cancer metastasis via the glycogen synthase kinase 3beta/beta-catenin pathway.	('expression', 'MPA', (68, 78))	('lung cancer', 'Disease', 'MESH:D008175', (111, 122))	('SDH5', 'Gene', (45, 49))	('glycogen synthase kinase 3beta', 'Gene', '2932', (142, 172))	('ZEB1', 'Gene', (82, 86))	('glycogen synthase kinase 3beta', 'Gene', (142, 172))	('EMT', 'CPA', (95, 98))	('lead to', 'Reg', (103, 110))	('augment', 'PosReg', (56, 63))	('loss', 'Var', (37, 41))	('lung cancer', 'Disease', (111, 122))	('induce', 'PosReg', (88, 94))	('lung cancer', 'Phenotype', 'HP:0100526', (111, 122))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('SDH5', 'Gene', '54949', (45, 49))
372232	31741753	Wnt-CM and L-CM were collected according to the directions from the ATCC and were added to the cells for 24 h. The following primary antibodies were used: anti-SDH5 (Cell Signaling Technology,(USA), anti-PD-L1 (Cell Signaling Technology, (USA), anti-ZEB1 (Sigma), anti-beta-catenin (Cell Signaling Technology, USA), anti-GSK-3 (Sigma), anti-phospho-GSK-3 (Ser-9) (Sigma), and anti-GAPDH (Abcam, UK).	('anti-phospho-GSK-3', 'Var', (336, 354))	('GAPDH', 'Gene', '2597', (381, 386))	('GAPDH', 'Gene', (381, 386))	('SDH5', 'Gene', '54949', (160, 164))	('anti-GSK-3', 'Var', (316, 326))	('SDH5', 'Gene', (160, 164))
372257	31741753	To further explore whether the high SDH5 expression-induced decrease in PD-L1 expression would eventually influence the function of T cells, we next assessed the relationship between SDH5 expression and the T-effector and IFN-gamma-associated gene signature, which has previously been associated with activated T cells, immune cytolytic activity, and IFN-gamma release.	('SDH5', 'Gene', '54949', (183, 187))	('decrease', 'NegReg', (60, 68))	('expression', 'MPA', (78, 88))	('function', 'MPA', (120, 128))	('SDH5', 'Gene', '54949', (36, 40))	('IFN-gamma', 'Gene', (351, 360))	('influence', 'Reg', (106, 115))	('IFN-gamma', 'Gene', '3458', (351, 360))	('IFN-gamma', 'Gene', '3458', (222, 231))	('IFN-gamma', 'Gene', (222, 231))	('SDH5', 'Gene', (183, 187))	('high', 'Var', (31, 35))	('PD-L1', 'Gene', (72, 77))	('SDH5', 'Gene', (36, 40))
372258	31741753	An integrated heatmap depicts the expression levels of T-effector and IFN-gamma-associated gene signatures in tumors with low SDH5 expression compared to those with high SDH5 expression (Figure 1(b)).	('expression', 'MPA', (34, 44))	('IFN-gamma', 'Gene', '3458', (70, 79))	('IFN-gamma', 'Gene', (70, 79))	('SDH5', 'Gene', '54949', (170, 174))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('SDH5', 'Gene', (126, 130))	('tumors', 'Disease', (110, 116))	('low', 'Var', (122, 125))	('tumors', 'Disease', 'MESH:D009369', (110, 116))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('SDH5', 'Gene', '54949', (126, 130))	('SDH5', 'Gene', (170, 174))
372263	31741753	The western blot results showed that the knockdown of SDH5 caused notably upregulated expression of PD-L1 (Figure 2 A,H292, B, HCC827, C,NCI1975).	('SDH5', 'Gene', (54, 58))	('upregulated', 'PosReg', (74, 85))	('SDH5', 'Gene', '54949', (54, 58))	('HCC827', 'CellLine', 'CVCL:2063', (127, 133))	('NCI1975', 'CellLine', 'CVCL:1511', (137, 144))	('expression', 'MPA', (86, 96))	('H292', 'CellLine', 'CVCL:0455', (118, 122))	('knockdown', 'Var', (41, 50))	('PD-L1', 'Gene', (100, 105))
372265	31741753	In addition, flow cytometry results showed that the knockdown of SDH5 expression increased the amount of PD-L1 expression on the cell membrane (Figure 2(g-i)).	('SDH5', 'Gene', (65, 69))	('amount', 'MPA', (95, 101))	('increased', 'PosReg', (81, 90))	('knockdown', 'Var', (52, 61))	('PD-L1 expression on the', 'MPA', (105, 128))	('SDH5', 'Gene', '54949', (65, 69))
372266	31741753	To summarize these results, we hypothesized that the inhibition of SDH5 can upregulate the expression level of PD-L1 at the transcriptional level and eventually affect the final immune status of the tumor.	('tumor', 'Disease', (199, 204))	('inhibition', 'Var', (53, 63))	('expression', 'MPA', (91, 101))	('SDH5', 'Gene', (67, 71))	('SDH5', 'Gene', '54949', (67, 71))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('upregulate', 'PosReg', (76, 86))	('PD-L1', 'Gene', (111, 116))	('affect', 'Reg', (161, 167))
372268	31741753	Our previous studies have shown that SDH5 plays a key role in the regulation of EMT by regulating the GSK-3beta-beta-catenin signaling pathway and that the inhibition of SDH5 induces upregulation of the EMT transcription factor ZEB1 protein.	('EMT', 'Protein', (203, 206))	('inhibition', 'Var', (156, 166))	('upregulation', 'PosReg', (183, 195))	('SDH5', 'Gene', (37, 41))	('SDH5', 'Gene', '54949', (170, 174))	('EMT', 'Gene', (80, 83))	('SDH5', 'Gene', '54949', (37, 41))	('GSK-3beta', 'Gene', '2932', (102, 111))	('GSK-3beta', 'Gene', (102, 111))	('regulating', 'Reg', (87, 97))	('SDH5', 'Gene', (170, 174))
372272	31741753	Next, ZEB1-siRNA and SDH5-siRNA were transfected or cotransfected at the same time into HCC827 and H1975 cells, and we found that the upregulation of PD-L1 protein induced by SDH5 knockdown could be reversed by ZEB1 knockdown (Figure 3(c,d)).	('knockdown', 'Var', (180, 189))	('SDH5', 'Gene', (175, 179))	('HCC827', 'CellLine', 'CVCL:2063', (88, 94))	('PD-L1', 'Gene', (150, 155))	('SDH5', 'Gene', (21, 25))	('protein', 'Protein', (156, 163))	('upregulation', 'PosReg', (134, 146))	('SDH5', 'Gene', '54949', (21, 25))	('SDH5', 'Gene', '54949', (175, 179))	('H1975', 'CellLine', 'CVCL:1511', (99, 104))
372279	31741753	By knocking down endogenous SDH5 with an siRNA, we observed the accumulation of cytoplasmic beta-catenin, the nuclear translocation of beta-catenin, and reduced membrane-associated beta-catenin (Figure 5(a,b)).	('SDH5', 'Gene', '54949', (28, 32))	('beta-catenin', 'Protein', (135, 147))	('reduced', 'NegReg', (153, 160))	('nuclear translocation', 'MPA', (110, 131))	('SDH5', 'Gene', (28, 32))	('membrane-associated beta-catenin', 'MPA', (161, 193))	('cytoplasmic beta-catenin', 'MPA', (80, 104))	('knocking down', 'Var', (3, 16))	('accumulation', 'PosReg', (64, 76))
372282	31741753	Whereas Wnt only slightly elicited EMT (Figure 5(c), left two lanes) in HCC827 cells, it significantly increased EMT when endogenous SDH5 was knocked down by SDH5-siRNA (Figure 5(c), right two lanes).	('SDH5', 'Gene', (133, 137))	('EMT', 'CPA', (35, 38))	('increased', 'PosReg', (103, 112))	('increased EMT', 'Phenotype', 'HP:0008151', (103, 116))	('lanes', 'Chemical', 'MESH:C480782', (62, 67))	('SDH5', 'Gene', (158, 162))	('HCC827', 'CellLine', 'CVCL:2063', (72, 78))	('SDH5', 'Gene', '54949', (133, 137))	('EMT', 'CPA', (113, 116))	('lanes', 'Chemical', 'MESH:C480782', (193, 198))	('SDH5', 'Gene', '54949', (158, 162))	('knocked', 'Var', (142, 149))	('elicited', 'Reg', (26, 34))
372284	31741753	Consistent with these results, beta-catenin/TCF transcriptional activity was increased upon the knockdown of SDH5 (Figure 5(e-f)).	('knockdown', 'Var', (96, 105))	('SDH5', 'Gene', '54949', (109, 113))	('TCF', 'Gene', (44, 47))	('TCF', 'Gene', '3172', (44, 47))	('increased', 'PosReg', (77, 86))	('SDH5', 'Gene', (109, 113))
372285	31741753	To demonstrate whether SDH5 upregulates ZEB1 by inducing beta-catenin transcription activity levels and ultimately affecting PD-L1, we knocked down beta-catenin and SDH5 at the same time and found that the upregulation of PD-L1 and ZEB1 protein induced by SDH5 knockdown was abolished (Figure 6c, HCC827 B, NCI-1975).	('inducing', 'PosReg', (48, 56))	('beta-catenin transcription activity levels', 'MPA', (57, 99))	('knockdown', 'Var', (261, 270))	('SDH5', 'Gene', (256, 260))	('NCI-1975', 'CellLine', 'CVCL:1511', (307, 315))	('SDH5', 'Gene', (23, 27))	('SDH5', 'Gene', '54949', (165, 169))	('SDH5', 'Gene', (165, 169))	('PD-L1', 'Protein', (222, 227))	('SDH5', 'Gene', '54949', (23, 27))	('SDH5', 'Gene', '54949', (256, 260))	('upregulation', 'PosReg', (206, 218))	('HCC827', 'CellLine', 'CVCL:2063', (297, 303))	('affecting', 'Reg', (115, 124))	('PD-L1', 'Gene', (125, 130))	('upregulates', 'PosReg', (28, 39))
372288	31741753	Taken together, these results led us to hypothesize that the loss of SDH5 could increase PD-L1 expression by activating the GSK3beta/beta-catenin/ZEB1 signaling pathway.	('activating', 'PosReg', (109, 119))	('SDH5', 'Gene', '54949', (69, 73))	('increase PD', 'Phenotype', 'HP:0008151', (80, 91))	('increase', 'PosReg', (80, 88))	('SDH5', 'Gene', (69, 73))	('PD-L1', 'Gene', (89, 94))	('GSK3beta/beta-catenin/ZEB1 signaling pathway', 'Pathway', (124, 168))	('loss', 'Var', (61, 65))	('expression', 'MPA', (95, 105))
372290	31741753	The strategy for targeted deletion of the mouse SDH5 gene is outlined in our previous study.	('SDH5', 'Gene', (48, 52))	('SDH5', 'Gene', '54949', (48, 52))	('mouse', 'Species', '10090', (42, 47))	('deletion', 'Var', (26, 34))
372313	31741753	Our previous study demonstrated that SDH5 depletion can facilitate EMT, leading to lung cancer metastasis.	('leading to', 'Reg', (72, 82))	('lung cancer', 'Disease', 'MESH:D008175', (83, 94))	('SDH5', 'Gene', (37, 41))	('facilitate', 'PosReg', (56, 66))	('EMT', 'CPA', (67, 70))	('SDH5', 'Gene', '54949', (37, 41))	('lung cancer', 'Disease', (83, 94))	('lung cancer', 'Phenotype', 'HP:0100526', (83, 94))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('depletion', 'Var', (42, 51))
372321	31741753	Moreover, in the current study, we found that high SDH5 expression inhibits the expression of multiple EMT-related transcription factors, such as ZEB1, from the TCGA data.	('high', 'Var', (46, 50))	('SDH5', 'Gene', (51, 55))	('expression', 'MPA', (80, 90))	('inhibits', 'NegReg', (67, 75))	('expression', 'Var', (56, 66))	('SDH5', 'Gene', '54949', (51, 55))
372342	27467530	Further studies revealed that the knockdown of SQSTM1 expression dramatically inhibited transformation of human lung epithelial cells upon chronic nickel exposure, whereas ectopic expression of SQSTM1 promoted such transformation.	('SQSTM1', 'Gene', (194, 200))	('human', 'Species', '9606', (106, 111))	('inhibited', 'NegReg', (78, 87))	('transformation of human lung epithelial cells', 'CPA', (88, 133))	('nickel', 'Chemical', 'MESH:D009532', (147, 153))	('SQSTM1', 'Gene', (47, 53))	('knockdown', 'Var', (34, 43))
372361	27467530	Paradoxically, SQSTM1 synergizes with autophagy for tumor growth in vivo and the knockdown of SQSTM1 shows significant inhibitory effects on autophagy activation and tumor growth of human colon cancer cells both in vitro and in a xenograft tumor model.	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('tumor', 'Disease', (52, 57))	('autophagy activation', 'CPA', (141, 161))	('colon cancer', 'Disease', (188, 200))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('autophagy', 'CPA', (38, 47))	('SQSTM1', 'Gene', (94, 100))	('tumor', 'Disease', (240, 245))	('tumor', 'Disease', 'MESH:D009369', (240, 245))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('inhibitory effects', 'NegReg', (119, 137))	('colon cancer', 'Phenotype', 'HP:0003003', (188, 200))	('human', 'Species', '9606', (182, 187))	('tumor', 'Disease', (166, 171))	('knockdown', 'Var', (81, 90))	('tumor', 'Phenotype', 'HP:0002664', (240, 245))	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('colon cancer', 'Disease', 'MESH:D015179', (188, 200))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))
372394	27467530	Consistently, ectopic expression of GFP-SQSTM1 in Beas-2B cells significantly increased nickel-induced cell transformation in comparison with Beas-2B(Vector) cells (Fig.	('Beas-2B', 'CellLine', 'CVCL:0168', (142, 149))	('Beas-2B', 'CellLine', 'CVCL:0168', (50, 57))	('GFP-SQSTM1', 'Gene', (36, 46))	('nickel-induced cell transformation', 'CPA', (88, 122))	('nickel', 'Chemical', 'MESH:D009532', (88, 94))	('increased', 'PosReg', (78, 87))	('ectopic expression', 'Var', (14, 32))
372399	27467530	The results showed a similar effect of SQSTM1 upregulation upon nickel exposure, whereas knockdown of SQSTM1 in BEP2D cells also attenuated nickel-induced cell transformation in Figure 2F-2H.	('attenuated', 'NegReg', (129, 139))	('SQSTM1', 'Gene', (39, 45))	('upregulation', 'PosReg', (46, 58))	('nickel-induced cell transformation in Figure 2F-2H', 'CPA', (140, 190))	('SQSTM1', 'Gene', (102, 108))	('knockdown', 'Var', (89, 98))	('nickel', 'Chemical', 'MESH:D009532', (64, 70))	('nickel', 'Chemical', 'MESH:D009532', (140, 146))
372405	27467530	This notion was further supported by formation of GFP-LC3B puncta in Beas-2B(GFP-LC3B) transfectants following nickel exposure (Fig.	('LC3B', 'Gene', (81, 85))	('Beas-2B', 'CellLine', 'CVCL:0168', (69, 76))	('nickel', 'Chemical', 'MESH:D009532', (111, 117))	('LC3B', 'Gene', '81631', (54, 58))	('transfectants', 'Var', (87, 100))	('LC3B', 'Gene', '81631', (81, 85))	('LC3B', 'Gene', (54, 58))
372407	27467530	Consistently, the results from western blotting also indicated that the increases of exogenous GFP-LC3B-II and endogenous LC3B-II were observed in Beas-2B(GFP-LC3B) transfectants upon nickel treatment (Fig.	('LC3B', 'Gene', '81631', (159, 163))	('LC3B', 'Gene', (99, 103))	('transfectants', 'Var', (165, 178))	('nickel', 'Chemical', 'MESH:D009532', (184, 190))	('increases', 'PosReg', (72, 81))	('LC3B', 'Gene', '81631', (99, 103))	('LC3B', 'Gene', '81631', (122, 126))	('LC3B', 'Gene', (159, 163))	('Beas-2B', 'CellLine', 'CVCL:0168', (147, 154))	('exogenous', 'MPA', (85, 94))	('LC3B', 'Gene', (122, 126))
372422	27467530	As shown in Figure 5B, MTOR phosphorylation at Ser2448, p-MTOR Ser2448, was dramatically inhibited at 3 h and thereafter following nickel exposure.	('Ser2448', 'Chemical', '-', (63, 70))	('MTOR', 'Gene', '2475', (58, 62))	('Ser2448', 'Var', (47, 54))	('inhibited', 'NegReg', (89, 98))	('Ser2448', 'Chemical', '-', (47, 54))	('MTOR', 'Gene', (23, 27))	('nickel', 'Chemical', 'MESH:D009532', (131, 137))	('MTOR', 'Gene', '2475', (23, 27))	('MTOR', 'Gene', (58, 62))
372433	27467530	The knockdown of ULK1 expression impaired nickel-induced cell autophagy in Beas-2B cells (Fig.	('nickel', 'Chemical', 'MESH:D009532', (42, 48))	('impaired', 'NegReg', (33, 41))	('Beas-2B', 'CellLine', 'CVCL:0168', (75, 82))	('nickel-induced cell autophagy', 'CPA', (42, 71))	('ULK1', 'Gene', (17, 21))	('knockdown', 'Var', (4, 13))	('ULK1', 'Gene', '8408', (17, 21))
372437	27467530	As expected, knockdown of BECN1 expression attenuated the nickel-induced LC3B-II level (Fig.	('nickel', 'Chemical', 'MESH:D009532', (58, 64))	('BECN1', 'Gene', '8678', (26, 31))	('BECN1', 'Gene', (26, 31))	('LC3B', 'Gene', (73, 77))	('LC3B', 'Gene', '81631', (73, 77))	('attenuated', 'NegReg', (43, 53))	('knockdown', 'Var', (13, 22))
372439	27467530	5F and 5H), revealing the specificity of inhibition of nickel-induced autophagy in Beas-2B(shULK1) and Beas-2B(shBECN1) transfectants.	('Beas-2B', 'CellLine', 'CVCL:0168', (83, 90))	('ULK1', 'Gene', (93, 97))	('Beas-2B', 'CellLine', 'CVCL:0168', (103, 110))	('ULK1', 'Gene', '8408', (93, 97))	('transfectants', 'Var', (120, 133))	('nickel', 'Chemical', 'MESH:D009532', (55, 61))	('BECN1', 'Gene', (113, 118))	('BECN1', 'Gene', '8678', (113, 118))	('inhibition', 'NegReg', (41, 51))
372442	27467530	The disruption of autophagy by 3-MA markedly elevated the basal level and nickel-induced levels of SQSTM1 protein abundance (Fig.	('autophagy', 'CPA', (18, 27))	('basal level', 'MPA', (58, 69))	('3-MA', 'Chemical', '-', (31, 35))	('SQSTM1', 'Gene', (99, 105))	('elevated', 'PosReg', (45, 53))	('disruption', 'Var', (4, 14))	('nickel', 'Chemical', 'MESH:D009532', (74, 80))	('levels', 'MPA', (89, 95))
372443	27467530	Consistently, inhibition of autophagy by either ectopic expression of PI3K-DA, or knockdown of ULK1 or BECN1 expression using their specific shRNAs also increased both basal and nickel-induced levels of SQSTM1 protein in Beas-2B cells (Fig.	('autophagy', 'CPA', (28, 37))	('nickel', 'Chemical', 'MESH:D009532', (178, 184))	('PI3', 'Gene', (70, 73))	('BECN1', 'Gene', '8678', (103, 108))	('Beas-2B', 'CellLine', 'CVCL:0168', (221, 228))	('increased', 'PosReg', (153, 162))	('ULK1', 'Gene', (95, 99))	('knockdown', 'Var', (82, 91))	('SQSTM1', 'Gene', (203, 209))	('BECN1', 'Gene', (103, 108))	('PI3', 'Gene', '5266', (70, 73))	('ULK1', 'Gene', '8408', (95, 99))	('inhibition', 'NegReg', (14, 24))
372454	27467530	The results showed that there were multiple potential transcription factor binding sites in the SQSTM1 promoter region, including those for JUN/AP-1, MYC/c-MYC, SP1, NFE2L2/NRF2, NFKB, and ETS1 (Fig.	('NFE2L2', 'Gene', (166, 172))	('MYC', 'Gene', '4609', (156, 159))	('c-MYC', 'Gene', '4609', (154, 159))	('MYC', 'Gene', '4609', (150, 153))	('ETS1', 'Gene', '2113', (189, 193))	('ETS1', 'Gene', (189, 193))	('NRF2', 'Gene', '4780', (173, 177))	('AP-1', 'Gene', (144, 148))	('MYC', 'Gene', (156, 159))	('SQSTM1', 'Gene', (96, 102))	('SP1', 'Var', (161, 164))	('AP-1', 'Gene', '3725', (144, 148))	('NFE2L2', 'Gene', '4780', (166, 172))	('NRF2', 'Gene', (173, 177))	('MYC', 'Gene', (150, 153))	('c-MYC', 'Gene', (154, 159))
372470	27467530	The results showed that knockdown of SQSTM1 expression reduced TNF mRNA level following nickel exposure (Fig.	('SQSTM1', 'Gene', (37, 43))	('reduced', 'NegReg', (55, 62))	('TNF mRNA level', 'MPA', (63, 77))	('nickel', 'Chemical', 'MESH:D009532', (88, 94))	('knockdown', 'Var', (24, 33))
372473	27467530	To elucidate the molecular mechanism underlying SQSTM1 upregulation of TNF expression, the TNF promoter-driven transcription activity and TNF mRNA stability were evaluated in Beas-2B(shSQSTM1) transfectants in comparison to Beas-2B(Nonsense) transfectants following nickel exposure.	('TNF', 'Gene', (71, 74))	('Beas-2B', 'CellLine', 'CVCL:0168', (175, 182))	('nickel', 'Chemical', 'MESH:D009532', (266, 272))	('SQSTM1', 'Gene', (48, 54))	('Beas-2B', 'CellLine', 'CVCL:0168', (224, 231))	('upregulation', 'PosReg', (55, 67))	('transfectants', 'Var', (193, 206))
372474	27467530	As shown in Figure 9F and 9G, knockdown of SQSTM1 only showed a slight effect on nickel-induced TNF promoter transcriptional activity (Fig.	('nickel', 'Chemical', 'MESH:D009532', (81, 87))	('knockdown', 'Var', (30, 39))	('SQSTM1', 'Gene', (43, 49))
372478	27467530	Moreover, inhibition of nickel-induced autophagy by 3-MA or knockdown of BECN1 could promote TNF mRNA abundance by nickel exposure (Fig.	('BECN1', 'Gene', (73, 78))	('inhibition', 'NegReg', (10, 20))	('3-MA', 'Chemical', '-', (52, 56))	('promote', 'PosReg', (85, 92))	('nickel', 'Chemical', 'MESH:D009532', (115, 121))	('BECN1', 'Gene', '8678', (73, 78))	('TNF mRNA abundance', 'MPA', (93, 111))	('knockdown', 'Var', (60, 69))	('nickel', 'Chemical', 'MESH:D009532', (24, 30))
372485	27467530	S10A, dramatically inhibits transformation of either Beas-2B cells (Fig.	('transformation', 'CPA', (28, 42))	('S10A', 'Var', (0, 4))	('Beas-2B', 'CellLine', 'CVCL:0168', (53, 60))	('S10A', 'SUBSTITUTION', 'None', (0, 4))	('inhibits', 'NegReg', (19, 27))
372486	27467530	S10B and S10C) following nickel-repeated exposure in comparison to their nonsense transfectants, revealing that TNF induction plays an important role in nickel-induced transformation of human bronchial epithelial cells.	('S10B', 'SUBSTITUTION', 'None', (0, 4))	('S10C', 'Mutation', 'p.S10C', (9, 13))	('nickel', 'Chemical', 'MESH:D009532', (25, 31))	('nickel', 'Chemical', 'MESH:D009532', (153, 159))	('human', 'Species', '9606', (186, 191))	('S10B', 'Var', (0, 4))	('TNF', 'Gene', (112, 115))
372487	27467530	Consistently, the stable knockdown of BECN1 expression in Beas-2B cells also significantly increased nickel-induced cell transformation of Beas-2B (Fig.	('BECN1', 'Gene', '8678', (38, 43))	('nickel', 'Chemical', 'MESH:D009532', (101, 107))	('Beas-2B', 'CellLine', 'CVCL:0168', (139, 146))	('nickel-induced cell transformation', 'CPA', (101, 135))	('BECN1', 'Gene', (38, 43))	('Beas-2B', 'CellLine', 'CVCL:0168', (58, 65))	('increased', 'PosReg', (91, 100))	('knockdown', 'Var', (25, 34))
372504	27467530	S11A), and cell migration (Fig.	('S11A', 'Var', (0, 4))	('cell migration', 'CPA', (11, 25))	('S11A', 'SUBSTITUTION', 'None', (0, 4))
372505	27467530	S11B and S11C).	('S11C', 'SUBSTITUTION', 'None', (9, 13))	('S11C', 'Var', (9, 13))	('S11B', 'SUBSTITUTION', 'None', (0, 4))	('S11B', 'Var', (0, 4))
372509	27467530	In the current studies, we evaluated the effects of nickel on cell autophagy and unexpectedly found that nickel activated autophagy rather than inhibited cell autophagy in Beas-2B cells.	('nickel', 'Chemical', 'MESH:D009532', (52, 58))	('nickel', 'Var', (105, 111))	('activated', 'PosReg', (112, 121))	('Beas-2B', 'CellLine', 'CVCL:0168', (172, 179))	('autophagy', 'CPA', (122, 131))	('nickel', 'Chemical', 'MESH:D009532', (105, 111))
372512	27467530	Our results showed that ectopic expression of activated-PI3K or knockdown of ULK1 or BECN1 expression dramatically inhibited nickel-induced autophagy, accompanied by the accumulation of GFP-SQSTM1 protein expression, revealing that autophagy induced by nickel exposure promoted SQSTM1 protein degradation.	('PI3', 'Gene', (56, 59))	('expression', 'MPA', (205, 215))	('nickel', 'Chemical', 'MESH:D009532', (125, 131))	('BECN1', 'Gene', (85, 90))	('ULK1', 'Gene', (77, 81))	('ULK1', 'Gene', '8408', (77, 81))	('nickel', 'Chemical', 'MESH:D009532', (253, 259))	('knockdown', 'Var', (64, 73))	('PI3', 'Gene', '5266', (56, 59))	('accumulation', 'PosReg', (170, 182))	('inhibited', 'NegReg', (115, 124))	('promoted', 'PosReg', (269, 277))	('BECN1', 'Gene', '8678', (85, 90))	('autophagy', 'CPA', (140, 149))
372514	27467530	Moreover, we found that ectopic expression of activated-PI3K or knockdown of ULK1 or BECN1, dramatically inhibited nickel-induced autophagy and elevated nickel-induced SQSTM1 protein expression, revealing that nickel-induced autophagy negatively regulates SQSTM1 protein expression following nickel exposure.	('PI3', 'Gene', (56, 59))	('nickel', 'Chemical', 'MESH:D009532', (292, 298))	('inhibited', 'NegReg', (105, 114))	('nickel', 'Chemical', 'MESH:D009532', (115, 121))	('nickel', 'Chemical', 'MESH:D009532', (210, 216))	('nickel', 'Chemical', 'MESH:D009532', (153, 159))	('BECN1', 'Gene', (85, 90))	('elevated', 'PosReg', (144, 152))	('SQSTM1', 'Gene', (168, 174))	('ULK1', 'Gene', (77, 81))	('knockdown', 'Var', (64, 73))	('ULK1', 'Gene', '8408', (77, 81))	('PI3', 'Gene', '5266', (56, 59))	('BECN1', 'Gene', '8678', (85, 90))	('nickel-induced autophagy', 'CPA', (115, 139))	('protein expression', 'MPA', (175, 193))
372524	27467530	We further found that blockage of JUN activation by ectopic expression of a dominant negative JUN mutant (TAM67) did not show any observable effect on SQSTM1 mRNA induction in Beas-2B cells following nickel exposure, whereas knockdown of RELA expression dramatically attenuated SQSTM1 mRNA induction under the same experimental conditions, demonstrating that RELA plays an important role for SQSTM1 transcriptional induction following nickel exposure.	('Beas-2B', 'CellLine', 'CVCL:0168', (176, 183))	('JUN', 'MPA', (34, 37))	('nickel', 'Chemical', 'MESH:D009532', (200, 206))	('attenuated', 'NegReg', (267, 277))	('SQSTM1 mRNA induction', 'MPA', (278, 299))	('nickel', 'Chemical', 'MESH:D009532', (435, 441))	('mutant', 'Var', (98, 104))
372526	27467530	This notion is consistently supported by the findings obtained from in vivo studies showing that RELA phosphorylation at Ser536 is markedly increased in mouse lung tissues following nickel inhalation (Fig.	('nickel', 'Chemical', 'MESH:D009532', (182, 188))	('mouse', 'Species', '10090', (153, 158))	('Ser536', 'Chemical', '-', (121, 127))	('RELA phosphorylation', 'MPA', (97, 117))	('increased', 'PosReg', (140, 149))	('Ser536', 'Var', (121, 127))
372538	27467530	Moreover, SQSTM1 protein increase by inhibition of autophagy with either 3-MA or knockdown of BECN1 also enhanced the TNF mRNA level following nickel exposure.	('3-MA', 'Chemical', '-', (73, 77))	('nickel', 'Chemical', 'MESH:D009532', (143, 149))	('inhibition', 'NegReg', (37, 47))	('autophagy', 'CPA', (51, 60))	('BECN1', 'Gene', '8678', (94, 99))	('TNF mRNA level', 'MPA', (118, 132))	('knockdown', 'Var', (81, 90))	('increase', 'PosReg', (25, 33))	('SQSTM1', 'Gene', (10, 16))	('enhanced', 'PosReg', (105, 113))	('BECN1', 'Gene', (94, 99))
372541	27467530	S11D), and promotion of cell migration (Fig.	('cell migration', 'CPA', (24, 38))	('promotion', 'PosReg', (11, 20))	('S11D', 'Var', (0, 4))	('S11D', 'SUBSTITUTION', 'None', (0, 4))
372545	27467530	As shown in Figure S13, knockdown of SQSTM1 did not affect expression of NCL (nucleolin) and ELAVL1/HUR, both of which have been reported to regulate their targeted mRNA stability.	('nucleolin', 'Gene', (78, 87))	('ELAVL1', 'Gene', (93, 99))	('SQSTM1', 'Gene', (37, 43))	('HUR', 'Gene', '1994', (100, 103))	('mRNA stability', 'MPA', (165, 179))	('HUR', 'Gene', (100, 103))	('nucleolin', 'Gene', '4691', (78, 87))	('expression', 'MPA', (59, 69))	('NCL', 'Gene', (73, 76))	('NCL', 'Gene', '4691', (73, 76))	('ELAVL1', 'Gene', '1994', (93, 99))	('knockdown', 'Var', (24, 33))
372547	27467530	The results did show that knockdown of SQSTM1 led to an inhibition of MAPK14 and MAPK1/3 phosphorylation as compared to these observed in Beas-2B(Nonsense) transfectants, suggesting their possible involvement in SQSTM1-mediated regulation of TNF mRNA stability.	('inhibition', 'NegReg', (56, 66))	('MAPK1', 'Gene', (81, 86))	('Beas-2B', 'CellLine', 'CVCL:0168', (138, 145))	('phosphorylation', 'MPA', (89, 104))	('involvement', 'Reg', (197, 208))	('SQSTM1', 'Gene', (39, 45))	('MAPK1', 'Gene', '5594', (70, 75))	('MAPK14', 'Gene', (70, 76))	('MAPK1', 'Gene', '5594', (81, 86))	('knockdown', 'Var', (26, 35))	('MAPK1', 'Gene', (70, 75))	('MAPK14', 'Gene', '1432', (70, 76))
372563	27467530	Beas-2B cells were cultured at 37 C with 5% CO2 in Dulbecco's modified Eagle's medium (DMEM; 11995065) supplemented with 10% fetal bovine serum (FBS; 26140079), 1% penicillin/streptomycin (15140163), 2 mM L-glutamine (25030164), all from Life Technologies.	('FBS', 'Disease', (145, 148))	('Beas-2B', 'CellLine', 'CVCL:0168', (0, 7))	('DMEM', 'Chemical', '-', (87, 91))	("Dulbecco's modified Eagle's medium", 'Chemical', '-', (51, 85))	('streptomycin', 'Chemical', 'MESH:D013307', (175, 187))	('CO2', 'Chemical', '-', (44, 47))	('25030164', 'Var', (218, 226))	('bovine', 'Species', '9913', (131, 137))	('penicillin', 'Chemical', 'MESH:D010406', (164, 174))	('FBS', 'Disease', 'MESH:D005198', (145, 148))	('L-glutamine', 'Chemical', 'MESH:D005973', (205, 216))	('15140163', 'Var', (189, 197))
372569	27467530	The antibodies specific against JUN (9165S), JUND (5000S), P-JUN Ser63 (2361S), P-JUN Ser73 (9164S), AKT (9272S), p-AKT Ser473 (9271S), RELA (8242S), PIK3CA (4255S), PARP (9542S), GAPDH (5174S), NFE2L2 (12721S), MTOR Pathway Antibody Sampler Kit (9964S), Autophagy Antibody Sampler Kit (4445S), RPS6KB1 Substrates Antibody Sampler Kit (2903S) and ULK1 Antibody Sampler Kit (8359T) were purchased from Cell Signaling Technology.	('ULK1', 'Gene', '8408', (347, 351))	('ULK1', 'Gene', (347, 351))	('NFE2L2', 'Gene', (195, 201))	('PIK3CA', 'Gene', '5290', (150, 156))	('AKT', 'Gene', (101, 104))	('RPS6KB1', 'Gene', (295, 302))	('JUND', 'Gene', (45, 49))	('AKT', 'Gene', (116, 119))	('GAPDH', 'Gene', '2597', (180, 185))	('2903S', 'Var', (336, 341))	('PARP', 'Gene', '1302', (166, 170))	('MTOR', 'Gene', (212, 216))	('JUND', 'Gene', '3727', (45, 49))	('MTOR', 'Gene', '2475', (212, 216))	('PIK3CA', 'Gene', (150, 156))	('AKT', 'Gene', '207', (101, 104))	('GAPDH', 'Gene', (180, 185))	('AKT', 'Gene', '207', (116, 119))	('RPS6KB1', 'Gene', '6198', (295, 302))	('PARP', 'Gene', (166, 170))	('NFE2L2', 'Gene', '4780', (195, 201))
372570	27467530	Antibodies to GFP (sc-390394), ETS1 (sc-55581), SP1 (sc-14027) and MYC (sc-788) were bought from Santa Cruz Biotechnology.	('MYC', 'Gene', '4609', (67, 70))	('GFP', 'Gene', (14, 17))	('MYC', 'Gene', (67, 70))	('ETS1', 'Gene', '2113', (31, 35))	('ETS1', 'Gene', (31, 35))	('sc-390394', 'Var', (19, 28))	('SP1 (sc-14027', 'Var', (48, 61))
372571	27467530	Antibodies that are specific against NFKB1 (ab32360) and SQSTM1 (ab155686) were bought from Abcam.	('NFKB1', 'Gene', (37, 42))	('NFKB1', 'Gene', '4790', (37, 42))	('ab32360', 'Var', (44, 51))
372595	27431502	UHRF1 gene silencing inhibits cell proliferation and promotes cell apoptosis in human cervical squamous cell carcinoma CaSki cells Up-regulation of UHRF1 has been observed in a variety of cancers and appears to serve as an independent prognostic factor.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (95, 118))	('gene silencing', 'Var', (6, 20))	('cancers', 'Disease', 'MESH:D009369', (188, 195))	('UHRF1', 'Gene', (148, 153))	('inhibits', 'NegReg', (21, 29))	('promotes', 'PosReg', (53, 61))	('human', 'Species', '9606', (80, 85))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (95, 118))	('Up-regulation', 'PosReg', (131, 144))	('CaSki', 'CellLine', 'CVCL:1100', (119, 124))	('cancers', 'Phenotype', 'HP:0002664', (188, 195))	('cancers', 'Disease', (188, 195))	('UHRF1', 'Gene', '29128', (0, 5))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('cell apoptosis', 'CPA', (62, 76))	('squamous cell carcinoma', 'Disease', (95, 118))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('cell proliferation', 'CPA', (30, 48))	('UHRF1', 'Gene', (0, 5))	('UHRF1', 'Gene', '29128', (148, 153))
372601	27431502	UHRF1 showed a high expression in CSCC and UHRF1 silencing can reduce proliferation and enhance apoptosis of the CaSki cells.	('silencing', 'Var', (49, 58))	('UHRF1', 'Gene', (43, 48))	('CaSki', 'CellLine', 'CVCL:1100', (113, 118))	('proliferation', 'CPA', (70, 83))	('apoptosis', 'CPA', (96, 105))	('reduce', 'NegReg', (63, 69))	('enhance', 'PosReg', (88, 95))
372647	27431502	Therefore, inhibiting U HRF1 was able to repress cell proliferation to stagnate the CSCC cells at G0/G1 stage.	('repress', 'NegReg', (41, 48))	('inhibiting', 'Var', (11, 21))	('HRF1', 'Gene', (24, 28))	('cell proliferation', 'CPA', (49, 67))	('HRF1', 'Gene', '7748', (24, 28))
372650	27431502	6), which further confirmed that the inhibition of UHRF1 promoted cell apoptosis of the CaSki cells.	('inhibition', 'Var', (37, 47))	('promoted', 'PosReg', (57, 65))	('cell apoptosis of', 'CPA', (66, 83))	('UHRF1', 'Gene', (51, 56))	('CaSki', 'CellLine', 'CVCL:1100', (88, 93))
372651	27431502	The experiment indicated that the tumor growth speed in the UHRF1 Silence group was slower than that in the Blank group and NC group (P < 0.05, Fig.	('Silence', 'Var', (66, 73))	('UHRF1', 'Gene', (60, 65))	('tumor', 'Disease', (34, 39))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('slower', 'NegReg', (84, 90))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
372652	27431502	The tumor in the UHRF1 Silence group was also thinner than that in the Blank group and the NC group (P < 0.05, Fig.	('tumor', 'Disease', (4, 9))	('thinner', 'NegReg', (46, 53))	('UHRF1', 'Gene', (17, 22))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('Silence', 'Var', (23, 30))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))
372653	27431502	7c), which further indicated that in the tumor-bearing nude mice model, the cell proliferation in the UHRF1 Silence group were significantly lower than the Blank group and the NC group.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('nude mice', 'Species', '10090', (55, 64))	('UHRF1', 'Gene', (102, 107))	('tumor', 'Disease', (41, 46))	('Silence', 'Var', (108, 115))	('cell proliferation', 'CPA', (76, 94))	('lower', 'NegReg', (141, 146))	('tumor', 'Disease', 'MESH:D009369', (41, 46))
372654	27431502	Therefore, the silent UHRF1 could inhibit the cell malignant transformation in the CaSki cells of the nude mice.	('UHRF1', 'Gene', (22, 27))	('cell malignant transformation in the CaSki cells', 'CPA', (46, 94))	('nude mice', 'Species', '10090', (102, 111))	('silent', 'Var', (15, 21))	('CaSki', 'CellLine', 'CVCL:1100', (83, 88))	('inhibit', 'NegReg', (34, 41))
372658	27431502	Consequently, UHRF1 is over-expressed in CSCC and silencing UHRF1 inhibits proliferation and promotes apopyosis of the CSCC CaSKi cells.	('apopyosis', 'CPA', (102, 111))	('UHRF1', 'Gene', (60, 65))	('inhibits', 'NegReg', (66, 74))	('promotes', 'PosReg', (93, 101))	('silencing', 'Var', (50, 59))	('proliferation', 'CPA', (75, 88))	('CSCC CaSKi', 'CellLine', 'CVCL:1100', (119, 129))
372664	27431502	The results indicated that silencing UHRF1 leads to a decrease in the proliferation of CaSki cells and the apoptosis of CaSKi increases (the activity of Caspase3, Caspase8, Caspase9, Bax apoptosis-related protein increase).	('CaSKi', 'CellLine', 'CVCL:1100', (120, 125))	('decrease', 'NegReg', (54, 62))	('UHRF1', 'Gene', (37, 42))	('silencing', 'Var', (27, 36))	('activity', 'MPA', (141, 149))	('Bax', 'Gene', (183, 186))	('proliferation', 'CPA', (70, 83))	('increase', 'PosReg', (213, 221))	('CaSki', 'CellLine', 'CVCL:1100', (87, 92))	('Bax', 'Gene', '581', (183, 186))	('Caspase3', 'Gene', (153, 161))	('Caspase8', 'Gene', '841', (163, 171))	('Caspase3', 'Gene', '836', (153, 161))	('Caspase9', 'Gene', (173, 181))	('apoptosis', 'CPA', (107, 116))	('Caspase9', 'Gene', '842', (173, 181))	('Caspase8', 'Gene', (163, 171))
372667	27431502	The results of nude mouse experiment indicated that tumor grow more slowly in UHRF1 silence group, implying that silencing UHRF1 can suppress the tumorigenesis of CaSKi cells in nude mouse.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('mouse', 'Species', '10090', (20, 25))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('tumor', 'Disease', (52, 57))	('tumor', 'Disease', (146, 151))	('mouse', 'Species', '10090', (183, 188))	('UHRF1', 'Gene', (123, 128))	('suppress', 'NegReg', (133, 141))	('CaSKi', 'CellLine', 'CVCL:1100', (163, 168))	('silencing', 'Var', (113, 122))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
372670	27431502	Alteration in UHRF1 expression is correlated with the degree of the lung cancer aggressiveness and it was detected in 50 % of the patients in an early clinical stage.	('lung cancer aggressiveness', 'Disease', (68, 94))	('expression', 'MPA', (20, 30))	('lung cancer', 'Phenotype', 'HP:0100526', (68, 79))	('Alteration', 'Var', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('UHRF1', 'Gene', (14, 19))	('patients', 'Species', '9606', (130, 138))	('lung cancer aggressiveness', 'Disease', 'MESH:D008175', (68, 94))	('aggressiveness', 'Phenotype', 'HP:0000718', (80, 94))
372672	27431502	UHRF1 mRNA and protein fluctuate with the cell cycle, inactivation or loss of UHRF1 blocks S-phase entry, and zebrafish with a depletion-of-function mutation in UHRF1 have reduced cell proliferation and promoted cell apoptosis in hepatocyte.	('UHRF1', 'Gene', (78, 83))	('reduced', 'NegReg', (172, 179))	('cell apoptosis in', 'CPA', (212, 229))	('UHRF1', 'Gene', (161, 166))	('loss', 'Var', (70, 74))	('zebrafish', 'Species', '7955', (110, 119))	('cell proliferation', 'CPA', (180, 198))	('promoted', 'PosReg', (203, 211))	('S-phase entry', 'MPA', (91, 104))	('mutation', 'Var', (149, 157))	('inactivation', 'Var', (54, 66))
372679	26159827	Restoration of miR-146a in SCC25 and UMSCC1 cells decreased in vitro invasive activity, suppressed tumor growth in vivo, and decreased the incidence of UMSCC1 lung metastasis.	('tumor', 'Disease', (99, 104))	('UMSCC1 lung metastasis', 'CPA', (152, 174))	('Restoration', 'Var', (0, 11))	('decreased', 'NegReg', (125, 134))	('UMSCC1', 'CellLine', 'CVCL:7707', (152, 158))	('invasive activity', 'CPA', (69, 86))	('decreased', 'NegReg', (50, 59))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('UMSCC1', 'CellLine', 'CVCL:7707', (37, 43))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('suppressed', 'NegReg', (88, 98))	('miR-146a', 'Gene', (15, 23))
372680	26159827	The transcription factor Sox2 was found to be a putative target of miR-146a.	('Sox2', 'Gene', '6657', (25, 29))	('Sox2', 'Gene', (25, 29))	('miR-146a', 'Var', (67, 75))
372690	26159827	Over 50 microRNAs, including miR-21, miR-7, miR-124, miR-134, and miR-155, have been reported in OSCC in the form of either overexpression or underexpression.	('miR-124', 'Var', (44, 51))	('miR-21', 'Gene', '406991', (29, 35))	('miR-134', 'Gene', '406924', (53, 60))	('miR-134', 'Gene', (53, 60))	('miR-155', 'Gene', (66, 73))	('miR-7', 'Gene', (37, 42))	('miR-21', 'Gene', (29, 35))	('miR-7', 'Gene', '10859', (37, 42))	('overexpression', 'PosReg', (124, 138))	('miR-155', 'Gene', '406947', (66, 73))
372692	26159827	The most highly dysregulated microRNA, miR-146a, was validated with human clinical OSCC materials.	('dysregulated', 'Reg', (16, 28))	('human', 'Species', '9606', (68, 73))	('miR-146a', 'Var', (39, 47))
372693	26159827	Functional assays confirmed the role of miR-146a as a metastasis suppressor and the transcription factor Sox2 was found to be a new putative target of miR-146a.	('metastasis suppressor', 'CPA', (54, 75))	('Sox2', 'Gene', '6657', (105, 109))	('Sox2', 'Gene', (105, 109))	('miR-146a', 'Var', (151, 159))	('miR-146a', 'Gene', (40, 48))
372694	26159827	Our data support that the loss of miR-146a is a contributor to OSCC aggressive behavior.	('miR-146a', 'Gene', (34, 42))	('aggressive behavior', 'Phenotype', 'HP:0000718', (68, 87))	('OSCC aggressive behavior', 'Disease', 'MESH:D001523', (63, 87))	('OSCC aggressive behavior', 'Disease', (63, 87))	('loss', 'Var', (26, 30))
372695	26159827	Several viral constructs were made to express miR-146a or luciferase in cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('miR-146a', 'Var', (46, 54))	('luciferase', 'Enzyme', (58, 68))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('cancer', 'Disease', (72, 78))
372707	26159827	For in vivo bioluminescence imaging, UMSCC1 cells were also engineered to express luciferase II and empty vector or luciferase II and miR-146a, designated as S12-vec and S12-146a cells, respectively.	('vec', 'Gene', '12562', (106, 109))	('vec', 'Gene', (106, 109))	('vec', 'Gene', (162, 165))	('luciferase', 'Gene', (116, 126))	('UMSCC1', 'CellLine', 'CVCL:7707', (37, 43))	('vec', 'Gene', '12562', (162, 165))	('luciferase', 'Gene', (82, 92))	('miR-146a', 'Var', (134, 142))
372761	26159827	Initial experiments utilized miR-146a-restored SCC25 cells (25p/146a) or vector control cells (25p/vec).	('25p/146a', 'Var', (60, 68))	('vec', 'Gene', '12562', (73, 76))	('vec', 'Gene', (73, 76))	('vec', 'Gene', (99, 102))	('vec', 'Gene', '12562', (99, 102))
372763	26159827	The average tumor size was significantly smaller in the miR-146a-restored group relative to the control group (Fig 4A, P<0.05).	('smaller', 'NegReg', (41, 48))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('tumor', 'Disease', (12, 17))	('miR-146a-restored', 'Var', (56, 73))
372773	26159827	Using the web-based bioinformatic tool RNA22, a target site for miR-146a was found in the coding region of transcription factor Sox2 mRNA, with a 6 nucleotide match near the 3' end (Fig 6A).	('miR-146a', 'Var', (64, 72))	('Sox2', 'Gene', '6657', (128, 132))	('Sox2', 'Gene', (128, 132))
372776	26159827	To further verify that Sox2 is bona fide target for miR-146a, we utilized a luciferase reporter assay for testing the effects of the target sequence in Sox2 mRNA.	('Sox2', 'Gene', '6657', (152, 156))	('Sox2', 'Gene', '6657', (23, 27))	('miR-146a', 'Var', (52, 60))	('Sox2', 'Gene', (152, 156))	('Sox2', 'Gene', (23, 27))
372778	26159827	When co-transfected into UMSCC1 cells along with the miR-146a expressing vector pBabe/146a, decreased reporter luciferase intensity was observed indicating that Sox2 is an effective target of miR-146a (Fig.	('Sox2', 'Gene', (161, 165))	('intensity', 'MPA', (122, 131))	('UMSCC1', 'CellLine', 'CVCL:7707', (25, 31))	('reporter', 'MPA', (102, 110))	('vec', 'Gene', '12562', (73, 76))	('vec', 'Gene', (73, 76))	('Sox2', 'Gene', '6657', (161, 165))	('decreased', 'NegReg', (92, 101))	('miR-146a', 'Var', (192, 200))
372782	26159827	Tumors from UMSCC1 miR-146a expressing cells exhibited lower levels of Sox2 staining and had a lower proliferation index relative to control (Fig.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('lower', 'NegReg', (95, 100))	('UMSCC1', 'Gene', (12, 18))	('miR-146a expressing', 'Var', (19, 38))	('Sox2', 'Gene', '6657', (71, 75))	('Tumors', 'Disease', (0, 6))	('levels', 'MPA', (61, 67))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('proliferation index', 'CPA', (101, 120))	('lower', 'NegReg', (55, 60))	('UMSCC1', 'CellLine', 'CVCL:7707', (12, 18))	('Sox2', 'Gene', (71, 75))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))
372795	26159827	A recent study reported that a G to C polymorphism (rs2910164) in pre-miR-146a was prevalent in OSCC patients with lymph node metastasis.	('rs2910164', 'Mutation', 'rs2910164', (52, 61))	('patients', 'Species', '9606', (101, 109))	('pre-miR-146a', 'Gene', (66, 78))	('rs2910164', 'Var', (52, 61))	('OSCC', 'Disease', (96, 100))	('prevalent', 'Reg', (83, 92))
372797	26159827	Polymorphism within the genomic sequence for the pre-mir-146a regulatory area has been reported to be associated with several cancers.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('Polymorphism', 'Var', (0, 12))	('associated', 'Reg', (102, 112))	('cancers', 'Phenotype', 'HP:0002664', (126, 133))	('cancers', 'Disease', (126, 133))	('mir-146a', 'Gene', (53, 61))	('cancers', 'Disease', 'MESH:D009369', (126, 133))	('mir-146a', 'Gene', '406938', (53, 61))
372798	26159827	The G to C polymorphism (rs2910164) in pre-mir-146a was not found in our cell lines.	('mir-146a', 'Gene', (43, 51))	('rs2910164', 'Mutation', 'rs2910164', (25, 34))	('mir-146a', 'Gene', '406938', (43, 51))	('rs2910164', 'Var', (25, 34))
372802	26159827	However the localization pattern and positivity in relation to differentiation status support the idea that the loss of miR-146a is associated with the development of more aggressive oral cancer.	('aggressive oral cancer', 'Disease', 'MESH:D009062', (172, 194))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('miR-146a', 'Gene', (120, 128))	('aggressive oral cancer', 'Disease', (172, 194))	('associated with', 'Reg', (132, 147))	('loss', 'Var', (112, 116))
372810	26159827	Silencing Sox2 induced mesenchymal-epithelial transition, which is quite consistent with the localization of miR-146a within the layers of normal stratified squamous epithelium in oral mucosa.	('mesenchymal-epithelial transition', 'CPA', (23, 56))	('Sox2', 'Gene', (10, 14))	('induced', 'Reg', (15, 22))	('Sox2', 'Gene', '6657', (10, 14))	('Silencing', 'Var', (0, 9))
372812	26159827	Our data demonstrating that Sox2 is a mir-146a target provide a novel mechanism by which loss of miR-146a may enhance OSCC progression to metastasis.	('mir-146a', 'Gene', (38, 46))	('loss', 'Var', (89, 93))	('Sox2', 'Gene', (28, 32))	('OSCC', 'Disease', (118, 122))	('enhance', 'PosReg', (110, 117))	('mir-146a', 'Gene', '406938', (38, 46))	('miR-146a', 'Gene', (97, 105))	('Sox2', 'Gene', '6657', (28, 32))
372813	26159827	It should be noted that other microRNAs, such as miR-124 and miR-134, have also been found to be involved in oral cancer progression.	('oral cancer', 'Disease', (109, 120))	('miR-124', 'Var', (49, 56))	('miR-134', 'Gene', '406924', (61, 68))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('involved', 'Reg', (97, 105))	('miR-134', 'Gene', (61, 68))	('oral cancer', 'Disease', 'MESH:D009062', (109, 120))
372817	26159827	Modulation of Sox2 and its downstream targets by miR-146a was suggested as a novel mechanism for regulation of tumor progression and metastasis.	('Modulation', 'Var', (0, 10))	('Sox2', 'Gene', (14, 18))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('miR-146a', 'Var', (49, 57))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumor', 'Disease', (111, 116))	('metastasis', 'CPA', (133, 143))	('Sox2', 'Gene', '6657', (14, 18))
372819	26159827	Restoration of miR-146a in cancer cells decreased in vitro invasive activity and suppressed tumor growth and metastasis.	('suppressed', 'NegReg', (81, 91))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('Restoration', 'Var', (0, 11))	('invasive activity', 'CPA', (59, 76))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('cancer', 'Disease', (27, 33))	('tumor', 'Disease', (92, 97))	('cancer', 'Disease', 'MESH:D009369', (27, 33))	('decreased', 'NegReg', (40, 49))	('miR-146a', 'Gene', (15, 23))
372820	26159827	Transcription factor Sox2 was found to be a putative target of miR-146a.	('Sox2', 'Gene', (21, 25))	('Sox2', 'Gene', '6657', (21, 25))	('miR-146a', 'Var', (63, 71))
372826	33249703	Furthermore, in nude mice, ADFP promoted tumour formation with high levels of p-Akt/Akt, Ki67 and proliferating cell nuclear antigen (PCNA).	('promoted', 'PosReg', (32, 40))	('ADFP', 'Var', (27, 31))	('Ki67', 'Gene', '17345', (89, 93))	('tumour', 'Phenotype', 'HP:0002664', (41, 47))	('tumour', 'Disease', 'MESH:D009369', (41, 47))	('nude mice', 'Species', '10090', (16, 25))	('Ki67', 'Gene', (89, 93))	('proliferating cell nuclear antigen', 'MPA', (98, 132))	('tumour', 'Disease', (41, 47))
372827	33249703	Similar to the effect of ADFP knock-down, MK-2206 (a phosphorylation inhibitor of Akt) reduced A549 and NCI-H1299 cell proliferation.	('NCI-H1299', 'CellLine', 'CVCL:0060', (104, 113))	('MK-2206', 'Chemical', 'MESH:C548887', (42, 49))	('MK-2206', 'Var', (42, 49))	('reduced', 'NegReg', (87, 94))	('A549', 'CellLine', 'CVCL:0023', (95, 99))
372828	33249703	In ADFP-overexpressing A549 and NCI-H1299 cells, proliferation was suppressed by MK-2206 and returned to the control level.	('MK-2206', 'Var', (81, 88))	('proliferation', 'CPA', (49, 62))	('NCI-H1299', 'CellLine', 'CVCL:0060', (32, 41))	('MK-2206', 'Chemical', 'MESH:C548887', (81, 88))	('A549', 'CellLine', 'CVCL:0023', (23, 27))	('suppressed', 'NegReg', (67, 77))
372834	33249703	Somatic copy number alterations are fairly prevalent, occurring both as early and late events during tumour evolution, including amplifications in EGFR, MET, KRAS, ERBB2 and MDM2, and deletions in LRP1B, PTPRD and CDKN2A.	('EGFR', 'Gene', (147, 151))	('amplifications', 'Var', (129, 143))	('MDM2', 'Gene', '4193', (174, 178))	('tumour', 'Phenotype', 'HP:0002664', (101, 107))	('tumour', 'Disease', 'MESH:D009369', (101, 107))	('MET', 'Gene', (153, 156))	('LRP1B', 'Gene', (197, 202))	('tumour', 'Disease', (101, 107))	('PTPRD', 'Gene', (204, 209))	('deletions', 'Var', (184, 193))	('EGFR', 'Gene', '1956', (147, 151))	('CDKN2A', 'Gene', (214, 220))	('LRP1B', 'Gene', '53353', (197, 202))	('ERBB2', 'Gene', (164, 169))	('MET', 'Gene', '79811', (153, 156))	('PTPRD', 'Gene', '5789', (204, 209))	('KRAS', 'Gene', '3845', (158, 162))	('CDKN2A', 'Gene', '1029', (214, 220))	('ERBB2', 'Gene', '2064', (164, 169))	('MDM2', 'Gene', (174, 178))	('KRAS', 'Gene', (158, 162))
372846	33249703	ADFP hinders the entry of lipase into lipid droplets, resulting in the accumulation of lipids in lipid droplets.	('ADFP', 'Var', (0, 4))	('lipid', 'Chemical', 'MESH:D008055', (38, 43))	('hinders', 'NegReg', (5, 12))	('lipid', 'Chemical', 'MESH:D008055', (87, 92))	('lipids', 'Chemical', 'MESH:D008055', (87, 93))	('lipid', 'Chemical', 'MESH:D008055', (97, 102))	('entry', 'MPA', (17, 22))	('accumulation of lipids in lipid droplets', 'MPA', (71, 111))
372854	33249703	24  Cao et al knocked down ADFP in the human kidney cancer cell line A498 using an oligonucleotide sequence and observed enhanced proliferation, invasion and migration abilities.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('kidney cancer', 'Disease', 'MESH:D007680', (45, 58))	('A498', 'CellLine', 'CVCL:1056', (69, 73))	('kidney cancer', 'Phenotype', 'HP:0009726', (45, 58))	('enhanced', 'PosReg', (121, 129))	('ADFP', 'Gene', (27, 31))	('oligonucleotide', 'Chemical', 'MESH:D009841', (83, 98))	('kidney cancer', 'Disease', (45, 58))	('migration abilities', 'CPA', (158, 177))	('proliferation', 'CPA', (130, 143))	('human', 'Species', '9606', (39, 44))	('invasion', 'CPA', (145, 153))	('knocked', 'Var', (14, 21))
372875	33249703	The primary antibodies used were as follows: anti-ADFP (1:500; AbGene, China), anti-p-Akt (Ser 473) (1:1000; CST), anti-Akt (1:1000; CST), anti-p-STAT3 (1:1000; Abcam), anti-STAT3 (1:1000; Abcam), anti-p-ERK (1:1000; CST, anti-ERK (1:1000; CST), anti-beta-catenin (1:1500; Santa, anti-NFkappaB (1:1500; Abcam), anti-Bcl-2 (1:1000; Abcam), anti-Bax (1:1500; Abcam) and anti-GAPDH (1:2000; Abcam).	('CST', 'Gene', '106478911', (240, 243))	('Bcl-2', 'Gene', (316, 321))	('ERK', 'Gene', (204, 207))	('1:1500', 'Var', (265, 271))	('Bax', 'Gene', '581', (344, 347))	('Ser', 'Chemical', 'MESH:D012694', (91, 94))	('STAT3', 'Gene', (174, 179))	('ERK', 'Gene', (227, 230))	('Bcl-2', 'Gene', '596', (316, 321))	('ERK', 'Gene', '2048', (204, 207))	('CST', 'Gene', (217, 220))	('CST', 'Gene', (240, 243))	('CST', 'Gene', '106478911', (133, 136))	('CST', 'Gene', '106478911', (109, 112))	('STAT3', 'Gene', '6774', (174, 179))	('ERK', 'Gene', '2048', (227, 230))	('beta-catenin', 'Gene', (251, 263))	('GAPDH', 'Gene', '2597', (373, 378))	('1:1500', 'Var', (349, 355))	('beta-catenin', 'Gene', '1499', (251, 263))	('STAT3', 'Gene', (146, 151))	('NFkappaB', 'Gene', '4790', (285, 293))	('STAT3', 'Gene', '6774', (146, 151))	('CST', 'Gene', (133, 136))	('CST', 'Gene', (109, 112))	('GAPDH', 'Gene', (373, 378))	('NFkappaB', 'Gene', (285, 293))	('Bax', 'Gene', (344, 347))	('CST', 'Gene', '106478911', (217, 220))
372912	33249703	We established stable ADFP knock-down A549 cells, ADFP knock-down NCI-H1299 cells, ADFP-overexpressing A549 cells, ADFP-overexpressing NCI-H1299 cells and respective control groups by lentivirus transfection.	('NCI-H1299', 'CellLine', 'CVCL:0060', (135, 144))	('A549', 'CellLine', 'CVCL:0023', (38, 42))	('A549', 'CellLine', 'CVCL:0023', (103, 107))	('knock-down', 'Var', (55, 65))	('NCI-H1299', 'CellLine', 'CVCL:0060', (66, 75))	('ADFP', 'Gene', (50, 54))
372913	33249703	ADFP overexpression in A549 and NCI-H1299 cells significantly promoted cell growth, as determined by the CCK-8 assay, whereas ADFP knock-down suppressed cell growth (Figure 1C).	('cell growth', 'CPA', (71, 82))	('NCI-H1299', 'CellLine', 'CVCL:0060', (32, 41))	('CCK', 'Chemical', 'MESH:D002766', (105, 108))	('ADFP', 'Gene', (0, 4))	('knock-down', 'Var', (131, 141))	('promoted', 'PosReg', (62, 70))	('A549', 'CellLine', 'CVCL:0023', (23, 27))	('suppressed', 'NegReg', (142, 152))
372914	33249703	The role of ADFP was further confirmed by the increased colony formation ability of ADFP-overexpressing A549 and NCI-H1299 cells and the reduced colony formation ability of ADFP knock-down A549 and NCI-H1299 cells (Figure 1D).	('A549', 'CellLine', 'CVCL:0023', (189, 193))	('NCI-H1299', 'CellLine', 'CVCL:0060', (198, 207))	('knock-down', 'Var', (178, 188))	('A549', 'CellLine', 'CVCL:0023', (104, 108))	('increased', 'PosReg', (46, 55))	('NCI-H1299', 'CellLine', 'CVCL:0060', (113, 122))	('colony formation ability', 'CPA', (145, 169))	('colony formation ability', 'CPA', (56, 80))	('reduced', 'NegReg', (137, 144))
372915	33249703	The results of EdU experiments showed that the proportions of proliferating ADFP knock-down A549 and NCI-H1299 cells were decreased, whereas the proportions of proliferating ADFP-overexpressing A549 and NCI-H1299 cells were increased (Figure 1E).	('NCI-H1299', 'CellLine', 'CVCL:0060', (101, 110))	('knock-down', 'Var', (81, 91))	('proliferating', 'CPA', (62, 75))	('A549', 'CellLine', 'CVCL:0023', (194, 198))	('NCI-H1299', 'CellLine', 'CVCL:0060', (203, 212))	('A549', 'CellLine', 'CVCL:0023', (92, 96))	('ADFP', 'Gene', (76, 80))	('decreased', 'NegReg', (122, 131))
372916	33249703	Furthermore, ADFP induced S phase arrest in A549 and NCI-H1299 cells (Figure 1F).	('arrest', 'Disease', (34, 40))	('NCI-H1299', 'CellLine', 'CVCL:0060', (53, 62))	('A549', 'CellLine', 'CVCL:0023', (44, 48))	('arrest', 'Disease', 'MESH:D006323', (34, 40))	('ADFP', 'Var', (13, 17))
372919	33249703	However, ADFP knock-down had no effect on the invasion of A549 cells, and ADFP overexpression did not affect the migration or invasion of A549 cells (Figure 2A,B).	('A549', 'CellLine', 'CVCL:0023', (138, 142))	('A549', 'CellLine', 'CVCL:0023', (58, 62))	('knock-down', 'Var', (14, 24))	('ADFP', 'Gene', (9, 13))
372921	33249703	The number of adherent ADFP knock-down A549 cells was decreased, but there was no significant change among other groups in adhesion assays (Figure 2D).	('ADFP', 'Gene', (23, 27))	('adherent', 'CPA', (14, 22))	('knock-down', 'Var', (28, 38))	('decreased', 'NegReg', (54, 63))	('A549', 'CellLine', 'CVCL:0023', (39, 43))
372922	33249703	To explore the tumorigenic function of ADFP in vivo, we inoculated ADFP knock-down NCI-H1299, ADFP-overexpressing NCI-H1299 and their respective control cells into the hypoderm of nude mice, to establish tumour-bearing mouse models (Figure 3A,E).	('nude mice', 'Species', '10090', (180, 189))	('tumour', 'Disease', (204, 210))	('ADFP', 'Gene', (67, 71))	('NCI-H1299', 'Gene', (83, 92))	('NCI-H1299', 'CellLine', 'CVCL:0060', (114, 123))	('mouse', 'Species', '10090', (219, 224))	('knock-down', 'Var', (72, 82))	('tumour', 'Phenotype', 'HP:0002664', (204, 210))	('NCI-H1299', 'CellLine', 'CVCL:0060', (83, 92))	('tumour', 'Disease', 'MESH:D009369', (204, 210))
372923	33249703	Compared with control groups, the tumour volumes in the ADFP knock-down NCI-H1299 group were significantly smaller (Figure 3B), whereas those in the ADFP-overexpressing NCI-H1299 group were larger (Figure 3F).	('knock-down', 'Var', (61, 71))	('NCI-H1299', 'CellLine', 'CVCL:0060', (169, 178))	('tumour', 'Disease', 'MESH:D009369', (34, 40))	('NCI-H1299', 'Gene', (72, 81))	('tumour', 'Disease', (34, 40))	('smaller', 'NegReg', (107, 114))	('NCI-H1299', 'CellLine', 'CVCL:0060', (72, 81))	('tumour', 'Phenotype', 'HP:0002664', (34, 40))
372924	33249703	At the end of the experiment, the tumour weights of nude mice injected with ADFP knock-down NCI-H1299 cells were significantly decreased (Figure 3C,D), and those from mice injected with ADFP-overexpressing NCI-H1299 cells were significantly increased (Figure 3G,H).	('mice', 'Species', '10090', (57, 61))	('knock-down', 'Var', (81, 91))	('increased', 'PosReg', (241, 250))	('decreased', 'NegReg', (127, 136))	('tumour', 'Disease', 'MESH:D009369', (34, 40))	('NCI-H1299', 'CellLine', 'CVCL:0060', (92, 101))	('tumour', 'Disease', (34, 40))	('ADFP knock-down', 'Var', (76, 91))	('NCI-H1299', 'Gene', (92, 101))	('nude mice', 'Species', '10090', (52, 61))	('mice', 'Species', '10090', (167, 171))	('NCI-H1299', 'CellLine', 'CVCL:0060', (206, 215))	('tumour', 'Phenotype', 'HP:0002664', (34, 40))
372925	33249703	Ki67 and PCNA expression levels were lower in mouse tumour tissues in the ADFP knock-down NCI-H1299 group and higher in those of the ADFP-overexpressing NCI-H1299 group (Figure 3I).	('NCI-H1299', 'CellLine', 'CVCL:0060', (90, 99))	('ADFP', 'Gene', (74, 78))	('NCI-H1299', 'CellLine', 'CVCL:0060', (153, 162))	('Ki67', 'Gene', '17345', (0, 4))	('knock-down', 'Var', (79, 89))	('tumour', 'Phenotype', 'HP:0002664', (52, 58))	('tumour', 'Disease', 'MESH:D009369', (52, 58))	('mouse', 'Species', '10090', (46, 51))	('Ki67', 'Gene', (0, 4))	('lower', 'NegReg', (37, 42))	('tumour', 'Disease', (52, 58))	('higher', 'PosReg', (110, 116))
372928	33249703	In the tumour-bearing mouse models mentioned above, p-Akt expression levels were lower in the tumour tissues of the ADFP knock-down NCI-H1299 group and higher in those of the ADFP-overexpressing NCI-H1299 group.	('tumour', 'Disease', (94, 100))	('higher', 'PosReg', (152, 158))	('lower', 'NegReg', (81, 86))	('NCI-H1299', 'CellLine', 'CVCL:0060', (132, 141))	('tumour', 'Phenotype', 'HP:0002664', (7, 13))	('knock-down', 'Var', (121, 131))	('NCI-H1299', 'CellLine', 'CVCL:0060', (195, 204))	('tumour', 'Phenotype', 'HP:0002664', (94, 100))	('p-Akt expression levels', 'MPA', (52, 75))	('tumour', 'Disease', 'MESH:D009369', (7, 13))	('mouse', 'Species', '10090', (22, 27))	('tumour', 'Disease', (7, 13))	('ADFP', 'Var', (116, 120))	('tumour', 'Disease', 'MESH:D009369', (94, 100))
372929	33249703	To address this, we inhibited the phosphorylation of Akt in control A549 and NCI-H1299 groups by treatment with 0.5 muM of MK-2206 (Figure S1C).	('phosphorylation', 'MPA', (34, 49))	('NCI-H1299', 'CellLine', 'CVCL:0060', (77, 86))	('inhibited', 'NegReg', (20, 29))	('Akt', 'Pathway', (53, 56))	('MK-2206', 'Var', (123, 130))	('A549', 'CellLine', 'CVCL:0023', (68, 72))	('MK-2206', 'Chemical', 'MESH:C548887', (123, 130))
372930	33249703	Consistent with the effect of ADFP knock-down, MK-2206 reduced the cell proliferation rate (Figure 4C,D), the proportion of proliferating cells (Figure 4E) and the number of colonies formed (Figure 4F).	('MK-2206', 'Var', (47, 54))	('cell proliferation rate', 'CPA', (67, 90))	('MK-2206', 'Chemical', 'MESH:C548887', (47, 54))	('reduced', 'NegReg', (55, 62))
372931	33249703	In ADFP-overexpressing A549 and NCI-H1299 cells, the cell proliferation rate (Figure 5A), the proportion of proliferating cells (Figure 5B) and the number of colonies formed (Figure 5C) were suppressed by MK-2206 back to the levels of the control group.	('suppressed', 'NegReg', (191, 201))	('ADFP-overexpressing', 'Var', (3, 22))	('MK-2206', 'Chemical', 'MESH:C548887', (205, 212))	('proportion of proliferating cells', 'CPA', (94, 127))	('NCI-H1299', 'CellLine', 'CVCL:0060', (32, 41))	('MK-2206', 'Var', (205, 212))	('cell proliferation rate', 'CPA', (53, 76))	('A549', 'CellLine', 'CVCL:0023', (23, 27))
372945	33249703	20  Furthermore, Cao et al found that ADFP knock-down in A498 cells (a human kidney cancer cell line) enhanced cell proliferation, migration and invasion.	('enhanced', 'PosReg', (102, 110))	('kidney cancer', 'Disease', (77, 90))	('migration', 'CPA', (131, 140))	('ADFP', 'Gene', (38, 42))	('cell proliferation', 'CPA', (111, 129))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('A498', 'CellLine', 'CVCL:1056', (57, 61))	('kidney cancer', 'Phenotype', 'HP:0009726', (77, 90))	('kidney cancer', 'Disease', 'MESH:D007680', (77, 90))	('invasion', 'CPA', (145, 153))	('knock-down', 'Var', (43, 53))	('human', 'Species', '9606', (71, 76))
372947	33249703	We established tumour-bearing mouse models with ADFP knock-down and ADFP-overexpressing NCI-H1299 cells and their respective control cells.	('tumour', 'Disease', 'MESH:D009369', (15, 21))	('tumour', 'Phenotype', 'HP:0002664', (15, 21))	('NCI-H1299', 'CellLine', 'CVCL:0060', (88, 97))	('tumour', 'Disease', (15, 21))	('ADFP', 'Gene', (48, 52))	('knock-down', 'Var', (53, 63))	('mouse', 'Species', '10090', (30, 35))
372948	33249703	The protein levels of Ki67 and PCNA, which are specific markers of cell proliferation, were reduced in the ADFP knock-down cells and increased in ADFP-overexpressing cells.	('PCNA', 'MPA', (31, 35))	('protein levels', 'MPA', (4, 18))	('Ki67', 'Gene', (22, 26))	('reduced', 'NegReg', (92, 99))	('increased', 'PosReg', (133, 142))	('ADFP', 'Gene', (107, 111))	('knock-down', 'Var', (112, 122))	('Ki67', 'Gene', '17345', (22, 26))
372949	33249703	Further, FCM showed that ADFP knock-down caused G1 phase arrest with a decrease in the proportion of S phase cells.	('FCM', 'Chemical', '-', (9, 12))	('decrease', 'NegReg', (71, 79))	('arrest', 'Disease', 'MESH:D006323', (57, 63))	('ADFP', 'Gene', (25, 29))	('arrest', 'Disease', (57, 63))	('knock-down', 'Var', (30, 40))
372953	33249703	The LAC cell proliferation level decreased in the presence of MK-2206, reaching the same level as observed in ADFP knock-down LAC cells.	('decreased', 'NegReg', (33, 42))	('LAC cell proliferation level', 'MPA', (4, 32))	('MK-2206', 'Chemical', 'MESH:C548887', (62, 69))	('MK-2206', 'Var', (62, 69))
372955	33249703	30 ,  31 ,  32  Akt hyperphosphorylation can lead to the instability of the genome and even cancer formation.	('cancer', 'Disease', (92, 98))	('Akt', 'Protein', (16, 19))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('instability of the genome', 'CPA', (57, 82))	('hyperphosphorylation', 'Var', (20, 40))	('lead to', 'Reg', (45, 52))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
372958	33249703	ADFP associated with HIF-2alpha promotes lipid storage and endoplasmic reticulum homeostasis under anaerobic conditions.	('HIF-2alpha', 'Gene', '2034', (21, 31))	('ADFP', 'Var', (0, 4))	('endoplasmic', 'MPA', (59, 70))	('lipid storage', 'MPA', (41, 54))	('lipid', 'Chemical', 'MESH:D008055', (41, 46))	('promotes', 'PosReg', (32, 40))	('HIF-2alpha', 'Gene', (21, 31))
372959	33249703	35  We consider that ADFP might help tumour cells survive hypoxia by enhancing anaerobic glycolysis.	('anaerobic glycolysis', 'MPA', (79, 99))	('ADFP', 'Var', (21, 25))	('tumour', 'Disease', (37, 43))	('enhancing', 'PosReg', (69, 78))	('hypoxia', 'Disease', (58, 65))	('hypoxia', 'Disease', 'MESH:D000860', (58, 65))	('tumour', 'Phenotype', 'HP:0002664', (37, 43))	('tumour', 'Disease', 'MESH:D009369', (37, 43))
373141	32630995	Although no further assessment and treatment were done in the current case, with provided information on the size of the lung tumor greater than 7cm, no assessment of lymph node and one extrathoracic distant metastasis, the TNM staging for the disease was T4NxM1, stage IV.	('TNM', 'Gene', '10178', (224, 227))	('lung tumor', 'Phenotype', 'HP:0100526', (121, 131))	('T4NxM1', 'Var', (256, 262))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('lung tumor', 'Disease', (121, 131))	('TNM', 'Gene', (224, 227))	('lung tumor', 'Disease', 'MESH:D008175', (121, 131))
373144	32630995	Whenever possible, tumor tissue should be assessed for the expression of programmed cell death-ligand (PD-L1) and the presence of a somatic driver mutation of epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), c-ROS oncogene 1 (ROS1), and B-Raf (BRAF), which confer sensitivity to a specific inhibitor prior to the therapy choice.	('BRAF', 'Gene', (270, 274))	('BRAF', 'Gene', '673', (270, 274))	('ROS1', 'Gene', '6098', (252, 256))	('mutation', 'Var', (147, 155))	('EGFR', 'Gene', (193, 197))	('tumor', 'Disease', (19, 24))	('PD-L1', 'Gene', (103, 108))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (200, 219))	('PD-L1', 'Gene', '29126', (103, 108))	('B-Raf', 'Gene', (263, 268))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('anaplastic lymphoma kinase', 'Gene', '238', (200, 226))	('c-ROS oncogene 1', 'Gene', '6098', (234, 250))	('anaplastic lymphoma kinase', 'Gene', (200, 226))	('ROS1', 'Gene', (252, 256))	('EGFR', 'Gene', '1956', (193, 197))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('lymphoma', 'Phenotype', 'HP:0002665', (211, 219))	('B-Raf', 'Gene', '673', (263, 268))	('ALK', 'Gene', '238', (228, 231))	('epidermal growth factor receptor', 'Gene', (159, 191))	('c-ROS oncogene 1', 'Gene', (234, 250))	('epidermal growth factor receptor', 'Gene', '1956', (159, 191))	('ALK', 'Gene', (228, 231))
373155	30318841	Specifically, IFITM1 depletion resulted in a significant reduction in sphere formation, migration, and invasion of NSCLC cells in vitro; these events were inversely correlated with the ectopic expression of IFITM1.	('IFITM1', 'Gene', (14, 20))	('reduction', 'NegReg', (57, 66))	('NSCLC', 'Disease', (115, 120))	('IFITM1', 'Gene', (207, 213))	('migration', 'CPA', (88, 97))	('NSCLC', 'Disease', 'MESH:D002289', (115, 120))	('depletion', 'Var', (21, 30))	('SCLC', 'Phenotype', 'HP:0030357', (116, 120))	('sphere formation', 'CPA', (70, 86))
373156	30318841	In addition, tumor development was significantly impaired in the absence of IFITM1 in vivo.	('tumor', 'Disease', (13, 18))	('IFITM1', 'Gene', (76, 82))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('absence', 'Var', (65, 72))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('impaired', 'NegReg', (49, 57))
373157	30318841	Mechanistically, epidermal growth factor receptor/sex-determining region Y-box 2 (EGFR/SOX2) signaling axis was compromised in the absence of IFITM1, and the ectopic expression of SOX2 partially rescued the defects caused by IFITM1 depletion.	('epidermal growth factor', 'Gene', (17, 40))	('SOX2', 'Gene', '6657', (87, 91))	('EGFR', 'Gene', (82, 86))	('compromised', 'NegReg', (112, 123))	('epidermal growth factor', 'Gene', '1950', (17, 40))	('SOX2', 'Gene', (87, 91))	('SOX2', 'Gene', '6657', (180, 184))	('SOX2', 'Gene', (180, 184))	('ectopic expression', 'Var', (158, 176))	('defects', 'MPA', (207, 214))	('EGFR', 'Gene', '1956', (82, 86))
373158	30318841	More importantly, using 226 patient-derived samples, we demonstrate that a high level of IFITM1 expression is associated with a poor overall survival (OS) rate in adenocarcinoma but not in squamous cell carcinoma.	('poor', 'NegReg', (128, 132))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (189, 212))	('adenocarcinoma', 'Disease', 'MESH:D000230', (163, 177))	('carcinoma', 'Phenotype', 'HP:0030731', (168, 177))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (189, 212))	('high', 'Var', (75, 79))	('squamous cell carcinoma', 'Disease', (189, 212))	('patient', 'Species', '9606', (28, 35))	('overall survival', 'MPA', (133, 149))	('adenocarcinoma', 'Disease', (163, 177))	('IFITM1', 'Gene', (89, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (203, 212))
373164	30318841	Cancer relapse and metastasis are suggested to be the most important factors contributing to the progression and poor prognosis of cancer.3 Epithelial-mesenchymal transition (EMT) is a key event in tumor metastasis.4 EMT is a reversible process, during which epithelial cells exhibit some properties of mesenchymal cells (including proteolysis and motility) and lose many of their epithelial characteristics (such as cell-cell adhesion and cell polarity).5 Other events, including invasion, chemo-resistance and the acquisition of stem cell-like characteristics, are also known to be related to EMT.4 In recent studies, cancer stem cells (CSCs) or tumor initiating cells (TICs), a subpopulation of cells within a tumor with dysregulated self-renewal properties of normal stem cells, are believed to be responsible for tumor initiation and progression as well as chemotherapy resistance.6 These events could explain rapid tumor relapse and a poor prognosis in cancer patients.7, 8 Several signaling pathways, such as Sonic Hedgehog,9 Wnt/beta-catenin,10 EGFR11 and SOX2,12 have been described to regulate the behavior of CSCs and EMT, and contribute to the development of several cancers, such as lung cancer.9  EGFR is a receptor tyrosine kinase (RTK) that is stimulated by its ligands such as EGF, amphiregulin, betacellulin, epiregulin, neuregulin, heparin-binding EGF, and transforming growth factor alpha (TGF-alpha).13 The receptors then dimerize and autophosphorylate, leading to the initiation of various downstream signaling pathways, mainly mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K)-activated AKT pathways.14 EGFR is found to be overexpressed in various cancers, including head and neck cancer.15 In cancer cells, it has been demonstrated that EGFR can be aberrantly activated by several mechanisms, including EGFR gene amplifications, activating mutations in the extracellular or tyrosine kinase domains, and autocrine/paracrine signaling mechanisms.16, 17 High expression of EGFR is correlated with metastatic disease and a poor prognosis of many cancers.18, 19 Specifically, in lung cancer patients, EGFR overexpression is associated with reduced survival, high risk of lymph node metastasis, and poor chemo-sensitivity.20, 21 Thus, it is required to better characterize essential molecules implicated in EGFR signaling.	('cancer', 'Disease', 'MESH:D009369', (2093, 2099))	('tumor', 'Phenotype', 'HP:0002664', (921, 926))	('AKT', 'Gene', '207', (1637, 1640))	('tumor', 'Phenotype', 'HP:0002664', (818, 823))	('tumor', 'Phenotype', 'HP:0002664', (713, 718))	('phosphoinositide 3-kinase', 'Gene', (1594, 1619))	('EGF', 'Gene', '1950', (1211, 1214))	('EGF', 'Gene', (2021, 2024))	('patients', 'Species', '9606', (966, 974))	('TGF-alpha', 'Gene', '7039', (1410, 1419))	('cancer', 'Disease', (1698, 1704))	('EGF', 'Gene', '1950', (1788, 1791))	('lung cancer', 'Disease', (1196, 1207))	('metastatic disease', 'Disease', 'MESH:C538445', (2045, 2063))	('cancer', 'Phenotype', 'HP:0002664', (620, 626))	('EGF', 'Gene', (1053, 1056))	('cancer', 'Disease', (2093, 2099))	('tumor', 'Disease', (921, 926))	('cancers', 'Disease', (1698, 1705))	('tumor', 'Disease', (198, 203))	('tumor', 'Disease', 'MESH:D009369', (921, 926))	('cancers', 'Disease', (1179, 1186))	('EGF', 'Gene', '1950', (2021, 2024))	('EGFR', 'Gene', (2147, 2151))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('EGF', 'Gene', (1788, 1791))	('EGFR', 'Gene', '1956', (1653, 1657))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('beta-catenin', 'Gene', '1499', (1037, 1049))	('lung cancer', 'Phenotype', 'HP:0100526', (1196, 1207))	('cancer', 'Disease', 'MESH:D009369', (959, 965))	('cancers', 'Disease', 'MESH:D009369', (1698, 1705))	('EGF', 'Gene', '1950', (1053, 1056))	('cancer', 'Disease', 'MESH:D009369', (2130, 2136))	('cancer', 'Disease', 'MESH:D009369', (1179, 1185))	('cancers', 'Disease', 'MESH:D009369', (1179, 1186))	('head and neck cancer', 'Phenotype', 'HP:0012288', (1717, 1737))	('EGFR', 'Gene', '1956', (2147, 2151))	('cancer', 'Disease', 'MESH:D009369', (1201, 1207))	('neck cancer', 'Disease', 'MESH:D006258', (1726, 1737))	('MAPK', 'Gene', '5594', (1584, 1588))	('lung cancer', 'Disease', (2125, 2136))	('tumor', 'Phenotype', 'HP:0002664', (648, 653))	('cancer', 'Disease', (1744, 1750))	('EGFR', 'Gene', (1653, 1657))	('EGFR', 'Gene', '1956', (1854, 1858))	('cancer', 'Disease', (959, 965))	('phosphoinositide 3-kinase', 'Gene', '5294', (1594, 1619))	('patients', 'Species', '9606', (2137, 2145))	('tumor', 'Disease', (818, 823))	('tumor', 'Disease', (713, 718))	('cancer', 'Disease', 'MESH:D009369', (1731, 1737))	('cancer', 'Disease', 'MESH:D009369', (620, 626))	('beta-catenin', 'Gene', (1037, 1049))	('tumor', 'Disease', 'MESH:D009369', (818, 823))	('transforming growth factor alpha', 'Gene', (1376, 1408))	('tumor', 'Disease', 'MESH:D009369', (713, 718))	('lung cancer', 'Phenotype', 'HP:0100526', (2125, 2136))	('cancers', 'Disease', (2093, 2100))	('EGFR', 'Gene', (1854, 1858))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('TICs', 'Phenotype', 'HP:0100033', (672, 676))	('amplifications', 'Var', (1864, 1878))	('EGFR', 'Gene', (2352, 2356))	('EGFR', 'Gene', '1956', (1053, 1057))	('cancers', 'Disease', 'MESH:D009369', (2093, 2100))	('EGFR', 'Gene', '1956', (2021, 2025))	('cancers', 'Phenotype', 'HP:0002664', (1698, 1705))	('EGF', 'Gene', (1653, 1656))	('EGFR', 'Gene', '1956', (1788, 1792))	('AKT', 'Gene', (1637, 1640))	('cancers', 'Phenotype', 'HP:0002664', (1179, 1186))	('cancer', 'Disease', (2130, 2136))	('cancer', 'Disease', 'MESH:D009369', (1698, 1704))	('cancer', 'Disease', (1179, 1185))	('cancers', 'Phenotype', 'HP:0002664', (2093, 2100))	('EGFR', 'Gene', '1956', (2352, 2356))	('metastatic disease', 'Disease', (2045, 2063))	('cancer', 'Disease', (1201, 1207))	('Cancer', 'Disease', (0, 6))	('EGFR', 'Gene', (1053, 1057))	('EGF', 'Gene', (2352, 2355))	('tumor', 'Disease', (648, 653))	('EGFR', 'Gene', (2021, 2025))	('EGFR', 'Gene', (1211, 1215))	('EGF', 'Gene', '1950', (2147, 2150))	('tumor', 'Disease', 'MESH:D009369', (648, 653))	('amphiregulin', 'Gene', (1299, 1311))	('EGF', 'Gene', (1294, 1297))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('MAPK', 'Gene', (1584, 1588))	('EGF', 'Gene', '1950', (1854, 1857))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('cancer', 'Disease', (1731, 1737))	('EGFR', 'Gene', (1788, 1792))	('EGF', 'Gene', '1950', (1653, 1656))	('cancer', 'Disease', (620, 626))	('neck cancer', 'Disease', (1726, 1737))	('SOX2', 'Gene', '6657', (1064, 1068))	('EGFR', 'Gene', '1956', (1211, 1215))	('SOX2', 'Gene', (1064, 1068))	('EGF', 'Gene', (2147, 2150))	('amphiregulin', 'Gene', '374', (1299, 1311))	('EGF', 'Gene', '1950', (2352, 2355))	('tumor initiation', 'Disease', 'MESH:D009369', (818, 834))	('EGF', 'Gene', '1950', (1367, 1370))	('EGF', 'Gene', (1211, 1214))	('TGF-alpha', 'Gene', (1410, 1419))	('cancer', 'Phenotype', 'HP:0002664', (959, 965))	('tumor initiation', 'Disease', (818, 834))	('EGF', 'Gene', (1854, 1857))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('lung cancer', 'Disease', 'MESH:D008175', (2125, 2136))	('EGF', 'Gene', '1950', (1294, 1297))	('cancer', 'Disease', (131, 137))	('lung cancer', 'Disease', 'MESH:D008175', (1196, 1207))	('cancer', 'Disease', 'MESH:D009369', (1744, 1750))	('cancer', 'Phenotype', 'HP:0002664', (1179, 1185))	('transforming growth factor alpha', 'Gene', '7124', (1376, 1408))	('mutations', 'Var', (1891, 1900))	('cancer', 'Phenotype', 'HP:0002664', (1201, 1207))	('EGF', 'Gene', (1367, 1370))
373199	30318841	NSCLC cell lines, H1650 and A549, were transduced with either nonsense control (shLacZ) or two independent IFITM1 shRNAs (642-shIFITM1 and 870-shIFITM1) and either sorted using flow cytometry or selected with puromycin.	('642-shIFITM1', 'Var', (122, 134))	('NSCLC', 'Disease', 'MESH:D002289', (0, 5))	('A549', 'CellLine', 'CVCL:0023', (28, 32))	('SCLC', 'Phenotype', 'HP:0030357', (1, 5))	('transduced', 'Reg', (39, 49))	('NSCLC', 'Disease', (0, 5))	('puromycin', 'Chemical', 'MESH:D011691', (209, 218))
373202	30318841	RT-qPCR results demonstrated that the expression levels of both IFITM2 and IFITM3 did not change by the depletion of IFITM1 (Supporting Information Fig.	('IFITM1', 'Gene', (117, 123))	('expression', 'MPA', (38, 48))	('IFITM3', 'Gene', '10410', (75, 81))	('depletion', 'Var', (104, 113))	('IFITM3', 'Gene', (75, 81))	('IFITM2', 'Gene', (64, 70))	('IFITM2', 'Gene', '10581', (64, 70))
373206	30318841	Relative to control cells, the proliferation rate of IFITM1-depleted H1650 and A549 cell lines decreased by approximately 36% and 43%, respectively, suggesting that cell proliferation was modestly impaired in the absence of IFITM1 in NSCLC cell lines (Fig.	('decreased', 'NegReg', (95, 104))	('IFITM1', 'Gene', (224, 230))	('NSCLC', 'Disease', (234, 239))	('A549', 'CellLine', 'CVCL:0023', (79, 83))	('NSCLC', 'Disease', 'MESH:D002289', (234, 239))	('impaired', 'NegReg', (197, 205))	('cell proliferation', 'CPA', (165, 183))	('SCLC', 'Phenotype', 'HP:0030357', (235, 239))	('absence', 'Var', (213, 220))
373217	30318841	Thus, we investigated whether IFITM1 was sufficient to drive these functions by gain of function of IFITM1 in H1299 and H1650.	('IFITM1', 'Gene', (100, 106))	('H1299', 'CellLine', 'CVCL:0060', (110, 115))	('H1299', 'Var', (110, 115))	('H1650', 'Var', (120, 125))	('gain of function', 'PosReg', (80, 96))
373218	30318841	1), ectopic expression of IFITM1 increased the sphere-forming, proliferation, and migration ability of H1299 and H1650 cells in vitro (Fig.	('migration ability', 'CPA', (82, 99))	('H1299', 'CellLine', 'CVCL:0060', (103, 108))	('proliferation', 'CPA', (63, 76))	('increased', 'PosReg', (33, 42))	('IFITM1', 'Gene', (26, 32))	('sphere-forming', 'CPA', (47, 61))	('ectopic expression', 'Var', (4, 22))
373224	30318841	Specifically, CDH1 expression was upregulated in the absence of IFITM1, whereas the expression of CDH2 and SNAIL was downregulated at both the RNA and protein levels.	('absence', 'Var', (53, 60))	('expression', 'MPA', (19, 29))	('CDH1', 'Gene', (14, 18))	('CDH2', 'Gene', (98, 102))	('CDH1', 'Gene', '999', (14, 18))	('upregulated', 'PosReg', (34, 45))	('downregulated', 'NegReg', (117, 130))	('CDH2', 'Gene', '1000', (98, 102))	('expression', 'MPA', (84, 94))	('SNAIL', 'Gene', '6615', (107, 112))	('SNAIL', 'Gene', (107, 112))
373225	30318841	Additionally, using a gelatin digestion assay, we showed that the enzymatic activity of MMP2 was inhibited in the absence of IFITM1 (Fig.	('absence', 'Var', (114, 121))	('IFITM1', 'Gene', (125, 131))	('enzymatic activity', 'MPA', (66, 84))	('MMP2', 'Gene', '4313', (88, 92))	('inhibited', 'NegReg', (97, 106))	('MMP2', 'Gene', (88, 92))
373227	30318841	To reveal the mechanisms by which IFITM1 deficiency led to the impaired ability of EMT signaling and cancer stem cell-like properties in NSCLC cell lines, we tested whether IFITM1 was related to CAV1 and EGFR signaling.	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('NSCLC', 'Disease', (137, 142))	('cancer', 'Disease', (101, 107))	('NSCLC', 'Disease', 'MESH:D002289', (137, 142))	('tested', 'Reg', (158, 164))	('CAV1', 'Gene', (195, 199))	('SCLC', 'Phenotype', 'HP:0030357', (138, 142))	('EMT signaling', 'MPA', (83, 96))	('deficiency', 'Var', (41, 51))	('EGFR', 'Gene', '1956', (204, 208))	('ability', 'MPA', (72, 79))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('IFITM1', 'Gene', (34, 40))	('EGFR', 'Gene', (204, 208))	('impaired', 'NegReg', (63, 71))	('CAV1', 'Gene', '857', (195, 199))
373229	30318841	We found that CAV1 expression was significantly upregulated in the absence of IFITM1 (Fig.	('absence', 'Var', (67, 74))	('expression', 'MPA', (19, 29))	('CAV1', 'Gene', '857', (14, 18))	('IFITM1', 'Gene', (78, 84))	('CAV1', 'Gene', (14, 18))	('upregulated', 'PosReg', (48, 59))
373230	30318841	Consistently, ectopic expression of IFITM1 in H1299 cells led to a downregulation of CAV1 (Fig.	('H1299', 'CellLine', 'CVCL:0060', (46, 51))	('downregulation', 'NegReg', (67, 81))	('CAV1', 'Gene', (85, 89))	('IFITM1', 'Gene', (36, 42))	('CAV1', 'Gene', '857', (85, 89))	('ectopic expression', 'Var', (14, 32))
373234	30318841	As shown in Figure 3 h-k, the reduced migratory ability of H1650 in the absence of IFITM1 was partially rescued by the simultaneous suppression of CAV-1 and IFITM1.	('H1650', 'Var', (59, 64))	('suppression', 'NegReg', (132, 143))	('CAV-1', 'Gene', (147, 152))	('migratory ability', 'CPA', (38, 55))	('reduced', 'NegReg', (30, 37))	('CAV-1', 'Gene', '857', (147, 152))
373235	30318841	Further, pEGFR level was also decreased in the absence of IFITM1 partly because of a higher level of CAV1 (Fig.	('EGFR', 'Gene', '1956', (10, 14))	('higher', 'PosReg', (85, 91))	('EGFR', 'Gene', (10, 14))	('CAV1', 'Gene', '857', (101, 105))	('absence', 'Var', (47, 54))	('IFITM1', 'Gene', (58, 64))	('CAV1', 'Gene', (101, 105))	('decreased', 'NegReg', (30, 39))
373240	30318841	The levels of pAKT and pSTAT3 were consistently much lower in the absence of IFITM1 (Fig.	('pSTAT3', 'MPA', (23, 29))	('AKT', 'Gene', '207', (15, 18))	('absence', 'Var', (66, 73))	('IFITM1', 'Gene', (77, 83))	('AKT', 'Gene', (15, 18))	('lower', 'NegReg', (53, 58))
373241	30318841	In addition, the RNA levels of SOX2, MYC, and EGR1 significantly decreased after knocking down IFITM1 (Fig.	('SOX2', 'Gene', (31, 35))	('SOX2', 'Gene', '6657', (31, 35))	('decreased', 'NegReg', (65, 74))	('MYC', 'Gene', '4609', (37, 40))	('EGR1', 'Gene', (46, 50))	('IFITM1', 'Gene', (95, 101))	('EGR1', 'Gene', '1958', (46, 50))	('MYC', 'Gene', (37, 40))	('knocking down', 'Var', (81, 94))
373242	30318841	Consistently with the results of RNA expressions, the levels of SOX2 and pAKT decreased after IFITM1 knockdown, whereas there was an increase in the levels of these proteins in response to IFITM1 overexpression (Fig.	('IFITM1', 'Gene', (94, 100))	('levels', 'MPA', (149, 155))	('AKT', 'Gene', '207', (74, 77))	('SOX2', 'Gene', '6657', (64, 68))	('levels', 'MPA', (54, 60))	('increase', 'PosReg', (133, 141))	('AKT', 'Gene', (74, 77))	('decreased', 'NegReg', (78, 87))	('SOX2', 'Gene', (64, 68))	('knockdown', 'Var', (101, 110))
373246	30318841	Since SOX2 was found to be a downstream signaling of IFITM1 in NSCLC cell lines, we investigated whether the functional defects caused by IFITM1 deficiency could be rescued by ectopic expression of SOX2.	('NSCLC', 'Disease', (63, 68))	('SOX2', 'Gene', '6657', (6, 10))	('NSCLC', 'Disease', 'MESH:D002289', (63, 68))	('IFITM1', 'Gene', (138, 144))	('SOX2', 'Gene', '6657', (198, 202))	('SOX2', 'Gene', (198, 202))	('deficiency', 'Var', (145, 155))	('SCLC', 'Phenotype', 'HP:0030357', (64, 68))	('SOX2', 'Gene', (6, 10))
373247	30318841	H1650 cells were transduced with either shLacZ+Vector, shIFITM1 + Vector, or shIFITM1 + SOX2 overexpression (OE).	('SOX2', 'Gene', '6657', (88, 92))	('shIFITM1 +', 'Var', (77, 87))	('SOX2', 'Gene', (88, 92))
373251	30318841	Importantly, overexpression of SOX2 in IFITM1-depleted cells (870-shIFITM1 + SOX2 OE) showed 75.8% of migration relative to cells transduced with control vector (shLacZ+Vector); this result suggested that the defects caused by IFITM1 deficiency were partially rescued by the ectopic expression of SOX2 (Fig.	('IFITM1', 'Gene', (227, 233))	('SOX2', 'Gene', (31, 35))	('SOX2', 'Gene', '6657', (31, 35))	('deficiency', 'Var', (234, 244))	('SOX2', 'Gene', '6657', (297, 301))	('SOX2', 'Gene', '6657', (77, 81))	('SOX2', 'Gene', (77, 81))	('SOX2', 'Gene', (297, 301))	('migration', 'CPA', (102, 111))
373252	30318841	At the molecular level, we found that MYC, EGR1, and phospho-beta-catenin were partially upregulated by SOX2 overexpression (Fig.	('EGR1', 'Gene', '1958', (43, 47))	('SOX2', 'Gene', '6657', (104, 108))	('beta-catenin', 'Gene', '1499', (61, 73))	('MYC', 'Gene', (38, 41))	('upregulated', 'PosReg', (89, 100))	('EGR1', 'Gene', (43, 47))	('beta-catenin', 'Gene', (61, 73))	('MYC', 'Gene', '4609', (38, 41))	('overexpression', 'Var', (109, 123))	('SOX2', 'Gene', (104, 108))
373259	30318841	When tumors were weighted after dissection, the weight of IFITM1 shRNA-transduced tumor was 36.8% of that of control (Fig.	('tumors', 'Disease', (5, 11))	('tumors', 'Disease', 'MESH:D009369', (5, 11))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumor', 'Disease', (5, 10))	('IFITM1', 'Var', (58, 64))	('tumor', 'Disease', (82, 87))	('tumors', 'Phenotype', 'HP:0002664', (5, 11))
373261	30318841	IFITM1 expression was significantly lower in IFITM1 shRNA-transduced tumors at both RNA and protein levels compared to their expression levels in tumors from the control mice (Fig.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('lower', 'NegReg', (36, 41))	('tumors', 'Phenotype', 'HP:0002664', (146, 152))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('tumors', 'Disease', 'MESH:D009369', (146, 152))	('expression', 'MPA', (7, 17))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('tumors', 'Disease', (69, 75))	('tumors', 'Disease', 'MESH:D009369', (69, 75))	('mice', 'Species', '10090', (170, 174))	('tumors', 'Disease', (146, 152))	('shRNA-transduced', 'Var', (52, 68))	('IFITM1', 'Gene', (0, 6))	('IFITM1', 'Gene', (45, 51))
373263	30318841	In agreement with our in vitro data, the levels of pEGFR, pAKT and SOX2 significantly decreased in the absence of IFITM1 (Fig.	('EGFR', 'Gene', '1956', (52, 56))	('AKT', 'Gene', (59, 62))	('EGFR', 'Gene', (52, 56))	('IFITM1', 'Gene', (114, 120))	('decreased', 'NegReg', (86, 95))	('SOX2', 'Gene', '6657', (67, 71))	('AKT', 'Gene', '207', (59, 62))	('SOX2', 'Gene', (67, 71))	('absence', 'Var', (103, 110))	('levels', 'MPA', (41, 47))
373264	30318841	Consistently, when control or IFITM1 shRNA-transduced H1650 cells were orthotopically injected into immunocompromised NSG mice, IFITM1-depleted cells displayed a much lower number of tumor nodules in the lungs as well as the liver compared to the control (lung, 7.7 vs. 2.5; liver, 29 vs. 3.5; Fig.	('mice', 'Species', '10090', (122, 126))	('lower', 'NegReg', (167, 172))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('tumor', 'Disease', (183, 188))	('IFITM1-depleted', 'Var', (128, 143))
373277	30318841	More importantly, we showed that IFITM1 was closely associated with a poor prognosis of adenocarcinoma, but not squamous cell carcinoma; this was evidenced by a significantly low OS rate of IFITM1-positive adenocarcinoma patients versus IFITM1-negative patients.	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('IFITM1-positive', 'Var', (190, 205))	('patients', 'Species', '9606', (221, 229))	('adenocarcinoma', 'Disease', 'MESH:D000230', (88, 102))	('adenocarcinoma', 'Disease', (206, 220))	('patients', 'Species', '9606', (253, 261))	('low', 'NegReg', (175, 178))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (112, 135))	('carcinoma', 'Phenotype', 'HP:0030731', (211, 220))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (112, 135))	('adenocarcinoma', 'Disease', 'MESH:D000230', (206, 220))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('squamous cell carcinoma', 'Disease', (112, 135))	('adenocarcinoma', 'Disease', (88, 102))
373279	30318841	reported that CD147 stimulation, which was implicated in tumor invasion, metastasis, and angiogenesis,48 could induce the expression of IFITM1 using a leukemic cell line.49 KRAS mutation was associated with higher expression of IFITM1 in rectal cancer.50 Analysis of the cancer genome atlas (TCGA) database identifies that three cases of IFITM1 mutations and one case of IFITM1 mutation are found in adenocarcinoma and squamous cell carcinoma, respectively.	('leukemic', 'Disease', (151, 159))	('KRAS', 'Gene', (173, 177))	('carcinoma', 'Phenotype', 'HP:0030731', (405, 414))	('rectal cancer', 'Disease', (238, 251))	('cancer', 'Phenotype', 'HP:0002664', (271, 277))	('tumor', 'Disease', (57, 62))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (419, 442))	('IFITM1', 'Gene', (338, 344))	('CD147', 'Gene', '682', (14, 19))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('rectal cancer', 'Disease', 'MESH:D012004', (238, 251))	('cancer', 'Phenotype', 'HP:0002664', (245, 251))	('carcinoma', 'Phenotype', 'HP:0030731', (433, 442))	('mutations', 'Var', (345, 354))	('adenocarcinoma and squamous cell carcinoma', 'Disease', 'MESH:D002294', (400, 442))	('cancer genome atlas', 'Disease', 'MESH:D009369', (271, 290))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('KRAS', 'Gene', '3845', (173, 177))	('cancer genome atlas', 'Disease', (271, 290))	('CD147', 'Gene', (14, 19))	('leukemic', 'Disease', 'MESH:D007938', (151, 159))
373286	30318841	We also found that cancer stem cell-like properties, mediated by EGFR signaling pathway, were critically impaired in the absence of IFITM1.	('cancer', 'Disease', 'MESH:D009369', (19, 25))	('EGFR', 'Gene', '1956', (65, 69))	('EGFR', 'Gene', (65, 69))	('impaired', 'NegReg', (105, 113))	('cancer', 'Disease', (19, 25))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('absence', 'Var', (121, 128))
373288	30318841	While MYC overexpression or dysregulation is related to the numerous oncogenic cascades, it has been reported to function as a tumor suppressor as well.56, 57 In addition, the reciprocal relationship between MYC and SOX2 has been implicated in the maintenance of stem cells and cancer development.41 They occupy more than 85% of the same gene promoters, and their interaction is related to the promotion of self-renewal, growth regulation, and cell cycle progression.57 EGR1, a downstream target of EGFR signaling,58 has been reported to interact with MYC and its interaction leads to the induction of apoptosis.43, 56 Our observations showed that IFITM1 depletion reduced the levels of pEGFR, SOX2, MYC, and EGR1; these effects were partly rescued by ectopic expression of SOX2.	('SOX2', 'Gene', '6657', (694, 698))	('MYC', 'Gene', (552, 555))	('SOX2', 'Gene', (694, 698))	('depletion', 'Var', (655, 664))	('SOX2', 'Gene', '6657', (774, 778))	('SOX2', 'Gene', (774, 778))	('SOX2', 'Gene', '6657', (216, 220))	('MYC', 'Gene', '4609', (6, 9))	('cancer', 'Disease', (278, 284))	('SOX2', 'Gene', (216, 220))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('cancer', 'Phenotype', 'HP:0002664', (278, 284))	('MYC', 'Gene', (700, 703))	('EGFR', 'Gene', '1956', (499, 503))	('EGFR', 'Gene', '1956', (688, 692))	('MYC', 'Gene', '4609', (552, 555))	('MYC', 'Gene', (208, 211))	('cancer', 'Disease', 'MESH:D009369', (278, 284))	('EGR1', 'Gene', (709, 713))	('IFITM1', 'Gene', (648, 654))	('reduced', 'NegReg', (665, 672))	('MYC', 'Gene', '4609', (700, 703))	('EGR1', 'Gene', '1958', (709, 713))	('levels', 'MPA', (677, 683))	('EGR1', 'Gene', (470, 474))	('MYC', 'Gene', (6, 9))	('MYC', 'Gene', '4609', (208, 211))	('tumor', 'Disease', (127, 132))	('EGR1', 'Gene', '1958', (470, 474))	('EGFR', 'Gene', (499, 503))	('EGFR', 'Gene', (688, 692))	('tumor', 'Disease', 'MESH:D009369', (127, 132))
373311	26655252	Aberrant TF activity can lead to dysregulation of genes involved in almost all known cellular processes related to tumorigenesis, such as apoptosis, proliferation, angiogenesis and metastasis.	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('Aberrant', 'Var', (0, 8))	('dysregulation', 'MPA', (33, 46))	('tumor', 'Disease', (115, 120))	('activity', 'MPA', (12, 20))	('proliferation', 'CPA', (149, 162))	('lead to', 'Reg', (25, 32))	('apoptosis', 'CPA', (138, 147))	('angiogenesis', 'CPA', (164, 176))	('metastasis', 'CPA', (181, 191))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
373327	26655252	In this study, we identified the dysregulated TF-miRNA FFLs in 13 tumor types through integrating the gene and miRNA expression data of matched tumor and normal samples from TCGA into a curated TF- and miRNA-mediated regulatory network.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Disease', (144, 149))	('tumor', 'Disease', (66, 71))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('miR', 'Gene', '220972', (202, 205))	('miR', 'Gene', (202, 205))	('dysregulated', 'Var', (33, 45))	('miR', 'Gene', '220972', (49, 52))	('miR', 'Gene', (49, 52))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('miR', 'Gene', '220972', (111, 114))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('miR', 'Gene', (111, 114))
373335	26655252	In summary, we identified the pan-cancer dysregulated FFLs, explored their function and demonstrated the potential ability to elucidate pathogenesis of cancer and develop novel anticancer drugs.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('pan-cancer', 'Disease', (30, 40))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('FFLs', 'Gene', (54, 58))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('cancer', 'Disease', (34, 40))	('pan-cancer', 'Disease', 'MESH:C537931', (30, 40))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('cancer', 'Disease', (181, 187))	('dysregulated', 'Var', (41, 53))
373343	26655252	For example, in bladder cancer, the genes were detected if they had CPM > 1 in at least 19 (38/2) samples.	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('bladder cancer', 'Disease', 'MESH:D001749', (16, 30))	('bladder cancer', 'Disease', (16, 30))	('bladder cancer', 'Phenotype', 'HP:0009725', (16, 30))	('CPM > 1', 'Var', (68, 75))
373380	26655252	Based on read counts, edgeR R package was used to identify the DE genes and DE mature miRNAs.	('miR', 'Gene', '220972', (86, 89))	('DE genes', 'Var', (63, 71))	('miR', 'Gene', (86, 89))
373389	26655252	Inhibition of ASF1B expression could decrease cell proliferation, indicating the potential of ASF1B to be a new target for treatment of cancer.	('decrease', 'NegReg', (37, 45))	('ASF1B', 'Gene', '55723', (94, 99))	('expression', 'MPA', (20, 30))	('ASF1B', 'Gene', (14, 19))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('cancer', 'Disease', (136, 142))	('Inhibition', 'Var', (0, 10))	('ASF1B', 'Gene', (94, 99))	('ASF1B', 'Gene', '55723', (14, 19))	('cell proliferation', 'CPA', (46, 64))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
373394	26655252	The in vitro and in vivo experiments demonstrated that inhibition of hsa-miR-183-5p could decrease prostate tumor growth.	('miR-183', 'Gene', (73, 80))	('decrease prostate', 'Phenotype', 'HP:0008687', (90, 107))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('prostate tumor', 'Disease', (99, 113))	('prostate tumor', 'Phenotype', 'HP:0100787', (99, 113))	('inhibition', 'Var', (55, 65))	('decrease', 'NegReg', (90, 98))	('prostate tumor', 'Disease', 'MESH:D011471', (99, 113))	('miR-183', 'Gene', '406959', (73, 80))
373497	26655252	The hypergeometric test showed that the dysregulated FFLs were significantly enriched with pan-cancer FFLs (P = 0.006), which indicated that the pan-cancer FFLs were reproducible to some extent.	('pan-cancer', 'Disease', 'MESH:C537931', (145, 155))	('pan-cancer', 'Disease', (91, 101))	('dysregulated', 'Var', (40, 52))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('pan-cancer', 'Disease', (145, 155))	('pan-cancer', 'Disease', 'MESH:C537931', (91, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))
373502	26655252	To our knowledge, this study represents the first one to identify dysregulated FFLs across multiple tumor types based on experimentally validated TF and miRNA regulations.	('FFLs', 'Gene', (79, 83))	('miR', 'Gene', '220972', (153, 156))	('miR', 'Gene', (153, 156))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('multiple tumor', 'Disease', (91, 105))	('dysregulated', 'Var', (66, 78))	('multiple tumor', 'Disease', 'MESH:D009369', (91, 105))
373531	31627272	Programmed Death Ligand 1 Indicates Pre-Existing Adaptive Immune Response by Tumor-Infiltrating CD8+ T Cells in Non-Small Cell Lung Cancer Aberrant expression of programmed death ligand 1 (PD-L1) on tumor cells impedes antitumor immunity and instigates immune evasion.	('impedes', 'NegReg', (211, 218))	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('Lung Cancer', 'Phenotype', 'HP:0100526', (127, 138))	('Non-Small Cell Lung Cancer', 'Disease', (112, 138))	('instigates', 'NegReg', (242, 252))	('CD8', 'Gene', (96, 99))	('Small Cell Lung Cancer', 'Phenotype', 'HP:0030357', (116, 138))	('Non-Small Cell Lung Cancer', 'Phenotype', 'HP:0030358', (112, 138))	('Cancer', 'Phenotype', 'HP:0002664', (132, 138))	('PD-L1', 'Gene', (189, 194))	('Tumor', 'Phenotype', 'HP:0002664', (77, 82))	('immune evasion', 'MPA', (253, 267))	('tumor', 'Disease', (199, 204))	('tumor', 'Disease', (223, 228))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('tumor', 'Disease', 'MESH:D009369', (223, 228))	('Non-Small Cell Lung Cancer', 'Disease', 'MESH:D002289', (112, 138))	('CD8', 'Gene', '925', (96, 99))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('Aberrant', 'Var', (139, 147))
373540	31627272	Moreover, Cox multivariate regression analysis showed that the combination of PD-L1 and CD8 were independent prognostic factors, which was more accurate in prediction of prognosis in NSCLC than individually.	('NSCLC', 'Phenotype', 'HP:0030358', (183, 188))	('CD8', 'Gene', '925', (88, 91))	('PD-L1', 'Gene', (78, 83))	('combination', 'Var', (63, 74))	('Cox', 'Gene', (10, 13))	('NSCLC', 'Disease', (183, 188))	('Cox', 'Gene', '1351', (10, 13))	('NSCLC', 'Disease', 'MESH:D002289', (183, 188))	('CD8', 'Gene', (88, 91))
373574	31627272	Interestingly, one exception was of particular note in the 25 samples with PD-L1 positivity, which was characterized by high PD-L1 expression but with poor CD8+ TIL infiltration.	('PD-L1', 'Protein', (125, 130))	('PD-L1', 'Gene', (75, 80))	('expression', 'MPA', (131, 141))	('CD8', 'Gene', (156, 159))	('positivity', 'Var', (81, 91))	('CD8', 'Gene', '925', (156, 159))
373582	31627272	Overexpression of PD-L1 in tumor cells seems to be indicative of impaired anti-tumor immunity and escape surveillance by the immune system.	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('escape', 'CPA', (98, 104))	('tumor', 'Disease', (79, 84))	('PD-L1', 'Gene', (18, 23))	('tumor', 'Disease', (27, 32))	('Overexpression', 'Var', (0, 14))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('impaired', 'NegReg', (65, 73))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
373585	31627272	In the present study, results from 138 patients were available for analysis, including 18.1% cases with PD-L1 positivity and 81.9% cases with PD-L1 negativity.	('positivity', 'Var', (110, 120))	('patients', 'Species', '9606', (39, 47))	('PD-L1', 'Gene', (104, 109))
373589	31627272	For survival analysis, patients were divided into two groups, one with positive PD-L1 expression and one with negative PD-L1 expression.	('patients', 'Species', '9606', (23, 31))	('expression', 'Var', (86, 96))	('PD-L1', 'Gene', (80, 85))	('positive', 'Reg', (71, 79))
373590	31627272	The Kaplan-Meier analysis highlighted significantly superior overall survival rates for the patients with PD-L1 positivity in comparison with those with PD-L1 negativity (p = 0.026; Figure 3C).	('superior', 'PosReg', (52, 60))	('patients', 'Species', '9606', (92, 100))	('PD-L1', 'Gene', (106, 111))	('overall survival', 'CPA', (61, 77))	('positivity', 'Var', (112, 122))
373591	31627272	Similarly, significantly increased overall survival was also observed in patients with high infiltration compared with low infiltration by CD8+ TILs (p = 0.002; Figure 3D).	('CD8', 'Gene', (139, 142))	('CD8', 'Gene', '925', (139, 142))	('increased', 'PosReg', (25, 34))	('high infiltration', 'Var', (87, 104))	('overall survival', 'MPA', (35, 51))	('patients', 'Species', '9606', (73, 81))
373601	31627272	Given that EGFR mutation or ALK fusion may alter the PD-L1 expression, we used two NSCLC cell lines, including NCI-H460 cells and NCI-H1975 cells, the latter characterized by EGFR-T790 mutation.	('PD-L1', 'Gene', (53, 58))	('mutation', 'Var', (16, 24))	('EGFR', 'Gene', (175, 179))	('alter', 'Reg', (43, 48))	('ALK', 'Gene', '238', (28, 31))	('NSCLC', 'Disease', (83, 88))	('EGFR', 'Gene', '1956', (11, 15))	('EGFR', 'Gene', (11, 15))	('NCI-H1975', 'CellLine', 'CVCL:1511', (130, 139))	('NSCLC', 'Disease', 'MESH:D002289', (83, 88))	('expression', 'MPA', (59, 69))	('ALK', 'Gene', (28, 31))	('NSCLC', 'Phenotype', 'HP:0030358', (83, 88))	('NCI-H460', 'CellLine', 'CVCL:0459', (111, 119))	('EGFR', 'Gene', '1956', (175, 179))
373608	31627272	PD-L1 has been traditionally considered as a negative co-stimulatory molecule promoted constitutively by oncogenic driver mutations and indicates defective adaptive immune response in many solid tumors.	('tumors', 'Disease', (195, 201))	('tumors', 'Disease', 'MESH:D009369', (195, 201))	('defective adaptive immune response', 'Phenotype', 'HP:0031404', (146, 180))	('tumors', 'Phenotype', 'HP:0002664', (195, 201))	('promoted', 'PosReg', (78, 86))	('adaptive immune response', 'CPA', (156, 180))	('PD-L1', 'Gene', (0, 5))	('mutations', 'Var', (122, 131))	('defective', 'NegReg', (146, 155))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))
373621	31627272	Furthermore, a randomized controlled trial showed that favorable overall survival rates were observed in patients with high expression of T-effector-IFN-gamma-associated genes, which was carried out in an NSCLC cohort pretreated by docetaxel or atezolizumab.	('patients', 'Species', '9606', (105, 113))	('high expression', 'Var', (119, 134))	('NSCLC', 'Phenotype', 'HP:0030358', (205, 210))	('IFN-gamma', 'Gene', '3458', (149, 158))	('IFN-gamma', 'Gene', (149, 158))	('NSCLC', 'Disease', (205, 210))	('NSCLC', 'Disease', 'MESH:D002289', (205, 210))	('docetaxel', 'Chemical', 'MESH:C067311', (232, 241))
373627	31627272	However, we reported that PD-L1 positivity in NSCLC samples is around 20% by immunohistochemistry and in a larger cohort, including 982 patients, 314 (32.0%) specimens were positive for PD-L1 expression.	('PD-L1', 'Protein', (186, 191))	('NSCLC', 'Disease', (46, 51))	('PD-L1', 'Gene', (26, 31))	('NSCLC', 'Disease', 'MESH:D002289', (46, 51))	('patients', 'Species', '9606', (136, 144))	('positivity', 'Var', (32, 42))	('positive', 'Reg', (173, 181))	('NSCLC', 'Phenotype', 'HP:0030358', (46, 51))
373633	31627272	Besides, loss of tumor suppressor PTEN function also increased PD-L1 expression and facilitated immune resistance in glioma.	('glioma', 'Disease', (117, 123))	('tumor', 'Disease', (17, 22))	('increased PD', 'Phenotype', 'HP:0008151', (53, 65))	('glioma', 'Disease', 'MESH:D005910', (117, 123))	('glioma', 'Phenotype', 'HP:0009733', (117, 123))	('facilitated', 'PosReg', (84, 95))	('expression', 'MPA', (69, 79))	('loss', 'Var', (9, 13))	('increased', 'PosReg', (53, 62))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('immune resistance', 'CPA', (96, 113))	('PTEN', 'Gene', (34, 38))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('PD-L1', 'Protein', (63, 68))	('PTEN', 'Gene', '5728', (34, 38))
373634	31627272	In a mouse model of pancreatitis, autophagy repressed by deletion of Atg5 dysregulated TBK1 signaling and upregulated PD-L1.	('autophagy', 'CPA', (34, 43))	('deletion', 'Var', (57, 65))	('upregulated', 'PosReg', (106, 117))	('pancreatitis', 'Disease', (20, 32))	('Atg5', 'Gene', (69, 73))	('TBK1', 'Gene', (87, 91))	('TBK1', 'Gene', '56480', (87, 91))	('pancreatitis', 'Phenotype', 'HP:0001733', (20, 32))	('mouse', 'Species', '10090', (5, 10))	('pancreatitis', 'Disease', 'MESH:D010195', (20, 32))	('dysregulated', 'PosReg', (74, 86))	('Atg5', 'Gene', '11793', (69, 73))	('PD-L1', 'MPA', (118, 123))
373665	31627272	After serum block, sections were incubated with anti-PD-L1 (Clone E1L3N, #13684, Cell Signaling Technology) and anti-CD8 (#ET1606-31, Hua An Co., Hangzhou, China) at 4  C overnight.	('CD8', 'Gene', '925', (117, 120))	('CD8', 'Gene', (117, 120))	('#ET1606-31', 'Var', (122, 132))
373688	33179318	Mechanistically, bioinformatics analysis, RNA immunoprecipitation, and dual luciferase reporter assay indicated that KRT17P3 acts as a molecular sponge for miR-497-5p and relieves the binding of miR-497-5p to its target gene mTOR.	('miR-497-5p', 'Chemical', '-', (195, 205))	('mTOR', 'Gene', '2475', (225, 229))	('relieves', 'NegReg', (171, 179))	('mTOR', 'Gene', (225, 229))	('binding', 'Interaction', (184, 191))	('KRT17P3', 'Gene', (117, 124))	('miR-497-5p', 'Chemical', '-', (156, 166))	('miR-497-5p', 'Var', (156, 166))
373693	33179318	Mechanistically, KRT17P3 acts as a molecular sponge for miR-497-5p and relieves the binding of miR-497-5p to its target gene mTOR.	('mTOR', 'Gene', '2475', (125, 129))	('mTOR', 'Gene', (125, 129))	('KRT17P3', 'Gene', (17, 24))	('miR-497-5p', 'Chemical', '-', (56, 66))	('miR-497-5p', 'Var', (56, 66))	('relieves', 'NegReg', (71, 79))	('binding', 'Interaction', (84, 91))	('miR-497-5p', 'Chemical', '-', (95, 105))	('miR-497-5p', 'Var', (95, 105))
373700	33179318	However, recent studies have implicated dysregulation of pseudogenes in diverse physiological and pathological processes, including cancer.	('cancer', 'Disease', (132, 138))	('implicated', 'Reg', (29, 39))	('dysregulation', 'Var', (40, 53))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('pseudogenes', 'Protein', (57, 68))	('cancer', 'Disease', 'MESH:D009369', (132, 138))
373702	33179318	5 ,  6 ,  7 ,  8 ,  9  For example, recent research has revealed that the pseudogene KRT19P3 suppresses gastric cancer growth and metastasis through the COPS7A-mediated NF-kappaB pathway.	('suppresses', 'NegReg', (93, 103))	('KRT19P3', 'Gene', '442114', (85, 92))	('COPS7A', 'Gene', '50813', (153, 159))	('NF-kappaB', 'Gene', (169, 178))	('gastric cancer', 'Disease', 'MESH:D013274', (104, 118))	('COPS7A', 'Gene', (153, 159))	('KRT19P3', 'Gene', (85, 92))	('gastric cancer', 'Phenotype', 'HP:0012126', (104, 118))	('NF-kappaB', 'Gene', '4790', (169, 178))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('pseudogene', 'Var', (74, 84))	('gastric cancer', 'Disease', (104, 118))
373707	33179318	10  Moreover, receiver operating characteristic curve analysis revealed that KRT17P3 constitutes a valuable biomarker for differentiating PR patients from PD patients indicating that KRT17P3 may be associated with drug resistance.	('KRT17P3', 'Var', (183, 190))	('PR', 'Gene', '140738', (138, 140))	('PD', 'Disease', 'MESH:D010300', (155, 157))	('drug resistance', 'Phenotype', 'HP:0020174', (214, 229))	('associated', 'Reg', (198, 208))	('drug', 'MPA', (214, 218))	('patients', 'Species', '9606', (158, 166))	('patients', 'Species', '9606', (141, 149))
373710	33179318	TCGA data analysis showed that the expression of KRT17P3 was increased both in lung adenocarcinoma (LUAD) and LUSC tissues, suggesting that the dysregulation of KRT17P3 is common in NSCLC.	('LUSC', 'Phenotype', 'HP:0030359', (110, 114))	('NSCLC', 'Disease', (182, 187))	('LUAD', 'Phenotype', 'HP:0030078', (100, 104))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (79, 98))	('NSCLC', 'Disease', 'MESH:D002289', (182, 187))	('dysregulation', 'Var', (144, 157))	('expression', 'MPA', (35, 45))	('increased', 'PosReg', (61, 70))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (79, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('NSCLC', 'Phenotype', 'HP:0030358', (182, 187))	('KRT17P3', 'Gene', (49, 56))	('lung adenocarcinoma', 'Disease', (79, 98))
373713	33179318	We demonstrate that dysregulation of KRT17P3 confers cisplatin sensitivity in A549 and SK-MES-1 NSCLC cells in vitro and in a mouse model in vivo.	('mouse', 'Species', '10090', (126, 131))	('cisplatin sensitivity', 'MPA', (53, 74))	('NSCLC', 'Disease', (96, 101))	('NSCLC', 'Phenotype', 'HP:0030358', (96, 101))	('KRT17P3', 'Gene', (37, 44))	('NSCLC', 'Disease', 'MESH:D002289', (96, 101))	('dysregulation', 'Var', (20, 33))	('cisplatin', 'Chemical', 'MESH:D002945', (53, 62))	('A549', 'CellLine', 'CVCL:0023', (78, 82))	('SK-MES-1', 'CellLine', 'CVCL:0630', (87, 95))
373750	33179318	Briefly, A549 cells were cotransfected with pKRT17P3 (Genechem) or control plasmid in the presence or absence of pMS2-GFP (Genechem) plasmid and were lysed with RIP lysis buffer.	('pMS2', 'Gene', '5395', (113, 117))	('A549', 'CellLine', 'CVCL:0023', (9, 13))	('pMS2', 'Gene', (113, 117))	('pKRT17P3', 'Var', (44, 52))
373761	33179318	We transfected specific shRNA-KRT17P3 and control shRNA-NC into A549 and SK-MES-1 cells to knock down KRT17P3 expression (Figure 2A).	('knock', 'Var', (91, 96))	('SK-MES-1', 'CellLine', 'CVCL:0630', (73, 81))	('KRT17P3', 'Gene', (102, 109))	('expression', 'MPA', (110, 120))	('A549', 'CellLine', 'CVCL:0023', (64, 68))
373762	33179318	As shown in Figure 2A, shRNA-KRT17P3 decreased the level of KRT17P3, while it did not affect the expression level of keratin 17, which suggested that shRNA-KRT17P3 specifically targeted KRT17P3.	('keratin 17', 'Gene', '3872', (117, 127))	('KRT17P3', 'MPA', (60, 67))	('level', 'MPA', (51, 56))	('keratin 17', 'Gene', (117, 127))	('shRNA-KRT17P3', 'Var', (23, 36))	('decreased', 'NegReg', (37, 46))
373763	33179318	CCK-8 assay results show that shRNA-KRT17P3 cells exhibited significantly increased cisplatin sensitivity (Figure 2B).	('increased', 'PosReg', (74, 83))	('shRNA-KRT17P3', 'Var', (30, 43))	('cisplatin sensitivity', 'MPA', (84, 105))	('cisplatin', 'Chemical', 'MESH:D002945', (84, 93))
373764	33179318	Calculation of the IC50 for shRNA-KRT17P3 and sh-NC in A549 cells (1.518 +- 0.187 muM versus 3.194 +- 0.336 muM; P < .05) and SK-MES-1 cells (6.92 +- 0.203 muM versus 9.936 +- 0.232; P < .05) verified the effect of shRNA-KRT17P3 in increasing cisplatin sensitivity (Figure 2C).	('increasing', 'PosReg', (232, 242))	('cisplatin sensitivity', 'MPA', (243, 264))	('A549', 'CellLine', 'CVCL:0023', (55, 59))	('cisplatin', 'Chemical', 'MESH:D002945', (243, 252))	('SK-MES-1', 'CellLine', 'CVCL:0630', (126, 134))	('shRNA-KRT17P3', 'Var', (215, 228))
373765	33179318	The results show that for both A549 and SK-MES-1 cells, the apoptotic rate of shRNA-KRT17P3-expressing cells with cisplatin treatment was significantly higher than that of shRNA-NC-expressing cells (both P < .01) (Figure 2D).	('shRNA-KRT17P3-expressing', 'Var', (78, 102))	('higher', 'PosReg', (152, 158))	('apoptotic rate', 'CPA', (60, 74))	('cisplatin', 'Chemical', 'MESH:D002945', (114, 123))	('A549', 'CellLine', 'CVCL:0023', (31, 35))	('SK-MES-1', 'CellLine', 'CVCL:0630', (40, 48))
373766	33179318	Interestingly, even in cells without cisplatin treatment, there was a difference between sh-KRT17P3 and sh-NC cells in terms of the fraction of Annexin V-positive cells (Figure 2D).	('Annexin V', 'Gene', '308', (144, 153))	('Annexin V', 'Gene', (144, 153))	('difference', 'Reg', (70, 80))	('cisplatin', 'Chemical', 'MESH:D002945', (37, 46))	('sh-KRT17P3', 'Var', (89, 99))
373768	33179318	Consistent with the results from Figure 2C, KRT17P3 shRNA enhanced cleaved PARP-1 levels in the presence of cisplatin exposure (Figure 2E).	('enhanced', 'PosReg', (58, 66))	('cisplatin', 'Chemical', 'MESH:D002945', (108, 117))	('KRT17P3 shRNA', 'Var', (44, 57))	('PARP-1', 'Gene', (75, 81))	('PARP-1', 'Gene', '142', (75, 81))
373769	33179318	These results suggest that the chemosensitivity of A549 and SK-MES-1 cells is increased by KRT17P3 knockdown, which is also associated with decreased cell proliferation.	('decreased', 'NegReg', (140, 149))	('chemosensitivity', 'CPA', (31, 47))	('cell proliferation', 'CPA', (150, 168))	('KRT17P3', 'Gene', (91, 98))	('A549', 'CellLine', 'CVCL:0023', (51, 55))	('SK-MES-1', 'CellLine', 'CVCL:0630', (60, 68))	('increased', 'PosReg', (78, 87))	('knockdown', 'Var', (99, 108))
373771	33179318	We measured the IC50 and found that KRT17P3-overexpressing cells were more resistant to cisplatin than the control cells (6.139 +- 0.18 muM versus 3.887 +- 0.16 muM for A549, P < .01; 14.44 +- 0.136 muM versus 11.28 +- 0.136 muM for SK-MES-1, P < .05) (Figure 3C).	('KRT17P3-overexpressing', 'Var', (36, 58))	('SK-MES-1', 'CellLine', 'CVCL:0630', (233, 241))	('cisplatin', 'Chemical', 'MESH:D002945', (88, 97))	('A549', 'CellLine', 'CVCL:0023', (169, 173))	('IC50', 'MPA', (16, 20))	('resistant', 'MPA', (75, 84))
373779	33179318	The binding site between KRT17P3 and miRNA-497-5p is shown in Figure 5A.	('binding', 'Interaction', (4, 11))	('5p', 'Chemical', '-', (47, 49))	('miRNA-497-5p', 'Var', (37, 49))	('KRT17P3', 'Gene', (25, 32))
373780	33179318	To confirm the interaction between miRNA-497-5p and KRT17P3, we constructed KRT17P3 luciferase reporter plasmids containing wild-type and mutant-binding sites for miR-497-5p and transfected them into 293T cells together with miR-497-5p mimic or a control mimic.	('KRT17P3', 'Gene', (76, 83))	('mutant-binding', 'Var', (138, 152))	('293T', 'CellLine', 'CVCL:0063', (200, 204))	('miR-497-5p', 'Chemical', '-', (163, 173))	('5p', 'Chemical', '-', (171, 173))	('5p', 'Chemical', '-', (233, 235))	('5p', 'Chemical', '-', (45, 47))	('miR-497-5p', 'Chemical', '-', (225, 235))
373781	33179318	The miR-497-5p mimic reduced the luciferase activity of the wild-type but not the mutant plasmid (Figure 5B).	('reduced', 'NegReg', (21, 28))	('luciferase', 'Enzyme', (33, 43))	('miR-497-5p', 'Chemical', '-', (4, 14))	('miR-497-5p mimic', 'Var', (4, 20))	('activity', 'MPA', (44, 52))
373782	33179318	To further verify the direct interaction between KRT17P3 and miR-497-5p, we overexpressed MS2-GFP-tagged KRT17P3 in A549 cells and performed GFP-RIP.	('MS2', 'Species', '2710868', (90, 93))	('MS2-GFP-tagged', 'Var', (90, 104))	('KRT17P3', 'Gene', (105, 112))	('miR-497-5p', 'Chemical', '-', (61, 71))	('A549', 'CellLine', 'CVCL:0023', (116, 120))
373783	33179318	The results suggest that the MS2-GFP-tagged KRT17P3 was specifically enriched for miR-497-5p (Figure 5C).	('KRT17P3', 'Gene', (44, 51))	('MS2', 'Species', '2710868', (29, 32))	('miR-497-5p', 'Chemical', '-', (82, 92))	('miR-497-5p', 'Var', (82, 92))
373784	33179318	Then we further conducted anti-Ago2 RIP in A549 cells transiently overexpressing miR-497-5p.	('Ago2', 'Gene', '27161', (31, 35))	('Ago2', 'Gene', (31, 35))	('miR-497-5p', 'Chemical', '-', (81, 91))	('miR-497-5p', 'Var', (81, 91))	('A549', 'CellLine', 'CVCL:0023', (43, 47))
373785	33179318	Endogenous KRT17P3 pulldown by AGO2 antibody was specifically enriched in miR-497-5p-transfected cells but not in empty vector-transfected cells (Figure 5D).	('AGO2', 'Gene', '27161', (31, 35))	('miR-497-5p-transfected', 'Var', (74, 96))	('AGO2', 'Gene', (31, 35))	('KRT17P3', 'Gene', (11, 18))	('pulldown', 'PosReg', (19, 27))	('miR-497-5p', 'Chemical', '-', (74, 84))
373786	33179318	These data suggested that miR-497-5p is a miRNA binding partner of KRT17P3.	('miR-497-5p', 'Var', (26, 36))	('KRT17P3', 'Gene', (67, 74))	('miR-497-5p', 'Chemical', '-', (26, 36))
373790	33179318	Consistently, the miR-497-5p inhibitor also decreased cisplatin-induced apoptosis and cleaved PARP-1 in sh-KRT17P3 cells (Figure 6C,D).	('cleaved', 'Var', (86, 93))	('miR-497-5p inhibitor', 'Var', (18, 38))	('PARP-1', 'Gene', (94, 100))	('cisplatin-induced', 'MPA', (54, 71))	('PARP-1', 'Gene', '142', (94, 100))	('cisplatin', 'Chemical', 'MESH:D002945', (54, 63))	('miR-497-5p', 'Chemical', '-', (18, 28))	('decreased', 'NegReg', (44, 53))
373792	33179318	The miR-497-5p mimic also increased cisplatin-induced apoptosis and expression level of cleaved PARP-1 in Lv-KRT17P3 cells (Figure 7C,D).	('PARP-1', 'Gene', (96, 102))	('PARP-1', 'Gene', '142', (96, 102))	('miR-497-5p', 'Chemical', '-', (4, 14))	('miR-497-5p mimic', 'Var', (4, 20))	('expression level', 'MPA', (68, 84))	('increased', 'PosReg', (26, 35))	('cisplatin-induced', 'MPA', (36, 53))	('cisplatin', 'Chemical', 'MESH:D002945', (36, 45))
373795	33179318	Among them, mTOR was predicted to be targeted by miR-497-5p through a recognition sequence in its 3' UTR (Figure 8A).	('miR-497-5p', 'Chemical', '-', (49, 59))	('mTOR', 'Gene', (12, 16))	('mTOR', 'Gene', '2475', (12, 16))	('miR-497-5p', 'Var', (49, 59))
373796	33179318	To verify this prediction, we performed luciferase reporter assays with plasmid containing the predicted wild type or mutant miR-497-5p binding site.	('mutant', 'Var', (118, 124))	('miR-497-5p', 'Chemical', '-', (125, 135))	('miR-497-5p', 'Gene', (125, 135))
373797	33179318	The miR-497-5p mimic significantly weakened the luciferase activity of the mTOR 3'UTR-WT, but not in its mutant plasmid (Figure 8B).	('activity', 'MPA', (59, 67))	('miR-497-5p', 'Chemical', '-', (4, 14))	('miR-497-5p mimic', 'Var', (4, 20))	('weakened', 'NegReg', (35, 43))	('luciferase', 'Enzyme', (48, 58))	('mTOR', 'Gene', (75, 79))	('mTOR', 'Gene', '2475', (75, 79))
373798	33179318	Furthermore, modulation of miR-497-5p expression changed the protein level of mTOR and phosphorylated-mTOR, as detected by Western blotting (Figure 8C).	('changed', 'Reg', (49, 56))	('miR-497-5p expression', 'Var', (27, 48))	('miR-497-5p', 'Chemical', '-', (27, 37))	('mTOR', 'Gene', (78, 82))	('mTOR', 'Gene', '2475', (78, 82))	('mTOR', 'Gene', (102, 106))	('mTOR', 'Gene', '2475', (102, 106))	('modulation', 'Var', (13, 23))
373799	33179318	These data suggest that mTOR is a direct target of miRNA-497-5p.	('5p', 'Chemical', '-', (61, 63))	('miRNA-497-5p', 'Var', (51, 63))	('mTOR', 'Gene', (24, 28))	('mTOR', 'Gene', '2475', (24, 28))
373801	33179318	The results verify that KRT17P3 induces the expression of mTOR and phosphorylated-mTOR, whereas KRT17P3 shRNA represses mTOR and phosphorylated-mTOR expression (Figure 8D).	('expression', 'MPA', (44, 54))	('mTOR', 'Gene', (58, 62))	('represses', 'NegReg', (110, 119))	('induces', 'PosReg', (32, 39))	('mTOR', 'Gene', '2475', (58, 62))	('mTOR', 'Gene', (82, 86))	('mTOR', 'Gene', '2475', (82, 86))	('mTOR', 'Gene', (120, 124))	('KRT17P3', 'Var', (96, 103))	('mTOR', 'Gene', '2475', (120, 124))	('KRT17P3', 'Gene', (24, 31))	('mTOR', 'Gene', (144, 148))	('mTOR', 'Gene', '2475', (144, 148))
373812	33179318	In vitro results demonstrate that KRT17P3 overexpression significantly reduces cell apoptosis and enhances cell viability, whereas KRT17P3 knockdown increases cell apoptosis and decreases cell viability upon cisplatin treatment.	('decreases', 'NegReg', (178, 187))	('KRT17P3 knockdown', 'Var', (131, 148))	('knockdown', 'Var', (139, 148))	('enhances', 'PosReg', (98, 106))	('increases', 'PosReg', (149, 158))	('cell viability', 'CPA', (107, 121))	('cisplatin', 'Chemical', 'MESH:D002945', (208, 217))	('cell apoptosis', 'CPA', (79, 93))	('KRT17P3', 'Gene', (34, 41))	('reduces', 'NegReg', (71, 78))	('cell apoptosis', 'CPA', (159, 173))
373813	33179318	In a xenografted mouse model, we observed that cisplatin, in combination with sh-KRT17P3, inhibits tumor growth, thus verifying that KRT17P3 promotes the resistance of NSCLC cells to cisplatin both in vitro and in vivo.	('tumor', 'Disease', (99, 104))	('mouse', 'Species', '10090', (17, 22))	('cisplatin', 'Chemical', 'MESH:D002945', (183, 192))	('NSCLC', 'Disease', 'MESH:D002289', (168, 173))	('inhibits', 'NegReg', (90, 98))	('KRT17P3', 'Var', (133, 140))	('resistance', 'MPA', (154, 164))	('NSCLC', 'Phenotype', 'HP:0030358', (168, 173))	('cisplatin', 'Chemical', 'MESH:D002945', (47, 56))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('promotes', 'PosReg', (141, 149))	('NSCLC', 'Disease', (168, 173))
373815	33179318	Among them, we focused on miR-497-5p because it is downregulated in multiple tumors and is involved in malignancy-associated processes, including cancer initiation, progression, metastasis, and chemosensitivity.	('miR-497-5p', 'Var', (26, 36))	('involved', 'Reg', (91, 99))	('tumors', 'Disease', (77, 83))	('cancer', 'Disease', (146, 152))	('tumors', 'Disease', 'MESH:D009369', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('malignancy', 'Disease', 'MESH:D009369', (103, 113))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('malignancy', 'Disease', (103, 113))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('downregulated', 'NegReg', (51, 64))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('metastasis', 'CPA', (178, 188))	('miR-497-5p', 'Chemical', '-', (26, 36))
373818	33179318	Conversely, miR-497-5p inhibitor attenuated the cisplatin sensitivity induced by KRT17P3 knockdown.	('cisplatin', 'Chemical', 'MESH:D002945', (48, 57))	('KRT17P3', 'Gene', (81, 88))	('cisplatin sensitivity', 'MPA', (48, 69))	('attenuated', 'NegReg', (33, 43))	('miR-497-5p', 'Chemical', '-', (12, 22))	('knockdown', 'Var', (89, 98))
373822	33179318	These results suggest that KRT17P3 and miR-497-5p directly interact, and that KRT17P3 promotes cisplatin resistance through "sponging" miR-497-5p.	('KRT17P3', 'Var', (78, 85))	('miR-497-5p', 'Chemical', '-', (135, 145))	('cisplatin', 'Chemical', 'MESH:D002945', (95, 104))	('promotes', 'PosReg', (86, 94))	('cisplatin resistance', 'MPA', (95, 115))	('miR-497-5p', 'Chemical', '-', (39, 49))
373824	33179318	Notably, miR-497-5p has been shown to regulate cisplatin chemosensitivity in many types of cancer through multiple targets.	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('miR-497-5p', 'Chemical', '-', (9, 19))	('miR-497-5p', 'Var', (9, 19))	('cisplatin', 'Chemical', 'MESH:D002945', (47, 56))	('regulate', 'Reg', (38, 46))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('cisplatin chemosensitivity', 'MPA', (47, 73))
373825	33179318	12 ,  22  In cervical cancer, miR-497-5p improves cisplatin chemosensitivity by regulating the expression of transketolase 22 , while in ovarian cancer, miR-497-5p increases cisplatin sensitivity by targeting the mTOR/P70S6K signaling pathway.	('cancer', 'Disease', (145, 151))	('increases', 'PosReg', (164, 173))	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('cisplatin sensitivity', 'MPA', (174, 195))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('miR-497-5p', 'Var', (153, 163))	('miR-497-5p', 'Chemical', '-', (30, 40))	('ovarian cancer', 'Disease', 'MESH:D010051', (137, 151))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('cisplatin', 'Chemical', 'MESH:D002945', (174, 183))	('expression', 'MPA', (95, 105))	('P70S6K', 'Gene', (218, 224))	('cancer', 'Disease', (22, 28))	('targeting', 'Reg', (199, 208))	('improves', 'PosReg', (41, 49))	('miR-497-5p', 'Chemical', '-', (153, 163))	('ovarian cancer', 'Disease', (137, 151))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('cisplatin chemosensitivity', 'MPA', (50, 76))	('P70S6K', 'Gene', '6198', (218, 224))	('mTOR', 'Gene', (213, 217))	('cervical', 'Disease', (13, 21))	('miR-497-5p', 'Var', (30, 40))	('ovarian cancer', 'Phenotype', 'HP:0100615', (137, 151))	('cisplatin', 'Chemical', 'MESH:D002945', (50, 59))	('regulating', 'Reg', (80, 90))	('mTOR', 'Gene', '2475', (213, 217))
373826	33179318	12  In the current study, we demonstrate that mTOR is a downstream target of miR-497-5p.	('mTOR', 'Gene', '2475', (46, 50))	('miR-497-5p', 'Var', (77, 87))	('mTOR', 'Gene', (46, 50))	('miR-497-5p', 'Chemical', '-', (77, 87))
373827	33179318	Treatment with miR-497-5p mimic markedly reduced mTOR expression and improved cisplatin chemosensitivity.	('reduced', 'NegReg', (41, 48))	('mTOR', 'Gene', (49, 53))	('mTOR', 'Gene', '2475', (49, 53))	('improved', 'PosReg', (69, 77))	('miR-497-5p', 'Chemical', '-', (15, 25))	('cisplatin', 'Chemical', 'MESH:D002945', (78, 87))	('miR-497-5p mimic', 'Var', (15, 31))	('cisplatin chemosensitivity', 'MPA', (78, 104))
373828	33179318	Furthermore, luciferase assays confirmed bioinformatics predictions that the mTOR 3'-UTR is a putative target of miR-497-5p.	('mTOR', 'Gene', '2475', (77, 81))	('miR-497-5p', 'Var', (113, 123))	('mTOR', 'Gene', (77, 81))	('miR-497-5p', 'Chemical', '-', (113, 123))
373829	33179318	In addition, Western blotting assays demonstrated that miR-497-5p expression suppresses protein levels of mTOR.	('suppresses', 'NegReg', (77, 87))	('protein levels', 'MPA', (88, 102))	('miR-497-5p', 'Chemical', '-', (55, 65))	('miR-497-5p expression', 'Var', (55, 76))	('mTOR', 'Gene', (106, 110))	('mTOR', 'Gene', '2475', (106, 110))
373832	33179318	Overexpression of mTOR has been found in various types of cancer and correlates with tumor progression and poor prognosis.	('tumor', 'Disease', (85, 90))	('mTOR', 'Gene', (18, 22))	('mTOR', 'Gene', '2475', (18, 22))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('found', 'Reg', (32, 37))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('Overexpression', 'Var', (0, 14))	('cancer', 'Disease', (58, 64))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))
373835	33179318	26 ,  27  Furthermore, the mTOR inhibitor CCI-779 is able to restore cisplatin sensitivity in small-cell lung cancer cell lines that are selected for cisplatin resistance, as well as cell lines derived from patients who failed cisplatin.	('lung cancer', 'Phenotype', 'HP:0100526', (105, 116))	('patients', 'Species', '9606', (207, 215))	('cisplatin', 'Chemical', 'MESH:D002945', (227, 236))	('cisplatin', 'Chemical', 'MESH:D002945', (69, 78))	('restore', 'PosReg', (61, 68))	('mTOR', 'Gene', (27, 31))	('CCI-779', 'Chemical', 'MESH:C401859', (42, 49))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('cisplatin sensitivity', 'MPA', (69, 90))	('small-cell lung cancer', 'Disease', 'MESH:D055752', (94, 116))	('CCI-779', 'Var', (42, 49))	('cisplatin', 'Chemical', 'MESH:D002945', (150, 159))	('small-cell lung cancer', 'Disease', (94, 116))	('mTOR', 'Gene', '2475', (27, 31))
373838	33179318	In conclusion, we show for the first time that KRT17P3 is involved in cisplatin resistance in NSCLC cells.	('NSCLC', 'Phenotype', 'HP:0030358', (94, 99))	('cisplatin', 'Chemical', 'MESH:D002945', (70, 79))	('involved', 'Reg', (58, 66))	('NSCLC', 'Disease', (94, 99))	('KRT17P3', 'Var', (47, 54))	('cisplatin resistance', 'MPA', (70, 90))	('NSCLC', 'Disease', 'MESH:D002289', (94, 99))
373839	33179318	Furthermore, miR-497-5p mediates cisplatin resistance exerted by KRT17P3, which involves the modulation of mTOR.	('mediates', 'Reg', (24, 32))	('miR-497-5p', 'Chemical', '-', (13, 23))	('mTOR', 'Gene', (107, 111))	('miR-497-5p', 'Var', (13, 23))	('mTOR', 'Gene', '2475', (107, 111))	('cisplatin', 'Chemical', 'MESH:D002945', (33, 42))	('modulation', 'MPA', (93, 103))	('KRT17P3', 'Gene', (65, 72))	('cisplatin resistance', 'MPA', (33, 53))
373919	29731977	Interestingly, the FH gene has not been described as an anticancer target but as a tumor suppressor gene whose loss of function due to germ line mutations results in hereditary leiomyomatosis and renal cell cancer (HLRCC) due to the accumulation of fumarate and succinate.	('tumor', 'Disease', (83, 88))	('mutations', 'Var', (145, 154))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('HLRCC', 'Disease', (215, 220))	('succinate', 'Chemical', 'MESH:D019802', (262, 271))	('fumarate', 'MPA', (249, 257))	('accumulation', 'PosReg', (233, 245))	('cancer', 'Disease', (207, 213))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('HLRCC', 'Disease', 'MESH:C535516', (215, 220))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('hereditary leiomyomatosis and renal cell cancer', 'Disease', 'MESH:C535516', (166, 213))	('renal cell cancer', 'Phenotype', 'HP:0005584', (196, 213))	('loss of function', 'NegReg', (111, 127))	('FH', 'Gene', '2271', (19, 21))	('fumarate', 'Chemical', 'MESH:D005650', (249, 257))	('cancer', 'Disease', 'MESH:D009369', (207, 213))	('results', 'Reg', (155, 162))	('cancer', 'Disease', (60, 66))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
373920	29731977	Renal cancers with non-functional FH genes have been shown to be more dependent on glycolysis and particularly sensitive to its inhibition, which is fully consistent with our predictions.	('glycolysis', 'MPA', (83, 93))	('inhibition', 'NegReg', (128, 138))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('Renal cancers', 'Disease', (0, 13))	('dependent', 'MPA', (70, 79))	('Renal cancers', 'Disease', 'MESH:D007680', (0, 13))	('cancers', 'Phenotype', 'HP:0002664', (6, 13))	('non-functional', 'Var', (19, 33))	('FH', 'Gene', '2271', (34, 36))
373932	29731977	High expression of AQP5 has been linked to higher proliferation and metastasis in lung cancer.	('lung cancer', 'Phenotype', 'HP:0100526', (82, 93))	('High', 'Var', (0, 4))	('higher', 'PosReg', (43, 49))	('metastasis in lung cancer', 'Disease', (68, 93))	('AQP5', 'Gene', '362', (19, 23))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('metastasis in lung cancer', 'Disease', 'MESH:D009362', (68, 93))	('AQP5', 'Gene', (19, 23))
373954	24390350	To explore the feasibility of creating a comprehensive catalog of cancer genes, we analyzed somatic point mutations in exome sequence from 4,742 tumor-normal pairs across 21 cancer types.	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('point mutations', 'Var', (100, 115))	('cancer', 'Disease', (174, 180))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('tumor', 'Disease', (145, 150))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('cancer', 'Disease', (66, 72))
373959	24390350	It is now possible to use genomic analysis identify cancer genes in an unbiased fashion, based on the presence of somatic mutations at a rate significantly higher than the expected background level.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('higher', 'PosReg', (156, 162))	('mutations', 'Var', (122, 131))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))
373963	24390350	For example, a study of 183 lung adenocarcinomas found that 15% of patients lacked even a single mutation affecting any of the ten known hallmarks of cancer, and 38% had three or fewer such mutations.	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (28, 48))	('patients', 'Species', '9606', (67, 75))	('hallmarks of cancer', 'Disease', 'MESH:D009369', (137, 156))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (28, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (38, 47))	('lacked', 'NegReg', (76, 82))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (28, 47))	('hallmarks of cancer', 'Disease', (137, 156))	('mutation', 'Var', (97, 105))	('lung adenocarcinomas', 'Disease', (28, 48))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
373964	24390350	In this paper, we analyzed somatic point mutations (substitutions and small insertion/deletions) in nearly 5000 TN pairs across 21 tumor types.	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('tumor', 'Disease', (131, 136))	('substitutions', 'Var', (52, 65))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))
373973	24390350	The dataset consists of 3,078,483 somatic single nucleotide variations (SSNVs), 77,270 small insertions and deletions (SINDELs), and 29,837 somatic di-/tri-/oligonucleotide variations (DNVs/TNVs/ONVs), with an average of 672 per TN pair.	('SINDELs', 'Disease', (119, 126))	('insertions', 'Var', (93, 103))	('deletions', 'Var', (108, 117))	('single nucleotide variations', 'Var', (42, 70))	('SINDELs', 'Disease', 'None', (119, 126))	('di-/tri-/oligonucleotide variations', 'Var', (148, 183))
373977	24390350	We analyzed these data to identify candidate cancer genes - by which we shall mean genes harboring somatic point mutations (that is, substitutions and small insertion/deletions) at a statistically significant rate or pattern in cancer.	('cancer', 'Disease', (228, 234))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('substitutions', 'Var', (133, 146))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('cancer', 'Disease', (45, 51))	('cancer', 'Disease', 'MESH:D009369', (228, 234))
373980	24390350	The mere presence of somatic mutations is insufficient to implicate a gene in cancer, inasmuch as 93% of genes carried mutations in at least five samples.	('cancer', 'Disease', (78, 84))	('insufficient', 'Disease', 'MESH:D000309', (42, 54))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('insufficient', 'Disease', (42, 54))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('mutations', 'Var', (119, 128))
374009	24390350	The current version (v65) contains 130 cancer genes driven by somatic point mutations (as well as additional genes mutated by other mechanisms), of which 82 are associated with one or more of the 21 tumor types studied here.	('tumor', 'Disease', (199, 204))	('cancer', 'Disease', (39, 45))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('driven by', 'Reg', (52, 61))	('point mutations', 'Var', (70, 85))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))
374018	24390350	We briefly describe these 33 genes not previously been reported as significantly mutated in cancer: Four genes encode anti-proliferative proteins, in which loss-of-function mutations would be expected to contribute to oncogenesis.	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('mutations', 'Var', (173, 182))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('loss-of-function', 'NegReg', (156, 172))
374019	24390350	A striking example is ARHGAP35 (previously called GRLF1), which encodes a Rho GTPase activating protein, for which only a single tumor type reaches statistical significance on its own, but which gives a strong signal (q = 2 x 10-12) in the combined set of ~5000 tumors (83 missense, 38 nonsense, 16 frameshift and 2 splice site).	('tumor', 'Phenotype', 'HP:0002664', (262, 267))	('tumor', 'Disease', (262, 267))	('ARHGAP35', 'Gene', '2909', (22, 30))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('frameshift and', 'Var', (299, 313))	('ARHGAP35', 'Gene', (22, 30))	('tumors', 'Disease', (262, 268))	('tumors', 'Phenotype', 'HP:0002664', (262, 268))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('GRLF1', 'Gene', (50, 55))	('tumors', 'Disease', 'MESH:D009369', (262, 268))	('tumor', 'Disease', 'MESH:D009369', (262, 267))	('tumor', 'Disease', (129, 134))	('GRLF1', 'Gene', '2909', (50, 55))	('missense', 'Var', (273, 281))	('nonsense', 'Var', (286, 294))
374021	24390350	Other examples are MGA, whose product competes with Myc for binding to Max and which resides in small focal deletions (containing <=4 genes) in ovarian and various epithelial cancers; the interferon regulatory factor IRF6, which is known to have tumor suppressive roles in keratinocytes and is mutated in head and neck squamous cancer; and the delta/notch-like EGF-repeat gene DNER.	('DNER', 'Gene', (377, 381))	('head and neck squamous cancer', 'Disease', 'MESH:D006258', (305, 334))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('Myc', 'Gene', '4609', (52, 55))	('deletions', 'Var', (108, 117))	('cancer', 'Phenotype', 'HP:0002664', (328, 334))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('cancers', 'Phenotype', 'HP:0002664', (175, 182))	('MGA', 'Disease', (19, 22))	('Myc', 'Gene', (52, 55))	('IRF6', 'Gene', '3664', (217, 221))	('tumor', 'Disease', (246, 251))	('epithelial cancers', 'Disease', (164, 182))	('DNER', 'Gene', '92737', (377, 381))	('IRF6', 'Gene', (217, 221))	('ovarian', 'Disease', (144, 151))	('epithelial cancers', 'Disease', 'MESH:D000077216', (164, 182))	('tumor', 'Disease', 'MESH:D009369', (246, 251))	('ovarian', 'Disease', 'MESH:D010051', (144, 151))	('squamous cancer', 'Phenotype', 'HP:0002860', (319, 334))	('head and neck squamous cancer', 'Phenotype', 'HP:0012288', (305, 334))
374023	24390350	Notably RHEB and RHOA encode small GTPases, in which recurrent mutations affect the 9-amino-acid effector domain (ED).	('mutations', 'Var', (63, 72))	('RHEB', 'Gene', '6009', (8, 12))	('9-amino-acid effector domain', 'MPA', (84, 112))	('affect', 'Reg', (73, 79))	('RHOA', 'Gene', '387', (17, 21))	('RHEB', 'Gene', (8, 12))	('RHOA', 'Gene', (17, 21))
374024	24390350	For RHEB, five tumors (2 endometrial and 3 kidney clear cell cancer) carry Y35N mutations, which alter the first amino acid of the ED.	('tumors', 'Disease', (15, 21))	('clear cell cancer', 'Phenotype', 'HP:0006770', (50, 67))	('Y35N mutations', 'Var', (75, 89))	('kidney clear cell cancer', 'Disease', 'MESH:D008649', (43, 67))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('RHEB', 'Gene', (4, 8))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('Y35N', 'Mutation', 'rs1057519949', (75, 79))	('RHEB', 'Gene', '6009', (4, 8))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('kidney clear cell cancer', 'Disease', (43, 67))	('tumors', 'Disease', 'MESH:D009369', (15, 21))
374025	24390350	For RHOA, six tumors (all head and neck) carry mutations affecting the ED: these include five E40Q mutations and a single Y42I mutation, which alter the seventh and ninth amino acids, respectively, of the ED.	('Y42I', 'Var', (122, 126))	('E40Q mutations', 'Var', (94, 108))	('ED', 'Gene', (71, 73))	('tumors', 'Disease', (14, 20))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('alter', 'Reg', (143, 148))	('RHOA', 'Gene', '387', (4, 8))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('E40Q', 'Mutation', 'rs1057519951', (94, 98))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('RHOA', 'Gene', (4, 8))	('Y42I', 'Mutation', 'p.Y42I', (122, 126))
374026	24390350	SOS1 encodes a guanine nucleotide exchange factor that promotes activation of Ras, in which gain-of-function mutations might contribute to oncogenesis.	('oncogenesis', 'CPA', (139, 150))	('Ras', 'Protein', (78, 81))	('promotes activation', 'PosReg', (55, 74))	('gain-of-function', 'PosReg', (92, 108))	('SOS1', 'Gene', (0, 4))	('mutations', 'Var', (109, 118))	('SOS1', 'Gene', '6654', (0, 4))
374027	24390350	Consistent with this notion, SOS1 carries N233Y mutations in six tumors (four endometrial and two lung adenocarcinoma) and R552 alterations in three tumors (two endometrial and one AML).	('N233Y', 'Var', (42, 47))	('SOS1', 'Gene', (29, 33))	('R552 alterations', 'Var', (123, 139))	('N233Y', 'Mutation', 'rs1057519963', (42, 47))	('tumors', 'Disease', (65, 71))	('tumors', 'Phenotype', 'HP:0002664', (149, 155))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('tumors', 'Disease', (149, 155))	('lung adenocarcinoma', 'Disease', (98, 117))	('SOS1', 'Gene', '6654', (29, 33))	('endometrial', 'Disease', (78, 89))	('tumors', 'Disease', 'MESH:D009369', (149, 155))	('AML', 'Disease', 'MESH:D015470', (181, 184))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (98, 117))	('AML', 'Disease', (181, 184))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (98, 117))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))
374028	24390350	Strikingly, the same R522 alterations in SOS1 have been found as germline mutations causing Noonan syndrome and been shown to cause gain-of-function resulting in Ras activation.	('Noonan syndrome', 'Disease', (92, 107))	('activation', 'PosReg', (166, 176))	('Noonan syndrome', 'Disease', 'MESH:D009634', (92, 107))	('SOS1', 'Gene', '6654', (41, 45))	('R522 alterations', 'Var', (21, 37))	('SOS1', 'Gene', (41, 45))	('Ras', 'Protein', (162, 165))	('gain-of-function', 'PosReg', (132, 148))
374030	24390350	Myocardin (MYOCD), which encodes a transcriptional regulator involved in differentiation and cell migration, has a cluster of 9 mutations at amino acids 750-770 (7 in melanoma, 1 head and neck, 1 lung adenocarcinoma) with a hotspot of four at S763.	('lung adenocarcinoma', 'Disease', (196, 215))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (196, 215))	('carcinoma', 'Phenotype', 'HP:0030731', (206, 215))	('MYOCD', 'Gene', (11, 16))	('mutations', 'Var', (128, 137))	('MYOCD', 'Gene', '93649', (11, 16))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (196, 215))	('melanoma', 'Phenotype', 'HP:0002861', (167, 175))	('melanoma', 'Disease', (167, 175))	('Myocardin', 'Gene', (0, 9))	('melanoma', 'Disease', 'MESH:D008545', (167, 175))	('Myocardin', 'Gene', '93649', (0, 9))
374032	24390350	These genes encode alpha kinase 2 (ALPK2); Bcl2-associated factor 1 (BCLAF1); a MAP kinase (MAP4K3) reported to post-transcriptionally regulate the apoptotic proteins Puma, Bad and Bim; a zinc-finger protein (ZNF750, which harbors many early frameshift and nonsense mutations in head and neck cancer and is the only known gene residing in a small current focal deletion in head and neck and lung squamous cancers); and Tumor Necrosis Factor (TNF, which harbors mutations in five diffuse large B-cell lymphomas that are tightly clustered in the region encoding the membrane/cytoplasmic domain, rather than the soluble Tnf protein).	('squamous cancer', 'Phenotype', 'HP:0002860', (396, 411))	('nonsense mutations', 'Var', (257, 275))	('Tumor', 'Phenotype', 'HP:0002664', (419, 424))	('head and neck cancer', 'Phenotype', 'HP:0012288', (279, 299))	('lung squamous cancers', 'Disease', 'MESH:D008175', (391, 412))	('frameshift', 'Var', (242, 252))	('lung squamous cancers', 'Disease', (391, 412))	('Tumor Necrosis Factor', 'Disease', (419, 440))	('lymphomas', 'Disease', (500, 509))	('lymphomas', 'Disease', 'MESH:D008223', (500, 509))	('Tumor Necrosis Factor', 'Disease', 'MESH:C536657', (419, 440))	('cancers', 'Phenotype', 'HP:0002664', (405, 412))	('cancer', 'Phenotype', 'HP:0002664', (293, 299))	('head and neck cancer', 'Disease', 'MESH:D006258', (279, 299))	('cancer', 'Phenotype', 'HP:0002664', (405, 411))	('lung squamous cancer', 'Phenotype', 'HP:0030359', (391, 411))
374033	24390350	These include CEP76 (encoding a centrosomal protein, whose depletion drives aberrant amplification of centrioles), which harbors early nonsense mutations in many tumor types and resides in a focal deletion peak in acute myeloid leukemia; RAD21 (encoding a protein crucial for chromosome segregation and double-strand break repair), which is mutated at significant rates in acute myeloid leukemia and also harbors mutations in other tumor types; the p53-binding protein TP53BP1 (encoding a check-point protein that binds to double-strand breaks), which does not reach significance in any single tumor type, but is significant in the combined data set due to truncating mutations in many tumor types; TPX2 (encoding a protein involved in mitotic spindle formation, whose depletion leads to aneuploidy); and ZRANB3 (encoding a translocase that helps to rescue stalled replication forks).	('CEP76', 'Gene', '79959', (14, 19))	('acute myeloid leukemia', 'Disease', (214, 236))	('tumor', 'Disease', (162, 167))	('mutations', 'Var', (668, 677))	('TP53BP1', 'Gene', '7158', (469, 476))	('ZRANB3', 'Gene', '84083', (805, 811))	('acute myeloid leukemia', 'Disease', (373, 395))	('tumor', 'Disease', (686, 691))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('tumor', 'Phenotype', 'HP:0002664', (594, 599))	('leads to', 'Reg', (779, 787))	('leukemia', 'Phenotype', 'HP:0001909', (387, 395))	('TP53BP1', 'Gene', (469, 476))	('RAD21', 'Gene', (238, 243))	('tumor', 'Disease', (432, 437))	('aneuploidy', 'Disease', (788, 798))	('TPX2', 'Gene', (699, 703))	('tumor', 'Disease', 'MESH:D009369', (686, 691))	('TPX2', 'Gene', '22974', (699, 703))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (220, 236))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (214, 236))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (379, 395))	('CEP76', 'Gene', (14, 19))	('tumor', 'Disease', 'MESH:D009369', (432, 437))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (373, 395))	('leukemia', 'Phenotype', 'HP:0001909', (228, 236))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (214, 236))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('RAD21', 'Gene', '5885', (238, 243))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (373, 395))	('ZRANB3', 'Gene', (805, 811))	('tumor', 'Phenotype', 'HP:0002664', (686, 691))	('truncating mutations', 'Var', (657, 677))	('tumor', 'Phenotype', 'HP:0002664', (432, 437))	('tumor', 'Disease', (594, 599))	('tumor', 'Disease', 'MESH:D009369', (594, 599))	('aneuploidy', 'Disease', 'MESH:D000782', (788, 798))
374036	24390350	MBD1 encodes a protein that binds methylated-CpG and is required for SETDB1 activity; it contains 5 mutations in endometrial cancer in the N-terminal methyl binding domain.	('mutations', 'Var', (100, 109))	('SETDB1', 'Gene', '9869', (69, 75))	('MBD1', 'Gene', '4152', (0, 4))	('endometrial cancer', 'Phenotype', 'HP:0012114', (113, 131))	('endometrial cancer', 'Disease', 'MESH:D016889', (113, 131))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('SETDB1', 'Gene', (69, 75))	('endometrial cancer', 'Disease', (113, 131))	('MBD1', 'Gene', (0, 4))
374038	24390350	EZH1 shows a similar pattern of mutations as seen in the well-established cancer gene EZH2, with truncating mutations along the gene and a hotspot of mutations within the SET domain.	('EZH1', 'Gene', (0, 4))	('truncating', 'MPA', (97, 107))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Disease', (74, 80))	('EZH2', 'Gene', '2146', (86, 90))	('mutations', 'Var', (32, 41))	('EZH1', 'Gene', '2145', (0, 4))	('mutations', 'Var', (150, 159))	('EZH2', 'Gene', (86, 90))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
374040	24390350	The histone protein HIST1H4E is mutated in multiple tumor types; two other histone genes, HIST1H1E and HIST1H3B, have previously been reported as significantly mutated in CLL and DLBCL, respectively.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('HIST1H4E', 'Gene', (20, 28))	('mutated', 'Var', (160, 167))	('DLBCL', 'Disease', (179, 184))	('multiple tumor', 'Disease', (43, 57))	('HIST1H3B', 'Gene', (103, 111))	('multiple tumor', 'Disease', 'MESH:D009369', (43, 57))	('HIST1H3B', 'Gene', '8358', (103, 111))	('HIST1H4E', 'Gene', '8367', (20, 28))	('HIST1H1E', 'Gene', (90, 98))	('HIST1H1E', 'Gene', '3008', (90, 98))	('CLL', 'Disease', (171, 174))
374042	24390350	These include the major histocompatibility protein HLA-B (loss of the HLA-A gene has been implicated in lung cancer), TAP1 (which processes intracellular peptides for presentation to the immune system) and CD1D (which presents lipid antigens to natural killer cells), the last of which shows a cluster of truncating mutations at the internalization domain that are likely to abolish antigen presentation function.	('lung cancer', 'Disease', 'MESH:D008175', (104, 115))	('implicated', 'Reg', (90, 100))	('truncating mutations', 'Var', (305, 325))	('loss', 'NegReg', (58, 62))	('CD1D', 'Gene', '912', (206, 210))	('abolish', 'NegReg', (375, 382))	('HLA-B', 'Gene', '3106', (51, 56))	('HLA-B', 'Gene', (51, 56))	('lipid', 'Chemical', 'MESH:D008055', (227, 232))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('CD1D', 'Gene', (206, 210))	('lung cancer', 'Disease', (104, 115))	('HLA-A', 'Gene', '3105', (70, 75))	('antigen presentation function', 'MPA', (383, 412))	('lung cancer', 'Phenotype', 'HP:0100526', (104, 115))	('TAP1', 'Gene', (118, 122))	('HLA-A', 'Gene', (70, 75))	('TAP1', 'Gene', '6890', (118, 122))
374043	24390350	PCBP1, whose protein product blocks translation of certain mRNAs by binding to Poly-C regions of mRNAs, carries two mutations in each of two nearby leucines (Leu100 and Leu102) that mediate dimerization of the protein's KH domains.	('translation', 'MPA', (36, 47))	('Leu100', 'Var', (158, 164))	('Leu102', 'Var', (169, 175))	('PCBP1', 'Gene', (0, 5))	('PCBP1', 'Gene', '5093', (0, 5))
374044	24390350	We speculate that disruption of PCBP1 leads to increased translation of one or more pro-oncogenic mRNAs.	('PCBP1', 'Gene', (32, 37))	('PCBP1', 'Gene', '5093', (32, 37))	('increased', 'PosReg', (47, 56))	('translation of one', 'MPA', (57, 75))	('disruption', 'Var', (18, 28))
374045	24390350	QKI encodes an RNA-binding protein that regulates pre-mRNA splicing, including the known cancer gene CDKN1B; the gene harbors C-terminal truncating mutations in several tumor types that likely remove the nuclear localization signal; and the gene resides in a recurrent deletion peak in glioblastoma and ovarian cancer.	('cancer', 'Disease', (311, 317))	('glioblastoma and ovarian cancer', 'Disease', 'MESH:D005909', (286, 317))	('cancer', 'Disease', (89, 95))	('CDKN1B', 'Gene', (101, 107))	('cancer', 'Phenotype', 'HP:0002664', (311, 317))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('tumor', 'Disease', (169, 174))	('mutations', 'Var', (148, 157))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('CDKN1B', 'Gene', '1027', (101, 107))	('cancer', 'Disease', 'MESH:D009369', (311, 317))	('QKI', 'Gene', (0, 3))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('regulates', 'Reg', (40, 49))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('ovarian cancer', 'Phenotype', 'HP:0100615', (303, 317))	('pre-mRNA splicing', 'MPA', (50, 67))	('remove', 'NegReg', (193, 199))	('nuclear localization signal', 'MPA', (204, 231))	('glioblastoma', 'Phenotype', 'HP:0012174', (286, 298))
374046	24390350	Finally, the ribosomal protein gene RPL5 contains early truncating mutations in glioblastoma and other tumor types and resides in a focally deleted region in glioblastoma; heterozygous loss of certain ribosomal proteins has been reported to contribute to cancer.	('heterozygous loss', 'Var', (172, 189))	('cancer', 'Phenotype', 'HP:0002664', (255, 261))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('glioblastoma', 'Phenotype', 'HP:0012174', (80, 92))	('glioblastoma', 'Phenotype', 'HP:0012174', (158, 170))	('RPL5', 'Gene', (36, 40))	('tumor', 'Disease', (103, 108))	('cancer', 'Disease', 'MESH:D009369', (255, 261))	('glioblastoma', 'Disease', (158, 170))	('glioblastoma', 'Disease', 'MESH:D005909', (158, 170))	('RPL5', 'Gene', '6125', (36, 40))	('cancer', 'Disease', (255, 261))	('contribute', 'Reg', (241, 251))	('glioblastoma', 'Disease', (80, 92))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('glioblastoma', 'Disease', 'MESH:D005909', (80, 92))
374048	24390350	It encodes a ubiquitin E3 ligase and harbors recurrent mutations at N93 (4 tumors) and D289 (3 tumors).	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('N93', 'Gene', (68, 71))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('D289', 'Var', (87, 91))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumors', 'Disease', (75, 81))	('tumors', 'Disease', (95, 101))
374049	24390350	Mutations in this gene may promote cancer by altering the substrate specificity of the E3 ligase in a manner that leads to accumulation of an oncogenic protein.	('accumulation', 'PosReg', (123, 135))	('oncogenic protein', 'MPA', (142, 159))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('altering', 'Reg', (45, 53))	('promote', 'PosReg', (27, 34))	('Mutations', 'Var', (0, 9))	('substrate specificity', 'MPA', (58, 79))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('cancer', 'Disease', (35, 41))
374066	24390350	Notably, ARHGAP35 appears in the Cancer5000 set because it is significantly mutated in endometrial cancer (although not discussed in the recent TCGA publication), but our RHT analysis also finds it to be significant in lung adenocarcinoma, lung squamous cell carcinoma, kidney clear cell, and head and neck cancer.	('endometrial cancer', 'Disease', (87, 105))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (240, 268))	('kidney clear cell', 'Disease', (270, 287))	('ARHGAP35', 'Gene', (9, 17))	('endometrial cancer', 'Disease', 'MESH:D016889', (87, 105))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (219, 238))	('head and neck cancer', 'Disease', 'MESH:D006258', (293, 313))	('ARHGAP35', 'Gene', '2909', (9, 17))	('Cancer', 'Phenotype', 'HP:0002664', (33, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (229, 238))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (245, 268))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (240, 268))	('lung squamous cell carcinoma', 'Disease', (240, 268))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (219, 238))	('Cancer', 'Disease', (33, 39))	('significant', 'Reg', (204, 215))	('carcinoma', 'Phenotype', 'HP:0030731', (259, 268))	('mutated', 'Var', (76, 83))	('Cancer', 'Disease', 'MESH:D009369', (33, 39))	('head and neck cancer', 'Phenotype', 'HP:0012288', (293, 313))	('cancer', 'Phenotype', 'HP:0002664', (307, 313))	('endometrial cancer', 'Phenotype', 'HP:0012114', (87, 105))	('lung adenocarcinoma', 'Disease', (219, 238))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
374073	24390350	Figure 5 shows that the current collection lacks the desired power to detect genes mutated at 5% above the background rate for 17 of the 21 tumor types and even at 10% for 7 of the tumor types.	('mutated', 'Var', (83, 90))	('tumor', 'Disease', (181, 186))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('tumor', 'Disease', (140, 145))
374075	24390350	Creating a reasonably comprehensive catalog of candidate cancer genes mutated in >= 2% of patients will require between ~650 samples (for tumors with ~0.5 mutations/Mb, such as neuroblastoma) to ~5300 samples (for melanoma, with 12.9 mutations/Mb).	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('neuroblastoma', 'Disease', 'MESH:D009447', (177, 190))	('cancer', 'Disease', (57, 63))	('melanoma', 'Phenotype', 'HP:0002861', (214, 222))	('melanoma', 'Disease', (214, 222))	('neuroblastoma', 'Disease', (177, 190))	('melanoma', 'Disease', 'MESH:D008545', (214, 222))	('tumors', 'Disease', (138, 144))	('tumors', 'Disease', 'MESH:D009369', (138, 144))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('neuroblastoma', 'Phenotype', 'HP:0003006', (177, 190))	('mutations/Mb', 'Var', (155, 167))	('patients', 'Species', '9606', (90, 98))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
374095	24390350	For tumor types that were originally aligned to builld hg18, liftOver (<http://genome.ucsc.edu/cgi-bin/hgLiftOver>) was used to convert the coordinates of each mutation to build hg19.	('tumor', 'Disease', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('mutation', 'Var', (160, 168))	('tumor', 'Disease', 'MESH:D009369', (4, 9))
374098	24390350	In order to remove common sequencing artifacts or residual germline variation, each mutation in the combined MAF file was subjected to a "Panel of Normals" filtering process using a panel of over 4000 BAM files from normal samples.	('MAF', 'Gene', '4094', (109, 112))	('MAF', 'Gene', (109, 112))	('mutation', 'Var', (84, 92))
374101	24390350	We used the following context categories: transitions at CpG dinucleotides, transitions at other C:G basepairs, transversions at C:G basepairs, mutations at A:T basepairs, and indels.	('indels', 'Var', (176, 182))	('CpG dinucleotides', 'Chemical', 'MESH:C015772', (57, 74))	('transversions', 'Var', (112, 125))	('mutations', 'Var', (144, 153))
374106	24390350	Genes with q<=0.1 in any tumor-type analysis or in the combined-cohort analysis were declared to be a member of the Cancer5000 list of significant cancer genes.	('Cancer', 'Disease', (116, 122))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('Cancer', 'Disease', 'MESH:D009369', (116, 122))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('Cancer', 'Phenotype', 'HP:0002664', (116, 122))	('tumor', 'Disease', (25, 30))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('cancer', 'Disease', (147, 153))	('q<=0.1', 'Var', (11, 17))
374185	26091477	A subsequent immunohistochemical examination of 186 RCCs obtained in our patient series resulted in a strong diffuse positivity of BSND and ATP6V1G3 proteins (both of which are involved in the regulation of membrane transport) in all the chromophobe RCC specimens (23/23 cases, 100%) but not in the clear cell RCC specimens (0/153 cases, 0%) or the papillary RCC specimens (0/10 cases, 0%).	('BSND', 'Gene', (131, 135))	('RCC', 'Phenotype', 'HP:0005584', (52, 55))	('papillary RCC', 'Disease', 'MESH:C538614', (349, 362))	('papillary RCC', 'Disease', (349, 362))	('RCC', 'Phenotype', 'HP:0005584', (310, 313))	('chromophobe RCC', 'Disease', 'MESH:C538614', (238, 253))	('ATP6V1G3', 'Var', (140, 148))	('RCC', 'Phenotype', 'HP:0005584', (359, 362))	('RCC', 'Phenotype', 'HP:0005584', (250, 253))	('proteins', 'Protein', (149, 157))	('patient', 'Species', '9606', (73, 80))	('chromophobe RCC', 'Disease', (238, 253))
374186	26091477	BSND and ATP6V1G3 protein expressions were also detected in renal oncocytoma (13/14 cases, 92.9%) and in the distal nephron, including the collecting duct, in the normal kidney.	('detected', 'Reg', (48, 56))	('protein', 'Protein', (18, 25))	('renal oncocytoma', 'Disease', 'MESH:C537750', (60, 76))	('renal oncocytoma', 'Disease', (60, 76))	('renal oncocytoma', 'Phenotype', 'HP:0011798', (60, 76))	('BSND', 'Gene', (0, 4))	('ATP6V1G3', 'Var', (9, 17))
374188	26091477	These results suggest that BSND and ATP6V1G3 are excellent novel immunohistochemical markers for differentiating between chromophobe RCC and other subtypes of RCC, including clear cell and papillary RCCs.	('chromophobe RCC', 'Disease', 'MESH:C538614', (121, 136))	('papillary RCC', 'Disease', 'MESH:C538614', (189, 202))	('papillary RCC', 'Disease', (189, 202))	('clear cell', 'Disease', (174, 184))	('RCC', 'Phenotype', 'HP:0005584', (133, 136))	('chromophobe RCC', 'Disease', (121, 136))	('BSND', 'Gene', (27, 31))	('RCC', 'Phenotype', 'HP:0005584', (199, 202))	('ATP6V1G3', 'Var', (36, 44))	('RCC', 'Phenotype', 'HP:0005584', (159, 162))
374199	26091477	Next, we examined the expression statuses of these genes in 200 primary renal tumors and 85 primary lung carcinomas, and found that BSND and ATP6V1G3 were highly sensitive and specific markers of chromophobe RCC.	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('renal tumors', 'Disease', (72, 84))	('RCC', 'Phenotype', 'HP:0005584', (208, 211))	('chromophobe RCC', 'Disease', (196, 211))	('renal tumor', 'Phenotype', 'HP:0009726', (72, 83))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('renal tumors', 'Phenotype', 'HP:0009726', (72, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('carcinomas', 'Phenotype', 'HP:0030731', (105, 115))	('ATP6V1G3', 'Var', (141, 149))	('primary lung carcinomas', 'Disease', 'MESH:D008175', (92, 115))	('chromophobe RCC', 'Disease', 'MESH:C538614', (196, 211))	('renal tumors', 'Disease', 'MESH:D007674', (72, 84))	('primary lung carcinomas', 'Disease', (92, 115))
374200	26091477	Our study suggests that evaluating the expression levels of BSND and ATP6V1G3 could be of great value for distinguishing between chromophobe RCC and other subtypes of RCC.	('RCC', 'Phenotype', 'HP:0005584', (141, 144))	('chromophobe RCC', 'Disease', (129, 144))	('ATP6V1G3', 'Var', (69, 77))	('chromophobe RCC', 'Disease', 'MESH:C538614', (129, 144))	('RCC', 'Phenotype', 'HP:0005584', (167, 170))
374222	26091477	Interestingly, strong diffuse positivity was observed in the immunohistochemical analyses for the BSND and ATP6V1G3 proteins in all the chromophobe RCC specimens (23/23 cases, 100%) but was not observed in the clear cell RCC specimens (0/153 cases, 0%) or the papillary RCC specimens (0/10 cases, 0%) (Figure 2A-L and Table 3).	('RCC', 'Phenotype', 'HP:0005584', (148, 151))	('RCC', 'Phenotype', 'HP:0005584', (221, 224))	('papillary RCC', 'Disease', (260, 273))	('chromophobe RCC', 'Disease', (136, 151))	('RCC', 'Phenotype', 'HP:0005584', (270, 273))	('BSND', 'Gene', (98, 102))	('ATP6V1G3', 'Var', (107, 115))	('chromophobe RCC', 'Disease', 'MESH:C538614', (136, 151))	('proteins', 'Protein', (116, 124))	('papillary RCC', 'Disease', 'MESH:C538614', (260, 273))
374223	26091477	None of the clear cell or papillary RCC specimens showed even a weak positivity for BSND immunostaining; on the other hand, weak diffuse or partial positivity for ATP6V1G3 was detected in some clear cell RCC specimens (8/153 cases, 5.2%) and 1 papillary RCC specimen (1/10 cases, 10%) (Figure 3 and Table 3).	('papillary RCC', 'Disease', (26, 39))	('clear', 'Disease', (193, 198))	('papillary RCC', 'Disease', 'MESH:C538614', (244, 257))	('detected', 'Reg', (176, 184))	('RCC', 'Phenotype', 'HP:0005584', (36, 39))	('RCC', 'Phenotype', 'HP:0005584', (204, 207))	('papillary RCC', 'Disease', (244, 257))	('ATP6V1G3', 'Var', (163, 171))	('papillary RCC', 'Disease', 'MESH:C538614', (26, 39))	('RCC', 'Phenotype', 'HP:0005584', (254, 257))
374224	26091477	Thus, when calculating the sensitivity and specificity using the immunohistochemical results based only on strong diffuse positivity, the sensitivity of BSND or ATP6V1G3 expression for the diagnosis of chromophobe RCC was 100%, and the specificity was 100%.	('BSND', 'Gene', (153, 157))	('ATP6V1G3', 'Var', (161, 169))	('chromophobe RCC', 'Disease', (202, 217))	('RCC', 'Phenotype', 'HP:0005584', (214, 217))	('chromophobe RCC', 'Disease', 'MESH:C538614', (202, 217))
374226	26091477	These results suggested that both BSND and ATP6V1G3 are excellent immunohistochemical markers for differentiating between chromophobe RCC and other RCC subtypes.	('ATP6V1G3', 'Var', (43, 51))	('RCC', 'Phenotype', 'HP:0005584', (148, 151))	('chromophobe RCC', 'Disease', (122, 137))	('RCC', 'Phenotype', 'HP:0005584', (134, 137))	('chromophobe RCC', 'Disease', 'MESH:C538614', (122, 137))
374227	26091477	We next examined the expression status of BSND and ATP6V1G3 in renal oncocytoma, since this benign tumor often shares common morphological and immunophenotypic features with chromophobe RCC.	('tumor', 'Disease', (99, 104))	('renal oncocytoma', 'Disease', (63, 79))	('RCC', 'Phenotype', 'HP:0005584', (186, 189))	('chromophobe RCC', 'Disease', (174, 189))	('ATP6V1G3', 'Var', (51, 59))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('renal oncocytoma', 'Disease', 'MESH:C537750', (63, 79))	('BSND', 'Gene', (42, 46))	('chromophobe RCC', 'Disease', 'MESH:C538614', (174, 189))	('renal oncocytoma', 'Phenotype', 'HP:0011798', (63, 79))
374228	26091477	Immunohistochemical analysis for the BSND and ATP6V1G3 proteins revealed strong diffuse positivity for both in most of the renal oncocytoma specimens (13/14 cases, 92.9%, for both proteins) (Figure 2M-O and Table 3), suggesting that BSND and ATP6V1G3 are immunohistochemical markers for renal oncocytoma as well as chromophobe RCC.	('chromophobe RCC', 'Disease', (315, 330))	('RCC', 'Phenotype', 'HP:0005584', (327, 330))	('renal oncocytoma', 'Disease', 'MESH:C537750', (287, 303))	('renal oncocytoma', 'Disease', 'MESH:C537750', (123, 139))	('renal oncocytoma', 'Disease', (287, 303))	('renal oncocytoma', 'Disease', (123, 139))	('chromophobe RCC', 'Disease', 'MESH:C538614', (315, 330))	('renal oncocytoma', 'Phenotype', 'HP:0011798', (287, 303))	('renal oncocytoma', 'Phenotype', 'HP:0011798', (123, 139))	('ATP6V1G3', 'Var', (242, 250))
374229	26091477	In the immunohistochemical analyses of renal tumors, we found that some components of normal kidney tissue were also immunoreactive for BSND and ATP6V1G3.	('renal tumors', 'Disease', 'MESH:D007674', (39, 51))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('renal tumor', 'Phenotype', 'HP:0009726', (39, 50))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('BSND', 'Gene', (136, 140))	('renal tumors', 'Disease', (39, 51))	('renal tumors', 'Phenotype', 'HP:0009726', (39, 51))	('ATP6V1G3', 'Var', (145, 153))
374230	26091477	On the other hand, ATP6V1G3 was expressed at differential intensities in the nephrons: strong expression was observed in the distal convoluted tubule and collecting duct, while weak expression was observed in the proximal tubule and the thick ascending limb of the loop of Henle and very weak expression was observed in the thin limb of the loop of Henle (Figure 4E-H).	('ATP6V1G3', 'Var', (19, 27))	('nephrons', 'Disease', (77, 85))	('nephrons', 'Disease', 'MESH:D007683', (77, 85))
374231	26091477	These results suggested that BSND and ATP6V1G3 are variably expressed in normal kidney tissue, predominantly in the distal nephrons.	('nephrons', 'Disease', (123, 131))	('ATP6V1G3', 'Var', (38, 46))	('BSND', 'Gene', (29, 33))	('nephrons', 'Disease', 'MESH:D007683', (123, 131))
374232	26091477	Four CpG sites (cg27058889, cg00812246, cg19971655, and cg22162435) near the transcription start site (TSS) of BSND and 2 sites (cg12958813 and cg13100753) near the ATP6V1G3 TSS showed significantly lower DNA methylation levels (beta values) in chromophobe RCC than in clear cell RCC and papillary RCC; these median beta values of BSND or ATP6V1G3 in chromophobe RCC were lower than those in the other 2 RCCs by more than 0.25 (Figure 5A-C).	('chromophobe RCC', 'Disease', (351, 366))	('cg19971655', 'Var', (40, 50))	('RCC', 'Phenotype', 'HP:0005584', (298, 301))	('papillary RCC', 'Disease', 'MESH:C538614', (288, 301))	('RCC', 'Phenotype', 'HP:0005584', (257, 260))	('papillary RCC', 'Disease', (288, 301))	('cg22162435', 'Var', (56, 66))	('RCC', 'Phenotype', 'HP:0005584', (280, 283))	('cg13100753', 'Var', (144, 154))	('chromophobe RCC', 'Disease', 'MESH:C538614', (245, 260))	('DNA methylation levels', 'MPA', (205, 227))	('cg00812246', 'Var', (28, 38))	('cg27058889', 'Var', (16, 26))	('lower', 'NegReg', (199, 204))	('lower', 'NegReg', (372, 377))	('chromophobe RCC', 'Disease', 'MESH:C538614', (351, 366))	('chromophobe RCC', 'Disease', (245, 260))	('RCC', 'Phenotype', 'HP:0005584', (404, 407))	('RCC', 'Phenotype', 'HP:0005584', (363, 366))	('BSND and 2', 'Gene', '7809', (111, 121))	('cg12958813', 'Var', (129, 139))
374234	26091477	Thus, we examined the expression status of BSND and ATP6V1G3 proteins in lung carcinomas.	('lung carcinomas', 'Disease', (73, 88))	('BSND', 'Gene', (43, 47))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('ATP6V1G3', 'Var', (52, 60))	('proteins', 'Protein', (61, 69))	('carcinomas', 'Phenotype', 'HP:0030731', (78, 88))	('examined', 'Reg', (9, 17))	('lung carcinomas', 'Disease', 'MESH:D008175', (73, 88))
374235	26091477	The results showed that BSND and ATP6V1G3 protein was not expressed in a total of 85 lung carcinomas, composed of 44 cases of squamous cell carcinoma of the lung and 41 cases of adenocarcinoma of the lung (Figure 6 and Table 3).	('ATP6V1G3', 'Var', (33, 41))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (183, 192))	('carcinomas', 'Phenotype', 'HP:0030731', (90, 100))	('lung carcinomas', 'Disease', 'MESH:D008175', (85, 100))	('squamous cell carcinoma of the lung', 'Disease', (126, 161))	('adenocarcinoma of the lung', 'Disease', (178, 204))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))	('carcinoma of the lung', 'Phenotype', 'HP:0100526', (183, 204))	('adenocarcinoma of the lung', 'Disease', 'MESH:D000077192', (178, 204))	('squamous cell carcinoma of the lung', 'Phenotype', 'HP:0030359', (126, 161))	('lung carcinomas', 'Disease', (85, 100))	('carcinoma of the lung', 'Phenotype', 'HP:0100526', (140, 161))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (126, 149))	('squamous cell carcinoma of the lung', 'Disease', 'MESH:D002294', (126, 161))
374236	26091477	These results implied that BSND and ATP6V1G3 are excellent immunohistochemical markers for differentiating between chromophobe RCC that has metastasized to the lung and primary lung carcinoma.	('primary lung carcinoma', 'Disease', 'MESH:D008175', (169, 191))	('chromophobe RCC', 'Disease', 'MESH:C538614', (115, 130))	('RCC', 'Phenotype', 'HP:0005584', (127, 130))	('primary lung carcinoma', 'Disease', (169, 191))	('ATP6V1G3', 'Var', (36, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (182, 191))	('chromophobe RCC', 'Disease', (115, 130))
374239	26091477	These results suggested that the expression levels of BSND and ATP6V1G3 were extremely low in various types of carcinoma.	('carcinoma', 'Disease', 'MESH:D002277', (111, 120))	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('BSND', 'Gene', (54, 58))	('carcinoma', 'Disease', (111, 120))	('ATP6V1G3', 'Var', (63, 71))	('expression levels', 'MPA', (33, 50))	('low', 'NegReg', (87, 90))
374242	26091477	Although weak positivity for ATP6V1G3 was detected in a subset of clear cell RCC (5.2%) and papillary RCC (10%), none of the clear cell or papillary RCC specimens showed even a weak positive signal for BSND.	('RCC', 'Phenotype', 'HP:0005584', (149, 152))	('RCC', 'Phenotype', 'HP:0005584', (77, 80))	('papillary RCC', 'Disease', 'MESH:C538614', (139, 152))	('RCC', 'Phenotype', 'HP:0005584', (102, 105))	('papillary RCC', 'Disease', (139, 152))	('papillary RCC', 'Disease', 'MESH:C538614', (92, 105))	('ATP6V1G3', 'Var', (29, 37))	('papillary RCC', 'Disease', (92, 105))
374244	26091477	Regarding the expression levels of BSND and ATP6V1G3 in carcinomas other than RCC, lung carcinomas were negative (0%) for these protein expressions when examined using immunohistochemical analyses, and the TCGA data showed that the mRNA expression levels of both genes were extremely low in 12 types of carcinoma, including lung carcinoma.	('carcinoma', 'Disease', (329, 338))	('lung carcinoma', 'Disease', (324, 338))	('mRNA expression levels', 'MPA', (232, 254))	('lung carcinomas', 'Disease', (83, 98))	('carcinoma', 'Disease', (303, 312))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('carcinomas', 'Phenotype', 'HP:0030731', (88, 98))	('carcinomas', 'Disease', 'MESH:D002277', (88, 98))	('carcinoma', 'Disease', (88, 97))	('BSND', 'Gene', (35, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (56, 65))	('carcinomas', 'Phenotype', 'HP:0030731', (56, 66))	('carcinomas', 'Disease', 'MESH:D002277', (56, 66))	('carcinoma', 'Disease', (56, 65))	('carcinoma', 'Disease', 'MESH:D002277', (329, 338))	('carcinoma', 'Disease', 'MESH:D002277', (303, 312))	('ATP6V1G3', 'Var', (44, 52))	('lung carcinoma', 'Disease', 'MESH:D008175', (324, 338))	('low', 'NegReg', (284, 287))	('carcinoma', 'Disease', 'MESH:D002277', (88, 97))	('carcinomas', 'Disease', (88, 98))	('lung carcinoma', 'Disease', 'MESH:D008175', (83, 97))	('carcinoma', 'Disease', 'MESH:D002277', (56, 65))	('carcinomas', 'Disease', (56, 66))	('expression', 'MPA', (14, 24))	('RCC', 'Phenotype', 'HP:0005584', (78, 81))	('lung carcinomas', 'Disease', 'MESH:D008175', (83, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (329, 338))	('carcinoma', 'Phenotype', 'HP:0030731', (303, 312))
374245	26091477	These results suggest that BSND and ATP6V1G3 might be useful immunohistochemical markers for the differential diagnosis of chromophobe RCC.	('chromophobe RCC', 'Disease', 'MESH:C538614', (123, 138))	('RCC', 'Phenotype', 'HP:0005584', (135, 138))	('chromophobe RCC', 'Disease', (123, 138))	('BSND', 'Gene', (27, 31))	('ATP6V1G3', 'Var', (36, 44))
374247	26091477	In the current study, the sensitivity of BSND or ATP6V1G3 expression for the diagnosis of chromophobe RCC was 100%, and the specificity was 100%, when calculated based only on strong diffuse positivity.	('chromophobe RCC', 'Disease', 'MESH:C538614', (90, 105))	('ATP6V1G3', 'Var', (49, 57))	('chromophobe RCC', 'Disease', (90, 105))	('BSND', 'Gene', (41, 45))	('RCC', 'Phenotype', 'HP:0005584', (102, 105))
374248	26091477	These values for BSND and ATP6V1G3 are superior or equal to those of any other immunohistochemical marker that has been used previously for the differential diagnosis of chromophobe RCC.	('ATP6V1G3', 'Var', (26, 34))	('chromophobe RCC', 'Disease', (170, 185))	('chromophobe RCC', 'Disease', 'MESH:C538614', (170, 185))	('RCC', 'Phenotype', 'HP:0005584', (182, 185))
374253	26091477	In our analysis, renal oncocytoma was also found to be positive at a high frequency (92.9%) for BSND and ATP6V1G3 immunostaining.	('positive', 'Reg', (55, 63))	('renal oncocytoma', 'Disease', 'MESH:C537750', (17, 33))	('renal oncocytoma', 'Phenotype', 'HP:0011798', (17, 33))	('BSND', 'Gene', (96, 100))	('renal oncocytoma', 'Disease', (17, 33))	('ATP6V1G3', 'Var', (105, 113))
374255	26091477	However, based on our results, BSND or ATP6V1G3 immunohistochemistry is not useful for differentiating between chromophobe RCC and renal oncocytoma.	('ATP6V1G3', 'Var', (39, 47))	('renal oncocytoma', 'Disease', 'MESH:C537750', (131, 147))	('renal oncocytoma', 'Disease', (131, 147))	('renal oncocytoma', 'Phenotype', 'HP:0011798', (131, 147))	('chromophobe RCC', 'Disease', 'MESH:C538614', (111, 126))	('RCC', 'Phenotype', 'HP:0005584', (123, 126))	('chromophobe RCC', 'Disease', (111, 126))
374257	26091477	Germline mutations of the BSND gene cause Bartter syndrome type IV, which is an autosomal recessive disease characterized by salt loss, hypokalemia, metabolic alkalosis, and sensorineural deafness.	('Germline mutations', 'Var', (0, 18))	('hypokalemia', 'Disease', (136, 147))	('sensorineural deafness', 'Disease', (174, 196))	('metabolic alkalosis', 'Disease', (149, 168))	('BSND', 'Gene', (26, 30))	('hypokalemia', 'Phenotype', 'HP:0002900', (136, 147))	('autosomal recessive disease', 'Disease', (80, 107))	('metabolic alkalosis', 'Phenotype', 'HP:0200114', (149, 168))	('sensorineural deafness', 'Disease', 'MESH:D006313', (174, 196))	('salt loss', 'Phenotype', 'HP:0000127', (125, 134))	('hypokalemia', 'Disease', 'MESH:D007008', (136, 147))	('alkalosis', 'Phenotype', 'HP:0001948', (159, 168))	('salt', 'Chemical', 'MESH:D012492', (125, 129))	('Bartter syndrome type IV', 'Disease', 'MESH:C537653', (42, 66))	('metabolic alkalosis', 'Disease', 'MESH:D000471', (149, 168))	('deafness', 'Phenotype', 'HP:0000365', (188, 196))	('cause', 'Reg', (36, 41))	('Bartter syndrome type IV', 'Disease', (42, 66))	('autosomal recessive disease', 'Disease', 'MESH:D030342', (80, 107))	('sensorineural deafness', 'Phenotype', 'HP:0000407', (174, 196))
374258	26091477	At present, several research papers examining germline mutations of the BSND gene in the Bartter syndrome family have been reported; however, the expression of BSND protein in RCC has not been previously reported.	('BSND', 'Gene', (72, 76))	('Bartter syndrome', 'Disease', (89, 105))	('RCC', 'Phenotype', 'HP:0005584', (176, 179))	('mutations', 'Var', (55, 64))	('Bartter syndrome', 'Disease', 'MESH:D001477', (89, 105))
374259	26091477	ATP6V1G3, another immunohistochemical marker identified in this study, is a subunit of vacuolar-H+ ATPase that couples ATP hydrolysis to proton pumping across membranes.	('ATP', 'Chemical', 'MESH:D000255', (99, 102))	('couples ATP hydrolysis', 'MPA', (111, 133))	('ATP', 'Chemical', 'MESH:D000255', (119, 122))	('ATP6V1G3', 'Var', (0, 8))	('vacuolar-H+ ATPase', 'Gene', '1769', (87, 105))	('ATP', 'Chemical', 'MESH:D000255', (0, 3))	('vacuolar-H+ ATPase', 'Gene', (87, 105))
374261	26091477	Clinically, a reduction in the mRNA expression of ATP6V1G3 in clear cell RCC has been previously reported; however, its expression status in chromophobe RCC has not been previously reported.	('chromophobe RCC', 'Disease', 'MESH:C538614', (141, 156))	('clear cell RCC', 'Disease', (62, 76))	('RCC', 'Phenotype', 'HP:0005584', (153, 156))	('chromophobe RCC', 'Disease', (141, 156))	('mRNA expression', 'MPA', (31, 46))	('ATP6V1G3', 'Var', (50, 58))	('reduction', 'NegReg', (14, 23))	('RCC', 'Phenotype', 'HP:0005584', (73, 76))
374268	26091477	We suspect that both BSND and ATP6V1G3 are members of the group of genes whose expressions are differentially influenced by the DNA methylation status between chromophobe RCC and other RCC subtypes, such as clear cell and papillary RCCs.	('influenced', 'Reg', (110, 120))	('papillary RCC', 'Disease', (222, 235))	('ATP6V1G3', 'Var', (30, 38))	('chromophobe RCC', 'Disease', 'MESH:C538614', (159, 174))	('RCC', 'Phenotype', 'HP:0005584', (232, 235))	('expressions', 'MPA', (79, 90))	('RCC', 'Phenotype', 'HP:0005584', (171, 174))	('chromophobe RCC', 'Disease', (159, 174))	('papillary RCC', 'Disease', 'MESH:C538614', (222, 235))	('RCC', 'Phenotype', 'HP:0005584', (185, 188))	('clear cell', 'Disease', (207, 217))
374269	26091477	An examination of the mRNA expression data from the TCGA database also revealed that the mRNA expression levels of BSND and ATP6V1G3 were extremely low in various human carcinomas in this study.	('BSND', 'Gene', (115, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (169, 178))	('carcinomas', 'Phenotype', 'HP:0030731', (169, 179))	('mRNA expression levels', 'MPA', (89, 111))	('carcinomas', 'Disease', 'MESH:D002277', (169, 179))	('ATP6V1G3', 'Var', (124, 132))	('human', 'Species', '9606', (163, 168))	('carcinomas', 'Disease', (169, 179))	('low', 'NegReg', (148, 151))
374278	31709529	Stat1-/- mice displayed increased tumor growth and metastasis compared to Stat1+/+ mice.	('metastasis', 'CPA', (51, 61))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('tumor', 'Disease', (34, 39))	('Stat1-/-', 'Var', (0, 8))	('mice', 'Species', '10090', (83, 87))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('mice', 'Species', '10090', (9, 13))	('increased', 'PosReg', (24, 33))
374279	31709529	Mechanistically, Stat1-/- mice displayed impaired CD4+ and CD8+ T cell expansion compared to Stat1+/+ mice.	('mice', 'Species', '10090', (102, 106))	('Stat1-/-', 'Var', (17, 25))	('CD8', 'Gene', (59, 62))	('CD8', 'Gene', '925', (59, 62))	('impaired', 'NegReg', (41, 49))	('CD4+', 'CPA', (50, 54))	('mice', 'Species', '10090', (26, 30))
374281	31709529	Interestingly TNF-alpha production by T cells in tumor bearing mice was suppressed by Stat1 deficiency.	('deficiency', 'Var', (92, 102))	('Stat1', 'Gene', (86, 91))	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('TNF-alpha', 'Gene', (14, 23))	('tumor', 'Disease', (49, 54))	('mice', 'Species', '10090', (63, 67))	('TNF-alpha', 'Gene', '21926', (14, 23))	('suppressed', 'NegReg', (72, 82))
374294	31709529	Indeed, STAT1 induction has been reported to enhance the production of PDL1 and IDO, which are recognized to contribute to an immunosuppressive tumor microenvironment and promote HNSCC.	('IDO', 'Gene', (80, 83))	('tumor', 'Disease', (144, 149))	('production', 'MPA', (57, 67))	('PDL1', 'Gene', (71, 75))	('induction', 'Var', (14, 23))	('enhance', 'PosReg', (45, 52))	('HNSCC', 'Phenotype', 'HP:0012288', (179, 184))	('promote', 'PosReg', (171, 178))	('IDO', 'Gene', '15930', (80, 83))	('STAT1', 'Gene', (8, 13))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('HNSCC', 'CPA', (179, 184))
374314	31709529	Cells were incubated with fluorochrome conjugated antibodies for CD11b, Ly6G, Ly6C, CD11c, F4-80, PD-L1, CD206, CD3, CD4, CD8 and PD-1.	('Ly6G', 'Gene', (72, 76))	('CD11b', 'Gene', (65, 70))	('PD-L1', 'Gene', '574058', (98, 103))	('PD-L1', 'Gene', (98, 103))	('Ly6G', 'Gene', '546644', (72, 76))	('CD8', 'Gene', (122, 125))	('CD8', 'Gene', '925', (122, 125))	('Ly6C', 'Var', (78, 82))	('CD206', 'Var', (105, 110))	('CD11c', 'Var', (84, 89))
374332	31709529	Primary tumor growth occurred very rapidly in LY2 injected Stat1-/- mice compared to Stat1+/+ mice (Figure 1A and D).	('LY2 injected Stat1-/-', 'Var', (46, 67))	('mice', 'Species', '10090', (68, 72))	('Primary tumor', 'Disease', (0, 13))	('Stat1-/-', 'Var', (59, 67))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('mice', 'Species', '10090', (94, 98))	('LY2', 'Chemical', '-', (46, 49))	('Primary tumor', 'Disease', 'MESH:D001932', (0, 13))
374336	31709529	Tumor weights were similarly larger in Stat1-/- than in Stat1+/+ mice (Figure 1C and E).	('Stat1-/-', 'Var', (39, 47))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('larger', 'PosReg', (29, 35))	('mice', 'Species', '10090', (65, 69))	('Tumor weights', 'CPA', (0, 13))
374338	31709529	However, as in the LY2 injected mice, tumor volumes were significantly higher in Stat1-/- mice compared to Stat1+/+ mice (Figure 1A and D).	('higher', 'PosReg', (71, 77))	('tumor', 'Disease', (38, 43))	('Stat1-/-', 'Var', (81, 89))	('mice', 'Species', '10090', (116, 120))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('mice', 'Species', '10090', (90, 94))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('mice', 'Species', '10090', (32, 36))	('LY2', 'Chemical', '-', (19, 22))
374339	31709529	Similarly, after 5 weeks post cancer cell injections, mouse weights in tumor bearing Stat1-/- mice were significantly lower than in Stat1+/+ mice (Figure 1B), while tumor weights were significantly higher in Stat1-/- mice compared to Stat1+/+ mice (Figure 1C and E).	('mice', 'Species', '10090', (217, 221))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('cancer', 'Disease', (30, 36))	('Stat1-/-', 'Var', (85, 93))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('mice', 'Species', '10090', (243, 247))	('mouse weights', 'CPA', (54, 67))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('mice', 'Species', '10090', (141, 145))	('mice', 'Species', '10090', (94, 98))	('mouse', 'Species', '10090', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('lower', 'NegReg', (118, 123))	('tumor', 'Disease', (71, 76))	('higher', 'PosReg', (198, 204))	('tumor', 'Disease', (165, 170))
374342	31709529	Histological analysis of Stat1-/- and Stat1+/+ mice revealed draining lymph node metastasis in 86% of tumor bearing Stat1-/- mice at 3 weeks post LY2 injection, while Stat1+/+ mice displayed 0% lymph node metastasis (Figure 1F and H).	('Stat1-/-', 'Var', (116, 124))	('draining lymph node metastasis', 'CPA', (61, 91))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('mice', 'Species', '10090', (125, 129))	('mice', 'Species', '10090', (176, 180))	('LY2', 'Chemical', '-', (146, 149))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('mice', 'Species', '10090', (47, 51))
374355	31709529	In the draining lymph node, PD-1 expressing CD4+ and CD8+ T cells were significantly higher in LY2 tumor bearing Stat1-/- mice compared to Stat1+/+ mice (Figure 3A and B).	('tumor', 'Disease', (99, 104))	('CD8', 'Gene', (53, 56))	('mice', 'Species', '10090', (122, 126))	('CD8', 'Gene', '925', (53, 56))	('higher', 'PosReg', (85, 91))	('PD-1', 'Gene', (28, 32))	('mice', 'Species', '10090', (148, 152))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('LY2', 'Chemical', '-', (95, 98))	('CD4+', 'Var', (44, 48))
374362	31709529	Our results show enhanced TIM3 expression in PD-1+ CD4+ T cells of tumor bearing Stat1-/- mice compared to Stat1+/+ mice (Figure 3G and H).	('mice', 'Species', '10090', (116, 120))	('enhanced', 'PosReg', (17, 25))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('PD-1+', 'Var', (45, 50))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('TIM3', 'Gene', (26, 30))	('expression', 'MPA', (31, 41))	('mice', 'Species', '10090', (90, 94))	('tumor', 'Disease', (67, 72))	('TIM3', 'Gene', '171285', (26, 30))
374368	31709529	Our analysis demonstrated a significant attenuation of TNF-alpha production by CD4+ and CD8+ T cells in the draining lymph nodes and spleens of tumor bearing Stat1-/- mice compared to Stat1+/+ mice (Figure 4A and B).	('tumor', 'Disease', (144, 149))	('CD8', 'Gene', '925', (88, 91))	('attenuation', 'NegReg', (40, 51))	('Stat1-/-', 'Var', (158, 166))	('CD4+', 'Var', (79, 83))	('mice', 'Species', '10090', (193, 197))	('TNF-alpha', 'Gene', (55, 64))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('TNF-alpha', 'Gene', '21926', (55, 64))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('mice', 'Species', '10090', (167, 171))	('CD8', 'Gene', (88, 91))
374370	31709529	IFN-gamma production by T cells in the draining lymph nodes were similar between Stat1-/- and Stat1+/+ mice in both metastatic and non-metastatic tumor models.	('Stat1-/-', 'Var', (81, 89))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('IFN-gamma', 'Gene', '15978', (0, 9))	('mice', 'Species', '10090', (103, 107))	('tumor', 'Disease', (146, 151))	('metastatic', 'CPA', (116, 126))	('IFN-gamma', 'Gene', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
374377	31709529	Transcripts for both the Th1 transcription factor, T-bet as well as Ifng were found to be significantly downregulated in Stat1-/- mice compared to Stat1+/+ mice (Figure 4F).	('mice', 'Species', '10090', (130, 134))	('T-bet', 'Gene', (51, 56))	('Transcripts', 'MPA', (0, 11))	('T-bet', 'Gene', '57765', (51, 56))	('Ifng', 'Gene', '15978', (68, 72))	('Ifng', 'Gene', (68, 72))	('Stat1-/-', 'Var', (121, 129))	('downregulated', 'NegReg', (104, 117))	('mice', 'Species', '10090', (156, 160))	('Th1 transcription factor', 'Gene', (25, 49))
374378	31709529	Perforin, a CD8+ T cell cytotoxicity molecule and Klrc1, also expressed on activated CD8 T cells, was significantly downregulated in Stat1-/- mice compared to Stat1+/+ mice (Figure 4F).	('Klrc1', 'Gene', (50, 55))	('Stat1-/-', 'Var', (133, 141))	('CD8', 'Gene', '925', (12, 15))	('downregulated', 'NegReg', (116, 129))	('CD8', 'Gene', (85, 88))	('CD8', 'Gene', '925', (85, 88))	('mice', 'Species', '10090', (168, 172))	('cytotoxicity', 'Disease', (24, 36))	('mice', 'Species', '10090', (142, 146))	('Klrc1', 'Gene', '16641', (50, 55))	('cytotoxicity', 'Disease', 'MESH:D064420', (24, 36))	('CD8', 'Gene', (12, 15))
374379	31709529	Interestingly we observed similar Tnf-alpha mRNA transcripts in the tumors of both Stat1+/+ and Stat1-/- tumor-bearing mice (Figure 4F).	('tumor', 'Disease', (68, 73))	('mice', 'Species', '10090', (119, 123))	('tumors', 'Disease', (68, 74))	('Tnf-alpha', 'Gene', (34, 43))	('tumors', 'Disease', 'MESH:D009369', (68, 74))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('Stat1+/+', 'Var', (83, 91))	('Tnf-alpha', 'Gene', '21926', (34, 43))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('tumor', 'Disease', (105, 110))
374380	31709529	Finally, the anti-apoptotic marker Bcl2 was downregulated in Stat1-/- mice compared to their Stat1+/+ counterparts (Figure 4F).	('Stat1-/-', 'Var', (61, 69))	('downregulated', 'NegReg', (44, 57))	('Bcl2', 'Gene', '12043', (35, 39))	('Bcl2', 'Gene', (35, 39))	('mice', 'Species', '10090', (70, 74))
374384	31709529	Our analysis revealed a significantly increased accumulation of CD11b+Ly6G+Ly6Cint populations in primary tumors, draining lymph nodes, spleens and bone marrow of LY2 tumor-bearing Stat1-/- mice compared to Stat1+/+ mice (Figure 5A-D).	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('Ly6G', 'Gene', (70, 74))	('primary tumor', 'Disease', 'MESH:D001932', (98, 111))	('mice', 'Species', '10090', (216, 220))	('tumors', 'Disease', (106, 112))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('Ly6G', 'Gene', '546644', (70, 74))	('LY2', 'Var', (163, 166))	('LY2', 'Chemical', '-', (163, 166))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('primary tumor', 'Disease', (98, 111))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('mice', 'Species', '10090', (190, 194))	('tumor', 'Disease', (167, 172))	('tumor', 'Disease', (106, 111))	('increased accumulation', 'PosReg', (38, 60))
374386	31709529	CD11b+Ly6G-Ly6Chi cell populations were increased in lymph nodes, spleens and bone marrow of LY2 but not B4B8 tumor bearing Stat1-/- mice compared to Stat1+/+ mice (Supplemental Figure 1).	('Ly6G', 'Gene', '546644', (6, 10))	('mice', 'Species', '10090', (133, 137))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('LY2', 'Var', (93, 96))	('LY2', 'Chemical', '-', (93, 96))	('B4B8', 'Species', '472952', (105, 109))	('increased', 'PosReg', (40, 49))	('mice', 'Species', '10090', (159, 163))	('Ly6G', 'Gene', (6, 10))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
374388	31709529	We observed significantly increased levels of Cxcl1 and Il-1 transcripts in tumor-bearing Stat1-/- mice compared to Stat1+/+ mice (Figure 5E and F).	('mice', 'Species', '10090', (99, 103))	('Cxcl1', 'Gene', '14825', (46, 51))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('Il-1', 'Gene', (56, 60))	('mice', 'Species', '10090', (125, 129))	('Il-1', 'Gene', '111343', (56, 60))	('increased', 'PosReg', (26, 35))	('Stat1-/-', 'Var', (90, 98))	('Cxcl1', 'Gene', (46, 51))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
374390	31709529	Our observation of increased accumulation of CD11b+Ly6G+Ly6Cint populations in tumors and lymphoid organs Stat1-/- mice led us to determine whether the absence of STAT1 interferes with the immunosuppressive properties to this population of cells.	('immunosuppressive properties', 'CPA', (189, 217))	('Ly6G', 'Gene', '546644', (51, 55))	('mice', 'Species', '10090', (115, 119))	('interferes', 'NegReg', (169, 179))	('STAT1', 'Gene', (163, 168))	('tumors', 'Disease', (79, 85))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('Ly6G', 'Gene', (51, 55))	('accumulation', 'PosReg', (29, 41))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('absence', 'Var', (152, 159))
374393	31709529	Our data demonstrated that CD11b+Ly6G+ cells from tumor bearing Stat1+/+ and Stat1-/- mice were equally able to suppress T cell proliferation (Figure 6C).	('Ly6G', 'Gene', (33, 37))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('mice', 'Species', '10090', (86, 90))	('Ly6G', 'Gene', '546644', (33, 37))	('suppress', 'NegReg', (112, 120))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('suppress T cell proliferation', 'Phenotype', 'HP:0030253', (112, 141))	('Stat1+/+', 'Var', (64, 72))	('T cell proliferation', 'CPA', (121, 141))	('tumor', 'Disease', (50, 55))
374397	31709529	We observed significantly increased expression of CD11b+F4/80+CD206+ cells (marker for M2-polarized macrophages) in the spleen and draining lymph nodes of Stat1-/- tumor bearing mice compared to Stat1+/+ mice (Figure 6E and F).	('tumor', 'Disease', (164, 169))	('mice', 'Species', '10090', (178, 182))	('CD11b+F4/80+CD206+', 'Var', (50, 68))	('increased', 'PosReg', (26, 35))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('mice', 'Species', '10090', (204, 208))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('expression', 'MPA', (36, 46))
374401	31709529	Using metastatic (LY2) and non-metastatic (B4B8) orthotopic models of HNSCC in immunocompetent BALB/c mice, we show that deletion of Stat1 results in significantly increased tumor growth, morbidity, metastatic potential and immune suppression, mediated by diminished anti-tumor T lymphocyte responses and accumulation of tumor-promoting, immunosuppressive MDSCs and TAMs.	('mice', 'Species', '10090', (102, 106))	('LY2', 'Chemical', '-', (18, 21))	('tumor', 'Disease', (321, 326))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('increased', 'PosReg', (164, 173))	('accumulation', 'PosReg', (305, 317))	('tumor', 'Disease', (272, 277))	('diminished', 'NegReg', (256, 266))	('tumor', 'Disease', 'MESH:D009369', (321, 326))	('Stat1', 'Gene', (133, 138))	('tumor', 'Disease', 'MESH:D009369', (272, 277))	('B4B8', 'Species', '472952', (43, 47))	('tumor', 'Phenotype', 'HP:0002664', (321, 326))	('metastatic potential', 'CPA', (199, 219))	('tumor', 'Disease', (174, 179))	('tumor', 'Phenotype', 'HP:0002664', (272, 277))	('immune suppression', 'CPA', (224, 242))	('HNSCC', 'Phenotype', 'HP:0012288', (70, 75))	('diminished anti-tumor T lymphocyte responses', 'Phenotype', 'HP:0031402', (256, 300))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('deletion', 'Var', (121, 129))	('morbidity', 'CPA', (188, 197))	('TAMs', 'Chemical', '-', (366, 370))
374403	31709529	Non tumor bearing Stat1-/- and Stat1+/+ mice have similar proportions of CD4+ and CD8+ T cells in their draining lymph nodes and spleens.	('CD8', 'Gene', (82, 85))	('CD8', 'Gene', '925', (82, 85))	('Non tumor', 'Disease', 'MESH:D009369', (0, 9))	('Non tumor', 'Disease', (0, 9))	('CD4+', 'Var', (73, 77))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('mice', 'Species', '10090', (40, 44))
374417	31709529	In our study, PD-1 expression was enhanced in Stat1-/- CD4+ and CD8+ T cells of tumor bearing mice.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('CD8', 'Gene', (64, 67))	('expression', 'MPA', (19, 29))	('enhanced', 'PosReg', (34, 42))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('CD8', 'Gene', '925', (64, 67))	('PD-1', 'Gene', (14, 18))	('tumor', 'Disease', (80, 85))	('mice', 'Species', '10090', (94, 98))	('Stat1-/-', 'Var', (46, 54))
374419	31709529	Other clinical studies support our results on the positive effects of STAT1 expression on epithelial and other solid tumors.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('positive', 'PosReg', (50, 58))	('STAT1', 'Gene', (70, 75))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('tumors', 'Disease', (117, 123))	('expression', 'Var', (76, 86))
374425	31709529	In a model of non-small cell lung cancer, Stat1 deficient mice upregulated the expression of both PD-1 and PDL1, resulting in a diminished anti-tumor immune response.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('tumor', 'Disease', (144, 149))	('PD-1', 'Gene', (98, 102))	('expression', 'MPA', (79, 89))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (14, 40))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('lung cancer', 'Disease', 'MESH:D008175', (29, 40))	('mice', 'Species', '10090', (58, 62))	('upregulated', 'PosReg', (63, 74))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('deficient', 'Var', (48, 57))	('PDL1', 'Gene', (107, 111))	('diminished', 'NegReg', (128, 138))	('lung cancer', 'Disease', (29, 40))	('lung cancer', 'Phenotype', 'HP:0100526', (29, 40))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (18, 40))
374430	31709529	Similar to PD-1/PDL1 blockade therapy, blocking CD69 using anti-CD69 antibodies attenuated tumor progression in breast carcinogenesis.	('breast carcinogenesis', 'Disease', (112, 133))	('attenuated tumor', 'Disease', (80, 96))	('breast carcinogenesis', 'Disease', 'MESH:D001943', (112, 133))	('CD69', 'Gene', (48, 52))	('attenuated tumor', 'Disease', 'MESH:C538265', (80, 96))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('blocking', 'Var', (39, 47))
374432	31709529	Although we did not observe any intrinsic deficiency of tumor bearing Stat1-/- T cells in producing IFNgamma, we did observe a significant downregulation of Ifng mRNA in tumors of Stat1-/- mice compared to Stat1+/+ mice.	('deficiency of tumor', 'Disease', 'MESH:D009369', (42, 61))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('mice', 'Species', '10090', (215, 219))	('mice', 'Species', '10090', (189, 193))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('deficiency of tumor', 'Disease', (42, 61))	('Ifng', 'Gene', '15978', (157, 161))	('tumors', 'Disease', 'MESH:D009369', (170, 176))	('Stat1-/-', 'Var', (180, 188))	('Ifng', 'Gene', (157, 161))	('tumors', 'Phenotype', 'HP:0002664', (170, 176))	('IFNgamma', 'Gene', (100, 108))	('IFNgamma', 'Gene', '15978', (100, 108))	('tumors', 'Disease', (170, 176))	('downregulation', 'NegReg', (139, 153))
374447	31709529	Indeed, recent reports demonstrate that STAT1 deficiency reprograms IFN-gamma signaling in macrophages toward a suppressive phenotype mediated by STAT3, which impairs their ability to trigger an effective adaptive immune response.	('IFN-gamma', 'Gene', '15978', (68, 77))	('reprograms', 'Reg', (57, 67))	('STAT1', 'Gene', (40, 45))	('deficiency', 'Var', (46, 56))	('IFN-gamma', 'Gene', (68, 77))
374460	31709529	Using metastatic and non-metastatic oral cancer cells in immunocompetent BALB/c mice we show that STAT1 suppresses T cell exhaustion, promotes TNF-alpha production in T cells, and inhibits accumulation of myeloid derived suppressor cells.	('suppresses', 'NegReg', (104, 114))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('TNF-alpha', 'Gene', (143, 152))	('promotes', 'PosReg', (134, 142))	('accumulation', 'CPA', (189, 201))	('STAT1', 'Var', (98, 103))	('T cell exhaustion', 'CPA', (115, 132))	('inhibits', 'NegReg', (180, 188))	('oral cancer', 'Disease', 'MESH:D009369', (36, 47))	('mice', 'Species', '10090', (80, 84))	('TNF-alpha', 'Gene', '21926', (143, 152))	('oral cancer', 'Disease', (36, 47))	('T cell exhaustion', 'Phenotype', 'HP:0005435', (115, 132))
374462	32398775	Mitochondrial DNA alterations may influence the cisplatin responsiveness of oral squamous cell carcinoma Cisplatin is the first-line chemotherapeutic agent for the treatment of oral squamous cell carcinoma (OSCC).	('oral squamous cell carcinoma', 'Disease', (76, 104))	('cisplatin', 'Chemical', 'MESH:D002945', (48, 57))	('oral squamous cell carcinoma', 'Disease', (177, 205))	('alterations', 'Var', (18, 29))	('Cisplatin', 'Chemical', 'MESH:D002945', (105, 114))	('influence', 'Reg', (34, 43))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (76, 104))	('Mitochondrial', 'MPA', (0, 13))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (177, 205))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (81, 104))	('carcinoma', 'Phenotype', 'HP:0030731', (196, 205))	('cisplatin responsiveness', 'MPA', (48, 72))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (182, 205))
374464	32398775	Recently, mitochondrial DNA (mtDNA) alterations have been reported in a variety of cancers.	('cancers', 'Disease', 'MESH:D009369', (83, 90))	('reported', 'Reg', (58, 66))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('alterations', 'Var', (36, 47))	('cancers', 'Phenotype', 'HP:0002664', (83, 90))	('mitochondrial DNA', 'Disease', (10, 27))	('cancers', 'Disease', (83, 90))
374466	32398775	By microarray analysis, we found that the tumour spheres profited from aberrant lipid and glucose metabolism and became resistant to cisplatin.	('tumour', 'Phenotype', 'HP:0002664', (42, 48))	('glucose metabolism', 'Disease', 'MESH:D044882', (90, 108))	('tumour', 'Disease', 'MESH:D009369', (42, 48))	('profited', 'Reg', (57, 65))	('lipid', 'Chemical', 'MESH:D008055', (80, 85))	('tumour', 'Disease', (42, 48))	('cisplatin', 'Chemical', 'MESH:D002945', (133, 142))	('glucose metabolism', 'Disease', (90, 108))	('aberrant', 'Var', (71, 79))
374470	32398775	We found that the lower cisplatin sensitivity of H103 could have been caused by a constellation of genetic and epigenetic changes in its mitochondrial genome.	('H103', 'Chemical', '-', (49, 53))	('epigenetic', 'Var', (111, 121))	('cisplatin sensitivity', 'MPA', (24, 45))	('lower', 'NegReg', (18, 23))	('cisplatin', 'Chemical', 'MESH:D002945', (24, 33))
374471	32398775	Future work may look into how changes in mtDNA translate into an impact on cell function and therefore cisplatin response.	('cell function', 'MPA', (75, 88))	('mtDNA', 'Gene', (41, 46))	('cisplatin', 'Chemical', 'MESH:D002945', (103, 112))	('changes', 'Var', (30, 37))	('cisplatin response', 'MPA', (103, 121))	('impact', 'Reg', (65, 71))
374477	32398775	Activation of these mechanisms depends on multiple factors including genetic changes, epigenetic alterations at both molecular and cellular levels, and heterogeneity among cancer cells.	('cancer', 'Disease', (172, 178))	('epigenetic alterations', 'Var', (86, 108))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))
374483	32398775	Interestingly, mtDNA alterations have been implicated in the development of cancer and chemoresistance.	('chemoresistance', 'CPA', (87, 102))	('implicated', 'Reg', (43, 53))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('mtDNA', 'Gene', (15, 20))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('alterations', 'Var', (21, 32))
374495	32398775	H103 formed fewer and smaller spheres, possibly because they were less responsive to growth factors, their parental cells were innately less active, or they had decreased self-renewal capacity.	('H103', 'Var', (0, 4))	('decreased', 'NegReg', (161, 170))	('fewer', 'NegReg', (12, 17))	('less', 'NegReg', (136, 140))	('self-renewal capacity', 'CPA', (171, 192))	('less', 'NegReg', (66, 70))	('H103', 'Chemical', '-', (0, 4))	('smaller', 'NegReg', (22, 29))
374500	32398775	Overexpression of CD338 has been linked to chemoresistance of CSCs in OSCC.	('linked', 'Reg', (33, 39))	('CD338', 'Gene', '9429', (18, 23))	('chemoresistance', 'CPA', (43, 58))	('Overexpression', 'Var', (0, 14))	('CD338', 'Gene', (18, 23))
374534	32398775	3, H103, which was more cisplatin-resistant, had significantly lower mtDNA content than SAS (P < 0.01).	('mtDNA content', 'CPA', (69, 82))	('H103', 'Var', (3, 7))	('lower', 'NegReg', (63, 68))	('H103', 'Chemical', '-', (3, 7))	('SAS', 'Gene', (88, 91))	('SAS', 'Gene', '54187', (88, 91))	('cisplatin', 'Chemical', 'MESH:D002945', (24, 33))
374538	32398775	Other works on hepatoma and small cell lung cancer reported that low mtDNA content reduced the sensitivity of cancer cells to ROS-induced cytotoxicity by: 1) causing a compensatory increase in the expression of antioxidant enzymes; 2) impairing mitochondrial respiration; and 3) increasing mitochondrial membrane potential (mitochondrial outer membrane permeability was decreased as a result).	('cytotoxicity', 'Disease', 'MESH:D064420', (138, 150))	('reduced', 'NegReg', (83, 90))	('hepatoma', 'Disease', (15, 23))	('increase', 'PosReg', (181, 189))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('sensitivity', 'MPA', (95, 106))	('small cell lung cancer', 'Disease', 'MESH:D055752', (28, 50))	('low', 'Var', (65, 68))	('cancer', 'Disease', (110, 116))	('mitochondrial outer membrane permeability', 'MPA', (324, 365))	('ROS', 'Chemical', 'MESH:D017382', (126, 129))	('small cell lung cancer', 'Disease', (28, 50))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('hepatoma', 'Disease', 'MESH:D006528', (15, 23))	('impairing', 'NegReg', (235, 244))	('mitochondrial membrane potential', 'MPA', (290, 322))	('expression', 'MPA', (197, 207))	('lung cancer', 'Phenotype', 'HP:0100526', (39, 50))	('cancer', 'Disease', (44, 50))	('mitochondrial respiration', 'MPA', (245, 270))	('cytotoxicity', 'Disease', (138, 150))	('increasing', 'PosReg', (279, 289))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (28, 50))	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
374539	32398775	In general, apart from directly disrupting the structure of mtDNA, cisplatin also induces the formation of ROS inside cells, causing oxidative stress and further DNA damage.	('induces', 'Reg', (82, 89))	('cisplatin', 'Var', (67, 76))	('oxidative stress', 'Phenotype', 'HP:0025464', (133, 149))	('causing', 'Reg', (125, 132))	('ROS', 'Chemical', 'MESH:D017382', (107, 110))	('oxidative stress', 'MPA', (133, 149))	('ROS', 'Protein', (107, 110))	('cisplatin', 'Chemical', 'MESH:D002945', (67, 76))	('formation', 'MPA', (94, 103))	('DNA damage', 'MPA', (162, 172))
374540	32398775	We found that the cells with lower mtDNA content were less sensitive to ROS-induced cytotoxicity, confirming prior findings that variation in mtDNA content marks the progress of malignant cells in their transformation into death-resistant tumours.	('death-resistant tumours', 'Disease', (223, 246))	('cytotoxicity', 'Disease', (84, 96))	('tumours', 'Phenotype', 'HP:0002664', (239, 246))	('mtDNA', 'Gene', (142, 147))	('cytotoxicity', 'Disease', 'MESH:D064420', (84, 96))	('death-resistant tumours', 'Disease', 'MESH:D003643', (223, 246))	('ROS', 'Chemical', 'MESH:D017382', (72, 75))	('variation', 'Var', (129, 138))	('tumour', 'Phenotype', 'HP:0002664', (239, 245))
374543	32398775	Further investigations should look into how variation in mtDNA content translates into an impact on cell function and cisplatin sensitivity.	('variation', 'Var', (44, 53))	('cell function', 'CPA', (100, 113))	('mtDNA', 'Gene', (57, 62))	('cisplatin', 'Chemical', 'MESH:D002945', (118, 127))	('impact', 'Reg', (90, 96))	('cisplatin sensitivity', 'MPA', (118, 139))
374550	32398775	We detected 50 mtDNA variants in total for SAS and SAS tumour spheres, and 24% of the variants were observed in the displacement loop of the mitochondrial genome (D-loop).	('SAS', 'Gene', (51, 54))	('variants', 'Var', (21, 29))	('SAS', 'Gene', '54187', (51, 54))	('SAS', 'Gene', (43, 46))	('tumour', 'Phenotype', 'HP:0002664', (55, 61))	('SAS tumour', 'Disease', (51, 61))	('SAS', 'Gene', '54187', (43, 46))	('SAS tumour', 'Disease', 'MESH:D009369', (51, 61))
374551	32398775	Overall, we found that the variants observed in SAS were also present in SAS tumour spheres, though several variants significantly differed in their allele fractions between the two samples (Table 4).	('variants', 'Var', (27, 35))	('SAS', 'Gene', '54187', (73, 76))	('SAS', 'Gene', '54187', (48, 51))	('tumour', 'Phenotype', 'HP:0002664', (77, 83))	('differed', 'Reg', (131, 139))	('SAS tumour', 'Disease', 'MESH:D009369', (73, 83))	('SAS', 'Gene', (73, 76))	('SAS tumour', 'Disease', (73, 83))	('SAS', 'Gene', (48, 51))
374556	32398775	Comparing the mtDNA profiles of SAS and H103, we found a D-loop mutation that was only present in SAS.	('SAS', 'Gene', '54187', (98, 101))	('D-loop mutation', 'Var', (57, 72))	('SAS', 'Gene', (32, 35))	('SAS', 'Gene', (98, 101))	('H103', 'Chemical', '-', (40, 44))	('SAS', 'Gene', '54187', (32, 35))
374558	32398775	Therefore, we deduced that the D310 mutation could alter mtDNA content and thus cisplatin response.	('mtDNA content', 'MPA', (57, 70))	('D310', 'Var', (31, 35))	('cisplatin', 'Chemical', 'MESH:D002945', (80, 89))	('alter', 'Reg', (51, 56))	('cisplatin response', 'MPA', (80, 98))
374559	32398775	Lacking the D310 mutation, H103 was less efficient at replicating its mitochondrial genome than SAS, hence lowering its mtDNA content as shown by our qPCR analysis (Fig.	('replicating', 'MPA', (54, 65))	('H103', 'Chemical', '-', (27, 31))	('less', 'NegReg', (36, 40))	('SAS', 'Gene', '54187', (96, 99))	('mtDNA content', 'MPA', (120, 133))	('D310', 'Var', (12, 16))	('mitochondrial genome', 'MPA', (70, 90))	('SAS', 'Gene', (96, 99))	('lowering', 'NegReg', (107, 115))
374560	32398775	The D310 mutation was previously correlated with an increase in the mtDNA copy number in human laryngeal squamous cell carcinoma.	('human', 'Species', '9606', (89, 94))	('increase', 'PosReg', (52, 60))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (105, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('squamous cell carcinoma', 'Disease', (105, 128))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (105, 128))	('D310', 'Var', (4, 8))	('mtDNA', 'Gene', (68, 73))
374561	32398775	Other works have also reported the importance of the D310 mutation in breast, gallbladder, and colorectal tumourigenesis.	('colorectal tumourigenesis', 'Disease', 'MESH:D015179', (95, 120))	('colorectal tumourigenesis', 'Disease', (95, 120))	('tumour', 'Phenotype', 'HP:0002664', (106, 112))	('breast', 'Disease', (70, 76))	('D310', 'Var', (53, 57))	('gallbladder', 'Disease', (78, 89))
374562	32398775	To date, many mtDNA deletions have been catalogued in MITOMAP (https://www.mitomap.org), a human mitochondrial genome database, and associated with various pathological conditions.	('mtDNA', 'Gene', (14, 19))	('human', 'Species', '9606', (91, 96))	('deletions', 'Var', (20, 29))	('associated', 'Reg', (132, 142))
374563	32398775	Among the reported mtDNA deletions, a common mtDNA deletion (4977-bp deletion between 8470-13459 bp) has been shown to promote the carcinogenesis of hepatocellular carcinoma and colorectal cancer.	('mtDNA', 'Gene', (45, 50))	('carcinogenesis of hepatocellular carcinoma', 'Disease', 'MESH:D006528', (131, 173))	('colorectal cancer', 'Phenotype', 'HP:0003003', (178, 195))	('promote', 'PosReg', (119, 126))	('colorectal cancer', 'Disease', (178, 195))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (149, 173))	('carcinoma', 'Phenotype', 'HP:0030731', (164, 173))	('colorectal cancer', 'Disease', 'MESH:D015179', (178, 195))	('carcinogenesis of hepatocellular carcinoma', 'Disease', (131, 173))	('4977-bp deletion', 'Var', (61, 77))
374564	32398775	The mtDNA deletion causes the loss of several genes that encode the OXPHOS proteins, namely ATP synthase Fo subunits 6 and 8, cytochrome c oxidase III, and NADH dehydrogenase subunits 3, 4, 4 L and 5.	('NADH dehydrogenase subunits 3, 4, 4 L and 5', 'Gene', '4537;4538;4539;4540', (156, 199))	('cytochrome c oxidase III', 'Gene', (126, 150))	('mtDNA', 'Gene', (4, 9))	('deletion', 'Var', (10, 18))	('loss', 'NegReg', (30, 34))	('cytochrome c oxidase III', 'Gene', '4514', (126, 150))
374565	32398775	To confirm this, we then used a PCR-based assay to detect the 4977-bp mtDNA deletion in the SAS and H103 cells, after they had been treated repeatedly with cisplatin.	('mtDNA', 'Gene', (70, 75))	('deletion', 'Var', (76, 84))	('H103', 'Chemical', '-', (100, 104))	('cisplatin', 'Chemical', 'MESH:D002945', (156, 165))	('SAS', 'Gene', '54187', (92, 95))	('SAS', 'Gene', (92, 95))	('4977-bp', 'Var', (62, 69))
374567	32398775	In addition, it has been reported that mtDNA deletions were less common in cancerous tissues than their benign counterparts in breast, gastric, and head and neck cancers.	('cancerous', 'Disease', 'MESH:D009369', (75, 84))	('less', 'NegReg', (60, 64))	('mtDNA', 'Gene', (39, 44))	('cancerous', 'Disease', (75, 84))	('deletions', 'Var', (45, 54))	('head and neck cancers', 'Disease', 'MESH:D006258', (148, 169))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('head and neck cancers', 'Phenotype', 'HP:0012288', (148, 169))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('cancers', 'Phenotype', 'HP:0002664', (162, 169))
374568	32398775	Hence, we suggest that large-scale mtDNA deletion is not required for oral cancer development and therefore is not a crucial factor affecting the cisplatin response.	('mtDNA', 'Gene', (35, 40))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('cisplatin', 'Chemical', 'MESH:D002945', (146, 155))	('cancer', 'Disease', (75, 81))	('deletion', 'Var', (41, 49))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))
374570	32398775	Much of prior research has focused on the relation between epigenetic changes in nuclear DNA and the development of cancer.	('nuclear DNA', 'Protein', (81, 92))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('epigenetic changes', 'Var', (59, 77))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))
374571	32398775	Thus, we hypothesised that the epigenetic modifications of mtDNA may influence mtDNA replication, altering mitochondrial function and the cellular response of OSCC to cisplatin.	('replication', 'CPA', (85, 96))	('epigenetic modifications', 'Var', (31, 55))	('cellular response of OSCC to cisplatin', 'MPA', (138, 176))	('influence', 'Reg', (69, 78))	('mitochondrial function', 'MPA', (107, 129))	('cisplatin', 'Chemical', 'MESH:D002945', (167, 176))	('mtDNA', 'Gene', (59, 64))	('altering', 'Reg', (98, 106))
374575	32398775	H103 was substantially more cisplatin-resistant than SAS and the tumour spheres.	('cisplatin', 'Chemical', 'MESH:D002945', (28, 37))	('SAS', 'Gene', '54187', (53, 56))	('H103', 'Var', (0, 4))	('cisplatin-resistant', 'MPA', (28, 47))	('tumour', 'Phenotype', 'HP:0002664', (65, 71))	('SAS', 'Gene', (53, 56))	('tumour', 'Disease', 'MESH:D009369', (65, 71))	('tumour', 'Disease', (65, 71))	('H103', 'Chemical', '-', (0, 4))
374584	32398775	Interestingly, blockade of glycolysis killed the drug-resistant cancer cells.	('blockade', 'Var', (15, 23))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('glycolysis', 'MPA', (27, 37))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
374586	32398775	The cisplatin resistance we observed for H103 was likely caused by a similar relationship between reduced mitochondrial function and aberrant cellular adaptation.	('H103', 'Var', (41, 45))	('H103', 'Chemical', '-', (41, 45))	('mitochondrial function', 'MPA', (106, 128))	('cisplatin resistance', 'MPA', (4, 24))	('reduced', 'NegReg', (98, 105))	('cisplatin', 'Chemical', 'MESH:D002945', (4, 13))
374587	32398775	We expected H103 to have uniformly lower expression levels of its mitochondrial genes when compared with SAS.	('expression levels', 'MPA', (41, 58))	('SAS', 'Gene', (105, 108))	('lower', 'NegReg', (35, 40))	('H103', 'Var', (12, 16))	('mitochondrial genes', 'MPA', (66, 85))	('SAS', 'Gene', '54187', (105, 108))	('H103', 'Chemical', '-', (12, 16))
374588	32398775	However, the microarray analysis showed that only the expression of MT-ND2 was significantly lower in H103 than SAS (Supplementary Tables S5; P = 0.0163).	('MT-ND2', 'Gene', (68, 74))	('expression', 'MPA', (54, 64))	('SAS', 'Gene', '54187', (112, 115))	('H103', 'Chemical', '-', (102, 106))	('MT-ND2', 'Gene', '4536', (68, 74))	('SAS', 'Gene', (112, 115))	('lower', 'NegReg', (93, 98))	('H103', 'Var', (102, 106))
374595	32398775	In this study, we found that three CpG sites in the mitochondrial COX1 and CYTB genes (MT-CO1 and MT-CYB respectively) of H103 were hypermethylated when compared with both SAS and SAS tumour spheres (Table 5).	('CYTB', 'Gene', (75, 79))	('SAS', 'Gene', (180, 183))	('COX1', 'Gene', '4512', (66, 70))	('SAS', 'Gene', '54187', (172, 175))	('hypermethylated', 'Var', (132, 147))	('MT-CO1', 'Gene', (87, 93))	('tumour', 'Phenotype', 'HP:0002664', (184, 190))	('COX1', 'Gene', (66, 70))	('CYTB', 'Gene', '4519', (75, 79))	('SAS', 'Gene', '54187', (180, 183))	('MT-CO1', 'Gene', '4512', (87, 93))	('SAS', 'Gene', (172, 175))	('SAS tumour', 'Disease', 'MESH:D009369', (180, 190))	('SAS tumour', 'Disease', (180, 190))	('H103', 'Var', (122, 126))	('H103', 'Chemical', '-', (122, 126))
374596	32398775	Through the microarray analysis, we found that H103 had marginally higher expression levels of most of the mitochondrial genes, including MT-CO1 and MT-CYB, than SAS, though the differences were not statistically meaningful (Supplementary Table S5).	('higher', 'PosReg', (67, 73))	('SAS', 'Gene', (162, 165))	('MT-CO1', 'Gene', (138, 144))	('H103', 'Chemical', '-', (47, 51))	('MT-CO1', 'Gene', '4512', (138, 144))	('SAS', 'Gene', '54187', (162, 165))	('expression levels', 'MPA', (74, 91))	('H103', 'Var', (47, 51))
374603	32398775	We found that SAS and SAS tumour spheres harboured a D-loop mutation that was absent in H103.	('SAS tumour', 'Disease', (22, 32))	('SAS tumour', 'Disease', 'MESH:D009369', (22, 32))	('D-loop mutation', 'Var', (53, 68))	('SAS', 'Gene', (22, 25))	('SAS', 'Gene', '54187', (14, 17))	('H103', 'Chemical', '-', (88, 92))	('SAS', 'Gene', '54187', (22, 25))	('tumour', 'Phenotype', 'HP:0002664', (26, 32))	('SAS', 'Gene', (14, 17))
374604	32398775	The mutation could have altered mtDNA content and therefore cisplatin response.	('altered', 'Reg', (24, 31))	('mtDNA content', 'MPA', (32, 45))	('mutation', 'Var', (4, 12))	('cisplatin response', 'MPA', (60, 78))	('cisplatin', 'Chemical', 'MESH:D002945', (60, 69))
374605	32398775	We also found that all the cells had intact mtDNA, suggesting that mtDNA deletion is not one of the factors affecting cisplatin sensitivity.	('deletion', 'Var', (73, 81))	('mtDNA', 'Gene', (67, 72))	('cisplatin', 'Chemical', 'MESH:D002945', (118, 127))
374607	32398775	We inferred that the reduced cisplatin sensitivity in H103 could have been caused by a variety of converging genetic mechanisms, of which mtDNA alterations are key drivers (low mtDNA content, point mutations and methylation changes), that disrupt mitochondrial function, apoptosis, and cisplatin response.	('reduced', 'NegReg', (21, 28))	('apoptosis', 'CPA', (271, 280))	('point mutations', 'Var', (192, 207))	('cisplatin', 'Chemical', 'MESH:D002945', (286, 295))	('cisplatin', 'Chemical', 'MESH:D002945', (29, 38))	('mitochondrial function', 'MPA', (247, 269))	('H103', 'Var', (54, 58))	('H103', 'Chemical', '-', (54, 58))	('disrupt', 'NegReg', (239, 246))	('cisplatin sensitivity', 'MPA', (29, 50))
374608	32398775	However, how the differences in mtDNA variants between H103 and SAS could have altered protein functions and cisplatin sensitivity has yet to be confirmed.	('protein functions', 'MPA', (87, 104))	('variants', 'Var', (38, 46))	('altered', 'Reg', (79, 86))	('H103', 'Chemical', '-', (55, 59))	('SAS', 'Gene', (64, 67))	('cisplatin', 'Chemical', 'MESH:D002945', (109, 118))	('SAS', 'Gene', '54187', (64, 67))
374664	31805986	All cancers arise as a result of the accumulation of somatic mutations, copy number alterations, and epigenetic modifications that alter transcription and protein expression.	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('copy number alterations', 'Var', (72, 95))	('cancers', 'Disease', 'MESH:D009369', (4, 11))	('arise as', 'Reg', (12, 20))	('epigenetic modifications', 'Var', (101, 125))	('cancers', 'Phenotype', 'HP:0002664', (4, 11))	('cancers', 'Disease', (4, 11))	('alter', 'Reg', (131, 136))
374667	31805986	Many previous studies have shown that DNA methylation is involved in many aspects of carcinogenesis and provides potential biomarkers for evaluating the diagnosis and prognosis of cancer.	('carcinogenesis', 'Disease', 'MESH:D063646', (85, 99))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('carcinogenesis', 'Disease', (85, 99))	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('methylation', 'Var', (42, 53))	('cancer', 'Disease', (180, 186))	('involved', 'Reg', (57, 65))
374670	31805986	MethHC enables users to browse the top 250 hyper- or hypo-methylated genes in 18 cancer types.	('hypo-methylated', 'Var', (53, 68))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('cancer', 'Disease', (81, 87))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('MethHC', 'Chemical', '-', (0, 6))
374679	31805986	Differential analysis is a common approach in cancer research by comparing tumor samples vs. normal samples for identifying aberrantly methylated CpGs.	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('cancer', 'Disease', (46, 52))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('aberrantly methylated', 'Var', (124, 145))	('tumor', 'Disease', (75, 80))
374683	31805986	Here, using SMART App, we can easily find that TRIM58 (cg10983544) is much hyper-methylated in stage II group in lung squamous cell carcinoma, indicating its clinical relevance (Fig.	('cg10983544', 'Var', (55, 65))	('lung squamous cell carcinoma', 'Disease', (113, 141))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (118, 141))	('cg10983544', 'Chemical', '-', (55, 65))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (113, 141))	('hyper-methylated', 'PosReg', (75, 91))
374684	31805986	For example, IDH1 mutation can cause hyper-methylation in lower grade glioma (LGG).	('glioma', 'Disease', (70, 76))	('glioma', 'Disease', 'MESH:D005910', (70, 76))	('glioma', 'Phenotype', 'HP:0009733', (70, 76))	('IDH1', 'Gene', (13, 17))	('mutation', 'Var', (18, 26))	('cause', 'Reg', (31, 36))	('hyper-methylation', 'MPA', (37, 54))
374685	31805986	When IDH1 is selected, the returned box plots showed that cg07640666, cg17353896 and cg24324379 were significantly hyper-methylated in the mutation group (Fig.	('cg07640666', 'Var', (58, 68))	('cg07640666', 'Chemical', '-', (58, 68))	('cg17353896', 'Chemical', '-', (70, 80))	('cg17353896', 'Var', (70, 80))	('hyper-methylated', 'PosReg', (115, 131))	('cg24324379', 'Var', (85, 95))	('cg24324379', 'Chemical', '-', (85, 95))
374686	31805986	With the SMART App, it is very interesting to observe that TRIM58 (cg04902327) shows a lower level of methylation with low-level copy number amplification, whereas other CpGs of TRIM58 show a positive correlation with CNV in lung squamous cell carcinoma (Fig.	('methylation', 'MPA', (102, 113))	('lung squamous cell carcinoma', 'Disease', (225, 253))	('cg04902327', 'Var', (67, 77))	('lower', 'NegReg', (87, 92))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (225, 253))	('carcinoma', 'Phenotype', 'HP:0030731', (244, 253))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (230, 253))
374693	31805986	None of these tools allow users to pick a cancer type and visualize the chromosomal distribution of the aberrantly methylated CpGs.	('aberrantly methylated', 'Var', (104, 125))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))
374696	31805986	For example, one can easily find that CpGs such as cg10983544 and cg20429172 are located at the promoter region of the transcript of TRIM58, and may ask whether these CpGs are aberrantly methylated and whether the methylation changes of these CpGs will lead to gene expression alterations.	('lead to', 'Reg', (253, 260))	('cg10983544', 'Var', (51, 61))	('cg10983544', 'Chemical', '-', (51, 61))	('cg20429172', 'Var', (66, 76))	('gene expression', 'MPA', (261, 276))	('alterations', 'Reg', (277, 288))	('TRIM58', 'Gene', (133, 139))	('methylation', 'MPA', (214, 225))
374714	30956779	Inhibitors against CTLA-4, PD-1, and PD-L1 proteins are in clinical use and have been responsible for long-lasting responses in different types of cancer.	('CTLA-4', 'Gene', '1493', (19, 25))	('PD-L1', 'Gene', (37, 42))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('PD-1', 'Gene', (27, 31))	('Inhibitors', 'Var', (0, 10))	('PD-1', 'Gene', '5133', (27, 31))	('PD-L1', 'Gene', '29126', (37, 42))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('proteins', 'Protein', (43, 51))	('CTLA-4', 'Gene', (19, 25))	('cancer', 'Disease', (147, 153))
374760	30956779	Specifically, SKCM_1 denotes the SKCM patients (n = 258) in the cluster with apparently higher immune gene expression signature, whereas SKCM_2 denotes the SKCM patients (n = 177) in the other cluster with an apparently lower immune gene expression signature.	('higher', 'PosReg', (88, 94))	('SKCM', 'Disease', (33, 37))	('patients', 'Species', '9606', (161, 169))	('SKCM_1', 'Var', (14, 20))	('patients', 'Species', '9606', (38, 46))	('immune gene expression signature', 'MPA', (95, 127))
374797	30956779	Although it is beyond the scope of the current study, in the future we plan to perform a thorough interrogation on the relationship between this global immune gene signature and oncogenic pathways, copy number alterations, mutational load, and established clinicopathological characteristics, such as tumor metastasis, grade, and stage.	('tumor metastasis', 'Disease', 'MESH:D009362', (301, 317))	('mutational load', 'Var', (223, 238))	('grade', 'CPA', (319, 324))	('tumor metastasis', 'Disease', (301, 317))	('tumor', 'Phenotype', 'HP:0002664', (301, 306))	('copy number alterations', 'Var', (198, 221))
374808	30956779	POLE was commonly mutated in endometrial and colorectal cancer, while MSI tumors frequently occurred in endometrial, stomach, and colon cancer.	('endometrial', 'Disease', (104, 115))	('MSI tumors', 'Disease', 'MESH:D009369', (70, 80))	('colorectal cancer', 'Phenotype', 'HP:0003003', (45, 62))	('stomach', 'Disease', (117, 124))	('mutated', 'Var', (18, 25))	('colon cancer', 'Phenotype', 'HP:0003003', (130, 142))	('colon cancer', 'Disease', 'MESH:D015179', (130, 142))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('endometrial', 'Disease', (29, 40))	('colorectal cancer', 'Disease', (45, 62))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('MSI tumors', 'Disease', (70, 80))	('occurred', 'Reg', (92, 100))	('colon cancer', 'Disease', (130, 142))	('colorectal cancer', 'Disease', 'MESH:D015179', (45, 62))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))
374832	30854090	E1s activate ubiquitin (Ub) and transfer Ub to E2s to form a thioester bond with the C terminus of Ub, and E3s mediate the final step of Ub transfer by interacting with the E2-Ub complex and a specific substrate.	('E3s', 'Var', (107, 110))	('activate', 'PosReg', (4, 12))	('interacting', 'Interaction', (152, 163))	('E2-Ub', 'Protein', (173, 178))	('E2-Ub', 'Chemical', '-', (173, 178))	('E1s', 'Var', (0, 3))	('thioester bond', 'MPA', (61, 75))
374838	30854090	In liver cancer, TRIM24 suppressed tumorigenesis in a murine model.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('TRIM24', 'Var', (17, 23))	('liver cancer', 'Disease', 'MESH:D006528', (3, 15))	('murine', 'Species', '10090', (54, 60))	('liver cancer', 'Phenotype', 'HP:0002896', (3, 15))	('suppressed', 'NegReg', (24, 34))	('tumor', 'Disease', (35, 40))	('liver cancer', 'Disease', (3, 15))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))
374851	30854090	The GES75037, GSE19804, and GSE43458 were selected according to the following criteria: (I) the samples were from human patients; and (II) that LUSC or LUAD patients were in the datasets.	('GSE43458', 'Var', (28, 36))	('GSE19804', 'Var', (14, 22))	('patients', 'Species', '9606', (157, 165))	('human', 'Species', '9606', (114, 119))	('GES75037', 'Var', (4, 12))	('patients', 'Species', '9606', (120, 128))
374854	30854090	Of the selected LUAD samples, 33,76, 43, and 107 samples had EGFR, KRAS, LKB1, and p53 mutations, respectively.	('p53', 'Gene', (83, 86))	('p53', 'Gene', '7157', (83, 86))	('LKB1', 'Gene', (73, 77))	('KRAS', 'Gene', (67, 71))	('LKB1', 'Gene', '6794', (73, 77))	('KRAS', 'Gene', '3845', (67, 71))	('EGFR', 'Gene', '1956', (61, 65))	('mutations', 'Var', (87, 96))	('EGFR', 'Gene', (61, 65))
374855	30854090	In selected LUSC samples, 128 samples had p53 mutations.	('p53', 'Gene', (42, 45))	('mutations', 'Var', (46, 55))	('p53', 'Gene', '7157', (42, 45))
374892	30854090	We performed a relationship between TRIM15 expression and prognoses in EGFR, LKB1, and KRAS wild-type and mutant LUAD patients and p53 wild-type and mutant LUAD and LUSC patients.	('LKB1', 'Gene', (77, 81))	('patients', 'Species', '9606', (170, 178))	('TRIM15', 'Gene', '89870', (36, 42))	('mutant', 'Var', (106, 112))	('KRAS', 'Gene', (87, 91))	('LKB1', 'Gene', '6794', (77, 81))	('KRAS', 'Gene', '3845', (87, 91))	('mutant', 'Var', (149, 155))	('p53', 'Gene', (131, 134))	('TRIM15', 'Gene', (36, 42))	('p53', 'Gene', '7157', (131, 134))	('EGFR', 'Gene', '1956', (71, 75))	('EGFR', 'Gene', (71, 75))	('patients', 'Species', '9606', (118, 126))
374893	30854090	We also saw differences in TRIM15 expression between mutant and wild-type patient tissues concerning all of the above four genes.	('patient', 'Species', '9606', (74, 81))	('expression', 'MPA', (34, 44))	('TRIM15', 'Gene', '89870', (27, 33))	('mutant', 'Var', (53, 59))	('differences', 'Reg', (12, 23))	('TRIM15', 'Gene', (27, 33))
374894	30854090	We found that patients with EGFR mutations had significantly higher TRIM15 expression compared with that of wild-type patients (Supplementary Fig.	('EGFR', 'Gene', '1956', (28, 32))	('higher', 'PosReg', (61, 67))	('EGFR', 'Gene', (28, 32))	('TRIM15', 'Gene', '89870', (68, 74))	('mutations', 'Var', (33, 42))	('TRIM15', 'Gene', (68, 74))	('patients', 'Species', '9606', (14, 22))	('patients', 'Species', '9606', (118, 126))
374895	30854090	In EGFR mutations LUAD patients, patients with low TRIM15 expression had a marginally different prognosis compared with those with high TRIM15 expression (Supplementary Fig.	('TRIM15', 'Gene', (51, 57))	('EGFR', 'Gene', '1956', (3, 7))	('EGFR', 'Gene', (3, 7))	('patients', 'Species', '9606', (33, 41))	('TRIM15', 'Gene', '89870', (136, 142))	('low', 'NegReg', (47, 50))	('patients', 'Species', '9606', (23, 31))	('mutations', 'Var', (8, 17))	('TRIM15', 'Gene', '89870', (51, 57))	('TRIM15', 'Gene', (136, 142))
374898	30854090	The expression of TRIM15 was significantly higher in tumor tissue than normal tissues (p<0.0001 in GSE75037 and GSE43458, p=.0007 in GSE19804), as show in Fig.	('TRIM15', 'Gene', (18, 24))	('GSE75037', 'Var', (99, 107))	('higher', 'PosReg', (43, 49))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('expression', 'MPA', (4, 14))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('GSE43458', 'Var', (112, 120))	('tumor', 'Disease', (53, 58))	('TRIM15', 'Gene', '89870', (18, 24))
374907	30854090	Based on the results of the GSEA analysis, cell cycle analysis showed that the cell cycle changed in cells with TRIM15 knocked down (Supplementary Fig.	('cell cycle', 'CPA', (79, 89))	('GSEA', 'Chemical', '-', (28, 32))	('knocked down', 'Var', (119, 131))	('changed', 'Reg', (90, 97))	('TRIM15', 'Gene', (112, 118))	('TRIM15', 'Gene', '89870', (112, 118))
374908	30854090	According to previous research, TRIM family proteins that account for a large proportion of E3s, play essential roles in many fundamental biological processes, especially in that of cancer development.	('play', 'Reg', (97, 101))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('roles', 'Reg', (112, 117))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('E3s', 'Var', (92, 95))	('cancer', 'Disease', (182, 188))
374927	30854090	Moreover, overexpressed TRIM15 indicated poorer prognoses, which could be related to high TRIM15 expression promoting migration.	('TRIM15', 'Gene', (90, 96))	('expression', 'MPA', (97, 107))	('TRIM15', 'Gene', '89870', (24, 30))	('promoting', 'PosReg', (108, 117))	('high', 'Var', (85, 89))	('migration', 'CPA', (118, 127))	('TRIM15', 'Gene', '89870', (90, 96))	('TRIM15', 'Gene', (24, 30))	('overexpressed', 'Var', (10, 23))
374929	30854090	We found that patients with EGFR mutations had significantly higher TRIM15 expression compared with wild-type patients.	('EGFR', 'Gene', '1956', (28, 32))	('higher', 'PosReg', (61, 67))	('EGFR', 'Gene', (28, 32))	('TRIM15', 'Gene', '89870', (68, 74))	('mutations', 'Var', (33, 42))	('TRIM15', 'Gene', (68, 74))	('patients', 'Species', '9606', (14, 22))	('patients', 'Species', '9606', (110, 118))
374930	30854090	And in EGFR mutations LUAD patients, prognosis of patients with low TRIM15 expression were marginally different compared with those with high TRIM15 expression.	('patients', 'Species', '9606', (50, 58))	('TRIM15', 'Gene', (142, 148))	('EGFR', 'Gene', (7, 11))	('mutations', 'Var', (12, 21))	('low', 'NegReg', (64, 67))	('TRIM15', 'Gene', '89870', (68, 74))	('patients', 'Species', '9606', (27, 35))	('TRIM15', 'Gene', '89870', (142, 148))	('TRIM15', 'Gene', (68, 74))	('expression', 'MPA', (75, 85))	('EGFR', 'Gene', '1956', (7, 11))
374932	30854090	The link with these important mutations also indirectly indicates that TRIM15 can be used as a prognostic indicator in lung cancer patients.	('patients', 'Species', '9606', (131, 139))	('lung cancer', 'Disease', (119, 130))	('lung cancer', 'Phenotype', 'HP:0100526', (119, 130))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('TRIM15', 'Gene', (71, 77))	('mutations', 'Var', (30, 39))	('lung cancer', 'Disease', 'MESH:D008175', (119, 130))	('TRIM15', 'Gene', '89870', (71, 77))
374935	30854090	Also, our cell cycle test results showed that knocking down TRIM15 significantly affected cell cycle progression, which indicates that TRIM15 might be necessary for tumor cell development.	('TRIM15', 'Gene', '89870', (60, 66))	('cell cycle progression', 'CPA', (90, 112))	('TRIM15', 'Gene', (135, 141))	('affected', 'Reg', (81, 89))	('knocking down', 'Var', (46, 59))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('TRIM15', 'Gene', (60, 66))	('TRIM15', 'Gene', '89870', (135, 141))	('tumor', 'Disease', (165, 170))
374947	28155630	Cancer is driven by genetic alterations, including single nucleotide variants (SNVs), small insertions or deletions, large copy-number variations (CNVs) and structural aberrations that accumulate during the lifetime.	('single nucleotide variants', 'Var', (51, 77))	('deletions', 'Var', (106, 115))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('insertions', 'Var', (92, 102))
374949	28155630	However, it is still a challenge to integrate information across the different omics data and distinguish driver mutations which can promote the cancer cell to proliferate infinitely and diffuse from passenger mutations whose changes represent neutral variation that does not influence cancer development.	('cancer', 'Disease', (145, 151))	('promote', 'PosReg', (133, 140))	('cancer', 'Phenotype', 'HP:0002664', (286, 292))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('mutations', 'Var', (113, 122))	('cancer', 'Disease', 'MESH:D009369', (286, 292))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('cancer', 'Disease', (286, 292))
374950	28155630	MutSig and MuSic, is to identify driver genes based on somatic mutation rates in cancer patient populations, that is, the most commonly occurring mutations are more likely to be drivers.	('patient', 'Species', '9606', (88, 95))	('mutations', 'Var', (146, 155))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('cancer', 'Disease', (81, 87))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))
374952	28155630	With the advent of the whole-genome measurements of somatic mutations and CNVs in the mass of cancer samples, many changes altered at network and pathway levels are found, not simply a point mutation.	('CNVs', 'Gene', (74, 78))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('mutations', 'Var', (60, 69))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
374970	28155630	The null hypothesis H 0 is that the gene mutations have no influence on the occurrence of the cancer, and the alternative hypothesis H 1 is that the cancer is related to the mutations of the genes.	('mutations', 'Var', (41, 50))	('cancer', 'Disease', (149, 155))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('mutations', 'Var', (174, 183))	('cancer', 'Disease', 'MESH:D009369', (149, 155))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
374977	28155630	The CGC is a database that catalogues genes whose mutations have been causally implicated in cancer, which has been widely served as benchmark in many cancer researches.	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('mutations', 'Var', (50, 59))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('cancer', 'Disease', (151, 157))	('implicated', 'Reg', (79, 89))	('cancer', 'Disease', 'MESH:D009369', (151, 157))
374981	28155630	In addition, CASP8, which is ranked 16 in our method while 58 in DriverNet, has been demonstrated that in human papillomavirus (-) HNSC, concurrent mutations of CASP8 with HRAS can target cell cycle, death, NF-kappaB and other oncogenic pathways.	('HRAS', 'Gene', '3265', (172, 176))	('cell cycle', 'CPA', (188, 198))	('mutations', 'Var', (148, 157))	('CASP8', 'Gene', (161, 166))	('HRAS', 'Gene', (172, 176))	('human papillomavirus', 'Species', '10566', (106, 126))	('death', 'CPA', (200, 205))	('oncogenic pathways', 'Pathway', (227, 245))	('target', 'Reg', (181, 187))	('NF-kappaB', 'Pathway', (207, 216))
374989	28155630	In addition, there are literatures suggesting that somatic gain-of-function mutations of PTPN11 are presented in breast cancer, lung adenocarcinomas and etc.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('lung adenocarcinomas', 'Disease', (128, 148))	('breast cancer', 'Disease', 'MESH:D001943', (113, 126))	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('mutations', 'Var', (76, 85))	('PTPN11', 'Gene', (89, 95))	('breast cancer', 'Disease', (113, 126))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (128, 148))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (128, 148))	('breast cancer', 'Phenotype', 'HP:0003002', (113, 126))	('gain-of-function', 'PosReg', (59, 75))	('PTPN11', 'Gene', '5781', (89, 95))
374996	28155630	The RB1 gene is tumor suppressor gene identified and loss of it is considered an accelerating event in retinoblastoma.	('retinoblastoma', 'Disease', 'MESH:D012175', (103, 117))	('retinoblastoma', 'Disease', (103, 117))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('RB1', 'Gene', '5925', (4, 7))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('retinoblastoma', 'Phenotype', 'HP:0009919', (103, 117))	('tumor', 'Disease', (16, 21))	('loss', 'Var', (53, 57))	('RB1', 'Gene', (4, 7))
375013	28155630	LNDriver can identify not only frequently mutations but also rare drivers.	('fre', 'Gene', (31, 34))	('mutations', 'Var', (42, 51))	('fre', 'Gene', '2487', (31, 34))
375018	28155630	CCDS Consensus coding sequences cDNA complementary DNA CGC Cancer gene census CNVs Copy-number variations DAVID Database for annotation, visualization and integrated discovery GAM Generalized additive model HNSC Head and neck squamous cell carcinoma HPRD Human protein reference database ICGC International cancer genome consortium KIRC Kidney renal clear cell carcinoma LNDriver Length-Net-Driver NGS Next-generation sequencing PWV Probability weight vector SNVs Single nucleotide variants TCGA The Cancer Genome Atlas THCA Thyroid carcinoma	('carcinoma', 'Phenotype', 'HP:0030731', (533, 542))	('Cancer', 'Disease', 'MESH:D009369', (500, 506))	('carcinoma', 'Disease', (240, 249))	('carcinoma', 'Disease', (533, 542))	('Human', 'Species', '9606', (255, 260))	('Cancer', 'Phenotype', 'HP:0002664', (59, 65))	('Kidney renal clear cell carcinoma', 'Disease', 'MESH:C538614', (337, 370))	('carcinoma', 'Disease', 'MESH:D002277', (361, 370))	('cancer', 'Disease', 'MESH:D009369', (307, 313))	('Cancer', 'Disease', (59, 65))	('neck squamous cell carcinoma', 'Disease', (221, 249))	('THCA', 'Phenotype', 'HP:0002890', (520, 524))	('carcinoma', 'Disease', 'MESH:D002277', (240, 249))	('carcinoma', 'Disease', 'MESH:D002277', (533, 542))	('PWV', 'Chemical', '-', (429, 432))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (221, 249))	('Cancer', 'Phenotype', 'HP:0002664', (500, 506))	('Kidney renal clear cell carcinoma', 'Disease', (337, 370))	('Cancer', 'Disease', 'MESH:D009369', (59, 65))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (226, 249))	('cancer', 'Disease', (307, 313))	('carcinoma', 'Phenotype', 'HP:0030731', (361, 370))	('Thyroid carcinoma', 'Phenotype', 'HP:0002890', (525, 542))	('Cancer', 'Disease', (500, 506))	('cancer', 'Phenotype', 'HP:0002664', (307, 313))	('carcinoma', 'Disease', (361, 370))	('Single nucleotide variants', 'Var', (464, 490))	('carcinoma', 'Phenotype', 'HP:0030731', (240, 249))
375019	25749525	Transcriptome-wide identification and study of cancer-specific splicing events across multiple tumors Dysregulation of alternative splicing (AS) is one of the molecular hallmarks of cancer, with splicing alteration of numerous genes in cancer patients.	('splicing alteration', 'Var', (195, 214))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('cancer', 'Disease', 'MESH:D009369', (236, 242))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('patients', 'Species', '9606', (243, 251))	('cancer', 'Disease', (236, 242))	('cancer', 'Disease', (47, 53))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('alternative splicing', 'MPA', (119, 139))	('cancer', 'Disease', (182, 188))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('tumors', 'Disease', (95, 101))	('Dysregulation', 'Var', (102, 115))
375027	25749525	This process is tightly controlled across different tissues and developmental stages, and dysregulation of AS is closely associated with various human diseases including cancer.	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('cancer', 'Disease', (170, 176))	('associated', 'Reg', (121, 131))	('human', 'Species', '9606', (145, 150))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('dysregulation', 'Var', (90, 103))
375028	25749525	The extensive alteration of AS is considered to be one of the molecular hallmarks of cancer, and affects numerous genes that are critical for tumor pathogenesis and progression (e.g.	('extensive alteration', 'Var', (4, 24))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('tumor', 'Disease', (142, 147))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('cancer', 'Disease', (85, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('affects', 'Reg', (97, 104))	('genes', 'Gene', (114, 119))
375030	25749525	While most genetic mutations occur at a low frequency in cancer patients (with a few exceptions like TP53), many identified cancer-specific AS events were found in more than half of the tumor samples, suggesting a predominant role of splicing dysregulation in cancer.	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('cancer', 'Disease', (124, 130))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('patients', 'Species', '9606', (64, 72))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('cancer', 'Disease', (57, 63))	('cancer', 'Disease', 'MESH:D009369', (260, 266))	('TP53', 'Gene', '7157', (101, 105))	('mutations', 'Var', (19, 28))	('cancer', 'Disease', (260, 266))	('tumor', 'Disease', (186, 191))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('TP53', 'Gene', (101, 105))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('cancer', 'Phenotype', 'HP:0002664', (260, 266))	('splicing', 'Var', (234, 242))	('cancer', 'Disease', 'MESH:D009369', (124, 130))
375031	25749525	For example, CD44 is a key mediator of cell-cell and cell-matrix interactions, migration and invasion, and different splicing isoforms of CD44 have been linked with tumor evasion and metastasis in many cancers.	('splicing isoforms', 'Var', (117, 134))	('migration', 'CPA', (79, 88))	('tumor', 'Disease', (165, 170))	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('CD44', 'Gene', '960', (13, 17))	('metastasis in many cancers', 'Disease', (183, 209))	('metastasis in many cancers', 'Disease', 'MESH:D009362', (183, 209))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('cancers', 'Phenotype', 'HP:0002664', (202, 209))	('CD44', 'Gene', (13, 17))	('CD44', 'Gene', '960', (138, 142))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('linked with', 'Reg', (153, 164))	('cell-cell', 'CellLine', 'CVCL:0320', (39, 48))	('CD44', 'Gene', (138, 142))
375035	25749525	For example, the splicing factor SRSF1 is found to act as a proto-oncogene to promote cell transformation, whereas the splicing suppressor RBM4 functions as a tumor suppressor to inhibit tumor progression.	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('cell transformation', 'CPA', (86, 105))	('promote', 'PosReg', (78, 85))	('RBM4', 'Gene', '5936', (139, 143))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('SRSF1', 'Gene', (33, 38))	('SRSF1', 'Gene', '6426', (33, 38))	('tumor', 'Disease', (159, 164))	('tumor', 'Disease', (187, 192))	('RBM4', 'Gene', (139, 143))	('splicing', 'Var', (17, 25))	('inhibit', 'NegReg', (179, 186))	('tumor', 'Disease', 'MESH:D009369', (159, 164))
375040	25749525	In this study, we performed a transcriptome-wide splicing comparison between thousands of tumor samples and paired normal controls to identify a large number of splicing events with altered splicing in cancer.	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('altered splicing', 'Var', (182, 198))	('cancer', 'Disease', 'MESH:D009369', (202, 208))	('cancer', 'Disease', (202, 208))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
375051	25749525	We focused on four major modes of AS for more detailed analysis: skipped exon (SE), retained intron (RI), alternative 3' splice site (A3SS) and alternative 5' splice site (A5SS).	('alternative', 'Var', (106, 117))	('skipped exon', 'Var', (65, 77))	('SE', 'Disease', 'None', (79, 81))
375060	25749525	Such overlap is significantly more than the overlap expected by chance (p = 10-6 by hypergeometric test), indicating that the function of these genes may be altered through either mutation or splicing changes to affect cancer progression.	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('function', 'MPA', (126, 134))	('splicing changes', 'Var', (192, 208))	('cancer', 'Disease', 'MESH:D009369', (219, 225))	('cancer', 'Disease', (219, 225))	('affect', 'Reg', (212, 218))	('mutation', 'Var', (180, 188))	('altered', 'Reg', (157, 164))
375061	25749525	This result also suggests that, in addition to point mutations and copy number variations, the alteration of splicing may serve as another important route to alter gene function in cancer.	('splicing', 'MPA', (109, 117))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('gene function', 'MPA', (164, 177))	('alteration', 'Var', (95, 105))	('alter', 'Reg', (158, 163))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('cancer', 'Disease', (181, 187))
375066	25749525	85%) of these cancer-specific AS events change consistently across different tumor types (i.e., with an increased or decreased PSI values in all three tumors) when comparing tumors to the cognate normal tissue, suggesting that the splicing change in these genes will likely generate similar functional consequences across different tumors.	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumors', 'Phenotype', 'HP:0002664', (174, 180))	('tumor', 'Phenotype', 'HP:0002664', (332, 337))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('cancer', 'Disease', 'MESH:D009369', (14, 20))	('tumors', 'Phenotype', 'HP:0002664', (332, 338))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumors', 'Disease', (174, 180))	('tumors', 'Disease', (151, 157))	('splicing change', 'Var', (231, 246))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumors', 'Disease', (332, 338))	('tumors', 'Disease', 'MESH:D009369', (174, 180))	('tumors', 'Disease', 'MESH:D009369', (151, 157))	('decreased', 'NegReg', (117, 126))	('PSI values', 'MPA', (127, 137))	('tumor', 'Disease', (332, 337))	('cancer', 'Disease', (14, 20))	('tumor', 'Disease', (174, 179))	('tumors', 'Disease', 'MESH:D009369', (332, 338))	('tumor', 'Disease', (151, 156))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('tumor', 'Disease', 'MESH:D009369', (332, 337))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('tumor', 'Disease', (77, 82))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
375087	25749525	Since disruption of reading frame often introduces premature stop codons that lead to NMD, the increased tendency of cancer-specific SEs to maintain reading frame suggests that these events tend to produce proteins with different functions rather than disrupting protein function via changing reading frame.	('NMD', 'Disease', (86, 89))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('lead to', 'Reg', (78, 85))	('SEs', 'Chemical', 'MESH:D012643', (133, 136))	('produce', 'Reg', (198, 205))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('disruption', 'Var', (6, 16))	('cancer', 'Disease', (117, 123))
375125	25749525	The extensive splicing mis-regulation and frequent mutations of certain splicing factors in cancer have suggested that some AS events may directly affect tumor biogenesis and progression, however the consequence of splicing mis-regulation on patient survival remains unclear.	('mutations', 'Var', (51, 60))	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('progression', 'CPA', (175, 186))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('splicing mis-regulation', 'Var', (14, 37))	('patient', 'Species', '9606', (242, 249))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('affect', 'Reg', (147, 153))	('tumor', 'Disease', (154, 159))
375126	25749525	The identification of cancer-specific AS events across a large number of patients makes it possible to test if splicing misregulation in certain genes can serve as a predictor of cancer prognosis.	('splicing misregulation', 'Var', (111, 133))	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('cancer', 'Disease', (22, 28))	('patients', 'Species', '9606', (73, 81))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('cancer', 'Disease', (179, 185))
375161	25749525	An unbiased clustering of these associated genes recapitulated two major cell cycle checkpoints (i.e., G1 to S and G2 to M transition) and several main control pathways for cell cycle progression (e.g., DNA repair and P53 signaling).	('cell cycle checkpoints', 'CPA', (73, 95))	('P53', 'Gene', (218, 221))	('genes', 'Var', (43, 48))	('P53', 'Gene', '7157', (218, 221))	('DNA repair', 'Pathway', (203, 213))	('cell cycle', 'CPA', (173, 183))	('recapitulated', 'Reg', (49, 62))
375167	25749525	Because dysregulation of splicing in cancer can often serve as a cancer progression indicator, the identification of a core set of cancer-specific AS events will likely help early cancer detection and thus improve the chance of cure.	('cancer', 'Disease', (131, 137))	('help', 'Reg', (169, 173))	('a cancer', 'Disease', (63, 71))	('dysregulation', 'Var', (8, 21))	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('cancer', 'Disease', (37, 43))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('improve', 'PosReg', (206, 213))	('a cancer', 'Disease', 'MESH:D009369', (63, 71))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('cancer', 'Disease', (180, 186))
375313	29567982	For example, tobacco smoking rates are lower than alcohol drinking rates but tobacco smoking has a much greater impact on cancer risk, and a much larger number of cancer types associated with it, leading to a much higher PAF.	('alcohol drinking', 'Phenotype', 'HP:0030955', (50, 66))	('PAF', 'Gene', '9768', (221, 224))	('tobacco smoking', 'Var', (77, 92))	('higher', 'PosReg', (214, 220))	('tobacco', 'Species', '4097', (77, 84))	('alcohol', 'Chemical', 'MESH:D000438', (50, 57))	('impact', 'Reg', (112, 118))	('tobacco', 'Species', '4097', (13, 20))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('PAF', 'Gene', (221, 224))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('cancer', 'Disease', (163, 169))	('cancer', 'Disease', 'MESH:D009369', (163, 169))
375366	29567982	PAFs for individual risk factor-cancer type combinations represent the fraction of that cancer attributable to that risk factor in isolation, when the effect of other risk factors has been controlled for in the relative risk figure.	('PAF', 'Gene', (0, 3))	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('cancer', 'Disease', (32, 38))	('PAF', 'Gene', '9768', (0, 3))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('combinations', 'Var', (44, 56))
375426	27717372	While dramatic responses have been seen in a number of patients treated with anti-PD-1 and anti-PD-L1 antibodies, responses have typically represented only a fraction of treated patients.	('PD-1', 'Gene', (82, 86))	('PD-1', 'Gene', '5133', (82, 86))	('patients', 'Species', '9606', (178, 186))	('anti-PD-L1', 'Var', (91, 101))	('patients', 'Species', '9606', (55, 63))
375476	27717372	In NSCLC and HNSCC samples, PD-L1 was generally expressed as a continuum, ranging from a few tumor cells and/or immune cells expressing PD-L1 to the majority of tumor cells and immune cells expressing the target.	('NSCLC', 'Disease', (3, 8))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('NSCLC', 'Disease', 'MESH:D002289', (3, 8))	('tumor', 'Disease', (93, 98))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('PD-L1', 'Var', (136, 141))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('tumor', 'Disease', (161, 166))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
375503	27717372	These results demonstrated the high specificity of SP263 for PD-L1.	('SP263', 'Chemical', '-', (51, 56))	('PD-L1', 'Disease', (61, 66))	('SP263', 'Var', (51, 56))
375524	27717372	The intra-day reproducibility of the PD-L1 (SP263) assay within a single staining run exceeded the 90 % pass criterion set for this study; overall percentage agreement (OPA) for PD-L1 high vs. low/no expression was 100.0 % with a 95 % confidence interval (CI) of 92.9-100.0.	('SP263', 'Chemical', '-', (44, 49))	('high', 'Var', (184, 188))	('PD-L1', 'Gene', (178, 183))
375535	27717372	Target specificity was also demonstrated by transfecting PD-L1 into cell lines with no endogenous PD-L1 expression, producing clear staining with the PD-L1 (SP263) assay, and no staining in cells transfected with PD-L2.	('PD-L1', 'Gene', (98, 103))	('PD-L2', 'Gene', (213, 218))	('PD-L2', 'Gene', '80380', (213, 218))	('transfecting', 'Var', (44, 56))	('SP263', 'Chemical', '-', (157, 162))	('staining', 'MPA', (132, 140))
375545	27717372	There may be differences in assay performance owing to the diversity of antibody clones with different affinities, raised against different areas (epitopes) on the PD-L1 molecule (e.g., clones E1L3N, SP142, and SP263 are raised to epitopes within the intracellular domain, and clones 22C3 and 28-8 to epitopes within the extracellular domain).	('SP263', 'Chemical', '-', (211, 216))	('SP142', 'Var', (200, 205))	('E1L3N', 'Var', (193, 198))	('SP263', 'Var', (211, 216))
375549	27717372	This can mean that the probability of response to anti-PD-1/PD-L1 treatment differs very little in patients with PD-L1 low/negative tumors just below the cut-off, and patients with PD-L1 high tumors just above the cut-off.	('tumors', 'Disease', (192, 198))	('tumors', 'Disease', 'MESH:D009369', (192, 198))	('tumors', 'Phenotype', 'HP:0002664', (192, 198))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('PD-1', 'Gene', (55, 59))	('PD-L1', 'Gene', (113, 118))	('PD-L1 high tumors', 'Disease', (181, 198))	('PD-1', 'Gene', '5133', (55, 59))	('patients', 'Species', '9606', (99, 107))	('patients', 'Species', '9606', (167, 175))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('PD-L1 high tumors', 'Disease', 'MESH:D010300', (181, 198))	('tumors', 'Disease', (132, 138))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('tumors', 'Disease', 'MESH:D009369', (132, 138))	('low/negative', 'Var', (119, 131))
375619	27618692	The median survival time for lung cancer patients with CPFE was 19.5 months, which was shorter than that of lung cancer patients with non-CPFE or a normal lung (53.1 months, P <0.001).	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('lung cancer', 'Disease', 'MESH:D008175', (108, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('lung cancer', 'Disease', 'MESH:D008175', (29, 40))	('CPFE', 'Chemical', '-', (55, 59))	('shorter', 'NegReg', (87, 94))	('lung cancer', 'Disease', (108, 119))	('patients', 'Species', '9606', (41, 49))	('patients', 'Species', '9606', (120, 128))	('CPFE', 'Chemical', '-', (138, 142))	('CPFE', 'Var', (55, 59))	('lung cancer', 'Phenotype', 'HP:0100526', (108, 119))	('lung cancer', 'Disease', (29, 40))	('lung cancer', 'Phenotype', 'HP:0100526', (29, 40))
375636	27618692	However, in one study that compared the outcome in the same lung cancer stage patients with or without CPFE, it was found that overall survival was significantly poorer in the CPFE group.	('lung cancer', 'Disease', (60, 71))	('lung cancer', 'Phenotype', 'HP:0100526', (60, 71))	('patients', 'Species', '9606', (78, 86))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('lung cancer', 'Disease', 'MESH:D008175', (60, 71))	('CPFE', 'Chemical', '-', (103, 107))	('poorer', 'NegReg', (162, 168))	('CPFE', 'Chemical', '-', (176, 180))	('CPFE', 'Var', (176, 180))
375649	25306110	Here, we demonstrate that in primary human cells, macroH2A1 participates in two physically and functionally distinct types of chromatin either marked by H3K27me3 or nine histone acetylations.	('macroH2A1', 'Gene', '26914', (50, 59))	('H3K27me3', 'Var', (153, 161))	('participates', 'Reg', (60, 72))	('histone', 'Reg', (170, 177))	('macroH2A1', 'Gene', (50, 59))	('human', 'Species', '9606', (37, 42))
375656	25306110	Through their ability to regulate transcription, these histone variants have been implicated in a variety of processes including tumor suppression, inhibition of reprograming and differentiation.	('differentiation', 'CPA', (179, 194))	('transcription', 'MPA', (34, 47))	('inhibition', 'NegReg', (148, 158))	('variants', 'Var', (63, 71))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('regulate', 'Reg', (25, 33))	('reprograming', 'CPA', (162, 174))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('implicated', 'Reg', (82, 92))	('histone', 'Protein', (55, 62))	('tumor', 'Disease', (129, 134))
375657	25306110	Macrodomains are roughly 25 kDa conserved globular domains which typically harbor the ability to interact with the NAD+-derived, the post-translational modifications (PTMs) mono(ADP-ribose) and poly(ADP-ribose) (PAR).	('interact', 'Interaction', (97, 105))	('NAD+', 'Chemical', 'MESH:D009243', (115, 119))	('mono(ADP-ribose', 'Var', (173, 188))
375665	25306110	This alteration in macroH2A1.1 expression has important effects on both the proliferation and metastatic potential of cancer cells which appears to be due, in part, to the loss of macroH2A1's interaction with PARP-1 (refs.).	('macroH2A1', 'Gene', '26914', (180, 189))	('interaction', 'Interaction', (192, 203))	('cancer', 'Disease', (118, 124))	('loss', 'NegReg', (172, 176))	('metastatic potential', 'CPA', (94, 114))	('alteration', 'Var', (5, 15))	('effects', 'Reg', (56, 63))	('macroH2A1', 'Gene', '26914', (19, 28))	('macroH2A1', 'Gene', (180, 189))	('macroH2A1', 'Gene', (19, 28))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('proliferation', 'CPA', (76, 89))	('macroH2A1.1', 'Gene', (19, 30))	('PARP-1', 'Gene', (209, 215))	('macroH2A1.1', 'Gene', '9555', (19, 30))	('PARP-1', 'Gene', '142', (209, 215))	('cancer', 'Disease', 'MESH:D009369', (118, 124))
375669	25306110	An association between macroH2A1 and repressive H3K27me3 was found both on the Xi and in autosomal macroH2A1-enriched chromatin domains.	('macroH2A1', 'Gene', '26914', (23, 32))	('macroH2A1', 'Gene', '26914', (99, 108))	('macroH2A1', 'Gene', (23, 32))	('macroH2A1', 'Gene', (99, 108))	('H3K27me3', 'Var', (48, 56))
375677	25306110	Furthermore, we demonstrate that macroH2A1 positively regulates two of these acetylations, H2BK12ac and H2BK120ac, in primary cells.	('acetylations', 'MPA', (77, 89))	('H2BK120ac', 'Var', (104, 113))	('macroH2A1', 'Gene', '26914', (33, 42))	('macroH2A1', 'Gene', (33, 42))	('H2BK12ac', 'Var', (91, 99))	('H2BK12ac', 'Chemical', '-', (91, 99))	('regulates', 'Reg', (54, 63))
375680	25306110	Specifically, the macroH2A1.1 variant and its ability to interact with PARP-1-catalyzed PAR chains are critical for the regulation of CBP-mediated H2B K12 and K120 acetylation and for the ability to regulate macroH2A1-target gene expression.	('H2B', 'Gene', (147, 150))	('macroH2A1', 'Gene', (18, 27))	('K12', 'Gene', '3859', (159, 162))	('macroH2A1', 'Gene', (208, 217))	('PARP-1', 'Gene', (71, 77))	('K12', 'Gene', '3859', (151, 154))	('K120', 'Chemical', '-', (159, 163))	('macroH2A1.1', 'Gene', (18, 29))	('K12', 'Gene', (159, 162))	('variant', 'Var', (30, 37))	('H2B', 'Gene', '8349', (147, 150))	('PARP-1', 'Gene', '142', (71, 77))	('macroH2A1', 'Gene', '26914', (18, 27))	('K12', 'Gene', (151, 154))	('CBP', 'Gene', '1387', (134, 137))	('macroH2A1', 'Gene', '26914', (208, 217))	('macroH2A1.1', 'Gene', '9555', (18, 29))	('regulate', 'Reg', (199, 207))	('interact', 'Interaction', (57, 65))	('CBP', 'Gene', (134, 137))
375681	25306110	The previously identified connection between macroH2A1 and H3K27me3 cannot, in itself, explain the more complicated association between macroH2A1 and transcriptional regulation.	('macroH2A1', 'Gene', (45, 54))	('transcriptional regulation', 'MPA', (150, 176))	('macroH2A1', 'Gene', '26914', (136, 145))	('H3K27me3', 'Var', (59, 67))	('macroH2A1', 'Gene', (136, 145))	('macroH2A1', 'Gene', '26914', (45, 54))
375685	25306110	By comparing our macroH2A1 ChIP-seq data to publically available ChIP-seq data for 26 histone marks in IMR90 cells, we found that macroH2A1 is enriched (odds ratio = 4) in chromatin marked by H3K27me3 (Fig.	('macroH2A1', 'Gene', (17, 26))	('H3K27me3', 'Var', (192, 200))	('macroH2A1', 'Gene', '26914', (130, 139))	('IMR90', 'CellLine', 'CVCL:0347', (103, 108))	('macroH2A1', 'Gene', '26914', (17, 26))	('macroH2A1', 'Gene', (130, 139))
375687	25306110	Furthermore, these macroH2A1-enriched histone PTMs segregate into two distinct types of chromatin; macroH2A1 either occupies regions marked by H3K27me3 or regions marked by the acetylations (Fig.	('macroH2A1', 'Gene', '26914', (19, 28))	('macroH2A1', 'Gene', (19, 28))	('macroH2A1', 'Gene', '26914', (99, 108))	('H3K27me3', 'Var', (143, 151))	('macroH2A1', 'Gene', (99, 108))	('acetylations', 'MPA', (177, 189))
375688	25306110	By quantifying the degree of overlap between the ten macroH2A1-enriched PTMs across the genome, we demonstrated that the set of acetylations and H3K27me3 represent two distinct, largely non-overlapping chromatin environments (Fig.	('H3K27me3', 'Var', (145, 153))	('macroH2A1', 'Gene', '26914', (53, 62))	('macroH2A1', 'Gene', (53, 62))	('acetylations', 'Var', (128, 140))
375694	25306110	Interestingly, loss of macroH2A1 in IMR90 cells enhanced cancer-relevant phenotypes including proliferation and anchorage-independent growth (Supplementary Fig.	('IMR90', 'CellLine', 'CVCL:0347', (36, 41))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('cancer', 'Disease', (57, 63))	('macroH2A1', 'Gene', '26914', (23, 32))	('anchorage-independent growth', 'CPA', (112, 140))	('enhanced', 'PosReg', (48, 56))	('macroH2A1', 'Gene', (23, 32))	('proliferation', 'CPA', (94, 107))	('loss', 'Var', (15, 19))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))
375699	25306110	We found that 35.6% of macroH2A1-regulated genes in IMR90 cells were downregulated upon macroH2A1 depletion, while 64.4% were upregulated (Fig.	('depletion', 'Var', (98, 107))	('macroH2A1', 'Gene', '26914', (88, 97))	('macroH2A1', 'Gene', '26914', (23, 32))	('macroH2A1', 'Gene', (23, 32))	('downregulated', 'NegReg', (69, 82))	('macroH2A1', 'Gene', (88, 97))	('upregulated', 'PosReg', (126, 137))	('IMR90', 'CellLine', 'CVCL:0347', (52, 57))
375700	25306110	Marked differences in the levels of these acetylations were not observed in genes upregulated by macroH2A1 depletion compared to downregulated genes (Supplementary Fig.	('depletion', 'Var', (107, 116))	('macroH2A1', 'Gene', '26914', (97, 106))	('upregulated', 'PosReg', (82, 93))	('macroH2A1', 'Gene', (97, 106))
375701	25306110	As an independent approach to determine the key features of genes regulated by macroH2A1, we categorized protein coding genes by their macroH2A1, H2BK12ac, and H3K27me3 occupancy, yielding eight categories (Supplementary Fig.	('macroH2A1', 'Gene', (79, 88))	('H2BK12ac', 'Var', (146, 154))	('macroH2A1', 'Gene', '26914', (135, 144))	('H2BK12ac', 'Chemical', '-', (146, 154))	('H3K27me3 occupancy', 'Var', (160, 178))	('macroH2A1', 'Gene', (135, 144))	('macroH2A1', 'Gene', '26914', (79, 88))
375704	25306110	While genes co-occupied by macroH2A1, H2BK12ac and H3K27me3 were also enriched for macroH2A1-regulated genes, no other category marked by H3K27me3 was significantly enriched, suggesting H3K27me3 alone is not a predictor for genes regulated by macroH2A1, consistent with the conclusions from the meta-gene analysis.	('H2BK12ac', 'Var', (38, 46))	('macroH2A1', 'Gene', (27, 36))	('macroH2A1', 'Gene', '26914', (243, 252))	('macroH2A1', 'Gene', (243, 252))	('H3K27me3', 'Var', (51, 59))	('macroH2A1', 'Gene', '26914', (27, 36))	('macroH2A1', 'Gene', '26914', (83, 92))	('H2BK12ac', 'Chemical', '-', (38, 46))	('H3K27me3', 'Var', (186, 194))	('macroH2A1', 'Gene', (83, 92))
375708	25306110	We confirmed the role of macroH2A1 in promoting H2BK120ac and H2BK12ac in several additional primary cells including skin fibroblasts, hepatocytes, and prostate and mammary epithelium (Fig.	('macroH2A1', 'Gene', (25, 34))	('H2BK120ac', 'Var', (48, 57))	('promoting', 'PosReg', (38, 47))	('H2BK12ac', 'Var', (62, 70))	('macroH2A1', 'Gene', '26914', (25, 34))	('H2BK12ac', 'Chemical', '-', (62, 70))
375709	25306110	Strikingly, macroH2A1-mediated regulation of H2BK12ac and H2BK120ac is unique to primary cells.	('macroH2A1', 'Gene', '26914', (12, 21))	('macroH2A1', 'Gene', (12, 21))	('K120', 'Chemical', '-', (61, 65))	('H2BK12ac', 'Var', (45, 53))	('H2BK120ac', 'Var', (58, 67))	('H2BK12ac', 'Chemical', '-', (45, 53))
375710	25306110	When macroH2A1 was depleted from five cancer or transformed cell lines, no alteration in H2BK12ac or H2BK120ac was observed (Fig.	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('H2BK120ac', 'Var', (101, 110))	('macroH2A1', 'Gene', '26914', (5, 14))	('K120', 'Chemical', '-', (104, 108))	('macroH2A1', 'Gene', (5, 14))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('H2BK12ac', 'Chemical', '-', (89, 97))	('cancer', 'Disease', (38, 44))	('H2BK12ac', 'Var', (89, 97))
375711	25306110	MacroH2A1 co-occupies 59% of regions marked by H2BK12ac or H2BK120ac, leaving 41% of these regions unoccupied by macroH2A1 (Fig.	('H2BK12ac', 'Chemical', '-', (47, 55))	('MacroH2A1', 'Gene', (0, 9))	('MacroH2A1', 'Gene', '26914', (0, 9))	('macroH2A1', 'Gene', '26914', (113, 122))	('H2BK12ac', 'Var', (47, 55))	('macroH2A1', 'Gene', (113, 122))	('H2BK120ac', 'Var', (59, 68))	('K120', 'Chemical', '-', (62, 66))
375712	25306110	We hypothesized that macroH2A1 was directly and locally promoting H2BK12ac and H2BK120ac in macroH2A1-containing domains.	('H2BK12ac', 'Chemical', '-', (66, 74))	('promoting', 'PosReg', (56, 65))	('H2BK12ac', 'Var', (66, 74))	('macroH2A1', 'Gene', '26914', (92, 101))	('macroH2A1', 'Gene', (92, 101))	('macroH2A1', 'Gene', '26914', (21, 30))	('H2BK120ac', 'Var', (79, 88))	('macroH2A1', 'Gene', (21, 30))
375714	25306110	To distinguish between these possibilities, we performed ChIP-qPCR for H2BK12ac and H2BK120ac in control and macroH2A1-depleted cells on 19 loci either containing or devoid of macroH2A1 (Fig.	('macroH2A1', 'Gene', (176, 185))	('H2BK120ac', 'Var', (84, 93))	('macroH2A1', 'Gene', '26914', (109, 118))	('H2BK12ac', 'Var', (71, 79))	('macroH2A1', 'Gene', (109, 118))	('H2BK12ac', 'Chemical', '-', (71, 79))	('macroH2A1', 'Gene', '26914', (176, 185))
375715	25306110	MacroH2A1 depletion reduced H2BK12ac and H2BK120ac specifically inside macroH2A1-containing regions, indicating that macroH2A1 locally directs H2BK12ac and H2BK120ac.	('H2BK12ac', 'Var', (28, 36))	('reduced', 'NegReg', (20, 27))	('H2BK120ac', 'Var', (41, 50))	('H2BK120ac', 'Var', (156, 165))	('macroH2A1', 'Gene', (117, 126))	('K120', 'Chemical', '-', (159, 163))	('MacroH2A1', 'Gene', (0, 9))	('K120', 'Chemical', '-', (44, 48))	('macroH2A1', 'Gene', '26914', (71, 80))	('MacroH2A1', 'Gene', '26914', (0, 9))	('macroH2A1', 'Gene', (71, 80))	('H2BK12ac', 'Var', (143, 151))	('H2BK12ac', 'Chemical', '-', (143, 151))	('macroH2A1', 'Gene', '26914', (117, 126))	('H2BK12ac', 'Chemical', '-', (28, 36))
375719	25306110	To test this, mononucleosomes isolated from primary IMR90 cells and A549 lung cancer cells were immunoprecipitated with antibodies against H2BK12ac, H2BK120ac, H3K27me3 or H3K4me3 as a control.	('H3K27me3', 'Var', (160, 168))	('K120', 'Chemical', '-', (152, 156))	('H2BK120ac', 'Var', (149, 158))	('H2BK12ac', 'Chemical', '-', (139, 147))	('A549 lung cancer', 'Disease', (68, 84))	('H2BK12ac', 'Var', (139, 147))	('IMR90', 'CellLine', 'CVCL:0347', (52, 57))	('lung cancer', 'Phenotype', 'HP:0100526', (73, 84))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('A549 lung cancer', 'Disease', 'MESH:D008175', (68, 84))
375720	25306110	While macroH2A1 was enriched in H3K27me3-containing nucleosomes in IMR90 or A549 cells, macroH2A1 was only associated with H2B K12 and K120 acetylated nucleosomes in the IMR90 cells, and not in A549 (Fig.	('IMR90', 'CellLine', 'CVCL:0347', (67, 72))	('macroH2A1', 'Gene', '26914', (88, 97))	('H2B', 'Gene', '8349', (123, 126))	('K120', 'Chemical', '-', (135, 139))	('A549', 'CellLine', 'CVCL:0023', (76, 80))	('K12', 'Gene', (135, 138))	('macroH2A1', 'Gene', (88, 97))	('IMR90', 'CellLine', 'CVCL:0347', (170, 175))	('H3K27me3-containing', 'Var', (32, 51))	('K12', 'Gene', '3859', (135, 138))	('A549', 'CellLine', 'CVCL:0023', (194, 198))	('macroH2A1', 'Gene', '26914', (6, 15))	('macroH2A1', 'Gene', (6, 15))	('H2B', 'Gene', (123, 126))	('K12', 'Gene', (127, 130))	('K12', 'Gene', '3859', (127, 130))
375728	25306110	Therefore, we hypothesized that macroH2A1.1 is specifically responsible for macroH2A1-mediated H2BK12ac and H2BK120ac.	('H2BK120ac', 'Var', (108, 117))	('macroH2A1', 'Gene', (76, 85))	('H2BK12ac', 'Chemical', '-', (95, 103))	('macroH2A1', 'Gene', '26914', (32, 41))	('macroH2A1.1', 'Gene', (32, 43))	('macroH2A1', 'Gene', (32, 41))	('H2BK12ac', 'Var', (95, 103))	('macroH2A1.1', 'Gene', '9555', (32, 43))	('macroH2A1', 'Gene', '26914', (76, 85))
375731	25306110	When we ectopically expressed macroH2A1.1 we observed a modest increase in global H2BK12ac and H2BK120ac (Fig.	('macroH2A1.1', 'Gene', '9555', (30, 41))	('increase', 'PosReg', (63, 71))	('H2BK12ac', 'Protein', (82, 90))	('global', 'MPA', (75, 81))	('H2BK120ac', 'Var', (95, 104))	('H2BK12ac', 'Chemical', '-', (82, 90))	('K120', 'Chemical', '-', (98, 102))	('macroH2A1.1', 'Gene', (30, 41))
375735	25306110	Additionally, macroH2A1.1 overexpression also led to significantly increased macroH2A1 occupancy at many loci normally devoid of macroH2A1.	('macroH2A1', 'Gene', (14, 23))	('macroH2A1', 'Gene', '26914', (129, 138))	('occupancy', 'MPA', (87, 96))	('macroH2A1', 'Gene', '26914', (77, 86))	('macroH2A1.1', 'Gene', '9555', (14, 25))	('macroH2A1', 'Gene', (129, 138))	('macroH2A1', 'Gene', (77, 86))	('increased', 'PosReg', (67, 76))	('macroH2A1', 'Gene', '26914', (14, 23))	('overexpression', 'Var', (26, 40))	('macroH2A1.1', 'Gene', (14, 25))
375740	25306110	To test this, we ectopically expressed point mutants (G224E and G314E) of macroH2A1.1 which cannot interact with NAD+-derived ligands (Fig.	('G314E', 'Mutation', 'p.G314E', (64, 69))	('G224E', 'Mutation', 'p.G224E', (54, 59))	('G314E', 'Var', (64, 69))	('macroH2A1.1', 'Gene', (74, 85))	('G224E', 'Var', (54, 59))	('macroH2A1.1', 'Gene', '9555', (74, 85))	('NAD+', 'Chemical', 'MESH:D009243', (113, 117))
375741	25306110	Both macroH2A1.1 point mutants phenocopied ectopic expression of macroH2A1.2, where reduction of H2BK12ac and H2BK120ac was observed (Fig.	('ectopic expression', 'MPA', (43, 61))	('H2BK12ac', 'Chemical', '-', (97, 105))	('H2BK12ac', 'Var', (97, 105))	('H2BK120ac', 'Var', (110, 119))	('reduction', 'NegReg', (84, 93))	('macroH2A1.2', 'Gene', (65, 76))	('macroH2A1.1', 'Gene', (5, 16))	('macroH2A1.1', 'Gene', '9555', (5, 16))	('macroH2A1.2', 'Gene', '9555', (65, 76))
375742	25306110	However, the macrodomain of macroH2A1.1 alone cannot regulate H2BK12ac and H2BK120ac in trans.	('macroH2A1.1', 'Gene', (28, 39))	('H2BK12ac', 'Gene', (62, 70))	('K120', 'Chemical', '-', (78, 82))	('macroH2A1.1', 'Gene', '9555', (28, 39))	('H2BK120ac', 'Var', (75, 84))	('H2BK12ac', 'Chemical', '-', (62, 70))
375755	25306110	To determine if the activity of a PARP family member is required for macroH2A1-mediated regulation of H2BK12ac and H2BK120ac, we inhibited PARP enzymatic activity with PJ-34, a pan-specific PARP inhibitor.	('inhibited', 'NegReg', (129, 138))	('macroH2A1', 'Gene', '26914', (69, 78))	('PJ-34', 'Chemical', 'MESH:C434926', (168, 173))	('H2BK120ac', 'Var', (115, 124))	('PARP', 'Gene', (34, 38))	('PARP', 'Gene', '142', (34, 38))	('PARP', 'Gene', '142', (190, 194))	('PARP', 'Gene', '142', (139, 143))	('H2BK12ac', 'Var', (102, 110))	('H2BK12ac', 'Chemical', '-', (102, 110))	('PARP', 'Gene', (139, 143))	('PARP', 'Gene', (190, 194))	('macroH2A1', 'Gene', (69, 78))
375758	25306110	Other histone PTMs, like H3K4me3, were unaffected either in primary or cancer cells (Fig.	('cancer', 'Disease', (71, 77))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('H3K4me3', 'Var', (25, 32))
375763	25306110	Finally, shRNA-mediated depletion of PARP-1 also reduced H2B K12 and K120 acetylation in primary cells but not cancer cells (Fig.	('K12', 'Gene', (61, 64))	('K12', 'Gene', '3859', (61, 64))	('K12', 'Gene', (69, 72))	('K12', 'Gene', '3859', (69, 72))	('reduced', 'NegReg', (49, 56))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('H2B', 'Gene', '8349', (57, 60))	('PARP-1', 'Gene', (37, 43))	('depletion', 'Var', (24, 33))	('PARP-1', 'Gene', '142', (37, 43))	('K120', 'Chemical', '-', (69, 73))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('H2B', 'Gene', (57, 60))
375768	25306110	Genes regulated by macroH2A1 were coordinately regulated by inhibition of PARP-1 activity either by PJ-34 or BYK204165 (Fig.	('K20', 'Gene', '54474', (111, 114))	('PJ-34', 'Chemical', 'MESH:C434926', (100, 105))	('macroH2A1', 'Gene', '26914', (19, 28))	('macroH2A1', 'Gene', (19, 28))	('inhibition', 'NegReg', (60, 70))	('PARP-1', 'Gene', (74, 80))	('PARP-1', 'Gene', '142', (74, 80))	('activity', 'MPA', (81, 89))	('K20', 'Gene', (111, 114))	('PJ-34', 'Var', (100, 105))
375769	25306110	In addition, ectopic expression of macroH2A1.2, which leads to macroH2A1.1 depletion (Fig 4c), mimics the effects seen in response to macroH2A1 depletion and PARP inhibition (Fig.	('macroH2A1.1', 'Gene', (63, 74))	('macroH2A1', 'Gene', (35, 44))	('depletion', 'NegReg', (75, 84))	('macroH2A1', 'Gene', '26914', (63, 72))	('macroH2A1.2', 'Gene', (35, 46))	('macroH2A1.1', 'Gene', '9555', (63, 74))	('PARP', 'Gene', (158, 162))	('macroH2A1', 'Gene', '26914', (134, 143))	('macroH2A1', 'Gene', (134, 143))	('ectopic expression', 'Var', (13, 31))	('macroH2A1', 'Gene', '26914', (35, 44))	('PARP', 'Gene', '142', (158, 162))	('macroH2A1', 'Gene', (63, 72))	('macroH2A1.2', 'Gene', '9555', (35, 46))
375773	25306110	We hypothesized that macroH2A1.1 regulates H2BK12ac and H2BK120ac and macroH2A1-target gene transcription by recruiting PAR-modified PARP-1.	('H2BK120ac', 'Var', (56, 65))	('PARP-1', 'Gene', '142', (133, 139))	('PAR-modified', 'MPA', (120, 132))	('recruiting', 'PosReg', (109, 119))	('macroH2A1', 'Gene', (70, 79))	('macroH2A1.1', 'Gene', '9555', (21, 32))	('H2BK12ac', 'Chemical', '-', (43, 51))	('PARP-1', 'Gene', (133, 139))	('K120', 'Chemical', '-', (59, 63))	('macroH2A1', 'Gene', '26914', (21, 30))	('macroH2A1', 'Gene', '26914', (70, 79))	('macroH2A1.1', 'Gene', (21, 32))	('macroH2A1', 'Gene', (21, 30))	('transcription', 'MPA', (92, 105))
375774	25306110	To test this model we performed ChIP-qPCR on a sample of eight genes either up- or downregulated upon macroH2A1 depletion (Supplementary Fig.	('depletion', 'Var', (112, 121))	('macroH2A1', 'Gene', '26914', (102, 111))	('downregulated', 'NegReg', (83, 96))	('up-', 'PosReg', (76, 79))	('macroH2A1', 'Gene', (102, 111))
375783	25306110	Using ChIP-qPCR analysis, we confirmed that TSA can reverse the loss of H2BK12ac and H2BK120ac in macroH2A1-depleted cells at macroH2A1-regulated genes (Fig.	('H2BK12ac', 'Chemical', '-', (72, 80))	('TSA', 'Chemical', '-', (44, 47))	('macroH2A1', 'Gene', '26914', (98, 107))	('H2BK12ac', 'Gene', (72, 80))	('macroH2A1', 'Gene', '26914', (126, 135))	('macroH2A1', 'Gene', (98, 107))	('H2BK120ac', 'Var', (85, 94))	('macroH2A1', 'Gene', (126, 135))
375793	25306110	Additionally, inhibition of PARP enzymatic activity prevents recruitment of CBP to these genes (Fig.	('CBP', 'Gene', (76, 79))	('recruitment', 'MPA', (61, 72))	('PARP', 'Gene', (28, 32))	('CBP', 'Gene', '1387', (76, 79))	('PARP', 'Gene', '142', (28, 32))	('inhibition', 'Var', (14, 24))	('prevents', 'NegReg', (52, 60))
375796	25306110	Treatment of IMR90 cells with a CBP/p300 inhibitor C646, led to a decrease in H2BK12ac and H2BK120ac (Supplementary Fig.	('CBP/p300', 'Gene', '1387;2033', (32, 40))	('decrease', 'NegReg', (66, 74))	('H2BK12ac', 'Protein', (78, 86))	('C646', 'Var', (51, 55))	('IMR90', 'CellLine', 'CVCL:0347', (13, 18))	('CBP/p300', 'Gene', (32, 40))	('H2BK12ac', 'Chemical', '-', (78, 86))	('H2BK120ac', 'Var', (91, 100))	('C646', 'Chemical', '-', (51, 55))
375797	25306110	In addition, IMR90 cells treated with C646 or CBP depleted (Supplementary Fig.	('depleted', 'NegReg', (50, 58))	('IMR90', 'CellLine', 'CVCL:0347', (13, 18))	('CBP', 'Gene', (46, 49))	('C646', 'Var', (38, 42))	('CBP', 'Gene', '1387', (46, 49))	('C646', 'Chemical', '-', (38, 42))
375798	25306110	8) mirrored the changes in macroH2A1-target gene expression seen upon macroH2A1 depletion (Fig.	('macroH2A1', 'Gene', (27, 36))	('macroH2A1', 'Gene', (70, 79))	('macroH2A1', 'Gene', '26914', (27, 36))	('depletion', 'Var', (80, 89))	('macroH2A1', 'Gene', '26914', (70, 79))
375799	25306110	Overall, these results demonstrate that recruitment of CBP is critical for macroH2A1 and PARP-1 to regulate H2BK12ac and H2BK120ac and regulate macroH2A1 target gene expression.	('regulate', 'Reg', (135, 143))	('H2BK120ac', 'Var', (121, 130))	('H2BK12ac', 'Chemical', '-', (108, 116))	('CBP', 'Gene', '1387', (55, 58))	('CBP', 'Gene', (55, 58))	('regulate', 'Reg', (99, 107))	('H2BK12ac', 'Gene', (108, 116))	('macroH2A1', 'Gene', '26914', (75, 84))	('PARP-1', 'Gene', '142', (89, 95))	('macroH2A1', 'Gene', (75, 84))	('macroH2A1', 'Gene', '26914', (144, 153))	('PARP-1', 'Gene', (89, 95))	('macroH2A1', 'Gene', (144, 153))	('expression', 'MPA', (166, 176))	('K120', 'Chemical', '-', (124, 128))
375808	25306110	Interestingly, S137 phosphorylated macroH2A1 is excluded from heterochromatin, suggesting it might be such a distinguishing feature.	('macroH2A1', 'Gene', '26914', (35, 44))	('S137 phosphorylated', 'Var', (15, 34))	('macroH2A1', 'Gene', (35, 44))
375809	25306110	A classic example is the promotion of H3 K4 and K79 methylation in response to H2B K120 mono-ubiquitylation.	('promotion', 'PosReg', (25, 34))	('K79', 'Gene', '338785', (48, 51))	('H2B', 'Gene', (79, 82))	('K120', 'Var', (83, 87))	('H3 K4', 'Protein', (38, 43))	('H2B', 'Gene', '8349', (79, 82))	('K79', 'Gene', (48, 51))	('K120', 'Chemical', '-', (83, 87))
375810	25306110	Histone variants have also been implicated in trans-histone regulatory dynamics.	('trans-histone', 'Chemical', '-', (46, 59))	('Histone', 'Protein', (0, 7))	('implicated', 'Reg', (32, 42))	('trans-histone regulatory dynamics', 'MPA', (46, 79))	('variants', 'Var', (8, 16))
375811	25306110	For example, H2A.Z nucleosomal incorporation is stimulated by H4K16ac.	('H4K16ac', 'Var', (62, 69))	('H2A.Z', 'Gene', '3015', (13, 18))	('H2A.Z', 'Gene', (13, 18))	('stimulated', 'PosReg', (48, 58))
375812	25306110	Here we have shown that histone variants can play an upstream role in trans-histone regulatory pathways by showing macroH2A1 promotes H2BK12ac and H2BK120ac.	('trans-histone', 'Chemical', '-', (70, 83))	('macroH2A1', 'Gene', (115, 124))	('H2BK12ac', 'Var', (134, 142))	('H2BK12ac', 'Chemical', '-', (134, 142))	('H2BK120ac', 'Var', (147, 156))	('promotes', 'PosReg', (125, 133))	('macroH2A1', 'Gene', '26914', (115, 124))
375839	25306110	Gene expression changes seen upon macroH2A1 depletion from primary cells mirrors the changes observed in cancers (Table 1 and Supplementary Table 3).	('cancers', 'Phenotype', 'HP:0002664', (105, 112))	('depletion', 'Var', (44, 53))	('cancers', 'Disease', (105, 112))	('cancers', 'Disease', 'MESH:D009369', (105, 112))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('macroH2A1', 'Gene', '26914', (34, 43))	('Gene expression', 'MPA', (0, 15))	('macroH2A1', 'Gene', (34, 43))
375856	25306110	IMR90 or A549 cell lines expressing either green fluorescent protein (GFP), macroH2A1.1, macroH2A1.1 point mutants G224E, G314E, macroH2A1.2 or GFP-macro1.1 were generated by retroviral-mediated transduction using the pQCXIP expression system (Clontech) followed selection in 1 mug/ml puromycin.	('macroH2A1.1', 'Gene', (76, 87))	('G314E', 'Var', (122, 127))	('macroH2A1.1', 'Gene', '9555', (89, 100))	('G314E', 'Mutation', 'p.G314E', (122, 127))	('IMR90', 'CellLine', 'CVCL:0347', (0, 5))	('G224E', 'Var', (115, 120))	('puromycin', 'Chemical', 'MESH:D011691', (285, 294))	('G224E', 'Mutation', 'p.G224E', (115, 120))	('macroH2A1.2', 'Gene', '9555', (129, 140))	('macroH2A1.1', 'Gene', '9555', (76, 87))	('A549', 'CellLine', 'CVCL:0023', (9, 13))	('macroH2A1.1', 'Gene', (89, 100))	('macroH2A1.2', 'Gene', (129, 140))
375858	25306110	Where indicated cells were treated with 10 muM PJ-34 (Enzo, ALX-270-289-M005), 10 muM BYK204165 (Sigma, B3188), 25 nM of Trichostain A (TSA) (Sigma, T8552), 75 muM of Sirtinol (Sigma, s7942) and 20 muM C646 (p300 and CBP inhibitor, Millipore-Calbiochem, 382113).	('PJ-34', 'Chemical', 'MESH:C434926', (47, 52))	('muM', 'Gene', '56925', (43, 46))	('p300', 'Gene', (208, 212))	('muM', 'Gene', '56925', (82, 85))	('muM', 'Gene', (43, 46))	('muM', 'Gene', (82, 85))	('p300', 'Gene', '2033', (208, 212))	('CBP', 'Gene', '1387', (217, 220))	('PJ-34', 'Var', (47, 52))	('muM', 'Gene', '56925', (160, 163))	('muM', 'Gene', (160, 163))	('K20', 'Gene', '54474', (88, 91))	('CBP', 'Gene', (217, 220))	('ALX', 'Gene', (60, 63))	('Sirtinol', 'Chemical', 'MESH:C439060', (167, 175))	('TSA', 'Chemical', '-', (136, 139))	('C646', 'Chemical', '-', (202, 206))	('muM', 'Gene', '56925', (198, 201))	('muM', 'Gene', (198, 201))	('Trichostain A', 'Chemical', '-', (121, 134))	('ALX', 'Gene', '84941', (60, 63))	('K20', 'Gene', (88, 91))
375871	25306110	Then immunoprecipitations were carried out using 150 mul supernatant of the MNase reaction, 200 mul HEGTw/300 buffer (20mM Tris PH 7.9, 1mM EDTA, 5% Glycerol, 0.1% Tween-20, 300mM NaCl), 40 mul Protein A beads and either no antibody (negative control), or antibody against H2BK12ac (10 mul), H2BK120ac (10 mul), H3K4me3 (2 mul) or H3K27me3 (3 mul).	('H3K27me3', 'Var', (331, 339))	('H2BK12ac', 'Protein', (273, 281))	('H3K4me3', 'Var', (312, 319))	('HEGTw', 'Chemical', '-', (100, 105))	('H2BK12ac', 'Chemical', '-', (273, 281))	('NaCl', 'Chemical', 'MESH:D012965', (180, 184))	('EDTA', 'Chemical', 'MESH:D004492', (140, 144))	('Tris', 'Chemical', '-', (123, 127))	('H2BK120ac', 'Var', (292, 301))
375878	25306110	The supernatant was used in immunoprecipitations at 4 C overnight with antibodies against histone H3 (4 mul), macroH2A1 (8 mul), H2BK12ac (5 mul), H2BK120ac (5 mul), PARP-1 (20 mul), CBP (5 mul), GCN5 (10 mul), PCAF(10 mul) as indicated, then incubated with 40 mul protein A-agarose beads at 4 C for 2 hr.	('macroH2A1', 'Gene', (110, 119))	('CBP', 'Gene', '1387', (183, 186))	('CBP', 'Gene', (183, 186))	('PARP-1', 'Gene', (166, 172))	('PCAF', 'Gene', '8850', (211, 215))	('GCN5', 'Gene', (196, 200))	('H2BK12ac', 'Var', (129, 137))	('PARP-1', 'Gene', '142', (166, 172))	('H2BK12ac', 'Chemical', '-', (129, 137))	('GCN5', 'Gene', '2648', (196, 200))	('agarose', 'Chemical', 'MESH:D012685', (275, 282))	('K120', 'Chemical', '-', (150, 154))	('PCAF', 'Gene', (211, 215))	('macroH2A1', 'Gene', '26914', (110, 119))
375900	25306110	Enriched functional annotations among genes regulated by depletion of macroH2A1 were determined with Ingenuity Pathway Analysis (Ingenuity Systems, version 18030641).	('macroH2A1', 'Gene', (70, 79))	('macroH2A1', 'Gene', '26914', (70, 79))	('depletion', 'Var', (57, 66))
375912	30348169	Targeting histone methyltransferase G9a inhibits growth and Wnt signaling pathway by epigenetically regulating HP1alpha and APC2 gene expression in non-small cell lung cancer Dysregulated histone methyltransferase G9a may represent a potential cancer therapeutic target.	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (148, 174))	('G9a', 'Gene', (214, 217))	('APC2', 'Gene', (124, 128))	('cancer', 'Disease', (168, 174))	('cancer', 'Disease', 'MESH:D009369', (244, 250))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('HP1alpha', 'Gene', (111, 119))	('G9a', 'Gene', (36, 39))	('regulating', 'Reg', (100, 110))	('epigenetically', 'Var', (85, 99))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (152, 174))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('G9a', 'Gene', '10919', (214, 217))	('APC2', 'Gene', '10297', (124, 128))	('cancer', 'Disease', (244, 250))	('HP1alpha', 'Gene', '23468', (111, 119))	('G9a', 'Gene', '10919', (36, 39))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('lung cancer', 'Phenotype', 'HP:0100526', (163, 174))	('inhibits', 'NegReg', (40, 48))
375918	30348169	Multiple tumor-associated genes including HP1alpha, APC2 are differentially expressed; and signaling pathways involved in cellular growth, adhesion, angiogenesis, hypoxia, apoptosis, and canonical Wnt signaling pathways are significantly altered in A549, H1299, and H1975 cells upon G9a knockdown.	('H1299', 'CellLine', 'CVCL:0060', (255, 260))	('cellular growth', 'CPA', (122, 137))	('altered', 'Reg', (238, 245))	('canonical Wnt signaling pathways', 'Pathway', (187, 219))	('APC2', 'Gene', (52, 56))	('tumor', 'Disease', (9, 14))	('H1975', 'Var', (266, 271))	('apoptosis', 'CPA', (172, 181))	('H1975', 'CellLine', 'CVCL:1511', (266, 271))	('HP1alpha', 'Gene', '23468', (42, 50))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('adhesion', 'CPA', (139, 147))	('hypoxia', 'Disease', (163, 170))	('signaling pathways', 'Pathway', (91, 109))	('angiogenesis', 'CPA', (149, 161))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('A549', 'CellLine', 'CVCL:0023', (249, 253))	('hypoxia', 'Disease', 'MESH:D000860', (163, 170))	('HP1alpha', 'Gene', (42, 50))
375920	30348169	Restoring HP1alpha and silencing APC2 respectively attenuated the inhibitory effects on cell proliferation and Wnt signaling pathway in cancer cells in which G9a was silenced or suppressed.	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('attenuated', 'NegReg', (51, 61))	('silencing', 'Var', (23, 32))	('cancer', 'Disease', (136, 142))	('cell proliferation', 'CPA', (88, 106))	('Wnt signaling pathway', 'Pathway', (111, 132))	('APC2', 'Gene', (33, 37))	('HP1alpha', 'Gene', (10, 18))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('HP1alpha', 'Gene', '23468', (10, 18))
375921	30348169	These findings demonstrate that overexpressed G9a represents a promising therapeutic target, and targeting G9a potentially suppresses growth and Wnt signaling pathway partially through down-regulating HP1alpha and epigenetically restoring these tumor suppressors such as APC2 that are silenced in NSCLC.	('epigenetically', 'Var', (214, 228))	('down-regulating', 'NegReg', (185, 200))	('HP1alpha', 'Gene', '23468', (201, 209))	('APC2', 'Gene', (271, 275))	('G9a', 'Gene', (107, 110))	('HP1alpha', 'Gene', (201, 209))	('restoring', 'PosReg', (229, 238))	('tumor', 'Disease', 'MESH:D009369', (245, 250))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('suppresses', 'NegReg', (123, 133))	('NSCLC', 'Disease', (297, 302))	('tumor', 'Disease', (245, 250))	('NSCLC', 'Disease', 'MESH:D002289', (297, 302))
375925	30348169	Recent studies have uncovered an important role for epigenetic changes in tumor progression and treatment resistance.	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('epigenetic changes', 'Var', (52, 70))	('tumor', 'Disease', (74, 79))	('treatment resistance', 'CPA', (96, 116))
375927	30348169	Studies have revealed that G9a is overexpressed in a number of cancers, including esophageal squamous cell carcinoma, hepatocellular carcinoma, brain cancer, multiple myeloma, and aggressive ovarian carcinoma; and overexpressed G9a is found to be associated with enhanced proliferation and metastasis of various cancer cells.	('multiple myeloma', 'Phenotype', 'HP:0006775', (158, 174))	('esophageal squamous cell carcinoma', 'Disease', (82, 116))	('G9a', 'Gene', (228, 231))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (118, 142))	('cancer', 'Disease', (312, 318))	('brain cancer', 'Disease', (144, 156))	('carcinoma', 'Phenotype', 'HP:0030731', (199, 208))	('enhanced', 'PosReg', (263, 271))	('overexpressed', 'PosReg', (34, 47))	('cancer', 'Phenotype', 'HP:0002664', (312, 318))	('multiple myeloma', 'Disease', 'MESH:D009101', (158, 174))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('hepatocellular carcinoma', 'Disease', (118, 142))	('cancer', 'Disease', (150, 156))	('overexpressed', 'Var', (214, 227))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (82, 116))	('aggressive ovarian carcinoma', 'Disease', 'MESH:D010051', (180, 208))	('cancers', 'Phenotype', 'HP:0002664', (63, 70))	('cancer', 'Disease', (63, 69))	('cancers', 'Disease', (63, 70))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('multiple myeloma', 'Disease', (158, 174))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (93, 116))	('cancer', 'Disease', 'MESH:D009369', (312, 318))	('brain cancer', 'Phenotype', 'HP:0030692', (144, 156))	('metastasis', 'CPA', (290, 300))	('aggressive ovarian carcinoma', 'Disease', (180, 208))	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('proliferation', 'CPA', (272, 285))	('brain cancer', 'Disease', 'MESH:D001932', (144, 156))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (191, 208))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (118, 142))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('cancers', 'Disease', 'MESH:D009369', (63, 70))
375928	30348169	G9a is shown to directly bind DNA methyltransferase 1 (DNMT1), and G9a and DNMT1 colocalize with H3K9me2 on heterochromatic regions of chromosome.	('DNMT1', 'Gene', (55, 60))	('DNMT1', 'Gene', '1786', (55, 60))	('colocalize', 'Reg', (81, 91))	('DNMT1', 'Gene', (75, 80))	('G9a', 'Var', (67, 70))	('H3K9me2', 'Protein', (97, 104))	('DNA methyltransferase 1', 'Gene', (30, 53))	('DNMT1', 'Gene', '1786', (75, 80))	('bind', 'Interaction', (25, 29))	('DNA methyltransferase 1', 'Gene', '1786', (30, 53))
375929	30348169	The complex of DNMT1 and G9a enhances DNA and histone methylation for stable repression of gene expression.	('enhances', 'PosReg', (29, 37))	('DNMT1', 'Gene', (15, 20))	('DNMT1', 'Gene', '1786', (15, 20))	('G9a', 'Var', (25, 28))	('complex', 'Var', (4, 11))
375930	30348169	Generally speaking, G9a may participate in carcinogenesis through either suppression of tumor suppressors, such as CDH1/E-Cadherin) and p53, or activation of oncogenic signaling pathways such as hypoxia-response via transcriptional repression of a number of critical tumor suppressors or inhibitors in a histone or non-histone dependent manner in various human cancers.	('participate', 'Reg', (28, 39))	('cancers', 'Disease', (361, 368))	('suppression', 'NegReg', (73, 84))	('tumor', 'Disease', 'MESH:D009369', (267, 272))	('hypoxia', 'Disease', 'MESH:D000860', (195, 202))	('p53', 'Gene', '7157', (136, 139))	('E-Cadherin', 'Gene', (120, 130))	('transcriptional', 'Var', (216, 231))	('carcinogenesis', 'Disease', (43, 57))	('tumor', 'Phenotype', 'HP:0002664', (267, 272))	('activation', 'PosReg', (144, 154))	('CDH1', 'Gene', '999', (115, 119))	('tumor', 'Disease', (88, 93))	('p53', 'Gene', (136, 139))	('carcinogenesis', 'Disease', 'MESH:D063646', (43, 57))	('repression', 'NegReg', (232, 242))	('cancers', 'Disease', 'MESH:D009369', (361, 368))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('CDH1', 'Gene', (115, 119))	('G9a', 'Var', (20, 23))	('human', 'Species', '9606', (355, 360))	('oncogenic signaling pathways', 'Pathway', (158, 186))	('cancer', 'Phenotype', 'HP:0002664', (361, 367))	('E-Cadherin', 'Gene', '999', (120, 130))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('hypoxia', 'Disease', (195, 202))	('tumor', 'Disease', (267, 272))	('cancers', 'Phenotype', 'HP:0002664', (361, 368))
375932	30348169	Another study demonstrated that G9a promoted invasion and metastasis by regulation of the epithelial cellular adhesion molecule (EpCAM) in lung cancer.	('lung cancer', 'Disease', (139, 150))	('epithelial cellular adhesion molecule', 'Gene', '4072', (90, 127))	('lung cancer', 'Phenotype', 'HP:0100526', (139, 150))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('regulation', 'Reg', (72, 82))	('lung cancer', 'Disease', 'MESH:D008175', (139, 150))	('EpCAM', 'Gene', (129, 134))	('EpCAM', 'Gene', '4072', (129, 134))	('epithelial cellular adhesion molecule', 'Gene', (90, 127))	('promoted', 'PosReg', (36, 44))	('G9a', 'Var', (32, 35))
375933	30348169	However, it is still largely unknown about the targeting genes and signaling pathways by which G9a is involved in the disease progression of lung cancer.	('G9a', 'Var', (95, 98))	('involved', 'Reg', (102, 110))	('lung cancer', 'Disease', (141, 152))	('lung cancer', 'Phenotype', 'HP:0100526', (141, 152))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('lung cancer', 'Disease', 'MESH:D008175', (141, 152))
375935	30348169	Inhibition of Wnt signaling pathway has been confirmed to suppress cellular proliferation in NSCLC cell lines, therefore, Wnt signaling pathway is a strong candidate target for therapy.	('NSCLC', 'Disease', (93, 98))	('cellular proliferation', 'CPA', (67, 89))	('NSCLC', 'Disease', 'MESH:D002289', (93, 98))	('Wnt signaling pathway', 'Pathway', (14, 35))	('Inhibition', 'Var', (0, 10))	('suppress', 'NegReg', (58, 66))
375938	30348169	Notably, APC2 is frequently inactivated by promoter methylation in lung cancer.	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('lung cancer', 'Disease', 'MESH:D008175', (67, 78))	('promoter methylation', 'Var', (43, 63))	('APC2', 'Gene', (9, 13))	('lung cancer', 'Disease', (67, 78))	('lung cancer', 'Phenotype', 'HP:0100526', (67, 78))
375941	30348169	Interestingly, a previous study showed that epigenetic silencing of Wnt antagonists SFRP-1 and Axin-2 was associated with H3K9me2 and aberrant Wnt/beta-catenin signaling in neuroendocrine tumors of gastrointestinal tract, showing a connection between methylated H3K9 and activation of Wnt signaling pathway.	('beta-catenin', 'Gene', '1499', (147, 159))	('aberrant', 'Var', (134, 142))	('tumors', 'Phenotype', 'HP:0002664', (188, 194))	('H3K9me2', 'Protein', (122, 129))	('SFRP-1', 'Gene', (84, 90))	('associated', 'Reg', (106, 116))	('Axin-2', 'Gene', (95, 101))	('epigenetic silencing', 'Var', (44, 64))	('Axin-2', 'Gene', '8313', (95, 101))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('neuroendocrine tumors of gastrointestinal tract', 'Disease', 'MESH:D018358', (173, 220))	('tumors of gastrointestinal tract', 'Phenotype', 'HP:0007378', (188, 220))	('beta-catenin', 'Gene', (147, 159))	('SFRP-1', 'Gene', '6422', (84, 90))	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (173, 194))	('neuroendocrine tumors of gastrointestinal tract', 'Disease', (173, 220))
375942	30348169	Based on the evidences described above, we hypothesize that targeting G9a may suppress crucial signaling pathways involved in cancer malignancy including Wnt signaling pathway through epigenetically modulate gene expression in NSCLC.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('G9a', 'Gene', (70, 73))	('cancer malignancy', 'Disease', 'MESH:D009369', (126, 143))	('crucial signaling pathways', 'Pathway', (87, 113))	('NSCLC', 'Disease', (227, 232))	('Wnt signaling pathway', 'Pathway', (154, 175))	('NSCLC', 'Disease', 'MESH:D002289', (227, 232))	('cancer malignancy', 'Disease', (126, 143))	('gene expression', 'MPA', (208, 223))	('targeting', 'Var', (60, 69))	('suppress', 'NegReg', (78, 86))	('modulate', 'Reg', (199, 207))	('epigenetically', 'Var', (184, 198))
375943	30348169	In this study, we first examined aberrant G9a expression and deciphered its transcriptional regulatory network and highlighted its complex role in gene expression, and we found that APC2 was dramatically upregulated upon G9a knockdown, while heterochromatin protein 1 alpha (HP1alpha), which binds euchromatic loci during the process of gene silencing in cooperation with DNMT1, was significantly downregulated.	('heterochromatin protein 1 alpha', 'Gene', (242, 273))	('HP1alpha', 'Gene', '23468', (275, 283))	('G9a', 'Var', (221, 224))	('heterochromatin protein 1 alpha', 'Gene', '23468', (242, 273))	('DNMT1', 'Gene', '1786', (372, 377))	('knockdown', 'Var', (225, 234))	('APC2', 'Gene', (182, 186))	('downregulated', 'NegReg', (397, 410))	('HP1alpha', 'Gene', (275, 283))	('upregulated', 'PosReg', (204, 215))	('DNMT1', 'Gene', (372, 377))
375945	30348169	We demonstrated that inhibition of G9a suppressed cellular proliferation and Wnt signaling pathway in NSCLC cells, suggesting overexpressed G9a represents a potential therapeutic target for NSCLC treatment.	('NSCLC', 'Disease', 'MESH:D002289', (102, 107))	('G9a', 'Protein', (35, 38))	('Wnt signaling pathway', 'Pathway', (77, 98))	('cellular proliferation', 'CPA', (50, 72))	('NSCLC', 'Disease', (190, 195))	('inhibition', 'Var', (21, 31))	('NSCLC', 'Disease', 'MESH:D002289', (190, 195))	('NSCLC', 'Disease', (102, 107))	('suppressed', 'NegReg', (39, 49))
375954	30348169	Both gene set enrichment analysis (GSEA) and database for annotation, visualization and integrated discovery (DAVID) were used to analyzed the Gene Ontology and canonical pathways significantly modulated by the knockdown of G9a.	('GSEA', 'Chemical', '-', (35, 39))	('modulated', 'Reg', (194, 203))	('knockdown', 'Var', (211, 220))	('canonical pathways', 'Pathway', (161, 179))	('G9a', 'Gene', (224, 227))
375972	30348169	Importantly, statistical analysis revealed that in comparison to corresponding normal lung tissues, G9a mRNA was significantly higher in NSCLC samples (ratio to normal = 1.7, P &lt; 0.01).	('NSCLC', 'Disease', 'MESH:D002289', (137, 142))	('NSCLC', 'Disease', (137, 142))	('higher', 'PosReg', (127, 133))	('G9a', 'Var', (100, 103))
375979	30348169	RNA sequencing (RNA-Seq) analysis was utilized to characterize global gene expression change upon knockdown of G9a in A549 and H1299 NSCLC cells.	('G9a', 'Gene', (111, 114))	('knockdown', 'Var', (98, 107))	('NSCLC', 'Disease', (133, 138))	('A549', 'CellLine', 'CVCL:0023', (118, 122))	('NSCLC', 'Disease', 'MESH:D002289', (133, 138))	('H1299', 'CellLine', 'CVCL:0060', (127, 132))
375980	30348169	Unsupervised hierarchical clustering analysis of RNA-Seq data depicts the changes in global gene expression profile in these lung cancer cells upon knockdown of G9a (Fig.	('lung cancer', 'Disease', 'MESH:D008175', (125, 136))	('changes', 'Reg', (74, 81))	('global gene expression profile', 'MPA', (85, 115))	('G9a', 'Var', (161, 164))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('lung cancer', 'Disease', (125, 136))	('lung cancer', 'Phenotype', 'HP:0100526', (125, 136))	('knockdown', 'Var', (148, 157))
375982	30348169	Remarkably, knockdown of G9a had pronounced effects on the expression of important cancer-associated proteins including HP1alpha encoded by Chromobox 5 (CBX5), ATP-binding cassette sub-family G member 2 (ABCG2), angiopoietin-like 4 (ANGPTL4), APC2, urokinase plasminogen activator (u-PA), Junctophilin-3 (JPH3), Talin 1 (TLN1), and telomerase reverse transcriptase (TERT) etc.	('u-PA', 'Gene', '5328', (282, 286))	('ATP-binding cassette sub-family G member 2', 'Gene', (160, 202))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('angiopoietin-like 4', 'Gene', '101090747', (212, 231))	('expression', 'MPA', (59, 69))	('Chromobox 5', 'Gene', '101091461', (140, 151))	('HP1alpha', 'Gene', (120, 128))	('Talin 1', 'Gene', (312, 319))	('Junctophilin-3', 'Gene', (289, 303))	('knockdown', 'Var', (12, 21))	('Junctophilin-3', 'Gene', '101090161', (289, 303))	('telomerase reverse transcriptase', 'Gene', '100144612', (332, 364))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('CBX5', 'Gene', '101091461', (153, 157))	('Talin 1', 'Gene', '101093057', (312, 319))	('u-PA', 'Gene', (282, 286))	('effects', 'Reg', (44, 51))	('G9a', 'Gene', (25, 28))	('HP1alpha', 'Gene', '23468', (120, 128))	('telomerase reverse transcriptase', 'Gene', (332, 364))	('CBX5', 'Gene', (153, 157))	('Chromobox 5', 'Gene', (140, 151))	('ATP-binding cassette sub-family G member 2', 'Gene', '101094017', (160, 202))	('angiopoietin-like 4', 'Gene', (212, 231))	('cancer', 'Disease', (83, 89))
375983	30348169	Differential gene expression of these selected genes upon knockdown of G9a in A549, H1299, and H1975 were validated by qRT-PCR (Fig.	('knockdown', 'Var', (58, 67))	('H1299', 'CellLine', 'CVCL:0060', (84, 89))	('G9a', 'Gene', (71, 74))	('A549', 'CellLine', 'CVCL:0023', (78, 82))	('H1975', 'CellLine', 'CVCL:1511', (95, 100))
375984	30348169	Using GSEA, we identified multiple gene sets from the Kyoto Encyclopedia of Genes and Genomes (KEGG) that were significantly enriched in lung cancer cells upon G9a knockdown (Fig.	('lung cancer', 'Disease', (137, 148))	('lung cancer', 'Phenotype', 'HP:0100526', (137, 148))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('lung cancer', 'Disease', 'MESH:D008175', (137, 148))	('knockdown', 'Var', (164, 173))	('GSEA', 'Chemical', '-', (6, 10))
375988	30348169	3a left panel, G9a siRNA significantly decreased the levels of G9a and H3K9-Me2 protien, knockdown of G9a resulted in a significant decrease of in vitro cellular proliferation in three NSCLC cells over 72 h post-transfection of G9a siRNA in comparison with control cells transfected with scramble siRNA (Fig.	('NSCLC', 'Disease', 'MESH:D002289', (185, 190))	('G9a', 'Var', (102, 105))	('in vitro cellular proliferation', 'CPA', (144, 175))	('levels', 'MPA', (53, 59))	('knockdown', 'Var', (89, 98))	('decreased', 'NegReg', (39, 48))	('G9a', 'Var', (228, 231))	('decrease', 'NegReg', (132, 140))	('H3K9-Me2', 'Chemical', '-', (71, 79))	('NSCLC', 'Disease', (185, 190))
375989	30348169	In addition, we found that knockdown of G9a induced cell cycle arrest of A549 in the G1/S phase (Additional file 2: Figure S1a) or H1299 cells in G2/M phase (Additional file 2: Figure S1b).	('cell cycle arrest', 'Phenotype', 'HP:0011018', (52, 69))	('knockdown', 'Var', (27, 36))	('A549', 'CellLine', 'CVCL:0023', (73, 77))	('H1299', 'CellLine', 'CVCL:0060', (131, 136))	('G9a', 'Gene', (40, 43))	('cell cycle arrest', 'CPA', (52, 69))
375991	30348169	Herein, we found that knockdown of G9a slightly upregulated wild-type p53 protein in A549 cells, but significantly inhibited the proliferation of all three NSCLC cells regardless of their p53 status (Additional file 2: Figure S2), indicating this regulation may be not critical to proliferation of NSCLC.	('A549', 'CellLine', 'CVCL:0023', (85, 89))	('NSCLC', 'Disease', 'MESH:D002289', (298, 303))	('p53', 'Gene', (70, 73))	('p53', 'Gene', '7157', (70, 73))	('knockdown', 'Var', (22, 31))	('G9a', 'Var', (35, 38))	('proliferation', 'CPA', (129, 142))	('p53', 'Gene', (188, 191))	('NSCLC', 'Disease', (156, 161))	('protein', 'Protein', (74, 81))	('inhibited', 'NegReg', (115, 124))	('NSCLC', 'Disease', (298, 303))	('p53', 'Gene', '7157', (188, 191))	('NSCLC', 'Disease', 'MESH:D002289', (156, 161))	('upregulated', 'PosReg', (48, 59))
375992	30348169	Interestingly, RNA-Seq analysis showed that knockdown of G9a downregulated HP1alpha in these NSCLC cells.	('NSCLC', 'Disease', (93, 98))	('downregulated', 'NegReg', (61, 74))	('NSCLC', 'Disease', 'MESH:D002289', (93, 98))	('G9a', 'Gene', (57, 60))	('HP1alpha', 'Gene', '23468', (75, 83))	('knockdown', 'Var', (44, 53))	('HP1alpha', 'Gene', (75, 83))
375994	30348169	Therefore, we tested if downregulation of HP1alpha contributed to the inhibition of cell proliferation seen when G9a was silenced, and found that knockdown of HP1alpha by siRNA significantly suppressed in vitro proliferation of A549, H1299 and H1975 cells (Additional file 2: Figure S3).	('knockdown', 'Var', (146, 155))	('suppressed', 'NegReg', (191, 201))	('HP1alpha', 'Gene', '23468', (159, 167))	('HP1alpha', 'Gene', '23468', (42, 50))	('H1299', 'CellLine', 'CVCL:0060', (234, 239))	('HP1alpha', 'Gene', (159, 167))	('downregulation', 'NegReg', (24, 38))	('A549', 'CellLine', 'CVCL:0023', (228, 232))	('cell proliferation', 'CPA', (84, 102))	('tested', 'Reg', (14, 20))	('HP1alpha', 'Gene', (42, 50))	('H1975', 'CellLine', 'CVCL:1511', (244, 249))
375998	30348169	UNC0638 treatment dramatically decreased H3K9Me2 protein level (upper panel) and cellular proliferation (lower panel) of A549 (Fig.	('UNC0638', 'Var', (0, 7))	('H3K9Me2 protein level', 'MPA', (41, 62))	('decreased', 'NegReg', (31, 40))	('A549', 'CellLine', 'CVCL:0023', (121, 125))	('cellular proliferation', 'CPA', (81, 103))
376001	30348169	The IC50 of UNC0638 was about 5.0, 2.5, and 3.5 muM for A549, H1299, and H1975 respectively.	('H1299', 'CellLine', 'CVCL:0060', (62, 67))	('UNC0638', 'Gene', (12, 19))	('H1975', 'CellLine', 'CVCL:1511', (73, 78))	('A549', 'CellLine', 'CVCL:0023', (56, 60))	('H1975', 'Var', (73, 78))	('H1299', 'Var', (62, 67))	('A549', 'Var', (56, 60))
376003	30348169	By using RNA-Seq and GSEA analysis, we found that knockdown of G9a enriched beta-catenin destruction complex disassembly and down-regulated Wnt signaling pathway, indicating targeting G9a may suppress Wnt signaling pathway.	('disassembly', 'NegReg', (109, 120))	('Wnt signaling pathway', 'Pathway', (140, 161))	('knockdown', 'Var', (50, 59))	('beta-catenin', 'Gene', (76, 88))	('down-regulated', 'NegReg', (125, 139))	('suppress', 'NegReg', (192, 200))	('Wnt signaling pathway', 'Pathway', (201, 222))	('beta-catenin', 'Gene', '1499', (76, 88))	('G9a', 'Gene', (63, 66))	('GSEA', 'Chemical', '-', (21, 25))
376007	30348169	TOPFlash-Luc reporter assays demonstrated that knockdown of G9a significantly suppressed both basic and the induced TCF transcriptional activity by Wnt3a, a ligand/activator of Wnt signaling pathway in A549 (Fig.	('TCF', 'Gene', '3172', (116, 119))	('A549', 'CellLine', 'CVCL:0023', (202, 206))	('G9a', 'Var', (60, 63))	('suppressed', 'NegReg', (78, 88))	('basic', 'MPA', (94, 99))	('Wnt3a', 'Gene', '89780', (148, 153))	('Wnt3a', 'Gene', (148, 153))	('TCF', 'Gene', (116, 119))
376015	30348169	By RNA-Seq, we found that APC2, which forms a destructive complex capable of binding beta-catenin to function as an important inhibitor of Wnt signaling pathway, was dramatically upregulated upon G9a knockdown, suggesting that targeting G9a would restore these genes silenced by epigenetic machinery.	('knockdown', 'Var', (200, 209))	('beta-catenin', 'Gene', '1499', (85, 97))	('G9a', 'Var', (196, 199))	('upregulated', 'PosReg', (179, 190))	('binding', 'Interaction', (77, 84))	('Wnt signaling pathway', 'Pathway', (139, 160))	('beta-catenin', 'Gene', (85, 97))	('APC2', 'Gene', (26, 30))
376016	30348169	To test this hypothesis, we suppressed G9a in A549, H1299, and H1975 cells by UNC0638 treatment, and quantitative RT-PCR (Fig.	('UNC0638', 'Var', (78, 85))	('suppressed', 'NegReg', (28, 38))	('A549', 'CellLine', 'CVCL:0023', (46, 50))	('G9a', 'Protein', (39, 42))	('H1299', 'CellLine', 'CVCL:0060', (52, 57))	('H1975', 'CellLine', 'CVCL:1511', (63, 68))
376018	30348169	Western blot analysis confirmed that UNC0638 treatment dramatically reduced the level of H3K9Me2, increased the levels of APC2, DKK1, and WIF1 proteins, and resulted in decreased beta-catenin in these cancer cells (Fig.	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('UNC0638', 'Var', (37, 44))	('beta-catenin', 'Gene', '1499', (179, 191))	('WIF1', 'Gene', (138, 142))	('cancer', 'Disease', (201, 207))	('APC2', 'MPA', (122, 126))	('H3K9Me2', 'Protein', (89, 96))	('WIF1', 'Gene', '11197', (138, 142))	('DKK1', 'Gene', '22943', (128, 132))	('increased', 'PosReg', (98, 107))	('levels', 'MPA', (112, 118))	('DKK1', 'Gene', (128, 132))	('decreased', 'NegReg', (169, 178))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('reduced', 'NegReg', (68, 75))	('beta-catenin', 'Gene', (179, 191))
376020	30348169	TOPFlash-Luc reporter assays showed that UNC0638 treatment significantly suppressed the luciferase activity in both A549 (Fig.	('luciferase', 'Enzyme', (88, 98))	('UNC0638', 'Var', (41, 48))	('activity', 'MPA', (99, 107))	('suppressed', 'NegReg', (73, 83))	('A549', 'CellLine', 'CVCL:0023', (116, 120))
376022	30348169	5c, right panel), and knockdown of APC2 by siRNA transfection partially attenuated the inhibitory effect of UNC0638 on Wnt3a-stimulated reporter activity in these two cells, indicating upregulation of APC2 contributed to Wnt inhibition upon suppression of G9a.	('inhibitory effect', 'MPA', (87, 104))	('attenuated', 'NegReg', (72, 82))	('Wnt3a', 'Gene', (119, 124))	('knockdown', 'Var', (22, 31))	('Wnt3a', 'Gene', '89780', (119, 124))	('APC2', 'Gene', (35, 39))	('upregulation', 'PosReg', (185, 197))
376025	30348169	Using RNA-Seq analysis, we found that besides APC2 other genes including ICAM5, JPH3, MGMT, MMP2, and RASSF1 whose expression are epigenetically silenced, were also upregulated with G9a inhibition (Additional file 2: Figure S5).	('G9a', 'Protein', (182, 185))	('JPH3', 'Gene', (80, 84))	('MGMT', 'Gene', (86, 90))	('MMP2', 'Gene', '4313', (92, 96))	('MGMT', 'Gene', '4255', (86, 90))	('RASSF1', 'Gene', '11186', (102, 108))	('upregulated', 'PosReg', (165, 176))	('ICAM5', 'Gene', '7087', (73, 78))	('APC2', 'Gene', (46, 50))	('inhibition', 'Var', (186, 196))	('ICAM5', 'Gene', (73, 78))	('RASSF1', 'Gene', (102, 108))	('MMP2', 'Gene', (92, 96))
376033	30348169	These data suggested that UNC0638 may restore these silenced genes' expression through promoter demethylation in non-small cell lung cancer cells.	('expression', 'MPA', (68, 78))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (113, 139))	('restore', 'PosReg', (38, 45))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (113, 139))	('promoter demethylation', 'Var', (87, 109))	('non-small cell lung cancer', 'Disease', (113, 139))	('lung cancer', 'Phenotype', 'HP:0100526', (128, 139))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (117, 139))	('UNC0638', 'Var', (26, 33))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
376035	30348169	Taken together, the above data indicate that G9a may contribute to lung cancer cellular proliferation partially through transcriptional suppression of Wnt inhibitors expression.	('contribute', 'Reg', (53, 63))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('lung cancer', 'Disease', 'MESH:D008175', (67, 78))	('Wnt', 'Protein', (151, 154))	('G9a', 'Var', (45, 48))	('suppression', 'NegReg', (136, 147))	('lung cancer', 'Disease', (67, 78))	('lung cancer', 'Phenotype', 'HP:0100526', (67, 78))
376039	30348169	The average tumor size in the mice treated with UNC0638 on day 28 after the implantation was significantly lower than the tumor weight in the mice treated with PBS (Fig.	('mice', 'Species', '10090', (30, 34))	('lower', 'NegReg', (107, 112))	('PBS', 'Disease', 'MESH:D011535', (160, 163))	('PBS', 'Disease', (160, 163))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('mice', 'Species', '10090', (142, 146))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('UNC0638', 'Var', (48, 55))	('tumor', 'Disease', (12, 17))	('tumor', 'Disease', (122, 127))
376040	30348169	These results revealed that UNC0638 significantly inhibited tumor growth in a NSG xenograft model.	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('UNC0638', 'Var', (28, 35))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Disease', (60, 65))	('inhibited', 'NegReg', (50, 59))
376043	30348169	Concurrently, beta-catenin was decreased in the xenograft tissues treated with UNC0638, indicating a suppression of Wnt signaling pathway activation.	('beta-catenin', 'Gene', (14, 26))	('Wnt signaling pathway', 'Pathway', (116, 137))	('beta-catenin', 'Gene', '1499', (14, 26))	('decreased', 'NegReg', (31, 40))	('UNC0638', 'Var', (79, 86))	('suppression', 'NegReg', (101, 112))
376048	30348169	We herein found that G9a inhibition significantly suppressed the proliferation of NSCLC cells regardless of p53 status, indicating this regulation may be not critical to NSCLC proliferation.	('proliferation', 'CPA', (65, 78))	('suppressed', 'NegReg', (50, 60))	('p53', 'Gene', (108, 111))	('p53', 'Gene', '7157', (108, 111))	('NSCLC', 'Disease', (170, 175))	('inhibition', 'Var', (25, 35))	('NSCLC', 'Disease', 'MESH:D002289', (170, 175))	('NSCLC', 'Disease', (82, 87))	('G9a', 'Protein', (21, 24))	('NSCLC', 'Disease', 'MESH:D002289', (82, 87))
376050	30348169	Therefore, G9a may contribute to malignancy through various molecules and mechanisms in cancers.	('contribute', 'Reg', (19, 29))	('cancers', 'Disease', 'MESH:D009369', (88, 95))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('G9a', 'Var', (11, 14))	('cancers', 'Disease', (88, 95))	('malignancy', 'Disease', 'MESH:D009369', (33, 43))	('malignancy', 'Disease', (33, 43))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))
376051	30348169	A previous study showed that G9a promoted lung cancer invasion and metastasis by silencing the cell adhesion molecule EpCAM, and knockdown of G9a in fast-growing cell lines led to a less aggressive phenotype.	('promoted', 'PosReg', (33, 41))	('G9a', 'Var', (29, 32))	('EpCAM', 'Gene', (118, 123))	('metastasis', 'CPA', (67, 77))	('knockdown', 'Var', (129, 138))	('silencing', 'NegReg', (81, 90))	('lung cancer', 'Disease', (42, 53))	('G9a', 'Var', (142, 145))	('lung cancer', 'Phenotype', 'HP:0100526', (42, 53))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('EpCAM', 'Gene', '4072', (118, 123))	('lung cancer', 'Disease', 'MESH:D008175', (42, 53))
376052	30348169	We only observed a minimal upregulation of EpCAM in two of three NSCLC cells upon G9a knockdown, indicating other molecular mechanisms and substrates through which G9a may promote carcinogenesis in NSCLC.	('carcinogenesis', 'Disease', 'MESH:D063646', (180, 194))	('knockdown', 'Var', (86, 95))	('G9a', 'Var', (164, 167))	('NSCLC', 'Disease', 'MESH:D002289', (65, 70))	('promote', 'PosReg', (172, 179))	('EpCAM', 'Gene', (43, 48))	('NSCLC', 'Disease', (65, 70))	('NSCLC', 'Disease', (198, 203))	('EpCAM', 'Gene', '4072', (43, 48))	('NSCLC', 'Disease', 'MESH:D002289', (198, 203))	('carcinogenesis', 'Disease', (180, 194))
376056	30348169	A study showed that G9a knockdown in breast cancer changed a cohort of genes involved in EMT, a phenotypic conversion linked with metastasis.	('breast cancer', 'Disease', (37, 50))	('breast cancer', 'Phenotype', 'HP:0003002', (37, 50))	('breast cancer', 'Disease', 'MESH:D001943', (37, 50))	('cohort of genes', 'MPA', (61, 76))	('EMT', 'CPA', (89, 92))	('knockdown', 'Var', (24, 33))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('changed', 'Reg', (51, 58))
376057	30348169	In their study, they found epithelial markers such as claudin and E-cadherin were upregulated after G9a depletion, whereas mesenchymal markers, including N-cadherin and vimentin, were downregulated.	('N-cadherin', 'Gene', (154, 164))	('epithelial', 'CPA', (27, 37))	('N-cadherin', 'Gene', '1000', (154, 164))	('vimentin', 'Gene', '7431', (169, 177))	('upregulated', 'PosReg', (82, 93))	('G9a', 'Var', (100, 103))	('vimentin', 'Gene', (169, 177))	('claudin', 'Protein', (54, 61))	('E-cadherin', 'Gene', (66, 76))	('E-cadherin', 'Gene', '999', (66, 76))	('depletion', 'Var', (104, 113))
376058	30348169	Consistent with previous studies, we also showed that knockdown of G9a significantly suppressed cell proliferation in human NSCLC cell lines.	('cell proliferation in human', 'CPA', (96, 123))	('knockdown', 'Var', (54, 63))	('suppressed', 'NegReg', (85, 95))	('G9a', 'Gene', (67, 70))	('NSCLC', 'Disease', (124, 129))	('NSCLC', 'Disease', 'MESH:D002289', (124, 129))	('human', 'Species', '9606', (118, 123))
376059	30348169	HP1 binds specific euchromatic loci in mammals during the process of gene silencing in conjunction with methylated H3K9 by G9a, however, mechanism of action of HP1 at euchromatic loci is not well understood.	('HP1', 'Gene', '23468', (160, 163))	('HP1', 'Gene', (160, 163))	('gene', 'Var', (69, 73))	('HP1', 'Gene', '23468', (0, 3))	('HP1', 'Gene', (0, 3))
376060	30348169	A previous study showed that the levels of all isoforms of HP1 were reduced after HDAC inhibition, indicating complex interactions between these chromatin modulators.	('levels', 'MPA', (33, 39))	('interactions', 'Interaction', (118, 130))	('reduced', 'NegReg', (68, 75))	('HP1', 'Gene', '23468', (59, 62))	('HP1', 'Gene', (59, 62))	('inhibition', 'Var', (87, 97))
376061	30348169	Interestingly, we herein found that both mRNA and protein level of HP1alpha were down-regulated upon G9a knockdown in these two cells, and we further found that G9a inhibitor UNC0638 significantly decreased HP1alpha that was accompanied by decreased H3K9-Me2 (Additional file 2: Figure S6), indicating HP1alpha may be also epigenetically regulated by H3K9Me2 and G9a, although the underlying mechanisms remain to be identified.	('HP1alpha', 'Gene', '23468', (207, 215))	('down-regulated', 'NegReg', (81, 95))	('HP1alpha', 'Gene', '23468', (302, 310))	('HP1alpha', 'Gene', (207, 215))	('decreased', 'NegReg', (240, 249))	('HP1alpha', 'Gene', (302, 310))	('UNC0638', 'Var', (175, 182))	('HP1alpha', 'Gene', '23468', (67, 75))	('HP1alpha', 'Gene', (67, 75))	('protein level', 'MPA', (50, 63))	('H3K9-Me2', 'MPA', (250, 258))	('decreased', 'NegReg', (197, 206))	('H3K9-Me2', 'Chemical', '-', (250, 258))
376062	30348169	A previous study demonstrated that overexpressed HP1 showed a significant correlation with disease progression and metastasis in breast cancer, and HP1alpha levels were associated with increased cell proliferation.	('metastasis in breast cancer', 'Disease', (115, 142))	('HP1', 'Gene', (49, 52))	('HP1', 'Gene', '23468', (148, 151))	('breast cancer', 'Phenotype', 'HP:0003002', (129, 142))	('HP1', 'Gene', (148, 151))	('cell proliferation', 'CPA', (195, 213))	('HP1alpha', 'Gene', '23468', (148, 156))	('overexpressed', 'Var', (35, 48))	('HP1alpha', 'Gene', (148, 156))	('disease progression', 'CPA', (91, 110))	('metastasis in breast cancer', 'Disease', 'MESH:D009362', (115, 142))	('HP1', 'Gene', '23468', (49, 52))	('increased', 'PosReg', (185, 194))	('correlation', 'Interaction', (74, 85))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
376063	30348169	We also observed that restoration of HP1alpha expression partially abolished inhibitory effect of G9a knockdown on cell proliferation, suggesting part of the effect of G9a on cancer cell proliferation was mediated by HP1alpha expression.	('HP1alpha', 'Gene', '23468', (217, 225))	('HP1alpha', 'Gene', (217, 225))	('cancer', 'Disease', (175, 181))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('knockdown', 'Var', (102, 111))	('G9a', 'Gene', (98, 101))	('HP1alpha', 'Gene', '23468', (37, 45))	('inhibitory effect', 'MPA', (77, 94))	('HP1alpha', 'Gene', (37, 45))	('cell proliferation', 'CPA', (115, 133))	('abolished', 'NegReg', (67, 76))	('mediated', 'Reg', (205, 213))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
376066	30348169	Studies have shown that Wnt signaling pathway can be enhanced by repression of expression of these Wnt inhibitors such as WIF1, SFRP, DDK1 through both genetic and epigenetic alterations in human cancers.	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('SFRP', 'Gene', (128, 132))	('cancers', 'Disease', 'MESH:D009369', (196, 203))	('DDK1', 'Gene', '92667', (134, 138))	('Wnt signaling pathway', 'Pathway', (24, 45))	('DDK1', 'Gene', (134, 138))	('cancers', 'Phenotype', 'HP:0002664', (196, 203))	('epigenetic alterations', 'Var', (164, 186))	('cancers', 'Disease', (196, 203))	('human', 'Species', '9606', (190, 195))	('repression', 'NegReg', (65, 75))	('WIF1', 'Gene', (122, 126))	('WIF1', 'Gene', '11197', (122, 126))	('enhanced', 'PosReg', (53, 61))
376067	30348169	Notably, expression of WIF1 is suppressed by promoter hypermethylation of WIF1 in NSCLC cells and tissues, and restoring WIF1 expression inhibits lung cancer cell growth.	('promoter hypermethylation', 'Var', (45, 70))	('restoring', 'Var', (111, 120))	('expression', 'MPA', (126, 136))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('lung cancer', 'Disease', 'MESH:D008175', (146, 157))	('lung cancer', 'Phenotype', 'HP:0100526', (146, 157))	('WIF1', 'Gene', (121, 125))	('WIF1', 'Gene', '11197', (121, 125))	('expression', 'MPA', (9, 19))	('WIF1', 'Gene', (74, 78))	('lung cancer', 'Disease', (146, 157))	('suppressed', 'NegReg', (31, 41))	('WIF1', 'Gene', (23, 27))	('NSCLC', 'Disease', (82, 87))	('inhibits', 'NegReg', (137, 145))	('WIF1', 'Gene', '11197', (23, 27))	('WIF1', 'Gene', '11197', (74, 78))	('NSCLC', 'Disease', 'MESH:D002289', (82, 87))
376068	30348169	We found that APC2, which forms a destruction complex capable of binding beta-catenin, was dramatically upregulated upon G9a knockdown.	('G9a knockdown', 'Var', (121, 134))	('knockdown', 'Var', (125, 134))	('beta-catenin', 'Gene', (73, 85))	('binding', 'Interaction', (65, 72))	('APC2', 'Gene', (14, 18))	('beta-catenin', 'Gene', '1499', (73, 85))	('upregulated', 'PosReg', (104, 115))
376070	30348169	Interestingly, APC2 is the most frequently inactivated tumor suppressor by promoter methylation in lung cancer.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('lung cancer', 'Disease', (99, 110))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Disease', (55, 60))	('promoter methylation', 'Var', (75, 95))	('lung cancer', 'Disease', 'MESH:D008175', (99, 110))	('APC2', 'Gene', (15, 19))	('lung cancer', 'Phenotype', 'HP:0100526', (99, 110))
376071	30348169	We demonstrated that targeting G9a suppressed Wnt signaling likely through restoring Wnt inhibitors such APC2, WIF1, and DKK1 expression.	('expression', 'MPA', (126, 136))	('WIF1', 'Gene', (111, 115))	('WIF1', 'Gene', '11197', (111, 115))	('targeting', 'Var', (21, 30))	('restoring', 'PosReg', (75, 84))	('suppressed', 'NegReg', (35, 45))	('Wnt signaling', 'MPA', (46, 59))	('DKK1', 'Gene', (121, 125))	('DKK1', 'Gene', '22943', (121, 125))	('APC2', 'Gene', (105, 109))	('G9a', 'Gene', (31, 34))
376077	30348169	Other studies demonstrated that methylation of H3K9 may collaborate with DNA methylation to regulate gene expression including these Wnt antagonists in human cancer.	('methylation', 'Var', (32, 43))	('H3K9', 'Protein', (47, 51))	('regulate gene expression', 'MPA', (92, 116))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('cancer', 'Disease', (158, 164))	('human', 'Species', '9606', (152, 157))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
376079	30348169	Consistently, a previous study revealed that H3K9me2 was associated with aberrant Wnt/beta-catenin signaling pathway in neuroendocrine tumors.	('neuroendocrine tumors', 'Disease', 'MESH:D018358', (120, 141))	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (120, 141))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('beta-catenin', 'Gene', (86, 98))	('neuroendocrine tumors', 'Disease', (120, 141))	('beta-catenin', 'Gene', '1499', (86, 98))	('H3K9me2', 'Var', (45, 52))	('aberrant', 'Var', (73, 81))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))	('associated', 'Reg', (57, 67))
376081	30348169	In summary, we found that G9a protein was overexpressed in a subgroup of NSCLC samples probably by gene amplification, hypoxia and/or other unknown mechanisms; in collaboration with HP1alpha and DNMT1, G9a epigenetically regulates gene expression through H3K9-Me2 and DNA methylation.	('HP1alpha', 'Gene', (182, 190))	('HP1alpha', 'Gene', '23468', (182, 190))	('gene expression', 'MPA', (231, 246))	('H3K9-Me2', 'Chemical', '-', (255, 263))	('overexpressed', 'PosReg', (42, 55))	('hypoxia', 'Disease', 'MESH:D000860', (119, 126))	('G9a epigenetically', 'Var', (202, 220))	('DNA methylation', 'Var', (268, 283))	('H3K9-Me2', 'Var', (255, 263))	('hypoxia', 'Disease', (119, 126))	('epigenetically', 'Var', (206, 220))	('NSCLC', 'Disease', (73, 78))	('DNMT1', 'Gene', (195, 200))	('regulates', 'Reg', (221, 230))	('NSCLC', 'Disease', 'MESH:D002289', (73, 78))	('DNMT1', 'Gene', '1786', (195, 200))
376082	30348169	Targeting G9a significantly inhibited in vitro and in vivo growth and Wnt signaling pathways partially through down-regulating HP1alpha and epigenetically restoring APC2, via promoter demethylation, which finally suppressed NSCLC progression (Fig.	('APC2', 'Gene', (165, 169))	('epigenetically', 'Var', (140, 154))	('down-regulating', 'NegReg', (111, 126))	('NSCLC', 'Disease', (224, 229))	('suppressed', 'NegReg', (213, 223))	('inhibited', 'NegReg', (28, 37))	('NSCLC', 'Disease', 'MESH:D002289', (224, 229))	('Wnt signaling pathways', 'Pathway', (70, 92))	('HP1alpha', 'Gene', '23468', (127, 135))	('HP1alpha', 'Gene', (127, 135))	('promoter demethylation', 'Var', (175, 197))
376123	30123241	For 2 out of the 12 data sets (breast invasive carcinoma, lung squamous cell carcinoma), the differential expression-based gene ranking outperforms the random forests-based gene ranking.	('breast invasive carcinoma, lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (31, 86))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (58, 86))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (63, 86))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('breast invasive carcinoma', 'Phenotype', 'HP:0003002', (31, 56))	('carcinoma', 'Phenotype', 'HP:0030731', (47, 56))	('t of ', 'Gene', '55079', (8, 13))	('t of ', 'Gene', (8, 13))	('differential', 'Var', (93, 105))	('outperforms', 'NegReg', (136, 147))
376234	27698488	High-throughput sequencing has identified thousands of somatic mutations across dozens of cancers, and there is a pressing need to identify the few that are pathologically relevant.	('mutations', 'Var', (63, 72))	('cancers', 'Disease', (90, 97))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('cancers', 'Disease', 'MESH:D009369', (90, 97))
376235	27698488	Here we use protein structure and interaction data to interrogate nonsynonymous somatic cancer mutations, identifying a set of 213 molecular interfaces (protein-protein, -small molecule or -nucleic acid) most often perturbed in cancer, highlighting several potentially novel cancer genes.	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('cancer', 'Disease', (228, 234))	('cancer', 'Phenotype', 'HP:0002664', (275, 281))	('perturbed', 'Reg', (215, 224))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('mutations', 'Var', (95, 104))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (275, 281))	('cancer', 'Disease', (275, 281))	('cancer', 'Disease', 'MESH:D009369', (228, 234))
376244	27698488	Using a recently developed method to define the effects of mutations on interfaces involving proteins, DNA/RNA and small-molecules, we defined a set of commonly perturbed interfaces in cancer, and show how these both highlight differences between cancers and identify distinct sub-types within specific cancers.	('cancers', 'Disease', 'MESH:D009369', (303, 310))	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('cancer', 'Disease', (303, 309))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('cancer', 'Disease', (247, 253))	('cancer', 'Disease', 'MESH:D009369', (247, 253))	('cancers', 'Disease', 'MESH:D009369', (247, 254))	('cancer', 'Phenotype', 'HP:0002664', (303, 309))	('cancers', 'Phenotype', 'HP:0002664', (247, 254))	('mutations', 'Var', (59, 68))	('cancers', 'Disease', (247, 254))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('cancers', 'Phenotype', 'HP:0002664', (303, 310))	('cancer', 'Disease', (185, 191))	('cancers', 'Disease', (303, 310))	('cancer', 'Disease', 'MESH:D009369', (303, 309))
376245	27698488	We used the mapped variants to identify a set of molecular interfaces that are most often perturbed in cancers.	('cancers', 'Disease', 'MESH:D009369', (103, 110))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('cancers', 'Phenotype', 'HP:0002664', (103, 110))	('variants', 'Var', (19, 27))	('cancers', 'Disease', (103, 110))
376254	27698488	The predominance of interfaces with small-molecules highlights their importance in cancer.	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('small-molecules', 'Var', (36, 51))	('cancer', 'Disease', (83, 89))
376257	27698488	The binding interfaces of metal co-factors with structural stabilization roles are also often perturbed by cancer missense variants (Table S1, Fig.	('perturbed', 'Reg', (94, 103))	('missense variants', 'Var', (114, 131))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('binding', 'Interaction', (4, 11))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('metal', 'Chemical', 'MESH:D008670', (26, 31))	('cancer', 'Disease', (107, 113))
376261	27698488	For example, mutations in malignant melanoma are predicted to disable the RAC1-DOCK1 interface but enable interactions between RAC1 and PAK3 (Figs S2 and S3).	('malignant melanoma', 'Disease', 'MESH:D008545', (26, 44))	('DOCK1', 'Gene', (79, 84))	('disable', 'NegReg', (62, 69))	('malignant melanoma', 'Disease', (26, 44))	('interactions', 'Interaction', (106, 118))	('RAC1', 'Gene', '5879', (74, 78))	('DOCK1', 'Gene', '1793', (79, 84))	('PAK3', 'Gene', '5063', (136, 140))	('RAC1', 'Gene', '5879', (127, 131))	('PAK3', 'Gene', (136, 140))	('RAC1', 'Gene', (74, 78))	('enable', 'PosReg', (99, 105))	('malignant melanoma', 'Phenotype', 'HP:0002861', (26, 44))	('RAC1', 'Gene', (127, 131))	('mutations', 'Var', (13, 22))
376264	27698488	S2), the latter mainly differing for mutations of KRAS and EGFR.	('differing', 'Reg', (23, 32))	('EGFR', 'Gene', (59, 63))	('KRAS', 'Gene', (50, 54))	('mutations', 'Var', (37, 46))	('KRAS', 'Gene', '3845', (50, 54))	('EGFR', 'Gene', '1956', (59, 63))
376265	27698488	We also identify known cancer specific mutations in PIK3CA, BRAF, IDH1 and other genes and as expected, TP53 perturbations are found in most cancers.	('cancers', 'Disease', 'MESH:D009369', (141, 148))	('IDH1', 'Gene', '3417', (66, 70))	('TP53', 'Gene', '7157', (104, 108))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('TP53', 'Gene', (104, 108))	('BRAF', 'Gene', (60, 64))	('BRAF', 'Gene', '673', (60, 64))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('PIK3CA', 'Gene', (52, 58))	('cancer', 'Disease', (23, 29))	('mutations', 'Var', (39, 48))	('cancer', 'Disease', 'MESH:D009369', (23, 29))	('cancers', 'Phenotype', 'HP:0002664', (141, 148))	('cancers', 'Disease', (141, 148))	('PIK3CA', 'Gene', '5290', (52, 58))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('IDH1', 'Gene', (66, 70))	('cancer', 'Disease', (141, 147))
376272	27698488	In four cancers, mutations at the N-terminal disordered region of the protein are predicted to perturb interactions with BTRC, FBXW11 and HLA-A, whereas only two of these cancers (liver cancers) have additional mutations at the armadillo region perturbing interactions with other proteins (Fig.	('BTRC', 'Gene', (121, 125))	('FBXW11', 'Gene', '23291', (127, 133))	('cancers', 'Phenotype', 'HP:0002664', (186, 193))	('cancers', 'Disease', (186, 193))	('HLA-A', 'Gene', (138, 143))	('liver cancers', 'Disease', (180, 193))	('mutations', 'Var', (17, 26))	('cancers', 'Phenotype', 'HP:0002664', (8, 15))	('cancers', 'Disease', (8, 15))	('cancers', 'Disease', 'MESH:D009369', (171, 178))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('disordered', 'Disease', 'MESH:D030342', (45, 55))	('BTRC', 'Gene', '8945', (121, 125))	('perturbing', 'Reg', (245, 255))	('interactions', 'Interaction', (256, 268))	('disordered', 'Disease', (45, 55))	('cancers', 'Disease', 'MESH:D009369', (186, 193))	('HLA-A', 'Gene', '3105', (138, 143))	('interactions', 'Interaction', (103, 115))	('liver cancers', 'Disease', 'MESH:D006528', (180, 193))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('cancers', 'Disease', 'MESH:D009369', (8, 15))	('perturb', 'Reg', (95, 102))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('mutations', 'Var', (211, 220))	('liver cancers', 'Phenotype', 'HP:0002896', (180, 193))	('cancers', 'Phenotype', 'HP:0002664', (171, 178))	('FBXW11', 'Gene', (127, 133))	('cancers', 'Disease', (171, 178))
376274	27698488	Particular interface perturbations involving specific amino acid changes in GTPases appear to be differentially selected among different cancer types and subtypes, potentially modulating interfaces differently as suggested previously for RHOA.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('RHOA', 'Gene', '387', (238, 242))	('modulating', 'Reg', (176, 186))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('RHOA', 'Gene', (238, 242))	('interfaces', 'MPA', (187, 197))	('amino acid changes', 'Var', (54, 72))	('cancer', 'Disease', (137, 143))
376275	27698488	For example, in malignant melanoma the most common oncogenic mutations at Gln-61 in NRAS (Q61R,K) are predicted to disable the guanine exchange factor SOS1 (as previously reported) and activator RASA1 interactions, whereas in pancreatic carcinoma KRAS mutations are more enabling of both of these proteins (Fig.	('malignant melanoma', 'Disease', (16, 34))	('SOS1', 'Gene', '6654', (151, 155))	('NRAS', 'Gene', (84, 88))	('SOS1', 'Gene', (151, 155))	('disable', 'NegReg', (115, 122))	('NRAS', 'Gene', '4893', (84, 88))	('interactions', 'Interaction', (201, 213))	('Gln', 'Chemical', 'MESH:D005973', (74, 77))	('RASA1', 'Gene', '5921', (195, 200))	('RASA1', 'Gene', (195, 200))	('pancreatic carcinoma KRAS', 'Disease', (226, 251))	('pancreatic carcinoma KRAS', 'Disease', 'MESH:C562463', (226, 251))	('malignant melanoma', 'Phenotype', 'HP:0002861', (16, 34))	('Q61R', 'SUBSTITUTION', 'None', (90, 94))	('Q61R', 'Var', (90, 94))	('malignant melanoma', 'Disease', 'MESH:D008545', (16, 34))	('carcinoma', 'Phenotype', 'HP:0030731', (237, 246))
376276	27698488	Mutations at the equivalent residue (Q209P,L) on both GNAQ and GNA11 alpha-subunits of heterotrimeric G proteins are predicted to perturb the interaction with regulatory beta-subunits and Regulator of G protein signalling (RGS), as well as with the effector phospholipase C beta 3 (PLCB3) (Table S1, Fig.	('phospholipase C beta 3', 'Gene', (258, 280))	('GNAQ', 'Gene', (54, 58))	('Regulator of G protein signalling', 'Gene', (188, 221))	('interaction', 'Interaction', (142, 153))	('perturb', 'Reg', (130, 137))	('regulatory beta-subunits', 'Protein', (159, 183))	('RGS', 'Gene', (223, 226))	('PLCB3', 'Gene', '5331', (282, 287))	('Q209P', 'SUBSTITUTION', 'None', (37, 42))	('Mutations', 'Var', (0, 9))	('GNA11', 'Gene', '2767', (63, 68))	('PLCB3', 'Gene', (282, 287))	('phospholipase C beta 3', 'Gene', '5331', (258, 280))	('heterotrimeric G proteins', 'Protein', (87, 112))	('RGS', 'Gene', '5308', (223, 226))	('Q209P', 'Var', (37, 42))	('Regulator of G protein signalling', 'Gene', '5308', (188, 221))	('GNA11', 'Gene', (63, 68))	('GNAQ', 'Gene', '2776', (54, 58))
376277	27698488	This suggests that the oncogenic effect of mutations of this conserved glutamine might result from modulation of interactions with regulatory/effector proteins, in addition to the effects on intrinsic and GAP-mediated GTP hydrolysis.	('oncogenic effect', 'CPA', (23, 39))	('intrinsic', 'MPA', (191, 200))	('GAP-mediated GTP hydrolysis', 'MPA', (205, 232))	('modulation', 'Reg', (99, 109))	('glutamine', 'Chemical', 'MESH:D005973', (71, 80))	('effects', 'Reg', (180, 187))	('mutations', 'Var', (43, 52))	('interactions', 'Interaction', (113, 125))
376278	27698488	In contrast, highly oncogenic mutations of Arg-201 on GNAS, which also interfere with nucleotide hydrolysis, are not predicted to significantly perturb any protein interface.	('GNAS', 'Gene', (54, 58))	('Arg', 'Chemical', 'MESH:D001120', (43, 46))	('perturb', 'Reg', (144, 151))	('nucleotide hydrolysis', 'MPA', (86, 107))	('mutations', 'Var', (30, 39))	('protein', 'Protein', (156, 163))	('Arg-201', 'Var', (43, 50))	('GNAS', 'Gene', '2778', (54, 58))	('oncogenic', 'Reg', (20, 29))
376284	27698488	Different mutations on Phosphoinositide-3-kinase alpha catalytic subunit (PIK3CA) correlated with two distinct (p = 1.97e-12, q = 2.36e-10; Table S3a) breast cancer subtypes: one defined by mutations in the alpha-helical domain that are predicted to disable interfaces with regulator N-terminal SH2 domains, and another that affects the highly oncogenic kinase domain mutation (H1047R) and is predicted to disable the C-terminal SH2 domain interface (Fig.	('interfaces', 'MPA', (258, 268))	('H1047R', 'Mutation', 'rs121913279', (378, 384))	('affects', 'Reg', (325, 332))	('mutations', 'Var', (190, 199))	('S3a', 'Gene', (146, 149))	('breast cancer', 'Disease', 'MESH:D001943', (151, 164))	('breast cancer', 'Phenotype', 'HP:0003002', (151, 164))	('H1047R', 'Var', (378, 384))	('breast cancer', 'Disease', (151, 164))	('disable', 'NegReg', (250, 257))	('disable', 'NegReg', (406, 413))	('Phosphoinositide-3-kinase alpha catalytic subunit (PIK3CA', 'Gene', '5290', (23, 80))	('S3a', 'Gene', '6189', (146, 149))	('mutations', 'Var', (10, 19))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('C-terminal SH2 domain interface', 'MPA', (418, 449))
376285	27698488	Interestingly, the N-terminal SH2 domain perturbed group is mutually exclusive with mutations affecting the interfaces of TP53 with DNA or co-regulators (p = 1.23e-3, q = 4.47e-2; Table S3a), with the latter being associated with poorer prognosis in breast carcinoma (a lower likelihood to completely remit: p = 6.17e-3, q = 8.63e-2; see Table S3a).	('breast carcinoma', 'Disease', 'MESH:D001943', (250, 266))	('TP53', 'Gene', (122, 126))	('S3a', 'Gene', (344, 347))	('breast carcinoma', 'Phenotype', 'HP:0003002', (250, 266))	('TP53', 'Gene', '7157', (122, 126))	('S3a', 'Gene', (186, 189))	('mutations', 'Var', (84, 93))	('S3a', 'Gene', '6189', (344, 347))	('breast carcinoma', 'Disease', (250, 266))	('S3a', 'Gene', '6189', (186, 189))	('carcinoma', 'Phenotype', 'HP:0030731', (257, 266))
376286	27698488	On the other hand, samples bearing PIK3CA mutations perturbing the N-terminal SH2 domain of regulatory subunits are associated with poorer prognosis in low grade glioma (p = 1.4e-3, q = 3.79e-2; Table S3a).	('glioma', 'Disease', (162, 168))	('S3a', 'Gene', (201, 204))	('S3a', 'Gene', '6189', (201, 204))	('poorer', 'NegReg', (132, 138))	('PIK3CA', 'Gene', (35, 41))	('perturbing', 'NegReg', (52, 62))	('PIK3CA', 'Gene', '5290', (35, 41))	('glioma', 'Disease', 'MESH:D005910', (162, 168))	('glioma', 'Phenotype', 'HP:0009733', (162, 168))	('mutations', 'Var', (42, 51))
376287	27698488	ALK mutations in autonomic ganglia neuroblastoma are principally located in two distinct kinase domain regions (Phe-core and alphaC/A-loop) and perturb different interfaces in a mutually exclusive fashion (p = 1.06e-2, q = 3.18e-2; Table S3a).	('S3a', 'Gene', (238, 241))	('autonomic ganglia neuroblastoma', 'Disease', 'MESH:D009447', (17, 48))	('ALK', 'Gene', '238', (0, 3))	('autonomic ganglia neuroblastoma', 'Disease', (17, 48))	('neuroblastoma', 'Phenotype', 'HP:0003006', (35, 48))	('perturb', 'Reg', (144, 151))	('ALK', 'Gene', (0, 3))	('S3a', 'Gene', '6189', (238, 241))	('mutations', 'Var', (4, 13))	('Phe', 'Chemical', 'MESH:D010649', (112, 115))
376288	27698488	In line with a recent report of the therapeutic stratification potential of neuroblastoma patients based on ALK genomic status, samples with mutations of the second group (including R1275), which are predicted to perturb a phosphosite-mediated dimerization interface in addition to the ATP binding pocket, are characterized by a different distribution of survival times in autonomic ganglia neuroblastoma (ranksum, p = 3.4e-2; Table S3a) and a significantly increased risk across cancers (Cox, p = 2.8e-3; Table S5b).	('phosphosite-mediated dimerization interface', 'MPA', (223, 266))	('ALK', 'Gene', '238', (108, 111))	('autonomic ganglia neuroblastoma', 'Disease', 'MESH:D009447', (373, 404))	('neuroblastoma', 'Disease', 'MESH:D009447', (391, 404))	('ALK', 'Gene', (108, 111))	('Cox', 'Gene', '1351', (489, 492))	('S3a', 'Gene', (433, 436))	('cancers', 'Disease', 'MESH:D009369', (480, 487))	('S3a', 'Gene', '6189', (433, 436))	('R1275', 'Var', (182, 187))	('Cox', 'Gene', (489, 492))	('mutations', 'Var', (141, 150))	('S5b', 'Gene', '5711', (512, 515))	('patients', 'Species', '9606', (90, 98))	('cancers', 'Phenotype', 'HP:0002664', (480, 487))	('neuroblastoma', 'Disease', (76, 89))	('perturb', 'Reg', (213, 220))	('cancers', 'Disease', (480, 487))	('neuroblastoma', 'Phenotype', 'HP:0003006', (76, 89))	('S5b', 'Gene', (512, 515))	('neuroblastoma', 'Disease', (391, 404))	('cancer', 'Phenotype', 'HP:0002664', (480, 486))	('ATP', 'Chemical', 'MESH:D000255', (286, 289))	('autonomic ganglia neuroblastoma', 'Disease', (373, 404))	('neuroblastoma', 'Phenotype', 'HP:0003006', (391, 404))	('neuroblastoma', 'Disease', 'MESH:D009447', (76, 89))
376289	27698488	Similarly, mutations perturbing the ATP binding pocket of the RPS6KA3 kinase are associated to a significant increased risk in liver cancers (Cox, p = 8.65e-4; Table S5a) as well as cross-cancer (p = 3.71e-2; Table S5b,c).	('mutations', 'Var', (11, 20))	('cross-cancer', 'Disease', (182, 194))	('liver cancers', 'Disease', (127, 140))	('S5b', 'Gene', (215, 218))	('Cox', 'Gene', (142, 145))	('ATP binding pocket', 'MPA', (36, 54))	('ATP', 'Chemical', 'MESH:D000255', (36, 39))	('perturbing', 'NegReg', (21, 31))	('RPS6KA3', 'Gene', '6197', (62, 69))	('S5a', 'Gene', (166, 169))	('liver cancers', 'Disease', 'MESH:D006528', (127, 140))	('cancers', 'Phenotype', 'HP:0002664', (133, 140))	('RPS6KA3', 'Gene', (62, 69))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('cross-cancer', 'Disease', 'MESH:C537866', (182, 194))	('liver cancers', 'Phenotype', 'HP:0002896', (127, 140))	('S5b', 'Gene', '5711', (215, 218))	('Cox', 'Gene', '1351', (142, 145))	('S5a', 'Gene', '5710', (166, 169))
376290	27698488	The severity of these mutations is in line with the RPS6KA3 suppressive role of the RAS-MAPK pathway which is lost upon inactivating mutation.	('RPS6KA3', 'Gene', (52, 59))	('RAS-MAPK pathway', 'Pathway', (84, 100))	('mutations', 'Var', (22, 31))	('RPS6KA3', 'Gene', '6197', (52, 59))
376293	27698488	Indeed, sample clusters with a predominance of KRAS-GTP-like perturbations (or IDH1-Mg++/IDH1-IDH1, or TP53 dimers) have a poorer prognosis in terms of complete remission compared to sample groups with either PIK3CA mutations perturbing PIK3R1 or PIK3R2 (Table S4e).	('perturbing', 'Var', (226, 236))	('complete', 'Disease', (152, 160))	('IDH1-IDH1', 'Disease', 'None', (89, 98))	('IDH1', 'Gene', (89, 93))	('IDH1', 'Gene', (79, 83))	('PIK3R2', 'Gene', '5296', (247, 253))	('TP53', 'Gene', '7157', (103, 107))	('PIK3CA', 'Gene', (209, 215))	('PIK3R1', 'Gene', '5295', (237, 243))	('IDH1', 'Gene', '3417', (89, 93))	('IDH1', 'Gene', '3417', (79, 83))	('IDH1', 'Gene', (94, 98))	('mutations perturbing', 'Var', (216, 236))	('KRAS', 'Gene', '3845', (47, 51))	('PIK3R1', 'Gene', (237, 243))	('TP53', 'Gene', (103, 107))	('IDH1', 'Gene', '3417', (94, 98))	('PIK3CA', 'Gene', '5290', (209, 215))	('IDH1-IDH1', 'Disease', (89, 98))	('KRAS', 'Gene', (47, 51))	('PIK3R2', 'Gene', (247, 253))
376294	27698488	Mutations affecting the KRAS/GTP interface and those targeting the CTNNB1 interfaces with FBXW11 or BTCR are largely mutually exclusive when considering all cancer types (Fig.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('KRAS', 'Gene', '3845', (24, 28))	('FBXW11', 'Gene', '23291', (90, 96))	('CTNNB1', 'Gene', '1499', (67, 73))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('Mutations', 'Var', (0, 9))	('cancer', 'Disease', (157, 163))	('FBXW11', 'Gene', (90, 96))	('CTNNB1', 'Gene', (67, 73))	('KRAS', 'Gene', (24, 28))
376296	27698488	KRAS/GTPase mutations have a shorter survival and higher hazard ratio (Cox, p = 3.67e-27; Table S5) than those within CTNNB1 (Fig.	('Cox', 'Gene', (71, 74))	('higher', 'PosReg', (50, 56))	('CTNNB1', 'Gene', '1499', (118, 124))	('mutations', 'Var', (12, 21))	('survival', 'MPA', (37, 45))	('CTNNB1', 'Gene', (118, 124))	('shorter', 'NegReg', (29, 36))	('Cox', 'Gene', '1351', (71, 74))	('KRAS', 'Gene', (0, 4))	('hazard ratio', 'MPA', (57, 69))	('KRAS', 'Gene', '3845', (0, 4))
376297	27698488	For example, PIK3CA mutations predicted to disable interfaces with regulator N-terminal SH2 domains (above) have a statistical significant cross-cancer lower survival and higher hazard ratio (Cox, p = 1.3e-2; Table S5b,c) than those predicted to affect the C-terminal SH2 domains.	('Cox', 'Gene', '1351', (192, 195))	('cross-cancer', 'Disease', 'MESH:C537866', (139, 151))	('PIK3CA', 'Gene', (13, 19))	('Cox', 'Gene', (192, 195))	('interfaces', 'Interaction', (51, 61))	('S5b', 'Gene', '5711', (215, 218))	('higher', 'PosReg', (171, 177))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('PIK3CA', 'Gene', '5290', (13, 19))	('hazard', 'MPA', (178, 184))	('lower', 'NegReg', (152, 157))	('S5b', 'Gene', (215, 218))	('disable', 'NegReg', (43, 50))	('cross-cancer', 'Disease', (139, 151))	('mutations', 'Var', (20, 29))	('survival', 'MPA', (158, 166))
376300	27698488	Interestingly, when considering all cancers, there is a significant difference in overall survival among these TP53 interface-defined tumour subtypes, with variants at the zinc binding site being associated with poorer overall survival (logrank, p = 3,12e-3; Fig.	('overall survival', 'MPA', (219, 235))	('poorer', 'NegReg', (212, 218))	('cancers', 'Disease', 'MESH:D009369', (36, 43))	('TP53', 'Gene', '7157', (111, 115))	('cancers', 'Phenotype', 'HP:0002664', (36, 43))	('tumour', 'Disease', 'MESH:D009369', (134, 140))	('cancers', 'Disease', (36, 43))	('tumour', 'Disease', (134, 140))	('variants', 'Var', (156, 164))	('TP53', 'Gene', (111, 115))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('tumour', 'Phenotype', 'HP:0002664', (134, 140))
376301	27698488	5d) as well as compared to mutually exclusive TP53 mutations perturbing alternative interfaces (i.e.	('perturbing', 'Reg', (61, 71))	('TP53', 'Gene', '7157', (46, 50))	('TP53', 'Gene', (46, 50))	('mutations', 'Var', (51, 60))
376303	27698488	Consistently, individuals affected by the latter variants have the greatest estimated hazard ratio compared to the other TP53-mediated interfaces (Table S5b) across all cancer types.	('cancer', 'Disease', (169, 175))	('variants', 'Var', (49, 57))	('TP53', 'Gene', '7157', (121, 125))	('TP53', 'Gene', (121, 125))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('S5b', 'Gene', '5711', (153, 156))	('S5b', 'Gene', (153, 156))	('cancer', 'Disease', 'MESH:D009369', (169, 175))
376305	27698488	The full value of HTS data is only apparent when considering genetic variants beside information about biological mechanism.	('variants', 'Var', (69, 77))	('HTS', 'Gene', '147495', (18, 21))	('HTS', 'Gene', (18, 21))
376306	27698488	In a recent pan-cancer survey of missense variants in protein structures, protein-mediated interfaces with either proteins, chemicals or DNA/RNA have also been considered in the context of 3D clustering.	('missense variants', 'Var', (33, 50))	('cancer', 'Disease', (16, 22))	('cancer', 'Disease', 'MESH:D009369', (16, 22))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))
376307	27698488	Additionally, a recent structure-based overview of missense cancer variants affecting protein-protein interactions has been reported, focusing on the identification of those interfaces significantly enriched in non-synonymous mutations.	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('protein-protein', 'Protein', (86, 101))	('cancer', 'Disease', (60, 66))	('affecting', 'Reg', (76, 85))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('variants', 'Var', (67, 75))
376314	27698488	We extracted confirmed somatic, missense, nonsynonymous mutations from version 74 of COSMIC genomes (http://cancer.sanger.ac.uk/wgs).	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('missense', 'Var', (32, 40))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
376315	27698488	We identified the most perturbed interactions in cancer by ranking each interacting pair based on the number of unique samples where a missense mutation was predicted to affect the interface.	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('affect', 'Reg', (170, 176))	('missense mutation', 'Var', (135, 152))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('interface', 'Interaction', (181, 190))	('cancer', 'Disease', (49, 55))	('interactions', 'Interaction', (33, 45))
376323	27698488	Cox's proportional hazard model were employed to predict hazard ratios and survival probability of patients affected by interface-perturbing mutations, employing age, sex and cancer type as covariates.	('mutations', 'Var', (141, 150))	('Cox', 'Gene', '1351', (0, 3))	('Cox', 'Gene', (0, 3))	('cancer', 'Disease', (175, 181))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('patients', 'Species', '9606', (99, 107))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
376379	24507984	Although the absolute recurrence rate was not significantly different statistically according to the nodal station on multivariate Cox model analysis, taking into account the interval to recurrence, the presence of extralobar nodal disease was a statistically significant predictor of disease recurrence (hazard ratio, 1.83; 95% confidence interval, 1.14-2.92; P = .011).	('nodal', 'Gene', (101, 106))	('disease', 'Disease', (285, 292))	('extralobar nodal disease', 'Disease', (215, 239))	('extralobar nodal disease', 'Disease', 'MESH:D013611', (215, 239))	('nodal', 'Gene', '4838', (101, 106))	('nodal', 'Gene', (226, 231))	('nodal', 'Gene', '4838', (226, 231))	('presence', 'Var', (203, 211))
376415	25553415	The nodule in S1+2b was found to be pleomorphic carcinoma, pT1aN0M0, stage IA.	('carcinoma', 'Phenotype', 'HP:0030731', (48, 57))	('pleomorphic carcinoma', 'Disease', 'MESH:D008228', (36, 57))	('S1+2b', 'Var', (14, 19))	('pleomorphic carcinoma', 'Disease', (36, 57))
376453	33928031	Prediction of Target-Drug Therapy by Identifying Gene Mutations in Lung Cancer With Histopathological Stained Image and Deep Learning Techniques Lung cancer is a kind of cancer with high morbidity and mortality which is associated with various gene mutations.	('mortality', 'Disease', (201, 210))	('Mutations', 'Var', (54, 63))	('Lung cancer', 'Disease', 'MESH:D008175', (145, 156))	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('Lung Cancer', 'Disease', (67, 78))	('cancer', 'Disease', (170, 176))	('Lung Cancer', 'Phenotype', 'HP:0100526', (67, 78))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('cancer', 'Disease', (150, 156))	('mortality', 'Disease', 'MESH:D003643', (201, 210))	('Lung cancer', 'Disease', (145, 156))	('Lung cancer', 'Phenotype', 'HP:0100526', (145, 156))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('Lung Cancer', 'Disease', 'MESH:D008175', (67, 78))	('Cancer', 'Phenotype', 'HP:0002664', (72, 78))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
376456	33928031	Therefore, we mainly focus on identifying mutant gene of lung cancer by analyzing the pathological images.	('mutant', 'Var', (42, 48))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('lung cancer', 'Disease', 'MESH:D008175', (57, 68))	('lung cancer', 'Disease', (57, 68))	('lung cancer', 'Phenotype', 'HP:0100526', (57, 68))
376457	33928031	In this study, we have proposed a method by identifying gene mutations in lung cancer with histopathological stained image and deep learning to predict target-drug therapy, referred to as DeepIMLH.	('lung cancer', 'Disease', (74, 85))	('lung cancer', 'Phenotype', 'HP:0100526', (74, 85))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('mutations', 'Var', (61, 70))	('lung cancer', 'Disease', 'MESH:D008175', (74, 85))
376468	33928031	However, there are genetic abnormalities carried by patients with adenocarcinoma who respond well to targeted-drug therapy, such as those carry EGFR mutations or ALK rearrangements.	('genetic abnormalities', 'Disease', (19, 40))	('EGFR', 'Gene', (144, 148))	('mutations', 'Var', (149, 158))	('genetic abnormalities', 'Disease', 'MESH:D030342', (19, 40))	('ALK', 'Gene', '238', (162, 165))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('adenocarcinoma', 'Disease', (66, 80))	('adenocarcinoma', 'Disease', 'MESH:D000230', (66, 80))	('ALK', 'Gene', (162, 165))	('EGFR', 'Gene', '1956', (144, 148))	('men', 'Species', '9606', (175, 178))	('patients', 'Species', '9606', (52, 60))
376491	33928031	It provided an approach to develop effective targeted therapy on basis of mutant genes of lung cancer, however, it need further studies to evaluate the effectiveness and reliability of designed model before applying to clinical practice.	('lung cancer', 'Disease', 'MESH:D008175', (90, 101))	('mutant genes', 'Var', (74, 86))	('lung cancer', 'Disease', (90, 101))	('lung cancer', 'Phenotype', 'HP:0100526', (90, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))
376496	33928031	Then cBioPortal was performed to identified potential mutant genes associated with lung cancer as bio-markers, such as AKT1, ALK, BRAF, FGFR1, FGFR2, HRAS, KRAS, MET, etc.	('HRAS', 'Gene', (150, 154))	('FGFR2', 'Gene', '2263', (143, 148))	('lung cancer', 'Disease', 'MESH:D008175', (83, 94))	('FGFR1', 'Gene', (136, 141))	('AKT1', 'Gene', (119, 123))	('KRAS', 'Gene', (156, 160))	('ALK', 'Gene', '238', (125, 128))	('lung cancer', 'Phenotype', 'HP:0100526', (83, 94))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('ALK', 'Gene', (125, 128))	('MET', 'Gene', '79811', (162, 165))	('FGFR1', 'Gene', '2260', (136, 141))	('lung cancer', 'Disease', (83, 94))	('associated', 'Reg', (67, 77))	('mutant', 'Var', (54, 60))	('AKT1', 'Gene', '207', (119, 123))	('HRAS', 'Gene', '3265', (150, 154))	('FGFR2', 'Gene', (143, 148))	('BRAF', 'Gene', '673', (130, 134))	('BRAF', 'Gene', (130, 134))	('KRAS', 'Gene', '3845', (156, 160))	('MET', 'Gene', (162, 165))
376539	33928031	In non-small cell lung cancer, some of patients present MET mutation, including MET protein over expression, MET mutation or rearrangement, which lead to non-regulated downstream signaling pathway.	('MET', 'Gene', (109, 112))	('non-regulated downstream signaling pathway', 'Pathway', (154, 196))	('patients', 'Species', '9606', (39, 47))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (3, 29))	('over expression', 'PosReg', (92, 107))	('MET', 'Gene', '79811', (56, 59))	('rearrangement', 'Var', (125, 138))	('lung cancer', 'Phenotype', 'HP:0100526', (18, 29))	('MET', 'Gene', (56, 59))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (3, 29))	('MET', 'Gene', '79811', (80, 83))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (7, 29))	('lead to', 'Reg', (146, 153))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('non-small cell lung cancer', 'Disease', (3, 29))	('MET', 'Gene', '79811', (109, 112))	('MET', 'Gene', (80, 83))	('men', 'Species', '9606', (134, 137))
376541	33928031	MET inhibitors have been went through clinical trials, the clinical data was promising now, which showed that MET mutation is a potential bio-marker to predict the response to target-drug therapy, as well as prediction of disease prognosis.	('MET', 'Gene', '79811', (0, 3))	('MET', 'Gene', '79811', (110, 113))	('MET', 'Gene', (0, 3))	('MET', 'Gene', (110, 113))	('mutation', 'Var', (114, 122))
376547	33928031	Early studies showed that inhibition of FGFRs can decrease cell proliferation and induce cell apoptosis in both in vitro and in vivo models with FGFR mutations, moreover, other studies also chose FGFRs as target for anticancer medical therapy.	('induce', 'Reg', (82, 88))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('inhibition', 'Var', (26, 36))	('cell apoptosis', 'CPA', (89, 103))	('cell proliferation', 'CPA', (59, 77))	('cancer', 'Disease', 'MESH:D009369', (220, 226))	('mutations', 'Var', (150, 159))	('cancer', 'Disease', (220, 226))	('FGFRs', 'Gene', (40, 45))	('FGFR', 'Gene', (145, 149))	('decrease', 'NegReg', (50, 58))
376548	33928031	For an example, multiple kinase FGFR/vascular endothelial growth factor receptor (VEGR) inhibitor gained the promising results in breast cancer with FGFR/FGFR3 amplification.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('breast cancer', 'Disease', (130, 143))	('breast cancer', 'Phenotype', 'HP:0003002', (130, 143))	('FGFR3', 'Gene', (154, 159))	('amplification', 'Var', (160, 173))	('FGFR3', 'Gene', '2261', (154, 159))	('breast cancer', 'Disease', 'MESH:D001943', (130, 143))
376553	33928031	Patients with FGFR mutation is potential a candidate for clinical trial for FGFR inhibitors.	('Patients', 'Species', '9606', (0, 8))	('mutation', 'Var', (19, 27))	('FGFR', 'Gene', (14, 18))
376554	33928031	The pharmacological or genetic mutation of FGFR induced autophagy; the mechanism remains unknown, which may involve both inhibition of ERK/MAPK pathway and decline.	('ERK', 'Gene', '5594', (135, 138))	('FGFR', 'Gene', (43, 47))	('autophagy', 'CPA', (56, 65))	('ERK', 'Gene', (135, 138))	('mutation', 'Var', (31, 39))	('inhibition', 'NegReg', (121, 131))	('induced', 'Reg', (48, 55))
376559	33928031	Mutated RAS coded proteins are the key drivers in many cancers and the distribution of RAS mutation varies between the difference of somatic tumors.	('RAS coded proteins', 'Protein', (8, 26))	('cancers', 'Disease', 'MESH:D009369', (55, 62))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('tumors', 'Disease', (141, 147))	('tumors', 'Disease', 'MESH:D009369', (141, 147))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('cancers', 'Phenotype', 'HP:0002664', (55, 62))	('Mutated', 'Var', (0, 7))	('cancers', 'Disease', (55, 62))
376563	33928031	AKT1 is a core factor in PI3K/AKT signaling pathway, and PI3Ks can specifically cause the three hydroxyl groups of phosphatidylinositol (PI).	('AKT', 'Gene', (0, 3))	('AKT1', 'Gene', '207', (0, 4))	('AKT1', 'Gene', (0, 4))	('PI3Ks', 'Var', (57, 62))	('AKT', 'Gene', '207', (30, 33))	('phosphatidylinositol', 'Chemical', 'MESH:D010716', (115, 135))	('AKT', 'Gene', '207', (0, 3))	('AKT', 'Gene', (30, 33))	('three hydroxyl groups of phosphatidylinositol', 'MPA', (90, 135))	('cause', 'Reg', (80, 85))
376564	33928031	The production of second messenger inositol such as PIP3, PIP3 can promote AKT transferring to the cell membrane and can be activated by PDK1/PDK2.	('PIP3', 'Var', (58, 62))	('PDK1', 'Gene', '5163', (137, 141))	('AKT', 'Gene', '207', (75, 78))	('PDK1', 'Gene', (137, 141))	('PIP3', 'Var', (52, 56))	('PDK2', 'Gene', '5164', (142, 146))	('inositol', 'Chemical', 'MESH:D007294', (35, 43))	('AKT', 'Gene', (75, 78))	('PIP3', 'Chemical', '-', (52, 56))	('PIP3', 'Chemical', '-', (58, 62))	('PDK2', 'Gene', (142, 146))	('promote', 'PosReg', (67, 74))
376566	33928031	Thereby, AKT signaling pathway can regulate multiple cell functions, however, the abnormally activated AKT signaling can cause tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('AKT', 'Gene', '207', (103, 106))	('AKT', 'Gene', '207', (9, 12))	('tumor', 'Disease', (127, 132))	('AKT', 'Gene', (103, 106))	('AKT', 'Gene', (9, 12))	('cause', 'Reg', (121, 126))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('abnormally', 'Var', (82, 92))
376567	33928031	For AKT1 gene mutations, everolimus and other mTOR inhibitors that have been on the market have good efficacy.	('AKT1', 'Gene', '207', (4, 8))	('AKT1', 'Gene', (4, 8))	('mTOR', 'Gene', '2475', (46, 50))	('mTOR', 'Gene', (46, 50))	('mutations', 'Var', (14, 23))	('everolimus', 'Chemical', 'MESH:D000068338', (25, 35))
376572	33928031	Since the smokers are significantly higher in China than United States, therefore, the occurrence of lung cancer might cause by other influencing factors in addition of gene mutations.	('lung cancer', 'Disease', 'MESH:D008175', (101, 112))	('cause', 'Reg', (119, 124))	('gene mutations', 'Var', (169, 183))	('lung cancer', 'Phenotype', 'HP:0100526', (101, 112))	('lung cancer', 'Disease', (101, 112))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
376601	33649833	Moreover, the present study detected the effect of GMPS knockdown on CC cell proliferation, clonal formation ability, aging and apoptosis, as well as on the expression levels of apoptosis-related proteins in tumor cells.	('aging', 'CPA', (118, 123))	('expression levels', 'MPA', (157, 174))	('tumor', 'Disease', 'MESH:D009369', (208, 213))	('clonal formation ability', 'CPA', (92, 116))	('CC cell proliferation', 'CPA', (69, 90))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('effect', 'Reg', (41, 47))	('GMPS', 'Gene', (51, 55))	('tumor', 'Disease', (208, 213))	('apoptosis', 'CPA', (128, 137))	('knockdown', 'Var', (56, 65))
376612	33649833	It has been reported that the expression of GMPS strongly affects the invasive capacity of melanoma cells and ultimately tumor growth, and angustmycin A, a nucleoside-analog inhibitor of GMPS produced by Streptomyces hygroscopicus efficiently suppresses melanoma cell invasion in vitro and tumorigenicity in immunocompromised mice.	('GMPS', 'Gene', (44, 48))	('suppresses', 'NegReg', (243, 253))	('expression', 'Var', (30, 40))	('melanoma', 'Disease', 'MESH:D008545', (91, 99))	('melanoma', 'Phenotype', 'HP:0002861', (254, 262))	('melanoma', 'Disease', (254, 262))	('tumor', 'Disease', (290, 295))	('angustmycin A', 'Chemical', 'MESH:C012182', (139, 152))	('tumor', 'Disease', (121, 126))	('affects', 'Reg', (58, 65))	('tumor', 'Disease', 'MESH:D009369', (290, 295))	('tumor', 'Disease', 'MESH:D009369', (121, 126))	('melanoma', 'Phenotype', 'HP:0002861', (91, 99))	('melanoma', 'Disease', (91, 99))	('tumor', 'Phenotype', 'HP:0002664', (290, 295))	('mice', 'Species', '10090', (326, 330))	('melanoma', 'Disease', 'MESH:D008545', (254, 262))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('nucleoside', 'Chemical', 'MESH:D009705', (156, 166))	('Streptomyces hygroscopicus', 'Species', '1912', (204, 230))
376650	33649833	There were three experimental groups of CC cell lines for this assay: i) Ctrl, siRNA negative control; ii) siRNA#1 transfection; and iii) siRNA#1 transfection combined with cisplatin (3 mug/ml; Qilu Pharmaceutical Co., Ltd.).	('transfection', 'Var', (115, 127))	('transfection', 'Var', (146, 158))	('cisplatin', 'Chemical', 'MESH:D002945', (173, 182))
376695	33649833	Among them, the high expression rate of GMPS was 70.93% (61/86) in patients with low-to-medium differentiation of cancer cells, and 30.23% (13/43) in patients with high differentiation of cancer cells.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('low-to-medium', 'Var', (81, 94))	('patients', 'Species', '9606', (67, 75))	('GMPS', 'Protein', (40, 44))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('patients', 'Species', '9606', (150, 158))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('cancer', 'Disease', (188, 194))	('cancer', 'Disease', (114, 120))
376696	33649833	The results demonstrated that, compared with the high differentiation of cancer cells, the expression rate of GMPS was increased in the group with low-to- medium differentiation of cancer cells (Table II; Fig.	('GMPS', 'Protein', (110, 114))	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('expression rate', 'MPA', (91, 106))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('low-to- medium differentiation', 'Var', (147, 177))	('cancer', 'Disease', (181, 187))	('increased', 'PosReg', (119, 128))
376704	33649833	The results of the clone formation experiments indicated that GMPS knockdown could significantly decrease the colony-forming ability of the two CC cell lines, the group of siRNA#1 combined with cisplatin was the most obviously decreased compared with the Ctrl siRNA group (Fig.	('decreased', 'NegReg', (227, 236))	('knockdown', 'Var', (67, 76))	('cisplatin', 'Chemical', 'MESH:D002945', (194, 203))	('GMPS', 'Gene', (62, 66))	('colony-forming ability of the two CC cell lines', 'CPA', (110, 157))	('decrease', 'NegReg', (97, 105))
376706	33649833	The senescence of the cells in each group was observed, and it was found that GMPS knockdown could induce the senescence of HeLa and SiHa cells (Fig.	('GMPS', 'Gene', (78, 82))	('senescence', 'MPA', (110, 120))	('HeLa', 'CellLine', 'CVCL:0030', (124, 128))	('knockdown', 'Var', (83, 92))	('induce', 'Reg', (99, 105))	('SiHa', 'CellLine', 'CVCL:0032', (133, 137))
376707	33649833	These findings indicated that GMPS knockdown facilitated apoptosis, and that GMPS may enhance the malignant phenotype of tumors via the apoptotic pathway.	('knockdown', 'Var', (35, 44))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('apoptosis', 'CPA', (57, 66))	('enhance', 'PosReg', (86, 93))	('GMPS', 'Gene', (30, 34))	('tumors', 'Disease', (121, 127))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('tumors', 'Disease', 'MESH:D009369', (121, 127))	('facilitated', 'PosReg', (45, 56))	('apoptotic pathway', 'Pathway', (136, 153))
376709	33649833	The experimental results demonstrated that the tumor growth rate of the sh-GMPS group was significantly slower compared with that of the HeLa sh-NC group (Fig.	('HeLa', 'CellLine', 'CVCL:0030', (137, 141))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('slower', 'NegReg', (104, 110))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('sh-GMPS', 'Var', (72, 79))	('tumor', 'Disease', (47, 52))
376711	33649833	Therefore, it was suggested that knockdown of GMPS exerted a tumor-suppressive effect on CC.	('GMPS', 'Gene', (46, 50))	('knockdown', 'Var', (33, 42))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Disease', (61, 66))
376712	33649833	In summary, knockdown of GMPS could suppress cancer growth rate in vitro and in vivo.	('GMPS could suppress cancer', 'Disease', 'MESH:D009369', (25, 51))	('knockdown', 'Var', (12, 21))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('GMPS could suppress cancer', 'Disease', (25, 51))
376714	33649833	Western blotting results indicated that, compared with the control group, Stat3 and p-Stat3 protein expression levels were markedly decreased in the GMPS siRNA knockdown group.	('Stat3', 'Gene', (86, 91))	('Stat3', 'Gene', '6774', (74, 79))	('knockdown', 'Var', (160, 169))	('Stat3', 'Gene', (74, 79))	('decreased', 'NegReg', (132, 141))	('Stat3', 'Gene', '6774', (86, 91))
376720	33649833	In the animal experiments, the western blotting results demonstrated that, compared with the control group, the expression levels of P53 and p-P53 were upregulated in the sh-GMPS group, while the expression levels of Stat3 and p-Stat3 were downregulated (Fig.	('upregulated', 'PosReg', (152, 163))	('Stat3', 'Gene', '6774', (229, 234))	('P53', 'Gene', (133, 136))	('Stat3', 'Gene', (229, 234))	('sh-GMPS', 'Var', (171, 178))	('P53', 'Gene', (143, 146))	('P53', 'Gene', '7157', (133, 136))	('P53', 'Gene', '7157', (143, 146))	('Stat3', 'Gene', '6774', (217, 222))	('expression levels', 'MPA', (112, 129))	('Stat3', 'Gene', (217, 222))
376729	33649833	The present study indicated that, among the 129 patients with CC, the expression rate of GMPS was higher in patients with low-to-medium differentiation of cancer cells compared with those with high cancer cell differentiation.	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('cancer', 'Disease', (198, 204))	('low-to-medium differentiation', 'Var', (122, 151))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('GMPS', 'Gene', (89, 93))	('higher', 'PosReg', (98, 104))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('patients', 'Species', '9606', (108, 116))	('patients', 'Species', '9606', (48, 56))	('cancer', 'Disease', (155, 161))	('cancer', 'Disease', 'MESH:D009369', (155, 161))	('expression rate', 'MPA', (70, 85))
376731	33649833	Dysregulation of the apoptotic mechanism is a sign of cancer development.	('Dysregulation', 'Var', (0, 13))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('apoptotic', 'CPA', (21, 30))	('cancer', 'Disease', (54, 60))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
376734	33649833	The animal experimental results showed that the tumor growth rate of the sh-GMPS group was significantly slower than that of the HeLa sh-NC group.	('slower', 'NegReg', (105, 111))	('tumor', 'Disease', (48, 53))	('HeLa', 'CellLine', 'CVCL:0030', (129, 133))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('sh-GMPS', 'Var', (73, 80))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
376737	33649833	As a cytoplasmic transcription factor, nuclear transport of Stat3 requires phosphorylation, and Stat3 is activated primarily by phosphorylation of the conserved tyrosine Tyr705 residue.	('tyrosine Tyr705', 'Var', (161, 176))	('Stat3', 'Gene', '6774', (60, 65))	('Stat3', 'Gene', (60, 65))	('Tyr705', 'Chemical', '-', (170, 176))	('tyrosine', 'Chemical', 'MESH:D014443', (161, 169))	('Stat3', 'Gene', '6774', (96, 101))	('nuclear transport', 'MPA', (39, 56))	('Stat3', 'Gene', (96, 101))	('phosphorylation', 'Var', (128, 143))
376739	33649833	The present study used siRNA to knock down GMPS, and CC cells were simultaneously treated with cisplatin.	('knock down', 'Var', (32, 42))	('cisplatin', 'Chemical', 'MESH:D002945', (95, 104))	('GMPS', 'Gene', (43, 47))
376740	33649833	Compared with the control group, the expression levels of Stat3 and p-Stat3 in the GMPS siRNA knockdown group were decreased.	('knockdown', 'Var', (94, 103))	('Stat3', 'Gene', (70, 75))	('decreased', 'NegReg', (115, 124))	('expression levels', 'MPA', (37, 54))	('Stat3', 'Gene', '6774', (58, 63))	('Stat3', 'Gene', (58, 63))	('Stat3', 'Gene', '6774', (70, 75))
376742	33649833	Previous studies have shown that Stat3 inhibition could activate p53 expression in human cancer cells and induce p53-mediated tumor cell apoptosis.	('inhibition', 'Var', (39, 49))	('p53', 'Gene', (65, 68))	('p53', 'Gene', '7157', (65, 68))	('Stat3', 'Gene', '6774', (33, 38))	('induce', 'PosReg', (106, 112))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('human', 'Species', '9606', (83, 88))	('Stat3', 'Gene', (33, 38))	('expression', 'MPA', (69, 79))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('activate', 'PosReg', (56, 64))	('cancer', 'Disease', (89, 95))	('p53', 'Gene', '7157', (113, 116))	('p53', 'Gene', (113, 116))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('tumor', 'Disease', (126, 131))
376743	33649833	The present study demonstrated that, after knocking down GMPS, both Stat3 and p-Stat3 expression levels were decreased, which was accompanied by increased P53 and p-P53 expression levels, resulting in the induction of senescence and apoptosis in CC cells.	('decreased', 'NegReg', (109, 118))	('Stat3', 'Gene', '6774', (80, 85))	('GMPS', 'Gene', (57, 61))	('senescence', 'CPA', (218, 228))	('Stat3', 'Gene', (80, 85))	('P53', 'Gene', '7157', (165, 168))	('increased', 'PosReg', (145, 154))	('P53', 'Gene', '7157', (155, 158))	('Stat3', 'Gene', '6774', (68, 73))	('P53', 'Gene', (165, 168))	('apoptosis', 'CPA', (233, 242))	('expression levels', 'MPA', (169, 186))	('P53', 'Gene', (155, 158))	('Stat3', 'Gene', (68, 73))	('induction', 'Reg', (205, 214))	('knocking down', 'Var', (43, 56))
376763	29151910	For patients with cervical cancer, the average age was 62.3+-13.5 years, and there were 35 cases (53.0%) of positive HPV infection, 57 cases of squamous cell carcinoma, 9 cases of adenocarcinoma, 5 cases of Stage I, 25 cases of Stage II, 28 cases of Stage III and 8 cases of Stage IV.	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (144, 167))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('HPV infection', 'Disease', 'MESH:D030361', (117, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (185, 194))	('positive', 'Var', (108, 116))	('carcinoma', 'Phenotype', 'HP:0030731', (158, 167))	('patients', 'Species', '9606', (4, 12))	('adenocarcinoma', 'Disease', (180, 194))	('HPV infection', 'Disease', (117, 130))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (144, 167))	('cervical cancer', 'Disease', (18, 33))	('cervical cancer', 'Disease', 'MESH:D002583', (18, 33))	('adenocarcinoma', 'Disease', 'MESH:D000230', (180, 194))	('squamous cell carcinoma', 'Disease', (144, 167))
376797	29151910	The knockdown of FOXC2 inhibits the movement and invasion of hepatoma carcinoma cells, reduces the expression of N-cadherin, matrix metalloproteinase-2 (MMP-2) and angiopoietin-2 and disturbs the EMT degree.	('expression', 'MPA', (99, 109))	('matrix metalloproteinase-2', 'Gene', '4313', (125, 151))	('FOXC2', 'Gene', (17, 22))	('hepatoma carcinoma', 'Disease', (61, 79))	('hepatoma carcinoma', 'Disease', 'MESH:D006528', (61, 79))	('knockdown', 'Var', (4, 13))	('inhibits', 'NegReg', (23, 31))	('angiopoietin-2', 'Gene', (164, 178))	('disturbs', 'Reg', (183, 191))	('EMT degree', 'CPA', (196, 206))	('matrix metalloproteinase-2', 'Gene', (125, 151))	('N-cadherin', 'Gene', (113, 123))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('MMP-2', 'Gene', '4313', (153, 158))	('N-cadherin', 'Gene', '1000', (113, 123))	('reduces', 'NegReg', (87, 94))	('angiopoietin-2', 'Gene', '285', (164, 178))	('hepatoma carcinoma', 'Phenotype', 'HP:0001402', (61, 79))	('MMP-2', 'Gene', (153, 158))
376799	29151910	EMT or expression of EMT transcription factor (such as FOXC2) in mammary epithelial cells obtains the tumor stem cell markers (CD44high/CD24low), and increases the degree of malignancy.	('malignancy', 'Disease', 'MESH:D009369', (174, 184))	('malignancy', 'Disease', (174, 184))	('CD44high/CD24low', 'Var', (127, 143))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('FOXC2', 'Gene', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('increases', 'PosReg', (150, 159))
376815	32824814	Moreover, the expression of PTTG3P, PTTG1 and PTTG2 depends on the type of mutation in TP53 gene, and they correlate with genes from p53 pathway.	('PTTG1', 'Gene', (36, 41))	('PTTG3P', 'Gene', '26255', (28, 34))	('TP53', 'Gene', '7157', (87, 91))	('PTTG1', 'Gene', '9232', (36, 41))	('PTTG2', 'Gene', '10744', (46, 51))	('PTTG3P', 'Gene', (28, 34))	('mutation', 'Var', (75, 83))	('TP53', 'Gene', (87, 91))	('p53', 'Gene', '7157', (133, 136))	('p53', 'Gene', (133, 136))	('depends', 'Reg', (52, 59))	('correlate', 'Reg', (107, 116))	('PTTG2', 'Gene', (46, 51))
376823	32824814	Moreover, patients with high expressions of PTTG3P, PTTG1 or PTTG2 have worse outcomes due to upregulation of oncogenic pathways and more aggressive phenotypes.	('PTTG3P', 'Gene', (44, 50))	('PTTG2', 'Gene', (61, 66))	('upregulation', 'PosReg', (94, 106))	('aggressive phenotypes', 'CPA', (138, 159))	('PTTG3P', 'Gene', '26255', (44, 50))	('PTTG1', 'Gene', (52, 57))	('patients', 'Species', '9606', (10, 18))	('PTTG1', 'Gene', '9232', (52, 57))	('PTTG2', 'Gene', '10744', (61, 66))	('high expressions', 'Var', (24, 40))	('oncogenic pathways', 'Pathway', (110, 128))
376834	32824814	The aforementioned functions include the capability to synthesize proteins due to events such as insertions, premature stop codons, frameshift-causing deletions and splicing errors.	('frameshift-causing', 'Reg', (132, 150))	('men', 'Species', '9606', (9, 12))	('premature stop codons', 'Var', (109, 130))	('splicing errors', 'Var', (165, 180))	('insertions', 'Var', (97, 107))
376838	32824814	It has also shown examples of ectopic expression of PTENP1 inhibited proliferation, colony formation and migration of HNSCC cells, which proves that PTENP1 may serve as a prognostic factor in patients with HNSCC.	('rat', 'Species', '10116', (108, 111))	('HNSCC', 'Disease', (206, 211))	('proliferation', 'CPA', (69, 82))	('rat', 'Species', '10116', (76, 79))	('PTENP1', 'Gene', '11191', (149, 155))	('colony formation', 'CPA', (84, 100))	('inhibited', 'NegReg', (59, 68))	('migration of HNSCC cells', 'CPA', (105, 129))	('patients', 'Species', '9606', (192, 200))	('ectopic expression', 'Var', (30, 48))	('PTENP1', 'Gene', (52, 58))	('PTENP1', 'Gene', '11191', (52, 58))	('PTENP1', 'Gene', (149, 155))
376853	32824814	indicated that PTTG2 silencing results in increased levels of p53 protein.	('increased', 'PosReg', (42, 51))	('PTTG2', 'Gene', (15, 20))	('levels', 'MPA', (52, 58))	('PTTG2', 'Gene', '10744', (15, 20))	('p53', 'Gene', (62, 65))	('p53', 'Gene', '7157', (62, 65))	('silencing', 'Var', (21, 30))
376855	32824814	Mutations in TP53 gene are prevalent in many cancers, including HNSCC.	('TP53', 'Gene', (13, 17))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('Mutations', 'Var', (0, 9))	('cancers', 'Disease', 'MESH:D009369', (45, 52))	('cancers', 'Phenotype', 'HP:0002664', (45, 52))	('HNSCC', 'Disease', (64, 69))	('TP53', 'Gene', '7157', (13, 17))	('cancers', 'Disease', (45, 52))	('prevalent', 'Reg', (27, 36))
376857	32824814	Mutations in p53 can be divided into two main groups: DNA contact mutations (such as R273H and R280K) and conformational mutations (such as R175H and V143A).	('R280K', 'Var', (95, 100))	('V143A', 'Var', (150, 155))	('V143A', 'Mutation', 'p.V143A', (150, 155))	('R280K', 'Mutation', 'rs121912660', (95, 100))	('R273H', 'Mutation', 'rs28934576', (85, 90))	('R175H', 'Mutation', 'rs28934578', (140, 145))	('p53', 'Gene', (13, 16))	('R273H', 'Var', (85, 90))	('p53', 'Gene', '7157', (13, 16))	('R175H', 'Var', (140, 145))
376858	32824814	Missense mutations in the DNA-binding domain are the most common ones among TP53 mutations.	('common', 'Reg', (58, 64))	('TP53', 'Gene', '7157', (76, 80))	('TP53', 'Gene', (76, 80))	('Missense mutations in', 'Var', (0, 21))
376859	32824814	It should be noted that besides loss-of-function of wild type p53 and dominant-negative forms of p53, some mutations cause gain-of-function and lead to tumor progression, metastatic potential as well as may influence drug resistance.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('drug resistance', 'CPA', (217, 232))	('mutations', 'Var', (107, 116))	('influence', 'Reg', (207, 216))	('p53', 'Gene', (97, 100))	('gain-of-function', 'PosReg', (123, 139))	('drug resistance', 'Phenotype', 'HP:0020174', (217, 232))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('p53', 'Gene', '7157', (62, 65))	('p53', 'Gene', '7157', (97, 100))	('tumor', 'Disease', (152, 157))	('metastatic potential', 'CPA', (171, 191))	('lead to', 'Reg', (144, 151))	('p53', 'Gene', (62, 65))	('loss-of-function', 'NegReg', (32, 48))
376861	32824814	Moreover, specific TP53 mutations are associated with different anatomical sites of HNSCC and modulate its cellular activity in different ways.	('associated', 'Reg', (38, 48))	('modulate', 'Reg', (94, 102))	('HNSCC', 'Disease', (84, 89))	('TP53', 'Gene', '7157', (19, 23))	('TP53', 'Gene', (19, 23))	('cellular activity', 'MPA', (107, 124))	('mutations', 'Var', (24, 33))
376865	32824814	The expression levels of PTTG3P, PTTG1 and PTTG2 genes were analyzed and correlated with clinicopathological parameters such as: age (<=60 vs. >60), gender (women vs. men), smoking category (1, 2 vs. 3, 4, 5), alcohol history (negative vs. positive), T-stage (T1 + T2 vs. T3 + T4), N-stage (N0 + N1 vs. N2 + N3), cancer grade (G1 + G2 vs. G3 + G4), cancer stage (I + II vs. III + IV), HPV p16 marker (negative vs. positive), perineural invasion (negative vs. positive), lymphovascular invasion (negative vs. positive), and lymphoid neck dissection status (negative vs. positive) in all localizations of the HNSCC samples.	('cancer', 'Phenotype', 'HP:0002664', (313, 319))	('N0 + N1', 'Var', (291, 298))	('men', 'Species', '9606', (159, 162))	('HPV', 'Species', '10566', (385, 388))	('PTTG3P', 'Gene', (25, 31))	('PTTG2', 'Gene', (43, 48))	('women', 'Species', '9606', (157, 162))	('cancer', 'Disease', (349, 355))	('p16', 'Gene', (389, 392))	('PTTG3P', 'Gene', '26255', (25, 31))	('cancer', 'Disease', 'MESH:D009369', (313, 319))	('men', 'Species', '9606', (167, 170))	('cancer', 'Phenotype', 'HP:0002664', (349, 355))	('PTTG1', 'Gene', (33, 38))	('p16', 'Gene', '1029', (389, 392))	('G1 + G2 vs. G3 + G4', 'Var', (327, 346))	('perineural invasion', 'CPA', (425, 444))	('alcohol', 'Chemical', 'MESH:D000438', (210, 217))	('cancer', 'Disease', 'MESH:D009369', (349, 355))	('PTTG2', 'Gene', '10744', (43, 48))	('cancer', 'Disease', (313, 319))	('PTTG1', 'Gene', '9232', (33, 38))
376869	32824814	Next, specific mutations in TP53, described previously by Caponio et al.	('mutations', 'Var', (15, 24))	('TP53', 'Gene', '7157', (28, 32))	('TP53', 'Gene', (28, 32))
376871	32824814	The mutant p53-interacting partners and genes transcriptionally activated by mutant p53 protein, described by Freed-Pastor and Prives, and their correlations with PTTG3P, PTTG1 or PTTG2 were evaluated using StarBase v3.0 database.	('p53', 'Gene', (11, 14))	('p53', 'Gene', '7157', (11, 14))	('PTTG3P', 'Gene', '26255', (163, 169))	('PTTG1', 'Gene', (171, 176))	('PTTG1', 'Gene', '9232', (171, 176))	('PTTG2', 'Gene', '10744', (180, 185))	('activated', 'PosReg', (64, 73))	('p53', 'Gene', (84, 87))	('PTTG3P', 'Gene', (163, 169))	('PTTG2', 'Gene', (180, 185))	('p53', 'Gene', '7157', (84, 87))	('protein', 'Protein', (88, 95))	('mutant', 'Var', (77, 83))
376897	32824814	In all analyzed genes, a significantly higher (p < 0.05) expression of mutant and wild type TP53 cases (compared to normal samples) was observed.	('expression', 'MPA', (57, 67))	('higher', 'PosReg', (39, 45))	('mutant', 'Var', (71, 77))	('TP53', 'Gene', '7157', (92, 96))	('TP53', 'Gene', (92, 96))
376900	32824814	In all examined cases, the highest expressions of PTTG3P, PTTG1 and PTTG2 were observed in wild type TP53 versus DNA contact mutations (p = 0.0127; p = 0.0072; p = 0.0323, respectively), Figure 4B.	('mutations', 'Var', (125, 134))	('PTTG2', 'Gene', '10744', (68, 73))	('TP53', 'Gene', '7157', (101, 105))	('expressions', 'MPA', (35, 46))	('PTTG2', 'Gene', (68, 73))	('PTTG1', 'Gene', (58, 63))	('PTTG3P', 'Gene', '26255', (50, 56))	('PTTG1', 'Gene', '9232', (58, 63))	('TP53', 'Gene', (101, 105))	('PTTG3P', 'Gene', (50, 56))
376901	32824814	Analysis of different division of TP53 mutation types showed significant differences between missense mutations versus wild type and truncating mutations versus wild type for PTTG3P and PTTG1 (p = 0.0011; p = 0.0025, respectively).	('PTTG3P', 'Gene', (175, 181))	('TP53', 'Gene', (34, 38))	('truncating mutations', 'Var', (133, 153))	('missense mutations', 'Var', (93, 111))	('PTTG3P', 'Gene', '26255', (175, 181))	('differences', 'Reg', (73, 84))	('PTTG1', 'Gene', (186, 191))	('TP53', 'Gene', '7157', (34, 38))	('PTTG1', 'Gene', '9232', (186, 191))
376902	32824814	Finally, for PTTG2, significant difference was observed only between missense mutations versus wild type TP53 (p = 0.0099), Figure 4B.	('PTTG2', 'Gene', '10744', (13, 18))	('PTTG2', 'Gene', (13, 18))	('TP53', 'Gene', '7157', (105, 109))	('TP53', 'Gene', (105, 109))	('missense mutations', 'Var', (69, 87))	('difference', 'Reg', (32, 42))
376903	32824814	Next, selected mutant p53-interacting partners and genes transcriptionally activated by mutant p53 protein were analyzed.	('p53', 'Gene', (22, 25))	('p53', 'Gene', '7157', (22, 25))	('p53', 'Gene', (95, 98))	('mutant', 'Var', (88, 94))	('p53', 'Gene', '7157', (95, 98))	('protein', 'Protein', (99, 106))
376904	32824814	In the case of mutant p53-interacting partners and PTTG3P statistically significant positive correlation (p < 0.05) of NF-YB, NF-YC, Pin1 and p73 expression, and negative of Ets-1, VDR and p63 was indicated.	('NF-YB', 'Gene', (119, 124))	('VDR', 'Gene', '7421', (181, 184))	('PTTG3P', 'Gene', (51, 57))	('NF-YB', 'Gene', '4801', (119, 124))	('expression', 'MPA', (146, 156))	('Pin1', 'Gene', (133, 137))	('PTTG3P', 'Gene', '26255', (51, 57))	('NF-YC', 'Gene', (126, 131))	('p53', 'Gene', '7157', (22, 25))	('Ets-1', 'Gene', '2113', (174, 179))	('p63', 'Gene', (189, 192))	('NF-YC', 'Gene', '4802', (126, 131))	('p53', 'Gene', (22, 25))	('Pin1', 'Gene', '5300', (133, 137))	('p63', 'Gene', '8626', (189, 192))	('VDR', 'Gene', (181, 184))	('mutant', 'Var', (15, 21))	('Ets-1', 'Gene', (174, 179))	('p73', 'Gene', '7161', (142, 145))	('p73', 'Gene', (142, 145))	('positive', 'PosReg', (84, 92))
376908	32824814	The group of genes transcriptionally activated by mutant p53 protein and positively correlated (R > 0.2, p < 0.05) with PTTG3P comprised CCNA2, KIF20A, MCM6, TIMM50, TERT, CENPA, CCNB2, CDK1, CCNB1, DUT, MIS18A, STMN1 and CDC25C, whereas in the group of negatively correlated (R < -0.17, p < 0.05) were IGF2, MMP3, CYP51A1 and MMP13.	('STMN1', 'Gene', (212, 217))	('MMP13', 'Gene', '4322', (327, 332))	('activated', 'PosReg', (37, 46))	('CDC25C', 'Gene', '995', (222, 228))	('DUT', 'Gene', '1854', (199, 202))	('mutant', 'Var', (50, 56))	('CCNB2', 'Gene', '9133', (179, 184))	('p53', 'Gene', '7157', (57, 60))	('CYP51A1', 'Gene', (315, 322))	('CDK1', 'Gene', '983', (186, 190))	('CCNB1', 'Gene', '891', (192, 197))	('CDK1', 'Gene', (186, 190))	('PTTG3P', 'Gene', (120, 126))	('CCNA2', 'Gene', '890', (137, 142))	('p53', 'Gene', (57, 60))	('PTTG3P', 'Gene', '26255', (120, 126))	('CYP51A1', 'Gene', '1595', (315, 322))	('TIMM50', 'Gene', '92609', (158, 164))	('IGF2', 'Gene', (303, 307))	('MIS18A', 'Gene', (204, 210))	('CENPA', 'Gene', (172, 177))	('MMP3', 'Gene', '4314', (309, 313))	('CCNB2', 'Gene', (179, 184))	('MCM6', 'Gene', '4175', (152, 156))	('CENPA', 'Gene', '1058', (172, 177))	('DUT', 'Gene', (199, 202))	('MIS18A', 'Gene', '54069', (204, 210))	('CCNB1', 'Gene', (192, 197))	('MMP3', 'Gene', (309, 313))	('KIF20A', 'Gene', (144, 150))	('protein', 'Protein', (61, 68))	('MCM6', 'Gene', (152, 156))	('STMN1', 'Gene', '3925', (212, 217))	('MMP13', 'Gene', (327, 332))	('TIMM50', 'Gene', (158, 164))	('IGF2', 'Gene', '3481', (303, 307))	('TERT', 'Gene', (166, 170))	('TERT', 'Gene', '7015', (166, 170))	('CDC25C', 'Gene', (222, 228))	('KIF20A', 'Gene', '10112', (144, 150))	('CCNA2', 'Gene', (137, 142))
376945	32824814	Our results indicated that expression levels of PTTG3P, PTTG1 and PTTG2 depend on TP53 mutation type.	('TP53', 'Gene', '7157', (82, 86))	('TP53', 'Gene', (82, 86))	('PTTG2', 'Gene', '10744', (66, 71))	('expression levels', 'MPA', (27, 44))	('PTTG3P', 'Gene', (48, 54))	('depend', 'Reg', (72, 78))	('PTTG2', 'Gene', (66, 71))	('PTTG1', 'Gene', (56, 61))	('mutation', 'Var', (87, 95))	('PTTG1', 'Gene', '9232', (56, 61))	('PTTG3P', 'Gene', '26255', (48, 54))
376948	32824814	The aforementioned genes interact with mutated and non-mutated p53.	('p53', 'Gene', (63, 66))	('p53', 'Gene', '7157', (63, 66))	('men', 'Species', '9606', (9, 12))	('interact', 'Reg', (25, 33))	('mutated', 'Var', (39, 46))
376949	32824814	NF-Y influences the cell cycle progression, Pin1 promotes mutant p53 gain-of-function, and PML enhances transcriptional activity of mutant p53.	('cell cycle progression', 'CPA', (20, 42))	('mutant', 'Var', (58, 64))	('p53', 'Gene', (65, 68))	('p53', 'Gene', '7157', (65, 68))	('enhances', 'PosReg', (95, 103))	('PML', 'Gene', (91, 94))	('transcriptional activity', 'MPA', (104, 128))	('mutant', 'Var', (132, 138))	('Pin1', 'Gene', '5300', (44, 48))	('p53', 'Gene', (139, 142))	('p53', 'Gene', '7157', (139, 142))	('Pin1', 'Gene', (44, 48))	('gain-of-function', 'PosReg', (69, 85))	('PML', 'Gene', '5371', (91, 94))	('influences', 'Reg', (5, 15))
376950	32824814	Only p73 interacts with specific mutated variants of p53 and is responsible for regulation of the cell cycle and induction of apoptosis.	('variants', 'Var', (41, 49))	('regulation', 'MPA', (80, 90))	('interacts', 'Interaction', (9, 18))	('responsible', 'Reg', (64, 75))	('apoptosis', 'CPA', (126, 135))	('p73', 'Gene', '7161', (5, 8))	('p53', 'Gene', (53, 56))	('p73', 'Gene', (5, 8))	('p53', 'Gene', '7157', (53, 56))	('cell cycle', 'CPA', (98, 108))
376953	32824814	To further investigate the connection between the PTTG gene family and p53, we analyzed genes transcriptionally activated by mutant p53.	('mutant', 'Var', (125, 131))	('p53', 'Gene', (132, 135))	('p53', 'Gene', '7157', (132, 135))	('p53', 'Gene', '7157', (71, 74))	('p53', 'Gene', (71, 74))
376957	32824814	These findings indicate that higher expression of PTTG3P, PTTG1 and PTTG2 is connected with activation of prosurvival and protumorigenic downstream genes by mutant p53 protein.	('higher', 'PosReg', (29, 35))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('protein', 'Protein', (168, 175))	('mutant', 'Var', (157, 163))	('PTTG2', 'Gene', '10744', (68, 73))	('activation', 'PosReg', (92, 102))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('PTTG3P', 'Gene', '26255', (50, 56))	('PTTG1', 'Gene', (58, 63))	('PTTG2', 'Gene', (68, 73))	('tumor', 'Disease', (125, 130))	('PTTG1', 'Gene', '9232', (58, 63))	('p53', 'Gene', (164, 167))	('PTTG3P', 'Gene', (50, 56))	('expression', 'MPA', (36, 46))	('p53', 'Gene', '7157', (164, 167))
376967	32824814	High expression of PTTG1 was found to be associated with advanced cancers and short disease-free survival.	('PTTG1', 'Gene', (19, 24))	('associated', 'Reg', (41, 51))	('High', 'Var', (0, 4))	('cancers', 'Disease', (66, 73))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('cancers', 'Phenotype', 'HP:0002664', (66, 73))	('short disease-free', 'Disease', 'MESH:D008569', (78, 96))	('short disease-free', 'Disease', (78, 96))	('cancers', 'Disease', 'MESH:D009369', (66, 73))	('PTTG1', 'Gene', '9232', (19, 24))
376968	32824814	Moreover Read et al., postulated that PTTG1IP does not reduce the stability of mutated p53 as it is observed in the case of mutant p53 protein in colorectal tumors.	('tumors', 'Phenotype', 'HP:0002664', (157, 163))	('colorectal tumors', 'Disease', 'MESH:D015179', (146, 163))	('p53', 'Gene', (87, 90))	('p53', 'Gene', '7157', (87, 90))	('PTTG1IP', 'Gene', (38, 45))	('mutant', 'Var', (124, 130))	('colorectal tumors', 'Disease', (146, 163))	('p53', 'Gene', (131, 134))	('PTTG1IP', 'Gene', '754', (38, 45))	('p53', 'Gene', '7157', (131, 134))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('protein', 'Protein', (135, 142))
376971	32824814	As mentioned above, a higher expression of PTTG3P was observed in pharyngeal tumors with HPV status.	('tumors', 'Disease', (77, 83))	('tumors', 'Disease', 'MESH:D009369', (77, 83))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('higher', 'PosReg', (22, 28))	('PTTG3P', 'Gene', '26255', (43, 49))	('pharyngeal tumors', 'Phenotype', 'HP:0100638', (66, 83))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('HPV', 'Species', '10566', (89, 92))	('HPV status', 'Var', (89, 99))	('PTTG3P', 'Gene', (43, 49))	('expression', 'MPA', (29, 39))	('men', 'Species', '9606', (3, 6))
376993	32824814	demonstrated similar results in gastric cancer:high expressions of PTTG3P were correlated with significantly shorter DFS.	('gastric cancer', 'Disease', (32, 46))	('PTTG3P', 'Gene', '26255', (67, 73))	('gastric cancer', 'Disease', 'MESH:D013274', (32, 46))	('high expressions', 'Var', (47, 63))	('rat', 'Species', '10116', (7, 10))	('DFS', 'Disease', (117, 120))	('gastric cancer', 'Phenotype', 'HP:0012126', (32, 46))	('PTTG3P', 'Gene', (67, 73))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('shorter', 'NegReg', (109, 116))
376998	32824814	GSEA analysis indicated that patients with low expressions of pseudogene PTTG3P, as well as PTTG1 and PTTG2 genes have significantly negatively enriched genes involved in some pathways, such as DNA repair, E2F targets, Myc targets and peroxisome.	('patients', 'Species', '9606', (29, 37))	('PTTG3P', 'Gene', '26255', (73, 79))	('PTTG1', 'Gene', (92, 97))	('low', 'NegReg', (43, 46))	('PTTG1', 'Gene', '9232', (92, 97))	('pseudogene', 'Var', (62, 72))	('PTTG2', 'Gene', (102, 107))	('Myc', 'Gene', '4609', (219, 222))	('Myc', 'Gene', (219, 222))	('involved', 'Reg', (159, 167))	('PTTG3P', 'Gene', (73, 79))	('PTTG2', 'Gene', '10744', (102, 107))	('pathways', 'Pathway', (176, 184))	('GSEA', 'Chemical', '-', (0, 4))	('negatively', 'NegReg', (133, 143))
377002	32824814	The result of DNA repair defects may be the accumulation of mutations that contribute to genomic instability and then to carcinogenesis.	('defects', 'Var', (25, 32))	('contribute', 'Reg', (75, 85))	('DNA repair', 'Gene', (14, 24))	('carcinogenesis', 'Disease', 'MESH:D063646', (121, 135))	('genomic instability', 'CPA', (89, 108))	('mutations', 'Var', (60, 69))	('carcinogenesis', 'Disease', (121, 135))
377013	32824814	This could potentially explain the observed worse patients' disease-free survival and more advanced cancers (higher grade) in the group of patients with high levels in comparison to patients with low levels of PTTG1.	('worse', 'NegReg', (44, 49))	('disease-free survival', 'CPA', (60, 81))	('cancers', 'Phenotype', 'HP:0002664', (100, 107))	('patients', 'Species', '9606', (50, 58))	('patients', 'Species', '9606', (139, 147))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('cancers', 'Disease', 'MESH:D009369', (100, 107))	('high levels', 'Var', (153, 164))	('patients', 'Species', '9606', (182, 190))	('PTTG1', 'Gene', (210, 215))	('PTTG1', 'Gene', '9232', (210, 215))	('cancers', 'Disease', (100, 107))
377024	32824814	Patients with low expressions of PTTG3P and PTTG2 displayed significantly longer disease-free survival.	('disease-free survival', 'CPA', (81, 102))	('low expressions', 'Var', (14, 29))	('longer', 'PosReg', (74, 80))	('PTTG3P', 'Gene', '26255', (33, 39))	('PTTG2', 'Gene', (44, 49))	('Patients', 'Species', '9606', (0, 8))	('PTTG3P', 'Gene', (33, 39))	('PTTG2', 'Gene', '10744', (44, 49))
377025	32824814	Analysis of gene correlations and GSEA indicated that patients with high expressions of PTTG3P, PTTG1 and PTTG2 have different expression patterns of genes associated with carcinogenesis pathways in comparison to patients with low expressions of these three transcripts.	('PTTG2', 'Gene', '10744', (106, 111))	('expression', 'MPA', (127, 137))	('patients', 'Species', '9606', (54, 62))	('PTTG3P', 'Gene', '26255', (88, 94))	('PTTG2', 'Gene', (106, 111))	('carcinogenesis', 'Disease', 'MESH:D063646', (172, 186))	('PTTG1', 'Gene', (96, 101))	('high expressions', 'Var', (68, 84))	('PTTG1', 'Gene', '9232', (96, 101))	('patients', 'Species', '9606', (213, 221))	('carcinogenesis', 'Disease', (172, 186))	('PTTG3P', 'Gene', (88, 94))	('GSEA', 'Chemical', '-', (34, 38))
377043	32295135	A recent study suggests that HNSCC patients with high T cell infiltrates show improved survival with ICI treatment.	('survival', 'MPA', (87, 95))	('HNSCC', 'Disease', (29, 34))	('HNSCC', 'Phenotype', 'HP:0012288', (29, 34))	('high T cell infiltrates', 'Var', (49, 72))	('patients', 'Species', '9606', (35, 43))	('improved', 'PosReg', (78, 86))
377059	32295135	TMVs expressing such modified GPI-ISMs are capable of inducing protective anti-tumor immunity in breast cancer and thymoma models.	('tumor', 'Disease', (79, 84))	('thymoma', 'Phenotype', 'HP:0100522', (115, 122))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('TMVs', 'Chemical', '-', (0, 4))	('modified', 'Var', (21, 29))	('inducing', 'PosReg', (54, 62))	('breast cancer', 'Disease', 'MESH:D001943', (97, 110))	('breast cancer', 'Phenotype', 'HP:0003002', (97, 110))	('breast cancer', 'Disease', (97, 110))	('thymoma', 'Disease', 'MESH:D013945', (115, 122))	('thymoma', 'Disease', (115, 122))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('GPI-ISM', 'Chemical', '-', (30, 37))
377109	32295135	We have observed that SCC VII tumor growth was delayed in mice vaccinated with TMV vaccine compared to PBS treated control mice (Supplementary Figure S2B,C).	('delayed', 'NegReg', (47, 54))	('SCC VII tumor', 'Disease', (22, 35))	('SCC VII tumor', 'Disease', 'MESH:D016538', (22, 35))	('mice', 'Species', '10090', (58, 62))	('TMV vaccine', 'Var', (79, 90))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('TMV', 'Chemical', '-', (79, 82))	('PBS', 'Chemical', 'MESH:D007854', (103, 106))	('mice', 'Species', '10090', (123, 127))
377112	32295135	To test whether TMV vaccine inhibits tumor growth in a therapeutic setting, SCC VII tumor-bearing mice were administered with TMV vaccine (100 microg/dose) s.c. on the right flank every week starting three days after tumor cell challenge on the left flank (d3, d10 for two doses or d3, d10, d17 and d24 for four doses).	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('SCC VII tumor', 'Disease', (76, 89))	('d17', 'Var', (291, 294))	('tumor', 'Disease', (217, 222))	('d24', 'Var', (299, 302))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', 'MESH:D009369', (217, 222))	('mice', 'Species', '10090', (98, 102))	('TMV', 'Chemical', '-', (16, 19))	('inhibits', 'NegReg', (28, 36))	('d10', 'Var', (261, 264))	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('d10', 'Var', (286, 289))	('tumor', 'Disease', (84, 89))	('tumor', 'Disease', (37, 42))	('TMV', 'Chemical', '-', (126, 129))	('SCC VII tumor', 'Disease', 'MESH:D016538', (76, 89))
377117	32295135	In order to determine the effect of dose and dosing schedule on the efficacy of TMV vaccine, we have administered C3H/HeJ mice with TMV vaccine s.c. three days after SCC VII cells were implanted s.c. Total amount of TMV vaccine administered per mouse is 400 mug as 400 mug once on d3 or 200 mug x 2 times on d3 and d10 or 100 mug every week for four doses on d3, d10, d17, and d24) (Figure 2).	('d24', 'Var', (377, 380))	('mice', 'Species', '10090', (122, 126))	('TMV', 'Chemical', '-', (132, 135))	('TMV', 'Chemical', '-', (80, 83))	('HeJ', 'CellLine', 'CVCL:0030', (118, 121))	('TMV', 'Chemical', '-', (216, 219))	('mouse', 'Species', '10090', (245, 250))	('d10', 'Var', (315, 318))
377124	32295135	The data show that TMV vaccine significantly increases the percentage of CD4+ T cell within the tumor, and, interestingly, no difference was observed in the percentage of CD8+ T cells (Figure 3B,C).	('increases', 'PosReg', (45, 54))	('TMV', 'Chemical', '-', (19, 22))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumor', 'Disease', (96, 101))	('CD4', 'Gene', (73, 76))	('CD4', 'Gene', '12504', (73, 76))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('TMV vaccine', 'Var', (19, 30))
377129	32295135	MOC2 is a highly aggressive metastatic tumor with negligible or no T cell infiltration in the tumors and is thus termed a "cold" tumor.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('MOC2', 'Var', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('tumor', 'Disease', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('tumors', 'Disease', (94, 100))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('tumor', 'Disease', (39, 44))	('tumor', 'Disease', (129, 134))
377142	32295135	Since IFN-gamma signaling mediates the tumor's response to immunotherapy and a defect in IFN-gamma signaling is one of the mechanisms of resistance to ICI therapy, it is possible that resistance of MOC2 tumor cells to anti-PD-1 antibody therapy could be attributed to a defective response to IFN-gamma.	('IFN-gamma', 'Gene', (292, 301))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('defect', 'Var', (79, 85))	('tumor', 'Disease', (203, 208))	('IFN-gamma', 'Gene', '15978', (89, 98))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('IFN-gamma', 'Gene', '15978', (6, 15))	('IFN-gamma', 'Gene', '15978', (292, 301))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('tumor', 'Disease', (39, 44))	('IFN-gamma', 'Gene', (89, 98))	('IFN-gamma', 'Gene', (6, 15))
377147	32295135	Our earlier studies using whole cell vaccines demonstrated that expression of GPI-B7-1 and GPI-IL-12 on the tumor cells induced anti-tumor protective immunity.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('induced', 'PosReg', (120, 127))	('B7-1', 'Gene', '12519', (82, 86))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumor', 'Disease', (108, 113))	('GPI', 'Chemical', 'MESH:D017261', (91, 94))	('expression', 'Var', (64, 74))	('B7-1', 'Gene', (82, 86))	('tumor', 'Disease', (133, 138))	('GPI-IL-12', 'Gene', (91, 100))	('GPI', 'Chemical', 'MESH:D017261', (78, 81))
377185	30029672	We identified a set of 40 candidate regions with methylation correlated to carboplatin response and corresponding inverse gene expression pattern even before therapy.	('carboplatin', 'Chemical', 'MESH:D016190', (75, 86))	('carboplatin response', 'MPA', (75, 95))	('correlated', 'Reg', (61, 71))	('inverse gene expression pattern', 'MPA', (114, 145))	('methylation', 'Var', (49, 60))
377186	30029672	This analysis led to the identification of a promoter CpG island methylation of LDL receptor-related protein 12 (LRP12) associated with increased resistance to carboplatin.	('LDL receptor-related protein 12', 'Gene', '29967', (80, 111))	('associated with', 'Reg', (120, 135))	('LRP12', 'Gene', (113, 118))	('methylation', 'Var', (65, 76))	('carboplatin', 'Chemical', 'MESH:D016190', (160, 171))	('increased', 'PosReg', (136, 145))	('LDL receptor-related protein 12', 'Gene', (80, 111))	('resistance to carboplatin', 'MPA', (146, 171))
377187	30029672	Validation in an independent patient cohort (n = 35) confirmed that LRP12 methylation status is predictive for therapeutic response of NSCLC patients to platin therapy with a sensitivity of 80% and a specificity of 84% (p < 0.01).	('patient', 'Species', '9606', (29, 36))	('NSCLC', 'Disease', (135, 140))	('patient', 'Species', '9606', (141, 148))	('NSCLC', 'Disease', 'MESH:D002289', (135, 140))	('LRP12', 'Gene', (68, 73))	('methylation status', 'Var', (74, 92))	('patients', 'Species', '9606', (141, 149))	('NSCLC', 'Phenotype', 'HP:0030358', (135, 140))
377188	30029672	Similarly, we find a shorter survival time for patients with LRP12 hypermethylation in the TCGA data set for NSCLC (lung adenocarcinoma).	('NSCLC', 'Disease', 'MESH:D002289', (109, 114))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (116, 135))	('shorter', 'NegReg', (21, 28))	('survival', 'MPA', (29, 37))	('patients', 'Species', '9606', (47, 55))	('hypermethylation', 'Var', (67, 83))	('NSCLC', 'Phenotype', 'HP:0030358', (109, 114))	('LRP12', 'Protein', (61, 66))	('lung adenocarcinoma', 'Disease', (116, 135))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (116, 135))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('NSCLC', 'Disease', (109, 114))
377190	30029672	We identify LRP12 DNA methylation as a powerful predictive marker for carboplatin resistance.	('LRP12', 'Gene', (12, 17))	('carboplatin', 'MPA', (70, 81))	('methylation', 'Var', (22, 33))	('carboplatin', 'Chemical', 'MESH:D016190', (70, 81))
377191	30029672	These findings outline a platform for the identification of epigenetic therapy resistance biomarkers based on PDX NSCLC models.	('NSCLC', 'Disease', 'MESH:D002289', (114, 119))	('NSCLC', 'Phenotype', 'HP:0030358', (114, 119))	('epigenetic therapy', 'Var', (60, 78))	('NSCLC', 'Disease', (114, 119))
377197	30029672	Furthermore, aberrant DNA methylation is a feature not only of early carcinogenesis, but also of therapy resistance mechanisms which makes them promising biomarker candidates.	('carcinogenesis', 'Disease', (69, 83))	('DNA', 'Protein', (22, 25))	('carcinogenesis', 'Disease', 'MESH:D063646', (69, 83))	('aberrant', 'Var', (13, 21))
377198	30029672	In NSCLC, systematic genome-wide approaches have identified global hypomethylations and promoter-associated hypermethylations, either by high-throughput methods or targeted approaches.	('promoter-associated', 'MPA', (88, 107))	('NSCLC', 'Disease', (3, 8))	('NSCLC', 'Disease', 'MESH:D002289', (3, 8))	('NSCLC', 'Phenotype', 'HP:0030358', (3, 8))	('hypomethylations', 'Var', (67, 83))
377286	30029672	As transcription factors regulate gene expression levels, and binding of transcription factors to DNA can be influenced by DNA methylation, we also analyzed ENCODE-defined TFBS for their differences in methylation levels.	('binding', 'Interaction', (62, 69))	('methylation', 'Var', (127, 138))	('gene expression levels', 'MPA', (34, 56))	('influenced', 'Reg', (109, 119))	('TFBS', 'Chemical', '-', (172, 176))
377287	30029672	Hypermethylated regions were highly enriched for binding sites of polycomb repressor complex 2 components, such as SUZ12 and EZH2: respectively, 34 and 20.5% of all binding sites of these TFs are hypermethylated, which corresponds to an odds ratio of 149 and 90.5 (Fig.	('binding', 'Interaction', (165, 172))	('SUZ12', 'Gene', '23512', (115, 120))	('EZH2', 'Gene', '2146', (125, 129))	('hypermethylated', 'Var', (196, 211))	('SUZ12', 'Gene', (115, 120))	('EZH2', 'Gene', (125, 129))
377289	30029672	NSCLC-specific hypomethylation in TFBS was found to be enriched for SWI/SNF chromatin remodeling factors (SMARCC1, 2) and FOS gene family members, like FOS, FOSL1, and FOSL2 (Fig.	('FOS', 'Gene', (122, 125))	('FOS', 'Gene', '2353', (122, 125))	('TFBS', 'Gene', (34, 38))	('FOS', 'Gene', '2353', (168, 171))	('NSCLC', 'Phenotype', 'HP:0030358', (0, 5))	('FOS', 'Gene', (152, 155))	('FOS', 'Gene', '2353', (152, 155))	('FOSL1', 'Gene', (157, 162))	('SWI/SNF', 'Gene', (68, 75))	('FOSL2', 'Gene', (168, 173))	('FOSL2', 'Gene', '2355', (168, 173))	('FOSL1', 'Gene', '8061', (157, 162))	('FOS', 'Gene', (157, 160))	('FOS', 'Gene', '2353', (157, 160))	('SMARCC1', 'Gene', '6599', (106, 113))	('TFBS', 'Chemical', '-', (34, 38))	('NSCLC', 'Disease', 'MESH:D002289', (0, 5))	('SMARCC1', 'Gene', (106, 113))	('hypomethylation', 'Var', (15, 30))	('NSCLC', 'Disease', (0, 5))	('FOS', 'Gene', (168, 171))
377291	30029672	This indicates that DNA methylation at TFBS is an important feature of cancer methylomes with a likely functional impact.	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('TFBS', 'Gene', (39, 43))	('cancer', 'Disease', (71, 77))	('TFBS', 'Chemical', '-', (39, 43))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('DNA', 'Var', (20, 23))
377292	30029672	To identify resistance DMRs (rDMRs), i.e., DMRs with potential applicability as biomarkers for chemotherapy resistance, we aimed to select genomic regions where DNA methylation is associated with tumor volume after carboplatin response in PDX.	('tumor', 'Disease', (196, 201))	('DMRs', 'Chemical', '-', (43, 47))	('DMRs', 'Chemical', '-', (23, 27))	('associated with', 'Reg', (180, 195))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('DNA', 'Var', (161, 164))	('DMRs', 'Chemical', '-', (30, 34))	('carboplatin', 'Chemical', 'MESH:D016190', (215, 226))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))
377296	30029672	These candidates are mainly located within introns (50.9%) and intergenic regions (37.4%); 5.6% are associated with exons, and 6.2% with promoter regions (2678 rDMRs at promoters of 2380 genes) (Fig.	('DMRs', 'Chemical', '-', (161, 165))	('associated', 'Reg', (100, 110))	('2678 rDMRs', 'Var', (155, 165))
377300	30029672	4d): The most significantly enriched binding sites with hypermethylation include binding sites for RNA polymerase III subunits (POLR3G, BRF1, RPC155) and binding sites for NFE2 (nuclear factor, erythroid 2) which is a paralog of NFE2L2.	('RPC155', 'Gene', (142, 148))	('binding', 'Interaction', (154, 161))	('binding', 'Interaction', (37, 44))	('NFE2L2', 'Gene', (229, 235))	('BRF1', 'Gene', (136, 140))	('NFE2L2', 'Gene', '4780', (229, 235))	('hypermethylation', 'Var', (56, 72))	('binding', 'Interaction', (81, 88))	('RPC155', 'Gene', '11128', (142, 148))	('POLR3G', 'Gene', '10622', (128, 134))	('BRF1', 'Gene', '2972', (136, 140))	('NFE2', 'Gene', (172, 176))	('POLR3G', 'Gene', (128, 134))
377313	30029672	Here, we find the promoter significantly hypomethylated, indicating a relevance in therapy resistance of carboplatin.	('carboplatin', 'Chemical', 'MESH:D016190', (105, 116))	('relevance', 'Reg', (70, 79))	('hypomethylated', 'Var', (41, 55))
377324	30029672	Cell viability of cells with LRP12 knockdown is significantly higher in presence of carboplatin compared to that with a control siRNA treatment (Additional file 2: Figure S8).	('knockdown', 'Var', (35, 44))	('carboplatin', 'Chemical', 'MESH:D016190', (84, 95))	('LRP12', 'Gene', (29, 34))	('Cell viability', 'CPA', (0, 14))	('higher', 'PosReg', (62, 68))
377331	30029672	Integrating clinical follow-up data of the same clinical validation cohort (second cohort), we generated Kaplan-Meier curves to test whether LRP12 methylation status impacts the survival of the patients after platin therapy.	('impacts', 'Reg', (166, 173))	('patients', 'Species', '9606', (194, 202))	('clinical', 'Species', '191496', (48, 56))	('survival', 'CPA', (178, 186))	('test', 'Reg', (128, 132))	('clinical', 'Species', '191496', (12, 20))	('methylation', 'Var', (147, 158))	('LRP12', 'Gene', (141, 146))
377333	30029672	Next, we used methylation data from 449 LUAD patients from the TCGA data set to investigate whether methylation of LRP12 is associated to survival.	('methylation', 'Var', (100, 111))	('patients', 'Species', '9606', (45, 53))	('LRP12', 'Protein', (115, 120))	('associated', 'Reg', (124, 134))
377345	30029672	It might also explain the increase in variant allele frequencies in PDXs compared to primary tumors.	('primary tumors', 'Disease', 'MESH:D009369', (85, 99))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('variant', 'Var', (38, 45))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('PDXs', 'Disease', (68, 72))	('increase', 'PosReg', (26, 34))	('primary tumors', 'Disease', (85, 99))
377348	30029672	Focal hypermethylations were mainly associated with promoter regions and in particular with TFBS.	('TFBS', 'Disease', (92, 96))	('associated', 'Reg', (36, 46))	('TFBS', 'Chemical', '-', (92, 96))	('Focal hypermethylations', 'Var', (0, 23))
377349	30029672	Epigenetically affected TFBS included binding sites of PRC2 components, like SUZ12, EZH2, RNA polymerase III, and FOS family members.	('PRC2', 'Gene', (55, 59))	('FOS', 'Gene', '2353', (114, 117))	('FOS', 'Gene', (114, 117))	('binding', 'Interaction', (38, 45))	('TFBS', 'Gene', (24, 28))	('EZH2', 'Gene', '2146', (84, 88))	('SUZ12', 'Gene', '23512', (77, 82))	('Epigenetically affected', 'Var', (0, 23))	('SUZ12', 'Gene', (77, 82))	('TFBS', 'Chemical', '-', (24, 28))	('EZH2', 'Gene', (84, 88))
377350	30029672	Interestingly, we found FOS target sites to be mainly hypomethylated which would prevent FOS binding and which might function as regulatory mechanism counter-acting cellular proliferation.	('prevent', 'NegReg', (81, 88))	('FOS', 'Gene', '2353', (89, 92))	('FOS', 'Gene', (24, 27))	('binding', 'Interaction', (93, 100))	('hypomethylated', 'Var', (54, 68))	('FOS', 'Gene', '2353', (24, 27))	('FOS', 'Gene', (89, 92))
377354	30029672	Enrichment analysis of the subset of the 2380 promoter-associated rDMRs revealed signaling pathways known to be involved in platinum resistance, like ephrin B and Wnt/beta-catenin signaling.	('signaling pathways', 'Pathway', (81, 99))	('platinum', 'Chemical', 'MESH:D010984', (124, 132))	('beta-catenin', 'Gene', '1499', (167, 179))	('rDMRs', 'Var', (66, 71))	('beta-catenin', 'Gene', (167, 179))	('revealed', 'Reg', (72, 80))	('DMRs', 'Chemical', '-', (67, 71))
377355	30029672	Upstream analyses and enrichment analyses of transcription factor binding sites showed DNA methylation, histone methylation, and chromatin re-modeling to be involved in carboplatin therapy resistance on several levels.	('DNA', 'Var', (87, 90))	('methylation', 'Var', (91, 102))	('involved', 'Reg', (157, 165))	('histone', 'MPA', (104, 111))	('carboplatin', 'Chemical', 'MESH:D016190', (169, 180))
377360	30029672	We have identified a candidate epigenetic predictive biomarker for platin therapy resistance in NSCLC.	('NSCLC', 'Phenotype', 'HP:0030358', (96, 101))	('NSCLC', 'Disease', 'MESH:D002289', (96, 101))	('NSCLC', 'Disease', (96, 101))	('epigenetic', 'Var', (31, 41))
377364	30029672	Additionally, we show that the tumor cells are outgrown in the PDXs which significantly facilitate the detection of epigenetic alterations.	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumor', 'Disease', (31, 36))	('epigenetic alterations', 'Var', (116, 138))	('detection', 'MPA', (103, 112))	('facilitate', 'PosReg', (88, 98))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
377365	30029672	Next urgent steps include an integration of the LRP12 epigenetic test into the Network Genomic Medicine (NGM) Lung Cancer platform, Europe's largest platform for molecular testing, to improve the accuracy of the prediction of platin therapy resistance and a transfer into clinical applications.	('clinical', 'Species', '191496', (272, 280))	('epigenetic test', 'Var', (54, 69))	('prediction', 'MPA', (212, 222))	('Lung Cancer', 'Disease', 'MESH:D008175', (110, 121))	('platin therapy resistance', 'MPA', (226, 251))	('Cancer', 'Phenotype', 'HP:0002664', (115, 121))	('Lung Cancer', 'Disease', (110, 121))	('LRP12', 'Gene', (48, 53))	('improve', 'PosReg', (184, 191))	('Lung Cancer', 'Phenotype', 'HP:0100526', (110, 121))
377376	28951780	Some samples were tested for the EGFR and/or ALK mutations to provide suitable mutational genotyping for adenocarcinoma by using the PCR assays.	('ALK', 'Gene', '238', (45, 48))	('adenocarcinoma', 'Disease', (105, 119))	('mutations', 'Var', (49, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('adenocarcinoma', 'Disease', 'MESH:D000230', (105, 119))	('EGFR', 'Gene', '1956', (33, 37))	('ALK', 'Gene', (45, 48))	('EGFR', 'Gene', (33, 37))
377378	28951780	6 cases of EBUS-TBNA samples from patients with lung adenocarcinoma referred for EGFR testing were analyzed, 4 patients were found to have EGFR gene mutations.	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (48, 67))	('mutations', 'Var', (149, 158))	('lung adenocarcinoma', 'Disease', (48, 67))	('EGFR', 'Gene', '1956', (139, 143))	('patients', 'Species', '9606', (111, 119))	('patients', 'Species', '9606', (34, 42))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (48, 67))	('EGFR', 'Gene', (139, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))	('EGFR', 'Gene', '1956', (81, 85))	('EGFR', 'Gene', (81, 85))
377385	28951780	Endobronchial ultrasound guided transbronchial needle aspiration (EBUS-TBNA) is widely used minimally invasive sampling technique that has been shown to have a high sensitivity and diagnostic and safe for diagnosis and staging of lung cancer.Multiple studies have shown that EBUS-TBNA can improve the diagnostic yield for sampling mediastinal and hilar lymph nodes when compared with other available alternatives, such as mediastinoscopy, video-assisted thoracoscopy and conventional TBNA.	('EBUS-TBNA', 'Var', (275, 284))	('lung cancer', 'Phenotype', 'HP:0100526', (230, 241))	('diagnostic yield', 'MPA', (301, 317))	('sampling', 'MPA', (322, 330))	('aspiration', 'Phenotype', 'HP:0002835', (54, 64))	('staging of lung cancer', 'Disease', (219, 241))	('improve', 'PosReg', (289, 296))	('staging of lung cancer', 'Disease', 'MESH:D008175', (219, 241))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))
377404	28951780	A part of lung adenocarcinoma cases have detected the presence of mutations in the Epidermal Growth Factor Receptor (EGFR) with Real-time quantitative PCR technology (their screen EGFR RGQ PCR Kit, QIAGEN Manchester Ltd).	('mutations', 'Var', (66, 75))	('lung adenocarcinoma', 'Disease', (10, 29))	('carcinoma', 'Phenotype', 'HP:0030731', (20, 29))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (10, 29))	('Epidermal Growth Factor Receptor', 'Gene', '1956', (83, 115))	('EGFR', 'Gene', '1956', (117, 121))	('Epidermal Growth Factor Receptor', 'Gene', (83, 115))	('EGFR', 'Gene', (117, 121))	('EGFR', 'Gene', '1956', (180, 184))	('EGFR', 'Gene', (180, 184))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (10, 29))
377422	28951780	4 cases were found to have EGFR gene Exon 21 L858R mutant (Fig.	('EGFR', 'Gene', '1956', (27, 31))	('EGFR', 'Gene', (27, 31))	('L858R', 'Var', (45, 50))	('L858R', 'Mutation', 'rs121434568', (45, 50))
377425	28951780	The targeted therapy was carried out on patients with mutated EGFR.	('patients', 'Species', '9606', (40, 48))	('mutated', 'Var', (54, 61))	('EGFR', 'Gene', '1956', (62, 66))	('EGFR', 'Gene', (62, 66))
377426	28951780	Major of patients symptoms improved or alleviated, especially patients targeted therapy to EGFR gene mutations (Fig.	('patients', 'Species', '9606', (9, 17))	('EGFR', 'Gene', (91, 95))	('mutations', 'Var', (101, 110))	('improved', 'PosReg', (27, 35))	('alleviated', 'NegReg', (39, 49))	('symptoms', 'MPA', (18, 26))	('EGFR', 'Gene', '1956', (91, 95))	('patients', 'Species', '9606', (62, 70))
377429	28951780	In a prospective direct comparison of EBUS-TBNA and mediastinoscopy to date in patients with suspected lung cancer, EBUS-TBNA demonstrated significantly superior sensitivity (91 vs. 78%, P = 0.007).	('lung cancer', 'Disease', 'MESH:D008175', (103, 114))	('superior', 'PosReg', (153, 161))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('EBUS-TBNA', 'Var', (116, 125))	('lung cancer', 'Disease', (103, 114))	('patients', 'Species', '9606', (79, 87))	('lung cancer', 'Phenotype', 'HP:0100526', (103, 114))
377448	28951780	In recent years, targeted therapy for advanced lung cancer especially in patients who had mutated EGFR with tyrosine kinase inhibitors (TKI) has changed the treatment modalities of lung cancer.	('EGFR', 'Gene', (98, 102))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('lung cancer', 'Disease', (47, 58))	('mutated', 'Var', (90, 97))	('lung cancer', 'Phenotype', 'HP:0100526', (47, 58))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('lung cancer', 'Disease', (181, 192))	('lung cancer', 'Phenotype', 'HP:0100526', (181, 192))	('EGFR', 'Gene', '1956', (98, 102))	('lung cancer', 'Disease', 'MESH:D008175', (47, 58))	('patients', 'Species', '9606', (73, 81))	('lung cancer', 'Disease', 'MESH:D008175', (181, 192))
377449	28951780	The status of EGFR gene mutation can predict the patient's therapy and prognosis.	('EGFR', 'Gene', '1956', (14, 18))	('EGFR', 'Gene', (14, 18))	('patient', 'Species', '9606', (49, 56))	('mutation', 'Var', (24, 32))	('predict', 'Reg', (37, 44))
377450	28951780	Some researchers had reported the efficacy of patients with EGFR mutations by targeted treatment was 73.7%, so anti-EGFR targeted therapy had been recommended as first-line treatment program with EGFR mutations of advanced lung cancer.	('EGFR', 'Gene', (196, 200))	('mutations', 'Var', (201, 210))	('EGFR', 'Gene', (60, 64))	('patients', 'Species', '9606', (46, 54))	('lung cancer', 'Disease', (223, 234))	('lung cancer', 'Phenotype', 'HP:0100526', (223, 234))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('EGFR', 'Gene', '1956', (60, 64))	('EGFR', 'Gene', '1956', (196, 200))	('lung cancer', 'Disease', 'MESH:D008175', (223, 234))	('EGFR', 'Gene', '1956', (116, 120))	('EGFR', 'Gene', (116, 120))
377452	28951780	A recent European consensus showed the EGFR gene mutations tissue should use surgery or biopsy samples hardly use the cell samples, but advanced cancer cases had not chance to operate or get the sample by routine examination, EBUS-TBNA can be available to get the tissue sample for gene testing.	('cancer', 'Disease', (145, 151))	('mutations', 'Var', (49, 58))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('EGFR', 'Gene', '1956', (39, 43))	('EGFR', 'Gene', (39, 43))	('cancer', 'Disease', 'MESH:D009369', (145, 151))
377454	28951780	In this investigation, only six cases tissue specimens by EBUS-TBNA tested the EGFR gene mutation; however, the feasibility was 100%.	('mutation', 'Var', (89, 97))	('EGFR', 'Gene', '1956', (79, 83))	('EGFR', 'Gene', (79, 83))
377455	28951780	First, the tissue type of EGFR or ALK gene mutation with high mutation rate majorly existed on lung adenocarcinoma, hardly on other kinds of carcinoma, only patients diagnosed with lung adenocarcinoma were recommended to have the gene testing.	('carcinoma', 'Disease', 'MESH:D002277', (141, 150))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (95, 114))	('patients', 'Species', '9606', (157, 165))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('carcinoma', 'Disease', (105, 114))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (181, 200))	('mutation', 'Var', (43, 51))	('carcinoma', 'Phenotype', 'HP:0030731', (191, 200))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (181, 200))	('carcinoma', 'Disease', (191, 200))	('existed', 'Reg', (84, 91))	('ALK', 'Gene', '238', (34, 37))	('EGFR', 'Gene', (26, 30))	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('carcinoma', 'Disease', 'MESH:D002277', (105, 114))	('carcinoma', 'Disease', (141, 150))	('lung adenocarcinoma', 'Disease', (95, 114))	('ALK', 'Gene', (34, 37))	('carcinoma', 'Disease', 'MESH:D002277', (191, 200))	('EGFR', 'Gene', '1956', (26, 30))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (95, 114))	('lung adenocarcinoma', 'Disease', (181, 200))
377474	28125611	Analysis of mice harbouring a mutation in the DNA-dependent protein kinase catalytic subunit (DNA-PKcs), a key enzyme in DNA damage repair by nonhomologous end joining (NHEJ), indicated that BSCs preferentially repair their DNA by this error-prone process.	('DNA-dependent protein kinase catalytic subunit', 'Gene', '19090', (46, 92))	('mutation', 'Var', (30, 38))	('BSCs', 'Chemical', '-', (191, 195))	('DNA', 'MPA', (224, 227))	('mice', 'Species', '10090', (12, 16))	('preferentially', 'PosReg', (196, 210))	('DNA-dependent protein kinase catalytic subunit', 'Gene', (46, 92))
377481	28125611	However, we demonstrate that basal stem cells predominately use nonhomologous end joining to repair DNA double-strand breaks, a notoriously error-prone pathway.	('DNA', 'Var', (100, 103))	('nonhomologous', 'Var', (64, 77))	('rat', 'Species', '10116', (19, 22))
377486	28125611	The failure of stem cells to repair DNA damage can contribute to tissue loss through damage-induced cell death, whereas unfaithful DNA repair in stem cells may invoke carcinogenesis through the accumulation of genetic aberrations.	('tissue loss', 'CPA', (65, 76))	('genetic aberrations', 'Var', (210, 229))	('invoke', 'Reg', (160, 166))	('carcinogenesis', 'CPA', (167, 181))	('rat', 'Species', '10116', (222, 225))	('damage-induced cell death', 'CPA', (85, 110))
377492	28125611	DSBs, which have been shown to arise after cigarette smoke exposure, are the most dangerous type of DNA lesion, as they can result in loss or gain of genetic information through insertions, deletions, or chromosomal translocations.	('insertions', 'Var', (178, 188))	('genetic information', 'MPA', (150, 169))	('chromosomal translocations', 'Var', (204, 230))	('gain', 'PosReg', (142, 146))	('loss', 'NegReg', (134, 138))	('DSBs', 'Disease', (0, 4))	('DSBs', 'Chemical', '-', (0, 4))	('deletions', 'Var', (190, 199))
377502	28125611	Collectively, our data indicate that error-prone DNA repair is a hallmark of lung SqCC and suggest that targeting NHEJ may play a role in SqCC prevention and/or treatment.	('SqCC', 'Phenotype', 'HP:0002860', (82, 86))	('lung SqCC', 'Disease', (77, 86))	('error-prone', 'Var', (37, 48))	('C', 'Chemical', 'MESH:D002244', (141, 142))	('NHEJ', 'Gene', (114, 118))	('C', 'Chemical', 'MESH:D002244', (84, 85))	('C', 'Chemical', 'MESH:D002244', (140, 141))	('SqCC', 'Phenotype', 'HP:0002860', (138, 142))	('C', 'Chemical', 'MESH:D002244', (85, 86))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('SqCC', 'Disease', (138, 142))
377550	28125611	To assess whether BSCs use NHEJ to repair their DNA, we analysed severe combined immune deficiency (SCIDPrkdc) mice, that have a mutation in Prkdc, leading to a 50% reduction in DNA-PKcs activity and impaired NHEJ.	('Prkdc', 'Gene', '19090', (104, 109))	('BSCs', 'Chemical', '-', (18, 22))	('severe combined immune deficiency', 'Phenotype', 'HP:0004430', (65, 98))	('immune deficiency', 'Disease', 'MESH:D007153', (81, 98))	('SCIDPrkdc', 'Disease', (100, 109))	('NHEJ', 'CPA', (209, 213))	('Prkdc', 'Gene', '19090', (141, 146))	('mutation', 'Var', (129, 137))	('combined immune deficiency', 'Phenotype', 'HP:0005387', (72, 98))	('immune deficiency', 'Phenotype', 'HP:0002721', (81, 98))	('Prkdc', 'Gene', (104, 109))	('impaired', 'NegReg', (200, 208))	('activity', 'MPA', (187, 195))	('SCIDPrkdc', 'Disease', 'None', (100, 109))	('immune deficiency', 'Disease', (81, 98))	('DNA-PKcs', 'Enzyme', (178, 186))	('Prkdc', 'Gene', (141, 146))	('mice', 'Species', '10090', (111, 115))	('reduction', 'NegReg', (165, 174))
377568	28125611	Strikingly, high expression of PRKDC or XRCC6 in lung SqCC was found to be associated with increased genomic instability (Fig 7G).	('XRCC6', 'Gene', '2547', (40, 45))	('high', 'Var', (12, 16))	('PRKDC', 'Gene', (31, 36))	('XRCC6', 'Gene', (40, 45))	('genomic instability', 'CPA', (101, 120))	('increased', 'PosReg', (91, 100))	('SqCC', 'Phenotype', 'HP:0002860', (54, 58))
377569	28125611	We propose that the use of NHEJ by BSCs could lead to the accumulation of genetic alterations that may culminate in SqCC formation in cigarette-smoking patients (Fig 8), although this hypothesis will need to be validated with functional studies in vivo.	('lead to', 'Reg', (46, 53))	('SqCC', 'Phenotype', 'HP:0002860', (116, 120))	('BSCs', 'Chemical', '-', (35, 39))	('genetic alterations', 'Var', (74, 93))	('SqCC formation', 'Disease', (116, 130))	('rat', 'Species', '10116', (86, 89))	('patients', 'Species', '9606', (152, 160))	('culminate', 'Reg', (103, 112))
377575	28125611	Loss of AT2 cells has been identified as a mechanism participating in the pathogenesis of idiopathic pulmonary fibrosis and emphysema-like diseases.	('idiopathic pulmonary fibrosis', 'Disease', 'MESH:D054990', (90, 119))	('emphysema-like diseases', 'Disease', 'MESH:D004646', (124, 147))	('emphysema-like diseases', 'Disease', (124, 147))	('emphysema', 'Phenotype', 'HP:0002097', (124, 133))	('idiopathic pulmonary fibrosis', 'Disease', (90, 119))	('AT2', 'Gene', (8, 11))	('pulmonary fibrosis', 'Phenotype', 'HP:0002206', (101, 119))	('Loss', 'Var', (0, 4))
377576	28125611	Different genetic mutations have been associated with the development of these diseases, including aberrations in telomere maintenance genes, SFTPC, MUC5B, and alpha-1 anti-trypsin.	('SFTPC', 'Gene', (142, 147))	('telomere maintenance genes', 'Gene', (114, 140))	('MUC5B', 'Gene', (149, 154))	('associated', 'Reg', (38, 48))	('rat', 'Species', '10116', (103, 106))	('SFTPC', 'Gene', '6440', (142, 147))	('alpha-1', 'Gene', '146', (160, 167))	('MUC5B', 'Gene', '727897', (149, 154))	('aberrations', 'Var', (99, 110))	('alpha-1', 'Gene', (160, 167))	('mutations', 'Var', (18, 27))
377585	28125611	Consistently, studies in mice have shown that depletion of luminal airway cells results in the expansion of BSCs and their differentiation into secretory cells and ciliated cells.	('depletion', 'Var', (46, 55))	('mice', 'Species', '10090', (25, 29))	('C', 'Chemical', 'MESH:D002244', (110, 111))	('BSCs', 'Chemical', '-', (108, 112))	('BSCs', 'CPA', (108, 112))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('differentiation', 'CPA', (123, 138))
377589	28125611	We propose the ability of BSCs to rapidly repair DNA through error-prone NHEJ allows the cells to survive longer and places them at greater risk than lung progenitor cells to accumulate mutations, which may ultimately lead to the induction of carcinogenesis (Fig 8).	('carcinogenesis', 'CPA', (243, 257))	('lead to', 'Reg', (218, 225))	('BSCs', 'Chemical', '-', (26, 30))	('mutations', 'Var', (186, 195))
377591	28125611	AT2 cells were found to act as the tumour-initiating cells in K-RasG12D-driven lung adenocarcinoma, whilst inactivation of Tp53 and Rb specifically in lung neuroendocrine cells resulted in small cell lung cancer.	('Tp53', 'Gene', (123, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('Tp53', 'Gene', '7157', (123, 127))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (79, 98))	('small cell lung cancer', 'Disease', (189, 211))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (189, 211))	('tumour', 'Phenotype', 'HP:0002664', (35, 41))	('inactivation', 'Var', (107, 119))	('tumour', 'Disease', 'MESH:D009369', (35, 41))	('lung cancer', 'Phenotype', 'HP:0100526', (200, 211))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (79, 98))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('lung adenocarcinoma', 'Disease', (79, 98))	('small cell lung cancer', 'Disease', 'MESH:D055752', (189, 211))	('resulted in', 'Reg', (177, 188))	('tumour', 'Disease', (35, 41))
377600	28125611	Our hypothesis will therefore need to be validated by introducing multiple genetic alterations in primary human lung cell subsets and determining their propensity for SqCC formation.	('SqCC', 'Phenotype', 'HP:0002860', (167, 171))	('human', 'Species', '9606', (106, 111))	('genetic alterations', 'Var', (75, 94))	('introducing', 'Reg', (54, 65))	('rat', 'Species', '10116', (87, 90))
377618	28125611	Cells were stained where appropriate with either anti-rabbit Alexa594 or anti-mouse Alexa594 (Molecular Probes) before analysis on a LSR Fortessa (BD Biosciences).	('Alexa594', 'Chemical', 'MESH:C417664', (84, 92))	('Alexa594', 'Chemical', 'MESH:C417664', (61, 69))	('anti-mouse', 'Var', (73, 83))	('rabbit', 'Species', '9986', (54, 60))	('mouse', 'Species', '10090', (78, 83))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('Alexa594', 'Gene', (84, 92))
377657	28125611	Taqman gene expression assays were used for MUC5AC (Hs0087365_mH) and FOXJ1 (HS00230964_m1) using 18S (HS99999901_s1) or GAPDH (HS99999905_m1) as reference genes (Life Technologies).	('HS99999901_s1', 'Var', (103, 116))	('Hs0087365_mH', 'Var', (52, 64))	('MUC5AC', 'Gene', '4586', (44, 50))	('HS99999901', 'CellLine', 'CVCL:W404', (103, 113))	('FOXJ1', 'Gene', '2302', (70, 75))	('HS99999905_m1', 'Var', (128, 141))	('HS00230964_m1', 'Var', (77, 90))	('MUC5AC', 'Gene', (44, 50))	('FOXJ1', 'Gene', (70, 75))
377679	33105726	Prognostic Significance of Oxidation Pathway Mutations in Recurrent Laryngeal Squamous Cell Carcinoma Organ preservation protocols have become first line therapy for the majority of advanced laryngeal cancers.	('cancers', 'Disease', 'MESH:D009369', (201, 208))	('cancers', 'Phenotype', 'HP:0002664', (201, 208))	('Oxidation Pathway', 'Pathway', (27, 44))	('cancers', 'Disease', (201, 208))	('Squamous Cell Carcinoma', 'Disease', 'MESH:D002294', (78, 101))	('laryngeal cancers', 'Phenotype', 'HP:0012118', (191, 208))	('laryngeal cancer', 'Phenotype', 'HP:0012118', (191, 207))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('Squamous Cell Carcinoma', 'Disease', (78, 101))	('Mutations', 'Var', (45, 54))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (78, 101))	('Carcinoma', 'Phenotype', 'HP:0030731', (92, 101))
377682	33105726	Here we show that mutations in the oxidation pathway, specifically the KEAP1-NFR2 pathway, predict survival in a cohort of patients undergoing salvage laryngectomy.	('KEAP1', 'Gene', (71, 76))	('oxidation pathway', 'Pathway', (35, 52))	('patients', 'Species', '9606', (123, 131))	('KEAP1', 'Gene', '9817', (71, 76))	('predict', 'Reg', (91, 98))	('mutations', 'Var', (18, 27))
377687	33105726	Patients with mutations in the Oxidation pathway had significantly worse five-year disease specific survival (1% vs. 76%, p = 0.02), while mutations in the HN-Immunity pathway were associated with improved five-year disease specific survival (100% vs. 62%, p = 0.02).	('HN-Immunity pathway', 'Pathway', (156, 175))	('mutations', 'Var', (139, 148))	('Oxidation pathway', 'Pathway', (31, 48))	('improved', 'PosReg', (197, 205))	('Patients', 'Species', '9606', (0, 8))	('worse', 'NegReg', (67, 72))	('mutations', 'Var', (14, 23))	('disease specific survival', 'CPA', (83, 108))
377688	33105726	Transcriptome analysis of recurrent tumors demonstrated that alterations in the Oxidation pathway were associated a positive Ragnum hypoxia signature score, consistent with enhanced pathway activity.	('hypoxia', 'Disease', 'MESH:D000860', (132, 139))	('tumors', 'Disease', 'MESH:D009369', (36, 42))	('Ragnum', 'Chemical', '-', (125, 131))	('alterations', 'Var', (61, 72))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))	('Oxidation pathway', 'Pathway', (80, 97))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('enhanced', 'PosReg', (173, 181))	('tumors', 'Disease', (36, 42))	('hypoxia', 'Disease', (132, 139))
377689	33105726	Alterations in the Oxidation pathway are associated with survival among patients with recurrent laryngeal cancer.	('laryngeal cancer', 'Phenotype', 'HP:0012118', (96, 112))	('survival', 'Disease', (57, 65))	('associated', 'Reg', (41, 51))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('Alterations', 'Var', (0, 11))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('cancer', 'Disease', (106, 112))	('Oxidation pathway', 'Pathway', (19, 36))	('patients', 'Species', '9606', (72, 80))
377694	33105726	When compared to primary laryngeal tumors in the Tumor Genome Atlas (TCGA), there was an increased frequency of alterations in multiple genes critical in tumorigenesis including CDKN2A, MTOR, PIK3CA, TET2, and TP53 among others.	('TET2', 'Gene', '54790', (200, 204))	('MTOR', 'Gene', (186, 190))	('Tumor', 'Phenotype', 'HP:0002664', (49, 54))	('CDKN2A', 'Gene', (178, 184))	('MTOR', 'Gene', '2475', (186, 190))	('laryngeal tumors', 'Phenotype', 'HP:0012118', (25, 41))	('PIK3CA', 'Gene', '5290', (192, 198))	('tumors', 'Disease', 'MESH:D009369', (35, 41))	('tumor', 'Disease', (154, 159))	('TP53', 'Gene', (210, 214))	('tumor', 'Disease', (35, 40))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('CDKN2A', 'Gene', '1029', (178, 184))	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('PIK3CA', 'Gene', (192, 198))	('TET2', 'Gene', (200, 204))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('alterations', 'Var', (112, 123))	('TP53', 'Gene', '7157', (210, 214))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumors', 'Disease', (35, 41))	('primary laryngeal tumors', 'Phenotype', 'HP:0012118', (17, 41))
377706	33105726	cN+ patients trended to lower five-year OS compared to cN0 patients [20% (95% CI 3-47%) vs. 50% (95% CI 36-64%), p = 0.08).	('lower', 'NegReg', (24, 29))	('patients', 'Species', '9606', (59, 67))	('cN+', 'Var', (0, 3))	('patients', 'Species', '9606', (4, 12))
377712	33105726	We then assigned pathogenicity scores to each of the alterations, and noted that many of the alterations (e.g., CDKN2A, FAT1, PIK3CA and/or TP53) were highly likely to have a pathogenic role in the tumor (Table S4).	('PIK3CA', 'Gene', (126, 132))	('CDKN2A', 'Gene', (112, 118))	('TP53', 'Gene', (140, 144))	('alterations', 'Var', (93, 104))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('pathogenic role', 'Reg', (175, 190))	('CDKN2A', 'Gene', '1029', (112, 118))	('PIK3CA', 'Gene', '5290', (126, 132))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('FAT1', 'Gene', '2195', (120, 124))	('FAT1', 'Gene', (120, 124))	('tumor', 'Disease', (198, 203))	('TP53', 'Gene', '7157', (140, 144))
377715	33105726	Additionally, TGFBR2 was mutated at a higher frequency in our cohort (12.9%) compared to primary laryngeal tumors in TCGA (2.8%).	('primary laryngeal tumors', 'Phenotype', 'HP:0012118', (89, 113))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumors', 'Disease', (107, 113))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('TGFBR2', 'Gene', (14, 20))	('tumors', 'Disease', 'MESH:D009369', (107, 113))	('laryngeal tumors', 'Phenotype', 'HP:0012118', (97, 113))	('mutated', 'Var', (25, 32))	('TGFBR2', 'Gene', '7048', (14, 20))
377716	33105726	Half of these TGFRB2 alterations are predicted to result in loss of function (LOF) with 3/4 of these representing Lys128Serfs*35 and the other Gln166Ter.	('Gln166Ter', 'Chemical', '-', (143, 152))	('Lys128Serfs', 'Chemical', '-', (114, 125))	('Lys128Serfs*35', 'Var', (114, 128))	('loss', 'NegReg', (60, 64))	('Gln166Ter', 'Var', (143, 152))	('TGFRB2', 'Gene', (14, 20))
377720	33105726	Patients with mutations in the Oxidation pathway had significantly worse five-year DSS [31% (95% CI 5-64%) vs. 76% (95% CI 61-86%), p = 0.02] and five-year OS [13% (95% CI 1-42%) vs. 51% (95% CI 36-63%), p = 0.01] compared to those patients without mutations in this pathway (Figure 3).	('patients', 'Species', '9606', (232, 240))	('Oxidation pathway', 'Pathway', (31, 48))	('DSS', 'MPA', (83, 86))	('Patients', 'Species', '9606', (0, 8))	('DSS', 'Chemical', '-', (83, 86))	('worse', 'NegReg', (67, 72))	('mutations', 'Var', (14, 23))
377721	33105726	Similarly, patients with mutations in the Differentiation/Stem/Epigenetic pathway had a significantly lower five-year DSS [47% (95% CI 25-67%) vs. 84% (95% CI 66%-93%), p = 0.005] and five-year OS [23% (95% CI 8-42%) vs. 59% (95% CI 41-73%), p = 0.007] compared to patients without mutations in this pathway.	('lower', 'NegReg', (102, 107))	('mutations', 'Var', (25, 34))	('five-year DSS', 'CPA', (108, 121))	('Differentiation/Stem/Epigenetic', 'Gene', (42, 73))	('patients', 'Species', '9606', (265, 273))	('DSS', 'Chemical', '-', (118, 121))	('patients', 'Species', '9606', (11, 19))
377722	33105726	Patients with mutations in both the Differentiation/Stem/Epigenetic and the Oxidation pathways performed the worst with significantly lower DSS [29% (95% CI 4-61) vs. 76% (95% CI 61-86%), p = 0.009] and OS [14% (95% CI 1-46%) vs. 50% (95% CI 35-62%), p = 0.03] compared to patients with either no mutations in these pathways or with a mutation in just one of these pathways.	('lower', 'NegReg', (134, 139))	('patients', 'Species', '9606', (273, 281))	('DSS', 'MPA', (140, 143))	('DSS', 'Chemical', '-', (140, 143))	('Patients', 'Species', '9606', (0, 8))	('mutations', 'Var', (14, 23))
377723	33105726	Patients with mutations in the HN-immunity pathways had significantly higher DSS [100% vs. 62% (95% CI 46-75%), p =0.02] compared to those patients without a mutation in this pathway.	('patients', 'Species', '9606', (139, 147))	('DSS', 'Chemical', '-', (77, 80))	('Patients', 'Species', '9606', (0, 8))	('HN-immunity pathways', 'Pathway', (31, 51))	('higher', 'PosReg', (70, 76))	('mutations', 'Var', (14, 23))	('DSS', 'MPA', (77, 80))
377725	33105726	The rate of Differentiation/Stem/Epigenetic pathways mutations was higher in the group of patients without mutations in the HN-immunity pathway (41%) compared to the rate in patients with mutations HN-immunity pathway (18%), suggesting these mutations may be less likely to occur together.	('higher', 'PosReg', (67, 73))	('Differentiation/Stem/Epigenetic', 'CPA', (12, 43))	('mutations', 'Var', (53, 62))	('patients', 'Species', '9606', (174, 182))	('patients', 'Species', '9606', (90, 98))
377726	33105726	In a multivariate analysis, the presence of mutations in the Oxidation pathway remained a significant predictor of DSS (HR 3.2, 95% CI 1.1-9.2, p = 0.03) and OS (HR 2.6, 95% CI 1.2-5.9, p = 0.02).	('mutations', 'Var', (44, 53))	('Oxidation pathway', 'Pathway', (61, 78))	('DSS', 'Disease', (115, 118))	('DSS', 'Chemical', '-', (115, 118))
377728	33105726	As no disease related deaths occurred in the cohort of patients with mutations in the HN-immunity pathway, no hazard ratio is available.	('mutations', 'Var', (69, 78))	('HN-immunity pathway', 'Pathway', (86, 105))	('deaths', 'Disease', 'MESH:D003643', (22, 28))	('deaths', 'Disease', (22, 28))	('patients', 'Species', '9606', (55, 63))
377729	33105726	We found a significantly higher proportion of patients who recurred within one year of initial treatment harbored a mutation in the oxidation pathway (23%), compared to patients who recurred after one year (3%), (Chi squared-p = 0.02), further supporting the role of the oxidation pathway in treatment failure.	('mutation', 'Var', (116, 124))	('patients', 'Species', '9606', (46, 54))	('patients', 'Species', '9606', (169, 177))	('oxidation pathway', 'Pathway', (132, 149))
377733	33105726	We utilized these data to test for an association between alterations in the oxidation pathway and oxidation pathway activity as represented by Ragnum hypoxia scores (Figure 4B).	('activity', 'MPA', (117, 125))	('hypoxia', 'Disease', 'MESH:D000860', (151, 158))	('oxidation pathway', 'Pathway', (77, 94))	('hypoxia', 'Disease', (151, 158))	('oxidation pathway', 'Pathway', (99, 116))	('Ragnum', 'Chemical', '-', (144, 150))	('alterations', 'Var', (58, 69))
377735	33105726	Further, samples containing mutations in KEAP1, CUL3 or NFE2L2 were all associated with positive scores.	('KEAP1', 'Gene', '9817', (41, 46))	('NFE2L2', 'Gene', '4780', (56, 62))	('KEAP1', 'Gene', (41, 46))	('CUL3', 'Gene', '8452', (48, 52))	('CUL3', 'Gene', (48, 52))	('NFE2L2', 'Gene', (56, 62))	('mutations', 'Var', (28, 37))
377736	33105726	We subsequently evaluated whether hypoxia scores were predictive of survival in our cohort and found that there is a trend towards worse five-year disease specific survival in patients with high Ragnum Scores compared to patients with low Ragnum scores, (67% vs. 100%, p = 0.2, Figure 4C) and likely limited by the low number of samples in the overall RNAseq cohort.	('Ragnum', 'Chemical', '-', (195, 201))	('patients', 'Species', '9606', (176, 184))	('patients', 'Species', '9606', (221, 229))	('high', 'Var', (190, 194))	('Ragnum', 'Gene', (195, 201))	('worse', 'NegReg', (131, 136))	('hypoxia', 'Disease', (34, 41))	('hypoxia', 'Disease', 'MESH:D000860', (34, 41))	('Ragnum', 'Chemical', '-', (239, 245))
377737	33105726	Evaluation of the Oxidation pathway revealed that the majority of mutations occurred in genes involved in the KEAP1/NRF2 pathway.	('mutations', 'Var', (66, 75))	('occurred', 'Reg', (76, 84))	('KEAP1', 'Gene', '9817', (110, 115))	('NRF2', 'Gene', '4780', (116, 120))	('KEAP1', 'Gene', (110, 115))	('NRF2', 'Gene', (116, 120))
377739	33105726	Further, we found that the majority of these recurrent samples were strongly positive (43/52) compared to moderately positive (1/52), weakly positive (6/52), or no staining (2/52), suggesting that the pathway is activated not just by mutations, but potentially by other mechanisms as well in these recurrent tumors.	('tumors', 'Disease', 'MESH:D009369', (308, 314))	('tumor', 'Phenotype', 'HP:0002664', (308, 313))	('tumors', 'Disease', (308, 314))	('mutations', 'Var', (234, 243))	('tumors', 'Phenotype', 'HP:0002664', (308, 314))
377740	33105726	Not surprisingly, given the high level of activity of the pathway in the majority of cases, there was no significant correlation between NRF2 protein expression with oxidation mutation status (p = 0.3), NRF2 mutation status (p = 0.5), or hypoxia score (p = 0.9) (data not shown).	('NRF2', 'Gene', (203, 207))	('mutation status', 'Var', (208, 223))	('oxidation', 'MPA', (166, 175))	('NRF2', 'Gene', '4780', (203, 207))	('NRF2', 'Gene', '4780', (137, 141))	('hypoxia', 'Disease', (238, 245))	('NRF2', 'Gene', (137, 141))	('hypoxia', 'Disease', 'MESH:D000860', (238, 245))
377741	33105726	We further leveraged sequencing data from TCGA to evaluate the association between oxidation pathway mutation status and survival (DSS and OS) in a cohort of previously untreated head and neck cancer patients (all head and neck cancer subsites).	('neck cancer', 'Disease', 'MESH:D006258', (223, 234))	('oxidation pathway', 'Pathway', (83, 100))	('patients', 'Species', '9606', (200, 208))	('head and neck cancer', 'Phenotype', 'HP:0012288', (179, 199))	('neck cancer', 'Disease', 'MESH:D006258', (188, 199))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('head and neck cancer', 'Phenotype', 'HP:0012288', (214, 234))	('neck cancer', 'Disease', (188, 199))	('DSS', 'Chemical', '-', (131, 134))	('mutation', 'Var', (101, 109))	('neck cancer subsites', 'Disease', (223, 243))	('neck cancer subsites', 'Disease', 'MESH:D006258', (223, 243))
377742	33105726	Using the TCGA Head and Neck Squamous Cell (HNSC) data set , we found that the presence of alterations (mutation or copy number variation) in the oxidation pathway predicted worse five-year DSS (55%, 95% CI 44-66% vs. 63%, 95% CI 55-71%, p = 0.02), with a trend towards worse OS (40%, 95% CI 29-51% vs. 49%, 95% CI 42-56, p = 0.06), Figure 4D.	('oxidation pathway', 'Pathway', (146, 163))	('worse', 'NegReg', (174, 179))	('copy number variation', 'Var', (116, 137))	('DSS', 'CPA', (190, 193))	('alterations', 'Var', (91, 102))	('DSS', 'Chemical', '-', (190, 193))	('presence', 'Var', (79, 87))
377744	33105726	We found that the presence of a pathway alteration was significantly associated with higher Buffa (p = 0.01), Ragnum (p = 0.009), and Winter (p = 0.002) hypoxia scores supporting the hypothesis that alterations predict pathway activity (Figure 4E).	('pathway', 'Pathway', (32, 39))	('pathway activity', 'MPA', (219, 235))	('higher', 'PosReg', (85, 91))	('alteration', 'Var', (40, 50))	('Ragnum', 'Chemical', '-', (110, 116))	('hypoxia', 'Disease', (153, 160))	('Buffa', 'MPA', (92, 97))	('hypoxia', 'Disease', 'MESH:D000860', (153, 160))
377751	33105726	We found frequent TP53, CDKN2A, and PIK3CA alterations and copy gain/amplification in multiple tyrosine kinase receptors, findings which are consistent with data from laryngeal tumors in TCGA.	('tumors', 'Phenotype', 'HP:0002664', (177, 183))	('TP53', 'Gene', '7157', (18, 22))	('PIK3CA', 'Gene', '5290', (36, 42))	('laryngeal tumors', 'Phenotype', 'HP:0012118', (167, 183))	('TP53', 'Gene', (18, 22))	('CDKN2A', 'Gene', (24, 30))	('tumors', 'Disease', 'MESH:D009369', (177, 183))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('CDKN2A', 'Gene', '1029', (24, 30))	('alterations', 'Var', (43, 54))	('tumors', 'Disease', (177, 183))	('PIK3CA', 'Gene', (36, 42))
377752	33105726	Notably, our cohort had recurrent loss-of-function (LOF) TGFBR2 alterations occurring at a higher frequency than previously cited.	('TGFBR2', 'Gene', (57, 63))	('alterations', 'Var', (64, 75))	('loss-of-function', 'NegReg', (34, 50))	('TGFBR2', 'Gene', '7048', (57, 63))
377753	33105726	Evaluation of the Oxidation pathway reveals mutations in two predominant genes including Kelch Like ECH Associated Protein 1 (KEAP1) and Nuclear Factor, Erythroid 2 Like 2 (NFE2L2 or NRF2).	('Nuclear Factor, Erythroid 2 Like 2', 'Gene', '4780', (137, 171))	('NFE2L2', 'Gene', (173, 179))	('NRF2', 'Gene', (183, 187))	('KEAP1', 'Gene', (126, 131))	('Kelch Like ECH Associated Protein 1', 'Gene', (89, 124))	('mutations', 'Var', (44, 53))	('Kelch Like ECH Associated Protein 1', 'Gene', '9817', (89, 124))	('NFE2L2', 'Gene', '4780', (173, 179))	('NRF2', 'Gene', '4780', (183, 187))	('KEAP1', 'Gene', '9817', (126, 131))
377755	33105726	This pathway has been found to be altered in multiple malignancies KEAP1 is a negative regulator of NRF2 and mutations lead to accumulation of NRF2 in the nucleus resulting in increased transcription of pro-tumorigenic genes.	('KEAP1', 'Gene', (67, 72))	('malignancies', 'Disease', (54, 66))	('NRF2', 'Gene', (100, 104))	('accumulation', 'PosReg', (127, 139))	('increased', 'PosReg', (176, 185))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('NRF2', 'Gene', '4780', (143, 147))	('transcription', 'MPA', (186, 199))	('mutations', 'Var', (109, 118))	('malignancies', 'Disease', 'MESH:D009369', (54, 66))	('tumor', 'Disease', (207, 212))	('KEAP1', 'Gene', '9817', (67, 72))	('NRF2', 'Gene', '4780', (100, 104))	('NRF2', 'Gene', (143, 147))
377756	33105726	Conversely, mutations in NRF2 are found in the binding site to KEAP1 making it resistant to negative regulation by KEAP1.	('KEAP1', 'Gene', '9817', (63, 68))	('NRF2', 'Gene', (25, 29))	('mutations', 'Var', (12, 21))	('KEAP1', 'Gene', (63, 68))	('KEAP1', 'Gene', '9817', (115, 120))	('KEAP1', 'Gene', (115, 120))	('NRF2', 'Gene', '4780', (25, 29))
377757	33105726	Mutations in this pathway are well established in lung cancer occurring in a quarter of squamous cell carcinomas and one third of adenocarcinomas.	('lung cancer', 'Disease', (50, 61))	('carcinomas', 'Phenotype', 'HP:0030731', (102, 112))	('adenocarcinomas', 'Disease', (130, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (88, 112))	('carcinomas', 'Phenotype', 'HP:0030731', (135, 145))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('lung cancer', 'Disease', 'MESH:D008175', (50, 61))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (88, 111))	('Mutations', 'Var', (0, 9))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('adenocarcinomas', 'Disease', 'MESH:D000230', (130, 145))	('lung cancer', 'Phenotype', 'HP:0100526', (50, 61))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (88, 112))	('squamous cell carcinomas', 'Disease', (88, 112))
377758	33105726	More recently, mutations in this pathway have been identified in breast and head and neck tumors.	('identified', 'Reg', (51, 61))	('mutations', 'Var', (15, 24))	('breast', 'Disease', (65, 71))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('neck tumors', 'Disease', 'MESH:D006258', (85, 96))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('neck tumors', 'Disease', (85, 96))	('head and neck tumors', 'Phenotype', 'HP:0012288', (76, 96))
377759	33105726	found a mutation frequency of 13% in previously untreated laryngeal squamous cell carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (68, 91))	('mutation', 'Var', (8, 16))	('squamous cell carcinoma', 'Disease', (68, 91))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (68, 91))
377760	33105726	Our RNAseq data suggest that mutations in the Oxidation pathway may predict increased activity as shown by increased hypoxia scores; however, this analysis was limited by the small number of samples with mutations (n = 3).	('increased', 'PosReg', (76, 85))	('increased', 'PosReg', (107, 116))	('activity', 'MPA', (86, 94))	('mutations', 'Var', (29, 38))	('Oxidation pathway', 'Pathway', (46, 63))	('hypoxia', 'Disease', 'MESH:D000860', (117, 124))	('hypoxia', 'Disease', (117, 124))
377765	33105726	We were also interested in evaluating for an association between tobacco use and oxidation pathway mutations given the generation of oxygen radicals with smoking.	('mutations', 'Var', (99, 108))	('tobacco', 'Species', '4097', (65, 72))	('oxygen', 'Chemical', 'MESH:D010100', (133, 139))	('oxidation pathway', 'Pathway', (81, 98))
377766	33105726	There were no significant associations between current or former tobacco use and oxidation pathway mutation status.	('tobacco', 'Species', '4097', (65, 72))	('oxidation pathway', 'Pathway', (81, 98))	('mutation', 'Var', (99, 107))
377768	33105726	Copy number evaluation of these rare tumors (recurrent larynx in never smokers) revealed copy number gain and amplifications in the RTK/PI3K/RAS and NOTCH pathways.	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('tumors', 'Disease', 'MESH:D009369', (37, 43))	('copy number', 'Var', (89, 100))	('gain', 'PosReg', (101, 105))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('amplifications', 'Var', (110, 124))	('tumors', 'Disease', (37, 43))	('NOTCH pathways', 'Pathway', (149, 163))
377769	33105726	Evaluation of this pathway reveals that the predominant mutations are within genes responsible for chromatin regulation including AT-rich interaction domain 1B (ARID1B), lysine methyltransferase 2C (KMT2C) and lysine methyltransferase 2D (KMT2D).	('AT-rich interaction domain 1B', 'Gene', (130, 159))	('AT-rich interaction domain 1B', 'Gene', '57492', (130, 159))	('mutations', 'Var', (56, 65))	('ARID1B', 'Gene', (161, 167))	('KMT2D', 'Gene', (239, 244))	('lysine methyltransferase 2D', 'Gene', (210, 237))	('KMT2D', 'Gene', '8085', (239, 244))	('lysine methyltransferase 2C', 'Gene', (170, 197))	('lysine methyltransferase 2D', 'Gene', '8085', (210, 237))	('ARID1B', 'Gene', '57492', (161, 167))	('KMT2C', 'Gene', '58508', (199, 204))	('KMT2C', 'Gene', (199, 204))	('lysine methyltransferase 2C', 'Gene', '58508', (170, 197))
377771	33105726	However, alterations within ARID1B and other subunits of the BAF complex also play a role in multiple malignancies including adenoid cystic, ovarian clear cell, colorectal cancer and, gastric cancer.	('gastric cancer', 'Disease', 'MESH:D013274', (184, 198))	('ovarian clear cell', 'Disease', 'MESH:D008649', (141, 159))	('colorectal cancer', 'Disease', (161, 178))	('adenoid cystic', 'Disease', (125, 139))	('malignancies', 'Disease', 'MESH:D009369', (102, 114))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('gastric cancer', 'Phenotype', 'HP:0012126', (184, 198))	('ovarian clear cell', 'Disease', (141, 159))	('play', 'Reg', (78, 82))	('alterations', 'Var', (9, 20))	('malignancies', 'Disease', (102, 114))	('ARID1B', 'Gene', '57492', (28, 34))	('colorectal cancer', 'Disease', 'MESH:D015179', (161, 178))	('colorectal cancer', 'Phenotype', 'HP:0003003', (161, 178))	('role', 'Reg', (85, 89))	('gastric cancer', 'Disease', (184, 198))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('ARID1B', 'Gene', (28, 34))
377772	33105726	Alterations in ARID1B and other chromatin regulators in hepatocellular carcinoma (HCC) predict degree of liver fibrosis and hepatic vein invasion, suggesting these genes may drive poor prognosis in some tumors.	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('tumors', 'Disease', (203, 209))	('tumors', 'Disease', 'MESH:D009369', (203, 209))	('Alterations', 'Var', (0, 11))	('liver fibrosis', 'Disease', (105, 119))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (56, 80))	('liver fibrosis', 'Phenotype', 'HP:0001395', (105, 119))	('tumors', 'Phenotype', 'HP:0002664', (203, 209))	('hepatocellular carcinoma', 'Disease', (56, 80))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (56, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('hepatic vein invasion', 'Disease', 'MESH:D056486', (124, 145))	('ARID1B', 'Gene', (15, 21))	('liver fibrosis', 'Disease', 'MESH:D008103', (105, 119))	('hepatic vein invasion', 'Disease', (124, 145))	('ARID1B', 'Gene', '57492', (15, 21))
377774	33105726	Further, these effects are most significant in ARID1B mutant cell lines, suggesting ARID1B as both a potential biomarker and therapeutic target in our cohort.	('ARID1B', 'Gene', '57492', (47, 53))	('ARID1B', 'Gene', (84, 90))	('mutant', 'Var', (54, 60))	('ARID1B', 'Gene', (47, 53))	('ARID1B', 'Gene', '57492', (84, 90))
377775	33105726	The most common mutations in this pathway were missense mutations in tumor growth factor beta receptor 2 (TGFBR2).	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('TGFBR2', 'Gene', (106, 112))	('missense mutations', 'Var', (47, 65))	('tumor', 'Disease', (69, 74))	('TGFBR2', 'Gene', '7048', (106, 112))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
377779	33105726	As such LOF mutations in TGFB may indicate increased anti-tumor immunity and may serve as a predictive biomarker in in our recurrent larynx cancer cohort.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('TGFB', 'Gene', (25, 29))	('mutations', 'Var', (12, 21))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('larynx cancer', 'Phenotype', 'HP:0012118', (133, 146))	('increased', 'PosReg', (43, 52))	('TGFB', 'Gene', '7040', (25, 29))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('LOF', 'NegReg', (8, 11))
377789	33105726	Goldex Helix Varseq v2.1.0 (Golden Helix, Bozeman, MT, USA) was used to annotate these variant calls and to filter the variants in the introns and intergenic regions.	('2.1', 'Gene', (21, 24))	('variant', 'Var', (87, 94))	('2.1', 'Gene', '6700', (21, 24))
377790	33105726	Variants with a minimum of 5 reads supporting the alternate allele in the tumor samples were considered as potential positives.	('Variants', 'Var', (0, 8))	('tumor', 'Disease', (74, 79))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))
377806	33105726	Clinical trials are warranted to explore the implications of specific genomic pathway mutations in patient selection and targeted therapy for patients with recurrent laryngeal cancer.	('patient', 'Species', '9606', (99, 106))	('mutations', 'Var', (86, 95))	('genomic pathway', 'Gene', (70, 85))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('laryngeal cancer', 'Phenotype', 'HP:0012118', (166, 182))	('patient', 'Species', '9606', (142, 149))	('patients', 'Species', '9606', (142, 150))	('cancer', 'Disease', (176, 182))	('cancer', 'Disease', 'MESH:D009369', (176, 182))
377807	33105726	The following are available online at , Figure S1: Oncoplots grouped by mutation for Stem/Differentiation/Epigenetic and Immune pathways, Figure S2: NRF2 Immunohistochemistry, Table S1: High Confidence SNV Data, Table S2: High Confidence INDEL Data, Table S3: SNV and INDEL QC, Table S4: VEST Scores, Table S5: Copy Number Variation (CNV) Scores, Table S6: RNAseq QC, Table S7: FPKM Data.	('NRF2', 'Gene', '4780', (149, 153))	('NRF2', 'Gene', (149, 153))	('Copy Number Variation', 'Var', (311, 332))
377863	32095316	Five prognosis-related hub RNAs (CDCA2, MTBP, CENPE, PBK, AL033384.1) were identified.	('CENPE', 'Gene', '1062', (46, 51))	('CDCA2', 'Gene', (33, 38))	('AL033384.1', 'Var', (58, 68))	('CDCA2', 'Gene', '157313', (33, 38))	('MTBP', 'Gene', '27085', (40, 44))	('PBK', 'Gene', (53, 56))	('MTBP', 'Gene', (40, 44))	('CENPE', 'Gene', (46, 51))	('PBK', 'Gene', '55872', (53, 56))
377864	32095316	Additionally, we constructed a prognostic scoring system for ESCC using ten signature RNAs (MLIP, TNFSF10, SIK2, LINC01068, LINC00601, TTTY14, AC084262.1, LINC01415, miR-5699-3p, miR-552-5p).	('TTTY14', 'Gene', (135, 141))	('MLIP', 'Gene', (92, 96))	('ESCC', 'Disease', (61, 65))	('LINC01415', 'Gene', (155, 164))	('LINC00601', 'Gene', (124, 133))	('TNFSF10', 'Gene', '8743', (98, 105))	('TTTY14', 'Gene', '83869', (135, 141))	('miR-552-5p', 'Var', (179, 189))	('LINC01415', 'Gene', '100132501', (155, 164))	('miR-5699-3p', 'Var', (166, 177))	('LINC01068', 'Gene', (113, 122))	('SIK2', 'Gene', (107, 111))	('SIK2', 'Gene', '23235', (107, 111))	('LINC00601', 'Gene', '101101772', (124, 133))	('ESCC', 'Disease', 'MESH:C562729', (61, 65))	('AC084262.1', 'Var', (143, 153))	('LINC01068', 'Gene', '103724388', (113, 122))	('TNFSF10', 'Gene', (98, 105))	('MLIP', 'Gene', '90523', (92, 96))
377878	32095316	For ESCC, researchers have identified multiple driving genes, including TP53, NOTCH1, FAM135B, EP300, and TET2, and the mutation status of FAM135B, EP300 and TET2 are associated with the prognosis of patients.	('EP300', 'Gene', (95, 100))	('ESCC', 'Disease', (4, 8))	('EP300', 'Gene', (148, 153))	('FAM135B', 'Gene', '51059', (86, 93))	('TP53', 'Gene', '7157', (72, 76))	('NOTCH1', 'Gene', (78, 84))	('FAM135B', 'Gene', (86, 93))	('TET2', 'Gene', '54790', (158, 162))	('TET2', 'Gene', (106, 110))	('FAM135B', 'Gene', '51059', (139, 146))	('NOTCH1', 'Gene', '4851', (78, 84))	('mutation', 'Var', (120, 128))	('ESCC', 'Disease', 'MESH:C562729', (4, 8))	('EP300', 'Gene', '2033', (95, 100))	('patients', 'Species', '9606', (200, 208))	('TET2', 'Gene', '54790', (106, 110))	('EP300', 'Gene', '2033', (148, 153))	('TP53', 'Gene', (72, 76))	('FAM135B', 'Gene', (139, 146))	('associated', 'Reg', (167, 177))	('TET2', 'Gene', (158, 162))
377905	32095316	The formulas for the three prognostic models were as follows: lncRNA-based prognostic score = (0.447 x expression level of LINC01068) + (0.3677 x expression level of LINC00601) + (0.3075 x expression level of TTTY14) + (-0.8750 x expression level of AC084262.1) + (-0.4744 x expression level of LINC01415); miRNA-based prognostic score = (1.2932 x expression level of miR-5699-3p) + (0.7202 x expression level of miR-552-5p); mRNA-based prognostic score = (0.5139 x expression level of MLIP) + (0.5746 x expression level of TNFSF10) + (-1.0069 x expression level of SIK2).	('LINC01068', 'Gene', (123, 132))	('LINC01415', 'Gene', (295, 304))	('LINC01415', 'Gene', '100132501', (295, 304))	('LINC01068', 'Gene', '103724388', (123, 132))	('MLIP', 'Gene', (486, 490))	('0.5139', 'Var', (457, 463))	('TTTY14', 'Gene', '83869', (209, 215))	('SIK2', 'Gene', (566, 570))	('TTTY14', 'Gene', (209, 215))	('LINC00601', 'Gene', (166, 175))	('TNFSF10', 'Gene', (524, 531))	('SIK2', 'Gene', '23235', (566, 570))	('LINC00601', 'Gene', '101101772', (166, 175))	('MLIP', 'Gene', '90523', (486, 490))	('TNFSF10', 'Gene', '8743', (524, 531))
377906	32095316	Of three prognostic models, seven RNAs were shown to be risky RNAs (LINC01068, LINC00601, TTTY14, miR-5699-3p, miR-552-5p, MLIP, TNFSF10, HR >1) and three RNAs were the protective RNAs (AC084262.1, LINC01415, SIK2, HR <1) (Figs.	('TTTY14', 'Gene', '83869', (90, 96))	('SIK2', 'Gene', '23235', (209, 213))	('SIK2', 'Gene', (209, 213))	('miR-5699-3p', 'Var', (98, 109))	('LINC01415', 'Gene', '100132501', (198, 207))	('MLIP', 'Gene', (123, 127))	('TTTY14', 'Gene', (90, 96))	('LINC01068', 'Gene', '103724388', (68, 77))	('LINC00601', 'Gene', (79, 88))	('TNFSF10', 'Gene', (129, 136))	('LINC00601', 'Gene', '101101772', (79, 88))	('MLIP', 'Gene', '90523', (123, 127))	('miR-552-5p', 'Var', (111, 121))	('LINC01068', 'Gene', (68, 77))	('TNFSF10', 'Gene', '8743', (129, 136))	('LINC01415', 'Gene', (198, 207))
377914	32095316	The formula was as follows: RNA-based prognostic score = (0.42895 x expression level of LINC01068) + (0.34829 x expression level of LINC00601) + (0.2185 x expression level of TTTY14) + (-1.393 x expression level of AC084262.1) + (-0.33364 x expression level of LINC01415) + (1.06024 x expression level of miR-5699-3p) + (0.34784 x expression level of miR-552-5p) + (0.3418 x expression level of MLIP) + (0.05437 x expression level of TNFSF10) + (-1.38365 x expression level of SIK2).	('SIK2', 'Gene', (477, 481))	('LINC01068', 'Gene', '103724388', (88, 97))	('SIK2', 'Gene', '23235', (477, 481))	('0.34784', 'Var', (321, 328))	('MLIP', 'Gene', (395, 399))	('LINC01068', 'Gene', (88, 97))	('TTTY14', 'Gene', (175, 181))	('TNFSF10', 'Gene', (434, 441))	('TTTY14', 'Gene', '83869', (175, 181))	('TNFSF10', 'Gene', '8743', (434, 441))	('LINC01415', 'Gene', (261, 270))	('LINC00601', 'Gene', '101101772', (132, 141))	('LINC01415', 'Gene', '100132501', (261, 270))	('LINC00601', 'Gene', (132, 141))	('MLIP', 'Gene', '90523', (395, 399))
377928	32095316	Of prognostic models, seven RNAs were shown to be risky RNAs (LINC01068, LINC00601, TTTY14, miR-5699-3p, miR-552-5p, MLIP, TNFSF10, HR >1) and three RNAs were the protective RNAs (AC084262.1, LINC01415, SIK2, HR <1).	('LINC01068', 'Gene', (62, 71))	('miR-5699-3p', 'Var', (92, 103))	('TTTY14', 'Gene', (84, 90))	('miR-552-5p', 'Var', (105, 115))	('TTTY14', 'Gene', '83869', (84, 90))	('SIK2', 'Gene', '23235', (203, 207))	('MLIP', 'Gene', '90523', (117, 121))	('LINC00601', 'Gene', (73, 82))	('LINC01415', 'Gene', (192, 201))	('LINC00601', 'Gene', '101101772', (73, 82))	('LINC01068', 'Gene', '103724388', (62, 71))	('LINC01415', 'Gene', '100132501', (192, 201))	('SIK2', 'Gene', (203, 207))	('TNFSF10', 'Gene', (123, 130))	('MLIP', 'Gene', (117, 121))	('TNFSF10', 'Gene', '8743', (123, 130))
377931	32095316	miR-552-5p facilitates osteosarcoma cell proliferation and metastasis by targeting WIF1, which means miR-552-5p may become a new target for the treatment of osteosarcoma.	('metastasis', 'CPA', (59, 69))	('osteosarcoma', 'Phenotype', 'HP:0002669', (157, 169))	('osteosarcoma', 'Disease', (157, 169))	('osteosarcoma', 'Disease', 'MESH:D012516', (157, 169))	('WIF1', 'Gene', (83, 87))	('facilitates', 'PosReg', (11, 22))	('miR-552-5p', 'Var', (0, 10))	('WIF1', 'Gene', '11197', (83, 87))	('targeting', 'Reg', (73, 82))	('osteosarcoma', 'Phenotype', 'HP:0002669', (23, 35))	('osteosarcoma', 'Disease', (23, 35))	('osteosarcoma', 'Disease', 'MESH:D012516', (23, 35))
377933	32095316	Frequent amplification of TNFSF10 was associated with the development and progression of esophageal cancer.	('esophageal cancer', 'Disease', (89, 106))	('associated with', 'Reg', (38, 53))	('esophageal cancer', 'Disease', 'MESH:D004938', (89, 106))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('Frequent amplification', 'Var', (0, 22))	('TNFSF10', 'Gene', (26, 33))	('TNFSF10', 'Gene', '8743', (26, 33))
377935	32095316	However, functional studies of the other RNAs (LINC01068, LINC00601, AC084262.1, LINC01415, miR-5699-3p, MLIP) have not been reported in cancer research.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('LINC01068', 'Gene', '103724388', (47, 56))	('miR-5699-3p', 'Var', (92, 103))	('LINC01415', 'Gene', (81, 90))	('MLIP', 'Gene', (105, 109))	('LINC01415', 'Gene', '100132501', (81, 90))	('LINC00601', 'Gene', (58, 67))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('LINC00601', 'Gene', '101101772', (58, 67))	('MLIP', 'Gene', '90523', (105, 109))	('cancer', 'Disease', (137, 143))	('LINC01068', 'Gene', (47, 56))
377941	31956298	EphA5 knockdown enhances the invasion and migration ability of esophageal squamous cell carcinoma via epithelial-mesenchymal transition through activating Wnt/beta-catenin pathway The erythropoietin-producing hepatocellular (Eph) receptor A5 (EphA5) has been found to be overexpressed in some malignant tumors and is associated with disease prognosis.	('beta-catenin', 'Gene', (159, 171))	('tumor', 'Phenotype', 'HP:0002664', (303, 308))	('beta-catenin', 'Gene', '1499', (159, 171))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('EphA5', 'Gene', '2044', (0, 5))	('epithelial-mesenchymal', 'CPA', (102, 124))	('esophageal squamous cell carcinoma', 'Disease', (63, 97))	('EphA5', 'Gene', (243, 248))	('associated', 'Reg', (317, 327))	('erythropoietin-producing hepatocellular (Eph) receptor A5', 'Gene', '2044', (184, 241))	('enhances', 'PosReg', (16, 24))	('EphA5', 'Gene', (0, 5))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (74, 97))	('EphA5', 'Gene', '2044', (243, 248))	('tumors', 'Phenotype', 'HP:0002664', (303, 309))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:C562729', (63, 97))	('malignant tumors', 'Disease', (293, 309))	('knockdown', 'Var', (6, 15))	('malignant tumors', 'Disease', 'MESH:D009369', (293, 309))
377949	31956298	The cell viability assay and colony formation assay revealed that EphA5 knockdown enhanced the proliferation of KYSE150 and KYSE450 cells in vitro.	('enhanced', 'PosReg', (82, 90))	('knockdown', 'Var', (72, 81))	('EphA5', 'Gene', (66, 71))	('proliferation', 'CPA', (95, 108))	('EphA5', 'Gene', '2044', (66, 71))
377950	31956298	The invasion and migration of ESCC cells were accelerated after EphA5 knockdown.	('knockdown', 'Var', (70, 79))	('accelerated', 'PosReg', (46, 57))	('EphA5', 'Gene', (64, 69))	('ESCC', 'Disease', (30, 34))	('EphA5', 'Gene', '2044', (64, 69))	('ESCC', 'Disease', 'MESH:C562729', (30, 34))
377953	31956298	EphA5 knockdown promotes the proliferation of esophageal squamous cell carcinoma,enhances invasion and migration ability via epithelial-mesenchymal transition through activating Wnt/beta-catenin pathway.	('promotes', 'PosReg', (16, 24))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:C562729', (46, 80))	('beta-catenin', 'Gene', '1499', (182, 194))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (57, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('EphA5', 'Gene', (0, 5))	('proliferation', 'CPA', (29, 42))	('epithelial-mesenchymal transition', 'CPA', (125, 158))	('enhances', 'PosReg', (81, 89))	('EphA5', 'Gene', '2044', (0, 5))	('knockdown', 'Var', (6, 15))	('esophageal squamous cell carcinoma', 'Disease', (46, 80))	('activating', 'PosReg', (167, 177))	('beta-catenin', 'Gene', (182, 194))
377972	31956298	Human esophageal carcinoma cell lines (KYSE30, KYSE 70, KYSE 140, KYSE150, KYSE 180, KYSE 410, KYSE450, KYSE510) and human normal esophageal epithelial cells (HEEC) were provided by the Chinese Academy of Cell Resource Center (Shanghai, China).	('KYSE30', 'Var', (39, 45))	('KYSE', 'Var', (56, 60))	('KYSE150', 'Var', (66, 73))	('KYSE 410', 'Var', (85, 93))	('Human', 'Species', '9606', (0, 5))	('human', 'Species', '9606', (117, 122))	('esophageal carcinoma', 'Disease', (6, 26))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (6, 26))	('HEEC', 'CellLine', 'CVCL:3285', (159, 163))	('KYSE510', 'Var', (104, 111))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (6, 26))	('KYSE 180', 'Var', (75, 83))	('carcinoma', 'Phenotype', 'HP:0030731', (17, 26))	('KYSE450', 'Var', (95, 102))
378004	31956298	The SI >= 3 was considered as EphA5-high expression tumors, those with 0 < SI < 3 were regarded as EphA5-low expression while others with SI = 0 regarded as EphA5-negative expression.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('EphA5', 'Gene', (157, 162))	('SI >= 3', 'Var', (4, 11))	('tumors', 'Disease', (52, 58))	('EphA5', 'Gene', (30, 35))	('EphA5', 'Gene', '2044', (157, 162))	('EphA5', 'Gene', '2044', (30, 35))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('EphA5', 'Gene', (99, 104))	('EphA5', 'Gene', '2044', (99, 104))
378006	31956298	EphA5 was rarely expressed in HEEC cells, but was highly expressed in KYSE150, KYSE450 and KYSE410 cells.	('KYSE410', 'Var', (91, 98))	('EphA5', 'Gene', (0, 5))	('EphA5', 'Gene', '2044', (0, 5))	('KYSE410', 'CellLine', 'CVCL:1352', (91, 98))	('HEEC', 'CellLine', 'CVCL:3285', (30, 34))
378017	31956298	Among 10 ESCC patients with high expression of EphA5, there were 7 patients with advanced tumor stage (T3 and T4), 8 patients with positive lymph nodes, and 9 patients with moderately differentiated squamous cell carcinoma.	('ESCC', 'Disease', (9, 13))	('squamous cell carcinoma', 'Disease', (199, 222))	('patients', 'Species', '9606', (67, 75))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('EphA5', 'Gene', (47, 52))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('EphA5', 'Gene', '2044', (47, 52))	('ESCC', 'Disease', 'MESH:C562729', (9, 13))	('high expression', 'Var', (28, 43))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (199, 222))	('patients', 'Species', '9606', (117, 125))	('patients', 'Species', '9606', (14, 22))	('carcinoma', 'Phenotype', 'HP:0030731', (213, 222))	('patients', 'Species', '9606', (159, 167))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (199, 222))
378024	31956298	The cell viability assay showed that EphA5 knockdown accelerated the proliferation of KYSE150 cells and KYSE450 cells (Fig.	('EphA5', 'Gene', (37, 42))	('proliferation', 'CPA', (69, 82))	('EphA5', 'Gene', '2044', (37, 42))	('accelerated', 'PosReg', (53, 64))	('knockdown', 'Var', (43, 52))
378025	31956298	We observed that the number of colonies formed by cells with EphA5 knockdown was more than that of negative controls (Fig.	('EphA5', 'Gene', '2044', (61, 66))	('knockdown', 'Var', (67, 76))	('EphA5', 'Gene', (61, 66))
378026	31956298	Having shown that EphA5 knockdown enhanced the cell proliferation, we then analyzed the cell apoptosis and cell cycle by flow cytometry.	('enhanced', 'PosReg', (34, 42))	('EphA5', 'Gene', '2044', (18, 23))	('EphA5', 'Gene', (18, 23))	('knockdown', 'Var', (24, 33))	('cell proliferation', 'CPA', (47, 65))
378029	31956298	In the wound-healing assay, the cells with EphA5 knockdown displayed significantly accelerated wound healing compared to the respective controls (Fig.	('knockdown', 'Var', (49, 58))	('wound healing', 'CPA', (95, 108))	('EphA5', 'Gene', (43, 48))	('EphA5', 'Gene', '2044', (43, 48))	('accelerated wound healing', 'Phenotype', 'HP:0001058', (83, 108))	('accelerated', 'PosReg', (83, 94))
378030	31956298	Transwell invasion assay revealed that EphA5 knockdown significantly increased the invaded number of cells and promoted the invasion ability (Fig.	('increased', 'PosReg', (69, 78))	('EphA5', 'Gene', (39, 44))	('EphA5', 'Gene', '2044', (39, 44))	('invaded number of cells', 'CPA', (83, 106))	('invasion ability', 'CPA', (124, 140))	('promoted', 'PosReg', (111, 119))	('knockdown', 'Var', (45, 54))
378033	31956298	As expected, E-cadherin was decreased, while N-cadherin and the relevant transcription factor Snail were remarkably increased in KYSE150 and KYSE450 cells with EphA5 knockdown compared with the controls cells (Fig.	('knockdown', 'Var', (166, 175))	('decreased', 'NegReg', (28, 37))	('Snail', 'Gene', '6615', (94, 99))	('EphA5', 'Gene', (160, 165))	('N-cadherin', 'Gene', (45, 55))	('EphA5', 'Gene', '2044', (160, 165))	('E-cadherin', 'Gene', (13, 23))	('E-cadherin', 'Gene', '999', (13, 23))	('increased', 'PosReg', (116, 125))	('Snail', 'Gene', (94, 99))	('N-cadherin', 'Gene', '1000', (45, 55))
378035	31956298	Consistently, silencing of EphA5 promoted EMT in KYSE150 and KYSE450 ESCC cells.	('silencing', 'Var', (14, 23))	('promoted', 'PosReg', (33, 41))	('EMT', 'CPA', (42, 45))	('ESCC', 'Disease', 'MESH:C562729', (69, 73))	('ESCC', 'Disease', (69, 73))	('EphA5', 'Gene', (27, 32))	('EphA5', 'Gene', '2044', (27, 32))
378036	31956298	To evaluate whether the effect of EphA5 knockdown on the EMT process was associated with Wnt/beta-catenin signaling pathway, the expression of total beta-catenin, GSK-3beta and phosphorylated GSK-3beta (p-GSK-3betaSer9) were investigated.	('GSK-3beta', 'Gene', (192, 201))	('beta-catenin', 'Gene', (93, 105))	('GSK-3beta', 'Gene', '2932', (163, 172))	('GSK-3beta', 'Gene', (163, 172))	('knockdown', 'Var', (40, 49))	('beta-catenin', 'Gene', (149, 161))	('associated', 'Reg', (73, 83))	('GSK-3beta', 'Gene', '2932', (205, 214))	('GSK-3beta', 'Gene', (205, 214))	('beta-catenin', 'Gene', '1499', (93, 105))	('EphA5', 'Gene', (34, 39))	('beta-catenin', 'Gene', '1499', (149, 161))	('EphA5', 'Gene', '2044', (34, 39))	('GSK-3beta', 'Gene', '2932', (192, 201))
378039	31956298	Moreover, beta-catenin expression could been observed in the cytoplasm and nucleus of cells with EphA5 knockdown, but it was only expressed on the cell membrane in the control groups (Fig.	('beta-catenin', 'Gene', (10, 22))	('EphA5', 'Gene', (97, 102))	('EphA5', 'Gene', '2044', (97, 102))	('beta-catenin', 'Gene', '1499', (10, 22))	('knockdown', 'Var', (103, 112))
378041	31956298	4a, b, EphA5 knockdown increased the expression of c-Myc and CyclinD1 compared with the negative controls.	('c-Myc', 'Gene', '4609', (51, 56))	('EphA5', 'Gene', '2044', (7, 12))	('c-Myc', 'Gene', (51, 56))	('CyclinD1', 'Gene', (61, 69))	('increased', 'PosReg', (23, 32))	('EphA5', 'Gene', (7, 12))	('expression', 'MPA', (37, 47))	('knockdown', 'Var', (13, 22))	('CyclinD1', 'Gene', '595', (61, 69))
378045	31956298	Thus, Wnt/beta-catenin signaling pathway was essential to the development of EMT triggered by EphA5 knockdown.	('beta-catenin', 'Gene', (10, 22))	('EphA5', 'Gene', (94, 99))	('EphA5', 'Gene', '2044', (94, 99))	('knockdown', 'Var', (100, 109))	('beta-catenin', 'Gene', '1499', (10, 22))
378049	31956298	The study revealed that high EphA5 expression in lung cancer indicated higher locoregional recurrence and lower cumulative overall patient survival.	('higher', 'PosReg', (71, 77))	('lower', 'NegReg', (106, 111))	('EphA5', 'Gene', (29, 34))	('lung cancer', 'Disease', 'MESH:D008175', (49, 60))	('locoregional recurrence', 'CPA', (78, 101))	('EphA5', 'Gene', '2044', (29, 34))	('expression', 'MPA', (35, 45))	('lung cancer', 'Disease', (49, 60))	('lung cancer', 'Phenotype', 'HP:0100526', (49, 60))	('high', 'Var', (24, 28))	('patient', 'Species', '9606', (131, 138))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
378059	31956298	KYSE150, KYSE450 and KYSE410 cells exhibited higher EphA5 expression than other ESCC cells.	('KYSE410', 'CellLine', 'CVCL:1352', (21, 28))	('ESCC', 'Disease', 'MESH:C562729', (80, 84))	('KYSE410', 'Var', (21, 28))	('KYSE450', 'Var', (9, 16))	('higher', 'PosReg', (45, 51))	('EphA5', 'Gene', (52, 57))	('KYSE150', 'Var', (0, 7))	('EphA5', 'Gene', '2044', (52, 57))	('ESCC', 'Disease', (80, 84))
378062	31956298	Our finds showed that EphA5 knockdown enhanced malignant characteristics of KYSE150 and KYSE450 cells in vitro,such as the ability of cell proliferation, migration and invasion.	('cell proliferation', 'CPA', (134, 152))	('EphA5', 'Gene', (22, 27))	('enhanced', 'PosReg', (38, 46))	('malignant characteristics', 'CPA', (47, 72))	('EphA5', 'Gene', '2044', (22, 27))	('knockdown', 'Var', (28, 37))	('invasion', 'CPA', (168, 176))	('migration', 'CPA', (154, 163))
378063	31956298	It seems to be contradictory with the results that high EphA5 expression is related to lymph node metastasis in ESCC patients.	('expression', 'MPA', (62, 72))	('ESCC', 'Disease', (112, 116))	('EphA5', 'Gene', '2044', (56, 61))	('high', 'Var', (51, 55))	('patients', 'Species', '9606', (117, 125))	('ESCC', 'Disease', 'MESH:C562729', (112, 116))	('lymph node metastasis', 'CPA', (87, 108))	('EphA5', 'Gene', (56, 61))	('related', 'Reg', (76, 83))
378064	31956298	To explain the contradictory data, an EphA5 overexpression plasmids was transfected into the EphA5 knockdown KYSE150 cells.	('EphA5', 'Gene', (38, 43))	('knockdown', 'Var', (99, 108))	('EphA5', 'Gene', '2044', (38, 43))	('EphA5', 'Gene', (93, 98))	('EphA5', 'Gene', '2044', (93, 98))
378065	31956298	We found that EphA5 overexpression could reverse the cancer-related characteristics in the KYSE150 cells with EphA5 knockdown.	('EphA5', 'Gene', '2044', (110, 115))	('reverse', 'NegReg', (41, 48))	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('knockdown', 'Var', (116, 125))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('EphA5', 'Gene', (14, 19))	('EphA5', 'Gene', '2044', (14, 19))	('EphA5', 'Gene', (110, 115))
378071	31956298	However, the current study did not find cell cycle and apoptosis changes in the ESCC cells with EphA5 knockdown.	('knockdown', 'Var', (102, 111))	('ESCC', 'Disease', 'MESH:C562729', (80, 84))	('EphA5', 'Gene', (96, 101))	('EphA5', 'Gene', '2044', (96, 101))	('ESCC', 'Disease', (80, 84))
378075	31956298	Thus, the expression of E-cadherin, N-cadherin, and Snail was measured in ESCC cells following EphA5 knocked down.	('N-cadherin', 'Gene', '1000', (36, 46))	('ESCC', 'Disease', (74, 78))	('E-cadherin', 'Gene', '999', (24, 34))	('expression', 'MPA', (10, 20))	('EphA5', 'Gene', (95, 100))	('Snail', 'Gene', (52, 57))	('E-cadherin', 'Gene', (24, 34))	('EphA5', 'Gene', '2044', (95, 100))	('ESCC', 'Disease', 'MESH:C562729', (74, 78))	('Snail', 'Gene', '6615', (52, 57))	('knocked down', 'Var', (101, 113))	('N-cadherin', 'Gene', (36, 46))
378079	31956298	Furthermore, the report found that loss of EphA5 resulted in higher expression of cancer stem cell (CSC) markers in HER2-positive breast cancer cells, including CD44+/CD24-/low, NANOG, CD133+.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('breast cancer', 'Phenotype', 'HP:0003002', (130, 143))	('HER2-positive breast cancer', 'Disease', (116, 143))	('expression', 'MPA', (68, 78))	('NANOG', 'Gene', '79923', (178, 183))	('higher', 'PosReg', (61, 67))	('EphA5', 'Gene', (43, 48))	('NANOG', 'Gene', (178, 183))	('loss', 'Var', (35, 39))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('CD133+', 'Var', (185, 191))	('EphA5', 'Gene', '2044', (43, 48))	('cancer', 'Disease', (137, 143))	('HER2-positive breast cancer', 'Disease', 'MESH:D001943', (116, 143))	('CD44+/CD24-/low', 'Var', (161, 176))
378085	31956298	And then to further confirm that the Wnt/beta-catenin pathway linked EphA5 and EMT, beta-catenin was depleted in the EphA5 knockdown cells by siRNA duplexes transfection.	('beta-catenin', 'Gene', (41, 53))	('beta-catenin', 'Gene', '1499', (41, 53))	('beta-catenin', 'Gene', '1499', (84, 96))	('beta-catenin', 'Gene', (84, 96))	('knockdown', 'Var', (123, 132))	('EphA5', 'Gene', (69, 74))	('EphA5', 'Gene', (117, 122))	('depleted', 'NegReg', (101, 109))	('EphA5', 'Gene', '2044', (69, 74))	('EphA5', 'Gene', '2044', (117, 122))
378086	31956298	Western blot analysis showed that beta-catenin depletion eliminated the effects of EphA5 knockdown on EMT, indicating a reversal of the EMT markers altered in the ESCC cells with EphA5 knockdown.	('EphA5', 'Gene', '2044', (83, 88))	('ESCC', 'Disease', (163, 167))	('eliminated', 'NegReg', (57, 67))	('beta-catenin', 'Gene', '1499', (34, 46))	('ESCC', 'Disease', 'MESH:C562729', (163, 167))	('EphA5', 'Gene', (179, 184))	('EphA5', 'Gene', '2044', (179, 184))	('knockdown', 'Var', (89, 98))	('EphA5', 'Gene', (83, 88))	('beta-catenin', 'Gene', (34, 46))
378090	31956298	The present study indicated that EphA5 knockdown increased the levels of N-cadherin and Snail, and yet decreased the E-cadherin expression.	('Snail', 'Gene', '6615', (88, 93))	('EphA5', 'Gene', (33, 38))	('knockdown', 'Var', (39, 48))	('increased', 'PosReg', (49, 58))	('decreased', 'NegReg', (103, 112))	('levels of', 'MPA', (63, 72))	('EphA5', 'Gene', '2044', (33, 38))	('N-cadherin', 'Gene', (73, 83))	('N-cadherin', 'Gene', '1000', (73, 83))	('E-cadherin', 'Gene', (117, 127))	('E-cadherin', 'Gene', '999', (117, 127))	('Snail', 'Gene', (88, 93))
378092	31956298	Together, these findings demonstrate that EphA5 knockdown can trigger EMT by activating Wnt/beta-catenin signaling in ESCC.	('ESCC', 'Disease', (118, 122))	('trigger', 'PosReg', (62, 69))	('EMT', 'CPA', (70, 73))	('beta-catenin', 'Gene', '1499', (92, 104))	('EphA5', 'Gene', (42, 47))	('beta-catenin', 'Gene', (92, 104))	('ESCC', 'Disease', 'MESH:C562729', (118, 122))	('EphA5', 'Gene', '2044', (42, 47))	('activating', 'PosReg', (77, 87))	('knockdown', 'Var', (48, 57))
378095	31956298	High EphA5 expression may promote lymph node metastasis, although this seems to be inconsistent with the in vitro results.	('promote', 'PosReg', (26, 33))	('High', 'Var', (0, 4))	('EphA5', 'Gene', (5, 10))	('EphA5', 'Gene', '2044', (5, 10))	('lymph node metastasis', 'CPA', (34, 55))
378141	31449588	Differential diagnosis at this point included myocarditis due to pembrolizumab, acute coronary syndrome (ACS), and Takotsubo cardiomyopathy in a cancer patient.	('cancer', 'Disease', (145, 151))	('acute coronary syndrome', 'Disease', (80, 103))	('pembrolizumab', 'Var', (65, 78))	('cardiomyopathy', 'Phenotype', 'HP:0001638', (125, 139))	('Takotsubo cardiomyopathy', 'Disease', 'MESH:D054549', (115, 139))	('myocarditis', 'Disease', 'MESH:D009205', (46, 57))	('coronary syndrome', 'Phenotype', 'HP:0001677', (86, 103))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('Takotsubo cardiomyopathy', 'Phenotype', 'HP:0011665', (115, 139))	('Takotsubo cardiomyopathy', 'Disease', (115, 139))	('acute coronary syndrome', 'Disease', 'MESH:D054058', (80, 103))	('myocarditis', 'Disease', (46, 57))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('patient', 'Species', '9606', (152, 159))	('pembrolizumab', 'Chemical', 'MESH:C582435', (65, 78))	('myocarditis', 'Phenotype', 'HP:0012819', (46, 57))
378174	31449588	Cisplatin, a platinum based chemotherapy, has been reported to cause vascular injury by direct endovascular damage, decreased activity of protein C (anticoagulant), increased von-Willebrand factor, and hypomagnesemia.	('endovascular damage', 'Disease', 'MESH:D004194', (95, 114))	('vascular injury', 'Disease', (69, 84))	('hypomagnesemia', 'Disease', 'MESH:C537153', (202, 216))	('cause', 'Reg', (63, 68))	('protein C', 'Protein', (138, 147))	('decreased activity of protein C', 'Phenotype', 'HP:0005543', (116, 147))	('endovascular damage', 'Disease', (95, 114))	('activity', 'MPA', (126, 134))	('von-Willebrand', 'Disease', 'MESH:D014842', (175, 189))	('von-Willebrand', 'Disease', (175, 189))	('platinum', 'Chemical', 'MESH:D010984', (13, 21))	('increased von-Willebrand factor', 'Phenotype', 'HP:0012147', (165, 196))	('hypomagnesemia', 'Disease', (202, 216))	('decreased', 'NegReg', (116, 125))	('Cisplatin', 'Chemical', 'MESH:D002945', (0, 9))	('vascular injury', 'Disease', 'MESH:D057772', (69, 84))	('Cisplatin', 'Var', (0, 9))	('increased', 'PosReg', (165, 174))	('hypomagnesemia', 'Phenotype', 'HP:0002917', (202, 216))
378178	31449588	In particular, 5-FU, capecitabine, bevacizumab, rituximab, and TKI (such as axitinib and sunitinib) have been associated with reversible cardiac dysfunction in the pattern of Takotsubo cardiomyopathy.	('Takotsubo cardiomyopathy', 'Phenotype', 'HP:0011665', (175, 199))	('Takotsubo cardiomyopathy', 'Disease', 'MESH:D054549', (175, 199))	('sunitinib', 'Chemical', 'MESH:D000077210', (89, 98))	('Takotsubo cardiomyopathy', 'Disease', (175, 199))	('rituximab', 'Chemical', 'MESH:D000069283', (48, 57))	('associated with', 'Reg', (110, 125))	('5-FU', 'Var', (15, 19))	('cardiac dysfunction', 'Disease', (137, 156))	('cardiomyopathy', 'Phenotype', 'HP:0001638', (185, 199))	('cardiac dysfunction', 'Disease', 'MESH:D006331', (137, 156))	('5-FU', 'Chemical', 'MESH:D005472', (15, 19))	('bevacizumab', 'Chemical', 'MESH:D000068258', (35, 46))	('axitinib', 'Chemical', 'MESH:D000077784', (76, 84))	('capecitabine', 'Chemical', 'MESH:D000069287', (21, 33))
378185	31449588	Inhibiting PD-1 has been shown to increase inflammation and cytotoxic activity via CD8+ T cells.	('Inhibiting', 'Var', (0, 10))	('CD8+ T cells', 'CPA', (83, 95))	('PD-1', 'Gene', '5133', (11, 15))	('cytotoxic activity', 'CPA', (60, 78))	('inflammation', 'Disease', 'MESH:D007249', (43, 55))	('PD-1', 'Gene', (11, 15))	('inflammation', 'Disease', (43, 55))	('increase', 'PosReg', (34, 42))
378226	31123404	These include tumor mutation burden (TMB) or tumor mutation load, neoantigen burden, DNA mismatch repair deficiency, and high microsatellite instability.	('TMB', 'Chemical', '-', (37, 40))	('neoantigen burden', 'MPA', (66, 83))	('tumor', 'Disease', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('high microsatellite instability', 'MPA', (121, 152))	('tumor', 'Disease', (45, 50))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('deficiency', 'Var', (105, 115))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
378253	31123404	Here, we followed the F1CDx approach to calculate the TMB for our panel, defining the cutoff values as TMB-high (>=20 mutations/Mb), TMB-medium (<20 mutations/Mb >=10 mutations/Mb) and TMB-low (<10 mutations/Mb).	('TMB', 'Chemical', '-', (133, 136))	('mutations/Mb', 'Var', (118, 130))	('F1CDx', 'Chemical', '-', (22, 27))	('TMB', 'Chemical', '-', (185, 188))	('TMB', 'Chemical', '-', (103, 106))	('TMB', 'Chemical', '-', (54, 57))	('<20 mutations/Mb', 'Var', (145, 161))
378256	31123404	We calculated the proportion of patient samples from 15 different cancers with mutations in each gene.	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('cancers', 'Phenotype', 'HP:0002664', (66, 73))	('cancers', 'Disease', (66, 73))	('cancers', 'Disease', 'MESH:D009369', (66, 73))	('patient', 'Species', '9606', (32, 39))	('mutations', 'Var', (79, 88))
378276	31123404	Some well-established cancer-associated genes, such as PI3KCA and TP53, were frequently mutated in most cancer types.	('PI3', 'Gene', (55, 58))	('TP53', 'Gene', '7157', (66, 70))	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('TP53', 'Gene', (66, 70))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('cancer', 'Disease', (22, 28))	('PI3', 'Gene', '5266', (55, 58))	('mutated', 'Var', (88, 95))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))
378283	31123404	TP53, EGFR, PIC3CA and KRAS were often mutated in TMB-low samples in LUAD.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('EGFR', 'Gene', (6, 10))	('PIC3CA', 'Gene', (12, 18))	('mutated', 'Var', (39, 46))	('KRAS', 'Gene', (23, 27))	('TMB', 'Chemical', '-', (50, 53))	('KRAS', 'Gene', '3845', (23, 27))	('EGFR', 'Gene', '1956', (6, 10))
378288	31123404	MUC16 (coding length, 43524 bp) encodes a transmembrane glycoprotein with a molecular weight of 2000 kDa, meaning that it also has a high risk of mutation TMB is defined as the number of somatic coding mutations per million bases.	('MUC16', 'Gene', (0, 5))	('mutation', 'Var', (146, 154))	('MUC16', 'Gene', '94025', (0, 5))	('TMB', 'Chemical', '-', (155, 158))
378291	31123404	However, the relationship of those hotspot mutations with TMB are still not well-understood.	('TMB', 'Chemical', '-', (58, 61))	('TMB', 'Disease', (58, 61))	('mutations', 'Var', (43, 52))
378293	31123404	Firstly, we defined hotspot mutations as highly frequent mutations found in at least ten samples in the complete set of cancer WES data (Figure S2).	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('mutations', 'Var', (28, 37))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))
378294	31123404	Next, we focused on those hotspot mutations which occurred in at least three samples in one cancer type.	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('mutations', 'Var', (34, 43))	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))
378295	31123404	Finally, a total of 150 unique mutations were investigated for their association to TMB level (327 cancer type-specific mutations).	('mutations', 'Var', (31, 40))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('TMB level', 'Disease', (84, 93))	('cancer', 'Disease', (99, 105))	('association', 'Interaction', (69, 80))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('TMB', 'Chemical', '-', (84, 87))
378296	31123404	For these mutations, we calculated the P-value using a Mann-Whitney U-test and the fold-change by the median TMB value in mutation-positive samples (samples containing the mutation) and mutation-negative samples (samples without the mutation), as listed in Figure S3.	('mutation', 'Var', (172, 180))	('mutation-positive', 'Reg', (122, 139))	('TMB', 'Chemical', '-', (109, 112))	('mutations', 'Var', (10, 19))
378297	31123404	Figure 3A shows that most of these hotspot mutations were associated with high TMB (101/327) and only a small number of mutations were associated with low TMB (5/327).	('mutations', 'Var', (43, 52))	('high TMB', 'Disease', (74, 82))	('TMB', 'Chemical', '-', (155, 158))	('TMB', 'Chemical', '-', (79, 82))
378298	31123404	We found that some hotspot mutations occurred in only one cancer type.	('mutations', 'Var', (27, 36))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('cancer', 'Disease', (58, 64))
378299	31123404	For example, the mutations P.S71L in OR2A5, P.G362E in CNTNAP2, P.F17F in BCL2L12 and P.T554I in SLC27A5 only occurred in SKCM and were associated with high TMB, with an adjusted-log10 (P-value)>1.3 and log2 (fold-change)>1.	('associated', 'Reg', (136, 146))	('CNTNAP2', 'Gene', (55, 62))	('BCL2L12', 'Gene', (74, 81))	('TMB', 'Chemical', '-', (157, 160))	('BCL2L12', 'Gene', '83596', (74, 81))	('F17F', 'Mutation', 'rs267605591', (66, 70))	('SLC27A5', 'Gene', '10998', (97, 104))	('T554I', 'Mutation', 'rs868246582', (88, 93))	('S71L', 'Mutation', 'rs149614119', (29, 33))	('P.G362E', 'Var', (44, 51))	('SLC27A5', 'Gene', (97, 104))	('OR2A5', 'Gene', (37, 42))	('OR2A5', 'Gene', '393046', (37, 42))	('CNTNAP2', 'Gene', '26047', (55, 62))	('P.F17F', 'Var', (64, 70))	('G362E', 'Mutation', 'p.G362E', (46, 51))	('high TMB', 'Disease', (152, 160))	('P.S71L', 'Var', (27, 33))	('P.T554I', 'Var', (86, 93))
378300	31123404	However, other hotspot mutations occurred in at least two cancer types.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('occurred', 'Reg', (33, 41))	('mutations', 'Var', (23, 32))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('cancer', 'Disease', (58, 64))
378301	31123404	For example, the mutation KRAS:P.G12V appeared in BRCA, COAD, LUAD, OV, PAAD, STAD and UCEC, but only in OV was this mutation was positively related to low TMB, with a -log10 (P-value) of 2.29 and log2 (fold-change) of -2.26.	('COAD', 'Disease', 'MESH:D029424', (56, 60))	('P.G12V', 'Var', (31, 37))	('low TMB', 'MPA', (152, 159))	('G12V', 'Mutation', 'rs121913529', (33, 37))	('COAD', 'Disease', (56, 60))	('BRCA', 'Gene', '672', (50, 54))	('TMB', 'Chemical', '-', (156, 159))	('KRAS', 'Gene', (26, 30))	('BRCA', 'Gene', (50, 54))	('KRAS', 'Gene', '3845', (26, 30))
378302	31123404	As shown in Figure 3A-B, only in LUAD were the mutations P.E746_A750del and P.L858R in EGFR significantly associated with low TMB (adjusted P-value <0.00006 and log2 (fold-change) of 4.28).	('TMB', 'Chemical', '-', (126, 129))	('L858R', 'Mutation', 'rs121434568', (78, 83))	('EGFR', 'Gene', '1956', (87, 91))	('A750del', 'Mutation', 'c.750delA', (64, 71))	('EGFR', 'Gene', (87, 91))	('low', 'NegReg', (122, 125))	('TMB', 'MPA', (126, 129))	('P.E746_A750del', 'Var', (57, 71))	('P.L858R', 'Var', (76, 83))
378303	31123404	In other words, samples with these two hotspot mutations were usually TMB-low in LUAD and would be targetable by first-generation tyrosine kinase inhibitors.	('LUAD', 'Disease', (81, 85))	('mutations', 'Var', (47, 56))	('TMB', 'Chemical', '-', (70, 73))
378304	31123404	Most colorectal patients with the BRAF P.V600E mutation were TMB-high, with a P-value of 8.21E-19 (fold-change: 31.9 vs 3.4).	('TMB', 'Chemical', '-', (61, 64))	('colorectal', 'Disease', 'MESH:D015179', (5, 15))	('patients', 'Species', '9606', (16, 24))	('colorectal', 'Disease', (5, 15))	('BRAF', 'Gene', '673', (34, 38))	('P.V600E', 'Var', (39, 46))	('BRAF', 'Gene', (34, 38))	('V600E', 'Mutation', 'rs113488022', (41, 46))
378305	31123404	However, the BRAF V600E mutation was associated with TMB-low in LUAD patients with P-value 0.015 (fold change: 1.9 vs 5.9).	('V600E', 'Var', (18, 23))	('BRAF', 'Gene', '673', (13, 17))	('BRAF', 'Gene', (13, 17))	('V600E', 'Mutation', 'rs113488022', (18, 23))	('patients', 'Species', '9606', (69, 77))	('TMB', 'Chemical', '-', (53, 56))	('TMB-low', 'Disease', (53, 60))
378306	31123404	In summary, our results indicated that some hotspot mutations were strongly associated with TMB level, either low or high.	('mutations', 'Var', (52, 61))	('TMB', 'Chemical', '-', (92, 95))	('TMB level', 'Disease', (92, 101))	('associated', 'Reg', (76, 86))
378310	31123404	TMB estimated from simulated F1CDx and MSK-IMPACT panels showed a high correlation to TMB estimated from WES, with R2 correlation values of 0.95 and 0.94, respectively, for total mutations (Figure 4A and B).	('TMB', 'Chemical', '-', (86, 89))	('TMB', 'Chemical', '-', (0, 3))	('MSK', 'Gene', '150094', (39, 42))	('F1CDx', 'Chemical', '-', (29, 34))	('MSK', 'Gene', (39, 42))	('mutations', 'Var', (179, 188))
378322	31123404	Besides, we found that randomly selected gene sets had little difference between F1CDx, MSK-IMPACT and F1CDX+MSK in almost all cancer types.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('F1CDX+MSK', 'Gene', '150094', (103, 112))	('F1CDx', 'Var', (81, 86))	('MSK', 'Gene', '150094', (88, 91))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('MSK', 'Gene', (88, 91))	('MSK', 'Gene', '150094', (109, 112))	('MSK', 'Gene', (109, 112))	('cancer', 'Disease', (127, 133))	('F1CDX+MSK', 'Gene', (103, 112))	('F1CDx', 'Chemical', '-', (81, 86))
378339	29317756	However, remarkably homogenous piRNA profiles are detected across patients with renal cell carcinoma, a cancer characterized by constitutive upregulation of hypoxia-related signaling induced by common mutation or loss of von Hippel-Lindau factor (VHL).	('renal cell carcinoma', 'Disease', (80, 100))	('loss', 'NegReg', (213, 217))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('upregulation', 'PosReg', (141, 153))	('hypoxia', 'Disease', 'MESH:D000860', (157, 164))	('von Hippel-Lindau factor', 'Gene', '7428', (221, 245))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (80, 100))	('VHL', 'Gene', (247, 250))	('hypoxia', 'Disease', (157, 164))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (80, 100))	('VHL', 'Gene', '7428', (247, 250))	('mutation', 'Var', (201, 209))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('patients', 'Species', '9606', (66, 74))	('von Hippel-Lindau factor', 'Gene', (221, 245))
378355	29317756	We found that piRNA expression was remarkably consistent between RCC tumours, a tumour type that commonly harbour loss-of-function mutations in von Hippel-Lindau factor (VHL), causing constitutive, oxygen-independent stabilization of HIF-1alpha and HIF-mediated upregulation of hypoxia-associated gene products.	('HIF-1alpha', 'Gene', '3091', (234, 244))	('tumour', 'Phenotype', 'HP:0002664', (69, 75))	('loss-of-function', 'NegReg', (114, 130))	('tumour', 'Disease', 'MESH:D009369', (69, 75))	('upregulation', 'PosReg', (262, 274))	('tumour', 'Disease', (69, 75))	('hypoxia', 'Disease', (278, 285))	('HIF-1alpha', 'Gene', (234, 244))	('VHL', 'Gene', (170, 173))	('von Hippel-Lindau factor', 'Gene', (144, 168))	('tumour', 'Phenotype', 'HP:0002664', (80, 86))	('tumour', 'Disease', 'MESH:D009369', (80, 86))	('hypoxia', 'Disease', 'MESH:D000860', (278, 285))	('RCC tumours', 'Disease', (65, 76))	('von Hippel-Lindau factor', 'Gene', '7428', (144, 168))	('tumour', 'Disease', (80, 86))	('mutations', 'Var', (131, 140))	('VHL', 'Gene', '7428', (170, 173))	('RCC tumours', 'Disease', 'MESH:C538614', (65, 76))	('stabilization', 'MPA', (217, 230))	('tumours', 'Phenotype', 'HP:0002664', (69, 76))	('oxygen', 'Chemical', 'MESH:D010100', (198, 204))
378365	29317756	The culture media used was: Dulbecco's Modified Eagle Medium supplemented with 10% Fetal-Bovine Serum (FBS) for PANC1 and Mia-Paca-2; Dulbecco's Modified Eagle Medium: F12 with 10% FBS for NCI-H841; RPMI1640 + 10% FBS for HCC15 and HCC4006; RPMI-1640 + 2 mM glutamine + 10% FBS for OE33; F12K with 10% FBS for A549; Eagle's MEM + 10% FBS for FaDu; MEM + 10% FBS for SiHa.	('SiHa', 'CellLine', 'CVCL:0032', (366, 370))	('RPMI1640 +', 'Var', (199, 209))	('Mia-Paca-2', 'Gene', '4253', (122, 132))	('A549', 'CellLine', 'CVCL:0023', (310, 314))	('Mia-Paca-2', 'Gene', (122, 132))	('Bovine', 'Species', '9913', (89, 95))	('HCC4006', 'CellLine', 'CVCL:1269', (232, 239))	('NCI-H841', 'CellLine', 'CVCL:1595', (189, 197))	('HCC15', 'CellLine', 'CVCL:2057', (222, 227))	('F12K', 'SUBSTITUTION', 'None', (288, 292))	('F12K', 'Var', (288, 292))	('PANC1', 'CellLine', 'CVCL:0480', (112, 117))
378373	29317756	For each tumour cell line analyzed, filtered reads were aligned to the human genome (GRCh37/hg19) using the STAR aligner, with specific parameters for short reads: i) only reads 23 bp or longer matched to the genome, ii) number of mismatches < = 5% of mapped length, and iii) splicing switched off.	('tumour', 'Disease', (9, 15))	('mismatches', 'Var', (231, 241))	('STAR', 'Gene', '6770', (108, 112))	('tumour', 'Phenotype', 'HP:0002664', (9, 15))	('STAR', 'Gene', (108, 112))	('tumour', 'Disease', 'MESH:D009369', (9, 15))	('human', 'Species', '9606', (71, 76))
378375	29317756	A549 cells were treated with siRNA to VHL at 5 nM using Dharmafect for 48 hrs at 21% O2 (Ambion, Inc. Cat#(Lot): non-targeting control #4390843, siRNA 1 VHL #4390824(s14789), siRNA 2 VHL #4392420(s14790), siRNA 3 VHL #4392420(s14791)).	('s14790', 'Var', (196, 202))	('VHL', 'Gene', '7428', (183, 186))	('VHL', 'Gene', (153, 156))	('A549', 'CellLine', 'CVCL:0023', (0, 4))	('VHL', 'Gene', '7428', (153, 156))	('VHL', 'Gene', (213, 216))	('s14789', 'Var', (166, 172))	('VHL', 'Gene', '7428', (213, 216))	('VHL', 'Gene', (38, 41))	('O2', 'Chemical', 'MESH:D010100', (85, 87))	('VHL', 'Gene', '7428', (38, 41))	('VHL', 'Gene', (183, 186))
378393	29317756	We previously observed remarkable homogeneneity in piRNA expression in RCC tumors, which are known to have a high frequency of loss-of-function mutations in the VHL gene that causes constitutive stabilization of HIF-1alpha.	('HIF-1alpha', 'Gene', (212, 222))	('loss-of-function', 'NegReg', (127, 143))	('RCC tumors', 'Disease', (71, 81))	('HIF-1alpha', 'Gene', '3091', (212, 222))	('VHL', 'Gene', (161, 164))	('VHL', 'Gene', '7428', (161, 164))	('mutations', 'Var', (144, 153))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('RCC tumors', 'Disease', 'MESH:C538614', (71, 81))
378395	29317756	To address this hypothesis we selected A549 lung adenocarcinoma cells (with the highest number of hypoxia-regulated piRNAs detectable at the sequencing level) to test the effect of siRNA-mediated knockdown of VHL on expression of DQ590404 and DQ596992, which were two of the most highly overexpressed hypoxia-regulated piRNAs in A549 cells.	('hypoxia', 'Disease', (301, 308))	('hypoxia', 'Disease', 'MESH:D000860', (301, 308))	('carcinoma', 'Phenotype', 'HP:0030731', (54, 63))	('A549 lung adenocarcinoma', 'Disease', 'MESH:D000077192', (39, 63))	('hypoxia', 'Disease', (98, 105))	('hypoxia', 'Disease', 'MESH:D000860', (98, 105))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (44, 63))	('DQ596992', 'Var', (243, 251))	('VHL', 'Gene', (209, 212))	('DQ590404', 'Var', (230, 238))	('test', 'Reg', (162, 166))	('A549 lung adenocarcinoma', 'Disease', (39, 63))	('VHL', 'Gene', '7428', (209, 212))	('A549', 'CellLine', 'CVCL:0023', (39, 43))	('A549', 'CellLine', 'CVCL:0023', (329, 333))
378396	29317756	We found that siRNA-mediated knockdown of VHL increased expression of both piRNAs (Fig.	('knockdown', 'Var', (29, 38))	('increased', 'PosReg', (46, 55))	('expression', 'MPA', (56, 66))	('VHL', 'Gene', (42, 45))	('VHL', 'Gene', '7428', (42, 45))
378397	29317756	4A,B), and that this induction was inhibited when VHL knockdown was combined with siRNA-mediated knockdown of HIF-1alpha, indicating that HIF-1alpha stabilization induced by VHL knockdown was responsible for the increase in piRNA expression.	('VHL', 'Gene', (50, 53))	('HIF-1alpha', 'Gene', '3091', (138, 148))	('piRNA', 'Gene', (224, 229))	('HIF-1alpha', 'Gene', (138, 148))	('HIF-1alpha', 'Gene', (110, 120))	('VHL', 'Gene', '7428', (50, 53))	('expression', 'MPA', (230, 240))	('VHL', 'Gene', (174, 177))	('VHL', 'Gene', '7428', (174, 177))	('knockdown', 'Var', (178, 187))	('increase', 'PosReg', (212, 220))	('HIF-1alpha', 'Gene', '3091', (110, 120))
378412	29317756	While this lack of clear classification between hypoxic and non-hypoxic ovarian cancer samples was not anticipated, it was expected in renal cell carcinomas because >75% of sporadic RCCs contain mutated or lost VHL.	('renal cell carcinomas', 'Disease', 'MESH:C538614', (135, 156))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (135, 156))	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('non-hypoxic ovarian cancer', 'Disease', (60, 86))	('VHL', 'Gene', (211, 214))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (135, 155))	('lost', 'NegReg', (206, 210))	('VHL', 'Gene', '7428', (211, 214))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('ovarian cancer', 'Phenotype', 'HP:0100615', (72, 86))	('renal cell carcinomas', 'Disease', (135, 156))	('carcinomas', 'Phenotype', 'HP:0030731', (146, 156))	('non-hypoxic ovarian cancer', 'Disease', 'MESH:D010051', (60, 86))	('RCC', 'Disease', 'MESH:C538614', (182, 185))	('RCC', 'Disease', (182, 185))	('mutated', 'Var', (195, 202))
378413	29317756	Loss of VHL function mimics hypoxia-mediated stabilization of HIF-1alpha, which then dimerizes with HIF-1beta to form HIF-1 and induce transcription.	('HIF-1alpha', 'Gene', (62, 72))	('VHL', 'Gene', '7428', (8, 11))	('HIF-1', 'Gene', '3091', (118, 123))	('HIF-1', 'Gene', (100, 105))	('HIF-1', 'Gene', (62, 67))	('HIF-1', 'Gene', (118, 123))	('HIF-1alpha', 'Gene', '3091', (62, 72))	('transcription', 'MPA', (135, 148))	('hypoxia', 'Disease', (28, 35))	('induce', 'PosReg', (128, 134))	('hypoxia', 'Disease', 'MESH:D000860', (28, 35))	('Loss', 'Var', (0, 4))	('HIF-1', 'Gene', '3091', (100, 105))	('VHL', 'Gene', (8, 11))	('HIF-1', 'Gene', '3091', (62, 67))
378414	29317756	Constitutively activated HIF-1 in renal tumours, in part attributed to mutated VHL, upregulates genes involved in the hypoxic response regardless of local cellular oxygen tensions.	('VHL', 'Gene', '7428', (79, 82))	('activated', 'PosReg', (15, 24))	('HIF-1 in renal tumours', 'Disease', (25, 47))	('oxygen', 'Chemical', 'MESH:D010100', (164, 170))	('upregulates', 'PosReg', (84, 95))	('genes', 'MPA', (96, 101))	('mutated', 'Var', (71, 78))	('HIF-1 in renal tumours', 'Disease', 'MESH:D007680', (25, 47))	('tumour', 'Phenotype', 'HP:0002664', (40, 46))	('VHL', 'Gene', (79, 82))	('tumours', 'Phenotype', 'HP:0002664', (40, 47))
378418	29317756	We observed increased expression of two different piRNAs when VHL was knocked down in A549 cells, and piRNA expression was decreased to control levels by simultaneous knockdown of HIF-1alpha (Fig.	('HIF-1alpha', 'Gene', (180, 190))	('increased', 'PosReg', (12, 21))	('knockdown', 'Var', (167, 176))	('A549', 'CellLine', 'CVCL:0023', (86, 90))	('knocked down', 'Var', (70, 82))	('VHL', 'Gene', (62, 65))	('expression', 'MPA', (108, 118))	('HIF-1alpha', 'Gene', '3091', (180, 190))	('VHL', 'Gene', '7428', (62, 65))	('expression', 'MPA', (22, 32))
378419	29317756	These data indicate that the VHL-mediated induction of DQ590404 and DQ596992 piRNAs is HIF-1alpha dependent, and suggest that the induction of piRNAs in hypoxic cells more generally may also be regulated by HIF-1.	('HIF-1alpha', 'Gene', (87, 97))	('VHL', 'Gene', (29, 32))	('HIF-1', 'Gene', (87, 92))	('DQ596992', 'Var', (68, 76))	('HIF-1', 'Gene', '3091', (207, 212))	('VHL', 'Gene', '7428', (29, 32))	('DQ590404', 'Var', (55, 63))	('HIF-1', 'Gene', (207, 212))	('HIF-1alpha', 'Gene', '3091', (87, 97))	('HIF-1', 'Gene', '3091', (87, 92))
378432	27081034	PRSS8 methylation and its significance in esophageal squamous cell carcinoma Esophageal cancer is one of the most common cancers worldwide, and the incidence and mortality is increasing rapidly in recent years in China, but the underlying mechanisms are largely unclear.	('cancers', 'Disease', (121, 128))	('cancers', 'Disease', 'MESH:D009369', (121, 128))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (42, 76))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('carcinoma Esophageal cancer', 'Phenotype', 'HP:0011459', (67, 94))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (53, 76))	('esophageal squamous cell carcinoma', 'Disease', (42, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('methylation', 'Var', (6, 17))	('Esophageal cancer', 'Disease', (77, 94))	('PRSS8', 'Gene', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('Esophageal cancer', 'Disease', 'MESH:D004938', (77, 94))	('cancers', 'Phenotype', 'HP:0002664', (121, 128))	('PRSS8', 'Gene', '5652', (0, 5))
378436	27081034	Methylation specific PCR showed that PRSS8 was hypermethylated in ESCC tissues and ESCC cell lines, which was linked to the downregulation of PRSS8 expression and decreased activities of PRSS8 promoter.	('PRSS8', 'Gene', (142, 147))	('PRSS8', 'Gene', (187, 192))	('PRSS8', 'Gene', (37, 42))	('PRSS8', 'Gene', '5652', (142, 147))	('activities', 'MPA', (173, 183))	('hypermethylated', 'Var', (47, 62))	('PRSS8', 'Gene', '5652', (187, 192))	('PRSS8', 'Gene', '5652', (37, 42))	('decreased', 'NegReg', (163, 172))	('expression', 'MPA', (148, 158))	('downregulation', 'NegReg', (124, 138))
378438	27081034	However, the restored PRSS8 and its tumor inhibition could be reversed by small interfering RNA targeting PRSS8.	('small interfering', 'Var', (74, 91))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('PRSS8', 'Gene', (22, 27))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('PRSS8', 'Gene', (106, 111))	('PRSS8', 'Gene', '5652', (22, 27))	('PRSS8', 'Gene', '5652', (106, 111))	('tumor', 'Disease', (36, 41))
378440	27081034	In conclusion, our finding showed that PRSS8 methylation and its stromal expression had important clinical significance in ESCC.	('PRSS8', 'Gene', (39, 44))	('PRSS8', 'Gene', '5652', (39, 44))	('methylation', 'Var', (45, 56))	('ESCC', 'Disease', (123, 127))
378443	27081034	Numerous studies have shown that the silence or decreased expression of tumor suppressor genes could be one of the major causes of esophageal carcinogenesis, in particular, promoter hypermethylation of tumor suppressor genes leads to silence and downregulation of gene expression, which is linked to tumor formation and progression.	('tumor', 'Phenotype', 'HP:0002664', (300, 305))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('silence', 'MPA', (234, 241))	('tumor', 'Disease', (202, 207))	('tumor', 'Disease', (300, 305))	('tumor', 'Disease', (72, 77))	('downregulation', 'NegReg', (246, 260))	('expression', 'MPA', (58, 68))	('promoter hypermethylation', 'Var', (173, 198))	('decreased', 'NegReg', (48, 57))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (131, 156))	('esophageal carcinogenesis', 'Disease', (131, 156))	('gene expression', 'MPA', (264, 279))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('tumor', 'Disease', 'MESH:D009369', (300, 305))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))
378444	27081034	In the present study, we found that PRSS8 (protease serine 8), a trypsin-like serine peptidase, is hypermethylated in ESCC tissues and ESCC cell lines.	('ESCC', 'Disease', (118, 122))	('hypermethylated', 'Var', (99, 114))	('protease serine 8', 'Gene', '5652', (43, 60))	('PRSS8', 'Gene', (36, 41))	('PRSS8', 'Gene', '5652', (36, 41))	('protease serine 8', 'Gene', (43, 60))
378450	27081034	In prostate cancer, reduced PRSS8 was associated with hypermethylation of PRSS8.	('prostate cancer', 'Phenotype', 'HP:0012125', (3, 18))	('reduced', 'NegReg', (20, 27))	('PRSS8', 'Gene', '5652', (28, 33))	('PRSS8', 'Gene', (74, 79))	('PRSS8', 'Gene', '5652', (74, 79))	('hypermethylation', 'Var', (54, 70))	('prostate cancer', 'Disease', (3, 18))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('PRSS8', 'Gene', (28, 33))	('prostate cancer', 'Disease', 'MESH:D011471', (3, 18))
378452	27081034	More importantly, the PRSS8 methylation likely played a crucial roles in ESCC, evidenced by restoration of PRSS8 by de-methylation agent and knockdown the restoration of PRSS8 in ESCC cells exhibiting inverse functions.	('knockdown', 'Var', (141, 150))	('played', 'Reg', (47, 53))	('PRSS8', 'Gene', '5652', (107, 112))	('PRSS8', 'Gene', (170, 175))	('PRSS8', 'Gene', '5652', (170, 175))	('de-methylation', 'NegReg', (116, 130))	('PRSS8', 'Gene', (22, 27))	('PRSS8', 'Gene', '5652', (22, 27))	('ESCC', 'Disease', (73, 77))	('PRSS8', 'Gene', (107, 112))
378471	27081034	To determine whether the reduction of PRSS8 in ESCC tissues and cell lines was caused by hypermethylation in PRSS8 promoter region, we used the methylation CpG island prediction software and identified one CpG island in PRSS8 promoter region (-4238 to -4116) (Figure 3A).	('reduction', 'NegReg', (25, 34))	('PRSS8', 'Gene', (220, 225))	('PRSS8', 'Gene', '5652', (38, 43))	('PRSS8', 'Gene', '5652', (220, 225))	('-4238 to -4116', 'Var', (243, 257))	('PRSS8', 'Gene', (109, 114))	('PRSS8', 'Gene', '5652', (109, 114))	('PRSS8', 'Gene', (38, 43))
378472	27081034	Figure 3B showed the examples of PRSS8 promoter region hypermethylation in ESCC tissues (4 clones) and in 2 ESCC cell lines (KYSE450 and EC9706) that showed undetectable PRSS8 level, but another 2 cell lines (TE1 and TE8) exhibited expression of PRSS8 and showed no methylation in PRSS 8 promoter region.	('EC9706', 'CellLine', 'CVCL:E307', (137, 143))	('hypermethylation', 'Var', (55, 71))	('TE1', 'Gene', (209, 212))	('PRSS8', 'Gene', (170, 175))	('PRSS8', 'Gene', (246, 251))	('PRSS 8', 'Gene', '5652', (281, 287))	('PRSS8', 'Gene', '5652', (170, 175))	('PRSS8', 'Gene', (33, 38))	('PRSS8', 'Gene', '5652', (33, 38))	('PRSS8', 'Gene', '5652', (246, 251))	('TE1', 'Gene', '57816', (209, 212))	('PRSS 8', 'Gene', (281, 287))
378473	27081034	To determine whether this CpG island at the PRSS8 promoter region has biological function, we then constructed reporters with truncated PRSS8 promoter region into pGL4 vector (Promega, Madison, WI).	('truncated', 'Var', (126, 135))	('pGL4', 'Gene', '6390', (163, 167))	('pGL4', 'Gene', (163, 167))	('PRSS8', 'Gene', (136, 141))	('PRSS8', 'Gene', (44, 49))	('PRSS8', 'Gene', '5652', (44, 49))	('PRSS8', 'Gene', '5652', (136, 141))
378477	27081034	These findings indicated that PRSS8 promoter methylation in KYSE450 cells significantly impacted promoter reporter activity, compared to TE1 cells that have no methylation, suggested that the CpG island in PRSS8 promoter region indeed has biological functions, and this region hypermethylation might lead to repression of PRSS8 expression.	('TE1', 'Gene', '57816', (137, 140))	('PRSS8', 'Gene', (206, 211))	('PRSS8', 'Gene', '5652', (206, 211))	('promoter reporter activity', 'MPA', (97, 123))	('repression', 'NegReg', (308, 318))	('PRSS8', 'Gene', (322, 327))	('TE1', 'Gene', (137, 140))	('methylation', 'Var', (45, 56))	('PRSS8', 'Gene', (30, 35))	('PRSS8', 'Gene', '5652', (322, 327))	('hypermethylation', 'Var', (277, 293))	('impacted', 'Reg', (88, 96))	('expression', 'MPA', (328, 338))	('PRSS8', 'Gene', '5652', (30, 35))
378488	27081034	In addition, restoration of PRSS8 led to cell cycle arrest at G1 phase in both KYSE450 and EC9706 cell lines, but this G1 phase arrest was attenuated by small interfering RNA, in comparison to the control groups (Table 2).	('cell cycle arrest', 'CPA', (41, 58))	('PRSS8', 'Gene', '5652', (28, 33))	('attenuated', 'NegReg', (139, 149))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (41, 58))	('small interfering RNA', 'Var', (153, 174))	('restoration', 'Var', (13, 24))	('PRSS8', 'Gene', (28, 33))	('EC9706', 'CellLine', 'CVCL:E307', (91, 97))
378496	27081034	Numerous studies have revealed that epigenetic alterations play a pathological role in cancer initiation and progression.	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('epigenetic alterations', 'Var', (36, 58))	('pathological role', 'Reg', (66, 83))	('cancer initiation', 'Disease', 'MESH:D009369', (87, 104))	('cancer initiation', 'Disease', (87, 104))
378497	27081034	Indeed, promoter hypermethylation-induced inactivation of tumor suppressor genes has been observed at the multistep process of carcinogenesis.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('inactivation', 'NegReg', (42, 54))	('carcinogenesis', 'Disease', 'MESH:D063646', (127, 141))	('carcinogenesis', 'Disease', (127, 141))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('promoter hypermethylation-induced', 'Var', (8, 41))
378499	27081034	In this study, we have found that PRSS8 promoter was hypermethylated in esophageal squamous cell carcinoma tissues and cancer cell lines, resulting in downregulation of PRSS8 at mRNA and protein levels, which was supported by the GEO Profiles (http://www.ncbi.nlm.nih.gov/geoprofiles/) and Oncomine (http://www.oncomine.com) online data (Supplemental Figure 1) showing that PRSS8 was significantly reduced in esophageal squamous cell carcinoma and adenocarcinoma in comparison with the adjacent non-tumor esophagus.	('PRSS8', 'Gene', '5652', (34, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('tumor', 'Disease', 'MESH:D009369', (499, 504))	('PRSS8', 'Gene', '5652', (169, 174))	('Oncomine', 'Chemical', '-', (290, 298))	('downregulation', 'NegReg', (151, 165))	('oncomine', 'Chemical', '-', (311, 319))	('carcinoma', 'Phenotype', 'HP:0030731', (453, 462))	('PRSS8', 'Gene', (34, 39))	('PRSS8', 'Gene', '5652', (374, 379))	('reduced', 'NegReg', (398, 405))	('tumor', 'Phenotype', 'HP:0002664', (499, 504))	('PRSS8', 'Gene', (169, 174))	('cancer', 'Disease', (119, 125))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (420, 443))	('PRSS8', 'Gene', (374, 379))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('esophageal squamous cell carcinoma tissues', 'Disease', (72, 114))	('carcinoma', 'Phenotype', 'HP:0030731', (434, 443))	('tumor esophagus', 'Phenotype', 'HP:0100751', (499, 514))	('hypermethylated', 'Var', (53, 68))	('esophageal squamous cell carcinoma and adenocarcinoma', 'Disease', 'MESH:D000077277', (409, 462))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (83, 106))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('tumor', 'Disease', (499, 504))	('esophageal squamous cell carcinoma tissues', 'Disease', 'MESH:D000077277', (72, 114))
378503	27081034	Previous studies have reported that the inactivation of tumor suppressor genes was one of the major causes of esophageal carcinogenesis, and hypermethylation-induced silence of tumor suppressors, such as P16, E-cadherin and selenium-binding protein 1, etc, are frequently observed in esophageal cancers.	('selenium-binding protein 1', 'Gene', (224, 250))	('esophageal cancers', 'Disease', 'MESH:D004938', (284, 302))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('esophageal carcinogenesis', 'Disease', (110, 135))	('cancer', 'Phenotype', 'HP:0002664', (295, 301))	('selenium-binding protein 1', 'Gene', '8991', (224, 250))	('E-cadherin', 'Gene', (209, 219))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (110, 135))	('cancers', 'Phenotype', 'HP:0002664', (295, 302))	('silence', 'NegReg', (166, 173))	('E-cadherin', 'Gene', '999', (209, 219))	('tumor', 'Disease', (177, 182))	('P16', 'Gene', '1029', (204, 207))	('tumor', 'Disease', (56, 61))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('causes', 'Reg', (100, 106))	('P16', 'Gene', (204, 207))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('inactivation', 'Var', (40, 52))	('esophageal cancers', 'Disease', (284, 302))	('hypermethylation-induced', 'Var', (141, 165))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('observed', 'Reg', (272, 280))
378505	27081034	We used the approaches of restoration by demethylation, truncated promoter reporters, and knockdown by small interfering RNA, to provide direct evidence identifying the critical role of PRSS8 in esophageal cancer.	('esophageal cancer', 'Disease', (195, 212))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('PRSS8', 'Gene', (186, 191))	('esophageal cancer', 'Disease', 'MESH:D004938', (195, 212))	('demethylation', 'Var', (41, 54))	('PRSS8', 'Gene', '5652', (186, 191))
378506	27081034	More interestingly, the alterations of PRSS8 expression were well correlated with esophageal cancer differentiation and outcomes of the ESCC patients, indicating that PRSS8 might be a useful biomarker for the evaluation of ESCC differentiation and for the prediction of ESCC outcomes.	('esophageal cancer', 'Disease', 'MESH:D004938', (82, 99))	('correlated', 'Reg', (66, 76))	('alterations', 'Var', (24, 35))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('PRSS8', 'Gene', (39, 44))	('expression', 'MPA', (45, 55))	('PRSS8', 'Gene', '5652', (39, 44))	('PRSS8', 'Gene', (167, 172))	('esophageal cancer', 'Disease', (82, 99))	('PRSS8', 'Gene', '5652', (167, 172))	('patients', 'Species', '9606', (141, 149))
378512	27081034	In conclusion, we have identified that PRSS8 acts as a tumor suppressor gene in ESCC, the hypermethylation of the promoter region leads to repression of expression, and reduced expression is significantly associated with cancer differentiation and survival.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('repression', 'NegReg', (139, 149))	('cancer', 'Disease', 'MESH:D009369', (221, 227))	('hypermethylation', 'Var', (90, 106))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('cancer', 'Disease', (221, 227))	('reduced', 'NegReg', (169, 176))	('tumor', 'Disease', (55, 60))	('PRSS8', 'Gene', (39, 44))	('survival', 'CPA', (248, 256))	('PRSS8', 'Gene', '5652', (39, 44))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('expression', 'MPA', (153, 163))	('associated', 'Reg', (205, 215))	('expression', 'MPA', (177, 187))	('ESCC', 'Disease', (80, 84))
378514	27081034	Taken together, our findings have demonstrated that PRSS8 methylation and its stromal expression has important clinical significance in esophageal squamous cell carcinoma.	('PRSS8', 'Gene', (52, 57))	('esophageal squamous cell carcinoma', 'Disease', (136, 170))	('PRSS8', 'Gene', '5652', (52, 57))	('methylation', 'Var', (58, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (161, 170))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (147, 170))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (136, 170))
378530	27081034	The genomic DNA for PRSS8 promoter reporter construction were extracted from the KYSE450 cells having hypermethylation in PRSS8 promoter, or from the TE1 having unmethylation in PRSS8 promoter region, respectively.	('PRSS8', 'Gene', '5652', (20, 25))	('TE1', 'Gene', (150, 153))	('PRSS8', 'Gene', '5652', (122, 127))	('PRSS8', 'Gene', (122, 127))	('PRSS8', 'Gene', (20, 25))	('TE1', 'Gene', '57816', (150, 153))	('hypermethylation', 'Var', (102, 118))	('PRSS8', 'Gene', (178, 183))	('PRSS8', 'Gene', '5652', (178, 183))
378538	27081034	The cells were collected for immunoblotting analysis using the following primary antibodies: anti-PRSS8, anti-P21, anti-Cyclin D1, anti-E-cadherin, anti-snail and anti-Twist (from Cell Signaling Technologies Inc., CA).	('P21', 'Gene', (110, 113))	('snail', 'Gene', (153, 158))	('Cyclin D1', 'Gene', '595', (120, 129))	('E-cadherin', 'Gene', (136, 146))	('E-cadherin', 'Gene', '999', (136, 146))	('PRSS8', 'Gene', (98, 103))	('Cyclin D1', 'Gene', (120, 129))	('P21', 'Gene', '1026', (110, 113))	('PRSS8', 'Gene', '5652', (98, 103))	('snail', 'Gene', '6615', (153, 158))	('anti-Twist', 'Var', (163, 173))
378543	27081034	As reported previously, the KYSE450 and EC9706 cells were seeded in a 100-mm Petri dish, then were treated with DAC or with treatment of DAC and transfection of siR-PRSS8.	('siR-PRSS8', 'Gene', (161, 170))	('DAC', 'Chemical', '-', (137, 140))	('DAC', 'Chemical', '-', (112, 115))	('siR-PRSS8', 'Gene', '5652', (161, 170))	('EC9706', 'CellLine', 'CVCL:E307', (40, 46))	('transfection', 'Var', (145, 157))
378545	27081034	The cells were treated with 30muM of DAC or with the treatment of DAC and transfection of siR-PRSS8.	('transfection', 'Var', (74, 86))	('DAC', 'Chemical', '-', (37, 40))	('DAC', 'Chemical', '-', (66, 69))	('siR-PRSS8', 'Gene', (90, 99))	('siR-PRSS8', 'Gene', '5652', (90, 99))
378555	26675419	The Cox multivariate regression analysis showed coexpressions of Cyclin-D1 and p53 a significant and independent predictor of overall survival (OR = 1.90, 95% CI = 1.45-4.82, p = 0.046) after adjusting the demographic, clinicopathological and radiological response.	('overall survival', 'CPA', (126, 142))	('p53', 'Gene', (79, 82))	('Cyclin-D1', 'Gene', '595', (65, 74))	('p53', 'Gene', '7157', (79, 82))	('Cox', 'Gene', (4, 7))	('coexpressions', 'Var', (48, 61))	('Cyclin-D1', 'Gene', (65, 74))	('Cox', 'Gene', '9377', (4, 7))
378625	26675419	EGFR overexpression and aberrant EGFR gene copy number have been associated with poorer prognosis and disease-specific survival in SCCHN.	('EGFR', 'Gene', (0, 4))	('aberrant', 'Var', (24, 32))	('overexpression', 'PosReg', (5, 19))	('SCCHN', 'Disease', (131, 136))	('EGFR', 'Gene', '1956', (33, 37))	('EGFR', 'Gene', (33, 37))	('EGFR', 'Gene', '1956', (0, 4))
378631	26675419	Similar data have been demonstrated in bladder cancer where abnormal p53 overexpression has also been found to be associated with decreased survival.	('bladder cancer', 'Phenotype', 'HP:0009725', (39, 53))	('bladder cancer', 'Disease', 'MESH:D001749', (39, 53))	('p53', 'Gene', (69, 72))	('p53', 'Gene', '7157', (69, 72))	('bladder cancer', 'Disease', (39, 53))	('overexpression', 'PosReg', (73, 87))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('abnormal', 'Var', (60, 68))	('survival', 'MPA', (140, 148))	('decreased', 'NegReg', (130, 139))
378632	26675419	Mutations of the tumor suppressor gene p53 are the most significant events in several human cancers.	('tumor', 'Disease', (17, 22))	('cancers', 'Phenotype', 'HP:0002664', (92, 99))	('human', 'Species', '9606', (86, 91))	('cancers', 'Disease', 'MESH:D009369', (92, 99))	('Mutations', 'Var', (0, 9))	('p53', 'Gene', (39, 42))	('cancers', 'Disease', (92, 99))	('p53', 'Gene', '7157', (39, 42))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
378633	26675419	Various studies have documented that more than 90% of the p53 gene mutations in SCCHN in general are missense mutations, which are caused by a change in amino acid and a probable increase in the stability of the protein which can be detected by immunohistochemical analysis due to stability of the protein.	('missense mutations', 'Var', (101, 119))	('change', 'Reg', (143, 149))	('amino acid', 'MPA', (153, 163))	('mutations', 'Var', (67, 76))	('SCCHN', 'Disease', (80, 85))	('p53', 'Gene', (58, 61))	('increase', 'PosReg', (179, 187))	('stability', 'MPA', (195, 204))	('p53', 'Gene', '7157', (58, 61))
378634	26675419	Studies have also strongly documented the correlation between the immunohistochemical overexpression of p53 protein and the presence of missense mutations within the p53 gene.	('p53', 'Gene', (104, 107))	('missense mutations', 'Var', (136, 154))	('p53', 'Gene', '7157', (104, 107))	('p53', 'Gene', (166, 169))	('p53', 'Gene', '7157', (166, 169))	('protein', 'Protein', (108, 115))	('overexpression', 'PosReg', (86, 100))
378636	26675419	In the present study, we have also found poor survival in patients where Cyclin-D1 and p53 were overexpressed as compared with moderate or negative expression, suggesting the possibility of occurrence of missense mutation in these patients and documenting the prognostic role of overexpressed p53 in OSCC.	('Cyclin-D1', 'Gene', '595', (73, 82))	('patients', 'Species', '9606', (58, 66))	('OSCC', 'Disease', (300, 304))	('patients', 'Species', '9606', (231, 239))	('p53', 'Gene', (293, 296))	('p53', 'Gene', (87, 90))	('p53', 'Gene', '7157', (87, 90))	('p53', 'Gene', '7157', (293, 296))	('Cyclin-D1', 'Gene', (73, 82))	('missense mutation', 'Var', (204, 221))	('occurrence', 'Reg', (190, 200))
378638	26675419	Direct targeting and inhibition of this pathway may increase radiosensitivity by antagonizing the radiation induced cellular defense mechanisms especially in tumors that have activated the PI3-K/AKT cascade.	('AKT', 'Gene', (195, 198))	('tumors', 'Disease', (158, 164))	('tumors', 'Phenotype', 'HP:0002664', (158, 164))	('antagonizing', 'NegReg', (81, 93))	('tumors', 'Disease', 'MESH:D009369', (158, 164))	('increase', 'PosReg', (52, 60))	('radiation induced cellular defense mechanisms', 'CPA', (98, 143))	('inhibition', 'Var', (21, 31))	('activated', 'PosReg', (175, 184))	('AKT', 'Gene', '207', (195, 198))	('radiosensitivity', 'MPA', (61, 77))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('increase radiosensitivity', 'Phenotype', 'HP:0010997', (52, 77))
378644	24700717	Epigenetic alterations in metastatic cutaneous carcinoma Squamous cell carcinoma (cSCC) and basal cell carcinomas are the two most common cutaneous carcinomas.	('cSCC', 'Phenotype', 'HP:0006739', (82, 86))	('basal cell carcinomas', 'Disease', (92, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('basal cell carcinomas', 'Phenotype', 'HP:0002671', (92, 113))	('carcinomas', 'Phenotype', 'HP:0030731', (103, 113))	('carcinoma', 'Disease', (103, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (47, 56))	('carcinoma', 'Disease', (47, 56))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (92, 112))	('carcinoma', 'Disease', (71, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (148, 157))	('cutaneous carcinomas', 'Disease', 'MESH:D018366', (138, 158))	('carcinoma', 'Disease', (148, 157))	('carcinoma', 'Disease', 'MESH:D002277', (103, 112))	('Epigenetic alterations', 'Var', (0, 22))	('Squamous cell carcinoma', 'Phenotype', 'HP:0002860', (57, 80))	('Squamous cell carcinoma', 'Disease', (57, 80))	('basal cell carcinomas', 'Disease', 'MESH:D002280', (92, 113))	('carcinoma', 'Disease', 'MESH:D002277', (71, 80))	('carcinomas', 'Phenotype', 'HP:0030731', (148, 158))	('Squamous cell carcinoma', 'Disease', 'MESH:D002294', (57, 80))	('carcinoma', 'Disease', 'MESH:D002277', (47, 56))	('cutaneous carcinomas', 'Disease', (138, 158))	('carcinoma', 'Disease', 'MESH:D002277', (148, 157))
378646	24700717	Metastatic cSCCs were found to be hypermethylated at FRZB (median methylation: 46.7% vs 4.7%; p=4x10-5).	('FRZB', 'Gene', '2487', (53, 57))	('methylation', 'MPA', (66, 77))	('Metastatic cSCCs', 'CPA', (0, 16))	('hypermethylated', 'Var', (34, 49))	('cSCC', 'Phenotype', 'HP:0006739', (11, 15))	('FRZB', 'Gene', (53, 57))
378647	24700717	Metastatic BCCs were found to be hypomethylated at MYCL2 (median methylation: 3.8% vs 83.4%, p=1.9x10-6).	('hypomethylated', 'Var', (33, 47))	('MYCL2', 'Gene', '4611', (51, 56))	('methylation', 'MPA', (65, 76))	('BCC', 'Phenotype', 'HP:0002671', (11, 14))	('MYCL2', 'Gene', (51, 56))
378649	24700717	Epigenetic profiling may prove useful in future diagnosis and prevention of advanced non-melanoma skin cancers.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('skin cancers', 'Phenotype', 'HP:0008069', (98, 110))	('non-melanoma skin cancers', 'Disease', 'MESH:D012878', (85, 110))	('Epigenetic', 'Var', (0, 10))	('melanoma', 'Phenotype', 'HP:0002861', (89, 97))	('non-melanoma skin cancers', 'Disease', (85, 110))	('cancers', 'Phenotype', 'HP:0002664', (103, 110))
378658	24700717	Epigenetic modifications, including DNA methylation, have been shown to play an integral role in carcinogenesis, cancer progression, and metastasis.	('play', 'Reg', (72, 76))	('carcinogenesis', 'Disease', (97, 111))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('DNA methylation', 'Var', (36, 51))	('cancer', 'Disease', (113, 119))	('Epigenetic modifications', 'Var', (0, 24))	('metastasis', 'CPA', (137, 147))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('carcinogenesis', 'Disease', 'MESH:D063646', (97, 111))
378659	24700717	Compared to normal tissues, tumors tend to be hypomethylated at intergenic distal regulatory regions and repetitive elements, which generally results in genomic instability, and hypermethylated at gene promoters, resulting in gene silencing.	('results in', 'Reg', (142, 152))	('tumors', 'Disease', (28, 34))	('tumors', 'Disease', 'MESH:D009369', (28, 34))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('hypermethylated', 'Var', (178, 193))	('hypomethylated', 'Var', (46, 60))	('gene', 'MPA', (226, 230))	('men', 'Species', '9606', (119, 122))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('genomic instability', 'MPA', (153, 172))
378660	24700717	Thus, quantification of epigenetic profiles across the genome can establish similarities or differences in tumor cell type of origin and can provide insight as to whether rare metastatic basal cancers actually represent a basal-like differentiation of squamous cell carcinomas.	('cancers', 'Disease', 'MESH:D009369', (193, 200))	('cancers', 'Phenotype', 'HP:0002664', (193, 200))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('cancers', 'Disease', (193, 200))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (252, 276))	('carcinoma', 'Phenotype', 'HP:0030731', (266, 275))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (252, 275))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (252, 276))	('carcinomas', 'Phenotype', 'HP:0030731', (266, 276))	('epigenetic profiles', 'Var', (24, 43))	('squamous cell carcinomas', 'Disease', (252, 276))
378691	24700717	A total of 444 individual CpG sites across 237 genes on the Goldengate Cancer Panel were linked to tumor suppression.	('tumor', 'Disease', (99, 104))	('CpG sites', 'Var', (26, 35))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('linked', 'Reg', (89, 95))	('Cancer', 'Phenotype', 'HP:0002664', (71, 77))
378722	24700717	For SCCs, there was no overall difference in mean methylation across all sites observed between the two groups (Wilcoxon p=0.18), while for BCCs, primary tumors that metastasized were more likely to be hypomethylated (Wilcoxon p=0.07; Figure 2).	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('primary tumors', 'Disease', (146, 160))	('BCC', 'Phenotype', 'HP:0002671', (140, 143))	('primary tumors', 'Disease', 'MESH:D009369', (146, 160))	('hypomethylated', 'Var', (202, 216))
378723	24700717	Additionally, comparing tumor suppressor methylation score as well as Polycomb Repressive Complex 2 occupancy score across metastatic and non-metastatic primary BCCs revealed a strong trend that had a similar pattern to that seen with mean methylation, with both tumor suppressor genes and PRC2 target genes hypomethylated in metastatic tumors, however, this did not reach statistical significance (Figure 2).	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumor', 'Phenotype', 'HP:0002664', (337, 342))	('tumor', 'Disease', 'MESH:D009369', (263, 268))	('tumor', 'Disease', (24, 29))	('tumor', 'Disease', (337, 342))	('tumor', 'Phenotype', 'HP:0002664', (263, 268))	('tumors', 'Disease', (337, 343))	('tumors', 'Disease', 'MESH:D009369', (337, 343))	('hypomethylated', 'Var', (308, 322))	('tumors', 'Phenotype', 'HP:0002664', (337, 343))	('tumor', 'Disease', (263, 268))	('BCC', 'Phenotype', 'HP:0002671', (161, 164))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('tumor', 'Disease', 'MESH:D009369', (337, 342))
378726	24700717	The top hit, a CpG site in the promoter region of FRZB, a modulator of Wnt signaling known to be involved in regulation of bone development, was found to be hypermethylated in metastatic (median methylation: 46.7%) compared to non-metastatic (median methylation: 4.7%) primary SCCs (p=4x10-5,q=0.14).	('men', 'Species', '9606', (135, 138))	('hypermethylated', 'Var', (157, 172))	('FRZB', 'Gene', (50, 54))	('metastatic', 'Disease', (176, 186))	('FRZB', 'Gene', '2487', (50, 54))
378727	24700717	Additionally, CpG sites associated with the developmental transcription factors TFAP2C and ASCL2 were also found to be hypermethylated in metastatic primary SCCs, while CpG sites associated with the actin protein ACTG2 were found to be hypomethylated in metastatic primary SCCs.	('ASCL2', 'Gene', '430', (91, 96))	('men', 'Species', '9606', (51, 54))	('hypermethylated', 'Var', (119, 134))	('metastatic primary SCCs', 'Disease', (138, 161))	('TFAP2C', 'Gene', (80, 86))	('ACTG2', 'Gene', '72', (213, 218))	('TFAP2C', 'Gene', '7022', (80, 86))	('ASCL2', 'Gene', (91, 96))	('ACTG2', 'Gene', (213, 218))
378730	24700717	Two CpG sites, both associated with the putative tumor suppressor gene MYCL2 (Figure 4), were found to be significantly hypomethylated in metastatic tumors compared to control primary BCC that did not metastasize (p=1.9x10-6, q=0.002 and p=3.7x10-5, q=0.028 respectively).	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('MYCL2', 'Gene', (71, 76))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('BCC', 'Phenotype', 'HP:0002671', (184, 187))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('tumor', 'Disease', (49, 54))	('tumors', 'Disease', (149, 155))	('tumors', 'Disease', 'MESH:D009369', (149, 155))	('tumor', 'Disease', (149, 154))	('hypomethylated', 'Var', (120, 134))	('tumors', 'Phenotype', 'HP:0002664', (149, 155))	('MYCL2', 'Gene', '4611', (71, 76))
378731	24700717	While not reaching statistical significance when adjusting for multiple comparisons (q<0.05), a number of other genes were also found to be differentially methylated (p<0.05) in metastatic BCCs (Supplementary Table 2).	('men', 'Species', '9606', (201, 204))	('differentially', 'Reg', (140, 154))	('metastatic BCCs', 'Disease', (178, 193))	('methylated', 'Var', (155, 165))	('BCC', 'Phenotype', 'HP:0002671', (189, 192))
378739	24700717	We identified epigenetic predictors of metastatic potential in both cSCC and BCC, with metastatic cSCC primaries hypermethylated at FRZB and metastatic BCC primaries hypomethylated at MYCL2.	('BCC', 'Phenotype', 'HP:0002671', (152, 155))	('cSCC', 'Phenotype', 'HP:0006739', (98, 102))	('cSCC', 'Phenotype', 'HP:0006739', (68, 72))	('FRZB', 'Gene', (132, 136))	('hypermethylated', 'Var', (113, 128))	('MYCL2', 'Gene', '4611', (184, 189))	('BCC', 'Phenotype', 'HP:0002671', (77, 80))	('metastatic potential', 'CPA', (39, 59))	('FRZB', 'Gene', '2487', (132, 136))	('MYCL2', 'Gene', (184, 189))
378745	24700717	Additionally, promoter methylation of FRZB was associated with a higher grade in non-invasive bladder cancer cases.	('bladder cancer', 'Disease', 'MESH:D001749', (94, 108))	('bladder cancer', 'Disease', (94, 108))	('promoter methylation', 'Var', (14, 34))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('FRZB', 'Gene', (38, 42))	('invasive bladder', 'Phenotype', 'HP:0100645', (85, 101))	('FRZB', 'Gene', '2487', (38, 42))	('bladder cancer', 'Phenotype', 'HP:0009725', (94, 108))	('higher', 'PosReg', (65, 71))	('associated', 'Reg', (47, 57))
378747	24700717	Our results, combined with previous findings, suggest that FRZB methylation could serve as a biomarker of tumor aggressiveness or metastatic potential at multiple cancer sites.	('tumor aggressiveness', 'Disease', (106, 126))	('FRZB', 'Gene', (59, 63))	('methylation', 'Var', (64, 75))	('aggressiveness', 'Phenotype', 'HP:0000718', (112, 126))	('FRZB', 'Gene', '2487', (59, 63))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (106, 126))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('metastatic potential', 'CPA', (130, 150))	('cancer', 'Disease', (163, 169))	('cancer', 'Disease', 'MESH:D009369', (163, 169))
378748	24700717	Metastatic BCCs were found to be hypomethylated across the genome, as well as at tumor suppressor genes and PRC2 target genes (Figure 2).	('hypomethylated', 'Var', (33, 47))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('BCC', 'Phenotype', 'HP:0002671', (11, 14))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('Metastatic BCCs', 'CPA', (0, 15))	('tumor', 'Disease', (81, 86))
378753	24700717	Of interest in the gene list with borderline significance, GNG7, involved in transmembrane signaling, has been shown to be hypermethylated in head and neck squamous cell carcinoma and fibroblast growth factor 9 (FGF9) is upregulated in cutaneous squamous cell carcinomas.	('GNG7', 'Gene', '2788', (59, 63))	('cutaneous squamous cell carcinomas', 'Disease', (236, 270))	('fibroblast growth factor 9', 'Gene', (184, 210))	('hypermethylated', 'Var', (123, 138))	('cutaneous squamous cell carcinomas', 'Disease', 'MESH:D002294', (236, 270))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (246, 269))	('neck squamous cell carcinoma', 'Disease', (151, 179))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (151, 179))	('FGF9', 'Gene', (212, 216))	('fibroblast growth factor 9', 'Gene', '2254', (184, 210))	('cutaneous squamous cell carcinoma', 'Phenotype', 'HP:0006739', (236, 269))	('FGF9', 'Gene', '2254', (212, 216))	('cutaneous squamous cell carcinomas', 'Phenotype', 'HP:0006739', (236, 270))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (156, 179))	('carcinoma', 'Phenotype', 'HP:0030731', (260, 269))	('carcinomas', 'Phenotype', 'HP:0030731', (260, 270))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (246, 270))	('carcinoma', 'Phenotype', 'HP:0030731', (170, 179))	('GNG7', 'Gene', (59, 63))	('upregulated', 'PosReg', (221, 232))
378764	24700717	However, epigenetic modification of functionally important genes may hold special significance in the improved management of metastatic cutaneous disease.	('cutaneous disease', 'Disease', 'MESH:D018366', (136, 153))	('epigenetic modification', 'Var', (9, 32))	('cutaneous disease', 'Disease', (136, 153))	('men', 'Species', '9606', (117, 120))
378901	29915168	Our results indicated that high dose CCRT was significantly associated with higher OS (P=0.026) and PFS (P=0.037) compared with low-dose CCRT.	('OS', 'Chemical', '-', (83, 85))	('CR', 'Chemical', '-', (138, 140))	('high dose', 'Var', (27, 36))	('PFS', 'CPA', (100, 103))	('CR', 'Chemical', '-', (38, 40))	('higher', 'PosReg', (76, 82))
378902	29915168	Compared with the excessive-dose group, high-dose CCRT tended to prolong the OS (P=0.033), as shown in Figure 4.	('prolong', 'PosReg', (65, 72))	('CR', 'Chemical', '-', (51, 53))	('high-dose CCRT', 'Var', (40, 54))	('OS', 'Chemical', '-', (77, 79))
378944	29915168	In recent years, due to the application of 3DRT and IMRT, higher doses can be administered, and greater biological effects can be achieved at the tumor area.	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('3DRT', 'Var', (43, 47))	('tumor', 'Disease', (146, 151))	('biological', 'MPA', (104, 114))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
378963	29915168	In addition, compared with a standard or excessive CCRT dose, high-dose CCRT generates more favorable survival outcomes.	('CR', 'Chemical', '-', (52, 54))	('CR', 'Chemical', '-', (73, 75))	('high-dose', 'Var', (62, 71))	('survival', 'CPA', (102, 110))
378972	33789221	Fifty-four percent of non-metastatic ASCC cases displayed mutations affecting cancer driver genes such as PIK3CA (21% of cases), TP53 (15%), FBXW7 (9%), and APC (6%).	('mutations', 'Var', (58, 67))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('APC', 'Disease', 'MESH:D011125', (157, 160))	('PIK3CA', 'Gene', (106, 112))	('cancer', 'Disease', (78, 84))	('PIK3CA', 'Gene', '5290', (106, 112))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('APC', 'Disease', (157, 160))	('non-metastatic ASCC', 'Disease', (22, 41))	('FBXW7', 'Gene', (141, 146))	('TP53', 'Gene', (129, 133))
378984	33789221	Low TIL density was found to be significantly associated with a decreased relapse-free rate (63%) compared with ASCC patients with high TIL density (92%).	('patients', 'Species', '9606', (117, 125))	('Low TIL density', 'Var', (0, 15))	('relapse-free rate', 'CPA', (74, 91))	('decreased', 'NegReg', (64, 73))
378985	33789221	Mutations affecting cancer driver genes such as PIK3CA and TP53 were also reported in ASCC.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('TP53', 'Gene', (59, 63))	('ASCC', 'Disease', (86, 90))	('PIK3CA', 'Gene', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (20, 26))	('Mutations', 'Var', (0, 9))	('cancer', 'Disease', (20, 26))	('PIK3CA', 'Gene', '5290', (48, 54))
378990	33789221	In addition to high-risk HPV infections, TP53 wild-type status and p16 protein overexpression have been proposed as predictive biomarkers of a better response to standard therapy in oropharyngeal and anogenital SCC.	('oropharyngeal', 'Disease', (182, 195))	('p16', 'Gene', '1029', (67, 70))	('HPV infections', 'Disease', 'MESH:D030361', (25, 39))	('p16', 'Gene', (67, 70))	('anogenital SCC', 'Disease', (200, 214))	('overexpression', 'PosReg', (79, 93))	('HPV infections', 'Disease', (25, 39))	('TP53', 'Var', (41, 45))
379011	33789221	DNA libraries were prepared with 100 ng of genomic DNA using the AmpliSeqTM for Illumina Cancer Hotspot Panel v2 Kit that allow the detection of 2800 COSMIC mutations from 50 oncogenes and tumor suppressor genes.	('Illumina Cancer', 'Disease', 'MESH:D009369', (80, 95))	('tumor', 'Disease', (189, 194))	('Cancer', 'Phenotype', 'HP:0002664', (89, 95))	('Kit', 'Gene', (113, 116))	('mutations', 'Var', (157, 166))	('Illumina Cancer', 'Disease', (80, 95))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('Kit', 'Gene', '3815', (113, 116))
379033	33789221	Whereas high-risk HPV-DNA (types -16, -18, -33 or -45) was detected in 95% of positive samples (63 out of 66), the remaining infected samples were positive for low-risk HPV genotypes (types -6, -11, -42 or -44).	('HPV', 'Species', '10566', (18, 21))	('types -6, -11, -42 or -44', 'Gene', 'None', (184, 209))	('infected', 'Disease', 'MESH:D007239', (125, 133))	('HPV', 'Species', '10566', (169, 172))	('types -16', 'Var', (27, 36))	('HPV-DNA', 'Gene', (18, 25))	('infected', 'Disease', (125, 133))
379046	33789221	Targeted DNA sequencing was performed in pretreatment biopsies from 44 patients using the Illumina Cancer Hotspot Panel v2, that allow the identification of 2800 COSMIC somatic mutations across 50 cancer driver genes.	('men', 'Species', '9606', (49, 52))	('cancer', 'Disease', 'MESH:D009369', (197, 203))	('Cancer', 'Phenotype', 'HP:0002664', (99, 105))	('patients', 'Species', '9606', (71, 79))	('cancer', 'Disease', (197, 203))	('mutations', 'Var', (177, 186))	('Illumina Cancer', 'Disease', (90, 105))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('Illumina Cancer', 'Disease', 'MESH:D009369', (90, 105))
379047	33789221	We detected 30 somatic mutations among 54% of ASCC cases (18 out of 33) including 28 nonsynonymous substitution, a frameshift InDel and a mutation at splicing sites (Supplementary Data 1).	('nonsynonymous substitution', 'Var', (85, 111))	('ASCC', 'Disease', (46, 50))	('men', 'Species', '9606', (172, 175))	('frameshift InDel', 'Var', (115, 131))
379048	33789221	Among these, we detected mutations affecting PIK3CA (21%), TP53 (15%), FBXW7 (9%), APC (6%) and single cases of mutations affecting KRAS, ATM, PTEN, RB1, JAK2, JAK3, NOTCH1, ERBB4, FGFR3 and KIT (Fig.	('KIT', 'Gene', '3815', (191, 194))	('JAK3', 'Gene', (160, 164))	('RB1', 'Gene', (149, 152))	('KRAS', 'Gene', (132, 136))	('FGFR3', 'Gene', (181, 186))	('PIK3CA', 'Gene', (45, 51))	('JAK2', 'Gene', (154, 158))	('FGFR3', 'Gene', '2261', (181, 186))	('mutations', 'Var', (25, 34))	('TP53', 'Gene', (59, 63))	('ERBB4', 'Gene', '2066', (174, 179))	('NOTCH1', 'Gene', (166, 172))	('JAK3', 'Gene', '3718', (160, 164))	('ERBB4', 'Gene', (174, 179))	('RB1', 'Gene', '5925', (149, 152))	('NOTCH1', 'Gene', '4851', (166, 172))	('ATM', 'Gene', '472', (138, 141))	('KIT', 'Gene', (191, 194))	('PIK3CA', 'Gene', '5290', (45, 51))	('PTEN', 'Gene', (143, 147))	('APC', 'Disease', 'MESH:D011125', (83, 86))	('APC', 'Disease', (83, 86))	('JAK2', 'Gene', '3717', (154, 158))	('KRAS', 'Gene', '3845', (132, 136))	('PTEN', 'Gene', '5728', (143, 147))	('ATM', 'Gene', (138, 141))
379049	33789221	Regions of potential focal amplification of PIK3CA and PTEN deletion were identified in only two ASCC cases (Fig.	('PIK3CA', 'Gene', (44, 50))	('PTEN', 'Gene', '5728', (55, 59))	('deletion', 'Var', (60, 68))	('PIK3CA', 'Gene', '5290', (44, 50))	('PTEN', 'Gene', (55, 59))
379051	33789221	A total of 10 PIK3CA alterations were observed in 8 samples, with two samples harboring multiple alterations (two mutations or mutation and gene amplification), and the majority were known oncogenic mutations (E545K, E542K).	('E542K', 'Mutation', 'rs121913273', (217, 222))	('E545K', 'Mutation', 'rs104886003', (210, 215))	('PIK3CA', 'Gene', (14, 20))	('E545K', 'Var', (210, 215))	('PIK3CA', 'Gene', '5290', (14, 20))	('E542K', 'Var', (217, 222))
379055	33789221	Interestingly, mutations previously reported by Exome-seq in metastatic ASCC were no detected in an Exome-seq study of localized ASCC and in our non-metastatic ASCC cohort, such as AKT1, BRAF, EGFR, FGFR2 and NRAS.	('AKT1', 'Gene', '207', (181, 185))	('metastatic ASCC', 'Disease', (61, 76))	('AKT1', 'Gene', (181, 185))	('BRAF', 'Gene', '673', (187, 191))	('mutations', 'Var', (15, 24))	('EGFR', 'Gene', '1956', (193, 197))	('FGFR2', 'Gene', '2263', (199, 204))	('EGFR', 'Gene', (193, 197))	('NRAS', 'Gene', (209, 213))	('NRAS', 'Gene', '4893', (209, 213))	('FGFR2', 'Gene', (199, 204))	('BRAF', 'Gene', (187, 191))
379057	33789221	In agreement with previous studies, we identified an average low mutation burden in non-metastatic ASCC, except for two cases with a higher mutational burden, one of them with a TP53 mutation and in which no mutations were detected in the MLH1 mismatch repair gene.	('MLH1', 'Gene', '4292', (239, 243))	('MLH1', 'Gene', (239, 243))	('men', 'Species', '9606', (8, 11))	('non-metastatic ASCC', 'Disease', (84, 103))	('mutation', 'Var', (183, 191))	('mutation burden', 'MPA', (65, 80))
379061	33789221	Interestingly, PIK3CA and FBXW7 mutations have also been reported in cervical squamous cell carcinomas and HPV-positive HNSCC.	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (78, 102))	('squamous cell carcinomas', 'Disease', (78, 102))	('PIK3CA', 'Gene', '5290', (15, 21))	('FBXW7', 'Gene', (26, 31))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (78, 102))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('HPV', 'Species', '10566', (107, 110))	('mutations', 'Var', (32, 41))	('carcinomas', 'Phenotype', 'HP:0030731', (92, 102))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (78, 101))	('reported', 'Reg', (57, 65))	('PIK3CA', 'Gene', (15, 21))
379065	33789221	Conversely, FBXW7 is a tumor suppressor gene which expression increases following TP53 activation, causes tumorigenesis in wild-type TP53 and FBXW7 mutated mice.	('TP53', 'Gene', (82, 86))	('activation', 'PosReg', (87, 97))	('FBXW7', 'Gene', (12, 17))	('causes', 'Reg', (99, 105))	('increases', 'PosReg', (62, 71))	('mutated', 'Var', (148, 155))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('expression', 'MPA', (51, 61))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('mice', 'Species', '10090', (156, 160))	('tumor', 'Disease', (23, 28))	('tumor', 'Disease', (106, 111))
379066	33789221	In this sense, FBXW7 mutations were exclusively detected in HPV-positive and TP53 wild-type ASCC cases (Fig.	('HPV', 'Species', '10566', (60, 63))	('mutations', 'Var', (21, 30))	('FBXW7', 'Gene', (15, 20))	('detected', 'Reg', (48, 56))
379067	33789221	No less relevant, FBXW7 causes proteasome-mediated degradation of NOTCH1, mTOR and several cancer driver genes such as CMYC, CCNE and JUN .	('JUN', 'Disease', (134, 137))	('proteasome-mediated degradation', 'MPA', (31, 62))	('CMYC', 'Gene', (119, 123))	('cancer', 'Disease', (91, 97))	('CCNE', 'Gene', (125, 129))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('mTOR', 'Gene', (74, 78))	('CMYC', 'Gene', '4609', (119, 123))	('mTOR', 'Gene', '2475', (74, 78))	('FBXW7', 'Var', (18, 23))	('NOTCH1', 'Gene', '4851', (66, 72))	('CCNE', 'Gene', '898', (125, 129))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('NOTCH1', 'Gene', (66, 72))
379068	33789221	Mutational inactivation of FBXW7 may promote proliferative and survival signaling through PI3K/AKT/mTOR, TP53 and NOTCH pathways in non-metastatic ASCC.	('NOTCH pathways', 'Pathway', (114, 128))	('proliferative', 'MPA', (45, 58))	('TP53', 'Pathway', (105, 109))	('promote', 'PosReg', (37, 44))	('AKT', 'Gene', '207', (95, 98))	('Mutational inactivation', 'Var', (0, 23))	('non-metastatic ASCC', 'Disease', (132, 151))	('FBXW7', 'Gene', (27, 32))	('AKT', 'Gene', (95, 98))	('mTOR', 'Gene', '2475', (99, 103))	('mTOR', 'Gene', (99, 103))
379076	33789221	When the CD3 and CD8 TIL distribution patterns were evaluated, a peritumoral infiltrating pattern was predominantly detected among moderate to high CD3 and CD8 tumors (80% and 64%, respectively) compared with the intratumoral / mixed patterns (20% and 36%, respectively).	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('detected', 'Reg', (116, 124))	('tumors', 'Disease', (160, 166))	('tumor', 'Disease', (218, 223))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('CD8', 'Gene', (17, 20))	('tumor', 'Disease', 'MESH:D009369', (218, 223))	('tumors', 'Disease', 'MESH:D009369', (160, 166))	('CD8', 'Gene', '925', (156, 159))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('tumor', 'Disease', (160, 165))	('moderate', 'Var', (131, 139))	('tumor', 'Disease', (69, 74))	('CD8', 'Gene', '925', (17, 20))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('CD3', 'Gene', (148, 151))	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('CD8', 'Gene', (156, 159))
379090	33789221	Moreover, increased CD3 and CD8 TILs were detected in high PD-L1 expressing tumors compared with low PD-L1 (p<0.05) and PD-L1 negative (p<0.001) tumors (Fig.	('CD8', 'Gene', (28, 31))	('PD-L1', 'Gene', (120, 125))	('PD-L1', 'Gene', '29126', (120, 125))	('tumors', 'Disease', 'MESH:D009369', (145, 151))	('high', 'Var', (54, 58))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('increased', 'PosReg', (10, 19))	('PD-L1', 'Gene', (101, 106))	('PD-L1', 'Gene', '29126', (101, 106))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('tumors', 'Disease', (76, 82))	('PD-L1', 'Gene', (59, 64))	('CD8', 'Gene', '925', (28, 31))	('PD-L1', 'Gene', '29126', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumors', 'Disease', (145, 151))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('CD3', 'MPA', (20, 23))
379121	31159869	Additionally, PD-L1, but not PD-L2, can bind to the cluster of differentiation 80 (CD80), which can result in a bidirectional immune inhibitory response.	('result in', 'Reg', (100, 109))	('bidirectional immune inhibitory response', 'MPA', (112, 152))	('CD80', 'Gene', '941', (83, 87))	('bind', 'Interaction', (40, 44))	('CD80', 'Gene', (83, 87))	('PD-L1', 'Var', (14, 19))
379122	31159869	Conversely, PD-L2, but not PD-L1, can bind the repulsive guidance molecule B (RGMB) receptor, a co-receptor for bone morphogenetic protein (BMP).	('bone morphogenetic protein', 'Gene', (112, 138))	('repulsive guidance molecule B', 'Gene', (47, 76))	('BMP', 'Gene', (140, 143))	('bone morphogenetic protein', 'Gene', '649', (112, 138))	('RGMB', 'Gene', (78, 82))	('repulsive guidance molecule B', 'Gene', '285704', (47, 76))	('BMP', 'Gene', '649', (140, 143))	('bind', 'Interaction', (38, 42))	('RGMB', 'Gene', '285704', (78, 82))	('PD-L2', 'Var', (12, 17))
379127	31159869	In general, PD-L2 expression is less prevalent than PD-L1 expression in cancer cells.	('cancer', 'Disease', (72, 78))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('PD-L2', 'Var', (12, 17))
379129	31159869	PD-L1 and PD-L2 mRNA expression can also be upregulated due to cancer cell-autonomous mechanisms, for example, mutation depending oncogenic signaling, resulting in intrinsic immune resistance.	('intrinsic immune resistance', 'MPA', (164, 191))	('mRNA expression', 'MPA', (16, 31))	('upregulated', 'PosReg', (44, 55))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('PD-L1', 'Gene', (0, 5))	('mutation', 'Var', (111, 119))	('PD-L2', 'Gene', (10, 15))	('cancer', 'Disease', (63, 69))
379133	31159869	Analysis of subgroups defined by PD-L1 expression showed that PD-L1 TPS >= 1%, >= 5%, and >= 10% were associated with improved response rates (31%, 36%, and 37%, respectively) in the CheckMate 057, whereas, an association between PD-L1 TPS and response rate was not evident from the CheckMate 017.	('>= 5%', 'Var', (79, 84))	('improved', 'PosReg', (118, 126))	('rat', 'Species', '10116', (253, 256))	('response', 'MPA', (127, 135))	('rat', 'Species', '10116', (136, 139))	('PD-L1', 'Gene', (62, 67))	('TPS >= 1%', 'Var', (68, 77))	('>= 10%', 'Var', (90, 96))
379134	31159869	In the KEYNOTE-001 and KEYNOTE-24 trials, which were the first trials to use first- and second-line therapies with PD-1 antibody, pembrolizumab, in advanced NSCLC patients, PD-L1 TPS >= 50% resulted in response rates of 52% and 45%, respectively.	('patients', 'Species', '9606', (163, 171))	('rat', 'Species', '10116', (211, 214))	('NSCLC', 'Phenotype', 'HP:0030358', (157, 162))	('pembrolizumab', 'Chemical', 'MESH:C582435', (130, 143))	('NSCLC', 'Disease', (157, 162))	('PD-L1 TPS', 'Var', (173, 182))	('NSCLC', 'Disease', 'MESH:D002289', (157, 162))
379238	31159869	In cancer, loss of function mutations in JAK2 are relatively often observed and can in principle result in decreased antigen presentation, lack of T cell infiltrates, tumor cell resistance to the anti-proliferative effects of IFN-gamma, and can prevent adaptive PD-L1 and PD-L2 expression upon IFN-gamma exposure.	('rat', 'Species', '10116', (160, 163))	('rat', 'Species', '10116', (208, 211))	('JAK2', 'Gene', (41, 45))	('lack', 'NegReg', (139, 143))	('IFN-gamma', 'Gene', '3458', (294, 303))	('IFN-gamma', 'Gene', (294, 303))	('prevent', 'NegReg', (245, 252))	('PD-L2', 'Protein', (272, 277))	('expression', 'MPA', (278, 288))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('loss of function', 'NegReg', (11, 27))	('IFN-gamma', 'Gene', '3458', (226, 235))	('IFN-gamma', 'Gene', (226, 235))	('tumor', 'Disease', (167, 172))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('antigen presentation', 'MPA', (117, 137))	('mutations', 'Var', (28, 37))	('PD-L1', 'Protein', (262, 267))	('JAK2', 'Gene', '3717', (41, 45))	('decreased', 'NegReg', (107, 116))	('cancer', 'Disease', (3, 9))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
379240	31159869	In LUSC, Chr9p21.3 allelic deletions of the tumor suppressor gene Cyclin-dependent kinase inhibitor 2A (CDKN2A) can, in addition, include co-deletion of JAK2, PD-L1, PD-L2.	('CDKN2A', 'Gene', '1029', (104, 110))	('PD-L2', 'Gene', (166, 171))	('JAK2', 'Gene', (153, 157))	('co-deletion', 'Var', (138, 149))	('Cyclin-dependent kinase inhibitor 2A', 'Gene', '1029', (66, 102))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('Cyclin-dependent kinase inhibitor 2A', 'Gene', (66, 102))	('JAK2', 'Gene', '3717', (153, 157))	('CDKN2A', 'Gene', (104, 110))	('tumor', 'Disease', (44, 49))	('PD-L1', 'Gene', (159, 164))
379241	31159869	Moreover, co-amplification of JAK2 and PD-L1 is observed in NSCLC and patients with JAK2 and PD-L1 co-amplification has a poorer overall survival and recurrence-free survival compared to patients with normal PD-L1 copy number.	('patients', 'Species', '9606', (70, 78))	('patients', 'Species', '9606', (187, 195))	('PD-L1', 'Gene', (39, 44))	('JAK2', 'Gene', (84, 88))	('recurrence-free survival', 'CPA', (150, 174))	('co-amplification', 'Var', (99, 115))	('JAK2', 'Gene', '3717', (30, 34))	('NSCLC', 'Disease', (60, 65))	('NSCLC', 'Phenotype', 'HP:0030358', (60, 65))	('JAK2', 'Gene', (30, 34))	('overall survival', 'CPA', (129, 145))	('co-amplification', 'Var', (10, 26))	('PD-L1', 'Gene', (93, 98))	('poorer', 'NegReg', (122, 128))	('JAK2', 'Gene', '3717', (84, 88))	('NSCLC', 'Disease', 'MESH:D002289', (60, 65))
379242	31159869	Copy number variation (CNV) is a characteristic of NSCLC and drives the expression profile of underlying genes.	('Copy number variation', 'Var', (0, 21))	('NSCLC', 'Disease', (51, 56))	('drives', 'Reg', (61, 67))	('NSCLC', 'Disease', 'MESH:D002289', (51, 56))	('expression profile', 'MPA', (72, 90))	('NSCLC', 'Phenotype', 'HP:0030358', (51, 56))
379269	29331675	True cancer driver genes are those whose perturbation pushes a cell towards a malignant phenotype.	('cancer', 'Disease', 'MESH:D009369', (5, 11))	('pushes', 'PosReg', (54, 60))	('cancer', 'Disease', (5, 11))	('perturbation', 'Var', (41, 53))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))
379270	29331675	Within this study, we define cancer driver genes as genes that fulfill all of the following criteria: (1) genes that are genetically and/or epigenetically deregulated in cancer, (2) genes whose genetic and epigenetic aberrations have a direct impact on their own functional gene expression levels, and (3) genes that are predicted to play regulatory roles high in the causal hierarchy of the origin of tumors.	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('cancer', 'Disease', (29, 35))	('tumors', 'Phenotype', 'HP:0002664', (402, 408))	('cancer', 'Disease', (170, 176))	('tumors', 'Disease', (402, 408))	('tumors', 'Disease', 'MESH:D009369', (402, 408))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('impact', 'Reg', (243, 249))	('functional gene expression levels', 'MPA', (263, 296))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('epigenetic aberrations', 'Var', (206, 228))	('cancer', 'Disease', 'MESH:D009369', (29, 35))	('tumor', 'Phenotype', 'HP:0002664', (402, 407))
379271	29331675	These include, for example, transcription factors, cell cycle genes or epigenetic modifying enzymes, whose altered state in cancer results in deregulation of downstream target genes; as well as upstream signaling molecules.	('cancer', 'Disease', (124, 130))	('deregulation', 'MPA', (142, 154))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('epigenetic modifying enzymes', 'Var', (71, 99))	('cell cycle genes', 'Gene', (51, 67))	('cancer', 'Disease', 'MESH:D009369', (124, 130))
379277	29331675	Integration of epigenomics data is essential to comprehensive analysis of cancer genomic analysis, as DNA methylation is a major mechanism of transcriptional deregulation in virtually all cancers.	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancers', 'Phenotype', 'HP:0002664', (188, 195))	('methylation', 'Var', (106, 117))	('cancers', 'Disease', (188, 195))	('cancer', 'Disease', (74, 80))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('cancers', 'Disease', 'MESH:D009369', (188, 195))	('cancer', 'Disease', (188, 194))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
379278	29331675	For example, cancer driver genes such as BRCA1 and MLH1, which are often altered by mutation in cancer, are also frequently deregulated by DNA methylation in other patients, with similar downstream consequences.	('deregulated', 'PosReg', (124, 135))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('BRCA1', 'Gene', '672', (41, 46))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('DNA methylation', 'Var', (139, 154))	('BRCA1', 'Gene', (41, 46))	('MLH1', 'Gene', '4292', (51, 55))	('cancer', 'Disease', (13, 19))	('cancer', 'Disease', 'MESH:D009369', (13, 19))	('MLH1', 'Gene', (51, 55))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('patients', 'Species', '9606', (164, 172))	('BRCA', 'Phenotype', 'HP:0003002', (41, 45))	('cancer', 'Disease', (96, 102))	('mutation', 'Var', (84, 92))
379295	29331675	To establish a list of cancer driver genes, we thus investigate the linear effects of copy number and DNA methylation on gene expression through a linear regression model performed on each gene independently: We used the R2 statistic to evaluate whether copy number has a significant positive effect (beta2 > 0) and DNA methylation a significant negative effect (beta1 < 0) on gene expression.	('positive', 'PosReg', (284, 292))	('negative', 'NegReg', (346, 354))	('beta2', 'Gene', (301, 306))	('cancer', 'Disease', (23, 29))	('cancer', 'Disease', 'MESH:D009369', (23, 29))	('copy number', 'Var', (254, 265))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('beta2', 'Gene', '10383', (301, 306))
379315	29331675	Four perturbation experiments measuring experimental targets of GPX2 knockdown in the A549 cell line were available in LINCS, including three shRNA experiments and a consensus signature derived from these three experiments.	('GPX2', 'Gene', '2877', (64, 68))	('A549', 'CellLine', 'CVCL:0023', (86, 90))	('knockdown', 'Var', (69, 78))	('GPX2', 'Gene', (64, 68))
379316	29331675	In one of these four experiments, a positive differential expression z-score for GPX2 was measured, and we therefore removed this experiment from the analysis since successful GPX2 knockdown is expected to result in a negative z-score.	('GPX2', 'Gene', '2877', (176, 180))	('GPX2', 'Gene', (176, 180))	('expression', 'MPA', (58, 68))	('GPX2', 'Gene', '2877', (81, 85))	('z-score', 'MPA', (227, 234))	('GPX2', 'Gene', (81, 85))	('knockdown', 'Var', (181, 190))
379325	29331675	AMARETTO modules capture the major oncogenic pathways whereas randomly permuted modules do not result in significant gene sets in all cancer sites (Fig.	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('oncogenic pathways', 'Pathway', (35, 53))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('AMARETTO', 'Var', (0, 8))
379335	29331675	Interestingly, for all cancers, a higher proportion of selected drivers are DNA methylation driven compared to DNA copy number driven genes (Supplementary Fig.	('cancers', 'Disease', 'MESH:D009369', (23, 30))	('cancers', 'Phenotype', 'HP:0002664', (23, 30))	('cancers', 'Disease', (23, 30))	('methylation', 'Var', (80, 91))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))
379337	29331675	We found that adding methylation driver genes led to an averaged R-squared increase of between 6% for LUSC up to 16% for BRCA when predicting cognate gene expression (Fig.	('BRCA', 'Phenotype', 'HP:0003002', (121, 125))	('BRCA', 'Gene', '672', (121, 125))	('methylation', 'Var', (21, 32))	('BRCA', 'Gene', (121, 125))	('LUSC', 'Phenotype', 'HP:0030359', (102, 106))	('increase', 'PosReg', (75, 83))
379360	29331675	We observed that the target genes of these modules that are activated by induced GPX2 expression are significantly repressed upon knockdown of GPX2 in the A549 cell line.	('knockdown', 'Var', (130, 139))	('A549', 'CellLine', 'CVCL:0023', (155, 159))	('activated', 'PosReg', (60, 69))	('GPX2', 'Gene', '2877', (143, 147))	('GPX2', 'Gene', '2877', (81, 85))	('GPX2', 'Gene', (81, 85))	('GPX2', 'Gene', (143, 147))	('expression', 'Var', (86, 96))
379380	29331675	To investigate this further, we tested the correlation of OAS2, as a marker of the IFN-responsive/M1 TAM signature, with both ligands for the immune checkpoint receptor PD-1: CD274, the gene encoding PD-L1, and PDCD1LG2, encoding PD-L2.	('tested', 'Reg', (32, 38))	('TAM', 'Chemical', '-', (101, 104))	('CD274', 'Var', (175, 180))	('IFN', 'Gene', '3439', (83, 86))	('PDCD1LG2', 'Gene', '80380', (211, 219))	('PD-L2', 'Gene', (230, 235))	('PD-L2', 'Gene', '80380', (230, 235))	('PD-1', 'Gene', (169, 173))	('PD-1', 'Gene', '5133', (169, 173))	('PDCD1LG2', 'Gene', (211, 219))	('IFN', 'Gene', (83, 86))
379383	29331675	AMARETTO first identifies cancer drivers, by considering genes with either DNA copy number or DNA methylation aberrations that have an effect on gene expression.	('cancer', 'Disease', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('effect', 'Reg', (135, 141))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('methylation aberrations', 'Var', (98, 121))	('gene expression', 'MPA', (145, 160))
379406	29331675	Given that OAS2 is a viral dsRNA sensor, and all of the IFN response subnetwork regulators were abnormally methylated, it is plausible that expression of this subnetwork reflects response to reactivation of HERVs, a frequent event in, and potential cause of, many cancers.	('IFN', 'Gene', (56, 59))	('abnormally', 'Var', (96, 106))	('cancers', 'Disease', 'MESH:D009369', (264, 271))	('cancers', 'Disease', (264, 271))	('cancers', 'Phenotype', 'HP:0002664', (264, 271))	('cancer', 'Phenotype', 'HP:0002664', (264, 270))	('HERVs', 'Species', '206037', (207, 212))	('IFN', 'Gene', '3439', (56, 59))	('HERVs', 'Protein', (207, 212))
379426	28507621	Expression of FGFR3 Protein and Gene Amplification in Urinary Bladder Lesions in Relation to Schistosomiasis Bladder cancer represents the fifth most common malignancy worldwide and a major cause of cancer-related morbidity and death.	('malignancy', 'Disease', 'MESH:D009369', (157, 167))	('death', 'Disease', (228, 233))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('Protein', 'Protein', (20, 27))	('malignancy', 'Disease', (157, 167))	('FGFR3', 'Gene', '2261', (14, 19))	('Schistosomiasis Bladder', 'Phenotype', 'HP:0001981', (93, 116))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('Schistosomiasis', 'Disease', (93, 108))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('FGFR3', 'Gene', (14, 19))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('Schistosomiasis', 'Disease', 'MESH:D012552', (93, 108))	('Gene Amplification', 'Var', (32, 50))	('cancer', 'Disease', (199, 205))	('Bladder cancer', 'Phenotype', 'HP:0009725', (109, 123))	('cancer', 'Disease', (117, 123))	('death', 'Disease', 'MESH:D003643', (228, 233))
379435	28507621	FGFR3 gene amplification was reported mainly in low grade and NNMBIC tumours.	('tumours', 'Disease', (69, 76))	('low grade', 'Disease', (48, 57))	('FGFR3', 'Gene', (0, 5))	('tumour', 'Phenotype', 'HP:0002664', (69, 75))	('tumours', 'Phenotype', 'HP:0002664', (69, 76))	('tumours', 'Disease', 'MESH:D009369', (69, 76))	('amplification', 'Var', (11, 24))	('FGFR3', 'Gene', '2261', (0, 5))
379446	28507621	Activating mutations and overexpression of FGFR3 are common in urothelial tumours with low malignant potential and low-stage and -grade urothelial carcinomas and are associated with a lower risk of progression and better survival in some subgroups.	('urothelial carcinomas', 'Disease', (136, 157))	('tumours', 'Phenotype', 'HP:0002664', (74, 81))	('Activating mutations', 'Var', (0, 20))	('FGFR3', 'Gene', (43, 48))	('urothelial tumours', 'Disease', (63, 81))	('urothelial carcinomas', 'Disease', 'MESH:D014526', (136, 157))	('FGFR3', 'Gene', '2261', (43, 48))	('tumour', 'Phenotype', 'HP:0002664', (74, 80))	('urothelial tumours', 'Disease', 'MESH:D014523', (63, 81))	('overexpression', 'PosReg', (25, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (147, 156))	('carcinomas', 'Phenotype', 'HP:0030731', (147, 157))
379447	28507621	FGFR3 mutations are linked to favourable (low grade/stage) pTa bladder cancer.	('bladder cancer', 'Disease', 'MESH:D001749', (63, 77))	('bladder cancer', 'Disease', (63, 77))	('FGFR3', 'Gene', (0, 5))	('pTa bladder', 'Phenotype', 'HP:0000384', (59, 70))	('bladder cancer', 'Phenotype', 'HP:0009725', (63, 77))	('linked', 'Reg', (20, 26))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('mutations', 'Var', (6, 15))	('FGFR3', 'Gene', '2261', (0, 5))
379448	28507621	Fibroblast Growth Factor receptor 3 (FGFR3) mutations are most common in low-risk NMIBC (non-muscle invasive bladder cancer), a subset of MIBC (muscle invasive bladder cancer) that carries FGFR3 mutations shows particularly poor prognosis.	('common', 'Reg', (63, 69))	('muscle invasive bladder cancer', 'Disease', 'MESH:D001749', (144, 174))	('non-muscle invasive bladder', 'Phenotype', 'HP:0000011', (89, 116))	('FGFR3', 'Gene', (189, 194))	('muscle invasive bladder cancer', 'Disease', (93, 123))	('FGFR3', 'Gene', '2261', (189, 194))	('FGFR3', 'Gene', (37, 42))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('NMIBC', 'Disease', (82, 87))	('NMIBC', 'Chemical', '-', (82, 87))	('muscle invasive bladder cancer', 'Disease', 'MESH:D001749', (93, 123))	('FGFR3', 'Gene', '2261', (37, 42))	('bladder cancer', 'Phenotype', 'HP:0009725', (160, 174))	('Fibroblast Growth Factor receptor 3', 'Gene', (0, 35))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('invasive bladder', 'Phenotype', 'HP:0100645', (151, 167))	('MIBC', 'Chemical', '-', (83, 87))	('mutations', 'Var', (195, 204))	('MIBC', 'Chemical', '-', (138, 142))	('Fibroblast Growth Factor receptor 3', 'Gene', '2261', (0, 35))	('bladder cancer', 'Phenotype', 'HP:0009725', (109, 123))	('-muscle invasive bladder cancer', 'Phenotype', 'HP:0006740', (92, 123))	('muscle invasive bladder cancer', 'Disease', (144, 174))	('invasive bladder', 'Phenotype', 'HP:0100645', (100, 116))	('mutations', 'Var', (44, 53))
379451	28507621	Subsequent larger studies established that FGFR3 mutations occur in around 50% of both lower and upper urinary tract tumours and these cluster in three distinct hotspots in exons 7, 10, and 15.	('mutations', 'Var', (49, 58))	('FGFR3', 'Gene', (43, 48))	('tumour', 'Phenotype', 'HP:0002664', (117, 123))	('upper urinary tract tumours', 'Disease', (97, 124))	('upper urinary tract tumours', 'Phenotype', 'HP:0010935', (97, 124))	('FGFR3', 'Gene', '2261', (43, 48))	('upper urinary tract tumours', 'Disease', 'MESH:D014571', (97, 124))	('tumours', 'Phenotype', 'HP:0002664', (117, 124))
379452	28507621	FGFR3 mutations are thought to induce a conformational change in the kinase domain resulting in ligand-independent receptor activation and signalling; they have also been shown to alter FGFR3 cellular localisation, inducing aberrant signalling from the endoplasmic reticulum.	('FGFR3', 'Gene', (0, 5))	('cellular localisation', 'MPA', (192, 213))	('FGFR3', 'Gene', '2261', (186, 191))	('FGFR3', 'Gene', (186, 191))	('signalling from the endoplasmic reticulum', 'MPA', (233, 274))	('inducing', 'Reg', (215, 223))	('alter', 'Reg', (180, 185))	('mutations', 'Var', (6, 15))	('FGFR3', 'Gene', '2261', (0, 5))
379453	28507621	FGFR3 mutation status was the strongest predictor of recurrence when compared with stage and grade.	('FGFR3', 'Gene', (0, 5))	('mutation', 'Var', (6, 14))	('FGFR3', 'Gene', '2261', (0, 5))
379454	28507621	This is the first mutation in bladder cancer that selectively identifies patients with favourable disease characteristics.	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('bladder cancer', 'Disease', 'MESH:D001749', (30, 44))	('bladder cancer', 'Disease', (30, 44))	('mutation', 'Var', (18, 26))	('patients', 'Species', '9606', (73, 81))	('bladder cancer', 'Phenotype', 'HP:0009725', (30, 44))
379455	28507621	While FGFR3 mutation or copy number gain is a rare event, studies of these tumours may shed light on how FGFR3 signalling contributes to urothelial carcinoma growth and proliferation.	('FGFR3', 'Gene', '2261', (6, 11))	('urothelial carcinoma growth', 'Disease', (137, 164))	('FGFR3', 'Gene', (105, 110))	('contributes', 'Reg', (122, 133))	('tumours', 'Disease', 'MESH:D009369', (75, 82))	('tumours', 'Disease', (75, 82))	('FGFR3', 'Gene', (6, 11))	('tumour', 'Phenotype', 'HP:0002664', (75, 81))	('proliferation', 'CPA', (169, 182))	('urothelial carcinoma growth', 'Disease', 'MESH:D006130', (137, 164))	('copy number', 'Var', (24, 35))	('FGFR3', 'Gene', '2261', (105, 110))	('mutation', 'Var', (12, 20))	('tumours', 'Phenotype', 'HP:0002664', (75, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (148, 157))
379459	28507621	In our study, we are aiming to evaluate the association of FGFR3 expression and gene mutation and its risk in the development of urothelial carcinoma (bilharzial and non-bilharzial), the effect on grading and staging of the tumour and the benefit of using this marker as a therapeutic target and diagnostic tool in bladder cancer patients.	('urothelial carcinoma', 'Disease', 'MESH:D014526', (129, 149))	('FGFR3', 'Gene', '2261', (59, 64))	('bilharzial', 'Chemical', '-', (151, 161))	('tumour', 'Phenotype', 'HP:0002664', (224, 230))	('FGFR3', 'Gene', (59, 64))	('bilharzial', 'Chemical', '-', (170, 180))	('mutation', 'Var', (85, 93))	('urothelial carcinoma', 'Disease', (129, 149))	('bladder cancer', 'Disease', (315, 329))	('bladder cancer', 'Disease', 'MESH:D001749', (315, 329))	('tumour', 'Disease', 'MESH:D009369', (224, 230))	('cancer', 'Phenotype', 'HP:0002664', (323, 329))	('patients', 'Species', '9606', (330, 338))	('tumour', 'Disease', (224, 230))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))	('association', 'Interaction', (44, 55))	('bladder cancer', 'Phenotype', 'HP:0009725', (315, 329))
379471	28507621	Cells with membrane cytoplasmic staining were considered positive: The intensity and extent of cells stained positively for FGFR3 was evaluated by assessing 10 high-power microscopic fields by two independent pathologists (OH &TA): *Score 0: All tumor cells are negative; *Score +1: Weak but detectable positivity in some or all cells; *Score +2: moderate but extensive positivity; and *Score +3: strong positivity (regardless of extent).	('tumor', 'Disease', 'MESH:D009369', (246, 251))	('FGFR3', 'Gene', '2261', (124, 129))	('extensive', 'MPA', (360, 369))	('; *Score +2', 'Var', (334, 345))	('; *Score +1', 'Var', (270, 281))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('detectable', 'MPA', (292, 302))	('tumor', 'Disease', (246, 251))	('FGFR3', 'Gene', (124, 129))	('are', 'NegReg', (258, 261))
379495	28507621	While all cases of SCC have FGFR3 gene amplification, most of the positive cases were of high grade and belong to the MIBC group (83.3%) with a significant difference at p-value < 0.01 compared to high grade and NMIBC group.	('SCC', 'Gene', '6317', (19, 22))	('FGFR3', 'Gene', '2261', (28, 33))	('NMIBC', 'Chemical', '-', (212, 217))	('amplification', 'Var', (39, 52))	('MIBC', 'Chemical', '-', (213, 217))	('FGFR3', 'Gene', (28, 33))	('SCC', 'Gene', (19, 22))	('MIBC', 'Chemical', '-', (118, 122))
379496	28507621	Almost all cases of SCC and TCC associated with bilharziasis report FGFR3 gene amplification with a significant difference between TCC on bilharzial compared to TCC bilharzial groups at P value < 0.05 (Table 5).	('FGFR3', 'Gene', '2261', (68, 73))	('bilharzial', 'Chemical', '-', (165, 175))	('bilharzial', 'Chemical', '-', (138, 148))	('SCC', 'Gene', (20, 23))	('bilharziasis', 'Disease', 'MESH:D012552', (48, 60))	('FGFR3', 'Gene', (68, 73))	('SCC', 'Gene', '6317', (20, 23))	('bilharziasis', 'Disease', (48, 60))	('amplification', 'Var', (79, 92))
379498	28507621	Amplified FGFR3 gene was reported in 85.7% of low-grade tumours with marked staining intensity showing a significant difference compared to the high-grade tumours at p-value < 0.01.	('tumours', 'Disease', (155, 162))	('tumours', 'Disease', 'MESH:D009369', (56, 63))	('tumours', 'Disease', (56, 63))	('FGFR3', 'Gene', '2261', (10, 15))	('tumour', 'Phenotype', 'HP:0002664', (56, 62))	('FGFR3', 'Gene', (10, 15))	('tumour', 'Phenotype', 'HP:0002664', (155, 161))	('tumours', 'Phenotype', 'HP:0002664', (155, 162))	('tumours', 'Phenotype', 'HP:0002664', (56, 63))	('tumours', 'Disease', 'MESH:D009369', (155, 162))	('Amplified', 'Var', (0, 9))
379514	28507621	who stated that SCC showed a predisposition to a high level of FGFR3 protein expression and mutation.	('expression', 'MPA', (77, 87))	('FGFR3', 'Gene', '2261', (63, 68))	('mutation', 'Var', (92, 100))	('protein', 'Protein', (69, 76))	('FGFR3', 'Gene', (63, 68))	('SCC', 'Gene', (16, 19))	('SCC', 'Gene', '6317', (16, 19))
379518	28507621	who stated that 63% of NMBIC group and 59% were at low-grade show FGFR3 gene amplification.	('FGFR3', 'Gene', '2261', (66, 71))	('FGFR3', 'Gene', (66, 71))	('amplification', 'Var', (77, 90))
379519	28507621	We found positivity for FGFR3gene amplification in almost all bilharziasis associated malignant cases (SCC and TCC).	('FGFR3', 'Gene', '2261', (24, 29))	('bilharziasis', 'Disease', 'MESH:D012552', (62, 74))	('SCC', 'Gene', (103, 106))	('FGFR3', 'Gene', (24, 29))	('bilharziasis', 'Disease', (62, 74))	('SCC', 'Gene', '6317', (103, 106))	('amplification', 'Var', (34, 47))
379523	28507621	FGFR3 point mutations, overexpression of FGFR3 protein has been described.	('overexpression', 'PosReg', (23, 37))	('FGFR3', 'Gene', '2261', (41, 46))	('FGFR3', 'Gene', (0, 5))	('point mutations', 'Var', (6, 21))	('FGFR3', 'Gene', (41, 46))	('FGFR3', 'Gene', '2261', (0, 5))
379524	28507621	Although this overexpression was associated strongly with the presence of FGFR3 mutations (up to 85% of FGFR3-mutated tumours show strong FGFR3 protein expression), FGFR3 overexpression was also found in 40% of tumours with wild-type FGFR3, particularly in those with an invasive phenotype.	('tumours', 'Disease', 'MESH:D009369', (211, 218))	('overexpression', 'PosReg', (171, 185))	('FGFR3', 'Gene', (165, 170))	('FGFR3', 'Gene', '2261', (104, 109))	('tumour', 'Phenotype', 'HP:0002664', (211, 217))	('FGFR3', 'Gene', '2261', (165, 170))	('FGFR3', 'Gene', (104, 109))	('mutations', 'Var', (80, 89))	('FGFR3', 'Gene', (234, 239))	('FGFR3', 'Gene', (138, 143))	('expression', 'MPA', (152, 162))	('FGFR3', 'Gene', '2261', (234, 239))	('FGFR3', 'Gene', (74, 79))	('FGFR3', 'Gene', '2261', (138, 143))	('tumours', 'Disease', (118, 125))	('FGFR3', 'Gene', '2261', (74, 79))	('tumours', 'Phenotype', 'HP:0002664', (118, 125))	('tumours', 'Disease', 'MESH:D009369', (118, 125))	('tumours', 'Disease', (211, 218))	('tumour', 'Phenotype', 'HP:0002664', (118, 124))	('tumours', 'Phenotype', 'HP:0002664', (211, 218))
379525	28507621	We detected FGFR3 gene amplification in 88.2% of the TCC cases; about 70% were of low grade, and 80% were in NMIBC group.	('FGFR3', 'Gene', (12, 17))	('NMIBC', 'Chemical', '-', (109, 114))	('amplification', 'Var', (23, 36))	('TCC', 'Disease', (53, 56))	('FGFR3', 'Gene', '2261', (12, 17))
379527	28507621	found in their study all FGFR3amplified samples showed concomitant FGFR3 mutations and FGFR3 protein overexpression.	('overexpression', 'PosReg', (101, 115))	('FGFR3', 'Gene', (67, 72))	('FGFR3', 'Gene', '2261', (25, 30))	('FGFR3', 'Gene', '2261', (87, 92))	('protein', 'Protein', (93, 100))	('FGFR3', 'Gene', (87, 92))	('FGFR3', 'Gene', (25, 30))	('FGFR3', 'Gene', '2261', (67, 72))	('mutations', 'Var', (73, 82))
379528	28507621	In conclusion, our findings suggest that invasive tumours may develop either from carcinoma in situ or Ta cases having multiple genetic alterations together including gene amplifications in bilharzial associated carcinomas.	('carcinomas', 'Phenotype', 'HP:0030731', (212, 222))	('tumours', 'Phenotype', 'HP:0002664', (50, 57))	('carcinomas', 'Disease', 'MESH:D002277', (212, 222))	('develop', 'PosReg', (62, 69))	('carcinomas', 'Disease', (212, 222))	('bilharzial', 'Chemical', '-', (190, 200))	('carcinoma in situ', 'Disease', 'MESH:D002278', (82, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('invasive tumours', 'Disease', (41, 57))	('carcinoma in situ', 'Disease', (82, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (212, 221))	('invasive tumours', 'Disease', 'MESH:D009361', (41, 57))	('gene amplifications', 'Var', (167, 186))	('tumour', 'Phenotype', 'HP:0002664', (50, 56))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (82, 99))
379531	24595008	Variations in the MHC Region Confer Risk to Esophageal Squamous Cell Carcinoma on the Subjects from High-Incidence Area in Northern China The human major histocompatibility complex (MHC) is the most important region in vertebrate genome, and is crucial in innate immunity.	('Esophageal Squamous Cell Carcinoma', 'Disease', (44, 78))	('Risk', 'Reg', (36, 40))	('human', 'Species', '9606', (142, 147))	('Esophageal Squamous Cell Carcinoma', 'Disease', 'MESH:D000077277', (44, 78))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (55, 78))	('Carcinoma', 'Phenotype', 'HP:0030731', (69, 78))	('Variations', 'Var', (0, 10))
379532	24595008	Recent studies have demonstrated the possible role of polymorphisms in the MHC region to high risk for esophageal squamous cell carcinoma (ESCC).	('polymorphisms', 'Var', (54, 67))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (103, 137))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (114, 137))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('esophageal squamous cell carcinoma', 'Disease', (103, 137))	('MHC region', 'Gene', (75, 85))
379533	24595008	Of the 24 promising SNPs analyzed, we identified three independent SNPs in the MHC region associated with ESCC: rs35399661 (P = 6.07E-06, OR = 1.71, 95%CI = 1.36-2.17), rs3763338 (P = 1.62E-05, OR = 0.63, 95%CI = 0.50-0.78) and rs2844695 (P = 7.60E-05, OR = 0.74, 95%CI = 0.64-0.86).	('rs35399661', 'Var', (112, 122))	('ESCC', 'Disease', (106, 110))	('rs3763338', 'Mutation', 'rs3763338', (169, 178))	('rs2844695', 'Mutation', 'rs2844695', (228, 237))	('rs2844695', 'Var', (228, 237))	('rs35399661', 'Mutation', 'rs35399661', (112, 122))	('rs3763338', 'Var', (169, 178))
379535	24595008	Further analyses showed that rs2844695 was preferentially associated with younger ESCC cases (P = 0.009).	('ESCC', 'Disease', (82, 86))	('rs2844695', 'Mutation', 'rs2844695', (29, 38))	('associated', 'Reg', (58, 68))	('rs2844695', 'Var', (29, 38))
379563	24595008	In brief, after dewaxing, inactivating, endogenous peroxidase activity and blocking cross-reactivity with pre-immune serum, the sections were incubated over night at 4 C with the primary antibodies (antibody for TRIM27 was diluted at 1:150 and the one for HLA-DQA1 was 1:100).	('HLA-DQA1', 'Gene', (256, 264))	('activity', 'MPA', (62, 70))	('TRIM27', 'Gene', (212, 218))	('inactivating', 'Var', (26, 38))	('HLA-DQA1', 'Gene', '3117', (256, 264))	('TRIM27', 'Gene', '5987', (212, 218))
379566	24595008	Since SNP rs17533090 was highly correlated with SNP rs35399661 and could be completely represented by the latter (D' = 1/r2 = 1 in HapMap CHB data), only the rs35399661 locus was kept for further statistical analysis.	('rs35399661', 'Mutation', 'rs35399661', (52, 62))	('HapMap CHB', 'Disease', (131, 141))	('SNP', 'Var', (48, 51))	('SNP rs17533090', 'Var', (6, 20))	('HapMap CHB', 'Disease', 'None', (131, 141))	('correlated', 'Interaction', (32, 42))	('rs35399661', 'Mutation', 'rs35399661', (158, 168))	('rs17533090', 'Mutation', 'rs17533090', (10, 20))
379567	24595008	Of the 24 promising SNPs analyzed, we identified three independent SNPs in the MHC region that associated with ESCC through CLRA: rs35399661 (P = 6.07E-06, OR = 1.71, 95%CI = 1.35-2.17), rs3763338 (P = 1.62E-05, OR = 0.63, 95%CI = 0.50-0.78) and rs2844695 (P = 7.60E-05, OR = 0.74, 95%CI = 0.64-0.86) (Table 1).	('rs35399661', 'Var', (130, 140))	('ESCC through', 'Disease', (111, 123))	('rs2844695', 'Mutation', 'rs2844695', (246, 255))	('rs2844695', 'Var', (246, 255))	('rs35399661', 'Mutation', 'rs35399661', (130, 140))	('rs3763338', 'Mutation', 'rs3763338', (187, 196))	('rs3763338', 'Var', (187, 196))	('associated', 'Reg', (95, 105))
379568	24595008	The Bonferroni corrected P values for rs35399661, rs3763338 and rs2844695 were 0.021, 0.057 and 0.267, respectively (Table 1).	('rs35399661', 'Var', (38, 48))	('rs3763338', 'Mutation', 'rs3763338', (50, 59))	('rs2844695', 'Mutation', 'rs2844695', (64, 73))	('rs3763338', 'Var', (50, 59))	('rs2844695', 'Var', (64, 73))	('rs35399661', 'Mutation', 'rs35399661', (38, 48))
379570	24595008	Signal I surrounding rs35399661 covers two (HLA-DQA1 and HLA-DRB1) genes (Figure 1); Signal II surrounding rs3763338 covers four (TRIM27, ZNF311, OR2W1 and OR2B3) genes (Figure 2); Signal III surrounding rs2844695 covers two (DPCR1 and C6 or f205) genes (Figure 3).	('rs35399661', 'Var', (21, 31))	('HLA-DRB1', 'Gene', '3123', (57, 65))	('rs2844695', 'Mutation', 'rs2844695', (204, 213))	('rs3763338', 'Mutation', 'rs3763338', (107, 116))	('HLA-DQA1', 'Gene', '3117', (44, 52))	('HLA-DRB1', 'Gene', (57, 65))	('ZNF311', 'Gene', (138, 144))	('rs2844695', 'Var', (204, 213))	('rs3763338', 'Var', (107, 116))	('OR2B3', 'Gene', '442184', (156, 161))	('OR2W1', 'Gene', '26692', (146, 151))	('ZNF311', 'Gene', '282890', (138, 144))	('DPCR1', 'Gene', (226, 231))	('HLA-DQA1', 'Gene', (44, 52))	('OR2W1', 'Gene', (146, 151))	('TRIM27', 'Gene', '5987', (130, 136))	('OR2B3', 'Gene', (156, 161))	('DPCR1', 'Gene', '135656', (226, 231))	('TRIM27', 'Gene', (130, 136))	('rs35399661', 'Mutation', 'rs35399661', (21, 31))
379571	24595008	To further correlate the three promising SNPs identified above with clinicopathological characteristics of ESCC, we performed stratified analyses of rs35399661, rs3763338 and rs2844695 by gender, age, family history, alcohol consumption, smoking status, tumor location, gross type, cancer cell differentiation, regional lymph node metastasis and pathological staging (Tables 2-3).	('rs3763338', 'Var', (161, 170))	('tumor', 'Disease', (254, 259))	('rs35399661', 'Mutation', 'rs35399661', (149, 159))	('cancer', 'Phenotype', 'HP:0002664', (282, 288))	('tumor', 'Disease', 'MESH:D009369', (254, 259))	('alcohol', 'Chemical', 'MESH:D000438', (217, 224))	('tumor', 'Phenotype', 'HP:0002664', (254, 259))	('ESCC', 'Disease', (107, 111))	('cancer', 'Disease', 'MESH:D009369', (282, 288))	('rs35399661', 'Var', (149, 159))	('rs2844695', 'Var', (175, 184))	('rs2844695', 'Mutation', 'rs2844695', (175, 184))	('cancer', 'Disease', (282, 288))	('rs3763338', 'Mutation', 'rs3763338', (161, 170))
379572	24595008	The chi2 test of each subgroup showed the rs2844695 was preferentially associated with younger ESCC cases (P = 0.009, OR = 1.32, 95%CI = 1.07-1.62) (Table 2).	('rs2844695', 'Var', (42, 51))	('ESCC', 'Disease', (95, 99))	('rs2844695', 'Mutation', 'rs2844695', (42, 51))
379573	24595008	To further demonstrated the clinical relevance of the two SNPs showing the association with ESCC, expression of TRIM27 (for rs3763338) and HLA-DQA1 (for rs35399661) proteins in ESCC and the neighboring normal tissues was determined using immunohistochemical analysis (Figure 4).	('ESCC', 'Disease', (92, 96))	('ESCC', 'Disease', (177, 181))	('rs35399661', 'Mutation', 'rs35399661', (153, 163))	('for rs3763338', 'Var', (120, 133))	('rs3763338', 'Mutation', 'rs3763338', (124, 133))	('HLA-DQA1', 'Gene', '3117', (139, 147))	('TRIM27', 'Gene', '5987', (112, 118))	('HLA-DQA1', 'Gene', (139, 147))	('TRIM27', 'Gene', (112, 118))
379585	24595008	Compared to many normal tissues, cancer cells are highly sensitized to apoptotic signals, and survive only because they have acquired lesions _ENREF_21.	('lesions _ENREF_21', 'Var', (134, 151))	('cancer', 'Disease', (33, 39))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))
379591	24595008	The presence of HLA-DQ expression in premalignant lesions and on some tumor cells appears to confer an advantage to the host in terms of restricted tumor growth _ENREF_24 and survival _ENREF_24through their role as initiators of CD4+ T helper cell responses against the tumor.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('HLA', 'Gene', (16, 19))	('survival', 'CPA', (175, 183))	('tumor', 'Disease', (148, 153))	('tumor', 'Disease', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (270, 275))	('advantage', 'PosReg', (103, 112))	('tumor', 'Phenotype', 'HP:0002664', (270, 275))	('restricted', 'NegReg', (137, 147))	('presence', 'Var', (4, 12))	('tumor', 'Disease', (270, 275))	('HLA', 'Gene', '3117', (16, 19))
379596	24595008	However, to our knowledge, the association between DPCR1 variations and risk of ESCC has not yet been investigated.	('DPCR1', 'Gene', '135656', (51, 56))	('DPCR1', 'Gene', (51, 56))	('ESCC', 'Disease', (80, 84))	('variations', 'Var', (57, 67))
379600	24595008	Our results demonstrated that rs2844695 was preferentially associated with younger ESCC cases.	('ESCC', 'Disease', (83, 87))	('rs2844695', 'Var', (30, 39))	('rs2844695', 'Mutation', 'rs2844695', (30, 39))	('associated', 'Reg', (59, 69))
379601	24595008	The other factors (gender, age, family history, alcohol consumption, smoking, tumor location, gross type, degree of differentiation, the regional lymph node metastasis and pathological stage) did not significantly alter the effects ofrs35399661 and rs3763338 on the risk to ESCC, indicating that the three SNPs identified as most promising from our study could provide orthologous information to existing clinicophthological covariates.	('ESCC', 'Disease', (274, 278))	('alcohol', 'Chemical', 'MESH:D000438', (48, 55))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('ofrs35399661', 'Var', (232, 244))	('rs3763338', 'Mutation', 'rs3763338', (249, 258))	('tumor', 'Disease', (78, 83))	('rs3763338', 'Var', (249, 258))	('rs35399661', 'Mutation', 'rs35399661', (234, 244))
379606	24595008	Furthermore, the percentage of patients expressing HLA-DQA1 is higher for negative family history than positive family history.	('HLA-DQA1', 'Gene', '3117', (51, 59))	('HLA-DQA1', 'Gene', (51, 59))	('patients', 'Species', '9606', (31, 39))	('negative family history', 'Var', (74, 97))	('higher', 'Reg', (63, 69))
379608	24595008	The limitation of the present study is the absence of replication in another independent samples for rs35399661 (HLA-DQA1 genes), rs3763338 (TRIM27 genes) and rs2844695 (DPCR1 genes).	('TRIM27', 'Gene', '5987', (141, 147))	('rs3763338', 'Mutation', 'rs3763338', (130, 139))	('DPCR1', 'Gene', '135656', (170, 175))	('rs2844695', 'Mutation', 'rs2844695', (159, 168))	('TRIM27', 'Gene', (141, 147))	('rs2844695', 'Var', (159, 168))	('rs35399661', 'Mutation', 'rs35399661', (101, 111))	('rs3763338', 'Var', (130, 139))	('HLA-DQA1', 'Gene', '3117', (113, 121))	('DPCR1', 'Gene', (170, 175))	('HLA-DQA1', 'Gene', (113, 121))	('rs35399661', 'Var', (101, 111))
379609	24595008	Interestingly, recent studies have demonstrated that polymorphisms occurred in HLA-DQA1 increase the risk and prognosis to lung squamous cell carcinoma and gastric cancer.	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (123, 151))	('HLA-DQA1', 'Gene', '3117', (79, 87))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (123, 151))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (128, 151))	('lung squamous cell carcinoma', 'Disease', (123, 151))	('gastric cancer', 'Disease', (156, 170))	('HLA-DQA1', 'Gene', (79, 87))	('increase', 'PosReg', (88, 96))	('gastric cancer', 'Disease', 'MESH:D013274', (156, 170))	('gastric cancer', 'Phenotype', 'HP:0012126', (156, 170))	('carcinoma', 'Phenotype', 'HP:0030731', (142, 151))	('polymorphisms', 'Var', (53, 66))
379617	33434185	The patient-derived cell xenograft model of chemoresistant OSCC displaying CMTM6 depletion restored the cisplatin-induced cell death and tumor burden substantially.	('tumor', 'Disease', (137, 142))	('cisplatin-induced', 'MPA', (104, 121))	('cisplatin', 'Chemical', 'MESH:D002945', (104, 113))	('depletion', 'Var', (81, 90))	('patient', 'Species', '9606', (4, 11))	('CMTM6', 'Gene', (75, 80))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('restored', 'PosReg', (91, 99))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
379620	33434185	Therefore, as CMTM6 facilitates tumor cells for immune evasion and mediates cisplatin resistance, it could be a promising therapeutic target for treating therapy-resistant OSCC.	('cisplatin', 'Chemical', 'MESH:D002945', (76, 85))	('facilitates', 'PosReg', (20, 31))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('immune evasion', 'MPA', (48, 62))	('mediates', 'Reg', (67, 75))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('cisplatin resistance', 'MPA', (76, 96))	('CMTM6', 'Var', (14, 19))	('tumor', 'Disease', (32, 37))
379632	33434185	TCRP1 expression is elevated specifically in cisplatin-resistant cells but not in 5FU-resistant cancer cells.	('cisplatin', 'Chemical', 'MESH:D002945', (45, 54))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('expression', 'MPA', (6, 16))	('TCRP1', 'Gene', (0, 5))	('5FU', 'Chemical', 'MESH:D005472', (82, 85))	('cisplatin-resistant', 'Var', (45, 64))	('elevated', 'PosReg', (20, 28))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('TCRP1', 'Gene', '23201', (0, 5))	('cancer', 'Disease', (96, 102))
379638	33434185	A genome-wide CRISPR-based screening in pancreatic cancer cell line identified that CMTM6 stabilizes programmed cell death ligand 1 (PD-L1) expression.	('stabilizes', 'NegReg', (90, 100))	('programmed cell death ligand 1', 'Gene', '29126', (101, 131))	('CMTM6', 'Var', (84, 89))	('expression', 'MPA', (140, 150))	('PD-L1', 'Gene', (133, 138))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (40, 57))	('PD-L1', 'Gene', '29126', (133, 138))	('programmed cell death ligand 1', 'Gene', (101, 131))	('pancreatic cancer', 'Disease', (40, 57))	('pancreatic cancer', 'Disease', 'MESH:D010190', (40, 57))
379639	33434185	Interestingly, CMTM6 interacts and colocalizes with PD-L1 in plasma membrane.	('PD-L1', 'Gene', '29126', (52, 57))	('CMTM6', 'Var', (15, 20))	('colocalizes', 'MPA', (35, 46))	('interacts', 'Interaction', (21, 30))	('PD-L1', 'Gene', (52, 57))
379640	33434185	Again, CMTM6 prevents the lysosome-mediated degradation of PD-L1, therefore, it stabilizes PD-L1 expression.	('PD-L1', 'Gene', (91, 96))	('prevents', 'NegReg', (13, 21))	('PD-L1', 'Gene', (59, 64))	('stabilizes', 'MPA', (80, 90))	('lysosome-mediated degradation', 'MPA', (26, 55))	('PD-L1', 'Gene', '29126', (91, 96))	('CMTM6', 'Var', (7, 12))	('PD-L1', 'Gene', '29126', (59, 64))	('expression', 'MPA', (97, 107))
379648	33434185	shRNA-based depletion of CMTM6 in cisplatin-resistant cells and in vivo patient-derived cell (PDC1) xenograft models restored drug-induced apoptosis as evident from substantial reduction of tumor burden.	('cisplatin', 'Chemical', 'MESH:D002945', (34, 43))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('CMTM6', 'Gene', (25, 30))	('PDC1', 'Gene', (94, 98))	('PDC1', 'Gene', '18566', (94, 98))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('reduction', 'NegReg', (177, 186))	('restored', 'PosReg', (117, 125))	('patient', 'Species', '9606', (72, 79))	('tumor', 'Disease', (190, 195))	('drug-induced apoptosis', 'CPA', (126, 148))	('depletion', 'Var', (12, 21))
379652	33434185	To explore the causative factors responsible for acquired cisplatin resistance in OSCC, we performed an unbiased and global proteomic profiling of H357CisS, H357CisR4M, and H357CisR8M cells.	('H357CisR4M', 'Var', (157, 167))	('H357CisS', 'Var', (147, 155))	('cisplatin', 'Chemical', 'MESH:D002945', (58, 67))	('H357CisR8M', 'Var', (173, 183))
379653	33434185	We identified 367 proteins to be differentially regulated in CisR4M and CisR8M as compared with cisplatin sensitive control cells (Supplemental Table 3).	('CisR4M', 'Var', (61, 67))	('cisplatin', 'Chemical', 'MESH:D002945', (96, 105))	('CisR8M', 'Var', (72, 78))	('proteins', 'Protein', (18, 26))
379654	33434185	The dendrogram and volcano plot show CMTM6 as the top-ranked upregulated protein in late cisplatin-resistant cells compared with early resistant cells and their sensitive counterpart (Figure 1D and Supplemental Figure 2).	('cisplatin', 'Chemical', 'MESH:D002945', (89, 98))	('upregulated', 'PosReg', (61, 72))	('CMTM6', 'Var', (37, 42))
379655	33434185	Based on these findings, CMTM6 was selected for further experimental validation and to explore its potential role in driving cisplatin resistance.	('CMTM6', 'Var', (25, 30))	('cisplatin resistance', 'MPA', (125, 145))	('cisplatin', 'Chemical', 'MESH:D002945', (125, 134))
379657	33434185	CMTM6 expression was evaluated in H357, SCC9, and SCC4 cell lines showing early and late chemoresistant patterns (H357CisR4M, H357CisR8M, SCC4CisR4M, SCC4CisR8M, SCC9CisR4M, and SCC9CisR8M).	('SCC9', 'CellLine', 'CVCL:1685', (40, 44))	('SCC4', 'CellLine', 'CVCL:1684', (150, 154))	('SCC4', 'CellLine', 'CVCL:1684', (138, 142))	('H357CisR4M', 'Var', (114, 124))	('SCC9CisR4M', 'Var', (162, 172))	('SCC4', 'CellLine', 'CVCL:1684', (50, 54))	('SCC4CisR8M', 'Var', (150, 160))	('SCC9', 'CellLine', 'CVCL:1685', (178, 182))	('SCC9', 'CellLine', 'CVCL:1685', (162, 166))	('H357CisR8M', 'Var', (126, 136))	('SCC4CisR4M', 'Var', (138, 148))
379658	33434185	Also, elevated CMTM6 expression was observed in A549CisR and A375CisR cells as compared with the sensitive cells (Figure 2, C and D).	('A549', 'CellLine', 'CVCL:0023', (48, 52))	('CMTM6', 'Gene', (15, 20))	('elevated', 'PosReg', (6, 14))	('A549CisR', 'Var', (48, 56))	('A375', 'CellLine', 'CVCL:0132', (61, 65))
379660	33434185	Based on real-time quantitative PCR (qRT-PCR) and IHC analysis, higher abundance of CMTM6 was observed in tumor tissues of nonresponders as compared with responder OSCC patients (Figure 2, E-G).	('patients', 'Species', '9606', (169, 177))	('CMTM6', 'Var', (84, 89))	('higher', 'PosReg', (64, 70))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Disease', (106, 111))
379669	33434185	Cell viability and cell death assay data suggested that CMTM6KD significantly sensitized the chemoresistant cells to cisplatin treatment (Figure 3, B and C, and Figure 4A).	('chemoresistant cells', 'CPA', (93, 113))	('CMTM6KD', 'Var', (56, 63))	('sensitized', 'Reg', (78, 88))	('cisplatin', 'Chemical', 'MESH:D002945', (117, 126))
379670	33434185	Similarly, after knocking down CMTM6 in patient-derived primary tumor cells not responding to taxol and platinum therapy (TP), PDC1 cells reversed resistance and became sensitive to cisplatin (Figure 3, B and C, and Figure 4A).	('patient', 'Species', '9606', (40, 47))	('platinum', 'Chemical', 'MESH:D010984', (104, 112))	('cisplatin', 'Chemical', 'MESH:D002945', (182, 191))	('tumor', 'Disease', (64, 69))	('CMTM6', 'Gene', (31, 36))	('taxol', 'Chemical', 'MESH:D017239', (94, 99))	('sensitive to cisplatin', 'MPA', (169, 191))	('reversed', 'NegReg', (138, 146))	('PDC1', 'Gene', '18566', (127, 131))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('PDC1', 'Gene', (127, 131))	('resistance', 'MPA', (147, 157))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('knocking down', 'Var', (17, 30))
379671	33434185	Immunoblotting data showed that knocking down CMTM6 in chemoresistant cells substantially increased cisplatin-induced cleaved poly (ADP-ribose) polymerase (PARP) and gamma-H2AX expression (Figure 4B).	('H2AX', 'Gene', (172, 176))	('cisplatin', 'Chemical', 'MESH:D002945', (100, 109))	('CMTM6', 'Gene', (46, 51))	('increased', 'PosReg', (90, 99))	('PARP', 'Gene', '142', (156, 160))	('knocking down', 'Var', (32, 45))	('poly (ADP-ribose) polymerase', 'Gene', '142', (126, 154))	('poly (ADP-ribose) polymerase', 'Gene', (126, 154))	('PARP', 'Gene', (156, 160))	('H2AX', 'Gene', '3014', (172, 176))
379674	33434185	Treatment with cisplatin (3 mg/kg) markedly reduced the tumor burden in the CMTM6 shRNA group but not in the control shRNA-treated (NTsh-treated) group (Figure 4, C-E).	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Disease', (56, 61))	('cisplatin', 'Chemical', 'MESH:D002945', (15, 24))	('reduced', 'NegReg', (44, 51))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('CMTM6 shRNA', 'Var', (76, 87))
379688	33434185	Therefore, we confirmed that CMTM6 interacted with Enolase-1 by coimmunoprecipitation and confocal microscopy (Figure 7, A and B).	('CMTM6', 'Var', (29, 34))	('interacted', 'Reg', (35, 45))	('Enolase-1', 'Gene', (51, 60))	('Enolase-1', 'Gene', '2023', (51, 60))
379690	33434185	We found substantial reduction of membrane Enolase-1 in CMTM6-KD cells (Figure 7C).	('Enolase-1', 'Gene', (43, 52))	('CMTM6-KD', 'Var', (56, 64))	('Enolase-1', 'Gene', '2023', (43, 52))	('reduction', 'NegReg', (21, 30))
379696	33434185	A heatmap of Wnt target genes from the transcriptome data set between NTSh and CMTM6Sh, with and without cisplatin treatment, depicted significant deregulation of Wnt target genes (Supplemental Figure 7, A and B).	('CMTM6Sh', 'Var', (79, 86))	('deregulation', 'MPA', (147, 159))	('cisplatin', 'Chemical', 'MESH:D002945', (105, 114))
379698	33434185	The immunoblotting and immunostaining data showed a substantial downregulation of beta-catenin, p-beta-catenin (S552), and nonphosphorylated active beta-catenin in CMTM6-KD cells as compared with control cells (Figure 9, A and B, and Supplemental Figure 8A).	('CMTM6-KD', 'Var', (164, 172))	('beta-catenin', 'Gene', (148, 160))	('downregulation', 'NegReg', (64, 78))	('beta-catenin', 'Gene', '1499', (148, 160))	('beta-catenin', 'Gene', (98, 110))	('beta-catenin', 'Gene', (82, 94))	('beta-catenin', 'Gene', '1499', (98, 110))	('beta-catenin', 'Gene', '1499', (82, 94))
379700	33434185	These data suggest that with the depletion of CMTM6, p-AKT S437 was reduced, in turn reducing p-GSK3beta S9.	('CMTM6', 'Var', (46, 51))	('AKT', 'Gene', (55, 58))	('reducing', 'NegReg', (85, 93))	('depletion', 'MPA', (33, 42))	('AKT', 'Gene', '207', (55, 58))	('GSK3beta', 'Gene', (96, 104))	('GSK3beta', 'Gene', '2931', (96, 104))
379706	33434185	Moreover, we evaluated the effect of CMTM6 KD on downstream target genes of the Wnt/beta-catenin signaling pathway.	('beta-catenin', 'Gene', (84, 96))	('beta-catenin', 'Gene', '1499', (84, 96))	('CMTM6 KD', 'Var', (37, 45))
379707	33434185	The immunoblotting and qRT-PCR data suggested that in CMTM6-KD chemoresistant cells, there was a significant downregulation of cyclin D, c-Myc, TCF4, and CD44, which were efficiently rescued upon ectopic overexpression of CMTM6 (Figure 11A and Supplemental Figure 8, C and D).	('cyclin D', 'MPA', (127, 135))	('TCF4', 'Gene', (144, 148))	('downregulation', 'NegReg', (109, 123))	('TCF4', 'Gene', '6925', (144, 148))	('c-Myc', 'Gene', (137, 142))	('CMTM6-KD', 'Var', (54, 62))	('c-Myc', 'Gene', '4609', (137, 142))	('CD4', 'Gene', (154, 157))	('CD4', 'Gene', '920', (154, 157))
379711	33434185	Similarly, ectopic overexpression of CMTM6 in CMTM6-KD cells and treatment with AKT inhibitor LY294002 resulted in reduced expression of beta-catenin and its target genes (Figure 11, D and E).	('overexpression', 'PosReg', (19, 33))	('LY294002', 'Chemical', 'MESH:C085911', (94, 102))	('beta-catenin', 'Gene', '1499', (137, 149))	('expression', 'MPA', (123, 133))	('AKT', 'Gene', '207', (80, 83))	('CMTM6', 'Var', (37, 42))	('reduced', 'NegReg', (115, 122))	('AKT', 'Gene', (80, 83))	('beta-catenin', 'Gene', (137, 149))
379717	33434185	Therefore, we measured ABC transporter expression in chemoresistant cells stably expressing NTSh or CMTM6ShRNA.	('measured', 'Reg', (14, 22))	('ABC transporter', 'Gene', '9429', (23, 38))	('ABC transporter', 'Gene', (23, 38))	('NTSh', 'Var', (92, 96))	('CMTM6ShRNA', 'Var', (100, 110))
379729	33434185	Our data suggest that CMTM6 regulates Wnt signaling through the AKT/GSK3beta axis.	('Wnt signaling', 'MPA', (38, 51))	('CMTM6', 'Var', (22, 27))	('regulates', 'Reg', (28, 37))	('AKT', 'Gene', '207', (64, 67))	('GSK3beta', 'Gene', (68, 76))	('GSK3beta', 'Gene', '2931', (68, 76))	('AKT', 'Gene', (64, 67))
379731	33434185	The data suggest that CMTM6 interacts with membrane Enolase-1, but the biological relevance of this interaction was not explored.	('interacts', 'Interaction', (28, 37))	('Enolase-1', 'Gene', '2023', (52, 61))	('CMTM6', 'Var', (22, 27))	('Enolase-1', 'Gene', (52, 61))
379733	33434185	We also demonstrate here that knocking down CMTM6 reduced membrane Enolase-1 expression.	('expression', 'MPA', (77, 87))	('Enolase-1', 'Gene', (67, 76))	('reduced', 'NegReg', (50, 57))	('CMTM6', 'Gene', (44, 49))	('Enolase-1', 'Gene', '2023', (67, 76))	('knocking down', 'Var', (30, 43))
379735	33434185	Therefore, we predict that CMTM6 stabilizes membrane Enolase-1 expression and activates the AKT/GSK3beta-mediated Wnt signaling.	('stabilizes', 'PosReg', (33, 43))	('expression', 'MPA', (63, 73))	('activates', 'PosReg', (78, 87))	('AKT', 'Gene', '207', (92, 95))	('Enolase-1', 'Gene', (53, 62))	('CMTM6', 'Var', (27, 32))	('Enolase-1', 'Gene', '2023', (53, 62))	('AKT', 'Gene', (92, 95))	('GSK3beta', 'Gene', (96, 104))	('GSK3beta', 'Gene', '2931', (96, 104))
379738	33434185	In conclusion, it was earlier established that CMTM6 is a novel protein, which stabilizes PD-L1 and potentiates the immune evasion by tumor cells.	('potentiates', 'PosReg', (100, 111))	('stabilizes', 'MPA', (79, 89))	('PD-L1', 'Gene', '29126', (90, 95))	('CMTM6', 'Var', (47, 52))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('tumor', 'Disease', (134, 139))	('PD-L1', 'Gene', (90, 95))
379740	33434185	Therefore, targeting CMTM6 can be a useful strategy to overcome therapy resistance in advanced squamous cell carcinomas.	('squamous cell carcinomas', 'Disease', (95, 119))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (95, 119))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (95, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('CMTM6', 'Var', (21, 26))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (95, 119))	('carcinomas', 'Phenotype', 'HP:0030731', (109, 119))
379824	32429325	Class II is commonly subdivided into two sub-classes (Table 1) based on sequence analysis: IIa (HDAC4, HDAC5, HDAC7, and HDAC9) and IIb (HDAC6 and HDAC10).	('HDAC10', 'Gene', '83933', (147, 153))	('HDAC5', 'Gene', '10014', (103, 108))	('IIb', 'Gene', (132, 135))	('HDAC5', 'Gene', (103, 108))	('HDAC6', 'Gene', '10013', (137, 142))	('HDAC7', 'Gene', '51564', (110, 115))	('HDAC6', 'Gene', (137, 142))	('IIb', 'Gene', '5658173', (132, 135))	('HDAC7', 'Gene', (110, 115))	('HDAC4', 'Var', (96, 101))	('HDAC10', 'Gene', (147, 153))	('HDAC9', 'Gene', '9734', (121, 126))	('HDAC9', 'Gene', (121, 126))
379842	32429325	Drosophila melanogaster (fruit fly) carries a total of 5 HDAC genes, translated in the following protein products: NP_001259507.1 located in Class IIa, NP_001259569.1 in Class IIb, NP_733048.1 in Class IV and two Class I HDACs: NP_647918.2 and NP_651978.2.	('NP_651978.2', 'Var', (244, 255))	('IIb', 'Gene', (176, 179))	('NP_733048.1', 'Var', (181, 192))	('IIb', 'Gene', '5658173', (176, 179))	('Drosophila melanogaster', 'Species', '7227', (0, 23))	('fruit fly', 'Species', '7227', (25, 34))	('HDAC genes', 'Gene', (57, 67))	('NP_001259569.1', 'Var', (152, 166))	('NP_001259507.1', 'Var', (115, 129))
379847	32429325	Arabidopsis in particular carries the largest number of HDAC genes in all species investigated (14, Table 2); this is the result of recent HDAC expansion, as this plant carries a cluster of three recently duplicated Class I HDAC loci, which are located in succession on its genome: NP_190052.1 (encoded by gene At3g44660), NP_190054.2 (At3g44680), and NP_190035.1 (At3g44490).	('At3', 'Species', '1239833', (311, 314))	('At3g44660', 'Var', (311, 320))	('At3', 'Species', '1239833', (336, 339))	('Arabidopsis', 'Species', '3702', (0, 11))	('At3g44680', 'Var', (336, 345))	('At3g44490', 'Var', (365, 374))	('At3', 'Species', '1239833', (365, 368))
379848	32429325	Two more highly homologous Arabidopsis Class I HDAC loci, represented by protein NP_198410.1 (gene At5g35600) and NP_201116.1 (gene At5g63110) are separated instead by more than 10 million nucleotides on the plant chromosome 5.	('At5', 'Species', '1239833', (99, 102))	('Arabidopsis', 'Species', '3702', (27, 38))	('gene At5g35600', 'Var', (94, 108))	('At5', 'Species', '1239833', (132, 135))	('gene At5g63110', 'Var', (127, 141))
379850	32429325	Sequences NP_563817.1 (Arabidopsis) and XP_015638622.1 (rice), dubbed HDAC8 by the NCBI annotation and in our tree (Figure 1, between Class IV and Class IIb) are even more separated from the rest of the organisms, and appear as a completely unique class of plant-specific HDACs.	('NP_563817.1', 'Var', (10, 21))	('HDAC8', 'Gene', (70, 75))	('Arabidopsis', 'Species', '3702', (23, 34))	('S', 'Chemical', 'MESH:D012694', (0, 1))	('IIb', 'Gene', (153, 156))	('IIb', 'Gene', '5658173', (153, 156))	('HDAC8', 'Gene', '55869', (70, 75))	('XP_015638622.1', 'Var', (40, 54))	('rice', 'Species', '4530', (56, 60))
379852	32429325	Schizosaccharomyces pombe (fission yeast) HDACs appear very similar to S.cerevisiae, with clear orthologs of Rpd3 (NP_595333.1), Hos2 (NP_594079.1) and Hda1 (NP_595104.1).	('Hda1', 'Gene', (152, 156))	('fission yeast', 'Species', '4896', (27, 40))	('Hos2', 'Gene', '852681', (129, 133))	('Hos2', 'Gene', (129, 133))	('NP_595333.1', 'Var', (115, 126))	('NP_594079.1', 'Var', (135, 146))	('Hda1', 'Gene', '855710', (152, 156))	('Schizosaccharomyces pombe', 'Species', '4896', (0, 25))	('S.cerevisiae', 'Species', '4932', (71, 83))
379886	32429325	These methodologies were applied for the identification of HDAC8 candidate substrates using, respectively, the specific HDAC8 inhibitor PCI-34051 and a recombinant HDAC8 protein in which tyrosine 100 is replaced with a p-benzoyl-L-phenylalanine (Bpa).	('tyrosine', 'Chemical', 'MESH:D014443', (187, 195))	('HDAC8', 'Gene', '55869', (59, 64))	('HDAC8', 'Gene', '55869', (120, 125))	('Bpa', 'Chemical', 'MESH:C488060', (246, 249))	('HDAC8', 'Gene', '55869', (164, 169))	('HDAC8', 'Gene', (120, 125))	('tyrosine 100', 'Var', (187, 199))	('HDAC8', 'Gene', (164, 169))	('HDAC8', 'Gene', (59, 64))	('p-benzoyl-L-phenylalanine', 'Chemical', 'MESH:C488060', (219, 244))
379894	32429325	HDAC8 has been shown to deacetylate ERRalpha, which results in an enhancement of the transcription factor function, and SMC3, one of the components of the cohesin complex, the deacetylation of which facilitates renewal of cohesin following its removal from chromatin during prophase or anaphase.	('acetyl', 'Chemical', '-', (26, 32))	('ERRalpha', 'Gene', '2101', (36, 44))	('HDAC8', 'Gene', '55869', (0, 5))	('deacetylate', 'Var', (24, 35))	('transcription factor function', 'MPA', (85, 114))	('facilitates', 'PosReg', (199, 210))	('acetyl', 'Chemical', '-', (178, 184))	('SMC3', 'Gene', '9126', (120, 124))	('deacetylation', 'Var', (176, 189))	('renewal', 'MPA', (211, 218))	('SMC3', 'Gene', (120, 124))	('cohesin', 'Protein', (222, 229))	('HDAC8', 'Gene', (0, 5))	('ERRalpha', 'Gene', (36, 44))	('enhancement', 'PosReg', (66, 77))
379898	32429325	For example, HDAC1 decrotonylates H3K4cr, H3K9cr, H3K23cr, H4K8cr, and H4K12cr in vitro; H3K8cr can be also decrotonylated by HDAC2 and HDAC8.	('HDAC2', 'Gene', (126, 131))	('HDAC2', 'Gene', '3066', (126, 131))	('HDAC8', 'Gene', '55869', (136, 141))	('H4K8cr', 'Var', (59, 65))	('H3K23cr', 'Var', (50, 57))	('H3K9cr', 'Var', (42, 48))	('HDAC8', 'Gene', (136, 141))	('H3K8cr', 'Var', (89, 95))	('H4K12cr', 'Var', (71, 78))	('H3K4cr', 'Var', (34, 40))
379901	32429325	About the catalytic activity, for vertebrate Class IIa HDACs, the catalytic Tyrosine 345 residue is replaced by a histidine side chain, which is too short to reach into the active site (Figure 3A).	('histidine', 'Chemical', 'MESH:D006639', (114, 123))	('Tyrosine', 'Chemical', 'MESH:D014443', (76, 84))	('catalytic', 'MPA', (66, 75))	('Tyrosine 345', 'Var', (76, 88))
379902	32429325	Due to the Y-H substitution, the catalytic activity of those enzymes on acetylated lysines of histone tail peptides is very low when compared to that of Class I HDACs.	('lysines', 'Chemical', 'MESH:D008239', (83, 90))	('catalytic activity', 'MPA', (33, 51))	('peptides', 'Chemical', 'MESH:D010455', (107, 115))	('Y-H substitution', 'Var', (11, 27))	('histone', 'Protein', (94, 101))	('low', 'NegReg', (124, 127))	('acetyl', 'Chemical', '-', (72, 78))
379903	32429325	This property is independent from the Y-H catalytic residue as replacement of H with a Y in Class IIa HDACs promotes deacetylation of acetylated histone tail peptides, but it does not impact on transcriptional repression.	('peptides', 'Chemical', 'MESH:D010455', (158, 166))	('acetyl', 'Chemical', '-', (134, 140))	('replacement', 'Var', (63, 74))	('acetyl', 'Chemical', '-', (119, 125))	('promotes', 'PosReg', (108, 116))	('deacetylation of acetylated histone tail peptides', 'MPA', (117, 166))
379932	32429325	Since simultaneous deletion of HDAC1 and 2 genes results in early embryonic lethality conditional mutants were produced to investigate their role during development.	('results in', 'Reg', (49, 59))	('deletion', 'Var', (19, 27))	('embryonic lethality', 'Disease', 'MESH:D020964', (66, 85))	('embryonic lethality', 'Disease', (66, 85))	('HDAC1', 'Gene', (31, 36))	('S', 'Chemical', 'MESH:D012694', (0, 1))
379938	32429325	In adult individuals, deletion of HDAC3 in hepatocytes causes an increase of adipogenesis leading to hepatosteatosis whereas its loss in the heart cause interstitial fibrosis.	('increase', 'PosReg', (65, 73))	('HDAC3', 'Gene', '8841', (34, 39))	('hepatosteatosis', 'Disease', 'None', (101, 116))	('leading to', 'Reg', (90, 100))	('interstitial fibrosis', 'Phenotype', 'HP:0005576', (153, 174))	('HDAC3', 'Gene', (34, 39))	('deletion', 'Var', (22, 30))	('loss', 'NegReg', (129, 133))	('fibrosis', 'Disease', (166, 174))	('hepatosteatosis', 'Disease', (101, 116))	('fibrosis', 'Disease', 'MESH:D005355', (166, 174))	('adipogenesis', 'MPA', (77, 89))
379948	32429325	Its deletions in mouse knockout models has been linked to cardiac defects, mainly depending on deregulation of one of its targets, transcription factor MEF2.	('cardiac defects', 'Disease', 'MESH:D006331', (58, 73))	('mouse', 'Species', '10090', (17, 22))	('deletions', 'Var', (4, 13))	('cardiac defects', 'Disease', (58, 73))	('deregulation', 'MPA', (95, 107))	('MEF2', 'Gene', (152, 156))	('linked', 'Reg', (48, 54))
379954	32429325	However, deletion of HDAC6 led to no evident defects in animal models, possibly due to redundancy of functions shared with HDAC10.	('deletion', 'Var', (9, 17))	('HDAC6', 'Gene', '10013', (21, 26))	('HDAC10', 'Gene', (123, 129))	('HDAC6', 'Gene', (21, 26))	('HDAC10', 'Gene', '83933', (123, 129))
379958	32429325	It is thought to have a role in immune cells development, and it has been recently shown that HDAC10 deletion improves Foxp3+ Treg cells suppressive function in vivo.	('deletion', 'Var', (101, 109))	('Foxp3', 'Gene', (119, 124))	('HDAC10', 'Gene', '83933', (94, 100))	('improves', 'PosReg', (110, 118))	('Foxp3', 'Gene', '50943', (119, 124))	('HDAC10', 'Gene', (94, 100))
379970	32429325	The interaction of SIN3A/HDAC1 complex with cell cycle regulators such as Rb and the Mxd1 family suggests that loss of SIN3A would cause an uncontrollably cell cycle progression.	('interaction', 'Interaction', (4, 15))	('SIN3A', 'Gene', (119, 124))	('loss', 'Var', (111, 115))	('Mxd1', 'Gene', (85, 89))	('cause', 'Reg', (131, 136))	('uncontrollably', 'MPA', (140, 154))	('Mxd1', 'Gene', '4084', (85, 89))
380007	32429325	After that, LSD1 demethylates H3-K4Me1-2 causing the reversibly transcriptional repression of the gene locus.	('H3-K4Me1-2', 'Var', (30, 40))	('demethylates H3-K4Me1-2', 'Var', (17, 40))	('LSD1', 'Gene', (12, 16))	('LSD1', 'Gene', '23028', (12, 16))	('reversibly transcriptional repression', 'MPA', (53, 90))
380008	32429325	Finally, the recruitment of histone methyltransferase such as G9a or SUV39H1 and methylation of "repressive" sites like H3-K9 induces a stable long-term silencing of targets through the binding to K9-methyl residues of the heterochromatin protein 1 (HP1) that generate the heterochromatinization of the locus.	('SUV39H1', 'Gene', (69, 76))	('H3-K9', 'Gene', (120, 125))	('methylation', 'Var', (81, 92))	('HP1', 'Gene', '23468', (250, 253))	('silencing', 'NegReg', (153, 162))	('HP1', 'Gene', (250, 253))	('SUV39H1', 'Gene', '6839', (69, 76))	('G9a', 'Gene', '10919', (62, 65))	('heterochromatin protein 1', 'Gene', '23468', (223, 248))	('G9a', 'Gene', (62, 65))	('binding', 'Interaction', (186, 193))	('heterochromatin protein 1', 'Gene', (223, 248))
380015	32429325	An aberrant protein levels of ZNF217 has been reported in many cancer cell lines and may cause unregulated targeting by the CoREST-LSD1 complex, with a profound effect on cancer progression.	('unregulated targeting', 'MPA', (95, 116))	('cause', 'Reg', (89, 94))	('protein levels', 'MPA', (12, 26))	('aberrant', 'Var', (3, 11))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('LSD1', 'Gene', '23028', (131, 135))	('CoREST', 'Gene', '23186', (124, 130))	('LSD1', 'Gene', (131, 135))	('cancer', 'Disease', (171, 177))	('CoREST', 'Gene', (124, 130))	('reported', 'Reg', (46, 54))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('ZNF217', 'Gene', (30, 36))	('ZNF217', 'Gene', '7764', (30, 36))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('cancer', 'Disease', (63, 69))	('effect', 'Reg', (161, 167))
380024	32429325	In particular, it has been demonstrated that NuRD complex binds methylated DNA in correspondence to the pericentric heterochromatin containing MBD2 proteins.	('methylated', 'Var', (64, 74))	('MBD2', 'Gene', (143, 147))	('MBD2', 'Gene', '8932', (143, 147))	('rice', 'Species', '4530', (106, 110))
380027	32429325	PWWP2A was correlated to H3K36me3 marked genes and PWWP2B to active promoters and enhancers.	('H3K36me3 marked', 'Var', (25, 40))	('PWWP2A', 'Gene', '70802', (0, 6))	('PWWP2B', 'Gene', (51, 57))	('PWWP2B', 'Gene', '101631', (51, 57))	('PWWP2A', 'Gene', (0, 6))
380029	32429325	Specifically, MBD2 and MBD3 mediates NuRD recruitment to methylated or hemi-methylated DNA, respectively.	('MBD3', 'Gene', (23, 27))	('mediates', 'Reg', (28, 36))	('MBD3', 'Gene', '53615', (23, 27))	('MBD2', 'Gene', '8932', (14, 18))	('hemi-methylated', 'Var', (71, 86))	('MBD2', 'Gene', (14, 18))	('S', 'Chemical', 'MESH:D012694', (0, 1))	('methylated', 'Var', (57, 67))
380031	32429325	Furthermore, WDR529 and UpSET30 recruits the complex to promoter regions.	('S', 'Chemical', 'MESH:D012694', (26, 27))	('UpSET30', 'Var', (24, 31))	('complex', 'MPA', (45, 52))	('WDR529', 'Var', (13, 19))
380033	32429325	For instance, in mESCs, it has been reported that after H3K36me3 deposition by SET2 on specific promoters of active genes, NuRD/HDAC complex are recruited to the action of PWWP2A/B and the deacetylation of H3K9ac by HDAC2 facilitates RNA Pol II transcriptional elongation.	('recruited', 'PosReg', (145, 154))	('facilitates', 'PosReg', (222, 233))	('SET2', 'Gene', (79, 83))	('deacetylation', 'Var', (189, 202))	('PWWP2A', 'Gene', '70802', (172, 178))	('HDAC2', 'Gene', (216, 221))	('HDAC2', 'Gene', '3066', (216, 221))	('S', 'Chemical', 'MESH:D012694', (79, 80))	('S', 'Chemical', 'MESH:D012694', (19, 20))	('H3K36me3', 'Var', (56, 64))	('RNA Pol II transcriptional', 'Enzyme', (234, 260))	('SET2', 'Gene', '29072', (79, 83))	('PWWP2A', 'Gene', (172, 178))	('acetyl', 'Chemical', '-', (191, 197))
380041	32429325	Specifically, the knockdown of CHD4, an ATPase subunit of NuRD complex (Figure 5), dramatically upregulates C4B expression, a critical component of the complement system, and this can trigger proliferation and tumor progression.	('C4B', 'Gene', '721', (108, 111))	('knockdown', 'Var', (18, 27))	('CHD4', 'Gene', (31, 35))	('expression', 'MPA', (112, 122))	('trigger', 'Reg', (184, 191))	('proliferation', 'CPA', (192, 205))	('S', 'Chemical', 'MESH:D012694', (0, 1))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('tumor', 'Disease', (210, 215))	('CHD4', 'Gene', '1108', (31, 35))	('upregulates', 'PosReg', (96, 107))	('tumor', 'Disease', 'MESH:D009369', (210, 215))	('C4B', 'Gene', (108, 111))
380071	32429325	Although, the production of the aberrant PML-RARalpha protein causes an increase in the binding affinity between RARalpha and NCoR/SMRT complex.	('SMRT', 'Gene', (131, 135))	('PML-RAR', 'Gene', (41, 48))	('increase', 'PosReg', (72, 80))	('RARalpha', 'Gene', '5914', (45, 53))	('NCoR', 'Gene', (126, 130))	('RARalpha', 'Gene', (45, 53))	('binding affinity', 'Interaction', (88, 104))	('PML-RAR', 'Gene', '84106', (41, 48))	('RARalpha', 'Gene', '5914', (113, 121))	('aberrant', 'Var', (32, 40))	('SMRT', 'Gene', '9612', (131, 135))	('RARalpha', 'Gene', (113, 121))	('NCoR', 'Gene', '9611', (126, 130))
380084	32429325	In mice, deletion of HDAC4 in the forebrain resulted in the impairment of memory, behavioral learning, and long-term synaptic plasticity.	('impairment of memory', 'Disease', 'MESH:D008569', (60, 80))	('impairment of memory', 'Disease', (60, 80))	('long-term synaptic plasticity', 'CPA', (107, 136))	('deletion', 'Var', (9, 17))	('mice', 'Species', '10090', (3, 7))	('behavioral learning', 'CPA', (82, 101))	('impairment of memory', 'Phenotype', 'HP:0002354', (60, 80))	('HDAC4', 'Gene', (21, 26))
380085	32429325	In human, the HDAC4 locus is deleted or mutated in patients with brachydactyly mental retardation (BDMR) syndrome, which is characterized by intellectual disabilities, developmental delays, behavioral abnormalities, and skeletal abnormalities.	('developmental delays', 'Disease', 'MESH:D002658', (168, 188))	('behavioral abnormalities', 'Disease', 'MESH:D001523', (190, 214))	('behavioral abnormalities', 'Phenotype', 'HP:0000708', (190, 214))	('human', 'Species', '9606', (3, 8))	('skeletal abnormalities', 'Disease', (220, 242))	('developmental delays', 'Disease', (168, 188))	('developmental delays', 'Phenotype', 'HP:0001263', (168, 188))	('brachydactyly', 'Phenotype', 'HP:0001156', (65, 78))	('behavioral abnormalities', 'Disease', (190, 214))	('brachydactyly mental retardation (BDMR) syndrome', 'Disease', 'MESH:C538317', (65, 113))	('intellectual disabilities', 'Phenotype', 'HP:0001249', (141, 166))	('skeletal abnormalities', 'Phenotype', 'HP:0000924', (220, 242))	('mutated', 'Var', (40, 47))	('patients', 'Species', '9606', (51, 59))	('mental retardation', 'Phenotype', 'HP:0001249', (79, 97))	('HDAC4', 'Gene', (14, 19))	('skeletal abnormalities', 'Disease', 'MESH:C538496', (220, 242))
380101	32429325	HDAC11 was shown to de-acetylate Lys24 and Lys49 at the N-terminus of the chromatin licensing and DNA replication factor 1 (Cdt1) and affect its proteasomal degradation.	('de-acetylate', 'NegReg', (20, 32))	('Lys49', 'Chemical', '-', (43, 48))	('Cdt1', 'Gene', '81620', (124, 128))	('acetyl', 'Chemical', '-', (23, 29))	('proteasomal degradation', 'MPA', (145, 168))	('Cdt1', 'Gene', (124, 128))	('affect', 'Reg', (134, 140))	('Lys24', 'Var', (33, 38))	('Lys49', 'Var', (43, 48))	('HDAC11', 'Gene', (0, 6))	('Lys24', 'Chemical', '-', (33, 38))
380105	32429325	However, deregulation of HDACs has been reported a role in the development and progression of several cancer types.	('role', 'Reg', (51, 55))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('deregulation', 'Var', (9, 21))	('HDACs', 'Protein', (25, 30))
380112	32429325	Silencing or inhibition of HDAC1 was proven to be effective in reducing acquired chemoresistance and aggressiveness in cellular models of ovarian and lung cancers.	('lung cancer', 'Phenotype', 'HP:0100526', (150, 161))	('aggressiveness', 'Phenotype', 'HP:0000718', (101, 115))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('reducing', 'NegReg', (63, 71))	('inhibition', 'Var', (13, 23))	('ovarian and lung cancers', 'Disease', 'MESH:D055370', (138, 162))	('lung cancers', 'Phenotype', 'HP:0100526', (150, 162))	('acquired chemoresistance', 'CPA', (72, 96))	('HDAC1', 'Gene', (27, 32))	('aggressiveness', 'Disease', 'MESH:D001523', (101, 115))	('cancers', 'Phenotype', 'HP:0002664', (155, 162))	('Silencing', 'Var', (0, 9))	('aggressiveness', 'Disease', (101, 115))	('S', 'Chemical', 'MESH:D012694', (0, 1))
380113	32429325	Conversely, in estrogen-receptor positive breast cancer a high expression of HDAC1 was shown to be a good prognostic factor.	('estrogen-receptor', 'Gene', '2099', (15, 32))	('HDAC1', 'Gene', (77, 82))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('estrogen-receptor', 'Gene', (15, 32))	('breast cancer', 'Disease', 'MESH:D001943', (42, 55))	('breast cancer', 'Phenotype', 'HP:0003002', (42, 55))	('breast cancer', 'Disease', (42, 55))	('high', 'Var', (58, 62))
380133	32429325	Overexpression of HDAC8 and 3 was associated with an improved survival in stage IV metastatic melanoma.	('melanoma', 'Disease', 'MESH:D008545', (94, 102))	('melanoma', 'Phenotype', 'HP:0002861', (94, 102))	('melanoma', 'Disease', (94, 102))	('HDAC8', 'Gene', '55869', (18, 23))	('Overexpression', 'Var', (0, 14))	('improved', 'PosReg', (53, 61))	('HDAC8', 'Gene', (18, 23))
380149	32429325	Survival analysis reported several significant associations in different tumor subtypes: high transcript levels are associated with a reduced OS in CESC, GBM, LGG, and KIRP, while it is a good prognostic factor in BLCA, DLBC, KICH, NBL, and THYM (Figure 6B).	('KICH', 'Disease', (226, 230))	('DLBC', 'Disease', (220, 224))	('NBL', 'Gene', (232, 235))	('CESC', 'Disease', (148, 152))	('KIRP', 'Disease', (168, 172))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('NBL', 'Gene', '9253', (232, 235))	('BLCA', 'Disease', (214, 218))	('LGG', 'Disease', (159, 162))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('KICH', 'Disease', 'None', (226, 230))	('high', 'Var', (89, 93))	('tumor', 'Disease', (73, 78))	('GBM', 'Disease', (154, 157))	('reduced', 'NegReg', (134, 141))	('S', 'Chemical', 'MESH:D012694', (150, 151))	('S', 'Chemical', 'MESH:D012694', (0, 1))	('S', 'Chemical', 'MESH:D012694', (143, 144))
380150	32429325	Overexpression has been previously reported to be associated with poor prognosis in pancreatic tumors.	('pancreatic tumors', 'Disease', 'MESH:D010190', (84, 101))	('Overexpression', 'Var', (0, 14))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('pancreatic tumors', 'Disease', (84, 101))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('pancreatic tumors', 'Phenotype', 'HP:0002894', (84, 101))
380152	32429325	Overexpression of HDAC7 is frequently reported in several hematologic malignancies like ALL and CLL, often correlated with poor outcomes.	('CLL', 'Phenotype', 'HP:0005550', (96, 99))	('CLL', 'Disease', (96, 99))	('ALL', 'Phenotype', 'HP:0006721', (88, 91))	('reported', 'Reg', (38, 46))	('HDAC7', 'Gene', (18, 23))	('hematologic malignancies', 'Disease', 'MESH:D019337', (58, 82))	('Overexpression', 'Var', (0, 14))	('hematologic malignancies', 'Disease', (58, 82))	('ALL', 'Disease', (88, 91))	('HDAC7', 'Gene', '51564', (18, 23))
380155	32429325	Low expression is associated with a significantly poorer OS in ACC and CHOL.	('ACC', 'Disease', (63, 66))	('S', 'Chemical', 'MESH:D012694', (58, 59))	('CHOL', 'Disease', (71, 75))	('Low expression', 'Var', (0, 14))	('CHOL', 'Disease', 'None', (71, 75))	('poorer', 'NegReg', (50, 56))	('ACC', 'Phenotype', 'HP:0006744', (63, 66))
380170	32429325	In the TCGA cohort, low expression is associated with a bad OS in BLCA and PCPG, while better outcomes are expected in HDAC10 low-expressing KIRC and THCA patients (Figure 6B).	('PCPG', 'Disease', (75, 79))	('THCA', 'Chemical', '-', (150, 154))	('low expression', 'Var', (20, 34))	('HDAC10', 'Gene', '83933', (119, 125))	('HDAC10', 'Gene', (119, 125))	('S', 'Chemical', 'MESH:D012694', (61, 62))	('patients', 'Species', '9606', (155, 163))	('BLCA', 'Disease', (66, 70))
380175	32429325	Low-expressing LUAD, NBL, and UVM patients experience worse OS (Figure 6B).	('Low-expressing', 'Var', (0, 14))	('LUAD', 'Disease', (15, 19))	('patients', 'Species', '9606', (34, 42))	('NBL', 'Gene', '9253', (21, 24))	('S', 'Chemical', 'MESH:D012694', (61, 62))	('NBL', 'Gene', (21, 24))
380188	32429325	Cell cycle blocks is mainly caused by the mis-regulation of key genes such as CDKN1A and AKT and by the hyperacetylation/activation of the tumor suppressor p53.	('caused', 'Reg', (28, 34))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('mis-regulation', 'Var', (42, 56))	('acetyl', 'Chemical', '-', (109, 115))	('CDKN1A', 'Gene', (78, 84))	('hyperacetylation/activation', 'PosReg', (104, 131))	('p53', 'Gene', (156, 159))	('AKT', 'Gene', '207', (89, 92))	('p53', 'Gene', '7157', (156, 159))	('tumor', 'Disease', (139, 144))	('CDKN1A', 'Gene', '1026', (78, 84))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('AKT', 'Gene', (89, 92))	('Cell cycle blocks', 'CPA', (0, 17))
380190	32429325	Ideally, the chemical pan-inhibition of HDACs should trigger a global hyperacetylation and, consequentially, an hyperactivation of many genes across the genome.	('trigger', 'Reg', (53, 60))	('acetyl', 'Chemical', '-', (75, 81))	('global hyperacetylation', 'MPA', (63, 86))	('hyperactivation', 'PosReg', (112, 127))	('pan-inhibition', 'Var', (22, 36))
380194	32429325	In vitro and in vivo studies have revealed an important link between ARID1A mutation status and SAHA sensitivity in ovarian cancer.	('SAHA sensitivity in ovarian cancer', 'Disease', 'MESH:D003807', (96, 130))	('ARID1A', 'Gene', '8289', (69, 75))	('SAHA sensitivity in ovarian cancer', 'Disease', (96, 130))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('ARID1A', 'Gene', (69, 75))	('mutation', 'Var', (76, 84))	('ovarian cancer', 'Phenotype', 'HP:0100615', (116, 130))
380199	32429325	The loss of Crebbp leads to reduced H3K27Ac and transcriptional downregulation of CDH1 which, in turn, promotes cell transformation.	('reduced', 'NegReg', (28, 35))	('downregulation', 'NegReg', (64, 78))	('Crebbp', 'Gene', (12, 18))	('CDH1', 'Gene', '999', (82, 86))	('cell transformation', 'CPA', (112, 131))	('promotes', 'PosReg', (103, 111))	('CDH1', 'Gene', (82, 86))	('H3K27Ac', 'Protein', (36, 43))	('loss', 'Var', (4, 8))
380200	32429325	Pracinostat treatment of DMS53 (human SCLC cells with CRISPR-generated CREBBP deletion) resulted in a widely increase in H3K27Ac, H3K18Ac, and increased CDH1 RNA and protein expression.	('Pracinostat', 'Chemical', 'MESH:C557525', (0, 11))	('CREBBP', 'Gene', (71, 77))	('increased', 'PosReg', (143, 152))	('DMS53', 'Chemical', '-', (25, 30))	('S', 'Chemical', 'MESH:D012694', (38, 39))	('S', 'Chemical', 'MESH:D012694', (27, 28))	('increase', 'PosReg', (109, 117))	('CREBBP', 'Gene', '1387', (71, 77))	('CDH1', 'Gene', (153, 157))	('S', 'Chemical', 'MESH:D012694', (57, 58))	('human', 'Species', '9606', (32, 37))	('CDH1', 'Gene', '999', (153, 157))	('DMS53', 'Var', (25, 30))	('H3K27Ac', 'Protein', (121, 128))	('H3K18Ac', 'Protein', (130, 137))
380204	32429325	Specifically, LBH589 treatment seems to induce a depletion of histone H2B ubiquitination via misregulation of the RNF20/RNF40/WAC E3 ligase complex axis.	('RNF40', 'Gene', (120, 125))	('ubiquitination', 'MPA', (74, 88))	('depletion', 'MPA', (49, 58))	('RNF40', 'Gene', '9810', (120, 125))	('RNF20', 'Gene', (114, 119))	('LBH589', 'Chemical', 'MESH:D000077767', (14, 20))	('histone H2B', 'Protein', (62, 73))	('misregulation', 'Var', (93, 106))	('LBH589', 'Var', (14, 20))	('RNF20', 'Gene', '56254', (114, 119))	('S', 'Chemical', 'MESH:D012694', (0, 1))
380226	32429325	Mocetinostat (MGCD0103), Entinostat (MS275), Chidamide (HBI-8000), K560, and K560(1a) are the best characterized HDACi benzamide compounds able to interfere in tumor cell growth of many types of tumor.	('tumor', 'Disease', (195, 200))	('Mocetinostat', 'Chemical', 'MESH:C523184', (0, 12))	('benzamide', 'Chemical', 'MESH:C037689', (119, 128))	('K560', 'Var', (77, 81))	('K560', 'Chemical', '-', (67, 71))	('K560', 'Chemical', '-', (77, 81))	('Entinostat', 'Chemical', 'MESH:C118739', (25, 35))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('Chidamide', 'Chemical', 'MESH:C547816', (45, 54))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('HBI-8000', 'Chemical', 'MESH:C000613826', (56, 64))	('interfere', 'NegReg', (147, 156))	('tumor', 'Disease', (160, 165))	('MGCD0103', 'Chemical', 'MESH:C523184', (14, 22))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('MS275', 'Chemical', 'MESH:C118739', (37, 42))
380233	32429325	Interestingly, Entinostat stimulate MHCII pathway only in the immunocompetent C57BL/6 mouse model, suggesting a strong coordination between the epigenetic modulation exerted by MS275 treatment and the consequent stimulation of adaptive immunity.	('Entinostat', 'Chemical', 'MESH:C118739', (15, 25))	('MHCII', 'Gene', '111364', (36, 41))	('stimulation', 'PosReg', (212, 223))	('mouse', 'Species', '10090', (86, 91))	('MS275', 'Var', (177, 182))	('epigenetic modulation', 'MPA', (144, 165))	('MHCII', 'Gene', (36, 41))	('MS275', 'Chemical', 'MESH:C118739', (177, 182))
380236	32429325	Specifically, cytofluorimetric and biochemical assays have revealed that MS275 and 5-fluorouracil co-treatment exert a synergistic effect triggering apoptosis via deregulation of key cell cycle related genes such as p53, CDKN1A, and cyclin A.	('CDKN1A', 'Gene', (221, 227))	('apoptosis', 'CPA', (149, 158))	('MS275', 'Var', (73, 78))	('CDKN1A', 'Gene', '1026', (221, 227))	('S', 'Chemical', 'MESH:D012694', (0, 1))	('cyclin A', 'Gene', (233, 241))	('deregulation', 'PosReg', (163, 175))	('S', 'Chemical', 'MESH:D012694', (74, 75))	('p53', 'Gene', '7157', (216, 219))	('triggering', 'Reg', (138, 148))	('MS275', 'Chemical', 'MESH:C118739', (73, 78))	('cyclin A', 'Gene', '890', (233, 241))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (83, 97))	('p53', 'Gene', (216, 219))
380240	32429325	In two recent studies, two putative HDAC1,2 benzamide specific inhibitors, K560 and K560(1a), were developed and tested for their neuroprotective abilities.	('neuroprotective abilities', 'CPA', (130, 155))	('K560', 'Chemical', '-', (84, 88))	('benzamide', 'Chemical', 'MESH:C037689', (44, 53))	('K560', 'Var', (84, 88))	('K560', 'Chemical', '-', (75, 79))	('K560', 'Var', (75, 79))
380241	32429325	Authors have shown how K560 benzamide drugs can exert neuroprotective abilities in MPP+ induced toxicity on in vitro SH-SY5Y retinoic acid differentiated cells.	('neuroprotective abilities', 'CPA', (54, 79))	('toxicity', 'Disease', 'MESH:D064420', (96, 104))	('benzamide', 'Chemical', 'MESH:C037689', (28, 37))	('toxicity', 'Disease', (96, 104))	('K560', 'Chemical', '-', (23, 27))	('SH-SY5Y', 'CellLine', 'CVCL:0019', (117, 124))	('K560', 'Var', (23, 27))	('retinoic acid', 'Chemical', 'MESH:D014212', (125, 138))	('MPP+', 'Chemical', 'MESH:C044202', (83, 87))
380242	32429325	Specifically, K560 treatment stimulates HDAC1,2 protein expression and abrogates the cell death effect of MPP+ by modulating key apoptosis-related factors such as claspin, XIAP, and livin, and observed an increased p53 activation through phosphorylation.	('claspin', 'Gene', (163, 170))	('cell death effect', 'CPA', (85, 102))	('K560', 'Var', (14, 18))	('livin', 'Gene', (182, 187))	('XIAP', 'Gene', (172, 176))	('XIAP', 'Gene', '331', (172, 176))	('abrogates', 'NegReg', (71, 80))	('MPP+', 'Chemical', 'MESH:C044202', (106, 110))	('p53', 'Gene', (215, 218))	('p53', 'Gene', '7157', (215, 218))	('livin', 'Gene', '79444', (182, 187))	('activation', 'PosReg', (219, 229))	('modulating', 'Reg', (114, 124))	('K560', 'Chemical', '-', (14, 18))	('phosphorylation', 'MPA', (238, 253))	('claspin', 'Gene', '63967', (163, 170))	('S', 'Chemical', 'MESH:D012694', (0, 1))	('stimulates', 'PosReg', (29, 39))
380260	32429325	Among these, FR901375 chromopeptide A, FR901375, largazole, spiruchostatin A, HC-toxin, trapoxin, and azumamide are currently investigated for their anti-tumorigenic potential.	('FR901375', 'Chemical', 'MESH:C482963', (39, 47))	('azumamide', 'Chemical', '-', (102, 111))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('FR901375', 'Chemical', 'MESH:C482963', (13, 21))	('HC-toxin', 'Disease', (78, 86))	('largazole', 'Chemical', 'MESH:C527895', (49, 58))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('trapoxin', 'Chemical', 'MESH:C067070', (88, 96))	('HC-toxin', 'Disease', 'MESH:D065766', (78, 86))	('FR901375', 'Var', (39, 47))	('FR901375 chromopeptide A', 'Chemical', '-', (13, 37))	('FR901375', 'Var', (13, 21))	('tumor', 'Disease', (154, 159))
380270	32429325	For example, inhibition of HDACs could modulate their action in genomic instability, often observed in cancer in the form of amplifications/deletions, chromosomic rearrangements, and chromothripsis.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('genomic instability', 'MPA', (64, 83))	('inhibition', 'Var', (13, 23))	('chromothripsis', 'Disease', (183, 197))	('modulate', 'Reg', (39, 47))	('chromothripsis', 'Disease', 'MESH:D000072837', (183, 197))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('HDACs', 'Protein', (27, 32))
380283	32509418	Cluster1 had worse prognosis, better anti-tumor characteristics and highest immune scores, but also accompanied by immunosuppression and T cell dysfunction.	('better', 'PosReg', (30, 36))	('tumor', 'Disease', (42, 47))	('Cluster1', 'Var', (0, 8))	('immune scores', 'MPA', (76, 89))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('T cell dysfunction', 'Phenotype', 'HP:0005435', (137, 155))
380323	32509418	S5a), which was consistent with the above results and previous reports that Th17 inhibited the anti-tumor effects of Th1 and Th2 cells.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('Th17', 'Var', (76, 80))	('tumor', 'Disease', (100, 105))	('inhibited', 'NegReg', (81, 90))	('tumor', 'Disease', 'MESH:D009369', (100, 105))
380338	32509418	Then, we compared some indicators based on copy number variations (CNVs) and somatic mutations, such as CNV burden, intratumoral heterogeneity (ITH), homologous recombination deficiency (HRD), loss of heterozygosity (LOH) and aneuploidy.	('aneuploidy', 'Disease', (226, 236))	('HRD', 'Disease', (187, 190))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumor', 'Disease', (121, 126))	('aneuploidy', 'Disease', 'MESH:D000782', (226, 236))	('HRD', 'Disease', 'None', (187, 190))	('deficiency', 'Disease', (175, 185))	('loss of heterozygosity', 'Var', (193, 215))	('deficiency', 'Disease', 'MESH:D007153', (175, 185))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
380342	32509418	Among the genes with significant mutations in HCC (top 15), we found that only TP53 was significant in three clusters (Fig.	('HCC', 'Gene', '619501', (46, 49))	('TP53', 'Gene', '7157', (79, 83))	('TP53', 'Gene', (79, 83))	('HCC', 'Phenotype', 'HP:0001402', (46, 49))	('mutations', 'Var', (33, 42))	('HCC', 'Gene', (46, 49))
380347	32509418	And most significant regions or genes related amplification or deletion were enriched in cluster1 immune subtype, such as TP53 deletion (Fig.	('TP53', 'Gene', (122, 126))	('amplification', 'Var', (46, 59))	('cluster1', 'Disease', (89, 97))	('deletion', 'Var', (63, 71))	('TP53', 'Gene', '7157', (122, 126))
380373	32509418	And also, inhibition of MMP9 could modulate immunosuppression in tumor.	('MMP9', 'Gene', '4318', (24, 28))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('tumor', 'Disease', (65, 70))	('modulate', 'Reg', (35, 43))	('inhibition', 'Var', (10, 20))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('MMP9', 'Gene', (24, 28))
380379	32509418	In addition, Type A with high MMP9 expression might be more suitable for immunotherapy (Additional file 3: Fig.	('MMP9', 'Gene', (30, 34))	('high', 'Var', (25, 29))	('expression', 'MPA', (35, 45))	('MMP9', 'Gene', '4318', (30, 34))
380394	32509418	However, cluster1 had poor survival, which may be caused by high expression of some classic or newly discovered immune checkpoints (PD1, CTLA4 and TIM-3), more infiltration of immunosuppressive cells (TAMs, Tregs and Th17 cells), and genomic alterations (TP53 mutation and deletion).	('TP53', 'Gene', (255, 259))	('CTLA4', 'Gene', '1493', (137, 142))	('TIM-3', 'Gene', (147, 152))	('TAMs', 'Chemical', 'MESH:D013629', (201, 205))	('CTLA4', 'Gene', (137, 142))	('PD1', 'Gene', '5133', (132, 135))	('TIM-3', 'Gene', '84868', (147, 152))	('deletion', 'Var', (273, 281))	('mutation', 'Var', (260, 268))	('PD1', 'Gene', (132, 135))	('expression', 'MPA', (65, 75))	('more infiltration', 'PosReg', (155, 172))	('TP53', 'Gene', '7157', (255, 259))
380410	32509418	Furthermore, MMP9 can be used as a biomarker of chemotherapy response, with high expression of MMP9 meaning better responsiveness to chemotherapy.	('MMP9', 'Gene', '4318', (95, 99))	('responsiveness to chemotherapy', 'MPA', (115, 145))	('better', 'PosReg', (108, 114))	('high expression', 'Var', (76, 91))	('MMP9', 'Gene', (13, 17))	('MMP9', 'Gene', (95, 99))	('MMP9', 'Gene', '4318', (13, 17))
380416	32509418	HCC Hepatocellular carcinoma TAM Tumor-associated macrophage MDSC Myeloid-derived suppressor cell TME Tumor microenvironment LncRNA Long non-coding RNA TCGA-LIHC The Cancer Genome Atlas-Liver hepatocellular carcinoma (TCGA-LIHC) ICGC The International Cancer Genome Consortium AFP alpha-Fetoprotein TMB Tumor mutation burden CNV Copy number variation ITH Intratumoral heterogeneity HRD Homologous recombination deficiency LOH Loss of heterozygosity OS Overall survival SVM Support vector machine Supplementary information accompanies this paper at 10.1186/s40164-020-00165-3.	('Cancer', 'Disease', (252, 258))	('HRD', 'Disease', (382, 385))	('TMB', 'Chemical', '-', (299, 302))	('HRD', 'Disease', 'None', (382, 385))	('Tumor', 'Phenotype', 'HP:0002664', (303, 308))	('HCC', 'Gene', '619501', (0, 3))	('HCC', 'Phenotype', 'HP:0001402', (0, 3))	('Cancer', 'Disease', 'MESH:D009369', (166, 172))	('Tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (360, 365))	('HCC', 'Gene', (0, 3))	('Cancer', 'Disease', 'MESH:D009369', (252, 258))	('TAM', 'Chemical', '-', (29, 32))	('carcinoma', 'Phenotype', 'HP:0030731', (207, 216))	('Hepatocellular carcinoma', 'Disease', (4, 28))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (192, 216))	('tumor', 'Disease', 'MESH:D009369', (360, 365))	('Hepatocellular carcinoma', 'Disease', 'MESH:D006528', (4, 28))	('deficiency', 'Disease', 'MESH:D007153', (411, 421))	('Atlas-Liver hepatocellular carcinoma', 'Disease', 'MESH:D006528', (180, 216))	('Atlas-Liver hepatocellular carcinoma', 'Disease', (180, 216))	('deficiency', 'Disease', (411, 421))	('tumor', 'Phenotype', 'HP:0002664', (360, 365))	('Hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (4, 28))	('Cancer', 'Phenotype', 'HP:0002664', (252, 258))	('Cancer', 'Phenotype', 'HP:0002664', (166, 172))	('carcinoma', 'Phenotype', 'HP:0030731', (19, 28))	('AFP', 'Gene', (277, 280))	('AFP', 'Gene', '174', (277, 280))	('variation', 'Var', (341, 350))	('Tumor', 'Phenotype', 'HP:0002664', (33, 38))	('Cancer', 'Disease', (166, 172))
380468	32258977	Van Workum et al performed propensity score-matched analysis to compare minimally invasive Ivor Lewis versus minimally invasive McKeown esophagectomy.36 They concluded that Ivor Lewis MIE was associated with a lower incidence of anastomotic leakage, 90-day mortality and other postoperative morbidities as compared to McKeown MIE in patients in whom both procedures were oncologically feasible.	('mortality', 'Disease', (257, 266))	('Ivor Lewis MIE', 'Var', (173, 187))	('MIE', 'Chemical', '-', (184, 187))	('anastomotic leakage', 'Disease', 'MESH:D057868', (229, 248))	('patients', 'Species', '9606', (333, 341))	('lower', 'NegReg', (210, 215))	('mortality', 'Disease', 'MESH:D003643', (257, 266))	('MIE', 'Chemical', '-', (326, 329))	('anastomotic leakage', 'Disease', (229, 248))
380489	32194745	IL-36gamma protein was primarily located in the cytoplasm, with a small quantity in the nucleus, and IL-36gamma mRNA and protein expression levels in lung cancer tissues were significantly higher compared with those in adjacent normal tissues.	('lung cancer', 'Phenotype', 'HP:0100526', (150, 161))	('lung cancer', 'Disease', (150, 161))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('lung cancer', 'Disease', 'MESH:D008175', (150, 161))	('IL-36gamma', 'Var', (101, 111))	('higher', 'PosReg', (189, 195))
380491	32194745	In addition, patients with adenocarcinoma with high IL-36gamma protein expression levels tended to longer post-operative survival times.	('longer', 'PosReg', (99, 105))	('high', 'Var', (47, 51))	('patients', 'Species', '9606', (13, 21))	('carcinoma', 'Phenotype', 'HP:0030731', (32, 41))	('post-operative survival times', 'CPA', (106, 135))	('adenocarcinoma', 'Disease', (27, 41))	('adenocarcinoma', 'Disease', 'MESH:D000230', (27, 41))
380502	32194745	Previous studies have demonstrated that IL-36gamma induces autoimmune diseases such as psoriasis, allergic rhinitis and allergic asthma, and is associated with type-1 immune responses.	('rhinitis', 'Phenotype', 'HP:0012384', (107, 115))	('allergic rhinitis', 'Disease', 'MESH:D065631', (98, 115))	('autoimmune diseases', 'Disease', 'MESH:D001327', (59, 78))	('asthma', 'Phenotype', 'HP:0002099', (129, 135))	('allergic asthma', 'Disease', 'MESH:D004342', (120, 135))	('associated', 'Reg', (144, 154))	('induces', 'Reg', (51, 58))	('allergic rhinitis', 'Disease', (98, 115))	('autoimmune diseases', 'Disease', (59, 78))	('allergic asthma', 'Disease', (120, 135))	('allergic rhinitis', 'Phenotype', 'HP:0003193', (98, 115))	('IL-36gamma', 'Var', (40, 50))	('psoriasis', 'Disease', 'MESH:D011565', (87, 96))	('autoimmune diseases', 'Phenotype', 'HP:0002960', (59, 78))	('psoriasis', 'Phenotype', 'HP:0003765', (87, 96))	('psoriasis', 'Disease', (87, 96))
380503	32194745	High IL-36gamma expression levels can stimulate immune differentiation of Th1-type cells, contributing to a positive immune response to infectious diseases.	('immune differentiation', 'CPA', (48, 70))	('High', 'Var', (0, 4))	('Th1', 'Gene', '51497', (74, 77))	('IL-36gamma', 'Protein', (5, 15))	('stimulate', 'PosReg', (38, 47))	('infectious diseases', 'Disease', (136, 155))	('Th1', 'Gene', (74, 77))	('infectious diseases', 'Disease', 'MESH:D003141', (136, 155))
380505	32194745	IL-36gamma is a novel antitumor cytokine that can promote proliferation of CD4+ T lymphocytes, CD8+ T lymphocytes, NK cells and gammadeltaT cells in vitro and in vivo, promoting tumor eradication in the TME.	('promoting', 'PosReg', (168, 177))	('tumor', 'Disease', (178, 183))	('IL-36gamma', 'Var', (0, 10))	('proliferation', 'CPA', (58, 71))	('promote', 'PosReg', (50, 57))	('CD8', 'Gene', '925', (95, 98))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('CD4', 'Gene', (75, 78))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('CD4', 'Gene', '920', (75, 78))	('CD8', 'Gene', (95, 98))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))
380507	32194745	Therefore, the present study aimed to determine if IL-36gamma had a similar association with the prognosis of patients with non-small cell lung carcinoma (NSCLC).	('non-small cell lung carcinoma', 'Disease', 'MESH:D002289', (124, 153))	('non-small cell lung carcinoma', 'Phenotype', 'HP:0030358', (124, 153))	('IL-36gamma', 'Var', (51, 61))	('non-small cell lung carcinoma', 'Disease', (124, 153))	('NSCLC', 'Disease', (155, 160))	('NSCLC', 'Disease', 'MESH:D002289', (155, 160))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('small cell lung carcinoma', 'Phenotype', 'HP:0030357', (128, 153))	('NSCLC', 'Phenotype', 'HP:0030358', (155, 160))	('patients', 'Species', '9606', (110, 118))
380508	32194745	By reviewing the The National Center for Biotechnology Information Gene Expression Database (NCBI GEO) database , it was identified that IL-36gamma was expressed in lung cancer, especially in lung squamous cell carcinoma.	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (192, 220))	('lung cancer', 'Disease', (165, 176))	('lung cancer', 'Phenotype', 'HP:0100526', (165, 176))	('expressed', 'Reg', (152, 161))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (197, 220))	('lung squamous cell carcinoma', 'Disease', (192, 220))	('carcinoma', 'Phenotype', 'HP:0030731', (211, 220))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('lung cancer', 'Disease', 'MESH:D008175', (165, 176))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (192, 220))	('IL-36gamma', 'Var', (137, 147))
380509	32194745	A previous study demonstrated that IL-36gamma greatly promoted the proliferation and activation of CD8+ cells and enhanced the antitumor immune response using animal models.	('promoted', 'PosReg', (54, 62))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('CD8', 'Gene', (99, 102))	('IL-36gamma', 'Var', (35, 45))	('CD8', 'Gene', '925', (99, 102))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumor', 'Disease', (131, 136))	('enhanced', 'PosReg', (114, 122))	('proliferation', 'CPA', (67, 80))	('activation', 'CPA', (85, 95))
380543	32194745	Kaplan-Meier survival analysis and a log-rank test demonstrated that patients with lung adenocarcinoma and high IL-36gamma protein expression levels experienced a longer survival time; however, this difference was not statistically significant (P=0.1343; Fig.	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('lung adenocarcinoma', 'Disease', (83, 102))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (83, 102))	('longer', 'PosReg', (163, 169))	('survival time', 'CPA', (170, 183))	('patients', 'Species', '9606', (69, 77))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (83, 102))	('high', 'Var', (107, 111))
380560	32194745	Our previous study showed that IL-36gamma promoted cell activation and expressed IFN-gamma, granzyme-B and other type 1 effectors in vitro by stimulating cultured human peripheral blood CD4+ T lymphocytes and CD8+ T lymphocytes.	('CD8', 'Gene', (209, 212))	('cell activation', 'CPA', (51, 66))	('IL-36gamma', 'Var', (31, 41))	('granzyme-B', 'Gene', (92, 102))	('CD8', 'Gene', '925', (209, 212))	('CD4', 'Gene', (186, 189))	('human', 'Species', '9606', (163, 168))	('promoted', 'PosReg', (42, 50))	('stimulating', 'PosReg', (142, 153))	('CD4', 'Gene', '920', (186, 189))	('granzyme-B', 'Gene', '3002', (92, 102))
380565	32194745	A recent breast cancer lung metastasis model study indicated that IL-36gamma has an important effect in improving the antitumor immune response by enhancing the type-1 immune response, inhibiting lung metastasis.	('improving', 'PosReg', (104, 113))	('IL-36gamma', 'Var', (66, 76))	('inhibiting', 'NegReg', (185, 195))	('breast cancer lung metastasis', 'Disease', 'MESH:D009362', (9, 38))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('lung metastasis', 'CPA', (196, 211))	('enhancing', 'PosReg', (147, 156))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('breast cancer', 'Phenotype', 'HP:0003002', (9, 22))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('type-1 immune response', 'MPA', (161, 183))	('breast cancer lung metastasis', 'Disease', (9, 38))	('tumor', 'Disease', (122, 127))
380566	32194745	Overall, these studies suggest that IL-36gamma, as an inflammatory cytokine, may serve an important role in inflammatory diseases and antitumor immunotherapy.	('inflammatory diseases', 'Disease', (108, 129))	('tumor', 'Disease', (138, 143))	('IL-36gamma', 'Var', (36, 46))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
380568	32194745	IL-36gamma may affect a variety of cells, including stromal cells, DCs, macrophages and lymphocytes by inducing a series of related inflammatory responses, including the promotion of synthesis and activity of IL-12, IL-8 and IL-6, and the chemokines CXCL1 and CCL20.	('IL-36gamma', 'Var', (0, 10))	('IL-6', 'Gene', (225, 229))	('inducing', 'PosReg', (103, 111))	('inflammatory', 'CPA', (132, 144))	('CCL20', 'Gene', (260, 265))	('IL-6', 'Gene', '3569', (225, 229))	('promotion', 'PosReg', (170, 179))	('CXCL1', 'Gene', (250, 255))	('IL-8', 'Gene', '3576', (216, 220))	('affect', 'Reg', (15, 21))	('activity', 'MPA', (197, 205))	('IL-8', 'Gene', (216, 220))	('CCL20', 'Gene', '6364', (260, 265))	('synthesis', 'MPA', (183, 192))	('IL-1', 'Gene', '3552', (209, 213))	('IL-1', 'Gene', (209, 213))	('CXCL1', 'Gene', '2919', (250, 255))
380574	32194745	It suggestes a potential antitumor effect of IL-36gamma in squamous cell carcinoma.	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (59, 82))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('IL-36gamma', 'Var', (45, 55))	('squamous cell carcinoma', 'Disease', (59, 82))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumor', 'Disease', (29, 34))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (59, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
380575	32194745	Furthermore, in the present study, survival analysis showed that patients with adenocarcinoma with high IL-36gamma protein expression levels had longer survival times (P>0.05); however, the lack of information on patient treatment is a limitation when evaluating the survival time of patients.	('patients', 'Species', '9606', (284, 292))	('patient', 'Species', '9606', (213, 220))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('high', 'Var', (99, 103))	('adenocarcinoma', 'Disease', (79, 93))	('survival times', 'CPA', (152, 166))	('patient', 'Species', '9606', (65, 72))	('adenocarcinoma', 'Disease', 'MESH:D000230', (79, 93))	('patients', 'Species', '9606', (65, 73))	('longer', 'PosReg', (145, 151))	('patient', 'Species', '9606', (284, 291))	('men', 'Species', '9606', (226, 229))
380589	31591862	However, with the development of advanced RT techniques, recent advances in immuno-oncology therapy targeting programmed death 1 (PD-1) and programmed death ligand 1 (PD-L1) and targeted agents for epidermal growth factor receptor (EGFR) mutation or anaplastic lymphoma kinase (ALK) translocation allowed new roles of RT in these patients.	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (250, 269))	('PD-L1', 'Gene', (167, 172))	('programmed death ligand 1', 'Gene', '29126', (140, 165))	('oncology', 'Phenotype', 'HP:0002664', (83, 91))	('PD-L1', 'Gene', '29126', (167, 172))	('patients', 'Species', '9606', (330, 338))	('epidermal growth factor receptor', 'Gene', (198, 230))	('PD-1', 'Gene', (130, 134))	('epidermal growth factor receptor', 'Gene', '1956', (198, 230))	('PD-1', 'Gene', '5133', (130, 134))	('programmed death 1', 'Gene', '5133', (110, 128))	('lymphoma', 'Phenotype', 'HP:0002665', (261, 269))	('EGFR', 'Gene', (232, 236))	('mutation', 'Var', (238, 246))	('programmed death 1', 'Gene', (110, 128))	('programmed death ligand 1', 'Gene', (140, 165))	('ALK', 'Gene', '238', (278, 281))	('ALK', 'Gene', (278, 281))	('EGFR', 'Gene', '1956', (232, 236))
380591	31591862	Recent phase II randomized clinical trials have shown that ablative RT, including stereotactic ablative body radiotherapy (SABR) and hypofractionated RT, to primary and metastatic sites improved progression-free survival (PFS) and overall survival (OS) in patients with oligometastatic NSCLC.	('ablative', 'Var', (59, 67))	('patients', 'Species', '9606', (256, 264))	('oligometastatic NSCLC', 'Disease', (270, 291))	('improved', 'PosReg', (186, 194))	('overall', 'MPA', (231, 238))	('NSCLC', 'Phenotype', 'HP:0030358', (286, 291))	('oligometastatic NSCLC', 'Disease', 'MESH:D002289', (270, 291))	('progression-free survival', 'CPA', (195, 220))
380604	31591862	Genomic analysis in patients with NSCLC has shown that primary tumors and lung metastasis share a common driver mutation.	('NSCLC', 'Disease', (34, 39))	('mutation', 'Var', (112, 120))	('NSCLC', 'Disease', 'MESH:D002289', (34, 39))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('primary tumor', 'Disease', (55, 68))	('NSCLC', 'Phenotype', 'HP:0030358', (34, 39))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('tumors', 'Disease', (63, 69))	('patients', 'Species', '9606', (20, 28))	('primary tumor', 'Disease', 'MESH:D001932', (55, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
380608	31591862	In both linear and parallel progression models, intratumoral heterogeneity of the primary tumor and earlier metastasis can lead to further disseminated metastases.	('heterogeneity', 'Var', (61, 74))	('primary tumor', 'Disease', 'MESH:D001932', (82, 95))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('lead to', 'Reg', (123, 130))	('metastases', 'Disease', (152, 162))	('tumor', 'Disease', (90, 95))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('metastases', 'Disease', 'MESH:D009362', (152, 162))	('tumor', 'Disease', (53, 58))	('primary tumor', 'Disease', (82, 95))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
380622	31591862	Epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) treatment improves OS in advanced NSCLC with EGFR mutation compared with standard first-line systemic treatment with a platinum-based doublet regimen.	('improves', 'PosReg', (80, 88))	('tyrosine', 'Chemical', 'None', (33, 41))	('NSCLC', 'Disease', (104, 109))	('Epidermal growth factor receptor', 'Gene', (0, 32))	('mutation', 'Var', (120, 128))	('EGFR', 'Gene', '1956', (115, 119))	('NSCLC', 'Disease', 'MESH:D002289', (104, 109))	('EGFR', 'Gene', '1956', (60, 64))	('EGFR', 'Gene', (115, 119))	('Epidermal growth factor receptor', 'Gene', '1956', (0, 32))	('NSCLC', 'Phenotype', 'HP:0030358', (104, 109))	('EGFR', 'Gene', (60, 64))	('platinum', 'Chemical', 'MESH:D010984', (189, 197))
380627	31591862	Although third-generation EGFR-TKI targeting the EGFR p.Thr790Met point mutation (T790M) shows superior PFS than standard EGFR-TKIs only targeting exon 19 deletion and exon 21 L858R point mutation, drug-resistant mutations eventually develop in approximately 40% of patients.	('L858R', 'Mutation', 'p.L858R', (176, 181))	('EGFR', 'Gene', (26, 30))	('p.Thr790Met', 'Mutation', 'p.T790M', (54, 65))	('patients', 'Species', '9606', (266, 274))	('EGFR', 'Gene', '1956', (49, 53))	('EGFR', 'Gene', (122, 126))	('EGFR', 'Gene', (49, 53))	('L858R', 'Var', (176, 181))	('T790M', 'Var', (82, 87))	('PFS', 'MPA', (104, 107))	('T790M', 'Mutation', 'p.T790M', (82, 87))	('EGFR', 'Gene', '1956', (26, 30))	('EGFR', 'Gene', '1956', (122, 126))	('p.Thr790Met', 'Var', (54, 65))
380635	31591862	In the multivariate analysis, exon 19 deletion (vs. exon 21 L858R point mutation), single metastasis (vs. multiple metastasis), and LAT for primary tumor (vs. no LAT for primary tumor) were associated with better OS.	('L858R', 'Var', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('LAT', 'Gene', '27040', (162, 165))	('primary tumor', 'Disease', 'MESH:D001932', (140, 153))	('LAT', 'Gene', '27040', (132, 135))	('exon 19 deletion', 'Var', (30, 46))	('primary tumor', 'Disease', (170, 183))	('L858R', 'Mutation', 'p.L858R', (60, 65))	('LAT', 'Gene', (162, 165))	('primary tumor', 'Disease', 'MESH:D001932', (170, 183))	('LAT', 'Gene', (132, 135))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('primary tumor', 'Disease', (140, 153))	('better', 'Disease', (206, 212))
380637	31591862	A single-arm phase II study (NCT01941654) investigated the effects of preemptive LAT to residual oligometastasis (ATOM) in patients with advanced NSCLC with exon 19 deletion or L858R point mutation.	('L858R point mutation', 'Var', (177, 197))	('exon 19 deletion', 'Var', (157, 173))	('NSCLC', 'Disease', (146, 151))	('LAT', 'Gene', '27040', (81, 84))	('patients', 'Species', '9606', (123, 131))	('L858R', 'Mutation', 'p.L858R', (177, 182))	('NSCLC', 'Disease', 'MESH:D002289', (146, 151))	('NSCLC', 'Phenotype', 'HP:0030358', (146, 151))	('NCT01941654', 'Chemical', 'MESH:C079985', (29, 40))	('LAT', 'Gene', (81, 84))
380642	31591862	In patients with lung adenocarcinoma, approximately one-fifth to one-third patients have EGFR mutation, echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (ALK) fusion, or c-ros oncogene 1 fusion.	('carcinoma', 'Phenotype', 'HP:0030731', (27, 36))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (153, 172))	('EGFR', 'Gene', (89, 93))	('patients', 'Species', '9606', (75, 83))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (17, 36))	('ALK', 'Gene', (181, 184))	('patients', 'Species', '9606', (3, 11))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (17, 36))	('lymphoma', 'Phenotype', 'HP:0002665', (164, 172))	('EGFR', 'Gene', '1956', (89, 93))	('mutation', 'Var', (94, 102))	('lung adenocarcinoma', 'Disease', (17, 36))	('ALK', 'Gene', '238', (181, 184))
380644	31591862	However, in patients with lung squamous cell carcinoma, the rate of EGFR mutation is extremely low.	('patients', 'Species', '9606', (12, 20))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (31, 54))	('lung squamous cell carcinoma', 'Disease', (26, 54))	('low', 'NegReg', (95, 98))	('EGFR', 'Gene', '1956', (68, 72))	('mutation', 'Var', (73, 81))	('EGFR', 'Gene', (68, 72))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (26, 54))	('carcinoma', 'Phenotype', 'HP:0030731', (45, 54))
380673	27650585	Recombinant canstatin suppressed the expression of vascular endothelial growth factor receptors (VEGFR)-1 and -2 stimulated by VEGF-A.	('vascular endothelial growth factor receptors (VEGFR)-1 and -2', 'Gene', '14254;16542', (51, 112))	('expression', 'MPA', (37, 47))	('suppressed', 'NegReg', (22, 32))	('VEGF-A', 'Var', (127, 133))
380677	27650585	Antilymphangiogenic signaling by recombinant canstatin is probably mediated by the suppression of the integrin alphavbeta3/VEGFR-1 and/or -2 signaling induced by VEGF-A.	('recombinant', 'Var', (33, 44))	('suppression', 'NegReg', (83, 94))	('VEGFR-1', 'Gene', (123, 130))	('VEGFR-1', 'Gene', '14254', (123, 130))	('Antilymphangiogenic signaling', 'MPA', (0, 29))	('canstatin', 'Gene', (45, 54))
380749	27650585	The level of the VEGF-C protein increased in CoCl2-treated cells by 15.2% compared to the level in CoCl2-untreated cells.	('CoCl2', 'Chemical', 'MESH:C018021', (99, 104))	('level', 'MPA', (4, 9))	('CoCl2-treated', 'Var', (45, 58))	('CoCl2', 'Chemical', 'MESH:C018021', (45, 50))	('VEGF-C', 'Gene', '22341', (17, 23))	('increased', 'PosReg', (32, 41))	('VEGF-C', 'Gene', (17, 23))
380803	27650585	Adenoviral murine VEGF-A injection stimulates in vivo lymphangiogenesis in the skin of the mouse ear 32.	('injection', 'Var', (25, 34))	('stimulates', 'PosReg', (35, 45))	('murine', 'Species', '10090', (11, 17))	('mouse', 'Species', '10090', (91, 96))	('lymphangiogenesis in the', 'CPA', (54, 78))
380832	26918356	High ANP32A expression with N2/N3 stage had an increased mortality risk than low ANP32A expressing OSCC patients with N0/N1 stage.	('ANP32A', 'Gene', (5, 11))	('si', 'Chemical', 'MESH:D012825', (18, 20))	('ANP32A', 'Gene', (81, 87))	('N2/N3 stage', 'Var', (28, 39))	('ANP32A', 'Gene', '8125', (81, 87))	('ANP32A', 'Gene', '8125', (5, 11))	('patients', 'Species', '9606', (104, 112))	('si', 'Chemical', 'MESH:D012825', (94, 96))
380833	26918356	Functional studies revealed that knockdown of ANP32A significantly decreased the migration and invasion ability thereby concomitantly increasing E-cadherin and decreasing Slug, Claudin-1 and Vimentin expression in vitro.	('increasing', 'PosReg', (134, 144))	('Vimentin', 'Gene', (191, 199))	('expression', 'MPA', (200, 210))	('invasion ability', 'CPA', (95, 111))	('Claudin-1', 'Gene', '9076', (177, 186))	('si', 'Chemical', 'MESH:D012825', (206, 208))	('E-cadherin', 'Gene', (145, 155))	('ANP32A', 'Gene', (46, 52))	('E-cadherin', 'Gene', '999', (145, 155))	('si', 'Chemical', 'MESH:D012825', (53, 55))	('Slug', 'Gene', (171, 175))	('knockdown', 'Var', (33, 42))	('si', 'Chemical', 'MESH:D012825', (166, 168))	('Claudin-1', 'Gene', (177, 186))	('si', 'Chemical', 'MESH:D012825', (140, 142))	('decreasing', 'NegReg', (160, 170))	('si', 'Chemical', 'MESH:D012825', (99, 101))	('ANP32A', 'Gene', '8125', (46, 52))	('Vimentin', 'Gene', '7431', (191, 199))	('decreased', 'NegReg', (67, 76))	('migration', 'CPA', (81, 90))	('Slug', 'Gene', '6591', (171, 175))
380864	26918356	The mortality density for patients with N2/N3 of lymph node metastasis and moderate/poor tumor differentiation was 23.5 and 9.0 per 100 people-years, respectively.	('si', 'Chemical', 'MESH:D012825', (67, 69))	('patients', 'Species', '9606', (26, 34))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('si', 'Chemical', 'MESH:D012825', (17, 19))	('N2/N3', 'Var', (40, 45))	('people', 'Species', '9606', (136, 142))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
380866	26918356	The independent mortality risk for patients with high ANP32A expression was non-significant as compared with those with low expression, regardless the use of Allred and IRS scoring systems (both P > 0.05).	('si', 'Chemical', 'MESH:D012825', (67, 69))	('ANP32A', 'Gene', (54, 60))	('si', 'Chemical', 'MESH:D012825', (130, 132))	('high', 'Var', (49, 53))	('patients', 'Species', '9606', (35, 43))	('ANP32A', 'Gene', '8125', (54, 60))	('si', 'Chemical', 'MESH:D012825', (80, 82))
380870	26918356	As compared to patients with N0/N1 stage and low ANP32A expression, the mortality hazard risk was multiplicatively enhanced among patients with N2/N3 stage and high ANP32A expression (aHR = 1.8, 95% CI, 1.1-3.8; P = 0.008 for multiplicative interaction, Table 3).	('patients', 'Species', '9606', (15, 23))	('N2/N3 stage', 'Var', (144, 155))	('ANP32A', 'Gene', '8125', (165, 171))	('ANP32A', 'Gene', '8125', (49, 55))	('patients', 'Species', '9606', (130, 138))	('ANP32A', 'Gene', (165, 171))	('si', 'Chemical', 'MESH:D012825', (178, 180))	('enhanced', 'PosReg', (115, 123))	('ANP32A', 'Gene', (49, 55))	('mortality', 'CPA', (72, 81))	('si', 'Chemical', 'MESH:D012825', (62, 64))
380871	26918356	Focusing on OSCC patients with N2/N3 stage of lymph node metastasis (N = 59), patients with Allred defined high level of ANP32A expression was observed to have a worse survival curves (P = 0.049 for log-rank tests, Figure 2) and a 2.1-fold higher hazard risk (95% CI, 1.0-4.2) than patients with low ANP32A expression.	('si', 'Chemical', 'MESH:D012825', (313, 315))	('ANP32A', 'Gene', '8125', (121, 127))	('ANP32A', 'Gene', '8125', (300, 306))	('si', 'Chemical', 'MESH:D012825', (134, 136))	('patients', 'Species', '9606', (78, 86))	('ANP32A', 'Gene', (121, 127))	('si', 'Chemical', 'MESH:D012825', (64, 66))	('ANP32A', 'Gene', (300, 306))	('patients', 'Species', '9606', (17, 25))	('high', 'Var', (107, 111))	('patients', 'Species', '9606', (282, 290))	('si', 'Chemical', 'MESH:D012825', (4, 6))
380892	26918356	In this present study, we found that lymph node metastasis (N2/N3) patients with high ANP32A expression had a worst prognosis at a 10 year follow up.	('patients', 'Species', '9606', (67, 75))	('ANP32A', 'Gene', '8125', (86, 92))	('high', 'Var', (81, 85))	('si', 'Chemical', 'MESH:D012825', (122, 124))	('lymph node metastasis', 'CPA', (37, 58))	('si', 'Chemical', 'MESH:D012825', (99, 101))	('ANP32A', 'Gene', (86, 92))	('si', 'Chemical', 'MESH:D012825', (55, 57))
380907	26918356	Abrogating ANP32A expression in highly invasive oral cancer cell decreases its metastasis and invasive levels.	('ANP32A', 'Gene', '8125', (11, 17))	('decreases', 'NegReg', (65, 74))	('si', 'Chemical', 'MESH:D012825', (43, 45))	('invasive oral cancer', 'Disease', (39, 59))	('Abrogating', 'Var', (0, 10))	('invasive oral cancer', 'Disease', 'MESH:D009062', (39, 59))	('ANP32A', 'Gene', (11, 17))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('expression', 'MPA', (18, 28))	('si', 'Chemical', 'MESH:D012825', (98, 100))	('invasive levels', 'CPA', (94, 109))	('metastasis', 'CPA', (79, 89))	('si', 'Chemical', 'MESH:D012825', (24, 26))	('si', 'Chemical', 'MESH:D012825', (86, 88))
380912	26918356	In this study, we found that knockdown of ANP32A decreased Snail, Vimentin, Claudin-1 and increased the level of E-cadherin expression in vitro.	('Claudin-1', 'Gene', '9076', (76, 85))	('ANP32A', 'Gene', '8125', (42, 48))	('knockdown', 'Var', (29, 38))	('Claudin-1', 'Gene', (76, 85))	('increased', 'PosReg', (90, 99))	('Vimentin', 'Gene', (66, 74))	('E-cadherin', 'Gene', (113, 123))	('si', 'Chemical', 'MESH:D012825', (130, 132))	('Snail', 'Gene', '6615', (59, 64))	('Snail', 'Gene', (59, 64))	('Vimentin', 'Gene', '7431', (66, 74))	('decreased', 'NegReg', (49, 58))	('ANP32A', 'Gene', (42, 48))	('E-cadherin', 'Gene', '999', (113, 123))
380916	26918356	High ANP32A expression was associated with high stage of lymphnode metastasis at cancer diagnosis, and the mortality hazard risk was multiplicatively enhanced among N2/N3 patients with high ANP32A expression.	('ANP32A', 'Gene', (5, 11))	('si', 'Chemical', 'MESH:D012825', (18, 20))	('enhanced', 'PosReg', (150, 158))	('High', 'Var', (0, 4))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('si', 'Chemical', 'MESH:D012825', (203, 205))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('cancer', 'Disease', (81, 87))	('patients', 'Species', '9606', (171, 179))	('si', 'Chemical', 'MESH:D012825', (74, 76))	('ANP32A', 'Gene', '8125', (190, 196))	('expression', 'MPA', (12, 22))	('ANP32A', 'Gene', '8125', (5, 11))	('si', 'Chemical', 'MESH:D012825', (94, 96))	('ANP32A', 'Gene', (190, 196))
380917	26918356	Our in vitro results further showed that, knockdown of ANP32A in oral cancer cells reduced its invasive and metastatic ability.	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('reduced', 'NegReg', (83, 90))	('oral cancer', 'Disease', 'MESH:D009062', (65, 76))	('ANP32A', 'Gene', '8125', (55, 61))	('si', 'Chemical', 'MESH:D012825', (99, 101))	('oral cancer', 'Disease', (65, 76))	('ANP32A', 'Gene', (55, 61))	('knockdown', 'Var', (42, 51))
380931	26918356	Endogenous peroxidase activity was blocked with 3% H2O2 in methanol, hydrated with gradient alcohol and phosphate-buffered saline solution, and incubated in 10 mmol/L citrate buffer (pH 6.0).	('methanol', 'Chemical', 'MESH:D000432', (59, 67))	('phosphate-buffered saline', 'Chemical', '-', (104, 129))	('alcohol', 'Chemical', 'MESH:D000438', (92, 99))	('Endogenous peroxidase', 'Enzyme', (0, 21))	('activity', 'MPA', (22, 30))	('citrate', 'Chemical', 'MESH:D019343', (167, 174))	('blocked', 'NegReg', (35, 42))	('H2O2', 'Chemical', 'MESH:D006861', (51, 55))	('H2O2', 'Var', (51, 55))
380962	26462025	Gene set enrichment analysis revealed that ERBB signaling pathway is significantly enriched in patients with PFS >=4 months (n = 12) than PFS < 4 months (n = 21) (p < 0.001).	('patients', 'Species', '9606', (95, 103))	('ERBB', 'Gene', (43, 47))	('enriched', 'Reg', (83, 91))	('ERBB', 'Gene', '1956', (43, 47))	('PFS >=4 months', 'Var', (109, 123))
380976	26462025	Over the past decade, molecularly targeted therapies, which block important oncogenic pathways, have made remarkable progress, especially in epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC).	('lung cancer', 'Phenotype', 'HP:0100526', (214, 225))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (199, 225))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('EGFR', 'Gene', (175, 179))	('cell lung cancer', 'Disease', (209, 225))	('NSCLC', 'Disease', (227, 232))	('epidermal growth factor receptor', 'Gene', (141, 173))	('NSCLC', 'Disease', 'MESH:D002289', (227, 232))	('cell lung cancer', 'Disease', 'MESH:D008175', (209, 225))	('mutation-positive', 'Var', (181, 198))	('epidermal growth factor receptor', 'Gene', '1956', (141, 173))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (203, 225))
380982	26462025	EGFR overexpression and amplification was frequently observed in ESCC and was correlated with advanced tumor stage and poor prognosis.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('EGFR', 'Gene', (0, 4))	('tumor', 'Disease', (103, 108))	('overexpression', 'PosReg', (5, 19))	('amplification', 'Var', (24, 37))	('ESCC', 'Disease', (65, 69))	('correlated', 'Reg', (78, 88))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
380986	26462025	Of note, a higher rate of disease control with gefitinib was observed in female patients with ESCC and high EGFR expression.	('patients', 'Species', '9606', (80, 88))	('EGFR', 'Gene', (108, 112))	('high', 'Var', (103, 107))	('gefitinib', 'Chemical', 'MESH:D000077156', (47, 56))	('ESCC', 'Disease', (94, 98))
380987	26462025	Erlotinib also exhibited higher ORR (15% vs. 0%) and longer time to progression (3.3 vs. 1.6 months) in ESCC, compared with adenocarcinoma.	('Erlotinib', 'Var', (0, 9))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('ESCC', 'Disease', (104, 108))	('ORR', 'MPA', (32, 35))	('adenocarcinoma', 'Disease', (124, 138))	('higher', 'PosReg', (25, 31))	('adenocarcinoma', 'Disease', 'MESH:D000230', (124, 138))	('Erlotinib', 'Chemical', 'MESH:D000069347', (0, 9))
381027	26462025	EGFR mutations were found in 3 patients (1 CB, 2 non-CB).	('found', 'Reg', (20, 25))	('patients', 'Species', '9606', (31, 39))	('EGFR', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))
381028	26462025	Interestingly, all these EGFR mutations were not classic drug-sensitive exon 19 and 21 mutations frequently identified in NSCLC, but atypical exon 20 mutations (V765M, C775Y, and G810D).	('V765M', 'Var', (161, 166))	('NSCLC', 'Disease', 'MESH:D002289', (122, 127))	('EGFR', 'Gene', (25, 29))	('C775Y', 'Mutation', 'p.C775Y', (168, 173))	('G810D', 'Var', (179, 184))	('G810D', 'Mutation', 'rs121913431', (179, 184))	('C775Y', 'Var', (168, 173))	('V765M', 'Mutation', 'rs374873413', (161, 166))	('NSCLC', 'Disease', (122, 127))
381032	26462025	Significant inhibition of tumor cell growth by dacomitinib was found in cells with high-EGFR expression (TE2 and TE3) in comparison to that against low-EGFR expressing HCE4 (Figure 5A-5C).	('TE2', 'Gene', '8260', (105, 108))	('dacomitinib', 'Chemical', 'MESH:C525726', (47, 58))	('TE2', 'Gene', (105, 108))	('inhibition', 'NegReg', (12, 22))	('high-EGFR expression', 'Var', (83, 103))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('HCE4', 'Chemical', '-', (168, 172))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))
381036	26462025	Taken together, high EGFR expression was associated with sensitivity to dacomitinib in ESCC cell lines.	('expression', 'MPA', (26, 36))	('EGFR', 'Gene', (21, 25))	('associated', 'Reg', (41, 51))	('high', 'Var', (16, 20))	('sensitivity to dacomitinib', 'MPA', (57, 83))	('dacomitinib', 'Chemical', 'MESH:C525726', (72, 83))
381062	26462025	Recently, whole exome sequencing studies in ESCC have been reported, uncovering recurrent somatic mutations in TP53 (60-93%), CDKN2A (3-8%), RB1 (8-9%), PIK3CA (7-9%) and PTEN (5%).	('PIK3CA', 'Gene', '5290', (153, 159))	('RB1', 'Gene', (141, 144))	('TP53', 'Gene', '7157', (111, 115))	('RB1', 'Gene', '5925', (141, 144))	('CDKN2A', 'Gene', (126, 132))	('TP53', 'Gene', (111, 115))	('mutations', 'Var', (98, 107))	('CDKN2A', 'Gene', '1029', (126, 132))	('PTEN', 'Gene', (171, 175))	('PTEN', 'Gene', '5728', (171, 175))	('PIK3CA', 'Gene', (153, 159))
381063	26462025	In our study, genes involved in cell cycle and apoptosis regulation were mutated in 69% of cases by somatic alterations of TP53 (61%), CDKN2A (8%) and MLH1 (8%), which was comparable to the previous reports.	('CDKN2A', 'Gene', (135, 141))	('CDKN2A', 'Gene', '1029', (135, 141))	('alterations', 'Var', (108, 119))	('apoptosis', 'CPA', (47, 56))	('MLH1', 'Gene', '4292', (151, 155))	('MLH1', 'Gene', (151, 155))	('mutated', 'Reg', (73, 80))	('cell cycle', 'CPA', (32, 42))	('TP53', 'Gene', '7157', (123, 127))	('TP53', 'Gene', (123, 127))
381064	26462025	Consistent with previous reports, we also found mutations in PI3K/mTOR pathway including PIK3CA (3%), PTEN (3%) and STK11 (3%).	('mTOR', 'Gene', (66, 70))	('STK11', 'Gene', (116, 121))	('mTOR', 'Gene', '2475', (66, 70))	('PIK3CA', 'Gene', (89, 95))	('STK11', 'Gene', '6794', (116, 121))	('PIK3CA', 'Gene', '5290', (89, 95))	('PTEN', 'Gene', (102, 106))	('PTEN', 'Gene', '5728', (102, 106))	('mutations', 'Var', (48, 57))
381065	26462025	Although somatic mutations in the EGFR tyrosine kinase domain have been associated with dramatic response to EGFR-TKIs in NSCLC, these drug-sensitive EGFR mutations are rare in ESCC.	('NSCLC', 'Disease', 'MESH:D002289', (122, 127))	('EGFR', 'Gene', (34, 38))	('ESCC', 'Disease', (177, 181))	('associated', 'Reg', (72, 82))	('NSCLC', 'Disease', (122, 127))	('mutations', 'Var', (17, 26))
381066	26462025	In our study, three patients harbored EGFR exon 20 mutations (V765M, G810D, C775Y).	('EGFR', 'Gene', (38, 42))	('C775Y', 'Mutation', 'p.C775Y', (76, 81))	('G810D', 'Var', (69, 74))	('V765M', 'Var', (62, 67))	('patients', 'Species', '9606', (20, 28))	('G810D', 'Mutation', 'rs121913431', (69, 74))	('V765M', 'Mutation', 'rs374873413', (62, 67))	('C775Y', 'Var', (76, 81))
381067	26462025	Interestingly, a NSCLC patient with V765M EGFR mutations had a partial response to gefitinib.	('V765M', 'Var', (36, 41))	('NSCLC', 'Disease', (17, 22))	('gefitinib', 'Chemical', 'MESH:D000077156', (83, 92))	('NSCLC', 'Disease', 'MESH:D002289', (17, 22))	('EGFR', 'Gene', (42, 46))	('V765M', 'Mutation', 'rs374873413', (36, 41))	('patient', 'Species', '9606', (23, 30))
381068	26462025	Consistent with this report, a case with V765M EGFR mutation in our study showed PFS of 4.1 months with 10% of tumor shrinkage.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumor', 'Disease', (111, 116))	('V765M', 'Var', (41, 46))	('EGFR', 'Gene', (47, 51))	('V765M', 'Mutation', 'rs374873413', (41, 46))
381069	26462025	The activating mutation (D820E) in exon 17 of KIT tyrosine kinase in a patient showing rapid progression within 28 days has been previously reported in imatinib-resistant gastrointestinal stromal tumors.	('tumors', 'Phenotype', 'HP:0002664', (196, 202))	('imatinib', 'Chemical', 'MESH:D000068877', (152, 160))	('activating', 'PosReg', (4, 14))	('gastrointestinal stromal tumors', 'Disease', (171, 202))	('gastrointestinal stromal tumors', 'Phenotype', 'HP:0100723', (171, 202))	('D820E', 'Var', (25, 30))	('patient', 'Species', '9606', (71, 78))	('D820E', 'Mutation', 'rs1057519711', (25, 30))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('gastrointestinal stromal tumors', 'Disease', 'MESH:D046152', (171, 202))
381087	26462025	Fresh or archival formalin-fixed paraffin embedded (FFPE) tumor tissues were collected at baseline for biomarker analysis, which included characterization of gene expression by Nanostring nCounter  Cancer Human Cancer Reference Kit, which is a sensitive assay quantifying mRNA transcripts of 230 genes using multiplexed, color-coded probes, and somatic mutations by Ion Torrent AmpliSeq Cancer Hotspot Panel v2 (CHPv2), which is a next generation sequencing assay detecting 2,800 Catalogue Of Somatic Mutations In Cancer (COSMIC) mutations from 50 genes.	('Cancer', 'Disease', (514, 520))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('Cancer', 'Phenotype', 'HP:0002664', (211, 217))	('mutations', 'Var', (530, 539))	('Cancer', 'Phenotype', 'HP:0002664', (514, 520))	('Cancer Human Cancer', 'Disease', (198, 217))	('OS', 'Chemical', '-', (523, 525))	('Cancer', 'Phenotype', 'HP:0002664', (387, 393))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('paraffin', 'Chemical', 'MESH:D010232', (33, 41))	('Mutations', 'Var', (501, 510))	('formalin', 'Chemical', 'MESH:D005557', (18, 26))	('Cancer Human Cancer', 'Disease', 'MESH:D009369', (198, 217))	('Cancer', 'Phenotype', 'HP:0002664', (198, 204))
381094	26462025	For the predictive biomarker analysis, we defined clinical benefit (CB) as PFS >= 4 months on dacomitinib based on the previous results that second-line therapies with either cytotoxic agent or EGFR inhibitors in R/M-ESCC have shown PFS of less than 4 months.	('inhibitors', 'Var', (199, 209))	('clinical', 'Species', '191496', (50, 58))	('dacomitinib', 'Chemical', 'MESH:C525726', (94, 105))	('EGFR', 'Gene', (194, 198))
381103	26462025	p-EGFR (Y1068), EGFR, p-AKT(S473), AKT, p-ERK (T202/Y204), and ERK secondary antibodies were purchased from Cell Signaling Technology (Beverly, MA, USA) and beta-actin from Santa Cruz biotechnology (Santa Cruz, CA, USA).	('Y1068', 'Var', (8, 13))	('beta-actin', 'Gene', '728378', (157, 167))	('beta-actin', 'Gene', (157, 167))	('p-ERK', 'Gene', '9451', (40, 45))	('p-ERK', 'Gene', (40, 45))
381113	25521201	Aberrant miRNA expressions have been linked to many diseases, and have been intensively investigated recently to discover miRNA biomarkers for the diagnosis of diseases including lung cancer.	('miRNA expressions', 'MPA', (9, 26))	('Aberrant', 'Var', (0, 8))	('lung cancer', 'Disease', (179, 190))	('lung cancer', 'Phenotype', 'HP:0100526', (179, 190))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('linked', 'Reg', (37, 43))	('lung cancer', 'Disease', 'MESH:D008175', (179, 190))
381125	25521201	We also established links between the diseases and chromosomal locus with the common target genes to show that most of the chromosomal loci have a high frequency of genomic alteration in lung cancer and that two sets of our biomarkers have confirmed associations with lung cancer.	('alteration', 'Var', (173, 183))	('lung cancer', 'Disease', 'MESH:D008175', (187, 198))	('lung cancer', 'Disease', 'MESH:D008175', (268, 279))	('cancer', 'Phenotype', 'HP:0002664', (273, 279))	('associations', 'Interaction', (250, 262))	('lung cancer', 'Disease', (268, 279))	('lung cancer', 'Phenotype', 'HP:0100526', (268, 279))	('lung cancer', 'Disease', (187, 198))	('lung cancer', 'Phenotype', 'HP:0100526', (187, 198))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))
381147	25521201	In fact, 6 of the 18 decision trees (DT2, DT3, DT4, DT9, DT10, and DT15) produce an accuracy of 100% consisting of 2 or 3 miRNAs.	('DT4', 'Var', (47, 50))	('DT2', 'Chemical', '-', (37, 40))	('DT10', 'Var', (57, 61))	('DT2', 'Var', (37, 40))	('DT9', 'Var', (52, 55))	('DT15', 'Var', (67, 71))	('DT4', 'Chemical', 'MESH:D003918', (47, 50))
381174	25521201	The other three important 2-miRNA rules are formed by miR-205 and miR-451, by miR-103 and miR-126, or by let-7a and miR-205.	('miR-103', 'Var', (78, 85))	('miR-205', 'Gene', (54, 61))	('miR-205', 'Gene', '406988', (54, 61))	('miR-205', 'Gene', (116, 123))	('miR-126', 'Gene', '406913', (90, 97))	('miR-451', 'Gene', '574411', (66, 73))	('miR-205', 'Gene', '406988', (116, 123))	('miR-126', 'Gene', (90, 97))	('miR-451', 'Gene', (66, 73))
381175	25521201	The best 3-miRNA rule is formed by miR-126, miR-205 and miR-182; the second best is by miR-100, miR-199a and miR-200c; and the third best is by miR-133a, miR-21 and miR-520a-AS.	('miR-21', 'Gene', (154, 160))	('miR-520a', 'Gene', '574467', (165, 173))	('miR-182', 'Gene', '406958', (56, 63))	('miR-200c', 'Gene', (109, 117))	('miR-205', 'Gene', (44, 51))	('miR-126', 'Gene', '406913', (35, 42))	('miR-200c', 'Gene', '406985', (109, 117))	('miR-100', 'Gene', (87, 94))	('miR-205', 'Gene', '406988', (44, 51))	('miR-21', 'Gene', '406991', (154, 160))	('miR-126', 'Gene', (35, 42))	('miR-133a', 'Var', (144, 152))	('miR-182', 'Gene', (56, 63))	('miR-199a', 'Var', (96, 104))	('miR-100', 'Gene', '406892', (87, 94))	('miR-520a', 'Gene', (165, 173))
381179	25521201	It has been previously reported that there are many chromosomal arms having frequent loss of heterozygosity, such as 1p, 3p, 4p, 4q, 5q, 8p, 9p (p16), 9q, 10p, 10q, 13q (Rb), 15q, 17p (p53), 18q, 19p, Xp, and Xq, in frequency order for lung cancer.	('p16', 'Gene', '1029', (145, 148))	('lung cancer', 'Phenotype', 'HP:0100526', (236, 247))	('p53', 'Gene', (185, 188))	('p53', 'Gene', '7157', (185, 188))	('10p', 'Var', (155, 158))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('15q', 'Var', (175, 178))	('lung cancer', 'Disease', 'MESH:D008175', (236, 247))	('p16', 'Gene', (145, 148))	('18q', 'Var', (191, 194))	('lung cancer', 'Disease', (236, 247))
381181	25521201	It was reported by that there are 5 cases of renal cell carcinoma with translocation involving Xp11.2 in children.	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (45, 65))	('Xp11.2', 'Gene', (95, 101))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (45, 65))	('translocation involving', 'Var', (71, 94))	('children', 'Species', '9606', (105, 113))	('renal cell carcinoma', 'Disease', (45, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (56, 65))
381197	25521201	It was found that: (i) the two miRNAs (miR-98 and miR-205) involved in our best rule have been both confirmed to associate with carcinoma; and (ii) Let-7a and miR-205 (in the second best rule) have been confirmed to be directly associated with lung cancer.	('miR-205', 'Gene', (50, 57))	('lung cancer', 'Disease', 'MESH:D008175', (244, 255))	('miR-205', 'Gene', '406988', (159, 166))	('miR-98', 'Gene', '407054', (39, 45))	('miR-98', 'Gene', (39, 45))	('Let-7a', 'Var', (148, 154))	('miR-205', 'Gene', '406988', (50, 57))	('carcinoma', 'Disease', 'MESH:D002277', (128, 137))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('lung cancer', 'Disease', (244, 255))	('carcinoma', 'Disease', (128, 137))	('lung cancer', 'Phenotype', 'HP:0100526', (244, 255))	('associate', 'Reg', (113, 122))	('associated', 'Reg', (228, 238))	('cancer', 'Phenotype', 'HP:0002664', (249, 255))	('miR-205', 'Gene', (159, 166))
381198	25521201	On the other hand, we did not find evidence in the literature to show the pair miR-451 and miR-205, or the pair miR-103 and miR-126 linked to lung cancer in any way (Table 8).	('miR-451', 'Gene', (79, 86))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('lung cancer', 'Disease', 'MESH:D008175', (142, 153))	('miR-205', 'Gene', (91, 98))	('linked', 'Reg', (132, 138))	('miR-205', 'Gene', '406988', (91, 98))	('miR-126', 'Gene', '406913', (124, 131))	('miR-126', 'Gene', (124, 131))	('lung cancer', 'Disease', (142, 153))	('miR-451', 'Gene', '574411', (79, 86))	('lung cancer', 'Phenotype', 'HP:0100526', (142, 153))	('miR-103', 'Var', (112, 119))
381199	25521201	In addition, from the miR2Disease, a manually various human diseases, the five miRNAs (miR-98, miR-205, miR-451, miR-126 and let-7a) have been found to be associated with lung cancer.	('let-7a', 'Var', (125, 131))	('miR-98', 'Gene', (87, 93))	('miR-451', 'Gene', (104, 111))	('miR-126', 'Gene', (113, 120))	('lung cancer', 'Disease', (171, 182))	('miR-205', 'Gene', (95, 102))	('associated', 'Reg', (155, 165))	('lung cancer', 'Phenotype', 'HP:0100526', (171, 182))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('miR-205', 'Gene', '406988', (95, 102))	('miR-451', 'Gene', '574411', (104, 111))	('lung cancer', 'Disease', 'MESH:D008175', (171, 182))	('miR-126', 'Gene', '406913', (113, 120))	('human', 'Species', '9606', (54, 59))	('miR-98', 'Gene', '407054', (87, 93))
381227	33826244	Recently, molecular therapeutics targeting receptor tyrosine kinase (RTK) aberrations in lung cancer, including epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK), and immunotherapies have been developed.	('epidermal growth factor receptor', 'Gene', (112, 144))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (156, 175))	('EGFR', 'Gene', (146, 150))	('epidermal growth factor receptor', 'Gene', '1956', (112, 144))	('lung cancer', 'Disease', 'MESH:D008175', (89, 100))	('anaplastic lymphoma kinase', 'Gene', '238', (156, 182))	('receptor tyrosine kinase', 'Gene', '5979', (43, 67))	('anaplastic lymphoma kinase', 'Gene', (156, 182))	('lung cancer', 'Phenotype', 'HP:0100526', (89, 100))	('lymphoma', 'Phenotype', 'HP:0002665', (167, 175))	('receptor tyrosine kinase', 'Gene', (43, 67))	('EGFR', 'Gene', '1956', (146, 150))	('ALK', 'Gene', '238', (184, 187))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('RTK', 'Gene', (69, 72))	('ALK', 'Gene', (184, 187))	('lung cancer', 'Disease', (89, 100))	('RTK', 'Gene', '5979', (69, 72))	('aberrations', 'Var', (74, 85))
381229	33826244	Gene therapy is a promising complementary, alternative treatment strategy for many cancers, with several approaches developed in this area.	('cancers', 'Disease', 'MESH:D009369', (83, 90))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('Gene', 'Var', (0, 4))	('cancers', 'Phenotype', 'HP:0002664', (83, 90))	('cancers', 'Disease', (83, 90))
381230	33826244	For example, normal gene insertion into tumor cells to replace a mutant gene (e.g., p53), infection with oncolytic viruses to selectively replicate and lyse tumor cells (e.g., replication-deficient adenovirus), and the tumor-specific expression of suicide genes which convert inactive pro-drugs into active drugs (e.g., herpes virus thymidine kinase [HSV-tk] combined with ganciclovir [GCV]).	('tumor', 'Disease', (157, 162))	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('GCV', 'Chemical', 'MESH:D015774', (386, 389))	('tumor', 'Disease', (219, 224))	('adenovirus', 'Species', '10508', (198, 208))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('mutant', 'Var', (65, 71))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('insertion', 'Var', (25, 34))	('ganciclovir', 'Chemical', 'MESH:D015774', (373, 384))	('infection', 'Disease', (90, 99))	('p53', 'Gene', (84, 87))	('p53', 'Gene', '7157', (84, 87))	('infection', 'Disease', 'MESH:D007239', (90, 99))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('tumor', 'Disease', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (219, 224))
381246	33826244	LC-1/Sq and LC-2/Ad were cultured in medium consisting of a mixture of Ham's F12 (N6658) (Sigma-Aldrich Corp.) and RPMI-1640 (R8758) (Sigma-Aldrich Corp.) at a 1:1 (v/v) ratio supplemented with 25 mM HEPES (15630106) (Thermo Fisher Scientific Inc., Waltham, MA), 10% (v/v) FBS (S0250) (Biowest SAS, France) and 100 Units/ml of penicillin and 100 microg/ml of streptomycin (15140122) (Thermo Fisher Scientific Inc.).	('penicillin', 'Chemical', 'MESH:D010406', (327, 337))	('streptomycin', 'Chemical', 'MESH:D013307', (359, 371))	('FBS', 'Disease', 'MESH:D005198', (273, 276))	('15140122', 'Var', (373, 381))	('FBS', 'Disease', (273, 276))	('RPMI-1640', 'Chemical', '-', (115, 124))
381263	33826244	The following primer pairs with a phosphate group at the 5  end were used for this study: for deletion of NFIC-binding motif, 5 -TAAGAGGGCATGCAATTCAGC-3  and 5 -CACCAGACCAGTTGAGGGAC-3 ; for deletion of GATA2-binding motif, 5'-TCCTCAGGATCAAGGACCAA-3' and 5 -CGGCTATAAAATCCCTGGGT-3 .	('deletion', 'Var', (94, 102))	('GATA2', 'Gene', (202, 207))	('deletion', 'Var', (190, 198))	('GATA2', 'Gene', '2624', (202, 207))	('NFIC', 'Gene', (106, 110))	('NFIC', 'Gene', '4782', (106, 110))	('phosphate', 'Chemical', 'MESH:D010710', (34, 43))
381283	33826244	Similarly, 2.5 x 103 cells of P STC-1-UPRT-PC-9/A549/H1299 were seeded into a well of 96-well plate and were cultured at 37 C. After 24 h, cell proliferation was stopped with 10 microg/ml of Mitomycin C (M3377) (Fujifilm Wako Pure Chemical Corp.).	('STC-1-UPRT', 'Gene', (32, 42))	('PC-9/A549', 'CellLine', 'CVCL:0023', (43, 52))	('M3377', 'Var', (204, 209))	('Mitomycin C', 'Chemical', 'MESH:D016685', (191, 202))	('H1299', 'CellLine', 'CVCL:0060', (53, 58))	('cell proliferation', 'CPA', (139, 157))	('UPRT-PC-9', 'CellLine', 'CVCL:B260', (38, 47))	('STC-1-UPRT', 'Gene', '6781;139596', (32, 42))
381317	33826244	Results show that STC-1 expression was high in H1299 and H1975, but slight or non-existent in LC-1/Sq, LC-2/Ad, and LK-2 (Figure 2A and B).	('H1299', 'Var', (47, 52))	('expression', 'MPA', (24, 34))	('high', 'PosReg', (39, 43))	('H1299', 'CellLine', 'CVCL:0060', (47, 52))	('STC-1', 'Gene', (18, 23))	('H1975', 'Var', (57, 62))	('H1975', 'CellLine', 'CVCL:1511', (57, 62))
381319	33826244	Using the database JASPAR (http://jaspar.genereg.net/) to elucidate the transcription factors that bind to -114, NFIC and GATA2 were identified as candidates (Figure 2E).	('GATA2', 'Gene', (122, 127))	('GATA2', 'Gene', '2624', (122, 127))	('NFIC', 'Gene', '4782', (113, 117))	('NFIC', 'Gene', (113, 117))	('to -114', 'Var', (104, 111))
381331	33826244	Both P STC-1-UPRT-PC-9 and P STC-1-Null-PC-9 formed visible tumor masses up to 30 days after inoculation.	('PC-9', 'CellLine', 'CVCL:B260', (40, 44))	('STC-1-UPRT', 'Gene', '6781;139596', (7, 17))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('P STC-1-Null-PC-9', 'Var', (27, 44))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('STC-1-UPRT', 'Gene', (7, 17))	('UPRT-PC-9', 'CellLine', 'CVCL:B260', (13, 22))	('tumor', 'Disease', (60, 65))	('PC-9', 'CellLine', 'CVCL:B260', (18, 22))
381350	33826244	Both LK-2-Luc/UPRT-PC-9 and LK-2-Luc/Null-PC-9 successfully formed visible tumor masses up to 30 days after inoculation.	('LK-2-Luc/UPRT-PC-9', 'Var', (5, 23))	('PC-9', 'CellLine', 'CVCL:B260', (19, 23))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('LK-2-Luc/Null-PC-9', 'Var', (28, 46))	('UPRT-PC-9', 'CellLine', 'CVCL:B260', (14, 23))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('PC-9', 'CellLine', 'CVCL:B260', (42, 46))	('tumor', 'Disease', (75, 80))
381351	33826244	Next, LK-2-Luc/UPRT-PC-9 or LK-2-Luc/Null-PC-9 were inoculated subcutaneously into BALB/c-nu/nu mice.	('mice', 'Species', '10090', (96, 100))	('LK-2-Luc/UPRT-PC-9', 'Var', (6, 24))	('UPRT-PC-9', 'CellLine', 'CVCL:B260', (15, 24))	('LK-2-Luc/Null-PC-9', 'Var', (28, 46))	('PC-9', 'CellLine', 'CVCL:B260', (20, 24))	('PC-9', 'CellLine', 'CVCL:B260', (42, 46))
381353	33826244	As shown in Figure 5D and E, the growth of LK-2-Luc/UPRT-PC-9 was significantly more arrested than in LK-2-Luc/Null-PC-9 in terms of both weight and volume.	('UPRT-PC-9', 'CellLine', 'CVCL:B260', (52, 61))	('growth', 'MPA', (33, 39))	('arrest', 'Disease', (85, 91))	('PC-9', 'CellLine', 'CVCL:B260', (57, 61))	('PC-9', 'CellLine', 'CVCL:B260', (116, 120))	('arrest', 'Disease', 'MESH:D006323', (85, 91))	('more', 'PosReg', (80, 84))	('LK-2-Luc/UPRT-PC-9', 'Var', (43, 61))
381354	33826244	Furthermore, we confirmed that the results observed for mice inoculated with LK-2-Luc/UPRT-PC-9 and treated with 5-FU were attributed to growth arrest of both LK-2-Luc and UPRT-PC-9, and not to that of UPRT-PC-9 alone.	('UPRT-PC-9', 'CellLine', 'CVCL:B260', (86, 95))	('LK-2-Luc', 'Var', (159, 167))	('5-FU', 'Chemical', 'MESH:D005472', (113, 117))	('mice', 'Species', '10090', (56, 60))	('growth arrest', 'Phenotype', 'HP:0001510', (137, 150))	('arrest', 'Disease', 'MESH:D006323', (144, 150))	('UPRT-PC-9', 'CellLine', 'CVCL:B260', (172, 181))	('UPRT-PC-9', 'CellLine', 'CVCL:B260', (202, 211))	('arrest', 'Disease', (144, 150))	('LK-2-Luc/UPRT-PC-9', 'Var', (77, 95))
381355	33826244	As observed using bioluminescence assay, the mice inoculated with LK-2-Luc/UPRT-PC-9 exhibited significantly more quenching of luminescence at days 19 and 24 than that exhibited by LK-2-Luc/Null-PC-9 by administration of 5-FU (Figure 5F).	('quenching', 'NegReg', (114, 123))	('luminescence', 'MPA', (127, 139))	('mice', 'Species', '10090', (45, 49))	('PC-9', 'CellLine', 'CVCL:B260', (80, 84))	('LK-2-Luc/UPRT-PC-9', 'Var', (66, 84))	('UPRT-PC-9', 'CellLine', 'CVCL:B260', (75, 84))	('5-FU', 'Chemical', 'MESH:D005472', (221, 225))	('PC-9', 'CellLine', 'CVCL:B260', (195, 199))	('more', 'PosReg', (109, 113))
381367	33826244	PC-9, A549, H1975, and H1650), and large cell carcinoma (e.g.	('carcinoma', 'Disease', 'MESH:D009369', (46, 55))	('A549', 'CellLine', 'CVCL:0023', (6, 10))	('carcinoma', 'Phenotype', 'HP:0030731', (46, 55))	('large cell carcinoma', 'Phenotype', 'HP:0030360', (35, 55))	('H1975', 'Var', (12, 17))	('H1975', 'CellLine', 'CVCL:1511', (12, 17))	('carcinoma', 'Disease', (46, 55))	('H1650', 'Var', (23, 28))	('PC-9', 'CellLine', 'CVCL:B260', (0, 4))	('H1650', 'CellLine', 'CVCL:1483', (23, 28))
381380	33826244	reported that CDC5L is involved in cell cycle progression, especially G2/M entry, and siRNA-mediated silencing of CDC5L induced G2/M arrest and apoptosis of bladder cancer cells.	('M arrest', 'Disease', 'MESH:D006323', (131, 139))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('M arrest', 'Disease', (131, 139))	('silencing', 'Var', (101, 110))	('bladder cancer', 'Phenotype', 'HP:0009725', (157, 171))	('CDC5L', 'Gene', '988', (114, 119))	('apoptosis', 'CPA', (144, 153))	('CDC5L', 'Gene', (14, 19))	('bladder cancer', 'Disease', 'MESH:D001749', (157, 171))	('bladder cancer', 'Disease', (157, 171))	('CDC5L', 'Gene', (114, 119))	('CDC5L', 'Gene', '988', (14, 19))
381381	33826244	22  Similarly, it has been reported that siRNA-mediated silencing of ECD also induced G2/M arrest and apoptosis, and overexpression of ECD promoted ubiquitination and proteasome degradation of p53, a tumor suppressor protein, in gastric tumor cells.	('silencing', 'Var', (56, 65))	('p53', 'Gene', (193, 196))	('apoptosis', 'CPA', (102, 111))	('ECD', 'Disease', 'MESH:C574275', (69, 72))	('ECD', 'Disease', (69, 72))	('proteasome degradation', 'MPA', (167, 189))	('M arrest', 'Disease', 'MESH:D006323', (89, 97))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))	('gastric tumor', 'Disease', (229, 242))	('gastric tumor', 'Disease', 'MESH:D013274', (229, 242))	('gastric tumor', 'Phenotype', 'HP:0006753', (229, 242))	('tumor', 'Disease', (200, 205))	('M arrest', 'Disease', (89, 97))	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('induced', 'Reg', (78, 85))	('promoted', 'PosReg', (139, 147))	('tumor', 'Disease', (237, 242))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('p53', 'Gene', '7157', (193, 196))	('ubiquitination', 'MPA', (148, 162))	('ECD', 'Disease', 'MESH:C574275', (135, 138))	('tumor', 'Disease', 'MESH:D009369', (237, 242))	('ECD', 'Disease', (135, 138))
381405	31766658	We identified five different mechanistic signatures of HPV insertions.	('HPV', 'Species', '10566', (55, 58))	('insertions', 'Var', (59, 69))	('HPV', 'Gene', (55, 58))
381408	31766658	The most common signature of HPV insertion was MJ-SC (26.9%), i.e., HPV-chromosomal junctions scattered at different loci.	('insertion', 'Var', (33, 42))	('MJ-SC', 'Disease', (47, 52))	('HPV', 'Species', '10566', (29, 32))	('HPV', 'Species', '10566', (68, 71))	('MJ', 'Chemical', 'MESH:C078587', (47, 49))	('HPV', 'Gene', (29, 32))
381411	31766658	Overall, the distribution of mechanistic signatures of HPV insertions in ASCC was different from that observed in cervical carcinoma and was associated with viral load and PIK3CA mutation.	('viral load', 'MPA', (157, 167))	('HPV', 'Species', '10566', (55, 58))	('cervical carcinoma', 'Disease', 'MESH:D002583', (114, 132))	('HPV', 'Gene', (55, 58))	('insertions', 'Var', (59, 69))	('PIK3CA', 'Gene', (172, 178))	('associated', 'Reg', (141, 151))	('PIK3CA', 'Gene', '5290', (172, 178))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('cervical carcinoma', 'Disease', (114, 132))	('ASCC', 'Gene', (73, 77))
381412	31766658	We confirmed recurrent targeting of NFIX by HPV integration, suggesting a role for this gene in ASCC carcinogenesis.	('NFIX', 'Gene', (36, 40))	('NFIX', 'Gene', '4784', (36, 40))	('HPV', 'Species', '10566', (44, 47))	('HPV integration', 'Var', (44, 59))	('ASCC', 'Disease', (96, 100))
381417	31766658	High-risk HPV (mainly, genotype 16) DNA is detected in up to 90%-95% of ASCC specimens.	('HPV', 'Species', '10566', (10, 13))	('genotype 16', 'Var', (23, 34))	('men', 'Species', '9606', (82, 85))	('ASCC', 'Disease', (72, 76))
381427	31766658	Integration of HPV DNA into the host genome has also been reported as a potential pathogenic mechanism.	('HPV DNA', 'Gene', (15, 22))	('HPV', 'Species', '10566', (15, 18))	('Integration', 'Var', (0, 11))
381429	31766658	This comprehensive approach was validated in a series of 72 cases of cervical squamous cell carcinoma using both tumor tissue biopsy and circulating viral DNA from blood samples and identified five mechanistic signatures of HPV status: episomal [EPI]; integrated in a truncated form revealing two HPV-chromosomal junctions (2J) either colinear [2J-COL] or noncolinear [2J-NL], or multiple (>2) hybrid junctions [MJ] clustering in a single chromosomal region [MJ-CL] or scattered over different chromosomal regions [MJ-SC] of the human genome.	('tumor', 'Disease', (113, 118))	('hybrid', 'Var', (394, 400))	('human', 'Species', '9606', (529, 534))	('MJ-CL', 'Disease', (459, 464))	('HPV', 'Species', '10566', (224, 227))	('MJ', 'Chemical', 'MESH:C078587', (515, 517))	('MJ-CL', 'Disease', 'MESH:D009207', (459, 464))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('HPV', 'Species', '10566', (297, 300))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (78, 101))	('MJ', 'Chemical', 'MESH:C078587', (459, 461))	('squamous cell carcinoma', 'Disease', (78, 101))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (78, 101))	('MJ', 'Chemical', 'MESH:C078587', (412, 414))
381467	31766658	The other HPV genotypes (8/93, 8.6%) were HPV6 (n = 3), HPV18 (n = 2), HPV33 (n = 1), HPV35 (n = 1), and HPV67 (n = 1).	('HPV', 'Species', '10566', (10, 13))	('HPV', 'Species', '10566', (86, 89))	('HPV', 'Species', '10566', (42, 45))	('HPV35', 'Var', (86, 91))	('HPV35', 'Species', '10587', (86, 91))	('HPV', 'Species', '10566', (56, 59))	('HPV67', 'Chemical', 'MESH:D053918', (105, 110))	('HPV33', 'Var', (71, 76))	('HPV6', 'Var', (42, 46))	('HPV', 'Species', '10566', (71, 74))	('HPV', 'Species', '10566', (105, 108))	('HPV33', 'Chemical', 'MESH:D053918', (71, 76))	('HPV67', 'Var', (105, 110))	('HPV18', 'Var', (56, 61))
381468	31766658	Previous mutational analysis of the PIK3CA gene performed on all tumor samples demonstrated that 22 patients (23.7%) harbored a PIK3CA hot spot mutation in exon 9 (n = 21) or exon 20 (n = 1).	('PIK3CA', 'Gene', '5290', (128, 134))	('tumor', 'Disease', (65, 70))	('PIK3CA', 'Gene', '5290', (36, 42))	('mutation', 'Var', (144, 152))	('patients', 'Species', '9606', (100, 108))	('PIK3CA', 'Gene', (128, 134))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('PIK3CA', 'Gene', (36, 42))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
381485	31766658	Of note, samples with 2J insertion displayed low viral load, while MJ insertion was associated with high viral load (p = 0.022).	('viral load', 'MPA', (49, 59))	('insertion', 'Var', (25, 34))	('low', 'NegReg', (45, 48))	('MJ', 'Chemical', 'MESH:C078587', (67, 69))	('viral load', 'MPA', (105, 115))
381486	31766658	Moreover, samples with viral integration (2J or MJ) more frequently harbored PIK3CA activating mutations (7/15, 46.7% and 11/36, 30.6%, respectively) than those harboring episomal HPV (4/42, 9.5%) (p = 0.0069).	('PIK3CA', 'Gene', (77, 83))	('harbored', 'Reg', (68, 76))	('viral integration', 'Var', (23, 40))	('PIK3CA', 'Gene', '5290', (77, 83))	('HPV', 'Species', '10566', (180, 183))	('mutations', 'Var', (95, 104))	('activating', 'PosReg', (84, 94))	('MJ', 'Chemical', 'MESH:C078587', (48, 50))
381494	31766658	Remarkably, four patients harbored HPV integration in the NFIX gene (4/51, 7.8%).	('HPV', 'Species', '10566', (35, 38))	('NFIX', 'Gene', '4784', (58, 62))	('HPV integration', 'Var', (35, 50))	('patients', 'Species', '9606', (17, 25))	('NFIX', 'Gene', (58, 62))
381503	31766658	Our analysis of HPV integration signatures in ASCC revealed the predominance of EPI (42/93, 45.2%) over MJ (MJ-SC: 25/93, 26.9%, MJ-CL: 9/93, 9.7%) and 2J (2J-COL: 7/93, 7.5%, 2J-NL: 2/93, 2.2%) insertions.	('insertions', 'Var', (195, 205))	('MJ', 'Chemical', 'MESH:C078587', (104, 106))	('MJ', 'Chemical', 'MESH:C078587', (108, 110))	('MJ-CL', 'Disease', (129, 134))	('MJ-CL', 'Disease', 'MESH:D009207', (129, 134))	('HPV', 'Species', '10566', (16, 19))	('MJ', 'Chemical', 'MESH:C078587', (129, 131))
381509	31766658	Viral integration was associated with increases in somatic DNA copy number and a nonsignificant trend toward a higher mutational burden, suggesting that tumors with HPV integration might be associated with more immunogenic tumors.	('increases', 'PosReg', (38, 47))	('immunogenic tumors', 'Disease', 'MESH:D009369', (211, 229))	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('HPV', 'Species', '10566', (165, 168))	('somatic DNA copy number', 'MPA', (51, 74))	('tumors', 'Disease', (223, 229))	('Viral integration', 'Var', (0, 17))	('tumors', 'Disease', 'MESH:D009369', (223, 229))	('tumors', 'Phenotype', 'HP:0002664', (223, 229))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('immunogenic tumors', 'Disease', (211, 229))	('tumors', 'Disease', (153, 159))	('associated', 'Reg', (190, 200))	('tumors', 'Phenotype', 'HP:0002664', (153, 159))	('tumors', 'Disease', 'MESH:D009369', (153, 159))
381512	31766658	Of note, samples with 2J insertions were associated with low viral load, while MJ samples were associated with high viral load (p = 0.022), suggesting that viral load is linked to the alternative mechanistic mode of HPV insertion proposed by Holmes et al..	('HPV', 'Species', '10566', (216, 219))	('viral load', 'MPA', (116, 126))	('MJ', 'Chemical', 'MESH:C078587', (79, 81))	('insertions', 'Var', (25, 35))	('viral load', 'MPA', (61, 71))
381513	31766658	Moreover, although HPV integration signatures had no prognostic impact in our cohort, low viral load was an independent prognostic factor predictive of shorter OS in our cohort (p = 0.011).	('shorter OS', 'Disease', (152, 162))	('HPV', 'Species', '10566', (19, 22))	('low viral', 'Var', (86, 95))
381514	31766658	Similar findings have been reported in cervical cancer, where low HPV viral load is associated with shorter survival and poor prognosis features including with poorly differentiated tumors and metastatic lymph node metastasis.	('HPV', 'Species', '10566', (66, 69))	('tumors', 'Phenotype', 'HP:0002664', (182, 188))	('HPV', 'Gene', (66, 69))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('cervical cancer', 'Disease', (39, 54))	('tumors', 'Disease', (182, 188))	('cervical cancer', 'Disease', 'MESH:D002583', (39, 54))	('tumors', 'Disease', 'MESH:D009369', (182, 188))	('shorter', 'NegReg', (100, 107))	('survival', 'CPA', (108, 116))	('low', 'Var', (62, 65))	('metastatic lymph node metastasis', 'CPA', (193, 225))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
381520	31766658	in cervical cancer, non-HPV-16 genotypes (particularly, HPV-18) have been associated with poor prognosis and low viral load, but the effect on RT outcome could not be assessed due to small sample size of the non-HPV-16 subgroup.	('viral load', 'MPA', (113, 123))	('low', 'NegReg', (109, 112))	('HPV', 'Species', '10566', (24, 27))	('cervical cancer', 'Disease', 'MESH:D002583', (3, 18))	('HPV', 'Species', '10566', (56, 59))	('cervical cancer', 'Disease', (3, 18))	('HPV-16', 'Species', '333760', (24, 30))	('HPV-16', 'Species', '333760', (212, 218))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('non-HPV-16', 'Var', (20, 30))	('HPV', 'Species', '10566', (212, 215))
381521	31766658	Interestingly, samples with viral integration (2J and MJ) more frequently harbored PIK3CA-activating mutations than those harboring episomal HPV (p = 0.0069).	('mutations', 'Var', (101, 110))	('HPV', 'Species', '10566', (141, 144))	('PIK3CA', 'Gene', '5290', (83, 89))	('MJ', 'Chemical', 'MESH:C078587', (54, 56))	('PIK3CA', 'Gene', (83, 89))	('viral integration', 'Var', (28, 45))	('harbored', 'Reg', (74, 82))
381522	31766658	It has been suggested that HPV creates a selective pressure that promotes the emergence of tumors with APOBEC-mediated driver mutations in HNSCC.	('tumors', 'Disease', (91, 97))	('tumors', 'Disease', 'MESH:D009369', (91, 97))	('HPV', 'Species', '10566', (27, 30))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('promotes', 'PosReg', (65, 73))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('mutations', 'Var', (126, 135))	('APOBEC-mediated', 'Gene', (103, 118))
381524	31766658	In particular, APOBEC activity is responsible for the generation of PIK3CA gene mutation across multiple cancers, which may explain the positive association between HPV integration and PIK3CA mutation in our series.	('PIK3CA', 'Gene', (68, 74))	('HPV', 'Species', '10566', (165, 168))	('cancers', 'Phenotype', 'HP:0002664', (105, 112))	('generation', 'Reg', (54, 64))	('cancers', 'Disease', (105, 112))	('responsible', 'Reg', (34, 45))	('cancers', 'Disease', 'MESH:D009369', (105, 112))	('PIK3CA', 'Gene', '5290', (68, 74))	('PIK3CA', 'Gene', (185, 191))	('PIK3CA', 'Gene', '5290', (185, 191))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('mutation', 'Var', (80, 88))
381526	31766658	We observed that HPV insertion occurred in both intergenic regions and in repeated sequences, as well as in intragenic regions.	('HPV', 'Species', '10566', (17, 20))	('HPV', 'Gene', (17, 20))	('insertion', 'Var', (21, 30))
381534	31766658	In lung cancer, silencing of NFIX induced a decrease in IL6ST, TIMP1, and ITGB1 gene expression and reduced cell proliferation, migration, and invasion processes.	('NFIX', 'Gene', (29, 33))	('lung cancer', 'Phenotype', 'HP:0100526', (3, 14))	('IL6ST', 'Gene', (56, 61))	('migration', 'CPA', (128, 137))	('silencing', 'Var', (16, 25))	('TIMP1', 'Gene', '7076', (63, 68))	('decrease', 'NegReg', (44, 52))	('ITGB1', 'Gene', '3688', (74, 79))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('IL6ST', 'Gene', '3572', (56, 61))	('invasion processes', 'CPA', (143, 161))	('lung cancer', 'Disease', (3, 14))	('expression', 'MPA', (85, 95))	('reduced', 'NegReg', (100, 107))	('TIMP1', 'Gene', (63, 68))	('NFIX', 'Gene', '4784', (29, 33))	('cell proliferation', 'CPA', (108, 126))	('lung cancer', 'Disease', 'MESH:D008175', (3, 14))	('ITGB1', 'Gene', (74, 79))
381537	31766658	In our study, HPV integration in the NFIX gene was associated with a trend towards longer OS in patients with HPV-positive ASCC (p = 0.05).	('HPV', 'Species', '10566', (14, 17))	('HPV', 'Species', '10566', (110, 113))	('integration', 'Var', (18, 29))	('NFIX', 'Gene', (37, 41))	('HPV integration', 'Var', (14, 29))	('NFIX', 'Gene', '4784', (37, 41))	('patients', 'Species', '9606', (96, 104))	('longer OS', 'Disease', (83, 92))
381548	31766658	Table S4: Clinical and biological characteristics of the 93 patients with HPV-positive anal squamous cell carcinoma (ASCC), according to HPV integration in NFIX gene.	('integration', 'Var', (141, 152))	('NFIX', 'Gene', (156, 160))	('patients', 'Species', '9606', (60, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('NFIX', 'Gene', '4784', (156, 160))	('HPV', 'Species', '10566', (74, 77))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (92, 115))	('squamous cell carcinoma', 'Disease', (92, 115))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (92, 115))	('HPV', 'Species', '10566', (137, 140))
381569	30288055	Cancer is somewhat similar to a micro-evolutionary process in which accrual of multiple mutations in cell growth genes leads to uncontrolled cell growth, which then generates growth-induced stress in a spatiotemporal manner.	('leads to', 'Reg', (119, 127))	('uncontrolled cell growth', 'MPA', (128, 152))	('in a', 'Gene', (197, 201))	('mutations', 'Var', (88, 97))	('growth-induced stress', 'MPA', (175, 196))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('cell growth genes', 'Gene', (101, 118))	('in a', 'Gene', '9118', (197, 201))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('generates', 'Reg', (165, 174))
381583	30288055	Bass et al reported that the knockdown of SOX2 in RNA interference experiments reduced proliferation and anchorage-independent growth of lung and esophageal squamous cell carcinoma cell lines in soft agar.	('anchorage-independent growth', 'CPA', (105, 133))	('RNA interference', 'MPA', (50, 66))	('SOX2', 'Gene', (42, 46))	('reduced', 'NegReg', (79, 86))	('knockdown', 'Var', (29, 38))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (146, 180))	('proliferation', 'CPA', (87, 100))	('esophageal squamous cell carcinoma', 'Disease', (146, 180))	('carcinoma', 'Phenotype', 'HP:0030731', (171, 180))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (157, 180))	('lung', 'Disease', (137, 141))
381584	30288055	The mechanism by which genetic alternation of SOX2 increases tumor progression has been correlated with PIK3CA, which resides in a broad amplicon spanning 3q26-28 along with SOX2.	('PIK3', 'Gene', (104, 108))	('SOX2', 'Gene', (46, 50))	('PIK3', 'Gene', '5294', (104, 108))	('in a', 'Gene', (126, 130))	('genetic alternation', 'Var', (23, 42))	('increases tumor', 'Disease', (51, 66))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('increases tumor', 'Disease', 'MESH:D009369', (51, 66))	('in a', 'Gene', '9118', (126, 130))
381608	30288055	The samples were then separated with SDS-PAGE gel and immunoblotted with the indicated antibodies: vimentin (ab92547; Abcam, Cambridge, UK), SMA (ab5694; Abcam), EpCAM (ab32392; Abcam), SOX2 (23064; Cell Signaling Technology, Danvers, MA, USA), CDH1 (4,065S; Cell Signaling Technology), CDH2 (4061; Cell Signaling Technology), FN1 (sc-18825; Santa Cruz Biotechnology), AKT (CSB-PA15905A0RB; Cusabio Life Science, Wuhan, China), p-AKT (S473; Cell Signaling Technology), GAPDH (919501; BioLegend, San Diego, CA, USA), and beta-actin (sc-4778; Santa Cruz Biotechnology).	('AKT', 'Gene', (430, 433))	('AKT', 'Gene', '207', (430, 433))	('CDH2', 'Gene', (287, 291))	('SMA', 'Gene', (141, 144))	('AKT', 'Gene', '207', (369, 372))	('CDH2', 'Gene', '1000', (287, 291))	('SMA', 'Gene', '6606', (141, 144))	('CDH1', 'Gene', (245, 249))	('GAPDH', 'Gene', '2597', (469, 474))	('GAPDH', 'Gene', (469, 474))	('CDH1', 'Gene', '999', (245, 249))	('AKT', 'Gene', (369, 372))	('beta-actin', 'Protein', (520, 530))	('CSB-PA15905A0RB', 'Var', (374, 389))
381641	30288055	Importantly, knockdown of SOX2 decreases the phosphorylation level of AKT kinase compared to negative control siRNA in both 2D and 3D cultures (Figure 3A).	('AKT', 'Gene', '207', (70, 73))	('decreases', 'NegReg', (31, 40))	('phosphorylation level', 'MPA', (45, 66))	('AKT', 'Gene', (70, 73))	('SOX2', 'Gene', (26, 30))	('knockdown', 'Var', (13, 22))
381650	30288055	This significant decrease in the resistance to vinblastine in SOX2 knockdown cells in 3D culture compared to 2D culture suggests that SOX2 plays an important role in the growth of cells in the 3D culture in response to vinblastine.	('SOX2', 'Gene', (62, 66))	('knockdown', 'Var', (67, 76))	('decrease', 'NegReg', (17, 25))	('resistance to vinblastine', 'MPA', (33, 58))	('vinblastine', 'Chemical', 'MESH:D014747', (47, 58))	('vinblastine', 'Chemical', 'MESH:D014747', (219, 230))
381670	30288055	In light of the studies demonstrating that stemness traits increase in response to cell-cell interaction, we hypothesize that poly-HEMA suspension cultures result in a densely crowded environment, which increases intercellular interactions and upregulates pluripotency genes, resulting in a self-renewal population in the spheroids.	('increases', 'PosReg', (203, 212))	('self-renewal population in the spheroids', 'CPA', (291, 331))	('intercellular interactions', 'MPA', (213, 239))	('in a', 'Gene', (163, 167))	('in a', 'Gene', '9118', (163, 167))	('in a', 'Gene', '9118', (286, 290))	('poly-HEMA', 'Chemical', 'MESH:D011102', (126, 135))	('in a', 'Gene', (286, 290))	('upregulates', 'PosReg', (244, 255))	('poly-HEMA', 'Var', (126, 135))	('pluripotency genes', 'Gene', (256, 274))
381671	30288055	Addressing this issue in detail is beyond the scope of this study; however, gaining a deeper understanding of spatiotemporal networks of gene expression in spheroids in poly-HEMA suspension and in vivo animal models, as well as identifying alternations of SOX2 in clinical NSCLC samples, will advance our fundamental understanding of the role of pluripotency genes in tumor progression.	('tumor', 'Phenotype', 'HP:0002664', (368, 373))	('tumor', 'Disease', (368, 373))	('poly-HEMA', 'Chemical', 'MESH:D011102', (169, 178))	('NSCLC', 'Phenotype', 'HP:0030358', (273, 278))	('SCLC', 'Phenotype', 'HP:0030357', (274, 278))	('NSCLC', 'Disease', (273, 278))	('SOX2', 'Gene', (256, 260))	('tumor', 'Disease', 'MESH:D009369', (368, 373))	('NSCLC', 'Disease', 'MESH:D002289', (273, 278))	('alternations', 'Var', (240, 252))
381673	32277007	Association analysis of driver-gene related genetic variants identified novel lung cancer susceptibility loci with 20,871 lung cancer cases and 15,971 controls A substantial proportion of cancer driver genes (CDGs) are also cancer predisposition genes.	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('variants', 'Var', (52, 60))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('lung cancer', 'Disease', 'MESH:D008175', (122, 133))	('cancer', 'Disease', (224, 230))	('lung cancer', 'Disease', (78, 89))	('CDGs', 'Chemical', '-', (209, 213))	('lung cancer', 'Phenotype', 'HP:0100526', (122, 133))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('cancer', 'Disease', (127, 133))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('lung cancer', 'Disease', 'MESH:D008175', (78, 89))	('cancer', 'Disease', (188, 194))	('cancer', 'Disease', 'MESH:D009369', (224, 230))	('lung cancer', 'Phenotype', 'HP:0100526', (78, 89))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('lung cancer', 'Disease', (122, 133))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('cancer', 'Disease', (83, 89))
381674	32277007	However, the associations between genetic variants in lung CDGs and the susceptibility to lung cancer have rarely been investigated.	('lung cancer', 'Disease', 'MESH:D008175', (90, 101))	('CDGs', 'Chemical', '-', (59, 63))	('variants', 'Var', (42, 50))	('lung cancer', 'Disease', (90, 101))	('lung cancer', 'Phenotype', 'HP:0100526', (90, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))
381675	32277007	We selected expression-related single nucleotide polymorphisms (eSNPs) and nonsynonymous variants of lung CDGs, and tested their associations with lung cancer risk in two large-scale genome-wide association studies (20,871 cases and 15,971 controls of European descent).	('tested', 'Reg', (116, 122))	('single nucleotide polymorphisms', 'Var', (31, 62))	('lung cancer', 'Disease', (147, 158))	('lung CDGs', 'Gene', (101, 110))	('lung cancer', 'Phenotype', 'HP:0100526', (147, 158))	('lung cancer', 'Disease', 'MESH:D008175', (147, 158))	('associations', 'Interaction', (129, 141))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('CDGs', 'Chemical', '-', (106, 110))
381677	32277007	We identified seven independent SNPs in five lung CDGs that were consistently associated with lung cancer risk in discovery (P < 0.001) and validation (P < 0.05) stages.	('associated with', 'Reg', (78, 93))	('SNPs', 'Var', (32, 36))	('lung cancer', 'Disease', 'MESH:D008175', (94, 105))	('lung CDGs', 'Gene', (45, 54))	('lung cancer', 'Disease', (94, 105))	('lung cancer', 'Phenotype', 'HP:0100526', (94, 105))	('CDGs', 'Chemical', '-', (50, 54))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
381678	32277007	Among these loci, rs78062588 in TPM3 (1q21.3) was a new lung cancer susceptibility locus (OR = 0.86, P = 1.65x10-6).	('lung cancer', 'Disease', 'MESH:D008175', (56, 67))	('TPM3', 'Gene', (32, 36))	('rs78062588', 'Var', (18, 28))	('rs78062588', 'Mutation', 'rs78062588', (18, 28))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('lung cancer', 'Disease', (56, 67))	('lung cancer', 'Phenotype', 'HP:0100526', (56, 67))
381680	32277007	Analysis of somatic alterations found that, in lung adenocarcinomas, rs78062588[C] allele (TPM3 in 1q21.3) was associated with elevated somatic copy number of TPM3 (OR = 1.16, P = 0.02).	('TPM3', 'Gene', (159, 163))	('rs78062588', 'Mutation', 'rs78062588', (69, 79))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (47, 66))	('carcinoma', 'Phenotype', 'HP:0030731', (57, 66))	('elevated', 'PosReg', (127, 135))	('lung adenocarcinomas', 'Disease', (47, 67))	('carcinomas', 'Phenotype', 'HP:0030731', (57, 67))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (47, 67))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (47, 67))	('rs78062588[C', 'Var', (69, 81))
381681	32277007	In lung adenocarcinomas, rs1611182 (HLA-A in 6p22.1) was associated with truncation mutations of the transcriptional misregulation in cancer pathway (OR = 0.66, P = 1.76x10-3).	('HLA-A', 'Gene', '3105', (36, 41))	('rs1611182', 'Var', (25, 34))	('rs1611182', 'Mutation', 'rs1611182', (25, 34))	('HLA-A', 'Gene', (36, 41))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (3, 22))	('carcinomas', 'Phenotype', 'HP:0030731', (13, 23))	('lung adenocarcinomas', 'Disease', (3, 23))	('truncation', 'MPA', (73, 83))	('carcinoma', 'Phenotype', 'HP:0030731', (13, 22))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (3, 23))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (3, 23))	('associated', 'Reg', (57, 67))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
381682	32277007	Genetic variants can regulate functions of lung CDGs and influence lung cancer susceptibility.	('influence', 'Reg', (57, 66))	('lung CDGs', 'Protein', (43, 52))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('lung cancer', 'Disease', 'MESH:D008175', (67, 78))	('regulate', 'Reg', (21, 29))	('CDGs', 'Chemical', '-', (48, 52))	('lung cancer', 'Disease', (67, 78))	('lung cancer', 'Phenotype', 'HP:0100526', (67, 78))	('Genetic variants', 'Var', (0, 16))	('functions', 'MPA', (30, 39))
381690	32277007	Based on The Cancer Genome Atlas (TCGA) research on lung cancer, the most commonly mutated oncogenes in lung adenocarcinoma (lung ADC) included KRAS, EGFR, BRAF, PIK3CA, and MET; mutations in tumor suppressors such as TP53, STK11, KEAP1, NF1, RB1, and CDKN2A were also frequently detected in lung ADC.	('PIK3CA', 'Gene', '5290', (162, 168))	('ADC', 'Gene', '113451', (130, 133))	('lung cancer', 'Disease', 'MESH:D008175', (52, 63))	('Cancer', 'Disease', (13, 19))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('CDKN2A', 'Gene', '1029', (252, 258))	('KEAP1', 'Gene', '9817', (231, 236))	('lung cancer', 'Phenotype', 'HP:0100526', (52, 63))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('ADC', 'Gene', (130, 133))	('KEAP1', 'Gene', (231, 236))	('EGFR', 'Gene', '1956', (150, 154))	('MET', 'Gene', (174, 177))	('Cancer', 'Disease', 'MESH:D009369', (13, 19))	('detected', 'Reg', (280, 288))	('RB1', 'Gene', (243, 246))	('TP53', 'Gene', (218, 222))	('PIK3CA', 'Gene', (162, 168))	('BRAF', 'Gene', '673', (156, 160))	('tumor', 'Disease', (192, 197))	('KRAS', 'Gene', '3845', (144, 148))	('BRAF', 'Gene', (156, 160))	('lung adenocarcinoma', 'Disease', (104, 123))	('lung cancer', 'Disease', (52, 63))	('STK11', 'Gene', (224, 229))	('ADC', 'Gene', '113451', (297, 300))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('mutations', 'Var', (179, 188))	('KRAS', 'Gene', (144, 148))	('lung ADC', 'Phenotype', 'HP:0030078', (292, 300))	('RB1', 'Gene', '5925', (243, 246))	('MET', 'Gene', '79811', (174, 177))	('EGFR', 'Gene', (150, 154))	('NF1', 'Gene', '4763', (238, 241))	('CDKN2A', 'Gene', (252, 258))	('lung ADC', 'Phenotype', 'HP:0030078', (125, 133))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (104, 123))	('ADC', 'Gene', (297, 300))	('Cancer', 'Phenotype', 'HP:0002664', (13, 19))	('TP53', 'Gene', '7157', (218, 222))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (104, 123))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('STK11', 'Gene', '6794', (224, 229))	('NF1', 'Gene', (238, 241))
381691	32277007	Although TP53, RB1, ARID1A, CDKN2A, PIK3CA, and NF1 were significantly mutated in both lung ADC and lung squamous cell carcinoma (lung SqCC), significantly mutated genes like NOTCH1 and HRAS were only identified in lung SqCC.	('ARID1A', 'Gene', '8289', (20, 26))	('NF1', 'Gene', '4763', (48, 51))	('NOTCH1', 'Gene', '4851', (175, 181))	('lung SqCC', 'Phenotype', 'HP:0030359', (215, 224))	('RB1', 'Gene', (15, 18))	('TP53', 'Gene', '7157', (9, 13))	('CDKN2A', 'Gene', '1029', (28, 34))	('PIK3CA', 'Gene', (36, 42))	('NF1', 'Gene', (48, 51))	('HRAS', 'Gene', '3265', (186, 190))	('HRAS', 'Gene', (186, 190))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('RB1', 'Gene', '5925', (15, 18))	('lung ADC', 'Phenotype', 'HP:0030078', (87, 95))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (100, 128))	('lung SqCC', 'Phenotype', 'HP:0030359', (130, 139))	('TP53', 'Gene', (9, 13))	('ADC', 'Gene', '113451', (92, 95))	('ARID1A', 'Gene', (20, 26))	('PIK3CA', 'Gene', '5290', (36, 42))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (100, 128))	('mutated', 'Var', (71, 78))	('NOTCH1', 'Gene', (175, 181))	('CDKN2A', 'Gene', (28, 34))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (105, 128))	('lung squamous cell carcinoma', 'Disease', (100, 128))	('ADC', 'Gene', (92, 95))
381693	32277007	Amplification of TERT and EGFR, as well as fusions involving ALK and ROS1 were commonly identified in lung ADC.	('EGFR', 'Gene', (26, 30))	('Amplification', 'Var', (0, 13))	('ADC', 'Gene', (107, 110))	('TERT', 'Gene', (17, 21))	('ALK', 'Gene', (61, 64))	('ROS1', 'Gene', (69, 73))	('TERT', 'Gene', '7015', (17, 21))	('fusions', 'Var', (43, 50))	('identified', 'Reg', (88, 98))	('ROS1', 'Gene', '6098', (69, 73))	('ADC', 'Gene', '113451', (107, 110))	('lung ADC', 'Phenotype', 'HP:0030078', (102, 110))	('EGFR', 'Gene', '1956', (26, 30))
381694	32277007	Deletions of CDKN2A have been identified in both lung ADC and SqCC.	('ADC', 'Gene', '113451', (54, 57))	('lung ADC', 'Phenotype', 'HP:0030078', (49, 57))	('CDKN2A', 'Gene', (13, 19))	('ADC', 'Gene', (54, 57))	('CDKN2A', 'Gene', '1029', (13, 19))	('identified', 'Reg', (30, 40))	('SqCC', 'Disease', (62, 66))	('Deletions', 'Var', (0, 9))
381696	32277007	In addition, susceptibility variants could regulate the functions of nearby cancer driver genes.	('regulate', 'Reg', (43, 51))	('functions', 'MPA', (56, 65))	('variants', 'Var', (28, 36))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))
381697	32277007	For example, rs2736100, a risk variant of lung cancer, is located in the first intron of driver gene TERT, and was associated with increased expression of TERT in lung tumors.	('TERT', 'Gene', '7015', (101, 105))	('rs2736100', 'Var', (13, 22))	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('increased', 'PosReg', (131, 140))	('rs2736100', 'Mutation', 'rs2736100', (13, 22))	('lung tumors', 'Disease', 'MESH:D008175', (163, 174))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('lung cancer', 'Disease', (42, 53))	('expression', 'MPA', (141, 151))	('lung cancer', 'Phenotype', 'HP:0100526', (42, 53))	('TERT', 'Gene', (101, 105))	('lung tumors', 'Disease', (163, 174))	('TERT', 'Gene', (155, 159))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('TERT', 'Gene', '7015', (155, 159))	('lung tumors', 'Phenotype', 'HP:0100526', (163, 174))	('lung cancer', 'Disease', 'MESH:D008175', (42, 53))
381698	32277007	However, the associations between common genetic variants in lung CDGs and lung cancer risk have rarely been explored.	('lung cancer', 'Disease', (75, 86))	('lung cancer', 'Phenotype', 'HP:0100526', (75, 86))	('variants', 'Var', (49, 57))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('CDGs', 'Chemical', '-', (66, 70))	('lung cancer', 'Disease', 'MESH:D008175', (75, 86))
381699	32277007	Therefore, we integrated lung CDGs, genetics of gene expression, and functional annotation databases with large-scale lung cancer GWAS datasets to systematically investigate the associations between lung CDG-related genetic variants and lung cancer risk.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('CDGs', 'Chemical', '-', (30, 34))	('variants', 'Var', (224, 232))	('lung cancer', 'Disease', 'MESH:D008175', (118, 129))	('cancer', 'Phenotype', 'HP:0002664', (242, 248))	('CDG', 'Chemical', '-', (30, 33))	('lung cancer', 'Disease', (237, 248))	('CDG', 'Chemical', '-', (204, 207))	('lung cancer', 'Phenotype', 'HP:0100526', (237, 248))	('lung cancer', 'Disease', (118, 129))	('lung cancer', 'Phenotype', 'HP:0100526', (118, 129))	('lung cancer', 'Disease', 'MESH:D008175', (237, 248))	('associations', 'Interaction', (178, 190))
381712	32277007	We mapped suggestive risk SNPs to lung CDGs based on the GTEx v6p release, and performed functional prediction for significant nonsynonymous variants using SIFT and PolyPhen2, which were implemented in ANNOVAR.	('v6p', 'Gene', (62, 65))	('v6p', 'Gene', '6987', (62, 65))	('GTEx', 'Chemical', '-', (57, 61))	('variants', 'Var', (141, 149))	('CDGs', 'Chemical', '-', (39, 43))
381720	32277007	We also assessed truncation mutations (frame shift insertion/deletion, nonsense, nonstop, and splice site mutations) in pathways that are recurrently altered in lung cancer, including cell cycle, spliceosome, Notch signaling pathway, transcriptional misregulation in cancer, Ras signaling pathway, and PI3K-Akt signaling pathway.	('cancer', 'Disease', (166, 172))	('Akt', 'Gene', (307, 310))	('cancer', 'Disease', (267, 273))	('Notch', 'Gene', (209, 214))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('cancer', 'Disease', 'MESH:D009369', (267, 273))	('lung cancer', 'Disease', (161, 172))	('lung cancer', 'Phenotype', 'HP:0100526', (161, 172))	('Akt', 'Gene', '207', (307, 310))	('cancer', 'Phenotype', 'HP:0002664', (267, 273))	('Ras signaling pathway', 'Pathway', (275, 296))	('mutations', 'Var', (106, 115))	('spliceosome', 'MPA', (196, 207))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('altered', 'Reg', (150, 157))	('Notch', 'Gene', '4851', (209, 214))	('lung cancer', 'Disease', 'MESH:D008175', (161, 172))
381732	32277007	Among these loci, rs78062588, which was mapped to TPM3 in chromosome 1q21.3, was a new lung cancer susceptibility locus (OR = 0.87, 95%CI: 0.81-0.92, P = 1.55x10-5 in the OncoArray dataset; OR = 0.82, 95%CI: 0.68-0.98, P = 3.11x10-2 in the DCEG Lung Cancer Study; and OR = 0.86, 95%CI: 0.81-0.91, P = 1.65x10-6 in the meta-analysis) (Table 1, Table 2, Supplementary Table S3).	('Cancer', 'Phenotype', 'HP:0002664', (250, 256))	('lung cancer', 'Disease', 'MESH:D008175', (87, 98))	('rs78062588', 'Var', (18, 28))	('Lung Cancer', 'Disease', (245, 256))	('rs78062588', 'Mutation', 'rs78062588', (18, 28))	('DCEG', 'Chemical', '-', (240, 244))	('Lung Cancer', 'Phenotype', 'HP:0100526', (245, 256))	('lung cancer', 'Disease', (87, 98))	('Lung Cancer', 'Disease', 'MESH:D008175', (245, 256))	('lung cancer', 'Phenotype', 'HP:0100526', (87, 98))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
381733	32277007	In addition, rs71658797 in FUBP1 (1p31.1), rs1655931 and rs2517586 in HLA-A (6p22.1), rs2887532 in KDM5A (12p13.33), rs7359276 and rs7161774 in IREB2 (15q25.1) had been reported by previous GWASs as lung cancer susceptibility loci (Table 1, Table 2, Supplementary Table S3).	('KDM5A', 'Gene', '5927', (99, 104))	('rs71658797', 'Var', (13, 23))	('rs1655931', 'Var', (43, 52))	('rs2517586', 'Var', (57, 66))	('lung cancer', 'Disease', (199, 210))	('FUBP1', 'Gene', (27, 32))	('KDM5A', 'Gene', (99, 104))	('rs7161774', 'Mutation', 'rs7161774', (131, 140))	('rs2887532', 'Var', (86, 95))	('rs71658797', 'Mutation', 'rs71658797', (13, 23))	('HLA-A', 'Gene', '3105', (70, 75))	('FUBP1', 'Gene', '8880', (27, 32))	('lung cancer', 'Disease', 'MESH:D008175', (199, 210))	('rs7359276', 'Var', (117, 126))	('IREB2', 'Gene', '3658', (144, 149))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('lung cancer', 'Phenotype', 'HP:0100526', (199, 210))	('rs2887532', 'Mutation', 'rs2887532', (86, 95))	('rs7161774', 'Var', (131, 140))	('IREB2', 'Gene', (144, 149))	('rs7359276', 'Mutation', 'rs7359276', (117, 126))	('rs2517586', 'Mutation', 'rs2517586', (57, 66))	('rs1655931', 'Mutation', 'rs1655931', (43, 52))	('HLA-A', 'Gene', (70, 75))
381735	32277007	Of these loci, rs2700389 in KALRN (3q21.1), rs79518818 in MGA (15q15.1), and rs62054832 in EFTUD2 (17q21.31) were first identified as risk loci for lung ADC, while rs148797791 in IRF6 (1q32.2) was found as a novel risk locus for lung SqCC.	('lung ADC', 'Phenotype', 'HP:0030078', (148, 156))	('lung SqCC', 'Phenotype', 'HP:0030359', (229, 238))	('KALRN', 'Gene', '8997', (28, 33))	('rs79518818', 'Mutation', 'rs79518818', (44, 54))	('rs62054832', 'Var', (77, 87))	('ADC', 'Gene', (153, 156))	('rs2700389', 'Var', (15, 24))	('rs79518818', 'Var', (44, 54))	('KALRN', 'Gene', (28, 33))	('rs148797791', 'Var', (164, 175))	('rs2700389', 'Mutation', 'rs2700389', (15, 24))	('EFTUD2', 'Gene', (91, 97))	('IRF6', 'Gene', (179, 183))	('rs62054832', 'Mutation', 'rs62054832', (77, 87))	('rs148797791', 'Mutation', 'rs148797791', (164, 175))	('IRF6', 'Gene', '3664', (179, 183))	('EFTUD2', 'Gene', '9343', (91, 97))	('ADC', 'Gene', '113451', (153, 156))
381736	32277007	SNPs rs7823498 in NRG1 (8p12), rs10757256 and rs1011970 in CDKN2A (9p21.3), rs79040073 in COPS2 (15q21.1), rs2281925 in ARFGAP1 (20q13.33), and rs17879961 in CHEK2 (22q12.1) had been reported by previous GWASs as lung cancer susceptibility loci.	('rs17879961', 'Mutation', 'rs17879961', (144, 154))	('rs79040073', 'Var', (76, 86))	('rs10757256', 'Var', (31, 41))	('lung cancer', 'Disease', (213, 224))	('ARFGAP1', 'Gene', '55738', (120, 127))	('rs2281925', 'Var', (107, 116))	('rs10757256', 'Mutation', 'rs10757256', (31, 41))	('ARFGAP1', 'Gene', (120, 127))	('CDKN2A', 'Gene', (59, 65))	('rs17879961', 'Var', (144, 154))	('NRG1', 'Gene', (18, 22))	('NRG1', 'Gene', '3084', (18, 22))	('rs79040073', 'Mutation', 'rs79040073', (76, 86))	('lung cancer', 'Disease', 'MESH:D008175', (213, 224))	('COPS2', 'Gene', (90, 95))	('CDKN2A', 'Gene', '1029', (59, 65))	('lung cancer', 'Phenotype', 'HP:0100526', (213, 224))	('rs7823498', 'Mutation', 'rs7823498', (5, 14))	('rs1011970', 'Var', (46, 55))	('CHEK2', 'Gene', (158, 163))	('rs1011970', 'Mutation', 'rs1011970', (46, 55))	('rs2281925', 'Mutation', 'rs2281925', (107, 116))	('COPS2', 'Gene', '9318', (90, 95))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('rs7823498', 'Var', (5, 14))	('CHEK2', 'Gene', '11200', (158, 163))
381737	32277007	Among 234 significant SNPs in overall lung cancer, three were nonsynonymous variants.	('lung cancer', 'Disease', (38, 49))	('lung cancer', 'Phenotype', 'HP:0100526', (38, 49))	('SNPs', 'Var', (22, 26))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('lung cancer', 'Disease', 'MESH:D008175', (38, 49))
381738	32277007	Two additional nonsynonymous variants (rs1136688 in HLA-A and rs17879961 in CHEK2) were identified in lung SqCC (Supplementary Table S6).	('rs17879961', 'Mutation', 'rs17879961', (62, 72))	('lung SqCC', 'Phenotype', 'HP:0030359', (102, 111))	('lung SqCC', 'Disease', (102, 111))	('CHEK2', 'Gene', (76, 81))	('CHEK2', 'Gene', '11200', (76, 81))	('rs1136688', 'Var', (39, 48))	('HLA-A', 'Gene', '3105', (52, 57))	('HLA-A', 'Gene', (52, 57))	('rs1136688', 'Mutation', 'rs1136688', (39, 48))	('rs17879961', 'Var', (62, 72))
381740	32277007	Notably, risk variant rs707910 in HLA-A (NM_001242758, c.G203A) was predicted as deleterious by SIFT and possibly damaging by Polyphen-2.	('rs707910', 'Var', (22, 30))	('NM_001242758', 'Var', (41, 53))	('HLA-A', 'Gene', '3105', (34, 39))	('c.G203A', 'Mutation', 'rs707910', (55, 62))	('Polyphen-2', 'Chemical', '-', (126, 136))	('c.G203A', 'Var', (55, 62))	('HLA-A', 'Gene', (34, 39))	('rs707910', 'Mutation', 'rs707910', (22, 30))
381741	32277007	SNP rs17879961 in CHEK2 (NM_007194, c.T470C) was predicted as tolerated by SIFT and possibly damaging by Polyphen-2.	('c.T470C', 'Var', (36, 43))	('CHEK2', 'Gene', '11200', (18, 23))	('rs17879961', 'Mutation', 'rs17879961', (4, 14))	('Polyphen-2', 'Chemical', '-', (105, 115))	('CHEK2', 'Gene', (18, 23))	('c.T470C', 'Mutation', 'rs17879961', (36, 43))	('NM_007194', 'Var', (25, 34))
381745	32277007	The protective rs78062588[C] allele (TPM3 in 1q21.3) was associated with increased expression of TPM3 in normal lung tissues (OR = 1.14, P = 0.04) and elevated somatic copy number of TPM3 in TCGA lung adenocarcinomas (OR = 1.16, P = 0.02) (Supplementary Fig.	('TPM3', 'Gene', (183, 187))	('TPM3', 'Gene', (97, 101))	('increased', 'PosReg', (73, 82))	('somatic copy number', 'CPA', (160, 179))	('carcinoma', 'Phenotype', 'HP:0030731', (206, 215))	('carcinomas', 'Phenotype', 'HP:0030731', (206, 216))	('rs78062588', 'Mutation', 'rs78062588', (15, 25))	('rs78062588[', 'Var', (15, 26))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (196, 215))	('elevated', 'PosReg', (151, 159))	('lung adenocarcinomas', 'Disease', (196, 216))	('expression', 'MPA', (83, 93))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (196, 216))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (196, 216))
381748	32277007	Among patients with lung ADC, we found that rs1611182 (HLA-A in 6p22.1), a risk SNP for lung ADCs, was associated with decreased frequency of truncation mutations in the transcriptional misregulation in cancer pathway (OR = 0.66, 95%CI: 0.50-0.85, P = 1.76x10-3, FDR < 0.25) (Table 3, Supplementary Table S8, Supplementary Fig.	('ADC', 'Gene', '113451', (25, 28))	('decreased', 'NegReg', (119, 128))	('ADC', 'Gene', (93, 96))	('truncation mutations', 'Var', (142, 162))	('lung ADC', 'Phenotype', 'HP:0030078', (88, 96))	('lung ADCs', 'Disease', (88, 97))	('lung ADCs', 'Disease', 'MESH:D008171', (88, 97))	('cancer', 'Disease', (203, 209))	('cancer', 'Disease', 'MESH:D009369', (203, 209))	('patients', 'Species', '9606', (6, 14))	('ADC', 'Gene', '113451', (93, 96))	('HLA-A', 'Gene', '3105', (55, 60))	('rs1611182', 'Mutation', 'rs1611182', (44, 53))	('lung ADC', 'Phenotype', 'HP:0030078', (20, 28))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('rs1611182', 'Var', (44, 53))	('ADC', 'Gene', (25, 28))	('HLA-A', 'Gene', (55, 60))
381749	32277007	The present study comprehensively incorporated lung cancer GWASs, lung CDGs, genetics of gene expression, somatic alterations in lung tumors, and functional annotation databases to investigate the associations of cancer driver gene-related genetic variants with lung cancer risk.	('lung tumors', 'Disease', 'MESH:D008175', (129, 140))	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (267, 273))	('lung tumors', 'Phenotype', 'HP:0100526', (129, 140))	('lung cancer GWASs', 'Disease', 'MESH:D008175', (47, 64))	('lung cancer', 'Disease', (262, 273))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('lung tumors', 'Disease', (129, 140))	('variants', 'Var', (248, 256))	('lung cancer GWASs', 'Disease', (47, 64))	('cancer', 'Disease', (213, 219))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('cancer', 'Disease', (267, 273))	('lung cancer', 'Disease', 'MESH:D008175', (262, 273))	('associations', 'Interaction', (197, 209))	('cancer', 'Phenotype', 'HP:0002664', (267, 273))	('lung cancer', 'Phenotype', 'HP:0100526', (262, 273))	('cancer', 'Disease', (52, 58))	('lung cancer', 'Disease', 'MESH:D008175', (47, 58))	('CDGs', 'Chemical', '-', (71, 75))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('lung cancer', 'Phenotype', 'HP:0100526', (47, 58))	('cancer', 'Disease', 'MESH:D009369', (213, 219))
381753	32277007	Incorporation of somatic alterations identified lung cancer risk variants that were associated with somatic alterations in lung CDGs or recurrently mutated pathways.	('lung cancer', 'Disease', 'MESH:D008175', (48, 59))	('variants', 'Var', (65, 73))	('CDGs', 'Chemical', '-', (128, 132))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('lung cancer', 'Disease', (48, 59))	('lung cancer', 'Phenotype', 'HP:0100526', (48, 59))
381757	32277007	Our results found that the protective allele of rs78062588 was associated with increased TPM3 expression as well as increased somatic copy number alterations of TPM3 in lung adenocarcinomas.	('increased', 'PosReg', (116, 125))	('increased', 'PosReg', (79, 88))	('rs78062588', 'Mutation', 'rs78062588', (48, 58))	('lung adenocarcinomas', 'Disease', (169, 189))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (169, 189))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (169, 189))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (169, 188))	('TPM3', 'Gene', (161, 165))	('expression', 'MPA', (94, 104))	('TPM3', 'Gene', (89, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (179, 188))	('carcinomas', 'Phenotype', 'HP:0030731', (179, 189))	('rs78062588', 'Var', (48, 58))
381764	32277007	Deletion of CDKN2A was frequently identified in lung tumors.	('CDKN2A', 'Gene', (12, 18))	('lung tumors', 'Disease', 'MESH:D008175', (48, 59))	('CDKN2A', 'Gene', '1029', (12, 18))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('identified', 'Reg', (34, 44))	('lung tumors', 'Phenotype', 'HP:0100526', (48, 59))	('lung tumors', 'Disease', (48, 59))	('Deletion', 'Var', (0, 8))
381771	32277007	Down-regulation of IRF6 in epithelial squamous cell carcinomas promotes ras-induced tumor formation and reintroduction of IRF6 strongly inhibits cell growth.	('cell growth', 'CPA', (145, 156))	('reintroduction', 'Var', (104, 118))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('carcinoma', 'Phenotype', 'HP:0030731', (52, 61))	('IRF6', 'Gene', (19, 23))	('carcinomas', 'Phenotype', 'HP:0030731', (52, 62))	('epithelial squamous cell carcinomas', 'Disease', 'MESH:D002294', (27, 62))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('IRF6', 'Gene', '3664', (19, 23))	('promotes', 'PosReg', (63, 71))	('epithelial squamous cell carcinomas', 'Disease', (27, 62))	('tumor', 'Disease', (84, 89))	('IRF6', 'Gene', (122, 126))	('Down-regulation', 'NegReg', (0, 15))	('IRF6', 'Gene', '3664', (122, 126))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (38, 62))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (38, 61))	('inhibits', 'NegReg', (136, 144))
381775	32277007	Consistent with the tumor suppressor role of IRF6, the risk allele of rs148797791 was associated with decreased expression of IRF6 in normal lung tissues.	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('IRF6', 'Gene', (45, 49))	('IRF6', 'Gene', (126, 130))	('IRF6', 'Gene', '3664', (126, 130))	('rs148797791', 'Mutation', 'rs148797791', (70, 81))	('IRF6', 'Gene', '3664', (45, 49))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('rs148797791', 'Var', (70, 81))	('decreased', 'NegReg', (102, 111))	('tumor', 'Disease', (20, 25))	('expression', 'MPA', (112, 122))
381776	32277007	These results indicate that germline variant might contribute to lung cancer risk by down-regulation of IRF6.	('lung cancer', 'Disease', 'MESH:D008175', (65, 76))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('lung cancer', 'Disease', (65, 76))	('down-regulation', 'NegReg', (85, 100))	('lung cancer', 'Phenotype', 'HP:0100526', (65, 76))	('IRF6', 'Gene', (104, 108))	('germline variant', 'Var', (28, 44))	('contribute', 'Reg', (51, 61))	('IRF6', 'Gene', '3664', (104, 108))
381779	32277007	In addition, deregulated RNA Splicing is involved in lung ADC, and cell cycle pathway is involved in both lung ADC and lung SqCC.	('ADC', 'Gene', '113451', (58, 61))	('ADC', 'Gene', (111, 114))	('involved', 'Reg', (89, 97))	('deregulated', 'Var', (13, 24))	('involved', 'Reg', (41, 49))	('lung ADC', 'Phenotype', 'HP:0030078', (53, 61))	('lung ADC', 'Phenotype', 'HP:0030078', (106, 114))	('lung SqCC', 'Disease', (119, 128))	('ADC', 'Gene', '113451', (111, 114))	('lung SqCC', 'Phenotype', 'HP:0030359', (119, 128))	('RNA Splicing', 'MPA', (25, 37))	('ADC', 'Gene', (58, 61))	('cell cycle pathway', 'Pathway', (67, 85))
381782	32277007	These results showed that genetic variants in lung CDGs contribute to lung cancer susceptibility.	('lung cancer', 'Disease', 'MESH:D008175', (70, 81))	('genetic variants', 'Var', (26, 42))	('CDGs', 'Chemical', '-', (51, 55))	('lung cancer', 'Disease', (70, 81))	('lung cancer', 'Phenotype', 'HP:0100526', (70, 81))	('lung CDGs', 'Gene', (46, 55))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('contribute', 'Reg', (56, 66))
381816	33403027	Related clinicopathological data including sample type, age at initial pathologic diagnosis, gender, histological types, smoking history, alcohol history, anatomic neoplasm subdivision, HPV status by p16 testing, perineural invasion present, histologic grade pathologic T, pathologic N, pathologic stage, OS status, OS time, RFS status, RFS time, DNA methylation, and gistic2 threshold-processed copy-number alteration (-1: copy deletion; 0: no change; +1: amplification) were obtained for secondary analysis.	('neoplasm', 'Disease', (164, 172))	('neoplasm', 'Disease', 'MESH:D009369', (164, 172))	('p16', 'Gene', '1029', (200, 203))	('neoplasm', 'Phenotype', 'HP:0002664', (164, 172))	('copy deletion', 'Var', (424, 437))	('HPV', 'Species', '10566', (186, 189))	('alcohol', 'Chemical', 'MESH:D000438', (138, 145))	('p16', 'Gene', (200, 203))
381817	33403027	The beta values of cg23454038 probes mapping 200 bp downstream of the transcription start sites of FOXD1 were defined as the FOXD1 promoter methylation level.	('FOXD1', 'Gene', '2297', (99, 104))	('cg23454038', 'Var', (19, 29))	('FOXD1', 'Gene', '2297', (125, 130))	('FOXD1', 'Gene', (99, 104))	('FOXD1', 'Gene', (125, 130))
381850	33403027	The Kaplan-Meier curve showed that high mRNA expression of FOXD1 was associated with poor overall survival rate (Figure 3A, log-rank P = 2.51E-4).	('FOXD1', 'Gene', '2297', (59, 64))	('poor', 'NegReg', (85, 89))	('high mRNA', 'Var', (35, 44))	('overall survival rate', 'CPA', (90, 111))	('FOXD1', 'Gene', (59, 64))
381852	33403027	These results showed that patients with high FOXD1 expression had worse overall survival than patients with lower FOXD1 expression (Figure 3B, log-rank P = 0.0098).	('high', 'Var', (40, 44))	('FOXD1', 'Gene', (114, 119))	('patients', 'Species', '9606', (94, 102))	('overall survival', 'MPA', (72, 88))	('worse', 'NegReg', (66, 71))	('FOXD1', 'Gene', '2297', (45, 50))	('patients', 'Species', '9606', (26, 34))	('FOXD1', 'Gene', '2297', (114, 119))	('expression', 'Var', (51, 61))	('FOXD1', 'Gene', (45, 50))
381854	33403027	As shown in the Table 3, univariate analysis showed that older age (HR = 1.318, 95% CI: 1.003-1.731, P = 0.045), female (HR = 1.349, 95% CI: 1.014-1.796, P = 0.040), positive perineural invasion (HR = 2.135, 95% CI: 1.516-3.007, P = 1.42E-05), advanced pathologic stage (HR = 1.754, 95% CI: 1.203-2.558, P = 0.004), and high FOXD1 expression (HR = 1.665, 95% CI: 1.264-2.194, P = 2.93E-04) were significantly associated with poor OS in patients with HNSCC.	('HNSCC', 'Phenotype', 'HP:0012288', (450, 455))	('poor OS', 'Disease', (425, 432))	('expression', 'MPA', (331, 341))	('FOXD1', 'Gene', (325, 330))	('patients', 'Species', '9606', (436, 444))	('high', 'Var', (320, 324))	('FOXD1', 'Gene', '2297', (325, 330))
381855	33403027	Using significant factors identified in the univariate analysis, multivariate analysis confirmed that high FOXD1 expression (HR = 1.849, 95% CI: 1.280-2.670, P = 0.001), positive perineural invasion (HR = 2.051, 95% CI: 1.436-2.931, P = 7.90E-05), and advanced pathologic stage (HR = 1.739, 95% CI: 1.051-2.877, P = 0.31) were independent risk factors for poor OS in patients with HNSCC.	('expression', 'MPA', (113, 123))	('poor OS', 'Disease', (356, 363))	('HNSCC', 'Disease', (381, 386))	('HNSCC', 'Phenotype', 'HP:0012288', (381, 386))	('positive perineural invasion', 'CPA', (170, 198))	('high', 'Var', (102, 106))	('FOXD1', 'Gene', '2297', (107, 112))	('patients', 'Species', '9606', (367, 375))	('FOXD1', 'Gene', (107, 112))
381857	33403027	The Kaplan-Meier curve for RFS showed that high FOXD1 expression was associated with poor RFS (Figure 4, log-rank P = 0.007).	('expression', 'MPA', (54, 64))	('FOXD1', 'Gene', (48, 53))	('FOXD1', 'Gene', '2297', (48, 53))	('high', 'Var', (43, 47))
381858	33403027	This finding was further confirmed by univariate Cox proportional hazard analysis (Table 4), in which patients with high FOXD1 expression in tumors were at significantly increased risk of recurrence compared to patients with low FOXD1 expression in tumors (HR = 1.725, 95% CI: 1.152-2.583, P = 0.008).	('FOXD1', 'Gene', (121, 126))	('tumors', 'Phenotype', 'HP:0002664', (249, 255))	('tumors', 'Disease', 'MESH:D009369', (249, 255))	('FOXD1', 'Gene', (229, 234))	('patients', 'Species', '9606', (211, 219))	('high', 'Var', (116, 120))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('patients', 'Species', '9606', (102, 110))	('tumor', 'Phenotype', 'HP:0002664', (249, 254))	('tumors', 'Disease', (141, 147))	('tumors', 'Disease', 'MESH:D009369', (141, 147))	('recurrence', 'CPA', (188, 198))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('FOXD1', 'Gene', '2297', (121, 126))	('FOXD1', 'Gene', '2297', (229, 234))	('tumors', 'Disease', (249, 255))
381859	33403027	Subsequently, multivariate analysis showed that high FOXD1 expression was an independent risk factor for RFS in patients with HNSCC (HR = 1.650, 95% CI: 1.058-2.575, P = 0.008) after adjustment for significant prognostic clinicpathological parameters (smoking history and pathologic stage).	('HNSCC', 'Disease', (126, 131))	('FOXD1', 'Gene', (53, 58))	('patients', 'Species', '9606', (112, 120))	('expression', 'MPA', (59, 69))	('HNSCC', 'Phenotype', 'HP:0012288', (126, 131))	('high', 'Var', (48, 52))	('FOXD1', 'Gene', '2297', (53, 58))	('RFS', 'Disease', (105, 108))
381862	33403027	We showed that DNA amplification was associated with increased FOXD1 expression (P = 0.007, compared to the copy deletion group, Figure 5A).	('FOXD1', 'Gene', '2297', (63, 68))	('expression', 'MPA', (69, 79))	('DNA amplification', 'Var', (15, 32))	('increased', 'PosReg', (53, 62))	('FOXD1', 'Gene', (63, 68))
381865	33403027	The results showed that bladder cancer, cell cycle, DNA replication, glycosaminoglycan biosynthesis chondroitin sulfate, homologous recombination, glycan biosynthesis, nucleotide excision repair, p53 signaling pathway, pyrimidine metabolism, and spliceosome were enriched in the high FOXD1 expression group (Figure 6).	('DNA replication', 'MPA', (52, 67))	('pyrimidine', 'MPA', (219, 229))	('glycan biosynthesis', 'MPA', (147, 166))	('pyrimidine', 'Chemical', 'MESH:C030986', (219, 229))	('FOXD1', 'Gene', (284, 289))	('bladder cancer', 'Disease', 'MESH:D001749', (24, 38))	('bladder cancer', 'Disease', (24, 38))	('glycan', 'Chemical', 'MESH:D011134', (147, 153))	('bladder cancer', 'Phenotype', 'HP:0009725', (24, 38))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('cell cycle', 'CPA', (40, 50))	('p53', 'Gene', '7157', (196, 199))	('FOXD1', 'Gene', '2297', (284, 289))	('chondroitin sulfate', 'Chemical', 'MESH:D002809', (100, 119))	('nucleotide excision repair', 'MPA', (168, 194))	('glycan', 'Chemical', 'MESH:D011134', (80, 86))	('p53', 'Gene', (196, 199))	('glycosaminoglycan', 'Chemical', 'MESH:D006025', (69, 86))	('glycosaminoglycan biosynthesis', 'MPA', (69, 99))	('high', 'Var', (279, 283))
381887	33403027	Consistent with these studies, the log-rank test performed in our study showed that high FOXD1 expression was associated with significantly worse OS in both TCGA cohort and the validation cohort.	('FOXD1', 'Gene', '2297', (89, 94))	('FOXD1', 'Gene', (89, 94))	('high', 'Var', (84, 88))	('expression', 'MPA', (95, 105))
381888	33403027	In addition, multivariate proportional hazard Cox regression analysis showed that high FOXD1 expression could serve as an independent indicator of poor prognosis in patients with HNSCC, which suggested that FOXD1 may be a promising prognostic biomarker and therapeutic target for HNSCC.	('high', 'Var', (82, 86))	('FOXD1', 'Gene', '2297', (87, 92))	('HNSCC', 'Phenotype', 'HP:0012288', (179, 184))	('FOXD1', 'Gene', (207, 212))	('FOXD1', 'Gene', '2297', (207, 212))	('expression', 'MPA', (93, 103))	('patients', 'Species', '9606', (165, 173))	('HNSCC', 'Phenotype', 'HP:0012288', (280, 285))	('FOXD1', 'Gene', (87, 92))	('HNSCC', 'Disease', (179, 184))
381892	33403027	Cancer results from accumulation of genetic and epigenetic modifications of oncogenes and tumor-suppressor genes, resulting in metabolic dysfunction and uncontrolled proliferation.	('genetic', 'Var', (36, 43))	('accumulation', 'PosReg', (20, 32))	('oncogenes', 'Protein', (76, 85))	('uncontrolled proliferation', 'CPA', (153, 179))	('tumor', 'Disease', (90, 95))	('resulting in', 'Reg', (114, 126))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('metabolic dysfunction', 'Disease', (127, 148))	('Cancer', 'Disease', (0, 6))	('metabolic dysfunction', 'Disease', 'MESH:D008659', (127, 148))	('epigenetic modifications', 'Var', (48, 72))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
381893	33403027	Amplification of DNA is the major genetic change that results in cancer-specific expression of critical genes.	('DNA', 'Gene', (17, 20))	('Amplification', 'Var', (0, 13))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('expression of critical genes', 'MPA', (81, 109))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))
381894	33403027	In addition, DNA methylation is an important epigenetic modification involved in the inactivation of numerous tumor suppressor genes.	('tumor', 'Disease', 'MESH:D009369', (110, 115))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('DNA methylation', 'Var', (13, 28))
381896	33403027	The results showed that DNA amplification was associated with elevated FOXD1 RNA expression.	('DNA amplification', 'Var', (24, 41))	('FOXD1', 'Gene', (71, 76))	('elevated', 'PosReg', (62, 70))	('FOXD1', 'Gene', '2297', (71, 76))	('expression', 'MPA', (81, 91))
381898	33403027	These findings indicated that both genetic and epigenetic alterations contributed to dysregulation of FOXD1 in HNSCC.	('contributed', 'Reg', (70, 81))	('HNSCC', 'Phenotype', 'HP:0012288', (111, 116))	('HNSCC', 'Disease', (111, 116))	('dysregulation', 'MPA', (85, 98))	('epigenetic alterations', 'Var', (47, 69))	('FOXD1', 'Gene', (102, 107))	('FOXD1', 'Gene', '2297', (102, 107))
381901	33403027	Genetic and epigenetic alterations contributed to upregulation of FOXD1 in HNSCC.	('upregulation', 'PosReg', (50, 62))	('FOXD1', 'Gene', '2297', (66, 71))	('epigenetic alterations', 'Var', (12, 34))	('HNSCC', 'Disease', (75, 80))	('HNSCC', 'Phenotype', 'HP:0012288', (75, 80))	('FOXD1', 'Gene', (66, 71))
381908	32546690	Pathway analysis indicated that aberrantly methylated DEGs mainly associated with the P13K-AKT signaling, cAMP signaling and cell cycle process.	('aberrantly methylated DEGs', 'Var', (32, 58))	('P13K', 'Mutation', 'p.P13K', (86, 90))	('AKT', 'Gene', '207', (91, 94))	('cAMP', 'Gene', (106, 110))	('DEGs', 'Var', (54, 58))	('cAMP', 'Gene', '820', (106, 110))	('cell cycle process', 'CPA', (125, 143))	('associated', 'Reg', (66, 76))	('AKT', 'Gene', (91, 94))
381910	32546690	Patients with high expression of AURKA were associated with shorter overall survival.	('AURKA', 'Gene', '6790', (33, 38))	('Patients', 'Species', '9606', (0, 8))	('AURKA', 'Gene', (33, 38))	('overall survival', 'MPA', (68, 84))	('high expression', 'Var', (14, 29))	('shorter', 'NegReg', (60, 67))
381914	32546690	DNA methylation is the most common epigenetic change, and it is closely related to gene expression regulation, embryonic development, X chromosome inactivation, genomic stability and genomic imprinting, and plays a significant role in cancer progression.	('role', 'Reg', (227, 231))	('cancer', 'Disease', (235, 241))	('cancer', 'Disease', 'MESH:D009369', (235, 241))	('methylation', 'Var', (4, 15))	('plays', 'Reg', (207, 212))	('related', 'Reg', (72, 79))	('DNA', 'Var', (0, 3))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))
381915	32546690	DNA methylation of gene promoters is associated with silencing of key genes, especially oncogenes and tumor suppressors and is considered to be a hallmark in many carcinomas.	('carcinoma', 'Phenotype', 'HP:0030731', (163, 172))	('oncogenes', 'Gene', (88, 97))	('carcinomas', 'Disease', 'MESH:D009369', (163, 173))	('carcinomas', 'Phenotype', 'HP:0030731', (163, 173))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('carcinomas', 'Disease', (163, 173))	('silencing', 'MPA', (53, 62))	('DNA methylation', 'Var', (0, 15))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))
381916	32546690	In the present research, we used publicly available datasets of gene expression (GSE20347, GSE38129) and gene methylation (GSE52826) to identify genes and pathways that were both abnormally methylated and differentially expressed between tumor tissues and normal esophagus from patients with ESCC.	('GSE20347', 'Var', (81, 89))	('differentially', 'Reg', (205, 219))	('GSE38129', 'Var', (91, 99))	('tumor', 'Disease', 'MESH:D009369', (238, 243))	('tumor', 'Phenotype', 'HP:0002664', (238, 243))	('tumor', 'Disease', (238, 243))	('ESCC', 'Disease', (292, 296))	('patients', 'Species', '9606', (278, 286))
381923	32546690	4G), while hypermethylated/low-expression genes were significantly enriched in Pancreatic secretion, Renin secretion, Amphetamine addiction, Salivary secretion, cAMP signaling pathway, Histidine metabolism, Long-term potentiation, Gastric acid secretion, Dopaminergic synapse and Circadian entrainment (Fig.	('Renin', 'Gene', (101, 106))	('Gastric acid secretion', 'Disease', (231, 253))	('cAMP', 'Gene', (161, 165))	('cAMP', 'Gene', '820', (161, 165))	('Amphetamine addiction', 'Disease', (118, 139))	('Circadian entrainment', 'Disease', (280, 301))	('Amphetamine', 'Chemical', 'MESH:D000661', (118, 129))	('Long-term potentiation', 'Disease', (207, 229))	('Histidine', 'MPA', (185, 194))	('Renin', 'Gene', '5972', (101, 106))	('Pancreatic secretion', 'Disease', 'MESH:D010195', (79, 99))	('Salivary secretion', 'Disease', (141, 159))	('hypermethylated/low-expression genes', 'Var', (11, 47))	('Pancreatic secretion', 'Disease', (79, 99))
381931	32546690	Hypermethylated/low-expression hub genes and hypomethylated/high-expression hub genes were then validated in another database TCGA to confirm the outcomes.	('hub', 'Gene', (76, 79))	('hub', 'Gene', '1993', (31, 34))	('hub', 'Gene', '1993', (76, 79))	('Hypermethylated/low-expression', 'Var', (0, 30))	('hub', 'Gene', (31, 34))	('Hypermethylated/low-expression', 'NegReg', (0, 30))
381942	32546690	Patients with high expression of AURKA were associated with shorter overall survival (Fig.	('AURKA', 'Gene', '6790', (33, 38))	('Patients', 'Species', '9606', (0, 8))	('AURKA', 'Gene', (33, 38))	('overall survival', 'MPA', (68, 84))	('high expression', 'Var', (14, 29))	('shorter', 'NegReg', (60, 67))
381944	32546690	Enrichment of these genes demonstrated that aberrant methylation indeed affects certain pathways and hub genes.	('pathways', 'Pathway', (88, 96))	('hub', 'Gene', (101, 104))	('aberrant methylation', 'Var', (44, 64))	('affects', 'Reg', (72, 79))	('hub', 'Gene', '1993', (101, 104))
381945	32546690	The GO enrichment analysis revealed that the primary biological processes of the hypomethylated/high-expression genes were involved in the regulation of extracellular matrix organization, extracellular structure organization, mitotic cell cycle process, cell cycle process, collagen catabolic process and nuclear division, while the hypermethylated/low-expression genes were primarily linked to response to cAMP, purine-containing compound, oxygen-containing compound, muscle system process, inorganic substance.	('cAMP', 'Gene', (407, 411))	('cAMP', 'Gene', '820', (407, 411))	('involved', 'Reg', (123, 131))	('collagen', 'CPA', (274, 282))	('hypomethylated/high-expression', 'Var', (81, 111))	('purine', 'Chemical', 'MESH:C030985', (413, 419))	('regulation', 'MPA', (139, 149))	('cell cycle process', 'CPA', (254, 272))	('mitotic cell cycle process', 'CPA', (226, 252))	('hypomethylated/high-expression', 'PosReg', (81, 111))	('nuclear division', 'CPA', (305, 321))	('extracellular matrix organization', 'CPA', (153, 186))	('extracellular structure organization', 'CPA', (188, 224))	('oxygen', 'Chemical', 'MESH:D010100', (441, 447))
381951	32546690	Furthermore, the enriched KEGG pathways of hypomethylated highly expressed genes were mainly linked to ECM-receptor interaction, Focal adhesion, Amoebiasis, PI3K-Akt signaling pathway and Cell cycle.	('Cell cycle', 'Disease', (188, 198))	('Amoebiasis', 'Disease', (145, 155))	('Akt', 'Gene', (162, 165))	('Focal adhesion', 'Disease', (129, 143))	('linked', 'Reg', (93, 99))	('hypomethylated', 'Var', (43, 57))	('Amoebiasis', 'Disease', 'MESH:D000562', (145, 155))	('KEGG pathways', 'Pathway', (26, 39))	('ECM-receptor interaction', 'Disease', (103, 127))	('Akt', 'Gene', '207', (162, 165))
381956	32546690	In contrast, hypermethylated/low-expression genes were related to Pancreatic secretion, Renin secretion, Amphetamine addiction, Salivary secretion and cAMP signaling pathway.	('Pancreatic secretion', 'Disease', (66, 86))	('Renin', 'Gene', '5972', (88, 93))	('Pancreatic secretion', 'Disease', 'MESH:D010195', (66, 86))	('Salivary secretion', 'Disease', (128, 146))	('Amphetamine', 'Chemical', 'MESH:D000661', (105, 116))	('Amphetamine addiction', 'Disease', (105, 126))	('Renin', 'Gene', (88, 93))	('cAMP', 'Gene', (151, 155))	('cAMP', 'Gene', '820', (151, 155))	('hypermethylated/low-expression genes', 'Var', (13, 49))	('related', 'Reg', (55, 62))
381970	32546690	The dysregulation of KIF14 has been confirmed in many human malignancies.	('malignancies', 'Disease', (60, 72))	('dysregulation', 'Var', (4, 17))	('KIF14', 'Gene', (21, 26))	('KIF14', 'Gene', '9928', (21, 26))	('malignancies', 'Disease', 'MESH:D009369', (60, 72))	('human', 'Species', '9606', (54, 59))
381978	32546690	Errors in the regulation mechanism of CDK1 directly lead to cell differentiation disorders, cell cycle disorders, malignant cell proliferation and abnormal transformation, and ultimately malignant tumor formation.	('abnormal transformation', 'CPA', (147, 170))	('malignant tumor', 'Disease', (187, 202))	('Errors', 'Var', (0, 6))	('CDK1', 'Gene', '983', (38, 42))	('malignant tumor', 'Disease', 'MESH:D009369', (187, 202))	('CDK1', 'Gene', (38, 42))	('cell differentiation disorders', 'CPA', (60, 90))	('cell cycle disorders', 'CPA', (92, 112))	('malignant cell proliferation', 'CPA', (114, 142))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('lead to', 'Reg', (52, 59))
381983	32546690	The mutation or overexpression of AURKA may also cause carcinogenesis.	('AURKA', 'Gene', (34, 39))	('overexpression', 'PosReg', (16, 30))	('mutation', 'Var', (4, 12))	('AURKA', 'Gene', '6790', (34, 39))	('cause', 'Reg', (49, 54))	('carcinogenesis', 'Disease', 'MESH:D063646', (55, 69))	('carcinogenesis', 'Disease', (55, 69))
382001	32546690	Current studies have shown that the mutation of the TGM1 gene is closely related to lamella stratified ichthyosis and may also affect the proliferation and differentiation of breast cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('ichthyosis', 'Disease', 'MESH:D007057', (103, 113))	('breast cancer', 'Disease', 'MESH:D001943', (175, 188))	('breast cancer', 'Phenotype', 'HP:0003002', (175, 188))	('breast cancer', 'Disease', (175, 188))	('proliferation', 'CPA', (138, 151))	('differentiation', 'CPA', (156, 171))	('ichthyosis', 'Phenotype', 'HP:0008064', (103, 113))	('TGM1', 'Gene', '7051', (52, 56))	('ichthyosis', 'Disease', (103, 113))	('TGM1', 'Gene', (52, 56))	('affect', 'Reg', (127, 133))	('mutation', 'Var', (36, 44))	('related', 'Reg', (73, 80))
382030	32546690	To confirm the results, we used the MEXPRESS to validate hypermethylated/low-expression hub genes and hypomethylated/ high-expression hub genes in the TCGA database.	('hub', 'Gene', '1993', (88, 91))	('hub', 'Gene', '1993', (134, 137))	('hypermethylated/low-expression', 'Var', (57, 87))	('hypermethylated/low-expression', 'NegReg', (57, 87))	('hub', 'Gene', (88, 91))	('hub', 'Gene', (134, 137))
382040	31059089	IL-17B, IL-17C and IL-17D exhibited lower alteration frequencies (0.8, 1.1 and 1.1%, respectively), and deep deletion accounted for the majority of changes.	('deep deletion', 'Var', (104, 117))	('IL-17C', 'Gene', '27189', (8, 14))	('IL-17C', 'Gene', (8, 14))	('IL-17D', 'Gene', (19, 25))	('IL-17B', 'Gene', '27190', (0, 6))	('alteration', 'MPA', (42, 52))	('IL-17B', 'Gene', (0, 6))	('IL-17D', 'Gene', '53342', (19, 25))
382041	31059089	The rates of point mutations in IL-17A through IL-17F family genes in lung cancer were 0.66, 0.18, 0.13, 0.09, 0.27 and 0.44% in the COSMIC database.	('IL-17A', 'Gene', '3605', (32, 38))	('lung cancer', 'Disease', 'MESH:D008175', (70, 81))	('point mutations', 'Var', (13, 28))	('IL-17A', 'Gene', (32, 38))	('lung cancer', 'Disease', (70, 81))	('IL-17F', 'Gene', (47, 53))	('lung cancer', 'Phenotype', 'HP:0100526', (70, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('IL-17F', 'Gene', '112744', (47, 53))
382047	31059089	Our results revealed that IL-17 family gene mutation rates were in general low and that amplification and deep deletion were the main mutation type.	('low', 'NegReg', (75, 78))	('amplification', 'Var', (88, 101))	('IL-17', 'Gene', '3605', (26, 31))	('deep deletion', 'Var', (106, 119))	('IL-17', 'Gene', (26, 31))
382058	31059089	For example, IL-17A produced by tumour-infiltrating immune cells was found to promote cancer cell growth through an IL-6/signal transducer and activator of transcription 3 (STAT3) pathway, and transfection with IL-17A was found to promote hepatocellular carcinoma (HCC) tumour growth via protein kinase B (AKT)-dependent activation of IL-6/Janus kinase 2 (JAK2)/STAT3 signalling.	('signal transducer and activator of transcription 3', 'Gene', '6774', (121, 171))	('AKT', 'Gene', '207', (306, 309))	('IL-17A', 'Gene', '3605', (13, 19))	('activation', 'PosReg', (321, 331))	('IL-6', 'Gene', '3569', (116, 120))	('carcinoma', 'Phenotype', 'HP:0030731', (254, 263))	('tumour growth', 'Disease', (270, 283))	('IL-17A', 'Gene', '3605', (211, 217))	('promote', 'PosReg', (231, 238))	('Janus kinase 2', 'Gene', '3717', (340, 354))	('JAK2', 'Gene', '3717', (356, 360))	('STAT3', 'Gene', (173, 178))	('IL-6', 'Gene', (116, 120))	('IL-17A', 'Gene', (13, 19))	('cancer', 'Disease', (86, 92))	('promote', 'PosReg', (78, 85))	('STAT3', 'Gene', '6774', (173, 178))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('AKT', 'Gene', (306, 309))	('STAT3', 'Gene', (362, 367))	('hepatocellular carcinoma (HCC) tumour', 'Disease', 'MESH:D006528', (239, 276))	('IL-17A', 'Gene', (211, 217))	('JAK2', 'Gene', (356, 360))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (239, 263))	('IL-6', 'Gene', '3569', (335, 339))	('tumour', 'Phenotype', 'HP:0002664', (32, 38))	('tumour', 'Phenotype', 'HP:0002664', (270, 276))	('transfection', 'Var', (193, 205))	('tumour', 'Disease', 'MESH:D009369', (32, 38))	('tumour', 'Disease', 'MESH:D009369', (270, 276))	('STAT3', 'Gene', '6774', (362, 367))	('tumour growth', 'Disease', 'MESH:D006130', (270, 283))	('tumour', 'Disease', (32, 38))	('tumour', 'Disease', (270, 276))	('IL-6', 'Gene', (335, 339))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('Janus kinase 2', 'Gene', (340, 354))
382091	31059089	A mutation analysis was performed in 169 cancer studies, including mutation, amplification and deletion.	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('mutation', 'Var', (67, 75))	('deletion', 'Var', (95, 103))	('amplification', 'Var', (77, 90))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (41, 47))
382096	31059089	P-values <0.05 were considered statistically significant The IL-17 family gene mutations in lung cancers were assessed using cBioPortal.	('cancers', 'Phenotype', 'HP:0002664', (97, 104))	('lung cancer', 'Phenotype', 'HP:0100526', (92, 103))	('lung cancers', 'Disease', 'MESH:D008175', (92, 104))	('lung cancers', 'Phenotype', 'HP:0100526', (92, 104))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('IL-17', 'Gene', '3605', (61, 66))	('IL-17', 'Gene', (61, 66))	('lung cancers', 'Disease', (92, 104))	('mutations', 'Var', (79, 88))
382098	31059089	1A, IL-17 genetic mutations in lung adenocarcinoma (TCGA; ) were not the highest compared with those in neuroendocrine prostate cancer (NEPC) (Trento/Cornell/Broad 2016) and breast cancer (BCCRC Xenograft) but were present in 10% of the 230 cases.	('neuroendocrine prostate cancer', 'Disease', 'MESH:D011471', (104, 134))	('breast cancer', 'Disease', 'MESH:D001943', (174, 187))	('prostate cancer', 'Phenotype', 'HP:0012125', (119, 134))	('carcinoma', 'Phenotype', 'HP:0030731', (41, 50))	('lung adenocarcinoma', 'Disease', (31, 50))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('breast cancer', 'Disease', (174, 187))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (31, 50))	('breast cancer', 'Phenotype', 'HP:0003002', (174, 187))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (31, 50))	('IL-17', 'Gene', (4, 9))	('IL-17', 'Gene', '3605', (4, 9))	('neuroendocrine prostate cancer', 'Disease', (104, 134))	('mutations', 'Var', (18, 27))
382101	31059089	IL17B, IL17C and IL17D exhibited lower alteration frequencies (0.8, 1.1 and 1.1%, respectively), and deep deletions accounted for the majority of changes.	('IL17', 'Gene', '3605', (17, 21))	('IL17', 'Gene', (0, 4))	('IL17', 'Gene', (7, 11))	('IL17', 'Gene', '3605', (0, 4))	('IL17C', 'Gene', '27189', (7, 12))	('deep deletions', 'Var', (101, 115))	('IL17', 'Gene', '3605', (7, 11))	('17D', 'Species', '2498238', (19, 22))	('IL17', 'Gene', (17, 21))	('IL17C', 'Gene', (7, 12))
382116	31059089	We also evaluated whether alterations in IL-17 family gene mRNA are associated with a specific histological type of non-small cell lung cancer (NSCLC) using cBioPortal (Fig.	('NSCLC', 'Disease', (144, 149))	('associated', 'Reg', (68, 78))	('IL-17', 'Gene', '3605', (41, 46))	('NSCLC', 'Disease', 'MESH:D002289', (144, 149))	('IL-17', 'Gene', (41, 46))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (116, 142))	('alterations', 'Var', (26, 37))	('non-small cell lung cancer', 'Disease', (116, 142))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (120, 142))	('mRNA', 'MPA', (59, 63))	('lung cancer', 'Phenotype', 'HP:0100526', (131, 142))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (116, 142))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
382136	31059089	Overexpression or exogeneous IL-17A can promote tumour growth, angiogenesis and metastasis.	('promote', 'PosReg', (40, 47))	('metastasis', 'CPA', (80, 90))	('IL-17A', 'Gene', (29, 35))	('exogeneous', 'Var', (18, 28))	('tumour', 'Phenotype', 'HP:0002664', (48, 54))	('tumour growth', 'Disease', (48, 61))	('tumour growth', 'Disease', 'MESH:D006130', (48, 61))	('IL-17A', 'Gene', '3605', (29, 35))	('angiogenesis', 'CPA', (63, 75))
382141	31059089	A number of studies have reported that IL-17 genetic family polymorphisms are associated with increased risk of cancer.	('associated', 'Reg', (78, 88))	('genetic family polymorphisms', 'Var', (45, 73))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('IL-17', 'Gene', (39, 44))	('IL-17', 'Gene', '3605', (39, 44))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))
382142	31059089	It was demonstrated that IL-17A and IL-17F gene polymorphisms were associated with an increased risk of lung cancer, gastric cancer, acute myeloid leukaemia, and colorectal cancer.	('acute myeloid leukaemia', 'Disease', (133, 156))	('IL-17F', 'Gene', (36, 42))	('gastric cancer', 'Disease', (117, 131))	('IL-17F', 'Gene', '112744', (36, 42))	('lung cancer', 'Disease', 'MESH:D008175', (104, 115))	('colorectal cancer', 'Phenotype', 'HP:0003003', (162, 179))	('lung cancer', 'Phenotype', 'HP:0100526', (104, 115))	('polymorphisms', 'Var', (48, 61))	('gastric cancer', 'Disease', 'MESH:D013274', (117, 131))	('myeloid leukaemia', 'Phenotype', 'HP:0012324', (139, 156))	('acute myeloid leukaemia', 'Disease', 'MESH:D007938', (133, 156))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('IL-17A', 'Gene', '3605', (25, 31))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('associated', 'Reg', (67, 77))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('colorectal cancer', 'Disease', 'MESH:D015179', (162, 179))	('gastric cancer', 'Phenotype', 'HP:0012126', (117, 131))	('lung cancer', 'Disease', (104, 115))	('colorectal cancer', 'Disease', (162, 179))	('IL-17A', 'Gene', (25, 31))
382143	31059089	Furthermore, IL-17A polymorphisms may upregulate IL-17A expression and are associated with clinicopathological features and tobacco smoking history in lung cancer patients.	('IL-17A', 'Gene', (49, 55))	('patients', 'Species', '9606', (163, 171))	('IL-17A', 'Gene', '3605', (13, 19))	('lung cancer', 'Phenotype', 'HP:0100526', (151, 162))	('polymorphisms', 'Var', (20, 33))	('lung cancer', 'Disease', 'MESH:D008175', (151, 162))	('lung cancer', 'Disease', (151, 162))	('expression', 'MPA', (56, 66))	('upregulate', 'PosReg', (38, 48))	('tobacco', 'Species', '4097', (124, 131))	('IL-17A', 'Gene', '3605', (49, 55))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('associated', 'Reg', (75, 85))	('IL-17A', 'Gene', (13, 19))
382146	31059089	The present results revealed that IL-17 family gene mutation rates were in general low, and amplification and deep deletion were the main mutation type.	('IL-17', 'Gene', (34, 39))	('IL-17', 'Gene', '3605', (34, 39))	('amplification', 'Var', (92, 105))	('mutation', 'Var', (52, 60))	('low', 'NegReg', (83, 86))
382162	31059089	Based on our results, we can conclude that IL-17 family gene mutation rates were in general low and that amplification and deep deletion were the main mutation type.	('low', 'NegReg', (92, 95))	('mutation', 'Var', (61, 69))	('IL-17', 'Gene', (43, 48))	('IL-17', 'Gene', '3605', (43, 48))
382177	32599841	Identification of Prognostic Organic Cation and Anion Transporters in Different Cancer Entities by In Silico Analysis The information derived from next generation sequencing technology allows the identification of deregulated genes, gene mutations, epigenetic modifications, and other genomic events that are associated with a given tumor entity.	('gene mutations', 'Var', (233, 247))	('tumor', 'Disease', (333, 338))	('epigenetic modifications', 'Var', (249, 273))	('deregulated', 'MPA', (214, 225))	('tumor', 'Disease', 'MESH:D009369', (333, 338))	('Cancer', 'Phenotype', 'HP:0002664', (80, 86))	('Cancer', 'Disease', (80, 86))	('tumor', 'Phenotype', 'HP:0002664', (333, 338))	('Cancer', 'Disease', 'MESH:D009369', (80, 86))
382258	32599841	In contrast to OCT1 and OCT2, OCT3 (SLC22A3) has a broad expression pattern and is able to transport a variety of substances including drugs and chemotherapeutics and high expression has an unfavorable prognostic value in cervical and urothelial cancer.	('expression pattern', 'MPA', (57, 75))	('OCT3', 'Gene', (30, 34))	('transport', 'MPA', (91, 100))	('OCT3', 'Gene', '6581', (30, 34))	('urothelial cancer', 'Disease', 'MESH:D014523', (235, 252))	('OCT2', 'Gene', '6582', (24, 28))	('high expression', 'Var', (167, 182))	('OCT2', 'Gene', (24, 28))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))	('OCT1', 'Gene', (15, 19))	('SLC22A3', 'Gene', (36, 43))	('SLC22A3', 'Gene', '6581', (36, 43))	('OCT1', 'Gene', '6580', (15, 19))	('urothelial cancer', 'Disease', (235, 252))
382262	32599841	In pancreatic cancer, high OCT3 protein expression correlated with better clinical outcome of the patients.	('OCT3', 'Gene', (27, 31))	('pancreatic cancer', 'Disease', (3, 20))	('pancreatic cancer', 'Disease', 'MESH:D010190', (3, 20))	('high', 'Var', (22, 26))	('OCT3', 'Gene', '6581', (27, 31))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('patients', 'Species', '9606', (98, 106))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (3, 20))
382272	32599841	It has also been shown that MATE1 expression is associated with better uptake of the tyrosine kinase inhibitor imatinib in chronic myeloid leukemia cells.	('better', 'PosReg', (64, 70))	('imatinib', 'Chemical', 'MESH:D000068877', (111, 119))	('leukemia', 'Phenotype', 'HP:0001909', (139, 147))	('chronic myeloid leukemia', 'Phenotype', 'HP:0005506', (123, 147))	('expression', 'Var', (34, 44))	('myeloid leukemia', 'Disease', (131, 147))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (131, 147))	('uptake of the tyrosine kinase inhibitor imatinib', 'MPA', (71, 119))	('MATE1', 'Gene', (28, 33))	('myeloid leukemia', 'Disease', 'MESH:D007951', (131, 147))	('MATE1', 'Gene', '55244', (28, 33))
382281	32599841	For example, high SLC35A1 expression is favorable for clear cell renal carcinoma but unfavorable for papillary and chromophobe renal cell carcinoma.	('expression', 'MPA', (26, 36))	('renal carcinoma', 'Phenotype', 'HP:0005584', (65, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('chromophobe renal cell carcinoma', 'Disease', (115, 147))	('clear cell renal carcinoma', 'Disease', (54, 80))	('SLC35A1', 'Gene', (18, 25))	('high', 'Var', (13, 17))	('clear cell renal carcinoma', 'Phenotype', 'HP:0006770', (54, 80))	('SLC35A1', 'Gene', '10559', (18, 25))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('chromophobe renal cell carcinoma', 'Disease', 'MESH:C538614', (115, 147))	('clear cell renal carcinoma', 'Disease', 'MESH:C538614', (54, 80))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (127, 147))
382296	32599841	High PLS3 expression has been shown to have poor prognosis in pancreatic cancer, acute myeloid leukemia, gastric cancer, and colorectal cancer.	('PLS3', 'Gene', (5, 9))	('pancreatic cancer', 'Disease', 'MESH:D010190', (62, 79))	('colorectal cancer', 'Phenotype', 'HP:0003003', (125, 142))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (81, 103))	('gastric cancer', 'Disease', 'MESH:D013274', (105, 119))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (87, 103))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (81, 103))	('High', 'Var', (0, 4))	('PLS3', 'Gene', '5358', (5, 9))	('pancreatic cancer', 'Disease', (62, 79))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('gastric cancer', 'Phenotype', 'HP:0012126', (105, 119))	('colorectal cancer', 'Disease', 'MESH:D015179', (125, 142))	('colorectal cancer', 'Disease', (125, 142))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (62, 79))	('acute myeloid leukemia', 'Disease', (81, 103))	('gastric cancer', 'Disease', (105, 119))	('leukemia', 'Phenotype', 'HP:0001909', (95, 103))
382300	32599841	For example the inhibition of MCT1 activity in T cells inhibited effective immune response by reducing the rapid T cell division during activation process.	('inhibited', 'NegReg', (55, 64))	('effective immune response', 'CPA', (65, 90))	('MCT1', 'Gene', (30, 34))	('MCT1', 'Gene', '6566', (30, 34))	('reducing', 'NegReg', (94, 102))	('rapid T cell division', 'CPA', (107, 128))	('inhibition', 'Var', (16, 26))
382305	32599841	MCT4 plays also an important role in cell migration and targeting MCT1 and MCT4 expression has been shown to reduce the malignant potential of pancreatic cancer.	('MCT4', 'Gene', '9123', (0, 4))	('malignant potential of', 'CPA', (120, 142))	('reduce', 'NegReg', (109, 115))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (143, 160))	('MCT1', 'Gene', (66, 70))	('MCT4', 'Gene', (0, 4))	('MCT4', 'Gene', (75, 79))	('targeting', 'Var', (56, 65))	('MCT1', 'Gene', '6566', (66, 70))	('pancreatic cancer', 'Disease', (143, 160))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('MCT4', 'Gene', '9123', (75, 79))	('pancreatic cancer', 'Disease', 'MESH:D010190', (143, 160))
382343	31089746	Cytl1 is specifically expressed in a rare population of human bone marrow and cord blood mononuclear cells that bear CD34 positivity and function as haematopoietic stem/progenitor cells.	('positivity', 'Var', (122, 132))	('CD34', 'Gene', '947', (117, 121))	('Cytl1', 'Gene', (0, 5))	('human', 'Species', '9606', (56, 61))	('CD34', 'Gene', (117, 121))
382370	31089746	Further, Cytl1 was found to be preferentially expressed in chondrocytes and in cartilage-rich tissues, and systemic expression of Cytl1 in vivo inhibits collagen antibody-induced arthritis in mice.	('cartilage-rich tissues', 'Disease', 'MESH:D002357', (79, 101))	('arthritis', 'Disease', 'MESH:D001168', (179, 188))	('arthritis', 'Phenotype', 'HP:0001369', (179, 188))	('mice', 'Species', '10090', (192, 196))	('inhibits', 'NegReg', (144, 152))	('cartilage-rich tissues', 'Disease', (79, 101))	('arthritis', 'Disease', (179, 188))	('Cytl1', 'Var', (130, 135))
382373	31089746	Collectively, multiple lines of evidence suggest that, rather than regulating physiological cartilage and bone development, Cytl1 is involved mainly in the maintenance of cartilage homeostasis, and that loss of Cytl1 function is associated with osteoarthritis progression.	('cartilage homeostasis', 'Disease', 'MESH:D002357', (171, 192))	('loss', 'Var', (203, 207))	('osteoarthritis', 'Phenotype', 'HP:0002758', (245, 259))	('osteoarthritis', 'Disease', (245, 259))	('cartilage', 'Disease', (92, 101))	('cartilage', 'Disease', 'MESH:D002357', (92, 101))	('cartilage homeostasis', 'Disease', (171, 192))	('osteoarthritis', 'Disease', 'MESH:D010003', (245, 259))	('cartilage', 'Disease', (171, 180))	('cartilage', 'Disease', 'MESH:D002357', (171, 180))	('rat', 'Species', '10116', (55, 58))	('associated', 'Reg', (229, 239))	('arthritis', 'Phenotype', 'HP:0001369', (250, 259))	('Cytl1', 'Gene', (211, 216))
382377	31089746	It was identified as one of the three candidate genes that harboured rare loss-of-function variants in both early-onset and familial colorectal cancer (CRC) in a study analysing in 3374 Finnish and 58,112 non-Finnish controls.	('familial colorectal cancer', 'Disease', 'MESH:D015179', (124, 150))	('early-onset', 'Disease', (108, 119))	('familial colorectal cancer', 'Disease', (124, 150))	('variants', 'Var', (91, 99))	('CRC', 'Phenotype', 'HP:0003003', (152, 155))	('colorectal cancer', 'Phenotype', 'HP:0003003', (133, 150))	('loss-of-function', 'NegReg', (74, 90))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
382384	31089746	Further, differential expression of Cytl1, together with Efnb1, and Tex26, was found in trophectoderm biopsies, which suggests that Cytl1 might be associated with successful embryo implantation and live birth.	('Cytl1', 'Gene', (36, 41))	('associated', 'Reg', (147, 157))	('Tex26', 'Gene', '122046', (68, 73))	('Efnb1', 'Gene', '1947', (57, 62))	('successful embryo implantation', 'CPA', (163, 193))	('live birth', 'CPA', (198, 208))	('Cytl1', 'Var', (132, 137))	('Tex26', 'Gene', (68, 73))	('expression', 'MPA', (22, 32))	('Efnb1', 'Gene', (57, 62))
382386	31089746	A recent genome-wide association study (GWAS) found that certain haplotypes within the Cytl1 gene were significantly associated with an increased risk of alcohol dependence (AD), suggesting that the Cytl1 gene may play an important role in the susceptibility to AD.	('alcohol dependence', 'Disease', (154, 172))	('AD', 'Phenotype', 'HP:0030955', (262, 264))	('AD', 'Disease', (262, 264))	('associated', 'Reg', (117, 127))	('alcohol dependence', 'Phenotype', 'HP:0030955', (154, 172))	('Cytl1', 'Gene', (87, 92))	('AD', 'Disease', 'MESH:D000544', (174, 176))	('AD', 'Disease', (174, 176))	('AD', 'Phenotype', 'HP:0030955', (174, 176))	('AD', 'Disease', 'MESH:D000544', (262, 264))	('haplotypes', 'Var', (65, 75))	('alcohol dependence', 'Disease', 'MESH:D000437', (154, 172))
382387	31089746	The possible underlying molecular and cellular mechanisms of this association are unknown and further studies are required to elucidate the significance of Cytl1 gene variants in relation to AD.	('variants', 'Var', (167, 175))	('AD', 'Disease', 'MESH:D000544', (191, 193))	('AD', 'Disease', (191, 193))	('AD', 'Phenotype', 'HP:0030955', (191, 193))	('Cytl1', 'Gene', (156, 161))
382401	31089746	In addition, Cytl1 also appears to activate the TGF-beta-SMAD signalling pathway via an unidentified receptor, and play an important role in cardiac fibrosis and heart failure.	('play', 'Reg', (115, 119))	('heart failure', 'Phenotype', 'HP:0001635', (162, 175))	('Cytl1', 'Var', (13, 18))	('cardiac fibrosis', 'Disease', 'MESH:D005355', (141, 157))	('TGF-beta', 'Gene', (48, 56))	('heart failure', 'Disease', 'MESH:D006333', (162, 175))	('activate', 'PosReg', (35, 43))	('heart failure', 'Disease', (162, 175))	('AD', 'Disease', 'MESH:D000544', (59, 61))	('AD', 'Phenotype', 'HP:0030955', (59, 61))	('TGF-beta', 'Gene', '7040', (48, 56))	('AD', 'Disease', (59, 61))	('cardiac fibrosis', 'Disease', (141, 157))
382471	26706028	In survival analysis with OCT4 expression, 22 recurrences and 13 deaths occurred in 83 cases of OCT4 high expression, while 7 recurrences and 3 deaths were observed in 65 cases of low expression.	('OCT4', 'Gene', (96, 100))	('deaths', 'Disease', 'MESH:D003643', (65, 71))	('deaths', 'Disease', (65, 71))	('OCT4', 'Gene', '5460', (96, 100))	('OCT4', 'Gene', '5460', (26, 30))	('deaths', 'Disease', 'MESH:D003643', (144, 150))	('deaths', 'Disease', (144, 150))	('OCT4', 'Gene', (26, 30))	('high expression', 'Var', (101, 116))
382472	26706028	The 5-year disease-free and overall survival rates were 89.2 and 95.4 % in low OCT4 expression and 73.5 and 84.3 % in high OCT4 expression.	('low', 'Var', (75, 78))	('disease-free', 'CPA', (11, 23))	('OCT4', 'Gene', '5460', (123, 127))	('OCT4', 'Gene', (123, 127))	('OCT4', 'Gene', '5460', (79, 83))	('OCT4', 'Gene', (79, 83))
382474	26706028	In survival analysis of SOX2, there were 20 recurrences and 8 deaths in 125 high-expression patients, while 8 recurrences and 7 deaths occurred in 36 low-expression patients during the 5-year follow-up period.	('deaths', 'Disease', (62, 68))	('SOX2', 'Gene', (24, 28))	('deaths', 'Disease', (128, 134))	('deaths', 'Disease', 'MESH:D003643', (128, 134))	('patients', 'Species', '9606', (92, 100))	('patients', 'Species', '9606', (165, 173))	('high-expression', 'Var', (76, 91))	('SOX2', 'Gene', '6657', (24, 28))	('deaths', 'Disease', 'MESH:D003643', (62, 68))
382476	26706028	High expression of SOX2 was associated with better overall survival than low expression (p = 0.025) (Fig.	('better', 'PosReg', (44, 50))	('High expression', 'Var', (0, 15))	('SOX2', 'Gene', (19, 23))	('SOX2', 'Gene', '6657', (19, 23))	('overall survival', 'MPA', (51, 67))
382479	26706028	OCT4 overexpression showed independent poor overall survival with a hazard ratio of 11.23 (p = 0.027), while high expression of SOX2 presented better disease-free and overall survival compared to low expression, as shown in Table 4 (p = 0.019 and p = 0.013, respectively).	('high expression', 'Var', (109, 124))	('disease-free', 'CPA', (150, 162))	('SOX2', 'Gene', '6657', (128, 132))	('SOX2', 'Gene', (128, 132))	('better', 'PosReg', (143, 149))	('poor', 'NegReg', (39, 43))	('overexpression', 'PosReg', (5, 19))	('overall survival', 'CPA', (167, 183))	('OCT4', 'Gene', '5460', (0, 4))	('OCT4', 'Gene', (0, 4))
382480	26706028	OCT4 and SOX2 are important transcriptional factors involved in maintenance of pluripotency and self-renewal in cancer stem cells, aberrant expression of OCT4 and SOX2 might contribute to carcinogenesis in various cancers.	('cancer', 'Disease', (112, 118))	('pluripotency', 'Disease', 'None', (79, 91))	('SOX2', 'Gene', '6657', (163, 167))	('SOX2', 'Gene', (163, 167))	('cancers', 'Disease', 'MESH:D009369', (214, 221))	('carcinogenesis', 'Disease', (188, 202))	('contribute to', 'Reg', (174, 187))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('OCT4', 'Gene', (0, 4))	('cancer', 'Disease', (214, 220))	('carcinogenesis', 'Disease', 'MESH:D063646', (188, 202))	('SOX2', 'Gene', (9, 13))	('SOX2', 'Gene', '6657', (9, 13))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('cancers', 'Phenotype', 'HP:0002664', (214, 221))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('cancers', 'Disease', (214, 221))	('OCT4', 'Gene', '5460', (154, 158))	('cancer', 'Disease', 'MESH:D009369', (214, 220))	('pluripotency', 'Disease', (79, 91))	('aberrant', 'Var', (131, 139))	('OCT4', 'Gene', '5460', (0, 4))	('OCT4', 'Gene', (154, 158))
382503	26706028	High expression of SOX2 was reported to be associated with a lack of cell differentiation and to contribute cell migration and invasion in cervical cancer cell line.	('cervical cancer', 'Disease', 'MESH:D002583', (139, 154))	('High', 'Var', (0, 4))	('cell differentiation', 'CPA', (69, 89))	('cervical cancer', 'Disease', (139, 154))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('invasion', 'CPA', (127, 135))	('SOX2', 'Gene', (19, 23))	('cell migration', 'CPA', (108, 122))	('SOX2', 'Gene', '6657', (19, 23))	('contribute', 'PosReg', (97, 107))
382505	26706028	In contrast, SOX2 expression was associated with prolonged survival in the current study.	('SOX2', 'Gene', (13, 17))	('expression', 'Var', (18, 28))	('prolonged', 'PosReg', (49, 58))	('SOX2', 'Gene', '6657', (13, 17))
382507	26706028	reported that SOX2 gene amplification and protein expression are associated with favorable survival outcomes in squamous cell lung cancer.	('SOX2', 'Gene', '6657', (14, 18))	('SOX2', 'Gene', (14, 18))	('squamous cell lung cancer', 'Disease', 'MESH:D002294', (112, 137))	('protein', 'Protein', (42, 49))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('gene amplification', 'Var', (19, 37))	('lung cancer', 'Phenotype', 'HP:0100526', (126, 137))	('squamous cell lung cancer', 'Disease', (112, 137))
382508	26706028	In addition, a recent meta-analysis reported that SOX2 expression presents a positive prognosis in non-small cell lung cancer.	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (99, 125))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (99, 125))	('SOX2', 'Gene', '6657', (50, 54))	('SOX2', 'Gene', (50, 54))	('non-small cell lung cancer', 'Disease', (99, 125))	('lung cancer', 'Phenotype', 'HP:0100526', (114, 125))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (103, 125))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('expression', 'Var', (55, 65))
382530	33551645	LncRNA GAS5 Suppressed Proliferation and Promoted Apoptosis in Laryngeal Squamous Cell Carcinoma by Targeting MiR-26a-5p and Modifying ULK2 Long noncoding RNAs growth arrest-specific 5 (GAS5) exerts important functions in modulating various tumor behaviors.	('growth arrest-', 'Phenotype', 'HP:0031164', (160, 174))	('Proliferation', 'CPA', (23, 36))	('growth arrest', 'Phenotype', 'HP:0001510', (160, 173))	('Squamous Cell Carcinoma', 'Disease', 'MESH:D002294', (73, 96))	('MiR-26a-5p', 'Gene', (110, 120))	('GAS5', 'Gene', '60674', (7, 11))	('Suppressed', 'NegReg', (12, 22))	('tumor', 'Disease', (241, 246))	('Apoptosis', 'CPA', (50, 59))	('Modifying', 'Var', (125, 134))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (73, 96))	('tumor', 'Disease', 'MESH:D009369', (241, 246))	('Squamous Cell Carcinoma', 'Disease', (73, 96))	('Targeting', 'Var', (100, 109))	('GAS5', 'Gene', '60674', (186, 190))	('growth arrest-specific 5', 'Gene', '60674', (160, 184))	('GAS5', 'Gene', (7, 11))	('growth arrest-specific 5', 'Gene', (160, 184))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))	('Promoted', 'PosReg', (41, 49))	('Carcinoma', 'Phenotype', 'HP:0030731', (87, 96))	('GAS5', 'Gene', (186, 190))
382535	33551645	MiR-26a-5p mimics inhibited apoptosis and autophagy, which were reversed by GAS5 and siGAS5 in AMC-HN-8 cells and Tu 177 cells, as well as ULK2 in AMC-HN-8 cells.	('AMC-HN-8', 'CellLine', 'CVCL:5966', (147, 155))	('autophagy', 'CPA', (42, 51))	('apoptosis', 'CPA', (28, 37))	('siGAS5', 'Var', (85, 91))	('inhibited', 'NegReg', (18, 27))	('MiR-26a-5p', 'Chemical', '-', (0, 10))	('AMC-HN-8', 'CellLine', 'CVCL:5966', (95, 103))
382544	33551645	With the in-depth study of epigenetics and genomics, despite being unable to be translated into proteins, the non-coding RNAs have been found to participate in various important regulatory processes such as epigenetics, regulation of gene expression at transcription and post-transcription levels, and are closely related to the occurrence and development of human diseases.	('related', 'Reg', (314, 321))	('participate', 'Reg', (145, 156))	('non-coding RNAs', 'Var', (110, 125))	('men', 'Species', '9606', (351, 354))	('human', 'Species', '9606', (359, 364))
382574	33551645	The primary antibody as followed: anti-LC3I (19 kDa; rabbit; 1:1000; ab48394; abcam), anti-LC3II (17 kDa; rabbit; 1:1000; ab48394; abcam), anti-p62 (51 kDa; mouse; 1:1000; ab56416; abcam), anti-Beclin1 (52 kDa; rabbit; 1:1000; ab62557; abcam), anti-ULK2 (113 kDa; rabbit; 1:1000; ab97695; Abcam) and anti-GAPDH (36 kDa; mouse; 1:1000; ab8245; Abcam).	('anti-LC3I', 'Var', (34, 43))	('anti-LC3II', 'Var', (86, 96))	('mouse', 'Species', '10090', (320, 325))	('GAPDH', 'Gene', '14433', (305, 310))	('mouse', 'Species', '10090', (157, 162))	('anti-ULK2', 'Var', (244, 253))	('GAPDH', 'Gene', (305, 310))
382582	33551645	After 24 h incubation, 6 ng of pmirGLO report vector carrying wild type (WT) or mutated (Mut) GAS5 was co-transfected with 100 nM miR-26a-5p mimic or 100 nM miR-26a-5p mimic control into the AMC-HN-8 cells.	('miR-26a-5p', 'Chemical', '-', (130, 140))	('mutated', 'Var', (80, 87))	('AMC-HN-8', 'CellLine', 'CVCL:5966', (191, 199))	('miR-26a-5p', 'Chemical', '-', (157, 167))	('GAS5', 'Gene', (94, 98))
382584	33551645	After 24 h incubation, 6 ng of pmirGLO report vector carrying WT or mutated Mut ULK2 was co-transfected with 100 nM miR-26a-5p mimic or 100 nM inhibitor into the AMC-HN-8 cells and Tu77 cell lines, respectively.	('Mut ULK2', 'Gene', (76, 84))	('Tu77', 'CellLine', 'CVCL:U380', (181, 185))	('miR-26a-5p', 'Chemical', '-', (116, 126))	('AMC-HN-8', 'CellLine', 'CVCL:5966', (162, 170))	('mutated', 'Var', (68, 75))
382590	33551645	The two cells were transfected with above plasmid to culture 24, 48 and 72 h, CCK-8 was used to detect the activity of AMC-HN-8 cells transfected with siGAS5, and the results showed that GAS5 low expression in AMC-HN-8 cell lines increased cell viability (Figure 1D), and high expression of GAS5 in Tu177 cell lines reduces cell viability (Figure 1E), and data from CCK-8 assay showed that up-regulation of GAS5 inhibited AMC-HN-8 cells viability at 48 and 72 h (Figure 1D), while silencing of GAS5 increased Tu177 cells viability at 48 and 72 h (Figure 1E).	('AMC-HN-8', 'CellLine', 'CVCL:5966', (422, 430))	('GAS5', 'Gene', (407, 411))	('silencing', 'Var', (481, 490))	('increased', 'PosReg', (499, 508))	('AMC-HN-8', 'CellLine', 'CVCL:5966', (210, 218))	('up-regulation', 'PosReg', (390, 403))	('CCK-8', 'Chemical', 'MESH:D012844', (78, 83))	('cell viability', 'CPA', (240, 254))	('cell viability', 'CPA', (324, 338))	('GAS5', 'Gene', (494, 498))	('reduces', 'NegReg', (316, 323))	('inhibited', 'NegReg', (412, 421))	('CCK-8', 'Chemical', 'MESH:D012844', (366, 371))	('increased', 'PosReg', (230, 239))	('AMC-HN-8', 'CellLine', 'CVCL:5966', (119, 127))	('GAS5', 'Gene', (187, 191))
382596	33551645	Furthermore, luciferase reporters containing a WT or mutant target site from lnc-GAS5 were also constructed, and miR-26a-5p mimic significantly reduced luciferase activity for the WT lnc- GAS5 reporter (Figure 4B).	('reduced', 'NegReg', (144, 151))	('lnc-GAS5', 'Gene', (77, 85))	('luciferase', 'Enzyme', (152, 162))	('miR-26a-5p', 'Var', (113, 123))	('activity', 'MPA', (163, 171))	('miR-26a-5p', 'Chemical', '-', (113, 123))
382601	33551645	To demonstrate the correlation between the effects of GAS5 on the expression level of autophagy-associated regulatory factors and miR-26a-5p, Western blot and qRT-PCR were used to determine the levels of LC3I, LC3II, p62 and Beclin1.	('Beclin1', 'Gene', (225, 232))	('LC3I', 'Var', (204, 208))	('LC3II', 'Gene', (210, 215))	('miR-26a-5p', 'Chemical', '-', (130, 140))
382609	33551645	To demonstrate the correlation between the effects of miR-26a-5p on the expression level of autophagy-associated regulatory factors and ULK2, Western blot and qRT-PCR were used to determine the levels of LC3I, LC3II, p62 and Beclin1.	('Beclin1', 'Gene', (225, 232))	('miR-26a-5p', 'Chemical', '-', (54, 64))	('LC3I', 'Var', (204, 208))	('ULK2', 'Gene', (136, 140))
382610	33551645	Western blot data showed that, after ULK2 treatment, the levels of LC3II and Beclin1 were significantly increased, while p62 level was decreased in AMC-HN-8 cells, which were reversed by mimic (Figure 11A and B).	('p62 level', 'MPA', (121, 130))	('increased', 'PosReg', (104, 113))	('levels', 'MPA', (57, 63))	('Beclin1', 'MPA', (77, 84))	('AMC-HN-8', 'CellLine', 'CVCL:5966', (148, 156))	('decreased', 'NegReg', (135, 144))	('men', 'Species', '9606', (47, 50))	('ULK2', 'Var', (37, 41))	('LC3II', 'MPA', (67, 72))
382619	33551645	GAS expression induces growth arrest and apoptosis in prostate cancer cells and breast cancer cells.	('growth arrest', 'Disease', (23, 36))	('prostate cancer', 'Disease', (54, 69))	('growth arrest', 'Disease', 'MESH:D006323', (23, 36))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('growth arrest', 'Phenotype', 'HP:0001510', (23, 36))	('GAS expression', 'Var', (0, 14))	('breast cancer', 'Disease', 'MESH:D001943', (80, 93))	('prostate cancer', 'Disease', 'MESH:D011471', (54, 69))	('apoptosis', 'CPA', (41, 50))	('breast cancer', 'Disease', (80, 93))	('breast cancer', 'Phenotype', 'HP:0003002', (80, 93))	('prostate cancer', 'Phenotype', 'HP:0012125', (54, 69))
382622	33551645	In our study, the expression of GAS5 was down-regulated in LSCC cell lines, overexpression GAS5 inhibited AMC-HN-8 cells proliferation, and siGAS5 promoted Tu 177 cells proliferation.	('GAS5', 'Gene', (32, 36))	('GAS5', 'Gene', (91, 95))	('siGAS5', 'Gene', (140, 146))	('AMC-HN-8', 'CellLine', 'CVCL:5966', (106, 114))	('overexpression', 'Var', (76, 90))	('Tu 177 cells proliferation', 'CPA', (156, 182))	('down-regulated', 'NegReg', (41, 55))	('promoted', 'PosReg', (147, 155))	('expression', 'MPA', (18, 28))	('inhibited', 'NegReg', (96, 105))
382632	33551645	As one of the autophagy genes, ULK2 overexpression significantly inhibited the proliferation of non-small cell lung cancer.	('small cell lung cancer', 'Phenotype', 'HP:0030357', (100, 122))	('proliferation', 'CPA', (79, 92))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (96, 122))	('ULK2', 'Gene', (31, 35))	('lung cancer', 'Phenotype', 'HP:0100526', (111, 122))	('inhibited', 'NegReg', (65, 74))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (96, 122))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('overexpression', 'Var', (36, 50))	('non-small cell lung cancer', 'Disease', (96, 122))
382658	30235512	For example, patients with lung adenocarcinoma harbouring epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) rearrangement are given first-line treatment with tyrosine kinase inhibitors and crizotinib, respectively, while patients with squamous cell carcinoma are contraindicated for bevacizumab therapy, as it is associated with life-threatening haemorrhage.	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (272, 295))	('patients', 'Species', '9606', (13, 21))	('ALK', 'Gene', '238', (140, 143))	('lung adenocarcinoma', 'Disease', (27, 46))	('haemorrhage', 'Disease', 'MESH:D006470', (383, 394))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (112, 131))	('carcinoma', 'Phenotype', 'HP:0030731', (286, 295))	('squamous cell carcinoma', 'Disease', (272, 295))	('ALK', 'Gene', (140, 143))	('rearrangement', 'Var', (145, 158))	('haemorrhage', 'Disease', (383, 394))	('EGFR', 'Gene', '1956', (92, 96))	('patients', 'Species', '9606', (258, 266))	('crizotinib', 'Chemical', 'MESH:D000077547', (226, 236))	('anaplastic lymphoma kinase', 'Gene', '238', (112, 138))	('bevacizumab', 'Chemical', 'MESH:D000068258', (320, 331))	('anaplastic lymphoma kinase', 'Gene', (112, 138))	('epidermal growth factor receptor', 'Gene', (58, 90))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (27, 46))	('carcinoma', 'Phenotype', 'HP:0030731', (37, 46))	('epidermal growth factor receptor', 'Gene', '1956', (58, 90))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (27, 46))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (272, 295))	('lymphoma', 'Phenotype', 'HP:0002665', (123, 131))	('mutations', 'Var', (98, 107))	('EGFR', 'Gene', (92, 96))
382735	30235512	Although most lung tumours can be accurately subtyped by co-expression of TTF1 and p63, a small percentage of cases showed overlapping (TTF1+/p63+) or indeterminate staining patterns (TTF1/weak p63+), leading to misinterpretation and incorrect diagnosis.	('TTF1', 'Gene', '7080', (136, 140))	('tumours', 'Phenotype', 'HP:0002664', (19, 26))	('TTF1', 'Gene', (136, 140))	('p63', 'Gene', '8626', (194, 197))	('TTF1', 'Gene', '7080', (74, 78))	('p63', 'Gene', (83, 86))	('p63', 'Gene', (142, 145))	('lung tumours', 'Disease', 'MESH:D008175', (14, 26))	('TTF1', 'Gene', (184, 188))	('lung tumours', 'Disease', (14, 26))	('TTF1', 'Gene', '7080', (184, 188))	('tumour', 'Phenotype', 'HP:0002664', (19, 25))	('p63', 'Gene', (194, 197))	('p63', 'Gene', '8626', (83, 86))	('p63', 'Gene', '8626', (142, 145))	('TTF1', 'Gene', (74, 78))	('co-expression', 'Var', (57, 70))
382773	30226543	Since miRNAs have been reported to be present in the blood of cancer patients, utilized for targeted cancer therapy and used in cancer prognosis, it is universally acknowledged that deregulated miRNA expression has an important effect on cellular genes which regulate the proliferation, metastasis and the cell cycle, leading to the progression of LSCC.	('leading to', 'Reg', (318, 328))	('effect', 'Reg', (228, 234))	('miR', 'Gene', (6, 9))	('patients', 'Species', '9606', (69, 77))	('miR', 'Gene', '220972', (194, 197))	('cancer', 'Disease', (128, 134))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('cellular genes', 'Gene', (238, 252))	('cancer', 'Disease', (62, 68))	('miR', 'Gene', (194, 197))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('deregulated', 'Var', (182, 193))	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('cancer', 'Disease', (101, 107))	('miR', 'Gene', '220972', (6, 9))	('metastasis', 'CPA', (287, 297))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('LSCC', 'Disease', (348, 352))
382775	30226543	Extracellular vesicles, particularly exosomes, which are membrane-bound particles ranging from 30-150 nm and not merely lipid vesicles, also carry cargoes including nucleic acids, proteins, receptors, lipids, and transcription factors.	('lipid', 'Chemical', 'MESH:D008055', (120, 125))	('nucleic acids', 'Var', (165, 178))	('lipids', 'Chemical', 'MESH:D008055', (201, 207))	('proteins', 'Protein', (180, 188))	('lipid', 'Chemical', 'MESH:D008055', (201, 206))
382806	30226543	To validate the results of sequencing, we selected 6 miRNAs (miR-1246, miR-122-5p, miR-320d, miR-4483, miR-30c-5p and let-7e-5p) for further research by RT-qPCR in all 3 cell lines and its exosomes.	('miR', 'Gene', '220972', (53, 56))	('miR-4483', 'Gene', (93, 101))	('miR', 'Gene', '220972', (61, 64))	('miR-1246', 'Gene', (61, 69))	('miR', 'Gene', '220972', (83, 86))	('miR', 'Gene', (93, 96))	('miR', 'Gene', (53, 56))	('miR', 'Gene', (61, 64))	('miR-122-5p', 'Gene', (71, 81))	('miR', 'Gene', (83, 86))	('miR', 'Gene', '220972', (71, 74))	('miR-122-5p', 'Gene', '100188847', (71, 81))	('miR-1246', 'Gene', '100302142', (61, 69))	('miR', 'Gene', '220972', (103, 106))	('miR-4483', 'Gene', '100616162', (93, 101))	('miR', 'Gene', (71, 74))	('miR', 'Gene', (103, 106))	('miR', 'Gene', '220972', (93, 96))	('let-7e-5p', 'Var', (118, 127))
382827	30226543	To validate the results of small RNA sequencing, RT-qPCR was carried out to detect 3 upregulated miRNAs (miR-320d, miR-1246 and miR-122-5p) and 3 downregulated miRNAs (miR-4483, miR-30c-5p and let-7e-5p) in exosomes derived from 3 cell lines.	('upregulated', 'PosReg', (85, 96))	('miR', 'Gene', '220972', (178, 181))	('miR', 'Gene', '220972', (115, 118))	('miR', 'Gene', '220972', (105, 108))	('miR-1246', 'Gene', (115, 123))	('miR-122-5p', 'Gene', (128, 138))	('miR', 'Gene', (178, 181))	('miR', 'Gene', '220972', (168, 171))	('miR-4483', 'Gene', '100616162', (168, 176))	('miR', 'Gene', '220972', (128, 131))	('miR', 'Gene', '220972', (97, 100))	('miR-122-5p', 'Gene', '100188847', (128, 138))	('let-7e-5p', 'Var', (193, 202))	('miR', 'Gene', (115, 118))	('miR', 'Gene', '220972', (160, 163))	('miR', 'Gene', (105, 108))	('miR', 'Gene', (168, 171))	('miR', 'Gene', (128, 131))	('miR-1246', 'Gene', '100302142', (115, 123))	('miR', 'Gene', (97, 100))	('miR-4483', 'Gene', (168, 176))	('miR', 'Gene', (160, 163))	('downregulated', 'NegReg', (146, 159))
382829	30226543	As anticipated, the results revealed that the expression level of miR-320d, miR-1246 and miR-122-5p was significantly upregulated, and miR-4483, miR-30c-5p and let-7e-5p was significantly downregulated in exosomes derived from all 3 cell lines, respectively (Fig.	('miR', 'Gene', (135, 138))	('miR', 'Gene', '220972', (66, 69))	('miR', 'Gene', '220972', (145, 148))	('miR', 'Gene', '220972', (76, 79))	('miR-122-5p', 'Gene', (89, 99))	('miR-1246', 'Gene', (76, 84))	('miR', 'Gene', '220972', (89, 92))	('expression level', 'MPA', (46, 62))	('miR', 'Gene', (66, 69))	('miR-122-5p', 'Gene', '100188847', (89, 99))	('let-7e-5p', 'Var', (160, 169))	('miR', 'Gene', (145, 148))	('miR', 'Gene', (76, 79))	('miR-4483', 'Gene', '100616162', (135, 143))	('downregulated', 'NegReg', (188, 201))	('miR', 'Gene', (89, 92))	('miR-1246', 'Gene', '100302142', (76, 84))	('miR', 'Gene', '220972', (135, 138))	('miR-4483', 'Gene', (135, 143))	('upregulated', 'PosReg', (118, 129))
382854	30226543	According to the results, miR-21, let-7f-5p and miR-27-3p were identified as the 3 most abundant miRNA types in cells, and these miRNAs had been previously reported to take part in tumor development, including gastric, laryngeal and esophageal carcinoma.	('miR-27', 'Gene', (48, 54))	('gastric', 'Disease', (210, 217))	('let-7f-5p', 'Var', (34, 43))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('miR', 'Gene', '220972', (129, 132))	('miR', 'Gene', '220972', (26, 29))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (233, 253))	('miR-21', 'Gene', '406991', (26, 32))	('miR-27', 'Gene', '407018', (48, 54))	('miR', 'Gene', '220972', (97, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (244, 253))	('esophageal carcinoma', 'Disease', (233, 253))	('miR', 'Gene', (129, 132))	('miR', 'Gene', (26, 29))	('miR', 'Gene', '220972', (48, 51))	('take', 'Reg', (168, 172))	('laryngeal', 'Disease', (219, 228))	('miR-21', 'Gene', (26, 32))	('miR', 'Gene', (97, 100))	('tumor', 'Disease', (181, 186))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (233, 253))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('miR', 'Gene', (48, 51))
382906	33364397	9  In HPV-positive tumors activating mutations in PIK3CA were more common, though HPV-negative HNSCC also exhibited high rates of PIK3CA mutations as well.	('PIK3CA', 'Gene', (130, 136))	('PIK3CA', 'Gene', '5290', (130, 136))	('HPV', 'Species', '10566', (6, 9))	('PIK3CA', 'Gene', '5290', (50, 56))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('HPV-positive tumors', 'Disease', 'MESH:D030361', (6, 25))	('mutations', 'Var', (37, 46))	('HNSCC', 'Phenotype', 'HP:0012288', (95, 100))	('HPV-positive tumors', 'Disease', (6, 25))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('HPV', 'Species', '10566', (82, 85))	('PIK3CA', 'Gene', (50, 56))
382912	33364397	Mutations in HLA genes responsible for antigen presentation are found in a subset of HNSCC at similar rates in HPV-positive and HPV-negative tumors (11% vs 7%, respectively).	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('HPV', 'Species', '10566', (128, 131))	('tumors', 'Disease', (141, 147))	('tumors', 'Disease', 'MESH:D009369', (141, 147))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('HPV', 'Species', '10566', (111, 114))	('Mutations', 'Var', (0, 9))	('HLA', 'Gene', (13, 16))	('found', 'Reg', (64, 69))	('HNSCC', 'Phenotype', 'HP:0012288', (85, 90))	('HNSCC', 'Disease', (85, 90))
382913	33364397	9  Disruption of tumor antigen presentation via mutations in the antigen presentation machinery (APM) interferes with the ability of the immune system to mount an adaptive response to tumor cells.	('interferes', 'NegReg', (102, 112))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('tumor', 'Disease', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('tumor', 'Disease', (184, 189))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('mutations', 'Var', (48, 57))
382971	33364397	61  The above studies suggest that alterations in autophagy underlies the sensitization of tumor cells to radiotherapy by vitamin D, although evidence of the clinical utility of vitamin D as a radiosensitizer remains outstanding.	('alterations', 'Var', (35, 46))	('vitamin D', 'Chemical', 'MESH:D014807', (122, 131))	('autophagy', 'CPA', (50, 59))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor', 'Disease', (91, 96))	('vitamin D', 'Chemical', 'MESH:D014807', (178, 187))
382989	33364397	Genetic sequence variants in vitamin D metabolism pathway genes have been shown to influence the risk and prognosis of HNSCC.	('vitamin D', 'Chemical', 'MESH:D014807', (29, 38))	('influence', 'Reg', (83, 92))	('HNSCC', 'Phenotype', 'HP:0012288', (119, 124))	('Genetic sequence variants', 'Var', (0, 25))	('HNSCC', 'Disease', (119, 124))
382990	33364397	Patients with HNSCC bearing the VDR FokI T/T genotype, which is a genetic variant thought to reduce the transcriptional activity of the activated VDR complex, experienced shorter progression-free survival even after adjustment for age, smoking status, and cancer stage.	('HNSCC', 'Phenotype', 'HP:0012288', (14, 19))	('shorter', 'NegReg', (171, 178))	('VDR', 'Gene', (32, 35))	('T/T', 'Var', (41, 44))	('progression-free survival', 'CPA', (179, 204))	('cancer', 'Disease', 'MESH:D009369', (256, 262))	('transcriptional activity', 'MPA', (104, 128))	('cancer', 'Disease', (256, 262))	('Patients', 'Species', '9606', (0, 8))	('men', 'Species', '9606', (222, 225))	('cancer', 'Phenotype', 'HP:0002664', (256, 262))	('reduce', 'NegReg', (93, 99))
383058	32437034	15  In vitro studies showed that these changes result in various posttranslational modifications, for example, upregulation of MMP-2, AP-1, and VEGF, 16 .	('upregulation', 'PosReg', (111, 123))	('VEGF', 'Gene', '7422', (144, 148))	('MMP-2', 'Gene', (127, 132))	('changes', 'Var', (39, 46))	('AP-1', 'Gene', '3726', (134, 138))	('AP-1', 'Gene', (134, 138))	('MMP-2', 'Gene', '4313', (127, 132))	('VEGF', 'Gene', (144, 148))
383082	32266137	Recent data has demonstrated that alterations in collagen XVII (BP180), a transmembrane protein and structural component of the ECM, can have profound effects on cancer invasiveness.	('effects', 'Reg', (151, 158))	('cancer invasiveness', 'Disease', 'MESH:D009362', (162, 181))	('cancer invasiveness', 'Disease', (162, 181))	('collagen', 'Gene', (49, 57))	('BP180', 'Gene', (64, 69))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('alterations', 'Var', (34, 45))
383086	32266137	Aberrant expression of collagen XVII has been reported in many epithelial cancers, ranging from squamous cell carcinoma to colon, pancreatic, mammary, and ovarian carcinoma.	('ovarian carcinoma', 'Disease', (155, 172))	('collagen XVII', 'Protein', (23, 36))	('pancreatic', 'Disease', 'MESH:D010195', (130, 140))	('cancers', 'Phenotype', 'HP:0002664', (74, 81))	('squamous cell carcinoma to colon', 'Disease', (96, 128))	('cancers', 'Disease', (74, 81))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('squamous cell carcinoma to colon', 'Disease', 'MESH:D002294', (96, 128))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (155, 172))	('Aberrant', 'Var', (0, 8))	('pancreatic', 'Disease', (130, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('cancers', 'Disease', 'MESH:D009369', (74, 81))	('reported', 'Reg', (46, 54))	('epithelial cancer', 'Phenotype', 'HP:0031492', (63, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (163, 172))	('mammary', 'Disease', (142, 149))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (96, 119))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (155, 172))
383098	32266137	Given notable recent discoveries in COL17A1 expression in cancers, as well as the role of aberrant collagen XVII ectodomain shedding in squamous cell carcinoma, it appears that collagen XVII may play a particularly important role in epithelial cancer growth and invasiveness.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('cancers', 'Phenotype', 'HP:0002664', (58, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (150, 159))	('aberrant', 'Var', (90, 98))	('cancers', 'Disease', (58, 65))	('COL17A1', 'Gene', (36, 43))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('cancers', 'Disease', 'MESH:D009369', (58, 65))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (136, 159))	('aberrant collagen', 'Phenotype', 'HP:0008271', (90, 107))	('squamous cell carcinoma', 'Disease', (136, 159))	('cancer', 'Disease', (58, 64))	('epithelial cancer', 'Phenotype', 'HP:0031492', (233, 250))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (136, 159))	('cancer', 'Disease', (244, 250))	('cancer', 'Disease', 'MESH:D009369', (244, 250))
383101	32266137	The importance of collagen XVII for the integrity of the dermoepidermal junction is demonstrated in inherited skin diseases caused by mutations in the COL17A1 gene, including junctional epidermolysis bullosa (JEB), and in numerous subepidermal blistering skin disorders with autoantibodies to collagen XVII (BP180), such as bullous pemphigoid (BP), linear IgA bullous dermatosis, lichen planus pemphigoides, and pemphigoid gestationis [Figure 1; ].	('skin diseases', 'Disease', (110, 123))	('COL17A1', 'Gene', (151, 158))	('junctional epidermolysis bullosa', 'Disease', 'MESH:D016109', (175, 207))	('skin diseases', 'Disease', 'MESH:D012871', (110, 123))	('junctional epidermolysis bullosa', 'Disease', (175, 207))	('skin disorders', 'Disease', (255, 269))	('caused', 'Reg', (124, 130))	('dermatosis', 'Disease', (368, 378))	('subepidermal blistering', 'Phenotype', 'HP:0008066', (231, 254))	('lichen planus pemphigoides', 'Disease', (380, 406))	('skin disorders', 'Disease', 'MESH:D012871', (255, 269))	('pemphigoid gestationis', 'Disease', (412, 434))	('blistering skin', 'Phenotype', 'HP:0008066', (244, 259))	('bullous pemphigoid', 'Disease', (324, 342))	('skin disorders', 'Phenotype', 'HP:0000951', (255, 269))	('mutations', 'Var', (134, 143))	('dermatosis', 'Disease', 'MESH:D012871', (368, 378))
383109	32266137	The physiological cleavage sites are eight to eleven aa C-terminal from the coiled-coils within the region Leu524-Gly526.	('coiled-coils', 'Protein', (76, 88))	('Leu524', 'Chemical', '-', (107, 113))	('Leu524-Gly526', 'Var', (107, 120))	('Gly526', 'Chemical', '-', (114, 120))
383112	32266137	Ectodomain shedding can be increased by mutations in the coiled-coil motifs Val492-Ile505, which induces non-physiologic shedding C-terminally from the furin motif, a non-physiologic cleavage site.	('increased', 'PosReg', (27, 36))	('Ile505', 'Chemical', '-', (83, 89))	('Ectodomain shedding', 'MPA', (0, 19))	('shedding', 'MPA', (121, 129))	('mutations', 'Var', (40, 49))	('Val492', 'Chemical', '-', (76, 82))	('induces', 'Reg', (97, 104))	('Val492-Ile505', 'Var', (76, 89))
383113	32266137	Likewise, deletion of the Ala528-Glu547, an area outside of the physiologic cleavage site, prevents ectodomain shedding.	('prevents', 'NegReg', (91, 99))	('Glu547', 'Chemical', '-', (33, 39))	('Ala528', 'Chemical', '-', (26, 32))	('ectodomain shedding', 'MPA', (100, 119))	('deletion', 'Var', (10, 18))
383117	32266137	Ablation of COL17A1 has been proven to result in the loss of self-renewal and differentiation capacity of hair follicle stem cells (HFSCs).	('self-renewal', 'CPA', (61, 73))	('Ablation', 'Var', (0, 8))	('COL17A1', 'Gene', (12, 19))	('loss', 'NegReg', (53, 57))	('differentiation capacity', 'CPA', (78, 102))	('HFSC', 'CellLine', 'None', (132, 136))
383124	32266137	This theory is proven in patients with junctional epidermolysis bullosa (JEB), a disorder characterized by mutations in the COL17A1 gene resulting in the absence of collagen XVII or expression of a structurally altered protein leading to subepidermal blistering and immature HDs.	('COL17A1', 'Gene', (124, 131))	('immature HDs', 'Disease', (266, 278))	('immature HDs', 'Disease', 'MESH:D013724', (266, 278))	('mutations', 'Var', (107, 116))	('expression', 'MPA', (182, 192))	('absence', 'NegReg', (154, 161))	('subepidermal blistering', 'Phenotype', 'HP:0008066', (238, 261))	('collagen', 'Protein', (165, 173))	('patients', 'Species', '9606', (25, 33))	('subepidermal', 'Disease', (238, 250))	('junctional epidermolysis bullosa', 'Disease', 'MESH:D016109', (39, 71))	('junctional epidermolysis bullosa', 'Disease', (39, 71))
383125	32266137	It is well-known that dysfunction of collagen XVII, either through genetic or autoantibody insult, leads to subepidermal blistering and skin inflammation.	('skin inflammation', 'Disease', 'MESH:D007249', (136, 153))	('leads to', 'Reg', (99, 107))	('collagen XVII', 'Protein', (37, 50))	('skin inflammation', 'Phenotype', 'HP:0011123', (136, 153))	('subepidermal', 'Disease', (108, 120))	('dysfunction', 'Var', (22, 33))	('skin inflammation', 'Disease', (136, 153))	('subepidermal blistering', 'Phenotype', 'HP:0008066', (108, 131))
383127	32266137	In a humanized NC16A mouse, mutation induced dysfunction of NC16A in basal keratinocytes (termed DeltaNC16A), leads to development of spontaneous skin inflammatory disease.	('mouse', 'Species', '10090', (21, 26))	('dysfunction', 'Var', (45, 56))	('leads to', 'Reg', (110, 118))	('skin inflammatory disease', 'Phenotype', 'HP:0011123', (146, 171))	('NC16A', 'Gene', (60, 65))	('skin inflammatory disease', 'Disease', 'MESH:D012871', (146, 171))	('skin inflammatory disease', 'Disease', (146, 171))	('human', 'Species', '9606', (5, 10))
383135	32266137	Viral mediated RNA interference knockdown of collagen XVII and/or beta4 disrupted the migration and invasion of less aggressive SCC cells.	('beta4', 'Gene', '5355', (66, 71))	('beta4', 'Gene', (66, 71))	('invasion of less aggressive SCC cells', 'CPA', (100, 137))	('knockdown', 'Var', (32, 41))	('SCC', 'Phenotype', 'HP:0002860', (128, 131))	('disrupted', 'NegReg', (72, 81))
383137	32266137	In a sample of tongue SCC samples, collagen XVII and laminin-332 were found to be co-localized at the invasive tumor fronts protruding into the surrounding tissue, and proteolytic shedding of collagen XVII enhanced its functioning as a chemotactic agent through its effects on transmigration of HSC-3 cells.	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('enhanced', 'PosReg', (206, 214))	('proteolytic shedding', 'Var', (168, 188))	('invasive tumor', 'Disease', 'MESH:D009361', (102, 116))	('transmigration of HSC-3 cells', 'CPA', (277, 306))	('effects', 'Reg', (266, 273))	('HSC-3', 'CellLine', 'CVCL:1288', (295, 300))	('functioning', 'MPA', (219, 230))	('SCC', 'Phenotype', 'HP:0002860', (22, 25))	('invasive tumor', 'Disease', (102, 116))
383140	32266137	In addition, quantitative PCR also confirmed COL17A1 expression and upregulation by transfection of miR-203a-3p inhibitor in oral SCC lines.	('COL17A1', 'Gene', (45, 52))	('miR-203a-3p', 'Chemical', '-', (100, 111))	('SCC', 'Phenotype', 'HP:0002860', (130, 133))	('upregulation', 'PosReg', (68, 80))	('miR-203a-3p', 'Var', (100, 111))
383151	32266137	In vitro treatment of melanoma cells with aa 507-529 sequence specific antibody against collagen XVII endodomain promoted apoptosis, reduction of tumor cell proliferation, and cell adhesion.	('aa 507-529', 'Var', (42, 52))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('promoted', 'PosReg', (113, 121))	('apoptosis', 'CPA', (122, 131))	('reduction', 'NegReg', (133, 142))	('tumor', 'Disease', (146, 151))	('melanoma', 'Disease', 'MESH:D008545', (22, 30))	('melanoma', 'Phenotype', 'HP:0002861', (22, 30))	('cell adhesion', 'CPA', (176, 189))	('melanoma', 'Disease', (22, 30))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
383152	32266137	Sequencing of COL17A1 gene from melanoma cDNA detected several point mutations and in-frame deletions in the ectodomain coding region, suggesting the contribution of post-translational degradation in ectodomain deficiency.	('melanoma', 'Disease', 'MESH:D008545', (32, 40))	('melanoma', 'Phenotype', 'HP:0002861', (32, 40))	('melanoma', 'Disease', (32, 40))	('point mutations', 'Var', (63, 78))	('deletions', 'Var', (92, 101))	('COL17A1', 'Gene', (14, 21))
383156	32266137	Decreasing the levels of MDSCs through treatment with specific antibodies resulted in the reduction of tumor volume, and the rate of metastatic development, demonstrating the role collagen XVII plays in curbing tumor invasion via regulation of MDSC infiltration.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('reduction', 'NegReg', (90, 99))	('rate', 'CPA', (125, 129))	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('tumor', 'Disease', (103, 108))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('tumor', 'Disease', (211, 216))	('antibodies', 'Var', (63, 73))	('curbing', 'NegReg', (203, 210))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
383166	32266137	Inhibition of this pathway in colorectal cancer metastasis blocked suspension survival, sphere formation, tumor initiation, and metastasis, reinforcing the role of collagen XVII as an important prognostic factor in colorectal cancer patients.	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('colorectal cancer', 'Disease', (30, 47))	('metastasis', 'CPA', (128, 138))	('tumor initiation', 'Disease', (106, 122))	('suspension survival', 'CPA', (67, 86))	('sphere formation', 'CPA', (88, 104))	('tumor initiation', 'Disease', 'MESH:D009369', (106, 122))	('colorectal cancer', 'Disease', 'MESH:D015179', (215, 232))	('colorectal cancer', 'Phenotype', 'HP:0003003', (30, 47))	('colorectal cancer', 'Phenotype', 'HP:0003003', (215, 232))	('colorectal cancer', 'Disease', 'MESH:D015179', (30, 47))	('Inhibition', 'Var', (0, 10))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('patients', 'Species', '9606', (233, 241))	('blocked', 'NegReg', (59, 66))	('colorectal cancer', 'Disease', (215, 232))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
383170	32266137	Blockade of the signaling pathway also decreased the metastatic potential of lung metastases in vivo.	('decreased', 'NegReg', (39, 48))	('Blockade', 'Var', (0, 8))	('lung metastases', 'Disease', (77, 92))	('lung metastases', 'Disease', 'MESH:D009362', (77, 92))
383183	32266137	Moreover, COL17A1 promoter was found to be hypomethylated in cervical carcinoma, head and neck squamous cell carcinoma, lung squamous cell carcinoma, and lung adenocarcinoma resulting in subsequent collagen XVII overexpression.	('cervical carcinoma', 'Disease', (61, 79))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (95, 118))	('overexpression', 'PosReg', (212, 226))	('lung adenocarcinoma', 'Disease', (154, 173))	('collagen XVII', 'MPA', (198, 211))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (120, 148))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (125, 148))	('COL17A1', 'Gene', (10, 17))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (154, 173))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (120, 148))	('lung squamous cell carcinoma', 'Disease', (120, 148))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (154, 173))	('hypomethylated', 'Var', (43, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (81, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (164, 173))	('carcinoma', 'Phenotype', 'HP:0030731', (139, 148))	('neck squamous cell carcinoma', 'Disease', (90, 118))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (90, 118))	('cervical carcinoma', 'Disease', 'MESH:D002583', (61, 79))
383186	32266137	The opposed direction of expression in breast cancer may be due to hypermethylation of the COL17A1 promoter.	('breast cancer', 'Phenotype', 'HP:0003002', (39, 52))	('hypermethylation', 'Var', (67, 83))	('COL17A1', 'Gene', (91, 98))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('breast cancer', 'Disease', 'MESH:D001943', (39, 52))	('breast cancer', 'Disease', (39, 52))
383190	32266137	In a variety of tumors, genetic aberrations in COL17A1, full-length collagen XVII overexpression, or the accumulation of its proteolytic components have been linked to increased invasiveness of tumors.	('increased', 'PosReg', (168, 177))	('genetic aberrations', 'Var', (24, 43))	('tumors', 'Disease', (194, 200))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('invasiveness of tumors', 'Disease', (178, 200))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('tumors', 'Disease', 'MESH:D009369', (16, 22))	('overexpression', 'PosReg', (82, 96))	('tumors', 'Disease', 'MESH:D009369', (194, 200))	('tumors', 'Phenotype', 'HP:0002664', (194, 200))	('accumulation', 'PosReg', (105, 117))	('invasiveness of tumors', 'Disease', 'MESH:D009361', (178, 200))	('COL17A1', 'Gene', (47, 54))	('tumors', 'Disease', (16, 22))	('linked', 'Reg', (158, 164))
383193	32266137	Likewise, HSC-3 cell cultures treated with NC16A-1 antibody exhibited reduced invasion, confirming the role of shedding in SCC metastasis.	('NC16A-1 antibody', 'Var', (43, 59))	('SCC', 'Phenotype', 'HP:0002860', (123, 126))	('reduced', 'NegReg', (70, 77))	('invasion', 'CPA', (78, 86))	('HSC-3', 'CellLine', 'CVCL:1288', (10, 15))
383212	31691516	The amplification and deep deletion mutation of LINC00426 gene was found in 0.5% of NSCLC patients.	('LINC00426', 'Gene', (48, 57))	('NSCLC', 'Phenotype', 'HP:0030358', (84, 89))	('found', 'Reg', (67, 72))	('NSCLC', 'Disease', (84, 89))	('deep deletion mutation', 'Var', (22, 44))	('LINC00426', 'Gene', '100188949', (48, 57))	('NSCLC', 'Disease', 'MESH:D002289', (84, 89))	('patients', 'Species', '9606', (90, 98))
383236	31691516	Amplification and deep deletion mutation of LINC00426 gene was found in 0.5% of NSCLC patients (Fig 2).	('NSCLC', 'Phenotype', 'HP:0030358', (80, 85))	('Amplification', 'Var', (0, 13))	('deep deletion mutation', 'Var', (18, 40))	('LINC00426', 'Gene', '100188949', (44, 53))	('NSCLC', 'Disease', (80, 85))	('NSCLC', 'Disease', 'MESH:D002289', (80, 85))	('LINC00426', 'Gene', (44, 53))	('found', 'Reg', (63, 68))	('patients', 'Species', '9606', (86, 94))
383238	31691516	The overall survival (OS) of LINC00426 high expression group was significantly higher than that of the low expression group (HR = 0.81, P = 0.044), while there was no significant difference between the high and low expression groups (HR = 0.97, P = 0.82) for disease-free survival (DFS).	('high expression', 'Var', (39, 54))	('higher', 'PosReg', (79, 85))	('LINC00426', 'Gene', '100188949', (29, 38))	('LINC00426', 'Gene', (29, 38))
383239	31691516	Subgroup analysis showed that the overall survival of lung adenocarcinoma patients in the LINC00426 high expression group was significantly better than that of the low expression group (HR = 0.68, P = 0.014).	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (54, 73))	('better', 'PosReg', (140, 146))	('LINC00426', 'Gene', (90, 99))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (54, 73))	('patients', 'Species', '9606', (74, 82))	('lung adenocarcinoma', 'Disease', (54, 73))	('high expression', 'Var', (100, 115))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))	('LINC00426', 'Gene', '100188949', (90, 99))
383262	31772627	Of note, dysregulation of targets of TOB1-AS1 was associated with the prognosis of NSCLC patients.	('TOB1-AS1', 'Gene', (37, 45))	('NSCLC', 'Disease', (83, 88))	('NSCLC', 'Disease', 'MESH:D002289', (83, 88))	('patients', 'Species', '9606', (89, 97))	('NSCLC', 'Phenotype', 'HP:0030358', (83, 88))	('associated', 'Reg', (50, 60))	('dysregulation', 'Var', (9, 22))
383301	31772627	The sequences of si-TOB1-AS1 were as follows: si-RNA1, 5'-GCACCCGATTAATTGAATA-3'; si-RNA2, 5'-GCGACTCGGATCCGTTTAT-3'; si-NC, 5'-TTCTCCGAACGTGTCACGT-3'.	('si-RNA1', 'Var', (46, 53))	('si-TOB1-AS1', 'Gene', '400604;5729', (17, 28))	('si-RNA2', 'Var', (82, 89))	("5'-TTCTCCGAACGTGTCACGT", 'Chemical', 'MESH:C068492', (125, 147))	('si-TOB1-AS1', 'Gene', (17, 28))	('si-NC', 'Var', (118, 123))
383328	31772627	The results revealed that the numbers of migrating cells in the TOB1-AS1 knockdown group were significantly increased by 3.67- and 2.3-fold of those in the control group of A549 cells (Fig.	('A549', 'CellLine', 'CVCL:0023', (173, 177))	('TOB1-AS1', 'Gene', (64, 72))	('increased', 'PosReg', (108, 117))	('knockdown', 'Var', (73, 82))
383329	31772627	Furthermore, in H1299 cells, TOB1-AS1 knockdown promoted cell migration by 5.3- and 3.3-fold of that in the control group (Fig.	('TOB1-AS1', 'Gene', (29, 37))	('H1299', 'CellLine', 'CVCL:0060', (16, 21))	('promoted', 'PosReg', (48, 56))	('cell migration', 'CPA', (57, 71))	('knockdown', 'Var', (38, 47))
383335	31772627	In addition, the expression levels of these 6 mRNAs were measured after the silencing of TOB1-AS1 in A549 cells.	('A549', 'CellLine', 'CVCL:0023', (101, 105))	('silencing', 'Var', (76, 85))	('expression levels', 'MPA', (17, 34))	('TOB1-AS1', 'Gene', (89, 97))
383336	31772627	The results indicated that knockdown of TOB1-AS1 using siRNA-1 significantly suppressed the expression of DYNC2LI1, E4F1, TSPYL4, COG7 and IP6K2 (Fig.	('suppressed', 'NegReg', (77, 87))	('knockdown', 'Var', (27, 36))	('TSPYL4', 'Gene', '23270', (122, 128))	('COG7', 'Gene', (130, 134))	('E4F1', 'Gene', '1877', (116, 120))	('TOB1-AS1', 'Gene', (40, 48))	('COG7', 'Gene', '91949', (130, 134))	('DYNC2LI1', 'Gene', (106, 114))	('DYNC2LI1', 'Gene', '51626', (106, 114))	('IP6K2', 'Gene', '51447', (139, 144))	('E4F1', 'Gene', (116, 120))	('TSPYL4', 'Gene', (122, 128))	('IP6K2', 'Gene', (139, 144))	('expression', 'MPA', (92, 102))
383354	31772627	Furthermore, silencing of TOB1-AS1 promoted A549 and H1299 cell migration and invasion.	('invasion', 'CPA', (78, 86))	('H1299', 'CellLine', 'CVCL:0060', (53, 58))	('TOB1-AS1', 'Gene', (26, 34))	('promoted', 'PosReg', (35, 43))	('A549', 'CellLine', 'CVCL:0023', (44, 48))	('silencing', 'Var', (13, 22))
383356	31772627	In spite of this, the present results indicate that knockdown of TOB1-AS1 promoted NSCLC proliferation and migration.	('promoted', 'PosReg', (74, 82))	('migration', 'CPA', (107, 116))	('NSCLC', 'Disease', (83, 88))	('NSCLC', 'Disease', 'MESH:D002289', (83, 88))	('NSCLC', 'Phenotype', 'HP:0030358', (83, 88))	('TOB1-AS1', 'Gene', (65, 73))	('knockdown', 'Var', (52, 61))
383372	31772627	It was also revealed that TOB1-AS1 in NSCLC samples was associated with a longer OS time.	('NSCLC', 'Disease', (38, 43))	('NSCLC', 'Disease', 'MESH:D002289', (38, 43))	('TOB1-AS1', 'Var', (26, 34))	('associated', 'Reg', (56, 66))	('NSCLC', 'Phenotype', 'HP:0030358', (38, 43))
383376	31149368	titled "Classification and mutation prediction from non-small cell lung cancer histopathology images using deep learning," the authors use a commercially available convolution neural network (CNN) platform (Google's Inception v3) to accurately classify different types of lung cancer and predict known and potential cancer driver mutations from hematoxylin and eosin (H&E) slides.	('H&E', 'Chemical', '-', (368, 371))	('cancer', 'Disease', (72, 78))	('lung cancer', 'Disease', 'MESH:D008175', (272, 283))	('cancer', 'Disease', (277, 283))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (52, 78))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('lung cancer', 'Phenotype', 'HP:0100526', (272, 283))	('cancer', 'Disease', (316, 322))	('cancer', 'Phenotype', 'HP:0002664', (277, 283))	('hematoxylin', 'Chemical', 'MESH:D006416', (345, 356))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (56, 78))	('eosin', 'Chemical', 'MESH:D004801', (361, 366))	('cancer', 'Phenotype', 'HP:0002664', (316, 322))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (52, 78))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('mutations', 'Var', (330, 339))	('cancer', 'Disease', 'MESH:D009369', (277, 283))	('lung cancer', 'Disease', 'MESH:D008175', (67, 78))	('lung cancer', 'Disease', (272, 283))	('cancer', 'Disease', 'MESH:D009369', (316, 322))	('lung cancer', 'Phenotype', 'HP:0100526', (67, 78))	('non-small cell lung cancer', 'Disease', (52, 78))
383381	31149368	Importantly, the authors subsequently trained their model to predict ten specific driver mutations in NSCLC, including STK11, EGFR, SETBP1, TP53, FAT1, and KRAS, with accuracies of 0.856, 0.826, 0.775, 0.760, 0.750, and 0.733, respectively, when validated on the TCGA test set.	('NSCLC', 'Disease', 'MESH:D002289', (102, 107))	('FAT1', 'Gene', (146, 150))	('EGFR', 'Gene', (126, 130))	('KRAS', 'Gene', (156, 160))	('STK11', 'Gene', (119, 124))	('TP53', 'Gene', (140, 144))	('SETBP1', 'Gene', '26040', (132, 138))	('FAT1', 'Gene', '2195', (146, 150))	('NSCLC', 'Phenotype', 'HP:0030358', (102, 107))	('STK11', 'Gene', '6794', (119, 124))	('SETBP1', 'Gene', (132, 138))	('mutations', 'Var', (89, 98))	('KRAS', 'Gene', '3845', (156, 160))	('NSCLC', 'Disease', (102, 107))	('TP53', 'Gene', '7157', (140, 144))	('EGFR', 'Gene', '1956', (126, 130))
383382	31149368	The CNN model used to predict the EGFR mutation was subsequently tested in an independent cohort of lung resection specimens from New York University (NYU) Langone Medical Center that contained both wild-type and known EGFR mutation status.	('EGFR', 'Gene', '1956', (219, 223))	('mutation', 'Var', (39, 47))	('EGFR', 'Gene', (34, 38))	('EGFR', 'Gene', (219, 223))	('EGFR', 'Gene', '1956', (34, 38))
383383	31149368	The CNN model predicted EGFR mutation status in the NYU cohort with ~69% accuracy, demonstrating better-than-chance estimates.	('EGFR', 'Gene', '1956', (24, 28))	('EGFR', 'Gene', (24, 28))	('mutation status', 'Var', (29, 44))
383399	31149368	However, several important studies published over the past decade have reminded the scientific community that there are tremendous amounts of information in tissue sections that can be used to predict molecular test status and/or predict patient outcomes with accuracy similar to molecular methods.	('molecular', 'Var', (201, 210))	('patient', 'Species', '9606', (238, 245))	('predict', 'Reg', (193, 200))
383503	29531222	miR-27a is decreased in cervical cancer cell lines and miR-27a-agomir inhibited the cell proliferation, migration, and invasion properties of HeLa (adenocarcinoma) cells, but not in SiHa cells (squamous cell carcinoma).	('HeLa', 'CellLine', 'CVCL:0030', (142, 146))	('cell proliferation', 'CPA', (84, 102))	('migration', 'CPA', (104, 113))	('invasion properties', 'CPA', (119, 138))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (194, 217))	('carcinoma', 'Phenotype', 'HP:0030731', (153, 162))	('carcinoma', 'Phenotype', 'HP:0030731', (208, 217))	('SiHa', 'CellLine', 'CVCL:0032', (182, 186))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (194, 217))	('cervical cancer', 'Disease', 'MESH:D002583', (24, 39))	('squamous cell carcinoma', 'Disease', (194, 217))	('miR-27a-agomir', 'Var', (55, 69))	('inhibited', 'NegReg', (70, 79))	('adenocarcinoma', 'Disease', (148, 162))	('cervical cancer', 'Disease', (24, 39))	('adenocarcinoma', 'Disease', 'MESH:D000230', (148, 162))
383504	29531222	Luciferase assays revealed that miR-27a directly targets the 3'-UTR of transforming growth factor beta receptor I (TGF-betaRI) and downregulates TGF-beta signaling.	('TGF-betaRI', 'Gene', (115, 125))	('TGF-beta signaling', 'MPA', (145, 163))	('miR-27a', 'Var', (32, 39))	('TGF-betaRI', 'Gene', '7046', (115, 125))	('transforming growth factor beta receptor I', 'Gene', '7046', (71, 113))	('downregulates', 'NegReg', (131, 144))	('transforming growth factor beta receptor I', 'Gene', (71, 113))
383505	29531222	The co-transfection of a TGF-betaRI expression vector largely restored the inhibition of TGF-beta signaling, cell proliferation, migration, and invasion mediated by miR-27a-agomir.	('cell proliferation', 'CPA', (109, 127))	('TGF-betaRI', 'Gene', '7046', (25, 35))	('inhibition', 'NegReg', (75, 85))	('invasion', 'CPA', (144, 152))	('migration', 'CPA', (129, 138))	('TGF-betaRI', 'Gene', (25, 35))	('TGF-beta signaling', 'MPA', (89, 107))	('miR-27a-agomir', 'Var', (165, 179))
383506	29531222	Also, miR-27a-agomir slows down the growth of subcutaneous HeLa xenografts and downregulates the TGF-betaRI expression and TGF-beta signaling in tumor in vivo.	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('TGF-betaRI', 'Gene', (97, 107))	('downregulates', 'NegReg', (79, 92))	('tumor', 'Disease', (145, 150))	('HeLa', 'CellLine', 'CVCL:0030', (59, 63))	('TGF-betaRI', 'Gene', '7046', (97, 107))	('TGF-beta signaling', 'MPA', (123, 141))	('expression', 'MPA', (108, 118))	('miR-27a-agomir', 'Var', (6, 20))	('slows down', 'NegReg', (21, 31))	('growth of subcutaneous HeLa xenografts', 'CPA', (36, 74))
383508	29531222	High TGF-betaRI correlated with deep stromal invasion and lymph node metastasis.	('High', 'Var', (0, 4))	('TGF-betaRI', 'Gene', (5, 15))	('lymph node metastasis', 'CPA', (58, 79))	('deep stromal invasion', 'CPA', (32, 53))	('TGF-betaRI', 'Gene', '7046', (5, 15))
383509	29531222	These results suggest that miR-27a acts as a tumor suppressor in cervical cancer, especially in adenocarcinoma, by inhibiting TGF-betaRI signaling pathway.	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('tumor', 'Disease', (45, 50))	('adenocarcinoma', 'Disease', (96, 110))	('inhibiting', 'NegReg', (115, 125))	('TGF-betaRI', 'Gene', (126, 136))	('cervical cancer', 'Disease', (65, 80))	('cervical cancer', 'Disease', 'MESH:D002583', (65, 80))	('adenocarcinoma', 'Disease', 'MESH:D000230', (96, 110))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('TGF-betaRI', 'Gene', '7046', (126, 136))	('miR-27a', 'Var', (27, 34))
383518	29531222	For example, E6/E7 oncoproteins of HPV 16 mediated miR-184 reduction and miR-27b increase that contributed to the accelerated proliferation of cervical cancer cells.	('HPV 16', 'Species', '333760', (35, 41))	('proliferation', 'CPA', (126, 139))	('E6/E7', 'Var', (13, 18))	('miR-184', 'Gene', (51, 58))	('cervical cancer', 'Disease', (143, 158))	('cervical cancer', 'Disease', 'MESH:D002583', (143, 158))	('miR-27b', 'Var', (73, 80))	('reduction', 'NegReg', (59, 68))	('HPV 16', 'Gene', (35, 41))	('increase', 'PosReg', (81, 89))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('accelerated', 'PosReg', (114, 125))
383522	29531222	The miR-27a expression level in the cervical cancer cell lines HeLa, SiHa, and C33A was significantly decreased compared with normal cervical epithelia, especially in the cervical adenocarcinoma (CADC) cell lines HeLa (HPV-18 positive) and C33A (HPV negative, gastric type adenocarcinoma), but not in CaSki cervical squamous cell carcinoma (CSCC) (Fig.	('cervical adenocarcinoma', 'Disease', 'MESH:D002575', (171, 194))	('carcinoma', 'Phenotype', 'HP:0030731', (278, 287))	('HPV', 'Species', '10566', (219, 222))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (316, 339))	('cervical adenocarcinoma', 'Disease', (171, 194))	('miR-27a', 'Gene', (4, 11))	('HeLa', 'CellLine', 'CVCL:0030', (63, 67))	('decreased', 'NegReg', (102, 111))	('gastric type adenocarcinoma', 'Disease', (260, 287))	('CaSki', 'CellLine', 'CVCL:1100', (301, 306))	('cervical cancer', 'Disease', (36, 51))	('cervical cancer', 'Disease', 'MESH:D002583', (36, 51))	('expression level', 'MPA', (12, 28))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (316, 339))	('HPV', 'Species', '10566', (246, 249))	('C33A', 'Var', (240, 244))	('HeLa', 'CellLine', 'CVCL:0030', (213, 217))	('carcinoma', 'Phenotype', 'HP:0030731', (330, 339))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('squamous cell carcinoma', 'Disease', (316, 339))	('SiHa', 'CellLine', 'CVCL:0032', (69, 73))	('gastric type adenocarcinoma', 'Disease', 'MESH:D013274', (260, 287))	('carcinoma', 'Phenotype', 'HP:0030731', (185, 194))
383523	29531222	To understand the functional significance of the abrogated miR-27a expression in tumor cells, we transfected control and miR-27a-agomir into cervical cancer cells and monitored changes in cell proliferation, apoptosis, migration, and invasion.	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('apoptosis', 'CPA', (208, 217))	('abrogated', 'Var', (49, 58))	('cell proliferation', 'CPA', (188, 206))	('invasion', 'CPA', (234, 242))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Disease', (81, 86))	('miR-27a', 'Gene', (59, 66))	('cervical cancer', 'Disease', (141, 156))	('cervical cancer', 'Disease', 'MESH:D002583', (141, 156))	('migration', 'CPA', (219, 228))	('miR-27a-agomir', 'Gene', (121, 135))
383524	29531222	In HeLa cells, miR-27a-agomir markedly reduced EdU-positive proliferating cells compared with the control (Fig.	('EdU-positive proliferating cells', 'CPA', (47, 79))	('EdU', 'Chemical', 'MESH:C031086', (47, 50))	('reduced', 'NegReg', (39, 46))	('HeLa', 'CellLine', 'CVCL:0030', (3, 7))	('miR-27a-agomir', 'Var', (15, 29))
383525	29531222	The proliferation index derived from flow cytometry analysis further confirmed the reduction of cell proliferation in the HeLa cells transfected with miR-27a-agomir (Fig.	('miR-27a-agomir', 'Var', (150, 164))	('reduction', 'NegReg', (83, 92))	('HeLa', 'CellLine', 'CVCL:0030', (122, 126))	('cell proliferation', 'CPA', (96, 114))
383526	29531222	In addition, miR-27a-agomir dramatically increased the apoptotic cell population and inhibited the migration and invasion abilities in HeLa cells (Fig.	('increased', 'PosReg', (41, 50))	('apoptotic cell population', 'CPA', (55, 80))	('inhibited', 'NegReg', (85, 94))	('HeLa', 'CellLine', 'CVCL:0030', (135, 139))	('miR-27a-agomir', 'Var', (13, 27))
383532	29531222	More importantly, miR-27a-agomir significantly reduced the TGF-betaRI level but not the TGF-betaRII level in HeLa cells, suggesting that miR-27a specifically targets TGF-betaRI rather than TGF-betaRII (Fig.	('HeLa', 'CellLine', 'CVCL:0030', (109, 113))	('TGF-betaRI', 'Gene', '7046', (189, 199))	('TGF-betaRI', 'Gene', (166, 176))	('TGF-betaRI', 'Gene', (88, 98))	('TGF-betaRII', 'Gene', '7048', (88, 99))	('TGF-betaRII', 'Gene', (88, 99))	('TGF-betaRI', 'Gene', '7046', (59, 69))	('targets', 'Reg', (158, 165))	('TGF-betaRI', 'Gene', '7046', (166, 176))	('miR-27a', 'Var', (137, 144))	('TGF-betaRI', 'Gene', '7046', (88, 98))	('TGF-betaRII', 'Gene', '7048', (189, 200))	('TGF-betaRII', 'Gene', (189, 200))	('reduced', 'NegReg', (47, 54))	('TGF-betaRI', 'Gene', (189, 199))	('TGF-betaRI', 'Gene', (59, 69))
383534	29531222	The miR-27a-3p antagomir, but not the miR-27a-5p antagomir, increased the TGF-betaRI mRNA level in HeLa cells (Supplemental Fig.	('TGF-betaRI', 'Gene', (74, 84))	('HeLa', 'CellLine', 'CVCL:0030', (99, 103))	('miR-27a-3p', 'Var', (4, 14))	('TGF-betaRI', 'Gene', '7046', (74, 84))	('increased', 'PosReg', (60, 69))
383535	29531222	S3A), which indicated that miR-27a might interact with TGF-betaRI through its 3p mature form.	('interact', 'Interaction', (41, 49))	('TGF-betaRI', 'Gene', (55, 65))	('TGF-betaRI', 'Gene', '7046', (55, 65))	('miR-27a', 'Var', (27, 34))
383537	29531222	We generated a mutation at the predicted miR-27a targeting site in the 3'-UTR of TGFbeta-RI mRNA and applied it to the same luciferase assay (Supplemental Fig.	('mutation', 'Var', (15, 23))	('TGFbeta', 'Gene', '7040', (81, 88))	('miR-27a', 'Gene', (41, 48))	('TGFbeta', 'Gene', (81, 88))
383539	29531222	Therefore, these results together allow us to conclude that miR-27a specifically targets the 3'-UTR of TGF-betaRI mRNA and inhibits its gene expression.	('TGF-betaRI', 'Gene', '7046', (103, 113))	('gene expression', 'MPA', (136, 151))	('miR-27a', 'Var', (60, 67))	('inhibits', 'NegReg', (123, 131))	('TGF-betaRI', 'Gene', (103, 113))
383541	29531222	qRT-PCR analyses revealed that miR-27a-agomir transfection significantly decreased SMAD2, SMAD3, and SMAD4, but not SMAD1, mRNA levels in HeLa cells.	('SMAD2', 'MPA', (83, 88))	('decreased', 'NegReg', (73, 82))	('SMAD1', 'Gene', (116, 121))	('SMAD3', 'Gene', '4088', (90, 95))	('SMAD1', 'Gene', '33529', (116, 121))	('SMAD3', 'Gene', (90, 95))	('miR-27a-agomir', 'Var', (31, 45))	('mRNA levels', 'MPA', (123, 134))	('HeLa', 'CellLine', 'CVCL:0030', (138, 142))
383543	29531222	Treatment with A8301, a TGF-betaRI kinase activity inhibitor, also reduced SMAD3 and SMAD4 expression in HeLa cells (Fig.	('SMAD3', 'Gene', (75, 80))	('expression', 'MPA', (91, 101))	('HeLa', 'CellLine', 'CVCL:0030', (105, 109))	('A8301', 'Chemical', '-', (15, 20))	('A8301', 'Var', (15, 20))	('reduced', 'NegReg', (67, 74))	('SMAD4', 'Gene', (85, 90))	('TGF-betaRI', 'Gene', (24, 34))	('SMAD3', 'Gene', '4088', (75, 80))	('TGF-betaRI', 'Gene', '7046', (24, 34))
383544	29531222	In C33A cells, both miR-27a agomir and A8301 decreased SMAD2 (Supplemental Fig.	('SMAD2', 'Gene', (55, 60))	('A8301', 'Var', (39, 44))	('decreased', 'NegReg', (45, 54))	('A8301', 'Chemical', '-', (39, 44))
383545	29531222	We further used two TGF-betaRI specific siRNAs to knockdown TGF-betaRI in HeLa, which also leaded to decreases in SMAD2 and SMAD3 mRNA accompanied with suppressed cell proliferation (Supplemental Fig.	('suppressed', 'NegReg', (152, 162))	('HeLa', 'CellLine', 'CVCL:0030', (74, 78))	('knockdown', 'Var', (50, 59))	('decreases', 'NegReg', (101, 110))	('TGF-betaRI', 'Gene', '7046', (20, 30))	('TGF-betaRI', 'Gene', (60, 70))	('SMAD3', 'Gene', '4088', (124, 129))	('TGF-betaRI', 'Gene', (20, 30))	('cell proliferation', 'CPA', (163, 181))	('SMAD3', 'Gene', (124, 129))	('TGF-betaRI', 'Gene', '7046', (60, 70))	('SMAD2', 'Protein', (114, 119))
383546	29531222	Additionally, the inhibition of TGF-betaRI and SMAD3 expression and SMAD3 phosphorylation by miR-27a-agomir transfection was confirmed by western blot assays (Fig.	('phosphorylation', 'CPA', (74, 89))	('SMAD3', 'Gene', (47, 52))	('inhibition', 'NegReg', (18, 28))	('SMAD3', 'Gene', '4088', (68, 73))	('TGF-betaRI', 'Gene', (32, 42))	('SMAD3', 'Gene', (68, 73))	('SMAD3', 'Gene', '4088', (47, 52))	('TGF-betaRI', 'Gene', '7046', (32, 42))	('expression', 'MPA', (53, 63))	('miR-27a-agomir', 'Var', (93, 107))
383547	29531222	Having demonstrated that miR-27a directly targets TGF-betaRI and inhibits the TGF-beta signaling pathway, we determined whether the miR-27a-agomir-mediated phenotypic changes of cervical cancer cells resulted from the suppressed TGF-beta signaling.	('inhibits', 'NegReg', (65, 73))	('miR-27a-agomir-mediated', 'Var', (132, 155))	('suppressed', 'NegReg', (218, 228))	('TGF-beta signaling', 'MPA', (229, 247))	('cervical cancer', 'Disease', (178, 193))	('TGF-betaRI', 'Gene', (50, 60))	('cervical cancer', 'Disease', 'MESH:D002583', (178, 193))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('TGF-betaRI', 'Gene', '7046', (50, 60))	('miR-27a', 'Var', (25, 32))	('TGF-beta signaling pathway', 'Pathway', (78, 104))
383549	29531222	The downregulated TGF-betaRI expression by miR-27a-agomir could be reactivated by the TGF-betaRI expression vector in HeLa cells, whereas TGF-betaRII expression was not affected (Fig.	('TGF-betaRI', 'Gene', (18, 28))	('TGF-betaRI', 'Gene', (138, 148))	('miR-27a-agomir', 'Var', (43, 57))	('TGF-betaRI', 'Gene', '7046', (86, 96))	('downregulated', 'NegReg', (4, 17))	('HeLa', 'CellLine', 'CVCL:0030', (118, 122))	('TGF-betaRI', 'Gene', '7046', (138, 148))	('TGF-betaRI', 'Gene', '7046', (18, 28))	('TGF-betaRII', 'Gene', '7048', (138, 149))	('expression', 'MPA', (29, 39))	('TGF-betaRI', 'Gene', (86, 96))	('TGF-betaRII', 'Gene', (138, 149))
383551	29531222	The SMAD3 mRNA level that was reduced by miR-27a-agomir could be rescued by co-transfecting with a TGF-betaRI expression vector in HeLa cells (Fig.	('SMAD3', 'Gene', '4088', (4, 9))	('HeLa', 'CellLine', 'CVCL:0030', (131, 135))	('SMAD3', 'Gene', (4, 9))	('miR-27a-agomir', 'Var', (41, 55))	('TGF-betaRI', 'Gene', (99, 109))	('TGF-betaRI', 'Gene', '7046', (99, 109))
383552	29531222	Western blot analysis detected a dramatic reduction of SMAD3 expression and phosphorylation when cells were treated with miR-27a-agomir and control vector.	('SMAD3', 'Gene', '4088', (55, 60))	('SMAD3', 'Gene', (55, 60))	('phosphorylation', 'MPA', (76, 91))	('miR-27a-agomir', 'Var', (121, 135))	('reduction', 'NegReg', (42, 51))	('expression', 'MPA', (61, 71))
383555	29531222	In addition, the co-transfection of miR-27a-agomir with a TGF-betaRI expression vector in HeLa cells significantly restored cell migration and invasion properties (Fig.	('TGF-betaRI', 'Gene', '7046', (58, 68))	('HeLa', 'CellLine', 'CVCL:0030', (90, 94))	('miR-27a-agomir', 'Var', (36, 50))	('invasion properties', 'CPA', (143, 162))	('cell migration', 'CPA', (124, 138))	('TGF-betaRI', 'Gene', (58, 68))	('restored', 'PosReg', (115, 123))
383556	29531222	In SiHa cells, however, the transfection of miR-27a-agomir, TGF-betaRI expression vector or the combination did not affect the cell phenotype (Fig.	('TGF-betaRI', 'Gene', '7046', (60, 70))	('SiHa', 'CellLine', 'CVCL:0032', (3, 7))	('TGF-betaRI', 'Gene', (60, 70))	('miR-27a-agomir', 'Var', (44, 58))
383557	29531222	These findings indicate that miR-27a inhibits HeLa cell proliferation, survival, migration, and invasion by downregulating TGF-betaRI.	('survival', 'CPA', (71, 79))	('HeLa', 'CellLine', 'CVCL:0030', (46, 50))	('downregulating', 'NegReg', (108, 122))	('miR-27a', 'Var', (29, 36))	('HeLa cell proliferation', 'CPA', (46, 69))	('invasion', 'CPA', (96, 104))	('TGF-betaRI', 'Gene', (123, 133))	('migration', 'CPA', (81, 90))	('inhibits', 'NegReg', (37, 45))	('TGF-betaRI', 'Gene', '7046', (123, 133))
383559	29531222	The tumor-bearing mice were randomly divided into three groups and were intratumorally injected with miR-27a-agomir, control agomir or PBS.	('tumor', 'Disease', (4, 9))	('miR-27a-agomir', 'Var', (101, 115))	('mice', 'Species', '10090', (18, 22))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('tumor', 'Disease', (77, 82))	('PBS', 'Chemical', 'MESH:D007854', (135, 138))
383560	29531222	After two weeks, the tumor size of the miR-27a-agomir group was significantly smaller compared with the control groups (Fig.	('miR-27a-agomir', 'Var', (39, 53))	('tumor', 'Disease', (21, 26))	('smaller', 'NegReg', (78, 85))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
383561	29531222	Moreover, the tumor growth in the miR-27a-agomir group was significantly slower than the control groups (Fig.	('tumor', 'Disease', (14, 19))	('miR-27a-agomir', 'Var', (34, 48))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('slower', 'NegReg', (73, 79))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
383574	29531222	In addition, high TGF-betaRI was significantly associated with age at diagnosis (P = 0.004), deep stromal invasion (P = 0.003), and lymph node metastasis (P = 0.036).	('TGF-betaRI', 'Gene', (18, 28))	('lymph node metastasis', 'CPA', (132, 153))	('high', 'Var', (13, 17))	('TGF-betaRI', 'Gene', '7046', (18, 28))	('deep stromal invasion', 'CPA', (93, 114))	('associated', 'Reg', (47, 57))
383579	29531222	Herein, we demonstrated that miR-27a is downregulated in cervical cancer, and elevated miR-27a antagonizes tumor progression by inhibiting TGF-betaRI expression and TGF-beta signaling.	('miR-27a', 'Var', (87, 94))	('cervical cancer', 'Disease', 'MESH:D002583', (57, 72))	('expression', 'MPA', (150, 160))	('TGF-betaRI', 'Gene', (139, 149))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('cervical cancer', 'Disease', (57, 72))	('downregulated', 'NegReg', (40, 53))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('miR-27a', 'Gene', (29, 36))	('TGF-betaRI', 'Gene', '7046', (139, 149))	('inhibiting', 'NegReg', (128, 138))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('antagonizes', 'NegReg', (95, 106))	('TGF-beta signaling', 'MPA', (165, 183))
383580	29531222	More importantly, low miR-27a, high TGF-betaRI, and the tumor-suppressor effects of miR-27a are predominantly observed in CADCs rather than in CSCCs.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('miR-27a', 'Protein', (22, 29))	('tumor', 'Disease', (56, 61))	('miR-27a', 'Var', (84, 91))	('TGF-betaRI', 'Gene', (36, 46))	('low', 'NegReg', (18, 21))	('TGF-betaRI', 'Gene', '7046', (36, 46))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('CADCs', 'Disease', (122, 127))
383583	29531222	Moreover, miR-27a-agomir could suppress cervical cancer cell proliferation, migration, and invasion in vitro, as well as inhibit tumor growth in vivo.	('inhibit', 'NegReg', (121, 128))	('tumor', 'Disease', (129, 134))	('invasion', 'CPA', (91, 99))	('migration', 'CPA', (76, 85))	('cervical cancer', 'Disease', 'MESH:D002583', (40, 55))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('cervical cancer', 'Disease', (40, 55))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('miR-27a-agomir', 'Var', (10, 24))	('suppress', 'NegReg', (31, 39))
383585	29531222	miR-27a has also been reported to be downregulated in colorectal cancer, oral squamous carcinoma, and esophageal carcinoma, in which miR-27a exhibited antitumor effects.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('downregulated', 'NegReg', (37, 50))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (102, 122))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (102, 122))	('colorectal cancer', 'Disease', 'MESH:D015179', (54, 71))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (78, 96))	('tumor', 'Disease', (155, 160))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('miR-27a', 'Var', (133, 140))	('colorectal cancer', 'Phenotype', 'HP:0003003', (54, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('oral squamous carcinoma', 'Disease', 'MESH:D002294', (73, 96))	('miR-27a', 'Gene', (0, 7))	('colorectal cancer', 'Disease', (54, 71))	('oral squamous carcinoma', 'Disease', (73, 96))	('esophageal carcinoma', 'Disease', (102, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))
383586	29531222	However, in several solid tumors, miR-27a was found to be an oncogenic miRNA.	('tumors', 'Disease', (26, 32))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('miR-27a', 'Var', (34, 41))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))
383593	29531222	We identified TGF-betaRI as a direct target of miR-27a, which contributed to the tumor suppressor role of miR-27a in cervical cancer.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('TGF-betaRI', 'Gene', '7046', (14, 24))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('miR-27a', 'Gene', (47, 54))	('TGF-betaRI', 'Gene', (14, 24))	('cervical cancer', 'Disease', 'MESH:D002583', (117, 132))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('cervical cancer', 'Disease', (117, 132))	('miR-27a', 'Var', (106, 113))	('tumor', 'Disease', (81, 86))
383597	29531222	This role-switch from a tumor suppressor to a tumor promoter of TGF-beta is considered to be partially attributed to mutations and loss of expression of TGF-betaR and SMAD proteins.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('TGF-betaR', 'Gene', (153, 162))	('mutations', 'Var', (117, 126))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Disease', (24, 29))	('tumor', 'Disease', (46, 51))	('loss of', 'NegReg', (131, 138))	('TGF-beta', 'Gene', (64, 72))	('expression', 'MPA', (139, 149))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
383600	29531222	Thus, miR-27a inhibits the TGF-beta pathway through targeting multiple factors involving TGF-betaRI and SMAD proteins via direct and indirect interactions, thereby favoring tumor progression.	('favoring', 'PosReg', (164, 172))	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('inhibits', 'NegReg', (14, 22))	('SMAD proteins', 'Protein', (104, 117))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumor', 'Disease', (173, 178))	('interactions', 'Interaction', (142, 154))	('TGF-betaRI', 'Gene', (89, 99))	('TGF-beta pathway', 'Pathway', (27, 43))	('targeting', 'Reg', (52, 61))	('miR-27a', 'Var', (6, 13))	('TGF-betaRI', 'Gene', '7046', (89, 99))
383604	29531222	Most CSCCs are HPV16-positive, whereas CADCs harbor predominantly HPV18 that is associated with an unfavorable prognosis.	('HPV', 'Species', '10566', (66, 69))	('HPV', 'Species', '10566', (15, 18))	('HPV18', 'Gene', (66, 71))	('HPV16-positive', 'Var', (15, 29))	('HPV16', 'Species', '333760', (15, 20))
383608	29531222	On the other hand, C33A is HPV-negative adenocarcinoma with p53 mutation (PMID:10410876), which mimics the genetic background of gastric subtype.	('adenocarcinoma', 'Disease', (40, 54))	('HPV', 'Species', '10566', (27, 30))	('C33A', 'Var', (19, 23))	('adenocarcinoma', 'Disease', 'MESH:D000230', (40, 54))	('p53', 'Gene', (60, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (45, 54))
383614	29531222	Our findings suggest that miR-27a inhibits TGF-beta signaling pathway in cervical cancer, which in turn suppresses tumor progression.	('suppresses', 'NegReg', (104, 114))	('TGF-beta signaling pathway', 'Pathway', (43, 69))	('cervical cancer', 'Disease', 'MESH:D002583', (73, 88))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('inhibits', 'NegReg', (34, 42))	('tumor', 'Disease', (115, 120))	('miR-27a', 'Var', (26, 33))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('cervical cancer', 'Disease', (73, 88))
383634	29531222	Once the tumor volume reached 100 mm3, the mice were randomly divided into three groups (n = 7/group) and injected intratumorally with 2 nmol miR-27a-agomir, agomir-NC, or PBS twice a week for two weeks.	('mice', 'Species', '10090', (43, 47))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('tumor', 'Disease', (9, 14))	('PBS', 'Chemical', 'MESH:D007854', (172, 175))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('miR-27a-agomir', 'Var', (142, 156))	('tumor', 'Disease', (120, 125))
383655	29531222	In the analysis of the correlation between the expression of miR-27a and TGF-betaRI and the clinico-pathological parameters of cervical cancer, the miR-27a expression was divided into two categories of "negative" (0) and "positive" (>=1); the TGF-betaRI expression was categorized as "low" (<6) and "high" (>=6).	('TGF-betaRI', 'Gene', (73, 83))	('miR-27a', 'Var', (148, 155))	('cervical cancer', 'Disease', 'MESH:D002583', (127, 142))	('TGF-betaRI', 'Gene', '7046', (73, 83))	('miR-27a', 'Gene', (61, 68))	('TGF-betaRI', 'Gene', (243, 253))	('cervical cancer', 'Disease', (127, 142))	('TGF-betaRI', 'Gene', '7046', (243, 253))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
383730	24509874	As in the present study, they also reported strong p63 positivity in squamous cell carcinoma.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (69, 92))	('p63', 'Gene', (51, 54))	('squamous cell carcinoma', 'Disease', (69, 92))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (69, 92))	('positivity', 'Var', (55, 65))	('p63', 'Gene', '8626', (51, 54))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))
383756	24509874	While some studies found 12%, 11%, 15.8%, and 30% (6, 8, 76, 78, respectively) immunohistochemical p63 positivity in adenocarcinoma, p63 was negative in adenocarcinoma in some other studies.	('p63', 'Gene', '8626', (99, 102))	('p63', 'Gene', '8626', (133, 136))	('positivity', 'Var', (103, 113))	('adenocarcinoma', 'Disease', (117, 131))	('carcinoma', 'Phenotype', 'HP:0030731', (158, 167))	('adenocarcinoma', 'Disease', 'MESH:D000230', (153, 167))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('adenocarcinoma', 'Disease', 'MESH:D000230', (117, 131))	('adenocarcinoma', 'Disease', (153, 167))	('p63', 'Gene', (99, 102))	('p63', 'Gene', (133, 136))
383802	24139065	However, the CTSB-shRNA significantly inhibited tumor metastases and prolonged survival in LL/2 metastatic model.	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('prolonged', 'PosReg', (69, 78))	('inhibited', 'NegReg', (38, 47))	('survival', 'CPA', (79, 87))	('tumor metastases', 'Disease', (48, 64))	('CTSB-shRNA', 'Var', (13, 23))	('tumor metastases', 'Disease', 'MESH:D009362', (48, 64))
383851	24139065	The membranes were blocked overnight with PBS containing 0.1% Tween 20 in 5% skimmed milk at 4 C, and subsequently probed by the primary antibodies: anti-CTSB (Biovisin Res, USA), Anti-Shh and anti-Ptch (Santa Cruz Biotechnology, Germany).	('anti-CTSB', 'Var', (149, 158))	('PBS', 'Gene', (42, 45))	('Shh', 'Gene', '6469', (185, 188))	('PBS', 'Gene', '1131', (42, 45))	('Tween 20', 'Chemical', 'MESH:D011136', (62, 70))	('Ptch', 'Gene', (198, 202))	('Ptch', 'Gene', '5727', (198, 202))	('Shh', 'Gene', (185, 188))
383896	24139065	The weight of tumor treated with CTSB-shRNA also showed no significant differences compared with controls.	('CTSB-shRNA', 'Var', (33, 43))	('tumor', 'Disease', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('tumor', 'Disease', 'MESH:D009369', (14, 19))
383904	24139065	As shown in Figure 5A, B, metastatic nodules and lung weight were obviously reduced in CTSB-shRNA treated mice.	('reduced', 'NegReg', (76, 83))	('lung weight', 'CPA', (49, 60))	('mice', 'Species', '10090', (106, 110))	('CTSB-shRNA', 'Var', (87, 97))
383905	24139065	The lung weight reached 0.6 +- 0.158, 0.56 +- 0.114, 0.56 +- 0.152, 0.24 +- 0.114 for PBS, Lipo, NC and CTSB-shRNA, respectively (P < 0.05).	('lung weight', 'CPA', (4, 15))	('PBS', 'Gene', (86, 89))	('PBS', 'Gene', '1131', (86, 89))	('Lipo', 'Gene', (91, 95))	('Lipo', 'Gene', '8091', (91, 95))	('0.56 +- 0.152', 'Var', (53, 66))
383933	24139065	Matrigel invasion assay showed the invasive capacity of lung cancer cells decreased nearly 80% after treatment with CTSB-shRNA.	('lung cancer', 'Disease', 'MESH:D008175', (56, 67))	('invasive capacity', 'CPA', (35, 52))	('Matrigel invasion assay', 'CPA', (0, 23))	('CTSB-shRNA', 'Var', (116, 126))	('decreased', 'NegReg', (74, 83))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('lung cancer', 'Disease', (56, 67))	('lung cancer', 'Phenotype', 'HP:0100526', (56, 67))	('men', 'Species', '9606', (106, 109))
383954	31389660	The oesophageal cancer cells treated with si-HOTAIR or miR-204 mimic exhibited decreased expression levels of HOXC8, Vimentin and MMP-9, but increased E-cadherin level.	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('Vimentin', 'Gene', (117, 125))	('oesophageal cancer', 'Disease', (4, 22))	('decreased', 'NegReg', (79, 88))	('increased', 'PosReg', (141, 150))	('HOXC8', 'MPA', (110, 115))	('oesophageal cancer', 'Disease', 'MESH:D009369', (4, 22))	('Vimentin', 'Gene', '7431', (117, 125))	('si-HOTAIR', 'Var', (42, 51))	('E-cadherin', 'Gene', (151, 161))	('MMP-9', 'Gene', '4318', (130, 135))	('miR-204', 'Gene', (55, 62))	('expression levels', 'MPA', (89, 106))	('E-cadherin', 'Gene', '999', (151, 161))	('MMP-9', 'Gene', (130, 135))
383955	31389660	Silenced HOTAIR or elevated miR-204 inhibited proliferation, migration and invasion, along with stimulated apoptosis of oesophageal cancer cells.	('inhibited', 'NegReg', (36, 45))	('oesophageal cancer', 'Disease', (120, 138))	('invasion', 'CPA', (75, 83))	('oesophageal cancer', 'Disease', 'MESH:D009369', (120, 138))	('elevated', 'PosReg', (19, 27))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('proliferation', 'CPA', (46, 59))	('apoptosis', 'CPA', (107, 116))	('migration', 'CPA', (61, 70))	('miR-204', 'Gene', (28, 35))	('stimulated', 'PosReg', (96, 106))	('HOTAIR', 'Var', (9, 15))
383980	31389660	Five oesophageal cancer cell lines, namely EC8712, EC8733, ECA109, EC9706 and EC8501 as well as normal oesophageal epithelial cell line HEEC (Shanghai Institute of Biochemistry and Cell Biology, Shanghai, China) were cultured in the RPMI 1640 medium containing 10% serum at 37 C with 5% CO2.	('EC8712', 'Var', (43, 49))	('oesophageal cancer', 'Disease', 'MESH:D009369', (5, 23))	('oesophageal cancer', 'Disease', (5, 23))	('CO2', 'Chemical', 'MESH:D002245', (287, 290))	('HEEC', 'CellLine', 'None', (136, 140))	('EC9706', 'Var', (67, 73))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
383986	31389660	The cells were treated with lysis buffer (25 mmol/L Tris-HCl pH = 7.4, 150 mmol/L NaCl, 0.5% NP-40, 2 mmol/L ethylenediamine tetraacetic acid (EDTA), 1 mmol/L NaF and 0.5 mmol/L dithiothreitol) containing RNasin (Takara, Dalian, Liaoning, China) and protease inhibitors (B14001a, Roche, Basel, Switzerland).	('NaCl', 'Chemical', 'MESH:D012965', (82, 86))	('RNasin', 'Chemical', 'MESH:C022052', (205, 211))	('dithiothreitol', 'Chemical', 'MESH:D004229', (178, 192))	('NaF', 'Gene', '3576', (159, 162))	('NaF', 'Gene', (159, 162))	('Tris-HCl', 'Chemical', 'MESH:C014843', (52, 60))	('B14001a', 'Var', (271, 278))	('EDTA', 'Chemical', 'MESH:D004492', (143, 147))	('ethylenediamine tetraacetic acid', 'Chemical', 'MESH:C017826', (109, 141))
384002	31389660	The membrane was then incubated with diluted primary antibodies to HOXC8 (ab79690, 1:200), E-cadherin (ab1416, 1:50), Vimentin (ab8978, 1:100), MMP-9 (ab73734, 1:500), and GAPDH (ab37168, 1:200) at 4 C overnight.	('GAPDH', 'Gene', '2597', (172, 177))	('MMP-9', 'Gene', (144, 149))	('Vimentin', 'Gene', (118, 126))	('ab1416', 'Var', (103, 109))	('GAPDH', 'Gene', (172, 177))	('E-cadherin', 'Gene', (91, 101))	('ab37168', 'Var', (179, 186))	('ab73734', 'Var', (151, 158))	('ab8978', 'Var', (128, 134))	('Vimentin', 'Gene', '7431', (118, 126))	('E-cadherin', 'Gene', '999', (91, 101))	('MMP-9', 'Gene', '4318', (144, 149))	('ab79690', 'Var', (74, 81))
384032	31389660	The RT-qPCR results (Figure 3) revealed that compared with the HEEC cell line, the expression of miR-204 was significantly lower while the expression of HOTAIR was higher in the EC8712, EC8733, ECA109, EC9706 and EC8501 cell lines (all P < 0.05).	('miR-204', 'Var', (97, 104))	('lower', 'NegReg', (123, 128))	('higher', 'PosReg', (164, 170))	('expression', 'MPA', (83, 93))	('expression', 'MPA', (139, 149))	('HEEC', 'CellLine', 'None', (63, 67))
384033	31389660	In order to ascertain as to whether HOTAIR or miR-204 could influence the expression of HOXC8 and proteins related to cell proliferation, migration and invasion, the relative expression levels of HOXC8, Vimentin, MMP-9 and E-cadherin were determined by RT-qPCR and western blot analysis means.	('invasion', 'CPA', (152, 160))	('expression', 'MPA', (74, 84))	('MMP-9', 'Gene', (213, 218))	('migration', 'CPA', (138, 147))	('miR-204', 'Var', (46, 53))	('ether', 'Chemical', 'MESH:D004987', (30, 35))	('HOXC8', 'Gene', (88, 93))	('Vimentin', 'Gene', '7431', (203, 211))	('influence', 'Reg', (60, 69))	('E-cadherin', 'Gene', (223, 233))	('E-cadherin', 'Gene', '999', (223, 233))	('MMP-9', 'Gene', '4318', (213, 218))	('Vimentin', 'Gene', (203, 211))
384035	31389660	When EC9706 cells were treated with the si-HOTAIR, not only did the expression of HOTAIR notably decrease but the mRNA and protein expression levels of HOXC8, Vimentin and MMP-9 were also decreased, while the expression of miR-204 and the mRNA and protein expression levels of E-cadherin were remarkably increased when compared with the control group (all P < 0.05).	('decreased', 'NegReg', (188, 197))	('expression', 'MPA', (209, 219))	('MMP-9', 'Gene', '4318', (172, 177))	('expression', 'MPA', (68, 78))	('si-HOTAIR', 'Var', (40, 49))	('MMP-9', 'Gene', (172, 177))	('E-cadherin', 'Gene', (277, 287))	('Vimentin', 'Gene', '7431', (159, 167))	('E-cadherin', 'Gene', '999', (277, 287))	('EC9706', 'Var', (5, 11))	('increased', 'PosReg', (304, 313))	('HOTAIR', 'Gene', (82, 88))	('decrease', 'NegReg', (97, 105))	('miR-204', 'MPA', (223, 230))	('Vimentin', 'Gene', (159, 167))
384036	31389660	When the EC9706 cells had been transfected with HOTAIR overexpression vectors (HOTAIR group), the expression of HOTAIR and the mRNA and protein expression levels of HOXC8, Vimentin and MMP-9 were elevated while that of miR-204 and the mRNA and protein expression levels of E-cadherin were considerably reduced when compared to the control group (all P < 0.05).	('MMP-9', 'Gene', (185, 190))	('Vimentin', 'Gene', (172, 180))	('reduced', 'NegReg', (302, 309))	('E-cadherin', 'Gene', (273, 283))	('EC9706', 'Var', (9, 15))	('E-cadherin', 'Gene', '999', (273, 283))	('Vimentin', 'Gene', '7431', (172, 180))	('HOTAIR', 'Gene', (112, 118))	('elevated', 'PosReg', (196, 204))	('miR-204', 'MPA', (219, 226))	('MMP-9', 'Gene', '4318', (185, 190))	('HOXC8', 'MPA', (165, 170))	('expression', 'MPA', (98, 108))
384038	31389660	In comparison to the blank group, the expression of HOTAIR and the mRNA and protein expression levels of HOXC8, Vimentin and MMP-9 exhibited notable decreases in the si-HOTAIR and si-HOTAIR + miR-204 mimic groups while the expression of miR-204 and the mRNA and protein expression levels of E-cadherin were significantly increased (all P < 0.05).	('expression', 'MPA', (38, 48))	('MMP-9', 'Gene', (125, 130))	('E-cadherin', 'Gene', (291, 301))	('expression', 'MPA', (223, 233))	('E-cadherin', 'Gene', '999', (291, 301))	('MMP-9', 'Gene', '4318', (125, 130))	('decreases', 'NegReg', (149, 158))	('Vimentin', 'Gene', (112, 120))	('increased', 'PosReg', (321, 330))	('si-HOTAIR', 'Var', (180, 189))	('Vimentin', 'Gene', '7431', (112, 120))	('si-HOTAIR', 'Var', (166, 175))
384039	31389660	In the miR-204 mimic group, the mRNA and protein expression levels of HOTAIR, HOXC8, Vimentin and MMP-9 were considerably decreased, whereas the expression of miR-204 and the mRNA and protein expression levels of E-cadherin were significantly increased (all P < 0.05).	('Vimentin', 'Gene', '7431', (85, 93))	('E-cadherin', 'Gene', (213, 223))	('expression', 'MPA', (145, 155))	('E-cadherin', 'Gene', '999', (213, 223))	('MMP-9', 'Gene', '4318', (98, 103))	('increased', 'PosReg', (243, 252))	('MMP-9', 'Gene', (98, 103))	('miR-204', 'Var', (159, 166))	('Vimentin', 'Gene', (85, 93))	('decreased', 'NegReg', (122, 131))
384041	31389660	In comparison to the si-HOTAIR and miR-204 mimic groups, the mRNA and protein expression levels of HOXC8, Vimentin and MMP-9 decreased in the si-HOTAIR + miR-204 mimic group while the expression of miR-204 and the mRNA and protein expression levels of E-cadherin were notably elevated (all P < 0.05).	('elevated', 'PosReg', (276, 284))	('E-cadherin', 'Gene', (252, 262))	('Vimentin', 'Gene', '7431', (106, 114))	('miR-204', 'Gene', (198, 205))	('MMP-9', 'Gene', '4318', (119, 124))	('decreased', 'NegReg', (125, 134))	('E-cadherin', 'Gene', '999', (252, 262))	('expression', 'MPA', (184, 194))	('Vimentin', 'Gene', (106, 114))	('si-HOTAIR', 'Var', (142, 151))	('MMP-9', 'Gene', (119, 124))
384043	31389660	The MTT assay (Figure 5A) results revealed there to be no significant difference in the EC9706 cells regarding the cell viability between the control group and NC group (P > 0.05), while reduced viability was identified in the si-HOTAIR group while enhanced levels were found in the HOTAIR group compared to the control group (both P < 0.05).	('si-HOTAIR', 'Var', (227, 236))	('reduced', 'NegReg', (187, 194))	('MTT', 'Chemical', 'MESH:C022616', (4, 7))	('viability', 'MPA', (195, 204))
384050	31389660	The results obtained in Figure 8 revealed there to be reduced tumor volume in the si-HOTAIR group.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('si-HOTAIR', 'Var', (82, 91))	('tumor', 'Disease', (62, 67))	('reduced', 'NegReg', (54, 61))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
384053	31389660	When this cell line was subjected to different treatment, the size, volume and the growth rate of the tumour in the miR-204 inhibitor and HOTAIR groups was significantly elevated when compared to the blank group but these tumour formation parameters were all reduced in the si-HOTAIR, miR-204 mimic and si-HOTAIR + miR-204 mimic groups (all P < 0.05).	('elevated', 'PosReg', (170, 178))	('tumour', 'Disease', 'MESH:D009369', (222, 228))	('tumour', 'Phenotype', 'HP:0002664', (102, 108))	('tumour', 'Disease', (222, 228))	('si-HOTAIR', 'Var', (274, 283))	('volume', 'CPA', (68, 74))	('size', 'CPA', (62, 66))	('tumour', 'Disease', 'MESH:D009369', (102, 108))	('tumour', 'Disease', (102, 108))	('reduced', 'NegReg', (259, 266))	('tumour', 'Phenotype', 'HP:0002664', (222, 228))
384058	31389660	Thus, silencing of HOTAIR could suppress the expression of HOXC8 via miR-204 and inhibit proliferation, migration and invasion while inducing apoptosis of oesophageal cancer cells.	('proliferation', 'CPA', (89, 102))	('suppress', 'NegReg', (32, 40))	('HOTAIR', 'Gene', (19, 25))	('inhibit', 'NegReg', (81, 88))	('HOXC8', 'Gene', (59, 64))	('expression', 'MPA', (45, 55))	('oesophageal cancer', 'Disease', 'MESH:D009369', (155, 173))	('oesophageal cancer', 'Disease', (155, 173))	('inducing', 'NegReg', (133, 141))	('apoptosis', 'CPA', (142, 151))	('miR-204', 'Gene', (69, 76))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('silencing', 'Var', (6, 15))
384068	31389660	In addition, through the mediation of the SIRT1/p53 signalling pathway, miR-204 has been reported to promote emitochondrial apoptosis in doxorubicin-treated prostate cancer cells.48  To conclude, this study illustrated that lncRNA HOTAIR could function as a ceRNA of miR-204, and the silencing of HOTAIR could reduce expression of HOXC8, which ultimately inhibited the proliferation, migration and invasion of oesophageal cancer cells (Figure 9).	('HOTAIR', 'Gene', (297, 303))	('doxorubicin', 'Chemical', 'MESH:D004317', (137, 148))	('silencing', 'Var', (284, 293))	('SIRT1', 'Gene', '23411', (42, 47))	('invasion of oesophageal cancer', 'Disease', 'MESH:D009362', (398, 428))	('cancer', 'Phenotype', 'HP:0002664', (422, 428))	('invasion of oesophageal cancer', 'Disease', (398, 428))	('p53', 'Gene', '7157', (48, 51))	('SIRT1', 'Gene', (42, 47))	('p53', 'Gene', (48, 51))	('proliferation', 'CPA', (369, 382))	('expression', 'MPA', (317, 327))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('migration', 'CPA', (384, 393))	('prostate cancer', 'Disease', 'MESH:D011471', (157, 172))	('prostate cancer', 'Phenotype', 'HP:0012125', (157, 172))	('prostate cancer', 'Disease', (157, 172))	('inhibited', 'NegReg', (355, 364))	('reduce', 'NegReg', (310, 316))
384069	31389660	This suggested that repression of HOTAIR could be clinically helpful to suppress oesophageal cancer progression and HOTAIR could be a promising target for oesophageal cancer treatment.	('oesophageal cancer', 'Disease', 'MESH:D009369', (81, 99))	('oesophageal cancer', 'Disease', (81, 99))	('suppress', 'NegReg', (72, 80))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('oesophageal cancer', 'Disease', 'MESH:D009369', (155, 173))	('HOTAIR', 'Gene', (34, 40))	('repression', 'Var', (20, 30))	('oesophageal cancer', 'Disease', (155, 173))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))
384075	31151431	The results of Cox multivariate analysis indicated that among these tumor biomarkers, CA19-9 (>= 37 vs. < 37) [hazard ratio (HR) = 2.130, 95% confidence interval (CI) = 1.138-3.986, p = 0.018] and CEA (>= 5 vs. < 5) (HR = 1.827, 95% CI = 1.089-3.064, p = 0.022) were the independent prognostic factors of poor OS.	('tumor', 'Disease', (68, 73))	('CA19-9', 'Chemical', 'MESH:C086528', (86, 92))	('OS', 'Chemical', '-', (310, 312))	('CEA', 'Gene', '1048', (197, 200))	('CEA', 'Gene', (197, 200))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('poor OS', 'Disease', (305, 312))	('CA19-9', 'Var', (86, 92))	('Cox', 'Gene', '1351', (15, 18))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('Cox', 'Gene', (15, 18))
384076	31151431	For the ESCC patients with CA19-9 < 37, CEA < 5 or SCC-Ag < 1.5, the surgery plus postoperative chemotherapy group had a significantly longer OS than the surgery group alone (p < 0.05), but this significant difference of OS between these two groups cannot be found in patients with CA19-9 >= 37, CEA >= 5 or SCC-Ag >= 1.5 (p > 0.05).	('patients', 'Species', '9606', (268, 276))	('CA19-9', 'Chemical', 'MESH:C086528', (27, 33))	('SCC', 'Gene', '6317', (308, 311))	('SCC', 'Gene', (51, 54))	('OS', 'Chemical', '-', (142, 144))	('patients', 'Species', '9606', (13, 21))	('CEA', 'Gene', '1048', (40, 43))	('SCC', 'Gene', '6317', (51, 54))	('CEA', 'Gene', (40, 43))	('SCC', 'Gene', (9, 12))	('OS', 'Chemical', '-', (221, 223))	('CEA', 'Gene', '1048', (296, 299))	('SCC', 'Gene', (308, 311))	('SCC', 'Gene', '6317', (9, 12))	('CA19-9 < 37', 'Var', (27, 38))	('CEA', 'Gene', (296, 299))	('CA19-9', 'Chemical', 'MESH:C086528', (282, 288))
384098	31151431	According to the manufacturer's protocols and previous study, the normal upper limits were used as the optimal cut-off values of CA19-9, CA72-4, CEA, Cyfra21-1 and SCC-Ag: 37 U/ml, 6 U/ml, 5 mug/L, 3.4 ng/ml and 1.5 ng/ml, respectively.	('CA72', 'Chemical', '-', (137, 141))	('CEA', 'Gene', (145, 148))	('CA72-4', 'Var', (137, 143))	('SCC', 'Gene', '6317', (164, 167))	('Cyfra21-1', 'Var', (150, 159))	('CA19-9', 'Var', (129, 135))	('CA19-9', 'Chemical', 'MESH:C086528', (129, 135))	('CEA', 'Gene', '1048', (145, 148))	('SCC', 'Gene', (164, 167))
384109	31151431	Our results showed that the high CEA and Cyfra21-1 were both significantly associated with older age and more advanced pN stage (p < 0.05), elevated SCC-Ag was significantly related to larger tumor size, more advanced pN stage and TNM stage, and CA72-4 was significantly associated with tumor size (p < 0.05).	('CEA', 'Gene', '1048', (33, 36))	('elevated', 'PosReg', (140, 148))	('pN stage', 'CPA', (218, 226))	('Cyfra21-1', 'Var', (41, 50))	('CA72', 'Chemical', '-', (246, 250))	('tumor', 'Disease', (287, 292))	('tumor', 'Disease', (192, 197))	('tumor', 'Disease', 'MESH:D009369', (287, 292))	('CEA', 'Gene', (33, 36))	('SCC', 'Gene', '6317', (149, 152))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('TNM', 'Gene', '10178', (231, 234))	('associated', 'Reg', (75, 85))	('TNM', 'Gene', (231, 234))	('SCC', 'Gene', (149, 152))	('related', 'Reg', (174, 181))	('tumor', 'Phenotype', 'HP:0002664', (287, 292))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('larger', 'PosReg', (185, 191))
384112	31151431	In univariate analysis, our result indicated that male patients, larger tumor size, advanced pT stage, advanced pN stage, advanced TNM stage, patients who did not receive postoperative chemotherapy and elevated CA19-9, CEA, Cyfra21-1 and SCC-Ag were significantly related to poor OS (p < 0.05, Fig.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('larger', 'PosReg', (65, 71))	('poor OS', 'Disease', (275, 282))	('OS', 'Chemical', '-', (280, 282))	('elevated', 'PosReg', (202, 210))	('CEA', 'Gene', (219, 222))	('TNM', 'Gene', '10178', (131, 134))	('SCC', 'Gene', '6317', (238, 241))	('advanced pT', 'Disease', (84, 95))	('TNM', 'Gene', (131, 134))	('CA19-9', 'Var', (211, 217))	('tumor', 'Disease', (72, 77))	('SCC', 'Gene', (238, 241))	('CA19-9', 'Chemical', 'MESH:C086528', (211, 217))	('CEA', 'Gene', '1048', (219, 222))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('related', 'Reg', (264, 271))	('Cyfra21-1', 'Var', (224, 233))	('patients', 'Species', '9606', (55, 63))	('patients', 'Species', '9606', (142, 150))
384114	31151431	Among these tumor biomarkers, CA19-9 (>= 37 vs. < 37) [hazard ratio (HR) = 2.130, 95% confidence interval (CI) = 1.138-3.986, p = 0.018] and CEA (>= 5 vs. < 5) (HR = 1.827, 95% CI = 1.089-3.064, p = 0.022) were the independent prognostic factors of poor OS (Table 2).	('CEA', 'Gene', (141, 144))	('CEA', 'Gene', '1048', (141, 144))	('OS', 'Chemical', '-', (254, 256))	('CA19-9', 'Var', (30, 36))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('CA19-9', 'Chemical', 'MESH:C086528', (30, 36))	('tumor', 'Disease', (12, 17))	('poor OS', 'Disease', (249, 256))
384119	31151431	Our result indicated that for the ESCC patients with CA19-9 < 37 U/ml, CEA < 5 mug/L or SCC-Ag < 1.5 ng/ml, the surgery plus postoperative chemotherapy group had a significantly longer OS than the surgery group alone (p < 0.05, Fig.	('patients', 'Species', '9606', (39, 47))	('SCC', 'Gene', (35, 38))	('longer', 'PosReg', (178, 184))	('CEA', 'Gene', (71, 74))	('CEA', 'Gene', '1048', (71, 74))	('CA19-9 < 37 U/ml', 'Var', (53, 69))	('CA19-9', 'Chemical', 'MESH:C086528', (53, 59))	('SCC', 'Gene', '6317', (35, 38))	('SCC', 'Gene', (88, 91))	('SCC', 'Gene', '6317', (88, 91))	('OS', 'Chemical', '-', (185, 187))
384121	31151431	On the other hand, regardless of patients with CA72-4 < 6 U/ml or CA72-4 >= 6 U/ml, or in patients with Cyfra21-1 < 3.4 ng/ml or Cyfra21-1 >= 3.4 ng/ml, our results showed that the surgery plus chemotherapy group had significantly longer or a tendency of longer OS than the surgery group alone (Additional file 1: Figure S1).	('CA72', 'Chemical', '-', (66, 70))	('patients', 'Species', '9606', (33, 41))	('OS', 'Chemical', '-', (262, 264))	('CA72-4', 'Var', (66, 72))	('longer', 'PosReg', (255, 261))	('Cyfra21-1 >=', 'Var', (129, 141))	('CA72', 'Chemical', '-', (47, 51))	('patients', 'Species', '9606', (90, 98))	('CA72-4 <', 'Var', (47, 55))
384130	31151431	found that Cyfra21-1 and SCC-Ag were both independently significant poor predictors of prognosis in patients with stage II ESCC.	('SCC', 'Gene', '6317', (124, 127))	('SCC', 'Gene', (25, 28))	('SCC', 'Gene', (124, 127))	('SCC', 'Gene', '6317', (25, 28))	('patients', 'Species', '9606', (100, 108))	('Cyfra21-1', 'Var', (11, 20))
384133	31151431	In this study, our results showed that CA19-9 and CEA were the only two independent prognostic indicators for poor OS among these five tumor biomarkers.	('CA19-9', 'Var', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('CEA', 'Gene', '1048', (50, 53))	('OS', 'Chemical', '-', (115, 117))	('tumor', 'Disease', (135, 140))	('poor OS', 'Disease', (110, 117))	('CEA', 'Gene', (50, 53))	('CA19-9', 'Chemical', 'MESH:C086528', (39, 45))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
384134	31151431	These aforementioned results showed that CA19-9 and CEA maybe were potentially superior to other tumor biomarkers as indicators for predicting prognosis in ESCC patients.	('SCC', 'Gene', (157, 160))	('CEA', 'Gene', '1048', (52, 55))	('CA19-9', 'Chemical', 'MESH:C086528', (41, 47))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('CEA', 'Gene', (52, 55))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('SCC', 'Gene', '6317', (157, 160))	('tumor', 'Disease', (97, 102))	('patients', 'Species', '9606', (161, 169))	('CA19-9', 'Var', (41, 47))
384142	31151431	Our result indicated that ESCC patients with low CA19-9, CEA, SCC-Ag may be more likely to benefit from the postoperative chemotherapy.	('SCC', 'Gene', (27, 30))	('CA19-9', 'Chemical', 'MESH:C086528', (49, 55))	('SCC', 'Gene', '6317', (62, 65))	('low CA19-9', 'Var', (45, 55))	('SCC', 'Gene', '6317', (27, 30))	('CEA', 'Gene', (57, 60))	('CEA', 'Gene', '1048', (57, 60))	('patients', 'Species', '9606', (31, 39))	('benefit', 'PosReg', (91, 98))	('CA19-9', 'Var', (49, 55))	('SCC', 'Gene', (62, 65))
384149	31151431	81772629, 81702431, 81602158 and 81602156), Individualized Medical Platform of National Clinical Research Center for Cancer (13ZCZCSY20300), Demonstrative research platform of clinical evaluation technology for new anticancer drugs (No.	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('81602158', 'Var', (20, 28))	('81602156', 'Var', (33, 41))	('Cancer', 'Disease', (117, 123))	('cancer', 'Disease', 'MESH:D009369', (219, 225))	('Cancer', 'Disease', 'MESH:D009369', (117, 123))	('cancer', 'Disease', (219, 225))	('Cancer', 'Phenotype', 'HP:0002664', (117, 123))
384192	28099906	NGS technology has made it possible to detect the genetic variants including single-nucleotide variant (SNV) and Insertion and Deletion (InDel) throughout the human genome with the high throughput sequencing (HTS) methodologies.	('single-nucleotide variant', 'Var', (77, 102))	('HTS', 'Disease', (209, 212))	('HTS', 'Disease', 'MESH:C537160', (209, 212))	('human', 'Species', '9606', (159, 164))
384219	28099906	We have discovered a total of 2840 and 5369 SNVs for the two samples of SCC respectively, 4275 and 3837 SNVs for the two samples of ASC respectively, and 4354, 2888, 3442 and 3276 SNVs for the four samples of AC respectively.	('4354', 'Var', (154, 158))	('SCC', 'Gene', (72, 75))	('SCC', 'Phenotype', 'HP:0002860', (72, 75))	('SCC', 'Gene', '6317', (72, 75))	('3442', 'Var', (166, 170))
384224	28099906	All these pancreatic cancer tissues possessed the same TP53 mutation site (Table 3).	('mutation', 'Var', (60, 68))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('pancreatic cancer', 'Disease', 'MESH:D010190', (10, 27))	('TP53', 'Gene', '7157', (55, 59))	('pancreatic cancer', 'Disease', (10, 27))	('TP53', 'Gene', (55, 59))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (10, 27))
384230	28099906	Gene Ontology (GO) analysis showed that these nine specific mutated genes were involved in the following main biological processes: regulation of oxidative stress-induced intrinsic apoptotic signaling pathway (GO:1902175) and cell death (GO:1903201) (Figure 2C) and in the following main molecular functions: oxygen binding (GO:0019825), drug transmembrane transporter activity (GO: 0015238) (Figure 2D).	('oxidative stress-induced', 'MPA', (146, 170))	('involved', 'Reg', (79, 87))	('cell death', 'CPA', (226, 236))	('mutated', 'Var', (60, 67))	('intrinsic apoptotic signaling pathway', 'Pathway', (171, 208))	('oxygen', 'Chemical', 'MESH:D010100', (309, 315))	('oxygen binding', 'Interaction', (309, 323))	('oxidative stress', 'Phenotype', 'HP:0025464', (146, 162))	('drug transmembrane transporter activity', 'MPA', (338, 377))
384235	28099906	Approximately 63~113 novel Inserts and Deletions have been found in each sample of the pancreatic carcinoma FFPE tissues (Table 6).	('pancreatic carcinoma FFPE tissues', 'Disease', (87, 120))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('pancreatic carcinoma FFPE tissues', 'Disease', 'MESH:C562463', (87, 120))	('Deletions', 'Var', (39, 48))	('Inserts', 'Var', (27, 34))
384239	28099906	Since these pathways are involved in malignant biological behaviors, such as metastasis, proliferation, evading apoptosis, angiogenesis, insensitive to anti-growth signals, resistant to chemotherapy, and stemness maintaining, et al., the aberrant expression of these genes could take part in the development and progression of pancreatic SCCs.	('take part', 'Reg', (279, 288))	('involved', 'Reg', (25, 33))	('men', 'Species', '9606', (303, 306))	('SCC', 'Phenotype', 'HP:0002860', (338, 341))	('aberrant', 'Var', (238, 246))	('pancreatic SCCs', 'Disease', (327, 342))	('pancreatic SCCs', 'Disease', 'MESH:D010195', (327, 342))
384270	28099906	Previous studies also find that CD44 and its variants were good markers of squamous epithelial differentiation in several types of normal epithelium and tumors.	('tumors', 'Disease', 'MESH:D009369', (153, 159))	('CD44', 'Gene', (32, 36))	('variants', 'Var', (45, 53))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumors', 'Disease', (153, 159))	('tumors', 'Phenotype', 'HP:0002664', (153, 159))	('CD44', 'Gene', '960', (32, 36))	('squamous epithelial', 'Disease', (75, 94))
384296	28099906	In 80%~90% of patients with pancreatic cancer, KRAS gene is frequently detected to be mutated at codon 12 and sometimes mutated at codons 13 or 61.	('mutated', 'Var', (86, 93))	('pancreatic cancer', 'Disease', (28, 45))	('pancreatic cancer', 'Disease', 'MESH:D010190', (28, 45))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (28, 45))	('KRAS', 'Gene', (47, 51))	('KRAS', 'Gene', '3845', (47, 51))	('patients', 'Species', '9606', (14, 22))	('mutated', 'Var', (120, 127))
384297	28099906	In the present study, for the oncogene KRAS, we have detected Gly12Arg mutation in pancreatic ACs, Gly12Asp mutation in SCC of pancreas, while no mutation of KRAS has been detected in pancreatic ASCs (Table 3).	('detected', 'Reg', (53, 61))	('pancreatic ASCs', 'Phenotype', 'HP:0001737', (184, 199))	('pancreatic ASCs', 'Disease', (184, 199))	('pancreatic', 'Disease', 'MESH:D010195', (83, 93))	('pancreatic', 'Disease', 'MESH:D010195', (184, 194))	('SCC', 'Phenotype', 'HP:0002860', (120, 123))	('Gly12Asp', 'Mutation', 'rs121913529', (99, 107))	('pancreatic', 'Disease', (83, 93))	('SCC', 'Gene', '6317', (120, 123))	('pancreatic', 'Disease', (184, 194))	('Gly12Arg', 'SUBSTITUTION', 'None', (62, 70))	('KRAS', 'Gene', '3845', (39, 43))	('Gly12Arg', 'Var', (62, 70))	('SCC', 'Gene', (120, 123))	('KRAS', 'Gene', '3845', (158, 162))	('Gly12Asp mutation', 'Var', (99, 116))	('pancreatic ASCs', 'Disease', 'MESH:D010195', (184, 199))	('KRAS', 'Gene', (39, 43))	('KRAS', 'Gene', (158, 162))
384299	28099906	In our analysis, TP53 possessed the same mutation (Pro72Arg) in the three groups.	('Pro72Arg', 'Chemical', '-', (51, 59))	('TP53', 'Gene', '7157', (17, 21))	('TP53', 'Gene', (17, 21))	('Pro72Arg', 'Var', (51, 59))
384301	28099906	SMAD4 has been detected to possess mutations of Pro292Ser and Arg496His in ASCs and SCCs, respectively, and no mutation of SMAD4 was detected in pancreatic ACs (Table 3).	('SCC', 'Gene', '6317', (84, 87))	('pancreatic', 'Disease', (145, 155))	('SMAD4', 'Gene', '4089', (0, 5))	('SMAD4', 'Gene', '4089', (123, 128))	('Arg496His', 'SUBSTITUTION', 'None', (62, 71))	('Pro292Ser', 'Chemical', '-', (48, 57))	('SMAD4', 'Gene', (0, 5))	('Pro292Ser', 'Var', (48, 57))	('Arg496His', 'Var', (62, 71))	('SMAD4', 'Gene', (123, 128))	('SCC', 'Gene', (84, 87))	('SCC', 'Phenotype', 'HP:0002860', (84, 87))	('pancreatic', 'Disease', 'MESH:D010195', (145, 155))
384303	28099906	Pancreatic ACs, ASCs and SCCs shared the common mutation Val2466Ala, while each of them also have some specific mutations (Table 3).	('SCC', 'Gene', (25, 28))	('SCC', 'Phenotype', 'HP:0002860', (25, 28))	('SCC', 'Gene', '6317', (25, 28))	('Val2466Ala', 'SUBSTITUTION', 'None', (57, 67))	('Val2466Ala', 'Var', (57, 67))	('Pancreatic', 'Disease', (0, 10))	('Pancreatic', 'Disease', 'MESH:D010195', (0, 10))
384305	28099906	We detected a common mutation: Arg521Lys of EGFR in all the three types of tissues, while only ACs and ASCs possessed the Leu861Glu mutation (Table 3).	('Leu861Glu', 'Var', (122, 131))	('Arg521Lys', 'Var', (31, 40))	('EGFR', 'Gene', '1956', (44, 48))	('Arg521Lys', 'SUBSTITUTION', 'None', (31, 40))	('EGFR', 'Gene', (44, 48))	('Leu861Glu', 'SUBSTITUTION', 'None', (122, 131))
384306	28099906	Besides the common and specific mutations for the studied biomarkers of pancreatic cancer, we also found some other new specific mutated genes in either pancreatic ACs or SCCs (Table 4, Table 5).	('SCC', 'Gene', (171, 174))	('pancreatic', 'Disease', 'MESH:D010195', (153, 163))	('pancreatic', 'Disease', (72, 82))	('SCC', 'Phenotype', 'HP:0002860', (171, 174))	('pancreatic', 'Disease', (153, 163))	('pancreatic cancer', 'Disease', (72, 89))	('SCC', 'Gene', '6317', (171, 174))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('pancreatic cancer', 'Disease', 'MESH:D010190', (72, 89))	('mutated genes', 'Var', (129, 142))	('pancreatic', 'Disease', 'MESH:D010195', (72, 82))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (72, 89))
384321	28099906	Studies also identified deletion of PTPRD in head and neck SCC.	('PTPRD', 'Gene', (36, 41))	('SCC', 'Gene', (59, 62))	('SCC', 'Phenotype', 'HP:0002860', (59, 62))	('SCC', 'Gene', '6317', (59, 62))	('deletion', 'Var', (24, 32))	('PTPRD', 'Gene', '5789', (36, 41))
384324	28099906	Taking together with previous study, the development and progression of pancreatic SCC could be driven by both specific gene mutations and uncontrolled gene expression network.	('mutations', 'Var', (125, 134))	('men', 'Species', '9606', (48, 51))	('pancreatic SCC', 'Disease', (72, 86))	('pancreatic SCC', 'Disease', 'MESH:D010195', (72, 86))	('SCC', 'Phenotype', 'HP:0002860', (83, 86))
384331	28099906	To the best of our knowledge, our study was the first investigation providing the list of differential mutations in pancreatic AC and SCC, which could provide valuable information for understanding the pathogenesis of pancreatic SCC and for further targeted drug development.	('mutations', 'Var', (103, 112))	('SCC', 'Phenotype', 'HP:0002860', (134, 137))	('SCC', 'Gene', '6317', (134, 137))	('pancreatic', 'Disease', 'MESH:D010195', (218, 228))	('pancreatic', 'Disease', (218, 228))	('pancreatic', 'Disease', 'MESH:D010195', (116, 126))	('SCC', 'Phenotype', 'HP:0002860', (229, 232))	('men', 'Species', '9606', (270, 273))	('SCC', 'Gene', (229, 232))	('pancreatic', 'Disease', (116, 126))	('pancreatic SCC', 'Disease', 'MESH:D010195', (218, 232))	('SCC', 'Gene', '6317', (229, 232))	('pancreatic SCC', 'Disease', (218, 232))	('SCC', 'Gene', (134, 137))
384354	24505469	Classification of Non-Small Cell Lung Cancer Based on Copy Number Alterations Lung cancer is one of the leading causes of cancer mortality worldwide and non-small cell lung cancer (NSCLC) accounts for the most part.	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (153, 179))	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('NSCLC', 'Disease', 'MESH:D002289', (181, 186))	('Non-Small Cell Lung Cancer', 'Disease', (18, 44))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('Lung Cancer', 'Phenotype', 'HP:0100526', (33, 44))	('Non-Small Cell Lung Cancer', 'Phenotype', 'HP:0030358', (18, 44))	('NSCLC', 'Disease', (181, 186))	('non-small cell lung cancer', 'Disease', (153, 179))	('lung cancer', 'Phenotype', 'HP:0100526', (168, 179))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('Small Cell Lung Cancer', 'Phenotype', 'HP:0030357', (22, 44))	('Lung cancer', 'Disease', 'MESH:D008175', (78, 89))	('NSCLC', 'Phenotype', 'HP:0030358', (181, 186))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('Lung cancer', 'Phenotype', 'HP:0100526', (78, 89))	('Lung cancer', 'Disease', (78, 89))	('cancer', 'Disease', (173, 179))	('Cancer', 'Phenotype', 'HP:0002664', (38, 44))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (157, 179))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (153, 179))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('Non-Small Cell Lung Cancer', 'Disease', 'MESH:D002289', (18, 44))	('cancer', 'Disease', (122, 128))	('Copy Number Alterations', 'Var', (54, 77))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('cancer', 'Disease', (83, 89))
384375	24505469	also explored the small-molecule inhibitor of the ALK tyrosine kinase could be used as the efficacious therapy in advanced ALK-positive tumors in an early-phase clinical trial.	('tumors', 'Disease', (136, 142))	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('tumors', 'Disease', 'MESH:D009369', (136, 142))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('small-molecule', 'Var', (18, 32))
384383	24505469	We used the copy number alterations data from the non-small cell lung cancer study of Huang et al..	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (50, 76))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('non-small cell lung cancer', 'Disease', (50, 76))	('lung cancer', 'Phenotype', 'HP:0100526', (65, 76))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (54, 76))	('copy number alterations', 'Var', (12, 35))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (50, 76))
384391	24505469	It is reported Wnt signaling pathway is activated during the carcinogenesis of NSCLC, and inhibition of Wnt-2-mediated signaling could induce non-small-cell lung cancer cells apoptosis.	('Wnt', 'Gene', (15, 18))	('Wnt', 'Gene', '7472', (15, 18))	('NSCLC', 'Disease', 'MESH:D002289', (79, 84))	('Wnt-2', 'Gene', (104, 109))	('lung cancer', 'Phenotype', 'HP:0100526', (157, 168))	('Wnt-2', 'Gene', '7472', (104, 109))	('NSCLC', 'Phenotype', 'HP:0030358', (79, 84))	('induce', 'PosReg', (135, 141))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('Wnt', 'Gene', '7472', (104, 107))	('inhibition', 'Var', (90, 100))	('cell lung cancer', 'Disease', (152, 168))	('Wnt', 'Gene', (104, 107))	('NSCLC', 'Disease', (79, 84))	('cell lung cancer', 'Disease', 'MESH:D008175', (152, 168))
384393	24505469	It is reported copy number gain in region 3q26 and in region 8p12 seem to be more common in squamous histology compared with adenocarcinoma.	('squamous histology', 'Disease', (92, 110))	('copy number gain', 'Var', (15, 31))	('adenocarcinoma', 'Disease', (125, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('common', 'Reg', (82, 88))	('adenocarcinoma', 'Disease', 'MESH:D000230', (125, 139))
384394	24505469	The analysis of our result shows that including these two regions, copy number alterations of 2q34, 10p15, 18q11, 8p23, 3p21, 3q27, 22q12, Xq13, 2q36, 10p11, 10p12 also have the significance in discrimination between SCC and ACA, and deserved further researches on them (Table 2).	('2q34', 'Var', (94, 98))	('p15', 'Gene', (102, 105))	('3q27', 'Var', (126, 130))	('SCC', 'Gene', (217, 220))	('ACA', 'Disease', (225, 228))	('p11', 'Gene', (153, 156))	('p15', 'Gene', '1030', (102, 105))	('SCC', 'Phenotype', 'HP:0002860', (217, 220))	('3p21', 'Var', (120, 124))	('SCC', 'Gene', '6317', (217, 220))	('Xq13', 'Var', (139, 143))	('8p23', 'Var', (114, 118))	('significance', 'Reg', (178, 190))	('p11', 'Gene', '8909', (153, 156))	('2q36', 'Var', (145, 149))
384411	24505469	A mutation in EphA2 (G391R) was identified in two of 28 squamous cell lung cancers (7%), but not in any adenocarcinomas or large-cell lung carcinomas.	('G391R', 'Mutation', 'rs34192549', (21, 26))	('squamous cell lung cancers', 'Disease', (56, 82))	('EphA2', 'Gene', '1969', (14, 19))	('large-cell lung carcinomas', 'Disease', 'MESH:D018287', (123, 149))	('cancers', 'Phenotype', 'HP:0002664', (75, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (139, 148))	('adenocarcinomas', 'Disease', 'MESH:D000230', (104, 119))	('G391R', 'Var', (21, 26))	('carcinomas', 'Phenotype', 'HP:0030731', (139, 149))	('lung cancers', 'Phenotype', 'HP:0100526', (70, 82))	('large-cell lung carcinomas', 'Disease', (123, 149))	('lung cancer', 'Phenotype', 'HP:0100526', (70, 81))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('adenocarcinomas', 'Disease', (104, 119))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('carcinomas', 'Phenotype', 'HP:0030731', (109, 119))	('squamous cell lung cancers', 'Disease', 'MESH:D002294', (56, 82))	('EphA2', 'Gene', (14, 19))
384415	24505469	Recently genome-wide association study (GWAS) of lung cancer in the Chinese population revealed that chromosome 5q32 (rs2895680 in PPP2R2B-STK32A-DPYSL3, P = 6.60x10-9) was lung cancer susceptibility loci and interacted with smoking dose.	('lung cancer', 'Disease', 'MESH:D008175', (49, 60))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('DPYSL3', 'Gene', '1809', (146, 152))	('lung cancer', 'Disease', 'MESH:D008175', (173, 184))	('PPP2R2B', 'Gene', '5521', (131, 138))	('DPYSL3', 'Gene', (146, 152))	('lung cancer', 'Disease', (49, 60))	('rs2895680', 'Mutation', 'rs2895680', (118, 127))	('lung cancer', 'Phenotype', 'HP:0100526', (49, 60))	('STK32A', 'Gene', (139, 145))	('rs2895680', 'Var', (118, 127))	('PPP2R2B', 'Gene', (131, 138))	('STK32A', 'Gene', '202374', (139, 145))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('lung cancer', 'Disease', (173, 184))	('lung cancer', 'Phenotype', 'HP:0100526', (173, 184))
384423	24505469	It is located at chromosome 3q26 and high-level amplification of SOX2 have been reported in approximately 20% of lung squamous cell carcinomas.	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (118, 142))	('SOX2', 'Gene', '6657', (65, 69))	('high-level amplification', 'Var', (37, 61))	('SOX2', 'Gene', (65, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (118, 141))	('carcinomas', 'Phenotype', 'HP:0030731', (132, 142))	('lung squamous cell carcinomas', 'Disease', (113, 142))	('reported', 'Reg', (80, 88))	('lung squamous cell carcinomas', 'Disease', 'MESH:D002294', (113, 142))
384440	24505469	In this study, we constructed a classifier based on copy number alterations (CNA) to distinguish two subgroups of NSCLC.	('copy number alterations', 'Var', (52, 75))	('NSCLC', 'Phenotype', 'HP:0030358', (114, 119))	('NSCLC', 'Disease', 'MESH:D002289', (114, 119))	('NSCLC', 'Disease', (114, 119))
384505	33375499	The results of a subgroup analysis in the JCOG9907 study showed that preoperative chemotherapy was more effective in clinical stage II or T1-2 esophageal cancer patients than in stage III or T3 patients, i.e., in patients with relatively early-stage disease.	('patients', 'Species', '9606', (194, 202))	('esophageal cancer', 'Disease', 'MESH:D004938', (143, 160))	('patients', 'Species', '9606', (161, 169))	('patients', 'Species', '9606', (213, 221))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('T1-2', 'Var', (138, 142))	('esophageal cancer', 'Disease', (143, 160))
384542	33375499	In 1999, a phase III trial conducted in the US in patients with T1-3N0-1M0 ESCC showed that CRT with CF concurrently with 50.4 Gy radiation yielded a significantly improved 5-year OS of 26%, as compared to 0% for radiation alone.	('patients', 'Species', '9606', (50, 58))	('improved', 'PosReg', (164, 172))	('T1-3N0-1M0', 'Var', (64, 74))	('CF', 'Chemical', '-', (101, 103))	('CRT', 'Gene', '799', (92, 95))	('CRT', 'Gene', (92, 95))
384572	29368602	LncRNAs, which are located in the nucleus and cytoplasm, mainly exert their function via epigenetic modification, transcriptional control and translational regulation.	('ncRNA', 'Gene', '220202', (1, 6))	('epigenetic modification', 'Var', (89, 112))	('exert', 'Reg', (64, 69))	('translational', 'MPA', (142, 155))	('ncRNA', 'Gene', (1, 6))
384592	29368602	To date, the dysregulated expression and involvement of lncRNAs have been reported in diverse cancers, including HNC, lung cancer, breast cancer, colorectal cancer (CRC), and esophageal squamous cell carcinoma (ESCC).	('cancers', 'Disease', 'MESH:D009369', (94, 101))	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('CRC', 'Phenotype', 'HP:0003003', (165, 168))	('carcinoma', 'Phenotype', 'HP:0030731', (200, 209))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('lung cancer', 'Disease', (118, 129))	('reported', 'Reg', (74, 82))	('HNC', 'Disease', (113, 116))	('expression', 'MPA', (26, 36))	('esophageal squamous cell carcinoma', 'Disease', (175, 209))	('colorectal cancer', 'Phenotype', 'HP:0003003', (146, 163))	('HNC', 'Phenotype', 'HP:0012288', (113, 116))	('cancers', 'Phenotype', 'HP:0002664', (94, 101))	('breast cancer', 'Phenotype', 'HP:0003002', (131, 144))	('cancers', 'Disease', (94, 101))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (186, 209))	('lung cancer', 'Disease', 'MESH:D008175', (118, 129))	('ncRNA', 'Gene', (57, 62))	('ncRNA', 'Gene', '220202', (57, 62))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('breast cancer', 'Disease', 'MESH:D001943', (131, 144))	('lung cancer', 'Phenotype', 'HP:0100526', (118, 129))	('breast cancer', 'Disease', (131, 144))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (175, 209))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('colorectal cancer', 'Disease', 'MESH:D015179', (146, 163))	('colorectal cancer', 'Disease', (146, 163))	('dysregulated', 'Var', (13, 25))
384623	29368602	Zhou and the colleagues, by employing siRNA to inhibit MALAT1 in HNC, indicated that the EMT, invasion and migration of HNC cells were attenuated possibly by inactivation of the beta-catenin and nuclear factor-kappaB (NF-kappaB) pathways, which are potent regulators of EMT; furthermore, the in vivo study demonstrated the suppression of EMT markers, N-cadherin and Vimentin, in MALAT1 knockdown HNC tumors.	('invasion', 'CPA', (94, 102))	('Vimentin', 'Gene', '7431', (366, 374))	('knockdown', 'Var', (386, 395))	('Vimentin', 'Gene', (366, 374))	('HNC tumors', 'Disease', 'MESH:D009369', (396, 406))	('attenuated', 'NegReg', (135, 145))	('MALAT1', 'Gene', (55, 61))	('N-cadherin', 'Gene', (351, 361))	('MALAT1', 'Gene', (379, 385))	('N-cadherin', 'Gene', '1000', (351, 361))	('HNC', 'Phenotype', 'HP:0012288', (65, 68))	('migration', 'CPA', (107, 116))	('HNC tumors', 'Disease', (396, 406))	('MALAT1', 'Gene', '378938', (55, 61))	('MALAT1', 'Gene', '378938', (379, 385))	('suppression', 'NegReg', (323, 334))	('tumor', 'Phenotype', 'HP:0002664', (400, 405))	('HNC', 'Phenotype', 'HP:0012288', (120, 123))	('beta-catenin', 'Gene', (178, 190))	('tumors', 'Phenotype', 'HP:0002664', (400, 406))	('EMT', 'CPA', (89, 92))	('inactivation', 'NegReg', (158, 170))	('beta-catenin', 'Gene', '1499', (178, 190))	('NF-kappaB', 'Gene', (218, 227))	('HNC', 'Phenotype', 'HP:0012288', (396, 399))	('NF-kappaB', 'Gene', '4790', (218, 227))
384627	29368602	Fang et al., with the same in vivo result, showed that MALAT1 knockdown might impair the migration of TSCC.	('MALAT1', 'Gene', '378938', (55, 61))	('MALAT1', 'Gene', (55, 61))	('migration of TSCC', 'CPA', (89, 106))	('impair', 'NegReg', (78, 84))	('knockdown', 'Var', (62, 71))
384629	29368602	Additionally, an animal study showed that overexpressing SPRR2A could impair distant metastasis, implying the pivotal role of SPRR2A in MALAT-1-mediated metastasis of TSCC.	('SPRR2A', 'Gene', (57, 63))	('SPRR2A', 'Gene', '6700', (126, 132))	('MALAT-1', 'Gene', '378938', (136, 143))	('MALAT-1', 'Gene', (136, 143))	('SPRR2A', 'Gene', (126, 132))	('impair', 'NegReg', (70, 76))	('distant metastasis', 'CPA', (77, 95))	('overexpressing', 'Var', (42, 56))	('SPRR2A', 'Gene', '6700', (57, 63))
384635	29368602	Further investigation that IQGAP1 knockdown could reverse its invasion phenotype pinpoints IQGAP1 as a downstream target of MALAT1.	('IQGAP1', 'Gene', (27, 33))	('MALAT1', 'Gene', '378938', (124, 130))	('MALAT1', 'Gene', (124, 130))	('IQGAP1', 'Gene', '8826', (91, 97))	('IQGAP1', 'Gene', (91, 97))	('knockdown', 'Var', (34, 43))	('IQGAP1', 'Gene', '8826', (27, 33))
384644	29368602	Their further data suggested that HOTAIR contributed to EMT by decreasing E-cadherin, the speculated mechanism of which is that HOTAIR could regulate the binding of the enhancer of zeste homolog 2 (EZH2), as well as trimethylation of lysine 27 in histone 3 (H3K27me3) to the promoter region of E-cadherin, thus enhancing the metastatic ability.	('enhancing', 'PosReg', (311, 320))	('enhancer of zeste homolog 2', 'Gene', '2146', (169, 196))	('metastatic ability', 'CPA', (325, 343))	('HOTAIR', 'Gene', (34, 40))	('regulate', 'Reg', (141, 149))	('trimethylation', 'Var', (216, 230))	('binding', 'Interaction', (154, 161))	('HOTAIR', 'Gene', '100124700', (128, 134))	('H3K27me3', 'Protein', (258, 266))	('enhancer of zeste homolog 2', 'Gene', (169, 196))	('EZH2', 'Gene', '2146', (198, 202))	('EZH2', 'Gene', (198, 202))	('lysine', 'Chemical', 'MESH:D008239', (234, 240))	('HOTAIR', 'Gene', (128, 134))	('E-cadherin', 'Gene', (74, 84))	('E-cadherin', 'Gene', '999', (74, 84))	('E-cadherin', 'Gene', (294, 304))	('E-cadherin', 'Gene', '999', (294, 304))	('decreasing', 'NegReg', (63, 73))	('HOTAIR', 'Gene', '100124700', (34, 40))
384645	29368602	Moreover, a study regarding laryngeal squamous cell carcinoma (LSCC) demonstrated that HOTAIR knockdown significantly decreases the invasive ability of cancer cells.	('knockdown', 'Var', (94, 103))	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('carcinoma', 'Phenotype', 'HP:0030731', (52, 61))	('HOTAIR', 'Gene', (87, 93))	('HOTAIR', 'Gene', '100124700', (87, 93))	('decreases', 'NegReg', (118, 127))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (38, 61))	('squamous cell carcinoma', 'Disease', (38, 61))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (38, 61))
384646	29368602	Further data implied that HOTAIR knockdown could attenuate the methylation level of phosphatase and tensin homolog deleted on chromosome ten (PTEN) via epigenetic modification, revealing a novel mechanism by which HOTAIR regulates LSCC invasion.	('PTEN', 'Gene', (142, 146))	('methylation level', 'MPA', (63, 80))	('HOTAIR', 'Gene', (214, 220))	('PTEN', 'Gene', '5728', (142, 146))	('knockdown', 'Var', (33, 42))	('HOTAIR', 'Gene', '100124700', (214, 220))	('HOTAIR', 'Gene', (26, 32))	('HOTAIR', 'Gene', '100124700', (26, 32))	('epigenetic modification', 'MPA', (152, 175))	('attenuate', 'NegReg', (49, 58))	('regulates', 'Reg', (221, 230))	('LSCC', 'Disease', (231, 235))
384655	29368602	After observing the positive correlation of UCA1 with the LNM of endometrial cancer, scholars have confirmed that the deficiency in UCA1 could reduce migration and invasion.	('UCA1', 'Gene', (132, 136))	('endometrial cancer', 'Disease', (65, 83))	('UCA1', 'Gene', '652995', (44, 48))	('reduce', 'NegReg', (143, 149))	('endometrial cancer', 'Phenotype', 'HP:0012114', (65, 83))	('UCA1', 'Gene', (44, 48))	('endometrial cancer', 'Disease', 'MESH:D016889', (65, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('deficiency', 'Var', (118, 128))	('UCA1', 'Gene', '652995', (132, 136))
384657	29368602	Beyond that, UCA1 silencing attenuates the migrating ability of melanoma cells.	('silencing', 'Var', (18, 27))	('attenuates', 'NegReg', (28, 38))	('melanoma', 'Phenotype', 'HP:0002861', (64, 72))	('melanoma', 'Disease', (64, 72))	('melanoma', 'Disease', 'MESH:D008545', (64, 72))	('UCA1', 'Gene', '652995', (13, 17))	('UCA1', 'Gene', (13, 17))
384659	29368602	As a lncRNA dysregulated in TSCC, UCA1 is closely related to its LNM, and its silencing markedly dampens cancer invasiveness.	('cancer invasiveness', 'Disease', 'MESH:D009362', (105, 124))	('dampens', 'NegReg', (97, 104))	('ncRNA', 'Gene', (6, 11))	('cancer invasiveness', 'Disease', (105, 124))	('silencing', 'Var', (78, 87))	('UCA1', 'Gene', '652995', (34, 38))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('UCA1', 'Gene', (34, 38))	('ncRNA', 'Gene', '220202', (6, 11))
384678	29368602	In addition, inhibition of HIT000218960 repressed migration and invasion of PTC possibly by downregulating high mobility group AT-hook 2 (HMGA2) mRNA level.	('PTC', 'Phenotype', 'HP:0002895', (76, 79))	('HIT000218960', 'Var', (27, 39))	('invasion', 'CPA', (64, 72))	('high mobility group AT-hook 2', 'Gene', (107, 136))	('inhibition', 'Var', (13, 23))	('migration', 'CPA', (50, 59))	('HMGA2', 'Gene', '8091', (138, 143))	('downregulating', 'NegReg', (92, 106))	('PTC', 'Gene', '8030', (76, 79))	('high mobility group AT-hook 2', 'Gene', '8091', (107, 136))	('HMGA2', 'Gene', (138, 143))	('PTC', 'Gene', (76, 79))
384680	29368602	Considering the other lncRNAs as a reference, the detailed mechanism through which HMGA2 is regulated by HIT000218960 is anticipated to be illuminated in the future.	('ncRNA', 'Gene', (23, 28))	('ncRNA', 'Gene', '220202', (23, 28))	('HMGA2', 'Gene', '8091', (83, 88))	('HMGA2', 'Gene', (83, 88))	('HIT000218960', 'Var', (105, 117))
384682	29368602	Additionally, knocking down ENST00000470135 could remarkably repress the migration and invasion of NPC cells.	('knocking down', 'Var', (14, 27))	('NPC', 'Phenotype', 'HP:0100630', (99, 102))	('NPC', 'Gene', (99, 102))	('ENST00000470135', 'Gene', (28, 43))	('NPC', 'Gene', '4864', (99, 102))	('repress', 'NegReg', (61, 68))
384687	29368602	Additionally, a lncRNA microarray based on LSCC samples suggested the upregulation of RP11-169D4.1-001, which was subsequently observed to be positively associated with the LNM of LSCC.	('upregulation', 'PosReg', (70, 82))	('LNM', 'Disease', (173, 176))	('RP11-169D4.1-001', 'Var', (86, 102))	('associated', 'Reg', (153, 163))	('ncRNA', 'Gene', (17, 22))	('LSCC', 'Disease', (180, 184))	('ncRNA', 'Gene', '220202', (17, 22))
384696	29368602	Moreover, miR-103 and miR-107 were demonstrated to reverse the effect by degrading NKILA, thereby enabling NF-kappaB activation and promoting metastasis.	('miR-103', 'Var', (10, 17))	('NKILA', 'Gene', '105416157', (83, 88))	('degrading', 'NegReg', (73, 82))	('miR-107', 'Gene', '406901', (22, 29))	('metastasis', 'CPA', (142, 152))	('activation', 'MPA', (117, 127))	('promoting', 'PosReg', (132, 141))	('miR-103', 'Chemical', '-', (10, 17))	('miR-107', 'Gene', (22, 29))	('NF-kappaB', 'Gene', '4790', (107, 116))	('NKILA', 'Gene', (83, 88))	('enabling', 'PosReg', (98, 106))	('NF-kappaB', 'Gene', (107, 116))
384701	29368602	In agreement, animal investigations also showed that NKILA knockdown contributed to more lung metastasis of TSCC.	('NKILA', 'Gene', (53, 58))	('TSCC', 'Disease', (108, 112))	('lung metastasis', 'CPA', (89, 104))	('NKILA', 'Gene', '105416157', (53, 58))	('knockdown', 'Var', (59, 68))	('more', 'PosReg', (84, 88))
384703	29368602	Based on microarray analysis, NONHSAT037832 was detected as a novel lncRNA remarkably downregulated in PTC, next implied to function as an inhibitor in the LNM of PTC.	('PTC', 'Phenotype', 'HP:0002895', (103, 106))	('NONHSAT037832', 'Var', (30, 43))	('PTC', 'Phenotype', 'HP:0002895', (163, 166))	('ncRNA', 'Gene', (69, 74))	('downregulated', 'NegReg', (86, 99))	('PTC', 'Gene', '8030', (103, 106))	('PTC', 'Gene', '8030', (163, 166))	('PTC', 'Gene', (163, 166))	('PTC', 'Gene', (103, 106))	('ncRNA', 'Gene', '220202', (69, 74))
384711	29368602	In addition, FOXC1 mRNA was remarkably reduced after the knockdown of FOXCUT, implying that FOXC1 expression is modulated by FOXCUT.	('FOXCUT', 'Gene', (125, 131))	('FOXC1', 'Gene', '2296', (13, 18))	('mRNA', 'MPA', (19, 23))	('FOXCUT', 'Gene', (70, 76))	('knockdown', 'Var', (57, 66))	('FOXCUT', 'Gene', '101927703', (125, 131))	('FOXC1', 'Gene', '2296', (92, 97))	('FOXCUT', 'Gene', '101927703', (70, 76))	('FOXC1', 'Gene', (92, 97))	('reduced', 'NegReg', (39, 46))	('FOXC1', 'Gene', (13, 18))
384712	29368602	Of note, the knockdown of FOXCUT or FOXC1 could suppress the migration of OSCC cells, possibly mediated by the reduction of the MMP2, MMP7, and MMP9 levels.	('reduction', 'NegReg', (111, 120))	('suppress', 'NegReg', (48, 56))	('MMP9', 'Gene', (144, 148))	('FOXCUT', 'Gene', '101927703', (26, 32))	('FOXC1', 'Gene', '2296', (36, 41))	('MMP9', 'Gene', '4318', (144, 148))	('MMP7', 'Gene', (134, 138))	('migration of OSCC cells', 'CPA', (61, 84))	('MMP2', 'Gene', (128, 132))	('FOXC1', 'Gene', (36, 41))	('MMP7', 'Gene', '4316', (134, 138))	('FOXCUT', 'Gene', (26, 32))	('MMP2', 'Gene', '4313', (128, 132))	('knockdown', 'Var', (13, 22))
384714	29368602	An in vitro study suggested that the FOXCUT-FOXC1 pair interacted with each other, and the silencing of FOXCUT inhibited the migration of NPC cells, along with the decrease in the MMP7, MMP9 and beta-catenin levels.	('NPC', 'Gene', (138, 141))	('FOXC1', 'Gene', '2296', (44, 49))	('NPC', 'Phenotype', 'HP:0100630', (138, 141))	('beta-catenin', 'Gene', '1499', (195, 207))	('FOXCUT', 'Gene', (104, 110))	('FOXCUT', 'Gene', '101927703', (37, 43))	('MMP9', 'Gene', (186, 190))	('NPC', 'Gene', '4864', (138, 141))	('FOXCUT', 'Gene', (37, 43))	('decrease', 'NegReg', (164, 172))	('MMP9', 'Gene', '4318', (186, 190))	('FOXCUT', 'Gene', '101927703', (104, 110))	('inhibited', 'NegReg', (111, 120))	('silencing', 'Var', (91, 100))	('FOXC1', 'Gene', (44, 49))	('MMP7', 'Gene', (180, 184))	('beta-catenin', 'Gene', (195, 207))	('MMP7', 'Gene', '4316', (180, 184))
384727	29368602	More importantly, the investigation has demonstrated the influence of H19 silencing on impairing the migration and invasion of LSCC; specifically, H19 might sponge miR-148a-3p, thereby releasing the DNA methyltransferase enzyme (DNMT1) which could be targeted by miR-148a-3p, and carrying out its function.	('H19', 'Gene', (147, 150))	('impairing', 'NegReg', (87, 96))	('migration', 'CPA', (101, 110))	('DNMT1', 'Gene', (229, 234))	('H19', 'Gene', '283120', (70, 73))	('miR-148a-3p', 'Var', (263, 274))	('DNMT1', 'Gene', '1786', (229, 234))	('H19', 'Gene', (70, 73))	('silencing', 'Var', (74, 83))	('carrying', 'Reg', (280, 288))	('H19', 'Gene', '283120', (147, 150))	('invasion', 'CPA', (115, 123))	('releasing', 'PosReg', (185, 194))
384736	29368602	LncRNA-ROR deficiency contributes to the suppressed tumor invasion with reduced expression levels of the EMT marker.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('reduced', 'NegReg', (72, 79))	('ROR', 'Gene', '100885779', (7, 10))	('ncRNA', 'Gene', '220202', (1, 6))	('tumor', 'Disease', (52, 57))	('deficiency', 'Var', (11, 21))	('suppressed', 'NegReg', (41, 51))	('expression levels', 'MPA', (80, 97))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('ncRNA', 'Gene', (1, 6))	('ROR', 'Gene', (7, 10))
384740	29368602	Additionally, silencing of LINC00673 could remarkably repress the invasive and migratory abilities of TSCC, similar to another finding in a GC study.	('silencing', 'Var', (14, 23))	('LINC00673', 'Gene', (27, 36))	('repress', 'NegReg', (54, 61))	('LINC00673', 'Gene', '100499467', (27, 36))	('GC', 'Phenotype', 'HP:0012126', (140, 142))
384741	29368602	Hepatocyte nuclear factor 1A antisense RNA (HNF1A-AS) is another lncRNA detected to be elevated in NPC, the knockdown of which could impair the migration of NPC cells.	('NPC', 'Gene', '4864', (157, 160))	('HNF1A', 'Gene', '6927', (44, 49))	('knockdown', 'Var', (108, 117))	('impair', 'NegReg', (133, 139))	('ncRNA', 'Gene', '220202', (66, 71))	('NPC', 'Phenotype', 'HP:0100630', (99, 102))	('HNF1A', 'Gene', (44, 49))	('NPC', 'Gene', (99, 102))	('NPC', 'Phenotype', 'HP:0100630', (157, 160))	('ncRNA', 'Gene', (66, 71))	('NPC', 'Gene', '4864', (99, 102))	('NPC', 'Gene', (157, 160))	('elevated', 'PosReg', (87, 95))
384744	29368602	Moreover, transfection of both lncRNAs into HNC cells reduced its migration significantly because these two lncRNAs might lead to EMT alterations.	('ncRNA', 'Gene', (32, 37))	('migration', 'CPA', (66, 75))	('EMT alterations', 'CPA', (130, 145))	('HNC', 'Phenotype', 'HP:0012288', (44, 47))	('ncRNA', 'Gene', (109, 114))	('lead to', 'Reg', (122, 129))	('ncRNA', 'Gene', '220202', (32, 37))	('reduced', 'NegReg', (54, 61))	('ncRNA', 'Gene', '220202', (109, 114))	('transfection', 'Var', (10, 22))
384752	29368602	CD8+ T cells among the tumor-infiltrating lymphocytes (TILs) express significantly higher levels of immune checkpoint receptors such as programmed cell death 1 (PD-1) than those in the peripheral blood.	('programmed cell', 'MPA', (136, 151))	('PD-1', 'Gene', (161, 165))	('CD8+', 'Var', (0, 4))	('PD-1', 'Gene', '5133', (161, 165))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('levels of', 'MPA', (90, 99))	('tumor', 'Disease', (23, 28))	('higher', 'PosReg', (83, 89))
384759	29368602	Although downregulated in lung cancer due to the hypermethylation of its promoter, lncAGER exhibits the anti-tumor function by first targeting miR-185, thereby increasing the advanced glycosylation end-product specific receptor (AGER) level in lung cancer cells, which is an important innate immune pattern-recognition receptor, and ultimately promoting the anti-tumor effect of human monocytes.	('increasing', 'PosReg', (160, 170))	('hypermethylation', 'Var', (49, 65))	('lung cancer', 'Disease', 'MESH:D008175', (26, 37))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('advanced glycosylation end-product specific receptor', 'Gene', '177', (175, 227))	('tumor', 'Phenotype', 'HP:0002664', (363, 368))	('AGER', 'Gene', (229, 233))	('downregulated', 'NegReg', (9, 22))	('cancer', 'Phenotype', 'HP:0002664', (249, 255))	('miR-185', 'Gene', '406961', (143, 150))	('lung cancer', 'Phenotype', 'HP:0100526', (26, 37))	('AGER', 'Gene', (86, 90))	('lung cancer', 'Disease', (244, 255))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('AGER', 'Gene', '177', (229, 233))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('promoting', 'PosReg', (344, 353))	('human', 'Species', '9606', (379, 384))	('tumor', 'Disease', (363, 368))	('AGER', 'Gene', '177', (86, 90))	('lung cancer', 'Disease', (26, 37))	('lung cancer', 'Disease', 'MESH:D008175', (244, 255))	('miR-185', 'Gene', (143, 150))	('tumor', 'Disease', 'MESH:D009369', (363, 368))	('lung cancer', 'Phenotype', 'HP:0100526', (244, 255))	('targeting', 'NegReg', (133, 142))	('tumor', 'Disease', (109, 114))
384762	29368602	Based on previous findings, there are three main mechanisms that are responsible for the aberrant expression of lncRNA in HNC, which are miRNAs, functional proteins such as RNA binding proteins (RBPs), NF-kappaB and TP53, and genetic changes such as genomic mutation and epigenetic alteration.	('TP53', 'Gene', (216, 220))	('aberrant', 'Var', (89, 97))	('ncRNA', 'Gene', (113, 118))	('RBP', 'Gene', (195, 198))	('RBP', 'Gene', '57794', (195, 198))	('NF-kappaB', 'Gene', '4790', (202, 211))	('TP53', 'Gene', '7157', (216, 220))	('NF-kappaB', 'Gene', (202, 211))	('genomic mutation', 'Var', (250, 266))	('HNC', 'Gene', (122, 125))	('epigenetic alteration', 'Var', (271, 292))	('ncRNA', 'Gene', '220202', (113, 118))	('HNC', 'Phenotype', 'HP:0012288', (122, 125))
384764	29368602	Specifically, lncRNA papillary thyroid carcinoma susceptibility candidate 3 (PTCSC3) could be remarkably decreased by the overexpression of miR-574-5p in thyroid carcinoma; additionally, in TSCC, miR-26a could upregulate the lncRNA maternally expressed gene 3 (MEG3) by binding to the DNA methyltransferase 3B transcript.	('maternally expressed gene 3', 'Gene', '55384', (232, 259))	('ncRNA', 'Gene', (226, 231))	('PTCSC3', 'Gene', '100886964', (77, 83))	('ncRNA', 'Gene', '220202', (226, 231))	('decreased', 'NegReg', (105, 114))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (31, 48))	('miR-574-5p', 'Var', (140, 150))	('miR-26a', 'Gene', (196, 203))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (154, 171))	('carcinoma', 'Phenotype', 'HP:0030731', (39, 48))	('thyroid carcinoma', 'Disease', (154, 171))	('miR-26a', 'Gene', '407015', (196, 203))	('MEG3', 'Gene', (261, 265))	('papillary thyroid carcinoma', 'Phenotype', 'HP:0002895', (21, 48))	('PTC', 'Phenotype', 'HP:0002895', (77, 80))	('DNA methyltransferase 3B', 'Gene', (285, 309))	('papillary thyroid carcinoma', 'Disease', (21, 48))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (154, 171))	('upregulate', 'PosReg', (210, 220))	('PTCSC3', 'Gene', (77, 83))	('binding', 'Interaction', (270, 277))	('DNA methyltransferase 3B', 'Gene', '1789', (285, 309))	('papillary thyroid carcinoma', 'Disease', 'MESH:D000077273', (21, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (162, 171))	('ncRNA', 'Gene', (15, 20))	('MEG3', 'Gene', '55384', (261, 265))	('ncRNA', 'Gene', '220202', (15, 20))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (31, 48))	('maternally expressed gene 3', 'Gene', (232, 259))
384769	29368602	As another representative of functional protein, TP53 could directly upregulate lncRNA LOC401317 in NPC cells, thereby suppressing tumor growth.Third, genetic changes such as single-nucleotide polymorphisms (SNPs) or epigenetic alterations within the non-coding genome could markedly affect the transcription of lncRNA; for instance, in PTC, the polymorphism of rs944289 in 14q13.3 could reduce the level of lncRNA PTCSC3 by abolishing the binding domain of CCAAT/enhancer binding proteins alpha and beta and subsequently inhibiting the activation of the PTCSC3 promoter.	('PTC', 'Phenotype', 'HP:0002895', (337, 340))	('PTC', 'Gene', '8030', (555, 558))	('TP53', 'Gene', '7157', (49, 53))	('ncRNA', 'Gene', (409, 414))	('reduce', 'NegReg', (388, 394))	('tumor', 'Disease', (131, 136))	('affect', 'Reg', (284, 290))	('PTC', 'Gene', (415, 418))	('ncRNA', 'Gene', (313, 318))	('ncRNA', 'Gene', '220202', (409, 414))	('PTC', 'Phenotype', 'HP:0002895', (415, 418))	('rs944289', 'Mutation', 'rs944289', (362, 370))	('polymorphism', 'Var', (346, 358))	('NPC', 'Gene', (100, 103))	('ncRNA', 'Gene', '220202', (313, 318))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('PTCSC3', 'Gene', (415, 421))	('PTC', 'Gene', (555, 558))	('binding', 'Interaction', (440, 447))	('PTC', 'Phenotype', 'HP:0002895', (555, 558))	('activation', 'MPA', (537, 547))	('PTCSC3', 'Gene', (555, 561))	('LOC401317', 'Gene', (87, 96))	('NPC', 'Gene', '4864', (100, 103))	('ncRNA', 'Gene', (81, 86))	('TP53', 'Gene', (49, 53))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('LOC401317', 'Gene', '401317', (87, 96))	('ncRNA', 'Gene', '220202', (81, 86))	('PTC', 'Gene', '8030', (337, 340))	('PTCSC3', 'Gene', '100886964', (415, 421))	('abolishing', 'NegReg', (425, 435))	('PTCSC3', 'Gene', '100886964', (555, 561))	('PTC', 'Gene', '8030', (415, 418))	('inhibiting', 'NegReg', (522, 532))	('beta', 'Protein', (500, 504))	('NPC', 'Phenotype', 'HP:0100630', (100, 103))	('PTC', 'Gene', (337, 340))
384770	29368602	Additionally, the silencing of lncRNA H19 in well-differentiated NPC cells is attributed to the epigenetic alteration, namely, hypermethylation of the H19 promoter region.	('silencing', 'NegReg', (18, 27))	('NPC', 'Gene', (65, 68))	('H19', 'Gene', '283120', (38, 41))	('ncRNA', 'Gene', (32, 37))	('H19', 'Gene', (151, 154))	('H19', 'Gene', (38, 41))	('NPC', 'Gene', '4864', (65, 68))	('ncRNA', 'Gene', '220202', (32, 37))	('hypermethylation', 'Var', (127, 143))	('NPC', 'Phenotype', 'HP:0100630', (65, 68))	('H19', 'Gene', '283120', (151, 154))
384771	29368602	Overall, the aberrant expression of lncRNAs in HNC is mainly controlled by the above three upstream regulators, and more upstream modulators are required to be uncovered.	('controlled', 'Reg', (61, 71))	('ncRNA', 'Gene', (37, 42))	('ncRNA', 'Gene', '220202', (37, 42))	('HNC', 'Phenotype', 'HP:0012288', (47, 50))	('expression', 'MPA', (22, 32))	('HNC', 'Disease', (47, 50))	('aberrant', 'Var', (13, 21))
384784	29368602	One good example of its preclinical study proposed that ASO of MALAT1 could inhibit lung cancer metastasis in vivo significantly.	('lung cancer', 'Phenotype', 'HP:0100526', (84, 95))	('inhibit', 'NegReg', (76, 83))	('MALAT1', 'Gene', '378938', (63, 69))	('MALAT1', 'Gene', (63, 69))	('lung cancer metastasis', 'Disease', 'MESH:D009362', (84, 106))	('lung cancer metastasis', 'Disease', (84, 106))	('ASO', 'Var', (56, 59))	('clinical', 'Species', '191496', (27, 35))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
384785	29368602	CRISPR/Cas9, as a relatively novel and efficient genome editing tool, has shed light on a novel way to edit lncRNA expression, while its specificity and efficacy remain to be further evaluated.	('ncRNA', 'Gene', '220202', (109, 114))	('edit', 'Var', (103, 107))	('ncRNA', 'Gene', (109, 114))
384787	29368602	In addition, small-molecule modulators involved in interrupting the lncRNA-protein interaction display high potential to target the lncRNA specifically, reducing its off-target effects.	('ncRNA', 'Gene', (133, 138))	('small-molecule', 'Var', (13, 27))	('ncRNA', 'Gene', '220202', (133, 138))	('modulators', 'Var', (28, 38))	('off-target effects', 'MPA', (166, 184))	('ncRNA', 'Gene', (69, 74))	('ncRNA', 'Gene', '220202', (69, 74))
384834	33244783	The secondary Abs were goat peroxidase-conjugated anti-rabbit IgG (#L3012; Signalway Antibody) and goat peroxidase-conjugated anti-mouse IgG (#AP124P; Millipore).	('mouse', 'Species', '10090', (131, 136))	('#AP124P;', 'Var', (142, 150))	('#L3012', 'Var', (67, 73))
384846	33244783	Pyruvic acid is converted to lactic acid using NADH (reduced form) generated by glycolysis, and NAD+ (oxidized form) during this conversion sustains the flow of the glycolytic.	('NADH', 'Chemical', 'MESH:D009243', (47, 51))	('lactic acid', 'Chemical', 'MESH:D019344', (29, 40))	('flow', 'MPA', (153, 157))	('NAD+', 'Chemical', 'MESH:D009243', (96, 100))	('lactic acid', 'MPA', (29, 40))	('NAD+', 'Var', (96, 100))	('Pyruvic acid', 'Chemical', 'MESH:D019289', (0, 12))	('NADH', 'MPA', (47, 51))
384925	33451333	However, only about ten clinical trials using inhibitors specifically targeting AURKB and most of them are still in phase I stage.	('inhibitors', 'Var', (46, 56))	('AURKB', 'Gene', (80, 85))	('AURKB', 'Gene', '9212', (80, 85))
384929	33451333	Gene amplification, transcriptional activation and inhibition of protein degradation could contribute to the elevated levels of AURKA expression in cancer tissues.	('cancer', 'Disease', (148, 154))	('inhibition', 'NegReg', (51, 61))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('expression', 'MPA', (134, 144))	('elevated', 'PosReg', (109, 117))	('protein degradation', 'MPA', (65, 84))	('contribute', 'Reg', (91, 101))	('levels', 'MPA', (118, 124))	('AURKA', 'Gene', '6790', (128, 133))	('activation', 'PosReg', (36, 46))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('Gene amplification', 'Var', (0, 18))	('AURKA', 'Gene', (128, 133))
384931	33451333	Given that overexpression and gene amplification of AURKA have been identified in diverse cancers, small molecule kinase inhibitors of AURKA have attracted considerable interest.	('AURKA', 'Gene', '6790', (52, 57))	('cancers', 'Disease', (90, 97))	('AURKA', 'Gene', '6790', (135, 140))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('AURKA', 'Gene', (52, 57))	('AURKA', 'Gene', (135, 140))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('overexpression', 'PosReg', (11, 25))	('gene amplification', 'Var', (30, 48))	('cancers', 'Disease', 'MESH:D009369', (90, 97))
384932	33451333	A series of AURKA kinase inhibitors (AKIs) have been produced over the past decades; inhibition of the expression or activity of AURKA by AKIs suppresses cancer cell proliferation, migration and invasion.	('AKIs suppresses cancer', 'Disease', 'MESH:D009369', (138, 160))	('activity', 'MPA', (117, 125))	('expression', 'MPA', (103, 113))	('inhibition', 'Var', (85, 95))	('AURKA', 'Gene', '6790', (129, 134))	('AURKA', 'Gene', '6790', (12, 17))	('AKIs suppresses cancer', 'Disease', (138, 160))	('AURKA', 'Gene', (12, 17))	('AURKA', 'Gene', (129, 134))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))
384951	33451333	There is overwhelming evidence of overexpression and gene amplification of AURKA in a wide range of cancers.	('cancers', 'Phenotype', 'HP:0002664', (100, 107))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('AURKA', 'Gene', '6790', (75, 80))	('overexpression', 'PosReg', (34, 48))	('gene amplification', 'Var', (53, 71))	('AURKA', 'Gene', (75, 80))	('cancers', 'Disease', 'MESH:D009369', (100, 107))	('cancers', 'Disease', (100, 107))
384952	33451333	The underlying mechanisms for AURKA upregulation in cancer include gene amplification, gene mutation, microRNA regulation, transcriptional or posttranscriptional modification, and others.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('microRNA regulation', 'MPA', (102, 121))	('upregulation', 'PosReg', (36, 48))	('AURKA', 'Gene', '6790', (30, 35))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('gene mutation', 'Var', (87, 100))	('gene amplification', 'Var', (67, 85))	('AURKA', 'Gene', (30, 35))
384979	33451333	Likewise, NEDD9 and PUM2 not only stimulate autophosphorylation and autoactivation of AURKA but also stabilize AURKA protein expression through disassociation from cdh.	('disassociation', 'Var', (144, 158))	('AURKA', 'Gene', '6790', (86, 91))	('AURKA', 'Gene', '6790', (111, 116))	('cdh', 'Protein', (164, 167))	('PUM2', 'Gene', (20, 24))	('autophosphorylation', 'MPA', (44, 63))	('stabilize', 'PosReg', (101, 110))	('AURKA', 'Gene', (111, 116))	('AURKA', 'Gene', (86, 91))	('autoactivation', 'MPA', (68, 82))	('stimulate', 'PosReg', (34, 43))	('expression', 'MPA', (125, 135))	('NEDD9', 'Gene', (10, 15))	('PUM2', 'Gene', '23369', (20, 24))	('NEDD9', 'Gene', '4739', (10, 15))
384982	33451333	These regulators are usually tumor suppressors, and inhibition of AURKA is one of the mechanisms explaining their tumor-suppressive functions.	('AURKA', 'Gene', '6790', (66, 71))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('AURKA', 'Gene', (66, 71))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumor', 'Disease', (114, 119))	('inhibition', 'Var', (52, 62))	('tumor', 'Disease', (29, 34))
384990	33451333	GSK-3beta interacts with AURKA and phosphorylates AURKA at Ser290/291 in vitro, after which autophosphorylation occurs at Ser349, which is an AURKA activity-inhibiting phosphorylation site.	('Ser349', 'Chemical', '-', (122, 128))	('AURKA', 'Gene', '6790', (142, 147))	('AURKA', 'Gene', '6790', (25, 30))	('Ser349', 'Var', (122, 128))	('autophosphorylation', 'MPA', (92, 111))	('Ser290', 'Chemical', '-', (59, 65))	('AURKA', 'Gene', (142, 147))	('AURKA', 'Gene', (25, 30))	('AURKA', 'Gene', '6790', (50, 55))	('interacts', 'Interaction', (10, 19))	('GSK-3beta', 'Gene', '2931', (0, 9))	('AURKA', 'Gene', (50, 55))	('GSK-3beta', 'Gene', (0, 9))
384998	33451333	Phosphorylation of AURKA by IKK2 targets it for beta-TRCP-mediated degradation and serves to maintain appropriate levels of AURKA to assure proper bipolar spindle assembly and mitotic progression.	('IKK2', 'Gene', (28, 32))	('levels', 'MPA', (114, 120))	('AURKA', 'Gene', '6790', (124, 129))	('AURKA', 'Gene', '6790', (19, 24))	('beta-TRCP', 'Gene', '8945', (48, 57))	('Phosphorylation', 'Var', (0, 15))	('beta-TRCP', 'Gene', (48, 57))	('targets', 'Reg', (33, 40))	('AURKA', 'Gene', (124, 129))	('AURKA', 'Gene', (19, 24))	('mitotic progression', 'CPA', (176, 195))	('IKK2', 'Gene', '3551', (28, 32))	('bipolar spindle assembly', 'CPA', (147, 171))
385004	33451333	VHL is an E3 ligase that multi-monoubiquitinates AURKA in quiescent cells and targets it for proteasome-mediated degradation under both normoxic and hypoxic conditions.	('AURKA', 'Gene', '6790', (49, 54))	('AURKA', 'Gene', (49, 54))	('proteasome-mediated degradation', 'MPA', (93, 124))	('hypoxic conditions', 'Disease', 'MESH:D000071069', (149, 167))	('hypoxic conditions', 'Disease', (149, 167))	('VHL', 'Gene', (0, 3))	('VHL', 'Gene', '7428', (0, 3))	('multi-monoubiquitinates', 'Var', (25, 48))
385015	33451333	Many of the substrates regulated by AURKA coordinate with AURKA to control mitotic progression, and aberrant expression of AURKA in a variety of human cancers has been linked with mitotic defects.	('linked', 'Reg', (168, 174))	('AURKA', 'Gene', (123, 128))	('AURKA', 'Gene', '6790', (58, 63))	('mitotic progression', 'CPA', (75, 94))	('AURKA', 'Gene', (58, 63))	('mitotic defects', 'Disease', (180, 195))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('human', 'Species', '9606', (145, 150))	('AURKA', 'Gene', '6790', (36, 41))	('aberrant expression', 'Var', (100, 119))	('cancers', 'Disease', 'MESH:D009369', (151, 158))	('AURKA', 'Gene', '6790', (123, 128))	('cancers', 'Phenotype', 'HP:0002664', (151, 158))	('AURKA', 'Gene', (36, 41))	('cancers', 'Disease', (151, 158))	('mitotic defects', 'Disease', 'MESH:C536987', (180, 195))
385022	33451333	ASAP is also a spindle-associated protein, deregulation of which induces severe mitotic defects.	('ASAP', 'Gene', '79884', (0, 4))	('ASAP', 'Gene', (0, 4))	('induces', 'Reg', (65, 72))	('mitotic defects', 'Disease', 'MESH:C536987', (80, 95))	('deregulation', 'Var', (43, 55))	('mitotic defects', 'Disease', (80, 95))
385024	33451333	The AURKA activator TPX2 is an AURKA substrate with phosphorylation sites at Ser121 and Ser125.	('Ser121', 'Var', (77, 83))	('AURKA', 'Gene', (4, 9))	('AURKA', 'Gene', '6790', (31, 36))	('Ser125', 'Chemical', '-', (88, 94))	('AURKA', 'Gene', (31, 36))	('TPX2', 'Gene', (20, 24))	('Ser121', 'Chemical', '-', (77, 83))	('Ser125', 'Var', (88, 94))	('AURKA', 'Gene', '6790', (4, 9))	('TPX2', 'Gene', '22974', (20, 24))
385034	33451333	Research has shown that AURKA phosphorylation of Twist at Ser123, Thr148 and Ser184 facilitates Twist-mediated promotion of EMT and chemoresistance in pancreatic cancer cells.	('pancreatic cancer', 'Disease', 'MESH:D010190', (151, 168))	('AURKA', 'Gene', (24, 29))	('Thr148', 'Chemical', '-', (66, 72))	('Thr148', 'Var', (66, 72))	('promotion', 'PosReg', (111, 120))	('Twist', 'Gene', '7291', (96, 101))	('Twist', 'Gene', '7291', (49, 54))	('Ser184', 'Var', (77, 83))	('Twist', 'Gene', (96, 101))	('Twist', 'Gene', (49, 54))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (151, 168))	('Ser123', 'Chemical', '-', (58, 64))	('Ser184', 'Chemical', '-', (77, 83))	('AURKA', 'Gene', '6790', (24, 29))	('facilitates', 'PosReg', (84, 95))	('pancreatic cancer', 'Disease', (151, 168))
385043	33451333	Phosphorylation of LDHB by AURKA at Ser162 amplifies its activity in reducing pyruvate to lactate, thus promoting glycolysis and biosynthesis and promoting tumor growth.	('glycolysis', 'MPA', (114, 124))	('AURKA', 'Gene', '6790', (27, 32))	('reducing pyruvate to lactate', 'MPA', (69, 97))	('biosynthesis', 'MPA', (129, 141))	('promoting', 'PosReg', (104, 113))	('promoting', 'PosReg', (146, 155))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('AURKA', 'Gene', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('Phosphorylation', 'MPA', (0, 15))	('Ser162', 'Var', (36, 42))	('Ser162', 'Chemical', '-', (36, 42))	('LDHB', 'Gene', (19, 23))	('tumor', 'Disease', (156, 161))	('lactate', 'Chemical', 'MESH:D019344', (90, 97))	('LDHB', 'Gene', '3945', (19, 23))	('pyruvate', 'Chemical', 'MESH:D019289', (78, 86))
385044	33451333	Recently, our research has indicated that phosphorylation of the scaffold and oncogenic protein SDCBP by AURKA maintains its protein stability and pro-proliferative functions.	('SDCBP', 'Gene', (96, 101))	('pro-proliferative functions', 'CPA', (147, 174))	('maintains', 'PosReg', (111, 120))	('protein stability', 'MPA', (125, 142))	('SDCBP', 'Gene', '6386', (96, 101))	('AURKA', 'Gene', '6790', (105, 110))	('phosphorylation', 'Var', (42, 57))	('AURKA', 'Gene', (105, 110))
385047	33451333	HURP protein stability and serum-independent growth are enhanced after phosphorylation.	('phosphorylation', 'Var', (71, 86))	('HURP', 'Gene', '9787', (0, 4))	('enhanced', 'PosReg', (56, 64))	('serum-independent growth', 'CPA', (27, 51))	('HURP', 'Gene', (0, 4))
385051	33451333	AURKA regulates LIMK2 kinase activity, subcellular localization and protein levels by directly phosphorylating LIMK2 at Ser283, Thr494 and Thr505.	('AURKA', 'Gene', (0, 5))	('LIMK2', 'Gene', '3985', (111, 116))	('LIMK2', 'Gene', (111, 116))	('LIMK2', 'Gene', '3985', (16, 21))	('regulates', 'Reg', (6, 15))	('LIMK2', 'Gene', (16, 21))	('Ser283', 'Var', (120, 126))	('Thr494', 'Var', (128, 134))	('Thr505', 'Var', (139, 145))	('Thr494', 'Chemical', '-', (128, 134))	('protein levels', 'MPA', (68, 82))	('AURKA', 'Gene', '6790', (0, 5))	('Ser283', 'Chemical', '-', (120, 126))	('Thr505', 'Chemical', '-', (139, 145))	('subcellular localization', 'MPA', (39, 63))
385052	33451333	The small GTPase RalA is also a target of AURKA; phosphorylation of RalA at Ser194 enhances cell migration and anchorage-independent growth.	('AURKA', 'Gene', (42, 47))	('RalA', 'Gene', (68, 72))	('RalA', 'Gene', (17, 21))	('Ser194', 'Chemical', '-', (76, 82))	('RalA', 'Gene', '5898', (68, 72))	('enhances', 'PosReg', (83, 91))	('RalA', 'Gene', '5898', (17, 21))	('cell migration', 'CPA', (92, 106))	('AURKA', 'Gene', '6790', (42, 47))	('phosphorylation', 'Var', (49, 64))	('anchorage-independent growth', 'CPA', (111, 139))
385053	33451333	ALDH1A1 is an AURKA substrate enzyme whose phosphorylation by AURKA at Thr267, Thr442 and Thr493 regulates ALDH1A1 protein stability, enhancing the role of this protein in the process of EMT.	('enhancing', 'PosReg', (134, 143))	('Thr267', 'Chemical', '-', (71, 77))	('Thr493', 'Var', (90, 96))	('Thr442', 'Chemical', '-', (79, 85))	('phosphorylation', 'MPA', (43, 58))	('AURKA', 'Gene', (14, 19))	('AURKA', 'Gene', (62, 67))	('ALDH1A1', 'Gene', '216', (0, 7))	('ALDH1A1', 'Gene', (107, 114))	('protein stability', 'MPA', (115, 132))	('ALDH1A1', 'Gene', '216', (107, 114))	('Thr493', 'Chemical', '-', (90, 96))	('regulates', 'Reg', (97, 106))	('ALDH1A1', 'Gene', (0, 7))	('AURKA', 'Gene', '6790', (14, 19))	('AURKA', 'Gene', '6790', (62, 67))
385056	33451333	However, Ser106 residue phosphorylation by AURKA has the opposite effect.	('AURKA', 'Gene', '6790', (43, 48))	('Ser106', 'Chemical', '-', (9, 15))	('AURKA', 'Gene', (43, 48))	('Ser106 residue', 'Var', (9, 23))
385058	33451333	Another study has revealed that the p53 Ser215 site is phosphorylated by AURKA.	('AURKA', 'Gene', '6790', (73, 78))	('p53', 'Gene', (36, 39))	('p53', 'Gene', '7157', (36, 39))	('AURKA', 'Gene', (73, 78))	('Ser215', 'Var', (40, 46))	('Ser215', 'Chemical', '-', (40, 46))
385061	33451333	Phosphorylation of RASSF1A by AURKA at Ser203 and Thr202 removes the ability of RASSF1A to interact with microtubules and induce M-phase cell cycle arrest.	('removes', 'NegReg', (57, 64))	('RASSF1A', 'Gene', '11186', (19, 26))	('RASSF1A', 'Gene', '11186', (80, 87))	('arrest', 'Disease', 'MESH:D006323', (148, 154))	('Thr202', 'Var', (50, 56))	('Phosphorylation', 'Var', (0, 15))	('interact', 'Interaction', (91, 99))	('arrest', 'Disease', (148, 154))	('RASSF1A', 'Gene', (80, 87))	('Ser203', 'Chemical', '-', (39, 45))	('AURKA', 'Gene', '6790', (30, 35))	('induce', 'Reg', (122, 128))	('Thr202', 'Chemical', '-', (50, 56))	('ability', 'MPA', (69, 76))	('RASSF1A', 'Gene', (19, 26))	('microtubules', 'Protein', (105, 117))	('AURKA', 'Gene', (30, 35))
385065	33451333	Phosphorylation of LKB1 at Ser299 causes LKB1 to dissociate from AMPK, resulting in impairment of the AMPK signaling pathway and facilitating non-small-cell lung cancer (NSCLC) growth and migration.	('LKB1', 'Gene', '6794', (19, 23))	('LKB1', 'Gene', '6794', (41, 45))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('Phosphorylation', 'Var', (0, 15))	('facilitating', 'PosReg', (129, 141))	('NSCLC', 'Disease', 'MESH:D002289', (170, 175))	('small-cell lung cancer', 'Disease', 'MESH:D055752', (146, 168))	('AMPK', 'Gene', (65, 69))	('LKB1', 'Gene', (19, 23))	('AMPK', 'Gene', '5564', (65, 69))	('small-cell lung cancer', 'Disease', (146, 168))	('Ser299', 'Var', (27, 33))	('LKB1', 'Gene', (41, 45))	('NSCLC', 'Disease', (170, 175))	('Ser299', 'Chemical', '-', (27, 33))	('lung cancer', 'Phenotype', 'HP:0100526', (157, 168))	('AMPK', 'Gene', (102, 106))	('impairment', 'NegReg', (84, 94))	('AMPK', 'Gene', '5564', (102, 106))
385072	33451333	Once YY1 is phosphorylated by AURKA at Ser365, its DNA-binding activity and transcriptional activity are abolished.	('YY1', 'Gene', '7528', (5, 8))	('DNA-binding', 'Interaction', (51, 62))	('YY1', 'Gene', (5, 8))	('Ser365', 'Var', (39, 45))	('transcriptional activity', 'MPA', (76, 100))	('AURKA', 'Gene', '6790', (30, 35))	('Ser365', 'Chemical', '-', (39, 45))	('abolished', 'NegReg', (105, 114))	('AURKA', 'Gene', (30, 35))
385075	33451333	AURKA-mediated phosphorylation of CHIP at Ser273 promotes androgen degradation in castration-resistant prostate cancer.	('AURKA', 'Gene', (0, 5))	('phosphorylation', 'Var', (15, 30))	('prostate cancer', 'Disease', 'MESH:D011471', (103, 118))	('promotes', 'PosReg', (49, 57))	('Ser273', 'Chemical', '-', (42, 48))	('prostate cancer', 'Phenotype', 'HP:0012125', (103, 118))	('AURKA', 'Gene', '6790', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('androgen degradation', 'MPA', (58, 78))	('prostate cancer', 'Disease', (103, 118))
385077	33451333	Phosphorylation by AURKA at Ser243 may account for the cancer-promoting effects of KCTD12.	('KCTD12', 'Gene', '115207', (83, 89))	('AURKA', 'Gene', '6790', (19, 24))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('Ser243', 'Chemical', '-', (28, 34))	('Ser243', 'Var', (28, 34))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('Phosphorylation', 'MPA', (0, 15))	('AURKA', 'Gene', (19, 24))	('KCTD12', 'Gene', (83, 89))	('cancer', 'Disease', (55, 61))
385087	33451333	In recent years, several small molecules that selectively target AURKA have been identified with anticancer activity in preclinical studies including LY3295668, BPR1K0609S1, LDD970, MK-8745, AKI603 and CYC3.	('BPR1K0609S1', 'Var', (161, 172))	('AURKA', 'Gene', (65, 70))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('cancer', 'Disease', (101, 107))	('LDD970', 'Var', (174, 180))	('LDD970', 'CellLine', 'CVCL:7312', (174, 180))	('MK-8745', 'Var', (182, 189))	('AKI603', 'Var', (191, 197))	('LY3295668', 'Var', (150, 159))	('LY3295668', 'Chemical', '-', (150, 159))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('AURKA', 'Gene', '6790', (65, 70))
385089	33451333	The common dose-limiting toxicity of specific AKIs, including MLN8237 and ENMD-2076, are neutropenia, somnolence and mucisitis.	('neutropenia', 'Phenotype', 'HP:0001875', (89, 100))	('neutropenia', 'Disease', 'MESH:D009503', (89, 100))	('toxicity', 'Disease', 'MESH:D064420', (25, 33))	('somnolence', 'Disease', (102, 112))	('toxicity', 'Disease', (25, 33))	('MLN8237', 'Chemical', 'MESH:C550258', (62, 69))	('somnolence', 'Disease', 'MESH:D006970', (102, 112))	('mucisitis', 'Disease', (117, 126))	('MLN8237', 'Var', (62, 69))	('neutropenia', 'Disease', (89, 100))
385090	33451333	MLN8237 is a highly selective small molecule inhibitor of AURKA with an IC50 of 1 nM.	('MLN8237', 'Chemical', 'MESH:C550258', (0, 7))	('MLN8237', 'Var', (0, 7))	('AURKA', 'Gene', '6790', (58, 63))	('AURKA', 'Gene', (58, 63))
385091	33451333	MLN8237 was developed as an enhancement of its predecessor, MLN8054, development of which was terminated after phase I studies due to central nervous system side effects, including dose-limiting somnolence.	('somnolence', 'Disease', (195, 205))	('MLN8237', 'Chemical', 'MESH:C550258', (0, 7))	('somnolence', 'Disease', 'MESH:D006970', (195, 205))	('MLN8237', 'Var', (0, 7))	('MLN8054', 'Chemical', 'MESH:C518940', (60, 67))
385092	33451333	MLN8237 has been shown to inhibit cell proliferation by impairing mitosis, inducing cell cycle arrest and autophagy, and accelerating cancer cell apoptosis and senescence in multiple cancer types.	('cancer', 'Disease', (183, 189))	('impairing mitosis', 'Disease', (56, 73))	('cell proliferation', 'CPA', (34, 52))	('MLN8237', 'Chemical', 'MESH:C550258', (0, 7))	('inhibit', 'NegReg', (26, 33))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('senescence', 'CPA', (160, 170))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('MLN8237', 'Var', (0, 7))	('arrest', 'Disease', 'MESH:D006323', (95, 101))	('impairing mitosis', 'Disease', 'MESH:D060825', (56, 73))	('accelerating', 'PosReg', (121, 133))	('inducing', 'PosReg', (75, 83))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('autophagy', 'CPA', (106, 115))	('arrest', 'Disease', (95, 101))	('cancer', 'Disease', 'MESH:D009369', (183, 189))
385093	33451333	The EMT process is also impeded by MLN8237 treatment in human epithelial ovarian and pancreatic cancer cells.	('epithelial ovarian and pancreatic cancer', 'Disease', 'MESH:D010195', (62, 102))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('MLN8237', 'Chemical', 'MESH:C550258', (35, 42))	('human', 'Species', '9606', (56, 61))	('EMT process', 'CPA', (4, 15))	('MLN8237 treatment', 'Var', (35, 52))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (85, 102))	('impeded', 'NegReg', (24, 31))
385094	33451333	Importantly, MLN8237 significantly increases the sensitivity of tumor cells to chemotherapy drugs or radiation.	('tumor', 'Disease', (64, 69))	('MLN8237', 'Chemical', 'MESH:C550258', (13, 20))	('increases', 'PosReg', (35, 44))	('sensitivity', 'MPA', (49, 60))	('MLN8237', 'Var', (13, 20))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
385095	33451333	Mechanistic studies have revealed that MLN8237 induces proteasomal degradation of N-myc in childhood neuroblastoma.	('MLN8237', 'Chemical', 'MESH:C550258', (39, 46))	('induces', 'Reg', (47, 54))	('MLN8237', 'Var', (39, 46))	('neuroblastoma', 'Disease', (101, 114))	('proteasomal degradation', 'MPA', (55, 78))	('N-myc', 'Gene', '4613', (82, 87))	('neuroblastoma', 'Phenotype', 'HP:0003006', (101, 114))	('N-myc', 'Gene', (82, 87))	('neuroblastoma', 'Disease', 'MESH:D009447', (101, 114))
385096	33451333	In THCA cells, MLN8237 disrupts c-Myc/AURKA complex formation, and c-Myc is a major determinant of MLN8237 responsiveness both in vitro and in vivo.	('MLN8237', 'Chemical', 'MESH:C550258', (99, 106))	('AURKA', 'Gene', (38, 43))	('MLN8237', 'Var', (15, 22))	('THCA', 'Phenotype', 'HP:0002890', (3, 7))	('c-Myc', 'Gene', '4609', (32, 37))	('c-Myc', 'Gene', '4609', (67, 72))	('c-Myc', 'Gene', (32, 37))	('c-Myc', 'Gene', (67, 72))	('AURKA', 'Gene', '6790', (38, 43))	('disrupts', 'NegReg', (23, 31))	('MLN8237', 'Chemical', 'MESH:C550258', (15, 22))
385097	33451333	MLN8237 has demonstrated efficacy in cell-derived and patient-derived xenograft (PDX) models of numerous tumor types, including glioblastoma, bladder cancer, esophageal adenocarcinoma, multiple myeloma, neuroblastoma and colon cancer.	('multiple myeloma', 'Disease', (185, 201))	('numerous tumor', 'Disease', (96, 110))	('MLN8237', 'Var', (0, 7))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (158, 183))	('esophageal adenocarcinoma', 'Disease', 'MESH:D000230', (158, 183))	('MLN8237', 'Chemical', 'MESH:C550258', (0, 7))	('esophageal adenocarcinoma', 'Disease', (158, 183))	('glioblastoma', 'Disease', 'MESH:D005909', (128, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (174, 183))	('numerous tumor', 'Disease', 'MESH:D009369', (96, 110))	('colon cancer', 'Phenotype', 'HP:0003003', (221, 233))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('multiple myeloma', 'Phenotype', 'HP:0006775', (185, 201))	('patient', 'Species', '9606', (54, 61))	('bladder cancer', 'Disease', 'MESH:D001749', (142, 156))	('bladder cancer', 'Disease', (142, 156))	('glioblastoma', 'Disease', (128, 140))	('bladder cancer', 'Phenotype', 'HP:0009725', (142, 156))	('glioblastoma', 'Phenotype', 'HP:0012174', (128, 140))	('multiple myeloma', 'Disease', 'MESH:D009101', (185, 201))	('neuroblastoma', 'Phenotype', 'HP:0003006', (203, 216))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('neuroblastoma and colon cancer', 'Disease', 'MESH:D015179', (203, 233))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))
385098	33451333	Due to its potent efficiency in preclinical studies, MLN8237 has been tested in clinical trials for multiple cancers and is the only AURKA inhibitor that has proceeded to phase III evaluation.	('MLN8237', 'Var', (53, 60))	('cancers', 'Disease', 'MESH:D009369', (109, 116))	('cancers', 'Phenotype', 'HP:0002664', (109, 116))	('cancers', 'Disease', (109, 116))	('AURKA', 'Gene', '6790', (133, 138))	('AURKA', 'Gene', (133, 138))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('MLN8237', 'Chemical', 'MESH:C550258', (53, 60))
385102	33451333	One phase II trial of MLN8237 in patients with ovarian cancer, fallopian tube cancer, peritoneal carcinoma, acute myelogenous leukemia and high-grade myelodysplastic syndrome showed that MLN8237 has modest single-agent antitumor activity.	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('acute myelogenous leukemia', 'Disease', (108, 134))	('fallopian tube cancer', 'Disease', (63, 84))	('myelodysplastic syndrome', 'Disease', (150, 174))	('peritoneal carcinoma', 'Disease', (86, 106))	('MLN8237', 'Var', (22, 29))	('leukemia', 'Phenotype', 'HP:0001909', (126, 134))	('acute myelogenous leukemia', 'Disease', 'MESH:D015470', (108, 134))	('peritoneal carcinoma', 'Disease', 'MESH:D010534', (86, 106))	('MLN8237', 'Chemical', 'MESH:C550258', (22, 29))	('MLN8237', 'Var', (187, 194))	('fallopian tube cancer', 'Disease', 'MESH:D005185', (63, 84))	('ovarian cancer', 'Disease', 'MESH:D010051', (47, 61))	('tumor', 'Disease', (223, 228))	('myelogenous leukemia', 'Phenotype', 'HP:0012324', (114, 134))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('myelodysplastic syndrome', 'Phenotype', 'HP:0002863', (150, 174))	('tumor', 'Disease', 'MESH:D009369', (223, 228))	('MLN8237', 'Chemical', 'MESH:C550258', (187, 194))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('myelodysplastic syndrome', 'Disease', 'MESH:D009190', (150, 174))	('patients', 'Species', '9606', (33, 41))	('ovarian cancer', 'Disease', (47, 61))	('acute myelogenous leukemia', 'Phenotype', 'HP:0004808', (108, 134))	('ovarian cancer', 'Phenotype', 'HP:0100615', (47, 61))
385103	33451333	In a multicenter phase II study, MLN8237 treatment obtained an objective response in 18% of 49 women with breast cancer and 21% of 48 participants with small-cell lung cancer.	('small-cell lung cancer', 'Disease', (152, 174))	('MLN8237', 'Chemical', 'MESH:C550258', (33, 40))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('breast cancer', 'Disease', (106, 119))	('breast cancer', 'Phenotype', 'HP:0003002', (106, 119))	('participants', 'Species', '9606', (134, 146))	('women', 'Species', '9606', (95, 100))	('lung cancer', 'Phenotype', 'HP:0100526', (163, 174))	('MLN8237 treatment', 'Var', (33, 50))	('small-cell lung cancer', 'Disease', 'MESH:D055752', (152, 174))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('breast cancer', 'Disease', 'MESH:D001943', (106, 119))
385104	33451333	In another phase II study of MLN8237 in advanced/metastatic sarcoma, occasional responses and prolonged stable disease were observed, and progression-free survival (PFS) was promising.	('sarcoma', 'Disease', 'MESH:D012509', (60, 67))	('MLN8237', 'Var', (29, 36))	('sarcoma', 'Disease', (60, 67))	('sarcoma', 'Phenotype', 'HP:0100242', (60, 67))	('MLN8237', 'Chemical', 'MESH:C550258', (29, 36))
385105	33451333	In castration-resistant neuroendocrine prostate cancer patients, those with AURKA and N-myc activation achieve significant clinical benefit from single-agent MLN8237 treatment.	('MLN8237 treatment', 'Var', (158, 175))	('AURKA', 'Gene', '6790', (76, 81))	('activation', 'PosReg', (92, 102))	('MLN8237', 'Chemical', 'MESH:C550258', (158, 165))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('AURKA', 'Gene', (76, 81))	('N-myc', 'Gene', (86, 91))	('benefit', 'PosReg', (132, 139))	('neuroendocrine prostate cancer', 'Disease', (24, 54))	('neuroendocrine prostate cancer', 'Disease', 'MESH:D011471', (24, 54))	('patients', 'Species', '9606', (55, 63))	('prostate cancer', 'Phenotype', 'HP:0012125', (39, 54))	('N-myc', 'Gene', '4613', (86, 91))
385106	33451333	Another phase II study has shown that in relapsed or refractory peripheral T-cell NHL (PTCL) patients, MLN8237 has antitumor activity with an overall response rate of 30%.	('tumor', 'Disease', (119, 124))	('NHL', 'Gene', '51750', (82, 85))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('MLN8237', 'Chemical', 'MESH:C550258', (103, 110))	('MLN8237', 'Var', (103, 110))	('NHL', 'Gene', (82, 85))	('patients', 'Species', '9606', (93, 101))
385107	33451333	In a recently reported phase III study conducted in patients with PTCL, although MLN8237 did not demonstrate superior efficacy over comparators, it did show antitumor activity and acceptable tolerability and safety.	('MLN8237', 'Chemical', 'MESH:C550258', (81, 88))	('MLN8237', 'Var', (81, 88))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('tumor', 'Disease', (161, 166))	('patients', 'Species', '9606', (52, 60))
385108	33451333	All these encouraging outcomes make MLN8237 a promising agent for cancer treatment.	('MLN8237', 'Var', (36, 43))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('MLN8237', 'Chemical', 'MESH:C550258', (36, 43))	('cancer', 'Disease', (66, 72))
385109	33451333	ENMD-2076, a novel, orally bioavailable multitarget inhibitor whose main targets are FLT3 (IC50 = 3 nM) and AURKA (IC50 = 14 nM), exhibits much greater potency against AURKA than against AURKB (IC50 = 350 nM).	('AURKA', 'Gene', (168, 173))	('ENMD-2076', 'Var', (0, 9))	('greater', 'PosReg', (144, 151))	('AURKA', 'Gene', '6790', (108, 113))	('FLT3', 'Gene', '2322', (85, 89))	('AURKB', 'Gene', '9212', (187, 192))	('AURKA', 'Gene', (108, 113))	('AURKA', 'Gene', '6790', (168, 173))	('FLT3', 'Gene', (85, 89))	('potency', 'MPA', (152, 159))	('AURKB', 'Gene', (187, 192))
385110	33451333	Because of its multitarget properties, ENMD-2076 inhibits the growth of a wide range of human solid tumor and hematopoietic cancer cell lines, with IC50 values ranging from 0.025 to 0.7 muM.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('growth', 'CPA', (62, 68))	('cancer', 'Disease', (124, 130))	('tumor', 'Disease', (100, 105))	('inhibits', 'NegReg', (49, 57))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('human', 'Species', '9606', (88, 93))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('cancer', 'Disease', 'MESH:D009369', (124, 130))	('ENMD-2076', 'Var', (39, 48))
385111	33451333	ENMD-2076 shows antitumor activity in colorectal cancer, multiple myeloma and triple-negative breast cancer both in vitro and in vivo.	('ENMD-2076', 'Var', (0, 9))	('multiple myeloma', 'Disease', (57, 73))	('colorectal cancer', 'Phenotype', 'HP:0003003', (38, 55))	('multiple myeloma', 'Phenotype', 'HP:0006775', (57, 73))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('colorectal cancer', 'Disease', (38, 55))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('multiple myeloma', 'Disease', 'MESH:D009101', (57, 73))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('breast cancer', 'Disease', 'MESH:D001943', (94, 107))	('colorectal cancer', 'Disease', 'MESH:D015179', (38, 55))	('breast cancer', 'Phenotype', 'HP:0003002', (94, 107))	('breast cancer', 'Disease', (94, 107))	('tumor', 'Disease', (20, 25))
385113	33451333	MK-5108 is a novel small molecule that shows robust selectivity for AURKA over AURKB (220-fold greater selectivity) and AURKC (190-fold greater selectivity).	('AURKC', 'Gene', (120, 125))	('AURKA', 'Gene', (68, 73))	('AURKB', 'Gene', '9212', (79, 84))	('AURKB', 'Gene', (79, 84))	('AURKC', 'Gene', '6795', (120, 125))	('MK-5108', 'Var', (0, 7))	('MK-5108', 'Chemical', 'MESH:C547876', (0, 7))	('AURKA', 'Gene', '6790', (68, 73))
385115	33451333	In EOC stem cells, MK-5108 induces cell cycle arrest by affecting the NF-kB pathway.	('MK-5108', 'Var', (19, 26))	('arrest', 'Disease', 'MESH:D006323', (46, 52))	('induces', 'Reg', (27, 34))	('NF-kB pathway', 'Pathway', (70, 83))	('affecting', 'Reg', (56, 65))	('MK-5108', 'Chemical', 'MESH:C547876', (19, 26))	('arrest', 'Disease', (46, 52))
385116	33451333	MK-5108 also decreases the rate of proliferation and increases intratumoral apoptosis in uterine leiomyosarcoma xenografts.	('decreases', 'NegReg', (13, 22))	('tumor', 'Disease', (68, 73))	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (97, 111))	('sarcoma', 'Phenotype', 'HP:0100242', (104, 111))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (97, 111))	('MK-5108', 'Var', (0, 7))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('uterine leiomyosarcoma', 'Phenotype', 'HP:0002891', (89, 111))	('MK-5108', 'Chemical', 'MESH:C547876', (0, 7))	('increases', 'PosReg', (53, 62))	('leiomyosarcoma', 'Disease', (97, 111))
385119	33451333	Even though the selective AURKA inhibitors might be less toxic than pan-inhibitors, it may also lead to drug resistance more easily, so it is necessary to develop broad Aurora kinase inhibitors to obtain drugs with greater potency for cancer treatment.	('inhibitors', 'Var', (32, 42))	('cancer', 'Disease', (235, 241))	('cancer', 'Disease', 'MESH:D009369', (235, 241))	('drug resistance', 'CPA', (104, 119))	('drug resistance', 'Phenotype', 'HP:0020174', (104, 119))	('AURKA', 'Gene', '6790', (26, 31))	('lead to', 'Reg', (96, 103))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))	('AURKA', 'Gene', (26, 31))
385120	33451333	AT9283 exhibits strong activity against several kinases.	('activity', 'MPA', (23, 31))	('AT9283', 'Var', (0, 6))	('kinases', 'Pathway', (48, 55))	('AT9283', 'Chemical', 'MESH:C535237', (0, 6))
385121	33451333	The ability of AT9283 to inhibit the growth and survival of tumor cells as well as xenografts has been demonstrated in imatinib-resistant BCR-ABL-positive leukemic cells, aggressive B-cell lymphoma and medulloblastoma.	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (182, 197))	('B-cell lymphoma', 'Disease', 'MESH:D016393', (182, 197))	('tumor', 'Disease', (60, 65))	('AT9283', 'Var', (15, 21))	('medulloblastoma', 'Disease', 'MESH:D008527', (202, 217))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('cell lymphoma', 'Phenotype', 'HP:0012191', (184, 197))	('AT9283', 'Chemical', 'MESH:C535237', (15, 21))	('medulloblastoma', 'Phenotype', 'HP:0002885', (202, 217))	('imatinib', 'Chemical', 'MESH:D000068877', (119, 127))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('growth', 'CPA', (37, 43))	('inhibit', 'NegReg', (25, 32))	('lymphoma', 'Phenotype', 'HP:0002665', (189, 197))	('BCR-ABL', 'Gene', '25', (138, 145))	('BCR-ABL', 'Gene', (138, 145))	('medulloblastoma', 'Disease', (202, 217))	('B-cell lymphoma', 'Disease', (182, 197))
385124	33451333	MK-0457, a pyrazoloquinazoline compound, inhibits all three Aurora kinases and inhibits FLT-3 and Abl kinases.	('Abl', 'Gene', '25', (98, 101))	('pyrazoloquinazoline', 'Chemical', '-', (11, 30))	('inhibits', 'NegReg', (41, 49))	('MK-0457', 'Chemical', 'MESH:C484810', (0, 7))	('inhibits', 'NegReg', (79, 87))	('MK-0457', 'Var', (0, 7))	('Abl', 'Gene', (98, 101))	('FLT-3', 'Gene', (88, 93))	('FLT-3', 'Gene', '2322', (88, 93))	('Aurora', 'Enzyme', (60, 66))
385127	33451333	MK-0457 induces accumulation of cells with >=4 N DNA content, inhibits cell cycle progression and induces apoptosis of anaplastic THCA cells.	('THCA', 'Phenotype', 'HP:0002890', (130, 134))	('induces', 'Reg', (98, 105))	('inhibits', 'NegReg', (62, 70))	('MK-0457', 'Chemical', 'MESH:C484810', (0, 7))	('cells with >=4 N DNA content', 'MPA', (32, 60))	('MK-0457', 'Var', (0, 7))	('apoptosis', 'CPA', (106, 115))	('cell cycle progression', 'CPA', (71, 93))	('accumulation', 'PosReg', (16, 28))
385129	33451333	The activity of MK-0457 was also assessed in two other phase I/II studies, both of which showed promising outcomes in patients with BCR-ABL T315I leukemia.	('BCR-ABL', 'Gene', (132, 139))	('BCR-ABL', 'Gene', '25', (132, 139))	('T315I', 'Var', (140, 145))	('T315I', 'Mutation', 'rs121913459', (140, 145))	('leukemia', 'Phenotype', 'HP:0001909', (146, 154))	('leukemia', 'Disease', 'MESH:D007938', (146, 154))	('MK-0457', 'Chemical', 'MESH:C484810', (16, 23))	('leukemia', 'Disease', (146, 154))	('patients', 'Species', '9606', (118, 126))
385131	33451333	PHA-739358 exhibits strong antiproliferative activity in BCR-ABL-positive leukemia cells, including those harboring the T315I mutation.	('leukemia', 'Phenotype', 'HP:0001909', (74, 82))	('T315I', 'Var', (120, 125))	('T315I', 'Mutation', 'rs121913459', (120, 125))	('BCR-ABL', 'Gene', (57, 64))	('BCR-ABL', 'Gene', '25', (57, 64))	('leukemia', 'Disease', (74, 82))	('antiproliferative activity', 'MPA', (27, 53))	('leukemia', 'Disease', 'MESH:D007938', (74, 82))
385132	33451333	The crystal structure of the Abl-T315I-PHA-739358 complex provides a possible structural explanation for the activity of PHA-739358 on the T315I mutation.	('Abl', 'Gene', (29, 32))	('activity', 'MPA', (109, 117))	('T315I', 'Var', (139, 144))	('Abl', 'Gene', '25', (29, 32))	('T315I', 'Mutation', 'rs121913459', (33, 38))	('T315I', 'Mutation', 'rs121913459', (139, 144))
385133	33451333	PHA-739358 also induces cell cycle arrest, apoptosis and autophagy and suppresses the EMT process.	('arrest', 'Disease', 'MESH:D006323', (35, 41))	('suppresses', 'NegReg', (71, 81))	('apoptosis', 'CPA', (43, 52))	('PHA-739358', 'Var', (0, 10))	('arrest', 'Disease', (35, 41))	('EMT process', 'CPA', (86, 97))	('autophagy', 'CPA', (57, 66))	('induces', 'Reg', (16, 23))
385134	33451333	In one study, PHA-739358 inhibited liver metastases from gastroenteropancreatic neuroendocrine tumors in an orthotopic xenograft model.	('metastases', 'Disease', 'MESH:D009362', (41, 51))	('PHA-739358', 'Var', (14, 24))	('gastroenteropancreatic neuroendocrine tumors', 'Disease', (57, 101))	('gastroenteropancreatic neuroendocrine tumors', 'Disease', 'MESH:C535650', (57, 101))	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (80, 101))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('inhibited', 'NegReg', (25, 34))	('metastases', 'Disease', (41, 51))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))
385135	33451333	In another study, PHA-739358 inhibited early-stage bone metastases based on an ex vivo model named the 'bone-in-culture array'.	('metastases', 'Disease', 'MESH:D009362', (56, 66))	('inhibited', 'NegReg', (29, 38))	('PHA-739358', 'Var', (18, 28))	('metastases', 'Disease', (56, 66))
385136	33451333	Several phase I/II clinical evaluations have been performed on PHA-739358 due to its encouraging antitumor effects.	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('PHA-739358', 'Var', (63, 73))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
385137	33451333	Other drugs including AMG900, AS703569, BI-847325, CYC116, PF-03814735, and SNS-314 are also in phase I clinical trials.	('SNS-314', 'Chemical', 'MESH:C532454', (76, 83))	('AMG900', 'Chemical', 'MESH:C555658', (22, 28))	('PF-03814735', 'Chemical', 'MESH:C550549', (59, 70))	('CYC116', 'Var', (51, 57))	('PF-03814735', 'Var', (59, 70))	('BI-847325', 'Var', (40, 49))	('AS703569', 'Var', (30, 38))	('BI-847325', 'Chemical', 'MESH:C000606531', (40, 49))	('AS703569', 'Chemical', 'MESH:C000592140', (30, 38))
385145	33451333	In patients with solid tumors, AS703569 in combination with the standard dose of gemcitabine produces preliminary signs of efficacy.	('solid tumors', 'Disease', (17, 29))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('patients', 'Species', '9606', (3, 11))	('AS703569', 'Var', (31, 39))	('solid tumors', 'Disease', 'MESH:D009369', (17, 29))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))	('AS703569', 'Chemical', 'MESH:C000592140', (31, 39))	('gemcitabine', 'Chemical', 'MESH:C056507', (81, 92))
385148	33451333	In addition, MLN8237 has a synergistic effect in association with vincristine and rituximab in aggressive B-cell NHL.	('MLN8237', 'Chemical', 'MESH:C550258', (13, 20))	('vincristine', 'Chemical', 'MESH:D014750', (66, 77))	('NHL', 'Gene', '51750', (113, 116))	('MLN8237', 'Var', (13, 20))	('NHL', 'Gene', (113, 116))	('rituximab', 'Chemical', 'MESH:D000069283', (82, 91))
385152	33451333	In a study on Myc-overexpressing lymphoma xenografts, a combination of cyclophosphamide and MLN8237 induced complete tumor regression in all mice, leading to improvements in survival.	('lymphoma', 'Disease', 'MESH:D008223', (33, 41))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('MLN8237', 'Chemical', 'MESH:C550258', (92, 99))	('lymphoma', 'Phenotype', 'HP:0002665', (33, 41))	('survival', 'CPA', (174, 182))	('tumor', 'Disease', (117, 122))	('MLN8237', 'Var', (92, 99))	('Myc', 'Gene', (14, 17))	('cyclophosphamide', 'Chemical', 'MESH:D003520', (71, 87))	('Myc', 'Gene', '17869', (14, 17))	('mice', 'Species', '10090', (141, 145))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('improvements', 'PosReg', (158, 170))	('lymphoma', 'Disease', (33, 41))
385155	33451333	Combined treatment with MLN8237 and eribulin leads to a synergistic increase in apoptosis in mammary tumors as well as cytotoxic autophagy in metastases through the LC3B/p62 axis and Akt pathway.	('LC3B', 'Gene', (165, 169))	('Akt', 'Gene', (183, 186))	('tumors', 'Disease', 'MESH:D009369', (101, 107))	('metastases', 'Disease', (142, 152))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('Akt', 'Gene', '207', (183, 186))	('MLN8237', 'Chemical', 'MESH:C550258', (24, 31))	('metastases', 'Disease', 'MESH:D009362', (142, 152))	('p62', 'Gene', '23636', (170, 173))	('increase', 'PosReg', (68, 76))	('LC3B', 'Gene', '81631', (165, 169))	('MLN8237', 'Var', (24, 31))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('p62', 'Gene', (170, 173))	('apoptosis', 'CPA', (80, 89))	('tumors', 'Disease', (101, 107))
385156	33451333	In multiple myeloma, studies on combined treatment with AT9283 and lenalidomide have shown significant synergistic antitumor effects of this regimen both in vitro and in vivo.	('AT9283', 'Chemical', 'MESH:C535237', (56, 62))	('multiple myeloma', 'Disease', (3, 19))	('tumor', 'Disease', (119, 124))	('AT9283', 'Var', (56, 62))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('lenalidomide', 'Chemical', 'MESH:D000077269', (67, 79))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('multiple myeloma', 'Phenotype', 'HP:0006775', (3, 19))	('multiple myeloma', 'Disease', 'MESH:D009101', (3, 19))
385159	33451333	PHA680632 treatment prior to radiation treatment leads to an additive effect in cancer cells, especially in p53-deficient cells in vitro or in vivo.	('p53', 'Gene', (108, 111))	('p53', 'Gene', '7157', (108, 111))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('additive effect', 'MPA', (61, 76))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('PHA680632', 'Chemical', 'MESH:C524543', (0, 9))	('PHA680632', 'Var', (0, 9))	('cancer', 'Disease', (80, 86))
385160	33451333	Another AURKA inhibitor, MLN8054, sensitizes androgen-insensitive prostate cancer to radiation; this sensitization is associated with sustained DNA double-strand breaks.	('prostate cancer', 'Disease', 'MESH:D011471', (66, 81))	('prostate cancer', 'Phenotype', 'HP:0012125', (66, 81))	('MLN8054', 'Chemical', 'MESH:C518940', (25, 32))	('AURKA', 'Gene', '6790', (8, 13))	('sensitizes', 'Reg', (34, 44))	('prostate cancer', 'Disease', (66, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('AURKA', 'Gene', (8, 13))	('MLN8054', 'Var', (25, 32))
385161	33451333	Two other AURKA inhibitors, MLN8237 and ENMD-2076, also enhance radiation sensitivity in cancer cells.	('ENMD-2076', 'Var', (40, 49))	('AURKA', 'Gene', (10, 15))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('enhance', 'PosReg', (56, 63))	('MLN8237', 'Chemical', 'MESH:C550258', (28, 35))	('cancer', 'Disease', (89, 95))	('MLN8237', 'Var', (28, 35))	('AURKA', 'Gene', '6790', (10, 15))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
385166	33451333	In addition, vorinostat and MK-0457 or MK-5108 combination treatment enhances lymphoma cell killing with reductions in c-Myc, hTERT, and microRNA levels.	('lymphoma', 'Disease', (78, 86))	('hTERT', 'Gene', (126, 131))	('vorinostat', 'Chemical', 'MESH:D000077337', (13, 23))	('MK-5108', 'Gene', (39, 46))	('MK-0457', 'Chemical', 'MESH:C484810', (28, 35))	('lymphoma', 'Disease', 'MESH:D008223', (78, 86))	('MK-0457', 'Var', (28, 35))	('lymphoma', 'Phenotype', 'HP:0002665', (78, 86))	('reductions', 'NegReg', (105, 115))	('microRNA levels', 'MPA', (137, 152))	('MK-5108', 'Chemical', 'MESH:C547876', (39, 46))	('enhances', 'PosReg', (69, 77))	('c-Myc', 'Gene', '4609', (119, 124))	('hTERT', 'Gene', '7015', (126, 131))	('c-Myc', 'Gene', (119, 124))
385170	33451333	EGFR inhibitors have been a major breakthrough for NSCLC treatment.	('EGFR', 'Gene', (0, 4))	('NSCLC', 'Disease', (51, 56))	('inhibitors', 'Var', (5, 15))	('NSCLC', 'Disease', 'MESH:D002289', (51, 56))	('EGFR', 'Gene', '1956', (0, 4))
385174	33451333	Both BRD4 and AURKA are regulators of the MYC gene at the translational and posttranslational levels, respectively, and targeting both of them simultaneously may produce synergistic antitumor effects.	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('produce', 'Reg', (162, 169))	('BRD4', 'Gene', (5, 9))	('AURKA', 'Gene', (14, 19))	('MYC', 'Gene', (42, 45))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('targeting', 'Var', (120, 129))	('tumor', 'Disease', (186, 191))	('BRD4', 'Gene', '23476', (5, 9))	('MYC', 'Gene', '4609', (42, 45))	('AURKA', 'Gene', '6790', (14, 19))
385175	33451333	JQ1 treatment to repress BRD4 activity together with MLN8237 treatment synergistically promotes cell death in c-Myc expressing human glioblastoma cells.	('glioblastoma', 'Disease', (133, 145))	('BRD4', 'Gene', '23476', (25, 29))	('human', 'Species', '9606', (127, 132))	('MLN8237', 'Var', (53, 60))	('c-Myc', 'Gene', '4609', (110, 115))	('glioblastoma', 'Disease', 'MESH:D005909', (133, 145))	('glioblastoma', 'Phenotype', 'HP:0012174', (133, 145))	('BRD4', 'Gene', (25, 29))	('c-Myc', 'Gene', (110, 115))	('death', 'Disease', 'MESH:D003643', (101, 106))	('death', 'Disease', (101, 106))	('promotes', 'PosReg', (87, 95))	('MLN8237', 'Chemical', 'MESH:C550258', (53, 60))	('activity', 'MPA', (30, 38))
385178	33451333	One study showed that AURKA and MDM2 antagonism with MLN8237 and Nutlin-3 halted melanoma growth by inducing growth arrest and senescence, limiting the lifespans of senescent cells, and enhancing tumor immune infiltration and clearance.	('tumor', 'Disease', (196, 201))	('growth arrest', 'Disease', (109, 122))	('melanoma', 'Phenotype', 'HP:0002861', (81, 89))	('melanoma', 'Disease', (81, 89))	('senescence', 'CPA', (127, 137))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('Nutlin-3', 'Chemical', 'MESH:C482205', (65, 73))	('lifespans', 'CPA', (152, 161))	('MLN8237', 'Var', (53, 60))	('MLN8237', 'Chemical', 'MESH:C550258', (53, 60))	('MDM2', 'Gene', (32, 36))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('halted', 'NegReg', (74, 80))	('growth arrest', 'Phenotype', 'HP:0001510', (109, 122))	('melanoma', 'Disease', 'MESH:D008545', (81, 89))	('enhancing', 'PosReg', (186, 195))	('MDM2', 'Gene', '4193', (32, 36))	('clearance', 'CPA', (226, 235))	('inducing', 'PosReg', (100, 108))	('growth arrest', 'Disease', 'MESH:D006323', (109, 122))	('AURKA', 'Gene', '6790', (22, 27))	('limiting', 'NegReg', (139, 147))	('AURKA', 'Gene', (22, 27))
385179	33451333	The other study showed that combined MK-0457 and Nutlin-3 treatment activated p53-dependent postmitotic checkpoints at pseudo-G1 phase and induced proapoptotic p53 signaling and mitochondrial apoptosis in AML.	('MK-0457', 'Var', (37, 44))	('mitochondrial apoptosis', 'CPA', (178, 201))	('AML', 'Disease', (205, 208))	('p53', 'Gene', (160, 163))	('activated', 'PosReg', (68, 77))	('postmitotic checkpoints at pseudo-G1 phase', 'CPA', (92, 134))	('p53', 'Gene', (78, 81))	('induced', 'PosReg', (139, 146))	('p53', 'Gene', '7157', (160, 163))	('Nutlin-3', 'Chemical', 'MESH:C482205', (49, 57))	('p53', 'Gene', '7157', (78, 81))	('MK-0457', 'Chemical', 'MESH:C484810', (37, 44))	('AML', 'Disease', 'MESH:D015470', (205, 208))
385182	33451333	In human neuroblastoma cells, MK-5108 increases the efficacy of an anti-ganglioside (GD2) 14G2a antibody, which is related to a reduction in N-Myc expression and an increase in PHLDA1 and p53 protein levels.	('MK-5108', 'Var', (30, 37))	('neuroblastoma', 'Disease', (9, 22))	('human', 'Species', '9606', (3, 8))	('expression', 'MPA', (147, 157))	('neuroblastoma', 'Phenotype', 'HP:0003006', (9, 22))	('ganglioside', 'Chemical', 'MESH:D005732', (72, 83))	('neuroblastoma', 'Disease', 'MESH:D009447', (9, 22))	('efficacy', 'MPA', (52, 60))	('increase', 'PosReg', (165, 173))	('PHLDA1', 'Gene', '22822', (177, 183))	('N-Myc', 'Gene', (141, 146))	('p53', 'Gene', '7157', (188, 191))	('GD2', 'Gene', (85, 88))	('N-Myc', 'Gene', '4613', (141, 146))	('p53', 'Gene', (188, 191))	('increases', 'PosReg', (38, 47))	('reduction', 'NegReg', (128, 137))	('PHLDA1', 'Gene', (177, 183))	('MK-5108', 'Chemical', 'MESH:C547876', (30, 37))
385183	33451333	In addition, combined treatment with an anti-GD2 14G2a antibody and MK-5108 leads to enhancement of the autophagy process in IMR-32 neuroblastoma cells.	('neuroblastoma', 'Disease', (132, 145))	('MK-5108', 'Gene', (68, 75))	('autophagy process', 'CPA', (104, 121))	('IMR-32', 'CellLine', 'CVCL:0346', (125, 131))	('neuroblastoma', 'Phenotype', 'HP:0003006', (132, 145))	('neuroblastoma', 'Disease', 'MESH:D009447', (132, 145))	('MK-5108', 'Chemical', 'MESH:C547876', (68, 75))	('enhancement', 'PosReg', (85, 96))	('combined', 'Interaction', (13, 21))	('anti-GD2 14G2a', 'Var', (40, 54))	('anti-GD2', 'Gene', (40, 48))
385184	33451333	A death receptor 5 agonist antibody has been found to initiate significant apoptosis in tumor cells undergoing therapy-induced senescence induced by MLN8237 treatment.	('death receptor 5', 'Gene', '8795', (2, 18))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('MLN8237', 'Chemical', 'MESH:C550258', (149, 156))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('MLN8237 treatment', 'Var', (149, 166))	('death receptor 5', 'Gene', (2, 18))	('tumor', 'Disease', (88, 93))
385202	33451333	This drug delivery technology has been applied to MLN8237 and the polysaccharide nanovesicle efficiently delivers low concentrations of MLN8237 to inhibit AURKA and disrupt the anchorage-independent growth of MCF-7 cell than free MLN8237.	('AURKA', 'Gene', '6790', (155, 160))	('disrupt', 'NegReg', (165, 172))	('polysaccharide', 'Chemical', 'MESH:D011134', (66, 80))	('MLN8237', 'Chemical', 'MESH:C550258', (136, 143))	('MCF-7', 'CellLine', 'CVCL:0031', (209, 214))	('AURKA', 'Gene', (155, 160))	('MLN8237', 'Var', (136, 143))	('MLN8237', 'Chemical', 'MESH:C550258', (230, 237))	('inhibit', 'NegReg', (147, 154))	('anchorage-independent growth', 'CPA', (177, 205))	('MLN8237', 'Chemical', 'MESH:C550258', (50, 57))
385211	33451333	Furthermore, due to the fact that AURKA exerts its function through specific substrates in certain cancers, inhibition of AURKA substrates instead of targeting AURKA kinase activity may decrease the adverse effects.	('AURKA', 'Gene', (34, 39))	('cancers', 'Disease', 'MESH:D009369', (99, 106))	('cancers', 'Phenotype', 'HP:0002664', (99, 106))	('function', 'MPA', (51, 59))	('cancers', 'Disease', (99, 106))	('AURKA', 'Gene', '6790', (160, 165))	('AURKA', 'Gene', '6790', (122, 127))	('AURKA', 'Gene', '6790', (34, 39))	('inhibition', 'Var', (108, 118))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('AURKA', 'Gene', (160, 165))	('AURKA', 'Gene', (122, 127))
385215	33451333	Furthermore, in the triple-negative breast cancer cells, cell lines with a p53 mutation and increased p53 expression are more sensitive to ENMD-2076 than cell lines with decreased p53 expression.	('breast cancer', 'Phenotype', 'HP:0003002', (36, 49))	('breast cancer', 'Disease', (36, 49))	('p53', 'Gene', '7157', (102, 105))	('p53', 'Gene', (180, 183))	('expression', 'MPA', (106, 116))	('p53', 'Gene', '7157', (180, 183))	('sensitive', 'MPA', (126, 135))	('increased', 'PosReg', (92, 101))	('p53', 'Gene', (75, 78))	('mutation', 'Var', (79, 87))	('p53', 'Gene', '7157', (75, 78))	('p53', 'Gene', (102, 105))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('breast cancer', 'Disease', 'MESH:D001943', (36, 49))
385226	33327874	Inhibition of miR-146b decreased cell proliferation, migration, and invasion of OSCC cells.	('miR-146b', 'Gene', (14, 22))	('miR-146b', 'Gene', '574447', (14, 22))	('Inhibition', 'Var', (0, 10))	('invasion of OSCC cells', 'CPA', (68, 90))	('cell proliferation', 'CPA', (33, 51))	('decreased', 'NegReg', (23, 32))
385241	33327874	Meanwhile, studies have shown that miRNA can inhibit oncogenes or promote the expression of tumor suppressor genes to play a role in cancer therapy.	('expression', 'MPA', (78, 88))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('miRNA', 'Var', (35, 40))	('oncogenes', 'Protein', (53, 62))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('promote', 'PosReg', (66, 73))	('cancer', 'Disease', (133, 139))	('tumor', 'Disease', (92, 97))	('inhibit', 'NegReg', (45, 52))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
385300	33327874	Figure 2B indicated that knockdown miR-146b expression significantly decreased cell proliferation at 48 h, 72 h, and 96 h (P < 0.05).	('miR-146b', 'Gene', (35, 43))	('cell proliferation at', 'CPA', (79, 100))	('decreased', 'NegReg', (69, 78))	('miR-146b', 'Gene', '574447', (35, 43))	('knockdown', 'Var', (25, 34))
385301	33327874	Also, cell migration analysis suggested that miR-146b knockdown significantly reduced the migration of SCC25 and SCC9 cells (P < 0.01) (Figure 2C).	('migration of SCC25', 'CPA', (90, 108))	('SCC9', 'CellLine', 'CVCL:1685', (113, 117))	('knockdown', 'Var', (54, 63))	('miR-146b', 'Gene', (45, 53))	('miR-146b', 'Gene', '574447', (45, 53))	('reduced', 'NegReg', (78, 85))	('SCC25', 'CellLine', 'CVCL:1682', (103, 108))
385302	33327874	In addition, cell invasion analysis suggested that knockdown of miR-146b also significantly reduced cell invasion (P < 0.01) (Figure 2D).	('miR-146b', 'Gene', '574447', (64, 72))	('cell invasion', 'CPA', (100, 113))	('reduced', 'NegReg', (92, 99))	('miR-146b', 'Gene', (64, 72))	('knockdown', 'Var', (51, 60))
385303	33327874	In summary, miR-146b knockdown treatment in SCC25 and SCC9 cells could inhibit OSCC cell proliferation, migration, and invasion.	('inhibit', 'NegReg', (71, 78))	('migration', 'CPA', (104, 113))	('invasion', 'CPA', (119, 127))	('SCC9', 'CellLine', 'CVCL:1685', (54, 58))	('SCC25', 'CellLine', 'CVCL:1682', (44, 49))	('miR-146b', 'Gene', (12, 20))	('men', 'Species', '9606', (36, 39))	('miR-146b', 'Gene', '574447', (12, 20))	('knockdown', 'Var', (21, 30))	('OSCC', 'Disease', (79, 83))
385308	33327874	However, no difference in luciferase activity was observed in SCC25 and SCC9 cells when we mutated the HBP1 binding site for miR-146b.	('HBP1', 'Gene', '26959', (103, 107))	('miR-146b', 'Gene', (125, 133))	('mutated', 'Var', (91, 98))	('luciferase', 'Enzyme', (26, 36))	('SCC25', 'CellLine', 'CVCL:1682', (62, 67))	('miR-146b', 'Gene', '574447', (125, 133))	('HBP1', 'Gene', (103, 107))	('SCC9', 'CellLine', 'CVCL:1685', (72, 76))
385310	33327874	Furthermore, qRT-PCR result suggested that miR-146b knockdown significantly promoted HBP1 expression (P < 0.01) (Figure 3B).	('miR-146b', 'Gene', '574447', (43, 51))	('expression', 'MPA', (90, 100))	('HBP1', 'Gene', (85, 89))	('miR-146b', 'Gene', (43, 51))	('HBP1', 'Gene', '26959', (85, 89))	('promoted', 'PosReg', (76, 84))	('knockdown', 'Var', (52, 61))
385318	33327874	However, cell proliferation was partially rescued by HBP1 co-inhibition (P < 0.01) (Figure 4A).	('HBP1', 'Gene', (53, 57))	('HBP1', 'Gene', '26959', (53, 57))	('cell proliferation', 'CPA', (9, 27))	('co-inhibition', 'Var', (58, 71))
385322	33327874	However, their expressions could be partially rescued by HBP1 inhibition (P < 0.01).	('expressions', 'MPA', (15, 26))	('HBP1', 'Gene', '26959', (57, 61))	('HBP1', 'Gene', (57, 61))	('inhibition', 'Var', (62, 72))
385323	33327874	In summary, knockdown of HBP1 effectively rescues the decreased malignant phenotype caused by miR-146b silencing.	('malignant phenotype', 'CPA', (64, 83))	('knockdown', 'Var', (12, 21))	('rescues', 'PosReg', (42, 49))	('miR-146b', 'Gene', (94, 102))	('miR-146b', 'Gene', '574447', (94, 102))	('decreased', 'NegReg', (54, 63))	('HBP1', 'Gene', (25, 29))	('HBP1', 'Gene', '26959', (25, 29))	('silencing', 'NegReg', (103, 112))
385333	33327874	miR-146b and mi R-146a belong to the miR-146 family.	('mi R-146a', 'Var', (13, 22))	('miR-146b', 'Gene', '574447', (0, 8))	('miR-146b', 'Gene', (0, 8))
385349	33327874	Yang et al used gene overexpression technique and detected that miR-381-3p suppresses the proliferation of OSCC cells by directly targeting FGFR2.	('FGFR2', 'Gene', '2263', (140, 145))	('miR-381-3p', 'Chemical', '-', (64, 74))	('targeting', 'Reg', (130, 139))	('suppresses', 'NegReg', (75, 85))	('miR-381-3p', 'Var', (64, 74))	('proliferation of OSCC cells', 'CPA', (90, 117))	('FGFR2', 'Gene', (140, 145))
385358	33327874	In addition, studies have shown that HBP1 mutations have been detected in invasive breast cancer, which further confirms that HBP1 has inhibitory effect on the formation of tumors.	('detected', 'Reg', (62, 70))	('invasive breast cancer', 'Disease', 'MESH:D001943', (74, 96))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('HBP1', 'Gene', '26959', (37, 41))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('HBP1', 'Gene', (37, 41))	('breast cancer', 'Phenotype', 'HP:0003002', (83, 96))	('invasive breast cancer', 'Disease', (74, 96))	('tumors', 'Disease', (173, 179))	('tumors', 'Disease', 'MESH:D009369', (173, 179))	('tumors', 'Phenotype', 'HP:0002664', (173, 179))	('HBP1', 'Gene', (126, 130))	('HBP1', 'Gene', '26959', (126, 130))	('mutations', 'Var', (42, 51))
385366	33327874	In conclusion, the present study indicated that miR-146b knockdown inhibited cell proliferation, migration, and invasion in OSCC cells by regulating HBP1.	('migration', 'CPA', (97, 106))	('inhibited', 'NegReg', (67, 76))	('miR-146b', 'Gene', (48, 56))	('HBP1', 'Gene', (149, 153))	('HBP1', 'Gene', '26959', (149, 153))	('invasion', 'CPA', (112, 120))	('knockdown', 'Var', (57, 66))	('miR-146b', 'Gene', '574447', (48, 56))	('regulating', 'Reg', (138, 148))	('cell proliferation', 'CPA', (77, 95))
385373	32081859	Here, the authors present ImmLnc, an algorithm that can help prioritise immune-related lncRNAs in cancer immunotherapy research Misregulation of gene expression programs has been found to cause a broad range of human diseases.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('Misregulation', 'Var', (128, 141))	('cause', 'Reg', (188, 193))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('human diseases', 'Disease', (211, 225))	('cancer', 'Disease', (98, 104))	('human', 'Species', '9606', (211, 216))
385413	32081859	Therefore, we reasoned that if lncRNAs identified by ImmLnc play important roles in immune regulation, then they would be more likely to be highly expressed in immune cells and to be correlated with immune cell infiltration in tumors.	('play', 'Reg', (60, 64))	('tumors', 'Disease', (227, 233))	('tumors', 'Disease', 'MESH:D009369', (227, 233))	('tumors', 'Phenotype', 'HP:0002664', (227, 233))	('ImmLnc', 'Var', (53, 59))	('correlated with', 'Reg', (183, 198))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))
385531	32081859	Moreover, we obtained the public multiplatform-based molecular subtypes of lung cancer from recent literature, including the classifiers based on DNA copy number variation, DNA methylation, miRNA and gene expression, protein expression, and Cluster-Of-Cluster-Assignments-based results.	('lung cancer', 'Disease', (75, 86))	('lung cancer', 'Phenotype', 'HP:0100526', (75, 86))	('copy number variation', 'Var', (150, 171))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('lung cancer', 'Disease', 'MESH:D008175', (75, 86))
385534	29650000	Favorable outcome of patients with lung adenocarcinoma harboring POLE mutations and expressing high PD-L1 Mutations in polymerase epsilon (POLE) confer favorable prognosis and outcomes in various cancer types, but their role in non-small cell lung cancer (NSCLC) is unknown.	('lung cancer', 'Phenotype', 'HP:0100526', (243, 254))	('NSCLC', 'Phenotype', 'HP:0030358', (256, 261))	('Mutations', 'Var', (106, 115))	('cancer', 'Disease', 'MESH:D009369', (196, 202))	('patients', 'Species', '9606', (21, 29))	('POLE', 'Gene', (139, 143))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (228, 254))	('cancer', 'Disease', (248, 254))	('lung adenocarcinoma', 'Disease', (35, 54))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (232, 254))	('cancer', 'Phenotype', 'HP:0002664', (248, 254))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (228, 254))	('mutations', 'Var', (70, 79))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (35, 54))	('cancer', 'Disease', (196, 202))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (35, 54))	('cancer', 'Disease', 'MESH:D009369', (248, 254))	('PD-L1', 'Gene', (100, 105))	('carcinoma', 'Phenotype', 'HP:0030731', (45, 54))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('NSCLC', 'Disease', 'MESH:D002289', (256, 261))	('non-small cell lung cancer', 'Disease', (228, 254))	('NSCLC', 'Disease', (256, 261))
385535	29650000	Utilizing the data of 513 patients with adenocarcinoma (LUAD) and 497 patients with squamous cell carcinoma (LUSC) from The Cancer Genome Atlas (TCGA) cohort, we tested the prognostic value of POLE mutations and programmed cell death ligand 1 (PD-L1) expression in the two main subtypes of NSCLC.	('adenocarcinoma', 'Disease', (40, 54))	('programmed cell death ligand 1', 'Gene', '29126', (212, 242))	('squamous cell carcinoma', 'Disease', (84, 107))	('patients', 'Species', '9606', (70, 78))	('adenocarcinoma', 'Disease', 'MESH:D000230', (40, 54))	('mutations', 'Var', (198, 207))	('PD-L1', 'Gene', (244, 249))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (124, 143))	('PD-L1', 'Gene', '29126', (244, 249))	('NSCLC', 'Disease', 'MESH:D002289', (290, 295))	('programmed cell death ligand 1', 'Gene', (212, 242))	('LUAD', 'Disease', (56, 60))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (84, 107))	('NSCLC', 'Disease', (290, 295))	('Cancer Genome Atlas', 'Disease', (124, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (45, 54))	('tested', 'Reg', (162, 168))	('NSCLC', 'Phenotype', 'HP:0030358', (290, 295))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('patients', 'Species', '9606', (26, 34))	('LUAD', 'Disease', 'None', (56, 60))	('Cancer', 'Phenotype', 'HP:0002664', (124, 130))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (84, 107))
385536	29650000	POLE mutation is a favorable biomarker for the improved overall survival (OS) of the LUSC patients (P = 0.033, 28 mutant vs. 469 wildtype patients), but not that of the LUAD patients (P = 0.12, 31 mutant vs. 482 wildtype patients).	('improved', 'PosReg', (47, 55))	('patients', 'Species', '9606', (221, 229))	('patients', 'Species', '9606', (138, 146))	('overall survival', 'MPA', (56, 72))	('mutant', 'Var', (114, 120))	('patients', 'Species', '9606', (174, 182))	('LUAD', 'Disease', 'None', (169, 173))	('LUAD', 'Disease', (169, 173))	('patients', 'Species', '9606', (90, 98))	('mutation', 'Var', (5, 13))
385537	29650000	POLE-mutant LUAD patients with high expression of PD-L1 (Mut-High, n = 6) exhibited improved OS (P = 0.024) when compared to POLE-mutant patients with low PD-L1 expression (Mut-Low, n = 24) and other patients without POLE mutation (n = 476).	('PD-L1', 'Gene', '29126', (155, 160))	('patients', 'Species', '9606', (200, 208))	('PD-L1', 'Gene', (50, 55))	('patients', 'Species', '9606', (137, 145))	('improved', 'PosReg', (84, 92))	('PD-L1', 'Gene', '29126', (50, 55))	('high expression', 'Var', (31, 46))	('LUAD', 'Disease', 'None', (12, 16))	('LUAD', 'Disease', (12, 16))	('patients', 'Species', '9606', (17, 25))	('PD-L1', 'Gene', (155, 160))
385539	29650000	Instead, the antitumor immune response was activated in Mut-High patients so that these patients were likely responding more effectively to immuno-oncology (IO) treatments; whereas genes involved with metabolic pathways were enriched in Mut-Low group, which may cause the decreased OS of these patients.	('IO', 'Chemical', '-', (157, 159))	('tumor', 'Disease', (17, 22))	('activated', 'PosReg', (43, 52))	('Mut-High', 'Var', (56, 64))	('patients', 'Species', '9606', (88, 96))	('patients', 'Species', '9606', (294, 302))	('oncology', 'Phenotype', 'HP:0002664', (147, 155))	('patients', 'Species', '9606', (65, 73))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
385543	29650000	POLE mutation is associated with an ultra-mutated phenotype and a good prognosis in uterine corpus endometrial carcinoma (UCEC) and a subgroup of colorectal tumors (CRC).	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('tumors', 'Phenotype', 'HP:0002664', (157, 163))	('colorectal tumors', 'Disease', 'MESH:D015179', (146, 163))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (99, 120))	('colorectal tumors', 'Disease', (146, 163))	('corpus endometrial carcinoma', 'Disease', (92, 120))	('corpus endometrial carcinoma', 'Disease', 'MESH:D016889', (92, 120))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('mutation', 'Var', (5, 13))
385544	29650000	In NSCLC, the mutations of POLE and DNA mismatch repair (MMR) genes result in ultra-mutation in both LUAD and LUSC.	('ultra-mutation', 'MPA', (78, 92))	('NSCLC', 'Disease', (3, 8))	('NSCLC', 'Disease', 'MESH:D002289', (3, 8))	('LUAD', 'Disease', (101, 105))	('LUAD', 'Disease', 'None', (101, 105))	('result in', 'Reg', (68, 77))	('MMR', 'Gene', (57, 60))	('NSCLC', 'Phenotype', 'HP:0030358', (3, 8))	('mutations', 'Var', (14, 23))
385549	29650000	POLE mutation alone could predict the overall survival (OS) for LUSC but not LUAD patients.	('overall survival', 'MPA', (38, 54))	('patients', 'Species', '9606', (82, 90))	('LUAD', 'Disease', 'None', (77, 81))	('LUSC', 'Disease', (64, 68))	('LUAD', 'Disease', (77, 81))	('mutation', 'Var', (5, 13))
385553	29650000	Analysis using genomic data across multiple types of cancers from the TCGA cohort (Additional file 1: Methods and Materials) showed that LUSC and LUAD are among the cancers with the most frequent POLE mutations (28/497 = 5.6% and 31/513 = 6.0%, respectively), which are close to the rates in UCEC (28/519 = 5.4%) and CRC cancers (32/594 = 5.4%).	('cancers', 'Disease', 'MESH:D009369', (53, 60))	('LUAD', 'Disease', (146, 150))	('cancers', 'Disease', 'MESH:D009369', (165, 172))	('UCEC', 'Disease', (292, 296))	('CRC cancers', 'Disease', 'MESH:D015179', (317, 328))	('cancers', 'Disease', 'MESH:D009369', (321, 328))	('LUAD', 'Disease', 'None', (146, 150))	('cancers', 'Phenotype', 'HP:0002664', (53, 60))	('cancers', 'Disease', (53, 60))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('cancers', 'Phenotype', 'HP:0002664', (165, 172))	('LUSC', 'Disease', (137, 141))	('cancers', 'Disease', (165, 172))	('CRC cancers', 'Disease', (317, 328))	('cancers', 'Phenotype', 'HP:0002664', (321, 328))	('mutations', 'Var', (201, 210))	('cancers', 'Disease', (321, 328))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('cancer', 'Phenotype', 'HP:0002664', (321, 327))
385554	29650000	However, compared to the UCEC cancer patients whose mutations mostly locate in the proofreading domain, the mutations in NSCLC patients are distributed across the POLE gene body (Additional file 2: Figure S1A).	('mutations', 'Var', (108, 117))	('patients', 'Species', '9606', (37, 45))	('cancer', 'Disease', (30, 36))	('NSCLC', 'Disease', (121, 126))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('patients', 'Species', '9606', (127, 135))	('NSCLC', 'Disease', 'MESH:D002289', (121, 126))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('NSCLC', 'Phenotype', 'HP:0030358', (121, 126))
385558	29650000	However, the presence of POLE mutations in LUAD patients (see Additional file 3: Table S2 for descriptive characteristics) were not associated with statistically significant improvement in OS (P = 0.12, Fig.	('mutations', 'Var', (30, 39))	('LUAD', 'Disease', 'None', (43, 47))	('LUAD', 'Disease', (43, 47))	('patients', 'Species', '9606', (48, 56))	('improvement', 'Reg', (174, 185))
385559	29650000	The mortality rate of POLE-mutant LUAD patients was 96.8% (30/31 patients) at 5.5-year follow-up, which was higher than the 90.9% (438/482) of POLE-wild patients.	('LUAD', 'Disease', 'None', (34, 38))	('LUAD', 'Disease', (34, 38))	('patients', 'Species', '9606', (153, 161))	('patients', 'Species', '9606', (39, 47))	('POLE-mutant', 'Var', (22, 33))	('patients', 'Species', '9606', (65, 73))	('higher', 'PosReg', (108, 114))
385562	29650000	Yet, analysis of TCGA samples with high- (top 20%, n = 102), low- (bottom 20%, n = 102), and intermediate (others, n = 302) PD-L1 expression levels, who had not received IO therapy treatments, did not demonstrate that the LUAD patients with high PD-L1 expression had longer OS (P = 0.13, Fig.	('PD-L1', 'Gene', (124, 129))	('LUAD', 'Disease', (222, 226))	('PD-L1', 'Gene', (246, 251))	('PD-L1', 'Gene', '29126', (124, 129))	('PD-L1', 'Gene', '29126', (246, 251))	('IO', 'Chemical', '-', (170, 172))	('LUAD', 'Disease', 'None', (222, 226))	('high', 'Var', (241, 245))	('patients', 'Species', '9606', (227, 235))
385567	29650000	It is worth noting that PD-L1 expression could not stratify POLE-wild LUAD patients by OS (P = 0.55, 93 High (top 20%) vs. 383 Low (others), Additional file 2: Figure S2A) although high expression levels of PD-L1 was associated with higher TMB (P = 0.0051, Additional file 2: Figure S2B).	('TMB', 'Disease', (240, 243))	('PD-L1', 'Gene', (207, 212))	('TMB', 'Chemical', '-', (240, 243))	('LUAD', 'Disease', (70, 74))	('patients', 'Species', '9606', (75, 83))	('higher', 'PosReg', (233, 239))	('expression levels', 'MPA', (186, 203))	('LUAD', 'Disease', 'None', (70, 74))	('high', 'Var', (181, 185))	('PD-L1', 'Gene', '29126', (207, 212))	('PD-L1', 'Gene', (24, 29))	('PD-L1', 'Gene', '29126', (24, 29))
385574	29650000	The results showed that Mut-High patients indeed contained lower TIL (P = 9.0e-4, Fig.	('Mut-High', 'Var', (24, 32))	('lower', 'NegReg', (59, 64))	('patients', 'Species', '9606', (33, 41))	('TIL', 'MPA', (65, 68))
385580	29650000	Gene expression analysis showed that signatures of immune response were upregulated in the Mut-High patients compared to the Mut-Low cases (Additional file 2: Figure S4A).	('upregulated', 'PosReg', (72, 83))	('patients', 'Species', '9606', (100, 108))	('immune response', 'CPA', (51, 66))	('Mut-High', 'Var', (91, 99))
385581	29650000	Further, GSEA showed that immune related pathways, such as T cell receptor signaling, JAK-STAT signaling, and B cell receptor signaling pathways, were activated in Mut-High group (Fig.	('immune related pathways', 'Pathway', (26, 49))	('T cell receptor signaling', 'MPA', (59, 84))	('GSEA', 'Chemical', '-', (9, 13))	('B cell receptor signaling pathways', 'Pathway', (110, 144))	('Mut-High group', 'Var', (164, 178))	('JAK-STAT signaling', 'MPA', (86, 104))	('activated', 'PosReg', (151, 160))
385583	29650000	Metabolic pathways related to retinol metabolism, and drug and xenobiotic metabolism through cytochrome p450 were activated in the Mut-Low group (Fig.	('Mut-Low', 'Var', (131, 138))	('retinol', 'Chemical', 'MESH:D014801', (30, 37))	('activated', 'PosReg', (114, 123))	('cytochrome p450', 'Enzyme', (93, 108))	('xenobiotic metabolism', 'Disease', (63, 84))	('Metabolic', 'Enzyme', (0, 9))	('xenobiotic metabolism', 'Disease', 'MESH:D008659', (63, 84))
385588	29650000	Our results identify the molecular signatures associated with POLE mutations and PD-L1 expression in LUAD and LUSC and may reveal a distinct response status to chemotherapy and immunotherapy, which needs further experiments to validate.	('POLE', 'Gene', (62, 66))	('PD-L1', 'Gene', (81, 86))	('LUAD', 'Disease', (101, 105))	('mutations', 'Var', (67, 76))	('LUAD', 'Disease', 'None', (101, 105))	('PD-L1', 'Gene', '29126', (81, 86))
385592	30519093	Tissue microarrays were conducted on 209 surgically resected T3N1-3M0 ESCC tumors, including 163 pairs of primary tumors (PTs) and their corresponding metastatic lymph nodes (MLNs).	('primary tumors', 'Disease', (106, 120))	('primary tumors', 'Disease', 'MESH:D009369', (106, 120))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('T3N1-3M0', 'Var', (61, 69))	('ESCC tumors', 'Disease', (70, 81))	('MLN', 'Gene', (175, 178))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('ESCC tumors', 'Disease', 'MESH:D004938', (70, 81))	('MLN', 'Gene', '4295', (175, 178))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))
385597	30519093	High expression of HDAC6 in MLNs but not in PTs suggests a poor prognosis for patients with resected T3N1-3M0 ESCC.	('T3N1-3M0', 'Var', (101, 109))	('MLN', 'Gene', '4295', (28, 31))	('expression', 'MPA', (5, 15))	('patients', 'Species', '9606', (78, 86))	('MLN', 'Gene', (28, 31))	('HDAC6', 'Gene', (19, 24))
385613	30519093	Its dysregulation relates to many kinds of cancers, with variable effects; high expression of HDAC6 has been shown to be associated with tumor development in hepatocellular cancer, pancreatic cancer, and glioblastoma, while decreased expression has been found to be associated with the suppression of proliferation, migration, or invasion in breast cancer, lung cancer, and gastric cancer.	('glioblastoma', 'Disease', 'MESH:D005909', (204, 216))	('high expression', 'Var', (75, 90))	('pancreatic cancer', 'Disease', 'MESH:D010190', (181, 198))	('breast cancer', 'Disease', (342, 355))	('lung cancer', 'Disease', (357, 368))	('cancers', 'Phenotype', 'HP:0002664', (43, 50))	('cancers', 'Disease', (43, 50))	('gastric cancer', 'Disease', 'MESH:D013274', (374, 388))	('proliferation', 'CPA', (301, 314))	('glioblastoma', 'Disease', (204, 216))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('pancreatic cancer', 'Disease', (181, 198))	('glioblastoma', 'Phenotype', 'HP:0012174', (204, 216))	('migration', 'CPA', (316, 325))	('suppression', 'NegReg', (286, 297))	('hepatocellular cancer', 'Disease', (158, 179))	('HDAC6', 'Gene', (94, 99))	('lung cancer', 'Disease', 'MESH:D008175', (357, 368))	('hepatocellular cancer', 'Phenotype', 'HP:0001402', (158, 179))	('gastric cancer', 'Phenotype', 'HP:0012126', (374, 388))	('cancer', 'Phenotype', 'HP:0002664', (349, 355))	('tumor', 'Disease', (137, 142))	('lung cancer', 'Phenotype', 'HP:0100526', (357, 368))	('hepatocellular cancer', 'Disease', 'MESH:D006528', (158, 179))	('cancers', 'Disease', 'MESH:D009369', (43, 50))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (181, 198))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('breast cancer', 'Phenotype', 'HP:0003002', (342, 355))	('associated', 'Reg', (121, 131))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('invasion', 'CPA', (330, 338))	('gastric cancer', 'Disease', (374, 388))	('cancer', 'Phenotype', 'HP:0002664', (362, 368))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('breast cancer', 'Disease', 'MESH:D001943', (342, 355))
385619	30519093	Additional selection criteria included 1) pathological proof of thoracic T3N1-3M0 ESCC according to the eighth edition American Joint Committee on Cancer TNM staging system, 2) the absence of neoadjuvant or adjuvant therapy, 3) complete surgical resection, 4) and sufficient formalin-fixed and paraffin-embedded PT and MLN samples for tissue micro-arrays (TMAs).	('TNM', 'Gene', (154, 157))	('TMAs', 'Chemical', '-', (356, 360))	('MLN', 'Gene', (319, 322))	('Cancer', 'Phenotype', 'HP:0002664', (147, 153))	('MLN', 'Gene', '4295', (319, 322))	('paraffin', 'Chemical', 'MESH:D010232', (294, 302))	('formalin', 'Chemical', 'MESH:D005557', (275, 283))	('TNM', 'Gene', '10178', (154, 157))	('T3N1-3M0', 'Var', (73, 81))
385655	30519093	The 5-year OS rates for high and low HDAC6 expression in MLNs were 12.1% and 21.4%, respectively (Figure 3A and B).	('low', 'NegReg', (33, 36))	('OS', 'Chemical', '-', (11, 13))	('MLN', 'Gene', (57, 60))	('high', 'Var', (24, 28))	('MLN', 'Gene', '4295', (57, 60))	('HDAC6', 'Gene', (37, 42))
385657	30519093	The 5-year OS rates for high and low HDAC6 expression in PTs were 17.4% and 18.0%, respectively (Figure 3C and D).	('HDAC6', 'Gene', (37, 42))	('OS', 'Chemical', '-', (11, 13))	('low', 'Var', (33, 36))
385662	30519093	In patients with pN2 and pN3, there was no significant difference in OS or DFS between high and low HDAC6 expression in MLNs (Figure 4C-F).	('pN3', 'Gene', (25, 28))	('pN2', 'Gene', (17, 20))	('OS', 'Chemical', '-', (69, 71))	('pN2', 'Gene', '351', (17, 20))	('MLN', 'Gene', (120, 123))	('HDAC6', 'Gene', (100, 105))	('high', 'Var', (87, 91))	('patients', 'Species', '9606', (3, 11))	('MLN', 'Gene', '4295', (120, 123))	('low', 'Var', (96, 99))	('pN3', 'Gene', '6336', (25, 28))	('DFS', 'MPA', (75, 78))
385675	30519093	Our previous study also revealed that high expression of C-terminal Hsp-interacting protein (CHIP) in MLNs suggests a poor prognosis for patients with resected T3N1-3M0 ESCC.	('C-terminal Hsp-interacting protein', 'Protein', (57, 91))	('MLN', 'Gene', (102, 105))	('patients', 'Species', '9606', (137, 145))	('MLN', 'Gene', '4295', (102, 105))	('T3N1-3M0 ESCC', 'Var', (160, 173))	('expression', 'MPA', (43, 53))
385678	30519093	In an ESCC in vitro model, Li et al confirmed its role in tumor progression by showing that cell proliferation and migration could both be significantly reduced after HDAC6 inhibition.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('HDAC6', 'Gene', (167, 172))	('migration', 'CPA', (115, 124))	('reduced', 'NegReg', (153, 160))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('cell proliferation', 'CPA', (92, 110))	('inhibition', 'Var', (173, 183))
385688	30519093	HDAC6 expression was decreased in MLNs compared to their paired PTs and may serve as an independent predictor for prognosis of complete surgically resected T3N1-3M0 ESCC patients.	('patients', 'Species', '9606', (170, 178))	('HDAC6', 'Gene', (0, 5))	('decreased', 'NegReg', (21, 30))	('expression', 'MPA', (6, 16))	('MLN', 'Gene', (34, 37))	('T3N1-3M0 ESCC', 'Var', (156, 169))	('MLN', 'Gene', '4295', (34, 37))
385697	30233226	Multiple mechanisms are related to the development of ESCC in achalasia, and they include bacterial overgrowth, food stasis, genetic alterations, and chronic inflammation.	('genetic alterations', 'Var', (125, 144))	('ESCC', 'Disease', (54, 58))	('men', 'Species', '9606', (46, 49))	('overgrowth', 'Phenotype', 'HP:0001548', (100, 110))	('achalasia', 'Phenotype', 'HP:0002571', (62, 71))	('inflammation', 'Disease', 'MESH:D007249', (158, 170))	('achalasia', 'Disease', (62, 71))	('achalasia', 'Disease', 'MESH:D004931', (62, 71))	('food stasis', 'Disease', (112, 123))	('inflammation', 'Disease', (158, 170))
385735	30233226	The cyclin D1 (CCND1) G870A polymorphism has also been associated with ESCC.	('G870A', 'Var', (22, 27))	('ESCC', 'Disease', (71, 75))	('CCND1', 'Gene', (15, 20))	('associated', 'Reg', (55, 65))	('CCND1', 'Gene', '595', (15, 20))	('cyclin D1', 'Gene', '595', (4, 13))	('G870A', 'Mutation', 'rs9344', (22, 27))	('cyclin D1', 'Gene', (4, 13))
385777	30233226	Regarding p53, in addition to overexpression in ESCC with achalasia, there are also mutational changes of that tumor suppressor.	('achalasia', 'Disease', 'MESH:D004931', (58, 67))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('p53', 'Gene', '7157', (10, 13))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('p53', 'Gene', (10, 13))	('achalasia', 'Phenotype', 'HP:0002571', (58, 67))	('tumor', 'Disease', (111, 116))	('mutational changes', 'Var', (84, 102))	('ESCC', 'Disease', (48, 52))	('achalasia', 'Disease', (58, 67))
385779	30233226	Other genetic abnormalities described in ESCC associated with achalasia include mutations that could be associated with advanced megaesophagus due to Chagas disease.	('advanced megaesophagus', 'Disease', (120, 142))	('mutations', 'Var', (80, 89))	('Chagas disease', 'Disease', (150, 164))	('genetic abnormalities', 'Disease', 'MESH:D030342', (6, 27))	('associated', 'Reg', (104, 114))	('genetic abnormalities', 'Disease', (6, 27))	('ESCC', 'Disease', (41, 45))	('achalasia', 'Phenotype', 'HP:0002571', (62, 71))	('Chagas disease', 'Disease', 'MESH:D014355', (150, 164))	('associated', 'Reg', (46, 56))	('achalasia', 'Disease', (62, 71))	('achalasia', 'Disease', 'MESH:D004931', (62, 71))
385780	30233226	A silent mutation at codon 88 of exon 7 of the FHIT gene and a mutation involving exon 6 of the TP53 gene, as well as mutations in exons 5 and 7 of that gene, have been reported.	('FHIT', 'Gene', (47, 51))	('TP53', 'Gene', (96, 100))	('mutations', 'Var', (118, 127))	('FHIT', 'Gene', '2272', (47, 51))	('TP53', 'Gene', '7157', (96, 100))
385812	30233226	Finally, several preventive strategies are under investigation to prevent ESCC (achalasia related or nonrelated) using agents such as nonsteroidal antiinflammatory drugs, selenium, alpha-difluoromethylornithine, and retinoids.	('achalasia', 'Disease', (80, 89))	('alpha-difluoromethylornithine', 'Var', (181, 210))	('achalasia', 'Disease', 'MESH:D004931', (80, 89))	('retinoids', 'Chemical', 'MESH:D012176', (216, 225))	('ESCC', 'Disease', (74, 78))	('alpha-difluoromethylornithine', 'Chemical', 'MESH:D000518', (181, 210))	('selenium', 'Chemical', 'MESH:D012643', (171, 179))	('achalasia', 'Phenotype', 'HP:0002571', (80, 89))
385824	29610553	In the PGE2 synthetic pathway, the isozymes cyclooxygenase (COX)-2 and microsomal PGE synthase-1 (mPGES-1) are induced by the pathophysiological conditions, and the hyperproduced PGE2 evokes the disease.	('disease', 'Disease', (195, 202))	('PGE2', 'Chemical', 'MESH:D015232', (179, 183))	('PGE2', 'Chemical', 'MESH:D015232', (7, 11))	('PGE2', 'Enzyme', (7, 11))	('mPGES-1', 'Gene', '64292', (98, 105))	('PGE2', 'Gene', (179, 183))	('hyperproduced', 'Var', (165, 178))	('evokes', 'Reg', (184, 190))	('mPGES-1', 'Gene', (98, 105))
385825	29610553	Clinically, COX inhibitors, namely non-steroidal anti-inflammatory drugs (NSAIDs), are commonly used for pyretolysis and pain relief, however, most NSAIDs target constitutive COX-1 and inducible COX-2 and cause side effects such as gastrointestinal toxicity and cardiovascular risk.	('pain', 'Phenotype', 'HP:0012531', (121, 125))	('NSAIDs', 'Var', (148, 154))	('pain', 'Disease', 'MESH:D010146', (121, 125))	('COX-1', 'Gene', '17708', (175, 180))	('pain', 'Disease', (121, 125))	('cardiovascular risk', 'Disease', (262, 281))	('COX-2', 'Gene', '17709', (195, 200))	('gastrointestinal toxicity', 'Disease', 'MESH:D005767', (232, 257))	('COX-1', 'Gene', (175, 180))	('gastrointestinal toxicity', 'Disease', (232, 257))	('COX-2', 'Gene', (195, 200))	('cause', 'Reg', (205, 210))	('target', 'Reg', (155, 161))
385924	26819410	DeltaNp63 activates the Fanconi anemia DNA repair pathway and limits the efficacy of cisplatin treatment in squamous cell carcinoma TP63, a member of the p53 gene family gene, encodes the DeltaNp63 protein and is one of the most frequently amplified genes in squamous cell carcinomas (SCC) of the head and neck (HNSCC) and lungs (LUSC).	('Fanconi anemia', 'Disease', 'MESH:D005199', (24, 38))	('squamous cell carcinoma', 'Disease', (108, 131))	('anemia', 'Phenotype', 'HP:0001903', (32, 38))	('limits', 'NegReg', (62, 68))	('SCC', 'Gene', '6317', (314, 317))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (259, 283))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (259, 282))	('SCC', 'Phenotype', 'HP:0002860', (285, 288))	('Fanconi anemia', 'Phenotype', 'HP:0001994', (24, 38))	('SCC', 'Gene', (314, 317))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (259, 283))	('DeltaNp63', 'Chemical', '-', (188, 197))	('TP63', 'Gene', (132, 136))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (108, 131))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (259, 282))	('SCC', 'Gene', '6317', (285, 288))	('p53', 'Gene', '7157', (154, 157))	('DeltaNp63', 'Var', (0, 9))	('activates', 'PosReg', (10, 19))	('squamous cell carcinomas', 'Disease', (259, 283))	('TP63', 'Gene', '8626', (132, 136))	('cisplatin', 'Chemical', 'MESH:D002945', (85, 94))	('SCC', 'Gene', (285, 288))	('SCC', 'Phenotype', 'HP:0002860', (314, 317))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (108, 131))	('carcinoma', 'Phenotype', 'HP:0030731', (273, 282))	('carcinomas', 'Phenotype', 'HP:0030731', (273, 283))	('p53', 'Gene', (154, 157))	('Fanconi anemia', 'Disease', (24, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('DeltaNp63', 'Chemical', '-', (0, 9))
385928	26819410	Mechanistically, DeltaNp63 bound an upstream enhancer of FANCD2 inactive in primary keratinocytes but aberrantly activated by DeltaNp63 in SCC.	('SCC', 'Gene', '6317', (139, 142))	('enhancer', 'PosReg', (45, 53))	('DeltaNp63', 'Chemical', '-', (17, 26))	('activated', 'PosReg', (113, 122))	('FANCD2', 'Gene', (57, 63))	('FA', 'Phenotype', 'HP:0001994', (57, 59))	('SCC', 'Gene', (139, 142))	('SCC', 'Phenotype', 'HP:0002860', (139, 142))	('DeltaNp63', 'Var', (126, 135))	('DeltaNp63', 'Chemical', '-', (126, 135))
385929	26819410	Consistently, depletion of FANCD2 sensitized to cisplatin similar to depletion of DeltaNp63.	('FANCD2', 'Gene', (27, 33))	('cisplatin', 'Chemical', 'MESH:D002945', (48, 57))	('FA', 'Phenotype', 'HP:0001994', (27, 29))	('depletion', 'Var', (14, 23))	('DeltaNp63', 'Chemical', '-', (82, 91))	('sensitized', 'Reg', (34, 44))
385930	26819410	Together, our results demonstrate that DeltaNp63 directly activates the FA pathway in SCC and limits the efficacy of cisplatin treatment.	('activates', 'PosReg', (58, 67))	('SCC', 'Gene', (86, 89))	('efficacy', 'MPA', (105, 113))	('limits', 'NegReg', (94, 100))	('FA pathway', 'Pathway', (72, 82))	('cisplatin', 'Chemical', 'MESH:D002945', (117, 126))	('SCC', 'Phenotype', 'HP:0002860', (86, 89))	('FA', 'Phenotype', 'HP:0001994', (72, 74))	('SCC', 'Gene', '6317', (86, 89))	('DeltaNp63', 'Var', (39, 48))	('DeltaNp63', 'Chemical', '-', (39, 48))
385931	26819410	Targeting DeltaNp63 therefore would not only inhibit SCC proliferation but also sensitize tumors to chemotherapy.	('sensitize', 'Reg', (80, 89))	('DeltaNp63', 'Chemical', '-', (10, 19))	('SCC', 'Gene', '6317', (53, 56))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumors', 'Disease', (90, 96))	('tumors', 'Disease', 'MESH:D009369', (90, 96))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('SCC', 'Gene', (53, 56))	('inhibit', 'NegReg', (45, 52))	('DeltaNp63', 'Var', (10, 19))	('SCC', 'Phenotype', 'HP:0002860', (53, 56))
385934	26819410	Recent tumor genome sequencing studies have revealed TP63 amplification in 20-25% of head and neck SCC (HNSCC) and 25-50% of lung SCC (LUSC).	('SCC', 'Gene', (130, 133))	('SCC', 'Phenotype', 'HP:0002860', (99, 102))	('SCC', 'Phenotype', 'HP:0002860', (130, 133))	('SCC', 'Gene', '6317', (99, 102))	('SCC', 'Phenotype', 'HP:0002860', (106, 109))	('tumor', 'Disease', (7, 12))	('TP63', 'Gene', '8626', (53, 57))	('SCC', 'Gene', '6317', (106, 109))	('SCC', 'Gene', '6317', (130, 133))	('TP63', 'Gene', (53, 57))	('tumor', 'Disease', 'MESH:D009369', (7, 12))	('SCC', 'Gene', (99, 102))	('amplification', 'Var', (58, 71))	('SCC', 'Gene', (106, 109))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
385937	26819410	DeltaNp63 was shown to override oncogenic Ras induced senescence in keratinocytes enabling malignant transformation and to drive squamous transdifferentiation of Kras/p53-induced lung adenocarcinomas into SCC, together indicating a contribution of aberrant DeltaNp63 expression to SCC development.	('SCC', 'Phenotype', 'HP:0002860', (281, 284))	('drive', 'Reg', (123, 128))	('malignant transformation', 'CPA', (91, 115))	('p53', 'Gene', '7157', (167, 170))	('SCC', 'Gene', '6317', (281, 284))	('SCC', 'Phenotype', 'HP:0002860', (205, 208))	('p53', 'Gene', (167, 170))	('carcinoma', 'Phenotype', 'HP:0030731', (189, 198))	('SCC', 'Gene', (281, 284))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (179, 199))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (179, 198))	('DeltaNp63', 'Var', (0, 9))	('override', 'PosReg', (23, 31))	('SCC', 'Gene', '6317', (205, 208))	('DeltaNp63', 'Chemical', '-', (257, 266))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (179, 199))	('carcinomas', 'Phenotype', 'HP:0030731', (189, 199))	('SCC', 'Gene', (205, 208))	('squamous transdifferentiation', 'CPA', (129, 158))	('DeltaNp63', 'Chemical', '-', (0, 9))	('lung adenocarcinomas', 'Disease', (179, 199))
385938	26819410	Moreover, a number of studies indicate an essential requirement for p63 in SCC development and maintenance.	('SCC', 'Phenotype', 'HP:0002860', (75, 78))	('SCC', 'Gene', '6317', (75, 78))	('p63', 'Var', (68, 71))	('SCC', 'Gene', (75, 78))
385939	26819410	Heterozygosity of the mouse homolog Trp63 prevented SCC development in a model of ASPP2-haploinsufficiency, and deletion of Trp63 in DMBA-induced SCC of the skin resulted in rapid tumor regression.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('ASPP2-haploinsufficiency', 'Disease', (82, 106))	('deletion', 'Var', (112, 120))	('SCC', 'Gene', '6317', (146, 149))	('SCC', 'Gene', '6317', (52, 55))	('Trp63', 'Gene', (124, 129))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('Trp63', 'Gene', (36, 41))	('SCC', 'Gene', (146, 149))	('SCC', 'Gene', (52, 55))	('mouse', 'Species', '10090', (22, 27))	('DMBA', 'Chemical', 'MESH:C082386', (133, 137))	('ASPP2-haploinsufficiency', 'Disease', 'MESH:D058495', (82, 106))	('prevented', 'NegReg', (42, 51))	('tumor', 'Disease', (180, 185))	('SCC', 'Phenotype', 'HP:0002860', (52, 55))	('SCC', 'Phenotype', 'HP:0002860', (146, 149))	('Trp63', 'Gene', '22061', (124, 129))	('Trp63', 'Gene', '22061', (36, 41))
385947	26819410	We observed that, under unstressed conditions, DeltaNp63 is essential for proliferation but not survival of HNSCC cells.	('SCC', 'Gene', (110, 113))	('SCC', 'Phenotype', 'HP:0002860', (110, 113))	('DeltaNp63', 'Var', (47, 56))	('DeltaNp63', 'Chemical', '-', (47, 56))	('SCC', 'Gene', '6317', (110, 113))
385950	26819410	Its central factor FANCD2 contains an enhancer with a p63 response element that is directly bound and aberrantly activated by DeltaNp63 in SCC.	('SCC', 'Gene', '6317', (139, 142))	('enhancer', 'PosReg', (38, 46))	('FA', 'Phenotype', 'HP:0001994', (19, 21))	('p63 response element', 'MPA', (54, 74))	('activated', 'PosReg', (113, 122))	('SCC', 'Gene', (139, 142))	('SCC', 'Phenotype', 'HP:0002860', (139, 142))	('DeltaNp63', 'Var', (126, 135))	('DeltaNp63', 'Chemical', '-', (126, 135))
385951	26819410	As FANCD2 is found to be essential for a cytotoxic cisplatin response, p63 targeting could prevent repair of cisplatin-induced ICL via the FA pathway and improve the chemotherapy response of p63-overexpressing SCC.	('prevent', 'NegReg', (91, 98))	('improve', 'PosReg', (154, 161))	('SCC', 'Gene', (210, 213))	('p63 targeting', 'Var', (71, 84))	('cisplatin', 'Chemical', 'MESH:D002945', (51, 60))	('SCC', 'Phenotype', 'HP:0002860', (210, 213))	('FA', 'Phenotype', 'HP:0001994', (3, 5))	('FA pathway', 'Pathway', (139, 149))	('repair of cisplatin-induced ICL', 'MPA', (99, 130))	('SCC', 'Gene', '6317', (210, 213))	('FA', 'Phenotype', 'HP:0001994', (139, 141))	('chemotherapy response', 'CPA', (166, 187))	('cisplatin', 'Chemical', 'MESH:D002945', (109, 118))
385972	26819410	Intensity data for each array were normalized by the LOESS method, expression levels (M-value) calculated by the ratio of Cy5 to Cy3 and filtered for a minimum intensity (A-value) of 5.	('Cy3', 'Chemical', '-', (129, 132))	('Cy5', 'Var', (122, 125))	('Cy5', 'Chemical', 'MESH:C085321', (122, 125))	('expression levels', 'MPA', (67, 84))
386001	26819410	For functional analysis we depleted p63 with an epiallelic series of siRNAs yielding different degrees of DeltaNp63 knockdown (Figure 1A).	('DeltaNp63', 'Chemical', '-', (106, 115))	('DeltaNp63', 'Gene', (106, 115))	('knockdown', 'Var', (116, 125))
386002	26819410	We included siRNAs targeting both p63 isoforms TAp63 and DeltaNp63 (p63si-S1 and p63si-R2) as well as siRNAs specific for DeltaNp63 as the major p63 isoform in SCC (p63si-S2 and p63si-R1).	('p63si-S2', 'Var', (165, 173))	('p63si-R2', 'Var', (81, 89))	('p63si-R1', 'Var', (178, 186))	('DeltaNp63', 'Chemical', '-', (57, 66))	('SCC', 'Gene', (160, 163))	('DeltaNp63', 'Chemical', '-', (122, 131))	('SCC', 'Phenotype', 'HP:0002860', (160, 163))	('SCC', 'Gene', '6317', (160, 163))
386006	26819410	Therefore, we concluded that DeltaNp63 is essential for proliferation but not survival in SCC independent of TAp73.	('DeltaNp63', 'Var', (29, 38))	('DeltaNp63', 'Chemical', '-', (29, 38))	('SCC', 'Gene', (90, 93))	('SCC', 'Phenotype', 'HP:0002860', (90, 93))	('SCC', 'Gene', '6317', (90, 93))	('TAp73', 'Chemical', '-', (109, 114))
386008	26819410	When we depleted DeltaNp63 in HNSCC cells using the epiallelic series of siRNAs we noted completely opposite effects on the cisplatin response depending on knockdown efficiency: partial depletion of DeltaNp63 (p63si-S1/S2) sensitized toward cisplatin, whereas the complete knockdown (p63si-R1/R2) rendered cells more resistant (Figure 2A).	('DeltaNp63', 'Chemical', '-', (17, 26))	('cisplatin', 'Chemical', 'MESH:D002945', (241, 250))	('cisplatin', 'Chemical', 'MESH:D002945', (124, 133))	('sensitized', 'Reg', (223, 233))	('DeltaNp63 (p63si-S1/S2', 'Var', (199, 221))	('SCC', 'Gene', (32, 35))	('p63si-R1/R2', 'Var', (284, 295))	('SCC', 'Phenotype', 'HP:0002860', (32, 35))	('depletion', 'NegReg', (186, 195))	('SCC', 'Gene', '6317', (32, 35))	('DeltaNp63', 'Chemical', '-', (199, 208))
386024	26819410	Moreover, a plethora of DNA repair pathways was altered upon p63 depletion in line with previous studies on mouse embryonic fibroblasts and primary keratinocytes.	('plethora', 'Phenotype', 'HP:0001050', (12, 20))	('DNA repair pathways', 'Pathway', (24, 43))	('altered', 'Reg', (48, 55))	('mouse', 'Species', '10090', (108, 113))	('p63 depletion', 'Var', (61, 74))
386026	26819410	qPCR and Western Blot analysis of major components of this pathway like FANCD2 and its upstream regulators RAD18 and USP1 confirmed a p63-dependent gene expression in several HNSCC cell lines (Figure 4) which cannot be explained solely by a cell cycle-dependent regulation (Supplementary Figure S7).	('RAD18', 'Gene', '56852', (107, 112))	('FANCD2', 'Gene', (72, 78))	('FA', 'Phenotype', 'HP:0001994', (72, 74))	('SCC', 'Gene', (177, 180))	('p63-dependent', 'Var', (134, 147))	('SCC', 'Phenotype', 'HP:0002860', (177, 180))	('SCC', 'Gene', '6317', (177, 180))	('RAD18', 'Gene', (107, 112))
386027	26819410	When primary keratinocytes were transduced with DeltaNp63alpha this proved sufficient to induce strong expression of FANCD2 along with the FA pathway genes FANCA, FANCI and RAD18 (Figure 4D).	('FANCD2', 'Gene', (117, 123))	('induce', 'PosReg', (89, 95))	('DeltaNp63', 'Chemical', '-', (48, 57))	('FA', 'Phenotype', 'HP:0001994', (117, 119))	('RAD18', 'Gene', (173, 178))	('FANCA', 'Gene', '2175', (156, 161))	('RAD18', 'Gene', '56852', (173, 178))	('expression', 'MPA', (103, 113))	('FANCI', 'Gene', (163, 168))	('FANCA', 'Gene', (156, 161))	('FA', 'Phenotype', 'HP:0001994', (163, 165))	('FA', 'Phenotype', 'HP:0001994', (139, 141))	('FANCI', 'Gene', '55215', (163, 168))	('FA', 'Phenotype', 'HP:0001994', (156, 158))	('DeltaNp63alpha', 'Var', (48, 62))
386028	26819410	We therefore conclude that DeltaNp63 transactivates the FA pathway in SCC.	('DeltaNp63', 'Var', (27, 36))	('DeltaNp63', 'Chemical', '-', (27, 36))	('FA pathway', 'Pathway', (56, 66))	('FA', 'Phenotype', 'HP:0001994', (56, 58))	('SCC', 'Gene', (70, 73))	('transactivates', 'PosReg', (37, 51))	('SCC', 'Phenotype', 'HP:0002860', (70, 73))	('SCC', 'Gene', '6317', (70, 73))
386031	26819410	In vitro EMSA demonstrated sequence-specific binding of DeltaNp63alpha, the major isoform in SCC, to this site (Figure 5B).	('DeltaNp63', 'Chemical', '-', (56, 65))	('binding', 'Interaction', (45, 52))	('SCC', 'Gene', (93, 96))	('SCC', 'Phenotype', 'HP:0002860', (93, 96))	('SCC', 'Gene', '6317', (93, 96))	('DeltaNp63alpha', 'Var', (56, 70))
386032	26819410	Moreover, transactivation of a luciferase-reporter by DeltaNp63alpha through this site provided evidence for its functionality (Figure 5C).	('DeltaNp63', 'Chemical', '-', (54, 63))	('DeltaNp63alpha', 'Var', (54, 68))	('luciferase-reporter', 'Enzyme', (31, 50))	('transactivation', 'MPA', (10, 25))
386033	26819410	Sequence specificity was confirmed by mutating strongly conserved pyrimidines which prevented binding and transactivation (Figure 5B and C).	('mutating', 'Var', (38, 46))	('transactivation', 'MPA', (106, 121))	('pyrimidines', 'Chemical', 'MESH:D011743', (66, 77))	('pyrimidines', 'Protein', (66, 77))	('binding', 'Interaction', (94, 101))	('prevented', 'NegReg', (84, 93))
386038	26819410	We conclude that DeltaNp63 in SCC binds to and aberrantly activates an enhancer 10 kb upstream of FANCD2.	('activates', 'PosReg', (58, 67))	('SCC', 'Gene', '6317', (30, 33))	('FA', 'Phenotype', 'HP:0001994', (98, 100))	('binds', 'Interaction', (34, 39))	('DeltaNp63', 'Chemical', '-', (17, 26))	('SCC', 'Gene', (30, 33))	('DeltaNp63', 'Var', (17, 26))	('enhancer', 'PosReg', (71, 79))	('SCC', 'Phenotype', 'HP:0002860', (30, 33))
386040	26819410	FANCD2 knockdown had no effect on proliferation of untreated cells but strongly enhanced the cisplatin response leading to reduced colony formation (Figure 6B).	('FANCD2', 'Gene', (0, 6))	('colony formation', 'CPA', (131, 147))	('FA', 'Phenotype', 'HP:0001994', (0, 2))	('cisplatin', 'Chemical', 'MESH:D002945', (93, 102))	('enhanced', 'PosReg', (80, 88))	('knockdown', 'Var', (7, 16))	('cisplatin response', 'MPA', (93, 111))	('reduced', 'NegReg', (123, 130))
386041	26819410	Enforced expression of FANCD2 rescued the cisplatin sensitivity induced by FANCD2 knockdown, excluding an off-target effect (Supplementary Figure S9).	('cisplatin', 'Chemical', 'MESH:D002945', (42, 51))	('rescued', 'PosReg', (30, 37))	('FA', 'Phenotype', 'HP:0001994', (23, 25))	('Supplementary Figure S9', 'Disease', 'MESH:D017034', (125, 148))	('Supplementary Figure S9', 'Disease', (125, 148))	('knockdown', 'Var', (82, 91))	('cisplatin sensitivity', 'MPA', (42, 63))	('FANCD2', 'Gene', (75, 81))	('FANCD2', 'Gene', (23, 29))	('FA', 'Phenotype', 'HP:0001994', (75, 77))
386043	26819410	This is consistent with FANCD2 being not the only FA pathway component downregulated by DeltaNp63 depletion (Figure 4) and further supported by cisplatin sensitization following knockdown of FANCA, FANCL, FANCI or RAD18 (Supplementary Figure S11).	('RAD18', 'Gene', (214, 219))	('FA', 'Phenotype', 'HP:0001994', (50, 52))	('cisplatin', 'Chemical', 'MESH:D002945', (144, 153))	('cisplatin sensitization', 'MPA', (144, 167))	('FANCA', 'Gene', '2175', (191, 196))	('RAD18', 'Gene', '56852', (214, 219))	('FANCL', 'Gene', (198, 203))	('knockdown', 'Var', (178, 187))	('FA', 'Phenotype', 'HP:0001994', (191, 193))	('FANCL', 'Gene', '55120', (198, 203))	('FANCD2', 'Gene', (24, 30))	('downregulated', 'NegReg', (71, 84))	('FA', 'Phenotype', 'HP:0001994', (24, 26))	('DeltaNp63', 'Var', (88, 97))	('FANCA', 'Gene', (191, 196))	('FANCI', 'Gene', (205, 210))	('FA', 'Phenotype', 'HP:0001994', (205, 207))	('FA', 'Phenotype', 'HP:0001994', (198, 200))	('FANCI', 'Gene', '55215', (205, 210))	('DeltaNp63', 'Chemical', '-', (88, 97))
386044	26819410	Consistent with its predicted contribution to DNA damage repair, depletion of FANCD2 antagonized the reduction of gammaH2A.X after cisplatin exposure in SCC cells and led to an accumulation of gammaH2A.X indicative of deficient DNA repair (Figure 6C and D).	('FA', 'Phenotype', 'HP:0001994', (78, 80))	('SCC', 'Gene', '6317', (153, 156))	('cisplatin', 'Chemical', 'MESH:D002945', (131, 140))	('gammaH2A.X', 'MPA', (193, 203))	('SCC', 'Phenotype', 'HP:0002860', (153, 156))	('depletion', 'Var', (65, 74))	('FANCD2', 'Gene', (78, 84))	('gammaH2A', 'Chemical', '-', (114, 122))	('SCC', 'Gene', (153, 156))	('gammaH2A', 'Chemical', '-', (193, 201))	('antagonized', 'NegReg', (85, 96))	('accumulation', 'PosReg', (177, 189))	('DNA repair', 'CPA', (228, 238))	('deficient', 'NegReg', (218, 227))
386047	26819410	Statistical analysis revealed a significant correlation of p63 with RAD18 and FANCD2 protein levels in both tumor types (Figure 7A-D).	('FA', 'Phenotype', 'HP:0001994', (78, 80))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('p63', 'Var', (59, 62))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('tumor', 'Disease', (108, 113))	('FANCD2', 'Gene', (78, 84))	('RAD18', 'Gene', (68, 73))	('RAD18', 'Gene', '56852', (68, 73))	('correlation', 'Interaction', (44, 55))
386049	26819410	Consistent with p63 transactivating FA pathway genes, a copy number gain of TP63 was found to correlate significantly with elevated expression of FANCD2 and RAD18 in both HNSCC and LUSC (Figure 7E and F).	('TP63', 'Gene', (76, 80))	('TP63', 'Gene', '8626', (76, 80))	('FANCD2', 'Gene', (146, 152))	('RAD18', 'Gene', (157, 162))	('elevated', 'PosReg', (123, 131))	('FA', 'Phenotype', 'HP:0001994', (146, 148))	('SCC', 'Gene', (173, 176))	('SCC', 'Phenotype', 'HP:0002860', (173, 176))	('RAD18', 'Gene', '56852', (157, 162))	('FA', 'Phenotype', 'HP:0001994', (36, 38))	('expression', 'MPA', (132, 142))	('gain', 'PosReg', (68, 72))	('SCC', 'Gene', '6317', (173, 176))	('copy number', 'Var', (56, 67))
386053	26819410	Although previous studies have demonstrated the release of tumor-suppressive TAp73 from DeltaNp63/TAp73 complexes upon DeltaNp63 depletion, anti-proliferative effects of DeltaNp63 were independent of TAp73 in our experiments despite high expression levels of tumor-suppressive TAp73 in some of the cell lines.	('release', 'MPA', (48, 55))	('DeltaNp63', 'Chemical', '-', (119, 128))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Disease', (59, 64))	('DeltaNp63', 'Chemical', '-', (170, 179))	('tumor', 'Disease', 'MESH:D009369', (259, 264))	('TAp73', 'Chemical', '-', (277, 282))	('TAp73', 'Chemical', '-', (200, 205))	('tumor', 'Phenotype', 'HP:0002664', (259, 264))	('DeltaNp63/TAp73', 'Gene', (88, 103))	('DeltaNp63', 'Chemical', '-', (88, 97))	('DeltaNp63', 'Var', (119, 128))	('tumor', 'Disease', (259, 264))	('TAp73', 'Chemical', '-', (98, 103))	('expression', 'MPA', (238, 248))	('TAp73', 'Chemical', '-', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
386057	26819410	In contrast to unstressed conditions, we observed DeltaNp63 to strongly modulate survival of SCC cells exposed to cisplatin.	('modulate', 'Reg', (72, 80))	('survival', 'CPA', (81, 89))	('DeltaNp63', 'Var', (50, 59))	('cisplatin', 'Chemical', 'MESH:D002945', (114, 123))	('SCC', 'Gene', (93, 96))	('SCC', 'Phenotype', 'HP:0002860', (93, 96))	('DeltaNp63', 'Chemical', '-', (50, 59))	('SCC', 'Gene', '6317', (93, 96))
386062	26819410	As cisplatin-induced lesions are particularly toxic during S-phase when replication forks encountering crosslinks collapse and form DNA breaks, cisplatin-crosslinks are expected to be less cytotoxic in a DeltaNp63-deficient, non-replicating compared to a DeltaNp63-expressing, replicating cell.	('cisplatin', 'Chemical', 'MESH:D002945', (3, 12))	('less', 'NegReg', (184, 188))	('DeltaNp63', 'Chemical', '-', (255, 264))	('cytotoxic', 'CPA', (189, 198))	('cisplatin-crosslinks', 'Var', (144, 164))	('DeltaNp63', 'Chemical', '-', (204, 213))	('cisplatin', 'Chemical', 'MESH:D002945', (144, 153))
386064	26819410	Importantly, although highly efficient depletion of DeltaNp63 strongly reduces the cytotoxicity of cisplatin, tumor cell proliferation and clonogenicity are nevertheless effectively inhibited under these conditions (Figure 2D).	('cytotoxicity', 'Disease', 'MESH:D064420', (83, 95))	('DeltaNp63', 'Chemical', '-', (52, 61))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('depletion', 'MPA', (39, 48))	('clonogenicity', 'CPA', (139, 152))	('inhibited', 'NegReg', (182, 191))	('cytotoxicity', 'Disease', (83, 95))	('reduces', 'NegReg', (71, 78))	('DeltaNp63', 'Var', (52, 61))	('cisplatin', 'Chemical', 'MESH:D002945', (99, 108))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
386065	26819410	Thus, SCC patients would benefit from DeltaNp63 inhibition both from impaired tumor cell proliferation, which occurs primarily at maximum DeltaNp63 inhibition, and from sensitization to chemotherapy at lower than maximal inhibition levels.	('DeltaNp63', 'Chemical', '-', (38, 47))	('DeltaNp63', 'Var', (138, 147))	('DeltaNp63', 'Gene', (38, 47))	('SCC', 'Gene', (6, 9))	('DeltaNp63', 'Chemical', '-', (138, 147))	('SCC', 'Phenotype', 'HP:0002860', (6, 9))	('impaired tumor', 'Disease', (69, 83))	('SCC', 'Gene', '6317', (6, 9))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('patients', 'Species', '9606', (10, 18))	('impaired tumor', 'Disease', 'MESH:D015417', (69, 83))
386069	26819410	In particular, the expression of FANCD2 and its upstream regulators RAD18 and USP1 are dependent on DeltaNp63 and their expression correlated significantly with p63 protein levels and TP63 copy number across a large number of human SCC samples of the lung and head and neck.	('p63 protein levels', 'MPA', (161, 179))	('TP63', 'Gene', '8626', (184, 188))	('human', 'Species', '9606', (226, 231))	('DeltaNp63', 'Var', (100, 109))	('correlated', 'Reg', (131, 141))	('expression', 'MPA', (120, 130))	('TP63', 'Gene', (184, 188))	('DeltaNp63', 'Chemical', '-', (100, 109))	('FANCD2', 'Gene', (33, 39))	('USP1', 'Gene', (78, 82))	('FA', 'Phenotype', 'HP:0001994', (33, 35))	('SCC', 'Gene', (232, 235))	('SCC', 'Phenotype', 'HP:0002860', (232, 235))	('RAD18', 'Gene', (68, 73))	('RAD18', 'Gene', '56852', (68, 73))	('SCC', 'Gene', '6317', (232, 235))
386073	26819410	This region bears histone modification marks characteristic of an enhancer (high H3K4me3, low H3K4me1) consistent with preferential binding of DeltaNp63 to enhancers.	('DeltaNp63', 'Chemical', '-', (143, 152))	('high H3K4me3', 'Var', (76, 88))	('binding', 'Interaction', (132, 139))	('low H3K4me1', 'Var', (90, 101))
386076	26819410	In support of this, we observed strong FANCD2 induction upon ectopic DeltaNp63alpha expression in primary normal human epidermal keratinocytes, indicating that DeltaNp63 is sufficient to trigger FANCD2 upregulation (Figure 4D).	('FA', 'Phenotype', 'HP:0001994', (195, 197))	('DeltaNp63', 'Chemical', '-', (69, 78))	('DeltaNp63', 'Var', (160, 169))	('DeltaNp63alpha', 'Gene', (69, 83))	('DeltaNp63', 'Chemical', '-', (160, 169))	('FANCD2', 'Gene', (39, 45))	('FA', 'Phenotype', 'HP:0001994', (39, 41))	('induction', 'MPA', (46, 55))	('upregulation', 'PosReg', (202, 214))	('human', 'Species', '9606', (113, 118))
386080	26819410	FANCD2 is therefore on the one hand a mediator of oncogenic functions of DeltaNp63 in SCC, on the other it has been classified as a tumor suppressor gene as its deletion predisposes to the development of multiple epithelial tumor types including SCC.	('SCC', 'Gene', (86, 89))	('DeltaNp63', 'Chemical', '-', (73, 82))	('DeltaNp63', 'Gene', (73, 82))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('FA', 'Phenotype', 'HP:0001994', (0, 2))	('SCC', 'Phenotype', 'HP:0002860', (86, 89))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumor', 'Disease', (224, 229))	('predisposes to', 'Reg', (170, 184))	('SCC', 'Gene', '6317', (86, 89))	('deletion', 'Var', (161, 169))	('SCC', 'Gene', (246, 249))	('tumor', 'Disease', (132, 137))	('epithelial tumor', 'Phenotype', 'HP:0031492', (213, 229))	('SCC', 'Phenotype', 'HP:0002860', (246, 249))	('SCC', 'Gene', '6317', (246, 249))	('tumor', 'Disease', 'MESH:D009369', (224, 229))
386081	26819410	For example, deficiency of the O6-methylguanine-DNA methyltransferase (MGMT), which repairs the mutagenic DNA lesion O6-methylguanine, predisposes mice to cancer while at the same time predicting increased responsiveness of glioblastoma patients to the alkylating drug temozolomide.	('O6-methylguanine-DNA methyltransferase', 'Gene', (31, 69))	('O6-methylguanine-DNA methyltransferase', 'Gene', '17314', (31, 69))	('patients', 'Species', '9606', (237, 245))	('cancer', 'Disease', 'MESH:D009369', (155, 161))	('responsiveness', 'MPA', (206, 220))	('increased', 'PosReg', (196, 205))	('mice', 'Species', '10090', (147, 151))	('deficiency', 'Var', (13, 23))	('temozolomide', 'Chemical', 'MESH:D000077204', (269, 281))	('glioblastoma', 'Disease', 'MESH:D005909', (224, 236))	('O6-methylguanine', 'Chemical', 'MESH:C008449', (31, 47))	('predisposes', 'Reg', (135, 146))	('glioblastoma', 'Disease', (224, 236))	('glioblastoma', 'Phenotype', 'HP:0012174', (224, 236))	('cancer', 'Disease', (155, 161))	('O6-methylguanine', 'Chemical', 'MESH:C008449', (117, 133))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('MGMT', 'Gene', '17314', (71, 75))	('MGMT', 'Gene', (71, 75))
386085	26819410	Intriguingly, we identified not only FANCD2 but also USP1 to be upregulated by DeltaNp63 (Figure 4).	('DeltaNp63', 'Chemical', '-', (79, 88))	('upregulated', 'PosReg', (64, 75))	('USP1', 'Gene', (53, 57))	('FANCD2', 'Gene', (37, 43))	('FA', 'Phenotype', 'HP:0001994', (37, 39))	('DeltaNp63', 'Var', (79, 88))
386088	26819410	USP1 upregulation by DeltaNp63 is therefore consistent with improved DNA crosslink repair in SCC cells.	('DNA crosslink repair', 'MPA', (69, 89))	('SCC', 'Gene', (93, 96))	('SCC', 'Phenotype', 'HP:0002860', (93, 96))	('upregulation', 'PosReg', (5, 17))	('USP1', 'Gene', (0, 4))	('DeltaNp63', 'Chemical', '-', (21, 30))	('improved', 'PosReg', (60, 68))	('DeltaNp63', 'Var', (21, 30))	('SCC', 'Gene', '6317', (93, 96))
386094	26819410	First, inhibition of DeltaNp63 would be beneficial for tumor therapy by preventing SCC cell proliferation.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('DeltaNp63', 'Gene', (21, 30))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('SCC', 'Gene', (83, 86))	('tumor', 'Disease', (55, 60))	('inhibition', 'Var', (7, 17))	('SCC', 'Phenotype', 'HP:0002860', (83, 86))	('SCC', 'Gene', '6317', (83, 86))	('preventing', 'NegReg', (72, 82))	('DeltaNp63', 'Chemical', '-', (21, 30))
386095	26819410	Second, targeting DeltaNp63 would prevent repair of DNA lesions such as interstrand crosslinks via the FA pathway and thereby sensitize SCC cells to the current first-line therapy with cisplatin.	('targeting', 'Var', (8, 17))	('SCC', 'Gene', (136, 139))	('SCC', 'Phenotype', 'HP:0002860', (136, 139))	('DeltaNp63', 'Chemical', '-', (18, 27))	('DeltaNp63', 'Gene', (18, 27))	('FA pathway', 'Pathway', (103, 113))	('FA', 'Phenotype', 'HP:0001994', (103, 105))	('SCC', 'Gene', '6317', (136, 139))	('prevent', 'NegReg', (34, 41))	('sensitize', 'Reg', (126, 135))	('cisplatin', 'Chemical', 'MESH:D002945', (185, 194))	('repair', 'MPA', (42, 48))
386112	27045798	Subsequently, deregulated miRNAs play an important role in the regulation of tumour recurrence and metastasis.	('miRNAs', 'Protein', (26, 32))	('tumour', 'Disease', 'MESH:D009369', (77, 83))	('tumour', 'Disease', (77, 83))	('deregulated', 'Var', (14, 25))	('metastasis', 'CPA', (99, 109))	('tumour', 'Phenotype', 'HP:0002664', (77, 83))
386122	27045798	The IC50 value of SCC084/R and SCC131/R cells were increased by 1.6 and 3.5 fold (R index) upon 72 h incubation with cisplatin respectively as compared to their parental cells corroborating the fact that the number of viable cells is significantly high in cisplatin-resistant cells (Fig.	('IC50', 'MPA', (4, 8))	('cisplatin', 'Chemical', 'MESH:D002945', (117, 126))	('increased', 'PosReg', (51, 60))	('SCC084/R', 'Var', (18, 26))	('cisplatin', 'Chemical', 'MESH:D002945', (256, 265))	('SCC131/R', 'Var', (31, 39))
386127	27045798	The shape and size were also significantly changed in cisplatin-resistant cells compare to parent cells.	('changed', 'Reg', (43, 50))	('cisplatin-resistant', 'Var', (54, 73))	('shape', 'CPA', (4, 9))	('cisplatin', 'Chemical', 'MESH:D002945', (54, 63))
386135	27045798	Collectively, these observations revealed that SCC084/R and SCC131/R cells confer resistance by abrogating the cisplatin-induced apoptosis.	('cisplatin', 'Chemical', 'MESH:D002945', (111, 120))	('cisplatin-induced', 'MPA', (111, 128))	('SCC084/R', 'Var', (47, 55))	('SCC131/R', 'Var', (60, 68))	('abrogating', 'NegReg', (96, 106))
386138	27045798	Doxorubicin accumulation study corroborates our results and revealed that doxorubicin accumulation was significantly reduced in SCC131/R cells compared to SCC131 cells (Fig.	('SCC131/R', 'Var', (128, 136))	('doxorubicin', 'Chemical', 'MESH:D004317', (74, 85))	('reduced', 'NegReg', (117, 124))	('Doxorubicin', 'Chemical', 'MESH:D004317', (0, 11))	('doxorubicin accumulation', 'MPA', (74, 98))
386145	27045798	The results of the sphere forming assay revealed that the tumour sphere forming-ability was significantly increased in cisplatin-resistant SCC084/R and SCC131/R cells compared to parental SCC084 and SCC131 cells.	('SCC131/R', 'Var', (152, 160))	('tumour', 'Phenotype', 'HP:0002664', (58, 64))	('cisplatin-resistant SCC084/R', 'Var', (119, 147))	('tumour', 'Disease', 'MESH:D009369', (58, 64))	('tumour', 'Disease', (58, 64))	('increased', 'PosReg', (106, 115))	('cisplatin', 'Chemical', 'MESH:D002945', (119, 128))	('SCC084/R', 'Var', (139, 147))
386149	27045798	CD44 and c-Myc protein expression were significantly increased in SCC084/R cells while c-Myc and Oct-4 proteins were significantly increased in SCC131/R cells compared to SCC084 and SCC131 respectively (Fig.	('c-Myc', 'Gene', '4609', (87, 92))	('increased', 'PosReg', (131, 140))	('c-Myc', 'Gene', (87, 92))	('c-Myc', 'Gene', '4609', (9, 14))	('CD44', 'Gene', '960', (0, 4))	('c-Myc', 'Gene', (9, 14))	('Oct-4', 'Gene', '5460', (97, 102))	('increased', 'PosReg', (53, 62))	('CD44', 'Gene', (0, 4))	('SCC084/R', 'Var', (66, 74))	('Oct-4', 'Gene', (97, 102))
386157	27045798	Interestingly, we discovered that irrespective of drug treatment the cellular migration was significantly increased in cisplatin-resistant cell line compared to their parental-sensitive cells (Fig.	('cellular migration', 'CPA', (69, 87))	('increased', 'PosReg', (106, 115))	('cisplatin-resistant', 'Var', (119, 138))	('cisplatin', 'Chemical', 'MESH:D002945', (119, 128))
386163	27045798	Finally, we have established 6 miRNA signatures (miR-130b, miR-134, miR-149, miR-491, miR-181d, miR-146b) which are significantly (p <= 0.05) differentially expressed and common in both the cisplatin resistant cell lines (SCC084/R and SCC131/R) compared to their parental cell lines (SCC084 and SCC131) (Fig.	('miR-134', 'Var', (59, 66))	('miR-130b', 'Var', (49, 57))	('miR-491', 'Gene', (77, 84))	('miR-181d', 'Var', (86, 94))	('cisplatin', 'Chemical', 'MESH:D002945', (190, 199))	('miR-146b', 'Var', (96, 104))	('miR-149', 'Var', (68, 75))	('miR-491', 'Gene', '574444', (77, 84))
386172	27045798	7 signalling cross-talk proteins (octagon shape) and 3 rate limiting enzymes (triangle shape) are found to be deregulated under cisplatin resistance in various multi cancer cell lines.	('signalling', 'Pathway', (2, 12))	('cisplatin', 'Chemical', 'MESH:D002945', (128, 137))	('multi cancer', 'Disease', (160, 172))	('multi cancer', 'Disease', 'MESH:D009369', (160, 172))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('deregulated', 'MPA', (110, 121))	('cisplatin', 'Var', (128, 137))
386176	27045798	All these results revealed the resistance specific signature of miRNAs which might have an intricate role in the development of cisplatin-resistant oral cancer cells with CSC and EMT-type properties.	('cisplatin', 'Chemical', 'MESH:D002945', (128, 137))	('oral cancer', 'Disease', 'MESH:D009062', (148, 159))	('miRNAs', 'Var', (64, 70))	('cisplatin-resistant', 'MPA', (128, 147))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('oral cancer', 'Disease', (148, 159))
386186	27045798	We have found that SCC131/R resistant cells were exacerbating drug resistance through overexpression of ABC-transporter efflux proteins, P-gp (ABCB1) and MRP1 (ABCC1) whereas SCC084/R might have the other resistance mechanism.	('exacerbating', 'PosReg', (49, 61))	('ABCC1', 'Gene', (160, 165))	('MRP1', 'Gene', (154, 158))	('SCC131/R resistant', 'Var', (19, 37))	('drug resistance', 'Phenotype', 'HP:0020174', (62, 77))	('ABCC1', 'Gene', '24565', (160, 165))	('drug resistance', 'MPA', (62, 77))	('ABC-transporter efflux proteins', 'MPA', (104, 135))	('overexpression', 'PosReg', (86, 100))	('P-gp', 'MPA', (137, 141))
386212	27045798	There are 6 miRNAs, miR-130b, miR-134, miR-149, miR-491, miR-181d, miR-146b, which are common in both the resistant cells.	('miR-130b', 'Var', (20, 28))	('miR-146b', 'Var', (67, 75))	('miR-134', 'Var', (30, 37))	('miR-491', 'Gene', '574444', (48, 55))	('miR-149', 'Var', (39, 46))	('miR-181d', 'Var', (57, 65))	('miR-491', 'Gene', (48, 55))
386229	27045798	In contrary it has also been found that low expression of miR-146b-5p predicts poor prognosis and poor outcome of large B-cell lymphoma treated with cyclophosphamide, doxorubicin, vincristine and prednisone.	('prednisone', 'Chemical', 'MESH:D011241', (196, 206))	('lymphoma', 'Disease', (127, 135))	('low', 'NegReg', (40, 43))	('doxorubicin', 'Chemical', 'MESH:D004317', (167, 178))	('miR-146b-5p', 'Var', (58, 69))	('lymphoma', 'Disease', 'MESH:D008223', (127, 135))	('cyclophosphamide', 'Chemical', 'MESH:D003520', (149, 165))	('lymphoma', 'Phenotype', 'HP:0002665', (127, 135))	('vincristine', 'Chemical', 'MESH:D014750', (180, 191))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (120, 135))
386230	27045798	Similarly, there is an evidence of low level of miR-146b-5p responsible for the prometastatic process through AUF1 gene expression and miR-146b-5p expression positively regulate the epithelial markers (E-cadherin, EpCAM) and repress the mesenchymal markers (N-cadherin, vimentin, twist2 and ZEB1.	('mesenchymal markers', 'CPA', (237, 256))	('AUF1', 'Gene', '3184', (110, 114))	('N-cadherin', 'Gene', (258, 268))	('N-cadherin', 'Gene', '1000', (258, 268))	('epithelial', 'CPA', (182, 192))	('EpCAM', 'Gene', (214, 219))	('twist2', 'Gene', (280, 286))	('vimentin', 'Gene', '7431', (270, 278))	('twist2', 'Gene', '117581', (280, 286))	('repress', 'NegReg', (225, 232))	('ZEB1', 'Gene', (291, 295))	('vimentin', 'Gene', (270, 278))	('E-cadherin', 'Gene', (202, 212))	('positively', 'PosReg', (158, 168))	('E-cadherin', 'Gene', '999', (202, 212))	('miR-146b-5p', 'Var', (135, 146))	('EpCAM', 'Gene', '4072', (214, 219))	('prometastatic process', 'CPA', (80, 101))	('regulate', 'Reg', (169, 177))	('ZEB1', 'Gene', '6935', (291, 295))	('AUF1', 'Gene', (110, 114))
386231	27045798	Consequently, the level of miR-181d expression also revealed as a putative biomarker for lymph-node metastasis of oral cancer, and correlated with clinicopathological features in ovarian cancer and suggested as a predictive biomarker for glioblastoma.	('ovarian cancer', 'Phenotype', 'HP:0100615', (179, 193))	('lymph-node metastasis', 'CPA', (89, 110))	('cancer', 'Disease', 'MESH:D009369', (187, 193))	('glioblastoma', 'Phenotype', 'HP:0012174', (238, 250))	('correlated', 'Reg', (131, 141))	('miR-181d', 'Var', (27, 35))	('cancer', 'Disease', (187, 193))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('oral cancer', 'Disease', 'MESH:D009062', (114, 125))	('cancer', 'Disease', (119, 125))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('oral cancer', 'Disease', (114, 125))	('glioblastoma', 'Disease', (238, 250))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
386304	34039257	lncRNAs participate in embryogenesis, angiogenesis, and cancer progression by exerting epigenetic changes in many processes, including inactivation of X chromatin, regulation of the function of key metabolic genes, cell cycle control, and cell differentiation (Yao et al.	('X chromatin', 'Protein', (151, 162))	('cell cycle control', 'CPA', (215, 233))	('regulation', 'Reg', (164, 174))	('participate', 'Reg', (8, 19))	('function', 'MPA', (182, 190))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('cell differentiation', 'CPA', (239, 259))	('inactivation', 'Var', (135, 147))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))
386336	34039257	The effect of p53-regulated lncRNA TUG1 on the proliferation of non-small cell lung cancer cells was partly exerted through epigenetic regulation of homeobox B7 (HOXB7).	('homeobox B7', 'Gene', (149, 160))	('lung cancer', 'Disease', 'MESH:D008175', (79, 90))	('effect', 'Reg', (4, 10))	('HOXB7', 'Gene', '3217', (162, 167))	('p53', 'Gene', (14, 17))	('p53', 'Gene', '7157', (14, 17))	('HOXB7', 'Gene', (162, 167))	('lung cancer', 'Disease', (79, 90))	('lung cancer', 'Phenotype', 'HP:0100526', (79, 90))	('exerted', 'Reg', (108, 115))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (64, 90))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (68, 90))	('proliferation', 'CPA', (47, 60))	('homeobox B7', 'Gene', '3217', (149, 160))	('epigenetic regulation', 'Var', (124, 145))
386340	34039257	3. lncRNA TUG1 affected proliferation by regulating wnt/beta-catenin signal pathway, miR-384, miR-498, miR-29c, miR-299-3p, or microRNA-9, in oral squamous cell carcinoma, nasopharyngeal carcinoma,esophageal squamous cell carcinoma, pancreatic cancer, breast cancer, respectively.	('miR-498', 'Gene', '574460', (94, 101))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (233, 250))	('miR-29c', 'Gene', (103, 110))	('affected', 'Reg', (15, 23))	('breast cancer', 'Phenotype', 'HP:0003002', (252, 265))	('beta-catenin', 'Gene', (56, 68))	('miR-498', 'Gene', (94, 101))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (172, 196))	('miR-299-3p', 'Var', (112, 122))	('beta-catenin', 'Gene', '1499', (56, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (222, 231))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (142, 170))	('microRNA-9', 'Var', (127, 137))	('breast cancer', 'Disease', 'MESH:D001943', (252, 265))	('oral squamous cell carcinoma', 'Disease', (142, 170))	('breast cancer', 'Disease', (252, 265))	('pancreatic cancer', 'Disease', 'MESH:D010190', (233, 250))	('cancer', 'Phenotype', 'HP:0002664', (259, 265))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (147, 170))	('carcinoma,esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (187, 231))	('miR-384', 'Gene', (85, 92))	('pancreatic cancer', 'Disease', (233, 250))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('carcinoma', 'Phenotype', 'HP:0030731', (187, 196))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (208, 231))	('regulating', 'Reg', (41, 51))	('miR-384', 'Gene', '494333', (85, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (161, 170))	('miR-29c', 'Gene', '407026', (103, 110))
386373	34039257	lncRNA TUG1 promoted the proliferation, migration, and invasion of osteosarcoma through competitively sponging of miR-219a-5p, resulting in the up-regulation of phosphatidylinositol-4, 5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) and the activation of the protein kinase B (AKT) signal pathway (Yang et al.).	('promoted', 'PosReg', (12, 20))	('protein kinase B', 'Gene', (268, 284))	('osteosarcoma', 'Disease', 'MESH:D012516', (67, 79))	('proliferation', 'CPA', (25, 38))	('osteosarcoma', 'Phenotype', 'HP:0002669', (67, 79))	('up-regulation', 'PosReg', (144, 157))	('AKT', 'Gene', (286, 289))	('activation', 'PosReg', (250, 260))	('phosphatidylinositol-4, 5-bisphosphate 3-kinase catalytic subunit alpha', 'Gene', '5290', (161, 232))	('miR-219a-5p', 'Var', (114, 125))	('PIK3CA', 'Gene', (234, 240))	('protein kinase B', 'Gene', '2185', (268, 284))	('PIK3CA', 'Gene', '5290', (234, 240))	('invasion', 'CPA', (55, 63))	('migration', 'CPA', (40, 49))	('osteosarcoma', 'Disease', (67, 79))	('AKT', 'Gene', '207', (286, 289))
386375	34039257	To sum up, lncRNA TUG1 promoted invasion and metastasis by some molecule, including miR-143p, miR-9-5p, miR-212-3p, miR-219a-5p, miR-140-5p, miR-212-3p, miR-335-5p, miR-132-3p, SOX4, RUNX2, PFN2, ROCK1,FOXA1, or POU2F1 in osteosarcoma.	('osteosarcoma', 'Disease', 'MESH:D012516', (222, 234))	('PFN2', 'Gene', (190, 194))	('SOX4', 'Gene', (177, 181))	('miR-212', 'Gene', '406994', (141, 148))	('ROCK1', 'Gene', (196, 201))	('miR-140', 'Gene', (129, 136))	('miR-143p', 'Gene', '406935', (84, 92))	('miR-335', 'Gene', (153, 160))	('promoted', 'PosReg', (23, 31))	('PFN2', 'Gene', '5217', (190, 194))	('miR-140', 'Gene', '406932', (129, 136))	('SOX4', 'Gene', '6659', (177, 181))	('miR-132-3p', 'Gene', (165, 175))	('miR-143p', 'Gene', (84, 92))	('miR-212', 'Gene', (104, 111))	('RUNX2', 'Gene', (183, 188))	('miR-9-5p', 'Gene', '407052', (94, 102))	('osteosarcoma', 'Phenotype', 'HP:0002669', (222, 234))	('invasion', 'CPA', (32, 40))	('POU2F1', 'Gene', '5451', (212, 218))	('RUNX2', 'Gene', '860', (183, 188))	('ROCK1', 'Gene', '6093', (196, 201))	('FOXA1', 'Gene', '3169', (202, 207))	('miR-212', 'Gene', (141, 148))	('miR-9-5p', 'Gene', (94, 102))	('POU2F1', 'Gene', (212, 218))	('FOXA1', 'Gene', (202, 207))	('miR-212', 'Gene', '406994', (104, 111))	('miR-335', 'Gene', '442904', (153, 160))	('osteosarcoma', 'Disease', (222, 234))	('miR-132-3p', 'Gene', '100302255', (165, 175))	('miR-219a-5p', 'Var', (116, 127))
386383	34039257	lncRNA TUG1 knockout promoted cell growth by promoting cell cycle progression and regulating the expression of cyclinD1 and CDK4 (Fan et al.).	('lncRNA TUG1', 'Gene', (0, 11))	('cyclinD1', 'Gene', (111, 119))	('knockout', 'Var', (12, 20))	('CDK4', 'Gene', '1019', (124, 128))	('promoting', 'PosReg', (45, 54))	('regulating', 'Reg', (82, 92))	('cell cycle progression', 'CPA', (55, 77))	('cyclinD1', 'Gene', '595', (111, 119))	('promoted', 'PosReg', (21, 29))	('cell growth', 'CPA', (30, 41))	('expression', 'MPA', (97, 107))	('CDK4', 'Gene', (124, 128))
386400	34039257	In tongue squamous cell carcinoma, down-regulation of lncRNA TUG1 inhibited cell proliferation, and silencing of lncRNA TUG1 regulated the progression of the cell cycle (Li et al.).	('tongue squamous cell carcinoma', 'Disease', (3, 33))	('silencing', 'Var', (100, 109))	('progression of the cell cycle', 'CPA', (139, 168))	('cell proliferation', 'CPA', (76, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (24, 33))	('inhibited', 'NegReg', (66, 75))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (10, 33))	('lncRNA TUG1', 'Gene', (54, 65))	('lncRNA TUG1', 'Gene', (113, 124))	('tongue squamous cell carcinoma', 'Disease', 'MESH:D002294', (3, 33))	('down-regulation', 'NegReg', (35, 50))	('regulated', 'Reg', (125, 134))
386401	34039257	TUG1 knockout blocked cell cycle, accelerated apoptosis and inhibitted the proliferation of pancreatic cancer cells (Hui Bingqing and Yetao).	('apoptosis', 'CPA', (46, 55))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('TUG1', 'Gene', (0, 4))	('knockout', 'Var', (5, 13))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (92, 109))	('pancreatic cancer', 'Disease', (92, 109))	('accelerated', 'PosReg', (34, 45))	('blocked', 'NegReg', (14, 21))	('inhibitted', 'NegReg', (60, 70))	('cell cycle', 'CPA', (22, 32))	('proliferation', 'CPA', (75, 88))	('pancreatic cancer', 'Disease', 'MESH:D010190', (92, 109))
386402	34039257	Knocking out the TUG1 reduced that enhancer of zeste homolog 2 (EZH2) binded to the promoter regions of Rho family GTPase 3 (RND3) and metallothionein 2A (MT2A) (Hui Bingqing and Yetao).	('TUG1', 'Gene', (17, 21))	('enhancer of zeste homolog 2', 'Gene', '2146', (35, 62))	('MT2A', 'Gene', '4502', (155, 159))	('metallothionein 2A', 'Gene', (135, 153))	('enhancer of zeste homolog 2', 'Gene', (35, 62))	('MT2A', 'Gene', (155, 159))	('binded', 'Interaction', (70, 76))	('EZH2', 'Gene', '2146', (64, 68))	('RND3', 'Gene', (125, 129))	('metallothionein 2A', 'Gene', '4502', (135, 153))	('EZH2', 'Gene', (64, 68))	('Knocking', 'Var', (0, 8))	('RND3', 'Gene', '390', (125, 129))
386407	34039257	lncRNA TUG1 knockout inhibited glucose consumption, lactic acid production, and reduced the cell viability of osteosarcoma cells.	('lactic acid production', 'MPA', (52, 74))	('lncRNA TUG1', 'Gene', (0, 11))	('knockout', 'Var', (12, 20))	('glucose consumption', 'MPA', (31, 50))	('osteosarcoma', 'Disease', (110, 122))	('reduced', 'NegReg', (80, 87))	('osteosarcoma', 'Phenotype', 'HP:0002669', (110, 122))	('osteosarcoma', 'Disease', 'MESH:D012516', (110, 122))	('inhibited', 'NegReg', (21, 30))	('lactic acid', 'Chemical', 'MESH:D019344', (52, 63))	('glucose', 'Chemical', 'MESH:D005947', (31, 38))
386409	34039257	The abnormal expression of lncRNA TUG1 significantly affected the expression of hexokinase-2 (HK2), which might be an important molecule through which lncRNA TUG1 affects glycolysis (Xiufu et al.).	('lncRNA TUG1', 'Gene', (27, 38))	('affected', 'Reg', (53, 61))	('abnormal', 'Var', (4, 12))	('glycolysis', 'MPA', (171, 181))	('expression', 'MPA', (66, 76))	('HK2', 'Gene', '3099', (94, 97))	('affects', 'Reg', (163, 170))	('hexokinase-2', 'Gene', (80, 92))	('HK2', 'Gene', (94, 97))	('hexokinase-2', 'Gene', '3099', (80, 92))
386410	34039257	HK2 gene knockout weakened the effect of lncRNA TUG1 overexpression on glycolysis in osteosarcoma cells (Xiufu et al.).	('HK2', 'Gene', '3099', (0, 3))	('knockout', 'Var', (9, 17))	('osteosarcoma', 'Phenotype', 'HP:0002669', (85, 97))	('osteosarcoma', 'Disease', (85, 97))	('osteosarcoma', 'Disease', 'MESH:D012516', (85, 97))	('glycolysis', 'MPA', (71, 81))	('HK2', 'Gene', (0, 3))	('weakened', 'NegReg', (18, 26))
386411	34039257	lncRNA TUG1 was up-regulated in AML patients and cells, and its knockout inhibited glycolysis in AML cells by targeting miR-185 (Weide et al.).	('glycolysis', 'MPA', (83, 93))	('lncRNA TUG1', 'Gene', (0, 11))	('AML', 'Disease', 'MESH:D015470', (32, 35))	('miR-185', 'Gene', (120, 127))	('patients', 'Species', '9606', (36, 44))	('knockout', 'Var', (64, 72))	('AML', 'Phenotype', 'HP:0004808', (97, 100))	('AML', 'Disease', (97, 100))	('AML', 'Phenotype', 'HP:0004808', (32, 35))	('up-regulated', 'PosReg', (16, 28))	('AML', 'Disease', (32, 35))	('inhibited', 'NegReg', (73, 82))	('AML', 'Disease', 'MESH:D015470', (97, 100))	('targeting', 'Reg', (110, 119))	('miR-185', 'Gene', '406961', (120, 127))
386415	34039257	Knockout of lncRNA TUG1 inhibited angiogenesis in ovarian cancer by regulating LRG1 (Mingjun et al.).	('ovarian cancer', 'Disease', 'MESH:D010051', (50, 64))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('LRG1', 'Gene', (79, 83))	('ovarian cancer', 'Disease', (50, 64))	('inhibited', 'NegReg', (24, 33))	('lncRNA TUG1', 'Gene', (12, 23))	('Knockout', 'Var', (0, 8))	('angiogenesis', 'CPA', (34, 46))	('LRG1', 'Gene', '116844', (79, 83))	('ovarian cancer', 'Phenotype', 'HP:0100615', (50, 64))
386420	34039257	lncRNA TUG1 regulated CCND2, through EZH2-related miR-194-5p silencing, to promote the growth of bladder cancer cells and confer cisplatin resistance (Gan et al.).	('growth', 'MPA', (87, 93))	('cisplatin resistance', 'MPA', (129, 149))	('promote', 'PosReg', (75, 82))	('bladder cancer', 'Disease', 'MESH:D001749', (97, 111))	('bladder cancer', 'Disease', (97, 111))	('CCND2', 'Gene', (22, 27))	('bladder cancer', 'Phenotype', 'HP:0009725', (97, 111))	('cisplatin', 'Chemical', 'MESH:D002945', (129, 138))	('CCND2', 'Gene', '894', (22, 27))	('silencing', 'Var', (61, 70))	('confer', 'Reg', (122, 128))	('miR-194-5p silencing', 'Var', (50, 70))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('EZH2', 'Gene', '2146', (37, 41))	('EZH2', 'Gene', (37, 41))
386423	34039257	lncRNA TUG1 knockout can induce apoptosis by inhibiting MET/Akt signalling, thus reducing the resistance of osteosarcoma cells to cisplatin (Zhou Qiang and Yuan).	('resistance', 'MPA', (94, 104))	('reducing', 'NegReg', (81, 89))	('lncRNA TUG1', 'Gene', (0, 11))	('knockout', 'Var', (12, 20))	('Akt', 'Gene', '207', (60, 63))	('induce', 'PosReg', (25, 31))	('osteosarcoma', 'Phenotype', 'HP:0002669', (108, 120))	('osteosarcoma', 'Disease', (108, 120))	('osteosarcoma', 'Disease', 'MESH:D012516', (108, 120))	('MET', 'Gene', '79811', (56, 59))	('inhibiting', 'NegReg', (45, 55))	('Akt', 'Gene', (60, 63))	('MET', 'Gene', (56, 59))	('cisplatin', 'Chemical', 'MESH:D002945', (130, 139))
386427	34039257	lncRNA TUG1 enhanced adriamycin resistance in AML by inhibiting the expression of miR-34a through EZH2 epigenetically (Li et al.).	('EZH2', 'Gene', (98, 102))	('expression', 'MPA', (68, 78))	('AML', 'Phenotype', 'HP:0004808', (46, 49))	('epigenetically', 'Var', (103, 117))	('AML', 'Disease', (46, 49))	('miR-34a', 'Gene', '407040', (82, 89))	('adriamycin', 'Chemical', 'MESH:D004317', (21, 31))	('enhanced', 'PosReg', (12, 20))	('adriamycin resistance', 'MPA', (21, 42))	('AML', 'Disease', 'MESH:D015470', (46, 49))	('miR-34a', 'Gene', (82, 89))	('inhibiting', 'NegReg', (53, 63))	('EZH2', 'Gene', '2146', (98, 102))
386434	34039257	Knockout of lncRNA TUG1 enhanced the radiosensitivity of prostate cancer through the lncRNA TUG1/miR-139-5p/structural maintenance of chromosomes protein 1A (SMC1A) axis (Dianhui et al.).	('prostate cancer', 'Disease', (57, 72))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('prostate cancer', 'Disease', 'MESH:D011471', (57, 72))	('enhanced', 'PosReg', (24, 32))	('lncRNA TUG1', 'Gene', (12, 23))	('Knockout', 'Var', (0, 8))	('prostate cancer', 'Phenotype', 'HP:0012125', (57, 72))	('radiosensitivity', 'CPA', (37, 53))
386436	34039257	The high expression of lncRNA TUG1 was associated with chemotherapy resistance and poor prognosis in oesophageal squamous cell carcinoma (Lin et al.).	('chemotherapy resistance', 'CPA', (55, 78))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (113, 136))	('oesophageal squamous cell carcinoma', 'Disease', (101, 136))	('associated', 'Reg', (39, 49))	('high', 'Var', (4, 8))	('lncRNA TUG1', 'Gene', (23, 34))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('oesophageal squamous cell carcinoma', 'Disease', 'MESH:D002294', (101, 136))
386451	34039257	At present, there are relatively fewer clinical studies on lncRNA TUG1, but existing studies suggest that lncRNA TUG1 may be an effective diagnostic or prognostic cancer biomarker.	('cancer', 'Disease', (163, 169))	('cancer', 'Disease', 'MESH:D009369', (163, 169))	('lncRNA TUG1', 'Var', (106, 117))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))
386464	34039257	Although lncRNA TUG1 could reduce the radiosensitivity of bladder cancer, it could also enhance the radiosensitivity of esophageal cancer.	('cancer', 'Disease', (131, 137))	('radiosensitivity', 'MPA', (38, 54))	('radiosensitivity', 'MPA', (100, 116))	('lncRNA', 'Var', (9, 15))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('bladder cancer', 'Phenotype', 'HP:0009725', (58, 72))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('reduce', 'NegReg', (27, 33))	('bladder cancer', 'Disease', 'MESH:D001749', (58, 72))	('bladder cancer', 'Disease', (58, 72))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('cancer', 'Disease', (66, 72))	('enhance', 'PosReg', (88, 95))
386469	34039257	If any of the key proteins in this signalling pathway are mutated, resulting in abnormal signal activation, it may induce the development of cancer (Shuang et al.).	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('induce', 'Reg', (115, 121))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('mutated', 'Var', (58, 65))	('cancer', 'Disease', (141, 147))	('signal activation', 'MPA', (89, 106))
386470	34039257	For example, activating the Wnt/beta-catenin signalling pathway regulated the invasion and proliferation of oesophageal squamous cell carcinoma, cervical cancer, bladder cancer, and colorectal cancer, and induced their epithelial cell transformation (Fu-Bing et al.).	('colorectal cancer', 'Phenotype', 'HP:0003003', (182, 199))	('cancer', 'Disease', (170, 176))	('cancer', 'Disease', (193, 199))	('beta-catenin', 'Gene', (32, 44))	('beta-catenin', 'Gene', '1499', (32, 44))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('activating', 'Var', (13, 23))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('epithelial cell transformation', 'CPA', (219, 249))	('colorectal cancer', 'Disease', 'MESH:D015179', (182, 199))	('induced', 'Reg', (205, 212))	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('colorectal cancer', 'Disease', (182, 199))	('proliferation', 'CPA', (91, 104))	('bladder cancer', 'Disease', 'MESH:D001749', (162, 176))	('bladder cancer', 'Disease', (162, 176))	('invasion', 'CPA', (78, 86))	('bladder cancer', 'Phenotype', 'HP:0009725', (162, 176))	('cancer', 'Disease', (154, 160))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (120, 143))	('oesophageal squamous cell carcinoma', 'Disease', (108, 143))	('oesophageal squamous cell carcinoma', 'Disease', 'MESH:D002294', (108, 143))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))
386476	34039257	lncRNA TUG1 promoted the proliferation, migration, and invasion of hepatoma cells by activating the JAK2/STAT3 pathway, upregulating the expression of AURKA, interacting with miR-216B-5p and inhibiting apoptosis by activating DLX2, or by down-regulating miR-142-3p to regulate the miR-29c-3p/COL1A1 axis.	('proliferation', 'CPA', (25, 38))	('STAT3', 'Gene', '6774', (105, 110))	('migration', 'CPA', (40, 49))	('miR-142-3p', 'Pathway', (254, 264))	('hepatoma', 'Disease', 'MESH:D006528', (67, 75))	('COL1A1', 'Gene', (292, 298))	('activating', 'PosReg', (215, 225))	('expression', 'MPA', (137, 147))	('interacting', 'Interaction', (158, 169))	('JAK2', 'Gene', '3717', (100, 104))	('miR-142-3p', 'Chemical', '-', (254, 264))	('promoted', 'PosReg', (12, 20))	('activating', 'PosReg', (85, 95))	('upregulating', 'PosReg', (120, 132))	('down-regulating', 'NegReg', (238, 253))	('hepatoma', 'Disease', (67, 75))	('miR-29c', 'Gene', '407026', (281, 288))	('miR-216B-5p', 'Var', (175, 186))	('DLX2', 'Gene', (226, 230))	('invasion', 'CPA', (55, 63))	('apoptosis', 'CPA', (202, 211))	('DLX2', 'Gene', '1746', (226, 230))	('JAK2', 'Gene', (100, 104))	('AURKA', 'Gene', '6790', (151, 156))	('inhibiting', 'NegReg', (191, 201))	('AURKA', 'Gene', (151, 156))	('miR-29c', 'Gene', (281, 288))	('STAT3', 'Gene', (105, 110))	('COL1A1', 'Gene', '1277', (292, 298))
386477	34039257	lncRNA TUG1 regulated downstream genes, including miR-143p, miR-9-5p, miR-212-3p, miR-140-5p, microRNA-212-3p, miR-335-5p and miR-219a-5p, to participate in the proliferation and invasion of osteosarcoma cells.	('miR-212', 'Gene', '406994', (70, 77))	('invasion', 'CPA', (179, 187))	('osteosarcoma', 'Phenotype', 'HP:0002669', (191, 203))	('miR-140', 'Gene', (82, 89))	('lncRNA TUG1', 'Gene', (0, 11))	('miR-140', 'Gene', '406932', (82, 89))	('miR-335', 'Gene', '442904', (111, 118))	('miR-143p', 'Gene', '406935', (50, 58))	('miR-9-5p', 'Gene', '407052', (60, 68))	('participate', 'Reg', (142, 153))	('miR-143p', 'Gene', (50, 58))	('osteosarcoma', 'Disease', (191, 203))	('miR-212', 'Gene', (70, 77))	('osteosarcoma', 'Disease', 'MESH:D012516', (191, 203))	('miR-9-5p', 'Gene', (60, 68))	('proliferation', 'CPA', (161, 174))	('miR-219a-5p', 'Var', (126, 137))	('miR-335', 'Gene', (111, 118))	('microRNA-212-3p', 'Var', (94, 109))
386493	33436560	This TRIM25/circNDUFB2/IGF2BPs ternary complex facilitates ubiquitination and degradation of IGF2BPs, with this effect enhanced by N6-methyladenosine (m6A) modification of circNDUFB2.	('NDUFB2', 'Gene', '4708', (176, 182))	('facilitates', 'PosReg', (47, 58))	('TRIM25', 'Gene', '7706', (5, 11))	('NDUFB2', 'Gene', (16, 22))	('IGF2', 'Gene', '3481', (23, 27))	('IGF2', 'Gene', (93, 97))	('NDUFB2', 'Gene', '4708', (16, 22))	('TRIM25', 'Gene', (5, 11))	('ubiquitination', 'MPA', (59, 73))	('degradation', 'MPA', (78, 89))	('IGF2', 'Gene', (23, 27))	('N6-methyladenosine', 'Chemical', 'MESH:C010223', (131, 149))	('N6-methyladenosine', 'Var', (131, 149))	('NDUFB2', 'Gene', (176, 182))	('IGF2', 'Gene', '3481', (93, 97))	('enhanced', 'PosReg', (119, 127))	('m6A', 'Chemical', '-', (151, 154))
386512	33436560	A subset of circRNAs with double-stranded structure prefers to bind and suppress activation of protein kinase R (PKR), thereby inhibiting innate immune responses.	('bind', 'Interaction', (63, 67))	('activation', 'MPA', (81, 91))	('protein kinase R', 'Gene', '5610', (95, 111))	('suppress', 'NegReg', (72, 80))	('PKR', 'Gene', (113, 116))	('innate immune responses', 'CPA', (138, 161))	('inhibiting', 'NegReg', (127, 137))	('PKR', 'Gene', '5610', (113, 116))	('double-stranded structure', 'Var', (26, 51))	('protein kinase R', 'Gene', (95, 111))
386524	33436560	We next analyzed correlation between circNDUFB2 expression and clinicopathologic features in patients with NSCLC and found that high expression of circNDUFB2 was negatively associated with tumor size, lymph node metastasis, and stage in NSCLC patients (Supplementary Table 1).	('negatively', 'NegReg', (162, 172))	('NSCLC', 'Disease', 'MESH:D002289', (237, 242))	('NDUFB2', 'Gene', (151, 157))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('patients', 'Species', '9606', (93, 101))	('NSCLC', 'Disease', (237, 242))	('patients', 'Species', '9606', (243, 251))	('NSCLC', 'Disease', 'MESH:D002289', (107, 112))	('associated', 'Reg', (173, 183))	('NSCLC', 'Phenotype', 'HP:0030358', (237, 242))	('NSCLC', 'Disease', (107, 112))	('NSCLC', 'Phenotype', 'HP:0030358', (107, 112))	('NDUFB2', 'Gene', '4708', (41, 47))	('lymph node metastasis', 'CPA', (201, 222))	('tumor', 'Disease', (189, 194))	('NDUFB2', 'Gene', (41, 47))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('high', 'Var', (128, 132))	('NDUFB2', 'Gene', '4708', (151, 157))
386542	33436560	Moreover, circNDUFB2 could be upregulated by QKI overexpression in NSCLC cells (Supplementary Fig.	('NDUFB2', 'Gene', '4708', (14, 20))	('upregulated', 'PosReg', (30, 41))	('NSCLC', 'Phenotype', 'HP:0030358', (67, 72))	('overexpression', 'Var', (49, 63))	('QKI', 'Gene', (45, 48))	('NSCLC', 'Disease', 'MESH:D002289', (67, 72))	('NSCLC', 'Disease', (67, 72))	('NDUFB2', 'Gene', (14, 20))	('QKI', 'Gene', '9444', (45, 48))
386555	33436560	Subsequently, in vitro studies showed that circNDUFB2 overexpression significantly suppressed proliferation, migration, and invasion of NSCLC cells (Fig.	('NSCLC', 'Disease', 'MESH:D002289', (136, 141))	('NDUFB2', 'Gene', (47, 53))	('NDUFB2', 'Gene', '4708', (47, 53))	('NSCLC', 'Phenotype', 'HP:0030358', (136, 141))	('proliferation', 'CPA', (94, 107))	('migration', 'CPA', (109, 118))	('overexpression', 'Var', (54, 68))	('invasion', 'CPA', (124, 132))	('suppressed', 'NegReg', (83, 93))	('NSCLC', 'Disease', (136, 141))
386556	33436560	2a, c, e), and circNDUFB2 knockdown remarkably promoted these phenotypes (Fig.	('promoted', 'PosReg', (47, 55))	('knockdown', 'Var', (26, 35))	('NDUFB2', 'Gene', '4708', (19, 25))	('NDUFB2', 'Gene', (19, 25))
386560	33436560	To further confirm the phenotypes of circNDUFB2 overexpression that were caused by circNDUFB2 instead of linear by-products from the pZW1-FCS-circNDUFB2, we constructed a linear-NDUFB2 vector (pZW1-FCS-linearNDUFB2) by deleting the upstream complementary sequences in pZW1-FCS-circNDUFB2 plasmid.	('NDUFB2', 'Gene', '4708', (87, 93))	('NDUFB2', 'Gene', (146, 152))	('NDUFB2', 'Gene', '4708', (208, 214))	('NDUFB2', 'Gene', (281, 287))	('NDUFB2', 'Gene', '4708', (146, 152))	('NDUFB2', 'Gene', (178, 184))	('NDUFB2', 'Gene', '4708', (281, 287))	('deleting', 'Var', (219, 227))	('NDUFB2', 'Gene', (41, 47))	('NDUFB2', 'Gene', '4708', (41, 47))	('NDUFB2', 'Gene', '4708', (178, 184))	('NDUFB2', 'Gene', (87, 93))	('NDUFB2', 'Gene', (208, 214))
386576	33436560	To explore whether KH domains of IGF2BPs are essential for interactions between IGF2BPs and circNDUFB2, we constructed IGF2BPs mutants with mutations of GxxG to GEEG in the KH domains as reported.	('IGF2', 'Gene', '3481', (33, 37))	('IGF2', 'Gene', '3481', (119, 123))	('IGF2', 'Gene', (33, 37))	('IGF2', 'Gene', (80, 84))	('IGF2', 'Gene', (119, 123))	('NDUFB2', 'Gene', (96, 102))	('mutations', 'Var', (140, 149))	('mutants', 'Var', (127, 134))	('NDUFB2', 'Gene', '4708', (96, 102))	('IGF2', 'Gene', '3481', (80, 84))
386577	33436560	Mutations in the KH domains distinctly reduced interactions between IGF2BPs and circNDUFB2 (Supplementary Fig.	('NDUFB2', 'Gene', (84, 90))	('interactions', 'Interaction', (47, 59))	('NDUFB2', 'Gene', '4708', (84, 90))	('IGF2', 'Gene', '3481', (68, 72))	('IGF2', 'Gene', (68, 72))	('Mutations', 'Var', (0, 9))	('reduced', 'NegReg', (39, 46))
386580	33436560	We next conducted circNDUFB2 mutant with mutations of "CGGACU" to "GCCUGA" and "UGGACA" to "ACCUGU" respectively (Supplementary Fig.	('mutations', 'Var', (41, 50))	('NDUFB2', 'Gene', '4708', (22, 28))	('NDUFB2', 'Gene', (22, 28))
386581	33436560	5g), and found that mutations in the circNDUFB2 remarkably reduced interactions between IGF2BPs and circNDUFB2 (Fig.	('IGF2', 'Gene', '3481', (88, 92))	('reduced', 'NegReg', (59, 66))	('NDUFB2', 'Gene', (41, 47))	('IGF2', 'Gene', (88, 92))	('NDUFB2', 'Gene', (104, 110))	('NDUFB2', 'Gene', '4708', (41, 47))	('NDUFB2', 'Gene', '4708', (104, 110))	('mutations', 'Var', (20, 29))	('interactions', 'Interaction', (67, 79))
386587	33436560	The interactions between circNDUFB2 and IGF2BPs were remarkably impaired by METTL3/14 knockdown (Fig.	('IGF2', 'Gene', '3481', (40, 44))	('knockdown', 'Var', (86, 95))	('NDUFB2', 'Gene', '4708', (29, 35))	('interactions', 'Interaction', (4, 16))	('impaired', 'NegReg', (64, 72))	('IGF2', 'Gene', (40, 44))	('METTL3/14', 'Gene', '56339;57721', (76, 85))	('METTL3/14', 'Gene', (76, 85))	('NDUFB2', 'Gene', (29, 35))
386590	33436560	5j, k), but protein levels of IGF2BPs were dramatically reduced in circNDUFB2 overexpression and increased in circNDUFB2 knockdown (Fig.	('knockdown', 'Var', (121, 130))	('NDUFB2', 'Gene', (71, 77))	('increased', 'PosReg', (97, 106))	('NDUFB2', 'Gene', '4708', (114, 120))	('protein levels', 'MPA', (12, 26))	('reduced', 'NegReg', (56, 63))	('NDUFB2', 'Gene', '4708', (71, 77))	('IGF2', 'Gene', '3481', (30, 34))	('overexpression', 'PosReg', (78, 92))	('NDUFB2', 'Gene', (114, 120))	('IGF2', 'Gene', (30, 34))
386591	33436560	Moreover, circNDUFB2 mutant did not affect protein levels of IGF2BPs (Fig.	('NDUFB2', 'Gene', '4708', (14, 20))	('mutant', 'Var', (21, 27))	('IGF2', 'Gene', '3481', (61, 65))	('protein levels', 'MPA', (43, 57))	('NDUFB2', 'Gene', (14, 20))	('IGF2', 'Gene', (61, 65))
386594	33436560	circNDUFB2 significantly increased the ubiquitination levels of IGF2BPs, but this effect was impaired by mutation of it (Fig.	('mutation', 'Var', (105, 113))	('increased', 'PosReg', (25, 34))	('IGF2', 'Gene', '3481', (64, 68))	('IGF2', 'Gene', (64, 68))	('NDUFB2', 'Gene', (4, 10))	('ubiquitination levels', 'MPA', (39, 60))	('NDUFB2', 'Gene', '4708', (4, 10))
386605	33436560	6d, e), but proteins levels of IGF2BPs were dramatically increased in TRIM25 knockdown and reduced in TRIM25 overexpression, respectively (Fig.	('IGF2', 'Gene', (31, 35))	('knockdown', 'Var', (77, 86))	('TRIM25', 'Gene', '7706', (102, 108))	('proteins levels', 'MPA', (12, 27))	('reduced', 'NegReg', (91, 98))	('increased', 'PosReg', (57, 66))	('TRIM25', 'Gene', '7706', (70, 76))	('TRIM25', 'Gene', (102, 108))	('IGF2', 'Gene', '3481', (31, 35))	('TRIM25', 'Gene', (70, 76))
386609	33436560	We then constructed a RNA-binding domain (RBD) deletion mutant of TRIM25 (lacking residues 470-508) with FLAG-tagged (termed TRIM25DeltaRBD), and confirmed that the deletion of RBD in TRIM25 significantly abolished the association between this protein and circNDUFB2 (Supplementary Fig.	('TRIM25', 'Gene', (66, 72))	('TRIM25', 'Gene', (125, 131))	('TRIM25', 'Gene', (184, 190))	('association', 'Interaction', (219, 230))	('RBD', 'Gene', (177, 180))	('NDUFB2', 'Gene', (260, 266))	('NDUFB2', 'Gene', '4708', (260, 266))	('deletion', 'Var', (47, 55))	('deletion', 'Var', (165, 173))	('abolished', 'NegReg', (205, 214))	('TRIM25', 'Gene', '7706', (125, 131))	('TRIM25', 'Gene', '7706', (184, 190))	('TRIM25', 'Gene', '7706', (66, 72))
386621	33436560	Furthermore, the ubiquitination of IGF2BPs was significantly reduced upon METTL3/14 knockdown (Supplementary Fig.	('METTL3/14', 'Gene', '56339;57721', (74, 83))	('ubiquitination', 'MPA', (17, 31))	('METTL3/14', 'Gene', (74, 83))	('knockdown', 'Var', (84, 93))	('IGF2', 'Gene', (35, 39))	('reduced', 'NegReg', (61, 68))	('IGF2', 'Gene', '3481', (35, 39))
386625	33436560	IGF2BPs knockdown remarkably reduced the abilities of migration and invasion as well as colony formation in H1650 cells (Supplementary Fig.	('knockdown', 'Var', (8, 17))	('H1650', 'CellLine', 'CVCL:1483', (108, 113))	('colony formation', 'CPA', (88, 104))	('reduced', 'NegReg', (29, 36))	('IGF2', 'Gene', '3481', (0, 4))	('IGF2', 'Gene', (0, 4))
386636	33436560	5d), whereas circNDUFB2 knockdown reduced the levels of these gene in NSCLC cells (Fig.	('reduced', 'NegReg', (34, 41))	('NSCLC', 'Disease', (70, 75))	('NDUFB2', 'Gene', (17, 23))	('NSCLC', 'Disease', 'MESH:D002289', (70, 75))	('NDUFB2', 'Gene', '4708', (17, 23))	('levels of', 'MPA', (46, 55))	('knockdown', 'Var', (24, 33))	('NSCLC', 'Phenotype', 'HP:0030358', (70, 75))
386639	33436560	Enzyme-linked immunosorbent assays (ELISAs) confirmed that circNDUFB2 overexpression dramatically increased the levels of CXCL10, CXCL11, CCL5, and IFNbeta in cell culture supernatants, and circNDUFB2 knockdown reduced the levels of these cytokines in cell culture supernatants (Fig.	('levels', 'MPA', (223, 229))	('CCL5', 'Gene', (138, 142))	('knockdown', 'Var', (201, 210))	('NDUFB2', 'Gene', '4708', (63, 69))	('CXCL10', 'Gene', '3627', (122, 128))	('CXCL11', 'Gene', (130, 136))	('CXCL10', 'Gene', (122, 128))	('NDUFB2', 'Gene', '4708', (194, 200))	('CXCL11', 'Gene', '6373', (130, 136))	('reduced', 'NegReg', (211, 218))	('increased', 'PosReg', (98, 107))	('CCL5', 'Gene', '6352', (138, 142))	('NDUFB2', 'Gene', (63, 69))	('overexpression', 'PosReg', (70, 84))	('NDUFB2', 'Gene', (194, 200))
386643	33436560	Our data from qRT-PCR analysis showed that RIG-I but not MDA5 knockdown abrogated immune responses induced by circNDUFB2 overexpression (Fig.	('MDA5', 'Gene', '64135', (57, 61))	('MDA5', 'Gene', (57, 61))	('abrogated', 'NegReg', (72, 81))	('immune responses', 'CPA', (82, 98))	('NDUFB2', 'Gene', '4708', (114, 120))	('RIG-I', 'Gene', '23586', (43, 48))	('RIG-I', 'Gene', (43, 48))	('overexpression', 'PosReg', (121, 135))	('NDUFB2', 'Gene', (114, 120))	('knockdown', 'Var', (62, 71))
386652	33436560	More importantly, RIG-I knockdown significantly abolished the upregulation of protein levels or phosphorylation levels of these genes as well as nuclear translocation of IRF3 and P65 induced by circNDUFB2 in A549 cells (Fig.	('NDUFB2', 'Gene', (198, 204))	('upregulation', 'MPA', (62, 74))	('NDUFB2', 'Gene', '4708', (198, 204))	('P65', 'Gene', '5970', (179, 182))	('P65', 'Gene', (179, 182))	('nuclear translocation', 'MPA', (145, 166))	('abolished', 'NegReg', (48, 57))	('IRF3', 'Gene', (170, 174))	('protein levels', 'MPA', (78, 92))	('RIG-I', 'Gene', '23586', (18, 23))	('IRF3', 'Gene', '3661', (170, 174))	('A549', 'CellLine', 'CVCL:0023', (208, 212))	('phosphorylation levels', 'MPA', (96, 118))	('knockdown', 'Var', (24, 33))	('RIG-I', 'Gene', (18, 23))
386653	33436560	Next, we performed ELISAs to measure the level of cytokines in cell culture supernatants and found that RIG-I knockdown significantly abrogated the induction of CXCL10, CXCL11, CCL5, and IFNbeta (Fig.	('knockdown', 'Var', (110, 119))	('CXCL11', 'Gene', (169, 175))	('RIG-I', 'Gene', (104, 109))	('CXCL11', 'Gene', '6373', (169, 175))	('CCL5', 'Gene', '6352', (177, 181))	('CXCL10', 'Gene', '3627', (161, 167))	('abrogated', 'NegReg', (134, 143))	('CCL5', 'Gene', (177, 181))	('CXCL10', 'Gene', (161, 167))	('RIG-I', 'Gene', '23586', (104, 109))
386654	33436560	To explore whether RIG-I binds circNDUFB2 at m6A modification sites, we performed RNA pull-down assay in NSCLC cells with circNDUFB2 or circNDUFB2 mutant (Fig.	('NSCLC', 'Disease', 'MESH:D002289', (105, 110))	('mutant', 'Var', (147, 153))	('m6A', 'Chemical', '-', (45, 48))	('RIG-I', 'Gene', '23586', (19, 24))	('NSCLC', 'Phenotype', 'HP:0030358', (105, 110))	('NDUFB2', 'Gene', (140, 146))	('NDUFB2', 'Gene', (126, 132))	('RIG-I', 'Gene', (19, 24))	('NDUFB2', 'Gene', '4708', (126, 132))	('NDUFB2', 'Gene', (35, 41))	('NDUFB2', 'Gene', '4708', (140, 146))	('NSCLC', 'Disease', (105, 110))	('NDUFB2', 'Gene', '4708', (35, 41))
386655	33436560	We noticed that mutation of m6A modification site in circNDUFB2 did not affect its interaction with RIG-I (Supplementary Fig.	('RIG-I', 'Gene', (100, 105))	('NDUFB2', 'Gene', (57, 63))	('mutation', 'Var', (16, 24))	('m6A', 'Var', (28, 31))	('NDUFB2', 'Gene', '4708', (57, 63))	('m6A', 'Chemical', '-', (28, 31))	('interaction', 'Interaction', (83, 94))	('RIG-I', 'Gene', '23586', (100, 105))
386656	33436560	Consistently, the expression level of anti-tumor immune-related genes has no significant difference between circNDUFB2 and circNDUFB2 mutant (Supplementary Fig.	('NDUFB2', 'Gene', (112, 118))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('NDUFB2', 'Gene', '4708', (112, 118))	('NDUFB2', 'Gene', (127, 133))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('expression', 'MPA', (18, 28))	('NDUFB2', 'Gene', '4708', (127, 133))	('tumor', 'Disease', (43, 48))	('mutant', 'Var', (134, 140))
386664	33436560	RIG-I knockdown partially restored the abilities of colony formation as well as migration and invasion reduced by circNDUFB2 overexpression (Supplementary Fig.	('invasion', 'CPA', (94, 102))	('NDUFB2', 'Gene', (118, 124))	('NDUFB2', 'Gene', '4708', (118, 124))	('reduced', 'NegReg', (103, 110))	('migration', 'CPA', (80, 89))	('RIG-I', 'Gene', '23586', (0, 5))	('RIG-I', 'Gene', (0, 5))	('knockdown', 'Var', (6, 15))	('overexpression', 'PosReg', (125, 139))	('colony formation', 'CPA', (52, 68))
386665	33436560	However, the inhibitory effects induced by circNDUFB2 mutant could be completely restored by RIG-I knockdown (Supplementary Fig.	('RIG-I', 'Gene', (93, 98))	('NDUFB2', 'Gene', (47, 53))	('NDUFB2', 'Gene', '4708', (47, 53))	('inhibitory effects', 'MPA', (13, 31))	('knockdown', 'Var', (99, 108))	('RIG-I', 'Gene', '23586', (93, 98))	('mutant', 'Var', (54, 60))
386694	33436560	Moreover, oncogenic driver mutations or gene rearrangements are commonly observed in NSCLC.	('NSCLC', 'Disease', (85, 90))	('NSCLC', 'Disease', 'MESH:D002289', (85, 90))	('NSCLC', 'Phenotype', 'HP:0030358', (85, 90))	('gene rearrangements', 'Var', (40, 59))	('observed', 'Reg', (73, 81))
386695	33436560	Variant allele frequencies for somatic mutations have shown that mutation in the epidermal growth factor receptor (EGFR) gene is usually present within NSCLC patients.	('present', 'Reg', (137, 144))	('NSCLC', 'Phenotype', 'HP:0030358', (152, 157))	('epidermal growth factor receptor', 'Gene', '1956', (81, 113))	('EGFR', 'Gene', '1956', (115, 119))	('NSCLC', 'Disease', (152, 157))	('NSCLC', 'Disease', 'MESH:D002289', (152, 157))	('mutation', 'Var', (65, 73))	('EGFR', 'Gene', (115, 119))	('patients', 'Species', '9606', (158, 166))	('epidermal growth factor receptor', 'Gene', (81, 113))
386696	33436560	Frequency of EGFR-activating mutation is 27% in LUAD and 9% in LUSC.	('mutation', 'Var', (29, 37))	('LUSC', 'Phenotype', 'HP:0030359', (63, 67))	('LUAD', 'Phenotype', 'HP:0030078', (48, 52))	('LUAD', 'Disease', (48, 52))	('EGFR', 'Gene', '1956', (13, 17))	('EGFR', 'Gene', (13, 17))
386697	33436560	However, the correlation between EGFR mutational status and circNDUFB2 is unknown and needs to be studied in the future.	('NDUFB2', 'Gene', (64, 70))	('EGFR', 'Gene', '1956', (33, 37))	('NDUFB2', 'Gene', '4708', (64, 70))	('EGFR', 'Gene', (33, 37))	('mutational', 'Var', (38, 48))
386705	33436560	N6-methyladenosine is the most abundant and reversible internal modification in mRNAs and circRNAs; recent studies have shown that m6A modification participates in circRNAs metabolism.	('circRNAs metabolism', 'MPA', (164, 183))	('participates', 'Reg', (148, 160))	('m6A', 'Var', (131, 134))	('N6-methyladenosine', 'Chemical', 'MESH:C010223', (0, 18))	('m6A', 'Chemical', '-', (131, 134))
386706	33436560	As m6A reader, IGF2BPs bind to thousands of target RNAs, and the capability of IGF2BPs binding to its targets can be affected by the level of m6A modification in RNAs.	('IGF2', 'Gene', '3481', (15, 19))	('m6A', 'Var', (142, 145))	('IGF2', 'Gene', (79, 83))	('m6A', 'Chemical', '-', (3, 6))	('m6A', 'Chemical', '-', (142, 145))	('binding', 'Interaction', (87, 94))	('IGF2', 'Gene', (15, 19))	('bind', 'Interaction', (23, 27))	('IGF2', 'Gene', '3481', (79, 83))	('affected', 'Reg', (117, 125))
386707	33436560	In this study, we revealed that m6A modification enriched in circNDUFB2 (Fig.	('NDUFB2', 'Gene', (65, 71))	('NDUFB2', 'Gene', '4708', (65, 71))	('m6A', 'Chemical', '-', (32, 35))	('m6A modification', 'Var', (32, 48))
386708	33436560	The level of m6A modification in circNDUFB2 impacted the strength of circNDUFB2 binding to IGF2BPs (Fig.	('NDUFB2', 'Gene', (37, 43))	('NDUFB2', 'Gene', '4708', (73, 79))	('NDUFB2', 'Gene', '4708', (37, 43))	('IGF2', 'Gene', '3481', (91, 95))	('m6A', 'Var', (13, 16))	('binding', 'Interaction', (80, 87))	('IGF2', 'Gene', (91, 95))	('m6A', 'Chemical', '-', (13, 16))	('NDUFB2', 'Gene', (73, 79))	('impacted', 'Reg', (44, 52))	('strength', 'MPA', (57, 65))
386714	33436560	Probably, it is due to the fact that the length of circNDUFB2 is 249 nt, and RIG-I is preferentially activated by short dsRNAs (<300 bp), whereas MDA5 is preferentially activated by longer dsRNAs (>4 kbp).	('preferentially', 'PosReg', (86, 100))	('RIG-I', 'Gene', '23586', (77, 82))	('RIG-I', 'Gene', (77, 82))	('MDA5', 'Gene', '64135', (146, 150))	('MDA5', 'Gene', (146, 150))	('<300', 'Var', (128, 132))	('NDUFB2', 'Gene', (55, 61))	('activated', 'PosReg', (101, 110))	('NDUFB2', 'Gene', '4708', (55, 61))
386744	33436560	For the mutant version of circNDUFB2, the sequence of "CGGACU" or "UGGACA" (in yellow background) was replaced with "GCCUGA" or "ACCUGU" (in blue background), respectively, using the Fast Mutagenesis Kit V2 (Vazyme, Nanjing, China) (Supplementary Fig.	('Kit', 'Gene', (200, 203))	('NDUFB2', 'Gene', (30, 36))	('mutant', 'Var', (8, 14))	('NDUFB2', 'Gene', '4708', (30, 36))	('Kit', 'Gene', '3815', (200, 203))
386823	31093350	The presence of HPV consistently imparts a favorable prognosis, even when detected in more aggressive phenotypes such as the basaloid squamous cell carcinoma.	('HPV', 'Species', '10566', (16, 19))	('HPV', 'Gene', (16, 19))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (134, 157))	('presence', 'Var', (4, 12))	('squamous cell carcinoma', 'Disease', (134, 157))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (134, 157))	('carcinoma', 'Phenotype', 'HP:0030731', (148, 157))
386826	31093350	Absence of p63 is often used to differentiate SCLC from squamous cell carcinoma of the lung yet in one case series 4 of 8 tested oropharyngeal SCCs were p63 positive suggesting poor reliability of this biomarker.	('SCC', 'Gene', (143, 146))	('p63', 'Gene', '8626', (153, 156))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (56, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('SCC', 'Phenotype', 'HP:0030357', (143, 146))	('p63', 'Gene', (11, 14))	('squamous cell carcinoma of the lung', 'Disease', 'MESH:D002294', (56, 91))	('SCC', 'Gene', '6317', (143, 146))	('SCLC', 'Gene', (46, 50))	('p63', 'Gene', '8626', (11, 14))	('SCLC', 'Gene', '7864', (46, 50))	('SCLC', 'Phenotype', 'HP:0030357', (46, 50))	('Absence', 'Var', (0, 7))	('p63', 'Gene', (153, 156))	('squamous cell carcinoma of the lung', 'Disease', (56, 91))
386837	31093350	We hope that HPV positivity portends a favorable prognosis in this case but from reviewing the few cases in the literature, it appears that these patients clinically behave similar to the aggressive nature of SCLC.	('SCLC', 'Phenotype', 'HP:0030357', (209, 213))	('positivity', 'Var', (17, 27))	('patients', 'Species', '9606', (146, 154))	('SCLC', 'Gene', '7864', (209, 213))	('HPV', 'Species', '10566', (13, 16))	('SCLC', 'Gene', (209, 213))	('HPV', 'Gene', (13, 16))
386838	31093350	Further studies are needed to determine the pathophysiology of how HPV results in SCC, only then can potential molecular targets be discovered which will lead to the development of targeted treatments.	('SCC', 'Gene', '6317', (82, 85))	('SCC', 'Phenotype', 'HP:0030357', (82, 85))	('results in', 'Reg', (71, 81))	('men', 'Species', '9606', (173, 176))	('HPV', 'Species', '10566', (67, 70))	('HPV', 'Var', (67, 70))	('SCC', 'Gene', (82, 85))	('men', 'Species', '9606', (195, 198))
386852	28652266	Among ncRNAs, long ncRNAs (lncRNAs) that are >200 bases long have been reported to interact with DNA-binding proteins, such as chromatin-modifying complexes and transcription factors, and regulate gene expression through epigenetic alterations in the nucleus or to function as a molecular sponge in the cytoplasm.	('gene expression', 'MPA', (197, 212))	('epigenetic alterations', 'Var', (221, 243))	('interact', 'Interaction', (83, 91))	('rat', 'Species', '10116', (236, 239))	('regulate', 'Reg', (188, 196))
386863	28652266	The expression of both JHDM1D and JHDM1D-AS1 was decreased by deletion of common 5' promoter regions of JHDM1D and JHDM1D-AS1 using guide RNA (gRNA)-mediated genome editing (Fig.	('JHDM1D', 'Gene', '80853', (23, 29))	('JHDM1D', 'Gene', '80853', (34, 40))	('JHDM1D', 'Gene', (104, 110))	('JHDM1D', 'Gene', (115, 121))	('JHDM1D-AS1', 'Gene', '100134229', (115, 125))	('expression', 'MPA', (4, 14))	('JHDM1D', 'Gene', '80853', (104, 110))	('JHDM1D-AS1', 'Gene', (34, 44))	('decreased', 'NegReg', (49, 58))	('JHDM1D', 'Gene', '80853', (115, 121))	('JHDM1D-AS1', 'Gene', '100134229', (34, 44))	('JHDM1D', 'Gene', (23, 29))	('deletion', 'Var', (62, 70))	('JHDM1D', 'Gene', (34, 40))	('JHDM1D-AS1', 'Gene', (115, 125))
386889	28652266	To investigate whether silencing of JHDM1D-AS1 small interfering RNAs (siRNAs) influences cancer cell growth in vitro and tumor growth in vivo, we knocked down JHDM1D-AS1 using siRNA (Fig.	('influences', 'Reg', (79, 89))	('JHDM1D-AS1', 'Gene', (36, 46))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('knocked down', 'Var', (147, 159))	('JHDM1D-AS1', 'Gene', (160, 170))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('JHDM1D-AS1', 'Gene', '100134229', (36, 46))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('JHDM1D-AS1', 'Gene', '100134229', (160, 170))	('cancer', 'Disease', (90, 96))	('tumor', 'Disease', (122, 127))
386891	28652266	4C) conditions in PANC-1 and AsPC-1 cells in vitro, inhibition of JHDM1D-AS1 significantly decreased the tumor growth of PANC-1 cells in vivo (Fig.	('PANC-1', 'Gene', (121, 127))	('AsPC-1', 'CellLine', 'CVCL:0152', (29, 35))	('JHDM1D-AS1', 'Gene', '100134229', (66, 76))	('PANC-1', 'Gene', (18, 24))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('inhibition', 'Var', (52, 62))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('PANC-1', 'Gene', '104066', (121, 127))	('JHDM1D-AS1', 'Gene', (66, 76))	('PANC-1', 'Gene', '104066', (18, 24))	('tumor', 'Disease', (105, 110))	('decreased', 'NegReg', (91, 100))
386927	28652266	A xenograft study revealed that JHDM1D-AS1 overexpression indeed increased tumor growth in vivo, accompanied by elevated blood vessel formation and macrophage infiltration.	('increased', 'PosReg', (65, 74))	('blood vessel formation', 'CPA', (121, 143))	('JHDM1D-AS1', 'Gene', (32, 42))	('rat', 'Species', '10116', (165, 168))	('elevated', 'PosReg', (112, 120))	('macrophage infiltration', 'CPA', (148, 171))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('JHDM1D-AS1', 'Gene', '100134229', (32, 42))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('overexpression', 'Var', (43, 57))	('tumor', 'Disease', (75, 80))
386944	28652266	Based on these results, we suggest that inhibition of the nutrient starvation-responsive lncRNA JHDM1D-AS1 can be a potential therapeutic approach for cancer in the future.	('inhibition', 'Var', (40, 50))	('JHDM1D-AS1', 'Gene', '100134229', (96, 106))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('cancer', 'Disease', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('JHDM1D-AS1', 'Gene', (96, 106))
386962	28652266	Prewashed magnetic Dynabeads (Life Technologies, MA) were incubated with anti-H3K27ac antibody (Millipore, MA) or anti-SREBP2 antibody (Cayman, MI) in ChIP dilution buffer (20 mM Tris-HCl [pH 8.0], 150 mM NaCl, 1 mM EDTA, 1% Triton X-100, protease inhibitor cocktail [Roche, Basel, Switzerland]) for 6 h by wheel rotating at 4 C. Subsequently, sonicated cross-linked nuclear lysates were added and incubated overnight at 4 C by wheel rotating.	('SREBP2', 'Gene', (119, 125))	('anti-H3K27ac', 'Var', (73, 85))	('Triton X-100', 'Chemical', 'MESH:D017830', (225, 237))	('NaCl', 'Chemical', 'MESH:D012965', (205, 209))	('Tris-HCl', 'Chemical', '-', (179, 187))	('SREBP2', 'Gene', '6721', (119, 125))
386991	25220908	A three-gene signature and clinical outcome in esophageal squamous cell carcinoma It is increasingly apparent that cancer development depends not only on genetic alterations, but also on epigenetic changes involving histone modifications.	('epigenetic changes', 'Var', (187, 205))	('cancer', 'Disease', (115, 121))	('esophageal squamous cell carcinoma', 'Disease', (47, 81))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (58, 81))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('histone', 'Protein', (216, 223))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (47, 81))	('genetic alterations', 'Var', (154, 173))	('cancer', 'Disease', 'MESH:D009369', (115, 121))
386994	25220908	The presence of a high-risk three-gene signature in the ESCC tumors was significantly associated with decreased overall survival (OS) of the patients.	('patients', 'Species', '9606', (141, 149))	('ESCC tumors', 'Disease', (56, 67))	('OS', 'Chemical', '-', (130, 132))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('overall survival', 'MPA', (112, 128))	('presence', 'Var', (4, 12))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('decreased', 'NegReg', (102, 111))	('ESCC tumors', 'Disease', 'MESH:D004938', (56, 67))
386999	25220908	Epigenetic alterations that involve modifications to histones are thought to play critical roles in cancer, with effects on processes ranging from tumor development to metastasis.	('Epigenetic alterations', 'Var', (0, 22))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('effects', 'Reg', (113, 120))	('histones', 'Protein', (53, 61))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('modifications', 'Var', (36, 49))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('metastasis', 'CPA', (168, 178))
387007	25220908	It is increasingly apparent that cancer development depends not only on genetic alterations, but also on epigenetic changes involving histone modifications.	('genetic alterations', 'Var', (72, 91))	('cancer', 'Disease', (33, 39))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('histone modifications', 'MPA', (134, 155))
387009	25220908	Specifically, the histone demethylase GASC1 (the gene amplified in squamous cell carcinoma 1), a member of the JmjC-domain-containing proteins, has been shown to be overexpressed, amplified, and/or mutated in such human cancers as breast cancer, prostate cancer, metastatic lung sarcomatoid carcinoma, and leukemia.	('sarcomatoid carcinoma', 'Phenotype', 'HP:0100242', (279, 300))	('mutated', 'Var', (198, 205))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('GASC1', 'Gene', (38, 43))	('cancers', 'Disease', 'MESH:D009369', (220, 227))	('cancer', 'Phenotype', 'HP:0002664', (255, 261))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('prostate cancer', 'Disease', 'MESH:D011471', (246, 261))	('prostate cancer', 'Phenotype', 'HP:0012125', (246, 261))	('human', 'Species', '9606', (214, 219))	('prostate cancer', 'Disease', (246, 261))	('carcinoma', 'Phenotype', 'HP:0030731', (291, 300))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (67, 90))	('metastatic lung sarcomatoid carcinoma', 'Disease', (263, 300))	('leukemia', 'Phenotype', 'HP:0001909', (306, 314))	('gene amplified in squamous cell carcinoma 1', 'Gene', (49, 92))	('cancers', 'Phenotype', 'HP:0002664', (220, 227))	('metastatic lung sarcomatoid carcinoma', 'Disease', 'MESH:C538614', (263, 300))	('cancers', 'Disease', (220, 227))	('breast cancer', 'Phenotype', 'HP:0003002', (231, 244))	('overexpressed', 'PosReg', (165, 178))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('leukemia', 'Disease', (306, 314))	('leukemia', 'Disease', 'MESH:D007938', (306, 314))	('breast cancer', 'Disease', 'MESH:D001943', (231, 244))	('gene amplified in squamous cell carcinoma 1', 'Gene', '23081', (49, 92))	('breast cancer', 'Disease', (231, 244))
387040	25220908	PPARG, MDM2, and NANOG were also independent factors for OS according to multivariable Cox proportional hazard regression analyses (Table 2).	('Cox', 'Gene', (87, 90))	('Cox', 'Gene', '1351', (87, 90))	('OS', 'Chemical', '-', (57, 59))	('NANOG', 'Var', (17, 22))
387052	25220908	Patients with a high-risk gene signature had a shorter OS than those with a low-risk gene signature (p < 0.001, Fig.	('OS', 'Chemical', '-', (55, 57))	('Patients', 'Species', '9606', (0, 8))	('shorter', 'NegReg', (47, 54))	('high-risk gene signature', 'Var', (16, 40))
387058	25220908	These studies suggest that the genes modulated by histone demethylases may serve as predictors for the poor prognosis of cancer patients.	('histone demethylases', 'Var', (50, 70))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('patients', 'Species', '9606', (128, 136))	('cancer', 'Disease', (121, 127))
387060	25220908	The presence of a high-risk three-gene signature in the ESCC tumors was significantly associated with decreased OS.	('OS', 'Chemical', '-', (112, 114))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('presence', 'Var', (4, 12))	('ESCC tumors', 'Disease', (56, 67))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('decreased', 'NegReg', (102, 111))	('ESCC tumors', 'Disease', 'MESH:D004938', (56, 67))
387065	25220908	Similarly, our analysis of a subgroup of patients with G2 disease showed that patients with a high-risk gene signature had a lower OS than patients with a low-risk gene signature.	('patients', 'Species', '9606', (139, 147))	('OS', 'Chemical', '-', (131, 133))	('patients', 'Species', '9606', (78, 86))	('patients', 'Species', '9606', (41, 49))	('lower', 'NegReg', (125, 130))	('high-risk gene signature', 'Var', (94, 118))
387067	25220908	In addition, as we can see in Supporting Information Tables 2 and 3, the number of ESCC patients with T1/T2 or G1/G3 is small in cohort 1 and cohort 2, which is the reason that they are not included in analysis.	('T1/T2', 'Var', (102, 107))	('patients', 'Species', '9606', (88, 96))	('G1/G3', 'Var', (111, 116))	('ESCC', 'Disease', (83, 87))
387074	25220908	Alternatively, NANOG may enhance proliferation of cancer cells.	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('enhance', 'PosReg', (25, 32))	('NANOG', 'Var', (15, 20))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))
387075	25220908	This concept was supported by reports of exogenous overexpression of NANOG in mesenchymal stem cells and NIH3T3 cells that promoted cell proliferation and enhanced colony formation.	('promoted', 'PosReg', (123, 131))	('NANOG', 'Var', (69, 74))	('enhanced', 'PosReg', (155, 163))	('cell proliferation', 'CPA', (132, 150))	('colony formation', 'CPA', (164, 180))	('NIH3T3', 'CellLine', 'CVCL:0594', (105, 111))	('overexpression', 'PosReg', (51, 65))
387076	25220908	In addition, NANOG upregulated the expression of ezrin, which is involved in tumor progression and regulates cellular activities including survival, adhesion, and migration/invasion by organizing membrane-cytoskeleton-associated complexes.	('upregulated', 'PosReg', (19, 30))	('migration/invasion', 'CPA', (163, 181))	('NANOG', 'Var', (13, 18))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('expression', 'MPA', (35, 45))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('ezrin', 'Gene', (49, 54))	('tumor', 'Disease', (77, 82))
387078	25220908	Despite the sometimes conflicting results from studies, the overall trend is that MDM2 expression is associated with decreased OS, increased recurrence, increased metastasis, and decreased response to therapeutic intervention in a wide variety of tumors.	('tumor', 'Phenotype', 'HP:0002664', (247, 252))	('decreased', 'NegReg', (179, 188))	('expression', 'Var', (87, 97))	('increased', 'PosReg', (131, 140))	('tumors', 'Disease', (247, 253))	('tumors', 'Disease', 'MESH:D009369', (247, 253))	('metastasis', 'CPA', (163, 173))	('tumors', 'Phenotype', 'HP:0002664', (247, 253))	('MDM2', 'Gene', (82, 86))	('increased', 'PosReg', (153, 162))	('decreased', 'NegReg', (117, 126))	('response to therapeutic intervention', 'MPA', (189, 225))	('OS', 'Chemical', '-', (127, 129))	('recurrence', 'CPA', (141, 151))
387098	25642447	On a molecular level, these cancers often have p53 mutations and many display chromosomal instability.	('chromosomal', 'MPA', (78, 89))	('cancers', 'Disease', (28, 35))	('chromosomal instability', 'Phenotype', 'HP:0040012', (78, 101))	('mutations', 'Var', (51, 60))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('cancers', 'Disease', 'MESH:D009369', (28, 35))	('cancers', 'Phenotype', 'HP:0002664', (28, 35))	('p53', 'Gene', (47, 50))	('p53', 'Gene', '7157', (47, 50))
387110	25642447	More recently, next-generation sequencing technologies have allowed multiple groups of researchers to sequence a large number of tumors to identify novel mutated tumor suppressor genes and oncogenes.	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('tumors', 'Disease', (129, 135))	('tumors', 'Disease', 'MESH:D009369', (129, 135))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('tumor', 'Disease', (162, 167))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('tumor', 'Disease', (129, 134))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('mutated', 'Var', (154, 161))
387116	25642447	Rare clusters of HNSCC have also been reported in families with germ-line mutations in CDKN2A and ATR.	('CDKN2A and ATR', 'Gene', '1029;545', (87, 101))	('HNSCC', 'Phenotype', 'HP:0012288', (17, 22))	('mutations', 'Var', (74, 83))	('HNSCC', 'Disease', (17, 22))
387118	25642447	It has been hypothesized that genetic differences in pathways such as DNA repair, carcinogen metabolism, and cell cycle control may increase the risk of carcinogenesis from exposure to tobacco or alcohol.	('carcinogenesis', 'Disease', (153, 167))	('cell cycle control', 'CPA', (109, 127))	('increase', 'PosReg', (132, 140))	('DNA repair', 'Gene', (70, 80))	('tobacco', 'Species', '4097', (185, 192))	('carcinogen', 'CPA', (82, 92))	('alcohol', 'Chemical', 'MESH:D000438', (196, 203))	('carcinogenesis', 'Disease', 'MESH:D063646', (153, 167))	('genetic differences', 'Var', (30, 49))
387120	25642447	Candidate gene-based studies have generated mixed results, with the notable exception of a nearly 9000 patient series that identified SNPs in multiple alcohol dehydrogenase (ADH) genes associated with a decreased risk of an upper aero-digestive malignancy.	('decreased', 'NegReg', (203, 212))	('malignancy', 'Disease', 'MESH:D009369', (245, 255))	('ADH', 'Gene', (174, 177))	('SNPs', 'Var', (134, 138))	('alcohol', 'Chemical', 'MESH:D000438', (151, 158))	('malignancy', 'Disease', (245, 255))	('patient', 'Species', '9606', (103, 110))
387121	25642447	Subsequently, a genome-wide association study in upper aero-digestive malignancies validated the ADH SNPs and also identified a SNP in HELQ (a DNA repair gene) as being associated with risk of malignancy.	('SNP', 'Var', (128, 131))	('malignancies', 'Disease', 'MESH:D009369', (70, 82))	('HELQ', 'Gene', '113510', (135, 139))	('associated', 'Reg', (169, 179))	('malignancy', 'Disease', 'MESH:D009369', (193, 203))	('malignancy', 'Disease', (193, 203))	('malignancies', 'Disease', (70, 82))	('HELQ', 'Gene', (135, 139))	('ADH', 'Gene', (97, 100))
387143	25642447	Since these initial studies, two other groups have looked at mutations specifically in oral cavity cancers (Table 1 for study details).	('cancers', 'Disease', 'MESH:D009369', (99, 106))	('cancers', 'Phenotype', 'HP:0002664', (99, 106))	('mutations', 'Var', (61, 70))	('cancers', 'Disease', (99, 106))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
387145	25642447	They identified several active mutational processes in HNSCC, including mutations due to tobacco exposure, aging, UV light, and alterations in the apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like (APOBEC) enzymes.	('catalytic', 'MPA', (185, 194))	('mutations', 'Var', (72, 81))	('tobacco', 'Species', '4097', (89, 96))	('HNSCC', 'Phenotype', 'HP:0012288', (55, 60))	('alterations', 'Reg', (128, 139))	('lip', 'Disease', 'MESH:D002971', (150, 153))	('HNSCC', 'Gene', (55, 60))	('lip', 'Disease', (150, 153))
387147	25642447	Although alterations in APOBEC have been shown to cause mutations in other malignancies, most prominently breast cancer, it is not clear these enzymes are active in HNSCC as of yet.	('cause', 'Reg', (50, 55))	('malignancies', 'Disease', 'MESH:D009369', (75, 87))	('mutations', 'Var', (56, 65))	('breast cancer', 'Disease', (106, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('APOBEC', 'Gene', (24, 30))	('breast cancer', 'Phenotype', 'HP:0003002', (106, 119))	('malignancies', 'Disease', (75, 87))	('alterations', 'Var', (9, 20))	('HNSCC', 'Phenotype', 'HP:0012288', (165, 170))	('breast cancer', 'Disease', 'MESH:D001943', (106, 119))
387150	25642447	In HPV-negative tumors, the predominant finding from these sequencing efforts was that a large number of tumor suppressor genes were mutated.	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('tumors', 'Disease', 'MESH:D009369', (16, 22))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumor', 'Disease', (16, 21))	('mutated', 'Var', (133, 140))	('tumors', 'Disease', (16, 22))	('tumor', 'Disease', (105, 110))	('HPV', 'Species', '10566', (3, 6))
387151	25642447	Of the non-coding mutations, an interesting one occurs in the promoter of TERT in nearly 20% of HNSCC, resulting in increased expression of telomerase.	('mutations', 'Var', (18, 27))	('HNSCC', 'Phenotype', 'HP:0012288', (96, 101))	('expression', 'MPA', (126, 136))	('TERT', 'Gene', '7015', (74, 78))	('telomerase', 'MPA', (140, 150))	('increased', 'PosReg', (116, 125))	('HNSCC', 'Gene', (96, 101))	('TERT', 'Gene', (74, 78))
387155	25642447	Mutations in TP53 appear to be acquired early in the pathogenesis of HNSCC and are present in pre-malignant lesions, suggesting an important role in early oncogenesis.	('TP53', 'Gene', (13, 17))	('HNSCC', 'Disease', (69, 74))	('HNSCC', 'Phenotype', 'HP:0012288', (69, 74))	('Mutations', 'Var', (0, 9))	('TP53', 'Gene', '7157', (13, 17))
387156	25642447	Most of the missense mutations in TP53 cluster in the DNA binding domain (DBD) whereas frame-shift and nonsense mutations are more equally distributed throughout the gene.	('missense mutations', 'Var', (12, 30))	('TP53', 'Gene', '7157', (34, 38))	('TP53', 'Gene', (34, 38))
387157	25642447	Since p53 forms a tetramer, many of these missense mutations are expected to have a dominant negative effect.	('p53', 'Gene', (6, 9))	('p53', 'Gene', '7157', (6, 9))	('tetramer', 'Protein', (18, 26))	('negative', 'NegReg', (93, 101))	('missense mutations', 'Var', (42, 60))
387158	25642447	Besides mutation, p53 may be inactivated in other ways such as via MDM2 over-expression or amplification (MDM2 is a negative regulator of p53) or deletion of CDKN2A (negatively regulates MDM2).	('deletion', 'Var', (146, 154))	('p53', 'Gene', (18, 21))	('p53', 'Gene', (138, 141))	('MDM2', 'Gene', '4193', (67, 71))	('p53', 'Gene', '7157', (18, 21))	('over-expression', 'PosReg', (72, 87))	('MDM2', 'Gene', (67, 71))	('p53', 'Gene', '7157', (138, 141))	('MDM2', 'Gene', '4193', (106, 110))	('CDKN2A', 'Gene', (158, 164))	('MDM2', 'Gene', (106, 110))	('CDKN2A', 'Gene', '1029', (158, 164))	('MDM2', 'Gene', '4193', (187, 191))	('MDM2', 'Gene', (187, 191))
387160	25642447	Whether alterations in TP53 are prognostic for overall survival has been somewhat controversial, with early studies showing conflicting results.	('TP53', 'Gene', (23, 27))	('alterations', 'Var', (8, 19))	('TP53', 'Gene', '7157', (23, 27))
387162	25642447	For instance, Poeta and colleagues examined a cohort of 420 patients treated with surgery +- radiotherapy and found that mutations in TP53 were associated with worse overall survival (HR = 1.4, p = 0.009).	('mutations', 'Var', (121, 130))	('associated', 'Reg', (144, 154))	('TP53', 'Gene', (134, 138))	('overall survival', 'MPA', (166, 182))	('patients', 'Species', '9606', (60, 68))	('TP53', 'Gene', '7157', (134, 138))	('worse', 'NegReg', (160, 165))
387163	25642447	Patients with truncating mutations or disrupting mutations in the DNA binding domain had significantly worse overall survival (HR = 1.7, p < 0.001), whereas non-functional mutations alone were not statistically associated with worse outcomes (HR = 1.2, p = 0.16).	('worse', 'NegReg', (103, 108))	('disrupting', 'NegReg', (38, 48))	('overall survival', 'MPA', (109, 125))	('Patients', 'Species', '9606', (0, 8))	('truncating mutations', 'Var', (14, 34))
387164	25642447	As p53 plays an integral role in handling genotoxic stress, multiple groups found that TP53 mutation results in worse outcomes in patients uniformly treated with either definitive radiotherapy or post-operative radiotherapy.	('p53', 'Gene', '7157', (3, 6))	('TP53', 'Gene', '7157', (87, 91))	('mutation', 'Var', (92, 100))	('TP53', 'Gene', (87, 91))	('patients', 'Species', '9606', (130, 138))	('p53', 'Gene', (3, 6))
387165	25642447	However, as TP53 mutations also are prognostic in patients treated with surgery alone, it is unclear if mutational status is a true predictive marker.	('patients', 'Species', '9606', (50, 58))	('prognostic', 'Reg', (36, 46))	('TP53', 'Gene', '7157', (12, 16))	('TP53', 'Gene', (12, 16))	('mutations', 'Var', (17, 26))
387169	25642447	Recent in-vitro work with HNSCC cell lines has suggested that a subset of p53 mutations may have a gain-of-function phenotype that promotes senescence and subsequent radio-resistance.	('mutations', 'Var', (78, 87))	('radio-resistance', 'CPA', (166, 182))	('p53', 'Gene', (74, 77))	('senescence', 'CPA', (140, 150))	('HNSCC', 'Phenotype', 'HP:0012288', (26, 31))	('p53', 'Gene', '7157', (74, 77))	('promotes', 'PosReg', (131, 139))
387170	25642447	There is homozygous deletion of CDKN2A in nearly 30% of HNSCC and the gene is mutated in another 10-20% of samples, and is frequently subject to LOH.	('HNSCC', 'Disease', (56, 61))	('CDKN2A', 'Gene', (32, 38))	('HNSCC', 'Phenotype', 'HP:0012288', (56, 61))	('CDKN2A', 'Gene', '1029', (32, 38))	('deletion', 'Var', (20, 28))
387171	25642447	Additional epigenetic alterations may lead to this gene being inactivated in up to 80% of tumors.	('inactivated', 'NegReg', (62, 73))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('tumors', 'Disease', (90, 96))	('tumors', 'Disease', 'MESH:D009369', (90, 96))	('epigenetic alterations', 'Var', (11, 33))
387176	25642447	Again, CDK4/6 inhibitor could serve as a method to target these tumors, and both p16 loss and CCND1 amplification are being investigated as biomarkers in the Palbociclib trial.	('Palbociclib', 'Chemical', 'MESH:C500026', (158, 169))	('tumors', 'Disease', (64, 70))	('amplification', 'Var', (100, 113))	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('CCND1', 'Gene', (94, 99))	('CDK4/6', 'Gene', '1019;1021', (7, 13))	('p16', 'Gene', '1029', (81, 84))	('CCND1', 'Gene', '595', (94, 99))	('loss', 'NegReg', (85, 89))	('CDK4/6', 'Gene', (7, 13))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('p16', 'Gene', (81, 84))
387177	25642447	In the TCGA data, genetic alteration of one of either CCND1 or CDKN2A occurs in nearly 60% of cases and in the study by Pickering et al, it was 94%.	('CDKN2A', 'Gene', '1029', (63, 69))	('CCND1', 'Gene', (54, 59))	('genetic alteration', 'Var', (18, 36))	('CCND1', 'Gene', '595', (54, 59))	('CDKN2A', 'Gene', (63, 69))
387178	25642447	RB1, the retinoblastoma gene, also appears to be either mutated or deleted in approximately 5% of patients.	('RB1', 'Gene', '5925', (0, 3))	('retinoblastoma', 'Disease', 'MESH:D012175', (9, 23))	('retinoblastoma', 'Disease', (9, 23))	('patients', 'Species', '9606', (98, 106))	('deleted', 'Var', (67, 74))	('retinoblastoma', 'Phenotype', 'HP:0009919', (9, 23))	('RB1', 'Gene', (0, 3))
387187	25642447	Unlike adenocarcinoma of the lung where mutations in the kinase domain result in constitutive activation of EGFR, such mutations are rare in HNSCC.	('EGFR', 'Gene', '1956', (108, 112))	('EGFR', 'Gene', (108, 112))	('mutations in', 'Var', (40, 52))	('HNSCC', 'Phenotype', 'HP:0012288', (141, 146))	('carcinoma', 'Phenotype', 'HP:0030731', (12, 21))	('constitutive', 'MPA', (81, 93))	('adenocarcinoma of the lung', 'Disease', 'MESH:D000077192', (7, 33))	('adenocarcinoma of the lung', 'Disease', (7, 33))	('carcinoma of the lung', 'Phenotype', 'HP:0100526', (12, 33))	('activation', 'PosReg', (94, 104))
387189	25642447	Of note, amplifications in EGFR appear to occur less frequently in HPV-positive patients, although the therapeutic implications of this are unclear.	('EGFR', 'Gene', '1956', (27, 31))	('EGFR', 'Gene', (27, 31))	('patients', 'Species', '9606', (80, 88))	('HPV-positive', 'Gene', (67, 79))	('HPV', 'Species', '10566', (67, 70))	('amplifications', 'Var', (9, 23))
387193	25642447	PIK3CA is the 2nd most commonly mutated gene across human cancers and alterations in this pathway are thought to play an important role in cancer cell growth, survival, and metabolism.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('alterations', 'Var', (70, 81))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('human', 'Species', '9606', (52, 57))	('cancers', 'Phenotype', 'HP:0002664', (58, 65))	('PIK3CA', 'Gene', (0, 6))	('cancers', 'Disease', (58, 65))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('PIK3CA', 'Gene', '5290', (0, 6))	('cancers', 'Disease', 'MESH:D009369', (58, 65))	('cancer', 'Disease', (58, 64))	('cancer', 'Disease', (139, 145))
387198	25642447	One mechanism of PI3K activation in HNSCC is by receptor-tyrosine kinases, such as EGFR.	('EGFR', 'Gene', '1956', (83, 87))	('EGFR', 'Gene', (83, 87))	('activation', 'PosReg', (22, 32))	('HNSCC', 'Phenotype', 'HP:0012288', (36, 41))	('tyrosine', 'Chemical', 'MESH:D014443', (57, 65))	('HNSCC', 'Disease', (36, 41))	('PI3K', 'Var', (17, 21))
387199	25642447	Although EGFR cannot directly active PI3K, if EGFR heterodimerizes with ERBB3 it can subsequently activate PI3K signaling.	('EGFR', 'Gene', '1956', (46, 50))	('PI3K signaling', 'Pathway', (107, 121))	('ERBB3', 'Gene', (72, 77))	('heterodimerizes', 'Var', (51, 66))	('EGFR', 'Gene', '1956', (9, 13))	('ERBB3', 'Gene', '2065', (72, 77))	('EGFR', 'Gene', (9, 13))	('EGFR', 'Gene', (46, 50))	('activate', 'PosReg', (98, 106))
387200	25642447	Another mechanism of activation of PI3K pathway in HNSCC involves mutation, with mutations occurring in PI3K catalytic subunit, p110alpha (encoded by PIK3CA gene).	('PI3K pathway', 'Pathway', (35, 47))	('PIK3CA', 'Gene', (150, 156))	('p110alpha', 'Gene', (128, 137))	('HNSCC', 'Phenotype', 'HP:0012288', (51, 56))	('p110alpha', 'Gene', '5290', (128, 137))	('PIK3CA', 'Gene', '5290', (150, 156))	('mutations', 'Var', (81, 90))	('activation', 'PosReg', (21, 31))	('mutation', 'Var', (66, 74))
387201	25642447	Approximately 20% of tumors have mutations in PIK3CA, however these mutations occur much more commonly in HPV-positive tumors compared to HPV-negative tumors.	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('mutations', 'Var', (33, 42))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumors', 'Disease', (119, 125))	('HPV', 'Species', '10566', (138, 141))	('tumors', 'Disease', (151, 157))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('HPV-positive tumors', 'Disease', (106, 125))	('HPV', 'Species', '10566', (106, 109))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))	('PIK3CA', 'Gene', '5290', (46, 52))	('tumors', 'Disease', 'MESH:D009369', (119, 125))	('tumors', 'Disease', 'MESH:D009369', (151, 157))	('tumors', 'Disease', (21, 27))	('HPV-positive tumors', 'Disease', 'MESH:D030361', (106, 125))	('tumors', 'Disease', 'MESH:D009369', (21, 27))	('PIK3CA', 'Gene', (46, 52))
387203	25642447	PTEN loss or mutation occurs in 3% of HNSCC.	('PTEN loss', 'Disease', (0, 9))	('mutation', 'Var', (13, 21))	('PTEN loss', 'Disease', 'MESH:D006223', (0, 9))	('HNSCC', 'Disease', (38, 43))	('HNSCC', 'Phenotype', 'HP:0012288', (38, 43))
387205	25642447	In general, agents targeting this pathway include sole PI3K inhibitors (isoform selective and pan-inhibitors), dual PI3K-mTOR inhibitors, AKT inhibitors, and mTOR inhibitors.	('mTOR', 'Gene', '2475', (121, 125))	('AKT', 'Gene', '207', (138, 141))	('mTOR', 'Gene', (121, 125))	('AKT', 'Gene', (138, 141))	('PI3K', 'Var', (55, 59))	('mTOR', 'Gene', (158, 162))	('mTOR', 'Gene', '2475', (158, 162))
387208	25642447	The discovery of recurrent mutations in NOTCH1 was one of the key novel findings of the initial HNSCC exome-sequencing projects.	('mutations', 'Var', (27, 36))	('HNSCC', 'Phenotype', 'HP:0012288', (96, 101))	('NOTCH1', 'Gene', '4851', (40, 46))	('NOTCH1', 'Gene', (40, 46))
387212	25642447	In TCGA data, NOTCH1 is mutated in 18.6% of cases, with over 35% of mutations leading to a frameshift or nonsense codon.	('frameshift', 'Var', (91, 101))	('leading to', 'Reg', (78, 88))	('nonsense codon', 'MPA', (105, 119))	('mutations', 'Var', (68, 77))	('NOTCH1', 'Gene', '4851', (14, 20))	('NOTCH1', 'Gene', (14, 20))
387213	25642447	This pattern of mutations has suggested that Notch's role in HNSCC may be as a tumor suppressor gene, although the exact mechanism of tumor suppression remains unclear.	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('tumor', 'Disease', (79, 84))	('mutations', 'Var', (16, 25))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('HNSCC', 'Phenotype', 'HP:0012288', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('HNSCC', 'Disease', (61, 66))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Disease', (134, 139))
387214	25642447	In a murine model, deletion of Notch1 results in hyperplasia and carcinogen-induced skin cancer, supporting a tumor suppressor function.	('skin cancer', 'Disease', (84, 95))	('skin cancer', 'Phenotype', 'HP:0008069', (84, 95))	('Notch1', 'Gene', (31, 37))	('skin cancer', 'Disease', 'MESH:D012878', (84, 95))	('deletion', 'Var', (19, 27))	('murine', 'Species', '10090', (5, 11))	('tumor', 'Disease', (110, 115))	('hyperplasia', 'Disease', 'MESH:D006965', (49, 60))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('hyperplasia', 'Disease', (49, 60))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
387215	25642447	In contrast, Notch1 mutations are oncogenic in T-cell acute lymphoblastic leukemia and cause ligand-independent cleavage of Notch1, ultimately leading to constitutive activation.	('leukemia', 'Phenotype', 'HP:0001909', (74, 82))	('constitutive activation', 'MPA', (154, 177))	('cleavage', 'MPA', (112, 120))	('Notch1', 'Gene', (124, 130))	('T-cell acute lymphoblastic leukemia', 'Disease', 'MESH:D054218', (47, 82))	('T-cell acute lymphoblastic leukemia', 'Disease', (47, 82))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (60, 82))	('T-cell acute lymphoblastic leukemia', 'Phenotype', 'HP:0006727', (47, 82))	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (54, 82))	('leading to', 'Reg', (143, 153))	('mutations', 'Var', (20, 29))	('Notch1', 'Gene', (13, 19))
387219	25642447	FBXW7 is ubiquitin ligase that targets Notch for degradation and is found mutated in 4.7% of cancers of HNSCC.	('FBXW7', 'Gene', '55294', (0, 5))	('cancers', 'Disease', (93, 100))	('cancers', 'Phenotype', 'HP:0002664', (93, 100))	('HNSCC', 'Phenotype', 'HP:0012288', (104, 109))	('FBXW7', 'Gene', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('Notch for degradation', 'MPA', (39, 60))	('mutated', 'Var', (74, 81))	('cancers', 'Disease', 'MESH:D009369', (93, 100))
387221	25642447	Genes involved in oxidative stress are altered by mutation or copy number change in nearly 20% of HNSCC, and by IHC, NRF2 is overexpressed in 90% of tumors.	('copy number change', 'Var', (62, 80))	('NRF2', 'Gene', (117, 121))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('NRF2', 'Gene', '4780', (117, 121))	('HNSCC', 'Disease', (98, 103))	('tumors', 'Disease', (149, 155))	('tumors', 'Disease', 'MESH:D009369', (149, 155))	('tumors', 'Phenotype', 'HP:0002664', (149, 155))	('HNSCC', 'Phenotype', 'HP:0012288', (98, 103))	('oxidative stress', 'Phenotype', 'HP:0025464', (18, 34))	('altered', 'Reg', (39, 46))	('mutation', 'Var', (50, 58))
387228	25642447	In HNSCC, NRF2 is mutated in 6% of patients and amplified in another 6%.	('HNSCC', 'Phenotype', 'HP:0012288', (3, 8))	('NRF2', 'Gene', (10, 14))	('mutated', 'Var', (18, 25))	('patients', 'Species', '9606', (35, 43))	('NRF2', 'Gene', '4780', (10, 14))	('HNSCC', 'Disease', (3, 8))
387229	25642447	Mutations are clustered in the Neh2 domain, specifically in two motifs important for binding with Keap1.	('Mutations', 'Var', (0, 9))	('Keap1', 'Gene', (98, 103))	('Keap1', 'Gene', '9817', (98, 103))	('binding', 'Interaction', (85, 92))
387230	25642447	The mutations appear to be gain-of-function mutations which inhibit interaction with KEAP1, and subsequently lead to an up-regulation of NRF2.	('KEAP1', 'Gene', (85, 90))	('inhibit', 'NegReg', (60, 67))	('NRF2', 'Gene', (137, 141))	('NRF2', 'Gene', '4780', (137, 141))	('up-regulation', 'PosReg', (120, 133))	('mutations', 'Var', (4, 13))	('KEAP1', 'Gene', '9817', (85, 90))	('interaction', 'Interaction', (68, 79))
387231	25642447	KEAP1 is mutated in 4% of tumors and rarely homozygously deleted.	('KEAP1', 'Gene', (0, 5))	('tumors', 'Disease', (26, 32))	('mutated', 'Var', (9, 16))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('KEAP1', 'Gene', '9817', (0, 5))	('tumors', 'Disease', 'MESH:D009369', (26, 32))
387232	25642447	The majority of mutations are missense mutations and they occur both in domains involved with binding to NRF2 and those responsible for binding to CUL3.	('NRF2', 'Gene', '4780', (105, 109))	('missense mutations', 'Var', (30, 48))	('binding', 'Interaction', (94, 101))	('CUL3', 'Gene', '8452', (147, 151))	('CUL3', 'Gene', (147, 151))	('mutations', 'Var', (16, 25))	('NRF2', 'Gene', (105, 109))
387234	25642447	Lastly, CUL3 is mutated or deleted in approximately 6% of patients.	('CUL3', 'Gene', (8, 12))	('deleted', 'Var', (27, 34))	('mutated', 'Var', (16, 23))	('patients', 'Species', '9606', (58, 66))	('CUL3', 'Gene', '8452', (8, 12))
387235	25642447	In the TCGA data set, genomic alterations in the NRF2 pathway have correlated with worse overall survival.	('NRF2', 'Gene', (49, 53))	('worse', 'NegReg', (83, 88))	('genomic alterations', 'Var', (22, 41))	('overall', 'MPA', (89, 96))	('NRF2', 'Gene', '4780', (49, 53))
387236	25642447	Although not yet validated in another HNSCC cohort, alterations in the NRF2 pathway may be prognostic in other malignancies such as NSCLC.	('alterations', 'Var', (52, 63))	('prognostic', 'Reg', (91, 101))	('NRF2', 'Gene', '4780', (71, 75))	('NSCLC', 'Disease', (132, 137))	('malignancies', 'Disease', 'MESH:D009369', (111, 123))	('NSCLC', 'Disease', 'MESH:D002289', (132, 137))	('NRF2', 'Gene', (71, 75))	('HNSCC', 'Phenotype', 'HP:0012288', (38, 43))	('malignancies', 'Disease', (111, 123))
387238	25642447	Similarly, NRF2 alterations as determined by expression signature also correlate with resistance to radiotherapy in cell-line models.	('NRF2', 'Gene', (11, 15))	('alterations', 'Var', (16, 27))	('resistance to radiotherapy', 'CPA', (86, 112))	('NRF2', 'Gene', '4780', (11, 15))
387239	25642447	The discovery of recurrent mutations in chromatin modifying genes was one of the major discoveries of cancer sequencing projects in general.	('mutations', 'Var', (27, 36))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('chromatin modifying genes', 'Gene', (40, 65))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))
387240	25642447	MLL2 (aka KMTD2) is a histone methyltransferase that is mutated in 19% of HNSCC.	('MLL2', 'Gene', (0, 4))	('HNSCC', 'Phenotype', 'HP:0012288', (74, 79))	('mutated', 'Var', (56, 63))	('MLL2', 'Gene', '9757', (0, 4))
387241	25642447	Over 50% of the mutations lead to a frame-shift, truncation or splice site alteration, suggesting a tumor suppressor function.	('frame-shift', 'MPA', (36, 47))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('lead to', 'Reg', (26, 33))	('tumor', 'Disease', (100, 105))	('mutations', 'Var', (16, 25))	('truncation', 'MPA', (49, 59))	('splice site alteration', 'MPA', (63, 85))	('tumor', 'Disease', 'MESH:D009369', (100, 105))
387242	25642447	MLL2 can methylate several lysine residues on histones, including H3K4, which is often associated with positive gene regulation.	('MLL2', 'Gene', (0, 4))	('MLL2', 'Gene', '9757', (0, 4))	('H3K4', 'Protein', (66, 70))	('lysine', 'Chemical', 'MESH:D008239', (27, 33))	('methylate', 'Var', (9, 18))
387243	25642447	In leukemia's, MLL translocations are quiet common and their role in carcinogenesis is much better understood than the role of the more recently discovered MLL2 point mutations.	('MLL2', 'Gene', '9757', (156, 160))	('MLL2', 'Gene', (156, 160))	('leukemia', 'Phenotype', 'HP:0001909', (3, 11))	('translocations', 'Var', (19, 33))	("leukemia's", 'Disease', 'MESH:D007938', (3, 13))	('leukemia', 'Disease', (3, 11))	('MLL', 'Gene', '4297', (156, 159))	('carcinogenesis', 'Disease', 'MESH:D063646', (69, 83))	('MLL', 'Gene', '4297', (15, 18))	('MLL', 'Gene', (156, 159))	('MLL', 'Gene', (15, 18))	('carcinogenesis', 'Disease', (69, 83))
387244	25642447	NSD1 is another histone methyltransferase that is mutated in 10% of patients, with, again, a strong bias towards truncating and nonsense mutations.	('NSD1', 'Gene', (0, 4))	('nonsense mutations', 'Var', (128, 146))	('mutated', 'Var', (50, 57))	('patients', 'Species', '9606', (68, 76))	('truncating', 'MPA', (113, 123))	('NSD1', 'Gene', '64324', (0, 4))
387249	25642447	Clustering analysis of mutations reported by the International Cancer Genome Consortium (ICGC) demonstrated that FAT1 and CAPS8 mutations may define a distinct subtype of HNSCC.	('mutations', 'Var', (128, 137))	('FAT1', 'Gene', '2195', (113, 117))	('FAT1', 'Gene', (113, 117))	('HNSCC', 'Disease', (171, 176))	('Cancer', 'Disease', (63, 69))	('Cancer', 'Phenotype', 'HP:0002664', (63, 69))	('HNSCC', 'Phenotype', 'HP:0012288', (171, 176))	('Cancer', 'Disease', 'MESH:D009369', (63, 69))	('CAPS8', 'Gene', (122, 127))
387250	25642447	FAT1 is mutated in 23% of tumors, with a predominance of nonsense and frame-shift mutations, suggesting a tumor suppressor function.	('frame-shift mutations', 'Var', (70, 91))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('nonsense', 'Var', (57, 65))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('FAT1', 'Gene', '2195', (0, 4))	('tumor', 'Disease', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('FAT1', 'Gene', (0, 4))	('tumors', 'Disease', (26, 32))
387253	25642447	Truncating mutations would inhibit this functionality and promote tumor cell growth.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('Truncating mutations', 'Var', (0, 20))	('tumor', 'Disease', (66, 71))	('promote', 'PosReg', (58, 65))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('inhibit', 'NegReg', (27, 34))
387254	25642447	Of note, the FAT family of genes (FAT1-4) are also mutated in glioblastoma, colorectal cancer, gastric, ovarian, and pancreatic cancers.	('pancreatic cancers', 'Phenotype', 'HP:0002894', (117, 135))	('glioblastoma', 'Disease', (62, 74))	('FAT', 'Gene', (34, 37))	('FAT1-4', 'Gene', (34, 40))	('pancreatic cancers', 'Disease', (117, 135))	('FAT', 'Gene', '2195', (34, 37))	('cancers', 'Phenotype', 'HP:0002664', (128, 135))	('glioblastoma', 'Phenotype', 'HP:0012174', (62, 74))	('colorectal cancer', 'Phenotype', 'HP:0003003', (76, 93))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('pancreatic cancers', 'Disease', 'MESH:D010190', (117, 135))	('gastric', 'Disease', (95, 102))	('mutated', 'Var', (51, 58))	('ovarian', 'Disease', (104, 111))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('FAT', 'Gene', (13, 16))	('ovarian', 'Disease', 'MESH:D010051', (104, 111))	('gastric', 'Disease', 'MESH:D013274', (95, 102))	('FAT', 'Gene', '2195', (13, 16))	('colorectal cancer', 'Disease', 'MESH:D015179', (76, 93))	('FAT1-4', 'Gene', '2195;2196;120114;79633', (34, 40))	('colorectal cancer', 'Disease', (76, 93))	('glioblastoma', 'Disease', 'MESH:D005909', (62, 74))
387260	25642447	Califano and colleagues studied 87 lesions - including hyperplasia, dysplasia, carcinoma in situ, and invasive cancer - using microsatellite analysis to determine which chromosomal losses occurred early in carcinogenesis.	('carcinoma', 'Disease', (79, 88))	('carcinoma', 'Disease', 'MESH:D002277', (79, 88))	('carcinogenesis', 'Disease', 'MESH:D063646', (206, 220))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('hyperplasia', 'Disease', 'MESH:D006965', (55, 66))	('dysplasia', 'Disease', 'MESH:D004476', (68, 77))	('chromosomal losses', 'Var', (169, 187))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('dysplasia', 'Disease', (68, 77))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('carcinogenesis', 'Disease', (206, 220))	('hyperplasia', 'Disease', (55, 66))
387263	25642447	Recent genomic analysis of squamous cell carcinoma of the esophagus also identified common deletions in 3p and 9p, and overall demonstrated a very similar copy number landscape to HNSCC, suggesting a close molecular relationship.	('carcinoma', 'Phenotype', 'HP:0030731', (41, 50))	('HNSCC', 'Phenotype', 'HP:0012288', (180, 185))	('squamous cell carcinoma of the esophagus', 'Disease', (27, 67))	('deletions', 'Var', (91, 100))	('squamous cell carcinoma of the esophagus', 'Disease', 'MESH:D002294', (27, 67))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (27, 50))
387266	25642447	Similarly, in head and neck cancer, increasing chromosomal instability has been associated with a worse outcome and a more severe malignant phenotype in multiple studies, including worse overall survival and higher risk of lymph node metastasis.	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('chromosomal instability', 'Phenotype', 'HP:0040012', (47, 70))	('head and neck cancer', 'Phenotype', 'HP:0012288', (14, 34))	('neck cancer', 'Disease', 'MESH:D006258', (23, 34))	('neck cancer', 'Disease', (23, 34))	('chromosomal instability', 'Var', (47, 70))
387270	25642447	HPV has long been known to induce malignancies such as cervical, anal, and vulvar cancers.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('HPV', 'Species', '10566', (0, 3))	('HPV', 'Var', (0, 3))	('malignancies', 'Disease', 'MESH:D009369', (34, 46))	('cancers', 'Phenotype', 'HP:0002664', (82, 89))	('induce', 'Reg', (27, 33))	('vulvar cancers', 'Disease', (75, 89))	('cervical', 'Disease', (55, 63))	('malignancies', 'Disease', (34, 46))	('vulvar cancers', 'Disease', 'MESH:D014846', (75, 89))	('anal', 'Disease', (65, 69))
387279	25642447	Recent work has suggested recurrent insertions in RAD51 and ERBB2.	('ERBB2', 'Gene', '2064', (60, 65))	('ERBB2', 'Gene', (60, 65))	('RAD51', 'Gene', (50, 55))	('RAD51', 'Gene', '5888', (50, 55))	('insertions', 'Var', (36, 46))
387287	25642447	For instance, both of the initial sequencing projects demonstrated 2-4 fold less mutations per megabase for HPV-positive tumors compared to their HPV-negative counterparts.	('less', 'NegReg', (76, 80))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('HPV', 'Species', '10566', (108, 111))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('HPV', 'Species', '10566', (146, 149))	('mutations', 'Var', (81, 90))	('HPV-positive tumors', 'Disease', 'MESH:D030361', (108, 127))	('HPV-positive tumors', 'Disease', (108, 127))
387290	25642447	Similarly, which genes are mutated is strongly influence by whether or not the malignancy is HPV-related.	('malignancy', 'Disease', 'MESH:D009369', (79, 89))	('mutated', 'Var', (27, 34))	('malignancy', 'Disease', (79, 89))	('influence', 'Reg', (47, 56))	('HPV', 'Species', '10566', (93, 96))
387292	25642447	In addition, mutations in PIK3CA appear to be more common in HPV-positive malignancies compared to HPV-negative malignancies (see above).	('common', 'Reg', (51, 57))	('malignancies', 'Disease', (112, 124))	('PIK3CA', 'Gene', '5290', (26, 32))	('malignancies', 'Disease', (74, 86))	('malignancies', 'Disease', 'MESH:D009369', (74, 86))	('HPV', 'Species', '10566', (99, 102))	('mutations', 'Var', (13, 22))	('malignancies', 'Disease', 'MESH:D009369', (112, 124))	('HPV', 'Species', '10566', (61, 64))	('PIK3CA', 'Gene', (26, 32))
387327	24231509	Auto-inhibition appears to involve both a pseudosubstrate site present in all PKC family members, and other regulatory-kinase domain packing interactions creating a `closed' inactive conformation.	('pseudosubstrate site', 'MPA', (42, 62))	("`closed' inactive conformation", 'MPA', (165, 195))	('rat', 'Species', '10116', (53, 56))	('interactions', 'Var', (141, 153))	('PKC', 'Gene', (78, 81))	('PKC', 'Gene', '112476', (78, 81))
387349	24231509	Site-directed mutagenesis indicates that Y325 phosphorylation is required for NGF-mediated PKCiota activation and subsequent NFkappaB activation, whereas T256 phosphorylation regulates nuclear-cytoplasmic PKCiota localization by modulating a canonical nuclear localization sequence (NLS).	('Y325', 'Var', (41, 45))	('T256', 'Var', (154, 158))	('nuclear-cytoplasmic', 'MPA', (185, 204))	('PKCiota', 'Gene', '5584', (205, 212))	('PKCiota', 'Gene', '5584', (91, 98))	('regulates', 'Reg', (175, 184))	('PKCiota', 'Gene', (205, 212))	('PKCiota', 'Gene', (91, 98))	('canonical nuclear localization sequence', 'MPA', (242, 281))	('Y325', 'Chemical', '-', (41, 45))	('NFkappaB', 'Gene', (125, 133))	('modulating', 'Reg', (229, 239))	('NFkappaB', 'Gene', '4790', (125, 133))
387363	24231509	Compelling evidence across multiple tumor types demonstrate that PRKCI is a relevant target of 3q26 amplification.	('amplification', 'Var', (100, 113))	('3q26 amplification', 'Var', (95, 113))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('PRKCI', 'Gene', '5584', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('PRKCI', 'Gene', (65, 70))	('rat', 'Species', '10116', (55, 58))	('tumor', 'Disease', (36, 41))
387364	24231509	PRKCI copy number gains are observed in ~80% of human primary lung squamous cell carcinomas (LSCC), ~70% of serous epithelial ovarian cancer and ~53% of ESCC tumors.	('tumors', 'Phenotype', 'HP:0002664', (158, 164))	('ovarian cancer', 'Phenotype', 'HP:0100615', (126, 140))	('lung squamous cell carcinomas', 'Disease', 'MESH:D002294', (62, 91))	('ESCC tumors', 'Disease', (153, 164))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('PRKCI', 'Gene', '5584', (0, 5))	('carcinomas', 'Phenotype', 'HP:0030731', (81, 91))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('serous epithelial ovarian cancer', 'Disease', (108, 140))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (67, 91))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (62, 90))	('human', 'Species', '9606', (48, 53))	('serous epithelial ovarian cancer', 'Disease', 'MESH:D000077216', (108, 140))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('lung squamous cell carcinomas', 'Disease', (62, 91))	('epithelial ovarian cancer', 'Phenotype', 'HP:0025318', (115, 140))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (67, 90))	('PRKCI', 'Gene', (0, 5))	('ESCC tumors', 'Disease', 'MESH:D004938', (153, 164))	('copy number gains', 'Var', (6, 23))
387365	24231509	Consistent with these published findings, analysis of human tumor genomic datasets from the Cancer Genome Atlas, and other large scale sequencing projects (compiled at http://www.cbioportal.org/public-portal/), demonstrates that PRKCI copy number gains are prominent in many major forms of human cancer, being most prevalent in cervical, head and neck, lung squamous and ovarian serous cancers (Figure 1A).	('cancer', 'Phenotype', 'HP:0002664', (296, 302))	('tumor', 'Disease', (60, 65))	('PRKCI', 'Gene', '5584', (229, 234))	('cervical', 'Disease', (328, 336))	('cancer', 'Disease', 'MESH:D009369', (386, 392))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('cancer', 'Disease', 'MESH:D009369', (296, 302))	('human', 'Species', '9606', (290, 295))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (92, 111))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('prevalent', 'Reg', (315, 324))	('gains', 'PosReg', (247, 252))	('human', 'Species', '9606', (54, 59))	('Cancer', 'Phenotype', 'HP:0002664', (92, 98))	('PRKCI', 'Gene', (229, 234))	('cancers', 'Phenotype', 'HP:0002664', (386, 393))	('copy number', 'Var', (235, 246))	('Cancer Genome Atlas', 'Disease', (92, 111))	('cancer', 'Disease', (386, 392))	('lung squamous and ovarian serous cancers', 'Disease', 'MESH:D010051', (353, 393))	('rat', 'Species', '10116', (218, 221))	('cancer', 'Phenotype', 'HP:0002664', (386, 392))	('cancer', 'Disease', (296, 302))
387366	24231509	Surprisingly however, other major tumor types such as bladder, breast, kidney, lung adenocarcinoma, stomach and uterine cancers also harbor frequent PRKCI copy number gains, albeit less frequently than the tumor types mentioned above.	('stomach', 'Disease', (100, 107))	('PRKCI', 'Gene', (149, 154))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (79, 98))	('bladder', 'Disease', (54, 61))	('breast', 'Disease', (63, 69))	('copy number gains', 'Var', (155, 172))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (79, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('kidney', 'Disease', (71, 77))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('tumor', 'Disease', (34, 39))	('cancers', 'Phenotype', 'HP:0002664', (120, 127))	('cancers', 'Disease', (120, 127))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('uterine cancers', 'Phenotype', 'HP:0010784', (112, 127))	('PRKCI', 'Gene', '5584', (149, 154))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('lung adenocarcinoma', 'Disease', (79, 98))	('tumor', 'Disease', (206, 211))	('cancers', 'Disease', 'MESH:D009369', (120, 127))	('tumor', 'Disease', 'MESH:D009369', (206, 211))
387367	24231509	Interestingly, gene expression data from these same tumor datasets reveal a strong positive correlation between PRKCI copy number gains and elevated PKCiota mRNA expression across these tumor types (Figure 1B).	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('PKCiota', 'Gene', (149, 156))	('PRKCI', 'Gene', '5584', (112, 117))	('tumor', 'Disease', (52, 57))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('PRKCI', 'Gene', (112, 117))	('tumor', 'Disease', (186, 191))	('elevated', 'PosReg', (140, 148))	('copy number gains', 'Var', (118, 135))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('PKCiota', 'Gene', '5584', (149, 156))
387368	24231509	Thus, tumor-specific gene copy number gain in PRKCI is a major genetic mechanism driving PKCiota expression in human tumors.	('PRKCI', 'Gene', (46, 51))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('PRKCI', 'Gene', '5584', (46, 51))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('tumor', 'Disease', (117, 122))	('human', 'Species', '9606', (111, 116))	('PKCiota', 'Gene', '5584', (89, 96))	('tumors', 'Disease', (117, 123))	('tumor', 'Disease', 'MESH:D009369', (6, 11))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('gene copy number gain', 'Var', (21, 42))	('PKCiota', 'Gene', (89, 96))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('tumor', 'Disease', (6, 11))
387370	24231509	Of approximately 9,000 human tumor samples derived from different tissues analyzed for PRKCI somatic mutations in the COSMIC database (http://cancer.sanger.ac.uk/cancergenome/projects/cosmic/), only 0.81% of tumors harbor a PRKCI mutation.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('cancer', 'Disease', (162, 168))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('tumors', 'Disease', 'MESH:D009369', (208, 214))	('PRKCI', 'Gene', '5584', (87, 92))	('PRKCI', 'Gene', '5584', (224, 229))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumor', 'Disease', (208, 213))	('human', 'Species', '9606', (23, 28))	('cancer', 'Disease', (142, 148))	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('mutations', 'Var', (101, 110))	('tumor', 'Disease', 'MESH:D009369', (208, 213))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('mutation', 'Var', (230, 238))	('tumors', 'Phenotype', 'HP:0002664', (208, 214))	('PRKCI', 'Gene', (87, 92))	('PRKCI', 'Gene', (224, 229))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('tumors', 'Disease', (208, 214))	('tumor', 'Disease', (29, 34))
387371	24231509	Although of low frequency, one mutated site (R471), which has been reported on multiple occasions, maps to a substrate docking domain required for PKCiota to support cellular polarization, while not influencing catalytic capacity per se.	('rat', 'Species', '10116', (114, 117))	('R471', 'Var', (45, 49))	('PKCiota', 'Gene', '5584', (147, 154))	('cellular polarization', 'MPA', (166, 187))	('PKCiota', 'Gene', (147, 154))
387372	24231509	Thus, R471 mutation mediates a change of function wherein one aspect of PKCiota output potential is selectively compromised.	('PKCiota', 'Gene', '5584', (72, 79))	('function', 'MPA', (41, 49))	('PKCiota', 'Gene', (72, 79))	('R471 mutation', 'Var', (6, 19))
387382	24231509	Although PRKCI gene copy gain is a major mechanism that drives PKCiota overexpression in some human tumor types, alternative mechanisms may also promote PKCiota overexpression.	('PKCiota', 'Gene', (63, 70))	('PKCiota', 'Gene', '5584', (153, 160))	('PRKCI', 'Gene', '5584', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('PRKCI', 'Gene', (9, 14))	('PKCiota', 'Gene', (153, 160))	('tumor', 'Disease', (100, 105))	('copy', 'Var', (20, 24))	('human', 'Species', '9606', (94, 99))	('PKCiota', 'Gene', '5584', (63, 70))	('promote', 'PosReg', (145, 152))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('overexpression', 'MPA', (161, 175))
387386	24231509	Furthermore, PKCiota activity has been shown to be primed by phosphorylation and, at least in the related PKCalpha it is documented that dephosphorylation at these sites can trigger PKC degradation.	('PKC', 'Gene', '112476', (13, 16))	('PKC', 'Gene', (106, 109))	('PKC', 'Gene', '112476', (106, 109))	('PKCalpha', 'Gene', '5578', (106, 114))	('trigger', 'Reg', (174, 181))	('PKCalpha', 'Gene', (106, 114))	('PKCiota', 'Gene', '5584', (13, 20))	('PKC', 'Gene', (13, 16))	('dephosphorylation', 'Var', (137, 154))	('PKCiota', 'Gene', (13, 20))	('PKC', 'Gene', (182, 185))	('PKC', 'Gene', '112476', (182, 185))
387389	24231509	Genetic or pharmacologic inhibition of PKCiota blocks transformed growth of NSCLC, ovarian cancer, ESCC, colon carcinoma, PDAC, and rhabdomyosarcoma cells.	('rhabdomyosarcoma', 'Disease', (132, 148))	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('growth', 'CPA', (66, 72))	('PKCiota', 'Gene', '5584', (39, 46))	('ovarian cancer', 'Phenotype', 'HP:0100615', (83, 97))	('NSCLC', 'Disease', (76, 81))	('PKCiota', 'Gene', (39, 46))	('PDAC', 'Disease', (122, 126))	('ESCC', 'Disease', (99, 103))	('NSCLC', 'Disease', 'MESH:D002289', (76, 81))	('ovarian cancer', 'Disease', 'MESH:D010051', (83, 97))	('inhibition', 'Var', (25, 35))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (132, 148))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('colon carcinoma', 'Disease', 'MESH:D015179', (105, 120))	('ovarian cancer', 'Disease', (83, 97))	('colon carcinoma', 'Disease', (105, 120))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (132, 148))
387394	24231509	Furthermore, transgenic caPKCiota mice develop mostly malignant carcinomas whereas non-transgenic mice develop mainly benign tubular adenomas.	('transgenic', 'Species', '10090', (87, 97))	('benign tubular adenomas', 'Disease', (118, 141))	('benign tubular adenomas', 'Disease', 'MESH:D000236', (118, 141))	('mice', 'Species', '10090', (34, 38))	('transgenic mice', 'Species', '10090', (87, 102))	('PKCiota', 'Gene', '5584', (26, 33))	('malignant carcinomas', 'Disease', 'MESH:D009369', (54, 74))	('PKCiota', 'Gene', (26, 33))	('transgenic', 'Var', (13, 23))	('malignant carcinomas', 'Disease', (54, 74))	('transgenic', 'Species', '10090', (13, 23))	('carcinomas', 'Phenotype', 'HP:0030731', (64, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))	('mice', 'Species', '10090', (98, 102))
387401	24231509	In this regard, patients with high PKCiota expressing gastric tumors are more likely to experience relapse, and elevated PKCiota in early stage NSCLC tumors is associated with poor outcome.	('PKCiota', 'Gene', (35, 42))	('gastric tumors', 'Disease', (54, 68))	('tumors', 'Phenotype', 'HP:0002664', (150, 156))	('NSCLC tumors', 'Disease', 'MESH:D009369', (144, 156))	('PKCiota', 'Gene', (121, 128))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('gastric tumors', 'Disease', 'MESH:D013274', (54, 68))	('patients', 'Species', '9606', (16, 24))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('gastric tumors', 'Phenotype', 'HP:0006753', (54, 68))	('high', 'Var', (30, 34))	('experience relapse', 'CPA', (88, 106))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('PKCiota', 'Gene', '5584', (35, 42))	('NSCLC tumors', 'Disease', (144, 156))	('PKCiota', 'Gene', '5584', (121, 128))
387408	24231509	ACFs are likely precursors to colon cancer and harbor many of the same genetic and biochemical alterations found in colon tumors, including activating K-Ras mutations.	('colon tumors', 'Disease', (116, 128))	('colon cancer', 'Phenotype', 'HP:0003003', (30, 42))	('colon cancer', 'Disease', 'MESH:D015179', (30, 42))	('rat', 'Species', '10116', (99, 102))	('K-Ras', 'Protein', (151, 156))	('mutations', 'Var', (157, 166))	('colon tumors', 'Phenotype', 'HP:0100273', (116, 128))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('colon cancer', 'Disease', (30, 42))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('tumors', 'Phenotype', 'HP:0002664', (122, 128))	('colon tumors', 'Disease', 'MESH:D015179', (116, 128))	('activating', 'PosReg', (140, 150))
387418	24231509	PKCiota is also required for maintenance of the transformed phenotype and in vivo tumorigenic potential of established human cancer cells harboring oncogenic KRAS mutations.	('KRAS', 'Gene', '3845', (158, 162))	('mutations', 'Var', (163, 172))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('PKCiota', 'Gene', '5584', (0, 7))	('cancer', 'Disease', (125, 131))	('KRAS', 'Gene', (158, 162))	('tumor', 'Disease', (82, 87))	('PKCiota', 'Gene', (0, 7))	('human', 'Species', '9606', (119, 124))
387419	24231509	Expression of kdPKCiota or RNAi knockdown of PKCiota in NSCLC cells that harbor an oncogenic KRas mutation resulted in reduced formation and growth of xenograft tumors in immune-deficient mice.	('mice', 'Species', '10090', (188, 192))	('growth', 'CPA', (141, 147))	('mutation', 'Var', (98, 106))	('PKCiota', 'Gene', (16, 23))	('formation', 'CPA', (127, 136))	('tumors', 'Phenotype', 'HP:0002664', (161, 167))	('NSCLC', 'Disease', (56, 61))	('xenograft tumors', 'Disease', (151, 167))	('NSCLC', 'Disease', 'MESH:D002289', (56, 61))	('xenograft tumors', 'Disease', 'MESH:D009369', (151, 167))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('PKCiota', 'Gene', '5584', (45, 52))	('reduced', 'NegReg', (119, 126))	('KRas', 'Gene', (93, 97))	('PKCiota', 'Gene', (45, 52))	('PKCiota', 'Gene', '5584', (16, 23))
387420	24231509	Greater than 90% of pancreatic tumors harbor oncogenic KRas mutation, and orthotopic implantation of KRas mutant pancreatic cancer cells depleted of PKCiota into the pancreas of nude mice led to decreased tumor burden, reduced markers of angiogenesis and fewer metastases.	('pancreatic tumors', 'Disease', (20, 37))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (113, 130))	('markers of', 'MPA', (227, 237))	('KRas', 'Gene', (55, 59))	('decreased tumor', 'Disease', 'MESH:D009369', (195, 210))	('mutant', 'Var', (106, 112))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('pancreatic cancer', 'Disease', 'MESH:D010190', (113, 130))	('KRas', 'Gene', (101, 105))	('decreased tumor', 'Disease', (195, 210))	('pancreatic tumors', 'Phenotype', 'HP:0002894', (20, 37))	('metastases', 'Disease', 'MESH:D009362', (261, 271))	('pancreatic cancer', 'Disease', (113, 130))	('PKCiota', 'Gene', '5584', (149, 156))	('metastases', 'Disease', (261, 271))	('reduced', 'NegReg', (219, 226))	('PKCiota', 'Gene', (149, 156))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('nude mice', 'Species', '10090', (178, 187))	('pancreatic tumors', 'Disease', 'MESH:D010190', (20, 37))
387423	24231509	As noted above, Src-mediated phosphorylation of tyrosine 325 was shown to be functionally required for Src activation of PKCiota in response to NGF.	('tyrosine', 'Chemical', 'MESH:D014443', (48, 56))	('Src', 'Gene', '6714', (16, 19))	('PKCiota', 'Gene', (121, 128))	('Src', 'Gene', (103, 106))	('Src', 'Gene', '6714', (103, 106))	('Src', 'Gene', (16, 19))	('tyrosine 325', 'Var', (48, 60))	('PKCiota', 'Gene', '5584', (121, 128))
387425	24231509	PKCiota-mediated phosphorylation abrogates the pro-apoptotic function of Bad, and enhances cell survival and decreased sensitivity of NNK treated NSCLC cells to VP-16 and cisplatin.	('decreased', 'NegReg', (109, 118))	('abrogates', 'NegReg', (33, 42))	('cisplatin', 'Chemical', 'MESH:D002945', (171, 180))	('pro-apoptotic function', 'MPA', (47, 69))	('NSCLC', 'Disease', (146, 151))	('enhances', 'PosReg', (82, 90))	('NSCLC', 'Disease', 'MESH:D002289', (146, 151))	('phosphorylation', 'Var', (17, 32))	('PKCiota', 'Gene', '5584', (0, 7))	('PKCiota', 'Gene', (0, 7))	('sensitivity', 'MPA', (119, 130))	('VP-16', 'Chemical', 'MESH:D005047', (161, 166))	('cell survival', 'CPA', (91, 104))
387426	24231509	Genetic or pharmacological inhibition of Src led to decreased aPKC activation loop phosphorylation and reduced proliferation of androgen dependent prostate cancer cells.	('prostate cancer', 'Disease', 'MESH:D011471', (147, 162))	('PKC', 'Gene', (63, 66))	('PKC', 'Gene', '112476', (63, 66))	('rat', 'Species', '10116', (118, 121))	('prostate cancer', 'Phenotype', 'HP:0012125', (147, 162))	('reduced', 'NegReg', (103, 110))	('decreased', 'NegReg', (52, 61))	('Src', 'Gene', (41, 44))	('proliferation', 'CPA', (111, 124))	('Src', 'Gene', '6714', (41, 44))	('prostate cancer', 'Disease', (147, 162))	('inhibition', 'Var', (27, 37))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))
387427	24231509	Additionally, inhibition of aPKC decreased v-Src-mediated morphological transformation, migration, matrix degradation and invasion of transformed NIH3T3 cells.	('rat', 'Species', '10116', (91, 94))	('matrix degradation', 'CPA', (99, 117))	('invasion', 'CPA', (122, 130))	('Src', 'Gene', (45, 48))	('migration', 'CPA', (88, 97))	('PKC', 'Gene', '112476', (29, 32))	('Src', 'Gene', '6714', (45, 48))	('NIH3T3', 'CellLine', 'CVCL:0594', (146, 152))	('PKC', 'Gene', (29, 32))	('decreased', 'NegReg', (33, 42))	('inhibition', 'Var', (14, 24))
387429	24231509	The PI3K lipid metabolite, PIP3, may promote aPKC activation through 3-phosphoinositide dependent protein kinase-1 (PDK-1) T403 loop phosphorylation.	('PDK-1', 'Gene', '5170', (116, 121))	('promote', 'PosReg', (37, 44))	('activation', 'PosReg', (50, 60))	('3-phosphoinositide dependent protein kinase-1', 'Gene', (69, 114))	('PIP3', 'Chemical', '-', (27, 31))	('PKC', 'Gene', (46, 49))	('PKC', 'Gene', '112476', (46, 49))	('PDK-1', 'Gene', (116, 121))	('lipid', 'Chemical', 'MESH:D008055', (9, 14))	('eta', 'Gene', (16, 19))	('T403 loop', 'Var', (123, 132))	('eta', 'Gene', '1909', (16, 19))	('3-phosphoinositide dependent protein kinase-1', 'Gene', '5170', (69, 114))	('PIP3', 'Var', (27, 31))
387430	24231509	Consistently, RNAi-mediated knockdown of PDK1 inhibited priming phosphorylation of PKCiota at T555 and reduced PKCiota expression in glioma cells.	('PKCiota', 'Gene', '5584', (111, 118))	('PKCiota', 'Gene', (83, 90))	('glioma', 'Disease', 'MESH:D005910', (133, 139))	('glioma', 'Phenotype', 'HP:0009733', (133, 139))	('PKCiota', 'Gene', (111, 118))	('reduced', 'NegReg', (103, 110))	('PDK1', 'Gene', '5163', (41, 45))	('priming phosphorylation', 'MPA', (56, 79))	('PDK1', 'Gene', (41, 45))	('glioma', 'Disease', (133, 139))	('knockdown', 'Var', (28, 37))	('PKCiota', 'Gene', '5584', (83, 90))	('inhibited', 'NegReg', (46, 55))
387431	24231509	Recently PI3K/PKCiota signaling has been linked to the alternative splicing of Bcl-x pre-mRNA to promote cell survival in NSCLC cells.	('NSCLC', 'Disease', 'MESH:D002289', (122, 127))	('PKCiota', 'Gene', '5584', (14, 21))	('PKCiota', 'Gene', (14, 21))	('Bcl-x', 'Gene', '598', (79, 84))	('cell survival', 'CPA', (105, 118))	('Bcl-x', 'Gene', (79, 84))	('alternative splicing', 'Var', (55, 75))	('NSCLC', 'Disease', (122, 127))	('promote', 'PosReg', (97, 104))
387434	24231509	Furthermore, over-expression of Bcl-x(L) could rescue PKCiota knockdown mediated inhibition of NSCLC cell growth in soft agar.	('NSCLC', 'Disease', 'MESH:D002289', (95, 100))	('PKCiota', 'Gene', '5584', (54, 61))	('inhibition', 'NegReg', (81, 91))	('agar', 'Chemical', 'MESH:D000362', (121, 125))	('Bcl-x(L)', 'Gene', '598', (32, 40))	('PKCiota', 'Gene', (54, 61))	('knockdown', 'Var', (62, 71))	('NSCLC', 'Disease', (95, 100))	('Bcl-x(L', 'Gene', (32, 39))	('over-expression', 'PosReg', (13, 28))
387438	24231509	PKCiota is activated upon treating K562 cells with taxol, and overexpression of PKCiota leads to enhanced resistance of K562 cells to taxol-induced apoptosis, whereas inhibition of PKCiota expression enhances taxol mediated apoptotic cell death of K562 cells.	('death', 'Disease', (239, 244))	('K562', 'CellLine', 'CVCL:0004', (120, 124))	('taxol', 'Chemical', 'MESH:D017239', (51, 56))	('enhanced', 'PosReg', (97, 105))	('taxol-induced apoptosis', 'MPA', (134, 157))	('enhances', 'PosReg', (200, 208))	('inhibition', 'Var', (167, 177))	('taxol', 'Chemical', 'MESH:D017239', (134, 139))	('death', 'Disease', 'MESH:D003643', (239, 244))	('PKCiota', 'Gene', '5584', (0, 7))	('resistance', 'MPA', (106, 116))	('PKCiota', 'Gene', (0, 7))	('PKCiota', 'Gene', '5584', (80, 87))	('PKCiota', 'Gene', (80, 87))	('K562', 'CellLine', 'CVCL:0004', (248, 252))	('PKCiota', 'Gene', '5584', (181, 188))	('K562', 'CellLine', 'CVCL:0004', (35, 39))	('PKCiota', 'Gene', (181, 188))	('taxol', 'Chemical', 'MESH:D017239', (209, 214))
387439	24231509	Furthermore, inhibition of Bcr-Abl blocked taxol-induced PKCiota activation and sensitized K562 cells to taxol mediated apoptosis.	('K562', 'CellLine', 'CVCL:0004', (91, 95))	('Bcr-Abl', 'Gene', (27, 34))	('Bcr-Abl', 'Gene', '25', (27, 34))	('PKCiota', 'Gene', '5584', (57, 64))	('inhibition', 'Var', (13, 23))	('sensitized', 'Reg', (80, 90))	('PKCiota', 'Gene', (57, 64))	('taxol', 'Chemical', 'MESH:D017239', (43, 48))	('taxol', 'Chemical', 'MESH:D017239', (105, 110))	('blocked', 'NegReg', (35, 42))
387440	24231509	In contrast, expression of caPKCiota protects K562 cells from chemotherapeutic drug-mediated apoptosis.	('expression', 'Var', (13, 23))	('PKCiota', 'Gene', (29, 36))	('K562', 'CellLine', 'CVCL:0004', (46, 50))	('PKCiota', 'Gene', '5584', (29, 36))
387448	24231509	Treatment of CML cells with taxol induces IkappaBalpha phosphorylation and NFkappaB nuclear translocation and transcriptional activation and disruption of PKCiota function sensitizes K562 cells to taxol-induced apoptosis and inhibits RelA transcriptional activity.	('PKCiota', 'Gene', (155, 162))	('transcriptional activation', 'MPA', (110, 136))	('RelA', 'Gene', (234, 238))	('nuclear translocation', 'MPA', (84, 105))	('disruption', 'Var', (141, 151))	('NFkappaB', 'Gene', '4790', (75, 83))	('phosphorylation', 'MPA', (55, 70))	('RelA', 'Gene', '5970', (234, 238))	('CML', 'Disease', 'MESH:D015464', (13, 16))	('apoptosis', 'CPA', (211, 220))	('NFkappaB', 'Gene', (75, 83))	('CML', 'Disease', (13, 16))	('taxol', 'Chemical', 'MESH:D017239', (197, 202))	('inhibits', 'NegReg', (225, 233))	('sensitizes', 'Reg', (172, 182))	('taxol', 'Chemical', 'MESH:D017239', (28, 33))	('IkappaBalpha', 'Gene', (42, 54))	('K562', 'CellLine', 'CVCL:0004', (183, 187))	('PKCiota', 'Gene', '5584', (155, 162))	('IkappaBalpha', 'Gene', '4792', (42, 54))
387449	24231509	Overexpression of NFkappaB in K562 cells with disrupted PKCiota function, rescues taxol-induced apoptosis.	('rescues', 'PosReg', (74, 81))	('PKCiota', 'Gene', (56, 63))	('taxol-induced', 'MPA', (82, 95))	('disrupted', 'Var', (46, 55))	('K562', 'CellLine', 'CVCL:0004', (30, 34))	('PKCiota', 'Gene', '5584', (56, 63))	('taxol', 'Chemical', 'MESH:D017239', (82, 87))	('NFkappaB', 'Gene', (18, 26))	('NFkappaB', 'Gene', '4790', (18, 26))
387458	24231509	Aberrant expression of genes associated with cellular transformation such as ErbB2, Ras, NOTCH and TGFbeta disrupt cell polarity and cause mislocalization of polarity complex components from the apical-lateral membrane.	('mislocalization', 'MPA', (139, 154))	('ErbB2', 'Gene', (77, 82))	('Aberrant expression', 'Var', (0, 19))	('TGFbeta', 'Gene', (99, 106))	('cell polarity', 'CPA', (115, 128))	('ErbB2', 'Gene', '2064', (77, 82))	('disrupt', 'NegReg', (107, 114))	('Ras', 'Gene', (84, 87))	('NOTCH', 'Gene', (89, 94))	('cause', 'Reg', (133, 138))
387459	24231509	Activation of ErbB2 disrupts cell polarity through a mechanism in which ErbB2 causes mislocalization of Par6 from the apical-lateral border and disassociates Par3 from the aPKC/Par6 complex.	('mislocalization', 'MPA', (85, 100))	('causes', 'Reg', (78, 84))	('disrupts', 'NegReg', (20, 28))	('Par6', 'Gene', '50855', (177, 181))	('Par6', 'Gene', (177, 181))	('ErbB2', 'Gene', (14, 19))	('PKC', 'Gene', (173, 176))	('PKC', 'Gene', '112476', (173, 176))	('ErbB2', 'Gene', (72, 77))	('cell polarity', 'CPA', (29, 42))	('Activation', 'Var', (0, 10))	('Par6', 'Gene', (104, 108))	('ErbB2', 'Gene', '2064', (14, 19))	('Par6', 'Gene', '50855', (104, 108))	('ErbB2', 'Gene', '2064', (72, 77))
387461	24231509	A recent report demonstrated that loss of Par3 cooperates with the intracellular domain of NOTCH (NICD) or H-Ras to induce breast tumorigenesis, tumor invasion and metastasis.	('H-Ras', 'Gene', '3265', (107, 112))	('induce', 'PosReg', (116, 122))	('rat', 'Species', '10116', (52, 55))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('loss', 'Var', (34, 38))	('eta', 'Gene', (165, 168))	('eta', 'Gene', '1909', (165, 168))	('breast tumor', 'Phenotype', 'HP:0100013', (123, 135))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('rat', 'Species', '10116', (23, 26))	('NICD', 'Disease', 'None', (98, 102))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('tumor', 'Disease', (145, 150))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('NICD', 'Disease', (98, 102))	('tumor', 'Disease', (130, 135))	('H-Ras', 'Gene', (107, 112))	('Par3', 'Gene', (42, 46))
387462	24231509	A model was proposed in which the loss of Par3 in transformed cells triggers mislocalization and activation of aPKC.	('mislocalization', 'MPA', (77, 92))	('PKC', 'Gene', '112476', (112, 115))	('loss', 'Var', (34, 38))	('activation', 'PosReg', (97, 107))	('triggers', 'Reg', (68, 76))	('PKC', 'Gene', (112, 115))	('Par3', 'Gene', (42, 46))
387466	24231509	RNAi mediated depletion of PKCiota, Par6 or Rac1 blocks transformation.	('PKCiota', 'Gene', (27, 34))	('transformation', 'CPA', (56, 70))	('Rac1', 'Gene', (44, 48))	('Rac1', 'Gene', '5879', (44, 48))	('Par6', 'Gene', (36, 40))	('Par6', 'Gene', '50855', (36, 40))	('depletion', 'Var', (14, 23))	('blocks', 'NegReg', (49, 55))	('PKCiota', 'Gene', '5584', (27, 34))
387467	24231509	Expression of PB1 domain mutants of PKCiota or Par6 that inhibit the PKCiota-Par6 interaction fail to restore transformation in PKCiota and Par6 knockdown cells respectively, and either decreased PKCiota or Par6 expression inhibits activation of Rac1, whereas expression of a constitutively active Rac1 allele (RacV12) in either PKCiota- or Par6-depleted NSCLC cells restores transformation.	('PKCiota', 'Gene', (69, 76))	('Par6', 'Gene', '50855', (207, 211))	('Par6', 'Gene', (207, 211))	('decreased PKCiota', 'Disease', 'MESH:D012021', (186, 203))	('PKCiota', 'Gene', '5584', (36, 43))	('Rac1', 'Gene', (246, 250))	('PKCiota', 'Gene', '5584', (329, 336))	('inhibits', 'NegReg', (223, 231))	('PKCiota', 'Gene', (36, 43))	('PKCiota', 'Gene', (329, 336))	('NSCLC', 'Disease', 'MESH:D002289', (355, 360))	('Rac', 'Gene', (246, 249))	('Par6', 'Gene', (341, 345))	('transformation', 'MPA', (376, 390))	('Par6', 'Gene', '50855', (341, 345))	('NSCLC', 'Disease', (355, 360))	('Rac1', 'Gene', (298, 302))	('Par6', 'Gene', (47, 51))	('Rac', 'Gene', '207', (298, 301))	('decreased PKCiota', 'Disease', (186, 203))	('Par6', 'Gene', '50855', (47, 51))	('PKCiota', 'Gene', '5584', (128, 135))	('Rac1', 'Gene', '5879', (246, 250))	('mutants', 'Var', (25, 32))	('Rac', 'Gene', '207', (311, 314))	('PKCiota', 'Gene', (128, 135))	('Par6', 'Gene', (77, 81))	('Par6', 'Gene', '50855', (77, 81))	('Par6', 'Gene', '50855', (140, 144))	('Par6', 'Gene', (140, 144))	('Rac', 'Gene', (298, 301))	('activation', 'MPA', (232, 242))	('PB1', 'Gene', (14, 17))	('Rac', 'Gene', '207', (246, 249))	('Rac1', 'Gene', '5879', (298, 302))	('PKCiota', 'Gene', '5584', (196, 203))	('Rac', 'Gene', (311, 314))	('PKCiota', 'Gene', (196, 203))	('PKCiota', 'Gene', '5584', (69, 76))
387470	24231509	RNAi-mediated knock down of ECT2 inhibits Rac1 activity and blocks transformed growth, invasion, and tumorigenicity of NSCLC cells.	('NSCLC', 'Disease', 'MESH:D002289', (119, 124))	('blocks', 'NegReg', (60, 66))	('ECT2', 'Gene', '1894', (28, 32))	('knock down', 'Var', (14, 24))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('transformed growth', 'CPA', (67, 85))	('inhibits', 'NegReg', (33, 41))	('ECT2', 'Gene', (28, 32))	('Rac1', 'Gene', '5879', (42, 46))	('invasion', 'CPA', (87, 95))	('activity', 'MPA', (47, 55))	('Rac1', 'Gene', (42, 46))	('NSCLC', 'Disease', (119, 124))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
387473	24231509	Knock down of either PKCiota or Par6 causes redistribution of ECT2 to the nucleus and loss of transformed growth and invasion.	('Par6', 'Gene', (32, 36))	('loss', 'NegReg', (86, 90))	('Knock down', 'Var', (0, 10))	('ECT2', 'Gene', '1894', (62, 66))	('Par6', 'Gene', '50855', (32, 36))	('PKCiota', 'Gene', '5584', (21, 28))	('ECT2', 'Gene', (62, 66))	('PKCiota', 'Gene', (21, 28))	('redistribution', 'MPA', (44, 58))
387478	24231509	Thus, ECT2 and PKCiota are genetically linked through coordinate gene amplification in NSCLC tumors, and biochemically and functionally linked in NSCLC transformation through formation of an oncogenic PKCiota-Par6- ECT2 complex that drives NSCLC cell transformation.	('NSCLC', 'Disease', (87, 92))	('gene amplification', 'Var', (65, 83))	('linked', 'Reg', (136, 142))	('PKCiota', 'Gene', '5584', (201, 208))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('PKCiota', 'Gene', (201, 208))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('NSCLC', 'Disease', 'MESH:D002289', (146, 151))	('ECT2', 'Gene', '1894', (215, 219))	('ECT2', 'Gene', (215, 219))	('NSCLC tumors', 'Disease', (87, 99))	('NSCLC', 'Disease', 'MESH:D002289', (240, 245))	('NSCLC', 'Disease', (146, 151))	('ECT2', 'Gene', '1894', (6, 10))	('NSCLC', 'Disease', (240, 245))	('NSCLC', 'Disease', 'MESH:D002289', (87, 92))	('ECT2', 'Gene', (6, 10))	('PKCiota', 'Gene', '5584', (15, 22))	('PKCiota', 'Gene', (15, 22))	('Par6', 'Gene', '50855', (209, 213))	('Par6', 'Gene', (209, 213))	('NSCLC tumors', 'Disease', 'MESH:D009369', (87, 99))
387482	24231509	Microarray analysis of PKCiota-regulated genes in glioblastoma cells identified RhoB as being up-regulated in PKCiota knockdown cells.	('glioblastoma', 'Disease', 'MESH:D005909', (50, 62))	('PKCiota', 'Gene', (110, 117))	('knockdown', 'Var', (118, 127))	('glioblastoma', 'Phenotype', 'HP:0012174', (50, 62))	('PKCiota', 'Gene', '5584', (23, 30))	('up-regulated', 'PosReg', (94, 106))	('PKCiota', 'Gene', (23, 30))	('RhoB', 'Gene', '388', (80, 84))	('RhoB', 'Gene', (80, 84))	('glioblastoma', 'Disease', (50, 62))	('PKCiota', 'Gene', '5584', (110, 117))
387483	24231509	Overexpression on RhoB in glioblastoma cells led to decreased proliferation, migration and invasion.	('glioblastoma', 'Disease', (26, 38))	('invasion', 'CPA', (91, 99))	('proliferation', 'CPA', (62, 75))	('RhoB', 'Gene', '388', (18, 22))	('decreased', 'NegReg', (52, 61))	('rat', 'Species', '10116', (80, 83))	('RhoB', 'Gene', (18, 22))	('glioblastoma', 'Disease', 'MESH:D005909', (26, 38))	('migration', 'CPA', (77, 86))	('glioblastoma', 'Phenotype', 'HP:0012174', (26, 38))	('Overexpression', 'Var', (0, 14))	('rat', 'Species', '10116', (69, 72))
387487	24231509	RNAi mediated depletion of PKCiota, Par6, or Rac1 inhibits MMP10 expression in NSCLC cells, and similar to PKCiota and Par6 knockdown, RNAi mediated knockdown of MMP10 blocks anchorage-independent growth and cell invasion.	('knockdown', 'Var', (149, 158))	('Par6', 'Gene', (119, 123))	('Par6', 'Gene', '50855', (119, 123))	('Rac1', 'Gene', (45, 49))	('PKCiota', 'Gene', '5584', (27, 34))	('PKCiota', 'Gene', '5584', (107, 114))	('PKCiota', 'Gene', (27, 34))	('PKCiota', 'Gene', (107, 114))	('expression', 'MPA', (65, 75))	('MMP10', 'Gene', '4319', (59, 64))	('cell invasion', 'CPA', (208, 221))	('MMP10', 'Gene', '4319', (162, 167))	('Par6', 'Gene', '50855', (36, 40))	('Par6', 'Gene', (36, 40))	('MMP10', 'Gene', (59, 64))	('depletion', 'NegReg', (14, 23))	('blocks', 'NegReg', (168, 174))	('Rac1', 'Gene', '5879', (45, 49))	('MMP10', 'Gene', (162, 167))	('inhibits', 'NegReg', (50, 58))	('NSCLC', 'Disease', 'MESH:D002289', (79, 84))	('anchorage-independent growth', 'CPA', (175, 203))	('NSCLC', 'Disease', (79, 84))
387495	24231509	RNAi-mediated knock down of PKCiota in lung adenocarcinoma (LAC) cell lines led to a significant reduction in expression of each of the four target genes, indicating that PKCiota regulates the expression of these four genes in LAC cells.	('reduction', 'NegReg', (97, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('PKCiota in lung adenocarcinoma', 'Disease', 'MESH:D000077192', (28, 58))	('PKCiota', 'Gene', (28, 35))	('knock down', 'Var', (14, 24))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (39, 58))	('PKCiota in lung adenocarcinoma', 'Disease', (28, 58))	('PKCiota', 'Gene', '5584', (171, 178))	('expression', 'MPA', (110, 120))	('PKCiota', 'Gene', (171, 178))	('PKCiota', 'Gene', '5584', (28, 35))
387496	24231509	RNAi-mediated knock down of each of these genes led to significant inhibition of anchorage independent growth and cellular invasion demonstrating that each of them play a role in LAC tranformation.	('anchorage independent growth', 'CPA', (81, 109))	('inhibition', 'NegReg', (67, 77))	('knock down', 'Var', (14, 24))	('rat', 'Species', '10116', (139, 142))	('cellular invasion', 'CPA', (114, 131))
387543	24231509	The crystal structure of the PKCiota-Par6 complex reveals that Cys69 is located within the conserved OPR, PC, and AID (OPCA) motif of PKCiota at the binding interface between PKCiota and Par6 in the complex.	('Par6', 'Gene', '50855', (187, 191))	('Par6', 'Gene', (187, 191))	('PKCiota', 'Gene', '5584', (134, 141))	('Par6', 'Gene', (37, 41))	('PKCiota', 'Gene', '5584', (29, 36))	('Par6', 'Gene', '50855', (37, 41))	('AID', 'Disease', (114, 117))	('PKCiota', 'Gene', (134, 141))	('Cys69', 'Var', (63, 68))	('PKCiota', 'Gene', (29, 36))	('PKCiota', 'Gene', '5584', (175, 182))	('AID', 'Disease', 'None', (114, 117))	('Cys69', 'Chemical', '-', (63, 68))	('PKCiota', 'Gene', (175, 182))
387544	24231509	Molecular modeling of the interaction between ATM and the PKCiota PB1 domain, predicts formation of an adduct between Cys69 and ATM that would cause steric hindrance to Par6 binding.	('binding', 'Interaction', (174, 181))	('Cys69', 'Var', (118, 123))	('Par6', 'Gene', (169, 173))	('Cys69', 'Chemical', '-', (118, 123))	('adduct', 'Interaction', (103, 109))	('Par6', 'Gene', '50855', (169, 173))	('PKCiota', 'Gene', '5584', (58, 65))	('interaction', 'Interaction', (26, 37))	('PKCiota', 'Gene', (58, 65))
387545	24231509	Mutation of PKCiota Cys69 to isoleucine (C69I) or valine (C69V), amino acids that frequently exist at this position in other PB1 domains, does not alter Par6 binding but makes PKCiota resistant to ATM inhibitory effects on PKCiota-Par6 binding in vitro.	('C69V', 'Mutation', 'p.C69V', (58, 62))	('PKCiota', 'Gene', '5584', (12, 19))	('Par6', 'Gene', '50855', (153, 157))	('Par6', 'Gene', (231, 235))	('Par6', 'Gene', (153, 157))	('PKCiota', 'Gene', (12, 19))	('Par6', 'Gene', '50855', (231, 235))	('Cys69', 'Var', (20, 25))	('C69V', 'Var', (58, 62))	('Cys69 to isoleucine', 'Mutation', 'p.C69I', (20, 39))	('PKCiota', 'Gene', '5584', (176, 183))	('C69I', 'Var', (41, 45))	('C69I', 'Mutation', 'p.C69I', (41, 45))	('PKCiota', 'Gene', (176, 183))	('PKCiota', 'Gene', '5584', (223, 230))	('PKCiota', 'Gene', (223, 230))	('Mutation', 'Var', (0, 8))	('valine', 'Chemical', 'MESH:D014633', (50, 56))	('binding', 'Interaction', (236, 243))
387546	24231509	Consistent with these findings, expression of the C69I PKCiota mutant in NSCLC cells supports transformed growth and renders these cells resistant to the inhibitory effects of ATM on transformed growth.	('PKCiota', 'Gene', (55, 62))	('transformed growth', 'CPA', (94, 112))	('supports', 'PosReg', (85, 93))	('NSCLC', 'Disease', (73, 78))	('C69I', 'Var', (50, 54))	('C69I', 'Mutation', 'p.C69I', (50, 54))	('NSCLC', 'Disease', 'MESH:D002289', (73, 78))	('PKCiota', 'Gene', '5584', (55, 62))
387556	24231509	Notably, until very recently, no compounds had shown any selectivity for the aPKC isoforms and much pharmacological dissection of the PKC family had exploited differences between compounds of decreasing specificity: Go6976 (cPKC specific;), bis-indolyl maleimide I (BIMI; cPKC and nPKC selective;) and Go6983 (cPKC, nPKC and aPKC selective); so, for example, a process inhibited by Go6983 but not BIMI provides consistent evidence on aPKC involvement (certainly not proof given the lack of absolute specificity for these kinases).	('PKC', 'Gene', (134, 137))	('PKC', 'Gene', '112476', (282, 285))	('PKC', 'Gene', '112476', (225, 228))	('PKC', 'Gene', '112476', (311, 314))	('PKC', 'Gene', '112476', (273, 276))	('Go6983', 'Var', (382, 388))	('inhibited', 'NegReg', (369, 378))	('PKC', 'Gene', (282, 285))	('PKC', 'Gene', (311, 314))	('PKC', 'Gene', (225, 228))	('PKC', 'Gene', (273, 276))	('PKC', 'Gene', '112476', (326, 329))	('PKC', 'Gene', '112476', (317, 320))	('PKC', 'Gene', '112476', (435, 438))	('PKC', 'Gene', (326, 329))	('PKC', 'Gene', '112476', (78, 81))	('PKC', 'Gene', '112476', (134, 137))	('PKC', 'Gene', (317, 320))	('PKC', 'Gene', (435, 438))	('PKC', 'Gene', (78, 81))
387558	24231509	The compound CRT0066854 is a thieno[2`,3-d] pyrimidine compound, which has been shown to display good kinase selectivity across a broad kinase panel (selectivity score S(80) at 1microM is ~0.02) with excellent selectivity for aPKCiota/zeta within the PKC family.	('PKC', 'Gene', (251, 254))	('PKC', 'Gene', '112476', (251, 254))	('PKCiota', 'Gene', (227, 234))	('PKC', 'Gene', (227, 230))	('PKC', 'Gene', '112476', (227, 230))	('kinase', 'MPA', (102, 108))	('thieno[2`,3-d] pyrimidine', 'Chemical', 'MESH:C000601850', (29, 54))	('eta', 'Gene', '1909', (236, 239))	('eta', 'Gene', (236, 239))	('CRT0066854', 'Var', (13, 23))	('PKCiota', 'Gene', '5584', (227, 234))
387562	24231509	Notably the CRT0066854 benzyl group forming part of the substituent in the 3 position displaces Phe543 of the PKCiota "NFD motif".	('Phe543', 'MPA', (96, 102))	('PKCiota', 'Gene', (110, 117))	('CRT0066854', 'Var', (12, 22))	('displaces', 'NegReg', (86, 95))	('PKCiota', 'Gene', '5584', (110, 117))
387564	24231509	CRT0066854 as noted above inhibits growth in soft agar and suppresses migration, and can suppress also the transformed morphology associated with mutant Ras expression.	('inhibits', 'NegReg', (26, 34))	('agar', 'Chemical', 'MESH:D000362', (50, 54))	('migration', 'CPA', (70, 79))	('growth in soft agar', 'CPA', (35, 54))	('Ras', 'Gene', (153, 156))	('mutant', 'Var', (146, 152))	('transformed morphology', 'CPA', (107, 129))	('suppresses', 'NegReg', (59, 69))	('suppress', 'NegReg', (89, 97))	('rat', 'Species', '10116', (73, 76))	('CRT0066854', 'Var', (0, 10))
387569	24231509	Acquisition of tumor-specific mutations in targeted molecules has become a recurrent theme and presents a major hurdle in achieving curative therapy in cancer patients.	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumor', 'Disease', (15, 20))	('mutations', 'Var', (30, 39))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('rat', 'Species', '10116', (134, 137))	('patients', 'Species', '9606', (159, 167))
387570	24231509	Interestingly, PKCiota has been shown to promote chemoresistance in a number of cancer types and inhibition of PKCiota sensitizes these tumor cells to chemotherapeutics.	('inhibition', 'Var', (97, 107))	('chemoresistance', 'CPA', (49, 64))	('PKCiota', 'Gene', '5584', (111, 118))	('PKCiota', 'Gene', (111, 118))	('PKCiota', 'Gene', '5584', (15, 22))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('promote', 'PosReg', (41, 48))	('PKCiota', 'Gene', (15, 22))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('tumor', 'Disease', (136, 141))	('cancer', 'Disease', (80, 86))
387573	24231509	Genetic ablation of PKCiota in a lung tumorigenesis model indicates that PKCiota plays a critical role in transformation of lung CSCs.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('lung tumor', 'Disease', (33, 43))	('PKCiota', 'Gene', (73, 80))	('lung tumor', 'Disease', 'MESH:D008175', (33, 43))	('lung tumor', 'Phenotype', 'HP:0100526', (33, 43))	('Genetic ablation', 'Var', (0, 16))	('PKCiota', 'Gene', '5584', (20, 27))	('PKCiota', 'Gene', '5584', (73, 80))	('PKCiota', 'Gene', (20, 27))	('lung CSCs', 'Disease', (124, 133))
387604	32235589	Multi-omics analysis, using integrated TCGA data of RNA expression, DNA methylation, point mutations, and copy number variation, demonstrated a prediction capability for poor patient outcomes.	('patient', 'Species', '9606', (175, 182))	('copy number variation', 'Var', (106, 127))	('point mutations', 'Var', (85, 100))
387627	32235589	Our findings indicate that NF1, a tumor-suppressor gene that negatively regulates the RAS signaling pathway was more often mutated in the high-risk subtype (14.1% versus 6.0% in the low-risk subtype, Fisher test p = 0.01).	('tumor', 'Disease', (34, 39))	('NF1', 'Gene', (27, 30))	('RAS signaling pathway', 'Pathway', (86, 107))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('negatively', 'NegReg', (61, 71))	('NF1', 'Gene', '4763', (27, 30))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('mutated', 'Var', (123, 130))
387641	32235589	Cytoplasmic translation (GO:0002181); cytoplasmic translation is linked with translation (GO:0006412) and the translation is further linked with gene expression (GO:0010467), which is concordant with widely accepted knowledge that gene expression and protein synthesis are upregulated in cancer.	('upregulated', 'PosReg', (273, 284))	('cancer', 'Disease', 'MESH:D009369', (288, 294))	('cancer', 'Disease', (288, 294))	('GO:0006412', 'Var', (90, 100))	('cancer', 'Phenotype', 'HP:0002664', (288, 294))
387656	32235589	The multi-omics analysis with TCGA LIHC showed more TP53 gene mutations in the high-risk subtype (Fisher test p = 0.042), but unfortunately, other genes such as EGFR were not investigated.	('EGFR', 'Gene', (161, 165))	('TP53', 'Gene', '7157', (52, 56))	('TP53', 'Gene', (52, 56))	('EGFR', 'Gene', '1956', (161, 165))	('mutations', 'Var', (62, 71))
387659	32235589	The authors found that TP53 and NF1 co-mutations were enriched in the oncogene-negative subset.	('co-mutations', 'Var', (36, 48))	('NF1', 'Gene', (32, 35))	('oncogene-negative subset', 'Disease', (70, 94))	('NF1', 'Gene', '4763', (32, 35))	('TP53', 'Gene', '7157', (23, 27))	('TP53', 'Gene', (23, 27))
387661	32235589	In our analysis, we found NF1 mutations were more enriched in the high-risk subtype, suggesting that the high-risk subtype we identified might correspond to the subset that has TP53 and NF1 co-mutations in.	('NF1', 'Gene', (186, 189))	('NF1', 'Gene', (26, 29))	('NF1', 'Gene', '4763', (186, 189))	('NF1', 'Gene', '4763', (26, 29))	('TP53', 'Gene', '7157', (177, 181))	('mutations', 'Var', (30, 39))	('TP53', 'Gene', (177, 181))
387676	32235589	It is important to note that, not only genetic factors, but also epigenetic factors, affect RET expression that influences the probability of patient survival.	('RET', 'Gene', (92, 95))	('affect', 'Reg', (85, 91))	('patient', 'Species', '9606', (142, 149))	('influences', 'Reg', (112, 122))	('RET', 'Gene', '5979', (92, 95))	('epigenetic factors', 'Var', (65, 83))	('genetic factors', 'Var', (39, 54))
387683	32235589	The practice guidelines in oncology illustrate a strategy of patient treatment based on the result of gene mutations, such as EGFR, ALK, ROS1, and PD-L1, but not considering RNA or miRNA expression levels.	('PD-L1', 'Gene', '29126', (147, 152))	('ROS1', 'Gene', (137, 141))	('patient', 'Species', '9606', (61, 68))	('mutations', 'Var', (107, 116))	('EGFR', 'Gene', (126, 130))	('ROS1', 'Gene', '6098', (137, 141))	('ALK', 'Gene', '238', (132, 135))	('oncology', 'Phenotype', 'HP:0002664', (27, 35))	('PD-L1', 'Gene', (147, 152))	('ALK', 'Gene', (132, 135))	('EGFR', 'Gene', '1956', (126, 130))
387691	32235589	Based on the TargetScanHuman analysis, miR-26 is one of four miRNAs that was predicted to bind to the ERO1B transcript and suppress gene expression.	('ERO1B', 'Gene', '56605', (102, 107))	('bind', 'Interaction', (90, 94))	('ERO1B', 'Gene', (102, 107))	('miR-26', 'Var', (39, 45))	('suppress', 'NegReg', (123, 131))	('gene expression', 'MPA', (132, 147))	('miR-26', 'Chemical', '-', (39, 45))
387692	32235589	As we mentioned in Section 3.4, KEGG miRNA analysis revealed that miR-501, miR-26, miR-507, miR-33, and miR-200/miR-429 were involved in lung-cancer subtypes.	('miR-507', 'Gene', (83, 90))	('miR-501', 'Gene', (66, 73))	('miR-26', 'Chemical', '-', (75, 81))	('miR-501', 'Gene', '574503', (66, 73))	('miR-429', 'Gene', (112, 119))	('miR-507', 'Gene', '574512', (83, 90))	('miR-429', 'Gene', '554210', (112, 119))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('miR-200', 'Chemical', '-', (104, 111))	('miR-33', 'Gene', '407039', (92, 98))	('miR-33', 'Gene', (92, 98))	('lung-cancer', 'Disease', 'MESH:D008175', (137, 148))	('miR-26', 'Var', (75, 81))	('involved', 'Reg', (125, 133))	('lung-cancer', 'Disease', (137, 148))
387697	32235589	For example, EGFR mutation is more often found in Asian American patients than Caucasian or African American patients.	('patients', 'Species', '9606', (109, 117))	('patients', 'Species', '9606', (65, 73))	('mutation', 'Var', (18, 26))	('EGFR', 'Gene', '1956', (13, 17))	('EGFR', 'Gene', (13, 17))
387770	30195190	A distinct class of antioxidant response elements is consistently activated in tumors with NRF2 mutations NRF2 is a redox-responsive transcription factor that regulates expression of cytoprotective genes via its interaction with DNA sequences known as antioxidant response elements (AREs).	('interaction', 'Interaction', (212, 223))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('NRF2', 'Gene', '4780', (91, 95))	('tumors', 'Disease', (79, 85))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('NRF2', 'Gene', '4780', (106, 110))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('expression', 'MPA', (169, 179))	('activated', 'PosReg', (66, 75))	('NRF2', 'Gene', (91, 95))	('regulates', 'Reg', (159, 168))	('NRF2', 'Gene', (106, 110))	('mutations', 'Var', (96, 105))
387772	30195190	Mutations that disrupt the interaction between NRF2 and KEAP1, an inhibitor of NRF2, lead to NRF2 hyperactivation and promote oncogenesis.	('NRF2', 'Gene', '4780', (93, 97))	('NRF2', 'Gene', (47, 51))	('NRF2', 'Gene', (79, 83))	('interaction', 'Interaction', (27, 38))	('KEAP1', 'Gene', '9817', (56, 61))	('NRF2', 'Gene', (93, 97))	('oncogenesis', 'CPA', (126, 137))	('NRF2', 'Gene', '4780', (47, 51))	('Mutations', 'Var', (0, 9))	('KEAP1', 'Gene', (56, 61))	('NRF2', 'Gene', '4780', (79, 83))	('promote', 'PosReg', (118, 125))	('hyperactivation', 'PosReg', (98, 113))
387774	30195190	We tested this possibility using an integrative genomics approach to get a precise view of the direct NRF2 target genes dysregulated in tumors with NRF2 hyperactivating mutations.	('tumors', 'Disease', (136, 142))	('tumors', 'Disease', 'MESH:D009369', (136, 142))	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('NRF2', 'Gene', (148, 152))	('NRF2', 'Gene', '4780', (102, 106))	('hyperactivating mutations', 'Var', (153, 178))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('NRF2', 'Gene', (102, 106))	('NRF2', 'Gene', '4780', (148, 152))
387780	30195190	This NRF2 cancer target gene set also serves as a reliable proxy for NRF2 activity, and high NRF2 activity is associated with significant decreases in survival in multiple cancer types.	('high', 'Var', (88, 92))	('NRF2', 'Gene', '4780', (93, 97))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('decreases', 'NegReg', (138, 147))	('NRF2', 'Gene', (69, 73))	('multiple cancer', 'Disease', 'MESH:D009369', (163, 178))	('NRF2', 'Gene', '4780', (5, 9))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('NRF2', 'Gene', (93, 97))	('NRF2 cancer', 'Disease', 'MESH:D009369', (5, 16))	('NRF2 cancer', 'Disease', (5, 16))	('NRF2', 'Gene', (5, 9))	('multiple cancer', 'Disease', (163, 178))	('activity', 'MPA', (98, 106))	('survival', 'MPA', (151, 159))	('NRF2', 'Gene', '4780', (69, 73))
387805	30195190	Although NRF2 activity is cytoprotective, limitation of its activity by KEAP1 is crucial: mutations that impair KEAP1-mediated degradation of NRF2 are associated with tumorigenesis.	('KEAP1', 'Gene', (112, 117))	('mutations', 'Var', (90, 99))	('NRF2', 'Gene', '4780', (9, 13))	('KEAP1', 'Gene', '9817', (72, 77))	('associated', 'Reg', (151, 161))	('NRF2', 'Gene', (142, 146))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('NRF2', 'Gene', (9, 13))	('KEAP1', 'Gene', (72, 77))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('degradation', 'MPA', (127, 138))	('KEAP1', 'Gene', '9817', (112, 117))	('impair', 'NegReg', (105, 111))	('tumor', 'Disease', (167, 172))	('NRF2', 'Gene', '4780', (142, 146))
387806	30195190	KEAP1 mutations leading to constitutive NRF2 activity were first observed in lung cancer, and cancer-associated NRF2 mutations disrupting KEAP1's inhibition of NRF2 were identified shortly thereafter.	('cancer', 'Disease', (82, 88))	('KEAP1', 'Gene', '9817', (0, 5))	('lung cancer', 'Disease', (77, 88))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('KEAP1', 'Gene', (0, 5))	('NRF2', 'Gene', '4780', (40, 44))	('NRF2', 'Gene', '4780', (160, 164))	('disrupting', 'NegReg', (127, 137))	('NRF2', 'Gene', '4780', (112, 116))	('mutations', 'Var', (6, 15))	('cancer', 'Disease', (94, 100))	('activity', 'MPA', (45, 53))	('mutations', 'Var', (117, 126))	('lung cancer', 'Disease', 'MESH:D008175', (77, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('NRF2', 'Gene', (40, 44))	('NRF2', 'Gene', (160, 164))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('NRF2', 'Gene', (112, 116))	('lung cancer', 'Phenotype', 'HP:0100526', (77, 88))	('KEAP1', 'Gene', '9817', (138, 143))	('KEAP1', 'Gene', (138, 143))	('inhibition', 'MPA', (146, 156))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
387808	30195190	Importantly, coding mutations in NRF2 or KEAP1 are not the only route to constitutive NRF2 activity.	('NRF2', 'Gene', '4780', (86, 90))	('coding mutations', 'Var', (13, 29))	('KEAP1', 'Gene', '9817', (41, 46))	('NRF2', 'Gene', '4780', (33, 37))	('NRF2', 'Gene', (86, 90))	('activity', 'MPA', (91, 99))	('KEAP1', 'Gene', (41, 46))	('NRF2', 'Gene', (33, 37))
387817	30195190	Specifically, we describe a set of direct NRF2 target genes consistently upregulated in tumors with oncogenic NRF2 mutations across multiple organ systems.	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('mutations', 'Var', (115, 124))	('NRF2', 'Gene', (110, 114))	('NRF2', 'Gene', (42, 46))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('upregulated', 'PosReg', (73, 84))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('tumors', 'Disease', (88, 94))	('NRF2', 'Gene', '4780', (110, 114))	('NRF2', 'Gene', '4780', (42, 46))
387818	30195190	This functionally important subset of NRF2 targets includes many of the core cytoprotective genes of the NRF2-mediated antioxidant response, and the expression of these NRF2 "cancer targets" is associated with poor outcome across a number of cancers.	('NRF2', 'Gene', (38, 42))	('cancers', 'Disease', 'MESH:D009369', (242, 249))	('cancers', 'Phenotype', 'HP:0002664', (242, 249))	('cancers', 'Disease', (242, 249))	('cancer', 'Disease', (242, 248))	('cancer', 'Disease', 'MESH:D009369', (242, 248))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('NRF2', 'Gene', '4780', (169, 173))	('NRF2', 'Gene', '4780', (105, 109))	('cancer', 'Disease', (175, 181))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('NRF2', 'Gene', (105, 109))	('NRF2', 'Gene', (169, 173))	('cancer', 'Phenotype', 'HP:0002664', (242, 248))	('NRF2', 'Gene', '4780', (38, 42))	('expression', 'Var', (149, 159))	('associated with', 'Reg', (194, 209))
387820	30195190	A recent analysis of transcriptome data from The Cancer Genome Atlas (TCGA) identified hundreds of gene expression changes that occur with cancer-associated NRF2 mutations that disrupt the NRF2-KEAP1 interaction interface.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('NRF2', 'Gene', (189, 193))	('mutations', 'Var', (162, 171))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('interaction', 'Interaction', (200, 211))	('KEAP1', 'Gene', '9817', (194, 199))	('disrupt', 'NegReg', (177, 184))	('Cancer Genome Atlas', 'Disease', (49, 68))	('NRF2', 'Gene', '4780', (157, 161))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (49, 68))	('NRF2', 'Gene', (157, 161))	('KEAP1', 'Gene', (194, 199))	('Cancer', 'Phenotype', 'HP:0002664', (49, 55))	('NRF2', 'Gene', '4780', (189, 193))	('cancer', 'Disease', (139, 145))
387823	30195190	We used this differential cancer gene expression data to identify genes commonly dysregulated across cancers with NRF2 hyperactivating mutations.	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('cancers', 'Disease', 'MESH:D009369', (101, 108))	('cancers', 'Phenotype', 'HP:0002664', (101, 108))	('cancer', 'Disease', (26, 32))	('cancers', 'Disease', (101, 108))	('cancer', 'Disease', (101, 107))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('NRF2', 'Gene', '4780', (114, 118))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('hyperactivating mutations', 'Var', (119, 144))	('NRF2', 'Gene', (114, 118))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))
387824	30195190	To explore the tissue specificity of gene expression changes in cancers with mutated NRF2, we compared the differential gene expression lists from the four cancers analyzed in to identify shared up- or downregulated gene sets.	('NRF2', 'Gene', (85, 89))	('cancers', 'Phenotype', 'HP:0002664', (156, 163))	('cancers', 'Disease', (156, 163))	('cancers', 'Disease', 'MESH:D009369', (156, 163))	('cancers', 'Disease', 'MESH:D009369', (64, 71))	('mutated', 'Var', (77, 84))	('cancers', 'Phenotype', 'HP:0002664', (64, 71))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('cancers', 'Disease', (64, 71))	('NRF2', 'Gene', '4780', (85, 89))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
387826	30195190	Thus, consistent with NRF2's long-recognized role as a transcriptional activator, oncogenic NRF2 is associated with a consistent gene activation signature.	('oncogenic', 'Var', (82, 91))	('NRF2', 'Gene', '4780', (92, 96))	('NRF2', 'Gene', '4780', (22, 26))	('NRF2', 'Gene', (92, 96))	('NRF2', 'Gene', (22, 26))
387828	30195190	The above results highlight a gene set commonly upregulated with oncogenic NRF2 in cancers derived from a variety of organ systems, yet the data do not provide information indicating a direct role for NRF2 in regulating these genes.	('cancers', 'Disease', 'MESH:D009369', (83, 90))	('NRF2', 'Gene', '4780', (201, 205))	('NRF2', 'Gene', (201, 205))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('NRF2', 'Gene', '4780', (75, 79))	('oncogenic', 'Var', (65, 74))	('upregulated', 'PosReg', (48, 59))	('cancers', 'Phenotype', 'HP:0002664', (83, 90))	('NRF2', 'Gene', (75, 79))	('cancers', 'Disease', (83, 90))
387831	30195190	We calculated the percent overlap between the ChIP-seq derived direct NRF2 targets and various groupings of the cancer upregulated genes (i.e., those upregulated with NRF2 mutation in 1-4 cancer types, 2-4 cancer types, etc.).	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('NRF2', 'Gene', '4780', (70, 74))	('cancer', 'Disease', (112, 118))	('upregulated', 'PosReg', (150, 161))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('NRF2', 'Gene', (70, 74))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('mutation', 'Var', (172, 180))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('NRF2', 'Gene', '4780', (167, 171))	('cancer', 'Disease', (188, 194))	('cancer', 'Disease', (206, 212))	('cancer', 'Disease', 'MESH:D009369', (206, 212))	('NRF2', 'Gene', (167, 171))
387837	30195190	And, as described multiple times above, KEAP1 is intimately linked to the NRF2 antioxidant pathway; KEAP1 is transcriptionally regulated by NRF2 as part of a negative feedback loop, but this feedback mechanism is broken in cancer cells carrying mutations that disrupt the NRF2-KEAP1 interaction interface.	('KEAP1', 'Gene', (40, 45))	('KEAP1', 'Gene', (277, 282))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('NRF2', 'Gene', (272, 276))	('mutations', 'Var', (245, 254))	('KEAP1', 'Gene', '9817', (100, 105))	('NRF2', 'Gene', '4780', (74, 78))	('interaction', 'Interaction', (283, 294))	('KEAP1', 'Gene', (100, 105))	('cancer', 'Disease', 'MESH:D009369', (223, 229))	('NRF2', 'Gene', '4780', (140, 144))	('cancer', 'Disease', (223, 229))	('KEAP1', 'Gene', '9817', (40, 45))	('KEAP1', 'Gene', '9817', (277, 282))	('NRF2', 'Gene', (74, 78))	('NRF2', 'Gene', '4780', (272, 276))	('NRF2', 'Gene', (140, 144))
387886	30195190	Indeed, a closer look at expression of these four classic NRF2 targets in tumors with no NFE2L2 mutation versus tumors with an NFE2L2 mutation reveals that HMOX1 is not as consistent in its activation by NFE2L2 mutation (Fig.	('NFE2L2', 'Gene', (127, 133))	('tumors', 'Disease', 'MESH:D009369', (112, 118))	('NRF2', 'Gene', '4780', (58, 62))	('tumors', 'Disease', 'MESH:D009369', (74, 80))	('NFE2L2', 'Gene', (204, 210))	('HMOX1', 'Gene', (156, 161))	('tumors', 'Disease', (112, 118))	('mutation', 'Var', (96, 104))	('activation', 'PosReg', (190, 200))	('NFE2L2', 'Gene', '4780', (89, 95))	('NRF2', 'Gene', (58, 62))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('NFE2L2', 'Gene', '4780', (127, 133))	('NFE2L2', 'Gene', (89, 95))	('HMOX1', 'Gene', '3162', (156, 161))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('NFE2L2', 'Gene', '4780', (204, 210))	('mutation', 'Var', (211, 219))	('tumors', 'Disease', (74, 80))
387891	30195190	Thus, ARE sequence and NRF2 binding strength are not sufficient to explain the less consistent induction of HMOX1 by oncogenic NRF2.	('HMOX1', 'Gene', (108, 113))	('HMOX1', 'Gene', '3162', (108, 113))	('NRF2', 'Gene', '4780', (23, 27))	('NRF2', 'Gene', '4780', (127, 131))	('oncogenic', 'Var', (117, 126))	('NRF2', 'Gene', (23, 27))	('NRF2', 'Gene', (127, 131))
387900	30195190	Taken together, these analyses suggest that oncogenic NRF2 is able to upregulate its cancer target genes in a variety of cell types because these genes contain fewer cell-specific repressive inputs, particularly in the chromatin environment surrounding their ARE-containing regulatory DNA regions.	('oncogenic', 'Var', (44, 53))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('NRF2', 'Gene', '4780', (54, 58))	('cancer', 'Disease', (85, 91))	('fewer', 'NegReg', (160, 165))	('upregulate', 'PosReg', (70, 80))	('NRF2', 'Gene', (54, 58))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
387910	30195190	Thus, although the NRF2 cancer target genes were identified based on changes associated with NRF2 mutation in a limited number of tumors, our inferred activity data might identify additional genetic alterations driving high NRF2 activity.	('tumors', 'Disease', (130, 136))	('tumors', 'Disease', 'MESH:D009369', (130, 136))	('NRF2', 'Gene', '4780', (93, 97))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('NRF2', 'Gene', (224, 228))	('mutation', 'Var', (98, 106))	('NRF2', 'Gene', '4780', (19, 23))	('NRF2', 'Gene', (93, 97))	('NRF2 cancer', 'Disease', 'MESH:D009369', (19, 30))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('NRF2 cancer', 'Disease', (19, 30))	('NRF2', 'Gene', (19, 23))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('NRF2', 'Gene', '4780', (224, 228))
387911	30195190	To test this possibility, we used a receiver operating characteristic (ROC) based approach to ask which cancer driver mutations are enriched in tumors with high NRF2 activity.	('tumors', 'Disease', (144, 150))	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('NRF2', 'Gene', (161, 165))	('tumors', 'Disease', 'MESH:D009369', (144, 150))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('activity', 'MPA', (166, 174))	('mutations', 'Var', (118, 127))	('NRF2', 'Gene', '4780', (161, 165))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))
387916	30195190	To calculate the AUC for a given driver gene, ranked tumors were called 'positive' if they had a mutation in the gene, and 'negative' if they had no mutation in the gene.	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('mutation', 'Var', (97, 105))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('tumors', 'Disease', (53, 59))
387917	30195190	For this analysis, AUC values closer to 1 correspond to enrichment (high NRF2 activity is a strong classifier for tumors with a mutation in given gene), 0.5 corresponds to no enrichment (random relationship between NRF2 activity and mutation), and values < 0.5 correspond to inverse relationships (low NRF2 activity identifies tumors with a mutation in given driver gene).	('NRF2', 'Gene', '4780', (73, 77))	('NRF2', 'Gene', '4780', (302, 306))	('tumors', 'Disease', 'MESH:D009369', (327, 333))	('tumor', 'Phenotype', 'HP:0002664', (327, 332))	('NRF2', 'Gene', '4780', (215, 219))	('activity', 'MPA', (307, 315))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('NRF2', 'Gene', (73, 77))	('NRF2', 'Gene', (302, 306))	('NRF2', 'Gene', (215, 219))	('tumors', 'Disease', (114, 120))	('tumors', 'Disease', (327, 333))	('tumors', 'Disease', 'MESH:D009369', (114, 120))	('mutation', 'Var', (128, 136))	('activity', 'MPA', (78, 86))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('mutation', 'Var', (341, 349))	('tumors', 'Phenotype', 'HP:0002664', (327, 333))
387920	30195190	Using this method, the top three genes with mutations associated with high NRF2 activity were NFE2L2/NRF2 (AUC = 0.843), KEAP1 (AUC = 0.826), and CUL3 (AUC = 0.609) (Fig.	('NRF2', 'Gene', '4780', (101, 105))	('NRF2', 'Gene', (101, 105))	('KEAP1', 'Gene', (121, 126))	('KEAP1', 'Gene', '9817', (121, 126))	('activity', 'MPA', (80, 88))	('NFE2L2', 'Gene', '4780', (94, 100))	('NRF2', 'Gene', '4780', (75, 79))	('mutations', 'Var', (44, 53))	('CUL3', 'Gene', '8452', (146, 150))	('CUL3', 'Gene', (146, 150))	('NFE2L2', 'Gene', (94, 100))	('NRF2', 'Gene', (75, 79))
387921	30195190	Importantly, in addition to mutations, NFE2L2/NRF2 amplification (copy number gain) and KEAP1 or CUL3 deletion (copy number loss) are also associated with high inferred NRF2 activity (Fig.	('NFE2L2', 'Gene', (39, 45))	('NRF2', 'Gene', '4780', (46, 50))	('NRF2', 'Gene', '4780', (169, 173))	('deletion', 'Var', (102, 110))	('NRF2', 'Gene', (46, 50))	('NRF2', 'Gene', (169, 173))	('KEAP1', 'Gene', '9817', (88, 93))	('CUL3', 'Gene', '8452', (97, 101))	('NFE2L2', 'Gene', '4780', (39, 45))	('CUL3', 'Gene', (97, 101))	('activity', 'MPA', (174, 182))	('KEAP1', 'Gene', (88, 93))	('amplification', 'Var', (51, 64))
387922	30195190	Together, mutations in these three genes can account for many of the "high NRF2" tumors in multiple cancer types (Fig.	('NRF2"', 'Gene', (75, 80))	('multiple cancer', 'Disease', (91, 106))	('tumors', 'Disease', (81, 87))	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('account for', 'Reg', (45, 56))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('multiple cancer', 'Disease', 'MESH:D009369', (91, 106))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('mutations', 'Var', (10, 19))	('NRF2"', 'Gene', '4780', (75, 80))
387932	30195190	No cancers showed a significant increase in overall survival with high NRF2 activity.	('increase', 'PosReg', (32, 40))	('activity', 'MPA', (76, 84))	('NRF2', 'Gene', '4780', (71, 75))	('cancers', 'Phenotype', 'HP:0002664', (3, 10))	('cancers', 'Disease', (3, 10))	('overall', 'MPA', (44, 51))	('high', 'Var', (66, 70))	('cancers', 'Disease', 'MESH:D009369', (3, 10))	('NRF2', 'Gene', (71, 75))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
387936	30195190	We then looked for differences in overall survival between the high and low NRF2 tumor sets.	('NRF2', 'Gene', '4780', (76, 80))	('NRF2', 'Gene', (76, 80))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('looked', 'Reg', (8, 14))	('high', 'Var', (63, 67))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('low', 'NegReg', (72, 75))	('tumor', 'Disease', (81, 86))
387938	30195190	Again, high expression of the NRF2 cancer target genes is primarily associated with decreased overall survival (Supplemental Fig.	('overall survival', 'MPA', (94, 110))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('NRF2 cancer', 'Disease', 'MESH:D009369', (30, 41))	('high', 'Var', (7, 11))	('NRF2 cancer', 'Disease', (30, 41))	('decreased', 'NegReg', (84, 93))
387939	30195190	6), and 11 cancer types showed a significant decrease in overall survival in the high NRF2 group using this method.	('NRF2', 'Gene', '4780', (86, 90))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('high', 'Var', (81, 85))	('NRF2', 'Gene', (86, 90))	('overall survival', 'MPA', (57, 73))	('decrease', 'NegReg', (45, 53))	('cancer', 'Disease', 'MESH:D009369', (11, 17))	('cancer', 'Disease', (11, 17))
387941	30195190	Overall, this work implies that, at least for certain cancers, high expression of the NRF2 cancer target genes is associated with significantly shortened overall survival times.	('NRF2 cancer', 'Disease', (86, 97))	('cancers', 'Phenotype', 'HP:0002664', (54, 61))	('cancers', 'Disease', (54, 61))	('cancers', 'Disease', 'MESH:D009369', (54, 61))	('shortened', 'NegReg', (144, 153))	('high', 'Var', (63, 67))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('overall survival times', 'CPA', (154, 176))	('NRF2 cancer', 'Disease', 'MESH:D009369', (86, 97))
387942	30195190	Dysregulation of transcription factor function is a common occurrence in cancer.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('Dysregulation', 'Var', (0, 13))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('transcription', 'Protein', (17, 30))
387944	30195190	Here, we focused on the transcription factor NRF2, which is often hyperactivated in cancer via mutations that disrupt the NRF2-KEAP1 interaction interface.	('interaction', 'Interaction', (133, 144))	('hyperactivated', 'PosReg', (66, 80))	('KEAP1', 'Gene', '9817', (127, 132))	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('NRF2', 'Gene', (45, 49))	('cancer', 'Disease', (84, 90))	('KEAP1', 'Gene', (127, 132))	('NRF2', 'Gene', '4780', (122, 126))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('mutations', 'Var', (95, 104))	('NRF2', 'Gene', '4780', (45, 49))	('NRF2', 'Gene', (122, 126))
387945	30195190	In fact, based on these mutations, NFE2L2 (which encodes NRF2) is considered a cancer driver gene in several cancer types, including carcinomas of the lung, bladder, head/neck, and uterus/endometrium; and KEAP1 is classified as a cancer driver in both lung carcinoma and adenocarcinoma.	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('carcinomas of the lung', 'Disease', (133, 155))	('mutations', 'Var', (24, 33))	('carcinoma', 'Phenotype', 'HP:0030731', (276, 285))	('NRF2', 'Gene', '4780', (57, 61))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('NFE2L2', 'Gene', '4780', (35, 41))	('cancer', 'Disease', (230, 236))	('lung carcinoma and adenocarcinoma', 'Disease', 'MESH:D000077192', (252, 285))	('cancer', 'Disease', (79, 85))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('cancer', 'Disease', (109, 115))	('KEAP1', 'Gene', '9817', (205, 210))	('carcinomas', 'Phenotype', 'HP:0030731', (133, 143))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('NRF2', 'Gene', (57, 61))	('NFE2L2', 'Gene', (35, 41))	('KEAP1', 'Gene', (205, 210))	('carcinomas of the lung', 'Disease', 'MESH:D008175', (133, 155))	('cancer', 'Disease', 'MESH:D009369', (230, 236))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (257, 266))
387946	30195190	To gain insight into the core oncogenic NRF2 regulatory network, we used an integrative genomics approach that combined our own ChIP-seq data with TCGA gene expression data to identify direct NRF2 target genes consistently upregulated by oncogenic NRF2 across multiple cancer contexts.	('oncogenic', 'Var', (238, 247))	('multiple cancer', 'Disease', (260, 275))	('NRF2', 'Gene', '4780', (40, 44))	('upregulated', 'PosReg', (223, 234))	('NRF2', 'Gene', (248, 252))	('cancer', 'Phenotype', 'HP:0002664', (269, 275))	('NRF2', 'Gene', '4780', (192, 196))	('NRF2', 'Gene', (40, 44))	('multiple cancer', 'Disease', 'MESH:D009369', (260, 275))	('NRF2', 'Gene', (192, 196))	('NRF2', 'Gene', '4780', (248, 252))
387951	30195190	However, when we compared these potential NRF2 targets to gene expression changes associated with oncogenic NRF2 mutation in carcinomas of the lung, bladder, head/neck, or uterus/endometrium, only 32 direct target genes were upregulated by NRF2 in at least two cancer types.	('upregulated', 'PosReg', (225, 236))	('mutation', 'Var', (113, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('NRF2', 'Gene', (240, 244))	('carcinomas', 'Phenotype', 'HP:0030731', (125, 135))	('NRF2', 'Gene', (108, 112))	('NRF2', 'Gene', (42, 46))	('cancer', 'Phenotype', 'HP:0002664', (261, 267))	('cancer', 'Disease', (261, 267))	('cancer', 'Disease', 'MESH:D009369', (261, 267))	('NRF2', 'Gene', '4780', (240, 244))	('carcinomas of the lung', 'Disease', 'MESH:D008175', (125, 147))	('NRF2', 'Gene', '4780', (108, 112))	('carcinomas of the lung', 'Disease', (125, 147))	('NRF2', 'Gene', '4780', (42, 46))
387954	30195190	HMOX1) share these features but fail to be consistently upregulated with oncogenic NRF2 mutations; thus, ARE sequence and NRF2 binding strength alone do not mechanistically differentiate NRF2-targeted cancer AREs from its non-cancer AREs.	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('NRF2', 'Gene', '4780', (187, 191))	('cancer', 'Disease', (201, 207))	('NRF2', 'Gene', (83, 87))	('mutations', 'Var', (88, 97))	('HMOX1', 'Gene', (0, 5))	('NRF2', 'Gene', '4780', (122, 126))	('NRF2', 'Gene', (187, 191))	('cancer', 'Disease', (226, 232))	('cancer', 'Disease', 'MESH:D009369', (226, 232))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('HMOX1', 'Gene', '3162', (0, 5))	('NRF2', 'Gene', (122, 126))	('NRF2', 'Gene', '4780', (83, 87))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
387964	30195190	We therefore used this expression signature to infer NRF2 activity across thousands of TCGA-profiled tumors, and test whether high NRF2 tumors are associated with the expected NRF2 pathway mutations.	('tumors', 'Disease', (136, 142))	('tumors', 'Disease', 'MESH:D009369', (136, 142))	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('NRF2', 'Gene', '4780', (131, 135))	('tumors', 'Disease', 'MESH:D009369', (101, 107))	('NRF2', 'Gene', '4780', (176, 180))	('high NRF2 tumors', 'Disease', 'MESH:D009369', (126, 142))	('NRF2', 'Gene', '4780', (53, 57))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('NRF2', 'Gene', (131, 135))	('NRF2', 'Gene', (176, 180))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('NRF2', 'Gene', (53, 57))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('mutations', 'Var', (189, 198))	('high NRF2 tumors', 'Disease', (126, 142))	('tumors', 'Disease', (101, 107))
387966	30195190	As discussed previously, mutations that disrupt NRF2-KEAP1 interaction lead to constitutive NRF2 activity.	('NRF2', 'Gene', '4780', (48, 52))	('mutations', 'Var', (25, 34))	('lead', 'Reg', (71, 75))	('constitutive', 'MPA', (79, 91))	('interaction', 'Interaction', (59, 70))	('activity', 'MPA', (97, 105))	('NRF2', 'Gene', (48, 52))	('NRF2', 'Gene', '4780', (92, 96))	('KEAP1', 'Gene', '9817', (53, 58))	('NRF2', 'Gene', (92, 96))	('KEAP1', 'Gene', (53, 58))
387968	30195190	Mutations in CUL3 have previously been linked to NRF2 activation in papillary renal cell carcinoma, and our analysis confirms this, although we also see CUL3 mutation associated with high NRF2 activity in breast, esophageal, and head/neck cancer (see Fig.	('esophageal', 'Disease', (213, 223))	('neck cancer', 'Phenotype', 'HP:0012288', (234, 245))	('breast', 'Disease', (205, 211))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('NRF2', 'Gene', '4780', (49, 53))	('papillary renal cell carcinoma', 'Phenotype', 'HP:0006766', (68, 98))	('CUL3', 'Gene', '8452', (13, 17))	('head/neck cancer', 'Disease', 'MESH:D006258', (229, 245))	('Mutations', 'Var', (0, 9))	('head/neck cancer', 'Disease', (229, 245))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))	('CUL3', 'Gene', (153, 157))	('papillary renal cell carcinoma', 'Disease', 'MESH:C538614', (68, 98))	('NRF2', 'Gene', (49, 53))	('NRF2', 'Gene', '4780', (188, 192))	('CUL3', 'Gene', (13, 17))	('activity', 'MPA', (193, 201))	('papillary renal cell carcinoma', 'Disease', (68, 98))	('mutation', 'Var', (158, 166))	('activation', 'PosReg', (54, 64))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (78, 98))	('NRF2', 'Gene', (188, 192))	('associated', 'Reg', (167, 177))	('CUL3', 'Gene', '8452', (153, 157))
387969	30195190	Importantly, we also found copy number variation in the NRF2-KEAP1-CUL3 axis is linked to high NRF2 activity: NRF2 copy number gain (amplification) and KEAP1 or CUL3 copy number loss (deletion) are all associated with high NRF2 activity.	('copy number', 'Var', (115, 126))	('KEAP1', 'Gene', '9817', (152, 157))	('KEAP1', 'Gene', (152, 157))	('CUL3', 'Gene', (67, 71))	('CUL3', 'Gene', (161, 165))	('NRF2', 'Gene', '4780', (223, 227))	('NRF2', 'Gene', '4780', (110, 114))	('gain', 'PosReg', (127, 131))	('copy number', 'Var', (166, 177))	('NRF2', 'Gene', '4780', (56, 60))	('NRF2', 'Gene', '4780', (95, 99))	('KEAP1', 'Gene', '9817', (61, 66))	('activity', 'MPA', (228, 236))	('KEAP1', 'Gene', (61, 66))	('NRF2', 'Gene', (223, 227))	('CUL3', 'Gene', '8452', (67, 71))	('NRF2', 'Gene', (110, 114))	('NRF2', 'Gene', (56, 60))	('CUL3', 'Gene', '8452', (161, 165))	('NRF2', 'Gene', (95, 99))
387970	30195190	This is consistent with the prevailing model where gain of function variation in NRF2 and loss of function variation in KEAP1 or CUL3 drive high NRF2 activity, and highlights the potential broad oncogenic impact of copy number variation across the NRF2-KEAP1-CUL3 axis.	('CUL3', 'Gene', (259, 263))	('loss of function', 'NegReg', (90, 106))	('gain of function', 'PosReg', (51, 67))	('KEAP1', 'Gene', '9817', (120, 125))	('NRF2', 'Gene', '4780', (248, 252))	('CUL3', 'Gene', (129, 133))	('NRF2', 'Gene', '4780', (145, 149))	('KEAP1', 'Gene', (120, 125))	('NRF2', 'Gene', '4780', (81, 85))	('variation', 'Var', (107, 116))	('KEAP1', 'Gene', '9817', (253, 258))	('CUL3', 'Gene', '8452', (259, 263))	('activity', 'MPA', (150, 158))	('KEAP1', 'Gene', (253, 258))	('variation', 'Var', (68, 77))	('NRF2', 'Gene', (248, 252))	('NRF2', 'Gene', (145, 149))	('NRF2', 'Gene', (81, 85))	('CUL3', 'Gene', '8452', (129, 133))
387973	30195190	In general, when comparing high NRF2 tumors (top 10%) to all other tumors of a given cancer type, high inferred NRF2 activity is associated with poor survival, with significant decreases in overall survival in 11 cancer types.	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('NRF2', 'Gene', '4780', (32, 36))	('overall survival', 'MPA', (190, 206))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('NRF2', 'Gene', '4780', (112, 116))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('cancer', 'Disease', (213, 219))	('tumors', 'Disease', (37, 43))	('high NRF2 tumors', 'Disease', (27, 43))	('poor', 'NegReg', (145, 149))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('activity', 'MPA', (117, 125))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('cancer', 'Disease', (85, 91))	('decreases', 'NegReg', (177, 186))	('NRF2', 'Gene', (32, 36))	('tumors', 'Disease', (67, 73))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('tumors', 'Disease', 'MESH:D009369', (37, 43))	('NRF2', 'Gene', (112, 116))	('high NRF2 tumors', 'Disease', 'MESH:D009369', (27, 43))	('high', 'Var', (98, 102))	('cancer', 'Disease', 'MESH:D009369', (213, 219))	('tumors', 'Disease', 'MESH:D009369', (67, 73))
387975	30195190	High NRF2 is associated with significant decreases in overall survival in four of these cancers, and three of the four (KIRP, BLCA, and LIHC) were also deemed significant in the thresholding-based comparisons.	('High', 'Var', (0, 4))	('decreases', 'NegReg', (41, 50))	('NRF2', 'Gene', '4780', (5, 9))	('cancers', 'Disease', 'MESH:D009369', (88, 95))	('overall survival', 'MPA', (54, 70))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('cancers', 'Disease', (88, 95))	('BLCA', 'Disease', (126, 130))	('LIHC', 'Disease', (136, 140))	('NRF2', 'Gene', (5, 9))	('LIHC', 'Disease', 'None', (136, 140))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))
387976	30195190	Thus, NRF2 hyperactivation is associated with decreased overall survival in multiple cancer types, and this relationship is especially evident for papillary renal cell carcinoma (KIRP), bladder carcinoma (BLCA), and hepatocellular carcinoma (LIHC).	('NRF2', 'Gene', (6, 10))	('hepatocellular carcinoma', 'Disease', (216, 240))	('LIHC', 'Disease', (242, 246))	('carcinoma', 'Phenotype', 'HP:0030731', (231, 240))	('bladder carcinoma', 'Disease', (186, 203))	('carcinoma', 'Phenotype', 'HP:0030731', (168, 177))	('overall survival', 'MPA', (56, 72))	('papillary renal cell carcinoma', 'Phenotype', 'HP:0006766', (147, 177))	('LIHC', 'Disease', 'None', (242, 246))	('decreased', 'NegReg', (46, 55))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (216, 240))	('papillary renal cell carcinoma', 'Disease', (147, 177))	('multiple cancer', 'Disease', 'MESH:D009369', (76, 91))	('papillary renal cell carcinoma', 'Disease', 'MESH:C538614', (147, 177))	('NRF2', 'Gene', '4780', (6, 10))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (216, 240))	('carcinoma', 'Phenotype', 'HP:0030731', (194, 203))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (186, 203))	('multiple cancer', 'Disease', (76, 91))	('bladder carcinoma', 'Disease', 'MESH:D001749', (186, 203))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (157, 177))	('hyperactivation', 'Var', (11, 26))
387992	30195190	We obtained the full list of genes differentially expressed in NRF2 mutant tumors from Araya et al., Supplementary Table 11 (RNA-seq Differential Expression).	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('NRF2', 'Gene', (63, 67))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumors', 'Disease', (75, 81))	('NRF2', 'Gene', '4780', (63, 67))	('mutant', 'Var', (68, 74))
388010	30195190	To assess the usefulness, or accuracy, of our 32 target NRF2 activity signature in classifying NRF2-related mutations or variants, we employed a receiver operator characteristic (ROC) curve approach on TCGA gene expression and mutation (or copy number variation) data.	('NRF2', 'Gene', '4780', (56, 60))	('mutations', 'Var', (108, 117))	('NRF2', 'Gene', (56, 60))	('variants', 'Var', (121, 129))	('NRF2', 'Gene', '4780', (95, 99))	('NRF2', 'Gene', (95, 99))
388092	25562415	Development and validation of the JAX Cancer Treatment Profile  for detection of clinically actionable mutations in solid tumors The continued development of targeted therapeutics for cancer treatment has required the concomitant development of more expansive methods for the molecular profiling of the patient's tumor.	('cancer', 'Disease', (184, 190))	('tumors', 'Disease', (122, 128))	('mutations', 'Var', (103, 112))	('tumors', 'Disease', 'MESH:D009369', (122, 128))	('tumors', 'Phenotype', 'HP:0002664', (122, 128))	('tumor', 'Disease', (313, 318))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('Cancer', 'Phenotype', 'HP:0002664', (38, 44))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('patient', 'Species', '9606', (303, 310))	('tumor', 'Disease', 'MESH:D009369', (313, 318))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('tumor', 'Disease', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (313, 318))
388096	25562415	The JAX-CTP  detects actionable variants, in the form of single nucleotide variations and small insertions and deletions (<=50bp) in 190 genes in specimens with a neoplastic cell content of >=10%.	('CTP', 'Chemical', 'MESH:D003570', (8, 11))	('insertions', 'Var', (96, 106))	('deletions', 'Var', (111, 120))
388100	25562415	Commonly used single-gene tests, such as for EGFR and BRAF, and small multiplexed "hotspot" panels detect very specific targetable mutations, but clinical research studies have led to an increasingly complex array of genomic alterations, either in isolation or in combinations, that influence sensitivity or resistance to targeted cancer therapeutics .	('mutations', 'Var', (131, 140))	('cancer', 'Disease', (331, 337))	('clinical', 'Species', '191496', (146, 154))	('influence', 'Reg', (283, 292))	('cancer', 'Disease', 'MESH:D009369', (331, 337))	('resistance', 'MPA', (308, 318))	('alterations', 'Var', (225, 236))	('cancer', 'Phenotype', 'HP:0002664', (331, 337))
388101	25562415	For example, TP53 mutations alone have been reported to increase progression-free survival upon bevacizumab treatment , but if a patient also has a KRAS mutation, the response to bevacizumab may be diminished or counter balanced .	('KRAS', 'Gene', (148, 152))	('diminished', 'NegReg', (198, 208))	('TP53', 'Gene', (13, 17))	('increase', 'PosReg', (56, 64))	('progression-free', 'MPA', (65, 81))	('patient', 'Species', '9606', (129, 136))	('bevacizumab', 'Chemical', 'MESH:D000068258', (179, 190))	('KRAS', 'Gene', '3845', (148, 152))	('TP53', 'Gene', '7157', (13, 17))	('bevacizumab', 'Chemical', 'MESH:D000068258', (96, 107))	('mutations', 'Var', (18, 27))
388105	25562415	The JAX-CTP  accurately detects single nucleotide polymorphisms (SNPs), small insertions and deletions (indels; up to 50-bp long) and gene-level amplifications (copy number variations (CNVs)) in clinical specimens with a sensitivity that is sufficient for samples with significant cellular heterogeneity.	('insertions', 'Var', (78, 88))	('CTP', 'Chemical', 'MESH:D003570', (8, 11))	('amplifications', 'Var', (145, 159))	('deletions', 'Var', (93, 102))	('single nucleotide polymorphisms', 'Var', (32, 63))	('clinical', 'Species', '191496', (195, 203))
388115	25562415	Exon-level copy number variation (CNV) profiles of the tumor samples were assessed with CONTRA  using a normal baseline (comprised of 3 unrelated HapMap samples: NA12877, NA12878, and NA18507) as a control.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('NA18507', 'Var', (184, 191))	('tumor', 'Disease', (55, 60))	('NA12878', 'Chemical', '-', (171, 178))	('NA12878', 'Var', (171, 178))	('NA12877', 'Var', (162, 169))
388119	25562415	Using the described analytical and post-analytical pipeline (Figure 1), the JAX-CTP  is designed to identify mutations in 190 potentially clinically actionable genes from FFPE tumor specimens with an allele frequency as low as 10%.	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('clinical', 'Species', '191496', (138, 146))	('FFPE tumor', 'Disease', 'MESH:D009369', (171, 181))	('CTP', 'Chemical', 'MESH:D003570', (80, 83))	('FFPE tumor', 'Disease', (171, 181))	('mutations', 'Var', (109, 118))
388122	25562415	Once clinically annotated, the variants are graded relative to their clinical utility for the specific tumor type and compiled into a clinical report to inform patient treatment.	('clinical', 'Species', '191496', (69, 77))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('variants', 'Var', (31, 39))	('tumor', 'Disease', (103, 108))	('clinical', 'Species', '191496', (5, 13))	('clinical', 'Species', '191496', (134, 142))	('patient', 'Species', '9606', (160, 167))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
388124	25562415	Given intra-tumor heterogeneity and/or the presence of small numbers of tumor cells in a specimen, one needs to be able to reliably identify mutations across a spectrum of allele frequencies.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('intra-tumor', 'Disease', (6, 17))	('intra-tumor', 'Disease', 'MESH:D009369', (6, 17))	('mutations', 'Var', (141, 150))	('tumor', 'Disease', (72, 77))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('tumor', 'Disease', (12, 17))	('tumor', 'Disease', 'MESH:D009369', (72, 77))
388125	25562415	To evaluate our variant (SNPs and small indels) detection capability at different allele frequencies, we designed a titration experiment that involved mixing of two pairs of HapMap samples (NA18507 + NA12878 and NA12882 + NA18507) such that the minor allele was present at the following frequencies: 2.5%, 3.75%, 5%, 7.5%, 10%, 20%, 40%, 45%, 46.25% and 47.5%.	('NA12882 + NA18507', 'Var', (212, 229))	('NA12878', 'Chemical', '-', (200, 207))	('NA18507 + NA12878', 'Var', (190, 207))
388129	25562415	The only variants that were not detected by our assay were the EGFR T790M* variant present at 1% and EGFR L858R variant present at 3% frequency.	('EGFR', 'Gene', (63, 67))	('L858R', 'Mutation', 'rs121434568', (106, 111))	('T790M', 'Mutation', 'rs121434569', (68, 73))	('L858R', 'Var', (106, 111))	('T790M*', 'Var', (68, 74))
388132	25562415	Specificity for the detection of micro-indels was assessed by a PCR-based validation of 27 unique indels of length 4-45 bp present at >=5% allele frequency across 41 FFPE tumor specimens and not present in HapMap control samples (NA12878, NA18507) (See Supplemental Table S4).	('FFPE tumor', 'Disease', (166, 176))	('NA18507', 'Var', (239, 246))	('NA12878', 'Chemical', '-', (230, 237))	('NA12878', 'Var', (230, 237))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('FFPE tumor', 'Disease', 'MESH:D009369', (166, 176))
388134	25562415	Additional assessment of the accuracy of indel detection was completed using the HorizonDX FFPE Quantitative Multiplex Reference Standard, which contains the 15bp deletion EGFR delE746-A750 at an allele frequency of 2%.	('delE746-A750', 'Var', (177, 189))	('EGFR', 'Gene', (172, 176))	('delE746', 'Mutation', 'p.746delE', (177, 184))
388136	25562415	This sample contained a heterozygous 6-bp deletion of AGGGGG and 11-bp insertion of CTTCACACACA between nucleotides 736 and 741 in exon 7 of the PMS2 gene, creating a frameshift change at codon 246 resulting in truncation of the PMS2 protein.	('truncation', 'MPA', (211, 221))	('protein', 'Protein', (234, 241))	('PMS2', 'Gene', '5395', (229, 233))	('PMS2', 'Gene', (145, 149))	('PMS2', 'Gene', (229, 233))	('deletion', 'Var', (42, 50))	('AGGGGG', 'Gene', (54, 60))	('PMS2', 'Gene', '5395', (145, 149))	('frameshift change', 'Var', (167, 184))
388137	25562415	The limit of detection for CNVs at different levels of tumor purity was assessed by mixing the DNA from two FFPE samples (1218_GES14_00876_CGACACAC_L002 - Lung Squamous cell carcinoma, SS_13_15281_GES14_00880_GACAGTGC_L002 - Colon Adenocarcinoma) with a HapMap control sample (NA12878) at different proportions to produce samples with 75%, 50%, and 25% tumor purity (See Supplemental Table S6).	('Squamous cell carcinoma', 'Phenotype', 'HP:0002860', (160, 183))	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Disease', (353, 358))	('Colon Adenocarcinoma', 'Disease', 'MESH:D003110', (225, 245))	('Lung Squamous cell carcinoma', 'Phenotype', 'HP:0030359', (155, 183))	('Colon Adenocarcinoma', 'Disease', (225, 245))	('1218_GES14_00876_CGACACAC_L002', 'Var', (122, 152))	('Squamous cell carcinoma', 'Disease', (160, 183))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('carcinoma', 'Phenotype', 'HP:0030731', (174, 183))	('Squamous cell carcinoma', 'Disease', 'MESH:D002294', (160, 183))	('tumor', 'Disease', (55, 60))	('NA12878', 'Chemical', '-', (277, 284))	('carcinoma', 'Phenotype', 'HP:0030731', (236, 245))	('tumor', 'Disease', 'MESH:D009369', (353, 358))	('tumor', 'Phenotype', 'HP:0002664', (353, 358))
388138	25562415	At a tumor purity of >= 75%, the assay is able to detect 100% of CNVs of copy number >= 5, and at a tumor purity of >= 50%, 100% of CNVs of copy number >= 6 are detected.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('CNVs', 'Var', (65, 69))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('tumor', 'Disease', (100, 105))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('tumor', 'Disease', (5, 10))	('tumor', 'Disease', 'MESH:D009369', (100, 105))
388139	25562415	Given our tumor purity requirement of 50% for acceptable FFPE specimens, the limit of detection for CNVs is copy number 6.	('tumor', 'Disease', (10, 15))	('copy number 6', 'Var', (108, 121))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('tumor', 'Phenotype', 'HP:0002664', (10, 15))
388144	25562415	Clinical research studies continue to demonstrate the impact of mutations in multiple pathways and show how those interact to cause sensitivity or resistance to both chemotherapeutic and targeted therapies.	('sensitivity', 'Disease', (132, 143))	('Clinical', 'Species', '191496', (0, 8))	('cause', 'Reg', (126, 131))	('resistance', 'CPA', (147, 157))	('mutations', 'Var', (64, 73))
388145	25562415	The JAX-CTP  is designed to identify mutations in 190 potentially actionable genes across multiple cancer relevant pathways (figure 4) to facilitate the selection of the appropriate therapeutic strategy.	('CTP', 'Chemical', 'MESH:D003570', (8, 11))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('cancer', 'Disease', (99, 105))	('mutations', 'Var', (37, 46))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
388148	25562415	Attaining samples that have very specific actionable mutations such as EGFR exon 19 deletion (DeltaE746 - A750) is easily accomplished and is useful for the assessment of sensitivity and limit of detection, but this does not address the specificity of an assay.	('DeltaE746', 'DELETION', 'None', (94, 103))	('EGFR', 'Gene', (71, 75))	('DeltaE746', 'Var', (94, 103))	('deletion', 'Var', (84, 92))
388149	25562415	Therefore, we independently verified 27 unique indels of length 4-45 bp present at >=5% allele frequency across 41 FFPE tumor specimens and not present in HapMap control samples (NA12878, NA18507).	('NA18507', 'Var', (188, 195))	('NA12878', 'Chemical', '-', (179, 186))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('NA12878', 'Var', (179, 186))	('FFPE tumor', 'Disease', 'MESH:D009369', (115, 125))	('FFPE tumor', 'Disease', (115, 125))
388150	25562415	The JAX-CTP  utilizes the latest state-of-the-art methodologies for the detection and clinical annotation of potentially actionable mutations in tumors in a clinical setting.	('CTP', 'Chemical', 'MESH:D003570', (8, 11))	('clinical', 'Species', '191496', (86, 94))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('mutations', 'Var', (132, 141))	('tumors', 'Disease', (145, 151))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('tumors', 'Disease', 'MESH:D009369', (145, 151))	('clinical', 'Species', '191496', (157, 165))
388154	25562415	The JAX-CTP  accurately detects SNP's, small indels and gene-level CNV's.	('SNP', 'Disease', (32, 35))	('CTP', 'Chemical', 'MESH:D003570', (8, 11))	('small indels', 'Var', (39, 51))
388155	25562415	The JAX-CTP  accurately detects variants at a 10% allele frequency.	('variants', 'Var', (32, 40))	('detects', 'Reg', (24, 31))	('CTP', 'Chemical', 'MESH:D003570', (8, 11))
388176	32397172	However, FDG-PET/CT is likely to yield false-negative results for small volumes of metabolically active tumors or well-differentiated pulmonary adenocarcinoma, and false-positive results for inflammatory nodules.	('pulmonary adenocarcinoma', 'Disease', 'MESH:D000230', (134, 158))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (149, 158))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('pulmonary adenocarcinoma', 'Phenotype', 'HP:0030078', (134, 158))	('FDG', 'Chemical', 'MESH:D019788', (9, 12))	('tumors', 'Disease', (104, 110))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('FDG-PET/CT', 'Var', (9, 19))	('pulmonary adenocarcinoma', 'Disease', (134, 158))
388279	28629367	Multiple chromosomal gains, amplifications and losses that represent regions potentially involved in etiology defined the pattern of abnormalities in the tumor genome.	('amplifications', 'Var', (28, 42))	('Multiple chromosomal gains', 'Phenotype', 'HP:0040012', (0, 26))	('losses', 'NegReg', (47, 53))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('tumor', 'Disease', (154, 159))
388280	28629367	The preponderance of chromosomal aberrations in African-American ESCC predicts concomitant changes in gene activity during carcinogenesis.	('changes', 'Reg', (91, 98))	('preponderance of chromosomal aberrations', 'Phenotype', 'HP:0040012', (4, 44))	('gene activity', 'MPA', (102, 115))	('chromosomal aberrations', 'Var', (21, 44))	('carcinogenesis', 'Disease', 'MESH:D063646', (123, 137))	('carcinogenesis', 'Disease', (123, 137))
388282	28629367	Particularly noteworthy is the dysregulation of NRF2 mediated oxidative stress genes and genes that encode drug-metabolizing enzymes and xenobiotics that may, in part, contribute to the aggressive nature of ESCC among blacks.	('NRF2', 'Gene', '4780', (48, 52))	('ESCC', 'Disease', (207, 211))	('NRF2', 'Gene', (48, 52))	('genes', 'Gene', (89, 94))	('oxidative stress', 'Phenotype', 'HP:0025464', (62, 78))	('dysregulation', 'Var', (31, 44))	('contribute', 'Reg', (168, 178))
388331	28629367	Our findings in African-American ESCC reveal dysregulation of genes involved in detox networks, including NRF2 pathway, which is a primary mediator of detoxification and metabolism responses (Additional file 5).	('NRF2', 'Gene', '4780', (106, 110))	('genes', 'Gene', (62, 67))	('dysregulation', 'Var', (45, 58))	('NRF2', 'Gene', (106, 110))	('detox', 'Pathway', (80, 85))
388338	28629367	Mutations in NFE2L2 confer malignant potential and resistance to therapy in advanced ESCC.	('NFE2L2', 'Gene', '4780', (13, 19))	('malignant potential', 'CPA', (27, 46))	('NFE2L2', 'Gene', (13, 19))	('ESCC', 'Disease', (85, 89))	('Mutations', 'Var', (0, 9))
388339	28629367	However, only 10% of Asian ESCC carry mutations in the NFE2L2 gene or its negative regulator KEAP1.	('KEAP1', 'Gene', '9817', (93, 98))	('KEAP1', 'Gene', (93, 98))	('NFE2L2', 'Gene', '4780', (55, 61))	('Asian ESCC', 'Disease', (21, 31))	('mutations', 'Var', (38, 47))	('NFE2L2', 'Gene', (55, 61))
388350	28629367	Therefore, the effect of the dysregulated NRF2 pathway may amplify the impairment of the dynamics of these pathways.	('NRF2', 'Gene', (42, 46))	('dysregulated', 'Var', (29, 41))	('NRF2', 'Gene', '4780', (42, 46))
388354	28629367	Recent studies that outlined the genomic and molecular characterization of esophageal carcinoma in the Asian population suggested the dysregulation of the receptor tyrosine kinase (RTK)-MAPK-PI3K, NOTCH, Hippo, cell cycle, and epigenetic pathways as the primary molecular mechanism of ESCC.	('Hippo', 'CPA', (204, 209))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (75, 95))	('epigenetic pathways', 'Pathway', (227, 246))	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('PI3', 'Gene', (191, 194))	('dysregulation', 'Var', (134, 147))	('RTK', 'Gene', '5979', (181, 184))	('receptor tyrosine kinase', 'Gene', (155, 179))	('PI3', 'Gene', '5266', (191, 194))	('receptor tyrosine kinase', 'Gene', '5979', (155, 179))	('ESCC', 'Disease', (285, 289))	('cell cycle', 'CPA', (211, 221))	('RTK', 'Gene', (181, 184))	('esophageal carcinoma', 'Disease', (75, 95))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (75, 95))	('NOTCH', 'Pathway', (197, 202))
388355	28629367	The amplification or over-expression of FGFR1, MET, EGFR, ERBB2, ERBB4, and IL7R was observed in the majority of the patients and has been suggested as main drivers for the ESCC tumorigenesis.	('tumor', 'Disease', (178, 183))	('ERBB4', 'Gene', '2066', (65, 70))	('MET', 'Gene', (47, 50))	('ESCC', 'Disease', (173, 177))	('over-expression', 'PosReg', (21, 36))	('EGFR', 'Gene', '1956', (52, 56))	('FGFR1', 'Gene', (40, 45))	('EGFR', 'Gene', (52, 56))	('FGFR1', 'Gene', '2260', (40, 45))	('ERBB2', 'Gene', '2064', (58, 63))	('ERBB4', 'Gene', (65, 70))	('IL7R', 'Gene', '3575', (76, 80))	('ERBB2', 'Gene', (58, 63))	('amplification', 'Var', (4, 17))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('IL7R', 'Gene', (76, 80))	('patients', 'Species', '9606', (117, 125))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))
388360	28629367	Overexpression of this gene may play a role in breast, and pancreatic cancer tumorigenesis.	('pancreatic cancer', 'Disease', 'MESH:D010190', (59, 76))	('play', 'Reg', (32, 36))	('pancreatic cancer', 'Disease', (59, 76))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (59, 76))	('Overexpression', 'Var', (0, 14))	('tumor', 'Disease', (77, 82))	('breast', 'Disease', (47, 53))
388365	28629367	We previously identified a single nucleotide mutation of SCEL gene in both normal and squamous cell carcinoma of esophagus in African-Americans.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (86, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (86, 109))	('squamous cell carcinoma', 'Disease', (86, 109))	('single nucleotide mutation', 'Var', (27, 53))	('SCEL', 'Gene', (57, 61))	('SCEL', 'Gene', '8796', (57, 61))	('carcinoma of esophagus', 'Phenotype', 'HP:0011459', (100, 122))
388393	28584720	Previous studies have found that low-risk HPV is associated with recurrent respiratory papillomatosis, while high-risk HPV is associated with laryngeal cancer.	('low-risk', 'Var', (33, 41))	('HPV', 'Species', '10566', (42, 45))	('respiratory papillomatosis', 'Disease', 'MESH:C535297', (75, 101))	('laryngeal cancer', 'Disease', (142, 158))	('associated', 'Reg', (49, 59))	('laryngeal cancer', 'Phenotype', 'HP:0012118', (142, 158))	('HPV', 'Species', '10566', (119, 122))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('laryngeal cancer', 'Disease', 'MESH:D007822', (142, 158))	('respiratory papillomatosis', 'Disease', (75, 101))
388425	28584720	However, the 5-year local/regional control rate was significantly better in HPV- positive tumors than in HPV-negative tumors (100% vs. 75%, p = 0.0494; Fig.	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('HPV', 'Species', '10566', (76, 79))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('better', 'PosReg', (66, 72))	('tumors', 'Disease', (90, 96))	('tumors', 'Disease', (118, 124))	('tumors', 'Disease', 'MESH:D009369', (90, 96))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('HPV- positive', 'Var', (76, 89))	('HPV', 'Species', '10566', (105, 108))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('local/regional control', 'CPA', (20, 42))	('tumors', 'Disease', 'MESH:D009369', (118, 124))
388465	28147343	The ribosomal protein gene RPL5 is a haploinsufficient tumor suppressor in multiple cancer types For many years, defects in the ribosome have been associated to cancer.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('RPL5', 'Gene', '6125', (27, 31))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('associated', 'Reg', (147, 157))	('cancer', 'Disease', (84, 90))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('haploinsufficient tumor', 'Disease', (37, 60))	('defects', 'Var', (113, 120))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('cancer', 'Disease', (161, 167))	('RPL5', 'Gene', (27, 31))	('haploinsufficient tumor', 'Disease', 'MESH:D058495', (37, 60))
388466	28147343	Recently, somatic mutations and deletions affecting ribosomal protein genes were identified in a few leukemias and solid tumor types.	('deletions', 'Var', (32, 41))	('leukemias', 'Phenotype', 'HP:0001909', (101, 110))	('leukemias', 'Disease', (101, 110))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumor', 'Disease', (121, 126))	('ribosomal protein genes', 'Gene', (52, 75))	('leukemias', 'Disease', 'MESH:D007938', (101, 110))	('leukemia', 'Phenotype', 'HP:0001909', (101, 109))	('identified', 'Reg', (81, 91))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
388469	28147343	RPL5 was located at a significant peak of heterozygous deletion or mutated in 11% of glioblastoma, 28% of melanoma and 34% of breast cancer samples.	('breast cancer', 'Disease', 'MESH:D001943', (126, 139))	('breast cancer', 'Phenotype', 'HP:0003002', (126, 139))	('glioblastoma', 'Disease', (85, 97))	('breast cancer', 'Disease', (126, 139))	('glioblastoma', 'Disease', 'MESH:D005909', (85, 97))	('mutated', 'Var', (67, 74))	('glioblastoma', 'Phenotype', 'HP:0012174', (85, 97))	('melanoma', 'Disease', 'MESH:D008545', (106, 114))	('melanoma', 'Phenotype', 'HP:0002861', (106, 114))	('melanoma', 'Disease', (106, 114))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
388470	28147343	Moreover, patients with low RPL5 expression displayed worse overall survival in glioblastoma and in one breast cancer cohort.	('glioblastoma', 'Phenotype', 'HP:0012174', (80, 92))	('one breast', 'Phenotype', 'HP:0012813', (100, 110))	('RPL5', 'Protein', (28, 32))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('breast cancer', 'Disease', 'MESH:D001943', (104, 117))	('breast cancer', 'Disease', (104, 117))	('overall survival', 'MPA', (60, 76))	('breast cancer', 'Phenotype', 'HP:0003002', (104, 117))	('patients', 'Species', '9606', (10, 18))	('low', 'Var', (24, 27))	('glioblastoma', 'Disease', (80, 92))	('glioblastoma', 'Disease', 'MESH:D005909', (80, 92))	('worse', 'NegReg', (54, 59))
388473	28147343	In conclusion, RPL5 heterozygous inactivation occurs at high incidence (11-34%) in multiple tumor types, currently representing the most common somatic ribosomal protein defect in cancer, and we demonstrate a tumor suppressor role for RPL5 in breast cancer.	('breast cancer', 'Disease', (243, 256))	('protein defect in cancer', 'Disease', (162, 186))	('breast cancer', 'Phenotype', 'HP:0003002', (243, 256))	('tumor', 'Disease', (209, 214))	('a tumor', 'Disease', 'MESH:D009369', (207, 214))	('a tumor', 'Disease', (207, 214))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))	('RPL5', 'Gene', (235, 239))	('RPL5', 'Gene', (15, 19))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('protein defect in cancer', 'Disease', 'MESH:D009369', (162, 186))	('tumor', 'Disease', 'MESH:D009369', (209, 214))	('tumor', 'Disease', (92, 97))	('breast cancer', 'Disease', 'MESH:D001943', (243, 256))	('heterozygous inactivation', 'Var', (20, 45))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))
388474	28147343	Cancers contain a variety of genomic lesions including mutations, translocations, copy number alterations and epigenetic changes that can result in altered protein functions.	('copy number alterations', 'Var', (82, 105))	('translocations', 'Var', (66, 80))	('mutations', 'Var', (55, 64))	('Cancers', 'Disease', (0, 7))	('Cancers', 'Phenotype', 'HP:0002664', (0, 7))	('protein functions', 'MPA', (156, 173))	('altered', 'Reg', (148, 155))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancers', 'Disease', 'MESH:D009369', (0, 7))	('result', 'Reg', (138, 144))	('epigenetic changes', 'Var', (110, 128))
388478	28147343	Somatic mutations and deletions affecting ribosomal protein genes occur in up to 20% of acute T-cell leukemia (T-ALL) cases, with the most frequent defects affecting RPL10 (also known as uL16; 7.9% of pediatric T-ALL cases) and RPL22 (eL22; 10%) and with rare defects in RPL5 (uL18) and RPL11 (uL5).	('RPL22', 'Gene', (228, 233))	('deletions', 'Var', (22, 31))	('ribosomal protein genes', 'Gene', (42, 65))	('RPL22', 'Gene', '6146', (228, 233))	('RPL11', 'Gene', '6135', (287, 292))	('RPL10', 'Gene', (166, 171))	('RPL10', 'Gene', '6134', (166, 171))	('acute T-cell leukemia', 'Disease', 'MESH:D054218', (88, 109))	('affecting', 'Reg', (156, 165))	('RPL5', 'Gene', (271, 275))	('RPL11', 'Gene', (287, 292))	('leukemia', 'Phenotype', 'HP:0001909', (101, 109))	('acute T-cell leukemia', 'Disease', (88, 109))
388480	28147343	The Cancer Genome Atlas (TCGA) pan-cancer analyses identified RPL5 and RPL22 as significantly mutated in glioblastoma multiforme (GBM, 2.8%) and uterine corpus endometrial carcinoma (UCEC, 10.9%) respectively, and inactivating RPL22 mutations have also been described in colorectal and gastric cancer.	('mutated', 'Var', (94, 101))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('RPL22', 'Gene', '6146', (71, 76))	('Cancer', 'Phenotype', 'HP:0002664', (4, 10))	('RPL22', 'Gene', (71, 76))	('cancer', 'Disease', (294, 300))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('cancer', 'Phenotype', 'HP:0002664', (294, 300))	('RPL5', 'Gene', (62, 66))	('RPL22', 'Gene', '6146', (227, 232))	('gastric cancer', 'Phenotype', 'HP:0012126', (286, 300))	('glioblastoma', 'Phenotype', 'HP:0012174', (105, 117))	('inactivating', 'Var', (214, 226))	('RPL22', 'Gene', (227, 232))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (4, 23))	('carcinoma', 'Phenotype', 'HP:0030731', (172, 181))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (160, 181))	('colorectal and gastric cancer', 'Disease', 'MESH:D013274', (271, 300))	('corpus endometrial carcinoma', 'Disease', (153, 181))	('corpus endometrial carcinoma', 'Disease', 'MESH:D016889', (153, 181))	('glioblastoma multiforme', 'Disease', (105, 128))	('cancer', 'Disease', 'MESH:D009369', (294, 300))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (105, 128))	('Cancer Genome Atlas', 'Disease', (4, 23))	('mutations', 'Var', (233, 242))	('cancer', 'Disease', (35, 41))
388482	28147343	Mutations reported for RPL10 in T-ALL are all missense mutations, with a strong mutational hotspot at residue arginine 98 (R98S), indicating an oncogenic role for these mutations.	('R98S', 'Mutation', 'p.R98S', (123, 127))	('Mutations', 'Var', (0, 9))	('arginine', 'Chemical', 'MESH:D001120', (110, 118))	('RPL10', 'Gene', '6134', (23, 28))	('RPL10', 'Gene', (23, 28))
388483	28147343	In contrast, all other somatic defects that have been identified so far in ribosomal protein genes are heterozygous and many of them are clearly inactivating mutations or deletions, suggesting roles as haploinsufficient tumor suppressors for these proteins in cancer.	('ribosomal protein', 'Gene', (75, 92))	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('inactivating', 'NegReg', (145, 157))	('deletions', 'Var', (171, 180))	('cancer', 'Disease', 'MESH:D009369', (260, 266))	('haploinsufficient tumor', 'Disease', 'MESH:D058495', (202, 225))	('cancer', 'Disease', (260, 266))	('haploinsufficient tumor', 'Disease', (202, 225))	('cancer', 'Phenotype', 'HP:0002664', (260, 266))
388484	28147343	Congenital heterozygous inactivating mutations and deletions affecting RPL5, RPL11 and RPS15 have also been described in Diamond Blackfan Anemia (DBA), a congenital syndrome belonging to a family of human disorders, ribosomopathies, caused by impaired ribosome biogenesis and function.	('Anemia', 'Disease', (138, 144))	('ribosomopathies', 'Disease', 'None', (216, 231))	('ribosomopathies', 'Disease', (216, 231))	('Anemia', 'Disease', 'MESH:D000740', (138, 144))	('RPS15', 'Gene', '6209', (87, 92))	('human', 'Species', '9606', (199, 204))	('RPS15', 'Gene', (87, 92))	('described', 'Reg', (108, 117))	('RPL5', 'Gene', (71, 75))	('congenital syndrome belonging', 'Disease', 'MESH:D000013', (154, 183))	('deletions', 'Var', (51, 60))	('RPL11', 'Gene', (77, 82))	('RPL11', 'Gene', '6135', (77, 82))	('congenital syndrome belonging', 'Disease', (154, 183))	('Anemia', 'Phenotype', 'HP:0001903', (138, 144))
388487	28147343	Besides the identification of somatic ribosome defects in cancer and the elevated cancer risks of ribosomopathy patients, the link between ribosome defects and cancer is supported by the observation that heterozygous inactivation of certain ribosomal protein genes induces tumor development in zebrafish.	('ribosome defects', 'Disease', 'MESH:D005128', (139, 155))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('cancer', 'Disease', (82, 88))	('tumor', 'Disease', (273, 278))	('elevated cancer', 'Disease', (73, 88))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('ribosome defects', 'Disease', (139, 155))	('cancer', 'Disease', (160, 166))	('tumor', 'Disease', 'MESH:D009369', (273, 278))	('ribosomal protein', 'Gene', (241, 258))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('ribosomopathy', 'Disease', 'None', (98, 111))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('ribosomopathy', 'Disease', (98, 111))	('zebrafish', 'Species', '7955', (294, 303))	('elevated cancer', 'Disease', 'MESH:D009369', (73, 88))	('heterozygous inactivation', 'Var', (204, 229))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('ribosome defects', 'Disease', 'MESH:D005128', (38, 54))	('tumor', 'Phenotype', 'HP:0002664', (273, 278))	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('induces', 'PosReg', (265, 272))	('patients', 'Species', '9606', (112, 120))	('ribosome defects', 'Disease', (38, 54))	('cancer', 'Disease', (58, 64))
388488	28147343	Moreover, Rpl11 and Rpl22 haploinsufficiency accelerates mouse lymphoma development and loss of one copy of Rpl5 or Rps24 (eS24) has been linked to development of rare soft tissue sarcomas in mice.	('Rpl22', 'Gene', '19934', (20, 25))	('linked', 'Reg', (138, 144))	('Rpl11', 'Gene', '67025', (10, 15))	('Rpl11', 'Gene', (10, 15))	('haploinsufficiency', 'Disease', 'MESH:D058495', (26, 44))	('eS24', 'Gene', '103943', (123, 127))	('eS24', 'Gene', (123, 127))	('sarcomas', 'Disease', 'MESH:D012509', (180, 188))	('haploinsufficiency', 'Disease', (26, 44))	('sarcomas', 'Phenotype', 'HP:0100242', (180, 188))	('sarcomas', 'Disease', (180, 188))	('Rpl5', 'Gene', (108, 112))	('lymphoma', 'Phenotype', 'HP:0002665', (63, 71))	('mice', 'Species', '10090', (192, 196))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (168, 188))	('Rps24', 'Gene', (116, 121))	('accelerates', 'PosReg', (45, 56))	('Rpl22', 'Gene', (20, 25))	('Rps24', 'Gene', '20088', (116, 121))	('lymphoma', 'Disease', (63, 71))	('loss', 'Var', (88, 92))	('lymphoma', 'Disease', 'MESH:D008223', (63, 71))	('Rpl5', 'Gene', '100503670', (108, 112))	('mouse', 'Species', '10090', (57, 62))
388494	28147343	RPL22 inactivation was reported to indirectly activate c-MYC expression, via an NF-kB - Lin28B - Let7 miRNA axis.	('inactivation', 'Var', (6, 18))	('c-MYC', 'Gene', (55, 60))	('RPL22', 'Gene', (0, 5))	('Lin28B', 'Gene', '389421', (88, 94))	('activate', 'PosReg', (46, 54))	('c-MYC', 'Gene', '4609', (55, 60))	('RPL22', 'Gene', '6146', (0, 5))	('Lin28B', 'Gene', (88, 94))
388498	28147343	We analyzed mutations from 4 926 tumors and copy number changes from 7 322 tumors across 16 different tumor types for the 81 genes encoding ribosomal proteins.	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('tumor', 'Disease', (102, 107))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('mutations', 'Var', (12, 21))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumors', 'Disease', (75, 81))	('tumors', 'Disease', 'MESH:D009369', (33, 39))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('tumor', 'Disease', (33, 38))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumors', 'Disease', (33, 39))	('tumor', 'Disease', (75, 80))
388501	28147343	Whereas somatic mutations in RPL5 had been described in 3% of GBM samples, we found that RPL5 heterozygous inactivation currently represents the most common somatic ribosome defect in human cancer.	('cancer', 'Disease', (190, 196))	('cancer', 'Disease', 'MESH:D009369', (190, 196))	('RPL5', 'Gene', (29, 33))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('heterozygous', 'Var', (94, 106))	('RPL5', 'Gene', (89, 93))	('human', 'Species', '9606', (184, 189))
388504	28147343	Overall, the frequency of such defects in individual ribosomal protein genes was below 3% in all cancer types (Supplementary Table 2).	('defects', 'Var', (31, 38))	('cancer', 'Disease', (97, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('ribosomal protein', 'Protein', (53, 70))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
388505	28147343	However, mutational frequency represents only one criterium to discriminate functional cancer drivers.	('mutational frequency', 'Var', (9, 29))	('cancer', 'Disease', (87, 93))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))
388509	28147343	RPSA was identified in Stomach Adenocarcinoma (STAD) because of a significant cluster of mutations (q-value: 0.004; OncodriveCLUST ) (Figure 1A-1B; Supplementary Figure 1).	('RPSA', 'Gene', (0, 4))	('RPSA', 'Gene', '3921', (0, 4))	('Stomach Adenocarcinoma', 'Disease', (23, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (36, 45))	('mutations', 'Var', (89, 98))	('Stomach Adenocarcinoma', 'Disease', 'MESH:D013274', (23, 45))
388510	28147343	RPS5 and RPS20 show an accumulation of high functional impact mutations, in STAD and UCEC respectively (q-values: 0.026 and 0.042; Oncodrive FM).	('mutations', 'Var', (62, 71))	('RPS5', 'Gene', '6193', (0, 4))	('RPS5', 'Gene', (0, 4))	('RPS20', 'Gene', (9, 14))	('RPS20', 'Gene', '6224', (9, 14))
388511	28147343	Accumulation of high functional impact mutations was also found for RPL5 in GBM (q-value: 0.0002) and SKCM (q-value: 0.004) and for RPL11 in SKCM (q-value: 0.0007).	('RPL11', 'Gene', '6135', (132, 137))	('RPL11', 'Gene', (132, 137))	('RPL5', 'Var', (68, 72))	('mutations', 'Var', (39, 48))
388512	28147343	Some of these mutations were clearly inactivating frameshift, nonsense or splice site mutations (Figure 1B), indicative of a tumor suppressor function.	('inactivating', 'NegReg', (37, 49))	('nonsense or splice site', 'Var', (62, 85))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('frameshift', 'Var', (50, 60))	('a tumor', 'Disease', 'MESH:D009369', (123, 130))	('a tumor', 'Disease', (123, 130))	('mutations', 'Var', (14, 23))
388514	28147343	Because these defects often encompass many genes, we increased the specificity of our screening for driver events by applying additional filtering criteria: i) that the ribosomal protein gene was included in the region of the deletion (or amplification) that is predicted to contain the cancer driving target gene; ii) that the same region does not include other known cancer genes; iii) that the ribosomal protein gene was also affected by mutations, in addition to the significant copy number change.	('ribosomal protein gene', 'Gene', (397, 419))	('cancer', 'Disease', (369, 375))	('cancer', 'Disease', (287, 293))	('cancer', 'Disease', 'MESH:D009369', (287, 293))	('cancer', 'Phenotype', 'HP:0002664', (369, 375))	('mutations', 'Var', (441, 450))	('affected', 'Reg', (429, 437))	('cancer', 'Phenotype', 'HP:0002664', (287, 293))	('cancer', 'Disease', 'MESH:D009369', (369, 375))
388523	28147343	However, a closer analysis showed that the known cancer genes are more than 7 Mbp away from RPL5 and also in this tumor type RPL5 was located in a pronounced deletion peak (Figure 2C).	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('tumor', 'Disease', (114, 119))	('RPL5', 'Var', (125, 129))	('Mbp', 'Gene', (78, 81))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('Mbp', 'Gene', '4155', (78, 81))	('cancer', 'Disease', (49, 55))
388524	28147343	RPL5 deletions were associated with 29-38% lower average RPL5 mRNA expression levels in GBM (p = 0.016), SKCM (p = 2.36e-04) and BRCA (p = 2.2e-16) (Figure 2D).	('BRCA', 'Gene', '672', (129, 133))	('RPL5', 'Gene', (0, 4))	('BRCA', 'Gene', (129, 133))	('RPL5 mRNA expression levels', 'MPA', (57, 84))	('deletions', 'Var', (5, 14))	('lower', 'NegReg', (43, 48))
388526	28147343	RPL5, the most commonly altered ribosomal protein we detected, was significantly mutated and deleted in GBM (11%) and SKCM (28%) and significantly deleted in BRCA (34%).	('BRCA', 'Gene', (158, 162))	('altered', 'Reg', (24, 31))	('deleted', 'Var', (93, 100))	('RPL5', 'Gene', (0, 4))	('ribosomal protein', 'Protein', (32, 49))	('BRCA', 'Gene', '672', (158, 162))
388532	28147343	Because RPL5 has been functionally linked to TP53 and c-MYC, we tested for an association between RPL5 defects and defects in c-MYC, TP53, or the negative TP53 regulators MDM4 and MDM2 (Figure 4 and Supplementary Figure 4).	('MDM2', 'Gene', '4193', (180, 184))	('MDM4', 'Gene', '4194', (171, 175))	('MDM4', 'Gene', (171, 175))	('TP53', 'Gene', (45, 49))	('TP53', 'Gene', '7157', (45, 49))	('c-MYC', 'Gene', '4609', (126, 131))	('defects', 'Var', (103, 110))	('c-MYC', 'Gene', '4609', (54, 59))	('defects', 'Var', (115, 122))	('TP53', 'Gene', '7157', (155, 159))	('tested', 'Reg', (64, 70))	('TP53', 'Gene', (155, 159))	('RPL5', 'Gene', (98, 102))	('c-MYC', 'Gene', (54, 59))	('TP53', 'Gene', '7157', (133, 137))	('c-MYC', 'Gene', (126, 131))	('TP53', 'Gene', (133, 137))	('MDM2', 'Gene', (180, 184))
388533	28147343	In BRCA, significant co-occurrence of RPL5 defects and TP53 pathway inactivation by TP53 inactivation or by mutation/amplification of MDM2 or MDM4 was detected.	('RPL5 defects', 'Gene', (38, 50))	('BRCA', 'Gene', (3, 7))	('inactivation', 'Var', (89, 101))	('BRCA', 'Gene', '672', (3, 7))	('TP53', 'Gene', (55, 59))	('MDM4', 'Gene', '4194', (142, 146))	('TP53', 'Gene', '7157', (55, 59))	('MDM2', 'Gene', '4193', (134, 138))	('MDM4', 'Gene', (142, 146))	('MDM2', 'Gene', (134, 138))	('TP53', 'Gene', '7157', (84, 88))	('TP53', 'Gene', (84, 88))	('inactivation', 'NegReg', (68, 80))	('mutation/amplification', 'Var', (108, 130))
388539	28147343	It represents a candidate tumor suppressor, based on its heterozygous inactivating mutations and focal deletions and based on the correlation of lower RPL5 expression with worse survival.	('RPL5', 'Protein', (151, 155))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('deletions', 'Var', (103, 112))	('lower', 'NegReg', (145, 150))	('expression', 'MPA', (156, 166))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))
388542	28147343	Triple negative breast cancer cell lines MCF7 (TP53 WT, RPL5 WT) and MDA-MB-231 (TP53 homozygous R280K missense mutation, RPL5 WT) were transduced with lentiviral vectors allowing inducible RPL5 protein knockdown of 30-50% (Figure 5A, Supplementary Figure 6, MCF7 p < 0.001 and MDA-MB-231 p = 0.001).	('breast cancer', 'Disease', (16, 29))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (278, 288))	('TP53', 'Gene', (47, 51))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (69, 79))	('MCF7', 'CellLine', 'CVCL:0031', (259, 263))	('breast cancer', 'Disease', 'MESH:D001943', (16, 29))	('TP53', 'Gene', '7157', (47, 51))	('MCF7', 'CellLine', 'CVCL:0031', (41, 45))	('R280K', 'Mutation', 'rs121912660', (97, 102))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('TP53', 'Gene', '7157', (81, 85))	('knockdown', 'Var', (203, 212))	('TP53', 'Gene', (81, 85))	('breast cancer', 'Phenotype', 'HP:0003002', (16, 29))
388543	28147343	Interestingly, this RPL5 knockdown induced proliferation of MCF7 cells, but not of MDA-MB-231 cells (Figure 5B, MCF7 p < 0.001 and MDA-MB-231 p = 0.597).	('MDA-MB-231', 'CellLine', 'CVCL:0062', (131, 141))	('MCF7', 'CellLine', 'CVCL:0031', (60, 64))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (83, 93))	('MCF7', 'CellLine', 'CVCL:0031', (112, 116))	('proliferation', 'CPA', (43, 56))	('knockdown', 'Var', (25, 34))
388546	28147343	In both subcutaneous breast cancer models, RPL5 knockdown significantly increased the tumor weight when sacrificing the animals (Figure 6A, MCF7 p = 0.009 and MDA-MB-231 p = 0.044).	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('increased', 'PosReg', (72, 81))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('breast cancer', 'Disease', 'MESH:D001943', (21, 34))	('tumor', 'Disease', (86, 91))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (159, 169))	('breast cancer', 'Disease', (21, 34))	('breast cancer', 'Phenotype', 'HP:0003002', (21, 34))	('RPL5', 'Gene', (43, 47))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('MCF7', 'CellLine', 'CVCL:0031', (140, 144))	('knockdown', 'Var', (48, 57))
388551	28147343	In addition, the shRPL5 induced mouse tumors showed reduced phosphorylation of CDK1/CDC2 at tyrosine 15, a dephosphoryation that is required for cell cycle progression from G2 to mitosis (Figure 6C, MCF7 p < 0.001 and MDA-MB-231 p = 0.001).	('phosphorylation', 'MPA', (60, 75))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumors', 'Disease', (38, 44))	('reduced', 'NegReg', (52, 59))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('tumors', 'Disease', 'MESH:D009369', (38, 44))	('shRPL5', 'Var', (17, 23))	('tyrosine', 'Chemical', 'MESH:D014443', (92, 100))	('mouse', 'Species', '10090', (32, 37))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (218, 228))	('CDK1/CDC2', 'Gene', (79, 88))	('mitosis', 'Disease', (179, 186))	('MCF7', 'CellLine', 'CVCL:0031', (199, 203))	('mitosis', 'Disease', 'None', (179, 186))
388552	28147343	These results are consistent with the enhanced proliferation associated with RPL5 knockdown in the cell culture experiments and the increased tumor weights in vivo.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('enhanced', 'PosReg', (38, 46))	('tumor', 'Disease', (142, 147))	('RPL5', 'Gene', (77, 81))	('knockdown', 'Var', (82, 91))	('increased', 'PosReg', (132, 141))	('proliferation', 'CPA', (47, 60))	('tumor', 'Disease', 'MESH:D009369', (142, 147))
388553	28147343	Changes in TP53, MDM2 and c-MYC protein levels upon RPL5 knockdown were assessed by immunoblotting, in vitro and in vivo (Figure 5C, Figure 6D-6E and Supplementary Figure 8).	('RPL5', 'Gene', (52, 56))	('c-MYC', 'Gene', '4609', (26, 31))	('TP53', 'Gene', '7157', (11, 15))	('TP53', 'Gene', (11, 15))	('MDM2', 'Gene', '4193', (17, 21))	('knockdown', 'Var', (57, 66))	('MDM2', 'Gene', (17, 21))	('c-MYC', 'Gene', (26, 31))	('Changes', 'Reg', (0, 7))
388555	28147343	MDM2 expression did not differ in vivo and it was upregulated in vitro only for MDA-MB-231.	('upregulated', 'PosReg', (50, 61))	('expression', 'MPA', (5, 15))	('MDA-MB-231', 'Var', (80, 90))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (80, 90))	('MDM2', 'Gene', '4193', (0, 4))	('MDM2', 'Gene', (0, 4))
388558	28147343	We aimed to identify novel ribosomal protein genes which are significantly targeted by genetic alterations and represent potential causative cancer genes.	('genetic alterations', 'Var', (87, 106))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('ribosomal protein genes', 'Gene', (27, 50))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('cancer', 'Disease', (141, 147))
388561	28147343	RPL22 was found to be significantly mutated in UCEC, according to a TCGA pan-cancer analysis.	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('UCEC', 'Disease', (47, 51))	('RPL22', 'Gene', (0, 5))	('mutated', 'Var', (36, 43))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('RPL22', 'Gene', '6146', (0, 5))
388562	28147343	However, most RPL22 mutations detected in TCGA UCEC are potentially caused by misalignment of reads to homologous regions in the genome.	('caused by', 'Reg', (68, 77))	('RPL22', 'Gene', '6146', (14, 19))	('mutations', 'Var', (20, 29))	('RPL22', 'Gene', (14, 19))
388564	28147343	RPS15 and RPL10 mutations have been reported in CLL and T-ALL, which are not represented in the TCGA dataset analyzed here.	('T-ALL', 'Disease', (56, 61))	('RPL10', 'Gene', '6134', (10, 15))	('CLL', 'Disease', (48, 51))	('mutations', 'Var', (16, 25))	('RPL10', 'Gene', (10, 15))	('reported', 'Reg', (36, 44))	('RPS15', 'Gene', '6209', (0, 5))	('RPS15', 'Gene', (0, 5))
388567	28147343	Other mechanisms such as methylation, regulation by microRNAs or long non-coding RNAs might further cause ribosomal protein dysregulation in cancer.	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('protein dysregulation', 'Disease', 'MESH:D021081', (116, 137))	('microRNAs', 'Var', (52, 61))	('methylation', 'Var', (25, 36))	('cause', 'Reg', (100, 105))	('long non-coding RNAs', 'Var', (65, 85))	('protein dysregulation', 'Disease', (116, 137))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('cancer', 'Disease', (141, 147))
388574	28147343	RPS5 and RPS20 show accumulation of high functional impact mutations, some of which may disrupt RNA interactions.	('disrupt', 'NegReg', (88, 95))	('RPS5', 'Gene', '6193', (0, 4))	('RNA interactions', 'Interaction', (96, 112))	('RPS5', 'Gene', (0, 4))	('RPS20', 'Gene', (9, 14))	('mutations', 'Var', (59, 68))	('RPS20', 'Gene', '6224', (9, 14))
388575	28147343	Most interestingly, both RPL11 and RPL5 present inactivating mutations and emerge as candidate cancer drivers in the same cancer type (SKCM).	('inactivating mutations', 'Var', (48, 70))	('RPL11', 'Gene', '6135', (25, 30))	('RPL5', 'Gene', (35, 39))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('cancer', 'Disease', (122, 128))	('RPL11', 'Gene', (25, 30))	('cancer', 'Disease', (95, 101))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))
388579	28147343	The observation of heterozygous inactivating RPL5 mutations and deletions across multiple tumor types suggested a role as haploinsufficient tumor suppressor gene.	('mutations', 'Var', (50, 59))	('haploinsufficient tumor', 'Disease', 'MESH:D058495', (122, 145))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('deletions', 'Var', (64, 73))	('tumor', 'Disease', (90, 95))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('haploinsufficient tumor', 'Disease', (122, 145))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('RPL5', 'Gene', (45, 49))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('tumor', 'Disease', (140, 145))
388580	28147343	It is interesting to note that the Rabadan group integrated TCGA data with known causative genes in cancer predisposing Mendelian diseases, such as DBA, and that they also pick up RPL5 as candidate tumor suppressor in GBM in their analyses.	('DBA', 'Disease', (148, 151))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('Mendelian diseases', 'Disease', (120, 138))	('TCGA', 'Gene', (60, 64))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('Mendelian diseases', 'Disease', 'MESH:D030342', (120, 138))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('RPL5', 'Var', (180, 184))	('tumor', 'Disease', (198, 203))
388581	28147343	In the current study, we show that the incidence of RPL5 alterations in GBM is much higher than previously assumed and that heterozygous RPL5 inactivation occurs at high incidence in GBM, SKCM and BRCA.	('alterations', 'Var', (57, 68))	('RPL5', 'Gene', (52, 56))	('BRCA', 'Gene', (197, 201))	('BRCA', 'Gene', '672', (197, 201))
388582	28147343	As such, RPL5 inactivation currently represents the most common somatic ribosome defect in cancer.	('RPL5 inactivation', 'Var', (9, 26))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))
388584	28147343	In this context, LUAD, KIRC, STAD and PRAD also show inactivating mutations or deletions in RPL5 (Supplementary Figure 9), suggesting that RPL5 may also act as a tumor suppressor in these tumor types.	('tumor', 'Disease', (188, 193))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('a tumor', 'Disease', 'MESH:D009369', (160, 167))	('tumor', 'Disease', (162, 167))	('deletions', 'Var', (79, 88))	('inactivating mutations', 'Var', (53, 75))	('RPL5', 'Gene', (92, 96))	('a tumor', 'Disease', (160, 167))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('tumor', 'Disease', 'MESH:D009369', (162, 167))
388585	28147343	In addition, RPL5 shows inactivating mutations in 2% of T-ALL samples and we showed that RPL5 is part of a minimal deleted region that is heterozygously deleted in 20-40% of advanced multiple myeloma cases (Supplementary Figure 10).	('inactivating mutations', 'Var', (24, 46))	('multiple myeloma', 'Phenotype', 'HP:0006775', (183, 199))	('multiple myeloma', 'Disease', 'MESH:D009101', (183, 199))	('multiple myeloma', 'Disease', (183, 199))	('RPL5', 'Gene', (13, 17))	('RPL5', 'Gene', (89, 93))
388587	28147343	Knockdown of RPL5 by ~50% in both TP53 WT MCF7 and TP53 mutant MDA-MB-231 breast cancer lines accelerated the tumor growth in vivo.	('TP53', 'Gene', '7157', (51, 55))	('MCF7', 'CellLine', 'CVCL:0031', (42, 46))	('breast cancer', 'Disease', (74, 87))	('breast cancer', 'Disease', 'MESH:D001943', (74, 87))	('TP53', 'Gene', (34, 38))	('TP53', 'Gene', (51, 55))	('mutant', 'Var', (56, 62))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (63, 73))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('TP53', 'Gene', '7157', (34, 38))	('accelerated', 'PosReg', (94, 105))	('breast cancer', 'Phenotype', 'HP:0003002', (74, 87))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
388589	28147343	The MDA-MB-231 cell line did not show significant proliferation changes in vitro upon RPL5 knockdown, although a significant increase in tumor growth was observed in vivo.	('RPL5', 'Gene', (86, 90))	('tumor', 'Disease', (137, 142))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (4, 14))	('increase', 'PosReg', (125, 133))	('knockdown', 'Var', (91, 100))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
388594	28147343	Loss of RPL5 in human primary lung fibroblasts does not induce cell cycle arrest by checkpoint activation but suppresses cell cycle progression by reducing translation rates, including translation of some cyclins.	('suppresses', 'NegReg', (110, 120))	('reducing', 'NegReg', (147, 155))	('RPL5', 'Gene', (8, 12))	('cell cycle progression', 'CPA', (121, 143))	('translation rates', 'MPA', (156, 173))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (63, 80))	('human', 'Species', '9606', (16, 21))	('cyclins', 'Protein', (205, 212))	('Loss', 'Var', (0, 4))	('translation', 'MPA', (185, 196))
388602	28147343	Moreover, we observed increased in vivo tumor volumes upon RPL5 knockdown, both in the TP53 wild type MCF7 and in the TP53 mutant MDA-MB-231 line and no consistent changes were observed in TP53 and MDM2 protein expression upon knock-down of RPL5 in these breast cancer cell lines.	('breast cancer', 'Disease', 'MESH:D001943', (255, 268))	('TP53', 'Gene', (189, 193))	('breast cancer', 'Disease', (255, 268))	('increased', 'PosReg', (22, 31))	('TP53', 'Gene', (118, 122))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (130, 140))	('TP53', 'Gene', '7157', (87, 91))	('TP53', 'Gene', '7157', (189, 193))	('cancer', 'Phenotype', 'HP:0002664', (262, 268))	('TP53', 'Gene', '7157', (118, 122))	('tumor', 'Disease', (40, 45))	('MDM2', 'Gene', (198, 202))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('TP53', 'Gene', (87, 91))	('breast cancer', 'Phenotype', 'HP:0003002', (255, 268))	('MCF7', 'CellLine', 'CVCL:0031', (102, 106))	('mutant', 'Var', (123, 129))	('MDM2', 'Gene', '4193', (198, 202))
388603	28147343	These results suggest that the RPL5 knockdown phenotype is likely TP53-independent.	('TP53', 'Gene', (66, 70))	('RPL5', 'Gene', (31, 35))	('knockdown', 'Var', (36, 45))	('TP53', 'Gene', '7157', (66, 70))
388606	28147343	c-MYC protein was upregulated in both breast cancer cell lines with RPL5 knockdown in vitro and in MDA-MB-231 tumors in vivo but downregulated in MCF7 tumors.	('downregulated', 'NegReg', (129, 142))	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('breast cancer', 'Phenotype', 'HP:0003002', (38, 51))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (99, 109))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('breast cancer', 'Disease', 'MESH:D001943', (38, 51))	('tumors', 'Disease', (151, 157))	('c-MYC', 'Gene', '4609', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('breast cancer', 'Disease', (38, 51))	('tumors', 'Disease', (110, 116))	('c-MYC', 'Gene', (0, 5))	('knockdown', 'Var', (73, 82))	('MCF7 tumors', 'Disease', (146, 157))	('MCF7 tumors', 'Disease', 'MESH:D009369', (146, 157))	('tumors', 'Disease', 'MESH:D009369', (151, 157))	('RPL5', 'Gene', (68, 72))	('tumors', 'Disease', 'MESH:D009369', (110, 116))	('upregulated', 'PosReg', (18, 29))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))
388608	28147343	However, c-MYC upregulation does not fully explain the proliferation and tumor growth advantage conferred by RPL5 knockdown since it also occurs in MCF7 tumors despite c-MYC downregulation.	('c-MYC', 'Gene', (168, 173))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('MCF7 tumors', 'Disease', 'MESH:D009369', (148, 159))	('knockdown', 'Var', (114, 123))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('c-MYC', 'Gene', (9, 14))	('downregulation', 'NegReg', (174, 188))	('tumor', 'Disease', (153, 158))	('c-MYC', 'Gene', '4609', (168, 173))	('tumor', 'Disease', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumors', 'Phenotype', 'HP:0002664', (153, 159))	('c-MYC', 'Gene', '4609', (9, 14))	('MCF7 tumors', 'Disease', (148, 159))
388612	28147343	These results may suggest that alterations targeting the TP53 pathway or c-MYC may co-operate with RPL5 in tumorigenesis, and/or that RPL5 inactivation may facilitate acquisition of these lesions.	('alterations', 'Var', (31, 42))	('TP53', 'Gene', '7157', (57, 61))	('tumor', 'Disease', (107, 112))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('c-MYC', 'Gene', '4609', (73, 78))	('c-MYC', 'Gene', (73, 78))	('facilitate', 'PosReg', (156, 166))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('TP53', 'Gene', (57, 61))	('acquisition', 'MPA', (167, 178))	('RPL5 inactivation', 'Var', (134, 151))
388613	28147343	In summary, we provide the first comprehensive analysis of defects in coding regions of ribosomal proteins across several cancer types using the TCGA platform.	('ribosomal proteins', 'Protein', (88, 106))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('coding regions', 'MPA', (70, 84))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('defects', 'Var', (59, 66))
388620	28147343	A gene was considered as significantly mutated in a cancer type if presenting a significantly high frequency of mutations (MutSig2.0), or a significant mutational clustering in a particular region (OncodriveCLUST), or a significant accumulation of mutations with predicted high impact on protein function (OncodriveFM).	('protein function', 'MPA', (288, 304))	('mutations', 'Var', (248, 257))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('mutational', 'Var', (152, 162))	('mutations', 'Var', (112, 121))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))
388621	28147343	Mechismo was used to predict the functional impact of residue changes on protein and RNA interactions and TransFIC was used to estimate the functional impact of mutations.	('residue changes', 'Var', (54, 69))	('protein', 'Protein', (73, 80))	('Mechismo', 'Chemical', '-', (0, 8))
388622	28147343	For a gene to be considered significantly deleted (or amplified) in a tumor entity, the following criteria had to be met: i) presence in a significant peak of deletion (or amplification) according to Gistic2.0; ii) presence in the 'wide peak' region predicted by Gistic2.0 that most likely harbors the target genes of the deletion (or amplification); iii) absence of other known cancer genes from Cancer Gene Census in the same 'wide peak'; iv) presence of mutations in at least 2% of samples; v) at least 5 samples in the tumor entity in which the gene is deleted (or amplified).	('cancer', 'Disease', (379, 385))	('tumor', 'Disease', 'MESH:D009369', (523, 528))	('cancer', 'Disease', 'MESH:D009369', (379, 385))	('Cancer', 'Disease', 'MESH:D009369', (397, 403))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('Cancer', 'Phenotype', 'HP:0002664', (397, 403))	('tumor', 'Phenotype', 'HP:0002664', (523, 528))	('tumor', 'Disease', (70, 75))	('a tumor', 'Disease', 'MESH:D009369', (68, 75))	('cancer', 'Phenotype', 'HP:0002664', (379, 385))	('tumor', 'Disease', (523, 528))	('deleted', 'Var', (557, 564))	('a tumor', 'Disease', (68, 75))	('Cancer', 'Disease', (397, 403))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
388626	28147343	The interaction between RPL5 inactivating mutations and deletions and TP53 inactivating mutations and deletions and with MDM2, MDM4 and c-MYC non inactivating mutations and amplifications was tested in BRCA, GBM and SKCM.	('BRCA', 'Gene', (202, 206))	('deletions', 'Var', (102, 111))	('TP53', 'Gene', '7157', (70, 74))	('c-MYC', 'Gene', '4609', (136, 141))	('deletions', 'Var', (56, 65))	('TP53', 'Gene', (70, 74))	('MDM4', 'Gene', '4194', (127, 131))	('c-MYC', 'Gene', (136, 141))	('RPL5', 'Gene', (24, 28))	('MDM2', 'Gene', '4193', (121, 125))	('BRCA', 'Gene', '672', (202, 206))	('MDM2', 'Gene', (121, 125))	('MDM4', 'Gene', (127, 131))
388644	28147343	For experimental work, a one-tailed T-test was used to determine whether RPL5 knockdown increased breast cancer tumor weights and two-tailed paired Student's t-tests when comparing breast cancer cells in various assays.	('breast cancer', 'Disease', 'MESH:D001943', (98, 111))	('breast cancer', 'Phenotype', 'HP:0003002', (98, 111))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('breast cancer', 'Disease', 'MESH:D001943', (181, 194))	('breast cancer', 'Phenotype', 'HP:0003002', (181, 194))	('breast cancer tumor', 'Phenotype', 'HP:0100013', (98, 117))	('knockdown', 'Var', (78, 87))	('breast cancer', 'Disease', (181, 194))	('breast cancer tumor', 'Disease', 'MESH:D001943', (98, 117))	('increased', 'PosReg', (88, 97))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('breast cancer tumor', 'Disease', (98, 117))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('RPL5', 'Gene', (73, 77))
388654	32437446	When CEP55 gene was selected as an independent prognostic factor, high expression of CEP55 was more disadvantageous to OS and RFS of LUAD patients (P<0.05), but no significant difference was found in LUSC patients (P>0.05).	('CEP55', 'Gene', '55165', (5, 10))	('patients', 'Species', '9606', (205, 213))	('CEP55', 'Gene', (5, 10))	('LUSC', 'Phenotype', 'HP:0030359', (200, 204))	('RFS', 'Disease', (126, 129))	('CEP55', 'Gene', '55165', (85, 90))	('CEP55', 'Gene', (85, 90))	('disadvantageous', 'NegReg', (100, 115))	('high', 'Var', (66, 70))	('LUAD', 'Phenotype', 'HP:0030078', (133, 137))	('patients', 'Species', '9606', (138, 146))
388666	32437446	Overexpression of CEP55 was significantly associated with a reduction in overall survival after surgery.	('reduction', 'NegReg', (60, 69))	('CEP55', 'Gene', '55165', (18, 23))	('Overexpression', 'Var', (0, 14))	('CEP55', 'Gene', (18, 23))	('overall survival', 'MPA', (73, 89))
388684	32437446	Meanwhile, we analyzed the expression of CEP55 in LUAD chip of GSE10072 and LUSC chip of GSE75037 using the GEO database.	('LUSC', 'Phenotype', 'HP:0030359', (76, 80))	('LUAD', 'Phenotype', 'HP:0030078', (50, 54))	('CEP55', 'Gene', '55165', (41, 46))	('CEP55', 'Gene', (41, 46))	('GSE10072', 'Var', (63, 71))
388701	32437446	Also, from the OS curve (Fig 3E) and RFS curve (Fig 3G), we could find that there was no significant difference between the OS and RFS of LUSC patients with high CEP55 expression and low CEP55 expression (P>0.05).	('CEP55', 'Gene', (187, 192))	('LUSC', 'Phenotype', 'HP:0030359', (138, 142))	('high', 'Var', (157, 161))	('patients', 'Species', '9606', (143, 151))	('CEP55', 'Gene', '55165', (162, 167))	('expression', 'MPA', (193, 203))	('CEP55', 'Gene', (162, 167))	('low', 'NegReg', (183, 186))	('CEP55', 'Gene', '55165', (187, 192))
388704	32437446	As shown in Table 3, the OS and RFS of LUAD patients were significantly correlated with clinical classification and CEP55 expression (P<0.05) rather than the age, gender and smoking history (P>0.05), which showed that clinical classification and CEP55 expression could be used as independent prognostic factors for LUAD patients, and high expression of CEP55 could be a predictor of poor prognosis.	('LUAD', 'Phenotype', 'HP:0030078', (315, 319))	('CEP55', 'Gene', (246, 251))	('patients', 'Species', '9606', (44, 52))	('CEP55', 'Gene', '55165', (116, 121))	('CEP55', 'Gene', (116, 121))	('CEP55', 'Gene', '55165', (353, 358))	('high', 'Var', (334, 338))	('CEP55', 'Gene', (353, 358))	('CEP55', 'Gene', '55165', (246, 251))	('LUAD', 'Phenotype', 'HP:0030078', (39, 43))	('LUAD', 'Disease', (315, 319))	('patients', 'Species', '9606', (320, 328))
388717	32437446	By constructing the ROC curve, we found that CEP55 can be used as a diagnostic marker for LUAD and LUSC, and people with high expression of CEP55 have a higher risk of cancer.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('LUAD', 'Disease', (90, 94))	('CEP55', 'Gene', '55165', (140, 145))	('CEP55', 'Gene', (140, 145))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('LUAD', 'Phenotype', 'HP:0030078', (90, 94))	('high expression', 'Var', (121, 136))	('LUSC', 'Phenotype', 'HP:0030359', (99, 103))	('people', 'Species', '9606', (109, 115))	('cancer', 'Disease', (168, 174))	('CEP55', 'Gene', '55165', (45, 50))	('CEP55', 'Gene', (45, 50))	('LUSC', 'Disease', (99, 103))
388719	32437446	Studies have shown that high expression of CEP55 can promote cancer proliferation, migration and invasion.	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('CEP55', 'Gene', '55165', (43, 48))	('CEP55', 'Gene', (43, 48))	('cancer', 'Disease', (61, 67))	('high expression', 'Var', (24, 39))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('invasion', 'CPA', (97, 105))	('migration', 'CPA', (83, 92))	('promote', 'PosReg', (53, 60))
388725	32437446	LUAD patients with high expression of CEP55 showed shorter OS and RFS time.	('patients', 'Species', '9606', (5, 13))	('high expression', 'Var', (19, 34))	('shorter', 'NegReg', (51, 58))	('CEP55', 'Gene', '55165', (38, 43))	('CEP55', 'Gene', (38, 43))	('LUAD', 'Phenotype', 'HP:0030078', (0, 4))
388747	30656409	In esophageal cancer, although the relationship between expression of MAGE-A, NY-ESO-1, LAGE-1, and TTK and prognosis value is still in a controversial situation, MAGE-A, NY-ESO-1, LAGE-1, and TTK are highly expressed and can induce specific CTL cells to produce particular killing effect on tumor cells, and some clinical trials have demonstrated that immunotherapy for esophageal cancer patients is effective and safe, which provides a new therapeutic strategy for the treatment of esophageal cancer in the future.	('TTK', 'Gene', (100, 103))	('cancer', 'Phenotype', 'HP:0002664', (495, 501))	('LAGE-1', 'Gene', '30848', (181, 187))	('LAGE-1', 'Gene', (88, 94))	('tumor', 'Phenotype', 'HP:0002664', (292, 297))	('NY-ESO-1', 'Gene', '1485', (78, 86))	('esophageal cancer', 'Disease', 'MESH:D004938', (3, 20))	('TTK', 'Gene', (193, 196))	('MAGE-A', 'Var', (163, 169))	('cancer', 'Phenotype', 'HP:0002664', (382, 388))	('NY-ESO-1', 'Gene', (78, 86))	('NY-ESO-1', 'Gene', '1485', (171, 179))	('esophageal cancer', 'Disease', (3, 20))	('esophageal cancer', 'Disease', 'MESH:D004938', (484, 501))	('LAGE-1', 'Gene', '30848', (88, 94))	('TTK', 'Gene', '7272', (100, 103))	('patients', 'Species', '9606', (389, 397))	('NY-ESO-1', 'Gene', (171, 179))	('esophageal cancer', 'Disease', 'MESH:D004938', (371, 388))	('esophageal cancer', 'Disease', (484, 501))	('tumor', 'Disease', (292, 297))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('LAGE-1', 'Gene', (181, 187))	('TTK', 'Gene', '7272', (193, 196))	('tumor', 'Disease', 'MESH:D009369', (292, 297))	('esophageal cancer', 'Disease', (371, 388))
388814	30656409	This study demonstrated that genetically engineered T cells expressing MAGE-A4-specific TCR could prevent the growth of esophageal cancer expressed MAGE-A4 in immunodeficient NOG mice (Shirakura et al.).	('prevent', 'NegReg', (98, 105))	('esophageal cancer', 'Disease', 'MESH:D004938', (120, 137))	('mice', 'Species', '10090', (179, 183))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('MAGE-A4', 'Var', (148, 155))	('esophageal cancer', 'Disease', (120, 137))	('immunodeficient', 'Disease', 'MESH:D007153', (159, 174))	('immunodeficient', 'Disease', (159, 174))	('growth', 'MPA', (110, 116))
388856	30656409	In three ESCC patients who had not undergone any treatment intervention before surgery, the cytotoxicity of CTLs induced by DCs carrying chimeric mRNA was significantly higher than that of mock DCs (p < 0.05) (Forghanifard et al.).	('higher', 'PosReg', (169, 175))	('cytotoxicity', 'Disease', (92, 104))	('cytotoxicity', 'Disease', 'MESH:D064420', (92, 104))	('patients', 'Species', '9606', (14, 22))	('chimeric mRNA', 'Var', (137, 150))
388921	30656409	Inhibition of TTK has emerged as a promising therapeutic strategy for the treatment of aneuploid tumors, with triple-negative breast cancer (TNBC) (Maia et al.	('aneuploid tumors', 'Disease', 'MESH:D000782', (87, 103))	('TTK', 'Gene', (14, 17))	('breast cancer', 'Disease', 'MESH:D001943', (126, 139))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('aneuploid tumors', 'Disease', (87, 103))	('TNBC', 'Disease', (141, 145))	('breast cancer', 'Phenotype', 'HP:0003002', (126, 139))	('breast cancer', 'Disease', (126, 139))	('TTK', 'Gene', '7272', (14, 17))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('Inhibition', 'Var', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('TNBC', 'Disease', 'None', (141, 145))
388923	30656409	Human cancer cells treated with Mps1 inhibitor exhibit effects consistent with Mps1 kinase inhibition, specifically spindle assembly checkpoint inactivation, leading to chromosome missegregation, aneuploidy, and ultimately cell death (Mason et al.).	('Human', 'Species', '9606', (0, 5))	('aneuploidy', 'Disease', (196, 206))	('Mps1', 'Gene', (32, 36))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('aneuploidy', 'Disease', 'MESH:D000782', (196, 206))	('inhibition', 'NegReg', (91, 101))	('spindle assembly checkpoint inactivation', 'Disease', (116, 156))	('cell death', 'CPA', (223, 233))	('cancer', 'Disease', 'MESH:D009369', (6, 12))	('Mps1', 'Gene', (79, 83))	('Mps1', 'Gene', '7272', (79, 83))	('cancer', 'Disease', (6, 12))	('inhibitor', 'Var', (37, 46))	('chromosome missegregation', 'CPA', (169, 194))	('Mps1', 'Gene', '7272', (32, 36))
388931	30656409	To solve the above problems, future research could take the expression of other members of the cancer-testis antigens family in esophageal cancer into account, considering whether there is a correlation expression among each antigen to cover more esophageal cancer patients; whether epigenetic modifying agents can effectively improve the expression of cancer-testis antigens in esophageal cancer (James et al.	('esophageal cancer', 'Disease', (379, 396))	('cancer-testis', 'Disease', (353, 366))	('cancer-testis', 'Disease', 'MESH:D013736', (95, 108))	('esophageal cancer', 'Disease', 'MESH:D004938', (128, 145))	('patients', 'Species', '9606', (265, 273))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (390, 396))	('esophageal cancer', 'Disease', (128, 145))	('esophageal cancer', 'Disease', 'MESH:D004938', (247, 264))	('expression', 'MPA', (339, 349))	('cancer', 'Phenotype', 'HP:0002664', (258, 264))	('cancer-testis', 'Disease', (95, 108))	('esophageal cancer', 'Disease', (247, 264))	('epigenetic', 'Var', (283, 293))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('cancer-testis', 'Disease', 'MESH:D013736', (353, 366))	('esophageal cancer', 'Disease', 'MESH:D004938', (379, 396))	('improve', 'PosReg', (327, 334))	('cancer', 'Phenotype', 'HP:0002664', (353, 359))
388940	28977839	Loss-of-function (LOF) genetic alterations of the IFNgamma-IRF1 pathway genes (IFNGR1, IFNGR2, JAK1, JAK2, STAT1, IRF1) were found in 64 (6.3%) of 1,016 patients.	('Loss-of-function', 'NegReg', (0, 16))	('IFNGR2', 'Gene', (87, 93))	('patients', 'Species', '9606', (153, 161))	('JAK1', 'Gene', (95, 99))	('JAK1', 'Gene', '3716', (95, 99))	('genetic alterations', 'Var', (23, 42))	('IFNGR2', 'Gene', '3460', (87, 93))	('IFNGR1', 'Gene', '3459', (79, 85))	('IFNGR1', 'Gene', (79, 85))
388941	28977839	These genetic defects occur prevalently in JAK2 (33 cases) and often through deletions (29 cases) of chromosome 9p24.1.	('deletions', 'Var', (77, 86))	('occur', 'Reg', (22, 27))	('genetic defects', 'Disease', 'MESH:D030342', (6, 21))	('genetic defects', 'Disease', (6, 21))
388942	28977839	JAK2 deletions were frequently, but not always, associated with deletions of PD-L1 gene (CD274), PD-L2 gene (PDCD1LG2), PTPRD, and CDKN2A/CDKN2B at the chromosome 9p24.1-9p21.3 region.	('PTPRD', 'Gene', '5789', (120, 125))	('PTPRD', 'Gene', (120, 125))	('PD-L2', 'Gene', (97, 102))	('PD-L2', 'Gene', '80380', (97, 102))	('CDKN2A', 'Gene', '1029', (131, 137))	('CD274', 'Gene', '29126', (89, 94))	('CDKN2B', 'Gene', '1030', (138, 144))	('associated', 'Reg', (48, 58))	('CDKN2B', 'Gene', (138, 144))	('deletions', 'Var', (64, 73))	('PD-L1', 'Gene', (77, 82))	('CD274', 'Gene', (89, 94))	('JAK2', 'Gene', (0, 4))	('PDCD1LG2', 'Gene', '80380', (109, 117))	('PD-L1', 'Gene', '29126', (77, 82))	('deletions', 'Var', (5, 14))	('CDKN2A', 'Gene', (131, 137))	('PDCD1LG2', 'Gene', (109, 117))
388945	28977839	Deletion of JAK2 or inhibition of the JAK2 kinase activity resulted in loss of IFNgamma-induced IRF1 and cell surface HLA-ABC in JAK2 wildtype NSCLC cells, whereas expression of exogenous JAK2 in H1573 cells restored the IFNgamma responses.	('HLA-A', 'Gene', (118, 123))	('NSCLC', 'Disease', (143, 148))	('JAK2', 'Gene', (12, 16))	('NSCLC', 'Disease', 'MESH:D002289', (143, 148))	('H1573', 'CellLine', 'CVCL:1478', (196, 201))	('NSCLC', 'Phenotype', 'HP:0030358', (143, 148))	('inhibition', 'NegReg', (20, 30))	('loss', 'NegReg', (71, 75))	('IFNgamma-induced IRF1', 'MPA', (79, 100))	('HLA-A', 'Gene', '3105', (118, 123))	('Deletion', 'Var', (0, 8))
388946	28977839	These findings show that JAK2 deficiency is the major mechanism of genetic defects of the IFNgamma-IRF1 pathway in NSCLC and reveal a previously unrecognized significance of chromosome 9p deletion in NSCLC.	('genetic defects', 'Disease', 'MESH:D030342', (67, 82))	('JAK2 deficiency', 'Disease', (25, 40))	('NSCLC', 'Phenotype', 'HP:0030358', (200, 205))	('genetic defects', 'Disease', (67, 82))	('JAK2 deficiency', 'Disease', 'MESH:D007153', (25, 40))	('NSCLC', 'Disease', (115, 120))	('NSCLC', 'Disease', (200, 205))	('deletion', 'Var', (188, 196))	('NSCLC', 'Disease', 'MESH:D002289', (115, 120))	('NSCLC', 'Disease', 'MESH:D002289', (200, 205))	('IFNgamma-IRF1 pathway', 'Pathway', (90, 111))	('NSCLC', 'Phenotype', 'HP:0030358', (115, 120))
388952	28977839	Defects in this IFNgamma-IRF1 regulated APM pathway allow tumors to escape immune surveillance, facilitate tumor development in animal models that include lung tumors, and are associated with resistance to anti-PD-1 immunotherapy in melanoma.	('tumor', 'Disease', (107, 112))	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('tumors', 'Disease', (160, 166))	('tumor', 'Disease', (58, 63))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('melanoma', 'Disease', 'MESH:D008545', (233, 241))	('tumors', 'Disease', 'MESH:D009369', (160, 166))	('IFNgamma-IRF1', 'Gene', (16, 29))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('facilitate', 'PosReg', (96, 106))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('lung tumors', 'Disease', 'MESH:D008175', (155, 166))	('Defects', 'Var', (0, 7))	('lung tumors', 'Phenotype', 'HP:0100526', (155, 166))	('tumor', 'Disease', (160, 165))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumors', 'Disease', (58, 64))	('APM pathway', 'Pathway', (40, 51))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('associated', 'Reg', (176, 186))	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('lung tumors', 'Disease', (155, 166))	('melanoma', 'Phenotype', 'HP:0002861', (233, 241))	('melanoma', 'Disease', (233, 241))
388953	28977839	Anti-PD-1 and anti-PD-L1 immunotherapies have resulted in superior clinical responses in non-small cell lung cancer (NSCLC).	('PD-L1', 'Gene', (19, 24))	('NSCLC', 'Disease', (117, 122))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (89, 115))	('PD-L1', 'Gene', '29126', (19, 24))	('NSCLC', 'Disease', 'MESH:D002289', (117, 122))	('lung cancer', 'Phenotype', 'HP:0100526', (104, 115))	('non-small cell lung cancer', 'Disease', (89, 115))	('Anti-PD-1', 'Var', (0, 9))	('NSCLC', 'Phenotype', 'HP:0030358', (117, 122))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (93, 115))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (89, 115))
388956	28977839	We previously found somatic loss-of-function (LOF) JAK1 mutations in 9.5% of uterine cancer in Total Cancer Care (TCC@) tumors.	('mutations', 'Var', (56, 65))	('tumors', 'Disease', (120, 126))	('tumors', 'Disease', 'MESH:D009369', (120, 126))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('loss-of-function', 'NegReg', (28, 44))	('Total Cancer', 'Disease', 'MESH:D009369', (95, 107))	('cancer', 'Disease', (85, 91))	('Total Cancer', 'Disease', (95, 107))	('uterine cancer', 'Phenotype', 'HP:0010784', (77, 91))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('JAK1', 'Gene', (51, 55))	('JAK1', 'Gene', '3716', (51, 55))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('Cancer', 'Phenotype', 'HP:0002664', (101, 107))
388957	28977839	Majority of these JAK1 mutations occurred as the result of frameshift mutations in polyhomonucleotide regions.	('JAK1', 'Gene', '3716', (18, 22))	('frameshift mutations', 'Var', (59, 79))	('occurred', 'Reg', (33, 41))	('mutations', 'Var', (23, 32))	('result', 'Reg', (49, 55))	('JAK1', 'Gene', (18, 22))
388959	28977839	This showed that 9% (30% x 30% = 9%) of endometrial cancer cases in TCGA had frame-shift truncating mutations.	('endometrial cancer', 'Disease', 'MESH:D016889', (40, 58))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('frame-shift truncating mutations', 'Var', (77, 109))	('endometrial cancer', 'Disease', (40, 58))	('endometrial cancer', 'Phenotype', 'HP:0012114', (40, 58))
388960	28977839	Moreover, missense LOF JAK1 mutations were reported in uterine leiomyosarcoma.	('leiomyosarcoma', 'Phenotype', 'HP:0100243', (63, 77))	('missense', 'Var', (10, 18))	('leiomyosarcoma', 'Disease', 'MESH:D007890', (63, 77))	('JAK1', 'Gene', (23, 27))	('JAK1', 'Gene', '3716', (23, 27))	('reported', 'Reg', (43, 51))	('mutations', 'Var', (28, 37))	('leiomyosarcoma', 'Disease', (63, 77))	('uterine leiomyosarcoma', 'Phenotype', 'HP:0002891', (55, 77))
388966	28977839	Specifically, we identified JAK2 deletion on chromosome 9p as the predominant mechanism of genetic defects in the IFNgamma receptor-IRF1 pathway genes.	('genetic defects', 'Disease', 'MESH:D030342', (91, 106))	('genetic defects', 'Disease', (91, 106))	('IFNgamma receptor-IRF1 pathway', 'Pathway', (114, 144))	('deletion', 'Var', (33, 41))	('JAK2', 'Gene', (28, 32))
388967	28977839	Deletions of PD-L1 (CD274) and PD-L2 (PDCD1LG2) genes were always accompanied by JAK2 deletion, suggesting that JAK2 deletion may be a mechanism to safeguard tumor cells from activated cytotoxic T cells in the absence of negative regulators PD-L1/PD-L2.	('CD274', 'Gene', '29126', (20, 25))	('PDCD1LG2', 'Gene', (38, 46))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('accompanied', 'Reg', (66, 77))	('JAK2', 'Gene', (112, 116))	('CD274', 'Gene', (20, 25))	('JAK2', 'Gene', (81, 85))	('PD-L2', 'Gene', '80380', (247, 252))	('deletion', 'Var', (86, 94))	('deletion', 'Var', (117, 125))	('PD-L1', 'Gene', (13, 18))	('PD-L1', 'Gene', '29126', (241, 246))	('PD-L2', 'Gene', (247, 252))	('PD-L2', 'Gene', '80380', (31, 36))	('PD-L1', 'Gene', '29126', (13, 18))	('tumor', 'Disease', (158, 163))	('PDCD1LG2', 'Gene', '80380', (38, 46))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('PD-L1', 'Gene', (241, 246))	('Deletions', 'Var', (0, 9))	('PD-L2', 'Gene', (31, 36))
388968	28977839	Knocking out JAK2 or inhibition of JAK2 kinase activity prevented presentation of MHC class I molecules on NSCLC cell surface.	('NSCLC', 'Disease', (107, 112))	('NSCLC', 'Disease', 'MESH:D002289', (107, 112))	('prevented', 'NegReg', (56, 65))	('JAK2', 'Gene', (13, 17))	('MHC class I', 'Gene', (82, 93))	('inhibition', 'Var', (21, 31))	('presentation', 'MPA', (66, 78))	('NSCLC', 'Phenotype', 'HP:0030358', (107, 112))	('Knocking out', 'Var', (0, 12))
388970	28977839	Our analysis suggests that JAK2 deletion offers tumor cells an advantage of evading immune surveillance and reveals a previously unknown functional significance of chromosome 9p deletion.	('deletion', 'Var', (32, 40))	('tumor', 'Disease', (48, 53))	('evading', 'MPA', (76, 83))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('JAK2', 'Gene', (27, 31))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
388973	28977839	To assess the spectrum and prevalence of genetic defects in the IFNgamma-IRF1 signaling pathway in NSCLC, we examined TCGA lung adenocarcinoma (LuAd) and lung squamous cell carcinoma (LuSc) data for apparent loss-of-function (LOF) gene alterations (homozygous deletion or truncating mutation) of the IFNgamma-IRF1 signaling pathway genes.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (159, 182))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (154, 182))	('lung squamous cell carcinoma', 'Disease', (154, 182))	('lung adenocarcinoma', 'Disease', (123, 142))	('IFNgamma-IRF1 signaling pathway', 'Pathway', (300, 331))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('loss-of-function', 'NegReg', (208, 224))	('NSCLC', 'Disease', 'MESH:D002289', (99, 104))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (123, 142))	('carcinoma', 'Phenotype', 'HP:0030731', (173, 182))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (123, 142))	('truncating mutation', 'Var', (272, 291))	('NSCLC', 'Disease', (99, 104))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (154, 182))	('LuSc', 'Phenotype', 'HP:0030359', (184, 188))	('gene alterations', 'Var', (231, 247))	('LuAd', 'Phenotype', 'HP:0030078', (144, 148))	('NSCLC', 'Phenotype', 'HP:0030358', (99, 104))	('genetic defects', 'Disease', 'MESH:D030342', (41, 56))	('genetic defects', 'Disease', (41, 56))
388977	28977839	Interestingly, 39 of 42 JAK2 copy number alternation (CNA) cases, including both amplification and deletion, coincided with CNAs of CD274 and PDCD1LG2 that encode PD-L1 and PD-L2, respectively, in LuAd and LuSc (Figure 1).	('copy', 'Var', (29, 33))	('PD-L1', 'Gene', (163, 168))	('PD-L2', 'Gene', (173, 178))	('PD-L2', 'Gene', '80380', (173, 178))	('CD274', 'Gene', (132, 137))	('PDCD1LG2', 'Gene', '80380', (142, 150))	('PD-L1', 'Gene', '29126', (163, 168))	('PDCD1LG2', 'Gene', (142, 150))	('JAK2', 'Gene', (24, 28))	('CD274', 'Gene', '29126', (132, 137))	('LuAd', 'Phenotype', 'HP:0030078', (197, 201))	('LuSc', 'Phenotype', 'HP:0030359', (206, 210))
388978	28977839	JAK2 was deleted in all of CD274 and PDCD1LG2 deletion cases.	('PDCD1LG2', 'Gene', (37, 45))	('deletion', 'Var', (46, 54))	('CD274', 'Gene', '29126', (27, 32))	('JAK2', 'Gene', (0, 4))	('PDCD1LG2', 'Gene', '80380', (37, 45))	('CD274', 'Gene', (27, 32))
388983	28977839	The TCGA data showed that JAK2 deletion in NSCLC was often associated with deletions of either PTPRD and/or CDKN2A/CDKN2B genes (Figure 1).	('PTPRD', 'Gene', '5789', (95, 100))	('JAK2 deletion', 'Var', (26, 39))	('PTPRD', 'Gene', (95, 100))	('CDKN2A', 'Gene', '1029', (108, 114))	('deletions', 'Var', (75, 84))	('CDKN2B', 'Gene', '1030', (115, 121))	('NSCLC', 'Phenotype', 'HP:0030358', (43, 48))	('associated', 'Reg', (59, 69))	('NSCLC', 'Disease', (43, 48))	('CDKN2A', 'Gene', (108, 114))	('CDKN2B', 'Gene', (115, 121))	('NSCLC', 'Disease', 'MESH:D002289', (43, 48))
388984	28977839	Thus, the mechanism of frequent JAK2 deletion in NSCLC may be a bystander event due to deletions of the tumor suppressor genes PTPRD and CDKN2A/CDKN2B because the proximity of these genes co-located at the chromosome 9p21.3-9p24.1 region.	('JAK2', 'Gene', (32, 36))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('NSCLC', 'Disease', (49, 54))	('deletion', 'Var', (37, 45))	('PTPRD', 'Gene', '5789', (127, 132))	('tumor', 'Disease', (104, 109))	('PTPRD', 'Gene', (127, 132))	('NSCLC', 'Disease', 'MESH:D002289', (49, 54))	('CDKN2A', 'Gene', (137, 143))	('deletions', 'Var', (87, 96))	('CDKN2B', 'Gene', (144, 150))	('CDKN2A', 'Gene', '1029', (137, 143))	('CDKN2B', 'Gene', '1030', (144, 150))	('NSCLC', 'Phenotype', 'HP:0030358', (49, 54))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
388985	28977839	However, it was observed previously in NSCLC that deletions in 9p24, 9p23, and 9p21 were not contiguous.	('NSCLC', 'Phenotype', 'HP:0030358', (39, 44))	('NSCLC', 'Disease', (39, 44))	('NSCLC', 'Disease', 'MESH:D002289', (39, 44))	('deletions', 'Var', (50, 59))	('9p24', 'Gene', (63, 67))
388990	28977839	CD274 and PDCD1LG2 deletions were always accompanied by JAK2 deletion (Figure 2A).	('accompanied', 'Reg', (41, 52))	('CD274', 'Gene', '29126', (0, 5))	('PDCD1LG2', 'Gene', '80380', (10, 18))	('PDCD1LG2', 'Gene', (10, 18))	('CD274', 'Gene', (0, 5))	('deletions', 'Var', (19, 28))
388991	28977839	JAK2 deletion was often, but not always, associated with PTPRD and/or CDKN2A/CDKN2B deletions (Figure 2B).	('deletion', 'Var', (5, 13))	('associated', 'Reg', (41, 51))	('CDKN2B', 'Gene', (77, 83))	('JAK2', 'Gene', (0, 4))	('CDKN2B', 'Gene', '1030', (77, 83))	('CDKN2A', 'Gene', (70, 76))	('CDKN2A', 'Gene', '1029', (70, 76))	('PTPRD', 'Gene', '5789', (57, 62))	('PTPRD', 'Gene', (57, 62))	('deletions', 'Var', (84, 93))
389000	28977839	A549, H661, H292, and H2172 are NSCLC cell lines without homozygous JAK2 deletions or mutation based on CCLE data.	('A549', 'CellLine', 'CVCL:0023', (0, 4))	('NSCLC', 'Phenotype', 'HP:0030358', (32, 37))	('H2172', 'Var', (22, 27))	('CCLE', 'Chemical', '-', (104, 108))	('H292', 'Var', (12, 16))	('H661', 'CellLine', 'CVCL:1577', (6, 10))	('NSCLC', 'Disease', (32, 37))	('H661', 'Var', (6, 10))	('H292', 'CellLine', 'CVCL:0455', (12, 16))	('NSCLC', 'Disease', 'MESH:D002289', (32, 37))	('H2172', 'CellLine', 'CVCL:1537', (22, 27))
389008	28977839	To determine if loss of JAK2 impairs the IFNgamma-induced MHC class I antigen presentation pathway, we knockout JAK2 in A549 cells using lentiviral CRISPR/Cas9 sgRNAs.	('impairs', 'NegReg', (29, 36))	('JAK2', 'Gene', (112, 116))	('MHC class I antigen', 'Gene', '100507703', (58, 77))	('loss', 'Var', (16, 20))	('JAK2', 'Gene', (24, 28))	('MHC class I antigen', 'Gene', (58, 77))	('knockout', 'Var', (103, 111))	('A549', 'CellLine', 'CVCL:0023', (120, 124))
389015	28977839	IFN-gamma induced pSTAT1, IRF1, TAP1, and LMP2 in H661 but not in the JAK2 knockout H661/KO cells.	('H661', 'CellLine', 'CVCL:1577', (50, 54))	('IRF1', 'Gene', (26, 30))	('pSTAT1', 'Gene', (18, 24))	('H661', 'CellLine', 'CVCL:1577', (84, 88))	('H661', 'Var', (50, 54))	('LMP2', 'Gene', (42, 46))	('LMP2', 'Gene', '5698', (42, 46))	('TAP1', 'Gene', (32, 36))	('IFN-gamma', 'Gene', '3458', (0, 9))	('IFN-gamma', 'Gene', (0, 9))
389017	28977839	Based on CCLE data (cbioportal.org), the NSCLC cell line H1623 has JAK2 deep deletion.	('NSCLC', 'Disease', (41, 46))	('H1623', 'CellLine', 'CVCL:1481', (57, 62))	('NSCLC', 'Disease', 'MESH:D002289', (41, 46))	('CCLE', 'Chemical', '-', (9, 13))	('NSCLC', 'Phenotype', 'HP:0030358', (41, 46))	('JAK2 deep deletion', 'Var', (67, 85))
389020	28977839	H1573 human NSCLC cells harbor JAK2 S507* nonsense mutation that results in truncation of both pseudo kinase and tyrosine kinase domain of JAK2.	('human', 'Species', '9606', (6, 11))	('tyrosine kinase domain', 'MPA', (113, 135))	('NSCLC', 'Phenotype', 'HP:0030358', (12, 17))	('JAK2', 'Gene', (139, 143))	('S507*', 'Var', (36, 41))	('NSCLC', 'Disease', (12, 17))	('pseudo kinase', 'MPA', (95, 108))	('truncation', 'MPA', (76, 86))	('tyrosine', 'Chemical', 'MESH:D014443', (113, 121))	('H1573', 'CellLine', 'CVCL:1478', (0, 5))	('NSCLC', 'Disease', 'MESH:D002289', (12, 17))	('S507*', 'SUBSTITUTION', 'None', (36, 41))	('JAK2', 'Gene', (31, 35))
389030	28977839	Chromosome 9p deletions have been observed frequently in NSCLC and in some other types of tumors such as glioma.	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('glioma', 'Disease', (105, 111))	('NSCLC', 'Phenotype', 'HP:0030358', (57, 62))	('Chromosome 9p', 'Gene', (0, 13))	('tumors', 'Disease', (90, 96))	('deletions', 'Var', (14, 23))	('tumors', 'Disease', 'MESH:D009369', (90, 96))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('observed', 'Reg', (34, 42))	('NSCLC', 'Disease', (57, 62))	('glioma', 'Disease', 'MESH:D005910', (105, 111))	('glioma', 'Phenotype', 'HP:0009733', (105, 111))	('NSCLC', 'Disease', 'MESH:D002289', (57, 62))
389032	28977839	The high incidence of JAK2 deletion in NSCLC was likely due in part to the frequent deletion of tumor suppressors CDKN2A/CDKN2B and PTPRD in the chromosome 9p arm in NSCLC.	('CDKN2B', 'Gene', '1030', (121, 127))	('NSCLC', 'Phenotype', 'HP:0030358', (166, 171))	('NSCLC', 'Phenotype', 'HP:0030358', (39, 44))	('CDKN2A', 'Gene', '1029', (114, 120))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('deletion', 'Var', (84, 92))	('JAK2', 'Gene', (22, 26))	('tumor', 'Disease', (96, 101))	('NSCLC', 'Disease', (166, 171))	('deletion', 'Var', (27, 35))	('NSCLC', 'Disease', 'MESH:D002289', (166, 171))	('PTPRD', 'Gene', '5789', (132, 137))	('NSCLC', 'Disease', (39, 44))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('PTPRD', 'Gene', (132, 137))	('NSCLC', 'Disease', 'MESH:D002289', (39, 44))	('CDKN2A', 'Gene', (114, 120))	('CDKN2B', 'Gene', (121, 127))
389033	28977839	However, it appears unlikely that JAK2 deletion was merely a bystander effect in which chromosome 9p deletion accidently extended beyond the CDKN2A/CDKN2B and PTPRD gene regions.	('deletion', 'Var', (101, 109))	('CDKN2B', 'Gene', (148, 154))	('CDKN2A', 'Gene', '1029', (141, 147))	('CDKN2B', 'Gene', '1030', (148, 154))	('chromosome 9p', 'Gene', (87, 100))	('PTPRD', 'Gene', '5789', (159, 164))	('PTPRD', 'Gene', (159, 164))	('CDKN2A', 'Gene', (141, 147))
389034	28977839	First, as previously reported, deletions of chromosome 9p were not contiguous (Figures 1, 2), suggesting that deletion of JAK2 conferred a functional selection advantage to the cancer cells.	('cancer', 'Disease', (177, 183))	('cancer', 'Disease', 'MESH:D009369', (177, 183))	('JAK2', 'Gene', (122, 126))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('deletion', 'Var', (110, 118))
389035	28977839	Second, there were cases in TCGA tumors and CCLC cancer cell lines in which JAK2 was deleted in the absence of CDKN2A/CDKN2B or PTPRD deletion (Figures 1, 2), suggesting that JAK2 deletion alone may have a functional benefit to cancer cells.	('benefit', 'PosReg', (217, 224))	('JAK2', 'Gene', (76, 80))	('PTPRD', 'Gene', (128, 133))	('tumors', 'Disease', 'MESH:D009369', (33, 39))	('cancer', 'Disease', (49, 55))	('CDKN2B', 'Gene', (118, 124))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('JAK2', 'Gene', (175, 179))	('CDKN2A', 'Gene', (111, 117))	('PTPRD', 'Gene', '5789', (128, 133))	('deletion', 'Var', (180, 188))	('cancer', 'Disease', (228, 234))	('CDKN2B', 'Gene', '1030', (118, 124))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('deleted', 'Var', (85, 92))	('CDKN2A', 'Gene', '1029', (111, 117))	('CCLC cancer', 'Disease', 'MESH:D009369', (44, 55))	('CCLC cancer', 'Disease', (44, 55))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumors', 'Disease', (33, 39))	('cancer', 'Disease', 'MESH:D009369', (228, 234))
389037	28977839	CD274 and PDCD1LG2 deletions were always accompanied by JAK2 deletion.	('accompanied', 'Reg', (41, 52))	('CD274', 'Gene', '29126', (0, 5))	('PDCD1LG2', 'Gene', '80380', (10, 18))	('PDCD1LG2', 'Gene', (10, 18))	('CD274', 'Gene', (0, 5))	('deletions', 'Var', (19, 28))
389038	28977839	Since PD-L1/PD-L2 suppress T cell-based immunity against tumor cells, deletions of PD-L1/PD-L2 could result in constitutively active tumor-targeting cytotoxic T cells.	('PD-L1', 'Gene', '29126', (83, 88))	('suppress', 'NegReg', (18, 26))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('PD-L2', 'Gene', (12, 17))	('PD-L2', 'Gene', '80380', (12, 17))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('PD-L2', 'Gene', (89, 94))	('PD-L1', 'Gene', (6, 11))	('PD-L2', 'Gene', '80380', (89, 94))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Disease', (133, 138))	('active', 'PosReg', (126, 132))	('PD-L1', 'Gene', (83, 88))	('deletions', 'Var', (70, 79))	('tumor', 'Disease', (57, 62))	('PD-L1', 'Gene', '29126', (6, 11))	('result in', 'Reg', (101, 110))
389041	28977839	Thus, JAK2 deletion is a potential mechanism to hide tumor cells from recognition by cytotoxic T cells, especially in the cases of CDC274 and PDCD1LG2 deletions.	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('PDCD1LG2', 'Gene', '80380', (142, 150))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('PDCD1LG2', 'Gene', (142, 150))	('deletions', 'Var', (151, 160))	('JAK2', 'Gene', (6, 10))	('CDC274', 'Gene', (131, 137))	('tumor', 'Disease', (53, 58))	('deletion', 'Var', (11, 19))
389046	28977839	Consistent with this notion, NSCLC patients with pre-existing high T-effector/IFNgamma-associated gene expression had improved overall survival in a recent atezolizumab clinical trial.	('NSCLC', 'Phenotype', 'HP:0030358', (29, 34))	('improved', 'PosReg', (118, 126))	('NSCLC', 'Disease', (29, 34))	('atezolizumab', 'Chemical', 'MESH:C000594389', (156, 168))	('overall survival', 'MPA', (127, 143))	('patients', 'Species', '9606', (35, 43))	('NSCLC', 'Disease', 'MESH:D002289', (29, 34))	('high', 'Var', (62, 66))
389051	28977839	Gain-of-function JAK2 mutant JAK2V617F is an established oncoprotein associated with myeloproliferative neoplasms (MPNs) polycythemia vera, essential thrombocythemia, and primary myelofibrosis.	('neoplasms', 'Phenotype', 'HP:0002664', (104, 113))	('essential thrombocythemia', 'Disease', (140, 165))	('myelofibrosis', 'Phenotype', 'HP:0011974', (179, 192))	('JAK2', 'Gene', (17, 21))	('myeloproliferative neoplasms (MPNs) polycythemia vera', 'Disease', 'MESH:D011087', (85, 138))	('Gain-of-function', 'PosReg', (0, 16))	('MPNs', 'Phenotype', 'HP:0005547', (115, 119))	('myeloproliferative neoplasms', 'Phenotype', 'HP:0005547', (85, 113))	('mutant JAK2V617F', 'Var', (22, 38))	('primary myelofibrosis', 'Disease', 'MESH:D055728', (171, 192))	('thrombocythemia', 'Phenotype', 'HP:0001894', (150, 165))	('essential thrombocythemia', 'Disease', 'MESH:D013920', (140, 165))	('primary myelofibrosis', 'Disease', (171, 192))	('JAK2V617F', 'Var', (29, 38))	('polycythemia', 'Phenotype', 'HP:0001901', (121, 133))
389052	28977839	Moreover, JAK2 activated STAT3 pathway has tumor promoting activity.	('STAT3', 'Gene', (25, 30))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('JAK2 activated', 'Var', (10, 24))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Disease', (43, 48))	('STAT3', 'Gene', '6774', (25, 30))
389054	28977839	Unorthodoxically, this study in NSCLC and the previous studies of JAK1 in uterine cancer also suggest that JAK1 and JAK2 have tumor suppressor function, deficiencies of them could allow tumor cells to escape T-cell mediated immune surveillance.	('tumor', 'Disease', (186, 191))	('cancer', 'Disease', (82, 88))	('NSCLC', 'Disease', (32, 37))	('uterine cancer', 'Phenotype', 'HP:0010784', (74, 88))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('JAK1', 'Gene', '3716', (107, 111))	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('NSCLC', 'Phenotype', 'HP:0030358', (32, 37))	('JAK1', 'Gene', '3716', (66, 70))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('JAK1', 'Gene', (107, 111))	('tumor', 'Disease', (126, 131))	('JAK2', 'Gene', (116, 120))	('allow', 'Reg', (180, 185))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('deficiencies', 'Var', (153, 165))	('NSCLC', 'Disease', 'MESH:D002289', (32, 37))	('JAK1', 'Gene', (66, 70))
389057	28977839	Antibodies to STAT1 (SC79877), IRF1 (SC497), and LMP2 (SC271354) were from Santa Cruz Biotechnologies.	('SC271354', 'Var', (55, 63))	('STAT1', 'Gene', (14, 19))	('LMP2', 'Gene', (49, 53))	('IRF1', 'Gene', (31, 35))	('LMP2', 'Gene', '5698', (49, 53))
389064	28977839	Human NSCLC cell lines A549, H661, H292, and H2172 were from a central repository at the H. Lee Moffitt Cancer Center and Research Institute and had been authenticated by STR analysis (ACTG Inc, Wheling, IL) as of September 2010.	('Human', 'Species', '9606', (0, 5))	('NSCLC', 'Disease', 'MESH:D002289', (6, 11))	('H661', 'CellLine', 'CVCL:1577', (29, 33))	('Lee Moffitt Cancer', 'Disease', 'MESH:D009369', (92, 110))	('H292', 'CellLine', 'CVCL:0455', (35, 39))	('NSCLC', 'Phenotype', 'HP:0030358', (6, 11))	('H2172', 'CellLine', 'CVCL:1537', (45, 50))	('Lee Moffitt Cancer', 'Disease', (92, 110))	('H2172', 'Var', (45, 50))	('A549', 'CellLine', 'CVCL:0023', (23, 27))	('NSCLC', 'Disease', (6, 11))	('Cancer', 'Phenotype', 'HP:0002664', (104, 110))
389095	27490678	Resection of advanced NSCLC in stage IIIA-T4 has been associated with high morbidity and mortality combined with disappointing long-term outcomes.	('Resection', 'Var', (0, 9))	('NSCLC', 'Disease', 'MESH:D002289', (22, 27))	('NSCLC', 'Disease', (22, 27))	('NSCLC', 'Phenotype', 'HP:0030358', (22, 27))
389107	27490678	After restaging confirmed a persistent yc-T4N0M0 tumor, complete resection was planned.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('yc-T4N0M0', 'Var', (39, 48))	('tumor', 'Disease', (49, 54))
389120	27490678	The pathological diagnosis was yp-T4N0M0 squamous cell carcinoma, and the histologic response for evaluating the tumor response to induction therapy was two (Ef2).	('yp-T4N0M0', 'Var', (31, 40))	('tumor', 'Disease', (113, 118))	('Ef2', 'Gene', '1938', (158, 161))	('Ef2', 'Gene', (158, 161))	('squamous cell carcinoma', 'Disease', (41, 64))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (41, 64))	('carcinoma', 'Phenotype', 'HP:0030731', (55, 64))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (41, 64))
389154	33477943	LSCC is strongly associated with cigarette smoking, with characteristics of PIK3CA mutation, DDR2 mutation, FGFR1 amplification, and SOX2 amplification.	('FGFR1', 'Gene', '2260', (108, 113))	('DDR2', 'Gene', (93, 97))	('amplification', 'Var', (114, 127))	('mutation', 'Var', (98, 106))	('associated', 'Reg', (17, 27))	('LSCC', 'Disease', (0, 4))	('mutation', 'Var', (83, 91))	('PIK3CA', 'Gene', (76, 82))	('SOX2', 'Gene', '6657', (133, 137))	('cigarette smoking', 'Disease', (33, 50))	('LSCC', 'Phenotype', 'HP:0030359', (0, 4))	('SOX2', 'Gene', (133, 137))	('DDR2', 'Gene', '4921', (93, 97))	('FGFR1', 'Gene', (108, 113))	('PIK3CA', 'Gene', '5290', (76, 82))
389161	33477943	Furthermore, NSCLC patients with high expression of both PRR11 and SKA2 show poorer prognosis compared to all other patient groups.	('PRR11', 'Gene', (57, 62))	('NSCLC', 'Disease', (13, 18))	('patient', 'Species', '9606', (19, 26))	('patients', 'Species', '9606', (19, 27))	('NSCLC', 'Disease', 'MESH:D002289', (13, 18))	('high expression', 'Var', (33, 48))	('patient', 'Species', '9606', (116, 123))	('NSCLC', 'Phenotype', 'HP:0030358', (13, 18))	('SKA2', 'Gene', (67, 71))
389175	33477943	Cells were maintained in RPMI 1640 medium (H520, H226, and H2170) or high glucose-DMEM (SK-MES-1) supplemented with 10% fetal bovine serum (Invitrogen, CA, USA), penicillin (100 IU/mL), and streptomycin (100 mug/mL).	('high glucose', 'Phenotype', 'HP:0003074', (69, 81))	('SK-MES-1', 'CellLine', 'CVCL:0630', (88, 96))	('H2170', 'Var', (59, 64))	('H520', 'Var', (43, 47))	('streptomycin', 'Chemical', 'MESH:D013307', (190, 202))	('RPMI', 'Chemical', '-', (25, 29))	('glucose', 'Chemical', 'MESH:D005947', (74, 81))	('H2170', 'CellLine', 'CVCL:1535', (59, 64))	('H226', 'CellLine', 'CVCL:J621', (49, 53))	('penicillin', 'Chemical', 'MESH:D010406', (162, 172))
389227	33477943	Consistent with their findings, we observed that neither the SMO inhibitor GDC-0449 nor the SMO agonist SAG altered the expression levels of GLI transcriptional targets in LSCC cells (Figure 5).	('GDC-0449', 'Chemical', 'MESH:C538724', (75, 83))	('GLI', 'Gene', '2735', (141, 144))	('GDC-0449', 'Var', (75, 83))	('LSCC', 'Phenotype', 'HP:0030359', (172, 176))	('SMO', 'Gene', '6608', (61, 64))	('SMO', 'Gene', '6608', (92, 95))	('SMO', 'Gene', (92, 95))	('GLI', 'Gene', (141, 144))	('SAG', 'Chemical', '-', (104, 107))	('expression levels', 'MPA', (120, 137))	('SMO', 'Gene', (61, 64))
389230	33477943	For instance, LSCC cells carry SMO mutations, which mitigate the efficiency of SMO agonists and antagonists.	('SMO', 'Gene', '6608', (31, 34))	('SMO', 'Gene', (31, 34))	('SMO', 'Gene', (79, 82))	('mutations', 'Var', (35, 44))	('LSCC', 'Phenotype', 'HP:0030359', (14, 18))	('SMO', 'Gene', '6608', (79, 82))
389231	33477943	Several SMO mutations, such as G497W and D437H, have been uncovered as actors in GDC-0449 resistance.	('D437H', 'Mutation', 'p.D437H', (41, 46))	('GDC-0449', 'Chemical', 'MESH:C538724', (81, 89))	('G497W', 'Var', (31, 36))	('SMO', 'Gene', '6608', (8, 11))	('SMO', 'Gene', (8, 11))	('D437H', 'Var', (41, 46))	('G497W', 'Mutation', 'p.G497W', (31, 36))
389244	33477943	BUB1 is a central component of the mitotic checkpoint for spindle assembly, mediating cell death in response to chromosome missegregation and thus suppressing spontaneous tumorigenesis.	('BUB1', 'Gene', (0, 4))	('chromosome missegregation', 'Var', (112, 137))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('suppressing', 'NegReg', (147, 158))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', (171, 176))	('BUB1', 'Gene', '699', (0, 4))
389333	30300991	TTF-1 positivity has also been reported in 85-95% of small cell lung carcinomas.	('small cell lung carcinomas', 'Disease', (53, 79))	('small cell lung carcinoma', 'Phenotype', 'HP:0030357', (53, 78))	('carcinomas', 'Phenotype', 'HP:0030731', (69, 79))	('positivity', 'Var', (6, 16))	('small cell lung carcinomas', 'Disease', 'MESH:D055752', (53, 79))	('small cell lung carcinomas', 'Phenotype', 'HP:0030357', (53, 79))	('TTF-1', 'Gene', '7080', (0, 5))	('TTF-1', 'Gene', (0, 5))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))
389345	30300991	Both carcinomas are AFP-positive, but CK19 positivity is more frequent in metastatic hepatoid adenocarcinoma than in primary hepatocellular carcinoma.	('CK19', 'Gene', '3880', (38, 42))	('hepatoid adenocarcinoma', 'Disease', (85, 108))	('hepatoid adenocarcinoma', 'Phenotype', 'HP:0012028', (85, 108))	('hepatoid adenocarcinoma', 'Disease', 'MESH:D000230', (85, 108))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (125, 149))	('carcinoma', 'Phenotype', 'HP:0030731', (5, 14))	('hepatocellular carcinoma', 'Disease', (125, 149))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (125, 149))	('AFP', 'Gene', (20, 23))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))	('AFP', 'Gene', '174', (20, 23))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('frequent', 'Reg', (62, 70))	('carcinomas', 'Phenotype', 'HP:0030731', (5, 15))	('positivity', 'Var', (43, 53))	('carcinomas', 'Disease', (5, 15))	('carcinomas', 'Disease', 'MESH:D002277', (5, 15))	('CK19', 'Gene', (38, 42))
389417	26395002	Mutational landscapes of tongue carcinoma reveal recurrent mutations in genes of therapeutic and prognostic relevance Carcinoma of the oral tongue (OTSCC) is the most common malignancy of the oral cavity, characterized by frequent recurrence and poor survival.	('malignancy', 'Disease', 'MESH:D009369', (174, 184))	('malignancy', 'Disease', (174, 184))	('Carcinoma of the oral', 'Phenotype', 'HP:0100649', (118, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (32, 41))	('tongue carcinoma', 'Disease', 'MESH:D014062', (25, 41))	('tongue carcinoma', 'Disease', (25, 41))	('Carcinoma of the oral tongue', 'Disease', 'MESH:D014062', (118, 146))	('malignancy of the oral cavity', 'Phenotype', 'HP:0100649', (174, 203))	('mutations', 'Var', (59, 68))	('Carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('Carcinoma of the oral tongue', 'Disease', (118, 146))	('tongue carcinoma', 'Phenotype', 'HP:0030415', (25, 41))
389419	26395002	While the most common mutation was in TP53, the OTSCC genetic landscape differed from previously described cohorts of patients with head and neck tumors: OTSCCs demonstrated frequent mutations in DST and RNF213, while alterations in CDKN2A and NOTCH1 were significantly less frequent.	('neck tumors', 'Disease', (141, 152))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('mutations', 'Var', (183, 192))	('RNF213', 'Gene', '57674', (204, 210))	('TP53', 'Gene', (38, 42))	('patients', 'Species', '9606', (118, 126))	('CDKN2A', 'Gene', (233, 239))	('DST', 'Gene', (196, 199))	('CDKN2A', 'Gene', '1029', (233, 239))	('tumors', 'Phenotype', 'HP:0002664', (146, 152))	('head and neck tumors', 'Phenotype', 'HP:0012288', (132, 152))	('RNF213', 'Gene', (204, 210))	('neck tumors', 'Disease', 'MESH:D006258', (141, 152))	('TP53', 'Gene', '7157', (38, 42))
389420	26395002	Despite a lack of previously reported NOTCH1 mutations, integrated analysis showed enrichments of alterations affecting Notch signaling in OTSCC.	('mutations', 'Var', (45, 54))	('OTSCC', 'Disease', (139, 144))	('NOTCH1', 'Gene', (38, 44))	('Notch signaling', 'MPA', (120, 135))	('men', 'Species', '9606', (89, 92))	('alterations', 'Var', (98, 109))
389421	26395002	Patients harboring mutations in actionable pathways were more likely to succumb from recurrent disease compared with those who did not, suggesting that the former should be considered for treatment with targeted compounds in future trials.	('Patients', 'Species', '9606', (0, 8))	('men', 'Species', '9606', (193, 196))	('mutations', 'Var', (19, 28))	('recurrent disease', 'Disease', (85, 102))
389437	26395002	For example, certain molecular alterations appear to be present in higher frequencies or unique to certain sites/subsites: these include PIK3CA mutations that are more prevalent in human papillomavirus (HPV)-induced oropharyngeal cancer, and alterations in USP9X, MLL4, ARID2, UNC13C, and TRPM3 in gingiva-buccal cancers.	('UNC13C', 'Gene', (277, 283))	('human papillomavirus', 'Species', '10566', (181, 201))	('alterations', 'Var', (242, 253))	('PIK3CA', 'Gene', '5290', (137, 143))	('cancer', 'Phenotype', 'HP:0002664', (313, 319))	('mutations', 'Var', (144, 153))	('prevalent', 'Reg', (168, 177))	('HPV', 'Species', '10566', (203, 206))	('gingiva-buccal cancers', 'Disease', (298, 320))	('oropharyngeal cancer', 'Disease', (216, 236))	('ARID2', 'Gene', '196528', (270, 275))	('TRPM3', 'Gene', (289, 294))	('PIK3CA', 'Gene', (137, 143))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('MLL4', 'Gene', '8085', (264, 268))	('MLL4', 'Gene', (264, 268))	('ARID2', 'Gene', (270, 275))	('USP9X', 'Gene', '8239', (257, 262))	('human papillomavirus', 'Disease', (181, 201))	('gingiva-buccal cancers', 'Disease', 'MESH:D005889', (298, 320))	('TRPM3', 'Gene', '80036', (289, 294))	('USP9X', 'Gene', (257, 262))	('UNC13C', 'Gene', '440279', (277, 283))	('cancers', 'Phenotype', 'HP:0002664', (313, 320))	('oropharyngeal cancer', 'Disease', 'MESH:D009959', (216, 236))
389441	26395002	For example, in a recent International Cancer Genome Consortium (ICGC) analysis of gingiva-buccal cancers, specific genetic changes appeared to be unique to patient ethnicity (Indian) or disease etiology (betel nut chewing).	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('Cancer', 'Disease', 'MESH:D009369', (39, 45))	('Cancer', 'Phenotype', 'HP:0002664', (39, 45))	('patient', 'Species', '9606', (157, 164))	('cancers', 'Phenotype', 'HP:0002664', (98, 105))	('gingiva-buccal cancers', 'Disease', 'MESH:D005889', (83, 105))	('gingiva-buccal cancers', 'Disease', (83, 105))	('Cancer', 'Disease', (39, 45))	('genetic changes', 'Var', (116, 131))
389479	26395002	Overall, 1,092 nonsynonymous somatic variations affecting 750 genes were detected, of which 992 were somatic SNVs and the remaining were somatic insertions or deletions (indels) (Additional file 4).	('deletions', 'Var', (159, 168))	('genes', 'Gene', (62, 67))	('indel', 'Chemical', '-', (170, 175))
389481	26395002	Subsequent technical validation by Sanger sequencing confirmed the presence of mutations in 28 genes (28/29, true-positive rate of 96.6 %), demonstrating that the algorithms used (GATK and PGS) for identifying mutations were reliable.	('PGS', 'Gene', (189, 192))	('PGS', 'Gene', '8905', (189, 192))	('mutations', 'Var', (79, 88))
389482	26395002	Overall, the whole-exome sequencing of the discovery set indicated 28 genes harboring somatic coding mutations in two or more oral tongue tumors (a list of these 28 genes is presented in Additional file 6).	('mutations', 'Var', (101, 110))	('oral tongue tumors', 'Disease', 'MESH:D014062', (126, 144))	('tongue tumors', 'Phenotype', 'HP:0100648', (131, 144))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('oral tongue tumors', 'Disease', (126, 144))	('tongue tumor', 'Phenotype', 'HP:0100648', (131, 143))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
389483	26395002	Nucleotide sequence contexts of somatic mutations can be indicative of specific mutagenesis mechanisms occurring in tumor cells.	('mutations', 'Var', (40, 49))	('tumor', 'Disease', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumor', 'Disease', 'MESH:D009369', (116, 121))
389484	26395002	Analyzing synonymous and non-synonymous alterations, we observed elevated rates of C > T transitions, particularly at CpG positions, consistent with deamination of 5-methyl-cytosine to uracil by APOBEC or other endogenous processes.	('uracil', 'Chemical', 'MESH:D014498', (185, 191))	('deamination of 5-methyl-cytosine to uracil', 'MPA', (149, 191))	('5-methyl-cytosine', 'Chemical', 'MESH:D044503', (164, 181))	('alterations', 'Var', (40, 51))	('elevated', 'PosReg', (65, 73))	('C > T', 'Var', (83, 88))
389488	26395002	To further investigate the precise frequency and distribution of somatic mutations in an expanded OTSCC cohort, we designed a panel with 465 genes including (a) the 28 candidate genes frequently mutated in the discovery set, (b) genes previously described as frequently mutated in HNSCC, and (c) recognized cancer genes that were manually curated (a list of all genes included in the target panel is presented in Additional file 10).	('cancer', 'Disease', (307, 313))	('cancer', 'Disease', 'MESH:D009369', (307, 313))	('cancer', 'Phenotype', 'HP:0002664', (307, 313))	('HNSCC', 'Phenotype', 'HP:0012288', (281, 286))	('mutated', 'Var', (195, 202))
389492	26395002	First, we excluded variants found in either public databases of germline SNVs [dbSNP (build 132), 1000 Genomes, and EVS (6500-SI-V2)] or in an in-house database of germline SNVs drawn from 523 normal Asian exomes.	('6500-SI-V2', 'Disease', 'MESH:D049932', (121, 131))	('6500-SI-V2', 'Disease', (121, 131))	('variants', 'Var', (19, 27))
389493	26395002	We initially also planned to exclude variants described in the beta version of the ExAC database, but preliminary tests showed that this filtering steps removes a significant proportion of the TP53 alterations in our cohorts (23 % discovery set and 22 % prevalence set).	('TP53', 'Gene', '7157', (193, 197))	('TP53', 'Gene', (193, 197))	('alterations', 'Var', (198, 209))	('removes', 'NegReg', (153, 160))
389494	26395002	Furthermore, the examination of the TCGA data for HNSCC also revealed that 22 % of the TP53 mutations described there were also present in the ExAC database, with a significant proportion of damaging missense mutations.	('TP53', 'Gene', '7157', (87, 91))	('TP53', 'Gene', (87, 91))	('mutations', 'Var', (92, 101))	('HNSCC', 'Phenotype', 'HP:0012288', (50, 55))	('missense mutations', 'Var', (200, 218))
389496	26395002	The rationale for this criterion is that somatic mutations usually present with variant read proportions substantially less than 0.5 in next-generation sequencing data, due to admixture of genomes from non-malignant cells in a tumor sample.	('tumor', 'Disease', 'MESH:D009369', (227, 232))	('tumor', 'Disease', (227, 232))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))	('variant', 'Var', (80, 87))
389497	26395002	By contrast, germline variants have read proportions of either 1 (for homozygous variants) or ~0.5 (for heterozygous variants) in regions where the tumor genome is diploid.	('tumor', 'Disease', (148, 153))	('variants', 'Var', (22, 30))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))
389498	26395002	We note that copy number gains or losses in tumor genomes may alter the expected variant read proportions of germline variants, so this two-step approach will not always exclude germline variants.	('copy number gains', 'Var', (13, 30))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('variant', 'MPA', (81, 88))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('losses', 'NegReg', (34, 40))	('alter', 'Reg', (62, 67))	('tumor', 'Disease', (44, 49))
389502	26395002	After applying the tumor-only filtering protocol to the prevalence set, 380 genes were detected as harboring SNVs or indels.	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('indel', 'Chemical', '-', (117, 122))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('SNVs', 'Var', (109, 113))	('tumor', 'Disease', (19, 24))	('indels', 'Var', (117, 123))
389503	26395002	Unsurprisingly, the most prevalent genetic alteration detected in this cohort comprised a broad spectrum of TP53 mutations (38.3 %).	('TP53', 'Gene', (108, 112))	('mutations', 'Var', (113, 122))	('TP53', 'Gene', '7157', (108, 112))
389505	26395002	This pattern of Asian OTSCC genetic mutations was compared with the profile of 172 exomes from oral cavity tumors available from TCGA (OC-TCGA).	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('oral cavity tumors', 'Phenotype', 'HP:0100649', (95, 113))	('tumors', 'Disease', (107, 113))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('mutations', 'Var', (36, 45))	('tumors', 'Disease', 'MESH:D009369', (107, 113))	('oral cavity tumor', 'Phenotype', 'HP:0100649', (95, 112))	('Asian OTSCC', 'Disease', (16, 27))
389508	26395002	Even after multiple hypothesis correction, mutation frequencies remained higher in Asian OTSCCs for DST (P = 0.001) and RNF213 (P = 0.033) (Fig.	('DST', 'Disease', (100, 103))	('RNF213', 'Gene', (120, 126))	('mutation', 'Var', (43, 51))	('RNF213', 'Gene', '57674', (120, 126))	('Asian OTSCCs', 'Disease', (83, 95))	('higher', 'PosReg', (73, 79))
389509	26395002	In contrast, OC-TCGAs exhibited more frequent mutations in TP53 (P < 0.001), CDKN2A (P = 0.005), and NOTCH1 (P = 0.019).	('mutations', 'Var', (46, 55))	('TP53', 'Gene', (59, 63))	('NOTCH1', 'Gene', (101, 107))	('CDKN2A', 'Gene', (77, 83))	('CDKN2A', 'Gene', '1029', (77, 83))	('TP53', 'Gene', '7157', (59, 63))
389515	26395002	Overall, 55 % of the OTSCC samples had mutations in at least one gene affecting the MAPK pathway, while EGFR, Notch, and ERBB signaling families where modified in 52 %, 32 % and 23 % of cases, respectively.	('EGFR', 'Gene', (104, 108))	('ERBB', 'Gene', '1956', (121, 125))	('MAPK pathway', 'Pathway', (84, 96))	('mutations', 'Var', (39, 48))	('OTSCC', 'Disease', (21, 26))	('ERBB', 'Gene', (121, 125))	('EGFR', 'Gene', '1956', (104, 108))
389516	26395002	Other core canonical signaling pathways frequently found mutated in OTSCC included mammalian target of rapamycin (mTOR), transforming growth factor beta-SMAD, chromatin remodeling genes, KIT, beta-catenin and apoptosis, many of which may have therapeutic implications.	('beta-catenin', 'Gene', '1499', (192, 204))	('core canonical signaling pathways', 'Pathway', (6, 39))	('KIT', 'Gene', (187, 190))	('apoptosis', 'CPA', (209, 218))	('mTOR', 'Gene', '2475', (114, 118))	('mTOR', 'Gene', (114, 118))	('mammalian target of rapamycin', 'Gene', '2475', (83, 112))	('beta-catenin', 'Gene', (192, 204))	('mammalian target of rapamycin', 'Gene', (83, 112))	('mutated', 'Var', (57, 64))
389519	26395002	Interestingly, mutations in the Notch signaling pathway were enriched in women compared with men (P = 0.04; Additional file 15).	('women', 'Species', '9606', (73, 78))	('men', 'Species', '9606', (93, 96))	('mutations', 'Var', (15, 24))	('men', 'Species', '9606', (75, 78))	('Notch signaling pathway', 'Pathway', (32, 55))
389520	26395002	Based on multivariate models that included clinico-pathologic correlates associated with prognosis (age, tobacco consumption, N stage and extra-capsular spread), modifications in the Notch pathway remained an independent predictor for DFS.	('Notch pathway', 'Pathway', (183, 196))	('tobacco', 'Species', '4097', (105, 112))	('DFS', 'Disease', (235, 238))	('modifications', 'Var', (162, 175))
389521	26395002	Patients with Notch pathway mutations were 3.3 times more likely to die with recurrent disease compared with those who did not have these alterations [p = 0.016, hazard ratio (HR) = 3.3, 95 % CI = 1.24-8.94; Fig.	('recurrent disease', 'Disease', (77, 94))	('mutations', 'Var', (28, 37))	('Notch pathway', 'Gene', (14, 27))	('Patients', 'Species', '9606', (0, 8))
389522	26395002	Analysis of TCGA data for oral cavity suggests a similar trend towards poorer OS in patients with alterations in this pathway, however this was not statistically significant (p = 0.13; data not shown).	('poorer', 'NegReg', (71, 77))	('alterations', 'Var', (98, 109))	('OS', 'Chemical', '-', (78, 80))	('patients', 'Species', '9606', (84, 92))
389526	26395002	Moreover, most of the mutations in this gene family were mutually exclusive, especially mutations affecting the MLL family of histone methyltransferases (Fig.	('MLL', 'Gene', (112, 115))	('MLL', 'Gene', '4297', (112, 115))	('affecting', 'Reg', (98, 107))	('mutations', 'Var', (88, 97))	('mutations', 'Var', (22, 31))
389527	26395002	Mutations affecting chromatin remodeling genes were significantly more frequent in older patients (p = 0.03; Additional file 15) and patients with mutations have significantly poorer DFS compared with those who did not (p = 0.01; Fig.	('mutations', 'Var', (147, 156))	('patients', 'Species', '9606', (133, 141))	('chromatin remodeling genes', 'Gene', (20, 46))	('poorer', 'NegReg', (176, 182))	('Mutations', 'Var', (0, 9))	('patients', 'Species', '9606', (89, 97))	('DFS', 'MPA', (183, 186))
389528	26395002	Patients with mutations in this pathway were 3.3 times more likely to die with recurrent disease compared with those who did not have these alterations (p = 0.03, HR = 3.3, 95 % CI = 1.12-9.55; Fig.	('Patients', 'Species', '9606', (0, 8))	('mutations', 'Var', (14, 23))	('recurrent disease', 'Disease', (79, 96))
389529	26395002	Again, analysis of TCGA data for tongue cancers suggests a similar trend towards poorer OS in patients with alterations in this pathway, although this was not statistically significant (P = 0.11; data not shown).	('poorer OS', 'Disease', (81, 90))	('cancers', 'Phenotype', 'HP:0002664', (40, 47))	('alterations', 'Var', (108, 119))	('patients', 'Species', '9606', (94, 102))	('tongue cancers', 'Disease', 'MESH:D014062', (33, 47))	('OS', 'Chemical', '-', (88, 90))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('tongue cancers', 'Disease', (33, 47))
389530	26395002	Patients harboring mutations in at least one member of this signaling pathway were 2.9 times more likely to develop recurrence and die (P = 0.037, HR = 2.9, 95 % CI = 1.07-7.73; Fig.	('recurrence', 'CPA', (116, 126))	('Patients', 'Species', '9606', (0, 8))	('mutations', 'Var', (19, 28))	('develop', 'PosReg', (108, 115))
389532	26395002	The majority of the PIK3CA mutations (four out of five) are known to be activating mutations, while about half the mutations in the ERBB family of genes (three out of six) occur in regions that affect signaling (extracellular domain or tyrosine kinase domain).	('mutations', 'Var', (27, 36))	('ERBB', 'Gene', '1956', (132, 136))	('PIK3CA', 'Gene', (20, 26))	('affect', 'Reg', (194, 200))	('PIK3CA', 'Gene', '5290', (20, 26))	('signaling', 'MPA', (201, 210))	('ERBB', 'Gene', (132, 136))
389541	26395002	Reassuringly, mutational analysis of our OTSCC cohort identified frequent nucleotide alterations in SYNE1, FAT1, MLL2/KMT2A, MLL3/KMT2C, PIK3CA, and CASP8 at similar frequencies reported by TCGA and ICGC.	('nucleotide alterations', 'Var', (74, 96))	('FAT1', 'Gene', '2195', (107, 111))	('SYNE1', 'Gene', '23345', (100, 105))	('PIK3CA', 'Gene', (137, 143))	('MLL3', 'Gene', (125, 129))	('FAT1', 'Gene', (107, 111))	('mutational', 'Var', (14, 24))	('KMT2A', 'Gene', (118, 123))	('MLL2', 'Gene', (113, 117))	('MLL3', 'Gene', '58508', (125, 129))	('SYNE1', 'Gene', (100, 105))	('KMT2C', 'Gene', (130, 135))	('PIK3CA', 'Gene', '5290', (137, 143))	('KMT2A', 'Gene', '4297', (118, 123))	('KMT2C', 'Gene', '58508', (130, 135))	('MLL2', 'Gene', '8085', (113, 117))	('CASP8', 'Gene', (149, 154))	('CASP8', 'Gene', '841', (149, 154))
389542	26395002	However, there were significantly fewer mutations in TP53, NOTCH1, and CDKN2A.	('CDKN2A', 'Gene', (71, 77))	('CDKN2A', 'Gene', '1029', (71, 77))	('mutations', 'Var', (40, 49))	('TP53', 'Gene', '7157', (53, 57))	('NOTCH1', 'Gene', (59, 65))	('fewer', 'NegReg', (34, 39))	('TP53', 'Gene', (53, 57))
389543	26395002	Mutations in the RAS genes were extremely infrequent (HRAS, n = 1/60, with no mutations in KRAS and NRAS) and mutations in EGFR notably absent.	('EGFR', 'Gene', (123, 127))	('NRAS', 'Gene', '4893', (100, 104))	('RAS', 'Gene', (17, 20))	('KRAS', 'Gene', '3845', (91, 95))	('HRAS', 'Gene', '3265', (54, 58))	('Mutations', 'Var', (0, 9))	('EGFR', 'Gene', '1956', (123, 127))	('KRAS', 'Gene', (91, 95))	('NRAS', 'Gene', (100, 104))	('HRAS', 'Gene', (54, 58))
389544	26395002	In contrast, several less well-characterized genes (DST and RNF213) were mutated at higher rates in Asian OTSCC than previously reported.	('RNF213', 'Gene', (60, 66))	('mutated', 'Var', (73, 80))	('RNF213', 'Gene', '57674', (60, 66))	('Asian OTSCC', 'Disease', (100, 111))	('DST', 'Gene', (52, 55))
389546	26395002	As predicted, these genetic alterations also differed from HPV-driven cancers involving the base of tongue, which had a higher frequency of activating mutations in PIK3CA, with loss of TRAF3 and amplification of E2F1.	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('PIK3CA', 'Gene', (164, 170))	('loss', 'NegReg', (177, 181))	('HPV-driven cancers', 'Disease', (59, 77))	('mutations', 'Var', (151, 160))	('PIK3CA', 'Gene', '5290', (164, 170))	('HPV-driven cancers', 'Disease', 'MESH:D030361', (59, 77))	('cancers', 'Phenotype', 'HP:0002664', (70, 77))	('amplification', 'Var', (195, 208))	('E2F1', 'Gene', (212, 216))	('TRAF3', 'Protein', (185, 190))	('activating', 'PosReg', (140, 150))
389548	26395002	Our analysis of OTSCC found no specific mutations unique to younger patients or non-smokers, although there was a tendency towards more frequent mutations in MLL2/KMT2A and PIK3CA in older patients.	('PIK3CA', 'Gene', '5290', (173, 179))	('KMT2A', 'Gene', (163, 168))	('MLL2', 'Gene', '8085', (158, 162))	('KMT2A', 'Gene', '4297', (163, 168))	('mutations', 'Var', (145, 154))	('patients', 'Species', '9606', (68, 76))	('MLL2', 'Gene', (158, 162))	('patients', 'Species', '9606', (189, 197))	('PIK3CA', 'Gene', (173, 179))
389553	26395002	We were initially surprised that NOTCH1 mutations were relatively infrequent in this cohort, although one previous study in esophageal squamous cell cancer had shown that NOTCH1 mutations are uncommon in Asian patients compared with matched Caucasian populations.	('NOTCH1', 'Gene', (33, 39))	('esophageal squamous cell cancer', 'Disease', 'MESH:D002294', (124, 155))	('NOTCH1', 'Gene', (171, 177))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (135, 155))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('patients', 'Species', '9606', (210, 218))	('esophageal squamous cell cancer', 'Disease', (124, 155))	('mutations', 'Var', (178, 187))
389554	26395002	These alterations were more common in women, and of concern, they conferred a poorer prognosis in these patients regardless of other factors or mutations, even on multivariate analysis.	('alterations', 'Var', (6, 17))	('common', 'Reg', (28, 34))	('women', 'Species', '9606', (38, 43))	('patients', 'Species', '9606', (104, 112))	('poorer', 'NegReg', (78, 84))
389557	26395002	Furthermore, in a tongue cancer model using mouse xenografts, the presence of NOTCH1 caused a dramatic reduction in tumor size compared with tumors in which this gene was absent.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('presence', 'Var', (66, 74))	('NOTCH1', 'Gene', (78, 84))	('tumors', 'Disease', (141, 147))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor', 'Disease', (141, 146))	('tongue cancer', 'Disease', (18, 31))	('tumors', 'Disease', 'MESH:D009369', (141, 147))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('tongue cancer', 'Disease', 'MESH:D014062', (18, 31))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('reduction', 'NegReg', (103, 112))	('tumor', 'Disease', (116, 121))	('mouse', 'Species', '10090', (44, 49))
389558	26395002	This apparent discordance between infrequent NOTCH1 mutations per se and a still defective Notch pathway through other gene mutations in 32 % of OTSCC patients highlights the importance of deregulating the Notch-driven epithelial cell differentiation program in OTSCC through a range of convergent targets.	('mutations', 'Var', (52, 61))	('mutations', 'Var', (124, 133))	('defective', 'NegReg', (81, 90))	('patients', 'Species', '9606', (151, 159))	('Notch pathway', 'Pathway', (91, 104))	('deregulating', 'Reg', (189, 201))	('OTSCC', 'Disease', (262, 267))	('NOTCH1', 'Gene', (45, 51))	('OTSCC', 'Disease', (145, 150))
389559	26395002	Interestingly, we observed a significantly higher frequency of MLL3/KMT2C mutations (16 %) in our cohort compared with mutations in the MLL homologs MLL2/KMT2A in OC-TCGA (Western/predominantly Caucasian population) and in MLL4/KMT2D in OSCC-GB.	('KMT2D', 'Gene', '8085', (228, 233))	('KMT2A', 'Gene', (154, 159))	('KMT2C', 'Gene', '58508', (68, 73))	('MLL3', 'Gene', (63, 67))	('KMT2C', 'Gene', (68, 73))	('MLL', 'Gene', (136, 139))	('MLL', 'Gene', '4297', (136, 139))	('MLL', 'Gene', (63, 66))	('MLL', 'Gene', '4297', (63, 66))	('MLL', 'Gene', '4297', (223, 226))	('MLL', 'Gene', (149, 152))	('MLL', 'Gene', '4297', (149, 152))	('MLL', 'Gene', (223, 226))	('MLL2', 'Gene', '8085', (149, 153))	('OSCC-GB', 'Chemical', '-', (237, 244))	('KMT2D', 'Gene', (228, 233))	('MLL2', 'Gene', (149, 153))	('KMT2A', 'Gene', '4297', (154, 159))	('MLL3', 'Gene', '58508', (63, 67))	('MLL4', 'Gene', '8085', (223, 227))	('mutations', 'Var', (74, 83))	('MLL4', 'Gene', (223, 227))
389560	26395002	Damaging mutations in MLL2/KMT2A were more frequently identified in smokers in our cohort, while the mutations in MLL4/KMT2D seem to be unique to the Indian population studied by the ICGC.	('MLL2', 'Gene', '8085', (22, 26))	('mutations', 'Var', (101, 110))	('mutations', 'Var', (9, 18))	('KMT2D', 'Gene', (119, 124))	('MLL2', 'Gene', (22, 26))	('KMT2D', 'Gene', '8085', (119, 124))	('KMT2A', 'Gene', (27, 32))	('MLL4', 'Gene', (114, 118))	('MLL4', 'Gene', '8085', (114, 118))	('KMT2A', 'Gene', '4297', (27, 32))
389561	26395002	The higher frequency of MLL3/KMT2C mutations in our cohort may therefore be a phenomenon associated with never-smoker OTSCC populations, and represents another example of convergent evolution on a critical pathway in OTSCC carcinogenesis.	('MLL3', 'Gene', '58508', (24, 28))	('KMT2C', 'Gene', '58508', (29, 34))	('KMT2C', 'Gene', (29, 34))	('men', 'Species', '9606', (83, 86))	('carcinogenesis', 'Disease', 'MESH:D063646', (223, 237))	('MLL3', 'Gene', (24, 28))	('carcinogenesis', 'Disease', (223, 237))	('mutations', 'Var', (35, 44))
389563	26395002	However, analysis of our cohort showed that at least half of the patients harbored potentially targetable mutations in signal transduction pathways, where targeted compounds are already available.	('patients', 'Species', '9606', (65, 73))	('signal transduction pathways', 'Pathway', (119, 147))	('mutations', 'Var', (106, 115))
389570	26395002	Further validation of this approach can be inferred from the fact that we found similar frequencies of mutations in a number of genes previously detected by TCGA, including USH2A, FAT1, PLEC, SYNE1, PIK3CA, MLL2/KMT2A, MLL3/KMT2C, CASP8 COL6A6, and ZFHX4.	('COL6A6', 'Gene', '131873', (237, 243))	('SYNE1', 'Gene', (192, 197))	('MLL2', 'Gene', (207, 211))	('FAT1', 'Gene', (180, 184))	('PIK3CA', 'Gene', '5290', (199, 205))	('CASP8', 'Gene', (231, 236))	('KMT2A', 'Gene', '4297', (212, 217))	('SYNE1', 'Gene', '23345', (192, 197))	('MLL3', 'Gene', '58508', (219, 223))	('mutations', 'Var', (103, 112))	('USH2A', 'Gene', '7399', (173, 178))	('TCGA', 'Gene', (157, 161))	('KMT2C', 'Gene', '58508', (224, 229))	('KMT2C', 'Gene', (224, 229))	('FAT1', 'Gene', '2195', (180, 184))	('PIK3CA', 'Gene', (199, 205))	('PLEC', 'Gene', '5339', (186, 190))	('USH2A', 'Gene', (173, 178))	('KMT2A', 'Gene', (212, 217))	('ZFHX4', 'Gene', (249, 254))	('MLL3', 'Gene', (219, 223))	('PLEC', 'Gene', (186, 190))	('COL6A6', 'Gene', (237, 243))	('MLL2', 'Gene', '8085', (207, 211))	('ZFHX4', 'Gene', '79776', (249, 254))	('CASP8', 'Gene', '841', (231, 236))
389572	26395002	In a study conducted at the Sanger Centre, investigators were able to identify base substitutions and small insertions/deletions in the exome data from 738 patients with myelodysplastic syndrome by comparison against one unmatched normal sample.	('patients', 'Species', '9606', (156, 164))	('myelodysplastic syndrome', 'Phenotype', 'HP:0002863', (170, 194))	('insertions/deletions', 'Var', (108, 128))	('myelodysplastic syndrome', 'Disease', (170, 194))	('base substitutions', 'Var', (79, 97))	('myelodysplastic syndrome', 'Disease', 'MESH:D009190', (170, 194))
389573	26395002	Along the same line, a Japanese study identified mutations in a cohort of 97 Japanese lung adenocarcinoma patients by filtering out germline variants present in an external exome dataset composite by 217 normal control exomes from individuals with the same ethnic background.	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('lung adenocarcinoma', 'Disease', (86, 105))	('mutations', 'Var', (49, 58))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (86, 105))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (86, 105))	('patients', 'Species', '9606', (106, 114))
389577	26395002	Of note, mutations in genes in the Notch pathway and the chromatin remodeling family were associated with poor prognosis in individuals with oral tongue tumors.	('tongue tumors', 'Phenotype', 'HP:0100648', (146, 159))	('Notch pathway', 'Pathway', (35, 48))	('mutations', 'Var', (9, 18))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('associated', 'Reg', (90, 100))	('tongue tumor', 'Phenotype', 'HP:0100648', (146, 158))	('oral tongue tumors', 'Disease', 'MESH:D014062', (141, 159))	('tumors', 'Phenotype', 'HP:0002664', (153, 159))	('oral tongue tumors', 'Disease', (141, 159))
389581	26395002	CI confidence interval DFS disease-free survival EGFR epidermal growth factor receptor GATK Genome Analysis Tool Kit GB gingiva-buccal GSEA Gene Set Enrichment Analysis HNSCC head and neck squamous cell carcinoma HPV human papillomavirus HR hazard ratio ICGC International Cancer Genome Consortium IGV Integrative Genomics Viewer indel insertion or deletion MAPK mitogen-activated protein kinase NPV negative predictive value OC oral cavity OS overall survival OSCC oral squamous cell carcinoma OTSCC oral tongue squamous cell carcinoma PCR polymerase chain reaction PPV positive predictive value SNV single-nucleotide variation TCGA The Cancer Genome Atlas	('Cancer', 'Phenotype', 'HP:0002664', (273, 279))	('deletion', 'Var', (349, 357))	('Cancer', 'Phenotype', 'HP:0002664', (638, 644))	('neck squamous cell carcinoma', 'Disease', (184, 212))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (184, 212))	('epidermal growth factor receptor', 'Gene', (54, 86))	('Cancer', 'Disease', (273, 279))	('carcinoma', 'Phenotype', 'HP:0030731', (485, 494))	('OS', 'Chemical', '-', (461, 463))	('EGFR', 'Gene', (49, 53))	('Cancer', 'Disease', (638, 644))	('epidermal growth factor receptor', 'Gene', '1956', (54, 86))	('HNSCC', 'Phenotype', 'HP:0012288', (169, 174))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (466, 494))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (189, 212))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (513, 536))	('single-nucleotide variation', 'Var', (601, 628))	('Cancer', 'Disease', 'MESH:D009369', (273, 279))	('oral squamous cell carcinoma', 'Disease', (466, 494))	('GSEA', 'Chemical', '-', (135, 139))	('human papillomavirus', 'Species', '10566', (217, 237))	('Cancer', 'Disease', 'MESH:D009369', (638, 644))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (638, 657))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (175, 212))	('HPV', 'Species', '10566', (213, 216))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (471, 494))	('carcinoma', 'Phenotype', 'HP:0030731', (203, 212))	('tongue squamous cell carcinoma', 'Phenotype', 'HP:0030413', (506, 536))	('EGFR', 'Gene', '1956', (49, 53))	('men', 'Species', '9606', (155, 158))	('oral tongue squamous cell carcinoma', 'Disease', 'MESH:D002294', (501, 536))	('Cancer Genome Atlas', 'Disease', (638, 657))	('indel', 'Chemical', '-', (330, 335))	('OS', 'Chemical', '-', (441, 443))	('carcinoma', 'Phenotype', 'HP:0030731', (527, 536))	('oral tongue squamous cell carcinoma', 'Disease', (501, 536))
389624	25452802	In the 80 cases of classic LCLC, the positive expression rates of 34betaE12, CK5/6 and P63 were 100, 76.3 and 52.5%, respectively; the positive expression rates of CK7 and TTF-1 were 100 and 51.3%, respectively; however, positive expression of Syn and CgA was not observed.	('TTF-1', 'Gene', (172, 177))	('Syn', 'Gene', (244, 247))	('CgA', 'Gene', (252, 255))	('CK5/6', 'Gene', '3852', (77, 82))	('P63', 'Gene', '8626', (87, 90))	('Syn', 'Gene', '6855', (244, 247))	('TTF-1', 'Gene', '7270', (172, 177))	('classic LCLC', 'Disease', (19, 31))	('CK7', 'Gene', (164, 167))	('CK5/6', 'Gene', (77, 82))	('34betaE12', 'Var', (66, 75))	('CK7', 'Gene', '3855', (164, 167))	('CgA', 'Gene', '1113', (252, 255))	('P63', 'Gene', (87, 90))
389644	25452802	In the present study, routine immunohistochemistry was performed on the LCLC tissues, including three squamous cell markers (CK5/6, 34betaE12 and P63), two glandular epithelial markers (TTF-1 and CK7) and two neuroendocrine markers (Syn and CgA).	('P63', 'Gene', (146, 149))	('CK5/6', 'Gene', '3852', (125, 130))	('34betaE12', 'Var', (132, 141))	('CgA', 'Gene', '1113', (241, 244))	('TTF-1', 'Gene', (186, 191))	('CK5/6', 'Gene', (125, 130))	('P63', 'Gene', '8626', (146, 149))	('Syn', 'Gene', (233, 236))	('CgA', 'Gene', (241, 244))	('TTF-1', 'Gene', '7270', (186, 191))	('CK7', 'Gene', (196, 199))	('CK7', 'Gene', '3855', (196, 199))	('Syn', 'Gene', '6855', (233, 236))
389762	32352191	Molecular methods to aid in this diagnosis specifically within the tonsil have not been investigated in veterinary species; however, similar to other anatomical locations such as the mammary gland, it is possible that positive labeling for cytokeratin19 in glandular carcinomas of the tonsil may differentiate them from squamous cell carcinoma.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (320, 343))	('cytokeratin19', 'Var', (240, 253))	('carcinoma', 'Phenotype', 'HP:0030731', (334, 343))	('differentiate', 'Reg', (296, 309))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (320, 343))	('squamous cell carcinoma', 'Disease', (320, 343))	('carcinomas', 'Disease', 'MESH:D009369', (267, 277))	('carcinomas of the tonsil', 'Phenotype', 'HP:0011110', (267, 291))	('carcinoma', 'Phenotype', 'HP:0030731', (267, 276))	('carcinomas', 'Phenotype', 'HP:0030731', (267, 277))	('carcinomas', 'Disease', (267, 277))	('glandular carcinomas', 'Phenotype', 'HP:0031493', (257, 277))
389813	31897242	Polymorphisms in the PVT1 Gene and Susceptibility to the Lung Cancer in a Chinese Northeast Population: a Case-control Study Background: Long non-coding RNA (lncRNA) PVT1 has been identified to be related to risk of a variety of cancers, such as gastric cancer, pancreatic cancer and follicular lymphoma.	('related', 'Reg', (197, 204))	('cancers', 'Disease', 'MESH:D009369', (229, 236))	('pancreatic cancer', 'Disease', (262, 279))	('gastric cancer', 'Disease', (246, 260))	('follicular lymphoma', 'Disease', 'MESH:D008224', (284, 303))	('PVT1', 'Gene', (166, 170))	('cancer', 'Phenotype', 'HP:0002664', (254, 260))	('PVT1', 'Gene', '5820', (166, 170))	('Lung Cancer', 'Disease', (57, 68))	('Polymorphisms', 'Var', (0, 13))	('PVT1', 'Gene', (21, 25))	('lymphoma', 'Phenotype', 'HP:0002665', (295, 303))	('gastric cancer', 'Disease', 'MESH:D013274', (246, 260))	('PVT1', 'Gene', '5820', (21, 25))	('follicular lymphoma', 'Disease', (284, 303))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (262, 279))	('cancers', 'Phenotype', 'HP:0002664', (229, 236))	('cancers', 'Disease', (229, 236))	('Cancer', 'Phenotype', 'HP:0002664', (62, 68))	('gastric cancer', 'Phenotype', 'HP:0012126', (246, 260))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('pancreatic cancer', 'Disease', 'MESH:D010190', (262, 279))	('Lung Cancer', 'Phenotype', 'HP:0100526', (57, 68))	('cancer', 'Phenotype', 'HP:0002664', (273, 279))
389816	31897242	Unconditional logistic regression analyses calculated the odds ratios (ORs) and their 95% confidence intervals (CIs) to assess the associations between polymorphisms of rs2608053, rs1561927, rs13254990 and susceptibility to lung cancer.	('lung cancer', 'Disease', 'MESH:D008175', (224, 235))	('rs13254990', 'Var', (191, 201))	('rs1561927', 'Var', (180, 189))	('rs13254990', 'DBSNP_MENTION', 'None', (191, 201))	('rs2608053', 'Var', (169, 178))	('associations', 'Interaction', (131, 143))	('lung cancer', 'Disease', (224, 235))	('lung cancer', 'Phenotype', 'HP:0100526', (224, 235))	('rs2608053', 'DBSNP_MENTION', 'None', (169, 178))	('rs1561927', 'DBSNP_MENTION', 'None', (180, 189))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))
389817	31897242	Results: There were no statistically significant associations between rs2608053 and rs1561927 polymorphisms in PVT1 and risk of lung cancer in the overall population.	('lung cancer', 'Disease', 'MESH:D008175', (128, 139))	('rs2608053', 'Var', (70, 79))	('rs1561927', 'Var', (84, 93))	('rs2608053', 'DBSNP_MENTION', 'None', (70, 79))	('lung cancer', 'Disease', (128, 139))	('PVT1', 'Gene', (111, 115))	('lung cancer', 'Phenotype', 'HP:0100526', (128, 139))	('rs1561927', 'DBSNP_MENTION', 'None', (84, 93))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
389818	31897242	The relationship between polymorphism rs13254990 in PVT1 gene and lung adenocarcinoma was significant.	('lung adenocarcinoma', 'Disease', (66, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('rs13254990', 'DBSNP_MENTION', 'None', (38, 48))	('rs13254990', 'Var', (38, 48))	('PVT1', 'Gene', (52, 56))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (66, 85))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (66, 85))
389822	31897242	Conclusion: The polymorphism rs13254990 in PVT1 gene is associated with the risk of lung adenocarcinoma in a Chinese northeast population.	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (84, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('rs13254990', 'Var', (29, 39))	('PVT1', 'Gene', (43, 47))	('rs13254990', 'DBSNP_MENTION', 'None', (29, 39))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (84, 103))	('associated', 'Reg', (56, 66))	('lung adenocarcinoma', 'Disease', (84, 103))
389831	31897242	Especially, the aberrant expression and mutations of lncRNAs are associated with tumorigenesis, metastasis and tumor stage.	('metastasis', 'CPA', (96, 106))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('lncRNAs', 'Gene', (53, 60))	('associated', 'Reg', (65, 75))	('tumor', 'Disease', (111, 116))	('mutations', 'Var', (40, 49))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Disease', (81, 86))	('aberrant expression', 'Var', (16, 35))
389836	31897242	PVT1 is involved in both physiological and pathological processes, in particular, the tumorigenesis in multifarious cancer, presenting the aberrant level of PVT1 in proliferation, angiogenesis and metastasis of human malignancy.	('angiogenesis', 'CPA', (180, 192))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('aberrant', 'Var', (139, 147))	('malignancy', 'Disease', 'MESH:D009369', (217, 227))	('multifarious cancer', 'Disease', 'MESH:D009369', (103, 122))	('tumor', 'Disease', (86, 91))	('malignancy', 'Disease', (217, 227))	('PVT1', 'Gene', (157, 161))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('metastasis', 'CPA', (197, 207))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('multifarious cancer', 'Disease', (103, 122))	('human', 'Species', '9606', (211, 216))	('proliferation', 'CPA', (165, 178))
389843	31897242	Therefore, we pay our attention to investigating whether PVT1 polymorphisms may be involved in the risk of lung cancer.	('PVT1', 'Gene', (57, 61))	('lung cancer', 'Disease', 'MESH:D008175', (107, 118))	('involved', 'Reg', (83, 91))	('polymorphisms', 'Var', (62, 75))	('lung cancer', 'Disease', (107, 118))	('lung cancer', 'Phenotype', 'HP:0100526', (107, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))
389844	31897242	Using high-throughput technologies, genome-wide association studies (GWAS) have shown evidence of more than one-third of single nucleotide polymorphisms (SNPs) lying within the lncRNAs, which may affect gene expression and function and consequently augment the risk of cancer.	('augment', 'NegReg', (249, 256))	('single nucleotide polymorphisms', 'Var', (121, 152))	('cancer', 'Phenotype', 'HP:0002664', (269, 275))	('gene expression', 'MPA', (203, 218))	('function', 'MPA', (223, 231))	('affect', 'Reg', (196, 202))	('cancer', 'Disease', (269, 275))	('cancer', 'Disease', 'MESH:D009369', (269, 275))
389845	31897242	Accumulating study demonstrated that PVT1 polymorphisms were associated with the risk of various kinds of malignant tumors such as Hodgkin lymphoma, pancreatic cancer, and follicular lymphoma.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (149, 166))	('PVT1', 'Gene', (37, 41))	('lymphoma', 'Phenotype', 'HP:0002665', (139, 147))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))	('malignant tumors', 'Disease', (106, 122))	('follicular lymphoma', 'Disease', 'MESH:D008224', (172, 191))	('follicular lymphoma', 'Disease', (172, 191))	('Hodgkin lymphoma', 'Disease', (131, 147))	('pancreatic cancer', 'Disease', 'MESH:D010190', (149, 166))	('polymorphisms', 'Var', (42, 55))	('malignant tumors', 'Disease', 'MESH:D009369', (106, 122))	('pancreatic cancer', 'Disease', (149, 166))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('Hodgkin lymphoma', 'Phenotype', 'HP:0012189', (131, 147))	('associated', 'Reg', (61, 71))	('lymphoma', 'Phenotype', 'HP:0002665', (183, 191))	('Hodgkin lymphoma', 'Disease', 'MESH:D006689', (131, 147))
389846	31897242	Moreover, the studies on the association between the SNPs in lncRNAs and the susceptibility of lung cancer were few so far.	('lung cancer', 'Disease', (95, 106))	('lung cancer', 'Phenotype', 'HP:0100526', (95, 106))	('SNPs', 'Var', (53, 57))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('lung cancer', 'Disease', 'MESH:D008175', (95, 106))
389851	31897242	Combining the previous studies of PVT1 polymorphisms on the risk of cancer, we selected three SNPs (rs2608053, rs1561927, rs13254990) to conduct the study ultimately.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('rs2608053', 'Var', (100, 109))	('rs1561927', 'Var', (111, 120))	('PVT1', 'Gene', (34, 38))	('rs13254990', 'Var', (122, 132))	('rs2608053', 'DBSNP_MENTION', 'None', (100, 109))	('rs1561927', 'DBSNP_MENTION', 'None', (111, 120))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('rs13254990', 'DBSNP_MENTION', 'None', (122, 132))	('cancer', 'Disease', (68, 74))
389854	31897242	Unconditional logistic regression analyses calculated the odds ratios (ORs) and their 95% confidence intervals (CIs) to evaluate the associations between SNP of rs2608053, rs1561927, rs13254990 and the risk of lung cancer and NSCLC.	('rs1561927', 'Var', (172, 181))	('rs13254990', 'DBSNP_MENTION', 'None', (183, 193))	('lung cancer', 'Disease', 'MESH:D008175', (210, 221))	('NSCLC', 'Disease', 'MESH:D002289', (226, 231))	('rs2608053', 'DBSNP_MENTION', 'None', (161, 170))	('rs1561927', 'DBSNP_MENTION', 'None', (172, 181))	('SCLC', 'Phenotype', 'HP:0030357', (227, 231))	('lung cancer', 'Disease', (210, 221))	('NSCLC', 'Phenotype', 'HP:0030358', (226, 231))	('lung cancer', 'Phenotype', 'HP:0100526', (210, 221))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('rs2608053', 'Var', (161, 170))	('associations', 'Interaction', (133, 145))	('NSCLC', 'Disease', (226, 231))	('rs13254990', 'Var', (183, 193))
389857	31897242	However, the smoking exposure was 48.0% in the patients, 23.7% in the controls, suggesting that the smoking exposure was a risk factor of lung cancer (P<0.001).Among control group, the genotype frequency distributions of three SNPs were in accordance with Hardy-Weinberg equilibrium (X2=0.131, P=0.72 for rs2608053; X2=0.559, P=0.455 for rs1561927; X2=0.003,P=0.955 for rs13254990) which indicated that the control we selected can represent the general population properly.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('lung cancer', 'Disease', 'MESH:D008175', (138, 149))	('rs1561927', 'Var', (338, 347))	('patients', 'Species', '9606', (47, 55))	('rs13254990', 'DBSNP_MENTION', 'None', (370, 380))	('rs13254990', 'Var', (370, 380))	('rs1561927', 'DBSNP_MENTION', 'None', (338, 347))	('rs2608053', 'Var', (305, 314))	('lung cancer', 'Disease', (138, 149))	('lung cancer', 'Phenotype', 'HP:0100526', (138, 149))	('rs2608053', 'DBSNP_MENTION', 'None', (305, 314))
389858	31897242	The unconditional logistic regression analysis was performed to reveal the association with three lncRNAs polymorphisms and the risk of lung cancer as well as NSCLC in Table 2.	('lung cancer', 'Phenotype', 'HP:0100526', (136, 147))	('polymorphisms', 'Var', (106, 119))	('NSCLC', 'Disease', (159, 164))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('NSCLC', 'Disease', 'MESH:D002289', (159, 164))	('lung cancer', 'Disease', 'MESH:D008175', (136, 147))	('lncRNAs', 'Gene', (98, 105))	('lung cancer', 'Disease', (136, 147))	('SCLC', 'Phenotype', 'HP:0030357', (160, 164))	('NSCLC', 'Phenotype', 'HP:0030358', (159, 164))	('association', 'Interaction', (75, 86))
389860	31897242	Similarly, rs1561927 and rs13254990 genetic variation was not significantly statistical significance in all models.	('rs1561927', 'DBSNP_MENTION', 'None', (11, 20))	('rs1561927', 'Var', (11, 20))	('rs13254990', 'DBSNP_MENTION', 'None', (25, 35))	('rs13254990', 'Var', (25, 35))
389863	31897242	To be precise, rs13254990 polymorphisms showed observably results in lung adenocarcinoma.	('results', 'Reg', (58, 65))	('lung adenocarcinoma', 'Disease', (69, 88))	('rs13254990', 'DBSNP_MENTION', 'None', (15, 25))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (69, 88))	('rs13254990', 'Var', (15, 25))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (69, 88))
389864	31897242	Composed with CC genotypes, the risk of lung adenocarcinoma was significantly increased in TT genotype carriers (adjusted OR=2.095, 95%CI=1.084-4.047, P=0.028).	('carriers', 'Var', (103, 111))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (40, 59))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (40, 59))	('carcinoma', 'Phenotype', 'HP:0030731', (50, 59))	('lung adenocarcinoma', 'Disease', (40, 59))	('increased', 'PosReg', (78, 87))
389866	31897242	Compared with the homozygous CC, the patients with the heterozygous CT had a lower risk of lung cancer in the non-smoking group of rs13254990 (adjusted OR=0.673, 95%CI=0.472-0.959, P=0.028).	('lower', 'NegReg', (77, 82))	('lung cancer', 'Phenotype', 'HP:0100526', (91, 102))	('patients', 'Species', '9606', (37, 45))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('rs13254990', 'DBSNP_MENTION', 'None', (131, 141))	('lung cancer', 'Disease', 'MESH:D008175', (91, 102))	('rs13254990', 'Var', (131, 141))	('lung cancer', 'Disease', (91, 102))
389870	31897242	For rs1561927, those carriers of AG and GG genotype with smoking exposure had a higher lung cancer risk by 7.108-fold and a higher NSCLC risk by 6.856-foldcompared with the carriers of AA with no smoking exposure (adjusted OR=7.108, 95%CI=2.363-21.376, P=0.000; adjusted OR=6.856, 95%CI=2.237-21.017, P=0.001).	('rs1561927', 'DBSNP_MENTION', 'None', (4, 13))	('lung cancer', 'Disease', 'MESH:D008175', (87, 98))	('NSCLC', 'Disease', (131, 136))	('SCLC', 'Phenotype', 'HP:0030357', (132, 136))	('lung cancer', 'Phenotype', 'HP:0100526', (87, 98))	('NSCLC', 'Disease', 'MESH:D002289', (131, 136))	('lung cancer', 'Disease', (87, 98))	('rs1561927', 'Var', (4, 13))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('higher', 'PosReg', (124, 130))	('NSCLC', 'Phenotype', 'HP:0030358', (131, 136))
389871	31897242	For rs2608053, the participants with both AG/AA genotype and smoking were possible to induce lung cancer and NSCLC compared with GG genotype with non-smoking exposure (adjusted OR=5.849, 95%CI=3.691-9.269, P=0.000; adjusted OR=5.472, 95%CI=3.418-8.762, P=0.000).	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('NSCLC', 'Disease', 'MESH:D002289', (109, 114))	('rs2608053', 'DBSNP_MENTION', 'None', (4, 13))	('participants', 'Species', '9606', (19, 31))	('SCLC', 'Phenotype', 'HP:0030357', (110, 114))	('lung cancer', 'Disease', 'MESH:D008175', (93, 104))	('induce', 'PosReg', (86, 92))	('NSCLC', 'Phenotype', 'HP:0030358', (109, 114))	('lung cancer', 'Disease', (93, 104))	('lung cancer', 'Phenotype', 'HP:0100526', (93, 104))	('rs2608053', 'Var', (4, 13))	('NSCLC', 'Disease', (109, 114))
389873	31897242	However, three measuring results of rs2608053, rs1561927 and rs13254990 were not statistically significant, which indicated that there was no additive interaction between gene-smoking factor of rs2608053, rs1561927 and rs13254990.	('rs13254990', 'Var', (61, 71))	('rs13254990', 'DBSNP_MENTION', 'None', (61, 71))	('rs1561927', 'Var', (205, 214))	('rs2608053', 'Var', (194, 203))	('rs13254990', 'Var', (219, 229))	('rs2608053', 'Var', (36, 45))	('rs1561927', 'Var', (47, 56))	('rs13254990', 'DBSNP_MENTION', 'None', (219, 229))	('rs2608053', 'DBSNP_MENTION', 'None', (194, 203))	('rs1561927', 'DBSNP_MENTION', 'None', (205, 214))	('rs2608053', 'DBSNP_MENTION', 'None', (36, 45))	('rs1561927', 'DBSNP_MENTION', 'None', (47, 56))
389877	31897242	This is the first study on the association between lncRNA PVT1 polymorphisms and the susceptibility of lung cancer.	('lung cancer', 'Disease', 'MESH:D008175', (103, 114))	('association', 'Interaction', (31, 42))	('polymorphisms', 'Var', (63, 76))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('lncRNA PVT1', 'Gene', (51, 62))	('lung cancer', 'Disease', (103, 114))	('lung cancer', 'Phenotype', 'HP:0100526', (103, 114))
389878	31897242	The homozygous variant genotype and recessive model of rs13254990 were considered to be related to prominent increase in the risk of lung adenocarcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (143, 152))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (133, 152))	('increase', 'PosReg', (109, 117))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (133, 152))	('lung adenocarcinoma', 'Disease', (133, 152))	('rs13254990', 'Var', (55, 65))	('rs13254990', 'DBSNP_MENTION', 'None', (55, 65))
389879	31897242	Additionally, the heterozygote CT genotype of rs13254990 decreased the susceptibility to lung cancer and NSCLC in nonsmokers.	('NSCLC', 'Disease', 'MESH:D002289', (105, 110))	('rs13254990', 'Var', (46, 56))	('rs13254990', 'DBSNP_MENTION', 'None', (46, 56))	('NSCLC', 'Phenotype', 'HP:0030358', (105, 110))	('lung cancer', 'Disease', (89, 100))	('lung cancer', 'Phenotype', 'HP:0100526', (89, 100))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('SCLC', 'Phenotype', 'HP:0030357', (106, 110))	('lung cancer', 'Disease', 'MESH:D008175', (89, 100))	('NSCLC', 'Disease', (105, 110))	('decreased', 'NegReg', (57, 66))
389886	31897242	PVT1-5 positively regulates posttranscriptional expression of SLC7A5 by sponging miR-126, resulting in the cell proliferation.	('miR-126', 'Gene', '406913', (81, 88))	('miR-126', 'Gene', (81, 88))	('SLC7A5', 'Gene', (62, 68))	('sponging', 'Var', (72, 80))	('cell proliferation', 'CPA', (107, 125))	('regulates', 'Reg', (18, 27))	('resulting in', 'Reg', (90, 102))	('SLC7A5', 'Gene', '8140', (62, 68))	('posttranscriptional expression', 'MPA', (28, 58))
389892	31897242	Consequently, we conducted our case-control study and stratified lung cancer into NSCLC, lung adenocarcinoma and lung squamous cell carcinoma to further analysis the association between PVT1 polymorphisms and lung cancer.	('lung cancer', 'Phenotype', 'HP:0100526', (209, 220))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (113, 141))	('lung cancer', 'Disease', 'MESH:D008175', (65, 76))	('lung squamous cell carcinoma', 'Disease', (113, 141))	('SCLC', 'Phenotype', 'HP:0030357', (83, 87))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (118, 141))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (89, 108))	('lung cancer', 'Phenotype', 'HP:0100526', (65, 76))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('lung adenocarcinoma', 'Disease', (89, 108))	('NSCLC', 'Disease', 'MESH:D002289', (82, 87))	('polymorphisms', 'Var', (191, 204))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('lung cancer', 'Disease', (209, 220))	('NSCLC', 'Disease', (82, 87))	('PVT1', 'Gene', (186, 190))	('NSCLC', 'Phenotype', 'HP:0030358', (82, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (89, 108))	('lung cancer', 'Disease', (65, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (113, 141))	('lung cancer', 'Disease', 'MESH:D008175', (209, 220))
389893	31897242	Emerging evidence of Genome-wide association study had demonstrated that SNPs located in PVT1 might be used as susceptibility factors to several cancers.	('cancers', 'Disease', (145, 152))	('cancers', 'Phenotype', 'HP:0002664', (145, 152))	('SNPs located', 'Var', (73, 85))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('PVT1', 'Gene', (89, 93))	('susceptibility', 'Reg', (111, 125))	('cancers', 'Disease', 'MESH:D009369', (145, 152))
389894	31897242	showed that PVT1 affected cell proliferation in breast cancer via increasing the GG genotype of rs13281615.	('rs13281615', 'DBSNP_MENTION', 'None', (96, 106))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('affected', 'Reg', (17, 25))	('breast cancer', 'Disease', 'MESH:D001943', (48, 61))	('breast cancer', 'Phenotype', 'HP:0003002', (48, 61))	('breast cancer', 'Disease', (48, 61))	('increasing', 'PosReg', (66, 76))	('cell proliferation', 'CPA', (26, 44))	('rs13281615', 'Var', (96, 106))
389895	31897242	Furthermore, PVT1 polymorphisms were regulated the prognosis of cancer, too.	('prognosis', 'CPA', (51, 60))	('PVT1', 'Gene', (13, 17))	('regulated', 'Reg', (37, 46))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('polymorphisms', 'Var', (18, 31))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
389896	31897242	illustrated that the presence of rs13281615 G > A polymorphism on PVT1 affected a favorable prognosis in colon cancer patients through modulating the activity of the PVT1/miR-146a/COX2 signaling pathway.	('COX2', 'Gene', '4513', (180, 184))	('miR-146a', 'Gene', (171, 179))	('colon cancer', 'Disease', 'MESH:D015179', (105, 117))	('affected', 'Reg', (71, 79))	('colon cancer', 'Disease', (105, 117))	('rs13281615', 'Var', (33, 43))	('rs13281615', 'DBSNP_MENTION', 'None', (33, 43))	('patients', 'Species', '9606', (118, 126))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('modulating', 'Reg', (135, 145))	('PVT1', 'Gene', (66, 70))	('miR-146a', 'Gene', '406938', (171, 179))	('presence', 'Var', (21, 29))	('COX2', 'Gene', (180, 184))	('colon cancer', 'Phenotype', 'HP:0003003', (105, 117))	('activity', 'MPA', (150, 158))
389897	31897242	conducted a genome-wide association study (GWAS) of 589 classical Hodgkin Lyphoma (cHL) patients and 5,199 free-controls and replication studies to identify predisposition loci of cHL, suggesting that rs2608053 might be associated with cHL (OR=1.20, 95%CI=1.12-1.28, P=1.16x10-7).	('Hodgkin Lyphoma', 'Disease', (66, 81))	('rs2608053', 'Var', (201, 210))	('associated', 'Reg', (220, 230))	('patients', 'Species', '9606', (88, 96))	('Hodgkin Lyphoma', 'Disease', 'MESH:D006689', (66, 81))	('Hodgkin Lyphoma', 'Phenotype', 'HP:0012189', (66, 81))	('rs2608053', 'DBSNP_MENTION', 'None', (201, 210))	('cHL', 'Disease', (236, 239))
389898	31897242	For rs1561927, it was identified as a risk locus for pancreatic cancer, which located at 455kb telomeric of PVT1, a nongenic region between PVT1 and LINC00977.	('rs1561927', 'DBSNP_MENTION', 'None', (4, 13))	('rs1561927', 'Var', (4, 13))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (53, 70))	('LINC00977', 'Gene', '728724', (149, 158))	('PVT1', 'Gene', (108, 112))	('pancreatic cancer', 'Disease', (53, 70))	('pancreatic cancer', 'Disease', 'MESH:D010190', (53, 70))	('LINC00977', 'Gene', (149, 158))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
389899	31897242	performed a case-control study and indicated that PVT1 rs1561927 G allele was significantly overrepresented in both pancreatic ductal adenocarcinoma (PDAC) cases and pancreatic neuroendocrine tumor (PNET) cases.	('PNET', 'Disease', 'MESH:D018358', (199, 203))	('pancreatic ductal adenocarcinoma', 'Disease', (116, 148))	('PDAC', 'Phenotype', 'HP:0006725', (150, 154))	('rs1561927', 'DBSNP_MENTION', 'None', (55, 64))	('PNET', 'Phenotype', 'HP:0030405', (199, 203))	('pancreatic neuroendocrine tumor', 'Disease', 'MESH:D018358', (166, 197))	('neuroendocrine tumor', 'Phenotype', 'HP:0100634', (177, 197))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (116, 148))	('PDAC', 'Disease', 'MESH:D021441', (150, 154))	('pancreatic neuroendocrine tumor', 'Disease', (166, 197))	('PDAC', 'Disease', (150, 154))	('PVT1', 'Gene', (50, 54))	('pancreatic neuroendocrine tumor', 'Phenotype', 'HP:0030405', (166, 197))	('overrepresented', 'PosReg', (92, 107))	('rs1561927', 'Var', (55, 64))	('carcinoma', 'Phenotype', 'HP:0030731', (139, 148))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (116, 148))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('PNET', 'Disease', (199, 203))
389900	31897242	revealed Follicular Lymphoma (FL) susceptibility loci rs13254990 by proceeding a large-scale two-stage GWAS in 4,523 patients and 13,344 controls of European ancestry.	('Follicular Lymphoma', 'Disease', 'MESH:D008224', (9, 28))	('Follicular Lymphoma', 'Disease', (9, 28))	('rs13254990', 'Var', (54, 64))	('rs13254990', 'DBSNP_MENTION', 'None', (54, 64))	('FL', 'Disease', 'MESH:D008224', (30, 32))	('patients', 'Species', '9606', (117, 125))	('Lymphoma', 'Phenotype', 'HP:0002665', (20, 28))
389902	31897242	In accordance with our study, we found that, as susceptibility loci, the polymorphisms of were associated with the risk of lung cancer in several stratified analysis.	('lung cancer', 'Disease', (123, 134))	('lung cancer', 'Phenotype', 'HP:0100526', (123, 134))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('polymorphisms', 'Var', (73, 86))	('lung cancer', 'Disease', 'MESH:D008175', (123, 134))	('associated', 'Reg', (95, 105))
389903	31897242	It was demonstrated in the analysis that rs13254990 polymorphism increased the risk of lung adenocarcinoma, but it decreased the risk of lung cancer and NCSLC susceptibility in nonsmokers.	('increased', 'PosReg', (65, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('lung adenocarcinoma', 'Disease', (87, 106))	('lung cancer', 'Disease', (137, 148))	('lung cancer', 'Phenotype', 'HP:0100526', (137, 148))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('decreased', 'NegReg', (115, 124))	('rs13254990', 'Var', (41, 51))	('lung cancer', 'Disease', 'MESH:D008175', (137, 148))	('rs13254990', 'DBSNP_MENTION', 'None', (41, 51))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (87, 106))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (87, 106))
389904	31897242	However, rs2608053 and rs1561927 polymorphisms were not related to the risk of lung cancer, which may due to different ethnicities and the lack of data about validate functional experiments.	('lung cancer', 'Disease', 'MESH:D008175', (79, 90))	('rs2608053', 'Var', (9, 18))	('lung cancer', 'Disease', (79, 90))	('rs1561927', 'Var', (23, 32))	('rs2608053', 'DBSNP_MENTION', 'None', (9, 18))	('lung cancer', 'Phenotype', 'HP:0100526', (79, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('rs1561927', 'DBSNP_MENTION', 'None', (23, 32))
389907	31897242	The polymorphism rs13254990 in PVT1 gene is associated with the risk of lung adenocarcinoma in a Chinese northeast population.	('associated', 'Reg', (44, 54))	('lung adenocarcinoma', 'Disease', (72, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (72, 91))	('rs13254990', 'Var', (17, 27))	('PVT1', 'Gene', (31, 35))	('rs13254990', 'DBSNP_MENTION', 'None', (17, 27))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (72, 91))
389908	31897242	LncRNA long non-coding RNA PVT1 plasmacytoma variant translocation 1 SNP single nucleotide polymorphism NSCLC non-small cell lung cancer AD lung adenocarcinoma SQ lung squamous cell carcinoma SCLC small cell lung cancer HWE Hardy-Weinberg equilibrium 95% CI 95% confidence interval OR odds ratio Real-Time PCR real-time polymerase chain reaction GWAS genome-wide association study	('NSCLC', 'Disease', (104, 109))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (110, 136))	('plasmacytoma', 'Phenotype', 'HP:0011857', (32, 44))	('plasmacytoma', 'Disease', (32, 44))	('NSCLC', 'Phenotype', 'HP:0030358', (104, 109))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (114, 136))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (140, 159))	('small cell lung cancer', 'Disease', 'MESH:D055752', (197, 219))	('carcinoma', 'Phenotype', 'HP:0030731', (150, 159))	('SCLC', 'Phenotype', 'HP:0030357', (105, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (182, 191))	('SCLC', 'Phenotype', 'HP:0030357', (192, 196))	('small cell lung cancer', 'Disease', (197, 219))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (110, 136))	('lung cancer', 'Phenotype', 'HP:0100526', (208, 219))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (163, 191))	('SQ', 'Phenotype', 'HP:0002860', (160, 162))	('AD', 'Disease', 'MESH:D000230', (137, 139))	('SCLC', 'Gene', '7864', (105, 109))	('SCLC', 'Gene', (105, 109))	('variant', 'Var', (45, 52))	('SCLC', 'Gene', '7864', (192, 196))	('SCLC', 'Gene', (192, 196))	('non-small cell lung cancer', 'Disease', (110, 136))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (140, 159))	('small cell lung cancer', 'Disease', 'MESH:D055752', (114, 136))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (197, 219))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (163, 191))	('AD', 'Disease', (137, 139))	('lung adenocarcinoma', 'Disease', (140, 159))	('NSCLC', 'Disease', 'MESH:D002289', (104, 109))	('plasmacytoma', 'Disease', 'MESH:D010954', (32, 44))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('lung squamous cell carcinoma', 'Disease', (163, 191))	('lung cancer', 'Phenotype', 'HP:0100526', (125, 136))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (168, 191))
390000	30045295	P53 gene mutation or over expression is considered as an indicator of poor prognosis in some malignancies.	('over expression', 'PosReg', (21, 36))	('gene mutation', 'Var', (4, 17))	('malignancies', 'Disease', 'MESH:D009369', (93, 105))	('P53', 'Gene', (0, 3))	('P53', 'Gene', '7157', (0, 3))	('malignancies', 'Disease', (93, 105))
390004	30045295	It had been reported that 57.1% of pulmonary SCC had mutations in exon 5 to 8 of the p53 gene, which might be related to the over-expression of p53 in pulmonary SCC.	('SCC', 'Gene', (161, 164))	('SCC', 'Gene', (45, 48))	('p53', 'Gene', '7157', (144, 147))	('SCC', 'Phenotype', 'HP:0030357', (161, 164))	('SCC', 'Gene', '6317', (161, 164))	('mutations in', 'Var', (53, 65))	('over-expression', 'PosReg', (125, 140))	('SCC', 'Gene', '6317', (45, 48))	('SCC', 'Phenotype', 'HP:0030357', (45, 48))	('p53', 'Gene', (85, 88))	('p53', 'Gene', '7157', (85, 88))	('p53', 'Gene', (144, 147))
390018	27144064	Alterations in genes other than EGFR/ALK/ROS1 in non-small cell lung cancer: trials and treatment options During the last decade, we have seen tremendous progress in the therapy of lung cancer.	('lung cancer', 'Phenotype', 'HP:0100526', (64, 75))	('ALK', 'Gene', (37, 40))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (53, 75))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (49, 75))	('Alterations', 'Var', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('ROS1', 'Gene', (41, 45))	('lung cancer', 'Disease', (181, 192))	('EGFR', 'Gene', '1956', (32, 36))	('lung cancer', 'Phenotype', 'HP:0100526', (181, 192))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('ROS1', 'Gene', '6098', (41, 45))	('lung cancer', 'Disease', 'MESH:D008175', (64, 75))	('ALK', 'Gene', '238', (37, 40))	('EGFR', 'Gene', (32, 36))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (49, 75))	('non-small cell lung cancer', 'Disease', (49, 75))	('lung cancer', 'Disease', 'MESH:D008175', (181, 192))
390019	27144064	Discovery of actionable mutations in EGFR and translocations in ALK and ROS1 have identified subsets of patients with excellent tumor response to oral targeted agents with manageable side effects.	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('ALK', 'Gene', (64, 67))	('translocations', 'Var', (46, 60))	('ROS1', 'Gene', '6098', (72, 76))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('EGFR', 'Gene', '1956', (37, 41))	('ROS1', 'Gene', (72, 76))	('tumor', 'Disease', (128, 133))	('ALK', 'Gene', '238', (64, 67))	('mutations', 'Var', (24, 33))	('EGFR', 'Gene', (37, 41))	('patients', 'Species', '9606', (104, 112))
390020	27144064	In this review, we highlight treatment options including corresponding clinical trials for oncogenic alterations affecting the receptor tyrosine kinases MET, FGFR, NTRK, RET, HER2, HER3, and HER4 as well as components of the RAS-RAF-MEK signaling pathway.	('alterations', 'Var', (101, 112))	('HER2', 'Gene', '2064', (175, 179))	('HER3', 'Gene', '2065', (181, 185))	('MET', 'Gene', (153, 156))	('NTRK', 'Gene', '4914;4915;4916', (164, 168))	('RET', 'Gene', (170, 173))	('MEK', 'Gene', '5609', (233, 236))	('FGFR', 'Gene', (158, 162))	('RAF', 'Gene', '22882', (229, 232))	('HER4', 'Gene', (191, 195))	('receptor tyrosine kinase', 'Gene', '5979', (127, 151))	('MEK', 'Gene', (233, 236))	('HER2', 'Gene', (175, 179))	('RAF', 'Gene', (229, 232))	('HER3', 'Gene', (181, 185))	('receptor tyrosine kinase', 'Gene', (127, 151))	('RET', 'Gene', '5979', (170, 173))	('NTRK', 'Gene', (164, 168))	('HER4', 'Gene', '2066', (191, 195))
390024	27144064	Adenocarcinoma of the lung is the commonest type of lung cancer with studies showing actionable mutations in as many as 64% of these patients.	('lung cancer', 'Disease', 'MESH:D008175', (52, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (5, 14))	('Adenocarcinoma of the lung', 'Disease', (0, 26))	('patients', 'Species', '9606', (133, 141))	('lung cancer', 'Disease', (52, 63))	('lung cancer', 'Phenotype', 'HP:0100526', (52, 63))	('Adenocarcinoma of the lung', 'Disease', 'MESH:D000077192', (0, 26))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('mutations', 'Var', (96, 105))
390026	27144064	In this article, we describe the various actionable genetic alterations in non-small cell lung cancer (NSCLC) other than EGFR, ALK, and ROS1 and delineate the clinical trials and treatment options associated with these pathways.	('genetic alterations', 'Var', (52, 71))	('EGFR', 'Gene', '1956', (121, 125))	('ROS1', 'Gene', (136, 140))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (75, 101))	('NSCLC', 'Disease', (103, 108))	('ROS1', 'Gene', '6098', (136, 140))	('non-small cell lung cancer', 'Disease', (75, 101))	('EGFR', 'Gene', (121, 125))	('NSCLC', 'Disease', 'MESH:D002289', (103, 108))	('ALK', 'Gene', (127, 130))	('lung cancer', 'Phenotype', 'HP:0100526', (90, 101))	('NSCLC', 'Phenotype', 'HP:0030358', (103, 108))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (79, 101))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (75, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('ALK', 'Gene', '238', (127, 130))
390027	27144064	A systematic analysis of literature was performed by using a Mesh (Medical subject headings) search in PubMed using the term NSCLC or with any of the following words: oncogenes, receptor tyrosine kinase, mutation, amplification, copy number, translocation, and inhibitor.	('mutation', 'Var', (204, 212))	('receptor tyrosine kinase', 'Gene', '5979', (178, 202))	('copy number', 'Var', (229, 240))	('NSCLC', 'Disease', (125, 130))	('amplification', 'Var', (214, 227))	('NSCLC', 'Disease', 'MESH:D002289', (125, 130))	('translocation', 'Var', (242, 255))	('NSCLC', 'Phenotype', 'HP:0030358', (125, 130))	('receptor tyrosine kinase', 'Gene', (178, 202))
390028	27144064	Candidate alterations were rated and chosen based on clinical relevance in terms of available therapeutic agents, reported clinical outcomes and applicable findings in other malignancies.	('malignancies', 'Disease', (174, 186))	('alterations', 'Var', (10, 21))	('malignancies', 'Disease', 'MESH:D009369', (174, 186))
390032	27144064	Mutations usually occur in codons 12, 13 and less commonly in codon 61, leading to constitutive activation of multiple signaling pathways including MAPK, PI3K/mTOR and RALGDS pathways.	('MAPK', 'Pathway', (148, 152))	('mTOR', 'Gene', (159, 163))	('mTOR', 'Gene', '2475', (159, 163))	('Mutations', 'Var', (0, 9))	('RALGDS', 'Gene', (168, 174))	('RALGDS', 'Gene', '5900', (168, 174))	('activation', 'PosReg', (96, 106))
390033	27144064	NRAS alterations have also been recently discovered in NSCLC, present in <1% of cases, predominantly in lung adenocarcinomas.	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (104, 124))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (104, 124))	('NSCLC', 'Disease', (55, 60))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('carcinomas', 'Phenotype', 'HP:0030731', (114, 124))	('NSCLC', 'Disease', 'MESH:D002289', (55, 60))	('alterations', 'Var', (5, 16))	('NRAS', 'Gene', (0, 4))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (104, 123))	('NSCLC', 'Phenotype', 'HP:0030358', (55, 60))	('NRAS', 'Gene', '4893', (0, 4))	('lung adenocarcinomas', 'Disease', (104, 124))
390034	27144064	Of interest is that while majority of patients with NRAS mutations were former or current smokers, the frequency of smoking-related transversion mutations were significantly less frequent compared to KRAS mutant NSCLC.	('NRAS', 'Gene', (52, 56))	('NSCLC', 'Disease', 'MESH:D002289', (212, 217))	('KRAS', 'Gene', (200, 204))	('NRAS', 'Gene', '4893', (52, 56))	('NSCLC', 'Phenotype', 'HP:0030358', (212, 217))	('KRAS', 'Gene', '3845', (200, 204))	('mutations', 'Var', (57, 66))	('less', 'NegReg', (174, 178))	('patients', 'Species', '9606', (38, 46))	('NSCLC', 'Disease', (212, 217))
390035	27144064	Analysis of TCGA database show that HRAS alterations are similarly clustered in codons 12, 13 and 61 but in comparison to KRAS and NRAS, appear to occur in slightly higher frequency in the squamous cell subtype (<3%) compared to adenocarcinoma subtype in NSCLC (<1%).	('squamous cell subtype', 'Disease', (189, 210))	('adenocarcinoma subtype', 'Disease', (229, 251))	('NSCLC', 'Disease', (255, 260))	('KRAS', 'Gene', '3845', (122, 126))	('adenocarcinoma subtype', 'Disease', 'MESH:D000230', (229, 251))	('NRAS', 'Gene', (131, 135))	('NSCLC', 'Disease', 'MESH:D002289', (255, 260))	('HRAS', 'Gene', '3265', (36, 40))	('NRAS', 'Gene', '4893', (131, 135))	('HRAS', 'Gene', (36, 40))	('carcinoma', 'Phenotype', 'HP:0030731', (234, 243))	('NSCLC', 'Phenotype', 'HP:0030358', (255, 260))	('KRAS', 'Gene', (122, 126))	('alterations', 'Var', (41, 52))
390037	27144064	While recent research efforts, as exemplified by the development of allosteric inhibitors of KRAS, are gaining momentum, these agents are not yet clinically available and have yet to demonstrate in vivo efficacy.	('KRAS', 'Gene', (93, 97))	('allosteric', 'Var', (68, 78))	('KRAS', 'Gene', '3845', (93, 97))
390039	27144064	MEK inhibitors demonstrated antitumor efficacy in early preclinical studies in both KRAS and NRAS mutants and have thus been most investigated in the clinical setting at this time.	('MEK', 'Gene', (0, 3))	('MEK', 'Gene', '5609', (0, 3))	('NRAS', 'Gene', '4893', (93, 97))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('KRAS', 'Gene', (84, 88))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('KRAS', 'Gene', '3845', (84, 88))	('mutants', 'Var', (98, 105))	('tumor', 'Disease', (32, 37))	('NRAS', 'Gene', (93, 97))
390040	27144064	Selumetinib, a MEK inhibitor in combination with docetaxel has shown increased response rate and progression-free survival (PFS) in KRAS mutant patients but did not meet the primary end point of overall survival(OS).	('KRAS', 'Gene', (132, 136))	('increased', 'PosReg', (69, 78))	('KRAS', 'Gene', '3845', (132, 136))	('docetaxel', 'Chemical', 'MESH:D000077143', (49, 58))	('patients', 'Species', '9606', (144, 152))	('progression-free survival', 'CPA', (97, 122))	('Selumetinib', 'Chemical', 'MESH:C517975', (0, 11))	('MEK', 'Gene', (15, 18))	('MEK', 'Gene', '5609', (15, 18))	('OS', 'Chemical', 'MESH:D009992', (212, 214))	('response rate', 'CPA', (79, 92))	('mutant', 'Var', (137, 143))
390041	27144064	Recent studies have shown that co-existing alterations such as in p53, STK 11 or CDKN2A/B may not only impact prognosis but also modify responses to therapy which provides an explanation for the variability in clinical outcomes and response to therapy.	('p53', 'Gene', '7157', (66, 69))	('modify', 'Reg', (129, 135))	('CDKN2A/B', 'Gene', '1029;1030', (81, 89))	('prognosis', 'MPA', (110, 119))	('impact', 'Reg', (103, 109))	('responses to therapy', 'MPA', (136, 156))	('alterations', 'Var', (43, 54))	('STK 11', 'Gene', '6794', (71, 77))	('STK 11', 'Gene', (71, 77))	('CDKN2A/B', 'Gene', (81, 89))	('p53', 'Gene', (66, 69))
390045	27144064	Other agents with recently reported clinical trial data in the last quarter of 2015 include the evaluation of the focal adhesion kinase inhibitor defactinib based on preclinical experiments demonstrating potent antitumor activity of this agent when KRAS mutation co-occurs with loss of p53 or INK4/p16.	('p16', 'Gene', (298, 301))	('defactinib', 'Chemical', 'MESH:C584510', (146, 156))	('loss', 'Var', (278, 282))	('KRAS', 'Gene', (249, 253))	('p53', 'Gene', (286, 289))	('tumor', 'Disease', 'MESH:D009369', (215, 220))	('p53', 'Gene', '7157', (286, 289))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('p16', 'Gene', '1029', (298, 301))	('INK4', 'Gene', '1029', (293, 297))	('INK4', 'Gene', (293, 297))	('KRAS', 'Gene', '3845', (249, 253))	('tumor', 'Disease', (215, 220))
390046	27144064	Interim results from a phase 2 Simon two-stage study enrolling KRAS mutant NSCLC (regardless of co-mutation status) showed that median PFS was 11.7 weeks, with approximately 25% of patients demonstrating some degree of tumor shrinkage although partial response (PR) rate by RECIST was technically only 10% in the 42 evaluable patients.	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('KRAS', 'Gene', '3845', (63, 67))	('tumor', 'Disease', (219, 224))	('NSCLC', 'Phenotype', 'HP:0030358', (75, 80))	('patients', 'Species', '9606', (326, 334))	('patients', 'Species', '9606', (181, 189))	('NSCLC', 'Disease', (75, 80))	('NSCLC', 'Disease', 'MESH:D002289', (75, 80))	('tumor', 'Disease', 'MESH:D009369', (219, 224))	('mutant', 'Var', (68, 74))	('shrinkage', 'NegReg', (225, 234))	('KRAS', 'Gene', (63, 67))
390047	27144064	There did not appear to be correlation between drug efficacy and co-mutation status of INK4/p16 or p53.	('p53', 'Gene', (99, 102))	('p16', 'Gene', (92, 95))	('co-mutation status', 'Var', (65, 83))	('INK4', 'Gene', '1029', (87, 91))	('INK4', 'Gene', (87, 91))	('p16', 'Gene', '1029', (92, 95))	('p53', 'Gene', '7157', (99, 102))
390048	27144064	Lastly, while the HSP90 inhibitor ganetespib showed cytotoxic activity in combination with MEK inhibitors in several KRAS mutant lung cancer cell lines, its further clinical development in non-ALK translocation NSCLC is uncertain with the termination of the phase 3 GALAXY-2 trial in late October 2015 due to futility in demonstrating OS improvement with the combination of ganetespib to docetaxel as second-line therapy in NSCLC compared to docetaxel alone.	('KRAS', 'Gene', (117, 121))	('HSP90', 'Gene', '3320', (18, 23))	('lung cancer', 'Disease', 'MESH:D008175', (129, 140))	('OS', 'Chemical', 'MESH:D009992', (335, 337))	('MEK', 'Gene', '5609', (91, 94))	('lung cancer', 'Phenotype', 'HP:0100526', (129, 140))	('ALK', 'Gene', '238', (193, 196))	('NSCLC', 'Disease', 'MESH:D002289', (424, 429))	('MEK', 'Gene', (91, 94))	('NSCLC', 'Disease', 'MESH:D002289', (211, 216))	('ALK', 'Gene', (193, 196))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('docetaxel', 'Chemical', 'MESH:D000077143', (388, 397))	('NSCLC', 'Disease', (424, 429))	('NSCLC', 'Disease', (211, 216))	('docetaxel', 'Chemical', 'MESH:D000077143', (442, 451))	('lung cancer', 'Disease', (129, 140))	('NSCLC', 'Phenotype', 'HP:0030358', (424, 429))	('NSCLC', 'Phenotype', 'HP:0030358', (211, 216))	('KRAS', 'Gene', '3845', (117, 121))	('HSP90', 'Gene', (18, 23))	('mutant', 'Var', (122, 128))
390051	27144064	Mutations in BRAF are reported in 4.9% of lung adenocarcinomas and 5%-20% of BRAF mutations are found concurrently with EGFR mutations.	('carcinoma', 'Phenotype', 'HP:0030731', (52, 61))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (42, 62))	('carcinomas', 'Phenotype', 'HP:0030731', (52, 62))	('BRAF', 'Gene', '673', (13, 17))	('BRAF', 'Gene', '673', (77, 81))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (42, 62))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (42, 61))	('BRAF', 'Gene', (77, 81))	('BRAF', 'Gene', (13, 17))	('Mutations', 'Var', (0, 9))	('mutations', 'Var', (82, 91))	('EGFR', 'Gene', '1956', (120, 124))	('lung adenocarcinomas', 'Disease', (42, 62))	('reported', 'Reg', (22, 30))	('EGFR', 'Gene', (120, 124))
390052	27144064	V600E is the most frequent mutation found in 50%-60% of NSCLC patients.	('NSCLC', 'Disease', (56, 61))	('NSCLC', 'Disease', 'MESH:D002289', (56, 61))	('V600E', 'Mutation', 'rs113488022', (0, 5))	('patients', 'Species', '9606', (62, 70))	('NSCLC', 'Phenotype', 'HP:0030358', (56, 61))	('V600E', 'Var', (0, 5))
390054	27144064	Vemurafenib and dabrafenib are two commercially available BRAF inhibitors, approved by the FDA for melanoma, with higher selectivity for the mutant activated V600E kinase relative to wildtype BRAF and CRAF.	('V600E', 'Var', (158, 163))	('mutant', 'Var', (141, 147))	('dabrafenib', 'Chemical', 'MESH:C561627', (16, 26))	('BRAF', 'Gene', '673', (192, 196))	('CRAF', 'Gene', (201, 205))	('Vemurafenib', 'Chemical', 'MESH:D000077484', (0, 11))	('BRAF', 'Gene', (192, 196))	('V600E', 'Mutation', 'rs113488022', (158, 163))	('CRAF', 'Gene', '5894', (201, 205))	('melanoma', 'Phenotype', 'HP:0002861', (99, 107))	('melanoma', 'Disease', (99, 107))	('BRAF', 'Gene', '673', (58, 62))	('melanoma', 'Disease', 'MESH:D008545', (99, 107))	('BRAF', 'Gene', (58, 62))
390056	27144064	In a phase 2 study of dabrafenib administered 150 mg twice daily in patients with BRAF V600E mutant advanced NSCLC, the predominant histology of patients enrolled was adenocarcinoma.	('patients', 'Species', '9606', (145, 153))	('NSCLC', 'Disease', 'MESH:D002289', (109, 114))	('V600E mutant', 'Var', (87, 99))	('BRAF', 'Gene', '673', (82, 86))	('dabrafenib', 'Chemical', 'MESH:C561627', (22, 32))	('adenocarcinoma', 'Disease', 'MESH:D000230', (167, 181))	('BRAF', 'Gene', (82, 86))	('patients', 'Species', '9606', (68, 76))	('NSCLC', 'Phenotype', 'HP:0030358', (109, 114))	('V600E', 'Mutation', 'rs113488022', (87, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (172, 181))	('NSCLC', 'Disease', (109, 114))	('adenocarcinoma', 'Disease', (167, 181))
390061	27144064	However, 40%-50% of BRAF mutations in NSCLC are non-V600 alterations where, in contradistinction with the increased kinase activity of the V600 alteration, many of these mutations may have impaired kinase function (e.g.	('NSCLC', 'Disease', (38, 43))	('mutations', 'Var', (25, 34))	('NSCLC', 'Disease', 'MESH:D002289', (38, 43))	('mutations', 'Var', (170, 179))	('BRAF', 'Gene', '673', (20, 24))	('NSCLC', 'Phenotype', 'HP:0030358', (38, 43))	('impaired', 'NegReg', (189, 197))	('BRAF', 'Gene', (20, 24))	('kinase function', 'MPA', (198, 213))
390062	27144064	D594A, G466V) that nonetheless still retain oncogenic activity either through transactivating the catalytically competent RAS or CRAF by facilitating dimerization or through abrogation of autoinhibition thus leading to constitutive kinase activity.	('abrogation', 'NegReg', (174, 184))	('catalytically', 'MPA', (98, 111))	('leading to', 'Reg', (208, 218))	('G466V', 'Var', (7, 12))	('G466V', 'Mutation', 'p.G466V', (7, 12))	('constitutive kinase activity', 'MPA', (219, 247))	('RAS', 'Protein', (122, 125))	('facilitating', 'PosReg', (137, 149))	('autoinhibition', 'MPA', (188, 202))	('transactivating', 'PosReg', (78, 93))	('D594A', 'Mutation', 'p.D594A', (0, 5))	('CRAF', 'Gene', (129, 133))	('dimerization', 'MPA', (150, 162))	('CRAF', 'Gene', '5894', (129, 133))	('D594A', 'Var', (0, 5))	('oncogenic', 'CPA', (44, 53))
390063	27144064	Due to the low frequency of these mutations, efficacy of first-generation BRAF mutant selective inhibitors is mostly characterized in preclinical models with non-V600 mutants (e.g.	('BRAF', 'Gene', (74, 78))	('BRAF', 'Gene', '673', (74, 78))	('mutations', 'Var', (34, 43))
390065	27144064	drug resistance with G469L mutation) specifically in NSCLC or in a different tumor type (e.g.	('NSCLC', 'Phenotype', 'HP:0030358', (53, 58))	('drug resistance', 'Phenotype', 'HP:0020174', (0, 15))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('G469L', 'Var', (21, 26))	('NSCLC', 'Disease', (53, 58))	('G469L', 'Mutation', 'rs1057519720', (21, 26))	('tumor', 'Disease', (77, 82))	('NSCLC', 'Disease', 'MESH:D002289', (53, 58))
390066	27144064	L597 mutation in melanoma sensitive to vemurafenib but this mutation has not been described to date in NSCLC).	('NSCLC', 'Disease', (103, 108))	('L597 mutation', 'Var', (0, 13))	('NSCLC', 'Disease', 'MESH:D002289', (103, 108))	('melanoma', 'Phenotype', 'HP:0002861', (17, 25))	('melanoma', 'Disease', (17, 25))	('NSCLC', 'Phenotype', 'HP:0030358', (103, 108))	('melanoma', 'Disease', 'MESH:D008545', (17, 25))	('vemurafenib', 'Chemical', 'MESH:D000077484', (39, 50))
390067	27144064	Although MEK inhibitors have demonstrated activity against some of these non-V600 alterations in the clinic in melanoma patients, clinical experience in NSCLC is sparse to date.	('melanoma', 'Disease', 'MESH:D008545', (111, 119))	('NSCLC', 'Phenotype', 'HP:0030358', (153, 158))	('melanoma', 'Phenotype', 'HP:0002861', (111, 119))	('melanoma', 'Disease', (111, 119))	('non-V600 alterations', 'Var', (73, 93))	('NSCLC', 'Disease', (153, 158))	('patients', 'Species', '9606', (120, 128))	('NSCLC', 'Disease', 'MESH:D002289', (153, 158))	('MEK', 'Gene', (9, 12))	('MEK', 'Gene', '5609', (9, 12))
390068	27144064	There is also limited evidence that dasatinib may have clinical activity in NSCLC against kinase-inactivating BRAF mutations, i.e.	('mutations', 'Var', (115, 124))	('NSCLC', 'Disease', (76, 81))	('NSCLC', 'Disease', 'MESH:D002289', (76, 81))	('BRAF', 'Gene', '673', (110, 114))	('BRAF', 'Gene', (110, 114))	('NSCLC', 'Phenotype', 'HP:0030358', (76, 81))	('dasatinib', 'Chemical', 'MESH:D000069439', (36, 45))
390071	27144064	Such deletion mutants are resistant to vemurafenib but sensitive to the RAF dimer inhibitor, LY3009120.	('deletion mutants', 'Var', (5, 21))	('LY3009120', 'Chemical', 'MESH:C000600963', (93, 102))	('RAF', 'Gene', (72, 75))	('RAF', 'Gene', '22882', (72, 75))	('vemurafenib', 'Chemical', 'MESH:D000077484', (39, 50))
390074	27144064	It represents 0.5% of BRAF alterations and clinical response to the multikinase inhibitor regorafenib was documented in a case report.	('BRAF', 'Gene', (22, 26))	('BRAF', 'Gene', '673', (22, 26))	('regorafenib', 'Chemical', 'MESH:C559147', (90, 101))	('alterations', 'Var', (27, 38))
390076	27144064	ARAF and CRAF mutations are found in less than 1%-2% of NSCLC.	('CRAF', 'Gene', '5894', (9, 13))	('NSCLC', 'Disease', (56, 61))	('CRAF', 'Gene', (9, 13))	('NSCLC', 'Disease', 'MESH:D002289', (56, 61))	('ARAF', 'Gene', '369', (0, 4))	('ARAF', 'Gene', (0, 4))	('mutations', 'Var', (14, 23))	('NSCLC', 'Phenotype', 'HP:0030358', (56, 61))
390077	27144064	The ARAF somatic mutation S214C had been described to be oncogenic and thought to be the driver mutation underlying clinical response to sorafenib in a patient with lung adenocarcinoma.	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (165, 184))	('ARAF', 'Gene', '369', (4, 8))	('S214C', 'Var', (26, 31))	('S214C', 'Mutation', 'rs1057519786', (26, 31))	('ARAF', 'Gene', (4, 8))	('sorafenib', 'Chemical', 'MESH:D000077157', (137, 146))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (165, 184))	('carcinoma', 'Phenotype', 'HP:0030731', (175, 184))	('patient', 'Species', '9606', (152, 159))	('lung adenocarcinoma', 'Disease', (165, 184))
390078	27144064	The CRAF somatic mutations S257 and S259 have also been described in lung cancer specimens.	('described', 'Reg', (56, 65))	('S259', 'Var', (36, 40))	('CRAF', 'Gene', (4, 8))	('lung cancer', 'Disease', 'MESH:D008175', (69, 80))	('CRAF', 'Gene', '5894', (4, 8))	('S257', 'Var', (27, 31))	('lung cancer', 'Disease', (69, 80))	('lung cancer', 'Phenotype', 'HP:0100526', (69, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
390080	27144064	Both these specific ARAF and CRAF mutations are thought to abrogate negative regulation of RAF1 activation as they are located in the CR2 domain that negatively regulates RAF1 activation.	('abrogate', 'NegReg', (59, 67))	('RAF1', 'Gene', (91, 95))	('regulates', 'Reg', (161, 170))	('activation', 'MPA', (176, 186))	('RAF1', 'Gene', '5894', (91, 95))	('CRAF', 'Gene', (29, 33))	('RAF1', 'Gene', (171, 175))	('RAF1', 'Gene', '5894', (171, 175))	('ARAF', 'Gene', '369', (20, 24))	('negatively', 'NegReg', (150, 160))	('ARAF', 'Gene', (20, 24))	('negative regulation', 'MPA', (68, 87))	('CRAF', 'Gene', '5894', (29, 33))	('CR2', 'Species', '2498238', (134, 137))	('mutations', 'Var', (34, 43))
390083	27144064	The most common mutation is K57N (approximately 60%) followed by Q56P (20%).	('K57N', 'Var', (28, 32))	('K57N', 'Mutation', 'rs869025608', (28, 32))	('Q56P', 'Var', (65, 69))	('Q56P', 'Mutation', 'rs1057519729', (65, 69))
390088	27144064	Aberrations in the HGF/MET signaling pathway occur through a variety of mechanisms including MET amplification, gene rearrangements, and mutations or through HGF or MET overexpression.	('HGF', 'Gene', (19, 22))	('HGF', 'Gene', (158, 161))	('HGF', 'Gene', '3082', (19, 22))	('HGF', 'Gene', '3082', (158, 161))	('MET amplification', 'Var', (93, 110))	('mutations', 'Var', (137, 146))	('gene rearrangements', 'Var', (112, 131))	('overexpression', 'PosReg', (169, 183))
390092	27144064	evaluating the oral multikinase ALK and MET inhibitor crizotinib showed that when MET high amplification is defined as a MET/centromere ratio of >5, a higher response rate of 50% was seen compared to response rates in patients with lower ratio.	('ALK', 'Gene', (32, 35))	('patients', 'Species', '9606', (218, 226))	('crizotinib', 'Chemical', 'MESH:D000077547', (54, 64))	('ALK', 'Gene', '238', (32, 35))	('MET high amplification', 'Var', (82, 104))
390093	27144064	MET exon 14 skipping mutations occur in about 3% of lung adenocarcinoma and tumors harboring them respond significantly to anti-MET targeted therapy as the splice site alteration renders it less susceptible to ubiquitination and subsequent protein degradation.	('less', 'NegReg', (190, 194))	('protein degradation', 'MPA', (240, 259))	('MET exon 14', 'Gene', (0, 11))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (52, 71))	('skipping mutations', 'Var', (12, 30))	('susceptible to ubiquitination', 'MPA', (195, 224))	('lung adenocarcinoma and tumors', 'Disease', 'MESH:D000077192', (52, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (62, 71))
390094	27144064	reported that MET exon 14 skipping alterations were present in 22% of pulmonary sarcomatoid carcinoma and could be used as a potential target for therapy.	('MET exon', 'Var', (14, 22))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('skipping alterations', 'Var', (26, 46))	('sarcomatoid carcinoma', 'Phenotype', 'HP:0100242', (80, 101))	('pulmonary sarcomatoid carcinoma', 'Disease', (70, 101))	('pulmonary sarcomatoid carcinoma', 'Disease', 'MESH:C538614', (70, 101))
390098	27144064	The FGFR signaling pathway is constitutively activated by point mutations, gene amplification and chromosomal translocations leading to altered cell proliferation, angiogenesis, cell migration and tumorigenesis.	('cell migration', 'CPA', (178, 192))	('cell proliferation', 'CPA', (144, 162))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('chromosomal translocations', 'Var', (98, 124))	('point mutations', 'Var', (58, 73))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('angiogenesis', 'CPA', (164, 176))	('FGFR signaling pathway', 'Pathway', (4, 26))	('altered', 'Reg', (136, 143))	('activated', 'PosReg', (45, 54))	('tumor', 'Disease', (197, 202))	('gene amplification', 'Var', (75, 93))
390100	27144064	Focal amplification of FGFR1 is predominantly found in squamous cell lung cancer (21%-22%) and less frequently in adenocarcinoma of lung (around 3%).	('Focal amplification', 'Var', (0, 19))	('FGFR1', 'Gene', (23, 28))	('squamous cell lung cancer', 'Disease', (55, 80))	('adenocarcinoma of lung', 'Disease', (114, 136))	('FGFR1', 'Gene', '2260', (23, 28))	('adenocarcinoma of lung', 'Disease', 'MESH:D000077192', (114, 136))	('lung cancer', 'Phenotype', 'HP:0100526', (69, 80))	('squamous cell lung cancer', 'Disease', 'MESH:D002294', (55, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('found', 'Reg', (46, 51))
390101	27144064	A subset of squamous cell carcinoma with FGFR1 amplification with increased MYC expression (40% cases) was found to be more susceptible to FGFR inhibition indicating a potential response-predictive biomarker.	('increased', 'PosReg', (66, 75))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (12, 35))	('amplification', 'Var', (47, 60))	('MYC', 'Gene', (76, 79))	('susceptible', 'MPA', (124, 135))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (12, 35))	('squamous cell carcinoma', 'Disease', (12, 35))	('carcinoma', 'Phenotype', 'HP:0030731', (26, 35))	('FGFR1', 'Gene', (41, 46))	('FGFR1', 'Gene', '2260', (41, 46))	('MYC', 'Gene', '4609', (76, 79))
390102	27144064	described FGFR2 and FGFR3 mutations in 3% of lung squamous cell carcinoma samples respectively.	('FGFR3', 'Gene', '2261', (20, 25))	('FGFR2', 'Gene', '2263', (10, 15))	('FGFR3', 'Gene', (20, 25))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (50, 73))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (45, 73))	('lung squamous cell carcinoma', 'Disease', (45, 73))	('mutations', 'Var', (26, 35))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))	('FGFR2', 'Gene', (10, 15))
390103	27144064	Using cell culture and xenograft models they showed that these mutations were oncogenic in nature and are sensitive to the receptor tyrosine kinase inhibitor pazopanib.	('mutations', 'Var', (63, 72))	('receptor tyrosine kinase', 'Gene', (123, 147))	('pazopanib', 'Chemical', 'MESH:C516667', (158, 167))	('receptor tyrosine kinase', 'Gene', '5979', (123, 147))
390104	27144064	Mutations in FGFR can occur both in the extracellular domain (ECD) and in the kinase domains and are transforming in nature.	('Mutations', 'Var', (0, 9))	('ECD', 'Disease', (62, 65))	('ECD', 'Disease', 'MESH:C574275', (62, 65))	('FGFR', 'Gene', (13, 17))
390105	27144064	FGFR ECD mutants facilitate covalent dimerization through the formation of intermolecular disulfide bonds.	('covalent dimerization', 'MPA', (28, 49))	('ECD', 'Disease', (5, 8))	('facilitate', 'PosReg', (17, 27))	('disulfide', 'Chemical', 'MESH:D004220', (90, 99))	('FGFR', 'Gene', (0, 4))	('mutants', 'Var', (9, 16))	('intermolecular disulfide bonds', 'MPA', (75, 105))	('ECD', 'Disease', 'MESH:C574275', (5, 8))
390106	27144064	FGFR fusions have also been described in lung cancer such as FGFR2-KIAA1967 fusion reported in lung squamous cell carcinoma and FGFR2-CIT fusion reported in lung adenocarcinomas.	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('carcinoma', 'Phenotype', 'HP:0030731', (167, 176))	('fusion', 'Var', (76, 82))	('FGFR2', 'Gene', '2263', (61, 66))	('carcinomas', 'Phenotype', 'HP:0030731', (167, 177))	('lung cancer', 'Disease', 'MESH:D008175', (41, 52))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (157, 177))	('lung cancer', 'Phenotype', 'HP:0100526', (41, 52))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (157, 176))	('KIAA1967', 'Gene', (67, 75))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (157, 177))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (100, 123))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (95, 123))	('lung squamous cell carcinoma', 'Disease', (95, 123))	('FGFR2', 'Gene', (128, 133))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('lung adenocarcinomas', 'Disease', (157, 177))	('KIAA1967', 'Gene', '57805', (67, 75))	('lung cancer', 'Disease', (41, 52))	('FGFR2', 'Gene', (61, 66))	('FGFR2', 'Gene', '2263', (128, 133))
390107	27144064	Smoking and tumor size were independent predictors of FGFR fusions.	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('tumor', 'Disease', (12, 17))	('fusions', 'Var', (59, 66))	('FGFR', 'Gene', (54, 58))
390110	27144064	Hyperphosphatemia is a mechanism-based toxicity caused by potent FGFR kinase inhibitors due to inhibition of the FGF23/Klotho signaling axis, thereby causing a decrease in renal phosphate excretion.	('FGF23', 'Gene', '8074', (113, 118))	('Hyperphosphatemia', 'Disease', (0, 17))	('inhibitors', 'Var', (77, 87))	('decrease', 'NegReg', (160, 168))	('Klotho', 'Gene', (119, 125))	('Klotho', 'Gene', '9365', (119, 125))	('inhibition', 'NegReg', (95, 105))	('renal phosphate excretion', 'MPA', (172, 197))	('phosphate', 'Chemical', 'MESH:D010710', (5, 14))	('FGFR', 'Gene', (65, 69))	('FGF23', 'Gene', (113, 118))	('Hyperphosphatemia', 'Phenotype', 'HP:0002905', (0, 17))	('phosphate', 'Chemical', 'MESH:D010710', (178, 187))	('Hyperphosphatemia', 'Disease', 'MESH:D054559', (0, 17))	('toxicity', 'Disease', 'MESH:D064420', (39, 47))	('toxicity', 'Disease', (39, 47))
390112	27144064	AZD4547 and BGJ398 are selective anti FGFR 1-3 inhibitors with potent preclinical anti-tumor activity in FGFR1 amplified squamous cell lung cancer cell lines and patient derived xenografts.	('FGFR1', 'Gene', (105, 110))	('AZD4547', 'Chemical', 'MESH:C572463', (0, 7))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('squamous cell lung cancer', 'Disease', 'MESH:D002294', (121, 146))	('squamous cell lung cancer', 'Disease', (121, 146))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Disease', (87, 92))	('FGFR1', 'Gene', '2260', (105, 110))	('BGJ398', 'Chemical', 'MESH:C568950', (12, 18))	('BGJ398', 'Gene', (12, 18))	('FGFR 1', 'Gene', (38, 44))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('patient', 'Species', '9606', (162, 169))	('AZD4547', 'Var', (0, 7))	('FGFR 1', 'Gene', '2260', (38, 44))	('lung cancer', 'Phenotype', 'HP:0100526', (135, 146))
390114	27144064	In a phase 1 multicenter expansion study of AZD4547 enrolling previously treated advanced FGFR amplified squamous cell lung cancer (defined as: FGFR1 CEP8 >2), 7 patients hadhigh amplification (FISH ratios >2.8) and the remaining 8 had low amplification (FISH ratios between 2-2.8).	('squamous cell lung cancer', 'Disease', 'MESH:D002294', (105, 130))	('patients', 'Species', '9606', (162, 170))	('AZD4547', 'Chemical', 'MESH:C572463', (44, 51))	('lung cancer', 'Phenotype', 'HP:0100526', (119, 130))	('FGFR1', 'Gene', (144, 149))	('hadhigh amplification', 'Var', (171, 192))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('squamous cell lung cancer', 'Disease', (105, 130))	('FGFR1', 'Gene', '2260', (144, 149))	('amplified', 'Var', (95, 104))	('AZD4547', 'Gene', (44, 51))
390118	27144064	The increase in serum phosphate concentration observed in this study provides evidence that AZD4547 at the dose of 80 mg orally twice daily caused pharmacologic target inhibition.	('serum phosphate concentration', 'MPA', (16, 45))	('phosphate', 'Chemical', 'MESH:D010710', (22, 31))	('AZD4547', 'Var', (92, 99))	('increase', 'PosReg', (4, 12))	('AZD4547', 'Chemical', 'MESH:C572463', (92, 99))
390121	27144064	Similarly for BGJ398, a phase 1 study dose escalation study of 21 patients with FGFR1 amplified lung squamous cell cancer showed low response rates despite patient selection.	('FGFR1', 'Gene', '2260', (80, 85))	('lung squamous cell cancer', 'Disease', 'MESH:D002294', (96, 121))	('BGJ398', 'Chemical', 'MESH:C568950', (14, 20))	('amplified', 'Var', (86, 95))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (101, 121))	('patient', 'Species', '9606', (66, 73))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('lung squamous cell cancer', 'Disease', (96, 121))	('patient', 'Species', '9606', (156, 163))	('FGFR1', 'Gene', (80, 85))	('patients', 'Species', '9606', (66, 74))
390123	27144064	Exploratory biomarker analysis revealed that four patients with high FGFR gene amplification by FISH did not derive any clinically meaningful efficacy outcome.	('high FGFR', 'Gene', (64, 73))	('amplification', 'Var', (79, 92))	('FGFR', 'Gene', (69, 73))	('patients', 'Species', '9606', (50, 58))
390125	27144064	Mutations in RET cause the multiple endocrine neoplasia type 2 syndrome and sporadic medullary thyroid cancer.	('medullary thyroid cancer', 'Phenotype', 'HP:0002865', (85, 109))	('endocrine neoplasia type 2 syndrome', 'Disease', (36, 71))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('RET', 'Gene', (13, 16))	('endocrine neoplasia type 2 syndrome', 'Disease', 'MESH:D018813', (36, 71))	('cause', 'Reg', (17, 22))	('neoplasia', 'Phenotype', 'HP:0002664', (46, 55))	('endocrine neoplasia', 'Phenotype', 'HP:0100568', (36, 55))	('thyroid cancer', 'Disease', (95, 109))	('Mutations', 'Var', (0, 9))	('thyroid cancer', 'Phenotype', 'HP:0002890', (95, 109))	('RET', 'Gene', '5979', (13, 16))	('thyroid cancer', 'Disease', 'MESH:D013964', (95, 109))
390126	27144064	RET fusion genes are present in 1%-2% of lung adenocarcinomas and are more likely to occur in patients younger than 60 years, non-smokers, in tumors with lymph node metastasis and in poorly differentiated tumors.	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (41, 61))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('carcinomas', 'Phenotype', 'HP:0030731', (51, 61))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))	('tumors', 'Phenotype', 'HP:0002664', (205, 211))	('lung adenocarcinomas', 'Disease', (41, 61))	('RET', 'Gene', '5979', (0, 3))	('patients', 'Species', '9606', (94, 102))	('fusion genes', 'Var', (4, 16))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumors', 'Disease', (142, 148))	('tumors', 'Disease', (205, 211))	('RET', 'Gene', (0, 3))	('tumors', 'Disease', 'MESH:D009369', (142, 148))	('tumors', 'Disease', 'MESH:D009369', (205, 211))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (41, 61))	('occur', 'Reg', (85, 90))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (41, 60))	('carcinoma', 'Phenotype', 'HP:0030731', (51, 60))
390135	27144064	investigated the presence of NTRK mutations in 538 primary lung carcinomas, including 17 typical carcinoids, A total of 10 atypical carcinoids, 39 small cell lung carcinomas, 29 large cell neuroendocrine carcinomas (LCNEC) and 443 NSCLCs by single-strand conformation polymorphism and sequencing of the tyrosine kinase domain of NTRK1, NTRK2 and NTRK3.	('NSCLC', 'Phenotype', 'HP:0030358', (231, 236))	('lung carcinomas', 'Disease', (59, 74))	('NTRK1', 'Gene', '4914', (329, 334))	('NTRK', 'Gene', (329, 333))	('NTRK', 'Gene', '4914;4915;4916', (29, 33))	('NTRK', 'Gene', (336, 340))	('small cell lung carcinomas', 'Disease', (147, 173))	('NTRK', 'Gene', '4914;4915;4916', (346, 350))	('NTRK2', 'Gene', '4915', (336, 341))	('neuroendocrine carcinomas', 'Disease', 'MESH:D018278', (189, 214))	('carcinoids', 'Phenotype', 'HP:0100570', (97, 107))	('NTRK1', 'Gene', (329, 334))	('lung carcinomas', 'Disease', 'MESH:D008175', (158, 173))	('NSCLCs', 'Disease', (231, 237))	('NTRK3', 'Gene', '4916', (346, 351))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))	('NTRK', 'Gene', '4914;4915;4916', (336, 340))	('carcinomas', 'Phenotype', 'HP:0030731', (64, 74))	('NTRK', 'Gene', '4914;4915;4916', (329, 333))	('NTRK3', 'Gene', (346, 351))	('small cell lung carcinomas', 'Disease', 'MESH:D055752', (147, 173))	('carcinoma', 'Phenotype', 'HP:0030731', (204, 213))	('NTRK2', 'Gene', (336, 341))	('carcinomas', 'Phenotype', 'HP:0030731', (204, 214))	('carcinoids', 'Phenotype', 'HP:0100570', (132, 142))	('NSCLCs', 'Disease', 'MESH:D002289', (231, 237))	('neuroendocrine carcinomas', 'Disease', (189, 214))	('tyrosine', 'Chemical', 'MESH:D014443', (303, 311))	('NTRK', 'Gene', (29, 33))	('neuroendocrine carcinomas', 'Phenotype', 'HP:0100634', (189, 214))	('carcinoma', 'Phenotype', 'HP:0030731', (163, 172))	('carcinomas', 'Phenotype', 'HP:0030731', (163, 173))	('NTRK', 'Gene', (346, 350))	('lung carcinomas', 'Disease', 'MESH:D008175', (59, 74))	('small cell lung carcinomas', 'Phenotype', 'HP:0030357', (147, 173))	('mutations', 'Var', (34, 43))
390137	27144064	These mutations play an important role in tumorigenesis and could possibly have important implications in selection of patients for targeted therapy.	('tumor', 'Disease', (42, 47))	('implications', 'Reg', (90, 102))	('patients', 'Species', '9606', (119, 127))	('play', 'Reg', (16, 20))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('mutations', 'Var', (6, 15))
390141	27144064	Next generation sequencing or fluorescence in situ hybridization demonstrated NTRK1 fusions in 3.3% of patient lung cancer tumor samples without known oncogenic alterations.	('NTRK1', 'Gene', '4914', (78, 83))	('fusions', 'Var', (84, 91))	('NTRK1', 'Gene', (78, 83))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('patient', 'Species', '9606', (103, 110))	('lung cancer tumor', 'Disease', 'MESH:D008175', (111, 128))	('lung cancer tumor', 'Disease', (111, 128))	('lung cancer', 'Phenotype', 'HP:0100526', (111, 122))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
390144	27144064	In this study, investigators screened 1,378 cases, identifying NTRK1 gene rearrangements at a frequency of 0.1%.	('rearrangements', 'Var', (74, 88))	('NTRK1', 'Gene', '4914', (63, 68))	('NTRK1', 'Gene', (63, 68))
390145	27144064	Human epidermal growth factor receptor plays a crucial role in normal homeostasis and dysregulation of this pathway results in carcinogenesis.	('Human', 'Species', '9606', (0, 5))	('epidermal growth factor receptor', 'Gene', (6, 38))	('carcinogenesis', 'Disease', 'MESH:D063646', (127, 141))	('results in', 'Reg', (116, 126))	('carcinogenesis', 'Disease', (127, 141))	('dysregulation', 'Var', (86, 99))	('epidermal growth factor receptor', 'Gene', '1956', (6, 38))	('Human', 'Protein', (0, 5))
390148	27144064	Alterations in HER2 in lung cancer are described in approximately 3% of adenocarcinomas, more commonly in nonsmokers and can be either mutations or amplifications.	('lung cancer', 'Disease', (23, 34))	('carcinomas', 'Phenotype', 'HP:0030731', (77, 87))	('lung cancer', 'Phenotype', 'HP:0100526', (23, 34))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('adenocarcinomas', 'Disease', 'MESH:D000230', (72, 87))	('Alterations', 'Var', (0, 11))	('HER2', 'Gene', (15, 19))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('HER2', 'Gene', '2064', (15, 19))	('adenocarcinomas', 'Disease', (72, 87))	('lung cancer', 'Disease', 'MESH:D008175', (23, 34))	('described', 'Reg', (39, 48))
390150	27144064	In contrast, HER2 exon 20 mutations seem to confer sensitivity to trastuzumab-based therapies and oral pan-HER inhibitors such as afatinib, dacomitinib and lapatinib.	('dacomitinib', 'Chemical', 'MESH:C525726', (140, 151))	('trastuzumab', 'Chemical', 'MESH:D000068878', (66, 77))	('lapatinib', 'Chemical', 'MESH:D000077341', (156, 165))	('sensitivity', 'MPA', (51, 62))	('mutations', 'Var', (26, 35))	('HER2', 'Gene', (13, 17))	('HER2', 'Gene', '2064', (13, 17))	('afatinib', 'Chemical', 'MESH:D000077716', (130, 138))
390153	27144064	NRG1 fusions were present in approximately 18% of KRAS-negative IMAs.	('fusions', 'Var', (5, 12))	('KRAS', 'Gene', (50, 54))	('NRG1', 'Gene', (0, 4))	('KRAS', 'Gene', '3845', (50, 54))	('NRG1', 'Gene', '3084', (0, 4))
390156	27144064	EZR-ERBB4 fusions are present in 1% of IMAs and activate HER4 via the coiled-coiled domain of EZR facilitating homodimerization of the kinase function of HER4.	('HER4', 'Gene', '2066', (57, 61))	('HER4', 'Gene', (57, 61))	('EZR', 'Gene', (94, 97))	('EZR', 'Gene', '7430', (0, 3))	('ERBB4', 'Gene', '2066', (4, 9))	('HER4', 'Gene', (154, 158))	('activate', 'PosReg', (48, 56))	('HER4', 'Gene', '2066', (154, 158))	('ERBB4', 'Gene', (4, 9))	('EZR', 'Gene', '7430', (94, 97))	('homodimerization', 'MPA', (111, 127))	('coiled-coiled domain', 'MPA', (70, 90))	('fusions', 'Var', (10, 17))	('EZR', 'Gene', (0, 3))
390158	27144064	We have outlined the salient features characterizing potentially druggable genetic alterations in NSCLC.	('genetic alterations', 'Var', (75, 94))	('NSCLC', 'Phenotype', 'HP:0030358', (98, 103))	('NSCLC', 'Disease', 'MESH:D002289', (98, 103))	('NSCLC', 'Disease', (98, 103))
390164	32099910	Partial silencing of fucosyltransferase 8 gene expression inhibits proliferation of Ishikawa cells, a cell line of endometrial cancer Endometrial cancer is the most common gynecologic malignancy and is associated with increased morbidity each year, including young people.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('people', 'Species', '9606', (265, 271))	('endometrial cancer', 'Disease', (115, 133))	('Endometrial cancer', 'Phenotype', 'HP:0012114', (134, 152))	('inhibits', 'NegReg', (58, 66))	('Partial silencing', 'Var', (0, 17))	('fucosyltransferase 8', 'Gene', (21, 41))	('Endometrial cancer', 'Disease', (134, 152))	('malignancy', 'Disease', 'MESH:D009369', (184, 194))	('malignancy', 'Disease', (184, 194))	('Endometrial cancer', 'Disease', 'MESH:D016889', (134, 152))	('endometrial cancer', 'Phenotype', 'HP:0012114', (115, 133))	('endometrial cancer', 'Disease', 'MESH:D016889', (115, 133))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('fucosyltransferase 8', 'Gene', '2530', (21, 41))	('endometrial cancer Endometrial cancer', 'Phenotype', 'HP:0012114', (115, 152))
390166	32099910	Therefore, we aimed to identify the expression of FUT8 in endometrial endometrioid carcinoma and investigate the effect of the partial silencing of the FUT8 gene on the cell proliferation of Ishikawa cells, an epithelial-like endometrial cancer cell line.	('endometrial cancer', 'Phenotype', 'HP:0012114', (226, 244))	('endometrial cancer', 'Disease', 'MESH:D016889', (226, 244))	('endometrial endometrioid carcinoma', 'Disease', 'MESH:D016889', (58, 92))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (70, 92))	('partial', 'Var', (127, 134))	('endometrial endometrioid carcinoma', 'Disease', (58, 92))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('endometrial cancer', 'Disease', (226, 244))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))	('FUT8', 'Gene', (152, 156))
390169	32099910	The proliferation assay showed FUT8 partial knockdown by transfection of siRNA significantly suppressed the proliferation of Ishikawa cells, concomitant with the upregulation in the gene expressions associated with the interesting pathways associated with de-ubiquitination, aspirin trigger, mesenchymal-epithelial transition (MET) et al.	('upregulation', 'PosReg', (162, 174))	('de-ubiquitination', 'MPA', (256, 273))	('aspirin', 'Chemical', 'MESH:D001241', (275, 282))	('proliferation of Ishikawa cells', 'CPA', (108, 139))	('mesenchymal-epithelial transition', 'Disease', (292, 325))	('suppressed', 'NegReg', (93, 103))	('siRNA', 'Gene', (73, 78))	('knockdown', 'Var', (44, 53))	('gene expressions', 'MPA', (182, 198))
390173	32099910	Silencing of fucosyltransferase 8 suppressed the proliferation of Ishikawa cells, an endometrial cancer cell line.	('endometrial cancer', 'Disease', 'MESH:D016889', (85, 103))	('fucosyltransferase 8', 'Gene', (13, 33))	('suppressed', 'NegReg', (34, 44))	('proliferation', 'CPA', (49, 62))	('fucosyltransferase 8', 'Gene', '2530', (13, 33))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('endometrial cancer', 'Disease', (85, 103))	('Silencing', 'Var', (0, 9))	('endometrial cancer', 'Phenotype', 'HP:0012114', (85, 103))
390179	32099910	Carbohydrate antigens, such as CA19-9 and CA125, are established tumor markers for diagnosing and treating various kinds of cancers, including endometrial cancer because the structure of the carbohydrate chain usually changes in cancer cells.	('endometrial cancer', 'Phenotype', 'HP:0012114', (143, 161))	('structure', 'MPA', (174, 183))	('cancer', 'Disease', 'MESH:D009369', (229, 235))	('carbohydrate', 'Chemical', 'MESH:D002241', (191, 203))	('CA19-9', 'Var', (31, 37))	('endometrial cancer', 'Disease', (143, 161))	('cancer', 'Disease', 'MESH:D009369', (124, 130))	('cancers', 'Disease', 'MESH:D009369', (124, 131))	('cancer', 'Disease', 'MESH:D009369', (155, 161))	('tumor', 'Disease', (65, 70))	('endometrial cancer', 'Disease', 'MESH:D016889', (143, 161))	('CA125', 'Gene', (42, 47))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('cancer', 'Disease', (229, 235))	('cancers', 'Phenotype', 'HP:0002664', (124, 131))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('cancers', 'Disease', (124, 131))	('cancer', 'Disease', (155, 161))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('cancer', 'Disease', (124, 130))	('changes', 'Reg', (218, 225))	('CA125', 'Gene', '94025', (42, 47))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))
390188	32099910	The specific objectives of the present study were to investigate 1) gene expression of FUT families in the tissues of a normal endometrium and endometrial endometrioid carcinoma, 2) tissue localization of FUT8 and Ulex europaeus Agglutinin 1 (UEA-1), a kind of lectin family specifically binding to fucose, in a normal endometrium and endometrial endometrioid carcinoma, 3) expression of FUT8 in Ishikawa cells, an endometrial cancer cell line, 4) the effects of partial silencing of the FUT8 gene on the proliferation of Ishikawa cells, and 5) the effects of partial silencing of the FUT8 gene on gene expression patterns by microarray analysis.	('carcinoma', 'Phenotype', 'HP:0030731', (168, 177))	('endometrial endometrioid carcinoma', 'Disease', 'MESH:D016889', (335, 369))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (347, 369))	('fucose', 'Chemical', 'MESH:D005643', (299, 305))	('endometrial cancer', 'Phenotype', 'HP:0012114', (415, 433))	('endometrial endometrioid carcinoma', 'Disease', (335, 369))	('endometrial endometrioid carcinoma', 'Disease', (143, 177))	('endometrial cancer', 'Disease', 'MESH:D016889', (415, 433))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (155, 177))	('partial', 'Var', (560, 567))	('FUT8', 'Gene', (488, 492))	('cancer', 'Phenotype', 'HP:0002664', (427, 433))	('carcinoma', 'Phenotype', 'HP:0030731', (360, 369))	('FUT8', 'Gene', (585, 589))	('endometrial cancer', 'Disease', (415, 433))	('endometrial endometrioid carcinoma', 'Disease', 'MESH:D016889', (143, 177))
390241	32099910	FUT8 greatly changes the carbohydrate chain structure.	('changes', 'Reg', (13, 20))	('carbohydrate', 'Chemical', 'MESH:D002241', (25, 37))	('FUT8', 'Var', (0, 4))	('carbohydrate chain structure', 'MPA', (25, 53))
390252	32099910	reported that a FUT8 gene deficiency resulted in the attenuation of responses to epidermal growth factor and hepatocyte growth factor in a human liver cancer-derived cell line HepG2.	('deficiency', 'Var', (26, 36))	('epidermal growth factor', 'Gene', '13645', (81, 104))	('FUT8', 'Gene', (16, 20))	('attenuation', 'NegReg', (53, 64))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('liver cancer', 'Phenotype', 'HP:0002896', (145, 157))	('cancer', 'Disease', (151, 157))	('human', 'Species', '9606', (139, 144))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('epidermal growth factor', 'Gene', (81, 104))	('HepG2', 'CellLine', 'CVCL:0027', (176, 181))
390253	32099910	The most apparent activations were observed in 2 de-ubiquitination pathways by partial silencing of FUT8, both of which was highly associated with ubiquitin specific protease 17 (USP17) families (Table3A).	('ubiquitin specific protease 17', 'Gene', (147, 177))	('ubiquitin specific protease 17', 'Gene', '391627', (147, 177))	('activations', 'PosReg', (18, 29))	('de-ubiquitination pathways', 'Pathway', (49, 75))	('partial silencing', 'Var', (79, 96))	('FUT8', 'Gene', (100, 104))	('USP17', 'Gene', '391627', (179, 184))	('USP17', 'Gene', (179, 184))
390257	32099910	Nevertheless, the present findings suggest a possibility that partial silencing of FUT8 may suppress cell proliferation of Ishikawa cells, at least partly, via activation of USP 17-associated pathways.	('activation', 'PosReg', (160, 170))	('USP 17', 'Gene', (174, 180))	('USP 17', 'Gene', '391627', (174, 180))	('cell proliferation of Ishikawa cells', 'CPA', (101, 137))	('partial silencing', 'Var', (62, 79))	('suppress', 'NegReg', (92, 100))	('FUT8', 'Gene', (83, 87))
390258	32099910	Partial silencing of FUT8 significantly elevated 3 aspirin triggered pathways (Table3A).	('elevated', 'PosReg', (40, 48))	('aspirin triggered pathways', 'Pathway', (51, 77))	('Partial silencing', 'Var', (0, 17))	('aspirin', 'Chemical', 'MESH:D001241', (51, 58))	('FUT8', 'Gene', (21, 25))
390261	32099910	It is interesting to speculate that decrease of core fuosylation by partial silencing FUT8 may affect aspirin triggered pathways.	('partial silencing', 'Var', (68, 85))	('aspirin', 'Chemical', 'MESH:D001241', (102, 109))	('affect', 'Reg', (95, 101))	('FUT8', 'Gene', (86, 90))	('aspirin triggered pathways', 'Pathway', (102, 128))	('core fuosylation', 'MPA', (48, 64))	('decrease', 'NegReg', (36, 44))
390264	32099910	Miwa et al., reported that the presence of the bisecting GlcNAc on mammary glycoproteins reduced mammary tumor cell progression.	('GlcNAc', 'Chemical', '-', (57, 63))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('reduced', 'NegReg', (89, 96))	('tumor', 'Disease', (105, 110))	('presence', 'Var', (31, 39))
390278	30005669	Transcriptome profiling and Gene Set Enrichment Analysis from HNSCC and breast cancer cells were used to identify expression changes relevant to specific cellular localizations, biological processes and signaling pathways after PPFIA1 knockdown.	('HNSCC', 'Phenotype', 'HP:0012288', (62, 67))	('knockdown', 'Var', (235, 244))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('PPFIA1', 'Gene', (228, 234))	('breast cancer', 'Disease', 'MESH:D001943', (72, 85))	('breast cancer', 'Disease', (72, 85))	('breast cancer', 'Phenotype', 'HP:0003002', (72, 85))	('PPFIA1', 'Gene', '8500', (228, 234))
390281	30005669	Importantly, we show that in all these cancer cells liprin-alpha1 knockdown leads to the upregulation of transmembrane protein CD82, which is a suppressor of metastasis in several solid tumors.	('cancer', 'Disease', (39, 45))	('solid tumors', 'Disease', 'MESH:D009369', (180, 192))	('solid tumors', 'Disease', (180, 192))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('tumors', 'Phenotype', 'HP:0002664', (186, 192))	('transmembrane protein', 'MPA', (105, 126))	('liprin-alpha1', 'Gene', (52, 65))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('upregulation', 'PosReg', (89, 101))	('CD82', 'Gene', (127, 131))	('knockdown', 'Var', (66, 75))
390297	30005669	Constructs for PPFIA1 were TRCN0000342514, TRCN0000380944, TRCN0000002969, and TRCN0000380097, named as shPPFIA1_14, shPPFIA1_44, shPPFIA1_69 and shPPFIA1_97, and for VIM they were TRCN0000029119 and TRCN0000029121 (Sigma-Aldrich, St. Louis, Missouri, U.S.).	('PPFIA1', 'Gene', '8500', (15, 21))	('PPFIA1', 'Gene', '8500', (148, 154))	('TRCN0000029119', 'Disease', 'None', (181, 195))	('TRCN0000029119', 'Disease', (181, 195))	('VIM', 'Gene', '7431', (167, 170))	('PPFIA1', 'Gene', '8500', (119, 125))	('TRCN0000002969', 'Var', (59, 73))	('PPFIA1', 'Gene', '8500', (106, 112))	('PPFIA1', 'Gene', (132, 138))	('PPFIA1', 'Gene', (148, 154))	('TRCN0000380097', 'Var', (79, 93))	('TRCN0000029121', 'Var', (200, 214))	('PPFIA1', 'Gene', '8500', (132, 138))	('PPFIA1', 'Gene', (15, 21))	('VIM', 'Gene', (167, 170))	('PPFIA1', 'Gene', (119, 125))	('PPFIA1', 'Gene', (106, 112))
390326	30005669	Statistical significance of the gene expression changes between liprin-alpha1 knockdown (shPPFIA1) and control cells (shScr) was evaluated by Wald test.	('liprin-alpha1', 'Protein', (64, 77))	('knockdown', 'Var', (78, 87))	('PPFIA1', 'Gene', (91, 97))	('PPFIA1', 'Gene', '8500', (91, 97))
390329	30005669	Gene set enrichment analysis was used to study whether a priori defined set of genes showed statistically significant, analogous differences between control (shScr) and liprin-alpha1 (shPPFIA1) knockdown cells.	('PPFIA1', 'Gene', (186, 192))	('knockdown', 'Var', (194, 203))	('PPFIA1', 'Gene', '8500', (186, 192))
390330	30005669	For knocking-down CD82 in shPPFIA1 HNSCC cells by using a siRNA pool for CD82 (Sigma-Aldrich), UT-SCC-42B cells were counted at 200000/ml, and seeded to six well plates.	('HNSCC', 'Phenotype', 'HP:0012288', (35, 40))	('PPFIA1', 'Gene', (28, 34))	('CD82', 'Gene', (18, 22))	('PPFIA1', 'Gene', '8500', (28, 34))	('knocking-down', 'Var', (4, 17))
390336	30005669	Liprin-alpha1 knockdown led to reduced lumen formation, actin cytoskeleton rearrangements and reduced F-actin containing cellular outgrowths in the UT-SCC-42B cell colonies (Fig.	('Liprin-alpha1', 'Gene', '8500', (0, 13))	('reduced', 'NegReg', (31, 38))	('lumen', 'MPA', (39, 44))	('Liprin-alpha1', 'Gene', (0, 13))	('F-actin containing', 'MPA', (102, 120))	('reduced', 'NegReg', (94, 101))	('actin cytoskeleton rearrangements', 'CPA', (56, 89))	('knockdown', 'Var', (14, 23))
390337	30005669	To understand the molecular mechanisms of liprin-alpha1 in cell adhesion and invasive growth properties, we carried out RNA sequencing to explore gene expression changes after PPFIA1 knockdown.	('knockdown', 'Var', (183, 192))	('PPFIA1', 'Gene', '8500', (176, 182))	('PPFIA1', 'Gene', (176, 182))
390339	30005669	In MDA-MB-231 breast cancer cells, there were 592 significantly differentially expressed genes after liprin-alpha1 knockdown compared to control cells whereas in UT-SCC-42A and UT-SCC-42B cell lines 1745 genes were significantly differentially expressed, when p-value was set under 0.05 (Additional file 2: Table S1 and GSE108392).	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('liprin-alpha1', 'Protein', (101, 114))	('differentially', 'Reg', (229, 243))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (3, 13))	('differentially', 'Reg', (64, 78))	('breast cancer', 'Disease', 'MESH:D001943', (14, 27))	('breast cancer', 'Disease', (14, 27))	('breast cancer', 'Phenotype', 'HP:0003002', (14, 27))	('knockdown', 'Var', (115, 124))
390348	30005669	In addition, knockdown of liprin-alpha1 had a negative effect on peptidase and hydrolase activity, and positive effect on regulation of cell death (including TP63) (Fig.	('peptidase', 'Enzyme', (65, 74))	('hydrolase', 'Enzyme', (79, 88))	('liprin-alpha1', 'Protein', (26, 39))	('TP63', 'Gene', '8626', (158, 162))	('positive', 'PosReg', (103, 111))	('TP63', 'Gene', (158, 162))	('negative', 'NegReg', (46, 54))	('knockdown', 'Var', (13, 22))	('activity', 'MPA', (89, 97))
390354	30005669	Interestingly, SORL1 also showed differences in gene expression after liprin-alpha1 knockdown in breast cancer and in HNSCC cell lines (Fig.	('differences', 'Reg', (33, 44))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('knockdown', 'Var', (84, 93))	('HNSCC', 'Phenotype', 'HP:0012288', (118, 123))	('breast cancer', 'Disease', 'MESH:D001943', (97, 110))	('liprin-alpha1', 'Gene', (70, 83))	('breast cancer', 'Phenotype', 'HP:0003002', (97, 110))	('breast cancer', 'Disease', (97, 110))	('gene expression', 'MPA', (48, 63))	('SORL1', 'Gene', (15, 20))
390362	30005669	After knocking down vimentin in MDA-MB-231 and Hs578T breast cancer cells, which highly express endogenous vimentin, liprin-alpha1 was not localized near the cell edge or after the leading edge as in control cells, although there were no significant changes at the protein expression levels in these breast cancer cell lines (Additional file 10: Figure S7D-E).	('knocking', 'Var', (6, 14))	('breast cancer', 'Disease', (54, 67))	('cancer', 'Phenotype', 'HP:0002664', (307, 313))	('Hs578T', 'CellLine', 'CVCL:0332', (47, 53))	('breast cancer', 'Disease', 'MESH:D001943', (300, 313))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (32, 42))	('breast cancer', 'Disease', (300, 313))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('breast cancer', 'Phenotype', 'HP:0003002', (300, 313))	('breast cancer', 'Disease', 'MESH:D001943', (54, 67))	('breast cancer', 'Phenotype', 'HP:0003002', (54, 67))
390363	30005669	Vimentin knockdown had effect on focal adhesion localization exemplified by cytoplasmic staining of vinculin after vimentin knockdown, and lack of liprin-alpha1 localization at the vicinity of focal adhesions (Additional file 10: Figure S7E).	('knockdown', 'Var', (124, 133))	('localization', 'MPA', (161, 173))	('Vimentin', 'Gene', '7431', (0, 8))	('knockdown', 'Var', (9, 18))	('liprin-alpha1', 'Protein', (147, 160))	('focal adhesion localization', 'MPA', (33, 60))	('effect', 'Reg', (23, 29))	('lack', 'NegReg', (139, 143))	('Vimentin', 'Gene', (0, 8))
390364	30005669	Vimentin knockdown in these cells was not compensated by upregulating keratin intermediate filaments.	('upregulating', 'PosReg', (57, 69))	('Vimentin', 'Gene', '7431', (0, 8))	('knockdown', 'Var', (9, 18))	('keratin intermediate filaments', 'Protein', (70, 100))	('Vimentin', 'Gene', (0, 8))
390365	30005669	On the contrary, keratin 13 expression was decreasing after knockdown of vimentin in breast cancer cell lines (Additional file 10: Figure S7D).	('vimentin', 'Protein', (73, 81))	('breast cancer', 'Disease', 'MESH:D001943', (85, 98))	('decreasing', 'NegReg', (43, 53))	('breast cancer', 'Disease', (85, 98))	('expression', 'MPA', (28, 38))	('breast cancer', 'Phenotype', 'HP:0003002', (85, 98))	('keratin 13', 'Gene', (17, 27))	('knockdown', 'Var', (60, 69))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('keratin 13', 'Gene', '3860', (17, 27))
390366	30005669	Furthermore, breast cancer cells with high endogenous vimentin expression were incapable for mesenchymal invasion inside three dimensional collagen I matrix after liprin-alpha1 knockdown due to disorganized vimentin network.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('breast cancer', 'Disease', 'MESH:D001943', (13, 26))	('breast cancer', 'Phenotype', 'HP:0003002', (13, 26))	('knockdown', 'Var', (177, 186))	('breast cancer', 'Disease', (13, 26))	('incapable', 'NegReg', (79, 88))
390367	30005669	Due to our results showing the association between liprin-alpha1 and CD82, we explored the significance of PPFIA1 amplification in survival of clinical HNSCC and breast cancer patients from The Cancer Genome Atlas (TCGA) data.	('patients', 'Species', '9606', (176, 184))	('Cancer', 'Disease', 'MESH:D009369', (194, 200))	('amplification', 'Var', (114, 127))	('PPFIA1', 'Gene', (107, 113))	('HNSCC', 'Phenotype', 'HP:0012288', (152, 157))	('association', 'Interaction', (31, 42))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('breast cancer', 'Disease', 'MESH:D001943', (162, 175))	('PPFIA1', 'Gene', '8500', (107, 113))	('breast cancer', 'Phenotype', 'HP:0003002', (162, 175))	('clinical', 'Species', '191496', (143, 151))	('breast cancer', 'Disease', (162, 175))	('Cancer', 'Phenotype', 'HP:0002664', (194, 200))	('Cancer', 'Disease', (194, 200))
390375	30005669	Liprin-alpha1 knockdown led to upregulation of CD82 cell surface protein, which inhibits formation of invasive structures called microprotrusions during cancer cell invasion.	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('Liprin-alpha1', 'Gene', '8500', (0, 13))	('Liprin-alpha1', 'Gene', (0, 13))	('cancer', 'Disease', (153, 159))	('knockdown', 'Var', (14, 23))	('inhibits', 'NegReg', (80, 88))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('formation of', 'MPA', (89, 101))	('CD82 cell surface protein', 'Protein', (47, 72))	('upregulation', 'PosReg', (31, 43))
390378	30005669	When we knocked down liprin-alpha1 in HNSCC and breast cancer cells grown in two-dimensional cell culture, CD82 was located at the vesicle-like structures and showed partial co-localization with caveolin-1.	('CD82', 'Gene', (107, 111))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('breast cancer', 'Disease', 'MESH:D001943', (48, 61))	('breast cancer', 'Phenotype', 'HP:0003002', (48, 61))	('breast cancer', 'Disease', (48, 61))	('co-localization', 'Interaction', (174, 189))	('knocked down', 'Var', (8, 20))	('liprin-alpha1', 'Protein', (21, 34))	('HNSCC', 'Phenotype', 'HP:0012288', (38, 43))
390382	30005669	Interestingly, sortilin-related receptor 1 (SORL1), which likely plays a role in endocytosis and sorting and it has association to Alzheimer's disease, was upregulated in liprin-alpha1 knockdown cells.	('SORL1', 'Gene', (44, 49))	('association', 'Interaction', (116, 127))	("Alzheimer's disease", 'Disease', 'MESH:D000544', (131, 150))	("Alzheimer's disease", 'Phenotype', 'HP:0002511', (131, 150))	("Alzheimer's disease", 'Disease', (131, 150))	('knockdown', 'Var', (185, 194))	('upregulated', 'PosReg', (156, 167))
390385	30005669	In HNSCC, ASAP3 (alias ACAP4) with a potential role in focal adhesions, beta1 integrin recycling and migration, was downregulated in liprin-alpha1 knockdown cells.	('HNSCC', 'Phenotype', 'HP:0012288', (3, 8))	('ASAP3', 'Gene', (10, 15))	('downregulated', 'NegReg', (116, 129))	('migration', 'CPA', (101, 110))	('ACAP4', 'Gene', (23, 28))	('alias', 'Disease', (17, 22))	('beta1 integrin', 'Gene', (72, 86))	('alias', 'Disease', 'None', (17, 22))	('ACAP4', 'Gene', '55616', (23, 28))	('beta1 integrin', 'Gene', '3688', (72, 86))	('knockdown', 'Var', (147, 156))	('ASAP3', 'Gene', '55616', (10, 15))
390386	30005669	Another gene related to adhesion, integrin inhibition and suppression of focal adhesion formation, SMURF1, was upregulated in liprin-alpha1 knockdown cells, which is also likely to have anti-tumor activity.	('focal', 'CPA', (73, 78))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('liprin-alpha1', 'Gene', (126, 139))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('tumor', 'Disease', (191, 196))	('SMURF1', 'Gene', '57154', (99, 105))	('SMURF1', 'Gene', (99, 105))	('knockdown', 'Var', (140, 149))	('upregulated', 'PosReg', (111, 122))
390388	30005669	Our previous data show regulative role of liprin-alpha1 on vimentin and indeed VIM was upregulated in HNSCC cells after liprin-alpha1 knockdown both in 2D and 3D cell culture platforms.	('liprin-alpha1', 'Gene', (120, 133))	('VIM', 'Gene', '7431', (79, 82))	('knockdown', 'Var', (134, 143))	('liprin-alpha1', 'Gene', (42, 55))	('upregulated', 'PosReg', (87, 98))	('HNSCC', 'Phenotype', 'HP:0012288', (102, 107))	('vimentin', 'Protein', (59, 67))	('VIM', 'Gene', (79, 82))
390391	30005669	Therefore, we next explored how PPFIA1 amplification influences the survival of the patients from HNSCC and breast cancer in clinical data.	('PPFIA1', 'Gene', '8500', (32, 38))	('patients', 'Species', '9606', (84, 92))	('clinical', 'Species', '191496', (125, 133))	('amplification', 'Var', (39, 52))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('HNSCC', 'Disease', (98, 103))	('PPFIA1', 'Gene', (32, 38))	('HNSCC', 'Phenotype', 'HP:0012288', (98, 103))	('breast cancer', 'Disease', 'MESH:D001943', (108, 121))	('influences', 'Reg', (53, 63))	('breast cancer', 'Phenotype', 'HP:0003002', (108, 121))	('breast cancer', 'Disease', (108, 121))
390392	30005669	Interestingly, in The Cancer Genome Atlas data PPFIA1 alteration was identified in 189 (36%) of 528 sequenced head and neck squamous cell carcinoma patients, whereas in breast cancer data set PPFIA1 amplification was identified in 439 (17%) of 2509 sequenced patients.	('alteration', 'Var', (54, 64))	('Cancer', 'Disease', (22, 28))	('PPFIA1', 'Gene', '8500', (47, 53))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('patients', 'Species', '9606', (148, 156))	('neck squamous cell carcinoma', 'Disease', (119, 147))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (119, 147))	('patients', 'Species', '9606', (259, 267))	('Cancer', 'Disease', 'MESH:D009369', (22, 28))	('PPFIA1', 'Gene', (192, 198))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (124, 147))	('PPFIA1', 'Gene', (47, 53))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (110, 147))	('breast cancer', 'Phenotype', 'HP:0003002', (169, 182))	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('Cancer', 'Phenotype', 'HP:0002664', (22, 28))	('PPFIA1', 'Gene', '8500', (192, 198))	('identified', 'Reg', (69, 79))	('breast cancer', 'Disease', 'MESH:D001943', (169, 182))	('breast cancer', 'Disease', (169, 182))
390393	30005669	Survival data showed shorter survival for altered patients when compared to patients with no alteration in both the HNSCC and in breast cancer data.	('breast cancer', 'Disease', (129, 142))	('patients', 'Species', '9606', (76, 84))	('breast cancer', 'Phenotype', 'HP:0003002', (129, 142))	('altered', 'Var', (42, 49))	('patients', 'Species', '9606', (50, 58))	('shorter', 'NegReg', (21, 28))	('survival', 'MPA', (29, 37))	('HNSCC', 'Phenotype', 'HP:0012288', (116, 121))	('breast cancer', 'Disease', 'MESH:D001943', (129, 142))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
390394	30005669	Clinical data emphasizes the importance of PPFIA1 amplification in cancer cell progression, and as a potential prognostic marker for HNSCC and breast cancer.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('breast cancer', 'Disease', 'MESH:D001943', (143, 156))	('PPFIA1', 'Gene', '8500', (43, 49))	('amplification', 'Var', (50, 63))	('Clinical', 'Species', '191496', (0, 8))	('cancer', 'Disease', (67, 73))	('breast cancer', 'Disease', (143, 156))	('breast cancer', 'Phenotype', 'HP:0003002', (143, 156))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('HNSCC', 'Disease', (133, 138))	('cancer', 'Disease', (150, 156))	('PPFIA1', 'Gene', (43, 49))	('HNSCC', 'Phenotype', 'HP:0012288', (133, 138))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
390402	29547932	Network-based integration of multi-omics data for prioritizing cancer genes Several molecular events are known to be cancer-related, including genomic aberrations, hypermethylation of gene promoter regions and differential expression of microRNAs.	('hypermethylation', 'Var', (164, 180))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('differential expression', 'MPA', (210, 233))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('cancer', 'Disease', (117, 123))	('cancer', 'Disease', (63, 69))
390408	29547932	However, in most cases it is not understood how the genetic aberrations contribute to cancer progression.	('genetic aberrations', 'Var', (52, 71))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('contribute', 'Reg', (72, 82))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('cancer', 'Disease', (86, 92))
390409	29547932	Genetic aberrations can be highly diverse among tumors of the same cancer type, and even among subclones of the same tumor.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumor', 'Disease', (48, 53))	('tumor', 'Disease', (117, 122))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('Genetic', 'Var', (0, 7))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumors of the same cancer', 'Disease', (48, 73))	('tumors of the same cancer', 'Disease', 'MESH:D009369', (48, 73))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
390410	29547932	It is assumed that only approximately 0.1% of the genetic aberrations in a tumor cell are actually driving cancer progression, such that their detection among the large number of neutral passenger mutations is challenging.	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('driving', 'Reg', (99, 106))	('genetic aberrations', 'Var', (50, 69))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('cancer', 'Disease', (107, 113))	('tumor', 'Disease', (75, 80))
390412	29547932	Besides genetic aberrations, other events such as epigenetic changes or miRNA differential expression can also contribute to cancer progression.	('cancer', 'Disease', (125, 131))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('miRNA', 'MPA', (72, 77))	('contribute', 'Reg', (111, 121))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('epigenetic changes', 'Var', (50, 68))
390413	29547932	For example, tumor suppressor genes can be silenced and inactivated by hypermethylation of their promoter region.	('tumor', 'Disease', (13, 18))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('inactivated', 'NegReg', (56, 67))	('hypermethylation', 'Var', (71, 87))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
390415	29547932	Several studies have focused on detecting cancer genome alterations and understanding how they affect the expression of the genes they hit, but only few investigated the changes that the genetic aberrations and epigenetic changes can provoke in other genes due to gene interactions.	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('alterations', 'Var', (56, 67))	('expression', 'MPA', (106, 116))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('affect', 'Reg', (95, 101))
390423	29547932	NetICS provides a comprehensive framework that assists in understanding how sample-specific aberration events can affect the same gene targets in different ways and in explaining inter-patient mutational heterogeneity.	('aberration', 'Var', (92, 102))	('affect', 'Reg', (114, 120))	('patient', 'Species', '9606', (185, 192))
390446	29547932	Pool1dir exhibited in general a lower performance compared to NetICS and reached its highest AUC for restart probabilities lower than 0.5, for all cancer types (Fig.	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('restart probabilities lower', 'MPA', (101, 128))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('Pool1dir', 'Var', (0, 8))	('cancer', 'Disease', (147, 153))	('performance', 'MPA', (38, 49))
390450	29547932	In specific, NetICS' AUC50 was statistically higher than the next highest performing method which was Pool1dir (Wilcoxon ranksum, ) in the uterine corpus endometrial carcinoma dataset.	('endometrial carcinoma', 'Disease', (154, 175))	('carcinoma', 'Phenotype', 'HP:0030731', (166, 175))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (154, 175))	('NetICS', 'Var', (13, 19))	('higher', 'PosReg', (45, 51))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (154, 175))
390451	29547932	Similarly, NetICS' AUC50 was statistically higher than the next highest performing method which was Pool2dir (Wilcoxon ranksum, ) in the liver hepatocellular carcinoma dataset.	('liver hepatocellular carcinoma', 'Disease', 'MESH:D006528', (137, 167))	('higher', 'PosReg', (43, 49))	('NetICS', 'Var', (11, 17))	('carcinoma', 'Phenotype', 'HP:0030731', (158, 167))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (143, 167))	('liver hepatocellular carcinoma', 'Disease', (137, 167))
390480	29547932	Loss of EP300 expression could be a potential cause of MYC upregulation, a known oncogene in breast cancer.	('MYC', 'Gene', (55, 58))	('MYC', 'Gene', '4609', (55, 58))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('breast cancer', 'Disease', 'MESH:D001943', (93, 106))	('breast cancer', 'Disease', (93, 106))	('breast cancer', 'Phenotype', 'HP:0003002', (93, 106))	('upregulation', 'PosReg', (59, 71))	('EP300', 'Gene', (8, 13))	('EP300', 'Gene', '2033', (8, 13))	('Loss', 'Var', (0, 4))
390481	29547932	We detected a mutually exclusive mutation pattern in the samples among ARNT, TP53, MYC and AKT1, further enhancing the idea that aberrations in these four genes might be alternative ways to disrupt the same cellular pathway (Supplementary Fig.	('AKT1', 'Gene', '207', (91, 95))	('AKT1', 'Gene', (91, 95))	('cellular pathway', 'Pathway', (207, 223))	('ARNT', 'Gene', '405', (71, 75))	('disrupt', 'Reg', (190, 197))	('MYC', 'Gene', (83, 86))	('aberrations', 'Var', (129, 140))	('MYC', 'Gene', '4609', (83, 86))	('TP53', 'Gene', (77, 81))	('TP53', 'Gene', '7157', (77, 81))	('ARNT', 'Gene', (71, 75))
390487	29547932	Somatic mutations detected in AKT1 (E17K) are known to exhibit oncogenic properties and activate downstream signaling by localizing AKT to the plasma membrane.	('AKT1', 'Gene', '207', (30, 34))	('localizing', 'MPA', (121, 131))	('AKT', 'Gene', '207', (132, 135))	('oncogenic properties', 'CPA', (63, 83))	('AKT1', 'Gene', (30, 34))	('E17K', 'Mutation', 'rs121434592', (36, 40))	('AKT', 'Gene', '207', (30, 33))	('AKT', 'Gene', (132, 135))	('E17K', 'Var', (36, 40))	('AKT', 'Gene', (30, 33))	('activate', 'PosReg', (88, 96))
390488	29547932	Interestingly, TP53 has been suggested to be indirectly regulated by MYC with the help of MDM2, and it would be interesting to examine how aberrations in MYC affect the expression of TP53.	('MYC', 'Gene', (69, 72))	('TP53', 'Gene', '7157', (183, 187))	('MYC', 'Gene', '4609', (154, 157))	('TP53', 'Gene', (183, 187))	('TP53', 'Gene', '7157', (15, 19))	('TP53', 'Gene', (15, 19))	('aberrations', 'Var', (139, 150))	('expression', 'MPA', (169, 179))	('MYC', 'Gene', (154, 157))	('affect', 'Reg', (158, 164))	('MDM2', 'Gene', '4193', (90, 94))	('MYC', 'Gene', '4609', (69, 72))	('MDM2', 'Gene', (90, 94))
390491	29547932	Thus, loss of CREBBP function by mutations mimics and abolishes TP53 function.	('loss', 'NegReg', (6, 10))	('abolishes', 'NegReg', (54, 63))	('CREBBP', 'Gene', '1387', (14, 20))	('function', 'MPA', (69, 77))	('mutations mimics', 'Var', (33, 49))	('TP53', 'Gene', '7157', (64, 68))	('TP53', 'Gene', (64, 68))	('CREBBP', 'Gene', (14, 20))	('mimics', 'Var', (43, 49))
390500	29547932	Inhibitors for XPO1 are a promising therapeutic strategy for lung and ovarian cancer.	('ovarian cancer', 'Phenotype', 'HP:0100615', (70, 84))	('Inhibitors', 'Var', (0, 10))	('lung and ovarian cancer', 'Disease', 'MESH:D010051', (61, 84))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('XPO1', 'Gene', '7514', (15, 19))	('XPO1', 'Gene', (15, 19))
390501	29547932	Another oncogene, PLCG1, recovered in top 1% of the ranked gene list in hepatocellular carcinoma, was recently also shown to exhibit recurrent activating mutations in angiosarcoma and somatic mutations in cutaneous T-cell lymphomas that lead to increased cell proliferative mechanisms.	('angiosarcoma', 'Phenotype', 'HP:0200058', (167, 179))	('PLCG1', 'Gene', (18, 23))	('activating', 'PosReg', (143, 153))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (72, 96))	('increased', 'PosReg', (245, 254))	('hepatocellular carcinoma', 'Disease', (72, 96))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (72, 96))	('angiosarcoma', 'Disease', 'MESH:D006394', (167, 179))	('cutaneous T-cell lymphomas', 'Disease', 'MESH:D016410', (205, 231))	('PLCG1', 'Gene', '5335', (18, 23))	('cell proliferative mechanisms', 'CPA', (255, 284))	('cutaneous T-cell lymphomas', 'Disease', (205, 231))	('mutations', 'Var', (154, 163))	('angiosarcoma', 'Disease', (167, 179))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))
390504	29547932	NetICS provides a flexible computational framework for per-sample network-based integration of a variety of data sources that include causal (genetic aberrations, differential methylation of the promoter region and miRNA differential expression) and consequential cancer events (gene and protein expression measurements).	('cancer', 'Phenotype', 'HP:0002664', (264, 270))	('cancer', 'Disease', 'MESH:D009369', (264, 270))	('cancer', 'Disease', (264, 270))	('differential methylation', 'Var', (163, 187))
390508	29547932	EP300) aberrant genes.	('EP300', 'Gene', '2033', (0, 5))	('aberrant genes', 'Var', (7, 21))	('EP300', 'Gene', (0, 5))
390512	29547932	NetICS provides insight on how aberration events that are very different between samples of the same cancer type can lead to the same expression changes in other genes due to gene interactions.	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('cancer', 'Disease', (101, 107))	('expression changes', 'MPA', (134, 152))	('aberration', 'Var', (31, 41))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('lead to', 'Reg', (117, 124))	('interactions', 'Interaction', (180, 192))
390513	29547932	The aberration events include aberrations in the genome, differential methylation and significantly differentially expressed miRNA between tumor and normal tissue.	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('differential', 'Reg', (57, 69))	('methylation', 'MPA', (70, 81))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('miRNA', 'MPA', (125, 130))	('tumor', 'Disease', (139, 144))	('aberrations', 'Var', (30, 41))	('differentially', 'Reg', (100, 114))
390517	29547932	A tumor suppressor can be mutated in one sample leading to its loss of function, whereas in another sample, the same tumor suppressor might not be mutated but still downregulated because of a nearby interacting gene which is genetically altered.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('downregulated', 'NegReg', (165, 178))	('tumor', 'Disease', 'MESH:D009369', (2, 7))	('tumor', 'Disease', (117, 122))	('tumor', 'Phenotype', 'HP:0002664', (2, 7))	('loss of function', 'NegReg', (63, 79))	('mutated', 'Var', (26, 33))	('tumor', 'Disease', (2, 7))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
390528	27655328	The involvement of miRNAs in cancer pathogenesis is well established, as they can behave as oncogenes or tumor suppressor genes depending on the cellular functions of their targets.	('cancer', 'Disease', (29, 35))	('miRNAs', 'Var', (19, 25))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumor', 'Disease', (105, 110))	('cancer', 'Disease', 'MESH:D009369', (29, 35))
390574	27655328	miRNAs are frequently located in the cancer-associated genomic regions or in fragile sites of the genome.	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('cancer', 'Disease', (37, 43))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('located', 'Reg', (22, 29))	('miRNAs', 'Var', (0, 6))
390587	27655328	Besides, high GMFB expression was related to poor disease-free survival and overall survival in patients with SOC (serous ovarian cancer).	('expression', 'MPA', (19, 29))	('serous ovarian cancer', 'Disease', (115, 136))	('serous ovarian cancer', 'Disease', 'MESH:D010051', (115, 136))	('GMFB', 'Gene', '2764', (14, 18))	('poor', 'NegReg', (45, 49))	('patients', 'Species', '9606', (96, 104))	('disease-free survival', 'CPA', (50, 71))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('GMFB', 'Gene', (14, 18))	('ovarian cancer', 'Phenotype', 'HP:0100615', (122, 136))	('high', 'Var', (9, 13))
390606	31830929	Human papillomavirus (HPV), mainly HPV16 followed by HPV18, is now recognized as a cause of a fraction of oropharyngeal cancers.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('Human papillomavirus', 'Species', '10566', (0, 20))	('HPV', 'Species', '10566', (35, 38))	('cancers', 'Phenotype', 'HP:0002664', (120, 127))	('HPV', 'Species', '10566', (22, 25))	('cause', 'Reg', (83, 88))	('cancers', 'Disease', (120, 127))	('cancers', 'Disease', 'MESH:D009369', (120, 127))	('HPV', 'Species', '10566', (53, 56))	('Human papillomavirus', 'Disease', (0, 20))	('HPV16', 'Species', '333760', (35, 40))	('HPV16', 'Var', (35, 40))
390615	31830929	In this study, we analyzed the transcript expression profiles and functions of E6 and E7 to delineate the role of HPV18 in esophageal (EC109 and EC9706) and tongue (Tca83) cancers based on cell lines established from Chinese.	('E7', 'Gene', '25479181', (86, 88))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('E6', 'Gene', 'None', (79, 81))	('EC9706', 'Var', (145, 151))	('esophageal', 'Disease', (123, 133))	('HPV', 'Species', '10566', (114, 117))	('Tca83', 'Chemical', '-', (165, 170))	('cancers', 'Disease', 'MESH:D009369', (172, 179))	('cancers', 'Phenotype', 'HP:0002664', (172, 179))	('cancers', 'Disease', (172, 179))	('HPV18', 'Gene', (114, 119))
390619	31830929	The EC109, EC9706 and Tca83 cell lines were generous gifts from Prof. Zeng Yi, the National Institute for Viral Disease Control and Prevention of Chinese Center for Disease Control and Prevention in 2012.	('EC9706', 'Var', (11, 17))	('Viral Disease', 'Disease', (106, 119))	('Viral Disease', 'Disease', 'MESH:D001102', (106, 119))	('Tca83', 'Chemical', '-', (22, 27))
390633	31830929	Viral genome integration resulting in disruption and loss of viral transcripts are remarkable features of HPV-mediated oncogenesis.	('disruption', 'MPA', (38, 48))	('Viral', 'Var', (0, 5))	('viral transcripts', 'MPA', (61, 78))	('loss', 'NegReg', (53, 57))	('HPV', 'Species', '10566', (106, 109))
390634	31830929	Therefore, we examined the HPV transcription profiles in esophageal (EC109 and EC9706), tongue (Tca83) and cervical (HeLa) cancer cell lines.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('HPV', 'Species', '10566', (27, 30))	('EC9706', 'Var', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('Tca83', 'Chemical', '-', (96, 101))	('EC109', 'Var', (69, 74))	('cancer', 'Disease', (123, 129))	('HeLa', 'CellLine', 'CVCL:0030', (117, 121))
390641	31830929	Whilst spliced E6 variant I (E6*I) and E7 were markedly higher in EC109, EC9706 and HeLa (E6*I: 412,299 - 491,899; E7: 599,610 - 626,397) compared to Tca83 (E6*I: 293,362; E7: 457,654) (Table 1).	('E6', 'Gene', 'None', (90, 92))	('Tca83', 'Chemical', '-', (150, 155))	('EC9706', 'Var', (73, 79))	('E7', 'Gene', '25479181', (39, 41))	('E6', 'Gene', 'None', (29, 31))	('E7', 'Gene', '25479181', (115, 117))	('HeLa', 'CellLine', 'CVCL:0030', (84, 88))	('E6', 'Gene', 'None', (15, 17))	('variant I', 'Var', (18, 27))	('higher', 'PosReg', (56, 62))	('E7', 'Gene', '25479181', (172, 174))	('E6', 'Gene', 'None', (157, 159))
390642	31830929	Furthermore, the E7 to E6 ratios in EC109 and EC9706 were nearly doubled relative to those in HeLa and Tca83 (Fig.	('HeLa', 'CellLine', 'CVCL:0030', (94, 98))	('EC109', 'Var', (36, 41))	('doubled', 'PosReg', (65, 72))	('EC9706', 'Var', (46, 52))	('Tca83', 'Chemical', '-', (103, 108))	('E7', 'Gene', '25479181', (17, 19))	('E6', 'Gene', 'None', (23, 25))
390645	31830929	Following the differential expression of HPV18 oncoproteins reported above, we next examined whether E6 and E7 oncoproteins in esophageal (EC109 and EC9706) and tongue (Tca83) cancer cells target key cellular proteins in a similar manner to cervical cancer cells, such as HeLa.	('HPV', 'Species', '10566', (41, 44))	('E7', 'Gene', '25479181', (108, 110))	('EC9706', 'Var', (149, 155))	('cancer', 'Disease', 'MESH:D009369', (250, 256))	('cancer', 'Disease', (250, 256))	('E6', 'Gene', 'None', (101, 103))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))	('cancer', 'Disease', (176, 182))	('HPV18', 'Gene', (41, 46))	('Tca83', 'Chemical', '-', (169, 174))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('HeLa', 'CellLine', 'CVCL:0030', (272, 276))
390650	31830929	2a and b (i)], downregulation of HPV18 E6 in all the esophageal (EC109 and EC9706) and tongue (Tca83) SCC cell lines resulted in a significant rescue of p53 as well as its downstream transactivation target, p21 [Fig.	('downregulation', 'NegReg', (15, 29))	('Tca83', 'Chemical', '-', (95, 100))	('SCC', 'Phenotype', 'HP:0002860', (102, 105))	('SCC', 'Gene', '6317', (102, 105))	('E6', 'Gene', 'None', (39, 41))	('p21', 'Gene', '644914', (207, 210))	('p21', 'Gene', (207, 210))	('p53', 'Gene', (153, 156))	('EC9706', 'Var', (75, 81))	('p53', 'Gene', '7157', (153, 156))	('HPV', 'Species', '10566', (33, 36))	('SCC', 'Gene', (102, 105))	('HPV18', 'Gene', (33, 38))	('rescue', 'PosReg', (143, 149))
390656	31830929	2a and b (iii)], and increased p107 was only found in EC9706 [Fig.	('EC9706', 'Var', (54, 60))	('p107', 'Gene', (31, 35))	('p107', 'Gene', '5933', (31, 35))
390660	31830929	We further examined whether these transcripts harbored mutations that could potentially lead to amino acid alterations, and subsequently affect E7-pRB recognition in EC109, EC9706 and Tca83 compared to HeLa.	('lead to', 'Reg', (88, 95))	('EC9706', 'Var', (173, 179))	('pRB', 'Gene', (147, 150))	('E7', 'Gene', '25479181', (144, 146))	('HeLa', 'CellLine', 'CVCL:0030', (202, 206))	('pRB', 'Gene', '5925', (147, 150))	('Tca83', 'Chemical', '-', (184, 189))	('affect', 'Reg', (137, 143))	('amino acid alterations', 'MPA', (96, 118))
390661	31830929	We observed that RB2 harbored same-sense mutations, corresponding to amino acid positions at T694, R679 and T864, while no exonic mutation was detected within RB1 (Additional file 1).	('RB1', 'Gene', (159, 162))	('R679', 'Var', (99, 103))	('RB1', 'Gene', '5925', (159, 162))	('T694', 'Var', (93, 97))	('T864', 'Var', (108, 112))	('RB2', 'Gene', '5934', (17, 20))	('RB2', 'Gene', (17, 20))
390666	31830929	In general, we observed a higher basal level of both total and phosphorylated AKT at position S473 [pAKT(S473)], ERK 1/2 phosphorylated at position T202/Y204 [pERK1/2(T202/Y204)], MMP2 and MMP9 in EC109, EC9706 and Tca83 compared to HeLa cells (Fig.	('MMP9', 'Gene', (189, 193))	('AKT', 'Gene', '207', (101, 104))	('Tca83', 'Chemical', '-', (215, 220))	('higher', 'PosReg', (26, 32))	('ERK', 'Gene', '5594', (160, 163))	('MMP9', 'Gene', '4318', (189, 193))	('EC9706', 'Var', (204, 210))	('AKT', 'Gene', '207', (78, 81))	('AKT', 'Gene', (101, 104))	('ERK', 'Gene', (160, 163))	('ERK', 'Gene', (113, 116))	('ERK', 'Gene', '5594', (113, 116))	('MMP2', 'Gene', (180, 184))	('HeLa', 'CellLine', 'CVCL:0030', (233, 237))	('basal level', 'MPA', (33, 44))	('AKT', 'Gene', (78, 81))	('MMP2', 'Gene', '4313', (180, 184))
390668	31830929	When HPV18 E6 and E7 in Tca83 cells were depleted using siRNA, we observed significant reduction in pERK1/2 (T202/Y204) and MMP2, together with a significant elevation in ERK1/2 in Tca83 [Fig.	('E6', 'Gene', 'None', (11, 13))	('ERK', 'Gene', '5594', (101, 104))	('E7', 'Gene', '25479181', (18, 20))	('T202/Y204', 'Var', (109, 118))	('ERK', 'Gene', (101, 104))	('Tca83', 'Chemical', '-', (181, 186))	('MMP2', 'Gene', (124, 128))	('Tca83', 'Chemical', '-', (24, 29))	('elevation', 'PosReg', (158, 167))	('ERK', 'Gene', '5594', (171, 174))	('ERK', 'Gene', (171, 174))	('HPV', 'Species', '10566', (5, 8))	('reduction', 'NegReg', (87, 96))	('MMP2', 'Gene', '4313', (124, 128))
390672	31830929	Downregulation of E6 and E7 resulted in a dramatic reduced level of AKT in EC109, but not in the other cells [Fig.	('level', 'MPA', (59, 64))	('EC109', 'Var', (75, 80))	('reduced', 'NegReg', (51, 58))	('Downregulation', 'NegReg', (0, 14))	('E6', 'Gene', 'None', (18, 20))	('AKT', 'Gene', '207', (68, 71))	('E7', 'Gene', '25479181', (25, 27))	('AKT', 'Gene', (68, 71))
390673	31830929	In addition, E6 and E7 downregulation had no significant effect on ERK activity, MMP2 and MMP9 levels in EC109 and EC9706.	('downregulation', 'NegReg', (23, 37))	('MMP2', 'Gene', (81, 85))	('EC9706', 'Var', (115, 121))	('ERK', 'Gene', '5594', (67, 70))	('ERK', 'Gene', (67, 70))	('MMP9', 'Gene', (90, 94))	('MMP2', 'Gene', '4313', (81, 85))	('MMP9', 'Gene', '4318', (90, 94))	('E7', 'Gene', '25479181', (20, 22))	('E6', 'Gene', 'None', (13, 15))
390681	31830929	Our results showed that ablation of E6 and E7 in HeLa led to a significant increased levels of full length caspases 8, 9 and 3 [Fig.	('caspases', 'Gene', 'None', (107, 115))	('full length', 'MPA', (95, 106))	('E7', 'Gene', '25479181', (43, 45))	('levels', 'MPA', (85, 91))	('caspases', 'Gene', (107, 115))	('E6', 'Gene', 'None', (36, 38))	('increased', 'PosReg', (75, 84))	('ablation', 'Var', (24, 32))	('HeLa', 'CellLine', 'CVCL:0030', (49, 53))
390684	31830929	However, we did not observe activation of these initiator and effector caspases in EC109 and EC9706 (Fig.	('caspases', 'Gene', 'None', (71, 79))	('EC9706', 'Var', (93, 99))	('EC109', 'Var', (83, 88))	('caspases', 'Gene', (71, 79))
390690	31830929	We observed a significant reduction in Ki67 expression in HeLa, EC9706 and Tca83, but not in EC109 upon ablation of E6 and E7 [Fig.	('Tca83', 'Chemical', '-', (75, 80))	('expression', 'MPA', (44, 54))	('Ki67', 'Gene', (39, 43))	('reduction', 'NegReg', (26, 35))	('EC9706', 'Var', (64, 70))	('E6', 'Gene', 'None', (116, 118))	('E7', 'Gene', '25479181', (123, 125))	('ablation', 'Var', (104, 112))	('HeLa', 'CellLine', 'CVCL:0030', (58, 62))
390692	31830929	Our results indicated that E6 and E7 promote proliferation of EC9706 and Tca83.	('E6', 'Gene', 'None', (27, 29))	('proliferation', 'CPA', (45, 58))	('promote', 'PosReg', (37, 44))	('Tca83', 'Gene', (73, 78))	('Tca83', 'Chemical', '-', (73, 78))	('E7', 'Gene', '25479181', (34, 36))	('EC9706', 'Var', (62, 68))
390693	31830929	Surprisingly, ablation of E6 and E7 was not adequate to initiate activation of caspase pathway in both EC109 and EC9706, as well as did not affect proliferation of EC109.	('caspase pathway', 'Pathway', (79, 94))	('E7', 'Gene', '25479181', (33, 35))	('E6', 'Gene', 'None', (26, 28))	('EC9706', 'Var', (113, 119))	('ablation', 'Var', (14, 22))
390704	31830929	Both EC109 and EC9706 expressed relatively higher levels of E7 and E6*I, while HeLa and Tca83 expressed relatively higher levels of E6.	('Tca83', 'Chemical', '-', (88, 93))	('higher', 'PosReg', (43, 49))	('E6', 'Gene', 'None', (132, 134))	('EC9706', 'Var', (15, 21))	('E6', 'Gene', 'None', (67, 69))	('E7', 'Gene', '25479181', (60, 62))	('HeLa', 'CellLine', 'CVCL:0030', (79, 83))	('EC109', 'Var', (5, 10))
390723	31830929	The role of HPV oncoproteins in EC109 and EC9706 in cellular targeting are indeed distinct from that in HeLa and Tca83.	('EC109', 'Var', (32, 37))	('Tca83', 'Chemical', '-', (113, 118))	('HeLa', 'CellLine', 'CVCL:0030', (104, 108))	('cellular targeting', 'MPA', (52, 70))	('HPV', 'Species', '10566', (12, 15))	('EC9706', 'Var', (42, 48))
390724	31830929	Although these cells share certain degrees of similarity, EC109 and EC9706 can differ from each other in term of HPV18 genome transcripts and subset of cellular proteins targeted by HPV oncoproteins.	('HPV', 'Species', '10566', (182, 185))	('HPV18', 'Gene', (113, 118))	('EC109', 'Var', (58, 63))	('EC9706', 'Var', (68, 74))	('HPV', 'Species', '10566', (113, 116))
390730	31830929	This could occur through perturbation of transforming growth factor-beta1 (TGF-beta1) signaling, which is important for epithelial-mesenchymal transition (EMT) of EC9706, and subsequently leading to inactivation of Fas-mediated apoptosis in a caspase-independent fashion.	('EC9706', 'Var', (163, 169))	('inactivation', 'NegReg', (199, 211))	('transforming growth factor-beta1', 'Gene', '7040', (41, 73))	('Fas-mediated', 'Pathway', (215, 227))	('perturbation', 'Var', (25, 37))	('transforming growth factor-beta1', 'Gene', (41, 73))	('TGF-beta1', 'Gene', '7040', (75, 84))	('TGF-beta1', 'Gene', (75, 84))
390744	31370883	Histone methyltransferase SMYD2: ubiquitous regulator of disease SET (Suppressor of variegation, Enhancer of Zeste, Trithorax) and MYND (Myeloid-Nervy-DEAF1) domain-containing protein 2 (SMYD2) is a protein methyltransferase that methylates histone H3 at lysine 4 (H3K4) or lysine 36 (H3K36) and diverse nonhistone proteins.	('Histone methyltransferase SMYD2', 'Gene', (0, 31))	('DEAF1', 'Gene', '10522', (151, 156))	('DEAF1', 'Gene', (151, 156))	('histone H3 at lysine 4 (H3K4', 'Protein', (241, 269))	('lysine', 'Chemical', 'MESH:D008239', (274, 280))	('SET', 'Gene', (65, 68))	('lysine', 'Chemical', 'MESH:D008239', (255, 261))	('Histone methyltransferase SMYD2', 'Gene', '56950', (0, 31))	('H3K4', 'Protein', (265, 269))	('lysine', 'Var', (274, 280))	('SET', 'Gene', '56950', (65, 68))
390745	31370883	Since aberrant SMYD2 expression and its dysfunction are often closely related to multiple diseases, SMYD2 is a promising candidate for the treatment of these diseases, such as cardiovascular disease and cancer.	('SMYD2', 'Gene', (15, 20))	('cardiovascular disease', 'Disease', (176, 198))	('multiple diseases', 'Disease', (81, 98))	('aberrant', 'Var', (6, 14))	('cardiovascular disease', 'Phenotype', 'HP:0001626', (176, 198))	('expression', 'MPA', (21, 31))	('cancer', 'Disease', (203, 209))	('cancer', 'Disease', 'MESH:D009369', (203, 209))	('cardiovascular disease', 'Disease', 'MESH:D002318', (176, 198))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('multiple diseases', 'Disease', 'MESH:D000015', (81, 98))	('related', 'Reg', (70, 77))	('dysfunction', 'MPA', (40, 51))
390750	31370883	PKMTs consist of two classes: SET (Suppressor of variegation, Enhancer of Zeste, Trithorax) domain-containing PKMTs and non-SET-domain-containing PKMTs, both of which are able to methylate lysine on its epsilon-amine group as mono (me1), di (me2), or tri (me3) methylation (Fig.	('SET', 'Gene', '56950', (124, 127))	('tri', 'MPA', (251, 254))	('tri (me3)', 'Chemical', '-', (251, 260))	('SET', 'Gene', (30, 33))	('lysine', 'Chemical', 'MESH:D008239', (189, 195))	('di (me2', 'Var', (238, 245))	('methylate', 'Var', (179, 188))	('amine', 'Chemical', 'MESH:D000588', (211, 216))	('SET', 'Gene', '56950', (30, 33))	('SET', 'Gene', (124, 127))	('mono (me1)', 'Chemical', '-', (226, 236))	('di (me2)', 'Chemical', '-', (238, 246))
390754	31370883	There are five members of the SET and MYND (Myeloid-Nervy-DEAF1) domain-containing (SMYD) protein family, which is a special class of PKMTs that methylate both histones and nonhistone targets (Fig.	('DEAF1', 'Gene', (58, 63))	('SET', 'Gene', (30, 33))	('histones', 'Protein', (160, 168))	('SET', 'Gene', '56950', (30, 33))	('DEAF1', 'Gene', '10522', (58, 63))	('methylate', 'Var', (145, 154))
390766	31370883	These results showed that the overall structure of SMYD2 is composed of five structurally distinct domains, including the S-sequence (1-46 aa), MYND domain (47-96 aa), insertion SET domain (97-243 aa), cysteine-rich post-SET domain (244-271 aa), and tetratrico-peptide repeat (TPR) domain (272-433 aa), which together form two large lobes that are separated by a deep groove.	('SET', 'Gene', '56950', (221, 224))	('rat', 'Species', '10116', (352, 355))	('SET', 'Gene', (178, 181))	('rat', 'Species', '10116', (253, 256))	('244-271', 'Var', (233, 240))	('SET', 'Gene', '56950', (178, 181))	('SMYD2', 'Gene', (51, 56))	('cysteine', 'Chemical', 'MESH:D003545', (202, 210))	('SET', 'Gene', (221, 224))
390768	31370883	The S-sequence is important for optimal enzymatic activity of SMYD2, while the post-SET domain is essential for enzymatic activity as removing it completely abolishes enzymatic activity.	('removing', 'Var', (134, 142))	('SET', 'Gene', (84, 87))	('SET', 'Gene', '56950', (84, 87))	('abolishes', 'NegReg', (157, 166))	('enzymatic activity', 'MPA', (167, 185))
390775	31370883	Modeling study of SMYD2 in complex with a p53 peptide indicates that monomethylation of p53-Lys372 mediated by SET7/9 might result in steric conflict of the methyl group with the surrounding residues of SMYD2 to inhibit SMYD2-mediated methylation of p53-Lys370.	('SMYD2-mediated methylation', 'MPA', (220, 246))	('steric', 'MPA', (134, 140))	('SET7/9', 'Gene', '80854', (111, 117))	('SET7/9', 'Gene', (111, 117))	('Lys372', 'Chemical', '-', (92, 98))	('inhibit', 'NegReg', (212, 219))	('Lys370', 'Chemical', '-', (254, 260))	('monomethylation', 'Var', (69, 84))	('result in', 'Reg', (124, 133))
390776	31370883	In addition, AZ505, a substrate-competitive inhibitor of SMYD2, binds in the peptide binding groove of SMYD2 to confine other substrates binding.	('rat', 'Species', '10116', (131, 134))	('AZ505', 'Chemical', 'MESH:C568821', (13, 18))	('AZ505', 'Var', (13, 18))	('rat', 'Species', '10116', (27, 30))	('SMYD2', 'Gene', (103, 108))	('binds', 'Interaction', (64, 69))
390779	31370883	For example, SMYD2 was reported to monomethylate p53 at K370 and pRb at K860 to inhibit the activities of these proteins.	('inhibit', 'NegReg', (80, 87))	('monomethylate', 'Var', (35, 48))	('activities', 'MPA', (92, 102))	('p53', 'Var', (49, 52))	('proteins', 'Protein', (112, 120))	('pRb', 'Gene', '5925', (65, 68))	('pRb', 'Gene', (65, 68))
390785	31370883	More importantly, several canonical nonhistone proteins, including p53 (K370me1), HSP90 (K616me1), PTEN (K313me1), RB (K860me1 and K810me1), ERalpha (K266me1), HSP90AB1 (K531me1 and K574me1), STAT3, p65, BMPR2, MAPKAPK3, ALK, and PARP1, have been reported to be methylated by SMYD2 to affect cell proliferation, cellular differentiation, and cell survival.	('MAPKAPK3', 'Gene', (211, 219))	('cellular differentiation', 'CPA', (312, 336))	('ALK', 'Gene', (221, 224))	('HSP90', 'Gene', '3320', (82, 87))	('K810me1', 'Var', (131, 138))	('K616me1', 'Var', (89, 96))	('affect', 'Reg', (285, 291))	('BMPR2', 'Gene', '659', (204, 209))	('K266me1', 'Var', (150, 157))	('HSP90AB1', 'Gene', (160, 168))	('K860me1', 'Var', (119, 126))	('K313me1', 'Var', (105, 112))	('RB', 'Phenotype', 'HP:0009919', (115, 117))	('HSP90', 'Gene', (160, 165))	('ERalpha', 'Gene', (141, 148))	('K574me1', 'Var', (182, 189))	('PTEN', 'Gene', (99, 103))	('cell survival', 'CPA', (342, 355))	('PARP1', 'Gene', (230, 235))	('HSP90', 'Gene', '3320', (160, 165))	('K370me1', 'Var', (72, 79))	('cell proliferation', 'CPA', (292, 310))	('BMPR2', 'Gene', (204, 209))	('ERalpha', 'Gene', '2099', (141, 148))	('RB', 'Gene', '5925', (115, 117))	('K266', 'Chemical', '-', (150, 154))	('SMYD2', 'Gene', (276, 281))	('PTEN', 'Gene', '5728', (99, 103))	('HSP90', 'Gene', (82, 87))	('HSP90AB1', 'Gene', '3326', (160, 168))	('rat', 'Species', '10116', (304, 307))	('ALK', 'Gene', '238', (221, 224))	('MAPKAPK3', 'Gene', '7867', (211, 219))	('PARP1', 'Gene', '142', (230, 235))
390787	31370883	AZ505, the first inhibitor of SMYD2 identified from a high-throughput chemical screen, shows greater selectivity toward SMYD2 than other KMTs (e.g., DOT1L and EZH2) with an inhibitory potency in the submicromolar range (IC50 = 0.12 muM).	('DOT1L', 'Gene', (149, 154))	('DOT1L', 'Gene', '84444', (149, 154))	('AZ505', 'Chemical', 'MESH:C568821', (0, 5))	('AZ505', 'Var', (0, 5))	('selectivity', 'MPA', (101, 112))
390788	31370883	AZ505 binds in the peptide binding groove of SMYD2 to competitively inhibit the binding of substrates, such as p53.	('AZ505', 'Chemical', 'MESH:C568821', (0, 5))	('inhibit', 'NegReg', (68, 75))	('AZ505', 'Var', (0, 5))	('binding', 'Interaction', (80, 87))	('SMYD2', 'Gene', (45, 50))	('rat', 'Species', '10116', (96, 99))
390791	31370883	More importantly, LLY-507 inhibits the proliferation of multiple tumor cell lines in a dose-dependent manner.	('inhibits', 'NegReg', (26, 34))	('rat', 'Species', '10116', (46, 49))	('tumor', 'Disease', (65, 70))	('LLY-507', 'Chemical', 'MESH:C000600304', (18, 25))	('LLY-507', 'Var', (18, 25))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
390793	31370883	Furthermore, A-893 showed 80-fold more activity than AZ505 when tested by a biochemical assay.	('AZ505', 'Chemical', 'MESH:C568821', (53, 58))	('activity', 'MPA', (39, 47))	('more', 'PosReg', (34, 38))	('A-893', 'Var', (13, 18))
390797	31370883	In addition, AZ506 and EPZ033294 are inhibitors of SMYD2 that can inhibit the proliferation of cancer cell lines and p53 methylation.	('p53', 'Protein', (117, 120))	('EPZ033294', 'Var', (23, 32))	('EPZ033294', 'Chemical', '-', (23, 32))	('methylation', 'MPA', (121, 132))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('cancer', 'Disease', (95, 101))	('rat', 'Species', '10116', (85, 88))	('inhibit', 'NegReg', (66, 73))	('AZ506', 'Var', (13, 18))	('SMYD2', 'Gene', (51, 56))	('AZ506', 'Chemical', '-', (13, 18))
390803	31370883	In addition, the mice with or without SMYD2 deficiency had similar cardiac function, which was assessed by MRI-analysis.	('cardiac function', 'CPA', (67, 83))	('mice', 'Species', '10090', (17, 21))	('deficiency', 'Var', (44, 54))	('SMYD2', 'Gene', (38, 43))
390804	31370883	Thus, these results indicate that SMYD2 is dispensable for mouse heart development, while it was reported that SMYD2 knockdown results in developmental delay and aberrant tail formation in zebrafish.	('zebrafish', 'Species', '7955', (189, 198))	('mouse', 'Species', '10090', (59, 64))	('aberrant tail formation', 'CPA', (162, 185))	('knockdown', 'Var', (117, 126))	('developmental delay', 'Phenotype', 'HP:0001263', (138, 157))	('developmental delay', 'Disease', 'MESH:D002658', (138, 157))	('developmental delay', 'Disease', (138, 157))	('SMYD2', 'Gene', (111, 116))
390808	31370883	reported that knockdown of SMYD2 in zebrafish leads to heart defect and cardiac dysfunction.	('cardiac dysfunction', 'Disease', (72, 91))	('zebrafish', 'Species', '7955', (36, 45))	('cardiac dysfunction', 'Disease', 'MESH:D006331', (72, 91))	('heart defect', 'Disease', (55, 67))	('heart defect', 'Disease', 'MESH:D006331', (55, 67))	('SMYD2', 'Gene', (27, 32))	('knockdown', 'Var', (14, 23))	('leads to', 'Reg', (46, 54))	('heart defect', 'Phenotype', 'HP:0030680', (55, 67))
390809	31370883	Their results demonstrated that SMYD2 deficiency zebrafish showed malformation of both the atrium and ventricle and also presented pericardial edema, elongation and thinning of the hearts, inflow tract edema, and reduced heart rate and cardiac function.	('edema', 'Phenotype', 'HP:0000969', (143, 148))	('deficiency', 'Var', (38, 48))	('edema', 'Disease', 'MESH:D004487', (143, 148))	('edema', 'Disease', (143, 148))	('zebrafish', 'Species', '7955', (49, 58))	('rat', 'Species', '10116', (21, 24))	('reduced', 'NegReg', (213, 220))	('edema', 'Phenotype', 'HP:0000969', (202, 207))	('thinning', 'CPA', (165, 173))	('pericardial edema', 'Disease', 'MESH:D004487', (131, 148))	('pericardial edema', 'Phenotype', 'HP:0001698', (131, 148))	('cardiac function', 'CPA', (236, 252))	('edema', 'Disease', 'MESH:D004487', (202, 207))	('SMYD2', 'Gene', (32, 37))	('rat', 'Species', '10116', (227, 230))	('elongation', 'CPA', (150, 160))	('heart rate', 'CPA', (221, 231))	('malformation', 'CPA', (66, 78))	('pericardial edema', 'Disease', (131, 148))	('edema', 'Disease', (202, 207))
390814	31370883	For example, the results of EZH2myh6-cre and EZH2cTNT-Cre knockout mice demonstrated that EZH2 is dispensable for heart repair, but EZH2Nkx2-5-cre knockout mice displayed later disruption of cardiomyocyte gene expression and heart development, and EZH2mef2c-AHF-Cre knockout mice showed postnatal myocardial pathology.	('mice', 'Species', '10090', (275, 279))	('disruption', 'NegReg', (177, 187))	('cardiomyocyte', 'Protein', (191, 204))	('EZH2Nkx2-5-cre', 'Var', (132, 146))	('mice', 'Species', '10090', (156, 160))	('rat', 'Species', '10116', (79, 82))	('heart development', 'CPA', (225, 242))	('postnatal myocardial pathology', 'CPA', (287, 317))	('mice', 'Species', '10090', (67, 71))
390815	31370883	A recently study demonstrated that SMYD2 is selectively glutathionylated at cysteine 13 in response to reactive oxygen species, and SMYD2 glutathionylation or oxidation decreases the viability of H9c2 cells and reduces myofibril integrity.	('SMYD2 glutathionylation', 'Var', (132, 155))	('cysteine', 'Chemical', 'MESH:D003545', (76, 84))	('H9c2', 'CellLine', 'CVCL:0286', (196, 200))	('glutathionylation', 'Var', (138, 155))	('myofibril integrity', 'CPA', (219, 238))	('reduces', 'NegReg', (211, 218))	('decreases', 'NegReg', (169, 178))	('viability', 'CPA', (183, 192))	('oxidation', 'Var', (159, 168))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (103, 126))	('rat', 'Species', '10116', (24, 27))
390817	31370883	In cobalt chloride-induced neonatal rat ventricular cardiomyocytes, SMYD2 expression levels are significantly decreased, and knockdown of SMYD2 promotes cobalt chloride-induced cardiomyocyte apoptosis by affecting p53 methylation and stability.	('knockdown', 'Var', (125, 134))	('stability', 'MPA', (234, 243))	('cardiomyocyte apoptosis', 'CPA', (177, 200))	('rat', 'Species', '10116', (36, 39))	('p53', 'Protein', (214, 217))	('promotes', 'PosReg', (144, 152))	('decreased', 'NegReg', (110, 119))	('cobalt chloride', 'Chemical', 'MESH:C018021', (3, 18))	('SMYD2', 'Gene', (138, 143))	('expression levels', 'MPA', (74, 91))	('affecting', 'Reg', (204, 213))	('cobalt chloride', 'Chemical', 'MESH:C018021', (153, 168))	('methylation', 'MPA', (218, 229))
390818	31370883	Moreover, cardiac-specific deletion of SMYD2 in mice promotes apoptotic cell death upon myocardial infarction (Fig.	('promotes', 'PosReg', (53, 61))	('SMYD2', 'Gene', (39, 44))	('myocardial infarction', 'Phenotype', 'HP:0001658', (88, 109))	('mice', 'Species', '10090', (48, 52))	('deletion', 'Var', (27, 35))	('myocardial infarction', 'Disease', 'MESH:D009203', (88, 109))	('apoptotic cell death', 'CPA', (62, 82))	('myocardial infarction', 'Disease', (88, 109))
390822	31370883	assessed global DNA methylation in peripheral blood mononuclear cell DNA from 92 AAA cases and 93 controls; their data showed that four CpGs (NC_000001.11: 214280412, 214280441, 214280507, and 214280600) were hypomethylated in the SMYD2 promoter upstream of the transcriptional start site in AAA patients compared to controls.	('AAA', 'Phenotype', 'HP:0005112', (81, 84))	('AAA', 'Gene', '100329167', (81, 84))	('AAA', 'Gene', (81, 84))	('214280441', 'Var', (167, 176))	('214280600', 'Var', (193, 202))	('AAA', 'Gene', '100329167', (292, 295))	('214280507', 'Var', (178, 187))	('AAA', 'Gene', (292, 295))	('AAA', 'Phenotype', 'HP:0005112', (292, 295))	('hypomethylated', 'Var', (209, 223))	('patients', 'Species', '9606', (296, 304))
390827	31370883	Hsp90 may also mediate the role of SMYD2 in AAA formation because Hsp90 is monomethylated by SMYD2, and the inhibition of Hsp90 could reduce AAA formation in murine models.	('Hsp90', 'Protein', (66, 71))	('AAA', 'Phenotype', 'HP:0005112', (44, 47))	('reduce', 'NegReg', (134, 140))	('AAA', 'Gene', '100329167', (44, 47))	('AAA', 'Gene', (44, 47))	('murine', 'Species', '10090', (158, 164))	('AAA', 'Gene', '100329167', (141, 144))	('AAA', 'Gene', (141, 144))	('Hsp90', 'Protein', (122, 127))	('AAA', 'Phenotype', 'HP:0005112', (141, 144))	('inhibition', 'Var', (108, 118))
390833	31370883	However, Set9-mediated p53 methylation at Lys372 (p53K372me1) could inhibit SMYD2-mediated methylation of Lys370 by blocking the interaction between p53 and SMYD2.	('Set9', 'Gene', (9, 13))	('SMYD2-mediated methylation', 'MPA', (76, 102))	('Lys372', 'Chemical', '-', (42, 48))	('Lys370', 'Var', (106, 112))	('inhibit', 'NegReg', (68, 75))	('blocking', 'NegReg', (116, 124))	('Lys370', 'Chemical', '-', (106, 112))	('Set9', 'Gene', '80854', (9, 13))	('interaction', 'Interaction', (129, 140))
390841	31370883	demonstrated that SMYD2 expressed at higher levels; furthermore, knockdown of SMYD2 in triple-negative breast cancer (TNBC) cell lines or inhibition of SMYD2 activity by AZ505 significantly reduced tumor growth in vivo.	('inhibition', 'NegReg', (138, 148))	('SMYD2', 'Gene', (78, 83))	('activity', 'MPA', (158, 166))	('BC', 'Phenotype', 'HP:0003002', (120, 122))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('breast cancer', 'Disease', 'MESH:D001943', (103, 116))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('reduced', 'NegReg', (190, 197))	('breast cancer', 'Disease', (103, 116))	('rat', 'Species', '10116', (7, 10))	('breast cancer', 'Phenotype', 'HP:0003002', (103, 116))	('tumor', 'Disease', (198, 203))	('knockdown', 'Var', (65, 74))	('AZ505', 'Chemical', 'MESH:C568821', (170, 175))
390842	31370883	Mechanistically, SMYD2 promotes TNBC cell proliferation and survival via methylation and activation of STAT3 and the p65 subunit of NF-kappaB.	('survival', 'CPA', (60, 68))	('STAT3', 'Protein', (103, 108))	('promotes', 'PosReg', (23, 31))	('p65 subunit of NF-kappaB', 'Gene', '5970', (117, 141))	('p65 subunit of NF-kappaB', 'Gene', (117, 141))	('BC', 'Phenotype', 'HP:0003002', (34, 36))	('SMYD2', 'Gene', (17, 22))	('methylation', 'Var', (73, 84))	('activation', 'PosReg', (89, 99))	('rat', 'Species', '10116', (49, 52))
390843	31370883	Estrogen signaling plays important roles in cell growth and differentiation, and its dysregulation leads to many human diseases, including a variety of human cancers (e.g., breast and ovarian cancer).	('dysregulation', 'Var', (85, 98))	('leads to', 'Reg', (99, 107))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('cancers', 'Phenotype', 'HP:0002664', (158, 165))	('cancers', 'Disease', (158, 165))	('breast and ovarian cancer', 'Disease', 'MESH:D010051', (173, 198))	('human', 'Species', '9606', (152, 157))	('cancers', 'Disease', 'MESH:D009369', (158, 165))	('ovarian cancer', 'Phenotype', 'HP:0100615', (184, 198))	('human diseases', 'Disease', (113, 127))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('human', 'Species', '9606', (113, 118))
390854	31370883	These results indicate that SMYD2-mediated methylation of PTEN at Lysine 313 diminishes the phosphorylation of PTEN at Serine 380, which subsequently results in AKT activation to promote breast cancer cell growth.	('diminishes', 'NegReg', (77, 87))	('PTEN', 'Gene', '5728', (58, 62))	('phosphorylation', 'MPA', (92, 107))	('breast cancer', 'Phenotype', 'HP:0003002', (187, 200))	('PTEN', 'Gene', (111, 115))	('breast cancer', 'Disease', (187, 200))	('methylation', 'Var', (43, 54))	('PTEN', 'Gene', '5728', (111, 115))	('promote', 'PosReg', (179, 186))	('AKT', 'Gene', (161, 164))	('Serine', 'Chemical', 'MESH:D012694', (119, 125))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('AKT', 'Gene', '207', (161, 164))	('breast cancer', 'Disease', 'MESH:D001943', (187, 200))	('Lysine', 'Chemical', 'MESH:D008239', (66, 72))	('activation', 'PosReg', (165, 175))	('PTEN', 'Gene', (58, 62))
390856	31370883	found that SMYD2 expression levels are significantly increased in high-grade serous ovarian carcinoma (HGSOC) clinical tissues, and knockdown of SMYD2 or inhibition of SMYD2 with LLY-507 accelerates apoptotic cell death.	('LLY-507', 'Chemical', 'MESH:C000600304', (179, 186))	('expression levels', 'MPA', (17, 34))	('rat', 'Species', '10116', (193, 196))	('knockdown', 'Var', (132, 141))	('serous ovarian carcinoma', 'Disease', 'MESH:D010051', (77, 101))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (84, 101))	('inhibition', 'Var', (154, 164))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('SMYD2', 'Gene', (11, 16))	('increased', 'PosReg', (53, 62))	('apoptotic cell death', 'CPA', (199, 219))	('SMYD2', 'Gene', (145, 150))	('accelerates', 'PosReg', (187, 198))	('serous ovarian carcinoma', 'Disease', (77, 101))
390858	31370883	PARP1 is considered an important target for the development of anticancer therapy, and its inhibitor, olaparib, was developed for BRCA1/2 mutated HGSOC.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('olaparib', 'Chemical', 'MESH:C531550', (102, 110))	('cancer', 'Disease', (67, 73))	('mutated', 'Var', (138, 145))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('BRCA1/2', 'Gene', (130, 137))	('PARP1', 'Gene', '142', (0, 5))	('BRCA1/2', 'Gene', '672;675', (130, 137))	('PARP1', 'Gene', (0, 5))
390860	31370883	Thus, the synergistic effect of LLY-507 and olaparib against HGSOC may be associated with the role of SMYD2 in PARP1 methylation.	('PARP1', 'Gene', '142', (111, 116))	('PARP1', 'Gene', (111, 116))	('LLY-507', 'Chemical', 'MESH:C000600304', (32, 39))	('HGSOC', 'Disease', (61, 66))	('synergistic effect', 'MPA', (10, 28))	('olaparib', 'Chemical', 'MESH:C531550', (44, 52))	('LLY-507', 'Var', (32, 39))
390861	31370883	The abovementioned studies indicate that SMYD2 is overexpressed in BC and HGSOC patients, and SMYD2 may function as a potential biomarker for diagnosing these cancers.	('cancers', 'Disease', (159, 166))	('BC', 'Phenotype', 'HP:0003002', (67, 69))	('patients', 'Species', '9606', (80, 88))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('overexpressed', 'PosReg', (50, 63))	('cancers', 'Phenotype', 'HP:0002664', (159, 166))	('cancers', 'Disease', 'MESH:D009369', (159, 166))	('SMYD2', 'Var', (94, 99))
390862	31370883	More importantly, the inhibition of SMYD2 could be a very efficient therapeutic strategy for BC and HGSOC; however, more specific inhibitors should be developed, and multicenter clinical trials should be performed to validate this hypothesis.	('inhibition', 'Var', (22, 32))	('BC', 'Phenotype', 'HP:0003002', (93, 95))	('SMYD2', 'Gene', (36, 41))	('rat', 'Species', '10116', (82, 85))	('HGSOC', 'Disease', (100, 105))
390864	31370883	Interestingly, in addition to Lysine 860, Lysine 810 of RB is also methylated by SMYD2, which enhances Serine 807/811 phosphorylation of RB, and mediates the role of SMYD2 in bladder cancer cell growth.	('enhances', 'PosReg', (94, 102))	('Lysine 810', 'Var', (42, 52))	('RB', 'Gene', '5925', (56, 58))	('bladder cancer', 'Phenotype', 'HP:0009725', (175, 189))	('mediates', 'Reg', (145, 153))	('RB', 'Phenotype', 'HP:0009919', (137, 139))	('Serine 807/811 phosphorylation', 'MPA', (103, 133))	('Lysine', 'Chemical', 'MESH:D008239', (30, 36))	('bladder cancer', 'Disease', 'MESH:D001749', (175, 189))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('RB', 'Phenotype', 'HP:0009919', (56, 58))	('Lysine', 'Chemical', 'MESH:D008239', (42, 48))	('bladder cancer', 'Disease', (175, 189))	('Serine', 'Chemical', 'MESH:D012694', (103, 109))	('RB', 'Gene', '5925', (137, 139))
390865	31370883	Moreover, methylated RB accelerates E2F transcriptional activity and promotes cell cycle progression.	('RB', 'Gene', '5925', (21, 23))	('promotes', 'PosReg', (69, 77))	('rat', 'Species', '10116', (30, 33))	('RB', 'Phenotype', 'HP:0009919', (21, 23))	('accelerates', 'PosReg', (24, 35))	('methylated', 'Var', (10, 20))	('transcriptional activity', 'MPA', (40, 64))	('E2F', 'Protein', (36, 39))	('cell cycle progression', 'CPA', (78, 100))
390866	31370883	Most importantly, the expression level of SMYD2 is significantly increased in human bladder carcinoma compared with nonneoplastic bladder tissues, which indicates that inhibitors of SMYD2 may have a therapeutic effect on bladder carcinoma.	('nonneoplastic bladder tissues', 'Disease', (116, 145))	('increased', 'PosReg', (65, 74))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (221, 238))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('carcinoma', 'Phenotype', 'HP:0030731', (229, 238))	('inhibitors', 'Var', (168, 178))	('expression level', 'MPA', (22, 38))	('SMYD2', 'Gene', (42, 47))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (84, 101))	('bladder carcinoma', 'Disease', (221, 238))	('SMYD2', 'Gene', (182, 187))	('bladder carcinoma', 'Disease', 'MESH:D001749', (221, 238))	('nonneoplastic bladder tissues', 'Disease', 'MESH:D001745', (116, 145))	('bladder carcinoma', 'Disease', (84, 101))	('bladder carcinoma', 'Disease', 'MESH:D001749', (84, 101))	('human', 'Species', '9606', (78, 83))
390871	31370883	They identified 1861 Kme1 sites in SMYD2-overexpressing ESCC cells, 35 of which were potently downregulated by both SMYD2 knockdown and SMYD2 inhibition by LLY-507.	('Kme1', 'Chemical', '-', (21, 25))	('SMYD2', 'Gene', (116, 121))	('knockdown', 'Var', (122, 131))	('LLY-507', 'Chemical', 'MESH:C000600304', (156, 163))	('downregulated', 'NegReg', (94, 107))
390876	31370883	High SMYD2 expression is correlated with a poor prognosis in ALL patients, and patients with low SMYD2 expression levels are more sensitive to chemotherapy.	('SMYD2', 'Gene', (5, 10))	('High', 'Var', (0, 4))	('ALL', 'Phenotype', 'HP:0006721', (61, 64))	('expression', 'MPA', (11, 21))	('patients', 'Species', '9606', (65, 73))	('patients', 'Species', '9606', (79, 87))
390877	31370883	SMYD2 is directly activated by the transcription factor MYC, and ablation of SMYD2 impedes the development of leukemia promoted by the fusion oncogene MLL-AF9.	('development', 'CPA', (95, 106))	('SMYD2', 'Gene', (77, 82))	('leukemia', 'Disease', (110, 118))	('leukemia', 'Phenotype', 'HP:0001909', (110, 118))	('MLL-AF9', 'Gene', (151, 158))	('leukemia', 'Disease', 'MESH:D007938', (110, 118))	('impedes', 'NegReg', (83, 90))	('ablation', 'Var', (65, 73))	('MLL-AF9', 'Gene', '4297', (151, 158))
390878	31370883	In addition, SMYD2 knockdown confers relative resistance of human acute myeloid leukemia cells to multiple classes of DNA damaging agents, which is associated with the compensatory upregulation of SET7/9.	('myeloid leukemia', 'Phenotype', 'HP:0012324', (72, 88))	('SET7/9', 'Gene', '80854', (197, 203))	('knockdown', 'Var', (19, 28))	('SMYD2', 'Gene', (13, 18))	('myeloid leukemia', 'Disease', (72, 88))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (66, 88))	('SET7/9', 'Gene', (197, 203))	('leukemia', 'Phenotype', 'HP:0001909', (80, 88))	('myeloid leukemia', 'Disease', 'MESH:D007951', (72, 88))	('resistance', 'CPA', (46, 56))	('human', 'Species', '9606', (60, 65))
390883	31370883	SMYD2 also methylates HSP90AB1 at lysines 531 and 574 to accelerate the proliferation of cancer cells.	('HSP90AB1', 'Gene', (22, 30))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('HSP90AB1', 'Gene', '3326', (22, 30))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('methylates', 'Var', (11, 21))	('rat', 'Species', '10116', (79, 82))	('cancer', 'Disease', (89, 95))	('lysines 531', 'Var', (34, 45))	('rat', 'Species', '10116', (63, 66))	('accelerate', 'PosReg', (57, 67))	('lysines', 'Chemical', 'MESH:D008239', (34, 41))
390885	31370883	SMYD2 overexpression has been observed in all the types of tumors investigated, and knockdown or inhibition of SMYD2 suppresses tumor cell growth by methylating different substrates in different cancers.	('rat', 'Species', '10116', (176, 179))	('tumor', 'Disease', (59, 64))	('knockdown', 'Var', (84, 93))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumors', 'Disease', 'MESH:D009369', (59, 65))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('cancers', 'Disease', 'MESH:D009369', (195, 202))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('inhibition', 'Var', (97, 107))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('suppresses', 'NegReg', (117, 127))	('tumor', 'Disease', (128, 133))	('SMYD2', 'Gene', (111, 116))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('methylating different substrates', 'MPA', (149, 181))	('tumors', 'Disease', (59, 65))	('cancers', 'Phenotype', 'HP:0002664', (195, 202))	('cancers', 'Disease', (195, 202))
390886	31370883	However, a recently published study offered a different conclusion; this study used CRISPR/Cas9 to genetically ablate SMYD2, and the results indicated that SMYD2 activity is dispensable for autonomous cancer cell proliferation.	('SMYD2', 'Gene', (118, 123))	('genetically', 'Var', (99, 110))	('autonomous cancer', 'Disease', 'MESH:D009369', (190, 207))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('rat', 'Species', '10116', (220, 223))	('autonomous cancer', 'Disease', (190, 207))	('ablate', 'NegReg', (111, 117))
390888	31370883	found that SMYD2 is upregulated in renal epithelial cells, kidney tissues from Pkd1 mutant mice, and autosomal dominant polycystic kidney disease (ADPKD) patients.	('mice', 'Species', '10090', (91, 95))	('autosomal dominant polycystic kidney disease', 'Disease', 'MESH:D007690', (101, 145))	('polycystic kidney', 'Phenotype', 'HP:0000113', (120, 137))	('autosomal dominant polycystic kidney disease', 'Disease', (101, 145))	('patients', 'Species', '9606', (154, 162))	('ADPKD', 'Disease', (147, 152))	('SMYD2', 'Gene', (11, 16))	('mutant', 'Var', (84, 90))	('upregulated', 'PosReg', (20, 31))	('ADPKD', 'Disease', 'MESH:D007690', (147, 152))	('Pkd1', 'Gene', '18763', (79, 83))	('kidney disease', 'Phenotype', 'HP:0000112', (131, 145))	('Pkd1', 'Gene', (79, 83))
390889	31370883	SMYD2 deficiency largely reverses renal cyst growth in Pkd1 mutant mice by suppressing the methylation and activation of STAT3 and p65 to inhibit cystic renal epithelial cell proliferation and survival (Fig.	('reverses', 'NegReg', (25, 33))	('rat', 'Species', '10116', (182, 185))	('Pkd1', 'Gene', '18763', (55, 59))	('methylation', 'MPA', (91, 102))	('Pkd1', 'Gene', (55, 59))	('suppressing', 'NegReg', (75, 86))	('p65', 'Gene', (131, 134))	('deficiency', 'Var', (6, 16))	('mice', 'Species', '10090', (67, 71))	('renal cyst', 'Phenotype', 'HP:0000107', (34, 44))	('SMYD2', 'Gene', (0, 5))	('renal', 'CPA', (34, 39))	('survival', 'CPA', (193, 201))	('cystic renal epithelial', 'Disease', 'MESH:D052177', (146, 169))	('inhibit', 'NegReg', (138, 145))	('STAT3', 'Gene', (121, 126))	('cystic renal epithelial', 'Disease', (146, 169))	('mutant', 'Var', (60, 66))	('activation', 'PosReg', (107, 117))
390890	31370883	RNAi-based screening of human lysine methyltransferases that regulate HIV-1 latency demonstrated that knockdown of SMYD2 reactivates latent HIV-1 in both T cell lines and primary CD4+ T cells via the SMYD2-H4K20me1-L3MBTL1 axis.	('reactivates latent', 'MPA', (121, 139))	('human', 'Species', '9606', (24, 29))	('rat', 'Species', '10116', (91, 94))	('knockdown', 'Var', (102, 111))	('lysine', 'Chemical', 'MESH:D008239', (30, 36))	('HIV-1', 'Species', '11676', (140, 145))	('L3MBTL1', 'Gene', (215, 222))	('L3MBTL1', 'Gene', '26013', (215, 222))	('SMYD2', 'Gene', (115, 120))	('HIV-1', 'Species', '11676', (70, 75))
390891	31370883	SMYD2 deficiency enhance autophagic cell death induced by BIX01294, an inhibitor of EHMT2.	('enhance', 'PosReg', (17, 24))	('BIX01294', 'Chemical', 'MESH:C518299', (58, 66))	('EHMT2', 'Gene', '10919', (84, 89))	('BIX01294', 'Var', (58, 66))	('autophagic cell death', 'CPA', (25, 46))	('SMYD2', 'Gene', (0, 5))	('deficiency', 'Var', (6, 16))	('EHMT2', 'Gene', (84, 89))
390895	31370883	SMYD2 specifically methylates the kinase domain of BMP type II receptor 2 (BMPR2) and then activates the BMP-induced phosphorylation of SMAD1/5 and subsequent nuclear localization and interaction with SMAD4 (Fig.	('SMAD1/5', 'Gene', (136, 143))	('BMP', 'Gene', (51, 54))	('nuclear localization', 'MPA', (159, 179))	('methylates', 'Var', (19, 29))	('SMAD4', 'Gene', (201, 206))	('BMP', 'Gene', '649', (105, 108))	('BMP type II receptor 2', 'Gene', '659', (51, 73))	('BMP', 'Gene', '649', (75, 78))	('BMP type II receptor 2', 'Gene', (51, 73))	('activates', 'PosReg', (91, 100))	('BMP', 'Gene', (105, 108))	('SMAD1/5', 'Gene', '4086;4090', (136, 143))	('BMP', 'Gene', (75, 78))	('interaction', 'Interaction', (184, 195))	('SMAD4', 'Gene', '4089', (201, 206))	('BMP', 'Gene', '649', (51, 54))	('BMPR2', 'Gene', (75, 80))	('BMPR2', 'Gene', '659', (75, 80))
390898	31370883	Interestingly, most studies have demonstrated that SMYD2 methylates nonhistone proteins, not histones, to achieve its function, which is consistent with the fact that SMYD2 primarily localizes to the cytoplasm.	('rat', 'Species', '10116', (40, 43))	('nonhistone proteins', 'Protein', (68, 87))	('function', 'MPA', (118, 126))	('methylates', 'Var', (57, 67))
390934	30734516	As shown in Figure 1, the areas under the ROC curves (AUCs) were 0.547, 0.541, and 0.531 for the SII, NLR, and PLR, respectively.	('SII', 'Disease', 'None', (97, 100))	('0.531', 'Var', (83, 88))	('SII', 'Disease', (97, 100))
390949	30734516	The results of multivariate analyses revealed that age (P < 0.001), tumor length (P = 0.001), lymphatic metastasis (P < 0.001), high SII values (P = 0.014), and high NLR values (P = 0.003) were independently associated with poor OS (Table S2).	('tumor', 'Disease', (68, 73))	('lymphatic metastasis', 'CPA', (94, 114))	('poor OS', 'Disease', (224, 231))	('high SII', 'Disease', 'MESH:D008228', (128, 136))	('high', 'Var', (161, 165))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('high SII', 'Disease', (128, 136))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))
391134	26193342	3a, were determined from two publicly available microarray datasets, GSE7670 and GSE10072.	('GSE10072', 'Var', (81, 89))	('GSE7670', 'Chemical', '-', (69, 76))	('GSE7670', 'Var', (69, 76))
391178	33841572	The OncomiR website was used to predict the E2F3 upstream microRNAs and determine their prognostic value in patients with NSCLC.	('NSCLC', 'Disease', 'MESH:D002289', (122, 127))	('E2F3', 'Var', (44, 48))	('NSCLC', 'Phenotype', 'HP:0030358', (122, 127))	('patients', 'Species', '9606', (108, 116))	('NSCLC', 'Disease', (122, 127))
391181	33841572	Thus, E2F3 was shown to have important oncogenic properties in the development of NSCLC, and it may become a potential biomarker for patients with NSCLC.	('NSCLC', 'Disease', (147, 152))	('NSCLC', 'Phenotype', 'HP:0030358', (82, 87))	('NSCLC', 'Disease', 'MESH:D002289', (147, 152))	('patients', 'Species', '9606', (133, 141))	('NSCLC', 'Phenotype', 'HP:0030358', (147, 152))	('E2F3', 'Var', (6, 10))	('NSCLC', 'Disease', (82, 87))	('NSCLC', 'Disease', 'MESH:D002289', (82, 87))
391188	33841572	Except for alterations in EGFR, KRAS oncogene mutations and MET gene amplification have also been shown to play an important role in the progression of lung cancer, and have contributed to the development of biomarker and targeted therapy.	('EGFR', 'Gene', (26, 30))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('role', 'Reg', (125, 129))	('mutations', 'Var', (46, 55))	('lung cancer', 'Disease', 'MESH:D008175', (152, 163))	('KRAS', 'Gene', (32, 36))	('KRAS', 'Gene', '3845', (32, 36))	('EGFR', 'Gene', '1956', (26, 30))	('contributed', 'Reg', (174, 185))	('MET', 'Gene', '79811', (60, 63))	('lung cancer', 'Phenotype', 'HP:0100526', (152, 163))	('MET', 'Gene', (60, 63))	('play', 'Reg', (107, 111))	('lung cancer', 'Disease', (152, 163))
391207	33841572	However, another previous study has focused on the impact of E2F3 on the tumorigenesis and prognosis in patients with NSCLC.	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('NSCLC', 'Phenotype', 'HP:0030358', (118, 123))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('E2F3', 'Var', (61, 65))	('NSCLC', 'Disease', (118, 123))	('tumor', 'Disease', (73, 78))	('NSCLC', 'Disease', 'MESH:D002289', (118, 123))	('patients', 'Species', '9606', (104, 112))
391210	33841572	Functional analysis was used to analyze the effect of E2F3 on tumor cell proliferation and apoptosis to ascertain the underlying mechanism of how E2F3 was involved in the tumorigenesis of NSCLC.	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('NSCLC', 'Disease', 'MESH:D002289', (188, 193))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('tumor', 'Disease', (62, 67))	('NSCLC', 'Phenotype', 'HP:0030358', (188, 193))	('involved', 'Reg', (155, 163))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', (171, 176))	('E2F3', 'Var', (146, 150))	('NSCLC', 'Disease', (188, 193))
391211	33841572	The present study revealed a new aspect of E2F3 in promoting NSCLC progression, which emphasized the value of E2F3 as a potential biomarker for the prediction of prognosis in patients with NSCLC.	('NSCLC', 'Disease', (189, 194))	('promoting', 'PosReg', (51, 60))	('NSCLC', 'Disease', 'MESH:D002289', (189, 194))	('NSCLC', 'Phenotype', 'HP:0030358', (61, 66))	('E2F3', 'Var', (43, 47))	('patients', 'Species', '9606', (175, 183))	('NSCLC', 'Disease', (61, 66))	('NSCLC', 'Phenotype', 'HP:0030358', (189, 194))	('NSCLC', 'Disease', 'MESH:D002289', (61, 66))
391244	33841572	The Kaplan-Meier plotter website was used to compare survival rates in patients with NSCLC (n=141) grouped by the expression levels of E2F3 and E2F3-associated miRNAs.	('NSCLC', 'Disease', (85, 90))	('E2F3', 'Var', (135, 139))	('NSCLC', 'Disease', 'MESH:D002289', (85, 90))	('patients', 'Species', '9606', (71, 79))	('NSCLC', 'Phenotype', 'HP:0030358', (85, 90))	('E2F3-associated', 'Var', (144, 159))
391274	33841572	In the Bhattacharjee cohort, E2F3 was overexpressed in LUAD (n=132), as compared with that in the non-tumor lung tissues without malignancy (n=17; fold change, 3.0).	('tumor lung', 'Phenotype', 'HP:0100526', (102, 112))	('E2F3', 'Var', (29, 33))	('malignancy', 'Disease', (129, 139))	('LUAD', 'Phenotype', 'HP:0030078', (55, 59))	('overexpressed', 'PosReg', (38, 51))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('malignancy', 'Disease', 'MESH:D009369', (129, 139))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))
391278	33841572	The results were confirmed using TCGA database, where E2F3 mRNA was significantly overexpressed in LUAD tissue (n=517), as compared with that in non-tumor tissues (n=59; fold change, 2.6; P<0.01).	('E2F3', 'Var', (54, 58))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('tumor', 'Disease', (149, 154))	('overexpressed', 'PosReg', (82, 95))	('LUAD', 'Phenotype', 'HP:0030078', (99, 103))
391279	33841572	E2F3 mRNA was also overexpressed in squamous cell carcinoma tissue (n=501), as compared with that in non-tumor tissues without malignancy (n=51; fold change, 2.3; P<0.01; Fig.	('malignancy', 'Disease', 'MESH:D009369', (127, 137))	('malignancy', 'Disease', (127, 137))	('carcinoma', 'Phenotype', 'HP:0030731', (50, 59))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (36, 59))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (36, 59))	('E2F3', 'Var', (0, 4))	('overexpressed', 'PosReg', (19, 32))	('squamous cell carcinoma', 'Disease', (36, 59))	('tumor', 'Disease', (105, 110))
391284	33841572	The IHC score of the E2F3 protein in the tumor tissues was significantly higher compared with that in the adjacent normal tissues (difference of median, 2.0; P<0.001; Fig.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Disease', (41, 46))	('E2F3', 'Var', (21, 25))	('protein', 'Protein', (26, 33))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('IHC score', 'MPA', (4, 13))	('higher', 'PosReg', (73, 79))
391285	33841572	Kaplan-Meier Plotter was used and the results revealed that the patients in the high E2F3 mRNA expression subgroup had a worse OS time, as compared with that in patients in the low expression subgroup within 2.5 years (P=0.019; Fig.	('E2F3', 'Gene', (85, 89))	('patients', 'Species', '9606', (161, 169))	('high', 'Var', (80, 84))	('patients', 'Species', '9606', (64, 72))
391289	33841572	siRNAs targeting E2F3 mRNA were designed and transfected into NSCLC A549 cell line.	('NSCLC', 'Disease', (62, 67))	('NSCLC', 'Disease', 'MESH:D002289', (62, 67))	('E2F3', 'Var', (17, 21))	('NSCLC', 'Phenotype', 'HP:0030358', (62, 67))	('A549', 'CellLine', 'CVCL:0023', (68, 72))
391290	33841572	The CCK-8 assay revealed that E2F3 knockdown significantly suppressed NSCLC cell proliferation in the A549 cells (Fig.	('knockdown', 'Var', (35, 44))	('NSCLC', 'Disease', (70, 75))	('suppressed', 'NegReg', (59, 69))	('NSCLC', 'Disease', 'MESH:D002289', (70, 75))	('E2F3', 'Gene', (30, 34))	('A549', 'CellLine', 'CVCL:0023', (102, 106))	('NSCLC', 'Phenotype', 'HP:0030358', (70, 75))	('CCK-8', 'Chemical', '-', (4, 9))
391291	33841572	To confirm the effect of E2F3 on apoptosis in tissues, IHC staining was performed on the TMA sections from 50 patients with NSCLC, to investigate the expression of Bcl-2, Bax and caspase-3 (Fig.	('Bax', 'Gene', '581', (171, 174))	('Bcl-2', 'Gene', '596', (164, 169))	('caspase-3', 'Gene', '836', (179, 188))	('NSCLC', 'Disease', (124, 129))	('Bax', 'Gene', (171, 174))	('NSCLC', 'Phenotype', 'HP:0030358', (124, 129))	('caspase-3', 'Gene', (179, 188))	('NSCLC', 'Disease', 'MESH:D002289', (124, 129))	('E2F3', 'Var', (25, 29))	('patients', 'Species', '9606', (110, 118))	('Bcl-2', 'Gene', (164, 169))
391301	33841572	The knockdown of E2F3 expression by siRNA significantly inhibited tumor cell migration at 24 and 48 h in A549 cell (Fig.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Disease', (66, 71))	('E2F3', 'Gene', (17, 21))	('A549', 'CellLine', 'CVCL:0023', (105, 109))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('inhibited', 'NegReg', (56, 65))	('knockdown', 'Var', (4, 13))
391306	33841572	S3A) and among them, E2F3 had a physical interaction with TEA domain transcription factor-3, transcription factor binding to IGHM enhancer-3, lethal malignant brain tumor like-2, vacuolar protein sorting-associated protein-72, RING1 and YY1 binding protein, transcription factor SP1 and bromodomain containing-8.	('IGHM', 'Gene', (125, 129))	('TEA domain transcription factor-3', 'Gene', (58, 91))	('interaction', 'Interaction', (41, 52))	('RING1', 'Gene', '6015', (227, 232))	('IGHM', 'Gene', '3507', (125, 129))	('brain tumor', 'Phenotype', 'HP:0030692', (159, 170))	('E2F3', 'Var', (21, 25))	('binding', 'Interaction', (114, 121))	('TEA domain transcription factor-3', 'Gene', '7005', (58, 91))	('RING1', 'Gene', (227, 232))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('malignant brain tumor', 'Disease', 'MESH:D001932', (149, 170))	('malignant brain tumor', 'Disease', (149, 170))
391312	33841572	The overexpression of E2F was reported in human gastric cancer, colon cancer and hepatocellular carcinoma and was also found in neuroendocrine tumors of the lung.	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('human', 'Species', '9606', (42, 47))	('gastric cancer', 'Disease', 'MESH:D013274', (48, 62))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('colon cancer', 'Phenotype', 'HP:0003003', (64, 76))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('neuroendocrine tumors', 'Disease', 'MESH:D018358', (128, 149))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (81, 105))	('overexpression', 'PosReg', (4, 18))	('gastric cancer', 'Phenotype', 'HP:0012126', (48, 62))	('colon cancer', 'Disease', 'MESH:D015179', (64, 76))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (128, 149))	('found', 'Reg', (119, 124))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (81, 105))	('colon cancer', 'Disease', (64, 76))	('hepatocellular carcinoma', 'Disease', (81, 105))	('E2F', 'Var', (22, 25))	('gastric cancer', 'Disease', (48, 62))	('neuroendocrine tumors', 'Disease', (128, 149))
391324	33841572	Other studies have reported the effect of E2F on tumor cell apoptosis in gastric cancer and head and neck carcinoma, suggesting an intensive impact of E2F3 in inhibiting tumor cell apoptosis.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('gastric cancer', 'Disease', 'MESH:D013274', (73, 87))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('head and neck carcinoma', 'Disease', 'MESH:D006258', (92, 115))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('gastric cancer', 'Phenotype', 'HP:0012126', (73, 87))	('tumor', 'Disease', (49, 54))	('E2F3', 'Var', (151, 155))	('tumor', 'Disease', (170, 175))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('inhibiting', 'NegReg', (159, 169))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('gastric cancer', 'Disease', (73, 87))
391335	33841572	As a result, the present study has revealed a new aspect, that E2F3 promoted tumor proliferation by inhibiting tumor cell apoptosis through the regulation of the Bcl-2 and apoptotic signaling pathway.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('promoted', 'PosReg', (68, 76))	('Bcl-2', 'Gene', (162, 167))	('Bcl-2', 'Gene', '596', (162, 167))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('inhibiting', 'NegReg', (100, 110))	('tumor', 'Disease', (111, 116))	('apoptotic signaling pathway', 'Pathway', (172, 199))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('E2F3', 'Var', (63, 67))	('tumor', 'Disease', (77, 82))
391339	33841572	However, during the treatment of TKIs in patients with activating mutations in EGFR, tumor cells developed resistance to TKIs, where alterations of E2F-target genes were frequently found.	('mutations', 'Var', (66, 75))	('tumor', 'Disease', (85, 90))	('resistance to TKIs', 'MPA', (107, 125))	('EGFR', 'Gene', '1956', (79, 83))	('EGFR', 'Gene', (79, 83))	('developed', 'PosReg', (97, 106))	('activating', 'PosReg', (55, 65))	('patients', 'Species', '9606', (41, 49))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))
391343	33841572	Transcriptional analysis of E2F3 will be performed in the future for the confirmation of the prognostic value of E2F3 in NSCLC.	('NSCLC', 'Disease', 'MESH:D002289', (121, 126))	('NSCLC', 'Disease', (121, 126))	('E2F3', 'Var', (113, 117))	('NSCLC', 'Phenotype', 'HP:0030358', (121, 126))
391355	33649292	Decreased migration and invasion potential were also observed in knockdown of GOLM1 in GOLM1KD PC9 cells in migration assay.	('PC9', 'CellLine', 'CVCL:B260', (95, 98))	('migration', 'CPA', (10, 19))	('invasion potential', 'CPA', (24, 42))	('Decreased', 'NegReg', (0, 9))	('migration assay', 'CPA', (108, 123))	('knockdown', 'Var', (65, 74))	('GOLM1', 'Gene', (78, 83))
391429	33649292	We performed GSEA and found that the expression of GOLM1 was mainly associated with malignancies, including "adherents junction", "cell cycle", "pathway in cancer" (Fig.	('malignancies', 'Disease', (84, 96))	('expression', 'Var', (37, 47))	('associated', 'Reg', (68, 78))	('cancer', 'Disease', (156, 162))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('GOLM1', 'Gene', (51, 56))	('GSEA', 'Chemical', '-', (13, 17))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('malignancies', 'Disease', 'MESH:D009369', (84, 96))
391461	33649292	The numbers of migrated PC9 cells were decreased in GOLM1 knockdown cells compared with those in the wild-type cells ((Fig.	('decreased', 'NegReg', (39, 48))	('PC9', 'CellLine', 'CVCL:B260', (24, 27))	('knockdown', 'Var', (58, 67))	('GOLM1', 'Gene', (52, 57))
391462	33649292	However, the numbers of migrated PC9 cells were increased in GOLM1OE PC9 cells compared with those in the wild-type cells (Fig.	('PC9', 'CellLine', 'CVCL:B260', (33, 36))	('increased', 'PosReg', (48, 57))	('PC9', 'CellLine', 'CVCL:B260', (69, 72))	('GOLM1OE PC9', 'Var', (61, 72))
391463	33649292	Transwell assays also revealed that the extent of invasion was significantly increased in GOLM1OE PC9 cells compared with WT cells while invasive ability of GOLM1KD cells was diminished compared with GOLM1WT cells (Fig.	('PC9', 'CellLine', 'CVCL:B260', (98, 101))	('invasion', 'CPA', (50, 58))	('GOLM1OE PC9', 'Var', (90, 101))	('increased', 'PosReg', (77, 86))
391467	33649292	We found that the tumor size in mice injected with GOLM1OE cells were significantly increased than those injected with GOLM1WT cells (Fig.	('tumor', 'Disease', (18, 23))	('GOLM1OE cells', 'Var', (51, 64))	('mice', 'Species', '10090', (32, 36))	('increased', 'PosReg', (84, 93))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
391469	33649292	The final weights of nude mice subcutaneously implanted with GOLM1OE cells were significantly lower than those of control mice (Fig.	('mice', 'Species', '10090', (122, 126))	('lower', 'NegReg', (94, 99))	('GOLM1OE', 'Var', (61, 68))	('nude mice', 'Species', '10090', (21, 30))	('mice', 'Species', '10090', (26, 30))
391471	33649292	The tumor weights of mice injected with GOLM1OE cells were significantly increased than those injected with GOLM1WT cells (Fig.	('tumor', 'Disease', (4, 9))	('increased', 'PosReg', (73, 82))	('mice', 'Species', '10090', (21, 25))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('GOLM1OE cells', 'Var', (40, 53))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))
391476	33649292	For GOLM1 overexpression, uptake was relatively less compared with WT which causing by necrosis of the tumor center.	('necrosis of the tumor', 'Disease', 'MESH:D009336', (87, 108))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('GOLM1', 'Gene', (4, 9))	('overexpression', 'Var', (10, 24))	('uptake', 'MPA', (26, 32))	('less', 'NegReg', (48, 52))	('necrosis of the tumor', 'Disease', (87, 108))
391482	33649292	To verify this finding, the dataset from TCGA database contains 496 patients with NSCLC which were grouped according to P53 mutation (n = 252) or not (n = 244), were downloaded, collated, and analyzed.	('P53', 'Gene', (120, 123))	('P53', 'Gene', '7157', (120, 123))	('patients', 'Species', '9606', (68, 76))	('mutation', 'Var', (124, 132))	('NSCLC', 'Disease', (82, 87))	('NSCLC', 'Disease', 'MESH:D002289', (82, 87))
391483	33649292	We found that there was no correlation between the expression of GOLM1 and the survival rate in NSCLC patients with P53 mutation (p = 0.06252), but a significant correlation was found in NSCLC patients expressing wild-type p53 (p = 0.02449) (see Supplementary Data F).	('patients', 'Species', '9606', (193, 201))	('NSCLC', 'Disease', (96, 101))	('p53', 'Gene', (223, 226))	('p53', 'Gene', '7157', (223, 226))	('P53', 'Gene', (116, 119))	('patients', 'Species', '9606', (102, 110))	('NSCLC', 'Disease', 'MESH:D002289', (96, 101))	('mutation', 'Var', (120, 128))	('NSCLC', 'Disease', (187, 192))	('P53', 'Gene', '7157', (116, 119))	('NSCLC', 'Disease', 'MESH:D002289', (187, 192))
391501	33649292	A current study has revealed that alterations in DNA copy number and methylation may be two important mechanisms used a dysregulated GOLM1 in lung adenocarcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (152, 161))	('lung adenocarcinoma', 'Disease', (142, 161))	('DNA', 'Gene', (49, 52))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (142, 161))	('GOLM1', 'Gene', (133, 138))	('methylation', 'Var', (69, 80))	('dysregulated', 'Var', (120, 132))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (142, 161))	('alterations', 'Var', (34, 45))
391522	33649292	P53 S315 and S392 are the earliest identified phosphorylation sites at the c-terminal.	('S392', 'Var', (13, 17))	('phosphor', 'Chemical', '-', (46, 54))	('P53', 'Gene', '7157', (0, 3))	('P53', 'Gene', (0, 3))
391523	33649292	Previous researches have revealed that phosphorylation at the ser392 site stabilizes p53 tetramers' formation.	('stabilizes', 'Reg', (74, 84))	('phosphor', 'Chemical', '-', (39, 47))	('phosphorylation', 'Var', (39, 54))	('ser392', 'Var', (62, 68))	('ser392', 'Chemical', '-', (62, 68))	('p53', 'Gene', (85, 88))	('p53', 'Gene', '7157', (85, 88))
391524	33649292	On the contrary, S392's phosphorylation was reversed by S315's phosphorylation on tetramer's formation and the stable activation of p53.	('activation', 'PosReg', (118, 128))	('S392', 'Var', (17, 21))	('p53', 'Gene', (132, 135))	('p53', 'Gene', '7157', (132, 135))	('phosphor', 'Chemical', '-', (63, 71))	('phosphorylation', 'MPA', (63, 78))	('phosphor', 'Chemical', '-', (24, 32))	('S315', 'Var', (56, 60))
391525	33649292	The phosphorylation at S315 inactivates P53 by enhancing its protein degradation.	('P53', 'Gene', (40, 43))	('inactivates', 'NegReg', (28, 39))	('P53', 'Gene', '7157', (40, 43))	('phosphor', 'Chemical', '-', (4, 12))	('protein degradation', 'MPA', (61, 80))	('phosphorylation', 'Var', (4, 19))	('enhancing', 'PosReg', (47, 56))
391526	33649292	In this study, the hyperphosphorylation of S315 in P53 in GOLM1-overexpressing cells was noticed comparing with WT cells which may deeply affect the formation of the P53 tetramer and further weak P53 mediated inhibition of tumor formation.	('P53', 'Gene', '7157', (166, 169))	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('tumor', 'Disease', (223, 228))	('affect', 'Reg', (138, 144))	('S315', 'Var', (43, 47))	('weak', 'NegReg', (191, 195))	('phosphor', 'Chemical', '-', (24, 32))	('P53', 'Gene', (196, 199))	('inhibition', 'NegReg', (209, 219))	('P53', 'Gene', '7157', (196, 199))	('P53', 'Gene', (51, 54))	('formation', 'MPA', (149, 158))	('tumor', 'Disease', 'MESH:D009369', (223, 228))	('P53', 'Gene', '7157', (51, 54))	('P53', 'Gene', (166, 169))
391527	33649292	In other words, GOLM1 overexpression enhances the aggressive malignant manner of cancer cells by reducing the stability of P53 (Fig.	('P53', 'Gene', (123, 126))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('GOLM1', 'Gene', (16, 21))	('enhances', 'PosReg', (37, 45))	('cancer', 'Disease', (81, 87))	('stability', 'MPA', (110, 119))	('P53', 'Gene', '7157', (123, 126))	('reducing', 'NegReg', (97, 105))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('overexpression', 'Var', (22, 36))
391535	31875161	Accumulative evidences have proved that abnormal expression of ITGA11, ITGB4 and ITGB8 are a common phenomenon in different malignances.	('ITGA11', 'Gene', '22801', (63, 69))	('ITGB8', 'Gene', '3696', (81, 86))	('ITGB4', 'Gene', (71, 76))	('ITGB4', 'Gene', '3691', (71, 76))	('ITGB8', 'Gene', (81, 86))	('abnormal', 'Var', (40, 48))	('ITGA11', 'Gene', (63, 69))
391554	31875161	Inhibition of ITGB4 in glioma cells would decrease the self-renewal abilities of glioma stem cells and suppress the malignant behaviors of glioma cells in vitro and in vivo.	('glioma', 'Disease', 'MESH:D005910', (23, 29))	('ITGB4', 'Gene', '3691', (14, 19))	('glioma', 'Phenotype', 'HP:0009733', (81, 87))	('glioma', 'Phenotype', 'HP:0009733', (23, 29))	('suppress', 'NegReg', (103, 111))	('glioma', 'Disease', (139, 145))	('glioma', 'Disease', (81, 87))	('glioma', 'Disease', (23, 29))	('glioma', 'Disease', 'MESH:D005910', (81, 87))	('glioma', 'Disease', 'MESH:D005910', (139, 145))	('decrease', 'NegReg', (42, 50))	('glioma', 'Phenotype', 'HP:0009733', (139, 145))	('Inhibition', 'Var', (0, 10))	('ITGB4', 'Gene', (14, 19))
391556	31875161	Silencing of ITGB4 could repress cell proliferation, colony forming ability and cell invasiveness.	('repress', 'NegReg', (25, 32))	('colony forming ability', 'CPA', (53, 75))	('cell invasiveness', 'CPA', (80, 97))	('cell proliferation', 'CPA', (33, 51))	('Silencing', 'Var', (0, 9))	('ITGB4', 'Gene', (13, 18))	('ITGB4', 'Gene', '3691', (13, 18))
391559	31875161	Additionally, the expression level of ITGB8 can be regulated by the tumor-promoting receptor tyrosine kinase-EphB4, while knockdown of ITGB8 may suppress migration and invasion in prostate cancer cell lines.	('tumor', 'Disease', (68, 73))	('prostate cancer', 'Disease', (180, 195))	('ITGB8', 'Gene', (38, 43))	('ITGB8', 'Gene', '3696', (135, 140))	('suppress', 'NegReg', (145, 153))	('expression level', 'MPA', (18, 34))	('EphB4', 'Gene', (109, 114))	('EphB4', 'Gene', '2050', (109, 114))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('ITGB8', 'Gene', (135, 140))	('knockdown', 'Var', (122, 131))	('prostate cancer', 'Disease', 'MESH:D011471', (180, 195))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('prostate cancer', 'Phenotype', 'HP:0012125', (180, 195))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('ITGB8', 'Gene', '3696', (38, 43))
391601	31875161	The univariate cox analysis indicated that high ITGB4 expression and advanced stages were significantly correlated with worse OS in LUAD (Table 2).	('ITGB4', 'Gene', (48, 53))	('expression', 'MPA', (54, 64))	('ITGB4', 'Gene', '3691', (48, 53))	('high', 'Var', (43, 47))	('LUAD', 'Phenotype', 'HP:0030078', (132, 136))	('LUAD', 'Disease', (132, 136))
391602	31875161	Meanwhile, multivariate cox analysis confirmed that high ITGB4 expression was an independent prognostic biomarker for patients with LUAD (HR: 1.417; 95%CI [1.042-1.926]; p = 0.026; Table 2).	('LUAD', 'Phenotype', 'HP:0030078', (132, 136))	('LUAD', 'Disease', (132, 136))	('high', 'Var', (52, 56))	('ITGB4', 'Gene', (57, 62))	('ITGB4', 'Gene', '3691', (57, 62))	('patients', 'Species', '9606', (118, 126))
391615	31875161	The aberrant expression of ITGA11, ITGB4, and ITGB8 have been reported in many cancers.	('cancers', 'Disease', (79, 86))	('ITGB8', 'Gene', '3696', (46, 51))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('ITGB4', 'Gene', (35, 40))	('ITGA11', 'Gene', '22801', (27, 33))	('reported', 'Reg', (62, 70))	('ITGB4', 'Gene', '3691', (35, 40))	('ITGB8', 'Gene', (46, 51))	('aberrant expression', 'Var', (4, 23))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('ITGA11', 'Gene', (27, 33))	('cancers', 'Disease', 'MESH:D009369', (79, 86))
391632	31875161	Moreover, the survival curve showed that high ITGB4 expression was strong correlated with inferior OS in LUAD.	('ITGB4', 'Gene', (46, 51))	('ITGB4', 'Gene', '3691', (46, 51))	('high', 'Var', (41, 45))	('expression', 'MPA', (52, 62))	('correlated', 'Reg', (74, 84))	('LUAD', 'Phenotype', 'HP:0030078', (105, 109))	('inferior OS in LUAD', 'Disease', (90, 109))
391633	31875161	The following univariate cox and multivariate cox regression analysis confirmed that high ITGB4 expression level was an independent prognostic biomarker for poor OS in LUAD.	('poor OS', 'Disease', (157, 164))	('LUAD', 'Disease', (168, 172))	('LUAD', 'Phenotype', 'HP:0030078', (168, 172))	('ITGB4', 'Gene', '3691', (90, 95))	('high', 'Var', (85, 89))	('ITGB4', 'Gene', (90, 95))	('expression level', 'MPA', (96, 112))
391649	31492847	Reciprocal regulatory mechanism between miR-214-3p and FGFR1 in FGFR1-amplified lung cancer MicroRNA (miRNA) and fibroblast growth factor receptor 1 (FGFR1) dysregulation are considered to play an important role in tumor proliferation, invasion, and metastasis.	('FGFR1', 'Gene', '2260', (55, 60))	('lung cancer', 'Disease', 'MESH:D008175', (80, 91))	('FGFR1', 'Gene', (150, 155))	('miR-214', 'Gene', (40, 47))	('dysregulation', 'Var', (157, 170))	('tumor', 'Disease', (215, 220))	('fibroblast growth factor receptor 1', 'Gene', (113, 148))	('FGFR1', 'Gene', (64, 69))	('tumor', 'Disease', 'MESH:D009369', (215, 220))	('FGFR1', 'Gene', '2260', (150, 155))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('lung cancer', 'Disease', (80, 91))	('lung cancer', 'Phenotype', 'HP:0100526', (80, 91))	('FGFR1', 'Gene', '2260', (64, 69))	('FGFR1', 'Gene', (55, 60))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('fibroblast growth factor receptor 1', 'Gene', '2260', (113, 148))	('miR-214', 'Gene', '406996', (40, 47))
391651	31492847	miR-214-3p was sharply decreased and showed a significantly negative correlation with FGFR1 in lung cancer patients (n = 30).	('negative', 'NegReg', (60, 68))	('lung cancer', 'Disease', (95, 106))	('lung cancer', 'Phenotype', 'HP:0100526', (95, 106))	('miR-214-3p', 'Var', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('3p', 'Chemical', '-', (8, 10))	('correlation', 'Interaction', (69, 80))	('FGFR1', 'Gene', (86, 91))	('lung cancer', 'Disease', 'MESH:D008175', (95, 106))	('FGFR1', 'Gene', '2260', (86, 91))	('decreased', 'NegReg', (23, 32))	('patients', 'Species', '9606', (107, 115))
391652	31492847	Luciferase reporter assay confirmed that miR-214-3p could downregulate FGFR1 by directly targeting 3'-untranslated region (UTR).	("3'-untranslated region", 'MPA', (99, 121))	('FGFR1', 'Gene', (71, 76))	('miR-214-3p', 'Var', (41, 51))	('3p', 'Chemical', '-', (49, 51))	('targeting', 'Reg', (89, 98))	('FGFR1', 'Gene', '2260', (71, 76))	('downregulate', 'NegReg', (58, 70))
391653	31492847	miR-214-3p inhibited the processes of epithelial-mesenchymal transition and Wnt/MAPK/AKT (Wnt/mitogen-activated protein kinase/AKT) signaling pathway by targeting FGFR1.	('FGFR1', 'Gene', (163, 168))	('FGFR1', 'Gene', '2260', (163, 168))	('processes', 'CPA', (25, 34))	('miR-214-3p', 'Var', (0, 10))	('epithelial-mesenchymal transition', 'CPA', (38, 71))	('mitogen-activated protein kinase/AKT', 'Gene', (94, 130))	('AKT', 'Gene', '207', (85, 88))	('mitogen-activated protein kinase/AKT', 'Gene', '207', (94, 130))	('3p', 'Chemical', '-', (8, 10))	('AKT', 'Gene', '207', (127, 130))	('AKT', 'Gene', (85, 88))	('inhibited', 'NegReg', (11, 20))	('targeting', 'Reg', (153, 162))	('AKT', 'Gene', (127, 130))
391654	31492847	Moreover, miR-214-3p not only established a negative feedback regulation loop with FGFR1 through ERK (extracellular signal-regulated kinase) but also developed a synergism with FGFR1 inhibitor AZD4547.	('extracellular signal-regulated kinase', 'Gene', (102, 139))	('FGFR1', 'Gene', (177, 182))	('ERK', 'Gene', (97, 100))	('negative feedback regulation loop', 'MPA', (44, 77))	('miR-214-3p', 'Var', (10, 20))	('FGFR1', 'Gene', '2260', (177, 182))	('3p', 'Chemical', '-', (18, 20))	('FGFR1', 'Gene', (83, 88))	('extracellular signal-regulated kinase', 'Gene', '5594', (102, 139))	('AZD4547', 'Chemical', 'MESH:C572463', (193, 200))	('FGFR1', 'Gene', '2260', (83, 88))	('ERK', 'Gene', '5594', (97, 100))	('synergism', 'Interaction', (162, 171))
391655	31492847	In conclusion, our study demonstrated the regulatory mechanism between miR-214-3p and FGFR1 in lung cancer.	('lung cancer', 'Disease', (95, 106))	('lung cancer', 'Phenotype', 'HP:0100526', (95, 106))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('3p', 'Chemical', '-', (79, 81))	('FGFR1', 'Gene', (86, 91))	('lung cancer', 'Disease', 'MESH:D008175', (95, 106))	('miR-214-3p', 'Var', (71, 81))	('FGFR1', 'Gene', '2260', (86, 91))
391657	31492847	Co-targeting miR-214-3p and FGFR1 could provide greater benefits to patients with FGFR1-amplified lung cancer.	('benefits', 'PosReg', (56, 64))	('3p', 'Chemical', '-', (21, 23))	('FGFR1', 'Gene', (82, 87))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('lung cancer', 'Disease', (98, 109))	('lung cancer', 'Phenotype', 'HP:0100526', (98, 109))	('FGFR1', 'Gene', '2260', (82, 87))	('FGFR1', 'Gene', (28, 33))	('patients', 'Species', '9606', (68, 76))	('FGFR1', 'Gene', '2260', (28, 33))	('lung cancer', 'Disease', 'MESH:D008175', (98, 109))	('miR-214-3p', 'Var', (13, 23))
391663	31492847	The discovery of molecularly targeted therapies for patients with EGFR mutation and ALK or ROS1 rearrangements has been a breakthrough in the treatment history of LADC.	('ROS1', 'Gene', (91, 95))	('ALK', 'Gene', (84, 87))	('EGFR', 'Gene', '1956', (66, 70))	('rearrangements', 'Var', (96, 110))	('EGFR', 'Gene', (66, 70))	('mutation', 'Var', (71, 79))	('ROS1', 'Gene', '6098', (91, 95))	('ALK', 'Gene', '238', (84, 87))	('patients', 'Species', '9606', (52, 60))
391665	31492847	Fibroblast growth factor receptor (FGFR) dysfunction is fairly common in a variety of cancers.	('dysfunction', 'Var', (41, 52))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('cancers', 'Phenotype', 'HP:0002664', (86, 93))	('cancers', 'Disease', (86, 93))	('FGFR', 'Gene', (35, 39))	('cancers', 'Disease', 'MESH:D009369', (86, 93))
391666	31492847	Meanwhile, FGFR1 amplification is the most common type, with 20% in LSQCC, 5-7% in SCLC, and 1-3% in LADC.	('LADC', 'Disease', (101, 105))	('LSQCC', 'Disease', (68, 73))	('FGFR1', 'Gene', (11, 16))	('amplification', 'Var', (17, 30))	('FGFR1', 'Gene', '2260', (11, 16))	('SCLC', 'Disease', (83, 87))	('SCLC', 'Disease', 'MESH:D018288', (83, 87))
391667	31492847	AZD4547 and BGJ398 are selective inhibitors of FGFR1, 2, and 3 in phase Ib clinical trials, whereas LY2874455 is a pan-FGFR inhibitor in phase I clinical trials.	('LY2874455', 'Var', (100, 109))	('AZD4547', 'Chemical', 'MESH:C572463', (0, 7))	('FGFR1', 'Gene', (47, 52))	('LY2874455', 'Chemical', 'MESH:C570663', (100, 109))	('FGFR1', 'Gene', '2260', (47, 52))	('BGJ398', 'Chemical', 'MESH:C568950', (12, 18))	('BGJ398', 'Gene', (12, 18))	('AZD4547', 'Var', (0, 7))
391677	31492847	Quantitative real-time PCR (qRT-PCR) demonstrated a lower expression of miR-214-3p in the tumor tissues of lung cancer (n = 30) than in non-tumor adjacent tissues (NATs) (Fig.	('miR-214-3p', 'Var', (72, 82))	('expression', 'MPA', (58, 68))	('3p', 'Chemical', '-', (80, 82))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('tumor', 'Disease', (90, 95))	('lower', 'NegReg', (52, 57))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('tumor tissues of lung cancer', 'Disease', 'MESH:D008175', (90, 118))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('lung cancer', 'Phenotype', 'HP:0100526', (107, 118))	('tumor tissues of lung cancer', 'Disease', (90, 118))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('tumor', 'Disease', (140, 145))
391679	31492847	A Kaplan-Meier analysis verified longer overall survival (OS) in LSQCC patents with high miR-214-3p in The Cancer Genome Atlas (TCGA) database (Fig.	('high miR-214-3p', 'Var', (84, 99))	('overall survival', 'MPA', (40, 56))	('LSQCC', 'Disease', (65, 70))	('3p', 'Chemical', '-', (97, 99))	('Cancer', 'Phenotype', 'HP:0002664', (107, 113))	('Cancer Genome Atlas', 'Disease', (107, 126))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (107, 126))	('miR-214-3p', 'Var', (89, 99))	('longer', 'PosReg', (33, 39))
391680	31492847	The miRNA profiles of SCLC in GSE27435 also demonstrated that longer OS in SCLC patients with high miR-214-3p (Fig.	('GSE27435', 'Var', (30, 38))	('patients', 'Species', '9606', (80, 88))	('3p', 'Chemical', '-', (107, 109))	('SCLC', 'Disease', (22, 26))	('SCLC', 'Disease', (75, 79))	('SCLC', 'Disease', 'MESH:D018288', (75, 79))	('SCLC', 'Disease', 'MESH:D018288', (22, 26))	('high miR-214-3p', 'Var', (94, 109))
391682	31492847	The above results revealed that both miR-214-3p and FGFR1 are involved in lung cancer progression.	('lung cancer', 'Disease', (74, 85))	('3p', 'Chemical', '-', (45, 47))	('lung cancer', 'Phenotype', 'HP:0100526', (74, 85))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('lung cancer', 'Disease', 'MESH:D008175', (74, 85))	('involved', 'Reg', (62, 70))	('miR-214-3p', 'Var', (37, 47))	('FGFR1', 'Gene', (52, 57))	('FGFR1', 'Gene', '2260', (52, 57))
391685	31492847	miR-214-3p inhibited proliferation in all of the cell lines, as determined by the CCK8 assay and colony formation (Fig.	('proliferation', 'CPA', (21, 34))	('colony formation', 'CPA', (97, 113))	('miR-214-3p', 'Var', (0, 10))	('3p', 'Chemical', '-', (8, 10))	('inhibited', 'NegReg', (11, 20))
391686	31492847	miR-214-3p inhibited migration and invasion as determined by scratch assay and transwell assay (Fig.	('inhibited', 'NegReg', (11, 20))	('3p', 'Chemical', '-', (8, 10))	('transwell assay', 'CPA', (79, 94))	('miR-214-3p', 'Var', (0, 10))
391687	31492847	The altered morphological characteristics of the cells caused by the inhibition of EMT process by miR-214-3p were presented (Fig.	('morphological characteristics of the cells', 'CPA', (12, 54))	('altered', 'Reg', (4, 11))	('EMT process', 'CPA', (83, 94))	('miR-214-3p', 'Var', (98, 108))	('inhibition', 'NegReg', (69, 79))	('3p', 'Chemical', '-', (106, 108))
391688	31492847	Moreover, miR-214-3p overexpression resulted in the downregulation of mesenchymal markers including vimentin (VIM) and Snail, as well as the upregulation of epithelial markers such as E-cadherin (E-cad) and ZO-1 in both H1581 and DMS114 cells (Fig.	('3p', 'Chemical', '-', (18, 20))	('overexpression', 'PosReg', (21, 35))	('E-cad', 'Gene', '999', (184, 189))	('ZO-1', 'Gene', (207, 211))	('mesenchymal', 'CPA', (70, 81))	('DMS114', 'Chemical', '-', (230, 236))	('Snail', 'Gene', '6615', (119, 124))	('miR-214-3p', 'Var', (10, 20))	('downregulation', 'NegReg', (52, 66))	('E-cad', 'Gene', (196, 201))	('epithelial', 'CPA', (157, 167))	('E-cadherin', 'Gene', (184, 194))	('E-cadherin', 'Gene', '999', (184, 194))	('upregulation', 'PosReg', (141, 153))	('VIM', 'Gene', '7431', (110, 113))	('vimentin', 'Gene', '7431', (100, 108))	('vimentin', 'Gene', (100, 108))	('E-cad', 'Gene', (184, 189))	('VIM', 'Gene', (110, 113))	('Snail', 'Gene', (119, 124))	('E-cad', 'Gene', '999', (196, 201))
391689	31492847	Conversely, the downregulation of miR-214-3p promoted proliferation, migration, and invasion in both cell lines (Fig.	('downregulation', 'NegReg', (16, 30))	('invasion', 'CPA', (84, 92))	('3p', 'Chemical', '-', (42, 44))	('promoted', 'PosReg', (45, 53))	('proliferation', 'CPA', (54, 67))	('miR-214-3p', 'Var', (34, 44))	('migration', 'CPA', (69, 78))
391690	31492847	These results indicated that miR-214-3p blocked the EMT process in FGFR1-amplified lung cancer cell lines as a tumor suppressor.	('FGFR1', 'Gene', (67, 72))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('lung cancer', 'Disease', 'MESH:D008175', (83, 94))	('blocked', 'NegReg', (40, 47))	('FGFR1', 'Gene', '2260', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumor', 'Disease', (111, 116))	('miR-214-3p', 'Var', (29, 39))	('lung cancer', 'Disease', (83, 94))	('3p', 'Chemical', '-', (37, 39))	('lung cancer', 'Phenotype', 'HP:0100526', (83, 94))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('EMT process', 'CPA', (52, 63))
391693	31492847	Meanwhile, FGFR1 had a sharp downregulation after miR-214-3p overexpression for 48 h, which was detected by western and qRT-PCR (Fig.	('downregulation', 'NegReg', (29, 43))	('3p', 'Chemical', '-', (58, 60))	('overexpression', 'PosReg', (61, 75))	('FGFR1', 'Gene', (11, 16))	('miR-214-3p', 'Var', (50, 60))	('FGFR1', 'Gene', '2260', (11, 16))
391694	31492847	To test whether the miR-214-3p directly regulates FGFR1, mutant (FGFR1 3'-UTR-MUT) 3'-UTR, and wild type (FGFR1 3'-UTR-WT), the regions of FGFR1 gene were separately cloned into the pGL3 vector downstream of the luciferase-coding region.	('FGFR1', 'Gene', (139, 144))	('FGFR1', 'Gene', '2260', (139, 144))	('pGL3', 'Gene', (182, 186))	('regulates', 'Reg', (40, 49))	('FGFR1', 'Gene', (50, 55))	('FGFR1', 'Gene', (106, 111))	('pGL3', 'Gene', '6391', (182, 186))	('3p', 'Chemical', '-', (28, 30))	('FGFR1', 'Gene', '2260', (50, 55))	('FGFR1', 'Gene', (65, 70))	('FGFR1', 'Gene', '2260', (106, 111))	('mutant', 'Var', (57, 63))	('FGFR1', 'Gene', '2260', (65, 70))
391695	31492847	The luciferase reporter assay indicated that miR-214-3p reduced the luciferase activity of the WT 3'-UTR reporter in all of the cell lines, but had no effect on the MUT 3'-UTR reporter (Fig.	('activity', 'MPA', (79, 87))	('miR-214-3p', 'Var', (45, 55))	('reduced', 'NegReg', (56, 63))	('luciferase', 'Enzyme', (68, 78))	('3p', 'Chemical', '-', (53, 55))
391696	31492847	3d-f), which suggested that FGFR1 expression was directly regulated by miR-214-3p.	('expression', 'MPA', (34, 44))	('3p', 'Chemical', '-', (79, 81))	('FGFR1', 'Gene', (28, 33))	('FGFR1', 'Gene', '2260', (28, 33))	('regulated', 'Reg', (58, 67))	('miR-214-3p', 'Var', (71, 81))
391697	31492847	To determine whether FGFR1 acts a pivotal role in miR-214-3p-induced alterations in cell proliferation and metastasis, H1581, DMS114, and HCC95 cells transfected with FGFR1 overexpression plasmid were used.	('3p', 'Chemical', '-', (58, 60))	('FGFR1', 'Gene', (167, 172))	('FGFR1', 'Gene', '2260', (21, 26))	('FGFR1', 'Gene', '2260', (167, 172))	('FGFR1', 'Gene', (21, 26))	('HCC95', 'CellLine', 'CVCL:5137', (138, 143))	('miR-214-3p-induced', 'Var', (50, 68))	('cell proliferation', 'CPA', (84, 102))	('DMS114', 'Chemical', '-', (126, 132))	('alterations', 'Reg', (69, 80))
391698	31492847	The inhibitory effects of miR-214-3p on proliferation (Fig.	('inhibitory', 'NegReg', (4, 14))	('proliferation', 'CPA', (40, 53))	('3p', 'Chemical', '-', (34, 36))	('miR-214-3p', 'Var', (26, 36))
391699	31492847	4c) induced by miR-214-3p were abrogated by FGFR1 overexpression in the cells.	('3p', 'Chemical', '-', (23, 25))	('abrogated', 'NegReg', (31, 40))	('FGFR1', 'Gene', (44, 49))	('overexpression', 'PosReg', (50, 64))	('FGFR1', 'Gene', '2260', (44, 49))	('miR-214-3p', 'Var', (15, 25))
391700	31492847	The downregulation of mesenchymal markers, including VIM and Snail, and the upregulation of epithelial marker, E-cad induced by miR-214-3p, were also rescued by FGFR1 restoration (Fig.	('E-cad', 'Gene', (111, 116))	('VIM', 'Gene', '7431', (53, 56))	('FGFR1', 'Gene', (161, 166))	('Snail', 'Gene', (61, 66))	('upregulation', 'PosReg', (76, 88))	('Snail', 'Gene', '6615', (61, 66))	('FGFR1', 'Gene', '2260', (161, 166))	('miR-214-3p', 'Var', (128, 138))	('epithelial', 'MPA', (92, 102))	('downregulation', 'NegReg', (4, 18))	('VIM', 'Gene', (53, 56))	('3p', 'Chemical', '-', (136, 138))	('E-cad', 'Gene', '999', (111, 116))
391702	31492847	Interestingly, MAPK/AKT (mitogen-activated protein kinase/AKT) signaling pathways as classic oncogenic pathways were regulated by both miR-214-3p and FGFR1.	('3p', 'Chemical', '-', (143, 145))	('AKT', 'Gene', (20, 23))	('mitogen-activated protein kinase/AKT', 'Gene', '207', (25, 61))	('AKT', 'Gene', (58, 61))	('FGFR1', 'Gene', (150, 155))	('miR-214-3p', 'Var', (135, 145))	('FGFR1', 'Gene', '2260', (150, 155))	('AKT', 'Gene', '207', (58, 61))	('AKT', 'Gene', '207', (20, 23))	('regulated', 'Reg', (117, 126))	('mitogen-activated protein kinase/AKT', 'Gene', (25, 61))
391704	31492847	Twenty-four hours after transfection of miR-214-3p-mimic, the levels of the proteins in Wnt/MAPK/AKT signaling pathways were markedly decreased (Fig.	('decreased', 'NegReg', (134, 143))	('AKT', 'Gene', '207', (97, 100))	('3p', 'Chemical', '-', (48, 50))	('AKT', 'Gene', (97, 100))	('levels of the proteins', 'MPA', (62, 84))	('miR-214-3p-mimic', 'Var', (40, 56))
391707	31492847	This effect of miR-214-3p on Wnt/MAPK/AKT signaling pathways was offset by FGFR1 overexpression (Fig.	('3p', 'Chemical', '-', (23, 25))	('AKT', 'Gene', (38, 41))	('FGFR1', 'Gene', (75, 80))	('FGFR1', 'Gene', '2260', (75, 80))	('overexpression', 'PosReg', (81, 95))	('miR-214-3p', 'Var', (15, 25))	('AKT', 'Gene', '207', (38, 41))
391708	31492847	The results suggested that miR-214-3p could not only downregulate FGFR1 by post-transcriptional regulation but also inhibit Wnt/MAPK/AKT pathways by suppressing the phosphorylation of FGFR1.	('FGFR1', 'Gene', '2260', (184, 189))	('downregulate', 'NegReg', (53, 65))	('miR-214-3p', 'Var', (27, 37))	('3p', 'Chemical', '-', (35, 37))	('AKT', 'Gene', '207', (133, 136))	('FGFR1', 'Gene', (66, 71))	('phosphorylation', 'MPA', (165, 180))	('inhibit', 'NegReg', (116, 123))	('AKT', 'Gene', (133, 136))	('suppressing', 'NegReg', (149, 160))	('FGFR1', 'Gene', (184, 189))	('FGFR1', 'Gene', '2260', (66, 71))	('post-transcriptional regulation', 'MPA', (75, 106))
391709	31492847	Interestingly, we found that miR-214-3p was downregulated by FGFR1 inhibitor AZD4547 and upregulated by the exogenous FGFR1 ligand FGF2 (Fig.	('downregulated', 'NegReg', (44, 57))	('FGFR1', 'Gene', '2260', (118, 123))	('FGFR1', 'Gene', (61, 66))	('inhibitor AZD4547', 'Var', (67, 84))	('upregulated', 'PosReg', (89, 100))	('FGF2', 'Gene', '2247', (131, 135))	('FGFR1', 'Gene', '2260', (61, 66))	('miR-214-3p', 'Var', (29, 39))	('AZD4547', 'Var', (77, 84))	('3p', 'Chemical', '-', (37, 39))	('FGF2', 'Gene', (131, 135))	('AZD4547', 'Chemical', 'MESH:C572463', (77, 84))	('FGFR1', 'Gene', (118, 123))
391710	31492847	To further investigate which signaling pathway downstream of FGFR1 could regulate the expression of miR-214-3p, Wnt pathway inhibitor XAV-939, the AKT pathway inhibitor MK-2206 2HCl, and the MAPK pathway inhibitor AZD6244 (Fig.	('FGFR1', 'Gene', (61, 66))	('miR-214-3p', 'Var', (100, 110))	('3p', 'Chemical', '-', (108, 110))	('FGFR1', 'Gene', '2260', (61, 66))	('expression', 'MPA', (86, 96))	('AZD6244', 'Chemical', 'MESH:C517975', (214, 221))	('AKT', 'Gene', '207', (147, 150))	('regulate', 'Reg', (73, 81))	('MK-2206 2HCl', 'Chemical', '-', (169, 181))	('XAV-939', 'Chemical', 'MESH:C544261', (134, 141))	('AKT', 'Gene', (147, 150))
391711	31492847	MiR-214-3p was only suppressed by AZD6244 (Fig.	('AZD6244', 'Chemical', 'MESH:C517975', (34, 41))	('MiR-214', 'Gene', (0, 7))	('3p', 'Chemical', '-', (8, 10))	('MiR-214', 'Gene', '406996', (0, 7))	('AZD6244', 'Var', (34, 41))
391712	31492847	AZD6244 could not suppress the level of miR-214-3p in the presence of FGF2 (Fig.	('FGF2', 'Gene', '2247', (70, 74))	('3p', 'Chemical', '-', (48, 50))	('miR-214-3p', 'MPA', (40, 50))	('AZD6244', 'Var', (0, 7))	('FGF2', 'Gene', (70, 74))	('AZD6244', 'Chemical', 'MESH:C517975', (0, 7))
391715	31492847	Meanwhile, the upregulation of miR-214-3p caused by ERK2_R67S plasmid transfection was not suppressed by FGFR1 inhibitor AZD4547 or MEK/ERK inhibitor AZD6244 (Fig.	('ERK', 'Gene', '5594', (52, 55))	('R67S', 'Mutation', 'rs567762331', (57, 61))	('FGFR1', 'Gene', (105, 110))	('ERK', 'Gene', (52, 55))	('ERK2', 'Gene', '5594', (52, 56))	('miR-214-3p', 'Var', (31, 41))	('FGFR1', 'Gene', '2260', (105, 110))	('AZD4547', 'Chemical', 'MESH:C572463', (121, 128))	('ERK', 'Gene', '5594', (136, 139))	('MEK', 'Gene', (132, 135))	('ERK2', 'Gene', (52, 56))	('3p', 'Chemical', '-', (39, 41))	('AZD6244', 'Chemical', 'MESH:C517975', (150, 157))	('ERK', 'Gene', (136, 139))	('MEK', 'Gene', '5609', (132, 135))
391716	31492847	Therefore, we verified that FGFR1 regulated the expression of miR-214-3p through ERK activation.	('miR-214-3p', 'Var', (62, 72))	('ERK', 'Gene', '5594', (81, 84))	('expression', 'MPA', (48, 58))	('FGFR1', 'Gene', (28, 33))	('ERK', 'Gene', (81, 84))	('3p', 'Chemical', '-', (70, 72))	('activation', 'PosReg', (85, 95))	('FGFR1', 'Gene', '2260', (28, 33))
391720	31492847	However, the IC50 for AZD4547 plus miR-214-3p was reduced to 0.01299 muM.	('AZD4547', 'Chemical', 'MESH:C572463', (22, 29))	('AZD4547', 'Var', (22, 29))	('miR-214-3p', 'Var', (35, 45))	('3p', 'Chemical', '-', (43, 45))
391722	31492847	The range of CI values was below 0.2 (CI <1), indicating a strong synergy between miR-214-3p and AZD4547 (Fig.	('AZD4547', 'Var', (97, 104))	('3p', 'Chemical', '-', (90, 92))	('AZD4547', 'Chemical', 'MESH:C572463', (97, 104))	('synergy', 'Interaction', (66, 73))	('miR-214-3p', 'Var', (82, 92))
391724	31492847	To further verify the synergism in vivo, subcutaneous mouse models and orthotopic lung cancer mouse models were established using H1581(Fig.	('H1581', 'Var', (130, 135))	('lung cancer', 'Phenotype', 'HP:0100526', (82, 93))	('orthotopic lung cancer', 'Disease', 'MESH:D008175', (71, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('mouse', 'Species', '10090', (94, 99))	('orthotopic lung cancer', 'Disease', (71, 93))	('mouse', 'Species', '10090', (54, 59))
391726	31492847	After a week, miR-214-3p antagomir or miR antagomir NC was injected into the implanted tumor every 3 days for a total of seven injections in subcutaneous mouse models.	('mouse', 'Species', '10090', (154, 159))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('miR-214-3p', 'Var', (14, 24))	('tumor', 'Disease', (87, 92))	('3p', 'Chemical', '-', (22, 24))	('tumor', 'Disease', 'MESH:D009369', (87, 92))
391727	31492847	The results indicated that the subcutaneous tumors in miR-214-3p antagomir group grew slower than the miR-NC antagomir group.	('tumors', 'Disease', (44, 50))	('tumors', 'Disease', 'MESH:D009369', (44, 50))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('3p', 'Chemical', '-', (62, 64))	('slower', 'NegReg', (86, 92))	('subcutaneous tumors', 'Phenotype', 'HP:0001482', (31, 50))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('miR-214-3p', 'Var', (54, 64))	('grew', 'CPA', (81, 85))
391733	31492847	In the LV-miR-214-3p group plus AZD4547 group, FGFR1 and mesenchymal markers Snail and VIM were significantly suppressed, while the epithelial marker E-cad was highly expressed (Fig.	('VIM', 'Gene', (87, 90))	('LV-miR-214-3p', 'Var', (7, 20))	('Snail', 'Gene', (77, 82))	('Snail', 'Gene', '6615', (77, 82))	('FGFR1', 'Gene', (47, 52))	('E-cad', 'Gene', '999', (150, 155))	('AZD4547', 'Var', (32, 39))	('E-cad', 'Gene', (150, 155))	('3p', 'Chemical', '-', (18, 20))	('FGFR1', 'Gene', '2260', (47, 52))	('AZD4547', 'Chemical', 'MESH:C572463', (32, 39))	('VIM', 'Gene', '7431', (87, 90))	('suppressed', 'NegReg', (110, 120))
391734	31492847	Overall, we demonstrated the antitumor synergism between miR-214-3p and AZD4547 in vitro and in vivo.	('3p', 'Chemical', '-', (65, 67))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('AZD4547', 'Chemical', 'MESH:C572463', (72, 79))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumor', 'Disease', (33, 38))	('miR-214-3p', 'Var', (57, 67))	('AZD4547', 'Var', (72, 79))
391739	31492847	Among them, miR-214-3p expression was significantly lower in tumor tissues than NATs, which might act as a tumor biomarker.	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('lower', 'NegReg', (52, 57))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('miR-214-3p', 'Var', (12, 22))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('3p', 'Chemical', '-', (20, 22))	('tumor', 'Disease', (61, 66))	('expression', 'MPA', (23, 33))
391740	31492847	More importantly, miR-214-3p was correlated to a favorable patient prognosis, indicating that miR-214-3p may act as a biomarker to predict the recurrence, and outcome for lung cancer patients.	('3p', 'Chemical', '-', (102, 104))	('lung cancer', 'Disease', (171, 182))	('miR-214-3p', 'Var', (18, 28))	('patient', 'Species', '9606', (59, 66))	('miR-214-3p', 'Var', (94, 104))	('lung cancer', 'Phenotype', 'HP:0100526', (171, 182))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('patient', 'Species', '9606', (183, 190))	('3p', 'Chemical', '-', (26, 28))	('lung cancer', 'Disease', 'MESH:D008175', (171, 182))	('patients', 'Species', '9606', (183, 191))
391741	31492847	We subsequently performed a profiling study on the proliferation, invasion, migration, and EMT of FGFR1-amplified cell lines, which confirmed the tumor-suppressive effect of miR-214-3p.	('3p', 'Chemical', '-', (182, 184))	('FGFR1', 'Gene', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('FGFR1', 'Gene', '2260', (98, 103))	('tumor', 'Disease', (146, 151))	('miR-214-3p', 'Var', (174, 184))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
391743	31492847	However, previous studies have shown that miR-214-3p could be tumor promoter or suppressor in different tumor types.	('miR-214-3p', 'Var', (42, 52))	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumor', 'Disease', (62, 67))	('tumor', 'Disease', (104, 109))	('3p', 'Chemical', '-', (50, 52))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
391744	31492847	On the one hand, miR-214-3p increased the resistance to erlotinib and stimulated tumor proliferation and invasion by targeting LHX6 in patients with LADC.	('increased', 'PosReg', (28, 37))	('invasion', 'CPA', (105, 113))	('miR-214-3p', 'Var', (17, 27))	('patients', 'Species', '9606', (135, 143))	('3p', 'Chemical', '-', (25, 27))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('targeting', 'Reg', (117, 126))	('LHX6', 'Gene', (127, 131))	('resistance to erlotinib', 'MPA', (42, 65))	('LHX6', 'Gene', '26468', (127, 131))	('stimulated', 'PosReg', (70, 80))	('tumor', 'Disease', (81, 86))	('erlotinib', 'Chemical', 'MESH:D000069347', (56, 65))
391745	31492847	Anti-miR-214 therapy has been shown to inhibit tumor progression in primary breast cancer tumors melanoma and pancreatic neuroendocrine cancer.	('melanoma', 'Phenotype', 'HP:0002861', (97, 105))	('neuroendocrine cancer', 'Phenotype', 'HP:0100634', (121, 142))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('inhibit', 'NegReg', (39, 46))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('tumor', 'Disease', (90, 95))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('pancreatic neuroendocrine cancer', 'Phenotype', 'HP:0030405', (110, 142))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('breast cancer tumors melanoma and pancreatic neuroendocrine cancer', 'Disease', 'MESH:C563985', (76, 142))	('breast cancer', 'Phenotype', 'HP:0003002', (76, 89))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('Anti-miR-214', 'Var', (0, 12))	('tumor', 'Disease', (47, 52))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
391746	31492847	On the other hand, miR-214-3p is downregulated and suppresses tumor proliferation and metastasis in other tumors such as cutaneous squamous cell carcinoma and esophageal squamous cell carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (184, 193))	('carcinoma', 'Phenotype', 'HP:0030731', (145, 154))	('tumors', 'Disease', (106, 112))	('suppresses', 'NegReg', (51, 61))	('miR-214-3p', 'Var', (19, 29))	('metastasis', 'CPA', (86, 96))	('tumor', 'Disease', (106, 111))	('downregulated', 'NegReg', (33, 46))	('cutaneous squamous cell carcinoma', 'Disease', (121, 154))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('cutaneous squamous cell carcinoma', 'Disease', 'MESH:D002294', (121, 154))	('esophageal squamous cell carcinoma', 'Disease', (159, 193))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (131, 154))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('3p', 'Chemical', '-', (27, 29))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (159, 193))	('tumor', 'Disease', (62, 67))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (170, 193))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
391748	31492847	Recent studies indicated that miR-214-3p inhibited proliferation or tumor progression by targeting FGFR1 in the differentiation process of osteogenic mesenchymal stem cells and colorectal cancer, which was consistent with our research.	('tumor', 'Disease', (68, 73))	('3p', 'Chemical', '-', (38, 40))	('colorectal cancer', 'Disease', (177, 194))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('targeting', 'Reg', (89, 98))	('FGFR1', 'Gene', (99, 104))	('colorectal cancer', 'Disease', 'MESH:D015179', (177, 194))	('proliferation', 'CPA', (51, 64))	('FGFR1', 'Gene', '2260', (99, 104))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('inhibited', 'NegReg', (41, 50))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('colorectal cancer', 'Phenotype', 'HP:0003003', (177, 194))	('miR-214-3p', 'Var', (30, 40))
391749	31492847	We confirmed that FGFR1 was a direct target of miR-214-3p and mediated the biological function of miR-214-3p in FGFR1-amplified lung cancer cells.	('FGFR1', 'Gene', (112, 117))	('lung cancer', 'Disease', 'MESH:D008175', (128, 139))	('3p', 'Chemical', '-', (55, 57))	('FGFR1', 'Gene', '2260', (112, 117))	('FGFR1', 'Gene', (18, 23))	('lung cancer', 'Disease', (128, 139))	('lung cancer', 'Phenotype', 'HP:0100526', (128, 139))	('miR-214-3p', 'Var', (98, 108))	('FGFR1', 'Gene', '2260', (18, 23))	('miR-214-3p', 'Var', (47, 57))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('3p', 'Chemical', '-', (106, 108))
391753	31492847	The role of Wnt signaling in carcinogenesis has most prominently been described for colorectal cancer, but aberrant Wnt signaling is observed in gastrointestinal cancers, leukemia, melanoma, breast cancer, and so on.	('carcinogenesis', 'Disease', (29, 43))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('colorectal cancer', 'Phenotype', 'HP:0003003', (84, 101))	('gastrointestinal cancers', 'Disease', (145, 169))	('breast cancer', 'Disease', (191, 204))	('breast cancer', 'Disease', 'MESH:D001943', (191, 204))	('carcinogenesis', 'Disease', 'MESH:D063646', (29, 43))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('melanoma', 'Phenotype', 'HP:0002861', (181, 189))	('melanoma', 'Disease', (181, 189))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('leukemia', 'Phenotype', 'HP:0001909', (171, 179))	('colorectal cancer', 'Disease', 'MESH:D015179', (84, 101))	('colorectal cancer', 'Disease', (84, 101))	('leukemia', 'Disease', 'MESH:D007938', (171, 179))	('leukemia', 'Disease', (171, 179))	('Wnt signaling', 'MPA', (116, 129))	('aberrant', 'Var', (107, 115))	('gastrointestinal cancers', 'Disease', 'MESH:D004067', (145, 169))	('cancers', 'Phenotype', 'HP:0002664', (162, 169))	('melanoma', 'Disease', 'MESH:D008545', (181, 189))	('breast cancer', 'Phenotype', 'HP:0003002', (191, 204))
391755	31492847	Previous studies suggest that both miR-214-3p and FGFR1 could regulate MAPK/PI3K-AKT signaling.	('FGFR1', 'Gene', (50, 55))	('AKT', 'Gene', '207', (81, 84))	('miR-214-3p', 'Var', (35, 45))	('FGFR1', 'Gene', '2260', (50, 55))	('3p', 'Chemical', '-', (43, 45))	('AKT', 'Gene', (81, 84))	('regulate', 'Reg', (62, 70))
391757	31492847	We confirmed that miR-214-3p inhibited the activity of Wnt/MAPK/PI3K-AKT signaling, and overexpression of FGFR1 offset this effect, which suggest that miR-214-3p inhibited Wnt/MAPK/PI3K-AKT signaling pathway by suppression of FGFR1.	('inhibited', 'NegReg', (29, 38))	('AKT', 'Gene', (69, 72))	('AKT', 'Gene', '207', (186, 189))	('FGFR1', 'Gene', (106, 111))	('FGFR1', 'Gene', (226, 231))	('miR-214-3p', 'Var', (151, 161))	('miR-214-3p', 'Var', (18, 28))	('3p', 'Chemical', '-', (159, 161))	('FGFR1', 'Gene', '2260', (226, 231))	('AKT', 'Gene', '207', (69, 72))	('FGFR1', 'Gene', '2260', (106, 111))	('suppression', 'NegReg', (211, 222))	('AKT', 'Gene', (186, 189))	('activity', 'MPA', (43, 51))	('inhibited', 'NegReg', (162, 171))	('3p', 'Chemical', '-', (26, 28))
391765	31492847	Here, we confirmed the antitumor synergism between miR-214-3p and AZD4547 in vitro and in vivo.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('3p', 'Chemical', '-', (59, 61))	('tumor', 'Disease', (27, 32))	('miR-214-3p', 'Var', (51, 61))	('AZD4547', 'Gene', (66, 73))	('AZD4547', 'Chemical', 'MESH:C572463', (66, 73))	('tumor', 'Disease', 'MESH:D009369', (27, 32))
391766	31492847	The underlying molecular mechanism of the synergy between miR-214-3p and AZD4547 has remained unknown.	('miR-214-3p', 'Var', (58, 68))	('3p', 'Chemical', '-', (66, 68))	('AZD4547', 'Chemical', 'MESH:C572463', (73, 80))	('AZD4547', 'Gene', (73, 80))
391768	31492847	FGFR1 inhibitor AZD4547 reduced the level of miR-214-3p by suppressing ERK activation in cell lines.	('activation', 'MPA', (75, 85))	('reduced', 'NegReg', (24, 31))	('ERK', 'Gene', '5594', (71, 74))	('AZD4547', 'Var', (16, 23))	('FGFR1', 'Gene', (0, 5))	('FGFR1', 'Gene', '2260', (0, 5))	('ERK', 'Gene', (71, 74))	('suppressing', 'NegReg', (59, 70))	('AZD4547', 'Chemical', 'MESH:C572463', (16, 23))	('3p', 'Chemical', '-', (53, 55))
391769	31492847	However, it was confirmed that miR-214-3p acted as a tumor suppressor by targeting FGFR1.	('miR-214-3p', 'Var', (31, 41))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('3p', 'Chemical', '-', (39, 41))	('targeting', 'Reg', (73, 82))	('FGFR1', 'Gene', (83, 88))	('tumor', 'Disease', (53, 58))	('FGFR1', 'Gene', '2260', (83, 88))
391770	31492847	Therefore, FGFR1 inhibitor AZD4547 might upregulate the level of FGFR1 and the pathway downstream of FGFR1 by inhibiting miR-214-3p.	('FGFR1', 'Gene', (101, 106))	('AZD4547', 'Chemical', 'MESH:C572463', (27, 34))	('FGFR1', 'Gene', (65, 70))	('level', 'MPA', (56, 61))	('inhibiting', 'NegReg', (110, 120))	('FGFR1', 'Gene', (11, 16))	('upregulate', 'PosReg', (41, 51))	('FGFR1', 'Gene', '2260', (65, 70))	('3p', 'Chemical', '-', (129, 131))	('FGFR1', 'Gene', '2260', (11, 16))	('miR-214-3p', 'MPA', (121, 131))	('FGFR1', 'Gene', '2260', (101, 106))	('AZD4547', 'Var', (27, 34))
391771	31492847	Meanwhile, we did notice that a dynamic balance between miR-214-3p and FGFR1 existed within 96 h after the addition of AZD4547, which need further exploration.	('FGFR1', 'Gene', (71, 76))	('FGFR1', 'Gene', '2260', (71, 76))	('AZD4547', 'Var', (119, 126))	('AZD4547', 'Chemical', 'MESH:C572463', (119, 126))	('3p', 'Chemical', '-', (64, 66))
391772	31492847	Previous studies identified DUSP6 deletion and NRAS amplification in drug-resistant H1581 cells, leading to the reactivation of MAPK pathway.	('DUSP6', 'Gene', (28, 33))	('DUSP6', 'Gene', '1848', (28, 33))	('MAPK pathway', 'Pathway', (128, 140))	('NRAS', 'Gene', (47, 51))	('reactivation', 'MPA', (112, 124))	('deletion', 'Var', (34, 42))	('NRAS', 'Gene', '4893', (47, 51))	('amplification', 'Var', (52, 65))
391777	31492847	As stated above, our findings in this study have demonstrated that miR-214-3p acts as a vital biological targeting inhibitor for FGFR1, which need further study for cancer treatment.	('FGFR1', 'Gene', (129, 134))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('FGFR1', 'Gene', '2260', (129, 134))	('cancer', 'Disease', (165, 171))	('miR-214-3p', 'Var', (67, 77))	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('3p', 'Chemical', '-', (75, 77))
391778	31492847	In summary, in this study we have discovered a negative feedback regulatory axis between miR-214-3p and FGFR1, as well as a synergistic antitumor effect between miR-214-3p and AZD4547.	('miR-214-3p', 'Var', (161, 171))	('negative', 'NegReg', (47, 55))	('AZD4547', 'Var', (176, 183))	('3p', 'Chemical', '-', (169, 171))	('3p', 'Chemical', '-', (97, 99))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('AZD4547', 'Chemical', 'MESH:C572463', (176, 183))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('miR-214-3p', 'Gene', (89, 99))	('FGFR1', 'Gene', (104, 109))	('FGFR1', 'Gene', '2260', (104, 109))	('tumor', 'Disease', (140, 145))
391786	31492847	The sequences of siFGFR1, siRNA-NC, WT ERK2, and autophosphorylation variant ERK2 p.R67S (ERK2_R67S) were described by us before.	('ERK2', 'Gene', (39, 43))	('ERK2', 'Gene', (77, 81))	('R67S', 'Mutation', 'rs567762331', (95, 99))	('FGFR1', 'Gene', '2260', (19, 24))	('ERK2', 'Gene', '5594', (90, 94))	('p.R67S', 'Mutation', 'rs567762331', (82, 88))	('ERK2', 'Gene', '5594', (77, 81))	('ERK2', 'Gene', '5594', (39, 43))	('ERK2', 'Gene', (90, 94))	('R67S', 'Mutation', 'rs567762331', (84, 88))	('p.R67S', 'Var', (82, 88))	('FGFR1', 'Gene', (19, 24))
391797	31492847	After transfected with miR-214-3p mimic or miR-214-3p inhibitor for 24 h, 10 muL CCK8 reagent was added into the medium per well.	('3p', 'Chemical', '-', (31, 33))	('miR-214-3p inhibitor', 'Var', (43, 63))	('miR-214-3p', 'Var', (23, 33))	('3p', 'Chemical', '-', (51, 53))
391812	31492847	Cells were co-transfected with miR-214 and WT-FGFR1 3'-UTR, miR-214 and MT-FGFR1 3'-UTR, miR-NC and WT-FGFR1 3'-UTR, and miR-NC and mt-FGFR1 3'-UTR.	('FGFR1', 'Gene', '2260', (46, 51))	('FGFR1', 'Gene', (75, 80))	('miR-214', 'Var', (60, 67))	('FGFR1', 'Gene', '2260', (75, 80))	('FGFR1', 'Gene', (103, 108))	('FGFR1', 'Gene', (46, 51))	('FGFR1', 'Gene', (135, 140))	('FGFR1', 'Gene', '2260', (103, 108))	('FGFR1', 'Gene', '2260', (135, 140))
391816	33593392	Genome-wide analysis identifies critical DNA methylations within NTRKs genes in colorectal cancer Neurotrophic tropomyosin receptor kinases (NTRKs) are a gene family function as oncogene or tumor suppressor gene in distinct cancers.	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('rectal cancer', 'Phenotype', 'HP:0100743', (84, 97))	('colorectal cancer', 'Disease', 'MESH:D015179', (80, 97))	('cancers', 'Phenotype', 'HP:0002664', (224, 231))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('colorectal cancer', 'Phenotype', 'HP:0003003', (80, 97))	('tumor', 'Disease', (190, 195))	('cancers', 'Disease', 'MESH:D009369', (224, 231))	('methylations', 'Var', (45, 57))	('TRK', 'Gene', (66, 69))	('colorectal cancer', 'Disease', (80, 97))	('TRK', 'Gene', '4914', (66, 69))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('cancers', 'Disease', (224, 231))	('TRK', 'Gene', (142, 145))	('TRK', 'Gene', '4914', (142, 145))
391821	33593392	The profiles in six CRC cohorts showed that NTRKs gene promoter was more frequently methylated in CRC compared to normal mucosa, which was associated with suppressed gene expression.	('expression', 'MPA', (171, 181))	('CRC', 'Disease', (98, 101))	('methylated', 'Var', (84, 94))	('TRK', 'Gene', (45, 48))	('TRK', 'Gene', '4914', (45, 48))
391822	33593392	We identified a specific methylated region within NTRK3 promoter targeted by cg27034819 and cg11525479 that best predicted survival outcome in CRC.	('cg11525479', 'Var', (92, 102))	('cg11525479', 'Chemical', '-', (92, 102))	('NTRK3', 'Gene', '4916', (50, 55))	('CRC', 'Disease', (143, 146))	('NTRK3', 'Gene', (50, 55))	('cg27034819', 'Chemical', '-', (77, 87))	('cg27034819', 'Var', (77, 87))	('predicted', 'Reg', (113, 122))
391825	33593392	Finally, NTRK3 promoter methylation also predicted survival in other tumors, including pancreatic cancer, glioblastoma and stomach adenocarcinoma.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('pancreatic cancer', 'Disease', (87, 104))	('predicted', 'Reg', (41, 50))	('NTRK3', 'Gene', '4916', (9, 14))	('pancreatic cancer', 'Disease', 'MESH:D010190', (87, 104))	('glioblastoma and stomach adenocarcinoma', 'Disease', 'MESH:D005909', (106, 145))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('NTRK3', 'Gene', (9, 14))	('methylation', 'Var', (24, 35))	('glioblastoma', 'Phenotype', 'HP:0012174', (106, 118))	('tumors', 'Disease', (69, 75))	('tumors', 'Disease', 'MESH:D009369', (69, 75))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (87, 104))
391826	33593392	This study highlights the essential value of NTRK3 methylation in prognostic evaluation and the potential to improve current prognostic models in CRC and other tumors.	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('CRC', 'Disease', (146, 149))	('NTRK3', 'Gene', '4916', (45, 50))	('NTRK3', 'Gene', (45, 50))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('methylation', 'Var', (51, 62))	('tumors', 'Disease', (160, 166))	('tumors', 'Disease', 'MESH:D009369', (160, 166))
391830	33593392	Among them, the aberrant methylation in gene promoters is prevalent across multiple cancers, which can lead to the inactivation of tumor suppressor genes.	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('aberrant methylation', 'Var', (16, 36))	('cancers', 'Phenotype', 'HP:0002664', (84, 91))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumor', 'Disease', (131, 136))	('methylation', 'Var', (25, 36))	('inactivation', 'NegReg', (115, 127))	('multiple cancers', 'Disease', (75, 91))	('lead', 'Reg', (103, 107))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('multiple cancers', 'Disease', 'MESH:D009369', (75, 91))
391832	33593392	The aberrations of NTRKs gene function were widely known to play an oncogenic role in multiple cancers.	('multiple cancers', 'Disease', (86, 102))	('aberrations', 'Var', (4, 15))	('cancers', 'Phenotype', 'HP:0002664', (95, 102))	('play', 'Reg', (60, 64))	('multiple cancers', 'Disease', 'MESH:D009369', (86, 102))	('TRK', 'Gene', (20, 23))	('TRK', 'Gene', '4914', (20, 23))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))
391833	33593392	Among them, NTRKs gene fusion was the best-characterized aberration, which promotes tumorigenesis through the constitutive activation of downstream cell growth and proliferative pathways.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('fusion', 'Var', (23, 29))	('promotes', 'PosReg', (75, 83))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('TRK', 'Gene', (13, 16))	('TRK', 'Gene', '4914', (13, 16))	('tumor', 'Disease', (84, 89))	('activation', 'PosReg', (123, 133))	('downstream cell', 'Pathway', (137, 152))
391835	33593392	Similar to gene fusion, the aberrant expression of NTRKs gene is a critical event in cancers.	('cancers', 'Disease', 'MESH:D009369', (85, 92))	('cancers', 'Phenotype', 'HP:0002664', (85, 92))	('aberrant', 'Var', (28, 36))	('cancers', 'Disease', (85, 92))	('TRK', 'Gene', (52, 55))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('TRK', 'Gene', '4914', (52, 55))
391838	33593392	Based on this, inhibition of NTRK2-encoded TRKB was shown to induce antitumor effects and cellular apoptosis.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('induce', 'PosReg', (61, 67))	('tumor', 'Disease', (72, 77))	('NTRK2', 'Gene', '4915', (29, 34))	('TRKB', 'Gene', '4915', (43, 47))	('TRKB', 'Gene', (43, 47))	('cellular apoptosis', 'CPA', (90, 108))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('inhibition', 'Var', (15, 25))	('NTRK2', 'Gene', (29, 34))
391841	33593392	A hypermethylated NTRKs gene promoter is associated with suppressed expression in multiple cancers, such as CRC, neuroblastoma, glioma, ovarian cancer and prostate cancer.	('multiple cancers', 'Disease', 'MESH:D009369', (82, 98))	('expression', 'MPA', (68, 78))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('neuroblastoma', 'Phenotype', 'HP:0003006', (113, 126))	('hypermethylated', 'Var', (2, 17))	('TRK', 'Gene', (19, 22))	('neuroblastoma, glioma, ovarian cancer', 'Disease', 'MESH:D009447', (113, 150))	('multiple cancers', 'Disease', (82, 98))	('TRK', 'Gene', '4914', (19, 22))	('ovarian cancer', 'Phenotype', 'HP:0100615', (136, 150))	('cancers', 'Phenotype', 'HP:0002664', (91, 98))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('prostate cancer', 'Disease', 'MESH:D011471', (155, 170))	('prostate cancer', 'Phenotype', 'HP:0012125', (155, 170))	('glioma', 'Phenotype', 'HP:0009733', (128, 134))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('prostate cancer', 'Disease', (155, 170))	('CRC', 'Disease', (108, 111))	('suppressed', 'NegReg', (57, 67))
391856	33593392	The primers and probe designed to target cg27034819 and cg11525479 were illustrated in Fig.	('cg11525479', 'Var', (56, 66))	('cg27034819', 'Chemical', '-', (41, 51))	('cg27034819', 'Var', (41, 51))	('cg11525479', 'Chemical', '-', (56, 66))
391860	33593392	The assessment of KRAS and BRAF mutation was performed in the Molecular Diagnostic Laboratory of the Sixth Affiliated Hospital of Sun Yat-sen University, as previously described.	('KRAS', 'Gene', (18, 22))	('KRAS', 'Gene', '3845', (18, 22))	('BRAF', 'Gene', '673', (27, 31))	('BRAF', 'Gene', (27, 31))	('mutation', 'Var', (32, 40))
391863	33593392	The characteristics of CRC cases with and without NTRK3 promoter hypermethylation were compared using the Wilcoxon rank-sum tests or Chi-square tests.	('NTRK3', 'Gene', '4916', (50, 55))	('NTRK3', 'Gene', (50, 55))	('CRC', 'Disease', (23, 26))	('promoter hypermethylation', 'Var', (56, 81))
391864	33593392	In addition, Cox proportional hazards analyses were used to obtain HRs and corresponding 95% confidence intervals (CI) for the association between NTRK3 promoter hypermethylation and DFS.	('association', 'Interaction', (127, 138))	('NTRK3', 'Gene', (147, 152))	('promoter hypermethylation', 'Var', (153, 178))	('NTRK3', 'Gene', '4916', (147, 152))	('DFS', 'Disease', (183, 186))
391865	33593392	The comparison between NTRK3 hypermethylation and known prognostic factors was assessed using likelihood ratio (LR) and Akaike information criterion (AIC) in competing models including or not including NTRK3 hypermethylation.	('NTRK3', 'Gene', '4916', (23, 28))	('NTRK3', 'Gene', (202, 207))	('AIC', 'Disease', 'MESH:D058540', (150, 153))	('hypermethylation', 'Var', (29, 45))	('NTRK3', 'Gene', (23, 28))	('NTRK3', 'Gene', '4916', (202, 207))	('AIC', 'Disease', (150, 153))
391868	33593392	In TCGA dataset, the normalized beta value of cg27034819 and cg11525479 (adjacent to cg27034819), targeting the downstream region of the promoter region in NTRK3, was extracted from 450K microarray and its association with survival outcome was analyzed.	('cg27034819', 'Chemical', '-', (85, 95))	('cg11525479', 'Chemical', '-', (61, 71))	('cg11525479', 'Var', (61, 71))	('NTRK3', 'Gene', '4916', (156, 161))	('cg27034819', 'Chemical', '-', (46, 56))	('NTRK3', 'Gene', (156, 161))	('cg27034819', 'Var', (46, 56))
391874	33593392	In the Cox proportional hazards analyses of 450K microarray probes targeting genomic loci within NTRKs gene, we found that the methylation of most CpG sites targeted by these probes was associated with poor survival outcomes in CRC (Fig.	('methylation', 'MPA', (127, 138))	('survival outcomes', 'CPA', (207, 224))	('TRK', 'Gene', (98, 101))	('TRK', 'Gene', '4914', (98, 101))	('probes', 'Var', (175, 181))	('poor', 'NegReg', (202, 206))	('associated with', 'Reg', (186, 201))
391875	33593392	Among them, the methylation of cg27034819 was top-ranked for predicting CRC death.	('CRC death', 'Disease', (72, 81))	('cg27034819', 'Chemical', '-', (31, 41))	('cg27034819', 'Var', (31, 41))	('predicting', 'Reg', (61, 71))	('CRC death', 'Disease', 'MESH:D015179', (72, 81))	('methylation', 'Var', (16, 27))
391876	33593392	Of note, we found the probe cg11525479 was very close to cg27034819 in their targeting loci (Fig.	('cg11525479', 'Var', (28, 38))	('cg11525479', 'Chemical', '-', (28, 38))	('cg27034819', 'Chemical', '-', (57, 67))	('cg27034819', 'Var', (57, 67))
391877	33593392	2e), and the methylation of cg11525479 also had a predictive value for CRC death that was superior to most probes.	('CRC death', 'Disease', (71, 80))	('cg11525479', 'Var', (28, 38))	('cg11525479', 'Chemical', '-', (28, 38))	('CRC death', 'Disease', 'MESH:D015179', (71, 80))
391878	33593392	These results suggested that the specific region within NTRK3 promoter targeted by cg27034819 and cg11525479 could be used to stratify the death risk of CRC.	('death', 'Disease', (139, 144))	('cg11525479', 'Var', (98, 108))	('cg11525479', 'Chemical', '-', (98, 108))	('CRC', 'Disease', (153, 156))	('NTRK3', 'Gene', (56, 61))	('cg27034819', 'Chemical', '-', (83, 93))	('cg27034819', 'Var', (83, 93))	('death', 'Disease', 'MESH:D003643', (139, 144))	('NTRK3', 'Gene', '4916', (56, 61))
391882	33593392	NTRK3 promoter hypermethylation was observed in 26 of 229 patients (11.35%), and it was more frequent in patients with MSI (P = 0.015; Table 1).	('NTRK3', 'Gene', (0, 5))	('patients', 'Species', '9606', (105, 113))	('MSI', 'Disease', (119, 122))	('NTRK3', 'Gene', '4916', (0, 5))	('hypermethylation', 'Var', (15, 31))	('patients', 'Species', '9606', (58, 66))
391883	33593392	Moreover, NTRK3 promoter hypermethylation was associated with KRAS mutation (P = 0.001; Table 1).	('KRAS', 'Gene', (62, 66))	('NTRK3', 'Gene', (10, 15))	('KRAS', 'Gene', '3845', (62, 66))	('promoter hypermethylation', 'Var', (16, 41))	('NTRK3', 'Gene', '4916', (10, 15))	('associated', 'Reg', (46, 56))
391885	33593392	In the Kaplan-Meier curve, significantly worse DFS outcomes were observed in patients with NTRK3 promoter hypermethylation compared to those with NTRK3 promoter hypomethylation (P = 0.012; Fig.	('NTRK3', 'Gene', '4916', (146, 151))	('promoter hypermethylation', 'Var', (97, 122))	('NTRK3', 'Gene', (146, 151))	('worse', 'NegReg', (41, 46))	('NTRK3', 'Gene', '4916', (91, 96))	('patients', 'Species', '9606', (77, 85))	('NTRK3', 'Gene', (91, 96))
391886	33593392	The prognostic value of NTRK3 promoter methylation status was further confirmed by univariate Cox proportional hazards (P = 0.014, HR 2.194, 95% CI [1.169, 4.117]; Table 2).	('NTRK3', 'Gene', '4916', (24, 29))	('NTRK3', 'Gene', (24, 29))	('methylation status', 'Var', (39, 57))
391887	33593392	Next, in the light of multivariate analysis, NTRK3 promoter hypermethylation was still a prognostic factor adjusted by age, TNM stage, and BRAF mutation (P = 0.004, HR 2.688, 95% CI [1.355, 5.333]; Table 2).	('BRAF', 'Gene', (139, 143))	('promoter', 'MPA', (51, 59))	('TNM', 'Gene', '10178', (124, 127))	('NTRK3', 'Gene', (45, 50))	('mutation', 'Var', (144, 152))	('TNM', 'Gene', (124, 127))	('BRAF', 'Gene', '673', (139, 143))	('NTRK3', 'Gene', '4916', (45, 50))
391890	33593392	A nomogram for predicting 3-year and 5-year DFS outcome was generated using the variables from the multivariate Cox model, including NTRK3 methylation, age at diagnosis, TNM stage, and BRAF mutation (Fig.	('mutation', 'Var', (190, 198))	('TNM', 'Gene', (170, 173))	('NTRK3', 'Gene', '4916', (133, 138))	('BRAF', 'Gene', '673', (185, 189))	('TNM', 'Gene', '10178', (170, 173))	('NTRK3', 'Gene', (133, 138))	('BRAF', 'Gene', (185, 189))	('methylation', 'Var', (139, 150))
391891	33593392	The model 1 had a lower AIC and a higher LR compared with the model 2 (AIC: 597.73 vs 600.69; LR: 6.91 vs 5.95, P = 0.005; Table 3), indicating that NTRK3 hypermethylation alone is better in predicting prognosis than rough TNM staging alone.	('hypermethylation', 'Var', (155, 171))	('NTRK3', 'Gene', '4916', (149, 154))	('TNM', 'Gene', '10178', (223, 226))	('AIC', 'Disease', 'MESH:D058540', (71, 74))	('lower', 'NegReg', (18, 23))	('AIC', 'Disease', (24, 27))	('NTRK3', 'Gene', (149, 154))	('TNM', 'Gene', (223, 226))	('AIC', 'Disease', (71, 74))	('AIC', 'Disease', 'MESH:D058540', (24, 27))
391892	33593392	In the comparison between model 2 and 3, after NTRK3 hypermethylation was added to TNM stage, a lower AIC and a higher LR were observed (AIC: 600.69 vs 592.41; LR: 5.95 vs 16.23, P = 0.002; Table 3).	('AIC', 'Disease', (102, 105))	('higher', 'PosReg', (112, 118))	('AIC', 'Disease', (137, 140))	('lower', 'NegReg', (96, 101))	('TNM', 'Gene', '10178', (83, 86))	('AIC', 'Disease', 'MESH:D058540', (102, 105))	('NTRK3', 'Gene', '4916', (47, 52))	('AIC', 'Disease', 'MESH:D058540', (137, 140))	('hypermethylation', 'Var', (53, 69))	('added', 'Reg', (74, 79))	('NTRK3', 'Gene', (47, 52))	('TNM', 'Gene', (83, 86))
391893	33593392	These results suggest NTRK3 hypermethylation could increase prognostic values of TNM staging.	('increase', 'PosReg', (51, 59))	('hypermethylation', 'Var', (28, 44))	('TNM', 'Gene', (81, 84))	('NTRK3', 'Gene', '4916', (22, 27))	('TNM', 'Gene', '10178', (81, 84))	('NTRK3', 'Gene', (22, 27))	('prognostic', 'CPA', (60, 70))
391895	33593392	As expected, after NTRK3 hypermethylation was included, model 5 had a lower AIC and a higher LR in comparison to model 4 (AIC: 516.49 vs 513.91; LR: 39.06 vs 43.64, P = 0.032; Table 3).	('AIC', 'Disease', 'MESH:D058540', (76, 79))	('hypermethylation', 'Var', (25, 41))	('NTRK3', 'Gene', '4916', (19, 24))	('AIC', 'Disease', (122, 125))	('lower', 'NegReg', (70, 75))	('AIC', 'Disease', 'MESH:D058540', (122, 125))	('AIC', 'Disease', (76, 79))	('NTRK3', 'Gene', (19, 24))
391896	33593392	Thus, the model recommended by AJCC may get increased discriminatory ability in predicting prognosis with NTRK3 hypermethylation.	('NTRK3', 'Gene', '4916', (106, 111))	('NTRK3', 'Gene', (106, 111))	('hypermethylation', 'Var', (112, 128))
391897	33593392	Both the methylation of cg27034819 and cg11525479 were analyzed on their associations with survival outcome in 23 tumors using TCGA methylation profiles generated by 450K microarray.	('cg11525479', 'Var', (39, 49))	('cg11525479', 'Chemical', '-', (39, 49))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('cg27034819', 'Chemical', '-', (24, 34))	('cg27034819', 'Var', (24, 34))	('tumors', 'Disease', (114, 120))	('tumors', 'Disease', 'MESH:D009369', (114, 120))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))
391898	33593392	Overall, similar to the conflicting findings from in vitro and in vivo studies on NTRKs gene, the association of their methylations with survival outcome varied in different tumors.	('association', 'Interaction', (98, 109))	('tumors', 'Disease', (174, 180))	('methylations', 'Var', (119, 131))	('tumors', 'Disease', 'MESH:D009369', (174, 180))	('tumors', 'Phenotype', 'HP:0002664', (174, 180))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('TRK', 'Gene', (83, 86))	('TRK', 'Gene', '4914', (83, 86))
391899	33593392	The hypermethylation of cg27034819 was significantly associated with worse survival outcome in colon adenocarcinoma (COAD; P = 0.008, HR 1.91, 95% CI [1.18, 3.09]), rectum adenocarcinoma (READ; P 0.006, HR 3.73, 95% CI [1.37, 10.15]), kidney chromophobe (KICH; P = 0.005, HR 7.36, 95% CI [1.83, 29.581], and pancreatic adenocarcinoma (PAAD; P = 0.001, HR 1.96, 95% CI [1.30, 2.96]) cohorts.	('carcinoma', 'Disease', (106, 115))	('carcinoma', 'Disease', 'MESH:D009369', (177, 186))	('carcinoma', 'Phenotype', 'HP:0030731', (324, 333))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (308, 333))	('cg27034819', 'Chemical', '-', (24, 34))	('carcinoma', 'Disease', 'MESH:D009369', (106, 115))	('carcinoma', 'Disease', (324, 333))	('carcinoma', 'Phenotype', 'HP:0030731', (177, 186))	('cg27034819', 'Gene', (24, 34))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('kidney chromophobe', 'Disease', (235, 253))	('hypermethylation', 'Var', (4, 20))	('carcinoma', 'Disease', (177, 186))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D000230', (308, 333))	('carcinoma', 'Disease', 'MESH:D009369', (324, 333))	('kidney chromophobe', 'Disease', 'MESH:D000238', (235, 253))	('pancreatic adenocarcinoma', 'Disease', (308, 333))
391901	33593392	In cg11525479 methylation analysis, a similar predictive value for worse survival were found in COAD, READ, and PAAD, and a similar predictive value for better survival were found in GBM, SKCM and STAD (Fig.	('COAD', 'Disease', (96, 100))	('GBM', 'Disease', (183, 186))	('SKCM', 'Disease', (188, 192))	('methylation', 'Var', (14, 25))	('cg11525479', 'Chemical', '-', (3, 13))	('READ', 'Disease', (102, 106))	('cg11525479', 'Gene', (3, 13))
391902	33593392	These results suggested a robust prognostic value of the methylation of the specific promoter region targeted by cg27034819 and cg11525479 in multiple tumors.	('cg27034819', 'Chemical', '-', (113, 123))	('cg27034819', 'Var', (113, 123))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumors', 'Disease', (151, 157))	('tumors', 'Disease', 'MESH:D009369', (151, 157))	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('methylation of the specific promoter region', 'MPA', (57, 100))	('cg11525479', 'Var', (128, 138))	('cg11525479', 'Chemical', '-', (128, 138))
391903	33593392	In this study, we found the NTRKs gene promoter was more frequently methylated in CRC compared to normal mucosa, which was associated with suppressed expression of NTRK2 and NTRK3.	('expression', 'MPA', (150, 160))	('NTRK3', 'Gene', (174, 179))	('methylated', 'Var', (68, 78))	('TRK', 'Gene', (29, 32))	('TRK', 'Gene', '4914', (29, 32))	('NTRK2', 'Gene', (164, 169))	('TRK', 'Gene', (175, 178))	('CRC', 'Disease', (82, 85))	('TRK', 'Gene', '4914', (175, 178))	('TRK', 'Gene', (165, 168))	('TRK', 'Gene', '4914', (165, 168))	('NTRK3', 'Gene', '4916', (174, 179))	('suppressed', 'NegReg', (139, 149))	('NTRK2', 'Gene', '4915', (164, 169))
391904	33593392	Through a screen of probes targeting NTRKs gene, we identified a specific methylated region within NTRK3 promoter targeted by cg27034819 and cg11525479 that was the most promising prognostic marker for CRC.	('cg27034819', 'Chemical', '-', (126, 136))	('cg27034819', 'Var', (126, 136))	('TRK', 'Gene', (38, 41))	('CRC', 'Disease', (202, 205))	('TRK', 'Gene', (100, 103))	('TRK', 'Gene', '4914', (38, 41))	('TRK', 'Gene', '4914', (100, 103))	('NTRK3', 'Gene', '4916', (99, 104))	('cg11525479', 'Var', (141, 151))	('cg11525479', 'Chemical', '-', (141, 151))	('NTRK3', 'Gene', (99, 104))
391905	33593392	We developed a QMSP assay to determine the methylation of this region that could be easily applied in clinical assay and validate its predictive value for survival outcome in a cohort of 229 CRC patients and 23 TCGA cohorts including a colon cancer cohort, a rectal cancer cohort and 21 cohorts of other tumor types.	('cancer', 'Disease', 'MESH:D009369', (266, 272))	('rectal cancer', 'Phenotype', 'HP:0100743', (259, 272))	('cancer', 'Disease', (242, 248))	('cancer', 'Disease', 'MESH:D009369', (242, 248))	('methylation', 'Var', (43, 54))	('CRC', 'Disease', (191, 194))	('cancer', 'Disease', (266, 272))	('tumor', 'Disease', 'MESH:D009369', (304, 309))	('colon cancer', 'Disease', 'MESH:D015179', (236, 248))	('colon cancer', 'Phenotype', 'HP:0003003', (236, 248))	('cancer', 'Phenotype', 'HP:0002664', (242, 248))	('tumor', 'Phenotype', 'HP:0002664', (304, 309))	('patients', 'Species', '9606', (195, 203))	('cancer', 'Phenotype', 'HP:0002664', (266, 272))	('colon cancer', 'Disease', (236, 248))	('tumor', 'Disease', (304, 309))	('QMSP', 'Chemical', '-', (15, 19))
391906	33593392	Using NTRK3 promoter methylation, age, TNM stage, and BRAF mutation, a novel nomogram predicting DFS outcome was developed and validated with a good prognostic performance.	('NTRK3', 'Gene', (6, 11))	('BRAF', 'Gene', (54, 58))	('BRAF', 'Gene', '673', (54, 58))	('TNM', 'Gene', (39, 42))	('NTRK3', 'Gene', '4916', (6, 11))	('mutation', 'Var', (59, 67))	('TNM', 'Gene', '10178', (39, 42))
391911	33593392	These results indicated that NTRK2 and NTRK3 may play a more important role of tumor suppressor in CRC, and methylation silencing of NTRK2 and NTRK3 would contribute more to CRC tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('NTRK3', 'Gene', (143, 148))	('tumor', 'Disease', (178, 183))	('NTRK2', 'Gene', (29, 34))	('tumor', 'Disease', (79, 84))	('NTRK2', 'Gene', (133, 138))	('NTRK3', 'Gene', '4916', (39, 44))	('NTRK2', 'Gene', '4915', (29, 34))	('CRC', 'Disease', (99, 102))	('NTRK2', 'Gene', '4915', (133, 138))	('NTRK3', 'Gene', (39, 44))	('CRC', 'Disease', (174, 177))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('NTRK3', 'Gene', '4916', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('contribute', 'Reg', (155, 165))	('methylation silencing', 'Var', (108, 129))
391915	33593392	The robustness of this assay includes the finding that the probe cg11525479 that was very close to cg27034819 also had a prognostic value superior to most probes.	('cg11525479', 'Var', (65, 75))	('cg27034819', 'Chemical', '-', (99, 109))	('cg11525479', 'Chemical', '-', (65, 75))	('cg27034819', 'Var', (99, 109))
391917	33593392	Using this assay in our CRC cohort, we found that NTRK3 promoter hypermethylation was associated with worse DFS validation.	('promoter hypermethylation', 'Var', (56, 81))	('associated', 'Reg', (86, 96))	('NTRK3', 'Gene', '4916', (50, 55))	('DFS', 'Disease', (108, 111))	('NTRK3', 'Gene', (50, 55))
391918	33593392	Furthermore, we revealed that NTRK3 promoter hypermethylation is highly associated with MSI and KRAS mutation that is known as response biomarkers for cancer treatment and have conflicting predictive value for survival.	('MSI', 'Disease', (88, 91))	('NTRK3', 'Gene', (30, 35))	('KRAS', 'Gene', '3845', (96, 100))	('promoter hypermethylation', 'Var', (36, 61))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('associated', 'Reg', (72, 82))	('NTRK3', 'Gene', '4916', (30, 35))	('cancer', 'Disease', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('KRAS', 'Gene', (96, 100))
391922	33593392	First, NTRK3 methylation status is better than rough TNM stage (I, II, III) in predicting prognosis in CRC.	('methylation', 'Var', (13, 24))	('TNM', 'Gene', (53, 56))	('NTRK3', 'Gene', (7, 12))	('TNM', 'Gene', '10178', (53, 56))	('NTRK3', 'Gene', '4916', (7, 12))	('CRC', 'Disease', (103, 106))
391923	33593392	Then, the addition of NTRK3 promoter methylation status in TNM stage and the AJCC models was shown to improve the predictive performance for DFS in CRC patients.	('TNM', 'Gene', '10178', (59, 62))	('improve', 'PosReg', (102, 109))	('CRC', 'Disease', (148, 151))	('NTRK3', 'Gene', '4916', (22, 27))	('methylation status', 'Var', (37, 55))	('DFS', 'Disease', (141, 144))	('TNM', 'Gene', (59, 62))	('NTRK3', 'Gene', (22, 27))	('patients', 'Species', '9606', (152, 160))
391927	33593392	In our analyses, NTRK3 hypermethylation was associated with worse survival in some tumors, such as CRC, kidney chromophobe, and pancreatic adenocarcinoma, but it is related to a better outcome in other tumors, including glioblastoma multiforme, skin Cutaneous Melanoma, and stomach adenocarcinoma.	('Melanoma', 'Phenotype', 'HP:0002861', (260, 268))	('NTRK3', 'Gene', (17, 22))	('tumors', 'Disease', 'MESH:D009369', (202, 208))	('pancreatic adenocarcinoma', 'Disease', (128, 153))	('CRC', 'Disease', (99, 102))	('carcinoma', 'Phenotype', 'HP:0030731', (287, 296))	('glioblastoma', 'Phenotype', 'HP:0012174', (220, 232))	('tumors', 'Disease', 'MESH:D009369', (83, 89))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('skin Cutaneous Melanoma', 'Disease', (245, 268))	('hypermethylation', 'Var', (23, 39))	('glioblastoma multiforme', 'Disease', (220, 243))	('stomach adenocarcinoma', 'Disease', 'MESH:D000230', (274, 296))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (220, 243))	('worse', 'NegReg', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('Cutaneous Melanoma', 'Phenotype', 'HP:0012056', (250, 268))	('tumors', 'Phenotype', 'HP:0002664', (202, 208))	('stomach adenocarcinoma', 'Disease', (274, 296))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D000230', (128, 153))	('kidney chromophobe', 'Disease', 'MESH:D000238', (104, 122))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (128, 153))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('kidney chromophobe', 'Disease', (104, 122))	('tumors', 'Disease', (202, 208))	('tumors', 'Disease', (83, 89))	('skin Cutaneous Melanoma', 'Disease', 'MESH:C562393', (245, 268))	('NTRK3', 'Gene', '4916', (17, 22))
391932	33593392	We found NTRKs gene was commonly suppressed by promoter methylation in CRC compared to normal mucosa.	('TRK', 'Gene', '4914', (10, 13))	('suppressed', 'NegReg', (33, 43))	('TRK', 'Gene', (10, 13))	('promoter methylation', 'Var', (47, 67))
391933	33593392	We identified the cg27034819-cg11525479 region within NTRK3 promoter as the most promising predictive marker for survival outcome, and it was validated in our CRC cohort and 23 TCGA cohorts including a colon cancer cohort, a rectal cancer cohort and 21 cohorts of other tumor types.	('cg11525479', 'Chemical', '-', (29, 39))	('cancer', 'Disease', 'MESH:D009369', (232, 238))	('rectal cancer', 'Phenotype', 'HP:0100743', (225, 238))	('cancer', 'Disease', (208, 214))	('tumor', 'Disease', (270, 275))	('cancer', 'Disease', (232, 238))	('NTRK3', 'Gene', '4916', (54, 59))	('cg27034819', 'Chemical', '-', (18, 28))	('tumor', 'Disease', 'MESH:D009369', (270, 275))	('colon cancer', 'Phenotype', 'HP:0003003', (202, 214))	('colon cancer', 'Disease', 'MESH:D015179', (202, 214))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('tumor', 'Phenotype', 'HP:0002664', (270, 275))	('cg27034819-cg11525479', 'Var', (18, 39))	('colon cancer', 'Disease', (202, 214))	('NTRK3', 'Gene', (54, 59))	('cancer', 'Disease', 'MESH:D009369', (208, 214))
391935	33593392	In addition, we observed a performance improvement of currently used prognostic models after the introduction of NTRK3 promoter methylation.	('performance', 'MPA', (27, 38))	('NTRK3', 'Gene', '4916', (113, 118))	('improvement', 'PosReg', (39, 50))	('methylation', 'Var', (128, 139))	('NTRK3', 'Gene', (113, 118))
391945	33511313	Ei@Lipo significantly inhibits tongue tumor through in situ.	('tongue tumor', 'Disease', (31, 43))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tongue tumor', 'Phenotype', 'HP:0100648', (31, 43))	('tongue tumor', 'Disease', 'MESH:D014062', (31, 43))	('inhibits', 'NegReg', (22, 30))	('Ei@', 'Var', (0, 3))
391978	33511313	With the presence of EVO and ICG, EI@Lipo presented both the chemo-antitumor effect and PDT effect on OSCC.	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('OSCC', 'Disease', (102, 106))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('ICG', 'Chemical', 'MESH:D007208', (29, 32))	('EVO', 'Chemical', 'MESH:C049639', (21, 24))	('tumor', 'Disease', (71, 76))	('EI@Lipo', 'Var', (34, 41))
391981	33511313	Guided by optical imaging and PET/CT imaging, EI@Lipo showed outstanding tumor inhibition via tri-modal combinatorial chemo/chemodynamic/photodynamic combinatorial therapy.	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('PET', 'Gene', (30, 33))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('EI@Lipo', 'Var', (46, 53))	('tumor', 'Disease', (73, 78))	('PET', 'Gene', '22095', (30, 33))
392003	33511313	To compare the singlet oxygen quantum yield of EI@Lipo and free ICG, the same method was adopted with SOSG.	('SOSG', 'Chemical', '-', (102, 106))	('singlet oxygen quantum yield', 'MPA', (15, 43))	('EI@Lipo', 'Var', (47, 54))	('singlet oxygen', 'Chemical', 'MESH:D026082', (15, 29))	('ICG', 'Chemical', 'MESH:D007208', (64, 67))
392040	33511313	After EI@Lipo penetrated deeply in a solid tumor model, PDT was conducted with 100 mW/cm2 808 nm laser for 15 min.	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Disease', (43, 48))	('EI@Lipo', 'Var', (6, 13))
392060	33511313	To compare their optical stability, a UV-Vis-NIR spectrophotometer was used to measure the light absorption of EI@Lipo and ICG under laser irradiation for 2 min and 4 min, respectively.	('light absorption', 'MPA', (91, 107))	('ICG', 'Chemical', 'MESH:D007208', (123, 126))	('EI@', 'Var', (111, 114))
392085	33511313	1I, the singlet oxygen level was significantly enhanced when EI@Lipo with H2O2 compared with ICG@Lipo with H2O2.	('H2O2', 'Chemical', 'MESH:D006861', (107, 111))	('enhanced', 'PosReg', (47, 55))	('singlet oxygen level', 'MPA', (8, 28))	('ICG', 'Chemical', 'MESH:D007208', (93, 96))	('H2O2', 'Chemical', 'MESH:D006861', (74, 78))	('H2O2', 'Var', (74, 78))	('EI@Lipo', 'Var', (61, 68))	('singlet oxygen', 'Chemical', 'MESH:D026082', (8, 22))
392086	33511313	In addition, the EI@Lipo +808 nm laser + H2O2 group produced the highest level of singlet oxygen (Fig.	('singlet oxygen', 'Chemical', 'MESH:D026082', (82, 96))	('singlet oxygen', 'MPA', (82, 96))	('EI@Lipo', 'Var', (17, 24))	('Lipo +808', 'Chemical', '-', (20, 29))	('H2O2', 'Chemical', 'MESH:D006861', (41, 45))
392087	33511313	Compared with the ICG@Lipo +808 nm laser group, the singlet oxygen level was much higher in the EI@Lipo +808 nm laser group.	('ICG', 'Chemical', 'MESH:D007208', (18, 21))	('singlet oxygen', 'Chemical', 'MESH:D026082', (52, 66))	('singlet oxygen level', 'MPA', (52, 72))	('higher', 'PosReg', (82, 88))	('Lipo +808', 'Chemical', '-', (22, 31))	('Lipo +808', 'Chemical', '-', (99, 108))	('EI@Lipo +808 nm laser', 'Var', (96, 117))
392088	33511313	In addition, its level was further boosted when H2O2 was added to EI@Lipo groups, yet there was no difference in the ICG@Lipo groups.	('boosted', 'PosReg', (35, 42))	('H2O2', 'Chemical', 'MESH:D006861', (48, 52))	('H2O2', 'Var', (48, 52))	('ICG', 'Chemical', 'MESH:D007208', (117, 120))
392089	33511313	Notably, even without 808 nm laser-excited, the EI@Lipo + H2O2 still greatly enhanced the singlet oxygen production (Fig.	('H2O2', 'Chemical', 'MESH:D006861', (58, 62))	('enhanced', 'PosReg', (77, 85))	('singlet oxygen production', 'MPA', (90, 115))	('EI@Lipo + H2O2', 'Var', (48, 62))	('singlet oxygen', 'Chemical', 'MESH:D026082', (90, 104))
392095	33511313	The Singlet oxygen production of ICG was 0.077, and the EI@Lipo revealed significantly enhanced singlet oxygen generation (5.65-fold, Phi 1O2 = 0.44).	('Singlet oxygen production', 'MPA', (4, 29))	('EI@Lipo', 'Var', (56, 63))	('O2', 'Chemical', 'MESH:D010100', (139, 141))	('singlet oxygen', 'Chemical', 'MESH:D026082', (96, 110))	('Singlet oxygen', 'Chemical', 'MESH:D026082', (4, 18))	('singlet oxygen generation', 'MPA', (96, 121))	('enhanced', 'PosReg', (87, 95))	('ICG', 'Chemical', 'MESH:D007208', (33, 36))
392105	33511313	3A, there was significant higher-level ROS signal in cells pre-incubated with EI@Lipo than the ROS level in cells treated with free ICG.	('ROS', 'Chemical', 'MESH:D017382', (39, 42))	('ROS signal', 'MPA', (39, 49))	('ICG', 'Chemical', 'MESH:D007208', (132, 135))	('EI@Lipo', 'Var', (78, 85))	('ROS', 'Chemical', 'MESH:D017382', (95, 98))	('higher-level', 'PosReg', (26, 38))
392108	33511313	S6B, the proliferation rates significantly decreased where there existed EVO, which was in a concentration-dependent way.	('S6B', 'Var', (0, 3))	('decreased', 'NegReg', (43, 52))	('EVO', 'Chemical', 'MESH:C049639', (73, 76))	('proliferation rates', 'CPA', (9, 28))
392110	33511313	In addition, with the delivery of nanoliposomes, EVO@Lipo and EI@Lipo represented better capability of anti-CAL 27 and Fadu cells compared with EVO-free drugs (p < 0.01, p < 0.001, respectively).	('Fadu cells', 'CPA', (119, 129))	('anti-CAL 27', 'CPA', (103, 114))	('EVO@Lipo', 'Var', (49, 57))	('EVO', 'Chemical', 'MESH:C049639', (49, 52))	('EVO', 'Chemical', 'MESH:C049639', (144, 147))	('EI@Lipo', 'Var', (62, 69))
392111	33511313	Furthermore, EI@Lipo +808 nm laser did best in inhibiting proliferation, which suggested the combination of chemodynamic, chemical catalysis dynamic, and photodynamic therapy displayed the most potent effect on anticancer cells (Fig.	('inhibiting', 'NegReg', (47, 57))	('proliferation', 'CPA', (58, 71))	('cancer', 'Disease', (215, 221))	('cancer', 'Disease', 'MESH:D009369', (215, 221))	('Lipo +808', 'Chemical', '-', (16, 25))	('EI@Lipo +808', 'Var', (13, 25))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))
392122	33511313	In addition, anticancer effect studies demonstrated that the EI@Lipo +808 nm laser (tri-modal therapy of chemodynamic, chemo-, and photodynamic) exhibited the most potent inhibition of anti-proliferation and anti-migration, especially for oral squamous carcinoma cells.	('oral squamous carcinoma', 'Disease', 'MESH:D002294', (239, 262))	('anti-migration', 'CPA', (208, 222))	('oral squamous carcinoma', 'Disease', (239, 262))	('inhibition', 'NegReg', (171, 181))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('carcinoma', 'Phenotype', 'HP:0030731', (253, 262))	('EI@Lipo +808 nm', 'Var', (61, 76))	('cancer', 'Disease', (17, 23))	('anti-proliferation', 'CPA', (185, 203))	('Lipo +808', 'Chemical', '-', (64, 73))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (244, 262))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
392129	33511313	In addition, in the EI@Lipo +808 nm laser group, the cooperation of EVO based chemical and ICG-based photodynamic effects led to the most considerable reduction in cell number and the largest number of red dead cells.	('cell number', 'CPA', (164, 175))	('red dead cells', 'CPA', (202, 216))	('Lipo +808', 'Chemical', '-', (23, 32))	('EVO', 'Chemical', 'MESH:C049639', (68, 71))	('ICG', 'Chemical', 'MESH:D007208', (91, 94))	('EI@Lipo +808 nm laser', 'Var', (20, 41))	('reduction', 'NegReg', (151, 160))
392130	33511313	EVO resulted in nearly 70% viable CAL 27 cells, but EVO@Lipo and EI@Lipo led to an increased proportion of early and late-stage apoptotic CAL 27 cells, indicating that it could hardly show its ability in the absence of a drug cargo (Fig.	('EVO', 'Chemical', 'MESH:C049639', (52, 55))	('EI@Lipo', 'Var', (65, 72))	('EVO@Lipo', 'Var', (52, 60))	('EVO', 'Chemical', 'MESH:C049639', (0, 3))
392135	33511313	As before, EVO containing groups led to the cleaved caspase-3 upregulated expression, and with the nanoliposome cargo, EVO@Lipo and EI@Lipo resulted in more expression of cleaved caspase-3; meanwhile, EI@Lipo +808 nm laser brought about the highest cleaved caspase-3 expression (Fig.	('expression', 'MPA', (74, 84))	('EVO', 'Var', (119, 122))	('EI@Lipo', 'Var', (132, 139))	('Lipo +808', 'Chemical', '-', (204, 213))	('expression', 'MPA', (157, 167))	('cleaved', 'MPA', (44, 51))	('caspase-3', 'Gene', '836', (179, 188))	('caspase-3', 'Gene', '836', (257, 266))	('caspase-3', 'Gene', '836', (52, 61))	('EVO', 'Chemical', 'MESH:C049639', (119, 122))	('cleaved', 'MPA', (171, 178))	('caspase-3', 'Gene', (179, 188))	('upregulated', 'PosReg', (62, 73))	('EVO', 'Chemical', 'MESH:C049639', (11, 14))	('caspase-3', 'Gene', (52, 61))	('more', 'PosReg', (152, 156))	('caspase-3', 'Gene', (257, 266))
392136	33511313	Therefore, tri-modal therapy of EI@Lipo +808 nm laser performed effectively antitumor capabilities by inducing apoptosis.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('Lipo +808', 'Chemical', '-', (35, 44))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('EI@Lipo +808', 'Var', (32, 44))	('tumor', 'Disease', (80, 85))	('inducing', 'PosReg', (102, 110))	('apoptosis', 'CPA', (111, 120))
392145	33511313	Compared with the EVO-treated group, EI@Lipo accumulated almost the whole spheroid with full of blue fluorescence (Fig.	('EI@Lipo', 'Var', (37, 44))	('blue fluorescence', 'MPA', (96, 113))	('EVO', 'Chemical', 'MESH:C049639', (18, 21))
392147	33511313	5C and Video 1 indicated that EI@Lipo could penetrate the inside of the tumor spheroid and then deliver the EVO drug to cells.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('EVO', 'Chemical', 'MESH:C049639', (108, 111))	('tumor', 'Disease', (72, 77))	('EI@Lipo', 'Var', (30, 37))	('deliver', 'MPA', (96, 103))	('EVO drug', 'MPA', (108, 116))	('tumor', 'Disease', 'MESH:D009369', (72, 77))
392151	33511313	Consequently, the EI@Lipo could penetrate deeply into the tumor spheroid.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('EI@Lipo', 'Var', (18, 25))
392152	33511313	In the tumor model, the photodynamic effect of EI@Lipo could still hold great power of energy for anticancer, even when the diameter of the tumor 3D model reached more than 500 mum, where there tended to be in a hypoxia environment.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('tumor', 'Disease', (7, 12))	('hypoxia', 'Disease', (212, 219))	('hypoxia', 'Disease', 'MESH:D000860', (212, 219))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))	('EI@Lipo', 'Var', (47, 54))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('tumor', 'Disease', 'MESH:D009369', (7, 12))	('tumor', 'Disease', (140, 145))
392156	33511313	It was observed that ICG and EI@Lipo exhibited comparable ICG accumulation in the tumor site at either 2 h, 4 h, 6 h, or 8 h post tail injection (Fig.	('ICG', 'Chemical', 'MESH:D007208', (21, 24))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('EI@Lipo', 'Var', (29, 36))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumor', 'Disease', (82, 87))	('ICG', 'Chemical', 'MESH:D007208', (58, 61))
392159	33511313	6A, EI@Lipo treated mice exhibited significantly enhanced fluorescence signals in the tumor tissue from 2 h to 8 h post-injection compared with free ICG.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Disease', (86, 91))	('enhanced', 'PosReg', (49, 57))	('mice', 'Species', '10090', (20, 24))	('ICG', 'Chemical', 'MESH:D007208', (149, 152))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('EI@Lipo', 'Var', (4, 11))
392160	33511313	In addition, the quantitative results demonstrated that EI@Lipo exhibited a 1.833-fold higher fluorescence signal at tumor sites 10 h post-injection (Fig.	('EI@Lipo', 'Var', (56, 63))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumor', 'Disease', (117, 122))	('fluorescence signal', 'MPA', (94, 113))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('higher', 'PosReg', (87, 93))
392161	33511313	Therefore, compared with free ICG, nanoliposomes remarkably enhanced the accumulation level in tumors and prolonged the circulation time in vivo.	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('nanoliposomes', 'Var', (35, 48))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('enhanced', 'PosReg', (60, 68))	('ICG', 'Chemical', 'MESH:D007208', (30, 33))	('circulation', 'MPA', (120, 131))	('tumors', 'Disease', (95, 101))	('prolonged', 'PosReg', (106, 115))
392162	33511313	Besides, a similar result could be observed that the aggregation location of ICG was similar, but EI@Lipo could deliver more ICG in the tumor site and stay longer.	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('ICG', 'Chemical', 'MESH:D007208', (125, 128))	('ICG', 'MPA', (125, 128))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('EI@Lipo', 'Var', (98, 105))	('ICG', 'Chemical', 'MESH:D007208', (77, 80))	('tumor', 'Disease', (136, 141))
392171	33511313	A total of 21 tumor-bearing mice were randomly divided into seven groups (n = 3): PBS, ICG@Lipo, EVO, EVO@Lipo, EI@Lipo, ICG@Lipo + 808 nm laser, and EI@Lipo + 808 nm laser.	('EVO', 'Chemical', 'MESH:C049639', (97, 100))	('tumor', 'Disease', (14, 19))	('mice', 'Species', '10090', (28, 32))	('EI@Lipo + 808 nm laser', 'Var', (150, 172))	('PBS', 'Chemical', '-', (82, 85))	('ICG', 'Chemical', 'MESH:D007208', (87, 90))	('ICG', 'Chemical', 'MESH:D007208', (121, 124))	('EVO', 'Chemical', 'MESH:C049639', (102, 105))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('EI@Lipo', 'Var', (112, 119))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('ICG@Lipo + 808 nm laser', 'Var', (121, 144))
392180	33511313	In contrast, treatments with EVO@Lipo and EI@Lipo induced significant tumor growth inhibition, which was due to enhanced EVO accumulation in the tumor with the delivery of nanoliposomes.	('enhanced', 'PosReg', (112, 120))	('EI@Lipo', 'Var', (42, 49))	('EVO accumulation', 'MPA', (121, 137))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumor', 'Disease', (70, 75))	('EVO', 'Chemical', 'MESH:C049639', (29, 32))	('tumor', 'Disease', (145, 150))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('EVO', 'Chemical', 'MESH:C049639', (121, 124))
392181	33511313	Having established that ICG@Lipo and EI@Lipo could produce ROS excited with 808 nm laser irradiation and that the combination of EVO and ICG exhibited great anticancer power in vitro, their abilities to produce NIR-triggered ROS were also investigated in vivo.	('ICG', 'Chemical', 'MESH:D007208', (137, 140))	('ROS', 'Chemical', 'MESH:D017382', (225, 228))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('ROS', 'Chemical', 'MESH:D017382', (59, 62))	('ICG', 'Chemical', 'MESH:D007208', (24, 27))	('ROS excited', 'MPA', (59, 70))	('EI@Lipo', 'Var', (37, 44))	('EVO', 'Chemical', 'MESH:C049639', (129, 132))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('cancer', 'Disease', (161, 167))
392184	33511313	In addition, the boosted EVO released from EI@Lipo was capable of triggering cascade-like chemotherapy to continuously destroy the remaining tumor cells after PDT, thus achieving the synergistic therapeutic effects of chemo-photodynamic therapy with great antitumor power.	('tumor', 'Disease', (260, 265))	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumor', 'Disease', 'MESH:D009369', (260, 265))	('tumor', 'Disease', (141, 146))	('synergistic', 'MPA', (183, 194))	('destroy', 'NegReg', (119, 126))	('achieving', 'PosReg', (169, 178))	('EI@Lipo', 'Var', (43, 50))	('EVO', 'Chemical', 'MESH:C049639', (25, 28))	('tumor', 'Phenotype', 'HP:0002664', (260, 265))
392188	33511313	In contrast, few Ki-67 positive cells were observed in tumor slices treated with EI@Lipo +808 nm (Ki-67 positive <10%), which revealed the lowest level of tumor cell proliferation.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('Ki-67', 'Gene', (17, 22))	('Lipo +808', 'Chemical', '-', (84, 93))	('Ki-67', 'Gene', '17345', (98, 103))	('tumor', 'Disease', (155, 160))	('tumor', 'Disease', (55, 60))	('EI@Lipo +808 nm', 'Var', (81, 96))	('Ki-67', 'Gene', (98, 103))	('Ki-67', 'Gene', '17345', (17, 22))
392189	33511313	Therefore, the tri-modal theranostic EI@Lipo held superior anticancer efficacy and drug delivery capacity.	('drug delivery capacity', 'CPA', (83, 105))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('superior', 'PosReg', (50, 58))	('EI@Lipo', 'Var', (37, 44))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('cancer', 'Disease', (63, 69))
392197	33511313	In contrast, the EI@Lipo based chemo/chemodynamic/photodynamic tri-modal therapy displayed an extraordinary capability against tongue squamous cell carcinoma.	('tongue squamous cell carcinoma', 'Disease', (127, 157))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (134, 157))	('EI@Lipo', 'Var', (17, 24))	('tongue squamous cell carcinoma', 'Disease', 'MESH:D002294', (127, 157))	('carcinoma', 'Phenotype', 'HP:0030731', (148, 157))
392205	33511313	Overall, the nano EI@Lipo is essentially a nano-biomaterial agent with dual imaging and tri-modal therapy properties for anticancer.	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('nano EI@Lipo', 'Var', (13, 25))
392235	31255175	The resection margins were free and the final TNM stage was T3N3aM0 (WHO 2017).	('TNM', 'Gene', (46, 49))	('TNM', 'Gene', '10178', (46, 49))	('T3N3aM0', 'Var', (60, 67))
392281	31255175	Radiological imaging and endoscopy were indicative of a T2N0M0 gastric cancer; hence, the multidisciplinary team decided to proceed to surgery, without administration of neoadjuvant treatment.	('gastric cancer', 'Disease', (63, 77))	('gastric cancer', 'Disease', 'MESH:D013274', (63, 77))	('T2N0M0', 'Var', (56, 62))	('men', 'Species', '9606', (187, 190))	('gastric cancer', 'Phenotype', 'HP:0012126', (63, 77))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))
392308	30487219	However, accumulating evidence has made it clear that tumorigenesis is not a cell-autonomous process but relies on dynamic and reciprocal interactions between the mutant tumor cells and their surrounding tumor microenvironment (TME).	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('mutant', 'Var', (163, 169))	('tumor', 'Disease', (170, 175))	('tumor', 'Disease', (204, 209))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumor', 'Disease', (54, 59))
392317	30487219	Notably, altering the cell-ECM interaction could revert an unorganized structure back into an acinar phenotype, indicating that the phenotype of malignant breast cancer cells is plastic and regulated by cell-ECM interactions.	('malignant breast cancer', 'Disease', 'MESH:D001943', (145, 168))	('malignant breast cancer', 'Disease', (145, 168))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('altering', 'Var', (9, 17))	('breast cancer', 'Phenotype', 'HP:0003002', (155, 168))
392348	30487219	To understand whether the heterogeneity observed in TUM622 acini mirrors that of the original tumor from which it was derived, we performed immunohistochemistry staining on the corresponding PDX as well as the original human tumor.	('tumor', 'Disease', 'MESH:D009369', (225, 230))	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('human', 'Species', '9606', (219, 224))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('tumor', 'Disease', (225, 230))	('tumor', 'Disease', (94, 99))	('TUM622', 'Var', (52, 58))
392356	30487219	In contrast, inhibition of Notch signaling, which was not significantly enriched in the GSEA, did not affect acinar morphogenesis of TUM622 cells (SI Appendix, Fig.	('inhibition', 'Var', (13, 23))	('acinar morphogenesis', 'CPA', (109, 129))	('GSEA', 'Chemical', '-', (88, 92))	('SI Appendix', 'Disease', 'MESH:D001063', (147, 158))	('SI Appendix', 'Disease', (147, 158))
392419	30487219	Since growth and tissue architecture are separable attributes in these acinar-like structures, we were able to further investigate how additional oncogenic insults and changes in TME contribute to loss of tissue architecture during LUSC tumorigenesis.	('tumor', 'Disease', (237, 242))	('loss', 'NegReg', (197, 201))	('changes', 'Var', (168, 175))	('TME', 'Gene', (179, 182))	('LUSC', 'Phenotype', 'HP:0030359', (232, 236))	('tumor', 'Disease', 'MESH:D009369', (237, 242))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))
392426	30487219	This is consistent with previous studies showing that SOX2 amplification is an early event during LUSC tumorigenesis and correlates with the progression between low- and high-grade dysplasia in vivo.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor', 'Disease', (103, 108))	('correlates', 'Reg', (121, 131))	('SOX2', 'Gene', '6657', (54, 58))	('SOX2', 'Gene', (54, 58))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('dysplasia', 'Disease', (181, 190))	('amplification', 'Var', (59, 72))	('LUSC', 'Phenotype', 'HP:0030359', (98, 102))	('dysplasia', 'Disease', 'MESH:D004476', (181, 190))
392448	30487219	These changes modulate the balance between growth and differentiation of tumor cells but also determine their invasiveness (Fig.	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('invasiveness', 'CPA', (110, 122))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('changes', 'Var', (6, 13))	('determine', 'Reg', (94, 103))	('tumor', 'Disease', (73, 78))	('balance', 'MPA', (27, 34))	('growth', 'CPA', (43, 49))	('modulate', 'Reg', (14, 22))
392519	33182283	In the risk factor analysis (Table 3), a low SOX2 IHC score was identified as a significant risk factor for 5-year OS (HR (95% CI): 2.39 (1.19-4.81), p = 0.015) and 5-year recurrence (HR (95% CI): 2.72 (1.32-5.59), p = 0.005) in the univariate analysis.	('low', 'Var', (41, 44))	('SOX2', 'Gene', '6657', (45, 49))	('SOX2', 'Gene', (45, 49))
392539	33182283	Regarding TNM classification, 0.03 [IQR: -0.61-0.38] for T3 and -4 and 0.38 [IQR: -0.36-0.72] for T1 and -2, which was a similar trend observed in the TMA cohort but not significant in the TCGA dataset (p = 0.141), 0.01 [-0.77-0.77] for patients without nodal metastasis (N-) and 0.15 [-0.35-0.63] for patients with node metastasis (N+), which was not significant (p = 0.664).	('TNM', 'Gene', '10178', (10, 13))	('T1 and -2', 'Gene', '921;292', (98, 107))	('TNM', 'Gene', (10, 13))	('0.38', 'Var', (71, 75))	('patients', 'Species', '9606', (237, 245))	('T3 and -4', 'Gene', '292', (57, 66))	('patients', 'Species', '9606', (302, 310))
392554	33182283	From the immune landscape of OPSCC in the TCGA-HNSC dataset (Figure S7), HPV+ cancers had a significantly higher rate of immune infiltration than HPV- cancers (83.7% vs. 16.3%, p = 0.001).	('6.3', 'Gene', '55558', (171, 174))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('6.3', 'Gene', (171, 174))	('HPV', 'Species', '10566', (73, 76))	('HPV+', 'Var', (73, 77))	('HPV', 'Species', '10566', (146, 149))	('cancers', 'Disease', 'MESH:D009369', (78, 85))	('OPSCC', 'Phenotype', 'HP:0012182', (29, 34))	('higher', 'PosReg', (106, 112))	('cancers', 'Phenotype', 'HP:0002664', (78, 85))	('cancers', 'Disease', (78, 85))	('cancers', 'Disease', 'MESH:D009369', (151, 158))	('cancers', 'Phenotype', 'HP:0002664', (151, 158))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('cancers', 'Disease', (151, 158))	('immune infiltration', 'CPA', (121, 140))
392560	33182283	HPV infection drives switches in SOX2 expression in the transformation zone in the uterine cervix, and SOX2 locus amplification was associated with HPV ISH positivity in vulvar carcinoma.	('locus amplification', 'Var', (108, 127))	('SOX2', 'Gene', (103, 107))	('switches', 'Reg', (21, 29))	('HPV', 'Species', '10566', (0, 3))	('vulvar carcinoma', 'Disease', (170, 186))	('expression', 'MPA', (38, 48))	('vulvar carcinoma', 'Disease', 'MESH:D014846', (170, 186))	('uterine cervix', 'Phenotype', 'HP:0030160', (83, 97))	('HPV infection', 'Disease', (0, 13))	('SOX2', 'Gene', '6657', (33, 37))	('HPV', 'Species', '10566', (148, 151))	('carcinoma', 'Phenotype', 'HP:0030731', (177, 186))	('SOX2', 'Gene', (33, 37))	('associated', 'Reg', (132, 142))	('HPV infection', 'Disease', 'MESH:D030361', (0, 13))	('SOX2', 'Gene', '6657', (103, 107))
392614	33087120	PanDM takes summary statistics from separate analyses as input and performs methylation site clustering, differential methylation detection, and pan-cancer pattern discovery.	('cancer', 'Disease', (149, 155))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('methylation', 'Var', (76, 87))	('cancer', 'Disease', 'MESH:D009369', (149, 155))	('PanDM', 'Chemical', '-', (0, 5))
392627	33087120	Aberrant DNA methylation has been confirmed as one of the hallmarks of cancer and has been proposed as a biomarker for cancer prognosis, diagnosis, treatment response, and therapeutic targets.	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('Aberrant', 'Var', (0, 8))	('cancer', 'Disease', (71, 77))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('DNA', 'Protein', (9, 12))	('cancer', 'Disease', (119, 125))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
392649	33087120	Next, they focused on DM CpG sites that are consistently hypermethylated or hypomethylated in at least 8 out of 15 cancer types, as well as those CpG sites that show DM in only a single cancer type.	('DM', 'Disease', 'MESH:D009223', (22, 24))	('cancer', 'Disease', (115, 121))	('hypomethylated', 'Var', (76, 90))	('hypermethylated', 'Var', (57, 72))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('DM', 'Disease', 'MESH:D009223', (166, 168))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('cancer', 'Disease', (186, 192))	('cancer', 'Disease', 'MESH:D009369', (186, 192))
392692	33087120	ag=k indicates that CpG site g belongs to pattern k. For DM pattern k, the probability of DM in cancer type c is equal to qkc.	('pattern k', 'Var', (60, 69))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('DM', 'Disease', 'MESH:D009223', (90, 92))	('cancer', 'Disease', (96, 102))	('DM', 'Disease', 'MESH:D009223', (57, 59))
392763	33087120	Dysregulated secretin receptors have been linked to aberrant methylation in breast cancer tissues.	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('aberrant methylation', 'MPA', (52, 72))	('secretin receptors', 'Protein', (13, 31))	('breast cancer', 'Disease', (76, 89))	('Dysregulated', 'Var', (0, 12))	('breast cancer', 'Disease', 'MESH:D001943', (76, 89))	('breast cancer', 'Phenotype', 'HP:0003002', (76, 89))	('linked', 'Reg', (42, 48))
392802	33087120	Moreover, the current approach enables PanDM to be applied to pan-cancer analyses of other types of functional genomic assays such as gene expression, SNP data, and copy number variation detection as long as p-values for each individual cancer type are provided.	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('PanDM', 'Chemical', '-', (39, 44))	('copy number', 'Var', (165, 176))	('cancer', 'Disease', 'MESH:D009369', (237, 243))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('cancer', 'Disease', (237, 243))	('cancer', 'Disease', (66, 72))
392922	31658709	Many studies have reported that lung volumes that receive >20.00 Gy and MLD are prone to radiation pneumonitis.	('pneumonitis', 'Disease', (99, 110))	('MLD', 'Var', (72, 75))	('pneumonitis', 'Disease', 'MESH:D011014', (99, 110))	('prone', 'Reg', (80, 85))
392924	31658709	in the United States; comparing long-term outcomes between 3D-CRT and IMRT, overall survival rates were significantly higher, locoregional control was significantly higher, and cardiac death was significantly lower after IMRT than after 3D-CRT.	('higher', 'PosReg', (118, 124))	('locoregional control', 'CPA', (126, 146))	('lower', 'NegReg', (209, 214))	('cardiac death', 'Disease', (177, 190))	('higher', 'PosReg', (165, 171))	('overall survival rates', 'CPA', (76, 98))	('cardiac death', 'Phenotype', 'HP:0001645', (177, 190))	('cardiac death', 'Disease', 'MESH:D003643', (177, 190))	('IMRT', 'Var', (221, 225))
392975	29990049	The main idea is to apply joint sparse canonical correlation analysis to detect a small set of methylated sites, which are associated with another set of genes either shared across cancers or specific to a particular group (group-specific) of cancers.	('methylated', 'Var', (95, 105))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('cancers', 'Phenotype', 'HP:0002664', (243, 250))	('cancers', 'Disease', 'MESH:D009369', (243, 250))	('cancers', 'Disease', 'MESH:D009369', (181, 188))	('cancers', 'Disease', (243, 250))	('cancers', 'Phenotype', 'HP:0002664', (181, 188))	('cancers', 'Disease', (181, 188))	('cancer', 'Phenotype', 'HP:0002664', (243, 249))
392983	29990049	On the other hand, the differences across multiple cancers could reveal group-specific patterns, which are crucial for the understanding and treatment of particular cancer types.	('multiple cancers', 'Disease', (42, 58))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('multiple cancers', 'Disease', 'MESH:D009369', (42, 58))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('cancer', 'Disease', (165, 171))	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('cancers', 'Phenotype', 'HP:0002664', (51, 58))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('differences', 'Var', (23, 34))
392984	29990049	An integrative statistics method was developed to identify miRNA-gene interactions that are either shared or group-specific across cancers.	('cancers', 'Disease', 'MESH:D009369', (131, 138))	('cancers', 'Phenotype', 'HP:0002664', (131, 138))	('cancers', 'Disease', (131, 138))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('miRNA-gene', 'Var', (59, 69))
392985	29990049	Moreover, in the studies of DNA methylation, it was concluded that some epigenetic changes are shared and some are cancer-type specific.	('epigenetic changes', 'Var', (72, 90))	('cancer', 'Disease', (115, 121))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))
393009	29990049	Accordingly, we assign each gene to a certain group of cancers as follows:  That means, for any cancer in Ci, the ith gene is detected to be affected by the selected methylated sites.	('cancers', 'Disease', 'MESH:D009369', (55, 62))	('methylated sites', 'Var', (166, 182))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('cancer', 'Disease', (96, 102))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('ith gene', 'Gene', (114, 122))	('cancers', 'Phenotype', 'HP:0002664', (55, 62))	('affected', 'Reg', (141, 149))	('cancer', 'Disease', (55, 61))	('cancers', 'Disease', (55, 62))
393010	29990049	Specifically, if  Ci  = K, the gene is shared by all studied cancers.	('Ci  = K', 'Var', (18, 25))	('cancers', 'Phenotype', 'HP:0002664', (61, 68))	('cancers', 'Disease', 'MESH:D009369', (61, 68))	('cancers', 'Disease', (61, 68))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))
393040	29990049	Overall, we can find that JSCCA is able to detect correlated DNA methylation and gene expression, and well classify both shared and group specific interactions.	('CCA', 'Gene', (28, 31))	('DNA methylation', 'Var', (61, 76))	('CCA', 'Gene', '2201', (28, 31))
393044	29990049	Table III listed all the pairs with p-value estimated from (10) as well as from the data of each single cancer using FastGGM.	('p-value', 'Var', (36, 43))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))
393047	29990049	In addition, 3 pairs (cg15518883 and SIT1, cg10590292 and BIN2, cg16068833 and cd52) were found to be cis-effect, where both pan-cancer and single cancer p-value are much lower than the average.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('BIN2', 'Gene', '51411', (58, 62))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('cg16068833', 'Var', (64, 74))	('cg10590292', 'Var', (43, 53))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('cg15518883', 'Var', (22, 32))	('cd52', 'Gene', '1043', (79, 83))	('BIN2', 'Gene', (58, 62))	('cancer', 'Disease', (147, 153))	('SIT1', 'Gene', (37, 41))	('SIT1', 'Gene', '27240', (37, 41))	('cd52', 'Gene', (79, 83))
393063	29990049	EGFR hypermethylation was found in breast cancer, lung tumors, and etc..	('lung tumors', 'Disease', (50, 61))	('EGFR', 'Gene', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('lung tumors', 'Phenotype', 'HP:0100526', (50, 61))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('breast cancer', 'Disease', 'MESH:D001943', (35, 48))	('found', 'Reg', (26, 31))	('breast cancer', 'Disease', (35, 48))	('hypermethylation', 'Var', (5, 21))	('lung tumors', 'Disease', 'MESH:D008175', (50, 61))	('breast cancer', 'Phenotype', 'HP:0003002', (35, 48))	('EGFR', 'Gene', '1956', (0, 4))
393065	29990049	Promoter methylation mediated silencing of Oncostatin M receptor-beta was found in the progression in colon cancer and was recognized as a novel therapeutic marker.	('found', 'Reg', (74, 79))	('colon cancer', 'Phenotype', 'HP:0003003', (102, 114))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('colon cancer', 'Disease', 'MESH:D015179', (102, 114))	('Promoter methylation', 'Var', (0, 20))	('silencing', 'NegReg', (30, 39))	('colon cancer', 'Disease', (102, 114))	('Oncostatin M receptor-beta', 'Protein', (43, 69))
393068	29990049	With pathways enriched by shared genes, PI3K signaling plays a crucial role in the growth and survival of cancer cells, and was shown to be related to epigenetic alterations.	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('related', 'Reg', (140, 147))	('cancer', 'Disease', (106, 112))	('PI3K', 'Var', (40, 44))	('survival', 'CPA', (94, 102))	('epigenetic alterations', 'Var', (151, 173))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
393069	29990049	Epigenetic dysregulation of the Jak/STAT pathway was identified in various cancers.	('Epigenetic dysregulation', 'Var', (0, 24))	('cancers', 'Disease', 'MESH:D009369', (75, 82))	('Jak/STAT pathway', 'Pathway', (32, 48))	('cancers', 'Phenotype', 'HP:0002664', (75, 82))	('cancers', 'Disease', (75, 82))	('identified', 'Reg', (53, 63))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))
393071	29990049	Findings further validate that the selected genes are affected by aberrant methylation in cancer progress.	('affected', 'Reg', (54, 62))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('aberrant methylation', 'Var', (66, 86))
393073	29990049	Of particular note, the methylation of ARHGDIB was identified to be related to squamous cell lung carcinoma and ovarian cancer.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('ovarian cancer', 'Disease', 'MESH:D010051', (112, 126))	('ovarian cancer', 'Disease', (112, 126))	('ARHGDIB', 'Gene', '397', (39, 46))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('squamous cell lung carcinoma', 'Disease', 'MESH:D002294', (79, 107))	('related', 'Reg', (68, 75))	('methylation', 'Var', (24, 35))	('squamous cell lung carcinoma', 'Phenotype', 'HP:0030359', (79, 107))	('squamous cell lung carcinoma', 'Disease', (79, 107))	('ARHGDIB', 'Gene', (39, 46))	('ovarian cancer', 'Phenotype', 'HP:0100615', (112, 126))
393074	29990049	For example, altered DNA methylation of ERBB2 was found to be related to PI3K pathway in breast cancer.	('ERBB2', 'Gene', '2064', (40, 45))	('PI3K pathway', 'Pathway', (73, 85))	('breast cancer', 'Disease', 'MESH:D001943', (89, 102))	('ERBB2', 'Gene', (40, 45))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('breast cancer', 'Disease', (89, 102))	('DNA methylation', 'MPA', (21, 36))	('breast cancer', 'Phenotype', 'HP:0003002', (89, 102))	('related', 'Reg', (62, 69))	('altered', 'Var', (13, 20))
393081	29843532	More importantly, using over 10 years' survival data from 502 patients with LUAD and 494 patients with LUSC, we found that high GOLM1 expression was associated with unfavorable OS and RFS in patients with LUAD, but not in patients with LUSC.	('patients', 'Species', '9606', (191, 199))	('expression', 'MPA', (134, 144))	('LUSC', 'Phenotype', 'HP:0030359', (103, 107))	('patients', 'Species', '9606', (222, 230))	('high', 'Var', (123, 127))	('LUAD', 'Disease', (205, 209))	('LUAD', 'Phenotype', 'HP:0030078', (76, 80))	('associated with', 'Reg', (149, 164))	('LUAD', 'Phenotype', 'HP:0030078', (205, 209))	('patients', 'Species', '9606', (89, 97))	('GOLM1', 'Gene', (128, 133))	('LUSC', 'Phenotype', 'HP:0030359', (236, 240))	('RFS', 'Disease', (184, 187))	('patients', 'Species', '9606', (62, 70))
393087	29843532	In hepatocellular carcinoma (HCC), aberrant GOLM1 expression enhances proliferation and migration of HCC cell lines and growth of xenograft tumors in mice via its regulation of membrane protein trafficking.	('carcinoma', 'Phenotype', 'HP:0030731', (18, 27))	('mice', 'Species', '10090', (150, 154))	('membrane protein trafficking', 'MPA', (177, 205))	('growth', 'CPA', (120, 126))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (3, 27))	('GOLM1', 'Gene', (44, 49))	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('xenograft tumors', 'Disease', (130, 146))	('proliferation', 'CPA', (70, 83))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('xenograft tumors', 'Disease', 'MESH:D009369', (130, 146))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (3, 27))	('HCC', 'Phenotype', 'HP:0001402', (101, 104))	('regulation', 'Reg', (163, 173))	('HCC', 'Phenotype', 'HP:0001402', (29, 32))	('hepatocellular carcinoma', 'Disease', (3, 27))	('aberrant', 'Var', (35, 43))	('enhances', 'PosReg', (61, 69))	('migration', 'CPA', (88, 97))
393115	29843532	Results showed that GOLM1 DNA amplification (+1/+2) was more common in patients with LUSC (n = 94, 18.9%; Figure 5A).	('patients', 'Species', '9606', (71, 79))	('LUSC', 'Disease', (85, 89))	('GOLM1 DNA amplification', 'Var', (20, 43))	('LUSC', 'Phenotype', 'HP:0030359', (85, 89))
393116	29843532	Inconsistent with LUAD, DNA deletion was associated with decreased GOLM1 expression in patients with LUSC (Figure 5A and B, P = .0024).	('LUSC', 'Phenotype', 'HP:0030359', (101, 105))	('LUAD', 'Phenotype', 'HP:0030078', (18, 22))	('DNA', 'Gene', (24, 27))	('expression', 'MPA', (73, 83))	('deletion', 'Var', (28, 36))	('patients', 'Species', '9606', (87, 95))	('decreased', 'NegReg', (57, 66))	('GOLM1', 'Gene', (67, 72))
393119	29843532	Dysregulated functions of the Golgi apparatus are associated with malignant transformation and pathological development of cancers.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('malignant transformation', 'CPA', (66, 90))	('pathological development', 'CPA', (95, 119))	('cancers', 'Disease', 'MESH:D009369', (123, 130))	('cancers', 'Phenotype', 'HP:0002664', (123, 130))	('cancers', 'Disease', (123, 130))	('Dysregulated', 'Var', (0, 12))	('associated', 'Reg', (50, 60))
393127	29843532	SOX2 gene amplification and protein overexpression are associated with better survival outcome in LUSC.	('SOX2', 'Gene', '6657', (0, 4))	('overexpression', 'PosReg', (36, 50))	('protein', 'Protein', (28, 35))	('LUSC', 'Phenotype', 'HP:0030359', (98, 102))	('amplification', 'Var', (10, 23))	('LUSC', 'Disease', (98, 102))	('SOX2', 'Gene', (0, 4))
393142	29843532	Actually, activating EGFR mutations are quite common in patients with LUAD (approximately 14%-19% of Western patients and 40%-48% of Asian patients) but are far less common in patients with LUSC (around 15% in Asian patients).	('EGFR', 'Gene', '1956', (21, 25))	('patients', 'Species', '9606', (56, 64))	('EGFR', 'Gene', (21, 25))	('patients', 'Species', '9606', (176, 184))	('patients', 'Species', '9606', (139, 147))	('patients', 'Species', '9606', (109, 117))	('LUAD', 'Disease', (70, 74))	('LUSC', 'Phenotype', 'HP:0030359', (190, 194))	('LUAD', 'Phenotype', 'HP:0030078', (70, 74))	('activating', 'PosReg', (10, 20))	('patients', 'Species', '9606', (216, 224))	('mutations', 'Var', (26, 35))
393144	29843532	In this study, we also preliminarily examined the potential mechanisms of GOLM1 dysregulation in NSCLC.	('examined', 'Reg', (37, 45))	('NSCLC', 'Disease', (97, 102))	('NSCLC', 'Disease', 'MESH:D002289', (97, 102))	('dysregulation', 'Var', (80, 93))	('GOLM1', 'Gene', (74, 79))	('NSCLC', 'Phenotype', 'HP:0030358', (97, 102))
393162	27884140	2014-001523-69 ClinicalTrials.gov number, NCT02624128  Epigenetic alterations, such as hypoacetylation of histones, play an important role in initiation and progression of several cancers, including squamous cell carcinoma of the head and neck (SCCHN).	('squamous cell carcinoma', 'Disease', (199, 222))	('cancers', 'Disease', 'MESH:D009369', (180, 187))	('cancers', 'Phenotype', 'HP:0002664', (180, 187))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('hypoacetylation', 'MPA', (87, 102))	('cancers', 'Disease', (180, 187))	('Epigenetic alterations', 'Var', (55, 77))	('carcinoma of the head and neck', 'Phenotype', 'HP:0012288', (213, 243))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (199, 222))	('histones', 'Protein', (106, 114))	('carcinoma', 'Phenotype', 'HP:0030731', (213, 222))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (199, 222))
393163	27884140	Since epigenetic alterations are dynamic and generally reversible, epigenetic manipulation has emerged as an attractive novel anticancer treatment.	('epigenetic manipulation', 'Var', (67, 90))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('cancer', 'Disease', (130, 136))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('epigenetic alterations', 'Var', (6, 28))
393197	27884140	In details, it has been demonstrated that tumor cells treated with cisplatin show increased EGFR activation which can be considered a survival response to the treatment.	('tumor', 'Disease', (42, 47))	('activation', 'PosReg', (97, 107))	('cisplatin', 'Var', (67, 76))	('cisplatin', 'Chemical', 'MESH:D002945', (67, 76))	('increased', 'PosReg', (82, 91))	('EGFR', 'Gene', '1956', (92, 96))	('EGFR', 'Gene', (92, 96))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
393208	27884140	Recently Yardley et al., have analyzed protein lysine acetylation in pre- and post-treatment samples collected in a subset of 49 breast cancer patients treated with the combination of the HDACi entinostat plus exemestane demonstrating that hyperacetylation of protein lysines in PBMC was associated with improved clinical outcome, as shown by the prolonged PFS in hyperacetylators versus low acetylators.	('hyperacetylation', 'Var', (240, 256))	('clinical outcome', 'MPA', (313, 329))	('49 breast cancer', 'Disease', 'MESH:D001943', (126, 142))	('PFS', 'MPA', (357, 360))	('breast cancer', 'Phenotype', 'HP:0003002', (129, 142))	('lysines', 'Chemical', 'MESH:D008239', (268, 275))	('49 breast cancer', 'Disease', (126, 142))	('lysine', 'Chemical', 'MESH:D008239', (268, 274))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('PBMC', 'Gene', (279, 283))	('patients', 'Species', '9606', (143, 151))	('lysine', 'Chemical', 'MESH:D008239', (47, 53))	('improved', 'PosReg', (304, 312))	('HDACi entinostat plus exemestane', 'Disease', 'MESH:D007625', (188, 220))	('protein', 'Protein', (260, 267))	('HDACi entinostat plus exemestane', 'Disease', (188, 220))
393212	27884140	There are evidences that cancer with moderate expression of EGFR are more sensitive to CTX compared with those that express very high levels of EGFR.	('EGFR', 'Gene', (144, 148))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('moderate expression', 'Var', (37, 56))	('CTX', 'Disease', 'MESH:D019294', (87, 90))	('CTX', 'Disease', (87, 90))	('EGFR', 'Gene', '1956', (60, 64))	('cancer', 'Disease', 'MESH:D009369', (25, 31))	('cancer', 'Disease', (25, 31))	('EGFR', 'Gene', '1956', (144, 148))	('EGFR', 'Gene', (60, 64))
393215	27884140	It has been observed that MET expression represent an independent predictor of reduced disease-free and overall survival in HNSCC patients.	('overall survival', 'CPA', (104, 120))	('reduced', 'NegReg', (79, 86))	('HNSCC', 'Disease', (124, 129))	('disease-free', 'CPA', (87, 99))	('patients', 'Species', '9606', (130, 138))	('MET expression', 'Var', (26, 40))
393223	27884140	We previously demonstrated that FcgammaRIIIa polymorphisms were significantly associated with response to anti-EGFR-based therapy in 49 colorectal cancer patients with KRAS wt tumors, The results suggested that prognosis is particularly unfavorable for patients carrying the FcgammaRIIIa-158F/F genotype.	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('EGFR', 'Gene', '1956', (111, 115))	('FcgammaRIIIa', 'Gene', '2214', (32, 44))	('patients', 'Species', '9606', (253, 261))	('tumors', 'Disease', 'MESH:D009369', (176, 182))	('colorectal cancer', 'Disease', 'MESH:D015179', (136, 153))	('FcgammaRIIIa', 'Gene', (275, 287))	('colorectal cancer', 'Disease', (136, 153))	('FcgammaRIIIa', 'Gene', '2214', (275, 287))	('associated', 'Reg', (78, 88))	('rectal cancer', 'Phenotype', 'HP:0100743', (140, 153))	('patients', 'Species', '9606', (154, 162))	('tumors', 'Phenotype', 'HP:0002664', (176, 182))	('EGFR', 'Gene', (111, 115))	('colorectal cancer', 'Phenotype', 'HP:0003003', (136, 153))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('tumors', 'Disease', (176, 182))	('polymorphisms', 'Var', (45, 58))	('FcgammaRIIIa', 'Gene', (32, 44))
393225	27884140	The study includes an explorative analysis of the potential prognostic or predictive role of several biomarkers with the aim of improving the knowledge of the mechanisms by which VPA enhances chemotherapy effect and of identifying early predictors of treatment response/resistance.	('VPA', 'Chemical', 'MESH:D014635', (179, 182))	('enhances', 'PosReg', (183, 191))	('VPA', 'Var', (179, 182))	('chemotherapy effect', 'CPA', (192, 211))
393272	27884140	Moreover, at baseline, at day -2 and eventually after 3-6 cycles (see above), EGFR, p-EGFR, MET, RAD51, XRCC1, gammaH2AX, will be measured as markers of treatment efficacy/resistance evaluated by real-time PCR with the specific primers and probes or by immunohistochemistry.	('gammaH2AX', 'Var', (111, 120))	('EGFR', 'Gene', '1956', (86, 90))	('RAD51', 'Gene', (97, 102))	('XRCC1', 'Gene', '7515', (104, 109))	('RAD51', 'Gene', '5888', (97, 102))	('EGFR', 'Gene', (86, 90))	('CR', 'Chemical', '-', (207, 209))	('EGFR', 'Gene', '1956', (78, 82))	('EGFR', 'Gene', (78, 82))	('MET', 'Var', (92, 95))	('XRCC1', 'Gene', (104, 109))
393360	27530152	(P < 0.0001, <0.0001, and <0.0001, respectively) Taking into consideration of all the above factors, the pre-CCRT CTC number showed its independent prognostic impact on disease-specific PFS and OS with hazard ratios (HRs) (95% confidence interval [CI]) of 3.113 (1.427-6.791) and 1.002 (1.000-1.004), respectively.	('TC', 'Chemical', 'MESH:D013667', (115, 117))	('pre-CCRT', 'Var', (105, 113))	('PF', 'Chemical', 'MESH:C002997', (186, 188))	('PFS', 'Disease', (186, 189))
393401	27530152	One other problem was the fact that some patients, mostly of cT4b status, who died of sudden massive tumour bleeding and/or sepsis from tracheoesophageal fistula during CCRT, caused shortening of the survival in this study.	('sepsis', 'Phenotype', 'HP:0100806', (124, 130))	('shortening', 'NegReg', (182, 192))	('survival', 'MPA', (200, 208))	('cT4b', 'Var', (61, 65))	('sudden massive tumour bleeding', 'Disease', (86, 116))	('patients', 'Species', '9606', (41, 49))	('sepsis', 'Disease', (124, 130))	('tracheoesophageal fistula', 'Disease', 'MESH:D014138', (136, 161))	('tracheoesophageal fistula', 'Phenotype', 'HP:0002575', (136, 161))	('sudden massive tumour bleeding', 'Disease', 'MESH:D003645', (86, 116))	('sepsis', 'Disease', 'MESH:D018805', (124, 130))	('tracheoesophageal fistula', 'Disease', (136, 161))	('tumour', 'Phenotype', 'HP:0002664', (101, 107))
393409	24386361	Genetic Variant rs401681 at 5p15.33 Modifies Susceptibility to Lung Cancer but Not Esophageal Squamous Cell Carcinoma The human 5p15.33 locus contains two well-known genes, the telomerase reverse transcriptase (TERT) and cleft lip and palate transmembrane 1-like (CLPTM1L) genes, which have been implicated in carcinogenesis.	('human', 'Species', '9606', (122, 127))	('Cancer', 'Phenotype', 'HP:0002664', (68, 74))	('telomerase reverse transcriptase', 'Gene', (177, 209))	('Esophageal Squamous Cell Carcinoma', 'Disease', 'MESH:D000077277', (83, 117))	('CLPTM1L', 'Gene', (264, 271))	('TERT', 'Gene', (211, 215))	('Lung Cancer', 'Phenotype', 'HP:0100526', (63, 74))	('TERT', 'Gene', '7015', (211, 215))	('Cancer', 'Disease', (68, 74))	('Variant rs401681', 'Var', (8, 24))	('telomerase reverse transcriptase', 'Gene', '7015', (177, 209))	('rs401681', 'Var', (16, 24))	('Esophageal Squamous Cell Carcinoma', 'Disease', (83, 117))	('Carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (94, 117))	('Cancer', 'Disease', 'MESH:D009369', (68, 74))	('cleft lip and palate', 'Phenotype', 'HP:0000202', (221, 241))	('cleft lip and palate', 'Disease', 'MESH:D002971', (221, 241))	('Modifies', 'Reg', (36, 44))	('carcinogenesis', 'Disease', (310, 324))	('cleft lip', 'Phenotype', 'HP:0410030', (221, 230))	('carcinogenesis', 'Disease', 'MESH:D063646', (310, 324))	('CLPTM1L', 'Gene', '81037', (264, 271))	('rs401681', 'Mutation', 'rs401681', (16, 24))
393410	24386361	A common sequence variant, rs401681, located in an intronic region of CLPTM1L, has been reported to be associated with lung cancer risk based on genome-wide association study.	('rs401681', 'Var', (27, 35))	('lung cancer', 'Disease', (119, 130))	('associated', 'Reg', (103, 113))	('lung cancer', 'Phenotype', 'HP:0100526', (119, 130))	('CLPTM1L', 'Gene', '81037', (70, 77))	('CLPTM1L', 'Gene', (70, 77))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('lung cancer', 'Disease', 'MESH:D008175', (119, 130))	('rs401681', 'Mutation', 'rs401681', (27, 35))
393411	24386361	In addition, genetic variants at 5p15.33, including rs401681, have been shown to be involved in the susceptibility to multiple malignancies.	('malignancies', 'Disease', 'MESH:D009369', (127, 139))	('rs401681', 'Var', (52, 60))	('malignancies', 'Disease', (127, 139))	('rs401681', 'Mutation', 'rs401681', (52, 60))	('susceptibility', 'Reg', (100, 114))	('involved', 'Reg', (84, 92))
393412	24386361	Nevertheless, the role of these TERT-CLPTM1L variants in the etiology of esophageal squamous cell carcinoma (ESCC) remains unknown.	('TERT', 'Gene', '7015', (32, 36))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (73, 107))	('CLPTM1L', 'Gene', '81037', (37, 44))	('CLPTM1L', 'Gene', (37, 44))	('variants', 'Var', (45, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('esophageal squamous cell carcinoma', 'Disease', (73, 107))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (84, 107))	('TERT', 'Gene', (32, 36))
393413	24386361	We genotyped the rs401681 polymorphism using TaqMan methodology and analyzed its association with the risk of lung cancer and ESCC in a case-control study of 1,479 cancer patients (726 with lung cancer and 753 with ESCC) and 860 healthy individuals.	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('lung cancer', 'Disease', (110, 121))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('lung cancer', 'Disease', (190, 201))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('patients', 'Species', '9606', (171, 179))	('rs401681', 'Mutation', 'rs401681', (17, 25))	('lung cancer', 'Disease', 'MESH:D008175', (110, 121))	('cancer', 'Disease', (195, 201))	('lung cancer', 'Disease', 'MESH:D008175', (190, 201))	('cancer', 'Disease', (164, 170))	('lung cancer', 'Phenotype', 'HP:0100526', (110, 121))	('lung cancer', 'Phenotype', 'HP:0100526', (190, 201))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('association', 'Interaction', (81, 92))	('cancer', 'Disease', (115, 121))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('ESCC', 'Disease', (126, 130))	('rs401681', 'Var', (17, 25))
393414	24386361	Logistic regression analyses revealed that rs401681 T genotypes were associated with a significantly decreased risk of lung cancer (CT vs. CC: adjusted OR = 0.782, 95% CI = 0.625-0.978, P = 0.031; CT/TT vs. CC: adjusted OR = 0.786; 95% CI = 0.635-0.972, P = 0.026).	('lung cancer', 'Disease', (119, 130))	('lung cancer', 'Phenotype', 'HP:0100526', (119, 130))	('decreased', 'NegReg', (101, 110))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('rs401681', 'Mutation', 'rs401681', (43, 51))	('lung cancer', 'Disease', 'MESH:D008175', (119, 130))	('rs401681 T', 'Var', (43, 53))
393415	24386361	Stratification analysis by histology type indicated that rs401681 T genotypes were associated with a significantly reduced risk of both adenocarcinoma and squamous cell carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('carcinoma', 'Phenotype', 'HP:0030731', (169, 178))	('reduced', 'NegReg', (115, 122))	('rs401681', 'Mutation', 'rs401681', (57, 65))	('rs401681 T', 'Var', (57, 67))	('adenocarcinoma and squamous cell carcinoma', 'Disease', 'MESH:D002294', (136, 178))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (155, 178))
393416	24386361	Furthermore, no significant association was observed between rs401681 and the risk of ESCC (CT vs. CC: adjusted OR = 0.910, 95% CI = 0.734-1.129, P = 0.392; TT vs. CC: adjusted OR = 0.897, 95%CI = 0.624-1.290, P = 0.558; CT/TT vs. CC: adjusted OR = 0.908, 95% CI = 0.740-1.114, P = 0.355).	('rs401681', 'Mutation', 'rs401681', (61, 69))	('rs401681', 'Var', (61, 69))	('ESCC', 'Disease', (86, 90))
393417	24386361	Our findings provide further evidence supporting rs401681 as a genetic variant associated with the risk of lung cancer.	('rs401681', 'Var', (49, 57))	('associated', 'Reg', (79, 89))	('rs401681', 'Mutation', 'rs401681', (49, 57))	('lung cancer', 'Disease', 'MESH:D008175', (107, 118))	('lung cancer', 'Disease', (107, 118))	('lung cancer', 'Phenotype', 'HP:0100526', (107, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))
393418	24386361	In addition, we investigated the correlation between the rs401681 variant and the risk of ESCC in a Han Chinese population, and our results suggest that this genetic variant may not be involved in ESCC risk.	('rs401681', 'Var', (57, 65))	('ESCC', 'Disease', (90, 94))	('rs401681', 'Mutation', 'rs401681', (57, 65))	('ESCC', 'Disease', (197, 201))
393422	24386361	Recently, genome-wide association studies (GWASs) have shown that common TERT-CLPTM1L variants at 5p15.33 may influence the risk of developing lung cancer as well as other types of cancer.	('cancer', 'Disease', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('CLPTM1L', 'Gene', '81037', (78, 85))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('CLPTM1L', 'Gene', (78, 85))	('TERT', 'Gene', '7015', (73, 77))	('lung cancer', 'Disease', (143, 154))	('lung cancer', 'Phenotype', 'HP:0100526', (143, 154))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('variants', 'Var', (86, 94))	('TERT', 'Gene', (73, 77))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('lung cancer', 'Disease', 'MESH:D008175', (143, 154))	('cancer', 'Disease', (181, 187))	('influence', 'Reg', (110, 119))
393425	24386361	TERT encodes the catalytic subunit of telomerase, an enzyme that maintains telomere ends by adding the telomere repeat TTAGGG.	('adding', 'PosReg', (92, 98))	('TTAGGG', 'Var', (119, 125))	('TERT', 'Gene', (0, 4))	('telomere', 'MPA', (75, 83))	('TERT', 'Gene', '7015', (0, 4))
393428	24386361	The rs401681 polymorphism, located in an intronic region of CLPTM1L, has been reported to be associated with lung cancer risk based on genome-wide association study.	('CLPTM1L', 'Gene', '81037', (60, 67))	('lung cancer', 'Disease', (109, 120))	('rs401681', 'Mutation', 'rs401681', (4, 12))	('CLPTM1L', 'Gene', (60, 67))	('lung cancer', 'Phenotype', 'HP:0100526', (109, 120))	('associated', 'Reg', (93, 103))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('lung cancer', 'Disease', 'MESH:D008175', (109, 120))	('rs401681', 'Var', (4, 12))
393429	24386361	found that rs401681 was significantly associated with lung cancer risk in the Asian population, whereas another study examining 501 lung cancer cases and 576 cancer-free controls detected no association between this genetic variant and risk of lung cancer in a population of the same ethnicity.	('rs401681', 'Var', (11, 19))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('cancer', 'Disease', (249, 255))	('cancer', 'Disease', (137, 143))	('cancer', 'Phenotype', 'HP:0002664', (249, 255))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('lung cancer', 'Disease', (54, 65))	('associated', 'Reg', (38, 48))	('cancer', 'Disease', (158, 164))	('lung cancer', 'Disease', (244, 255))	('lung cancer', 'Disease', (132, 143))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('rs401681', 'Mutation', 'rs401681', (11, 19))	('cancer', 'Disease', 'MESH:D009369', (249, 255))	('lung cancer', 'Disease', 'MESH:D008175', (54, 65))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('lung cancer', 'Disease', 'MESH:D008175', (244, 255))	('lung cancer', 'Phenotype', 'HP:0100526', (54, 65))	('lung cancer', 'Disease', 'MESH:D008175', (132, 143))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('lung cancer', 'Phenotype', 'HP:0100526', (244, 255))	('lung cancer', 'Phenotype', 'HP:0100526', (132, 143))	('cancer', 'Disease', (59, 65))
393430	24386361	Additionally, a study in a Korean population found that rs401681 was associated with a significantly decreased risk of lung cancer under a dominant model for the variant allele.	('lung cancer', 'Disease', (119, 130))	('lung cancer', 'Phenotype', 'HP:0100526', (119, 130))	('rs401681', 'Var', (56, 64))	('rs401681', 'Mutation', 'rs401681', (56, 64))	('decreased', 'NegReg', (101, 110))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('lung cancer', 'Disease', 'MESH:D008175', (119, 130))
393433	24386361	In most cases, the common genetic variants that have been associated with cancer risk seem to be specific to a particular cancer type.	('variants', 'Var', (34, 42))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('cancer', 'Disease', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
393434	24386361	However, single-nucleotide polymorphisms (SNPs) in the TERT-CLPTM1L region, including rs401681, have shown possible associations in multiple cancers.	('CLPTM1L', 'Gene', '81037', (60, 67))	('single-nucleotide polymorphisms', 'Var', (9, 40))	('multiple cancers', 'Disease', (132, 148))	('CLPTM1L', 'Gene', (60, 67))	('rs401681', 'Var', (86, 94))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('rs401681', 'Mutation', 'rs401681', (86, 94))	('multiple cancers', 'Disease', 'MESH:D009369', (132, 148))	('TERT', 'Gene', (55, 59))	('TERT', 'Gene', '7015', (55, 59))	('cancers', 'Phenotype', 'HP:0002664', (141, 148))	('associations', 'Reg', (116, 128))
393435	24386361	Recently, rs401681[C] was reported to be associated with an increased risk of basal cell carcinoma and lung, urinary bladder, prostate and cervix cancers.	('rs401681', 'Mutation', 'rs401681', (10, 18))	('associated', 'Reg', (41, 51))	('lung', 'Disease', (103, 107))	('cervix cancers', 'Phenotype', 'HP:0030079', (139, 153))	('prostate', 'Disease', (126, 134))	('rs401681[', 'Var', (10, 19))	('basal cell carcinoma', 'Disease', 'MESH:D002280', (78, 98))	('basal cell carcinoma', 'Disease', (78, 98))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('urinary bladder', 'Disease', (109, 124))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (78, 98))	('cervix cancers', 'Disease', 'MESH:D002583', (139, 153))	('cancers', 'Phenotype', 'HP:0002664', (146, 153))	('cervix cancers', 'Disease', (139, 153))
393436	24386361	Conversely, rs401681[C] appears to confer protection against cutaneous melanoma.	('rs401681[', 'Var', (12, 21))	('melanoma', 'Phenotype', 'HP:0002861', (71, 79))	('rs401681', 'Mutation', 'rs401681', (12, 20))	('cutaneous melanoma', 'Disease', (61, 79))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (61, 79))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (61, 79))
393437	24386361	Moreover, a recent GWAS demonstrated that rs401681 may modify individual susceptibility to pancreatic cancer.	('rs401681', 'Var', (42, 50))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('rs401681', 'Mutation', 'rs401681', (42, 50))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (91, 108))	('pancreatic cancer', 'Disease', (91, 108))	('modify', 'Reg', (55, 61))	('pancreatic cancer', 'Disease', 'MESH:D010190', (91, 108))
393438	24386361	The rs401681 polymorphism has been widely studied in different ethnicities and cancer types.	('rs401681', 'Mutation', 'rs401681', (4, 12))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('rs401681', 'Var', (4, 12))
393450	24386361	The associations between the rs401681 polymorphism and cancer risk were estimated by computing the odds ratios (ORs) and their 95% confidence intervals (CIs) through logistic regression analyses for crude ORs and adjusted ORs when adjusting for age, sex and smoking and drinking status.	('associations', 'Interaction', (4, 16))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('rs401681', 'Mutation', 'rs401681', (29, 37))	('rs401681', 'Var', (29, 37))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('cancer', 'Disease', (55, 61))
393456	24386361	The genotype and allele frequencies of the rs401681 polymorphism in the lung cancer and ESCC patients and healthy controls are presented in Table 2.	('ESCC', 'Disease', (88, 92))	('lung cancer', 'Disease', (72, 83))	('lung cancer', 'Phenotype', 'HP:0100526', (72, 83))	('rs401681', 'Mutation', 'rs401681', (43, 51))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('rs401681', 'Var', (43, 51))	('patients', 'Species', '9606', (93, 101))	('lung cancer', 'Disease', 'MESH:D008175', (72, 83))
393459	24386361	As shown in Table 3, logistic regression analyses revealed that rs401681 T genotypes were associated with a significantly decreased risk of lung cancer (CT vs. CC: adjusted OR = 0.782, 95% CI = 0.625-0.978, P = 0.031; CT/TT vs. CC: adjusted OR = 0.786; 95% CI = 0.635-0.972, P = 0.026).	('lung cancer', 'Disease', (140, 151))	('rs401681 T', 'Var', (64, 74))	('lung cancer', 'Phenotype', 'HP:0100526', (140, 151))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('rs401681', 'Mutation', 'rs401681', (64, 72))	('lung cancer', 'Disease', 'MESH:D008175', (140, 151))	('decreased', 'NegReg', (122, 131))
393460	24386361	Moreover, the rs401681 T allele was borderline significantly associated with a lower risk of lung cancer.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('rs401681', 'Mutation', 'rs401681', (14, 22))	('lung cancer', 'Disease', 'MESH:D008175', (93, 104))	('rs401681 T', 'Var', (14, 24))	('lung cancer', 'Disease', (93, 104))	('lung cancer', 'Phenotype', 'HP:0100526', (93, 104))
393461	24386361	We further evaluated the association between rs401681 and lung cancer risk stratified by histology type.	('rs401681', 'Mutation', 'rs401681', (45, 53))	('rs401681', 'Var', (45, 53))	('evaluated', 'Reg', (11, 20))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('lung cancer', 'Disease', (58, 69))	('lung cancer', 'Phenotype', 'HP:0100526', (58, 69))	('lung cancer', 'Disease', 'MESH:D008175', (58, 69))
393462	24386361	As shown in Figure 1, stratification analysis by histology type indicated that rs401681 T genotypes were associated with a significantly reduced risk of both adenocarcinoma and squamous cell carcinoma, but not with small-cell carcinoma.	('rs401681', 'Mutation', 'rs401681', (79, 87))	('adenocarcinoma and squamous cell carcinoma', 'Disease', 'MESH:D002294', (158, 200))	('small-cell carcinoma', 'Disease', 'MESH:D018288', (215, 235))	('rs401681 T', 'Var', (79, 89))	('carcinoma', 'Phenotype', 'HP:0030731', (163, 172))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (177, 200))	('carcinoma', 'Phenotype', 'HP:0030731', (191, 200))	('carcinoma', 'Phenotype', 'HP:0030731', (226, 235))	('small-cell carcinoma', 'Phenotype', 'HP:0030357', (215, 235))	('small-cell carcinoma', 'Disease', (215, 235))	('reduced', 'NegReg', (137, 144))
393463	24386361	For the patients with esophageal carcinoma, the genotype frequencies of the rs401681 variant were not significantly different between the cases and controls.	('rs401681', 'Mutation', 'rs401681', (76, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (33, 42))	('rs401681', 'Var', (76, 84))	('esophageal carcinoma', 'Disease', (22, 42))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (22, 42))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (22, 42))	('patients', 'Species', '9606', (8, 16))
393464	24386361	In addition, the rs401681 T allele was less frequent among cases than among controls, though this difference was not statistically significant (Table 2).	('rs401681', 'Mutation', 'rs401681', (17, 25))	('rs401681 T', 'Var', (17, 27))	('less', 'NegReg', (39, 43))
393465	24386361	Following adjustment for age, sex and smoking and drinking status in a multivariate logistic regression analysis, no significant association was observed between rs401681 and the susceptibility to esophageal carcinoma (CT vs. CC: adjusted OR = 0.910, 95%CI = 0.734-1.129; TT vs. CC: adjusted OR = 0.897, 95%CI = 0.624-1.290; CT/TT vs. CC: adjusted OR = 0.908, 95%CI = 0.740-1.114) (Table 3).	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (197, 217))	('carcinoma', 'Phenotype', 'HP:0030731', (208, 217))	('rs401681', 'Var', (162, 170))	('rs401681', 'Mutation', 'rs401681', (162, 170))	('esophageal carcinoma', 'Disease', (197, 217))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (197, 217))
393467	24386361	A previous study indicated that telomere dysfunction may act as both a potent tumor suppressor and promoter in the lung epithelial compartment, depending on the status of the telomere dysfunction-induced checkpoint.	('telomere dysfunction', 'Var', (32, 52))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Disease', (78, 83))
393470	24386361	The exact functional relevance of the rs401681 polymorphism regarding its association with lung cancer currently remains unclear, but some previous studies provide a link to this association.	('lung cancer', 'Phenotype', 'HP:0100526', (91, 102))	('rs401681', 'Mutation', 'rs401681', (38, 46))	('rs401681', 'Var', (38, 46))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('lung cancer', 'Disease', 'MESH:D008175', (91, 102))	('association', 'Interaction', (74, 85))	('lung cancer', 'Disease', (91, 102))
393472	24386361	For example, CLPTM1L rs402710, which is in strong LD with rs401681, has been reported to be associated with significantly higher levels of bulky aromatic/hydrophobic DNA adducts in lung tissue adjacent to tumors.	('tumors', 'Disease', 'MESH:D009369', (205, 211))	('rs401681', 'Var', (58, 66))	('rs402710', 'Var', (21, 29))	('rs402710', 'Mutation', 'rs402710', (21, 29))	('rs401681', 'Mutation', 'rs401681', (58, 66))	('CLPTM1L', 'Gene', '81037', (13, 20))	('higher', 'PosReg', (122, 128))	('CLPTM1L', 'Gene', (13, 20))	('bulky aromatic/hydrophobic DNA adducts', 'MPA', (139, 177))	('tumors', 'Phenotype', 'HP:0002664', (205, 211))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumors', 'Disease', (205, 211))
393473	24386361	Moreover, rs401681[C] has been shown to be associated with shorter telomeres.	('shorter', 'NegReg', (59, 66))	('rs401681[', 'Var', (10, 19))	('rs401681', 'Mutation', 'rs401681', (10, 18))
393474	24386361	Consistent with previous observations from a pooled analysis, the results of our case-control study suggested that rs401681 T genotypes were associated with a significantly reduced risk of both lung adenocarcinoma and squamous cell carcinoma.	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (194, 213))	('carcinoma', 'Phenotype', 'HP:0030731', (204, 213))	('adenocarcinoma and squamous cell carcinoma', 'Disease', 'MESH:D002294', (199, 241))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (218, 241))	('reduced', 'NegReg', (173, 180))	('lung adenocarcinoma', 'Disease', (194, 213))	('rs401681', 'Mutation', 'rs401681', (115, 123))	('rs401681 T', 'Var', (115, 125))	('carcinoma', 'Phenotype', 'HP:0030731', (232, 241))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (194, 213))
393475	24386361	confirmed that two independent susceptibility variants at 5p15.33 (TERT rs2736100 and CLPTM1L rs401681) act as determinants of lung cancer risk, differentially impacting lung cancer histology.	('TERT', 'Gene', (67, 71))	('lung cancer', 'Disease', (127, 138))	('TERT', 'Gene', '7015', (67, 71))	('lung cancer', 'Phenotype', 'HP:0100526', (127, 138))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('CLPTM1L', 'Gene', '81037', (86, 93))	('lung cancer', 'Disease', 'MESH:D008175', (170, 181))	('rs401681', 'Var', (94, 102))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('rs401681', 'Mutation', 'rs401681', (94, 102))	('CLPTM1L', 'Gene', (86, 93))	('rs2736100', 'Mutation', 'rs2736100', (72, 81))	('lung cancer', 'Disease', 'MESH:D008175', (127, 138))	('lung cancer', 'Disease', (170, 181))	('lung cancer', 'Phenotype', 'HP:0100526', (170, 181))	('impacting', 'Reg', (160, 169))
393476	24386361	The risk associated with rs2736100 is largely confined to adenocarcinoma.	('rs2736100', 'Var', (25, 34))	('adenocarcinoma', 'Disease', (58, 72))	('adenocarcinoma', 'Disease', 'MESH:D000230', (58, 72))	('rs2736100', 'Mutation', 'rs2736100', (25, 34))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))
393477	24386361	However, rs401681 influences the risk of all lung cancer histologies, but its strongest effect is on squamous cell carcinoma.	('lung cancer', 'Disease', 'MESH:D008175', (45, 56))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (101, 124))	('influences', 'Reg', (18, 28))	('rs401681', 'Mutation', 'rs401681', (9, 17))	('lung cancer', 'Disease', (45, 56))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (101, 124))	('rs401681', 'Var', (9, 17))	('lung cancer', 'Phenotype', 'HP:0100526', (45, 56))	('squamous cell carcinoma', 'Disease', (101, 124))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))
393478	24386361	A recent meta-analysis by cancer type demonstrated that rs401681 [T] carriers show a modestly increased risk of pancreatic carcinoma and skin melanoma.	('pancreatic carcinoma', 'Disease', 'MESH:C562463', (112, 132))	('cancer', 'Disease', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('skin melanoma', 'Disease', (137, 150))	('rs401681', 'Mutation', 'rs401681', (56, 64))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('pancreatic carcinoma', 'Disease', (112, 132))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('skin melanoma', 'Disease', 'MESH:D008545', (137, 150))	('melanoma', 'Phenotype', 'HP:0002861', (142, 150))	('rs401681 [T', 'Var', (56, 67))
393480	24386361	In the present case-control study, the rs401681 T allele was less frequent among the esophageal cancer cases than the controls, though this difference was not statistically significant.	('esophageal cancer', 'Disease', 'MESH:D004938', (85, 102))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('less', 'NegReg', (61, 65))	('rs401681', 'Mutation', 'rs401681', (39, 47))	('rs401681 T', 'Var', (39, 49))	('esophageal cancer', 'Disease', (85, 102))
393481	24386361	Following adjustment for age, sex and smoking and drinking status in a multivariate logistic regression analysis, no significant association was found between rs401681 and the susceptibility to ESCC.	('ESCC', 'Disease', (194, 198))	('rs401681', 'Var', (159, 167))	('rs401681', 'Mutation', 'rs401681', (159, 167))
393482	24386361	Several studies have reported an association between short telomeres and an increased risk of esophageal cancer.	('esophageal cancer', 'Disease', (94, 111))	('short telomeres', 'Phenotype', 'HP:0031413', (53, 68))	('esophageal cancer', 'Disease', 'MESH:D004938', (94, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('short telomeres', 'Var', (53, 68))
393483	24386361	A previous genome-wide association study demonstrated that four SNPs (rs621559 on 1p34.2, rs398652 on 14q21, rs6028466 on 20q11.22 and rs654128 on 6q22.1) were associated with leukocyte telomere length in Caucasian populations.	('rs621559', 'Var', (70, 78))	('rs398652', 'Mutation', 'rs398652', (90, 98))	('rs654128', 'Mutation', 'rs654128', (135, 143))	('rs654128 on', 'Var', (135, 146))	('rs6028466 on', 'Var', (109, 121))	('leukocyte', 'MPA', (176, 185))	('rs6028466', 'Mutation', 'rs6028466', (109, 118))	('rs621559', 'Mutation', 'rs621559', (70, 78))	('rs398652 on', 'Var', (90, 101))	('associated', 'Reg', (160, 170))
393485	24386361	found that both rs621559 and rs398652 were significantly associated with ESCC risk in additive, recessive or dominant genetic models.	('rs621559', 'Mutation', 'rs621559', (16, 24))	('rs398652', 'Mutation', 'rs398652', (29, 37))	('rs621559', 'Var', (16, 24))	('rs398652', 'Var', (29, 37))	('ESCC', 'Disease', (73, 77))	('associated', 'Reg', (57, 67))
393486	24386361	However, in the present study, we detected no association between rs401681 and the risk of ESCC, although rs401681[C] has been reported to be associated with shorter telomeres with nominal significance.	('rs401681', 'Mutation', 'rs401681', (106, 114))	('shorter', 'NegReg', (158, 165))	('rs401681', 'Var', (66, 74))	('ESCC', 'Disease', (91, 95))	('rs401681', 'Mutation', 'rs401681', (66, 74))	('rs401681[', 'Var', (106, 115))
393488	24386361	In summary, our findings suggested that rs401681 may modify susceptibility to lung cancer but not ESCC.	('lung cancer', 'Disease', (78, 89))	('lung cancer', 'Phenotype', 'HP:0100526', (78, 89))	('modify', 'Reg', (53, 59))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('rs401681', 'Var', (40, 48))	('lung cancer', 'Disease', 'MESH:D008175', (78, 89))	('rs401681', 'Mutation', 'rs401681', (40, 48))
393494	33795683	KIMAT1 knockdown suppresses not only KRAS expression but also KRAS downstream signaling, thereby arresting lung cancer growth in vitro and in vivo.	('arresting lung cancer', 'Disease', 'MESH:D012131', (97, 118))	('KRAS', 'Gene', (62, 66))	('expression', 'Species', '29278', (42, 52))	('KRAS', 'Gene', '3845', (62, 66))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('arresting lung cancer', 'Disease', (97, 118))	('KRAS', 'Gene', (37, 41))	('suppresses', 'NegReg', (17, 27))	('lung cancer', 'Phenotype', 'HP:0100526', (107, 118))	('knockdown', 'Var', (7, 16))	('KRAS', 'Gene', '3845', (37, 41))	('KIMAT1', 'Gene', (0, 6))
393495	33795683	Taken together, this study uncovers a role for KIMAT1 in maintaining a positive feedback loop that sustains KRAS signaling during lung cancer progression and provides a proof of principle that interfering with KIMAT1 could be a strategy to hamper KRAS-induced tumorigenesis.	('KRAS', 'Gene', (108, 112))	('KIMAT1', 'Gene', (210, 216))	('tumor', 'Disease', (260, 265))	('lung cancer', 'Phenotype', 'HP:0100526', (130, 141))	('positive feedback loop', 'MPA', (71, 93))	('hamper', 'NegReg', (240, 246))	('KRAS', 'Gene', '3845', (108, 112))	('tumor', 'Disease', 'MESH:D009369', (260, 265))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('lung cancer', 'Disease', 'MESH:D008175', (130, 141))	('tumor', 'Phenotype', 'HP:0002664', (260, 265))	('interfering', 'Var', (193, 204))	('KRAS', 'Gene', (247, 251))	('KRAS', 'Gene', '3845', (247, 251))	('lung cancer', 'Disease', (130, 141))
393496	33795683	Wild-type KRAS amplification is known to induce KRAS activation in cancer leading to poor prognostic outcomes.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('KRAS', 'Gene', (48, 52))	('KRAS', 'Gene', '3845', (10, 14))	('cancer', 'Disease', (67, 73))	('amplification', 'Var', (15, 28))	('activation', 'PosReg', (53, 63))	('KRAS', 'Gene', '3845', (48, 52))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('KRAS', 'Gene', (10, 14))
393497	33795683	Here the authors identify a KRAS-responsive lncRNA, KIMAT1 that maintains KRAS signalling in lung cancer, suggesting that its targeting may prevent KRAS-driven tumourigenesis.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('KRAS', 'Gene', (148, 152))	('KRAS', 'Gene', (28, 32))	('KRAS', 'Gene', '3845', (28, 32))	('lung cancer', 'Disease', 'MESH:D008175', (93, 104))	('targeting', 'Var', (126, 135))	('prevent', 'NegReg', (140, 147))	('KRAS', 'Gene', '3845', (148, 152))	('KRAS', 'Gene', (74, 78))	('lung cancer', 'Disease', (93, 104))	('KRAS', 'Gene', '3845', (74, 78))	('lung cancer', 'Phenotype', 'HP:0100526', (93, 104))	('maintains', 'PosReg', (64, 73))
393498	33795683	While drugs that inhibit KRAS for therapeutic gain begin to be available in the clinic for patients with specific KRAS mutations, the functional role of KRASWT amplification, which has recently been shown to be a secondary means of KRAS activation in cancer, remains mostly unexplored.	('KRASWT', 'Gene', '3845', (153, 159))	('patients', 'Species', '9606', (91, 99))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('KRAS', 'Gene', '3845', (232, 236))	('KRAS', 'Gene', (153, 157))	('KRAS', 'Gene', (114, 118))	('KRAS', 'Gene', (232, 236))	('KRAS', 'Gene', '3845', (153, 157))	('KRAS', 'Gene', '3845', (114, 118))	('cancer', 'Disease', 'MESH:D009369', (251, 257))	('mutations', 'Var', (119, 128))	('cancer', 'Disease', (251, 257))	('KRAS', 'Gene', (25, 29))	('KRASWT', 'Gene', (153, 159))	('KRAS', 'Gene', '3845', (25, 29))
393509	33795683	Through in silico analysis of KRAS copy number alteration (CNA) in human clinical samples from the Cancer Genome Atlas (TCGA), we identified high level amplification of the KRAS gene, as previously reported, as well KRAS copy number gain (see methods) in both lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC), with consequent increase of KRAS mRNA (Fig.	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (291, 319))	('lung squamous cell carcinoma', 'Disease', (291, 319))	('Cancer', 'Phenotype', 'HP:0002664', (99, 105))	('KRAS', 'Gene', (173, 177))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (260, 279))	('KRAS', 'Gene', (30, 34))	('KRAS', 'Gene', '3845', (216, 220))	('gain', 'PosReg', (233, 237))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (260, 279))	('carcinoma', 'Phenotype', 'HP:0030731', (310, 319))	('Cancer', 'Disease', (99, 105))	('carcinoma', 'Phenotype', 'HP:0030731', (270, 279))	('KRAS', 'Gene', (216, 220))	('copy number', 'Var', (221, 232))	('increase', 'PosReg', (344, 352))	('Cancer', 'Disease', 'MESH:D009369', (99, 105))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (291, 319))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (296, 319))	('KRAS', 'Gene', '3845', (356, 360))	('lung adenocarcinoma', 'Disease', (260, 279))	('KRAS', 'Gene', '3845', (173, 177))	('LUSC', 'Phenotype', 'HP:0030359', (321, 325))	('KRAS', 'Gene', (356, 360))	('human', 'Species', '9606', (67, 72))	('KRAS', 'Gene', '3845', (30, 34))	('LUAD', 'Phenotype', 'HP:0030078', (281, 285))
393510	33795683	17% of LUAD patients with KRAS gain/amplification also harbored a mutant KRAS allele (Supplementary Data 1).	('patients', 'Species', '9606', (12, 20))	('KRAS', 'Gene', (73, 77))	('gain/amplification', 'PosReg', (31, 49))	('LUAD', 'Phenotype', 'HP:0030078', (7, 11))	('LUAD', 'Disease', (7, 11))	('mutant', 'Var', (66, 72))	('KRAS', 'Gene', '3845', (73, 77))	('harbored', 'Reg', (55, 63))	('KRAS', 'Gene', (26, 30))	('KRAS', 'Gene', '3845', (26, 30))
393511	33795683	Kaplan-Meier survival analysis revealed that patients with amplified KRAS had a poorer disease-free survival compared to patients with nonamplified KRAS status (Fig.	('KRAS', 'Gene', (69, 73))	('KRAS', 'Gene', (148, 152))	('KRAS', 'Gene', '3845', (69, 73))	('KRAS', 'Gene', '3845', (148, 152))	('poorer', 'NegReg', (80, 86))	('disease-free survival', 'CPA', (87, 108))	('patients', 'Species', '9606', (45, 53))	('patients', 'Species', '9606', (121, 129))	('amplified', 'Var', (59, 68))
393513	33795683	We carried out RNA sequencing (RNA-seq) analysis after overexpression (OE) of either KRASWT or KRASG12D in H1299 cells, which although harboring an NRAS mutation do not depend on NRAS signaling.	('KRAS', 'Gene', '3845', (95, 99))	('NRAS', 'Gene', (148, 152))	('KRASWT', 'Gene', '3845', (85, 91))	('KRASWT', 'Gene', (85, 91))	('NRAS', 'Gene', '4893', (148, 152))	('expression', 'Species', '29278', (59, 69))	('NRAS', 'Gene', '4893', (179, 183))	('KRAS', 'Gene', (95, 99))	('NRAS', 'Gene', (179, 183))	('KRAS', 'Gene', (85, 89))	('KRAS', 'Gene', '3845', (85, 89))	('mutation', 'Var', (153, 161))
393522	33795683	Additionally, silencing or inhibition of molecules upstream or downstream of KRAS led to KIMAT1 downregulation (Supplementary Fig.	('silencing', 'Var', (14, 23))	('KRAS', 'Gene', (77, 81))	('downregulation', 'NegReg', (96, 110))	('KRAS', 'Gene', '3845', (77, 81))	('KIMAT1', 'Gene', (89, 95))	('inhibition', 'NegReg', (27, 37))
393524	33795683	In both cell lines KRASWT OE increased cell proliferation and 3D cell invasion with a rescue of the phenotype upon KIMAT1 knockdown (KD), evidencing that KIMAT1 is a crucial mediator of KRAS-induced tumorigenesis (Supplementary Fig.	('tumor', 'Disease', (199, 204))	('KRAS', 'Gene', (186, 190))	('KIMAT1', 'Gene', (115, 121))	('KRASWT', 'Gene', '3845', (19, 25))	('3D cell invasion', 'CPA', (62, 78))	('KRASWT', 'Gene', (19, 25))	('KRAS', 'Gene', (19, 23))	('increased', 'PosReg', (29, 38))	('knockdown', 'Var', (122, 131))	('KRAS', 'Gene', '3845', (19, 23))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('KRAS', 'Gene', '3845', (186, 190))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('cell proliferation', 'CPA', (39, 57))
393534	33795683	Previously published ChIP-seq data from A549 cells revealed increased level of MYC-binding proximal to the TSS and overlapping with H3K4me3 and H3K27ac peaks, as expected in the case of a direct binding (Fig.	('MYC-binding', 'Protein', (79, 90))	('H3K27ac', 'Var', (144, 151))	('A549', 'CellLine', 'CVCL:0023', (40, 44))	('increased', 'PosReg', (60, 69))
393538	33795683	As expected, MYC silencing reduced the expression of the reporter gene fused to the MER-101-1 sequence with a rescue of the luciferase activity upon deletion of the two MYC-binding sites.	('deletion', 'Var', (149, 157))	('luciferase', 'Enzyme', (124, 134))	('silencing reduced', 'NegReg', (17, 34))	('activity', 'MPA', (135, 143))	('expression', 'MPA', (39, 49))	('expression', 'Species', '29278', (39, 49))	('MYC', 'Gene', (13, 16))
393539	33795683	2e) while MYC silencing reduced KIMAT1 expression (Fig.	('silencing', 'Var', (14, 23))	('reduced', 'NegReg', (24, 31))	('KIMAT1', 'Gene', (32, 38))	('MYC', 'Protein', (10, 13))	('expression', 'Species', '29278', (39, 49))
393543	33795683	KIMAT1 silencing dramatically reduced cell proliferation, 3D cell invasion and clonogenic ability in several cancer cell lines and induced remarkable cell death (Fig.	('cell proliferation', 'CPA', (38, 56))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('cancer', 'Disease', (109, 115))	('3D cell invasion', 'CPA', (58, 74))	('KIMAT1', 'Gene', (0, 6))	('clonogenic ability', 'CPA', (79, 97))	('reduced', 'NegReg', (30, 37))	('death', 'Disease', 'MESH:D003643', (155, 160))	('death', 'Disease', (155, 160))	('silencing', 'Var', (7, 16))
393556	33795683	Using DHX9 or NPM1 deletion mutants (Supplementary Fig.	('NPM1', 'Gene', '4869', (14, 18))	('deletion mutants', 'Var', (19, 35))	('DHX9', 'Gene', (6, 10))	('DHX9', 'Gene', '1660', (6, 10))	('NPM1', 'Gene', (14, 18))
393557	33795683	6b) followed by CLIP assay we observed that deletion of the two DHX9 dsRBDs and the NPM1 DRBD domain abolished KIMAT1 binding (Fig.	('NPM1', 'Gene', (84, 88))	('DHX9', 'Gene', (64, 68))	('KIMAT1', 'Protein', (111, 117))	('DHX9', 'Gene', '1660', (64, 68))	('deletion', 'Var', (44, 52))	('abolished', 'NegReg', (101, 110))	('NPM1', 'Gene', '4869', (84, 88))
393558	33795683	Next, to determine whether deletion of DHX9 or NPM1 binding sites in KIMAT1 could abrogate its biological effects, we cloned KIMAT1 full-length and deletion constructs in a lentiviral vector.	('deletion', 'Var', (148, 156))	('DHX9', 'Gene', (39, 43))	('NPM1', 'Gene', (47, 51))	('biological', 'MPA', (95, 105))	('DHX9', 'Gene', '1660', (39, 43))	('deletion', 'Var', (27, 35))	('binding', 'Interaction', (52, 59))	('abrogate', 'NegReg', (82, 90))	('NPM1', 'Gene', '4869', (47, 51))
393559	33795683	Overexpression of the mutants gave rise to a lower number of colonies compared to cells transfected with KIMAT1 full length (Supplementary Fig.	('lower', 'NegReg', (45, 50))	('mutants', 'Var', (22, 29))	('expression', 'Species', '29278', (4, 14))
393562	33795683	Notably, KIMAT1 depletion decreased whereas KIMAT1 OE or KRAS OE induced DHX9 and NPM1 (Fig.	('NPM1', 'Gene', (82, 86))	('DHX9', 'Gene', (73, 77))	('KIMAT1', 'Var', (44, 50))	('KRAS', 'Gene', (57, 61))	('KRAS', 'Gene', '3845', (57, 61))	('NPM1', 'Gene', '4869', (82, 86))	('DHX9', 'Gene', '1660', (73, 77))	('decreased', 'NegReg', (26, 35))	('KIMAT1', 'MPA', (9, 15))
393564	33795683	7c) and KIMAT1 silencing increased the polyubiquitination of DHX9 and NPM1 (Supplementary Fig.	('increased', 'PosReg', (25, 34))	('DHX9', 'Gene', (61, 65))	('polyubiquitination', 'MPA', (39, 57))	('KIMAT1', 'Gene', (8, 14))	('NPM1', 'Gene', '4869', (70, 74))	('silencing', 'Var', (15, 24))	('DHX9', 'Gene', '1660', (61, 65))	('NPM1', 'Gene', (70, 74))
393566	33795683	In accordance with a role in promoting tumor progression, high expression of DHX9/NPM1/KIMAT1 was associated with poor overall survival in lung cancer patients (Fig.	('lung cancer', 'Disease', (139, 150))	('DHX9', 'Gene', (77, 81))	('poor', 'NegReg', (114, 118))	('DHX9', 'Gene', '1660', (77, 81))	('expression', 'Species', '29278', (63, 73))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('NPM1', 'Gene', (82, 86))	('lung cancer', 'Disease', 'MESH:D008175', (139, 150))	('high expression', 'Var', (58, 73))	('patients', 'Species', '9606', (151, 159))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('overall survival', 'MPA', (119, 135))	('NPM1', 'Gene', '4869', (82, 86))	('tumor', 'Disease', (39, 44))	('lung cancer', 'Phenotype', 'HP:0100526', (139, 150))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
393572	33795683	GSEA analysis revealed that KIMAT1 KD led to suppression of genes positively regulated by KRAS and enrichment of genes negatively regulated by KRAS (Fig.	('suppression', 'NegReg', (45, 56))	('KRAS', 'Gene', (90, 94))	('KRAS', 'Gene', '3845', (90, 94))	('KRAS', 'Gene', (143, 147))	('KRAS', 'Gene', '3845', (143, 147))	('GSEA', 'Chemical', '-', (0, 4))	('KIMAT1 KD', 'Var', (28, 37))
393573	33795683	KIMAT1 silencing reduced KRAS endogenous levels as well as ERKs and AKT phosphorylation and c-RAF level, supporting the existence of a positive feedback loop (Supplementary Fig.	('c-RAF', 'Gene', '5894', (92, 97))	('ERKs', 'Pathway', (59, 63))	('AKT', 'Gene', (68, 71))	('KIMAT1', 'Gene', (0, 6))	('AKT', 'Gene', '207', (68, 71))	('c-RAF', 'Gene', (92, 97))	('KRAS', 'Gene', (25, 29))	('silencing', 'Var', (7, 16))	('reduced', 'NegReg', (17, 24))	('KRAS', 'Gene', '3845', (25, 29))
393581	33795683	To test this hypothesis, we profiled miRNA expression of KIMAT1 KD compared to control cells by next-generation sequencing (NGS).	('miRNA expression', 'MPA', (37, 53))	('expression', 'Species', '29278', (43, 53))	('KIMAT1 KD', 'Var', (57, 66))
393583	33795683	A majority of the upregulated miRNAs upon KIMAT1 KD turned out to have tumor suppressor properties whereas most of the downregulated miRNAs have been previously reported to have oncogenic roles.	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('upregulated', 'PosReg', (18, 29))	('tumor', 'Disease', (71, 76))	('KIMAT1 KD', 'Var', (42, 51))
393586	33795683	Interestingly, network analysis revealed that genes belonging to pathways activated by KIMAT1, including the KRAS pathway, were predicted targets of the KIMAT1-suppressed miRNAs (Supplementary Fig.	('KIMAT1-suppressed', 'Var', (153, 170))	('KRAS', 'Gene', '3845', (109, 113))	('KIMAT1', 'Gene', (87, 93))	('KRAS', 'Gene', (109, 113))
393589	33795683	In support of this hypothesis, KIMAT1 KD promoted Drosha-mediated pri-miR-27b in vitro processing, performed by incubating radio-labeled pri-miR-27b with immunoprecipitated Drosha from H1299 cells (Fig.	('Drosha', 'Gene', (173, 179))	('Drosha', 'Gene', (50, 56))	('KIMAT1 KD', 'Var', (31, 40))	('promoted', 'PosReg', (41, 49))	('Drosha', 'Gene', '29102', (173, 179))	('miR-27b', 'Gene', '407019', (70, 77))	('miR-27b', 'Gene', '407019', (141, 148))	('Drosha', 'Gene', '29102', (50, 56))	('miR-27b', 'Gene', (70, 77))	('miR-27b', 'Gene', (141, 148))
393603	33795683	Two different cell lines were transfected with a luciferase vector carrying a segment of pri-let-27b, -let-7b, -17-5p and -18a between the luciferase gene and the polyadenylation signal (Supplementary Fig.	('luciferase', 'Gene', (139, 149))	('pri-let-27b', 'Var', (89, 100))	('let-7b', 'Gene', '406884', (103, 109))	('let-7b', 'Gene', (103, 109))
393609	33795683	Having assessed that KIMAT1 KD induced downregulation of miR-17-5p, -18a, -375 and 10b-5p via DHX9 and NPM1, we sought to address how KIMAT1 KD could lead to the induction of miR-200 family members, miR-7, -27a, -27b, -139 and let-7b, considered to have TS function in lung cancer.	('DHX9', 'Gene', '1660', (94, 98))	('miR-200', 'Gene', (175, 182))	('lung cancer', 'Disease', (269, 280))	('KIMAT1 KD', 'Var', (134, 143))	('NPM1', 'Gene', (103, 107))	('let-7b', 'Gene', (227, 233))	('DHX9', 'Gene', (94, 98))	('miR-7', 'Gene', '10859', (199, 204))	('miR-17-5p', 'Gene', '406952', (57, 66))	('miR-17-5p', 'Gene', (57, 66))	('lung cancer', 'Disease', 'MESH:D008175', (269, 280))	('lung cancer', 'Phenotype', 'HP:0100526', (269, 280))	('KIMAT1', 'Var', (21, 27))	('NPM1', 'Gene', '4869', (103, 107))	('let-7b', 'Gene', '406884', (227, 233))	('induction', 'PosReg', (162, 171))	('miR-7', 'Gene', (199, 204))	('cancer', 'Phenotype', 'HP:0002664', (274, 280))	('downregulation', 'NegReg', (39, 53))
393617	33795683	Because KIMAT1 KD induces MYC downregulation, we were surprised not to see an effect on pri-miR-17-5p and pri-miR-18a, members of the well-known MYC-induced miR-17-92 cluster upon KIMAT1 silencing.	('miR-18a', 'Gene', (110, 117))	('downregulation', 'NegReg', (30, 44))	('KIMAT1 KD', 'Var', (8, 17))	('MYC', 'MPA', (26, 29))	('miR-17-92', 'Gene', '407975', (157, 166))	('miR-18a', 'Gene', '406953', (110, 117))	('miR-17-5p', 'Gene', '406952', (92, 101))	('miR-17-5p', 'Gene', (92, 101))	('miR-17-92', 'Gene', (157, 166))
393623	33795683	H1299 and H460 cell lines were transfected with a luciferase vector carrying a segment of pri-27b, pri-let-7b, pri-miR-17 and pri-miR-18a between the luciferase gene and polyadenylation signal.	('miR-18a', 'Gene', '406953', (130, 137))	('miR-17', 'Gene', (115, 121))	('let-7b', 'Gene', '406884', (103, 109))	('let-7b', 'Gene', (103, 109))	('miR-17', 'Gene', '406952', (115, 121))	('miR-18a', 'Gene', (130, 137))	('pri-27b', 'Var', (90, 97))
393624	33795683	p21 silencing caused an increase in the luciferase activity in cells transfected with pri-27b and let-7b but not in cells transfected with miR-17 and miR-18a, while p21 OE resulted in the opposite effect (Supplementary Fig.	('activity', 'MPA', (51, 59))	('increase', 'PosReg', (24, 32))	('p21', 'Gene', (0, 3))	('miR-17', 'Gene', (139, 145))	('p21', 'Gene', (165, 168))	('let-7b', 'Gene', '406884', (98, 104))	('miR-18a', 'Gene', '406953', (150, 157))	('let-7b', 'Gene', (98, 104))	('luciferase', 'Enzyme', (40, 50))	('miR-17', 'Gene', '406952', (139, 145))	('pri-27b', 'Var', (86, 93))	('miR-18a', 'Gene', (150, 157))	('silencing', 'NegReg', (4, 13))	('p21', 'Gene', '1026', (0, 3))	('p21', 'Gene', '1026', (165, 168))
393633	33795683	p21 silencing increased the capacity of the cells to proliferate, whilst p21 OE induced significant cell death (Supplementary Fig.	('increased', 'PosReg', (14, 23))	('p21', 'Gene', '1026', (73, 76))	('p21', 'Gene', (0, 3))	('death', 'Disease', 'MESH:D003643', (105, 110))	('death', 'Disease', (105, 110))	('p21', 'Gene', (73, 76))	('p21', 'Gene', '1026', (0, 3))	('silencing', 'Var', (4, 13))
393634	33795683	7g), revealing that the substantial apoptosis observed upon KIMAT1 KD could mainly be mediated by p21.	('p21', 'Gene', '1026', (98, 101))	('apoptosis', 'CPA', (36, 45))	('KIMAT1 KD', 'Var', (60, 69))	('p21', 'Gene', (98, 101))
393647	33795683	In a rescue in vivo experiment, ortothopic injection of cancer cells simultaneously overexpressing KIMAT1 and harboring DHX9 or NPM1 deletion (DHX9 KO or NPM1 KO) halted KIMAT1-mediated metastatic effects, suggesting that DHX9 and NPM1 are important mediators of KIMAT1 function (Supplementary Fig.	('NPM1', 'Gene', (231, 235))	('DHX9', 'Gene', (143, 147))	('DHX9', 'Gene', (222, 226))	('NPM1', 'Gene', '4869', (128, 132))	('DHX9', 'Gene', (120, 124))	('DHX9', 'Gene', '1660', (222, 226))	('deletion', 'Var', (133, 141))	('DHX9', 'Gene', '1660', (120, 124))	('DHX9', 'Gene', '1660', (143, 147))	('NPM1', 'Gene', '4869', (231, 235))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('NPM1', 'Gene', (154, 158))	('NPM1', 'Gene', '4869', (154, 158))	('NPM1', 'Gene', (128, 132))	('halted', 'NegReg', (163, 169))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('cancer', 'Disease', (56, 62))
393649	33795683	KRASWT OE is able to activate in vitro the same oncogenic pathways as mutant KRAS, fostering cell migration and invasion and therefore, lung cancer progression.	('KRAS', 'Gene', '3845', (0, 4))	('lung cancer', 'Phenotype', 'HP:0100526', (136, 147))	('activate', 'PosReg', (21, 29))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('mutant', 'Var', (70, 76))	('invasion', 'CPA', (112, 120))	('fostering', 'PosReg', (83, 92))	('lung cancer', 'Disease', 'MESH:D008175', (136, 147))	('KRAS', 'Gene', (77, 81))	('cell migration', 'CPA', (93, 107))	('KRASWT', 'Gene', '3845', (0, 6))	('oncogenic pathways', 'Pathway', (48, 66))	('KRAS', 'Gene', '3845', (77, 81))	('KRASWT', 'Gene', (0, 6))	('KRAS', 'Gene', (0, 4))	('lung cancer', 'Disease', (136, 147))
393656	33795683	KIMAT1 silencing reduced 3D cell invasion and induced substantial programmed cell death in cancer and not in normal cells, suggesting that it is essential for cancer survival.	('cancer', 'Disease', (159, 165))	('death', 'Disease', 'MESH:D003643', (82, 87))	('death', 'Disease', (82, 87))	('3D cell invasion', 'CPA', (25, 41))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('KIMAT1', 'Gene', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('silencing', 'Var', (7, 16))	('reduced', 'NegReg', (17, 24))
393657	33795683	Although KIMAT1 expression is lower in cells with a mutational KRAS status compared to those with amplified KRAS, the biological effects upon KIMAT1 manipulation in these cells are similar to those observed in cells with KRAS amplification.	('KRAS', 'Gene', (108, 112))	('lower', 'NegReg', (30, 35))	('KIMAT1', 'Gene', (142, 148))	('KRAS', 'Gene', '3845', (63, 67))	('KIMAT1', 'Gene', (9, 15))	('mutational', 'Var', (52, 62))	('KRAS', 'Gene', (221, 225))	('KRAS', 'Gene', '3845', (108, 112))	('KRAS', 'Gene', '3845', (221, 225))	('expression', 'Species', '29278', (16, 26))	('expression', 'MPA', (16, 26))	('KRAS', 'Gene', (63, 67))
393688	33795683	The patient-derived xenograft (IC11LC13), from a patient with a lung squamous cell carcinoma harboring 6 copies of KRASWT and loss of function mutation in p53 was transplanted subcutaneously onto mice.	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (64, 92))	('p53', 'Gene', (155, 158))	('p53', 'Gene', '7157', (155, 158))	('mice', 'Species', '10090', (196, 200))	('loss of function', 'NegReg', (126, 142))	('lung squamous cell carcinoma', 'Disease', (64, 92))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (69, 92))	('patient', 'Species', '9606', (4, 11))	('mutation', 'Var', (143, 151))	('patient', 'Species', '9606', (49, 56))	('KRASWT', 'Gene', '3845', (115, 121))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (64, 92))	('KRASWT', 'Gene', (115, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))
393697	33795683	2.5 x 106 H1299 or H460 cells stably expressing KIMAT1 or a control vector (Ev) and the luciferase gene (luc2+), or H1299 DHX9 KO, NPM1 KO cells using the CRISPR/Cas9 editing system were injected with a 0.5 ml insulin syringe percutaneously into the left lateral thorax, at the lateral dorsal axillary line of 5-7 weeks old NSG mice (8 mice per group).	('NPM1', 'Gene', (131, 135))	('mice', 'Species', '10090', (328, 332))	('mice', 'Species', '10090', (336, 340))	('DHX9', 'Gene', (122, 126))	('NPM1', 'Gene', '4869', (131, 135))	('DHX9', 'Gene', '1660', (122, 126))	('KIMAT1', 'Var', (48, 54))
393715	33795683	Deletion of MYC-binding sites was obtained using the QuickChange Mutagenesis Kit (Stratagene).	('Kit', 'Gene', (77, 80))	('Kit', 'Gene', '3815', (77, 80))	('MYC-binding', 'Protein', (12, 23))	('Deletion', 'Var', (0, 8))
393717	33795683	Pri-miR-27b containing the stem-loop sequence plus 150 flanking bp was PCR amplified with a T7 containing forward primer and purified PCR product in vitro transcribed in the presence of alpha32P CTP (PerkinElmer).	('CTP', 'Chemical', 'MESH:D003570', (195, 198))	('alpha32P', 'Var', (186, 194))	('miR-27b', 'Gene', '407019', (4, 11))	('miR-27b', 'Gene', (4, 11))
393734	33795683	The integrative analysis was performed using data from KIMAT1 KD or DHX9/NPM1 KD RNA-seq to find shared enriched pathways within the sets of differentially expressed (DE) genes which are predicted targets of a pre-defined set of miRNAs.	('NPM1', 'Gene', '4869', (73, 77))	('DHX9', 'Gene', (68, 72))	('DHX9', 'Gene', '1660', (68, 72))	('differentially', 'Var', (141, 155))	('NPM1', 'Gene', (73, 77))
393772	33795683	2.0 x 103 cells either transfected with KIMAT1 GpRs or DHX9 and NPM1 siRNAs, DHX9 KO and NPM1 KO cells or with stable overexpression of KIMAT1, were cultured on ultra-low attachment plates (ULA, Corning) and incubated at 37  C for 10-15 days.	('DHX9', 'Gene', (77, 81))	('NPM1', 'Gene', (64, 68))	('DHX9', 'Gene', '1660', (77, 81))	('DHX9', 'Gene', (55, 59))	('NPM1', 'Gene', (89, 93))	('KIMAT1', 'Var', (40, 46))	('NPM1', 'Gene', '4869', (64, 68))	('NPM1', 'Gene', '4869', (89, 93))	('DHX9', 'Gene', '1660', (55, 59))	('expression', 'Species', '29278', (122, 132))
393821	33324675	IGFLR1 was expressed on the surface of T cells of mouse, and its high expression enhances inflammatory infiltration and activation.	('IGFLR1', 'Gene', (0, 6))	('activation', 'CPA', (120, 130))	('enhances', 'PosReg', (81, 89))	('high', 'Var', (65, 69))	('mouse', 'Species', '10090', (50, 55))
393860	33324675	Figure 2E showed the correlation between IGFLR1 expression level and DNA methylation, copy number and clinical data in ccRCC in detail.	('RCC', 'Disease', 'MESH:C538614', (121, 124))	('IGFLR1', 'Gene', (41, 47))	('RCC', 'Disease', (121, 124))	('ccRCC', 'Phenotype', 'HP:0006770', (119, 124))	('copy', 'Var', (86, 90))
393868	33324675	The expression level of IGFL1 was higher in ccRCC samples with IGFLR1-high-expression than that with IGFLR1-low-expression (0.025 vs. 0.008, p < 0.001) (Supplementary Figure S2B).	('expression level', 'MPA', (4, 20))	('ccRCC', 'Phenotype', 'HP:0006770', (44, 49))	('RCC', 'Disease', (46, 49))	('IGFL1', 'Gene', '374918', (24, 29))	('higher', 'PosReg', (34, 40))	('RCC', 'Disease', 'MESH:C538614', (46, 49))	('IGFLR1-high-expression', 'Var', (63, 85))	('IGFL1', 'Gene', (24, 29))
393889	33324675	Survival analysis and Cox regression analysis indicated that expression of IGFLR1 was a prognostic factor in ccRCC patients, rather than an independent prognostic factor.	('patients', 'Species', '9606', (115, 123))	('RCC', 'Disease', 'MESH:C538614', (111, 114))	('ccRCC', 'Phenotype', 'HP:0006770', (109, 114))	('RCC', 'Disease', (111, 114))	('expression', 'Var', (61, 71))	('IGFLR1', 'Gene', (75, 81))
393890	33324675	In the present study, we carefully examined the prognostic value of IGFLR1 in ccRCC patients using TCGA-KIRC cohort, and confirmed that the expression of IGFLR1 was an independent prognostic factor for ccRCC.	('ccRCC', 'Phenotype', 'HP:0006770', (78, 83))	('patients', 'Species', '9606', (84, 92))	('RCC', 'Disease', (80, 83))	('RCC', 'Disease', 'MESH:C538614', (204, 207))	('RCC', 'Disease', (204, 207))	('RCC', 'Disease', 'MESH:C538614', (80, 83))	('expression', 'Var', (140, 150))	('ccRCC', 'Phenotype', 'HP:0006770', (202, 207))	('IGFLR1', 'Gene', (154, 160))
393900	33324675	In addition to angiogenesis, MDSC also promoted tumor development through immunosuppression, targeting T cells primarily.	('promoted', 'PosReg', (39, 47))	('tumor', 'Disease', (48, 53))	('MDSC', 'Var', (29, 33))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
393909	33324675	Regarding the therapeutic value of IGFLR1, firstly, IGFLR1 can be used as a potential target, and inhibiting the expression of IGFLR1 may slow the progression of RCC tumors.	('expression', 'MPA', (113, 123))	('IGFLR1', 'Gene', (127, 133))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('progression', 'CPA', (147, 158))	('RCC tumors', 'Disease', 'MESH:C538614', (162, 172))	('slow', 'NegReg', (138, 142))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))	('inhibiting', 'Var', (98, 108))	('RCC tumors', 'Disease', (162, 172))
393910	33324675	Besides, IGFLR1 expression was significantly positively correlated with CD8+T cell and MDSC infiltration, suggesting that inhibition of CD8+T cell and MDSC activation may also slow down the progression of RCC.	('inhibition', 'Var', (122, 132))	('CD8', 'Gene', (136, 139))	('RCC', 'Disease', (205, 208))	('RCC', 'Disease', 'MESH:C538614', (205, 208))	('slow down', 'NegReg', (176, 185))	('IGFLR1', 'Gene', (9, 15))	('CD8', 'Gene', '925', (136, 139))	('CD8', 'Gene', (72, 75))	('CD8', 'Gene', '925', (72, 75))
393912	33324675	In addition, K-M survival curve showed that, patients with high IGFLR1 expression had significantly shorter survival time and worse prognosis.	('expression', 'MPA', (71, 81))	('IGFLR1', 'Gene', (64, 70))	('shorter', 'NegReg', (100, 107))	('high', 'Var', (59, 63))	('patients', 'Species', '9606', (45, 53))	('survival time', 'CPA', (108, 121))	('high IGFLR1 expression', 'Phenotype', 'HP:0030269', (59, 81))
393927	32312834	In cancer, DeltaNp63alpha is overexpressed in various primary tumors, such as lung squamous cell carcinomas, head and neck squamous cell carcinomas, basal-like bladder cancer and ovarian cancer.	('lung squamous cell carcinomas', 'Disease', 'MESH:D002294', (78, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('ovarian cancer', 'Disease', (179, 193))	('cancer', 'Disease', (168, 174))	('neck squamous cell carcinomas', 'Disease', (118, 147))	('ovarian cancer', 'Phenotype', 'HP:0100615', (179, 193))	('cancer', 'Disease', 'MESH:D009369', (187, 193))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('carcinomas', 'Phenotype', 'HP:0030731', (137, 147))	('neck squamous cell carcinomas', 'Disease', 'MESH:D000077195', (118, 147))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('bladder cancer', 'Disease', 'MESH:D001749', (160, 174))	('tumors', 'Disease', (62, 68))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (123, 147))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('bladder cancer', 'Disease', (160, 174))	('carcinomas', 'Phenotype', 'HP:0030731', (97, 107))	('lung squamous cell carcinomas', 'Disease', (78, 107))	('bladder cancer', 'Phenotype', 'HP:0009725', (160, 174))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (83, 107))	('tumors', 'Disease', 'MESH:D009369', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (123, 146))	('DeltaNp63alpha', 'Var', (11, 25))	('DeltaNp63', 'Chemical', '-', (11, 20))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (83, 106))	('cancer', 'Disease', (187, 193))	('ovarian cancer', 'Disease', 'MESH:D010051', (179, 193))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('cancer', 'Disease', (3, 9))	('overexpressed', 'PosReg', (29, 42))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('head and neck squamous cell carcinomas', 'Phenotype', 'HP:0012288', (109, 147))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
393929	32312834	Importantly, tumor cells with high invasion capacity express low levels of DeltaNp63, which induces an epithelial to mesenchymal transition (EMT) program in these cells.	('tumor', 'Disease', (13, 18))	('induces', 'Reg', (92, 99))	('DeltaNp63', 'Var', (75, 84))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('DeltaNp63', 'Chemical', '-', (75, 84))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('epithelial to mesenchymal transition', 'CPA', (103, 139))
393934	32312834	In particular, the loss of DeltaNp63 in epithelial-like bladder cancer cells promotes EMT and enhance invasion, while the induction of DeltaNp63 in mesenchymal-like bladder cancer cells triggers the mesenchymal to epithelial transition (MET) and suppresses invasion.	('DeltaNp63', 'Chemical', '-', (135, 144))	('enhance', 'PosReg', (94, 101))	('invasion', 'CPA', (257, 265))	('bladder cancer', 'Disease', 'MESH:D001749', (56, 70))	('bladder cancer', 'Disease', (56, 70))	('promotes', 'PosReg', (77, 85))	('DeltaNp63', 'Gene', (27, 36))	('mesenchymal to epithelial transition', 'CPA', (199, 235))	('bladder cancer', 'Phenotype', 'HP:0009725', (56, 70))	('triggers', 'PosReg', (186, 194))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('suppresses', 'NegReg', (246, 256))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('loss', 'Var', (19, 23))	('bladder cancer', 'Disease', 'MESH:D001749', (165, 179))	('bladder cancer', 'Disease', (165, 179))	('DeltaNp63', 'Var', (135, 144))	('DeltaNp63', 'Chemical', '-', (27, 36))	('invasion', 'CPA', (102, 110))	('bladder cancer', 'Phenotype', 'HP:0009725', (165, 179))	('EMT', 'CPA', (86, 89))
393941	32312834	these cells initially express DeltaNp63 followed by a silencing of DeltaNp63 and then a re-expression of DeltaNp63) efficiently metastasized and colonized the lungs of mice with mammary tumors.	('colonized', 'CPA', (145, 154))	('metastasized', 'CPA', (128, 140))	('silencing', 'NegReg', (54, 63))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('mice', 'Species', '10090', (168, 172))	('tumors', 'Phenotype', 'HP:0002664', (186, 192))	('tumors', 'Disease', (186, 192))	('tumors', 'Disease', 'MESH:D009369', (186, 192))	('DeltaNp63', 'Var', (30, 39))	('DeltaNp63', 'Gene', (67, 76))	('DeltaNp63', 'Chemical', '-', (67, 76))	('DeltaNp63', 'Chemical', '-', (105, 114))	('DeltaNp63', 'Chemical', '-', (30, 39))
393942	32312834	Further, we identified a novel network of four TGFbeta-Smad3 regulated microRNAs, including miR-22-3p, miR-30a-5p, miR-203a-3p and miR-222-3p, which target DeltaNp63 and efficiently silence it.	('miR-203', 'Gene', (115, 122))	('miR-30a', 'Gene', '407029', (103, 110))	('silence', 'NegReg', (182, 189))	('miR-203', 'Gene', '406986', (115, 122))	('DeltaNp63', 'Chemical', '-', (156, 165))	('miR-22-3p', 'Gene', (92, 101))	('DeltaNp63', 'Gene', (156, 165))	('miR-22-3p', 'Gene', '407008', (92, 101))	('Smad3', 'Gene', '4088', (55, 60))	('miR-30a', 'Gene', (103, 110))	('miR-222-3p', 'Chemical', '-', (131, 141))	('miR-222-3p', 'Var', (131, 141))	('Smad3', 'Gene', (55, 60))
393966	32312834	1F), indicating that loss of DeltaNp63 is associated with tumor progression.	('loss', 'Var', (21, 25))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('associated', 'Reg', (42, 52))	('DeltaNp63', 'Chemical', '-', (29, 38))	('DeltaNp63', 'Gene', (29, 38))	('tumor', 'Disease', 'MESH:D009369', (58, 63))
393969	32312834	To determine whether these features were also induced in breast cancer upon loss of DeltaNp63, we made use of the MCF-10A breast cancer progression model.	('breast cancer', 'Disease', (57, 70))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('breast cancer', 'Disease', (122, 135))	('breast cancer', 'Phenotype', 'HP:0003002', (57, 70))	('breast cancer', 'Phenotype', 'HP:0003002', (122, 135))	('loss', 'Var', (76, 80))	('MCF-10A', 'CellLine', 'CVCL:0598', (114, 121))	('DeltaNp63', 'Chemical', '-', (84, 93))	('DeltaNp63', 'Gene', (84, 93))	('breast cancer', 'Disease', 'MESH:D001943', (57, 70))	('breast cancer', 'Disease', 'MESH:D001943', (122, 135))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
393982	32312834	The second cohort was on doxycycline diet for 3 weeks, then switched to control diet for 3 more weeks to oscillate the expression of DeltaNp63 "low then high DeltaNp63 expression" (Group 2).	('DeltaNp63 "low', 'Var', (133, 147))	('DeltaNp63 expression', 'MPA', (158, 178))	('DeltaNp63', 'Chemical', '-', (133, 142))	('doxycycline', 'Chemical', 'MESH:D004318', (25, 36))	('DeltaNp63', 'Chemical', '-', (158, 167))
393985	32312834	Additionally, primary tumors from group 3 with "low DeltaNp63" showed decreased expression of DeltaNp63 and Ki67 compared to group 1 and group 2 (Supplementary Fig.	('tumors', 'Phenotype', 'HP:0002664', (22, 28))	('DeltaNp63', 'Chemical', '-', (52, 61))	('DeltaNp63', 'Chemical', '-', (94, 103))	('DeltaNp63', 'Protein', (94, 103))	('tumors', 'Disease', 'MESH:D009369', (22, 28))	('decreased', 'NegReg', (70, 79))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('Ki67', 'Var', (108, 112))	('expression', 'MPA', (80, 90))	('DeltaNp63', 'Var', (52, 61))	('tumors', 'Disease', (22, 28))
393993	32312834	The depletion of DeltaNp63 in primary tumor cells, while inhibiting cell proliferation, also triggered a cell migration and invasion program that could potentially increase intravasation into the blood circulation (Fig.	('inhibiting', 'NegReg', (57, 67))	('tumor', 'Disease', (38, 43))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('DeltaNp63', 'Chemical', '-', (17, 26))	('DeltaNp63', 'Gene', (17, 26))	('intravasation into the blood circulation', 'MPA', (173, 213))	('cell proliferation', 'CPA', (68, 86))	('depletion', 'Var', (4, 13))	('triggered', 'Reg', (93, 102))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('cell migration', 'CPA', (105, 119))	('increase', 'PosReg', (164, 172))
393996	32312834	Since our data show that DeltaNp63 promotes cancer cell proliferation and formation of primary tumors, we further determined whether the expression of DeltaNp63 is also required for the establishment of distant metastases to the lungs, thus explaining why an oscillatory expression of this isoform enhances metastasis as shown previously in this study.	('DeltaNp63', 'Chemical', '-', (25, 34))	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('DeltaNp63', 'Chemical', '-', (151, 160))	('DeltaNp63', 'Gene', (151, 160))	('metastasis', 'CPA', (307, 317))	('enhances', 'PosReg', (298, 306))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('promotes', 'PosReg', (35, 43))	('metastases', 'Disease', (211, 221))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('metastases', 'Disease', 'MESH:D009362', (211, 221))	('formation', 'CPA', (74, 83))	('tumors', 'Disease', (95, 101))	('DeltaNp63', 'Var', (25, 34))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
394001	32312834	The results showed that depletion of DeltaNp63 in circulating tumor cells ("low DeltaNp63", Group 3) resulted in a significant decrease in the number of RFP-positive cells in the lungs compared to control tumor cells with "high DeltaNp63" expression (Group 1).	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('DeltaNp63', 'Chemical', '-', (80, 89))	('RFP', 'Gene', '19720', (153, 156))	('decrease', 'NegReg', (127, 135))	('DeltaNp63', 'Var', (37, 46))	('tumor', 'Disease', (62, 67))	('DeltaNp63', 'Chemical', '-', (228, 237))	('DeltaNp63', 'Chemical', '-', (37, 46))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumor', 'Disease', (205, 210))	('depletion', 'MPA', (24, 33))	('RFP', 'Gene', (153, 156))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
394011	32312834	S2H), indicating that cancer cells expressing DeltaNp63 exhibit favorable characteristics to colonize distant lungs and that only cells that escape DeltaNp63 depletion are capable of colonization.	('colonize distant lungs', 'CPA', (93, 115))	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('DeltaNp63', 'Var', (46, 55))	('DeltaNp63', 'Chemical', '-', (148, 157))	('DeltaNp63', 'Chemical', '-', (46, 55))	('cancer', 'Disease', (22, 28))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))
394012	32312834	Taken together, these in vivo data demonstrated that DeltaNp63 is required for both extravasation and colonization of breast tumor cells at distant lungs.	('breast tumor', 'Disease', 'MESH:D001943', (118, 130))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('DeltaNp63', 'Var', (53, 62))	('breast tumor', 'Disease', (118, 130))	('DeltaNp63', 'Chemical', '-', (53, 62))	('breast tumor', 'Phenotype', 'HP:0100013', (118, 130))
394013	32312834	To determine whether DeltaNp63 regulates genes and pathways relevant to cancer progression and dissemination in our in vivo model, we injected MCF10DCIS-i-shDeltaNp63 cells into the mammary fat pads of nude mice and fed them with either control or dox diet.	('cancer', 'Disease', (72, 78))	('dox', 'Chemical', 'MESH:D004318', (248, 251))	('MCF10DCIS-i-shDeltaNp63', 'Var', (143, 166))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('DCIS', 'Phenotype', 'HP:0030075', (148, 152))	('regulates', 'Reg', (31, 40))	('nude mice', 'Species', '10090', (202, 211))	('DeltaNp63', 'Chemical', '-', (157, 166))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (143, 152))	('DeltaNp63', 'Chemical', '-', (21, 30))
394015	32312834	Differential binding profiles of DeltaNp63 and Pol II between the MCF10DCIS-control and MCF10DCIS-shDeltaNp63 tumors were compared to identify DeltaNp63-induced and -repressed gene signatures.	('MCF10DCIS', 'CellLine', 'CVCL:5552', (66, 75))	('binding', 'Interaction', (13, 20))	('DeltaNp63', 'Chemical', '-', (100, 109))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('DeltaNp63', 'Chemical', '-', (33, 42))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (88, 97))	('DCIS', 'Phenotype', 'HP:0030075', (93, 97))	('tumors', 'Disease', (110, 116))	('tumors', 'Disease', 'MESH:D009369', (110, 116))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('DCIS', 'Phenotype', 'HP:0030075', (71, 75))	('MCF10DCIS-shDeltaNp63', 'Var', (88, 109))	('Pol II', 'Gene', (47, 53))	('DeltaNp63', 'Chemical', '-', (143, 152))
394016	32312834	This data is in accordance with previously reported roles of DeltaNp63 in developmental processes and cell motility regulation, indicating that DeltaNp63 regulates a large network of downstream target genes during cancer progression.	('cancer', 'Disease', (214, 220))	('regulates', 'Reg', (154, 163))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('DeltaNp63', 'Chemical', '-', (61, 70))	('DeltaNp63', 'Var', (144, 153))	('DeltaNp63', 'Chemical', '-', (144, 153))	('cancer', 'Disease', 'MESH:D009369', (214, 220))
394024	32312834	Remarkably, DeltaNp63 expression was dramatically reduced when MCF10A, MCF10DCIS and MCF10CA1D cells were treated with TGFbeta (Fig.	('MCF10CA1D', 'CellLine', 'CVCL:6683', (85, 94))	('MCF10A', 'CellLine', 'CVCL:0598', (63, 69))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (71, 80))	('DeltaNp63', 'Chemical', '-', (12, 21))	('DeltaNp63', 'Gene', (12, 21))	('MCF10A', 'Var', (63, 69))	('reduced', 'NegReg', (50, 57))	('DCIS', 'Phenotype', 'HP:0030075', (76, 80))	('expression', 'MPA', (22, 32))
394026	32312834	To determine whether TGFbeta signaling regulated DeltaNp63, we treated MCF10A, MCF10DCIS, and MCFCA1D cells with LY2157299, an inhibitor of TGFbeta-receptor I (TGFbetaRI), to inactivate the TGFbeta signaling cascade.	('MCF10DCIS', 'CellLine', 'CVCL:5552', (79, 88))	('LY2157299', 'Var', (113, 122))	('MCFCA1D', 'CellLine', 'CVCL:6495', (94, 101))	('MCF10A', 'CellLine', 'CVCL:0598', (71, 77))	('inactivate', 'NegReg', (175, 185))	('DeltaNp63', 'Chemical', '-', (49, 58))	('TGFbeta signaling cascade', 'Pathway', (190, 215))	('DCIS', 'Phenotype', 'HP:0030075', (84, 88))	('LY2157299', 'Chemical', 'MESH:C557799', (113, 122))
394031	32312834	The ablation of Smad3 in MCF10A and MCF10DCIS cells restored DeltaNp63 expression (Fig.	('MCF10A', 'CellLine', 'CVCL:0598', (25, 31))	('Smad3', 'Gene', (16, 21))	('DCIS', 'Phenotype', 'HP:0030075', (41, 45))	('DeltaNp63 expression', 'MPA', (61, 81))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (36, 45))	('ablation', 'Var', (4, 12))	('restored', 'PosReg', (52, 60))	('DeltaNp63', 'Chemical', '-', (61, 70))	('Smad3', 'Gene', '4088', (16, 21))
394035	32312834	To do this, we inhibited the activation of the signaling cascade using LY2157299 in MCF10DCIS cells, which had high level of p-Smad2/3 compared to MCF10A and MCF10CA1D (Fig.	('inhibited', 'NegReg', (15, 24))	('MCF10A', 'CellLine', 'CVCL:0598', (147, 153))	('MCF10CA1D', 'CellLine', 'CVCL:6683', (158, 167))	('DCIS', 'Phenotype', 'HP:0030075', (89, 93))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (84, 93))	('Smad2/3', 'Gene', (127, 134))	('LY2157299', 'Chemical', 'MESH:C557799', (71, 80))	('Smad2/3', 'Gene', '4087;4088', (127, 134))	('LY2157299', 'Var', (71, 80))
394044	32312834	Using this method, we identified differentially expressed-microRNAs upon TGFbeta treatment including several known targets of TGFbeta signaling such as miR-181, miR-145 and miR-21, further confirming the activation of TGFbeta signaling in these cells (Fig.	('miR-21', 'Gene', '406991', (173, 179))	('miR-21', 'Gene', (173, 179))	('miR-181', 'Var', (152, 159))	('miR-145', 'Gene', (161, 168))	('miR-145', 'Gene', '406937', (161, 168))	('TGFbeta', 'Gene', (73, 80))
394047	32312834	Among the 64 microRNAs, 9 microRNAs, including miR-10b-5p, miR-21-5p, miR-22-3p, miR-30a-5p, miR-141-3p, miR-181a-5p, miR-200a-3p, miR-203a-3p and miR-222-3p, were selected for further validation based on predicted binding affinity to the 3'UTR of TP63 and previously reported connections with breast cancer and/or p63 (Fig.	('TP63', 'Gene', (248, 252))	('breast cancer', 'Disease', (294, 307))	('miR-30a', 'Gene', '407029', (81, 88))	('TP63', 'Gene', '8626', (248, 252))	('miR-21', 'Gene', '406991', (59, 65))	('connections', 'Interaction', (277, 288))	('miR-203', 'Gene', (131, 138))	('miR-181a-5p', 'Var', (105, 116))	('cancer', 'Phenotype', 'HP:0002664', (301, 307))	('p63', 'Gene', (315, 318))	('miR-30a', 'Gene', (81, 88))	('miR-203', 'Gene', '406986', (131, 138))	('miR-22-3p', 'Gene', '407008', (70, 79))	('p63', 'Gene', '8626', (315, 318))	('miR-21', 'Gene', (59, 65))	('miR-222-3p', 'Chemical', '-', (147, 157))	('binding', 'Interaction', (215, 222))	('miR-22-3p', 'Gene', (70, 79))	('breast cancer', 'Phenotype', 'HP:0003002', (294, 307))	('miR-141-3p', 'Var', (93, 103))	('breast cancer', 'Disease', 'MESH:D001943', (294, 307))
394048	32312834	We then overexpressed mimics of these 9 microRNAs and found that miR-22-3p, miR-30a-5p, miR-203a-3p and miR-222-3p downregulated DeltaNp63 protein level in MCF10DCIS cells (Fig.	('miR-22-3p', 'Gene', '407008', (65, 74))	('DCIS', 'Phenotype', 'HP:0030075', (161, 165))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (156, 165))	('miR-30a', 'Gene', '407029', (76, 83))	('miR-203', 'Gene', '406986', (88, 95))	('miR-203', 'Gene', (88, 95))	('DeltaNp63', 'Chemical', '-', (129, 138))	('DeltaNp63 protein level', 'MPA', (129, 152))	('miR-22-3p', 'Gene', (65, 74))	('downregulated', 'NegReg', (115, 128))	('miR-222-3p', 'Chemical', '-', (104, 114))	('miR-30a', 'Gene', (76, 83))	('miR-222-3p', 'Var', (104, 114))
394049	32312834	A similar reduction in DeltaNp63 expression was obtained in MCF10A and MCF10CA1D cells (Supplementary Fig.	('MCF10A', 'Var', (60, 66))	('DeltaNp63', 'Chemical', '-', (23, 32))	('MCF10A', 'CellLine', 'CVCL:0598', (60, 66))	('expression', 'MPA', (33, 43))	('reduction', 'NegReg', (10, 19))	('DeltaNp63', 'Gene', (23, 32))	('MCF10CA1D', 'CellLine', 'CVCL:6683', (71, 80))
394055	32312834	Mutations in the binding sites of miR-22-3p (Fig.	('miR-22-3p', 'Gene', (34, 43))	('Mutations', 'Var', (0, 9))	('miR-22-3p', 'Gene', '407008', (34, 43))
394061	32312834	Likewise, we found that microRNA upregulation by TGFbeta was rescued by knocking down Smad3 in MCF10DCIS cells (Fig.	('knocking down', 'Var', (72, 85))	('Smad3', 'Gene', '4088', (86, 91))	('DCIS', 'Phenotype', 'HP:0030075', (100, 104))	('upregulation', 'PosReg', (33, 45))	('TGFbeta', 'Gene', (49, 56))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (95, 104))	('Smad3', 'Gene', (86, 91))	('microRNA', 'MPA', (24, 32))
394070	32312834	In addition, the inhibition of endogenous TGFbeta signaling by LY2157299 in MCF10DCIS cells also reduced the expression of all 4 microRNAs (Fig.	('DCIS', 'Phenotype', 'HP:0030075', (81, 85))	('LY2157299', 'Chemical', 'MESH:C557799', (63, 72))	('expression', 'MPA', (109, 119))	('endogenous TGFbeta signaling', 'MPA', (31, 59))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (76, 85))	('LY2157299', 'Var', (63, 72))	('reduced', 'NegReg', (97, 104))	('inhibition', 'NegReg', (17, 27))
394071	32312834	The overexpression of all 4 microRNAs using microRNA mimics in the presence of LY2157299 rescued the migration and invasion capacity of MCF10DCIS cells (Fig.	('rescued', 'PosReg', (89, 96))	('migration', 'CPA', (101, 110))	('LY2157299', 'Var', (79, 88))	('LY2157299', 'Chemical', 'MESH:C557799', (79, 88))	('DCIS', 'Phenotype', 'HP:0030075', (141, 145))	('invasion capacity', 'CPA', (115, 132))	('MCF10DCIS', 'CellLine', 'CVCL:5552', (136, 145))
394072	32312834	Together, these data demonstrate that canonical TGFbeta signaling modulates the expression of DeltaNp63 via a network of 4 TGFbeta-induced microRNAs, including miR-22-3p, miR-30a-5p, miR-203a-3p and miR-222-3p.	('miR-203', 'Gene', '406986', (183, 190))	('miR-203', 'Gene', (183, 190))	('miR-22-3p', 'Gene', (160, 169))	('modulates', 'Reg', (66, 75))	('miR-22-3p', 'Gene', '407008', (160, 169))	('miR-30a', 'Gene', (171, 178))	('DeltaNp63', 'Chemical', '-', (94, 103))	('DeltaNp63', 'Gene', (94, 103))	('miR-222-3p', 'Chemical', '-', (199, 209))	('miR-222-3p', 'Var', (199, 209))	('expression', 'MPA', (80, 90))	('miR-30a', 'Gene', '407029', (171, 178))
394081	32312834	In accordance with our previous findings, treatment with TGFbetaRI inhibitor, LY2157299, also restored DeltaNp63 expression in these cells (Fig.	('DeltaNp63', 'Chemical', '-', (103, 112))	('DeltaNp63', 'Gene', (103, 112))	('restored', 'PosReg', (94, 102))	('LY2157299', 'Var', (78, 87))	('LY2157299', 'Chemical', 'MESH:C557799', (78, 87))
394085	32312834	Indeed, miR-22-3p, miR-30a-5p, miR-203a-3p and miR-222-3p expression was increased in COLO16, RDEB2 and IC1 cells treated with TGFbeta (Fig.	('miR-30a', 'Gene', (19, 26))	('increased', 'PosReg', (73, 82))	('miR-203', 'Gene', '406986', (31, 38))	('miR-222-3p', 'Chemical', '-', (47, 57))	('miR-222-3p', 'Var', (47, 57))	('expression', 'MPA', (58, 68))	('miR-22-3p', 'Gene', (8, 17))	('miR-22-3p', 'Gene', '407008', (8, 17))	('IC1', 'Gene', '105259599', (104, 107))	('miR-30a', 'Gene', '407029', (19, 26))	('IC1', 'Gene', (104, 107))	('miR-203', 'Gene', (31, 38))
394088	32312834	Indeed, H226, H1703 and H2286 lines showed significantly higher expression of miR-22-3p, miR-30a-5p and miR-222-3p compared to HCC95 (Supplementary Fig.	('miR-30a', 'Gene', (89, 96))	('expression', 'MPA', (64, 74))	('H226', 'CellLine', 'CVCL:J621', (8, 12))	('higher', 'PosReg', (57, 63))	('miR-22-3p', 'Gene', (78, 87))	('H1703', 'CellLine', 'CVCL:1490', (14, 19))	('miR-22-3p', 'Gene', '407008', (78, 87))	('miR-30a', 'Gene', '407029', (89, 96))	('HCC95', 'CellLine', 'CVCL:5137', (127, 132))	('miR-222-3p', 'Chemical', '-', (104, 114))	('miR-222-3p', 'Var', (104, 114))
394090	32312834	Moreover, treatment of LY2157299 in H226, H170 and H2286 lines not only induced expression of DeltaNp63 (Supplementary Fig.	('H226', 'CellLine', 'CVCL:J621', (36, 40))	('DeltaNp63', 'Chemical', '-', (94, 103))	('DeltaNp63', 'Gene', (94, 103))	('induced', 'Reg', (72, 79))	('expression', 'MPA', (80, 90))	('LY2157299', 'Chemical', 'MESH:C557799', (23, 32))	('LY2157299', 'Var', (23, 32))
394102	32312834	However, the suppressive function of DeltaNp63 on the cell adhesion and motility through regulation of different transcription factors and microRNAs has been demonstrated in multiple cell lines and cancers, indicating tumor suppressive activities of DeltaNp63 in cell migration and invasion.	('DeltaNp63', 'Gene', (37, 46))	('cell adhesion', 'CPA', (54, 67))	('cancers', 'Phenotype', 'HP:0002664', (198, 205))	('tumor', 'Disease', 'MESH:D009369', (218, 223))	('motility', 'CPA', (72, 80))	('cancers', 'Disease', (198, 205))	('DeltaNp63', 'Var', (250, 259))	('cancers', 'Disease', 'MESH:D009369', (198, 205))	('DeltaNp63', 'Chemical', '-', (37, 46))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('cell migration', 'CPA', (263, 277))	('DeltaNp63', 'Chemical', '-', (250, 259))	('suppressive', 'NegReg', (13, 24))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('tumor', 'Disease', (218, 223))	('invasion', 'CPA', (282, 290))
394110	32312834	The most common mechanistic explanation for high p63 in these cancers is the amplification of chromosome 3q.	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('p63', 'Gene', (49, 52))	('amplification', 'Var', (77, 90))	('p63', 'Gene', '8626', (49, 52))	('cancers', 'Disease', 'MESH:D009369', (62, 69))	('cancers', 'Phenotype', 'HP:0002664', (62, 69))	('cancers', 'Disease', (62, 69))
394115	32312834	Activated TGFbeta signaling has been strongly associated with increased metastatic dissemination via induction of an EMT program in tumor cells.	('increased', 'PosReg', (62, 71))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('metastatic dissemination', 'CPA', (72, 96))	('TGFbeta', 'Protein', (10, 17))	('Activated', 'Var', (0, 9))	('tumor', 'Disease', (132, 137))	('EMT program', 'CPA', (117, 128))	('associated', 'Reg', (46, 56))
394119	32312834	The four TGFbeta-induced microRNAs identified as upstream regulators of DeltaNp63, including miR-22-3p, miR-30a-5p, miR-203a-3p and miR-222-3p, exhibit inhibitory effects on the protein expression of DeltaNp63.	('miR-22-3p', 'Gene', (93, 102))	('miR-222-3p', 'Chemical', '-', (132, 142))	('miR-222-3p', 'Var', (132, 142))	('inhibitory effects', 'MPA', (152, 170))	('protein expression', 'MPA', (178, 196))	('TGFbeta-induced', 'Gene', (9, 24))	('DeltaNp63', 'Gene', (72, 81))	('DeltaNp63', 'Chemical', '-', (72, 81))	('miR-30a', 'Gene', '407029', (104, 111))	('miR-22-3p', 'Gene', '407008', (93, 102))	('DeltaNp63', 'Chemical', '-', (200, 209))	('DeltaNp63', 'Gene', (200, 209))	('miR-30a', 'Gene', (104, 111))	('miR-203', 'Gene', (116, 123))	('miR-203', 'Gene', '406986', (116, 123))
394128	32312834	Conversely, miR-222-3p has been implicated as oncogenes in breast cancer metastasis by promoting EMT in basal-like breast cancer.	('breast cancer metastasis', 'Disease', 'MESH:D001943', (59, 83))	('miR-222-3p', 'Chemical', '-', (12, 22))	('miR-222-3p', 'Var', (12, 22))	('breast cancer', 'Disease', 'MESH:D001943', (59, 72))	('promoting', 'PosReg', (87, 96))	('breast cancer metastasis', 'Disease', (59, 83))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('EMT', 'CPA', (97, 100))	('breast cancer', 'Phenotype', 'HP:0003002', (59, 72))	('breast cancer', 'Disease', 'MESH:D001943', (115, 128))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('breast cancer', 'Disease', (115, 128))	('breast cancer', 'Phenotype', 'HP:0003002', (115, 128))
394145	30367574	The GDC portal publicly provides dataset of the following genomic experiments of more than 40 tumor types: DNA sequencing, Copy Number Variation, Somatic Mutations, DNA Methylation Gene Expression Quantification, and miRNA Expression Quantification.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('Copy Number Variation', 'Var', (123, 144))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Disease', (94, 99))	('Mutations', 'Var', (154, 163))	('GDC', 'Chemical', '-', (4, 7))
394149	30367574	Example of a logic formula or ("if then" rule) on gene expression data is the following "if ENSG00000167676.3 < 16.15 OR ENSG00000166819.10 < 15.28 then the sample can be classified as tumoral".	('ENSG00000167676.3', 'Var', (92, 109))	('tumoral', 'Disease', (185, 192))	('tumoral', 'Disease', 'MESH:D009369', (185, 192))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('ENSG00000166819.10 < 15.28', 'Var', (121, 147))
394182	30367574	Previous studies have already shown that mutations within this gene are possible causes of lung cancer (LUSC).	('mutations', 'Var', (41, 50))	('lung cancer', 'Phenotype', 'HP:0100526', (91, 102))	('causes', 'Reg', (81, 87))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('lung cancer', 'Disease', 'MESH:D008175', (91, 102))	('lung cancer', 'Disease', (91, 102))
394188	30367574	Similar observations can be made for the genes COL13A1 (ENSG00000197467.12), MRGBP (ENSG00000101189.6), and following.	('COL13A1', 'Gene', (47, 54))	('ENSG00000101189.6', 'Var', (84, 101))	('MRGBP', 'Gene', (77, 82))	('MRGBP', 'Gene', '55257', (77, 82))	('COL13A1', 'Gene', '1305', (47, 54))
394191	30367574	As the reader can see, the genes COLGALT1 (ENSG00000130309.9) and AC012531.25 (ENSG00000260597.1) is the most frequent couple that appears in the rules occurring 250 times.	('COLGALT1', 'Gene', '79709', (33, 41))	('ENSG00000260597.1', 'Var', (79, 96))	('COLGALT1', 'Gene', (33, 41))	('ENSG00000130309.9', 'Var', (43, 60))
394192	30367574	In particular, AC012531.25 is always extracted together with COLGALT1, because its number of occurrences as single gene is exactly 250.	('AC012531.25', 'Var', (15, 26))	('COLGALT1', 'Gene', '79709', (61, 69))	('COLGALT1', 'Gene', (61, 69))
394197	30367574	Existing studies on the GABRD gene confirm that alterations in its expression can play a key role in differentiating tumor cells.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('alterations', 'Var', (48, 59))	('tumor', 'Disease', (117, 122))	('play', 'Reg', (82, 86))	('GABRD', 'Gene', '2563', (24, 29))	('GABRD', 'Gene', (24, 29))	('expression', 'MPA', (67, 77))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
394205	30367574	We highlight that previous research confirms the relationship between the alteration of the expression of the first three most occurring genes - SPRY2 (ENSG00000136158.9), VEGFD (ENSG00000165197.4), and MMP11 (ENSG00000099953.8) - and the predisposition to Breast Cancer.	('ENSG00000136158.9', 'Var', (152, 169))	('alteration', 'Var', (74, 84))	('SPRY2', 'Gene', (145, 150))	('MMP11', 'Gene', '4320', (203, 208))	('Breast Cancer', 'Phenotype', 'HP:0003002', (257, 270))	('SPRY2', 'Gene', '10253', (145, 150))	('VEGFD', 'Gene', (172, 177))	('ENSG00000165197.4', 'Var', (179, 196))	('Breast Cancer', 'Disease', (257, 270))	('Breast Cancer', 'Disease', 'MESH:D001943', (257, 270))	('Cancer', 'Phenotype', 'HP:0002664', (264, 270))	('ENSG00000099953.8', 'Var', (210, 227))	('MMP11', 'Gene', (203, 208))	('VEGFD', 'Gene', '2277', (172, 177))
394285	28367236	In addition to environmental or life-style associated factors, family history of malignancy was traced in 26.4% in the current study, suggesting a potential role of gene mutations and polymorphisms in the development of MPC.	('malignancy', 'Disease', (81, 91))	('malignancy', 'Disease', 'MESH:D009369', (81, 91))	('MPC', 'Disease', (220, 223))	('polymorphisms', 'Var', (184, 197))	('MPC', 'Chemical', '-', (220, 223))
394300	28367236	Some authors figured out, even if the rate of radical resection of esophageal lesion was comparable, the presence of additional head and neck tumors was associated with a worse long-term prognosis.	('esophageal lesion', 'Disease', (67, 84))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('presence', 'Var', (105, 113))	('neck tumors', 'Disease', 'MESH:D006258', (137, 148))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))	('head and neck tumors', 'Phenotype', 'HP:0012288', (128, 148))	('neck tumors', 'Disease', (137, 148))	('esophageal lesion', 'Disease', 'MESH:D004935', (67, 84))
394312	28367236	Since low BMI has been identified as a significant inverse prognostic factor, how to reduce treatment toxicity became a vital question.	('toxicity', 'Disease', 'MESH:D064420', (102, 110))	('toxicity', 'Disease', (102, 110))	('low BMI', 'Phenotype', 'HP:0045082', (6, 13))	('low', 'Var', (6, 9))	('BMI', 'MPA', (10, 13))
394413	26160986	Furthermore, in a combined analysis, patients with low EphA7-expressing tumors showed a shorter overall survival than those with high expression, resulting in a five-year overall survival rate of 47.4% vs. 52.6%, respectively (p=0.016).	('shorter', 'NegReg', (88, 95))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('patients', 'Species', '9606', (37, 45))	('EphA7', 'Gene', '2045', (55, 60))	('tumors', 'Disease', (72, 78))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('overall survival', 'MPA', (96, 112))	('low', 'Var', (51, 54))	('EphA7', 'Gene', (55, 60))
394466	26160986	Significant association between low cytoplasmic EphA7 expression and lymph node metastasis was observed (rs=0.344; p<0.001).	('EphA7', 'Gene', '2045', (48, 53))	('low cytoplasmic', 'Var', (32, 47))	('EphA7', 'Gene', (48, 53))	('lymph node metastasis', 'CPA', (69, 90))
394471	26160986	The survival rate of patients with low EphA7 expression was significantly lower than in patients with high EphA7 expression (5-year survival rate 52.6% vs 47.4%, respectively; p=0.016; Fig.	('EphA7', 'Gene', (39, 44))	('EphA7', 'Gene', '2045', (107, 112))	('patients', 'Species', '9606', (88, 96))	('survival', 'CPA', (4, 12))	('patients', 'Species', '9606', (21, 29))	('EphA7', 'Gene', '2045', (39, 44))	('low', 'Var', (35, 38))	('lower', 'NegReg', (74, 79))	('EphA7', 'Gene', (107, 112))
394477	26160986	It has been reported that high EphA2 expression results in poor survival in ESCC.	('EphA2', 'Gene', (31, 36))	('high', 'Var', (26, 30))	('survival', 'MPA', (64, 72))	('EphA2', 'Gene', '1969', (31, 36))	('poor', 'NegReg', (59, 63))	('expression', 'MPA', (37, 47))	('ESCC', 'Disease', (76, 80))
394487	26160986	We speculate that the result was attributed to truncated EphA7 protein expression in esophageal cancer.	('esophageal cancer', 'Disease', 'MESH:D004938', (85, 102))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('EphA7', 'Gene', (57, 62))	('EphA7', 'Gene', '2045', (57, 62))	('truncated', 'Var', (47, 56))	('esophageal cancer', 'Disease', (85, 102))
394490	26160986	Previous studies demonstrated that high EphA7 expression was closely related to carcinogenesis, progression, clinical biological behaviors, and prognosis of glioblastoma multiforme and gallbladder adenocarcinoma.	('gallbladder adenocarcinoma', 'Disease', (185, 211))	('EphA7', 'Gene', '2045', (40, 45))	('glioblastoma multiforme', 'Disease', (157, 180))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (157, 180))	('glioblastoma', 'Phenotype', 'HP:0012174', (157, 169))	('EphA7', 'Gene', (40, 45))	('gallbladder adenocarcinoma', 'Disease', 'MESH:D005705', (185, 211))	('carcinoma', 'Phenotype', 'HP:0030731', (202, 211))	('carcinogenesis', 'Disease', 'MESH:D063646', (80, 94))	('expression', 'MPA', (46, 56))	('high', 'Var', (35, 39))	('related', 'Reg', (69, 76))	('carcinogenesis', 'Disease', (80, 94))
394494	26160986	Tyrosine phosphorylation of Eph/Eprin system promotes cellular transformation, invasion, proliferation, and also inhibits cellular spread or migration mediated via JAK2, PI3K or ILK signal transduction pathways.	('proliferation', 'CPA', (89, 102))	('Eph', 'Gene', '2041', (28, 31))	('JAK2', 'Gene', '3717', (164, 168))	('Tyrosine phosphorylation', 'Var', (0, 24))	('cellular spread', 'CPA', (122, 137))	('Eph', 'Gene', (28, 31))	('ILK', 'Gene', (178, 181))	('cellular transformation', 'CPA', (54, 77))	('promotes', 'PosReg', (45, 53))	('JAK2', 'Gene', (164, 168))	('Tyrosine', 'Chemical', 'MESH:D014443', (0, 8))	('ILK', 'Gene', '3611', (178, 181))	('invasion', 'CPA', (79, 87))	('inhibits', 'NegReg', (113, 121))
394495	26160986	However, downregulation of EphA7 resulting from methylation in human colorectal cancer leads to biological and histopathological effects associated with carcinogenesis and differentiation.	('downregulation', 'NegReg', (9, 23))	('carcinogenesis', 'Disease', (153, 167))	('EphA7', 'Gene', '2045', (27, 32))	('human', 'Species', '9606', (63, 68))	('colorectal cancer', 'Phenotype', 'HP:0003003', (69, 86))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('carcinogenesis', 'Disease', 'MESH:D063646', (153, 167))	('colorectal cancer', 'Disease', (69, 86))	('EphA7', 'Gene', (27, 32))	('colorectal cancer', 'Disease', 'MESH:D015179', (69, 86))	('methylation', 'Var', (48, 59))
394502	26100984	Large-scale transcriptional profiling studies in each cancer type have reported aberrant gene expression associated with cancer development.	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('cancer', 'Disease', (54, 60))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('aberrant', 'Var', (80, 88))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('cancer', 'Disease', (121, 127))
394508	26100984	Integrating genetic and epigenetic profiles found that deregulated RBPs were frequently caused by genetic rather than epigenetic alterations.	('RBP', 'Gene', (67, 70))	('caused by', 'Reg', (88, 97))	('RBP', 'Gene', '57794', (67, 70))	('deregulated', 'Var', (55, 66))
394510	26100984	Dysregulated transcription across cancer types reveals the importance of RBPs in carcinogenesis.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('carcinogenesis', 'Disease', 'MESH:D063646', (81, 95))	('transcription', 'MPA', (13, 26))	('carcinogenesis', 'Disease', (81, 95))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('cancer', 'Disease', (34, 40))	('Dysregulated', 'Var', (0, 12))	('RBP', 'Gene', (73, 76))	('RBP', 'Gene', '57794', (73, 76))
394511	26100984	The aberrant expression of RBPs is caused by genetic alterations and spreads their effect to cancer-related genes.	('caused by', 'Reg', (35, 44))	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('RBP', 'Gene', (27, 30))	('aberrant', 'Var', (4, 12))	('RBP', 'Gene', '57794', (27, 30))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('genetic alterations', 'Var', (45, 64))
394512	26100984	In addition, disruption of tissue-specific genes contributes to the corresponding cancer pathology.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('disruption', 'Var', (13, 23))	('tissue-specific genes', 'Gene', (27, 48))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))
394517	26100984	Compared to TFs, expression alteration of RNA-binding proteins (RBPs), master regulators at the post-transcriptional level, was less studied but deregulated transcriptions of several RBPs also have been reported to play a critical role in human cancers.	('cancers', 'Disease', 'MESH:D009369', (245, 252))	('cancers', 'Phenotype', 'HP:0002664', (245, 252))	('play', 'Reg', (215, 219))	('transcriptions', 'MPA', (157, 171))	('RBP', 'Gene', '57794', (64, 67))	('cancers', 'Disease', (245, 252))	('RBP', 'Gene', (183, 186))	('human', 'Species', '9606', (239, 244))	('cancer', 'Phenotype', 'HP:0002664', (245, 251))	('deregulated', 'Var', (145, 156))	('RBP', 'Gene', '57794', (183, 186))	('RBP', 'Gene', (64, 67))
394520	26100984	Additionally, aberrant expression of microRNAs (miRNAs) and long non-coding RNAs' (lncRNAs') also led to cancer development.	('microRNAs', 'Protein', (37, 46))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('long', 'Protein', (60, 64))	('aberrant expression', 'Var', (14, 33))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('led to', 'Reg', (98, 104))
394531	26100984	Mutations in COSMIC with frameshift, germline and missense mutations were also significantly changed across most cancer types, while those with large deletions, translocations and splicing mutations were not (Figure 1, Table 1).	('germline', 'Var', (37, 45))	('missense mutations', 'Var', (50, 68))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('changed', 'Reg', (93, 100))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('cancer', 'Disease', (113, 119))	('frameshift', 'Var', (25, 35))
394554	26100984	These results suggested that the aberrant expression of RBPs was caused by genetic alterations rather than epigenetic alterations.	('genetic alterations', 'Var', (75, 94))	('RBP', 'Gene', (56, 59))	('RBP', 'Gene', '57794', (56, 59))	('caused by', 'Reg', (65, 74))	('aberrant', 'Var', (33, 41))
394565	26100984	Dysregulated transcription of RBPs plays an important role in cancer development.	('RBP', 'Gene', '57794', (30, 33))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('transcription', 'MPA', (13, 26))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('Dysregulated', 'Var', (0, 12))	('RBP', 'Gene', (30, 33))
394574	26100984	Pairwise Spearman correlations were calculated between the copy number alterations/DNA methylation alterations and gene expression changes for differentially and non-differentially expressed RBPs.	('RBP', 'Gene', '57794', (191, 194))	('RBP', 'Gene', (191, 194))	('copy number alterations/DNA', 'Var', (59, 86))
394578	26100984	This work was supported by grants CCSG (P30 CA068485), BETRNet (U01 CA163056), Breast (P50 CA098131), and GI (P50 CA095103).	('U01', 'CellLine', 'CVCL:2220', (64, 67))	('P30', 'Gene', '201161', (40, 43))	('P50', 'Gene', (87, 90))	('P30', 'Gene', (40, 43))	('P50', 'Gene', (110, 113))	('U01 CA163056', 'Var', (64, 76))	('P50', 'Gene', '8874', (110, 113))	('P50', 'Gene', '8874', (87, 90))
394634	31143549	Several of studies have found that the mechanism underlying the tumor resistance to chemotherapeutic drugs is associated with complicated and varied cellular signaling pathways, in which, mutations in one or multiple molecules cause tumor cell invasion and drug resistance.	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('tumor', 'Disease', (64, 69))	('drug resistance', 'CPA', (257, 272))	('drug resistance', 'Phenotype', 'HP:0020174', (257, 272))	('tumor', 'Disease', (233, 238))	('cause', 'Reg', (227, 232))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('mutations', 'Var', (188, 197))	('tumor', 'Disease', 'MESH:D009369', (233, 238))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
394673	31143549	The results revealed that the expression of P5CR1 in lung adenocarcinoma was significantly higher in grade IIB-IIIB group than in grade IA-IIA group (P < 0.001), but no significant correlation was detected with gender, age, or tissue part (P > 0.05; Table 1).	('grade IIB-IIIB', 'Var', (101, 115))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (53, 72))	('expression', 'MPA', (30, 40))	('higher', 'PosReg', (91, 97))	('lung adenocarcinoma', 'Disease', (53, 72))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (53, 72))	('P5CR1', 'Gene', '5831', (44, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))	('P5CR1', 'Gene', (44, 49))
394693	31143549	The P5CRs-proline metabolic cycle reaction is not only closely associated with the body's tricarboxylic acid cycle, urea cycle, and pentose phosphate pathway, but it also plays a regulatory role in the proliferation and apoptosis of cells, as well as, skin, bone, brain, and other tissues' development and in the process of occurrence and development of oral, head and neck, lymphoma, and other tumors.	('lymphoma', 'Phenotype', 'HP:0002665', (375, 383))	('tumors', 'Disease', (395, 401))	('tumors', 'Phenotype', 'HP:0002664', (395, 401))	('P5CRs', 'Chemical', '-', (4, 9))	('tumors', 'Disease', 'MESH:D009369', (395, 401))	('P5CRs-proline', 'Var', (4, 17))	('pentose phosphate', 'Chemical', 'MESH:D010428', (132, 149))	('apoptosis', 'CPA', (220, 229))	('proline', 'Chemical', 'MESH:D011392', (10, 17))	('urea', 'Chemical', 'MESH:D014508', (116, 120))	('tricarboxylic acid', 'Chemical', 'MESH:D014233', (90, 108))	('lymphoma', 'Disease', (375, 383))	('lymphoma', 'Disease', 'MESH:D008223', (375, 383))	('tumor', 'Phenotype', 'HP:0002664', (395, 400))	('oral', 'Disease', (354, 358))
394697	31143549	Also, P5CRs may reduce the production of reactive oxygen species in the mitochondria through oxidative respiratory chain process involved in NADP+ to increase the survival rate of tumor cells.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('reduce', 'NegReg', (16, 22))	('P5CRs', 'Var', (6, 11))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('tumor', 'Disease', (180, 185))	('oxidative respiratory chain process', 'MPA', (93, 128))	('P5CRs', 'Chemical', '-', (6, 11))	('NADP+', 'Chemical', 'MESH:D009249', (141, 146))	('increase', 'PosReg', (150, 158))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (41, 64))
394703	31143549	The cell migration was detected by the scratch test, and the silencing of the PYCR1 gene did not affect the migration of lung adenocarcinoma cells significantly.	('lung adenocarcinoma', 'Disease', (121, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (121, 140))	('PYCR1', 'Gene', '5831', (78, 83))	('cell migration', 'CPA', (4, 18))	('silencing', 'Var', (61, 70))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (121, 140))	('PYCR1', 'Gene', (78, 83))
394711	31143549	Although the results of the study indicated that silencing of PYCR1 gene showed no significant effect on the migration of lung adenocarcinoma cells, while significantly promoted the invasiveness.	('promoted', 'PosReg', (169, 177))	('silencing', 'Var', (49, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('PYCR1', 'Gene', (62, 67))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (122, 141))	('PYCR1', 'Gene', '5831', (62, 67))	('lung adenocarcinoma', 'Disease', (122, 141))	('invasiveness', 'CPA', (182, 194))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (122, 141))
394719	31143549	This study demonstrated that silencing the PYCR1 gene can enhance the sensitivity to cisplatin that rendered PYCR1 as a promising candidate target for the treatment of lung adenocarcinoma.	('enhance', 'PosReg', (58, 65))	('PYCR1', 'Gene', (43, 48))	('PYCR1', 'Gene', (109, 114))	('silencing', 'Var', (29, 38))	('sensitivity to cisplatin', 'MPA', (70, 94))	('PYCR1', 'Gene', '5831', (43, 48))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (168, 187))	('PYCR1', 'Gene', '5831', (109, 114))	('carcinoma', 'Phenotype', 'HP:0030731', (178, 187))	('lung adenocarcinoma', 'Disease', (168, 187))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (168, 187))	('cisplatin', 'Chemical', 'MESH:D002945', (85, 94))
394735	28849037	Consequently, using NSCLC cell lines, it was demonstrated that the knockdown of IRF4 expression significantly reduced the cell proliferation rate and colony formation, whereas IRF4-overexpression significantly increased them.	('NSCLC', 'Disease', 'MESH:D002289', (20, 25))	('reduced', 'NegReg', (110, 117))	('knockdown', 'Var', (67, 76))	('colony formation', 'CPA', (150, 166))	('IRF4', 'Gene', '3662', (80, 84))	('IRF4', 'Gene', (80, 84))	('IRF4', 'Gene', '3662', (176, 180))	('IRF4', 'Gene', (176, 180))	('NSCLC', 'Phenotype', 'HP:0030358', (20, 25))	('NSCLC', 'Disease', (20, 25))	('cell proliferation rate', 'CPA', (122, 145))
394736	28849037	Notably, the IRF4 knockdown significantly decreased the expression levels of Notch1 and Notch2 mRNA, and phosphorylated protein kinase B (AKT), whereas IRF4 overexpression resulted in the opposite.	('knockdown', 'Var', (18, 27))	('protein kinase B', 'Gene', '2185', (120, 136))	('Notch1', 'Gene', '4851', (77, 83))	('decreased', 'NegReg', (42, 51))	('Notch2', 'Gene', '4853', (88, 94))	('AKT', 'Gene', '207', (138, 141))	('AKT', 'Gene', (138, 141))	('expression levels', 'MPA', (56, 73))	('IRF4', 'Gene', (152, 156))	('IRF4', 'Gene', '3662', (152, 156))	('protein kinase B', 'Gene', (120, 136))	('IRF4', 'Gene', '3662', (13, 17))	('phosphorylated', 'MPA', (105, 119))	('Notch1', 'Gene', (77, 83))	('IRF4', 'Gene', (13, 17))	('Notch2', 'Gene', (88, 94))
394752	28849037	In vitro experiments showed that IRF4 knockdown by shRNA significantly reduced cell proliferation and colony number of NSCLC cells; whereas IRF4 overexpression showed the absolutely opposite results.	('NSCLC', 'Disease', 'MESH:D002289', (119, 124))	('cell proliferation', 'CPA', (79, 97))	('NSCLC', 'Phenotype', 'HP:0030358', (119, 124))	('IRF4', 'Gene', '3662', (33, 37))	('reduced', 'NegReg', (71, 78))	('IRF4', 'Gene', (33, 37))	('IRF4', 'Gene', '3662', (140, 144))	('NSCLC', 'Disease', (119, 124))	('knockdown', 'Var', (38, 47))	('IRF4', 'Gene', (140, 144))
394768	28849037	Val1744, Cell Signaling, Danvers, MA), anti-Notch2 (1:500, cat.	('Val1744', 'Var', (0, 7))	('Notch2', 'Gene', (44, 50))	('Notch2', 'Gene', '4853', (44, 50))
394803	28849037	The IRF4 expression was significantly decreased by IRF4 knockdown in A549, which is determined by western blot analysis (Fig.	('IRF4', 'Gene', '3662', (51, 55))	('decreased', 'NegReg', (38, 47))	('IRF4', 'Gene', (51, 55))	('IRF4', 'Gene', (4, 8))	('IRF4', 'Gene', '3662', (4, 8))	('A549', 'CellLine', 'CVCL:0023', (69, 73))	('expression', 'MPA', (9, 19))	('knockdown', 'Var', (56, 65))
394804	28849037	3B, cell proliferation was significantly suppressed in A549 that with IRF4 knockdown in a time-dependent manner.	('IRF4', 'Gene', '3662', (70, 74))	('cell proliferation', 'CPA', (4, 22))	('IRF4', 'Gene', (70, 74))	('A549', 'CellLine', 'CVCL:0023', (55, 59))	('suppressed', 'NegReg', (41, 51))	('knockdown', 'Var', (75, 84))
394805	28849037	And IRF4 knockdown also markedly reduced the colony number in A549 cells (Fig.	('IRF4', 'Gene', '3662', (4, 8))	('knockdown', 'Var', (9, 18))	('IRF4', 'Gene', (4, 8))	('A549', 'CellLine', 'CVCL:0023', (62, 66))	('colony number in A549 cells', 'CPA', (45, 72))	('reduced', 'NegReg', (33, 40))
394807	28849037	3D) and the cell proliferation rate and colony number of LC-AI cells were markedly reduced by IRF4 knockdown (Fig.	('reduced', 'NegReg', (83, 90))	('IRF4', 'Gene', '3662', (94, 98))	('IRF4', 'Gene', (94, 98))	('knockdown', 'Var', (99, 108))	('cell proliferation rate', 'CPA', (12, 35))	('colony number', 'CPA', (40, 53))
394811	28849037	4A and B, IRF4 knockdown significantly decreased both the mRNA expression of Notch1 and Notch2 in A549 cells; whereas IRF4 overexpression markedly increased the mRNA expression of Notch1 and Notch2 in A549 cells.	('A549', 'CellLine', 'CVCL:0023', (98, 102))	('mRNA expression', 'MPA', (58, 73))	('IRF4', 'Gene', (118, 122))	('Notch2', 'Gene', (191, 197))	('IRF4', 'Gene', '3662', (10, 14))	('Notch2', 'Gene', '4853', (88, 94))	('mRNA expression', 'MPA', (161, 176))	('decreased', 'NegReg', (39, 48))	('increased', 'PosReg', (147, 156))	('IRF4', 'Gene', (10, 14))	('Notch2', 'Gene', '4853', (191, 197))	('Notch1', 'Gene', (180, 186))	('Notch1', 'Gene', '4851', (180, 186))	('Notch1', 'Gene', (77, 83))	('Notch1', 'Gene', '4851', (77, 83))	('knockdown', 'Var', (15, 24))	('A549', 'CellLine', 'CVCL:0023', (201, 205))	('IRF4', 'Gene', '3662', (118, 122))	('Notch2', 'Gene', (88, 94))
394813	28849037	Indeed, IRF4 knockdown significantly suppressed the protein expression of Notch1, Notch2 and phosphorylation of AKT (p-AKT) in A549 and LC-AI cells (Fig.	('Notch1', 'Gene', '4851', (74, 80))	('protein expression', 'MPA', (52, 70))	('Notch2', 'Gene', (82, 88))	('AKT', 'Gene', (119, 122))	('AKT', 'Gene', '207', (119, 122))	('AKT', 'Gene', (112, 115))	('AKT', 'Gene', '207', (112, 115))	('IRF4', 'Gene', '3662', (8, 12))	('Notch2', 'Gene', '4853', (82, 88))	('IRF4', 'Gene', (8, 12))	('Notch1', 'Gene', (74, 80))	('phosphorylation', 'MPA', (93, 108))	('knockdown', 'Var', (13, 22))	('A549', 'CellLine', 'CVCL:0023', (127, 131))	('suppressed', 'NegReg', (37, 47))
394815	28849037	Furthermore, A549 cells with IRF4 overexpression (IRF4) were treated with Notch pathway inhibitor MK-0752 (20 microM) or DMSO for 48 h. Western blotting was performed and the results showed that MK-0752 could significantly reverse the effect of IRF4 overexpressionon activation of Akt signaling in A549 cells (Fig.	('Notch', 'Gene', '31293', (74, 79))	('A549', 'CellLine', 'CVCL:0023', (13, 17))	('activation', 'PosReg', (267, 277))	('MK-0752', 'Chemical', 'MESH:C554093', (98, 105))	('Akt', 'Gene', '207', (281, 284))	('IRF4', 'Gene', '3662', (50, 54))	('IRF4', 'Gene', (50, 54))	('IRF4', 'Gene', '3662', (29, 33))	('Notch', 'Gene', (74, 79))	('IRF4', 'Gene', (29, 33))	('IRF4', 'Gene', '3662', (245, 249))	('MK-0752', 'Var', (195, 202))	('IRF4', 'Gene', (245, 249))	('MK-0752', 'Chemical', 'MESH:C554093', (195, 202))	('DMSO', 'Chemical', 'MESH:D004121', (121, 125))	('Akt', 'Gene', (281, 284))	('overexpressionon', 'PosReg', (250, 266))	('A549', 'CellLine', 'CVCL:0023', (298, 302))
394823	28849037	The cell proliferation rate and colony number of A549 and LC-AI were significantly declined when IRF4 expression was knocked down.	('expression', 'MPA', (102, 112))	('cell proliferation rate', 'CPA', (4, 27))	('A549', 'CellLine', 'CVCL:0023', (49, 53))	('IRF4', 'Gene', '3662', (97, 101))	('IRF4', 'Gene', (97, 101))	('knocked down', 'Var', (117, 129))	('declined', 'NegReg', (83, 91))
394833	28849037	In the cells with IRF4 overexpressed that treated with MK-0752, it showed the significant decreased cell proliferation rate and colony number as compared with cells treated with DMSO.	('IRF4', 'Gene', '3662', (18, 22))	('IRF4', 'Gene', (18, 22))	('cell proliferation rate', 'CPA', (100, 123))	('decreased', 'NegReg', (90, 99))	('colony number', 'CPA', (128, 141))	('DMSO', 'Chemical', 'MESH:D004121', (178, 182))	('MK-0752', 'Var', (55, 62))	('MK-0752', 'Chemical', 'MESH:C554093', (55, 62))
394835	28849037	Previous study indicated that low level of IRF4 is a common feature of CLL, and the deregulated IRF4-Notch axis may represent a major pathway in the molecular pathogenesis of CLL.	('Notch', 'Gene', '31293', (101, 106))	('CLL', 'Disease', (175, 178))	('IRF4', 'Gene', '3662', (96, 100))	('IRF4', 'Gene', (96, 100))	('deregulated', 'Var', (84, 95))	('CLL', 'Phenotype', 'HP:0005550', (71, 74))	('Notch', 'Gene', (101, 106))	('CLL', 'Disease', (71, 74))	('IRF4', 'Gene', '3662', (43, 47))	('IRF4', 'Gene', (43, 47))	('CLL', 'Phenotype', 'HP:0005550', (175, 178))
394894	27453804	A full immunohistochemical panel revealed the tumor to be p63, 34BE12, E-cadherin, pancytokeratin (PCK), and cytokeratin 5/6 (CK5/6)-positive.	('cytokeratin 5/6', 'Gene', '3852', (109, 124))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('p63', 'Gene', (58, 61))	('cytokeratin 5/6', 'Gene', (109, 124))	('E-cadherin', 'Gene', (71, 81))	('E-cadherin', 'Gene', '999', (71, 81))	('tumor', 'Disease', (46, 51))	('p63', 'Gene', '8626', (58, 61))	('34BE12', 'Var', (63, 69))	('CK5/6', 'Gene', '3852', (126, 131))	('CK5/6', 'Gene', (126, 131))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
394942	29286069	The raw data (CEL files) of GSE43580, GSE50081, GSE68793 and GSE33532 were downloaded from the Affymetrix Human Genome U133 Plus 2.0 Array platform (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GPL570).	('GSE50081', 'Var', (38, 46))	('GSE33532', 'Var', (61, 69))	('GSE43580', 'Var', (28, 36))	('Human', 'Species', '9606', (106, 111))
394952	29286069	Among the seven microarray datasets downloaded from the GEO, five datasets (GSE43580, GSE50081, GSE42127, GSE41271 and GSE68793) were included in the meta-analysis for DEGs following MetaQC analysis.	('GSE41271', 'Var', (106, 114))	('GSE68793', 'Var', (119, 127))	('eta', 'Gene', (151, 154))	('GSE43580', 'Var', (76, 84))	('eta', 'Gene', '1909', (184, 187))	('GSE42127', 'Var', (96, 104))	('eta', 'Gene', (184, 187))	('GSE50081', 'Var', (86, 94))	('eta', 'Gene', '1909', (151, 154))
394963	29286069	In addition, high expression of CAV1 has shown to be associated with poor prognosis in patients with NSCLC.	('high', 'Var', (13, 17))	('NSCLC', 'Disease', (101, 106))	('CAV1', 'Gene', '857', (32, 36))	('NSCLC', 'Disease', 'MESH:D002289', (101, 106))	('associated', 'Reg', (53, 63))	('patients', 'Species', '9606', (87, 95))	('CAV1', 'Gene', (32, 36))
394976	29286069	In addition, a high expression of NDRG1 may promote the progression of lung squamous cell carcinoma by upregulating vascular endothelial growth factor-A and interleukin-8/C-X-C-motif chemokine ligand 8.	('vascular endothelial growth factor-A', 'Gene', '7422', (116, 152))	('high expression', 'Var', (15, 30))	('promote', 'PosReg', (44, 51))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (76, 99))	('NDRG1', 'Gene', '10397', (34, 39))	('interleukin-8', 'Gene', (157, 170))	('C-X-C-motif chemokine ligand 8', 'Gene', (171, 201))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('vascular endothelial growth factor-A', 'Gene', (116, 152))	('upregulating', 'PosReg', (103, 115))	('C-X-C-motif chemokine ligand 8', 'Gene', '3576', (171, 201))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (71, 99))	('progression', 'CPA', (56, 67))	('NDRG1', 'Gene', (34, 39))	('lung squamous cell carcinoma', 'Disease', (71, 99))	('interleukin-8', 'Gene', '3576', (157, 170))
394983	29286069	Previous multivariate analysis revealed patients with high expression levels of INSR had shorter overall survival rates, compared with those with low expression levels.	('high expression levels', 'Var', (54, 76))	('overall survival', 'MPA', (97, 113))	('patients', 'Species', '9606', (40, 48))	('INSR', 'Gene', '3643', (80, 84))	('INSR', 'Gene', (80, 84))	('shorter', 'NegReg', (89, 96))
394984	29286069	A truncated version of RXR-alpha has been demonstrated to significantly contribute to the anchorage-independent growth of cancer cells by activation of the PI3K/AKT pathway.	('cancer', 'Disease', (122, 128))	('RXR-alpha', 'Gene', '6256', (23, 32))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('anchorage-independent growth', 'CPA', (90, 118))	('AKT', 'Gene', '207', (161, 164))	('RXR-alpha', 'Gene', (23, 32))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('contribute', 'Reg', (72, 82))	('truncated', 'Var', (2, 11))	('activation', 'PosReg', (138, 148))	('AKT', 'Gene', (161, 164))
395028	28854885	Studies were included if: they measured the accuracy of pleural NSE for differentiating MPE and BPE in humans; they presented sufficient data to calculate true positive (TP), false positive (FP), false negative (FN), and true negative (TN) rates, and they were published in English.	('false', 'Var', (196, 201))	('pleural NSE', 'Disease', (56, 67))	('TP', 'Chemical', '-', (170, 172))	('humans', 'Species', '9606', (103, 109))	('pleural NSE', 'Disease', 'MESH:D010995', (56, 67))
395033	28854885	Among patients with MPE, 101 had NSCLC (90, lung adenocarcinoma; 11, lung squamous cell carcinoma); 11, small cell lung carcinoma; 18, metastatic carcinoma; 5, lymphoma, and 1, malignant mesothelioma.	('NSCLC', 'Phenotype', 'HP:0030358', (33, 38))	('malignant mesothelioma', 'Disease', (177, 199))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('lung adenocarcinoma', 'Disease', (44, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('small cell lung carcinoma', 'Phenotype', 'HP:0030357', (104, 129))	('patients', 'Species', '9606', (6, 14))	('carcinoma', 'Disease', (88, 97))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (177, 199))	('carcinoma', 'Disease', 'MESH:D002277', (146, 155))	('carcinoma', 'Disease', (120, 129))	('lymphoma', 'Phenotype', 'HP:0002665', (160, 168))	('carcinoma', 'Phenotype', 'HP:0030731', (54, 63))	('carcinoma', 'Disease', (54, 63))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (44, 63))	('MPE', 'Var', (20, 23))	('SCLC', 'Phenotype', 'HP:0030357', (34, 38))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (44, 63))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (69, 97))	('carcinoma', 'Disease', 'MESH:D002277', (88, 97))	('carcinoma', 'Disease', 'MESH:D002277', (120, 129))	('small cell lung carcinoma', 'Disease', 'MESH:D055752', (104, 129))	('NSCLC', 'Disease', 'MESH:D002289', (33, 38))	('lymphoma', 'Disease', (160, 168))	('lymphoma', 'Disease', 'MESH:D008223', (160, 168))	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('carcinoma', 'Disease', 'MESH:D002277', (54, 63))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (177, 199))	('carcinoma', 'Disease', (146, 155))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (74, 97))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (69, 97))	('lung squamous cell carcinoma', 'Disease', (69, 97))	('NSCLC', 'Disease', (33, 38))	('small cell lung carcinoma', 'Disease', (104, 129))
395039	28854885	After adjusted by pleural protein, the patients with MPE remained have a higher levels of NSE in serum and pleural effusion than patients with BPE (Additional file 1: Fig.	('levels', 'MPA', (80, 86))	('patients', 'Species', '9606', (39, 47))	('patients', 'Species', '9606', (129, 137))	('NSE', 'Gene', '2026', (90, 93))	('pleural effusion', 'Disease', 'MESH:D010996', (107, 123))	('pleural effusion', 'Disease', (107, 123))	('pleural effusion', 'Phenotype', 'HP:0002202', (107, 123))	('MPE', 'Var', (53, 56))	('NSE', 'Gene', (90, 93))	('higher', 'PosReg', (73, 79))
395081	27517633	Base on the results of multi-phase study, we found that miR-324-3p was significantly up-regulated, whereas mir-1285 was significantly down-regulated in plasma of stage I LSCC patients compared to healthy controls.	('mir-1285', 'Var', (107, 115))	('down-regulated', 'NegReg', (134, 148))	('miR-324', 'Gene', '442898', (56, 63))	('stage I LSCC', 'Disease', (162, 174))	('patients', 'Species', '9606', (175, 183))	('miR-324', 'Gene', (56, 63))	('LSCC', 'Phenotype', 'HP:0030359', (170, 174))	('3p', 'Chemical', '-', (64, 66))	('up-regulated', 'PosReg', (85, 97))
395082	27517633	ROC analysis showed that AUC of miR-324-3p and miR-1285 were 0.79 and 0.85, respectively.	('miR-324', 'Gene', '442898', (32, 39))	('miR-1285', 'Var', (47, 55))	('miR-1285', 'Chemical', '-', (47, 55))	('miR-324', 'Gene', (32, 39))	('3p', 'Chemical', '-', (40, 42))
395103	27517633	After excluding low abundant miRNAs (Ct value > 37 and non-detectable in over 25% of samples), The 20 most significant dysregulated miRNAs (up-regulated: miR-105, miR-302a, miR-302c, miR-324-3p, miR-517b, miR-519a, miR-872, miR205, miR-628-5p, and miR-34a; down-regulated: miR-190, miR-10b#, miR-1255b, miR1260, miR1285, miR144#, miR151-3p, miR-27#, miR-942, and miR-656) were selected for further analysis.	('miR205', 'Gene', (224, 230))	('miR151', 'Gene', (330, 336))	('miR-517b', 'Gene', (195, 203))	('miR144', 'Gene', '406936', (321, 327))	('miR-656', 'Gene', '724026', (363, 370))	('miR-628', 'Gene', '693213', (232, 239))	('3p', 'Chemical', '-', (191, 193))	('miR144', 'Gene', (321, 327))	('miR-190', 'Gene', (273, 280))	('miR-302c', 'Gene', (173, 181))	('miR-302a', 'Gene', (163, 171))	('miR1260', 'Gene', '100302236', (303, 310))	('miR1260', 'Gene', (303, 310))	('miR-324', 'Gene', (183, 190))	('miR-27', 'Gene', '407018', (341, 347))	('miR205', 'Gene', '406988', (224, 230))	('miR-10b', 'Gene', (282, 289))	('miR-190', 'Gene', '406965', (273, 280))	('miR-302c', 'Gene', '442895', (173, 181))	('miR-34a', 'Gene', (248, 255))	('3p', 'Chemical', '-', (337, 339))	('miR-105', 'Var', (154, 161))	('miR-10b', 'Gene', '406903', (282, 289))	('miR-517b', 'Gene', '574483', (195, 203))	('miR-942', 'Gene', (350, 357))	('miR-34a', 'Gene', '407040', (248, 255))	('miR-324', 'Gene', '442898', (183, 190))	('miR-302a', 'Gene', '407028', (163, 171))	('miR-1255b', 'Var', (292, 301))	('miR151', 'Gene', '442893', (330, 336))	('miR1285', 'Var', (312, 319))	('miR-942', 'Gene', '100126331', (350, 357))	('miR-27', 'Gene', (341, 347))	('miR-656', 'Gene', (363, 370))	('miR-628', 'Gene', (232, 239))
395107	27517633	Thus, the remaining four miRNAs (miR-324-3p, miR-628-5p, miR-1285, and miR-302c) were selected for further evaluation.	('miR-1285', 'Var', (57, 65))	('3p', 'Chemical', '-', (41, 43))	('miR-1285', 'Chemical', '-', (57, 65))	('miR-302c', 'Gene', (71, 79))	('miR-628', 'Gene', (45, 52))	('miR-302c', 'Gene', '442895', (71, 79))	('miR-324', 'Gene', '442898', (33, 40))	('miR-628', 'Gene', '693213', (45, 52))	('miR-324', 'Gene', (33, 40))
395108	27517633	Compared to healthy controls, miR-324-3p was significantly up-regulated, whereas miR-1285 was significantly down-regulated in stage I LSCC patients (Figure 3).	('3p', 'Chemical', '-', (38, 40))	('up-regulated', 'PosReg', (59, 71))	('patients', 'Species', '9606', (139, 147))	('miR-1285', 'Var', (81, 89))	('miR-1285', 'Chemical', '-', (81, 89))	('miR-324', 'Gene', '442898', (30, 37))	('LSCC', 'Phenotype', 'HP:0030359', (134, 138))	('down-regulated', 'NegReg', (108, 122))	('stage I LSCC', 'Disease', (126, 138))	('miR-324', 'Gene', (30, 37))
395110	27517633	Since only plasma miR-324-3p and miR-1285 showed consistence expression pattern among TLDA set, training set and validation set, we focused on investigating these 2 miRNAs in the subsequent studies.	('miR-324', 'Gene', '442898', (18, 25))	('miR-1285', 'Chemical', '-', (33, 41))	('miR-1285', 'Var', (33, 41))	('miR-324', 'Gene', (18, 25))	('3p', 'Chemical', '-', (26, 28))
395111	27517633	Our data showed that the area under the curve (AUC) of miR-324-3p in the training set (Figure 4A) and validation set (Figure 4B) was 0.85 (95% confidence interval (CI) = 0.75 to 0.95; sensitivity = 83.3%, specificity = 83.3%) and 0.80 (95% CI = 0.69 to 0.91; sensitivity = 83.3%, specificity = 66.7%), respectively, while the AUC of miR-1285 in the training set (Figure 4C) and validation set (Figure 4D) was 0.93 (95% CI = 0.87 to 0.99; sensitivity = 90.0%, specificity = 86.7%) and 0.85 (95% CI= 0.74 to 0.96; sensitivity = 83.3%, specificity = 86.7%), respectively.	('miR-324', 'Gene', '442898', (55, 62))	('3p', 'Chemical', '-', (63, 65))	('miR-1285', 'Var', (333, 341))	('miR-1285', 'Chemical', '-', (333, 341))	('miR-324', 'Gene', (55, 62))
395113	27517633	The AUC of miR-324-3p (Figure 4G) and miR-1285 (Figure 4H) were 0.79 (95% CI = 0.73 to 0.86; sensitivity = 72.2%, specificity = 75.6%) and 0.85 (95% CI = 0.79 to 0.91; sensitivity = 86.5%, specificity = 77.5%), respectively.	('miR-1285', 'Chemical', '-', (38, 46))	('miR-324', 'Gene', (11, 18))	('3p', 'Chemical', '-', (19, 21))	('miR-1285', 'Var', (38, 46))	('miR-324', 'Gene', '442898', (11, 18))
395116	27517633	In addition, a significant difference in the expression levels of miRNA-324-3p and miR-1285 between LSCC and lung benign disease was observed.	('expression levels', 'MPA', (45, 62))	('lung benign disease', 'Disease', 'MESH:D008171', (109, 128))	('difference', 'Reg', (27, 37))	('3p', 'Chemical', '-', (76, 78))	('LSCC', 'Disease', (100, 104))	('miR-1285', 'Chemical', '-', (83, 91))	('lung benign disease', 'Disease', (109, 128))	('LSCC', 'Phenotype', 'HP:0030359', (100, 104))	('miR-1285', 'Var', (83, 91))	('miRNA-324-3p', 'Var', (66, 78))
395117	27517633	These results indicated that miR-324-3p and miR-1285 are indeed LSCC-specific.	('miR-1285', 'Var', (44, 52))	('miR-1285', 'Chemical', '-', (44, 52))	('LSCC', 'Phenotype', 'HP:0030359', (64, 68))	('LSCC-specific', 'Disease', (64, 77))	('miR-324', 'Gene', '442898', (29, 36))	('3p', 'Chemical', '-', (37, 39))	('miR-324', 'Gene', (29, 36))
395120	27517633	And no significant differences of plasma level of miR-1285 were observed in pancreatic cancer, thyroid cancer and colorectal cancer (Figure 6).	('miR-1285', 'Var', (50, 58))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('colorectal cancer', 'Disease', 'MESH:D015179', (114, 131))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('pancreatic cancer', 'Disease', (76, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('colorectal cancer', 'Phenotype', 'HP:0003003', (114, 131))	('pancreatic cancer', 'Disease', 'MESH:D010190', (76, 93))	('thyroid cancer', 'Disease', (95, 109))	('thyroid cancer', 'Phenotype', 'HP:0002890', (95, 109))	('colorectal cancer', 'Disease', (114, 131))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (76, 93))	('thyroid cancer', 'Disease', 'MESH:D013964', (95, 109))	('miR-1285', 'Chemical', '-', (50, 58))
395121	27517633	The discrepancy of the miR-324-3p and miR-1285 between cancer and control in these tumor types were inconsistent with those in LSCC.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('miR-324', 'Gene', (23, 30))	('3p', 'Chemical', '-', (31, 33))	('LSCC', 'Disease', (127, 131))	('tumor', 'Disease', (83, 88))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('LSCC', 'Phenotype', 'HP:0030359', (127, 131))	('miR-324', 'Gene', '442898', (23, 30))	('miR-1285', 'Var', (38, 46))	('miR-1285', 'Chemical', '-', (38, 46))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('cancer', 'Disease', (55, 61))
395122	27517633	Therefore, these results further supported the specificity of the changes of miR-324-3p and miR-1285 in early stage LSCC.	('miR-1285', 'Chemical', '-', (92, 100))	('miR-1285', 'Var', (92, 100))	('LSCC', 'Phenotype', 'HP:0030359', (116, 120))	('miR-324', 'Gene', '442898', (77, 84))	('changes', 'Reg', (66, 73))	('3p', 'Chemical', '-', (85, 87))	('miR-324', 'Gene', (77, 84))
395123	27517633	We examined the association of plasma levels of miR-324-3p and miR-1285 with clinical factors in early-stage LSCC.	('LSCC', 'Phenotype', 'HP:0030359', (109, 113))	('3p', 'Chemical', '-', (56, 58))	('miR-324', 'Gene', '442898', (48, 55))	('miR-1285', 'Chemical', '-', (63, 71))	('early-stage LSCC', 'Disease', (97, 113))	('miR-324', 'Gene', (48, 55))	('miR-1285', 'Var', (63, 71))
395126	27517633	The 90 patients were divided into high and low plasma levels of miR-324-3p or miR- 1285 groups using a cut-off point of the median expression value.	('miR-324', 'Gene', (64, 71))	('3p', 'Chemical', '-', (72, 74))	('miR-', 'Var', (78, 82))	('miR-324', 'Gene', '442898', (64, 71))	('patients', 'Species', '9606', (7, 15))
395131	27517633	Overall, 560 target genes were identified, 331 of which were targeted by miR-324-3p and 235 by miR-1285.	('miR-1285', 'Chemical', '-', (95, 103))	('miR-324', 'Gene', '442898', (73, 80))	('miR-1285', 'Var', (95, 103))	('miR-324', 'Gene', (73, 80))	('3p', 'Chemical', '-', (81, 83))
395134	27517633	These results indicated a potentially critical functional role of miR-324-3p and miR-1285 in the progression of lung cancer.	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('lung cancer', 'Disease', (112, 123))	('lung cancer', 'Phenotype', 'HP:0100526', (112, 123))	('miR-324', 'Gene', (66, 73))	('miR-1285', 'Var', (81, 89))	('miR-1285', 'Chemical', '-', (81, 89))	('lung cancer', 'Disease', 'MESH:D008175', (112, 123))	('3p', 'Chemical', '-', (74, 76))	('miR-324', 'Gene', '442898', (66, 73))
395140	27517633	However, our current study did not reveal some of the commonly reported dysregulated miRNAs in lung cancer, such as Let-7, miR-21, or miR-155.	('miR-21', 'Gene', (123, 129))	('lung cancer', 'Disease', (95, 106))	('miR-155', 'Gene', (134, 141))	('lung cancer', 'Phenotype', 'HP:0100526', (95, 106))	('Let-7', 'Var', (116, 121))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('lung cancer', 'Disease', 'MESH:D008175', (95, 106))	('miR-21', 'Gene', '406991', (123, 129))	('miR-155', 'Gene', '406947', (134, 141))
395142	27517633	In the subsequent three-stage validation, our current data showed that miR-324-3p and miR-1285 could be highly promising as diagnostic biomarkers for early stage LSCC.	('early', 'Disease', (150, 155))	('3p', 'Chemical', '-', (79, 81))	('miR-324', 'Gene', '442898', (71, 78))	('LSCC', 'Phenotype', 'HP:0030359', (162, 166))	('miR-1285', 'Chemical', '-', (86, 94))	('miR-324', 'Gene', (71, 78))	('miR-1285', 'Var', (86, 94))
395146	27517633	The results showed that altered levels of miR-324-3p and miR-1285 only occurred in the LSCC plasma.	('miR-1285', 'Var', (57, 65))	('miR-1285', 'Chemical', '-', (57, 65))	('miR-324', 'Gene', (42, 49))	('3p', 'Chemical', '-', (50, 52))	('LSCC', 'Phenotype', 'HP:0030359', (87, 91))	('miR-324', 'Gene', '442898', (42, 49))
395147	27517633	In addition, we also assessed the plasma expression of miR324-3p and mir-1285 in other tumor types including pancreatic cancer, thyroid cancer, colorectal cancer and breast cancer.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('thyroid cancer', 'Phenotype', 'HP:0002890', (128, 142))	('breast cancer', 'Disease', 'MESH:D001943', (166, 179))	('breast cancer', 'Disease', (166, 179))	('pancreatic cancer', 'Disease', (109, 126))	('colorectal cancer', 'Disease', 'MESH:D015179', (144, 161))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('3p', 'Chemical', '-', (62, 64))	('colorectal cancer', 'Disease', (144, 161))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (109, 126))	('thyroid cancer', 'Disease', (128, 142))	('tumor', 'Disease', (87, 92))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('mir-1285', 'Var', (69, 77))	('colorectal cancer', 'Phenotype', 'HP:0003003', (144, 161))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('miR324', 'Gene', '442898', (55, 61))	('thyroid cancer', 'Disease', 'MESH:D013964', (128, 142))	('pancreatic cancer', 'Disease', 'MESH:D010190', (109, 126))	('breast cancer', 'Phenotype', 'HP:0003002', (166, 179))	('miR324', 'Gene', (55, 61))
395148	27517633	The discrepancy of the miR-324-3p and miR-1285 between cancer and control in these tumor types were different from those in LSCC.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('miR-324', 'Gene', (23, 30))	('3p', 'Chemical', '-', (31, 33))	('tumor', 'Disease', (83, 88))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('LSCC', 'Disease', (124, 128))	('miR-324', 'Gene', '442898', (23, 30))	('miR-1285', 'Var', (38, 46))	('miR-1285', 'Chemical', '-', (38, 46))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('LSCC', 'Phenotype', 'HP:0030359', (124, 128))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('cancer', 'Disease', (55, 61))
395149	27517633	Thus, these results supported the specificity of the expression pattern of miR-324-3p and miR-1285 in early stage LSCC.	('miR-1285', 'Var', (90, 98))	('LSCC', 'Phenotype', 'HP:0030359', (114, 118))	('3p', 'Chemical', '-', (83, 85))	('miR-324', 'Gene', '442898', (75, 82))	('miR-324', 'Gene', (75, 82))	('miR-1285', 'Chemical', '-', (90, 98))
395153	27517633	The repression of PTPN14 could promote intrahepatic cholangiocarcinoma cell growth.	('PTPN14', 'Gene', (18, 24))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (39, 70))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('promote', 'PosReg', (31, 38))	('repression', 'Var', (4, 14))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (52, 70))	('PTPN14', 'Gene', '5784', (18, 24))	('intrahepatic cholangiocarcinoma', 'Disease', (39, 70))
333255	27517633	Dysregulation of TGF-beta signaling pathway is important in cancer progression and cell invasion.	('Dysregulation', 'Var', (0, 13))	('cell invasion', 'CPA', (83, 96))	('TGF-beta signaling pathway', 'Pathway', (17, 43))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('cancer', 'Disease', (60, 66))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
395160	27517633	found that high expression levels of VGEF-B is associated poor survival of LSCC patients.	('patients', 'Species', '9606', (80, 88))	('LSCC', 'Disease', (75, 79))	('LSCC', 'Phenotype', 'HP:0030359', (75, 79))	('high', 'Var', (11, 15))	('VGEF-B', 'Gene', (37, 43))	('survival', 'MPA', (63, 71))
395166	27517633	Moreover, they showed that miR-1285-3p could directly repress expression of JUN oncogene in HCC cells, indicating a potential tumor suppressor role of miR-1285-3p.	('miR-1285-3p', 'Var', (27, 38))	('JUN oncogene', 'Gene', (76, 88))	('expression', 'MPA', (62, 72))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('miR-1285', 'Chemical', '-', (151, 159))	('miR-1285', 'Chemical', '-', (27, 35))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('HCC', 'Phenotype', 'HP:0001402', (92, 95))	('3p', 'Chemical', '-', (160, 162))	('repress', 'NegReg', (54, 61))	('3p', 'Chemical', '-', (36, 38))	('tumor', 'Disease', (126, 131))
395167	27517633	However, the level of miR-1285 in bronchial lavage samples of lung cancer patients was up-regulated compared to those of patients with benign lung disease.	('benign lung disease', 'Disease', (135, 154))	('up-regulated', 'PosReg', (87, 99))	('miR-1285', 'Chemical', '-', (22, 30))	('lung disease', 'Phenotype', 'HP:0002088', (142, 154))	('patients', 'Species', '9606', (74, 82))	('miR-1285', 'Var', (22, 30))	('lung cancer', 'Phenotype', 'HP:0100526', (62, 73))	('lung cancer', 'Disease', (62, 73))	('benign lung disease', 'Disease', 'MESH:D008171', (135, 154))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('lung cancer', 'Disease', 'MESH:D008175', (62, 73))	('patients', 'Species', '9606', (121, 129))
395169	27517633	In summary, our current study identified plasma levels of miR-324-3p and miR-1285 as potential diagnostic biomarkers for early stage LSCC.	('3p', 'Chemical', '-', (66, 68))	('miR-324', 'Gene', (58, 65))	('LSCC', 'Disease', (133, 137))	('LSCC', 'Phenotype', 'HP:0030359', (133, 137))	('miR-324', 'Gene', '442898', (58, 65))	('miR-1285', 'Var', (73, 81))	('miR-1285', 'Chemical', '-', (73, 81))
395206	27883053	However, their DNA replication system malfunctions, often in cancer, and leaves de novo mutational signatures, furthermore copy number alterations (CNA) and loss of heterozygosity (LOH).	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('copy number alterations', 'Var', (123, 146))	('malfunctions', 'Reg', (38, 50))	('cancer', 'Disease', (61, 67))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('loss of', 'NegReg', (157, 164))
395271	27883053	We measured tITH of 11 time point data with first time point data (MCF10A), MCF10A-HRAS, XT1-XT8, M1 and M2, and compared with reported number of clones from original research (Fig.	('MCF10A', 'CellLine', 'CVCL:0598', (76, 82))	('MCF10A-HRAS', 'CellLine', 'CVCL:0598', (76, 87))	('MCF10A-HRAS', 'Var', (76, 87))	('XT1', 'Gene', (89, 92))	('MCF10A', 'CellLine', 'CVCL:0598', (67, 73))	('XT1', 'Gene', '64131', (89, 92))
395273	27883053	However, we observed the abrupt elevation of tITH between MCF10A-HRAS and XT1 (from 0.109 to 0.346).	('tITH', 'MPA', (45, 49))	('MCF10A-HRAS', 'Var', (58, 69))	('elevation', 'PosReg', (32, 41))	('XT1', 'Gene', (74, 77))	('XT1', 'Gene', '64131', (74, 77))	('MCF10A-HRAS', 'CellLine', 'CVCL:0598', (58, 69))
395275	27883053	The divergence of major clones occurred at MCF10A-HRAS   XT1, XT2   XT3, XT5   XT6, and XT8   M. tITH values steadily increased as the number of subclones increased (Fig.	('MCF10A-HRAS', 'Var', (43, 54))	('increased', 'PosReg', (118, 127))	('XT1', 'Gene', (57, 60))	('XT1', 'Gene', '64131', (57, 60))	('MCF10A-HRAS', 'CellLine', 'CVCL:0598', (43, 54))
395276	27883053	tITH increased at MCF10A-HRAS   XT1 (from 0.109 to 0.346), XT2   XT3 (from 0.349 to 0.350), XT5   XT6 (from 0.349 to 0.356) and XT8   M (from 0.358 to 0.384 at M1, and 0.371 at M2).	('XT1', 'Gene', (32, 35))	('MCF10A-HRAS', 'CellLine', 'CVCL:0598', (18, 29))	('XT1', 'Gene', '64131', (32, 35))	('increased', 'PosReg', (5, 14))	('XT8   M', 'Var', (128, 135))
395281	27883053	Cell cycle and central dogma related pathways such as Parkinson's disease, Ribosome, mRNA surveillance pathway, Cell cycle, and DNA replication were at the top of the positively correlated pathway list in HRAS mutated cell lines (Fig.	('mutated', 'Var', (210, 217))	('HRAS', 'Gene', '3265', (205, 209))	("Parkinson's disease", 'Disease', (54, 73))	("Parkinson's disease", 'Disease', 'MESH:D010300', (54, 73))	('mRNA surveillance pathway', 'Pathway', (85, 110))	('HRAS', 'Gene', (205, 209))	('Ribosome', 'Pathway', (75, 83))
395282	27883053	This finding was confirmed in a study that reports the central dogma and cell cycle related pathways became more heterogeneous as the mutated HRAS activated MAP kinase cascades downstream and effects on transcriptional control and cell growth.	('HRAS', 'Gene', '3265', (142, 146))	('transcriptional', 'MPA', (203, 218))	('effects', 'Reg', (192, 199))	('HRAS', 'Gene', (142, 146))	('mutated', 'Var', (134, 141))	('activated', 'PosReg', (147, 156))	('MAP kinase cascades downstream', 'Pathway', (157, 187))	('cell cycle related pathways', 'Pathway', (73, 100))
395291	27883053	In the original study, missense mutations on RAD54B and PMS1 were reported, and they were connected by direct edges to Fanconni anemia pathway in STRING PIN (PMS1-FAN1 and RAD51-RAD54B).	('missense mutations', 'Var', (23, 41))	('RAD54B', 'Gene', (178, 184))	('RAD51', 'Gene', (172, 177))	('PMS1', 'Gene', '5378', (158, 162))	('RAD54B', 'Gene', (45, 51))	('PIN', 'Gene', (153, 156))	('FAN1', 'Gene', (163, 167))	('PMS1', 'Gene', (56, 60))	('RAD51', 'Gene', '5888', (172, 177))	('PMS1', 'Gene', '5378', (56, 60))	('FAN1', 'Gene', '22909', (163, 167))	('PIN', 'Gene', '8655', (153, 156))	('Fanconni anemia', 'Disease', 'MESH:D000740', (119, 134))	('Fanconni anemia', 'Disease', (119, 134))	('anemia', 'Phenotype', 'HP:0001903', (128, 134))	('RAD54B', 'Gene', '25788', (178, 184))	('RAD54B', 'Gene', '25788', (45, 51))	('PMS1', 'Gene', (158, 162))
395333	33760127	The present study performed a series of experiments to investigate the impact of MIR4713HG on OTSCC and revealed that upregulation of MIR4713HG had a crucial role in promoting cell proliferation and metastasis of OTSCC cell lines both in vitro and in vivo.	('MIR4713HG', 'Var', (134, 143))	('upregulation', 'PosReg', (118, 130))	('MIR4713HG', 'Chemical', '-', (81, 90))	('promoting', 'PosReg', (166, 175))	('MIR4713HG', 'Chemical', '-', (134, 143))	('cell proliferation', 'CPA', (176, 194))	('metastasis', 'CPA', (199, 209))
395334	33760127	By applying bioinformatics analyses, micro RNA let-7c-5p was observed to physically bind with MIR4713HG, and the knockdown of let-7c-5p could counteract the influence of MIR4713HG on OTSCC.	('let-7c', 'Gene', '406885', (47, 53))	('let-7c', 'Gene', '406885', (126, 132))	('bind', 'Interaction', (84, 88))	('knockdown', 'Var', (113, 122))	('let-7c', 'Gene', (47, 53))	('let-7c', 'Gene', (126, 132))	('MIR4713HG', 'Chemical', '-', (170, 179))	('MIR4713HG', 'Chemical', '-', (94, 103))
395336	33760127	In conclusion, the present study demonstrated that lncRNA MIR4713HG acted as a pro-tumor factor facilitating cell proliferation and metastasis of OTSCC via affecting the let-7c-5p/TMC7 signaling pathway, which presents as a promising therapeutic target in OTSCC.	('cell proliferation', 'CPA', (109, 127))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('TMC7', 'Gene', '79905', (180, 184))	('OTSCC', 'Disease', (146, 151))	('facilitating', 'PosReg', (96, 108))	('lncRNA MIR4713HG', 'Var', (51, 67))	('tumor', 'Disease', (83, 88))	('metastasis', 'CPA', (132, 142))	('let-7c', 'Gene', (170, 176))	('MIR4713HG', 'Chemical', '-', (58, 67))	('let-7c', 'Gene', '406885', (170, 176))	('affecting', 'Reg', (156, 165))	('TMC7', 'Gene', (180, 184))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
395342	33760127	The present study investigated the expression levels of MIR4713HG in OSTCC tissues and cell lines, and evaluated its influence on cell proliferation, invasion, migration and tumorigenesis of OTSCC.	('tumor', 'Disease', (174, 179))	('migration', 'CPA', (160, 169))	('MIR4713HG', 'Var', (56, 65))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('MIR4713HG', 'Chemical', '-', (56, 65))	('influence', 'Reg', (117, 126))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))
395343	33760127	Furthermore, the interaction between MIR4713HG and let-7c-5p, and their downstream target genes were investigated.	('MIR4713HG', 'Chemical', '-', (37, 46))	('let-7c', 'Gene', (51, 57))	('MIR4713HG', 'Var', (37, 46))	('let-7c', 'Gene', '406885', (51, 57))
395345	33760127	MIR4713HG and let-7c-5p RNASeq data from OTSCC samples were downloaded from the Cancer Genome Atlas (TCGA) database (https://cancergenome.nih.gov/).	('MIR4713HG', 'Var', (0, 9))	('let-7c', 'Gene', (14, 20))	('MIR4713HG', 'Chemical', '-', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('let-7c', 'Gene', '406885', (14, 20))	('Cancer', 'Phenotype', 'HP:0002664', (80, 86))	('Cancer', 'Disease', (80, 86))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('Cancer', 'Disease', 'MESH:D009369', (80, 86))
395346	33760127	MIR4713HG and let-7c-5p were identified according to the Ensembl data-base (http://www.ensembl.org/index.html, version 89) The edgeR package was used to normalize gene expression of MIR4713HG and let-7c-5p in TSCC and normal tissues.	('let-7c', 'Gene', '406885', (196, 202))	('TSCC', 'Disease', (209, 213))	('let-7c', 'Gene', (14, 20))	('MIR4713HG', 'Chemical', '-', (0, 9))	('MIR4713HG', 'Var', (182, 191))	('let-7c', 'Gene', '406885', (14, 20))	('MIR4713HG', 'Chemical', '-', (182, 191))	('let-7c', 'Gene', (196, 202))
395383	33760127	The fragment of MIR4713HG containing the target sequence of let-7c-5p was amplified via RT-qPCR and then inserted into a pmirGLO vector (Promega Corporation) to form the wild-type MIR4713HG reporter vector (MIR4713HG-WT).	('MIR4713HG', 'Chemical', '-', (207, 216))	('MIR4713HG', 'Chemical', '-', (16, 25))	('let-7c', 'Gene', (60, 66))	('MIR4713HG', 'Chemical', '-', (180, 189))	('MIR4713HG', 'Var', (16, 25))	('let-7c', 'Gene', '406885', (60, 66))
395384	33760127	An additional expression vector was also constructed by inserting a mutated binding site and was termed MIR4713HG-mutated-type (MIR4713HG-MUT).	('MIR4713HG', 'Chemical', '-', (128, 137))	('binding', 'Interaction', (76, 83))	('MIR4713HG-mutated-type', 'Var', (104, 126))	('MIR4713HG', 'Chemical', '-', (104, 113))
395386	33760127	When the confluency reached ~80%, cells were co-transfected with MIR4713HG-WT or MIR4713HG-MUT and let-7c-5p mimics or the negative control at 37 C for 48 h using Lipofectamine  2000 (Invitrogen; Thermo Fisher Scientific, Inc.), in accordance with the manufacturer's protocol.	('MIR4713HG', 'Chemical', '-', (81, 90))	('MIR4713HG', 'Chemical', '-', (65, 74))	('let-7c', 'Gene', (99, 105))	('MIR4713HG-WT', 'Var', (65, 77))	('Lipofectamine  2000', 'Chemical', 'MESH:C086724', (163, 182))	('let-7c', 'Gene', '406885', (99, 105))	('MIR4713HG-MUT', 'Var', (81, 94))
395388	33760127	To test the binding specificity, the sequences that interact with the let-7c-5p seed sequence were mutated, and the mutant TMC7 3'-UTR was inserted into an equivalent luciferase reporter.	('TMC7', 'Gene', (123, 127))	('let-7c', 'Gene', (70, 76))	('let-7c', 'Gene', '406885', (70, 76))	('TMC7', 'Gene', '79905', (123, 127))	('mutant', 'Var', (116, 122))
395403	33760127	5174S; Cell Signaling Technology, Inc.), followed by incubation with horseradish peroxidase-conjugated secondary antibodies for 60 min at 37 C (both 1:500; product codes ab6789 or ab6721; both from Abcam).	('ab6789', 'Var', (170, 176))	('horseradish', 'Species', '3704', (69, 80))	('ab6721', 'Var', (180, 186))
395408	33760127	According to the RNA-sequencing data, the expression of MIR4713HG was significantly upregulated in OTSCC tissues compared with normal tissues and its expression was stage-dependent in OTSCC, indicating its potential role in tumor progression (Fig.	('expression', 'MPA', (150, 160))	('upregulated', 'PosReg', (84, 95))	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('expression', 'MPA', (42, 52))	('tumor', 'Disease', (224, 229))	('OTSCC', 'Disease', (99, 104))	('MIR4713HG', 'Var', (56, 65))	('MIR4713HG', 'Chemical', '-', (56, 65))	('OTSCC', 'Disease', (184, 189))	('tumor', 'Disease', 'MESH:D009369', (224, 229))
395409	33760127	To investigate the prognostic value of MIR4713HG, the present study extracted the expression data of MIR4713HG from 113 patients with OTSCC.The expression level of MIR4713HG was significantly higher in patients with OTSCC (Fig.	('MIR4713HG', 'Chemical', '-', (39, 48))	('MIR4713HG', 'Var', (164, 173))	('MIR4713HG', 'Chemical', '-', (164, 173))	('OTSCC', 'Disease', (216, 221))	('higher', 'PosReg', (192, 198))	('patients', 'Species', '9606', (202, 210))	('patients', 'Species', '9606', (120, 128))	('MIR4713HG', 'Chemical', '-', (101, 110))	('expression level', 'MPA', (144, 160))
395410	33760127	Furthermore, the high expression of MIR4713HG indicated an unfavorable prognosis in OTSCC (Fig.	('MIR4713HG', 'Var', (36, 45))	('OTSCC', 'Disease', (84, 89))	('MIR4713HG', 'Chemical', '-', (36, 45))
395411	33760127	To confirm the online data, the present study performed RT-PCR in order to determine the expression level of MIR4713HG in 20 paired OTSCC and adjacent non-tumor tissues (Fig.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('MIR4713HG', 'Var', (109, 118))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('MIR4713HG', 'Chemical', '-', (109, 118))	('tumor', 'Disease', (155, 160))
395412	33760127	Additionally, the present study also examined the expression levels of MIR4713HG in multiple OTSCC cell lines (CAL-27, SCC-9, SCC-4, SCC-15 and SCC-25) and HPLF cell line.	('examined', 'Reg', (37, 45))	('HPLF', 'Disease', 'None', (156, 160))	('MIR4713HG', 'Chemical', '-', (71, 80))	('SCC-4', 'CellLine', 'CVCL:1684', (126, 131))	('SCC-9', 'CellLine', 'CVCL:1685', (119, 124))	('HPLF', 'Disease', (156, 160))	('MIR4713HG', 'Var', (71, 80))
395413	33760127	It was revealed that the expression of MIR4713HG was significantly increased in OTSCC cell lines as well (Fig.	('MIR4713HG', 'Chemical', '-', (39, 48))	('expression', 'MPA', (25, 35))	('increased', 'PosReg', (67, 76))	('OTSCC', 'Disease', (80, 85))	('MIR4713HG', 'Var', (39, 48))
395414	33760127	The differential expression of MIR4713HG in OTSCC and adjacent non-tumor tissues suggests that MIR4713HG may have an important role in the progression of OTSCC.	('MIR4713HG', 'Var', (95, 104))	('MIR4713HG', 'Chemical', '-', (95, 104))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('OTSCC', 'Disease', (154, 159))	('MIR4713HG', 'Var', (31, 40))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('MIR4713HG', 'Chemical', '-', (31, 40))	('tumor', 'Disease', (67, 72))
395415	33760127	To further investigate the regulating role of MIR4713HG in OTSCC, the present study performed a series of malignancy-associated experiments on CAL-27 and SCC-9 cell lines.	('malignancy', 'Disease', (106, 116))	('SCC-9', 'CellLine', 'CVCL:1685', (154, 159))	('OTSCC', 'Disease', (59, 64))	('MIR4713HG', 'Var', (46, 55))	('MIR4713HG', 'Chemical', '-', (46, 55))	('malignancy', 'Disease', 'MESH:D009369', (106, 116))
395416	33760127	First, the present study constructed MIR4713HG-overexpressing/knockdown cell lines via pcDNA-MIR4713HG and sh-MIR4713HG, respectively.	('MIR4713HG', 'Chemical', '-', (37, 46))	('sh-MIR4713HG', 'Chemical', '-', (107, 119))	('MIR4713HG-overexpressing/knockdown', 'Var', (37, 71))	('pcDNA-MIR4713HG', 'Var', (87, 102))	('MIR4713HG', 'Chemical', '-', (110, 119))	('sh-MIR4713HG', 'Var', (107, 119))	('MIR4713HG', 'Chemical', '-', (93, 102))
395417	33760127	The expression of MIR4713HG was significantly upregulated/downregulated in constructed cell lines (Fig.	('MIR4713HG', 'Var', (18, 27))	('expression', 'MPA', (4, 14))	('MIR4713HG', 'Chemical', '-', (18, 27))	('upregulated/downregulated', 'NegReg', (46, 71))	('upregulated/downregulated', 'PosReg', (46, 71))
395418	33760127	MTT assays were performed to assess the effect of MIR4713HG expression level on OTSCC cell proliferation.	('MIR4713HG', 'Chemical', '-', (50, 59))	('OTSCC', 'Disease', (80, 85))	('MIR4713HG', 'Var', (50, 59))	('MTT', 'Chemical', 'MESH:C070243', (0, 3))
395419	33760127	After 72 h of observation, the present study clearly identified that the overexpression of MIR4713HG improved the OTSCC cell proliferation rate, and the administration of sh-MIR4713HG achieved the exact opposite effect (Fig.	('MIR4713HG', 'Chemical', '-', (91, 100))	('MIR4713HG', 'Chemical', '-', (174, 183))	('OTSCC cell proliferation rate', 'CPA', (114, 143))	('improved', 'PosReg', (101, 109))	('sh-MIR4713HG', 'Chemical', '-', (171, 183))	('overexpression', 'PosReg', (73, 87))	('MIR4713HG', 'Var', (91, 100))
395420	33760127	In the colony formation assay, MIR4713HG-overexpressing OTSCC cells formed more clones on the culture dish after 14 days compared with the control group, while the clonogenicity of OTSCC cells was compromised after MIR4713HG-knockdown (Fig.	('MIR4713HG', 'Chemical', '-', (215, 224))	('MIR4713HG-overexpressing', 'Var', (31, 55))	('MIR4713HG-knockdown', 'Var', (215, 234))	('more', 'PosReg', (75, 79))	('MIR4713HG', 'Chemical', '-', (31, 40))	('clones on the', 'CPA', (80, 93))
395422	33760127	In the EdU cell proliferation assay, the staining intensity was significantly stronger in MIR4713HG-overexpressing OTSCC cells and weaker in MIR4713HG-knockdown OTSCC cells, confirming the positive effect of MIR4713HG on OTSCC growth (Fig.	('staining intensity', 'MPA', (41, 59))	('stronger', 'PosReg', (78, 86))	('MIR4713HG-overexpressing', 'Var', (90, 114))	('MIR4713HG', 'Chemical', '-', (90, 99))	('MIR4713HG', 'Chemical', '-', (141, 150))	('EdU', 'Chemical', '-', (7, 10))	('weaker', 'NegReg', (131, 137))	('MIR4713HG', 'Chemical', '-', (208, 217))
395424	33760127	To evaluate the regulatory role of MIR4713HG in cellular migration and metastasis in OTSCC, the present study performed a wound healing assay and Transwell assay.	('MIR4713HG', 'Var', (35, 44))	('OTSCC', 'Disease', (85, 90))	('MIR4713HG', 'Chemical', '-', (35, 44))
395425	33760127	The wound healing results revealed that the overexpression of MIR4713HG accelerated the migration rate of OTSCC cells while the downregulation of MIR4713HG slowed down the migration rate (Fig.	('MIR4713HG', 'Var', (62, 71))	('migration rate', 'CPA', (88, 102))	('overexpression', 'PosReg', (44, 58))	('MIR4713HG', 'Chemical', '-', (62, 71))	('MIR4713HG', 'Var', (146, 155))	('MIR4713HG', 'Chemical', '-', (146, 155))	('accelerated', 'PosReg', (72, 83))	('migration rate', 'CPA', (172, 186))	('slowed down', 'NegReg', (156, 167))	('downregulation', 'NegReg', (128, 142))
395426	33760127	The Transwell assay results indicated that MIR4713HG was a contributing factor in OTSCC metastasis, as overexpression of MIR4713HG improved the invasion rate of OTSCC cells, while the downregulation of MIR4713HG decreased the invasion rate (Fig.	('decreased', 'NegReg', (212, 221))	('MIR4713HG', 'Chemical', '-', (43, 52))	('OTSCC', 'Disease', (82, 87))	('invasion rate', 'CPA', (226, 239))	('invasion rate', 'CPA', (144, 157))	('MIR4713HG', 'Chemical', '-', (202, 211))	('MIR4713HG', 'Var', (121, 130))	('improved', 'PosReg', (131, 139))	('overexpression', 'PosReg', (103, 117))	('MIR4713HG', 'Chemical', '-', (121, 130))	('downregulation', 'NegReg', (184, 198))
395427	33760127	To further investigate the impact of MIR4713HG on the tumorigenicity of OTSCC in vivo, 12 nude mice were injected with transfected OTSCC cells (6 sh-MIR4713HG mice and 6 sh-NC mice).	('MIR4713HG', 'Chemical', '-', (37, 46))	('mice', 'Species', '10090', (95, 99))	('sh-MIR4713HG', 'Chemical', '-', (146, 158))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('mice', 'Species', '10090', (176, 180))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('sh-MIR4713HG', 'Var', (146, 158))	('mice', 'Species', '10090', (159, 163))	('tumor', 'Disease', (54, 59))	('MIR4713HG', 'Chemical', '-', (149, 158))	('nude mice', 'Species', '10090', (90, 99))
395430	33760127	The volume of tumors in the sh-MIR4713HG group was smaller than that of the sh-NC group (Fig.	('sh-MIR4713HG', 'Chemical', '-', (28, 40))	('sh-MIR4713HG', 'Var', (28, 40))	('smaller', 'NegReg', (51, 58))	('tumors', 'Disease', (14, 20))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
395431	33760127	The tumor weight was decreased in the sh-MIR4713HG group compared with the sh-NC group (Fig.	('tumor', 'Disease', (4, 9))	('decreased', 'NegReg', (21, 30))	('sh-MIR4713HG', 'Var', (38, 50))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('sh-MIR4713HG', 'Chemical', '-', (38, 50))
395434	33760127	The knockdown of MIR4713HG increased the expression levels of E-cadherin and suppressed the expression of vimentin (Fig.	('suppressed', 'NegReg', (77, 87))	('vimentin', 'Gene', (106, 114))	('expression levels', 'MPA', (41, 58))	('E-cadherin', 'Gene', '999', (62, 72))	('increased', 'PosReg', (27, 36))	('MIR4713HG', 'Var', (17, 26))	('MIR4713HG', 'Chemical', '-', (17, 26))	('vimentin', 'Gene', '7431', (106, 114))	('E-cadherin', 'Gene', (62, 72))	('expression', 'MPA', (92, 102))
395435	33760127	4D and E), suggesting that MIR4713HG affects the metastatic process of OTSCC via accelerating EMT.	('EMT', 'CPA', (94, 97))	('accelerating', 'PosReg', (81, 93))	('MIR4713HG', 'Var', (27, 36))	('affects', 'Reg', (37, 44))	('metastatic process', 'CPA', (49, 67))	('MIR4713HG', 'Chemical', '-', (27, 36))
395437	33760127	Macroscopically, the mice injected with MIR4713HG-knockdown OTSCC cells exhibited statistically less lung metastasis than the control mice (Fig.	('OTSCC', 'Gene', (60, 65))	('MIR4713HG', 'Chemical', '-', (40, 49))	('mice', 'Species', '10090', (134, 138))	('MIR4713HG-knockdown', 'Var', (40, 59))	('mice', 'Species', '10090', (21, 25))	('lung metastasis', 'CPA', (101, 116))	('less', 'NegReg', (96, 100))
395438	33760127	In addition, the expression of MIR4713HG was downregulated in the subcutaneous tumor tissue transfected with sh-MIR4173HG (Fig.	('sh-MIR4173HG', 'Var', (109, 121))	('tumor', 'Disease', (79, 84))	('expression', 'MPA', (17, 27))	('MIR4713HG', 'Var', (31, 40))	('downregulated', 'NegReg', (45, 58))	('MIR4713HG', 'Chemical', '-', (31, 40))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('subcutaneous tumor', 'Phenotype', 'HP:0001482', (66, 84))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
395439	33760127	Using publicly available DIANA Tools, the present study successfully observed let-7c-5p directly binding with MIR4713HG (Fig.	('MIR4713HG', 'Var', (110, 119))	('binding', 'Interaction', (97, 104))	('MIR4713HG', 'Chemical', '-', (110, 119))	('let-7c', 'Gene', (78, 84))	('let-7c', 'Gene', '406885', (78, 84))
395440	33760127	To test the direct binding of let-7c-5p to MIR4713HG, a luciferase reporter assay was performed as previously described.	('MIR4713HG', 'Chemical', '-', (43, 52))	('MIR4713HG', 'Var', (43, 52))	('let-7c', 'Gene', (30, 36))	('binding', 'Interaction', (19, 26))	('let-7c', 'Gene', '406885', (30, 36))
395442	33760127	Furthermore, the present study introduced point mutations into the corresponding sites in MIR4713HG to eliminate the predicted let-7c-5p binding sites.	('let-7c', 'Gene', '406885', (127, 133))	('point mutations', 'Var', (42, 57))	('MIR4713HG', 'Var', (90, 99))	('MIR4713HG', 'Chemical', '-', (90, 99))	('let-7c', 'Gene', (127, 133))	('eliminate', 'NegReg', (103, 112))
395444	33760127	According to the RT-PCR results, the expression of let-7c-5p increased after MIR4713HG knockdown and decreased after MIR4713HG overexpression (Fig.	('MIR4713HG', 'Chemical', '-', (77, 86))	('let-7c', 'Gene', (51, 57))	('decreased', 'NegReg', (101, 110))	('MIR4713HG knockdown', 'Var', (77, 96))	('MIR4713HG', 'Var', (117, 126))	('let-7c', 'Gene', '406885', (51, 57))	('increased', 'PosReg', (61, 70))	('overexpression', 'PosReg', (127, 141))	('MIR4713HG', 'Chemical', '-', (117, 126))	('expression', 'MPA', (37, 47))	('knockdown', 'Var', (87, 96))
395446	33760127	The expression of let-7c-5p was negatively correlated with MIR4713HG (Fig.	('MIR4713HG', 'Var', (59, 68))	('let-7c', 'Gene', (18, 24))	('MIR4713HG', 'Chemical', '-', (59, 68))	('expression', 'MPA', (4, 14))	('let-7c', 'Gene', '406885', (18, 24))	('negatively', 'NegReg', (32, 42))
395449	33760127	MIR4713HG overexpression significantly improved cell proliferation and let-7c-5p mimics suppressed the cell viability and clonogenicity compared with the NC group.	('MIR4713HG', 'Var', (0, 9))	('MIR4713HG', 'Chemical', '-', (0, 9))	('let-7c', 'Gene', (71, 77))	('cell proliferation', 'CPA', (48, 66))	('let-7c', 'Gene', '406885', (71, 77))	('suppressed', 'NegReg', (88, 98))	('improved', 'PosReg', (39, 47))
395450	33760127	The let-7c-5p mimics partially rescued the stimulative effects of MIR4713HG overexpression on OTSCC cell proliferation (Fig.	('let-7c', 'Gene', '406885', (4, 10))	('MIR4713HG', 'Var', (66, 75))	('MIR4713HG', 'Chemical', '-', (66, 75))	('OTSCC cell proliferation', 'CPA', (94, 118))	('let-7c', 'Gene', (4, 10))
395451	33760127	The addition of let-7c-5p mimics partially rescued the improved metastatic potential of OTSCC cells induced by MIR4713HG overexpression compared with pcDNA-MIR4713HG group (Fig.	('improved', 'PosReg', (55, 63))	('MIR4713HG', 'Var', (111, 120))	('let-7c', 'Gene', (16, 22))	('metastatic potential of', 'CPA', (64, 87))	('MIR4713HG', 'Chemical', '-', (111, 120))	('let-7c', 'Gene', '406885', (16, 22))	('MIR4713HG', 'Chemical', '-', (156, 165))
395454	33760127	According to the results of the luciferase reporter assay, the administration of let-7c-5p mimics resulted in a reduction of luciferase reporter activity compared with the control group, and the introduction of point mutations into TMC7 eliminated the predicted let-7c-5p binding sites (Fig.	('point mutations', 'Var', (211, 226))	('let-7c', 'Gene', (262, 268))	('let-7c', 'Gene', '406885', (262, 268))	('TMC7', 'Gene', '79905', (232, 236))	('eliminated', 'NegReg', (237, 247))	('reduction', 'NegReg', (112, 121))	('let-7c', 'Gene', (81, 87))	('binding', 'Interaction', (272, 279))	('let-7c', 'Gene', '406885', (81, 87))	('TMC7', 'Gene', (232, 236))	('luciferase', 'Enzyme', (125, 135))
395461	33760127	The overexpression of MIR4713HG significantly increased the expression of TMC7, while the knockdown of MIR4713HG suppressed the expression of TMC7 and both effects were counteracted by let-7c-5p mimics and inhibitor, respectively (Fig.	('expression', 'MPA', (60, 70))	('suppressed', 'NegReg', (113, 123))	('TMC7', 'Gene', (74, 78))	('let-7c', 'Gene', '406885', (185, 191))	('increased', 'PosReg', (46, 55))	('TMC7', 'Gene', '79905', (74, 78))	('MIR4713HG', 'Chemical', '-', (22, 31))	('TMC7', 'Gene', (142, 146))	('MIR4713HG', 'Var', (103, 112))	('MIR4713HG', 'Chemical', '-', (103, 112))	('expression', 'MPA', (128, 138))	('MIR4713HG', 'Var', (22, 31))	('TMC7', 'Gene', '79905', (142, 146))	('let-7c', 'Gene', (185, 191))
395462	33760127	Based on TCGA database, the expression of TMC7 was positively correlated with MIR4713HG in OTSCC tumors and its expression pattern was confirmed in 20 paired OTSCC tumor and adjacent non-tumor tissues (Fig.	('tumor', 'Disease', (164, 169))	('tumor', 'Disease', (187, 192))	('tumors', 'Disease', (97, 103))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('MIR4713HG', 'Var', (78, 87))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('tumor', 'Disease', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('tumors', 'Disease', 'MESH:D009369', (97, 103))	('MIR4713HG', 'Chemical', '-', (78, 87))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('OTSCC', 'Disease', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('correlated', 'Reg', (62, 72))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('expression', 'MPA', (28, 38))	('TMC7', 'Gene', (42, 46))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('TMC7', 'Gene', '79905', (42, 46))
395465	33760127	It was revealed that the knockdown of TMC7 could reverse the improved cell proliferation and clonogenicity in OTSCC induced by MIR4713HG overexpression (Fig.	('improved', 'PosReg', (61, 69))	('MIR4713HG', 'Var', (127, 136))	('MIR4713HG', 'Chemical', '-', (127, 136))	('TMC7', 'Gene', (38, 42))	('cell proliferation', 'CPA', (70, 88))	('clonogenicity', 'CPA', (93, 106))	('overexpression', 'PosReg', (137, 151))	('TMC7', 'Gene', '79905', (38, 42))	('OTSCC', 'Disease', (110, 115))	('knockdown', 'Var', (25, 34))
395466	33760127	In the wound healing assay, the improved cell migration ability induced by MIR4713HG overexpression was counteracted by TMC7 knockdown (Fig.	('MIR4713HG', 'Var', (75, 84))	('TMC7', 'Gene', (120, 124))	('MIR4713HG', 'Chemical', '-', (75, 84))	('improved', 'PosReg', (32, 40))	('TMC7', 'Gene', '79905', (120, 124))	('cell migration ability', 'CPA', (41, 63))
395467	33760127	In addition, according to the western blotting results, the overexpression of MIR4713HG accelerated the EMT process in OTSCC, while TMC7 knockdown reversed this effect (Fig.	('MIR4713HG', 'Chemical', '-', (78, 87))	('TMC7', 'Gene', '79905', (132, 136))	('accelerated', 'PosReg', (88, 99))	('overexpression', 'PosReg', (60, 74))	('EMT process', 'CPA', (104, 115))	('TMC7', 'Gene', (132, 136))	('MIR4713HG', 'Var', (78, 87))
395475	33760127	The present study first revealed that MIR4713HG was upregulated in OTSCC tissues and exhibited itself as an unfavorable prognostic factor in OTSCC patients.	('OTSCC', 'Disease', (67, 72))	('MIR4713HG', 'Var', (38, 47))	('MIR4713HG', 'Chemical', '-', (38, 47))	('upregulated', 'PosReg', (52, 63))	('patients', 'Species', '9606', (147, 155))	('OTSCC', 'Disease', (141, 146))
395476	33760127	To further investigate the function of MIR4713HG, the present study performed gain- or loss-of-function experiments by transfecting OTSCC cell lines with MIR4713HG-overexpressing plasmid or sh-MIR4713HG.	('MIR4713HG', 'Chemical', '-', (39, 48))	('MIR4713HG', 'Chemical', '-', (193, 202))	('MIR4713HG', 'Chemical', '-', (154, 163))	('sh-MIR4713HG', 'Chemical', '-', (190, 202))	('MIR4713HG-overexpressing', 'PosReg', (154, 178))	('MIR4713HG-overexpressing', 'Var', (154, 178))	('sh-MIR4713HG', 'Var', (190, 202))
395477	33760127	The results revealed that MIR4713HG positively regulated the proliferation and clonogenicity of OTSCC cells.	('MIR4713HG', 'Chemical', '-', (26, 35))	('regulated', 'Reg', (47, 56))	('clonogenicity of', 'CPA', (79, 95))	('proliferation', 'CPA', (61, 74))	('MIR4713HG', 'Var', (26, 35))
395478	33760127	Furthermore, in the wound healing and Transwell assays, it was revealed that the upregulation of MIR4713HG was correlated with improved migration and metastasis of OTSCC cells.	('MIR4713HG', 'Var', (97, 106))	('OTSCC', 'Disease', (164, 169))	('upregulation', 'PosReg', (81, 93))	('metastasis', 'CPA', (150, 160))	('migration', 'CPA', (136, 145))	('MIR4713HG', 'Chemical', '-', (97, 106))	('improved', 'PosReg', (127, 135))
395479	33760127	To test the tumor regulating role of MIR4713HG in vivo, the present study constructed xenograft tumor mouse models and lung metastasis mouse models.	('MIR4713HG', 'Chemical', '-', (37, 46))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('tumor', 'Disease', (96, 101))	('mouse', 'Species', '10090', (135, 140))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('tumor', 'Disease', (12, 17))	('mouse', 'Species', '10090', (102, 107))	('MIR4713HG', 'Var', (37, 46))
395480	33760127	Notably, the knockdown of MIR4713HG significantly slowed down the process of tumor growth and suppressed the progression of tumor metastasis in OTSCC in vivo.	('MIR4713HG', 'Chemical', '-', (26, 35))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('tumor', 'Disease', (77, 82))	('tumor', 'Disease', (124, 129))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumor metastasis', 'Disease', 'MESH:D009362', (124, 140))	('tumor metastasis', 'Disease', (124, 140))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('suppressed', 'NegReg', (94, 104))	('slowed down', 'NegReg', (50, 61))	('knockdown', 'Var', (13, 22))	('MIR4713HG', 'Var', (26, 35))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
395483	33760127	The present study revealed that knockdown of MIR4713HG upregulated E-cadherin expression and downregulated the expression of N-cadherin and vimentin, which indicated that knockdown of MIR4713HG significantly inhibited EMT.	('inhibited', 'NegReg', (208, 217))	('expression', 'MPA', (78, 88))	('N-cadherin', 'Gene', '1000', (125, 135))	('E-cadherin', 'Gene', (67, 77))	('E-cadherin', 'Gene', '999', (67, 77))	('MIR4713HG', 'Var', (45, 54))	('expression', 'MPA', (111, 121))	('N-cadherin', 'Gene', (125, 135))	('upregulated', 'PosReg', (55, 66))	('downregulated', 'NegReg', (93, 106))	('EMT', 'CPA', (218, 221))	('MIR4713HG', 'Var', (184, 193))	('MIR4713HG', 'Chemical', '-', (45, 54))	('vimentin', 'Gene', '7431', (140, 148))	('MIR4713HG', 'Chemical', '-', (184, 193))	('vimentin', 'Gene', (140, 148))
395484	33760127	With further investigation, the present study successfully identified that let-7c-5p physically bonds with MIR4713HG.	('bonds', 'Interaction', (96, 101))	('let-7c', 'Gene', (75, 81))	('MIR4713HG', 'Var', (107, 116))	('MIR4713HG', 'Chemical', '-', (107, 116))	('let-7c', 'Gene', '406885', (75, 81))
395486	33760127	The results revealed that the addition of let-7c-5p counteracted the improved cell proliferation and clonogenicity induced by MIR4713HG, and suppressed the increased metastasis potential in OTSCC cells caused by MIR4713HG overexpression.	('MIR4713HG', 'Var', (212, 221))	('MIR4713HG', 'Var', (126, 135))	('improved', 'PosReg', (69, 77))	('overexpression', 'PosReg', (222, 236))	('MIR4713HG', 'Chemical', '-', (212, 221))	('MIR4713HG', 'Chemical', '-', (126, 135))	('let-7c', 'Gene', '406885', (42, 48))	('metastasis potential', 'CPA', (166, 186))	('increased', 'PosReg', (156, 165))	('suppressed', 'NegReg', (141, 151))	('clonogenicity', 'CPA', (101, 114))	('let-7c', 'Gene', (42, 48))	('OTSCC', 'Disease', (190, 195))	('cell proliferation', 'CPA', (78, 96))
395487	33760127	Furthermore, it was revealed that expression of let-7c-5p was downregulated in OTSCC and negatively correlated with MIR4713HG.	('MIR4713HG', 'Chemical', '-', (116, 125))	('expression', 'MPA', (34, 44))	('correlated', 'Interaction', (100, 110))	('let-7c', 'Gene', '406885', (48, 54))	('downregulated', 'NegReg', (62, 75))	('OTSCC', 'Disease', (79, 84))	('negatively', 'NegReg', (89, 99))	('let-7c', 'Gene', (48, 54))	('MIR4713HG', 'Var', (116, 125))
395491	33760127	Furthermore, the overexpression of MIR4713HG could increase the expression of TMC7, and in rescue experiments, the knockdown of TMC7 could counteract the effect induced by MIR4713HG overexpression on OTSCC cells.	('increase', 'PosReg', (51, 59))	('expression', 'MPA', (64, 74))	('MIR4713HG', 'Var', (35, 44))	('TMC7', 'Gene', '79905', (78, 82))	('TMC7', 'Gene', (128, 132))	('MIR4713HG', 'Chemical', '-', (172, 181))	('MIR4713HG', 'Chemical', '-', (35, 44))	('TMC7', 'Gene', (78, 82))	('TMC7', 'Gene', '79905', (128, 132))	('knockdown', 'Var', (115, 124))
395492	33760127	In conclusion, the present study demonstrated that MIR4713HG was significantly upregulated in both OTSCC tissues and cell lines.	('MIR4713HG', 'Var', (51, 60))	('upregulated', 'PosReg', (79, 90))	('MIR4713HG', 'Chemical', '-', (51, 60))	('OTSCC', 'Disease', (99, 104))
395493	33760127	MIR4713HG acted as a pro-tumor factor, facilitating cell proliferation and metastasis.	('MIR4713HG', 'Var', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('MIR4713HG', 'Chemical', '-', (0, 9))	('cell proliferation', 'CPA', (52, 70))	('tumor', 'Disease', (25, 30))	('facilitating', 'PosReg', (39, 51))	('metastasis', 'CPA', (75, 85))	('tumor', 'Disease', 'MESH:D009369', (25, 30))
395494	33760127	Furthermore, the present study identified that MIR4713HG directly bound with let-7c-5p, and that let-7c-5p regulated malignant behaviors of OTSCC via affecting the expression of TMC7.	('malignant behaviors of OTSCC', 'CPA', (117, 145))	('let-7c', 'Gene', (97, 103))	('affecting', 'Reg', (150, 159))	('expression', 'MPA', (164, 174))	('TMC7', 'Gene', (178, 182))	('let-7c', 'Gene', '406885', (97, 103))	('let-7c', 'Gene', (77, 83))	('let-7c', 'Gene', '406885', (77, 83))	('TMC7', 'Gene', '79905', (178, 182))	('MIR4713HG', 'Var', (47, 56))	('regulated', 'Reg', (107, 116))	('MIR4713HG', 'Chemical', '-', (47, 56))
395495	33760127	Collectively, MIR4713HG aggravated the malignant behaviors in OTSCC via affecting the let-7c-5p/TMC7 signaling pathway, and could be a promising therapeutic target in OTSCC.	('let-7c', 'Gene', (86, 92))	('MIR4713HG', 'Var', (14, 23))	('TMC7', 'Gene', (96, 100))	('let-7c', 'Gene', '406885', (86, 92))	('MIR4713HG', 'Chemical', '-', (14, 23))	('TMC7', 'Gene', '79905', (96, 100))	('affecting', 'Reg', (72, 81))	('OTSCC', 'Disease', (62, 67))	('aggravated', 'PosReg', (24, 34))	('malignant behaviors', 'CPA', (39, 58))
395510	31594934	For example, the activation of ESR1 can globally increase eRNA transcription in breast cancer.	('increase', 'PosReg', (49, 57))	('activation', 'Var', (17, 27))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('breast cancer', 'Disease', 'MESH:D001943', (80, 93))	('ESR1', 'Gene', (31, 35))	('eRNA transcription', 'MPA', (58, 76))	('breast cancer', 'Disease', (80, 93))	('breast cancer', 'Phenotype', 'HP:0003002', (80, 93))	('ESR1', 'Gene', '2099', (31, 35))
395548	31594934	The majority (185/229, 80.8%) of these genes are correlated with eRNAs in at least one cancer type (Fig.	('correlated', 'Reg', (49, 59))	('eRNAs in', 'Disease', (65, 73))	('genes', 'Var', (39, 44))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cancer type', 'Disease', (87, 98))	('cancer type', 'Disease', 'MESH:D009369', (87, 98))
395556	31594934	3H), such as PSEN2-associated eRNA (PSEN2e, ENSR00000257043), RBX1-associated eRNA (PBX1e, ENSR00000257043), and NOTCH4 associated eRNA (NOTCH4e, ENSR00000320261).	('ENSR00000257043', 'Var', (44, 59))	('RBX1', 'Gene', '9978', (62, 66))	('RBX1', 'Gene', (62, 66))
395557	31594934	More interestingly, the putative target genes of the remaining eRNAs (146/217, 67.4%) are in cross-pathways, such as MDM2-associated eRNA (MDM2e, ENSR00000053727) in the p53 pathway, CDK6-associated eRNA (CDK6e, ENSR00000215101) in the cell cycle pathway, and RNF43-associated eRNA (RNF43e, ENSR00000096250) in the Wnt pathway (Supplementary Fig.	('MDM2', 'Gene', (139, 143))	('Wnt pathway', 'Pathway', (315, 326))	('cell cycle pathway', 'Pathway', (236, 254))	('MDM2', 'Gene', '4193', (117, 121))	('p53', 'Gene', (170, 173))	('ENSR00000215101', 'Var', (212, 227))	('p53', 'Gene', '7157', (170, 173))	('CDK6', 'Gene', '1021', (183, 187))	('CDK6', 'Gene', (205, 209))	('CDK6', 'Gene', (183, 187))	('CDK6', 'Gene', '1021', (205, 209))	('MDM2', 'Gene', (117, 121))	('MDM2', 'Gene', '4193', (139, 143))
395578	31594934	High level of NET1e was associated with worse survival (log-rank test p-value = 0.0004, Fig.	('NET1', 'Gene', (14, 18))	('NET1', 'Gene', '10276', (14, 18))	('High level', 'Var', (0, 10))	('worse', 'NegReg', (40, 45))
395583	31594934	This region harbors classical enhancer features, such as the enrichment of histone H3K4me1 modification; it also exhibits strong enrichment of active enhancer markers such as histone H3K27ac modification and binding of transcription co-factor p300 (Fig.	('histone', 'Var', (175, 182))	('p300', 'Gene', '2033', (243, 247))	('H3K4me1', 'Chemical', 'MESH:C024755', (83, 90))	('binding', 'Interaction', (208, 215))	('p300', 'Gene', (243, 247))	('histone', 'Var', (75, 82))
395587	31594934	To further characterize NET1e, we applied CRISPR activation (CRISPR/dCas9-SAM) to epigenetically induce NET1e expression in MCF7 cells (Fig.	('NET1', 'Gene', (24, 28))	('epigenetically', 'Var', (82, 96))	('NET1', 'Gene', (104, 108))	('NET1', 'Gene', '10276', (104, 108))	('NET1', 'Gene', '10276', (24, 28))	('expression', 'MPA', (110, 120))	('induce', 'PosReg', (97, 103))
395590	31594934	To delineate a role of the eRNA per se, we designed three locked nucleic acid GapmeR (LNAs) to knockdown NET1e.	('NET1', 'Gene', (105, 109))	('knockdown', 'Var', (95, 104))	('NET1', 'Gene', '10276', (105, 109))
395596	31594934	More importantly, expression of NET1e is negatively correlated (sensitive, Spearman's correlation, FDR <0.05) with 14 and 15 compounds response (AUC) while positively correlated (resistance, Spearman's correlation, FDR < 0.05) with 56 and 31 compounds response (AUC) in CTRP and GDSC, respectively, which suggested that altered expression of NET1e could influence response to these drugs (Fig.	('NET1', 'Gene', (342, 346))	('negatively', 'NegReg', (41, 51))	('NET1', 'Gene', '10276', (342, 346))	('compounds', 'MPA', (242, 251))	('response to these drugs', 'MPA', (364, 387))	('altered', 'Var', (320, 327))	('NET1', 'Gene', '10276', (32, 36))	('NET1', 'Gene', (32, 36))	('influence', 'Reg', (354, 363))
395600	31594934	Cells showed strong growth inhibition when we knocked down NET1e in MCF7 (Fig.	('MCF7', 'Gene', (68, 72))	('NET1', 'Gene', (59, 63))	('NET1', 'Gene', '10276', (59, 63))	('growth inhibition', 'CPA', (20, 37))	('knocked down', 'Var', (46, 58))
395641	31594934	The annotation from ENCODE and Roadmap considered H3K4me1 and H3K27ac marks, and annotation from FANTOM considered CAGE marks.	('H3K4me1', 'Var', (50, 57))	('H3K27ac marks', 'Var', (62, 75))	('H3K4me1', 'Chemical', 'MESH:C024755', (50, 57))
395665	31594934	For NET1e eRNA knockdown, a mixture of NET1e LNA 1, 2, and 3 was transfected into the cell.	('NET1', 'Gene', (4, 8))	('knockdown', 'Var', (15, 24))	('NET1', 'Gene', '10276', (39, 43))	('NET1', 'Gene', '10276', (4, 8))	('NET1', 'Gene', (39, 43))
395666	31594934	In brief, we generated the MCF7 stable cell line expressing dCAS9-VP64-Blast and Lenti MS2-p65-HSF1-Hygro using lentivirus.	('dCAS9-VP64-Blast', 'Var', (60, 76))	('HSF1', 'Gene', (95, 99))	('p65', 'Gene', (91, 94))	('HSF1', 'Gene', '3297', (95, 99))	('p65', 'Gene', '5970', (91, 94))	('VP64', 'Chemical', 'MESH:D005047', (66, 70))
395768	24444077	Immunohistochemically, the epidermoid cells of the tumor were positive to pan-CK (AE1/AE3), CK5/6, CK7 and p63, but negative to CD5.	('pan-CK', 'Var', (74, 80))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('CK7', 'Gene', (99, 102))	('CD5', 'Gene', (128, 131))	('positive', 'Reg', (62, 70))	('tumor', 'Disease', (51, 56))	('p63', 'Gene', (107, 110))	('AE1/AE3', 'Gene', (82, 89))	('CD5', 'Gene', '921', (128, 131))	('AE1/AE3', 'Gene', '6521;6508', (82, 89))	('CK5/6', 'Gene', (92, 97))	('CK5/6', 'Gene', '3852', (92, 97))	('p63', 'Gene', '8626', (107, 110))	('CK7', 'Gene', '3855', (99, 102))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
395774	24444077	By immunohistochemical staining, the neoplastic cells revealed the positivity for pan-CK (AE1/AE3), CK5/6, CK19 and p63, as well as negativity for CD5 and CD117 (Figure 4).	('CK19', 'Gene', (107, 111))	('CD117', 'Var', (155, 160))	('CD5', 'Gene', '921', (147, 150))	('p63', 'Gene', (116, 119))	('CK5/6', 'Gene', (100, 105))	('CK5/6', 'Gene', '3852', (100, 105))	('CK19', 'Gene', '3880', (107, 111))	('p63', 'Gene', '8626', (116, 119))	('AE1/AE3', 'Gene', (90, 97))	('AE1/AE3', 'Gene', '6521;6508', (90, 97))	('pan-CK', 'Protein', (82, 88))	('CD5', 'Gene', (147, 150))
395877	30736820	Modeling double strand break susceptibility to interrogate structural variation in cancer Structural variants (SVs) are known to play important roles in a variety of cancers, but their origins and functional consequences are still poorly understood.	('cancer', 'Disease', (166, 172))	('cancers', 'Disease', (166, 173))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('cancers', 'Disease', 'MESH:D009369', (166, 173))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('structural variation', 'Var', (59, 79))	('roles', 'Reg', (144, 149))	('cancers', 'Phenotype', 'HP:0002664', (166, 173))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('cancer', 'Disease', (83, 89))
395887	30736820	Some SVs have apparently direct consequences; for example, amplification of oncogenes leading to overexpression, deletion of tumor suppressors leading to dysfunction, and translocations generating oncogenic fusion proteins.	('oncogenes', 'Gene', (76, 85))	('oncogenic fusion proteins', 'Protein', (197, 222))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('deletion', 'Var', (113, 121))	('overexpression', 'MPA', (97, 111))	('tumor', 'Disease', (125, 130))	('translocations', 'Var', (171, 185))	('amplification', 'Var', (59, 72))
395889	30736820	In analyses of tumor SNVs, variants are routinely prioritized based on algorithms including corrections for estimates of SNV mutation rate variation, but analogous methods are not yet applied to SVs.	('variants', 'Var', (27, 35))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumor', 'Disease', (15, 20))	('SNV', 'Gene', (121, 124))
395904	30736820	This is consistent with observations that structural variants disproportionately accumulate within the early replicating, relatively gene-rich regions of the genome in cancer, and are relatively depleted in late replicating heterochromatin.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('cancer', 'Disease', (168, 174))	('structural variants', 'Var', (42, 61))	('variants', 'Var', (53, 61))
395908	30736820	Given the critical roles of CTCF in chromatin architecture and regulation, there has been intense interest in the causes and effects of structural variants disrupting CTCF binding sites.	('binding', 'Interaction', (172, 179))	('CTCF', 'Gene', '10664', (167, 171))	('CTCF', 'Gene', (28, 32))	('structural variants', 'Var', (136, 155))	('CTCF', 'Gene', '10664', (28, 32))	('CTCF', 'Gene', (167, 171))	('disrupting', 'NegReg', (156, 166))
395917	30736820	The Cancer Genome Atlas (TCGA) produced consistently processed copy number variant (CNV) calls from SNP chip data for 23,084 patients across 33 cohorts (Additional file 1: Figure S7).	('Cancer', 'Phenotype', 'HP:0002664', (4, 10))	('copy number', 'Var', (63, 74))	('Cancer Genome Atlas', 'Disease', (4, 23))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (4, 23))	('patients', 'Species', '9606', (125, 133))
395925	30736820	Certain classes of relatively simple SVs (deletions, duplications, inversions, translocations) are often the product of one or two DSBs, while more complex intrachromosomal rearrangements can be difficult to classify accurately, and may have origins in poorly understood phenomena such as chromothripsis.	('duplications', 'Var', (53, 65))	('DSBs', 'Chemical', '-', (131, 135))	('chromothripsis', 'Disease', (289, 303))	('deletions', 'Var', (42, 51))	('chromothripsis', 'Disease', 'MESH:D000072837', (289, 303))	('SVs', 'Disease', (37, 40))	('translocations', 'Var', (79, 93))
395960	30736820	The variable importance metrics also show certain features to be more influential in particular cell types, with CTCF and H3K36me3 having more predictive power in MCF7 than in NHEK or K562.	('H3K36me3', 'Var', (122, 130))	('MCF7', 'CellLine', 'CVCL:0031', (163, 167))	('CTCF', 'Gene', (113, 117))	('K562', 'CellLine', 'CVCL:0004', (184, 188))	('MCF7', 'Disease', (163, 167))	('CTCF', 'Gene', '10664', (113, 117))
395965	30736820	In spite of variable sample sizes, the classes of simple SV likely to arise by one or two DSBs (deletions, duplications, inversions, translocations) showed significant increases in predicted DSB susceptibility.	('simple SV', 'Disease', (50, 59))	('DSBs', 'Chemical', '-', (90, 94))	('increases', 'PosReg', (168, 177))	('inversions', 'Var', (121, 131))	('deletions', 'Var', (96, 105))	('duplications', 'Var', (107, 119))	('translocations', 'Var', (133, 147))	('arise', 'Reg', (70, 75))	('DSB', 'Disease', (191, 194))
395971	30736820	For example, a recent study of intra-tumor diversification in colorectal cancer suggests that most mutations occur during the final clonal expansion of these tumors, resulting from mutational processes that are absent from normal colorectal cells.	('tumors', 'Disease', (158, 164))	('tumors', 'Phenotype', 'HP:0002664', (158, 164))	('intra-tumor', 'Disease', (31, 42))	('mutational processes', 'MPA', (181, 201))	('colorectal cancer', 'Disease', 'MESH:D015179', (62, 79))	('tumors', 'Disease', 'MESH:D009369', (158, 164))	('colorectal cancer', 'Phenotype', 'HP:0003003', (62, 79))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('resulting from', 'Reg', (166, 180))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('mutations', 'Var', (99, 108))	('intra-tumor', 'Disease', 'MESH:D009369', (31, 42))	('colorectal cancer', 'Disease', (62, 79))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))
396020	30379973	MiRNA abnormalities are crucial for the formation and development of cancer and have a regulatory effect on the sensitivity of various cancer treatments.	('cancer', 'Disease', (135, 141))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('abnormalities', 'Var', (6, 19))	('cancer', 'Disease', 'MESH:D009369', (135, 141))	('cancer', 'Disease', (69, 75))	('MiRNA', 'MPA', (0, 5))
396023	30379973	Although miRNAs do not encode proteins, they can be used to regulate the expression level of a target gene by base-pairing with the transcripts of the target protein-encoding gene to reduce or inhibit the target gene.	('expression level', 'MPA', (73, 89))	('inhibit', 'NegReg', (193, 200))	('base-pairing', 'Var', (110, 122))	('miR', 'Gene', (9, 12))	('miR', 'Gene', '220972', (9, 12))	('regulate', 'MPA', (60, 68))	('reduce', 'NegReg', (183, 189))
396032	30379973	The following retrieval models are used for retrieval, search terms were: microrna-375 OR miR-375 OR mirna-375 OR hsa-miR-375 OR MicroRNA375.	('miR-375', 'Gene', (90, 97))	('miR-375', 'Gene', (118, 125))	('miR-375', 'Gene', '494324', (118, 125))	('microrna-375', 'Var', (74, 86))	('mirna-375', 'Var', (101, 110))	('miR-375', 'Gene', '494324', (90, 97))	('A375', 'CellLine', 'CVCL:0132', (136, 140))
396049	30379973	Study 4 (GSE77790) determined potential miR-375 target genes in pancreatic cancer and esophageal cancer (Panc-1 and sw1990 & TE8 and TE9).	('miR-375', 'Gene', '494324', (40, 47))	('sw1990', 'CellLine', 'CVCL:7347', (116, 122))	('sw1990 &', 'Var', (116, 124))	('GSE', 'Chemical', '-', (9, 12))	('esophageal cancer', 'Disease', (86, 103))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (64, 81))	('esophageal cancer', 'Disease', 'MESH:D004938', (86, 103))	('miR-375', 'Gene', (40, 47))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('pancreatic cancer', 'Disease', (64, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('pancreatic cancer', 'Disease', 'MESH:D010190', (64, 81))	('Panc-1', 'CellLine', 'CVCL:0480', (105, 111))
396050	30379973	The study collected miR-375 target genes with GPL20844 and included 62,976 probes.	('miR-375', 'Gene', '494324', (20, 27))	('miR-375', 'Gene', (20, 27))	('GPL20844', 'Var', (46, 54))
396061	30379973	KEGG pathway enrichment found that these genes had regulatory effects in amino acid biosynthesis and metabolic pathway, e.g, cysteine and methionine metabolism and metabolic pathways (Table 3).	('metabolic pathway', 'Pathway', (101, 118))	('metabolic pathways', 'Pathway', (164, 182))	('KEGG', 'Chemical', '-', (0, 4))	('regulatory effects', 'Reg', (51, 69))	('cysteine', 'Chemical', 'MESH:D003545', (125, 133))	('amino acid biosynthesis', 'MPA', (73, 96))	('genes', 'Var', (41, 46))	('methionine', 'Chemical', 'MESH:D008715', (138, 148))
396089	30379973	The extracellular domain of VASN is composed of leucine-rich tandem repeats, epidermal growth factor (EGF) -like motifs and fibronectin type iii motifs.	('VASN', 'Gene', (28, 32))	('leucine-rich tandem repeats', 'Var', (48, 75))	('VASN', 'Gene', '114990', (28, 32))
396099	30379973	Both MAT2B variants (overexpressed V1, V2) interact with GIT1.	('interact', 'Reg', (43, 51))	('V1, V2', 'Gene', '136319;6983', (35, 41))	('MAT2B', 'Gene', '27430', (5, 10))	('variants', 'Var', (11, 19))	('GIT1', 'Gene', '28964', (57, 61))	('MAT2B', 'Gene', (5, 10))	('GIT1', 'Gene', (57, 61))
396107	30379973	The expression level of miR-375 was inhibited in DU145 and PC-3 cell lines and clinical samples, and cell proliferation and invasion were inhibited by targeting Sec23 homolog A and yes-associated protein 1(SEC23A and YAP1), while inducing apoptosis and ectopic recovery of cell cycle arrest.	('clinical samples', 'Species', '191496', (79, 95))	('YAP1', 'Gene', (217, 221))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (273, 290))	('inhibited', 'NegReg', (138, 147))	('miR-375', 'Gene', '494324', (24, 31))	('SEC23A', 'Gene', (206, 212))	('ectopic recovery', 'CPA', (253, 269))	('inhibited', 'NegReg', (36, 45))	('miR-375', 'Gene', (24, 31))	('SEC23A', 'Gene', '10484', (206, 212))	('Sec23', 'Gene', (161, 166))	('targeting', 'Var', (151, 160))	('DU145', 'CellLine', 'CVCL:0105', (49, 54))	('expression level', 'MPA', (4, 20))	('inducing', 'NegReg', (230, 238))	('apoptosis', 'CPA', (239, 248))	('YAP1', 'Gene', '10413', (217, 221))	('invasion', 'CPA', (124, 132))	('PC-3', 'CellLine', 'CVCL:0035', (59, 63))	('cell proliferation', 'CPA', (101, 119))
396114	30379973	In her2-positive breast cancer and oral squamous cell carcinoma, silencing of miR-375 leads to up-regulation of IGF1R, which was found to be a direct target of miR-375.	('miR-375', 'Gene', '494324', (160, 167))	('silencing', 'Var', (65, 74))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('breast cancer', 'Disease', 'MESH:D001943', (17, 30))	('carcinoma', 'Phenotype', 'HP:0030731', (54, 63))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (35, 63))	('IGF1R', 'Gene', (112, 117))	('breast cancer', 'Disease', (17, 30))	('miR-375', 'Gene', '494324', (78, 85))	('IGF1R', 'Gene', '3480', (112, 117))	('breast cancer', 'Phenotype', 'HP:0003002', (17, 30))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (40, 63))	('miR-375', 'Gene', (160, 167))	('her2', 'Gene', '2064', (3, 7))	('miR-375', 'Gene', (78, 85))	('oral squamous cell carcinoma', 'Disease', (35, 63))	('up-regulation', 'PosReg', (95, 108))	('her2', 'Gene', (3, 7))
396122	30379973	Targeting small nucleotide siRNA or aptamer of VASN may be a promising drug therapy for HCC.	('VASN', 'Gene', (47, 51))	('small nucleotide', 'Var', (10, 26))	('HCC', 'Disease', (88, 91))	('VASN', 'Gene', '114990', (47, 51))	('aptamer', 'Var', (36, 43))
396139	30379973	In addition to interacting with MAT II, the mutations of MAT2B can interact with other else proteins, for example, including HuR.	('interact', 'Reg', (67, 75))	('MAT2B', 'Gene', '27430', (57, 62))	('interacting', 'Reg', (15, 26))	('HuR', 'Gene', '1994', (125, 128))	('HuR', 'Gene', (125, 128))	('MAT II', 'Gene', (32, 38))	('mutations', 'Var', (44, 53))	('MAT II', 'Gene', '27430', (32, 38))	('MAT2B', 'Gene', (57, 62))
396148	26094024	Statistical analysis showed a strong correlation between the frequency and distribution of CAFs and the clinicopathological characteristics of patients with cN0 OTSCC, including pathological stage (P = 0.001), T classification (P = 0.001), and N classification (P = 0.009).	('cN0', 'Var', (157, 160))	('SCC', 'Gene', (163, 166))	('patients', 'Species', '9606', (143, 151))	('SCC', 'Gene', '6317', (163, 166))	('T classification', 'CPA', (210, 226))
396175	26094024	A total of 178 tissue specimens were removed from patients with cN0 oral tongue cancer, none of whom had received radiotherapy or chemotherapy prior to surgery.	('cN0', 'Var', (64, 67))	('patients', 'Species', '9606', (50, 58))	('oral tongue cancer', 'Disease', (68, 86))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('oral tongue cancer', 'Disease', 'MESH:D014062', (68, 86))	('men', 'Species', '9606', (27, 30))
396222	26094024	Statistical analysis showed a correlation between the frequency and distribution of CAFs as determined by immunohistochemistry and the clinicopathological characteristics of cN0 oral tongue cancer, including pathologic stage (P = 0.001), T classification (P = 0.004), N classification (P = 0.024), recurrence (P = 0.010) and vital status (P = 0.001).	('cN0', 'Var', (174, 177))	('T classification', 'CPA', (238, 254))	('oral tongue cancer', 'Disease', (178, 196))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('oral tongue cancer', 'Disease', 'MESH:D014062', (178, 196))
396223	26094024	A survival analysis showed a clear negative correlation between the frequency and the distribution of CAFs with the overall survival and the disease-free survival of patients with cN0 tongue squamous cell cancer (P < 0.001, P = 0.002, respectively) (Figure 1b).	('tongue squamous cell cancer', 'Phenotype', 'HP:0030413', (184, 211))	('tongue squamous cell cancer', 'Disease', 'MESH:D002294', (184, 211))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (191, 211))	('negative', 'NegReg', (35, 43))	('tongue squamous cell cancer', 'Disease', (184, 211))	('disease-free survival', 'CPA', (141, 162))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('cN0', 'Var', (180, 183))	('overall survival', 'CPA', (116, 132))	('patients', 'Species', '9606', (166, 174))
396232	26094024	A flow cytometric analysis revealed that the S/G2 peak was more common in OTSCC cells grown in CM from CAFs compared with OTSCC cells grown in CM from NFs (Figure 4c, d).	('S/G2', 'SUBSTITUTION', 'None', (45, 49))	('SCC', 'Gene', (76, 79))	('SCC', 'Gene', (124, 127))	('SCC', 'Gene', '6317', (76, 79))	('S/G2', 'Var', (45, 49))	('SCC', 'Gene', '6317', (124, 127))
396237	26094024	In clinical practice, head and neck surgeons depend primarily on the TNM classification system to plan treatment strategies, and no consensus exists on the optimal treatment of patients with cN0 oral tongue cancer.	('oral tongue cancer', 'Disease', (195, 213))	('TNM', 'Gene', '10178', (69, 72))	('men', 'Species', '9606', (169, 172))	('men', 'Species', '9606', (108, 111))	('patients', 'Species', '9606', (177, 185))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('TNM', 'Gene', (69, 72))	('cN0', 'Var', (191, 194))	('oral tongue cancer', 'Disease', 'MESH:D014062', (195, 213))
396247	26094024	Statistical analysis showed a correlation between the frequency and distribution of CAFs, as determined by immunohistochemistry and the clinicopathological characteristics of patients with cN0 oral tongue cancer, including pathologic stage, T classification, N classification, recurrence and vital status.	('cN0', 'Var', (189, 192))	('oral tongue cancer', 'Disease', 'MESH:D014062', (193, 211))	('patients', 'Species', '9606', (175, 183))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('oral tongue cancer', 'Disease', (193, 211))
396308	28289590	Susceptibility to Oral Squamous Cell Carcinoma: Correlation with Variants of CYP1A1-MspI, GSTT1, GSTM1, ALDH2, EC-SOD and Lifestyle Factors In order to investigate the association between polymorphisms in genes encoding metabolizing enzymes (CYP1A1-MspI, EC-SOD (extracellular superoxide dismutase), GSTT1, GSTM1, ALDH2), cigarette and alcohol consumption, and the risk of oral squamous cell carcinoma, we conducted a prospective case-control study comprised of 750 individuals with oral squamous cell carcinoma (OSCC) and 750 healthy individuals.	('EC-SOD', 'Gene', '6649', (255, 261))	('Oral Squamous Cell Carcinoma', 'Disease', 'MESH:D002294', (18, 46))	('carcinoma', 'Phenotype', 'HP:0030731', (502, 511))	('EC-SOD', 'Gene', '6649', (111, 117))	('Oral Squamous Cell Carcinoma', 'Disease', (18, 46))	('GSTT1', 'Gene', '2952', (90, 95))	('Carcinoma', 'Phenotype', 'HP:0030731', (37, 46))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (373, 401))	('GSTM1', 'Gene', (307, 312))	('OSCC', 'Chemical', '-', (513, 517))	('oral squamous cell carcinoma', 'Disease', (373, 401))	('ALDH2', 'Gene', '217', (314, 319))	('CYP1A1', 'Gene', (77, 83))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (378, 401))	('ALDH2', 'Gene', (104, 109))	('GSTT1', 'Gene', (90, 95))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (483, 511))	('GSTM1', 'Gene', (97, 102))	('oral squamous cell carcinoma', 'Disease', (483, 511))	('CYP1A1', 'Gene', (242, 248))	('GSTT1', 'Gene', '2952', (300, 305))	('CYP1A1', 'Gene', '1543', (77, 83))	('EC-SOD', 'Gene', (255, 261))	('EC-SOD', 'Gene', (111, 117))	('GSTM1', 'Gene', '2944', (307, 312))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (23, 46))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (488, 511))	('carcinoma', 'Phenotype', 'HP:0030731', (392, 401))	('Variants', 'Var', (65, 73))	('ALDH2', 'Gene', '217', (104, 109))	('alcohol', 'Chemical', 'MESH:D000438', (336, 343))	('CYP1A1', 'Gene', '1543', (242, 248))	('GSTT1', 'Gene', (300, 305))	('GSTM1', 'Gene', '2944', (97, 102))	('ALDH2', 'Gene', (314, 319))
396314	28289590	In brief, genetic polymorphism of CYP1A1, EC-SOD, GSTT1, GSTM1, and ALDH2 and smoking and drinking history are closely associated with susceptibility to OSCC.	('CYP1A1', 'Gene', '1543', (34, 40))	('ALDH2', 'Gene', '217', (68, 73))	('EC-SOD', 'Gene', '6649', (42, 48))	('OSCC', 'Disease', (153, 157))	('GSTT1', 'Gene', (50, 55))	('GSTM1', 'Gene', '2944', (57, 62))	('associated with susceptibility', 'Reg', (119, 149))	('GSTT1', 'Gene', '2952', (50, 55))	('ALDH2', 'Gene', (68, 73))	('GSTM1', 'Gene', (57, 62))	('OSCC', 'Chemical', '-', (153, 157))	('EC-SOD', 'Gene', (42, 48))	('CYP1A1', 'Gene', (34, 40))	('genetic polymorphism', 'Var', (10, 30))
396326	28289590	Other metabolizing enzymes, with variations in their respective genes, have also been previously implicated in cancer susceptibility.	('implicated', 'Reg', (97, 107))	('metabolizing enzymes', 'Enzyme', (6, 26))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('variations', 'Var', (33, 43))
396331	28289590	Genetic polymorphism in ALDH2 has been previously investigated and shown to be associated with specific cancer types.	('associated', 'Reg', (79, 89))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('ALDH2', 'Gene', '217', (24, 29))	('ALDH2', 'Gene', (24, 29))	('cancer', 'Disease', (104, 110))	('Genetic polymorphism', 'Var', (0, 20))	('cancer', 'Disease', 'MESH:D009369', (104, 110))
396334	28289590	Thus, the specific contribution of polymorphisms in genes encoding enzymes involved in biotransformation of alcohol and tobacco components remains unclear; specifically, the role in promoting OSCC requires further study.	('promoting', 'PosReg', (182, 191))	('OSCC', 'Chemical', '-', (192, 196))	('tobacco', 'Species', '4097', (120, 127))	('OSCC', 'Disease', (192, 196))	('polymorphisms', 'Var', (35, 48))	('alcohol', 'Chemical', 'MESH:D000438', (108, 115))
396340	28289590	Based on SI values, the participants were divided into the following categories: non smokers, individuals with SI <=400, and individuals with SI 400.	('SI <=400', 'Var', (111, 119))	('participants', 'Species', '9606', (24, 36))	('SI', 'Chemical', '-', (111, 113))	('SI 400', 'Var', (142, 148))	('SI', 'Chemical', '-', (142, 144))	('SI', 'Chemical', '-', (9, 11))
396368	28289590	Thus, the presence of two or more variants in the OSCC population was significantly more common than in controls (p <0.01).	('OSCC', 'Gene', (50, 54))	('common', 'Reg', (89, 95))	('variants', 'Var', (34, 42))	('OSCC', 'Chemical', '-', (50, 54))
396371	28289590	Smokers with five variant genotypes were 32-times more likely to have OSCC.	('OSCC', 'Chemical', '-', (70, 74))	('OSCC', 'Disease', (70, 74))	('variant', 'Var', (18, 25))
396373	28289590	In the patient group, the presence of multiple variant genotypes and an SI>400 was significantly more common compared to the control group (p <0.01).	('common', 'Reg', (102, 108))	('SI>400', 'Var', (72, 78))	('SI', 'Chemical', '-', (72, 74))	('patient', 'Species', '9606', (7, 14))
396375	28289590	The presence of multiple variants and alcohol consumption was significantly more common in patients compared to the control group; furthermore, as with smoking, the drinking behavior and combined variant genotypes had a synergistic effect on the likelihood of cancer.	('variants', 'Var', (25, 33))	('patients', 'Species', '9606', (91, 99))	('cancer', 'Disease', 'MESH:D009369', (260, 266))	('cancer', 'Disease', (260, 266))	('alcohol', 'Chemical', 'MESH:D000438', (38, 45))	('variant', 'Var', (196, 203))	('cancer', 'Phenotype', 'HP:0002664', (260, 266))
396376	28289590	In the patient group, the presence of multiple variants and a DI >3000 was significantly more common compared to the control group (p <0.01).	('patient', 'Species', '9606', (7, 14))	('DI >3000', 'Var', (62, 70))	('common', 'Reg', (94, 100))
396377	28289590	In the patient group, there were significantly more patients who had multiple variants and were positive for both smoking and drinking history as compared to the control group.	('patient', 'Species', '9606', (7, 14))	('positive', 'Reg', (96, 104))	('patient', 'Species', '9606', (52, 59))	('variants', 'Var', (78, 86))	('patients', 'Species', '9606', (52, 60))
396384	28289590	This finding, aligned with prior studies, shed light on the involvement of the CYP1A1-MspI polymorphism in carcinogenesis through modified enzymatic activity.	('CYP1A1', 'Gene', (79, 85))	('CYP1A1', 'Gene', '1543', (79, 85))	('enzymatic activity', 'MPA', (139, 157))	('involvement', 'Reg', (60, 71))	('polymorphism', 'Var', (91, 103))	('carcinogenesis', 'Disease', 'MESH:D063646', (107, 121))	('modified', 'Reg', (130, 138))	('carcinogenesis', 'Disease', (107, 121))
396390	28289590	The GST polymorphisms are also correlated with cancer susceptibility.	('GST', 'Gene', '373156', (4, 7))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('cancer', 'Disease', (47, 53))	('GST', 'Gene', (4, 7))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('polymorphisms', 'Var', (8, 21))	('correlated', 'Reg', (31, 41))
396395	28289590	Furthermore, ALDH2 gene polymorphism is correlated with a variety of tumors.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('ALDH2', 'Gene', '217', (13, 18))	('polymorphism', 'Var', (24, 36))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('ALDH2', 'Gene', (13, 18))	('correlated', 'Reg', (40, 50))	('tumors', 'Disease', (69, 75))	('tumors', 'Disease', 'MESH:D009369', (69, 75))
396396	28289590	Our study confirmed the correlation between ALDH2 (non G/G) genotypes and increased susceptibility to OSCC.	('OSCC', 'Chemical', '-', (102, 106))	('ALDH2', 'Gene', (44, 49))	('OSCC', 'Disease', (102, 106))	('non G/G) genotypes', 'Var', (51, 69))	('genotypes', 'Var', (60, 69))	('ALDH2', 'Gene', '217', (44, 49))
396398	28289590	In the patient group, the percentage of patients with a combination of variant genotypes (more than two genotypes) was significantly higher than that of the control group; the relative risks of OSCC in such patients were significantly increased.	('patient', 'Species', '9606', (40, 47))	('patients', 'Species', '9606', (207, 215))	('variant', 'Var', (71, 78))	('patient', 'Species', '9606', (7, 14))	('patients', 'Species', '9606', (40, 48))	('OSCC', 'Disease', (194, 198))	('higher', 'PosReg', (133, 139))	('increased', 'PosReg', (235, 244))	('patient', 'Species', '9606', (207, 214))	('OSCC', 'Chemical', '-', (194, 198))
396399	28289590	Previous studies have shown that OSCC patients are more likely to carry multiple variants and have a history of smoking or drinking; the interaction of two or more of these factors enhances risk.	('patients', 'Species', '9606', (38, 46))	('OSCC', 'Disease', (33, 37))	('OSCC', 'Chemical', '-', (33, 37))	('enhances', 'PosReg', (181, 189))	('interaction', 'Interaction', (137, 148))	('variants', 'Var', (81, 89))
396400	28289590	Our simultaneous analyses confirmed these previous results, as individuals with both multiple variant genotypes and a smoking and drinking history exhibited a significantly higher risk of OSCC.	('OSCC', 'Disease', (188, 192))	('variant', 'Var', (94, 101))	('OSCC', 'Chemical', '-', (188, 192))
396407	27918595	Since dysregulation of the sonic hedgehog pathway plays an important role in carcinogenesis, we aimed to assess whether members of the sonic hedgehog-signaling pathway may act as prognostic factors in patients with HPV negative head and neck squamous cell carcinoma.	('patients', 'Species', '9606', (201, 209))	('neck squamous cell carcinoma', 'Disease', (237, 265))	('sonic hedgehog', 'Gene', '6469', (135, 149))	('carcinogenesis', 'Disease', 'MESH:D063646', (77, 91))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (242, 265))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (237, 265))	('carcinogenesis', 'Disease', (77, 91))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (228, 265))	('dysregulation', 'Var', (6, 19))	('carcinoma', 'Phenotype', 'HP:0030731', (256, 265))	('sonic hedgehog', 'Gene', (27, 41))	('HPV', 'Species', '10566', (215, 218))	('sonic hedgehog', 'Gene', (135, 149))	('sonic hedgehog', 'Gene', '6469', (27, 41))
396423	27918595	In recent years, HPV positivity has been identified as a major prognostic marker in oropharyngeal squamous cell carcinoma patients.	('HPV', 'Gene', (17, 20))	('positivity', 'Var', (21, 31))	('oropharyngeal squamous cell carcinoma', 'Disease', 'MESH:D002294', (84, 121))	('patients', 'Species', '9606', (122, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (98, 121))	('oropharyngeal squamous cell carcinoma', 'Disease', (84, 121))	('HPV', 'Species', '10566', (17, 20))	('oropharyngeal squamous cell carcinoma', 'Phenotype', 'HP:0012182', (84, 121))
396489	27918595	Kaplan-Meier univariate analysis revealed better overall survival (p = 0.02; Fig 2B) as well as better disease-free survival (p = 0.04; Fig 2C) for patients overexpressing Gli-2.	('patients', 'Species', '9606', (148, 156))	('overall survival', 'CPA', (49, 65))	('better', 'PosReg', (42, 48))	('better', 'PosReg', (96, 102))	('disease-free survival', 'CPA', (103, 124))	('Gli-2', 'Gene', (172, 177))	('overexpressing', 'Var', (157, 171))
396504	27918595	In particular, HPV positive patients demonstrate a significantly improved outcome after both primary and adjuvant radiotherapy when compared to HPV negative patients.	('HPV', 'Species', '10566', (144, 147))	('improved', 'PosReg', (65, 73))	('patients', 'Species', '9606', (157, 165))	('HPV', 'Species', '10566', (15, 18))	('HPV', 'Gene', (15, 18))	('patients', 'Species', '9606', (28, 36))	('positive', 'Var', (19, 27))
396523	27918595	However, few studies show the positive prognostic effects of cross-talks of proteins of the sonic hedgehog pathway with various growth factors.	('sonic hedgehog', 'Gene', (92, 106))	('cross-talks', 'Var', (61, 72))	('proteins', 'Protein', (76, 84))	('sonic hedgehog', 'Gene', '6469', (92, 106))
396524	27918595	In lung adenocarcinoma, the presence of Shh and Gli-1 correlated with better overall survival, showing association with EGFR overexpression, whereas TGF-ss acts as a tumor promoter by transcriptionally inducing Gli-proteins and thus mediating tumor survival.	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('TGF-ss', 'Var', (149, 155))	('Shh', 'Gene', (40, 43))	('lung adenocarcinoma', 'Disease', (3, 22))	('tumor', 'Disease', (243, 248))	('Gli', 'Gene', '2735', (48, 51))	('tumor', 'Disease', 'MESH:D009369', (243, 248))	('Shh', 'Gene', '6469', (40, 43))	('EGFR', 'Gene', (120, 124))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (3, 22))	('Gli', 'Gene', (48, 51))	('Gli-1', 'Gene', '2735', (48, 53))	('tumor', 'Disease', (166, 171))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (3, 22))	('overall survival', 'MPA', (77, 93))	('mediating', 'Reg', (233, 242))	('Gli', 'Gene', '2735', (211, 214))	('carcinoma', 'Phenotype', 'HP:0030731', (13, 22))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('presence', 'Var', (28, 36))	('Gli-1', 'Gene', (48, 53))	('better', 'PosReg', (70, 76))	('Gli', 'Gene', (211, 214))	('EGFR', 'Gene', '1956', (120, 124))	('overexpression', 'PosReg', (125, 139))	('inducing', 'PosReg', (202, 210))
396529	27918595	It has also been shown that Gli-2 expression was associated with cell death in mice that were treated with radiation therapy for intrahepatic carcinoma.	('intrahepatic carcinoma', 'Disease', (129, 151))	('associated', 'Reg', (49, 59))	('Gli-2', 'Gene', (28, 33))	('expression', 'Var', (34, 44))	('mice', 'Species', '10090', (79, 83))	('intrahepatic carcinoma', 'Phenotype', 'HP:0001402', (129, 151))	('death', 'Disease', 'MESH:D003643', (70, 75))	('death', 'Disease', (70, 75))	('carcinoma', 'Phenotype', 'HP:0030731', (142, 151))	('intrahepatic carcinoma', 'Disease', 'MESH:D002780', (129, 151))
396534	27351213	Overexpression of the oncostatin-M receptor in cervical squamous cell carcinoma is associated with epithelial-mesenchymal transition and poor overall survival Copy-number gain of the oncostatin-M receptor (OSMR) occurs frequently in cervical squamous cell carcinoma (SCC) and is associated with adverse clinical outcome.	('SCC', 'Gene', '6317', (267, 270))	('gain', 'PosReg', (171, 175))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (56, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('squamous cell carcinoma', 'Disease', (56, 79))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (242, 265))	('clinical', 'Species', '191496', (303, 311))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (56, 79))	('oncostatin-M receptor', 'Gene', '9180', (183, 204))	('oncostatin-M receptor', 'Gene', (183, 204))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (242, 265))	('carcinoma', 'Phenotype', 'HP:0030731', (256, 265))	('squamous cell carcinoma', 'Disease', (242, 265))	('oncostatin-M receptor', 'Gene', '9180', (22, 43))	('oncostatin-M receptor', 'Gene', (22, 43))	('Copy-number', 'Var', (159, 170))	('SCC', 'Gene', (267, 270))	('SCC', 'Phenotype', 'HP:0002860', (267, 270))
396547	27351213	Early studies identified oncogenes of potential significance in cervical SCC, by screening for genes located in regions of frequent copy-number gain (CNG) that showed significant associations between expression levels and copy number.	('SCC', 'Gene', (73, 76))	('SCC', 'Phenotype', 'HP:0002860', (73, 76))	('expression levels', 'MPA', (200, 217))	('copy-number', 'Var', (132, 143))	('SCC', 'Gene', '6317', (73, 76))	('copy', 'MPA', (222, 226))	('associations', 'Interaction', (179, 191))
396552	27351213	Other groups independently showed chromosome 5p CNG in >60% of advanced cervical carcinomas, while OSMR was overexpressed at 3.1-fold greater levels in 30 cervical carcinomas compared with 20 cases of normal cervical squamous epithelium.	('carcinomas', 'Disease', (164, 174))	('carcinomas', 'Disease', 'MESH:D002277', (164, 174))	('chromosome 5p CNG', 'Var', (34, 51))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('carcinomas', 'Phenotype', 'HP:0030731', (81, 91))	('carcinomas', 'Disease', 'MESH:D002277', (81, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (164, 173))	('carcinomas', 'Disease', (81, 91))	('carcinomas', 'Phenotype', 'HP:0030731', (164, 174))
396553	27351213	Importantly, we found that OSMR CNG was associated with significantly adverse clinical outcome in cervical SCC, with a relative risk of death vs cases without CNG of 3.6.	('SCC', 'Gene', (107, 110))	('SCC', 'Phenotype', 'HP:0002860', (107, 110))	('clinical', 'Species', '191496', (78, 86))	('SCC', 'Gene', '6317', (107, 110))	('OSMR CNG', 'Var', (27, 35))
396565	27351213	In addition, we reanalysed our previous microarray gene expression profiling of 32 samples of lesional epithelium microdissected from cervical high-grade SILs (HSILs) and low-grade SILs (LSILs) and 12 samples of normal ectocervical squamous epithelium (set 4; Gene Expression Ommibus Accession Number GSE27678).	('SILs', 'Disease', (188, 192))	('SILs', 'Disease', (154, 158))	('SILs', 'Disease', 'None', (161, 165))	('SILs', 'Disease', 'None', (181, 185))	('SILs', 'Disease', (161, 165))	('SILs', 'Disease', (181, 185))	('SILs', 'Disease', 'None', (154, 158))	('low-grade', 'Var', (171, 180))	('SILs', 'Disease', 'None', (188, 192))
396578	27351213	Cells were treated for 2 h with medium supplemented with TG101348 (Axon Medchem BV, Groningen, The Netherlands), a small-molecule inhibitor of JAK2.	('JAK2', 'Gene', '3717', (143, 147))	('TG101348', 'Chemical', 'MESH:C528327', (57, 65))	('TG101348', 'Var', (57, 65))	('JAK2', 'Gene', (143, 147))
396581	27351213	STAT3 or OSMR were each depleted using four pooled siRNAs (ON-TARGETplus SMARTpool L-003544 or L-008050 respectively, both Dharmacon, Lafayette, CO, USA), compared with cells treated with non-targeting control (NTC) pooled siRNAs (siCONTROL non-targeting siRNA-1, Dharmacon).	('L-003544', 'Var', (83, 91))	('STAT3', 'Gene', '6774', (0, 5))	('STAT3', 'Gene', (0, 5))	('L-008050', 'Var', (95, 103))
396611	27351213	To investigate the role of JAK2, cells were treated with OSM for 15 min, followed by assessment of STAT3 phosphorylation by western blotting after 30 min and measurement of Snail transcript levels after 24 h. In this experiment, cells pretreated with the small-molecule JAK2 inhibitor TG101348 for 2 h prior to the addition of OSM showed reduced STAT3 phosphorylation and Snail induction (Figure 4A).	('Snail', 'Gene', '6615', (173, 178))	('TG101348', 'Var', (285, 293))	('reduced', 'NegReg', (338, 345))	('JAK2', 'Gene', (270, 274))	('TG101348', 'Chemical', 'MESH:C528327', (285, 293))	('JAK2', 'Gene', '3717', (27, 31))	('STAT3', 'Gene', '6774', (346, 351))	('STAT3', 'Gene', '6774', (99, 104))	('STAT3', 'Gene', (346, 351))	('STAT3', 'Gene', (99, 104))	('Snail', 'Gene', (372, 377))	('JAK2', 'Gene', (27, 31))	('Snail', 'Gene', '6615', (372, 377))	('Snail', 'Gene', (173, 178))	('JAK2', 'Gene', '3717', (270, 274))
396627	27351213	Importantly, the SCCs with high OSMR expression showed a highly significant adverse overall survival, compared with those with low expression (P=0.006; Figure 6E).	('high OSMR expression', 'Var', (27, 47))	('SCC', 'Phenotype', 'HP:0002860', (17, 20))	('SCC', 'Gene', '6317', (17, 20))	('adverse', 'NegReg', (76, 83))	('overall survival', 'CPA', (84, 100))	('SCC', 'Gene', (17, 20))
396636	27351213	Our present and previous in vitro data demonstrate that exogenous OSM rapidly induces a consistent pattern of EMT-like changes in OSMR overexpressing cervical SCC cells, with downregulation of E-cadherin and upregulation of several mesenchymal markers.	('E-cadherin', 'Gene', (193, 203))	('SCC', 'Gene', (159, 162))	('downregulation', 'NegReg', (175, 189))	('E-cadherin', 'Gene', '999', (193, 203))	('SCC', 'Phenotype', 'HP:0002860', (159, 162))	('upregulation', 'PosReg', (208, 220))	('SCC', 'Gene', '6317', (159, 162))	('EMT-like changes', 'CPA', (110, 126))	('exogenous', 'Var', (56, 65))
396664	27351213	These data resonate with those in breast adenocarcinoma, where high OSMR expression correlates with shorter overall survival and recurrence free survival, together with features of EMT.	('breast adenocarcinoma', 'Disease', 'MESH:D000230', (34, 55))	('overall', 'MPA', (108, 115))	('carcinoma', 'Phenotype', 'HP:0030731', (46, 55))	('OSMR', 'Gene', (68, 72))	('shorter', 'NegReg', (100, 107))	('breast adenocarcinoma', 'Phenotype', 'HP:0003002', (34, 55))	('recurrence free survival', 'CPA', (129, 153))	('expression', 'MPA', (73, 83))	('high', 'Var', (63, 67))	('breast adenocarcinoma', 'Disease', (34, 55))
396675	32915499	HNRNPM, HNRNPUL1, and HNRNPL showed high mutation frequencies, and most hnRNP genes were frequently mutated in uterine corpus endometrial carcinoma (UCEC).	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('mutated', 'Var', (100, 107))	('hnRNP', 'Gene', (72, 77))	('endometrial carcinoma', 'Disease', (126, 147))	('HNRNPM', 'Gene', (0, 6))	('HNRNPM', 'Gene', '4670', (0, 6))	('hnRNP', 'Gene', '3183', (72, 77))	('HNRNPL', 'Gene', '3191', (22, 28))	('HNRNPUL1', 'Gene', '11100', (8, 16))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (126, 147))	('HNRNPL', 'Gene', (22, 28))	('HNRNPUL1', 'Gene', (8, 16))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (126, 147))
396676	32915499	HNRNPA2B1 showed widespread copy number amplification across various cancer types.	('copy number amplification', 'Var', (28, 53))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('HNRNPA2B1', 'Gene', '3181', (0, 9))	('HNRNPA2B1', 'Gene', (0, 9))	('cancer', 'Disease', (69, 75))
396683	32915499	1 ,  2  Almost each transcript derived from human genes undergoes diverse patterns of alternative splicing (AS) including exclusion or inclusion of ''cassette'' exons, changes of AS sites, intron retentions, alternative promoter or terminator, and mutually exclusive exons.	('human', 'Species', '9606', (44, 49))	('as', 'Gene', '112935892', (151, 153))	('AS', 'Gene', '112935892', (179, 181))	('AS', 'Gene', '112935892', (108, 110))	('changes', 'Var', (168, 175))	('intron', 'MPA', (189, 195))	('alternative splicing', 'MPA', (86, 106))
396684	32915499	3 ,  4  Alternative splicing of pre-mRNA is responsible various aspects of biological processes and aberrant AS contribute to a series of disorders even cancer.	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('cancer', 'Disease', (153, 159))	('contribute', 'Reg', (112, 122))	('responsible', 'Reg', (44, 55))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('as', 'Gene', '112935892', (64, 66))	('disorders', 'Disease', (138, 147))	('Alternative splicing', 'Var', (8, 28))	('AS', 'Gene', '112935892', (109, 111))
396692	32915499	16  In pancreas cancer, hnRNP E1 cancer cell metastasis via controlling the alternative splicing of integrin beta1, a membrane receptor involved in cell adhesion, immune response and metastatic diffusion of cancer cells.	('cancer', 'Disease', (33, 39))	('as', 'Gene', '112935892', (186, 188))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('alternative splicing', 'Var', (76, 96))	('as', 'Gene', '112935892', (51, 53))	('cancer', 'Disease', (207, 213))	('cancer', 'Disease', (16, 22))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('pancreas cancer', 'Disease', 'MESH:D010190', (7, 22))	('pancreas cancer', 'Phenotype', 'HP:0002894', (7, 22))	('integrin beta1', 'Gene', '3688', (100, 114))	('as', 'Gene', '112935892', (48, 50))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('pancreas cancer', 'Disease', (7, 22))	('cancer', 'Disease', 'MESH:D009369', (207, 213))	('hnRNP E1', 'Gene', '5093', (24, 32))	('cancer', 'Disease', 'MESH:D009369', (16, 22))	('as', 'Gene', '112935892', (13, 15))	('hnRNP E1', 'Gene', (24, 32))	('integrin beta1', 'Gene', (100, 114))
396698	32915499	It is anticipated that the comprehensive pan-cancer analysis could shed light on the way alternative splicing lead to cancer.	('cancer', 'Disease', (118, 124))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('lead to', 'Reg', (110, 117))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('alternative', 'Var', (89, 100))	('cancer', 'Disease', (45, 51))	('cancer', 'Disease', 'MESH:D009369', (118, 124))
396702	32915499	All of the TCGA data including TPM (Transcripts Per Kilobase Million) expression, copy number variation, mutation and clinical information (survival status, stages, grades, survival time) were download from UCSC XENA (https://xenabrowser.net/).	('copy number variation', 'Var', (82, 103))	('as', 'Gene', '112935892', (57, 59))	('TCGA', 'Gene', (11, 15))	('TPM', 'Gene', (31, 34))
396721	32915499	The mutation frequency of hnRNP genes were analysed, and the results indicated that most hnRNP genes were frequently mutated in UCEC (Figure 2A).	('UCEC', 'Disease', (128, 132))	('mutated', 'Var', (117, 124))	('hnRNP', 'Gene', (26, 31))	('hnRNP', 'Gene', (89, 94))	('hnRNP', 'Gene', '3183', (26, 31))	('hnRNP', 'Gene', '3183', (89, 94))
396723	32915499	Several cancers such as THCA, PCPG and UVM demonstrated rare hnRNP gene mutations.	('cancers', 'Disease', 'MESH:D009369', (8, 15))	('mutations', 'Var', (72, 81))	('PCPG', 'Disease', (30, 34))	('cancers', 'Phenotype', 'HP:0002664', (8, 15))	('cancers', 'Disease', (8, 15))	('THCA', 'Disease', (24, 28))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('hnRNP', 'Gene', '3183', (61, 66))	('hnRNP', 'Gene', (61, 66))	('UVM', 'Disease', (39, 42))	('as', 'Gene', '112935892', (21, 23))
396726	32915499	The results indicated that colorectal cancer and lung cancer cell lines suggested frequent mutations of most hnRNP genes.	('lung cancer', 'Disease', 'MESH:D008175', (49, 60))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('colorectal cancer', 'Phenotype', 'HP:0003003', (27, 44))	('colorectal cancer', 'Disease', (27, 44))	('lung cancer', 'Disease', (49, 60))	('mutations', 'Var', (91, 100))	('lung cancer', 'Phenotype', 'HP:0100526', (49, 60))	('hnRNP', 'Gene', (109, 114))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('hnRNP', 'Gene', '3183', (109, 114))	('colorectal cancer', 'Disease', 'MESH:D015179', (27, 44))
396727	32915499	In addition, the copy number variations of hnRNP genes were also investigated across different cancer types (Figure 2D): HNRNPA2B1 gene showed widespread copy number amplification across various cancer types whereas almost no CNV was detected in LAML.	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('HNRNPA2B1', 'Gene', '3181', (121, 130))	('HNRNPA2B1', 'Gene', (121, 130))	('cancer', 'Disease', (195, 201))	('copy number', 'Var', (154, 165))	('cancer', 'Disease', (95, 101))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('hnRNP', 'Gene', (43, 48))	('as', 'Gene', '112935892', (231, 233))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('hnRNP', 'Gene', '3183', (43, 48))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('as', 'Gene', '112935892', (213, 215))
396751	32915499	20  In lung cancer, knockdown of HNRNPA1 suppressed the viability and growth as well as induced cell cycle arrest of lung cancer cells.	('lung cancer', 'Disease', (7, 18))	('viability', 'CPA', (56, 65))	('suppressed', 'NegReg', (41, 51))	('knockdown', 'Var', (20, 29))	('induced', 'Reg', (88, 95))	('arrest of lung cancer', 'Disease', (107, 128))	('lung cancer', 'Disease', 'MESH:D008175', (7, 18))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (96, 113))	('lung cancer', 'Disease', 'MESH:D008175', (117, 128))	('growth', 'CPA', (70, 76))	('HNRNPA1', 'Gene', '3178', (33, 40))	('lung cancer', 'Phenotype', 'HP:0100526', (7, 18))	('lung cancer', 'Phenotype', 'HP:0100526', (117, 128))	('arrest of lung cancer', 'Disease', 'MESH:D012131', (107, 128))	('HNRNPA1', 'Gene', (33, 40))	('as', 'Gene', '112935892', (77, 79))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('as', 'Gene', '112935892', (85, 87))
396759	32915499	27  It is worth noting that most hnRNP genes were frequently mutated in UCEC, a certain type of cancer with high global mutation burden.	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('hnRNP', 'Gene', (33, 38))	('hnRNP', 'Gene', '3183', (33, 38))	('mutated', 'Var', (61, 68))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Disease', (96, 102))	('UCEC', 'Disease', (72, 76))
396760	32915499	28  Several cancers such as THCA, PCPG and UVM demonstrated rare hnRNP gene mutations.	('hnRNP', 'Gene', (65, 70))	('as', 'Gene', '112935892', (25, 27))	('cancers', 'Disease', 'MESH:D009369', (12, 19))	('PCPG', 'Disease', (34, 38))	('mutations', 'Var', (76, 85))	('cancers', 'Phenotype', 'HP:0002664', (12, 19))	('cancers', 'Disease', (12, 19))	('THCA', 'Disease', (28, 32))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('UVM', 'Disease', (43, 46))	('hnRNP', 'Gene', '3183', (65, 70))
396761	32915499	Besides, human cancer cell lines analysis based on CCLE demonstrated that colorectal cancer and lung cancer cell lines possess frequent mutations of most hnRNP genes.	('cancer', 'Disease', 'MESH:D009369', (15, 21))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('human', 'Species', '9606', (9, 14))	('as', 'Gene', '112935892', (43, 45))	('mutations', 'Var', (136, 145))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('lung cancer', 'Disease', 'MESH:D008175', (96, 107))	('lung cancer', 'Phenotype', 'HP:0100526', (96, 107))	('colorectal cancer', 'Phenotype', 'HP:0003003', (74, 91))	('hnRNP', 'Gene', '3183', (154, 159))	('cancer', 'Disease', (15, 21))	('cancer', 'Disease', (85, 91))	('hnRNP', 'Gene', (154, 159))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('cancer', 'Disease', (101, 107))	('colorectal cancer', 'Disease', 'MESH:D015179', (74, 91))	('lung cancer', 'Disease', (96, 107))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('colorectal cancer', 'Disease', (74, 91))
396762	32915499	Future investigations concerning the mutations of hnRNP genes in lung cancer and colorectal cancer might reveal critical evidence of contribution of hnRNPs in the development of cancer.	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('hnRNP', 'Gene', '3183', (149, 154))	('colorectal cancer', 'Disease', 'MESH:D015179', (81, 98))	('lung cancer', 'Disease', 'MESH:D008175', (65, 76))	('colorectal cancer', 'Disease', (81, 98))	('hnRNP', 'Gene', (149, 154))	('lung cancer', 'Phenotype', 'HP:0100526', (65, 76))	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', (92, 98))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('mutations', 'Var', (37, 46))	('hnRNP', 'Gene', '3183', (50, 55))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('colorectal cancer', 'Phenotype', 'HP:0003003', (81, 98))	('lung cancer', 'Disease', (65, 76))	('cancer', 'Disease', (178, 184))	('hnRNP', 'Gene', (50, 55))	('cancer', 'Disease', 'MESH:D009369', (70, 76))
396763	32915499	In addition, the copy number variations investigation revealed that HNRNPA2B1 gene showed widespread copy number amplification across various cancer types whereas almost no CNV was detected in LAML.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('copy number amplification', 'Var', (101, 126))	('as', 'Gene', '112935892', (160, 162))	('as', 'Gene', '112935892', (178, 180))	('HNRNPA2B1', 'Gene', '3181', (68, 77))	('HNRNPA2B1', 'Gene', (68, 77))	('cancer', 'Disease', (142, 148))
396779	32915499	Previously, high HNRNPUL2 expression has been reported to predict poor survival of multiple cancers.	('expression', 'MPA', (26, 36))	('high', 'Var', (12, 16))	('cancers', 'Phenotype', 'HP:0002664', (92, 99))	('HNRNPUL2', 'Gene', '221092', (17, 25))	('cancers', 'Disease', 'MESH:D009369', (92, 99))	('cancers', 'Disease', (92, 99))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('HNRNPUL2', 'Gene', (17, 25))	('poor survival', 'CPA', (66, 79))	('as', 'Gene', '112935892', (38, 40))
396785	32915499	In summary, our study systematically demonstrated the expression, mutation, copy number variation, functional pathways and prognostic value of alternative splicing regulator hnRNPs across a series of cancers.	('hnRNP', 'Gene', '3183', (174, 179))	('cancers', 'Disease', 'MESH:D009369', (200, 207))	('cancers', 'Phenotype', 'HP:0002664', (200, 207))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('cancers', 'Disease', (200, 207))	('copy number variation', 'Var', (76, 97))	('mutation', 'Var', (66, 74))	('hnRNP', 'Gene', (174, 179))
396792	32326378	Dysfunction of the Mismatch DNA repair (MMR) mechanism has also been associated with a poor prognosis of these cancers, while a cross-talk between specific miRNAs and MMR genes has been previously proposed.	('cancers', 'Disease', 'MESH:D009369', (111, 118))	('cancers', 'Phenotype', 'HP:0002664', (111, 118))	('Dysfunction', 'Var', (0, 11))	('cancers', 'Disease', (111, 118))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))
396795	32326378	Inhibition of miR-21 restored the NNK-induced reduced MSH2 phenotype in both NCI and FaDu, indicating that miR-21 might contribute to MSH2 regulation.	('FaDu', 'Chemical', '-', (85, 89))	('miR-21', 'Gene', '406991', (14, 20))	('MSH2 phenotype', 'MPA', (54, 68))	('miR-21', 'Gene', (107, 113))	('miR-21', 'Gene', (14, 20))	('reduced', 'NegReg', (46, 53))	('NNK', 'Chemical', 'MESH:C016583', (34, 37))	('Inhibition', 'Var', (0, 10))	('miR-21', 'Gene', '406991', (107, 113))
396797	32326378	We provide novel findings that deregulated miR-21, miR-155, and miR-422a and MMR gene expression patterns may be valuable biomarkers for lung and head and neck squamous cell cancer progression in smokers.	('miR-155', 'Gene', '406947', (51, 58))	('miR-422a', 'Gene', '494334', (64, 72))	('neck squamous cell cancer', 'Disease', 'MESH:D002294', (155, 180))	('MMR', 'Gene', (77, 80))	('miR-21', 'Gene', '406991', (43, 49))	('miR-422a', 'Gene', (64, 72))	('miR-155', 'Gene', (51, 58))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (160, 180))	('neck squamous cell cancer', 'Disease', (155, 180))	('deregulated', 'Var', (31, 42))	('miR-21', 'Gene', (43, 49))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('head and neck squamous cell cancer', 'Phenotype', 'HP:0012288', (146, 180))
396807	32326378	We understand that a functional DNA repair mechanism that includes the recognition and repair of mismatch DNA errors during DNA replication is essential in eliminating the harmful effect of several environmental risk factors, such as NNK, on the exposed cells.	('NNK', 'Chemical', 'MESH:C016583', (234, 237))	('eliminating', 'NegReg', (156, 167))	('men', 'Species', '9606', (205, 208))	('mismatch DNA errors', 'Var', (97, 116))
396869	32326378	We determined the cell viability by comparing the mean values of cells exposed to NNK versus the mean values of untreated cells, for each cancer cell line.	('cancer', 'Disease', (138, 144))	('NNK', 'Chemical', 'MESH:C016583', (82, 85))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('NNK', 'Var', (82, 85))	('cancer', 'Disease', 'MESH:D009369', (138, 144))
396878	32326378	Scoring of nuclear MLH1 revealed statistically significantly lower MLH1 levels in NCI and FaDu exposed to 1 muM or 2 muM of NNK, compared to untreated controls (Figure 2A-b,B-b) [p < 0.05, t-test; means (SD); multiple comparisons by Holm-Sidak].	('lower', 'NegReg', (61, 66))	('MLH1', 'Gene', (67, 71))	('FaDu', 'Chemical', '-', (90, 94))	('muM', 'Gene', '56925', (108, 111))	('muM', 'Gene', '56925', (117, 120))	('muM', 'Gene', (108, 111))	('muM', 'Gene', (117, 120))	('NNK', 'Chemical', 'MESH:C016583', (124, 127))	('NNK', 'Var', (124, 127))
396885	32326378	Specifically, we found that both NCI and FaDu exposed to 2 muM of NNK produced significantly lower transcriptional levels of hMSH2 and hMLH1 compared to those exposed to 1 muM (Figure 4A-a,B-a; Supplementary Table S3).	('FaDu', 'Chemical', '-', (41, 45))	('muM', 'Gene', '56925', (172, 175))	('muM', 'Gene', '56925', (59, 62))	('transcriptional levels', 'MPA', (99, 121))	('muM', 'Gene', (172, 175))	('hMLH1', 'Gene', (135, 140))	('muM', 'Gene', (59, 62))	('lower', 'NegReg', (93, 98))	('hMSH2', 'Gene', '4436', (125, 130))	('men', 'Species', '9606', (200, 203))	('NNK', 'Chemical', 'MESH:C016583', (66, 69))	('NNK', 'Var', (66, 69))	('hMLH1', 'Gene', '4292', (135, 140))	('hMSH2', 'Gene', (125, 130))
396887	32326378	As shown in Table 1, hMSH2 showed a 2-fold and 5.7-fold decrease in its mRNAs, in NCI and FaDu cells, respectively, exposed to 2 muM of NNK, as compared to those exposed to 1 muM.	('muM', 'Gene', (129, 132))	('muM', 'Gene', (175, 178))	('FaDu', 'Chemical', '-', (90, 94))	('mRNAs', 'MPA', (72, 77))	('muM', 'Gene', '56925', (129, 132))	('NNK', 'Chemical', 'MESH:C016583', (136, 139))	('hMSH2', 'Gene', '4436', (21, 26))	('hMSH2', 'Gene', (21, 26))	('decrease', 'NegReg', (56, 64))	('NNK', 'Var', (136, 139))	('muM', 'Gene', '56925', (175, 178))
396894	32326378	We found that both NCI and FaDu exposed to 2 muM of NNK produced significantly higher miR-21 and miR-155 levels compared to cells exposed to 1 muM (Figure 5A-a,B-a).	('high', 'Gene', (79, 83))	('miR-21', 'Gene', '406991', (86, 92))	('muM', 'Gene', '56925', (143, 146))	('FaDu', 'Chemical', '-', (27, 31))	('muM', 'Gene', (143, 146))	('NNK', 'Var', (52, 55))	('muM', 'Gene', '56925', (45, 48))	('high', 'Gene', '104137', (79, 83))	('miR-21', 'Gene', (86, 92))	('miR-155', 'Gene', '406947', (97, 104))	('muM', 'Gene', (45, 48))	('miR-155', 'Gene', (97, 104))	('NNK', 'Chemical', 'MESH:C016583', (52, 55))
396895	32326378	We also found that NCI exposed to 2 muM of NNK produced significantly lower levels of miR-422a compared to those exposed to 1 muM (Figure 5C-a,D-a) (Supplementary Table S4).	('muM', 'Gene', '56925', (126, 129))	('men', 'Species', '9606', (155, 158))	('miR-422a', 'Gene', (86, 94))	('NNK', 'Chemical', 'MESH:C016583', (43, 46))	('muM', 'Gene', (126, 129))	('lower', 'NegReg', (70, 75))	('NNK', 'Var', (43, 46))	('muM', 'Gene', '56925', (36, 39))	('miR-422a', 'Gene', '494334', (86, 94))	('muM', 'Gene', (36, 39))
396902	32326378	Elisa revealed that inhibition of miR-21 prevents the reduced MSH2 phenotype induced by NNK in NCI and FaDu treated cells (Figure 6).	('miR-21', 'Gene', (34, 40))	('NNK', 'Chemical', 'MESH:C016583', (88, 91))	('inhibition', 'Var', (20, 30))	('FaDu', 'Chemical', '-', (103, 107))	('reduced', 'NegReg', (54, 61))	('miR-21', 'Gene', '406991', (34, 40))	('NNK', 'Gene', (88, 91))	('MSH2 phenotype', 'MPA', (62, 76))
396904	32326378	However, inhibition of miR-21 prevented the NNK-induced MSH2 depletion in treated cells (Figure 6, Supplementary Table S5).	('miR-21', 'Gene', (23, 29))	('NNK', 'Chemical', 'MESH:C016583', (44, 47))	('prevented', 'NegReg', (30, 39))	('depletion', 'MPA', (61, 70))	('miR-21', 'Gene', '406991', (23, 29))	('men', 'Species', '9606', (105, 108))	('MSH2', 'Gene', (56, 60))	('inhibition', 'Var', (9, 19))
396909	32326378	In particular, NCI exposed to 1 muM or 2 muM of NNK exhibited a similar increase in cell viability compared to untreated controls (Figure 7A).	('increase', 'PosReg', (72, 80))	('muM', 'Gene', '56925', (41, 44))	('muM', 'Gene', (41, 44))	('muM', 'Gene', '56925', (32, 35))	('cell viability', 'CPA', (84, 98))	('NNK', 'Chemical', 'MESH:C016583', (48, 51))	('muM', 'Gene', (32, 35))	('NNK', 'Var', (48, 51))
396910	32326378	Although FaDu exposed to both 1 muM and 2 muM of NNK increased cell viability compared to untreated controls, it appeared that 2 muM of NNK induced significantly higher survival rates compared to 1 muM, in FaDu (Figure 7B).	('FaDu', 'Chemical', '-', (206, 210))	('muM', 'Gene', (198, 201))	('high', 'Gene', (162, 166))	('muM', 'Gene', (129, 132))	('survival rates', 'CPA', (169, 183))	('muM', 'Gene', '56925', (198, 201))	('muM', 'Gene', '56925', (42, 45))	('high', 'Gene', '104137', (162, 166))	('cell viability', 'CPA', (63, 77))	('muM', 'Gene', '56925', (32, 35))	('muM', 'Gene', (42, 45))	('NNK', 'Chemical', 'MESH:C016583', (136, 139))	('increased', 'PosReg', (53, 62))	('muM', 'Gene', '56925', (129, 132))	('FaDu', 'Chemical', '-', (9, 13))	('NNK', 'Chemical', 'MESH:C016583', (49, 52))	('muM', 'Gene', (32, 35))	('NNK', 'Var', (136, 139))
396915	32326378	However, NNK produced a reduced MMR phenotype and miRNA deregulations in both LSCC and HSCC cells.	('NNK', 'Chemical', 'MESH:C016583', (9, 12))	('LSCC', 'Disease', (78, 82))	('reduced', 'NegReg', (24, 31))	('NNK', 'Var', (9, 12))	('MMR phenotype', 'CPA', (32, 45))	('miRNA deregulations', 'MPA', (50, 69))
396929	32326378	We also showed that inhibition of miR-21 significantly decreases NNK-induced cell survival.	('miR-21', 'Gene', (34, 40))	('inhibition', 'Var', (20, 30))	('decreases', 'NegReg', (55, 64))	('NNK-induced cell survival', 'CPA', (65, 90))	('NNK', 'Chemical', 'MESH:C016583', (65, 68))	('miR-21', 'Gene', '406991', (34, 40))
396936	32326378	The defect in the DNA repair mechanism leads to mutation due to unrepaired NNK-induced DNA adducts.	('leads to', 'Reg', (39, 47))	('mutation', 'Var', (48, 56))	('NNK', 'Chemical', 'MESH:C016583', (75, 78))
396937	32326378	Although damaged or mutated DNA can be removed by apoptosis, cell survival due to either upregulation of the antiapoptotic mechanism or mutations that occur in cancer-related regions may result in uncontrolled cellular growth (antiapoptotic process) and tumor development.	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('tumor', 'Disease', (254, 259))	('men', 'Species', '9606', (267, 270))	('cancer', 'Disease', (160, 166))	('result in', 'Reg', (187, 196))	('tumor', 'Disease', 'MESH:D009369', (254, 259))	('uncontrolled', 'MPA', (197, 209))	('mutations', 'Var', (136, 145))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('upregulation', 'PosReg', (89, 101))	('cell survival', 'CPA', (61, 74))	('tumor', 'Phenotype', 'HP:0002664', (254, 259))
396942	32326378	This observation supports the hypothesis that NNK can not only alter the level of MMR proteins, but may, in parallel, affect modifications of NER proteins, resulting in defective DNA repair.	('NNK', 'Chemical', 'MESH:C016583', (46, 49))	('DNA repair', 'MPA', (179, 189))	('affect', 'Reg', (118, 124))	('level of MMR proteins', 'MPA', (73, 94))	('NNK', 'Var', (46, 49))	('NER proteins', 'Protein', (142, 154))	('alter', 'Reg', (63, 68))	('modifications', 'MPA', (125, 138))	('defective', 'NegReg', (169, 178))
396943	32326378	It is believed that NNK can affect the level of proteins related to DNA repair mechanisms by inducing the formation of pyridyloxobutyl and methyl adducts.	('affect', 'Reg', (28, 34))	('level of proteins', 'MPA', (39, 56))	('formation', 'MPA', (106, 115))	('inducing', 'Reg', (93, 101))	('NNK', 'Chemical', 'MESH:C016583', (20, 23))	('NNK', 'Var', (20, 23))
396947	32326378	Hypo- or hyper- methylation of miRNA was considered to represent a new level of complexity in gene regulation in human cancers, suggesting miR-21 or miR-155 promoter hypo-methylation and miR-422a hyper-methylation, as previously reported for miR-373, as potential epigenetic modifications caused by tobacco carcinogenic effects on MMR.	('miR-21', 'Gene', '406991', (139, 145))	('miR-373', 'Gene', '442918', (242, 249))	('miR-422a', 'Gene', (187, 195))	('miR-422a', 'Gene', '494334', (187, 195))	('miR-155', 'Gene', '406947', (149, 156))	('cancers', 'Disease', 'MESH:D009369', (119, 126))	('cancers', 'Phenotype', 'HP:0002664', (119, 126))	('cancers', 'Disease', (119, 126))	('miR-21', 'Gene', (139, 145))	('tobacco', 'Species', '4097', (299, 306))	('hyper-methylation', 'Var', (196, 213))	('hypo-methylation', 'Var', (166, 182))	('miR-155', 'Gene', (149, 156))	('carcinogenic', 'Disease', 'MESH:D063646', (307, 319))	('carcinogenic', 'Disease', (307, 319))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('human', 'Species', '9606', (113, 118))	('miR-373', 'Gene', (242, 249))
396949	32326378	Subsequently, NNK-induced miRNA deregulations can affect MMR gene expression, either thought post-transcriptional modifications or through DNA methylation by targeting DNA methyltransferases or methylation-related proteins.	('targeting', 'Reg', (158, 167))	('expression', 'MPA', (66, 76))	('affect', 'Reg', (50, 56))	('deregulations', 'Var', (32, 45))	('NNK', 'Chemical', 'MESH:C016583', (14, 17))	('MMR gene', 'Gene', (57, 65))
396950	32326378	Our novel findings showed that either a low or high NNK dose can cause a significant upregulation of "oncomirs" miR-21 and miR-155 and downregulation of "tumor suppressor" miR-422a, as well as a decrease in hMSH2 and hMLH1 at both transcriptional and protein expression levels in exposed lung and head and neck squamous cancer cells.	('NNK', 'Var', (52, 55))	('head and neck squamous cancer', 'Disease', 'MESH:D006258', (297, 326))	('cancer', 'Phenotype', 'HP:0002664', (320, 326))	('high', 'Gene', (47, 51))	('tumor', 'Disease', (154, 159))	('hMSH2', 'Gene', '4436', (207, 212))	('miR-21', 'Gene', '406991', (112, 118))	('decrease', 'NegReg', (195, 203))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('miR-155', 'Gene', (123, 130))	('hMSH2', 'Gene', (207, 212))	('hMLH1', 'Gene', (217, 222))	('hMLH1', 'Gene', '4292', (217, 222))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('miR-21', 'Gene', (112, 118))	('upregulation', 'PosReg', (85, 97))	('miR-155', 'Gene', '406947', (123, 130))	('miR-422a', 'Gene', (172, 180))	('squamous cancer', 'Phenotype', 'HP:0002860', (311, 326))	('head and neck squamous cancer', 'Phenotype', 'HP:0012288', (297, 326))	('miR-422a', 'Gene', '494334', (172, 180))	('downregulation', 'NegReg', (135, 149))	('NNK', 'Chemical', 'MESH:C016583', (52, 55))	('high', 'Gene', '104137', (47, 51))
396954	32326378	It is thought that high levels of MMR can positively contribute to the efficacy of chemotherapy, while a significant number of preclinical and clinical data have shown that inactivation of hMLH1 and hMSH2 promotes resistance to cisplatin and carboplatin-based chemotherapy.	('contribute', 'Reg', (53, 63))	('hMLH1', 'Gene', (189, 194))	('resistance to cisplatin', 'MPA', (214, 237))	('hMLH1', 'Gene', '4292', (189, 194))	('hMSH2', 'Gene', '4436', (199, 204))	('hMSH2', 'Gene', (199, 204))	('high', 'Gene', (19, 23))	('cisplatin', 'Chemical', 'MESH:D002945', (228, 237))	('carboplatin', 'Chemical', 'MESH:D016190', (242, 253))	('high', 'Gene', '104137', (19, 23))	('promotes', 'PosReg', (205, 213))	('inactivation', 'Var', (173, 185))
396956	32326378	Recently, there has been increasing interest in assessing the predictive value of a defective MMR mechanism in various types of cancer, including lung and head and neck cancer.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('cancer', 'Disease', (169, 175))	('MMR', 'Gene', (94, 97))	('head and neck cancer', 'Phenotype', 'HP:0012288', (155, 175))	('lung', 'Disease', (146, 150))	('head and neck cancer', 'Disease', 'MESH:D006258', (155, 175))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('defective', 'Var', (84, 93))	('cancer', 'Disease', 'MESH:D009369', (169, 175))	('cancer', 'Disease', (128, 134))
396958	32326378	The fact that NNK, in addition to its mutagenic effect, which is manifested by inducing DNA defects, can simultaneously suppress the DNA repair mechanism and promote cellular antiapoptosis, supports its carcinogenic potency.	('NNK', 'Var', (14, 17))	('DNA repair mechanism', 'MPA', (133, 153))	('inducing', 'Reg', (79, 87))	('cellular antiapoptosis', 'CPA', (166, 188))	('promote', 'PosReg', (158, 165))	('carcinogenic', 'Disease', 'MESH:D063646', (203, 215))	('carcinogenic', 'Disease', (203, 215))	('NNK', 'Chemical', 'MESH:C016583', (14, 17))	('suppress', 'NegReg', (120, 128))
396959	32326378	Our observation that NNK caused a decrease in the expression of MMR genes in lung and head and neck squamous cancer cells may support the theory that exposure of these cells to tobacco smoke could have a potential modulatory effect in the treatment and natural history of the disease.	('men', 'Species', '9606', (244, 247))	('head and neck squamous cancer', 'Phenotype', 'HP:0012288', (86, 115))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('squamous cancer', 'Phenotype', 'HP:0002860', (100, 115))	('decrease', 'NegReg', (34, 42))	('MMR genes', 'Gene', (64, 73))	('NNK', 'Chemical', 'MESH:C016583', (21, 24))	('NNK', 'Var', (21, 24))	('tobacco', 'Species', '4097', (177, 184))	('expression', 'MPA', (50, 60))	('head and neck squamous cancer', 'Disease', 'MESH:D006258', (86, 115))
396960	32326378	In summary, the current study shows that NNK, either at a high or low dose, can cause deregulation in miR-21, miR-155 and miR-422a, and downregulation of MMR genes.	('deregulation', 'MPA', (86, 98))	('high', 'Gene', (58, 62))	('miR-21', 'Gene', (102, 108))	('miR-155', 'Gene', '406947', (110, 117))	('downregulation', 'NegReg', (136, 150))	('miR-422a', 'Gene', '494334', (122, 130))	('high', 'Gene', '104137', (58, 62))	('NNK', 'Chemical', 'MESH:C016583', (41, 44))	('MMR genes', 'Gene', (154, 163))	('miR-21', 'Gene', '406991', (102, 108))	('miR-155', 'Gene', (110, 117))	('miR-422a', 'Gene', (122, 130))	('NNK', 'Var', (41, 44))
396961	32326378	In addition to promoting the deregulation of the MMR mechanism, NNK can simultaneously enhance the viability of cancer cells, potentially promoting cancer progression.	('cancer', 'Disease', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('MMR', 'Protein', (49, 52))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('promoting', 'PosReg', (138, 147))	('deregulation', 'MPA', (29, 41))	('NNK', 'Chemical', 'MESH:C016583', (64, 67))	('promoting', 'PosReg', (15, 24))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('enhance', 'PosReg', (87, 94))	('NNK', 'Var', (64, 67))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))
396962	32326378	Finally, inhibition of miR-21 can restore NNK-induced MSH2 reduction and decreases cell survival.	('miR-21', 'Gene', (23, 29))	('NNK-induced MSH2', 'MPA', (42, 58))	('decreases', 'NegReg', (73, 82))	('cell survival', 'CPA', (83, 96))	('restore', 'PosReg', (34, 41))	('miR-21', 'Gene', '406991', (23, 29))	('reduction', 'NegReg', (59, 68))	('NNK', 'Chemical', 'MESH:C016583', (42, 45))	('inhibition', 'Var', (9, 19))
397020	32323780	The human KYSE-70, EC109, KYSE-510, TE1, TE13, EC1 and EC9706 ESCC cell lines and the normal esophageal squamous epithelium HET-1A cell line were provided by Basic Medical Sciences of Zhengzhou University (Zhengzhou, China).	('EC1', 'Gene', (47, 50))	('HET-1A', 'CellLine', 'CVCL:3702', (124, 130))	('EC1', 'Gene', (19, 22))	('human', 'Species', '9606', (4, 9))	('EC9706', 'Var', (55, 61))	('EC1', 'Gene', '4819', (47, 50))	('ESCC', 'Disease', 'MESH:C562729', (62, 66))	('KYSE-510', 'CellLine', 'CVCL:1354', (26, 34))	('EC109', 'CellLine', 'CVCL:6898', (19, 24))	('EC9706', 'CellLine', 'CVCL:E307', (55, 61))	('ESCC', 'Disease', (62, 66))	('EC1', 'Gene', '4819', (19, 22))
397048	32323780	Moreover, silencing of NLRP3 significantly decreased tumor cell invasion in the TE13 cells (P<0.0001) and KYSE-70 (P=0.0002) cells, as well as migration in the TE13 (P<0.0001) and KYSE-70 (P=0.0037) cells (Fig.	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Disease', (53, 58))	('migration', 'CPA', (143, 152))	('decreased', 'NegReg', (43, 52))	('silencing', 'Var', (10, 19))	('NLRP3', 'Gene', (23, 28))
397050	32323780	As compared with the pcDNA-3.1(+) plasmid-transfected cells, the CCK-8 assay results showed that pcDNA-3.1(+)-NLRP3-transfected (OE-NLRP3) KYSE-510 cells had an increased viability (P=0.002), however, EC9706 cells showed no significant increase in viability (P=0.60) (Fig.	('increased', 'PosReg', (161, 170))	('pcDNA-3.1(+)-NLRP3-transfected', 'Var', (97, 127))	('KYSE-510', 'CellLine', 'CVCL:1354', (139, 147))	('EC9706', 'CellLine', 'CVCL:E307', (201, 207))
397051	32323780	Consistently, the wound-healing capability of the cells was also strongly increased in the EC9706 (P=0.045) and KYSE-510 (P=0.021) cells following NLRP3 overexpression (Fig.	('overexpression', 'PosReg', (153, 167))	('KYSE-510', 'CellLine', 'CVCL:1354', (112, 120))	('NLRP3', 'Gene', (147, 152))	('increased', 'PosReg', (74, 83))	('EC9706', 'Var', (91, 97))	('wound-healing capability of the cells', 'CPA', (18, 55))	('EC9706', 'CellLine', 'CVCL:E307', (91, 97))
397063	32323780	These data indicate that patients with a high NLRP3 expression may have a more malignant clinical phenotype.	('NLRP3', 'Gene', (46, 51))	('expression', 'MPA', (52, 62))	('patients', 'Species', '9606', (25, 33))	('high', 'Var', (41, 45))
397075	30948501	Then, we found high expression of GHET1 is a useful biomarker to discriminate cervical cancer tissues from non-tumorous tissues, and associated with advanced clinical stage, lymph node metastasis, distant metastasis and poor histological grade in cervical cancer patients.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('high expression', 'Var', (15, 30))	('associated with', 'Reg', (133, 148))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('patients', 'Species', '9606', (263, 271))	('distant metastasis', 'CPA', (197, 215))	('cervical cancer', 'Disease', 'MESH:D002583', (78, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cervical cancer', 'Disease', 'MESH:D002583', (247, 262))	('tumor', 'Disease', (111, 116))	('cervical cancer', 'Disease', (78, 93))	('GHET1', 'Gene', '102723099', (34, 39))	('cervical cancer', 'Disease', (247, 262))	('lymph node metastasis', 'CPA', (174, 195))	('cancer', 'Phenotype', 'HP:0002664', (256, 262))	('GHET1', 'Gene', (34, 39))
397076	30948501	The survival analysis showed high GHET1 expression was an independent unfavorable prognostic factor in cervical cancer patients.	('high', 'Var', (29, 33))	('expression', 'MPA', (40, 50))	('patients', 'Species', '9606', (119, 127))	('GHET1', 'Gene', '102723099', (34, 39))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('GHET1', 'Gene', (34, 39))	('cervical cancer', 'Disease', (103, 118))	('cervical cancer', 'Disease', 'MESH:D002583', (103, 118))
397078	30948501	The loss-of-function study indicated knockdown of GHET1 expression markedly inhibits cervical cancer cell proliferation, migration, and invasion.	('migration', 'CPA', (121, 130))	('loss-of-function', 'NegReg', (4, 20))	('cervical cancer', 'Disease', 'MESH:D002583', (85, 100))	('knockdown', 'Var', (37, 46))	('GHET1', 'Gene', '102723099', (50, 55))	('inhibits', 'NegReg', (76, 84))	('cervical cancer', 'Disease', (85, 100))	('invasion', 'CPA', (136, 144))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('GHET1', 'Gene', (50, 55))
397114	30948501	As shown in Table 1, high expression of GHET1 was associated with advanced clinical stage (I-IIA vs IIB-IV, P<0.001), lymph node metastasis (absent vs present, P<0.001), distant metastasis (absent vs present vs, P=0.010) and poor histological grade (well vs moderately/poorly, P=0.003).	('distant metastasis', 'CPA', (170, 188))	('lymph node metastasis', 'CPA', (118, 139))	('GHET1', 'Gene', '102723099', (40, 45))	('advanced clinical stage', 'CPA', (66, 89))	('high expression', 'Var', (21, 36))	('GHET1', 'Gene', (40, 45))	('poor histological', 'CPA', (225, 242))
397117	30948501	In addition, the univariate Cox regression analysis suggested that advanced clinical stage (P=0.012), lymph node metastasis (P=0.001), distant metastasis (P=0.010), poor histological grade (P=0.012), and high GHET1 expression (P<0.001) were poor prognostic factors for overall survival in patients with cervical cancer (Table 2).	('patients', 'Species', '9606', (289, 297))	('Cox', 'Gene', '1351', (28, 31))	('Cox', 'Gene', (28, 31))	('GHET1', 'Gene', '102723099', (209, 214))	('high', 'Var', (204, 208))	('cancer', 'Phenotype', 'HP:0002664', (312, 318))	('GHET1', 'Gene', (209, 214))	('cervical cancer', 'Disease', (303, 318))	('cervical cancer', 'Disease', 'MESH:D002583', (303, 318))	('expression', 'MPA', (215, 225))
397118	30948501	Then, high GHET1 expression was identified as an independent unfavorable prognostic factor in cervical cancer patients through multivariate Cox regression analysis (P=0.001, Table 2).	('GHET1', 'Gene', (11, 16))	('Cox', 'Gene', '1351', (140, 143))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('patients', 'Species', '9606', (110, 118))	('expression', 'MPA', (17, 27))	('Cox', 'Gene', (140, 143))	('high', 'Var', (6, 10))	('GHET1', 'Gene', '102723099', (11, 16))	('cervical cancer', 'Disease', (94, 109))	('cervical cancer', 'Disease', 'MESH:D002583', (94, 109))
397123	30948501	The results showed the migratory and invasive capabilities of cervical cancer cells were dramatically decreased after transfecting with si-GHET1 (P<0.001, Figure 4C,D).	('GHET1', 'Gene', '102723099', (139, 144))	('transfecting', 'Var', (118, 130))	('GHET1', 'Gene', (139, 144))	('cervical cancer', 'Disease', (62, 77))	('cervical cancer', 'Disease', 'MESH:D002583', (62, 77))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('decreased', 'NegReg', (102, 111))
397138	30948501	indicated that high levels of GHET1 were associated with advanced clinical stage, larger tumor size, and present lymph node metastasis in breast cancer patients.	('associated', 'Reg', (41, 51))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('breast cancer', 'Disease', 'MESH:D001943', (138, 151))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('breast cancer', 'Phenotype', 'HP:0003002', (138, 151))	('GHET1', 'Gene', '102723099', (30, 35))	('GHET1', 'Gene', (30, 35))	('patients', 'Species', '9606', (152, 160))	('breast cancer', 'Disease', (138, 151))	('high levels', 'Var', (15, 26))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
397144	30948501	In our research, we found that cervical cancer patients with high expression of GHET1 had a worse overall survival time than patients with low expression of GHET1 through Kaplan-Meier method and log-rank test, and high GHET1 expression was identified as an independent unfavorable prognostic factor in cervical cancer patients through univariate and multivariate Cox regression analysis.	('patients', 'Species', '9606', (47, 55))	('cervical cancer', 'Disease', (31, 46))	('cervical cancer', 'Disease', 'MESH:D002583', (31, 46))	('worse', 'NegReg', (92, 97))	('cancer', 'Phenotype', 'HP:0002664', (311, 317))	('patients', 'Species', '9606', (125, 133))	('Cox', 'Gene', (363, 366))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('GHET1', 'Gene', '102723099', (80, 85))	('GHET1', 'Gene', (80, 85))	('overall survival time', 'CPA', (98, 119))	('GHET1', 'Gene', '102723099', (157, 162))	('GHET1', 'Gene', (157, 162))	('high expression', 'Var', (61, 76))	('patients', 'Species', '9606', (318, 326))	('cervical cancer', 'Disease', 'MESH:D002583', (302, 317))	('GHET1', 'Gene', '102723099', (219, 224))	('cervical cancer', 'Disease', (302, 317))	('Cox', 'Gene', '1351', (363, 366))	('GHET1', 'Gene', (219, 224))
397145	30948501	Similar results in non-small cell lung cancer, patients with high GHET1 expression had short overall survival time and high GHET1 expression was an independent unfavorable prognostic predictor for overall survival.	('GHET1', 'Gene', '102723099', (124, 129))	('overall survival', 'MPA', (93, 109))	('non-small cell lung cancer', 'Disease', (19, 45))	('GHET1', 'Gene', (66, 71))	('high', 'Var', (119, 123))	('short', 'NegReg', (87, 92))	('GHET1', 'Gene', (124, 129))	('high', 'Var', (61, 65))	('patients', 'Species', '9606', (47, 55))	('lung cancer', 'Phenotype', 'HP:0100526', (34, 45))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (23, 45))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (19, 45))	('GHET1', 'Gene', '102723099', (66, 71))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (19, 45))
397146	30948501	showed that hepatocellular carcinoma cases with high GHET1 expression had poor prognosis and high GHET1 expression was an independent poor prognostic factor for overall survival.	('carcinoma', 'Phenotype', 'HP:0030731', (27, 36))	('GHET1', 'Gene', '102723099', (53, 58))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (12, 36))	('GHET1', 'Gene', '102723099', (98, 103))	('GHET1', 'Gene', (53, 58))	('hepatocellular carcinoma', 'Disease', (12, 36))	('GHET1', 'Gene', (98, 103))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (12, 36))	('high', 'Var', (48, 52))
397148	30948501	Generally, high GHET1 expression is an unfavorable biomarker for most human cancers.	('cancers', 'Disease', 'MESH:D009369', (76, 83))	('cancers', 'Phenotype', 'HP:0002664', (76, 83))	('cancers', 'Disease', (76, 83))	('GHET1', 'Gene', '102723099', (16, 21))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('human', 'Species', '9606', (70, 75))	('GHET1', 'Gene', (16, 21))	('high', 'Var', (11, 15))	('expression', 'MPA', (22, 32))
397152	30948501	In our results, we preliminarily found that knockdown of GHET1 expression markedly inhibited cell proliferation, migration, and invasion in cervical cancer, which was consistent with its function in other cancers.	('cancers', 'Disease', 'MESH:D009369', (205, 212))	('cancers', 'Disease', (205, 212))	('cervical cancer', 'Disease', (140, 155))	('cervical cancer', 'Disease', 'MESH:D002583', (140, 155))	('cell proliferation', 'CPA', (93, 111))	('inhibited', 'NegReg', (83, 92))	('GHET1', 'Gene', (57, 62))	('GHET1', 'Gene', '102723099', (57, 62))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('migration', 'CPA', (113, 122))	('knockdown', 'Var', (44, 53))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('invasion', 'CPA', (128, 136))	('cancers', 'Phenotype', 'HP:0002664', (205, 212))
397388	30127874	High Skp2 protein expression in patients with LUAD was associated with reduced overall survival (OS; P<0.001), but not in patients with LUSC (P=0.686).	('patients', 'Species', '9606', (32, 40))	('protein', 'Protein', (10, 17))	('High', 'Var', (0, 4))	('Skp2', 'Gene', '6502', (5, 9))	('LUAD', 'Phenotype', 'HP:0030078', (46, 50))	('patients', 'Species', '9606', (122, 130))	('LUAD', 'Disease', (46, 50))	('reduced', 'NegReg', (71, 78))	('Skp2', 'Gene', (5, 9))	('LUSC', 'Phenotype', 'HP:0030359', (136, 140))	('overall survival', 'MPA', (79, 95))
397393	30127874	LUSC with high Skp2 expression may have robust proliferation ability.	('expression', 'MPA', (20, 30))	('Skp2', 'Gene', '6502', (15, 19))	('high', 'Var', (10, 14))	('Skp2', 'Gene', (15, 19))	('LUSC', 'Phenotype', 'HP:0030359', (0, 4))
397437	30127874	The majority of Skp2 expression scores were <0.025 in the LUAD group, while scores >0.250 were observed more frequently in LUSC (Fig.	('LUAD', 'Phenotype', 'HP:0030078', (58, 62))	('<0.025', 'Var', (44, 50))	('Skp2', 'Gene', '6502', (16, 20))	('LUSC', 'Phenotype', 'HP:0030359', (123, 127))	('LUSC', 'Disease', (123, 127))	('Skp2', 'Gene', (16, 20))
397450	30127874	In the TCGA cohort of patients with LUAD and LUSC, Skp2 expression was highly expressed in the TP53, NF1 and RB1 mutation groups, compared with the unaltered group.	('RB1', 'Gene', '5925', (109, 112))	('mutation', 'Var', (113, 121))	('Skp2', 'Gene', (51, 55))	('NF1', 'Gene', (101, 104))	('highly', 'PosReg', (71, 77))	('NF1', 'Gene', '4763', (101, 104))	('patients', 'Species', '9606', (22, 30))	('expression', 'MPA', (56, 66))	('LUAD', 'Phenotype', 'HP:0030078', (36, 40))	('RB1', 'Gene', (109, 112))	('TP53', 'Gene', '7157', (95, 99))	('Skp2', 'Gene', '6502', (51, 55))	('TP53', 'Gene', (95, 99))	('LUSC', 'Phenotype', 'HP:0030359', (45, 49))
397458	30127874	This indicated that alterations of lung cancer associated oncogenes modulating these pathways may contribute to the aberration of Skp2 expression.	('alterations', 'Var', (20, 31))	('Skp2', 'Gene', (130, 134))	('modulating', 'Reg', (68, 78))	('lung cancer', 'Disease', 'MESH:D008175', (35, 46))	('contribute', 'Reg', (98, 108))	('lung cancer', 'Disease', (35, 46))	('Skp2', 'Gene', '6502', (130, 134))	('lung cancer', 'Phenotype', 'HP:0100526', (35, 46))	('expression', 'MPA', (135, 145))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))
397459	30127874	The association between lung cancer mutations and Skp2 expression were then investigated.	('Skp2', 'Gene', '6502', (50, 54))	('mutations', 'Var', (36, 45))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('lung cancer', 'Disease', (24, 35))	('lung cancer', 'Phenotype', 'HP:0100526', (24, 35))	('Skp2', 'Gene', (50, 54))	('lung cancer', 'Disease', 'MESH:D008175', (24, 35))
397462	30127874	Different driver gene mutation frequencies may be one reason for the distinct expression patterns of Skp2 in LUSC and LUAD; however, this would not fully explain the difference of Skp2 expression between LUAD and LUSC.	('LUSC', 'Phenotype', 'HP:0030359', (213, 217))	('mutation', 'Var', (22, 30))	('Skp2', 'Gene', '6502', (180, 184))	('Skp2', 'Gene', '6502', (101, 105))	('Skp2', 'Gene', (101, 105))	('LUSC', 'Phenotype', 'HP:0030359', (109, 113))	('Skp2', 'Gene', (180, 184))	('LUAD', 'Phenotype', 'HP:0030078', (204, 208))	('LUAD', 'Phenotype', 'HP:0030078', (118, 122))
397469	30127874	In the present study, it was demonstrated that a high expression of Skp2 may indicate a poor prognosis in LUAD, but it was not observed in LUSC.	('LUAD', 'Phenotype', 'HP:0030078', (106, 110))	('LUSC', 'Phenotype', 'HP:0030359', (139, 143))	('Skp2', 'Gene', '6502', (68, 72))	('high', 'Var', (49, 53))	('Skp2', 'Gene', (68, 72))	('LUAD', 'Disease', (106, 110))
397484	29207658	A recent study associated the methylation of homologous recombination genes with expression of immune checkpoints in lung squamous cell carcinoma.	('methylation', 'Var', (30, 41))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (117, 145))	('associated', 'Reg', (15, 25))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (117, 145))	('lung squamous cell carcinoma', 'Disease', (117, 145))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (122, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('expression', 'MPA', (81, 91))
397486	29207658	Further, the multivariate Cox regression analysis showed that the morbidity of patients with high expression of RAD51B was decreased by 26% compared to those with low expression (HR=0.74, 95%CI: 0.59-0.93), especially for the patients with squamous cell carcinoma (HR=0.68, 95%CI: 0.51-0.90).	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (240, 263))	('squamous cell carcinoma', 'Disease', (240, 263))	('morbidity', 'MPA', (66, 75))	('decreased', 'NegReg', (123, 132))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (240, 263))	('RAD51B', 'Gene', (112, 118))	('patients', 'Species', '9606', (226, 234))	('patients', 'Species', '9606', (79, 87))	('high expression', 'Var', (93, 108))	('carcinoma', 'Phenotype', 'HP:0030731', (254, 263))	('Cox', 'Gene', '1351', (26, 29))	('Cox', 'Gene', (26, 29))
397487	29207658	In conclusion, RAD51B in mRNA level can be an important indicator to decide the prognosis of NSCLC and its overexpression predicts a preferable prognosis for NSCLC.	('NSCLC', 'Disease', (158, 163))	('NSCLC', 'Disease', (93, 98))	('NSCLC', 'Disease', 'MESH:D002289', (158, 163))	('NSCLC', 'Disease', 'MESH:D002289', (93, 98))	('RAD51B', 'Var', (15, 21))	('NSCLC', 'Phenotype', 'HP:0030358', (158, 163))	('overexpression', 'PosReg', (107, 121))	('NSCLC', 'Phenotype', 'HP:0030358', (93, 98))
397488	29207658	Our results serve as a foundation for the investigation of the role of RAD51B in NSCLC, which may lead to potential therapeutic innovations.	('NSCLC', 'Phenotype', 'HP:0030358', (81, 86))	('RAD51B', 'Var', (71, 77))	('NSCLC', 'Disease', 'MESH:D002289', (81, 86))	('NSCLC', 'Disease', (81, 86))
397496	29207658	Furthermore, targetable mutations and targeted therapy resistance development in 50% of NSCLC cases emphasizes the significance for developing new prognostic indicators and alternative therapeutic strategies for treating NSCLC.	('NSCLC', 'Phenotype', 'HP:0030358', (88, 93))	('NSCLC', 'Disease', (221, 226))	('NSCLC', 'Disease', 'MESH:D002289', (88, 93))	('NSCLC', 'Disease', 'MESH:D002289', (221, 226))	('NSCLC', 'Disease', (88, 93))	('mutations', 'Var', (24, 33))	('NSCLC', 'Phenotype', 'HP:0030358', (221, 226))
397497	29207658	Notably, DNA double-strand breaks (DSBs) are particularly detrimental which can result in mutations and chromosomal translocations and may induce cancer.	('result in', 'Reg', (80, 89))	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('chromosomal translocations', 'CPA', (104, 130))	('DSBs', 'Chemical', '-', (35, 39))	('mutations', 'CPA', (90, 99))	('DNA double-strand breaks', 'Var', (9, 33))	('induce', 'Reg', (139, 145))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))
397498	29207658	Previous researches have shown that the aberration of its expression has significant effects on tumorigenesis and tumor progression.	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('expression', 'MPA', (58, 68))	('tumor', 'Disease', (96, 101))	('tumor', 'Disease', (114, 119))	('effects', 'Reg', (85, 92))	('aberration', 'Var', (40, 50))	('tumor', 'Disease', 'MESH:D009369', (96, 101))
397499	29207658	It has also been suggested that RAD51 homologues (RAD51B, RAD51C, RAD51D, XRCC2, and XRCC3) are important cofactors for RAD51 protein in the process of chain transfer or chain interaction to initiate DNA homologous pairing.	('RAD51D', 'Gene', '5892', (66, 72))	('XRCC3', 'Gene', (85, 90))	('RAD51D', 'Gene', (66, 72))	('RAD51C', 'Gene', '5889', (58, 64))	('XRCC3', 'Gene', '7517', (85, 90))	('XRCC2', 'Gene', '7516', (74, 79))	('RAD51C', 'Gene', (58, 64))	('RAD51', 'Var', (120, 125))	('XRCC2', 'Gene', (74, 79))
397500	29207658	In addition to their independent functions, they were observed to form two major complexes: one defined as BCDX2 is made of RAD51B, RAD51C, RAD51D and XRCC2, whereas the other named CX3 consists of RAD51C and XRCC3.	('RAD51D', 'Gene', (140, 146))	('RAD51B', 'Var', (124, 130))	('RAD51C', 'Gene', '5889', (132, 138))	('RAD51C', 'Gene', (198, 204))	('RAD51C', 'Gene', (132, 138))	('XRCC3', 'Gene', (209, 214))	('RAD51C', 'Gene', '5889', (198, 204))	('XRCC2', 'Gene', '7516', (151, 156))	('XRCC3', 'Gene', '7517', (209, 214))	('XRCC2', 'Gene', (151, 156))	('RAD51D', 'Gene', '5892', (140, 146))
397507	29207658	Hence, we hypothesize that RAD51 homologues may have a positive correlation with lung cancer prognosis.	('lung cancer', 'Disease', (81, 92))	('lung cancer', 'Phenotype', 'HP:0100526', (81, 92))	('RAD51', 'Var', (27, 32))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('lung cancer', 'Disease', 'MESH:D008175', (81, 92))
397510	29207658	Herein, we show that RAD51B overexpression could indicate an increase in the overall survival rate of NSCLC patients, which suggests that RAD51B could act as a new potential biomarker and a predictor of better prognosis of NSCLC patients.	('NSCLC', 'Disease', 'MESH:D002289', (102, 107))	('patients', 'Species', '9606', (229, 237))	('NSCLC', 'Disease', (223, 228))	('RAD51B', 'Var', (138, 144))	('NSCLC', 'Disease', 'MESH:D002289', (223, 228))	('NSCLC', 'Phenotype', 'HP:0030358', (102, 107))	('overall survival', 'CPA', (77, 93))	('overexpression', 'PosReg', (28, 42))	('increase', 'PosReg', (61, 69))	('patients', 'Species', '9606', (108, 116))	('NSCLC', 'Phenotype', 'HP:0030358', (223, 228))	('NSCLC', 'Disease', (102, 107))	('RAD51B', 'Gene', (21, 27))
397511	29207658	At the beginning, we analyzed the relationship between the prognosis of NSCLC and RAD51 family mRNA levels that are available from the TCGA database, including RAD51B, RAD51C, RAD51D, XRCC2, and XRCC3, however, no significant correlation was found except for RAD51B (data not shown).	('RAD51C', 'Gene', (168, 174))	('NSCLC', 'Disease', (72, 77))	('RAD51D', 'Gene', '5892', (176, 182))	('XRCC3', 'Gene', (195, 200))	('NSCLC', 'Disease', 'MESH:D002289', (72, 77))	('RAD51D', 'Gene', (176, 182))	('RAD51B', 'Var', (160, 166))	('XRCC3', 'Gene', '7517', (195, 200))	('XRCC2', 'Gene', '7516', (184, 189))	('NSCLC', 'Phenotype', 'HP:0030358', (72, 77))	('RAD51C', 'Gene', '5889', (168, 174))	('XRCC2', 'Gene', (184, 189))
397512	29207658	Hence, our analysis focuses on RAD51B associated with NSCLC in mRNA level, as follows.	('RAD51B', 'Var', (31, 37))	('associated with', 'Reg', (38, 53))	('NSCLC', 'Phenotype', 'HP:0030358', (54, 59))	('NSCLC', 'Disease', (54, 59))	('NSCLC', 'Disease', 'MESH:D002289', (54, 59))
397513	29207658	In Table 1, we found that there was a higher expression level of RAD51B in NSCLC patients with male, squamous cell carcinoma, EGFR mutation, and no KRAS mutation than the reference groups (all P<0.05).	('KRAS', 'Gene', (148, 152))	('RAD51B', 'Gene', (65, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('EGFR', 'Gene', (126, 130))	('NSCLC', 'Phenotype', 'HP:0030358', (75, 80))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (101, 124))	('KRAS', 'Gene', '3845', (148, 152))	('patients', 'Species', '9606', (81, 89))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (101, 124))	('EGFR', 'Gene', '1956', (126, 130))	('squamous cell carcinoma', 'Disease', (101, 124))	('NSCLC', 'Disease', (75, 80))	('higher', 'PosReg', (38, 44))	('NSCLC', 'Disease', 'MESH:D002289', (75, 80))	('expression level', 'MPA', (45, 61))	('mutation', 'Var', (131, 139))
397517	29207658	For the total patients, we found that patients with high RAD51B expression have a longer median survival time than those with low RAD51B expression (P=0.013, Figure 1A).	('longer', 'PosReg', (82, 88))	('RAD51B', 'Var', (57, 63))	('patients', 'Species', '9606', (38, 46))	('patients', 'Species', '9606', (14, 22))	('high RAD51B', 'Var', (52, 63))	('median survival time', 'CPA', (89, 109))
397523	29207658	However, a significantly better prognosis effect for RAD51B was not found in NSCLC patients with adenocarcinoma (HR=0.78, 95%CI: 0.53~1.16).	('NSCLC', 'Disease', 'MESH:D002289', (77, 82))	('adenocarcinoma', 'Disease', 'MESH:D000230', (97, 111))	('patients', 'Species', '9606', (83, 91))	('NSCLC', 'Phenotype', 'HP:0030358', (77, 82))	('RAD51B', 'Var', (53, 59))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('adenocarcinoma', 'Disease', (97, 111))	('NSCLC', 'Disease', (77, 82))
397527	29207658	This result implies that RAD51B could be a candidate prognostic factor for NSCLC patients.	('RAD51B', 'Var', (25, 31))	('NSCLC', 'Phenotype', 'HP:0030358', (75, 80))	('patients', 'Species', '9606', (81, 89))	('NSCLC', 'Disease', (75, 80))	('NSCLC', 'Disease', 'MESH:D002289', (75, 80))
397528	29207658	Furthermore, after adjustment for some potential confounding factors, the multivariate Cox regression analysis showed that the death risk of patients with high expressions of RAD51B decreased by 26% compared to those with low expression, especially for NSCLC patients with squamous cell carcinoma.	('patients', 'Species', '9606', (259, 267))	('decreased', 'NegReg', (182, 191))	('NSCLC', 'Phenotype', 'HP:0030358', (253, 258))	('death', 'Disease', 'MESH:D003643', (127, 132))	('Cox', 'Gene', '1351', (87, 90))	('carcinoma', 'Phenotype', 'HP:0030731', (287, 296))	('RAD51B', 'Gene', (175, 181))	('death', 'Disease', (127, 132))	('NSCLC', 'Disease', (253, 258))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (273, 296))	('NSCLC', 'Disease', 'MESH:D002289', (253, 258))	('Cox', 'Gene', (87, 90))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (273, 296))	('high expressions', 'Var', (155, 171))	('patients', 'Species', '9606', (141, 149))	('squamous cell carcinoma', 'Disease', (273, 296))
397531	29207658	Recently, a few researches have focused on a genetic level to study the association between RAD51B genetic variants and the risk of the male breast cancer in a GWAS study, and the association with death risk of glioblastoma in a case-control study.	('glioblastoma', 'Phenotype', 'HP:0012174', (211, 223))	('death', 'Disease', (197, 202))	('association', 'Interaction', (72, 83))	('variants', 'Var', (107, 115))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('RAD51B', 'Gene', (92, 98))	('breast cancer', 'Disease', 'MESH:D001943', (141, 154))	('breast cancer', 'Disease', (141, 154))	('breast cancer', 'Phenotype', 'HP:0003002', (141, 154))	('glioblastoma', 'Disease', (211, 223))	('glioblastoma', 'Disease', 'MESH:D005909', (211, 223))	('death', 'Disease', 'MESH:D003643', (197, 202))
397532	29207658	In accord with our findings, in terms of the epigenetic level, Rieke reported that hypermethylation of RAD51B was associated with an immune-evasive phenotype in squamous cell carcinoma in a recent publication, which indicates that DNA methylation-mediated decrease in RAD51B expression levels may predict a poorer prognosis because of activated immune evasion.	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (161, 184))	('RAD51B', 'Gene', (103, 109))	('expression levels', 'MPA', (275, 292))	('squamous cell carcinoma', 'Disease', (161, 184))	('hypermethylation', 'Var', (83, 99))	('decrease', 'NegReg', (256, 264))	('associated', 'Reg', (114, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (175, 184))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (161, 184))
397534	29207658	Furthermore, the finding of Osamu Date shows that haploinsufficiency of RAD51B leads to aberrant homologous recombination repair as well as centrosome fragmentation and increased aneuploidy in HCT116 cells, which indicates that loss of the proper biallelic expression of RAD51B is likely to be linked with malignant transformation by inducing chromosome instability.	('RAD51B', 'Gene', (72, 78))	('aneuploidy', 'Disease', 'MESH:D000782', (179, 189))	('chromosome instability', 'Phenotype', 'HP:0040012', (343, 365))	('aneuploidy', 'Disease', (179, 189))	('inducing', 'Reg', (334, 342))	('increased', 'PosReg', (169, 178))	('haploinsufficiency', 'Disease', (50, 68))	('homologous recombination repair', 'MPA', (97, 128))	('centrosome fragmentation', 'CPA', (140, 164))	('chromosome instability', 'CPA', (343, 365))	('loss', 'Var', (228, 232))	('linked', 'Reg', (294, 300))	('RAD51B', 'Gene', (271, 277))	('HCT116', 'CellLine', 'CVCL:0291', (193, 199))	('haploinsufficiency', 'Disease', 'MESH:D058495', (50, 68))
397535	29207658	Also, RAD51B has been shown to interact directly with P53, implying its function as a tumor suppressor.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('RAD51B', 'Var', (6, 12))	('interact', 'Interaction', (31, 39))	('tumor', 'Disease', (86, 91))	('P53', 'Protein', (54, 57))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
397536	29207658	In uterine leiomyoma, the phenomenon of frequent inactivation of RAD51B by translocation between chromosomes 12 and 14 was noticed, supporting a positive role of RAD51B in tumorigenesis.	('translocation', 'Var', (75, 88))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('RAD51B', 'Gene', (65, 71))	('leiomyoma', 'Disease', (11, 20))	('inactivation', 'NegReg', (49, 61))	('tumor', 'Disease', (172, 177))	('uterine leiomyoma', 'Phenotype', 'HP:0000131', (3, 20))	('leiomyoma', 'Disease', 'MESH:D007889', (11, 20))	('tumor', 'Disease', 'MESH:D009369', (172, 177))
397539	29207658	A recent report found that overexpression of the wild-type RAD51B protein of CHO cells containing a mutant P53 can induce G1 delay, which could cause senescence of normal cells but control the proliferation of cancer cells, indicating that hyperexpression of RAD51B may play a positive role in cancer prognosis.	('RAD51B', 'Gene', (59, 65))	('senescence', 'MPA', (150, 160))	('mutant', 'Var', (100, 106))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('cancer', 'Disease', 'MESH:D009369', (294, 300))	('cause', 'Reg', (144, 149))	('cancer', 'Disease', (294, 300))	('G1 delay', 'MPA', (122, 130))	('cancer', 'Disease', 'MESH:D009369', (210, 216))	('proliferation', 'MPA', (193, 206))	('overexpression', 'PosReg', (27, 41))	('cancer', 'Phenotype', 'HP:0002664', (294, 300))	('P53', 'Gene', (107, 110))	('cancer', 'Disease', (210, 216))
397541	29207658	Besides, evidence demonstrates that RAD51B could interact with RAD51C to form a highly stable heterodimer, facilitating RAD51 to replace RPA from the nucleo filaments and promoting the DNA strand exchange activity of RAD51-ssDNA filaments.	('RAD51C', 'Gene', (63, 69))	('RAD51C', 'Gene', '5889', (63, 69))	('RPA', 'MPA', (137, 140))	('DNA strand exchange activity', 'MPA', (185, 213))	('promoting', 'PosReg', (171, 180))	('RAD51', 'Var', (120, 125))
397544	29207658	Intriguingly, in contrast to our findings on RAD51B, others showed that hyperexpression of RAD51B in a subset of GC (Gastric Cancer) was significantly associated with poor prognosis and resistance to chemotherapy.	('hyperexpression', 'Var', (72, 87))	('associated', 'Reg', (151, 161))	('RAD51B', 'Gene', (91, 97))	('Gastric Cancer', 'Phenotype', 'HP:0012126', (117, 131))	('resistance', 'CPA', (186, 196))	('Cancer', 'Phenotype', 'HP:0002664', (125, 131))	('Gastric Cancer', 'Disease', (117, 131))	('Gastric Cancer', 'Disease', 'MESH:D013274', (117, 131))
397547	29207658	Nevertheless, our results provide statistical evidence for RAD51B as an independent factor affecting the prognosis of NSCLC, especially for the patients with squamous cell carcinoma.	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (158, 181))	('RAD51B', 'Var', (59, 65))	('NSCLC', 'Phenotype', 'HP:0030358', (118, 123))	('affecting', 'Reg', (91, 100))	('patients', 'Species', '9606', (144, 152))	('NSCLC', 'Disease', (118, 123))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (158, 181))	('NSCLC', 'Disease', 'MESH:D002289', (118, 123))	('carcinoma', 'Phenotype', 'HP:0030731', (172, 181))	('squamous cell carcinoma', 'Disease', (158, 181))
397552	29207658	As a result, we found the P70 (>6.39) as the optimum cutoff point of RAD51B, which classifies the NSCLC patients significantly after performing the Log-rank test.	('P70', 'Gene', '84959', (26, 29))	('RAD51B', 'Var', (69, 75))	('NSCLC', 'Phenotype', 'HP:0030358', (98, 103))	('P70', 'Gene', (26, 29))	('NSCLC', 'Disease', (98, 103))	('patients', 'Species', '9606', (104, 112))	('NSCLC', 'Disease', 'MESH:D002289', (98, 103))
397557	29207658	NSCLC Non-small-cell lung cancer HR Hazard ratio DSBs DNA double-strand breaks OS Overall survival CHO Chinese hamster ovary HCT116 Human colorectal cancer cell line RAD Radiation-repair gene XRCC X-ray repair cross-complementing	('Non-small-cell lung cancer', 'Disease', (6, 32))	('DSBs', 'Var', (49, 53))	('NSCLC', 'Phenotype', 'HP:0030358', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('colorectal cancer', 'Phenotype', 'HP:0003003', (138, 155))	('Non-small-cell lung cancer', 'Disease', 'MESH:D002289', (6, 32))	('Chinese hamster', 'Species', '10029', (103, 118))	('OS', 'Chemical', '-', (79, 81))	('HCT116', 'CellLine', 'CVCL:0291', (125, 131))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('Human', 'Species', '9606', (132, 137))	('colorectal cancer', 'Disease', 'MESH:D015179', (138, 155))	('NSCLC', 'Disease', 'MESH:D002289', (0, 5))	('Non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (6, 32))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (10, 32))	('lung cancer', 'Phenotype', 'HP:0100526', (21, 32))	('colorectal cancer', 'Disease', (138, 155))	('DSBs', 'Chemical', '-', (49, 53))	('NSCLC', 'Disease', (0, 5))
397569	30552330	As a result of the selective pressure that TMZ applies in a clinical setting, cells with abnormal MGMT expression and/or inactivation of MMR proteins gain a survival advantage and contribute to resistance to therapy.	('abnormal', 'Var', (89, 97))	('survival advantage', 'CPA', (157, 175))	('inactivation', 'Var', (121, 133))	('MMR proteins', 'Gene', (137, 149))	('TMZ', 'Chemical', 'MESH:D000077204', (43, 46))	('MGMT', 'Gene', (98, 102))	('resistance', 'CPA', (194, 204))	('MGMT', 'Gene', '4255', (98, 102))	('gain', 'PosReg', (150, 154))
397584	30552330	These profiles could then be used to identify small molecule combinations that maximize the efficacy for GBM and other cancer types.	('combinations', 'Var', (61, 73))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('GBM', 'Disease', (105, 108))	('cancer', 'Disease', (119, 125))	('GBM', 'Phenotype', 'HP:0012174', (105, 108))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
397604	30552330	In addition to the compound-specific pharmacological relevance, we found that TCS, in contrast to the average replicate signatures, significantly reduced cell-specific bias thus improving the integration and comparability of the GBM PDX L1000 data with the LINCS L1000 reference data (Supplementary Figure 1).	('GBM', 'Phenotype', 'HP:0012174', (229, 232))	('TCS', 'Var', (78, 81))	('TCS', 'Chemical', '-', (78, 81))	('cell-specific bias', 'MPA', (154, 172))	('comparability', 'MPA', (208, 221))	('reduced', 'NegReg', (146, 153))	('improving', 'PosReg', (178, 187))	('integration', 'MPA', (192, 203))
397612	30552330	More specifically, BI-2536 is a PLK/BRD4 inhibitor, TG101348 is a dual JAK2/BRD4 inhibitor and XMD11-50 is a dual LRRK2/BRD4 inhibitor.	('BRD4', 'Gene', (36, 40))	('JAK2', 'Gene', '3717', (71, 75))	('XMD11-50', 'Chemical', '-', (95, 103))	('TG101348', 'Var', (52, 60))	('BI-2536', 'Chemical', 'MESH:C518477', (19, 26))	('JAK2', 'Gene', (71, 75))	('TG101348', 'Chemical', 'MESH:C528327', (52, 60))	('LRRK2', 'Gene', (114, 119))	('BRD4', 'Gene', (120, 124))	('BI-2536', 'Var', (19, 26))	('BRD4', 'Gene', '23476', (76, 80))	('BRD4', 'Gene', '23476', (36, 40))	('LRRK2', 'Gene', '120892', (114, 119))	('BRD4', 'Gene', '23476', (120, 124))	('BRD4', 'Gene', (76, 80))
397630	30552330	We identified the Aurora kinase B inhibitor GSK-1070916 as the most orthogonal compound to JQ1 in the glioblastoma gene expression background (Fig.	('glioblastoma', 'Disease', (102, 114))	('glioblastoma', 'Disease', 'MESH:D005909', (102, 114))	('glioblastoma', 'Phenotype', 'HP:0012174', (102, 114))	('Aurora kinase B', 'Gene', (18, 33))	('GSK-1070916', 'Var', (44, 55))	('Aurora kinase B', 'Gene', '9212', (18, 33))	('GSK-1070916', 'Chemical', 'MESH:C544308', (44, 55))
397631	30552330	GSK-1070916 also has a very low CR value, indicating that its transcriptional signature is not similar to the JQ1 reference signature, and the highest OS as the overall most transcriptionally orthogonal to GBM-JQ1.	('OS', 'Chemical', '-', (151, 153))	('GSK-1070916', 'Chemical', 'MESH:C544308', (0, 11))	('GBM', 'Phenotype', 'HP:0012174', (206, 209))	('CR', 'Chemical', '-', (32, 34))	('CR value', 'MPA', (32, 40))	('GSK-1070916', 'Var', (0, 11))
397638	30552330	As a negative control, we identified SR1277, a casein kinase 1delta inhibitor, as a compound with both a low CR value and a low DR value, and thus predicted to have a sub-synergistic effect in combination with JQ1.	('SR1277', 'Var', (37, 43))	('low', 'NegReg', (105, 108))	('CR value', 'MPA', (109, 117))	('SR1277', 'Chemical', '-', (37, 43))	('DR value', 'MPA', (128, 136))	('CR', 'Chemical', '-', (109, 111))	('casein kinase 1delta', 'Gene', '1453', (47, 67))	('casein kinase 1delta', 'Gene', (47, 67))
397640	30552330	We found that the combination of GSK-1070916 and JQ1 produced a synergistic effect (Fig.	('JQ1', 'Gene', (49, 52))	('GSK-1070916', 'Var', (33, 44))	('synergistic effect', 'MPA', (64, 82))	('GSK-1070916', 'Chemical', 'MESH:C544308', (33, 44))	('combination', 'Interaction', (18, 29))
397641	30552330	5f) and the combination of SR1277 and JQ1 produced a sub-synergistic effect (Fig.	('JQ1', 'Var', (38, 41))	('SR1277', 'Chemical', '-', (27, 33))	('SR1277', 'Var', (27, 33))	('sub-synergistic effect', 'MPA', (53, 75))
397646	30552330	6 and Supplementary Figure 4, JQ1 synergized with alisertib in vitro, and a combination of alisertib and JQ1 reduced tumor growth of GBM22 cells in vivo more than either treatment alone.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('GBM', 'Phenotype', 'HP:0012174', (133, 136))	('alisertib', 'Var', (91, 100))	('combination', 'Var', (76, 87))	('tumor', 'Disease', (117, 122))	('alisertib', 'Chemical', 'MESH:C550258', (50, 59))	('JQ1', 'Gene', (105, 108))	('GBM22', 'Gene', (133, 138))	('reduced', 'NegReg', (109, 116))	('alisertib', 'Chemical', 'MESH:C550258', (91, 100))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
397647	30552330	In addition, mice treated with the JQ1+alisertib combination did not have reduced weight relative to mice treated with control vehicle.	('mice', 'Species', '10090', (13, 17))	('JQ1+alisertib', 'Var', (35, 48))	('reduced weight', 'Phenotype', 'HP:0004325', (74, 88))	('mice', 'Species', '10090', (101, 105))	('alisertib', 'Chemical', 'MESH:C550258', (39, 48))	('reduced', 'NegReg', (74, 81))
397659	30552330	We utilized SynergySeq to identify the compound that was most discordant to the GBM disease signature and orthogonal to JQ1, GSK-1070916, an Aurora kinase B/C inhibitor.	('GSK-1070916', 'Var', (125, 136))	('GBM disease', 'Disease', (80, 91))	('Aurora kinase B', 'Gene', (141, 156))	('GSK-1070916', 'Chemical', 'MESH:C544308', (125, 136))	('GBM', 'Phenotype', 'HP:0012174', (80, 83))	('Aurora kinase B', 'Gene', '9212', (141, 156))
397660	30552330	We demonstrated that combining GSK-1070916 with JQ1 induces synergy in reducing proliferation of GBM cells and that another Aurora kinase inhibitor, alisertib, synergizes with JQ1 to reduce tumor growth in vitro and in vivo.	('reducing', 'NegReg', (71, 79))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('GSK-1070916', 'Chemical', 'MESH:C544308', (31, 42))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('alisertib', 'Chemical', 'MESH:C550258', (149, 158))	('tumor', 'Disease', (190, 195))	('GBM', 'Phenotype', 'HP:0012174', (97, 100))	('reduce', 'NegReg', (183, 189))	('GSK-1070916', 'Var', (31, 42))
397694	30552330	In all screens, reduced cell proliferation was measured by normalizing the raw fluorescent values to the negative control (DMSO, 0% reduction) and the positive control (Velcade, 100% reduction) using the following formula: where LO is the raw luminescent output value, EC0 is the mean raw luminescent of the negative control, and EC100 is the mean raw luminescent output of the positive control.	('EC0', 'Var', (269, 272))	('cell proliferation', 'CPA', (24, 42))	('reduction', 'NegReg', (132, 141))	('DMSO', 'Chemical', 'MESH:D004121', (123, 127))	('reduced', 'NegReg', (16, 23))	('Velcade', 'Chemical', 'MESH:D000069286', (169, 176))
397704	30552330	When the tumors reached 200 mm3 mice were injected with either DMSO, JQ1, alisertib, or JQ1+alisertib.	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('alisertib', 'Chemical', 'MESH:C550258', (92, 101))	('tumors', 'Disease', (9, 15))	('JQ1+alisertib', 'Var', (88, 101))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('alisertib', 'Chemical', 'MESH:C550258', (74, 83))	('mice', 'Species', '10090', (32, 36))	('DMSO', 'Chemical', 'MESH:D004121', (63, 67))	('tumors', 'Disease', 'MESH:D009369', (9, 15))
397713	29207620	In this study, we detected a significant association between the rs408014 and rs7771314 SNPs at the TXNDC5 locus and cervical carcinoma using the Taqman genotyping method.	('TXNDC5', 'Gene', '81567', (100, 106))	('rs408014', 'Var', (65, 73))	('cervical carcinoma', 'Disease', (117, 135))	('rs7771314', 'Mutation', 'rs7771314', (78, 87))	('cervical carcinoma', 'Disease', 'MESH:D002575', (117, 135))	('rs408014', 'Mutation', 'rs408014', (65, 73))	('rs7771314', 'Var', (78, 87))	('TXNDC5', 'Gene', (100, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))
397715	29207620	Additionally, inhibition of TXNDC5 expression using siRNA prevented tube-like structure formation, an experimental indicator of vasculogenic mimicry and metastasis, in HeLa cervical tumor cells.	('TXNDC5', 'Gene', '81567', (28, 34))	('HeLa cervical tumor', 'Disease', (168, 187))	('prevented', 'NegReg', (58, 67))	('TXNDC5', 'Gene', (28, 34))	('cervical tumor', 'Phenotype', 'HP:0030159', (173, 187))	('tube-like structure formation', 'CPA', (68, 97))	('HeLa cervical tumor', 'Disease', 'MESH:D002583', (168, 187))	('inhibition', 'Var', (14, 24))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
397716	29207620	Inhibiting TXNDC5 expression simultaneously led to the increased expression of SERPINF1 (serpin peptidase inhibitor, clade F) and TRAF1 (TNF receptor-associated factor 1), which have been reported to inhibit angiogenesis and metastasis as well as induce apoptosis.	('TNF receptor-associated factor 1', 'Gene', (137, 169))	('TRAF1', 'Gene', '7185', (130, 135))	('Inhibiting', 'Var', (0, 10))	('induce', 'Reg', (247, 253))	('inhibit', 'NegReg', (200, 207))	('TNF receptor-associated factor 1', 'Gene', '7185', (137, 169))	('increased', 'PosReg', (55, 64))	('SERPINF1', 'Gene', (79, 87))	('TRAF1', 'Gene', (130, 135))	('apoptosis', 'CPA', (254, 263))	('expression', 'MPA', (65, 75))	('TXNDC5', 'Gene', (11, 17))	('TXNDC5', 'Gene', '81567', (11, 17))
397720	29207620	The present study suggests that TXNDC5 is a susceptibility gene in cervical cancer, and high expression of this gene contributes to abnormal angiogenesis, vasculogenic mimicry and metastasis by down-regulating SERPINF1 and TRAF1 expression.	('TXNDC5', 'Gene', (32, 38))	('metastasis', 'CPA', (180, 190))	('cervical cancer', 'Disease', (67, 82))	('high expression', 'Var', (88, 103))	('SERPINF1', 'Protein', (210, 218))	('vasculogenic mimicry', 'CPA', (155, 175))	('TRAF1', 'Gene', '7185', (223, 228))	('contributes', 'Reg', (117, 128))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('down-regulating', 'NegReg', (194, 209))	('TXNDC5', 'Gene', '81567', (32, 38))	('abnormal angiogenesis', 'CPA', (132, 153))	('TRAF1', 'Gene', (223, 228))	('cervical cancer', 'Disease', 'MESH:D002583', (67, 82))	('expression', 'MPA', (229, 239))
397734	29207620	A case-control analysis revealed a significant association of rs9505298, rs7771314, rs2815128, rs13210097 and rs9392182 SNPs in the TXNDC5 gene with cervical carcinoma, esophageal carcinoma, and liver cancer, but the results were not verified in independent cohorts with large numbers of samples using other genotyping method.	('rs13210097', 'Mutation', 'rs13210097', (95, 105))	('liver cancer', 'Disease', 'MESH:D006528', (195, 207))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('cervical carcinoma', 'Disease', 'MESH:D002575', (149, 167))	('rs9392182', 'Mutation', 'rs9392182', (110, 119))	('TXNDC5', 'Gene', (132, 138))	('liver cancer', 'Phenotype', 'HP:0002896', (195, 207))	('liver cancer', 'Disease', (195, 207))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (169, 189))	('carcinoma', 'Phenotype', 'HP:0030731', (158, 167))	('rs7771314', 'Mutation', 'rs7771314', (73, 82))	('rs9505298', 'Var', (62, 71))	('TXNDC5', 'Gene', '81567', (132, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (180, 189))	('rs7771314', 'Var', (73, 82))	('esophageal carcinoma', 'Disease', (169, 189))	('rs2815128', 'Mutation', 'rs2815128', (84, 93))	('rs9505298', 'Mutation', 'rs9505298', (62, 71))	('rs9392182 SNPs', 'Var', (110, 124))	('rs13210097', 'Var', (95, 105))	('rs2815128', 'Var', (84, 93))	('cervical carcinoma', 'Disease', (149, 167))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (169, 189))
397736	29207620	Five SNPs in the TXNDC5 locus, including rs2815128, rs408014, rs4959462, rs7763203 and rs7771314, were genotyped using the Taqman genotyping method in patient cohorts of breast cancer, cervical carcinoma, colorectal cancer, esophageal carcinoma, gastric carcinoma, liver cancer, lung cancer, and rectal carcinoma as well as healthy controls.	('liver cancer', 'Disease', 'MESH:D006528', (265, 277))	('rectal carcinoma', 'Disease', (296, 312))	('rs408014', 'Var', (52, 60))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (224, 244))	('rs4959462', 'Var', (62, 71))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('carcinoma', 'Phenotype', 'HP:0030731', (254, 263))	('gastric carcinoma', 'Disease', 'MESH:D013274', (246, 263))	('lung cancer', 'Disease', 'MESH:D008175', (279, 290))	('gastric carcinoma', 'Disease', (246, 263))	('colorectal cancer', 'Disease', 'MESH:D015179', (205, 222))	('cancer', 'Phenotype', 'HP:0002664', (271, 277))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('liver cancer', 'Phenotype', 'HP:0002896', (265, 277))	('rectal carcinoma', 'Disease', 'MESH:D012004', (296, 312))	('cervical carcinoma', 'Disease', (185, 203))	('patient', 'Species', '9606', (151, 158))	('rs2815128', 'Mutation', 'rs2815128', (41, 50))	('liver cancer', 'Disease', (265, 277))	('rs4959462', 'Mutation', 'rs4959462', (62, 71))	('lung cancer', 'Phenotype', 'HP:0100526', (279, 290))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (246, 263))	('colorectal cancer', 'Disease', (205, 222))	('breast cancer', 'Phenotype', 'HP:0003002', (170, 183))	('rs2815128', 'Var', (41, 50))	('cervical carcinoma', 'Disease', 'MESH:D002575', (185, 203))	('TXNDC5', 'Gene', (17, 23))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (224, 244))	('carcinoma', 'Phenotype', 'HP:0030731', (235, 244))	('breast cancer', 'Disease', 'MESH:D001943', (170, 183))	('rs7763203', 'Mutation', 'rs7763203', (73, 82))	('breast cancer', 'Disease', (170, 183))	('cancer', 'Phenotype', 'HP:0002664', (284, 290))	('rs7771314', 'Mutation', 'rs7771314', (87, 96))	('esophageal carcinoma', 'Disease', (224, 244))	('rs7763203', 'Var', (73, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (194, 203))	('rs7771314', 'Var', (87, 96))	('colorectal cancer', 'Phenotype', 'HP:0003003', (205, 222))	('lung cancer', 'Disease', (279, 290))	('rectal carcinoma', 'Phenotype', 'HP:0100743', (296, 312))	('TXNDC5', 'Gene', '81567', (17, 23))	('carcinoma', 'Phenotype', 'HP:0030731', (303, 312))	('rs408014', 'Mutation', 'rs408014', (52, 60))
397737	29207620	The case-control analysis exhibited a significant difference in the allele frequency of rs408014 (odds ratio = 1.328862; 95% CI = [1.035893~1.704689], p = 0.025157) between cervical carcinoma patients and controls.	('rs408014', 'Mutation', 'rs408014', (88, 96))	('patients', 'Species', '9606', (192, 200))	('carcinoma', 'Phenotype', 'HP:0030731', (182, 191))	('cervical carcinoma', 'Disease', 'MESH:D002575', (173, 191))	('cervical carcinoma', 'Disease', (173, 191))	('rs408014', 'Var', (88, 96))
397738	29207620	The analysis also revealed a significant difference in the allele frequency (odds ratio=0.512561; 95% CI = [0.303152~0.866624], p = 0.011327) and the gene frequency (p = 0.033817) of rs7771314 between cervical carcinoma patients and the controls.	('carcinoma', 'Phenotype', 'HP:0030731', (210, 219))	('rs7771314', 'Mutation', 'rs7771314', (183, 192))	('difference', 'Reg', (41, 51))	('patients', 'Species', '9606', (220, 228))	('rs7771314', 'Var', (183, 192))	('cervical carcinoma', 'Disease', 'MESH:D002575', (201, 219))	('cervical carcinoma', 'Disease', (201, 219))
397739	29207620	In addition, the analysis revealed a significant difference in the allele frequency (odds ratio = 0.553230; 95% CI = [0.323325~0.946612], p = 0.028771) of rs2815128 between breast cancer patients and controls.	('patients', 'Species', '9606', (187, 195))	('breast cancer', 'Phenotype', 'HP:0003002', (173, 186))	('rs2815128', 'Var', (155, 164))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('rs2815128', 'Mutation', 'rs2815128', (155, 164))	('breast cancer', 'Disease', 'MESH:D001943', (173, 186))	('breast cancer', 'Disease', (173, 186))
397741	29207620	Significant differences in the allelic or genotypic frequencies of rs4959462 and rs7763203 (p > 0.05) were not detected by genotyping among patients with breast cancer, cervical carcinoma, colorectal cancer, esophageal carcinoma, gastric carcinoma, liver cancer, lung cancer or rectal carcinoma and the controls.	('gastric carcinoma', 'Disease', 'MESH:D013274', (230, 247))	('colorectal cancer', 'Phenotype', 'HP:0003003', (189, 206))	('lung cancer', 'Disease', (263, 274))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('gastric carcinoma', 'Disease', (230, 247))	('liver cancer', 'Disease', 'MESH:D006528', (249, 261))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (230, 247))	('rectal carcinoma', 'Phenotype', 'HP:0100743', (278, 294))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (208, 228))	('cancer', 'Phenotype', 'HP:0002664', (255, 261))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('carcinoma', 'Phenotype', 'HP:0030731', (238, 247))	('rectal carcinoma', 'Disease', (278, 294))	('patients', 'Species', '9606', (140, 148))	('lung cancer', 'Disease', 'MESH:D008175', (263, 274))	('liver cancer', 'Phenotype', 'HP:0002896', (249, 261))	('cervical carcinoma', 'Disease', (169, 187))	('colorectal cancer', 'Disease', 'MESH:D015179', (189, 206))	('liver cancer', 'Disease', (249, 261))	('rs4959462', 'Var', (67, 76))	('lung cancer', 'Phenotype', 'HP:0100526', (263, 274))	('carcinoma', 'Phenotype', 'HP:0030731', (285, 294))	('rectal carcinoma', 'Disease', 'MESH:D012004', (278, 294))	('breast cancer', 'Phenotype', 'HP:0003002', (154, 167))	('colorectal cancer', 'Disease', (189, 206))	('cervical carcinoma', 'Disease', 'MESH:D002575', (169, 187))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (208, 228))	('carcinoma', 'Phenotype', 'HP:0030731', (219, 228))	('breast cancer', 'Disease', 'MESH:D001943', (154, 167))	('rs4959462', 'Mutation', 'rs4959462', (67, 76))	('breast cancer', 'Disease', (154, 167))	('rs7763203', 'Mutation', 'rs7763203', (81, 90))	('cancer', 'Phenotype', 'HP:0002664', (268, 274))	('carcinoma', 'Phenotype', 'HP:0030731', (178, 187))	('esophageal carcinoma', 'Disease', (208, 228))	('rs7763203', 'Var', (81, 90))
397760	29207620	HeLa cells treated with anti-TXNDC5 and anti-SERPINF1; anti-TXNDC5 and TRAF1 siRNA; or anti-TXNDC5, anti-SERPINF1 and TRAF1 siRNA exhibited significantly increased tube-like structures compared with cells treated with anti-TXNDC5 alone.	('TXNDC5', 'Gene', '81567', (223, 229))	('TRAF1', 'Gene', '7185', (71, 76))	('TXNDC5', 'Gene', (92, 98))	('TRAF1', 'Gene', (118, 123))	('TXNDC5', 'Gene', (60, 66))	('anti-SERPINF1', 'Var', (40, 53))	('TXNDC5', 'Gene', '81567', (29, 35))	('TRAF1', 'Gene', (71, 76))	('tube-like structures', 'CPA', (164, 184))	('TXNDC5', 'Gene', (29, 35))	('TXNDC5', 'Gene', (223, 229))	('TXNDC5', 'Gene', '81567', (92, 98))	('TXNDC5', 'Gene', '81567', (60, 66))	('anti-SERPINF1', 'Var', (100, 113))	('HeLa', 'CellLine', 'CVCL:0030', (0, 4))	('TRAF1', 'Gene', '7185', (118, 123))	('increased', 'PosReg', (154, 163))
397782	29207620	In the present study, Taqman genotyping demonstrated a significant association between rs408014 and rs7771314 in the TXNDC5 locus and cervical carcinoma.	('rs7771314', 'Mutation', 'rs7771314', (100, 109))	('cervical carcinoma', 'Disease', 'MESH:D002575', (134, 152))	('cervical carcinoma', 'Disease', (134, 152))	('rs408014', 'Var', (87, 95))	('rs7771314', 'Var', (100, 109))	('TXNDC5', 'Gene', (117, 123))	('carcinoma', 'Phenotype', 'HP:0030731', (143, 152))	('rs408014', 'Mutation', 'rs408014', (87, 95))	('TXNDC5', 'Gene', '81567', (117, 123))
397785	29207620	This case-control analysis revealed a significant difference in allele frequencies and genotype frequencies for rs9505298, rs7771314, rs2815128, rs13210097 and rs9392182 among patients with breast cancer, cervical carcinoma, esophageal carcinoma, gastric carcinoma and liver cancer.	('cervical carcinoma', 'Disease', (205, 223))	('gastric carcinoma and liver cancer', 'Disease', 'MESH:D013274', (247, 281))	('breast cancer', 'Disease', (190, 203))	('breast cancer', 'Disease', 'MESH:D001943', (190, 203))	('rs9505298', 'Var', (112, 121))	('cervical carcinoma', 'Disease', 'MESH:D002575', (205, 223))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (247, 264))	('carcinoma', 'Phenotype', 'HP:0030731', (255, 264))	('carcinoma', 'Phenotype', 'HP:0030731', (214, 223))	('rs9505298', 'Mutation', 'rs9505298', (112, 121))	('rs7771314', 'Mutation', 'rs7771314', (123, 132))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (225, 245))	('rs2815128', 'Mutation', 'rs2815128', (134, 143))	('rs13210097', 'Var', (145, 155))	('rs7771314', 'Var', (123, 132))	('carcinoma', 'Phenotype', 'HP:0030731', (236, 245))	('esophageal carcinoma', 'Disease', (225, 245))	('rs13210097', 'Mutation', 'rs13210097', (145, 155))	('rs2815128', 'Var', (134, 143))	('rs9392182', 'Mutation', 'rs9392182', (160, 169))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('rs9392182', 'Var', (160, 169))	('patients', 'Species', '9606', (176, 184))	('cancer', 'Phenotype', 'HP:0002664', (275, 281))	('liver cancer', 'Phenotype', 'HP:0002896', (269, 281))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (225, 245))	('breast cancer', 'Phenotype', 'HP:0003002', (190, 203))
397786	29207620	The results of the current study, which were completed using the Taqman genotyping method, are consistent with results of previous studies and confirms the strong association between rs7771314 and cervical tumor risk.	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('rs7771314', 'Mutation', 'rs7771314', (183, 192))	('tumor', 'Disease', (206, 211))	('rs7771314', 'Var', (183, 192))	('tumor', 'Disease', 'MESH:D009369', (206, 211))	('cervical tumor', 'Phenotype', 'HP:0030159', (197, 211))
397796	29207620	found that the proportion of poorly differentiated gastric adenocarcinomas was significantly increased in tumors with high TXNDC5 expression compared with specimens with low TXNDC5 expression.	('high', 'Var', (118, 122))	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('TXNDC5', 'Gene', (174, 180))	('tumors', 'Disease', (106, 112))	('increased', 'PosReg', (93, 102))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('TXNDC5', 'Gene', (123, 129))	('gastric adenocarcinomas', 'Disease', 'MESH:D013274', (51, 74))	('gastric adenocarcinomas', 'Disease', (51, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('carcinomas', 'Phenotype', 'HP:0030731', (64, 74))	('TXNDC5', 'Gene', '81567', (123, 129))	('TXNDC5', 'Gene', '81567', (174, 180))
397797	29207620	Lymph node metastasis and the depth of tumor invasion were significantly increased in specimens that exhibited high TXNDC5 expression compared with specimens with low TXNDC5 expression.	('increased', 'PosReg', (73, 82))	('TXNDC5', 'Gene', (116, 122))	('TXNDC5', 'Gene', (167, 173))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('TXNDC5', 'Gene', '81567', (116, 122))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('TXNDC5', 'Gene', '81567', (167, 173))	('tumor', 'Disease', (39, 44))	('Lymph node metastasis', 'CPA', (0, 21))	('high', 'Var', (111, 115))
397798	29207620	A survival analysis by the same group revealed that the prognosis of patients who exhibited high TXNDC5 expression was significantly poorer than that of patients who exhibited low TXNDC5 expression.	('poorer', 'NegReg', (133, 139))	('TXNDC5', 'Gene', '81567', (180, 186))	('high', 'Var', (92, 96))	('patients', 'Species', '9606', (153, 161))	('TXNDC5', 'Gene', '81567', (97, 103))	('TXNDC5', 'Gene', (180, 186))	('patients', 'Species', '9606', (69, 77))	('TXNDC5', 'Gene', (97, 103))
397803	29207620	The silencing of TXNDC5 expression also restrains the growth and proliferation of gastric cancer cells.	('gastric cancer', 'Phenotype', 'HP:0012126', (82, 96))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('TXNDC5', 'Gene', (17, 23))	('gastric cancer', 'Disease', 'MESH:D013274', (82, 96))	('restrains', 'NegReg', (40, 49))	('gastric cancer', 'Disease', (82, 96))	('TXNDC5', 'Gene', '81567', (17, 23))	('silencing', 'Var', (4, 13))
397837	29207620	To confirm the pathway from TXNDC5 to SERPINF1 and TRAF1 that stimulates cell migration and vasculogenic mimicry, we simultaneously transfected HeLa cells with anti-TXNDC5, anti-SERPINF1 and TRAF1 siRNA and observed tube-like structure formation.	('anti-SERPINF1', 'Var', (173, 186))	('TRAF1', 'Gene', (51, 56))	('TXNDC5', 'Gene', '81567', (28, 34))	('TXNDC5', 'Gene', '81567', (165, 171))	('observed', 'Reg', (207, 215))	('TRAF1', 'Gene', (191, 196))	('TXNDC5', 'Gene', (165, 171))	('cell migration', 'CPA', (73, 87))	('TXNDC5', 'Gene', (28, 34))	('TRAF1', 'Gene', '7185', (51, 56))	('HeLa', 'CellLine', 'CVCL:0030', (144, 148))	('TRAF1', 'Gene', '7185', (191, 196))	('tube-like structure formation', 'CPA', (216, 245))
397838	29207620	We found that the treatment of these cells with anti-TXNDC5 and anti-SERPINF1 or anti-TXNDC5 and TRAF1 siRNA considerably rescued the ability to form tube-like structures compared with treatment with anti-TXNDC5 siRNA alone.	('TXNDC5', 'Gene', (205, 211))	('TXNDC5', 'Gene', '81567', (86, 92))	('anti-SERPINF1', 'Var', (64, 77))	('rescued', 'PosReg', (122, 129))	('TXNDC5', 'Gene', '81567', (205, 211))	('TRAF1', 'Gene', '7185', (97, 102))	('TXNDC5', 'Gene', '81567', (53, 59))	('TXNDC5', 'Gene', (86, 92))	('TRAF1', 'Gene', (97, 102))	('TXNDC5', 'Gene', (53, 59))
397842	29207620	Inactivation of NR4A1 decreased TXNDC5 expression, resulting in activation of the ROS/endoplasmic reticulum stress and proapoptotic pathways.	('TXNDC5', 'Gene', (32, 38))	('ROS', 'Chemical', 'MESH:D017382', (82, 85))	('TXNDC5', 'Gene', '81567', (32, 38))	('proapoptotic pathways', 'Pathway', (119, 140))	('NR4A1', 'Gene', (16, 21))	('activation', 'PosReg', (64, 74))	('NR4A1', 'Gene', '3164', (16, 21))	('Inactivation', 'Var', (0, 12))	('decreased', 'NegReg', (22, 31))
397853	29207620	The tag SNPs rs2815128, rs408014, rs4959462, rs7763203 and rs7771314 were selected on the basis of linkage disequilibrium patterns that were observed in samples obtained from the Han Chinese population of Beijing, which was genotyped as part of the International HapMap Project.	('rs2815128', 'Var', (13, 22))	('rs2815128', 'Mutation', 'rs2815128', (13, 22))	('rs7771314', 'Var', (59, 68))	('rs408014', 'Var', (24, 32))	('rs7763203', 'Var', (45, 54))	('rs4959462', 'Var', (34, 43))	('rs4959462', 'Mutation', 'rs4959462', (34, 43))	('rs408014', 'Mutation', 'rs408014', (24, 32))	('rs7763203', 'Mutation', 'rs7763203', (45, 54))	('rs7771314', 'Mutation', 'rs7771314', (59, 68))
397888	29207620	To confirm the pathogenic pathway of TXNDC5, we simultaneously transfected HeLa cells with anti-TXNDC5, anti-SERPINF1 or anti-TRAF1 siRNA and observed the tube-like formation ability of the treated cells.	('tube-like formation ability', 'CPA', (155, 182))	('TXNDC5', 'Gene', (37, 43))	('TXNDC5', 'Gene', '81567', (96, 102))	('TRAF1', 'Gene', '7185', (126, 131))	('TXNDC5', 'Gene', '81567', (37, 43))	('HeLa', 'CellLine', 'CVCL:0030', (75, 79))	('TRAF1', 'Gene', (126, 131))	('TXNDC5', 'Gene', (96, 102))	('anti-SERPINF1', 'Var', (104, 117))
397889	29207620	The targeting sequence of anti- SERPINF1S siRNA is 5' CCAGAATTTGACCTTGATA 3', and the targeting sequence of anti-TRAF1 siRNA is 5' GAACCCATCTGTCGCTCTT 3'.	('anti-', 'Var', (26, 31))	('TRAF1', 'Gene', '7185', (113, 118))	('TRAF1', 'Gene', (113, 118))
397900	28331188	MALAT1 was identified as an oncogene, and the high expression of MALAT1 was associated with metastasis and poor survival across cancers.	('cancers', 'Disease', 'MESH:D009369', (128, 135))	('cancers', 'Phenotype', 'HP:0002664', (128, 135))	('MALAT1', 'Gene', '378938', (0, 6))	('MALAT1', 'Gene', '378938', (65, 71))	('cancers', 'Disease', (128, 135))	('metastasis', 'CPA', (92, 102))	('MALAT1', 'Gene', (0, 6))	('MALAT1', 'Gene', (65, 71))	('associated with', 'Reg', (76, 91))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('poor survival', 'CPA', (107, 120))	('high expression', 'Var', (46, 61))
397901	28331188	Another lncRNA, DANCR was reported to block the repression effect of miR-214, miR-320a, and miR-199a on CTNNB1 in hepatocellular carcinoma.	('CTNNB1', 'Gene', '1499', (104, 110))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (114, 138))	('hepatocellular carcinoma', 'Disease', (114, 138))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (114, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('miR-199a', 'Var', (92, 100))	('miR-214', 'Gene', '406996', (69, 76))	('CTNNB1', 'Gene', (104, 110))	('miR-320a', 'Gene', (78, 86))	('DANCR', 'Gene', (16, 21))	('miR-320a', 'Gene', '407037', (78, 86))	('DANCR', 'Gene', '57291', (16, 21))	('miR-214', 'Gene', (69, 76))
397903	28331188	According to recent study on lncRNA GAS5, the allele deletion of rs145204276 was associated with decreased CRC risk and less possibility of lymph-node metastasis.	('rs145204276', 'Mutation', 'rs145204276', (65, 76))	('CRC', 'Disease', (107, 110))	('GAS5', 'Gene', '60674', (36, 40))	('decreased', 'NegReg', (97, 106))	('rs145204276', 'Var', (65, 76))	('GAS5', 'Gene', (36, 40))
397921	28331188	To avoid overfit due to cancer heterogeneity, resampling (80% samples, 10,000 repeats) was used to evaluate the performance of risks score, and the results indicates that 97.8% resampling was significantly associated with risk score (p < 0.05), as shown in Figure S1.	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('associated', 'Reg', (206, 216))	('risk score', 'MPA', (222, 232))	('cancer', 'Disease', (24, 30))	('cancer', 'Disease', 'MESH:D009369', (24, 30))	('resampling', 'Var', (177, 187))
397948	27809798	Many studies have demonstrated that abnormal protein expressions and gene mutations are correlated with the ontogenesis and progression of lung cancer, and reliable biomarkers derived from these abnormal molecules are more likely to help make the medical decision for individualized therapy.	('lung cancer', 'Disease', (139, 150))	('correlated', 'Reg', (88, 98))	('protein', 'Protein', (45, 52))	('lung cancer', 'Disease', 'MESH:D008175', (139, 150))	('mutations', 'Var', (74, 83))	('lung cancer', 'Phenotype', 'HP:0100526', (139, 150))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
398023	25994056	Fortunately, enhancers can also be identified using patterns of 5-methylcytosine, an epigenetic mark that is maintained more stably than protein marks, and can be detected genome-wide in as few as 1,000 cells.	('patterns', 'Var', (52, 60))	('5-methylcytosine', 'Var', (64, 80))	('5-methylcytosine', 'Chemical', 'MESH:D044503', (64, 80))
398046	25994056	To identify enhancers that displayed cancer-specific changes in DNA methylation, we applied a t-test to identify enhancer probes that were significantly hypermethylated or hypomethylated within tumor samples of each cancer type, relative to TCGA adjacent normal samples from the same tissue (Fig.	('hypermethylated', 'Var', (153, 168))	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('cancer', 'Disease', (37, 43))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('hypomethylated within tumor', 'Disease', (172, 199))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('cancer', 'Disease', (216, 222))	('cancer', 'Disease', 'MESH:D009369', (216, 222))	('hypomethylated within tumor', 'Disease', 'MESH:D001929', (172, 199))
398047	25994056	1b; see Methods for details); a list of the identified hypermethylated or hypomethylated enhancer probes for each tumor type can be found in Additional file 3.	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumor', 'Disease', (114, 119))	('hypomethylated', 'Var', (74, 88))	('hypermethylated', 'Var', (55, 70))
398048	25994056	We identified many more hypomethylated enhancer probes than hypermethylated probes for each of the 10 cancer types (Fig.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('enhancer', 'PosReg', (39, 47))	('hypomethylated', 'Var', (24, 38))
398049	25994056	Interestingly, most of the probes showing DNA methylation changes were found to have similar changes in DNA methylation in more than one cancer type.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('changes', 'Var', (58, 65))	('cancer', 'Disease', (137, 143))	('changes', 'Reg', (93, 100))	('DNA methylation', 'MPA', (104, 119))
398050	25994056	However, some probes were uniquely hypermethylated or hypomethylated in only one of the 10 tumor types.	('hypomethylated', 'Var', (54, 68))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor', 'Disease', (91, 96))	('tumor', 'Disease', 'MESH:D009369', (91, 96))
398051	25994056	We note that it is not possible for us to be certain that the adjacent tissues collected by TCGA correspond to the same cell type from which the cancer arose, and therefore some of these methylation changes may correspond to tissue-specific differences rather than changes arising in the cancer.	('cancer', 'Disease', (145, 151))	('cancer', 'Disease', 'MESH:D009369', (288, 294))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('cancer', 'Disease', (288, 294))	('methylation', 'MPA', (187, 198))	('changes', 'Var', (199, 206))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('cancer', 'Phenotype', 'HP:0002664', (288, 294))
398053	25994056	For example, in a ChIA-PET study using an antibody for RNA polymerase II, Li et al.	('RNA polymerase', 'Protein', (55, 69))	('ChIA', 'Gene', '27159', (18, 22))	('ChIA', 'Gene', (18, 22))	('antibody', 'Var', (42, 50))
398059	25994056	Using this method, we identified a total of 11,972 hypomethylated probe-gene pairs and 2,308 hypermethylated probe-gene pairs in the set of 10 tumor types (Fig.	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('hypomethylated', 'Var', (51, 65))	('tumor', 'Disease', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
398060	25994056	3a), with the number of hypomethylated probe-gene pairs ranging from 499 to 3,847 in different tumor types, and the number of hypermethylated probe-gene pairs ranging from 119 to 464 (see Additional file 5 for a breakdown by type).	('hypomethylated', 'Var', (24, 38))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Disease', (95, 100))
398063	25994056	Although the enhancer-gene pairs that we identified were highly specific for a certain tumor type, we found that approximately 34 % of the genes identified as regulated by a hypomethylated probe and approximately 17 % of the genes identified as regulated by a hypermethylated probe were targets in more than one tumor type (Fig.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Disease', 'MESH:D009369', (312, 317))	('tumor', 'Disease', (87, 92))	('tumor', 'Phenotype', 'HP:0002664', (312, 317))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('tumor', 'Disease', (312, 317))	('hypomethylated', 'Var', (174, 188))
398066	25994056	As indicated above, many of the genes that we identified as linked to enhancers with cancer-associated DNA methylation differences were actually identified in more than one cancer type, suggesting that they may have some common function in tumor initiation or progression.	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('tumor initiation', 'Disease', 'MESH:D009369', (240, 256))	('cancer', 'Disease', (173, 179))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('methylation differences', 'Var', (107, 130))	('tumor initiation', 'Disease', (240, 256))	('cancer', 'Disease', (85, 91))	('enhancers', 'PosReg', (70, 79))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('tumor', 'Phenotype', 'HP:0002664', (240, 245))
398068	25994056	The 1,959 genes linked to hypomethylated (activated) enhancer probes correspond to genes upregulated in cancer, and the 284 genes linked to hypermethylated (inactivated) probes correspond to genes downregulated in cancer.	('downregulated', 'NegReg', (197, 210))	('cancer', 'Disease', (214, 220))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('upregulated', 'PosReg', (89, 100))	('hypomethylated', 'Var', (26, 40))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('enhancer', 'PosReg', (53, 61))	('probes', 'Var', (62, 68))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (214, 220))
398075	25994056	Some of these motifs were common to various different cancers, such as AP1, which was enriched within nine of the 10 cancer types.	('AP1', 'Gene', '2353', (71, 74))	('cancers', 'Phenotype', 'HP:0002664', (54, 61))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('cancers', 'Disease', (54, 61))	('motifs', 'Var', (14, 20))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('cancers', 'Disease', 'MESH:D009369', (54, 61))	('cancer', 'Disease', (54, 60))	('common', 'Reg', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('cancer', 'Disease', (117, 123))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('AP1', 'Gene', (71, 74))
398084	25994056	In addition, GATA3 expression is correlated with longer disease-free survival and evidence suggests that it can prevent or reverse the epithelial to mesenchymal transition that is characteristic of cancer metastasis.	('epithelial to mesenchymal transition', 'CPA', (135, 171))	('prevent', 'NegReg', (112, 119))	('expression', 'Var', (19, 29))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('cancer metastasis', 'Disease', (198, 215))	('GATA3', 'Gene', (13, 18))	('reverse', 'NegReg', (123, 130))	('GATA3', 'Gene', '2625', (13, 18))	('cancer metastasis', 'Disease', 'MESH:D009362', (198, 215))
398105	25994056	We identified from 5,147 to 26,787 hypomethylated probes in different tumor types, corresponding to between 4,841 and 21,374 distinct enhancer regions.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', (70, 75))	('hypomethylated probes', 'Var', (35, 56))	('enhancer', 'PosReg', (134, 142))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
398129	25994056	For instance, we found that GATA-containing enhancer hypomethylation occurred primarily in the subset of breast cancer cases belonging to the Luminal subtype, which also had high expression of the GATA3 gene (Fig.	('expression', 'MPA', (179, 189))	('breast cancer', 'Gene', '672', (105, 118))	('GATA', 'Gene', (197, 201))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('GATA3', 'Gene', (197, 202))	('breast cancer', 'Gene', (105, 118))	('GATA', 'Gene', '55278', (197, 201))	('enhancer', 'PosReg', (44, 52))	('hypomethylation', 'Var', (53, 68))	('GATA3', 'Gene', '2625', (197, 202))	('GATA', 'Gene', (28, 32))	('GATA', 'Gene', '55278', (28, 32))	('breast cancer', 'Phenotype', 'HP:0003002', (105, 118))
398131	25994056	Understanding the genome-wide transcriptional consequences of molecular subtypes will be particularly relevant for those that are defined by genetic mutation of transcriptional regulators; indeed, transcription factors make up the largest functional class within the list of 127 cancer genes with so-called 'driver' mutations identified by TCGA.	("'driver'", 'PosReg', (307, 315))	('mutations', 'Var', (316, 325))	('cancer', 'Phenotype', 'HP:0002664', (279, 285))	('TCGA', 'Gene', (340, 344))	('cancer', 'Disease', (279, 285))	('cancer', 'Disease', 'MESH:D009369', (279, 285))
398134	25994056	For instance, FOXA1 is most frequently mutated in Breast and Bladder cancer, and ELMER identified it in these specific cancers.	('FOXA1', 'Gene', (14, 19))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('cancers', 'Disease', 'MESH:D009369', (119, 126))	('Breast and Bladder cancer', 'Disease', 'MESH:D001749', (50, 75))	('cancers', 'Phenotype', 'HP:0002664', (119, 126))	('mutated', 'Var', (39, 46))	('cancers', 'Disease', (119, 126))	('Bladder cancer', 'Phenotype', 'HP:0009725', (61, 75))	('FOXA1', 'Gene', '3169', (14, 19))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
398135	25994056	Likewise, FOXA2 and SOX17 are primarily mutated in endometrial cancers, and ELMER identified network alterations specifically in this cancer type (UCEC).	('FOXA2', 'Gene', (10, 15))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('endometrial cancers', 'Disease', 'MESH:D016889', (51, 70))	('SOX17', 'Gene', '64321', (20, 25))	('endometrial cancer', 'Phenotype', 'HP:0012114', (51, 69))	('mutated', 'Var', (40, 47))	('endometrial cancers', 'Disease', (51, 70))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('cancers', 'Phenotype', 'HP:0002664', (63, 70))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('FOXA2', 'Gene', '3170', (10, 15))	('cancer', 'Disease', (63, 69))	('SOX17', 'Gene', (20, 25))
398136	25994056	NFE2L2 is most frequently mutated in lung squamous cell carcinoma (LUSC), the same cancer type where ELMER detected NFE2L2 alterations.	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (37, 65))	('lung squamous cell carcinoma', 'Disease', (37, 65))	('NFE2L2', 'Gene', (116, 122))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('carcinoma', 'Phenotype', 'HP:0030731', (56, 65))	('NFE2L2', 'Gene', '4780', (0, 6))	('mutated', 'Var', (26, 33))	('NFE2L2', 'Gene', (0, 6))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (37, 65))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (42, 65))	('NFE2L2', 'Gene', '4780', (116, 122))	('cancer', 'Disease', (83, 89))
398139	25994056	Our results indicate that hypomethylation of AP-1-containing enhancers is a common feature of many or most cancer types (including nine of our 10 cancer types, see Fig.	('AP-1-containing', 'Gene', (45, 60))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('cancer', 'Disease', (146, 152))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('hypomethylation', 'Var', (26, 41))	('cancer', 'Disease', (107, 113))
398142	25994056	Phosphorylation of JUN can lead to histone acetylation at AP-1 motif-containing enhancers by inhibiting their association with the Mbd3 component of the NuRD complex.	('Phosphorylation', 'Var', (0, 15))	('JUN', 'Gene', (19, 22))	('association', 'Interaction', (110, 121))	('Mbd3', 'Gene', (131, 135))	('AP-1', 'Gene', (58, 62))	('lead to', 'Reg', (27, 34))	('inhibiting', 'NegReg', (93, 103))	('Mbd3', 'Gene', '53615', (131, 135))	('histone acetylation', 'MPA', (35, 54))
398146	25994056	Interestingly, high expression of ZNF703 has been shown to correlate with poor prognosis in patients with luminal B breast cancer.	('high', 'Var', (15, 19))	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('breast cancer', 'Phenotype', 'HP:0003002', (116, 129))	('breast cancer', 'Gene', '672', (116, 129))	('patients', 'Species', '9606', (92, 100))	('ZNF703', 'Gene', '80139', (34, 40))	('breast cancer', 'Gene', (116, 129))	('ZNF703', 'Gene', (34, 40))
398155	25994056	However, the most important output of this work may actually be the identification of enhancers in which mutations in individual transcription factor binding sites can be responsible for cancer risk or cancer progression.	('cancer', 'Disease', 'MESH:D009369', (187, 193))	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('cancer', 'Disease', (187, 193))	('cancer', 'Disease', 'MESH:D009369', (202, 208))	('mutations', 'Var', (105, 114))	('responsible', 'Reg', (171, 182))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('cancer', 'Disease', (202, 208))
398157	25994056	Somatic enhancer mutations are predicted to affect cancer progression, although these have not yet been identified due to the overwhelming use of exon sequencing as a means to identify new cancer mutations.	('enhancer', 'PosReg', (8, 16))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('affect', 'Reg', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('cancer', 'Disease', (51, 57))	('mutations', 'Var', (17, 26))	('cancer', 'Disease', (189, 195))
398179	25994056	Genes associated with hypo- or hypermethylated enhancer probes in more than one cancer type were selected for GO analysis.	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('hypo-', 'Var', (22, 27))	('hypermethylated', 'Var', (31, 46))	('cancer', 'Disease', (80, 86))
398224	32922538	Moreover, we observed that LUCAT1 is an important vitD-regulated lncRNA and that transiently or stably silenced LUCAT1 significantly inhibited OSCC proliferation.	('LUCAT1', 'Gene', '100505994', (112, 118))	('LUCAT1', 'Gene', (112, 118))	('silenced', 'Var', (103, 111))	('inhibited', 'NegReg', (133, 142))	('OSCC proliferation', 'CPA', (143, 161))	('LUCAT1', 'Gene', '100505994', (27, 33))	('LUCAT1', 'Gene', (27, 33))
398284	32922538	In addition, the growth curves generated by CCK-8 assays indicated that knockdown of LUCAT1 expression remarkably impaired SCC9 and CAL27 cell growth, which was consistent with the colony formation results (Figure 3D).	('LUCAT1', 'Gene', '100505994', (85, 91))	('LUCAT1', 'Gene', (85, 91))	('SCC9', 'CellLine', 'CVCL:1685', (123, 127))	('knockdown', 'Var', (72, 81))	('impaired', 'NegReg', (114, 122))
398287	32922538	As shown in Figure 4B, knockdown of LUCAT1 expression markedly inhibited cell proliferation compared to that in the control cells.	('LUCAT1', 'Gene', '100505994', (36, 42))	('LUCAT1', 'Gene', (36, 42))	('knockdown', 'Var', (23, 32))	('cell proliferation', 'CPA', (73, 91))	('inhibited', 'NegReg', (63, 72))
398293	32922538	Additionally, we found that the xenografts generated by CAL27 shLUCAT1 cells had lower Ki-67 expression than the xenografts generated by CAL27 scramblecells (Figure 4F).	('lower', 'NegReg', (81, 86))	('Ki-67', 'Protein', (87, 92))	('CAL27', 'Var', (56, 61))	('LUCAT1', 'Gene', '100505994', (64, 70))	('LUCAT1', 'Gene', (64, 70))	('Ki-67', 'Chemical', '-', (87, 92))
398308	32922538	Additionally, 1,25(OH)2D3 has been shown to inhibit the growth of HNSCC cells through the upregulation of cell cycle inhibitor p18 expression.	('p18', 'Gene', (127, 130))	('upregulation', 'PosReg', (90, 102))	('growth', 'CPA', (56, 62))	('inhibit', 'NegReg', (44, 51))	('expression', 'MPA', (131, 141))	('1,25(OH)2D3', 'Var', (14, 25))	('p18', 'Gene', '100689229', (127, 130))	('cell', 'Protein', (106, 110))	('1,25(OH)2D3', 'Chemical', 'MESH:D002117', (14, 25))
398311	32922538	Recently, efforts have been dedicated to elucidating the biological functions and clinical impact of long noncoding RNAs, and studies have revealed that lncRNAs might be novel biomarkers for several types of human cancers, including OSCC.	('lncRNAs', 'Var', (153, 160))	('cancers', 'Phenotype', 'HP:0002664', (214, 221))	('cancers', 'Disease', (214, 221))	('cancers', 'Disease', 'MESH:D009369', (214, 221))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('OSCC', 'Disease', (233, 237))	('human', 'Species', '9606', (208, 213))
398314	32922538	High LUCAT1 expression was an independent prognostic factor for liver cancer.	('liver cancer', 'Disease', (64, 76))	('High', 'Var', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('LUCAT1', 'Gene', '100505994', (5, 11))	('LUCAT1', 'Gene', (5, 11))	('expression', 'MPA', (12, 22))	('liver cancer', 'Phenotype', 'HP:0002896', (64, 76))	('liver cancer', 'Disease', 'MESH:D006528', (64, 76))
398323	32922538	Therefore, a western blot experiment was performed showing that low expression of LUCAT1 can significantly inhibit the activation of the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) pathway, thus affecting the proliferation of OSCC.	('inhibit', 'NegReg', (107, 114))	('low expression', 'Var', (64, 78))	('ERK', 'Gene', '5594', (214, 217))	('affecting', 'Reg', (233, 242))	('LUCAT1', 'Gene', '100505994', (82, 88))	('ERK', 'Gene', (214, 217))	('LUCAT1', 'Gene', (82, 88))	('proliferation of OSCC', 'CPA', (247, 268))
398333	31423188	Hypermethylation of the PTTG1IP promoter leads to low expression in early-stage non-small cell lung cancer Despite the clinical requirement for early diagnosis, the early events in lung cancer and their mechanisms are not fully understood.	('lung cancer', 'Disease', (95, 106))	('low', 'NegReg', (50, 53))	('Hypermethylation', 'Var', (0, 16))	('PTTG1IP', 'Gene', '754', (24, 31))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (186, 192))	('PTTG1IP', 'Gene', (24, 31))	('lung cancer', 'Disease', (181, 192))	('lung cancer', 'Disease', 'MESH:D008175', (95, 106))	('lung cancer', 'Phenotype', 'HP:0100526', (95, 106))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', (186, 192))	('lung cancer', 'Disease', 'MESH:D008175', (181, 192))	('expression', 'MPA', (54, 64))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (84, 106))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('lung cancer', 'Phenotype', 'HP:0100526', (181, 192))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (80, 106))
398338	31423188	Reduced representation bisulfite sequencing (RRBS) analysis of six paired early-stage NSCLC tissue samples indicated that the CpG island shore of the PTTG1IP promoter is hypermethylated in lung cancer tissues, which was further validated in 12 paired early-stage NSCLC samples via bisulfite amplicon sequencing.	('lung cancer', 'Disease', 'MESH:D008175', (189, 200))	('hypermethylated', 'Var', (170, 185))	('bisulfite', 'Chemical', 'MESH:C042345', (23, 32))	('NSCLC', 'Phenotype', 'HP:0030358', (263, 268))	('bisulfite', 'Chemical', 'MESH:C042345', (281, 290))	('NSCLC', 'Disease', (86, 91))	('NSCLC', 'Disease', 'MESH:D002289', (86, 91))	('lung cancer', 'Phenotype', 'HP:0100526', (189, 200))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('NSCLC', 'Disease', (263, 268))	('lung cancer', 'Disease', (189, 200))	('NSCLC', 'Disease', 'MESH:D002289', (263, 268))	('PTTG1IP', 'Gene', (150, 157))	('NSCLC', 'Phenotype', 'HP:0030358', (86, 91))	('PTTG1IP', 'Gene', '754', (150, 157))	('RRBS', 'Chemical', '-', (45, 49))
398347	31423188	Previous studies have reported that aberrant epigenetic changes are one of the most frequent cancer-associated events and are regarded as important mechanisms in carcinogenesis.	('aberrant epigenetic changes', 'Var', (36, 63))	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('carcinogenesis', 'Disease', 'MESH:D063646', (162, 176))	('carcinogenesis', 'Disease', (162, 176))
398350	31423188	Previously, accumulating evidence has confirmed that tumor tissues can be characterized by hypermethylation at promoter-associated CpG islands (CGIs) or global hypomethylation of the genome compared with normal tissues.	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('hypermethylation', 'Var', (91, 107))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Disease', (53, 58))
398351	31423188	Hao et al reported that methylation patterns can predict prognosis and survival, and identified an association between differential methylation of CpG sites and the expression of cancer-associated genes.	('survival', 'CPA', (71, 79))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('expression', 'MPA', (165, 175))	('prognosis', 'CPA', (57, 66))	('methylation', 'Var', (24, 35))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('CpG', 'Gene', (147, 150))	('cancer', 'Disease', (179, 185))	('predict', 'Reg', (49, 56))
398400	31423188	However, regional DNA methylation analysis demonstrated that the region from 2,000 bp upstream to 1,000 bp downstream of the TSS was hypomethylated both in tumor tissues and adjacent tissues, although CpG loci were very concentrated in this region.	('hypomethylated', 'Var', (133, 147))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('tumor', 'Disease', (156, 161))
398403	31423188	Therefore, hypermethylation of the CGI shore region within the PTTG1IP gene promoter might be associated with its low expression.	('hypermethylation', 'Var', (11, 27))	('PTTG1IP', 'Gene', (63, 70))	('PTTG1IP', 'Gene', '754', (63, 70))	('associated', 'Reg', (94, 104))	('expression', 'MPA', (118, 128))
398405	31423188	Hypermethylation was identified in >50% of the cancer tissues in the sample pairs.	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('Hypermethylation', 'Var', (0, 16))	('cancer', 'Disease', (47, 53))	('cancer', 'Disease', 'MESH:D009369', (47, 53))
398410	31423188	These results suggest that hypermethylation in the CGI shore within the PTTG1IP promoter is essential for silencing of PTTG1IP.	('PTTG1IP', 'Gene', (119, 126))	('hypermethylation', 'Var', (27, 43))	('PTTG1IP', 'Gene', '754', (119, 126))	('PTTG1IP', 'Gene', '754', (72, 79))	('PTTG1IP', 'Gene', (72, 79))	('silencing', 'MPA', (106, 115))
398418	31423188	Epigenetic biomarkers, particularly DNA methylation, have become one of the most promising options for improving cancer diagnosis and have several advantages compared with other markers, including gene expression or genetic markers.	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('DNA methylation', 'Var', (36, 51))	('cancer', 'Disease', (113, 119))	('Epigenetic', 'Var', (0, 10))	('improving', 'PosReg', (103, 112))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
398419	31423188	One surprising finding in cancer biology that has emerged from TCGA sequencing projects is the wide diversity of mutations that promote cancer development.	('cancer', 'Disease', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('cancer', 'Disease', (136, 142))	('mutations', 'Var', (113, 122))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('promote', 'PosReg', (128, 135))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
398420	31423188	DNA methylation changes are covalent modifications that are very stable and usually occur early in carcinogenesis.	('changes', 'Var', (16, 23))	('carcinogenesis', 'Disease', 'MESH:D063646', (99, 113))	('carcinogenesis', 'Disease', (99, 113))	('methylation changes', 'Var', (4, 23))
398422	31423188	This epigenetic modification can also be detected in different biological fluids and is one of the most promising noninvasive cancer detection tools.	('epigenetic modification', 'Var', (5, 28))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))
398438	31423188	Expression data for all genes in lung adenocarcinoma, breast cancer, colorectal cancer, kidney cancer, melanoma, liver cancer and ovarian cancer (GSE1007, GSE20347, GSE32323, GSE6344, GSE3189, GSE14520 and GSE14407) were downloaded from the Gene Expression Omnibus database in NCBI.	('ovarian cancer', 'Disease', 'MESH:D010051', (130, 144))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (33, 52))	('colorectal cancer', 'Phenotype', 'HP:0003003', (69, 86))	('GSE3189', 'Chemical', '-', (184, 191))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('GSE1007', 'Chemical', '-', (146, 153))	('GSE6344', 'Chemical', '-', (175, 182))	('kidney cancer', 'Disease', 'MESH:D007680', (88, 101))	('liver cancer', 'Disease', 'MESH:D006528', (113, 125))	('breast cancer', 'Disease', 'MESH:D001943', (54, 67))	('melanoma', 'Phenotype', 'HP:0002861', (103, 111))	('melanoma', 'Disease', (103, 111))	('breast cancer', 'Disease', (54, 67))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('ovarian cancer', 'Disease', (130, 144))	('kidney cancer', 'Phenotype', 'HP:0009726', (88, 101))	('liver cancer', 'Phenotype', 'HP:0002896', (113, 125))	('colorectal cancer', 'Disease', 'MESH:D015179', (69, 86))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('kidney cancer', 'Disease', (88, 101))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('ovarian cancer', 'Phenotype', 'HP:0100615', (130, 144))	('liver cancer', 'Disease', (113, 125))	('colorectal cancer', 'Disease', (69, 86))	('lung adenocarcinoma', 'Disease', (33, 52))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('GSE14520', 'Var', (193, 201))	('melanoma', 'Disease', 'MESH:D008545', (103, 111))	('GSE32323', 'Var', (165, 173))	('carcinoma', 'Phenotype', 'HP:0030731', (43, 52))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (33, 52))	('GSE3189', 'Var', (184, 191))	('GSE1007', 'Var', (146, 153))	('breast cancer', 'Phenotype', 'HP:0003002', (54, 67))
398439	31423188	The ID_REF for PTTG1IP is 200677_at.	('PTTG1IP', 'Gene', '754', (15, 22))	('PTTG1IP', 'Gene', (15, 22))	('200677_at', 'Var', (26, 35))
398442	31423188	Further investigation demonstrated that DNA methylation at the shore of the CGI in the promoter region was negatively associated with PTTG1IP expression.	('methylation', 'Var', (44, 55))	('negatively', 'NegReg', (107, 117))	('expression', 'MPA', (142, 152))	('PTTG1IP', 'Gene', (134, 141))	('PTTG1IP', 'Gene', '754', (134, 141))
398446	31423188	Of course, prior to application in the clinic, further investigations are required to verify whether hypermethylation of the PTTG1IP promoter can be detected in body fluids, including sputum and plasma, from patients with early-stage NSCLC.	('NSCLC', 'Disease', (234, 239))	('patients', 'Species', '9606', (208, 216))	('NSCLC', 'Disease', 'MESH:D002289', (234, 239))	('hypermethylation', 'Var', (101, 117))	('detected', 'Reg', (149, 157))	('PTTG1IP', 'Gene', (125, 132))	('PTTG1IP', 'Gene', '754', (125, 132))	('NSCLC', 'Phenotype', 'HP:0030358', (234, 239))
398690	31156297	More than 5 kg weight loss is the indicator of poor prognosis, while albumin <30 g/L increase the risk of postoperative anastomosis leakage.	('weight loss', 'Phenotype', 'HP:0001824', (15, 26))	('albumin', 'Protein', (69, 76))	('postoperative anastomosis leakage', 'Disease', (106, 139))	('loss', 'NegReg', (22, 26))	('postoperative anastomosis leakage', 'Disease', 'MESH:D010149', (106, 139))	('<30 g/L', 'Var', (77, 84))
398703	31156297	For patients with T1-3N0-1M0 esophageal carcinoma, right transthoracic MIE is recommended, especially for those have underwent neoadjuvant radio/chemotherapy.	('T1-3N0-1M0', 'Var', (18, 28))	('carcinoma', 'Phenotype', 'HP:0030731', (40, 49))	('patients', 'Species', '9606', (4, 12))	('esophageal carcinoma', 'Disease', (29, 49))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (29, 49))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (29, 49))
398712	31156297	However, three-field dissection is associated with more complications, especially recurrent laryngeal nerve paralysis, anastomosis leakage, and aspiration pneumonia.	('aspiration pneumonia', 'Phenotype', 'HP:0011951', (144, 164))	('anastomosis leakage', 'Disease', (119, 138))	('paralysis', 'Phenotype', 'HP:0003470', (108, 117))	('laryngeal nerve paralysis', 'Disease', 'MESH:D014826', (92, 117))	('laryngeal nerve paralysis', 'Disease', (92, 117))	('laryngeal nerve paralysis', 'Phenotype', 'HP:0001605', (92, 117))	('aspiration pneumonia', 'Disease', (144, 164))	('aspiration', 'Phenotype', 'HP:0002835', (144, 154))	('three-field', 'Var', (9, 20))	('aspiration pneumonia', 'Disease', 'MESH:D011015', (144, 164))	('pneumonia', 'Phenotype', 'HP:0002090', (155, 164))
398716	31156297	For example: upper segment of thoracic esophageal cancer, or when cervical lymph nodes metastasis is suspected before surgery, or fast biopsy confirmed metastasis of any recurrent laryngeal nerve lymph nodes (left or right).	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('thoracic esophageal cancer', 'Disease', (30, 56))	('metastasis', 'Var', (152, 162))	('thoracic esophageal cancer', 'Disease', 'MESH:D004938', (30, 56))
398738	31156297	(2) Adjuvant radiotherapy/concurrent radiochemotherapy 1) R1 (include circular edge) or R2 resection; 2) For squamous carcinoma, R0 resection, pathologically N+, or T4N0, lymph node capsule involved.	('squamous carcinoma', 'Disease', (109, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('R0 resection', 'Var', (129, 141))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (109, 127))	('squamous carcinoma', 'Disease', 'MESH:D002294', (109, 127))	('T4N0', 'Var', (165, 169))
398739	31156297	For adenocarcinoma, pathologically N+, or N3-4aN0, or T2N0 lower segment of thoracic esophageal/esophagogastric junction adenocarcinoma with risk factor(s) (e.g.	('N3-4aN0', 'Var', (42, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (9, 18))	('thoracic esophageal/esophagogastric junction adenocarcinoma', 'Disease', 'MESH:D013899', (76, 135))	('esophagogastric junction adenocarcinoma', 'Phenotype', 'HP:0011459', (96, 135))	('adenocarcinoma', 'Disease', (4, 18))	('adenocarcinoma', 'Disease', (121, 135))	('adenocarcinoma', 'Disease', 'MESH:D000230', (121, 135))	('T2N0', 'Var', (54, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('adenocarcinoma', 'Disease', 'MESH:D000230', (4, 18))
398778	31156297	Concurrent radiochemotherapy V20<=28%; (2) Heart: V30<=40%, V40<=30%; (3) Cord PRV: Dmax<=45 Gy;  (4) Stomach: V40<=40%, Dmax<=55-60 Gy;  (5) Intestine: V40<=40%, Dmax<=55 Gy;  (6) Kidneys: V20<=30%; (7) Liver: V30<=30%.	('Dmax<=55-60', 'Var', (121, 132))	('P', 'Chemical', 'MESH:D010758', (79, 80))	('V40<=40%', 'Var', (111, 119))	('V20', 'Var', (190, 193))	('V20', 'Var', (29, 32))	('V40<=40%', 'Var', (153, 161))
398832	31156297	Based on current available large randomized controlled clinical studies on esophageal cancer, we recommend neoadjuvant chemotherapy for patients with clinically T3-4N0M0 or T1-3N1-3M0 resectable esophageal cancer to increase theen-bloc (R0) dissection rate and improve overall survival (OS), without increasing postoperative complications.	('esophageal cancer', 'Disease', (195, 212))	('esophageal cancer', 'Disease', 'MESH:D004938', (75, 92))	('T1-3N1-3M0', 'Var', (173, 183))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('esophageal cancer', 'Disease', 'MESH:D004938', (195, 212))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('overall', 'MPA', (269, 276))	('improve', 'PosReg', (261, 268))	('T3-4N0M0', 'Var', (161, 169))	('patients', 'Species', '9606', (136, 144))	('esophageal cancer', 'Disease', (75, 92))	('increase', 'PosReg', (216, 224))
398835	31156297	We recommend neoadjuvant chemotherapy for patients with resectable adenocarcinoma locating in lower segment of esophagus or esophagogastric junction to improve 5-year survival without increasing postoperative mortality and morbidity.	('adenocarcinoma', 'Disease', (67, 81))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('adenocarcinoma', 'Disease', 'MESH:D000230', (67, 81))	('locating', 'Var', (82, 90))	('improve', 'PosReg', (152, 159))	('patients', 'Species', '9606', (42, 50))
398884	31156297	Further research indicates the patients with EGFR mutation may be potentially benefit from EGFR-TKIs.	('EGFR', 'Gene', (91, 95))	('EGFR', 'Gene', (45, 49))	('patients', 'Species', '9606', (31, 39))	('EGFR', 'Gene', '1956', (45, 49))	('benefit', 'PosReg', (78, 85))	('EGFR', 'Gene', '1956', (91, 95))	('mutation', 'Var', (50, 58))
398949	31156297	The threshold of 0-I subtype and 0-IIa subtype is 1.0 mm of elevation (the single cup of openned biopsy forceps is approximately 1.2 mm), while the thresholds of 0-III and 0-IIc is 0.5 mm of depression (half of one cup of biopsy forceps is approximately 0.6 mm).	('elevation', 'PosReg', (60, 69))	('0-IIa', 'Var', (33, 38))	('depression', 'Phenotype', 'HP:0000716', (191, 201))	('depression', 'Disease', 'MESH:D000275', (191, 201))	('depression', 'Disease', (191, 201))
398966	31156297	For those with lymph node metastasis, or with distant metastasis, or limited SM2/SM3 esophageal cancer with high-risk of lymph node metastasis, surgery is still the preferred treatment.	('SM2/SM3', 'Var', (77, 84))	('esophageal cancer', 'Disease', 'MESH:D004938', (85, 102))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('distant metastasis', 'CPA', (46, 64))	('lymph node metastasis', 'CPA', (15, 36))	('esophageal cancer', 'Disease', (85, 102))
398971	31156297	On diagnosis of regional lymph node metastasis, the sensitivity of EUS is 80%, obviously higher than CT (50%) and PET (57%).	('higher', 'PosReg', (89, 95))	('P', 'Chemical', 'MESH:D010758', (114, 115))	('regional lymph node', 'Disease', (16, 35))	('EUS', 'Var', (67, 70))
398980	31156297	Indications for esophageal squamous carcinoma (a) Absolute indications: 1) T1a esophageal squamous carcinoma limited in epithelium (M1) or lamina propria mucosa (M2), without evidence of lymph node metastasis; 2) Precancerous lesions.	('esophageal squamous carcinoma', 'Disease', (79, 108))	('Precancerous lesions', 'Disease', 'MESH:D011230', (213, 233))	('T1a', 'Var', (75, 78))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('Precancerous lesions', 'Disease', (213, 233))	('carcinoma', 'Phenotype', 'HP:0030731', (36, 45))	('esophageal squamous carcinoma', 'Disease', 'MESH:D000077277', (16, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (27, 45))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (90, 108))	('esophageal squamous carcinoma', 'Disease', (16, 45))	('esophageal squamous carcinoma', 'Disease', 'MESH:D000077277', (79, 108))
398987	31156297	Relative contraindications: 1) Positive non-lift sign; 2) Patients with coagulation disorders that not corrected, or those who is taking anti-coagulate agents; 3) Lesion invades to deep layer of submucosa; patients refuse or are not suitable for surgery.	('coagulation disorders', 'Disease', 'MESH:D025861', (72, 93))	('P', 'Chemical', 'MESH:D010758', (58, 59))	('coagulation disorders', 'Disease', (72, 93))	('P', 'Chemical', 'MESH:D010758', (31, 32))	('patients', 'Species', '9606', (206, 214))	('coagulation disorders', 'Phenotype', 'HP:0001928', (72, 93))	('Patients', 'Species', '9606', (58, 66))	('Lesion', 'Var', (163, 169))
399076	31156297	We do not recommend postoperative adjuvant radiotherapy or chemotherapy for completely resected (R0 resection) T2-3N0M0 esophageal squamous carcinoma or T2N0M0 esophageal adenocarcinoma.	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (160, 185))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (131, 149))	('esophageal adenocarcinoma', 'Disease', (160, 185))	('esophageal squamous carcinoma', 'Disease', (120, 149))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (160, 185))	('T2N0M0', 'Var', (153, 159))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))	('T2-3N0M0', 'Var', (111, 119))	('esophageal squamous carcinoma', 'Disease', 'MESH:D000077277', (120, 149))	('carcinoma', 'Phenotype', 'HP:0030731', (176, 185))
399077	31156297	For pathological T4N0 or T1-4N1-3M0 esophageal squamous carcinoma underwent R0 resection, postoperative adjuvant radiotherapy or chemotherapy can be considered.	('squamous carcinoma', 'Phenotype', 'HP:0002860', (47, 65))	('T1-4N1-3M0', 'Var', (25, 35))	('esophageal squamous carcinoma', 'Disease', 'MESH:D000077277', (36, 65))	('esophageal squamous carcinoma', 'Disease', (36, 65))	('T4N0', 'Var', (17, 21))	('carcinoma', 'Phenotype', 'HP:0030731', (56, 65))
399078	31156297	Fluorouracil-based postoperative radiochemotherapy is the choice for R0 resected T3N0M0 and T1-2N1M0, or R1/R2 resected esophageal adenocarcinoma.	('R1/R2', 'Gene', '910;6241', (105, 110))	('Fluorouracil', 'Chemical', 'MESH:D005472', (0, 12))	('R1/R2', 'Gene', (105, 110))	('T1-2N1M0', 'Var', (92, 100))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (120, 145))	('esophageal adenocarcinoma', 'Disease', (120, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (120, 145))	('T3N0M0', 'Var', (81, 87))
399079	31156297	For T1-3N1-2M0 and some resectable T4aN0-1M0 esophageal cancer, preoperative neoadjuvant radiochemotherapy/radiotherapy/chemotherapy and post-therapy reassessment are recommended.	('T4aN0-1M0', 'Var', (35, 44))	('esophageal cancer', 'Disease', (45, 62))	('esophageal cancer', 'Disease', 'MESH:D004938', (45, 62))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))
399209	28714874	Cyclin D1 in two cell lines was significantly decreased after 0.5 and 1.0 muM of PG treatments, which was consistent with the result of cell cycle analysis (P < 0.05; Figure 2A,B).	('muM', 'Gene', (74, 77))	('Cyclin D1', 'Gene', '595', (0, 9))	('PG treatments', 'Var', (81, 94))	('decreased', 'NegReg', (46, 55))	('muM', 'Gene', '56925', (74, 77))	('men', 'Species', '9606', (89, 92))	('Cyclin D1', 'Gene', (0, 9))	('PG', 'Chemical', 'MESH:D011353', (81, 83))
399217	28714874	While the protein levels of PI3K class III in OECM1 cells were markedly down-regulated in 0.5 and 1.0 muM of PG treatments (P < 0.05; Figure 3D).	('protein levels', 'MPA', (10, 24))	('muM', 'Gene', (102, 105))	('men', 'Species', '9606', (117, 120))	('0.5', 'Var', (90, 93))	('down-regulated', 'NegReg', (72, 86))	('PG treatments', 'Var', (109, 122))	('PI3K', 'Protein', (28, 32))	('muM', 'Gene', '56925', (102, 105))	('PG', 'Chemical', 'MESH:D011353', (109, 111))
399220	28714874	The protein levels of mTOR in OECM1 cells were also reduced in 0.5 and 1.0 muM of PG treatments (P < 0.05; Figure 4B).	('PG', 'Chemical', 'MESH:D011353', (82, 84))	('protein levels', 'MPA', (4, 18))	('reduced', 'NegReg', (52, 59))	('men', 'Species', '9606', (90, 93))	('PG treatments', 'Var', (82, 95))	('muM', 'Gene', '56925', (75, 78))	('mTOR', 'Gene', '2475', (22, 26))	('mTOR', 'Gene', (22, 26))	('muM', 'Gene', (75, 78))
399222	28714874	Additionally, the P62 protein levels in SAS and OECM1 cells were significantly elevated in 1.0 muM of PG treatments as compared with the untreated controls (P < 0.05; Figure 5A,B).	('PG', 'Chemical', 'MESH:D011353', (102, 104))	('P62', 'Gene', '8878', (18, 21))	('P62', 'Gene', (18, 21))	('men', 'Species', '9606', (110, 113))	('PG treatments', 'Var', (102, 115))	('muM', 'Gene', '56925', (95, 98))	('elevated', 'PosReg', (79, 87))	('muM', 'Gene', (95, 98))
399223	28714874	When compared with the untreated controls, the protein levels of LC3-I in SAS and OECM1 cells were elevated in 1.0 muM of PG treatments (P < 0.05; Figure 5C).	('men', 'Species', '9606', (130, 133))	('LC3', 'Gene', '84557', (65, 68))	('LC3', 'Gene', (65, 68))	('protein levels', 'MPA', (47, 61))	('PG treatments', 'Var', (122, 135))	('muM', 'Gene', '56925', (115, 118))	('elevated', 'PosReg', (99, 107))	('muM', 'Gene', (115, 118))	('PG', 'Chemical', 'MESH:D011353', (122, 124))
399225	28714874	The protein levels of LC3-II were markedly up-regulated in SAS cells with various concentrations of PG treatment for 24 h as compared with the untreated controls (P < 0.05; Figure 5E).	('protein levels', 'MPA', (4, 18))	('men', 'Species', '9606', (108, 111))	('PG', 'Chemical', 'MESH:D011353', (100, 102))	('rat', 'Species', '10116', (89, 92))	('LC3', 'Gene', '84557', (22, 25))	('PG treatment', 'Var', (100, 112))	('LC3', 'Gene', (22, 25))	('up-regulated', 'PosReg', (43, 55))
399227	28714874	These Western-blotting findings showed that autophagic cell death could be induced by PG treatment in oral cancer cells, which might occur through different signal pathways.	('autophagic cell death', 'CPA', (44, 65))	('oral cancer', 'Disease', 'MESH:D009062', (102, 113))	('oral cancer', 'Disease', (102, 113))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('men', 'Species', '9606', (94, 97))	('PG', 'Chemical', 'MESH:D011353', (86, 88))	('PG treatment', 'Var', (86, 98))
399229	28714874	Two carbazole alkaloids derived from Murraya koenigii (L.) Sprengel (Rutaceae) leaves, mahanine and isomahanine, resulted in increased accumulation of p62/sequestosome1 (p62/SQSTM1), with coordinated expression of LC3-II and cleaved caspase-3, suggesting inhibition of autophagic flux associated with carbazole alkaloid-induced apoptosis in the OSCC cell line CLS-354.	('Murraya koenigii', 'Species', '159030', (37, 53))	('SQSTM1', 'Gene', (174, 180))	('p62/sequestosome1', 'Gene', '8878', (151, 168))	('carbazole alkaloid', 'Chemical', '-', (301, 319))	('LC3', 'Gene', (214, 217))	('autophagic flux', 'CPA', (269, 284))	('mahanine', 'Var', (87, 95))	('isomahanine', 'Var', (100, 111))	('SQSTM1', 'Gene', '8878', (174, 180))	('carbazole alkaloid', 'Chemical', '-', (4, 22))	('isomahanine', 'Chemical', 'MESH:C465290', (100, 111))	('mahanine', 'Chemical', 'MESH:C465290', (103, 111))	('OSCC', 'Chemical', '-', (345, 349))	('LC3', 'Gene', '84557', (214, 217))	('caspase-3', 'Gene', '836', (233, 242))	('increased accumulation', 'PosReg', (125, 147))	('carbazole alkaloids', 'Chemical', '-', (4, 23))	('p62/sequestosome1', 'Gene', (151, 168))	('mahanine', 'Chemical', 'MESH:C465290', (87, 95))	('CLS', 'Chemical', 'MESH:D002713', (360, 363))	('caspase-3', 'Gene', (233, 242))	('inhibition', 'NegReg', (255, 265))
399230	28714874	Protein levels of LC3-II and p62 in human breast cancer cell lines MCF-7 and MDA-MB-231 are induced by ramalin that derived from the Antarctic lichen Ramalina terebrata.	('p62', 'Var', (29, 32))	('Antarctic lichen Ramalina terebrata', 'Disease', 'MESH:D018459', (133, 168))	('induced', 'Reg', (92, 99))	('LC3', 'Gene', '84557', (18, 21))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('breast cancer', 'Disease', 'MESH:D001943', (42, 55))	('LC3', 'Gene', (18, 21))	('breast cancer', 'Phenotype', 'HP:0003002', (42, 55))	('breast cancer', 'Disease', (42, 55))	('Protein', 'MPA', (0, 7))	('MCF-7', 'CellLine', 'CVCL:0031', (67, 72))	('human', 'Species', '9606', (36, 41))	('Antarctic lichen Ramalina terebrata', 'Disease', (133, 168))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (77, 87))
399235	28714874	Conversely, isomahanine, a carbazole alkaloid, obviously induces autophagic flux as shown by an increase in punctate GFP-LC3 and the LC3-II/LC3-I ratio with a concomitant p62 level decrease in multidrug-resistant human oral squamous cell carcinoma cells.	('LC3', 'Gene', '84557', (140, 143))	('decrease', 'NegReg', (181, 189))	('p62 level', 'MPA', (171, 180))	('induces', 'PosReg', (57, 64))	('LC3', 'Gene', (133, 136))	('LC3', 'Gene', '84557', (121, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (238, 247))	('isomahanine', 'Var', (12, 23))	('human', 'Species', '9606', (213, 218))	('LC3', 'Gene', (140, 143))	('LC3', 'Gene', '84557', (133, 136))	('increase', 'PosReg', (96, 104))	('isomahanine', 'Chemical', 'MESH:C465290', (12, 23))	('rat', 'Species', '10116', (146, 149))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (219, 247))	('carbazole alkaloid', 'Chemical', '-', (27, 45))	('LC3', 'Gene', (121, 124))	('oral squamous cell carcinoma', 'Disease', (219, 247))	('autophagic flux', 'CPA', (65, 80))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (224, 247))
399241	28714874	Moreover, mTOR dephosphorylation reduced downstream protein p70S6K activation and finally inhibited ribosomal protein S6 (rpS6) phosphorylation.	('mTOR', 'Gene', (10, 14))	('ribosomal protein S6', 'Gene', '6194', (100, 120))	('p70S6K', 'Gene', (60, 66))	('activation', 'PosReg', (67, 77))	('rpS6', 'Gene', '6194', (122, 126))	('dephosphorylation', 'Var', (15, 32))	('p70S6K', 'Gene', '6198', (60, 66))	('rpS6', 'Gene', (122, 126))	('ribosomal protein S6', 'Gene', (100, 120))	('reduced', 'NegReg', (33, 40))	('inhibited', 'NegReg', (90, 99))	('mTOR', 'Gene', '2475', (10, 14))
399247	28714874	Two oral cancer cells were incubated with 0.4 muM PG and 0.4 muM PG plus 5 mM of autophagic inhibitor 3-methyladenine (3MA) for 24 h when compared with the untreated control cells.	('0.4', 'Var', (57, 60))	('muM', 'Gene', (61, 64))	('PG', 'Chemical', 'MESH:D011353', (65, 67))	('oral cancer', 'Disease', (4, 15))	('oral cancer', 'Disease', 'MESH:D009062', (4, 15))	('muM', 'Gene', '56925', (46, 49))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('3-methyladenine', 'Chemical', 'MESH:C025946', (102, 117))	('3MA', 'Chemical', 'MESH:C025946', (119, 122))	('PG', 'Chemical', 'MESH:D011353', (50, 52))	('muM', 'Gene', (46, 49))	('muM', 'Gene', '56925', (61, 64))
399257	28714874	The structural modification of the C-ring of prodigiosenes results in an anti-cancer activity of human K562 chronic myelogenous leukemia cells in both in vitro and in vivo assays.	('myelogenous leukemia', 'Disease', 'MESH:D007951', (116, 136))	('chronic myelogenous leukemia', 'Phenotype', 'HP:0005506', (108, 136))	('cancer', 'Disease', (78, 84))	('human', 'Species', '9606', (97, 102))	('structural modification', 'Var', (4, 27))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('leukemia', 'Phenotype', 'HP:0001909', (128, 136))	('K562', 'CellLine', 'CVCL:0004', (103, 107))	('myelogenous leukemia', 'Disease', (116, 136))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('myelogenous leukemia', 'Phenotype', 'HP:0012324', (116, 136))
399258	28714874	From these data, PGs are thought to play critical roles in cancer therapy via inducing cell death.	('inducing', 'Reg', (78, 86))	('PGs', 'Chemical', 'MESH:D010715', (17, 20))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('PGs', 'Var', (17, 20))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('cell death', 'CPA', (87, 97))
399266	28714874	Thereby, our findings provide the first evidence of increased autophagic signals were involved cell death by PG treatment in OECM1 and SAS cells.	('increased', 'PosReg', (52, 61))	('PG treatment', 'Var', (109, 121))	('men', 'Species', '9606', (117, 120))	('autophagic signals', 'CPA', (62, 80))	('PG', 'Chemical', 'MESH:D011353', (109, 111))
399270	28714874	The PI3K Class III can be triggered through insulin and insulin-like receptors, for reduction of its signal to Akt; therefore, stimulating the protein level of mTOR, which is a central regulator of autophagy.	('insulin', 'Disease', 'MESH:D007333', (56, 63))	('PI3K', 'Var', (4, 8))	('insulin', 'Disease', (56, 63))	('reduction', 'NegReg', (84, 93))	('Akt', 'Gene', (111, 114))	('stimulating', 'PosReg', (127, 138))	('mTOR', 'Gene', '2475', (160, 164))	('insulin', 'Disease', 'MESH:D007333', (44, 51))	('mTOR', 'Gene', (160, 164))	('insulin', 'Disease', (44, 51))	('signal to', 'MPA', (101, 110))	('protein level', 'MPA', (143, 156))	('Akt', 'Gene', '207', (111, 114))
399273	28714874	Autophagy is also promoted by AMP activated protein kinase (AMPK), which is a key energy sensor to maintain energy homeostasis.	('AMPK', 'Gene', (60, 64))	('promoted', 'PosReg', (18, 26))	('AMP activated', 'Var', (30, 43))	('Autophagy', 'CPA', (0, 9))	('AMPK', 'Gene', '5563', (60, 64))
399307	28714874	Furthermore, PG could mediate AMPKalpha, PI3K class III/Akt signal pathway and directly or indirectly exerts the inhibition of mTOR and Beclin-1 and the induction of p62/LC3 resulting in cell autophagy.	('PG', 'Chemical', 'MESH:D011353', (13, 15))	('mTOR', 'Gene', '2475', (127, 131))	('Akt', 'Gene', '207', (56, 59))	('AMPKalpha', 'CPA', (30, 39))	('Beclin-1', 'Gene', (136, 144))	('PI3K', 'Var', (41, 45))	('Akt', 'Gene', (56, 59))	('Beclin-1', 'Gene', '8678', (136, 144))	('inhibition', 'NegReg', (113, 123))	('LC3', 'Gene', '84557', (170, 173))	('mTOR', 'Gene', (127, 131))	('induction', 'Reg', (153, 162))	('LC3', 'Gene', (170, 173))	('cell autophagy', 'CPA', (187, 201))	('AMPKalpha', 'Chemical', '-', (30, 39))
399397	25977750	An important example is the discovery of epidermal growth factor receptor gene (EGFR) alterations, and the successful administration of EGFR tyrosine kinase inhibitors (TKIs) in lung cancer patients whose tumor harbors EGFR alterations.	('lung cancer', 'Disease', 'MESH:D008175', (178, 189))	('EGFR', 'Gene', '1956', (219, 223))	('alterations', 'Var', (224, 235))	('lung cancer', 'Disease', (178, 189))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('patients', 'Species', '9606', (190, 198))	('EGFR', 'Gene', (219, 223))	('lung cancer', 'Phenotype', 'HP:0100526', (178, 189))	('tyrosine kinase', 'Gene', '7294', (141, 156))	('EGFR', 'Gene', '1956', (80, 84))	('EGFR', 'Gene', (80, 84))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumor', 'Disease', (205, 210))	('tyrosine kinase', 'Gene', (141, 156))	('EGFR', 'Gene', '1956', (136, 140))	('EGFR', 'Gene', (136, 140))	('alterations', 'Var', (86, 97))
399506	25977750	This approach may potentially improve the detection specificity, and may prove to be of diagnostic significance, as patients with poorly differentiated carcinomas may benefit from molecular screening for EGFR, KRAS or ALK mutations.	('carcinoma', 'Phenotype', 'HP:0030731', (152, 161))	('KRAS', 'Gene', '3845', (210, 214))	('ALK', 'Gene', (218, 221))	('patients', 'Species', '9606', (116, 124))	('benefit', 'Reg', (167, 174))	('carcinomas', 'Phenotype', 'HP:0030731', (152, 162))	('EGFR', 'Gene', '1956', (204, 208))	('carcinomas', 'Disease', (152, 162))	('carcinomas', 'Disease', 'MESH:D002277', (152, 162))	('mutations', 'Var', (222, 231))	('ALK', 'Gene', '238', (218, 221))	('EGFR', 'Gene', (204, 208))	('KRAS', 'Gene', (210, 214))
399519	33246949	Germline genomic patterns are associated with cancer risk, oncogenic pathways, and clinical outcomes Germline variants when organized as genomic patterns are associated with cancer risk, oncogenic pathways, and clinical outcomes.	('associated', 'Reg', (30, 40))	('oncogenic', 'CPA', (59, 68))	('oncogenic pathways', 'Pathway', (187, 205))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('associated', 'Reg', (158, 168))	('cancer', 'Disease', (46, 52))	('variants', 'Var', (110, 118))	('cancer', 'Disease', (174, 180))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))
399532	33246949	As the cancer-driving genetic germline variants distribute sparsely across genomes and are restricted to a small set of genes, investigations of germline genetic variants have been largely restricted to the known cancer driver genes including tumor suppressors and the ones closely related to DNA repair, oncogenic signaling pathways, and cell cycle.	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('cancer', 'Disease', 'MESH:D009369', (7, 13))	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('cancer', 'Disease', 'MESH:D009369', (213, 219))	('variants', 'Var', (162, 170))	('tumor', 'Disease', 'MESH:D009369', (243, 248))	('cancer', 'Disease', (7, 13))	('cancer', 'Disease', (213, 219))	('variants', 'Var', (39, 47))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))	('tumor', 'Disease', (243, 248))
399533	33246949	For example, individuals diagnosed with colorectal cancer among the first-degree relatives who have Lynch syndrome have been shown to carry DNA repair defects that disabled DNA damage resurrection in germ lines and therefore accumulated genetic alterations that led to colon cancer.	('colon cancer', 'Disease', (269, 281))	('Lynch syndrome', 'Disease', (100, 114))	('colorectal cancer', 'Disease', (40, 57))	('age', 'Gene', '5973', (180, 183))	('led to', 'Reg', (262, 268))	('cancer', 'Phenotype', 'HP:0002664', (275, 281))	('Lynch syndrome', 'Disease', 'MESH:D003123', (100, 114))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('accumulated', 'PosReg', (225, 236))	('colorectal cancer', 'Disease', 'MESH:D015179', (40, 57))	('colorectal cancer', 'Phenotype', 'HP:0003003', (40, 57))	('colon cancer', 'Phenotype', 'HP:0003003', (269, 281))	('colon cancer', 'Disease', 'MESH:D015179', (269, 281))	('age', 'Gene', (180, 183))	('defects', 'Var', (151, 158))	('genetic alterations', 'Var', (237, 256))	('disabled', 'NegReg', (164, 172))
399534	33246949	Germline mutated Ras has been shown to be associated with developmental disorders and cardiofaciocutaneous syndrome.	('developmental disorders', 'Disease', (58, 81))	('associated', 'Reg', (42, 52))	('developmental disorders', 'Disease', 'MESH:D002658', (58, 81))	('Germline mutated', 'Var', (0, 16))	('cardiofaciocutaneous syndrome', 'Disease', 'MESH:C535579', (86, 115))	('cardiofaciocutaneous syndrome', 'Disease', (86, 115))	('Ras', 'Gene', (17, 20))
399535	33246949	Germline BRCA1/2 mutations are known to be directly associated with increased risks in multiple cancer types including breast and ovarian cancers.	('cancer', 'Disease', (138, 144))	('ovarian cancers', 'Phenotype', 'HP:0100615', (130, 145))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('BRCA1/2', 'Gene', (9, 16))	('associated', 'Reg', (52, 62))	('cancer', 'Disease', (96, 102))	('cancers', 'Phenotype', 'HP:0002664', (138, 145))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('BRCA1/2', 'Gene', '672;675', (9, 16))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('breast and ovarian cancers', 'Disease', 'MESH:D001943', (119, 145))	('mutations', 'Var', (17, 26))	('cancer', 'Disease', 'MESH:D009369', (138, 144))
399537	33246949	This analysis, on the one hand, supports the idea that the important cancer-related information is implicated in germline genomes, but on the other hand, each of the selected variants has a small penetrance for a small fraction (i.e., 1 to 2%) of the population only (i.e., depending on allele frequencies), indicating that individual germline variants could not be a sole informative descriptor of germline genomes.	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('variants', 'Var', (175, 183))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('cancer', 'Disease', (69, 75))
399558	33246949	Last, as the DP20masked condition might reduce the influence of repeat sequences and outlier samples, we also included the CGGP genomic pattern matrix and the genomic pattern's weighing factor matrix of DP20masked condition for each TCGA sample available in data S1 and S2, respectively.	('DP20masked', 'Var', (203, 213))	('CGGP', 'Chemical', '-', (123, 127))	('DP20masked', 'Var', (13, 23))
399561	33246949	CGGP_F was characterized by A>G and T>C variants, while CGGP_A and CGGP_D contained mainly C/T>T/C and G/A>A/G variants.	('C/T>T/C', 'Var', (91, 98))	('CGGP', 'Chemical', '-', (67, 71))	('G/A>A/G', 'Var', (103, 110))	('CGGP', 'Chemical', '-', (0, 4))	('T>C', 'Var', (36, 39))	('CGGP', 'Chemical', '-', (56, 60))
399566	33246949	Conspicuous signals in CGGP_E led to the formation of a local triple nucleotide profile of repeated nucleotides, including CAC>CCC, GAG>GGG, ACA>AAA, GCG>GGG, CGC>CCC, TGT>TTT, CTC>CCC, and GTG>GGG.	('CGC', 'Gene', (159, 162))	('GTG', 'Gene', (190, 193))	('CGGP', 'Chemical', '-', (23, 27))	('TGT>TTT', 'Var', (168, 175))	('GAG>GGG', 'Var', (132, 139))	('GCG>GGG', 'Var', (150, 157))	('GTG', 'Gene', '2678', (190, 193))	('CGGP_E', 'Gene', (23, 29))	('ACA>AAA', 'Var', (141, 148))
399584	33246949	Previously, the Catalogue of Somatic Mutations in Cancer (COSMIC) has identified 30 tumor somatic mutational signatures (http://cancer.sanger.ac.uk/cosmic/signatures), in which signatures 4 and 29 have been reported to be the somatic mutational imprints of tobacco smoking and tobacco chewing habit in tumors.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (302, 307))	('tobacco', 'Species', '4097', (277, 284))	('tumors', 'Disease', (302, 308))	('cancer', 'Disease', (128, 134))	('Cancer', 'Phenotype', 'HP:0002664', (50, 56))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumors', 'Disease', 'MESH:D009369', (302, 308))	('tobacco', 'Species', '4097', (257, 264))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('Cancer', 'Disease', (50, 56))	('tumor', 'Disease', (302, 307))	('tumor', 'Disease', 'MESH:D009369', (302, 307))	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('Cancer', 'Disease', 'MESH:D009369', (50, 56))	('Mutations', 'Var', (37, 46))	('tumors', 'Phenotype', 'HP:0002664', (302, 308))	('chewing habit', 'Phenotype', 'HP:0005216', (285, 298))	('tumor', 'Disease', (84, 89))
399612	33246949	Genes containing mutations that fitted CGGP_E were examined and compared between the two groups.	('CGGP_E', 'Gene', (39, 45))	('CGGP', 'Chemical', '-', (39, 43))	('mutations', 'Var', (17, 26))
399613	33246949	Well-known cancer drivers, such as fibronectin type III (FN3), receptors of tyrosine kinases (RTKs), and genes encoding epidermal growth factor (EGF)-like domain proteins and insulin-like growth factor binding proteins, were significantly more frequently mutated in the upper quartile group [false discovery rate (FDR) < 0.05; data S3].	('mutated', 'Var', (255, 262))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('fibronectin type', 'Protein', (35, 51))	('cancer', 'Disease', 'MESH:D009369', (11, 17))	('cancer', 'Disease', (11, 17))
399614	33246949	These results suggested that the presence of CGGP_E in germ lines might introduce significantly more mutations to RTKs and other cancer driver genes, which, in turn, could induce higher carcinogenesis risks for individuals when exposed to mutagenic agents.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('mutations', 'Var', (101, 110))	('induce', 'Reg', (172, 178))	('CGGP_E', 'Gene', (45, 51))	('age', 'Gene', '5973', (242, 245))	('age', 'Gene', '5973', (249, 252))	('cancer', 'Disease', (129, 135))	('presence', 'Var', (33, 41))	('more', 'PosReg', (96, 100))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('CGGP', 'Chemical', '-', (45, 49))	('RTKs', 'Gene', (114, 118))	('higher', 'PosReg', (179, 185))	('carcinogenesis', 'Disease', 'MESH:D063646', (186, 200))	('age', 'Gene', (242, 245))	('age', 'Gene', (249, 252))	('carcinogenesis', 'Disease', (186, 200))
399624	33246949	Across six cancer types (LUSC, BLCA, COAD, OV, PAAD, and THCA), AKAP9 mutation was significantly associated with higher weighing factors of CGGP_C, D, or G. For BLCA, COAD, GBM, OV, and SKCM, KMT2D mutation was significantly associated with higher weighing factors of CGGP_A, CGGP_B, CGGP_B and F, CGGP_E, and CGGP_F and G. Some associations were observed in individual cancer types.	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('CGGP', 'Chemical', '-', (298, 302))	('CGGP', 'Chemical', '-', (140, 144))	('cancer', 'Disease', 'MESH:D009369', (370, 376))	('KMT2D', 'Gene', (192, 197))	('COAD', 'Disease', (167, 171))	('COAD', 'Disease', 'MESH:D029424', (37, 41))	('cancer', 'Disease', 'MESH:D009369', (11, 17))	('cancer', 'Disease', (370, 376))	('KMT2D', 'Gene', '8085', (192, 197))	('CGGP', 'Chemical', '-', (310, 314))	('CGGP', 'Chemical', '-', (276, 280))	('cancer', 'Phenotype', 'HP:0002664', (370, 376))	('AKAP9', 'Gene', '10142', (64, 69))	('COAD', 'Disease', (37, 41))	('CGGP', 'Chemical', '-', (284, 288))	('AKAP9', 'Gene', (64, 69))	('COAD', 'Disease', 'MESH:D029424', (167, 171))	('mutation', 'Var', (70, 78))	('CGGP', 'Chemical', '-', (268, 272))	('cancer', 'Disease', (11, 17))
399631	33246949	Genomic patterns CGGP_E, D, and G have more contributions to cancer samples than noncancer samples in most cancer types, whereas CGGP_A and F have smaller contributions to cancer samples than noncancer samples in most cancer types (Fig.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('cancer', 'Disease', 'MESH:D009369', (218, 224))	('CGGP', 'Chemical', '-', (129, 133))	('CGGP', 'Chemical', '-', (17, 21))	('cancer', 'Disease', (84, 90))	('cancer', 'Disease', (195, 201))	('cancer', 'Disease', (61, 67))	('CGGP_E', 'Var', (17, 23))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('cancer', 'Disease', (172, 178))	('cancer', 'Disease', (107, 113))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('cancer', 'Disease', (218, 224))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))
399639	33246949	Patients who carried the CGGP_D + CGGP_E combination in their germline genomes were significantly enriched with six COSMIC signatures in their corresponding tumor tissues in comparison with patients without this CGGP combination, implying that germline genomic patterns had the potential to shape or select somatic mutational processes during tumorigenesis.	('tumor', 'Disease', (157, 162))	('patients', 'Species', '9606', (190, 198))	('select', 'Reg', (300, 306))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('CGGP', 'Chemical', '-', (212, 216))	('CGGP_D + CGGP_E', 'Var', (25, 40))	('tumor', 'Disease', 'MESH:D009369', (343, 348))	('Patients', 'Species', '9606', (0, 8))	('CGGP', 'Chemical', '-', (25, 29))	('shape', 'Reg', (291, 296))	('CGGP', 'Chemical', '-', (34, 38))	('tumor', 'Phenotype', 'HP:0002664', (343, 348))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('tumor', 'Disease', (343, 348))
399640	33246949	In summary, these results suggested that CGGPs or their combinations could be associated with triggering of endogenous mutations in tumors and could shape the carcinogenesis and tumor proliferation process.	('carcinogenesis', 'Disease', (159, 173))	('tumor', 'Disease', (178, 183))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('carcinogenesis', 'Disease', 'MESH:D063646', (159, 173))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('shape', 'Reg', (149, 154))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('tumor', 'Disease', (132, 137))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('CGGPs', 'Chemical', '-', (41, 46))	('tumors', 'Disease', (132, 138))	('mutations', 'Var', (119, 128))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('tumors', 'Disease', 'MESH:D009369', (132, 138))
399646	33246949	For example, either single CGGP_A, B, C, D, and G or the combinations of CGGP_A + CGGP_G, CGGP_B + CGGP_C, CGGP_B + CGGP_F, and CGGP_C + CGGP_G were significantly different between the basal and luminal breast cancer subtypes.	('luminal breast cancer', 'Disease', (195, 216))	('CGGP', 'Chemical', '-', (116, 120))	('luminal breast cancer', 'Disease', 'MESH:D001943', (195, 216))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('CGGP', 'Chemical', '-', (27, 31))	('CGGP', 'Chemical', '-', (107, 111))	('CGGP', 'Chemical', '-', (137, 141))	('CGGP', 'Chemical', '-', (82, 86))	('CGGP', 'Chemical', '-', (99, 103))	('breast cancer', 'Phenotype', 'HP:0003002', (203, 216))	('CGGP', 'Chemical', '-', (73, 77))	('different', 'Reg', (163, 172))	('CGGP', 'Chemical', '-', (128, 132))	('CGGP', 'Chemical', '-', (90, 94))	('basal and', 'Disease', (185, 194))	('CGGP_C + CGGP_G', 'Var', (128, 143))	('CGGP_A', 'Gene', (73, 79))	('CGGP_B + CGGP_F', 'Var', (107, 122))	('CGGP_B + CGGP_C', 'Var', (90, 105))
399662	33246949	These results suggested that for these nine common cancer types, clinical outcomes were partially determined by the CGGPs in germline genomes.	('CGGPs', 'Chemical', '-', (116, 121))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('CGGPs', 'Var', (116, 121))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('determined by', 'Reg', (98, 111))
399675	33246949	For example, divergence of adenosine triphosphate (ATP)-related metabolism between kidney cancer's normal tissue subgroups 1 and 3 transformed to differences in immune response functions in tumors.	('adenosine', 'Chemical', 'MESH:D000241', (27, 36))	('kidney cancer', 'Disease', 'MESH:D007680', (83, 96))	('tumors', 'Disease', 'MESH:D009369', (190, 196))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('kidney cancer', 'Phenotype', 'HP:0009726', (83, 96))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('ATP', 'Chemical', 'MESH:D000255', (51, 54))	('immune response functions', 'MPA', (161, 186))	('divergence', 'Var', (13, 23))	('kidney cancer', 'Disease', (83, 96))	('tumors', 'Phenotype', 'HP:0002664', (190, 196))	('tumors', 'Disease', (190, 196))	('differences', 'Reg', (146, 157))
399678	33246949	In this study, germline genomes paired with tumor genomes of 7214 cancer patients of European ancestry and germline genomes of 16,670 noncancer individuals were analyzed to reveal enriched sequential context-dependent variant profiles that could be associated with cancer risk, tumorigenesis, and clinical outcomes.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('tumor', 'Phenotype', 'HP:0002664', (278, 283))	('cancer', 'Disease', 'MESH:D009369', (265, 271))	('tumor', 'Disease', (278, 283))	('variant', 'Var', (218, 225))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('cancer', 'Phenotype', 'HP:0002664', (265, 271))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('patients', 'Species', '9606', (73, 81))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('cancer', 'Disease', (137, 143))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('cancer', 'Disease', (265, 271))	('tumor', 'Disease', 'MESH:D009369', (278, 283))	('tumor', 'Disease', (44, 49))	('associated', 'Reg', (249, 259))	('cancer', 'Disease', (66, 72))
399689	33246949	For example, the germline subgroups defined by CGGPs were significantly associated with tumor histological subtypes, mechanisms of carcinogenesis, and prognosis for at least 13 common cancer types, and the strengths of CGGPs in germline genomes were associated with key somatic cancer drivers in paired tumors.	('cancer', 'Disease', (184, 190))	('CGGPs', 'Var', (219, 224))	('tumor', 'Phenotype', 'HP:0002664', (303, 308))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('associated', 'Reg', (72, 82))	('tumors', 'Disease', (303, 309))	('cancer', 'Disease', (278, 284))	('carcinogenesis', 'Disease', (131, 145))	('cancer', 'Phenotype', 'HP:0002664', (278, 284))	('carcinogenesis', 'Disease', 'MESH:D063646', (131, 145))	('tumors', 'Disease', 'MESH:D009369', (303, 309))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('tumor', 'Disease', (88, 93))	('CGGPs', 'Chemical', '-', (47, 52))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('tumor', 'Disease', (303, 308))	('cancer', 'Disease', 'MESH:D009369', (278, 284))	('associated', 'Reg', (250, 260))	('tumor', 'Disease', 'MESH:D009369', (303, 308))	('CGGPs', 'Chemical', '-', (219, 224))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumors', 'Phenotype', 'HP:0002664', (303, 309))
399692	33246949	These results suggest that congenital germline variants encode some subtle causalities of tumorigenesis and metastasis.	('variants', 'Var', (47, 55))	('tumor', 'Disease', (90, 95))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))
399693	33246949	The quantitative analysis of germline variants provides intriguing depictions of genomic features, which are associated with genetic diseases.	('genetic diseases', 'Disease', 'MESH:D030342', (125, 141))	('genetic diseases', 'Disease', (125, 141))	('variants', 'Var', (38, 46))
399702	33246949	It has been reported that certain COSMIC signatures in tumors are significantly associated with tumor driver gene mutations.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('mutations', 'Var', (114, 123))	('tumor', 'Disease', (96, 101))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('tumor', 'Disease', (55, 60))	('associated', 'Reg', (80, 90))	('tumors', 'Disease', (55, 61))	('tumors', 'Disease', 'MESH:D009369', (55, 61))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('COSMIC signatures', 'MPA', (34, 51))
399705	33246949	found that COSMIC signature 2 was also significantly associated with PIK3CA mutation in HNSC.	('PIK3CA', 'Gene', '5290', (69, 75))	('mutation', 'Var', (76, 84))	('PIK3CA', 'Gene', (69, 75))	('associated', 'Reg', (53, 63))
399706	33246949	These results implied the causality of CGGP_G for PIK3CA mutation in HNSC tumors.	('mutation', 'Var', (57, 65))	('CGGP', 'Chemical', '-', (39, 43))	('PIK3CA', 'Gene', '5290', (50, 56))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('HNSC tumors', 'Disease', (69, 80))	('PIK3CA', 'Gene', (50, 56))	('HNSC tumors', 'Disease', 'MESH:D009369', (69, 80))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))
399707	33246949	These examples provide an argument against the bad-luck hypothesis, which proposes that tumorigenesis is a purely random process of DNA replication errors and heredity plays a minimal role in tumorigenesis.	('tumor', 'Disease', (192, 197))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('errors', 'Var', (148, 154))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('tumor', 'Disease', (88, 93))
399724	33246949	Theoretically, germline homozygous and heterozygous variants would have variant allele frequency (VAF) signals residing around 1.0 and 0.5, respectively, with subtle influences introduced by the systemic sequencing and variant calling bias.	('variant', 'MPA', (72, 79))	('variants', 'Var', (52, 60))	('AF', 'Disease', 'MESH:D001281', (99, 101))
399725	33246949	Among the variants derived from peripheral blood of cancer patients, we observed a visible subset with VAF ranging from 0.2 to 0.3, implying that putative somatic mutations generated from clonal hematopoiesis existed across the population (fig.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('hematopoiesis', 'Disease', (195, 208))	('variants', 'Var', (10, 18))	('AF', 'Disease', 'MESH:D001281', (104, 106))	('hematopoiesis', 'Disease', 'MESH:C536227', (195, 208))	('patients', 'Species', '9606', (59, 67))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))
399731	33246949	We termed the "trinucleotide profile" of a variant as the trinucleotide form by the immediate 5' sequential context of the variant (i.e., the previous nucleotide), the variant itself, and the immediate 3' sequential context (i.e., the next nucleotide).	('variant', 'Var', (123, 130))	('variant', 'Var', (43, 50))	('trinucleotide', 'Chemical', '-', (58, 71))	('trinucleotide', 'Chemical', '-', (15, 28))
399736	33246949	The rationale behind this was that germline genome, by nature, carried much more variants compared to somatic mutations in tumor genome, and the variants were less informative than the de novo mutations in tumors.	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('tumor', 'Disease', (123, 128))	('tumors', 'Phenotype', 'HP:0002664', (206, 212))	('tumor', 'Disease', (206, 211))	('tumors', 'Disease', (206, 212))	('tumors', 'Disease', 'MESH:D009369', (206, 212))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('tumor', 'Disease', 'MESH:D009369', (206, 211))	('variants', 'Var', (81, 89))
399974	32549791	In the present report, LINC00662 was overexpressed in OSCC and its silencing could alleviate radioresistance of OSCC.	('LINC00662', 'Gene', '148189', (23, 32))	('OSCC', 'Disease', (112, 116))	('silencing', 'Var', (67, 76))	('alleviate', 'NegReg', (83, 92))	('radioresistance', 'CPA', (93, 108))	('LINC00662', 'Gene', (23, 32))
399982	32549791	Increasing evidence has indicated that aberrantly-expressed lncRNAs participate in cell proliferation, migration, invasion and even the radioresistance of human cancers.	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('radioresistance', 'CPA', (136, 151))	('lncRNAs', 'Protein', (60, 67))	('cell proliferation', 'CPA', (83, 101))	('human', 'Species', '9606', (155, 160))	('participate', 'Reg', (68, 79))	('cancers', 'Disease', 'MESH:D009369', (161, 168))	('aberrantly-expressed', 'Var', (39, 59))	('cancers', 'Phenotype', 'HP:0002664', (161, 168))	('cancers', 'Disease', (161, 168))	('invasion', 'CPA', (114, 122))	('migration', 'CPA', (103, 112))
399994	32549791	For example, AK4 is a prognostic marker that facilitates metastasis in lung cancer via silencing ATF3, a transcription factor.	('silencing', 'Var', (87, 96))	('ATF3', 'Gene', (97, 101))	('lung cancer', 'Disease', 'MESH:D008175', (71, 82))	('facilitates', 'PosReg', (45, 56))	('AK4', 'Gene', '205', (13, 16))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('metastasis', 'CPA', (57, 67))	('AK4', 'Gene', (13, 16))	('ATF3', 'Gene', '467', (97, 101))	('lung cancer', 'Disease', (71, 82))	('lung cancer', 'Phenotype', 'HP:0100526', (71, 82))
399999	32549791	Mechanism experiments demonstrated that the silencing of LINC00662 improved the radiosensitivity of OSCC cells.	('LINC00662', 'Gene', '148189', (57, 66))	('radiosensitivity of OSCC cells', 'CPA', (80, 110))	('silencing', 'Var', (44, 53))	('improved', 'PosReg', (67, 75))	('LINC00662', 'Gene', (57, 66))
400025	32549791	The whole cell lysate was incubated in RIP buffer where magnetic beads were absorbed by anti-hnPNRC (ab133607; 1:100; Abcam, Cambridge, MA, USA) or anti-IgG (ab218427; 1:100; CST, Boston, MA, USA).	('ab218427; 1:100;', 'Var', (158, 174))	('CST', 'Gene', '106478911', (175, 178))	('ab133607; 1:100;', 'Var', (101, 117))	('CST', 'Gene', (175, 178))
400033	32549791	The membranes were incubated with primary antibodies against cleaved PARP (ab32064; Abcam), PARP (ab74290; Abcam), cleaved caspase-3 (ab2302; Abcam), caspase-3 (ab13847; Abcam), hnRNPC (ab97541; Abcam), AK4 (ab232888; Abcam) or GAPDH (sc-32233; Santa Cruz Biotechnology, Santa Cruz, CA, USA) at 4  C overnight.	('hnRNPC', 'Gene', '3183', (178, 184))	('caspase-3', 'Gene', '836', (150, 159))	('PARP', 'Gene', (92, 96))	('caspase-3', 'Gene', '836', (123, 132))	('PARP', 'Gene', '142', (69, 73))	('caspase-3', 'Gene', (150, 159))	('PARP', 'Gene', '142', (92, 96))	('hnRNPC', 'Gene', (178, 184))	('PARP', 'Gene', (69, 73))	('ab97541;', 'Var', (186, 194))	('caspase-3', 'Gene', (123, 132))	('GAPDH', 'Gene', '2597', (228, 233))	('GAPDH', 'Gene', (228, 233))	('AK4', 'Gene', '205', (203, 206))	('ab74290;', 'Var', (98, 106))	('AK4', 'Gene', (203, 206))
400041	32549791	LINC00662 expression was significantly reduced by transfection of sh-LINC00662#1/2, as examined by qRT-PCR (Fig.	('LINC00662', 'Gene', '148189', (0, 9))	('LINC00662', 'Gene', (0, 9))	('expression', 'MPA', (10, 20))	('LINC00662', 'Gene', (69, 78))	('LINC00662', 'Gene', '148189', (69, 78))	('reduced', 'NegReg', (39, 46))	('transfection', 'Var', (50, 62))
400045	32549791	Importantly, combination of irradiation and LINC00662 silencing markedly reinforced the declining trend of cell survival fraction (Fig.	('LINC00662', 'Gene', (44, 53))	('silencing', 'Var', (54, 63))	('LINC00662', 'Gene', '148189', (44, 53))	('cell survival fraction', 'CPA', (107, 129))
400047	32549791	Silenced LINC00662 further increased proportion of cells at G0/G1 phrase caused by 4Gy radiation (Additional file 2: Figure S1B).	('Silenced', 'Var', (0, 8))	('LINC00662', 'Gene', '148189', (9, 18))	('increased', 'PosReg', (27, 36))	('LINC00662', 'Gene', (9, 18))
400048	32549791	In flow cytometry assay, apoptosis was obviously enhanced by radiation exposure or by transfection of sh-LINC00662#2.	('LINC00662', 'Gene', '148189', (105, 114))	('LINC00662', 'Gene', (105, 114))	('enhanced', 'PosReg', (49, 57))	('transfection', 'Var', (86, 98))	('apoptosis', 'CPA', (25, 34))
400049	32549791	Combination of radiation exposure and the knockdown of LINC00662 further enhanced cell apoptosis rates of CAL27 and SCC-4 cells (Fig.	('cell apoptosis rates', 'CPA', (82, 102))	('SCC-4', 'Gene', '23383', (116, 121))	('CAL27', 'CellLine', 'CVCL:1107', (106, 111))	('enhanced', 'PosReg', (73, 81))	('SCC-4', 'Gene', (116, 121))	('LINC00662', 'Gene', '148189', (55, 64))	('LINC00662', 'Gene', (55, 64))	('knockdown', 'Var', (42, 51))
400051	32549791	Western blotting demonstrated that the expression level of cleaved-PARP and cleaved caspase-3 decreased after 4Gy irradiation or silence of LINC00662.	('PARP', 'Gene', (67, 71))	('LINC00662', 'Gene', '148189', (140, 149))	('LINC00662', 'Gene', (140, 149))	('caspase-3', 'Gene', (84, 93))	('PARP', 'Gene', '142', (67, 71))	('decreased', 'NegReg', (94, 103))	('silence', 'Var', (129, 136))	('caspase-3', 'Gene', '836', (84, 93))	('expression level', 'MPA', (39, 55))
400053	32549791	In the meanwhile, expression of total PARP or caspase-3 showed no changes to 4Gy irradiation or silence of LINC00662 (Fig.	('silence', 'Var', (96, 103))	('caspase-3', 'Gene', (46, 55))	('PARP', 'Gene', (38, 42))	('caspase-3', 'Gene', '836', (46, 55))	('LINC00662', 'Gene', (107, 116))	('expression', 'MPA', (18, 28))	('LINC00662', 'Gene', '148189', (107, 116))	('PARP', 'Gene', '142', (38, 42))
400055	32549791	Moreover, we constructed the LINC00662-KO plasmid to knock out LINC00662 expression.	('knock', 'Var', (53, 58))	('LINC00662', 'Gene', (63, 72))	('LINC00662', 'Gene', '148189', (63, 72))	('LINC00662', 'Gene', '148189', (29, 38))	('LINC00662', 'Gene', (29, 38))
400056	32549791	LINC00662 expression was significantly knocked out by transfection of LINC00662-KO (Additional file 3: Figure S2A).	('LINC00662', 'Gene', '148189', (0, 9))	('LINC00662', 'Gene', (0, 9))	('expression', 'MPA', (10, 20))	('LINC00662', 'Gene', '148189', (70, 79))	('LINC00662', 'Gene', (70, 79))	('knocked out', 'NegReg', (39, 50))	('transfection', 'Var', (54, 66))
400058	32549791	In conclusion, all these data revealed that LINC00662 served as an oncogene in OSCC cells, and LINC00662 knockdown or knockout improved radiosensitivity of OSCC cells.	('LINC00662', 'Gene', (95, 104))	('LINC00662', 'Gene', '148189', (44, 53))	('LINC00662', 'Gene', '148189', (95, 104))	('LINC00662', 'Gene', (44, 53))	('knockdown', 'Var', (105, 114))	('radiosensitivity of OSCC', 'CPA', (136, 160))	('knockout', 'Var', (118, 126))	('improved', 'PosReg', (127, 135))
400065	32549791	Besides, knockout of LINC00662 had no influences on the mRNA and protein level of hnRNPC (Fig.	('knockout', 'Var', (9, 17))	('LINC00662', 'Gene', (21, 30))	('LINC00662', 'Gene', '148189', (21, 30))	('hnRNPC', 'Gene', (82, 88))	('hnRNPC', 'Gene', '3183', (82, 88))
400074	32549791	As a result, AK4 expression was significantly reduced by knockdown of hnRNPC (Fig.	('hnRNPC', 'Gene', '3183', (70, 76))	('expression', 'MPA', (17, 27))	('knockdown', 'Var', (57, 66))	('AK4', 'Gene', '205', (13, 16))	('reduced', 'NegReg', (46, 53))	('AK4', 'Gene', (13, 16))	('hnRNPC', 'Gene', (70, 76))
400075	32549791	Besides, qRT-PCR displayed that the remaining mRNA of AK4 was reduced when actinomycin D was added, and this phenomenon was aggravated by the knockdown of hnRNPC, showing the positive regulation of hnRNPC on the stability of AK4 mRNA (Fig.	('hnRNPC', 'Gene', (198, 204))	('AK4', 'Gene', '205', (225, 228))	('AK4', 'Gene', '205', (54, 57))	('hnRNPC', 'Gene', '3183', (155, 161))	('actinomycin D', 'MPA', (75, 88))	('AK4', 'Gene', (225, 228))	('hnRNPC', 'Gene', '3183', (198, 204))	('AK4', 'Gene', (54, 57))	('actinomycin D', 'Chemical', 'MESH:D003609', (75, 88))	('hnRNPC', 'Gene', (155, 161))	('knockdown', 'Var', (142, 151))	('reduced', 'NegReg', (62, 69))
400076	32549791	After that, we constructed hnRNPC-KO plasmids to evaluate the effects of hnRNPC knockout on AK4.	('knockout', 'Var', (80, 88))	('hnRNPC', 'Gene', (73, 79))	('AK4', 'Gene', '205', (92, 95))	('hnRNPC', 'Gene', '3183', (73, 79))	('AK4', 'Gene', (92, 95))	('hnRNPC', 'Gene', (27, 33))	('hnRNPC', 'Gene', '3183', (27, 33))
400078	32549791	Knockout out of hnRNPC remarkably reduced AK4 expression (Fig.	('reduced', 'NegReg', (34, 41))	('hnRNPC', 'Gene', (16, 22))	('hnRNPC', 'Gene', '3183', (16, 22))	('Knockout', 'Var', (0, 8))	('AK4', 'Gene', '205', (42, 45))	('AK4', 'Gene', (42, 45))
400079	32549791	Also, knockout out of hnRNPC aggravated degradation of AK4 caused by actinomycin D (Fig.	('actinomycin D', 'Chemical', 'MESH:D003609', (69, 82))	('AK4', 'Gene', (55, 58))	('AK4', 'Gene', '205', (55, 58))	('hnRNPC', 'Gene', (22, 28))	('aggravated', 'PosReg', (29, 39))	('hnRNPC', 'Gene', '3183', (22, 28))	('degradation', 'MPA', (40, 51))	('knockout out', 'Var', (6, 18))
400085	32549791	Also, knockout of LINC00662 dramatically reduced AK4 expression at both mRNA and protein level (Fig.	('AK4', 'Gene', (49, 52))	('reduced', 'NegReg', (41, 48))	('LINC00662', 'Gene', '148189', (18, 27))	('LINC00662', 'Gene', (18, 27))	('knockout', 'Var', (6, 14))	('expression', 'MPA', (53, 63))	('AK4', 'Gene', '205', (49, 52))
400090	32549791	Finally, qRT-PCR demonstrated that in both CAL27 and SCC-4 cells, actinomycin D inhibited the RNA synthesis of AK4, which was exacerbated after LIN00662 was downregulated but restored when hnRNPC was upregulated (Fig.	('hnRNPC', 'Gene', '3183', (189, 195))	('AK4', 'Gene', '205', (111, 114))	('RNA synthesis', 'MPA', (94, 107))	('downregulated', 'NegReg', (157, 170))	('SCC-4', 'Gene', (53, 58))	('AK4', 'Gene', (111, 114))	('inhibited', 'NegReg', (80, 89))	('SCC-4', 'Gene', '23383', (53, 58))	('CAL27', 'CellLine', 'CVCL:1107', (43, 48))	('actinomycin D', 'Chemical', 'MESH:D003609', (66, 79))	('LIN00662', 'Var', (144, 152))	('hnRNPC', 'Gene', (189, 195))	('exacerbated', 'PosReg', (126, 137))
400099	32549791	Next, the rescue assays were conducted using AK4 overexpression to rescue LINC00662 knockdown in cell radio-resistance.	('LINC00662', 'Gene', (74, 83))	('cell radio-resistance', 'MPA', (97, 118))	('knockdown', 'Var', (84, 93))	('AK4', 'Gene', '205', (45, 48))	('LINC00662', 'Gene', '148189', (74, 83))	('AK4', 'Gene', (45, 48))
400100	32549791	CCK-8 experiment demonstrated that under 4Gy irradiation, cell viability of CAL27 and SCC-4 cells was further repressed by LINC00662 knockdown but rescued by AK4 overexpression (Fig.	('repressed', 'PosReg', (110, 119))	('SCC-4', 'Gene', (86, 91))	('cell viability', 'CPA', (58, 72))	('CAL27', 'CellLine', 'CVCL:1107', (76, 81))	('LINC00662', 'Gene', (123, 132))	('LINC00662', 'Gene', '148189', (123, 132))	('AK4', 'Gene', '205', (158, 161))	('knockdown', 'Var', (133, 142))	('AK4', 'Gene', (158, 161))	('SCC-4', 'Gene', '23383', (86, 91))
400101	32549791	In colony formation assay, the increasing of radiation decreased the survival fraction of CAL27 and SCC-4 cells gradually, which was reinforced by the silencing of LINC00662 but restored by the overexpression of AK4 (Fig.	('silencing', 'Var', (151, 160))	('SCC-4', 'Gene', (100, 105))	('CAL27', 'CellLine', 'CVCL:1107', (90, 95))	('LINC00662', 'Gene', (164, 173))	('LINC00662', 'Gene', '148189', (164, 173))	('survival fraction', 'CPA', (69, 86))	('AK4', 'Gene', '205', (212, 215))	('decreased', 'NegReg', (55, 64))	('SCC-4', 'Gene', '23383', (100, 105))	('AK4', 'Gene', (212, 215))
400102	32549791	Under 4Gy radiation, cell cycle was arrested when LINC00662 was knocked down whereas, this effect was neutralized when AK4 was overexpressed (Additional file 4: Figure S3A).	('knocked down', 'Var', (64, 76))	('cell cycle', 'CPA', (21, 31))	('AK4', 'Gene', '205', (119, 122))	('arrest', 'Disease', 'MESH:D006323', (36, 42))	('AK4', 'Gene', (119, 122))	('LINC00662', 'Gene', '148189', (50, 59))	('arrest', 'Disease', (36, 42))	('LINC00662', 'Gene', (50, 59))
400104	32549791	Finally, western blot disclosed that after 4Gy radiation, cleaved PARP and cleaved caspase-3 levels were also reduced after LINC00662 was knocked down but partly abolished when AK4 was overexpressed (Fig.	('PARP', 'Gene', '142', (66, 70))	('AK4', 'Gene', '205', (177, 180))	('reduced', 'NegReg', (110, 117))	('AK4', 'Gene', (177, 180))	('caspase-3', 'Gene', '836', (83, 92))	('PARP', 'Gene', (66, 70))	('knocked down', 'Var', (138, 150))	('LINC00662', 'Gene', '148189', (124, 133))	('LINC00662', 'Gene', (124, 133))	('caspase-3', 'Gene', (83, 92))
400107	32549791	AK4 expression was significantly down-regulated at both mRNA and protein levels by transfection of sh-AK4 (Additional file 5: Figure S4A and Additional file 1F).	('expression', 'MPA', (4, 14))	('AK4', 'Gene', '205', (102, 105))	('AK4', 'Gene', (102, 105))	('transfection', 'Var', (83, 95))	('AK4', 'Gene', '205', (0, 3))	('down-regulated', 'NegReg', (33, 47))	('AK4', 'Gene', (0, 3))
400108	32549791	CCK-8 and colony formation assay depicted that silenced AK4 rescued the promoting effects of LINC00662 overexpression on cell viability and proliferation under radiation exposure (Additional file 5: Figure S4B, C).	('proliferation', 'CPA', (140, 153))	('AK4', 'Gene', (56, 59))	('promoting', 'PosReg', (72, 81))	('cell viability', 'CPA', (121, 135))	('LINC00662', 'Gene', (93, 102))	('overexpression', 'PosReg', (103, 117))	('LINC00662', 'Gene', '148189', (93, 102))	('AK4', 'Gene', '205', (56, 59))	('silenced', 'Var', (47, 55))
400110	32549791	Flow cytometry apoptosis assay and western analysis of apoptosis-related proteins revealed that under 4Gy irradiation exposure, silenced AK4 restored the suppressive effects of LINC00662 overexpression on cell apoptosis (Additional file 5: Figure S4E-F).	('LINC00662', 'Gene', (177, 186))	('cell apoptosis', 'CPA', (205, 219))	('suppressive', 'MPA', (154, 165))	('silenced', 'Var', (128, 136))	('AK4', 'Gene', '205', (137, 140))	('AK4', 'Gene', (137, 140))	('LINC00662', 'Gene', '148189', (177, 186))
400118	32549791	In addition, the silencing or knockout of LINC00662 could promote the radiosensitivity of OSCC cells by inhibiting cell proliferation, migration and invasion, and inducing apoptosis and cell cycle arrest.	('cell cycle arrest', 'Phenotype', 'HP:0011018', (186, 203))	('promote', 'PosReg', (58, 65))	('radiosensitivity', 'CPA', (70, 86))	('knockout', 'Var', (30, 38))	('LINC00662', 'Gene', '148189', (42, 51))	('LINC00662', 'Gene', (42, 51))	('arrest', 'Disease', 'MESH:D006323', (197, 203))	('inhibiting', 'NegReg', (104, 114))	('inducing', 'Reg', (163, 171))	('cell proliferation', 'CPA', (115, 133))	('apoptosis', 'CPA', (172, 181))	('arrest', 'Disease', (197, 203))	('silencing', 'Var', (17, 26))
400133	32549791	Overexpression of AK4 was reported to promote lung cancer metastasis.	('AK4', 'Gene', (18, 21))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('lung cancer', 'Disease', 'MESH:D008175', (46, 57))	('Overexpression', 'Var', (0, 14))	('promote', 'PosReg', (38, 45))	('AK4', 'Gene', '205', (18, 21))	('lung cancer', 'Disease', (46, 57))	('lung cancer', 'Phenotype', 'HP:0100526', (46, 57))
400170	31370263	Inhibition of ACE exerts antihypertensive effects and lowers serum and renal chemerin protein.	('hypertensive', 'Disease', 'MESH:D006973', (29, 41))	('ACE', 'Gene', '1636', (14, 17))	('Inhibition', 'Var', (0, 10))	('lowers', 'NegReg', (54, 60))	('hypertensive', 'Disease', (29, 41))	('ACE', 'Gene', (14, 17))
400199	31370263	In a melanoma model, chemerin transfected cancer cells exhibited a growth inhibitory immune cell distribution in the tumor microenvironment, which was characterized by a higher number of NK and T cells and a relative decline of MDSC and pDCs.	('pDC', 'Gene', (237, 240))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('higher', 'PosReg', (170, 176))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('melanoma', 'Phenotype', 'HP:0002861', (5, 13))	('tumor', 'Disease', (117, 122))	('melanoma', 'Disease', (5, 13))	('MDSC', 'MPA', (228, 232))	('T cells', 'CPA', (194, 201))	('melanoma', 'Disease', 'MESH:D008545', (5, 13))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('pDC', 'Gene', '5132', (237, 240))	('decline', 'NegReg', (217, 224))	('transfected', 'Var', (30, 41))	('growth inhibitory immune', 'MPA', (67, 91))
400210	31370263	Chemerin binding to CMKLR1, but not to GPR1 or CCRL2, strongly increases intracellular calcium concentration, decreases cyclic AMP levels and induces the phosphorylation of p42-p44 MAP kinases, through the Gi class of G proteins.	('decreases', 'NegReg', (110, 119))	('induces', 'Reg', (142, 149))	('GPR1', 'Gene', (39, 43))	('p42', 'Gene', '23552', (173, 176))	('cyclic AMP levels', 'MPA', (120, 137))	('Chemerin', 'Gene', (0, 8))	('cyclic AMP', 'Chemical', 'MESH:D000242', (120, 130))	('increases intracellular calcium concentration', 'Phenotype', 'HP:0003575', (63, 108))	('intracellular calcium concentration', 'MPA', (73, 108))	('Chemerin', 'Gene', '5919', (0, 8))	('increases', 'PosReg', (63, 72))	('CCRL2', 'Gene', '9034', (47, 52))	('G proteins', 'Protein', (218, 228))	('GPR1', 'Gene', '2825', (39, 43))	('binding', 'Interaction', (9, 16))	('CCRL2', 'Gene', (47, 52))	('calcium', 'Chemical', 'MESH:D002118', (87, 94))	('phosphorylation', 'MPA', (154, 169))	('CMKLR1', 'Var', (20, 26))	('p42', 'Gene', (173, 176))
400236	31370263	These results were supported by a study observing the same effect of chemerin on angiogenesis and even more demonstrated that chemerin mediated the formation of blood vessels to a similar extent as VEGF.	('VEGF', 'Gene', (198, 202))	('chemerin', 'Var', (126, 134))	('angiogenesis', 'CPA', (81, 93))	('formation of blood vessels', 'CPA', (148, 174))	('VEGF', 'Gene', '7422', (198, 202))
400240	31370263	Knockdown of chemerin receptor CMKLR1, but not of CCRL2, completely inhibited the chemerin-induced migration and angiogenesis of HUVECs, which indicated that chemerin promoted the migration and angiogenic activities mainly through CMKLR1.	('CCRL2', 'Gene', '9034', (50, 55))	('CMKLR1', 'Var', (231, 237))	('chemerin-induced', 'MPA', (82, 98))	('migration', 'CPA', (180, 189))	('promoted', 'PosReg', (167, 175))	('angiogenesis', 'CPA', (113, 125))	('inhibited', 'NegReg', (68, 77))	('angiogenic activities', 'CPA', (194, 215))	('chemerin receptor', 'Gene', '1240', (13, 30))	('chemerin receptor', 'Gene', (13, 30))	('CCRL2', 'Gene', (50, 55))
400251	31370263	In contrast to this study on a small patients  collective, in a metaanalysis of publicly available DNA microarray data of 3951 breast cancer patients, chemerin expression was observed to be significantly lower in breast cancer tissue than in a normal breast (p = 2.17 x 10-7) and use of Kaplan-Meier plotter software revealed that high chemerin expression in breast cancer tissue did not affect overall survival (OS), but turned out to negatively affect relapse-free survival (RFS; p = 0.015; Figure 2).	('breast cancer', 'Phenotype', 'HP:0003002', (213, 226))	('breast cancer', 'Phenotype', 'HP:0003002', (127, 140))	('breast cancer', 'Disease', (359, 372))	('cancer', 'Phenotype', 'HP:0002664', (366, 372))	('patients', 'Species', '9606', (141, 149))	('breast cancer', 'Disease', 'MESH:D001943', (213, 226))	('breast cancer', 'Disease', 'MESH:D001943', (127, 140))	('patients', 'Species', '9606', (37, 45))	('OS', 'Chemical', '-', (413, 415))	('breast cancer', 'Disease', (213, 226))	('breast cancer', 'Disease', (127, 140))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('affect', 'Reg', (447, 453))	('high', 'Var', (331, 335))	('relapse-free survival', 'CPA', (454, 475))	('expression', 'MPA', (160, 170))	('breast cancer', 'Phenotype', 'HP:0003002', (359, 372))	('negatively', 'NegReg', (436, 446))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('breast cancer', 'Disease', 'MESH:D001943', (359, 372))	('lower', 'NegReg', (204, 209))
400252	31370263	In contrast, high CMKLR1 expression, which did not significantly differ between normal and tumorigenic breast, had robust beneficial effects on RFS of breast cancer patients, but did not affect OS.	('breast cancer', 'Disease', 'MESH:D001943', (151, 164))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('high CMKLR1', 'Var', (13, 24))	('breast cancer', 'Phenotype', 'HP:0003002', (151, 164))	('breast cancer', 'Disease', (151, 164))	('OS', 'Chemical', '-', (194, 196))	('patients', 'Species', '9606', (165, 173))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('beneficial effects', 'PosReg', (122, 140))	('tumor', 'Disease', (91, 96))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('RFS', 'MPA', (144, 147))
400253	31370263	Chemerin receptor GPR1 was found to be up-regulated in cancer tissue (p = 0.002), and high expression of GPR1 also led to prolonged RFS (p = 0.00082), but did not affect OS of breast cancer patients.	('patients', 'Species', '9606', (190, 198))	('GPR1', 'Gene', '2825', (105, 109))	('OS', 'Chemical', '-', (170, 172))	('up-regulated', 'PosReg', (39, 51))	('GPR1', 'Gene', '2825', (18, 22))	('cancer', 'Disease', (183, 189))	('Chemerin receptor', 'Gene', '1240', (0, 17))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('cancer', 'Disease', (55, 61))	('RFS', 'MPA', (132, 135))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('high expression', 'Var', (86, 101))	('breast cancer', 'Phenotype', 'HP:0003002', (176, 189))	('GPR1', 'Gene', (105, 109))	('cancer', 'Disease', 'MESH:D009369', (183, 189))	('prolonged', 'PosReg', (122, 131))	('GPR1', 'Gene', (18, 22))	('breast cancer', 'Disease', 'MESH:D001943', (176, 189))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('breast cancer', 'Disease', (176, 189))	('Chemerin receptor', 'Gene', (0, 17))
400274	31370263	The prolonged OS of patients with high expression of CMKLR1 and CCRL2 clearly suggested an anti-tumoral effect of serum chemerin being activated in ovarian cancer tissue.	('activated', 'PosReg', (135, 144))	('OS', 'Chemical', '-', (14, 16))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('ovarian cancer', 'Disease', (148, 162))	('high expression', 'Var', (34, 49))	('CCRL2', 'Gene', '9034', (64, 69))	('tumor', 'Disease', (96, 101))	('CMKLR1', 'Gene', (53, 59))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('ovarian cancer', 'Phenotype', 'HP:0100615', (148, 162))	('patients', 'Species', '9606', (20, 28))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('ovarian cancer', 'Disease', 'MESH:D010051', (148, 162))	('CCRL2', 'Gene', (64, 69))
400286	31370263	Multi-variable Cox regression analysis suggested expression of chemerin to be an independent predictor of a better prognosis for patients with NSCLC.	('NSCLC', 'Disease', (143, 148))	('patients', 'Species', '9606', (129, 137))	('NSCLC', 'Disease', 'MESH:D002289', (143, 148))	('NSCLC', 'Phenotype', 'HP:0030358', (143, 148))	('expression', 'Var', (49, 59))
400304	31370263	In line with these studies, the analysis of publicly available DNA microarray data of 876 gastric cancer patients by means of the Kaplan-Meier plotter software demonstrated that high chemerin tumor expression reduced OS of gastric cancer patients (p = 0.0059; Figure 5) and also higher tissue expression of CMKLR1 and GPR1 significantly decreased OS of gastric cancer patients (p = 0.0085 or p = 1.7 x 10-7, respectively).	('gastric cancer', 'Disease', 'MESH:D013274', (90, 104))	('gastric cancer', 'Disease', 'MESH:D013274', (223, 237))	('high', 'Var', (178, 182))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('gastric cancer', 'Phenotype', 'HP:0012126', (353, 367))	('gastric cancer', 'Phenotype', 'HP:0012126', (90, 104))	('GPR1', 'Gene', '2825', (318, 322))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('patients', 'Species', '9606', (368, 376))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('tumor', 'Disease', (192, 197))	('patients', 'Species', '9606', (105, 113))	('gastric cancer', 'Phenotype', 'HP:0012126', (223, 237))	('OS', 'Chemical', '-', (347, 349))	('gastric cancer', 'Disease', (353, 367))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('patients', 'Species', '9606', (238, 246))	('gastric cancer', 'Disease', (90, 104))	('CMKLR1', 'Gene', (307, 313))	('decreased', 'NegReg', (337, 346))	('cancer', 'Phenotype', 'HP:0002664', (361, 367))	('reduced', 'NegReg', (209, 216))	('gastric cancer', 'Disease', (223, 237))	('higher', 'PosReg', (279, 285))	('gastric cancer', 'Disease', 'MESH:D013274', (353, 367))	('GPR1', 'Gene', (318, 322))	('OS', 'Chemical', '-', (217, 219))
400319	31370263	Supporting the mentioned studies suggesting a tumor-suppressive role of chemerin, the metaanalysis of publicly available gene expression data of 364 patients with HCC by means of the Kaplan-Meier plotter software revealed that high chemerin expression in cancer tissue significantly increased patients' OS (p = 0.00027) and progression-free survival (PFS; p = 0.012).	('cancer', 'Phenotype', 'HP:0002664', (255, 261))	('patients', 'Species', '9606', (149, 157))	('HCC', 'Phenotype', 'HP:0001402', (163, 166))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('OS', 'Chemical', '-', (303, 305))	('patients', 'Species', '9606', (293, 301))	('cancer', 'Disease', 'MESH:D009369', (255, 261))	('chemerin', 'Protein', (232, 240))	('tumor', 'Disease', (46, 51))	('expression', 'MPA', (241, 251))	('increased', 'PosReg', (283, 292))	('progression-free survival', 'CPA', (324, 349))	("patients' OS", 'CPA', (293, 305))	('cancer', 'Disease', (255, 261))	('high', 'Var', (227, 231))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
400330	31370263	It was shown that chemerin was independently able to prognosticate AML patients, and high chemerin expression was associated with positive prognosis.	('AML', 'Disease', 'MESH:D015470', (67, 70))	('AML', 'Phenotype', 'HP:0004808', (67, 70))	('patients', 'Species', '9606', (71, 79))	('AML', 'Disease', (67, 70))	('high', 'Var', (85, 89))
400333	31370263	Chemerin was found to be down-regulated in melanoma and high chemerin mRNA expression in tumors correlated with improved outcome in human melanoma.	('melanoma', 'Disease', 'MESH:D008545', (138, 146))	('melanoma', 'Phenotype', 'HP:0002861', (138, 146))	('tumors', 'Disease', (89, 95))	('melanoma', 'Disease', (138, 146))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('melanoma', 'Phenotype', 'HP:0002861', (43, 51))	('chemerin', 'Gene', (61, 69))	('melanoma', 'Disease', (43, 51))	('Chemerin', 'Gene', (0, 8))	('down-regulated', 'NegReg', (25, 39))	('melanoma', 'Disease', 'MESH:D008545', (43, 51))	('human', 'Species', '9606', (132, 137))	('mRNA expression', 'MPA', (70, 85))	('improved', 'PosReg', (112, 120))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('Chemerin', 'Gene', '5919', (0, 8))	('high', 'Var', (56, 60))
400361	31285693	Deregulated expression by miRNAs could increase the risk of metabolic diseases, such as diabetes and obesity, by disrupting signaling pathways.	('obesity', 'Disease', 'MESH:D009765', (101, 108))	('Deregulated', 'Var', (0, 11))	('miRNAs', 'Gene', (26, 32))	('disrupting', 'NegReg', (113, 123))	('obesity', 'Disease', (101, 108))	('metabolic diseases', 'Disease', 'MESH:D008659', (60, 78))	('increase', 'PosReg', (39, 47))	('obesity', 'Phenotype', 'HP:0001513', (101, 108))	('signaling pathways', 'Pathway', (124, 142))	('diabetes', 'Disease', (88, 96))	('expression', 'MPA', (12, 22))	('metabolic diseases', 'Disease', (60, 78))	('diabetes', 'Disease', 'MESH:D003920', (88, 96))
400369	31285693	Increasing studies have provided insight into the mechanism underlying the effects of abnormal miR-146a-5p on various cancers.	('cancers', 'Disease', (118, 125))	('cancers', 'Disease', 'MESH:D009369', (118, 125))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('miR-146a', 'Gene', '406938', (95, 103))	('abnormal', 'Var', (86, 94))	('effects', 'Reg', (75, 82))	('miR-146a', 'Gene', (95, 103))	('cancers', 'Phenotype', 'HP:0002664', (118, 125))
400373	31285693	Additionally, to examine the mechanism underlying the effects of aberrant miR-146a-5p in solid cancers, a pathway analysis and protein interaction network analysis were conducted.	('cancers', 'Phenotype', 'HP:0002664', (95, 102))	('aberrant', 'Var', (65, 73))	('solid cancers', 'Disease', (89, 102))	('miR-146a', 'Gene', '406938', (74, 82))	('solid cancers', 'Disease', 'MESH:D009369', (89, 102))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('miR-146a', 'Gene', (74, 82))
400375	31285693	The search terms for English-language databases included "miR146", "miRNA146", "microRNA146", "microRNA146a", "miR146a", "miRNA146a", "microRNA-146a-5p", "miRNA-146a-5p", and "miR-146a-5p" as well as "cancer", "carcinoma", "adenocarcinoma", "sarcoma", "tumor", "neoplas*", and "malignan*", using "OR" to connect terms.	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('cancer', 'Disease', (201, 207))	('tumor', 'Disease', 'MESH:D009369', (253, 258))	('miR-146a', 'Gene', '406938', (176, 184))	('miRNA146a', 'Var', (122, 131))	('miRNA-146a', 'Gene', (155, 165))	('carcinoma', 'Phenotype', 'HP:0030731', (229, 238))	('tumor', 'Phenotype', 'HP:0002664', (253, 258))	('miRNA-146a', 'Gene', '406938', (155, 165))	('carcinoma', 'Phenotype', 'HP:0030731', (211, 220))	('sarcoma', 'Phenotype', 'HP:0100242', (242, 249))	('"carcinoma", "adenocarcinoma", "sarcoma"', 'Disease', 'MESH:D000230', (210, 250))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('tumor', 'Disease', (253, 258))	('miR-146a', 'Gene', (176, 184))	('microRNA-146a', 'Gene', '406938', (135, 148))	('microRNA-146a', 'Gene', (135, 148))
400410	31285693	The association between high miR-146a-5p expression and improved survival was found in reproductive system cancers (HR 0.784, 95% CI 0.650-0.946, I2 = 0.00%) and respiratory system cancers (HR 0.780, 95% CI 0.636-0.957, I2 = 0.00%) (Fig.	('system cancers', 'Disease', (100, 114))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('respiratory system cancers', 'Disease', (162, 188))	('miR-146a', 'Gene', '406938', (29, 37))	('system cancers', 'Disease', 'MESH:D009369', (174, 188))	('system cancers', 'Disease', 'MESH:D009369', (100, 114))	('improved', 'PosReg', (56, 64))	('respiratory system cancers', 'Disease', 'MESH:D015619', (162, 188))	('cancers', 'Phenotype', 'HP:0002664', (181, 188))	('high', 'Var', (24, 28))	('survival', 'MPA', (65, 73))	('cancers', 'Phenotype', 'HP:0002664', (107, 114))	('miR-146a', 'Gene', (29, 37))
400450	31285693	A recent meta-analysis concluded that the outcome of NSCLC was better in the experimental group with high levels of miR-146a-5p than in a group with low levels of expression, and indicated the potential prognostic role of miR-146a-5p.	('miR-146a', 'Gene', (222, 230))	('NSCLC', 'Phenotype', 'HP:0030358', (53, 58))	('miR-146a', 'Gene', (116, 124))	('high levels', 'Var', (101, 112))	('miR-146a', 'Gene', '406938', (116, 124))	('better', 'PosReg', (63, 69))	('miR-146a', 'Gene', '406938', (222, 230))	('NSCLC', 'Disease', (53, 58))	('NSCLC', 'Disease', 'MESH:D002289', (53, 58))
400457	31285693	It has been reported that abnormal expression levels or mutations in PLC-gamma (a PLC member) are related to the occurrence of breast cancer, gastric cancer, and oral squamous cell carcinoma.	('oral squamous cell carcinoma', 'Disease', (162, 190))	('gastric cancer', 'Disease', (142, 156))	('mutations', 'Var', (56, 65))	('gastric cancer', 'Disease', 'MESH:D013274', (142, 156))	('breast cancer', 'Disease', 'MESH:D001943', (127, 140))	('related', 'Reg', (98, 105))	('expression levels', 'MPA', (35, 52))	('breast cancer', 'Disease', (127, 140))	('PLC-gamma', 'Gene', (69, 78))	('gastric cancer', 'Phenotype', 'HP:0012126', (142, 156))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (162, 190))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (167, 190))	('breast cancer', 'Phenotype', 'HP:0003002', (127, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (181, 190))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('abnormal', 'Var', (26, 34))
400464	31285693	It has been suggested that the abnormal regulation of renal AQPs would lead to diseases correlated with water balance disorders in the kidney, such as diabetes insipidus and hyponatremia.	('lead to', 'Reg', (71, 78))	('diabetes insipidus', 'Disease', 'MESH:D003919', (151, 169))	('abnormal regulation', 'Var', (31, 50))	('hyponatremia', 'Phenotype', 'HP:0002902', (174, 186))	('diabetes insipidus', 'Phenotype', 'HP:0000873', (151, 169))	('water balance disorders', 'Disease', 'MESH:D000069578', (104, 127))	('balance disorders', 'Phenotype', 'HP:0002172', (110, 127))	('water balance disorders', 'Disease', (104, 127))	('hyponatremia', 'Disease', 'MESH:D007010', (174, 186))	('water balance', 'Phenotype', 'HP:0000969', (104, 117))	('diseases', 'Disease', (79, 87))	('diabetes insipidus', 'Disease', (151, 169))	('hyponatremia', 'Disease', (174, 186))	('renal', 'Protein', (54, 59))
400497	31285693	discovered that abnormal ADCY5 expression was correlated to tumor aggressiveness and DNA Methylation of ADCY5 might lead to unsatisfied outcomes for patients with lung cancer.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('lung cancer', 'Disease', 'MESH:D008175', (163, 174))	('patients', 'Species', '9606', (149, 157))	('DNA Methylation', 'Var', (85, 100))	('ADCY5', 'Gene', '111', (25, 30))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (60, 80))	('ADCY5', 'Gene', '111', (104, 109))	('correlated', 'Reg', (46, 56))	('lead to', 'Reg', (116, 123))	('expression', 'MPA', (31, 41))	('ADCY5', 'Gene', (25, 30))	('lung cancer', 'Phenotype', 'HP:0100526', (163, 174))	('ADCY5', 'Gene', (104, 109))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('lung cancer', 'Disease', (163, 174))	('aggressiveness', 'Phenotype', 'HP:0000718', (66, 80))	('abnormal', 'Var', (16, 24))	('tumor aggressiveness', 'Disease', (60, 80))
400516	28558019	DEK overexpression also increased the maximum rate of oxygen consumption and therefore increased the potential for oxidative phosphorylation (OxPhos).	('increased', 'PosReg', (87, 96))	('DEK', 'Gene', (0, 3))	('oxygen', 'Chemical', 'MESH:D010100', (54, 60))	('oxygen consumption', 'MPA', (54, 72))	('overexpression', 'Var', (4, 18))	('DEK', 'Gene', '7913', (0, 3))	('increased', 'PosReg', (24, 33))
400547	28558019	DEK overexpression was sufficient to increase baseline and maximum rates of lactic acid fermentation and maximum oxygen consumption in both cell types.	('oxygen', 'Chemical', 'MESH:D010100', (113, 119))	('overexpression', 'Var', (4, 18))	('oxygen consumption', 'MPA', (113, 131))	('lactic acid fermentation', 'MPA', (76, 100))	('DEK', 'Gene', '7913', (0, 3))	('increase', 'PosReg', (37, 45))	('lactic acid', 'Chemical', 'MESH:D019344', (76, 87))	('DEK', 'Gene', (0, 3))
400566	28558019	Interestingly, while OCR at baseline was similar between R780 and R-DEK NIKS (Fig 2A) and C-SCC1 cells (Fig 2B), the OCR after FCCP injection was increased with DEK overexpression (Fig 2A-2D).	('C-SCC1', 'CellLine', 'CVCL:7707', (90, 96))	('increased', 'PosReg', (146, 155))	('DEK', 'Gene', '7913', (68, 71))	('DEK', 'Gene', '7913', (161, 164))	('FCCP', 'Chemical', 'MESH:D002259', (127, 131))	('R780', 'Var', (57, 61))	('OCR', 'MPA', (117, 120))	('overexpression', 'PosReg', (165, 179))	('DEK', 'Gene', (68, 71))	('DEK', 'Gene', (161, 164))	('SCC', 'Phenotype', 'HP:0002860', (92, 95))
400574	28558019	R780 and R-DEK NIKS and their respective media were collected on day 2 post plating, when cell numbers were indistinguishable (Fig 1C and 1D) and cells were at equal sub-confluency (Fig 1A and 1B, lower panel).	('DEK', 'Gene', '7913', (11, 14))	('R780', 'Var', (0, 4))	('DEK', 'Gene', (11, 14))
400577	28558019	Thus, the data revealed that high DEK expression is sufficient to alter cellular metabolite profiles.	('high', 'Var', (29, 33))	('cellular metabolite profiles', 'MPA', (72, 100))	('DEK', 'Gene', '7913', (34, 37))	('alter', 'Reg', (66, 71))	('DEK', 'Gene', (34, 37))
400585	28558019	In order to better quantify consumption, production, uptake and excretion for each metabolite, we compared bucket intensities present in the R780 and R-DEK media samples to the bucket intensities detected in F-media alone (unconditioned media).	('DEK', 'Gene', '7913', (152, 155))	('R780', 'Var', (141, 145))	('DEK', 'Gene', (152, 155))
400597	28558019	Most of the 20 intracellular metabolites altered with DEK expression were increased and included the amino acids tyrosine, valine, glutamate, alanine, proline, and asparagine along with other non-amino acid metabolites creatine, p-creatine, taurine, myo-inositol, GPC, NAD+, fumarate and succinate, with the last two being TCA cycle intermediates.	('GPC', 'Chemical', 'MESH:D005997', (264, 267))	('taurine', 'Chemical', 'MESH:D013654', (241, 248))	('asparagine', 'MPA', (164, 174))	('DEK', 'Gene', (54, 57))	('succinate', 'Chemical', 'MESH:D019802', (288, 297))	('p-creatine', 'MPA', (229, 239))	('alanine', 'MPA', (142, 149))	('amino acids tyrosine', 'MPA', (101, 121))	('DEK', 'Gene', '7913', (54, 57))	('myo-inositol', 'MPA', (250, 262))	('p-creatine', 'Chemical', 'MESH:D010725', (229, 239))	('creatine', 'Chemical', 'MESH:D003401', (231, 239))	('succinate', 'MPA', (288, 297))	('taurine', 'MPA', (241, 248))	('increased', 'PosReg', (74, 83))	('fumarate', 'Chemical', 'MESH:D005650', (275, 283))	('expression', 'Var', (58, 68))	('myo-inositol', 'Chemical', 'MESH:D007294', (250, 262))	('asparagine', 'Chemical', 'MESH:D001216', (164, 174))	('alanine', 'Chemical', 'MESH:D000409', (142, 149))	('creatine', 'MPA', (219, 227))	('glutamate', 'Chemical', 'MESH:D018698', (131, 140))	('tyrosine', 'Chemical', 'MESH:D014443', (113, 121))	('valine', 'Chemical', 'MESH:D014633', (123, 129))	('NAD+', 'Chemical', 'MESH:D009243', (269, 273))	('NAD+', 'MPA', (269, 273))	('GPC', 'MPA', (264, 267))	('proline', 'Chemical', 'MESH:D011392', (151, 158))	('intracellular metabolites', 'MPA', (15, 40))	('valine', 'MPA', (123, 129))	('TCA', 'Chemical', 'MESH:D014233', (323, 326))	('fumarate', 'MPA', (275, 283))	('proline', 'MPA', (151, 158))	('creatine', 'Chemical', 'MESH:D003401', (219, 227))	('glutamate', 'MPA', (131, 140))
400602	28558019	For instance, bucket intensities of alanine and DMA were higher in the R-DEK and R780 samples compared to unconditioned media; albeit greater in the R-DEK samples suggesting DEK increases their production and excretion (Fig 4F).	('DEK', 'Gene', '7913', (73, 76))	('DEK', 'Gene', (73, 76))	('DMA', 'Chemical', 'MESH:C034516', (48, 51))	('higher', 'PosReg', (57, 63))	('bucket intensities', 'MPA', (14, 32))	('alanine', 'MPA', (36, 43))	('DEK', 'Gene', '7913', (174, 177))	('increases', 'PosReg', (178, 187))	('excretion', 'MPA', (209, 218))	('alanine', 'Chemical', 'MESH:D000409', (36, 43))	('DEK', 'Gene', '7913', (151, 154))	('DMA', 'MPA', (48, 51))	('R780', 'Var', (81, 85))	('DEK', 'Gene', (174, 177))	('production', 'MPA', (194, 204))	('DEK', 'Gene', (151, 154))
400615	28558019	DEK expression also consistently decreased choline, p-choline, aspartate, and GSH (Fig 5A), metabolites involved in choline metabolism, protein and nucleotide synthesis, and oxidative stress reduction (Fig 5C).	('GSH', 'MPA', (78, 81))	('aspartate', 'MPA', (63, 72))	('DEK', 'Gene', (0, 3))	('choline', 'Chemical', 'MESH:D002794', (43, 50))	('choline', 'Chemical', 'MESH:D002794', (116, 123))	('GSH', 'Chemical', '-', (78, 81))	('oxidative stress', 'Phenotype', 'HP:0025464', (174, 190))	('decreased choline', 'Phenotype', 'HP:0025048', (33, 50))	('metabolites involved', 'MPA', (92, 112))	('choline', 'MPA', (43, 50))	('DEK', 'Gene', '7913', (0, 3))	('aspartate', 'Chemical', 'MESH:D001224', (63, 72))	('expression', 'Var', (4, 14))	('p-choline', 'MPA', (52, 61))	('decreased', 'NegReg', (33, 42))	('p-choline', 'Chemical', 'MESH:D010767', (52, 61))	('choline', 'Chemical', 'MESH:D002794', (54, 61))	('oxidative stress reduction', 'MPA', (174, 200))
400633	28558019	Importantly, the extent of regulation of glucose and lactate between R-DEK versus R780 samples was in line with previous reports where similar regulation was linked to physiologically relevant outcomes.	('lactate', 'Chemical', 'MESH:D019344', (53, 60))	('DEK', 'Gene', '7913', (71, 74))	('R780', 'Var', (82, 86))	('DEK', 'Gene', (71, 74))	('glucose', 'Chemical', 'MESH:D005947', (41, 48))	('regulation', 'MPA', (27, 37))
400634	28558019	For example, in pancreatic ductal adenocarcinomas that are strictly dependent on Kras mutations, mutated Kras caused a 1.2-1.5 fold increase in glucose consumption and a 1.3-1.4 fold increase in lactate production that was sufficient to increase hexosamine and nucleotide synthesis that contributed to anabolic metabolism.	('mutations', 'Var', (86, 95))	('Kras', 'Gene', (105, 109))	('glucose consumption', 'Disease', (144, 163))	('increase', 'PosReg', (237, 245))	('pancreatic ductal adenocarcinomas', 'Disease', (16, 49))	('increase', 'PosReg', (132, 140))	('increase', 'PosReg', (183, 191))	('mutated', 'Var', (97, 104))	('Kras', 'Gene', '3845', (105, 109))	('Kras', 'Gene', (81, 85))	('hexosamine', 'Chemical', 'MESH:D006595', (246, 256))	('carcinoma', 'Phenotype', 'HP:0030731', (39, 48))	('lactate production', 'MPA', (195, 213))	('anabolic metabolism', 'MPA', (302, 321))	('Kras', 'Gene', '3845', (81, 85))	('lactate', 'Chemical', 'MESH:D019344', (195, 202))	('pancreatic ductal adenocarcinomas', 'Disease', 'MESH:D021441', (16, 49))	('glucose consumption', 'Disease', 'MESH:D014397', (144, 163))
400638	28558019	In addition to such biological consequences, the extent of metabolic deregulation caused by DEK overexpression is similar to reported changes in cancer versus normal tissue.	('cancer', 'Disease', (145, 151))	('overexpression', 'Var', (96, 110))	('DEK', 'Gene', '7913', (92, 95))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('metabolic deregulation', 'MPA', (59, 81))	('DEK', 'Gene', (92, 95))	('cancer', 'Disease', 'MESH:D009369', (145, 151))
400643	28558019	Interestingly, DEK knockdown repressed LDHA expression according to a previously published RNA sequencing study (S1A and S1B Fig), and repressed other key metabolic enzymes that drive glucose metabolism in HNSCC such as FASN, PDK1, PKM2, and HK2.	('NS', 'Disease', 'MESH:D009404', (207, 209))	('PKM2', 'Gene', '5315', (232, 236))	('HK2', 'Gene', (242, 245))	('PDK1', 'Gene', '5163', (226, 230))	('HK2', 'Gene', '3099', (242, 245))	('DEK', 'Gene', '7913', (15, 18))	('knockdown', 'Var', (19, 28))	('glucose', 'Chemical', 'MESH:D005947', (184, 191))	('FASN', 'Gene', (220, 224))	('PDK1', 'Gene', (226, 230))	('FASN', 'Gene', '2194', (220, 224))	('DEK', 'Gene', (15, 18))	('SCC', 'Gene', (208, 211))	('LDHA', 'Gene', (39, 43))	('SCC', 'Phenotype', 'HP:0002860', (208, 211))	('LDHA', 'Gene', '3939', (39, 43))	('PKM2', 'Gene', (232, 236))	('SCC', 'Gene', '6317', (208, 211))
400697	28558019	A t-test was used to determine significance between R780 and R-DEK samples from the independent experiments.	('R780', 'Var', (52, 56))	('DEK', 'Gene', (63, 66))	('DEK', 'Gene', '7913', (63, 66))
400698	28558019	R780 empty vector or R-DEK cells were plated in 10 wells of a 96-well plate at a density of 10,000 cells per well.	('DEK', 'Gene', (23, 26))	('R780', 'Var', (0, 4))	('DEK', 'Gene', '7913', (23, 26))
400700	28558019	A total of 8 replicates of NIKS and C-SCC1 R780 empty vector control cells and R-DEK overexpression vector cells were collected at 80% confluency.	('DEK', 'Gene', '7913', (81, 84))	('SCC', 'Phenotype', 'HP:0002860', (38, 41))	('C-SCC1', 'Gene', (36, 42))	('DEK', 'Gene', (81, 84))	('R780', 'Var', (43, 47))	('C-SCC1', 'CellLine', 'CVCL:7707', (36, 42))
400723	28558019	Significance was determined using a student's t-test to compare R780 to R-DEK samples from three independent experiments.	('DEK', 'Gene', (74, 77))	('DEK', 'Gene', '7913', (74, 77))	('R780', 'Var', (64, 68))
400756	28086903	Moreover, studies from Smad-/- mice have testified that the loss of Smad3 induced IgG2a expression, leading to an obvious enhanced Th2 reaction and Th1/Th2 shift.	('Th', 'Chemical', 'MESH:D013910', (152, 154))	('enhanced', 'PosReg', (122, 130))	('Th', 'Chemical', 'MESH:D013910', (148, 150))	('IgG2a', 'Gene', '668478', (82, 87))	('induced', 'Reg', (74, 81))	('Smad3', 'Gene', (68, 73))	('mice', 'Species', '10090', (31, 35))	('Th1/Th2 shift', 'CPA', (148, 161))	('loss', 'Var', (60, 64))	('IgG2a', 'Gene', (82, 87))	('expression', 'MPA', (88, 98))	('Th2 reaction', 'CPA', (131, 143))	('Th', 'Chemical', 'MESH:D013910', (131, 133))
400776	28086903	The synergism of congeneric immune factors and antagonism of alien regulators might worsen the immune imbalance in cervical cancer microenvironment.	('worsen', 'PosReg', (84, 90))	('cervical cancer', 'Disease', 'MESH:D002583', (115, 130))	('immune imbalance', 'Phenotype', 'HP:0002958', (95, 111))	('cervical cancer', 'Disease', (115, 130))	('antagonism', 'Var', (47, 57))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('immune imbalance', 'MPA', (95, 111))	('Th', 'Chemical', 'MESH:D013910', (0, 2))	('imbalance', 'Phenotype', 'HP:0002172', (102, 111))	('synergism', 'Var', (4, 13))
400814	28086903	For instance, we did not find any relationship between FoxP3 mRNA and Smad3mRNA.As previously mentioned, phosphorylation of Smad3 is the functional variant in pathways which mediated FoxP3 transcription.	('FoxP3', 'Gene', '50943', (55, 60))	('phosphorylation', 'Var', (105, 120))	('transcription', 'MPA', (189, 202))	('FoxP3', 'Gene', '50943', (183, 188))	('FoxP3', 'Gene', (55, 60))	('pathways', 'Pathway', (159, 167))	('FoxP3', 'Gene', (183, 188))	('Smad3', 'Gene', (124, 129))
400849	32779402	They verified by PCR that exosomal microRNAs (miR-378a, miR-379, miR-200b-5p, and miR-139-5p) can be used to distinguish lung cancer patients from healthy people, exosomal microRNAs (miR-151a-5p, miR-154-3p, miR-200b-5p, miR-629, miR-100, and miR-30a-3p) can distinguish AC patients from lung granuloma patients.	('lung cancer', 'Disease', 'MESH:D008175', (121, 132))	('miR-200b', 'Gene', (208, 216))	('miR-378a', 'Gene', '494327', (46, 54))	('miR-154', 'Gene', '406946', (196, 203))	('patients', 'Species', '9606', (133, 141))	('lung granuloma', 'Disease', (288, 302))	('lung cancer', 'Phenotype', 'HP:0100526', (121, 132))	('miR-151a', 'Gene', (183, 191))	('miR-378a', 'Gene', (46, 54))	('miR-379', 'Gene', '494328', (56, 63))	('miR-154', 'Gene', (196, 203))	('patients', 'Species', '9606', (274, 282))	('miR-629', 'Gene', '693214', (221, 228))	('miR-200b', 'Gene', '406984', (65, 73))	('miR-379', 'Gene', (56, 63))	('miR-629', 'Gene', (221, 228))	('miR-200b', 'Gene', '406984', (208, 216))	('miR-100', 'Gene', (230, 237))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('lung cancer', 'Disease', (121, 132))	('patients', 'Species', '9606', (303, 311))	('miR-30a-3p', 'Var', (243, 253))	('people', 'Species', '9606', (155, 161))	('lung granuloma', 'Disease', 'MESH:D016726', (288, 302))	('granuloma', 'Phenotype', 'HP:0032252', (293, 302))	('miR-100', 'Gene', '406892', (230, 237))	('miR-200b', 'Gene', (65, 73))	('miR-151a', 'Gene', '442893', (183, 191))
400851	32779402	Zhou et al identified six disordered plasma exosomal miRNAs (miR-19b-3p, miR-21-5p, miR-221-3p, miR-584-5p, miR-425-5p, and miR-409-3p).	('miR-21-5p', 'Gene', (73, 82))	('miR-221', 'Gene', '407006', (84, 91))	('miR-584-5p', 'Var', (96, 106))	('miR-409-3p', 'Var', (124, 134))	('miR-21-5p', 'Gene', '406997', (73, 82))	('miR-425', 'Gene', (108, 115))	('miR-221', 'Gene', (84, 91))	('miR-425', 'Gene', '494337', (108, 115))	('miR-19b-3p', 'Var', (61, 71))
400853	32779402	43  Other relevant evidence comes from the work of Jin et al, they found that the changes of plasma exosomal miR-181-5p, miR-30a-3p, miR-30e-3p, and miR-361-5p in AC patients were significant, while miR-10b-5p, miR-15b-5p, and miR-320b are squamous cell carcinoma (SCC) patients specific.	('miR-320b', 'Var', (227, 235))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (240, 263))	('squamous cell carcinoma', 'Disease', (240, 263))	('patients', 'Species', '9606', (270, 278))	('miR-30a-3p', 'Var', (121, 131))	('miR-15b', 'Gene', (211, 218))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (240, 263))	('SCC', 'Phenotype', 'HP:0002860', (265, 268))	('miR-361', 'Gene', '494323', (149, 156))	('miR-361', 'Gene', (149, 156))	('carcinoma', 'Phenotype', 'HP:0030731', (254, 263))	('miR-30e-3p', 'Var', (133, 143))	('patients', 'Species', '9606', (166, 174))	('miR-10b-5p', 'Var', (199, 209))	('miR-15b', 'Gene', '406949', (211, 218))
400855	32779402	The combination of four exosomal miRNAs (miR-181a-5p, miR-21-5p, miR-106a-5p, and miR-93-5p) can be used to detect SCC, and the AUC area of the four miRNAs groups during training, testing, and external validation stage was 0.795, 0.827, and 0.914 respectively.	('miR-181a-5p', 'Var', (41, 52))	('detect', 'Reg', (108, 114))	('miR-21-5p', 'Gene', (54, 63))	('miR-106a', 'Gene', '406899', (65, 73))	('miR-21-5p', 'Gene', '406997', (54, 63))	('miR-93-5p', 'Gene', '100126325', (82, 91))	('miR-93-5p', 'Gene', (82, 91))	('SCC', 'Phenotype', 'HP:0002860', (115, 118))	('SCC', 'Disease', (115, 118))	('miR-106a', 'Gene', (65, 73))
400857	32779402	In the work of Zhang et al, they showed that three exosomal miRNAs combinations (miR-106a-5p, miR-20a-5p, and miR-93-5p) have an effective diagnostic value in male patients with SCC(AUC = 0.832).	('SCC', 'Phenotype', 'HP:0002860', (178, 181))	('miR-106a', 'Gene', '406899', (81, 89))	('miR-20a-5p', 'Var', (94, 104))	('SCC', 'Disease', (178, 181))	('miR-93-5p', 'Gene', '100126325', (110, 119))	('miR-93-5p', 'Gene', (110, 119))	('miR-106a', 'Gene', (81, 89))	('patients', 'Species', '9606', (164, 172))
400865	32779402	49   Recently, Wu et al reported that in early NSCLC patients, the levels of serum miRNAs (miR-21-5p, miR-141-3p, miR-222-3p, and miR-486-5p) increased significantly, as did the levels of serum exosomal miRNAs (miR-146a-5p and miR-486-5p).	('increased', 'PosReg', (142, 151))	('patients', 'Species', '9606', (53, 61))	('serum miRNAs', 'MPA', (77, 89))	('SCLC', 'Phenotype', 'HP:0030357', (48, 52))	('levels', 'MPA', (67, 73))	('miR-486-5p', 'Var', (130, 140))	('miR-222-3p', 'MPA', (114, 124))	('NSCLC', 'Disease', (47, 52))	('miR-141-3p', 'Var', (102, 112))	('miR-21-5p', 'Gene', (91, 100))	('miR-21-5p', 'Gene', '406997', (91, 100))	('NSCLC', 'Disease', 'MESH:D002289', (47, 52))
400873	32779402	They also demonstrated in vitro that increasing the expression of miR-7797 in the A549 cell line inhibited the proliferation of lung cancer cells.	('miR-7797', 'Var', (66, 74))	('increasing', 'PosReg', (37, 47))	('lung cancer', 'Disease', 'MESH:D008175', (128, 139))	('miR-7797', 'Chemical', '-', (66, 74))	('proliferation of', 'CPA', (111, 127))	('expression', 'MPA', (52, 62))	('lung cancer', 'Disease', (128, 139))	('lung cancer', 'Phenotype', 'HP:0100526', (128, 139))	('inhibited', 'NegReg', (97, 106))	('A549', 'CellLine', 'CVCL:0023', (82, 86))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
400878	32779402	Specifically, lung adenocarcinoma was diagnosed specifically through the three exosomal miRNAs of miR-1-3p, miR-144-5p, and miR-150-5p.	('lung adenocarcinoma', 'Disease', (14, 33))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (14, 33))	('miR-150-5p', 'Var', (124, 134))	('diagnosed', 'Reg', (38, 47))	('miR-144', 'Gene', (108, 115))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (14, 33))	('miR-144', 'Gene', '406936', (108, 115))	('carcinoma', 'Phenotype', 'HP:0030731', (24, 33))	('miR-1-3p', 'Var', (98, 106))
400879	32779402	The authors also assessed the diagnostic capabilities of miR-1-3p, miR-144-5p, and miR-150-5p, and the reported AUC values were 0.914, 0.939 and 0.925 respectively.	('miR-144', 'Gene', '406936', (67, 74))	('miR-150-5p', 'Var', (83, 93))	('miR-1-3p', 'Var', (57, 65))	('miR-144', 'Gene', (67, 74))
400888	32779402	58  Five newly discovered plasma exosomal miR-151a-5p, miR-10b-5p, miR-192-5p, miR-106b-3p, and miR-484 have also shown prognostic value.	('miR-192', 'Gene', (67, 74))	('miR-10b-5p', 'Var', (55, 65))	('miR-484', 'Gene', '619553', (96, 103))	('miR-106b', 'Gene', (79, 87))	('miR-106b', 'Gene', '406900', (79, 87))	('miR-151a', 'Gene', '442893', (42, 50))	('miR-151a', 'Gene', (42, 50))	('miR-484', 'Gene', (96, 103))	('miR-192', 'Gene', '406967', (67, 74))
400890	32779402	59  Another interesting result is that compared with patients with partial remission (PR) using immunotherapy, patients with progressive disease (PD) have significantly higher exosomal has-miR-320d, has-miR-320c, and has-miR-320b.	('higher', 'PosReg', (169, 175))	('patients', 'Species', '9606', (53, 61))	('progressive disease', 'Disease', (125, 144))	('exosomal has-miR-320d', 'MPA', (176, 197))	('progressive disease', 'Disease', 'MESH:D018450', (125, 144))	('has-miR-320b', 'Var', (217, 229))	('has-miR-320c', 'Var', (199, 211))	('patients', 'Species', '9606', (111, 119))
400901	32779402	What's more, the team of researchers demonstrated in vitro experiments that after knocking down MALAT-1 in the NSCLC cell line, the growth and proliferation of tumor cells were inhibited, and the apoptosis of tumor cells was promoted.	('inhibited', 'NegReg', (177, 186))	('promoted', 'PosReg', (225, 233))	('tumor', 'Disease', (209, 214))	('NSCLC', 'Disease', (111, 116))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('SCLC', 'Phenotype', 'HP:0030357', (112, 116))	('NSCLC', 'Disease', 'MESH:D002289', (111, 116))	('MALAT-1', 'Gene', '378938', (96, 103))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('tumor', 'Disease', 'MESH:D009369', (209, 214))	('tumor', 'Disease', (160, 165))	('knocking down', 'Var', (82, 95))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))	('MALAT-1', 'Gene', (96, 103))
400918	32779402	Chen et al Pointed out that the expression levels of has-circ-0001492, has-circ-0001346, has-circ-0000690, and has-circ-0001439 were higher in the plasma exosomes of patients with early AC, especially the highest expression of has-circ-0001492.	('has-circ-0001439', 'Var', (111, 127))	('has-circ-0001492', 'Var', (53, 69))	('has-circ-0000690', 'Var', (89, 105))	('higher', 'PosReg', (133, 139))	('has-circ-0001346', 'Var', (71, 87))	('has-circ-0001492', 'Var', (227, 243))	('expression levels', 'MPA', (32, 49))	('early AC', 'Disease', (180, 188))	('patients', 'Species', '9606', (166, 174))
400921	32779402	71  Wang et al demonstrated that increased expression of has-circ-0014235 and has-circ-0025580 in plasma exosomes of patients with lung squamous cell carcinoma.	('has-circ-0025580', 'Var', (78, 94))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (131, 159))	('carcinoma', 'Phenotype', 'HP:0030731', (150, 159))	('increased', 'PosReg', (33, 42))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (131, 159))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (136, 159))	('has-circ-0014235', 'Var', (57, 73))	('patients', 'Species', '9606', (117, 125))	('expression', 'MPA', (43, 53))	('lung squamous cell carcinoma', 'Disease', (131, 159))
400948	32083006	HK2 depletion or inhibition decreased the glycolysis and tumor growth via activating AMPK signaling pathway, which downregulated mTORC1 activity.	('inhibition decreased', 'NegReg', (17, 37))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('depletion', 'Var', (4, 13))	('AMPK', 'Gene', (85, 89))	('mTORC1', 'Gene', (129, 135))	('AMPK', 'Gene', '5564', (85, 89))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Disease', (57, 62))	('glycolysis', 'MPA', (42, 52))	('mTORC1', 'Gene', '382056', (129, 135))	('HK2', 'Protein', (0, 3))	('downregulated', 'NegReg', (115, 128))	('activity', 'MPA', (136, 144))
400951	32083006	Our study suggests that HK2 depletion in combination with metformin might be a novel effective strategy for lung SCCs therapy.	('lung SCC', 'Disease', 'MESH:D002294', (108, 116))	('SCCs', 'Disease', 'MESH:D002294', (113, 117))	('HK2', 'Protein', (24, 27))	('depletion', 'Var', (28, 37))	('metformin', 'Chemical', 'MESH:D008687', (58, 67))	('SCCs', 'Disease', (113, 117))	('SCCs', 'Phenotype', 'HP:0002860', (113, 117))	('lung SCC', 'Disease', (108, 116))	('SCC', 'Phenotype', 'HP:0002860', (113, 116))
400955	32083006	Compared with lung adenocarcinoma (ADC), there are no effective therapeutic strategies for SCC, which is associated with fewer known somatic mutations vulnerable to targeted therapy (e.g., EGFR mutations, ALK rearrangement).	('SCC', 'Disease', (91, 94))	('EGFR', 'Gene', '1956', (189, 193))	('lung adenocarcinoma', 'Disease', (14, 33))	('EGFR', 'Gene', (189, 193))	('SCC', 'Disease', 'MESH:D002294', (91, 94))	('mutations', 'Var', (194, 203))	('ALK', 'Gene', '238', (205, 208))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (14, 33))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (14, 33))	('carcinoma', 'Phenotype', 'HP:0030731', (24, 33))	('ALK', 'Gene', (205, 208))	('SCC', 'Phenotype', 'HP:0002860', (91, 94))
400973	32083006	In addition, metformin could reduce the generation of reactive oxygen species at the complex 1 and prevent mitochondrial-mediated apoptosis, suggesting its potential protective effect against oxidative stress-induced cell death.	('mitochondrial-mediated apoptosis', 'CPA', (107, 139))	('metformin', 'Var', (13, 22))	('prevent', 'NegReg', (99, 106))	('oxidative stress', 'Phenotype', 'HP:0025464', (192, 208))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (54, 77))	('generation of reactive oxygen species', 'MPA', (40, 77))	('metformin', 'Chemical', 'MESH:D008687', (13, 22))	('reduce', 'NegReg', (29, 35))
400975	32083006	Moreover, screening of public databases from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) led us to further focus on the AMPK-mTORC1 pathway in lung SCC patients with high HK2 expression.	('AMPK', 'Gene', (141, 145))	('mTORC1', 'Gene', (146, 152))	('patients', 'Species', '9606', (173, 181))	('SCC', 'Phenotype', 'HP:0002860', (169, 172))	('Cancer', 'Phenotype', 'HP:0002664', (49, 55))	('lung SCC', 'Disease', (164, 172))	('mTORC1', 'Gene', '382056', (146, 152))	('HK2', 'Protein', (192, 195))	('lung SCC', 'Disease', 'MESH:D002294', (164, 172))	('AMPK', 'Gene', '5564', (141, 145))	('high', 'Var', (187, 191))
400976	32083006	Therefore, we examined the cancer cell-killing effect of the combination of HK2 ablation and metformin in vitro and in vivo.	('HK2', 'Gene', (76, 79))	('ablation', 'Var', (80, 88))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('cancer', 'Disease', (27, 33))	('cancer', 'Disease', 'MESH:D009369', (27, 33))	('metformin', 'Chemical', 'MESH:D008687', (93, 102))
400977	32083006	The combination of HK2 depletion and metformin treatment could significantly induce lung SCC apoptosis, providing a scientific foundation for further exploration of a new therapeutic strategy to improve the outcome and quality of life of patients with lung SCC.	('induce', 'PosReg', (77, 83))	('metformin', 'Chemical', 'MESH:D008687', (37, 46))	('depletion', 'Var', (23, 32))	('SCC', 'Phenotype', 'HP:0002860', (257, 260))	('lung SCC', 'Disease', (84, 92))	('lung SCC', 'Disease', 'MESH:D002294', (84, 92))	('lung SCC', 'Disease', (252, 260))	('lung SCC', 'Disease', 'MESH:D002294', (252, 260))	('HK2', 'Protein', (19, 22))	('patients', 'Species', '9606', (238, 246))	('SCC', 'Phenotype', 'HP:0002860', (89, 92))
400997	32083006	BSA (V900933) and Dulbecco's Modified Eagle's Medium-high glucose (D0422-100ML) were from Sigma-Aldrich.	('V900933', 'Var', (5, 12))	('D0422', 'Chemical', '-', (67, 72))	('high glucose', 'Phenotype', 'HP:0003074', (53, 65))	("Dulbecco's Modified Eagle's Medium-high", 'Chemical', '-', (18, 57))	('D0422-100ML', 'Var', (67, 78))	('glucose', 'Chemical', 'MESH:D005947', (58, 65))
400999	32083006	Glucose Colorimetric Assay Kit (K686-100) and Lactate Colorimetric Assay Kit (K627-100) were from BioVision.	('K627-100', 'Var', (78, 86))	('K686-100', 'Var', (32, 40))	('Lactate', 'Chemical', 'MESH:D019344', (46, 53))	('Glucose', 'Chemical', 'MESH:D005947', (0, 7))
401001	32083006	Anti-phospho-AMPK (Thr172) antibody (#2535S), Anti-AMPKalpha Antibody (#2532), anti-p70-S6K (9202S), anti-phospo-p70-S6K (Thr389) (9234S), anti-Hexokinase 2 (2867S), anti-phospho-4EBP1 (Thr70) (13396) and anti-4EBP1 (9644s) were from Cell Signaling Technology.	('4EBP1', 'Gene', '1978', (210, 215))	('Hexokinase 2', 'Gene', '3099', (144, 156))	('p70-S6K', 'Gene', (84, 91))	('p70-S6K', 'Gene', '6198', (113, 120))	('p70-S6K', 'Gene', (113, 120))	('Thr70', 'Chemical', '-', (186, 191))	('4EBP1', 'Gene', (210, 215))	('4EBP1', 'Gene', '1978', (179, 184))	('AMPK', 'Gene', (13, 17))	('Thr389', 'Chemical', '-', (122, 128))	('Thr172', 'Chemical', '-', (19, 25))	('AMPK', 'Gene', '5564', (13, 17))	('AMPK', 'Gene', (51, 55))	('#2532', 'Var', (71, 76))	('AMPK', 'Gene', '5564', (51, 55))	('Hexokinase 2', 'Gene', (144, 156))	('p70-S6K', 'Gene', '6198', (84, 91))	('4EBP1', 'Gene', (179, 184))
401002	32083006	Anti beta-actin-HRP (PM053-7) from MBL.	('PM053-7', 'Var', (21, 28))	('MBL', 'Gene', '50639', (35, 38))	('MBL', 'Gene', (35, 38))
401017	32083006	Consistent with these results from patient samples, information on various SCC and ADC cell lines from the TCPA website (http://tcpaportal.org/) demonstrated that the expression level of HK2 was increased in SCC cells(NCI-H520, NCI-H2170, NCI-H226, NCI-H1703, SK-MES-1) compared with that in ADC cells(A549, NCI-H1299, PC9, NCI-H1944, NCI-H1651) (Figure 1D).	('expression level', 'MPA', (167, 183))	('NCI-H1651', 'CellLine', 'CVCL:1484', (335, 344))	('SCC', 'Phenotype', 'HP:0002860', (208, 211))	('increased', 'PosReg', (195, 204))	('NCI-H520', 'CellLine', 'CVCL:1566', (218, 226))	('NCI-H2170', 'CellLine', 'CVCL:1535', (228, 237))	('NCI-H520', 'Var', (218, 226))	('HK2', 'Protein', (187, 190))	('NCI-H1944', 'CellLine', 'CVCL:1508', (324, 333))	('SCC', 'Disease', 'MESH:D002294', (208, 211))	('A549', 'CellLine', 'CVCL:0023', (302, 306))	('PC9', 'Gene', '255738', (319, 322))	('SCC', 'Disease', (208, 211))	('SCC', 'Phenotype', 'HP:0002860', (75, 78))	('PC9', 'Gene', (319, 322))	('NCI-H1299', 'CellLine', 'CVCL:0060', (308, 317))	('SCC', 'Disease', 'MESH:D002294', (75, 78))	('patient', 'Species', '9606', (35, 42))	('NCI-H1703', 'CellLine', 'CVCL:1490', (249, 258))	('NCI-H226', 'CellLine', 'CVCL:1544', (239, 247))	('SK-MES-1', 'CellLine', 'CVCL:0630', (260, 268))	('SCC', 'Disease', (75, 78))
401020	32083006	The results indicated that patients with high HK2 expression (n = 100) had worse Progression Free Survival (RFS) than those with low HK2 expression (n = 100) (Figure 1H).	('Progression Free Survival', 'CPA', (81, 106))	('HK2', 'Protein', (46, 49))	('expression', 'Var', (50, 60))	('high', 'Var', (41, 45))	('RFS', 'Disease', (108, 111))	('patients', 'Species', '9606', (27, 35))	('RFS', 'Disease', 'MESH:D005198', (108, 111))	('worse', 'NegReg', (75, 80))
401025	32083006	Moreover, H226 and H520 cells showed greater sensitivity to treatment with lonidamine, a small-molecule hexokinase inhibitor, in terms of inhibition of cell proliferation, than did PC9 and A549 cells (Figure 2B and Supplementary Figure 2A).	('inhibition', 'NegReg', (138, 148))	('lonidamine', 'Chemical', 'MESH:C016371', (75, 85))	('A549', 'CellLine', 'CVCL:0023', (189, 193))	('lonidamine', 'Var', (75, 85))	('hexokinase', 'Gene', (104, 114))	('PC9', 'Gene', (181, 184))	('hexokinase', 'Gene', '3098', (104, 114))	('cell proliferation', 'CPA', (152, 170))	('PC9', 'Gene', '255738', (181, 184))
401037	32083006	Therefore, we hypothesized that inhibiting HK2 induces activation of the AMPK signaling pathway and inhibition of the mTOR pathway, which could be related to the increased energy stress in lung squamous tumors.	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('tumors', 'Phenotype', 'HP:0002664', (203, 209))	('lung squamous tumors', 'Disease', 'MESH:D002294', (189, 209))	('mTOR', 'Gene', (118, 122))	('HK2', 'Gene', (43, 46))	('mTOR', 'Gene', '2475', (118, 122))	('lung squamous tumors', 'Disease', (189, 209))	('squamous tumor', 'Phenotype', 'HP:0002860', (194, 208))	('inhibiting', 'Var', (32, 42))	('AMPK', 'Gene', (73, 77))	('AMPK', 'Gene', '5564', (73, 77))	('inhibition', 'NegReg', (100, 110))	('activation', 'PosReg', (55, 65))
401039	32083006	HK2 depletion or inhibition have been shown to decrease aerobic glycolysis of SCC, so we detected the expression of the phosphorylation level of AMPK (Thr172), the activate form of AMPK pathway.	('aerobic glycolysis', 'MPA', (56, 74))	('AMPK', 'Gene', (145, 149))	('SCC', 'Disease', (78, 81))	('AMPK', 'Gene', '5564', (145, 149))	('decrease', 'NegReg', (47, 55))	('depletion', 'Var', (4, 13))	('inhibition', 'Var', (17, 27))	('AMPK', 'Gene', (181, 185))	('AMPK', 'Gene', '5564', (181, 185))	('SCC', 'Disease', 'MESH:D002294', (78, 81))	('Thr172', 'Chemical', '-', (151, 157))	('HK2', 'Protein', (0, 3))	('SCC', 'Phenotype', 'HP:0002860', (78, 81))
401040	32083006	As shown, the AMPK pathway was significantly activated neither HK2 silencing nor its inhibition with lonidamine (Figure 4A).	('AMPK', 'Gene', '5564', (14, 18))	('silencing', 'Var', (67, 76))	('AMPK', 'Gene', (14, 18))	('activated', 'PosReg', (45, 54))	('HK2', 'Protein', (63, 66))	('lonidamine', 'Chemical', 'MESH:C016371', (101, 111))
401042	32083006	Western blotting results suggested that HK2 depletion significantly decreased the activity of the mTORC1 pathway as indicated by the level of S6K1 (Thr389) and 4EBP1 (Thr70) phosphorylation (Figure 4B).	('decreased', 'NegReg', (68, 77))	('Thr389', 'Chemical', '-', (148, 154))	('mTORC1', 'Gene', '382056', (98, 104))	('depletion', 'Var', (44, 53))	('4EBP1', 'Gene', '1978', (160, 165))	('S6K1', 'Gene', '6198', (142, 146))	('HK2', 'Protein', (40, 43))	('S6K1', 'Gene', (142, 146))	('mTORC1', 'Gene', (98, 104))	('activity', 'MPA', (82, 90))	('Thr70', 'Chemical', '-', (167, 172))	('4EBP1', 'Gene', (160, 165))
401043	32083006	Indeed, analysis of the respiration rate following HK2 silencing showed increased oxygen consumption rates (OCRs) and respiration in H226-siHK2-transfected cells compared with those in control cells (Figures 4G,H), and the same tendency was found for H520-siHK2-transfected cells (Figures 4I, J).	('oxygen', 'Chemical', 'MESH:D010100', (82, 88))	('increased', 'PosReg', (72, 81))	('OCRs', 'Chemical', '-', (108, 112))	('H226-siHK2-transfected', 'Var', (133, 155))	('respiration', 'MPA', (118, 129))	('silencing', 'Var', (55, 64))	('oxygen consumption rates', 'MPA', (82, 106))	('HK2', 'Gene', (51, 54))	('respiration', 'MPA', (24, 35))
401046	32083006	Since silencing HK2 reduced the rate of glycolysis and up-regulated oxidative phosphorylation as a compensatory mechanism, we hypothesized that targeting both metabolic pathways may be a potentially effective therapeutic strategy for SCC.	('up-regulated', 'PosReg', (55, 67))	('HK2', 'Gene', (16, 19))	('reduced', 'NegReg', (20, 27))	('SCC', 'Phenotype', 'HP:0002860', (234, 237))	('glycolysis', 'MPA', (40, 50))	('SCC', 'Disease', (234, 237))	('oxidative phosphorylation', 'MPA', (68, 93))	('rate', 'MPA', (32, 36))	('SCC', 'Disease', 'MESH:D002294', (234, 237))	('silencing', 'Var', (6, 15))
401052	32083006	As expected, the AMPK pathway was activated either HK2 silencing or metformin treatment alone, and the activation becomes more pronounced in the combined application of HK2 silencing and metformin treatment (Figure 5G).	('metformin', 'Chemical', 'MESH:D008687', (187, 196))	('HK2', 'Protein', (169, 172))	('silencing', 'Var', (55, 64))	('AMPK', 'Gene', '5564', (17, 21))	('AMPK', 'Gene', (17, 21))	('metformin', 'Chemical', 'MESH:D008687', (68, 77))	('activated', 'PosReg', (34, 43))	('HK2', 'Var', (51, 54))
401053	32083006	However, mTORC1 activity, as measured by phosphorylated S6K (Thr389) and 4EBP1 (Thr70) levels, was more strongly diminished in H226-siHK2-transfected cells treated with metformin, and this inhibition effect was dose-dependent (Figure 5H).	('mTORC1', 'Gene', (9, 15))	('4EBP1', 'Gene', '1978', (73, 78))	('Thr70', 'Chemical', '-', (80, 85))	('Thr389', 'Chemical', '-', (61, 67))	('diminished', 'NegReg', (113, 123))	('4EBP1', 'Gene', (73, 78))	('H226-siHK2-transfected', 'Var', (127, 149))	('mTORC1', 'Gene', '382056', (9, 15))	('S6K', 'MPA', (56, 59))	('activity', 'MPA', (16, 24))	('metformin', 'Chemical', 'MESH:D008687', (169, 178))
401058	32083006	As shown in Figure 6C, the expression level of cleaved PARP increased under HK2 depletion alone or under the combination of HK2 depletion and metformin treatment.	('PARP', 'Gene', '1302', (55, 59))	('cleaved', 'MPA', (47, 54))	('PARP', 'Gene', (55, 59))	('expression level', 'MPA', (27, 43))	('depletion', 'Var', (80, 89))	('increased', 'PosReg', (60, 69))	('metformin', 'Chemical', 'MESH:D008687', (142, 151))
401060	32083006	HK2 depletion or metformin alone also significantly inhibited colony formation; importantly, the combination of metformin and HK2 depletion decreased tumor growth much more substantially than either treatment alone (Figures 6D-G).	('colony formation', 'CPA', (62, 78))	('decreased', 'NegReg', (140, 149))	('depletion', 'Var', (130, 139))	('metformin', 'Chemical', 'MESH:D008687', (112, 121))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('HK2', 'Gene', (126, 129))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('metformin', 'Chemical', 'MESH:D008687', (17, 26))	('inhibited', 'NegReg', (52, 61))	('tumor', 'Disease', (150, 155))
401061	32083006	Furthermore, we examined the tumorigenicity (n = 6 per group) of these cells in vivo and found that the tumorigenicity of H226-siHK2 and H226-siNC-Met was significantly decreased compared with that of control H226-siNS cells.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumor', 'Disease', (104, 109))	('H226-siNC-Met', 'Var', (137, 150))	('H226-siHK2', 'Var', (122, 132))	('tumor', 'Disease', (29, 34))	('decreased', 'NegReg', (169, 178))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
401063	32083006	Taken together, the combination of HK2 depletion and metformin treatment could lead to more tumor cell apoptosis and reduce tumor growth.	('depletion', 'Var', (39, 48))	('HK2', 'Protein', (35, 38))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('metformin', 'Chemical', 'MESH:D008687', (53, 62))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Disease', (124, 129))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('more', 'PosReg', (87, 91))	('reduce', 'NegReg', (117, 123))	('tumor', 'Disease', (92, 97))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
401072	32083006	In normal and tumor cells, lonidamine reduces oxygen consumption, while it increases aerobic glycolysis in normal cells and inhibits aerobic glycolysis in tumor cells.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('tumor', 'Disease', (14, 19))	('oxygen consumption', 'MPA', (46, 64))	('reduces', 'NegReg', (38, 45))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('inhibits', 'NegReg', (124, 132))	('tumor', 'Disease', (155, 160))	('lonidamine', 'Chemical', 'MESH:C016371', (27, 37))	('aerobic glycolysis', 'MPA', (85, 103))	('aerobic glycolysis', 'MPA', (133, 151))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('lonidamine', 'Var', (27, 37))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('oxygen', 'Chemical', 'MESH:D010100', (46, 52))	('increases', 'PosReg', (75, 84))
401073	32083006	HK2 was the key enzyme in SCC aerobic glycolysis, so the lonidamine could also reduce the enzyme activity of hexokinase in SCC.	('SCC', 'Disease', (26, 29))	('SCC', 'Phenotype', 'HP:0002860', (123, 126))	('enzyme activity', 'MPA', (90, 105))	('hexokinase', 'Gene', '3098', (109, 119))	('SCC', 'Disease', (123, 126))	('lonidamine', 'Chemical', 'MESH:C016371', (57, 67))	('lonidamine', 'Var', (57, 67))	('SCC', 'Disease', 'MESH:D002294', (26, 29))	('reduce', 'NegReg', (79, 85))	('SCC', 'Disease', 'MESH:D002294', (123, 126))	('hexokinase', 'Gene', (109, 119))	('SCC', 'Phenotype', 'HP:0002860', (26, 29))
401076	32083006	Importantly, glutamine metabolism was shown to be altered in an adaptive manner in lung SCC following chronic mTOR inhibition, which could explain the decrease in glycolysis observed in patients.	('mTOR', 'Gene', (110, 114))	('mTOR', 'Gene', '2475', (110, 114))	('glycolysis', 'MPA', (163, 173))	('lung SCC', 'Disease', 'MESH:D002294', (83, 91))	('decrease', 'NegReg', (151, 159))	('altered', 'Reg', (50, 57))	('glutamine metabolism', 'MPA', (13, 33))	('inhibition', 'Var', (115, 125))	('glutamine', 'Chemical', 'MESH:D005973', (13, 22))	('lung SCC', 'Disease', (83, 91))	('SCC', 'Phenotype', 'HP:0002860', (88, 91))	('patients', 'Species', '9606', (186, 194))
401080	32083006	Another recent study demonstrated that HK2 deficiency markedly increased the susceptibility of hepatocellular carcinoma cells to the FDA-approved drug, sorafenib, and also enhanced the inhibitory effects of sorafenib on tumor growth in vivo.	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('increased', 'PosReg', (63, 72))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('hepatocellular carcinoma', 'Disease', (95, 119))	('enhanced', 'PosReg', (172, 180))	('tumor', 'Disease', (220, 225))	('HK2', 'Gene', (39, 42))	('sorafenib', 'Chemical', 'MESH:D000077157', (152, 161))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (95, 119))	('inhibitory effects', 'MPA', (185, 203))	('susceptibility', 'MPA', (77, 91))	('sorafenib', 'Chemical', 'MESH:D000077157', (207, 216))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (95, 119))	('tumor', 'Disease', 'MESH:D009369', (220, 225))	('deficiency', 'Var', (43, 53))
401084	32083006	Deregulated tumor cell metabolism is recognized as one of the hallmarks of cancer.	('Deregulated', 'Var', (0, 11))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('hallmarks of cancer', 'Disease', 'MESH:D009369', (62, 81))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('hallmarks of cancer', 'Disease', (62, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('tumor', 'Disease', (12, 17))
401087	32083006	Our study provides a framework for understanding the basis of HK2 dependency in lung SCC tumors and further suggests a novel therapeutic rationale for combing HK2 depletion with metformin treatment to suppress oxygen respiration to place cancer cells in a greater state of energy stress to suppress growth.	('lung SCC', 'Disease', (80, 88))	('depletion', 'Var', (163, 172))	('cancer', 'Disease', (238, 244))	('cancer', 'Disease', 'MESH:D009369', (238, 244))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('suppress', 'NegReg', (201, 209))	('lung SCC', 'Disease', 'MESH:D002294', (80, 88))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('metformin', 'Chemical', 'MESH:D008687', (178, 187))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('oxygen', 'Chemical', 'MESH:D010100', (210, 216))	('oxygen respiration', 'MPA', (210, 228))	('SCC', 'Phenotype', 'HP:0002860', (85, 88))	('tumor', 'Disease', (89, 94))	('HK2', 'Gene', (159, 162))
401089	26176534	Pro-Inflammatory Cytokine IL-1beta Up-Regulates CXC Chemokine Receptor 4 via Notch and ERK Signaling Pathways in Tongue Squamous Cell Carcinoma Chronic inflammation contributes to tumor development through the induction of oncogenic mutations, genomic instability, early tumor promotion, and enhanced angiogenesis.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('Chronic inflammation', 'Disease', 'MESH:D007249', (144, 164))	('Tongue Squamous Cell Carcinoma', 'Disease', 'MESH:D002294', (113, 143))	('Carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('tumor', 'Phenotype', 'HP:0002664', (271, 276))	('induction', 'Reg', (210, 219))	('Tongue Squamous Cell Carcinoma', 'Disease', (113, 143))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (120, 143))	('Chronic inflammation', 'Disease', (144, 164))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('genomic instability', 'CPA', (244, 263))	('Up-Regulates', 'PosReg', (35, 47))	('ERK', 'Gene', '5594', (87, 90))	('oncogenic', 'CPA', (223, 232))	('angiogenesis', 'CPA', (301, 313))	('enhanced', 'PosReg', (292, 300))	('tumor', 'Disease', (271, 276))	('IL-1beta', 'Gene', '3553', (26, 34))	('tumor', 'Disease', 'MESH:D009369', (271, 276))	('ERK', 'Gene', (87, 90))	('Tongue Squamous Cell Carcinoma', 'Phenotype', 'HP:0030413', (113, 143))	('tumor', 'Disease', (180, 185))	('IL-1beta', 'Gene', (26, 34))	('CXC', 'MPA', (48, 51))	('mutations', 'Var', (233, 242))
401096	26176534	Pharmacological inhibition of Notch signaling reversed the up-regulation of CXCR4 induced by IL-1beta, suggesting that Notch signaling may be involved in the growth and metastasis of cancers via up-regulation of CXCR4.	('metastasis of cancers', 'Disease', 'MESH:D009362', (169, 190))	('CXCR4', 'Gene', (76, 81))	('IL-1beta', 'Gene', '3553', (93, 101))	('CXCR4', 'Gene', '7852', (212, 217))	('Notch signaling', 'Var', (119, 134))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('involved', 'Reg', (142, 150))	('metastasis of cancers', 'Disease', (169, 190))	('CXCR4', 'Gene', (212, 217))	('CXCR4', 'Gene', '7852', (76, 81))	('IL-1beta', 'Gene', (93, 101))	('up-regulation', 'PosReg', (195, 208))	('up-regulation', 'PosReg', (59, 72))	('cancers', 'Phenotype', 'HP:0002664', (183, 190))
401107	26176534	Polymorphisms of IL-1beta, IL-1 receptor 1 (IL-R1), or IL-1 receptor antagonist (IL-1Ra) are associated with an increased risk of various solid malignant tumors, including gastric cancer, pancreatic cancer, lung cancer, prostate cancer, and breast cancer.	('IL-1', 'Gene', (55, 59))	('gastric cancer', 'Phenotype', 'HP:0012126', (172, 186))	('IL-1 receptor antagonist', 'Gene', '3557', (55, 79))	('pancreatic cancer', 'Disease', (188, 205))	('IL-1Ra', 'Gene', (81, 87))	('IL-1', 'Gene', '3552', (27, 31))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('lung cancer', 'Disease', 'MESH:D008175', (207, 218))	('Polymorphisms', 'Var', (0, 13))	('cancer', 'Phenotype', 'HP:0002664', (248, 254))	('IL-1beta', 'Gene', '3553', (17, 25))	('gastric cancer', 'Disease', (172, 186))	('IL-1', 'Gene', '3552', (17, 21))	('lung cancer', 'Phenotype', 'HP:0100526', (207, 218))	('IL-1', 'Gene', (27, 31))	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('IL-1Ra', 'Gene', '3557', (81, 87))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (188, 205))	('IL-1beta', 'Gene', (17, 25))	('breast cancer', 'Phenotype', 'HP:0003002', (241, 254))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('IL-1', 'Gene', (17, 21))	('gastric cancer', 'Disease', 'MESH:D013274', (172, 186))	('malignant tumors', 'Disease', 'MESH:D018198', (144, 160))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('IL-1', 'Gene', '3552', (81, 85))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))	('prostate cancer', 'Disease', 'MESH:D011471', (220, 235))	('IL-R1', 'Gene', (44, 49))	('IL-1', 'Gene', '3552', (55, 59))	('prostate cancer', 'Phenotype', 'HP:0012125', (220, 235))	('IL-1 receptor antagonist', 'Gene', (55, 79))	('malignant tumors', 'Disease', (144, 160))	('breast cancer', 'Disease', 'MESH:D001943', (241, 254))	('breast cancer', 'Disease', (241, 254))	('associated with', 'Reg', (93, 108))	('prostate cancer', 'Disease', (220, 235))	('lung cancer', 'Disease', (207, 218))	('pancreatic cancer', 'Disease', 'MESH:D010190', (188, 205))	('IL-1', 'Gene', (81, 85))
401110	26176534	Stomach-specific expression of human IL-1beta in transgenic mice leads to spontaneous gastric inflammation and cancer that correlates with early recruitment of myeloid-derived suppressor cells (MDSCs) to the stomach.	('transgenic mice', 'Species', '10090', (49, 64))	('IL-1beta', 'Gene', (37, 45))	('IL-1beta', 'Gene', '3553', (37, 45))	('leads to', 'Reg', (65, 73))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('gastric inflammation', 'Disease', (86, 106))	('human', 'Species', '9606', (31, 36))	('gastric inflammation', 'Phenotype', 'HP:0005263', (86, 106))	('expression', 'Var', (17, 27))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('gastric inflammation', 'Disease', 'MESH:D007249', (86, 106))
401115	26176534	A wide variety of potential drugs targeting CXCL12/CXCR4 and downstream signaling pathways, including peptides, small molecules, antibodies, and small interfering RNA, have been tested for cancer therapy.	('CXCL12', 'Gene', '6387', (44, 50))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('CXCR4', 'Gene', (51, 56))	('small interfering RNA', 'Var', (145, 166))	('CXCR4', 'Gene', '7852', (51, 56))	('CXCL12', 'Gene', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('cancer', 'Disease', (189, 195))
401117	26176534	Hypoxia is a prominent regulator of CXCR4 via HIF-1alpha, and inhibition of HIF-1alpha decreases the metastasis of cancers.	('Hypoxia', 'Disease', 'MESH:D000860', (0, 7))	('CXCR4', 'Gene', '7852', (36, 41))	('cancers', 'Phenotype', 'HP:0002664', (115, 122))	('Hypoxia', 'Disease', (0, 7))	('HIF-1alpha', 'Gene', (76, 86))	('HIF-1alpha decreases the metastasis of cancers', 'Disease', (76, 122))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('HIF-1alpha', 'Gene', (46, 56))	('CXCR4', 'Gene', (36, 41))	('HIF-1alpha decreases the metastasis of cancers', 'Disease', 'MESH:D009362', (76, 122))	('inhibition', 'Var', (62, 72))	('HIF-1alpha', 'Gene', '3091', (76, 86))	('HIF-1alpha', 'Gene', '3091', (46, 56))
401186	26176534	Moreover, Notch inhibition by the inhibitor L685458 decreased the up-regulation of CXCR4 induced by 1 h of IL-1beta treatment (Fig 5D and 5E).	('IL-1beta', 'Gene', '3553', (107, 115))	('up-regulation', 'PosReg', (66, 79))	('L685458', 'Chemical', 'MESH:C410009', (44, 51))	('decreased', 'NegReg', (52, 61))	('CXCR4', 'Gene', '7852', (83, 88))	('CXCR4', 'Gene', (83, 88))	('L685458', 'Var', (44, 51))	('IL-1beta', 'Gene', (107, 115))
401187	26176534	Notch inhibition also decreased the induction of IL-1beta transcript induced by IL-1beta (Fig 5F and 5G).	('induction', 'MPA', (36, 45))	('IL-1beta', 'Gene', '3553', (80, 88))	('Notch inhibition', 'Var', (0, 16))	('IL-1beta', 'Gene', (49, 57))	('IL-1beta', 'Gene', '3553', (49, 57))	('IL-1beta', 'Gene', (80, 88))	('decreased', 'NegReg', (22, 31))
401197	26176534	Western blot results also showed that ERK inhibition reversed IL-1beta-induced CXCR4 protein up-regulation (Fig 6H).	('CXCR4', 'Gene', '7852', (79, 84))	('inhibition', 'Var', (42, 52))	('IL-1beta', 'Gene', '3553', (62, 70))	('IL-1beta', 'Gene', (62, 70))	('CXCR4', 'Gene', (79, 84))	('ERK', 'Gene', '5594', (38, 41))	('ERK', 'Gene', (38, 41))
401222	26176534	The blockade of ERK signaling inhibits tumor growth in various types of cancer, including gastric cancer, renal cell carcinoma, and rhabdomyosarcoma.	('gastric cancer', 'Disease', 'MESH:D013274', (90, 104))	('blockade', 'Var', (4, 12))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (132, 148))	('cancer', 'Disease', (98, 104))	('cancer', 'Disease', (72, 78))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('ERK', 'Gene', '5594', (16, 19))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('gastric cancer', 'Phenotype', 'HP:0012126', (90, 104))	('renal cell carcinoma', 'Disease', (106, 126))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (106, 126))	('inhibits', 'NegReg', (30, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('ERK', 'Gene', (16, 19))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('tumor', 'Disease', (39, 44))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('gastric cancer', 'Disease', (90, 104))	('rhabdomyosarcoma', 'Disease', (132, 148))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (106, 126))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (132, 148))
401233	26176534	The expression of a specific inhibitor of the Notch transcription complex, dominant negative MAML1 (DN-MAML), in murine skin led to the development of cutaneous squamous cell carcinoma.	('MAML1', 'Gene', (93, 98))	('led to', 'Reg', (125, 131))	('cutaneous squamous cell carcinoma', 'Phenotype', 'HP:0006739', (151, 184))	('cutaneous squamous cell carcinoma', 'Disease', 'MESH:D002294', (151, 184))	('dominant negative', 'Var', (75, 92))	('murine', 'Species', '10090', (113, 119))	('MAML1', 'Gene', '103806', (93, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (175, 184))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (161, 184))	('cutaneous squamous cell carcinoma', 'Disease', (151, 184))
401238	26176534	Inhibition of Notch signaling decreased CXCR4 expression.	('CXCR4', 'Gene', '7852', (40, 45))	('CXCR4', 'Gene', (40, 45))	('Inhibition', 'Var', (0, 10))	('Notch signaling', 'Pathway', (14, 29))	('decreased', 'NegReg', (30, 39))
401239	26176534	However, the inhibition of Notch signaling by a gamma-secretase inhibitor or knockout of the down-stream transcription factor RBP-J has been reported to significantly increase cell surface, total protein, and mRNA levels of CXCR4 in mesenchymal stem cells.	('CXCR4', 'Gene', (224, 229))	('Notch signaling', 'Gene', (27, 42))	('total protein', 'MPA', (190, 203))	('knockout', 'Var', (77, 85))	('cell surface', 'CPA', (176, 188))	('RBP-J', 'Gene', (126, 131))	('CXCR4', 'Gene', '7852', (224, 229))	('inhibition', 'NegReg', (13, 23))	('increase', 'PosReg', (167, 175))	('RBP-J', 'Gene', '3516', (126, 131))
401240	26176534	In endothelial cells, the expression of the Notch ligand Dll4 inhibited attachment and migration in response to stromal-derived growth factor 1 (SDF1) due to the down-regulation of CXCR4.	('SDF1', 'Gene', (145, 149))	('SDF1', 'Gene', '6387', (145, 149))	('down-regulation', 'NegReg', (162, 177))	('expression', 'Var', (26, 36))	('CXCR4', 'Gene', '7852', (181, 186))	('Dll4', 'Gene', (57, 61))	('Dll4', 'Gene', '54567', (57, 61))	('stromal-derived growth factor 1', 'Gene', (112, 143))	('stromal-derived growth factor 1', 'Gene', '6387', (112, 143))	('inhibited', 'NegReg', (62, 71))	('CXCR4', 'Gene', (181, 186))
401246	24586454	These results suggest that overexpressed MCP-1 in cancer cells may promote HNSCC progression through upregulating pro-survival signaling pathways.	('overexpressed', 'Var', (27, 40))	('cancer', 'Disease', (50, 56))	('pro-survival signaling pathways', 'Pathway', (114, 145))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('HNSCC', 'Disease', (75, 80))	('HNSCC', 'Phenotype', 'HP:0012288', (75, 80))	('upregulating', 'PosReg', (101, 113))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('MCP-1', 'Gene', (41, 46))	('promote', 'PosReg', (67, 74))
401247	24586454	High cellular MCP-1 expression is related to poor overall survival rate in HNSCC patients.	('MCP-1', 'Gene', (14, 19))	('patients', 'Species', '9606', (81, 89))	('HNSCC', 'Disease', (75, 80))	('HNSCC', 'Phenotype', 'HP:0012288', (75, 80))	('poor', 'NegReg', (45, 49))	('High cellular', 'Var', (0, 13))
401250	24586454	Infection by the human papilloma virus (HPV), especially serotype 16, has also been implicated in malignancies of the oropharynx.	('implicated', 'Reg', (84, 94))	('papilloma', 'Phenotype', 'HP:0012740', (23, 32))	('human papilloma virus', 'Species', '10566', (17, 38))	('malignancies of the oropharynx', 'Phenotype', 'HP:0100638', (98, 128))	('HPV', 'Species', '10566', (40, 43))	('malignancies of the oropharynx', 'Disease', (98, 128))	('serotype', 'Var', (57, 65))	('HPV', 'Gene', (40, 43))
401254	24586454	Aberrantly regulated cellular signaling is known to play an important role in tumor development.	('Aberrantly', 'Var', (0, 10))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('men', 'Species', '9606', (91, 94))	('tumor', 'Disease', (78, 83))
401255	24586454	Overactivation of the PI3K-Akt pathway supports cancer progression through multiple mechanisms.	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('PI3K-Akt pathway', 'Pathway', (22, 38))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('Overactivation', 'Var', (0, 14))
401257	24586454	Inhibition of glycogen synthase kinase 3beta (GSK3beta) by Akt not only results in accumulation of several oncogenic proteins, including beta-catenin, c-myc, Snail, and cyclin D1 (CCND1), but also reduces expression of E-cadherin, a factor critical for contact inhibition.	('beta-catenin', 'Gene', '1499', (137, 149))	('cyclin D1', 'Gene', (169, 178))	('GSK3beta', 'Gene', '2932', (46, 54))	('accumulation', 'PosReg', (83, 95))	('E-cadherin', 'Gene', (219, 229))	('E-cadherin', 'Gene', '999', (219, 229))	('cyclin D1', 'Gene', '595', (169, 178))	('Snail', 'Gene', '6615', (158, 163))	('c-myc', 'Gene', (151, 156))	('glycogen synthase kinase 3beta', 'Gene', (14, 44))	('CCND1', 'Gene', '595', (180, 185))	('GSK3beta', 'Gene', (46, 54))	('reduces', 'NegReg', (197, 204))	('Inhibition', 'Var', (0, 10))	('expression', 'MPA', (205, 215))	('CCND1', 'Gene', (180, 185))	('c-myc', 'Gene', '4609', (151, 156))	('Snail', 'Gene', (158, 163))	('glycogen synthase kinase 3beta', 'Gene', '2932', (14, 44))	('beta-catenin', 'Gene', (137, 149))
401258	24586454	Another effect of PI3K-Akt signaling is the downregulation of apoptosis via disabling proapoptotic proteins such as caspase 9 and Bad.	('caspase 9', 'Gene', (116, 125))	('downregulation', 'NegReg', (44, 58))	('disabling', 'NegReg', (76, 85))	('caspase 9', 'Gene', '842', (116, 125))	('PI3K-Akt', 'Var', (18, 26))	('apoptosis', 'CPA', (62, 71))	('Bad', 'MPA', (130, 133))	('proapoptotic proteins', 'MPA', (86, 107))
401261	24586454	Deregulation of inflammatory processes is highly associated with cancer progression.	('Deregulation', 'Var', (0, 12))	('associated', 'Reg', (49, 59))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('inflammatory', 'CPA', (16, 28))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))
401284	24586454	Antibodies against fibronectin, snail, dysadherin, STAT3, phosphorylated STAT3 (Y705), vimentin, and MCP-1 were purchased from Abcam (Cambridge, UK).	('dysadherin', 'Gene', '53827', (39, 49))	('vimentin', 'Gene', '7431', (87, 95))	('fibronectin', 'Gene', '2335', (19, 30))	('Y705', 'Var', (80, 84))	('vimentin', 'Gene', (87, 95))	('snail', 'Gene', (32, 37))	('fibronectin', 'Gene', (19, 30))	('dysadherin', 'Gene', (39, 49))	('snail', 'Gene', '6615', (32, 37))
401307	24586454	In contrast, inhibition of PI3K-Akt signaling by LY294002 significantly reduced survivin expression and antagonized the effect of MCP-1 on cell survival (Fig.	('PI3K-Akt signaling', 'Pathway', (27, 45))	('reduced', 'NegReg', (72, 79))	('LY294002', 'Var', (49, 57))	('expression', 'MPA', (89, 99))	('antagonized', 'NegReg', (104, 115))	('survivin', 'Gene', '11799', (80, 88))	('LY294002', 'Chemical', 'MESH:C085911', (49, 57))	('cell survival', 'CPA', (139, 152))	('inhibition', 'NegReg', (13, 23))	('survivin', 'Gene', (80, 88))
401334	33490273	Dysregulation of the CD8 T cell function is closely related to defective antitumor immune responses.	('Dysregulation', 'Var', (0, 13))	('CD8', 'Gene', (21, 24))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('CD8', 'Gene', '925', (21, 24))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('defective', 'NegReg', (63, 72))	('tumor', 'Disease', (77, 82))
401341	33490273	The Cancer Genome Atlas (TCGA) database provides data on the gene expression, mutation, methylation, and copy number variation in more than 18 million cancer cases.	('mutation', 'Var', (78, 86))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('Cancer', 'Phenotype', 'HP:0002664', (4, 10))	('Cancer', 'Disease', (4, 10))	('cancer', 'Disease', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('Cancer', 'Disease', 'MESH:D009369', (4, 10))
401352	33490273	Tumor Immune Dysfunction and Exclusion (TIDE) analysis indicated that the high expression of DHX37 is associated with worse prognosis in breast cancer.	('breast cancer', 'Disease', 'MESH:D001943', (137, 150))	('breast cancer', 'Phenotype', 'HP:0003002', (137, 150))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('DHX37', 'Gene', (93, 98))	('associated', 'Reg', (102, 112))	('high expression', 'Var', (74, 89))	('breast cancer', 'Disease', (137, 150))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
401356	33490273	Various mutations of DHX37 were detected in human cancers.	('human', 'Species', '9606', (44, 49))	('DHX37', 'Gene', (21, 26))	('cancers', 'Disease', 'MESH:D009369', (50, 57))	('cancers', 'Phenotype', 'HP:0002664', (50, 57))	('cancers', 'Disease', (50, 57))	('mutations', 'Var', (8, 17))	('detected', 'Reg', (32, 40))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))
401367	33490273	In this study, the COSMIC database was used for identifying mutations of DHX37 in human cancers.	('DHX37', 'Gene', (73, 78))	('cancers', 'Disease', 'MESH:D009369', (88, 95))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('cancers', 'Disease', (88, 95))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('mutations', 'Var', (60, 69))	('human', 'Species', '9606', (82, 87))
401378	33490273	In human cancers, nonsense, missense, and synonymous substitution were major types of DHX37 somatic mutations.	('cancers', 'Disease', 'MESH:D009369', (9, 16))	('cancers', 'Phenotype', 'HP:0002664', (9, 16))	('cancers', 'Disease', (9, 16))	('DHX37', 'Gene', (86, 91))	('missense', 'Var', (28, 36))	('human', 'Species', '9606', (3, 8))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('synonymous substitution', 'Var', (42, 65))	('nonsense', 'Var', (18, 26))
401380	33490273	According to different cancer types, missense substitutions were observed in all cancer types, with a percentage of 10%-100%.	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('cancer', 'Disease', (81, 87))	('cancer', 'Disease', (23, 29))	('cancer', 'Disease', 'MESH:D009369', (23, 29))	('observed', 'Reg', (65, 73))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('missense substitutions', 'Var', (37, 59))
401381	33490273	Cancers with over 50% missense substitutions were cervix carcinoma (50%), large intestine carcinoma (52.78%), ovary carcinoma (50%), salivary gland carcinoma (100%), skin carcinoma (63.64%), thyroid carcinoma (85.71%), and urinary tract carcinoma (54.55%).	('missense substitutions', 'Var', (22, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('Cancers', 'Disease', (0, 7))	('carcinoma', 'Disease', 'MESH:D009369', (171, 180))	('carcinoma', 'Disease', 'MESH:D009369', (116, 125))	('Cancers', 'Phenotype', 'HP:0002664', (0, 7))	('carcinoma', 'Phenotype', 'HP:0030731', (57, 66))	('carcinoma', 'Disease', (90, 99))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (191, 208))	('salivary gland carcinoma', 'Phenotype', 'HP:0100684', (133, 157))	('carcinoma', 'Disease', (57, 66))	('urinary tract carcinoma', 'Disease', (223, 246))	('cervix carcinoma', 'Phenotype', 'HP:0030079', (50, 66))	('urinary tract carcinoma', 'Disease', 'MESH:D014571', (223, 246))	('carcinoma', 'Disease', (199, 208))	('salivary gland carcinoma', 'Disease', (133, 157))	('cervix carcinoma', 'Disease', (50, 66))	('carcinoma', 'Disease', 'MESH:D009369', (90, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (148, 157))	('ovary carcinoma', 'Disease', (110, 125))	('carcinoma', 'Disease', 'MESH:D009369', (57, 66))	('carcinoma', 'Disease', (237, 246))	('salivary gland carcinoma', 'Disease', 'MESH:D012468', (133, 157))	('carcinoma', 'Disease', (148, 157))	('skin carcinoma', 'Disease', (166, 180))	('carcinoma', 'Disease', 'MESH:D009369', (199, 208))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancers', 'Disease', 'MESH:D009369', (0, 7))	('carcinoma', 'Phenotype', 'HP:0030731', (171, 180))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('carcinoma', 'Disease', (116, 125))	('ovary carcinoma', 'Phenotype', 'HP:0025318', (110, 125))	('carcinoma', 'Disease', (171, 180))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (191, 208))	('skin carcinoma', 'Disease', 'MESH:D012878', (166, 180))	('cervix carcinoma', 'Disease', 'MESH:D002583', (50, 66))	('thyroid carcinoma', 'Disease', (191, 208))	('carcinoma', 'Disease', 'MESH:D009369', (237, 246))	('ovary carcinoma', 'Disease', 'MESH:D010051', (110, 125))	('carcinoma', 'Disease', 'MESH:D009369', (148, 157))
401382	33490273	Synonymous substitutions occurred in many kinds of cancers except salivary gland cancer and thyroid cancer.	('cancers', 'Disease', (51, 58))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('Synonymous substitutions', 'Var', (0, 24))	('thyroid cancer', 'Disease', (92, 106))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('cancer', 'Disease', (81, 87))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('thyroid cancer', 'Phenotype', 'HP:0002890', (92, 106))	('thyroid cancer', 'Disease', 'MESH:D013964', (92, 106))	('cancers', 'Phenotype', 'HP:0002664', (51, 58))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('occurred', 'Reg', (25, 33))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('cancers', 'Disease', 'MESH:D009369', (51, 58))	('salivary gland cancer', 'Phenotype', 'HP:0100684', (66, 87))
401386	33490273	Frameshift deletion was found in large intestine carcinoma (2.78%), pancreas carcinoma (10%), skin carcinoma (3.03%), and stomach carcinoma (3.85%).	('carcinoma', 'Disease', 'MESH:D009369', (77, 86))	('stomach carcinoma', 'Phenotype', 'HP:0012126', (122, 139))	('pancreas carcinoma', 'Disease', 'MESH:D010190', (68, 86))	('skin carcinoma', 'Disease', 'MESH:D012878', (94, 108))	('pancreas carcinoma', 'Disease', (68, 86))	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('carcinoma', 'Disease', 'MESH:D009369', (99, 108))	('carcinoma', 'Disease', 'MESH:D009369', (130, 139))	('stomach carcinoma', 'Disease', (122, 139))	('carcinoma', 'Disease', (49, 58))	('found', 'Reg', (24, 29))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('Frameshift deletion', 'Var', (0, 19))	('carcinoma', 'Disease', (77, 86))	('carcinoma', 'Disease', 'MESH:D009369', (49, 58))	('skin carcinoma', 'Disease', (94, 108))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('stomach carcinoma', 'Disease', 'MESH:D013274', (122, 139))	('carcinoma', 'Disease', (99, 108))	('carcinoma', 'Disease', (130, 139))
401387	33490273	No frameshift insertion of DHX37 was found in any cancer.	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('DHX37', 'Gene', (27, 32))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('frameshift insertion', 'Var', (3, 23))
401388	33490273	A > C mutation was found in hematopoietic and lymphoid carcinoma (20%) and kidney carcinoma (20%).	('kidney carcinoma', 'Disease', (75, 91))	('lymphoid carcinoma', 'Disease', (46, 64))	('carcinoma', 'Phenotype', 'HP:0030731', (55, 64))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('lymphoid carcinoma', 'Disease', 'MESH:D009369', (46, 64))	('kidney carcinoma', 'Disease', 'MESH:D007680', (75, 91))	('A > C', 'Var', (0, 5))	('kidney carcinoma', 'Phenotype', 'HP:0005584', (75, 91))
401390	33490273	C > G mutation was seen in breast carcinoma (10%) and large intestine carcinoma (7.41%).	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('carcinoma', 'Disease', (34, 43))	('breast carcinoma', 'Disease', 'MESH:D001943', (27, 43))	('breast carcinoma', 'Disease', (27, 43))	('carcinoma', 'Disease', (70, 79))	('carcinoma', 'Disease', 'MESH:D009369', (34, 43))	('carcinoma', 'Phenotype', 'HP:0030731', (34, 43))	('breast carcinoma', 'Phenotype', 'HP:0003002', (27, 43))	('carcinoma', 'Disease', 'MESH:D009369', (70, 79))	('C > G mutation', 'Var', (0, 14))
401400	33490273	The high expression of DHX37 was significantly associated with unfavorable prognosis in esophageal adenocarcinoma (P = 0.0055), kidney renal clear cell carcinoma (P = 0.0011), liver hepatocellular carcinoma (P = 0.025), lung adenocarcinoma (P = 0.00095), head-neck squamous cell carcinoma (P = 0.017), and sarcoma(P = 0.0014).	('carcinoma', 'Phenotype', 'HP:0030731', (152, 161))	('kidney renal clear cell carcinoma', 'Disease', 'MESH:C538614', (128, 161))	('esophageal adenocarcinoma', 'Disease', (88, 113))	('high expression', 'Var', (4, 19))	('carcinoma', 'Phenotype', 'HP:0030731', (230, 239))	('associated', 'Reg', (47, 57))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (220, 239))	('carcinoma', 'Phenotype', 'HP:0030731', (279, 288))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('head-neck squamous cell carcinoma', 'Disease', (255, 288))	('liver hepatocellular carcinoma', 'Disease', (176, 206))	('DHX37', 'Gene', (23, 28))	('kidney renal clear cell carcinoma', 'Disease', (128, 161))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (220, 239))	('head-neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (255, 288))	('sarcoma', 'Disease', 'MESH:D012509', (306, 313))	('sarcoma', 'Disease', (306, 313))	('carcinoma', 'Phenotype', 'HP:0030731', (197, 206))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (182, 206))	('head-neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (255, 288))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (265, 288))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (88, 113))	('liver hepatocellular carcinoma', 'Disease', 'MESH:D006528', (176, 206))	('sarcoma', 'Phenotype', 'HP:0100242', (306, 313))	('esophageal adenocarcinoma', 'Disease', 'MESH:D000230', (88, 113))	('lung adenocarcinoma', 'Disease', (220, 239))
401401	33490273	However, the opposite results were observed in lung squamous cell carcinoma (P = 0.0065), rectum adenocarcinoma (P = 0.0023), stomach adenocarcinoma (P = 0.0091), uterine corpus endometrial carcinoma (P = 0.023), and thyroid carcinoma(P = 0.0015), in which the high expression of DHX37 was correlated with favorable prognosis.	('carcinoma', 'Phenotype', 'HP:0030731', (66, 75))	('stomach adenocarcinoma', 'Disease', (126, 148))	('DHX37', 'Gene', (280, 285))	('carcinoma', 'Phenotype', 'HP:0030731', (190, 199))	('endometrial carcinoma', 'Disease', (178, 199))	('rectum adenocarcinoma', 'Disease', (90, 111))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (217, 234))	('high', 'Var', (261, 265))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (47, 75))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (52, 75))	('thyroid carcinoma', 'Disease', (217, 234))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (178, 199))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (217, 234))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (178, 199))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (47, 75))	('lung squamous cell carcinoma', 'Disease', (47, 75))	('carcinoma', 'Phenotype', 'HP:0030731', (225, 234))	('carcinoma', 'Phenotype', 'HP:0030731', (139, 148))	('rectum adenocarcinoma', 'Disease', 'MESH:D012004', (90, 111))	('stomach adenocarcinoma', 'Disease', 'MESH:D000230', (126, 148))
401404	33490273	According to the data in TCGA tumor samples, the copy numbers of DHX37 were positively correlated with TIM3, LAG3 and NCOR2, while they were negatively correlated with PD-L1, RGS16 and TOX (Figure 6).	('TIM3', 'Gene', (103, 107))	('LAG3', 'Gene', (109, 113))	('TIM3', 'Gene', '84868', (103, 107))	('LAG3', 'Gene', '3902', (109, 113))	('negatively', 'NegReg', (141, 151))	('NCOR2', 'Gene', '9612', (118, 123))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('correlated', 'Interaction', (87, 97))	('RGS16', 'Gene', (175, 180))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('copy numbers', 'Var', (49, 61))	('RGS16', 'Gene', '6004', (175, 180))	('NCOR2', 'Gene', (118, 123))	('tumor', 'Disease', (30, 35))	('DHX37', 'Gene', (65, 70))
401412	33490273	Previous studies showed that DHX37 is specifically expressed in somatic cells of developing human testis, and pathogenic variants of DHX37 are a frequent cause of nonsyndromic 46, XY gonadal dysgenesis.	('cause', 'Reg', (154, 159))	('variants', 'Var', (121, 129))	('gonadal dysgenesis', 'Phenotype', 'HP:0000133', (183, 201))	('46, XY gonadal dysgenesis', 'Phenotype', 'HP:0008668', (176, 201))	('DHX37', 'Gene', (133, 138))	('human', 'Species', '9606', (92, 97))
401421	33490273	Among all the mutations, missense substitution was the most frequently occurred mutation and was found in all tumor types.	('missense substitution', 'Var', (25, 46))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('occurred', 'Reg', (71, 79))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
401422	33490273	Salivary gland carcinoma had 100% missense substitution, and thyroid carcinoma had 85.71%, suggesting that abnormal amino acid sequence of DHX37 may account for tumor development of these two cancers.	('missense substitution', 'Var', (34, 55))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (61, 78))	('cancers', 'Phenotype', 'HP:0002664', (192, 199))	('cancers', 'Disease', (192, 199))	('thyroid carcinoma', 'Disease', (61, 78))	('tumor', 'Disease', (161, 166))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('account', 'Reg', (149, 156))	('carcinoma', 'Phenotype', 'HP:0030731', (15, 24))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('Salivary gland carcinoma', 'Phenotype', 'HP:0100684', (0, 24))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (61, 78))	('carcinoma', 'Disease', (15, 24))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))	('carcinoma', 'Disease', (69, 78))	('cancers', 'Disease', 'MESH:D009369', (192, 199))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('carcinoma', 'Disease', 'MESH:D009369', (15, 24))	('DHX37', 'Gene', (139, 144))	('carcinoma', 'Disease', 'MESH:D009369', (69, 78))	('abnormal amino acid', 'Phenotype', 'HP:0004337', (107, 126))
401423	33490273	Besides, nonsense mutation, inframe insertion, inframe deletion, and frameshift deletion were observed in various tumor types, indicating that structural and functional changes of DHX37 are vital to tumor initiation and progression.	('inframe insertion', 'Var', (28, 45))	('tumor', 'Disease', (199, 204))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('frameshift deletion', 'Var', (69, 88))	('DHX37', 'Gene', (180, 185))	('tumor initiation', 'Disease', (199, 215))	('inframe deletion', 'Var', (47, 63))	('observed', 'Reg', (94, 102))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumor', 'Disease', (114, 119))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('tumor initiation', 'Disease', 'MESH:D009369', (199, 215))	('nonsense mutation', 'Var', (9, 26))
401431	33490273	These findings support our hypothesis that the high expression of DHX37 indicates an increased risk of tumor immune suppression and tumor progression.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('DHX37', 'Gene', (66, 71))	('tumor', 'Disease', (103, 108))	('high', 'Var', (47, 51))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumor', 'Disease', (132, 137))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
401440	33490273	Interestingly, the high expression of DHX37 was associated with favorable prognosis in lung squamous cell carcinoma, rectum adenocarcinoma, stomach adenocarcinoma, uterine corpus endometrial carcinoma, and thyroid carcinoma, which seemed to be not consistent with its role in cancer immune.	('thyroid carcinoma', 'Disease', (206, 223))	('endometrial carcinoma', 'Disease', (179, 200))	('cancer', 'Disease', 'MESH:D009369', (276, 282))	('carcinoma', 'Phenotype', 'HP:0030731', (153, 162))	('stomach adenocarcinoma', 'Disease', 'MESH:D000230', (140, 162))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (206, 223))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (87, 115))	('high expression', 'Var', (19, 34))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (179, 200))	('carcinoma', 'Phenotype', 'HP:0030731', (214, 223))	('rectum adenocarcinoma', 'Disease', 'MESH:D012004', (117, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (191, 200))	('stomach adenocarcinoma', 'Disease', (140, 162))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (179, 200))	('DHX37', 'Gene', (38, 43))	('cancer', 'Disease', (276, 282))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (87, 115))	('cancer', 'Phenotype', 'HP:0002664', (276, 282))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (92, 115))	('lung squamous cell carcinoma', 'Disease', (87, 115))	('rectum adenocarcinoma', 'Disease', (117, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (206, 223))
401506	29331415	In the present study, we found that NgBR knockdown inhibited epithelial:mesenchymal transition (EMT) in non-small cell lung cancer (NSCLC) cells in vitro and metastasis of NSCLC cells in vivo.	('non-small cell lung cancer', 'Disease', (104, 130))	('lung cancer', 'Phenotype', 'HP:0100526', (119, 130))	('NSCLC', 'Disease', (172, 177))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (108, 130))	('NSCLC', 'Disease', 'MESH:D002289', (172, 177))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (104, 130))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('epithelial:mesenchymal transition', 'CPA', (61, 94))	('NSCLC', 'Disease', (132, 137))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (104, 130))	('metastasis', 'CPA', (158, 168))	('NSCLC', 'Disease', 'MESH:D002289', (132, 137))	('inhibited', 'NegReg', (51, 60))	('knockdown', 'Var', (41, 50))	('NgBR', 'Gene', (36, 40))
401519	29331415	NgBR is also overexpressed in hepatocellular carcinoma tissues, which decreases the survival and chemoresistance of patients with hepatocellular carcinoma to 5fluorouracil because of the ubiquitination of p53, At the molecular level, NgBR functions as a docking site for prenylated Ras isoforms (H-Ras and K-Ras) and promotes their localization to the plasma membrane and subsequent activation.	('carcinoma', 'Phenotype', 'HP:0030731', (145, 154))	('decreases', 'NegReg', (70, 79))	('docking', 'Interaction', (254, 261))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (30, 54))	('localization', 'MPA', (332, 344))	('Ras', 'Chemical', 'MESH:D011883', (308, 311))	('H-Ras', 'Gene', (296, 301))	('activation', 'PosReg', (383, 393))	('patients', 'Species', '9606', (116, 124))	('5fluorouracil', 'Chemical', 'MESH:D005472', (158, 171))	('p53', 'Gene', '7157', (205, 208))	('K-Ras', 'Gene', '3845', (306, 311))	('hepatocellular carcinoma', 'Disease', (30, 54))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (130, 154))	('Ras', 'Chemical', 'MESH:D011883', (298, 301))	('survival', 'CPA', (84, 92))	('p53', 'Gene', (205, 208))	('Ras', 'Chemical', 'MESH:D011883', (282, 285))	('NgBR', 'Var', (234, 238))	('carcinoma', 'Phenotype', 'HP:0030731', (45, 54))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (130, 154))	('chemoresistance', 'CPA', (97, 112))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (30, 54))	('promotes', 'PosReg', (317, 325))	('hepatocellular carcinoma', 'Disease', (130, 154))	('K-Ras', 'Gene', (306, 311))	('H-Ras', 'Gene', '3265', (296, 301))
401560	29331415	Furthermore, high NgBR expression in NSCLC tissues was associated with tumor lymph node metastasis (p = .024; Table 1).	('high', 'Var', (13, 17))	('NgBR', 'Gene', (18, 22))	('associated', 'Reg', (55, 65))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('NSCLC', 'Disease', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('NSCLC', 'Disease', 'MESH:D002289', (37, 42))	('tumor', 'Disease', (71, 76))	('expression', 'MPA', (23, 33))
401563	29331415	Overall survival analysis indicated that patients with high NgBR expression showed significantly lower survival rates than patients with low NgBR expression (p = 9.5e-10; Fig.	('survival', 'MPA', (103, 111))	('high NgBR expression', 'Var', (55, 75))	('patients', 'Species', '9606', (123, 131))	('patients', 'Species', '9606', (41, 49))	('lower', 'NegReg', (97, 102))
401570	29331415	In contrast, NgBR knockdown in H1299 cells decreased N-cadherin and vimentin expression but increased E-cadherin expression (Fig.	('NgBR', 'Gene', (13, 17))	('knockdown', 'Var', (18, 27))	('expression', 'MPA', (77, 87))	('N-cadherin', 'Protein', (53, 63))	('H1299', 'CellLine', 'CVCL:0060', (31, 36))	('increased', 'PosReg', (92, 101))	('vimentin', 'Protein', (68, 76))	('E-cadherin expression', 'MPA', (102, 123))	('decreased', 'NegReg', (43, 52))
401573	29331415	Results of NgBR knockdown in H520 and H460 cells were consistent with those obtained using H1299 cells (Fig.	('H460', 'CellLine', 'CVCL:0459', (38, 42))	('H1299', 'CellLine', 'CVCL:0060', (91, 96))	('knockdown', 'Var', (16, 25))	('NgBR', 'Gene', (11, 15))
401579	29331415	3B), whereas NgBR knockdown exerted opposite effects in H1299 cells (Fig.	('NgBR', 'Gene', (13, 17))	('knockdown', 'Var', (18, 27))	('H1299', 'CellLine', 'CVCL:0060', (56, 61))
401583	29331415	Moreover, NgBR knockdown suppressed NgBR-induced migration and invasion of H1299 cells (Figs.	('invasion of H1299 cells', 'CPA', (63, 86))	('knockdown', 'Var', (15, 24))	('NgBR', 'Gene', (10, 14))	('suppressed', 'NegReg', (25, 35))	('NgBR-induced', 'Gene', (36, 48))	('H1299', 'CellLine', 'CVCL:0060', (75, 80))
401586	29331415	In tumor cells, EMT is modulated at different levels, including epigenetic modification, transcriptional regulation, alternative gene splicing, and/or protein stability alteration and subcellular localization.	('epigenetic modification', 'Var', (64, 87))	('tumor', 'Disease', (3, 8))	('alteration', 'Reg', (169, 179))	('protein', 'MPA', (151, 158))	('tumor', 'Disease', 'MESH:D009369', (3, 8))	('transcriptional', 'MPA', (89, 104))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))
401589	29331415	Stable NgBR knockdown in H1299 cells by using an shRNA (Fig.	('H1299', 'CellLine', 'CVCL:0060', (25, 30))	('knockdown', 'Var', (12, 21))	('NgBR', 'Gene', (7, 11))
401590	29331415	4B) and transient NgBR knockdown in A549 and H1299 cells (Fig.	('NgBR', 'Gene', (18, 22))	('H1299', 'CellLine', 'CVCL:0060', (45, 50))	('A549', 'CellLine', 'CVCL:0023', (36, 40))	('knockdown', 'Var', (23, 32))
401592	29331415	4C and S5D), whereas NgBR knockdown decreased the Snaill mRNA level but did not significantly change the Twistl mRNA level in H1299 cells (Figs.	('Snaill mRNA level', 'MPA', (50, 67))	('NgBR', 'Gene', (21, 25))	('knockdown', 'Var', (26, 35))	('H1299', 'CellLine', 'CVCL:0060', (126, 131))	('decreased', 'NegReg', (36, 45))
401598	29331415	In contrast, NgBR knockdown decreased p-ERKl/2 level in A549 and H1299 cells (Figs.	('NgBR', 'Gene', (13, 17))	('knockdown', 'Var', (18, 27))	('ERKl/2', 'Gene', (40, 46))	('decreased', 'NegReg', (28, 37))	('A549', 'CellLine', 'CVCL:0023', (56, 60))	('ERKl/2', 'Gene', '5594', (40, 46))	('H1299', 'CellLine', 'CVCL:0060', (65, 70))
401602	29331415	Our results showed that treatment with 10 muM U0126 suppressed NgBR overexpression-induced p-ERKl/2 and Snaill levels in A549 (Fig.	('muM', 'Gene', '56925', (42, 45))	('U0126', 'Chemical', 'MESH:C113580', (46, 51))	('ERKl/2', 'Gene', '5594', (93, 99))	('NgBR', 'Gene', (63, 67))	('A549', 'CellLine', 'CVCL:0023', (121, 125))	('muM', 'Gene', (42, 45))	('suppressed', 'NegReg', (52, 62))	('Snaill levels', 'MPA', (104, 117))	('U0126', 'Var', (46, 51))	('ERKl/2', 'Gene', (93, 99))
401604	29331415	Moreover, results of wound healing assay showed that U0126 abrogated NgBR-induced migration of A549 (Fig.	('U0126', 'Var', (53, 58))	('NgBR-induced', 'Gene', (69, 81))	('U0126', 'Chemical', 'MESH:C113580', (53, 58))	('abrogated', 'NegReg', (59, 68))	('A549', 'CellLine', 'CVCL:0023', (95, 99))
401612	29331415	However, in H1299 cells, NgBR knockdown inactivated ERK1/2 and downregulated Snaill expression, which upregulated E-cadherin protein expression.	('Snaill', 'Gene', (77, 83))	('expression', 'MPA', (133, 143))	('ERK1/2', 'Gene', (52, 58))	('ERK1/2', 'Gene', '5595;5594', (52, 58))	('NgBR', 'Gene', (25, 29))	('upregulated', 'PosReg', (102, 113))	('H1299', 'CellLine', 'CVCL:0060', (12, 17))	('downregulated', 'NegReg', (63, 76))	('E-cadherin protein', 'Protein', (114, 132))	('knockdown', 'Var', (30, 39))	('inactivated', 'NegReg', (40, 51))	('expression', 'MPA', (84, 94))
401613	29331415	Furthermore, NgBR overexpression reversed the effect of NgBR knockdown on ERK1/2, Snail1, and E-cadherin expression.	('E-cadherin', 'Protein', (94, 104))	('Snail1', 'Gene', (82, 88))	('knockdown', 'Var', (61, 70))	('Snail1', 'Gene', '6615', (82, 88))	('ERK1/2', 'Gene', (74, 80))	('NgBR', 'Gene', (56, 60))	('expression', 'MPA', (105, 115))	('ERK1/2', 'Gene', '5595;5594', (74, 80))
401618	29331415	6A and S7), whereas NgBR knockdown reduced the translocation of both K-Ras and H-Ras to the plasma membrane of H1299 cells (Fig.	('H1299', 'CellLine', 'CVCL:0060', (111, 116))	('reduced', 'NegReg', (35, 42))	('translocation', 'MPA', (47, 60))	('NgBR', 'Gene', (20, 24))	('K-Ras', 'Gene', '3845', (69, 74))	('H-Ras', 'Gene', '3265', (79, 84))	('H-Ras', 'Gene', (79, 84))	('knockdown', 'Var', (25, 34))	('K-Ras', 'Gene', (69, 74))
401628	29331415	Tumor lesions were visible in the lung tissues of A549-NgBR mice but were negligible in the lung tissues of A549-NC mice (Fig.	('mice', 'Species', '10090', (116, 120))	('Tumor', 'Disease', 'MESH:D009369', (0, 5))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('Tumor', 'Disease', (0, 5))	('A549', 'CellLine', 'CVCL:0023', (108, 112))	('A549', 'CellLine', 'CVCL:0023', (50, 54))	('A549-NgBR', 'Var', (50, 59))	('mice', 'Species', '10090', (60, 64))	('A549-NC', 'CellLine', 'CVCL:0023', (108, 115))
401629	29331415	Microscopically, the number of lung metastatic nodules was higher in A549-NgBR mice than in A549-NC mice.	('mice', 'Species', '10090', (100, 104))	('A549', 'CellLine', 'CVCL:0023', (69, 73))	('mice', 'Species', '10090', (79, 83))	('lung metastatic nodules', 'CPA', (31, 54))	('A549-NgBR', 'Var', (69, 78))	('A549-NC', 'CellLine', 'CVCL:0023', (92, 99))	('A549', 'CellLine', 'CVCL:0023', (92, 96))	('higher', 'PosReg', (59, 65))
401630	29331415	In contrast, H1299-shNgBR mice showed fewer number of lung metastatic nodules than H1299-NC mice (Fig.	('lung metastatic nodules', 'CPA', (54, 77))	('H1299-shNgBR', 'Var', (13, 25))	('mice', 'Species', '10090', (92, 96))	('mice', 'Species', '10090', (26, 30))	('H1299', 'CellLine', 'CVCL:0060', (13, 18))	('fewer', 'NegReg', (38, 43))	('H1299', 'CellLine', 'CVCL:0060', (83, 88))
401631	29331415	Furthermore, lung lymph node metastasis was observed in A549-NgBR and H1299-NC mice but not in A549-NC and H1299-shNgBR mice (Fig.	('H1299', 'CellLine', 'CVCL:0060', (70, 75))	('H1299', 'CellLine', 'CVCL:0060', (107, 112))	('mice', 'Species', '10090', (120, 124))	('observed', 'Reg', (44, 52))	('A549-NC', 'CellLine', 'CVCL:0023', (95, 102))	('mice', 'Species', '10090', (79, 83))	('A549', 'CellLine', 'CVCL:0023', (56, 60))	('A549-NgBR', 'Var', (56, 65))	('H1299-NC', 'Var', (70, 78))	('lung lymph node metastasis', 'CPA', (13, 39))	('A549', 'CellLine', 'CVCL:0023', (95, 99))
401638	29331415	We found that high NgBR expression was associated with the lymph node metastasis of NSCLC cells.	('associated with', 'Reg', (39, 54))	('lymph node metastasis of', 'CPA', (59, 83))	('expression', 'MPA', (24, 34))	('NSCLC', 'Disease', (84, 89))	('high', 'Var', (14, 18))	('NSCLC', 'Disease', 'MESH:D002289', (84, 89))	('NgBR', 'Gene', (19, 23))
401639	29331415	Moreover, lymph node metastasis was observed in A549-NgBR and H1299-NC mice, indicating that NgBR promoted the lymph node metastasis of NSCLC cells, which is the most common form of metastasis in NSCLC or all malignancies of epithelial origin in the clinical setting.	('mice', 'Species', '10090', (71, 75))	('NSCLC', 'Disease', 'MESH:D002289', (136, 141))	('H1299', 'CellLine', 'CVCL:0060', (62, 67))	('NSCLC', 'Disease', (196, 201))	('lymph node metastasis', 'CPA', (111, 132))	('malignancies', 'Disease', 'MESH:D009369', (209, 221))	('NSCLC', 'Disease', 'MESH:D002289', (196, 201))	('promoted', 'PosReg', (98, 106))	('NgBR', 'Var', (93, 97))	('A549', 'CellLine', 'CVCL:0023', (48, 52))	('malignancies', 'Disease', (209, 221))	('NSCLC', 'Disease', (136, 141))
401642	29331415	However, NgBR knockdown exerted opposite effects on NSCLC cells both in vitro and in vivo, indicating that NgBR is necessary for EMT and for promoting lung cancer metastasis.	('NSCLC', 'Disease', (52, 57))	('promoting', 'PosReg', (141, 150))	('lung cancer', 'Phenotype', 'HP:0100526', (151, 162))	('NSCLC', 'Disease', 'MESH:D002289', (52, 57))	('lung cancer', 'Disease', (151, 162))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('knockdown', 'Var', (14, 23))	('lung cancer', 'Disease', 'MESH:D008175', (151, 162))
401649	29331415	Results of the present study showed that NgBR knockdown upregulated E-cadherin expression by decreasing Snaill expression level but did not significantly alter Twist1 mRNA and protein expression levels.	('Snaill expression level', 'MPA', (104, 127))	('Twist1', 'Gene', '7291', (160, 166))	('expression', 'MPA', (79, 89))	('knockdown', 'Var', (46, 55))	('NgBR', 'Gene', (41, 45))	('upregulated', 'PosReg', (56, 67))	('Twist1', 'Gene', (160, 166))	('E-cadherin', 'Protein', (68, 78))	('decreasing', 'NegReg', (93, 103))
401651	29331415	CHX treatment did not significantly alter Snail1 protein levels in NgBR-overexpressing A549 and H1299 cells (data not shown), indicating that NgBR upregulated Snaill expression at the transcriptional level to suppress E-cadherin expression and to promote EMT in NSCLC cells.	('NSCLC', 'Disease', (262, 267))	('H1299', 'CellLine', 'CVCL:0060', (96, 101))	('A549', 'CellLine', 'CVCL:0023', (87, 91))	('NgBR', 'Var', (142, 146))	('E-cadherin', 'Protein', (218, 228))	('upregulated', 'PosReg', (147, 158))	('promote', 'PosReg', (247, 254))	('NSCLC', 'Disease', 'MESH:D002289', (262, 267))	('Snail1', 'Gene', (42, 48))	('Snail1', 'Gene', '6615', (42, 48))	('CHX', 'Chemical', 'MESH:D003513', (0, 3))	('Snaill', 'Gene', (159, 165))	('suppress', 'NegReg', (209, 217))
401654	29331415	Alteration of Ras activity is associated with cancer development and progression.	('associated', 'Reg', (30, 40))	('activity', 'MPA', (18, 26))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('Alteration', 'Var', (0, 10))	('cancer', 'Disease', (46, 52))	('Ras', 'Chemical', 'MESH:D011883', (14, 17))	('Ras', 'Protein', (14, 17))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('progression', 'CPA', (69, 80))
401655	29331415	For example, mutations in the Ras genes are frequently detected in pancreatic and lung cancers, which result in the constitutive activation of downstream signaling pathways that regulate cell proliferation and apoptosis.	('detected', 'Reg', (55, 63))	('lung cancer', 'Phenotype', 'HP:0100526', (82, 93))	('lung cancers', 'Phenotype', 'HP:0100526', (82, 94))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cell proliferation', 'CPA', (187, 205))	('activation', 'PosReg', (129, 139))	('cancers', 'Phenotype', 'HP:0002664', (87, 94))	('downstream signaling pathways', 'Pathway', (143, 172))	('Ras', 'Gene', (30, 33))	('mutations', 'Var', (13, 22))	('apoptosis', 'CPA', (210, 219))	('Ras', 'Chemical', 'MESH:D011883', (30, 33))	('pancreatic and lung cancers', 'Disease', 'MESH:D008175', (67, 94))
401658	29331415	We previously showed that NgBRexpression activated Ras by promoting its plasma membrane localization in breast cancer cells.	('promoting', 'PosReg', (58, 67))	('Ras', 'Chemical', 'MESH:D011883', (51, 54))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('breast cancer', 'Disease', 'MESH:D001943', (104, 117))	('Ras', 'Protein', (51, 54))	('plasma membrane localization', 'MPA', (72, 100))	('breast cancer', 'Disease', (104, 117))	('breast cancer', 'Phenotype', 'HP:0003002', (104, 117))	('NgBRexpression', 'Var', (26, 40))
401660	29331415	We found that NgBR knockdown reduced the plasma membrane localization and activation of Ras in NSCLC cells, whereas NgBR overexpression activated the MEK/ERK signaling pathway, which acts downstream of Ras.	('NSCLC', 'Disease', 'MESH:D002289', (95, 100))	('MEK', 'Gene', '5609', (150, 153))	('Ras', 'Chemical', 'MESH:D011883', (202, 205))	('knockdown', 'Var', (19, 28))	('plasma membrane localization', 'MPA', (41, 69))	('activated', 'PosReg', (136, 145))	('NgBR', 'Gene', (14, 18))	('ERK', 'Gene', '5594', (154, 157))	('activation', 'PosReg', (74, 84))	('reduced', 'NegReg', (29, 36))	('ERK', 'Gene', (154, 157))	('Ras', 'Chemical', 'MESH:D011883', (88, 91))	('MEK', 'Gene', (150, 153))	('NSCLC', 'Disease', (95, 100))	('Ras', 'Protein', (88, 91))
401669	31276202	Overall, the highest quintiles of circulating kynurenine, KTR, QA and neopterin were associated with a 20-30% higher risk of lung cancer, and tryptophan with a 15% lower risk compared with the lowest quintile (all Ptrend <0.05).	('lung cancer', 'Disease', 'MESH:D008175', (125, 136))	('neopterin', 'Chemical', 'MESH:D019798', (70, 79))	('kynurenine', 'Var', (46, 56))	('neopterin', 'Gene', (70, 79))	('lung cancer', 'Phenotype', 'HP:0100526', (125, 136))	('QA', 'Chemical', 'MESH:D017378', (63, 65))	('tryptophan', 'Chemical', 'MESH:D014364', (142, 152))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('KTR', 'Chemical', '-', (58, 61))	('lung cancer', 'Disease', (125, 136))	('kynurenine', 'Chemical', 'MESH:D007737', (46, 56))	('KTR', 'Gene', (58, 61))
401712	31276202	In addition to matching on cohort, race (US only), sex, date of blood draw, date of birth, and the combination of smoking status with years of quitting and number (for former smokers) and number of cigarettes per day (for current smokers), the multivariable conditional logistic regression models included the following reported risk factors for lung cancer and determinants of kynurenine metabolites as potential confounders: cotinine concentration (continuous, a biomarker of recent nicotine intake) , educational attainment (six categories), body mass index (BMI) in kg/m2 (<18.5, 18.5- <25, 25- <30, >=30), and eGFR.	('eGFR', 'Gene', (615, 619))	('cancer', 'Phenotype', 'HP:0002664', (351, 357))	('cotinine concentration', 'MPA', (427, 449))	('lung cancer', 'Disease', (346, 357))	('included', 'Reg', (297, 305))	('kynurenine', 'Chemical', 'MESH:D007737', (378, 388))	('lung cancer', 'Phenotype', 'HP:0100526', (346, 357))	('<18.5', 'Var', (577, 582))	('cotinine', 'Chemical', 'MESH:D003367', (427, 435))	('lung cancer', 'Disease', 'MESH:D008175', (346, 357))	('eGFR', 'Gene', '1956', (615, 619))
401728	31276202	The highest quintiles of circulating kynurenine, KTR, QA, and neopterin were associated with a 22-31% higher risk of lung cancer as compared with the lowest quintiles after controlling for smoking status, duration and intensity, circulating levels of cotinine, and other potential confounders (Table 2).	('KTR', 'Gene', (49, 52))	('kynurenine', 'Var', (37, 47))	('neopterin', 'Gene', (62, 71))	('cotinine', 'Chemical', 'MESH:D003367', (251, 259))	('lung cancer', 'Disease', (117, 128))	('KTR', 'Chemical', '-', (49, 52))	('lung cancer', 'Phenotype', 'HP:0100526', (117, 128))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('lung cancer', 'Disease', 'MESH:D008175', (117, 128))	('kynurenine', 'Chemical', 'MESH:D007737', (37, 47))	('QA', 'Chemical', 'MESH:D017378', (54, 56))	('neopterin', 'Chemical', 'MESH:D019798', (62, 71))
401729	31276202	In contrast, the highest quintile of tryptophan was associated with a 15% lower risk of lung cancer compared with the lowest quintile (Table 2).	('lung cancer', 'Disease', (88, 99))	('tryptophan', 'Var', (37, 47))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('lung cancer', 'Disease', 'MESH:D008175', (88, 99))	('tryptophan', 'Chemical', 'MESH:D014364', (37, 47))	('lower', 'NegReg', (74, 79))	('lung cancer', 'Phenotype', 'HP:0100526', (88, 99))
401751	31276202	The stronger associations between kynurenine or KTR and risk of lung cancer in individuals within <2 years of blood draw may reflect potential reverse causation.	('lung cancer', 'Disease', (64, 75))	('KTR', 'Chemical', '-', (48, 51))	('lung cancer', 'Phenotype', 'HP:0100526', (64, 75))	('kynurenine', 'Chemical', 'MESH:D007737', (34, 44))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('kynurenine', 'Var', (34, 44))	('lung cancer', 'Disease', 'MESH:D008175', (64, 75))	('KTR', 'Protein', (48, 51))
401754	31276202	Inhibition of IDO by 1-methyltryptophan significantly delayed the tumor outgrowth in a mouse model of Lewis Lung carcinoma .	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('mouse', 'Species', '10090', (87, 92))	('tumor', 'Disease', (66, 71))	('1-methyltryptophan', 'Chemical', 'MESH:C525396', (21, 39))	('Lung carcinoma', 'Disease', (108, 122))	('delayed', 'NegReg', (54, 61))	('Lung carcinoma', 'Disease', 'MESH:D008175', (108, 122))	('Inhibition', 'Var', (0, 10))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('IDO', 'Gene', (14, 17))
401755	31276202	Kynurenine can promote the proliferation of regulatory T cells, which suppress the antitumor immune response, contributing to cancer immune escape .	('promote', 'PosReg', (15, 22))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('suppress', 'NegReg', (70, 78))	('Kynurenine', 'Var', (0, 10))	('tumor', 'Disease', (87, 92))	('proliferation', 'CPA', (27, 40))	('cancer', 'Disease', (126, 132))	('contributing', 'Reg', (110, 122))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('regulatory T cells', 'CPA', (44, 62))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('Kynurenine', 'Chemical', 'MESH:D007737', (0, 10))
401758	31276202	Lung squamous cell carcinoma is more strongly associated with polycyclic aromatic hydrocarbons present in tobacco smoke  whereas adenocarcinoma is more strongly associated with tobacco-specific nitrosamines such as 4-(methylnitrosamine)-1-(3-pyridyl)-1-butanone (NNK) in animal models .	('adenocarcinoma', 'Disease', (129, 143))	('4-(methylnitrosamine)-1-(3-pyridyl)-1-butanone', 'Chemical', '-', (215, 261))	('polycyclic', 'Var', (62, 72))	('associated', 'Reg', (161, 171))	('nitrosamines', 'Chemical', 'MESH:D009602', (194, 206))	('NNK', 'Chemical', 'MESH:C016583', (263, 266))	('carcinoma', 'Phenotype', 'HP:0030731', (19, 28))	('Lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (0, 28))	('tobacco', 'Species', '4097', (106, 113))	('polycyclic aromatic hydrocarbons', 'Chemical', 'MESH:D011084', (62, 94))	('adenocarcinoma', 'Disease', 'MESH:D000230', (129, 143))	('Lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (0, 28))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (5, 28))	('associated', 'Reg', (46, 56))	('tobacco', 'Species', '4097', (177, 184))	('Lung squamous cell carcinoma', 'Disease', (0, 28))
401787	31760935	There is an opportunity for deep learning methods to analyze the lung cancer epigenetic data to determine their subtypes for appropriate treatment.	('lung cancer', 'Disease', 'MESH:D008175', (65, 76))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('epigenetic', 'Var', (77, 87))	('lung cancer', 'Disease', (65, 76))	('lung cancer', 'Phenotype', 'HP:0100526', (65, 76))
401795	31760935	In order to understand the heterogeneity of lung cancer, many researchers have done a lot of work based on immune-response genes, DNA mutations and DNA methylation.	('lung cancer', 'Phenotype', 'HP:0100526', (44, 55))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('lung cancer', 'Disease', 'MESH:D008175', (44, 55))	('mutations', 'Var', (134, 143))	('lung cancer', 'Disease', (44, 55))
401821	31760935	In this work, we demonstrate that the epigenetic data of lung cancer samples is capable of unsupervised deep learning with VAEs.	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('lung cancer', 'Disease', 'MESH:D008175', (57, 68))	('VAEs', 'Disease', (123, 127))	('epigenetic', 'Var', (38, 48))	('lung cancer', 'Disease', (57, 68))	('VAEs', 'Disease', 'MESH:C538007', (123, 127))	('lung cancer', 'Phenotype', 'HP:0100526', (57, 68))
401892	26557759	The presence of the higher content of IL-23 in supernatants of PBMCs was more frequent for tumours with more aggressive behaviour determined by higher total score of TFG scale (characterised by 14-21 points) in comparison with less invasive carcinomas (not exceeding 6-13 points in TFG) (p = 0.02).	('tumours', 'Phenotype', 'HP:0002664', (91, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (241, 250))	('carcinomas', 'Phenotype', 'HP:0030731', (241, 251))	('tumours', 'Disease', 'MESH:D009369', (91, 98))	('tumour', 'Phenotype', 'HP:0002664', (91, 97))	('IL-23', 'Gene', (38, 43))	('aggressive behaviour', 'Phenotype', 'HP:0000718', (109, 129))	('tumours', 'Disease', (91, 98))	('higher', 'PosReg', (144, 150))	('content', 'MPA', (27, 34))	('IL-23', 'Gene', '51561', (38, 43))	('invasive carcinomas', 'Disease', (232, 251))	('aggressive behaviour', 'CPA', (109, 129))	('invasive carcinomas', 'Disease', 'MESH:D009361', (232, 251))	('presence', 'Var', (4, 12))	('TFG', 'Chemical', '-', (282, 285))	('TFG', 'Chemical', '-', (166, 169))
401922	26557759	revealed two genetic variants for IL-23R, rs6682925, and rs10889677, which play a particular role in the pathogenesis of multiple cancers.	('rs6682925', 'Mutation', 'rs6682925', (42, 51))	('multiple cancers', 'Disease', (121, 137))	('cancers', 'Phenotype', 'HP:0002664', (130, 137))	('multiple cancers', 'Disease', 'MESH:D009369', (121, 137))	('rs6682925', 'Var', (42, 51))	('rs10889677', 'Var', (57, 67))	('IL-23R', 'Gene', (34, 40))	('rs10889677', 'Mutation', 'rs10889677', (57, 67))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('IL-23R', 'Gene', '149233', (34, 40))
401923	26557759	This was confirmed by Zhou et al., who in their studies pointed to the genetic variant rs10889677, which increases the probability of malignant transformation of a great number of solid tumours.	('solid tumours', 'Disease', (180, 193))	('rs10889677', 'Var', (87, 97))	('rs10889677', 'Mutation', 'rs10889677', (87, 97))	('tumour', 'Phenotype', 'HP:0002664', (186, 192))	('tumours', 'Phenotype', 'HP:0002664', (186, 193))	('malignant transformation', 'CPA', (134, 158))	('increases', 'PosReg', (105, 114))	('solid tumours', 'Disease', 'MESH:D009369', (180, 193))
401932	26557759	noted a significant association between IL-17F and IL-23R polymorphism and the location, histology, and architecture of tumours in patients with colorectal cancer (CRC).	('patients', 'Species', '9606', (131, 139))	('colorectal cancer', 'Disease', 'MESH:D015179', (145, 162))	('tumour', 'Phenotype', 'HP:0002664', (120, 126))	('IL-23R', 'Gene', '149233', (51, 57))	('polymorphism', 'Var', (58, 70))	('tumours', 'Phenotype', 'HP:0002664', (120, 127))	('IL-17F', 'Gene', (40, 46))	('colorectal cancer', 'Phenotype', 'HP:0003003', (145, 162))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('tumours', 'Disease', 'MESH:D009369', (120, 127))	('tumours', 'Disease', (120, 127))	('colorectal cancer', 'Disease', (145, 162))	('IL-23R', 'Gene', (51, 57))	('IL-17F', 'Gene', '112744', (40, 46))
401940	24671188	Mass-spectrometry based mutation analysis however is a relatively simple and high-throughput method suitable for formalin-fixed, paraffin-embedded (FFPE) tumour material.	('tumour', 'Phenotype', 'HP:0002664', (154, 160))	('tumour', 'Disease', 'MESH:D009369', (154, 160))	('formalin', 'Chemical', 'MESH:D005557', (113, 121))	('tumour', 'Disease', (154, 160))	('mutation', 'Var', (24, 32))	('paraffin', 'Chemical', 'MESH:D010232', (129, 137))
401944	24671188	Using frequency data from the online Catalogue of Somatic Mutations in Cancer, we selected 171 somatic hotspot mutations in the 13 most important genes for gynaecological cancers, being BRAF, CDKN2A, CTNNB1, FBXW7, FGFR2, FGFR3, FOXL2, HRAS, KRAS, NRAS, PIK3CA, PPP2R1A and PTEN.	('FGFR3', 'Gene', (222, 227))	('CTNNB1', 'Gene', '1499', (200, 206))	('PIK3CA', 'Gene', '5290', (254, 260))	('PTEN', 'Gene', (274, 278))	('KRAS', 'Gene', '3845', (242, 246))	('HRAS', 'Gene', '3265', (236, 240))	('FGFR3', 'Gene', '2261', (222, 227))	('HRAS', 'Gene', (236, 240))	('NRAS', 'Gene', (248, 252))	('mutations', 'Var', (111, 120))	('KRAS', 'Gene', (242, 246))	('PPP2R1A', 'Gene', '5518', (262, 269))	('CDKN2A', 'Gene', (192, 198))	('cancers', 'Disease', 'MESH:D009369', (171, 178))	('CTNNB1', 'Gene', (200, 206))	('PTEN', 'Gene', '5728', (274, 278))	('FBXW7', 'Gene', '55294', (208, 213))	('Cancer', 'Phenotype', 'HP:0002664', (71, 77))	('PPP2R1A', 'Gene', (262, 269))	('PIK3CA', 'Gene', (254, 260))	('FGFR2', 'Gene', (215, 220))	('CDKN2A', 'Gene', '1029', (192, 198))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('BRAF', 'Gene', '673', (186, 190))	('FOXL2', 'Gene', '668', (229, 234))	('BRAF', 'Gene', (186, 190))	('NRAS', 'Gene', '4893', (248, 252))	('FOXL2', 'Gene', (229, 234))	('cancers', 'Phenotype', 'HP:0002664', (171, 178))	('FGFR2', 'Gene', '2263', (215, 220))	('cancers', 'Disease', (171, 178))	('FBXW7', 'Gene', (208, 213))
401948	24671188	Evaluating a broad range of key cancer gene mutations across diverse cancers has the potential for identifying clinically relevant mutations.	('cancers', 'Disease', 'MESH:D009369', (69, 76))	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('cancers', 'Phenotype', 'HP:0002664', (69, 76))	('cancer', 'Disease', (32, 38))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('mutations', 'Var', (44, 53))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Disease', (69, 75))	('cancers', 'Disease', (69, 76))
401962	24671188	A meta-analysis of the COSMIC (Catalogue of Somatic Mutations in Cancer) online database, was performed to design a MALDI-TOF-based, high-throughput mutation panel that covers somatic mutations in 13 genes that are most frequently reported to be involved in gynaecological malignancies.	('malignancies', 'Disease', 'MESH:D009369', (273, 285))	('TOF', 'Gene', '55079', (122, 125))	('involved', 'Reg', (246, 254))	('mutations', 'Var', (184, 193))	('TOF', 'Gene', (122, 125))	('malignancies', 'Disease', (273, 285))	('Cancer', 'Phenotype', 'HP:0002664', (65, 71))
401970	24671188	Second, in order to cover a high percentage of the reported variants per gene, the most frequent mutations were selected to obtain a fair gynaecological-tissue-specific coverage, as only hotspot mutations were appropriate for analysis with the MALDI-TOF technique.	('mutations', 'Var', (97, 106))	('variants', 'Var', (60, 68))	('TOF', 'Gene', '55079', (250, 253))	('TOF', 'Gene', (250, 253))
401972	24671188	vulvar, cervical, endometrial or ovarian cancer), at least 30% of all reported mutations occurred on less than 10 different sites on the gene.	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('cervical', 'Disease', (8, 16))	('endometrial or ovarian cancer', 'Disease', (18, 47))	('ovarian cancer', 'Phenotype', 'HP:0100615', (33, 47))	('endometrial or ovarian cancer', 'Disease', 'MESH:D016889', (18, 47))	('occurred', 'Reg', (89, 97))	('mutations', 'Var', (79, 88))
401976	24671188	The first panel we designated 'GynCarta 1.0' (Sequenom, Hamburg, Germany) consisted of 89 assays (12 multiplexes) to detect 154 mutations in 12 genes that met our inclusion criteria: BRAF, CDKN2A, CTNNB1, FBXW7, FGFR2, FGFR3, FOXL2, HRAS, KRAS, NRAS, PIK3CA, and PTEN.	('CTNNB1', 'Gene', (197, 203))	('FOXL2', 'Gene', '668', (226, 231))	('PIK3CA', 'Gene', (251, 257))	('NRAS', 'Gene', '4893', (245, 249))	('FOXL2', 'Gene', (226, 231))	('CDKN2A', 'Gene', '1029', (189, 195))	('mutations', 'Var', (128, 137))	('FGFR3', 'Gene', (219, 224))	('KRAS', 'Gene', '3845', (239, 243))	('HRAS', 'Gene', '3265', (233, 237))	('FGFR3', 'Gene', '2261', (219, 224))	('FBXW7', 'Gene', (205, 210))	('HRAS', 'Gene', (233, 237))	('NRAS', 'Gene', (245, 249))	('PTEN', 'Gene', (263, 267))	('CTNNB1', 'Gene', '1499', (197, 203))	('KRAS', 'Gene', (239, 243))	('PIK3CA', 'Gene', '5290', (251, 257))	('FGFR2', 'Gene', (212, 217))	('PTEN', 'Gene', '5728', (263, 267))	('BRAF', 'Gene', '673', (183, 187))	('FBXW7', 'Gene', '55294', (205, 210))	('FGFR2', 'Gene', '2263', (212, 217))	('BRAF', 'Gene', (183, 187))	('CDKN2A', 'Gene', (189, 195))
401977	24671188	Mutant and wild type alleles were then discriminated using MALDI-TOF mass spectrometry.	('Mutant', 'Var', (0, 6))	('TOF', 'Gene', '55079', (65, 68))	('TOF', 'Gene', (65, 68))
401991	24671188	Furthermore, for a random30% (163 samples), KRAS and PIK3CA mutations were validated using allele-specific qPCR as described previously on 7 mutation variants of KRAS (p.G12C, p.G12R, p.G12S, p.G12V, p.G12A, p.G12D, p.G13D) and 3 mutation variants of PIK3CA (p.E542K, p.E545K, p.H1047R), and a concordance rate of 99.4% was attained.	('p.G12R', 'Var', (176, 182))	('PIK3CA', 'Gene', (251, 257))	('p.E545K', 'Var', (268, 275))	('KRAS', 'Gene', '3845', (162, 166))	('p.G13D', 'Var', (216, 222))	('p.G12V', 'Var', (192, 198))	('KRAS', 'Gene', (44, 48))	('p.G12S', 'Var', (184, 190))	('p.H1047R', 'Var', (277, 285))	('KRAS', 'Gene', (162, 166))	('p.G12A', 'Var', (200, 206))	('p.G12D', 'Var', (208, 214))	('p.G12A', 'Mutation', 'rs121913529', (200, 206))	('p.G13D', 'Mutation', 'rs112445441', (216, 222))	('p.E545K', 'Mutation', 'rs104886003', (268, 275))	('p.G12S', 'Mutation', 'rs121913530', (184, 190))	('PIK3CA', 'Gene', '5290', (53, 59))	('p.G12V', 'Mutation', 'rs121913529', (192, 198))	('p.H1047R', 'Mutation', 'rs121913279', (277, 285))	('p.G12R', 'Mutation', 'rs121913530', (176, 182))	('PIK3CA', 'Gene', '5290', (251, 257))	('p.G12C', 'Mutation', 'rs121913530', (168, 174))	('p.E542K', 'Mutation', 'rs121913273', (259, 266))	('p.G12C', 'Var', (168, 174))	('p.G12D', 'Mutation', 'rs121913529', (208, 214))	('p.E542K', 'Var', (259, 266))	('KRAS', 'Gene', '3845', (44, 48))	('PIK3CA', 'Gene', (53, 59))
401993	24671188	With the first mutational data from GynCarta 1.0 and literature reports of new oncogenic mutations, we were able to improve the GynCarta 1.0 panel by removing assays of mutations that were not detected (CDKN2A D108Y, D108XA, Y108XC; FGFR3 Y373C, A391E, K650Q, K650E, K650T, K650M, S371C; KRAS G13S and NRAS G13V, G13A, G13D, G13C, G13R, G13S) and by adding 10 new hotspot mutations of the already included genes.	('D108Y', 'Mutation', 'rs121913381', (210, 215))	('G13C', 'Mutation', 'rs121434595', (325, 329))	('G13S', 'Mutation', 'rs121913535', (293, 297))	('NRAS', 'Gene', '4893', (302, 306))	('KRAS', 'Gene', '3845', (288, 292))	('G13R', 'Mutation', 'rs121434595', (331, 335))	('CDKN2A', 'Gene', '1029', (203, 209))	('Y373C', 'Mutation', 'rs121913485', (239, 244))	('G13D', 'Mutation', 'rs112445441', (319, 323))	('D108XA', 'Var', (217, 223))	('Y373C', 'Var', (239, 244))	('KRAS', 'Gene', (288, 292))	('G13A', 'Mutation', 'rs121434596', (313, 317))	('G13A', 'Var', (313, 317))	('G13D', 'Var', (319, 323))	('K650T', 'Var', (267, 272))	('A391E', 'Var', (246, 251))	('K650Q', 'Var', (253, 258))	('S371C', 'Mutation', 'rs121913484', (281, 286))	('NRAS', 'Gene', (302, 306))	('D108XA', 'Mutation', 'p.D108XA', (217, 223))	('K650E', 'Mutation', 'rs78311289', (260, 265))	('G13S', 'Mutation', 'rs121913535', (337, 341))	('K650T', 'Mutation', 'rs121913105', (267, 272))	('G13C', 'Var', (325, 329))	('D108Y', 'Var', (210, 215))	('K650E', 'Var', (260, 265))	('FGFR3', 'Gene', (233, 238))	('FGFR3', 'Gene', '2261', (233, 238))	('Y108XC', 'Var', (225, 231))	('A391E', 'Mutation', 'rs28931615', (246, 251))	('K650M', 'Var', (274, 279))	('K650Q', 'Mutation', 'rs78311289', (253, 258))	('CDKN2A', 'Gene', (203, 209))	('K650M', 'Mutation', 'rs121913105', (274, 279))	('G13V', 'Mutation', 'rs121434596', (307, 311))
401996	24671188	The most mutations were detected in endometrial carcinomas (177 samples (64%)), followed by ovarian carcinomas (33 samples (37%)), cervical carcinomas (67 samples (33%)), and vulvar carcinomas (5 samples (20%)).	('mutations', 'Var', (9, 18))	('vulvar carcinomas', 'Phenotype', 'HP:0030416', (175, 192))	('carcinoma', 'Phenotype', 'HP:0030731', (48, 57))	('carcinomas', 'Phenotype', 'HP:0030731', (48, 58))	('cervical carcinomas', 'Disease', (131, 150))	('endometrial carcinomas', 'Disease', (36, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (182, 191))	('carcinomas', 'Phenotype', 'HP:0030731', (182, 192))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))	('carcinomas', 'Phenotype', 'HP:0030731', (140, 150))	('vulvar carcinomas', 'Disease', (175, 192))	('endometrial carcinomas', 'Disease', 'MESH:D016889', (36, 58))	('detected', 'Reg', (24, 32))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('carcinomas', 'Phenotype', 'HP:0030731', (100, 110))	('vulvar carcinomas', 'Disease', 'MESH:D014846', (175, 192))	('cervical carcinomas', 'Disease', 'MESH:D002575', (131, 150))	('ovarian carcinomas', 'Disease', 'MESH:D010051', (92, 110))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (36, 58))	('ovarian carcinomas', 'Disease', (92, 110))	('ovarian carcinomas', 'Phenotype', 'HP:0025318', (92, 110))
401997	24671188	PIK3CA was mutated most frequently (122 samples), followed by PTEN (97 samples) and KRAS (64 samples).	('PTEN', 'Gene', (62, 66))	('PTEN', 'Gene', '5728', (62, 66))	('KRAS', 'Gene', (84, 88))	('PIK3CA', 'Gene', (0, 6))	('PIK3CA', 'Gene', '5290', (0, 6))	('KRAS', 'Gene', '3845', (84, 88))	('mutated', 'Var', (11, 18))
401999	24671188	Mutation genotyping using GynCarta 2.0 detected an additional 36 mutations: 4 on FGFR2 and 5 on PIK3CA.	('FGFR2 and 5', 'Gene', '2263;53834', (81, 92))	('PIK3CA', 'Gene', (96, 102))	('PIK3CA', 'Gene', '5290', (96, 102))	('mutations', 'Var', (65, 74))
402000	24671188	PPP2R1A mutations were detected in 27 samples (7 cervical, 18 endometrial, 2 ovarian and 0 vulvar samples).	('PPP2R1A', 'Gene', '5518', (0, 7))	('PPP2R1A', 'Gene', (0, 7))	('detected', 'Reg', (23, 31))	('mutations', 'Var', (8, 17))
402001	24671188	PIK3CA mutations were detected twice as frequently as predicted in cervical cancer (N = 23 predicted and N = 51 detected) and in endometrial cancer (N = 32 predicted and N = 71 detected).	('endometrial cancer', 'Phenotype', 'HP:0012114', (129, 147))	('cervical cancer', 'Disease', (67, 82))	('endometrial cancer', 'Disease', 'MESH:D016889', (129, 147))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('PIK3CA', 'Gene', (0, 6))	('PIK3CA', 'Gene', '5290', (0, 6))	('endometrial cancer', 'Disease', (129, 147))	('cervical cancer', 'Disease', 'MESH:D002583', (67, 82))	('mutations', 'Var', (7, 16))
402002	24671188	PTEN mutations were also detected more frequently in endometrial cancer than predicted (N = 35 predicted and N = 104 detected).	('endometrial cancer', 'Disease', 'MESH:D016889', (53, 71))	('endometrial cancer', 'Disease', (53, 71))	('mutations', 'Var', (5, 14))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('endometrial cancer', 'Phenotype', 'HP:0012114', (53, 71))	('PTEN', 'Gene', (0, 4))	('PTEN', 'Gene', '5728', (0, 4))	('detected', 'Reg', (25, 33))
402003	24671188	However, no PTEN mutations were detected in vulvar cancer although N = 8 mutations were predicted.	('vulvar cancer', 'Disease', (44, 57))	('vulvar cancer', 'Disease', 'MESH:D014846', (44, 57))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('PTEN', 'Gene', (12, 16))	('PTEN', 'Gene', '5728', (12, 16))	('mutations', 'Var', (17, 26))	('vulvar cancer', 'Phenotype', 'HP:0030416', (44, 57))
402013	24671188	In endometrial (and ovarian cancer), PIK3CA mutations are found most frequently on hotspots located on exon 9 and exon 20, with an even distribution between these exons (33% and 45%).	('PIK3CA', 'Gene', '5290', (37, 43))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('ovarian cancer', 'Phenotype', 'HP:0100615', (20, 34))	('ovarian cancer', 'Disease', 'MESH:D010051', (20, 34))	('mutations', 'Var', (44, 53))	('ovarian cancer', 'Disease', (20, 34))	('endometrial', 'Disease', (3, 14))	('found', 'Reg', (58, 63))	('PIK3CA', 'Gene', (37, 43))
402014	24671188	In cervical cancer however, mutations almost exclusively occur on loci on exon 9 (47 out of 50 (94%) PIK3CA mutations).	('PIK3CA', 'Gene', '5290', (101, 107))	('mutations', 'Var', (108, 117))	('cervical cancer', 'Disease', 'MESH:D002583', (3, 18))	('cervical cancer', 'Disease', (3, 18))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('mutations', 'Var', (28, 37))	('PIK3CA', 'Gene', (101, 107))	('occur', 'Reg', (57, 62))
402025	24671188	Therefore, we created a MALDI-TOF-based mutation panel designed specifically to detect a wide range of the most common hotspot mutations that have been reported in various types of gynaecological tumours.	('tumour', 'Phenotype', 'HP:0002664', (196, 202))	('tumours', 'Phenotype', 'HP:0002664', (196, 203))	('TOF', 'Gene', '55079', (30, 33))	('tumours', 'Disease', 'MESH:D009369', (196, 203))	('tumours', 'Disease', (196, 203))	('mutations', 'Var', (127, 136))	('TOF', 'Gene', (30, 33))
402030	24671188	From other studies using different techniques, it is known that KRAS is mutated in 15-20% of all endometrial cancers.	('mutated', 'Var', (72, 79))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('cancers', 'Phenotype', 'HP:0002664', (109, 116))	('KRAS', 'Gene', (64, 68))	('endometrial cancer', 'Phenotype', 'HP:0012114', (97, 115))	('endometrial cancers', 'Disease', 'MESH:D016889', (97, 116))	('KRAS', 'Gene', '3845', (64, 68))	('endometrial cancers', 'Disease', (97, 116))
402032	24671188	Satisfactory coverage of the genes in our panel was achieved for the mutations we studied, and the mutation spectra generated in this study are thus a reliable representation of the mutation frequencies in gynaecological malignancies in the genes that are selected for this panel.	('mutations', 'Var', (69, 78))	('malignancies', 'Disease', (221, 233))	('malignancies', 'Disease', 'MESH:D009369', (221, 233))
402034	24671188	Both genes have mutations scattered widely throughout the gene and were therefore not suited for a MALDI-TOF approach.	('mutations', 'Var', (16, 25))	('TOF', 'Gene', '55079', (105, 108))	('TOF', 'Gene', (105, 108))
402039	24671188	Additionally, loss of PTEN can also be caused by other molecular alterations, such as LOH and promoter hypermethylation.	('promoter hypermethylation', 'Var', (94, 119))	('LOH', 'Var', (86, 89))	('PTEN', 'Gene', (22, 26))	('caused', 'Reg', (39, 45))	('PTEN', 'Gene', '5728', (22, 26))	('loss', 'NegReg', (14, 18))
402043	24671188	However, since CDKN2A mutations in squamous cell carcinoma of the skin are reported to be more often point mutations than (large) deletions, we believe that adding CDKN2A point mutations to the panel can give valuable information, especially for vulvar cancer.	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('squamous cell carcinoma of the skin', 'Phenotype', 'HP:0006739', (35, 70))	('CDKN2A', 'Gene', (15, 21))	('squamous cell carcinoma of the skin', 'Disease', 'MESH:D002294', (35, 70))	('vulvar cancer', 'Disease', 'MESH:D014846', (246, 259))	('cancer', 'Phenotype', 'HP:0002664', (253, 259))	('CDKN2A', 'Gene', '1029', (15, 21))	('CDKN2A', 'Gene', (164, 170))	('mutations', 'Var', (22, 31))	('squamous cell carcinoma of the skin', 'Disease', (35, 70))	('CDKN2A', 'Gene', '1029', (164, 170))	('vulvar cancer', 'Disease', (246, 259))	('vulvar cancer', 'Phenotype', 'HP:0030416', (246, 259))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (35, 58))
402044	24671188	Although numbers are very low, results from research on CDKN2A imutations in vulvar and penile squamous cell carcinoma strengthen this hypothesis.	('penile squamous cell carcinoma', 'Disease', 'MESH:D004414', (88, 118))	('penile squamous cell carcinoma', 'Disease', (88, 118))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (95, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('vulvar', 'Disease', (77, 83))	('imutations', 'Var', (63, 73))	('CDKN2A', 'Gene', (56, 62))	('CDKN2A', 'Gene', '1029', (56, 62))
402045	24671188	FBXW7 appears to have a low coverage by the panel, but this is influenced by the fact that it has been investigated and found to be mutated in relatively small numbers of gynaecological tumours.	('FBXW7', 'Gene', '55294', (0, 5))	('tumours', 'Disease', 'MESH:D009369', (186, 193))	('tumours', 'Disease', (186, 193))	('mutated', 'Var', (132, 139))	('FBXW7', 'Gene', (0, 5))	('tumour', 'Phenotype', 'HP:0002664', (186, 192))	('tumours', 'Phenotype', 'HP:0002664', (186, 193))
402047	24671188	In comparison, MALDI-TOF data analysis is much more straightforward, particularly when analysing mutations with known clinical relevance.	('TOF', 'Gene', '55079', (21, 24))	('mutations', 'Var', (97, 106))	('TOF', 'Gene', (21, 24))
402048	24671188	The panel we present here covers the most frequent mutations in gynaecological cancers, with a few exceptions.	('cancers', 'Disease', (79, 86))	('mutations', 'Var', (51, 60))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('cancers', 'Disease', 'MESH:D009369', (79, 86))
402052	24671188	Mutations in the PI3K/Akt-pathway are frequent and overlap, however some distinguishing mutations were identified.	('Mutations', 'Var', (0, 9))	('Akt', 'Gene', '207', (22, 25))	('Akt', 'Gene', (22, 25))
402053	24671188	An example is the finding that PIK3CA exon 20 mutations only rarely occur in cervical cancer, whereas they are a frequent finding in endometrial cancers.	('endometrial cancer', 'Phenotype', 'HP:0012114', (133, 151))	('occur', 'Reg', (68, 73))	('mutations', 'Var', (46, 55))	('endometrial cancers', 'Disease', 'MESH:D016889', (133, 152))	('cervical cancer', 'Disease', (77, 92))	('endometrial cancers', 'Disease', (133, 152))	('cervical cancer', 'Disease', 'MESH:D002583', (77, 92))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('PIK3CA', 'Gene', (31, 37))	('PIK3CA', 'Gene', '5290', (31, 37))	('cancers', 'Phenotype', 'HP:0002664', (145, 152))
402064	24671188	In conclusion, we designed, validated and used a novel mass spectrometry-based mutation panel to identify somatic mutations in a large cohort of gynaecological malignancies.	('mutations', 'Var', (114, 123))	('gynaecological', 'Disease', (145, 159))	('malignancies', 'Disease', (160, 172))	('malignancies', 'Disease', 'MESH:D009369', (160, 172))
402158	33477333	The cell construction with knockdown of SAE1 was verified by genomic sequencing and quantitative real-time PCR.	('knockdown', 'Var', (27, 36))	('SAE1', 'Gene', '10055', (40, 44))	('SAE1', 'Gene', (40, 44))
402186	33477333	Results of both univariate and multivariate analyses revealed that high SAE1 protein expression level is strongly associated with metastasis (Table 2).	('SAE1', 'Gene', '10055', (72, 76))	('high', 'Var', (67, 71))	('metastasis', 'CPA', (130, 140))	('associated', 'Reg', (114, 124))	('SAE1', 'Gene', (72, 76))
402192	33477333	We demonstrated that patients with high SAE1 expression exhibited worse overall survival (OS) (HR = 1.873, p = 0.0004), disease-survival (DSS) (HR = 2.070, p = 0.0016), and progression-free survival (PFS) (HR = 1.809, p < 0.0001) over a follow-up period of 10 years (Figure 4A-C).	('SAE1', 'Gene', (40, 44))	('overall survival', 'CPA', (72, 88))	('worse', 'NegReg', (66, 71))	('disease-survival', 'CPA', (120, 136))	('SAE1', 'Gene', '10055', (40, 44))	('patients', 'Species', '9606', (21, 29))	('progression-free survival', 'CPA', (173, 198))	('high', 'Var', (35, 39))
402200	33477333	To gain inside into the significance of SAE1 in hepatocarcinogenesis, we knocked down the gene using CRISPRi and validated the knockdown efficacy by real-time PCR analysis.	('hepatocarcinogenesis', 'Disease', 'MESH:D063646', (48, 68))	('SAE1', 'Gene', (40, 44))	('SAE1', 'Gene', '10055', (40, 44))	('hepatocarcinogenesis', 'Disease', (48, 68))	('knocked', 'Var', (73, 80))
402202	33477333	Consistent with these data, results of our western blot analysis show that silencing SAE1, elicited upregulated expression of drivers of cancer progression CDK4 and cyclin B1 (a CCNB1 gene product), concomitantly with downregulated tumor suppressors FOXO1 and KLF9 proteins in HCC cell line Huh7 (Figure 5E).	('cyclin B1', 'Gene', '891', (165, 174))	('downregulated', 'NegReg', (218, 231))	('cyclin B1', 'Gene', (165, 174))	('CDK4', 'Gene', (156, 160))	('cancer', 'Disease', (137, 143))	('upregulated', 'PosReg', (100, 111))	('expression', 'MPA', (112, 122))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('CDK4', 'Gene', '1019', (156, 160))	('HCC', 'Gene', '619501', (277, 280))	('SAE1', 'Gene', (85, 89))	('CCNB1', 'Gene', (178, 183))	('SAE1', 'Gene', '10055', (85, 89))	('tumor', 'Disease', (232, 237))	('FOXO1', 'Gene', '2308', (250, 255))	('KLF9', 'Gene', '687', (260, 264))	('HCC', 'Gene', (277, 280))	('tumor', 'Disease', 'MESH:D009369', (232, 237))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('silencing', 'Var', (75, 84))	('Huh7', 'CellLine', 'CVCL:0336', (291, 295))	('FOXO1', 'Gene', (250, 255))	('KLF9', 'Gene', (260, 264))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('CCNB1', 'Gene', '891', (178, 183))
402211	33477333	Recently, it was reported that the SUMO2-mediated SUMOylation of the supposedly tumor suppressor, liver kinase B1 (LKB1), facilitated hepatocarcinogenesis and disease progression in in vivo mice models and human HCC cohort, especially in hypoxic conditions.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('hepatocarcinogenesis', 'Disease', (134, 154))	('disease progression', 'CPA', (159, 178))	('human', 'Species', '9606', (206, 211))	('HCC', 'Gene', (212, 215))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('hypoxic conditions', 'Disease', 'MESH:D000071069', (238, 256))	('liver kinase B1', 'Gene', '20869', (98, 113))	('tumor', 'Disease', (80, 85))	('LKB1', 'Gene', (115, 119))	('facilitated', 'PosReg', (122, 133))	('HCC', 'Gene', '619501', (212, 215))	('liver kinase B1', 'Gene', (98, 113))	('SUMOylation', 'Var', (50, 61))	('hypoxic conditions', 'Disease', (238, 256))	('LKB1', 'Gene', '20869', (115, 119))	('mice', 'Species', '10090', (190, 194))	('hepatocarcinogenesis', 'Disease', 'MESH:D063646', (134, 154))
402214	33477333	Accruing evidence from numerous studies have suggested that dysregulated SAE1 expression and/or activity contributes to uncontrolled cell proliferation, development of cancer, angiogenesis, invasion and metastasis.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('uncontrolled', 'MPA', (120, 132))	('activity', 'MPA', (96, 104))	('expression', 'MPA', (78, 88))	('SAE1', 'Gene', '10055', (73, 77))	('dysregulated', 'Var', (60, 72))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('cancer', 'Disease', (168, 174))	('SAE1', 'Gene', (73, 77))	('angiogenesis', 'CPA', (176, 188))	('contributes', 'Reg', (105, 116))	('metastasis', 'CPA', (203, 213))
402219	33477333	Additionally, and with clinical relevance, we demonstrated that the overexpression of SAE1 is associated with poor prognosis, as evident in the shorter overall or disease-specific, and relapse-free survival time of patients with high expression of SAE1 in our HCC cohort and freely accessible larger HCC cohorts.	('patients', 'Species', '9606', (215, 223))	('SAE1', 'Gene', '10055', (86, 90))	('SAE1', 'Gene', (86, 90))	('shorter', 'NegReg', (144, 151))	('HCC', 'Gene', '619501', (260, 263))	('overexpression', 'PosReg', (68, 82))	('HCC', 'Gene', (300, 303))	('relapse-free survival time', 'CPA', (185, 211))	('SAE1', 'Gene', (248, 252))	('HCC', 'Gene', '619501', (300, 303))	('HCC', 'Gene', (260, 263))	('SAE1', 'Gene', '10055', (248, 252))	('high', 'Var', (229, 233))
402222	33477333	This is consistent with contemporary knowledge that loss of FOXO1 promotes tumor growth and metastasis, and accruing evidence that SUMOs such as SAE1 are essential for the regulation of several cellular processes, including transcriptional regulation, transcript processing, genomic replication and DNA damage repair, where efficiency or inefficiency of the later determines initiation of mitosis or delayed mitotic entry, S-phase arrest, and altered cell cycle progression; this has significant implication for diseases such as cancer, and suggests that SAE1 is a potential therapeutic target for patients with HCC.	('HCC', 'Gene', '619501', (612, 615))	('SAE1', 'Gene', (555, 559))	('arrest', 'Disease', 'MESH:D006323', (431, 437))	('SAE1', 'Gene', '10055', (555, 559))	('HCC', 'Gene', (612, 615))	('cancer', 'Disease', 'MESH:D009369', (529, 535))	('tumor', 'Disease', (75, 80))	('altered', 'Reg', (443, 450))	('metastasis', 'CPA', (92, 102))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('initiation of mitosis', 'Disease', 'MESH:D007319', (375, 396))	('patients', 'Species', '9606', (598, 606))	('FOXO1', 'Gene', '2308', (60, 65))	('loss', 'Var', (52, 56))	('promotes', 'PosReg', (66, 74))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('arrest', 'Disease', (431, 437))	('cancer', 'Disease', (529, 535))	('SAE1', 'Gene', (145, 149))	('FOXO1', 'Gene', (60, 65))	('cell cycle progression', 'CPA', (451, 473))	('SAE1', 'Gene', '10055', (145, 149))	('cancer', 'Phenotype', 'HP:0002664', (529, 535))	('initiation of mitosis', 'Disease', (375, 396))
402224	33477333	Similarly, the prognostic relevance of SAE1 expression was shown with stage dependent AUCs ranging from 0.9091 for stage I to 1.00 for stage IV, and Kaplan-Meier plots indicating worse clinical outcome for patients with high SAE1 expression compared to their counterparts with low SAE1 expression.	('SAE1', 'Gene', (225, 229))	('SAE1', 'Gene', '10055', (225, 229))	('SAE1', 'Gene', (281, 285))	('SAE1', 'Gene', (39, 43))	('SAE1', 'Gene', '10055', (281, 285))	('high', 'Var', (220, 224))	('SAE1', 'Gene', '10055', (39, 43))	('patients', 'Species', '9606', (206, 214))	('expression', 'Var', (230, 240))
402235	32493705	Novel variants of ELP2 and PIAS1 in the interferon gamma signaling pathway are associated with non-small cell lung cancer survival Interferon gamma (IFNgamma) is a pleiotropic cytokine that plays critical immunomodulatory roles in intercellular communication in innate and adaptive immune responses.	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (95, 121))	('cancer', 'Disease', (115, 121))	('associated', 'Reg', (79, 89))	('IFNgamma', 'Gene', (149, 157))	('variants', 'Var', (6, 14))	('IFNgamma', 'Gene', '3458', (149, 157))	('interferon gamma', 'Gene', '3458', (40, 56))	('Interferon gamma', 'Gene', '3458', (131, 147))	('Interferon gamma', 'Gene', (131, 147))	('PIAS1', 'Gene', '8554', (27, 32))	('ELP2', 'Gene', (18, 22))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('ELP2', 'Gene', '55250', (18, 22))	('lung cancer', 'Phenotype', 'HP:0100526', (110, 121))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (99, 121))	('PIAS1', 'Gene', (27, 32))	('interferon gamma', 'Gene', (40, 56))	('cancer', 'Disease', 'MESH:D009369', (115, 121))
402238	32493705	The combined analysis identified two independent potentially functional single-nucleotide polymorphisms (SNPs), ELP2 rs7242481G>A and PIAS1 rs1049493T>C, to be significantly associated with NSCLC survival, with a combined hazards ratio (HR) of 0.85 [95% CI= 0.78-0.92, P<0.0001] and 0.87 (0.81-0.93, P<0.0001), respectively.	('associated with', 'Reg', (174, 189))	('ELP2', 'Gene', '55250', (112, 116))	('PIAS1', 'Gene', '8554', (134, 139))	('rs1049493T>C', 'DBSNP_MENTION', 'None', (140, 152))	('rs7242481G>A', 'DBSNP_MENTION', 'None', (117, 129))	('ELP2', 'Gene', (112, 116))	('PIAS1', 'Gene', (134, 139))	('NSCLC', 'Disease', (190, 195))	('rs1049493T>C', 'Var', (140, 152))	('NSCLC', 'Disease', 'MESH:D002289', (190, 195))	('rs7242481G>A', 'Var', (117, 129))
402239	32493705	Expression quantitative trait loci analyses showed that the survival-associated ELP2 rs7242481A allele was significantly associated with increased mRNA expression levels of ELP2 in 373 lymphoblastoid cell lines and 369 whole blood samples.	('ELP2', 'Gene', (173, 177))	('rs7242481A', 'Var', (85, 95))	('rs7242481', 'Mutation', 'rs7242481', (85, 94))	('mRNA expression levels', 'MPA', (147, 169))	('increased', 'PosReg', (137, 146))	('ELP2', 'Gene', (80, 84))	('ELP2', 'Gene', '55250', (80, 84))	('ELP2', 'Gene', '55250', (173, 177))
402240	32493705	The PIAS1 rs1049493C allele was significantly associated with decreased mRNA expression levels of PIAS1 in 383 normal lung tissues and 369 whole blood samples.	('PIAS1', 'Gene', (98, 103))	('PIAS1', 'Gene', '8554', (4, 9))	('decreased', 'NegReg', (62, 71))	('PIAS1', 'Gene', (4, 9))	('rs1049493C', 'Var', (10, 20))	('rs1049493', 'Mutation', 'rs1049493', (10, 19))	('mRNA expression levels', 'MPA', (72, 94))	('PIAS1', 'Gene', '8554', (98, 103))
402241	32493705	Genetic variants of IFNgamma signaling genes are potential prognostic markers for NSCLC survival, likely through modulating the expression of key genes involved in host immune response.	('modulating', 'Reg', (113, 123))	('IFNgamma', 'Gene', (20, 28))	('expression', 'MPA', (128, 138))	('IFNgamma', 'Gene', '3458', (20, 28))	('NSCLC', 'Disease', (82, 87))	('Genetic variants', 'Var', (0, 16))	('NSCLC', 'Disease', 'MESH:D002289', (82, 87))
402242	32493705	Once validated, these variants could be useful predictors of NSCLC survival.	('NSCLC', 'Disease', 'MESH:D002289', (61, 66))	('variants', 'Var', (22, 30))	('NSCLC', 'Disease', (61, 66))
402251	32493705	To date, genome-wide association studies (GWASs) investigating millions of SNPs at the same time have identified few SNPs that are associated with cancer survival, because a hypothesis-free GWAS focuses on the most-significant SNPs or genes with a significant P value after the stringent multiple testing correction.	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('associated', 'Reg', (131, 141))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('cancer', 'Disease', (147, 153))	('SNPs', 'Var', (227, 231))
402257	32493705	Furthermore, the roles of genetic variants of candidate IFNgamma signaling genes and their biological functions in tumor growth or suppression remain unknown.	('IFNgamma', 'Gene', (56, 64))	('variants', 'Var', (34, 42))	('IFNgamma', 'Gene', '3458', (56, 64))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumor', 'Disease', (115, 120))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
402258	32493705	In the present study, therefore, we hypothesize that genetic variants in genes related to the IFNgamma signaling pathway, a critical cascade in the activation of both innate and adaptive immune responses, are associated with the survival of NSCLC patients.	('associated with', 'Reg', (209, 224))	('IFNgamma', 'Gene', (94, 102))	('genetic variants', 'Var', (53, 69))	('NSCLC', 'Disease', (241, 246))	('survival', 'MPA', (229, 237))	('IFNgamma', 'Gene', '3458', (94, 102))	('NSCLC', 'Disease', 'MESH:D002289', (241, 246))	('patients', 'Species', '9606', (247, 255))
402272	32493705	After multiple testing correction by BFDP<=0.80, we identified 340 SNPs that were significantly associated with NSCLC OS (P<0.05), of which 48 SNPs in two genes remained significant after further replication by the HLCS genotyping dataset.	('associated with', 'Reg', (96, 111))	('SNPs', 'Var', (67, 71))	('NSCLC OS', 'Disease', (112, 120))	('NSCLC OS', 'Disease', 'MESH:C567932', (112, 120))
402275	32493705	In the PLCO dataset with complete adjustment for available covariates, patients with the protective ELP2 rs7242481 A (i.e., GA+AA) allele or PIAS1 rs1049493 C (i.e., TC+CC) allele had a better OS and DSS (Ptrend=0.004 and Ptrend=0.009 for ELP2 rs7242481 A, respectively; Ptrend=0.006 and Ptrend=0.023 PIAS1 rs1049493 C, respectively) (Table 3).	('ELP2', 'Gene', '55250', (239, 243))	('rs7242481', 'Mutation', 'rs7242481', (244, 253))	('PIAS1', 'Gene', (301, 306))	('DSS', 'Gene', (200, 203))	('ELP2', 'Gene', (239, 243))	('patients', 'Species', '9606', (71, 79))	('DSS', 'Gene', '5376', (200, 203))	('ELP2', 'Gene', (100, 104))	('ELP2', 'Gene', '55250', (100, 104))	('OS', 'Chemical', '-', (193, 195))	('rs7242481 A', 'Var', (105, 116))	('PIAS1', 'Gene', '8554', (141, 146))	('better', 'PosReg', (186, 192))	('rs1049493', 'Mutation', 'rs1049493', (147, 156))	('rs7242481', 'Mutation', 'rs7242481', (105, 114))	('PIAS1', 'Gene', (141, 146))	('PIAS1', 'Gene', '8554', (301, 306))	('rs1049493', 'Mutation', 'rs1049493', (307, 316))
402278	32493705	We first combined the significant protective genotypes (i.e., ELP2 rs7242481 TA+AA and PIAS1 rs1049493 CC into a genetic score as the number of protective genotypes (NPGs).	('rs1049493', 'Mutation', 'rs1049493', (93, 102))	('PIAS1', 'Gene', '8554', (87, 92))	('rs7242481 TA+AA', 'Var', (67, 82))	('ELP2', 'Gene', '55250', (62, 66))	('ELP2', 'Gene', (62, 66))	('rs7242481', 'Mutation', 'rs7242481', (67, 76))	('PIAS1', 'Gene', (87, 92))	('rs1049493 CC', 'Var', (93, 105))
402279	32493705	As shown in Table 3, the increased genetic score of the NPGs was associated with a better survival in the multivariate analysis in the PLCO dataset (Ptrend<0.0004 for OS and Ptrend=0.002 for DSS).	('DSS', 'Gene', (191, 194))	('increased', 'PosReg', (25, 34))	('DSS', 'Gene', '5376', (191, 194))	('NPGs', 'Gene', (56, 60))	('better', 'PosReg', (83, 89))	('OS', 'Chemical', '-', (167, 169))	('survival', 'CPA', (90, 98))	('genetic score', 'Var', (35, 48))
402281	32493705	As shown in Table 3, the increased genetic score of the NPAs was associated with a better survival in the multivariate analysis in the PLCO dataset (Ptrend<0.0001 for OS and Ptrend=0.0006 for DSS).	('increased', 'PosReg', (25, 34))	('NPAs', 'Gene', (56, 60))	('DSS', 'Gene', (192, 195))	('DSS', 'Gene', '5376', (192, 195))	('better', 'PosReg', (83, 89))	('OS', 'Chemical', '-', (167, 169))	('survival', 'CPA', (90, 98))	('genetic score', 'Var', (35, 48))
402282	32493705	When we dichotomized all the patients into genetic scores of 0-1 and 2-4 NPAs, the 2-4 score group had a significantly better survival (HR=0.77, 95% CI=0.67-0.89, P=0.0004 for OS and HR=0.79, 95% CI=0.68-0.91, P=0.002 for DSS), in comparison with the 0-1 score group.	('patients', 'Species', '9606', (29, 37))	('OS', 'Chemical', '-', (176, 178))	('2-4 score', 'Var', (83, 92))	('better', 'PosReg', (119, 125))	('survival', 'CPA', (126, 134))	('DSS', 'Gene', (222, 225))	('DSS', 'Gene', '5376', (222, 225))
402289	32493705	In the RNA-Seq data of lymphoblastoid cell lines from 373 European descendants available from the 1000 Genomes Project, the ELP2 rs7242481 A allele showed a significant correlation with increased mRNA expression levels of ELP2 in all additive, dominant and recessive models (P=9.8x10-5, P=0.005 and P<2x10-4, respectively; Figure 3a, Supplementary Figure 8a and 8b); however, there was no significant correlation between the PIAS1 rs1049493 C allele and mRNA expression levels of PIAS1 in all three genetic models (Figure 3d, Supplementary Figure 8c and 8d).	('ELP2', 'Gene', (222, 226))	('PIAS1', 'Gene', (480, 485))	('ELP2', 'Gene', '55250', (222, 226))	('PIAS1', 'Gene', '8554', (425, 430))	('increased', 'PosReg', (186, 195))	('PIAS1', 'Gene', (425, 430))	('rs1049493', 'Mutation', 'rs1049493', (431, 440))	('ELP2', 'Gene', (124, 128))	('rs1049493 C', 'Var', (431, 442))	('ELP2', 'Gene', '55250', (124, 128))	('rs7242481', 'Mutation', 'rs7242481', (129, 138))	('mRNA expression levels', 'MPA', (196, 218))	('rs7242481 A', 'Var', (129, 140))	('mRNA expression levels', 'MPA', (454, 476))	('PIAS1', 'Gene', '8554', (480, 485))
402290	32493705	Then, we performed eQTL by using the data of 369 whole blood samples and 383 normal lung tissue from the GTEx project and found that the rs7242481 A allele remained significantly correlated with a higher expression level of ELP2 in whole blood samples but not in normal lung tissues (P=2.63x10-15 and P=0.141, respectively) (Figure 3c and 3b).	('higher', 'PosReg', (197, 203))	('ELP2', 'Gene', '55250', (224, 228))	('ELP2', 'Gene', (224, 228))	('expression level', 'MPA', (204, 220))	('rs7242481 A', 'Var', (137, 148))	('rs7242481', 'Mutation', 'rs7242481', (137, 146))
402291	32493705	The rs1049493 C allele was correlated with a lower expression level of PIAS1 in both normal lung tissues and whole blood (P=0.008 and P=0.0002) (Figure 3e and 3f).	('PIAS1', 'Gene', '8554', (71, 76))	('rs1049493 C', 'Var', (4, 15))	('PIAS1', 'Gene', (71, 76))	('lower', 'NegReg', (45, 50))	('rs1049493', 'Mutation', 'rs1049493', (4, 13))	('expression level', 'MPA', (51, 67))
402299	32493705	In the present study, we identified and validated two potentially functional and independent SNPs (i.e., ELP2 rs7242481 and PIAS1 rs1049493) that were significantly associated with the survival of NSCLC in Caucasian populations.	('ELP2', 'Gene', '55250', (105, 109))	('rs7242481', 'Mutation', 'rs7242481', (110, 119))	('rs7242481', 'Var', (110, 119))	('associated with', 'Reg', (165, 180))	('NSCLC', 'Disease', 'MESH:D002289', (197, 202))	('PIAS1', 'Gene', (124, 129))	('rs1049493', 'Mutation', 'rs1049493', (130, 139))	('PIAS1', 'Gene', '8554', (124, 129))	('NSCLC', 'Disease', (197, 202))	('rs1049493', 'Var', (130, 139))	('ELP2', 'Gene', (105, 109))
402300	32493705	We also found that ELP2 rs7242481 A allele was significantly associated with an increased mRNA expression of ELP2 in 373 lymphoblastoid cell lines from the 1000 Genomes Project and an increased mRNA expression level in 369 whole blood samples from the GTEx project.	('ELP2', 'Gene', (109, 113))	('rs7242481', 'Mutation', 'rs7242481', (24, 33))	('increased', 'PosReg', (80, 89))	('increased', 'PosReg', (184, 193))	('ELP2', 'Gene', (19, 23))	('mRNA expression level', 'MPA', (194, 215))	('ELP2', 'Gene', '55250', (19, 23))	('ELP2', 'Gene', '55250', (109, 113))	('mRNA expression', 'MPA', (90, 105))	('rs7242481 A', 'Var', (24, 35))
402301	32493705	Additionally, we also found that PIAS1 rs1049493 C allele was significantly associated with a lower mRNA expression level of PIAS1 in 383 normal lung tissues and 369 whole blood samples from the GTEx project.	('PIAS1', 'Gene', (33, 38))	('rs1049493', 'Mutation', 'rs1049493', (39, 48))	('mRNA expression level', 'MPA', (100, 121))	('PIAS1', 'Gene', '8554', (125, 130))	('lower', 'NegReg', (94, 99))	('rs1049493 C', 'Var', (39, 50))	('PIAS1', 'Gene', '8554', (33, 38))	('PIAS1', 'Gene', (125, 130))
402307	32493705	In the present study, we found that the rs7242481 A allele was significantly associated with an increased mRNA expression level of ELP2 in lymphoblastoid cell lines and whole blood tissues; this finding is consistent with the results from other studies, suggesting that the novel genetic variant rs7242481 A allele may affect survival of NSCLC patients through increasing ELP2 mRNA expression, likely inhibiting oncogenic effects of the activated STAT3.	('mRNA expression level', 'MPA', (106, 127))	('survival', 'CPA', (326, 334))	('rs7242481 A', 'Var', (296, 307))	('rs7242481', 'Mutation', 'rs7242481', (296, 305))	('NSCLC', 'Disease', (338, 343))	('rs7242481', 'Mutation', 'rs7242481', (40, 49))	('rs7242481 A', 'Var', (40, 51))	('ELP2', 'Gene', '55250', (372, 376))	('NSCLC', 'Disease', 'MESH:D002289', (338, 343))	('STAT3', 'Gene', '6774', (447, 452))	('affect', 'Reg', (319, 325))	('increasing', 'PosReg', (361, 371))	('ELP2', 'Gene', '55250', (131, 135))	('ELP2', 'Gene', (372, 376))	('ELP2', 'Gene', (131, 135))	('STAT3', 'Gene', (447, 452))	('patients', 'Species', '9606', (344, 352))
402310	32493705	According to the ENCODE database, ELP2 rs7242481G>A is located in a DNase I hypersensitive site with highly observable levels of histone modifications in H3K4Me3 and H3K27Ac acetylation, suggesting that the ELP2 rs7242481 G>A SNP may lead to significantly enhanced transcriptional activities of ELP2.	('enhanced', 'PosReg', (256, 264))	('ELP2', 'Gene', (295, 299))	('rs7242481G>A', 'Var', (39, 51))	('ELP2', 'Gene', '55250', (295, 299))	('ELP2', 'Gene', '55250', (34, 38))	('ELP2', 'Gene', '55250', (207, 211))	('ELP2', 'Gene', (34, 38))	('rs7242481 G>A', 'Var', (212, 225))	('transcriptional activities', 'MPA', (265, 291))	('rs7242481G>A', 'DBSNP_MENTION', 'None', (39, 51))	('rs7242481', 'Mutation', 'rs7242481', (39, 48))	('ELP2', 'Gene', (207, 211))	('rs7242481', 'Mutation', 'rs7242481', (212, 221))
402312	32493705	Recent studies suggest that the deregulation in SUMO (small ubiquitin-like modifier)-related pathways may lead to oncogenic transformation of tumor suppressors such as PML (promyelocytic leukemia protein).	('promyelocytic leukemia', 'Phenotype', 'HP:0004836', (173, 195))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('PML', 'Gene', '5371', (168, 171))	('promyelocytic leukemia protein', 'Gene', '5371', (173, 203))	('SUMO', 'Gene', (48, 52))	('tumor', 'Disease', (142, 147))	('deregulation', 'Var', (32, 44))	('lead to', 'Reg', (106, 113))	('PML', 'Gene', (168, 171))	('promyelocytic leukemia protein', 'Gene', (173, 203))	('oncogenic transformation', 'CPA', (114, 138))	('leukemia', 'Phenotype', 'HP:0001909', (187, 195))	('tumor', 'Disease', 'MESH:D009369', (142, 147))
402317	32493705	In the present study, we showed that the PIAS1 rs1049493 C allele was associated with lower mRNA expression levels of PIAS1 in whole blood and normal lung tissues, suggesting that the novel rs1049493 C variant allele may affect survival of NSCLC by lowering PIAS1 mRNA expression levels; however, it must be noted that the directionality of PIAS1 rs1049493 C allele yielded mixed results between mRNA levels of PIAS1 and NSCLC survival.	('PIAS1', 'Gene', '8554', (258, 263))	('affect', 'Reg', (221, 227))	('rs1049493 C', 'Var', (190, 201))	('PIAS1', 'Gene', (41, 46))	('NSCLC', 'Disease', (421, 426))	('PIAS1', 'Gene', (341, 346))	('PIAS1', 'Gene', (411, 416))	('rs1049493', 'Mutation', 'rs1049493', (190, 199))	('PIAS1', 'Gene', (118, 123))	('rs1049493', 'Mutation', 'rs1049493', (47, 56))	('NSCLC', 'Disease', 'MESH:D002289', (240, 245))	('PIAS1', 'Gene', '8554', (41, 46))	('PIAS1', 'Gene', '8554', (341, 346))	('PIAS1', 'Gene', (258, 263))	('rs1049493', 'Var', (47, 56))	('rs1049493', 'Mutation', 'rs1049493', (347, 356))	('lowering', 'NegReg', (249, 257))	('NSCLC', 'Disease', (240, 245))	('PIAS1', 'Gene', '8554', (411, 416))	('PIAS1', 'Gene', '8554', (118, 123))	('NSCLC', 'Disease', 'MESH:D002289', (421, 426))
402320	32493705	According to the ENCODE database, PIAS1 rs1049493 T>C is located in a DNase I hypersensitive site with observable levels of histone modifications in H3K4Me1 acetylation, suggesting that the PIAS1 rs1049493 T>C SNP may lead to altered transcriptional activities of PIAS1.	('altered', 'Reg', (226, 233))	('rs1049493 T', 'Var', (40, 51))	('transcriptional activities', 'MPA', (234, 260))	('PIAS1', 'Gene', '8554', (190, 195))	('PIAS1', 'Gene', '8554', (264, 269))	('PIAS1', 'Gene', '8554', (34, 39))	('rs1049493', 'Mutation', 'rs1049493', (40, 49))	('PIAS1', 'Gene', (34, 39))	('PIAS1', 'Gene', (264, 269))	('rs1049493 T>C', 'Var', (196, 209))	('rs1049493', 'Mutation', 'rs1049493', (196, 205))	('PIAS1', 'Gene', (190, 195))
402322	32493705	Also, further functional investigation into the mechanisms of the ELP2 rs7242481 and PIAS1 rs1049493 SNPs are warranted.	('PIAS1', 'Gene', '8554', (85, 90))	('PIAS1', 'Gene', (85, 90))	('rs1049493', 'Mutation', 'rs1049493', (91, 100))	('ELP2', 'Gene', (66, 70))	('rs7242481', 'Mutation', 'rs7242481', (71, 80))	('ELP2', 'Gene', '55250', (66, 70))	('rs7242481', 'Var', (71, 80))	('rs1049493', 'Var', (91, 100))
402329	31391500	Ruthenium(II) complexes with 6-methyl-2-thiouracil selectively reduce cell proliferation, cause DNA double-strand break and trigger caspase-mediated apoptosis through JNK/p38 pathways in human acute promyelocytic leukemia cells Ruthenium(II) complexes with 6-methyl-2-thiouracil cis-[Ru(6m2tu)2(PPh3)2] (1) and [Ru(6m2tu)2(dppb)] (2) (where PPh3 = triphenylphosphine; dppb = 1,4-bis(diphenylphosphino)butane; and 6m2tu = 6-methyl-2-thiouracil) are potent cytotoxic agents and able to bind DNA.	('Ruthenium(II)', 'Chemical', '-', (228, 241))	('triphenylphosphine', 'Chemical', 'MESH:C061896', (348, 366))	('JNK', 'Gene', (167, 170))	('p38', 'Gene', (171, 174))	('reduce', 'NegReg', (63, 69))	('[Ru(6m2tu)2(dppb)]', 'Chemical', '-', (311, 329))	('JNK', 'Gene', '5599', (167, 170))	('promyelocytic leukemia', 'Disease', (199, 221))	('leukemia', 'Phenotype', 'HP:0001909', (213, 221))	('DNA', 'Gene', (96, 99))	('6-methyl-2-thiouracil', 'Chemical', 'MESH:C000599236', (257, 278))	('1,4-bis(diphenylphosphino)butane', 'Chemical', '-', (375, 407))	('6m2tu', 'Chemical', '-', (287, 292))	('bind', 'Interaction', (484, 488))	('6m2tu', 'Chemical', '-', (413, 418))	('acute promyelocytic leukemia', 'Phenotype', 'HP:0004836', (193, 221))	('p38', 'Gene', '5594', (171, 174))	('dppb', 'Chemical', '-', (323, 327))	('cell proliferation', 'CPA', (70, 88))	('Ruthenium(II)', 'Chemical', '-', (0, 13))	('6-methyl-2-thiouracil', 'Chemical', 'MESH:C000599236', (421, 442))	('promyelocytic leukemia', 'Disease', 'MESH:D015473', (199, 221))	('complexes', 'Var', (14, 23))	('-[Ru(6m2tu)2', 'Chemical', '-', (282, 294))	('PPh3', 'Gene', (295, 299))	('dppb', 'Chemical', '-', (368, 372))	('6m2tu', 'Chemical', '-', (315, 320))	('PPh3', 'Gene', (341, 345))	('PPh3', 'Gene', '5531', (295, 299))	('human', 'Species', '9606', (187, 192))	('6-methyl-2-thiouracil', 'Chemical', 'MESH:C000599236', (29, 50))	('PPh3', 'Gene', '5531', (341, 345))
402334	31391500	In addition, both metal complexes induced phosphorylation of histone H2AX (S139), JNK2 (T183/Y185) and p38alpha (T180/Y182), and cotreatment with JNK/SAPK and p38 MAPK inhibitors reduced complexes-induced apoptosis, indicating DNA double-strand break and activation of caspase-mediated apoptosis through JNK/p38 pathways.	('T183/Y185', 'Var', (88, 97))	('p38alpha', 'Gene', (103, 111))	('JNK/SAPK', 'Gene', '5599;5601', (146, 154))	('histone H2AX', 'Gene', '3014', (61, 73))	('I', 'Chemical', 'MESH:D007455', (0, 1))	('p38', 'Gene', '5594', (103, 106))	('JNK2', 'Gene', '5601', (82, 86))	('p38alpha', 'Gene', '1432', (103, 111))	('p38', 'Gene', '5594', (308, 311))	('complexes-induced apoptosis', 'CPA', (187, 214))	('caspase-mediated apoptosis', 'Pathway', (269, 295))	('JNK2', 'Gene', (82, 86))	('activation', 'PosReg', (255, 265))	('p38', 'Gene', (159, 162))	('JNK/SAPK', 'Gene', (146, 154))	('T180/Y182', 'Var', (113, 122))	('JNK', 'Gene', (146, 149))	('p38', 'Gene', (103, 106))	('metal', 'Chemical', 'MESH:D008670', (18, 23))	('phosphorylation', 'MPA', (42, 57))	('JNK', 'Gene', '5599', (146, 149))	('JNK', 'Gene', (304, 307))	('JNK', 'Gene', (82, 85))	('S139', 'Var', (75, 79))	('histone H2AX', 'Gene', (61, 73))	('p38', 'Gene', '5594', (159, 162))	('JNK', 'Gene', '5599', (304, 307))	('p38', 'Gene', (308, 311))	('JNK', 'Gene', '5599', (82, 85))	('reduced', 'NegReg', (179, 186))
402349	31391500	Ruthenium(II) complexes with 6-methyl-2-thiouracil ligand, cis-[Ru(6m2tu)2(PPh3)2] (1) and [Ru(6m2tu)2(dppb)] (2), were obtained as previously described by Correa.	('PPh3', 'Gene', (75, 79))	('-[Ru(6m2tu)2', 'Chemical', '-', (62, 74))	('PPh3', 'Gene', '5531', (75, 79))	('Ruthenium(II)', 'Chemical', '-', (0, 13))	('[Ru(6m2tu)2(dppb)]', 'Chemical', '-', (91, 109))	('[Ru(6m2tu)2', 'Var', (91, 102))	('6-methyl-2-thiouracil', 'Chemical', 'MESH:C000599236', (29, 50))
402370	31391500	Protection assays using a pan-caspase inhibitor (Z-VAD(Ome)-FMK, Cayman Chemical; Ann Arbor, MI, USA), JNK/SAPK inhibitor (SP 600125; Cayman Chemical), p38 MAPK inhibitor (PD 169316; Cayman Chemical) and MEK inhibitor (U-0126; Cayman Chemical), were also evaluated.	('SP 600125', 'Chemical', 'MESH:C432165', (123, 132))	('I', 'Chemical', 'MESH:D007455', (94, 95))	('PD 169316', 'Var', (172, 181))	('JNK/SAPK', 'Gene', '5599;5601', (103, 111))	('p38', 'Gene', (152, 155))	('U-0126', 'Chemical', 'MESH:C113580', (219, 225))	('Z-VAD(Ome)-FMK', 'Chemical', 'MESH:C476093', (49, 63))	('MEK', 'Gene', (204, 207))	('p38', 'Gene', '5594', (152, 155))	('JNK/SAPK', 'Gene', (103, 111))	('PD 169316', 'Chemical', 'MESH:C408604', (172, 181))	('MEK', 'Gene', '5609', (204, 207))
402430	31391500	Finally, viability of BAD (Bcl-2-associated death promoter) mutant cell line BAD KO SV40 MEF (immortalized mouse embryonic fibroblast with the BAD gene knocked out) and its parental cell line WT SV40 MEF (wild-type immortalized mouse embryonic fibroblasts) were examined after 72 h of treatment with ruthenium(II) complexes with 6-methyl-2-thiouracil by alamar blue assay to assess the role of BAD protein in cytotoxicity caused by these complexes.	('6-methyl-2-thiouracil', 'Chemical', 'MESH:C000599236', (329, 350))	('WT SV40 MEF', 'Disease', 'MESH:C536751', (192, 203))	('alamar blue', 'Chemical', 'MESH:C005843', (354, 365))	('mouse', 'Species', '10090', (107, 112))	('cytotoxicity', 'Disease', (409, 421))	('BAD KO SV40 MEF', 'Disease', (77, 92))	('ruthenium(II)', 'Chemical', '-', (300, 313))	('BAD KO SV40 MEF', 'Disease', 'None', (77, 92))	('Bcl-2-associated death promoter', 'Gene', '12015', (27, 58))	('Bcl-2-associated death promoter', 'Gene', (27, 58))	('mouse', 'Species', '10090', (228, 233))	('mutant', 'Var', (60, 66))	('WT SV40 MEF', 'Disease', (192, 203))	('cytotoxicity', 'Disease', 'MESH:D064420', (409, 421))
402440	31391500	Phospho-JNK2 (T183/Y185), phospho-p38alpha (T180/Y182) and phospho-ERK1 (T202/Y204) expressions were also quantified after 15 and 30 min of incubation.	('T180/Y182', 'Var', (44, 53))	('p38alpha', 'Gene', (34, 42))	('ERK1', 'Gene', '5595', (67, 71))	('ERK1', 'Gene', (67, 71))	('T183/Y185', 'Var', (14, 23))	('JNK2', 'Gene', '5601', (8, 12))	('JNK2', 'Gene', (8, 12))	('p38alpha', 'Gene', '1432', (34, 42))
402445	31391500	Moreover, cotreatment with a JNK/SAPK inhibitor (SP 600125) and a p38 MAPK inhibitor (PD 169316), but not a MEK (mitogen-activated protein kinase kinase) inhibitor (U-0126) that inhibits the activation of ERK1/2, reduced the apoptosis caused by both complexes, indicating apoptotic cell death through JNK/p38 pathways in HL-60 cells (Fig.	('mitogen-activated protein kinase kinase', 'Gene', '5609', (113, 152))	('JNK', 'Gene', (301, 304))	('U-0126', 'Chemical', 'MESH:C113580', (165, 171))	('MEK', 'Gene', '5609', (108, 111))	('JNK', 'Gene', '5599', (301, 304))	('p38', 'Gene', (305, 308))	('p38', 'Gene', (66, 69))	('mitogen-activated protein kinase kinase', 'Gene', (113, 152))	('MEK', 'Gene', (108, 111))	('JNK/SAPK', 'Gene', (29, 37))	('p38', 'Gene', '5594', (305, 308))	('reduced', 'NegReg', (213, 220))	('PD 169316', 'Chemical', 'MESH:C408604', (86, 95))	('apoptosis', 'CPA', (225, 234))	('HL-60', 'CellLine', 'CVCL:0002', (321, 326))	('JNK', 'Gene', (29, 32))	('ERK1/2', 'Gene', (205, 211))	('JNK', 'Gene', '5599', (29, 32))	('p38', 'Gene', '5594', (66, 69))	('ERK1/2', 'Gene', '5595;5594', (205, 211))	('SP 600125', 'Var', (49, 58))	('JNK/SAPK', 'Gene', '5599;5601', (29, 37))	('SP 600125', 'Chemical', 'MESH:C432165', (49, 58))
402483	31391500	In recent studies, ruthenium(II) complex with methylimidazole induced cell cycle arrest at G0/G1 phase and caused apoptosis through ROS, MAPK and AKT signaling pathways in human lung carcinoma A549 cells, meanwhile ruthenium(II) complex with xanthoxylin caused S-phase arrest and ERK1/2-mediated apoptosis in HepG2 cells by a p53-independent pathway.	('methylimidazole', 'Var', (46, 61))	('S-phase arrest', 'CPA', (261, 275))	('complex', 'Var', (33, 40))	('ERK1/2', 'Gene', (280, 286))	('methylimidazole', 'Chemical', '-', (46, 61))	('I', 'Chemical', 'MESH:D007455', (0, 1))	('HepG2', 'CellLine', 'CVCL:0027', (309, 314))	('ERK1/2', 'Gene', '5595;5594', (280, 286))	('p53', 'Gene', '7157', (326, 329))	('carcinoma', 'Phenotype', 'HP:0030731', (183, 192))	('cell cycle arrest', 'CPA', (70, 87))	('ROS', 'Pathway', (132, 135))	('xanthoxylin', 'Chemical', 'MESH:C064382', (242, 253))	('p53', 'Gene', (326, 329))	('lung carcinoma', 'Disease', (178, 192))	('ruthenium(II)', 'Chemical', '-', (215, 228))	('I', 'Chemical', 'MESH:D007455', (29, 30))	('I', 'Chemical', 'MESH:D007455', (226, 227))	('I', 'Chemical', 'MESH:D007455', (30, 31))	('ROS', 'Chemical', 'MESH:D017382', (132, 135))	('apoptosis', 'CPA', (114, 123))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (70, 87))	('I', 'Chemical', 'MESH:D007455', (225, 226))	('human', 'Species', '9606', (172, 177))	('A549', 'CellLine', 'CVCL:0023', (193, 197))	('lung carcinoma', 'Disease', 'MESH:D008175', (178, 192))	('AKT signaling pathways', 'Pathway', (146, 168))	('MAPK', 'Pathway', (137, 141))	('ruthenium(II)', 'Chemical', '-', (19, 32))
402495	31391500	In studies of in vitro cellular underlying mechanism, the complexes cause DNA double-strand break and trigger caspase-mediated apoptosis through JNK/p38 pathways in HL-60 cells (Fig.	('JNK', 'Gene', (145, 148))	('caspase-mediated apoptosis', 'CPA', (110, 136))	('p38', 'Gene', (149, 152))	('DNA double-strand break', 'MPA', (74, 97))	('complexes', 'Var', (58, 67))	('cause', 'Reg', (68, 73))	('JNK', 'Gene', '5599', (145, 148))	('trigger', 'Reg', (102, 109))	('I', 'Chemical', 'MESH:D007455', (0, 1))	('HL-60', 'CellLine', 'CVCL:0002', (165, 170))	('p38', 'Gene', '5594', (149, 152))
402500	30035125	Comprehensive interrogation and genome-wide annotation of intercellular differential DNA methylation and its association in long noncoding RNAs (lncRNA) regulation are open questions in carcinoma epigenetics studies.	('carcinoma', 'Disease', 'MESH:D002277', (186, 195))	('carcinoma', 'Phenotype', 'HP:0030731', (186, 195))	('methylation', 'Var', (89, 100))	('long', 'MPA', (124, 128))	('carcinoma', 'Disease', (186, 195))
402594	33299876	Overexpression of P4HA1 Is Correlated with Poor Survival and Immune Infiltrates in Lung Adenocarcinoma Lung adenocarcinoma (LUAD) is a major pathological type of lung cancer.	('Lung adenocarcinoma', 'Disease', (103, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('P4HA1', 'Gene', '5033', (18, 23))	('lung cancer', 'Disease', 'MESH:D008175', (162, 173))	('Lung adenocarcinoma', 'Disease', 'MESH:D000077192', (103, 122))	('LUAD', 'Phenotype', 'HP:0030078', (124, 128))	('Lung Adenocarcinoma', 'Disease', (83, 102))	('P4HA1', 'Gene', (18, 23))	('lung cancer', 'Disease', (162, 173))	('Overexpression', 'Var', (0, 14))	('lung cancer', 'Phenotype', 'HP:0100526', (162, 173))	('Lung Adenocarcinoma', 'Disease', 'MESH:D000077192', (83, 102))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('Infiltrates in Lung', 'Phenotype', 'HP:0002113', (68, 87))	('Lung Adenocarcinoma', 'Phenotype', 'HP:0030078', (83, 102))
402609	33299876	Although the treatment of targeting driver mutations involving epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) fusion oncogenes showed significant survival benefits, limited patients could benefit from them.	('ALK', 'Gene', (135, 138))	('lymphoma', 'Phenotype', 'HP:0002665', (118, 126))	('EGFR', 'Gene', '1956', (97, 101))	('epidermal growth factor receptor', 'Gene', (63, 95))	('ALK', 'Gene', '238', (135, 138))	('anaplastic lymphoma kinase', 'Gene', '238', (107, 133))	('EGFR', 'Gene', (97, 101))	('mutations', 'Var', (43, 52))	('patients', 'Species', '9606', (203, 211))	('epidermal growth factor receptor', 'Gene', '1956', (63, 95))	('benefits', 'PosReg', (185, 193))	('survival', 'CPA', (176, 184))	('anaplastic lymphoma kinase', 'Gene', (107, 133))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (107, 126))
402624	33299876	Overexpression of P4HA1 was related to adverse prognosis.	('P4HA1', 'Gene', (18, 23))	('P4HA1', 'Gene', '5033', (18, 23))	('Overexpression', 'Var', (0, 14))
402682	33299876	Boxplots for SCNAs of P4HA1 suggested that arm-level deletion and high amplification of P4HA1 were closely correlated with six infiltrating immune cells in LUAD (Figure 8(c)).	('P4HA1', 'Gene', (22, 27))	('correlated', 'Reg', (107, 117))	('P4HA1', 'Gene', (88, 93))	('deletion', 'Var', (53, 61))	('P4HA1', 'Gene', '5033', (88, 93))	('P4HA1', 'Gene', '5033', (22, 27))	('LUAD', 'Phenotype', 'HP:0030078', (156, 160))
402716	33299876	Aberrant ubiquitin pathway has been functionally linked to the development and progression of many human diseases, including human tumors.	('Aberrant', 'Var', (0, 8))	('linked', 'Reg', (49, 55))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('ubiquitin pathway', 'Pathway', (9, 26))	('human', 'Species', '9606', (125, 130))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('tumors', 'Disease', (131, 137))	('tumors', 'Disease', 'MESH:D009369', (131, 137))	('human', 'Species', '9606', (99, 104))
402717	33299876	In lung cancer, it was reported that TRIM59 induced ABHD5 ubiquitination, leading to its proteasome-dependent degradation, whereas ABHD5 deficiency leads to metabolic reprogramming of macrophages and activation of NLRP3 inflammatory microsomes, generating an inflammatory environment for tumor development.	('NLRP3', 'Gene', (214, 219))	('ubiquitination', 'MPA', (58, 72))	('lung cancer', 'Phenotype', 'HP:0100526', (3, 14))	('NLRP3', 'Gene', '114548', (214, 219))	('leading to', 'Reg', (74, 84))	('activation', 'PosReg', (200, 210))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('proteasome-dependent degradation', 'MPA', (89, 121))	('tumor', 'Disease', (288, 293))	('lung cancer', 'Disease', (3, 14))	('tumor', 'Disease', 'MESH:D009369', (288, 293))	('TRIM59', 'Gene', (37, 43))	('deficiency', 'Var', (137, 147))	('TRIM59', 'Gene', '286827', (37, 43))	('ABHD5', 'Gene', '51099', (52, 57))	('metabolic reprogramming', 'CPA', (157, 180))	('ABHD5', 'Gene', '51099', (131, 136))	('ABHD5', 'Gene', (52, 57))	('ABHD5', 'Gene', (131, 136))	('tumor', 'Phenotype', 'HP:0002664', (288, 293))	('lung cancer', 'Disease', 'MESH:D008175', (3, 14))
402720	33299876	Its defects will result in a phenotype called microsatellite instability (MSI), which recently received increasing attention as a significant biomarker to predict the response to cancer immunotherapy.	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('result in', 'Reg', (17, 26))	('microsatellite', 'MPA', (46, 60))	('cancer', 'Disease', (179, 185))	('defects', 'Var', (4, 11))
402721	33299876	The genotype of mismatch repair genes has also been reported to be associated with the development of lung cancer.	('lung cancer', 'Phenotype', 'HP:0100526', (102, 113))	('mismatch repair genes', 'Gene', (16, 37))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('lung cancer', 'Disease', (102, 113))	('genotype', 'Var', (4, 12))	('lung cancer', 'Disease', 'MESH:D008175', (102, 113))	('associated with', 'Reg', (67, 82))
402724	33299876	Nucleotide excision repair (NER) inhibits tumorigenesis caused by mutations of genes through repairing structurally unrelated DNA damage.	('mutations', 'Var', (66, 75))	('tumor', 'Disease', (42, 47))	('genes', 'Gene', (79, 84))	('repairing structurally unrelated DNA damage', 'MPA', (93, 136))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('inhibits', 'NegReg', (33, 41))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
402726	33299876	Mutated P53 loses its original cancer-suppressive effect.	('P53', 'Gene', '7157', (8, 11))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('loses', 'NegReg', (12, 17))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('P53', 'Gene', (8, 11))	('cancer', 'Disease', (31, 37))	('Mutated', 'Var', (0, 7))
402727	33299876	Compared with wild-type P53, mutant P53 is less sensitive to degradation, resulting in its high expression in vivo.	('P53', 'Gene', '7157', (36, 39))	('mutant', 'Var', (29, 35))	('expression', 'MPA', (96, 106))	('P53', 'Gene', (24, 27))	('P53', 'Gene', '7157', (24, 27))	('P53', 'Gene', (36, 39))
402743	33299876	The presence of TIBs is extremely beneficial for long-term overall survival (OS), recurrence-free survival (RFS), or disease-specific survival (DSS) of NSCLC.	('NSCLC', 'Phenotype', 'HP:0030358', (152, 157))	('recurrence-free survival', 'CPA', (82, 106))	('TIBs', 'Gene', (16, 20))	('NSCLC', 'Disease', (152, 157))	('SCLC', 'Phenotype', 'HP:0030357', (153, 157))	('disease-specific survival', 'CPA', (117, 142))	('NSCLC', 'Disease', 'MESH:D002289', (152, 157))	('beneficial', 'PosReg', (34, 44))	('presence', 'Var', (4, 12))
402748	33299876	Overexpression of P4HA1 is associated with poor prognosis.	('P4HA1', 'Gene', (18, 23))	('P4HA1', 'Gene', '5033', (18, 23))	('Overexpression', 'Var', (0, 14))
402750	33299876	Meanwhile, aberrant P4HA1 expression is associated with different abundance of immune infiltrating cells (CD4+ T cells and B cells) in LUAD.	('CD4', 'Gene', (106, 109))	('CD4', 'Gene', '920', (106, 109))	('aberrant', 'Var', (11, 19))	('P4HA1', 'Gene', (20, 25))	('LUAD', 'Phenotype', 'HP:0030078', (135, 139))	('P4HA1', 'Gene', '5033', (20, 25))
402760	33206698	UTMC with STAT3-MB caused significantly lower CAL33 cell viability compared to UTMC with STAT3-LPX (56.8+-8.4% vs 84.5+-8.8%, respectively, p<0.05).	('w', 'Chemical', 'MESH:D014414', (84, 85))	('LPX', 'Chemical', '-', (95, 98))	('w', 'Chemical', 'MESH:D014414', (5, 6))	('MB', 'Chemical', 'MESH:D008751', (16, 18))	('UTMC', 'Chemical', '-', (0, 4))	('STAT3-MB', 'Var', (10, 18))	('UTMC', 'Chemical', '-', (79, 83))	('w', 'Chemical', 'MESH:D014414', (42, 43))	('CAL33 cell viability', 'CPA', (46, 66))	('lower', 'NegReg', (40, 45))
402761	33206698	In vivo, UTMC with STAT3-MB had strong anti-tumor effects, with significantly less tumor burden and greater survival compared to that of UTMC with microbubbles loaded with a mutant control decoy and untreated control groups (p<0.05).	('STAT3-MB', 'Var', (19, 27))	('tumor', 'Disease', (83, 88))	('MB', 'Chemical', 'MESH:D008751', (25, 27))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('tumor', 'Disease', (44, 49))	('on', 'Gene', '20692', (182, 184))	('greater', 'PosReg', (100, 107))	('UTMC', 'Chemical', '-', (137, 141))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('w', 'Chemical', 'MESH:D014414', (167, 168))	('survival', 'CPA', (108, 116))	('w', 'Chemical', 'MESH:D014414', (142, 143))	('UTMC', 'Chemical', '-', (9, 13))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('less', 'NegReg', (78, 82))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('w', 'Chemical', 'MESH:D014414', (14, 15))	('on', 'Gene', '20692', (210, 212))	('on', 'Gene', '20692', (35, 37))	('w', 'Chemical', 'MESH:D014414', (59, 60))	('decoy', 'Chemical', '-', (189, 194))
402768	33206698	Numerous studies have reported that phosphorylation at a single tyrosine residue (Y705) in the transactivation domain of STAT3, by Janus associated kinase (JAK) or c-Src, results in the proliferation and maintenance of multiple cancers including HNSCC and correlates with lower survival rates.	('cancers', 'Disease', 'MESH:D009369', (228, 235))	('w', 'Chemical', 'MESH:D014414', (274, 275))	('on', 'Gene', '20692', (49, 51))	('c-Src', 'Gene', '6714', (164, 169))	('lower', 'NegReg', (272, 277))	('HNSCC', 'Disease', (246, 251))	('on', 'Gene', '20692', (197, 199))	('cancers', 'Phenotype', 'HP:0002664', (228, 235))	('cancers', 'Disease', (228, 235))	('HNSCC', 'Phenotype', 'HP:0012288', (246, 251))	('on', 'Gene', '20692', (108, 110))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('STAT3', 'Gene', (121, 126))	('results in', 'Reg', (171, 181))	('w', 'Chemical', 'MESH:D014414', (267, 268))	('tyrosine', 'Chemical', 'MESH:D014443', (64, 72))	('c-Src', 'Gene', (164, 169))	('Y705', 'Var', (82, 86))	('maintenance', 'CPA', (204, 215))
402778	33206698	UTMC-mediated delivery of various nucleic acid therapies has been shown to increase their anti-cancer efficacy in cancers such as glioma, prostate, melanoma, pharyngeal, and pancreatic cancers.	('pancreatic cancers', 'Phenotype', 'HP:0002894', (174, 192))	('cancers', 'Phenotype', 'HP:0002664', (114, 121))	('melanoma', 'Disease', 'MESH:D008545', (148, 156))	('cancers', 'Disease', (114, 121))	('glioma', 'Disease', (130, 136))	('pancreatic cancers', 'Disease', (174, 192))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('cancers', 'Phenotype', 'HP:0002664', (185, 192))	('glioma', 'Disease', 'MESH:D005910', (130, 136))	('cancer', 'Disease', (185, 191))	('cancers', 'Disease', (185, 192))	('pharyngeal', 'Disease', (158, 168))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('cancer', 'Disease', (95, 101))	('pancreatic cancers', 'Disease', 'MESH:D010190', (174, 192))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('nucleic acid', 'Var', (34, 46))	('glioma', 'Phenotype', 'HP:0009733', (130, 136))	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('cancers', 'Disease', 'MESH:D009369', (114, 121))	('melanoma', 'Phenotype', 'HP:0002861', (148, 156))	('melanoma', 'Disease', (148, 156))	('UTMC', 'Chemical', '-', (0, 4))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('increase', 'PosReg', (75, 83))	('cancers', 'Disease', 'MESH:D009369', (185, 192))	('prostate', 'Disease', (138, 146))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('w', 'Chemical', 'MESH:D014414', (69, 70))	('cancer', 'Disease', (114, 120))
402796	33206698	The headspace of the vial was filled with perfluorobutane gas (FluoroMed, LP, Round Rock, TX, USA) and vortexed for 45 s using a dental amalgamator, resulting in microbubbles carrying STAT3 decoy (STAT3-MB) or mutant decoy (STAT3-MB-mut) via charge-charge interaction.	('mutant', 'Var', (210, 216))	('w', 'Chemical', 'MESH:D014414', (37, 38))	('STAT3 decoy', 'Var', (184, 195))	('decoy', 'Chemical', '-', (190, 195))	('w', 'Chemical', 'MESH:D014414', (26, 27))	('on', 'Gene', '20692', (265, 267))	('MB', 'Chemical', 'MESH:D008751', (203, 205))	('charge-charge', 'MPA', (242, 255))	('MB', 'Chemical', 'MESH:D008751', (230, 232))	('perfluorobutane', 'Chemical', 'MESH:C108042', (42, 57))	('decoy', 'Chemical', '-', (217, 222))
402825	33206698	Lipofectamine complexes were formulated by mixing the appropriate proportions of STAT3 or mutant decoy and lipofectamine 2000 (Life Technologies, Waltham, MA, USA), and incubated for 5 min prior to the in vitro studies.	('for 5', 'Gene', '109647', (179, 184))	('on', 'Gene', '20692', (74, 76))	('lipofectamine', 'Chemical', 'MESH:C086724', (107, 120))	('mutant', 'Var', (90, 96))	('decoy', 'Chemical', '-', (97, 102))	('Lipofectamine', 'Chemical', 'MESH:C086724', (0, 13))	('w', 'Chemical', 'MESH:D014414', (24, 25))	('for 5', 'Gene', (179, 184))
402883	33206698	STAT3 decoy had a greater cytotoxic effect than its mutant control when delivered by lipofectamine (p<0.001), and the cell viability of no treatment control and mutant treated cells was similar.	('on', 'Gene', '20692', (60, 62))	('STAT3', 'Var', (0, 5))	('w', 'Chemical', 'MESH:D014414', (67, 68))	('cytotoxic effect', 'CPA', (26, 42))	('w', 'Chemical', 'MESH:D014414', (182, 183))	('decoy', 'Chemical', '-', (6, 11))	('lipofectamine', 'Chemical', 'MESH:C086724', (85, 98))	('on', 'Gene', '20692', (150, 152))
402886	33206698	STAT3-MB + UTMC resulted in significantly lower CAL33 cell viability (56.8+-8.4%) compared to that of STAT3-LPX + UTMC (84.5+-8.8%, p<0.05) (Fig 1B).	('LPX', 'Chemical', '-', (108, 111))	('UTMC', 'Chemical', '-', (114, 118))	('lower', 'NegReg', (42, 47))	('STAT3-MB + UTMC', 'Var', (0, 15))	('w', 'Chemical', 'MESH:D014414', (44, 45))	('CAL33 cell viability', 'CPA', (48, 68))	('UTMC', 'Chemical', '-', (11, 15))	('MB', 'Chemical', 'MESH:D008751', (6, 8))
402888	33206698	In CAL33 luc+ cells where luciferase expression is driven by a STAT3-responsive promoter, STAT3-MB + UTMC caused a ~45% reduction in luciferase activity which was significantly (p<0.05) greater than that of mutant microbubble (<10%) (Fig 1C).	('w', 'Chemical', 'MESH:D014414', (153, 154))	('STAT3-MB +', 'Var', (90, 100))	('on', 'Gene', '20692', (127, 129))	('UTMC', 'Chemical', '-', (101, 105))	('on', 'Gene', '20692', (45, 47))	('luciferase', 'Enzyme', (133, 143))	('on', 'Gene', '20692', (73, 75))	('w', 'Chemical', 'MESH:D014414', (20, 21))	('MB', 'Chemical', 'MESH:D008751', (96, 98))	('activity', 'MPA', (144, 152))	('w', 'Chemical', 'MESH:D014414', (159, 160))
402892	33206698	Fig 2B depicts data from experiments with CAL33 cells receiving no treatment (left), UTMC-mediated delivery of mutant decoy-microbubble (middle), or STAT3-MB (right).	('w', 'Chemical', 'MESH:D014414', (37, 38))	('mutant', 'Var', (111, 117))	('decoy-microbubble', 'Protein', (118, 135))	('UTMC', 'Chemical', '-', (85, 89))	('decoy', 'Chemical', '-', (118, 123))	('MB', 'Chemical', 'MESH:D008751', (155, 157))
402893	33206698	Compared to untreated cells or STAT3-MB-mut + UTMC treated cells, STAT3-MB + UTMC treatment was associated with reduced viability and increased apoptosis.	('UTMC', 'Chemical', '-', (77, 81))	('MB', 'Chemical', 'MESH:D008751', (37, 39))	('w', 'Chemical', 'MESH:D014414', (92, 93))	('apoptosis', 'CPA', (144, 153))	('MB', 'Chemical', 'MESH:D008751', (72, 74))	('STAT3-MB + UTMC', 'Var', (66, 81))	('reduced', 'NegReg', (112, 119))	('increased', 'PosReg', (134, 143))	('w', 'Chemical', 'MESH:D014414', (107, 108))	('UTMC', 'Chemical', '-', (46, 50))
402896	33206698	By Day 12, the STAT3 decoy treated mice had a 2-fold reduction (p<0.05) in tumor volume compared to that of the no treatment control group and a 1.5-fold reduction (p<0.05) compared to that of STAT3-MB-mut + UTMC, respectively (Fig 3D).	('on', 'Gene', '20692', (126, 128))	('UTMC', 'Chemical', '-', (208, 212))	('decoy', 'Chemical', '-', (21, 26))	('on', 'Gene', '20692', (60, 62))	('on', 'Gene', '20692', (161, 163))	('STAT3 decoy', 'Var', (15, 26))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('mice', 'Species', '10090', (35, 39))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('MB', 'Chemical', 'MESH:D008751', (199, 201))	('tumor', 'Disease', (75, 80))
402897	33206698	Mice treated with STAT3-MB-mut + UTMC did not exhibit a significant difference in tumor volume compared to that of untreated control mice at any point during the study.	('on', 'Gene', '20692', (126, 128))	('UTMC', 'Chemical', '-', (33, 37))	('mice', 'Species', '10090', (133, 137))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('w', 'Chemical', 'MESH:D014414', (13, 14))	('STAT3-MB-mut + UTMC', 'Var', (18, 37))	('Mice', 'Species', '10090', (0, 4))	('tumor', 'Disease', (82, 87))	('MB', 'Chemical', 'MESH:D008751', (24, 26))
402899	33206698	It should be noted that in the untreated control and mutant-treated control groups, several mice were euthanized according to protocol before Day 15 due to tumor growth exceeding 1000 mm3, thereby precluding tumor volume comparisons between treatment groups at this time point (Fig 3D).	('on', 'Gene', '20692', (229, 231))	('tumor', 'Disease', 'MESH:D009369', (208, 213))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('w', 'Chemical', 'MESH:D014414', (236, 237))	('on', 'Gene', '20692', (42, 44))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('on', 'Gene', '20692', (69, 71))	('w', 'Chemical', 'MESH:D014414', (165, 166))	('tumor', 'Disease', (208, 213))	('tumor', 'Disease', (156, 161))	('mutant-treated', 'Var', (53, 67))	('mice', 'Species', '10090', (92, 96))	('w', 'Chemical', 'MESH:D014414', (97, 98))
402901	33206698	Aligned with this finding, UTMC-mediated STAT3 decoy delivery increased tumor doubling time compared to that of untreated control (4.2+-0.4 vs 3.5+-0.4 days, p<0.05) and mutant control decoy (3.7+-0.4, p = 0.056), resulting in reduced mortality of the STAT3 decoy treated mice.	('increased', 'PosReg', (62, 71))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('w', 'Chemical', 'MESH:D014414', (8, 9))	('on', 'Gene', '20692', (178, 180))	('reduced', 'NegReg', (227, 234))	('on', 'Gene', '20692', (123, 125))	('mortality', 'Disease', (235, 244))	('tumor', 'Disease', (72, 77))	('UTMC', 'Chemical', '-', (27, 31))	('mice', 'Species', '10090', (272, 276))	('decoy', 'Chemical', '-', (47, 52))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('mutant', 'Var', (170, 176))	('mortality', 'Disease', 'MESH:D003643', (235, 244))	('decoy', 'Chemical', '-', (185, 190))	('decoy', 'Chemical', '-', (258, 263))
402903	33206698	UTMC-mediated delivery of STAT3 decoy or mutant decoy was performed in a separate group of CAL33 tumor-bearing mice, and tumors were harvested 48 h later and analyzed for target gene expression.	('decoy', 'Chemical', '-', (48, 53))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('w', 'Chemical', 'MESH:D014414', (128, 129))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('mutant', 'Var', (41, 47))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumors', 'Disease', (121, 127))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('tumor', 'Disease', (121, 126))	('w', 'Chemical', 'MESH:D014414', (54, 55))	('decoy', 'Chemical', '-', (32, 37))	('tumor', 'Disease', (97, 102))	('mice', 'Species', '10090', (111, 115))	('UTMC', 'Chemical', '-', (0, 4))	('tumors', 'Disease', 'MESH:D009369', (121, 127))	('on', 'Gene', '20692', (191, 193))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
402905	33206698	UTMC-mediated delivery of mutant control decoy did not confer significant decreases in the respective protein expression compared to that of no treatment control.	('decoy', 'Chemical', '-', (41, 46))	('on', 'Gene', '20692', (34, 36))	('on', 'Gene', '20692', (56, 58))	('UTMC', 'Chemical', '-', (0, 4))	('on', 'Gene', '20692', (155, 157))	('decreases', 'NegReg', (74, 83))	('on', 'Gene', '20692', (118, 120))	('mutant', 'Var', (26, 32))
402907	33206698	STAT3-MB treated tumors demonstrated extensive regions of apoptotic (TUNEL-positive) cells compared to no treatment control and mutant-treated tumors (Fig 6B).	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('tumors', 'Disease', (17, 23))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('tumors', 'Disease', (143, 149))	('tumors', 'Disease', 'MESH:D009369', (143, 149))	('STAT3-MB', 'Var', (0, 8))	('on', 'Gene', '20692', (117, 119))	('on', 'Gene', '20692', (51, 53))	('on', 'Gene', '20692', (27, 29))	('MB', 'Chemical', 'MESH:D008751', (6, 8))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
402931	33206698	We demonstrated that compared to negative controls (no treatment control or STAT3-MB-mut + UTMC), cultured (human) CAL33 cells treated with STAT3-MB + UTMC experienced: (1) greater cytotoxicity as shown by MTT assay; (2) more apoptosis as shown by flow cytometry; and (3) a strong trend in decreased protein expression of downstream target genes Bcl-xL as shown by Western blot.	('decreased', 'NegReg', (290, 299))	('MB', 'Chemical', 'MESH:D008751', (146, 148))	('w', 'Chemical', 'MESH:D014414', (242, 243))	('greater', 'PosReg', (173, 180))	('MB', 'Chemical', 'MESH:D008751', (82, 84))	('w', 'Chemical', 'MESH:D014414', (359, 360))	('w', 'Chemical', 'MESH:D014414', (200, 201))	('UTMC', 'Chemical', '-', (91, 95))	('apoptosis', 'CPA', (226, 235))	('MTT', 'Chemical', 'MESH:C070243', (206, 209))	('on', 'Gene', '20692', (316, 318))	('more', 'PosReg', (221, 225))	('Bcl-xL', 'MPA', (346, 352))	('w', 'Chemical', 'MESH:D014414', (135, 136))	('on', 'Gene', '20692', (277, 279))	('UTMC', 'Chemical', '-', (151, 155))	('cytotoxicity', 'Disease', (181, 193))	('on', 'Gene', '20692', (6, 8))	('on', 'Gene', '20692', (43, 45))	('cytotoxicity', 'Disease', 'MESH:D064420', (181, 193))	('w', 'Chemical', 'MESH:D014414', (324, 325))	('STAT3-MB + UTMC', 'Var', (140, 155))	('on', 'Gene', '20692', (66, 68))	('human', 'Species', '9606', (108, 113))	('w', 'Chemical', 'MESH:D014414', (251, 252))
402934	33206698	Importantly, UTMC-mediated delivery of mutant control decoy did not result in tumor growth suppression or target gene downregulation compared to untreated control mice, indicating that the therapeutic effect was not simply due to the delivery of ultrasound.	('w', 'Chemical', 'MESH:D014414', (208, 209))	('on', 'Gene', '20692', (47, 49))	('UTMC', 'Chemical', '-', (13, 17))	('tumor growth suppression', 'Disease', (78, 102))	('tumor growth suppression', 'Disease', 'MESH:D006130', (78, 102))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('on', 'Gene', '20692', (100, 102))	('mice', 'Species', '10090', (163, 167))	('decoy', 'Chemical', '-', (54, 59))	('w', 'Chemical', 'MESH:D014414', (120, 121))	('mutant', 'Var', (39, 45))	('w', 'Chemical', 'MESH:D014414', (87, 88))	('on', 'Gene', '20692', (130, 132))	('on', 'Gene', '20692', (156, 158))
402942	33206698	The potential for inherent toxicity from the UTMC itself may account for why tumors treated with the mutant decoy-loaded microbubble + UTMC experience a mild reduction, albeit statistically insignificant, in tumor growth.	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('w', 'Chemical', 'MESH:D014414', (217, 218))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('decoy', 'Chemical', '-', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Disease', (208, 213))	('tumors', 'Disease', (77, 83))	('w', 'Chemical', 'MESH:D014414', (73, 74))	('tumor', 'Disease', 'MESH:D009369', (208, 213))	('toxicity', 'Disease', 'MESH:D064420', (27, 35))	('on', 'Gene', '20692', (165, 167))	('UTMC', 'Chemical', '-', (135, 139))	('tumors', 'Disease', 'MESH:D009369', (77, 83))	('toxicity', 'Disease', (27, 35))	('w', 'Chemical', 'MESH:D014414', (92, 93))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('UTMC', 'Chemical', '-', (45, 49))	('mutant', 'Var', (101, 107))	('tumor', 'Disease', (77, 82))
402947	33206698	Although it remains to be proven, such data suggest that UTMC confers a comparable intratumoral concentration of decoy to what is achieved by an order of magnitude greater dose of intravenously administered STAT3 decoy.	('UTMC', 'Chemical', '-', (57, 61))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('on', 'Gene', '20692', (107, 109))	('on', 'Gene', '20692', (63, 65))	('on', 'Gene', '20692', (97, 99))	('w', 'Chemical', 'MESH:D014414', (122, 123))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('decoy', 'Chemical', '-', (113, 118))	('UTMC', 'Var', (57, 61))	('tumor', 'Disease', (88, 93))	('decoy', 'Chemical', '-', (213, 218))
403007	32468043	Following propofol treatment for 48 h, and/or transfection with miR-21-5p mimic and/or pcDNA3-MAPK10 for 48 h, the A549 and H1299 cells were harvested for use in subsequent experiments.	('men', 'Species', '9606', (179, 182))	('men', 'Species', '9606', (24, 27))	('H1299', 'CellLine', 'CVCL:0060', (124, 129))	('MAPK10', 'Gene', (94, 100))	('propofol', 'Chemical', 'MESH:D015742', (10, 18))	('MAPK10', 'Gene', '5602', (94, 100))	('A549', 'CellLine', 'CVCL:0023', (115, 119))	('miR-21-5p', 'Gene', (64, 73))	('miR-21-5p', 'Gene', '406997', (64, 73))	('transfection', 'Var', (46, 58))
403010	32468043	Following propofol treatment and/or transfection with miR-21-5p mimic and/or pcDNA3-MAPK10 for 48 h, 10 microl CCK-8 solution was added to each well.	('men', 'Species', '9606', (24, 27))	('propofol', 'Chemical', 'MESH:D015742', (10, 18))	('MAPK10', 'Gene', (84, 90))	('miR-21-5p', 'Gene', (54, 63))	('CCK-8', 'Chemical', '-', (111, 116))	('miR-21-5p', 'Gene', '406997', (54, 63))	('MAPK10', 'Gene', '5602', (84, 90))	('transfection', 'Var', (36, 48))
403110	32468043	For example, Acetyl-11-Keto-beta-Boswellic acid has some anti-cancer effects by stimulating NSCLC apoptosis, KCP10043F reduces NSCLC proliferation by inducing caspase-mediated apoptosis and ASB16-AS1 promotes the progression of NSCLC by decreasing cell apoptosis.	('caspase-mediated apoptosis', 'CPA', (159, 185))	('NSCLC', 'Disease', 'MESH:D002289', (127, 132))	('AS1', 'Gene', (196, 199))	('ASB16', 'Gene', (190, 195))	('NSCLC', 'Disease', 'MESH:D002289', (228, 233))	('NSCLC', 'Disease', 'MESH:D002289', (92, 97))	('NSCLC', 'Disease', (127, 132))	('KCP10043F', 'Var', (109, 118))	('cancer', 'Disease', (62, 68))	('NSCLC', 'Disease', (228, 233))	('NSCLC', 'Disease', (92, 97))	('reduces', 'NegReg', (119, 126))	('KCP10043F', 'Chemical', '-', (109, 118))	('cell apoptosis', 'CPA', (248, 262))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('AS1', 'Gene', '5729', (196, 199))	('inducing', 'PosReg', (150, 158))	('ASB16', 'Gene', '92591', (190, 195))	('promotes', 'PosReg', (200, 208))	('stimulating', 'PosReg', (80, 91))	('decreasing', 'NegReg', (237, 247))	('cancer', 'Disease', 'MESH:D009369', (62, 68))
403122	30583098	Currently, it is well accepted that both innate and adaptive immunity play an important role in tumor immunosurveillance, and type 1 interferon (IFN) is critical for eliciting an effective antitumor immunity by bridging innate and adaptive immunity, because type 1 IFN, produced by antigen-presenting dendritic cells (DCs) in the tumor microenvironment, not only activates the innate immune response but also facilitates T cell cross-priming and infiltration.	('tumor immunosurveillance', 'Disease', (96, 120))	('type 1 interferon (IFN', 'Gene', (126, 148))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumor', 'Disease', (330, 335))	('activates', 'PosReg', (363, 372))	('type 1 interferon (IFN)', 'Gene', '3439', (126, 149))	('IFN', 'Gene', (145, 148))	('IFN', 'Gene', (265, 268))	('tumor', 'Disease', 'MESH:D009369', (330, 335))	('facilitates', 'PosReg', (409, 420))	('tumor', 'Disease', (193, 198))	('innate immune response', 'CPA', (377, 399))	('tumor', 'Phenotype', 'HP:0002664', (330, 335))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('tumor', 'Disease', (96, 101))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('type 1', 'Var', (258, 264))	('IFN', 'Gene', '3439', (265, 268))	('IFN', 'Gene', '3439', (145, 148))	('tumor immunosurveillance', 'Disease', 'MESH:D009369', (96, 120))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))
403127	30583098	The phosphorylated IRF3 translocates into the nucleus and induces the production of type I IFN and other cytokines associated with immunity regulation.	('IFN', 'Gene', (91, 94))	('induces', 'Reg', (58, 65))	('phosphorylated', 'Var', (4, 18))	('IRF3', 'Gene', (19, 23))	('IRF3', 'Gene', '3661', (19, 23))	('IFN', 'Gene', '3439', (91, 94))
403128	30583098	As a stimulator of type 1 IFN, the cGAS/STING pathway is reported to trigger a spontaneous antitumor T cell response in vivo, whereas the deficiency of STING or IRF3 shows an impaired spontaneous T cell response against tumors.	('spontaneous', 'MPA', (184, 195))	('IRF3', 'Gene', (161, 165))	('IRF3', 'Gene', '3661', (161, 165))	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('IFN', 'Gene', (26, 29))	('tumors', 'Phenotype', 'HP:0002664', (220, 226))	('tumor', 'Disease', (220, 225))	('tumors', 'Disease', (220, 226))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumors', 'Disease', 'MESH:D009369', (220, 226))	('deficiency', 'Var', (138, 148))	('impaired', 'NegReg', (175, 183))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Disease', 'MESH:D009369', (220, 225))	('tumor', 'Disease', (95, 100))	('IFN', 'Gene', '3439', (26, 29))
403141	30583098	It has been reported that hypermethylation of the MB21D1 or TMEM173 gene promoter contributes to its downregulation in certain cancer types.	('downregulation', 'NegReg', (101, 115))	('TMEM173', 'Gene', '340061', (60, 67))	('MB21D1', 'Gene', (50, 56))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('hypermethylation', 'Var', (26, 42))	('MB21D1', 'Gene', '115004', (50, 56))	('cancer', 'Disease', (127, 133))	('TMEM173', 'Gene', (60, 67))
403145	30583098	For the TMEM173 gene (Figure 2B), it is significantly hypomethylated in COAD, HNSC, KIRC, PAAD, SKCM, and THCA, but hypermethylated in BRCA, LUAD, LUSC, PRAD, and UCEC.	('COAD', 'Disease', 'MESH:D029424', (72, 76))	('THCA', 'Phenotype', 'HP:0002890', (106, 110))	('HNSC', 'Phenotype', 'HP:0012288', (78, 82))	('LUAD', 'Phenotype', 'HP:0030078', (141, 145))	('hypermethylated', 'Var', (116, 131))	('BRCA', 'Phenotype', 'HP:0003002', (135, 139))	('LUSC', 'Phenotype', 'HP:0030359', (147, 151))	('COAD', 'Disease', (72, 76))	('hypomethylated', 'Var', (54, 68))	('BRCA', 'Gene', '672', (135, 139))	('TMEM173', 'Gene', (8, 15))	('BRCA', 'Gene', (135, 139))	('PAAD', 'Phenotype', 'HP:0006725', (90, 94))	('TMEM173', 'Gene', '340061', (8, 15))
403151	30583098	The methylation and expression of TBK1 are weakly correlated in all of the methylation-differentiated tumors, and there is no correlation in KIRC (Table 1).	('expression', 'MPA', (20, 30))	('tumors', 'Disease', (102, 108))	('methylation', 'MPA', (4, 15))	('tumors', 'Disease', 'MESH:D009369', (102, 108))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('TBK1', 'Gene', (34, 38))	('TBK1', 'Gene', '29110', (34, 38))	('methylation-differentiated', 'Var', (75, 101))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))
403152	30583098	Similarly, IRF3 shows a low correlation in all of the methylation-differentiated tumors (Table 1).	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('tumors', 'Disease', (81, 87))	('IRF3', 'Gene', (11, 15))	('IRF3', 'Gene', '3661', (11, 15))	('methylation-differentiated', 'Var', (54, 80))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))
403153	30583098	The impaired ability of STING to sense cGAMP caused by a SNP in the TMEM173 gene has been reported in a previous study, suggesting that gene mutations may also affect the activity of cGAS/STING signaling.	('TMEM173', 'Gene', (68, 75))	('mutations', 'Var', (141, 150))	('TMEM173', 'Gene', '340061', (68, 75))	('ability', 'MPA', (13, 20))	('affect', 'Reg', (160, 166))	('impaired', 'NegReg', (4, 12))	('cGAS/STING signaling', 'MPA', (183, 203))	('cGAMP', 'Chemical', 'MESH:C584311', (39, 44))	('activity', 'MPA', (171, 179))	('SNP', 'Var', (57, 60))
403155	30583098	The result showed that various frequent mutations are present in the MB21D1, TMEM173, TBK1, and IRF3 genes in all the detected cancer types, and that the average mutation rate is comparable among the MB21D1, TMEM173, TBK1, and IRF3 genes.	('TMEM173', 'Gene', '340061', (208, 215))	('TBK1', 'Gene', (217, 221))	('IRF3', 'Gene', (227, 231))	('MB21D1', 'Gene', (200, 206))	('TMEM173', 'Gene', '340061', (77, 84))	('MB21D1', 'Gene', '115004', (69, 75))	('IRF3', 'Gene', (96, 100))	('IRF3', 'Gene', '3661', (227, 231))	('mutations', 'Var', (40, 49))	('cancer', 'Disease', (127, 133))	('TMEM173', 'Gene', (208, 215))	('TBK1', 'Gene', '29110', (86, 90))	('MB21D1', 'Gene', '115004', (200, 206))	('IRF3', 'Gene', '3661', (96, 100))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('TBK1', 'Gene', (86, 90))	('TMEM173', 'Gene', (77, 84))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('MB21D1', 'Gene', (69, 75))	('TBK1', 'Gene', '29110', (217, 221))
403157	30583098	Furthermore, the top three highest mutations rates for the TBK1 gene are present in CESC, COAD, and UCEC (Figure 3).	('COAD', 'Disease', 'MESH:D029424', (90, 94))	('CESC', 'Disease', (84, 88))	('TBK1', 'Gene', (59, 63))	('COAD', 'Disease', (90, 94))	('TBK1', 'Gene', '29110', (59, 63))	('UCEC', 'Disease', (100, 104))	('mutations', 'Var', (35, 44))
403159	30583098	The highest mutation rates for the MB21D1, TMEM173, TBK1, and IRF3 genes are all present in UCEC, suggesting that cGAS/STING signaling in UCEC may be significantly impaired.	('MB21D1', 'Gene', '115004', (35, 41))	('TBK1', 'Gene', '29110', (52, 56))	('TMEM173', 'Gene', (43, 50))	('TMEM173', 'Gene', '340061', (43, 50))	('IRF3', 'Gene', (62, 66))	('IRF3', 'Gene', '3661', (62, 66))	('TBK1', 'Gene', (52, 56))	('cGAS/STING signaling', 'MPA', (114, 134))	('MB21D1', 'Gene', (35, 41))	('mutation', 'Var', (12, 20))	('impaired', 'NegReg', (164, 172))
403160	30583098	Although the mutation rates of these genes in the tumors are relatively high, because the mutated amino acids are not located in the functional regions of these genes, it appears that most of the mutations might not affect the ability of STING to bind cyclic diguanylate (CDN), the enzyme activity of cGAS, the kinase activity of TBK1, or the ability of IRF3 to act as a transcription factor.	('cGAS', 'Enzyme', (301, 305))	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('IRF3', 'Gene', (354, 358))	('enzyme activity', 'MPA', (282, 297))	('CDN', 'Chemical', '-', (272, 275))	('TBK1', 'Gene', (330, 334))	('kinase activity', 'MPA', (311, 326))	('IRF3', 'Gene', '3661', (354, 358))	('bind', 'Interaction', (247, 251))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('TBK1', 'Gene', '29110', (330, 334))	('tumors', 'Disease', (50, 56))	('cyclic diguanylate', 'Chemical', '-', (252, 270))	('mutations', 'Var', (196, 205))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))
403170	30583098	By analyzing a transcriptome dataset from 40 patients with metastatic melanoma in a clinical trial to evaluate the benefit of CTLA-4 blockade, we revealed that patients with high expression of TMEM173 (Figure 4B) or TBK1 (Figure 4C) yield more considerable clinical benefit to anti-CTLA-4 therapy and had longer survival time than those patients with low expression of TMEM173 or TBK1, respectively, whereas the expression of MB21D1 or IRF3 has no impact on the clinical benefit for patients of CTLA-4 blockade (data not shown).	('CTLA-4', 'Gene', (282, 288))	('melanoma', 'Disease', 'MESH:D008545', (70, 78))	('TBK1', 'Gene', (216, 220))	('patients', 'Species', '9606', (483, 491))	('patients', 'Species', '9606', (45, 53))	('TMEM173', 'Gene', (193, 200))	('CTLA-4', 'Gene', '1493', (495, 501))	('MB21D1', 'Gene', '115004', (426, 432))	('clinical', 'CPA', (257, 265))	('TMEM173', 'Gene', (369, 376))	('longer', 'PosReg', (305, 311))	('CTLA-4', 'Gene', (495, 501))	('patients', 'Species', '9606', (337, 345))	('TBK1', 'Gene', '29110', (380, 384))	('melanoma', 'Phenotype', 'HP:0002861', (70, 78))	('melanoma', 'Disease', (70, 78))	('IRF3', 'Gene', (436, 440))	('TBK1', 'Gene', (380, 384))	('high expression', 'Var', (174, 189))	('CTLA-4', 'Gene', '1493', (126, 132))	('CTLA-4', 'Gene', (126, 132))	('TMEM173', 'Gene', '340061', (193, 200))	('TMEM173', 'Gene', '340061', (369, 376))	('survival', 'CPA', (312, 320))	('patients', 'Species', '9606', (160, 168))	('IRF3', 'Gene', '3661', (436, 440))	('MB21D1', 'Gene', (426, 432))	('TBK1', 'Gene', '29110', (216, 220))	('CTLA-4', 'Gene', '1493', (282, 288))	('benefit', 'PosReg', (266, 273))
403177	30583098	By contrast, a high IRF3 expression predicts a poor prognosis in COAD, KIRC, and PRAD patients but indicates a good prognosis only in PAAD patients (Figure 5C; Figure S8).	('high', 'Var', (15, 19))	('IRF3', 'Gene', (20, 24))	('IRF3', 'Gene', '3661', (20, 24))	('patients', 'Species', '9606', (139, 147))	('PRAD', 'Disease', (81, 85))	('expression', 'MPA', (25, 35))	('COAD', 'Disease', (65, 69))	('PAAD', 'Phenotype', 'HP:0006725', (134, 138))	('COAD', 'Disease', 'MESH:D029424', (65, 69))	('patients', 'Species', '9606', (86, 94))
403187	30583098	For example, the expression of TBK1 and IRF3 is significantly upregulated, whereas the promoters of these genes are also hypermethylated in KIRC and LUSC tissues compared with that in normal tissues.	('TBK1', 'Gene', '29110', (31, 35))	('expression', 'MPA', (17, 27))	('LUSC', 'Phenotype', 'HP:0030359', (149, 153))	('IRF3', 'Gene', (40, 44))	('upregulated', 'PosReg', (62, 73))	('TBK1', 'Gene', (31, 35))	('hypermethylated', 'Var', (121, 136))	('IRF3', 'Gene', '3661', (40, 44))
403195	30583098	As a hallmark of cancer, genomic instability drives tumor evolution by activating STING signaling and promoting cancer progression, which may explain why this signaling is universally elevated in pan-cancer.	('cancer', 'Disease', (112, 118))	('tumor', 'Disease', (52, 57))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('pan-cancer', 'Disease', (196, 206))	('cancer', 'Disease', (17, 23))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('activating', 'PosReg', (71, 81))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))	('cancer', 'Disease', 'MESH:D009369', (200, 206))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('STING signaling', 'MPA', (82, 97))	('elevated', 'PosReg', (184, 192))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('genomic instability', 'Var', (25, 44))	('pan-cancer', 'Disease', 'MESH:C537931', (196, 206))	('promoting', 'PosReg', (102, 111))	('cancer', 'Disease', (200, 206))
403228	29232380	Silencing GRP78 increased the radiosensitivity of oropharyngeal carcinoma cells and inhibited radiation-induced DNA double-strand-break (DSB) repair and autophagy.	('oropharyngeal carcinoma', 'Disease', 'MESH:D009959', (50, 73))	('GRP78', 'Gene', '3309', (10, 15))	('oropharyngeal carcinoma', 'Phenotype', 'HP:0012182', (50, 73))	('GRP78', 'Gene', (10, 15))	('autophagy', 'CPA', (153, 162))	('oropharyngeal carcinoma', 'Disease', (50, 73))	('increased', 'PosReg', (16, 25))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))	('radiation-induced', 'CPA', (94, 111))	('Silencing', 'Var', (0, 9))	('radiosensitivity', 'CPA', (30, 46))	('inhibited', 'NegReg', (84, 93))
403229	29232380	More interestingly, silencing GRP78 abrogated resistance to cetuximab and radiation in Detroit562 cells and had a synergistic effect with cetuximab in increasing the radiosensitivity of FaDu cells.	('cetuximab', 'Chemical', 'MESH:D000068818', (138, 147))	('resistance to cetuximab', 'MPA', (46, 69))	('radiosensitivity', 'CPA', (166, 182))	('increasing', 'PosReg', (151, 161))	('abrogated', 'NegReg', (36, 45))	('Detroit562', 'CellLine', 'CVCL:1171', (87, 97))	('GRP78', 'Gene', '3309', (30, 35))	('GRP78', 'Gene', (30, 35))	('silencing', 'Var', (20, 29))	('cetuximab', 'Chemical', 'MESH:D000068818', (60, 69))
403236	29232380	The prognosis of HPV (+) oropharyngeal carcinoma patients was significantly better than that of HPV (-) patients after radical radiotherapy, suggesting that HPV (+) patients have higher intrinsic radiosensitivity than HPV (-) patients.	('HPV', 'Species', '10566', (96, 99))	('HPV', 'Species', '10566', (157, 160))	('oropharyngeal carcinoma', 'Disease', (25, 48))	('intrinsic radiosensitivity', 'MPA', (186, 212))	('oropharyngeal carcinoma', 'Disease', 'MESH:D009959', (25, 48))	('HPV', 'Species', '10566', (218, 221))	('carcinoma', 'Phenotype', 'HP:0030731', (39, 48))	('oropharyngeal carcinoma', 'Phenotype', 'HP:0012182', (25, 48))	('patients', 'Species', '9606', (226, 234))	('patients', 'Species', '9606', (165, 173))	('patients', 'Species', '9606', (49, 57))	('HPV (+', 'Var', (157, 163))	('higher', 'PosReg', (179, 185))	('patients', 'Species', '9606', (104, 112))	('HPV', 'Species', '10566', (17, 20))
403241	29232380	However, cetuximab improves the efficacy of radiotherapy in only a subgroup of patients with head and neck squamous cell carcinoma (HNSCC), with 50% of patient still experiencing local recurrence, and EGFR levels cannot predict the efficacy of cetuximab combined with radiotherapy.	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('neck squamous cell carcinoma', 'Disease', (102, 130))	('cetuximab', 'Chemical', 'MESH:D000068818', (244, 253))	('efficacy', 'MPA', (32, 40))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (93, 130))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (102, 130))	('improves', 'PosReg', (19, 27))	('EGFR', 'Gene', '1956', (201, 205))	('cetuximab', 'Chemical', 'MESH:D000068818', (9, 18))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (107, 130))	('HNSCC', 'Phenotype', 'HP:0012288', (132, 137))	('EGFR', 'Gene', (201, 205))	('patient', 'Species', '9606', (79, 86))	('patients', 'Species', '9606', (79, 87))	('patient', 'Species', '9606', (152, 159))	('cetuximab', 'Var', (9, 18))
403271	29232380	We pretreated FaDu and Detroit562 oropharyngeal carcinoma cells with 50 mug/mL cetuximab, and the results of the colony formation assay showed that cetuximab increased the radiosensitivity of FaDu cells, with a radiation sensitization ratio of 1.14, but showed no radiosensitization effects in Detroit562 cells.	('Detroit562', 'CellLine', 'CVCL:1171', (23, 33))	('cetuximab', 'Chemical', 'MESH:D000068818', (148, 157))	('Detroit562', 'CellLine', 'CVCL:1171', (294, 304))	('Detroit562 oropharyngeal carcinoma', 'Disease', (23, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (48, 57))	('radiosensitivity', 'MPA', (172, 188))	('Detroit562 oropharyngeal carcinoma', 'Disease', 'MESH:D009959', (23, 57))	('oropharyngeal carcinoma', 'Phenotype', 'HP:0012182', (34, 57))	('radiation sensitization', 'Phenotype', 'HP:0011133', (211, 234))	('cetuximab', 'Var', (148, 157))	('increased', 'PosReg', (158, 167))	('cetuximab', 'Chemical', 'MESH:D000068818', (79, 88))
403283	29232380	Silencing IRE1alpha and ATF6 inhibited GRP78 protein expression, while silencing PERK had no significant effect on GRP78 protein expression (Fig 1C).	('inhibited', 'NegReg', (29, 38))	('PERK', 'Gene', '9451', (81, 85))	('ATF6', 'Gene', (24, 28))	('protein', 'Protein', (45, 52))	('GRP78', 'Gene', (115, 120))	('IRE1alpha', 'Gene', (10, 19))	('IRE1alpha', 'Gene', '2081', (10, 19))	('GRP78', 'Gene', (39, 44))	('GRP78', 'Gene', '3309', (115, 120))	('GRP78', 'Gene', '3309', (39, 44))	('ATF6', 'Gene', '22926', (24, 28))	('Silencing', 'Var', (0, 9))	('PERK', 'Gene', (81, 85))
403294	29232380	The results showed that silencing GRP78 increased the radiosensitivity of FaDu and Detroit562 cells, and the radiosensitization ratios (SER) of FaDu and Detroit562 cells were 1.19 and 1.21, respectively (Fig 2C), suggesting that the radiosensitization effect of cetuximab was related to its inhibition of radiation-induced sustained overexpression of GRP78.	('GRP78', 'Gene', '3309', (34, 39))	('cetuximab', 'Chemical', 'MESH:D000068818', (262, 271))	('SER', 'Chemical', '-', (136, 139))	('GRP78', 'Gene', (351, 356))	('GRP78', 'Gene', '3309', (351, 356))	('inhibition', 'NegReg', (291, 301))	('overexpression', 'PosReg', (333, 347))	('increased', 'PosReg', (40, 49))	('radiosensitivity', 'MPA', (54, 70))	('Detroit562', 'CellLine', 'CVCL:1171', (83, 93))	('Detroit562', 'CellLine', 'CVCL:1171', (153, 163))	('GRP78', 'Gene', (34, 39))	('silencing', 'Var', (24, 33))
403295	29232380	It was reported that an EGFR-targeted inhibitor could inhibit DNA double-strand break repair and autophagy to increase radiosensitivity in malignancies.	('EGFR', 'Gene', '1956', (24, 28))	('increase', 'PosReg', (110, 118))	('increase radiosensitivity', 'Phenotype', 'HP:0010997', (110, 135))	('DNA double-strand', 'MPA', (62, 79))	('inhibitor', 'Var', (38, 47))	('malignancies', 'Disease', (139, 151))	('inhibit', 'NegReg', (54, 61))	('EGFR', 'Gene', (24, 28))	('autophagy', 'CPA', (97, 106))	('malignancies', 'Disease', 'MESH:D009369', (139, 151))	('radiosensitivity', 'CPA', (119, 135))
403297	29232380	Western blot analysis showed that silencing GRP78 inhibited the radiation-induced expression of the DNA double-strand break repair protein DNA-PK and increased the phosphorylation level of ATM.	('ATM', 'Gene', '472', (189, 192))	('expression', 'MPA', (82, 92))	('GRP78', 'Gene', '3309', (44, 49))	('DNA-PK', 'Gene', (139, 145))	('DNA-PK', 'Gene', '5591', (139, 145))	('ATM', 'Gene', (189, 192))	('increased', 'PosReg', (150, 159))	('GRP78', 'Gene', (44, 49))	('silencing', 'Var', (34, 43))	('inhibited', 'NegReg', (50, 59))
403298	29232380	In addition, silencing GRP78 also inhibited the protein expression of the autophagy marker LC3B and the related protein Atg16L1 (Fig 3A).	('protein expression', 'MPA', (48, 66))	('Atg16L1', 'Gene', '55054', (120, 127))	('inhibited', 'NegReg', (34, 43))	('GRP78', 'Gene', (23, 28))	('autophagy', 'CPA', (74, 83))	('LC3B', 'Gene', '81631', (91, 95))	('LC3B', 'Gene', (91, 95))	('GRP78', 'Gene', '3309', (23, 28))	('Atg16L1', 'Gene', (120, 127))	('silencing', 'Var', (13, 22))
403302	29232380	In addition, silencing GRP78 increased the radiation-induced expression of the apoptosis marker protein cleaved caspase-3 and cleaved PARP (Fig 3A).	('cleaved caspase-3', 'MPA', (104, 121))	('PARP', 'Gene', (134, 138))	('increased', 'PosReg', (29, 38))	('GRP78', 'Gene', (23, 28))	('cleaved', 'MPA', (126, 133))	('GRP78', 'Gene', '3309', (23, 28))	('PARP', 'Gene', '142', (134, 138))	('expression', 'MPA', (61, 71))	('silencing', 'Var', (13, 22))
403303	29232380	Furthermore, inhibition of autophagy increases radiation-induced tumour cell apoptosis.	('autophagy', 'CPA', (27, 36))	('inhibition', 'Var', (13, 23))	('tumour', 'Phenotype', 'HP:0002664', (65, 71))	('increases', 'PosReg', (37, 46))	('tumour', 'Disease', 'MESH:D009369', (65, 71))	('tumour', 'Disease', (65, 71))
403304	29232380	Therefore, we hypothesize that the increased radiosensitivity of oropharyngeal carcinoma cells upon silencing GRP78 is related to radiation-induced autophagy and DNA double-strand break repair.	('increased', 'PosReg', (35, 44))	('oropharyngeal carcinoma', 'Disease', (65, 88))	('silencing', 'Var', (100, 109))	('radiosensitivity', 'CPA', (45, 61))	('GRP78', 'Gene', (110, 115))	('GRP78', 'Gene', '3309', (110, 115))	('increased radiosensitivity', 'Phenotype', 'HP:0010997', (35, 61))	('oropharyngeal carcinoma', 'Disease', 'MESH:D009959', (65, 88))	('oropharyngeal carcinoma', 'Phenotype', 'HP:0012182', (65, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))
403305	29232380	To confirm this hypothesis, we used the broad-spectrum inhibitor of DNA double-strand break repair, Ly294002, and the autophagy inhibitor, 3-MA, to treat oropharyngeal carcinoma cells.	('carcinoma', 'Phenotype', 'HP:0030731', (168, 177))	('oropharyngeal carcinoma', 'Disease', 'MESH:D009959', (154, 177))	('oropharyngeal carcinoma', 'Phenotype', 'HP:0012182', (154, 177))	('Ly294002', 'Var', (100, 108))	('3-MA', 'Chemical', 'MESH:C025946', (139, 143))	('oropharyngeal carcinoma', 'Disease', (154, 177))	('Ly294002', 'Chemical', 'MESH:C085911', (100, 108))
403306	29232380	The results of cloning showed that Ly294002 and 3-MA could increase the radiosensitivity of oropharyngeal carcinoma cells.	('Ly294002', 'Chemical', 'MESH:C085911', (35, 43))	('oropharyngeal carcinoma', 'Disease', 'MESH:D009959', (92, 115))	('3-MA', 'Chemical', 'MESH:C025946', (48, 52))	('oropharyngeal carcinoma', 'Phenotype', 'HP:0012182', (92, 115))	('radiosensitivity of', 'CPA', (72, 91))	('Ly294002', 'Var', (35, 43))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('oropharyngeal carcinoma', 'Disease', (92, 115))	('increase', 'PosReg', (59, 67))
403307	29232380	The results showed that Ly294002 and 3-MA inhibited the radiation-induced expression of the cell proliferation regulatory protein EGR1 and anti-apoptotic protein Bcl-2, while they increased the radiation-induced expression of the apoptosis marker protein cleaved PARP (Fig 4B).	('expression', 'MPA', (74, 84))	('EGR1', 'Gene', '1958', (130, 134))	('Ly294002', 'Chemical', 'MESH:C085911', (24, 32))	('Bcl-2', 'Gene', (162, 167))	('Bcl-2', 'Gene', '596', (162, 167))	('increased', 'PosReg', (180, 189))	('expression', 'MPA', (212, 222))	('Ly294002', 'Var', (24, 32))	('inhibited', 'NegReg', (42, 51))	('PARP', 'Gene', '142', (263, 267))	('EGR1', 'Gene', (130, 134))	('3-MA', 'Chemical', 'MESH:C025946', (37, 41))	('PARP', 'Gene', (263, 267))
403308	29232380	The results of the CCK-8 analysis also showed that Ly294002 and 3-MA further reduced the proliferation of cells inhibited by radiation alone (Fig 4C).	('proliferation', 'CPA', (89, 102))	('Ly294002', 'Chemical', 'MESH:C085911', (51, 59))	('Ly294002', 'Var', (51, 59))	('reduced', 'NegReg', (77, 84))	('3-MA', 'Chemical', 'MESH:C025946', (64, 68))
403309	29232380	Flow cytometry also demonstrated that Ly294002 and 3-MA increased radiation-induced apoptosis (Fig 4D).	('radiation-induced apoptosis', 'CPA', (66, 93))	('Ly294002', 'Chemical', 'MESH:C085911', (38, 46))	('3-MA', 'Chemical', 'MESH:C025946', (51, 55))	('increased', 'PosReg', (56, 65))	('Ly294002', 'Var', (38, 46))
403310	29232380	These results confirmed that the inhibition of radiation-induced DNA double-strand break repair and autophagy and a subsequent increase in apoptosis might mediate the radiosensitization effect of GRP78 silencing in oropharyngeal carcinoma cells.	('GRP78', 'Gene', '3309', (196, 201))	('GRP78', 'Gene', (196, 201))	('oropharyngeal carcinoma', 'Phenotype', 'HP:0012182', (215, 238))	('inhibition', 'NegReg', (33, 43))	('autophagy', 'CPA', (100, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (229, 238))	('oropharyngeal carcinoma', 'Disease', (215, 238))	('silencing', 'Var', (202, 211))	('DNA double-strand break repair', 'CPA', (65, 95))	('apoptosis', 'CPA', (139, 148))	('oropharyngeal carcinoma', 'Disease', 'MESH:D009959', (215, 238))
403312	29232380	The results of the colony survival assay showed that silencing GRP78 abrogated the radioresistance in Detroit562 cells after treatment with cetuximab, and the SER was 1.24.	('abrogated', 'NegReg', (69, 78))	('GRP78', 'Gene', '3309', (63, 68))	('Detroit562', 'CellLine', 'CVCL:1171', (102, 112))	('radioresistance in Detroit562 cells', 'CPA', (83, 118))	('SER', 'Chemical', '-', (159, 162))	('silencing', 'Var', (53, 62))	('cetuximab', 'Chemical', 'MESH:D000068818', (140, 149))	('GRP78', 'Gene', (63, 68))
403313	29232380	Interestingly, silencing GRP78 further increased the radiosensitization effect of cetuximab on FaDu cells; the SERs were 1.11 and 1.32, respectively (Fig 5A).	('GRP78', 'Gene', '3309', (25, 30))	('GRP78', 'Gene', (25, 30))	('radiosensitization effect', 'MPA', (53, 78))	('silencing', 'Var', (15, 24))	('increased', 'PosReg', (39, 48))	('cetuximab', 'Chemical', 'MESH:D000068818', (82, 91))	('SERs', 'Chemical', 'MESH:D012694', (111, 115))
403315	29232380	Silencing GRP78 combined with cetuximab treatment significantly inhibited the proliferation of Detroit562 cells, and the effect was more pronounced than radiation alone or radiation combined with cetuximab (P < 0.05 compared with IR; P < 0.01 compared with IR + cetuximab).	('Detroit562', 'CellLine', 'CVCL:1171', (95, 105))	('GRP78', 'Gene', '3309', (10, 15))	('cetuximab', 'Chemical', 'MESH:D000068818', (262, 271))	('GRP78', 'Gene', (10, 15))	('inhibited', 'NegReg', (64, 73))	('proliferation of Detroit562 cells', 'CPA', (78, 111))	('Silencing', 'Var', (0, 9))	('cetuximab', 'Chemical', 'MESH:D000068818', (30, 39))	('cetuximab', 'Chemical', 'MESH:D000068818', (196, 205))
403316	29232380	Interestingly, cetuximab administration after GRP78 silencing led to a more pronounced inhibition of radiation-inhibited FaDu cell proliferation than cetuximab alone (Fig 5B).	('inhibition', 'NegReg', (87, 97))	('silencing', 'Var', (52, 61))	('GRP78', 'Gene', (46, 51))	('cetuximab', 'Chemical', 'MESH:D000068818', (15, 24))	('GRP78', 'Gene', '3309', (46, 51))	('cetuximab', 'Chemical', 'MESH:D000068818', (150, 159))	('radiation-inhibited FaDu cell proliferation', 'CPA', (101, 144))
403317	29232380	We further detected apoptosis and found that cetuximab alone had no effect on radiation-induced apoptosis in Detroit562 cells, whereas silencing of GRP78 led to a significantly increased apoptosis rate compared with radiation alone or radiation combined with cetuximab (P < 0.05 compared with IR; P = 0.05 compared with IR + cetuximab).	('Detroit562', 'CellLine', 'CVCL:1171', (109, 119))	('cetuximab', 'Chemical', 'MESH:D000068818', (45, 54))	('apoptosis', 'CPA', (187, 196))	('GRP78', 'Gene', (148, 153))	('silencing', 'Var', (135, 144))	('GRP78', 'Gene', '3309', (148, 153))	('increased', 'PosReg', (177, 186))	('cetuximab', 'Chemical', 'MESH:D000068818', (259, 268))	('cetuximab', 'Chemical', 'MESH:D000068818', (325, 334))
403318	29232380	Cetuximab alone increased radiation-induced FaDu cell apoptosis, and this effect was further enhanced by GRP78 silencing (Fig 5C).	('silencing', 'Var', (111, 120))	('radiation-induced FaDu cell apoptosis', 'CPA', (26, 63))	('increased', 'PosReg', (16, 25))	('GRP78', 'Gene', (105, 110))	('enhanced', 'PosReg', (93, 101))	('Cetuximab', 'Chemical', 'MESH:D000068818', (0, 9))	('GRP78', 'Gene', '3309', (105, 110))
403319	29232380	These results suggested that silencing GRP78 could abrogate radioresistance after treatment with cetuximab.	('radioresistance', 'CPA', (60, 75))	('silencing', 'Var', (29, 38))	('cetuximab', 'Chemical', 'MESH:D000068818', (97, 106))	('GRP78', 'Gene', (39, 44))	('GRP78', 'Gene', '3309', (39, 44))	('abrogate', 'NegReg', (51, 59))
403326	29232380	A Kaplan-Meier survival analysis showed that oropharyngeal carcinoma patients with EGFR and GRP78 co-overexpression had the worst prognosis with respect to overall survival (P < 0.05, Fig 6C).	('EGFR', 'Gene', '1956', (83, 87))	('oropharyngeal carcinoma', 'Disease', (45, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (59, 68))	('EGFR', 'Gene', (83, 87))	('oropharyngeal carcinoma', 'Disease', 'MESH:D009959', (45, 68))	('GRP78', 'Gene', '3309', (92, 97))	('oropharyngeal carcinoma', 'Phenotype', 'HP:0012182', (45, 68))	('overall', 'MPA', (156, 163))	('GRP78', 'Gene', (92, 97))	('patients', 'Species', '9606', (69, 77))	('co-overexpression', 'Var', (98, 115))
403333	29232380	Previous studies have suggested several molecular mechanisms, such as the association of K-RAS mutations and acquired RAS or EGFR mutations implicated in cetuximab resistance.	('K-RAS', 'Gene', (89, 94))	('EGFR', 'Gene', '1956', (125, 129))	('EGFR', 'Gene', (125, 129))	('mutations', 'Var', (130, 139))	('RAS', 'Gene', (118, 121))	('mutations', 'Var', (95, 104))	('cetuximab', 'Chemical', 'MESH:D000068818', (154, 163))	('association', 'Interaction', (74, 85))	('K-RAS', 'Gene', '3845', (89, 94))
403348	29232380	The cleavage of ATF6 leads to the transcription of genes required to restore ER homeostasis.	('transcription of genes', 'MPA', (34, 56))	('cleavage', 'Var', (4, 12))	('leads to', 'Reg', (21, 29))	('ATF6', 'Gene', '22926', (16, 20))	('ATF6', 'Gene', (16, 20))
403353	29232380	The results of this study demonstrate that cetuximab increases the radiosensitivity of oropharyngeal carcinoma cells via the inhibition of radiation-induced IRE1alpha/ATF6-GRP78 and that the silencing of GRP78 abrogates the resistance of Detroit562 cells to cetuximab and radiation.	('IRE1alpha', 'Gene', '2081', (157, 166))	('GRP78', 'Gene', '3309', (204, 209))	('GRP78', 'Gene', (204, 209))	('silencing', 'Var', (191, 200))	('ATF6', 'Gene', (167, 171))	('inhibition', 'NegReg', (125, 135))	('GRP78', 'Gene', '3309', (172, 177))	('GRP78', 'Gene', (172, 177))	('resistance', 'CPA', (224, 234))	('IRE1alpha', 'Gene', (157, 166))	('cetuximab', 'Chemical', 'MESH:D000068818', (258, 267))	('abrogates', 'NegReg', (210, 219))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('oropharyngeal carcinoma', 'Disease', (87, 110))	('ATF6', 'Gene', '22926', (167, 171))	('radiosensitivity', 'CPA', (67, 83))	('cetuximab', 'Chemical', 'MESH:D000068818', (43, 52))	('oropharyngeal carcinoma', 'Phenotype', 'HP:0012182', (87, 110))	('oropharyngeal carcinoma', 'Disease', 'MESH:D009959', (87, 110))	('increases', 'PosReg', (53, 62))	('Detroit562', 'CellLine', 'CVCL:1171', (238, 248))
403357	29232380	Our study indicates that silencing GRP78 inhibits radiation-induced autophagy; this subsequently leads to increased radiation-induced apoptosis, which regulates the radiosensitivity of oropharyngeal carcinoma cells.	('silencing', 'Var', (25, 34))	('radiation-induced autophagy', 'CPA', (50, 77))	('inhibits', 'NegReg', (41, 49))	('GRP78', 'Gene', (35, 40))	('oropharyngeal carcinoma', 'Disease', (185, 208))	('GRP78', 'Gene', '3309', (35, 40))	('oropharyngeal carcinoma', 'Disease', 'MESH:D009959', (185, 208))	('radiation-induced apoptosis', 'CPA', (116, 143))	('oropharyngeal carcinoma', 'Phenotype', 'HP:0012182', (185, 208))	('increased', 'PosReg', (106, 115))	('carcinoma', 'Phenotype', 'HP:0030731', (199, 208))
403362	29232380	indicated that misregulation of DNA damage repair pathways in HPV-positive head and neck squamous cell carcinoma contribute to cellular radiosensitivity.	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (84, 112))	('cellular radiosensitivity', 'CPA', (127, 152))	('HPV-positive', 'Gene', (62, 74))	('contribute', 'Reg', (113, 123))	('DNA damage repair pathways', 'Pathway', (32, 58))	('cellular radiosensitivity', 'Phenotype', 'HP:0010997', (127, 152))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (89, 112))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (75, 112))	('misregulation', 'Var', (15, 28))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('neck squamous cell carcinoma', 'Disease', (84, 112))	('HPV', 'Species', '10566', (62, 65))
403368	29232380	To confirm this hypothesis, we transfected cells with siRNA to silence GRP78, and a subsequent colony formation assay showed that inhibition of GRP78 increased the radiosensitivity of oropharyngeal carcinoma cells.	('GRP78', 'Gene', (144, 149))	('inhibition', 'Var', (130, 140))	('oropharyngeal carcinoma', 'Disease', (184, 207))	('carcinoma', 'Phenotype', 'HP:0030731', (198, 207))	('silence', 'NegReg', (63, 70))	('oropharyngeal carcinoma', 'Disease', 'MESH:D009959', (184, 207))	('increased', 'PosReg', (150, 159))	('GRP78', 'Gene', '3309', (71, 76))	('GRP78', 'Gene', (71, 76))	('oropharyngeal carcinoma', 'Phenotype', 'HP:0012182', (184, 207))	('GRP78', 'Gene', '3309', (144, 149))
403369	29232380	The mechanism of action was that the silencing of GRP78 inhibited radiation-induced cell autophagy and DNA double-strand break repair, which increased radiation-induced apoptosis.	('increased', 'PosReg', (141, 150))	('silencing', 'Var', (37, 46))	('GRP78', 'Gene', (50, 55))	('DNA double-strand break', 'MPA', (103, 126))	('GRP78', 'Gene', '3309', (50, 55))	('inhibited', 'NegReg', (56, 65))	('radiation-induced cell autophagy', 'CPA', (66, 98))
403370	29232380	In addition, the silencing of GRP78 abrogated radioresistance after treatment with cetuximab.	('cetuximab', 'Chemical', 'MESH:D000068818', (83, 92))	('GRP78', 'Gene', (30, 35))	('abrogated', 'NegReg', (36, 45))	('GRP78', 'Gene', '3309', (30, 35))	('silencing', 'Var', (17, 26))	('radioresistance', 'CPA', (46, 61))
403371	29232380	Interestingly, we found that silencing GRP78 further increased the radiosensitization effect of cetuximab in FaDu cells.	('cetuximab', 'Chemical', 'MESH:D000068818', (96, 105))	('silencing', 'Var', (29, 38))	('GRP78', 'Gene', (39, 44))	('radiosensitization effect', 'MPA', (67, 92))	('GRP78', 'Gene', '3309', (39, 44))	('increased', 'PosReg', (53, 62))
403376	28642617	Here we demonstrate that in podoplanin-positive LSCC cells, their growth was abrogated by podoplanin knockout in vivo but not in vitro.	('podoplanin', 'Gene', (90, 100))	('knockout', 'Var', (101, 109))	('podoplanin', 'Gene', '10630', (28, 38))	('LSCC', 'Phenotype', 'HP:0030359', (48, 52))	('abrogated', 'NegReg', (77, 86))	('growth', 'MPA', (66, 72))	('podoplanin', 'Gene', (28, 38))	('podoplanin', 'Gene', '10630', (90, 100))
403377	28642617	Conversely, ectopic expression of podoplanin promoted cell growth in vivo and facilitated intratumoral platelet activation.	('podoplanin', 'Gene', '10630', (34, 44))	('ectopic expression', 'Var', (12, 30))	('facilitated', 'PosReg', (78, 89))	('cell growth', 'CPA', (54, 65))	('promoted', 'PosReg', (45, 53))	('podoplanin', 'Gene', (34, 44))	('intratumoral platelet activation', 'CPA', (90, 122))
403388	28642617	PMPA is essential for blood-lymphatic separation during development, and sphingosine-1-phosphate released from platelets during PMPA maintain the integrity of high endothelial venules during immune responses.	('integrity', 'MPA', (146, 155))	('lymphatic separation', 'Phenotype', 'HP:0001004', (28, 48))	('sphingosine-1-phosphate', 'Chemical', 'MESH:C060506', (73, 96))	('PMPA', 'Chemical', '-', (0, 4))	('PMPA', 'Chemical', '-', (128, 132))	('PMPA', 'Var', (128, 132))
403392	28642617	In this study, to elucidate the mechanism underlying the role of podoplanin in tumour progression, we knocked out or ectopically expressed podoplanin in lung cancer cells.	('podoplanin', 'Gene', (65, 75))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('podoplanin', 'Gene', (139, 149))	('lung cancer', 'Disease', 'MESH:D008175', (153, 164))	('ectopically expressed', 'Var', (117, 138))	('tumour', 'Phenotype', 'HP:0002664', (79, 85))	('lung cancer', 'Disease', (153, 164))	('podoplanin', 'Gene', '10630', (65, 75))	('knocked out', 'Var', (102, 113))	('lung cancer', 'Phenotype', 'HP:0100526', (153, 164))	('tumour', 'Disease', 'MESH:D009369', (79, 85))	('tumour', 'Disease', (79, 85))	('podoplanin', 'Gene', '10630', (139, 149))
403402	28642617	Interestingly PC-10 DeltaPDPN cells could barely form tumours in vivo (PC-10 DeltaPDPN#1; 0/6, PC-10 DeltaPDPN #2; 1/6), though PC-10 (parent) cells did form tumours in vivo (5/6, Fig.	('tumour', 'Phenotype', 'HP:0002664', (158, 164))	('PC-10', 'CellLine', 'CVCL:7088', (128, 133))	('tumours', 'Phenotype', 'HP:0002664', (158, 165))	('tumours', 'Disease', 'MESH:D009369', (54, 61))	('DeltaPDPN', 'Var', (20, 29))	('tumours', 'Disease', (54, 61))	('tumours', 'Disease', 'MESH:D009369', (158, 165))	('PC-10', 'CellLine', 'CVCL:7088', (71, 76))	('tumours', 'Disease', (158, 165))	('PC-10', 'CellLine', 'CVCL:7088', (95, 100))	('tumour', 'Phenotype', 'HP:0002664', (54, 60))	('PC-10', 'CellLine', 'CVCL:7088', (14, 19))	('tumours', 'Phenotype', 'HP:0002664', (54, 61))
403459	28642617	Nevertheless, SCC-015 cell growth was promoted by murine EGF (Supplementary Fig.	('SCC-015 cell growth', 'CPA', (14, 33))	('murine', 'Species', '10090', (50, 56))	('promoted', 'PosReg', (38, 46))	('SCC-015', 'CellLine', 'CVCL:9024', (14, 21))	('murine', 'Var', (50, 56))
403485	28642617	There is evidence that a P2Y12 inhibitor, MRS 2395, also suppressed TCIPA, and clopidogrel suppressed tumour growth by inhibiting platelet aggregation.	('suppressed', 'NegReg', (91, 101))	('clopidogrel', 'Chemical', 'MESH:D000077144', (79, 90))	('tumour', 'Phenotype', 'HP:0002664', (102, 108))	('tumour growth', 'Disease', 'MESH:D006130', (102, 115))	('platelet aggregation', 'Phenotype', 'HP:0003540', (130, 150))	('inhibiting', 'NegReg', (119, 129))	('suppressed', 'NegReg', (57, 67))	('P2Y12', 'Gene', '64805', (25, 30))	('MRS', 'Var', (42, 45))	('TCIPA', 'MPA', (68, 73))	('platelet aggregation', 'Disease', (130, 150))	('platelet aggregation', 'Disease', 'MESH:D001791', (130, 150))	('P2Y12', 'Gene', (25, 30))	('tumour growth', 'Disease', (102, 115))
403496	28642617	These findings indicated that LSCC cells hijacked PMPA, which is essential in the process of homeostasis during malignant progression.	('hijacked', 'Var', (41, 49))	('PMPA', 'Chemical', '-', (50, 54))	('PMPA', 'Protein', (50, 54))	('LSCC', 'Phenotype', 'HP:0030359', (30, 34))
403521	28642617	Cell growth between PC-10 and PC-10 DeltaPDPN or between A549/Neo and A549/PDPN was measured by performing a CellTiter-Glo luminescent cell viability assay (Promega, Madison, WI, USA) according to the manufacturer's protocols.	('DeltaPDPN', 'Var', (36, 45))	('A549/PDPN', 'Gene', (70, 79))	('A549', 'CellLine', 'CVCL:0023', (70, 74))	('PC-10', 'CellLine', 'CVCL:7088', (30, 35))	('PC-10', 'CellLine', 'CVCL:7088', (20, 25))	('A549', 'CellLine', 'CVCL:0023', (57, 61))	('A549/PDPN', 'Gene', '10630', (70, 79))
403625	33125148	RASA1 contains the following domains: Src homology 2 and 3 (SH2 and SH3), N-terminal C2A and C2B, GTPase-activating protein (GAP), and pleckstrin homology (PH), which is attached to a Bruton's tyrosine kinase (Btk) motif.	('GAP', 'Gene', (125, 128))	('GAP', 'Gene', '5921', (125, 128))	("Bruton's tyrosine kinase", 'Gene', '695', (184, 208))	('Btk', 'Gene', (210, 213))	('C2B', 'Var', (93, 96))	('Btk', 'Gene', '695', (210, 213))	('GTP', 'Chemical', '-', (98, 101))	("Bruton's tyrosine kinase", 'Gene', (184, 208))
403631	33125148	RASA1 mutation or epigenetic inactivation has been revealed in numerous human cancers, which has attracted interest for further investigation.	('mutation', 'Var', (6, 14))	('human', 'Species', '9606', (72, 77))	('cancers', 'Disease', 'MESH:D009369', (78, 85))	('cancers', 'Phenotype', 'HP:0002664', (78, 85))	('cancers', 'Disease', (78, 85))	('revealed', 'Reg', (51, 59))	('epigenetic inactivation', 'Var', (18, 41))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('RASA1', 'Gene', (0, 5))
403640	33125148	RASA1 is necessary for the normal development and function of T cells and a study has revealed that RASA1-deficiency in mice increased apoptosis of CD4+CD8+ double-positive thymocytes.	('apoptosis', 'CPA', (135, 144))	('mice', 'Species', '10090', (120, 124))	('increased', 'PosReg', (125, 134))	('RASA1-deficiency', 'Var', (100, 116))	('CD4', 'Gene', (148, 151))	('RASA1-deficiency', 'Gene', (100, 116))	('CD4', 'Gene', '12504', (148, 151))	('men', 'Species', '9606', (41, 44))
403643	33125148	Since RASA1 is a central player of angiogenesis, studies have focused on RASA1 mutation or loss-of-function in vascular diseases such as capillary malformation-arteriovenous malformation (CM-AVM) syndrome, Klippel-Trenaunay-Weber syndrome (KTWS), Sturgeon-Weber syndrome (SWS), vein of Galen aneurysmal malformation (VGAM), MEF2C-related disorders, and Parkes-Weber syndrome (PKWS).	('CM', 'Phenotype', 'HP:0025104', (188, 190))	('vascular diseases', 'Disease', (111, 128))	('SWS', 'Disease', (272, 275))	('Weber syndrome', 'Phenotype', 'HP:0002277', (256, 270))	('Klippel-Trenaunay-Weber syndrome', 'Disease', (206, 238))	('aneurysmal malformation', 'Phenotype', 'HP:0002617', (292, 315))	('Sturgeon-Weber syndrome', 'Disease', (247, 270))	('Weber syndrome', 'Phenotype', 'HP:0002277', (224, 238))	('Sturgeon-Weber syndrome', 'Disease', 'MESH:D020526', (247, 270))	('RASA1', 'Gene', (73, 78))	('vascular diseases', 'Disease', 'MESH:D000783', (111, 128))	('KTWS', 'Gene', (240, 244))	('MEF2C', 'Gene', '4208', (324, 329))	('Klippel-Trenaunay-Weber syndrome', 'Disease', 'MESH:D007715', (206, 238))	('capillary malformation', 'Phenotype', 'HP:0025104', (137, 159))	('KTWS', 'Gene', '791122', (240, 244))	('Galen aneurysmal malformation', 'Disease', 'MESH:C536535', (286, 315))	('arteriovenous malformation', 'Phenotype', 'HP:0100026', (160, 186))	('mutation', 'Var', (79, 87))	('vein of Galen aneurysmal malformation', 'Phenotype', 'HP:0030713', (278, 315))	('SWS', 'Disease', 'MESH:D013341', (272, 275))	('Galen aneurysmal malformation', 'Disease', (286, 315))	('MEF2C', 'Gene', (324, 329))	('Weber syndrome', 'Phenotype', 'HP:0002277', (360, 374))	('Parkes-Weber syndrome', 'Disease', (353, 374))	('capillary malformation-arteriovenous malformation (CM-AVM) syndrome', 'Disease', 'MESH:D002538', (137, 204))	('Parkes-Weber syndrome', 'Disease', 'MESH:D013341', (353, 374))	('VGAM', 'Phenotype', 'HP:0030713', (317, 321))	('loss-of-function', 'NegReg', (91, 107))
403647	33125148	Mutations in RAP1A have been associated with KTWS and interact with RASA1 and Krev interaction trapped protein 1 (KRIT1).	('Krev interaction trapped protein 1', 'Gene', '889', (78, 112))	('KRIT1', 'Gene', (114, 119))	('KTWS', 'Gene', '791122', (45, 49))	('interact', 'Reg', (54, 62))	('RAP1A', 'Gene', '5906', (13, 18))	('KRIT1', 'Gene', '889', (114, 119))	('KTWS', 'Gene', (45, 49))	('RAP1A', 'Gene', (13, 18))	('Mutations', 'Var', (0, 9))	('associated', 'Reg', (29, 39))	('Krev interaction trapped protein 1', 'Gene', (78, 112))
403648	33125148	Patients with SWS harbour vascular malformations in the face, eyes, and brain due to a mutation in RASA1.	('Patients', 'Species', '9606', (0, 8))	('RASA1', 'Gene', (99, 104))	('mutation', 'Var', (87, 95))	('SWS harbour vascular malformations', 'Disease', (14, 48))	('SWS harbour vascular malformations', 'Disease', 'MESH:D013341', (14, 48))
403650	33125148	VGAM encompasses a rare vascular malformation in the brain of children caused by RASA1, endoglin, and activin receptor-like kinase 1 (ACVRL1) mutations, which encode for ALK1 and SMAD4.	('VGAM', 'Disease', (0, 4))	('mutations', 'Var', (142, 151))	('ALK1', 'Gene', (170, 174))	('children', 'Species', '9606', (62, 70))	('SMAD4', 'Gene', '4089', (179, 184))	('ALK1', 'Gene', '94', (170, 174))	('activin receptor-like kinase 1', 'Gene', (102, 132))	('endoglin', 'Gene', (88, 96))	('SMAD4', 'Gene', (179, 184))	('caused', 'Reg', (71, 77))	('ACVRL1', 'Gene', (134, 140))	('activin receptor-like kinase 1', 'Gene', '94', (102, 132))	('RASA1', 'Gene', (81, 86))	('VGAM', 'Phenotype', 'HP:0030713', (0, 4))	('ACVRL1', 'Gene', '94', (134, 140))	('endoglin', 'Gene', '2022', (88, 96))
403653	33125148	Moreover, RASA1 mutation and a decrease in MECP2 and CDKL5 expression have been correlated with this disease.	('MECP2', 'Gene', '4204', (43, 48))	('mutation', 'Var', (16, 24))	('CDKL5', 'Gene', (53, 58))	('decrease', 'NegReg', (31, 39))	('expression', 'MPA', (59, 69))	('MECP2', 'Gene', (43, 48))	('CDKL5', 'Gene', '6792', (53, 58))	('RASA1', 'Gene', (10, 15))
403654	33125148	PKWS is a rare vascular malformation syndrome with extensive capillary malformations that appear at birth or during early childhood and patients exhibit mutation of RASA1 that leads to a loss of function.	('loss', 'NegReg', (187, 191))	('vascular malformation syndrome', 'Disease', 'MESH:D000014', (15, 45))	('capillary malformation', 'Phenotype', 'HP:0025104', (61, 83))	('extensive capillary malformations', 'Disease', (51, 84))	('vascular malformation syndrome', 'Disease', (15, 45))	('capillary malformations', 'Phenotype', 'HP:0025104', (61, 84))	('patients', 'Species', '9606', (136, 144))	('extensive capillary malformations', 'Disease', 'MESH:D000014', (51, 84))	('PKWS', 'Disease', (0, 4))	('RASA1', 'Gene', (165, 170))	('mutation', 'Var', (153, 161))
403655	33125148	ENG, ACVRL1, and SMAD4 are components of transforming growth factor-beta (TGB-beta) signalling and mutations in these genes can cause HHT, which is the most commonly inherited vascular disorder.	('HHT', 'Disease', (134, 137))	('transforming growth factor-beta', 'Gene', (41, 72))	('ENG', 'Gene', (0, 3))	('transforming growth factor-beta', 'Gene', '7124', (41, 72))	('SMAD4', 'Gene', '4089', (17, 22))	('inherited vascular disorder', 'Disease', (166, 193))	('ACVRL1', 'Gene', (5, 11))	('HHT', 'Disease', 'MESH:D013683', (134, 137))	('vascular disorder', 'Phenotype', 'HP:0002597', (176, 193))	('mutations', 'Var', (99, 108))	('SMAD4', 'Gene', (17, 22))	('ACVRL1', 'Gene', '94', (5, 11))	('cause', 'Reg', (128, 133))	('inherited vascular disorder', 'Disease', 'MESH:D000783', (166, 193))	('ENG', 'Gene', '2022', (0, 3))
403662	33125148	Another study has linked tricuspid atresia, a congenital heart defect with fatal consequences, with the homozygous RASA1 germline mutation c.1583A>G (p.Tyr528Cys).	('tricuspid atresia', 'Disease', (25, 42))	('congenital heart defect', 'Disease', 'MESH:D006330', (46, 69))	('heart defect', 'Phenotype', 'HP:0030680', (57, 69))	('tricuspid atresia', 'Phenotype', 'HP:0011662', (25, 42))	('c.1583A>G', 'Mutation', 'rs145752649', (139, 148))	('p.Tyr528Cys', 'Mutation', 'rs145752649', (150, 161))	('congenital heart defect', 'Disease', (46, 69))	('c.1583A>G', 'Var', (139, 148))	('congenital heart defect', 'Phenotype', 'HP:0001627', (46, 69))	('tricuspid atresia', 'Disease', 'MESH:D018785', (25, 42))
403672	33125148	In tumour development, mutations of Ras at residues 12, 13, or 61 affect the activity of intracellular guanosine triohosphte (GTP), which alternates between GDP and GTP forms and activates RasGAP proteins and Ras by Ras GTPase, regulating the guanine nucleotide exchange factors (RasGEFs).	('RasGAP proteins', 'Protein', (189, 204))	('Ras', 'Protein', (209, 212))	('affect', 'Reg', (66, 72))	('tumour', 'Phenotype', 'HP:0002664', (3, 9))	('GDP', 'Chemical', 'MESH:D006153', (157, 160))	('tumour', 'Disease', 'MESH:D009369', (3, 9))	('guanine nucleotide', 'Chemical', 'MESH:D006150', (243, 261))	('Ras', 'Gene', (36, 39))	('mutations', 'Var', (23, 32))	('GTP', 'Chemical', '-', (220, 223))	('tumour', 'Disease', (3, 9))	('activates', 'PosReg', (179, 188))	('activity', 'MPA', (77, 85))	('guanine nucleotide exchange factors', 'MPA', (243, 278))	('GTP', 'Chemical', '-', (165, 168))	('guanosine triohosphte', 'Chemical', '-', (103, 124))	('GTP', 'Chemical', '-', (126, 129))	('men', 'Species', '9606', (17, 20))
403674	33125148	It has been revealed that abnormal or downregulation of RASA1 expression affects tumorigenesis and the continued technological development in the field of molecular biology allows for more in-depth research, where it has been found that the expression of RASA1 in most tumour cells is associated with intracellular miRNA.	('RASA1', 'Gene', (56, 61))	('intracellular miRNA', 'Disease', (301, 320))	('RASA1', 'Gene', (255, 260))	('tumorigenesis', 'CPA', (81, 94))	('downregulation', 'NegReg', (38, 52))	('associated', 'Reg', (285, 295))	('men', 'Species', '9606', (134, 137))	('tumour', 'Phenotype', 'HP:0002664', (269, 275))	('tumour', 'Disease', 'MESH:D009369', (269, 275))	('affects', 'Reg', (73, 80))	('abnormal', 'Var', (26, 34))	('tumour', 'Disease', (269, 275))
403677	33125148	The occurrence of lung cancer has been linked to RASA1 mutations by next-generation sequencing.	('lung cancer', 'Disease', 'MESH:D008175', (18, 29))	('RASA1', 'Gene', (49, 54))	('mutations', 'Var', (55, 64))	('linked', 'Reg', (39, 45))	('lung cancer', 'Phenotype', 'HP:0100526', (18, 29))	('lung cancer', 'Disease', (18, 29))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))
403680	33125148	Mutations of EGFR result in drug resistance and relapse in patients with non-small cell lung cancer (NSCLC).	('non-small cell lung cancer', 'Disease', (73, 99))	('NSCLC', 'Phenotype', 'HP:0030358', (101, 106))	('NSCLC', 'Disease', (101, 106))	('drug resistance', 'CPA', (28, 43))	('drug resistance', 'Phenotype', 'HP:0020174', (28, 43))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('NSCLC', 'Disease', 'MESH:D002289', (101, 106))	('Mutations', 'Var', (0, 9))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (77, 99))	('patients', 'Species', '9606', (59, 67))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (73, 99))	('result in', 'Reg', (18, 27))	('EGFR', 'Gene', '1956', (13, 17))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (73, 99))	('EGFR', 'Gene', (13, 17))	('relapse', 'CPA', (48, 55))	('lung cancer', 'Phenotype', 'HP:0100526', (88, 99))
403682	33125148	Kitajima and Barbie classified NF1 or RASA1 mutations in small-cell lung carcinoma and proposed the clinical evaluation of MAPK inhibition in an analysis of large genomic datasets of NSCLC [MSK-IMPACT dataset at MSKCC (n=2,004) and TCGA combined lung cancer dataset (n=1,144)].	('NSCLC', 'Phenotype', 'HP:0030358', (183, 188))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('NSCLC', 'Disease', (183, 188))	('lung cancer', 'Disease', 'MESH:D008175', (246, 257))	('lung carcinoma', 'Disease', 'MESH:D008175', (68, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))	('NSCLC', 'Disease', 'MESH:D002289', (183, 188))	('mutations', 'Var', (44, 53))	('lung carcinoma', 'Disease', (68, 82))	('NF1', 'Gene', (31, 34))	('lung cancer', 'Disease', (246, 257))	('lung cancer', 'Phenotype', 'HP:0100526', (246, 257))	('RASA1', 'Gene', (38, 43))
403683	33125148	RASA1 and NF1 mutations are strong drivers of NSCLC.	('NSCLC', 'Disease', (46, 51))	('NSCLC', 'Disease', 'MESH:D002289', (46, 51))	('NF1', 'Gene', (10, 13))	('RASA1', 'Gene', (0, 5))	('mutations', 'Var', (14, 23))	('NSCLC', 'Phenotype', 'HP:0030358', (46, 51))
403685	33125148	A previous study has revealed that FGFR-2 mutation is an important driver of lung cancer, which has become a key target of lung cancer drug development.	('lung cancer', 'Phenotype', 'HP:0100526', (77, 88))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('FGFR-2', 'Gene', (35, 41))	('lung cancer', 'Disease', (123, 134))	('lung cancer', 'Phenotype', 'HP:0100526', (123, 134))	('lung cancer', 'Disease', 'MESH:D008175', (77, 88))	('mutation', 'Var', (42, 50))	('lung cancer', 'Disease', 'MESH:D008175', (123, 134))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('FGFR-2', 'Gene', '2263', (35, 41))	('men', 'Species', '9606', (147, 150))	('lung cancer', 'Disease', (77, 88))
403688	33125148	Colorectal specimens including 468 colorectal tumour samples from a large personalised medicine initiative and 17 paired primary-metastatic and 2 metastatic-metastatic specimens from 18 CRC patients were analysed by next-generation sequencing to reveal the presence of RASA1 mutations.	('mutations', 'Var', (275, 284))	('colorectal tumour', 'Disease', 'MESH:D015179', (35, 52))	('patients', 'Species', '9606', (190, 198))	('colorectal tumour', 'Disease', (35, 52))	('RASA1', 'Gene', (269, 274))	('men', 'Species', '9606', (173, 176))	('men', 'Species', '9606', (16, 19))	('Colorectal', 'Disease', (0, 10))	('CRC', 'Phenotype', 'HP:0003003', (186, 189))	('tumour', 'Phenotype', 'HP:0002664', (46, 52))	('Colorectal', 'Disease', 'MESH:D015179', (0, 10))
403700	33125148	RASA1 is as an effector of KRAS mutation and may play an important role as a drug treatment target.	('KRAS', 'Gene', (27, 31))	('mutation', 'Var', (32, 40))	('KRAS', 'Gene', '3845', (27, 31))	('men', 'Species', '9606', (87, 90))
403701	33125148	However, studies using CRISPR technology have described that only loss of NF1 promotes resistance to EGFR inhibition.	('promotes', 'PosReg', (78, 86))	('NF1', 'Gene', (74, 77))	('loss', 'Var', (66, 70))	('EGFR', 'Gene', '1956', (101, 105))	('EGFR', 'Gene', (101, 105))
403703	33125148	Mutations of RASA1 have been found by detecting RASA1 and other members of the RasGAP family through sequencing of liver cancer tissue genes.	('RASA1', 'Gene', (48, 53))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('liver cancer', 'Phenotype', 'HP:0002896', (115, 127))	('detecting', 'Reg', (38, 47))	('Mutations', 'Var', (0, 9))	('liver cancer', 'Disease', 'MESH:D006528', (115, 127))	('liver cancer', 'Disease', (115, 127))	('RASA1', 'Gene', (13, 18))
403715	33125148	Breast cancer is the second leading cause of cancer related-deaths in women (2.08 million new cases and 0.62 million deaths in 2018) and although the genotyping of breast cancers and the subsequent targeted treatment significantly improve the curative rate to more than 65%, it remains necessary to discover more tumour markers for further treatment optimisation.	('improve', 'PosReg', (231, 238))	('Breast cancer', 'Phenotype', 'HP:0003002', (0, 13))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('breast cancers', 'Disease', 'MESH:D001943', (164, 178))	('breast cancers', 'Disease', (164, 178))	('men', 'Species', '9606', (345, 348))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('breast cancers', 'Phenotype', 'HP:0003002', (164, 178))	('deaths', 'Disease', 'MESH:D003643', (117, 123))	('tumour', 'Phenotype', 'HP:0002664', (313, 319))	('breast cancer', 'Phenotype', 'HP:0003002', (164, 177))	('deaths', 'Disease', (60, 66))	('cancer', 'Disease', (7, 13))	('tumour', 'Disease', 'MESH:D009369', (313, 319))	('women', 'Species', '9606', (70, 75))	('tumour', 'Disease', (313, 319))	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('genotyping', 'Var', (150, 160))	('men', 'Species', '9606', (72, 75))	('cancer', 'Disease', (171, 177))	('deaths', 'Disease', 'MESH:D003643', (60, 66))	('cancer', 'Disease', (45, 51))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('men', 'Species', '9606', (212, 215))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('Breast cancer', 'Disease', 'MESH:D001943', (0, 13))	('curative rate', 'CPA', (243, 256))	('cancers', 'Phenotype', 'HP:0002664', (171, 178))	('cancer', 'Disease', 'MESH:D009369', (7, 13))	('Breast cancer', 'Disease', (0, 13))	('deaths', 'Disease', (117, 123))
403717	33125148	This is consistent with a study that demonstrated the presence of 7 genetic mutations in breast cancer, which included RASA1 mutations.	('mutations', 'Var', (125, 134))	('breast cancer', 'Disease', 'MESH:D001943', (89, 102))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('breast cancer', 'Disease', (89, 102))	('breast cancer', 'Phenotype', 'HP:0003002', (89, 102))	('RASA1', 'Gene', (119, 124))
403726	33125148	RASA1 mutation and abnormal expression is also regarded as a contributing factor to the development of gynaecologic tumours such as cervical and ovarian cancer.	('tumour', 'Phenotype', 'HP:0002664', (116, 122))	('tumours', 'Phenotype', 'HP:0002664', (116, 123))	('expression', 'MPA', (28, 38))	('mutation', 'Var', (6, 14))	('ovarian cancer', 'Phenotype', 'HP:0100615', (145, 159))	('tumours', 'Disease', 'MESH:D009369', (116, 123))	('men', 'Species', '9606', (95, 98))	('tumours', 'Disease', (116, 123))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('contributing', 'Reg', (61, 73))	('RASA1', 'Gene', (0, 5))	('cervical and ovarian cancer', 'Disease', 'MESH:D002575', (132, 159))
403734	33125148	Lubeck et al confirmed that a lack of RasGAP alone in T cells in RASA1 and NF1 double-deficient mice leads to the development of T cell acute lymphoblastic leukaemia/lymphoma.	('acute lymphoblastic leukaemia', 'Phenotype', 'HP:0006721', (136, 165))	('T cell acute lymphoblastic leukaemia/lymphoma', 'Disease', 'MESH:D054218', (129, 174))	('mice', 'Species', '10090', (96, 100))	('men', 'Species', '9606', (121, 124))	('RasGAP', 'Protein', (38, 44))	('NF1', 'Gene', (75, 78))	('lack', 'Var', (30, 34))	('T cell acute lymphoblastic leukaemia/lymphoma', 'Disease', (129, 174))	('lymphoma', 'Phenotype', 'HP:0002665', (166, 174))
403739	33125148	By sequencing the entire genome of 50 paired primary tumours of the tongue and 120 OSCC from male individuals in Taiwan, it has been revealed that RASA1 variants are related to cigarette smoking, betel nut chewing, human papillomavirus infection, and tumour stage.	('RASA1', 'Gene', (147, 152))	('related', 'Reg', (166, 173))	('tumour', 'Phenotype', 'HP:0002664', (53, 59))	('tumour', 'Phenotype', 'HP:0002664', (251, 257))	('tumours', 'Disease', 'MESH:D009369', (53, 60))	('tumour', 'Disease', (53, 59))	('tumours', 'Disease', (53, 60))	('papillomavirus infection', 'Disease', 'MESH:D030361', (221, 245))	('tumour', 'Disease', 'MESH:D009369', (251, 257))	('betel', 'Chemical', '-', (196, 201))	('papillomavirus infection', 'Phenotype', 'HP:0012740', (221, 245))	('tumour', 'Disease', (251, 257))	('variants', 'Var', (153, 161))	('tumours', 'Phenotype', 'HP:0002664', (53, 60))	('tumour', 'Disease', 'MESH:D009369', (53, 59))	('human', 'Species', '9606', (215, 220))	('papillomavirus infection', 'Disease', (221, 245))
403740	33125148	The development of betel quid chewing-associated tongue carcinomas has been revealed to be related to mutations in RASA1 and CpG islands.	('betel', 'Chemical', '-', (19, 24))	('carcinomas', 'Phenotype', 'HP:0030731', (56, 66))	('related', 'Reg', (91, 98))	('RASA1', 'Gene', (115, 120))	('carcinoma', 'Phenotype', 'HP:0030731', (56, 65))	('CpG islands', 'Gene', (125, 136))	('tongue carcinomas', 'Disease', (49, 66))	('mutations', 'Var', (102, 111))	('tongue carcinomas', 'Disease', 'MESH:D014062', (49, 66))	('men', 'Species', '9606', (11, 14))
403744	33125148	Kent et al reported that the expression of RASA1 was decreased in pancreatic cancer cells and further study revealed that RNAi knockdown of RASA1 significantly enhanced the progression of pancreatic cancer for both Capan-1 and MiaPaCa2 cell lines consistent with the miR-31 overexpression phenotype.	('progression', 'CPA', (173, 184))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('miR-31', 'Gene', '407035', (267, 273))	('pancreatic cancer', 'Disease', (66, 83))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (188, 205))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (66, 83))	('pancreatic cancer', 'Disease', 'MESH:D010190', (66, 83))	('expression', 'MPA', (29, 39))	('RASA1', 'Gene', (140, 145))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('miR-31', 'Gene', (267, 273))	('pancreatic cancer', 'Disease', (188, 205))	('knockdown', 'Var', (127, 136))	('enhanced', 'PosReg', (160, 168))	('pancreatic cancer', 'Disease', 'MESH:D010190', (188, 205))	('MiaPaCa2', 'CellLine', 'CVCL:0428', (227, 235))
403756	33125148	Mutations in RASA1 are also present in gastric cancer.	('gastric cancer', 'Disease', (39, 53))	('gastric cancer', 'Disease', 'MESH:D013274', (39, 53))	('present', 'Reg', (28, 35))	('gastric cancer', 'Phenotype', 'HP:0012126', (39, 53))	('Mutations', 'Var', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('RASA1', 'Gene', (13, 18))
403760	33125148	Mutation or aberrant expression of RASA1 has also been revealed to be related to the development of cutaneous squamous cell carcinoma and sarcoma.	('cutaneous squamous cell carcinoma', 'Disease', (100, 133))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (110, 133))	('sarcoma', 'Disease', (138, 145))	('RASA1', 'Gene', (35, 40))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('sarcoma', 'Phenotype', 'HP:0100242', (138, 145))	('Mutation', 'Var', (0, 8))	('men', 'Species', '9606', (92, 95))	('cutaneous squamous cell carcinoma', 'Disease', 'MESH:D002294', (100, 133))	('related', 'Reg', (70, 77))	('sarcoma', 'Disease', 'MESH:D012509', (138, 145))	('aberrant expression', 'Var', (12, 31))
403763	33125148	In this review, we revealed that mutations or aberrant expression of RASA1 are present in almost all cancers and tumour cells and that during the development of tumours, Ras/Raf/MEK/ERK play a central role.	('mutations', 'Var', (33, 42))	('tumours', 'Disease', (161, 168))	('cancers', 'Disease', 'MESH:D009369', (101, 108))	('MEK', 'Gene', '5609', (178, 181))	('Raf', 'Gene', (174, 177))	('tumours', 'Phenotype', 'HP:0002664', (161, 168))	('men', 'Species', '9606', (153, 156))	('tumours', 'Disease', 'MESH:D009369', (161, 168))	('ERK', 'Gene', '5594', (182, 185))	('aberrant expression', 'Var', (46, 65))	('RASA1', 'Gene', (69, 74))	('MEK', 'Gene', (178, 181))	('tumour', 'Phenotype', 'HP:0002664', (113, 119))	('tumour', 'Disease', 'MESH:D009369', (113, 119))	('tumour', 'Phenotype', 'HP:0002664', (161, 167))	('tumour', 'Disease', 'MESH:D009369', (161, 167))	('tumour', 'Disease', (113, 119))	('tumour', 'Disease', (161, 167))	('ERK', 'Gene', (182, 185))	('Raf', 'Gene', '22882', (174, 177))	('cancers', 'Phenotype', 'HP:0002664', (101, 108))	('cancers', 'Disease', (101, 108))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))
403767	33125148	In addition, loss of RASA1 function can enhance RAS-ERK signal amplification.	('ERK', 'Gene', '5594', (52, 55))	('ERK', 'Gene', (52, 55))	('enhance', 'PosReg', (40, 47))	('loss', 'Var', (13, 17))	('RASA1', 'Gene', (21, 26))
403769	33125148	Some studies have revealed that aberrant RASA1 expression activates PI3K/AKT signalling.	('activates', 'PosReg', (58, 67))	('RASA1', 'Gene', (41, 46))	('AKT', 'Gene', (73, 76))	('PI3', 'Gene', '5266', (68, 71))	('PI3', 'Gene', (68, 71))	('aberrant', 'Var', (32, 40))	('AKT', 'Gene', '207', (73, 76))
403776	33125148	Normal or balanced expression levels of RASA1 promote normal blood vessel development; aberrant or imbalanced RASA1 expression levels result vascular-related diseases such as CM-AVM or KTWS.	('vascular-related diseases', 'Disease', (141, 166))	('KTWS', 'Gene', '791122', (185, 189))	('result', 'Reg', (134, 140))	('RASA1', 'Gene', (110, 115))	('KTWS', 'Gene', (185, 189))	('CM-AVM', 'Disease', (175, 181))	('aberrant', 'Var', (87, 95))	('CM', 'Phenotype', 'HP:0025104', (175, 177))	('men', 'Species', '9606', (81, 84))	('imbalance', 'Phenotype', 'HP:0002172', (99, 108))	('expression levels', 'MPA', (116, 133))	('imbalanced', 'Var', (99, 109))
403782	33125148	Therefore, for some cancers with a less clear mechanism of action, the aberrant expression of RASA1 may be used to advance cancer treatment strategies.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('RASA1', 'Gene', (94, 99))	('men', 'Species', '9606', (135, 138))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('cancer', 'Disease', 'MESH:D009369', (20, 26))	('cancer', 'Disease', (20, 26))	('cancer', 'Disease', (123, 129))	('cancers', 'Phenotype', 'HP:0002664', (20, 27))	('cancers', 'Disease', (20, 27))	('cancers', 'Disease', 'MESH:D009369', (20, 27))	('aberrant expression', 'Var', (71, 90))	('advance', 'PosReg', (115, 122))
403786	32155325	Here, WGCNA modeling yielded blue and brown comethylation modules that were significantly associated with OSCC status.	('associated', 'Reg', (90, 100))	('OSCC status', 'Disease', (106, 117))	('WGCNA', 'Chemical', '-', (6, 11))	('blue', 'Var', (29, 33))
403791	32155325	Pearson's correlation analysis showed that methylation levels of cg06509239 and cg18335068 were negatively related to OSR1 and ZNF677 expression levels, respectively.	('methylation levels', 'MPA', (43, 61))	('OSR1', 'Gene', (118, 122))	('ZNF677', 'Gene', '342926', (127, 133))	('negatively', 'NegReg', (96, 106))	('OSR1', 'Gene', '130497', (118, 122))	('cg06509239', 'Var', (65, 75))	('cg18335068', 'Chemical', '-', (80, 90))	('cg18335068', 'Var', (80, 90))	('ZNF677', 'Gene', (127, 133))	('cg06509239', 'Chemical', '-', (65, 75))
403821	32155325	The primers used for the each target gene CpG sites (OSR1 cg06509239 and ZNF677 cg18335068) and for the internal reference gene (ACTB) are listed in Table 1.	('cg06509239', 'Var', (58, 68))	('OSR1', 'Gene', (53, 57))	('ACTB', 'Gene', (129, 133))	('ZNF677', 'Gene', '342926', (73, 79))	('cg18335068', 'Chemical', '-', (80, 90))	('OSR1', 'Gene', '130497', (53, 57))	('cg18335068', 'Var', (80, 90))	('ACTB', 'Gene', '60', (129, 133))	('cg06509239', 'Chemical', '-', (58, 68))	('ZNF677', 'Gene', (73, 79))
403830	32155325	In the sample dendrogram and trait heat map, the samples and related clinical information were connected by WGCNA, with two outlier samples (GSM944918 and GSM944919) excluded using the flashClust function (Figure 1A).	('GSM944918', 'Var', (141, 150))	('GSM944919', 'Var', (155, 164))	('WGCNA', 'Chemical', '-', (108, 113))
403860	32155325	The results showed that methylation levels of cg06509239 and cg18335068 were negatively related to OSR1 (R 2 = .255) and ZNF677 (R 2 = .2724) mRNA levels, respectively.	('mRNA levels', 'MPA', (142, 153))	('cg06509239', 'Chemical', '-', (46, 56))	('ZNF677', 'Gene', '342926', (121, 127))	('methylation levels', 'MPA', (24, 42))	('OSR1', 'Gene', (99, 103))	('OSR1', 'Gene', '130497', (99, 103))	('cg06509239', 'Var', (46, 56))	('negatively', 'NegReg', (77, 87))	('ZNF677', 'Gene', (121, 127))	('cg18335068', 'Chemical', '-', (61, 71))	('cg18335068', 'Var', (61, 71))
403862	32155325	In Figure 7C, methylation ratio of cg06509239 (R 2 = .2679) and cg18335068 (R 2 = .1994) was also decreased, accompanied by the increase in expression levels of OSR1 and ZNF677 (P < .05) in a negatively dependent manner.	('ZNF677', 'Gene', (170, 176))	('increase', 'PosReg', (128, 136))	('cg18335068', 'Chemical', '-', (64, 74))	('cg18335068', 'Var', (64, 74))	('cg06509239', 'Var', (35, 45))	('OSR1', 'Gene', (161, 165))	('ZNF677', 'Gene', '342926', (170, 176))	('OSR1', 'Gene', '130497', (161, 165))	('cg06509239', 'Chemical', '-', (35, 45))	('decreased', 'NegReg', (98, 107))	('methylation ratio', 'MPA', (14, 31))	('expression levels', 'MPA', (140, 157))
403863	32155325	Thus, these findings demonstrate that the decrease in OSR1 and ZNF677 expression levels in OSCC samples could be associated with the hypermethylated-CpG sites.	('OSR1', 'Gene', (54, 58))	('ZNF677', 'Gene', '342926', (63, 69))	('expression levels', 'MPA', (70, 87))	('OSR1', 'Gene', '130497', (54, 58))	('hypermethylated-CpG', 'Var', (133, 152))	('decrease', 'NegReg', (42, 50))	('ZNF677', 'Gene', (63, 69))
403872	32155325	Three hub methylated-CpG sites (cg21376883, cg06509239, and cg18335068) and their associated genes were characterized by divergent methylated patterns, expression FC, and significant association with survival outcomes.	('cg06509239', 'Chemical', '-', (44, 54))	('cg21376883', 'Var', (32, 42))	('hub', 'Gene', '1993', (6, 9))	('cg21376883', 'Chemical', '-', (32, 42))	('association', 'Interaction', (183, 194))	('cg18335068', 'Chemical', '-', (60, 70))	('hub', 'Gene', (6, 9))	('cg18335068', 'Var', (60, 70))	('cg06509239', 'Var', (44, 54))
403875	32155325	However, hypermethylated-cg21376883 in OSCC samples was not correlated with the low levels of ACTN2 (Data not shown).	('cg21376883', 'Chemical', '-', (25, 35))	('ACTN2', 'Gene', (94, 99))	('OSCC', 'Disease', (39, 43))	('ACTN2', 'Gene', '88', (94, 99))	('hypermethylated-cg21376883', 'Var', (9, 35))
403876	32155325	cg21376883 was an independent favorable prognostic indicator for OSCC survival (Logrank P = .015).	('cg21376883', 'Var', (0, 10))	('OSCC', 'Disease', (65, 69))	('cg21376883', 'Chemical', '-', (0, 10))
403880	32155325	However, hypermethylation CpG site ZNF677-cg18335068 (log-rank P = .0048) was associated with an improved prognosis using the data from MethSurv.	('cg18335068', 'Chemical', '-', (42, 52))	('ZNF677', 'Gene', '342926', (35, 41))	('improved', 'PosReg', (97, 105))	('hypermethylation', 'Var', (9, 25))	('MethSurv', 'Chemical', '-', (136, 144))	('ZNF677', 'Gene', (35, 41))
403881	32155325	Because of 2 public data onto overall survival be used, it seems like that hypermethylation of cg18335068 and lower expression of ZNF677 in OSCC are inconsistent with the tumor suppressor functions in other cancers.	('expression', 'MPA', (116, 126))	('cancers', 'Disease', 'MESH:D009369', (207, 214))	('cancers', 'Phenotype', 'HP:0002664', (207, 214))	('cg18335068', 'Gene', (95, 105))	('ZNF677', 'Gene', (130, 136))	('cancers', 'Disease', (207, 214))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('lower', 'NegReg', (110, 115))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('OSCC', 'Disease', (140, 144))	('ZNF677', 'Gene', '342926', (130, 136))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', (171, 176))	('hypermethylation', 'Var', (75, 91))	('cg18335068', 'Chemical', '-', (95, 105))
403883	32155325	The odd-skipped related 1 (OSR1) gene, located on human chromosome 2p24.1, is a transcription factor that plays a part in the regulation of embryonic heart and urogenital development.42 OSR1 methylation is closely related to the development of several different cancer types.43 Methylation of OSR1 has been shown to be a sensitive indicator of the detection of recurrent urothelial cell carcinoma.44 In addition, OSR1 hypermethylation was identified as an independent predictor of poor survival in gastric cancer patients.45 OSR1 also showed clinical potential as a biomarker in lung adenocarcinoma,46 owing to the inactivity of the Wnt signaling pathway resulting from a decrease in SOX9 and beta-catenin levels.47 Moreover, OSR1 blocks cell migration and invasion through inhibiting the NF-kappaB pathway in tongue squamous cell carcinoma.43 OSR1 could serve as a novel epigenetic silenced tumor suppressor downregulating invasion and proliferation in renal cell carcinoma.48 In this study, OSR1 methylated cg06509239 was highly correlated with OSCC status and negatively associated with expression levels in MethHC and our cohort.	('cg06509239', 'Var', (1009, 1019))	('NF-kappaB', 'Gene', '4790', (789, 798))	('OSR1', 'Gene', '130497', (186, 190))	('OSR1', 'Gene', (525, 529))	('carcinoma', 'Phenotype', 'HP:0030731', (589, 598))	('beta-catenin', 'Gene', '1499', (693, 705))	('patients', 'Species', '9606', (513, 521))	('OSR1', 'Gene', '130497', (844, 848))	('tumor', 'Disease', (892, 897))	('OSR1', 'Gene', (293, 297))	('human', 'Species', '9606', (50, 55))	('gastric cancer', 'Disease', (498, 512))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (817, 840))	('cancer', 'Disease', 'MESH:D009369', (506, 512))	('OSR1', 'Gene', '130497', (993, 997))	('OSR1', 'Gene', '130497', (413, 417))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (954, 974))	('tumor', 'Disease', 'MESH:D009369', (892, 897))	('associated', 'Interaction', (1074, 1084))	('renal cell carcinoma', 'Disease', (954, 974))	('OSR1', 'Gene', '130497', (525, 529))	('OSR1', 'Gene', '130497', (27, 31))	('carcinoma', 'Phenotype', 'HP:0030731', (831, 840))	('carcinoma', 'Phenotype', 'HP:0030731', (387, 396))	('OSR1', 'Gene', (726, 730))	('odd-skipped related 1', 'Gene', (4, 25))	('cancer', 'Disease', (262, 268))	('gastric cancer', 'Disease', 'MESH:D013274', (498, 512))	('embryonic heart', 'Disease', 'MESH:D006331', (140, 155))	('SOX9', 'Gene', (684, 688))	('correlated', 'Reg', (1031, 1041))	('OSR1', 'Gene', '130497', (293, 297))	('cancer', 'Phenotype', 'HP:0002664', (262, 268))	('embryonic heart', 'Disease', (140, 155))	('urothelial cell carcinoma', 'Disease', (371, 396))	('OSR1', 'Gene', (27, 31))	('methylated cg06509239', 'Var', (998, 1019))	('negatively', 'NegReg', (1063, 1073))	('expression levels', 'MPA', (1090, 1107))	('tumor', 'Phenotype', 'HP:0002664', (892, 897))	('lung adenocarcinoma', 'Disease', (579, 598))	('OSCC status', 'MPA', (1047, 1058))	('tongue squamous cell carcinoma', 'Disease', 'MESH:D002294', (810, 840))	('OSR1', 'Gene', (186, 190))	('carcinoma', 'Phenotype', 'HP:0030731', (965, 974))	('odd-skipped related 1', 'Gene', '130497', (4, 25))	('cancer', 'Disease', (506, 512))	('OSR1', 'Gene', '130497', (726, 730))	('urothelial cell carcinoma', 'Disease', 'MESH:C538614', (371, 396))	('OSR1', 'Gene', (844, 848))	('cg06509239', 'Chemical', '-', (1009, 1019))	('NF-kappaB', 'Gene', (789, 798))	('beta-catenin', 'Gene', (693, 705))	('SOX9', 'Gene', '6662', (684, 688))	('cancer', 'Phenotype', 'HP:0002664', (506, 512))	('gastric cancer', 'Phenotype', 'HP:0012126', (498, 512))	('OSR1', 'Gene', (993, 997))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (579, 598))	('OSR1', 'Gene', (413, 417))	('tongue squamous cell carcinoma', 'Disease', (810, 840))	('cancer', 'Disease', 'MESH:D009369', (262, 268))
403884	32155325	In OSCC, the low levels of OSR1 were probably downregulated by the high ratio of methylated cg06509239.	('cg06509239', 'Chemical', '-', (92, 102))	('OSR1', 'Gene', (27, 31))	('OSR1', 'Gene', '130497', (27, 31))	('methylated cg06509239', 'Var', (81, 102))	('downregulated', 'NegReg', (46, 59))	('cg06509239', 'Var', (92, 102))	('OSCC', 'Disease', (3, 7))
403885	32155325	Thus, OSR1 expression and its CpG spot cg06509239 could serve as prognostic indicators for OSCC.	('cg06509239', 'Chemical', '-', (39, 49))	('OSCC', 'Disease', (91, 95))	('OSR1', 'Gene', (6, 10))	('OSR1', 'Gene', '130497', (6, 10))	('cg06509239', 'Var', (39, 49))
403890	27716417	A focused analysis of tumors from six tissues reveals that rare patient-specific gene CNAs often have stronger effects on signature genes than frequent gene CNAs.	('tumors', 'Phenotype', 'HP:0002664', (22, 28))	('patient', 'Species', '9606', (64, 71))	('stronger effects', 'PosReg', (102, 118))	('CNAs', 'Var', (86, 90))	('tumors', 'Disease', 'MESH:D009369', (22, 28))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('tumors', 'Disease', (22, 28))	('signature genes', 'MPA', (122, 137))
403891	27716417	Although only a relatively small fraction of all mutations in any given cancer cell contributes to tumorigenesis, it is emerging that many more genes than previously thought determine clinically relevant endpoints such as proliferation rates, metastatic potential, or drug resistance.	('tumor', 'Disease', (99, 104))	('determine', 'Reg', (174, 183))	('mutations', 'Var', (49, 58))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('drug resistance', 'CPA', (268, 283))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('metastatic potential', 'CPA', (243, 263))	('drug resistance', 'Phenotype', 'HP:0020174', (268, 283))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('proliferation rates', 'CPA', (222, 241))	('cancer', 'Disease', (72, 78))
403894	27716417	mutations that are more frequent than expected by chance in a specific cohort) are more likely to have tumor-related effects, individual cancer risks are most likely not fully explained by frequent mutations alone.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor', 'Disease', (103, 108))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('cancer', 'Disease', (137, 143))	('mutations', 'Var', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
403895	27716417	Rare mutations could act in combination with frequent mutations or they may, entirely independent from frequent mutations, establish a significant risk for the patient on their own.	('patient', 'Species', '9606', (160, 167))	('establish', 'Reg', (123, 132))	('mutations', 'Var', (5, 14))
403896	27716417	Quantifying the risks associated with rare mutations has been complicated by the following reasons: (1) by definition, only a few patients carry these mutations, which reduces the probability of observing them in clinical studies, (2) even if they are observed, it is often difficult to quantify cancer risks statistically by comparing carriers with non-carriers due to insufficient statistical power, (3) complex interactions with other mutations (epistasis) may hide effects when analyzing single mutations in isolation, and (4) rare mutations of individual genes may have weak effects, but the co-occurrence of a sufficient number of such mutations in the same cell could significantly increase cancer risks.	('insufficient', 'Disease', 'MESH:D000309', (370, 382))	('cancer', 'Phenotype', 'HP:0002664', (296, 302))	('cancer', 'Phenotype', 'HP:0002664', (698, 704))	('insufficient', 'Disease', (370, 382))	('cancer', 'Disease', (698, 704))	('increase', 'PosReg', (689, 697))	('patients', 'Species', '9606', (130, 138))	('mutations', 'Var', (43, 52))	('cancer', 'Disease', 'MESH:D009369', (296, 302))	('interactions', 'Interaction', (414, 426))	('cancer', 'Disease', 'MESH:D009369', (698, 704))	('cancer', 'Disease', (296, 302))	('mutations', 'Var', (151, 160))	('mutations', 'Var', (642, 651))
403898	27716417	Apart from SNVs, DNA copy number alterations (CNAs) and chromosomal instability are a hallmark of cancer.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('chromosomal instability', 'Phenotype', 'HP:0040012', (56, 79))	('chromosomal instability', 'CPA', (56, 79))	('cancer', 'Disease', (98, 104))	('DNA copy number alterations', 'Var', (17, 44))
403899	27716417	Further, CNA-affected genes with altered expression levels are more likely to be involved in tumorigenesis than affected genes with unchanged expression levels.	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('expression', 'MPA', (41, 51))	('involved', 'Reg', (81, 89))	('tumor', 'Disease', (93, 98))	('CNA-affected', 'Disease', (9, 21))	('altered', 'Var', (33, 40))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
403901	27716417	All these methods (and many others) have greatly contributed to the identification of potential CNA tumor driver mutations and a better understanding of tumorigenesis, but none of these methods allows us to quantify the impact of rare gene CNAs.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('tumor', 'Disease', (100, 105))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('mutations', 'Var', (113, 122))	('tumor', 'Disease', 'MESH:D009369', (100, 105))
403904	27716417	Recently, another study proposed a network-based method that enables the identification of rare mutations involved in the perturbation of pathways and protein complexes involved in tumorigenesis.	('tumor', 'Disease', (181, 186))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('mutations', 'Var', (96, 105))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))
403966	27716417	We confirm that an increased HAX1 copy number contributes to an increased HAX1 expression level with downstream effects on the expression of TSEN15 (Additional file 3: Table S2).	('HAX1', 'Gene', (29, 33))	('TSEN15', 'Gene', '116461', (141, 147))	('HAX1', 'Gene', '10456', (74, 78))	('HAX1', 'Gene', (74, 78))	('expression', 'MPA', (127, 137))	('copy number', 'Var', (34, 45))	('TSEN15', 'Gene', (141, 147))	('increased', 'PosReg', (19, 28))	('increased', 'PosReg', (64, 73))	('HAX1', 'Gene', '10456', (29, 33))	('effects', 'Reg', (112, 119))	('expression level', 'MPA', (79, 95))
403968	27716417	Our impact analysis further predicts TSEN15 as a downstream target of two other high-impact gene deletions of PLXNB2 and CHAC1 that both strongly impact on the expression of TSEN15.	('expression', 'MPA', (160, 170))	('PLXNB2', 'Gene', '23654', (110, 116))	('impact', 'Reg', (146, 152))	('CHAC1', 'Gene', (121, 126))	('TSEN15', 'Gene', (174, 180))	('TSEN15', 'Gene', '116461', (37, 43))	('TSEN15', 'Gene', '116461', (174, 180))	('deletions', 'Var', (97, 106))	('PLXNB2', 'Gene', (110, 116))	('TSEN15', 'Gene', (37, 43))	('CHAC1', 'Gene', '79094', (121, 126))
403973	27716417	The amplification of the oncogene EGFR on chromosome 7 is involved in GBM etiology.	('EGFR', 'Gene', (34, 38))	('involved', 'Reg', (58, 66))	('GBM', 'Disease', (70, 73))	('amplification', 'Var', (4, 17))	('EGFR', 'Gene', '1956', (34, 38))
403978	27716417	For example, amplifications of the tumor suppressor genes WAC in GBM (97 tumors with amplifications vs 218 tumors with normal gene copy number, Fig.	('tumor', 'Disease', (107, 112))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumors', 'Disease', (73, 79))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('WAC', 'Gene', (58, 61))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('tumor', 'Disease', (35, 40))	('tumors', 'Disease', 'MESH:D009369', (73, 79))	('GBM', 'Gene', (65, 68))	('amplifications', 'Var', (85, 99))	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('amplifications', 'Var', (13, 27))	('tumors', 'Disease', (107, 113))	('tumor', 'Disease', (73, 78))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('tumors', 'Disease', 'MESH:D009369', (107, 113))
403979	27716417	4 a, chromosome 10, p-arm) and CDH1 in OV (61 tumors with amplifications vs 174 tumors with normal gene copy number, Fig.	('CDH1', 'Gene', (31, 35))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('amplifications', 'Var', (58, 72))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('CDH1', 'Gene', '999', (31, 35))	('tumors', 'Disease', (80, 86))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('tumors', 'Disease', (46, 52))	('tumors', 'Disease', 'MESH:D009369', (46, 52))
403981	27716417	We revealed considerable variation between patients with respect to how many and to what extent gene CNAs affect survival signature genes.	('gene CNAs', 'Var', (96, 105))	('patients', 'Species', '9606', (43, 51))	('CNAs', 'Var', (101, 105))	('survival', 'MPA', (113, 121))	('affect', 'Reg', (106, 112))
403987	27716417	In conclusion, the patient-specific expression pattern of survival signature genes can substantially be driven by individual rare gene CNAs, which is consistent with recent findings that patient-specific mutation patterns impact on survival.	('driven', 'Reg', (104, 110))	('patient', 'Species', '9606', (19, 26))	('impact', 'Reg', (222, 228))	('CNAs', 'Var', (135, 139))	('patient', 'Species', '9606', (187, 194))	('expression', 'MPA', (36, 46))
403990	27716417	Second, we considered single-gene tests to determine if patients with a specific gene CNA had significant differences in survival compared to patients without this gene CNA.	('patients', 'Species', '9606', (56, 64))	('survival', 'MPA', (121, 129))	('differences', 'Reg', (106, 117))	('patients', 'Species', '9606', (142, 150))	('CNA', 'Var', (86, 89))
403993	27716417	A first hypothesis was that rare high-impact mutations occur later in the tumor etiology and affect different endpoints than frequent gene CNAs.	('mutations', 'Var', (45, 54))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('affect', 'Reg', (93, 99))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor', 'Disease', (74, 79))
404017	27716417	Based on the score derivation, negative scores are expected to be associated with shorter patient survival than positive scores.	('negative scores', 'Var', (31, 46))	('patient survival', 'CPA', (90, 106))	('patient', 'Species', '9606', (90, 97))	('shorter', 'NegReg', (82, 89))
404032	27716417	The contributions of patient-specific rare and frequent gene CNAs tend to be rather tumor type-specific.	('gene CNAs', 'Var', (56, 65))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('patient', 'Species', '9606', (21, 28))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumor', 'Disease', (84, 89))
404033	27716417	Thus, although the number of cellular endpoints that have to be altered is limited, the space of possible mutational patterns affecting the aggressiveness of a tumor (and ultimately patient survival) is practically unlimited.	('aggressiveness', 'Disease', 'MESH:D001523', (140, 154))	('aggressiveness', 'Disease', (140, 154))	('affecting', 'Reg', (126, 135))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('patient', 'Species', '9606', (182, 189))	('aggressiveness', 'Phenotype', 'HP:0000718', (140, 154))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('mutational', 'Var', (106, 116))	('tumor', 'Disease', (160, 165))
404039	27716417	In addition, the importance of rare and frequent gene CNAs to distinguish between short and long patient survival was also highly tumor type-specific.	('gene CNAs', 'Var', (49, 58))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('patient', 'Species', '9606', (97, 104))	('tumor', 'Disease', (130, 135))
404040	27716417	Further, we found many survival impact genes that are well-established cancer genes in one tissue to be also mutated (with a large predicted impact) in other tumors.	('tumors', 'Disease', (158, 164))	('tumors', 'Phenotype', 'HP:0002664', (158, 164))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('tumors', 'Disease', 'MESH:D009369', (158, 164))	('cancer', 'Disease', (71, 77))	('mutated', 'Var', (109, 116))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('survival impact genes', 'Gene', (23, 44))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))
404047	27716417	Third, the impact scoring (which integrates both models) was predictive for survival in four out of five independent clinical cohorts that were not used for any of the previous analyses, revealing the tumor type-specific contributions of rare and frequent gene CNAs for the separation into long- and short-lived patients.	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('patients', 'Species', '9606', (312, 320))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('gene CNAs', 'Var', (256, 265))	('tumor', 'Disease', (201, 206))
404059	27716417	We have demonstrated this potential for the recurrent duplication of chromosome 7 in glioblastomas, suggesting additional driver genes apart from the known role of EGFR.	('EGFR', 'Gene', (164, 168))	('glioblastomas', 'Phenotype', 'HP:0012174', (85, 98))	('duplication', 'Var', (54, 65))	('glioblastomas', 'Disease', 'MESH:D005909', (85, 98))	('glioblastomas', 'Disease', (85, 98))	('glioblastoma', 'Phenotype', 'HP:0012174', (85, 97))	('EGFR', 'Gene', '1956', (164, 168))
404060	27716417	Since copy number changes play a role in many other diseases or genetic disorders (e.g.	('genetic disorders', 'Disease', (64, 81))	('play', 'Reg', (26, 30))	('role', 'Reg', (33, 37))	('copy number changes', 'Var', (6, 25))	('genetic disorders', 'Disease', 'MESH:D030342', (64, 81))
404108	27716417	The q values of the selected high-impact genes were less than 0.006 for all TCGA cohorts (q value cutoffs: AML < 0.0053, GBM < 0.0048, HNSC < 0.0058, LUAD < 0.0056, OV < 0.0046, and SKCM < 0.0049).	('OV < 0.0046', 'Var', (165, 176))	('HNSC < 0.0058', 'Var', (135, 148))	('AML', 'Disease', 'MESH:D015470', (107, 110))	('AML', 'Disease', (107, 110))
404139	27716417	AML Acute myeloid leukemia BRCA Breast invasive carcinoma CCLE Cancer cell line encyclopedia CCTN Cancer cell transcriptional network CLCGP Clinical lung cancer genome project CNA Copy number alteration CNV Copy number variation COAD Colon adenocarcinoma GBM Glioblastoma multiforme HNSC Head and neck squamous cell carcinoma lasso Least absolute shrinkage and selection operator LINCS Library of Integrated Network-based Cellular Signatures LUAD Lung adenocarcinoma LUSC Lung squamous cell carcinoma OV Ovarian serous cystadenocarcinoma RF Random forest RSF Random survival forest SKCM Skin cutaneous melanoma SNV Single nucleotide variation STAD Stomach adenocarcinoma TCGA The cancer genome atlas THCA Thyroid carcinoma	('Stomach adenocarcinoma', 'Disease', 'MESH:D013274', (648, 670))	('adenocarcinoma', 'Disease', (452, 466))	('Skin cutaneous melanoma', 'Disease', 'MESH:C562393', (587, 610))	('lung cancer', 'Disease', (149, 160))	('adenocarcinoma', 'Disease', 'MESH:D000230', (240, 254))	('adenocarcinoma', 'Disease', 'MESH:D000230', (452, 466))	('adenocarcinoma', 'Disease', (656, 670))	('carcinoma', 'Phenotype', 'HP:0030731', (245, 254))	('Ovarian serous cystadenocarcinoma', 'Disease', 'MESH:D018284', (504, 537))	('RSF', 'Chemical', '-', (555, 558))	('Glioblastoma', 'Phenotype', 'HP:0012174', (259, 271))	('BRCA', 'Gene', (27, 31))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (297, 325))	('Colon adenocarcinoma', 'Disease', 'MESH:D003110', (234, 254))	('cancer', 'Phenotype', 'HP:0002664', (680, 686))	('Ovarian serous cystadenocarcinoma', 'Phenotype', 'HP:0012887', (504, 537))	('Cancer', 'Disease', (63, 69))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('Breast invasive carcinoma', 'Phenotype', 'HP:0003002', (32, 57))	('carcinoma', 'Disease', (528, 537))	('Thyroid carcinoma', 'Phenotype', 'HP:0002890', (705, 722))	('adenocarcinoma', 'Disease', (523, 537))	('Cancer', 'Disease', 'MESH:D009369', (63, 69))	('carcinoma', 'Disease', (661, 670))	('BRCA', 'Gene', '672', (27, 31))	('AML', 'Disease', 'MESH:D015470', (0, 3))	('carcinoma', 'Disease', 'MESH:D002277', (528, 537))	('adenocarcinoma', 'Disease', 'MESH:D000230', (523, 537))	('squamous cell carcinoma', 'Disease', (477, 500))	('Cancer', 'Disease', (98, 104))	('carcinoma', 'Disease', 'MESH:D002277', (661, 670))	('Cancer', 'Phenotype', 'HP:0002664', (63, 69))	('Lung adenocarcinoma', 'Phenotype', 'HP:0030078', (447, 466))	('adenocarcinoma', 'Disease', 'MESH:D000230', (656, 670))	('Breast invasive carcinoma', 'Disease', (32, 57))	('carcinoma', 'Disease', 'MESH:D002277', (713, 722))	('Cancer', 'Disease', 'MESH:D009369', (98, 104))	('Skin cutaneous melanoma', 'Disease', (587, 610))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (477, 500))	('carcinoma', 'Disease', 'MESH:D002277', (491, 500))	('carcinoma', 'Disease', 'MESH:D002277', (316, 325))	('COAD', 'Disease', 'MESH:D029424', (229, 233))	('cancer', 'Disease', 'MESH:D009369', (680, 686))	('carcinoma', 'Disease', 'MESH:D002277', (457, 466))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (477, 500))	('carcinoma', 'Disease', (48, 57))	('Cancer', 'Phenotype', 'HP:0002664', (98, 104))	('carcinoma', 'Disease', (713, 722))	('Acute myeloid leukemia', 'Disease', (4, 26))	('carcinoma', 'Phenotype', 'HP:0030731', (491, 500))	('carcinoma', 'Phenotype', 'HP:0030731', (316, 325))	('Colon adenocarcinoma', 'Disease', (234, 254))	('lung cancer', 'Disease', 'MESH:D008175', (149, 160))	('Acute myeloid leukemia', 'Disease', 'MESH:D015470', (4, 26))	('carcinoma', 'Disease', (491, 500))	('carcinoma', 'Disease', (316, 325))	('neck squamous cell carcinoma', 'Disease', (297, 325))	('carcinoma', 'Disease', 'MESH:D002277', (48, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (457, 466))	('carcinoma', 'Disease', (457, 466))	('leukemia', 'Phenotype', 'HP:0001909', (18, 26))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (302, 325))	('Breast invasive carcinoma', 'Disease', 'MESH:D018270', (32, 57))	('CCLE', 'Chemical', '-', (58, 62))	('melanoma', 'Phenotype', 'HP:0002861', (602, 610))	('carcinoma', 'Phenotype', 'HP:0030731', (48, 57))	('Glioblastoma multiforme', 'Disease', 'MESH:D005909', (259, 282))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (302, 325))	('Stomach adenocarcinoma', 'Disease', (648, 670))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('carcinoma', 'Disease', (245, 254))	('COAD', 'Disease', (229, 233))	('AML', 'Disease', (0, 3))	('Acute myeloid leukemia', 'Phenotype', 'HP:0004808', (4, 26))	('Ovarian serous cystadenocarcinoma', 'Disease', (504, 537))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (592, 610))	('lung cancer', 'Phenotype', 'HP:0100526', (149, 160))	('cancer', 'Disease', (680, 686))	('carcinoma', 'Disease', 'MESH:D002277', (245, 254))	('cancer', 'Disease', (154, 160))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (10, 26))	('adenocarcinoma', 'Disease', (240, 254))	('Single nucleotide variation', 'Var', (615, 642))	('Glioblastoma multiforme', 'Disease', (259, 282))
404274	31888490	In tumor-normal, knock down/knock out analysis in primary cultures, or drug trial studies, an incorrectly identified sample can have egregious effects on the resulting data.	('tumor', 'Phenotype', 'HP:0002664', (3, 8))	('tumor', 'Disease', (3, 8))	('knock down/knock', 'Var', (17, 33))	('tumor', 'Disease', 'MESH:D009369', (3, 8))
404322	31888490	This work was supported in part by The Ohio State University Comprehensive Cancer Center and the National Institutes of Health (NIH) [P30 CA016058 (Genomics Shared Resource)]; the NIH grant R50 CA211524-03 to P.Y., and allocations of computation resources from the Ohio Supercomputer Center.	('Cancer', 'Disease', 'MESH:D009369', (75, 81))	('R50 CA211524-03', 'Var', (190, 205))	('Cancer', 'Phenotype', 'HP:0002664', (75, 81))	('Cancer', 'Disease', (75, 81))
404360	24260446	Targeting of Histone Deacetylases to Reactivate Tumour Suppressor Genes and Its Therapeutic Potential in a Human Cervical Cancer Xenograft Model Aberrant histone acetylation plays an essential role in the neoplastic process via the epigenetic silencing of tumour suppressor genes (TSGs); therefore, the inhibition of histone deacetylases (HDAC) has become a promising target in cancer therapeutics.	('Cancer', 'Phenotype', 'HP:0002664', (122, 128))	('histone deacetylase', 'Gene', '9734', (317, 336))	('cancer', 'Disease', 'MESH:D009369', (378, 384))	('Aberrant', 'Var', (145, 153))	('Cancer', 'Disease', (122, 128))	('TSG', 'Gene', '57045', (281, 284))	('epigenetic silencing', 'Var', (232, 252))	('tumour', 'Phenotype', 'HP:0002664', (256, 262))	('TSG', 'Gene', (281, 284))	('histone deacetylase', 'Gene', (317, 336))	('tumour', 'Disease', 'MESH:D009369', (256, 262))	('tumour', 'Disease', (256, 262))	('Cancer', 'Disease', 'MESH:D009369', (122, 128))	('neoplastic process', 'Phenotype', 'HP:0002664', (205, 223))	('cancer', 'Disease', (378, 384))	('Human', 'Species', '9606', (107, 112))	('HDAC', 'Gene', '9734', (339, 343))	('cancer', 'Phenotype', 'HP:0002664', (378, 384))	('Tumour', 'Phenotype', 'HP:0002664', (48, 54))	('HDAC', 'Gene', (339, 343))
404366	24260446	Notably, VPA restored RARbeta2 expression via epigenetic modulation.	('RARbeta', 'Gene', (22, 29))	('epigenetic modulation', 'Var', (46, 67))	('expression', 'MPA', (31, 41))	('RARbeta', 'Gene', '5915', (22, 29))	('VPA', 'Chemical', 'MESH:D014635', (9, 12))
404379	24260446	Studies of epithelial tumours have consistently shown that the downregulation of RARbeta2 is a crucial event in malignancy and that the subsequent aberrant expression of E-cadherin/beta-catenin complexes correlates with the conversion of early-stage tumours into invasive malignancies.	('tumours', 'Phenotype', 'HP:0002664', (250, 257))	('tumours', 'Disease', 'MESH:D009369', (250, 257))	('epithelial tumours', 'Disease', 'MESH:D000077216', (11, 29))	('tumour', 'Phenotype', 'HP:0002664', (250, 256))	('downregulation', 'NegReg', (63, 77))	('beta-catenin', 'Gene', (181, 193))	('E-cadherin', 'Gene', (170, 180))	('E-cadherin', 'Gene', '999', (170, 180))	('beta-catenin', 'Gene', '1499', (181, 193))	('tumours', 'Disease', (22, 29))	('malignancy', 'Disease', 'MESH:D009369', (112, 122))	('epithelial tumours', 'Disease', (11, 29))	('invasive malignancies', 'Disease', (263, 284))	('RARbeta', 'Gene', '5915', (81, 88))	('tumours', 'Phenotype', 'HP:0002664', (22, 29))	('tumour', 'Phenotype', 'HP:0002664', (22, 28))	('RARbeta', 'Gene', (81, 88))	('invasive malignancies', 'Disease', 'MESH:D009369', (263, 284))	('tumours', 'Disease', 'MESH:D009369', (22, 29))	('aberrant', 'Var', (147, 155))	('tumours', 'Disease', (250, 257))	('expression', 'MPA', (156, 166))	('epithelial tumour', 'Phenotype', 'HP:0031492', (11, 28))	('malignancy', 'Disease', (112, 122))
404380	24260446	The loss of RARbeta2 expression in tumour cells has been attributed to the silencing of the gene promoter region via histone deacetylation and hypermethylation.	('histone', 'MPA', (117, 124))	('expression', 'MPA', (21, 31))	('silencing', 'NegReg', (75, 84))	('tumour', 'Phenotype', 'HP:0002664', (35, 41))	('RARbeta', 'Gene', '5915', (12, 19))	('tumour', 'Disease', 'MESH:D009369', (35, 41))	('hypermethylation', 'Var', (143, 159))	('loss', 'NegReg', (4, 8))	('RARbeta', 'Gene', (12, 19))	('tumour', 'Disease', (35, 41))
404453	24260446	The hyperacetylation of lysine 9 on histone H3 (H3K9ac) is usually associated with actively transcribed genes.	('hyperacetylation', 'Var', (4, 20))	('H3K9ac', 'Gene', '126961', (48, 54))	('H3', 'Gene', '126961', (44, 46))	('H3K9ac', 'Gene', (48, 54))	('H3', 'Gene', '126961', (48, 50))	('associated', 'Reg', (67, 77))	('lysine', 'Chemical', 'MESH:D008239', (24, 30))
404465	24260446	Consistent with the tumor volume data, the mean tumor weight of the control group was 0.99+-0.09 g, while the tumor weights for the VPA, ATRA, and the combination treatment groups were 0.402+-0.02 g, 0.618+-0.16 g, and 0.264+-0.09 g, respectively (Figure 3C).	('0.264+-0.09 g', 'Var', (219, 232))	('tumor', 'Disease', (48, 53))	('ATRA', 'Chemical', 'MESH:D014212', (137, 141))	('0.402+-0.02 g', 'Var', (185, 198))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('0.618+-0.16 g', 'Var', (200, 213))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('VPA', 'Chemical', 'MESH:D014635', (132, 135))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('tumor', 'Disease', (20, 25))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
404487	24260446	Therefore, the combination treatment reactivated RARbeta2 expression via epigenetic modification, sequentially enhancing the expression of target genes, including E-cadherin, involucrin, and loricrin (Figures 4 and 6).	('RARbeta', 'Gene', '5915', (49, 56))	('E-cadherin', 'Gene', '999', (163, 173))	('expression', 'MPA', (58, 68))	('involucrin', 'Disease', (175, 185))	('reactivated', 'Var', (37, 48))	('expression', 'MPA', (125, 135))	('enhancing', 'PosReg', (111, 120))	('RARbeta', 'Gene', (49, 56))	('epigenetic modification', 'Var', (73, 96))	('E-cadherin', 'Gene', (163, 173))
404490	24260446	Epigenetic silencing of TSGs is a salient feature of tumour cells.	('tumour', 'Phenotype', 'HP:0002664', (53, 59))	('tumour', 'Disease', (53, 59))	('TSG', 'Gene', '57045', (24, 27))	('Epigenetic silencing', 'Var', (0, 20))	('tumour', 'Disease', 'MESH:D009369', (53, 59))	('TSG', 'Gene', (24, 27))
404491	24260446	Recent studies have indicated that aberrant HDAC activity disturbs normal epigenetic processes through inappropriate deacetylation, thereby leading to euchromatin gene silencing.	('normal epigenetic processes', 'MPA', (67, 94))	('deacetylation', 'MPA', (117, 130))	('aberrant', 'Var', (35, 43))	('disturbs', 'NegReg', (58, 66))	('leading to', 'Reg', (140, 150))	('HDAC', 'Gene', (44, 48))	('euchromatin gene silencing', 'MPA', (151, 177))	('HDAC', 'Gene', '9734', (44, 48))
404495	24260446	Recent studies have verified that the combination of local histone deacetylation and CpG island methylation results in the strong epigenetic repression of RARbeta2 and E-cadherin and, therefore, resistance to the growth inhibitory effects of retinoic acid.	('resistance', 'CPA', (195, 205))	('retinoic acid', 'Chemical', 'MESH:D014212', (242, 255))	('RARbeta', 'Gene', '5915', (155, 162))	('RARbeta', 'Gene', (155, 162))	('methylation', 'Var', (96, 107))	('deacetylation', 'Var', (67, 80))	('E-cadherin', 'Gene', (168, 178))	('E-cadherin', 'Gene', '999', (168, 178))	('epigenetic repression', 'MPA', (130, 151))
404500	24260446	E-cadherin-mediated adhesion plays an essential role in epidermal cell differentiation via the PI3K/Akt pathway by binding to beta-catenin, whereas the ablation of E-cadherin impairs both the survival and the differentiation of epidermal keratinocytes.	('Akt', 'Gene', (100, 103))	('ablation', 'Var', (152, 160))	('beta-catenin', 'Gene', '1499', (126, 138))	('survival', 'CPA', (192, 200))	('impairs', 'NegReg', (175, 182))	('Akt', 'Gene', '207', (100, 103))	('E-cadherin', 'Gene', (164, 174))	('E-cadherin', 'Gene', (0, 10))	('binding', 'Interaction', (115, 122))	('epidermal cell differentiation', 'CPA', (56, 86))	('E-cadherin', 'Gene', '999', (164, 174))	('differentiation of epidermal keratinocytes', 'CPA', (209, 251))	('E-cadherin', 'Gene', '999', (0, 10))	('beta-catenin', 'Gene', (126, 138))
404502	24260446	However, as previous studies indicate, the aberrant acetylation of histones on the RARbeta2 promoter, especially at the core region of the RARE, results in decreased or silenced RARbeta2 expression in many cancer types, including cervical cancer.	('RAR', 'Gene', (83, 86))	('cervical cancer', 'Disease', (230, 245))	('cervical cancer', 'Disease', 'MESH:D002583', (230, 245))	('RAR', 'Gene', (139, 142))	('RAR', 'Gene', '5915', (178, 181))	('cancer', 'Disease', (239, 245))	('cancer', 'Disease', (206, 212))	('RARbeta', 'Gene', '5915', (178, 185))	('RAR', 'Gene', '5915', (83, 86))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))	('RAR', 'Gene', '5915', (139, 142))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('RARbeta', 'Gene', (178, 185))	('RARbeta', 'Gene', '5915', (83, 90))	('decreased', 'NegReg', (156, 165))	('RARbeta', 'Gene', (83, 90))	('acetylation', 'MPA', (52, 63))	('RAR', 'Gene', (178, 181))	('cancer', 'Disease', 'MESH:D009369', (239, 245))	('silenced', 'NegReg', (169, 177))	('expression', 'MPA', (187, 197))	('cancer', 'Disease', 'MESH:D009369', (206, 212))	('aberrant', 'Var', (43, 51))
404538	32656741	The DEK oncogene was initially identified as a target of recurrent t(6;9) translocation, resulting in a fusion with the nuclear pore complex protein-encoding gene NUP214 in a subset of patients with acute myeloid leukemia (AML).	('AML', 'Phenotype', 'HP:0004808', (223, 226))	('AML', 'Disease', (223, 226))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (199, 221))	('NUP214', 'Gene', (163, 169))	('leukemia', 'Phenotype', 'HP:0001909', (213, 221))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (199, 221))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (205, 221))	('NUP214', 'Gene', '8021', (163, 169))	('acute myeloid leukemia', 'Disease', (199, 221))	('patients', 'Species', '9606', (185, 193))	('translocation', 'Var', (74, 87))	('fusion', 'Interaction', (104, 110))	('AML', 'Disease', 'MESH:D015470', (223, 226))
404540	32656741	Some reports in humans and Drosophila have demonstrated that DEK inhibits the histone acetyltransferases p300 and p300/CBP-associating factor (PCAF), resulting in histone H3 and H4 hypoacetylation.	('p300', 'Gene', '2033', (114, 118))	('PCAF', 'Gene', (143, 147))	('inhibits', 'NegReg', (65, 73))	('p300', 'Gene', '2033', (105, 109))	('humans', 'Species', '9606', (16, 22))	('histone', 'MPA', (163, 170))	('Drosophila', 'Species', '7227', (27, 37))	('H4 hypoacetylation', 'MPA', (178, 196))	('PCAF', 'Gene', '8850', (143, 147))	('p300', 'Gene', (105, 109))	('p300', 'Gene', (114, 118))	('DEK', 'Var', (61, 64))
404548	32656741	Thus, abnormalities in the regions of DEK that are necessary for maintaining its normal protein structure might be associated with cancer and cancer stem/progenitor cells.	('cancer', 'Disease', (131, 137))	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('protein structure', 'MPA', (88, 105))	('associated', 'Reg', (115, 125))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('abnormalities', 'Var', (6, 19))	('cancer', 'Disease', (142, 148))
404551	32656741	Dysregulation of DEK is also thought to promote tumorigenesis and sustained proliferation of cancer stem cells.	('promote', 'PosReg', (40, 47))	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('tumor', 'Disease', (48, 53))	('Dysregulation', 'Var', (0, 13))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('sustained proliferation', 'CPA', (66, 89))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('DEK', 'Gene', (17, 20))
404569	32656741	NSCLC patients with DEK-expressing tumors had a lower disease-free survival rate and overall survival rate than patients without DEK expression.	('NSCLC', 'Disease', 'MESH:D002289', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('lower disease-free', 'Disease', (48, 66))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('patients', 'Species', '9606', (112, 120))	('NSCLC', 'Phenotype', 'HP:0030358', (0, 5))	('tumors', 'Disease', (35, 41))	('patients', 'Species', '9606', (6, 14))	('DEK-expressing', 'Var', (20, 34))	('tumors', 'Disease', 'MESH:D009369', (35, 41))	('overall survival', 'CPA', (85, 101))	('NSCLC', 'Disease', (0, 5))	('lower disease-free', 'Disease', 'MESH:D008569', (48, 66))
404570	32656741	In early stage NSCLC, patients with DEK expression had lower disease-free and overall survival rates than patients without DEK expression.	('NSCLC', 'Phenotype', 'HP:0030358', (15, 20))	('lower disease-free', 'Disease', 'MESH:D008569', (55, 73))	('patients', 'Species', '9606', (22, 30))	('lower disease-free', 'Disease', (55, 73))	('NSCLC', 'Disease', (15, 20))	('patients', 'Species', '9606', (106, 114))	('NSCLC', 'Disease', 'MESH:D002289', (15, 20))	('overall survival rates', 'CPA', (78, 100))	('DEK expression', 'Var', (36, 50))
404596	32656741	And then, expression of the DEK-AFF2 protein induced a cytotoxic T cell response against SCC-9 cells.	('AFF2', 'Gene', (32, 36))	('cytotoxic T cell response against SCC-9', 'CPA', (55, 94))	('SCC-9', 'CellLine', 'CVCL:1685', (89, 94))	('AFF2', 'Gene', '2334', (32, 36))	('induced', 'Reg', (45, 52))	('protein', 'Protein', (37, 44))	('expression', 'Var', (10, 20))	('SCC', 'Phenotype', 'HP:0002860', (89, 92))
404629	27721600	Conversely, deregulation of these pathways is shown in cancer stem cell (CSC) regulation and maintenance.	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('deregulation', 'Var', (12, 24))	('cancer', 'Disease', (55, 61))
404636	27721600	Aberrant Hh signaling is associated with the development and progression of a wide range of human malignancies.	('Hh', 'Gene', '42737', (9, 11))	('Aberrant', 'Var', (0, 8))	('associated', 'Reg', (25, 35))	('malignancies', 'Disease', (98, 110))	('men', 'Species', '9606', (52, 55))	('malignancies', 'Disease', 'MESH:D009369', (98, 110))	('human', 'Species', '9606', (92, 97))
404638	27721600	Aberrant activation of Hh signaling is also suggested to play a role in other cancers that have no known mutational basis, such as glioma, breast, esophageal, gastric, pancreatic, prostate, chondrosarcoma and small-cell lung carcinoma.	('glioma', 'Disease', (131, 137))	('chondrosarcoma', 'Disease', (190, 204))	('chondrosarcoma', 'Disease', 'MESH:D002813', (190, 204))	('cancers', 'Disease', 'MESH:D009369', (78, 85))	('small-cell lung carcinoma', 'Phenotype', 'HP:0030357', (209, 234))	('glioma', 'Disease', 'MESH:D005910', (131, 137))	('small-cell lung carcinoma', 'Disease', (209, 234))	('activation', 'PosReg', (9, 19))	('Aberrant', 'Var', (0, 8))	('Hh', 'Gene', '42737', (23, 25))	('gastric', 'Disease', (159, 166))	('breast', 'Disease', (139, 145))	('pancreatic', 'Disease', 'MESH:D010195', (168, 178))	('glioma', 'Phenotype', 'HP:0009733', (131, 137))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (190, 204))	('prostate', 'Disease', (180, 188))	('esophageal', 'Disease', (147, 157))	('cancers', 'Phenotype', 'HP:0002664', (78, 85))	('cancers', 'Disease', (78, 85))	('pancreatic', 'Disease', (168, 178))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('small-cell lung carcinoma', 'Disease', 'MESH:D055752', (209, 234))	('carcinoma', 'Phenotype', 'HP:0030731', (225, 234))
404646	27721600	Overexpression of the Hh signaling pathway has been described in several malignancies and is associated with a poor prognosis.	('described', 'Reg', (52, 61))	('malignancies', 'Disease', 'MESH:D009369', (73, 85))	('Overexpression', 'Var', (0, 14))	('malignancies', 'Disease', (73, 85))	('Hh', 'Gene', '42737', (22, 24))
404675	27721600	It has been postulated that CSCs within the bulk tumor may escape conventional therapies, thus leading to disease relapse.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('CSCs', 'Var', (28, 32))	('tumor', 'Disease', (49, 54))	('leading to', 'Reg', (95, 105))	('disease relapse', 'CPA', (106, 121))
404680	27721600	For example, in medulloblastoma and basal cell carcinomas, SHH signaling can be initiated because of PTCH-1 mutations, whereas in small cell lung cancer and intestinal adenocarcinoma, its activation is associated with high expression of the SHH ligand.	('SHH', 'Gene', (241, 244))	('SHH', 'Gene', (59, 62))	('PTCH-1', 'Gene', (101, 107))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (130, 152))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('basal cell carcinomas', 'Phenotype', 'HP:0002671', (36, 57))	('initiated', 'PosReg', (80, 89))	('intestinal adenocarcinoma', 'Disease', (157, 182))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (36, 56))	('carcinoma', 'Phenotype', 'HP:0030731', (47, 56))	('carcinomas', 'Phenotype', 'HP:0030731', (47, 57))	('medulloblastoma and basal cell carcinomas', 'Disease', 'MESH:D008527', (16, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (173, 182))	('small cell lung cancer', 'Disease', 'MESH:D055752', (130, 152))	('SHH', 'Gene', '6469', (241, 244))	('lung cancer', 'Phenotype', 'HP:0100526', (141, 152))	('SHH', 'Gene', '6469', (59, 62))	('small cell lung cancer', 'Disease', (130, 152))	('mutations', 'Var', (108, 117))	('intestinal adenocarcinoma', 'Disease', 'MESH:D007414', (157, 182))	('activation', 'PosReg', (188, 198))	('PTCH-1', 'Gene', '5727', (101, 107))	('medulloblastoma', 'Phenotype', 'HP:0002885', (16, 31))
404692	27721600	Inhibition of the SHH/Gli pathway activity/function is a potential therapeutic strategy for the treatment of SCC patients.	('SCC', 'Phenotype', 'HP:0002860', (109, 112))	('SCC', 'Gene', '6317', (109, 112))	('SHH', 'Gene', (18, 21))	('patients', 'Species', '9606', (113, 121))	('activity/function', 'MPA', (34, 51))	('men', 'Species', '9606', (101, 104))	('Gli', 'Gene', (22, 25))	('Inhibition', 'Var', (0, 10))	('Gli', 'Gene', '2735', (22, 25))	('SCC', 'Gene', (109, 112))	('SHH', 'Gene', '6469', (18, 21))
404698	27721600	Thus, activation of Hh pathway which is an important signaling mechanism crucial in embryogenesis may have a link to carcinogenesis, and the aberrant regulation of this pathway can result in the development of tumors.	('men', 'Species', '9606', (202, 205))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('aberrant regulation', 'Var', (141, 160))	('tumors', 'Disease', (210, 216))	('carcinogenesis', 'Disease', 'MESH:D063646', (117, 131))	('tumors', 'Phenotype', 'HP:0002664', (210, 216))	('Hh', 'Gene', '42737', (20, 22))	('tumors', 'Disease', 'MESH:D009369', (210, 216))	('result in', 'Reg', (181, 190))	('carcinogenesis', 'Disease', (117, 131))	('activation', 'PosReg', (6, 16))
404714	27387955	Although iodine chromoendoscopy has been widely accepted for detection of early esophageal squamous cell carcinoma (SCC), it cannot be applied to head and neck lesions in conventional endoscopy because iodine causes severe mucosal irritation, which can result in aspiration into the airways.	('neck lesions', 'Disease', (155, 167))	('SCC', 'Gene', (116, 119))	('mucosal irritation', 'Disease', 'MESH:D052016', (223, 241))	('head and neck lesions', 'Phenotype', 'HP:0012288', (146, 167))	('result in', 'Reg', (253, 262))	('iodine', 'Var', (202, 208))	('iodine', 'Chemical', 'MESH:D007455', (202, 208))	('aspiration', 'Phenotype', 'HP:0002835', (263, 273))	('SCC', 'Gene', '6317', (116, 119))	('aspiration', 'Disease', (263, 273))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (80, 114))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (91, 114))	('iodine', 'Chemical', 'MESH:D007455', (9, 15))	('neck lesions', 'Disease', 'MESH:D006258', (155, 167))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('mucosal irritation', 'Disease', (223, 241))	('esophageal squamous cell carcinoma', 'Disease', (80, 114))
404720	27387955	It has also been demonstrated that gGlu-HMRG can improve endoscopic detection of colitis-associated cancer with a higher target-to-background ratio than conventional white light colonoscopy in a murine model.	('gGlu-HMRG', 'Chemical', '-', (35, 44))	('colitis-associated cancer', 'Disease', 'MESH:D003092', (81, 106))	('gGlu-HMRG', 'Var', (35, 44))	('colitis', 'Phenotype', 'HP:0002583', (81, 88))	('endoscopic detection', 'MPA', (57, 77))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('murine', 'Species', '10090', (195, 201))	('colitis-associated cancer', 'Disease', (81, 106))	('improve', 'PosReg', (49, 56))
404757	27387955	The fluorescence intensity of the tumor lesion increased immediately after gGlu-HMRG spraying and rose to a mean intensity of 7 at 13 min, while that of normal mucosa remained <2 (Fig.	('tumor lesion', 'Disease', 'MESH:D051437', (34, 46))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('fluorescence intensity', 'MPA', (4, 26))	('gGlu-HMRG', 'Chemical', '-', (75, 84))	('increased', 'PosReg', (47, 56))	('gGlu-HMRG', 'Var', (75, 84))	('tumor lesion', 'Disease', (34, 46))	('rose', 'PosReg', (98, 102))
404767	27387955	Accordingly, it has been demonstrated that topical spraying of gGlu-HMRG could provide immediate and specific enhancement of cells overexpressing GGT in animal models.	('enhancement', 'PosReg', (110, 121))	('GGT', 'Gene', '102724197', (146, 149))	('gGlu-HMRG', 'Var', (63, 72))	('cells', 'CPA', (125, 130))	('GGT', 'Gene', (146, 149))	('gGlu-HMRG', 'Chemical', '-', (63, 72))
404768	27387955	In addition, it has been recently demonstrated, in a pilot study of fluorescence imaging of endoscopically resected colorectal tumors, that topical spraying of gGlu-HMRG enabled rapid and selective fluorescence imaging of 54 % and 76 % of adenomas and carcinomas in adenoma, respectively.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('adenoma', 'Disease', (266, 273))	('adenoma', 'Disease', (239, 246))	('colorectal tumors', 'Disease', 'MESH:D015179', (116, 133))	('gGlu-HMRG', 'Chemical', '-', (160, 169))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('gGlu-HMRG', 'Var', (160, 169))	('carcinoma', 'Phenotype', 'HP:0030731', (252, 261))	('adenomas and carcinomas', 'Disease', 'MESH:D000236', (239, 262))	('carcinomas', 'Phenotype', 'HP:0030731', (252, 262))	('fluorescence imaging', 'MPA', (198, 218))	('adenoma', 'Disease', 'MESH:D000236', (266, 273))	('adenoma', 'Disease', 'MESH:D000236', (239, 246))	('colorectal tumors', 'Disease', (116, 133))
404776	27387955	In conclusion, topical spraying of gGlu-HMRG enabled rapid and specific fluorescence imaging of superficial HNSCC, and appears to be useful in the early detection of HNSCC.	('SCC', 'Gene', (168, 171))	('gGlu-HMRG', 'Chemical', '-', (35, 44))	('gGlu-HMRG', 'Var', (35, 44))	('SCC', 'Gene', '6317', (168, 171))	('fluorescence imaging', 'MPA', (72, 92))	('SCC', 'Gene', (110, 113))	('SCC', 'Gene', '6317', (110, 113))
404785	24892421	In addition, clotrimazole induced apoptosis in OSCC cells, and significantly down-regulated the anti-apoptotic protein Bcl-2 and up-regulated the pro-apoptotic protein Bax.	('down-regulated', 'NegReg', (77, 91))	('clotrimazole', 'Var', (13, 25))	('anti-apoptotic protein Bcl-2', 'MPA', (96, 124))	('SCC', 'Gene', (48, 51))	('SCC', 'Phenotype', 'HP:0002860', (48, 51))	('clotrimazole', 'Chemical', 'MESH:D003022', (13, 25))	('SCC', 'Gene', '6317', (48, 51))	('up-regulated', 'PosReg', (129, 141))
404797	24892421	Moreover, clotrimazole effectively decreased glucose consumption and energy metabolism by inhibiting glycolysis and ATP production, and then led to reduction of tumor cell viability.	('reduction', 'NegReg', (148, 157))	('clotrimazole', 'Var', (10, 22))	('glycolysis', 'MPA', (101, 111))	('ATP', 'Chemical', 'MESH:D000255', (116, 119))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('decreased glucose consumption', 'Disease', (35, 64))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('ATP production', 'MPA', (116, 130))	('energy metabolism', 'MPA', (69, 86))	('inhibiting', 'NegReg', (90, 100))	('tumor', 'Disease', (161, 166))	('decreased glucose consumption', 'Disease', 'MESH:D014397', (35, 64))	('clotrimazole', 'Chemical', 'MESH:D003022', (10, 22))
404851	24892421	Sections were then incubated with PCNA antibody (1:100) and cleaved caspase-3 antibody (1:1000) at 4 C overnight, followed by peroxidase-conjugated goat anti-rabbit secondary antibody for 1 h at room temperature.	('caspase-3', 'Gene', '836', (68, 77))	('rat', 'Species', '10116', (205, 208))	('1:1000', 'Var', (88, 94))	('PCNA', 'Gene', (34, 38))	('rabbit', 'Species', '9986', (158, 164))	('caspase-3', 'Gene', (68, 77))	('goat', 'Species', '9925', (148, 152))	('PCNA', 'Gene', '5111', (34, 38))
404862	24892421	Additionally, at the concentration of 30 microM clotrimazole, cell colony formation was strongly reduced by 95.0%, 95.5% and 93.0%, respectively (P<0.001), as compared with the respective control groups (Fig.2B).	('clotrimazole', 'Chemical', 'MESH:D003022', (48, 60))	('clotrimazole', 'Var', (48, 60))	('reduced', 'NegReg', (97, 104))	('cell colony formation', 'CPA', (62, 83))	('rat', 'Species', '10116', (28, 31))
404881	24892421	Consistent with our in vitro results, intraperitoneal administration of clotrimazole strikingly decreased the tumor volume of CAL27 cell xenograft in nude mice by 57.9% (P = 0.042, Fig.6A,B), and the mean weights of the excised tumors were approximately 53.6% lower in clotrimazole-treated mice than in control mice (P = 0.035, Fig.6C).	('tumor', 'Disease', 'MESH:D009369', (228, 233))	('tumors', 'Phenotype', 'HP:0002664', (228, 234))	('rat', 'Species', '10116', (62, 65))	('mice', 'Species', '10090', (290, 294))	('decreased', 'NegReg', (96, 105))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('nude mice', 'Species', '10090', (150, 159))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('CAL27', 'CellLine', 'CVCL:1107', (126, 131))	('tumors', 'Disease', (228, 234))	('mice', 'Species', '10090', (155, 159))	('clotrimazole', 'Var', (72, 84))	('tumors', 'Disease', 'MESH:D009369', (228, 234))	('clotrimazole', 'Chemical', 'MESH:D003022', (269, 281))	('clotrimazole', 'Chemical', 'MESH:D003022', (72, 84))	('mice', 'Species', '10090', (311, 315))	('tumor', 'Disease', (110, 115))	('tumor', 'Disease', (228, 233))	('lower', 'NegReg', (260, 265))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
404910	24892421	Liu et al observed that clotrimazole arrested cell cycle at G0/G1 phase correlating with the overexpression of p27Kip and the decrease of cyclin D1.	('cyclin D1', 'Gene', (138, 147))	('arrest', 'Disease', 'MESH:D006323', (37, 43))	('decrease', 'NegReg', (126, 134))	('p27Kip', 'Var', (111, 117))	('arrest', 'Disease', (37, 43))	('cell cycle', 'CPA', (46, 56))	('cyclin D1', 'Gene', '595', (138, 147))	('overexpression', 'PosReg', (93, 107))	('clotrimazole', 'Chemical', 'MESH:D003022', (24, 36))
404911	24892421	Furthermore, our results demonstrated that clotrimazole significantly induced apoptosis in OSCC cell lines which was further proven by our in vivo experiment.	('apoptosis', 'CPA', (78, 87))	('rat', 'Species', '10116', (32, 35))	('SCC', 'Gene', '6317', (92, 95))	('clotrimazole', 'Chemical', 'MESH:D003022', (43, 55))	('induced', 'Reg', (70, 77))	('clotrimazole', 'Var', (43, 55))	('SCC', 'Gene', (92, 95))	('SCC', 'Phenotype', 'HP:0002860', (92, 95))
404943	28243631	The authors concluded that aberrant miRNA panels have HCC "tumor type specificity" and may be affected by etiologic factors.	('tumor', 'Disease', (59, 64))	('aberrant', 'Var', (27, 35))	('HCC', 'Gene', '619501', (54, 57))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('HCC', 'Phenotype', 'HP:0001402', (54, 57))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('HCC', 'Gene', (54, 57))
404945	28243631	Anomalous expression of miRNAs have been implicated in a wide variety of cancers, including hepatocellular carcinoma (HCC), one of the most common cancers and the third leading cause of cancer death worldwide.	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('cancer death', 'Disease', 'MESH:D003643', (186, 198))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (92, 116))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('cancers', 'Disease', (73, 80))	('HCC', 'Gene', '619501', (118, 121))	('Anomalous expression', 'Var', (0, 20))	('cancer death', 'Disease', (186, 198))	('HCC', 'Phenotype', 'HP:0001402', (118, 121))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('miRNAs', 'Gene', (24, 30))	('cancers', 'Disease', 'MESH:D009369', (147, 154))	('implicated', 'Reg', (41, 51))	('HCC', 'Gene', (118, 121))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (92, 116))	('hepatocellular carcinoma', 'Disease', (92, 116))	('cancers', 'Disease', 'MESH:D009369', (73, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('cancers', 'Phenotype', 'HP:0002664', (147, 154))	('cancers', 'Disease', (147, 154))
404999	28243631	Percentages of correctly classified HCC tissues were 96% and 99% for the 48 paired and 302 unpaired tumor tissues respectively [Table 2], suggesting the promise of aberrantly expressed miRNAs as HCC biomarkers.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('aberrantly expressed miRNAs', 'Var', (164, 191))	('HCC', 'Gene', '619501', (36, 39))	('tumor', 'Disease', (100, 105))	('HCC', 'Phenotype', 'HP:0001402', (36, 39))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('HCC', 'Gene', (195, 198))	('HCC', 'Phenotype', 'HP:0001402', (195, 198))	('HCC', 'Gene', '619501', (195, 198))	('HCC', 'Gene', (36, 39))	('miRNAs', 'Var', (185, 191))
405001	28243631	We observed 40 miRNAs significantly deregulated in HCC tumors (P < 0.05) with over 2-fold changes [Supplementary Figure 4], and 14 (let-7c, miR-21, miR-99a, miR-125b, miR-130a, miR-139, miR-144, miR-145, miR-150, miR-199a, miR-223, miR-378, miR-455 and miR-486) overlap with those identified in TCGA data.	('miR-378', 'Gene', '494327', (232, 239))	('miR-455', 'Gene', '619556', (241, 248))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('miR-199a', 'Var', (213, 221))	('miR-139', 'Gene', '406931', (177, 184))	('miR-99a', 'Gene', (148, 155))	('miR-21', 'Gene', (140, 146))	('miR-486', 'Gene', (253, 260))	('let-7c', 'Gene', (132, 138))	('miR-150', 'Gene', (204, 211))	('miR-125b', 'Var', (157, 165))	('miR-130a', 'Gene', '406919', (167, 175))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('miR-223', 'Gene', (223, 230))	('HCC tumors', 'Disease', (51, 61))	('miR-139', 'Gene', (177, 184))	('miR-145', 'Gene', '406937', (195, 202))	('miR-144', 'Gene', (186, 193))	('miR-130a', 'Gene', (167, 175))	('miR-455', 'Gene', (241, 248))	('deregulated', 'NegReg', (36, 47))	('let-7c', 'Gene', '406885', (132, 138))	('miR-486', 'Gene', '619554', (253, 260))	('HCC tumors', 'Disease', 'MESH:D006528', (51, 61))	('miR-145', 'Gene', (195, 202))	('miR-99a', 'Gene', '407055', (148, 155))	('changes', 'Reg', (90, 97))	('miR-223', 'Gene', '407008', (223, 230))	('HCC', 'Phenotype', 'HP:0001402', (51, 54))	('miR-378', 'Gene', (232, 239))	('miR-150', 'Gene', '406942', (204, 211))	('miR-21', 'Gene', '406991', (140, 146))	('miR-144', 'Gene', '406936', (186, 193))
405002	28243631	Eight miRNAs (miR-122, miR-1180, miR-199a, miR-182, miR-152, miR-125b, miR-18a and miR-10a) with various expression levels in TCGA data were randomly selected and evaluated by TaqMan quantitative reverse transcription polymerase chain reaction (RT-PCR) in 66 paired HCC tissues from CUMC.	('miR-122', 'Gene', '406906', (14, 21))	('miR-122', 'Gene', (14, 21))	('miR-125b', 'Var', (61, 69))	('miR-18a', 'Gene', '406953', (71, 78))	('miR-199a', 'Var', (33, 41))	('miR-10a', 'Gene', '406902', (83, 90))	('HCC', 'Gene', '619501', (266, 269))	('miR-182', 'Gene', (43, 50))	('HCC', 'Gene', (266, 269))	('miR-1180', 'Gene', '100302256', (23, 31))	('HCC', 'Phenotype', 'HP:0001402', (266, 269))	('miR-152', 'Gene', '406943', (52, 59))	('miR-152', 'Gene', (52, 59))	('miR-18a', 'Gene', (71, 78))	('miR-182', 'Gene', '406958', (43, 50))	('miR-10a', 'Gene', (83, 90))	('miR-1180', 'Gene', (23, 31))
405004	28243631	Subgroup analyses for three HCC-specific major etiologic factors (alcohol abuse, HBV and HCV infection) by two-sample t-tests, we identified 4 upregulated (miR-10b, miR-21, miR-500a and miR-532) and 8 downregulated miRNAs panel significantly associated with alcohol-related HCC [Table 3, Supplementary Figure 5A].	('miR-500a', 'Var', (173, 181))	('miR-532', 'Var', (186, 193))	('miR-10b', 'Gene', (156, 163))	('miR-21', 'Gene', (165, 171))	('miR-10b', 'Gene', '406903', (156, 163))	('HCV infection', 'Disease', 'MESH:D006526', (89, 102))	('HBV', 'Species', '10407', (81, 84))	('HCC', 'Gene', '619501', (274, 277))	('miRNAs', 'Gene', (215, 221))	('HCC', 'Phenotype', 'HP:0001402', (274, 277))	('alcohol', 'Chemical', 'MESH:D000438', (66, 73))	('HCV infection', 'Disease', (89, 102))	('alcohol', 'Chemical', 'MESH:D000438', (258, 265))	('HCC', 'Gene', '619501', (28, 31))	('associated', 'Reg', (242, 252))	('HCC', 'Gene', (274, 277))	('HCC', 'Phenotype', 'HP:0001402', (28, 31))	('alcohol abuse', 'Disease', (66, 79))	('upregulated', 'PosReg', (143, 154))	('HCC', 'Gene', (28, 31))	('alcohol abuse', 'Disease', 'MESH:D000437', (66, 79))	('downregulated', 'NegReg', (201, 214))	('miR-21', 'Gene', '406991', (165, 171))	('alcohol abuse', 'Phenotype', 'HP:0030955', (66, 79))
405033	28243631	Accumulating evidence based on genome-wide and candidate miRNA approaches have uncovered miRNAs dysregulation in HCC acting as either oncogenes or tumor suppressors.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('HCC', 'Gene', '619501', (113, 116))	('HCC', 'Phenotype', 'HP:0001402', (113, 116))	('miRNAs', 'Var', (89, 95))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('dysregulation', 'Var', (96, 109))	('HCC', 'Gene', (113, 116))
405052	28243631	These data strongly suggested the complicated network of miRNA alterations in tumorigenesis that needs further clarification.	('rat', 'Species', '10116', (67, 70))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Disease', (78, 83))	('miRNA', 'Var', (57, 62))
405062	28243631	Therefore, "tumor common" miRNAs aberrantly expressed in various tumors may provide clues to further investigate their common similar underlying mechanisms in tumorigenesis.	('aberrantly', 'Var', (33, 43))	('tumor', 'Disease', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('tumors', 'Disease', (65, 71))	('tumor', 'Disease', (159, 164))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumor', 'Disease', (12, 17))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
405072	28243631	We also observed that the changes of miRNAs in tumor tissue detected by RT-qPCR were minor compared to those by RNA-seq [Supplementary Table 3].	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('miRNAs', 'MPA', (37, 43))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('RT-qPCR', 'Var', (72, 79))	('tumor', 'Disease', (47, 52))
405073	28243631	In conclusion, our study identified 33 miRNAs significantly aberrantly expressed in HCC tumors with over 2-fold changes, and for the first time distinguished 5 of them as having "HCC tumor type specificity", while another 8 are "tumor common" alterations.	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('changes', 'Reg', (112, 119))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('HCC tumors', 'Disease', 'MESH:D006528', (84, 94))	('HCC tumor', 'Disease', (179, 188))	('aberrantly', 'Var', (60, 70))	('tumor', 'Disease', (88, 93))	('HCC tumor', 'Disease', 'MESH:D006528', (84, 93))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('HCC tumor', 'Disease', 'MESH:D006528', (179, 188))	('HCC', 'Phenotype', 'HP:0001402', (84, 87))	('tumor', 'Disease', (229, 234))	('tumor', 'Disease', (183, 188))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('HCC', 'Phenotype', 'HP:0001402', (179, 182))	('tumor', 'Disease', 'MESH:D009369', (229, 234))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('HCC tumors', 'Disease', (84, 94))	('rat', 'Species', '10116', (247, 250))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))
405166	28167973	This method also identified exclusively dead cells, and CA/CAPE treatment resulted in diminishment of life of HNSCC cells.	('SCC', 'Phenotype', 'HP:0002860', (112, 115))	('CA/CAPE', 'Gene', '10592', (56, 63))	('CA/CAPE', 'Gene', (56, 63))	('treatment', 'Var', (64, 73))	('SCC', 'Gene', '6317', (112, 115))	('diminishment', 'NegReg', (86, 98))	('SCC', 'Gene', (112, 115))
405227	28028355	The pathogenesis of squamous cell carcinoma is highly complex, involving an accumulation of genetic modifications within the esophageal mucosa, causing progressive changes that result in invasive carcinoma.	('causing', 'Reg', (144, 151))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (20, 43))	('squamous cell carcinoma', 'Disease', (20, 43))	('genetic modifications', 'Var', (92, 113))	('invasive carcinoma', 'Disease', 'MESH:D009361', (187, 205))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (20, 43))	('esophageal mucosa', 'Disease', (125, 142))	('result in', 'Reg', (177, 186))	('invasive carcinoma', 'Disease', (187, 205))	('esophageal mucosa', 'Disease', 'MESH:D004941', (125, 142))	('carcinoma', 'Phenotype', 'HP:0030731', (34, 43))	('carcinoma', 'Phenotype', 'HP:0030731', (196, 205))
405229	28028355	Genetic mutations within cyclin D1 and the tumour suppressor gene, TP53, are among the most frequently isolated genetic abnormalities from esophageal squamous cell carcinomas.	('tumour', 'Disease', 'MESH:D009369', (43, 49))	('genetic abnormalities', 'Disease', (112, 133))	('tumour', 'Disease', (43, 49))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (150, 174))	('esophageal squamous cell carcinomas', 'Disease', (139, 174))	('esophageal squamous cell carcinomas', 'Disease', 'MESH:D000077277', (139, 174))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (150, 173))	('TP53', 'Gene', '7157', (67, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (164, 173))	('TP53', 'Gene', (67, 71))	('Genetic mutations', 'Var', (0, 17))	('carcinomas', 'Phenotype', 'HP:0030731', (164, 174))	('cyclin D1', 'Gene', '595', (25, 34))	('tumour', 'Phenotype', 'HP:0002664', (43, 49))	('cyclin D1', 'Gene', (25, 34))	('genetic abnormalities', 'Disease', 'MESH:D030342', (112, 133))
405231	28028355	TP53 mutations have been reported in as little as 10% and up to 80% of esophageal squamous cell carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('esophageal squamous cell carcinoma', 'Disease', (71, 105))	('mutations', 'Var', (5, 14))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (71, 105))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (82, 105))
405232	28028355	Additionally, mutations to the TP53 gene are also found in dysplastic lesions, indicating TP53 mutations may be an event in the early stages of esophageal squamous cell carcinoma carcinogenesis.	('event', 'Reg', (115, 120))	('carcinoma', 'Phenotype', 'HP:0030731', (169, 178))	('TP53', 'Gene', '7157', (31, 35))	('TP53', 'Gene', '7157', (90, 94))	('TP53', 'Gene', (31, 35))	('dysplastic lesions', 'Disease', 'MESH:D021782', (59, 77))	('TP53', 'Gene', (90, 94))	('mutations', 'Var', (95, 104))	('dysplastic lesions', 'Disease', (59, 77))	('esophageal squamous cell carcinoma carcinogenesis', 'Disease', (144, 193))	('esophageal squamous cell carcinoma carcinogenesis', 'Disease', 'MESH:D000077277', (144, 193))	('mutations', 'Var', (14, 23))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (155, 178))
405233	28028355	TP53 mutations produce abnormal TP53 protein that accumulates in the nuclei of cells which may be identified by immunohistochemistry.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('accumulates', 'PosReg', (50, 61))	('TP53', 'Gene', '7157', (32, 36))	('mutations', 'Var', (5, 14))	('TP53', 'Gene', (32, 36))	('protein', 'Protein', (37, 44))
405234	28028355	Positive p53 staining has been demonstrated in the non-cancerous cells adjacent to tumors and in cells lacking the commonly identified TP53 mutations; indicating poor specificity and sensitivity of the technique and potentially additional mutations within the gene accounting for the positive staining.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('non-cancer', 'Disease', 'MESH:D009369', (51, 61))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('TP53', 'Gene', '7157', (135, 139))	('tumors', 'Disease', (83, 89))	('p53', 'Gene', (9, 12))	('p53', 'Gene', '7157', (9, 12))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('TP53', 'Gene', (135, 139))	('tumors', 'Disease', 'MESH:D009369', (83, 89))	('mutations', 'Var', (140, 149))	('non-cancer', 'Disease', (51, 61))
405257	28028355	p53 mutations can cause accumulation of non-functional protein that has increased stability and a longer half-life than the native protein.	('p53', 'Gene', (0, 3))	('p53', 'Gene', '7157', (0, 3))	('increased', 'PosReg', (72, 81))	('accumulation', 'PosReg', (24, 36))	('stability', 'MPA', (82, 91))	('mutations', 'Var', (4, 13))	('non-functional protein', 'MPA', (40, 62))
405295	28028355	Developing a risk prediction model, the authors reported eight significant predictors for adenocarcinoma: decanal, nonanal, phenol, ethyl phenol, methyl phenol, hexanoic acid, heptanal, and butyric acid, with sensitivity and specificity of 98% and 91.7% respectively when compared to normal upper GI tract.	('hexanoic', 'MPA', (161, 169))	('ethyl phenol', 'Chemical', '-', (132, 144))	('phenol', 'Chemical', 'MESH:D019800', (138, 144))	('phenol', 'Chemical', 'MESH:D019800', (124, 130))	('heptanal', 'MPA', (176, 184))	('phenol', 'Chemical', 'MESH:D019800', (153, 159))	('hexanoic acid', 'Chemical', 'MESH:C037652', (161, 174))	('methyl phenol', 'Var', (146, 159))	('ethyl phenol', 'Chemical', '-', (147, 159))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('ethyl phenol', 'Var', (132, 144))	('adenocarcinoma', 'Disease', (90, 104))	('methyl phenol', 'Chemical', 'MESH:C077977', (146, 159))	('adenocarcinoma', 'Disease', 'MESH:D000230', (90, 104))	('butyric acid', 'Chemical', 'MESH:D020148', (190, 202))	('heptanal', 'Chemical', 'MESH:C046204', (176, 184))
405372	25180083	After the second course of chemotherapy, a significant decrease in ROMs level was observed in responders (CR/PR) (491 +- 116 vs. 391 +- 71 U. CARR, p = 0.014) (Figure 3a), while no change in ROMs level was found in non-responders (SD/PD) (471 +- 63 vs. 452 +- 60 U. CARR; p = 0.387) (Figure 3b).	('CR', 'Chemical', 'MESH:D002857', (106, 108))	('491 +- 116', 'Var', (114, 124))	('CARR', 'Gene', '407', (142, 146))	('ROMs level', 'MPA', (67, 77))	('CARR', 'Gene', (142, 146))	('ROMs', 'Chemical', '-', (191, 195))	('CARR', 'Gene', '407', (266, 270))	('decrease', 'NegReg', (55, 63))	('PD', 'Disease', 'MESH:D010300', (234, 236))	('CARR', 'Gene', (266, 270))	('ROMs', 'Chemical', '-', (67, 71))
405433	31765387	Cancer is a heterogeneous disease that is driven by oncogene activations such as genetic mutation, gene amplification, chromosomal rearrangement, and transposable elements.	('chromosomal rearrangement', 'Var', (119, 144))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('genetic mutation', 'Var', (81, 97))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('gene amplification', 'Var', (99, 117))	('transposable elements', 'Var', (150, 171))
405528	31765387	By integrating the sub-networks of patients on each cancer data set, we obtained the statistic information of individual specific sub-networks of TP53 including frequency as personalized driver genes, the SNVs mutation frequency, mean differential expression fold change (the absolute value of log2 fold change between normal expression data and tumor expression data), and mean network degree in individual specific sub-networks (Table 1).	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('TP53', 'Gene', '7157', (146, 150))	('tumor', 'Phenotype', 'HP:0002664', (346, 351))	('TP53', 'Gene', (146, 150))	('mutation', 'Var', (210, 218))	('tumor', 'Disease', 'MESH:D009369', (346, 351))	('SNVs', 'Gene', (205, 209))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('patients', 'Species', '9606', (35, 43))	('differential expression fold change', 'MPA', (235, 270))	('tumor', 'Disease', (346, 351))
405546	31765387	Cancer is known as a disease mainly caused by gene alterations.	('gene alterations', 'Var', (46, 62))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('caused', 'Reg', (36, 42))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))
405679	31132886	During treatment with pembrolizumab, he did experience a mild rash, which was evaluated by dermatology and felt to be more consistent with his known history of rosacea than an immunotherapy-related rash.	('rash', 'Disease', 'MESH:D005076', (198, 202))	('rosacea', 'Phenotype', 'HP:0001041', (160, 167))	('rosacea', 'Disease', (160, 167))	('rash', 'Disease', (198, 202))	('rash', 'Phenotype', 'HP:0000988', (198, 202))	('rash', 'Disease', 'MESH:D005076', (62, 66))	('pembrolizumab', 'Var', (22, 35))	('pembrolizumab', 'Chemical', 'MESH:C582435', (22, 35))	('rash', 'Disease', (62, 66))	('rash', 'Phenotype', 'HP:0000988', (62, 66))
405690	31132886	Other factors that have been found to be in play include the tumor microenvironment with tumor infiltrating lymphocytes, mutational load, and DNA mismatch repair deficiency.	('mutational load', 'Var', (121, 136))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Disease', (89, 94))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('deficiency', 'Var', (162, 172))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (61, 66))
405724	26882224	Lung cancer is a heterogeneous disease involving somatic mutations and epigenetic dysregulation of a number of signaling pathways.	('epigenetic dysregulation', 'Var', (71, 95))	('Lung cancer', 'Phenotype', 'HP:0100526', (0, 11))	('Lung cancer', 'Disease', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))	('Lung cancer', 'Disease', 'MESH:D008175', (0, 11))
405725	26882224	Several Receptor Tyrosine Kinases (RTKs) (EGFR, IGF-1R, and cMet), as well as the GTPase Kras, have been implicated as oncogenes, whereas loss-of-function mutations are most frequently found in p53, RB and p16INK4a.	('cMet', 'Gene', '4233', (60, 64))	('EGFR', 'Gene', '1956', (42, 46))	('mutations', 'Var', (155, 164))	('EGFR', 'Gene', (42, 46))	('loss-of-function', 'NegReg', (138, 154))	('p53', 'Gene', (194, 197))	('p16INK4a', 'Gene', (206, 214))	('cMet', 'Gene', (60, 64))	('p53', 'Gene', '7157', (194, 197))	('IGF-1R', 'Gene', '3480', (48, 54))	('p16INK4a', 'Gene', '1029', (206, 214))	('IGF-1R', 'Gene', (48, 54))	('RB', 'Disease', 'MESH:D012175', (199, 201))
405737	26882224	Dysregulation of each of these three receptors has been causally linked to lung cancer development, progression, and increased resistance to chemotherapy.	('lung cancer', 'Disease', (75, 86))	('lung cancer', 'Phenotype', 'HP:0100526', (75, 86))	('linked', 'Reg', (65, 71))	('Dysregulation', 'Var', (0, 13))	('men', 'Species', '9606', (94, 97))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('lung cancer', 'Disease', 'MESH:D008175', (75, 86))
405773	26882224	In all patients, presence of SULF2 staining of either tumor cells or stroma was associated with a 42% increase in the risk of death, but this result was not statistically significant (p = 0.39).	('SULF2 staining', 'Var', (29, 43))	('death', 'Disease', 'MESH:D003643', (126, 131))	('death', 'Disease', (126, 131))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('presence', 'Var', (17, 25))	('tumor', 'Disease', (54, 59))	('patients', 'Species', '9606', (7, 15))
405787	26882224	Conversely in patients with SCC, SULF2 staining in tumor cells was associated with a significantly decreased risk of death (89%, p = 0.02).	('decreased', 'NegReg', (99, 108))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('SCC', 'Gene', (28, 31))	('tumor', 'Disease', (51, 56))	('death', 'Disease', 'MESH:D003643', (117, 122))	('death', 'Disease', (117, 122))	('SCC', 'Gene', '6317', (28, 31))	('patients', 'Species', '9606', (14, 22))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('SULF2 staining', 'Var', (33, 47))
405801	26882224	In keeping, our results show for the first time that SULF2 at the protein level is associated with overall survival in NSCLC, thus confirming its important role in carcinogenesis and potential as a predictive biomarker.	('NSCLC', 'Disease', 'MESH:D002289', (119, 124))	('carcinogenesis', 'Disease', 'MESH:D063646', (164, 178))	('SULF2', 'Var', (53, 58))	('associated', 'Reg', (83, 93))	('carcinogenesis', 'Disease', (164, 178))	('NSCLC', 'Disease', (119, 124))
405806	26882224	SULFs selectively remove the critical 6OS modifications from HSPGs, and in so doing, SULFs prevent ligand sequestration, allowing these ligands to interact with their corresponding receptors.	('modifications', 'Var', (42, 55))	('HSPG', 'Gene', '960', (61, 65))	('6OS', 'Protein', (38, 41))	('ligand sequestration', 'MPA', (99, 119))	('HSPG', 'Gene', (61, 65))	('remove', 'NegReg', (18, 24))	('interact', 'Interaction', (147, 155))
405808	26882224	Aberrant activation of the aforementioned signaling pathways has been implicated in many forms of carcinogenesis.	('carcinogenesis', 'Disease', 'MESH:D063646', (98, 112))	('activation', 'PosReg', (9, 19))	('Aberrant', 'Var', (0, 8))	('carcinogenesis', 'Disease', (98, 112))	('men', 'Species', '9606', (32, 35))	('implicated', 'Reg', (70, 80))
405814	26882224	Moreover, in malignant astrocytoma, and pancreatic, colorectal, and lung cancer cell lines SULF2 knockdown led to reduced proliferation and decreased growth of xenografts in mice, likely due to its effect on signaling pathways induced by HSPG binding factors.	('lung cancer', 'Phenotype', 'HP:0100526', (68, 79))	('mice', 'Species', '10090', (174, 178))	('reduced', 'NegReg', (114, 121))	('colorectal', 'Disease', 'MESH:D015179', (52, 62))	('malignant astrocytoma', 'Disease', 'MESH:D020339', (13, 34))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('SULF2', 'Gene', (91, 96))	('growth', 'CPA', (150, 156))	('decreased growth', 'Phenotype', 'HP:0001510', (140, 156))	('HSPG', 'Gene', '960', (238, 242))	('knockdown', 'Var', (97, 106))	('lung cancer', 'Disease', (68, 79))	('HSPG', 'Gene', (238, 242))	('malignant astrocytoma', 'Disease', (13, 34))	('pancreatic', 'Disease', 'MESH:D010195', (40, 50))	('proliferation', 'CPA', (122, 135))	('colorectal', 'Disease', (52, 62))	('decreased', 'NegReg', (140, 149))	('astrocytoma', 'Phenotype', 'HP:0009592', (23, 34))	('pancreatic', 'Disease', (40, 50))	('lung cancer', 'Disease', 'MESH:D008175', (68, 79))
405817	26882224	Importantly, high expression of SULF2 was associated with worse prognosis in patients with adenocarcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('high', 'Var', (13, 17))	('adenocarcinoma', 'Disease', 'MESH:D000230', (91, 105))	('patients', 'Species', '9606', (77, 85))	('adenocarcinoma', 'Disease', (91, 105))	('SULF2', 'Protein', (32, 37))
405819	26882224	Surprisingly, SULF2 staining of tumor cells in patients with squamous cell carcinoma was associated with a better survival rate.	('SULF2 staining', 'Var', (14, 28))	('better', 'PosReg', (107, 113))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('patients', 'Species', '9606', (47, 55))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (61, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (61, 84))	('survival rate', 'CPA', (114, 127))	('squamous cell carcinoma', 'Disease', (61, 84))	('tumor', 'Disease', (32, 37))
405842	26882224	We showed for the first time that SULF2 staining of tumor cells was associated with a trend towards worse overall survival in patients with lung adenocarcinomas.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumor', 'Disease', (52, 57))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (140, 159))	('SULF2 staining', 'Var', (34, 48))	('worse', 'NegReg', (100, 105))	('carcinoma', 'Phenotype', 'HP:0030731', (150, 159))	('patients', 'Species', '9606', (126, 134))	('lung adenocarcinomas', 'Disease', (140, 160))	('overall survival', 'MPA', (106, 122))	('carcinomas', 'Phenotype', 'HP:0030731', (150, 160))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (140, 160))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (140, 160))
405849	26018876	EGFR mutations and ALK translocation are the most effectively targeted oncogenes in NSCLC.	('NSCLC', 'Phenotype', 'HP:0030358', (84, 89))	('ALK', 'Gene', (19, 22))	('EGFR', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))	('NSCLC', 'Disease', (84, 89))	('ALK', 'Gene', '238', (19, 22))	('NSCLC', 'Disease', 'MESH:D002289', (84, 89))	('EGFR', 'Gene', '1956', (0, 4))	('SCLC', 'Phenotype', 'HP:0030357', (85, 89))
405850	26018876	EGFR mutations and ALK gene rearrangements are successfully being targeted with specific tyrosine kinase inhibitors.	('ALK', 'Gene', (19, 22))	('EGFR', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))	('ALK', 'Gene', '238', (19, 22))	('EGFR', 'Gene', '1956', (0, 4))
405859	26018876	The discovery of activating epidermal growth factor receptor (EGFR) mutations as predictors of a response to EGFR tyrosine kinase inhibitor (TKI) therapy profoundly changed the therapeutic landscape of lung adenocarcinoma.	('lung adenocarcinoma', 'Disease', (202, 221))	('EGFR', 'Gene', '1956', (62, 66))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (202, 221))	('activating', 'PosReg', (17, 27))	('epidermal growth factor receptor', 'Gene', (28, 60))	('EGFR', 'Gene', (62, 66))	('EGFR', 'Gene', '1956', (109, 113))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (202, 221))	('carcinoma', 'Phenotype', 'HP:0030731', (212, 221))	('mutations', 'Var', (68, 77))	('EGFR', 'Gene', (109, 113))	('epidermal growth factor receptor', 'Gene', '1956', (28, 60))	('changed', 'Reg', (165, 172))
405860	26018876	More recently, targeted therapies directed at NSCLC harboring anaplastic lymphoma kinase (ALK) fusions and ROS1 fusions have produced similar results in terms of overall response rate (ORR) and progression-free survival (PFS).	('anaplastic lymphoma kinase', 'Gene', '238', (62, 88))	('ALK', 'Gene', '238', (90, 93))	('NSCLC', 'Disease', (46, 51))	('progression-free survival', 'CPA', (194, 219))	('fusions', 'Var', (95, 102))	('ROS1', 'Gene', (107, 111))	('NSCLC', 'Disease', 'MESH:D002289', (46, 51))	('ALK', 'Gene', (90, 93))	('ROS1', 'Gene', '6098', (107, 111))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (62, 81))	('anaplastic lymphoma kinase', 'Gene', (62, 88))	('lymphoma', 'Phenotype', 'HP:0002665', (73, 81))	('SCLC', 'Phenotype', 'HP:0030357', (47, 51))	('NSCLC', 'Phenotype', 'HP:0030358', (46, 51))
405863	26018876	This review aims at providing an overview on genomic aberrations beyond the well-known and established EGFR mutations and ALK rearrangements.	('EGFR', 'Gene', '1956', (103, 107))	('mutations', 'Var', (108, 117))	('EGFR', 'Gene', (103, 107))	('ALK', 'Gene', (122, 125))	('ALK', 'Gene', '238', (122, 125))
405865	26018876	A rearrangement of ROS1 has initially been described in glioblastoma.	('glioblastoma', 'Phenotype', 'HP:0012174', (56, 68))	('rearrangement', 'Var', (2, 15))	('described', 'Reg', (43, 52))	('glioblastoma', 'Disease', (56, 68))	('glioblastoma', 'Disease', 'MESH:D005909', (56, 68))	('ROS1', 'Gene', (19, 23))	('ROS1', 'Gene', '6098', (19, 23))
405866	26018876	In 2007 ROS1 rearrangement was found in NSCLC cell lines and primary tumors.	('primary tumors', 'Disease', 'MESH:D009369', (61, 75))	('ROS1', 'Gene', '6098', (8, 12))	('SCLC', 'Phenotype', 'HP:0030357', (41, 45))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('rearrangement', 'Var', (13, 26))	('NSCLC', 'Phenotype', 'HP:0030358', (40, 45))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('primary tumors', 'Disease', (61, 75))	('NSCLC', 'Disease', (40, 45))	('ROS1', 'Gene', (8, 12))	('found', 'Reg', (31, 36))	('NSCLC', 'Disease', 'MESH:D002289', (40, 45))
405868	26018876	A ROS1 rearrangement has been described in 0.7%-1.7% of NSCLC patients.	('ROS1', 'Gene', '6098', (2, 6))	('NSCLC', 'Disease', (56, 61))	('rearrangement', 'Var', (7, 20))	('NSCLC', 'Disease', 'MESH:D002289', (56, 61))	('SCLC', 'Phenotype', 'HP:0030357', (57, 61))	('patients', 'Species', '9606', (62, 70))	('NSCLC', 'Phenotype', 'HP:0030358', (56, 61))	('ROS1', 'Gene', (2, 6))
405869	26018876	Similar to previously described oncogenic aberrations in lung cancer, ROS1 translocation is predominantly found in younger patients with adenocarcinoma histology who are never or former light smokers.	('translocation', 'Var', (75, 88))	('adenocarcinoma', 'Disease', (137, 151))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('patients', 'Species', '9606', (123, 131))	('found', 'Reg', (106, 111))	('oncogenic aberrations in lung cancer', 'Disease', (32, 68))	('adenocarcinoma', 'Disease', 'MESH:D000230', (137, 151))	('ROS1', 'Gene', (70, 74))	('oncogenic aberrations in lung cancer', 'Disease', 'MESH:D008175', (32, 68))	('ROS1', 'Gene', '6098', (70, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (142, 151))	('lung cancer', 'Phenotype', 'HP:0100526', (57, 68))
405870	26018876	However, ROS1 translocations have also been described in squamous cell histology.	('ROS1', 'Gene', '6098', (9, 13))	('translocations', 'Var', (14, 28))	('squamous cell histology', 'Disease', (57, 80))	('described', 'Reg', (44, 53))	('ROS1', 'Gene', (9, 13))
405878	26018876	This cohort study confirms the findings from the prospective trial that crizotinib is a highly active therapeutic option in NSCLC patients harboring a ROS1 rearrangement.	('ROS1', 'Gene', (151, 155))	('NSCLC', 'Disease', (124, 129))	('ROS1', 'Gene', '6098', (151, 155))	('SCLC', 'Phenotype', 'HP:0030357', (125, 129))	('rearrangement', 'Var', (156, 169))	('NSCLC', 'Disease', 'MESH:D002289', (124, 129))	('patients', 'Species', '9606', (130, 138))	('crizotinib', 'Chemical', 'MESH:D000077547', (72, 82))	('NSCLC', 'Phenotype', 'HP:0030358', (124, 129))
405879	26018876	Other agents are currently investigated for ROS1-positive lung cancer patients including foretinib, ceritinib, AP26113, PF-06463922 as well as HSP90 inhibitors.	('patients', 'Species', '9606', (70, 78))	('ROS1-positive lung cancer', 'Disease', (44, 69))	('HSP90', 'Gene', (143, 148))	('ceritinib', 'Chemical', 'MESH:C586847', (100, 109))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('lung cancer', 'Phenotype', 'HP:0100526', (58, 69))	('ROS1-positive lung cancer', 'Disease', 'MESH:D008175', (44, 69))	('HSP90', 'Gene', '3320', (143, 148))	('PF-06463922', 'Var', (120, 131))	('AP26113', 'Var', (111, 118))	('PF-06463922', 'Chemical', 'MESH:C000590786', (120, 131))	('foretinib', 'Chemical', 'MESH:C544831', (89, 98))	('AP26113', 'Chemical', 'MESH:C000598580', (111, 118))
405881	26018876	Mechanism of acquired resistance to crizotinib was partly mediated by the ROS1 G2032R mutation in a patients with metastatic adenocarcinoma harboring CD74-ROS1 fusion or EGFR pathway activation in a patient with NSCLC harboring SDC4-ROS1 fusion.	('NSCLC', 'Disease', 'MESH:D002289', (212, 217))	('SCLC', 'Phenotype', 'HP:0030357', (213, 217))	('EGFR', 'Gene', (170, 174))	('adenocarcinoma', 'Disease', (125, 139))	('patients', 'Species', '9606', (100, 108))	('G2032R', 'Mutation', 'rs1057519788', (79, 85))	('ROS1', 'Gene', '6098', (155, 159))	('NSCLC', 'Disease', (212, 217))	('ROS1', 'Gene', '6098', (74, 78))	('crizotinib', 'Chemical', 'MESH:D000077547', (36, 46))	('patient', 'Species', '9606', (199, 206))	('CD74', 'Gene', '972', (150, 154))	('ROS1', 'Gene', '6098', (233, 237))	('NSCLC', 'Phenotype', 'HP:0030358', (212, 217))	('mediated', 'Reg', (58, 66))	('G2032R', 'Var', (79, 85))	('adenocarcinoma', 'Disease', 'MESH:D000230', (125, 139))	('activation', 'PosReg', (183, 193))	('EGFR', 'Gene', '1956', (170, 174))	('patient', 'Species', '9606', (100, 107))	('ROS1', 'Gene', (155, 159))	('ROS1', 'Gene', (74, 78))	('CD74', 'Gene', (150, 154))	('ROS1', 'Gene', (233, 237))	('SDC4', 'Gene', '6385', (228, 232))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('SDC4', 'Gene', (228, 232))
405882	26018876	Recently, novel ROS1 mutations in lung cancer cell lines as well as epithelial-to-mesenchymal transition have been described to confer resistance to crizotinib.	('ROS1', 'Gene', (16, 20))	('ROS1', 'Gene', '6098', (16, 20))	('lung cancer', 'Disease', (34, 45))	('lung cancer', 'Phenotype', 'HP:0100526', (34, 45))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('lung cancer', 'Disease', 'MESH:D008175', (34, 45))	('crizotinib', 'Chemical', 'MESH:D000077547', (149, 159))	('resistance', 'MPA', (135, 145))	('mutations', 'Var', (21, 30))
405883	26018876	In a preclinical model, the c-MET/RET/VEGFR inhibitor cabozantinib has shown activity in acquired ROS1 inhibitor-resistant mutations.	('ROS1', 'Gene', (98, 102))	('RET', 'Gene', '5979', (34, 37))	('VEGFR', 'Gene', '3791', (38, 43))	('ROS1', 'Gene', '6098', (98, 102))	('c-MET', 'Gene', '4233', (28, 33))	('RET', 'Gene', (34, 37))	('VEGFR', 'Gene', (38, 43))	('activity', 'MPA', (77, 85))	('cabozantinib', 'Chemical', 'MESH:C558660', (54, 66))	('c-MET', 'Gene', (28, 33))	('mutations', 'Var', (123, 132))
405885	26018876	AP26113 is a small molecule with activity against ALK and ROS1 also inhibiting ROS1-positive cell lines with a ROS1 resistance mutation.	('AP26113', 'Var', (0, 7))	('ALK', 'Gene', (50, 53))	('inhibiting', 'NegReg', (68, 78))	('ROS1', 'Gene', (58, 62))	('ROS1', 'Gene', (79, 83))	('ROS1', 'Gene', '6098', (58, 62))	('ALK', 'Gene', '238', (50, 53))	('ROS1', 'Gene', (111, 115))	('AP26113', 'Chemical', 'MESH:C000598580', (0, 7))	('ROS1', 'Gene', '6098', (79, 83))	('ROS1', 'Gene', '6098', (111, 115))
405886	26018876	Foretinib has shown preclinical activity in cell lines harboring ROS1 translocations and also in cell lines with the G2032R resistance mutation.	('translocations', 'Var', (70, 84))	('G2032R', 'Mutation', 'rs1057519788', (117, 123))	('ROS1', 'Gene', (65, 69))	('Foretinib', 'Chemical', 'MESH:C544831', (0, 9))	('G2032R', 'Var', (117, 123))	('ROS1', 'Gene', '6098', (65, 69))
405887	26018876	PF-06463922 is another potent and selective ALK/ROS1 inhibitor showing efficacy in a preclinical model even in cell lines resistant to crizotinib.	('ALK', 'Gene', (44, 47))	('ROS1', 'Gene', (48, 52))	('ALK', 'Gene', '238', (44, 47))	('ROS1', 'Gene', '6098', (48, 52))	('PF-06463922', 'Var', (0, 11))	('PF-06463922', 'Chemical', 'MESH:C000590786', (0, 11))	('crizotinib', 'Chemical', 'MESH:D000077547', (135, 145))
405888	26018876	Another approach currently investigated in crizotinib resistant patients harboring ALK or ROS1 translocations is the combination of ALK/ROS1 and heat shock protein 90 (HSP90) inhibitors.	('ALK', 'Gene', '238', (83, 86))	('crizotinib', 'Chemical', 'MESH:D000077547', (43, 53))	('ROS1', 'Gene', (136, 140))	('patients', 'Species', '9606', (64, 72))	('HSP90', 'Gene', (168, 173))	('ALK', 'Gene', '238', (132, 135))	('ROS1', 'Gene', '6098', (136, 140))	('heat shock protein 90', 'Gene', '3320', (145, 166))	('HSP90', 'Gene', '3320', (168, 173))	('translocations', 'Var', (95, 109))	('heat shock protein 90', 'Gene', (145, 166))	('ROS1', 'Gene', (90, 94))	('ALK', 'Gene', (83, 86))	('shock', 'Phenotype', 'HP:0031273', (150, 155))	('ROS1', 'Gene', '6098', (90, 94))	('ALK', 'Gene', (132, 135))
405890	26018876	BRAF mutations have initially been described in malignant melanoma where 40%-60% of tumors harbor an activating V600E BRAF mutation.	('malignant melanoma', 'Phenotype', 'HP:0002861', (48, 66))	('BRAF', 'Gene', (118, 122))	('V600E', 'Mutation', 'rs113488022', (112, 117))	('V600E', 'Var', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('malignant melanoma', 'Disease', 'MESH:D008545', (48, 66))	('malignant melanoma', 'Disease', (48, 66))	('tumors', 'Disease', (84, 90))	('tumors', 'Disease', 'MESH:D009369', (84, 90))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('activating', 'PosReg', (101, 111))	('melanoma', 'Phenotype', 'HP:0002861', (58, 66))
405891	26018876	Subsequently, BRAF mutations have also been detected in colorectal cancer, papillary thyroid cancer and other solid tumors.	('solid tumors', 'Disease', 'MESH:D009369', (110, 122))	('colorectal cancer', 'Disease', 'MESH:D015179', (56, 73))	('colorectal cancer', 'Phenotype', 'HP:0003003', (56, 73))	('papillary thyroid cancer', 'Phenotype', 'HP:0002895', (75, 99))	('mutations', 'Var', (19, 28))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('solid tumors', 'Disease', (110, 122))	('detected', 'Reg', (44, 52))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('colorectal cancer', 'Disease', (56, 73))	('thyroid cancer', 'Phenotype', 'HP:0002890', (85, 99))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('BRAF', 'Gene', (14, 18))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))	('papillary thyroid cancer', 'Disease', (75, 99))	('papillary thyroid cancer', 'Disease', 'MESH:D000077273', (75, 99))
405892	26018876	BRAF targeting TKIs (dabrafenib, vemurafenib) are approved for BRAF mutated malignant melanoma based on pivotal phase III trials.	('melanoma', 'Phenotype', 'HP:0002861', (86, 94))	('malignant melanoma', 'Phenotype', 'HP:0002861', (76, 94))	('malignant melanoma', 'Disease', 'MESH:D008545', (76, 94))	('vemurafenib', 'Chemical', 'MESH:D000077484', (33, 44))	('malignant melanoma', 'Disease', (76, 94))	('dabrafenib', 'Chemical', 'MESH:C561627', (21, 31))	('mutated', 'Var', (68, 75))	('BRAF', 'Gene', (63, 67))
405893	26018876	In lung adenocarcinoma BRAF mutations are found in 1%-5%, half of them harboring the classical V600E mutation.	('V600E', 'Mutation', 'rs113488022', (95, 100))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (3, 22))	('lung adenocarcinoma BRAF', 'Disease', (3, 27))	('lung adenocarcinoma BRAF', 'Disease', 'MESH:D000077192', (3, 27))	('carcinoma', 'Phenotype', 'HP:0030731', (13, 22))	('mutations', 'Var', (28, 37))	('V600E', 'Var', (95, 100))
405894	26018876	BRAF V600E mutations are associated with light/never smoker status, micropapillary histology and occur more frequently in female patients.	('V600E', 'Mutation', 'rs113488022', (5, 10))	('associated', 'Reg', (25, 35))	('patients', 'Species', '9606', (129, 137))	('V600E', 'Var', (5, 10))	('BRAF', 'Gene', (0, 4))	('micropapillary', 'Disease', (68, 82))
405899	26018876	Preclinical data suggest resistance in non-V600E BRAF mutant melanoma cell lines.	('non-V600E', 'Var', (39, 48))	('V600E', 'Mutation', 'rs113488022', (43, 48))	('melanoma', 'Phenotype', 'HP:0002861', (61, 69))	('melanoma', 'Disease', (61, 69))	('melanoma', 'Disease', 'MESH:D008545', (61, 69))	('BRAF', 'Gene', (49, 53))
405900	26018876	This finding is supported by a recent case report showing a rapid tumor progression in a patient with a BRAF G469L mutation undergoing therapy with vemurafenib.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('patient', 'Species', '9606', (89, 96))	('tumor', 'Disease', (66, 71))	('G469L', 'Var', (109, 114))	('vemurafenib', 'Chemical', 'MESH:D000077484', (148, 159))	('G469L', 'Mutation', 'rs1057519720', (109, 114))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('BRAF', 'Gene', (104, 108))
405902	26018876	Preclinical data suggests that BRAF activating mutations may predict sensitivity to inhibition of MEK which is supported by clinical response seen with MEK TKIs in BRAF mutated melanoma.	('MEK', 'Gene', (98, 101))	('mutated', 'Var', (169, 176))	('sensitivity', 'MPA', (69, 80))	('melanoma', 'Disease', 'MESH:D008545', (177, 185))	('mutations', 'Var', (47, 56))	('melanoma', 'Phenotype', 'HP:0002861', (177, 185))	('melanoma', 'Disease', (177, 185))	('BRAF', 'Gene', (164, 168))	('BRAF', 'Gene', (31, 35))
405903	26018876	Ongoing trials in BRAF mutated lung adenocarcinoma investigate BRAF-, MEK- and AKT-inhibitors.	('carcinoma', 'Phenotype', 'HP:0030731', (41, 50))	('lung adenocarcinoma', 'Disease', (31, 50))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (31, 50))	('AKT', 'Gene', (79, 82))	('mutated', 'Var', (23, 30))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (31, 50))	('AKT', 'Gene', '207', (79, 82))	('BRAF', 'Gene', (18, 22))
405905	26018876	KRAS mutations are detected in approximately 20%-25% of lung adenocarcinoma and 4% of lung squamous cell carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (66, 75))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (86, 114))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (56, 75))	('lung adenocarcinoma', 'Disease', (56, 75))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (86, 114))	('mutations', 'Var', (5, 14))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (56, 75))	('detected', 'Reg', (19, 27))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (91, 114))	('lung squamous cell carcinoma', 'Disease', (86, 114))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('KRAS', 'Gene', (0, 4))
405906	26018876	Contrary to most other oncogenic driver mutations, KRAS is more often found in smokers and is detected at lower frequency in East Asian patient cohorts.	('patient', 'Species', '9606', (136, 143))	('found', 'Reg', (70, 75))	('KRAS', 'Var', (51, 55))
405907	26018876	Mutations in KRAS are usually mutually exclusive with other oncogenic driver aberrations including EGFR, BRAF, HER2 mutations and ALK and ROS1 rearrangements.	('HER2', 'Gene', (111, 115))	('EGFR', 'Gene', '1956', (99, 103))	('EGFR', 'Gene', (99, 103))	('HER2', 'Gene', '2064', (111, 115))	('ALK', 'Gene', '238', (130, 133))	('ALK', 'Gene', (130, 133))	('ROS1', 'Gene', (138, 142))	('Mutations', 'Var', (0, 9))	('ROS1', 'Gene', '6098', (138, 142))	('KRAS', 'Gene', (13, 17))	('BRAF', 'Disease', (105, 109))
405908	26018876	KRAS mutations in NSCLC most often occur in codons 12 or 13 and with a lower frequency in codon 61.	('NSCLC', 'Disease', (18, 23))	('occur', 'Reg', (35, 40))	('NSCLC', 'Disease', 'MESH:D002289', (18, 23))	('mutations', 'Var', (5, 14))	('NSCLC', 'Phenotype', 'HP:0030358', (18, 23))	('SCLC', 'Phenotype', 'HP:0030357', (19, 23))	('KRAS', 'Gene', (0, 4))
405909	26018876	HRAS and NRAS mutations are very uncommon in NSCLC.	('HRAS', 'Gene', (0, 4))	('NSCLC', 'Disease', (45, 50))	('NRAS', 'Gene', (9, 13))	('NSCLC', 'Disease', 'MESH:D002289', (45, 50))	('NRAS', 'Gene', '4893', (9, 13))	('SCLC', 'Phenotype', 'HP:0030357', (46, 50))	('HRAS', 'Gene', '3265', (0, 4))	('mutations', 'Var', (14, 23))	('NSCLC', 'Phenotype', 'HP:0030358', (45, 50))
405910	26018876	In early stage lung cancer, KRAS mutations are neither of prognostic relevance nor are they predictive for the use of adjuvant chemotherapy.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('KRAS', 'Gene', (28, 32))	('lung cancer', 'Disease', 'MESH:D008175', (15, 26))	('mutations', 'Var', (33, 42))	('lung cancer', 'Disease', (15, 26))	('lung cancer', 'Phenotype', 'HP:0100526', (15, 26))
405911	26018876	However, a large meta-analysis detected a negative prognostic impact of RAS mutations in NSCLC, especially in adenocarcinoma patients.	('NSCLC', 'Disease', 'MESH:D002289', (89, 94))	('mutations', 'Var', (76, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('SCLC', 'Phenotype', 'HP:0030357', (90, 94))	('NSCLC', 'Phenotype', 'HP:0030358', (89, 94))	('negative', 'NegReg', (42, 50))	('RAS', 'Gene', (72, 75))	('adenocarcinoma', 'Disease', (110, 124))	('adenocarcinoma', 'Disease', 'MESH:D000230', (110, 124))	('NSCLC', 'Disease', (89, 94))	('patients', 'Species', '9606', (125, 133))
405912	26018876	In metastatic NSCLC KRAS mutations did not predict response to standard chemotherapy.	('mutations', 'Var', (25, 34))	('NSCLC', 'Disease', (14, 19))	('NSCLC', 'Disease', 'MESH:D002289', (14, 19))	('SCLC', 'Phenotype', 'HP:0030357', (15, 19))	('NSCLC', 'Phenotype', 'HP:0030358', (14, 19))	('KRAS', 'Gene', (20, 24))
405913	26018876	However, KRAS mutations seem to negatively predict response to EGFR TKIs.	('EGFR', 'Gene', '1956', (63, 67))	('KRAS', 'Gene', (9, 13))	('EGFR', 'Gene', (63, 67))	('negatively', 'NegReg', (32, 42))	('predict', 'Reg', (43, 50))	('mutations', 'Var', (14, 23))
405915	26018876	The most promising approach for KRAS mutant lung cancer seems to be the inhibition of MEK in combination with conventional chemotherapy.	('lung cancer', 'Phenotype', 'HP:0100526', (44, 55))	('MEK', 'Protein', (86, 89))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('lung cancer', 'Disease', 'MESH:D008175', (44, 55))	('inhibition', 'NegReg', (72, 82))	('KRAS mutant', 'Var', (32, 43))	('lung cancer', 'Disease', (44, 55))
405916	26018876	In a phase II trial in 87 previously treated KRAS mutant NSCLC patients the addition of the MEK1/2 inhibitor selumetinib to docetaxel improved ORR (37% vs. 0%, p < 0.0001) and median PFS (5.3 vs. 2.1 months, HR 0.58, p = 0.014) with a trend towards longer overall survival (9.4 vs. 5.2 months, HR 0.80, p = 0.21).	('improved', 'PosReg', (134, 142))	('longer', 'PosReg', (249, 255))	('ORR', 'MPA', (143, 146))	('SCLC', 'Phenotype', 'HP:0030357', (58, 62))	('NSCLC', 'Phenotype', 'HP:0030358', (57, 62))	('docetaxel', 'Chemical', 'MESH:D000077143', (124, 133))	('MEK1/2', 'Gene', '5604;5605', (92, 98))	('selumetinib', 'Chemical', 'MESH:C517975', (109, 120))	('PFS', 'MPA', (183, 186))	('mutant', 'Var', (50, 56))	('MEK1/2', 'Gene', (92, 98))	('patients', 'Species', '9606', (63, 71))	('NSCLC', 'Disease', (57, 62))	('KRAS', 'Gene', (45, 49))	('NSCLC', 'Disease', 'MESH:D002289', (57, 62))
405920	26018876	However, trametinib single agent could not improve the outcome of KRAS mutant patients compared to docetaxel in the second-line setting.	('patients', 'Species', '9606', (78, 86))	('mutant', 'Var', (71, 77))	('trametinib', 'Chemical', 'MESH:C560077', (9, 19))	('docetaxel', 'Chemical', 'MESH:D000077143', (99, 108))	('KRAS', 'Gene', (66, 70))
405922	26018876	Other therapeutic approaches for KRAS mutant lung cancer are the inhibition of other downstream signaling pathways as PI3K and focal adhesion kinase (FAK).	('mutant', 'Var', (38, 44))	('focal adhesion kinase', 'Gene', '5747', (127, 148))	('lung cancer', 'Disease', 'MESH:D008175', (45, 56))	('PI3K', 'Pathway', (118, 122))	('FAK', 'Gene', (150, 153))	('FAK', 'Gene', '5747', (150, 153))	('KRAS', 'Gene', (33, 37))	('lung cancer', 'Disease', (45, 56))	('focal adhesion kinase', 'Gene', (127, 148))	('lung cancer', 'Phenotype', 'HP:0100526', (45, 56))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))
405923	26018876	Furthermore, direct KRAS G12C inhibitors have shown activity in preclinical models.	('KRAS G12C', 'Var', (20, 29))	('activity', 'MPA', (52, 60))	('G12C', 'Mutation', 'rs121913530', (25, 29))
405925	26018876	NRAS mutations have been found in 1% of NSCLC, more commonly in adenocarcinoma patients with a smoking history.	('SCLC', 'Phenotype', 'HP:0030357', (41, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))	('adenocarcinoma', 'Disease', (64, 78))	('NSCLC', 'Phenotype', 'HP:0030358', (40, 45))	('mutations', 'Var', (5, 14))	('adenocarcinoma', 'Disease', 'MESH:D000230', (64, 78))	('NRAS', 'Gene', (0, 4))	('patients', 'Species', '9606', (79, 87))	('NSCLC', 'Disease', (40, 45))	('found', 'Reg', (25, 30))	('NRAS', 'Gene', '4893', (0, 4))	('NSCLC', 'Disease', 'MESH:D002289', (40, 45))
405929	26018876	In NSCLC, amplification of HER2 detected by FISH is found in 2%-4% of NSCLC patients.	('found', 'Reg', (52, 57))	('patients', 'Species', '9606', (76, 84))	('NSCLC', 'Disease', (3, 8))	('SCLC', 'Phenotype', 'HP:0030357', (4, 8))	('NSCLC', 'Disease', 'MESH:D002289', (3, 8))	('NSCLC', 'Disease', (70, 75))	('NSCLC', 'Disease', 'MESH:D002289', (70, 75))	('amplification', 'Var', (10, 23))	('NSCLC', 'Phenotype', 'HP:0030358', (3, 8))	('SCLC', 'Phenotype', 'HP:0030357', (71, 75))	('HER2', 'Gene', (27, 31))	('NSCLC', 'Phenotype', 'HP:0030358', (70, 75))	('HER2', 'Gene', '2064', (27, 31))
405931	26018876	HER2 aberrations are more prevalent in adenocarcinoma patients and HER2 amplification is a negative prognostic marker as shown in a recent meta-analysis.	('adenocarcinoma', 'Disease', 'MESH:D000230', (39, 53))	('patients', 'Species', '9606', (54, 62))	('HER2', 'Gene', (67, 71))	('prevalent', 'Reg', (26, 35))	('HER2', 'Gene', '2064', (0, 4))	('aberrations', 'Var', (5, 16))	('HER2', 'Gene', (0, 4))	('HER2', 'Gene', '2064', (67, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (44, 53))	('adenocarcinoma', 'Disease', (39, 53))
405932	26018876	About 1%-2% of adenocarcinoma patients harbor mutations in the exon 20 of HER2.	('adenocarcinoma', 'Disease', 'MESH:D000230', (15, 29))	('adenocarcinoma', 'Disease', (15, 29))	('HER2', 'Gene', (74, 78))	('HER2', 'Gene', '2064', (74, 78))	('patients', 'Species', '9606', (30, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (20, 29))	('mutations in the exon', 'Var', (46, 67))
405933	26018876	These mutations are not clearly associated with HER2 amplification.	('HER2', 'Gene', '2064', (48, 52))	('HER2', 'Gene', (48, 52))	('mutations', 'Var', (6, 15))
405935	26018876	However, in a European cohort study HER2 mutation positive adenocarcinoma has been shown to be responsive to HER2-targeted therapies with an ORR of 50% and a disease control rate of 83%.	('mutation positive', 'Var', (41, 58))	('HER2', 'Gene', (36, 40))	('HER2', 'Gene', (109, 113))	('HER2', 'Gene', '2064', (36, 40))	('adenocarcinoma', 'Disease', (59, 73))	('HER2', 'Gene', '2064', (109, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))	('adenocarcinoma', 'Disease', 'MESH:D000230', (59, 73))
405937	26018876	Afatinib, a TKI with activity against ERBB family members is approved for EGFR mutation positive adenocarcinoma and has shown clinical activity in lung cancer patients harboring a HER2 mutation even after failure of other EGFR- or HER2-targeting therapies.	('ERBB', 'Gene', '1956', (38, 42))	('HER2', 'Gene', (180, 184))	('HER2', 'Gene', '2064', (231, 235))	('lung cancer', 'Phenotype', 'HP:0100526', (147, 158))	('EGFR', 'Gene', '1956', (222, 226))	('EGFR', 'Gene', (74, 78))	('adenocarcinoma', 'Disease', 'MESH:D000230', (97, 111))	('mutation', 'Var', (185, 193))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('Afatinib', 'Chemical', 'MESH:D000077716', (0, 8))	('HER2', 'Gene', (231, 235))	('HER2', 'Gene', '2064', (180, 184))	('lung cancer', 'Disease', (147, 158))	('EGFR', 'Gene', '1956', (74, 78))	('mutation', 'Var', (79, 87))	('patients', 'Species', '9606', (159, 167))	('EGFR', 'Gene', (222, 226))	('ERBB', 'Gene', (38, 42))	('adenocarcinoma', 'Disease', (97, 111))	('lung cancer', 'Disease', 'MESH:D008175', (147, 158))
405941	26018876	Homodimerization and autophosphorylation of MET leads to the activation of various intracellular signaling pathways including RAS-RAF-MAPK and PI3K-AKT-mTOR.	('AKT', 'Gene', '207', (148, 151))	('mTOR', 'Gene', (152, 156))	('Homodimerization', 'Var', (0, 16))	('mTOR', 'Gene', '2475', (152, 156))	('activation', 'PosReg', (61, 71))	('AKT', 'Gene', (148, 151))	('autophosphorylation', 'MPA', (21, 40))	('intracellular signaling pathways', 'Pathway', (83, 115))	('RAF', 'Gene', (130, 133))	('MET', 'Gene', (44, 47))	('RAF', 'Gene', '22882', (130, 133))
405942	26018876	In lung cancer, MET mutations are rarely detected, amplifications are found in around 2%-5% of NSCLC, predominantly in adenocarcinoma.	('NSCLC', 'Disease', 'MESH:D002289', (95, 100))	('adenocarcinoma', 'Disease', (119, 133))	('SCLC', 'Phenotype', 'HP:0030357', (96, 100))	('lung cancer', 'Disease', (3, 14))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('lung cancer', 'Phenotype', 'HP:0100526', (3, 14))	('adenocarcinoma', 'Disease', 'MESH:D000230', (119, 133))	('NSCLC', 'Phenotype', 'HP:0030358', (95, 100))	('amplifications', 'Var', (51, 65))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('lung cancer', 'Disease', 'MESH:D008175', (3, 14))	('found', 'Reg', (70, 75))	('NSCLC', 'Disease', (95, 100))
405944	26018876	MET amplification has been described as one potential mechanism of resistance towards EGFR inhibition in EGFR mutant lung adenocarcinoma.	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (117, 136))	('EGFR', 'Gene', '1956', (86, 90))	('mutant', 'Var', (110, 116))	('EGFR', 'Gene', '1956', (105, 109))	('EGFR', 'Gene', (86, 90))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (117, 136))	('EGFR', 'Gene', (105, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('lung adenocarcinoma', 'Disease', (117, 136))
405957	26018876	However, in a small cohort of KRAS mutation positive patients the combination therapy achieved a significant prolongation of median PFS (HR 0.18, p = 0.006).	('patients', 'Species', '9606', (53, 61))	('KRAS', 'Gene', (30, 34))	('prolongation', 'PosReg', (109, 121))	('mutation', 'Var', (35, 43))
405964	26018876	In NSCLC RET translocations can be detected in about 1.5% of patients predominantly in younger, light or never smokers with adenocarcinoma histology and poorly differentiated tumors.	('tumors', 'Disease', (175, 181))	('tumors', 'Disease', 'MESH:D009369', (175, 181))	('NSCLC', 'Disease', (3, 8))	('tumors', 'Phenotype', 'HP:0002664', (175, 181))	('SCLC', 'Phenotype', 'HP:0030357', (4, 8))	('NSCLC', 'Disease', 'MESH:D002289', (3, 8))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('patients', 'Species', '9606', (61, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('RET', 'Gene', '5979', (9, 12))	('adenocarcinoma', 'Disease', (124, 138))	('NSCLC', 'Phenotype', 'HP:0030358', (3, 8))	('adenocarcinoma', 'Disease', 'MESH:D000230', (124, 138))	('translocations', 'Var', (13, 27))	('RET', 'Gene', (9, 12))
405965	26018876	RET translocations seem to occur mutually exclusive with other known oncogenic driver mutations or translocations.	('translocations', 'Var', (4, 18))	('RET', 'Gene', '5979', (0, 3))	('RET', 'Gene', (0, 3))
405976	26018876	In NSCLC mutations and amplifications are detected in 2% and 12%-17%, respectively.	('NSCLC', 'Disease', (3, 8))	('SCLC', 'Phenotype', 'HP:0030357', (4, 8))	('NSCLC', 'Disease', 'MESH:D002289', (3, 8))	('mutations', 'Var', (9, 18))	('NSCLC', 'Phenotype', 'HP:0030358', (3, 8))
405977	26018876	The incidence of PIK3CA mutations seems to be higher in lung squamous cell carcinoma.	('PIK3CA', 'Gene', (17, 23))	('higher', 'Reg', (46, 52))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (56, 84))	('PIK3CA', 'Gene', '5290', (17, 23))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (61, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (56, 84))	('lung squamous cell carcinoma', 'Disease', (56, 84))	('mutations', 'Var', (24, 33))
405978	26018876	PIK3CA mutations can occur in combination with other known driver mutations like EGFR or KRAS mutations as well as in the setting of acquired EGFR TKI resistance.	('mutations', 'Var', (7, 16))	('EGFR', 'Gene', '1956', (142, 146))	('EGFR', 'Gene', (142, 146))	('occur', 'Reg', (21, 26))	('PIK3CA', 'Gene', (0, 6))	('PIK3CA', 'Gene', '5290', (0, 6))	('EGFR', 'Gene', '1956', (81, 85))	('EGFR', 'Gene', (81, 85))
405979	26018876	The fact that up to 70% of patients with a PIK3CA mutation harbor other coexisting mutations or rearrangements in other oncogenes supports the hypothesis that PIK3CA mutations are not oncogenic driver mutations per se in NSCLC.	('PIK3CA', 'Gene', '5290', (43, 49))	('NSCLC', 'Disease', (221, 226))	('NSCLC', 'Disease', 'MESH:D002289', (221, 226))	('patients', 'Species', '9606', (27, 35))	('SCLC', 'Phenotype', 'HP:0030357', (222, 226))	('PIK3CA', 'Gene', (159, 165))	('PIK3CA', 'Gene', '5290', (159, 165))	('NSCLC', 'Phenotype', 'HP:0030358', (221, 226))	('mutation', 'Var', (50, 58))	('PIK3CA', 'Gene', (43, 49))
405980	26018876	Preclinical data suggest that tumors harboring PIK3CA mutations are highly sensitive to PI3K inhibitors.	('tumors', 'Disease', (30, 36))	('PIK3CA', 'Gene', (47, 53))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('PIK3CA', 'Gene', '5290', (47, 53))	('mutations', 'Var', (54, 63))	('sensitive', 'MPA', (75, 84))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))
405981	26018876	Clinical trials with PI3K inhibitors as well as mTOR inhibitors are ongoing.	('mTOR', 'Gene', '2475', (48, 52))	('mTOR', 'Gene', (48, 52))	('PI3K', 'Var', (21, 25))
405984	26018876	FGFR amplifications have been detected in about 20% of squamous cell carcinomas and in a lower frequency (about 5%) of adenocarcinomas.	('adenocarcinomas', 'Disease', 'MESH:D000230', (119, 134))	('amplifications', 'Var', (5, 19))	('adenocarcinomas', 'Disease', (119, 134))	('carcinomas', 'Phenotype', 'HP:0030731', (69, 79))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (55, 78))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('FGFR', 'Gene', (0, 4))	('carcinomas', 'Phenotype', 'HP:0030731', (124, 134))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (55, 79))	('squamous cell carcinomas', 'Disease', (55, 79))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (55, 79))	('detected', 'Reg', (30, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))
405985	26018876	FGFR1 amplification is more common in male smokers and associated with a poor outcome.	('common', 'Reg', (28, 34))	('associated', 'Reg', (55, 65))	('FGFR1', 'Gene', (0, 5))	('FGFR1', 'Gene', '2260', (0, 5))	('amplification', 'Var', (6, 19))
405986	26018876	However, the negative prognostic impact of FGFR1 amplifications was not confirmed in a Caucasian patient cohort.	('FGFR1', 'Gene', '2260', (43, 48))	('FGFR1', 'Gene', (43, 48))	('amplifications', 'Var', (49, 63))	('patient', 'Species', '9606', (97, 104))
405989	26018876	In NSCLC DDR2 mutations have been described with a frequency of nearly 4%.	('DDR2', 'Gene', '4921', (9, 13))	('NSCLC', 'Disease', (3, 8))	('SCLC', 'Phenotype', 'HP:0030357', (4, 8))	('DDR2', 'Gene', (9, 13))	('NSCLC', 'Disease', 'MESH:D002289', (3, 8))	('NSCLC', 'Phenotype', 'HP:0030358', (3, 8))	('mutations', 'Var', (14, 23))
405990	26018876	In a preclinical model the multikinase TKI dasatinib with activity against DDR2 showed activity in squamous carcinoma cell lines harboring DDR2 mutations.	('DDR2', 'Gene', '4921', (139, 143))	('squamous carcinoma', 'Disease', (99, 117))	('dasatinib', 'Chemical', 'MESH:D000069439', (43, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('DDR2', 'Gene', (139, 143))	('activity', 'MPA', (87, 95))	('DDR2', 'Gene', '4921', (75, 79))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (99, 117))	('DDR2', 'Gene', (75, 79))	('mutations', 'Var', (144, 153))	('squamous carcinoma', 'Disease', 'MESH:D002294', (99, 117))
405991	26018876	Currently, a clinical trial with dasatinib in DDR2 mutant NSCLC is ongoing.	('NSCLC', 'Disease', (58, 63))	('SCLC', 'Phenotype', 'HP:0030357', (59, 63))	('NSCLC', 'Disease', 'MESH:D002289', (58, 63))	('DDR2', 'Gene', (46, 50))	('mutant', 'Var', (51, 57))	('NSCLC', 'Phenotype', 'HP:0030358', (58, 63))	('dasatinib', 'Chemical', 'MESH:D000069439', (33, 42))	('DDR2', 'Gene', '4921', (46, 50))
405992	26018876	MEK1 (also named MAP2K1) is a serine-threonine kinase with mutations occurring in approximately 1% of NSCLC (mostly adenocarcinoma).	('NSCLC', 'Disease', 'MESH:D002289', (102, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('SCLC', 'Phenotype', 'HP:0030357', (103, 107))	('MEK1', 'Gene', '5604', (0, 4))	('MAP2K1', 'Gene', (17, 23))	('NSCLC', 'Phenotype', 'HP:0030358', (102, 107))	('MAP2K1', 'Gene', '5604', (17, 23))	('occurring', 'Reg', (69, 78))	('mutations', 'Var', (59, 68))	('MEK1', 'Gene', (0, 4))	('NSCLC', 'Disease', (102, 107))	('mostly adenocarcinoma', 'Disease', 'MESH:D000230', (109, 130))	('mostly adenocarcinoma', 'Disease', (109, 130))
405993	26018876	NTRIK1 fusions have recently been described approximately 3% in never smokers with lung adenocarcinoma not harboring other oncogenic driver aberrations.	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('lung adenocarcinoma', 'Disease', (83, 102))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (83, 102))	('fusions', 'Var', (7, 14))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (83, 102))	('NTRIK1', 'Gene', (0, 6))
405999	26018876	PTEN mutations occur in 4%-8% of NSCLC and are more commonly detected in squamous cell histology and in patients with a smoking history.	('NSCLC', 'Phenotype', 'HP:0030358', (33, 38))	('squamous cell histology', 'Disease', (73, 96))	('SCLC', 'Phenotype', 'HP:0030357', (34, 38))	('mutations', 'Var', (5, 14))	('NSCLC', 'Disease', (33, 38))	('detected', 'Reg', (61, 69))	('PTEN', 'Gene', (0, 4))	('NSCLC', 'Disease', 'MESH:D002289', (33, 38))	('patients', 'Species', '9606', (104, 112))	('PTEN', 'Gene', '5728', (0, 4))
406001	26018876	The therapeutic landscape of NSCLC therapy has profoundly changed since the first discovery of activating EGFR mutations and the development of specific EGFR TKIs.	('mutations', 'Var', (111, 120))	('SCLC', 'Phenotype', 'HP:0030357', (30, 34))	('NSCLC', 'Phenotype', 'HP:0030358', (29, 34))	('EGFR', 'Gene', '1956', (153, 157))	('NSCLC', 'Disease', (29, 34))	('EGFR', 'Gene', '1956', (106, 110))	('EGFR', 'Gene', (153, 157))	('NSCLC', 'Disease', 'MESH:D002289', (29, 34))	('activating', 'PosReg', (95, 105))	('EGFR', 'Gene', (106, 110))
406015	26018876	The five targeted therapies included erlotinib (EGFR mutations), the MEK inhibitor selumetinib (KRAS, HRAS, NRAS, and BRAF mutations), the AKT inhibitor MK2206 (PIK3CA, AKT1, and PTEN mutations), lapatinib (HER2 mutations), and sunitinib (KIT and PDGFRA mutations).	('HRAS', 'Gene', (102, 106))	('EGFR', 'Gene', '1956', (48, 52))	('AKT', 'Gene', '207', (139, 142))	('HER2', 'Gene', '2064', (207, 211))	('PIK3CA', 'Gene', '5290', (161, 167))	('MEK', 'Enzyme', (69, 72))	('PTEN', 'Gene', (179, 183))	('lapatinib', 'Chemical', 'MESH:D000077341', (196, 205))	('selumetinib', 'Chemical', 'MESH:C517975', (83, 94))	('NRAS', 'Gene', '4893', (108, 112))	('sunitinib', 'Chemical', 'MESH:D000077210', (228, 237))	('MK2206', 'Chemical', 'MESH:C548887', (153, 159))	('PTEN', 'Gene', '5728', (179, 183))	('HER2', 'Gene', (207, 211))	('AKT', 'Gene', (169, 172))	('EGFR', 'Gene', (48, 52))	('PIK3CA', 'Gene', (161, 167))	('mutations', 'Var', (53, 62))	('AKT', 'Gene', (139, 142))	('AKT1', 'Gene', '207', (169, 173))	('PDGFRA', 'Gene', '5156', (247, 253))	('NRAS', 'Gene', (108, 112))	('PDGFRA', 'Gene', (247, 253))	('erlotinib', 'Chemical', 'MESH:D000069347', (37, 46))	('AKT1', 'Gene', (169, 173))	('HRAS', 'Gene', '3265', (102, 106))	('mutations', 'Var', (123, 132))	('AKT', 'Gene', '207', (169, 172))
406022	33989301	Hazards ratios (HR) and 95% confidence intervals (CI) were collected to estimate the correlation between overexpression and amplification of FGFR1 and survival outcomes of HNSCC patients.	('HNSCC', 'Disease', (172, 177))	('patients', 'Species', '9606', (178, 186))	('FGFR1', 'Gene', (141, 146))	('amplification', 'Var', (124, 137))	('FGFR1', 'Gene', '2260', (141, 146))
406026	33989301	The present study demonstrated that HNSCC patients with FGFR1 overexpression and amplification were more likely to exhibit poorer survival.	('poorer', 'NegReg', (123, 129))	('amplification', 'Var', (81, 94))	('FGFR1', 'Gene', (56, 61))	('overexpression', 'PosReg', (62, 76))	('HNSCC', 'Disease', (36, 41))	('patients', 'Species', '9606', (42, 50))	('FGFR1', 'Gene', '2260', (56, 61))
406036	33989301	Substantial evidence further indicates that genomic driver aberrations, such as mutations, amplifications and translocations may cause a dysregulation in the FGF-FGFR pathway and play an important role in tumor development.	('amplifications', 'Var', (91, 105))	('FGF', 'Gene', '2246;2247', (162, 165))	('cause', 'Reg', (129, 134))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('mutations', 'Var', (80, 89))	('translocations', 'Var', (110, 124))	('FGF', 'Gene', (158, 161))	('dysregulation', 'MPA', (137, 150))	('FGF', 'Gene', '2246;2247', (158, 161))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumor', 'Disease', (205, 210))	('play', 'Reg', (179, 183))	('FGF', 'Gene', (162, 165))
406042	33989301	The inclusion criteria of the meta-analysis were the following: 1) patients diagnosed with HNSCC; 2) association between the overexpression and amplification of FGFR1 and overall survival (OS); and 3) the language of publications that was confined to English.	('FGFR1', 'Gene', (161, 166))	('patients', 'Species', '9606', (67, 75))	('FGFR1', 'Gene', '2260', (161, 166))	('association', 'Interaction', (101, 112))	('amplification', 'Var', (144, 157))	('HNSCC', 'Disease', (91, 96))	('overall survival', 'MPA', (171, 187))	('overexpression', 'PosReg', (125, 139))
406056	33989301	The combined results of these studies indicated overexpression and amplification of FGFR1 were associated with poor OS (HR, 1.97; 95% CI, 1.49-2.61, P<0.001).	('FGFR1', 'Gene', (84, 89))	('FGFR1', 'Gene', '2260', (84, 89))	('amplification', 'Var', (67, 80))	('overexpression', 'PosReg', (48, 62))	('poor OS', 'MPA', (111, 118))
406063	33989301	Goke et al reported that FGFR1 amplification was a frequent event in primary and metastatic HNSCC and that it could be used as a poor prognostic indicator.	('FGFR1', 'Gene', '2260', (25, 30))	('primary', 'Disease', (69, 76))	('FGFR1', 'Gene', (25, 30))	('amplification', 'Var', (31, 44))
406064	33989301	Dubot et al demonstrated that FGFR1 amplification was associated with lower survival and that it could be used as a prognostic biomarker for patients with HNSCC.	('FGFR1', 'Gene', (30, 35))	('HNSCC', 'Disease', (155, 160))	('survival', 'MPA', (76, 84))	('FGFR1', 'Gene', '2260', (30, 35))	('amplification', 'Var', (36, 49))	('lower', 'NegReg', (70, 75))	('patients', 'Species', '9606', (141, 149))
406066	33989301	Kim et al recently found that FGFR1 amplification may serve as an independent prognostic factor for DFS in hypopharyngeal and laryngeal squamous cell carcinoma.	('hypopharyngeal', 'Disease', (107, 121))	('FGFR1', 'Gene', (30, 35))	('FGFR1', 'Gene', '2260', (30, 35))	('carcinoma', 'Phenotype', 'HP:0030731', (150, 159))	('amplification', 'Var', (36, 49))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (136, 159))	('DFS', 'Disease', (100, 103))	('squamous cell carcinoma', 'Disease', (136, 159))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (136, 159))
406071	33989301	The results indicated that overexpression and amplification of FGFR1 significantly predicted poor OS in HPV negative HNSCC patients.	('HPV', 'Species', '10566', (104, 107))	('amplification', 'Var', (46, 59))	('poor', 'Disease', (93, 97))	('patients', 'Species', '9606', (123, 131))	('FGFR1', 'Gene', (63, 68))	('FGFR1', 'Gene', '2260', (63, 68))
406072	33989301	A recent study reported that 7.1% of all tumor types exhibited genetic alterations and that FGFR1 was involved in almost 50% of these alterations.	('FGFR1', 'Gene', (92, 97))	('genetic alterations', 'Var', (63, 82))	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Disease', (41, 46))	('FGFR1', 'Gene', '2260', (92, 97))	('exhibited', 'Reg', (53, 62))	('tumor', 'Disease', 'MESH:D009369', (41, 46))
406082	33989301	According to the results of the present study, the FGFR inhibitors may hold a therapeutic potential against HNSCC.	('HNSCC', 'Disease', (108, 113))	('FGF', 'Gene', (51, 54))	('inhibitors', 'Var', (56, 66))	('FGF', 'Gene', '2246;2247', (51, 54))
406086	33989301	The results demonstrated that patients with overexpression and amplification of FGFR1 were more likely to exhibit poor prognosis.	('FGFR1', 'Gene', '2260', (80, 85))	('poor prognosis', 'CPA', (114, 128))	('overexpression', 'PosReg', (44, 58))	('patients', 'Species', '9606', (30, 38))	('FGFR1', 'Gene', (80, 85))	('amplification', 'Var', (63, 76))
406093	33565732	COSMIC, cBioPortal, and CCLE were used to examine FZD2 mutations in human cancers.	('human', 'Species', '9606', (68, 73))	('mutations', 'Var', (55, 64))	('cancers', 'Disease', 'MESH:D009369', (74, 81))	('CCLE', 'Chemical', '-', (24, 28))	('cancers', 'Phenotype', 'HP:0002664', (74, 81))	('cancers', 'Disease', (74, 81))	('FZD2', 'Gene', '2535', (50, 54))	('FZD2', 'Gene', (50, 54))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
406123	33565732	The catalog of somatic mutations in cancer (COSMIC) database (https://cancer.sanger.ac.uk/cosmic/) collects millions of coding mutations, noncoding mutations, genome rearrangements, fusion genes, copy number abnormalities, and gene expression variations in the human genome [12].	('fusion genes', 'Var', (182, 194))	('number abnormalities', 'Disease', 'MESH:D007674', (201, 221))	('variations', 'Var', (243, 253))	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('cancer', 'Disease', (36, 42))	('human', 'Species', '9606', (261, 266))	('number abnormalities', 'Disease', (201, 221))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))
406124	33565732	In this study, COSMIC was used to examine FZD2 mutations in human cancers.	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('FZD2', 'Gene', '2535', (42, 46))	('FZD2', 'Gene', (42, 46))	('mutations', 'Var', (47, 56))	('cancers', 'Phenotype', 'HP:0002664', (66, 73))	('cancers', 'Disease', (66, 73))	('cancers', 'Disease', 'MESH:D009369', (66, 73))	('human', 'Species', '9606', (60, 65))
406127	33565732	The Cancer Cell Line Encyclopedia (CCLE) project dataset is a compilation of gene expression data from human cancer cell lines and was used to analyze FZD2 mutations in various cancer cell lines [14].	('cancer', 'Disease', (177, 183))	('cancer', 'Disease', 'MESH:D009369', (177, 183))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('FZD2', 'Gene', '2535', (151, 155))	('FZD2', 'Gene', (151, 155))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('mutations', 'Var', (156, 165))	('human', 'Species', '9606', (103, 108))	('cancer', 'Disease', (109, 115))	('CCLE', 'Chemical', '-', (35, 39))	('Cancer', 'Disease', (4, 10))	('Cancer', 'Phenotype', 'HP:0002664', (4, 10))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('Cancer', 'Disease', 'MESH:D009369', (4, 10))
406128	33565732	Tumor mutation burden (TMB) is defined as the total number of somatic gene coding errors, base substitutions, insertions, or deletions detected per million bases.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('TMB', 'Chemical', '-', (23, 26))	('insertions', 'Var', (110, 120))	('deletions', 'Var', (125, 134))	('Tumor mutation burden', 'Disease', (0, 21))	('base substitutions', 'Var', (90, 108))
406152	33565732	According to the median expression of FZD2 across the different cancer types, patients were divided into either a high or low expression group; when analyzed, it was found that the survival difference between the high and low expression groups was significant and that patients with high FZD2 expression had earlier recurrence after tumor resection (Fig.	('earlier', 'PosReg', (308, 315))	('tumor', 'Disease', (333, 338))	('tumor', 'Phenotype', 'HP:0002664', (333, 338))	('high', 'Var', (283, 287))	('FZD2', 'Gene', (38, 42))	('FZD2', 'Gene', '2535', (38, 42))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('patients', 'Species', '9606', (78, 86))	('recurrence', 'CPA', (316, 326))	('tumor', 'Disease', 'MESH:D009369', (333, 338))	('expression', 'MPA', (293, 303))	('FZD2', 'Gene', '2535', (288, 292))	('FZD2', 'Gene', (288, 292))	('patients', 'Species', '9606', (269, 277))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
406153	33565732	COSMIC provides information about FZD2 mutations in different cancers, including missense mutations, nonsense mutations, and synonymous mutations (Figs 3A and Fig.	('missense mutations', 'Var', (81, 99))	('FZD2', 'Gene', (34, 38))	('FZD2', 'Gene', '2535', (34, 38))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('mutations', 'Var', (39, 48))	('nonsense mutations', 'Var', (101, 119))	('cancers', 'Disease', 'MESH:D009369', (62, 69))	('cancers', 'Phenotype', 'HP:0002664', (62, 69))	('synonymous mutations', 'Var', (125, 145))	('cancers', 'Disease', (62, 69))
406156	33565732	C>T and G>A mutations were found to be the most common in the FZD2 coding chain, while A>T and T>A mutations were rare.	('G>A mutations', 'Var', (8, 21))	('C>T', 'Var', (0, 3))	('FZD2', 'Gene', '2535', (62, 66))	('FZD2', 'Gene', (62, 66))	('common', 'Reg', (48, 54))
406159	33565732	Among these, the mutation rate was higher in esophagogastric adenocarcinoma and endometrial carcinoma (Fig.	('carcinoma', 'Phenotype', 'HP:0030731', (66, 75))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('mutation', 'Var', (17, 25))	('esophagogastric adenocarcinoma', 'Phenotype', 'HP:0011459', (45, 75))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (80, 101))	('adenocarcinoma and endometrial carcinoma', 'Disease', 'MESH:D016889', (61, 101))	('higher', 'Reg', (35, 41))
406160	33565732	Missense mutations and silent mutations were also found in cancer cell lines (Fig.	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('Missense mutations', 'Var', (0, 18))
406195	33565732	In addition, the latest research has found that FZD2 is more highly expressed in hepatocellular carcinoma tissues than in adjacent tissues, and the recurrence-free survival rate of patients with high FZD2 expression is significantly lower than that of patients with low expression.	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('recurrence-free survival rate', 'CPA', (148, 177))	('patients', 'Species', '9606', (252, 260))	('FZD2', 'Gene', '2535', (48, 52))	('FZD2', 'Gene', (48, 52))	('highly', 'PosReg', (61, 67))	('lower', 'NegReg', (233, 238))	('FZD2', 'Gene', '2535', (200, 204))	('high', 'Var', (195, 199))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (81, 105))	('patients', 'Species', '9606', (181, 189))	('hepatocellular carcinoma', 'Disease', (81, 105))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (81, 105))	('FZD2', 'Gene', (200, 204))	('expression', 'MPA', (205, 215))
406196	33565732	Furthermore, FZD2 expression is significantly correlated with the mesenchymal phenotype in HCC cell lines, and knocking out FZD2 can inhibit the migration and invasiveness of liver cancer cells [23].	('liver cancer', 'Phenotype', 'HP:0002896', (175, 187))	('FZD2', 'Gene', '2535', (13, 17))	('FZD2', 'Gene', (13, 17))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('knocking out', 'Var', (111, 123))	('invasiveness of liver cancer', 'Disease', (159, 187))	('migration', 'CPA', (145, 154))	('FZD2', 'Gene', '2535', (124, 128))	('inhibit', 'NegReg', (133, 140))	('FZD2', 'Gene', (124, 128))	('invasiveness of liver cancer', 'Disease', 'MESH:D006528', (159, 187))
406204	33565732	Knockout of FZD7 or use of Wnt/beta-catenin inhibitors has been shown to reduce the stemness and chemoresistance of GC cells [33].	('chemoresistance', 'CPA', (97, 112))	('beta-catenin', 'Gene', (31, 43))	('GC', 'Phenotype', 'HP:0012126', (116, 118))	('beta-catenin', 'Gene', '1499', (31, 43))	('Knockout', 'Var', (0, 8))	('FZD7', 'Gene', '8324', (12, 16))	('FZD7', 'Gene', (12, 16))	('reduce', 'NegReg', (73, 79))
406205	33565732	FZD8 is highly expressed in human lung cancer tissue samples and cell lines, and knockout of FZD8 can increase the sensitivity of lung cancer cells to paclitaxel [34].	('lung cancer', 'Phenotype', 'HP:0100526', (130, 141))	('paclitaxel', 'Chemical', 'MESH:D017239', (151, 161))	('FZD8', 'Gene', '8325', (93, 97))	('lung cancer', 'Disease', (34, 45))	('FZD8', 'Gene', (93, 97))	('human', 'Species', '9606', (28, 33))	('lung cancer', 'Phenotype', 'HP:0100526', (34, 45))	('knockout', 'Var', (81, 89))	('lung cancer', 'Disease', 'MESH:D008175', (130, 141))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('lung cancer', 'Disease', 'MESH:D008175', (34, 45))	('increase', 'PosReg', (102, 110))	('sensitivity', 'MPA', (115, 126))	('FZD8', 'Gene', '8325', (0, 4))	('lung cancer', 'Disease', (130, 141))	('FZD8', 'Gene', (0, 4))
406221	33565732	Those with high TMB expression have been shown to benefit more from immune checkpoint inhibitor therapy [44].	('TMB', 'Chemical', '-', (16, 19))	('TMB', 'Protein', (16, 19))	('benefit', 'PosReg', (50, 57))	('high', 'Var', (11, 15))
406222	33565732	TMB reflects the total number of replacement and insertion/deletion mutations per megabase in the exon coding region of the evaluated gene in the tumor cell genome.	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('TMB', 'Chemical', '-', (0, 3))	('tumor', 'Disease', (146, 151))	('insertion/deletion mutations', 'Var', (49, 77))	('replacement', 'Var', (33, 44))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
406223	33565732	Driving gene mutations can lead to tumors, and a large number of somatic mutations can produce new antigens, which can activate T cells and cause immune responses [45].	('T cells', 'CPA', (128, 135))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('cause', 'Reg', (140, 145))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('immune responses', 'CPA', (146, 162))	('tumors', 'Disease', (35, 41))	('tumors', 'Disease', 'MESH:D009369', (35, 41))	('lead to', 'Reg', (27, 34))	('mutations', 'Var', (13, 22))	('activate', 'PosReg', (119, 127))	('mutations', 'Var', (73, 82))	('produce', 'Reg', (87, 94))
406226	33565732	Studies have shown that frameshift mutations of AXIN2 and TCF7L2 are common in GC with high MSI, and these mutations may promote the development of GC through the control of Wnt signaling [46].	('mutations', 'Var', (107, 116))	('AXIN2', 'Gene', (48, 53))	('development', 'CPA', (133, 144))	('AXIN2', 'Gene', '8313', (48, 53))	('GC', 'Phenotype', 'HP:0012126', (79, 81))	('TCF7L2', 'Gene', (58, 64))	('GC', 'Phenotype', 'HP:0012126', (148, 150))	('TCF7L2', 'Gene', '6934', (58, 64))	('promote', 'PosReg', (121, 128))	('frameshift mutations', 'Var', (24, 44))
406228	33565732	It was also found that FZD2 was mutated in breast, endometrial, large intestine, liver, lung, skin, and stomach cancer.	('endometrial', 'Disease', (51, 62))	('skin', 'Disease', (94, 98))	('stomach cancer', 'Disease', 'MESH:D013274', (104, 118))	('stomach cancer', 'Phenotype', 'HP:0012126', (104, 118))	('liver', 'Disease', (81, 86))	('FZD2', 'Gene', (23, 27))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('large intestine', 'Disease', (64, 79))	('mutated', 'Var', (32, 39))	('stomach cancer', 'Disease', (104, 118))	('breast', 'Disease', (43, 49))	('FZD2', 'Gene', '2535', (23, 27))	('lung', 'Disease', (88, 92))
406265	33299884	Another study revealed that high body mass index (BMI) was positively associated with the incidence of several types of cancer, while patients with high BMI at the time of initial diagnosis had higher two/five-year survival rates than those with low BMI.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('higher', 'PosReg', (194, 200))	('high BMI', 'Var', (148, 156))	('low BMI', 'Phenotype', 'HP:0045082', (246, 253))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('associated', 'Reg', (70, 80))	('patients', 'Species', '9606', (134, 142))	('high body mass index', 'Phenotype', 'HP:0031418', (28, 48))	('two/five-year survival rates', 'CPA', (201, 229))
406279	33299884	The patients were divided into four groups based on BMI: normal weight (18 kg/m2 <= BMI < 25 kg/m2), high weight (25 kg/m2 <= BMI < 30 kg/m2), obese (30 kg/m2 <= BMI<40 kg/m2), and extremely obese (BMI >= 40 kg/m2).	('obese', 'Disease', 'MESH:D009765', (191, 196))	('25 kg/m2 <=', 'Var', (114, 125))	('30 kg/m2 <= BMI', 'Var', (150, 165))	('obese', 'Disease', 'MESH:D009765', (143, 148))	('obese', 'Disease', (191, 196))	('patients', 'Species', '9606', (4, 12))	('obese', 'Disease', (143, 148))
406289	33299884	Mutations, copy number variations (CNVs), and controlling expression levels of obesity-related genes were downloaded from TCGA.	('Mutations', 'Var', (0, 9))	('obesity', 'Disease', (79, 86))	('obesity', 'Disease', 'MESH:D009765', (79, 86))	('obesity', 'Phenotype', 'HP:0001513', (79, 86))
406316	33299884	As displayed in Figure 2(c), for each of the five obesity-related genes (LEPR, MTCH2, MC4R, LEP, and KCTD15), the patients in a high-expression group had a greater cancer survival rate than those in the low/medium-expression groups (P < 0.05).	('KCTD15', 'Gene', '79047', (101, 107))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('LEP', 'Gene', '3952', (92, 95))	('KCTD15', 'Gene', (101, 107))	('obesity', 'Disease', (50, 57))	('greater', 'PosReg', (156, 163))	('patients', 'Species', '9606', (114, 122))	('LEP', 'Gene', (92, 95))	('obesity', 'Disease', 'MESH:D009765', (50, 57))	('LEPR', 'Gene', '3953', (73, 77))	('cancer', 'Disease', (164, 170))	('LEP', 'Gene', '3952', (73, 76))	('LEPR', 'Gene', (73, 77))	('MC4R', 'Gene', (86, 90))	('high-expression', 'Var', (128, 143))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('MTCH2', 'Gene', '23788', (79, 84))	('LEP', 'Gene', (73, 76))	('obesity', 'Phenotype', 'HP:0001513', (50, 57))	('MC4R', 'Gene', '4160', (86, 90))	('MTCH2', 'Gene', (79, 84))
406319	33299884	For patients with six types of cancer (KIRC, LUAD, LGG, GBM, UCEC, and BLCA), those in the PCSK1 low/medium-expression group had higher survival probability than those in the high-expression group.	('LUAD', 'Phenotype', 'HP:0030078', (45, 49))	('LUAD', 'Disease', (45, 49))	('LGG', 'Disease', (51, 54))	('PCSK1', 'Gene', '5122', (91, 96))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('survival', 'CPA', (136, 144))	('higher', 'PosReg', (129, 135))	('GBM', 'Disease', (56, 59))	('UCEC', 'Disease', (61, 65))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('patients', 'Species', '9606', (4, 12))	('PCSK1', 'Gene', (91, 96))	('cancer', 'Disease', (31, 37))	('low/medium-expression', 'Var', (97, 118))
406320	33299884	However, for patients with SKCM, patients with high expression level of PCSK1 may benefit from a superior survival probability than those with low/medium expression level.	('patients', 'Species', '9606', (33, 41))	('PCSK1', 'Gene', (72, 77))	('survival', 'CPA', (106, 114))	('patients', 'Species', '9606', (13, 21))	('high expression level', 'Var', (47, 68))	('PCSK1', 'Gene', '5122', (72, 77))	('benefit', 'PosReg', (82, 89))
406330	33299884	However, the mutation rates of five obesity-related genes in few cancer tissues were >0.05 (i.e., LEPR in SKCM (0.11), UCEC (0.07), and LUSC (0.07) and PCSK1 in SKCM (0.09) and UCEC (0.06)).	('obesity', 'Disease', 'MESH:D009765', (36, 43))	('obesity', 'Phenotype', 'HP:0001513', (36, 43))	('mutation', 'Var', (13, 21))	('LEPR', 'Gene', (98, 102))	('PCSK1', 'Gene', (152, 157))	('obesity', 'Disease', (36, 43))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('PCSK1', 'Gene', '5122', (152, 157))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('LEPR', 'Gene', '3953', (98, 102))
406335	33299884	Then, for each of the 33 types of cancer, the expression levels of the 13 obesity-related genes were divided into different groups based on the seven factors as follows: (1) patients' gender (male or female), (2) patients' race (African-American, Caucasian, and Asian), (3) menopausal status (premenopause, perimenopause, and postmenopause), (4) history of smoking (smoker, nonsmoker, reformed smoker #1 (<=15 years), and reformed smoker #2 (>15 years)), (5) tumor grade (grade 1, grade 2, grade 3, and grade 4), (6) BMI (normal weight (18 kg/m2 <= BMI < 25 kg/m2), high weight (25 kg/m2 <= BMI < 30 kg/m2), obese (30 kg/m2 <= BMI < 40 kg/m2), and extremely obese (BMI >= 40 kg/m2)), and (7) history of drinking (occasional drinker, social drinker, daily drinker, weekly drinker, and nondrinker).	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('menopausal status', 'Phenotype', 'HP:0008209', (274, 291))	('tumor', 'Phenotype', 'HP:0002664', (459, 464))	('patients', 'Species', '9606', (213, 221))	('obese', 'Disease', (658, 663))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('obesity', 'Disease', (74, 81))	('obese', 'Disease', 'MESH:D009765', (658, 663))	('30 kg/m2 <= BMI < 40 kg/m2', 'Var', (615, 641))	('obesity', 'Disease', 'MESH:D009765', (74, 81))	('tumor', 'Disease', (459, 464))	('obese', 'Disease', (608, 613))	('25 kg/m2 <= BMI < 30 kg/m2', 'Var', (579, 605))	('tumor', 'Disease', 'MESH:D009369', (459, 464))	('3 obesity', 'Phenotype', 'HP:0025501', (72, 81))	('obese', 'Disease', 'MESH:D009765', (608, 613))	('patients', 'Species', '9606', (174, 182))	('cancer', 'Disease', (34, 40))	('obesity', 'Phenotype', 'HP:0001513', (74, 81))
406382	33299884	For the majority of obesity-related genes, cancer patients who were in low/medium-expression level group had a superior prognosis than those in the high-expression level group.	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('patients', 'Species', '9606', (50, 58))	('cancer', 'Disease', (43, 49))	('obesity', 'Phenotype', 'HP:0001513', (20, 27))	('low/medium-expression level', 'Var', (71, 98))	('obesity', 'Disease', 'MESH:D009765', (20, 27))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('obesity', 'Disease', (20, 27))
406385	33299884	However, for three types of cancer (SKCM, ACC, and LUAD), patients in the high-expression group for GPR120 gene could benefit from a greater prognosis as compared to those in the low/medium-expression level group.	('LUAD', 'Phenotype', 'HP:0030078', (51, 55))	('patients', 'Species', '9606', (58, 66))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('high-expression', 'Var', (74, 89))	('benefit', 'PosReg', (118, 125))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('GPR120', 'Gene', '338557', (100, 106))	('GPR120', 'Gene', (100, 106))	('cancer', 'Disease', (28, 34))
406386	33299884	Moreover, for four types of cancer (KIRP, UVM, CESC, and LUSC), patients in the high-expression level group for SH2B1 gene experienced a better prognosis than those in the low/medium-expression level group.	('SH2B1', 'Gene', (112, 117))	('better', 'PosReg', (137, 143))	('high-expression level', 'Var', (80, 101))	('patients', 'Species', '9606', (64, 72))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('UVM', 'Disease', (42, 45))	('CESC', 'Disease', (47, 51))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('cancer', 'Disease', (28, 34))	('SH2B1', 'Gene', '25970', (112, 117))
406391	33299884	According to the Kaplan-Meier survival curves, patients with kidney cancer in the low/medium-expression level group for each of LEPR and NEGR1 genes had a long-time life expectancy in comparison to those in the high-expression level group.	('NEGR1', 'Gene', (137, 142))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('kidney cancer', 'Disease', (61, 74))	('LEPR', 'Gene', '3953', (128, 132))	('patients', 'Species', '9606', (47, 55))	('low/medium-expression level', 'Var', (82, 109))	('kidney cancer', 'Disease', 'MESH:D007680', (61, 74))	('kidney cancer', 'Phenotype', 'HP:0009726', (61, 74))	('LEPR', 'Gene', (128, 132))	('NEGR1', 'Gene', '257194', (137, 142))
406392	33299884	However, patients with kidney cancer in the high-expression level group for each of TMEM18 and SH2B1 genes had a long life expectancy than those who in the low/medium-expression level group.	('kidney cancer', 'Disease', (23, 36))	('SH2B1', 'Gene', '25970', (95, 100))	('patients', 'Species', '9606', (9, 17))	('TMEM18', 'Gene', '129787', (84, 90))	('SH2B1', 'Gene', (95, 100))	('TMEM18', 'Gene', (84, 90))	('high-expression level', 'Var', (44, 65))	('kidney cancer', 'Disease', 'MESH:D007680', (23, 36))	('kidney cancer', 'Phenotype', 'HP:0009726', (23, 36))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
406399	33299884	Once mutations or modify alterations occur for obesity gene, microenvironment probably impacts behavior and adaptive evolution of cancer cells.	('behavior', 'CPA', (95, 103))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('cancer', 'Disease', (130, 136))	('obesity', 'Disease', 'MESH:D009765', (47, 54))	('mutations', 'Var', (5, 14))	('obesity', 'Disease', (47, 54))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('impacts', 'Reg', (87, 94))	('obesity', 'Phenotype', 'HP:0001513', (47, 54))
406489	28852427	Therefore, aberrant methylation CpG sites have been considered potential prognostic factors not only in OSCC but also in other cancers as well.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('cancers', 'Disease', 'MESH:D009369', (127, 134))	('aberrant methylation', 'Var', (11, 31))	('cancers', 'Phenotype', 'HP:0002664', (127, 134))	('cancers', 'Disease', (127, 134))	('OSCC', 'Disease', (104, 108))
406504	28852427	Associations between characteristics and overall survival were evaluated by Cox proportional hazard models, while hazard ratio (HR) and 95% confidence interval (95% CI) were described as per 1% methylation increment.	('Cox', 'Gene', (76, 79))	('methylation increment', 'Var', (194, 215))	('Associations', 'Interaction', (0, 12))	('Cox', 'Gene', '1351', (76, 79))
406537	28852427	Demethylation of hypermethylated AJAP1 reactivates its mRNA expression.	('reactivates', 'NegReg', (39, 50))	('Demethylation', 'Var', (0, 13))	('AJAP1', 'Gene', '55966', (33, 38))	('AJAP1', 'Gene', (33, 38))	('mRNA expression', 'MPA', (55, 70))	('hypermethylated', 'Var', (17, 32))
406541	28852427	Conversely, FOXA2 also is downregulated in lung cancer through epigenetic silencing of hypermethylation.	('downregulated', 'NegReg', (26, 39))	('lung cancer', 'Disease', (43, 54))	('lung cancer', 'Phenotype', 'HP:0100526', (43, 54))	('epigenetic silencing', 'Var', (63, 83))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('hypermethylation', 'Protein', (87, 103))	('FOXA2', 'Gene', '3170', (12, 17))	('FOXA2', 'Gene', (12, 17))	('lung cancer', 'Disease', 'MESH:D008175', (43, 54))
406545	28852427	HOXC4 and HOXB4 are hypermethylated and downregulated in high-risk groups, and hypermethylation of HOXB4 is inversely correlated with decreased expression as an epigenetic biomarker for OSCC.	('decreased', 'NegReg', (134, 143))	('HOXB4', 'Gene', (10, 15))	('OSCC', 'Disease', (186, 190))	('hypermethylation', 'Var', (79, 95))	('HOXB4', 'Gene', '3214', (99, 104))	('downregulated', 'NegReg', (40, 53))	('expression', 'MPA', (144, 154))	('HOXB4', 'Gene', '3214', (10, 15))	('HOXC4', 'Gene', (0, 5))	('HOXB4', 'Gene', (99, 104))	('HOXC4', 'Gene', '3221', (0, 5))
406548	28852427	Although this gene's function is still not known well, we measured a strong negative correlation of ZNF570 methylation and expression, both of which were significant in patient prognosis.	('ZNF570', 'Gene', (100, 106))	('expression', 'MPA', (123, 133))	('significant', 'Reg', (154, 165))	('ZNF570', 'Gene', '148268', (100, 106))	('patient', 'Species', '9606', (169, 176))	('negative', 'NegReg', (76, 84))	('methylation', 'Var', (107, 118))
406554	26667048	Hypomethylation of smoking-related genes is associated with future lung cancer in four prospective cohorts DNA hypomethylation in certain genes is associated with tobacco exposure but it is unknown whether these methylation changes translate into increased lung cancer risk.	('associated', 'Reg', (147, 157))	('lung cancer', 'Disease', 'MESH:D008175', (257, 268))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('lung cancer', 'Disease', 'MESH:D008175', (67, 78))	('cancer', 'Phenotype', 'HP:0002664', (262, 268))	('lung cancer', 'Disease', (257, 268))	('lung cancer', 'Phenotype', 'HP:0100526', (257, 268))	('tobacco', 'Species', '4097', (163, 170))	('hypomethylation', 'Var', (111, 126))	('lung cancer', 'Disease', (67, 78))	('lung cancer', 'Phenotype', 'HP:0100526', (67, 78))
406555	26667048	In an epigenome-wide study of DNA from pre-diagnostic blood samples from 132 case-control pairs in the NOWAC cohort, we observe that the most significant associations with lung cancer risk are for cg05575921 in AHRR (OR for 1 s.d.=0.37, 95% CI: 0.31-0.54, P-value=3.3 x 10-11) and cg03636183 in F2RL3 (OR for 1 s.d.=0.40, 95% CI: 0.31-0.56, P-value=3.9 x 10-10), previously shown to be strongly hypomethylated in smokers.	('associations', 'Interaction', (154, 166))	('AHRR', 'Gene', '57491', (211, 215))	('lung cancer', 'Disease', (172, 183))	('AHRR', 'Gene', (211, 215))	('F2RL3', 'Gene', (295, 300))	('cg05575921', 'Chemical', '-', (197, 207))	('lung cancer', 'Phenotype', 'HP:0100526', (172, 183))	('cg05575921', 'Var', (197, 207))	('cg03636183', 'Chemical', '-', (281, 291))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('cg03636183', 'Var', (281, 291))	('F2RL3', 'Gene', '9002', (295, 300))	('lung cancer', 'Disease', 'MESH:D008175', (172, 183))
406557	26667048	The replication and mediation analyses suggest that residual confounding is unlikely to explain the observed associations and that hypomethylation of these CpG sites may mediate the effect of tobacco on lung cancer risk.	('tobacco', 'Species', '4097', (192, 199))	('lung cancer', 'Phenotype', 'HP:0100526', (203, 214))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('hypomethylation', 'Var', (131, 146))	('lung cancer', 'Disease', (203, 214))	('mediate', 'Reg', (170, 177))	('lung cancer', 'Disease', 'MESH:D008175', (203, 214))
406559	26667048	Here, the authors show that hypomethylation of smoke-related genes is associated with future increase in lung cancer risk.	('lung cancer', 'Phenotype', 'HP:0100526', (105, 116))	('increase', 'PosReg', (93, 101))	('hypomethylation', 'Var', (28, 43))	('associated', 'Reg', (70, 80))	('lung cancer', 'Disease', 'MESH:D008175', (105, 116))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('lung cancer', 'Disease', (105, 116))	('smoke-related genes', 'Gene', (47, 66))
406563	26667048	In particular, our previous study of 1,000 healthy subjects from the EPIC and Norwegian Women and Cancer (NOWAC) cohorts indicated that smokers had 19% lower methylation levels at the AHRR CpG site cg05575921 compared with never-smokers.	('methylation levels', 'MPA', (158, 176))	('Cancer', 'Phenotype', 'HP:0002664', (98, 104))	('AHRR', 'Gene', (184, 188))	('lower', 'NegReg', (152, 157))	('cg05575921', 'Chemical', '-', (198, 208))	('cg05575921', 'Var', (198, 208))	('Women', 'Species', '9606', (88, 93))	('AHRR', 'Gene', '57491', (184, 188))
406572	26667048	Supplementary Table 1 shows the main information about involvement in cancer pathways for the probes listed in Table 1: for all the CpGs except two (cg02451831 and cg03898802) there is evidence of involvement in cancer pathways.	('men', 'Species', '9606', (62, 65))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))	('involvement', 'Reg', (197, 208))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('cg02451831', 'Var', (149, 159))	('cancer', 'Disease', (212, 218))	('cancer', 'Disease', 'MESH:D009369', (212, 218))	('men', 'Species', '9606', (204, 207))	('cg03898802', 'Var', (164, 174))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('men', 'Species', '9606', (6, 9))
406573	26667048	CpGs in the AHRR and F2RL3 genes displayed the most significant associations with risk consistent with previous observations of smoking being associated with reduced methylation in healthy subjects.	('reduced', 'NegReg', (158, 165))	('F2RL3', 'Gene', '9002', (21, 26))	('AHRR', 'Gene', '57491', (12, 16))	('AHRR', 'Gene', (12, 16))	('F2RL3', 'Gene', (21, 26))	('methylation', 'MPA', (166, 177))	('CpGs', 'Var', (0, 4))
406574	26667048	In particular, the cg05575921 probe in the AHRR gene emerged as the CpG site most strongly associated with both tobacco exposure and lung cancer risk (odds ratio (OR) for lung cancer per 1 standard deviation (s.d.)	('lung cancer', 'Disease', 'MESH:D008175', (171, 182))	('lung cancer', 'Disease', (133, 144))	('tobacco', 'Species', '4097', (112, 119))	('lung cancer', 'Phenotype', 'HP:0100526', (133, 144))	('AHRR', 'Gene', '57491', (43, 47))	('lung cancer', 'Disease', (171, 182))	('lung cancer', 'Phenotype', 'HP:0100526', (171, 182))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('lung cancer', 'Disease', 'MESH:D008175', (133, 144))	('AHRR', 'Gene', (43, 47))	('cg05575921', 'Var', (19, 29))	('cg05575921', 'Chemical', '-', (19, 29))	('associated with', 'Reg', (91, 106))
406575	26667048	Sensitivity analyses excluding cases with time from blood collection to diagnosis of <2 years showed no significant differences in effect estimates (OR: 0.36, 95% CI: 0.27-0.52 for cg05575921 and OR: 0.40, 95% CI: 0.29-0.56 for cg03636183).	('cg05575921', 'Chemical', '-', (181, 191))	('cg03636183', 'Var', (228, 238))	('cg05575921', 'Var', (181, 191))	('cg03636183', 'Chemical', '-', (228, 238))
406577	26667048	Table 2 shows the results for the probes associated with cancer risk in the AHRR and F2RL3 genes after adjustment for smoking (for example, smoking status coded as never, former, current): the overall association remained basically unchanged (OR for 1 s.d.=0.39, 95% CI: 0.24-0.61, P-value=2.55 x 10-5 for cg05575921 and OR for 1 s.d.=0.51, 95% CI: 0.35-0.73, P-value=4.19 x 10-4 for cg03636183).	('F2RL3', 'Gene', '9002', (85, 90))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('cg05575921', 'Chemical', '-', (306, 316))	('cg05575921', 'Var', (306, 316))	('cancer', 'Disease', (57, 63))	('AHRR', 'Gene', (76, 80))	('F2RL3', 'Gene', (85, 90))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('men', 'Species', '9606', (109, 112))	('AHRR', 'Gene', '57491', (76, 80))	('cg03636183', 'Chemical', '-', (384, 394))
406578	26667048	To validate our results arising from the NOWAC study, we analysed the cg05575921 and cg03636183 probes in three independent samples: a case-control study nested within MCCS including 367 case-control pairs, a case-control study nested within the NSHDS including 234 case-control pairs and a case-control study nested within the EPIC HD cohort, including 63 case-control pairs, all of which were matched on smoking status (see Methods for details).	('HD', 'Disease', 'MESH:D006816', (248, 250))	('cg05575921', 'Chemical', '-', (70, 80))	('cg05575921', 'Gene', (70, 80))	('HD', 'Disease', 'MESH:D006816', (333, 335))	('cg03636183', 'Chemical', '-', (85, 95))	('cg03636183', 'Var', (85, 95))
406579	26667048	Consistent with the results from the NOWAC study, methylation levels in the MCCS, NSHDS and EPIC HD studies were clearly inversely associated with lung cancer risk for both the cg05575921 and cg03636183 CpG sites.	('methylation levels', 'MPA', (50, 68))	('HD', 'Disease', 'MESH:D006816', (97, 99))	('HD', 'Disease', 'MESH:D006816', (84, 86))	('lung cancer', 'Disease', (147, 158))	('lung cancer', 'Phenotype', 'HP:0100526', (147, 158))	('cg05575921', 'Chemical', '-', (177, 187))	('cg05575921', 'Var', (177, 187))	('associated with', 'Reg', (131, 146))	('lung cancer', 'Disease', 'MESH:D008175', (147, 158))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('inversely', 'NegReg', (121, 130))	('cg03636183', 'Chemical', '-', (192, 202))	('cg03636183', 'Var', (192, 202))
406580	26667048	The overall OR estimates were slightly weaker in MCCS than in NOWAC (OR: 0.62, 95% CI: 0.50-0.78, P=2.91 x 10-5 for cg05575921 and OR: 0.70, 95% CI: 0.58-0.85, P=2.21 x 10-4 for cg03636183), but more comparable in NOWAC to NSHDS and EPIC HD (OR: 0.42, 95% CI: 0.30-0.58, P=2.06 x 10-7 for cg05575921 and OR: 0.61, 95% CI: 0.47-0.79, P=1.56 x 10-4 for cg03636183 in NSHDS; OR: 0.45, 95% CI: 0.22-0.92, P=2.95 x 10-2 for cg05575921 and OR: 0.62, 95% CI: 0.38-1.04, P=7.02 x 10-2 for cg03636183 in EPIC HD; Table 2).	('cg05575921', 'Chemical', '-', (419, 429))	('cg03636183', 'Var', (481, 491))	('HD', 'Disease', 'MESH:D006816', (238, 240))	('cg05575921', 'Var', (419, 429))	('cg03636183', 'Var', (351, 361))	('cg03636183', 'Chemical', '-', (481, 491))	('cg03636183', 'Chemical', '-', (351, 361))	('cg05575921', 'Chemical', '-', (289, 299))	('HD', 'Disease', 'MESH:D006816', (500, 502))	('HD', 'Disease', 'MESH:D006816', (225, 227))	('cg05575921', 'Var', (289, 299))	('HD', 'Disease', 'MESH:D006816', (367, 369))	('cg05575921', 'Chemical', '-', (116, 126))	('cg03636183', 'Chemical', '-', (178, 188))
406583	26667048	To further evaluate the associations of the cg05575921 and cg03636183 CpG sites with lung cancer risk, we conducted stratified risk analysis by categories of smoking status.	('cg03636183', 'Chemical', '-', (59, 69))	('lung cancer', 'Disease', (85, 96))	('cg03636183', 'Var', (59, 69))	('associations', 'Interaction', (24, 36))	('lung cancer', 'Phenotype', 'HP:0100526', (85, 96))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('lung cancer', 'Disease', 'MESH:D008175', (85, 96))	('cg05575921', 'Chemical', '-', (44, 54))	('cg05575921', 'Var', (44, 54))
406585	26667048	This pattern was evident also in MCCS, NSHDS and EPIC HD for both the cg05575921 and cg03636183 CpG sites (Table 2).	('cg05575921', 'Chemical', '-', (70, 80))	('HD', 'Disease', 'MESH:D006816', (54, 56))	('cg05575921', 'Var', (70, 80))	('HD', 'Disease', 'MESH:D006816', (41, 43))	('cg03636183', 'Chemical', '-', (85, 95))	('cg03636183', 'Var', (85, 95))
406586	26667048	The associations between smoking cessation and the mean methylation levels in the cg05575921 probe (AHRR gene) and the cg03636183 probe (F2RL3 gene) in NOWAC are shown in Fig.	('AHRR', 'Gene', (100, 104))	('F2RL3', 'Gene', '9002', (137, 142))	('F2RL3', 'Gene', (137, 142))	('AHRR', 'Gene', '57491', (100, 104))	('methylation levels', 'MPA', (56, 74))	('cg03636183', 'Chemical', '-', (119, 129))	('cg05575921', 'Chemical', '-', (82, 92))	('cg03636183', 'Var', (119, 129))	('cg05575921', 'Var', (82, 92))
406588	26667048	The effect of smoking (never versus former versus current; time since quitting smoking; smoking duration) on methylation beta levels for cg05575921 and cg03636183 in MCCS and in NSHDS are shown in Fig.	('cg05575921', 'Chemical', '-', (137, 147))	('cg05575921', 'Var', (137, 147))	('cg03636183', 'Var', (152, 162))	('methylation beta levels', 'MPA', (109, 132))	('cg03636183', 'Chemical', '-', (152, 162))	('HD', 'Disease', 'MESH:D006816', (180, 182))
406599	26667048	Although the results described above from the analysis of a discovery set and three validation sets seem to provide evidence that hypomethylation of the cg05575921 and cg03636183 probes is associated with both tobacco exposure and lung cancer risk, the key question is whether their hypomethylation is involved in the causal pathway, or whether they are simply epiphenomena of smoking habits (that is, the association of DNA methylation with lung cancer risk is confounded by smoking).	('lung cancer', 'Disease', (231, 242))	('cg03636183', 'Var', (168, 178))	('lung cancer', 'Phenotype', 'HP:0100526', (442, 453))	('cg03636183', 'Chemical', '-', (168, 178))	('lung cancer', 'Phenotype', 'HP:0100526', (231, 242))	('cancer', 'Phenotype', 'HP:0002664', (447, 453))	('tobacco', 'Disease', (210, 217))	('cg05575921', 'Chemical', '-', (153, 163))	('associated', 'Reg', (189, 199))	('lung cancer', 'Disease', 'MESH:D008175', (442, 453))	('lung cancer', 'Disease', 'MESH:D008175', (231, 242))	('tobacco', 'Species', '4097', (210, 217))	('men', 'Species', '9606', (369, 372))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('involved', 'Reg', (302, 310))	('hypomethylation', 'Var', (130, 145))	('cg05575921', 'Gene', (153, 163))	('lung cancer', 'Disease', (442, 453))
406600	26667048	To bring some clarity to this question, we used mediation analysis to quantify the amount by which cg05575921 (AHRR gene) and cg03636183 (F2RL3 gene) methylation might mediate the effect of smoking on lung cancer incidence.	('cg05575921', 'Var', (99, 109))	('methylation', 'Var', (150, 161))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('F2RL3', 'Gene', '9002', (138, 143))	('lung cancer', 'Disease', 'MESH:D008175', (201, 212))	('AHRR', 'Gene', (111, 115))	('mediate', 'Reg', (168, 175))	('F2RL3', 'Gene', (138, 143))	('cg05575921', 'Chemical', '-', (99, 109))	('lung cancer', 'Phenotype', 'HP:0100526', (201, 212))	('cg03636183', 'Chemical', '-', (126, 136))	('cg03636183', 'Var', (126, 136))	('lung cancer', 'Disease', (201, 212))	('AHRR', 'Gene', '57491', (111, 115))
406603	26667048	The proportion of the smoking-induced risk increase explained by cg05575921 AHRR-probe was found to be ~31% (0.31, 95% CI: 0.18-0.46) and 32% (0.32, 95% CI: 0.20-0.53) for the cg03636183 F2RL3-probe.	('F2RL3', 'Gene', (187, 192))	('cg05575921', 'Chemical', '-', (65, 75))	('cg03636183', 'Chemical', '-', (176, 186))	('cg05575921', 'Var', (65, 75))	('AHRR', 'Gene', (76, 80))	('F2RL3', 'Gene', '9002', (187, 192))	('AHRR', 'Gene', '57491', (76, 80))
406604	26667048	Considering the two genes together, their methylation appeared to mediate ~37% (0.37, 95% CI: 0.19-0.66) of the total effect of smoking on lung cancer odds (Fig.	('lung cancer', 'Disease', (139, 150))	('lung cancer', 'Disease', 'MESH:D008175', (139, 150))	('methylation', 'Var', (42, 53))	('lung cancer', 'Phenotype', 'HP:0100526', (139, 150))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
406605	26667048	The results of mediation analysis were similar when we included the mean methylation of a group of ten AHRR (cg05575921, cg03991871, cg12806681, cg23916896, cg01899089, cg26703534, cg14817490, cg25648203, cg21161138 and cg24090911) and two F2RL3 probes (cg03636183 and cg04259305) located in the body of the gene and significantly associated with lung cancer after false discovery rate correction (data not shown).	('cg03636183', 'Var', (254, 264))	('cg23916896', 'Var', (145, 155))	('F2RL3', 'Gene', '9002', (240, 245))	('cg14817490', 'Var', (181, 191))	('cg24090911', 'Var', (220, 230))	('lung cancer', 'Disease', (347, 358))	('cancer', 'Phenotype', 'HP:0002664', (352, 358))	('cg05575921', 'Chemical', '-', (109, 119))	('cg03636183', 'Chemical', '-', (254, 264))	('cg25648203', 'Var', (193, 203))	('AHRR', 'Gene', (103, 107))	('F2RL3', 'Gene', (240, 245))	('lung cancer', 'Disease', 'MESH:D008175', (347, 358))	('cg05575921', 'Var', (109, 119))	('cg03991871', 'Var', (121, 131))	('lung cancer', 'Phenotype', 'HP:0100526', (347, 358))	('cg21161138', 'Var', (205, 215))	('cg26703534', 'Var', (169, 179))	('AHRR', 'Gene', '57491', (103, 107))	('cg01899089', 'Var', (157, 167))	('cg04259305', 'Var', (269, 279))	('methylation', 'Var', (73, 84))	('cg12806681', 'Var', (133, 143))	('associated with', 'Reg', (331, 346))
406606	26667048	In conclusion, this analysis suggests (i) that methylation of the smoking-related AHRR and F2RL3 CpG sites might be relevant to lung cancer aetiology and (ii) would explain approximately one-third of the risk increase induced by tobacco exposure.	('lung cancer', 'Disease', 'MESH:D008175', (128, 139))	('F2RL3', 'Gene', (91, 96))	('AHRR', 'Gene', '57491', (82, 86))	('methylation', 'Var', (47, 58))	('relevant', 'Reg', (116, 124))	('lung cancer', 'Disease', (128, 139))	('lung cancer', 'Phenotype', 'HP:0100526', (128, 139))	('AHRR', 'Gene', (82, 86))	('F2RL3', 'Gene', '9002', (91, 96))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('tobacco', 'Species', '4097', (229, 236))
406609	26667048	Here, we present data from four prospective cohort studies that convincingly demonstrate that hypomethylation in specific CpG sites of the AHRR and F2RL3 genes is associated with increased risk of subsequent lung cancer.	('lung cancer', 'Phenotype', 'HP:0100526', (208, 219))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('F2RL3', 'Gene', '9002', (148, 153))	('hypomethylation', 'Var', (94, 109))	('AHRR', 'Gene', (139, 143))	('associated', 'Reg', (163, 173))	('lung cancer', 'Disease', 'MESH:D008175', (208, 219))	('AHRR', 'Gene', '57491', (139, 143))	('F2RL3', 'Gene', (148, 153))	('lung cancer', 'Disease', (208, 219))
406611	26667048	AHRR is the repressor of the aryl hydrocarbon receptor, a key regulator of the relationships between the cell and the external environment, including the effects of stressors such as dioxins and polycyclic aromatic hydrocarbons (that are contained in tobacco smoke).	('AHRR', 'Gene', (0, 4))	('tobacco', 'Species', '4097', (251, 258))	('dioxins', 'Chemical', 'MESH:D004147', (183, 190))	('polycyclic aromatic hydrocarbons', 'Chemical', 'MESH:D011084', (195, 227))	('AHRR', 'Gene', '57491', (0, 4))	('aryl hydrocarbon receptor', 'Gene', '196', (29, 54))	('aryl hydrocarbon receptor', 'Gene', (29, 54))	('polycyclic', 'Var', (195, 205))	('men', 'Species', '9606', (134, 137))
406612	26667048	AHRR is expressed in all tissues, where it controls cell proliferation and apoptosis; it is upregulated and epigenetically modified in lung alveolar macrophages of smokers.	('epigenetically modified', 'Var', (108, 131))	('upregulated', 'PosReg', (92, 103))	('AHRR', 'Gene', (0, 4))	('lung alveolar', 'Disease', 'MESH:D008171', (135, 148))	('AHRR', 'Gene', '57491', (0, 4))	('lung alveolar', 'Disease', (135, 148))
406617	26667048	A recent study reported that hypomethylation of F2RL3 is predictive of total mortality and the authors suggested that the adverse health effects of smoking might be mediated in part by pathways related to F2RL3 methylation.	('methylation', 'Var', (211, 222))	('F2RL3', 'Gene', '9002', (48, 53))	('F2RL3', 'Gene', (205, 210))	('F2RL3', 'Gene', '9002', (205, 210))	('F2RL3', 'Gene', (48, 53))	('hypomethylation', 'Var', (29, 44))
406618	26667048	The main question arising from our previous studies of healthy subjects was whether methylation changes in the AHRR and F2RL3 genes are causally involved in lung cancer aetiology by mediating the risk induced by tobacco smoking.	('AHRR', 'Gene', (111, 115))	('lung cancer', 'Disease', (157, 168))	('F2RL3', 'Gene', (120, 125))	('tobacco', 'Species', '4097', (212, 219))	('lung cancer', 'Phenotype', 'HP:0100526', (157, 168))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('involved', 'Reg', (145, 153))	('lung cancer', 'Disease', 'MESH:D008175', (157, 168))	('F2RL3', 'Gene', '9002', (120, 125))	('AHRR', 'Gene', '57491', (111, 115))	('methylation changes', 'Var', (84, 103))
406622	26667048	In addition, the observation that smoking-associated hypomethylation in these specific CpG sites is reversible following smoking cessation is compatible with the gradual decrease in lung cancer risk that former smokers experience.	('lung cancer', 'Disease', (182, 193))	('lung cancer', 'Phenotype', 'HP:0100526', (182, 193))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('hypomethylation', 'Var', (53, 68))	('decrease', 'NegReg', (170, 178))	('lung cancer', 'Disease', 'MESH:D008175', (182, 193))
406623	26667048	A full evaluation of the causal relevance of AHRR and F2RL3 methylation in lung cancer aetiology requires additional investigations, such as a Mendelian randomization analysis of a sufficiently powered study.	('lung cancer', 'Disease', (75, 86))	('lung cancer', 'Phenotype', 'HP:0100526', (75, 86))	('methylation', 'Var', (60, 71))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('F2RL3', 'Gene', (54, 59))	('lung cancer', 'Disease', 'MESH:D008175', (75, 86))	('AHRR', 'Gene', '57491', (45, 49))	('F2RL3', 'Gene', '9002', (54, 59))	('AHRR', 'Gene', (45, 49))
406624	26667048	Hypomethylation of certain CpG sites/genes, which extends beyond smoking cessation for several years, as observed for the two probes identified in this study, might be more closely associated with lung cancer risk than transient hypomethylation.	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('lung cancer', 'Disease', 'MESH:D008175', (197, 208))	('Hypomethylation', 'Var', (0, 15))	('associated with', 'Reg', (181, 196))	('lung cancer', 'Disease', (197, 208))	('lung cancer', 'Phenotype', 'HP:0100526', (197, 208))
406625	26667048	In previous analyses of healthy subjects, we generally observed a relatively rapid reversal of smoking-related methylation changes, but for a group of probes including cg05575921 and cg03636183 reversal is slower or not apparent even after decades.	('cg05575921', 'Var', (168, 178))	('cg03636183', 'Chemical', '-', (183, 193))	('methylation', 'MPA', (111, 122))	('cg03636183', 'Var', (183, 193))	('cg05575921', 'Chemical', '-', (168, 178))
406626	26667048	A larger study is required to evaluate whether reversal of methylation alterations in cg05575921 and cg03636183 occurs at the same rate as the decrease in the risk of lung cancer in former smokers.	('cg05575921', 'Chemical', '-', (86, 96))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('lung cancer', 'Disease', (167, 178))	('cg05575921', 'Var', (86, 96))	('decrease', 'NegReg', (143, 151))	('lung cancer', 'Phenotype', 'HP:0100526', (167, 178))	('cg03636183', 'Chemical', '-', (101, 111))	('cg03636183', 'Var', (101, 111))	('lung cancer', 'Disease', 'MESH:D008175', (167, 178))
406627	26667048	We speculate that exposure to toxic agents leads to clonal expansion of cells that are hypomethylated in CpGs of genes involved in activation of a pathway reactive to environmental insults, and this imbalance in the proportion of methylated DNA in stem cells persists, remaining mitotically stable through subsequent cell divisions.	('activation', 'PosReg', (131, 141))	('men', 'Species', '9606', (174, 177))	('hypomethylated', 'Var', (87, 101))	('imbalance', 'Phenotype', 'HP:0002172', (199, 208))
406628	26667048	The association of hypomethylation at the two selected CpG sites with lung cancer was nominally stronger for former than for current smokers in all our studies but this observation could be due to chance or residual confounding by factors related or unrelated to smoking.	('lung cancer', 'Disease', 'MESH:D008175', (70, 81))	('association', 'Interaction', (4, 15))	('lung cancer', 'Disease', (70, 81))	('lung cancer', 'Phenotype', 'HP:0100526', (70, 81))	('stronger', 'PosReg', (96, 104))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('hypomethylation', 'Var', (19, 34))
406629	26667048	In conclusion, our study shows that smoking-induced hypomethylation in the AHRR and F2RL3 genes is associated with important risk increases of subsequent lung cancer, and indicates that these specific methylation alterations may mediate the carcinogenic effect of tobacco exposure in lung cancer aetiology.	('lung cancer', 'Disease', (284, 295))	('lung cancer', 'Disease', (154, 165))	('F2RL3', 'Gene', (84, 89))	('AHRR', 'Gene', (75, 79))	('lung cancer', 'Phenotype', 'HP:0100526', (284, 295))	('lung cancer', 'Phenotype', 'HP:0100526', (154, 165))	('increases', 'PosReg', (130, 139))	('cancer', 'Phenotype', 'HP:0002664', (289, 295))	('AHRR', 'Gene', '57491', (75, 79))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('F2RL3', 'Gene', '9002', (84, 89))	('lung cancer', 'Disease', 'MESH:D008175', (284, 295))	('lung cancer', 'Disease', 'MESH:D008175', (154, 165))	('hypomethylation', 'Var', (52, 67))	('tobacco', 'Species', '4097', (264, 271))	('carcinogenic', 'Disease', 'MESH:D063646', (241, 253))	('carcinogenic', 'Disease', (241, 253))
406688	26667048	We performed mediation analysis to assess whether methylation of cg05575921 (AHRR) and cg03636183 (F2RL3) probes mediated the effect of smoking (ever smoking versus never smoking) on lung cancer risk using parametric G-computation achieved by Monte Carlo simulations and adapted to deal with the case-control design following VanderWeele and Vamsteelandt.	('F2RL3', 'Gene', '9002', (99, 104))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('cg05575921', 'Chemical', '-', (65, 75))	('AHRR', 'Gene', '57491', (77, 81))	('cg03636183', 'Chemical', '-', (87, 97))	('cg05575921', 'Var', (65, 75))	('F2RL3', 'Gene', (99, 104))	('cg03636183', 'Var', (87, 97))	('lung cancer', 'Disease', 'MESH:D008175', (183, 194))	('lung cancer', 'Phenotype', 'HP:0100526', (183, 194))	('lung cancer', 'Disease', (183, 194))	('AHRR', 'Gene', (77, 81))	('methylation', 'Var', (50, 61))
406696	26667048	Hypomethylation of smoking-related genes is associated with future lung cancer in four prospective cohorts.	('Hypomethylation', 'Var', (0, 15))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('lung cancer', 'Disease', 'MESH:D008175', (67, 78))	('lung cancer', 'Disease', (67, 78))	('lung cancer', 'Phenotype', 'HP:0100526', (67, 78))	('associated with', 'Reg', (44, 59))
406700	33858415	ALPL was downregulated in LUAD, and the disease-free survival rate of patients with low ALPL was significantly reduced.	('patients', 'Species', '9606', (70, 78))	('low', 'Var', (84, 87))	('low ALPL', 'Phenotype', 'HP:0003282', (84, 92))	('reduced', 'NegReg', (111, 118))	('ALPL', 'Gene', (88, 92))	('disease-free survival rate', 'CPA', (40, 66))	('LUAD', 'Disease', (26, 30))	('downregulated', 'NegReg', (9, 22))	('LUAD', 'Phenotype', 'HP:0030078', (26, 30))	('ALPL', 'Gene', (0, 4))
406713	33858415	Various mutations in this gene have been shown to affect its activity and cause a decrease in serum ALPL levels, resulting in hypercalcemia and hypokalemia.	('decrease', 'NegReg', (82, 90))	('mutations', 'Var', (8, 17))	('affect', 'Reg', (50, 56))	('hypercalcemia and hypokalemia', 'Disease', 'MESH:D007008', (126, 155))	('decrease in serum ALPL', 'Phenotype', 'HP:0003282', (82, 104))	('activity', 'MPA', (61, 69))	('hypercalcemia', 'Phenotype', 'HP:0003072', (126, 139))	('hypokalemia', 'Phenotype', 'HP:0002900', (144, 155))	('serum ALPL levels', 'MPA', (94, 111))
406714	33858415	Dysfunction of this enzyme is related to the development of multiple diseases, including diabetes mellitus, liver disease, stork and Alzheimer's disease.	("Alzheimer's disease", 'Disease', (133, 152))	('diabetes mellitus', 'Disease', 'MESH:D003920', (89, 106))	('Dysfunction', 'Var', (0, 11))	('multiple diseases', 'Disease', (60, 77))	('stork', 'Disease', (123, 128))	('liver disease', 'Phenotype', 'HP:0001392', (108, 121))	('related', 'Reg', (30, 37))	('liver disease', 'Disease', (108, 121))	("Alzheimer's disease", 'Disease', 'MESH:D000544', (133, 152))	('multiple diseases', 'Disease', 'MESH:D003141', (60, 77))	('diabetes mellitus', 'Phenotype', 'HP:0000819', (89, 106))	('liver disease', 'Disease', 'MESH:D008107', (108, 121))	('diabetes mellitus', 'Disease', (89, 106))	("Alzheimer's disease", 'Phenotype', 'HP:0002511', (133, 152))
406716	33858415	found that knockdown of ALPL can reduce prostate cancer cell migration.	('ALPL', 'Gene', (24, 28))	('prostate cancer', 'Disease', (40, 55))	('reduce prostate', 'Phenotype', 'HP:0008687', (33, 48))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('prostate cancer', 'Disease', 'MESH:D011471', (40, 55))	('knockdown', 'Var', (11, 20))	('prostate cancer', 'Phenotype', 'HP:0012125', (40, 55))	('reduce', 'NegReg', (33, 39))
406721	33858415	Translocations in MYC occur often in hematopoietic cancers, and it was reported to be the third most frequently amplified gene in human cancers in a whole-genome copy number analysis.	('Translocations', 'Var', (0, 14))	('hematopoietic cancers', 'Disease', (37, 58))	('cancers', 'Disease', 'MESH:D009369', (51, 58))	('cancers', 'Phenotype', 'HP:0002664', (136, 143))	('cancers', 'Disease', (136, 143))	('MYC', 'Gene', (18, 21))	('cancers', 'Disease', 'MESH:D009369', (136, 143))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('cancers', 'Phenotype', 'HP:0002664', (51, 58))	('MYC', 'Gene', '4609', (18, 21))	('cancers', 'Disease', (51, 58))	('hematopoietic cancers', 'Disease', 'MESH:D009369', (37, 58))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('human', 'Species', '9606', (130, 135))
406725	33858415	The antibodies against RhoA (2117S), ERK1/2 (4695S), and p-ERK1/2 (4370S) were purchased from Cell Signaling Technology (Beverly, MA, USA).	('ERK1/2', 'Gene', (59, 65))	('ERK1/2', 'Gene', '5595;5594', (59, 65))	('4370S', 'Var', (67, 72))	('ERK1/2', 'Gene', (37, 43))	('ERK1/2', 'Gene', '5595;5594', (37, 43))	('2117S', 'Var', (29, 34))
406743	33858415	At age 4-5 weeks, the mice were randomized and injected with cells [A549 (vector), A549 (ALPL), HCC827 (vector), and HCC827 (ALPL)] via the lateral tail vein (3 x 106 cells in 100 muL PBS/mouse).	('HCC827', 'Var', (96, 102))	('mouse', 'Species', '10090', (188, 193))	('PBS', 'Chemical', 'MESH:D007854', (184, 187))	('lateral tail', 'Phenotype', 'HP:0002825', (140, 152))	('A549', 'CellLine', 'CVCL:0023', (83, 87))	('A549', 'Var', (83, 87))	('A549', 'CellLine', 'CVCL:0023', (68, 72))	('mice', 'Species', '10090', (22, 26))	('HCC827', 'Var', (117, 123))
406779	33858415	These data suggested that ALPL-downregulated c-Myc expression in LUAD resulted in reduced RhoA expression, which in turn resulted in decreased LUAD cell migration and invasion.	('LUAD', 'Phenotype', 'HP:0030078', (65, 69))	('c-Myc', 'Gene', (45, 50))	('invasion', 'CPA', (167, 175))	('ALPL-downregulated', 'Var', (26, 44))	('RhoA expression', 'CPA', (90, 105))	('LUAD cell migration', 'CPA', (143, 162))	('reduced', 'NegReg', (82, 89))	('LUAD', 'Phenotype', 'HP:0030078', (143, 147))	('decreased', 'NegReg', (133, 142))	('c-Myc', 'Gene', '4609', (45, 50))
406790	33858415	It has been reported that degradation of c-Myc usually occurs via classical ubiquitin-dependent degradation pathways, in which ERK- and GSK-3-mediated phosphorylation of c-Myc at Ser62 and Thr58 tags it for degradation.	('c-Myc', 'Gene', '4609', (41, 46))	('c-Myc', 'Gene', '4609', (170, 175))	('c-Myc', 'Gene', (41, 46))	('Thr58', 'Chemical', '-', (189, 194))	('degradation', 'MPA', (26, 37))	('c-Myc', 'Gene', (170, 175))	('Ser62', 'Chemical', '-', (179, 184))	('Ser62', 'Var', (179, 184))
406792	33858415	After treatment with MG132, c-Myc accumulated in both the control A549 and A549 (ALPL) cells, with no significant difference between the two cell lines.	('c-Myc', 'Gene', (28, 33))	('MG132', 'Chemical', 'MESH:C072553', (21, 26))	('A549', 'CellLine', 'CVCL:0023', (66, 70))	('MG132', 'Var', (21, 26))	('c-Myc', 'Gene', '4609', (28, 33))	('accumulated', 'PosReg', (34, 45))	('A549', 'CellLine', 'CVCL:0023', (75, 79))
406793	33858415	However, levels of p-c-Myc (Thr58/Ser62) were much higher in A549 (ALPL) cells than in control cells (Fig.	('c-Myc', 'Gene', '4609', (21, 26))	('A549', 'Var', (61, 65))	('levels', 'MPA', (9, 15))	('Thr58', 'Chemical', '-', (28, 33))	('c-Myc', 'Gene', (21, 26))	('higher', 'PosReg', (51, 57))	('Ser62', 'Chemical', '-', (34, 39))	('A549', 'CellLine', 'CVCL:0023', (61, 65))
406799	33858415	Phosphorylation of ERK was almost completely inhibited in the PD-98059-treated cells, while c-Myc expression increased and the p-c-Myc (Thr58/Ser62) level decreased (Fig.	('inhibited', 'NegReg', (45, 54))	('c-Myc', 'Gene', '4609', (92, 97))	('c-Myc', 'Gene', '4609', (129, 134))	('Phosphorylation', 'MPA', (0, 15))	('decreased', 'NegReg', (155, 164))	('PD-98059-treated', 'Var', (62, 78))	('c-Myc', 'Gene', (129, 134))	('PD-98059', 'Chemical', 'MESH:C093973', (62, 70))	('Thr58', 'Chemical', '-', (136, 141))	('c-Myc', 'Gene', (92, 97))	('increased', 'PosReg', (109, 118))	('ERK', 'Protein', (19, 22))	('Ser62', 'Chemical', '-', (142, 147))	('expression', 'MPA', (98, 108))
406825	33858415	We demonstrate here that ALPL enhances the ubiquitin-dependent degradation of c-Myc by p-ERK.	('ubiquitin-dependent degradation', 'MPA', (43, 74))	('enhances', 'PosReg', (30, 38))	('c-Myc', 'Gene', '4609', (78, 83))	('c-Myc', 'Gene', (78, 83))	('p-ERK', 'Var', (87, 92))
406846	33013829	Their functions in immune regulation include acting against pathogen invasion, removing mutant cells, and triggering inflammation.	('inflammation', 'Disease', 'MESH:D007249', (117, 129))	('mutant', 'Var', (88, 94))	('triggering', 'Reg', (106, 116))	('inflammation', 'Disease', (117, 129))
406851	33013829	Reactive oxygen/nitrogen species (ROS/RNS) produced by immune cells and epithelial cells fight against microbial invasion and eliminate the mutant cell.	('nitrogen', 'Chemical', 'MESH:D009584', (16, 24))	('RNS', 'Chemical', 'MESH:D011886', (38, 41))	('ROS', 'Chemical', '-', (34, 37))	('microbial invasion', 'CPA', (103, 121))	('eliminate', 'NegReg', (126, 135))	('mutant', 'Var', (140, 146))
406917	33013829	The dysfunction of the PI3K/AKT/mTOR pathway interferes with the normal cell-cycle and causes tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('AKT', 'Gene', (28, 31))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('mTOR', 'Gene', '2475', (32, 36))	('interferes', 'NegReg', (45, 55))	('dysfunction', 'Var', (4, 15))	('normal cell-cycle', 'CPA', (65, 82))	('mTOR', 'Gene', (32, 36))	('tumor', 'Disease', (94, 99))	('causes', 'Reg', (87, 93))	('AKT', 'Gene', '207', (28, 31))
406918	33013829	Similarly, NPTX1 and NPTX2 can inhibit cyclin A2 and CDK2 through the Rb/E2F signaling pathway, respectively, thus inducing G0/G1 arrest in pancreatic cancer.	('pancreatic cancer', 'Disease', 'MESH:D010190', (140, 157))	('CDK2', 'Gene', '1017', (53, 57))	('NPTX1', 'Gene', (11, 16))	('NPTX1', 'Gene', '4884', (11, 16))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (140, 157))	('arrest', 'Disease', 'MESH:D006323', (130, 136))	('cyclin A2', 'Gene', (39, 48))	('inducing', 'Reg', (115, 123))	('NPTX2', 'Var', (21, 26))	('Rb/E2F signaling pathway', 'Pathway', (70, 94))	('cyclin A2', 'Gene', '890', (39, 48))	('inhibit', 'NegReg', (31, 38))	('CDK2', 'Gene', (53, 57))	('arrest', 'Disease', (130, 136))	('pancreatic cancer', 'Disease', (140, 157))
406919	33013829	Overexpression of NPTX2 has been identified as a prognosis factor in clear cell renal cell carcinoma, and its interaction with AMPA-selective glutamate receptor-4 affects tumor cell viability and metastasis.	('AMPA-selective glutamate receptor-4', 'Gene', '2893', (127, 162))	('clear cell renal cell carcinoma', 'Disease', (69, 100))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (80, 100))	('AMPA-selective glutamate receptor-4', 'Gene', (127, 162))	('interaction', 'Interaction', (110, 121))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (69, 100))	('Overexpression', 'Var', (0, 14))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', (171, 176))	('affects', 'Reg', (163, 170))	('metastasis', 'CPA', (196, 206))	('NPTX2', 'Gene', (18, 23))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (69, 100))
406922	33013829	On the contrary, a low level of NPTX2 showed better response to neoadjuvant chemoradiation (CRT) treatment in rectal adenocarcinomas.	('adenocarcinomas', 'Disease', 'MESH:D000230', (117, 132))	('NPTX2', 'Gene', (32, 37))	('better', 'PosReg', (45, 51))	('adenocarcinomas', 'Disease', (117, 132))	('low level', 'Var', (19, 28))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('response', 'MPA', (52, 60))
406942	33013829	Furthermore, the N-terminal domain of PTX3 enhances tissue repair and remodeling functions.	('N-terminal domain', 'Var', (17, 34))	('enhances', 'PosReg', (43, 51))	('tissue repair', 'CPA', (52, 65))	('PTX3', 'Gene', (38, 42))	('PTX3', 'Gene', '5806', (38, 42))	('remodeling functions', 'CPA', (70, 90))
406959	33013829	For short pentraxins, low expression of CRP showed better survival outcomes in kidney renal papillary cell carcinoma (KIRP) than high CRP expression (Figure 4A).	('low expression', 'Var', (22, 36))	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('kidney renal papillary cell carcinoma', 'Disease', 'MESH:C538614', (79, 116))	('CRP', 'Gene', '1401', (40, 43))	('CRP', 'Gene', (40, 43))	('CRP', 'Gene', (134, 137))	('renal papillary cell carcinoma', 'Phenotype', 'HP:0006766', (86, 116))	('CRP', 'Gene', '1401', (134, 137))	('kidney renal papillary cell carcinoma', 'Disease', (79, 116))	('pentraxins', 'Chemical', '-', (10, 20))
406962	33013829	We revealed that low NPTX1 expression improved the survival outcomes in patients with adrenocortical carcinoma (ACC), urothelial bladder carcinoma (BCLA), kidney renal papillary cell carcinoma (KIRP), stomach adenocarcinoma (STAD) and uveal melanoma (UVM), (Figures 4D-H).	('melanoma', 'Phenotype', 'HP:0002861', (241, 249))	('NPTX1', 'Gene', '4884', (21, 26))	('expression', 'MPA', (27, 37))	('uveal melanoma', 'Disease', 'MESH:C536494', (235, 249))	('uveal melanoma', 'Disease', (235, 249))	('carcinoma', 'Phenotype', 'HP:0030731', (183, 192))	('carcinoma', 'Phenotype', 'HP:0030731', (214, 223))	('ACC', 'Phenotype', 'HP:0006744', (112, 115))	('uveal melanoma', 'Phenotype', 'HP:0007716', (235, 249))	('low', 'Var', (17, 20))	('AD', 'Disease', (227, 229))	('AD', 'Phenotype', 'HP:0002511', (227, 229))	('survival outcomes', 'CPA', (51, 68))	('improved', 'PosReg', (38, 46))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('kidney renal papillary cell carcinoma', 'Disease', 'MESH:C538614', (155, 192))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (86, 110))	('renal papillary cell carcinoma', 'Phenotype', 'HP:0006766', (162, 192))	('UVM', 'Phenotype', 'HP:0007716', (251, 254))	('stomach adenocarcinoma', 'Disease', 'MESH:D000230', (201, 223))	('urothelial bladder carcinoma', 'Disease', 'MESH:D001749', (118, 146))	('AD', 'Disease', 'MESH:D000544', (227, 229))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (86, 110))	('urothelial bladder carcinoma', 'Disease', (118, 146))	('stomach adenocarcinoma', 'Disease', (201, 223))	('NPTX1', 'Gene', (21, 26))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (129, 146))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('adrenocortical carcinoma', 'Disease', (86, 110))	('kidney renal papillary cell carcinoma', 'Disease', (155, 192))	('patients', 'Species', '9606', (72, 80))
406963	33013829	Patients that showed high expression of NPTX2 frequently exhibited worse survival outcomes for glioblastoma multiforme (GBM), kidney renal papillary cell carcinoma (KIRP), lung squamous cell carcinoma (LUSC) and uveal melanoma (UVM), (Figures 4I-L).	('glioblastoma multiforme', 'Disease', (95, 118))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (95, 118))	('uveal melanoma', 'Phenotype', 'HP:0007716', (212, 226))	('renal papillary cell carcinoma', 'Phenotype', 'HP:0006766', (133, 163))	('uveal melanoma', 'Disease', (212, 226))	('carcinoma', 'Phenotype', 'HP:0030731', (191, 200))	('NPTX2', 'Gene', (40, 45))	('Patients', 'Species', '9606', (0, 8))	('kidney renal papillary cell carcinoma', 'Disease', 'MESH:C538614', (126, 163))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (172, 200))	('UVM', 'Phenotype', 'HP:0007716', (228, 231))	('LUSC', 'Phenotype', 'HP:0030359', (202, 206))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (177, 200))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (172, 200))	('lung squamous cell carcinoma', 'Disease', (172, 200))	('melanoma', 'Phenotype', 'HP:0002861', (218, 226))	('glioblastoma', 'Phenotype', 'HP:0012174', (95, 107))	('high expression', 'Var', (21, 36))	('carcinoma', 'Phenotype', 'HP:0030731', (154, 163))	('kidney renal papillary cell carcinoma', 'Disease', (126, 163))	('uveal melanoma', 'Disease', 'MESH:C536494', (212, 226))
406991	27829391	Analysis of ESCC patient samples indicated that patients with high stromal Activin A expression had low epithelial ACVRIB, the Activin type I receptor.	('Activin A', 'Gene', (75, 84))	('Activin', 'Gene', (127, 134))	('Activin A', 'Gene', '29200', (75, 84))	('Activin', 'Gene', '83729', (75, 82))	('patient', 'Species', '9606', (17, 24))	('ACVRIB', 'Chemical', '-', (115, 121))	('patient', 'Species', '9606', (48, 55))	('Activin', 'Gene', '83729', (127, 134))	('low', 'NegReg', (100, 103))	('Activin', 'Gene', (75, 82))	('high', 'Var', (62, 66))	('patients', 'Species', '9606', (48, 56))	('epithelial ACVRIB', 'MPA', (104, 121))
407003	27829391	In vivo knock-down of inhibin betaA in mice leads to incomplete development and defects in squamous tissue wound healing.	('inhibin', 'Gene', (22, 29))	('defects', 'NegReg', (80, 87))	('incomplete', 'NegReg', (53, 63))	('squamous tissue wound healing', 'CPA', (91, 120))	('knock-down', 'Var', (8, 18))	('mice', 'Species', '10090', (39, 43))
407020	27829391	Primary esophageal keratinocytes expressing dominant-negative mutants of E-cadherin and TbetaRII (ECdnT), established as previously described, were cultured in keratinocyte serum-free media (KSFM) supplemented with 40 mug/mL bovine pituitary extract, 1 ng/mL epidermal growth factor (EGF), and 1 % P/S (Gibco).	('rat', 'Species', '10116', (162, 165))	('EGF', 'Gene', (284, 287))	('mutants', 'Var', (62, 69))	('P', 'Chemical', 'MESH:D010758', (298, 299))	('P', 'Chemical', 'MESH:D010758', (0, 1))	('EGF', 'Gene', '521832', (284, 287))	('epidermal growth factor', 'Gene', (259, 282))	('epidermal growth factor', 'Gene', '521832', (259, 282))	('rat', 'Species', '10116', (21, 24))	('E-cadherin and TbetaRII', 'Gene', '282637', (73, 96))	('bovine', 'Species', '9913', (225, 231))
407073	27829391	Similarly, A83-01 treatment, while increasing cell invasion in the ECdnT cultures with empty vector control, could not restore cell invasion in the Fibro-ActA cultures (Fig.	('cell invasion', 'CPA', (127, 140))	('cell invasion', 'CPA', (46, 59))	('increasing', 'PosReg', (35, 45))	('A83-01', 'Var', (11, 17))	('A83-01', 'Chemical', 'MESH:C507011', (11, 17))
407077	27829391	Laminin 5gamma2 was upregulated in the Fibro-ActA cultures treated with both nAb and A83-01, the only tested marker to do so (Fig.	('Laminin 5gamma2', 'Protein', (0, 15))	('nAb', 'Var', (77, 80))	('upregulated', 'PosReg', (20, 31))	('A83-01', 'Var', (85, 91))	('A83-01', 'Chemical', 'MESH:C507011', (85, 91))
407079	27829391	Epithelial cell proliferation, measured by Ki67, was inhibited with the addition of A83-01 to all cultures, but was unaltered in the presence of nAb (Fig.	('inhibited', 'NegReg', (53, 62))	('A83-01', 'Var', (84, 90))	('rat', 'Species', '10116', (23, 26))	('A83-01', 'Chemical', 'MESH:C507011', (84, 90))	('Epithelial cell proliferation', 'CPA', (0, 29))	('Ki67', 'Chemical', '-', (43, 47))
407101	27829391	Deposition of collagen IV, a common characteristic of cancer cells, was increased overall in TE-11 (Fig.	('TE-11', 'Var', (93, 98))	('increased', 'PosReg', (72, 81))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('cancer', 'Disease', (54, 60))	('Deposition of collagen IV', 'MPA', (0, 25))	('TE', 'Chemical', 'MESH:D013691', (93, 95))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
407123	27829391	ACVR2 mutations have been described to attenuate Activin A signaling in prostate cancer and microsatellite unstable colon cancer.	('microsatellite unstable colon cancer', 'Disease', 'MESH:D015179', (92, 128))	('prostate cancer', 'Disease', 'MESH:D011471', (72, 87))	('colon cancer', 'Phenotype', 'HP:0003003', (116, 128))	('microsatellite unstable colon cancer', 'Disease', (92, 128))	('ACVR2', 'Gene', '92', (0, 5))	('prostate cancer', 'Phenotype', 'HP:0012125', (72, 87))	('Activin A', 'Gene', (49, 58))	('Activin A', 'Gene', '29200', (49, 58))	('prostate cancer', 'Disease', (72, 87))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('ACVR2', 'Gene', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('attenuate', 'NegReg', (39, 48))	('mutations', 'Var', (6, 15))
407124	27829391	The mutations identified are similar to the well-characterized frameshift mutations in TGFBR2.	('TGFBR2', 'Gene', (87, 93))	('frameshift mutations', 'Var', (63, 83))	('TGFBR2', 'Gene', '7048', (87, 93))
407125	27829391	Inactivation of ACVRIB so far has only been identified in pancreatic cancer as a consequence of a somatic mutation, and homologous deletion is associated with an aggressive phenotype in pancreatic cancer.	('pancreatic cancer', 'Disease', (58, 75))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (186, 203))	('pancreatic cancer', 'Disease', 'MESH:D010190', (58, 75))	('associated with', 'Reg', (143, 158))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('ACVRIB', 'Gene', (16, 22))	('pancreatic cancer', 'Disease', (186, 203))	('ACVRIB', 'Chemical', '-', (16, 22))	('pancreatic cancer', 'Disease', 'MESH:D010190', (186, 203))	('homologous deletion', 'Var', (120, 139))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (58, 75))	('Inactivation', 'Var', (0, 12))
407136	27829391	This inhibition is a consequence of intact Activin A signaling; however, loss of ACVRIB allows esophageal cancer cells, such as TE-11 cells, to escape Activin A-dependent regulation.	('Activin A', 'Gene', '29200', (43, 52))	('loss', 'Var', (73, 77))	('esophageal cancer', 'Disease', 'MESH:D004938', (95, 112))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('Activin A', 'Gene', '29200', (151, 160))	('Activin A', 'Gene', (151, 160))	('ACVRIB', 'Gene', (81, 87))	('TE', 'Chemical', 'MESH:D013691', (128, 130))	('ACVRIB', 'Chemical', '-', (81, 87))	('esophageal cancer', 'Disease', (95, 112))	('Activin A', 'Gene', (43, 52))
407165	27829391	Dysregulation of the Activin A pathway may be a way in which cancer cells can adapt to circumvent inhibitory environmental factors.	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('Dysregulation', 'Var', (0, 13))	('Activin A', 'Gene', '29200', (21, 30))	('Activin A', 'Gene', (21, 30))	('cancer', 'Disease', (61, 67))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))
407170	33391449	Besides, LOXL1-AS1 knockdown impaired ESCC cells proliferation, migration and invasion capabilities in vitro.	('LOXL1', 'Gene', (9, 14))	('impaired', 'NegReg', (29, 37))	('invasion capabilities', 'CPA', (78, 99))	('knockdown', 'Var', (19, 28))	('AS1', 'Gene', (15, 18))	('AS1', 'Gene', '5729', (15, 18))	('ESCC', 'Disease', (38, 42))	('migration', 'CPA', (64, 73))	('LOXL1', 'Gene', '4016', (9, 14))
407171	33391449	Furthermore, inhibiting LOXL1-AS1 in ESCC cells increased the percentage of cells at the G1 phase, accompanied by reducing in S phase in contrast to scramble control, and silencing of LOXL1-AS1 evoked ESCC cell apoptosis.	('increased', 'PosReg', (48, 57))	('ESCC cell apoptosis', 'CPA', (201, 220))	('AS1', 'Gene', '5729', (190, 193))	('AS1', 'Gene', (190, 193))	('S phase', 'MPA', (126, 133))	('AS1', 'Gene', (30, 33))	('AS1', 'Gene', '5729', (30, 33))	('reducing', 'NegReg', (114, 122))	('LOXL1', 'Gene', '4016', (24, 29))	('silencing', 'Var', (171, 180))	('LOXL1', 'Gene', (24, 29))	('evoked', 'Reg', (194, 200))	('inhibiting', 'Var', (13, 23))	('LOXL1', 'Gene', '4016', (184, 189))	('LOXL1', 'Gene', (184, 189))
407181	33391449	Furthermore, accumulating evidence indicated that dysregulated lncRNAs could act as tumor suppressors or oncogenes to participate in cancer progression.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('participate', 'Reg', (118, 129))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('cancer', 'Disease', (133, 139))	('dysregulated', 'Var', (50, 62))	('tumor', 'Disease', (84, 89))	('lncRNAs', 'Protein', (63, 70))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
407183	33391449	Additionally, knockdown lncRNA FOXD3-AS1 inhibited cutaneous malignant melanoma cells proliferation, invasion and migration via regulating miR-325/MAP3K2 axis.	('malignant melanoma', 'Disease', (61, 79))	('FOXD3', 'Gene', '27022', (31, 36))	('malignant melanoma', 'Disease', 'MESH:D008545', (61, 79))	('MAP3K2', 'Gene', (147, 153))	('MAP3K2', 'Gene', '10746', (147, 153))	('AS1', 'Gene', '5729', (37, 40))	('AS1', 'Gene', (37, 40))	('FOXD3', 'Gene', (31, 36))	('inhibited', 'NegReg', (41, 50))	('knockdown', 'Var', (14, 23))	('miR-325', 'Gene', (139, 146))	('regulating', 'Reg', (128, 138))	('malignant melanoma', 'Phenotype', 'HP:0002861', (61, 79))	('miR-325', 'Gene', '442899', (139, 146))	('cutaneous malignant melanoma', 'Phenotype', 'HP:0012056', (51, 79))
407187	33391449	For example, knockdown of LOXL1-AS1 dramatically inhibited osteosarcoma cell proliferation, migration and invasion through suppressing PI3K-AKT pathway.	('AKT', 'Gene', (140, 143))	('osteosarcoma', 'Phenotype', 'HP:0002669', (59, 71))	('osteosarcoma', 'Disease', (59, 71))	('suppressing', 'NegReg', (123, 134))	('AS1', 'Gene', (32, 35))	('osteosarcoma', 'Disease', 'MESH:D012516', (59, 71))	('AS1', 'Gene', '5729', (32, 35))	('LOXL1', 'Gene', (26, 31))	('LOXL1', 'Gene', '4016', (26, 31))	('invasion', 'CPA', (106, 114))	('migration', 'CPA', (92, 101))	('AKT', 'Gene', '207', (140, 143))	('knockdown', 'Var', (13, 22))	('inhibited', 'NegReg', (49, 58))
407220	33391449	The results showed that knockdown of LOXL1-AS1 could efficiently inhibit ESCC cell proliferation (Fig.	('LOXL1', 'Gene', '4016', (37, 42))	('LOXL1', 'Gene', (37, 42))	('AS1', 'Gene', '5729', (43, 46))	('AS1', 'Gene', (43, 46))	('inhibit', 'NegReg', (65, 72))	('ESCC', 'Disease', (73, 77))	('knockdown', 'Var', (24, 33))
407223	33391449	To this end, transwell assays were carried out and we found ESCC cell migration and invasion abilities were decreased when knocking down of LOXL1-AS1 in KYSE30 and EC109 cells (Fig.	('AS1', 'Gene', '5729', (146, 149))	('AS1', 'Gene', (146, 149))	('ESCC cell migration', 'CPA', (60, 79))	('LOXL1', 'Gene', '4016', (140, 145))	('LOXL1', 'Gene', (140, 145))	('decreased', 'NegReg', (108, 117))	('invasion abilities', 'CPA', (84, 102))	('EC109', 'CellLine', 'CVCL:6898', (164, 169))	('knocking down', 'Var', (123, 136))
407226	33391449	The results manifested that inhibiting LOXL1-AS1 in KYSE30 cells increased the percentage of cells at the G1 phase, accompanied by reducing in S phase in contrast to scramble control (Fig.	('AS1', 'Gene', '5729', (45, 48))	('increased', 'PosReg', (65, 74))	('LOXL1', 'Gene', '4016', (39, 44))	('S phase', 'MPA', (143, 150))	('LOXL1', 'Gene', (39, 44))	('inhibiting', 'Var', (28, 38))	('reducing', 'NegReg', (131, 139))	('cells at the G1 phase', 'CPA', (93, 114))	('AS1', 'Gene', (45, 48))
407228	33391449	Using the Annexin V/PI double-staining method to measure the apoptotic percentage, flow cytometry assays demonstrated that silencing of LOXL1-AS1 induced ESCC cell apoptosis (Fig.	('AS1', 'Gene', (142, 145))	('Annexin V', 'Gene', '308', (10, 19))	('Annexin V', 'Gene', (10, 19))	('LOXL1', 'Gene', '4016', (136, 141))	('ESCC', 'Disease', (154, 158))	('LOXL1', 'Gene', (136, 141))	('silencing', 'Var', (123, 132))	('AS1', 'Gene', '5729', (142, 145))
407237	33391449	Moreover, we performed qRT-PCR to measure the expression of DESC1 after silencing of LOXL1-AS1 and observed that DESC1 was markedly elevated in ESCC cells (Fig.	('elevated', 'PosReg', (132, 140))	('DESC1', 'Gene', (60, 65))	('silencing', 'Var', (72, 81))	('AS1', 'Gene', '5729', (91, 94))	('AS1', 'Gene', (91, 94))	('LOXL1', 'Gene', '4016', (85, 90))	('LOXL1', 'Gene', (85, 90))	('ESCC', 'Disease', (144, 148))	('DESC1', 'MPA', (113, 118))
407247	33391449	For example, LOXL1-AS1 acted as a ceRNA to upregulate USF1 via sponging miR-708-5p and facilitated the tumorigenesis and stemness of gastric carcinoma.	('miR-708', 'Gene', (72, 79))	('facilitated', 'PosReg', (87, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('sponging', 'Var', (63, 71))	('upregulate', 'PosReg', (43, 53))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor', 'Disease', (103, 108))	('AS1', 'Gene', '5729', (19, 22))	('AS1', 'Gene', (19, 22))	('LOXL1', 'Gene', '4016', (13, 18))	('stemness of gastric carcinoma', 'Disease', 'MESH:D013274', (121, 150))	('LOXL1', 'Gene', (13, 18))	('USF1', 'Gene', (54, 58))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (133, 150))	('USF1', 'Gene', '7391', (54, 58))	('miR-708', 'Gene', '100126333', (72, 79))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('stemness of gastric carcinoma', 'Disease', (121, 150))
407250	33391449	Silencing of LOXL1-AS1 apparently inhibited ESCC cells proliferation, migration and invasion capabilities.	('invasion capabilities', 'CPA', (84, 105))	('ESCC', 'Disease', (44, 48))	('migration', 'CPA', (70, 79))	('AS1', 'Gene', '5729', (19, 22))	('inhibited', 'NegReg', (34, 43))	('AS1', 'Gene', (19, 22))	('LOXL1', 'Gene', '4016', (13, 18))	('LOXL1', 'Gene', (13, 18))	('Silencing', 'Var', (0, 9))
407252	33391449	Meanwhile, silencing of LOXL1-AS1 accelerated ESCC cell apoptosis.	('silencing', 'Var', (11, 20))	('ESCC', 'Disease', (46, 50))	('AS1', 'Gene', '5729', (30, 33))	('accelerated', 'PosReg', (34, 45))	('AS1', 'Gene', (30, 33))	('LOXL1', 'Gene', '4016', (24, 29))	('LOXL1', 'Gene', (24, 29))
407270	31454136	Here, we highlight that targeting valosin-containing protein (VCP) improves radiation sensitivity in esophageal squamous cell carcinoma (ESCC) cell lines and show the potential of using VCP as a prognosis marker in locally advanced ESCC treated with radiation therapy.	('esophageal squamous cell carcinoma', 'Disease', 'MESH:C562729', (101, 135))	('radiation sensitivity', 'MPA', (76, 97))	('valosin-containing protein', 'Gene', (34, 60))	('ESCC', 'Disease', (232, 236))	('improves', 'PosReg', (67, 75))	('ESCC', 'Disease', (137, 141))	('targeting', 'Var', (24, 33))	('VCP', 'Gene', (62, 65))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (112, 135))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('esophageal squamous cell carcinoma', 'Disease', (101, 135))	('ESCC', 'Disease', 'MESH:C562729', (137, 141))	('ESCC', 'Disease', 'MESH:C562729', (232, 236))	('valosin-containing protein', 'Gene', '7415', (34, 60))
407287	31454136	KYSE70, KYSE140, KYSE150, KYSE410, KYSE450, and KYSE510 cells were maintained in RPMI-1640, 10% FBS, and 1% streptomycin/penicillin.	('KYSE510', 'CellLine', 'CVCL:1354', (48, 55))	('KYSE410', 'Var', (26, 33))	('KYSE450', 'Var', (35, 42))	('KYSE510', 'Var', (48, 55))	('KYSE150', 'Var', (17, 24))	('KYSE140', 'Var', (8, 15))	('penicillin', 'Chemical', 'MESH:D010406', (121, 131))
407294	31454136	Cells were seeded (400 cells/well for KYSE140; 200 cells/well for KYSE70) in 6-well plates in 2 mL medium and incubated for 24 hours at 37 C in a 5% CO2 incubator.	('KYSE70', 'Var', (66, 72))	('CO2', 'Chemical', 'MESH:D002245', (149, 152))	('KYSE140', 'Var', (38, 45))
407315	31454136	Among the 7 different ESCC cells, KYSE140 is associated with the highest expression of VCP (Figure 1A,B).	('ESCC', 'Disease', (22, 26))	('KYSE140', 'Var', (34, 41))	('expression', 'MPA', (73, 83))	('ESCC', 'Disease', 'MESH:C562729', (22, 26))	('VCP', 'Gene', (87, 90))
407321	31454136	To evaluate the efficacy of VCP inhibitor in combination with radiation therapy, colony formation assays were undertaken in ESCC cells (KYSE70 and KYSE140).	('KYSE140', 'Var', (147, 154))	('ESCC', 'Disease', (124, 128))	('KYSE70', 'Var', (136, 142))	('ESCC', 'Disease', 'MESH:C562729', (124, 128))
407325	31454136	Together, these data suggested that inhibition of VCP sensitizes ESCC cells to radiation therapy.	('inhibition', 'Var', (36, 46))	('ESCC', 'Disease', 'MESH:C562729', (65, 69))	('sensitizes', 'Reg', (54, 64))	('ESCC', 'Disease', (65, 69))	('VCP', 'Protein', (50, 53))
407331	31454136	Collectively, these data suggested that VCP inhibition enhanced radiation-mediated apoptosis and this enhancement was tumor cell-specific.	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('inhibition', 'Var', (44, 54))	('radiation-mediated apoptosis', 'CPA', (64, 92))	('enhanced', 'PosReg', (55, 63))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumor', 'Disease', (118, 123))	('VCP', 'Protein', (40, 43))
407332	31454136	An accumulation of unfolded proteins and misfolded proteins resulted in ER stress response in tumor cells.25 The ER stress response is an adaptive mechanism that contributes to cell survival; however, increased ER stress is associated with CHOP overexpression, and would predispose the cells to ER stress-mediated apoptosis.26, 27 Previous studies described radiation-induced ER stress in cancer cells.27, 28, 29 Valosin-containing protein inhibitors have been reported to trigger the misfolded protein accumulation and activate the UPR in various cancer cell lines.30 Therefore, we presumed that inhibiting a key component of the ER stress response might result in an elevated level of protein burden in the ER of tumor cells.	('inhibiting', 'Var', (597, 607))	('Valosin-containing protein', 'Gene', '7415', (413, 439))	('tumor', 'Disease', 'MESH:D009369', (715, 720))	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (715, 720))	('cancer', 'Phenotype', 'HP:0002664', (389, 395))	('tumor', 'Disease', (715, 720))	('tumor', 'Disease', (94, 99))	('cancer', 'Disease', (548, 554))	('Valosin-containing protein', 'Gene', (413, 439))	('cancer', 'Disease', 'MESH:D009369', (548, 554))	('cancer', 'Phenotype', 'HP:0002664', (548, 554))	('level of protein burden', 'MPA', (678, 701))	('elevated', 'PosReg', (669, 677))	('cancer', 'Disease', (389, 395))	('cancer', 'Disease', 'MESH:D009369', (389, 395))
407343	31454136	Patients with low VCP expression had better survival than those in the high VCP expression group.	('survival', 'CPA', (44, 52))	('VCP', 'Protein', (18, 21))	('Patients', 'Species', '9606', (0, 8))	('better', 'PosReg', (37, 43))	('low', 'Var', (14, 17))
407344	31454136	Based on univariate analyses, high expression of VCP (P = .005, HR = 0.457 [95% CI, 0.265-0.789]) and lymph node metastases (P = .001, HR = 0.255 [95% CI, 0.123-0.527]) were statistically significant predictors for poor survival.	('poor', 'NegReg', (215, 219))	('high', 'Var', (30, 34))	('VCP', 'Gene', (49, 52))	('metastases', 'Disease', (113, 123))	('metastases', 'Disease', 'MESH:D009362', (113, 123))
407348	31454136	In line with previous reports, our analysis also showed cancer cells with high VCP expression are sensitive to VCP inhibitor.	('high', 'Var', (74, 78))	('sensitive', 'MPA', (98, 107))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('VCP', 'Gene', (79, 82))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))
407367	31454136	Yamamoto et al15, 16 reported that high expression of VCP was associated with increased incidence of cancer progression in gastric carcinoma and esophageal cancer patients who received surgical resection.	('gastric carcinoma and esophageal cancer', 'Disease', 'MESH:D013274', (123, 162))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('VCP', 'Gene', (54, 57))	('patients', 'Species', '9606', (163, 171))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('cancer', 'Disease', (156, 162))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('cancer', 'Disease', (101, 107))	('high expression', 'Var', (35, 50))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (123, 140))
407380	28104840	Among these cancer hallmarks is immune evasion, which is accomplished by neoantigen editing, defects in antigen presentation and inhibition of tumor infiltration, and/or cytotoxic activities of immune cells.	('defects', 'Var', (93, 100))	('neoantigen editing', 'Var', (73, 91))	('tumor', 'Disease', (143, 148))	('antigen presentation', 'MPA', (104, 124))	('cancer hallmarks', 'Disease', (12, 28))	('cancer hallmarks', 'Disease', 'MESH:D009369', (12, 28))	('cytotoxic activities', 'CPA', (170, 190))	('inhibition', 'NegReg', (129, 139))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('immune evasion', 'Disease', (32, 46))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
407382	28104840	Understanding how SCNAs and mutation load affect tumor evolution, and through what mechanisms, is a key objective in cancer research.	('affect', 'Reg', (42, 48))	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('mutation load', 'Var', (28, 41))	('tumor', 'Disease', (49, 54))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('cancer', 'Disease', (117, 123))
407386	28104840	First, we found that, for most tumors, there was a positive correlation between SCNA levels and the total number of mutations.	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumors', 'Disease', (31, 37))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('SCNA levels', 'MPA', (80, 91))	('tumors', 'Disease', 'MESH:D009369', (31, 37))	('mutations', 'Var', (116, 125))
407387	28104840	Second, tumors harboring activating oncogenic mutations in the receptor tyrosine kinase-RAS-phosphatidylinositol 3-kinase pathway showed fewer SCNAs, a finding at odds with the hypothesis of oncogene-driven genomic instability.	('receptor tyrosine kinase', 'Gene', (63, 87))	('mutations', 'Var', (46, 55))	('phosphatidylinositol 3-kinase', 'Gene', '5290', (92, 121))	('receptor tyrosine kinase', 'Gene', '5979', (63, 87))	('activating', 'PosReg', (25, 35))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('phosphatidylinositol 3-kinase', 'Gene', (92, 121))	('tumors', 'Disease', (8, 14))	('tumors', 'Disease', 'MESH:D009369', (8, 14))	('tumors', 'Phenotype', 'HP:0002664', (8, 14))	('fewer', 'NegReg', (137, 142))	('SCNAs', 'Disease', (143, 148))
407391	28104840	The combination of the tumor SCNA score and the tumor mutational load was a better predictor of survival after immunotherapy than either biomarker alone.	('tumor', 'Disease', (48, 53))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('mutational', 'Var', (54, 64))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Disease', (23, 28))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
407396	28104840	A high load of tumor neoantigens (reflecting a high level of point mutations) promotes the detection of tumors by the immune system, limiting immune evasion.	('point mutations', 'Var', (61, 76))	('promotes', 'PosReg', (78, 86))	('detection', 'MPA', (91, 100))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('immune evasion', 'MPA', (142, 156))	('tumor', 'Disease', (104, 109))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumors', 'Disease', (104, 110))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('tumor', 'Disease', (15, 20))	('limiting', 'NegReg', (133, 141))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
407406	28104840	Antibody-mediated inactivation of inhibitory molecules, such as cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and programmed death-ligand 1 (PD-L1), has produced durable responses in a subset (20 to 30%) of patients with advanced tumors.	('cytotoxic T lymphocyte-associated protein 4', 'Gene', (64, 107))	('patients', 'Species', '9606', (214, 222))	('cytotoxic T lymphocyte-associated protein 4', 'Gene', '1493', (64, 107))	('CTLA-4', 'Gene', '1493', (109, 115))	('tumors', 'Disease', (237, 243))	('inactivation', 'Var', (18, 30))	('programmed death-ligand 1', 'Gene', (121, 146))	('programmed death-ligand 1', 'Gene', '29126', (121, 146))	('PD-L1', 'Gene', '29126', (148, 153))	('tumors', 'Disease', 'MESH:D009369', (237, 243))	('tumors', 'Phenotype', 'HP:0002664', (237, 243))	('responses', 'MPA', (177, 186))	('CTLA-4', 'Gene', (109, 115))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))	('PD-L1', 'Gene', (148, 153))
407410	28104840	Cytolytic immune infiltrates have also been shown to correlate with the total number of mutations in certain human tumor types, although the mechanisms controlling immune infiltration are not well understood.	('human', 'Species', '9606', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumor', 'Disease', (115, 120))	('mutations', 'Var', (88, 97))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
407412	28104840	We have uncovered unanticipated relationships of SCNA levels with mutation number, with classes of cancer drivers, and with cell proliferation and immune infiltration signatures.	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('relationships', 'Interaction', (32, 45))	('SCNA levels', 'MPA', (49, 60))	('cancer', 'Disease', (99, 105))	('mutation', 'Var', (66, 74))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
407418	28104840	In contrast with a previous report showing that SCNAs are more abundant in tumors with a low mutation burden, we found a positive correlation between the number (n) of mutations and SCNA level (Fig.	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('SCNA level', 'MPA', (182, 192))	('tumors', 'Disease', (75, 81))	('mutations', 'Var', (168, 177))
407421	28104840	The distribution of the number of mutations in these tumor types is bimodal, with most of the samples bearing ~100 exonic mutations on average and the remaining samples having a ~10-fold higher number of mutations (hypermutated; fig.	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('exonic mutations', 'Var', (115, 131))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Disease', (53, 58))
407422	28104840	The negative correlation between mutations and SCNAs in CRC and UCEC tumors was dependent on the presence of these hypermutated samples (Fig.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('CRC', 'Disease', (56, 59))	('CRC', 'Phenotype', 'HP:0030731', (56, 59))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('mutations', 'Var', (33, 42))	('tumors', 'Disease', 'MESH:D009369', (69, 75))	('tumors', 'Disease', (69, 75))
407423	28104840	Thus, within individual cancer types, the number of mutations tends to positively correlate with the SCNA level.	('mutations', 'Var', (52, 61))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('cancer', 'Disease', (24, 30))	('cancer', 'Disease', 'MESH:D009369', (24, 30))	('SCNA level', 'Disease', (101, 111))
407424	28104840	Next, we separated mutations in driver genes, that is, tumor suppressor genes (TSGs) or oncogenes (OGs), as predicted by TUSON Explorer, and mutations in passenger genes, that is, genes not predicted to be cancer drivers.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('oncogenes', 'Gene', (88, 97))	('mutations', 'Var', (19, 28))	('tumor', 'Disease', (55, 60))	('cancer', 'Disease', (206, 212))	('cancer', 'Disease', 'MESH:D009369', (206, 212))
407427	28104840	To investigate how alterations in different classes of cancer drivers relate to aneuploidy, we analyzed the correlations between SCNA levels and mutations in sets of TSGs and OGs acting in 14 different cancer pathways (table S2B).	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('mutations', 'Var', (145, 154))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('aneuploidy', 'Disease', (80, 90))	('cancer', 'Disease', 'MESH:D009369', (202, 208))	('aneuploidy', 'Disease', 'MESH:D000782', (80, 90))	('TSGs', 'Gene', (166, 170))	('cancer', 'Disease', (202, 208))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('acting', 'Reg', (179, 185))	('SCNA levels', 'MPA', (129, 140))	('cancer', 'Disease', (55, 61))
407428	28104840	Mutations in only one pathway showed a negative correlation with SCNAs: the receptor tyrosine kinase (RTK) pathway, which also includes phosphatidylinositol 3-kinase (PI3K) and RAS pathway genes (Fig.	('RTK', 'Gene', '5979', (102, 105))	('phosphatidylinositol 3-kinase', 'Gene', '5290', (136, 165))	('receptor tyrosine kinase', 'Gene', (76, 100))	('receptor tyrosine kinase', 'Gene', '5979', (76, 100))	('Mutations', 'Var', (0, 9))	('phosphatidylinositol 3-kinase', 'Gene', (136, 165))	('RTK', 'Gene', (102, 105))	('RAS pathway', 'Pathway', (177, 188))
407435	28104840	The level of pS345Chk1, a physical marker of S phase, was also increased in high aneuploidy tumors (fig.	('increased', 'PosReg', (63, 72))	('high aneuploidy tumors', 'Disease', (76, 98))	('pS345Chk1', 'Var', (13, 22))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('high aneuploidy tumors', 'Disease', 'MESH:D000782', (76, 98))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))
407474	28104840	In CRC, lung adenocarcinoma (LUAD), and UCEC, tumors with high mutation burden showed an increased immune signature score, consistent with previous observations (Fig.	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (8, 27))	('carcinoma', 'Phenotype', 'HP:0030731', (18, 27))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('CRC', 'Disease', (3, 6))	('mutation burden', 'Var', (63, 78))	('lung adenocarcinoma', 'Disease', (8, 27))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('immune signature score', 'MPA', (99, 121))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (8, 27))	('LUAD', 'Phenotype', 'HP:0030078', (29, 33))	('tumors', 'Disease', (46, 52))	('increased', 'PosReg', (89, 98))	('CRC', 'Phenotype', 'HP:0030731', (3, 6))	('tumors', 'Disease', 'MESH:D009369', (46, 52))
407475	28104840	In contrast, in all cancer types except gliomas, tumor samples with high arm/chromosome SCNA levels showed a significant decrease in the immune signature score (~50% difference on average) (Fig.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('high', 'Var', (68, 72))	('gliomas', 'Phenotype', 'HP:0009733', (40, 47))	('gliomas', 'Disease', (40, 47))	('tumor', 'Disease', (49, 54))	('cancer', 'Disease', 'MESH:D009369', (20, 26))	('gliomas', 'Disease', 'MESH:D005910', (40, 47))	('immune signature score', 'MPA', (137, 159))	('cancer', 'Disease', (20, 26))	('decrease', 'NegReg', (121, 129))	('glioma', 'Phenotype', 'HP:0009733', (40, 46))
407477	28104840	Compared to mutation number, the level of SCNAs showed a stronger correlation with the cytotoxic immune signature in most of the tumor types examined, even in those where mutation number positively correlated with the SCNA level (Fig.	('cytotoxic immune signature', 'MPA', (87, 113))	('SCNA level', 'MPA', (218, 228))	('correlation', 'Interaction', (66, 77))	('correlated', 'Reg', (198, 208))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('tumor', 'Disease', (129, 134))	('mutation number', 'Var', (171, 186))
407485	28104840	We used least absolute shrinkage and selection operator (lasso) to determine the contribution of SCNA level, the total number of point mutations, TP53 mutations, patient age, patient gender, and tumor stage to both signatures.	('tumor', 'Disease', (195, 200))	('TP53', 'Gene', '7157', (146, 150))	('patient', 'Species', '9606', (175, 182))	('TP53', 'Gene', (146, 150))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('patient', 'Species', '9606', (162, 169))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('mutations', 'Var', (151, 160))
407488	28104840	6A), as were mutations in TP53, a negative regulator of cell cycle entry.	('TP53', 'Gene', (26, 30))	('mutations', 'Var', (13, 22))	('TP53', 'Gene', '7157', (26, 30))
407492	28104840	The total number of mutations was selected by lasso in three tumor types (CRC, LUAD, and UCEC) (Fig.	('tumor', 'Disease', (61, 66))	('LUAD', 'Disease', (79, 83))	('LUAD', 'Phenotype', 'HP:0030078', (79, 83))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('CRC', 'Phenotype', 'HP:0030731', (74, 77))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('mutations', 'Var', (20, 29))
407497	28104840	First, we assessed tumor SCNA levels and mutational load in patients who did or did not achieve long-term survival after treatment.	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('patients', 'Species', '9606', (60, 68))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('tumor', 'Disease', (19, 24))	('mutational', 'Var', (41, 51))
407502	28104840	Next, we examined survival after stratifying the patients into two equal groups (that is, upper and lower 50%) based on either the tumor SCNA level or mutational load.	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('mutational load', 'Var', (151, 166))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumor', 'Disease', (131, 136))	('patients', 'Species', '9606', (49, 57))
407504	28104840	A higher number of tumor mutations correlated with better survival (HR = 0.68, P = 0.079; Fig.	('mutations', 'Var', (25, 34))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('survival', 'CPA', (58, 66))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('better', 'PosReg', (51, 57))	('tumor', 'Disease', (19, 24))
407511	28104840	In this data set, a higher number of tumor mutations predicted better survival (HR = 0.61, P = 0.039; table S6C and fig.	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('mutations', 'Var', (43, 52))	('better', 'PosReg', (63, 69))	('survival', 'CPA', (70, 78))
407512	28104840	The correlation of both high mutation number and low SCNA level with better survival may be due to the role of an antitumor immune response in predicting a better outcome even in the absence of immunotherapy, an observation that has been previously described.	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('SCNA level', 'MPA', (53, 63))	('high mutation number', 'Var', (24, 44))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumor', 'Disease', (118, 123))	('better', 'PosReg', (69, 75))
407515	28104840	Overall, these data indicate that tumor SCNA levels and mutational load can be used together to predict patients' survival after immunotherapy.	('mutational', 'Var', (56, 66))	('tumor', 'Disease', (34, 39))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('patients', 'Species', '9606', (104, 112))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
407519	28104840	We uncovered relationships between the level of SCNAs and mutations in driver genes acting in specific cancer pathways that deepen our understanding of tumor evolution.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('mutations', 'Var', (58, 67))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('tumor', 'Disease', (152, 157))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))
407520	28104840	Unexpectedly, the level of SCNAs negatively correlated with mutations in driver genes involved in the RTK pathway, such as EGFR, PIK3CA, KRAS, and BRAF.	('EGFR', 'Gene', (123, 127))	('PIK3CA', 'Gene', (129, 135))	('RTK', 'Gene', '5979', (102, 105))	('PIK3CA', 'Gene', '5290', (129, 135))	('BRAF', 'Gene', (147, 151))	('negatively', 'NegReg', (33, 43))	('BRAF', 'Gene', '673', (147, 151))	('KRAS', 'Gene', (137, 141))	('RTK', 'Gene', (102, 105))	('mutations', 'Var', (60, 69))	('KRAS', 'Gene', '3845', (137, 141))
407522	28104840	Our analysis suggests that mutated OGs (which may behave differently in vivo than in an experimental overexpression setting) may not represent a significant source of genomic instability and SCNAs in human tumors.	('mutated', 'Var', (27, 34))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('tumors', 'Phenotype', 'HP:0002664', (206, 212))	('tumors', 'Disease', 'MESH:D009369', (206, 212))	('tumors', 'Disease', (206, 212))	('human', 'Species', '9606', (200, 205))	('OGs', 'Protein', (35, 38))
407529	28104840	Because the number of mutations predicts patients' survival independently of the SCNA level, combining the SCNA level with the number of mutations results in a further improvement of survival prediction.	('patients', 'Species', '9606', (41, 49))	('survival', 'MPA', (183, 191))	('mutations', 'Var', (22, 31))	('improvement', 'PosReg', (168, 179))
407531	28104840	Thus, one hypothesis is that protein imbalance may impair a tumor signal needed for cytotoxic immune cell infiltration.	('imbalance', 'Var', (37, 46))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('imbalance', 'Phenotype', 'HP:0002172', (37, 46))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('impair', 'NegReg', (51, 57))	('protein', 'Protein', (29, 36))	('tumor', 'Disease', (60, 65))
407533	28104840	An alternative, speculative hypothesis involves the relative concentration of neoantigen peptides in high versus low aneuploidy tumors.	('aneuploidy tumors', 'Disease', 'MESH:D000782', (117, 134))	('aneuploidy tumors', 'Disease', (117, 134))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('high', 'Var', (101, 105))
407537	28104840	These hypotheses also predict that the role of aneuploidy in promoting cancer immune escape is dependent on the presence of neoantigens, thus mutations.	('mutations', 'Var', (142, 151))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('aneuploidy', 'Disease', 'MESH:D000782', (47, 57))	('cancer', 'Disease', (71, 77))	('aneuploidy', 'Disease', (47, 57))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('promoting', 'PosReg', (61, 70))
407540	28104840	Information on both point mutations and copy number changes can simultaneously be derived from sequencing performed on patient tumors.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('patient', 'Species', '9606', (119, 126))	('tumors', 'Disease', (127, 133))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('tumors', 'Disease', 'MESH:D009369', (127, 133))	('copy number changes', 'Var', (40, 59))	('point mutations', 'Var', (20, 35))
407545	28104840	To determine SCNA calls, i.e., the presence or absence of amplifications or deletions, we considered different noise thresholds in different tumor types based on tumor purity.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumor', 'Disease', (162, 167))	('tumor', 'Disease', (141, 146))	('deletions', 'Var', (76, 85))	('tumor', 'Disease', 'MESH:D009369', (162, 167))
407559	28104840	For the focal SCNAs (deletions or amplifications involving a region smaller than 50% of a chromosome arm), we applied GISTIC2 to the segmentation file (from all tumor samples) of the copy number data, after excluding the arm-level (and chromosome-level) copy number changes.	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('tumor', 'Disease', (161, 166))	('deletions', 'Var', (21, 30))
407560	28104840	The focal SCNA events (amplification and deletion) resulting from GISTIC2 analysis are listed in table S1, B and C. To distinguish between arm and chromosome events, among the arm-level SCNA events, all cases where both arms of a chromosome had the same copy number change (in value and sign) were considered as chromosome SCNA events, while all the others were considered as arm SCNA events (table S1D).	('S1, B and C', 'Gene', '5707', (103, 114))	('copy number', 'Var', (254, 265))	('chromosome SCNA', 'Disease', (312, 327))
407561	28104840	We first determined in each tumor sample whether each arm, chromosome or focal region (focal events listed in table S1, B and C) was amplified, highly amplified, deleted, or highly deleted.	('tumor', 'Disease', (28, 33))	('S1, B and C', 'Gene', '5707', (116, 127))	('deleted', 'Var', (162, 169))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
407567	28104840	For each TSG or OG, we defined a tumor sample as mutated in that predicted driver gene if the tumor contained at least one mutation predicted to be functionally relevant.	('mutated', 'Var', (49, 56))	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumor', 'Disease', (94, 99))	('tumor', 'Disease', (33, 38))
407568	28104840	Specifically, for each OG, recurrent mutations were defined as all the missense mutations recurring in the same position (same amino-acid residue) with a frequency of 20% among all missense mutations (in the OG) or a frequency of 5% and a minimum total absolute number of 10 mutations among all tumor samples.	('missense mutations', 'Var', (71, 89))	('missense mutations', 'Var', (181, 199))	('tumor', 'Disease', 'MESH:D009369', (295, 300))	('mutations', 'Var', (37, 46))	('tumor', 'Phenotype', 'HP:0002664', (295, 300))	('tumor', 'Disease', (295, 300))
407569	28104840	S1A, for CRC, UCEC, STAD, and other tumor types, the distribution of the number of mutations across samples is bimodal, highlighting the presence of a subset of hypermutated tumors.	('tumor', 'Disease', (174, 179))	('mutations', 'Var', (83, 92))	('tumors', 'Disease', (174, 180))	('CRC', 'Disease', (9, 12))	('tumors', 'Disease', 'MESH:D009369', (174, 180))	('CRC', 'Phenotype', 'HP:0030731', (9, 12))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('tumor', 'Disease', (36, 41))	('tumors', 'Phenotype', 'HP:0002664', (174, 180))
407590	28104840	For each of these genomic regions, the frequency of amplification and deletion across samples within each tumor type was determined.	('deletion', 'Var', (70, 78))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Disease', (106, 111))
407592	28104840	Both Pearson and Spearman correlation between the net frequencies of copy number changes at the focal-level versus arm-level across the 807 genomic regions are reported for each tumor type in table S5D.	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('tumor', 'Disease', (178, 183))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('copy number', 'Var', (69, 80))
407629	28104840	Multivariable Cox proportional hazard model was applied considering the combination of low SCNA level (bottom 50%) and immunotherapy treatment and combination of high N of mutations and immunotherapy treatment as predictors, in addition to other covariates to control for differences between the three data sets (table S6D).	('Cox', 'Gene', (14, 17))	('mutations', 'Var', (172, 181))	('SCNA level', 'MPA', (91, 101))	('Cox', 'Gene', '1351', (14, 17))
407636	28659182	The selective MCL-1 inhibitor UMI-77 caused dissociation of MCL-1 from the proapoptotic protein BAX and BAK, and enhanced KYSE150 and KYSE510 cells to cisplatin-induced apoptosis accompanied by caspase-3 activation and PARP cleavage.	('caspase-3', 'Gene', '836', (194, 203))	('cisplatin', 'Chemical', 'MESH:D002945', (151, 160))	('activation', 'PosReg', (204, 214))	('BAK', 'Gene', (104, 107))	('caspase-3', 'Gene', (194, 203))	('PARP', 'Gene', '1302', (219, 223))	('UMI-77', 'Chemical', 'MESH:C000592878', (30, 36))	('BAX', 'Gene', (96, 99))	('PARP', 'Gene', (219, 223))	('dissociation', 'MPA', (44, 56))	('KYSE510', 'CellLine', 'CVCL:1354', (134, 141))	('BAX', 'Gene', '581', (96, 99))	('BAK', 'Gene', '578', (104, 107))	('MCL-1', 'Gene', (60, 65))	('enhanced', 'PosReg', (113, 121))	('UMI-77', 'Var', (30, 36))
407654	28659182	Genetic silencing of Mcl-1 sensitizes a spectrum of cancers, such as melanoma, non-small cell lung and hepatocellular cancers to chemotherapy.	('cancers', 'Disease', (118, 125))	('melanoma', 'Disease', 'MESH:D008545', (69, 77))	('cancers', 'Disease', (52, 59))	('cancers', 'Disease', 'MESH:D009369', (118, 125))	('Mcl-1', 'Gene', '4170', (21, 26))	('cancers', 'Phenotype', 'HP:0002664', (52, 59))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('Genetic silencing', 'Var', (0, 17))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('Mcl-1', 'Gene', (21, 26))	('hepatocellular cancers', 'Disease', (103, 125))	('melanoma', 'Disease', (69, 77))	('hepatocellular cancers', 'Disease', 'MESH:D006528', (103, 125))	('non-small cell lung', 'Disease', (79, 98))	('melanoma', 'Phenotype', 'HP:0002861', (69, 77))	('cancers', 'Phenotype', 'HP:0002664', (118, 125))	('sensitizes', 'Reg', (27, 37))	('cancers', 'Disease', 'MESH:D009369', (52, 59))
407656	28659182	For instance, microRNA-193b enhances the cytotoxicity of cisplatin to hepatocellular carcinoma cells by targeting Mcl-1.	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (70, 94))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (70, 94))	('Mcl-1', 'Gene', '4170', (114, 119))	('hepatocellular carcinoma', 'Disease', (70, 94))	('cytotoxicity', 'Disease', (41, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('cisplatin', 'Chemical', 'MESH:D002945', (57, 66))	('enhances', 'PosReg', (28, 36))	('Mcl-1', 'Gene', (114, 119))	('microRNA-193b', 'Var', (14, 27))	('cytotoxicity', 'Disease', 'MESH:D064420', (41, 53))
407660	28659182	Knockdown of MCL-1 also enhances sensitivity to cisplatin in gastric cancer cells expressing high levels of MCL-1.	('MCL-1', 'Gene', (13, 18))	('cisplatin', 'Chemical', 'MESH:D002945', (48, 57))	('Knockdown', 'Var', (0, 9))	('gastric cancer', 'Disease', (61, 75))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('gastric cancer', 'Disease', 'MESH:D013274', (61, 75))	('gastric cancer', 'Phenotype', 'HP:0012126', (61, 75))	('sensitivity to cisplatin', 'MPA', (33, 57))	('enhances', 'PosReg', (24, 32))
407664	28659182	The combination of UMI-77 and cisplatin induced apoptosis more significantly compared with treatment of UMI-77 or cisplatin alone by causing caspase-3 activation and PARP cleavage.	('apoptosis', 'CPA', (48, 57))	('caspase-3', 'Gene', (141, 150))	('UMI-77', 'Chemical', 'MESH:C000592878', (19, 25))	('caspase-3', 'Gene', '836', (141, 150))	('cisplatin', 'Chemical', 'MESH:D002945', (114, 123))	('PARP', 'Gene', '1302', (166, 170))	('UMI-77', 'Chemical', 'MESH:C000592878', (104, 110))	('cisplatin', 'Chemical', 'MESH:D002945', (30, 39))	('PARP', 'Gene', (166, 170))	('activation', 'PosReg', (151, 161))	('UMI-77', 'Var', (19, 25))
407665	28659182	In addition, the results demonstrated that UMI-77 prevented MCL-1/BAX and MCL-1/BAK complexes formation.	('UMI-77', 'Chemical', 'MESH:C000592878', (43, 49))	('BAX', 'Gene', (66, 69))	('BAK', 'Gene', (80, 83))	('BAX', 'Gene', '581', (66, 69))	('prevented', 'NegReg', (50, 59))	('BAK', 'Gene', '578', (80, 83))	('UMI-77', 'Var', (43, 49))
407676	28659182	The KYSE150, KYSE510, Eca109, and TE-1 ESCC cell lines were obtained and grown in RPMI-1640 medium supplemented with 10% FBS and 1% antibiotics as previously reported.	('KYSE510', 'Var', (13, 20))	('FBS', 'Disease', (121, 124))	('RPMI-1640 medium', 'Chemical', '-', (82, 98))	('KYSE510', 'CellLine', 'CVCL:1354', (13, 20))	('FBS', 'Disease', 'MESH:D005198', (121, 124))
407690	28659182	Primary antibodies were used for immunoblotting: MCL-1 (#5453), cleaved caspase-3 (#9664), cleaved PARP (#5625), BCL-2 (#2870), BCL-xL (#2764), BAX (#5023) and BAK (#6947) from Cell Signaling Technology; beta-actin (A5316) from Sigma-Aldrich; GAPDH (sc-47,724) from Santa Cruz Biotechnology.	('caspase-3', 'Gene', '836', (72, 81))	('BAK', 'Gene', (160, 163))	('#2870', 'Var', (120, 125))	('BCL-xL', 'Gene', '598', (128, 134))	('caspase-3', 'Gene', (72, 81))	('BAK', 'Gene', '578', (160, 163))	('GAPDH', 'Gene', (243, 248))	('PARP', 'Gene', '1302', (99, 103))	('BCL-2', 'Gene', '596', (113, 118))	('BCL-2', 'Gene', (113, 118))	('BAX', 'Gene', (144, 147))	('#9664', 'Var', (83, 88))	('BCL-xL', 'Gene', (128, 134))	('BAX', 'Gene', '581', (144, 147))	('beta-actin', 'Gene', '728378', (204, 214))	('PARP', 'Gene', (99, 103))	('#5625', 'Var', (105, 110))	('#5023', 'Var', (149, 154))	('GAPDH', 'Gene', '2597', (243, 248))	('beta-actin', 'Gene', (204, 214))
407691	28659182	Secondary antibodies were anti-rabbit IgG HRP (#7074) and anti-mouse IgG HRP (#7076) and purchased from Cell Signaling Technology.	('rabbit', 'Species', '9986', (31, 37))	('mouse', 'Species', '10090', (63, 68))	('#7076', 'Var', (78, 83))	('#7074', 'Var', (47, 52))
407702	28659182	Immunocomplexes were resolved by SDS-PAGE and co-immunoprecipitated proteins were detected using anti-BAX (#5023, Cell Signaling Technology) and anti-BAK (#6947, Cell Signaling Technology) antibodies, respectively.	('#5023', 'Var', (107, 112))	('BAK', 'Gene', '578', (150, 153))	('BAX', 'Gene', (102, 105))	('SDS', 'Chemical', 'MESH:D012967', (33, 36))	('BAX', 'Gene', '581', (102, 105))	('BAK', 'Gene', (150, 153))	('#6947', 'Var', (155, 160))
407705	28659182	old) were randomly divided into two groups (n = 10) and subcutaneously injected in the flank with KYSE150-shGFP or KYSE150-shMCL-1#2 esophageal carcinoma cells (2 x 106).	('esophageal carcinoma', 'Disease', 'MESH:D004938', (133, 153))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (133, 153))	('KYSE150-shGFP', 'Var', (98, 111))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('KYSE150-shMCL-1', 'Var', (115, 130))	('esophageal carcinoma', 'Disease', (133, 153))
407732	28659182	The results demonstrate that diminishment of MCL-1 expression significantly reduces the tumorigenic properties of esophageal squamous cancer cells in vitro.	('esophageal squamous cancer', 'Disease', 'MESH:D004938', (114, 140))	('esophageal squamous cancer', 'Disease', (114, 140))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('MCL-1', 'Gene', (45, 50))	('diminishment', 'Var', (29, 41))	('reduces', 'NegReg', (76, 83))	('expression', 'MPA', (51, 61))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('squamous cancer', 'Phenotype', 'HP:0002860', (125, 140))	('tumor', 'Disease', (88, 93))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
407733	28659182	We next determined whether knockdown of MCL-1 could suppress tumor growth in vivo.	('knockdown', 'Var', (27, 36))	('suppress', 'NegReg', (52, 60))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('MCL-1', 'Gene', (40, 45))	('tumor', 'Disease', (61, 66))
407734	28659182	The results showed that the tumor in the KYSE150-shGFP group grew faster than that in the KYSE150-shMCL-1 group (Fig.	('tumor', 'Disease', (28, 33))	('grew', 'CPA', (61, 65))	('faster', 'PosReg', (66, 72))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('KYSE150-shGFP', 'Var', (41, 54))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
407735	28659182	The tumor volumes were decreased in the KYSE150-shMCL-1 group (Fig.	('tumor', 'Disease', (4, 9))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('decreased', 'NegReg', (23, 32))	('KYSE150-shMCL-1', 'Var', (40, 55))
407736	28659182	The tumor weights were decreased in the KYSE150-shMCL-1 group (Fig.	('tumor', 'Disease', (4, 9))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('decreased', 'NegReg', (23, 32))	('KYSE150-shMCL-1', 'Var', (40, 55))
407737	28659182	The IHC results showed that knockdown of MCL-1 dramatically decreased Ki67 staining in tumor tissue, which indicated that down-regulation of MCL-1 inhibited tumor cell proliferation in vivo (Fig.	('Ki67', 'Gene', (70, 74))	('tumor', 'Disease', (157, 162))	('decreased', 'NegReg', (60, 69))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('MCL-1', 'Gene', (141, 146))	('inhibited', 'NegReg', (147, 156))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('tumor', 'Disease', (87, 92))	('Ki67', 'Gene', '17345', (70, 74))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('knockdown', 'Var', (28, 37))	('down-regulation', 'NegReg', (122, 137))
407738	28659182	These results suggest that blocking MCL-1 expression significantly reduces the tumorigenic properties of esophageal squamous cancer cells in vivo.	('tumor', 'Disease', (79, 84))	('blocking', 'Var', (27, 35))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('esophageal squamous cancer', 'Disease', 'MESH:D004938', (105, 131))	('esophageal squamous cancer', 'Disease', (105, 131))	('squamous cancer', 'Phenotype', 'HP:0002860', (116, 131))	('MCL-1', 'Gene', (36, 41))	('reduces', 'NegReg', (67, 74))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
407744	28659182	The results demonstrated that knockdown of MCL-1 combined treatment with cisplatin enhanced cleavage of caspase-3 and PARP in both KYSE150 (Fig.	('cleavage', 'MPA', (92, 100))	('cisplatin', 'Chemical', 'MESH:D002945', (73, 82))	('enhanced', 'PosReg', (83, 91))	('caspase-3', 'Gene', '836', (104, 113))	('PARP', 'Gene', '1302', (118, 122))	('knockdown', 'Var', (30, 39))	('MCL-1', 'Gene', (43, 48))	('PARP', 'Gene', (118, 122))	('caspase-3', 'Gene', (104, 113))
407749	28659182	The results indicate that suppression of MCL-1 effectively enhances the sensitivity of ESCC cells to cisplatin and suggest that manipulating antiapoptotic proteins such as MCL-1 can potentiate the anticancer effect of common chemotherapeutic drug cisplatin.	('MCL-1', 'Gene', (172, 177))	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('cisplatin', 'Chemical', 'MESH:D002945', (247, 256))	('potentiate', 'PosReg', (182, 192))	('MCL-1', 'Gene', (41, 46))	('cancer', 'Disease', (201, 207))	('cisplatin', 'Chemical', 'MESH:D002945', (101, 110))	('sensitivity', 'MPA', (72, 83))	('suppression', 'NegReg', (26, 37))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('enhances', 'PosReg', (59, 67))	('manipulating', 'Var', (128, 140))
407750	28659182	Since attenuation of MCL-1 by RNA interference lowered the threshold at which KYSE150 and KYSE510 cells undergo apoptosis and led to sensitization of these cells to undergo apoptosis triggered by cisplatin (Figs.	('cisplatin', 'Chemical', 'MESH:D002945', (196, 205))	('apoptosis', 'CPA', (112, 121))	('apoptosis', 'CPA', (173, 182))	('lowered', 'NegReg', (47, 54))	('KYSE510', 'Var', (90, 97))	('attenuation', 'NegReg', (6, 17))	('RNA interference', 'MPA', (30, 46))	('threshold', 'MPA', (59, 68))	('KYSE510', 'CellLine', 'CVCL:1354', (90, 97))	('sensitization', 'Reg', (133, 146))
407764	28659182	For instance, various CDK inhibitors, such as flavopiridol, roscovitine , and SNS-032, diminish MCL-1 levels and induce apoptosis in a variety of cell types.	('CDK', 'Protein', (22, 25))	('diminish', 'NegReg', (87, 95))	('SNS-032', 'Var', (78, 85))	('diminish MCL', 'Phenotype', 'HP:0025066', (87, 99))	('induce', 'PosReg', (113, 119))	('SNS-032', 'Chemical', 'MESH:C484864', (78, 85))	('apoptosis', 'CPA', (120, 129))	('flavopiridol', 'Chemical', 'MESH:C077990', (46, 58))	('MCL-1 levels', 'MPA', (96, 108))	('roscovitine', 'Chemical', 'MESH:D000077546', (60, 71))
407765	28659182	AZD8055, an mTORC1/2 inhibitor, reduces MCL-1 expression in KRAS- and BRAF-mutant colorectal cancer cells.	('colorectal cancer', 'Disease', (82, 99))	('AZD8055', 'Var', (0, 7))	('mTORC1/2', 'Gene', '74343;382056', (12, 20))	('AZD8055', 'Chemical', 'MESH:C546624', (0, 7))	('colorectal cancer', 'Phenotype', 'HP:0003003', (82, 99))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('colorectal cancer', 'Disease', 'MESH:D015179', (82, 99))	('MCL-1 expression', 'MPA', (40, 56))	('KRAS', 'Gene', (60, 64))	('reduces', 'NegReg', (32, 39))	('KRAS', 'Gene', '3845', (60, 64))	('BRAF', 'Gene', '673', (70, 74))	('mTORC1/2', 'Gene', (12, 20))	('BRAF', 'Gene', (70, 74))
407766	28659182	The USP9X inhibitor WP1130 lowers MCL-1 levels in chronic myelogenous leukemia and enhances sensitivity to apoptosis by facilitating MCL-1 degradation.	('WP1130', 'Var', (20, 26))	('lowers', 'NegReg', (27, 33))	('myelogenous leukemia', 'Phenotype', 'HP:0012324', (58, 78))	('USP9X', 'Gene', (4, 9))	('sensitivity to apoptosis', 'MPA', (92, 116))	('USP9X', 'Gene', '8239', (4, 9))	('chronic myelogenous leukemia', 'Phenotype', 'HP:0005506', (50, 78))	('WP1130', 'Chemical', 'MESH:C519751', (20, 26))	('MCL-1 levels', 'MPA', (34, 46))	('leukemia', 'Phenotype', 'HP:0001909', (70, 78))	('chronic myelogenous leukemia', 'Disease', (50, 78))	('MCL-1 degradation', 'MPA', (133, 150))	('enhances', 'PosReg', (83, 91))	('chronic myelogenous leukemia', 'Disease', 'MESH:D015464', (50, 78))
407772	28659182	Our results indicated that UMI-77 also induced apoptosis in ESCC cells when administrated as single agent (Figs.	('apoptosis', 'CPA', (47, 56))	('UMI-77', 'Var', (27, 33))	('UMI-77', 'Chemical', 'MESH:C000592878', (27, 33))
407781	28659182	reported that (-)-Gossypol enhances the antitumor efficacy of cisplatin through inhibition of APE1 repair and redox activity in non-small cell lung cancer.	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (128, 154))	('cisplatin', 'Chemical', 'MESH:D002945', (62, 71))	('APE1', 'Gene', (94, 98))	('inhibition', 'NegReg', (80, 90))	('non-small cell lung cancer', 'Disease', (128, 154))	('APE1', 'Gene', '328', (94, 98))	('lung cancer', 'Phenotype', 'HP:0100526', (143, 154))	('-)-Gossypol', 'Var', (15, 26))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (132, 154))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (128, 154))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('enhances', 'PosReg', (27, 35))	('(-)-Gossypol', 'Chemical', 'MESH:D006072', (14, 26))	('redox activity', 'MPA', (110, 124))	('tumor', 'Disease', (44, 49))
407782	28659182	Furthermore, synergistic antitumor effects have been observed when MCL-1 inhibitors combined not only with cytoxic drugs but also with other chemotherapeutic agents.	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumor', 'Disease', (29, 34))	('combined', 'Interaction', (84, 92))	('MCL-1', 'Gene', (67, 72))	('inhibitors', 'Var', (73, 83))
407787	28659182	The enhanced apoptosis when cisplatin in combination with MCL-1 knockdown (Figs.	('cisplatin', 'Chemical', 'MESH:D002945', (28, 37))	('MCL-1', 'Gene', (58, 63))	('enhanced', 'PosReg', (4, 12))	('apoptosis', 'CPA', (13, 22))	('knockdown', 'Var', (64, 73))
407795	28659182	reported that the combination of ABT-263 and AZD8055, an mTORC1/2 inhibitor that reduced MCL-1 protein levels, potently suppresses tumor progression across a variety of preclinical small cell lung cancer experimental models.	('mTORC1/2', 'Gene', (57, 65))	('small cell lung cancer', 'Disease', (181, 203))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('mTORC1/2', 'Gene', '74343;382056', (57, 65))	('ABT-263', 'Chemical', 'MESH:C528561', (33, 40))	('AZD8055', 'Var', (45, 52))	('suppresses', 'NegReg', (120, 130))	('MCL-1 protein levels', 'MPA', (89, 109))	('AZD8055', 'Chemical', 'MESH:C546624', (45, 52))	('lung cancer', 'Phenotype', 'HP:0100526', (192, 203))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumor', 'Disease', (131, 136))	('small cell lung cancer', 'Disease', 'MESH:D055752', (181, 203))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (181, 203))	('reduced', 'NegReg', (81, 88))	('reduced MCL', 'Phenotype', 'HP:0025066', (81, 92))
407796	28659182	Potent and selective small-molecule MCL-1 inhibitors A-1210477 synergizes with the BCL-2 and BCL-xL inhibitor ABT-263 to kill a variety of cancer cell lines.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('ABT-263', 'Chemical', 'MESH:C528561', (110, 117))	('BCL-2', 'Gene', '596', (83, 88))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('inhibitors A-1210477', 'Var', (42, 62))	('BCL-xL', 'Gene', '598', (93, 99))	('BCL-2', 'Gene', (83, 88))	('BCL-xL', 'Gene', (93, 99))	('MCL-1', 'Gene', (36, 41))	('A-1210477', 'Var', (53, 62))	('cancer', 'Disease', (139, 145))
407815	28659182	Our results suggests that MCL-1 contributes to the development of ESCC and provide insights into the potential role of MCL-1 as a therapeutic target in ESCC chemotherapy and show that antagonizing MCL-1 function with RNAi-mediated knockdown or small molecule MCL-1 inhibitor UMI-77 sensitizes ESCC cells to cisplatin-induced apoptosis.	('cisplatin-induced apoptosis', 'CPA', (307, 334))	('antagonizing', 'Var', (184, 196))	('cisplatin', 'Chemical', 'MESH:D002945', (307, 316))	('ESCC', 'Disease', (66, 70))	('ESCC', 'Disease', (293, 297))	('sensitizes', 'Reg', (282, 292))	('UMI-77', 'Chemical', 'MESH:C000592878', (275, 281))
407825	26788120	P. gingivalis was detected immunohistochemically in 61 % of cancerous tissues, 12 % of adjacent tissues and was undetected in normal esophageal mucosa.	('P. gingivalis', 'Species', '837', (0, 13))	('P. gingivalis', 'Var', (0, 13))	('cancerous', 'Disease', (60, 69))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('cancerous', 'Disease', 'MESH:D009369', (60, 69))
407828	26788120	These findings demonstrate for the first time that P. gingivalis infects the epithelium of the esophagus of ESCC patients, establish an association between infection with P. gingivalis and the progression of ESCC, and suggest P. gingivalis infection could be a biomarker for this disease.	('P. gingivalis', 'Species', '837', (226, 239))	('ESCC', 'Disease', (208, 212))	('P. gingivalis infection', 'Disease', 'MESH:C000656865', (226, 249))	('P. gingivalis', 'Species', '837', (171, 184))	('patients', 'Species', '9606', (113, 121))	('P. gingivalis', 'Var', (51, 64))	('P. gingivalis', 'Species', '837', (51, 64))	('P. gingivalis infection', 'Disease', (226, 249))	('association', 'Interaction', (136, 147))
407843	26788120	Since esophageal squamous cells are histologically similar to oral squamous cells and esophageal infection arising from the oral niche is highly plausible, we hypothesized that P. gingivalis may be associated with ESCC.	('ESCC', 'Disease', (214, 218))	('esophageal infection', 'Disease', (86, 106))	('esophageal infection', 'Disease', 'MESH:D004941', (86, 106))	('associated', 'Reg', (198, 208))	('P. gingivalis', 'Var', (177, 190))	('P. gingivalis', 'Species', '837', (177, 190))
407844	26788120	1, P. gingivalis was detected in cancerous and adjacent esophageal mucosa, but not healthy mucosa.	('P. gingivalis', 'Species', '837', (3, 16))	('P. gingivalis', 'Var', (3, 16))	('cancerous', 'Disease', (33, 42))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('cancerous', 'Disease', 'MESH:D009369', (33, 42))
407858	26788120	Since an association between P. gingivalis infection and ESCC had been demonstrated, we next sought to determine if the presence of P. gingivalis antigens is associated with the progression of esophageal cancer.	('associated with', 'Reg', (158, 173))	('P. gingivalis infection', 'Disease', (29, 52))	('ESCC', 'Disease', (57, 61))	('P. gingivalis infection', 'Disease', 'MESH:C000656865', (29, 52))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('esophageal cancer', 'Disease', (193, 210))	('presence', 'Var', (120, 128))	('P. gingivalis', 'Species', '837', (29, 42))	('P. gingivalis', 'Species', '837', (132, 145))	('association', 'Interaction', (9, 20))	('esophageal cancer', 'Disease', 'MESH:D004938', (193, 210))
407860	26788120	While the presence of P. gingivalis was not significantly associated with age, gender, or smoking history of the patients, the presence of P. gingivalis was positively related to differentiation, lymph node metastasis and the TNM stage of ESCC (p < 0.05).	('P. gingivalis', 'Species', '837', (22, 35))	('differentiation', 'CPA', (179, 194))	('patients', 'Species', '9606', (113, 121))	('ESCC', 'Disease', (239, 243))	('related', 'Reg', (168, 175))	('P. gingivalis', 'Var', (139, 152))	('TNM stage', 'CPA', (226, 235))	('lymph node metastasis', 'CPA', (196, 217))	('P. gingivalis', 'Species', '837', (139, 152))	('presence', 'Var', (127, 135))
407861	26788120	A positive immunohistochemical signal for P. gingivalis was 90 % in the poorly differentiated tissues, which was significantly higher than that of well or moderately differentiated samples (p < 0.05) (Table 5).	('P. gingivalis', 'Var', (42, 55))	('higher', 'PosReg', (127, 133))	('P. gingivalis', 'Species', '837', (42, 55))
407864	26788120	Additionally, the presence of P. gingivalis was closely related to the TNM stage of ESCC.	('P. gingivalis', 'Var', (30, 43))	('related', 'Reg', (56, 63))	('P. gingivalis', 'Species', '837', (30, 43))	('ESCC', 'Disease', (84, 88))	('TNM stage', 'Disease', (71, 80))
407869	26788120	However, the mean survival time for patients with positive P. gingivalis antigen expression was 20.139 months, significantly lower than that of P. gingivalis negative group (25.971 months) or all patients (23.981 months) (both p < 0.05) (Table 6).	('positive P. gingivalis', 'Var', (50, 72))	('P. gingivalis', 'Species', '837', (144, 157))	('patients', 'Species', '9606', (36, 44))	('P. gingivalis', 'Species', '837', (59, 72))	('patients', 'Species', '9606', (196, 204))	('survival time', 'CPA', (18, 31))	('lower', 'NegReg', (125, 130))
407875	26788120	Moreover, our analysis indicates that the presence of P. gingivalis correlates with multiple clinicopathologic factors, including cancer cell differentiation, metastasis, and overall survival ESCC rate.	('P. gingivalis', 'Species', '837', (54, 67))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('metastasis', 'CPA', (159, 169))	('ESCC rate', 'PosReg', (192, 201))	('cancer', 'Disease', (130, 136))	('presence', 'Var', (42, 50))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('P. gingivalis', 'Var', (54, 67))	('overall survival', 'CPA', (175, 191))
407879	26788120	In this regard, both our group and others have demonstrated that P. gingivalis activates JAK2 and GSK3beta pathways, thus increasing the production of IL-6 in epithelial cells.	('production of IL-6', 'MPA', (137, 155))	('P. gingivalis', 'Species', '837', (65, 78))	('P. gingivalis', 'Var', (65, 78))	('increasing', 'PosReg', (122, 132))	('GSK3beta pathways', 'Pathway', (98, 115))	('activates', 'PosReg', (79, 88))
407884	26788120	Thirdly, P. gingivalis inhibits epithelial cell apoptosis by a number of mechanisms, including activation of Jak1/Akt/Stat3, enhancing the Bcl2 (antiapoptotic): Bax (proapoptotic) ratio, blocking the release of the apoptosis effector cytochrome c, and the activation of downstream caspases.	('release', 'MPA', (200, 207))	('apoptosis effector cytochrome c', 'MPA', (215, 246))	('epithelial cell apoptosis', 'CPA', (32, 57))	('blocking', 'NegReg', (187, 195))	('activation', 'PosReg', (256, 266))	('activation', 'PosReg', (95, 105))	('enhancing', 'PosReg', (125, 134))	('P. gingivalis', 'Species', '837', (9, 22))	('P. gingivalis', 'Var', (9, 22))	('Jak1/Akt/Stat3', 'Pathway', (109, 123))	('inhibits', 'NegReg', (23, 31))
407885	26788120	Moreover, P. gingivalis can upregulate microRNAs, such as miR-203, which suppress apoptosis in primary gingival epithelial cells.	('suppress', 'NegReg', (73, 81))	('P. gingivalis', 'Var', (10, 23))	('miR-203', 'Chemical', '-', (58, 65))	('apoptosis', 'CPA', (82, 91))	('P. gingivalis', 'Species', '837', (10, 23))	('miR-203', 'Gene', (58, 65))	('upregulate', 'PosReg', (28, 38))
407887	26788120	Lastly, in oral squamous cell carcinoma (OSCC) cells, P. gingivalis promotes cellular migration through activation of the ERK1/2-Ets1, p38/HSP27, and PAR2/NF-kappaB pathways to induce pro-matrix metalloproteinase (MMP)-9 expression.	('p38/HSP27', 'Protein', (135, 144))	('activation', 'PosReg', (104, 114))	('promotes', 'PosReg', (68, 76))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (11, 39))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (16, 39))	('oral squamous cell carcinoma', 'Disease', (11, 39))	('PAR2/NF-kappaB pathways', 'Pathway', (150, 173))	('carcinoma', 'Phenotype', 'HP:0030731', (30, 39))	('P. gingivalis', 'Var', (54, 67))	('expression', 'MPA', (221, 231))	('induce', 'PosReg', (177, 183))	('cellular migration', 'CPA', (77, 95))	('P. gingivalis', 'Species', '837', (54, 67))	('ERK1/2-Ets1', 'Pathway', (122, 133))	('MMP)-9', 'Gene', (214, 220))
407892	26788120	Should P. gingivalis prove to cause ESCC, the implications are enormous.	('P. gingivalis', 'Species', '837', (7, 20))	('ESCC', 'Disease', (36, 40))	('P. gingivalis', 'Var', (7, 20))	('cause', 'Reg', (30, 35))
407899	26788120	Dysbiosis of the microbiota in the esophagus could potentially cause or exacerbate the severity of esophageal disorders.	('esophageal disorders', 'Disease', 'MESH:D004935', (99, 119))	('cause', 'Reg', (63, 68))	('exacerbate', 'PosReg', (72, 82))	('esophageal disorders', 'Disease', (99, 119))	('severity', 'MPA', (87, 95))	('Dysbiosis', 'Var', (0, 9))
407900	26788120	Thus, a further possibility to be tested is that esophageal infection with P. gingivalis leads to shift in the microbiome involved in the development of esophageal cancer.	('P. gingivalis', 'Species', '837', (75, 88))	('P. gingivalis', 'Var', (75, 88))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('esophageal infection', 'Disease', (49, 69))	('shift', 'Reg', (98, 103))	('esophageal infection', 'Disease', 'MESH:D004941', (49, 69))	('esophageal cancer', 'Disease', (153, 170))	('esophageal cancer', 'Disease', 'MESH:D004938', (153, 170))
407920	29212506	Chromosome 9p copy number gains involving PD-L1 are associated with a specific proliferation and immune-modulating gene expression program active across major cancer types Inhibition of the PD-L1/PD-1 immune checkpoint axis represents one of the most promising approaches of immunotherapy for various cancer types.	('cancer', 'Disease', (159, 165))	('PD-L1', 'Gene', '29126', (42, 47))	('PD-1', 'Gene', (196, 200))	('PD-L1', 'Gene', (190, 195))	('PD-1', 'Gene', '5133', (196, 200))	('cancer', 'Disease', 'MESH:D009369', (301, 307))	('PD-L1', 'Gene', '29126', (190, 195))	('copy number gains', 'Var', (14, 31))	('active', 'MPA', (139, 145))	('associated', 'Reg', (52, 62))	('cancer', 'Disease', (301, 307))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('PD-L1', 'Gene', (42, 47))	('cancer', 'Phenotype', 'HP:0002664', (301, 307))	('cancer', 'Disease', 'MESH:D009369', (159, 165))
407922	29212506	Recently, recurrent copy number gains (CNG) in chromosome 9p involving PD-L1 were detected in many cancer types including lung cancer, melanoma, bladder cancer, head and neck cancer, cervical cancer, soft tissue sarcoma, prostate cancer, gastric cancer, ovarian cancer, and triple-negative breast cancer.	('soft tissue sarcoma', 'Disease', 'MESH:D012509', (200, 219))	('cervical cancer', 'Disease', (183, 198))	('cancer', 'Disease', (153, 159))	('gastric cancer', 'Disease', (238, 252))	('soft tissue sarcoma', 'Disease', (200, 219))	('cancer', 'Disease', (175, 181))	('gains', 'PosReg', (32, 37))	('cancer', 'Disease', (192, 198))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('bladder cancer', 'Phenotype', 'HP:0009725', (145, 159))	('lung cancer', 'Disease', 'MESH:D008175', (122, 133))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('breast cancer', 'Phenotype', 'HP:0003002', (290, 303))	('cancer', 'Disease', 'MESH:D009369', (297, 303))	('lung cancer', 'Phenotype', 'HP:0100526', (122, 133))	('cancer', 'Disease', (246, 252))	('melanoma', 'Disease', (135, 143))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('gastric cancer', 'Disease', 'MESH:D013274', (238, 252))	('melanoma', 'Phenotype', 'HP:0002861', (135, 143))	('PD-L1', 'Gene', (71, 76))	('ovarian cancer', 'Disease', 'MESH:D010051', (254, 268))	('PD-L1', 'Gene', '29126', (71, 76))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('detected', 'Reg', (82, 90))	('cancer', 'Disease', (230, 236))	('cancer', 'Disease', (127, 133))	('breast cancer', 'Disease', 'MESH:D001943', (290, 303))	('breast cancer', 'Disease', (290, 303))	('cancer', 'Disease', (262, 268))	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('head and neck cancer', 'Phenotype', 'HP:0012288', (161, 181))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('sarcoma', 'Phenotype', 'HP:0100242', (212, 219))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('cancer', 'Disease', 'MESH:D009369', (192, 198))	('prostate cancer', 'Disease', 'MESH:D011471', (221, 236))	('gastric cancer', 'Phenotype', 'HP:0012126', (238, 252))	('ovarian cancer', 'Disease', (254, 268))	('prostate cancer', 'Phenotype', 'HP:0012125', (221, 236))	('cancer', 'Disease', 'MESH:D009369', (246, 252))	('cancer', 'Disease', (297, 303))	('lung cancer', 'Disease', (122, 133))	('melanoma', 'Disease', 'MESH:D008545', (135, 143))	('prostate cancer', 'Disease', (221, 236))	('ovarian cancer', 'Phenotype', 'HP:0100615', (254, 268))	('head and neck cancer', 'Disease', 'MESH:D006258', (161, 181))	('cancer', 'Disease', (99, 105))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('copy number', 'Var', (20, 31))	('cancer', 'Disease', 'MESH:D009369', (230, 236))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (200, 219))	('cancer', 'Disease', 'MESH:D009369', (262, 268))	('cervical cancer', 'Disease', 'MESH:D002583', (183, 198))	('bladder cancer', 'Disease', 'MESH:D001749', (145, 159))	('bladder cancer', 'Disease', (145, 159))
407930	29212506	PD-L1 copy number gains (CNG) are prevalent in significant subsets of different cancers including triple negative breast cancer, Hodgkin's lymphoma, cancer of unknown primary, NSCLC, SCLC, and gastric cancer.	('lymphoma', 'Phenotype', 'HP:0002665', (139, 147))	('cancers', 'Disease', 'MESH:D009369', (80, 87))	('cancer', 'Disease', (201, 207))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('SCLC', 'Disease', 'MESH:D018288', (177, 181))	('gastric cancer', 'Disease', 'MESH:D013274', (193, 207))	("Hodgkin's lymphoma", 'Disease', (129, 147))	('PD-L1', 'Gene', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('SCLC', 'Disease', 'MESH:D018288', (183, 187))	('PD-L1', 'Gene', '29126', (0, 5))	('cancer', 'Disease', (80, 86))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('gastric cancer', 'Phenotype', 'HP:0012126', (193, 207))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('SCLC', 'Disease', (183, 187))	('cancers', 'Phenotype', 'HP:0002664', (80, 87))	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('cancer', 'Disease', (149, 155))	('cancers', 'Disease', (80, 87))	('SCLC', 'Disease', (177, 181))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('NSCLC', 'Disease', 'MESH:D002289', (176, 181))	("Hodgkin's lymphoma", 'Phenotype', 'HP:0012189', (129, 147))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('breast cancer', 'Phenotype', 'HP:0003002', (114, 127))	('copy number gains', 'Var', (6, 23))	('gastric cancer', 'Disease', (193, 207))	("Hodgkin's lymphoma", 'Disease', 'MESH:D006689', (129, 147))	('NSCLC', 'Disease', (176, 181))	('breast cancer', 'Disease', 'MESH:D001943', (114, 127))	('prevalent', 'Reg', (34, 43))	('cancer', 'Disease', (121, 127))	('cancer', 'Disease', 'MESH:D009369', (149, 155))	('breast cancer', 'Disease', (114, 127))
407931	29212506	In particular, Hodgkin's lymphomas harboring PD-L1 CNG were reported to exhibit increased PD-L1 expression and to respond well to immune checkpoint inhibition.	('PD-L1', 'Gene', '29126', (45, 50))	('PD-L1', 'Gene', '29126', (90, 95))	('increased', 'PosReg', (80, 89))	("Hodgkin's lymphomas", 'Disease', 'MESH:D006689', (15, 34))	('expression', 'MPA', (96, 106))	("Hodgkin's lymphoma", 'Phenotype', 'HP:0012189', (15, 33))	("Hodgkin's lymphomas", 'Phenotype', 'HP:0012189', (15, 34))	("Hodgkin's lymphomas", 'Disease', (15, 34))	('lymphomas', 'Phenotype', 'HP:0002665', (25, 34))	('lymphoma', 'Phenotype', 'HP:0002665', (25, 33))	('CNG', 'Var', (51, 54))	('increased PD', 'Phenotype', 'HP:0008151', (80, 92))	('PD-L1', 'Gene', (45, 50))	('PD-L1', 'Gene', (90, 95))
407937	29212506	PD-L1 copy numbers alterations were evaluated using the calls reported by the TCGA consortium based on Affymetrix SNP 6.0 array data and the GISTIC 2.0 algorithm.	('PD-L1', 'Gene', (0, 5))	('PD-L1', 'Gene', '29126', (0, 5))	('copy numbers', 'Var', (6, 18))
407957	29212506	Before, we showed that approximately half of the PD-L1 CNGs in the major cancer types occur together with amplification of chromosome 9p or the entire chromosome 9 (non-focal gains), while the other half of PD-L1 CNGs frequently co-occurs with gain of a 38-gene core amplified region located in chromosome 9p24 (focal gains).	('cancer', 'Disease', (73, 79))	('gain', 'PosReg', (244, 248))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('PD-L1', 'Gene', (207, 212))	('PD-L1', 'Gene', '29126', (49, 54))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('PD-L1', 'Gene', '29126', (207, 212))	('amplification', 'Var', (106, 119))	('PD-L1', 'Gene', (49, 54))
407961	29212506	In keeping with these data, we recently demonstrated that PD-L1 amplification accompanied by overexpression can also be used to identify patients with solid tumors who benefit from PD-1 blockade.	('PD-L1', 'Gene', '29126', (58, 63))	('tumors', 'Phenotype', 'HP:0002664', (157, 163))	('PD-1', 'Gene', (181, 185))	('solid tumors', 'Disease', (151, 163))	('amplification', 'Var', (64, 77))	('PD-1', 'Gene', '5133', (181, 185))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('patients', 'Species', '9606', (137, 145))	('PD-L1', 'Gene', (58, 63))	('solid tumors', 'Disease', 'MESH:D009369', (151, 163))
407963	29212506	Testing for PD-L1 amplifications could be easily implemented in a routine setting using in situ hybridization based assays such as FISH or using targeted DNA sequencing.	('PD-L1', 'Gene', (12, 17))	('FISH', 'Disease', (131, 135))	('FISH', 'Disease', 'None', (131, 135))	('PD-L1', 'Gene', '29126', (12, 17))	('amplifications', 'Var', (18, 32))
407965	29212506	Copy number and gene expression analyses uncovered additional potential drug targets, such as amplified and overexpressed JAK2 (Table 1), which has been implicated in the regulation of PD-L1 expression and appears to play a role in tumor growth and resistance to chemotherapy.	('JAK2', 'Gene', '3717', (122, 126))	('amplified', 'Var', (94, 103))	('play', 'Reg', (217, 221))	('tumor', 'Disease', 'MESH:D009369', (232, 237))	('overexpressed', 'PosReg', (108, 121))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('JAK2', 'Gene', (122, 126))	('PD-L1', 'Gene', (185, 190))	('tumor', 'Disease', (232, 237))	('role', 'Reg', (224, 228))	('PD-L1', 'Gene', '29126', (185, 190))
407981	29212506	Conversely, this IDO1-mediated mechanism of immune suppression can be exploited therapeutically by inhibition of the catalytic activity of IDO1 suggesting that dual inhibition of both PD-1 and IDO1 could be a promising approach to enhance efficacy of checkpoint blockade.	('IDO1', 'Gene', '3620', (193, 197))	('IDO1', 'Gene', '3620', (139, 143))	('inhibition', 'Var', (99, 109))	('IDO1', 'Gene', '3620', (17, 21))	('IDO1', 'Gene', (193, 197))	('PD-1', 'Gene', (184, 188))	('PD-1', 'Gene', '5133', (184, 188))	('IDO1', 'Gene', (139, 143))	('catalytic activity', 'MPA', (117, 135))	('enhance', 'PosReg', (231, 238))	('IDO1', 'Gene', (17, 21))
407986	29212506	Recently, overexpression of TTK, another checkpoint in mitosis, was reported to occur in triple negative breast cancers, which frequently harbor PD-L1 amplifications.	('mitosis', 'Disease', 'None', (55, 62))	('breast cancers', 'Disease', 'MESH:D001943', (105, 119))	('breast cancers', 'Disease', (105, 119))	('TTK', 'Gene', (28, 31))	('PD-L1', 'Gene', '29126', (145, 150))	('TTK', 'Gene', '7272', (28, 31))	('cancers', 'Phenotype', 'HP:0002664', (112, 119))	('amplifications', 'Var', (151, 165))	('breast cancers', 'Phenotype', 'HP:0003002', (105, 119))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('PD-L1', 'Gene', (145, 150))	('mitosis', 'Disease', (55, 62))	('breast cancer', 'Phenotype', 'HP:0003002', (105, 118))
407987	29212506	In line with this finding, our analysis showed upregulation of TTK across many cancers that harbor CNG of 9p involving PD-L1.	('TTK', 'Gene', (63, 66))	('cancers', 'Disease', (79, 86))	('CNG of', 'Var', (99, 105))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('TTK', 'Gene', '7272', (63, 66))	('PD-L1', 'Gene', (119, 124))	('upregulation', 'PosReg', (47, 59))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('PD-L1', 'Gene', '29126', (119, 124))	('cancers', 'Disease', 'MESH:D009369', (79, 86))
407990	29212506	On a genome-wide scale, recurrent patterns of copy number alterations have been discovered across patients and cancer types suggesting their shaping by selective pressures and roles in tumor genesis and tumor growth.	('tumor', 'Disease', (185, 190))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('tumor', 'Disease', (203, 208))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('patients', 'Species', '9606', (98, 106))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('copy number alterations', 'Var', (46, 69))
407991	29212506	In a recent pan-cancer analysis, a copy number alteration signature has been linked up-regulation of glycolysis, while chromosome 8p loss in breast cancer has been linked to alterations in lipid metabolism.	('cancer', 'Disease', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('lipid', 'Chemical', 'MESH:D008055', (189, 194))	('copy number alteration', 'Var', (35, 57))	('cancer', 'Disease', 'MESH:D009369', (16, 22))	('glycolysis', 'MPA', (101, 111))	('cancer', 'Disease', (16, 22))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('breast cancer', 'Disease', 'MESH:D001943', (141, 154))	('loss', 'NegReg', (133, 137))	('up-regulation', 'PosReg', (84, 97))	('breast cancer', 'Disease', (141, 154))	('alterations', 'Reg', (174, 185))	('breast cancer', 'Phenotype', 'HP:0003002', (141, 154))	('lipid metabolism', 'MPA', (189, 205))
407992	29212506	Our observations support a view of copy number alterations as hard-wired genetic changes that maintain cancer hallmarks including 'self-sufficiency in growth' and 'evasion from the immune system' from Hanahan's and Weinberg's list.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('cancer', 'Disease', (103, 109))	("'self-sufficiency", 'MPA', (130, 147))	('copy number alterations', 'Var', (35, 58))	("'evasion", 'MPA', (163, 171))	('sufficiency in growth', 'Phenotype', 'HP:0001510', (136, 157))	('alterations', 'Var', (47, 58))	('cancer', 'Disease', 'MESH:D009369', (103, 109))
408007	29057314	However, many of these targeted alterations are relatively common in lung adenocarcinoma (LUAD), a major subtype of NSCLC, but are rarely present in lung squamous cell carcinoma (LSQCC), the other major subtype of NSCLC, demonstrating that these NSCLC tumor subtypes exhibit very distinct genetic and phenotypic features.	('lung adenocarcinoma', 'Disease', (69, 88))	('LUAD', 'Phenotype', 'HP:0030078', (90, 94))	('NSCLC', 'Disease', (246, 251))	('NSCLC', 'Disease', (214, 219))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('NSCLC', 'Disease', 'MESH:D002289', (116, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (168, 177))	('NSCLC', 'Phenotype', 'HP:0030358', (246, 251))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (149, 177))	('NSCLC', 'Phenotype', 'HP:0030358', (214, 219))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (69, 88))	('tumor', 'Phenotype', 'HP:0002664', (252, 257))	('LSQCC', 'Phenotype', 'HP:0030359', (179, 184))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (69, 88))	('NSCLC', 'Disease', (116, 121))	('LSQCC', 'Chemical', '-', (179, 184))	('NSCLC', 'Phenotype', 'HP:0030358', (116, 121))	('alterations', 'Var', (32, 43))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (149, 177))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (154, 177))	('NSCLC tumor', 'Disease', (246, 257))	('lung squamous cell carcinoma', 'Disease', (149, 177))	('NSCLC tumor', 'Disease', 'MESH:D009369', (246, 257))	('NSCLC', 'Disease', 'MESH:D002289', (246, 251))	('NSCLC', 'Disease', 'MESH:D002289', (214, 219))
408013	29057314	Metabolic analysis in a panel of LSQCC and LUAD cell lines uncovered distinct metabolic phenotypes that could be grouped into highly glycolytic LSQCC cell lines that were susceptible to genetic GLUT1 knockdown, and relatively glucose-independent LUAD cell lines that displayed little sensitivity to the loss of GLUT1.	('knockdown', 'Var', (200, 209))	('LSQCC', 'Chemical', '-', (144, 149))	('LSQCC', 'Disease', (144, 149))	('glycolytic', 'MPA', (133, 143))	('LSQCC', 'Phenotype', 'HP:0030359', (33, 38))	('glucose', 'Chemical', 'MESH:D005947', (226, 233))	('LUAD', 'Phenotype', 'HP:0030078', (246, 250))	('LSQCC', 'Chemical', '-', (33, 38))	('LUAD', 'Phenotype', 'HP:0030078', (43, 47))	('LSQCC', 'Phenotype', 'HP:0030359', (144, 149))
408020	29057314	Oncogenic PI3K/Akt/mTOR signaling is known to increase glycolytic capacity through multiple mechanisms including increased stabilization of HIF-1alpha under non-hypoxic conditions, therefore we hypothesized that aberrant PI3K-mediated translational stabilization of HIF-1alpha contributes to elevated GLUT1 in LSQCC.	('Akt', 'Gene', '207', (15, 18))	('LSQCC', 'Chemical', '-', (310, 315))	('aberrant', 'Var', (212, 220))	('LSQCC', 'Phenotype', 'HP:0030359', (310, 315))	('HIF-1alpha', 'Gene', '3091', (266, 276))	('HIF-1alpha', 'Gene', '3091', (140, 150))	('PI3K-mediated', 'Protein', (221, 234))	('Akt', 'Gene', (15, 18))	('glycolytic capacity', 'MPA', (55, 74))	('HIF-1alpha', 'Gene', (266, 276))	('LSQCC', 'Disease', (310, 315))	('GLUT1', 'MPA', (301, 306))	('elevated', 'PosReg', (292, 300))	('HIF-1alpha', 'Gene', (140, 150))
408026	29057314	Our original work is partially supported by the National Cancer Institute (NCI) of the National Institutes of Health (NIH), R21CA208746 (J.K.) and American Lung Association, LCD-400239 (J.K.).	('Cancer', 'Disease', (57, 63))	('Cancer', 'Phenotype', 'HP:0002664', (57, 63))	('Cancer', 'Disease', 'MESH:D009369', (57, 63))	('R21CA208746', 'Var', (124, 135))
408045	33364188	However, in the tumor process, the activation and high expression of ICPs can inhibit the function of immune cells and mediate tumor immune escape.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('high expression', 'Var', (50, 65))	('ICPs', 'Protein', (69, 73))	('mediate', 'Reg', (119, 126))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('tumor', 'Disease', (127, 132))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('inhibit', 'NegReg', (78, 85))	('function of immune cells', 'CPA', (90, 114))	('tumor', 'Disease', (16, 21))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('activation', 'PosReg', (35, 45))
408048	33364188	PD-L1 and CD8+ TILs, as important factors of anti-tumor immune response, often determine the efficacy of anti-programmed death receptor 1 (PD-1)/PD-L1 antibodies in various solid tumors.	('determine', 'Reg', (79, 88))	('PD-L1', 'Gene', '29126', (145, 150))	('anti-programmed', 'Var', (105, 120))	('tumors', 'Disease', (179, 185))	('CD8', 'Gene', (10, 13))	('tumors', 'Phenotype', 'HP:0002664', (179, 185))	('CD8', 'Gene', '925', (10, 13))	('PD-L1', 'Gene', (0, 5))	('PD-L1', 'Gene', (145, 150))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('tumors', 'Disease', 'MESH:D009369', (179, 185))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('PD-L1', 'Gene', '29126', (0, 5))	('tumor', 'Disease', (50, 55))	('tumor', 'Disease', (179, 184))
408052	33364188	Conversely, patients with a lack of PD-L1 in TILs were observed to have unobstructed tumor progression, suggesting that PD-L1 blockade neither promotes CD8+ T cell immunity nor prevents effective T cells from infiltrating tumors.	('tumor', 'Disease', (85, 90))	('PD-L1', 'Gene', (120, 125))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('PD-L1', 'Gene', '29126', (120, 125))	('tumors', 'Disease', (222, 228))	('patients', 'Species', '9606', (12, 20))	('CD8', 'Gene', (152, 155))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumors', 'Disease', 'MESH:D009369', (222, 228))	('tumor', 'Disease', (222, 227))	('tumor', 'Disease', 'MESH:D009369', (222, 227))	('prevents', 'NegReg', (177, 185))	('PD-L1', 'Gene', (36, 41))	('blockade', 'Var', (126, 134))	('promotes', 'PosReg', (143, 151))	('PD-L1', 'Gene', '29126', (36, 41))	('tumors', 'Phenotype', 'HP:0002664', (222, 228))	('CD8', 'Gene', '925', (152, 155))
408100	33364188	Since PD-L1 expression is not a predictor of PD-1 blocking response, assessing the ratio of PD-L1 to TILs is a key factor in precisely predicting immune checkpoint inhibitor response in patients with high/low PD-L1 expression, which can compensate for PD -L1 expression limitations.	('high/low', 'NegReg', (200, 208))	('high/low', 'Var', (200, 208))	('PD-L1', 'Gene', (92, 97))	('PD-L1', 'Gene', (209, 214))	('PD-L1', 'Gene', (6, 11))	('PD-L1', 'Gene', '29126', (92, 97))	('immune checkpoint inhibitor', 'MPA', (146, 173))	('PD-L1', 'Gene', '29126', (209, 214))	('PD-L1', 'Gene', '29126', (6, 11))	('patients', 'Species', '9606', (186, 194))	('expression', 'MPA', (215, 225))
408145	33364188	However, only a part of the tumor patients with PD-L1 expression showed a clinical response, while other patients (without PD-L1 staining) showed clinical benefit, indicating that there may be other factors in the tumor microenvironment (such as the expression of PD-L1 in stromal cell), which affected the benefits patients.	('PD-L1', 'Gene', '29126', (264, 269))	('PD-L1', 'Gene', '29126', (48, 53))	('tumor', 'Disease', (28, 33))	('patients', 'Species', '9606', (105, 113))	('tumor', 'Disease', 'MESH:D009369', (214, 219))	('expression', 'Var', (54, 64))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('PD-L1', 'Gene', '29126', (123, 128))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('PD-L1', 'Gene', (123, 128))	('patients', 'Species', '9606', (34, 42))	('PD-L1', 'Gene', (264, 269))	('tumor', 'Disease', (214, 219))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('PD-L1', 'Gene', (48, 53))	('patients', 'Species', '9606', (316, 324))
408167	31642613	CIN cervical intraepithelial neoplasia CSCC cervical squamous cell carcinoma DEG differentially expressed gene DEmiRNA differentially expressed miRNA FDR false discovery rate GEO Gene Expression Omnibus GO gene ontology KEGG Kyoto Encyclopedia of Genes and Genomes N normal control PPI protein-protein interaction Cervical carcinoma is one of the leading causes of cancer-related mortality in the world and accounts for 10-15% of tumor-related deaths in women 1.	('carcinoma', 'Disease', 'MESH:D002277', (323, 332))	('CIN', 'Disease', 'MESH:D018290', (0, 3))	('N', 'Chemical', 'MESH:D009584', (116, 117))	('cervical intraepithelial neoplasia', 'Phenotype', 'HP:0032242', (4, 38))	('women', 'Species', '9606', (454, 459))	('cancer', 'Disease', (365, 371))	('CIN', 'Phenotype', 'HP:0032242', (0, 3))	('PPI protein-protein', 'Var', (282, 301))	('carcinoma', 'Disease', 'MESH:D002277', (67, 76))	('cancer', 'Phenotype', 'HP:0002664', (365, 371))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (53, 76))	('intraepithelial neoplasia', 'Phenotype', 'HP:0032187', (13, 38))	('N', 'Chemical', 'MESH:D009584', (147, 148))	('N', 'Chemical', 'MESH:D009584', (265, 266))	('cervical intraepithelial neoplasia', 'Disease', (4, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (323, 332))	('N', 'Chemical', 'MESH:D009584', (2, 3))	('tumor', 'Disease', (430, 435))	('carcinoma', 'Disease', (323, 332))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (53, 76))	('tumor', 'Disease', 'MESH:D009369', (430, 435))	('cancer', 'Disease', 'MESH:D009369', (365, 371))	('CIN', 'Disease', (0, 3))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('squamous cell carcinoma', 'Disease', (53, 76))	('neoplasia', 'Phenotype', 'HP:0002664', (29, 38))	('DEG', 'Chemical', 'MESH:C042934', (77, 80))	('carcinoma', 'Disease', (67, 76))	('cervical intraepithelial neoplasia', 'Disease', 'MESH:D018290', (4, 38))	('tumor', 'Phenotype', 'HP:0002664', (430, 435))
408195	31642613	A total of 1375 DEGs were obtained with FDR < 0.05 in CIN compared with N, among which the expression level of 719 genes was increased and the expression level of 656 genes was decreased.	('N', 'Chemical', 'MESH:D009584', (72, 73))	('increased', 'PosReg', (125, 134))	('expression level', 'MPA', (91, 107))	('DEG', 'Chemical', 'MESH:C042934', (16, 19))	('decreased', 'NegReg', (177, 186))	('CIN', 'Phenotype', 'HP:0032242', (54, 57))	('expression level', 'MPA', (143, 159))	('CIN', 'Disease', 'MESH:D018290', (54, 57))	('N', 'Chemical', 'MESH:D009584', (56, 57))	('FDR < 0.05', 'Var', (40, 50))	('CIN', 'Disease', (54, 57))
408210	31642613	Based on the CIN-specific DEmiRNA-target interaction network, has-miR-24 (degree = 64), has-miR-149 (degree = 45) and has-miR-519d (degree = 38) were the top three DEmiRNAs that regulated most DEGs.	('CIN', 'Disease', (13, 16))	('miR-149', 'Gene', (92, 99))	('miR-149', 'Gene', '406941', (92, 99))	('miR-519d', 'Gene', '574480', (122, 130))	('DEG', 'Chemical', 'MESH:C042934', (193, 196))	('N', 'Chemical', 'MESH:D009584', (31, 32))	('has-miR-24', 'Var', (62, 72))	('miR-519d', 'Gene', (122, 130))	('CIN', 'Phenotype', 'HP:0032242', (13, 16))	('CIN', 'Disease', 'MESH:D018290', (13, 16))	('N', 'Chemical', 'MESH:D009584', (15, 16))	('N', 'Chemical', 'MESH:D009584', (169, 170))
408213	31642613	Based on the CIN-specific DEmiRNA-target interaction network, has-miR-26b (degree = 212), has-miR-16 (degree = 98) and has-let-7a (degree = 82) were the top three DEmiRNAs.	('CIN', 'Disease', (13, 16))	('miR-26b', 'Gene', '407017', (66, 73))	('N', 'Chemical', 'MESH:D009584', (168, 169))	('miR-16', 'Gene', (94, 100))	('N', 'Chemical', 'MESH:D009584', (15, 16))	('N', 'Chemical', 'MESH:D009584', (31, 32))	('CIN', 'Phenotype', 'HP:0032242', (13, 16))	('miR-16', 'Gene', '51573', (94, 100))	('has-let-7a', 'Var', (119, 129))	('CIN', 'Disease', 'MESH:D018290', (13, 16))	('miR-26b', 'Gene', (66, 73))
408217	31642613	Figure 7, immortalization of host cell by virus (FDR = 0.00243696), dTMP biosynthetic process (FDR = 0.00243696), deoxyribonucleoside monophosphate biosynthetic process (FDR = 0.00243696), inhibin-betaglycan-ActRII complex (FDR = 0.00593324), fibroblast growth factor 2 binding (FDR = 0.00477304) and CD4 receptor binding (FDR = 0.00477304) were the most significantly enriched GO terms.	('fibroblast growth factor 2', 'Gene', '2247', (243, 269))	('dTMP', 'Chemical', 'MESH:C113124', (68, 72))	('FDR = 0.00243696', 'Var', (170, 186))	('FDR = 0.00477304', 'Var', (279, 295))	('deoxyribonucleoside monophosphate', 'Chemical', 'MESH:D003853', (114, 147))	('CD4 receptor', 'Gene', (301, 313))	('FDR = 0.00477304', 'Var', (323, 339))	('CD4 receptor', 'Gene', '920', (301, 313))	('fibroblast growth factor 2', 'Gene', (243, 269))	('binding', 'Interaction', (270, 277))	('FDR = 0.00243696', 'Var', (95, 111))
408230	31642613	Abnormal cell proliferation and genomic instability were caused by dysregulation of CDKs 15.	('CDKs', 'Gene', (84, 88))	('dysregulation', 'Var', (67, 80))	('CDKs', 'Gene', '983;12534', (84, 88))	('Abnormal cell proliferation', 'Phenotype', 'HP:0031377', (0, 27))	('caused by', 'Reg', (57, 66))	('genomic instability', 'CPA', (32, 51))
408231	31642613	According to our integrated analysis, up-regulated CDK1 was modulated by hsa-miR-205 and hsa-miR-24 in the tissues of CIN versus N and by hsa-miR-195 and hsa-miR-497 in CIN versus CSCC, which have the same pattern in a previous study 16.	('hsa-miR-497', 'Gene', (154, 165))	('N', 'Chemical', 'MESH:D009584', (171, 172))	('miR-205', 'Gene', '406988', (77, 84))	('modulated', 'Reg', (60, 69))	('CDK1', 'Gene', (51, 55))	('CIN', 'Disease', 'MESH:D018290', (118, 121))	('CDK1', 'Gene', '983', (51, 55))	('up-regulated', 'PosReg', (38, 50))	('hsa-miR-497', 'Gene', '574456', (154, 165))	('CIN', 'Phenotype', 'HP:0032242', (118, 121))	('CIN', 'Disease', (169, 172))	('miR-205', 'Gene', (77, 84))	('N', 'Chemical', 'MESH:D009584', (120, 121))	('CIN', 'Disease', 'MESH:D018290', (169, 172))	('N', 'Chemical', 'MESH:D009584', (129, 130))	('miR-195', 'Gene', '406971', (142, 149))	('CIN', 'Phenotype', 'HP:0032242', (169, 172))	('miR-195', 'Gene', (142, 149))	('CIN', 'Disease', (118, 121))	('hsa-miR-24', 'Var', (89, 99))
408247	31642613	22 reported that the gene of SASH1 inhibited the metastatic progression of hepatocarcinoma cells via regulating the sonic hedgehog signaling pathway.	('regulating', 'Reg', (101, 111))	('gene', 'Var', (21, 25))	('SASH1', 'Gene', (29, 34))	('hepatocarcinoma', 'Disease', 'None', (75, 90))	('hepatocarcinoma', 'Disease', (75, 90))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('sonic hedgehog signaling pathway', 'Pathway', (116, 148))	('inhibited', 'NegReg', (35, 44))	('SASH1', 'Gene', '23328', (29, 34))
408274	30425526	To date, circRNA_100876 has been found to be highly expressed in lung cancer, with its high expression being negatively correlated with the prognosis of non-small-cell lung cancer, suggesting that circRNA_100876 promotes metastatic potential.	('lung cancer', 'Disease', 'MESH:D008175', (65, 76))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('metastatic potential', 'CPA', (221, 241))	('lung cancer', 'Disease', (168, 179))	('promotes', 'PosReg', (212, 220))	('lung cancer', 'Phenotype', 'HP:0100526', (168, 179))	('lung cancer', 'Disease', (65, 76))	('lung cancer', 'Phenotype', 'HP:0100526', (65, 76))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (153, 179))	('negatively', 'NegReg', (109, 119))	('lung cancer', 'Disease', 'MESH:D008175', (168, 179))	('circRNA_100876', 'Var', (197, 211))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (157, 179))
408275	30425526	The expression pattern and biological function of circRNA_100876 in esophageal squamous cell carcinoma (ESCC) remain unknown.	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (68, 102))	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (79, 102))	('esophageal squamous cell carcinoma', 'Disease', (68, 102))	('circRNA_100876', 'Var', (50, 64))
408300	30425526	Using the medium expression value of circRNA_100876 as the cut-off point for the Pearson chi-squared test and Kaplan-Meier's plot, it was found that circRNA_100876 expression was strongly correlated with tumor invasion depth (P=0.017), lymph node metastasis (P=0.027), and vascular invasion (P=0.036; Table 2).	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('tumor', 'Disease', (204, 209))	('lymph node metastasis', 'CPA', (236, 257))	('vascular invasion', 'CPA', (273, 290))	('circRNA_100876', 'Var', (149, 163))	('correlated', 'Reg', (188, 198))
408301	30425526	Patients with higher circRNA_100876 expression had shorter recurrence-free survival (median, 41 vs 23 months; P=0.029; Figure 1C) and overall survival time (median, 46 vs 30 months; P=0.021; Figure 1D) than those with lower circRNA_100876 expression, indicating that circRNA_100876 expression was linked to the clinical progression of ESCC and might represent a promising prognostic biomarker.	('circRNA_100876 expression', 'Var', (21, 46))	('shorter', 'NegReg', (51, 58))	('linked', 'Reg', (297, 303))	('recurrence-free survival', 'CPA', (59, 83))	('overall survival time', 'CPA', (134, 155))	('Patients', 'Species', '9606', (0, 8))	('ESCC', 'Disease', (335, 339))
408306	30425526	The average volume of xenograft tumors grown from circRNA_100876-knockdown TE-1 cells was 75.27+-7.51 mm3 at day 16, while that of the mice inoculated with NC sequence-infected TE-1 cells was 472.20+-142.71 mm3, which was significantly larger than that of circRNA_100876 silencing group (P<0.05; Figure 2D).	('circRNA_100876-knockdown', 'Var', (50, 74))	('larger', 'PosReg', (236, 242))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('mice', 'Species', '10090', (135, 139))	('tumors', 'Disease', (32, 38))	('tumors', 'Disease', 'MESH:D009369', (32, 38))
408309	30425526	Hence, circRNA_100876 depletion restricted ESCC progression, partially by eliminating cell cycle arrest and inhibiting apoptosis.	('cell cycle arrest', 'Phenotype', 'HP:0011018', (86, 103))	('ESCC', 'Disease', (43, 47))	('depletion', 'Var', (22, 31))	('arrest', 'Disease', 'MESH:D006323', (97, 103))	('restricted', 'NegReg', (32, 42))	('eliminating', 'NegReg', (74, 85))	('apoptosis', 'CPA', (119, 128))	('arrest', 'Disease', (97, 103))	('inhibiting', 'NegReg', (108, 118))
408310	30425526	CircRNA_100876 promotes extracellular matrix degradation by competing with MMP13 for miR-136.	('MMP13', 'Gene', (75, 80))	('MMP13', 'Gene', '4322', (75, 80))	('miR-136', 'Gene', (85, 92))	('extracellular matrix degradation', 'CPA', (24, 56))	('miR-136', 'Gene', '406927', (85, 92))	('CircRNA_100876', 'Var', (0, 14))	('promotes', 'PosReg', (15, 23))
408311	30425526	The EMT process was also restrained after circRNA_100876 knockdown, which was characterized by upregulation of epithelial-phenotype E-cadherin and downregulation of mesenchymal-phenotype N-cadherin, vimentin, and the EMT-associated transcription factor Snail (Figure 4B).	('N-cadherin', 'Gene', '1000', (187, 197))	('epithelial-phenotype', 'CPA', (111, 131))	('E-cadherin', 'Gene', (132, 142))	('mesenchymal-phenotype', 'CPA', (165, 186))	('E-cadherin', 'Gene', '999', (132, 142))	('knockdown', 'Var', (57, 66))	('EMT process', 'CPA', (4, 15))	('downregulation', 'NegReg', (147, 161))	('upregulation', 'PosReg', (95, 107))	('vimentin', 'Protein', (199, 207))	('N-cadherin', 'Gene', (187, 197))	('circRNA_100876 knockdown', 'Var', (42, 66))	('restrained', 'NegReg', (25, 35))
408312	30425526	Therefore, we concluded that circRNA_100876 promoted cell migration, invasion, and EMT progression in ESCC, thus facilitating cancer metastasis.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('promoted', 'PosReg', (44, 52))	('cancer metastasis', 'Disease', 'MESH:D009362', (126, 143))	('ESCC', 'Disease', (102, 106))	('facilitating', 'PosReg', (113, 125))	('circRNA_100876', 'Var', (29, 43))	('invasion', 'CPA', (69, 77))	('cell migration', 'CPA', (53, 67))	('EMT progression', 'CPA', (83, 98))	('cancer metastasis', 'Disease', (126, 143))
408315	30425526	Altered circ_100876 expression has been identified in lung squamous cell carcinoma.	('Altered circ_100876 expression', 'Var', (0, 30))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (54, 82))	('identified', 'Reg', (40, 50))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (59, 82))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (54, 82))	('lung squamous cell carcinoma', 'Disease', (54, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
408316	30425526	Circ_100876 expression levels in ESCC tissues were markedly higher than those in the corresponding noncancerous tissues.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('ESCC', 'Disease', (33, 37))	('higher', 'PosReg', (60, 66))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('expression levels', 'MPA', (12, 29))	('Circ_100876', 'Var', (0, 11))
408317	30425526	Moreover, there was a significant correlation between elevated circ_100876 expression and the presence of lymph node metastasis, advanced tumor staging, and poor prognosis of ESCC patients.	('tumor', 'Disease', (138, 143))	('circ_100876', 'Var', (63, 74))	('elevated', 'PosReg', (54, 62))	('patients', 'Species', '9606', (180, 188))	('ESCC', 'Disease', (175, 179))	('lymph node metastasis', 'CPA', (106, 127))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('expression', 'MPA', (75, 85))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
408318	30425526	Our findings indicate that circRNA_100876 should be considered as a crucial molecular marker for ESCC patients.	('patients', 'Species', '9606', (102, 110))	('ESCC', 'Disease', (97, 101))	('circRNA_100876', 'Var', (27, 41))
408320	30425526	CircRNA_100876 depletion reduced tumor growth in nude mice.	('depletion', 'Var', (15, 24))	('nude mice', 'Species', '10090', (49, 58))	('reduced', 'NegReg', (25, 32))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumor', 'Disease', (33, 38))
408321	30425526	These findings coupled with our discovery of the positive relationship between tissue circRNA_100876 expression and lymph node metastasis suggested that elevated circRNA_100876 expression in ESCC tissues might enhance distant metastasis and thus result in unfavorable outcomes in ESCC patients.	('ESCC', 'Disease', (280, 284))	('elevated', 'PosReg', (153, 161))	('distant metastasis', 'CPA', (218, 236))	('result in', 'Reg', (246, 255))	('enhance', 'PosReg', (210, 217))	('circRNA_100876', 'Var', (162, 176))	('patients', 'Species', '9606', (285, 293))
408324	30425526	In the current study, we found that circRNA_100876 depletion led to upregulation of the protein levels of E-cadherin and downregulation of N-cadherin and vimentin in ESCC cells, suggesting that absence of circRNA_100876 might reverse EMT process.	('protein levels', 'MPA', (88, 102))	('EMT process', 'CPA', (234, 245))	('upregulation', 'PosReg', (68, 80))	('vimentin', 'Protein', (154, 162))	('E-cadherin', 'Gene', (106, 116))	('downregulation', 'NegReg', (121, 135))	('N-cadherin', 'Gene', (139, 149))	('depletion', 'Var', (51, 60))	('E-cadherin', 'Gene', '999', (106, 116))	('circRNA_100876', 'Var', (36, 50))	('N-cadherin', 'Gene', '1000', (139, 149))
408327	30425526	Additional studies to elucidate the functional mechanisms of circRNA_100876 in ESCC and other cancers are essential.	('cancers', 'Disease', 'MESH:D009369', (94, 101))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('ESCC', 'Disease', (79, 83))	('cancers', 'Phenotype', 'HP:0002664', (94, 101))	('circRNA_100876', 'Var', (61, 75))	('cancers', 'Disease', (94, 101))
408353	29209073	In most of the cancer types we analyzed (Supplementary Figure 1), omic similarity matrices are positively aligned and mRNA aligns closely with miRNA, methylation and copy number, but weakly with somatic mutation.	('copy number', 'Var', (166, 177))	('mRNA', 'MPA', (118, 122))	('cancer', 'Disease', (15, 21))	('cancer', 'Disease', 'MESH:D009369', (15, 21))	('miRNA', 'MPA', (143, 148))	('methylation', 'MPA', (150, 161))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))
408366	29209073	This is not surprising since PRS consisting of common single nucleotide polymorphisms (SNPs) were identified in a genome-wide association study (GWAS) as being associated with cancer risk rather than prognosis.	('ith cancer', 'Disease', (172, 182))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('ith cancer', 'Disease', 'MESH:D009369', (172, 182))	('single nucleotide polymorphisms', 'Var', (54, 85))	('associated', 'Reg', (160, 170))
408371	29209073	3c) across cancer types is most apparent, followed by copy number and somatic mutation (rho = 0.719), while the correlation of C-indices between miRNA and somatic mutation (rho = -0.103) is low.	('cancer', 'Disease', (11, 17))	('cancer', 'Disease', 'MESH:D009369', (11, 17))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('copy number', 'Var', (54, 65))
408387	29209073	Specifically, we compared the prognostic powers of (a) the kernel machine learning method for genome-wide aggregation of mRNA transcripts; (b) pre-specified prognostic signatures, including the metagene signatures and the ESTIMATE immune signatures developed across multiple cancer types; (c) the PAM50 breast cancer classifier or the MammaPrint signature that predicts distant metastasis for early stage breast cancer; (d) LGG subtypes defined by IDH1 mutation and co-deletion of chromosome 1p/19q; and (e) algorithmically selecting mRNA transcripts by L1 penalized Cox regression (LASSO).	('breast cancer', 'Disease', 'MESH:D001943', (405, 418))	('breast cancer', 'Disease', (405, 418))	('IDH1', 'Gene', '3417', (448, 452))	('cancer', 'Disease', 'MESH:D009369', (275, 281))	('cancer', 'Disease', (310, 316))	('cancer', 'Phenotype', 'HP:0002664', (310, 316))	('cancer', 'Disease', (412, 418))	('Cox', 'Gene', '1351', (567, 570))	('ran', 'Gene', (127, 130))	('ran', 'Gene', '5901', (127, 130))	('cancer', 'Phenotype', 'HP:0002664', (412, 418))	('co-deletion', 'Var', (466, 477))	('distant metastasis', 'CPA', (370, 388))	('Cox', 'Gene', (567, 570))	('breast cancer', 'Phenotype', 'HP:0003002', (303, 316))	('mutation', 'Var', (453, 461))	('ran', 'Gene', (540, 543))	('ran', 'Gene', '5901', (540, 543))	('cancer', 'Disease', 'MESH:D009369', (310, 316))	('cancer', 'Disease', (275, 281))	('IDH1', 'Gene', (448, 452))	('breast cancer', 'Phenotype', 'HP:0003002', (405, 418))	('cancer', 'Phenotype', 'HP:0002664', (275, 281))	('breast cancer', 'Disease', (303, 316))	('breast cancer', 'Disease', 'MESH:D001943', (303, 316))	('cancer', 'Disease', 'MESH:D009369', (412, 418))
408389	29209073	On average, the kernel method improves C-index over the metagene and immune signatures by 0.018 and 0.052 (P = 0.14 and 1.62*10-4) respectively, across cancer types.	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('improves', 'PosReg', (30, 38))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('metagene', 'Var', (56, 64))	('C-index', 'MPA', (39, 46))
408390	29209073	There are a few exceptions in which the metagene and immune signatures perform slightly better than the kernel method, including the metagene signature in UCEC (C-index = 0.728 v.s 0.667 by the kernel machine learning method), in LUAD (C-index = 0.626 v.s 0.606), in COAD (C-index = 0.604 v.s 0.583), and in GB (C-index = 0.585 v.s 0.572), as well as the immune signature in STAD (0.594 v.s 0.571) and in GB (C-index = 0.594 v.s 0.572).	('GB', 'Phenotype', 'HP:0012174', (405, 407))	('0.594', 'Var', (381, 386))	('COAD', 'Disease', 'MESH:D029424', (267, 271))	('COAD', 'Disease', (267, 271))	('GB', 'Phenotype', 'HP:0012174', (308, 310))
408405	29209073	In contrast, external validation of clinical variables resulted in a C-index decrease from 0.703 (in TCGA LUAD) to 0.621 (in the NCI study), an overall reduction of 11.66%, which may reflect the discrepancy between the study populations (the NCI study included early stage patients) or the evaluation criteria of clinical variables between the two studies.	('patients', 'Species', '9606', (273, 281))	('decrease', 'NegReg', (77, 85))	('C-index', 'MPA', (69, 76))	('0.621', 'Var', (115, 120))	('reduction', 'NegReg', (152, 161))
408423	29209073	Among the different omics data types, mRNA expression most frequently provides the highest C-index for predicting patients' survival outcome compared to the other molecular profiles in our analysis, suggesting that the resulting expression of mutated genes may be more important for patients' survival than the underlying mutational patterns.	('patients', 'Species', '9606', (283, 291))	('mutated', 'Var', (243, 250))	('C-index', 'MPA', (91, 98))	('expression', 'MPA', (229, 239))	('patients', 'Species', '9606', (114, 122))
408483	27029057	Expression of epithelial-mesenchymal transition-related genes increases with copy number in multiple cancer types Epithelial-mesenchymal transition (EMT) is a cellular process through which epithelial cells transform into mesenchymal cells.	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('increases', 'PosReg', (62, 71))	('cancer', 'Disease', (101, 107))	('Expression', 'MPA', (0, 10))	('copy number', 'Var', (77, 88))	('epithelial-mesenchymal transition-related genes', 'Gene', (14, 61))	('Epithelial-mesenchymal transition', 'Disease', (114, 147))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))
408486	27029057	Based on curated 377 EMT-implicated genes from the literature, we identified 212 EMT-implicated genes associated with more frequent copy number gains (CNGs) than copy number losses (CNLs) using data from The Cancer Genome Atlas (TCGA).	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (208, 227))	('Cancer', 'Phenotype', 'HP:0002664', (208, 214))	('copy number gains', 'Var', (132, 149))	('copy number loss', 'Disease', (162, 178))	('EMT-implicated', 'Gene', (81, 95))	('copy number loss', 'Disease', 'MESH:D016388', (162, 178))	('Cancer Genome Atlas', 'Disease', (208, 227))
408494	27029057	CNVs can be classified into two major groups: copy number gain (CNG, an increased number of copies of a gene in the genome) and copy number loss (CNL, a reduced number of copies of a gene in the human genome).	('copy number', 'Var', (46, 57))	('human', 'Species', '9606', (195, 200))	('gain', 'PosReg', (58, 62))	('copy number loss', 'Disease', (128, 144))	('copy number loss', 'Disease', 'MESH:D016388', (128, 144))
408515	27029057	Over 80% of the esophageal carcinoma patients had at least one deletion event in one of the 71 EMT-implicated genes.	('carcinoma', 'Phenotype', 'HP:0030731', (27, 36))	('patients', 'Species', '9606', (37, 45))	('esophageal carcinoma', 'Disease', (16, 36))	('deletion', 'Var', (63, 71))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (16, 36))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (16, 36))
408518	27029057	The consistent detection of these highly frequent mutations in multiple cancers and cell lines may imply that frequent CNGs in these 71 EMT-implicated genes are important for cancer progression.	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('mutations', 'Var', (50, 59))	('multiple cancers', 'Disease', 'MESH:D009369', (63, 79))	('cancer', 'Disease', (175, 181))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('multiple cancers', 'Disease', (63, 79))	('cancer', 'Disease', (72, 78))
408523	27029057	In this same prostate cancer cohort, there were also frequent CNGs of MTDH and ESRP1 (Figure 3D, 3H).	('MTDH', 'Gene', '92140', (70, 74))	('CNGs', 'Var', (62, 66))	('ESRP1', 'Gene', '54845', (79, 84))	('MTDH', 'Gene', (70, 74))	('ESRP1', 'Gene', (79, 84))	('prostate cancer', 'Disease', (13, 28))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('prostate cancer', 'Disease', 'MESH:D011471', (13, 28))	('prostate cancer', 'Phenotype', 'HP:0012125', (13, 28))
408524	27029057	There were repeat copies of PIK3CA and ECT2 in approximately 45% of patients in a TCGA lung squamous cell carcinoma cohort (Figure 3C, 3F).	('ECT2', 'Gene', (39, 43))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (87, 115))	('PIK3CA', 'Gene', (28, 34))	('ECT2', 'Gene', '1894', (39, 43))	('patients', 'Species', '9606', (68, 76))	('repeat copies', 'Var', (11, 24))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('lung squamous cell carcinoma cohort', 'Disease', 'MESH:D002294', (87, 122))	('PIK3CA', 'Gene', '5290', (28, 34))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (92, 115))	('lung squamous cell carcinoma cohort', 'Disease', (87, 122))
408525	27029057	Likewise, there were frequent CNGs of EGFR in a TCGA glioblastoma multiforme cohort (~45%), and of ERBB2 in nearly 14% of cases from a TCGA stomach cancer cohort.	('EGFR', 'Gene', '1956', (38, 42))	('stomach cancer', 'Disease', (140, 154))	('glioblastoma multiforme cohort', 'Disease', 'MESH:D005909', (53, 83))	('ERBB2', 'Gene', (99, 104))	('EGFR', 'Gene', (38, 42))	('ERBB2', 'Gene', '2064', (99, 104))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('glioblastoma', 'Phenotype', 'HP:0012174', (53, 65))	('stomach cancer', 'Disease', 'MESH:D013274', (140, 154))	('stomach cancer', 'Phenotype', 'HP:0012126', (140, 154))	('CNGs', 'Var', (30, 34))	('glioblastoma multiforme cohort', 'Disease', (53, 83))
408526	27029057	In summary, copy number changes of these apoptosis-related genes were highly frequent in certain cancer types, which may imply that apoptosis is critical in different cancer EMT processes.	('cancer', 'Disease', (97, 103))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('copy number changes', 'Var', (12, 31))	('cancer', 'Disease', (167, 173))	('frequent', 'Reg', (77, 85))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('apoptosis-related genes', 'Gene', (41, 64))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
408535	27029057	In total, nine genes with six or more links, and all of them are associated with positive regulation of the phosphate metabolic process (GO:0045937, corrected P-value = 1.241E-9) and the regulation of phosphorylation (GO:0042325, corrected P-value = 8.013E-9).	('phosphate', 'Chemical', 'MESH:D010710', (108, 117))	('regulation', 'MPA', (187, 197))	('GO:0045937', 'Var', (137, 147))	('positive regulation', 'PosReg', (81, 100))	('phosphorylation', 'MPA', (201, 216))	('phosphate metabolic process', 'MPA', (108, 135))
408536	27029057	In addition, eight of the nine genes are related to a "pathway in cancer" (corrected P-value = 4.424E-9), wound healing (GO:0042060, corrected P-value = 8.013E-9), response to growth factors (GO:0070848, corrected P-value = 8.013E-9), abnormal extra-embryonic tissue morphology (corrected P-value = 1.587E-5), abnormal embryonic growth/weight/body size (corrected P-value = 4.224E-5), and embryonic lethality during organogenesis (corrected P-value = 4.580E-5).	('GO:0070848', 'Var', (192, 202))	('abnormal embryonic growth/', 'Phenotype', 'HP:0001507', (310, 336))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('extra-embryonic tissue morphology', 'CPA', (244, 277))	('abnormal embryonic growth', 'Disease', (310, 335))	('GO:0042060', 'Var', (121, 131))	('related', 'Reg', (41, 48))	('embryonic lethality', 'Disease', 'MESH:D020964', (389, 408))	('embryonic lethality', 'Disease', (389, 408))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('abnormal embryonic growth', 'Disease', 'MESH:D006130', (310, 335))	('wound healing', 'CPA', (106, 119))	('cancer', 'Disease', (66, 72))
408545	27029057	Overall, the systematic combination of gene expression and CNG data in ovarian cancer revealed that the gene dosage effects of CNGs in EMT-implicated genes may increase gene expression.	('ovarian cancer', 'Disease', 'MESH:D010051', (71, 85))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('ovarian cancer', 'Phenotype', 'HP:0100615', (71, 85))	('ovarian cancer', 'Disease', (71, 85))	('increase', 'PosReg', (160, 168))	('CNGs', 'Var', (127, 131))	('gene expression', 'MPA', (169, 184))
408547	27029057	EMT is a critical process for cancer metastasis, and large-scale gene copy gains in EMT-implicated genes may induce their up-regulation.	('cancer metastasis', 'Disease', 'MESH:D009362', (30, 47))	('EMT-implicated genes', 'Gene', (84, 104))	('up-regulation', 'PosReg', (122, 135))	('gene copy gains', 'Var', (65, 80))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('cancer metastasis', 'Disease', (30, 47))
408549	27029057	CNGs in these stem cell-related genes may invoke harmful stemness that promotes cancer cell proliferation.	('CNGs', 'Var', (0, 4))	('promotes', 'PosReg', (71, 79))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('invoke', 'Reg', (42, 48))	('harmful stemness', 'CPA', (49, 65))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('cancer', 'Disease', (80, 86))
408556	27029057	According to the most recent CNV map of the human genome, an estimated 4.8-9.5% of the genome is subject to copy number change.	('human', 'Species', '9606', (44, 49))	('copy number change', 'Var', (108, 126))	('subject', 'Reg', (97, 104))
408558	27029057	Although the majority of CNVs may not be directly linked to tumorigenesis, they may activate gene expression, according to our results.	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('activate', 'PosReg', (84, 92))	('gene expression', 'MPA', (93, 108))	('tumor', 'Disease', (60, 65))	('CNVs', 'Var', (25, 29))
408559	27029057	These gene expression changes may promote cancer progression through broader gene-gene interactions.	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('changes', 'Var', (22, 29))	('interactions', 'Interaction', (87, 99))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('promote', 'PosReg', (34, 41))
408560	27029057	For example, CNVs in genes encoding tumor suppressors and oncogenic transcription factors/microRNAs may have more profound effects on their target genes than on these genes themselves.	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('CNVs', 'Var', (13, 17))	('effects', 'Reg', (123, 130))	('tumor', 'Disease', (36, 41))
408577	27029057	TCGA The Cancer Genome Atlas EMT Epithelial-Mesenchymal Transition CNV Copy Number Variation CNG Copy Number Gain CNL Copy Number Loss.	('Epithelial-Mesenchymal Transition', 'CPA', (33, 66))	('Cancer Genome Atlas', 'Disease', (9, 28))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (9, 28))	('Copy Number', 'MPA', (97, 108))	('Copy Number Variation', 'Var', (71, 92))	('Cancer', 'Phenotype', 'HP:0002664', (9, 15))
408607	26392858	In addition to the low frequency of ALK rearrangements in lung SqCC, ALK testing is not routinely performed in patients with lung SqCC on the basis of National Comprehensive Cancer Network guidelines.	('ALK', 'Gene', '238', (69, 72))	('SqCC', 'Phenotype', 'HP:0002860', (130, 134))	('Cancer', 'Disease', (174, 180))	('lung', 'Disease', (58, 62))	('ALK', 'Gene', '238', (36, 39))	('Cancer', 'Disease', 'MESH:D009369', (174, 180))	('SqCC', 'Phenotype', 'HP:0002860', (63, 67))	('Cancer', 'Phenotype', 'HP:0002664', (174, 180))	('ALK', 'Gene', (69, 72))	('rearrangements', 'Var', (40, 54))	('ALK', 'Gene', (36, 39))	('patients', 'Species', '9606', (111, 119))
408614	26392858	reported that NSCLC patients with EML4-ALK fusion genes are relatively insensitive to cytotoxic chemotherapy for postoperative recurrent disease or advanced disease, whereas it is now widely recognized that treatment of these patients with the ALK-targeted agent, crizotinib, significantly improves clinical outcomes.	('fusion genes', 'Var', (43, 55))	('NSCLC', 'Disease', (14, 19))	('ALK', 'Gene', (39, 42))	('ALK', 'Gene', '238', (244, 247))	('improves', 'PosReg', (290, 298))	('EML4', 'Gene', (34, 38))	('postoperative recurrent disease', 'Disease', (113, 144))	('NSCLC', 'Disease', 'MESH:D002289', (14, 19))	('clinical', 'MPA', (299, 307))	('ALK', 'Gene', '238', (39, 42))	('patients', 'Species', '9606', (20, 28))	('patients', 'Species', '9606', (226, 234))	('ALK', 'Gene', (244, 247))	('EML4', 'Gene', '27436', (34, 38))	('crizotinib', 'Chemical', 'MESH:D000077547', (264, 274))	('NSCLC', 'Phenotype', 'HP:0030358', (14, 19))	('postoperative recurrent disease', 'Disease', 'MESH:D010149', (113, 144))
408617	26392858	However, considering the low efficacy of gefitinib in non-adenocarcinoma NSCLC patients harboring EGFR mutations, it remains unclear whether ALK-positive non-adenocarcinoma NSCLC patients show a marked response to ALK-targeted therapy that is as good as that of ALK-positive lung adenocarcinoma patients.	('lung adenocarcinoma', 'Disease', (275, 294))	('ALK', 'Gene', (214, 217))	('gefitinib', 'Chemical', 'MESH:D000077156', (41, 50))	('non-adenocarcinoma NSCLC', 'Disease', 'MESH:D000230', (54, 78))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))	('NSCLC', 'Phenotype', 'HP:0030358', (73, 78))	('EGFR', 'Gene', (98, 102))	('mutations', 'Var', (103, 112))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (275, 294))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (275, 294))	('patients', 'Species', '9606', (179, 187))	('non-adenocarcinoma NSCLC', 'Disease', 'MESH:D000230', (154, 178))	('NSCLC', 'Phenotype', 'HP:0030358', (173, 178))	('carcinoma', 'Phenotype', 'HP:0030731', (285, 294))	('non-adenocarcinoma NSCLC', 'Disease', (54, 78))	('EGFR', 'Gene', '1956', (98, 102))	('ALK', 'Gene', '238', (141, 144))	('ALK', 'Gene', '238', (262, 265))	('carcinoma', 'Phenotype', 'HP:0030731', (163, 172))	('patients', 'Species', '9606', (295, 303))	('ALK', 'Gene', (262, 265))	('patients', 'Species', '9606', (79, 87))	('ALK', 'Gene', (141, 144))	('ALK', 'Gene', '238', (214, 217))	('non-adenocarcinoma NSCLC', 'Disease', (154, 178))
408620	26392858	The heavy smoking history of the present case is not concordant with one of the clinical features of ALK-positive NSCLC, in that ALK rearrangements are often seen in never or light ex-smokers.	('ALK', 'Gene', (101, 104))	('NSCLC', 'Phenotype', 'HP:0030358', (114, 119))	('rearrangements', 'Var', (133, 147))	('ALK', 'Gene', (129, 132))	('ALK', 'Gene', '238', (101, 104))	('NSCLC', 'Disease', (114, 119))	('ALK', 'Gene', '238', (129, 132))	('NSCLC', 'Disease', 'MESH:D002289', (114, 119))
408632	33565282	The serum CD109 levels were elevated in patients with advanced stage disease due to the node metastasis status, and the probability of overall and relapse-free survival was significantly lower in patients with a high levels of serum CD109.	('serum CD109 levels', 'MPA', (4, 22))	('high levels', 'Var', (212, 223))	('patients', 'Species', '9606', (40, 48))	('patients', 'Species', '9606', (196, 204))	('lower', 'NegReg', (187, 192))	('elevated', 'PosReg', (28, 36))
408637	33565282	Recently, numerous blood cancer biomarkers have been developed and applied, including CEA in lung and gastrointestinal cancer, PSA in prostate cancer, and CA19-9 in pancreatic cancer.	('CEA', 'Gene', '1084', (86, 89))	('pancreatic cancer', 'Disease', 'MESH:D010190', (165, 182))	('numerous blood cancer', 'Disease', 'MESH:D007022', (10, 31))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('pancreatic cancer', 'Disease', (165, 182))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('numerous blood cancer', 'Disease', (10, 31))	('prostate cancer', 'Disease', 'MESH:D011471', (134, 149))	('CA19-9', 'Var', (155, 161))	('prostate cancer', 'Phenotype', 'HP:0012125', (134, 149))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('gastrointestinal cancer', 'Disease', 'MESH:D004067', (102, 125))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('blood cancer', 'Phenotype', 'HP:0001909', (19, 31))	('lung', 'Disease', (93, 97))	('prostate cancer', 'Disease', (134, 149))	('gastrointestinal cancer', 'Disease', (102, 125))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (165, 182))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (102, 125))	('PSA', 'Disease', (127, 130))	('CEA', 'Gene', (86, 89))
408642	33565282	2   CD109, TGF-beta/smad signaling modulator, is a glycosylphosphatidylinositol (GPI)-anchored cell surface glycoprotein and a member of the alpha2-macroglobulin (alpha2M)-C3, C4 and C5 family.	('alpha2M', 'Gene', (163, 170))	('TGF-beta', 'Gene', (11, 19))	('cell surface glycoprotein', 'Gene', (95, 120))	('glycosylphosphatidylinositol (GPI)-anchored', 'Disease', 'MESH:C537277', (51, 94))	('alpha2-macroglobulin', 'Gene', '2', (141, 161))	('TGF-beta', 'Gene', '7039', (11, 19))	('alpha2-macroglobulin', 'Gene', (141, 161))	('cell surface glycoprotein', 'Gene', '9308', (95, 120))	('alpha2M', 'Gene', '2', (163, 170))	('CD109', 'Var', (4, 9))
408648	33565282	11 ,  12   Our previous data suggested that soluble CD109 would be present in the sera of SCC patients, and that it may have a potential application as a novel biomarker, similar to SCC-Ag.	('SCC', 'Gene', (182, 185))	('SCC', 'Phenotype', 'HP:0002860', (182, 185))	('patients', 'Species', '9606', (94, 102))	('CD109', 'Var', (52, 57))	('SCC', 'Gene', '6317', (182, 185))	('SCC', 'Gene', (90, 93))	('SCC', 'Phenotype', 'HP:0002860', (90, 93))	('SCC', 'Gene', '6317', (90, 93))
408675	33565282	The CD109 expression in these pathological analyses suggests that serum CD109 is associated with advanced HNSCC involving lymph node metastasis.	('HNSCC', 'Phenotype', 'HP:0012288', (106, 111))	('serum', 'Var', (66, 71))	('SCC', 'Gene', (108, 111))	('SCC', 'Phenotype', 'HP:0002860', (108, 111))	('SCC', 'Gene', '6317', (108, 111))	('CD109', 'Gene', (72, 77))	('associated', 'Reg', (81, 91))
408677	33565282	As shown in Figure 6B, not only the OS rate but also the RFS rate was significantly lower in patients with a CD109 index of >=1.6 than in others (p = 0.026 and p = 0.017, respectively).	('CD109 index', 'Var', (109, 120))	('patients', 'Species', '9606', (93, 101))	('lower', 'NegReg', (84, 89))	('RFS', 'MPA', (57, 60))
408692	33565282	demonstrated:using a glioblastoma cell line:that CD109 attenuates TGF-beta1 signaling, whereas it enhances EGF signaling, cell migration and invasion.	('invasion', 'CPA', (141, 149))	('EGF', 'Gene', '1950', (107, 110))	('glioblastoma', 'Disease', (21, 33))	('CD109', 'Var', (49, 54))	('TGF-beta1', 'Gene', '7040', (66, 75))	('TGF-beta1', 'Gene', (66, 75))	('enhances', 'PosReg', (98, 106))	('attenuates', 'NegReg', (55, 65))	('glioblastoma', 'Disease', 'MESH:D005909', (21, 33))	('glioblastoma', 'Phenotype', 'HP:0012174', (21, 33))	('EGF', 'Gene', (107, 110))	('cell migration', 'CPA', (122, 136))
408712	32410646	Knockout of survivin reduced the tumorigenic properties of OSCC cells in vitro and in vivo.	('reduced', 'NegReg', (21, 28))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('Knockout', 'Var', (0, 8))	('survivin', 'Gene', (12, 20))	('tumor', 'Disease', (33, 38))
408740	32410646	Primary antibodies against Survivin (#2808), cleaved-PARP (#9532), VDAC1 (#4661), Bax (#14796), cleaved-caspase 3 (#9664), cytochrome C (#11940), ubiquitin (#43124), beta-actin (#3700), ubiquitin (#3936), p-Survivin Thr34 (#8888), alpha-tubulin (#3873), p-Akt Ser473 (#4060), p-Wee1 Ser642 (#4910), His-tag (#12698), HA-tag (#2367), p-CDK1 Tyr15 (#4539), and p-CDK1 Thr161 (#9114) were obtained from Cell Signaling Technology, Inc. (Beverly, MA).	('Thr161', 'Chemical', '-', (366, 372))	('Ser642', 'Chemical', '-', (283, 289))	('alpha-tubulin', 'Gene', (231, 244))	('Bax', 'Gene', (82, 85))	('Bax', 'Gene', '581', (82, 85))	('CDK1', 'Gene', '983', (361, 365))	('CDK1', 'Gene', (361, 365))	('PARP', 'Gene', (53, 57))	('#4910', 'Var', (291, 296))	('#12698', 'Var', (308, 314))	('caspase 3', 'Gene', (104, 113))	('caspase 3', 'Gene', '836', (104, 113))	('cytochrome C', 'Gene', (123, 135))	('Wee1', 'Gene', (278, 282))	('VDAC1', 'Gene', (67, 72))	('Akt', 'Gene', (256, 259))	('#4060', 'Var', (268, 273))	('CDK1', 'Gene', '983', (335, 339))	('CDK1', 'Gene', (335, 339))	('VDAC1', 'Gene', '7416', (67, 72))	('cytochrome C', 'Gene', '54205', (123, 135))	('alpha-tubulin', 'Gene', '10376', (231, 244))	('Thr34', 'Chemical', '-', (216, 221))	('Akt', 'Gene', '207', (256, 259))	('Wee1', 'Gene', '7465', (278, 282))	('Ser473', 'Chemical', '-', (260, 266))	('PARP', 'Gene', '1302', (53, 57))	('Tyr15', 'Chemical', '-', (340, 345))
408786	32410646	The MTS data revealed that knockout of survivin inhibited cell viability significantly in CAL27 and SCC25 cells (Fig.	('cell viability', 'CPA', (58, 72))	('knockout', 'Var', (27, 35))	('survivin', 'Protein', (39, 47))	('inhibited', 'NegReg', (48, 57))	('SCC25', 'CellLine', 'CVCL:1682', (100, 105))
408791	32410646	These results support the notion that survivin is overexpressed in OSCC tissues and cell lines, and that knockout of survivin reduces the tumorigenic properties of OSCC cells.	('reduces', 'NegReg', (126, 133))	('knockout', 'Var', (105, 113))	('tumor', 'Disease', (138, 143))	('survivin', 'Gene', (117, 125))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
408819	32410646	Moreover, treated with MG132 extended the half-life over 4 h with either xanthohumol treated or not (Fig.	('extended', 'PosReg', (29, 37))	('half-life over 4 h', 'MPA', (42, 60))	('xanthohumol', 'Chemical', 'MESH:C104536', (73, 84))	('MG132', 'Var', (23, 28))	('MG132', 'Chemical', 'MESH:C072553', (23, 28))
408827	32410646	Consistently, knockdown of Fbxl7 by siRNA impaired xanthohumol-induced survivin ubiquitination in OSCC cells (Fig.	('Fbxl7', 'Gene', '23194', (27, 32))	('Fbxl7', 'Gene', (27, 32))	('xanthohumol', 'Chemical', 'MESH:C104536', (51, 62))	('knockdown', 'Var', (14, 23))	('xanthohumol-induced survivin ubiquitination', 'MPA', (51, 94))	('impaired', 'NegReg', (42, 50))
408830	32410646	The ubiquitination analysis showed that double mutation of K90/91 substantially decreased xanthohumol-induced survivin ubiquitination when compare to survivin wild type (Fig.	('K90/91', 'Gene', (59, 65))	('xanthohumol-induced survivin ubiquitination', 'MPA', (90, 133))	('xanthohumol', 'Chemical', 'MESH:C104536', (90, 101))	('decreased', 'NegReg', (80, 89))	('double mutation', 'Var', (40, 55))
408831	32410646	In addition, the survivin K90/91R mutant exhibited a robust reduction of ubiquitination either treated with xanthohumol or not (Fig.	('K90/91R', 'Var', (26, 33))	('reduction', 'NegReg', (60, 69))	('xanthohumol', 'Chemical', 'MESH:C104536', (108, 119))	('ubiquitination', 'MPA', (73, 87))	('survivin', 'Gene', (17, 25))
408836	32410646	The phosphorylation of Akt on Ser473 was inhibited with xanthohumol treatment (Fig.	('Akt', 'Gene', '207', (23, 26))	('phosphorylation', 'MPA', (4, 19))	('Ser473', 'Var', (30, 36))	('Akt', 'Gene', (23, 26))	('Ser473', 'Chemical', '-', (30, 36))	('inhibited', 'NegReg', (41, 50))	('xanthohumol', 'Chemical', 'MESH:C104536', (56, 67))
408838	32410646	The previous study showed that Akt-dependent phosphorylation at Ser642 promotes the localization of Wee1 from nuclear to cytoplasmic, which is required for G2/M cell cycle arrest.	('Akt', 'Gene', (31, 34))	('arrest', 'Disease', (172, 178))	('Wee1', 'Gene', (100, 104))	('promotes', 'PosReg', (71, 79))	('Ser642', 'Var', (64, 70))	('Wee1', 'Gene', '7465', (100, 104))	('Ser642', 'Chemical', '-', (64, 70))	('Akt', 'Gene', '207', (31, 34))	('localization', 'MPA', (84, 96))	('arrest', 'Disease', 'MESH:D006323', (172, 178))
408841	32410646	However, the phosphorylation of CDK1 on Thr161, which was a marker of CDK1 activation, was reduced dose-dependently (Fig.	('CDK1', 'Gene', (32, 36))	('CDK1', 'Gene', '983', (70, 74))	('CDK1', 'Gene', '983', (32, 36))	('phosphorylation', 'MPA', (13, 28))	('Thr161', 'Var', (40, 46))	('reduced', 'NegReg', (91, 98))	('Thr161', 'Chemical', '-', (40, 46))	('CDK1', 'Gene', (70, 74))
408842	32410646	Moreover, knockdown of Akt by siRNA inhibited the phosphorylation of Wee1 (Ser642), CDK1 (Thr161), and survivin (Thr34), whereas the phosphorylation of CDK1 on Tyr15 was upregulated (Fig.	('CDK1', 'Gene', (152, 156))	('phosphorylation', 'MPA', (50, 65))	('inhibited', 'NegReg', (36, 45))	('Wee1', 'Gene', (69, 73))	('survivin', 'Protein', (103, 111))	('CDK1', 'Gene', (84, 88))	('phosphorylation', 'MPA', (133, 148))	('CDK1', 'Gene', '983', (84, 88))	('Akt', 'Gene', '207', (23, 26))	('Ser642', 'Chemical', '-', (75, 81))	('Wee1', 'Gene', '7465', (69, 73))	('Thr161', 'Chemical', '-', (90, 96))	('Akt', 'Gene', (23, 26))	('Thr34', 'Chemical', '-', (113, 118))	('Tyr15', 'Chemical', '-', (160, 165))	('knockdown', 'Var', (10, 19))	('upregulated', 'PosReg', (170, 181))	('CDK1', 'Gene', '983', (152, 156))
408843	32410646	Furthermore, ectopic overexpression of constitutively activated Akt, Myr-Akt1, rescued xanthohumol-induced reduction of phosphorylation of Wee1 (Ser642), CDK1 (Thr161), and survivin (Thr34) (Fig.	('Akt', 'Gene', (73, 76))	('Akt', 'Gene', '207', (73, 76))	('Akt1', 'Gene', (73, 77))	('phosphorylation', 'MPA', (120, 135))	('Akt', 'Gene', '207', (64, 67))	('CDK1', 'Gene', '983', (154, 158))	('Thr34', 'Chemical', '-', (183, 188))	('CDK1', 'Gene', (154, 158))	('Wee1', 'Gene', (139, 143))	('Thr161', 'Chemical', '-', (160, 166))	('Akt', 'Gene', (64, 67))	('xanthohumol', 'Chemical', 'MESH:C104536', (87, 98))	('Akt1', 'Gene', '207', (73, 77))	('Wee1', 'Gene', '7465', (139, 143))	('Ser642', 'Var', (145, 151))	('reduction', 'NegReg', (107, 116))	('Ser642', 'Chemical', '-', (145, 151))
408850	32410646	The result showed that xanthohumol-induced a much stronger reduction of protein level of survivin T34A mutant (Fig.	('xanthohumol', 'Chemical', 'MESH:C104536', (23, 34))	('T34A mutant', 'Var', (98, 109))	('survivin', 'Gene', (89, 97))	('T34A', 'Mutation', 'rs574523664', (98, 102))	('protein level', 'MPA', (72, 85))	('reduction', 'NegReg', (59, 68))
408851	32410646	Moreover, the T34A mutation shortened the half-life of survivin from around 45 min to 15 min (Fig.	('survivin', 'Protein', (55, 63))	('half-life', 'MPA', (42, 51))	('shortened', 'NegReg', (28, 37))	('T34A', 'Mutation', 'rs574523664', (14, 18))	('T34A mutation', 'Var', (14, 27))
408853	32410646	The result showed that mutation of T34 to Ala increased survivin ubiquitination substantially after xanthohumol treatment (Fig.	('survivin ubiquitination', 'MPA', (56, 79))	('Ala', 'Chemical', 'MESH:D000409', (42, 45))	('T34', 'Gene', (35, 38))	('mutation', 'Var', (23, 31))	('increased', 'PosReg', (46, 55))	('xanthohumol', 'Chemical', 'MESH:C104536', (100, 111))
408862	32410646	A similar inhibitory effect was also observed in SCC25 xenograft tumors, and the tumor size of xanthohumol-treated group was significantly smaller than that of vehicle-treated group (Fig.	('xanthohumol', 'Chemical', 'MESH:C104536', (95, 106))	('xanthohumol-treated', 'Var', (95, 114))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('SCC25', 'Gene', (49, 54))	('tumor', 'Disease', (65, 70))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumors', 'Disease', (65, 71))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('SCC25', 'CellLine', 'CVCL:1682', (49, 54))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumor', 'Disease', (81, 86))	('smaller', 'NegReg', (139, 146))
408873	32410646	Consistently, xanthohumol, but not single dose of irradiation, decreased the cell viability and colony formation of CAL27-IR and SCC25-IR cells (Fig.	('SCC25', 'CellLine', 'CVCL:1682', (129, 134))	('decreased', 'NegReg', (63, 72))	('xanthohumol', 'Chemical', 'MESH:C104536', (14, 25))	('xanthohumol', 'Var', (14, 25))	('colony formation', 'CPA', (96, 112))	('cell viability', 'CPA', (77, 91))
408879	32410646	Strikingly, xanthohumol delayed tumor development in both CAL27 and CAL27-IR derived xenografts, and the combination of xanthohumol sensitized CAL27-IR xenograft to radiotherapy (Fig.	('xanthohumol', 'Chemical', 'MESH:C104536', (120, 131))	('delayed', 'NegReg', (24, 31))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('CAL27-IR', 'Var', (143, 151))	('sensitized', 'Reg', (132, 142))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('combination', 'Var', (105, 116))	('tumor', 'Disease', (32, 37))	('xanthohumol', 'Chemical', 'MESH:C104536', (12, 23))
408885	32410646	Moreover, a high level of survivin is related to enhanced angiogenesis, tumor invasion and metastasis, and chemo/radioresistance, and downregulation of survivin reversed these functions.	('downregulation', 'Var', (134, 148))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('chemo/radioresistance', 'CPA', (107, 128))	('tumor', 'Disease', (72, 77))	('enhanced', 'PosReg', (49, 57))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('angiogenesis', 'CPA', (58, 70))	('survivin', 'Protein', (26, 34))
408896	32410646	Mutation of Thr34 to Ala promoted survivin ubiquitination and reduced protein half-life, which may contribute to xanthohumol-mediated anti-tumor activity in vitro and in vivo.	('survivin', 'Protein', (34, 42))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('xanthohumol', 'Chemical', 'MESH:C104536', (113, 124))	('Thr34 to Ala', 'Mutation', 'p.T34A', (12, 24))	('Mutation', 'Var', (0, 8))	('protein half-life', 'MPA', (70, 87))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('Thr34', 'Gene', (12, 17))	('promoted', 'PosReg', (25, 33))	('ubiquitination', 'MPA', (43, 57))	('reduced', 'NegReg', (62, 69))
408903	32410646	Exception of lysine-48 mediated survivin ubiquitination is required for degradation, lysine-63 linked polyubiquitination chains regulate chromosome alignment and segregation in mitosis.	('chromosome alignment', 'CPA', (137, 157))	('mitosis', 'Disease', (177, 184))	('mitosis', 'Disease', 'None', (177, 184))	('lysine-63 linked', 'Var', (85, 101))	('lysine', 'Chemical', 'MESH:D008239', (85, 91))	('regulate', 'Reg', (128, 136))	('lysine', 'Chemical', 'MESH:D008239', (13, 19))
408911	32410646	YM155 robustly inhibits survivin activity via disruption of Sp1-DNA interaction in the survivin core promoter, thus inhibits survivin transcription, whereas xanthohumol is a potential survivin inhibitor which regulates survivin expression through posttranslational modification.	('Sp1-DNA interaction', 'Protein', (60, 79))	('disruption', 'Var', (46, 56))	('survivin', 'Protein', (24, 32))	('xanthohumol', 'Chemical', 'MESH:C104536', (157, 168))	('survivin', 'Protein', (125, 133))	('YM155', 'Chemical', 'MESH:C523798', (0, 5))	('YM155', 'Var', (0, 5))	('inhibits', 'NegReg', (15, 23))	('inhibits', 'NegReg', (116, 124))
408924	32410646	This work was supported by the National Natural Science Foundation of China (No.81904262, No.81401548, and No.81972837) and the Natural Science Foundation of Hunan Province (2018JJ3787, 2018JJ2604, 2019JJ50682).	('No.81401548', 'Var', (90, 101))	('2018JJ2604', 'CellLine', 'CVCL:6553', (186, 196))	('No.81904262', 'Var', (77, 88))	('No.81972837', 'Var', (107, 118))	('2018JJ3787', 'Var', (174, 184))
409024	32873299	In breast cancer, inhibition of AKT2 can not only effectively prevent the transformation of mesenchymal non-cancer stem cells (non-CSC) into epithelial cells but also reduce the invasive and colony formation abilities of non-CSC and CSC.	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('reduce', 'NegReg', (167, 173))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('AKT2', 'Gene', (32, 36))	('breast cancer', 'Disease', (3, 16))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('prevent', 'NegReg', (62, 69))	('cancer', 'Disease', 'MESH:D009369', (10, 16))	('inhibition', 'Var', (18, 28))	('transformation', 'CPA', (74, 88))	('cancer', 'Disease', (10, 16))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
409025	32873299	In colon cancer, the expression of AKT2 can affect the DNA repair ability and radiosensitivity.	('AKT2', 'Gene', (35, 39))	('affect', 'Reg', (44, 50))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('colon cancer', 'Phenotype', 'HP:0003003', (3, 15))	('colon cancer', 'Disease', 'MESH:D015179', (3, 15))	('expression', 'Var', (21, 31))	('radiosensitivity', 'CPA', (78, 94))	('DNA repair ability', 'CPA', (55, 73))	('colon cancer', 'Disease', (3, 15))
409080	32873299	Taken together, these results suggested that high AKT2 expression could be regarded as an predictive indicator for poor prognosis in LUAD patients.	('expression', 'MPA', (55, 65))	('high', 'Var', (45, 49))	('AKT2', 'Protein', (50, 54))	('LUAD', 'Disease', (133, 137))	('patients', 'Species', '9606', (138, 146))
409083	32873299	The results showed that knockdown of AKT2 expression significantly inhibited tumor cell proliferation (Fig.	('inhibited', 'NegReg', (67, 76))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('AKT2', 'Gene', (37, 41))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Disease', (77, 82))	('knockdown', 'Var', (24, 33))
409084	32873299	EdU staining experiments further confirmed that cell proliferation was attenuated after AKT2 knockdown (Fig.	('knockdown', 'Var', (93, 102))	('AKT2', 'Gene', (88, 92))	('cell proliferation', 'CPA', (48, 66))	('attenuated', 'NegReg', (71, 81))	('EdU', 'Chemical', '-', (0, 3))
409086	32873299	However, we did not observe any effect on the apoptosis of tumor cells after inhibiting the expression of AKT2, indicating that AKT2 may control cell proliferation via cell cycle regulation (Fig.	('tumor', 'Disease', (59, 64))	('cell proliferation', 'CPA', (145, 163))	('control', 'Reg', (137, 144))	('cell cycle regulation', 'CPA', (168, 189))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('AKT2', 'Var', (128, 132))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
409087	32873299	After transfection of si-AKT2 in A549 and H1299 cells, the expression of not only EMT-related markers (N-cadherin, Vimentin and Slug) but also some matrix metalloproteinases (MMP2, MMP7, and MMP9) was significantly decreased.	('Slug', 'Protein', (128, 132))	('Vimentin', 'Gene', (115, 123))	('matrix metalloproteinases', 'Enzyme', (148, 173))	('H1299', 'CellLine', 'CVCL:0060', (42, 47))	('si-AKT2', 'Var', (22, 29))	('expression', 'MPA', (59, 69))	('N-cadherin', 'Protein', (103, 113))	('Vimentin', 'Gene', '7431', (115, 123))	('A549', 'CellLine', 'CVCL:0023', (33, 37))	('decreased', 'NegReg', (215, 224))
409089	32873299	These results demonstrated that knockdown of AKT2 expression inhibited tumor cell migration and invasion in LUAD.	('invasion in', 'CPA', (96, 107))	('inhibited', 'NegReg', (61, 70))	('LUAD', 'Disease', (108, 112))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('knockdown', 'Var', (32, 41))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Disease', (71, 76))	('AKT2', 'Gene', (45, 49))
409092	32873299	In contrast, miR-124 inhibitor transfection induced upregulated AKT2 expression (Fig.	('miR', 'Gene', '220972', (13, 16))	('miR', 'Gene', (13, 16))	('AKT2', 'Gene', (64, 68))	('expression', 'MPA', (69, 79))	('transfection', 'Var', (31, 43))	('upregulated', 'PosReg', (52, 63))
409093	32873299	To further confirm that AKT2 is a direct target of miR-124, we synthesized plasmids containing the 3'-UTR region (746-753) of AKT2, which was predicted as a potential binding site.	('miR', 'Gene', '220972', (51, 54))	('746-753', 'Var', (114, 121))	('miR', 'Gene', (51, 54))	('AKT2', 'Gene', (126, 130))
409103	32873299	Finally, we also found that the expression levels of EMT markers, MMPs, p-AKT and p-Erk were significantly decreased at the mRNA and protein levels after miR-124 transfection (Fig.	('miR', 'Gene', '220972', (154, 157))	('miR', 'Gene', (154, 157))	('p-Erk', 'Gene', (82, 87))	('decreased', 'NegReg', (107, 116))	('MMPs', 'Gene', '4313;17390;4316;17393;4318;17395', (66, 70))	('MMPs', 'Gene', (66, 70))	('transfection', 'Var', (162, 174))	('expression levels', 'MPA', (32, 49))	('p-AKT', 'Gene', (72, 77))
409120	32873299	As an important downstream component of the PI3K pathway, activated AKT2 can promote the transcription of the downstream substrate rapamycin (mTOR) and transcription factors Forkhead family (FOXO), which is involved in protein synthesis, cell proliferation, metastasis and survival processes.	('rapamycin', 'Chemical', 'MESH:D020123', (131, 140))	('promote', 'PosReg', (77, 84))	('transcription', 'MPA', (89, 102))	('activated', 'Var', (58, 67))	('mTOR', 'Gene', (142, 146))	('mTOR', 'Gene', '2475', (142, 146))	('AKT2', 'Gene', (68, 72))	('FOXO', 'Gene', (191, 195))
409123	32873299	The results showed that silencing AKT2 expression decreased cell proliferation via cell cycle arrest, while apoptosis was not affected.	('cell proliferation', 'CPA', (60, 78))	('arrest', 'Disease', 'MESH:D006323', (94, 100))	('decreased', 'NegReg', (50, 59))	('arrest', 'Disease', (94, 100))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (83, 100))	('AKT2', 'Gene', (34, 38))	('silencing', 'Var', (24, 33))
409126	32873299	Our data showed that the mRNA and protein expression levels of EMT markers (N-cadherin, Vimentin and Slug), MMP7, p-AKT, and p-Erk were consistently decreased after AKT2 knockdown in LUAD cells.	('knockdown', 'Var', (170, 179))	('Vimentin', 'Gene', (88, 96))	('AKT2', 'Gene', (165, 169))	('p-Erk', 'MPA', (125, 130))	('MMP7', 'Gene', (108, 112))	('decreased', 'NegReg', (149, 158))	('Vimentin', 'Gene', '7431', (88, 96))	('p-AKT', 'Protein', (114, 119))
409173	30729033	Furthermore, we identified the hyper-methylation (>0.7) and hypo-methylation (<0.3) CpGs from the original 450 K array data and calculated their percentages among all the CpGs for the tumor and normal samples of the 13 cancers (Fig.	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('hyper', 'Disease', (31, 36))	('tumor', 'Disease', (184, 189))	('cancers', 'Disease', 'MESH:D009369', (219, 226))	('cancers', 'Phenotype', 'HP:0002664', (219, 226))	('cancers', 'Disease', (219, 226))	('hypo-methylation', 'Var', (60, 76))	('hyper', 'Disease', 'MESH:D053307', (31, 36))
409175	30729033	As an example, the overlap between DMGs, DEGs and genes with somatic mutation of LUSC is shown in Fig.	('mutation', 'Var', (69, 77))	('LUSC', 'Gene', (81, 85))	('DMGs', 'Chemical', '-', (35, 39))
409187	30729033	TRIP13 promoted early steps of the DNA double-strand break repair and its presence was associated with progression in prostate cancer and squamous cell carcinoma of the head and neck.	('prostate cancer', 'Disease', (118, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (152, 161))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (138, 161))	('DNA double-strand break repair', 'MPA', (35, 65))	('TRIP13', 'Gene', '9319', (0, 6))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (138, 161))	('TRIP13', 'Gene', (0, 6))	('presence', 'Var', (74, 82))	('prostate cancer', 'Disease', 'MESH:D011471', (118, 133))	('squamous cell carcinoma', 'Disease', (138, 161))	('prostate cancer', 'Phenotype', 'HP:0012125', (118, 133))	('promoted', 'PosReg', (7, 15))	('associated with', 'Reg', (87, 102))
409197	30729033	It was also reported that pancreatic cancer genomes show aberrations in the axonal guidance pathway genes.	('axonal', 'Pathway', (76, 82))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (26, 43))	('aberrations', 'Var', (57, 68))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('pancreatic cancer', 'Disease', (26, 43))	('pancreatic cancer', 'Disease', 'MESH:D010190', (26, 43))
409258	30729033	Furthermore, HG-9-91-01(SIK1) was reported to induce anti-inflammatory phenotype and could be used to treat certain autoimmune diseases, we speculate that it can be repurposed to treat cancers as four of the top five enriched pathways in the pan-cancers analysis are closely related to inflammatory processing or inflammation response.	('SIK1', 'Gene', (24, 28))	('SIK1', 'Gene', '150094', (24, 28))	('cancers', 'Phenotype', 'HP:0002664', (185, 192))	('inflammation', 'Disease', 'MESH:D007249', (313, 325))	('cancers', 'Disease', (185, 192))	('HG-9-91-01', 'CellLine', 'CVCL:8000', (13, 23))	('cancers', 'Phenotype', 'HP:0002664', (246, 253))	('anti-inflammatory phenotype', 'MPA', (53, 80))	('cancers', 'Disease', (246, 253))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('HG-9-91-01', 'Var', (13, 23))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))	('autoimmune diseases', 'Disease', 'MESH:D001327', (116, 135))	('autoimmune diseases', 'Disease', (116, 135))	('inflammation', 'Disease', (313, 325))	('autoimmune diseases', 'Phenotype', 'HP:0002960', (116, 135))	('autoimmune disease', 'Phenotype', 'HP:0002960', (116, 134))	('cancers', 'Disease', 'MESH:D009369', (185, 192))	('induce', 'PosReg', (46, 52))	('cancers', 'Disease', 'MESH:D009369', (246, 253))
409304	26568543	Second, these analyses have validated that p53 inactivating mutations remain the predominant genetic defect identified, substantiating prior studies and emphasizing the observation that the majority of tumors harbor loss of function mutations.	('tumors', 'Phenotype', 'HP:0002664', (202, 208))	('tumors harbor loss', 'Disease', (202, 220))	('tumors harbor loss', 'Disease', 'MESH:C537062', (202, 220))	('p53', 'Gene', '7157', (43, 46))	('inactivating mutations', 'Var', (47, 69))	('p53', 'Gene', (43, 46))	('mutations', 'Var', (233, 242))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))
409310	26568543	p53 is a ubiquitous tumor suppressor which is critically altered in a number of human cancers, with up to two-thirds of HNSCC harboring mutations in exons 5-8.	('p53', 'Gene', (0, 3))	('p53', 'Gene', '7157', (0, 3))	('SCC', 'Gene', (122, 125))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('SCC', 'Gene', '6317', (122, 125))	('ubiquitous tumor', 'Disease', 'MESH:D009369', (9, 25))	('mutations in exons', 'Var', (136, 154))	('human', 'Species', '9606', (80, 85))	('cancers', 'Phenotype', 'HP:0002664', (86, 93))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('cancers', 'Disease', (86, 93))	('ubiquitous tumor', 'Disease', (9, 25))	('cancers', 'Disease', 'MESH:D009369', (86, 93))	('HNSCC', 'Phenotype', 'HP:0012288', (120, 125))
409311	26568543	Mutations in p53 dysregulate the cell cycle and monitoring of genomic integrity, thereby leading to aberrant proliferation, disrupted apoptosis, and defective DNA repair, while the HPV viral oncogene E6 targets p53 for degradation (Figure 1).	('defective', 'NegReg', (149, 158))	('DNA', 'MPA', (159, 162))	('dysregulate', 'Reg', (17, 28))	('p53', 'Gene', (211, 214))	('apoptosis', 'CPA', (134, 143))	('Mutations', 'Var', (0, 9))	('p53', 'Gene', '7157', (211, 214))	('leading to', 'Reg', (89, 99))	('rat', 'Species', '10116', (116, 119))	('p53', 'Gene', (13, 16))	('cell cycle', 'CPA', (33, 43))	('disrupted', 'NegReg', (124, 133))	('p53', 'Gene', '7157', (13, 16))
409312	26568543	Clinically, alterations in p53 function are associated with resistance to radiation and cisplatin-based chemotherapeutics, emphasizing the importance of this master regulator in HNSCC pathogenesis.	('associated', 'Reg', (44, 54))	('HNSCC', 'Phenotype', 'HP:0012288', (178, 183))	('p53', 'Gene', '7157', (27, 30))	('alterations', 'Var', (12, 23))	('rat', 'Species', '10116', (16, 19))	('function', 'MPA', (31, 39))	('SCC', 'Gene', (180, 183))	('cisplatin', 'Chemical', 'MESH:D002945', (88, 97))	('SCC', 'Gene', '6317', (180, 183))	('p53', 'Gene', (27, 30))
409313	26568543	Recent whole exome sequencing analyses have validated these observations in cell lines and in vitro models, confirming that p53 mutations are common in HNSCC with loss of function mutations predominating.	('p53', 'Gene', (124, 127))	('SCC', 'Gene', '6317', (154, 157))	('mutations', 'Var', (128, 137))	('p53', 'Gene', '7157', (124, 127))	('HNSCC', 'Phenotype', 'HP:0012288', (152, 157))	('loss of function', 'NegReg', (163, 179))	('SCC', 'Gene', (154, 157))
409314	26568543	Stransky and collegues analyzed 74 tumor-normal pairs with their analysis suggesting 63% contained mutations or deletions in p53.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('deletions', 'Var', (112, 121))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('contained', 'Reg', (89, 98))	('p53', 'Gene', (125, 128))	('p53', 'Gene', '7157', (125, 128))	('tumor', 'Disease', (35, 40))	('mutations', 'Var', (99, 108))
409315	26568543	Analyses from the Cancer Genome Atlas of 279 HNSCCs identified mutations in p53 in 84% of HPV- tumors, with only 3% (one of 36) of HPV+ tumors containing a p53 mutation (Figure 2).	('mutations', 'Var', (63, 72))	('HPV- tumors', 'Disease', 'MESH:D030361', (90, 101))	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('HPV- tumors', 'Disease', (90, 101))	('SCC', 'Gene', '6317', (47, 50))	('p53', 'Gene', (76, 79))	('p53', 'Gene', '7157', (76, 79))	('HNSCC', 'Phenotype', 'HP:0012288', (45, 50))	('p53', 'Gene', (156, 159))	('p53', 'Gene', '7157', (156, 159))	('HPV+ tumors', 'Disease', (131, 142))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('HPV+ tumors', 'Disease', 'MESH:D030361', (131, 142))	('Cancer', 'Phenotype', 'HP:0002664', (18, 24))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('SCC', 'Gene', (47, 50))
409316	26568543	Similarly, inactivating mutations in the cell cycle regulator CDKN2A were found in 58% of HPV- tumors.	('inactivating mutations', 'Var', (11, 33))	('found', 'Reg', (74, 79))	('HPV- tumors', 'Disease', (90, 101))	('CDKN2A', 'Gene', (62, 68))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('CDKN2A', 'Gene', '1029', (62, 68))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('HPV- tumors', 'Disease', 'MESH:D030361', (90, 101))
409317	26568543	Thus, a major conclusion of these whole exome sequencing analyses has been validating the near universal loss-of-function of p53 and CDKN2A inactivation in smoking/alcohol-related HNSCC.	('SCC', 'Gene', (182, 185))	('inactivation', 'Var', (140, 152))	('HNSCC', 'Phenotype', 'HP:0012288', (180, 185))	('SCC', 'Gene', '6317', (182, 185))	('p53', 'Gene', (125, 128))	('alcohol', 'Chemical', 'MESH:D000438', (164, 171))	('p53', 'Gene', '7157', (125, 128))	('CDKN2A', 'Gene', (133, 139))	('CDKN2A', 'Gene', '1029', (133, 139))	('loss-of-function', 'NegReg', (105, 121))
409318	26568543	The challenge with p53and CDKN2A loss-of-function mutations is reactivation and/or replacing these critical cell cycle regulators.	('CDKN2A', 'Gene', (26, 32))	('mutations', 'Var', (50, 59))	('CDKN2A', 'Gene', '1029', (26, 32))	('p53', 'Gene', (19, 22))	('p53', 'Gene', '7157', (19, 22))	('loss-of-function', 'NegReg', (33, 49))
409321	26568543	Loss of function mutations in TGFbetaR2 as well as in SMAD2 and SMAD4 have been identified.	('TGFbeta', 'Gene', '7040;21803', (30, 37))	('TGFbeta', 'Gene', (30, 37))	('SMAD2', 'Gene', '4087', (54, 59))	('Loss of function', 'NegReg', (0, 16))	('SMAD4', 'Gene', (64, 69))	('mutations', 'Var', (17, 26))	('SMAD2', 'Gene', (54, 59))
409323	26568543	Animal data from mice confirm this complex signaling dichotomy: Conditional deletion of SMAD4 triggers genomic instability through activation of TGFbeta1 and other SMADs, while deletion of TGFbetaR2 acts cooperatively with KRAS to promote metastases.	('TGFbeta1', 'Gene', (145, 153))	('activation', 'PosReg', (131, 141))	('metastases', 'Disease', 'MESH:D009362', (239, 249))	('mice', 'Species', '10090', (17, 21))	('triggers', 'Reg', (94, 102))	('promote', 'PosReg', (231, 238))	('TGFbeta1', 'Gene', '21803', (145, 153))	('deletion', 'Var', (177, 185))	('SMAD4', 'Gene', (88, 93))	('rat', 'Species', '10116', (209, 212))	('TGFbeta', 'Gene', (145, 152))	('metastases', 'Disease', (239, 249))	('TGFbeta', 'Gene', '7040;21803', (189, 196))	('TGFbeta', 'Gene', '7040;21803', (145, 152))	('TGFbeta', 'Gene', (189, 196))	('genomic instability', 'MPA', (103, 122))
409324	26568543	In whole exome sequencing, comparison of mutations by subset analyses of anatomical site revealed unique mutations in TGFbetaR2 in oral cavity tumors, consistent with previous described functions in animal models.	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('tumors', 'Disease', (143, 149))	('tumors', 'Disease', 'MESH:D009369', (143, 149))	('mutations', 'Var', (105, 114))	('TGFbeta', 'Gene', (118, 125))	('oral cavity tumors', 'Phenotype', 'HP:0100649', (131, 149))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('TGFbeta', 'Gene', '7040;21803', (118, 125))
409325	26568543	Given that TGFbeta inhibitors are readily available and already being used in clinical trials for non-small cell lung cancer, colorectal cancer, and prostate cancer, inhibition of these differentiation pathways in HNSCC may be an accessible and exciting avenue for novel therapeutics.	('non-small cell lung cancer', 'Disease', (98, 124))	('TGFbeta', 'Gene', '7040;21803', (11, 18))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('lung cancer', 'Phenotype', 'HP:0100526', (113, 124))	('SCC', 'Gene', '6317', (216, 219))	('colorectal cancer', 'Disease', 'MESH:D015179', (126, 143))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (98, 124))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('SCC', 'Gene', (216, 219))	('colorectal cancer', 'Disease', (126, 143))	('prostate cancer', 'Disease', 'MESH:D011471', (149, 164))	('prostate cancer', 'Phenotype', 'HP:0012125', (149, 164))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (102, 124))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('TGFbeta', 'Gene', (11, 18))	('HNSCC', 'Phenotype', 'HP:0012288', (214, 219))	('prostate cancer', 'Disease', (149, 164))	('inhibition', 'Var', (166, 176))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (98, 124))	('colorectal cancer', 'Phenotype', 'HP:0003003', (126, 143))
409326	26568543	Sequencing data has also provided a rich array of data implicating loss of function mutations in additional pathways of differentiation in HNSCC, defining major new potential therapeutic targets.	('SCC', 'Gene', (141, 144))	('HNSCC', 'Phenotype', 'HP:0012288', (139, 144))	('mutations', 'Var', (84, 93))	('SCC', 'Gene', '6317', (141, 144))	('loss of function', 'NegReg', (67, 83))
409327	26568543	NOTCH1 loss-of-function mutations, for example, were noted in 11-19% of tumors, with another 11-14% containing NOTCH2 or NOTCH3 mutations (Figure 2A).	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('mutations', 'Var', (128, 137))	('loss-of-function', 'NegReg', (7, 23))	('NOTCH2', 'Gene', (111, 117))	('NOTCH3', 'Gene', (121, 127))	('tumors', 'Disease', (72, 78))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('NOTCH3', 'Gene', '4854', (121, 127))	('NOTCH1', 'Gene', '4851', (0, 6))	('NOTCH1', 'Gene', (0, 6))	('NOTCH2', 'Gene', '4853', (111, 117))	('mutations', 'Var', (24, 33))
409328	26568543	Interestingly, these same tumors had mutations in gene sets associated with differentiation such as IRF6 and TP63, implying that these genes may act together with NOTCH1 to ultimately trigger the development of immature, dedifferentiated, highly proliferative basaloid cells.	('NOTCH1', 'Gene', (163, 169))	('trigger', 'Reg', (184, 191))	('TP63', 'Gene', (109, 113))	('TP63', 'Gene', '8626', (109, 113))	('immature', 'CPA', (211, 219))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('rat', 'Species', '10116', (253, 256))	('mutations', 'Var', (37, 46))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('IRF6', 'Gene', (100, 104))	('IRF6', 'Gene', '3664', (100, 104))	('NOTCH1', 'Gene', '4851', (163, 169))	('tumors', 'Disease', (26, 32))
409330	26568543	Thus, dysregulation of programs involving cellular differentiation appears to be a critical component of HNSCC tumor biology.	('HNSCC tumor', 'Disease', 'MESH:D000077195', (105, 116))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('HNSCC tumor', 'Disease', (105, 116))	('dysregulation', 'Var', (6, 19))	('HNSCC', 'Phenotype', 'HP:0012288', (105, 110))
409331	26568543	In addition, inhibition of NOTCH activation has been associated with an increased risk of cutaneous SCC, with a recent phase III trial with the gamma-secretase inhibitor semagacestat halted due to an increased rate of cutaneous SCC in the treatment arm compared to placebo.	('SCC', 'Gene', (100, 103))	('cutaneous', 'Disease', (218, 227))	('inhibition', 'Var', (13, 23))	('SCC', 'Gene', '6317', (100, 103))	('SCC', 'Gene', (228, 231))	('rat', 'Species', '10116', (210, 213))	('SCC', 'Gene', '6317', (228, 231))	('NOTCH', 'Gene', (27, 32))
409333	26568543	Other tumor suppressor pathways have also been identified using unbiased approaches: FAT1, which has well described roles in aberrant Wnt signaling, was mutated in 12-23% of tumors (Figure 2A).	('tumor', 'Disease', (174, 179))	('tumors', 'Disease', (174, 180))	('tumors', 'Disease', 'MESH:D009369', (174, 180))	('mutated', 'Var', (153, 160))	('FAT1', 'Gene', '2195', (85, 89))	('tumor', 'Disease', 'MESH:D009369', (6, 11))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('tumors', 'Phenotype', 'HP:0002664', (174, 180))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('FAT1', 'Gene', (85, 89))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('tumor', 'Disease', (6, 11))
409335	26568543	In addition, FAT1 appears to regulate cell migration and invasiveness (Figure 3), suggesting that there may be multiple effects of FAT1 mutations on HNSCC tumorigenesis.	('FAT1', 'Gene', '2195', (131, 135))	('rat', 'Species', '10116', (46, 49))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('FAT1', 'Gene', (131, 135))	('HNSCC', 'Phenotype', 'HP:0012288', (149, 154))	('FAT1', 'Gene', '2195', (13, 17))	('mutations', 'Var', (136, 145))	('FAT1', 'Gene', (13, 17))	('HNSCC tumor', 'Disease', 'MESH:D000077195', (149, 160))	('effects', 'Reg', (120, 127))	('HNSCC tumor', 'Disease', (149, 160))
409336	26568543	Additional mutations and deletions were identified in apopotosis-related genes (CASP8, DDX3X), histone methyltransferases (PRDM9, EZH2, NSD1) as well as Ajuba, a centrosomal protein that regulates cell division and vertebrate ciliogenesis in an EGFR-RAS-MAPK-dependent manner (Figure 2A and C); however, further work is required to biologically characterize the mechanism and impact of these mutations on tumorigenesis.	('EZH2', 'Gene', (130, 134))	('mutations', 'Var', (11, 20))	('EZH2', 'Gene', '2146', (130, 134))	('EGFR', 'Gene', '1956', (245, 249))	('NSD1', 'Gene', '64324', (136, 140))	('CASP8', 'Gene', '841', (80, 85))	('rat', 'Species', '10116', (221, 224))	('DDX3X', 'Gene', '1654', (87, 92))	('CASP8', 'Gene', (80, 85))	('PRDM9', 'Gene', (123, 128))	('tumor', 'Disease', (405, 410))	('PRDM9', 'Gene', '56979', (123, 128))	('tumor', 'Disease', 'MESH:D009369', (405, 410))	('EGFR', 'Gene', (245, 249))	('NSD1', 'Gene', (136, 140))	('Ajuba', 'Gene', '84962', (153, 158))	('apopotosis', 'Disease', (54, 64))	('Ajuba', 'Gene', (153, 158))	('tumor', 'Phenotype', 'HP:0002664', (405, 410))	('apopotosis', 'Disease', 'None', (54, 64))	('DDX3X', 'Gene', (87, 92))
409337	26568543	Nevertheless, identification of these mutations emphasizes the major role tumor suppressor pathways play in HNSCC pathogenesis.	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('HNSCC', 'Phenotype', 'HP:0012288', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('SCC', 'Gene', (110, 113))	('tumor', 'Disease', (74, 79))	('SCC', 'Gene', '6317', (110, 113))	('mutations', 'Var', (38, 47))
409347	26568543	For example, mutations in the DNA repair gene MSH2 or MLH1 become synthetically lethal when combined with inhibitors of DNA polymerase due to the accumulation of double strand breaks.	('MLH1', 'Gene', '4292', (54, 58))	('MLH1', 'Gene', (54, 58))	('accumulation', 'PosReg', (146, 158))	('double strand breaks', 'MPA', (162, 182))	('MSH2', 'Gene', (46, 50))	('mutations', 'Var', (13, 22))	('MSH2', 'Gene', '4436', (46, 50))
409352	26568543	For example, inhibition of stress-activated p38 mitogen-activated protein kinase MAPKAP kinase 2 (MK2), ATM, and SGK2 or PAK3 may sensitize tumor cells to chemotherapy (MK2, ATM) or induce autophagy (SGK2) or apopotosis (PAK3).	('SGK2', 'Gene', '10110', (200, 204))	('apopotosis', 'Disease', (209, 219))	('MK2', 'Gene', (169, 172))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('p38', 'Gene', (44, 47))	('sensitize', 'Reg', (130, 139))	('ATM', 'Gene', (104, 107))	('MK2', 'Gene', (98, 101))	('chemotherapy', 'CPA', (155, 167))	('autophagy', 'CPA', (189, 198))	('apopotosis', 'Disease', 'None', (209, 219))	('ATM', 'Gene', (174, 177))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('MAPKAP kinase 2', 'Gene', '9261', (81, 96))	('PAK3', 'Gene', (121, 125))	('p38', 'Gene', '1432', (44, 47))	('induce', 'PosReg', (182, 188))	('MK2', 'Gene', '9261', (169, 172))	('SGK2', 'Gene', (113, 117))	('MK2', 'Gene', '9261', (98, 101))	('PAK3', 'Gene', '5063', (121, 125))	('PAK3', 'Gene', (221, 225))	('ATM', 'Gene', '472', (104, 107))	('MAPKAP kinase 2', 'Gene', (81, 96))	('inhibition', 'Var', (13, 23))	('SGK2', 'Gene', (200, 204))	('SGK2', 'Gene', '10110', (113, 117))	('ATM', 'Gene', '472', (174, 177))	('PAK3', 'Gene', '5063', (221, 225))	('tumor', 'Disease', (140, 145))
409353	26568543	Recent computational analyses have identified multiple candidate kinase genes which serve as synthetic lethal partners of p53 mutants including polo-like kinase 1, cyclin-dependent kinase 1, and aurora kinase A.	('aurora', 'Disease', (195, 201))	('cyclin-dependent kinase 1', 'Gene', (164, 189))	('cyclin-dependent kinase 1', 'Gene', '983', (164, 189))	('polo-like kinase 1', 'Gene', '5347', (144, 162))	('p53', 'Gene', '7157', (122, 125))	('polo-like kinase 1', 'Gene', (144, 162))	('mutants', 'Var', (126, 133))	('p53', 'Gene', (122, 125))
409354	26568543	Within head and neck oncology, this approach has been put into practice with an RNAi kinome viability screen in p53 mutant HNSCC cells to identify oncogenes that may be targeted in this mutational context.	('HNSCC', 'Phenotype', 'HP:0012288', (123, 128))	('oncology', 'Phenotype', 'HP:0002664', (21, 29))	('SCC', 'Gene', (125, 128))	('p53', 'Gene', (112, 115))	('mutant', 'Var', (116, 122))	('head and neck oncology', 'Phenotype', 'HP:0012288', (7, 29))	('SCC', 'Gene', '6317', (125, 128))	('p53', 'Gene', '7157', (112, 115))
409357	26568543	This inhibitor is now part of a phase I clinical trial to determine whether it may be useful in combination with neoadjuvant weekly docetaxel and cisplatin prior to surgery in p53 mutant HNSCC.	('SCC', 'Gene', (189, 192))	('p53', 'Gene', (176, 179))	('cisplatin', 'Chemical', 'MESH:D002945', (146, 155))	('mutant', 'Var', (180, 186))	('p53', 'Gene', '7157', (176, 179))	('SCC', 'Gene', '6317', (189, 192))	('HNSCC', 'Phenotype', 'HP:0012288', (187, 192))	('docetaxel', 'Chemical', 'MESH:D000077143', (132, 141))
409359	26568543	In vitro studies have identified a role for EGFR signaling in HNSCC, but sequencing analyses suggest only 6% of HPV- and 15% of HPV+ contain mutations or amplification of EGFR (Figure 2B).	('EGFR', 'Gene', (171, 175))	('HNSCC', 'Phenotype', 'HP:0012288', (62, 67))	('mutations', 'Var', (141, 150))	('SCC', 'Gene', '6317', (64, 67))	('amplification', 'Var', (154, 167))	('EGFR', 'Gene', '1956', (44, 48))	('EGFR', 'Gene', (44, 48))	('EGFR', 'Gene', '1956', (171, 175))	('SCC', 'Gene', (64, 67))
409361	26568543	In HNSCC, candidate sequencing studies have shown that EGFR is overexpressed most commonly through gene amplification and increased copy number, rather than activating mutations or truncation mutants such as EGFRvIII.	('SCC', 'Gene', '6317', (5, 8))	('EGFR', 'Gene', '1956', (55, 59))	('overexpressed', 'PosReg', (63, 76))	('HNSCC', 'Phenotype', 'HP:0012288', (3, 8))	('copy', 'MPA', (132, 136))	('EGFR', 'Gene', (55, 59))	('EGFR', 'Gene', '1956', (208, 212))	('SCC', 'Gene', (5, 8))	('EGFR', 'Gene', (208, 212))	('increased', 'PosReg', (122, 131))	('gene amplification', 'Var', (99, 117))	('rat', 'Species', '10116', (145, 148))
409367	26568543	These findings suggest that other mechanisms may be activated upon EGFR inhibition or redundant activators of cell survival may limit treatment efficacy, consistent with whole exome studies suggesting oncogenes have low mutant allele frequencies and rarely drive HNSCC (Figure 2C).	('SCC', 'Gene', (265, 268))	('SCC', 'Gene', '6317', (265, 268))	('drive', 'Reg', (257, 262))	('HNSCC', 'Phenotype', 'HP:0012288', (263, 268))	('inhibition', 'Var', (72, 82))	('EGFR', 'Gene', '1956', (67, 71))	('EGFR', 'Gene', (67, 71))	('limit', 'NegReg', (128, 133))
409369	26568543	One exception for targeted therapy may be activating Ras or PI3K mutations which occur at higher frequency in HPV+ cancers, offering a specific context in which targeted therapy may facilitate de-intensification of chemoradiation.	('PI3', 'Gene', '5266', (60, 63))	('cancers', 'Phenotype', 'HP:0002664', (115, 122))	('HPV+ cancers', 'Disease', (110, 122))	('activating', 'PosReg', (42, 52))	('PI3', 'Gene', (60, 63))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('HPV+ cancers', 'Disease', 'MESH:D030361', (110, 122))	('Ras', 'Gene', (53, 56))	('mutations', 'Var', (65, 74))
409370	26568543	PI3K signaling is frequently altered in HNSCC through several mechanisms including: loss of function mutations in PTEN which negatively regulate PI3K (40% of HNSCC) and activating mutations in PI3KCA (6-11% of HNSCC).	('loss of function', 'NegReg', (84, 100))	('SCC', 'Gene', (212, 215))	('PI3', 'Gene', (145, 148))	('PI3', 'Gene', (193, 196))	('HNSCC', 'Phenotype', 'HP:0012288', (210, 215))	('PI3', 'Gene', '5266', (0, 3))	('SCC', 'Gene', '6317', (42, 45))	('SCC', 'Gene', '6317', (160, 163))	('mutations', 'Var', (101, 110))	('SCC', 'Gene', (42, 45))	('PTEN', 'Gene', (114, 118))	('SCC', 'Gene', (160, 163))	('altered', 'Reg', (29, 36))	('HNSCC', 'Phenotype', 'HP:0012288', (40, 45))	('PI3', 'Gene', (0, 3))	('HNSCC', 'Phenotype', 'HP:0012288', (158, 163))	('negatively', 'NegReg', (125, 135))	('SCC', 'Gene', '6317', (212, 215))	('PTEN', 'Gene', '5728', (114, 118))	('PI3', 'Gene', '5266', (145, 148))	('PI3', 'Gene', '5266', (193, 196))
409371	26568543	Recent data suggests that the PTEN gene may exhibit a gene dosage effect, with loss of a single allele promoting tumor growth.	('tumor', 'Disease', (113, 118))	('loss', 'Var', (79, 83))	('promoting', 'PosReg', (103, 112))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('PTEN', 'Gene', (30, 34))	('PTEN', 'Gene', '5728', (30, 34))
409372	26568543	Interestingly, in the case PI3KCA, mutations may be associated with HPV+ OPSCC, raising the possibility that PI3K acts synergistically with HPV E6 and E7 proteins in this HNSCC subset.	('PI3', 'Gene', '5266', (109, 112))	('SCC', 'Gene', '6317', (75, 78))	('PI3', 'Gene', '5266', (27, 30))	('associated', 'Reg', (52, 62))	('PI3', 'Gene', (109, 112))	('SCC', 'Gene', (173, 176))	('HNSCC', 'Phenotype', 'HP:0012288', (171, 176))	('SCC', 'Gene', (75, 78))	('PI3', 'Gene', (27, 30))	('SCC', 'Gene', '6317', (173, 176))	('mutations', 'Var', (35, 44))
409374	26568543	While KRAS is frequently mutated in other cancers, HNSCC is associated primarily with HRAS mutations especially in patients with extensive tobacco exposure.	('cancers', 'Disease', (42, 49))	('SCC', 'Gene', '6317', (53, 56))	('patients', 'Species', '9606', (115, 123))	('tobacco', 'Species', '4097', (139, 146))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('HRAS', 'Gene', '3265', (86, 90))	('HNSCC', 'Phenotype', 'HP:0012288', (51, 56))	('HRAS', 'Gene', (86, 90))	('mutations', 'Var', (91, 100))	('cancers', 'Phenotype', 'HP:0002664', (42, 49))	('SCC', 'Gene', (53, 56))	('cancers', 'Disease', 'MESH:D009369', (42, 49))	('associated', 'Reg', (60, 70))
409375	26568543	Like PI3K, HRAS mutations are also associated with HPV+ tumors.	('HRAS', 'Gene', '3265', (11, 15))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('PI3', 'Gene', '5266', (5, 8))	('associated', 'Reg', (35, 45))	('mutations', 'Var', (16, 25))	('PI3', 'Gene', (5, 8))	('HPV+ tumors', 'Disease', 'MESH:D030361', (51, 62))	('HRAS', 'Gene', (11, 15))	('HPV+ tumors', 'Disease', (51, 62))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))
409377	26568543	Recent sequencing analyses have validated these in vitro observations identifying amplifications or mutations (specifically the exon 9 helical domain) of PI3K in 56% of HPV+ HNSCC and 34% of HPV- tumors (Figure 2B).	('mutations', 'Var', (100, 109))	('PI3', 'Gene', '5266', (154, 157))	('tumors', 'Phenotype', 'HP:0002664', (196, 202))	('HPV- tumors', 'Disease', 'MESH:D030361', (191, 202))	('amplifications', 'Var', (82, 96))	('PI3', 'Gene', (154, 157))	('SCC', 'Gene', (176, 179))	('HPV- tumors', 'Disease', (191, 202))	('SCC', 'Gene', '6317', (176, 179))	('HNSCC', 'Phenotype', 'HP:0012288', (174, 179))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))
409378	26568543	Activating mutations in HRAS were also described in 5-8% of HNSCC tumors (Figure 2A).	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('HNSCC tumors', 'Disease', (60, 72))	('HRAS', 'Gene', (24, 28))	('Activating mutations', 'Var', (0, 20))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('HNSCC tumors', 'Disease', 'MESH:D000077195', (60, 72))	('HNSCC', 'Phenotype', 'HP:0012288', (60, 65))	('HRAS', 'Gene', '3265', (24, 28))
409382	26568543	We now know that HPV- cancers are those that are driven by traditional risk factors such as smoking and alcohol, with carcinogenesis dependent on the acquisition of multiple epigenetic and genetic alterations yielding a premalignant progenitor which then undergoes additional alterations to become an invasive malignancy.	('carcinogenesis', 'Disease', (118, 132))	('genetic alterations', 'Var', (189, 208))	('rat', 'Species', '10116', (201, 204))	('cancers', 'Phenotype', 'HP:0002664', (22, 29))	('HPV- cancers', 'Disease', 'MESH:D030361', (17, 29))	('rat', 'Species', '10116', (280, 283))	('malignancy', 'Disease', 'MESH:D009369', (310, 320))	('malignancy', 'Disease', (310, 320))	('epigenetic', 'Var', (174, 184))	('HPV- cancers', 'Disease', (17, 29))	('alcohol', 'Chemical', 'MESH:D000438', (104, 111))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('carcinogenesis', 'Disease', 'MESH:D063646', (118, 132))
409387	26568543	In contrast, HPV+ tumors are driven by HPV infection, usually by serotype16, with the integration of viral DNA into the host genome and the activation of specific and consistent molecular regulators including p16 (INK4A) and viral proteins E6 and E7 (Figure 1).	('HPV+ tumors', 'Disease', 'MESH:D030361', (13, 24))	('HPV infection', 'Disease', (39, 52))	('HPV+ tumors', 'Disease', (13, 24))	('rat', 'Species', '10116', (91, 94))	('serotype16', 'Var', (65, 75))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('HPV infection', 'Disease', 'MESH:D030361', (39, 52))	('p16', 'Var', (209, 212))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
409388	26568543	Cell lines transfected with p16 and the alternate transcript p14arf displayed markedly inhibited growth, arresting in G1consistent with a role for p16 in blocking the G1-S transition.	('p14', 'Gene', (61, 64))	('G1-S transition', 'CPA', (167, 182))	('p14', 'Gene', '1029', (61, 64))	('p16', 'Var', (28, 31))	('arrest', 'Disease', 'MESH:D006323', (105, 111))	('inhibited', 'NegReg', (87, 96))	('G1consistent', 'CPA', (118, 130))	('growth', 'MPA', (97, 103))	('arrest', 'Disease', (105, 111))
409389	26568543	Indeed, transfection of p16-INK4A adenovirus demonstrated a 96% reduction in proliferation of HNSCC cell lines and in vivo studies in nude mice showed a significant decline in xenograft tumor growth.	('rat', 'Species', '10116', (52, 55))	('p16-INK4A', 'Var', (24, 33))	('SCC', 'Gene', (96, 99))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('rat', 'Species', '10116', (84, 87))	('xenograft tumor', 'Disease', 'MESH:D009369', (176, 191))	('HNSCC', 'Phenotype', 'HP:0012288', (94, 99))	('nude mice', 'Species', '10090', (134, 143))	('SCC', 'Gene', '6317', (96, 99))	('reduction', 'NegReg', (64, 73))	('xenograft tumor', 'Disease', (176, 191))	('decline', 'NegReg', (165, 172))
409392	26568543	There is also growing evidence that tumor-immune interactions may explain the improved response of HPV+ tumors: HPV positivity is associated with a more substantial lymphocyte response and animal models suggest that immunocompetence is essential for complete tumor eradication.	('positivity', 'Var', (116, 126))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumor', 'Disease', 'MESH:D009369', (259, 264))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('tumor', 'Disease', (104, 109))	('lymphocyte response', 'CPA', (165, 184))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (259, 264))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumor', 'Disease', (259, 264))	('HPV+ tumors', 'Disease', 'MESH:D030361', (99, 110))	('tumor', 'Disease', (36, 41))	('HPV+ tumors', 'Disease', (99, 110))
409397	26568543	At the level of individual genes, recent whole exome sequencing studies suggest that HPV+ tumors have infrequent mutations in p53 and CDKN2A in stark contrast to HPV- tumors where these genes are commonly altered.	('p53', 'Gene', '7157', (126, 129))	('HPV- tumors', 'Disease', 'MESH:D030361', (162, 173))	('HPV+ tumors', 'Disease', 'MESH:D030361', (85, 96))	('HPV- tumors', 'Disease', (162, 173))	('CDKN2A', 'Gene', (134, 140))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumors', 'Phenotype', 'HP:0002664', (167, 173))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('mutations', 'Var', (113, 122))	('CDKN2A', 'Gene', '1029', (134, 140))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('p53', 'Gene', (126, 129))	('HPV+ tumors', 'Disease', (85, 96))
409398	26568543	Interestingly, HPV+ are distinguished by recurrent deletions and truncation mutations in TNF receptor-associated factor 3 (TRAF3), which has been implicated in innate and acquired viral response to EBV, HPV, and HIV.	('TRAF3', 'Gene', '7187', (123, 128))	('truncation mutations', 'Var', (65, 85))	('TNF receptor-associated factor 3', 'Gene', '7187', (89, 121))	('TRAF3', 'Gene', (123, 128))	('deletions', 'Var', (51, 60))	('TNF receptor-associated factor 3', 'Gene', (89, 121))
409399	26568543	Loss of TRAF3 promotes aberrant NFkappaB signaling with diverse downstream effects on cytokine signaling and cell death.	('NFkappaB', 'Gene', '4790', (32, 40))	('TRAF3', 'Gene', (8, 13))	('cytokine signaling', 'MPA', (86, 104))	('promotes', 'PosReg', (14, 22))	('TRAF3', 'Gene', '7187', (8, 13))	('Loss', 'Var', (0, 4))	('NFkappaB', 'Gene', (32, 40))
409407	26568543	For example, we have defined a mutant allele tumor heterogeneity (MATH) score which is defined as the ratio of the width to the center of the distribution of mutant-allele fractions at tumor-specific mutated loci (Figure 4A).	('tumor', 'Disease', (185, 190))	('mutant', 'Var', (31, 37))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumor', 'Disease', (45, 50))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('rat', 'Species', '10116', (102, 105))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
409408	26568543	MATH scores were calculated for 74 HNSCC with publicly available next-generation sequencing data, revealing higher scores in three well-established patient cohorts with poor outcomes, namely tumors with inactivating mutations in TP53 (compared to wildtype or non-disruptive mutations), HPV- tumors (compared to HPV+ tumors), and HPV- tumors from smokers with higher pack-years of smoking.	('inactivating mutations', 'Var', (203, 225))	('SCC', 'Gene', '6317', (37, 40))	('tumor', 'Phenotype', 'HP:0002664', (334, 339))	('tumors', 'Phenotype', 'HP:0002664', (316, 322))	('tumors', 'Disease', (334, 340))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('SCC', 'Gene', (37, 40))	('tumors', 'Disease', (191, 197))	('tumors', 'Phenotype', 'HP:0002664', (291, 297))	('HNSCC', 'Phenotype', 'HP:0012288', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (316, 321))	('HPV- tumors', 'Disease', 'MESH:D030361', (286, 297))	('tumors', 'Disease', 'MESH:D009369', (334, 340))	('TP53', 'Gene', '7157', (229, 233))	('tumors', 'Disease', (316, 322))	('tumor', 'Phenotype', 'HP:0002664', (291, 296))	('tumors', 'Disease', 'MESH:D009369', (191, 197))	('HPV+ tumors', 'Disease', 'MESH:D030361', (311, 322))	('higher', 'PosReg', (108, 114))	('tumors', 'Disease', (291, 297))	('tumors', 'Phenotype', 'HP:0002664', (191, 197))	('HPV- tumors', 'Disease', (286, 297))	('HPV- tumors', 'Disease', 'MESH:D030361', (329, 340))	('tumors', 'Disease', 'MESH:D009369', (316, 322))	('patient', 'Species', '9606', (148, 155))	('tumors', 'Disease', 'MESH:D009369', (291, 297))	('rat', 'Species', '10116', (74, 77))	('tumors', 'Phenotype', 'HP:0002664', (334, 340))	('HPV- tumors', 'Disease', (329, 340))	('TP53', 'Gene', (229, 233))	('HPV+ tumors', 'Disease', (311, 322))
409412	26568543	Tumor MATH scores were calculated based on whole-exome sequencing data, revealing a substantiating association between high MATH scores and decreased overall survival (hazard ratio of 2.2 for high vs. low heterogeneity).	('decreased', 'NegReg', (140, 149))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('high MATH scores', 'Var', (119, 135))	('overall survival', 'MPA', (150, 166))	('rat', 'Species', '10116', (175, 178))
409429	26568543	EDNRB hypermethylation was found in 10% of HNSCC patients (compared to 0% in controls), while DCC hypermethylation and p16 hypermethylation were rarely detected.	('DCC', 'Gene', (94, 97))	('hypermethylation', 'Var', (6, 22))	('EDNRB', 'Gene', (0, 5))	('SCC', 'Gene', (45, 48))	('HNSCC', 'Phenotype', 'HP:0012288', (43, 48))	('DCC', 'Gene', '1630', (94, 97))	('SCC', 'Gene', '6317', (45, 48))	('EDNRB', 'Gene', '1910', (0, 5))	('patients', 'Species', '9606', (49, 57))	('found', 'Reg', (27, 32))
409430	26568543	Thus, EDNRB hypermethylation may be a highly specific albeit insensitive biomarker for HNSCC.	('HNSCC', 'Phenotype', 'HP:0012288', (87, 92))	('EDNRB', 'Gene', (6, 11))	('SCC', 'Gene', '6317', (89, 92))	('hypermethylation', 'Var', (12, 28))	('EDNRB', 'Gene', '1910', (6, 11))	('SCC', 'Gene', (89, 92))
409435	26568543	Based on their analyses, patients with low EGFR, high HPV/p16, or low p53 with low Bcl-XL have improved overall survival and disease-free survival.	('overall survival', 'CPA', (104, 120))	('p53', 'Gene', (70, 73))	('p53', 'Gene', '7157', (70, 73))	('low', 'Var', (39, 42))	('EGFR', 'Gene', '1956', (43, 47))	('patients', 'Species', '9606', (25, 33))	('improved', 'PosReg', (95, 103))	('high HPV/p16', 'Var', (49, 61))	('disease-free survival', 'CPA', (125, 146))	('Bcl-XL', 'Gene', '598', (83, 89))	('EGFR', 'Gene', (43, 47))	('Bcl-XL', 'Gene', (83, 89))
409443	26568543	There is now growing evidence that dysregulation of miRNAs through direct genetic mutation, epigenetic changes, modifications in biogenesis, altered transcription factor expression, or changes in target sites may contribute to tumor progression.	('epigenetic changes', 'Var', (92, 110))	('transcription factor expression', 'MPA', (149, 180))	('altered', 'Reg', (141, 148))	('tumor', 'Disease', (227, 232))	('contribute', 'Reg', (213, 223))	('miRNAs', 'Protein', (52, 58))	('changes', 'Reg', (185, 192))	('modifications', 'Reg', (112, 125))	('dysregulation', 'Var', (35, 48))	('tumor', 'Disease', 'MESH:D009369', (227, 232))	('biogenesis', 'MPA', (129, 139))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))
409446	26568543	In contrast, miR-99 dysregulation and downregulation promotes OSCC survival through likely regulation of mTOR signaling, consistent with a tumor suppressor function.	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('promotes', 'PosReg', (53, 61))	('SCC', 'Gene', (63, 66))	('downregulation', 'NegReg', (38, 52))	('tumor', 'Disease', (139, 144))	('dysregulation', 'Var', (20, 33))	('SCC', 'Gene', '6317', (63, 66))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('miR-99', 'Gene', (13, 19))	('mTOR signaling', 'MPA', (105, 119))	('regulation', 'Reg', (91, 101))
409449	26568543	These analyses identified decreased expression of Let-7c-5p and miR-100-5p in tumors compared to normal tissue, with a corresponding association with increased target gene expression of the cell cycle protein CDK6, transcription elongation factor E2F1, mitosis protein PLK1, and transcription factor HMGA2.	('mitosis', 'Disease', (253, 260))	('CDK6', 'Gene', (209, 213))	('miR-100-5p', 'Var', (64, 74))	('E2F1', 'Gene', '1869', (247, 251))	('PLK1', 'Gene', '5347', (269, 273))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('decreased', 'NegReg', (26, 35))	('HMGA2', 'Gene', (300, 305))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('mitosis', 'Disease', 'None', (253, 260))	('tumors', 'Disease', (78, 84))	('Let-7c-5p', 'Var', (50, 59))	('HMGA2', 'Gene', '8091', (300, 305))	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('PLK1', 'Gene', (269, 273))	('expression', 'MPA', (172, 182))	('CDK6', 'Gene', '1021', (209, 213))	('E2F1', 'Gene', (247, 251))	('increased', 'PosReg', (150, 159))	('expression', 'MPA', (36, 46))
409453	26568543	For example, p53 mutations, CDKN2A loss-of-function mutations, chr 3q amplification, changes in oxidative stress genes, and heavy smoking were associated with the classical subtype, while NOTCH1 mutations and HRAS-CASP8 co-mutations were associated with the basal subtype, suggesting that disrupted cell death is a common findings in this latter subtype.	('mutations', 'Var', (52, 61))	('HRAS', 'Gene', (209, 213))	('changes', 'Reg', (85, 92))	('loss-of-function', 'NegReg', (35, 51))	('p53', 'Gene', '7157', (13, 16))	('oxidative stress', 'Phenotype', 'HP:0025464', (96, 112))	('NOTCH1', 'Gene', '4851', (188, 194))	('CDKN2A', 'Gene', (28, 34))	('NOTCH1', 'Gene', (188, 194))	('mutations', 'Var', (17, 26))	('HRAS', 'Gene', '3265', (209, 213))	('p53', 'Gene', (13, 16))	('CDKN2A', 'Gene', '1029', (28, 34))	('classical', 'Disease', (163, 172))	('oxidative stress genes', 'MPA', (96, 118))	('basal', 'Disease', (258, 263))	('CASP8', 'Gene', (214, 219))	('CASP8', 'Gene', '841', (214, 219))
409454	26568543	The atypical subtype lacked chr 7 amplifications, and the mesenchymal subtype had mutations in genes involved in innate immunity such as CD56.	('CD56', 'Gene', (137, 141))	('chr', 'Protein', (28, 31))	('lacked', 'NegReg', (21, 27))	('mutations', 'Var', (82, 91))	('CD56', 'Gene', '4684', (137, 141))	('mesenchymal', 'CPA', (58, 69))
409455	26568543	In addition, TCGA has also leveraged unsupervised clustering analysis of copy number alterations (CNAs) to delineate additional HNSCC cohorts.	('SCC', 'Gene', (130, 133))	('SCC', 'Gene', '6317', (130, 133))	('HNSCC', 'Phenotype', 'HP:0012288', (128, 133))	('rat', 'Species', '10116', (89, 92))	('copy', 'Var', (73, 77))
409456	26568543	For example, this group describes an "M" class of tumors, which is driven primarily by mutations rather than CNAs.	('rat', 'Species', '10116', (97, 100))	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('tumors', 'Disease', (50, 56))	('mutations', 'Var', (87, 96))
409457	26568543	This cohort consists of a subset of oral cavity tumors with a characteristic three gene pattern of HRAS activating mutations, inactivating CASP8 mutations, and wild type p53.	('HRAS', 'Gene', (99, 103))	('mutations', 'Var', (145, 154))	('tumors', 'Disease', (48, 54))	('tumors', 'Disease', 'MESH:D009369', (48, 54))	('oral cavity tumors', 'Phenotype', 'HP:0100649', (36, 54))	('p53', 'Gene', (170, 173))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('activating', 'PosReg', (104, 114))	('p53', 'Gene', '7157', (170, 173))	('inactivating', 'Var', (126, 138))	('CASP8', 'Gene', (139, 144))	('HRAS', 'Gene', '3265', (99, 103))	('CASP8', 'Gene', '841', (139, 144))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
409458	26568543	This cohort had a more favorable clinical outcome with what appears to be an alternative tumorigenesis pathway involving Ras and alterations in cell death/NFkappaB.	('rat', 'Species', '10116', (133, 136))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('Ras', 'Protein', (121, 124))	('NFkappaB', 'Gene', (155, 163))	('alterations', 'Var', (129, 140))	('NFkappaB', 'Gene', '4790', (155, 163))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
409465	26568543	There has been recent interest in epigenetic changes, including histone modification, as a driver of tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('epigenetic changes', 'Var', (34, 52))	('histone modification', 'Var', (64, 84))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
409466	26568543	Epigenetic changes have been touted as a major method for tumor resistance to chemotherapy, with cancer stem cells serving as a depot of self-renewing and self-propagating cells that may underlie treatment resistance.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('cancer', 'Disease', (97, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('Epigenetic changes', 'Var', (0, 18))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
409478	26568543	They found that tumors with more CD3 cells tended to have decreased rates of metastasis; however, multivariate analyses suggested that the difference was only statistically significant for HPV+ tumors.	('tumors', 'Disease', (16, 22))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('HPV+ tumors', 'Disease', 'MESH:D030361', (189, 200))	('decreased', 'NegReg', (58, 67))	('HPV+ tumors', 'Disease', (189, 200))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('metastasis', 'CPA', (77, 87))	('tumors', 'Disease', 'MESH:D009369', (16, 22))	('tumors', 'Disease', 'MESH:D009369', (194, 200))	('rat', 'Species', '10116', (68, 71))	('tumors', 'Phenotype', 'HP:0002664', (194, 200))	('tumors', 'Disease', (194, 200))	('CD3 cells', 'Var', (33, 42))
409508	26568543	Most mutations identified based on sequencing analyses are loss of function mutations in known and putative tumor suppressor genes that may require novel approaches such as synthetic lethality.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('loss of function', 'NegReg', (59, 75))	('mutations', 'Var', (5, 14))	('tumor', 'Disease', (108, 113))
409509	26568543	One exception for targeted therapy may be activating Ras or PI3K mutations which occur at high frequency in HPV+ cancers, offering a potential avenue for therapy that may facilitate deintensification of chemoradiation therapy.	('HPV+ cancers', 'Disease', (108, 120))	('PI3', 'Gene', '5266', (60, 63))	('activating', 'PosReg', (42, 52))	('PI3', 'Gene', (60, 63))	('cancers', 'Phenotype', 'HP:0002664', (113, 120))	('HPV+ cancers', 'Disease', 'MESH:D030361', (108, 120))	('Ras', 'Protein', (53, 56))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('mutations', 'Var', (65, 74))
409510	26568543	Identification of genes implicated in tumor-immune interactions as well as loss of function mutations suggest that immunotherapy and modulation of immune surveillance may be a valuable therapeutic approach, supporting ongoing immunotherapy clinical trials.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('loss of function', 'NegReg', (75, 91))	('mutations', 'Var', (92, 101))	('tumor', 'Disease', 'MESH:D009369', (38, 43))
409568	33213447	Unexpectedly, a number of alterations in basal-like breast cancer were identified that distinguished it from other subtypes, which could bring future clinical benefits.	('breast cancer', 'Disease', 'MESH:D001943', (52, 65))	('fits', 'Disease', 'MESH:D012640', (163, 167))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('breast cancer', 'Disease', (52, 65))	('alterations', 'Var', (26, 37))	('breast cancer', 'Phenotype', 'HP:0003002', (52, 65))	('fits', 'Disease', (163, 167))
409572	33213447	It postulates that carcinogenesis is determined by alterations in cancer regulatory genes, of which two crucial groups are tumor suppressors and oncogenes, both responsible for apoptosis and proliferation regulation being utmost importance in the model of cancer platform.	('alterations', 'Var', (51, 62))	('tumor', 'Disease', (123, 128))	('carcinogenesis', 'Disease', (19, 33))	('cancer', 'Disease', 'MESH:D009369', (256, 262))	('cancer', 'Phenotype', 'HP:0002664', (256, 262))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('cancer', 'Disease', (256, 262))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('cancer', 'Disease', (66, 72))
409579	33213447	GCCN3/4GGC, GCCN3/4GGG or CCCCAGGC while the binding of transcription factors' themselves is dictated by a proline-rich motif located in the activation domain (excluding AP-2delta, which lacks these critical residues).	('GGC', 'Gene', (7, 10))	('AP-2delta', 'Gene', (170, 179))	('binding', 'Interaction', (45, 52))	('GGC', 'Gene', (31, 34))	('GGC', 'Gene', '79017', (7, 10))	('GGC', 'Gene', '79017', (31, 34))	('AP-2delta', 'Gene', '83741', (170, 179))	('proline', 'Chemical', 'MESH:D011392', (107, 114))	('dictated by', 'Reg', (93, 104))	('GCCN3/4GGG', 'Var', (12, 22))
409582	33213447	It was suggested that in the case of mutation, the loss of TF activity of AP-2 members can lead to the impairment of proliferation, differentiation and apoptosis processes, suggesting AP-2 activity may play role in development.	('impairment', 'NegReg', (103, 113))	('AP-2', 'Gene', '7020', (184, 188))	('proliferation', 'CPA', (117, 130))	('mutation', 'Var', (37, 45))	('activity', 'MPA', (62, 70))	('apoptosis processes', 'CPA', (152, 171))	('AP-2', 'Gene', '7020', (74, 78))	('AP-2', 'Gene', (184, 188))	('AP-2', 'Gene', (74, 78))	('loss', 'NegReg', (51, 55))
409586	33213447	The other case of chemoresistance (to 5-fluorouracil) was shown in colorectal cancer upregulating AP-2gamma while endometrial cancer example demonstrated that knockdown of this AP-2 member sensitizes cells to megestrol acetate via Estrogen receptor alpha (ERalpha) expression upregulation.	('AP-2', 'Gene', (98, 102))	('megestrol acetate', 'Chemical', 'MESH:D019290', (209, 226))	('upregulating', 'PosReg', (85, 97))	('AP-2', 'Gene', (177, 181))	('ERalpha', 'Gene', '2099', (256, 263))	('AP-2gamma', 'Gene', '7022', (98, 107))	('AP-2gamma', 'Gene', (98, 107))	('upregulation', 'PosReg', (276, 288))	('AP-2', 'Gene', '7020', (98, 102))	('colorectal cancer', 'Phenotype', 'HP:0003003', (67, 84))	('Estrogen receptor alpha', 'Gene', '2099', (231, 254))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('AP-2', 'Gene', '7020', (177, 181))	('Estrogen receptor alpha', 'Gene', (231, 254))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (38, 52))	('endometrial cancer', 'Phenotype', 'HP:0012114', (114, 132))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('sensitizes', 'Reg', (189, 199))	('knockdown', 'Var', (159, 168))	('endometrial cancer', 'Disease', (114, 132))	('colorectal cancer', 'Disease', 'MESH:D015179', (67, 84))	('endometrial cancer', 'Disease', 'MESH:D016889', (114, 132))	('ERalpha', 'Gene', (256, 263))	('colorectal cancer', 'Disease', (67, 84))
409593	33213447	Latest data regarding contribution in cancer indicates that AP-2beta overexpression has been found to promote tumor growth in both breast and thyroid cancer and predicted poor prognosis or tumor progression, respectively.	('tumor', 'Disease', (189, 194))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('thyroid cancer', 'Phenotype', 'HP:0002890', (142, 156))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('overexpression', 'Var', (69, 83))	('tumor', 'Disease', (110, 115))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('promote', 'PosReg', (102, 109))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('cancer', 'Disease', (150, 156))	('AP-2beta', 'Gene', (60, 68))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('cancer', 'Disease', (38, 44))	('breast and thyroid cancer', 'Disease', 'MESH:D001943', (131, 156))	('AP-2beta', 'Gene', '7021', (60, 68))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
409661	33213447	Among the others, signaling pathways such as Wnt, Notch (for KIRP) or ERBB (for BRCA) were implicated in explanation which is coherent with other research.	('BRCA', 'Gene', '672', (80, 84))	('ERBB', 'Gene', '1956', (70, 74))	('BRCA', 'Gene', (80, 84))	('Notch', 'Var', (50, 55))	('ERBB', 'Gene', (70, 74))
409672	33213447	Nevertheless, the tumors could be distinguished using modules 2, 11 and 19 which included genes related to cell adhesion, regulation of cell cycle arrest and inactivation of MAPK activity.	('activity', 'MPA', (179, 187))	('arrest', 'Disease', (147, 153))	('MAPK', 'Gene', (174, 178))	('inactivation', 'Var', (158, 170))	('tumors', 'Disease', (18, 24))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('arrest', 'Disease', 'MESH:D006323', (147, 153))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
409682	33213447	The last mentioned might be supported by a threefold difference in the frequency of EGFR mutations between LUSC and LUAD during a previous pan-cancer analysis.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('EGFR', 'Gene', '1956', (84, 88))	('mutations', 'Var', (89, 98))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('cancer', 'Disease', (143, 149))	('EGFR', 'Gene', (84, 88))
409703	31097696	To systematically investigate the role of fusions in tumour cell fitness, we utilized RNA-sequencing data from 1011 human cancer cell lines to functionally link 8354 fusion events with genomic data, sensitivity to >350 anti-cancer drugs and CRISPR-Cas9 loss-of-fitness effects.	('8354', 'Var', (161, 165))	('tumour cell fitness', 'Disease', (53, 72))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (224, 230))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('tumour', 'Phenotype', 'HP:0002664', (53, 59))	('loss-of-fitness effects', 'NegReg', (253, 276))	('tumour cell fitness', 'Disease', 'MESH:D012640', (53, 72))	('cancer', 'Disease', (224, 230))	('human', 'Species', '9606', (116, 121))
409706	31097696	In addition, recurrent YAP1-MAML2 fusions were identified as activators of Hippo-pathway signaling in multiple cancer types.	('Hippo-pathway signaling', 'Pathway', (75, 98))	('MAML2', 'Gene', '84441', (28, 33))	('MAML2', 'Gene', (28, 33))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('fusions', 'Var', (34, 41))	('activators', 'PosReg', (61, 71))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('YAP1', 'Gene', (23, 27))	('YAP1', 'Gene', '10413', (23, 27))
409708	31097696	Gene fusions are observed in many cancers but their link to tumour fitness is largely unknown.	('tumour fitness', 'Disease', (60, 74))	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('Gene fusions', 'Var', (0, 12))	('observed', 'Reg', (17, 25))	('tumour fitness', 'Disease', 'MESH:D012640', (60, 74))	('cancers', 'Phenotype', 'HP:0002664', (34, 41))	('cancers', 'Disease', (34, 41))	('tumour', 'Phenotype', 'HP:0002664', (60, 66))	('cancers', 'Disease', 'MESH:D009369', (34, 41))
409709	31097696	Here, transcriptomic analysis combined with pharmacological and CRISPR-Cas9 screening of cancer cell lines was used to evaluate the functional linkage between fusions and tumour fitness.	('fusions', 'Var', (159, 166))	('tumour', 'Phenotype', 'HP:0002664', (171, 177))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('tumour fitness', 'Disease', 'MESH:D012640', (171, 185))	('cancer', 'Disease', (89, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('tumour fitness', 'Disease', (171, 185))
409711	31097696	Critically, the chimeric protein encoded by fusions may be a tumour-specific target for treatment, resulting in significant clinical benefit for patients.	('patients', 'Species', '9606', (145, 153))	('tumour', 'Disease', 'MESH:D009369', (61, 67))	('fusions', 'Var', (44, 51))	('tumour', 'Disease', (61, 67))	('clinical', 'MPA', (124, 132))	('tumour', 'Phenotype', 'HP:0002664', (61, 67))	('benefit', 'PosReg', (133, 140))
409712	31097696	The exchange of coding or regulatory sequences between genes can result in aberrant functionality of the fusion protein, and deregulation of the partner genes, including overexpression of oncogenes and decreased expression of tumour suppressor genes (TSGs).	('deregulation', 'MPA', (125, 137))	('tumour', 'Phenotype', 'HP:0002664', (226, 232))	('functionality', 'MPA', (84, 97))	('decreased', 'NegReg', (202, 211))	('expression', 'MPA', (212, 222))	('tumour', 'Disease', 'MESH:D009369', (226, 232))	('exchange', 'Var', (4, 12))	('tumour', 'Disease', (226, 232))	('oncogenes', 'Gene', (188, 197))	('fusion protein', 'Protein', (105, 119))	('overexpression', 'PosReg', (170, 184))
409715	31097696	Previous studies have focused on the identification of fusions, or have investigated the function of specific gene fusions; for example, in the setting of acute myeloid leukemia (AML).	('AML', 'Disease', (179, 182))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (155, 177))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (161, 177))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (155, 177))	('acute myeloid leukemia', 'Disease', (155, 177))	('AML', 'Disease', 'MESH:D015470', (179, 182))	('leukemia', 'Phenotype', 'HP:0001909', (169, 177))	('fusions', 'Var', (55, 62))
409719	31097696	Here, we report a comprehensive functional landscape of fusions using RNA-sequencing (RNA-seq) data for 1011 human cancer cell lines.	('fusions', 'Var', (56, 63))	('cancer', 'Disease', (115, 121))	('human', 'Species', '9606', (109, 114))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('cancer', 'Disease', 'MESH:D009369', (115, 121))
409733	31097696	An empirical permutation test identified known oncogenic fusions enriched in specific cancer types that are consistent with their pathognomonic nature, such as ABL1 fusions in chronic myeloid leukemia (false discovery rate (FDR) <1%, n = 9), EWSR1-FLI1 fusions in Ewing's sarcoma (FDR <1%, n = 24) and FGFR3 fusions in bladder cancer (FDR <1%, n = 3) (Supplementary Fig.	('FGFR3', 'Gene', '2261', (302, 307))	('sarcoma', 'Phenotype', 'HP:0100242', (272, 279))	('FLI1', 'Gene', '2313', (248, 252))	('fusions', 'Var', (253, 260))	('bladder cancer', 'Disease', 'MESH:D001749', (319, 333))	('ABL1', 'Gene', (160, 164))	('fusions', 'Var', (308, 315))	('fusions', 'Var', (165, 172))	('bladder cancer', 'Disease', (319, 333))	('cancer', 'Disease', (327, 333))	('bladder cancer', 'Phenotype', 'HP:0009725', (319, 333))	('ABL1', 'Gene', '25', (160, 164))	("Ewing's sarcoma", 'Phenotype', 'HP:0012254', (264, 279))	('cancer', 'Phenotype', 'HP:0002664', (327, 333))	('EWSR1', 'Gene', (242, 247))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (184, 200))	('chronic myeloid leukemia', 'Disease', (176, 200))	('cancer', 'Disease', (86, 92))	("Ewing's sarcoma", 'Disease', 'MESH:C563168', (264, 279))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('leukemia', 'Phenotype', 'HP:0001909', (192, 200))	('cancer', 'Disease', 'MESH:D009369', (327, 333))	('FLI1', 'Gene', (248, 252))	("Ewing's sarcoma", 'Disease', (264, 279))	('FGFR3', 'Gene', (302, 307))	('chronic myeloid leukemia', 'Phenotype', 'HP:0005506', (176, 200))	('chronic myeloid leukemia', 'Disease', 'MESH:D015464', (176, 200))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('EWSR1', 'Gene', '2130', (242, 247))
409734	31097696	In summary, using multiple algorithms and stringent criteria we built a comprehensive landscape of fusions in cancer cell lines, most of which occur at a low frequency, and reflect the prevalence and tissue specificity in tumour samples.	('tumour', 'Disease', 'MESH:D009369', (222, 228))	('cancer', 'Disease', (110, 116))	('tumour', 'Disease', (222, 228))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('tumour', 'Phenotype', 'HP:0002664', (222, 228))	('fusions', 'Var', (99, 106))	('cancer', 'Disease', 'MESH:D009369', (110, 116))
409741	31097696	In support of this observation, we validated by Sanger sequencing and fluorescence in situ hybridization (FISH) a previously uncharacterized RWDD1-ROS1 fusion in the OCUB-M cell line, which is derived from a triple-negative breast cancer (Supplementary Fig.	('ROS1', 'Gene', (147, 151))	('breast cancer', 'Disease', 'MESH:D001943', (224, 237))	('breast cancer', 'Phenotype', 'HP:0003002', (224, 237))	('ROS1', 'Gene', '6098', (147, 151))	('breast cancer', 'Disease', (224, 237))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('fusion', 'Var', (152, 158))
409744	31097696	Interestingly, in a dataset of 590 breast cancer patients, we identified a triple-negative and a HER2+ tumour-carrying in-frame fusions involving the ROS1 kinase domain (Supplementary Fig.	('fusions', 'Var', (128, 135))	('HER2', 'Gene', (97, 101))	('HER2', 'Gene', '2064', (97, 101))	('ROS1', 'Gene', (150, 154))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('ROS1', 'Gene', '6098', (150, 154))	('tumour', 'Phenotype', 'HP:0002664', (103, 109))	('tumour', 'Disease', 'MESH:D009369', (103, 109))	('breast cancer', 'Disease', 'MESH:D001943', (35, 48))	('breast cancer', 'Disease', (35, 48))	('patients', 'Species', '9606', (49, 57))	('breast cancer', 'Phenotype', 'HP:0003002', (35, 48))	('tumour', 'Disease', (103, 109))
409746	31097696	We used an established statistical model to perform an analysis of variance (ANOVA) linking the 431 recurrent gene fusions (n >= 2 cell lines; in-frame and not in frame fusions) with 308,634 IC50 (half-maximal inhibitory concentration) values for 409 anti-cancer drugs (334 unique compounds) screened across 982 cell lines by the GDSC project (Fig.	('cancer', 'Phenotype', 'HP:0002664', (256, 262))	('fusions', 'Var', (115, 122))	('cancer', 'Disease', (256, 262))	('cancer', 'Disease', 'MESH:D009369', (256, 262))
409748	31097696	Preliminary analyses indicated that mutations in cancer driver genes co-occurring with fusions in cell lines were frequent confounders when identifying fusion-specific associations.	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('cancer', 'Disease', (49, 55))	('mutations', 'Var', (36, 45))	('cancer', 'Disease', 'MESH:D009369', (49, 55))
409749	31097696	To control for this, we first identified associations between 717 cancer driver mutations and copy number alterations with drug sensitivity, and then used them as a covariate in the ANOVA to identify fusion-specific associations (Supplementary Data 6).	('associations', 'Interaction', (41, 53))	('mutations', 'Var', (80, 89))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('copy number alterations', 'Var', (94, 117))	('drug sensitivity', 'Phenotype', 'HP:0020174', (123, 139))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('cancer', 'Disease', (66, 72))
409750	31097696	For instance, the association of NKD1-ADCY7 with BRAF-inhibitor dabrafenib was explained by the presence of a coincident BRAF mutation in one highly sensitive cell line (Supplementary Fig.	('BRAF', 'Gene', (121, 125))	('NKD1', 'Gene', (33, 37))	('mutation', 'Var', (126, 134))	('association', 'Interaction', (18, 29))	('ADCY7', 'Gene', '113', (38, 43))	('ADCY7', 'Gene', (38, 43))	('dabrafenib', 'Chemical', 'MESH:C561627', (64, 74))	('BRAF', 'Gene', '673', (49, 53))	('BRAF', 'Gene', '673', (121, 125))	('BRAF', 'Gene', (49, 53))	('NKD1', 'Gene', '85407', (33, 37))
409753	31097696	Following manual curation, most associations between fusions and drug sensitivity could be readily explained by known interactions (n = 66; 30%), mutations in secondary genes (n = 7; 3%), and fusions that were either not in frame (n = 77; 34%) or not detected in patient samples (n = 131; 57%).	('patient', 'Species', '9606', (263, 270))	('mutations', 'Var', (146, 155))	('fusions', 'Var', (53, 60))	('associations', 'Interaction', (32, 44))	('fusions', 'Var', (192, 199))	('interactions', 'Interaction', (118, 130))	('drug sensitivity', 'Phenotype', 'HP:0020174', (65, 81))	('drug sensitivity', 'Disease', (65, 81))
409758	31097696	We identified mapping sgRNA for 2821 (26%) fusion transcripts, of which only 99 (4%; representing 103 fusion events) were significantly associated with decreased cell fitness in at least one CRISPR dataset (FES FDR <5%; Fig.	('decreased', 'NegReg', (152, 161))	('fusion transcripts', 'Var', (43, 61))	('FES', 'Chemical', '-', (207, 210))	('cell fitness', 'CPA', (162, 174))
409763	31097696	Overall, for most tested fusions, we did not detect evidence supporting a functional role in cancer cell fitness.	('fusions', 'Var', (25, 32))	('cancer cell fitness', 'Disease', 'MESH:C538614', (93, 112))	('cancer cell fitness', 'Disease', (93, 112))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))
409765	31097696	Rare RAF1 fusions occur in patient tumours and are biomarkers of response to mitogen-activated protein kinase pathway inhibition.	('tumours', 'Disease', (35, 42))	('RAF1', 'Gene', '5894', (5, 9))	('RAF1', 'Gene', (5, 9))	('patient', 'Species', '9606', (27, 34))	('tumour', 'Phenotype', 'HP:0002664', (35, 41))	('tumours', 'Phenotype', 'HP:0002664', (35, 42))	('tumours', 'Disease', 'MESH:D009369', (35, 42))	('fusions', 'Var', (10, 17))
409766	31097696	We identified an in-frame ATG7-RAF1 fusion in PL18, a pancreatic adenocarcinoma cell line (Fig.	('ATG7', 'Gene', '10533', (26, 30))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (54, 79))	('ATG7', 'Gene', (26, 30))	('RAF1', 'Gene', (31, 35))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D010190', (54, 79))	('RAF1', 'Gene', '5894', (31, 35))	('fusion', 'Var', (36, 42))	('pancreatic adenocarcinoma', 'Disease', (54, 79))
409767	31097696	The fusion removes the N-terminal regulatory region, but retains an intact RAF1 protein kinase domain, suggesting it results in constitutive kinase activation.	('removes', 'NegReg', (11, 18))	('fusion', 'Var', (4, 10))	('RAF1', 'Gene', (75, 79))	('N-terminal regulatory region', 'MPA', (23, 51))	('RAF1', 'Gene', '5894', (75, 79))	('constitutive kinase activation', 'MPA', (128, 158))	('results in', 'Reg', (117, 127))
409770	31097696	Unlike >90% of pancreatic tumours and cell lines that have activating mutations in KRAS, PL18 has a wild-type KRAS allele, but retained potent sensitivity to downstream MEK (mitogen-activated protein kinase kinase) pathway inhibitors trametinib and PD0325901 (Fig.	('KRAS', 'Gene', (83, 87))	('PL18', 'Gene', (89, 93))	('mitogen-activated protein kinase kinase', 'Gene', '5609', (174, 213))	('mutations', 'Var', (70, 79))	('sensitivity', 'MPA', (143, 154))	('KRAS', 'Gene', '3845', (83, 87))	('mitogen-activated protein kinase kinase', 'Gene', (174, 213))	('tumours', 'Phenotype', 'HP:0002664', (26, 33))	('KRAS', 'Gene', '3845', (110, 114))	('PD0325901', 'Chemical', 'MESH:C506614', (249, 258))	('trametinib', 'Chemical', 'MESH:C560077', (234, 244))	('tumour', 'Phenotype', 'HP:0002664', (26, 32))	('MEK', 'Gene', (169, 172))	('pancreatic tumours', 'Disease', (15, 33))	('MEK', 'Gene', '5609', (169, 172))	('pancreatic tumours', 'Disease', 'MESH:D010190', (15, 33))	('KRAS', 'Gene', (110, 114))
409771	31097696	An ATG7-RAF1 rearrangement was previously reported in another KRAS wild-type pancreatic cancer model.	('RAF1', 'Gene', '5894', (8, 12))	('KRAS', 'Gene', (62, 66))	('RAF1', 'Gene', (8, 12))	('rearrangement', 'Var', (13, 26))	('pancreatic cancer', 'Disease', 'MESH:D010190', (77, 94))	('KRAS', 'Gene', '3845', (62, 66))	('ATG7', 'Gene', '10533', (3, 7))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (77, 94))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('pancreatic cancer', 'Disease', (77, 94))	('ATG7', 'Gene', (3, 7))
409773	31097696	Together, our analysis supports emerging evidence for rare recurrent and potentially therapeutically actionable RAF1 rearrangements in KRAS wild-type pancreatic cancer.	('pancreatic cancer', 'Disease', 'MESH:D010190', (150, 167))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('rearrangements', 'Var', (117, 131))	('RAF1', 'Gene', (112, 116))	('RAF1', 'Gene', '5894', (112, 116))	('KRAS', 'Gene', (135, 139))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (150, 167))	('KRAS', 'Gene', '3845', (135, 139))	('pancreatic cancer', 'Disease', (150, 167))
409774	31097696	BRD4-NUTM1 fusions genetically define NUT midline carcinoma (NMC), a rare and aggressive neoplasm that usually arises in the midline of the body with marked sensitivity to BET bromodomain inhibitors.	('aggressive neoplasm', 'Disease', (78, 97))	('BET', 'Gene', (172, 175))	('BRD4', 'Gene', '23476', (0, 4))	('neoplasm', 'Phenotype', 'HP:0002664', (89, 97))	('NUT midline carcinoma', 'Disease', (38, 59))	('carcinoma', 'Phenotype', 'HP:0030731', (50, 59))	('NUTM1', 'Gene', '256646', (5, 10))	('BRD4', 'Gene', (0, 4))	('BET', 'Gene', '92737', (172, 175))	('aggressive neoplasm', 'Disease', 'MESH:D001523', (78, 97))	('fusions', 'Var', (11, 18))	('NUT midline carcinoma', 'Disease', 'MESH:D009436', (38, 59))	('NUTM1', 'Gene', (5, 10))
409775	31097696	We identified a novel in-frame BRD4-NUTM1 fusion in SBC-3, a cell line established from a 24-year-old male diagnosed with small-cell lung carcinoma (SCLC), and confirmed the fusion by Sanger sequencing and FISH (Fig.	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('NUTM1', 'Gene', (36, 41))	('SBC-3', 'CellLine', 'CVCL:1678', (52, 57))	('SCLC', 'Disease', (149, 153))	('BRD4', 'Gene', '23476', (31, 35))	('SCLC', 'Disease', 'MESH:D018288', (149, 153))	('small-cell lung carcinoma', 'Disease', (122, 147))	('fusion', 'Var', (42, 48))	('BRD4', 'Gene', (31, 35))	('NUTM1', 'Gene', '256646', (36, 41))	('small-cell lung carcinoma', 'Disease', 'MESH:D055752', (122, 147))
409780	31097696	The BRD4-NUTM1 fusion was specifically associated with high NUTM1 transcript expression in cell lines (Fig.	('fusion', 'Var', (15, 21))	('NUTM1', 'Gene', '256646', (60, 65))	('BRD4', 'Gene', '23476', (4, 8))	('NUTM1', 'Gene', (60, 65))	('transcript expression', 'MPA', (66, 87))	('BRD4', 'Gene', (4, 8))	('NUTM1', 'Gene', '256646', (9, 14))	('associated', 'Reg', (39, 49))	('NUTM1', 'Gene', (9, 14))
409786	31097696	Thus, although we cannot exclude misclassification of SBC-3 cells, our preclinical data support evidence that functional NUTM1 fusions are present in tumours diagnosed as lung cancer, and could represent an actionable driver event in these tumours with immediate potential clinical implications.	('tumours', 'Phenotype', 'HP:0002664', (150, 157))	('lung cancer', 'Disease', 'MESH:D008175', (171, 182))	('tumour', 'Phenotype', 'HP:0002664', (150, 156))	('lung cancer', 'Disease', (171, 182))	('lung cancer', 'Phenotype', 'HP:0100526', (171, 182))	('tumours', 'Disease', 'MESH:D009369', (150, 157))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('tumours', 'Disease', (150, 157))	('tumour', 'Phenotype', 'HP:0002664', (240, 246))	('tumours', 'Phenotype', 'HP:0002664', (240, 247))	('fusions', 'Var', (127, 134))	('NUTM1', 'Gene', '256646', (121, 126))	('NUTM1', 'Gene', (121, 126))	('SBC-3', 'CellLine', 'CVCL:1678', (54, 59))	('tumours', 'Disease', 'MESH:D009369', (240, 247))	('tumours', 'Disease', (240, 247))
409789	31097696	Here, we detected and validated two unreported canonical R-spondin fusions in cancer cell lines derived from biliary tract (EGI-1; PTPRK-RSPO3 fusion) and esophagus (ESO51; EIF3E-RSPO2 fusion) by PCR and FISH (Fig.	('RSPO2', 'Gene', (179, 184))	('ESO51', 'Chemical', '-', (166, 171))	('RSPO3', 'Gene', '84870', (137, 142))	('RSPO3', 'Gene', (137, 142))	('fusions', 'Var', (67, 74))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('RSPO2', 'Gene', '340419', (179, 184))	('R-spondin', 'Gene', (57, 66))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('PTPRK', 'Gene', (131, 136))	('PTPRK', 'Gene', '5796', (131, 136))
409793	31097696	This was in contrast to SNU1411, a positive control CRC cell line model addicted to WNT pathway activation by rearranged RSPO3, which was sensitive to multiple porcupine inhibitors.	('rearranged', 'Var', (110, 120))	('RSPO3', 'Gene', '84870', (121, 126))	('RSPO3', 'Gene', (121, 126))	('SNU1411', 'Chemical', '-', (24, 31))	('WNT pathway', 'Pathway', (84, 95))	('activation', 'PosReg', (96, 106))
409796	31097696	This may be because RSPO2/3 fusions act as paracrine signals to enhance WNT ligands and so are not readily detected by pooled CRISPR screens designed to unveil cell intrinsic gene dependencies.	('enhance', 'PosReg', (64, 71))	('WNT', 'Protein', (72, 75))	('RSPO2', 'Gene', '340419', (20, 25))	('fusions', 'Var', (28, 35))	('RSPO2', 'Gene', (20, 25))
409797	31097696	Recurrent YAP1-MAML2 fusions were identified in AM-38 (glioblastoma), ES-2 (ovarian carcinoma), and SAS (head and neck carcinoma) cell lines (Fig.	('YAP1', 'Gene', (10, 14))	('ovarian carcinoma', 'Disease', (76, 93))	('fusions', 'Var', (21, 28))	('MAML2', 'Gene', '84441', (15, 20))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (76, 93))	('SAS', 'Gene', '6302', (100, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('ES-2', 'Gene', (70, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('glioblastoma', 'Disease', 'MESH:D005909', (55, 67))	('SAS', 'Gene', (100, 103))	('neck carcinoma', 'Disease', (114, 128))	('ES-2', 'Gene', '8220', (70, 74))	('neck carcinoma', 'Disease', 'MESH:D006258', (114, 128))	('YAP1', 'Gene', '10413', (10, 14))	('glioblastoma', 'Disease', (55, 67))	('MAML2', 'Gene', (15, 20))	('glioblastoma', 'Phenotype', 'HP:0012174', (55, 67))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (76, 93))
409798	31097696	YAP1-MAML2 fusions have been reported in nasopharyngeal carcinomas and in a sample from a patient with skin cancer, but not in the three tumour types reported here (Fig.	('YAP1', 'Gene', '10413', (0, 4))	('tumour type', 'Disease', 'MESH:D009369', (137, 148))	('nasopharyngeal carcinomas', 'Disease', 'MESH:D000077274', (41, 66))	('MAML2', 'Gene', (5, 10))	('carcinoma', 'Phenotype', 'HP:0030731', (56, 65))	('nasopharyngeal carcinomas', 'Disease', (41, 66))	('skin cancer', 'Disease', 'MESH:D012878', (103, 114))	('YAP1', 'Gene', (0, 4))	('carcinomas', 'Phenotype', 'HP:0030731', (56, 66))	('tumour type', 'Disease', (137, 148))	('nasopharyngeal carcinomas', 'Phenotype', 'HP:0100630', (41, 66))	('MAML2', 'Gene', '84441', (5, 10))	('fusions', 'Var', (11, 18))	('tumour', 'Phenotype', 'HP:0002664', (137, 143))	('skin cancer', 'Disease', (103, 114))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('skin cancer', 'Phenotype', 'HP:0008069', (103, 114))	('reported', 'Reg', (29, 37))	('patient', 'Species', '9606', (90, 97))
409801	31097696	We found that YAP1-MAML2 fusions were significantly associated with decreased cell fitness when targeted in the CRISPR screen (Figs.	('decreased', 'NegReg', (68, 77))	('YAP1', 'Gene', (14, 18))	('YAP1', 'Gene', '10413', (14, 18))	('cell fitness', 'CPA', (78, 90))	('MAML2', 'Gene', '84441', (19, 24))	('MAML2', 'Gene', (19, 24))	('fusions', 'Var', (25, 32))
409803	31097696	YAP1 aberrant activation is linked with poor prognosis, chemoresistance, and resistance to cell death in multiple solid tumours.	('multiple solid tumours', 'Disease', 'MESH:D009369', (105, 127))	('chemoresistance', 'CPA', (56, 71))	('YAP1', 'Gene', (0, 4))	('multiple solid tumours', 'Disease', (105, 127))	('YAP1', 'Gene', '10413', (0, 4))	('tumours', 'Phenotype', 'HP:0002664', (120, 127))	('resistance to cell death', 'CPA', (77, 101))	('aberrant', 'Var', (5, 13))	('tumour', 'Phenotype', 'HP:0002664', (120, 126))
409811	31097696	Overall, our findings that recurrent YAP1-MAML2 fusion are associated with increased YAP1 signaling and required for cell fitness support targeting the Hippo signaling cascade in YAP1-MAML2-fusion-positive tumours.	('YAP1', 'Gene', (179, 183))	('YAP1', 'Gene', '10413', (179, 183))	('YAP1', 'Gene', (85, 89))	('YAP1', 'Gene', '10413', (85, 89))	('MAML2', 'Gene', '84441', (42, 47))	('MAML2', 'Gene', (42, 47))	('tumour', 'Phenotype', 'HP:0002664', (206, 212))	('fusion', 'Var', (48, 54))	('tumours', 'Phenotype', 'HP:0002664', (206, 213))	('tumours', 'Disease', 'MESH:D009369', (206, 213))	('MAML2', 'Gene', (184, 189))	('YAP1', 'Gene', '10413', (37, 41))	('MAML2', 'Gene', '84441', (184, 189))	('increased', 'PosReg', (75, 84))	('YAP1', 'Gene', (37, 41))	('tumours', 'Disease', (206, 213))
409816	31097696	Furthermore, this approach captures fusions that induce gain-of-function or dominant-negative effects, but is not able to identify loss-of-function effects, such as inactivation of a tumour suppressor.	('tumour', 'Disease', (183, 189))	('inactivation', 'Var', (165, 177))	('fusions', 'Var', (36, 43))	('tumour', 'Phenotype', 'HP:0002664', (183, 189))	('tumour', 'Disease', 'MESH:D009369', (183, 189))	('gain-of-function', 'PosReg', (56, 72))
409818	31097696	Despite these limitations, our finding that most fusions tested do not have supporting functional evidence, including fusions with cancer drivers genes, emphasizes the importance of analyses to ascribe function when interpreting fusions identified using genomic sequencing.	('cancer', 'Disease', (131, 137))	('fusions', 'Var', (118, 125))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('fusions', 'Var', (49, 56))
409821	31097696	We provide specific and previously undescribed data on fusions involving RAF1, ROS1, and BRD4 that suggest that existing drugs could be repurposed for use in rare pancreatic, breast, and lung cancers.	('BRD4', 'Gene', '23476', (89, 93))	('lung cancers', 'Phenotype', 'HP:0100526', (187, 199))	('lung cancer', 'Phenotype', 'HP:0100526', (187, 198))	('pancreatic', 'Disease', (163, 173))	('lung cancers', 'Disease', (187, 199))	('cancers', 'Phenotype', 'HP:0002664', (192, 199))	('ROS1', 'Gene', (79, 83))	('BRD4', 'Gene', (89, 93))	('ROS1', 'Gene', '6098', (79, 83))	('RAF1', 'Gene', (73, 77))	('RAF1', 'Gene', '5894', (73, 77))	('lung cancers', 'Disease', 'MESH:D008175', (187, 199))	('breast', 'Disease', (175, 181))	('pancreatic', 'Disease', 'MESH:D010195', (163, 173))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('fusions', 'Var', (55, 62))
409823	31097696	More broadly, these results support the use of validated oncogenic fusions as therapeutic biomarkers in diverse histologies, and the utility of basket trials for clinical development of drugs targeting fusion proteins irrespective of tumour type, such as the type used for the development of entrectinib in solid tumours with ALK, ROS1, and NTRK fusions.	('ALK', 'Gene', (326, 329))	('solid tumours', 'Disease', (307, 320))	('tumour', 'Phenotype', 'HP:0002664', (234, 240))	('tumour', 'Phenotype', 'HP:0002664', (313, 319))	('tumour type', 'Disease', (234, 245))	('tumours', 'Phenotype', 'HP:0002664', (313, 320))	('ROS1', 'Gene', (331, 335))	('fusions', 'Var', (346, 353))	('tumour type', 'Disease', 'MESH:D009369', (234, 245))	('ROS1', 'Gene', '6098', (331, 335))	('ALK', 'Gene', '238', (326, 329))	('solid tumours', 'Disease', 'MESH:D009369', (307, 320))	('NTRK', 'Gene', (341, 345))
409824	31097696	A notable exception in our analysis was the differential sensitivity to WNT pathway inhibition of CRC vs. biliary tract and esophageal cancer cell lines with canonical R-spondin fusions.	('esophageal cancer', 'Disease', (124, 141))	('inhibition', 'NegReg', (84, 94))	('esophageal cancer', 'Disease', 'MESH:D004938', (124, 141))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('fusions', 'Var', (178, 185))	('R-spondin', 'Protein', (168, 177))
409827	31097696	We identified and functionally evaluated less well-studied gene fusions, as exemplified by YAP1-MAML2 rearrangements, which are required for cell fitness in multiple histology and associated with increased YAP1 signaling.	('increased', 'PosReg', (196, 205))	('YAP1', 'Gene', (91, 95))	('YAP1', 'Gene', (206, 210))	('YAP1', 'Gene', '10413', (206, 210))	('MAML2', 'Gene', (96, 101))	('MAML2', 'Gene', '84441', (96, 101))	('YAP1', 'Gene', '10413', (91, 95))	('rearrangements', 'Var', (102, 116))
409847	31097696	Under the null hypothesis that gene alterations distribute homogeneously across cancer types (i.e., any sample from any cancer type has the same likelihood of having the gene G fused), we permuted 10,000 times the initially observed matrix using the algorithm BiRewire implemented in an R package.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('alterations', 'Var', (36, 47))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('cancer', 'Disease', (80, 86))
409856	31097696	The 717 cancer functional events used in the analysis included 281 genes with somatic coding mutations, 424 copy number altered chromosomal segments and methylation status for 12 segments that included any gene altered by point mutations.	('cancer', 'Disease', (8, 14))	('mutations', 'Var', (93, 102))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('copy number', 'Var', (108, 119))	('cancer', 'Disease', 'MESH:D009369', (8, 14))
409860	31097696	CRISPR screening data for EGI-1, ESO51, H3118, SAS, SBC-3, and SNU1411 were generated ad hoc for this study at the Sanger Institute, following the CRISPR screening pipeline used to screen cell lines part of the Project Score.	('SNU1411', 'Var', (63, 70))	('SBC-3', 'CellLine', 'CVCL:1678', (52, 57))	('SAS', 'Gene', '6302', (47, 50))	('ESO51', 'Chemical', '-', (33, 38))	('SAS', 'Gene', (47, 50))	('ESO51', 'Gene', (33, 38))	('SNU1411', 'Chemical', '-', (63, 70))
409874	31097696	For interphase and metaphase FISH, probes were labeled directly with Atto488-XX-dUTP, Cy3-XX-dUTP, Texas Red-12-dUTP, and Cy5-XX-dUTP (Jena Bioscience), respectively.	('-dUTP', 'Chemical', 'MESH:C027078', (79, 84))	('Cy3-XX-dUTP', 'Var', (86, 97))	('Atto488-XX-dUTP', 'Var', (69, 84))	('Texas Red-12-dUTP', 'Chemical', '-', (99, 116))	('Cy5-XX-dUTP', 'Var', (122, 133))	('-dUTP', 'Chemical', 'MESH:C027078', (111, 116))	('-dUTP', 'Chemical', 'MESH:C027078', (128, 133))	('Cy5', 'Chemical', 'MESH:C085321', (122, 125))	('-dUTP', 'Chemical', 'MESH:C027078', (92, 97))	('Cy3', 'Chemical', '-', (86, 89))
409927	28767587	The pooled HR with 95% CI is shown in Figure 7 (HR = 2.40, 95% CI = 1.48-3.88, P = .0004), indicating that patients with lung cancer with low HDAC1 mRNA or protein expression showed better OS than patients with high HDAC1 expression.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('lung cancer', 'Disease', 'MESH:D008175', (121, 132))	('HDAC1', 'Gene', '3065', (142, 147))	('patients', 'Species', '9606', (197, 205))	('better', 'PosReg', (182, 188))	('HDAC1', 'Gene', (216, 221))	('lung cancer', 'Disease', (121, 132))	('lung cancer', 'Phenotype', 'HP:0100526', (121, 132))	('HDAC1', 'Gene', '3065', (216, 221))	('protein', 'Protein', (156, 163))	('HDAC1', 'Gene', (142, 147))	('patients', 'Species', '9606', (107, 115))	('low', 'Var', (138, 141))	('mRNA', 'MPA', (148, 152))
409932	28767587	Finally, we found that patients with lung cancer with low HDAC1 expression showed better OS than those with high HDAC1 expression.	('lung cancer', 'Disease', (37, 48))	('lung cancer', 'Phenotype', 'HP:0100526', (37, 48))	('better', 'PosReg', (82, 88))	('HDAC1', 'Gene', (113, 118))	('patients', 'Species', '9606', (23, 31))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('low', 'Var', (54, 57))	('HDAC1', 'Gene', (58, 63))	('expression', 'Var', (64, 74))	('HDAC1', 'Gene', '3065', (113, 118))	('lung cancer', 'Disease', 'MESH:D008175', (37, 48))	('HDAC1', 'Gene', '3065', (58, 63))
409942	28767587	For example, patients with gastric cancer with low HDAC1 expression showed better OS than those with high HDAC1 expression.	('better', 'PosReg', (75, 81))	('HDAC1', 'Gene', '3065', (51, 56))	('gastric cancer', 'Phenotype', 'HP:0012126', (27, 41))	('expression', 'Var', (57, 67))	('HDAC1', 'Gene', (106, 111))	('patients', 'Species', '9606', (13, 21))	('low', 'Var', (47, 50))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('HDAC1', 'Gene', '3065', (106, 111))	('HDAC1', 'Gene', (51, 56))	('gastric cancer', 'Disease', (27, 41))	('gastric cancer', 'Disease', 'MESH:D013274', (27, 41))
409945	28767587	In this analysis, we found that patients with lung cancer with low HDAC1 expression has better OS than those with high HDAC1 expression, indicating that HDAC1 might be a good prognostic marker for patients with lung cancer and could help screen out high-risk patients with lung cancer.	('lung cancer', 'Phenotype', 'HP:0100526', (211, 222))	('patients', 'Species', '9606', (197, 205))	('HDAC1', 'Gene', (119, 124))	('HDAC1', 'Gene', '3065', (153, 158))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('lung cancer', 'Disease', 'MESH:D008175', (273, 284))	('lung cancer', 'Disease', (46, 57))	('lung cancer', 'Phenotype', 'HP:0100526', (273, 284))	('cancer', 'Phenotype', 'HP:0002664', (278, 284))	('patients', 'Species', '9606', (259, 267))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('low', 'NegReg', (63, 66))	('HDAC1', 'Gene', '3065', (119, 124))	('lung cancer', 'Disease', (211, 222))	('HDAC1', 'Gene', (67, 72))	('lung cancer', 'Disease', 'MESH:D008175', (46, 57))	('HDAC1', 'Gene', (153, 158))	('lung cancer', 'Phenotype', 'HP:0100526', (46, 57))	('expression', 'Var', (73, 83))	('patients', 'Species', '9606', (32, 40))	('lung cancer', 'Disease', (273, 284))	('HDAC1', 'Gene', '3065', (67, 72))	('lung cancer', 'Disease', 'MESH:D008175', (211, 222))
409952	28767587	This meta-analysis suggests that the expression level of HDAC1 might be a high risk factor for lung cancer, especially in Asian populations.	('lung cancer', 'Disease', (95, 106))	('expression level', 'Var', (37, 53))	('lung cancer', 'Phenotype', 'HP:0100526', (95, 106))	('risk factor', 'Reg', (79, 90))	('HDAC1', 'Gene', (57, 62))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('lung cancer', 'Disease', 'MESH:D008175', (95, 106))	('HDAC1', 'Gene', '3065', (57, 62))
409980	28918043	It has been reported that miR-206/133b can be discovered in slow myofibers in adult muscle, and its expression is regulated by a network of myogenic genes, such as MyoD, a kind of muscle regulatory factor (MRF).	('muscle regulatory factor', 'Gene', (180, 204))	('regulated', 'Reg', (114, 123))	('muscle regulatory factor', 'Gene', '745', (180, 204))	('MyoD', 'Gene', (164, 168))	('expression', 'MPA', (100, 110))	('MyoD', 'Gene', '4654', (164, 168))	('MRF', 'Gene', (206, 209))	('miR-206/133b', 'Var', (26, 38))	('MRF', 'Gene', '745', (206, 209))
409982	28918043	Both miR-206 and miR-133b are significantly downregulated in lung cancer (Table 1), suggesting they may play parts in lung tumorigenesis.	('miR-206', 'Var', (5, 12))	('lung cancer', 'Disease', (61, 72))	('lung cancer', 'Phenotype', 'HP:0100526', (61, 72))	('downregulated', 'NegReg', (44, 57))	('lung tumor', 'Disease', (118, 128))	('miR-133b', 'Var', (17, 25))	('lung tumor', 'Disease', 'MESH:D008175', (118, 128))	('play parts', 'Reg', (104, 114))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('lung cancer', 'Disease', 'MESH:D008175', (61, 72))	('lung tumor', 'Phenotype', 'HP:0100526', (118, 128))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
409986	28918043	MET is the tyrosine kinase receptor of the hepatocyte growth factor (HGF) and greatly relates to tumorigenesis.	('hepatocyte growth factor', 'Gene', (43, 67))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('relates', 'Reg', (86, 93))	('HGF', 'Gene', (69, 72))	('hepatocyte growth factor', 'Gene', '3082', (43, 67))	('tumor', 'Disease', (97, 102))	('HGF', 'Gene', '3082', (69, 72))	('MET', 'Var', (0, 3))
409989	28918043	In lung squamous cell carcinoma, miR-206 was identified to be decreased and upregulation of it markedly boosted cell apoptosis and gave rise to cell-cycle arrest.	('miR-206', 'Var', (33, 40))	('cell apoptosis', 'CPA', (112, 126))	('upregulation', 'PosReg', (76, 88))	('lung squamous cell carcinoma', 'Disease', (3, 31))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (3, 31))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (8, 31))	('boosted', 'PosReg', (104, 111))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('cell-cycle arrest', 'CPA', (144, 161))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (3, 31))	('gave rise', 'Reg', (131, 140))
409990	28918043	Further investigations confirmed that MET and EGFR were the direct targets of miR-206, and the signal pathway was inhibition of their downstream phosphorylation of ERK1/2 and AKT.	('miR-206', 'Var', (78, 85))	('inhibition', 'NegReg', (114, 124))	('ERK1/2', 'Gene', '5595;5594', (164, 170))	('AKT', 'Gene', (175, 178))	('EGFR', 'Gene', '1956', (46, 50))	('AKT', 'Gene', '207', (175, 178))	('EGFR', 'Gene', (46, 50))	('ERK1/2', 'Gene', (164, 170))
409991	28918043	discovered miR-206 was able to significantly reduce expression of MET, and it was demonstrated as a direct target of miR-206 in lung adenocarcinoma (LAC) cell.	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('LAC', 'Phenotype', 'HP:0030078', (149, 152))	('lung adenocarcinoma', 'Disease', (128, 147))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (128, 147))	('miR-206', 'Var', (11, 18))	('expression', 'MPA', (52, 62))	('rat', 'Species', '10116', (89, 92))	('MET', 'MPA', (66, 69))	('reduce', 'NegReg', (45, 51))	('miR-206', 'Var', (117, 124))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (128, 147))
409992	28918043	However, fiow cytometry assay suggested miR-206 slightly led to HCC827 and A549 cell death in the early stage, whereas the HCC827 cell apoptosis rate was remarkably higher after treatment of miR-206 than in the negative control group at a later time.	('A549 cell death', 'Disease', (75, 90))	('HCC827', 'CellLine', 'CVCL:2063', (64, 70))	('HCC827', 'CPA', (64, 70))	('HCC827', 'CellLine', 'CVCL:2063', (123, 129))	('led to', 'Reg', (57, 63))	('rat', 'Species', '10116', (145, 148))	('higher', 'PosReg', (165, 171))	('A549 cell death', 'Disease', 'MESH:D003643', (75, 90))	('miR-206', 'Var', (191, 198))	('miR-206', 'Var', (40, 47))	('HCC827', 'Gene', (123, 129))
409994	28918043	miR-133b was also disclosed to correlate with tumor stages, visceral pleura, migration, and EGFR mRNA expression, as well as to contributed to lung cancer cell apoptosis in NSCLC.	('NSCLC', 'Phenotype', 'HP:0030358', (173, 178))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('miR-133b', 'Var', (0, 8))	('rat', 'Species', '10116', (80, 83))	('lung cancer', 'Disease', (143, 154))	('lung cancer', 'Phenotype', 'HP:0100526', (143, 154))	('contributed', 'Reg', (128, 139))	('tumor', 'Disease', (46, 51))	('SCLC', 'Phenotype', 'HP:0030357', (174, 178))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('NSCLC', 'Disease', (173, 178))	('lung cancer', 'Disease', 'MESH:D008175', (143, 154))	('EGFR', 'Gene', '1956', (92, 96))	('NSCLC', 'Disease', 'MESH:D002289', (173, 178))	('EGFR', 'Gene', (92, 96))	('visceral pleura', 'Disease', 'MESH:D054363', (60, 75))	('visceral pleura', 'Disease', (60, 75))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
409999	28918043	Myeloid cell leukemia 1 (MCL-1) and B cell CLL/lymphoma 2 like 2 (BCL2L2), the members of the BCL-2 family, were validated as the targets of miR-133b.	('leukemia', 'Phenotype', 'HP:0001909', (13, 21))	('BCL2L2', 'Gene', '599', (66, 72))	('MCL-1', 'Gene', '4170', (25, 30))	('MCL-1', 'Gene', (25, 30))	('lymphoma', 'Phenotype', 'HP:0002665', (47, 55))	('BCL2L2', 'Gene', (66, 72))	('BCL-2', 'Gene', '596', (94, 99))	('Myeloid cell leukemia 1', 'Gene', '4170', (0, 23))	('miR-133b', 'Var', (141, 149))	('Myeloid cell leukemia 1', 'Gene', (0, 23))	('BCL-2', 'Gene', (94, 99))	('B cell CLL/lymphoma 2 like 2', 'Gene', (36, 64))	('B cell CLL/lymphoma 2 like 2', 'Gene', '599', (36, 64))	('Myeloid cell leukemia', 'Phenotype', 'HP:0012324', (0, 21))
410002	28918043	Further assays verified that both Bcl-2 and c-Met were the appropriate targets of miR-206, and miR-206 prominently reduced their levels in NSCLC.	('Bcl', 'Phenotype', 'HP:0012191', (34, 37))	('miR-206', 'Var', (95, 102))	('NSCLC', 'Phenotype', 'HP:0030358', (139, 144))	('miR-206', 'Var', (82, 89))	('reduced', 'NegReg', (115, 122))	('NSCLC', 'Disease', (139, 144))	('NSCLC', 'Disease', 'MESH:D002289', (139, 144))	('c-Met', 'Gene', (44, 49))	('c-Met', 'Gene', '4233', (44, 49))	('Bcl-2', 'Gene', (34, 39))	('Bcl-2', 'Gene', '596', (34, 39))	('SCLC', 'Phenotype', 'HP:0030357', (140, 144))
410003	28918043	Taking all these findings into consideration, we suppose the miR-206/133b cluster might be a promoter in lung cancer cell apoptosis.	('lung cancer', 'Phenotype', 'HP:0100526', (105, 116))	('miR-206/133b cluster', 'Var', (61, 81))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('lung cancer', 'Disease', 'MESH:D008175', (105, 116))	('promoter', 'PosReg', (93, 101))	('rat', 'Species', '10116', (38, 41))	('lung cancer', 'Disease', (105, 116))
410007	28918043	There is a growing body of evidence showing that the miR-206/133b cluster participates in a great deal of tumor cell proliferation.	('rat', 'Species', '10116', (124, 127))	('participates', 'Reg', (74, 86))	('miR-206/133b', 'Var', (53, 65))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Disease', (106, 111))
410009	28918043	revealed that miR-206 could suppress colorectal cancer cell proliferation by targeting formin-like 2 (FMNL2), which was validated as an emerging member of diaphanous-related formins (DRFs).	('suppress', 'NegReg', (28, 36))	('colorectal cancer', 'Disease', (37, 54))	('targeting', 'Reg', (77, 86))	('rat', 'Species', '10116', (67, 70))	('formin-like 2', 'Gene', (87, 100))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('colorectal cancer', 'Disease', 'MESH:D015179', (37, 54))	('FMNL2', 'Gene', (102, 107))	('miR-206', 'Var', (14, 21))	('formin-like 2', 'Gene', '114793', (87, 100))	('colorectal cancer', 'Phenotype', 'HP:0003003', (37, 54))
410017	28918043	Our research group disclosed that restoration of miR-206 does not merely boost lung cancer cell apoptosis but also represses proliferation by binding to Bcl-2 and c-Met mRNA.	('lung cancer', 'Disease', 'MESH:D008175', (79, 90))	('rat', 'Species', '10116', (132, 135))	('boost', 'PosReg', (73, 78))	('miR-206', 'Gene', (49, 56))	('represses', 'NegReg', (115, 124))	('Bcl-2', 'Gene', (153, 158))	('proliferation', 'CPA', (125, 138))	('c-Met', 'Gene', (163, 168))	('lung cancer', 'Disease', (79, 90))	('rat', 'Species', '10116', (39, 42))	('c-Met', 'Gene', '4233', (163, 168))	('Bcl-2', 'Gene', '596', (153, 158))	('binding', 'Interaction', (142, 149))	('lung cancer', 'Phenotype', 'HP:0100526', (79, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('restoration', 'Var', (34, 45))	('Bcl', 'Phenotype', 'HP:0012191', (153, 156))
410020	28918043	In this section, evidence shows that the miR-206/133b cluster acts as a suppressor in lung cancer cell proliferation.	('rat', 'Species', '10116', (110, 113))	('lung cancer', 'Phenotype', 'HP:0100526', (86, 97))	('lung cancer', 'Disease', (86, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('miR-206/133b', 'Var', (41, 53))	('lung cancer', 'Disease', 'MESH:D008175', (86, 97))
410031	28918043	The underlying mechanism of miR-206-regulated angiogenesis was suppression of the 14-3-3z/STAT3/HIF-1alpha/VEGF signaling pathway.	('STAT3', 'Gene', '6774', (90, 95))	('miR-206-regulated', 'Var', (28, 45))	('HIF-1alpha', 'Gene', (96, 106))	('suppression', 'NegReg', (63, 74))	('VEGF', 'Gene', (107, 111))	('STAT3', 'Gene', (90, 95))	('HIF-1alpha', 'Gene', '3091', (96, 106))	('VEGF', 'Gene', '7422', (107, 111))	('angiogenesis', 'CPA', (46, 58))
410033	28918043	HGF was able to induce tubules formation and metastasis of human umbilical vein endothelial cells (HUVECs), whereas miR-206 dramatically repressed it and the mechanism correlated with blocking PI3k/Akt/mTOR molecular pathways.	('metastasis', 'CPA', (45, 55))	('human', 'Species', '9606', (59, 64))	('miR-206', 'Var', (116, 123))	('Akt', 'Gene', '207', (198, 201))	('mTOR', 'Gene', (202, 206))	('HGF', 'Gene', (0, 3))	('HGF', 'Gene', '3082', (0, 3))	('blocking', 'NegReg', (184, 192))	('Akt', 'Gene', (198, 201))	('mTOR', 'Gene', '2475', (202, 206))	('induce', 'PosReg', (16, 22))	('tubules formation', 'CPA', (23, 40))
410037	28918043	Nevertheless, up to now, miR-133b has not been reported to participate in lung cancer angiogenesis.	('lung cancer', 'Disease', (74, 85))	('lung cancer', 'Phenotype', 'HP:0100526', (74, 85))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('miR-133b', 'Var', (25, 33))	('lung cancer', 'Disease', 'MESH:D008175', (74, 85))
410042	28918043	E-selectin targeting PEGylated-thioaptamer is able to block breast cancer metastasis.	('block breast cancer metastasis', 'Disease', 'MESH:D009362', (54, 84))	('E-selectin', 'Gene', '6401', (0, 10))	('E-selectin', 'Gene', (0, 10))	('block breast cancer metastasis', 'Disease', (54, 84))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('PEGylated-thioaptamer', 'Var', (21, 42))	('breast cancer', 'Phenotype', 'HP:0003002', (60, 73))
410043	28918043	Accumulating evidence suggests that dysregulation of E-cadherin results in tumor metastasis and an unsatisfactory prognosis in a variety of human tumors.	('dysregulation', 'Var', (36, 49))	('human', 'Species', '9606', (140, 145))	('tumors', 'Phenotype', 'HP:0002664', (146, 152))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('tumor metastasis', 'Disease', 'MESH:D009362', (75, 91))	('tumor metastasis', 'Disease', (75, 91))	('E-cadherin', 'Gene', (53, 63))	('E-cadherin', 'Gene', '999', (53, 63))	('tumors', 'Disease', 'MESH:D009369', (146, 152))	('results in', 'Reg', (64, 74))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumors', 'Disease', (146, 152))
410045	28918043	HGF was able to induce EMT and contribute to migration and invasion of lung cancer A549 and 95D cells, while miR-206 markedly blocked HGF-induced EMT, as well as attenuating lung cancer cell migration and invasion by modulating c-Met and its downstream PI3k/Akt/mTOR molecular pathway.	('lung cancer', 'Disease', (174, 185))	('modulating', 'Reg', (217, 227))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('c-Met', 'Gene', (228, 233))	('blocked', 'NegReg', (126, 133))	('EMT', 'CPA', (23, 26))	('invasion', 'CPA', (59, 67))	('rat', 'Species', '10116', (48, 51))	('miR-206', 'Var', (109, 116))	('lung cancer', 'Disease', 'MESH:D008175', (71, 82))	('HGF', 'Gene', '3082', (0, 3))	('lung cancer', 'Disease', 'MESH:D008175', (174, 185))	('Akt', 'Gene', (258, 261))	('lung cancer', 'Phenotype', 'HP:0100526', (71, 82))	('mTOR', 'Gene', (262, 266))	('lung cancer', 'Phenotype', 'HP:0100526', (174, 185))	('migration', 'CPA', (45, 54))	('HGF', 'Gene', (0, 3))	('EMT', 'CPA', (146, 149))	('HGF', 'Gene', '3082', (134, 137))	('c-Met', 'Gene', '4233', (228, 233))	('Akt', 'Gene', '207', (258, 261))	('invasion', 'CPA', (205, 213))	('mTOR', 'Gene', '2475', (262, 266))	('attenuating', 'NegReg', (162, 173))	('rat', 'Species', '10116', (194, 197))	('HGF', 'Gene', (134, 137))	('A549', 'CellLine', 'CVCL:0023', (83, 87))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('lung cancer', 'Disease', (71, 82))
410046	28918043	miR-206 and miR-140 have been previously described to suppress lung cancer cell proliferation.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('lung cancer', 'Disease', 'MESH:D008175', (63, 74))	('miR-140', 'Gene', '406932', (12, 19))	('miR-206', 'Var', (0, 7))	('suppress', 'NegReg', (54, 62))	('lung cancer', 'Disease', (63, 74))	('miR-140', 'Gene', (12, 19))	('lung cancer', 'Phenotype', 'HP:0100526', (63, 74))	('rat', 'Species', '10116', (87, 90))
410053	28918043	uncovered that FSCN1 was a direct target of miR-133b and increased in NSCLC cells.	('miR-133b', 'Var', (44, 52))	('NSCLC', 'Disease', (70, 75))	('NSCLC', 'Disease', 'MESH:D002289', (70, 75))	('increased', 'PosReg', (57, 66))	('SCLC', 'Phenotype', 'HP:0030357', (71, 75))	('FSCN1', 'Gene', (15, 20))	('FSCN1', 'Gene', '6624', (15, 20))	('NSCLC', 'Phenotype', 'HP:0030358', (70, 75))
410063	28918043	LK-L1C/K6W/L8C, a novel synthesized amphiphilic peptide, has been demonstrated as being able to induce cancer cell apoptosis by the miR-29b-p53-mediated pathway.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('induce', 'PosReg', (96, 102))	('miR-29b', 'Gene', '407024', (132, 139))	('LK-L1C/K6W/L8C', 'Var', (0, 14))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('p53', 'Gene', (140, 143))	('miR-29b', 'Gene', (132, 139))	('p53', 'Gene', '7157', (140, 143))	('rat', 'Species', '10116', (73, 76))
410066	28918043	Cisplatin-resistant H1299/DDP and A549/DDP cells were inclined to appear EMT, invasion, and migration.	('A549', 'CellLine', 'CVCL:0023', (34, 38))	('EMT', 'CPA', (73, 76))	('invasion', 'CPA', (78, 86))	('rat', 'Species', '10116', (95, 98))	('Cisplatin', 'Chemical', 'MESH:D002945', (0, 9))	('migration', 'CPA', (92, 101))	('A549/DDP', 'Var', (34, 42))	('H1299', 'CellLine', 'CVCL:0060', (20, 25))	('appear', 'PosReg', (66, 72))
410068	28918043	Further assays revealed miR-206 blocked EMT, cell metastasis, and cisplatin resistance by targeting MET and repressing its downstream PI3k/Akt/mTOR molecular pathway.	('cell metastasis', 'CPA', (45, 60))	('Akt', 'Gene', '207', (139, 142))	('cisplatin', 'Chemical', 'MESH:D002945', (66, 75))	('blocked', 'NegReg', (32, 39))	('repressing', 'NegReg', (108, 118))	('Akt', 'Gene', (139, 142))	('cisplatin resistance', 'MPA', (66, 86))	('miR-206', 'Var', (24, 31))	('MET', 'MPA', (100, 103))	('EMT', 'CPA', (40, 43))	('mTOR', 'Gene', '2475', (143, 147))	('targeting', 'Reg', (90, 99))	('mTOR', 'Gene', (143, 147))
410069	28918043	PF-04691502, a dual PI3K/mTOR suppressor, in combination with VEGF small interfering RNA (siRNA), blocked NSCLC, which may be useful for lung cancer patient therapy.	('NSCLC', 'Disease', 'MESH:D002289', (106, 111))	('lung cancer', 'Disease', (137, 148))	('lung cancer', 'Phenotype', 'HP:0100526', (137, 148))	('blocked', 'NegReg', (98, 105))	('SCLC', 'Phenotype', 'HP:0030357', (107, 111))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('NSCLC', 'Phenotype', 'HP:0030358', (106, 111))	('VEGF', 'Gene', '7422', (62, 66))	('lung cancer', 'Disease', 'MESH:D008175', (137, 148))	('mTOR', 'Gene', '2475', (25, 29))	('patient', 'Species', '9606', (149, 156))	('VEGF', 'Gene', (62, 66))	('NSCLC', 'Disease', (106, 111))	('mTOR', 'Gene', (25, 29))	('PF-04691502', 'Var', (0, 11))
410071	28918043	found miR-133b was able to promote sensitivity of NSCLC cells toward gefitinib chemotherapy, of which mechanisms may include the EGFR-related pathway.	('SCLC', 'Phenotype', 'HP:0030357', (51, 55))	('gefitinib', 'Chemical', 'MESH:D000077156', (69, 78))	('miR-133b', 'Var', (6, 14))	('NSCLC', 'Phenotype', 'HP:0030358', (50, 55))	('sensitivity', 'MPA', (35, 46))	('promote', 'PosReg', (27, 34))	('EGFR', 'Gene', '1956', (129, 133))	('NSCLC', 'Disease', (50, 55))	('EGFR', 'Gene', (129, 133))	('NSCLC', 'Disease', 'MESH:D002289', (50, 55))
410074	28918043	miR-133b was also verified to correlate with radiation therapy in lung cancer cells, and it was low expressed in radioresistant lung cancer cells.	('lung cancer', 'Disease', 'MESH:D008175', (128, 139))	('miR-133b', 'Var', (0, 8))	('correlate', 'Reg', (30, 39))	('lung cancer', 'Disease', (66, 77))	('lung cancer', 'Phenotype', 'HP:0100526', (66, 77))	('lung cancer', 'Disease', (128, 139))	('lung cancer', 'Phenotype', 'HP:0100526', (128, 139))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('radiation', 'Disease', (45, 54))	('lung cancer', 'Disease', 'MESH:D008175', (66, 77))
410076	28918043	demonstrated that cationic lipids combined with pre-miR-133b significantly elevated the level of mature miR-133b in the lung cancer A549 cell and in the mouse model.	('lipids', 'Chemical', 'MESH:D008055', (27, 33))	('lung cancer', 'Disease', (120, 131))	('lung cancer', 'Phenotype', 'HP:0100526', (120, 131))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('elevated', 'PosReg', (75, 83))	('A549', 'CellLine', 'CVCL:0023', (132, 136))	('miR-133b', 'Var', (104, 112))	('mouse', 'Species', '10090', (153, 158))	('level of', 'MPA', (88, 96))	('rat', 'Species', '10116', (7, 10))	('lung cancer', 'Disease', 'MESH:D008175', (120, 131))
410078	28918043	Furthermore, the miR-206/133b cluster correlates with lung cancer patients' prognosis and survival.	('lung cancer', 'Disease', (54, 65))	('lung cancer', 'Phenotype', 'HP:0100526', (54, 65))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('lung cancer', 'Disease', 'MESH:D008175', (54, 65))	('miR-206/133b', 'Var', (17, 29))	('patients', 'Species', '9606', (66, 74))
410079	28918043	discovered TRIB2 was higher in lung cancer samples and linked to a poorer prognosis, whereas miR-206 could inhibited TRIB2-related activity in lung cancer cells.	('lung cancer', 'Disease', 'MESH:D008175', (31, 42))	('TRIB2', 'Gene', '28951', (117, 122))	('TRIB2', 'Gene', '28951', (11, 16))	('TRIB2', 'Gene', (11, 16))	('linked', 'Reg', (55, 61))	('lung cancer', 'Disease', (143, 154))	('lung cancer', 'Phenotype', 'HP:0100526', (143, 154))	('activity', 'MPA', (131, 139))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('lung cancer', 'Disease', (31, 42))	('lung cancer', 'Phenotype', 'HP:0100526', (31, 42))	('higher', 'PosReg', (21, 27))	('lung cancer', 'Disease', 'MESH:D008175', (143, 154))	('miR-206', 'Var', (93, 100))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('TRIB2', 'Gene', (117, 122))	('inhibited', 'NegReg', (107, 116))
410080	28918043	This investigation implied miR-206 may be beneficial for lung cancer patients' survival.	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('miR-206', 'Var', (27, 34))	('lung cancer', 'Disease', (57, 68))	('lung cancer', 'Disease', 'MESH:D008175', (57, 68))	('patients', 'Species', '9606', (69, 77))	('beneficial', 'PosReg', (42, 52))	('lung cancer', 'Phenotype', 'HP:0100526', (57, 68))
410081	28918043	investigated a cohort of 116 NSCLC patients, studying the relationship between expression of miR-206/14-3-3z and prognosis.	('SCLC', 'Phenotype', 'HP:0030357', (30, 34))	('NSCLC', 'Phenotype', 'HP:0030358', (29, 34))	('miR-206/14-3-3z', 'Var', (93, 108))	('NSCLC', 'Disease', (29, 34))	('patients', 'Species', '9606', (35, 43))	('NSCLC', 'Disease', 'MESH:D002289', (29, 34))
410083	28918043	However, miR-133b was also found to positively associate with lung cancer patients' overall survival.	('patients', 'Species', '9606', (74, 82))	('lung cancer', 'Phenotype', 'HP:0100526', (62, 73))	('lung cancer', 'Disease', (62, 73))	('overall survival', 'CPA', (84, 100))	('associate', 'Reg', (47, 56))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('lung cancer', 'Disease', 'MESH:D008175', (62, 73))	('miR-133b', 'Var', (9, 17))
410084	28918043	These findings suggested miR-133b may be beneficial for lung cancer patients' prognosis.	('lung cancer', 'Disease', 'MESH:D008175', (56, 67))	('miR-133b', 'Var', (25, 33))	('patients', 'Species', '9606', (68, 76))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('lung cancer', 'Disease', (56, 67))	('lung cancer', 'Phenotype', 'HP:0100526', (56, 67))
410085	28918043	This section mainly generalizes the role of the miR-206/133b cluster in lung cancer treatment and prognosis.	('miR-206/133b', 'Var', (48, 60))	('lung cancer', 'Disease', (72, 83))	('lung cancer', 'Phenotype', 'HP:0100526', (72, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('lung cancer', 'Disease', 'MESH:D008175', (72, 83))
410095	28918043	In NNK-induced rat lung tumor experiments, both miR-206 and miR-133b were found to be upregulated in the rats' serum in the early phase of NNK-induced lung tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('rat', 'Species', '10116', (15, 18))	('NNK', 'Chemical', 'MESH:C016583', (139, 142))	('rat', 'Species', '10116', (105, 108))	('rats', 'Species', '10116', (105, 109))	('lung tumor', 'Phenotype', 'HP:0100526', (151, 161))	('lung tumor', 'Disease', 'MESH:D008175', (19, 29))	('lung tumor', 'Disease', (19, 29))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('NNK', 'Chemical', 'MESH:C016583', (3, 6))	('upregulated', 'PosReg', (86, 97))	('miR-206', 'Var', (48, 55))	('lung tumor', 'Disease', (151, 161))	('lung tumor', 'Phenotype', 'HP:0100526', (19, 29))	('lung tumor', 'Disease', 'MESH:D008175', (151, 161))	('miR-133b', 'Var', (60, 68))
410096	28918043	However, serum miR-206 and miR-133b were remarkably decreased in a late-stage study, which corresponded with the result in NNK-induced rat lung tumor tissues.	('lung tumor', 'Disease', (139, 149))	('rat', 'Species', '10116', (135, 138))	('lung tumor', 'Disease', 'MESH:D008175', (139, 149))	('decreased', 'NegReg', (52, 61))	('miR-133b', 'Var', (27, 35))	('NNK', 'Chemical', 'MESH:C016583', (123, 126))	('lung tumor', 'Phenotype', 'HP:0100526', (139, 149))	('serum miR-206', 'MPA', (9, 22))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))
410099	28918043	Further investigations are required to determine whether miR-133b and miR-206 are diagnosed biomarkers in lung cancer patients.	('lung cancer', 'Disease', (106, 117))	('lung cancer', 'Phenotype', 'HP:0100526', (106, 117))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('miR-206', 'Var', (70, 77))	('lung cancer', 'Disease', 'MESH:D008175', (106, 117))	('patients', 'Species', '9606', (118, 126))	('miR-133b', 'Var', (57, 65))
410100	28918043	In this review, we summarized the roles and mechanisms of the miR-206/133b cluster in lung cancer.	('miR-206/133b', 'Var', (62, 74))	('lung cancer', 'Phenotype', 'HP:0100526', (86, 97))	('lung cancer', 'Disease', (86, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('lung cancer', 'Disease', 'MESH:D008175', (86, 97))
410101	28918043	We discovered miR-206 and miR-133b could promote cell apoptosis, repress cell proliferation, block tumor angiogenesis, and inhibit cell migration and invasion in lung cancer.	('miR-133b', 'Var', (26, 34))	('lung cancer', 'Disease', 'MESH:D008175', (162, 173))	('repress', 'NegReg', (65, 72))	('rat', 'Species', '10116', (139, 142))	('rat', 'Species', '10116', (85, 88))	('miR-206', 'Var', (14, 21))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('promote', 'PosReg', (41, 48))	('inhibit', 'NegReg', (123, 130))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('cell proliferation', 'CPA', (73, 91))	('cell apoptosis', 'CPA', (49, 63))	('lung cancer', 'Disease', (162, 173))	('lung cancer', 'Phenotype', 'HP:0100526', (162, 173))	('block tumor', 'Disease', 'MESH:D006327', (93, 104))	('block tumor', 'Disease', (93, 104))
410104	28918043	Altogether, these findings indicated the miR-206/133b cluster acted as a suppressor in lung cancer by targeting diverse genes and related molecular pathways, which might provide evidence for clinical applications and further study.	('lung cancer', 'Disease', 'MESH:D008175', (87, 98))	('targeting', 'Reg', (102, 111))	('genes', 'Gene', (120, 125))	('lung cancer', 'Disease', (87, 98))	('lung cancer', 'Phenotype', 'HP:0100526', (87, 98))	('molecular pathways', 'Pathway', (138, 156))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('miR-206/133b', 'Var', (41, 53))
410116	27422932	In this study, C-ion RT showed favorable local control with reasonable toxicities, but the results were still unsatisfactory.	('toxicities', 'Disease', 'MESH:D064420', (71, 81))	('C', 'Chemical', 'MESH:D002244', (15, 16))	('C-ion', 'Var', (15, 20))	('toxicities', 'Disease', (71, 81))	('local control', 'CPA', (41, 54))
410193	27422932	It was shown that C-ion RT resulted in favorable OS and LC rates regardless of histological type or tumor size, compared with the conventional treatment.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('C', 'Chemical', 'MESH:D002244', (18, 19))	('LC rates', 'CPA', (56, 64))	('tumor', 'Disease', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('C', 'Chemical', 'MESH:D002244', (57, 58))	('C-ion', 'Var', (18, 23))
410198	27422932	Although the number of patients in this study was small, C-ion RT for locally advanced cervical cancer with bladder invasion showed favorable OS and LC rates, compared with earlier reports for the standard treatment.	('patients', 'Species', '9606', (23, 31))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('LC rates', 'CPA', (149, 157))	('C-ion', 'Var', (57, 62))	('C', 'Chemical', 'MESH:D002244', (57, 58))	('C', 'Chemical', 'MESH:D002244', (150, 151))	('cervical cancer', 'Disease', 'MESH:D002583', (87, 102))	('cervical cancer', 'Disease', (87, 102))
410202	27422932	In addition, C-ion RT had a shorter overall treatment time than standard radiotherapy for cervical cancer.	('shorter', 'NegReg', (28, 35))	('C-ion', 'Var', (13, 18))	('cervical cancer', 'Disease', (90, 105))	('cervical cancer', 'Disease', 'MESH:D002583', (90, 105))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('C', 'Chemical', 'MESH:D002244', (13, 14))
410207	27422932	reported that clinical outcomes of C-ion RT for locally advanced adenocarcinoma of the uterine cervix were relatively better than those of conventional treatments.	('C-ion', 'Var', (35, 40))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('C', 'Chemical', 'MESH:D002244', (35, 36))	('uterine cervix', 'Phenotype', 'HP:0030160', (87, 101))	('adenocarcinoma', 'Disease', (65, 79))	('adenocarcinoma', 'Disease', 'MESH:D000230', (65, 79))
410231	27422932	In conclusion, C-ion RT showed a favorable OS and LC rate regardless of histological type or tumor size, compared with conventional treatment, but the results were still unsatisfactory.	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('C', 'Chemical', 'MESH:D002244', (51, 52))	('C', 'Chemical', 'MESH:D002244', (15, 16))	('tumor', 'Disease', (93, 98))	('C-ion', 'Var', (15, 20))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
410241	26323639	SOX2 gene amplification was observed in 22 patients and protein overexpression in 26 patients.	('SOX2', 'Gene', '6657', (0, 4))	('patients', 'Species', '9606', (43, 51))	('overexpression', 'PosReg', (64, 78))	('patients', 'Species', '9606', (85, 93))	('amplification', 'Var', (10, 23))	('SOX2', 'Gene', (0, 4))	('protein', 'MPA', (56, 63))
410242	26323639	SOX2 overexpression showed significant association with SOX2 gene amplification (p=0.002).	('SOX2', 'Gene', '6657', (0, 4))	('SOX2', 'Gene', (0, 4))	('SOX2', 'Gene', '6657', (56, 60))	('SOX2', 'Gene', (56, 60))	('overexpression', 'PosReg', (5, 19))	('gene amplification', 'Var', (61, 79))	('association', 'Interaction', (39, 50))
410291	26323639	Analysis of the correlation between SOX2 gene amplification and protein expression showed significant association of SOX2 overexpression with SOX2 gene amplification (p=0.002) (Table 2).	('SOX2', 'Gene', (142, 146))	('SOX2', 'Gene', '6657', (117, 121))	('SOX2', 'Gene', '6657', (142, 146))	('gene amplification', 'Var', (147, 165))	('SOX2', 'Gene', (117, 121))	('SOX2', 'Gene', '6657', (36, 40))	('overexpression', 'PosReg', (122, 136))	('SOX2', 'Gene', (36, 40))
410299	26323639	However, SOX2 amplification did not show association with OS (Table 4, Fig.	('SOX2', 'Gene', '6657', (9, 13))	('OS', 'Chemical', '-', (58, 60))	('SOX2', 'Gene', (9, 13))	('amplification', 'Var', (14, 27))
410302	26323639	SOX2 amplification also did not show association with DFS (Table 4, Fig.	('SOX2', 'Gene', '6657', (0, 4))	('amplification', 'Var', (5, 18))	('DFS', 'Disease', (54, 57))	('SOX2', 'Gene', (0, 4))
410323	26323639	Several previous studies investigated whether SOX2 amplification was associated with prognosis in non-small cell lung cancer.	('lung cancer', 'Phenotype', 'HP:0100526', (113, 124))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (98, 124))	('SOX2', 'Gene', '6657', (46, 50))	('associated', 'Reg', (69, 79))	('SOX2', 'Gene', (46, 50))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('non-small cell lung cancer', 'Disease', (98, 124))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (102, 124))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (98, 124))	('amplification', 'Var', (51, 64))
410324	26323639	Although some reported that SOX2 amplification showed close correlation with poor prognosis, others reported that patients with amplification had a good survival outcome.	('SOX2', 'Gene', '6657', (28, 32))	('amplification', 'Var', (128, 141))	('SOX2', 'Gene', (28, 32))	('amplification', 'Var', (33, 46))	('patients', 'Species', '9606', (114, 122))
410326	26323639	However, our findings showed that SOX2 amplification is not associated with survival.	('amplification', 'Var', (39, 52))	('SOX2', 'Gene', '6657', (34, 38))	('associated', 'Reg', (60, 70))	('SOX2', 'Gene', (34, 38))
410330	26323639	However, as several studies showed that the use of small interfering RNA to knockdown SOX2 decreased the growth and radioresistance of cancer cells in contrast to clinical studies, it remains unclear whether this could result in a feasible therapeutic approach.	('cancer', 'Disease', (135, 141))	('small interfering RNA', 'Var', (51, 72))	('knockdown', 'Var', (76, 85))	('SOX2', 'Gene', '6657', (86, 90))	('cancer', 'Disease', 'MESH:D009369', (135, 141))	('SOX2', 'Gene', (86, 90))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('decreased', 'NegReg', (91, 100))
410340	26323639	In addition, despite a very strong positive relationship between SOX2 protein overexpression and gene amplification, gene amplification of SOX2 did not show significant association with OS or DFS, in contrast to SOX2 overexpression.	('SOX2', 'Gene', '6657', (65, 69))	('SOX2', 'Gene', (65, 69))	('DFS', 'Disease', (192, 195))	('OS', 'Chemical', '-', (186, 188))	('gene amplification', 'Var', (117, 135))	('SOX2', 'Gene', '6657', (139, 143))	('SOX2', 'Gene', (139, 143))	('association', 'Interaction', (169, 180))	('SOX2', 'Gene', (212, 216))	('SOX2', 'Gene', '6657', (212, 216))
410341	26323639	Similarly, in a recent large retrospective study, only SOX2 overexpression showed significant association with better overall survival, although significant positive correlation was observed between SOX2 protein overexpression and gene amplification.	('SOX2', 'Gene', (199, 203))	('SOX2', 'Gene', (55, 59))	('SOX2', 'Gene', '6657', (55, 59))	('better', 'PosReg', (111, 117))	('overall', 'MPA', (118, 125))	('gene amplification', 'Var', (231, 249))	('SOX2', 'Gene', '6657', (199, 203))
410349	31991588	However, clinical response rates to anti-CTLA-4 antibodies are lower while the rates of immunotherapy-related adverse events (irAE) are higher than with anti-PD-1 antibodies.	('lower', 'NegReg', (63, 68))	('higher', 'PosReg', (136, 142))	('clinical', 'Species', '191496', (9, 17))	('PD-1', 'Gene', (158, 162))	('clinical response', 'CPA', (9, 26))	('anti-CTLA-4 antibodies', 'Var', (36, 58))	('antibodies', 'Var', (48, 58))	('immunotherapy-related adverse events', 'Disease', (88, 124))	('PD-1', 'Gene', '6622', (158, 162))
410351	31991588	To reinvigorate CTLA-4-targeted immunotherapy, we and others have reported that rather than blocking CTLA-4 interaction with its cognate targets, CD80 and CD86, anti-CTLA-4 antibodies achieve their therapeutic responses through selective depletion of regulatory T cells in the tumor microenvironment.	('therapeutic responses', 'CPA', (198, 219))	('CD80', 'Gene', '941', (146, 150))	('anti-CTLA-4 antibodies', 'Var', (161, 183))	('tumor', 'Disease', 'MESH:D009369', (277, 282))	('interaction', 'Interaction', (108, 119))	('CD86', 'Gene', '942', (155, 159))	('CD80', 'Gene', (146, 150))	('tumor', 'Phenotype', 'HP:0002664', (277, 282))	('CD86', 'Gene', (155, 159))	('tumor', 'Disease', (277, 282))	('depletion', 'NegReg', (238, 247))	('antibodies', 'Var', (173, 183))
410352	31991588	Accordingly, we have developed a new generation of anti-CTLA-4 antibodies with reduced irAE and enhanced antibody-dependent cell-mediated cytotoxicity/phagocytosis (ADCC/ADCP).	('cytotoxicity', 'Disease', 'MESH:D064420', (138, 150))	('reduced', 'NegReg', (79, 86))	('enhanced', 'PosReg', (96, 104))	('irAE', 'MPA', (87, 91))	('antibodies', 'Var', (63, 73))	('cytotoxicity', 'Disease', (138, 150))	('anti-CTLA-4', 'Gene', (51, 62))	('anti-CTLA-4 antibodies', 'Var', (51, 73))
410357	31991588	Surprisingly, non-small cell lung carcinoma (NSCLC) is predicted to be highly responsive to anti-CTLA-4 antibodies.	('non-small cell lung carcinoma', 'Disease', 'MESH:D002289', (14, 43))	('non-small cell lung carcinoma', 'Phenotype', 'HP:0030358', (14, 43))	('anti-CTLA-4', 'Var', (92, 103))	('NSCLC', 'Disease', (45, 50))	('non-small cell lung carcinoma', 'Disease', (14, 43))	('NSCLC', 'Disease', 'MESH:D002289', (45, 50))	('small cell lung carcinoma', 'Phenotype', 'HP:0030357', (18, 43))	('carcinoma', 'Phenotype', 'HP:0030731', (34, 43))
410358	31991588	Single-cell RNAseq analysis and flow cytometry of human NSCLC-infiltrating T cells supports the potential of anti-CTLA-4 antibodies to selectively deplete intratumoral Treg.	('NSCLC', 'Disease', (56, 61))	('anti-CTLA-4', 'Gene', (109, 120))	('anti-CTLA-4 antibodies', 'Var', (109, 131))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('NSCLC', 'Disease', 'MESH:D002289', (56, 61))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('human', 'Species', '9606', (50, 55))	('antibodies', 'Var', (121, 131))	('Treg', 'Chemical', '-', (168, 172))	('tumor', 'Disease', (160, 165))	('deplete', 'NegReg', (147, 154))
410359	31991588	Conclusions: Our in silico and experimental analyses suggest that non-small cell lung carcinoma will likely respond to a new generation of anti-CTLA-4 monoclonal antibodies.	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('non-small cell lung carcinoma', 'Phenotype', 'HP:0030358', (66, 95))	('non-small cell lung carcinoma', 'Disease', 'MESH:D002289', (66, 95))	('anti-CTLA-4', 'Gene', (139, 150))	('non-small cell lung carcinoma', 'Disease', (66, 95))	('small cell lung carcinoma', 'Phenotype', 'HP:0030357', (70, 95))	('anti-CTLA-4', 'Var', (139, 150))
410360	31991588	Our approach provides an objective ranking of the sensitivity of human cancers to anti-CTLA-4 antibodies.	('human', 'Species', '9606', (65, 70))	('cancers', 'Disease', 'MESH:D009369', (71, 78))	('cancers', 'Phenotype', 'HP:0002664', (71, 78))	('anti-CTLA-4', 'Var', (82, 93))	('cancers', 'Disease', (71, 78))	('anti-CTLA-4', 'Gene', (82, 93))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))
410362	31991588	As the first immune checkpoint explored for cancer immunotherapy, CTLA-4 was validated as an immunotherapeutic target after FDA approval of Ipilimumab for human use, either as monotherapy for melanoma, or as part of combination therapy with the anti-PD-1 antibody, Nivolumab, in melanoma, renal cancer, and colorectal cancer with microsatellite instability.	('cancer', 'Disease', (318, 324))	('colorectal cancer', 'Phenotype', 'HP:0003003', (307, 324))	('Ipilimumab', 'Chemical', 'MESH:D000074324', (140, 150))	('cancer', 'Disease', (295, 301))	('cancer', 'Phenotype', 'HP:0002664', (318, 324))	('cancer', 'Phenotype', 'HP:0002664', (295, 301))	('PD-1', 'Gene', (250, 254))	('microsatellite instability', 'Var', (330, 356))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('renal cancer', 'Disease', (289, 301))	('renal cancer', 'Phenotype', 'HP:0009726', (289, 301))	('melanoma', 'Disease', 'MESH:D008545', (192, 200))	('melanoma', 'Disease', 'MESH:D008545', (279, 287))	('cancer', 'Disease', 'MESH:D009369', (318, 324))	('colorectal cancer', 'Disease', 'MESH:D015179', (307, 324))	('cancer', 'Disease', 'MESH:D009369', (295, 301))	('renal cancer', 'Disease', 'MESH:D007680', (289, 301))	('colorectal cancer', 'Disease', (307, 324))	('PD-1', 'Gene', '6622', (250, 254))	('Nivolumab', 'Chemical', 'MESH:D000077594', (265, 274))	('cancer', 'Disease', (44, 50))	('human', 'Species', '9606', (155, 160))	('melanoma', 'Phenotype', 'HP:0002861', (192, 200))	('melanoma', 'Disease', (192, 200))	('melanoma', 'Phenotype', 'HP:0002861', (279, 287))	('melanoma', 'Disease', (279, 287))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
410366	31991588	An important development in cancer immunotherapy is a re-evaluation of the mechanism by which anti-CTLA-4 antibodies induce tumor rejection.	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('tumor', 'Disease', (124, 129))	('anti-CTLA-4', 'Var', (94, 105))	('induce', 'PosReg', (117, 123))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('cancer', 'Disease', (28, 34))	('anti-CTLA-4', 'Gene', (94, 105))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
410368	31991588	Second, several groups, including ours, have reported that the therapeutic effect of anti-CTLA-4 antibodies requires ADCC activity that selectively depletes regulatory T cells in the tumor microenvironment.	('depletes', 'NegReg', (148, 156))	('antibodies', 'Var', (97, 107))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('anti-CTLA-4', 'Gene', (85, 96))	('anti-CTLA-4 antibodies', 'Var', (85, 107))	('tumor', 'Disease', (183, 188))	('regulatory T cells', 'MPA', (157, 175))	('ADCC', 'Protein', (117, 121))
410369	31991588	These two lines of fundamental studies have inspired the development of the next generation of anti-CTLA-4 antibodies with enhanced ADCC activity or preferential activation in the tumor microenvironment.	('enhanced', 'PosReg', (123, 131))	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('anti-CTLA-4', 'Gene', (95, 106))	('tumor', 'Disease', (180, 185))	('activity', 'MPA', (137, 145))	('ADCC', 'Protein', (132, 136))	('anti-CTLA-4', 'Var', (95, 106))
410400	31991588	Cells were stained with fluorochrome-conjugated monoclonal antibodies against mouse CD8 (Cat# 100748, Biolegend, Cat# 45-0081-82, eBioscience), mouse CD4 (Cat# 100453, Biolegend, Cat# 100531, Biolegend), mouse CD45 (Cat# 103151, Biolegend, Cat# 47-0451-82, eBioscience), mouse Foxp3 (Cat# 48-5773-82, Thermo Fisher Scientific, Cat# 17-5773-82, eBioscience), human CTLA-4 (Cat# 369604, Biolegend), and Mouse IgG2a, kappa Isotype Ctrl CTLA-4 (Cat# 400214, Biolegend).	('mouse', 'Species', '10090', (144, 149))	('CD8', 'Gene', '925', (84, 87))	('CD45', 'Gene', '19264', (210, 214))	('mouse', 'Species', '10090', (271, 276))	('Mouse', 'Species', '10090', (401, 406))	('IgG2a', 'Gene', '668478', (407, 412))	('Cat', 'Var', (216, 219))	('IgG2a', 'Gene', (407, 412))	('mouse', 'Species', '10090', (204, 209))	('mouse', 'Species', '10090', (78, 83))	('human', 'Species', '9606', (358, 363))	('Cat# 369604', 'Var', (372, 383))	('CD8', 'Gene', (84, 87))	('CD45', 'Gene', (210, 214))
410406	31991588	We used the following formula to estimate the total ranking number for each cancer type: where the RANKADCC represents the "ADCC Features" partitioning, that was the mean value of 3 ranking numbers based on the estimated cell fraction of Treg cells, FCGR3A gene expression, and FCGR3A SNP rate for V158F.	('FCGR3A', 'Gene', '2214', (250, 256))	('Treg', 'Chemical', '-', (238, 242))	('FCGR3A', 'Gene', '2214', (278, 284))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('FCGR3A', 'Gene', (250, 256))	('V158F', 'Mutation', 'rs396991', (298, 303))	('V158F', 'Var', (298, 303))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('FCGR3A', 'Gene', (278, 284))
410413	31991588	We and others have previously reported that anti-CTLA-4 antibodies, including Ipilimumab selectively depleted Treg in the mouse tumor microenvironment but not in the spleen.	('Treg', 'CPA', (110, 114))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('anti-CTLA-4', 'Gene', (44, 55))	('Treg', 'Chemical', '-', (110, 114))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('Ipilimumab', 'Chemical', 'MESH:D000074324', (78, 88))	('antibodies', 'Var', (56, 66))	('tumor', 'Disease', (128, 133))	('depleted', 'NegReg', (101, 109))	('mouse', 'Species', '10090', (122, 127))
410414	31991588	More recently, we reported that pH-sensitive anti-CTLA-4 antibodies are more effective in ADCC and tumor rejection, which raise the issue as to whether increasing ADCC activity jeopardizes the selectivity of the antibodies.	('tumor', 'Disease', (99, 104))	('antibodies', 'Var', (57, 67))	('ADCC', 'Disease', (90, 94))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('anti-CTLA-4', 'Gene', (45, 56))	('anti-CTLA-4 antibodies', 'Var', (45, 67))
410462	31991588	The increased mutation rates lead to an expanded pool of potential neo-tumor antigens that also correlate with responsiveness to Ipilimumab (Supplementary Materials Figure S2A).	('Ipilimumab', 'Chemical', 'MESH:D000074324', (129, 139))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('mutation', 'Var', (14, 22))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('pool of', 'MPA', (49, 56))	('tumor', 'Disease', (71, 76))
410488	31991588	Since this population also expressed the highest levels of CTLA-4 (Figure 6c), it is liely that ADCC-competent anti-CTLA-4 would be highly selective for activated Treg in NSCLC.	('NSCLC', 'Disease', (171, 176))	('Treg', 'Chemical', '-', (163, 167))	('NSCLC', 'Disease', 'MESH:D002289', (171, 176))	('anti-CTLA-4', 'Var', (111, 122))
410498	31991588	In addition, in a mouse model with the human FcR system, it was demonstrated that binding to FCGRIIIA is critical for optimal ADCC of Treg and tumor rejection by anti-CTLA-4 antibodies.	('tumor', 'Disease', (143, 148))	('mouse', 'Species', '10090', (18, 23))	('Treg', 'Chemical', '-', (134, 138))	('Treg', 'CPA', (134, 138))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('anti-CTLA-4', 'Var', (162, 173))	('human', 'Species', '9606', (39, 44))	('binding', 'Interaction', (82, 89))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('anti-CTLA-4', 'Gene', (162, 173))
410510	31991588	Therefore, it is likely multiple cancer types may well respond to anti-CTLA-4 therapy if appropriate antibodies are employed.	('anti-CTLA-4', 'Var', (66, 77))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('multiple cancer', 'Disease', 'MESH:D009369', (24, 39))	('multiple cancer', 'Disease', (24, 39))
410513	31991588	Our re-analysis of scRNAseq data of tumor-infiltrating T cells in NSCLC patients suggests that selective Treg depletion is achievable with anti-CTLA-4 antibodies.	('Treg', 'Chemical', '-', (105, 109))	('NSCLC', 'Disease', (66, 71))	('NSCLC', 'Disease', 'MESH:D002289', (66, 71))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('depletion', 'NegReg', (110, 119))	('tumor', 'Disease', (36, 41))	('anti-CTLA-4', 'Var', (139, 150))	('patients', 'Species', '9606', (72, 80))
410514	31991588	While the high ranking suggests NSCLC as a prime candidate for new anti-CTLA-4 antibodies, it is worth considering the fact that multiple randomized trials have failed to show significant improvement in survival of patients receiving Ipilimumab in combination with chemotherapy.	('patients', 'Species', '9606', (215, 223))	('anti-CTLA-4', 'Gene', (67, 78))	('anti-CTLA-4 antibodies', 'Var', (67, 89))	('antibodies', 'Var', (79, 89))	('NSCLC', 'Disease', (32, 37))	('Ipilimumab', 'Chemical', 'MESH:D000074324', (234, 244))	('NSCLC', 'Disease', 'MESH:D002289', (32, 37))
410517	31991588	Therefore, a new generation of anti-CTLA-4 antibodies must show higher anti-tumor activity in order to achieve better outcomes.	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('anti-CTLA-4', 'Var', (31, 42))	('tumor', 'Disease', (76, 81))	('anti-CTLA-4', 'Gene', (31, 42))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
410520	31991588	In this context, we recently showed that increasing pH sensitivity of anti-CTLA-4 antibodies improves both therapeutic effect and safety when compared directly with Ipilimumab.	('therapeutic effect', 'CPA', (107, 125))	('safety', 'CPA', (130, 136))	('antibodies', 'Var', (82, 92))	('Ipilimumab', 'Chemical', 'MESH:D000074324', (165, 175))	('anti-CTLA-4', 'Gene', (70, 81))	('anti-CTLA-4 antibodies', 'Var', (70, 92))	('improves', 'PosReg', (93, 101))
410521	31991588	Since Treg has been implicated in pathogenesis and prognosis of multiple cancer types, it is anticipated that anti-CTLA-4 antibodies that effectively and selectively deplete Treg in tumor microenvironment would have a broad impact in cancer immunotherapy.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('multiple cancer', 'Disease', (64, 79))	('tumor', 'Disease', (182, 187))	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('antibodies', 'Var', (122, 132))	('deplete', 'NegReg', (166, 173))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('Treg', 'Chemical', '-', (174, 178))	('multiple cancer', 'Disease', 'MESH:D009369', (64, 79))	('cancer', 'Disease', 'MESH:D009369', (234, 240))	('Treg', 'Chemical', '-', (6, 10))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('cancer', 'Disease', (234, 240))	('Treg', 'Protein', (174, 178))	('anti-CTLA-4', 'Gene', (110, 121))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
410522	31991588	In summary, our in silico and experimental analyses suggest that non-small cell lung carcinoma will likely respond to a new generation of anti-CTLA-4 monoclonal antibodies.	('anti-CTLA-4', 'Gene', (138, 149))	('non-small cell lung carcinoma', 'Phenotype', 'HP:0030358', (65, 94))	('non-small cell lung carcinoma', 'Disease', (65, 94))	('small cell lung carcinoma', 'Phenotype', 'HP:0030357', (69, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('anti-CTLA-4', 'Var', (138, 149))	('non-small cell lung carcinoma', 'Disease', 'MESH:D002289', (65, 94))
410530	31991588	TCGA The Cancer Genome Atlas  GSEA Gene-set Enrichment Analysis  ADCC Antibody Dependent Cell-mediated Cytotoxicity/phagocytosis  ADCP Antibody Dependent Cell-mediated Phagocytosis  NSCLC Non Small Cell Lung Cancer  TMB Tumor Mutation Burden	('Cancer Genome Atlas', 'Disease', (9, 28))	('Cytotoxicity', 'Disease', 'MESH:D064420', (103, 115))	('NSCLC', 'Disease', (182, 187))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (9, 28))	('TMB', 'Chemical', '-', (216, 219))	('Tumor', 'Phenotype', 'HP:0002664', (220, 225))	('NSCLC', 'Disease', 'MESH:D002289', (182, 187))	('Mutation', 'Var', (226, 234))	('Cytotoxicity', 'Disease', (103, 115))	('Non Small Cell Lung Cancer  TMB Tumor', 'Disease', (188, 225))	('Lung Cancer', 'Phenotype', 'HP:0100526', (203, 214))	('Small Cell Lung Cancer', 'Phenotype', 'HP:0030357', (192, 214))	('GSEA', 'Chemical', '-', (30, 34))	('Cancer', 'Phenotype', 'HP:0002664', (9, 15))	('Cancer', 'Phenotype', 'HP:0002664', (208, 214))
410544	32080184	In cancer in particular, genomic instability, epigenetic modifications, and alterations in transcription factors impact miRNA loci, which can change the expression of precursor miRNA, resulting in altered levels of both the 5p and 3p strands.	('alterations', 'Var', (76, 87))	('transcription factors', 'Gene', (91, 112))	('miR', 'Gene', '220972', (120, 123))	('miR', 'Gene', (120, 123))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('genomic instability', 'Var', (25, 44))	('altered', 'Reg', (197, 204))	('cancer', 'Disease', (3, 9))	('change', 'Reg', (142, 148))	('miR', 'Gene', (177, 180))	('miR', 'Gene', '220972', (177, 180))	('epigenetic modifications', 'Var', (46, 70))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
410550	32080184	In miR-17 transgenic mice, both the 5p and 3p strands are overexpressed and the mice are predisposed to hepatocellular carcinoma.	('transgenic', 'Var', (10, 20))	('overexpressed', 'PosReg', (58, 71))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (104, 128))	('mice', 'Species', '10090', (21, 25))	('hepatocellular carcinoma', 'Disease', (104, 128))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (104, 128))	('mice', 'Species', '10090', (80, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('miR-17', 'Gene', (3, 9))	('transgenic mice', 'Species', '10090', (10, 25))
410551	32080184	Moreover, forced co-overexpression of miR-17-5p and 3p strands increased prostate cancer xenograft growth and invasion.	('prostate cancer', 'Disease', (73, 88))	('miR-17-5p', 'Gene', '406952', (38, 47))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('increased', 'PosReg', (63, 72))	('3p strands', 'Var', (52, 62))	('miR-17-5p', 'Gene', (38, 47))	('prostate cancer', 'Disease', 'MESH:D011471', (73, 88))	('prostate cancer', 'Phenotype', 'HP:0012125', (73, 88))	('invasion', 'CPA', (110, 118))
410565	32080184	Genome-scale si/shRNA or CRISPR-based loss-of-function screens for 290 diverse cancer cell lines were available for the 9 cancer types we studied here (Methods section, Supplementary Table 2).	('cancer type', 'Disease', (122, 133))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('loss-of-function', 'NegReg', (38, 54))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('cancer type', 'Disease', 'MESH:D009369', (122, 133))	('si/shRNA', 'Var', (13, 21))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))
410566	32080184	This massive-scale resource provided an unprecedented opportunity to understand the relationship between miRNA expression and cell viability/growth from miRNA regulating genes that reduce the viability/growth of specific cancer cells upon their inactivation.	('miR', 'Gene', (105, 108))	('miR', 'Gene', '220972', (153, 156))	('miR', 'Gene', (153, 156))	('cancer', 'Disease', 'MESH:D009369', (221, 227))	('viability/growth', 'CPA', (192, 208))	('cancer', 'Disease', (221, 227))	('reduce', 'NegReg', (181, 187))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('inactivation', 'Var', (245, 257))	('miR', 'Gene', '220972', (105, 108))
410580	32080184	These cell lines correspond to eight cancer types (BLCA, BRCA, ESCA, LIHC, LUAD, LUSC, STAD, UCEC) in TCGA in which miR-30a and/or miR-145 strands were downregulated (Fig.	('LUAD', 'Disease', (75, 79))	('miR-145', 'Gene', (131, 138))	('cancer type', 'Disease', (37, 48))	('STAD', 'Disease', (87, 91))	('cancer type', 'Disease', 'MESH:D009369', (37, 48))	('ESCA', 'Disease', (63, 67))	('LUSC', 'Disease', (81, 85))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('BRCA', 'Gene', '672', (57, 61))	('downregulated', 'NegReg', (152, 165))	('LIHC', 'Disease', (69, 73))	('BRCA', 'Gene', (57, 61))	('miR-30a', 'Var', (116, 123))
410591	32080184	For 14 different cancers, we identified 178 KEGG pathways (5p/3p pair-pathway-cancer combinations = 1252) that were altered in one or more cancer types potentially due to dysregulation of at least one 5p/3p pair (Fig.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('cancer type', 'Disease', 'MESH:D009369', (139, 150))	('dysregulation', 'Var', (171, 184))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('cancers', 'Phenotype', 'HP:0002664', (17, 24))	('cancers', 'Disease', (17, 24))	('cancer', 'Disease', (17, 23))	('cancers', 'Disease', 'MESH:D009369', (17, 24))	('cancer type', 'Disease', (139, 150))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))	('KEGG pathways', 'Pathway', (44, 57))	('altered', 'Reg', (116, 123))	('cancer', 'Disease', (139, 145))
410599	32080184	The top five recurrently associated 5p/3p-pathway pairs were comprised of two upregulated miRNA that recurrently downregulated three pathways (miR-17-5p/3p-Proteoglycans in cancer, miR-17-5p/3p-Rap1 signaling, and miR-93-5p/3p-Vascular smooth muscle contraction) and two downregulated 5p/3p pairs (miR-30a-5p/3p and miR-145-5p/3p) that recurrently upregulated cell cycle pathway genes in at least 2/3rd of the cancer types in which the 5p/3p pairs were dysregulated (Fig.	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('Rap1', 'Gene', (194, 198))	('cell cycle pathway', 'Pathway', (360, 378))	('miR', 'Gene', '220972', (298, 301))	('miR', 'Gene', (214, 217))	('cancer type', 'Disease', 'MESH:D009369', (410, 421))	('miR', 'Gene', (181, 184))	('miR', 'Gene', '220972', (90, 93))	('miR-93', 'Gene', (214, 220))	('pathways', 'Pathway', (133, 141))	('cancer', 'Disease', 'MESH:D009369', (410, 416))	('downregulated', 'NegReg', (113, 126))	('miR', 'Gene', (298, 301))	('miR-93', 'Gene', '407051', (214, 220))	('miR', 'Gene', (90, 93))	('cancer', 'Disease', (173, 179))	('miR', 'Gene', '220972', (143, 146))	('miR', 'Gene', '220972', (316, 319))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('miR-17-5p', 'Gene', '406952', (181, 190))	('dysregulated', 'Var', (453, 465))	('miR-17-5p', 'Gene', (181, 190))	('miR-17-5p', 'Gene', '406952', (143, 152))	('miR', 'Gene', '220972', (214, 217))	('miR', 'Gene', (143, 146))	('miR-17-5p', 'Gene', (143, 152))	('cancer', 'Disease', (410, 416))	('miR', 'Gene', '220972', (181, 184))	('Rap1', 'Gene', '5906', (194, 198))	('miR', 'Gene', (316, 319))	('cancer', 'Phenotype', 'HP:0002664', (410, 416))	('upregulated', 'PosReg', (348, 359))	('cancer type', 'Disease', (410, 421))
410607	32080184	With the analysis of microarray expression profiles (GSE48414) from the Gene Expression Omnibus database, we determined significant downregulation of both miR-145-5p (3.12-fold-change; P = 2.52 x 10-16; t-test) and miR-145-3p (4.20-fold-change; P = 2.64 x 10-21; t-test) in the lung adenocarcinoma patient cohort compared to normal lung tissue (Fig.	('downregulation', 'NegReg', (132, 146))	('lung adenocarcinoma', 'Disease', (278, 297))	('patient', 'Species', '9606', (298, 305))	('miR-145-5p', 'Gene', (155, 165))	('miR-145-3p', 'Var', (215, 225))	('carcinoma', 'Phenotype', 'HP:0030731', (288, 297))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (278, 297))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (278, 297))
410608	32080184	Furthermore, analyzing another independent data set (GSE107008), we determined transcriptome-wide mRNA expression changes induced by overexpression of either the miR-145-5p or 3p strand in LUAD and ESCA cancer cell lines.	('cancer', 'Disease', (203, 209))	('cancer', 'Disease', 'MESH:D009369', (203, 209))	('overexpression', 'PosReg', (133, 147))	('mRNA expression changes', 'MPA', (98, 121))	('miR-145-5p', 'Var', (162, 172))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))
410609	32080184	Using GSEA with the gene sets available in the KEGG or Reactome databases, we determined that overexpression of miR-145-5p or miR-145-3p resulted in suppression of pathways involved in cell cycle progression (Fig.	('cell cycle progression', 'CPA', (185, 207))	('miR-145-5p', 'Var', (112, 122))	('suppression', 'NegReg', (149, 160))	('pathways', 'Pathway', (164, 172))	('miR-145-3p', 'Var', (126, 136))	('GSEA', 'Chemical', '-', (6, 10))
410610	32080184	Cell cycle, DNA replication, and mitotic cell cycle were among the top ten downregulated pathways that significantly decreased (FDR = 0) with increased expression of miR-145-5p or miR-145-3p in both LUAD and ESCA cancer cell lines.	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('miR-145-5p', 'Var', (166, 176))	('miR-145-3p', 'Var', (180, 190))	('increased', 'PosReg', (142, 151))	('decreased', 'NegReg', (117, 126))	('Cell cycle', 'CPA', (0, 10))	('cancer', 'Disease', 'MESH:D009369', (213, 219))	('cancer', 'Disease', (213, 219))	('DNA replication', 'CPA', (12, 27))	('mitotic cell cycle', 'CPA', (33, 51))	('expression', 'MPA', (152, 162))
410612	32080184	Furthermore, using quantitative reverse transcription PCR (qRT-PCR) we confirmed significant downregulation of both miR-30a-5p (P = 1.98 x 10-6; t-test) and miR-30a-3p (P = 2.60 x 10-8, t-test) in our own lung adenocarcinoma patient cohort compared to normal lung tissue (Fig.	('miR-30a-5p', 'Gene', (116, 126))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (205, 224))	('miR-30a-3p', 'Var', (157, 167))	('lung adenocarcinoma', 'Disease', (205, 224))	('carcinoma', 'Phenotype', 'HP:0030731', (215, 224))	('downregulation', 'NegReg', (93, 107))	('patient', 'Species', '9606', (225, 232))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (205, 224))
410613	32080184	Similarly, we determined levels of miR-30a-5p and miR-30a-3p were significantly (P < 6.63 x 10-4, t-test) reduced across a panel of lung adenocarcinoma cell lines compared to a normal bronchial epithelial cell line (Fig.	('miR-30a-3p', 'Var', (50, 60))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (132, 151))	('lung adenocarcinoma', 'Disease', (132, 151))	('carcinoma', 'Phenotype', 'HP:0030731', (142, 151))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (132, 151))	('miR-30a-5p', 'Var', (35, 45))	('reduced', 'NegReg', (106, 113))
410615	32080184	Using GSEA, based on KEGG and Reactome databases, we determined several cell cycle-linked pathways, including cell cycle, mitotic cell cycle, DNA replication, mitotic prometaphase, and mitotic M-M/G1 phase were in the top ten pathway list that were significantly (FDR < 0.05 for KEGG and FDR = 0 for Reactome) downregulated in both miR-30a-5p and miR-30a-3p transfected lung adenocarcinoma cells (Fig.	('cell cycle-linked pathways', 'Pathway', (72, 98))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (370, 389))	('miR-30a-3p transfected', 'Var', (347, 369))	('miR-30a-5p', 'Var', (332, 342))	('mitotic', 'CPA', (122, 129))	('cell cycle', 'CPA', (110, 120))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (370, 389))	('carcinoma', 'Phenotype', 'HP:0030731', (380, 389))	('lung adenocarcinoma', 'Disease', (370, 389))	('downregulated', 'NegReg', (310, 323))	('GSEA', 'Chemical', '-', (6, 10))	('mitotic', 'CPA', (159, 166))
410616	32080184	The cell cycle pathway was predicted to be regulated by miR-145-5p/3p in 6 different TCGA cancers (BLCA, ESCA, LUAD, LUSC, STAD, UCEC) and by miR-30a-5p/3p in four cancers (ESCA, LUAD, LUSC, STAD).	('LUSC', 'Disease', (185, 189))	('cancers', 'Disease', (90, 97))	('miR-30a-5p/3p', 'Var', (142, 155))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('regulated', 'Reg', (43, 52))	('cell cycle pathway', 'Pathway', (4, 22))	('LUSC', 'Disease', (117, 121))	('miR-145-5p/3p', 'Var', (56, 69))	('cancers', 'Phenotype', 'HP:0002664', (164, 171))	('LUAD', 'Disease', (111, 115))	('cancers', 'Disease', (164, 171))	('cancers', 'Disease', 'MESH:D009369', (164, 171))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('ESCA', 'Disease', (105, 109))	('STAD', 'Disease', (123, 127))	('cancers', 'Disease', 'MESH:D009369', (90, 97))	('LUAD', 'Disease', (179, 183))
410618	32080184	We determined that individual patients with higher cell cycle activation signals had significantly lower expression of miR-145-5p, miR-145-3p, miR-30a-5p, and miR-30a-3p compared to patients with a lower cell cycle activation signal of the above cancer types, except UCEC (Supplementary Fig.	('cancer type', 'Disease', 'MESH:D009369', (246, 257))	('lower', 'NegReg', (99, 104))	('miR-145-3p', 'Var', (131, 141))	('higher', 'PosReg', (44, 50))	('UCEC', 'Disease', (267, 271))	('miR-30a-3p', 'Var', (159, 169))	('cell cycle', 'CPA', (51, 61))	('miR-30a-5p', 'Var', (143, 153))	('miR-145-5p', 'Var', (119, 129))	('patients', 'Species', '9606', (30, 38))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))	('patients', 'Species', '9606', (182, 190))	('cancer type', 'Disease', (246, 257))	('expression', 'MPA', (105, 115))
410620	32080184	As previous reports confirmed increased miR-145-5p and miR-145-3p expression decreases proliferation and movement of lung adenocarcinoma, lung squamous cell carcinoma, and bladder cancer cell lines, we focused on miR-30a.	('movement of lung adenocarcinoma', 'Disease', (105, 136))	('movement of lung adenocarcinoma', 'Disease', 'MESH:C538231', (105, 136))	('miR-145-3p', 'Var', (55, 65))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('bladder cancer', 'Phenotype', 'HP:0009725', (172, 186))	('miR-145-5p', 'Var', (40, 50))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (138, 166))	('carcinoma', 'Phenotype', 'HP:0030731', (157, 166))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (117, 136))	('bladder cancer', 'Disease', 'MESH:D001749', (172, 186))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (143, 166))	('lung squamous cell carcinoma', 'Disease', (138, 166))	('decreases', 'NegReg', (77, 86))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('bladder cancer', 'Disease', (172, 186))
410621	32080184	Our RNA-seq data revealed significantly downregulated genes (>=2-fold-change with BH adjusted P < 0.05) either in miR-30a-5p or miR-30a-3p transfected lung adenocarcinoma cells compared to the cells transfected with negative control RNA.	('downregulated', 'NegReg', (40, 53))	('BH', 'Chemical', '-', (82, 84))	('miR-30a-3p', 'Var', (128, 138))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (151, 170))	('carcinoma', 'Phenotype', 'HP:0030731', (161, 170))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (151, 170))	('miR-30a-5p', 'Var', (114, 124))	('lung adenocarcinoma', 'Disease', (151, 170))
410623	32080184	Increased levels of either miR-30a-5p or 3p at two different concentrations resulted in decreased lung cancer cell growth compared to the control RNA in both lung cancer lines (Fig.	('lung cancer', 'Disease', (158, 169))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('lung cancer', 'Phenotype', 'HP:0100526', (158, 169))	('lung cancer', 'Phenotype', 'HP:0100526', (98, 109))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('miR-30a-5p', 'Var', (27, 37))	('decreased lung cancer', 'Disease', 'MESH:D008175', (88, 109))	('lung cancer', 'Disease', 'MESH:D008175', (158, 169))	('lung cancer', 'Disease', 'MESH:D008175', (98, 109))	('decreased lung cancer', 'Disease', (88, 109))	('decreased lung', 'Phenotype', 'HP:0002089', (88, 102))
410624	32080184	As previously reported, miR-30a-5p inhibited cell migration in A549 cells.	('miR-30a-5p', 'Var', (24, 34))	('A549', 'CellLine', 'CVCL:0023', (63, 67))	('cell migration in A549 cells', 'CPA', (45, 73))	('inhibited', 'NegReg', (35, 44))
410626	32080184	Since pathways can be modulated by changes in gene expression due to genetic alterations (e.g., copy number) or epigenetic modification (e.g., methylation), we investigated whether miR-30a and miR-145-mediated cell cycle pathway modulation in 14 TCGA cancer types were influenced by such modifications.	('influenced', 'Reg', (269, 279))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('methylation', 'Var', (143, 154))	('cancer type', 'Disease', (251, 262))	('modulation', 'Reg', (229, 239))	('modulated', 'Reg', (22, 31))	('miR-30a', 'Gene', (181, 188))	('modifications', 'Var', (288, 301))	('copy number', 'Var', (96, 107))	('changes', 'Reg', (35, 42))	('cancer type', 'Disease', 'MESH:D009369', (251, 262))	('miR-145-mediated', 'Gene', (193, 209))	('epigenetic modification', 'Var', (112, 135))
410628	32080184	For LUAD, we identified predicted target mRNA that had significant negative associations (BH adjusted regression P < 0.05) with miR-30a-5p, 30a-3p, 145-5p, and 145-3p.	('30a-3p', 'Var', (140, 146))	('BH', 'Chemical', '-', (90, 92))	('145-3p', 'Var', (160, 166))	('associations', 'Interaction', (76, 88))	('145-5p', 'Var', (148, 154))	('miR-30a-5p', 'Var', (128, 138))	('negative', 'NegReg', (67, 75))
410632	32080184	The results suggest pan-cancer suppression of cell cycle pathway genes by miR-145 and miR-30a 5p/3p pairs are independent from DNA copy number and methylation changes.	('suppression', 'NegReg', (31, 42))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('cell cycle pathway genes', 'Gene', (46, 70))	('miR-30a', 'Var', (86, 93))	('miR-145', 'Var', (74, 81))	('cancer', 'Disease', (24, 30))	('cancer', 'Disease', 'MESH:D009369', (24, 30))
410633	32080184	To estimate the impact of 5p/3p combined-mediated regulation of gene expression, we stratified patient samples from individual cancer types into lower and higher groups based on median expression of miR-30a-5p and miR-30a-3p.	('cancer type', 'Disease', (127, 138))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('patient', 'Species', '9606', (95, 102))	('cancer type', 'Disease', 'MESH:D009369', (127, 138))	('miR-30a-5p', 'Var', (199, 209))	('miR-30a-3p', 'Var', (214, 224))
410634	32080184	Notably, we observed cell cycle regulating genes recurrently associated with both miR-30a-5p and 3p had higher expression in the low-sample group and lower expression in the high sample group across cancer types (Fig.	('lower', 'NegReg', (150, 155))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('cancer type', 'Disease', 'MESH:D009369', (199, 210))	('miR-30a-5p', 'Var', (82, 92))	('cancer type', 'Disease', (199, 210))	('expression', 'MPA', (111, 121))	('cell cycle regulating genes', 'Gene', (21, 48))	('expression', 'MPA', (156, 166))	('higher', 'PosReg', (104, 110))	('associated', 'Reg', (61, 71))
410635	32080184	To evaluate the biological consequences when both strands of miR-30a are dysregulated, we simultaneously overexpressed miR-30a-5p and miR-30a-3p in A549 and H1993 lung cancer cell lines.	('miR-30a-3p', 'Var', (134, 144))	('lung cancer', 'Disease', 'MESH:D008175', (163, 174))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('miR-30a-5p', 'Var', (119, 129))	('A549', 'CellLine', 'CVCL:0023', (148, 152))	('lung cancer', 'Phenotype', 'HP:0100526', (163, 174))	('overexpressed', 'PosReg', (105, 118))	('lung cancer', 'Disease', (163, 174))	('H1993', 'CellLine', 'CVCL:1512', (157, 162))
410636	32080184	Moreover, the combination of both miR-30a-5p and miR-30a-3p at a lower concentration resulted in either a similar effect (H1993 cells) or a greater negative effect (A549 cells) on cell growth compared to when either miR-30a-5p or miR-30a-3p were overexpressed individually at twice the concentration (Fig.	('A549', 'CellLine', 'CVCL:0023', (165, 169))	('cell growth', 'CPA', (180, 191))	('miR-30a-5p', 'Var', (34, 44))	('miR-30a-3p', 'Var', (49, 59))	('negative', 'NegReg', (148, 156))	('H1993', 'CellLine', 'CVCL:1512', (122, 127))
410638	32080184	Transwell migration assays showed that both miR-30a-5p and miR-30a-3p together had a cooperative negative effect on lung cancer cell migration (Fig.	('lung cancer', 'Disease', (116, 127))	('miR-30a-5p', 'Var', (44, 54))	('lung cancer', 'Phenotype', 'HP:0100526', (116, 127))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('miR-30a-3p', 'Var', (59, 69))	('negative', 'NegReg', (97, 105))	('lung cancer', 'Disease', 'MESH:D008175', (116, 127))
410654	32080184	Altogether, the data reveal that miR-145-5p, miR-145-3p, miR-30a-5p, and miR-30a-3p are coordinately downregulated by multiple cancers due to their regulation of core processes that inhibit tumorigenesis and tumor progression that significantly contribute to patient survival.	('miR-145-3p', 'Var', (45, 55))	('multiple cancers', 'Disease', (118, 134))	('miR-30a-5p', 'Var', (57, 67))	('miR-145-5p', 'Var', (33, 43))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('tumor', 'Disease', 'MESH:D009369', (208, 213))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('multiple cancers', 'Disease', 'MESH:D009369', (118, 134))	('tumor', 'Disease', (190, 195))	('regulation', 'Reg', (148, 158))	('inhibit', 'NegReg', (182, 189))	('miR-30a-3p', 'Var', (73, 83))	('tumor', 'Disease', (208, 213))	('cancers', 'Phenotype', 'HP:0002664', (127, 134))	('downregulated', 'NegReg', (101, 114))	('patient', 'Species', '9606', (259, 266))
410660	32080184	Utilizing RNAi and CRISPR, two independent screening platforms, we determined reproducible associations between miRNA 5p/3p dysregulation and modulation of cancer cell viability/growth across cancers.	('cancer', 'Disease', (156, 162))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('miR', 'Gene', '220972', (112, 115))	('miR', 'Gene', (112, 115))	('cancers', 'Disease', 'MESH:D009369', (192, 199))	('cancers', 'Phenotype', 'HP:0002664', (192, 199))	('dysregulation', 'Var', (124, 137))	('cancer', 'Disease', (192, 198))	('cancers', 'Disease', (192, 199))	('cancer', 'Disease', 'MESH:D009369', (192, 198))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))
410665	32080184	Taken together, these two massive-scale data analyses allowed us to pinpoint miRNA 5p/3p pairs whose dysregulation may consequently drive pathway/systems-level changes to favor cancer cells for survival, growth, and progression, referred to as phenotypic plasticity in cancer.	('changes', 'Reg', (160, 167))	('miR', 'Gene', (77, 80))	('cancer', 'Disease', (177, 183))	('cancer', 'Disease', 'MESH:D009369', (177, 183))	('cancer', 'Phenotype', 'HP:0002664', (269, 275))	('growth', 'CPA', (204, 210))	('progression', 'CPA', (216, 227))	('dysregulation', 'Var', (101, 114))	('favor', 'PosReg', (171, 176))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('cancer', 'Disease', (269, 275))	('cancer', 'Disease', 'MESH:D009369', (269, 275))	('miR', 'Gene', '220972', (77, 80))
410671	32080184	Our study examined whether individual strands of high-confidence miR-145 and miR-30a can independently suppress the genes in crucial tumorigenic processes.	('genes', 'MPA', (116, 121))	('suppress', 'NegReg', (103, 111))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('miR-30a', 'Var', (77, 84))	('tumor', 'Disease', (133, 138))	('miR-145', 'Var', (65, 72))
410676	32080184	We also determined miR-30a-5p and 3p forced expression consequently reduced lung cancer cell proliferation and movement.	('lung cancer', 'Disease', 'MESH:D008175', (76, 87))	('miR-30a-5p', 'Var', (19, 29))	('movement', 'CPA', (111, 119))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('lung cancer', 'Disease', (76, 87))	('lung cancer', 'Phenotype', 'HP:0100526', (76, 87))	('reduced', 'NegReg', (68, 75))
410720	32080184	Lung cell lines were cultured in RPMI-1640 media supplemented with 10% FBS and penicillin/streptomycin (H460, H2087, H2110, H441, PC9, and H1299) and with additional L-glutamine (Beas2B, A549, H1993, and H1435).	('penicillin', 'Chemical', 'MESH:D010406', (79, 89))	('H441', 'Var', (124, 128))	('A549', 'Var', (187, 191))	('H2110', 'Var', (117, 122))	('H2087', 'CellLine', 'CVCL:1524', (110, 115))	('L-glutamine', 'Chemical', 'MESH:D005973', (166, 177))	('H1435', 'Var', (204, 209))	('PC9', 'Gene', '255738', (130, 133))	('streptomycin', 'Chemical', 'MESH:D013307', (90, 102))	('A549', 'CellLine', 'CVCL:0023', (187, 191))	('H1299', 'CellLine', 'CVCL:0060', (139, 144))	('H1993', 'CellLine', 'CVCL:1512', (193, 198))	('H1993', 'Var', (193, 198))	('RPMI-1640 media', 'Chemical', '-', (33, 48))	('H1299', 'Var', (139, 144))	('PC9', 'Gene', (130, 133))	('H460', 'Var', (104, 108))	('H2087', 'Var', (110, 115))	('Beas2B', 'Chemical', '-', (179, 185))	('H2110', 'CellLine', 'CVCL:1530', (117, 122))
410729	32080184	Lung adenocarcinoma cells (A549 and H1993) were transfected with individual miRNA mimics (25, 50, or 100 nM), a combination of miRNA mimics, and/or negative control RNA (equal amounts of RNA were transfected for each experiment).	('A549', 'CellLine', 'CVCL:0023', (27, 31))	('miR', 'Gene', '220972', (127, 130))	('miR', 'Gene', (127, 130))	('25', 'Var', (90, 92))	('miR', 'Gene', '220972', (76, 79))	('Lung adenocarcinoma', 'Phenotype', 'HP:0030078', (0, 19))	('miR', 'Gene', (76, 79))	('Lung adenocarcinoma', 'Disease', (0, 19))	('carcinoma', 'Phenotype', 'HP:0030731', (10, 19))	('H1993', 'CellLine', 'CVCL:1512', (36, 41))	('Lung adenocarcinoma', 'Disease', 'MESH:C538231', (0, 19))
410743	31867162	PEP06 polypeptide 30 is a novel cluster-dissociating agent inhibiting alphav integrin/FAK/Src signaling in oral squamous cell carcinoma cells Collectively migrating tumor cells have been recently implicated in enhanced metastasis of epithelial malignancies.	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('Src', 'Gene', '6714', (90, 93))	('enhanced', 'PosReg', (210, 218))	('PEP06', 'Var', (0, 5))	('malignancies', 'Disease', 'MESH:D009369', (244, 256))	('epithelial malignancies', 'Phenotype', 'HP:0031492', (233, 256))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (112, 135))	('Src', 'Gene', (90, 93))	('inhibiting', 'NegReg', (59, 69))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (107, 135))	('metastasis', 'CPA', (219, 229))	('FAK', 'Gene', (86, 89))	('FAK', 'Gene', '5747', (86, 89))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('malignancies', 'Disease', (244, 256))	('oral squamous cell carcinoma', 'Disease', (107, 135))	('tumor', 'Disease', (165, 170))
410745	31867162	According to the emerging therapeutic concept, dissociation of tumor clusters into single cells could significantly suppress metastasis-seeding ability of carcinomas.	('tumor', 'Disease', (63, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (155, 164))	('carcinomas', 'Disease', 'MESH:D009369', (155, 165))	('carcinomas', 'Phenotype', 'HP:0030731', (155, 165))	('carcinomas', 'Disease', (155, 165))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('suppress', 'NegReg', (116, 124))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('dissociation', 'Var', (47, 59))
410749	31867162	Following PEP06 treatment, cell clustering on fibronectin, migration, multicellular aggregation, anchorage-independent survival and colony formation of OSCC were significantly inhibited.	('fibronectin', 'Gene', '2335', (46, 57))	('cell clustering on', 'CPA', (27, 45))	('multicellular aggregation', 'CPA', (70, 95))	('inhibited', 'NegReg', (176, 185))	('PEP06', 'Chemical', '-', (10, 15))	('PEP06', 'Var', (10, 15))	('fibronectin', 'Gene', (46, 57))	('colony formation of OSCC', 'CPA', (132, 156))	('migration', 'CPA', (59, 68))	('anchorage-independent survival', 'CPA', (97, 127))
410750	31867162	Moreover, PEP06 suppressed alphav integrin/FAK/Src signaling in OSCC cells.	('suppressed', 'NegReg', (16, 26))	('FAK', 'Gene', (43, 46))	('PEP06', 'Chemical', '-', (10, 15))	('Src', 'Gene', (47, 50))	('FAK', 'Gene', '5747', (43, 46))	('Src', 'Gene', '6714', (47, 50))	('PEP06', 'Var', (10, 15))
410752	31867162	Overall, these results suggest that PEP06 polypeptide 30 inhibiting alphav integrin/FAK/Src signaling and disrupting E-cadherin-based intercellular junctions possesses anti-metastatic potential in OSCC by acting as a cluster-dissociating therapeutic agent.	('inhibiting', 'NegReg', (57, 67))	('PEP06', 'Var', (36, 41))	('FAK', 'Gene', (84, 87))	('anti-metastatic potential', 'CPA', (168, 193))	('FAK', 'Gene', '5747', (84, 87))	('OSCC', 'Disease', (197, 201))	('Src', 'Gene', '6714', (88, 91))	('disrupting', 'NegReg', (106, 116))	('E-cadherin', 'Gene', (117, 127))	('E-cadherin', 'Gene', '999', (117, 127))	('PEP06', 'Chemical', '-', (36, 41))	('Src', 'Gene', (88, 91))
410753	31867162	PEP06 polypeptide 30, acting as a cluster-dissociating therapeutic agent, possesses the effect of anti-metastatic potential in oral squamous cell carcinoma by inhibiting alphav integrin/FAK/Src signaling and disrupting E-cadherin-based intercellular junctions.	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (127, 155))	('FAK', 'Gene', (186, 189))	('FAK', 'Gene', '5747', (186, 189))	('Src', 'Gene', (190, 193))	('PEP06', 'Chemical', '-', (0, 5))	('PEP06', 'Var', (0, 5))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (132, 155))	('Src', 'Gene', '6714', (190, 193))	('oral squamous cell carcinoma', 'Disease', (127, 155))	('E-cadherin', 'Gene', (219, 229))	('E-cadherin', 'Gene', '999', (219, 229))	('inhibiting', 'NegReg', (159, 169))	('disrupting', 'NegReg', (208, 218))
410761	31867162	Another study has demonstrated an association between the presence of CTC clusters in blood of peripheral vein and poor prognosis of patients with lung cancer.	('patients', 'Species', '9606', (133, 141))	('lung cancer', 'Disease', (147, 158))	('lung cancer', 'Phenotype', 'HP:0100526', (147, 158))	('CTC clusters', 'Var', (70, 82))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('lung cancer', 'Disease', 'MESH:D008175', (147, 158))
410781	31867162	We showed here that PEP06 polypeptide targeting the alphav integrin/FAK/Src signaling pathway significantly suppressed cell clustering on fibronectin, migration, multicellular aggregation, anchorage-independent survival and colony formation of OSCC in vitro.	('migration', 'CPA', (151, 160))	('multicellular aggregation', 'CPA', (162, 187))	('PEP06', 'Chemical', '-', (20, 25))	('fibronectin', 'Gene', (138, 149))	('PEP06', 'Var', (20, 25))	('FAK', 'Gene', (68, 71))	('FAK', 'Gene', '5747', (68, 71))	('anchorage-independent survival', 'CPA', (189, 219))	('Src', 'Gene', '6714', (72, 75))	('colony formation of OSCC', 'CPA', (224, 248))	('suppressed', 'NegReg', (108, 118))	('Src', 'Gene', (72, 75))	('fibronectin', 'Gene', '2335', (138, 149))
410783	31867162	Our results indicate that suppression of alphav integrin/FAK/Src signaling is likely the underlying molecular mechanism by which PEP06 elicits cluster-dissociating potential in OSCC cells, suggesting the perspectivity of PEP06-based therapy for eliminating OSCC metastasis.	('Src', 'Gene', (61, 64))	('Src', 'Gene', '6714', (61, 64))	('FAK', 'Gene', (57, 60))	('suppression', 'NegReg', (26, 37))	('alphav', 'Protein', (41, 47))	('FAK', 'Gene', '5747', (57, 60))	('cluster-dissociating potential', 'MPA', (143, 173))	('PEP06', 'Chemical', '-', (221, 226))	('OSCC', 'Disease', (257, 261))	('elicits', 'Reg', (135, 142))	('PEP06', 'Chemical', '-', (129, 134))	('PEP06', 'Var', (129, 134))
410817	31867162	Subsequently, samples were incubated with primary antibodies against E-cadherin (1:200; Cat#610181, BD Transduction Laboratories, San Diego, CA, USA) and phosphorylated Src (Tyr416, 1:400; Cat#6943, Cell Signaling Technology Inc.) at 4  C overnight, followed by detection with the corresponding secondary antibodies.	('E-cadherin', 'Gene', '999', (69, 79))	('E-cadherin', 'Gene', (69, 79))	('Cat', 'Gene', (88, 91))	('Cat', 'Gene', '847', (88, 91))	('Cat', 'Gene', (189, 192))	('Cat', 'Gene', '847', (189, 192))	('Src', 'Gene', (169, 172))	('Tyr416', 'Var', (174, 180))	('Src', 'Gene', '6714', (169, 172))	('Tyr416', 'Chemical', '-', (174, 180))
410829	31867162	Notably, unlike the control and endostatin groups, where adherent cells gathered in multicellular clusters, the majority of PEP06-treated cells existed in a dispersed pattern (Fig.	('endostatin', 'Gene', '80781', (32, 42))	('endostatin', 'Gene', (32, 42))	('PEP06', 'Chemical', '-', (124, 129))	('PEP06-treated', 'Var', (124, 137))
410832	31867162	2E, the numbers of migrated CAL 27 cells in the PEP06 groups were significantly lower as compared to controls.	('PEP06', 'Var', (48, 53))	('lower', 'NegReg', (80, 85))	('PEP06', 'Chemical', '-', (48, 53))
410834	31867162	Collectively, these results indicate that PEP06 could diminish cancer cell clustering on fibronectin and dramatically suppress OSCC migration in vitro.	('suppress', 'NegReg', (118, 126))	('PEP06', 'Chemical', '-', (42, 47))	('PEP06', 'Var', (42, 47))	('diminish', 'NegReg', (54, 62))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('fibronectin', 'Gene', '2335', (89, 100))	('OSCC migration', 'CPA', (127, 141))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('fibronectin', 'Gene', (89, 100))	('cancer', 'Disease', (63, 69))
410841	31867162	On the basis of these findings, we hypothesized that PEP06 polypeptide could also affect the colony formation of OSCC cells.	('PEP06', 'Var', (53, 58))	('colony formation of OSCC cells', 'CPA', (93, 123))	('affect', 'Reg', (82, 88))	('PEP06', 'Chemical', '-', (53, 58))
410843	31867162	3D, PEP06 treatment led to remarkable suppression of colony formation by CAL 27 cells.	('PEP06', 'Chemical', '-', (4, 9))	('colony formation by CAL 27 cells', 'CPA', (53, 85))	('PEP06', 'Var', (4, 9))	('suppression', 'NegReg', (38, 49))
410844	31867162	We found that the numbers of colonies in PEP06-treated samples were significantly decreased on day 8 in comparison to controls (Fig.	('PEP06-treated', 'Var', (41, 54))	('decreased', 'NegReg', (82, 91))	('PEP06', 'Chemical', '-', (41, 46))
410849	31867162	Upon integrin clustering, FAK is autophosphorylated at Tyr397 site and activates Src kinase through Tyr416 phosphorylation, thereby triggering multiple molecular pathways implicated in oral tumorigenesis.	('Src', 'Gene', (81, 84))	('Src', 'Gene', '6714', (81, 84))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('Tyr416', 'Var', (100, 106))	('FAK', 'Gene', (26, 29))	('FAK', 'Gene', '5747', (26, 29))	('Tyr416', 'Chemical', '-', (100, 106))	('Tyr397', 'Chemical', '-', (55, 61))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('activates', 'PosReg', (71, 80))	('tumor', 'Disease', (190, 195))	('triggering', 'Reg', (132, 142))	('molecular pathways', 'Pathway', (152, 170))
410851	31867162	It was observed that PEP06 prevented phosphorylation of FAK and Src at Tyr397 and Tyr416 sites, respectively, without affecting the abundance of total Src.	('phosphorylation', 'MPA', (37, 52))	('PEP06', 'Chemical', '-', (21, 26))	('Src', 'Gene', (64, 67))	('Src', 'Gene', (151, 154))	('Src', 'Gene', '6714', (64, 67))	('FAK', 'Gene', '5747', (56, 59))	('PEP06', 'Var', (21, 26))	('Src', 'Gene', '6714', (151, 154))	('Tyr397', 'Chemical', '-', (71, 77))	('prevented', 'NegReg', (27, 36))	('Tyr416', 'Var', (82, 88))	('Tyr416', 'Chemical', '-', (82, 88))	('FAK', 'Gene', (56, 59))
410854	31867162	Overall, these results demonstrate that PEP06 acts as a potent inhibitor of the alphav integrin/FAK/Src signaling pathway in OSCC cells.	('PEP06', 'Chemical', '-', (40, 45))	('PEP06', 'Var', (40, 45))	('Src', 'Gene', (100, 103))	('Src', 'Gene', '6714', (100, 103))	('FAK', 'Gene', '5747', (96, 99))	('FAK', 'Gene', (96, 99))
410855	31867162	In order to gain further insight into the inhibitory effects produced by PEP06, we analyzed the cellular distribution of active Src (Tyr416) and E-cadherin in adherent OSCC cells.	('E-cadherin', 'Gene', '999', (145, 155))	('PEP06', 'Chemical', '-', (73, 78))	('Src', 'Gene', (128, 131))	('Src', 'Gene', '6714', (128, 131))	('PEP06', 'Var', (73, 78))	('Tyr416', 'Chemical', '-', (133, 139))	('E-cadherin', 'Gene', (145, 155))
410857	31867162	In contrast, PEP06-treated cells displayed pronounced perturbation of the proteins critical for cell-cell contacts coincident with delocalization of E-cadherin.	('PEP06', 'Chemical', '-', (13, 18))	('perturbation', 'NegReg', (54, 66))	('PEP06-treated', 'Var', (13, 26))	('proteins', 'Protein', (74, 82))	('E-cadherin', 'Gene', (149, 159))	('E-cadherin', 'Gene', '999', (149, 159))
410863	31867162	Together, these results support the notion that PEP06 polypeptide has the potential to inhibit E-cadherin-based collective migration of OSCC cells.	('PEP06', 'Chemical', '-', (48, 53))	('E-cadherin', 'Gene', (95, 105))	('PEP06', 'Var', (48, 53))	('E-cadherin', 'Gene', '999', (95, 105))	('inhibit', 'NegReg', (87, 94))
410872	31867162	Aceto and colleagues have shown that knockdown of plakoglobin, a component of adherent junctions and desmosomes, led to disruption of cell-cell contacts in a monolayer of breast cancer cells and failure of cluster formation, thereby suppression of lung metastases in vivo.	('breast cancer', 'Disease', 'MESH:D001943', (171, 184))	('cluster formation', 'CPA', (206, 223))	('lung metastases', 'Disease', (248, 263))	('Ace', 'Gene', '1636', (0, 3))	('Ace', 'Gene', (0, 3))	('lung metastases', 'Disease', 'MESH:D009362', (248, 263))	('breast cancer', 'Disease', (171, 184))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('breast cancer', 'Phenotype', 'HP:0003002', (171, 184))	('knockdown', 'Var', (37, 46))	('plakoglobin', 'Gene', (50, 61))	('disruption', 'NegReg', (120, 130))	('failure', 'NegReg', (195, 202))	('cell-cell contacts', 'CPA', (134, 152))	('suppression', 'NegReg', (233, 244))
410874	31867162	The present study demonstrates that PEP06 targeting alphav integrins disrupts intercellular integrity, indicating this novel polypeptide as a potential therapeutic agent for limiting cluster-based metastasis of OSCC.	('PEP06', 'Var', (36, 41))	('intercellular integrity', 'CPA', (78, 101))	('disrupts', 'NegReg', (69, 77))	('cluster-based metastasis', 'CPA', (183, 207))	('alphav integrins', 'Protein', (52, 68))	('PEP06', 'Chemical', '-', (36, 41))
410878	31867162	Consistently, PEP06-mediated abrogation of OSCC collective movement in vitro was evident by impaired intercellular integrity in migrating cells, paralleled by pronounced loss of phosphorylated Src (Tyr416) and E-cadherin from cell-cell junctions.	('phosphorylated', 'MPA', (178, 192))	('OSCC collective movement', 'CPA', (43, 67))	('PEP06', 'Chemical', '-', (14, 19))	('abrogation', 'NegReg', (29, 39))	('loss', 'NegReg', (170, 174))	('Tyr416', 'Chemical', '-', (198, 204))	('impaired', 'NegReg', (92, 100))	('Src', 'Gene', (193, 196))	('E-cadherin', 'Gene', (210, 220))	('intercellular integrity', 'CPA', (101, 124))	('PEP06-mediated', 'Var', (14, 28))	('Src', 'Gene', '6714', (193, 196))	('E-cadherin', 'Gene', '999', (210, 220))
410884	31867162	Here, we propose that PEP06-induced suppression of the alphav integrin/FAK/Src pathway contributes to inhibition of multicellular aggregation and anchorage-independent survival, ultimately leading to diminished colony formation of OSCC cells.	('FAK', 'Gene', (71, 74))	('Src', 'Gene', (75, 78))	('Src', 'Gene', '6714', (75, 78))	('FAK', 'Gene', '5747', (71, 74))	('multicellular aggregation', 'MPA', (116, 141))	('colony formation of OSCC cells', 'CPA', (211, 241))	('suppression', 'NegReg', (36, 47))	('inhibition', 'NegReg', (102, 112))	('diminished', 'NegReg', (200, 210))	('anchorage-independent survival', 'CPA', (146, 176))	('PEP06-induced', 'Var', (22, 35))	('PEP06', 'Chemical', '-', (22, 27))
410886	31867162	It has been also demonstrated that upon blockade of FAK signaling in a microfluidic model mimicking microcirculation in vitro tumor cell clusters dissociate into single cells and fail to traverse through capillary-sized constrictions, pointing toward FAK as a target for limiting cluster-driven metastasis.	('blockade', 'Var', (40, 48))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('FAK', 'Gene', (251, 254))	('FAK', 'Gene', '5747', (251, 254))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('FAK', 'Gene', (52, 55))	('FAK', 'Gene', '5747', (52, 55))	('tumor', 'Disease', (126, 131))
410888	31867162	It is noteworthy that beyond affecting phosphorylation of FAK in OSCC cells, PEP06 polypeptide also decreased the level of total FAK.	('phosphorylation', 'MPA', (39, 54))	('FAK', 'Gene', '5747', (129, 132))	('PEP06 polypeptide', 'Var', (77, 94))	('FAK', 'Gene', (129, 132))	('FAK', 'Gene', (58, 61))	('FAK', 'Gene', '5747', (58, 61))	('decreased', 'NegReg', (100, 109))	('PEP06', 'Chemical', '-', (77, 82))
410893	31867162	On contrary, it has been reported that inhibition of beta1 integrin in E-cadherin-positive triple-negative breast cancer enhances metastatic colonization in lungs of tumor-bearing animals.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('inhibition', 'Var', (39, 49))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('E-cadherin', 'Gene', (71, 81))	('E-cadherin', 'Gene', '999', (71, 81))	('beta1 integrin', 'Gene', '3688', (53, 67))	('tumor', 'Disease', (166, 171))	('breast cancer', 'Disease', 'MESH:D001943', (107, 120))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('breast cancer', 'Disease', (107, 120))	('breast cancer', 'Phenotype', 'HP:0003002', (107, 120))	('enhances', 'PosReg', (121, 129))	('beta1 integrin', 'Gene', (53, 67))	('metastatic colonization in lungs', 'CPA', (130, 162))
410895	31867162	In this regard, further in vivo experiments are warranted for elucidating the pharmacological effects PEP06 in OSCC with particular focus on its anti-angiogenic potential.	('PEP06', 'Chemical', '-', (102, 107))	('anti-angiogenic potential', 'CPA', (145, 170))	('OSCC', 'Disease', (111, 115))	('PEP06', 'Var', (102, 107))
410896	31867162	Given the crucial role of alphav integrin/FAK/Src signaling in the pathogenesis of multiple carcinomas, it is likely that PEP06 could also act as alphav integrin antagonist and produce beneficial effects on other solid tumors.	('Src', 'Gene', '6714', (46, 49))	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('PEP06', 'Chemical', '-', (122, 127))	('FAK', 'Gene', '5747', (42, 45))	('tumors', 'Disease', (219, 225))	('tumors', 'Disease', 'MESH:D009369', (219, 225))	('PEP06', 'Var', (122, 127))	('tumors', 'Phenotype', 'HP:0002664', (219, 225))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('carcinomas', 'Disease', 'MESH:D009369', (92, 102))	('carcinomas', 'Phenotype', 'HP:0030731', (92, 102))	('carcinomas', 'Disease', (92, 102))	('FAK', 'Gene', (42, 45))	('beneficial effects', 'PosReg', (185, 203))	('Src', 'Gene', (46, 49))
410897	31867162	In summary, our results demonstrated that PEP06 inhibiting the alphav integrin/FAK/Src signaling pathway significantly suppressed cell clustering on fibronectin, migration, multicellular aggregation, anchorage-independent survival and colony formation of OSCC in vitro.	('PEP06', 'Chemical', '-', (42, 47))	('colony formation of OSCC', 'CPA', (235, 259))	('suppressed', 'NegReg', (119, 129))	('migration', 'CPA', (162, 171))	('fibronectin', 'Gene', (149, 160))	('PEP06', 'Var', (42, 47))	('inhibiting', 'NegReg', (48, 58))	('multicellular aggregation', 'CPA', (173, 198))	('Src', 'Gene', (83, 86))	('FAK', 'Gene', '5747', (79, 82))	('Src', 'Gene', '6714', (83, 86))	('cell clustering on', 'CPA', (130, 148))	('fibronectin', 'Gene', '2335', (149, 160))	('FAK', 'Gene', (79, 82))	('anchorage-independent survival', 'CPA', (200, 230))
410900	31289610	GPCR-mediated PI3K pathway mutations in pediatric and adult thyroid cancer Whole exome sequencing (WES) recently identified frequent mutations in the genes of GPCR-mediated PI3K pathway (LPAR4, PIK3CA, and PTEN) in a Chinese population with papillary thyroid cancers (PTCs).	('mutations', 'Var', (27, 36))	('papillary thyroid cancers', 'Disease', (241, 266))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('LPAR4', 'Gene', (187, 192))	('thyroid cancer', 'Disease', (60, 74))	('papillary thyroid cancer', 'Phenotype', 'HP:0002895', (241, 265))	('PIK3CA', 'Gene', (194, 200))	('GPCR', 'Gene', '23566', (0, 4))	('thyroid cancer', 'Disease', 'MESH:D013964', (251, 265))	('LPAR4', 'Gene', '2846', (187, 192))	('GPCR', 'Gene', '23566', (159, 163))	('mutations', 'Var', (133, 142))	('thyroid cancer', 'Phenotype', 'HP:0002890', (251, 265))	('thyroid cancer', 'Disease', 'MESH:D013964', (60, 74))	('papillary thyroid cancers', 'Phenotype', 'HP:0002895', (241, 266))	('cancer', 'Phenotype', 'HP:0002664', (259, 265))	('thyroid cancer', 'Phenotype', 'HP:0002890', (60, 74))	('PTEN', 'Gene', (206, 210))	('PTC', 'Gene', (268, 271))	('PTC', 'Gene', '5979', (268, 271))	('cancers', 'Phenotype', 'HP:0002664', (259, 266))	('papillary thyroid cancers', 'Disease', 'MESH:D000077273', (241, 266))	('GPCR', 'Gene', (0, 4))	('GPCR', 'Gene', (159, 163))
410901	31289610	The study found LPAR4 mutations as novel gene mutations in adult population with differentiated thyroid cancer (DTC).	('thyroid cancer', 'Disease', (96, 110))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('thyroid cancer', 'Disease', 'MESH:D013964', (96, 110))	('LPAR4', 'Gene', '2846', (16, 21))	('DTC', 'Chemical', '-', (112, 115))	('mutations', 'Var', (22, 31))	('LPAR4', 'Gene', (16, 21))	('thyroid cancer', 'Phenotype', 'HP:0002890', (96, 110))
410902	31289610	Here, we determine the prevalence of somatic mutations in this pathway (LPAR4 (exon 1), PIK3CA (exons 9 and 20) and PTEN (exons 5, 6, 7 and 8) in 323 thyroid samples consisting of 17 multinodular goiters (MNG), 89 pediatric DTCs, 204 adult DTCs, and 13 aggressive thyroid cancers including 10 poorly differentiated (PDTC) and 3 anaplastic thyroid cancer (ATC) from another ethnic population.	('cancer', 'Phenotype', 'HP:0002664', (272, 278))	('multinodular goiters', 'Disease', 'MESH:C564546', (183, 203))	('cancers', 'Phenotype', 'HP:0002664', (272, 279))	('PTEN', 'Gene', (116, 120))	('anaplastic thyroid cancer', 'Phenotype', 'HP:0011779', (328, 353))	('thyroid cancer', 'Disease', 'MESH:D013964', (339, 353))	('multinodular goiters', 'Phenotype', 'HP:0005987', (183, 203))	('aggressive thyroid cancers', 'Disease', 'MESH:D013964', (253, 279))	('multinodular goiters', 'Disease', (183, 203))	('PIK3CA', 'Gene', (88, 94))	('DTC', 'Chemical', '-', (224, 227))	('thyroid cancer', 'Phenotype', 'HP:0002890', (339, 353))	('DTC', 'Chemical', '-', (240, 243))	('thyroid cancer', 'Disease', 'MESH:D013964', (264, 278))	('cancer', 'Phenotype', 'HP:0002664', (347, 353))	('LPAR4', 'Gene', (72, 77))	('poorly differentiated', 'Disease', (293, 314))	('goiters', 'Phenotype', 'HP:0000853', (196, 203))	('DTC', 'Chemical', '-', (317, 320))	('LPAR4', 'Gene', '2846', (72, 77))	('mutations', 'Var', (45, 54))	('thyroid cancer', 'Phenotype', 'HP:0002890', (264, 278))	('thyroid cancer', 'Disease', (339, 353))	('aggressive thyroid cancers', 'Disease', (253, 279))
410903	31289610	We found 3.37% and 2.45% (includes Q214H, a novel PTEN mutation) in GPCR-mediated PI3K pathway of pediatric and adult DTCs, respectively.	('DTC', 'Chemical', '-', (118, 121))	('GPCR', 'Gene', (68, 72))	('Q214H', 'Mutation', 'rs1366963451', (35, 40))	('GPCR', 'Gene', '23566', (68, 72))	('Q214H', 'Var', (35, 40))
410904	31289610	Analyses of 507 DTCs from thyroid Cancer Genome Atlas data (TCGA) revealed a low prevalence of mutations in this pathway (1.18%).	('DTC', 'Chemical', '-', (16, 19))	('Cancer', 'Phenotype', 'HP:0002664', (34, 40))	('Cancer', 'Disease', (34, 40))	('thyroid Cancer', 'Phenotype', 'HP:0002890', (26, 40))	('Cancer', 'Disease', 'MESH:D009369', (34, 40))	('mutations', 'Var', (95, 104))
410906	31289610	By contrast, analyses of 117 aggressive thyroid cancers (PDTC and ATC) from TCGA showed 13% of mutations in this pathway.	('ATC', 'Disease', (66, 69))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('thyroid cancer', 'Phenotype', 'HP:0002890', (40, 54))	('aggressive thyroid cancers', 'Disease', 'MESH:D013964', (29, 55))	('DTC', 'Chemical', '-', (58, 61))	('mutations', 'Var', (95, 104))	('aggressive thyroid cancers', 'Disease', (29, 55))	('cancers', 'Phenotype', 'HP:0002664', (48, 55))
410907	31289610	Moreover, analyses of 1080 pan-cancer cell lines and 9020 solid tumors of TCGA data revealed high rates of mutations in this pathway (cell lines, 24.8%; tumors, 24.8%).	('pan-cancer', 'Disease', 'MESH:C537931', (27, 37))	('tumors', 'Disease', (64, 70))	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('mutations', 'Var', (107, 116))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('solid tumors', 'Disease', (58, 70))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('pan-cancer', 'Disease', (27, 37))	('tumors', 'Disease', (153, 159))	('tumors', 'Phenotype', 'HP:0002664', (153, 159))	('solid tumors', 'Disease', 'MESH:D009369', (58, 70))	('tumors', 'Disease', 'MESH:D009369', (153, 159))
410909	31289610	Our study reveals a low prevalence of GPCR-mediated PI3K pathway mutations both in pediatric and adult DTCs corroborating the TCGA data and suggests a significant role of this pathway only in a small portion of DTCs.	('GPCR', 'Gene', '23566', (38, 42))	('DTC', 'Chemical', '-', (211, 214))	('GPCR', 'Gene', (38, 42))	('DTC', 'Chemical', '-', (103, 106))	('mutations', 'Var', (65, 74))
410910	31289610	The high prevalence of mutations in this pathway in other solid malignancies suggests an important role in their pathogenesis making it an attractive target for therapeutic intervention both in a small subset of DTCs and other solid cancers.	('malignancies', 'Disease', 'MESH:D009369', (64, 76))	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('malignancies', 'Disease', (64, 76))	('DTCs', 'Disease', (212, 216))	('mutations', 'Var', (23, 32))	('cancers', 'Phenotype', 'HP:0002664', (233, 240))	('solid cancers', 'Disease', (227, 240))	('DTC', 'Chemical', '-', (212, 215))	('solid cancers', 'Disease', 'MESH:D009369', (227, 240))
410917	31289610	The most prevalent genetic alterations are the hotspot point mutation BRAFV600E, RAS single point mutations, and fusions in RET/PTC, NTRK1/3 and PAX8-PPARgamma.	('RET', 'Gene', '5979', (124, 127))	('NTRK1', 'Gene', '4914', (133, 138))	('prevalent', 'Reg', (9, 18))	('fusions', 'Var', (113, 120))	('RAS', 'Gene', (81, 84))	('PPARgamma', 'Gene', (150, 159))	('BRAFV600E', 'Var', (70, 79))	('PAX8', 'Gene', '7849', (145, 149))	('BRAFV600E', 'Mutation', 'rs113488022', (70, 79))	('PTC', 'Gene', '5979', (128, 131))	('PPARgamma', 'Gene', '5468', (150, 159))	('NTRK1', 'Gene', (133, 138))	('RET', 'Gene', (124, 127))	('PAX8', 'Gene', (145, 149))	('PTC', 'Gene', (128, 131))	('single point mutations', 'Var', (85, 107))
410918	31289610	A low frequency of mutations has also been reported in the receptor tyrosine kinases (RTKs) including EGFR and members of the phosphatidylinositol-3 kinase (PI3K) pathway such as PIK3CA, PTEN and AKT1.	('AKT1', 'Gene', (196, 200))	('mutations', 'Var', (19, 28))	('EGFR', 'Gene', '1956', (102, 106))	('EGFR', 'Gene', (102, 106))	('AKT1', 'Gene', '207', (196, 200))
410919	31289610	Previous studies also reported some point mutations in the genes of metabolic and regulatory pathways which include IDH1 and TERT.	('IDH1', 'Gene', (116, 120))	('reported', 'Reg', (22, 30))	('TERT', 'Gene', (125, 129))	('IDH1', 'Gene', '3417', (116, 120))	('point mutations', 'Var', (36, 51))	('TERT', 'Gene', '7015', (125, 129))
410920	31289610	Somatic alterations of these genes are strongly associated with distinct clinicopathological features of the tumors.	('tumors', 'Disease', 'MESH:D009369', (109, 115))	('associated', 'Reg', (48, 58))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('Somatic alterations', 'Var', (0, 19))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumors', 'Disease', (109, 115))
410924	31289610	In addition to the frequent occurrence of the oncogenic mutations of BRAFV600E and NRAS, mutations in the other critical genes such as TERT, TP53, EIF1AX, PIK3CA, PTEN, ALK, and mTOR mutations were frequently detected in PDTC and ATC.	('TERT', 'Gene', '7015', (135, 139))	('TP53', 'Gene', (141, 145))	('PIK3CA', 'Gene', (155, 161))	('mTOR', 'Gene', (178, 182))	('BRAFV600E', 'Mutation', 'rs113488022', (69, 78))	('PTEN', 'Gene', (163, 167))	('ALK', 'Gene', '238', (169, 172))	('ALK', 'Gene', (169, 172))	('mTOR', 'Gene', '2475', (178, 182))	('detected', 'Reg', (209, 217))	('NRAS', 'Gene', '4893', (83, 87))	('TP53', 'Gene', '7157', (141, 145))	('EIF1AX', 'Gene', (147, 153))	('ATC', 'Disease', (230, 233))	('BRAFV600E', 'Var', (69, 78))	('PDTC', 'Disease', (221, 225))	('DTC', 'Chemical', '-', (222, 225))	('NRAS', 'Gene', (83, 87))	('EIF1AX', 'Gene', '1964', (147, 153))	('TERT', 'Gene', (135, 139))
410937	31289610	Overall, GPCR-mediated PI3K pathway genes harbored mutations in 3.37% (3/89) and 2.45% (5/204) of pediatric and adult DTCs, respectively.	('GPCR', 'Gene', (9, 13))	('mutations', 'Var', (51, 60))	('DTC', 'Chemical', '-', (118, 121))	('pediatric', 'Disease', (98, 107))	('GPCR', 'Gene', '23566', (9, 13))
410938	31289610	PIK3CA mutations occurred in 2.24% (2/89) of pediatric DTC (both cases were conventional PTCs) and in 1.5% of (3/204) adult DTC [two in follicular variant PTC (FV-PTC) and one in tall cell variant (TPTC)].	('PTC', 'Gene', '5979', (163, 166))	('DTC', 'Chemical', '-', (124, 127))	('PTC', 'Gene', '5979', (199, 202))	('PTC', 'Gene', (89, 92))	('PTC', 'Gene', '5979', (155, 158))	('PIK3CA', 'Gene', (0, 6))	('PTC', 'Gene', '5979', (89, 92))	('PTC', 'Gene', (199, 202))	('occurred', 'Reg', (17, 25))	('TPTC', 'Chemical', 'MESH:C012594', (198, 202))	('PTC', 'Gene', (163, 166))	('PTC', 'Gene', (155, 158))	('DTC', 'Chemical', '-', (55, 58))	('mutations', 'Var', (7, 16))
410939	31289610	PTEN mutations were present in1.1% (1/89) of pediatric conventional PTC and 1% (2/204) adult DTC (1 conventional PTC and 1 follicular variant PTC).	('DTC', 'Chemical', '-', (93, 96))	('PTC', 'Gene', (113, 116))	('PTC', 'Gene', (68, 71))	('PTC', 'Gene', '5979', (113, 116))	('mutations', 'Var', (5, 14))	('PTC', 'Gene', '5979', (142, 145))	('PTC', 'Gene', '5979', (68, 71))	('PTEN', 'Gene', (0, 4))	('PTC', 'Gene', (142, 145))
410941	31289610	Overall, in both pediatric and adult DTCs, PIK3CA mutations were found in 1.7% (5/293) and the PTEN mutations were found in 1% (3/293).	('mutations', 'Var', (50, 59))	('DTC', 'Chemical', '-', (37, 40))	('PTEN', 'Gene', (95, 99))	('found', 'Reg', (65, 70))	('PIK3CA', 'Gene', (43, 49))
410944	31289610	All the mutation positive samples were further analyzed for hotspot and non-hotspot mutations of commonly mutated genes in DTC which include BRAFV600E and TERT promoter mutations.	('BRAFV600E', 'Var', (141, 150))	('BRAFV600E', 'Mutation', 'rs113488022', (141, 150))	('DTC', 'Chemical', '-', (123, 126))	('TERT', 'Gene', (155, 159))	('TERT', 'Gene', '7015', (155, 159))
410945	31289610	We found 2 samples concomitantly harboring PIK3CA and BRAF mutations and one of the two BRAF mutations was a non-hotspot frameshift mutation (1798inTAC) and the other one was the common BRAFV600E mutation.	('BRAF', 'Gene', (54, 58))	('BRAFV600E', 'Mutation', 'rs113488022', (186, 195))	('1798inTAC', 'Var', (142, 151))	('mutations', 'Var', (59, 68))	('PIK3CA', 'Gene', (43, 49))
410946	31289610	Similarly, two samples with PTEN mutations coexisted with BRAFV600E hotspot mutation.	('PTEN', 'Gene', (28, 32))	('BRAFV600E', 'Var', (58, 67))	('BRAFV600E', 'Mutation', 'rs113488022', (58, 67))	('mutations', 'Var', (33, 42))
410948	31289610	As illustrated in Figure 2A and 2B, PIK3CA mutations occur in both exons 9 and 20 coding helical and kinase domains of the p110alpha, respectively.	('mutations', 'Var', (43, 52))	('p110alpha', 'Gene', '5290', (123, 132))	('PIK3CA', 'Gene', (36, 42))	('occur', 'Reg', (53, 58))	('p110alpha', 'Gene', (123, 132))
410950	31289610	Six (Q530R, A533V, E545Q, S553T, C984Y, and R992Q) out of these seven PIK3CA mutations were missense single point mutations and one (T1659del) had a single nucleotide deletion (Table 2).	('C984Y', 'SUBSTITUTION', 'None', (33, 38))	('E545Q', 'Mutation', 'rs104886003', (19, 24))	('R992Q', 'Var', (44, 49))	('Q530R', 'Mutation', 'rs748157088', (5, 10))	('A533V', 'Var', (12, 17))	('A533V', 'Mutation', 'p.A533V', (12, 17))	('T1659del', 'Mutation', 'c.1659delT', (133, 141))	('C984Y', 'Var', (33, 38))	('PIK3CA', 'Gene', (70, 76))	('Q530R', 'Var', (5, 10))	('S553T', 'Mutation', 'p.S553T', (26, 31))	('E545Q', 'Var', (19, 24))	('S553T', 'Var', (26, 31))	('R992Q', 'Mutation', 'p.R992Q', (44, 49))
410953	31289610	Figure 3A-3C shows the PTEN mutations identified in DTCs and of 3 mutations, one occurred in the phosphatase domain, and other two in the C2 domain.	('DTC', 'Chemical', '-', (52, 55))	('mutations', 'Var', (28, 37))	('occurred', 'Reg', (81, 89))	('PTEN', 'Gene', (23, 27))
410955	31289610	As we found a low frequency of mutations in the GPCR-mediated PI3K pathway in the pediatric and adult DTCs of Saudi Arabian origin, we attempted to analyze the TCGA data of DTCs to determine whether the different cohort analyzed in the TCGA show a different prevalence of mutations in this pathway.	('mutations', 'Var', (31, 40))	('DTC', 'Chemical', '-', (173, 176))	('GPCR', 'Gene', '23566', (48, 52))	('DTC', 'Chemical', '-', (102, 105))	('GPCR', 'Gene', (48, 52))
410956	31289610	As seen in Figure 4A OncoPrint, 0.2% (1/507) of cases had a somatic missense mutation in LPAR4; 0.4% (2/507) of the cases had missense mutations in PIK3CA and 1.2 % (6/507) cases harbored PTEN mutations consisting mainly of missense mutations and deep deletions.	('PIK3CA and 1', 'Gene', '5290', (148, 160))	('missense mutations', 'Var', (126, 144))	('harbored', 'Reg', (179, 187))	('PTEN', 'Gene', (188, 192))	('missense mutations', 'Var', (224, 242))	('deep deletions', 'Var', (247, 261))	('missense mutation', 'Var', (68, 85))	('LPAR4', 'Gene', '2846', (89, 94))	('LPAR4', 'Gene', (89, 94))
410957	31289610	Overall, the GPCR-mediated pathway genes showed mutations in only 1.8% (9/507) of PTCs (Figure 4A-4C).	('PTC', 'Gene', (82, 85))	('GPCR', 'Gene', (13, 17))	('PTC', 'Gene', '5979', (82, 85))	('mutations', 'Var', (48, 57))	('GPCR', 'Gene', '23566', (13, 17))
410960	31289610	As illustrated in Figure 5A and 5B, this pathway harbors mutations in 30% (10/33) and 6% (5/84) of ATC and PDTC, respectively.	('mutations', 'Var', (57, 66))	('PDTC', 'Gene', (107, 111))	('DTC', 'Chemical', '-', (108, 111))	('ATC', 'Gene', (99, 102))
410961	31289610	As seen in Figure 5C-5F, each PIK3CA and PTEN genes harbored somatic mutations in 7% (8/117) of aggressive thyroid cancers (PDTCs and ATCs) while no mutation was found in LPAR4 gene.	('PIK3CA', 'Gene', (30, 36))	('mutations', 'Var', (69, 78))	('DTC', 'Chemical', '-', (125, 128))	('cancers', 'Phenotype', 'HP:0002664', (115, 122))	('thyroid cancer', 'Phenotype', 'HP:0002890', (107, 121))	('aggressive thyroid cancers', 'Disease', 'MESH:D013964', (96, 122))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('aggressive thyroid cancers', 'Disease', (96, 122))	('PTEN', 'Gene', (41, 45))	('LPAR4', 'Gene', '2846', (171, 176))	('LPAR4', 'Gene', (171, 176))
410962	31289610	Overall the GPCR-mediated pathway genes mutations were detected in 13% (15/117) of aggressive thyroid cancers (PDTCs and ATCs).	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('detected', 'Reg', (55, 63))	('aggressive thyroid cancers', 'Disease', 'MESH:D013964', (83, 109))	('GPCR', 'Gene', (12, 16))	('thyroid cancer', 'Phenotype', 'HP:0002890', (94, 108))	('aggressive thyroid cancers', 'Disease', (83, 109))	('mutations', 'Var', (40, 49))	('DTC', 'Chemical', '-', (112, 115))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))	('GPCR', 'Gene', '23566', (12, 16))
410963	31289610	Furthermore, our analyses of this pathway genes revealed that the presence of PIK3CA mutation significantly predicts a poor overall survival (p = 0.0289) in patients with aggressive phenotypes suggesting a vital role of PIK3CA mutation in PDTCs and ATCs (Figure 5G).	('overall survival', 'MPA', (124, 140))	('PIK3CA', 'Gene', (78, 84))	('presence', 'Var', (66, 74))	('poor', 'NegReg', (119, 123))	('PDTCs', 'Disease', (239, 244))	('PIK3CA', 'Gene', (220, 226))	('ATCs', 'Disease', (249, 253))	('mutation', 'Var', (85, 93))	('patients', 'Species', '9606', (157, 165))	('DTC', 'Chemical', '-', (240, 243))
410967	31289610	We found 186 mutated genes in the TCGA data of aggressive thyroid cancers (PDTC and ATC).	('aggressive thyroid cancers', 'Disease', (47, 73))	('DTC', 'Chemical', '-', (76, 79))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('cancers', 'Phenotype', 'HP:0002664', (66, 73))	('aggressive thyroid cancers', 'Disease', 'MESH:D013964', (47, 73))	('thyroid cancer', 'Phenotype', 'HP:0002890', (58, 72))	('mutated genes', 'Var', (13, 26))
410973	31289610	From the OncoPrint (Figure 7A-7F), 3.3% (2/60) of cases had a somatic mutation in LPAR4 gene and all the alterations were missense mutations.	('missense', 'Var', (122, 130))	('mutation', 'Var', (70, 78))	('LPAR4', 'Gene', (82, 87))	('LPAR4', 'Gene', '2846', (82, 87))
410974	31289610	A high rate of 50% (1/2) LPAR4 mutations was found in prostate cancer cell line but only two cell lines were reported.	('LPAR4', 'Gene', '2846', (25, 30))	('mutations', 'Var', (31, 40))	('prostate cancer', 'Disease', (54, 69))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('LPAR4', 'Gene', (25, 30))	('prostate cancer', 'Disease', 'MESH:D011471', (54, 69))	('prostate cancer', 'Phenotype', 'HP:0012125', (54, 69))
410977	31289610	The PTEN showed mutations in 20% (1/5) of breast cancer, 16.67% (1/6) of brain and leukemia followed by 14.29% (1/7) of colon cancer cell lines.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('brain and leukemia', 'Disease', 'MESH:D007938', (73, 91))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('leukemia', 'Phenotype', 'HP:0001909', (83, 91))	('breast cancer', 'Disease', 'MESH:D001943', (42, 55))	('mutations', 'Var', (16, 25))	('colon cancer', 'Disease', 'MESH:D015179', (120, 132))	('breast cancer', 'Phenotype', 'HP:0003002', (42, 55))	('colon cancer', 'Phenotype', 'HP:0003003', (120, 132))	('breast cancer', 'Disease', (42, 55))	('colon cancer', 'Disease', (120, 132))	('PTEN', 'Gene', (4, 8))
410981	31289610	To confirm the high frequency of GPCR-mediated pathway mutations found in human cancer cell lines, we analyzed the pan-cancer sequencing data from TCGA.	('GPCR', 'Gene', (33, 37))	('pan-cancer', 'Disease', 'MESH:C537931', (115, 125))	('mutations', 'Var', (55, 64))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('cancer', 'Disease', (119, 125))	('GPCR', 'Gene', '23566', (33, 37))	('pan-cancer', 'Disease', (115, 125))	('human', 'Species', '9606', (74, 79))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('cancer', 'Disease', (80, 86))
410983	31289610	Lung adenocarcinoma revealed 3.18% (21/660), the highest frequency of mutation in this gene followed by 2.89% (14/484) in lung squamous cell carcinoma and 2.56% (1/39) cutaneous melanoma (Figure 8B).	('cutaneous melanoma', 'Disease', (168, 186))	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (168, 186))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (168, 186))	('adenocarcinoma', 'Disease', (5, 19))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (122, 150))	('adenocarcinoma', 'Disease', 'MESH:D000230', (5, 19))	('lung squamous cell carcinoma', 'Disease', (122, 150))	('melanoma', 'Phenotype', 'HP:0002861', (178, 186))	('Lung adenocarcinoma', 'Phenotype', 'HP:0030078', (0, 19))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (127, 150))	('mutation', 'Var', (70, 78))	('carcinoma', 'Phenotype', 'HP:0030731', (10, 19))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (122, 150))
410984	31289610	PIK3CA had mutations in 18% (1625/9020) of tumors (Figure 8C and 8G) and it was frequently mutated in breast mixed ductal and lobular carcinoma 51.72% (45/87) followed by 48.94% of breast invasive lobular (69/141) and 40.47 % of ductal carcinoma (607/1500), respectively Figure 8D.	('mutations', 'Var', (11, 20))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (229, 245))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (126, 143))	('lobular carcinoma', 'Disease', (126, 143))	('breast invasive lobular', 'Disease', (181, 204))	('mutated', 'Var', (91, 98))	('PIK3CA', 'Gene', (0, 6))	('lobular carcinoma', 'Disease', 'MESH:D018275', (126, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (236, 245))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumors', 'Disease', (43, 49))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('ductal carcinoma', 'Disease', 'MESH:D044584', (229, 245))	('ductal carcinoma', 'Disease', (229, 245))	('tumors', 'Disease', 'MESH:D009369', (43, 49))
410985	31289610	PTEN showed a 6% (551/9020) of mutations in pan-human solid cancers (Figure 8E and 8G).	('solid cancers', 'Disease', (54, 67))	('mutations', 'Var', (31, 40))	('cancers', 'Phenotype', 'HP:0002664', (60, 67))	('solid cancers', 'Disease', 'MESH:D009369', (54, 67))	('human', 'Species', '9606', (48, 53))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
410986	31289610	As illustrated in Figure 8F, PTEN harbored high frequent mutations in uterine endometrioid carcinoma [51.79% (159/307)] next to cervical endometrioid carcinoma [33.33% (1/3)] and lung squamous cell carcinoma 11.57% (56/484)].	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (184, 207))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (137, 159))	('endometrioid carcinoma', 'Disease', (78, 100))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (179, 207))	('PTEN', 'Gene', (29, 33))	('endometrioid carcinoma', 'Disease', 'MESH:D016889', (137, 159))	('carcinoma', 'Phenotype', 'HP:0030731', (198, 207))	('cervical endometrioid carcinoma', 'Phenotype', 'HP:0012889', (128, 159))	('endometrioid carcinoma', 'Disease', (137, 159))	('carcinoma', 'Phenotype', 'HP:0030731', (150, 159))	('lung squamous cell carcinoma', 'Disease', (179, 207))	('mutations', 'Var', (57, 66))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (78, 100))	('endometrioid carcinoma', 'Disease', 'MESH:D016889', (78, 100))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (179, 207))
410988	31289610	This pathway's mutations were frequently observed in 58.96% (181/307) of uterine endometrioid carcinoma, 52.87% (46/87) of breast mixed ductal and lobular carcinoma, 51.77% (73/141) of breast invasive lobular carcinoma (Figure 8H).	('lobular carcinoma', 'Phenotype', 'HP:0030076', (201, 218))	('endometrioid carcinoma', 'Disease', 'MESH:D016889', (81, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (155, 164))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('endometrioid carcinoma', 'Disease', (81, 103))	('lobular carcinoma', 'Disease', (147, 164))	('mutations', 'Var', (15, 24))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (81, 103))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (147, 164))	('breast invasive lobular carcinoma', 'Disease', 'MESH:D018275', (185, 218))	('lobular carcinoma', 'Disease', 'MESH:D018275', (201, 218))	('observed', 'Reg', (41, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (209, 218))	('breast invasive lobular carcinoma', 'Disease', (185, 218))	('lobular carcinoma', 'Disease', 'MESH:D018275', (147, 164))
410990	31289610	To determine any relationship between oncogenic activation and loss of tumor suppressor function in the GPCR-mediated PI3K pathway, mutations in the LPAR4, PIK3CA, and PTEN mutations were analyzed in relation to each other both in pan-cancer cell lines and pan-solid tumor samples (Table 4).	('loss of tumor', 'Disease', (63, 76))	('PTEN', 'Gene', (168, 172))	('GPCR', 'Gene', '23566', (104, 108))	('tumor', 'Disease', 'MESH:D009369', (267, 272))	('mutations', 'Var', (132, 141))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('LPAR4', 'Gene', '2846', (149, 154))	('tumor', 'Phenotype', 'HP:0002664', (267, 272))	('pan-cancer', 'Disease', 'MESH:C537931', (231, 241))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('GPCR', 'Gene', (104, 108))	('LPAR4', 'Gene', (149, 154))	('tumor', 'Disease', (267, 272))	('loss of tumor', 'Disease', 'MESH:D009369', (63, 76))	('tumor', 'Disease', (71, 76))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))	('PIK3CA', 'Gene', (156, 162))	('pan-cancer', 'Disease', (231, 241))
410991	31289610	Our analyses demonstrated that PIK3CA and PTEN mutations co-occurred significantly in pan-cancer cell lines (p = <0.001).	('PTEN', 'Gene', (42, 46))	('pan-cancer', 'Disease', 'MESH:C537931', (86, 96))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('mutations', 'Var', (47, 56))	('PIK3CA', 'Gene', (31, 37))	('pan-cancer', 'Disease', (86, 96))
411001	31289610	Recently, WES of a Chinese population with PTCs revealed frequent mutations in the GPCR-mediated PI3K pathway and identified mutations of LPAR4 as novel PTC driver alterations.	('mutations', 'Var', (66, 75))	('mutations', 'Var', (125, 134))	('PTC', 'Gene', (153, 156))	('LPAR4', 'Gene', '2846', (138, 143))	('GPCR', 'Gene', '23566', (83, 87))	('LPAR4', 'Gene', (138, 143))	('PTC', 'Gene', '5979', (153, 156))	('PTC', 'Gene', (43, 46))	('PTC', 'Gene', '5979', (43, 46))	('GPCR', 'Gene', (83, 87))
411009	31289610	Our study revealed GPCR-mediated PI3K pathway mutations in 3.37% and 2.45% of pediatric and adult DTCs, respectively.	('GPCR', 'Gene', (19, 23))	('mutations', 'Var', (46, 55))	('pediatric', 'Disease', (78, 87))	('DTC', 'Chemical', '-', (98, 101))	('GPCR', 'Gene', '23566', (19, 23))
411012	31289610	However, a relatively high frequency (6.6%) of this pathway-mutations was found in a Chinese population with DTC suggesting that ethnic differences, sample selection, and sequencing method are likely to influence the prevalence of mutations in this pathway.	('mutations', 'Var', (231, 240))	('DTC', 'Chemical', '-', (109, 112))	('influence', 'Reg', (203, 212))
411013	31289610	Moreover, consistent with previous studies, our study also suggests that PI3K pathway alterations are quite rare events and may indicate that the GPCR-mediated PI3K pathway genes are mutated only in a small fraction of DTCs.	('PI3K pathway', 'Pathway', (73, 85))	('GPCR', 'Gene', '23566', (146, 150))	('GPCR', 'Gene', (146, 150))	('DTC', 'Chemical', '-', (219, 222))	('alterations', 'Var', (86, 97))
411015	31289610	In this study, of 293 DTC cases, 5 harbored 7 different PIK3CA mutations as two cases had concomitant mutations (Q530R; A533V and S553T; T1659del).	('T1659del', 'Mutation', 'c.1659delT', (137, 145))	('A533V', 'Var', (120, 125))	('PIK3CA', 'Gene', (56, 62))	('Q530R', 'Mutation', 'rs748157088', (113, 118))	('293 DTC', 'CellLine', 'CVCL:0J31', (18, 25))	('A533V', 'Mutation', 'p.A533V', (120, 125))	('S553T', 'Mutation', 'p.S553T', (130, 135))	('S553T; T1659del', 'Var', (130, 145))	('Q530R; A533V', 'Var', (113, 125))
411017	31289610	PI3K pathway mutations are reported to be mutually exclusive in human cancers including thyroid cancer.	('human', 'Species', '9606', (64, 69))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('thyroid cancer', 'Phenotype', 'HP:0002890', (88, 102))	('thyroid cancer', 'Disease', (88, 102))	('PI3K pathway', 'Pathway', (0, 12))	('cancers', 'Disease', 'MESH:D009369', (70, 77))	('cancers', 'Phenotype', 'HP:0002664', (70, 77))	('mutations', 'Var', (13, 22))	('cancers', 'Disease', (70, 77))	('thyroid cancer', 'Disease', 'MESH:D013964', (88, 102))
411018	31289610	However, only one case had concomitant PIK3CA and PTEN mutation suggesting a weaker oncogenic potential of PIK3CA and requirement of a loss of tumor suppressor-like PTEN.	('loss of tumor', 'Disease', 'MESH:D009369', (135, 148))	('weaker', 'NegReg', (77, 83))	('PTEN', 'Gene', (50, 54))	('loss of tumor', 'Disease', (135, 148))	('PIK3CA', 'Var', (107, 113))	('mutation', 'Var', (55, 63))	('PIK3CA', 'Gene', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('oncogenic potential', 'CPA', (84, 103))
411019	31289610	Recent deep sequencing of DTCs (PTCs) identified PIK3CA and PTEN mutations in samples with distant metastasis suggesting that the DTCs with these mutations are likely to progress into aggressive poorly differentiated thyroid cancer (PDTCs).	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('mutations', 'Var', (146, 155))	('PTC', 'Gene', '5979', (32, 35))	('thyroid cancer', 'Disease', 'MESH:D013964', (217, 231))	('DTC', 'Chemical', '-', (26, 29))	('PTEN', 'Gene', (60, 64))	('PIK3CA', 'Gene', (49, 55))	('DTC', 'Chemical', '-', (130, 133))	('DTC', 'Chemical', '-', (234, 237))	('progress', 'PosReg', (170, 178))	('thyroid cancer', 'Phenotype', 'HP:0002890', (217, 231))	('thyroid cancer', 'Disease', (217, 231))	('mutations', 'Var', (65, 74))	('PTC', 'Gene', (32, 35))
411020	31289610	Further, PIK3CA/PTEN mutation-positive samples were negative for the most commonly identified TERT promoter mutations.	('TERT', 'Gene', (94, 98))	('TERT', 'Gene', '7015', (94, 98))	('mutations', 'Var', (108, 117))
411021	31289610	BRAF mutation in combination with a gain-of-function PIK3CA or loss-of-function PTEN/TP 53 mutation scenario has only been seen in the ATCs.	('gain-of-function', 'PosReg', (36, 52))	('TP 53', 'Gene', (85, 90))	('loss-of-function', 'NegReg', (63, 79))	('TP 53', 'Gene', '7157', (85, 90))	('mutation', 'Var', (5, 13))
411022	31289610	A recent study demonstrated that BRAF mutant induced PTC was indolent and could not lead to end-stage disease.	('mutant', 'Var', (38, 44))	('PTC', 'Gene', (53, 56))	('BRAF', 'Gene', (33, 37))	('PTC', 'Gene', '5979', (53, 56))
411023	31289610	Similarly, PIK3CA mutant was unable to transform thyrocytes on its own but when co-expressed with BRAF mutant, that lead to the development of lethal ATC in mice suggesting that tumors bearing both BRAF and PIK3CA mutations are likely to progress into PDTCs and lethal ATCs.	('mice', 'Species', '10090', (157, 161))	('tumors', 'Disease', (178, 184))	('tumors', 'Disease', 'MESH:D009369', (178, 184))	('tumors', 'Phenotype', 'HP:0002664', (178, 184))	('BRAF', 'Gene', (198, 202))	('mutations', 'Var', (214, 223))	('lethal ATCs', 'Disease', (262, 273))	('DTC', 'Chemical', '-', (253, 256))	('PDTCs', 'Disease', (252, 257))	('progress', 'PosReg', (238, 246))	('PIK3CA', 'Gene', (207, 213))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))
411024	31289610	On the other hand, thyroid cancer patients with PIK3CA mutations were shown to have a distinct pathological profile as PIK3CA mutations are likely to arise during the tumor progression.	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('mutations', 'Var', (55, 64))	('PIK3CA', 'Gene', (119, 125))	('thyroid cancer', 'Disease', (19, 33))	('PIK3CA', 'Gene', (48, 54))	('arise', 'Reg', (150, 155))	('thyroid cancer', 'Phenotype', 'HP:0002890', (19, 33))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('thyroid cancer', 'Disease', 'MESH:D013964', (19, 33))	('patients', 'Species', '9606', (34, 42))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('mutations', 'Var', (126, 135))	('tumor', 'Disease', (167, 172))
411025	31289610	It has been shown that BRAFV600E and PTEN loss facilitates the progression of thyroid cancers when the fibroblast-mediated collagen remodeling takes place within the tumor microenvironment suggesting a possibility of synergism in tumor progression.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('tumor', 'Disease', (230, 235))	('thyroid cancers', 'Disease', 'MESH:D013964', (78, 93))	('facilitates', 'PosReg', (47, 58))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('tumor', 'Disease', (166, 171))	('PTEN', 'Gene', (37, 41))	('BRAFV600E', 'Var', (23, 32))	('tumor', 'Disease', 'MESH:D009369', (230, 235))	('BRAFV600E', 'Mutation', 'rs113488022', (23, 32))	('cancers', 'Phenotype', 'HP:0002664', (86, 93))	('thyroid cancer', 'Phenotype', 'HP:0002890', (78, 92))	('progression', 'CPA', (63, 74))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))	('thyroid cancers', 'Disease', (78, 93))	('loss', 'NegReg', (42, 46))
411028	31289610	Although the low prevalence of GPCR-mediated PI3K pathway mutations is identified both in this study and TCGA data, they are located in the important functional domains including helical and kinase domains and interact with the important key players in the signaling network, and hence the mutations are likely to be oncogenic/tumor progression drivers.	('mutations', 'Var', (58, 67))	('tumor', 'Phenotype', 'HP:0002664', (327, 332))	('GPCR', 'Gene', '23566', (31, 35))	('tumor', 'Disease', (327, 332))	('located', 'Reg', (125, 132))	('interact', 'Reg', (210, 218))	('mutations', 'Var', (290, 299))	('GPCR', 'Gene', (31, 35))	('tumor', 'Disease', 'MESH:D009369', (327, 332))
411031	31289610	In contrast, analyses of TCGA data of aggressive thyroid cancers (PDTC and ATC) showed an overall 13% mutation rate in this pathway.	('thyroid cancer', 'Phenotype', 'HP:0002890', (49, 63))	('aggressive thyroid cancers', 'Disease', 'MESH:D013964', (38, 64))	('DTC', 'Chemical', '-', (67, 70))	('mutation', 'Var', (102, 110))	('cancers', 'Phenotype', 'HP:0002664', (57, 64))	('aggressive thyroid cancers', 'Disease', (38, 64))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))
411032	31289610	Interestingly, this pathway had mutations in 30% of ATCs but only in 6% of PDTC.	('mutations', 'Var', (32, 41))	('ATCs', 'Disease', (52, 56))	('DTC', 'Chemical', '-', (76, 79))
411033	31289610	PIK3CA was found to be mutated in 7% of cases and PTEN mutations were also found in 7% while mutation was not detected in LPAR4.	('mutations', 'Var', (55, 64))	('PTEN', 'Gene', (50, 54))	('found', 'Reg', (75, 80))	('PIK3CA', 'Gene', (0, 6))	('mutated', 'Var', (23, 30))	('LPAR4', 'Gene', '2846', (122, 127))	('LPAR4', 'Gene', (122, 127))
411035	31289610	Patients bearing PIK3CA mutations showed a significant poor overall survival (p = 0.0289) compared with people bearing wild-type PIK3CA suggesting the important role of this gene in aggressive thyroid cancer.	('people', 'Species', '9606', (104, 110))	('PIK3CA', 'Gene', (17, 23))	('thyroid cancer', 'Phenotype', 'HP:0002890', (193, 207))	('Patients', 'Species', '9606', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('poor', 'NegReg', (55, 59))	('mutations', 'Var', (24, 33))	('aggressive thyroid cancer', 'Disease', (182, 207))	('aggressive thyroid cancer', 'Disease', 'MESH:D013964', (182, 207))
411037	31289610	Alternatively, ethnic differences might be the reason for this apparent difference in the rate of mutations in PDTC and ATC in our study compared to TCGA data.	('mutations', 'Var', (98, 107))	('ATC', 'Gene', (120, 123))	('DTC', 'Chemical', '-', (112, 115))	('PDTC', 'Gene', (111, 115))
411040	31289610	Unlike the low prevalence observed in DTCs and thyroid TCGA, both pan-cancer cell lines (24.8%) and tumors (24.8%) had high mutation frequency which is even higher than (6.6%) that reported in DTC from a Chinese population.	('pan-cancer', 'Disease', 'MESH:C537931', (66, 76))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('mutation frequency', 'Var', (124, 142))	('DTC', 'Chemical', '-', (193, 196))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('tumors', 'Disease', (100, 106))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('pan-cancer', 'Disease', (66, 76))	('DTC', 'Chemical', '-', (38, 41))
411041	31289610	LPAR4 mutations in pan-tumors (0.8%) were comparable to that of DTCs though pan-cancer cell lines had a slightly higher prevalence (3.3%).	('LPAR4', 'Gene', '2846', (0, 5))	('tumors', 'Disease', (23, 29))	('pan-cancer', 'Disease', 'MESH:C537931', (76, 86))	('tumors', 'Disease', 'MESH:D009369', (23, 29))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('DTC', 'Chemical', '-', (64, 67))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('pan-cancer', 'Disease', (76, 86))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))	('mutations', 'Var', (6, 15))	('LPAR4', 'Gene', (0, 5))
411042	31289610	LPAR4 mutations have previously been reported in 16% (1/6) only in human colon cancer cell lines and recently in PTCs.	('colon cancer', 'Disease', (73, 85))	('PTC', 'Gene', (113, 116))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('PTC', 'Gene', '5979', (113, 116))	('colon cancer', 'Phenotype', 'HP:0003003', (73, 85))	('human', 'Species', '9606', (67, 72))	('colon cancer', 'Disease', 'MESH:D015179', (73, 85))	('LPAR4', 'Gene', '2846', (0, 5))	('LPAR4', 'Gene', (0, 5))	('mutations', 'Var', (6, 15))
411043	31289610	However, PIK3CA and PTEN showed more frequent mutation rates in pan-cancer cell lines and tumors and were very consistent with the previous reports suggesting that more proven contribution of this pathway gene in the pathogenesis of solid pan-tumors.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('tumors', 'Disease', (243, 249))	('tumors', 'Disease', 'MESH:D009369', (243, 249))	('pan-cancer', 'Disease', (64, 74))	('tumors', 'Phenotype', 'HP:0002664', (243, 249))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('mutation', 'Var', (46, 54))	('tumors', 'Disease', (90, 96))	('tumors', 'Disease', 'MESH:D009369', (90, 96))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('pan-cancer', 'Disease', 'MESH:C537931', (64, 74))	('PIK3CA', 'Gene', (9, 15))	('PTEN', 'Gene', (20, 24))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))
411047	31289610	It has been widely demonstrated that PIK3CA and PTEN mutations were mutually exclusive; suggesting that tumorigenic signaling through the PI3K pathway could occur either with activation of PIK3CA/inactivation of PTEN.	('PIK3CA/inactivation', 'Gene', (189, 208))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumor', 'Disease', (104, 109))	('activation', 'PosReg', (175, 185))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('PIK3CA/inactivation', 'Var', (189, 208))	('PTEN', 'Gene', (212, 216))	('occur', 'Reg', (157, 162))	('PI3K pathway', 'Pathway', (138, 150))
411048	31289610	In contrast, it has been reported that coexistence of PIK3CA/PTEN mutations at high frequency (26%) in endometrial carcinoma.	('mutations', 'Var', (66, 75))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (103, 124))	('endometrial carcinoma', 'Disease', (103, 124))	('PIK3CA/PTEN', 'Gene', (54, 65))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (103, 124))
411049	31289610	Further, PIK3CA mutations were more frequent in tumors with PTEN mutations (46%) compared with those without PTEN mutations (24%) and this concomitant mutations (1.3%) have also been reported from Chinese breast cancers.	('tumors', 'Disease', (48, 54))	('tumors', 'Disease', 'MESH:D009369', (48, 54))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('mutations', 'Var', (16, 25))	('cancers', 'Phenotype', 'HP:0002664', (212, 219))	('PTEN', 'Gene', (60, 64))	('breast cancers', 'Phenotype', 'HP:0003002', (205, 219))	('PIK3CA', 'Gene', (9, 15))	('breast cancer', 'Phenotype', 'HP:0003002', (205, 218))	('breast cancers', 'Disease', 'MESH:D001943', (205, 219))	('breast cancers', 'Disease', (205, 219))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('mutations', 'Var', (65, 74))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))
411050	31289610	Further, an oncogenic PIK3CA mutation coupled with PTEN loss was shown to initiate ovarian tumors in mice.	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('mutation', 'Var', (29, 37))	('loss', 'NegReg', (56, 60))	('initiate', 'PosReg', (74, 82))	('ovarian tumors', 'Disease', 'MESH:D010051', (83, 97))	('PTEN', 'Gene', (51, 55))	('mice', 'Species', '10090', (101, 105))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('PIK3CA', 'Gene', (22, 28))	('ovarian tumors', 'Disease', (83, 97))	('ovarian tumors', 'Phenotype', 'HP:0100615', (83, 97))
411051	31289610	This unique genetic representation indicates that the combination of PIK3CA/PTEN alterations might play an important synergistic role in tumorigenesis of these cancers.	('PIK3CA/PTEN', 'Gene', (69, 80))	('cancers', 'Disease', 'MESH:D009369', (160, 167))	('tumor', 'Disease', (137, 142))	('cancers', 'Phenotype', 'HP:0002664', (160, 167))	('cancers', 'Disease', (160, 167))	('play', 'Reg', (99, 103))	('alterations', 'Var', (81, 92))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
411057	31289610	In conclusion, data from our study and TCGA data of thyroid showed a similar low prevalence of mutations in GPCR-mediated PI3K pathway genes.	('mutations', 'Var', (95, 104))	('GPCR', 'Gene', '23566', (108, 112))	('GPCR', 'Gene', (108, 112))
411058	31289610	These results suggest that this pathway contributes to the pathogenesis of a smaller portion of DTCs but may have a major role in the progression of tumors harboring mutations in this pathway, leading to more aggressiveness and metastasis leading to PDTC and ATC.	('more', 'PosReg', (204, 208))	('aggressiveness', 'Disease', 'MESH:D001523', (209, 223))	('mutations', 'Var', (166, 175))	('aggressiveness', 'Disease', (209, 223))	('metastasis', 'CPA', (228, 238))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('aggressiveness', 'Phenotype', 'HP:0000718', (209, 223))	('PDTC', 'Disease', (250, 254))	('ATC', 'Disease', (259, 262))	('tumors', 'Disease', (149, 155))	('tumors', 'Disease', 'MESH:D009369', (149, 155))	('tumors', 'Phenotype', 'HP:0002664', (149, 155))	('DTC', 'Chemical', '-', (251, 254))	('DTC', 'Chemical', '-', (96, 99))
411059	31289610	In addition, TCGA data analyses reveal that GPCR-mediated PI3K pathway genes are frequently mutated and they are likely playing a key role in the pathogenesis of PDTC and ATC and other human solid malignancies.	('DTC', 'Chemical', '-', (163, 166))	('PDTC', 'Disease', (162, 166))	('human', 'Species', '9606', (185, 190))	('GPCR', 'Gene', (44, 48))	('playing', 'Reg', (120, 127))	('malignancies', 'Disease', 'MESH:D009369', (197, 209))	('mutated', 'Var', (92, 99))	('role', 'Reg', (134, 138))	('ATC', 'Disease', (171, 174))	('GPCR', 'Gene', '23566', (44, 48))	('malignancies', 'Disease', (197, 209))
411067	31289610	All the mutation-positive cases were further screened for the common mutations in exon 15 of BRAF and TERT promoter using primers as described earlier.	('mutations in', 'Var', (69, 81))	('BRAF', 'Gene', (93, 97))	('TERT', 'Gene', '7015', (102, 106))	('TERT', 'Gene', (102, 106))
411069	31289610	The sequencing results were read against the GeneBank Accession No: LPAR4 (NM_005296.2), PIK3CA (NM_006218.3), PTEN (NM_000314.6), BRAF (NM_004333.4) and TERT (AF098956.1).	('LPAR4', 'Gene', (68, 73))	('NM_006218.3', 'Var', (97, 108))	('TERT', 'Gene', (154, 158))	('NM_004333.4', 'Var', (137, 148))	('NM_000314.6', 'Var', (117, 128))	('NM_005296.2', 'Var', (75, 86))	('TERT', 'Gene', '7015', (154, 158))	('LPAR4', 'Gene', '2846', (68, 73))
411072	31289610	PTEN mutations identified in pediatric/adult DTCs were viewed and plotted using NGL viewer, a WebGL based 3D viewer powered by MMTF (Macromolecular Transmission Format) as described before.	('NGL', 'Gene', '2064', (80, 83))	('mutations', 'Var', (5, 14))	('NGL', 'Gene', (80, 83))	('DTC', 'Chemical', '-', (45, 48))	('PTEN', 'Gene', (0, 4))
411075	31289610	Our analyses showed 3600 mutated genes in DTC.	('mutated genes', 'Var', (25, 38))	('DTC', 'Chemical', '-', (42, 45))	('DTC', 'Disease', (42, 45))
411084	31289610	Kaplan-Meier plots with a log-rank test were used to calculate the overall and disease-free survival of pan-solid tumors (except thyroid cancer) with at least one mutation or without mutation in the query gene.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('thyroid cancer', 'Phenotype', 'HP:0002890', (129, 143))	('solid tumors', 'Disease', (108, 120))	('thyroid cancer', 'Disease', (129, 143))	('mutation', 'Var', (163, 171))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('solid tumors', 'Disease', 'MESH:D009369', (108, 120))	('thyroid cancer', 'Disease', 'MESH:D013964', (129, 143))
411202	27128408	The presence of CAFs could thus serve as a potential prognostic marker in multiple cancers, including OSCC.	('cancers', 'Phenotype', 'HP:0002664', (83, 90))	('CAFs', 'Chemical', '-', (16, 20))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('OSCC', 'Disease', (102, 106))	('multiple cancers', 'Disease', (74, 90))	('presence', 'Var', (4, 12))	('multiple cancers', 'Disease', 'MESH:D009369', (74, 90))	('CAFs', 'Gene', (16, 20))
411243	33993055	This research was supported by the Program for Developing Next-generation Researchers (Japan Science and Technology Agency), KAKEN (18K15923, 21K07217, JSPS), FOREST-Souhatsu, CREST (JST).	('CREST', 'Gene', (176, 181))	('18K15923', 'Var', (132, 140))	('CREST', 'Gene', '269397', (176, 181))
411253	33993055	In vitro NIR-PIT targeting GPR87 only injured GPR87-expressing cells and did not affect non-targeted cells.	('GPR87', 'Var', (27, 32))	('GPR87-expressing', 'Gene', (46, 62))	('injured', 'NegReg', (38, 45))	('NIR-PIT', 'Chemical', '-', (9, 16))
411262	33993055	High GPR87 expression in lung and pancreatic cancer is associated with a worse prognosis.	('pancreatic cancer', 'Disease', 'MESH:D010190', (34, 51))	('lung', 'Disease', (25, 29))	('High', 'Var', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (34, 51))	('GPR87', 'Gene', (5, 10))	('pancreatic cancer', 'Disease', (34, 51))
411265	33993055	Near-infrared photoimmunotherapy (NIR-PIT) is an emerging cancer modality, where IRDye700DX (IR700), a photosensitiser, is bound to an antibody, and near-infrared-light irradiation specifically destroys the targeting cell.	('IRDye700DX', 'Var', (81, 91))	('IR700', 'Chemical', '-', (93, 98))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('bound', 'Interaction', (123, 128))	('NIR-PIT', 'Chemical', '-', (34, 41))	('destroys', 'NegReg', (194, 202))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('cancer', 'Disease', (58, 64))
411271	33993055	The HAMA response is significantly reduced or abolished by chimerisation and humanisation.	('reduced', 'NegReg', (35, 42))	('HAMA response', 'MPA', (4, 17))	('abolished', 'NegReg', (46, 55))	('chimerisation', 'Var', (59, 72))	('human', 'Species', '9606', (77, 82))
411274	33993055	The aim of this study was to develop NIR-PIT targeting GPR87, and the therapeutic targets were MPM and lung cancer.	('lung cancer', 'Disease', 'MESH:D008175', (103, 114))	('MPM', 'Disease', (95, 98))	('GPR87', 'Var', (55, 60))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('lung cancer', 'Disease', (103, 114))	('lung cancer', 'Phenotype', 'HP:0100526', (103, 114))	('NIR-PIT', 'Chemical', '-', (37, 44))
411303	33993055	Cells (1 x 105) were seeded onto 12-well plates and incubated with moGPR87ab-IR700 or huGPR87ab-IR700 at 10 mug/mL for 12 h at 37  C. The medium was replaced with PBS after washing twice.	('IR700', 'Chemical', '-', (96, 101))	('huGPR87ab-IR700', 'Var', (86, 101))	('moGPR87ab-IR700', 'Var', (67, 82))	('IR700', 'Chemical', '-', (77, 82))	('PBS', 'Chemical', 'MESH:D007854', (163, 166))	('huGPR87ab', 'Chemical', '-', (86, 95))
411336	33993055	The mice were injected with 200 mug of huGPR87-IR700 on day -1 (9 days after tumour cell injection into mice) and irradiated with NIR-light laser at 50 J/cm2 on day 0 and again at 100 J/cm2 on day 1 at 100 mW/cm2.	('mice', 'Species', '10090', (4, 8))	('tumour', 'Disease', 'MESH:D009369', (77, 83))	('huGPR87-IR700', 'Var', (39, 52))	('mice', 'Species', '10090', (104, 108))	('tumour', 'Disease', (77, 83))	('IR700', 'Chemical', '-', (47, 52))	('tumour', 'Phenotype', 'HP:0002664', (77, 83))
411337	33993055	Tumour volume and luciferase activity were measured immediately before administration of huGPR87-IR700 (day-1), and on day 0 and 1 before NIR-irradiation, and on day 2, 3, 4 and 7.	('Tumour volume', 'CPA', (0, 13))	('IR700', 'Chemical', '-', (97, 102))	('activity', 'MPA', (29, 37))	('huGPR87-IR700', 'Var', (89, 102))	('Tumour', 'Phenotype', 'HP:0002664', (0, 6))	('luciferase', 'Enzyme', (18, 28))
411338	33993055	Mice seeded with pleura were injected with 200 mug of huGPR87ab-IR700 on day 0 (5 days after tumour cell injection into the mice), and therefore the larger tumour was irradiated with NIR-light laser at 45 J/cm2 at 60 mW/cm2 on day 1.	('huGPR87ab', 'Chemical', '-', (54, 63))	('tumour', 'Disease', 'MESH:D009369', (156, 162))	('huGPR87ab-IR700', 'Var', (54, 69))	('tumour', 'Disease', (93, 99))	('tumour', 'Disease', (156, 162))	('mice', 'Species', '10090', (124, 128))	('tumour', 'Phenotype', 'HP:0002664', (156, 162))	('tumour', 'Phenotype', 'HP:0002664', (93, 99))	('Mice', 'Species', '10090', (0, 4))	('tumour', 'Disease', 'MESH:D009369', (93, 99))	('IR700', 'Chemical', '-', (64, 69))
411339	33993055	Luciferase activity was measured immediately before administration of huGPR87-IR700 (day 0) and on day 1 (before NIR-irradiation), 2, 3 and 4.	('Luciferase', 'Enzyme', (0, 10))	('huGPR87-IR700', 'Var', (70, 83))	('activity', 'MPA', (11, 19))	('IR700', 'Chemical', '-', (78, 83))
411343	33993055	The integrity of the huGPR87ab-IR700 conjugate was confirmed by observing strong IR700-fluorescence, which was detected in the band of huGPR87ab, while huGPR87ab alone had no detectable fluorescent signals on SDS-PAGE (Fig.	('IR700-fluorescence', 'MPA', (81, 99))	('huGPR87ab', 'Chemical', '-', (135, 144))	('IR700', 'Chemical', '-', (31, 36))	('SDS', 'Chemical', 'MESH:D012967', (209, 212))	('huGPR87ab', 'Var', (135, 144))	('huGPR87ab', 'Chemical', '-', (21, 30))	('IR700', 'Chemical', '-', (81, 86))	('huGPR87ab', 'Chemical', '-', (152, 161))
411345	33993055	On binding with GPR87-CHO cells, which were stably GPR87-overexpressing strains, both moGPR87ab-IR700 and huGPR87ab-IR700 showed similar reactions; almost no signals were observed in either 3T3 mouse fibroblasts or human normal bronchial epithelial cell line HBEC3.	('mouse fibroblasts', 'CellLine', 'CVCL:0594', (194, 211))	('moGPR87ab-IR700', 'Var', (86, 101))	('binding', 'Interaction', (3, 10))	('IR700', 'Chemical', '-', (96, 101))	('HBEC3', 'CellLine', 'CVCL:X491', (259, 264))	('huGPR87ab', 'Chemical', '-', (106, 115))	('huGPR87ab-IR700', 'Var', (106, 121))	('GPR87-CHO', 'CellLine', 'CVCL:U007', (16, 25))	('IR700', 'Chemical', '-', (116, 121))	('human', 'Species', '9606', (215, 220))
411348	33993055	3c), confirming that huGPR87ab-IR700 bound to GPR87 proteins.	('huGPR87ab-IR700', 'Var', (21, 36))	('IR700', 'Chemical', '-', (31, 36))	('bound', 'Interaction', (37, 42))	('huGPR87ab', 'Chemical', '-', (21, 30))
411349	33993055	These results indicated that huGPR87ab and IR700 were conjugated properly, and the binding was stronger with huGPR87ab than with moGPR87ab-IR700.	('huGPR87ab', 'Chemical', '-', (29, 38))	('stronger', 'PosReg', (95, 103))	('binding', 'Interaction', (83, 90))	('huGPR87ab', 'Chemical', '-', (109, 118))	('IR700', 'Chemical', '-', (139, 144))	('IR700', 'Chemical', '-', (43, 48))	('huGPR87ab', 'Var', (109, 118))
411350	33993055	The fluorescent signals obtained with huGPR87ab-IR700 from H1975 (NSLAC), H661 (large cell lung carcinoma), H226 (NSLSCC), SBC3, SBC5 (SCLC), MSTO-211H, and H2373 (MPM) were evaluated using flow cytometry.	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('H2373', 'CellLine', 'CVCL:A533', (157, 162))	('H661', 'CellLine', 'CVCL:1577', (74, 78))	('SCLC', 'Disease', (135, 139))	('SCLC', 'Disease', 'MESH:D018288', (135, 139))	('lung carcinoma', 'Disease', (91, 105))	('huGPR87ab-IR700', 'Var', (38, 53))	('H661', 'Var', (74, 78))	('lung carcinoma', 'Disease', 'MESH:D008175', (91, 105))	('large cell lung carcinoma', 'Phenotype', 'HP:0030360', (80, 105))	('huGPR87ab', 'Chemical', '-', (38, 47))	('H226', 'CellLine', 'CVCL:J621', (108, 112))	('H1975', 'CellLine', 'CVCL:1511', (59, 64))	('IR700', 'Chemical', '-', (48, 53))
411351	33993055	Fluorescent signals from lung carcinoma and malignant mesothelioma cells were higher for huGPR87ab-IR700 than for moGPR87ab-IR700 (Fig.	('lung carcinoma', 'Disease', (25, 39))	('IR700', 'Chemical', '-', (124, 129))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (44, 66))	('huGPR87ab-IR700', 'Var', (89, 104))	('higher', 'PosReg', (78, 84))	('huGPR87ab', 'Chemical', '-', (89, 98))	('IR700', 'Chemical', '-', (99, 104))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (44, 66))	('malignant mesothelioma', 'Disease', (44, 66))	('Fluorescent signals', 'MPA', (0, 19))	('carcinoma', 'Phenotype', 'HP:0030731', (30, 39))	('lung carcinoma', 'Disease', 'MESH:D008175', (25, 39))
411352	33993055	These data indicated that GPR87 is widely expressed, and huGPR87ab-IR700 had sufficient binding affinity to lung carcinoma and malignant mesothelioma cell lines.	('lung carcinoma', 'Disease', (108, 122))	('huGPR87ab', 'Chemical', '-', (57, 66))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (127, 149))	('binding affinity', 'Interaction', (88, 104))	('IR700', 'Chemical', '-', (67, 72))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (127, 149))	('huGPR87ab-IR700', 'Var', (57, 72))	('lung carcinoma', 'Disease', 'MESH:D008175', (108, 122))	('malignant mesothelioma', 'Disease', (127, 149))
411353	33993055	Moreover, huGPR87ab-IR700 had a higher affinity to the protein in vitro than moGPR87ab-IR700.	('IR700', 'Chemical', '-', (87, 92))	('higher', 'PosReg', (32, 38))	('protein', 'Protein', (55, 62))	('affinity', 'Interaction', (39, 47))	('huGPR87ab', 'Chemical', '-', (10, 19))	('huGPR87ab-IR700', 'Var', (10, 25))	('IR700', 'Chemical', '-', (20, 25))
411359	33993055	In vitro NIR-PIT with huGPR87-IR700 was also performed with SBC5-luc (SCLC) and H2373-luc (MPM), and similar results were obtained (Fig.	('SCLC', 'Disease', 'MESH:D018288', (70, 74))	('huGPR87-IR700', 'Var', (22, 35))	('H2373', 'CellLine', 'CVCL:A533', (80, 85))	('IR700', 'Chemical', '-', (30, 35))	('NIR-PIT', 'Chemical', '-', (9, 16))	('H2373-luc', 'Var', (80, 89))	('SCLC', 'Disease', (70, 74))
411361	33993055	These cellular changes were observed within 30 min after NIR-light irradiation, suggesting that necrotic cell death was rapidly induced by NIR-PIT.	('NIR-PIT', 'Chemical', '-', (139, 146))	('NIR-PIT', 'Var', (139, 146))	('necrotic cell death', 'Disease', (96, 115))	('necrotic cell death', 'Disease', 'MESH:D003643', (96, 115))
411362	33993055	Next, to quantify the effect of NIR-PIT in vitro, we performed a cytotoxicity assay after 24 h using luciferase activity quantitation with PC9-luc, SBC5, and H2373-luc.	('cytotoxicity', 'Disease', 'MESH:D064420', (65, 77))	('H2373', 'CellLine', 'CVCL:A533', (158, 163))	('luciferase', 'Enzyme', (101, 111))	('PC9', 'CellLine', 'CVCL:B260', (139, 142))	('H2373-luc', 'Var', (158, 167))	('NIR-PIT', 'Chemical', '-', (32, 39))	('cytotoxicity', 'Disease', (65, 77))	('activity', 'MPA', (112, 120))
411366	33993055	After 200 microg of GPR87hu-IR700 injection, high fluorescence was observed across the whole mouse body; the tumour was then gradually visualised over the subsequent 1 h (Fig.	('GPR87hu-IR700', 'Var', (20, 33))	('tumour', 'Disease', 'MESH:D009369', (109, 115))	('mouse', 'Species', '10090', (93, 98))	('tumour', 'Disease', (109, 115))	('fluorescence', 'MPA', (50, 62))	('IR700', 'Chemical', '-', (28, 33))	('tumour', 'Phenotype', 'HP:0002664', (109, 115))
411371	33993055	These results indicated that huGPR87ab-IR700 is distributed specifically in GPR87-expressing tumours.	('huGPR87ab', 'Chemical', '-', (29, 38))	('tumours', 'Disease', (93, 100))	('IR700', 'Chemical', '-', (39, 44))	('tumours', 'Phenotype', 'HP:0002664', (93, 100))	('tumour', 'Phenotype', 'HP:0002664', (93, 99))	('huGPR87ab-IR700', 'Var', (29, 44))	('tumours', 'Disease', 'MESH:D009369', (93, 100))
411378	33993055	In summary, GPR87-targeted NIR-PIT with huGPR87ab-IR700 was effective against the flank tumour and successfully achieved site-specific tumour ablation.	('huGPR87ab-IR700', 'Var', (40, 55))	('NIR-PIT', 'Chemical', '-', (27, 34))	('tumour ablation', 'Disease', 'MESH:D009369', (135, 150))	('huGPR87ab', 'Chemical', '-', (40, 49))	('tumour', 'Phenotype', 'HP:0002664', (135, 141))	('tumour ablation', 'Disease', (135, 150))	('flank tumour', 'Disease', 'MESH:D021501', (82, 94))	('IR700', 'Chemical', '-', (50, 55))	('tumour', 'Phenotype', 'HP:0002664', (88, 94))	('flank tumour', 'Disease', (82, 94))
411386	33993055	The rate of EGFR mutation, the most common mutation in lung cancer, is 10-40%, and it is rare in NSLSCC.	('lung cancer', 'Disease', 'MESH:D008175', (55, 66))	('mutation', 'Var', (17, 25))	('lung cancer', 'Disease', (55, 66))	('EGFR', 'Gene', '13649', (12, 16))	('lung cancer', 'Phenotype', 'HP:0100526', (55, 66))	('EGFR', 'Gene', (12, 16))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
411391	33993055	Clinical experience shows that the murine variable region of the chimeric mAb induces HAMA and produces humanised antibodies.	('HAMA', 'MPA', (86, 90))	('induces', 'Reg', (78, 85))	('human', 'Species', '9606', (104, 109))	('humanised antibodies', 'MPA', (104, 124))	('chimeric', 'Var', (65, 73))	('murine', 'Species', '10090', (35, 41))
411408	33993055	This indicates that NIR-PIT may cause damage to organs.	('NIR-PIT', 'Chemical', '-', (20, 27))	('NIR-PIT', 'Var', (20, 27))	('damage', 'CPA', (38, 44))	('cause', 'Reg', (32, 37))
411414	33993055	Patients with high GPR87 expression are expected to be treated with GPR87ab-IR700 followed by NIR irradiation from the body surface or transendoscopically or transdrainally using a fiber light source.	('GPR87ab-IR700', 'Var', (68, 81))	('high GPR87 expression', 'Var', (14, 35))	('IR700', 'Chemical', '-', (76, 81))	('Patients', 'Species', '9606', (0, 8))
411416	33993055	In conclusion, the present study demonstrated the frequently expressed high levels of GPR87 in lung cancer and MPM.	('lung cancer', 'Disease', (95, 106))	('lung cancer', 'Phenotype', 'HP:0100526', (95, 106))	('GPR87', 'Var', (86, 91))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('lung cancer', 'Disease', 'MESH:D008175', (95, 106))	('MPM', 'Disease', (111, 114))
411451	28815199	Multiple mutations accumulate over years of growth affecting many aspects of cell development and regulation until one or more clones emerge with all hallmarks of cancer.	('mutations', 'Var', (9, 18))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('affecting', 'Reg', (51, 60))	('cancer', 'Disease', (163, 169))	('cancer', 'Disease', 'MESH:D009369', (163, 169))
411452	28815199	With continued tumor growth, cells compete for nutrients in the microenvironment, additional mutations accumulate, and progression leads to a genetically heterogeneous neoplasm.	('neoplasm', 'Disease', (168, 176))	('mutations', 'Var', (93, 102))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('neoplasm', 'Phenotype', 'HP:0002664', (168, 176))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('neoplasm', 'Disease', 'MESH:D009369', (168, 176))	('tumor', 'Disease', (15, 20))	('leads to', 'Reg', (131, 139))
411454	28815199	Some patients with P-450 system polymorphisms have an even greater propensity to activate these cigarette smoke procarcinogens to carcinogens.	('polymorphisms', 'Var', (32, 45))	('activate', 'PosReg', (81, 89))	('patients', 'Species', '9606', (5, 13))	('P-450', 'Var', (19, 24))
411455	28815199	In addition, the normal mucosa cells of patients with lung squamous cell carcinoma frequently have tumor protein p53 (TP53) mutations.	('tumor', 'Disease', (99, 104))	('mutations', 'Var', (124, 133))	('patients', 'Species', '9606', (40, 48))	('TP53', 'Gene', '7157', (118, 122))	('TP53', 'Gene', (118, 122))	('p53', 'Gene', '7157', (113, 116))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (54, 82))	('p53', 'Gene', (113, 116))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (59, 82))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (54, 82))	('lung squamous cell carcinoma', 'Disease', (54, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
411456	28815199	TP53 mutations are early events in the progression from in situ to invasive squamous cell carcinoma.	('TP53', 'Gene', '7157', (0, 4))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (76, 99))	('TP53', 'Gene', (0, 4))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('invasive squamous cell carcinoma', 'Disease', (67, 99))	('mutations', 'Var', (5, 14))	('invasive squamous cell carcinoma', 'Disease', 'MESH:D002294', (67, 99))
411457	28815199	TP53 mutations are found in 10% to 50% of the cells of squamous cell dysplasia and in 60% to 90% of carcinoma in situ cells.	('squamous cell dysplasia', 'Disease', (55, 78))	('TP53', 'Gene', '7157', (0, 4))	('carcinoma', 'Disease', 'MESH:D002277', (100, 109))	('TP53', 'Gene', (0, 4))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (100, 117))	('carcinoma', 'Disease', (100, 109))	('mutations', 'Var', (5, 14))	('squamous cell dysplasia', 'Disease', 'MESH:D002294', (55, 78))	('squamous cell dysplasia', 'Phenotype', 'HP:0002860', (55, 78))
411458	28815199	TP53 mutations are also identified in 75% to 90% of small cell lung carcinoma cells.	('small cell lung carcinoma', 'Disease', (52, 77))	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))	('carcinoma', 'Phenotype', 'HP:0030731', (68, 77))	('small cell lung carcinoma', 'Disease', 'MESH:D055752', (52, 77))	('small cell lung carcinoma', 'Phenotype', 'HP:0030357', (52, 77))
411483	27294619	Protein structure guided discovery of functional mutations across 19 cancer types Local concentrations of mutations are well-known in human cancers.	('human', 'Species', '9606', (134, 139))	('mutations', 'Var', (49, 58))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('cancers', 'Phenotype', 'HP:0002664', (140, 147))	('cancers', 'Disease', (140, 147))	('cancers', 'Disease', 'MESH:D009369', (140, 147))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('cancer', 'Disease', (69, 75))
411485	27294619	In addition, we identified 369 rare mutations from genes including TP53, PTEN, VHL, EGFR, and FBXW7 and 99 medium recurrence mutations from genes such as RUNX1, MTOR, CA3, PI3, and PTPN11, all residing within clusters having potential functional implications.	('CA3', 'Gene', (167, 170))	('CA3', 'Gene', '761', (167, 170))	('MTOR', 'Gene', (161, 165))	('MTOR', 'Gene', '2475', (161, 165))	('VHL', 'Gene', '7428', (79, 82))	('PTPN11', 'Gene', (181, 187))	('RUNX1', 'Gene', (154, 159))	('TP53', 'Gene', (67, 71))	('VHL', 'Gene', (79, 82))	('RUNX1', 'Gene', '861', (154, 159))	('FBXW7', 'Gene', (94, 99))	('mutations', 'Var', (125, 134))	('PTEN', 'Gene', (73, 77))	('PTPN11', 'Gene', '5781', (181, 187))	('PI3', 'Gene', '5266', (172, 175))	('PTEN', 'Gene', '5728', (73, 77))	('mutations', 'Var', (36, 45))	('FBXW7', 'Gene', '55294', (94, 99))	('TP53', 'Gene', '7157', (67, 71))	('EGFR', 'Gene', (84, 88))	('PI3', 'Gene', (172, 175))
411488	27294619	The vast majority of mutations are incidental with no discernable role in tumor development.	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor', 'Disease', (74, 79))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('mutations', 'Var', (21, 30))
411489	27294619	For example, MuPIT, an extension of LS-SNP/PDB, maps sequence variants onto protein structures, Interactome3D annotates protein-protein interactions with structural details, other web tools map and visualize variants on protein structures, SpacePAC identifies mutation clusters via simulation, CLUMPS clusters cancer genes and examines protein-protein interactions where at least one protein is known to be cancer related, and Mechismo identifies interaction sites contributing to the binding forces between proteins and other peptides.	('cancer', 'Disease', 'MESH:D009369', (407, 413))	('cancer', 'Disease', (310, 316))	('protein-protein', 'Protein', (336, 351))	('cancer', 'Disease', (407, 413))	('CLUMPS clusters cancer', 'Disease', 'MESH:C563527', (294, 316))	('variants', 'Var', (62, 70))	('CLUMPS clusters cancer', 'Disease', (294, 316))	('cancer', 'Phenotype', 'HP:0002664', (310, 316))	('cancer', 'Phenotype', 'HP:0002664', (407, 413))	('variants', 'Var', (208, 216))	('cancer', 'Disease', 'MESH:D009369', (310, 316))
411491	27294619	It identifies significant spatial mutation and mutation-drug clusters in the form of novel or rare mutations co-clustering with known hotspot residues, medium recurrent mutations that collectively exhibit enrichment, cancer type-specific mutation clusters within and between proteins, and mutations potentially interacting with cancer drugs.	('mutations', 'Var', (169, 178))	('mutations', 'Var', (289, 298))	('cancer', 'Disease', (328, 334))	('mutations', 'Var', (99, 108))	('interacting', 'Reg', (311, 322))	('cancer', 'Disease', (217, 223))	('cancer', 'Disease', 'MESH:D009369', (328, 334))	('cancer', 'Disease', 'MESH:D009369', (217, 223))	('cancer', 'Phenotype', 'HP:0002664', (328, 334))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))
411493	27294619	We applied HotSpot3D to somatic non-truncational mutations (549,295 unique missense mutations and 4,201 in frame indels) in 4,405 samples from 19 major cancer types (Methods).	('cancer', 'Disease', (152, 158))	('missense mutations', 'Var', (75, 93))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))
411498	27294619	TP53 has the highest cluster closeness, a result of both numerous mutations in close proximity (192 unique mutations) and mutation recurrence (38 hotspot residues) throughout the gene.	('mutations', 'Var', (66, 75))	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))
411499	27294619	We observed a shift towards higher cluster closeness for mutation clusters in cancer genes as compared to non-cancer genes (P   5.3e-13) (Figure 2a inset) (Methods).	('mutation', 'Var', (57, 65))	('cancer', 'Disease', (110, 116))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('higher', 'PosReg', (28, 34))	('non-cancer', 'Disease', (106, 116))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('non-cancer', 'Disease', 'MESH:D009369', (106, 116))	('cancer', 'Disease', 'MESH:D009369', (110, 116))
411503	27294619	However, the mutational patterns of non-truncational mutations in TSGs have not been intensively studied.	('non-truncational mutations', 'Var', (36, 62))	('TSG', 'Gene', (66, 69))	('TSG', 'Gene', '57045', (66, 69))
411510	27294619	2a), having 95% and 86% of their respective mutation clusters specific to KIRC, and DNMT3A with 91% specificity to AML.	('DNMT3A', 'Gene', (84, 90))	('AML', 'Disease', 'MESH:D015470', (115, 118))	('DNMT3A', 'Gene', '1788', (84, 90))	('mutation', 'Var', (44, 52))	('AML', 'Disease', (115, 118))
411511	27294619	High-specificity clusters can be the result of a hotspot site having most of its mutations in one cancer type, as is the case with DNMT3A residue Arg882.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('cancer', 'Disease', (98, 104))	('Arg882', 'Chemical', '-', (146, 152))	('DNMT3A', 'Gene', (131, 137))	('Arg882', 'Var', (146, 152))	('DNMT3A', 'Gene', '1788', (131, 137))
411514	27294619	The PIK3CA(4) cluster at centroid Arg88 is primarily UCEC specific (54% of its mutations) and is distributed among three different residues (Arg38, Glu39, and Arg88) that show little BRCA specificity.	('Arg88', 'Chemical', '-', (34, 39))	('Glu39', 'Var', (148, 153))	('Arg88', 'Chemical', '-', (159, 164))	('Arg88', 'Var', (159, 164))	('BRCA', 'Gene', '672', (183, 187))	('PIK3CA', 'Gene', (4, 10))	('BRCA', 'Gene', (183, 187))	('Arg38', 'Chemical', '-', (141, 146))	('PIK3CA', 'Gene', '5290', (4, 10))	('Arg38', 'Var', (141, 146))	('Glu39', 'Chemical', '-', (148, 153))	('Arg88', 'Var', (34, 39))	('mutations', 'Var', (79, 88))
411515	27294619	Conversely, the PIK3CA(1) cluster is primarily BRCA specific (69% of its mutations), and the His1047 centroid is primarily responsible for the overall BRCA specificity.	('BRCA', 'Gene', '672', (151, 155))	('PIK3CA', 'Gene', '5290', (16, 22))	('BRCA', 'Gene', (151, 155))	('His', 'Chemical', 'MESH:D006639', (93, 96))	('BRCA', 'Gene', '672', (47, 51))	('PIK3CA', 'Gene', (16, 22))	('mutations', 'Var', (73, 82))	('BRCA', 'Gene', (47, 51))
411517	27294619	We found mild GBM specificity in PIK3CA across 4 residues (Arg38, Glu39, Arg88, and Cys90) in the PIK3CA(4) cluster and CESC specificity at Glu726 in the PIK3CA(6) cluster.	('Arg38', 'Chemical', '-', (59, 64))	('PIK3CA', 'Gene', (154, 160))	('PIK3CA', 'Gene', '5290', (33, 39))	('Cys90', 'Var', (84, 89))	('PIK3CA', 'Gene', (98, 104))	('Arg88', 'Var', (73, 78))	('Glu39', 'Var', (66, 71))	('Arg38', 'Var', (59, 64))	('PIK3CA', 'Gene', '5290', (98, 104))	('Arg88', 'Chemical', '-', (73, 78))	('PIK3CA', 'Gene', '5290', (154, 160))	('Glu726', 'Chemical', '-', (140, 146))	('Glu39', 'Chemical', '-', (66, 71))	('PIK3CA', 'Gene', (33, 39))	('Cys90', 'Chemical', '-', (84, 89))
411520	27294619	KEAP1/NFE2L2 showed mutual exclusivity, with KEAP1 mutations in adenocarcinomas LUAD and STAD and NFE2L2 mutations in multiple other cancer types (Figure 3d).	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))	('mutations', 'Var', (51, 60))	('adenocarcinomas LUAD', 'Disease', 'MESH:D000230', (64, 84))	('STAD', 'Disease', (89, 93))	('KEAP1', 'Gene', (0, 5))	('NFE2L2', 'Gene', '4780', (98, 104))	('KEAP1', 'Gene', '9817', (45, 50))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('STAD', 'Disease', 'None', (89, 93))	('NFE2L2', 'Gene', '4780', (6, 12))	('cancer', 'Disease', (133, 139))	('NFE2L2', 'Gene', (98, 104))	('mutations', 'Var', (105, 114))	('KEAP1', 'Gene', (45, 50))	('NFE2L2', 'Gene', (6, 12))	('adenocarcinomas LUAD', 'Disease', (64, 84))	('KEAP1', 'Gene', '9817', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
411521	27294619	Two of the residues, Arg415 and Arg483 from KEAP1, have been experimentally validated and shown both to be in the KEAP1 binding pocket and to play a major role in the stability of the KEAP1/NFE2L2 complex.	('play', 'Reg', (142, 146))	('Arg415', 'Chemical', '-', (21, 27))	('Arg483', 'Var', (32, 38))	('KEAP1', 'Gene', (44, 49))	('role', 'Reg', (155, 159))	('KEAP1', 'Gene', '9817', (114, 119))	('KEAP1', 'Gene', '9817', (184, 189))	('Arg415', 'Var', (21, 27))	('KEAP1', 'Gene', '9817', (44, 49))	('stability', 'MPA', (167, 176))	('NFE2L2', 'Gene', '4780', (190, 196))	('KEAP1', 'Gene', (114, 119))	('KEAP1', 'Gene', (184, 189))	('Arg483', 'Chemical', '-', (32, 38))	('NFE2L2', 'Gene', (190, 196))
411522	27294619	We also identified 4 TCEB1 residues, Arg82, Ser67, Ser86, and Tyr79 in UCEC, BRCA, UCEC, and KIRC, respectively, clustering with 7 VHL residues, Cys162, Leu153, Leu158, Leu169, Ser168, Gly114, and Val165 in KIRC; Tyr79 has been experimentally validated to disrupt the TCEB1/VHL complex (Figure 3d and Supplementary Table 11).	('Val165', 'Chemical', '-', (197, 203))	('Arg82', 'Var', (37, 42))	('Ser86', 'Chemical', '-', (51, 56))	('TCEB1', 'Gene', (21, 26))	('TCEB1', 'Gene', '6921', (268, 273))	('BRCA', 'Gene', '672', (77, 81))	('Ser67', 'Chemical', '-', (44, 49))	('VHL', 'Gene', (274, 277))	('Tyr79', 'Var', (213, 218))	('TCEB1', 'Gene', '6921', (21, 26))	('Tyr79', 'Var', (62, 67))	('Cys162', 'Chemical', '-', (145, 151))	('disrupt', 'NegReg', (256, 263))	('Leu153', 'Chemical', '-', (153, 159))	('BRCA', 'Gene', (77, 81))	('Leu153', 'Var', (153, 159))	('Gly114', 'Chemical', '-', (185, 191))	('VHL', 'Gene', (131, 134))	('Arg82', 'Chemical', '-', (37, 42))	('VHL', 'Gene', '7428', (274, 277))	('Tyr79', 'Chemical', '-', (213, 218))	('Tyr79', 'Chemical', '-', (62, 67))	('Ser67', 'Var', (44, 49))	('VHL', 'Gene', '7428', (131, 134))	('TCEB1', 'Gene', (268, 273))	('Leu158', 'Var', (161, 167))	('Leu169', 'Chemical', '-', (169, 175))	('Leu158', 'Chemical', '-', (161, 167))	('Ser168', 'Chemical', '-', (177, 183))
411524	27294619	TP53, PTEN, VHL, EGFR, and FBXW7 contain the top 5 clusters contributing the most novel functional mutations.	('VHL', 'Gene', (12, 15))	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('VHL', 'Gene', '7428', (12, 15))	('FBXW7', 'Gene', '55294', (27, 32))	('FBXW7', 'Gene', (27, 32))	('mutations', 'Var', (99, 108))	('PTEN', 'Gene', (6, 10))	('PTEN', 'Gene', '5728', (6, 10))	('EGFR', 'Gene', (17, 21))
411527	27294619	For this particular cluster, we have 3 hotspot residues Gly12, Gly13, and Gln61 (Figure 5a).	('Gly13', 'Var', (63, 68))	('Gly12', 'Chemical', '-', (56, 61))	('Gln61', 'Var', (74, 79))	('Gly13', 'Chemical', '-', (63, 68))	('Gly12', 'Var', (56, 61))	('Gln61', 'Chemical', '-', (74, 79))
411528	27294619	Additional possible functional mutations outside of hotspot residues are Ile36M, Ala59Glu/Gly/Thr (each in one sample), and Glu62Lys.	('Ile36M', 'Var', (73, 79))	('Ala59Glu', 'Var', (81, 89))	('Glu62Lys', 'SUBSTITUTION', 'None', (124, 132))	('Ala59Glu', 'SUBSTITUTION', 'None', (81, 89))	('Ile36', 'Chemical', '-', (73, 78))	('Glu62Lys', 'Var', (124, 132))	('Gly', 'Chemical', 'MESH:D005998', (90, 93))	('Thr', 'Chemical', 'MESH:D013912', (94, 97))
411530	27294619	Ala59 has a higher closeness centrality than expected due to its close proximity to highly mutated residues (Gln61, Gly12, and Gly13).	('Gln61', 'Chemical', '-', (109, 114))	('Gly13', 'Var', (127, 132))	('Ala59', 'Chemical', '-', (0, 5))	('Gly13', 'Chemical', '-', (127, 132))	('Gln61', 'Var', (109, 114))	('Gly12', 'Chemical', '-', (116, 121))	('Gly12', 'Var', (116, 121))
411533	27294619	Additionally, it contained another hotspot at Glu203, mutated 5 times (Figure 5b).	('Glu203', 'Chemical', '-', (46, 52))	('mutated', 'Var', (54, 61))	('Glu203', 'Var', (46, 52))
411534	27294619	Other potential functional candidates in this cluster are Arg47Gln (mutated only once, but having geodesic length of 5.9 A from the centroid) and Asn122Asp and Glu333Ala (likewise mutated once, but geodesics within 10 A of centroid).	('Glu333Ala', 'Var', (160, 169))	('Asn122Asp', 'SUBSTITUTION', 'None', (146, 155))	('Arg47Gln', 'Var', (58, 66))	('Glu333Ala', 'SUBSTITUTION', 'None', (160, 169))	('Arg47Gln', 'SUBSTITUTION', 'None', (58, 66))	('Asn122Asp', 'Var', (146, 155))
411535	27294619	Experimental evidence exists for our prediction that rare mutation Arg47Gln is functional in cancer (Supplementary Table 11).	('cancer', 'Disease', (93, 99))	('Arg47Gln', 'Var', (67, 75))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('Arg47Gln', 'SUBSTITUTION', 'None', (67, 75))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))
411536	27294619	Arg47Gln led to increased phosphorylation of downstream kinases ERK1/2, supporting the activating potential of the mutation.	('ERK1/2', 'Gene', '5595;5594', (64, 70))	('Arg47Gln', 'Var', (0, 8))	('increased', 'PosReg', (16, 25))	('Arg47Gln', 'SUBSTITUTION', 'None', (0, 8))	('ERK1/2', 'Gene', (64, 70))	('phosphorylation', 'MPA', (26, 41))
411538	27294619	Two separate inter-molecular clusters (Figure 5c) account for 28.6% of the SMAD2/SMAD3/SMAD4 missense mutations and in-frame indels.	('SMAD2', 'Gene', (75, 80))	('SMAD3', 'Gene', (81, 86))	('SMAD4', 'Gene', '4089', (87, 92))	('missense mutations', 'Var', (93, 111))	('SMAD3', 'Gene', '4088', (81, 86))	('SMAD2', 'Gene', '4087', (75, 80))	('SMAD4', 'Gene', (87, 92))
411539	27294619	For one of the complexes (purple cluster, Figure 5c), we were able to identify 7 rare variants, each mutated only once from SMAD2 (Leu442Val, Leu446Val, Ser276Leu), SMAD3 (Gln405Leu), and SMAD4 (Asp355Gly, Pro356Leu, Ser357Pro) and all in close spatial proximity with the SMAD4 Arg361 hotspot (Arg361Cys/His/Pro/Ser).	('Leu446Val', 'Chemical', '-', (142, 151))	('Arg361', 'Chemical', '-', (294, 300))	('SMAD4', 'Gene', '4089', (272, 277))	('Asp355Gly', 'Var', (195, 204))	('Pro', 'Chemical', 'MESH:D011392', (308, 311))	('Asp355Gly', 'SUBSTITUTION', 'None', (195, 204))	('SMAD2', 'Gene', (124, 129))	('Arg361Cys', 'Var', (294, 303))	('Ser357Pro', 'Var', (217, 226))	('SMAD4', 'Gene', (188, 193))	('Leu442Val', 'Chemical', '-', (131, 140))	('His', 'Chemical', 'MESH:D006639', (304, 307))	('Ser', 'Chemical', 'MESH:D012694', (312, 315))	('SMAD3', 'Gene', '4088', (165, 170))	('Ser357Pro', 'SUBSTITUTION', 'None', (217, 226))	('Ser', 'Chemical', 'MESH:D012694', (217, 220))	('Leu442Val', 'Var', (131, 140))	('Pro356Leu', 'Var', (206, 215))	('Ser', 'Chemical', 'MESH:D012694', (153, 156))	('SMAD4', 'Gene', (272, 277))	('SMAD4', 'Gene', '4089', (188, 193))	('Gln405Leu', 'SUBSTITUTION', 'None', (172, 181))	('Ser276Leu', 'Var', (153, 162))	('Pro356Leu', 'SUBSTITUTION', 'None', (206, 215))	('SMAD3', 'Gene', (165, 170))	('Leu446Val', 'Var', (142, 151))	('Arg361', 'Chemical', '-', (278, 284))	('Ser276Leu', 'SUBSTITUTION', 'None', (153, 162))	('SMAD2', 'Gene', '4087', (124, 129))	('Pro', 'Chemical', 'MESH:D011392', (206, 209))	('Arg361Cys', 'SUBSTITUTION', 'None', (294, 303))	('Pro', 'Chemical', 'MESH:D011392', (223, 226))	('Gln405Leu', 'Var', (172, 181))
411540	27294619	In addition, Asp450Asn in SMAD2 is mutated only once and is the closest spatially (2.6A) to the SMAD4 hotspot residue, making it another functional candidate.	('Asp450Asn', 'Var', (13, 22))	('Asp450Asn', 'SUBSTITUTION', 'None', (13, 22))	('SMAD4', 'Gene', '4089', (96, 101))	('SMAD2', 'Gene', '4087', (26, 31))	('SMAD2', 'Gene', (26, 31))	('SMAD4', 'Gene', (96, 101))
411541	27294619	Recent work confirms our prediction that mutations (Asp450 and Ser276 from SMAD2) in close proximity to the Arg361 hotspot on SMAD4 destabilize the SMAD2/4 and SMAD3/4 complexes (Supplementary Table 11).	('SMAD2', 'Gene', (75, 80))	('Ser276', 'Var', (63, 69))	('SMAD2', 'Gene', (148, 153))	('SMAD4', 'Gene', (126, 131))	('SMAD4', 'Gene', '4089', (126, 131))	('SMAD2', 'Gene', '4087', (148, 153))	('SMAD2/4', 'Gene', (148, 155))	('Arg361', 'Chemical', '-', (108, 114))	('Asp450', 'Chemical', '-', (52, 58))	('Ser276', 'Chemical', '-', (63, 69))	('SMAD2', 'Gene', '4087', (75, 80))	('SMAD3', 'Gene', '4088', (160, 165))	('SMAD3', 'Gene', (160, 165))	('destabilize', 'NegReg', (132, 143))	('SMAD2/4', 'Gene', '4087;4089', (148, 155))
411543	27294619	For example, the cluster in RUNX1 contains Arg162 recurrently mutated 4 times, Pro113 mutated twice, and four other singleton mutations (Leu161Pro, Val118Ala, Asp160Gly, and Ala134Pro).	('Leu161Pro', 'Var', (137, 146))	('Val118Ala', 'Var', (148, 157))	('Ala134Pro', 'SUBSTITUTION', 'None', (174, 183))	('Asp160Gly', 'SUBSTITUTION', 'None', (159, 168))	('RUNX1', 'Gene', (28, 33))	('Asp160Gly', 'Var', (159, 168))	('Leu161Pro', 'SUBSTITUTION', 'None', (137, 146))	('Pro113', 'Chemical', '-', (79, 85))	('Val118Ala', 'SUBSTITUTION', 'None', (148, 157))	('Arg162', 'Var', (43, 49))	('Arg162', 'Chemical', '-', (43, 49))	('Ala134Pro', 'Var', (174, 183))	('RUNX1', 'Gene', '861', (28, 33))
411544	27294619	The other SMAD2/3/4 cluster (orange cluster, Figure 5c) contains Asp537 (SMAD4) mutated 4 times, Arg268 (SMAD3) mutated 3 times, Pro305 (SMAD2) mutated twice, and four singletons (Arg531 and Leu533 from SMAD4, Asp304 and Asp300 from SMAD2).	('SMAD4', 'Gene', (73, 78))	('SMAD2', 'Gene', '4087', (10, 15))	('Arg531', 'Chemical', '-', (180, 186))	('SMAD2', 'Gene', '4087', (233, 238))	('mutated', 'Var', (80, 87))	('Asp304', 'Chemical', '-', (210, 216))	('SMAD3', 'Gene', '4088', (105, 110))	('SMAD2/3', 'Gene', (10, 17))	('Leu533', 'Var', (191, 197))	('Pro305', 'Var', (129, 135))	('SMAD2', 'Gene', '4087', (137, 142))	('SMAD2', 'Gene', (233, 238))	('SMAD2', 'Gene', (10, 15))	('SMAD4', 'Gene', '4089', (73, 78))	('SMAD4', 'Gene', (203, 208))	('Asp537', 'Var', (65, 71))	('Leu533', 'Chemical', '-', (191, 197))	('SMAD3', 'Gene', (105, 110))	('Arg531', 'Var', (180, 186))	('SMAD2', 'Gene', (137, 142))	('SMAD2/3', 'Gene', '4088', (10, 17))	('SMAD4', 'Gene', '4089', (203, 208))	('Arg268', 'Chemical', '-', (97, 103))	('Arg268', 'Var', (97, 103))	('Pro305', 'Chemical', '-', (129, 135))	('Asp300', 'Chemical', '-', (221, 227))	('Asp537', 'Chemical', '-', (65, 71))
411546	27294619	This cluster contains Arg506, Gly543, and Glu758 from CUL1 and Met50 from RBX1, which are all mutated twice, and 6 remaining mutations that are singletons (Supplementary Table 16).	('Glu758', 'Var', (42, 48))	('RBX1', 'Gene', (74, 78))	('RBX1', 'Gene', '9978', (74, 78))	('Gly543', 'Chemical', '-', (30, 36))	('Arg506', 'Chemical', '-', (22, 28))	('Met50', 'Var', (63, 68))	('CUL1', 'Gene', (54, 58))	('Glu758', 'Chemical', '-', (42, 48))	('CUL1', 'Gene', '8454', (54, 58))	('Arg506', 'Var', (22, 28))	('Gly543', 'Var', (30, 36))
411547	27294619	In cancer, mutations within extracellular and kinase domains of Receptor Tyrosine Kinases (RTKs) can cause ligand-independent activation, leading to autophosphorylation.	('mutations', 'Var', (11, 20))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('cancer', 'Disease', (3, 9))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))	('ligand-independent activation', 'MPA', (107, 136))	('leading to', 'Reg', (138, 148))	('autophosphorylation', 'MPA', (149, 168))
411549	27294619	EGFR is an excellent test case because of the high number of mutations found across multiple patient samples and the two most significant clusters being highly cancer specific.	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('cancer', 'Disease', (160, 166))	('mutations', 'Var', (61, 70))	('patient', 'Species', '9606', (93, 100))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))
411551	27294619	We used the RPPA values to examine EGFR protein expression and site-specific phosphorylation at major autophosphorylation sites pTyr1173 and pTyr1068.	('pTyr1068', 'Chemical', '-', (141, 149))	('pTyr1173', 'Chemical', '-', (128, 136))	('pTyr1173', 'Var', (128, 136))	('pTyr1068', 'Var', (141, 149))
411553	27294619	The mean protein and phosphoprotein (pTyr1173 and pTyr1068) levels were significantly higher in GBM samples with mutations from the Ala289 cluster as compared to wild type EGFR, P=2.3e-8, P=1.9e-5, P=1.5e-6, respectively (Figure 6a) Means were also higher than for samples with EGFR mutations outside of any cluster, but there were insufficient data to establish this observation as statistically significant.	('pTyr1068', 'Chemical', '-', (50, 58))	('Ala289', 'Gene', (132, 138))	('Ala289', 'Chemical', '-', (132, 138))	('higher', 'PosReg', (249, 255))	('mutations', 'Var', (113, 122))	('higher', 'PosReg', (86, 92))	('pTyr1173', 'Chemical', '-', (37, 45))
411554	27294619	Mean protein and phosphoprotein (pTyr1173 and pTyr1068) levels were again significantly higher for samples containing a mutation in the Leu858 cluster, P=0.01, P=0.04, P=4.6e-5, respectively (Figure 6a).	('pTyr1068', 'Chemical', '-', (46, 54))	('higher', 'PosReg', (88, 94))	('Leu858', 'Var', (136, 142))	('pTyr1173', 'Chemical', '-', (33, 41))	('Leu858', 'Chemical', '-', (136, 142))
411555	27294619	We also conducted validation on one ERBB2 cluster in the kinase domain having its centroid at Val842Ile using RPPA data for ERBB2 protein expression and autophosphorylation site pTyr1248.	('ERBB2', 'Gene', (36, 41))	('ERBB2', 'Gene', '2064', (36, 41))	('Val842Ile', 'Mutation', 'rs1057519738', (94, 103))	('pTyr1248', 'Var', (178, 186))	('ERBB2', 'Gene', '2064', (124, 129))	('pTyr1248', 'Chemical', '-', (178, 186))	('ERBB2', 'Gene', (124, 129))
411556	27294619	This cluster exhibited the same trend as the two EGFR clusters; the mean protein and phosphoprotein (pTyr1248) levels were the highest for samples having mutations in the Val842Ile cluster (Methods).	('Val842Ile', 'Mutation', 'rs1057519738', (171, 180))	('pTyr1248', 'Chemical', '-', (101, 109))	('highest', 'Reg', (127, 134))	('Val842Ile', 'Var', (171, 180))	('mutations', 'Var', (154, 163))
411557	27294619	We also performed EGFR phosphorylation experiments on mutations from the EGFR Leu858Arg cluster in cultured NIH3T3 cells to more conclusively assess functional predictions from HotSpot3D.	('Leu858Arg', 'Chemical', '-', (78, 87))	('mutations', 'Var', (54, 63))	('EGFR', 'Gene', (73, 77))	('Leu858Arg', 'Var', (78, 87))	('NIH3T3', 'CellLine', 'CVCL:0594', (108, 114))
411558	27294619	This cluster included well-known mutations such as Leu858Arg, Gly719Ala, and Thr790Met.	('Leu858Arg', 'Var', (51, 60))	('Thr790Met', 'SUBSTITUTION', 'None', (77, 86))	('Thr790Met', 'Var', (77, 86))	('Gly719Ala', 'SUBSTITUTION', 'None', (62, 71))	('Gly719Ala', 'Var', (62, 71))	('Leu858Arg', 'Chemical', '-', (51, 60))
411559	27294619	Additional rare mutations, having no available direct evidence of autophosphorylation consequence, include Asp761Asn, Ile789Met, Arg831His, and Leu833Phe, although a few reports suggested weak/partial response to tyrosine kinase inhibitors in samples with other known druggable mutations.	('Asp761Asn', 'Var', (107, 116))	('Leu833Phe', 'Var', (144, 153))	('Arg831His', 'SUBSTITUTION', 'None', (129, 138))	('Ile789Met', 'Var', (118, 127))	('Ile789Met', 'SUBSTITUTION', 'None', (118, 127))	('Asp761Asn', 'SUBSTITUTION', 'None', (107, 116))	('Leu833Phe', 'Chemical', '-', (144, 153))	('Arg831His', 'Var', (129, 138))
411561	27294619	Leu858Arg, Gly719Ala, and Thr790Met have higher levels of normalized pEGFR (0.79, 0.89, and 1.08, respectively), indicating ligand-independent activation.	('Thr790Met', 'SUBSTITUTION', 'None', (26, 35))	('Thr790Met', 'Var', (26, 35))	('Leu858Arg', 'Chemical', '-', (0, 9))	('normalized pEGFR', 'MPA', (58, 74))	('Leu858Arg', 'Var', (0, 9))	('Gly719Ala', 'SUBSTITUTION', 'None', (11, 20))	('Gly719Ala', 'Var', (11, 20))
411562	27294619	Asp761Asn, Ile789Met, Arg831His, and Leu833Phe also yielded higher levels of normalized pEGFR (0.78, 0.38, 0.32, and 0.55, respectively), suggesting potential ligand-independent activation as well (Figure 6b).	('Ile789Met', 'Var', (11, 20))	('Arg831His', 'Var', (22, 31))	('Asp761Asn', 'SUBSTITUTION', 'None', (0, 9))	('higher', 'PosReg', (60, 66))	('Leu833Phe', 'Chemical', '-', (37, 46))	('Asp761Asn', 'Var', (0, 9))	('Arg831His', 'SUBSTITUTION', 'None', (22, 31))	('Leu833Phe', 'Var', (37, 46))	('Ile789Met', 'SUBSTITUTION', 'None', (11, 20))
411563	27294619	In addition, similar to Thr790Met and Gly719Ala, Asp761Asn shows a much higher normalized pEGFR level (1.76) when compared to the wild type (1.08) under EGF stimulation.	('Asp761Asn', 'Var', (49, 58))	('Thr790Met', 'SUBSTITUTION', 'None', (24, 33))	('Asp761Asn', 'SUBSTITUTION', 'None', (49, 58))	('Gly719Ala', 'SUBSTITUTION', 'None', (38, 47))	('Gly719Ala', 'Var', (38, 47))	('higher', 'PosReg', (72, 78))	('Thr790Met', 'Var', (24, 33))
411564	27294619	Furthermore, we performed an experiment examining sensitivity of the EGFR variants to gefitinib.	('variants', 'Var', (74, 82))	('gefitinib', 'Chemical', 'MESH:D000077156', (86, 95))	('EGFR', 'Gene', (69, 73))
411569	27294619	Among the kinase-drug clusters, BRAF (a serine/threonine kinase) with sorafenib (a tyrosine kinase inhibitor) tops the list due to hotspots at Val600 and Lys601.	('Lys601', 'Chemical', '-', (154, 160))	('BRAF', 'Gene', '673', (32, 36))	('Lys601', 'Var', (154, 160))	('sorafenib', 'Chemical', 'MESH:D000077157', (70, 79))	('BRAF', 'Gene', (32, 36))	('Val600', 'Var', (143, 149))	('Val600', 'Chemical', '-', (143, 149))
411570	27294619	Interestingly, there are 8 unique BRAF mutations in this cluster: Arg462Lys, Gly469Ala/Arg, Asp594Gly/His/Asn, Gly596Asp, and Val600Arg that are each observed in one or two samples.	('Arg462Lys', 'Var', (66, 75))	('Asn', 'Chemical', 'MESH:D001216', (106, 109))	('His', 'Chemical', 'MESH:D006639', (102, 105))	('Arg', 'Chemical', 'MESH:D001120', (87, 90))	('Arg', 'Chemical', 'MESH:D001120', (132, 135))	('Val600Arg', 'Var', (126, 135))	('Gly469Ala', 'Var', (77, 86))	('Gly596Asp', 'Var', (111, 120))	('Gly469Ala', 'SUBSTITUTION', 'None', (77, 86))	('Val600Arg', 'SUBSTITUTION', 'None', (126, 135))	('Gly596Asp', 'SUBSTITUTION', 'None', (111, 120))	('Asp594Gly', 'SUBSTITUTION', 'None', (92, 101))	('BRAF', 'Gene', '673', (34, 38))	('Arg462Lys', 'SUBSTITUTION', 'None', (66, 75))	('Asp594Gly', 'Var', (92, 101))	('BRAF', 'Gene', (34, 38))	('Arg', 'Chemical', 'MESH:D001120', (66, 69))
411571	27294619	Three of these mutations (Arg462Lys, Gly469Arg, Gly596Asp) are not in the current releases of MyCancerGenome (MCG), CancerDR (CDR), Personalized Cancer Therapy (PCT), or Gene-Drug Knowledge Database (GDKD), and eight (Gly469Ala, Asp594Gly/His/Asn, Val600Glu/Lys/Arg, and Lys601Glu) are present in at least one or more of these databases, but have unknown effects on drug binding affinity.	('Gly596Asp', 'Var', (48, 57))	('Arg', 'Chemical', 'MESH:D001120', (26, 29))	('Asp594Gly', 'Var', (229, 238))	('Lys601Glu', 'Var', (271, 280))	('Arg', 'Chemical', 'MESH:D001120', (43, 46))	('Cancer', 'Phenotype', 'HP:0002664', (145, 151))	('Lys601Glu', 'Mutation', 'rs121913364', (271, 280))	('Gly469Arg', 'Var', (37, 46))	('Arg462Lys', 'SUBSTITUTION', 'None', (26, 35))	('Cancer', 'Phenotype', 'HP:0002664', (96, 102))	('Arg462Lys', 'Var', (26, 35))	('Arg', 'Chemical', 'MESH:D001120', (262, 265))	('drug binding affinity', 'Interaction', (366, 387))	('Gly469Arg', 'Mutation', 'rs121913357', (37, 46))	('CD', 'Chemical', 'MESH:D002104', (126, 128))	('Asn', 'Chemical', 'MESH:D001216', (243, 246))	('His', 'Chemical', 'MESH:D006639', (239, 242))	('Cancer', 'Phenotype', 'HP:0002664', (116, 122))	('Val600Glu', 'SUBSTITUTION', 'None', (248, 257))	('Gly469Ala', 'Var', (218, 227))	('Val600Glu', 'Var', (248, 257))	('Gly469Ala', 'SUBSTITUTION', 'None', (218, 227))	('Gly596Asp', 'SUBSTITUTION', 'None', (48, 57))	('Asp594Gly', 'SUBSTITUTION', 'None', (229, 238))	('Thr', 'Chemical', 'MESH:D013912', (0, 3))
411572	27294619	Our analysis lends weight to the potential druggability of the 3 functionally unknown, unique BRAF mutations (Figure 7c).	('mutations', 'Var', (99, 108))	('BRAF', 'Gene', (94, 98))	('BRAF', 'Gene', '673', (94, 98))
411573	27294619	We also found two drug-mutation clusters of ERBB3 in which 8 of the 9 unique mutations were not catalogued in these databases (from the extracellular domain cluster: Val104Leu/Met, Ala245Val, Gly284Arg in GDKD, Lys329Glu/Thr, R103H, and R388Q and from the kinase cluster: L792V) and V104 is the centroid mutated in 11 samples.	('R103H', 'Var', (226, 231))	('Gly284Arg', 'SUBSTITUTION', 'None', (192, 201))	('R388Q', 'Var', (237, 242))	('ERBB3', 'Gene', (44, 49))	('ERBB3', 'Gene', '2065', (44, 49))	('Val104Leu', 'SUBSTITUTION', 'None', (166, 175))	('R388Q', 'Mutation', 'rs570637025', (237, 242))	('R103H', 'Mutation', 'rs778104039', (226, 231))	('Ala245Val', 'SUBSTITUTION', 'None', (181, 190))	('L792V', 'Var', (272, 277))	('Val104Leu', 'Var', (166, 175))	('L792V', 'Mutation', 'p.L792V', (272, 277))	('Lys329Glu', 'Var', (211, 220))	('V104', 'Var', (283, 287))	('Gly284Arg', 'Var', (192, 201))	('Lys329Glu', 'SUBSTITUTION', 'None', (211, 220))	('Ala245Val', 'Var', (181, 190))	('Thr', 'Chemical', 'MESH:D013912', (221, 224))
411576	27294619	None of the three mutations of the PDK3 drug-mutation cluster have been reported in the four druggable mutation databases (Arg299Cys/Ser and Phe324Leu).	('Arg299Cys', 'Var', (123, 132))	('Phe324Leu', 'SUBSTITUTION', 'None', (141, 150))	('Phe324Leu', 'Var', (141, 150))	('PDK3', 'Gene', '5165', (35, 39))	('PDK3', 'Gene', (35, 39))	('Arg299Cys', 'SUBSTITUTION', 'None', (123, 132))	('Ser', 'Chemical', 'MESH:D012694', (133, 136))
411577	27294619	The three mutations of NTRK1 were likewise not found in these databases (Arg649Leu/Trp and Arg702Cys) and are observed with an acetic ion binding in the C-terminal lobe adjacent to the binding pocket and DFG motif (within 10A).	('DFG', 'Chemical', '-', (204, 207))	('NTRK1', 'Gene', '4914', (23, 28))	('acetic ion', 'MPA', (127, 137))	('Arg702Cys', 'SUBSTITUTION', 'None', (91, 100))	('Arg702Cys', 'Var', (91, 100))	('Arg649Leu', 'SUBSTITUTION', 'None', (73, 82))	('acetic', 'Chemical', 'MESH:D019342', (127, 133))	('binding', 'Interaction', (138, 145))	('Arg649Leu', 'Var', (73, 82))	('NTRK1', 'Gene', (23, 28))	('Trp', 'Chemical', 'MESH:D014364', (83, 86))
411579	27294619	The ESR1 cluster with Cc = 4.6, has 4 unique mutations interacting with 5 different compounds: raloxifene, estradiol, estrone, estriol, and diethylstilbestrol (Figure 7e).	('mutations', 'Var', (45, 54))	('ESR1', 'Gene', (4, 8))	('estradiol', 'Chemical', 'MESH:D004958', (107, 116))	('diethylstilbestrol', 'Chemical', 'MESH:D004054', (140, 158))	('estrone', 'Chemical', 'MESH:D004970', (118, 125))	('ESR1', 'Gene', '2099', (4, 8))	('raloxifene', 'Chemical', 'MESH:D020849', (95, 105))	('interacting', 'Interaction', (55, 66))	('estriol', 'Chemical', 'MESH:D004964', (127, 134))
411581	27294619	Arg394His/Leu mutations in ESR1 form significant pairs with all 5 compounds and could potentially affect their responses (Figure 7e).	('pairs', 'Interaction', (49, 54))	('responses', 'MPA', (111, 120))	('Arg394His', 'SUBSTITUTION', 'None', (0, 9))	('ESR1', 'Gene', (27, 31))	('affect', 'Reg', (98, 104))	('ESR1', 'Gene', '2099', (27, 31))	('Arg394His', 'Var', (0, 9))	('Leu', 'Chemical', 'MESH:D007930', (10, 13))
411582	27294619	Peroxisome proliferator-activated receptor delta (PPARD) is found with 2 unique mutations, His287Arg and His287Tyr, adjacent to icosapent, a micronutrient which has been used to treat a variety of symptoms and diseases and most notably has been suggested to improve chemotherapy response.	('PPARD', 'Gene', (50, 55))	('His287Tyr', 'Mutation', 'p.H287Y', (105, 114))	('His287Arg', 'Var', (91, 100))	('PPARD', 'Gene', '5467', (50, 55))	('His287Arg', 'Mutation', 'p.H287R', (91, 100))	('Peroxisome proliferator-activated receptor delta', 'Gene', '5467', (0, 48))	('His287Tyr', 'Var', (105, 114))	('icosapent', 'Chemical', 'MESH:C495711', (128, 137))	('improve', 'PosReg', (258, 265))	('Peroxisome proliferator-activated receptor delta', 'Gene', (0, 48))	('chemotherapy response', 'CPA', (266, 287))
411583	27294619	Another PPAR drug-mutation cluster involves 6 unique PPARG mutations that are associated with 4 drugs (indomethacin, pioglitazone, rosiglitazone, and telmisartan) (Supplementary Table 18).	('associated', 'Reg', (78, 88))	('PPAR', 'Gene', '5465', (53, 57))	('PPARG', 'Gene', '5468', (53, 58))	('PPAR', 'Gene', (8, 12))	('indomethacin', 'Chemical', 'MESH:D007213', (103, 115))	('PPARG', 'Gene', (53, 58))	('PPAR', 'Gene', (53, 57))	('rosiglitazone', 'Chemical', 'MESH:D000077154', (131, 144))	('telmisartan', 'Chemical', 'MESH:D000077333', (150, 161))	('mutations', 'Var', (59, 68))	('PPAR', 'Gene', '5465', (8, 12))	('pioglitazone', 'Chemical', 'MESH:D000077205', (117, 129))
411584	27294619	The action site for indomethacin, a non-steroidal anti-inflammatory drug (NSAID), neighbors all 6 mutations of the cluster, while the sites for pioglitazone and rosiglitazone (anti-diabetic drugs) and telmisartan (an angiotensin II receptor antagonist (ARB)) neighbor two (Ile277Asn and Ile290Met), three (Ile290Met, Arg316Cys, and His494Tyr), and two (Arg316Cys and E352K) mutations, respectively.	('Arg316Cys', 'Var', (317, 326))	('E352K', 'Var', (367, 372))	('Ile290Met', 'Var', (306, 315))	('E352K', 'Mutation', 'rs530007199', (367, 372))	('pioglitazone', 'Chemical', 'MESH:D000077205', (144, 156))	('His494Tyr', 'Var', (332, 341))	('His494Tyr', 'Mutation', 'rs1394762881', (332, 341))	('Ile290Met', 'Mutation', 'p.I290M', (306, 315))	('indomethacin', 'Chemical', 'MESH:D007213', (20, 32))	('diabetic', 'Disease', 'MESH:D003920', (181, 189))	('Arg316Cys', 'Mutation', 'rs1364613522', (353, 362))	('Ile277Asn', 'Var', (273, 282))	('diabetic', 'Disease', (181, 189))	('Ile290Met', 'Var', (287, 296))	('Ile277Asn', 'Mutation', 'p.I277N', (273, 282))	('telmisartan', 'Chemical', 'MESH:D000077333', (201, 212))	('Ile290Met', 'Mutation', 'p.I290M', (287, 296))	('Arg316Cys', 'Var', (353, 362))	('mutations', 'Var', (98, 107))	('Arg316Cys', 'Mutation', 'rs1364613522', (317, 326))	('rosiglitazone', 'Chemical', 'MESH:D000077154', (161, 174))
411586	27294619	Both clusters of ESR1 and PPARG exist in the hormone receptor domain, suggesting that drug binding in this region may be affected by cancer mutations.	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('PPARG', 'Gene', '5468', (26, 31))	('ESR1', 'Gene', '2099', (17, 21))	('cancer', 'Disease', (133, 139))	('PPARG', 'Gene', (26, 31))	('affected', 'Reg', (121, 129))	('mutations', 'Var', (140, 149))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('ESR1', 'Gene', (17, 21))	('drug binding', 'Interaction', (86, 98))
411588	27294619	Although there are only three unique mutations (Val390Leu, Asp400Tyr, and Phe401Leu) observed in the ABL1 drug cluster, the cluster closeness measure is significantly increased due to the four drugs involved.	('ABL1', 'Gene', '25', (101, 105))	('Val390Leu', 'Var', (48, 57))	('ABL1', 'Gene', (101, 105))	('cluster closeness', 'MPA', (124, 141))	('increased', 'PosReg', (167, 176))	('Asp400Tyr', 'Var', (59, 68))	('Phe401Leu', 'Var', (74, 83))	('Val390Leu', 'SUBSTITUTION', 'None', (48, 57))	('Asp400Tyr', 'SUBSTITUTION', 'None', (59, 68))	('Phe401Leu', 'SUBSTITUTION', 'None', (74, 83))
411589	27294619	Each of the Asp400 and Phe401 residues, from the DFG motif, controls blocking of the binding pocket by conformational changes and therefore modulates the binding of imatinib and nilotinib.	('binding', 'Interaction', (154, 161))	('imatinib', 'MPA', (165, 173))	('modulates', 'Reg', (140, 149))	('nilotinib', 'MPA', (178, 187))	('nilotinib', 'Chemical', 'MESH:C498826', (178, 187))	('DFG', 'Chemical', '-', (49, 52))	('conformational changes', 'MPA', (103, 125))	('Phe401', 'Chemical', '-', (23, 29))	('blocking of the', 'MPA', (69, 84))	('imatinib', 'Chemical', 'MESH:D000068877', (165, 173))	('Asp400', 'Var', (12, 18))	('Phe401', 'Var', (23, 29))	('Asp400', 'Chemical', '-', (12, 18))	('binding', 'Interaction', (85, 92))
411591	27294619	Both Thr315 in ABL1 and Thr790 in EGFR are shown to confer drug resistance to TKI therapy, indicating similarly positioned mutations in drug families have the same effects within a drug class.	('Thr790', 'Chemical', '-', (24, 30))	('confer', 'Reg', (52, 58))	('EGFR', 'Gene', (34, 38))	('Thr315', 'Var', (5, 11))	('ABL1', 'Gene', '25', (15, 19))	('drug resistance', 'Phenotype', 'HP:0020174', (59, 74))	('Thr315', 'Chemical', '-', (5, 11))	('Thr790', 'Var', (24, 30))	('drug resistance', 'MPA', (59, 74))	('ABL1', 'Gene', (15, 19))
411592	27294619	Further, we found that the DFG motif is also mutated in BTK (PheGly540LeuCys), another tyrosine kinase.	('BTK', 'Gene', '695', (56, 59))	('Leu', 'Chemical', 'MESH:D007930', (70, 73))	('DFG', 'Chemical', '-', (27, 30))	('mutated', 'Var', (45, 52))	('BTK', 'Gene', (56, 59))
411593	27294619	Notably, mutations in three genes, ABL1, BTK (including Leu528Phe), and BMX (Gly424Glu), are within the spatial interaction range of dasatinib (Supplementary Fig.	('Gly424Glu', 'Var', (77, 86))	('Leu528Phe', 'Var', (56, 65))	('BMX', 'Gene', '660', (72, 75))	('ABL1', 'Gene', '25', (35, 39))	('mutations', 'Var', (9, 18))	('BTK', 'Gene', (41, 44))	('ABL1', 'Gene', (35, 39))	('Gly424Glu', 'SUBSTITUTION', 'None', (77, 86))	('Leu528Phe', 'Chemical', '-', (56, 65))	('BMX', 'Gene', (72, 75))	('BTK', 'Gene', '695', (41, 44))	('dasatinib', 'Chemical', 'MESH:D000069439', (133, 142))
411594	27294619	Overall, HotSpot3D provides the means to identify complex, multi-dimensional interactions among drugs and mutations and consequently to find alternative therapeutics that may provide greater flexibility in treating a wide range of genetic diseases.	('genetic diseases', 'Disease', 'MESH:D030342', (231, 247))	('genetic diseases', 'Disease', (231, 247))	('interactions', 'Interaction', (77, 89))	('mutations', 'Var', (106, 115))
411595	27294619	The enormous numbers of available variants and protein structures offer an unprecedented resource for investigating the direct impact these variants have upon protein structures, which is fundamentally important to the design of targeted cancer drugs.	('cancer', 'Disease', (238, 244))	('cancer', 'Disease', 'MESH:D009369', (238, 244))	('variants', 'Var', (140, 148))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))
411598	27294619	The larger implications of this work are threefold: 1) using non-cancer drugs for treating cancers, 2) applying cancer-type specific drugs for treating patients with other types of cancers, and 3) employing targeted drugs for treating patients with non-canonical cancer mutations that cluster with known druggable mutations.	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', (263, 269))	('non-cancer', 'Disease', 'MESH:D009369', (61, 71))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('cancers', 'Disease', 'MESH:D009369', (181, 188))	('cancer', 'Phenotype', 'HP:0002664', (263, 269))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('cancer', 'Disease', (65, 71))	('non-canonical cancer', 'Disease', 'MESH:D009369', (249, 269))	('cancers', 'Disease', 'MESH:D009369', (91, 98))	('non-cancer', 'Disease', (61, 71))	('patients', 'Species', '9606', (235, 243))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('mutations', 'Var', (270, 279))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (263, 269))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('cancers', 'Phenotype', 'HP:0002664', (181, 188))	('cancer', 'Disease', (181, 187))	('cancers', 'Disease', (181, 188))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('patients', 'Species', '9606', (152, 160))	('cancers', 'Phenotype', 'HP:0002664', (91, 98))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('cancer', 'Disease', (91, 97))	('cancers', 'Disease', (91, 98))	('non-canonical cancer', 'Disease', (249, 269))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))
411615	27294619	For a given MAF or VCF input, transcript ID and amino acid change information from Ensembl annotation must be provided for each variant.	('variant', 'Var', (128, 135))	('VCF', 'Gene', (19, 22))	('VCF', 'Gene', '1714', (19, 22))	('MAF', 'Gene', '4094', (12, 15))	('MAF', 'Gene', (12, 15))
411631	27294619	Using the subset of the TCGA cohort having available RPPA data, we examined EGFR protein expression and site-specific phosphorylation at major autophosphorylation sites pTyr1173 and pTyr1068.	('pTyr1068', 'Var', (182, 190))	('pTyr1068', 'Chemical', '-', (182, 190))	('EGFR', 'Gene', (76, 80))	('pTyr1173', 'Chemical', '-', (169, 177))	('pTyr1173', 'Var', (169, 177))
411632	27294619	We examined GBM samples, dividing them into 3 categories: having mutations from the EGFR Ala289 cluster, having mutations outside of any cluster, and having no EGFR mutation.	('EGFR Ala289', 'Gene', (84, 95))	('Ala289', 'Chemical', '-', (89, 95))	('mutations', 'Var', (65, 74))
411639	27294619	Cells were transiently transfected with wild-type or mutant EGFR constructs using Lipofectamine 2000 reagent (Life Technologies) in 6-well plates.	('Lipofectamine 2000 reagent', 'Chemical', '-', (82, 108))	('EGFR', 'Gene', (60, 64))	('mutant', 'Var', (53, 59))
411644	27294619	The following antibodies were used for immunoblotting: anti-phospho-EGFR Tyr1068 (Abcam, Tyr1092 in the unprocessed EGFR), anti-EGFR (Abcam) and anti-beta-Tubulin (DSHB).	('Tyr1092', 'Chemical', '-', (89, 96))	('anti-beta-Tubulin', 'Protein', (145, 162))	('Tyr1092', 'Var', (89, 96))	('Tyr1068', 'Var', (73, 80))	('anti-EGFR', 'Var', (123, 132))	('Tyr1068', 'Chemical', '-', (73, 80))
411648	27294619	PCT, or the Personalized Cancer Therapy, contains druggability information for variants of 24 cancer-related genes and over 140 gene variant-drug interactions supported by clinical evidence.	('variants', 'Var', (79, 87))	('Cancer', 'Phenotype', 'HP:0002664', (25, 31))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('interactions', 'Interaction', (146, 158))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
411649	27294619	GDKD, or the Gene-Drug Knowledge Database, provides information on predictive genomic markers for over 40 malignancies and tumor-type sensitivity/resistance for specific gene variants to approved or experimental drugs.	('malignancies', 'Disease', 'MESH:D009369', (106, 118))	('variants', 'Var', (175, 183))	('tumor', 'Disease', (123, 128))	('malignancies', 'Disease', (106, 118))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
411713	27766936	Specifically, all the genes in the table were queried to get annotations of pathways using KEGG Mapper - Search Pathway, of gene ontology using Ensembl BioMart, of cancer-related diseases using Catalogue of Somatic Mutations In Cancer (COSMIC), and of human-related diseases using Online Mendelian Inheritance In Man (OMIM).	('Cancer', 'Disease', 'MESH:D009369', (228, 234))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('Mutations', 'Var', (215, 224))	('cancer', 'Disease', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('Man', 'Species', '9606', (313, 316))	('Cancer', 'Phenotype', 'HP:0002664', (228, 234))	('Cancer', 'Disease', (228, 234))	('human', 'Species', '9606', (252, 257))
411780	27766936	It is interesting that the HNSC_shared_GO_in_NH_TL and KICH_shared_GO_in_NH_TL have many common GO terms like mitotic sister chromatid segregation, G1/S transition of mitotic cell cycle, regulation of transcription involved in G1/S transition of mitotic cell cycle, and others.	('KICH_shared_GO_in_NH_TL', 'Var', (55, 78))	('mitotic sister chromatid segregation', 'CPA', (110, 146))	('KICH', 'Chemical', '-', (55, 59))
411781	27766936	HNSC_shared_GO_in_NL_TH and KICH_shared_GO_in_NL_TH have the exact two common GO terms, histone deacetylase complex and positive regulation of transporter activity.	('KICH', 'Chemical', '-', (28, 32))	('KICH_shared_GO_in_NL_TH', 'Var', (28, 51))	('positive regulation', 'MPA', (120, 139))
411785	27766936	Our study assumed that the tumor is activated via mRNAs mutation directly targeted by miRNAs.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumor', 'Disease', (27, 32))	('mRNAs', 'Gene', (50, 55))	('mutation', 'Var', (56, 64))	('tumor', 'Disease', 'MESH:D009369', (27, 32))
411797	27272679	Significance of duon mutations in cancer genomes Functional mutations in coding regions not only affect the structure and function of the protein products, but may also modulate their expression in some cases.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('duon', 'Gene', (16, 20))	('function of the', 'MPA', (122, 137))	('protein', 'Protein', (138, 145))	('modulate', 'Reg', (169, 177))	('affect', 'Reg', (97, 103))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('structure', 'MPA', (108, 117))	('cancer', 'Disease', (34, 40))	('expression', 'MPA', (184, 194))	('mutations', 'Var', (60, 69))	('mutations', 'Var', (21, 30))
411799	27272679	In a survey covering 4606 samples from 19 cancer types, and integrating allelic expression, overall mRNA expression, regulatory motif perturbation, and chromatin signatures in one composite index called REDACT score, we identified potential duon mutations.	('mutations', 'Var', (246, 255))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))
411800	27272679	Several such mutations are detected in known cancer genes in multiple cancer types.	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('multiple cancer', 'Disease', 'MESH:D009369', (61, 76))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('mutations', 'Var', (13, 22))	('cancer', 'Disease', (45, 51))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('cancer', 'Disease', (70, 76))	('detected', 'Reg', (27, 35))	('multiple cancer', 'Disease', (61, 76))
411801	27272679	For instance a potential duon mutation in TP53 is associated with increased expression of the mutant allelic gene copy, thereby possibly amplifying the functional effects on the downstream pathways.	('TP53', 'Gene', '7157', (42, 46))	('increased', 'PosReg', (66, 75))	('amplifying', 'PosReg', (137, 147))	('mutation', 'Var', (30, 38))	('TP53', 'Gene', (42, 46))	('expression', 'MPA', (76, 86))	('duon', 'Reg', (25, 29))
411802	27272679	Another potential duon mutation in SF3B1 is associated with abnormal splicing and changes in angiogenesis and matrix degradation related pathways.	('associated', 'Reg', (44, 54))	('SF3B1', 'Gene', '23451', (35, 40))	('mutation', 'Var', (23, 31))	('changes', 'Reg', (82, 89))	('splicing', 'MPA', (69, 77))	('SF3B1', 'Gene', (35, 40))	('abnormal', 'Var', (60, 68))	('angiogenesis', 'CPA', (93, 105))
411805	27272679	There are several reported instances of mutations in regulatory elements within protein coding genes in cancer.	('mutations', 'Var', (40, 49))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))
411806	27272679	For instance, HIF1A protein-level expression is regulated by oxygen-controlled ubiquitination that is disrupted by deletions and missense mutations.	('oxygen', 'Chemical', 'MESH:D010100', (61, 67))	('missense mutations', 'Var', (129, 147))	('oxygen-controlled ubiquitination', 'MPA', (61, 93))	('HIF1A', 'Gene', (14, 19))	('HIF1A', 'Gene', '3091', (14, 19))	('protein-level expression', 'MPA', (20, 44))	('deletions', 'Var', (115, 124))	('disrupted', 'Reg', (102, 111))
411807	27272679	A recurrent, somatic, synonymous mutation (F17F) in BCL2L12 increases its expression by altering the binding site of miR-671-5p in melanoma, which in turn affects its interaction with TP53, inhibiting apoptosis.	('BCL2L12', 'Gene', '83596', (52, 59))	('interaction', 'Interaction', (167, 178))	('F17F', 'Mutation', 'rs267605591', (43, 47))	('TP53', 'Gene', '7157', (184, 188))	('miR-671', 'Gene', '768213', (117, 124))	('affects', 'Reg', (155, 162))	('binding', 'Interaction', (101, 108))	('increases', 'PosReg', (60, 69))	('expression', 'MPA', (74, 84))	('melanoma', 'Disease', 'MESH:D008545', (131, 139))	('apoptosis', 'CPA', (201, 210))	('TP53', 'Gene', (184, 188))	('inhibiting', 'NegReg', (190, 200))	('altering', 'Reg', (88, 96))	('F17F', 'Var', (43, 47))	('miR-671', 'Gene', (117, 124))	('melanoma', 'Phenotype', 'HP:0002861', (131, 139))	('melanoma', 'Disease', (131, 139))	('BCL2L12', 'Gene', (52, 59))
411810	27272679	But the significance of the mutations, which create or perturb duon elements, denoted as 'duon mutations' from here after, in diseases such as cancer remains poorly understood.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('perturb', 'Reg', (55, 62))	('mutations', 'Var', (28, 37))
411811	27272679	We conducted a survey covering 4606 samples from 19 cancer types, and identified recurrent, potential duon mutations after integrating mRNA and protein expression, allelic expression imbalance, epigenetic makeup, regulatory potential, and pathway data (Supplementary Table 1; Flow chart of analysis pipeline used in our approach presented as Supplementary Fig.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('mutations', 'Var', (107, 116))	('imbalance', 'Phenotype', 'HP:0002172', (183, 192))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('duon', 'Gene', (102, 106))
411812	27272679	Our initial dataset included all the major, adult cancer types and had a total of 1,061,980 somatic, exonic point mutations and InDels (Fig.	('adult cancer', 'Disease', 'MESH:C535836', (44, 56))	('InDels', 'Var', (128, 134))	('adult cancer', 'Disease', (44, 56))	('exonic point mutations', 'Var', (101, 123))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))
411813	27272679	While the criteria for duon mutation are still evolving, here we define that a recurrent, potential duon mutation (pDM) would have at least the following attributes - (i) it is recurrently detected in one or more cancer cohorts, (ii) it alters protein sequence (e.g.	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('mutation', 'Var', (105, 113))	('duon', 'Gene', (100, 104))	('alters', 'Reg', (237, 243))	('cancer', 'Disease', 'MESH:D009369', (213, 219))	('protein sequence', 'MPA', (244, 260))	('cancer', 'Disease', (213, 219))
411814	27272679	Thus, we evaluated the pDMs for 6 types of evidence (i) Recurrence: only those mutations which were present in at least 3 samples as well as >1% samples in a cohort were considered, (ii) mRNA-level Expression change: the target genes were expected to show significantly different mRNA expression in affected samples compared to other samples in the cohort (p-value < 0.05) (iii) overlap with DNase hypersensitive regions: mutations that overlapped with DNase hypersensitive regions in reference tissue or cell lines were prioritized, (iv) Allelic expression imbalance: mutant gene copy was expected to show systematic difference in allelic expression compared to the wild-type gene copy.	('hypersensitive', 'Disease', (398, 412))	('difference', 'Reg', (618, 628))	('allelic expression', 'MPA', (632, 650))	('imbalance', 'Phenotype', 'HP:0002172', (558, 567))	('hypersensitive', 'Disease', 'MESH:D004342', (459, 473))	('hypersensitive', 'Disease', (459, 473))	('hypersensitive', 'Disease', 'MESH:D004342', (398, 412))	('mutant', 'Var', (569, 575))
411815	27272679	Wherever possible, we combined tumor purity, exomeseq and RNAseq data to examine allelic expression imbalance of the mutant allele after adjusting for tumor purity and clonality.	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('imbalance', 'Phenotype', 'HP:0002172', (100, 109))	('mutant', 'Var', (117, 123))	('tumor', 'Disease', (31, 36))	('tumor', 'Disease', (151, 156))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
411817	27272679	We found that (i) it is recurrent with population allele frequency >1% in the 1000 Genomes Project cohort, (ii) it is a known eQTL variant, (iii) it overlaps with DNase hypersensitive region, ChIP peaks and TFBS motif.	('TFBS', 'Chemical', '-', (207, 211))	('variant', 'Var', (131, 138))	('hypersensitive', 'Disease', (169, 183))	('hypersensitive', 'Disease', 'MESH:D004342', (169, 183))
411818	27272679	In the analysis of 4606 samples from 19 cancer types we found 146 somatic mutations in 135 protein coding genes that were recurrent (R) and were associated with mRNA-level expression changes (E); of them 121 variants in 108 genes also had evidence for regulatory potential (D, C, or T) as well.	('regulatory potential', 'MPA', (252, 272))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('mutations', 'Var', (74, 83))	('associated', 'Reg', (145, 155))	('cancer', 'Disease', (40, 46))	('variants', 'Var', (208, 216))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('mRNA-level expression changes', 'MPA', (161, 190))
411819	27272679	Among these mutations, several were in known cancer genes (including TP53, SF3B1, APC and PTEN; Fig.	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('APC', 'Disease', 'MESH:D011125', (82, 85))	('TP53', 'Gene', '7157', (69, 73))	('PTEN', 'Gene', (90, 94))	('mutations', 'Var', (12, 21))	('APC', 'Disease', (82, 85))	('TP53', 'Gene', (69, 73))	('PTEN', 'Gene', '5728', (90, 94))	('SF3B1', 'Gene', '23451', (75, 80))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('cancer', 'Disease', (45, 51))	('SF3B1', 'Gene', (75, 80))
411821	27272679	We found a recurrent missense mutation in TP53 (Chr17:7578457:C > A; p.R158L) in lung adenocarcinoma (5 samples) and lung squamous cell carcinoma (5 samples) with attributes consistent with the definition of pDM (Fig.	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (81, 100))	('TP53', 'Gene', '7157', (42, 46))	('p.R158L', 'Mutation', 'rs587782144', (69, 76))	('C > A; p.R158L', 'Var', (62, 76))	('missense mutation', 'Var', (21, 38))	('TP53', 'Gene', (42, 46))	('7578457:C > A', 'Mutation', 'g.7578457C>A', (54, 67))	('lung adenocarcinoma', 'Disease', (81, 100))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (117, 145))	('lung squamous cell carcinoma', 'Disease', (117, 145))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (81, 100))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (122, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))
411822	27272679	This mutation in the DNA binding domain is known to affect TP53 structure and function (Fig.	('structure', 'MPA', (64, 73))	('TP53', 'Gene', (59, 63))	('mutation', 'Var', (5, 13))	('TP53', 'Gene', '7157', (59, 63))	('affect', 'Reg', (52, 58))	('function', 'MPA', (78, 86))
411825	27272679	The position was mutated in multiple different cancer types, and the C > A substitution was detected in lung cancer, head and neck cancer patient samples, as well as cancer cell lines analyzed in the COSMIC project (Fig.	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('head and neck cancer', 'Phenotype', 'HP:0012288', (117, 137))	('detected', 'Reg', (92, 100))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('lung cancer', 'Disease', 'MESH:D008175', (104, 115))	('cancer', 'Disease', (47, 53))	('lung cancer', 'Phenotype', 'HP:0100526', (104, 115))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('head and neck cancer', 'Disease', 'MESH:D006258', (117, 137))	('C > A substitution', 'Var', (69, 87))	('cancer', 'Disease', (166, 172))	('cancer', 'Disease', (109, 115))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('cancer', 'Disease', (131, 137))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('lung cancer', 'Disease', (104, 115))	('patient', 'Species', '9606', (138, 145))
411827	27272679	In addition, the mutant allele had significantly higher expression level compared to the wild-type allele in all the affected samples, which is evident after adjusting for tumor purity and clonality (see Methods; Binomial test with Fisher's combined p-value < 0.001) (Fig.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('higher', 'PosReg', (49, 55))	('tumor', 'Disease', (172, 177))	('expression level', 'MPA', (56, 72))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('mutant', 'Var', (17, 23))
411828	27272679	Furthermore, an increase in expression of the mutant TP53 copy was matched with a corresponding decrease in the expression of the TP53 wild type copy, perhaps due to transcriptional feedback mechanism (Fig.	('expression', 'MPA', (28, 38))	('decrease', 'NegReg', (96, 104))	('increase', 'PosReg', (16, 24))	('mutant', 'Var', (46, 52))	('TP53', 'Gene', '7157', (53, 57))	('TP53', 'Gene', '7157', (130, 134))	('TP53', 'Gene', (130, 134))	('TP53', 'Gene', (53, 57))	('expression', 'MPA', (112, 122))
411829	27272679	To assess the pathway-level consequences of the likely dual effects of the p.R158L pDM in TP53, we used iPAGE, an information-theoretic pathway analysis framework, that calculates statistical significance of enriched pathway using a randomization-based statistical test.	('iPAGE', 'Chemical', '-', (104, 109))	('p.R158L', 'Mutation', 'rs587782144', (75, 82))	('TP53', 'Gene', '7157', (90, 94))	('TP53', 'Gene', (90, 94))	('p.R158L', 'Var', (75, 82))
411830	27272679	We determined gene expression changes in the lung cancer samples carrying p.R158L mutation relative to other samples in the same lung cancer cohorts and specified them as input for iPAGE.	('iPAGE', 'Chemical', '-', (181, 186))	('lung cancer', 'Disease', 'MESH:D008175', (45, 56))	('lung cancer', 'Disease', (129, 140))	('lung cancer', 'Phenotype', 'HP:0100526', (129, 140))	('p.R158L', 'Var', (74, 81))	('lung cancer', 'Disease', (45, 56))	('p.R158L', 'Mutation', 'rs587782144', (74, 81))	('lung cancer', 'Phenotype', 'HP:0100526', (45, 56))	('lung cancer', 'Disease', 'MESH:D008175', (129, 140))	('gene expression', 'MPA', (14, 29))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
411831	27272679	Interestingly, we found several known apoptosis and TP53-associated pathways were affected in the samples with the TP53 p.R158L mutation (Supplementary Fig.	('TP53', 'Gene', '7157', (52, 56))	('affected', 'Reg', (82, 90))	('p.R158L', 'Var', (120, 127))	('TP53', 'Gene', '7157', (115, 119))	('TP53', 'Gene', (52, 56))	('apoptosis', 'Pathway', (38, 47))	('TP53', 'Gene', (115, 119))	('p.R158L', 'Mutation', 'rs587782144', (120, 127))
411833	27272679	We found that many of the TP53 target genes had systematic expression changes in the lung cancer samples carrying p.R158L mutation.	('TP53', 'Gene', (26, 30))	('lung cancer', 'Disease', (85, 96))	('p.R158L', 'Mutation', 'rs587782144', (114, 121))	('lung cancer', 'Phenotype', 'HP:0100526', (85, 96))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('lung cancer', 'Disease', 'MESH:D008175', (85, 96))	('changes', 'Reg', (70, 77))	('expression', 'MPA', (59, 69))	('p.R158L', 'Var', (114, 121))	('TP53', 'Gene', '7157', (26, 30))
411834	27272679	For example, TP53 transcriptionally activates CDKN1A (p21), which in turn suppresses CDK4 leading to G1 arrest and subsequently cause cell cycle arrest in normal cells, and p.R158L mutation is expected to affect the normal TP53 function.	('TP53', 'Gene', (13, 17))	('p.R158L', 'Mutation', 'rs587782144', (173, 180))	('arrest', 'Disease', 'MESH:D006323', (145, 151))	('affect', 'Reg', (205, 211))	('CDK4', 'Gene', (85, 89))	('cause', 'Reg', (128, 133))	('arrest', 'Disease', 'MESH:D006323', (104, 110))	('TP53', 'Gene', '7157', (223, 227))	('suppresses', 'NegReg', (74, 84))	('p.R158L', 'Var', (173, 180))	('CDK4', 'Gene', '1019', (85, 89))	('TP53', 'Gene', '7157', (13, 17))	('p21', 'Gene', (54, 57))	('arrest', 'Disease', (145, 151))	('activates', 'PosReg', (36, 45))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (134, 151))	('CDKN1A', 'Gene', (46, 52))	('CDKN1A', 'Gene', '1026', (46, 52))	('TP53', 'Gene', (223, 227))	('arrest', 'Disease', (104, 110))	('p21', 'Gene', '1026', (54, 57))
411835	27272679	Consistently, we observed that the samples with p.R158L pDM had low CDKN1A expression relative to other samples in the cohort.	('p.R158L', 'Mutation', 'rs587782144', (48, 55))	('low', 'NegReg', (64, 67))	('CDKN1A', 'Gene', (68, 74))	('CDKN1A', 'Gene', '1026', (68, 74))	('p.R158L pDM', 'Var', (48, 59))	('expression', 'MPA', (75, 85))
411837	27272679	To address this question, we focused on only the samples that have p.R158L mutations, and ranked them based on mutant TP53 allelic expression patterns.	('p.R158L', 'Mutation', 'rs587782144', (67, 74))	('TP53', 'Gene', (118, 122))	('p.R158L', 'Var', (67, 74))	('TP53', 'Gene', '7157', (118, 122))
411840	27272679	We did not observe similar association between expression levels of TP53 and CDKN1A when samples with other TP53 mutations or wild type TP53 were analyzed (Supplementary Figs 6 and 7), indicating that expression variation of TP53 in the samples with wild type TP53 or other TP53 missense mutations did not have similar effects on the TP53 downstream targets such as CDKN1A.	('TP53', 'Gene', '7157', (334, 338))	('variation', 'Var', (212, 221))	('TP53', 'Gene', (108, 112))	('expression', 'MPA', (201, 211))	('missense mutations', 'Var', (279, 297))	('TP53', 'Gene', (68, 72))	('TP53', 'Gene', '7157', (136, 140))	('TP53', 'Gene', (274, 278))	('TP53', 'Gene', (260, 264))	('CDKN1A', 'Gene', (366, 372))	('CDKN1A', 'Gene', '1026', (366, 372))	('TP53', 'Gene', (225, 229))	('TP53', 'Gene', '7157', (108, 112))	('TP53', 'Gene', (334, 338))	('TP53', 'Gene', '7157', (274, 278))	('TP53', 'Gene', '7157', (68, 72))	('TP53', 'Gene', (136, 140))	('TP53', 'Gene', '7157', (260, 264))	('CDKN1A', 'Gene', (77, 83))	('TP53', 'Gene', '7157', (225, 229))	('CDKN1A', 'Gene', '1026', (77, 83))
411841	27272679	Another missense mutation in SF3B1 (Chr2:198266834:T > C; p.K700E), detected in eight breast cancer samples, also carried the signatures of pDM.	('SF3B1', 'Gene', '23451', (29, 34))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('breast cancer', 'Disease', 'MESH:D001943', (86, 99))	('breast cancer', 'Phenotype', 'HP:0003002', (86, 99))	('breast cancer', 'Disease', (86, 99))	('T > C; p.K700E', 'Var', (51, 65))	('SF3B1', 'Gene', (29, 34))	('p.K700E', 'Mutation', 'rs559063155', (58, 65))
411842	27272679	The p.K700E mutation was present in the HEAT-repeat domain that is involved in mRNA splicing (Fig.	('p.K700E', 'Var', (4, 11))	('HEAT-repeat', 'Disease', 'MESH:D000647', (40, 51))	('HEAT-repeat', 'Disease', (40, 51))	('p.K700E', 'Mutation', 'rs559063155', (4, 11))
411843	27272679	This mutation was also reported in other cancer types including haematopoietic, pancreatic and central nervous system cancers (Fig.	('cancer', 'Disease', (118, 124))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('cancers', 'Phenotype', 'HP:0002664', (118, 125))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('pancreatic and central nervous system cancers', 'Disease', 'MESH:D010190', (80, 125))	('nervous system cancers', 'Phenotype', 'HP:0004375', (103, 125))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('reported', 'Reg', (23, 31))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('mutation', 'Var', (5, 13))	('haematopoietic', 'Disease', (64, 78))
411844	27272679	The samples with SF3B1 p.K700E mutation had relatively higher expression of the mutant allele, which in turn contributed to higher overall mRNA expression (Fig.	('mRNA expression', 'MPA', (139, 154))	('SF3B1', 'Gene', (17, 22))	('expression', 'MPA', (62, 72))	('p.K700E', 'Mutation', 'rs559063155', (23, 30))	('p.K700E', 'Var', (23, 30))	('SF3B1', 'Gene', '23451', (17, 22))	('higher', 'PosReg', (124, 130))	('higher', 'PosReg', (55, 61))
411845	27272679	For each sample, we obtained isoform level mRNA expression data, and calculated sample-level splicing entropy using a method by Ritchie et al.. We focused on the breast cancer samples that had p.K700E mutation in the cohort, ranking them based on SF3B1 mRNA expression level; we found positive correlation (r = 0.48) between the pDM expression and sample-level splicing entropy (Fig.	('p.K700E', 'Mutation', 'rs559063155', (193, 200))	('p.K700E', 'Var', (193, 200))	('SF3B1', 'Gene', (247, 252))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('breast cancer', 'Disease', 'MESH:D001943', (162, 175))	('breast cancer', 'Phenotype', 'HP:0003002', (162, 175))	('breast cancer', 'Disease', (162, 175))	('SF3B1', 'Gene', '23451', (247, 252))
411847	27272679	8), indicating variation in expression of wild type copy of SF3B1 alone is unable to recapitulate the observed effects.	('SF3B1', 'Gene', (60, 65))	('variation', 'Var', (15, 24))	('SF3B1', 'Gene', '23451', (60, 65))
411848	27272679	To evaluate pathway level significance of the SF3B1 p.K700E pDM, we estimated isoform abundance for each gene, and accordingly calculated gene-level splicing entropy.	('p.K700E', 'Mutation', 'rs559063155', (52, 59))	('SF3B1', 'Gene', (46, 51))	('p.K700E pDM', 'Var', (52, 63))	('SF3B1', 'Gene', '23451', (46, 51))
411850	27272679	This analysis showed enrichment for VEGF pathway and matrix metalloproteinases, indicating that high expression of the p.K700E was associated with changes in splicing patterns in pathways, especially those involved in angiogenesis and matrix degradation (Supplementary Fig.	('VEGF', 'Gene', (36, 40))	('angiogenesis', 'CPA', (218, 230))	('pathways', 'Pathway', (179, 187))	('changes', 'Reg', (147, 154))	('p.K700E', 'Mutation', 'rs559063155', (119, 126))	('splicing patterns', 'MPA', (158, 175))	('p.K700E', 'Var', (119, 126))	('VEGF', 'Gene', '7422', (36, 40))
411851	27272679	Interestingly, we found in-frame deletion pDM in two cancer genes WRN (c2305-2307; ACTAAAGAA > ACTAAA, pK506-E507 deletion, REDACT score: RED*cT) and CBL (c1506-1508; AATTATGAT > AATTAT, pY455-D456 deletion, REDACT score: REd*cT) in pancreatic adenocarcinoma (PAAD).	('c1506-1508;', 'Var', (155, 166))	('c2305-2307;', 'Var', (71, 82))	('CBL', 'Gene', '867', (150, 153))	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D010190', (233, 258))	('deletion', 'Var', (33, 41))	('pancreatic adenocarcinoma', 'Disease', (233, 258))	('carcinoma', 'Phenotype', 'HP:0030731', (249, 258))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (233, 258))	('pY455-D456 deletion', 'Var', (187, 206))	('REd*cT', 'Var', (222, 228))	('CBL', 'Gene', (150, 153))
411853	27272679	The CBL pDM deletion was detected in eight PAAD samples, it was associated with up-regulation of this gene, and overlapped SOX5 binding site.	('deletion', 'Var', (12, 20))	('SOX5', 'Gene', (123, 127))	('up-regulation', 'PosReg', (80, 93))	('CBL', 'Gene', (4, 7))	('CBL', 'Gene', '867', (4, 7))	('SOX5', 'Gene', '6660', (123, 127))
411856	27272679	As an example, we found a recurrent TP53 mutation (in breast and head neck cancer) that was predicted to result in gain of NHLH1 binding site, and was associated with down regulation of TP53 expression in both cancer type.	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('gain', 'PosReg', (115, 119))	('TP53', 'Gene', (36, 40))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('breast and head neck cancer', 'Disease', 'MESH:D006258', (54, 81))	('mutation', 'Var', (41, 49))	('TP53', 'Gene', (186, 190))	('cancer', 'Disease', 'MESH:D009369', (210, 216))	('binding', 'Interaction', (129, 136))	('expression', 'MPA', (191, 201))	('NHLH1', 'Gene', '4807', (123, 128))	('head neck cancer', 'Phenotype', 'HP:0012288', (65, 81))	('TP53', 'Gene', '7157', (36, 40))	('down regulation', 'NegReg', (167, 182))	('cancer', 'Disease', (75, 81))	('TP53', 'Gene', '7157', (186, 190))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('NHLH1', 'Gene', (123, 128))	('cancer', 'Disease', (210, 216))
411857	27272679	Integrating evidence from overall mRNA expression, allelic expression, regulatory motif perturbation, and chromatin signatures, we identify potential duon mutations in 4606 samples from 19 different cancer types.	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('duon', 'Gene', (150, 154))	('mutations', 'Var', (155, 164))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('cancer', 'Disease', (199, 205))
411859	27272679	First, intra-tumor spatial heterogeneity has the potential to introduce discrepancies when comparing mRNA and protein expression levels, or allelic proportions in exome and RNAseq data from the same tumor sample.	('tumor', 'Disease', (199, 204))	('tumor', 'Disease', (13, 18))	('intra-tumor', 'Disease', (7, 18))	('heterogeneity', 'Var', (27, 40))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('intra-tumor', 'Disease', 'MESH:D009369', (7, 18))	('introduce', 'Reg', (62, 71))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
411860	27272679	For instance, mutations in a gene with DNase hypersensitive sites spanning most of the coding regions cannot have significant p-value for D, but it still may be functionally relevant while classifying functional relevance of these mutations.	('hypersensitive', 'Disease', (45, 59))	('mutations', 'Var', (14, 23))	('hypersensitive', 'Disease', 'MESH:D004342', (45, 59))
411861	27272679	Nevertheless, our findings present evidence for recurrent, potential duon mutations in the genomes of different types of cancer.	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('mutations', 'Var', (74, 83))	('duon', 'Gene', (69, 73))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('cancer', 'Disease', (121, 127))
411862	27272679	Furthermore, our study suggests that potential duon mutations in cancer genes may have under-appreciated significance for downstream pathways.	('mutations', 'Var', (52, 61))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))
411864	27272679	Lastly, our findings highlight the impact of regulatory mutations in tumorigenesis and contribute to the ongoing debate about the early molecular alterations during tumor development.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('mutations', 'Var', (56, 65))	('tumor', 'Disease', (69, 74))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('tumor', 'Disease', (165, 170))
411865	27272679	point mutations, small InDels) for 4606 samples from 19 different cancer-types, as provided by the Cancer Genome Atlas (TCGA; https://tcga-data.nci.nih.gov/tcga/).	('Cancer', 'Phenotype', 'HP:0002664', (99, 105))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('point mutations', 'Var', (0, 15))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('cancer', 'Disease', (66, 72))
411870	27272679	For instance, if a pDM score of 'REd*Ct' would indicate that the mutation is recurrent, associated with altered mRNA expression and ChIP-seq peaks, but it does not overlap with DNase hypersensitive regions and known transcription factor binding motifs, while allelic expression data is not available.	('hypersensitive', 'Disease', 'MESH:D004342', (183, 197))	('altered', 'Reg', (104, 111))	('mRNA expression', 'MPA', (112, 127))	('hypersensitive', 'Disease', (183, 197))	('mutation', 'Var', (65, 73))	('ChIP-seq', 'MPA', (132, 140))
411871	27272679	So, to estimate statistical significance of overlap with DNase hypersensitive sites, we used a simple null model, and randomly shuffled the somatic mutations within respective candidate gene regions 10,000 times, and counted the number of times (n) the mutations overlap with DNase hypersensitive regions, by chance alone, such that n/10000 indicates the permutation p-value.	('hypersensitive', 'Disease', (282, 296))	('hypersensitive', 'Disease', (63, 77))	('hypersensitive', 'Disease', 'MESH:D004342', (63, 77))	('mutations', 'Var', (253, 262))	('n/10000', 'Var', (333, 340))	('hypersensitive', 'Disease', 'MESH:D004342', (282, 296))
411875	27272679	Additionally, two-control analyses were performed to show effects of both p.R158L missense mutation and associated expression changes.	('expression', 'MPA', (115, 125))	('p.R158L', 'Mutation', 'rs587782144', (74, 81))	('p.R158L', 'Var', (74, 81))
411876	27272679	First, to test whether any missense mutation in TP53 systematically affect CDKN1A expression in a fashion similar to p.R158L, we selected several other TP53 somatic mutations that were recurrent in different TCGA cancer types (Lower grade glioma (LGG), Lung squamous cell carcinoma (LUSC), Lung adenocarcinoma (LUAD), Head and neck (HNSC), and Bladder (BLCA) cancers), but were not classified as duon mutations; we estimated correlation in RNAseq expression between TP53 and CDKN1A (Supplementary Fig.	('Lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (253, 281))	('CDKN1A', 'Gene', (75, 81))	('CDKN1A', 'Gene', '1026', (75, 81))	('cancer', 'Phenotype', 'HP:0002664', (359, 365))	('TP53', 'Gene', '7157', (152, 156))	('Lung adenocarcinoma', 'Disease', (290, 309))	('TP53', 'Gene', (466, 470))	('Lung squamous cell carcinoma', 'Disease', (253, 281))	('cancers', 'Phenotype', 'HP:0002664', (359, 366))	('TP53', 'Gene', '7157', (48, 52))	('p.R158L', 'Mutation', 'rs587782144', (117, 124))	('expression', 'MPA', (82, 92))	('missense mutation', 'Var', (27, 44))	('cancers', 'Disease', (359, 366))	('cancer', 'Disease', (213, 219))	('mutations', 'Var', (165, 174))	('cancer', 'Disease', 'MESH:D009369', (359, 365))	('affect', 'Reg', (68, 74))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('carcinoma', 'Phenotype', 'HP:0030731', (300, 309))	('Lung adenocarcinoma', 'Phenotype', 'HP:0030078', (290, 309))	('Lung adenocarcinoma', 'Disease', 'MESH:D000077192', (290, 309))	('glioma', 'Disease', (239, 245))	('CDKN1A', 'Gene', (475, 481))	('TP53', 'Gene', (152, 156))	('TP53', 'Gene', '7157', (466, 470))	('CDKN1A', 'Gene', '1026', (475, 481))	('glioma', 'Phenotype', 'HP:0009733', (239, 245))	('glioma', 'Disease', 'MESH:D005910', (239, 245))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (258, 281))	('cancers', 'Disease', 'MESH:D009369', (359, 366))	('TP53', 'Gene', (48, 52))	('cancer', 'Disease', 'MESH:D009369', (213, 219))	('carcinoma', 'Phenotype', 'HP:0030731', (272, 281))	('cancer', 'Disease', (359, 365))
411877	27272679	Second, to test whether the extent of association between TP53 and CDKN1A expression for the TP53 p.R158L mutant samples is rather common among TP53 wild type samples, we performed permutation analysis.	('TP53', 'Gene', '7157', (144, 148))	('TP53', 'Gene', (144, 148))	('p.R158L', 'Var', (98, 105))	('association', 'Interaction', (38, 49))	('CDKN1A', 'Gene', '1026', (67, 73))	('TP53', 'Gene', '7157', (58, 62))	('TP53', 'Gene', (58, 62))	('TP53', 'Gene', '7157', (93, 97))	('TP53', 'Gene', (93, 97))	('p.R158L', 'Mutation', 'rs587782144', (98, 105))	('CDKN1A', 'Gene', (67, 73))
411878	27272679	We randomly selected 10 samples wild-type TP53, 1000 times from the LUAD and LUSC cohorts of TCGA, and each time calculated correlation coefficient value between expression of CDKN1A and TP53, and then compared that with the observed association between TP53 and CDKN1A expression in p.R158L mutant samples (Supplementary Fig.	('CDKN1A', 'Gene', (263, 269))	('TP53', 'Gene', '7157', (42, 46))	('TP53', 'Gene', '7157', (254, 258))	('TP53', 'Gene', (254, 258))	('CDKN1A', 'Gene', '1026', (263, 269))	('TP53', 'Gene', '7157', (187, 191))	('p.R158L', 'Mutation', 'rs587782144', (284, 291))	('TP53', 'Gene', (42, 46))	('TP53', 'Gene', (187, 191))	('CDKN1A', 'Gene', (176, 182))	('p.R158L', 'Var', (284, 291))	('CDKN1A', 'Gene', '1026', (176, 182))
411879	27272679	For functional analysis of SF3B1 mutation, as SF3B1 is a core spliceosome factor our aim is to evaluate the extent of non-specific alternative transcript disruptions in the samples containing mutation in SF3B1.	('mutation', 'Var', (33, 41))	('SF3B1', 'Gene', '23451', (204, 209))	('mutation', 'Var', (192, 200))	('SF3B1', 'Gene', (27, 32))	('SF3B1', 'Gene', (46, 51))	('SF3B1', 'Gene', (204, 209))	('SF3B1', 'Gene', '23451', (27, 32))	('SF3B1', 'Gene', '23451', (46, 51))
411880	27272679	We hypothesized that, in a samples where SF3B1 is mutated the splicing machinery is impaired, the distribution of isoforms may be more disordered than in unaffected samples and to quantify this we modified previously published method of calculating isoform entropy by Ritchie et.	('disordered', 'Disease', (135, 145))	('impaired', 'NegReg', (84, 92))	('SF3B1', 'Gene', (41, 46))	('mutated', 'Var', (50, 57))	('SF3B1', 'Gene', '23451', (41, 46))	('distribution', 'MPA', (98, 110))	('splicing machinery', 'MPA', (62, 80))	('disordered', 'Disease', 'MESH:D030342', (135, 145))
411882	27272679	For the TP53 pDM analysis, we transformed the expression data using the equation: where for any gene p is the Student's t-test p-value between the mutant samples and other samples in the same lung cancer cohorts, and s indicates the direction of change in the expression between the two groups of samples.	('mutant', 'Var', (147, 153))	('lung cancer', 'Disease', (192, 203))	('lung cancer', 'Phenotype', 'HP:0100526', (192, 203))	('TP53', 'Gene', '7157', (8, 12))	('TP53', 'Gene', (8, 12))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('lung cancer', 'Disease', 'MESH:D008175', (192, 203))
411883	27272679	For the pDM in SF3B1, we calculated entropy for each gene in eight samples of breast cancer that contains p.K700E mutation.	('entropy', 'MPA', (36, 43))	('breast cancer', 'Phenotype', 'HP:0003002', (78, 91))	('SF3B1', 'Gene', '23451', (15, 20))	('p.K700E', 'Mutation', 'rs559063155', (106, 113))	('p.K700E', 'Var', (106, 113))	('breast cancer', 'Disease', 'MESH:D001943', (78, 91))	('SF3B1', 'Gene', (15, 20))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('breast cancer', 'Disease', (78, 91))
411885	27272679	Similar to the control analysis for TP53, randomly selected 8 samples wild-type SF3B1, 1000 times from the TCGA BRCA cohort, and each time calculated correlation coefficient value between expression of SF3B1 and splicing entropy, and compared that with the observed association between SF3B1 expression and splicing entropy in p.K700E mutant samples (Supplementary Fig.	('SF3B1', 'Gene', '23451', (80, 85))	('p.K700E', 'Mutation', 'rs559063155', (327, 334))	('p.K700E mutant', 'Var', (327, 341))	('SF3B1', 'Gene', (202, 207))	('SF3B1', 'Gene', (286, 291))	('TP53', 'Gene', '7157', (36, 40))	('SF3B1', 'Gene', (80, 85))	('TP53', 'Gene', (36, 40))	('SF3B1', 'Gene', '23451', (202, 207))	('SF3B1', 'Gene', '23451', (286, 291))
411886	27272679	Significance of duon mutations in cancer genomes.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('duon', 'Gene', (16, 20))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('cancer', 'Disease', (34, 40))	('mutations', 'Var', (21, 30))
411895	32252688	There was no significant homozygous loss and the most recurrent hemizygous deletion involved the B3GAT1 gene on chromosome 11q25.	('deletion', 'Var', (75, 83))	('B3GAT1', 'Gene', '27087', (97, 103))	('B3GAT1', 'Gene', (97, 103))
411912	32252688	Apart from copy number aberrations, mutational analyses have shown recurrent inactivating mutations in TP53, and NOTCH1 as well as activating events in PIK3CA.	('TP53', 'Gene', '7157', (103, 107))	('PIK3CA', 'Gene', '5290', (152, 158))	('cop', 'Gene', '114769', (11, 14))	('TP53', 'Gene', (103, 107))	('NOTCH1', 'Gene', '4851', (113, 119))	('NOTCH1', 'Gene', (113, 119))	('activating', 'PosReg', (131, 141))	('cop', 'Gene', (11, 14))	('PIK3CA', 'Gene', (152, 158))	('inactivating mutations', 'Var', (77, 99))
411913	32252688	A single genomic study, performed on African patients from Malawi, recapitulated patterns of gene mutations and copy number changes (gains of CCND1, TP63, MYC, ERBB2, EGFR, MYCL1 and losses of CDKN2A/CDKN2B), similar to those observed in Asian and North American ESCC patients .	('MYCL1', 'Gene', '4610', (173, 178))	('CDKN2B', 'Gene', '1030', (200, 206))	('gains', 'PosReg', (133, 138))	('cop', 'Gene', (112, 115))	('patients', 'Species', '9606', (45, 53))	('MYC', 'Gene', '4609', (155, 158))	('patients', 'Species', '9606', (268, 276))	('CDKN2A', 'Gene', (193, 199))	('ERBB2', 'Gene', (160, 165))	('CCND1', 'Gene', '595', (142, 147))	('EGFR', 'Gene', (167, 171))	('CCND1', 'Gene', (142, 147))	('TP63', 'Gene', (149, 153))	('ERBB2', 'Gene', '2064', (160, 165))	('losses', 'NegReg', (183, 189))	('CDKN2A', 'Gene', '1029', (193, 199))	('MYC', 'Gene', (173, 176))	('cop', 'Gene', '114769', (112, 115))	('CDKN2B', 'Gene', (200, 206))	('TP63', 'Gene', '8626', (149, 153))	('MYC', 'Gene', (155, 158))	('MYCL1', 'Gene', (173, 178))	('mutations', 'Var', (98, 107))	('EGFR', 'Gene', '1956', (167, 171))	('MYC', 'Gene', '4609', (173, 176))
411943	32252688	Although the function of the TPRG1 gene is not well established, amplification and/or activating mutations in Cis regulatory elements of this gene associated with its increased expression have recently been reported in diffuse large B-cell lymphomas, suggesting potential oncogenic activity.	('mutations', 'Var', (97, 106))	('TPRG1', 'Gene', (29, 34))	('lymphomas', 'Phenotype', 'HP:0002665', (240, 249))	('B-cell lymphomas', 'Phenotype', 'HP:0012191', (233, 249))	('activating', 'PosReg', (86, 96))	('increased', 'PosReg', (167, 176))	('lymphoma', 'Phenotype', 'HP:0002665', (240, 248))	('cell lymphoma', 'Phenotype', 'HP:0012191', (235, 248))	('amplification', 'Var', (65, 78))	('expression', 'MPA', (177, 187))	('lymphomas', 'Disease', (240, 249))	('TPRG1', 'Gene', '285386', (29, 34))	('lymphomas', 'Disease', 'MESH:D008223', (240, 249))
411957	32252688	Twenty-six tumor samples were assessed for Shank2, cortactin and cyclin D1 protein expression; of these, 22 cases had DNA gain of all three genes and 19/22 (86%) overexpressed Shank2 (score3), 16/22 (72%) overexpressed cortactin, while only 5/22 cases (22%) overexpressed cyclin D1, (score of 3).	('cyclin D1', 'Gene', (65, 74))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('Shank2', 'Gene', '22941', (43, 49))	('cyclin D1', 'Gene', '595', (65, 74))	('Shank2', 'Gene', '22941', (176, 182))	('cortactin', 'Gene', '2017', (51, 60))	('DNA', 'Var', (118, 121))	('tumor', 'Disease', (11, 16))	('overexpressed', 'PosReg', (162, 175))	('Shank2', 'Gene', (43, 49))	('overexpressed', 'PosReg', (205, 218))	('tumor', 'Disease', 'MESH:D009369', (11, 16))	('cortactin', 'Gene', (219, 228))	('cyclin D1', 'Gene', '595', (272, 281))	('cortactin', 'Gene', (51, 60))	('cyclin D1', 'Gene', (272, 281))	('cortactin', 'Gene', '2017', (219, 228))	('Shank2', 'Gene', (176, 182))
411964	32252688	Co-amplification of CTTN, SHANK2 and CCND1 genes has been reported previously in oral squamous cell carcinoma.	('CTTN', 'Gene', '2017', (20, 24))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (86, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('SHANK2', 'Gene', (26, 32))	('SHANK2', 'Gene', '22941', (26, 32))	('oral squamous cell carcinoma', 'Disease', (81, 109))	('reported', 'Reg', (58, 66))	('CCND1', 'Gene', (37, 42))	('CCND1', 'Gene', '595', (37, 42))	('CTTN', 'Gene', (20, 24))	('Co-amplification', 'Var', (0, 16))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (81, 109))
411982	32252688	CTTN gain/ increased expression alone has been associated with ESCC metastasis and functional studies further demonstrated that inhibition of CTTN expression decreased tumor growth and lung metastasis.	('CTTN', 'Gene', (142, 146))	('decreased tumor', 'Disease', 'MESH:D002303', (158, 173))	('CTTN', 'Gene', '2017', (142, 146))	('gain/', 'PosReg', (5, 10))	('expression', 'MPA', (21, 31))	('CTTN', 'Gene', (0, 4))	('ESCC', 'Disease', (63, 67))	('lung metastasis', 'CPA', (185, 200))	('decreased tumor', 'Disease', (158, 173))	('inhibition', 'Var', (128, 138))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('CTTN', 'Gene', '2017', (0, 4))
411990	32252688	Although this gene has not been linked to ESCC pathogenesis, its distal neighbor gene, TP63 showed gains in a wider peak region, in 20 of the 21 cases with gains at 3q28.	('gains', 'PosReg', (99, 104))	('ESCC', 'Disease', (42, 46))	('TP63', 'Gene', (87, 91))	('TP63', 'Gene', '8626', (87, 91))	('gains', 'Var', (156, 161))
411992	32252688	Of note, TPRG1 is highly expressed in normal esophageal tissue and an intergenic susceptibility locus (rs6791479) was identified in a genome-wide association study of cutaneous squamous cell carcinoma in between the TP63 and TPRG1 genes.	('cutaneous squamous cell carcinoma', 'Disease', 'MESH:D002294', (167, 200))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (177, 200))	('carcinoma', 'Phenotype', 'HP:0030731', (191, 200))	('TP63', 'Gene', '8626', (216, 220))	('rs6791479', 'Mutation', 'rs6791479', (103, 112))	('cutaneous squamous cell carcinoma', 'Disease', (167, 200))	('TP63', 'Gene', (216, 220))	('TPRG1', 'Gene', '285386', (225, 230))	('TPRG1', 'Gene', (9, 14))	('rs6791479', 'Var', (103, 112))	('TPRG1', 'Gene', '285386', (9, 14))	('TPRG1', 'Gene', (225, 230))
412003	32252688	BAC Bacterial artificial chromosome ESCC Esophageal squamous carcinoma FFPE Formalin fixed paraffin embedded FISH Fluorescence in situ hybridisation GEO Gene Expression Omnibus GISTIC Genomic Identification of Significant Targets in Cancer IHC Immunohistochemistry PCR Polymerase chain reaction SCNV Somatic cop number variants SNP Single nucleotide polymorphism SSC Saline sodium citrate Supplementary information accompanies this paper at 10.1186/s12885-020-06788-3.	('variants', 'Var', (319, 327))	('Saline sodium citrate', 'Chemical', '-', (367, 388))	('squamous carcinoma', 'Disease', 'MESH:D002294', (52, 70))	('Cancer', 'Disease', 'MESH:D009369', (233, 239))	('Cancer', 'Disease', (233, 239))	('cop', 'Gene', (308, 311))	('squamous carcinoma', 'Disease', (52, 70))	('Formalin', 'Chemical', 'MESH:D005557', (76, 84))	('cop', 'Gene', '114769', (308, 311))	('Esophageal squamous carcinoma', 'Phenotype', 'HP:0011459', (41, 70))	('paraffin', 'Chemical', 'MESH:D010232', (91, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('Cancer', 'Phenotype', 'HP:0002664', (233, 239))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (52, 70))
412007	30665373	Glutathione S-transferase pi 1 variant and squamous cell carcinoma susceptibility: a meta-analysis of 52 case-control studies There are several meta-analyses on the genetic relationship between the rs1695 polymorphism within the GSTP1 (glutathione S-transferase pi 1) gene and the risk of different SCC (squamous cell carcinoma) diseases, such as ESCC (oesophageal SCC), HNSCC (head and neck SCC), LSCC (lung SCC), and SSCC (skin SCC).	('Glutathione S-transferase pi 1', 'Gene', (0, 30))	('rs1695', 'Mutation', 'rs1695', (198, 204))	('SCC', 'Gene', (299, 302))	('carcinoma', 'Phenotype', 'HP:0030731', (318, 327))	('SCC', 'Gene', '6317', (409, 412))	('carcinoma', 'Phenotype', 'HP:0030731', (57, 66))	('SCC', 'Gene', '6317', (399, 402))	('SCC', 'Gene', '6317', (392, 395))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (304, 327))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (43, 66))	('SCC', 'Gene', (409, 412))	('SCC', 'Gene', '6317', (430, 433))	('SCC', 'Gene', (399, 402))	('SCC', 'Gene', (392, 395))	('rs1695 polymorphism', 'Var', (198, 217))	('squamous cell carcinoma', 'Disease', (304, 327))	('Glutathione S-transferase pi 1', 'Gene', '2950', (0, 30))	('squamous cell carcinoma', 'Disease', (43, 66))	('SCC', 'Gene', (430, 433))	('SCC', 'Gene', '6317', (373, 376))	('GSTP1', 'Gene', '2950', (229, 234))	('glutathione S-transferase pi 1', 'Gene', (236, 266))	('GSTP1', 'Gene', (229, 234))	('SCC', 'Gene', '6317', (365, 368))	('SCC', 'Gene', '6317', (348, 351))	('SCC', 'Gene', (373, 376))	('SCC', 'Gene', '6317', (420, 423))	('SCC', 'Gene', '6317', (299, 302))	('SCC', 'Gene', (365, 368))	('SCC', 'Gene', (348, 351))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (304, 327))	('SCC', 'Gene', (420, 423))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (43, 66))	('glutathione S-transferase pi 1', 'Gene', '2950', (236, 266))
412008	30665373	Herein, an updated meta-analysis was performed to evaluate the probable impact of GSTP1 rs1695 on the susceptibility to different SCC diseases under six genetic models (allele, carrier, homozygote, heterozygote, dominant, and recessive).	('GSTP1', 'Gene', (82, 87))	('rs1695', 'Mutation', 'rs1695', (88, 94))	('GSTP1', 'Gene', '2950', (82, 87))	('SCC diseases', 'Disease', 'MESH:D004194', (130, 142))	('rs1695', 'Var', (88, 94))	('SCC diseases', 'Disease', (130, 142))
412011	30665373	The rs1695 polymorphism within the GSTP1 gene is not associated with the risk of overall SCC or a specific SCC type, including ESCC, HNSCC, LSCC, and SSCC.	('SCC', 'Gene', '6317', (135, 138))	('rs1695 polymorphism', 'Var', (4, 23))	('SCC', 'Gene', (141, 144))	('SCC', 'Gene', '6317', (89, 92))	('SCC', 'Gene', (128, 131))	('SCC', 'Gene', '6317', (151, 154))	('GSTP1', 'Gene', '2950', (35, 40))	('SCC', 'Gene', (107, 110))	('GSTP1', 'Gene', (35, 40))	('SCC', 'Gene', '6317', (141, 144))	('SCC', 'Gene', (135, 138))	('SCC', 'Gene', '6317', (128, 131))	('SCC', 'Gene', '6317', (107, 110))	('rs1695', 'Mutation', 'rs1695', (4, 10))	('SCC', 'Gene', (89, 92))	('SCC', 'Gene', (151, 154))
412016	30665373	Two variants within the KLF5 (Kruppel-like factor 5) gene on chromosome 13q22.1, namely, rs1924966 and rs115797771, may be relevant to ESCC (oesophageal SCC) susceptibility.	('KLF5', 'Gene', (24, 28))	('rs1924966', 'Var', (89, 98))	('Kruppel-like factor 5', 'Gene', '688', (30, 51))	('SCC', 'Gene', (136, 139))	('SCC', 'Gene', '6317', (153, 156))	('Kruppel-like factor 5', 'Gene', (30, 51))	('rs1924966', 'Mutation', 'rs1924966', (89, 98))	('KLF5', 'Gene', '688', (24, 28))	('SCC', 'Gene', '6317', (136, 139))	('rs115797771', 'Var', (103, 114))	('SCC', 'Gene', (153, 156))	('rs115797771', 'Mutation', 'rs115797771', (103, 114))
412017	30665373	Herein, we determined whether GSTP1 (glutathione S-transferase pi 1) gene polymorphism is associated with the susceptibility to different SCC patterns.	('GSTP1', 'Gene', (30, 35))	('SCC', 'Gene', (138, 141))	('associated', 'Reg', (90, 100))	('glutathione S-transferase pi 1', 'Gene', (37, 67))	('SCC', 'Gene', '6317', (138, 141))	('GSTP1', 'Gene', '2950', (30, 35))	('susceptibility', 'Reg', (110, 124))	('glutathione S-transferase pi 1', 'Gene', '2950', (37, 67))	('polymorphism', 'Var', (74, 86))
412020	30665373	Two common polymorphisms, namely, rs1695 A/G polymorphism in exon five (p.Ile105Val) and rs1138272 C/T polymorphism in exon six (p.Ala114Val), have been reported.	('rs1138272 C/T', 'Var', (89, 102))	('p.Ile105Val', 'Mutation', 'rs1695', (72, 83))	('rs1695 A/G', 'Var', (34, 44))	('rs1138272', 'Mutation', 'rs1138272', (89, 98))	('p.Ala114Val', 'Mutation', 'rs1138272', (129, 140))	('rs1695', 'Mutation', 'rs1695', (34, 40))
412021	30665373	Several SCC/GSTP1 rs1695-associated meta-analyses with conflicting conclusions have been reported.	('rs1695', 'Mutation', 'rs1695', (18, 24))	('GSTP1', 'Gene', '2950', (12, 17))	('GSTP1', 'Gene', (12, 17))	('rs1695-associated', 'Var', (18, 35))	('SCC', 'Gene', (8, 11))	('SCC', 'Gene', '6317', (8, 11))
412022	30665373	enrolled three case-control studies, performed a meta-analysis to assess the association between GSTP1 rs1695 and ESCC risk in Caucasian populations, and found a borderline significant association.	('GSTP1', 'Gene', '2950', (97, 102))	('GSTP1', 'Gene', (97, 102))	('rs1695', 'Var', (103, 109))	('SCC', 'Gene', (115, 118))	('rs1695', 'Mutation', 'rs1695', (103, 109))	('SCC', 'Gene', '6317', (115, 118))
412023	30665373	enrolled 21 case-control studies to perform a meta-analysis concerning the role of the GSTP1 rs1695 polymorphism in the risk of oesophageal cancers, including EAC (oesophageal adenocarcinoma) and ESCC.	('SCC', 'Gene', '6317', (197, 200))	('carcinoma', 'Phenotype', 'HP:0030731', (181, 190))	('oesophageal cancers', 'Disease', (128, 147))	('rs1695', 'Mutation', 'rs1695', (93, 99))	('GSTP1', 'Gene', '2950', (87, 92))	('GSTP1', 'Gene', (87, 92))	('oesophageal adenocarcinoma', 'Disease', (164, 190))	('cancers', 'Phenotype', 'HP:0002664', (140, 147))	('SCC', 'Gene', (197, 200))	('oesophageal cancers', 'Disease', 'MESH:D009369', (128, 147))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('oesophageal adenocarcinoma', 'Disease', 'MESH:D005764', (164, 190))	('rs1695', 'Var', (93, 99))
412026	30665373	Accordingly, we performed an updated meta-analysis with a relatively larger sample size to reevaluate the potential impact of the GSTP1 rs1695 A/G polymorphism on the susceptibility to SCC diseases, mainly including ESCC, SSCC, HNSCC (head and neck SCC), and LSCC (lung SCC).	('SCC diseases', 'Disease', 'MESH:D004194', (185, 197))	('GSTP1', 'Gene', '2950', (130, 135))	('GSTP1', 'Gene', (130, 135))	('SCC diseases', 'Disease', (185, 197))	('SCC', 'Gene', '6317', (249, 252))	('SCC', 'Gene', '6317', (185, 188))	('SCC', 'Gene', '6317', (217, 220))	('SCC', 'Gene', (249, 252))	('SCC', 'Gene', '6317', (270, 273))	('rs1695', 'Var', (136, 142))	('SCC', 'Gene', (185, 188))	('SCC', 'Gene', (217, 220))	('SCC', 'Gene', '6317', (230, 233))	('SCC', 'Gene', '6317', (223, 226))	('SCC', 'Gene', (270, 273))	('SCC', 'Gene', (230, 233))	('SCC', 'Gene', '6317', (260, 263))	('SCC', 'Gene', (223, 226))	('rs1695', 'Mutation', 'rs1695', (136, 142))	('SCC', 'Gene', (260, 263))
412029	30665373	Eligible case-control studies provided sufficient genotype frequency data of the GSTP1 gene rs1695 polymorphism in each case and control group.	('rs1695', 'Mutation', 'rs1695', (92, 98))	('rs1695 polymorphism', 'Var', (92, 111))	('GSTP1', 'Gene', '2950', (81, 86))	('GSTP1', 'Gene', (81, 86))
412030	30665373	The allele (allele G vs. A), carrier (carrier G vs. A), homozygote (GG vs. AA), heterozygote (AG vs. AA), dominant (AG + GG vs. AA), and recessive (GG vs. AA+AG) models were utilized to target the GSTP1 gene rs1695 G/A polymorphism.	('GSTP1', 'Gene', '2950', (197, 202))	('rs1695', 'Mutation', 'rs1695', (208, 214))	('rs1695 G/A polymorphism', 'Var', (208, 231))	('GSTP1', 'Gene', (197, 202))
412033	30665373	These data suggest that the rs1695 polymorphism within the GSTP1 gene does not contribute to the risk of overall SCC.	('rs1695 polymorphism', 'Var', (28, 47))	('SCC', 'Gene', '6317', (113, 116))	('GSTP1', 'Gene', (59, 64))	('GSTP1', 'Gene', '2950', (59, 64))	('rs1695', 'Mutation', 'rs1695', (28, 34))	('SCC', 'Gene', (113, 116))
412036	30665373	As a result, the GSTP1 gene rs1695 polymorphism is not likely related to the genetic susceptibility of a specific SCC type, including ESCC, HNSCC, LSCC, and SSCC.	('SCC', 'Gene', '6317', (158, 161))	('SCC', 'Gene', (114, 117))	('SCC', 'Gene', (142, 145))	('GSTP1', 'Gene', (17, 22))	('rs1695', 'Var', (28, 34))	('SCC', 'Gene', (148, 151))	('SCC', 'Gene', (135, 138))	('SCC', 'Gene', '6317', (142, 145))	('SCC', 'Gene', '6317', (114, 117))	('rs1695', 'Mutation', 'rs1695', (28, 34))	('SCC', 'Gene', '6317', (148, 151))	('GSTP1', 'Gene', '2950', (17, 22))	('SCC', 'Gene', (158, 161))	('SCC', 'Gene', '6317', (135, 138))
412038	30665373	In the current meta-analysis, we first focused on the genetic relationship between the GSTP1 rs1695 A/G polymorphism and the risk of overall SCC and then conducted subgroup analyses by the specific histological status.	('rs1695', 'Mutation', 'rs1695', (93, 99))	('SCC', 'Gene', (141, 144))	('GSTP1', 'Gene', (87, 92))	('SCC', 'Gene', '6317', (141, 144))	('GSTP1', 'Gene', '2950', (87, 92))	('rs1695 A/G', 'Var', (93, 103))
412042	30665373	The GSTP1 rs1695 A/G polymorphism is significantly related to the risk of ESCC in the Kashmiri population.	('SCC', 'Gene', '6317', (75, 78))	('GSTP1', 'Gene', (4, 9))	('SCC', 'Gene', (75, 78))	('related', 'Reg', (51, 58))	('rs1695 A/G', 'Var', (10, 20))	('rs1695', 'Mutation', 'rs1695', (10, 16))	('GSTP1', 'Gene', '2950', (4, 9))
412043	30665373	Similarly, GSTP1 rs1695 may be an independent risk factor for ESCC in Western populations.	('SCC', 'Gene', (63, 66))	('GSTP1', 'Gene', (11, 16))	('rs1695', 'Var', (17, 23))	('SCC', 'Gene', '6317', (63, 66))	('rs1695', 'Mutation', 'rs1695', (17, 23))	('GSTP1', 'Gene', '2950', (11, 16))	('risk', 'Reg', (46, 50))
412045	30665373	Therefore, a meta-analysis was required to comprehensively evaluate the role of the GSTP1 rs1695 A/G polymorphism in ESCC risk.	('GSTP1', 'Gene', '2950', (84, 89))	('SCC', 'Gene', (118, 121))	('SCC', 'Gene', '6317', (118, 121))	('rs1695 A/G', 'Var', (90, 100))	('GSTP1', 'Gene', (84, 89))	('rs1695', 'Mutation', 'rs1695', (90, 96))
412046	30665373	Herein, we recruited 15 case-control studies involving 1934 cases and 3951 controls and performed a new meta-analysis to examine the association between the GSTP1 rs1695 A/G polymorphism and ESCC susceptibility.	('rs1695', 'Mutation', 'rs1695', (163, 169))	('GSTP1', 'Gene', (157, 162))	('association', 'Interaction', (133, 144))	('SCC', 'Gene', '6317', (192, 195))	('GSTP1', 'Gene', '2950', (157, 162))	('rs1695 A/G', 'Var', (163, 173))	('SCC', 'Gene', (192, 195))
412048	30665373	Similarly, inconsistent results regarding an association between the GSTP1 rs1695 A/G polymorphism and LSCC risk have been reported in different races and geographical locations.	('rs1695 A/G', 'Var', (75, 85))	('rs1695', 'Mutation', 'rs1695', (75, 81))	('SCC', 'Gene', (104, 107))	('GSTP1', 'Gene', (69, 74))	('SCC', 'Gene', '6317', (104, 107))	('GSTP1', 'Gene', '2950', (69, 74))
412049	30665373	Here, we failed to detect a positive correlation between GSTP1 rs1695 and LSCC susceptibility, consistent with the prior meta-analysis of Feng in 2013 and Xu in 2014.	('rs1695', 'Mutation', 'rs1695', (63, 69))	('GSTP1', 'Gene', (57, 62))	('SCC', 'Gene', '6317', (75, 78))	('rs1695', 'Var', (63, 69))	('GSTP1', 'Gene', '2950', (57, 62))	('SCC', 'Gene', (75, 78))
412051	30665373	enrolled 28 case-control studies to perform a meta-analysis regarding the genetic effect of the GSTP1 rs1695 A/G polymorphism on overall head and neck cancer.	('neck cancer', 'Disease', 'MESH:D006258', (146, 157))	('neck cancer', 'Disease', (146, 157))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('rs1695 A/G', 'Var', (102, 112))	('GSTP1', 'Gene', (96, 101))	('rs1695', 'Mutation', 'rs1695', (102, 108))	('GSTP1', 'Gene', '2950', (96, 101))	('head and neck cancer', 'Phenotype', 'HP:0012288', (137, 157))
412052	30665373	The authors were unable to identify a positive association between the GSTP1 rs1695 A/G polymorphism and the risk of overall head and neck cancer.	('GSTP1', 'Gene', (71, 76))	('rs1695 A/G', 'Var', (77, 87))	('GSTP1', 'Gene', '2950', (71, 76))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('rs1695', 'Mutation', 'rs1695', (77, 83))	('head and neck cancer', 'Phenotype', 'HP:0012288', (125, 145))	('neck cancer', 'Disease', 'MESH:D006258', (134, 145))	('neck cancer', 'Disease', (134, 145))
412053	30665373	Nevertheless, the potential role of GSTP1 rs1695 in the susceptibility to HNSCC was not assessed.	('SCC', 'Gene', (76, 79))	('GSTP1', 'Gene', '2950', (36, 41))	('rs1695', 'Var', (42, 48))	('SCC', 'Gene', '6317', (76, 79))	('rs1695', 'Mutation', 'rs1695', (42, 48))	('GSTP1', 'Gene', (36, 41))
412054	30665373	Therefore, we performed a subgroup meta-analysis of HNSCC involving 18 case-control studies, but did not identify an association between GSTP1 rs1695 and HNSCC risk.	('SCC', 'Gene', '6317', (54, 57))	('GSTP1', 'Gene', (137, 142))	('rs1695', 'Var', (143, 149))	('SCC', 'Gene', (156, 159))	('GSTP1', 'Gene', '2950', (137, 142))	('rs1695', 'Mutation', 'rs1695', (143, 149))	('SCC', 'Gene', (54, 57))	('SCC', 'Gene', '6317', (156, 159))
412056	30665373	Herein, we did not identify an association between the GSTP1 rs1695 A/G polymorphism and SSCC risk, consistent with the prior meta-analyses regarding the correlation between GSTP1 rs1695 and the susceptibility to cutaneous cancer in 2015.	('rs1695', 'Mutation', 'rs1695', (180, 186))	('cutaneous cancer', 'Disease', 'MESH:D009369', (213, 229))	('GSTP1', 'Gene', '2950', (55, 60))	('cutaneous cancer', 'Phenotype', 'HP:0008069', (213, 229))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('GSTP1', 'Gene', (174, 179))	('cutaneous cancer', 'Disease', (213, 229))	('SCC', 'Gene', (90, 93))	('SCC', 'Gene', '6317', (90, 93))	('GSTP1', 'Gene', (55, 60))	('rs1695', 'Mutation', 'rs1695', (61, 67))	('GSTP1', 'Gene', '2950', (174, 179))	('rs1695', 'Var', (61, 67))
412058	30665373	The rs1695 A/G polymorphism within the GSTP1 gene can result in the substitution of Ile (isoleucine) for Val (valine) at amino acid position 105, which may lower the cytosolic enzyme activity of GSTP1 protein.	('rs1695', 'Mutation', 'rs1695', (4, 10))	('GSTP1', 'Gene', (195, 200))	('result in', 'Reg', (54, 63))	('GSTP1', 'Gene', '2950', (39, 44))	('valine', 'Chemical', 'MESH:D014633', (110, 116))	('Val', 'Chemical', 'MESH:D014633', (105, 108))	('rs1695 A/G', 'Var', (4, 14))	('cytosolic enzyme activity', 'MPA', (166, 191))	('GSTP1', 'Gene', '2950', (195, 200))	('Ile (isoleucine', 'Chemical', 'MESH:D007532', (84, 99))	('lower', 'NegReg', (156, 161))	('GSTP1', 'Gene', (39, 44))
412059	30665373	Although significant associations were not obtained in our overall meta-analysis or subgroup analyses by pathological type, we cannot rule out the potential genetic effect of the GSTP1 rs1695 A/G polymorphism.	('rs1695', 'Mutation', 'rs1695', (185, 191))	('rs1695 A/G', 'Var', (185, 195))	('GSTP1', 'Gene', '2950', (179, 184))	('GSTP1', 'Gene', (179, 184))
412060	30665373	The currently available data of genotypic and allelic frequency from the on-line databases led us to only target the rs1695 polymorphism of the GSTP1 gene.	('GSTP1', 'Gene', '2950', (144, 149))	('GSTP1', 'Gene', (144, 149))	('rs1695', 'Var', (117, 123))	('rs1695', 'Mutation', 'rs1695', (117, 123))
412061	30665373	Other possible functional polymorphisms of the GSTP1 gene, such as rs1138272, or relative haplotypes will be important to examine in the future.	('rs1138272', 'Var', (67, 76))	('rs1138272', 'Mutation', 'rs1138272', (67, 76))	('GSTP1', 'Gene', '2950', (47, 52))	('GSTP1', 'Gene', (47, 52))
412062	30665373	We should also pay attention to the genetic relationship between GSTP1/GSTM1/GSTT1 polymorphisms and the risk of SCC.	('GSTT1', 'Gene', (77, 82))	('SCC', 'Gene', '6317', (113, 116))	('GSTP1', 'Gene', (65, 70))	('GSTM1', 'Gene', '2944', (71, 76))	('GSTT1', 'Gene', '2952', (77, 82))	('GSTM1', 'Gene', (71, 76))	('polymorphisms', 'Var', (83, 96))	('GSTP1', 'Gene', '2950', (65, 70))	('SCC', 'Gene', (113, 116))
412063	30665373	In general, based on the currently published data, the GSTP1 gene rs1695 polymorphism is not associated with the susceptibility to overall SCC diseases, including ESCC, HNSCC, LSCC, and skin SCC.	('SCC', 'Gene', (171, 174))	('rs1695 polymorphism', 'Var', (66, 85))	('SCC', 'Gene', '6317', (139, 142))	('GSTP1', 'Gene', '2950', (55, 60))	('SCC diseases', 'Disease', 'MESH:D004194', (139, 151))	('SCC', 'Gene', '6317', (164, 167))	('SCC', 'Gene', '6317', (171, 174))	('SCC', 'Gene', (177, 180))	('GSTP1', 'Gene', (55, 60))	('SCC diseases', 'Disease', (139, 151))	('SCC', 'Gene', (191, 194))	('SCC', 'Gene', (139, 142))	('SCC', 'Gene', '6317', (177, 180))	('rs1695', 'Mutation', 'rs1695', (66, 72))	('SCC', 'Gene', (164, 167))	('SCC', 'Gene', '6317', (191, 194))
412066	29673101	After the training (32 LSCC vs. 31 NCs), the testing (55 LSCC vs. 55 NCs), and the external validation (15 LSCC vs. 15 NCs) stages via qRT-PCR, a four-miRNA signature (miR-181a-5p, miR-21-5p, miR-106a-5p, and miR-93-5p) was identified for LSCC detection.	('miR-21-5p', 'Gene', '406997', (181, 190))	('miR-181a-5p', 'Var', (168, 179))	('LSCC', 'Phenotype', 'HP:0030359', (23, 27))	('LSCC', 'Phenotype', 'HP:0030359', (57, 61))	('miR-106a', 'Gene', '406899', (192, 200))	('LSCC', 'Phenotype', 'HP:0030359', (239, 243))	('miR-106a', 'Gene', (192, 200))	('miR-21-5p', 'Gene', (181, 190))	('LSCC', 'Phenotype', 'HP:0030359', (107, 111))	('miR-93-5p', 'Gene', '100126325', (209, 218))	('miR-93-5p', 'Gene', (209, 218))
412074	29673101	Previous researches indicate that deregulation of miRNAs is involved in initiation and progression of various cancers 7.	('cancers', 'Disease', (110, 117))	('miRNAs', 'Protein', (50, 56))	('deregulation', 'Var', (34, 46))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('cancers', 'Phenotype', 'HP:0002664', (110, 117))	('cancers', 'Disease', 'MESH:D009369', (110, 117))	('involved', 'Reg', (60, 68))
412077	29673101	For example, based on quantitative reverse transcription-polymerase chain reaction (qRT-PCR), we have developed a panel of six plasma miRNA biomarkers, including miR-19b-3p, miR-21-5p, miR-221-3p, miR-409-3p, miR-425-5p, and miR-584-5p for the specific diagnosis of AC 13.	('miR-221-3p', 'Var', (185, 195))	('miR-19b-3p', 'Var', (162, 172))	('miR-425-5p', 'Gene', (209, 219))	('miR-409-3p', 'Var', (197, 207))	('AC 13', 'Disease', (266, 271))	('miR-584-5p', 'Var', (225, 235))	('miR-425-5p', 'Gene', '100422898', (209, 219))	('miR-21-5p', 'Gene', (174, 183))	('miR-21-5p', 'Gene', '406997', (174, 183))
412078	29673101	Furthermore, we have previously identified a three-miRNA peripheral serum signature consisting of miR-93-5p, miR-106a-5p and miR-20a-5p for the detection of male patients with LSCC from normal controls (NCs) 14.	('patients', 'Species', '9606', (162, 170))	('miR-106a', 'Gene', '406899', (109, 117))	('miR-106a', 'Gene', (109, 117))	('miR-20a-5p', 'Var', (125, 135))	('miR-93-5p', 'Gene', '100126325', (98, 107))	('miR-93-5p', 'Gene', (98, 107))	('LSCC', 'Disease', (176, 180))	('LSCC', 'Phenotype', 'HP:0030359', (176, 180))
412098	29673101	Next, of those 12 miRNAs, consistent up-regulation of four miRNAs (miR-181a-5p, miR-21-5p, miR-106a-5p, and miR-93-5p) were detected in the plasma samples of all LSCC patients, with mean fold change (FC) >1.5 and P-value <0.05.	('miR-93-5p', 'Gene', '100126325', (108, 117))	('miR-93-5p', 'Gene', (108, 117))	('miR-106a', 'Gene', (91, 99))	('miR-21-5p', 'Gene', (80, 89))	('patients', 'Species', '9606', (167, 175))	('miR-21-5p', 'Gene', '406997', (80, 89))	('up-regulation', 'PosReg', (37, 50))	('miR-181a-5p', 'Var', (67, 78))	('LSCC', 'Disease', (162, 166))	('LSCC', 'Phenotype', 'HP:0030359', (162, 166))	('miR-106a', 'Gene', '406899', (91, 99))
412103	29673101	The AUCs for miR-181a-5p, miR-21-5p, miR-106a-5p, and miR-93-5p were 0.731 (95% confidence interval (CI): 0.661-0.800), 0.739 (95% CI: 0.670-0.808), 0.737 (95% CI: 0.667-0.807), and 0.687 (95% CI: 0.614-0.761), respectively (Fig.	('miR-106a', 'Gene', '406899', (37, 45))	('miR-106a', 'Gene', (37, 45))	('miR-93-5p', 'Gene', '100126325', (54, 63))	('miR-93-5p', 'Gene', (54, 63))	('miR-21-5p', 'Gene', (26, 35))	('miR-21-5p', 'Gene', '406997', (26, 35))	('miR-181a-5p', 'Var', (13, 24))
412105	29673101	The corresponding AUCs of TNM stages I, II, and III were 0.785, 0.786, and 0.784, respectively (Fig.	('TNM', 'Gene', '10178', (26, 29))	('0.786', 'Var', (64, 69))	('0.784', 'Var', (75, 80))	('TNM', 'Gene', (26, 29))
412109	29673101	However, contrary result showed that miR-181a-5p expressed statistically lower level in tumor samples.	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('lower', 'NegReg', (73, 78))	('tumor', 'Disease', (88, 93))	('miR-181a-5p', 'Var', (37, 48))
412110	29673101	But three of the four miRNAs (miR-21-5p, miR-106a-5p, and miR-93-5p) showed no significant result expect miR-181a-5p, which was found down-regulated in tumor tissues as well (Fig.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('miR-21-5p', 'Gene', '406997', (30, 39))	('miR-93-5p', 'Gene', '100126325', (58, 67))	('miR-93-5p', 'Gene', (58, 67))	('down-regulated', 'NegReg', (134, 148))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('miR-106a', 'Gene', '406899', (41, 49))	('tumor', 'Disease', (152, 157))	('miR-106a', 'Gene', (41, 49))	('miR-21-5p', 'Gene', (30, 39))	('miR-181a-5p', 'Var', (105, 116))
412111	29673101	The p-value for miR-181a-5p, miR-21-5p, and miR-106a-5p was 0.2701, 0.7624, and 0.1627, respectively.	('miR-106a', 'Gene', '406899', (44, 52))	('miR-106a', 'Gene', (44, 52))	('miR-21-5p', 'Gene', (29, 38))	('miR-21-5p', 'Gene', '406997', (29, 38))	('0.1627', 'Var', (80, 86))	('miR-181a-5p', 'Var', (16, 27))
412114	29673101	As a result, except miR-21-5p (P = 0.0012), miR-181a-5p, miR-106a-5p, and miR-93-5p have no significant difference between female patients and NCs (Fig.	('miR-21-5p', 'Gene', (20, 29))	('miR-21-5p', 'Gene', '406997', (20, 29))	('miR-106a', 'Gene', '406899', (57, 65))	('miR-106a', 'Gene', (57, 65))	('patients', 'Species', '9606', (130, 138))	('miR-93-5p', 'Gene', '100126325', (74, 83))	('miR-93-5p', 'Gene', (74, 83))	('miR-181a-5p', 'Var', (44, 55))
412120	29673101	Consequently, four up-regulated plasma miRNAs (miR-181a-5p, miR-21-5p, miR-106a-5p, and miR-93-5p) showed higher accuracy and were identified for LSCC screening.	('miR-181a-5p', 'Var', (47, 58))	('miR-106a', 'Gene', '406899', (71, 79))	('miR-106a', 'Gene', (71, 79))	('higher', 'PosReg', (106, 112))	('LSCC', 'Disease', (146, 150))	('up-regulated', 'PosReg', (19, 31))	('miR-93-5p', 'Gene', (88, 97))	('miR-93-5p', 'Gene', '100126325', (88, 97))	('LSCC', 'Phenotype', 'HP:0030359', (146, 150))	('miR-21-5p', 'Gene', (60, 69))	('miR-21-5p', 'Gene', '406997', (60, 69))
412136	29673101	Aberrantly increased miR-21-5p could promote lung tumorigenesis and inhibit cell apoptosis via the Ras/MEK/ERK and activate EGFR signaling pathway 33, 34.	('ERK', 'Gene', '5594', (107, 110))	('ERK', 'Gene', (107, 110))	('Aberrantly', 'Var', (0, 10))	('miR-21-5p', 'Gene', (21, 30))	('miR-21-5p', 'Gene', '406997', (21, 30))	('increased', 'PosReg', (11, 20))	('promote', 'PosReg', (37, 44))	('EGFR', 'Gene', '1956', (124, 128))	('inhibit', 'NegReg', (68, 75))	('MEK', 'Gene', (103, 106))	('EGFR', 'Gene', (124, 128))	('MEK', 'Gene', '5609', (103, 106))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('activate', 'PosReg', (115, 123))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('cell apoptosis', 'CPA', (76, 90))	('tumor', 'Disease', (50, 55))
412140	29673101	Unlike the deregulation of the three miRNAs above acting in one direction consistently in a variety of cancers, miR-181a-5p was found up-regulated in gastric cancer 42 and hepatocellular carcinoma 43, while down-regulated in other carcinoma, such as glioblastomas 44, breast cancer 45, and lymphocytic leukemia 46.	('cancers', 'Disease', 'MESH:D009369', (103, 110))	('carcinoma', 'Phenotype', 'HP:0030731', (231, 240))	('gastric cancer', 'Disease', (150, 164))	('leukemia', 'Phenotype', 'HP:0001909', (302, 310))	('carcinoma', 'Disease', (231, 240))	('breast cancer', 'Phenotype', 'HP:0003002', (268, 281))	('up-regulated', 'PosReg', (134, 146))	('down-regulated', 'NegReg', (207, 221))	('glioblastomas', 'Phenotype', 'HP:0012174', (250, 263))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (172, 196))	('carcinoma', 'Disease', 'MESH:D002277', (187, 196))	('breast cancer', 'Disease', 'MESH:D001943', (268, 281))	('breast cancer', 'Disease', (268, 281))	('gastric cancer', 'Disease', 'MESH:D013274', (150, 164))	('lymphocytic leukemia', 'Disease', (290, 310))	('cancers', 'Phenotype', 'HP:0002664', (103, 110))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('cancers', 'Disease', (103, 110))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (172, 196))	('carcinoma', 'Disease', 'MESH:D002277', (231, 240))	('glioblastomas', 'Disease', (250, 263))	('gastric cancer', 'Phenotype', 'HP:0012126', (150, 164))	('miR-181a-5p', 'Var', (112, 123))	('glioblastomas', 'Disease', 'MESH:D005909', (250, 263))	('cancer', 'Phenotype', 'HP:0002664', (275, 281))	('carcinoma', 'Phenotype', 'HP:0030731', (187, 196))	('hepatocellular carcinoma', 'Disease', (172, 196))	('lymphocytic leukemia', 'Disease', 'MESH:D007945', (290, 310))	('carcinoma', 'Disease', (187, 196))
412143	29673101	The Hippo pathway can regulate organ size in diverse species, whereas deregulation of the pathway may induce tumors and occur in a broad range of carcinomas, including lung cancer 50.	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('occur', 'Reg', (120, 125))	('tumors', 'Disease', 'MESH:D009369', (109, 115))	('induce', 'PosReg', (102, 108))	('organ', 'MPA', (31, 36))	('lung cancer', 'Disease', (168, 179))	('regulate', 'Reg', (22, 30))	('lung cancer', 'Phenotype', 'HP:0100526', (168, 179))	('deregulation', 'Var', (70, 82))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('carcinomas', 'Phenotype', 'HP:0030731', (146, 156))	('carcinomas', 'Disease', (146, 156))	('carcinomas', 'Disease', 'MESH:D002277', (146, 156))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('lung cancer', 'Disease', 'MESH:D008175', (168, 179))	('tumors', 'Disease', (109, 115))
412154	29673101	MiR-181a-5p was found down-regulated in NSCLC tissues and significantly inhibited NSCLC by targeting oncogene KRAS in Ma's study 55.	('NSCLC', 'Disease', 'MESH:D002289', (40, 45))	('down-regulated', 'NegReg', (22, 36))	('MiR-181a-5p', 'Var', (0, 11))	('NSCLC', 'Phenotype', 'HP:0030358', (82, 87))	('targeting', 'Reg', (91, 100))	('KRAS', 'Gene', '3845', (110, 114))	('NSCLC', 'Phenotype', 'HP:0030358', (40, 45))	('inhibited', 'NegReg', (72, 81))	('NSCLC', 'Disease', (40, 45))	('NSCLC', 'Disease', (82, 87))	('KRAS', 'Gene', (110, 114))	('NSCLC', 'Disease', 'MESH:D002289', (82, 87))
412155	29673101	In addition, by analyzing the miRNA profiles of male LSCC patients based on TCGA dataset, the reduced expression of miR-181a-5p was in accordance with our finding in tissue while the other three miRNAs showed no difference.	('LSCC', 'Disease', (53, 57))	('reduced', 'NegReg', (94, 101))	('expression', 'MPA', (102, 112))	('LSCC', 'Phenotype', 'HP:0030359', (53, 57))	('patients', 'Species', '9606', (58, 66))	('miR-181a-5p', 'Var', (116, 127))
412165	29673101	In summary, we established a four-miRNA signature (miR-181a-5p, miR-21-5p, miR-106a-5p, and miR-93-5p) in plasma associated with male LSCC patients.	('patients', 'Species', '9606', (139, 147))	('miR-106a', 'Gene', '406899', (75, 83))	('LSCC', 'Disease', (134, 138))	('miR-181a-5p', 'Var', (51, 62))	('miR-106a', 'Gene', (75, 83))	('miR-93-5p', 'Gene', '100126325', (92, 101))	('miR-93-5p', 'Gene', (92, 101))	('LSCC', 'Phenotype', 'HP:0030359', (134, 138))	('male LSCC', 'Disease', (129, 138))	('miR-21-5p', 'Gene', (64, 73))	('miR-21-5p', 'Gene', '406997', (64, 73))
412168	25907283	In this study, we identified MARK2 as frequently disrupted by DNA hypomethylation and copy gain, resulting in concordant overexpression in independent lung tumor cohorts and we demonstrate a role for MARK2 in lung tumor biology.	('lung tumor', 'Phenotype', 'HP:0100526', (209, 219))	('copy gain', 'Var', (86, 95))	('lung tumor', 'Phenotype', 'HP:0100526', (151, 161))	('expression', 'Species', '29278', (125, 135))	('MARK2', 'Gene', '2011', (200, 205))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('lung tumor', 'Disease', (209, 219))	('MARK2', 'Gene', (29, 34))	('MARK2', 'Gene', '2011', (29, 34))	('MARK2', 'Gene', (200, 205))	('lung tumor', 'Disease', 'MESH:D008175', (209, 219))	('overexpression', 'PosReg', (121, 135))	('lung tumor', 'Disease', (151, 161))	('lung tumor', 'Disease', 'MESH:D008175', (151, 161))
412176	25907283	Although progress has been made over the last decade in identifying actionable mutations driving a small percentage of lung tumors, much remains to be understood about lung cancer biology.	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('lung cancer', 'Disease', (168, 179))	('lung cancer', 'Phenotype', 'HP:0100526', (168, 179))	('lung tumors', 'Phenotype', 'HP:0100526', (119, 130))	('lung tumors', 'Disease', (119, 130))	('lung tumor', 'Phenotype', 'HP:0100526', (119, 129))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('lung cancer', 'Disease', 'MESH:D008175', (168, 179))	('lung tumors', 'Disease', 'MESH:D008175', (119, 130))	('mutations', 'Var', (79, 88))
412186	25907283	In the BCCRC cohort, genetic alterations were defined relative to patient matched non-malignant tissue, whereas alterations in TCGA tumors were defined with reference to the beta value median (DNA methylation) and RSEM distribution (mRNA expression: RNA-Seq relative abundance estimation by Expectation-Maximization) of available normal tissues (125 with methylation and 108 cases with RNAseq).	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('patient', 'Species', '9606', (66, 73))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('expression', 'Species', '29278', (238, 248))	('tumors', 'Disease', (132, 138))	('methylation', 'Var', (355, 366))	('tumors', 'Disease', 'MESH:D009369', (132, 138))
412193	25907283	MARK2 levels were modulated in cell lines using stable lentiviral shRNA constructs and a tetracycline inducible expression system using a non-tagged wild-type MARK2 expression vector or a kinase-dead MARK2 (T208A/S212A) mutant expression vector.	('MARK2', 'Gene', (0, 5))	('S212A', 'Mutation', 'p.S212A', (213, 218))	('T208A', 'Var', (207, 212))	('expression', 'Species', '29278', (165, 175))	('MARK2', 'Gene', '2011', (159, 164))	('expression', 'Species', '29278', (227, 237))	('MARK2', 'Gene', '2011', (200, 205))	('MARK2', 'Gene', (159, 164))	('MARK2', 'Gene', (200, 205))	('T208A', 'SUBSTITUTION', 'None', (207, 212))	('expression', 'Species', '29278', (112, 122))	('MARK2', 'Gene', '2011', (0, 5))	('tetracycline', 'Chemical', 'MESH:D013752', (89, 101))
412195	25907283	To investigate cancer pathways associated with MARK2, transcription factor reporter assays were performed using the Cignal Finder Cancer 10-Pathway Reporter assay which assesses: WNT, NOTCH, p53, TGFbeta, E2F, NFkappaB, Myc/Max, HIF1A, ERK, and JNK.	('Cancer', 'Disease', (130, 136))	('Cancer', 'Disease', 'MESH:D009369', (130, 136))	('cancer', 'Disease', (15, 21))	('cancer', 'Disease', 'MESH:D009369', (15, 21))	('Cancer', 'Phenotype', 'HP:0002664', (130, 136))	('E2F', 'Var', (205, 208))	('MARK2', 'Gene', '2011', (47, 52))	('MARK2', 'Gene', (47, 52))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))
412200	25907283	Cells resuspended in PBS containing propidium iodide (0.02 mg/ml) and RNase A (0.05 mg/ml) were left 30 min at room temperature in the dark and cellular fluorescence was measured using a FACSCanto (Becton-Dickinson).	('cellular fluorescence', 'MPA', (144, 165))	('0.02 mg/ml', 'Var', (54, 64))	('propidium iodide', 'Chemical', 'MESH:D011419', (36, 52))	('PBS', 'Chemical', 'MESH:D007854', (21, 24))	('0.05', 'Var', (79, 83))
412202	25907283	Pre-ranked gene set enrichment analyses (GSEA) were performed on gene expression data generated for PLKO and shMARK2 cell lines (H1650, H1993, H1693).	('MARK2', 'Gene', '2011', (111, 116))	('expression', 'Species', '29278', (70, 80))	('H1693', 'CellLine', 'CVCL:1488', (143, 148))	('MARK2', 'Gene', (111, 116))	('H1693', 'Var', (143, 148))	('H1650', 'Var', (129, 134))	('GSEA', 'Chemical', '-', (41, 45))	('H1993', 'CellLine', 'CVCL:1512', (136, 141))	('H1650', 'CellLine', 'CVCL:1483', (129, 134))
412211	25907283	We observed a high frequency of hypomethylation (33.8%) and copy number gain (20.8%) with 30% of tumors displaying concurrent and significantly correlated copy number gain or hypomethylation and overexpression (Fig.1A-C, Supplementary Table 2).	('expression', 'Species', '29278', (199, 209))	('hypomethylation', 'Var', (175, 190))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('overexpression', 'PosReg', (195, 209))	('hypomethylation', 'Var', (32, 47))	('tumors', 'Disease', (97, 103))	('copy number', 'Var', (155, 166))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('copy', 'MPA', (60, 64))	('tumors', 'Disease', 'MESH:D009369', (97, 103))	('gain', 'PosReg', (167, 171))
412212	25907283	In the fraction of tumors not harboring copy number gains or hypomethylation alterations, we suspect MARK2 overexpression may be driven by alternative epigenetic mechanisms, such as miRNA or other non-coding RNAs, which we were unable to assess.	('tumors', 'Disease', (19, 25))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('copy number', 'Var', (40, 51))	('MARK2', 'Gene', '2011', (101, 106))	('expression', 'Species', '29278', (111, 121))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('MARK2', 'Gene', (101, 106))	('hypomethylation alterations', 'Var', (61, 88))	('overexpression', 'PosReg', (107, 121))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))
412216	25907283	At the DNA level, TCGA LUAD tumors displayed similar frequencies of MARK2 hypomethylation (27.8%), copy number gain (26.1%) and overexpression (50.9%) as the BCCRC cohort, validating our findings (Fig.1A&F).	('overexpression', 'PosReg', (128, 142))	('copy number', 'Var', (99, 110))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('gain', 'PosReg', (111, 115))	('LUAD tumors', 'Disease', 'MESH:D009369', (23, 34))	('LUAD tumors', 'Disease', (23, 34))	('expression', 'Species', '29278', (132, 142))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('MARK2', 'Gene', '2011', (68, 73))	('MARK2', 'Gene', (68, 73))
412217	25907283	While the 482 LUSC samples showed overexpression (60.8%) and hypomethylation (33.4%) frequencies similar to the two LUAD cohorts, copy number alterations of MARK2 were rare (4.6% showed gain) in LUSC (Fig.1A&F).	('expression', 'Species', '29278', (38, 48))	('MARK2', 'Gene', (157, 162))	('gain', 'PosReg', (186, 190))	('MARK2', 'Gene', '2011', (157, 162))	('copy number alterations', 'Var', (130, 153))	('LUSC', 'Disease', (195, 199))
412218	25907283	Examination of DNA sequence data revealed mutations to be a rare mechanism of MARK2 disruption in lung cancer (2/230 LUAD and 3/482 LUSC, TCGA data, Fig.1A).	('MARK2 disruption in lung cancer', 'Disease', 'MESH:D008175', (78, 109))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('lung cancer', 'Phenotype', 'HP:0100526', (98, 109))	('MARK2 disruption in lung cancer', 'Disease', (78, 109))	('mutations', 'Var', (42, 51))
412219	25907283	Taken together, these results demonstrate MARK2 is frequently overexpressed in NSCLC, irrespective of histological subtype, and that overexpression is likely mediated by DNA hypomethylation and to a lesser extent DNA copy gain.	('hypomethylation', 'Var', (174, 189))	('MARK2', 'Gene', '2011', (42, 47))	('MARK2', 'Gene', (42, 47))	('NSCLC', 'Disease', 'MESH:D002289', (79, 84))	('overexpressed', 'PosReg', (62, 75))	('NSCLC', 'Disease', (79, 84))	('expression', 'Species', '29278', (137, 147))
412221	25907283	To assess the phenotypic effects of MARK2 expression, we chose LUAD cell lines with high (H1693, H1650 and H1993) and low (H2228, H1395 and H1437) MARK2 protein expression (Fig.2A).	('expression', 'Species', '29278', (161, 171))	('H2228', 'Var', (123, 128))	('H1993', 'CellLine', 'CVCL:1512', (107, 112))	('expression', 'Species', '29278', (42, 52))	('MARK2', 'Gene', (147, 152))	('H1437', 'Var', (140, 145))	('H1693', 'CellLine', 'CVCL:1488', (90, 95))	('protein', 'Protein', (153, 160))	('H1650', 'Var', (97, 102))	('H1993', 'Var', (107, 112))	('H1650', 'CellLine', 'CVCL:1483', (97, 102))	('H1437', 'CellLine', 'CVCL:1472', (140, 145))	('H2228', 'CellLine', 'CVCL:1543', (123, 128))	('H1395', 'Var', (130, 135))	('MARK2', 'Gene', '2011', (36, 41))	('MARK2', 'Gene', (36, 41))	('H1693', 'Var', (90, 95))	('MARK2', 'Gene', '2011', (147, 152))
412222	25907283	MARK2 knockdown (shMARK2, efficiency shown in Fig.2B and Supplementary Fig.1&3) significantly decreased cell viability in all cell lines (Fig.2C); however, the cell lines expressing higher endogenous levels of MARK2 were more sensitive to knockdown than those with low expression.	('MARK2', 'Gene', (0, 5))	('expressing', 'PosReg', (171, 181))	('significantly', 'NegReg', (80, 93))	('expression', 'Species', '29278', (269, 279))	('MARK2', 'Gene', '2011', (210, 215))	('MARK2', 'Gene', (210, 215))	('decreased cell', 'CPA', (94, 108))	('MARK2', 'Gene', '2011', (19, 24))	('higher endogenous', 'MPA', (182, 199))	('MARK2', 'Gene', (19, 24))	('knockdown', 'Var', (6, 15))	('MARK2', 'Gene', '2011', (0, 5))
412225	25907283	Similar results were observed for colony formation assays in soft agar (CFSA), with knockdown significantly impairing anchorage-independent growth of all cell lines to similar extents, suggesting MARK2 may play a role in establishing anchorage-independent growth (Fig.2D).	('MARK2', 'Gene', '2011', (196, 201))	('MARK2', 'Gene', (196, 201))	('impairing', 'NegReg', (108, 117))	('knockdown', 'Var', (84, 93))	('anchorage-independent growth', 'CPA', (234, 262))	('anchorage-independent growth', 'CPA', (118, 146))
412228	25907283	As expected, in the absence of tetracycline, knockdown of MARK2 significantly decreased viability (Fig.2F).	('tetracycline', 'Chemical', 'MESH:D013752', (31, 43))	('MARK2', 'Gene', (58, 63))	('decreased', 'NegReg', (78, 87))	('viability', 'CPA', (88, 97))	('knockdown', 'Var', (45, 54))	('MARK2', 'Gene', '2011', (58, 63))
412229	25907283	Tetracycline-induced MARK2 expression abrogated the effect of knockdown and led to increased viability relative to LACZ controls, which showed no difference in cell viability upon exposure to tetracycline (Fig.2F).	('MARK2', 'Gene', '2011', (21, 26))	('MARK2', 'Gene', (21, 26))	('increased', 'PosReg', (83, 92))	('expression', 'Species', '29278', (27, 37))	('Tetracycline', 'Chemical', 'MESH:D013752', (0, 12))	('knockdown', 'MPA', (62, 71))	('viability', 'CPA', (93, 102))	('tetracycline', 'Chemical', 'MESH:D013752', (192, 204))	('expression', 'Var', (27, 37))	('abrogated', 'NegReg', (38, 47))
412232	25907283	Lastly, we aimed to determine whether the detrimental effect of MARK2 knockdown on lung cancer cell viability was dependent on its kinase activity.	('MARK2', 'Gene', (64, 69))	('lung cancer', 'Disease', 'MESH:D008175', (83, 94))	('knockdown', 'Var', (70, 79))	('lung cancer', 'Disease', (83, 94))	('lung cancer', 'Phenotype', 'HP:0100526', (83, 94))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('MARK2', 'Gene', '2011', (64, 69))
412235	25907283	In all three lines, the MARK2 kinase inhibitor failed to reduce cell viability below 50% of control cells, suggesting the dramatic reduction in cell viability upon MARK2 knockdown is not kinase-dependent (Fig.	('MARK2', 'Gene', '2011', (164, 169))	('reduction', 'NegReg', (131, 140))	('MARK2', 'Gene', (164, 169))	('knockdown', 'Var', (170, 179))	('MARK2', 'Gene', (24, 29))	('cell', 'MPA', (144, 148))	('MARK2', 'Gene', '2011', (24, 29))
412236	25907283	To confirm this observation, we assessed whether a kinase-dead form of MARK2 was capable of rescuing the shRNA-mediated MARK2 knockdown phenotype.	('MARK2', 'Gene', '2011', (71, 76))	('MARK2', 'Gene', (71, 76))	('knockdown', 'Var', (126, 135))	('MARK2', 'Gene', '2011', (120, 125))	('MARK2', 'Gene', (120, 125))
412237	25907283	We generated the well-characterized T208A/S212A kinase-dead MARK2 mutant.	('S212A', 'Mutation', 'p.S212A', (42, 47))	('T208A', 'Var', (36, 41))	('MARK2', 'Gene', '2011', (60, 65))	('T208A', 'SUBSTITUTION', 'None', (36, 41))	('MARK2', 'Gene', (60, 65))
412238	25907283	Non-synonymous mutations at the threonine 208 and serine 212 residues abrogate MARK2 kinase activity by preventing phosphorylation of MARK2, rendering its substrate cleft in an open conformation which prevents MARK2 catalytic activity.	('MARK2', 'Gene', '2011', (134, 139))	('serine', 'Chemical', 'MESH:D012694', (50, 56))	('abrogate', 'NegReg', (70, 78))	('MARK2', 'Gene', (79, 84))	('kinase', 'Enzyme', (85, 91))	('preventing', 'NegReg', (104, 114))	('MARK2', 'Gene', '2011', (210, 215))	('MARK2', 'Gene', (210, 215))	('threonine', 'Chemical', 'MESH:D013912', (32, 41))	('catalytic activity', 'MPA', (216, 234))	('phosphorylation', 'MPA', (115, 130))	('activity', 'MPA', (92, 100))	('serine 212', 'Var', (50, 60))	('MARK2', 'Gene', (134, 139))	('MARK2', 'Gene', '2011', (79, 84))	('prevents', 'NegReg', (201, 209))
412239	25907283	MTT assays were then conducted to assess cell viability in H1437 cells co-transduced with LACZ (control)/wild-type-MARK2/kinase-dead-MARK2 (T208A/S212A) and shMARK2.	('T208A', 'SUBSTITUTION', 'None', (140, 145))	('MARK2', 'Gene', '2011', (159, 164))	('S212A', 'Mutation', 'p.S212A', (146, 151))	('MARK2', 'Gene', '2011', (115, 120))	('T208A', 'Var', (140, 145))	('MTT', 'Chemical', 'MESH:C070243', (0, 3))	('MARK2', 'Gene', (159, 164))	('MARK2', 'Gene', (115, 120))	('MARK2', 'Gene', '2011', (133, 138))	('MARK2', 'Gene', (133, 138))	('H1437', 'CellLine', 'CVCL:1472', (59, 64))
412240	25907283	As previously shown (Fig.2C), MARK2 knockdown (shMARK2-LACZ) resulted in significantly reduced cell viability compared to control cells (PLKO-LACZ), however, both wild-type (shMARK2-WT) and kinase-dead mutant (shMARK2-MUT) cells showed significantly improved viability compared to cells with knockdown alone (shMARK2-LACZ), demonstrating the ability of both wild-type and kinase-dead MARK2 to rescue the knockdown phenotype (Fig.3B).	('MARK2', 'Gene', '2011', (384, 389))	('MARK2', 'Gene', '2011', (176, 181))	('MARK2', 'Gene', '2011', (311, 316))	('MARK2', 'Gene', (30, 35))	('MARK2', 'Gene', '2011', (49, 54))	('knockdown', 'Var', (36, 45))	('WT', 'Disease', 'MESH:C536751', (182, 184))	('viability', 'CPA', (259, 268))	('MARK2', 'Gene', '2011', (212, 217))	('cell viability', 'CPA', (95, 109))	('MARK2', 'Gene', (384, 389))	('MARK2', 'Gene', (176, 181))	('reduced', 'NegReg', (87, 94))	('MARK2', 'Gene', '2011', (30, 35))	('MARK2', 'Gene', (311, 316))	('MARK2', 'Gene', (49, 54))	('improved', 'PosReg', (250, 258))	('MARK2', 'Gene', (212, 217))	('mutant', 'Var', (202, 208))
412252	25907283	Since DNA repair was among the most significant gene sets and pathways associated with MARK2 in our analyses (Fig.4B, Supplementary Fig.4 and Supplementary Tables 4-6), we investigated whether MARK2 knockdown influenced DNA damage by assessing gammaH2AX levels, an indicator of impaired DNA damage response (DDR).	('MARK2', 'Gene', '2011', (87, 92))	('assessing', 'Reg', (234, 243))	('MARK2', 'Gene', (87, 92))	('influenced', 'Reg', (209, 219))	('gammaH2AX levels', 'MPA', (244, 260))	('MARK2', 'Gene', '2011', (193, 198))	('MARK2', 'Gene', (193, 198))	('gammaH2AX', 'Chemical', '-', (244, 253))	('knockdown', 'Var', (199, 208))	('DNA damage', 'MPA', (220, 230))
412253	25907283	Indeed, we observed an increase of gammaH2AX in MARK2 knockdown cells compared to controls, providing direct evidence of a potential role for MARK2 in DDR (Fig.4C).	('MARK2', 'Gene', '2011', (48, 53))	('MARK2', 'Gene', (48, 53))	('knockdown', 'Var', (54, 63))	('MARK2', 'Gene', '2011', (142, 147))	('MARK2', 'Gene', (142, 147))	('increase', 'PosReg', (23, 31))	('gammaH2AX', 'Protein', (35, 44))	('gammaH2AX', 'Chemical', '-', (35, 44))
412254	25907283	Our observations of impaired DDR upon MARK2 knockdown and in MARK2 lowly expressing tumors combined with a previously described association of MARK2 expression with cisplatin sensitivity prompted us to investigate the potential clinical relevance of MARK2 in the context of lung cancer treatment with cisplatin - a DNA damaging agent and standard first line chemotherapy for the treatment of NSCLC.	('MARK2', 'Gene', (143, 148))	('lung cancer', 'Phenotype', 'HP:0100526', (274, 285))	('MARK2', 'Gene', (38, 43))	('expression', 'Species', '29278', (149, 159))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('impaired', 'NegReg', (20, 28))	('MARK2', 'Gene', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('NSCLC', 'Disease', 'MESH:D002289', (392, 397))	('cancer', 'Phenotype', 'HP:0002664', (279, 285))	('cisplatin', 'Chemical', 'MESH:D002945', (301, 310))	('knockdown', 'Var', (44, 53))	('tumors', 'Disease', (84, 90))	('DDR', 'MPA', (29, 32))	('cisplatin', 'Chemical', 'MESH:D002945', (165, 174))	('MARK2', 'Gene', (250, 255))	('MARK2', 'Gene', '2011', (38, 43))	('lung cancer', 'Disease', (274, 285))	('MARK2', 'Gene', '2011', (143, 148))	('NSCLC', 'Disease', (392, 397))	('MARK2', 'Gene', '2011', (61, 66))	('tumors', 'Disease', 'MESH:D009369', (84, 90))	('lung cancer', 'Disease', 'MESH:D008175', (274, 285))	('MARK2', 'Gene', '2011', (250, 255))
412255	25907283	Dose-response assays revealed 2 out of 3 lines with low MARK2 expression (H2228 and H1437) had significantly lower IC50s than the 3 cell lines with high MARK2 expression (p=0.012, Supplementary Figure 5 and Supplementary Table 7).	('IC50s', 'MPA', (115, 120))	('lower', 'NegReg', (109, 114))	('H2228', 'CellLine', 'CVCL:1543', (74, 79))	('expression', 'Species', '29278', (62, 72))	('H1437', 'CellLine', 'CVCL:1472', (84, 89))	('MARK2', 'Gene', (56, 61))	('MARK2', 'Gene', '2011', (56, 61))	('expression', 'Species', '29278', (159, 169))	('50s', 'Species', '1214577', (117, 120))	('MARK2', 'Gene', '2011', (153, 158))	('H2228', 'Var', (74, 79))	('MARK2', 'Gene', (153, 158))	('H1437', 'Var', (84, 89))
412258	25907283	Integration of LCCL expression and IC50 data from the Sanger drug sensitivity projects comparing cell lines with the highest (n=15) and lowest (n=15) MARK2 expression further validated our observations; LCCLs with high MARK2 expression had significantly higher cisplatin IC50 values than those with low expression (Fig.5B, p=1.45x10-2).	('high', 'Var', (214, 218))	('cisplatin', 'Chemical', 'MESH:D002945', (261, 270))	('MARK2', 'Gene', '2011', (219, 224))	('MARK2', 'Gene', (219, 224))	('higher', 'PosReg', (254, 260))	('expression', 'Species', '29278', (303, 313))	('expression', 'Species', '29278', (156, 166))	('drug sensitivity', 'Phenotype', 'HP:0020174', (61, 77))	('expression', 'Species', '29278', (225, 235))	('MARK2', 'Gene', '2011', (150, 155))	('MARK2', 'Gene', (150, 155))	('cisplatin IC50 values', 'MPA', (261, 282))	('expression', 'Species', '29278', (20, 30))
412262	25907283	Furthermore, we noted that there was an increased population of cells in the G2/M phase in high compared to low MARK2 expressing cells.	('high', 'Var', (91, 95))	('MARK2', 'Gene', '2011', (112, 117))	('MARK2', 'Gene', (112, 117))	('G2/M phase', 'CPA', (77, 87))
412263	25907283	Taken together, these results suggest that the reduced DNA damage sustained in high MARK2 expressing cells likely contributes to the increased resistance of these cell lines to cisplatin, highlighting the potential clinical relevance of MARK2 expression.	('expression', 'Species', '29278', (243, 253))	('MARK2', 'Gene', '2011', (237, 242))	('DNA damage', 'MPA', (55, 65))	('MARK2', 'Gene', (237, 242))	('MARK2', 'Gene', '2011', (84, 89))	('cisplatin', 'Chemical', 'MESH:D002945', (177, 186))	('high', 'Var', (79, 83))	('MARK2', 'Gene', (84, 89))	('resistance', 'MPA', (143, 153))	('increased', 'PosReg', (133, 142))	('reduced', 'NegReg', (47, 54))
412266	25907283	Moreover, its overexpression appears to be mediated by DNA alterations, specifically DNA hypomethylation and to a lesser extent DNA copy gains.	('overexpression', 'PosReg', (14, 28))	('hypomethylation', 'Var', (89, 104))	('expression', 'Species', '29278', (18, 28))
412269	25907283	Treatment of cells exhibiting the highest MARK2 levels (H1993, H1650, and H1693) with an ATP competitive inhibitor specific for MARK2's kinase activity revealed only a small reduction in cell viability, as opposed to the large effect we observed upon shRNA-mediated knockdown.	('H1693', 'Var', (74, 79))	('MARK2', 'Gene', '2011', (42, 47))	('MARK2', 'Gene', (42, 47))	('ATP', 'Chemical', 'MESH:D000255', (89, 92))	('H1650', 'Var', (63, 68))	('H1993', 'CellLine', 'CVCL:1512', (56, 61))	('H1693', 'CellLine', 'CVCL:1488', (74, 79))	('MARK2', 'Gene', '2011', (128, 133))	('H1650', 'CellLine', 'CVCL:1483', (63, 68))	('cell viability', 'CPA', (187, 201))	('MARK2', 'Gene', (128, 133))	('reduction', 'NegReg', (174, 183))
412271	25907283	To address this hypothesis, we assessed whether a kinase-dead mutant form of MARK2 (T208A/S212A) was capable of rescuing the drastically reduced viability we observed upon shRNA-mediated MARK2 knockdown.	('viability', 'MPA', (145, 154))	('T208A', 'Var', (84, 89))	('MARK2', 'Gene', '2011', (187, 192))	('S212A', 'Mutation', 'p.S212A', (90, 95))	('MARK2', 'Gene', (187, 192))	('T208A', 'SUBSTITUTION', 'None', (84, 89))	('MARK2', 'Gene', '2011', (77, 82))	('MARK2', 'Gene', (77, 82))	('reduced', 'NegReg', (137, 144))
412285	25907283	Although we validated the negative correlation between MARK2 expression and NF-kappaB activation by assessing p65 levels, none of the NF-kappaB pathway components upstream of p65 were altered upon manipulating MARK2 expression, suggesting MARK2 does not function through the canonical NF-kappaB pathway.	('manipulating', 'Var', (197, 209))	('expression', 'Species', '29278', (216, 226))	('p65 levels', 'MPA', (110, 120))	('MARK2', 'Gene', (210, 215))	('MARK2', 'Gene', '2011', (210, 215))	('MARK2', 'Gene', (55, 60))	('MARK2', 'Gene', '2011', (55, 60))	('MARK2', 'Gene', '2011', (239, 244))	('altered', 'Reg', (184, 191))	('MARK2', 'Gene', (239, 244))	('expression', 'Species', '29278', (61, 71))
412287	25907283	Our experiments revealed an increase in NF-kappaB activation upon MARK2 knockdown, and the latter significantly reduced lung cancer cell viability.	('MARK2', 'Gene', '2011', (66, 71))	('lung cancer', 'Disease', (120, 131))	('lung cancer', 'Phenotype', 'HP:0100526', (120, 131))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('MARK2', 'Gene', (66, 71))	('activation', 'PosReg', (50, 60))	('NF-kappaB', 'Protein', (40, 49))	('reduced', 'NegReg', (112, 119))	('lung cancer', 'Disease', 'MESH:D008175', (120, 131))	('knockdown', 'Var', (72, 81))	('increase', 'PosReg', (28, 36))
412288	25907283	Thus, it is possible that in the context of MARK2 knockdown/DNA damage, NF-kappaB behaves as a tumor suppressor and consequently, could potentially impair cell growth in MARK2 knockdown cells.	('tumor', 'Disease', (95, 100))	('MARK2', 'Gene', '2011', (170, 175))	('MARK2', 'Gene', (170, 175))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('impair', 'NegReg', (148, 154))	('knockdown/DNA', 'Var', (50, 63))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('NF-kappaB', 'Gene', (72, 81))	('MARK2', 'Gene', '2011', (44, 49))	('MARK2', 'Gene', (44, 49))	('cell growth', 'CPA', (155, 166))
412295	25907283	In summary, we describe for the first time highly frequent DNA and RNA level disruption of MARK2 in clinical NSCLC cases, and provide multi-faceted evidence supporting a novel potential role for MARK2 in the DNA damage response pathway as well as cisplatin sensitivity.	('MARK2', 'Gene', (195, 200))	('NSCLC', 'Disease', 'MESH:D002289', (109, 114))	('disruption', 'Var', (77, 87))	('cisplatin', 'Chemical', 'MESH:D002945', (247, 256))	('DNA damage response pathway', 'Pathway', (208, 235))	('MARK2', 'Gene', (91, 96))	('MARK2', 'Gene', '2011', (195, 200))	('MARK2', 'Gene', '2011', (91, 96))	('NSCLC', 'Disease', (109, 114))
412296	25907283	BCCRC British Columbia Cancer Research Centre CDC25 cell division cycle 25A E2F E2 transcription factor HDAC Histone deacetylase H2AX histone 2A family member X LCCL lung cancer cell line LUAD lung adenocarcinoma LUSC squamous cell carcinoma MARK Microtubule affinity-regulating kinase Max Myc-Associated Factor X Myc Myelocytomatosis oncogene cellular homolog NF-kappaB Nuclear factor kappa B NSCLC Non-small cell lung cancer RT-qPCR Real time quantitative polymerase chain reaction sh short hairpin RNA DDR DNA damage response TCGA The Cancer Genome Atlas TP53 tumor protein p53 We describe for the first time highly frequent DNA and RNA level disruption of MARK2 in clinical NSCLC cases, and provide evidence supporting a novel role for MARK2 in affecting the oncogenic properties of several lung tumor phenotypes including response to the DNA damaging chemotherapeutic agent, cisplatin.	('Non-small cell lung cancer', 'Disease', (400, 426))	('Cancer', 'Disease', (23, 29))	('Cancer', 'Disease', (538, 544))	('MARK', 'Gene', (660, 664))	('TP53', 'Gene', '7157', (558, 562))	('response to', 'MPA', (827, 838))	('carcinoma', 'Phenotype', 'HP:0030731', (232, 241))	('squamous cell carcinoma', 'Disease', (218, 241))	('tumor', 'Phenotype', 'HP:0002664', (563, 568))	('lung cancer', 'Disease', (166, 177))	('tumor', 'Phenotype', 'HP:0002664', (800, 805))	('MARK', 'Gene', '4139', (740, 744))	('lung cancer', 'Disease', 'MESH:D008175', (415, 426))	('MARK2', 'Gene', '2011', (740, 745))	('MARK2', 'Gene', '2011', (660, 665))	('Non-small cell lung cancer', 'Phenotype', 'HP:0030358', (400, 426))	('NSCLC', 'Disease', 'MESH:D002289', (394, 399))	('lung tumor', 'Disease', (795, 805))	('MARK', 'Gene', (740, 744))	('lung adenocarcinoma', 'Disease', (193, 212))	('cisplatin', 'Chemical', 'MESH:D002945', (880, 889))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (538, 557))	('Cancer', 'Disease', 'MESH:D009369', (23, 29))	('lung cancer', 'Phenotype', 'HP:0100526', (415, 426))	('Cancer', 'Disease', 'MESH:D009369', (538, 544))	('cancer', 'Phenotype', 'HP:0002664', (420, 426))	('lung tumor', 'Phenotype', 'HP:0100526', (795, 805))	('NSCLC', 'Disease', 'MESH:D002289', (678, 683))	('NSCLC', 'Disease', (394, 399))	('Cancer Genome Atlas', 'Disease', (538, 557))	('lung cancer', 'Disease', 'MESH:D008175', (166, 177))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (218, 241))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (404, 426))	('NSCLC', 'Disease', (678, 683))	('TP53', 'Gene', (558, 562))	('disruption', 'Var', (646, 656))	('affecting', 'Reg', (749, 758))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (193, 212))	('lung cancer', 'Phenotype', 'HP:0100526', (166, 177))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('Non-small cell lung cancer', 'Disease', 'MESH:D002289', (400, 426))	('Myelocytomatosis', 'Disease', (318, 334))	('tumor', 'Disease', (800, 805))	('MARK2', 'Gene', (740, 745))	('tumor', 'Disease', (563, 568))	('carcinoma', 'Phenotype', 'HP:0030731', (203, 212))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (193, 212))	('MARK2', 'Gene', (660, 665))	('lung tumor', 'Disease', 'MESH:D008175', (795, 805))	('MARK', 'Gene', '4139', (660, 664))	('Cancer', 'Phenotype', 'HP:0002664', (23, 29))	('Cancer', 'Phenotype', 'HP:0002664', (538, 544))	('tumor', 'Disease', 'MESH:D009369', (563, 568))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (218, 241))	('MARK', 'Gene', '4139', (242, 246))	('tumor', 'Disease', 'MESH:D009369', (800, 805))	('Myelocytomatosis', 'Disease', 'None', (318, 334))	('MARK', 'Gene', (242, 246))
412366	24699047	In addition, our results may clarify why VEGF blockage decreases the incidence of BM from lung adenocarcinoma, but not that of BM from lung squamous cell carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('lung adenocarcinoma', 'Disease', (90, 109))	('VEGF', 'Gene', '7422', (41, 45))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (90, 109))	('blockage', 'Var', (46, 54))	('decreases', 'NegReg', (55, 64))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (135, 163))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (140, 163))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (90, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (154, 163))	('VEGF', 'Gene', (41, 45))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (135, 163))	('lung squamous cell carcinoma', 'Disease', (135, 163))
412375	24699047	For the endoglin epitope retrieval, specimens were pre-treated with proteinase K (S3020, DAKO Cytomation, Glostrup, Denmark) at room temperature for 15 min, while the SMA antigen was unmasked by microwave oven pre-treatment in 10 mM, pH 6.0 sodium citrate buffer for 3 cycles x 5 min.	('sodium citrate', 'Chemical', 'MESH:D000077559', (241, 255))	('S3020', 'Var', (82, 87))	('endoglin', 'Gene', (8, 16))	('endoglin', 'Gene', '2022', (8, 16))
412395	24619077	Prevalence of human papillomavirus among oesophageal squamous cell carcinoma cases: systematic review and meta-analysis Oncogenic human papillomavirus (HPV) has been hypothesised as a risk factor for oesophageal squamous cell carcinoma (OSCC), but aetiological research has been limited by the varying methodology used for establishing HPV prevalence.	('HPV', 'Species', '10566', (336, 339))	('oesophageal squamous cell carcinoma', 'Disease', (41, 76))	('human papillomavirus', 'Species', '10566', (130, 150))	('oesophageal squamous cell carcinoma', 'Disease', (200, 235))	('HPV', 'Species', '10566', (152, 155))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (53, 76))	('human papillomavirus', 'Species', '10566', (14, 34))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('oesophageal squamous cell carcinoma', 'Disease', 'MESH:D002294', (41, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (226, 235))	('Oncogenic', 'Var', (120, 129))	('oesophageal squamous cell carcinoma', 'Disease', 'MESH:D002294', (200, 235))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (212, 235))
412420	24619077	The following rank order of sensitivity (from most to least sensitive), based on a meta-analysis of invasive cervical cancer, was assumed: SPF10, GP5+/6+, L1C1/2, MY09/11, PU1M/2R, GP5/6, L1, E6, E7, HPV-16 specific, and HPV-18 specific.	('GP5/6', 'Var', (181, 186))	('cancer', 'Disease', (118, 124))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('SPF10', 'Var', (139, 144))	('GP5+/6+', 'Var', (146, 153))	('L1C1/2', 'Var', (155, 161))	('HPV', 'Species', '10566', (200, 203))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('HPV', 'Species', '10566', (221, 224))	('PU1M/2R', 'Var', (172, 179))	('MY09/11', 'Var', (163, 170))	('HPV-16', 'Species', '333760', (200, 206))
412452	24619077	The average prevalence of HPV (95% confidence interval (CI)) was 0.278 (95% CI: 0.233, 0.322) by PCR; 0.242 (95% CI: 0.157, 0.328) by ISH; 0.305 (95% CI: 0.160, 0.450) by immunohistochemistry; 0.321 (95% CI: 0.156, 0.486) by L1 serology; and 0.166 (95% CI: 0.097, 0.234) by Southern blot (Supplementary Table 2).	('HPV', 'Disease', (26, 29))	('0.305', 'Var', (139, 144))	('0.242', 'Var', (102, 107))	('HPV', 'Species', '10566', (26, 29))	('men', 'Species', '9606', (295, 298))
412454	24619077	The median prevalence of overall HPV positivity was 0.211 by PCR; 0.221 by ISH; 0.232 by immunohistochemistry; 0.275 by L1 serology; and 0.180 by Southern blot (Supplementary Table 2).	('0.232', 'Var', (80, 85))	('HPV', 'Species', '10566', (33, 36))	('HPV', 'Gene', (33, 36))	('men', 'Species', '9606', (167, 170))	('0.180', 'Var', (137, 142))
412459	24619077	HPV-16 prevalence was 0.185 (95% CI: 0.142, 0.228) for PCR; 0.255 (95% CI: 0.114, 0.397) for ISH; 0.359 (95% CI: -0.101, 0.819) for immunohistochemistry; 0.173 (95% CI: 0.087, 0.259) for L1 serology; and 0.187 (95% CI: 0.116, 0.259) for Southern blot.	('0.255', 'Var', (60, 65))	('PCR', 'Disease', (55, 58))	('HPV-16', 'Species', '333760', (0, 6))	('HPV-16', 'Gene', (0, 6))
412503	24619077	An association between HPV and OSCC is biologically plausible on the basis of (1) the close proximity and histologic similarities between oesophageal and oral squamous epithelium - suggesting that the oesophagus could be exposed to HPV in a similar fashion as the oral cavity and oropharynx; (2) the detection of HPV DNA in both benign oesophageal squamous cell papillomas and malignant OSCC tumour samples; (3) in vivo studies in cattle, showing that bovine papillomavirus leads to the development of papillomas, then to squamous cell carcinoma; and (4) in vitro experiments of human oesophageal epithelial cells where HPV-18 was shown to be an initiating factor in cancer transformation.	('papillomas', 'Disease', (362, 372))	('cancer', 'Disease', (667, 673))	('cattle', 'Species', '9913', (431, 437))	('malignant OSCC tumour', 'Disease', (377, 398))	('men', 'Species', '9606', (494, 497))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (522, 545))	('bovine papillomavirus', 'Species', '10571', (452, 473))	('cancer', 'Phenotype', 'HP:0002664', (667, 673))	('bovine', 'Var', (452, 458))	('HPV', 'Species', '10566', (313, 316))	('papillomas', 'Disease', 'MESH:D010212', (502, 512))	('HPV', 'Species', '10566', (232, 235))	('tumour', 'Phenotype', 'HP:0002664', (392, 398))	('papillomas', 'Phenotype', 'HP:0012740', (502, 512))	('human', 'Species', '9606', (579, 584))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (522, 545))	('papillomas', 'Disease', (502, 512))	('papillomavirus', 'Var', (459, 473))	('malignant OSCC tumour', 'Disease', 'MESH:D009369', (377, 398))	('HPV', 'Species', '10566', (620, 623))	('benign oesophageal squamous cell papillomas', 'Disease', (329, 372))	('cancer', 'Disease', 'MESH:D009369', (667, 673))	('men', 'Species', '9606', (570, 573))	('squamous cell papillomas', 'Phenotype', 'HP:0031021', (348, 372))	('squamous cell carcinoma', 'Disease', (522, 545))	('benign oesophageal squamous cell papillomas', 'Disease', 'MESH:D010212', (329, 372))	('papillomas', 'Disease', 'MESH:D010212', (362, 372))	('carcinoma', 'Phenotype', 'HP:0030731', (536, 545))	('oesophageal squamous cell papillomas', 'Phenotype', 'HP:0031463', (336, 372))	('papillomas', 'Phenotype', 'HP:0012740', (362, 372))	('HPV', 'Species', '10566', (23, 26))
412504	24619077	However, counterarguments have been suggested, including the lack of association between OSCC and immunosuppression or previous HPV-associated disease and wide variability in case-series report of HPV positivity in OSCC cases - ranging worldwide from over 70% positivity to 0%.	('OSCC', 'Disease', (215, 219))	('HPV', 'Species', '10566', (128, 131))	('HPV', 'Species', '10566', (197, 200))	('positivity', 'Var', (201, 211))	('HPV', 'Gene', (197, 200))	('men', 'Species', '9606', (20, 23))
412521	24619077	In summary, our results suggest that HPV prevalence in OSCC tumours is highest in Africa and Asia, especially in the regions of China with a high incidence of OSCC, and that high-risk HPV-16 is the most commonly identified HPV type in OSCC tumours.	('OSCC tumours', 'Disease', 'MESH:D009369', (235, 247))	('OSCC', 'Disease', (159, 163))	('HPV type in OSCC tumours', 'Disease', 'MESH:D030361', (223, 247))	('HPV', 'Species', '10566', (223, 226))	('tumour', 'Phenotype', 'HP:0002664', (240, 246))	('tumours', 'Phenotype', 'HP:0002664', (240, 247))	('HPV', 'Species', '10566', (184, 187))	('OSCC tumours', 'Disease', 'MESH:D009369', (55, 67))	('OSCC tumours', 'Disease', (55, 67))	('high-risk', 'Var', (174, 183))	('tumour', 'Phenotype', 'HP:0002664', (60, 66))	('HPV', 'Species', '10566', (37, 40))	('HPV-16', 'Species', '333760', (184, 190))	('HPV type in OSCC tumours', 'Disease', (223, 247))	('HPV', 'Gene', (37, 40))	('tumours', 'Phenotype', 'HP:0002664', (60, 67))
412543	33687056	The polymorphism rs17336700 of the PSMD7 gene is considered to be linked with ankylosing spondylitis.	('polymorphism rs17336700', 'Var', (4, 27))	('ankylosing spondylitis', 'Disease', 'MESH:D013167', (78, 100))	('linked', 'Reg', (66, 72))	('rs17336700', 'Mutation', 'rs17336700', (17, 27))	('PSMD7', 'Gene', (35, 40))	('ankylosing spondylitis', 'Disease', (78, 100))
412546	33687056	Down-regulated PSMD7 inhibits the expression of key cell cycle-related proteins and promotes the stability of p21 and p27 in breast cancer cells.	('p27', 'Gene', (118, 121))	('Down-regulated', 'Var', (0, 14))	('inhibits', 'NegReg', (21, 29))	('expression', 'MPA', (34, 44))	('p21', 'Gene', (110, 113))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('stability', 'MPA', (97, 106))	('breast cancer', 'Disease', 'MESH:D001943', (125, 138))	('p21', 'Gene', '644914', (110, 113))	('PSMD7', 'Gene', (15, 20))	('p27', 'Gene', '5715', (118, 121))	('breast cancer', 'Disease', (125, 138))	('breast cancer', 'Phenotype', 'HP:0003002', (125, 138))	('promotes', 'PosReg', (84, 92))
412575	33687056	As shown in Figure 1E,F, the IHC assays were performed by using antibodies CAB019379 and HPA056069, respectively.	('HPA', 'Disease', 'MESH:D010661', (89, 92))	('HPA', 'Disease', (89, 92))	('CAB019379', 'Var', (75, 84))
412582	33687056	As shown in Figure 2E,F,G, high expression of PSMD7 was correlated with an unfavorable prognosis of HNSCC patients (OS, P=0.0014; DSS, P=0.00078; PFI, P=0.014).	('HNSCC', 'Disease', (100, 105))	('HNSCC', 'Phenotype', 'HP:0012288', (100, 105))	('PSMD7', 'Gene', (46, 51))	('DSS', 'Gene', (130, 133))	('high expression', 'Var', (27, 42))	('patients', 'Species', '9606', (106, 114))	('DSS', 'Gene', '5376', (130, 133))	('HNSC', 'Phenotype', 'HP:0012288', (100, 104))	('correlated', 'Reg', (56, 66))
412594	33687056	As shown in Figure 4C, the infiltration levels of CD8 T cells, activated CD4 T cell, T cells follicular helper, Tregs, resting NK cells, monocytes and M1 macrophages were significantly increased in PSMD7-Low expression group.	('CD8', 'Gene', (50, 53))	('PSMD7-Low expression', 'Var', (198, 218))	('CD8', 'Gene', '925', (50, 53))	('infiltration levels', 'MPA', (27, 46))	('increased', 'PosReg', (185, 194))
412599	33687056	As shown in Figure 5, high expression of PSMD7 was significantly associated with poor prognosis in the HNSCC patient cohorts with all Tregs, all activated NK cell, decreased monocytes, enriched M0 macrophages, all M1 macrophages, all activated dendritic cells, enriched activated mast cells, decreased eosinophils and decreased neutrophils.	('HNSCC', 'Phenotype', 'HP:0012288', (103, 108))	('high expression', 'Var', (22, 37))	('eosinophils', 'MPA', (302, 313))	('patient', 'Species', '9606', (109, 116))	('decreased monocytes', 'Phenotype', 'HP:0012312', (164, 183))	('decreased', 'NegReg', (292, 301))	('PSMD7', 'Gene', (41, 46))	('neutrophils', 'MPA', (328, 339))	('decreased eosinophils', 'Phenotype', 'HP:0031891', (292, 313))	('HNSC', 'Phenotype', 'HP:0012288', (103, 107))	('decreased', 'NegReg', (318, 327))
412600	33687056	These findings indicated that high PSMD7 expression may influence prognosis of HNSCC patients partially through immune infiltration.	('HNSCC', 'Disease', (79, 84))	('high PSMD7', 'Var', (30, 40))	('immune infiltration', 'CPA', (112, 131))	('patients', 'Species', '9606', (85, 93))	('HNSC', 'Phenotype', 'HP:0012288', (79, 83))	('influence', 'Reg', (56, 65))	('HNSCC', 'Phenotype', 'HP:0012288', (79, 84))
412607	33687056	PSMD7 expression was correlated with various clinicopathological features, including tumor grade, population, HPV infection and TP53 mutation.	('tumor', 'Disease', (85, 90))	('mutation', 'Var', (133, 141))	('TP53', 'Gene', '7157', (128, 132))	('TP53', 'Gene', (128, 132))	('HPV infection', 'Disease', 'MESH:D030361', (110, 123))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('correlated', 'Reg', (21, 31))	('HPV infection', 'Disease', (110, 123))
412609	33687056	High expression of PSMD7 was significantly associated with poor prognostic outcomes, including OS, DSS and PFI.	('High', 'Var', (0, 4))	('DSS', 'Gene', (99, 102))	('DSS', 'Gene', '5376', (99, 102))	('PFI', 'Disease', (107, 110))	('associated', 'Reg', (43, 53))	('PSMD7', 'Gene', (19, 24))
412612	33687056	demonstrated that PSMD7 level was significantly up-regulated in breast cancer tissues using IHC analysis, and high expression of PSMD7 was associated with poor survival of patients with breast cancer.	('breast cancer', 'Phenotype', 'HP:0003002', (64, 77))	('up-regulated', 'PosReg', (48, 60))	('PSMD7 level', 'MPA', (18, 29))	('breast cancer', 'Disease', 'MESH:D001943', (186, 199))	('associated', 'Reg', (139, 149))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('breast cancer', 'Disease', (186, 199))	('patients', 'Species', '9606', (172, 180))	('high expression', 'Var', (110, 125))	('breast cancer', 'Phenotype', 'HP:0003002', (186, 199))	('PSMD7', 'Gene', (129, 134))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('breast cancer', 'Disease', 'MESH:D001943', (64, 77))	('poor', 'NegReg', (155, 159))	('breast cancer', 'Disease', (64, 77))
412613	33687056	has reported that knockdown of PSMD7-induced ESCC apoptosis via a caspase-3 dependent pathway and decreased cells proliferation.	('knockdown', 'Var', (18, 27))	('PSMD7-induced', 'Gene', (31, 44))	('caspase-3', 'Gene', '836', (66, 75))	('ESCC', 'Disease', (45, 49))	('cells proliferation', 'CPA', (108, 127))	('decreased', 'NegReg', (98, 107))	('caspase-3', 'Gene', (66, 75))	('apoptosis', 'CPA', (50, 59))
412615	33687056	Similarly, our findings indicated that PSMD7 was found highly expressed in both BC and ESCC tissues than in corresponding normal tissues, and increased PSMD7 suggested an inferior prognosis in patients with BC or ESCC (results not shown).	('patients', 'Species', '9606', (193, 201))	('increased', 'PosReg', (142, 151))	('PSMD7', 'Var', (152, 157))	('ESCC', 'Disease', (87, 91))	('ESCC', 'Disease', (213, 217))
412616	33687056	Importantly, high expressed PSMD7 was associated with several tumor-relative pathways, including PI3K_AKT_mTOR, P53, KRAS, angiogenesis et al.	('KRAS', 'Gene', (117, 121))	('associated with', 'Reg', (38, 53))	('PSMD7', 'Gene', (28, 33))	('P53', 'Gene', (112, 115))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', (62, 67))	('KRAS', 'Gene', '3845', (117, 121))	('angiogenesis', 'Disease', (123, 135))	('P53', 'Gene', '7157', (112, 115))	('high expressed', 'Var', (13, 27))	('mTOR', 'Gene', (106, 110))	('mTOR', 'Gene', '2475', (106, 110))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
412644	32878637	Bioinformatics prediction and in vitro experiments indicated that LINC00301 (83-123 nucleotide [nt]) can directly bind to the enhancer of zeste homolog 2 (EZH2) (612-727 amino acid [aa]) to promote H3K27me3 at the ELL protein-associated factor 2 (EAF2) promoter.	('p', 'Gene', '23436', (253, 254))	('enhancer of zeste homolog 2', 'Gene', (126, 153))	('p', 'Gene', '23436', (15, 16))	('H3K27me3', 'Var', (198, 206))	('nt', 'Chemical', 'MESH:D009711', (47, 49))	('nt', 'Chemical', 'MESH:D009711', (96, 98))	('p', 'Gene', '23436', (41, 42))	('bind', 'Interaction', (114, 118))	('LINC00301', 'Gene', (66, 75))	('enhancer of zeste homolog 2', 'Gene', '2146', (126, 153))	('LINC00301', 'Gene', '283197', (66, 75))	('p', 'Gene', '23436', (218, 219))	('p', 'Gene', '23436', (190, 191))
412654	32878637	LncRNAs can also be deemed as prognostic or diagnostic markers based on their clinical significance in tumor outcomes.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('p', 'Gene', '23436', (30, 31))	('tumor', 'Disease', (103, 108))	('LncRNAs', 'Var', (0, 7))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
412657	32878637	revealed that silencing the MIR22HG initiates cell death or survival signaling through targeting the p21, MET, and YBX1in NSCLC.	('survival', 'CPA', (60, 68))	('silencing', 'Var', (14, 23))	('NSCLC', 'Disease', 'MESH:D002289', (122, 127))	('MET', 'Gene', '79811', (106, 109))	('MET', 'Gene', (106, 109))	('MIR22HG', 'Gene', (28, 35))	('YBX1', 'Gene', '4904', (115, 119))	('MIR22HG', 'Gene', '84981', (28, 35))	('YBX1', 'Gene', (115, 119))	('targeting', 'Reg', (87, 96))	('p21', 'Gene', (101, 104))	('death', 'Disease', 'MESH:D003643', (51, 56))	('p21', 'Gene', '644914', (101, 104))	('death', 'Disease', (51, 56))	('NSCLC', 'Disease', (122, 127))	('cell', 'CPA', (46, 50))
412688	32878637	Ten human NSCLC cell lines (H1299, 95D, SK-MES-1, H460, H520, SK-LU-1, H1975, A549, H157, and SPC-A-1) and 2 normal lung epithelial cell lines, that is, 16HBE and BEAS-2B, were bought from the Institute of Biochemistry and Cell Biology (IBCB) of the Chinese Academy of Sciences (CAS) (Shanghai, China).	('NSCLC', 'Disease', (10, 15))	('16HBE', 'CellLine', 'CVCL:0112', (153, 158))	('human', 'Species', '9606', (4, 9))	('NSCLC', 'Disease', 'MESH:D002289', (10, 15))	('p', 'Gene', '23436', (122, 123))	('SK-MES-1', 'CellLine', 'CVCL:0630', (40, 48))	('SPC-A-1', 'Gene', '27032', (94, 101))	('SPC-A-1', 'Gene', (94, 101))	('SK-LU-1', 'CellLine', 'CVCL:0629', (62, 69))	('H1975', 'CellLine', 'CVCL:1511', (71, 76))	('H1299', 'Var', (28, 33))	('A549', 'CellLine', 'CVCL:0023', (78, 82))	('H1299', 'CellLine', 'CVCL:0060', (28, 33))	('H460', 'CellLine', 'CVCL:0459', (50, 54))
412690	32878637	H1299, 95D, SK-MES-1, H460, H520, SK-LU-1, H1975, A549, H157, and SPC-A-1 were cultured in RPMI 1640 (Gibco, Grand Island, NY, USA) medium supplemented with 10% fetal bovine serum (FBS), 100 U/ml penicillin, and 100 mg/ml streptomycin (Gibco); 16HBE cells were cultured in alpha-MEM medium plus 0.5 mg/mL human fibronectin, 1 mg/mL bovine serum albumin (BSA) and fraction V, and 3 mg/mL PureCol; BEAS-2B cells were cultured in BEBM medium supplemented with 0.01 mg/mL fibronectin, 0.03 mg/mL bovine collagen type I, and 0.01 mg/mL BSA; LA-4 cells were cultured in Ham's F12K medium with 2 mM L-glutamine adjusted to contain 1.5 g/L sodium bicarbonate (SB), 15% FBS; KLN 205 cells were cultured in EMEM medium supplemented with 10% FBS; MLE-12 cells were cultured in HITES medium supplemented with 2% FBS in humidified air at 37  C with 5% CO2.	('MLE-12', 'CellLine', 'CVCL:3751', (736, 742))	('p', 'Gene', '23436', (290, 291))	('F12K', 'Var', (570, 574))	('p', 'Gene', '23436', (782, 783))	('P', 'Gene', '23436', (387, 388))	('bovine', 'Species', '9913', (167, 173))	('H460', 'CellLine', 'CVCL:0459', (22, 26))	('fibronectin', 'Gene', '2335', (311, 322))	('p', 'Gene', '23436', (510, 511))	('nt', 'Chemical', 'MESH:D009711', (447, 449))	('fibronectin', 'Gene', (468, 479))	('SPC-A-1', 'Gene', (66, 73))	('nt', 'Chemical', 'MESH:D009711', (147, 149))	('p', 'Gene', '23436', (142, 143))	('P', 'Gene', '23436', (92, 93))	('H1975', 'CellLine', 'CVCL:1511', (43, 48))	('fibronectin, 1', 'Gene', '2335', (311, 325))	('serum albumin', 'Gene', '280717', (339, 352))	('nt', 'Chemical', 'MESH:D009711', (717, 719))	('F12K', 'SUBSTITUTION', 'None', (570, 574))	('SPC-A-1', 'Gene', '27032', (66, 73))	('fibronectin', 'Gene', '2335', (468, 479))	('P', 'Gene', '23436', (67, 68))	('bovine', 'Species', '9913', (492, 498))	('p', 'Gene', '23436', (712, 713))	('SK-LU-1', 'CellLine', 'CVCL:0629', (34, 41))	('KLN', 'Chemical', '-', (666, 669))	('nt', 'Chemical', 'MESH:D009711', (787, 789))	('p', 'Gene', '23436', (141, 142))	('serum albumin', 'Gene', (339, 352))	('p', 'Gene', '23436', (442, 443))	('bovine', 'Species', '9913', (332, 338))	('p', 'Gene', '23436', (226, 227))	('SK-MES-1', 'CellLine', 'CVCL:0630', (12, 20))	('nt', 'Chemical', 'MESH:D009711', (618, 620))	('p', 'Gene', '23436', (196, 197))	('A549', 'CellLine', 'CVCL:0023', (50, 54))	('p', 'Gene', '23436', (781, 782))	('LA-4', 'Chemical', '-', (536, 540))	('p', 'Gene', '23436', (275, 276))	('16HBE', 'CellLine', 'CVCL:0112', (244, 249))	('fibronectin', 'Gene', (311, 322))	('p', 'Gene', '23436', (711, 712))	('H1299', 'CellLine', 'CVCL:0060', (0, 5))	('human', 'Species', '9606', (305, 310))	('p', 'Gene', '23436', (441, 442))
412695	32878637	A549 and SPC-A-1 cells were infected with the concentrated supernatant containing lentivirus with 10 mug/mL polybrene (TR1003G, MilliporeSigma) for 24 hrs, and then 2 mug/ml puromycin (AAJ67236XF, Alfa Aesar) was added to select for 3-5 days.	('p', 'Gene', '23436', (61, 62))	('nt', 'Chemical', 'MESH:D009711', (84, 86))	('A549', 'CellLine', 'CVCL:0023', (0, 4))	('polybrene', 'Chemical', 'MESH:D006583', (108, 117))	('nt', 'Chemical', 'MESH:D009711', (68, 70))	('p', 'Gene', '23436', (133, 134))	('AAJ67236XF', 'Var', (185, 195))	('infected', 'Disease', 'MESH:D007239', (28, 36))	('p', 'Gene', '23436', (174, 175))	('nt', 'Chemical', 'MESH:D009711', (51, 53))	('infected', 'Disease', (28, 36))	('nt', 'Chemical', 'MESH:D009711', (73, 75))	('SPC-A-1', 'Gene', '27032', (9, 16))	('SPC-A-1', 'Gene', (9, 16))	('puromycin', 'Chemical', 'MESH:D011691', (174, 183))	('p', 'Gene', '23436', (108, 109))
412700	32878637	The following primary antibodies were applied: rabbit anti-EZH2 (5246S, 1: 1000 dilution, Cell Signaling Technology (CST), USA), rabbit anti-EAF2 (14159S, 1: 1000 dilution, CST, USA), rabbit anti-VHL (68547S, 1: 1,000 dilution, CST, USA), rabbit anti-HIF-1alpha (36169S, 1: 1,000 dilution, CST, USA), and rabbit anti-beta-actin (4970 L, 1: 1,000 dilution, CST, USA).	('HIF-1alpha', 'Gene', (251, 261))	('nt', 'Chemical', 'MESH:D009711', (23, 25))	('nt', 'Chemical', 'MESH:D009711', (247, 249))	('p', 'Gene', '23436', (40, 41))	('nt', 'Chemical', 'MESH:D009711', (192, 194))	('4970 L', 'Var', (329, 335))	('36169S', 'Var', (263, 269))	('nt', 'Chemical', 'MESH:D009711', (137, 139))	('68547S', 'Var', (201, 207))	('p', 'Gene', '23436', (258, 259))	('nt', 'Chemical', 'MESH:D009711', (313, 315))	('p', 'Gene', '23436', (14, 15))	('HIF-1alpha', 'Gene', '3091', (251, 261))	('nt', 'Chemical', 'MESH:D009711', (55, 57))	('VHL', 'Gene', (196, 199))	('VHL', 'Gene', '7428', (196, 199))	('14159S', 'Var', (147, 153))	('p', 'Gene', '23436', (39, 40))
412706	32878637	In detail, 5,000 (A549 and SPC-A-1) or 20,000 (A549, 95D, H1299, SPC-A-1) cells per well were seeded and cultured in 24- or 6-well plates for 14 days.	('SPC-A-1', 'Gene', (27, 34))	('A549', 'CellLine', 'CVCL:0023', (18, 22))	('SPC-A-1', 'Gene', '27032', (65, 72))	('SPC-A-1', 'Gene', (65, 72))	('SPC-A-1', 'Gene', '27032', (27, 34))	('H1299', 'Var', (58, 63))	('H1299', 'CellLine', 'CVCL:0060', (58, 63))	('p', 'Gene', '23436', (131, 132))	('p', 'Gene', '23436', (80, 81))	('A549', 'CellLine', 'CVCL:0023', (47, 51))	('A549', 'Var', (47, 51))
412717	32878637	In detail, 1 x 107 A549 and SPC-A-1 cells were washed with cold 1 x PBS for twice and then collected and lysed in 1 mL ice-cold polysomal lysis buffer (10 mM HEPES pH 7.0, 5 mM MgCl2, 1 mM dithiothreitol (DTT), 100 mM KCl, 0.5% NP-40, supplemented with protease inhibitor cocktail (B14002, Bimake) and protector RNase inhibitor (3335399001, Roche).	('HEPES', 'Chemical', 'MESH:D006531', (158, 163))	('MgCl2', 'Chemical', 'MESH:D015636', (177, 182))	('nt', 'Chemical', 'MESH:D009711', (243, 245))	('SPC-A-1', 'Gene', (28, 35))	('PBS', 'Chemical', '-', (68, 71))	('p', 'Gene', '23436', (302, 303))	('dithiothreitol', 'Chemical', 'MESH:D004229', (189, 203))	('NP-40', 'Chemical', 'MESH:C010615', (228, 233))	('p', 'Gene', '23436', (238, 239))	('p', 'Gene', '23436', (128, 129))	('KCl', 'Chemical', 'MESH:D011189', (218, 221))	('B14002', 'Chemical', '-', (282, 288))	('p', 'Gene', '23436', (253, 254))	('DTT', 'Chemical', 'MESH:D004229', (205, 208))	('SPC-A-1', 'Gene', '27032', (28, 35))	('p', 'Gene', '23436', (237, 238))	('polysomal lysis', 'Chemical', '-', (128, 143))	('B14002', 'Var', (282, 288))	('3335399001', 'Var', (329, 339))	('p', 'Gene', '23436', (164, 165))	('A549', 'CellLine', 'CVCL:0023', (19, 23))
412719	32878637	Next, 50 muL protein G magnetic beads (161-4023, Bio-Rad) were washed twice by cold NT2 buffer, and pre-blocked by 1x PBS plus 5 mg/mL BSA, after washing for twice by NT2 buffer, and the pre-blocked beads were incubated with 5 mug of rabbit IgG (2729S, CST), EZH2 (5246S, CST), SUZ12 (3737S, CST), WDR5(13105S, CST), or LSD1 (2184S, CST) antibodies with rotation at room temperature (RT) for 1 hrs.	('PBS', 'Chemical', '-', (118, 121))	('5246S', 'Var', (265, 270))	('NT2', 'Chemical', 'MESH:C068951', (167, 170))	('p', 'Gene', '23436', (187, 188))	('LSD1', 'Gene', (320, 324))	('SUZ12', 'Gene', '23512', (278, 283))	('p', 'Gene', '23436', (122, 123))	('nt', 'Chemical', 'MESH:D009711', (339, 341))	('p', 'Gene', '23436', (374, 375))	('LSD1', 'Gene', '23028', (320, 324))	('WDR5', 'Gene', (298, 302))	('p', 'Gene', '23436', (13, 14))	('SUZ12', 'Gene', (278, 283))	('3737S', 'Var', (285, 290))	('p', 'Gene', '23436', (100, 101))	('NT2', 'Chemical', 'MESH:C068951', (84, 87))	('WDR5', 'Gene', '11091', (298, 302))	('2184S', 'Var', (326, 331))
412723	32878637	LINC00301 was constructed into the pGEM-3Z vector (P2151, Promega) using KpnI (R3142, New England Biolabs) and NheI (R3131, New England Biolabs) restriction enzyme cutting site.	('p', 'Gene', '23436', (74, 75))	('P', 'Gene', '23436', (58, 59))	('R3142', 'Var', (79, 84))	('P', 'Gene', '23436', (51, 52))	('nt', 'Chemical', 'MESH:D009711', (27, 29))	('LINC00301', 'Gene', '283197', (0, 9))	('LINC00301', 'Gene', (0, 9))	('p', 'Gene', '23436', (35, 36))	('R3131', 'Var', (117, 122))
412725	32878637	Sense and antisense of LINC00301 RNA were transcribed using MEGAscript  T7 Transcription Kit (AM1334, Invitrogen, USA) and MEGAscript  SP6 Transcription Kit (AM1330, Invitrogen, USA) in vitro, respectively.	('LINC00301', 'Gene', (23, 32))	('AM1334', 'Var', (94, 100))	('LINC00301', 'Gene', '283197', (23, 32))	('p', 'Gene', '23436', (196, 197))	('AM1330', 'Var', (158, 164))	('nt', 'Chemical', 'MESH:D009711', (11, 13))	('p', 'Gene', '23436', (68, 69))	('p', 'Gene', '23436', (83, 84))	('p', 'Gene', '23436', (147, 148))	('p', 'Gene', '23436', (131, 132))	('P', 'Gene', '23436', (136, 137))
412733	32878637	Then, the fixed cells were additionally handled by 1% pepsin (10108057001, Roche) and followed by dehydration using 70%, 90%, and 100% ethanol.	('p', 'Gene', '23436', (54, 55))	('dehydration', 'Phenotype', 'HP:0001944', (98, 109))	('dehydration', 'Disease', 'MESH:D003681', (98, 109))	('ethanol', 'Chemical', 'MESH:D000431', (135, 142))	('10108057001', 'Var', (62, 73))	('dehydration', 'Disease', (98, 109))	('p', 'Gene', '23436', (56, 57))
412761	32878637	Cell apoptosis was determined by FITC Annexin V Apoptosis Detection Kit I (556547, Becton-Dickinson, FL, NJ, USA) according to the manufacturer's procedure.	('Annexin V', 'Gene', '308', (38, 47))	('FITC', 'Chemical', 'MESH:D016650', (33, 37))	('Annexin V', 'Gene', (38, 47))	('556547', 'Var', (75, 81))	('p', 'Gene', '23436', (6, 7))	('p', 'Gene', '23436', (146, 147))	('p', 'Gene', '23436', (49, 50))	('p', 'Gene', '23436', (51, 52))	('p', 'Gene', '23436', (8, 9))
412768	32878637	After lysing red blood cells by RBC Lysis Buffer (420301, BioLegend) for 10 min on ice, single-cell suspensions were subjected to blockage with TruStain FcX  (anti-mouse CD16/32) antibody (101319, BioLegend) for 10 min on ice and followed by incubating with the related antibodies for 25 min at RT.	('101319', 'Var', (189, 195))	('mouse', 'Species', '10090', (164, 169))	('nt', 'Chemical', 'MESH:D009711', (271, 273))	('CD16/32', 'Gene', (170, 177))	('p', 'Gene', '23436', (103, 104))	('nt', 'Chemical', 'MESH:D009711', (180, 182))	('CD16/32', 'Gene', '14131;14130', (170, 177))	('420301', 'Var', (50, 56))	('nt', 'Chemical', 'MESH:D009711', (160, 162))
412769	32878637	Mouse antibodies were bought from BioLegend CD3 (100203, BioLegend), CD4(100407, BioLegend), and CD25(101915, BioLegend).	('CD3', 'Gene', '28134', (44, 47))	('nt', 'Chemical', 'MESH:D009711', (7, 9))	('Mouse', 'Species', '10090', (0, 5))	('CD3', 'Gene', (44, 47))	('100407', 'Var', (73, 79))
412793	32878637	We then found that LINC00301 is higher expressed in NSCLC cell lines, including SPC-A-1, H460, SK-MES-1, 95D, A549, H157, H1299, SK-LU-1, H520, and H1975, compared with 16HBE and BEAS-2B (normal lung epithelial cells) (Fig.	('16HBE', 'CellLine', 'CVCL:0112', (169, 174))	('LINC00301', 'Gene', (19, 28))	('H460', 'CellLine', 'CVCL:0459', (89, 93))	('NSCLC', 'Disease', (52, 57))	('LINC00301', 'Gene', '283197', (19, 28))	('A549', 'CellLine', 'CVCL:0023', (110, 114))	('H1299', 'Var', (122, 127))	('SK-MES-1', 'CellLine', 'CVCL:0630', (95, 103))	('SK-LU-1', 'CellLine', 'CVCL:0629', (129, 136))	('NSCLC', 'Disease', 'MESH:D002289', (52, 57))	('p', 'Gene', '23436', (41, 42))	('p', 'Gene', '23436', (158, 159))	('H1975', 'CellLine', 'CVCL:1511', (148, 153))	('H1299', 'CellLine', 'CVCL:0060', (122, 127))	('SPC-A-1', 'Gene', (80, 87))	('SPC-A-1', 'Gene', '27032', (80, 87))	('p', 'Gene', '23436', (201, 202))
412800	32878637	In addition, Kaplan-Meier analysis revealed that high LINC00301 levels are correlated to worse OS (p = 0.0190, log-rank test, Fig.	('LINC00301', 'Gene', '283197', (54, 63))	('p', 'Gene', '23436', (99, 100))	('high', 'Var', (49, 53))	('p', 'Gene', '23436', (15, 16))	('LINC00301', 'Gene', (54, 63))	('worse OS', 'Disease', (89, 97))
412806	32878637	The qPCR results revealed sh-1 is the most efficient shRNA in LINC00301 knockdown (KD) (Fig.	('sh-1', 'Gene', (26, 30))	('sh-1', 'Gene', '100125848', (26, 30))	('LINC00301', 'Gene', (62, 71))	('P', 'Gene', '23436', (5, 6))	('nt', 'Chemical', 'MESH:D009711', (50, 52))	('knockdown', 'Var', (72, 81))	('LINC00301', 'Gene', '283197', (62, 71))
412812	32878637	The results demonstrated that silencing LINC00301 induced a shrink of A549, SPC-A-1, 95D, and H1299 cell growth compared to their counterparts (Fig.	('H1299', 'CellLine', 'CVCL:0060', (94, 99))	('nt', 'Chemical', 'MESH:D009711', (133, 135))	('LINC00301', 'Gene', '283197', (40, 49))	('SPC-A-1', 'Gene', (76, 83))	('LINC00301', 'Gene', (40, 49))	('p', 'Gene', '23436', (137, 138))	('A549', 'CellLine', 'CVCL:0023', (70, 74))	('silencing', 'Var', (30, 39))	('SPC-A-1', 'Gene', '27032', (76, 83))	('shrink', 'NegReg', (60, 66))	('A549', 'CPA', (70, 74))	('p', 'Gene', '23436', (115, 116))
412816	32878637	Silencing LINC00301 suppressed cell growth, migration, and invasion, in contrast to the sh-NC group (Fig.	('p', 'Gene', '23436', (22, 23))	('p', 'Gene', '23436', (98, 99))	('nt', 'Chemical', 'MESH:D009711', (74, 76))	('LINC00301', 'Gene', (10, 19))	('invasion', 'CPA', (59, 67))	('LINC00301', 'Gene', '283197', (10, 19))	('Silencing', 'Var', (0, 9))	('cell growth', 'CPA', (31, 42))	('p', 'Gene', '23436', (23, 24))
412821	32878637	Our results showed that silencing LINC00301 facilitates cell cycle arrest and apoptosis, whereas LINC00301 OE represses these processes in A549, SPC-A-1, 95D, and H1299 cells (Fig.	('LINC00301', 'Gene', '283197', (97, 106))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (56, 73))	('p', 'Gene', '23436', (81, 82))	('p', 'Gene', '23436', (112, 113))	('SPC-A-1', 'Gene', (145, 152))	('H1299', 'CellLine', 'CVCL:0060', (163, 168))	('p', 'Gene', '23436', (126, 127))	('p', 'Gene', '23436', (79, 80))	('arrest', 'Disease', 'MESH:D006323', (67, 73))	('SPC-A-1', 'Gene', '27032', (145, 152))	('LINC00301', 'Gene', (34, 43))	('A549', 'CellLine', 'CVCL:0023', (139, 143))	('LINC00301', 'Gene', '283197', (34, 43))	('arrest', 'Disease', (67, 73))	('LINC00301', 'Gene', (97, 106))	('facilitates', 'PosReg', (44, 55))	('silencing', 'Var', (24, 33))
412847	32878637	S3C), and also LA-4 and KLN-205 cells showed a relatively higher TGF-beta1 mRNA level than that of in MLE-12 cells (Additional file 1: Fig.	('TGF-beta1 mRNA level', 'MPA', (65, 85))	('MLE-12', 'CellLine', 'CVCL:3751', (102, 108))	('higher', 'PosReg', (58, 64))	('KLN-205', 'Var', (24, 31))	('KLN', 'Chemical', '-', (24, 27))	('LA-4', 'Chemical', '-', (15, 19))
412853	32878637	Chromatin methylation and deacetylation may silence or activate gene expression.	('p', 'Gene', '23436', (71, 72))	('Chromatin methylation', 'Var', (0, 21))	('activate', 'PosReg', (55, 63))	('silence', 'NegReg', (44, 51))	('deacetylation', 'Var', (26, 39))
412859	32878637	Our results demonstrated that silencing DNMT1 did not markedly influence LINC00301 expression, indicating that DNA methylation is not involved in LINC00301 upregulation in NSCLC cells (Fig.	('p', 'Gene', '23436', (157, 158))	('p', 'Gene', '23436', (85, 86))	('NSCLC', 'Disease', (172, 177))	('NSCLC', 'Disease', 'MESH:D002289', (172, 177))	('DNMT1', 'Gene', (40, 45))	('DNMT1', 'Gene', '1786', (40, 45))	('LINC00301', 'Gene', (73, 82))	('LINC00301', 'Gene', (146, 155))	('silencing', 'Var', (30, 39))	('LINC00301', 'Gene', '283197', (73, 82))	('LINC00301', 'Gene', '283197', (146, 155))
412860	32878637	To further identify whether DNA methylation is exactly not affect LINC00301 expression, we also knocked down DNMT3A and DNMT3B in A549 and SPC-A-1 cells and used qPCR to examine LINC00301 expression level.	('p', 'Gene', '23436', (78, 79))	('DNMT3A', 'Gene', (109, 115))	('P', 'Gene', '23436', (163, 164))	('DNMT3A', 'Gene', '1788', (109, 115))	('DNMT3B', 'Gene', '1789', (120, 126))	('P', 'Gene', '23436', (140, 141))	('LINC00301', 'Gene', (178, 187))	('nt', 'Chemical', 'MESH:D009711', (14, 16))	('LINC00301', 'Gene', (66, 75))	('DNMT3B', 'Gene', (120, 126))	('LINC00301', 'Gene', '283197', (178, 187))	('LINC00301', 'Gene', '283197', (66, 75))	('knocked', 'Var', (96, 103))	('SPC-A-1', 'Gene', '27032', (139, 146))	('A549', 'CellLine', 'CVCL:0023', (130, 134))	('SPC-A-1', 'Gene', (139, 146))	('p', 'Gene', '23436', (190, 191))
412861	32878637	And the results showed that silence of DNMT3A and DNMT3B did not significantly influence LINC00301 expression in A549 and SPC-A-1 cells (Additional file 1: Figs.	('DNMT3A', 'Gene', (39, 45))	('SPC-A-1', 'Gene', (122, 129))	('DNMT3A', 'Gene', '1788', (39, 45))	('nt', 'Chemical', 'MESH:D009711', (74, 76))	('silence', 'Var', (28, 35))	('SPC-A-1', 'Gene', '27032', (122, 129))	('DNMT3B', 'Gene', (50, 56))	('DNMT3B', 'Gene', '1789', (50, 56))	('LINC00301', 'Gene', '283197', (89, 98))	('LINC00301', 'Gene', (89, 98))	('A549', 'CellLine', 'CVCL:0023', (113, 117))	('p', 'Gene', '23436', (101, 102))
412869	32878637	A549 and SPC-A-1 cells were transfected with si-EZH2 (EZH2 is a histone-lysine N-methyltransferase enzyme).	('SPC-A-1', 'Gene', (9, 16))	('si-EZH2', 'Var', (45, 52))	('A549', 'CellLine', 'CVCL:0023', (0, 4))	('SPC-A-1', 'Gene', '27032', (9, 16))
412870	32878637	Silencing EZH2 did not markedly influence LINC00301 expression, indicating that histone methylation is not involved in LINC00301 upregulation in NSCLC cells (Fig.	('p', 'Gene', '23436', (130, 131))	('p', 'Gene', '23436', (54, 55))	('NSCLC', 'Disease', (145, 150))	('LINC00301', 'Gene', (119, 128))	('NSCLC', 'Disease', 'MESH:D002289', (145, 150))	('LINC00301', 'Gene', '283197', (119, 128))	('LINC00301', 'Gene', (42, 51))	('Silencing', 'Var', (0, 9))	('LINC00301', 'Gene', '283197', (42, 51))
412871	32878637	In addition, to further identify whether histone methylation did exactly not affect LINC00301 expression, we knocked down LSD1 in A549 and SPC-A-1 cells, using qPCR to examine LINC00301 expression level.	('LINC00301', 'Gene', (84, 93))	('LINC00301', 'Gene', '283197', (84, 93))	('knocked', 'Var', (109, 116))	('nt', 'Chemical', 'MESH:D009711', (27, 29))	('p', 'Gene', '23436', (188, 189))	('P', 'Gene', '23436', (140, 141))	('p', 'Gene', '23436', (96, 97))	('LINC00301', 'Gene', (176, 185))	('LINC00301', 'Gene', '283197', (176, 185))	('P', 'Gene', '23436', (161, 162))	('LSD1', 'Gene', (122, 126))	('SPC-A-1', 'Gene', '27032', (139, 146))	('A549', 'CellLine', 'CVCL:0023', (130, 134))	('SPC-A-1', 'Gene', (139, 146))	('LSD1', 'Gene', '23028', (122, 126))
412877	32878637	qPCR results demonstrated that silencing FOXC1 significantly contributed to LINC00301 downregulation (Fig.	('silencing', 'Var', (31, 40))	('FOXC1', 'Gene', (41, 46))	('P', 'Gene', '23436', (1, 2))	('nt', 'Chemical', 'MESH:D009711', (56, 58))	('nt', 'Chemical', 'MESH:D009711', (63, 65))	('downregulation', 'NegReg', (86, 100))	('LINC00301', 'Gene', '283197', (76, 85))	('LINC00301', 'Gene', (76, 85))
412878	32878637	To confirm that LINC00301 is a transcriptional target of FOXC1, we cloned serialized truncations of LINC00301 promoters into the pGL3-basic vector and measured the luciferase activity after transfecting them into HEK-293 T cells.	('LINC00301', 'Gene', '283197', (100, 109))	('nt', 'Chemical', 'MESH:D009711', (209, 211))	('LINC00301', 'Gene', (16, 25))	('p', 'Gene', '23436', (129, 130))	('LINC00301', 'Gene', '283197', (16, 25))	('truncations', 'Var', (85, 96))	('luciferase', 'Enzyme', (164, 174))	('nt', 'Chemical', 'MESH:D009711', (121, 123))	('measured', 'Reg', (151, 159))	('HEK-293 T', 'CellLine', 'CVCL:0063', (213, 222))	('p', 'Gene', '23436', (110, 111))	('LINC00301', 'Gene', (100, 109))	('p', 'Gene', '23436', (39, 40))	('activity', 'MPA', (175, 183))
412886	32878637	To clarify which FOXC1 binding sites are responsible for the FOXC1-induced transcriptional activation of LINC00301, chromatin immunoprecipitation (ChIP) assay was conducted to identify that FOXC1 could directly bind to site 6 (- 1395 to - 1388 nt) on the LINC00301 promoter in NSCLC cell lines (Fig.	('p', 'Gene', '23436', (132, 133))	('LINC00301', 'Gene', (105, 114))	('- 1395', 'Var', (227, 233))	('NSCLC', 'Disease', (277, 282))	('p', 'Gene', '23436', (44, 45))	('nt', 'Chemical', 'MESH:D009711', (179, 181))	('p', 'Gene', '23436', (137, 138))	('LINC00301', 'Gene', '283197', (105, 114))	('bind', 'Interaction', (211, 215))	('FOXC1', 'Gene', (190, 195))	('p', 'Gene', '23436', (83, 84))	('p', 'Gene', '23436', (265, 266))	('nt', 'Chemical', 'MESH:D009711', (244, 246))	('LINC00301', 'Gene', '283197', (255, 264))	('LINC00301', 'Gene', (255, 264))	('P', 'Gene', '23436', (150, 151))	('FOXC1-induced', 'Gene', (61, 74))	('NSCLC', 'Disease', 'MESH:D002289', (277, 282))
412895	32878637	We observed that LINC00301 deficiency in NSCLC cells specifically decreased di- and trimethylation at H3K27 without affecting the levels of di- and trimethylation at H3K9 sites (Fig.	('p', 'Gene', '23436', (54, 55))	('NSCLC', 'Disease', (41, 46))	('decreased', 'NegReg', (66, 75))	('NSCLC', 'Disease', 'MESH:D002289', (41, 46))	('LINC00301', 'Gene', (17, 26))	('deficiency', 'Var', (27, 37))	('H3K27', 'Protein', (102, 107))	('LINC00301', 'Gene', '283197', (17, 26))
412899	32878637	Di- and trimethylation at H3K27 are generally catalyzed by the histone methyltransferase polycomb repressive complex 2 (PRC2), an eminent molecular target of numerous regulatory lncRNAs.	('p', 'Gene', '23436', (112, 113))	('p', 'Gene', '23436', (89, 90))	('trimethylation', 'Var', (8, 22))	('Di-', 'MPA', (0, 3))	('H3K27', 'Protein', (26, 31))	('p', 'Gene', '23436', (100, 101))	('nt', 'Chemical', 'MESH:D009711', (135, 137))	('P', 'Gene', '23436', (120, 121))
412912	32878637	Eliminating the related sequences of LINC00301 (Delta83-Delta123) obliterated its interaction with EZH2 (Fig.	('obliterated', 'NegReg', (66, 77))	('LINC00301', 'Gene', (37, 46))	('Delta83-Delta123', 'Var', (48, 64))	('LINC00301', 'Gene', '283197', (37, 46))	('Delta83', 'Mutation', 'c.del83', (48, 55))	('nt', 'Chemical', 'MESH:D009711', (83, 85))	('Delta123', 'Mutation', 'c.del123', (56, 64))	('interaction', 'Interaction', (82, 93))
412921	32878637	Trimethylation at H3K27 is catalyzed by EZH2, which is widely reported as a molecular target of several regulatory lncRNA in NSCLC.	('NSCLC', 'Disease', (125, 130))	('p', 'Gene', '23436', (64, 65))	('NSCLC', 'Disease', 'MESH:D002289', (125, 130))	('Trimethylation', 'Var', (0, 14))	('EZH2', 'Gene', (40, 44))	('H3K27', 'Protein', (18, 23))
412924	32878637	The results demonstrated that the silence of LINC00301 remarkably increased the EAF2 mRNA level in both A549 and SPC-A-1 cells (Fig.	('increased', 'PosReg', (66, 75))	('A549', 'CellLine', 'CVCL:0023', (104, 108))	('silence', 'Var', (34, 41))	('EAF2 mRNA level', 'MPA', (80, 95))	('LINC00301', 'Gene', (45, 54))	('SPC-A-1', 'Gene', (113, 120))	('LINC00301', 'Gene', '283197', (45, 54))	('SPC-A-1', 'Gene', '27032', (113, 120))
412927	32878637	Subsequently, A549 and SPC-A-1 cells were transfected with pLenti-CMV-NC or LINC00301 OE, and the results showed that INC00301 overexpression markedly restrained the mRNA and protein levels of EAF2 in NSCLC (Fig.	('A549', 'CellLine', 'CVCL:0023', (14, 18))	('restrained', 'NegReg', (151, 161))	('p', 'Gene', '23436', (133, 134))	('p', 'Gene', '23436', (175, 176))	('nt', 'Chemical', 'MESH:D009711', (62, 64))	('p', 'Gene', '23436', (59, 60))	('NSCLC', 'Disease', (201, 206))	('SPC-A-1', 'Gene', '27032', (23, 30))	('INC00301', 'Var', (118, 126))	('EAF2', 'Protein', (193, 197))	('nt', 'Chemical', 'MESH:D009711', (8, 10))	('NSCLC', 'Disease', 'MESH:D002289', (201, 206))	('LINC00301', 'Gene', '283197', (76, 85))	('LINC00301', 'Gene', (76, 85))	('SPC-A-1', 'Gene', (23, 30))
412932	32878637	Therefore, LINC00301 represses EAF2 expression by directly binding with EZH2 to mediate H3K27me3 at the EAF2 promoter in NSCLC cells.	('H3K27me3', 'Var', (88, 96))	('p', 'Gene', '23436', (109, 110))	('binding', 'Interaction', (59, 66))	('EAF2', 'Gene', (31, 35))	('NSCLC', 'Disease', (121, 126))	('p', 'Gene', '23436', (38, 39))	('NSCLC', 'Disease', 'MESH:D002289', (121, 126))	('LINC00301', 'Gene', (11, 20))	('LINC00301', 'Gene', '283197', (11, 20))	('p', 'Gene', '23436', (23, 24))
412953	32878637	Results revealed that high HIF1alpha mRNA level in NSCLC patients is significantly correlated with an improved OS and PFS survival of NSCLC patients (Additional file 1: Figs.	('p', 'Gene', '23436', (57, 58))	('nt', 'Chemical', 'MESH:D009711', (78, 80))	('NSCLC', 'Disease', 'MESH:D002289', (134, 139))	('nt', 'Chemical', 'MESH:D009711', (62, 64))	('high', 'Var', (22, 26))	('NSCLC', 'Disease', (51, 56))	('p', 'Gene', '23436', (140, 141))	('patients', 'Species', '9606', (57, 65))	('P', 'Gene', '23436', (118, 119))	('NSCLC', 'Disease', 'MESH:D002289', (51, 56))	('patients', 'Species', '9606', (140, 148))	('nt', 'Chemical', 'MESH:D009711', (145, 147))	('p', 'Gene', '23436', (104, 105))	('p', 'Gene', '23436', (33, 34))	('NSCLC', 'Disease', (134, 139))
412971	32878637	However, no substantial inhibition was detected at the reporter vector with a mutant HIF1A 3'-UTR (Fig.	('p', 'Gene', '23436', (57, 58))	('nt', 'Chemical', 'MESH:D009711', (82, 84))	('HIF1A', 'Gene', (85, 90))	('nt', 'Chemical', 'MESH:D009711', (18, 20))	('mutant', 'Var', (78, 84))
412978	32878637	LINC00301 OE and HIF1A OE treatment significantly enhanced HIF1alpha protein levels in A549 and SPC-A-1 cells (Fig.	('HIF1A', 'Var', (17, 22))	('SPC-A-1', 'Gene', (96, 103))	('A549', 'CellLine', 'CVCL:0023', (87, 91))	('SPC-A-1', 'Gene', '27032', (96, 103))	('LINC00301', 'Gene', '283197', (0, 9))	('LINC00301', 'Gene', (0, 9))	('nt', 'Chemical', 'MESH:D009711', (45, 47))	('p', 'Gene', '23436', (69, 70))	('enhanced', 'PosReg', (50, 58))	('p', 'Gene', '23436', (65, 66))	('nt', 'Chemical', 'MESH:D009711', (33, 35))
412993	32878637	S11A), while we found that the higher FOXC1 expression subgroup significantly exhibited a poorer prognosis than the lower FOXC1 expression subgroup in the higher LINC00301 expression group (p < 0.0001) (Additional file 1: Fig.	('p', 'Gene', '23436', (46, 47))	('p', 'Gene', '23436', (130, 131))	('p', 'Gene', '23436', (187, 188))	('S11A', 'Var', (0, 4))	('p', 'Gene', '23436', (174, 175))	('S11A', 'SUBSTITUTION', 'None', (0, 4))	('p', 'Gene', '23436', (62, 63))	('p', 'Gene', '23436', (90, 91))	('p', 'Gene', '23436', (146, 147))	('LINC00301', 'Gene', (162, 171))	('nt', 'Chemical', 'MESH:D009711', (73, 75))	('p', 'Gene', '23436', (97, 98))	('LINC00301', 'Gene', '283197', (162, 171))	('FOXC1', 'Gene', (38, 43))	('p', 'Gene', '23436', (190, 191))
412995	32878637	S11C), while we found that the higher EZH2 expression subgroup significantly exhibited a poorer prognosis than the lower EZH2 expression subgroup in the higher LINC00301 expression group (p = 0.0010) (Additional file 1: Fig.	('p', 'Gene', '23436', (61, 62))	('LINC00301', 'Gene', '283197', (160, 169))	('p', 'Gene', '23436', (144, 145))	('p', 'Gene', '23436', (89, 90))	('S11C', 'SUBSTITUTION', 'None', (0, 4))	('nt', 'Chemical', 'MESH:D009711', (72, 74))	('p', 'Gene', '23436', (185, 186))	('p', 'Gene', '23436', (188, 189))	('p', 'Gene', '23436', (172, 173))	('p', 'Gene', '23436', (96, 97))	('p', 'Gene', '23436', (45, 46))	('S11C', 'Var', (0, 4))	('p', 'Gene', '23436', (128, 129))	('LINC00301', 'Gene', (160, 169))
413012	32878637	And results indicated that silencing EZH2, EAF2, and VHL had no significant effect on miR-1276 expression in A549 and SPC-A-1 cells, which indicated that FOXC1/LINC00301/EZH2/EAF2/pVHL/HIF1alpha and FOXC1/LINC00301/miR-1276/HIF1alpha pathways are at least relatively independent (Additional file 1: Figs.	('p', 'Gene', '23436', (97, 98))	('SPC-A-1', 'Gene', '27032', (118, 125))	('VHL', 'Gene', (181, 184))	('LINC00301', 'Gene', '283197', (160, 169))	('LINC00301', 'Gene', (205, 214))	('p', 'Gene', '23436', (230, 231))	('miR-1276', 'Gene', (215, 223))	('VHL', 'Gene', (53, 56))	('p', 'Gene', '23436', (271, 272))	('A549', 'CellLine', 'CVCL:0023', (109, 113))	('VHL', 'Gene', '7428', (181, 184))	('miR-1276', 'Gene', '100302121', (215, 223))	('p', 'Gene', '23436', (191, 192))	('VHL', 'Gene', '7428', (53, 56))	('p', 'Gene', '23436', (180, 181))	('nt', 'Chemical', 'MESH:D009711', (73, 75))	('LINC00301', 'Gene', (160, 169))	('miR-1276', 'Gene', (86, 94))	('silencing', 'Var', (27, 36))	('LINC00301', 'Gene', '283197', (205, 214))	('p', 'Gene', '23436', (234, 235))	('SPC-A-1', 'Gene', (118, 125))	('miR-1276', 'Gene', '100302121', (86, 94))	('nt', 'Chemical', 'MESH:D009711', (276, 278))
413016	32878637	S13A-B), while LINC00301 OE plus EZH2 KD significantly repressed tumor growth derived in nude mice when compared with LINC00301 OE group (Additional file 1: Figs.	('p', 'Gene', '23436', (57, 58))	('LINC00301', 'Gene', '283197', (15, 24))	('LINC00301', 'Gene', '283197', (118, 127))	('tumor', 'Disease', (65, 70))	('LINC00301', 'Gene', (118, 127))	('S13A', 'SUBSTITUTION', 'None', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('EZH2', 'Var', (33, 37))	('nude mice', 'Species', '10090', (89, 98))	('p', 'Gene', '23436', (28, 29))	('p', 'Gene', '23436', (107, 108))	('S13A', 'Var', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('p', 'Gene', '23436', (135, 136))	('nt', 'Chemical', 'MESH:D009711', (50, 52))	('LINC00301', 'Gene', (15, 24))
413037	32878637	These findings indicate that high LINC00301 expression act as a key player in the pathogenesis of NSCLC.	('high', 'Var', (29, 33))	('p', 'Gene', '23436', (82, 83))	('p', 'Gene', '23436', (46, 47))	('p', 'Gene', '23436', (68, 69))	('LINC00301', 'Gene', (34, 43))	('LINC00301', 'Gene', '283197', (34, 43))	('NSCLC', 'Disease', (98, 103))	('NSCLC', 'Disease', 'MESH:D002289', (98, 103))
413045	32878637	EZH2 is a key content of the PRC2 complex and mediates H3K27me2 or H3K27me3 in the handles of promoter districts in genes.	('nt', 'Chemical', 'MESH:D009711', (19, 21))	('p', 'Gene', '23436', (94, 95))	('H3K27me3', 'Var', (67, 75))	('mediates', 'Reg', (46, 54))	('P', 'Gene', '23436', (29, 30))	('nt', 'Chemical', 'MESH:D009711', (16, 18))	('H3K27me2', 'Var', (55, 63))	('p', 'Gene', '23436', (37, 38))
413046	32878637	Herein, we found that LINC00301 directly binds with EZH2 and facilitates H3K27me2/H3K27me3 at the EAF2 promoter to suppress its transcription.	('binds', 'Interaction', (41, 46))	('LINC00301', 'Gene', (22, 31))	('p', 'Gene', '23436', (136, 137))	('LINC00301', 'Gene', '283197', (22, 31))	('p', 'Gene', '23436', (117, 118))	('p', 'Gene', '23436', (103, 104))	('p', 'Gene', '23436', (118, 119))	('facilitates', 'PosReg', (61, 72))	('H3K27me2/H3K27me3', 'Var', (73, 90))
413047	32878637	EAF2 represses HIF1alpha transcriptional activity by interrupting its interaction with the coactivator CBP/p300.	('p300', 'Gene', '2033', (107, 111))	('p', 'Gene', '23436', (60, 61))	('interaction', 'Interaction', (70, 81))	('p', 'Gene', '23436', (21, 22))	('p300', 'Gene', (107, 111))	('p', 'Gene', '23436', (107, 108))	('p', 'Gene', '23436', (7, 8))	('EAF2', 'Var', (0, 4))	('p', 'Gene', '23436', (33, 34))	('nt', 'Chemical', 'MESH:D009711', (54, 56))	('nt', 'Chemical', 'MESH:D009711', (71, 73))
413112	28607528	In the multivariate analysis, high expression of LAMP3 (P = 0.048) was significantly linked to the poor overall survival, similarly as the degree of tumor differentiation (P = 0.020) and advanced TNM stage (P = 0.001) were always regarded as significant predictors of poor prognosis of OSCC patients (Table 3).	('LAMP3', 'Gene', (49, 54))	('OSCC', 'Disease', (286, 290))	('high expression', 'Var', (30, 45))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('poor', 'NegReg', (99, 103))	('patients', 'Species', '9606', (291, 299))	('tumor', 'Disease', (149, 154))	('linked', 'Reg', (85, 91))	('overall survival', 'MPA', (104, 120))
413113	28607528	Kaplan-Meier survival curves showed that OSCC patients with high expression of LAMP3 exhibited a significantly poor survival time compared with those with low expression of LAMP3 (Figure 3(a)).	('patients', 'Species', '9606', (46, 54))	('high expression', 'Var', (60, 75))	('survival time', 'CPA', (116, 129))	('OSCC', 'Disease', (41, 45))	('LAMP3', 'Gene', (79, 84))	('poor', 'NegReg', (111, 115))
413125	28607528	reported that LAMP3 is also involved in tamoxifen resistance in MCF7 breast cancer cells through the modulation of autophagy, while knockdown of this gene presents an increased sensitivity toward tamoxifen.	('modulation', 'Reg', (101, 111))	('knockdown', 'Var', (132, 141))	('autophagy', 'CPA', (115, 124))	('tamoxifen', 'Chemical', 'MESH:D013629', (40, 49))	('tamoxifen resistance', 'MPA', (40, 60))	('involved', 'Reg', (28, 36))	('tamoxifen', 'Chemical', 'MESH:D013629', (196, 205))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('increased', 'PosReg', (167, 176))	('breast cancer', 'Phenotype', 'HP:0003002', (69, 82))	('sensitivity toward tamoxifen', 'MPA', (177, 205))	('MCF7 breast cancer', 'Disease', (64, 82))	('LAMP3', 'Gene', (14, 19))	('MCF7 breast cancer', 'Disease', 'MESH:D001943', (64, 82))
413126	28607528	In addition, high LAMP3 expression predicts poor survival in patients with cervix cancer and esophageal squamous cell carcinoma.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (104, 127))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (93, 127))	('expression', 'MPA', (24, 34))	('high', 'Var', (13, 17))	('cervix cancer', 'Phenotype', 'HP:0030079', (75, 88))	('poor', 'NegReg', (44, 48))	('patients', 'Species', '9606', (61, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('cervix cancer', 'Disease', 'MESH:D002583', (75, 88))	('esophageal squamous cell carcinoma', 'Disease', (93, 127))	('cervix cancer', 'Disease', (75, 88))
413131	28607528	Univariate and multivariate analyses exhibited that positive LAMP3 expression, degree of differentiation, and TNM stage were independent prognostic factors affecting the survival of patients with OSCC, and Kaplan-Meier analysis showed that the lifespan of patients with positive LAMP3 expression was shorter than that of patients with negative expression.	('LAMP3', 'Gene', (279, 284))	('patients', 'Species', '9606', (321, 329))	('patients', 'Species', '9606', (256, 264))	('shorter', 'NegReg', (300, 307))	('lifespan', 'CPA', (244, 252))	('patients', 'Species', '9606', (182, 190))	('positive', 'Var', (270, 278))
413145	33613118	Results: ITGB1 mRNA and protein expression levels were higher in H460R than in the parental H460 cells.	('H460R', 'Mutation', 'rs1207479001', (65, 70))	('ITGB1', 'Gene', (9, 14))	('H460R', 'Var', (65, 70))	('higher', 'PosReg', (55, 61))	('ITGB1', 'Gene', '3688', (9, 14))
413149	33613118	Silencing ITGB1 suppressed the expression and intracellular translocation of Yes-associated protein 1 (YAP1), a downstream effector of ITGB1.	('suppressed', 'NegReg', (16, 26))	('ITGB1', 'Gene', '3688', (135, 140))	('ITGB1', 'Gene', (10, 15))	('Yes-associated protein 1', 'Gene', (77, 101))	('YAP1', 'Gene', (103, 107))	('YAP1', 'Gene', '10413', (103, 107))	('expression', 'MPA', (31, 41))	('intracellular translocation', 'MPA', (46, 73))	('ITGB1', 'Gene', (135, 140))	('ITGB1', 'Gene', '3688', (10, 15))	('Silencing', 'Var', (0, 9))	('Yes-associated protein 1', 'Gene', '10413', (77, 101))
413162	33613118	Meanwhile, ITGB1 inhibition enhances radiosensitivity and impairs DNA repair, thereby increasing residual DNA damage levels in head and neck squamous cell carcinoma (HNSCC) and pancreatic carcinoma cells.	('carcinoma', 'Phenotype', 'HP:0030731', (155, 164))	('neck squamous cell carcinoma', 'Disease', (136, 164))	('pancreatic carcinoma', 'Disease', (177, 197))	('HNSCC', 'Phenotype', 'HP:0012288', (166, 171))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (136, 164))	('ITGB1', 'Gene', (11, 16))	('impairs', 'NegReg', (58, 65))	('pancreatic carcinoma', 'Disease', 'MESH:D010190', (177, 197))	('inhibition', 'Var', (17, 27))	('DNA repair', 'MPA', (66, 76))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (127, 164))	('residual DNA damage levels', 'MPA', (97, 123))	('enhances', 'PosReg', (28, 36))	('increasing', 'PosReg', (86, 96))	('ITGB1', 'Gene', '3688', (11, 16))	('carcinoma', 'Phenotype', 'HP:0030731', (188, 197))	('radiosensitivity', 'MPA', (37, 53))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (141, 164))
413170	33613118	More importantly, it has also been observed that radiotherapy may induce EMT in vivo, demonstrated by comparing surgically resected NSCLC specimens before and after radiotherapy.	('NSCLC', 'Phenotype', 'HP:0030358', (132, 137))	('EMT', 'CPA', (73, 76))	('induce', 'PosReg', (66, 72))	('NSCLC', 'Disease', (132, 137))	('radiotherapy', 'Var', (49, 61))	('NSCLC', 'Disease', 'MESH:D002289', (132, 137))
413176	33613118	DNA double-strand breaks (DNA-DSBs), one of the main types of ionizing radiation-induced damage, invoke various DNA repair mechanisms.	('invoke', 'Reg', (97, 103))	('double-strand breaks', 'Var', (4, 24))	('DSBs', 'Chemical', 'MESH:C007563', (30, 34))
413208	33613118	The membranes were blocked with 5% (w/v) skim milk at room temperature and immunoblotted at 4  C overnight with primary antibodies against ITGB1 (Cat#12594-1-AP), E-cadherin (Cat#20874-1-AP), N-cadherin (Cat#22018-1-AP), CDC25c (Cat#16485-1-AP), GAPDH (Cat#60004-1-Ig), Histone H3 (Cat#17168-1-AP), YAP1(Cat#66900-1-Ig), and Zeb1 (Cat#21544-1-AP) from Proteintech (Chicago, IL, USA); gammaH2AX (Cat#ab81299), ATM(Cat#ab32420), CHK2 (Cat#ab109413), and phospho-CHK2 (Cat#ab32148) from Abcam, (San Diego, CA, USA); Snai (Cat#6032) phospho-CDC25c(Cat#AF3258) and phospho-ATM (Cat#AF4120) from Affinity Biosciences (Cincinnati, OH, USA); and vimentin (Cat#5741) from Cell Signaling Technology (Beverly, MA, USA).	('Zeb1', 'Gene', '6935', (325, 329))	('CDC25c', 'Gene', '995', (537, 543))	('CHK2', 'Gene', '11200', (427, 431))	('CDC25c', 'Gene', (537, 543))	('E-cadherin', 'Gene', (163, 173))	('Zeb1', 'Gene', (325, 329))	('ATM', 'Gene', '472', (568, 571))	('ITGB1', 'Gene', '3688', (139, 144))	('E-cadherin', 'Gene', '999', (163, 173))	('YAP1', 'Gene', '10413', (299, 303))	('CHK2', 'Gene', (460, 464))	('GAPDH', 'Gene', '2597', (246, 251))	('CDC25c', 'Gene', (221, 227))	('ATM', 'Gene', '472', (409, 412))	('N-cadherin', 'Gene', (192, 202))	('YAP1', 'Gene', (299, 303))	('Cat#AF4120', 'Var', (573, 583))	('N-cadherin', 'Gene', '1000', (192, 202))	('ATM', 'Gene', (568, 571))	('CHK2', 'Gene', '11200', (460, 464))	('GAPDH', 'Gene', (246, 251))	('Cat#6032', 'Var', (519, 527))	('CHK2', 'Gene', (427, 431))	('CDC25c', 'Gene', '995', (221, 227))	('vimentin', 'Gene', '7431', (638, 646))	('gammaH2AX', 'Chemical', '-', (384, 393))	('ITGB1', 'Gene', (139, 144))	('ATM', 'Gene', (409, 412))	('vimentin', 'Gene', (638, 646))
413218	33613118	Compared with the parental line, H460R had significantly higher colony formation ability and a lower rate of apoptosis post-irradiation (Fig.	('colony formation ability', 'CPA', (64, 88))	('lower', 'NegReg', (95, 100))	('H460R', 'Var', (33, 38))	('higher', 'PosReg', (57, 63))	('apoptosis', 'CPA', (109, 118))	('H460R', 'Mutation', 'rs1207479001', (33, 38))
413222	33613118	We confirmed that ITGB1 was more highly expressed in H460R cells than in H460 cells (Fig.	('H460R', 'Var', (53, 58))	('highly', 'PosReg', (33, 39))	('ITGB1', 'Gene', (18, 23))	('ITGB1', 'Gene', '3688', (18, 23))	('H460R', 'Mutation', 'rs1207479001', (53, 58))
413231	33613118	NSCLC patients with high ITGB1 expression had poorer prognosis than those with low ITGB1 expression (Fig.	('NSCLC', 'Disease', 'MESH:D002289', (0, 5))	('ITGB1', 'Gene', (83, 88))	('ITGB1', 'Gene', (25, 30))	('NSCLC', 'Phenotype', 'HP:0030358', (0, 5))	('high', 'Var', (20, 24))	('patients', 'Species', '9606', (6, 14))	('ITGB1', 'Gene', '3688', (83, 88))	('NSCLC', 'Disease', (0, 5))	('ITGB1', 'Gene', '3688', (25, 30))
413232	33613118	Univariate analysis revealed that high ITGB1 expression significantly correlated with poor overall survival (HR: 1.431; 95% CI: 1.221-1.667; P < 0.01).	('ITGB1', 'Gene', '3688', (39, 44))	('overall survival', 'MPA', (91, 107))	('high', 'Var', (34, 38))	('expression', 'MPA', (45, 55))	('ITGB1', 'Gene', (39, 44))	('poor', 'NegReg', (86, 90))
413242	33613118	These data indicated that ITGB1 expression was correlated with radiosensitivity, and inhibition of ITGB1 could reverse the intrinsic and acquired radioresistance of NSCLC.	('ITGB1', 'Gene', (99, 104))	('NSCLC', 'Disease', 'MESH:D002289', (165, 170))	('inhibition', 'Var', (85, 95))	('reverse', 'NegReg', (111, 118))	('ITGB1', 'Gene', '3688', (26, 31))	('ITGB1', 'Gene', '3688', (99, 104))	('NSCLC', 'Phenotype', 'HP:0030358', (165, 170))	('NSCLC', 'Disease', (165, 170))	('ITGB1', 'Gene', (26, 31))
413249	33613118	These results indicate that ITGB1 inhibition enhances radiation-induced G2/M arrest and apoptosis.	('apoptosis', 'CPA', (88, 97))	('inhibition', 'Var', (34, 44))	('ITGB1', 'Gene', (28, 33))	('M arrest', 'Disease', 'MESH:D006323', (75, 83))	('M arrest', 'Disease', (75, 83))	('enhances', 'PosReg', (45, 53))	('ITGB1', 'Gene', '3688', (28, 33))
413250	33613118	To further investigate the underlying mechanism associated with ITGB1-induced radioresistance of NSCLC cells, we performed an immunofluorescence assay to detect the expression of gammaH2AX post-irradiation or in the absence of irradiation.	('ITGB1', 'Gene', (64, 69))	('NSCLC', 'Disease', (97, 102))	('gammaH2AX', 'Chemical', '-', (179, 188))	('ITGB1', 'Gene', '3688', (64, 69))	('gammaH2AX', 'Var', (179, 188))	('NSCLC', 'Disease', 'MESH:D002289', (97, 102))	('NSCLC', 'Phenotype', 'HP:0030358', (97, 102))
413261	33613118	These results indicate that ITGB1 inhibition suppresses DNA damage repair, thus reversing the intrinsic and acquired radioresistance of NSCLC cells.	('NSCLC', 'Disease', 'MESH:D002289', (136, 141))	('inhibition', 'Var', (34, 44))	('ITGB1', 'Gene', (28, 33))	('NSCLC', 'Phenotype', 'HP:0030358', (136, 141))	('DNA damage repair', 'MPA', (56, 73))	('suppresses', 'NegReg', (45, 55))	('reversing', 'NegReg', (80, 89))	('NSCLC', 'Disease', (136, 141))	('ITGB1', 'Gene', '3688', (28, 33))
413263	33613118	Knockdown of ITGB1 was associated with strong inhibition of N-cadherin, vimentin, Snail, and Zeb1 expression and up-regulation of E-cadherin expression in A549 cells.	('N-cadherin', 'Gene', (60, 70))	('Snail', 'Gene', (82, 87))	('Snail', 'Gene', '6615', (82, 87))	('Knockdown', 'Var', (0, 9))	('ITGB1', 'Gene', (13, 18))	('inhibition', 'NegReg', (46, 56))	('N-cadherin', 'Gene', '1000', (60, 70))	('vimentin', 'Gene', '7431', (72, 80))	('vimentin', 'Gene', (72, 80))	('E-cadherin', 'Gene', (130, 140))	('E-cadherin', 'Gene', '999', (130, 140))	('Zeb1', 'Gene', (93, 97))	('Zeb1', 'Gene', '6935', (93, 97))	('A549', 'CellLine', 'CVCL:0023', (155, 159))	('expression', 'MPA', (141, 151))	('ITGB1', 'Gene', '3688', (13, 18))	('up-regulation', 'PosReg', (113, 126))	('expression', 'MPA', (98, 108))
413268	33613118	Furthermore, survival analyses of NSCLC patients in GEPIA2 showed that high levels of these two genes predicted significantly shorter overall survival and worse disease-free survival (Fig.	('NSCLC', 'Disease', (34, 39))	('shorter', 'NegReg', (126, 133))	('high', 'Var', (71, 75))	('GEPIA2', 'Gene', (52, 58))	('disease-free survival', 'CPA', (161, 182))	('patients', 'Species', '9606', (40, 48))	('worse', 'NegReg', (155, 160))	('NSCLC', 'Disease', 'MESH:D002289', (34, 39))	('NSCLC', 'Phenotype', 'HP:0030358', (34, 39))	('overall', 'MPA', (134, 141))
413270	33613118	Western blot analysis showed that YAP1 was down-regulated when ITGB1 was knocked down in A549 cells, whereas YAP1 expression was up-regulated in the H522-ITGB1 group (Fig.	('down-regulated', 'NegReg', (43, 57))	('ITGB1', 'Gene', (154, 159))	('A549', 'CellLine', 'CVCL:0023', (89, 93))	('YAP1', 'Gene', (34, 38))	('ITGB1', 'Gene', (63, 68))	('YAP1', 'Gene', '10413', (109, 113))	('YAP1', 'Gene', '10413', (34, 38))	('ITGB1', 'Gene', '3688', (154, 159))	('up-regulated', 'PosReg', (129, 141))	('knocked down', 'Var', (73, 85))	('ITGB1', 'Gene', '3688', (63, 68))	('expression', 'MPA', (114, 124))	('YAP1', 'Gene', (109, 113))
413271	33613118	Western blotting showed that ITGB1 knockdown significantly impaired YAP1 nuclear localization in A549 cells (Fig.	('knockdown', 'Var', (35, 44))	('ITGB1', 'Gene', (29, 34))	('nuclear localization', 'MPA', (73, 93))	('ITGB1', 'Gene', '3688', (29, 34))	('A549', 'CellLine', 'CVCL:0023', (97, 101))	('YAP1', 'Gene', '10413', (68, 72))	('impaired', 'NegReg', (59, 67))	('YAP1', 'Gene', (68, 72))
413278	33613118	In HNSCC, ITGB1 inhibition enhances radiosensitivity and impairs DNA repair, resulting in increased residual DNA damage levels.	('HNSCC', 'Phenotype', 'HP:0012288', (3, 8))	('ITGB1', 'Gene', (10, 15))	('increased', 'PosReg', (90, 99))	('impairs', 'NegReg', (57, 64))	('residual DNA damage levels', 'MPA', (100, 126))	('radiosensitivity', 'MPA', (36, 52))	('DNA repair', 'MPA', (65, 75))	('enhances', 'PosReg', (27, 35))	('ITGB1', 'Gene', '3688', (10, 15))	('inhibition', 'Var', (16, 26))
413287	33613118	Both silencing and overexpression of ITGB1 revealed that it was associated with clonogenic survival rate, cell viability, and resistance to radiation-induced apoptosis.	('associated', 'Reg', (64, 74))	('ITGB1', 'Gene', '3688', (37, 42))	('silencing', 'Var', (5, 14))	('resistance to radiation-induced apoptosis', 'CPA', (126, 167))	('clonogenic survival rate', 'CPA', (80, 104))	('ITGB1', 'Gene', (37, 42))	('cell viability', 'CPA', (106, 120))
413289	33613118	Irradiation induces DNA-DSBs, and the ability to repair DNA-DSBs is closely associated with sensitivity to radiotherapy.	('DSBs', 'Chemical', 'MESH:C007563', (24, 28))	('Irradiation', 'Var', (0, 11))	('DSBs', 'Chemical', 'MESH:C007563', (60, 64))	('DNA-DSBs', 'Disease', (20, 28))	('induces', 'Reg', (12, 19))
413290	33613118	gammaH2AX, an early marker of DNA-DSBs, is positively associated with radiosensitivity.	('DSBs', 'Chemical', 'MESH:C007563', (34, 38))	('gammaH2AX', 'Chemical', '-', (0, 9))	('radiosensitivity', 'Disease', (70, 86))	('gammaH2AX', 'Var', (0, 9))	('associated', 'Reg', (54, 64))
413293	33613118	Irradiation-induced DNA-DSBs are primarily repaired by nonhomologous end-joining and homologous recombination.	('nonhomologous', 'Var', (55, 68))	('DSBs', 'Chemical', 'MESH:C007563', (24, 28))	('DNA-DSBs', 'Disease', (20, 28))
413298	33613118	found that ATM phosphorylation and CHK2 expression were significantly higher in GBM-R2M2 than GBM-Par cells, which resulted in more efficient DNA repair, cell motility, and survival after irradiation.	('expression', 'MPA', (40, 50))	('cell motility', 'CPA', (154, 167))	('CHK2', 'Gene', '11200', (35, 39))	('more efficient', 'PosReg', (127, 141))	('ATM', 'Gene', (11, 14))	('GBM-R2M2', 'Var', (80, 88))	('higher', 'PosReg', (70, 76))	('CHK2', 'Gene', (35, 39))	('ATM', 'Gene', '472', (11, 14))	('survival', 'CPA', (173, 181))	('DNA repair', 'CPA', (142, 152))
413304	33613118	Interestingly, co-expression of the four mesenchymal markers (N-cadherin, Vimentin, Snail, and Zeb1) predicted significantly poor overall survival and worse disease-free survival (Fig.	('Zeb1', 'Gene', (95, 99))	('Snail', 'Gene', '6615', (84, 89))	('Zeb1', 'Gene', '6935', (95, 99))	('Vimentin', 'Gene', '7431', (74, 82))	('disease-free survival', 'CPA', (157, 178))	('worse', 'NegReg', (151, 156))	('N-cadherin', 'Gene', (62, 72))	('Vimentin', 'Gene', (74, 82))	('N-cadherin', 'Gene', '1000', (62, 72))	('Snail', 'Gene', (84, 89))	('overall survival', 'CPA', (130, 146))	('co-expression', 'Var', (15, 28))	('poor', 'NegReg', (125, 129))
413307	33613118	We showed that blocking ITGB1 down-regulated the expression of mesenchymal genes and the EMT-promoting gene ZEB1 while up-regulating E-cadherin protein expression.	('ZEB1', 'Gene', (108, 112))	('down-regulated', 'NegReg', (30, 44))	('mesenchymal genes', 'Gene', (63, 80))	('ITGB1', 'Gene', (24, 29))	('E-cadherin', 'Gene', (133, 143))	('expression', 'MPA', (49, 59))	('expression', 'MPA', (152, 162))	('up-regulating', 'PosReg', (119, 132))	('E-cadherin', 'Gene', '999', (133, 143))	('ITGB1', 'Gene', '3688', (24, 29))	('blocking', 'Var', (15, 23))	('ZEB1', 'Gene', '6935', (108, 112))
413310	33613118	In our study, depletion of YAP1 enhanced H460R radiosensitivity.	('YAP1', 'Gene', (27, 31))	('YAP1', 'Gene', '10413', (27, 31))	('H460R', 'Mutation', 'rs1207479001', (41, 46))	('H460R radiosensitivity', 'MPA', (41, 63))	('depletion', 'Var', (14, 23))	('enhanced', 'PosReg', (32, 40))
413313	33613118	Our study revealed that ITGB1 silencing reduced total YAP1 expression and inhibited YAP1 nuclear localization.	('YAP1', 'Gene', '10413', (84, 88))	('inhibited', 'NegReg', (74, 83))	('ITGB1', 'Gene', (24, 29))	('reduced', 'NegReg', (40, 47))	('expression', 'MPA', (59, 69))	('YAP1', 'Gene', (54, 58))	('ITGB1', 'Gene', '3688', (24, 29))	('silencing', 'Var', (30, 39))	('YAP1', 'Gene', (84, 88))	('YAP1', 'Gene', '10413', (54, 58))	('nuclear localization', 'MPA', (89, 109))
413315	33613118	In conclusion, our results suggest that ITGB1 promotes EMT by targeting YAP1 and influences the DNA damage response by affecting cell cycle checkpoints, apoptosis, and ATM/CHK2 signalling, whereas inhibiting ITGB1 reverses those effects and improves NSCLC radiosensitivity.	('cell', 'MPA', (129, 133))	('EMT', 'CPA', (55, 58))	('targeting', 'NegReg', (62, 71))	('ATM', 'Gene', (168, 171))	('affecting', 'Reg', (119, 128))	('YAP1', 'Gene', '10413', (72, 76))	('ITGB1', 'Gene', (208, 213))	('CHK2', 'Gene', '11200', (172, 176))	('apoptosis', 'MPA', (153, 162))	('YAP1', 'Gene', (72, 76))	('DNA damage response', 'MPA', (96, 115))	('inhibiting', 'Var', (197, 207))	('ITGB1', 'Gene', (40, 45))	('NSCLC', 'Disease', 'MESH:D002289', (250, 255))	('ITGB1', 'Gene', '3688', (208, 213))	('improves', 'PosReg', (241, 249))	('ATM', 'Gene', '472', (168, 171))	('NSCLC', 'Disease', (250, 255))	('NSCLC', 'Phenotype', 'HP:0030358', (250, 255))	('ITGB1', 'Gene', '3688', (40, 45))	('CHK2', 'Gene', (172, 176))	('promotes', 'PosReg', (46, 54))	('influences', 'Reg', (81, 91))
413320	32858747	Cancer is characterized by genomic instability leading to deletion or amplification of oncogenes or tumor suppressors.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Disease', (100, 105))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('amplification', 'MPA', (70, 83))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('deletion', 'Var', (58, 66))	('oncogenes', 'Gene', (87, 96))	('tumor', 'Disease', 'MESH:D009369', (100, 105))
413331	32858747	In agreement with this, we and others have observed that alterations in lncRNAs are inherent to cancer and can impact several hallmarks of the disease (reviewed in; and).	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('hallmarks of the disease', 'Disease', (126, 150))	('alterations', 'Var', (57, 68))	('hallmarks of the disease', 'Disease', 'MESH:D003141', (126, 150))	('lncRNAs', 'Protein', (72, 79))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('impact', 'Reg', (111, 117))	('cancer', 'Disease', (96, 102))
413336	32858747	Here, we analyzed >7,000 tumors of 25 different types of cancer in order to detect the genomic copy number alterations in lncRNAs positively or negatively selected during tumor progression.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('tumors', 'Disease', (25, 31))	('alterations', 'Var', (107, 118))	('tumor', 'Disease', (25, 30))	('cancer', 'Disease', (57, 63))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('tumors', 'Disease', 'MESH:D009369', (25, 31))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('lncRNAs', 'Gene', (122, 129))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', (171, 176))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('negatively', 'NegReg', (144, 154))
413338	32858747	Among them, we identified and characterized amplified lncRNA associated with lung cancer-1 (ALAL-1).	('lung cancer', 'Phenotype', 'HP:0100526', (77, 88))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('lncRNA', 'Protein', (54, 60))	('lung cancer', 'Disease', 'MESH:D008175', (77, 88))	('associated', 'Reg', (61, 71))	('amplified', 'Var', (44, 53))	('lung cancer', 'Disease', (77, 88))
413345	32858747	For a comprehensive view of all the genes, coding and noncoding, affected by the copy number alterations, the SCNAs were classified based on the annotation of the genes contained in them (GENCODE v19), as well as taking into consideration their known cancer driver features (Fig.	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('alterations', 'Var', (93, 104))	('affected', 'Reg', (65, 73))	('cancer', 'Disease', 'MESH:D009369', (251, 257))	('cancer', 'Disease', (251, 257))	('copy number alterations', 'Var', (81, 104))
413359	32858747	Analysis of the TCGA lung adenocarcinoma (LUAD) cohort showed that 43/493 (8.72%) tumors contain the alteration CNA_623.	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (21, 40))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('CNA_623', 'Var', (112, 119))	('tumors', 'Disease', (82, 88))	('LUAD', 'Phenotype', 'HP:0030078', (42, 46))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (21, 40))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('lung adenocarcinoma', 'Disease', (21, 40))	('carcinoma', 'Phenotype', 'HP:0030731', (31, 40))
413370	32858747	DNA methylation changes are common in various types of cancers, and altered methylation associates with changes in gene expression.	('cancers', 'Disease', 'MESH:D009369', (55, 62))	('changes', 'Var', (16, 23))	('cancers', 'Phenotype', 'HP:0002664', (55, 62))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('methylation', 'MPA', (76, 87))	('changes', 'Reg', (104, 111))	('altered', 'Var', (68, 75))	('cancers', 'Disease', (55, 62))	('gene expression', 'MPA', (115, 130))
413371	32858747	We analyzed the DNA methylation of the ALAL-1 locus in lung cancer and found two differentially methylated CpGs mapping to the 5' end of ALAL-1 (both cg26394282, P value = 1.89e-24 in LUAD and cg16230352, P value = 3.05e-19 in LUSC; Fig.	('LUSC', 'Phenotype', 'HP:0030359', (227, 231))	('lung cancer', 'Disease', 'MESH:D008175', (55, 66))	('LUAD', 'Phenotype', 'HP:0030078', (184, 188))	('cg26394282', 'Var', (150, 160))	('lung cancer', 'Disease', (55, 66))	('lung cancer', 'Phenotype', 'HP:0100526', (55, 66))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('cg16230352', 'Var', (193, 203))
413372	32858747	2, F-H), suggesting that hypomethylation of the ALAL-1 gene in tumors could explain the observed higher level of the lncRNA in those tumors that do not present amplification of the locus.	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('higher', 'PosReg', (97, 103))	('hypomethylation', 'Var', (25, 40))	('ALAL-1', 'Gene', (48, 54))	('tumors', 'Disease', (133, 139))	('tumors', 'Disease', 'MESH:D009369', (133, 139))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumors', 'Disease', (63, 69))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('lncRNA', 'MPA', (117, 123))
413374	32858747	To experimentally test the potential oncogenic role of ALAL-1, we set out to identify lung cancer cell lines with a genetic background similar to the one present in the tumor samples (i.e., amplification of ALAL-1).	('amplification', 'Var', (190, 203))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('lung cancer', 'Phenotype', 'HP:0100526', (86, 97))	('lung cancer', 'Disease', (86, 97))	('ALAL-1', 'Gene', (207, 213))	('tumor', 'Disease', (169, 174))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('lung cancer', 'Disease', 'MESH:D008175', (86, 97))
413375	32858747	For this, we interrogated The Cancer Cell Line Encyclopedia (CCLE), in which around 12% of the lung cancer cell lines bear amplification of ALAL-1 (Fig.	('ALAL-1', 'Gene', (140, 146))	('lung cancer', 'Disease', (95, 106))	('lung cancer', 'Phenotype', 'HP:0100526', (95, 106))	('Cancer', 'Disease', 'MESH:D009369', (30, 36))	('Cancer', 'Disease', (30, 36))	('Cancer', 'Phenotype', 'HP:0002664', (30, 36))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('lung cancer', 'Disease', 'MESH:D008175', (95, 106))	('amplification', 'Var', (123, 136))
413381	32858747	While the genomic deletion of ALAL-1 indicates a role of the gene in cancer cells, it does not allow determining whether the observed effect is due to the removal of the DNA sequence or to the decrease of ALAL-1 RNA levels.	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('decrease of ALAL', 'Phenotype', 'HP:0000430', (193, 209))	('DNA', 'Protein', (170, 173))	('ALAL-1 RNA levels', 'MPA', (205, 222))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('decrease', 'NegReg', (193, 201))	('deletion', 'Var', (18, 26))	('ALAL-1', 'Gene', (30, 36))	('cancer', 'Disease', (69, 75))
413386	32858747	S2, K-S) and increased the tumor volumes formed in mice injected with ALAL-1 A549 overxpression cells (Fig.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('mice', 'Species', '10090', (51, 55))	('tumor', 'Disease', (27, 32))	('K-S', 'Var', (4, 7))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('A549', 'CellLine', 'CVCL:0023', (77, 81))	('increased', 'PosReg', (13, 22))
413398	32858747	S4 B), we did not observe any effect on IKBKB expression upon ALAL-1 truncation by CRISPR or by siRNA knockdown (Fig.	('truncation', 'Var', (69, 79))	('IKBKB', 'Gene', '3551', (40, 45))	('IKBKB', 'Gene', (40, 45))	('ALAL-1', 'Gene', (62, 68))
413411	32858747	While the enforced expression of full-length ALAL-1 resulted in increased clonogenic capacity of cells with ALAL-1 deletion, the overexpression of SART3 alone, interacting or not with ALAL-1 fragments, did not have this effect (Fig.	('deletion', 'Var', (115, 123))	('clonogenic capacity', 'CPA', (74, 93))	('ALAL-1', 'Gene', (108, 114))	('SART3', 'Gene', '9733', (147, 152))	('increased', 'PosReg', (64, 73))	('SART3', 'Gene', (147, 152))
413412	32858747	These results suggest that the central part of the ALAL-1 sequence is responsible for the specific interaction between ALAL-1 and SART3, which is required for lncRNA function; however, ALAL-1 truncations are not sufficient to induce a phenotype of increased cell proliferation, suggesting that additional regions of the lncRNA may be necessary for ALAL-1 cellular activity.	('increased', 'PosReg', (248, 257))	('cell proliferation', 'CPA', (258, 276))	('ALAL-1', 'Gene', (185, 191))	('SART3', 'Gene', '9733', (130, 135))	('truncations', 'Var', (192, 203))	('SART3', 'Gene', (130, 135))
413420	32858747	To understand the functional relationship between ALAL-1 and SART3, we knocked down one or the other and performed RNA-seq to identify gene expression changes in untreated or TNF-treated HCC95 cells.	('HCC95', 'CellLine', 'CVCL:5137', (187, 192))	('knocked', 'Var', (71, 78))	('TNF', 'Gene', '7124', (175, 178))	('SART3', 'Gene', '9733', (61, 66))	('SART3', 'Gene', (61, 66))	('TNF', 'Gene', (175, 178))
413449	32858747	Interestingly, several genes affected by either ALAL-1 or SART3 depletion encode for inflammatory factors or are components of NF-kappaB and IL-8 signaling pathways, regulating inflammatory mediators (Fig.	('depletion', 'Var', (64, 73))	('NF-kappaB', 'Gene', '4790', (127, 136))	('encode', 'Reg', (74, 80))	('inflammatory mediators', 'MPA', (177, 199))	('NF-kappaB', 'Gene', (127, 136))	('SART3', 'Gene', '9733', (58, 63))	('IL-8', 'Gene', '3576', (141, 145))	('IL-8', 'Gene', (141, 145))	('regulating', 'Reg', (166, 176))	('SART3', 'Gene', (58, 63))
413457	32858747	Compared with tumors without ALAL-1 amplification, lung adenocarcinomas with amplified ALAL-1 presented significantly lower levels of several immune populations, such as T memory, T follicular helper, and dendritic cells (Fig.	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (51, 71))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (51, 71))	('T memory', 'Disease', 'MESH:D008569', (170, 178))	('T follicular helper', 'CPA', (180, 199))	('T memory', 'Disease', (170, 178))	('tumors', 'Disease', (14, 20))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('levels of several immune populations', 'MPA', (124, 160))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('ALAL-1', 'Gene', (87, 93))	('amplified', 'Var', (77, 86))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (51, 70))	('lower', 'NegReg', (118, 123))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('lung adenocarcinomas', 'Disease', (51, 71))
413463	32858747	Together, our results suggest that by influencing the levels of pro-tumoral inflammatory mediators in the microenvironment, ALAL-1 reduces the infiltration by immune populations favoring tumor progression.	('tumor', 'Disease', (68, 73))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('ALAL-1', 'Var', (124, 130))	('infiltration by immune populations', 'MPA', (143, 177))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('reduces', 'NegReg', (131, 138))	('tumor', 'Disease', (187, 192))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('levels of', 'MPA', (54, 63))	('influencing', 'Reg', (38, 49))
413473	32858747	Moreover, knockdown of ALAL-1 diminishes the localization of USP4 into the nucleus mediated by SART3, suggesting that the presence of ALAL-1 favors the nuclear import of USP4.	('ALAL-1', 'Gene', (23, 29))	('SART3', 'Gene', (95, 100))	('nuclear import', 'MPA', (152, 166))	('localization', 'MPA', (45, 57))	('USP4', 'Gene', (170, 174))	('SART3', 'Gene', '9733', (95, 100))	('USP4', 'Gene', '7375', (61, 65))	('USP4', 'Gene', (61, 65))	('USP4', 'Gene', '7375', (170, 174))	('knockdown', 'Var', (10, 19))	('diminishes', 'NegReg', (30, 40))	('favors', 'PosReg', (141, 147))	('ALAL-1', 'Gene', (134, 140))
413477	32858747	Indeed, the gene expression changes common to SART3 and ALAL-1 knockdown could be the result of the alteration of regulatory activity of the USP4-dependent ubiquitination level of proteins.	('SART3', 'Gene', '9733', (46, 51))	('alteration', 'Reg', (100, 110))	('USP4', 'Gene', (141, 145))	('SART3', 'Gene', (46, 51))	('ALAL-1', 'Gene', (56, 62))	('USP4', 'Gene', '7375', (141, 145))	('changes', 'Reg', (28, 35))	('gene expression', 'MPA', (12, 27))	('knockdown', 'Var', (63, 72))	('regulatory activity', 'MPA', (114, 133))
413481	32858747	Our observations therefore point to ALAL-1 as a possible target for lung cancer therapies, suggesting that the in vivo inhibition of ALAL-1 could have a "double-hit" anti-tumor effect: on one hand, by decreasing the autonomous capacity of cells to survive and proliferate and, on the other hand, by promoting immune infiltration and response against the tumor.	('immune infiltration', 'CPA', (309, 328))	('promoting', 'PosReg', (299, 308))	('decreasing', 'NegReg', (201, 211))	('ALAL-1', 'Gene', (133, 139))	('lung cancer', 'Disease', (68, 79))	('tumor', 'Disease', 'MESH:D009369', (354, 359))	('lung cancer', 'Phenotype', 'HP:0100526', (68, 79))	('tumor', 'Phenotype', 'HP:0002664', (354, 359))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('inhibition', 'Var', (119, 129))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('tumor', 'Disease', (354, 359))	('lung cancer', 'Disease', 'MESH:D008175', (68, 79))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', (171, 176))
413530	32858747	To determine the number of migratory cells, the lower cells were analyzed by flow cytometry with Perfect count microspheres (Cytognos) and fluorochrome-conjugated mAbs against CD3-BV421 (UCHT1), CD8-PeCy7 (RPA-T8), CD4-FITC (OKT4), CD19-PE (HIB19), CD56-APC (HCD56), and CD14-BV510 (M5E2).	('CD14', 'Gene', (271, 275))	('CD19', 'Gene', (232, 236))	('CD3-BV421', 'Var', (176, 185))	('CD56', 'Gene', (260, 264))	('APC', 'Gene', (254, 257))	('CD8', 'Gene', (195, 198))	('CD56', 'Gene', '4684', (260, 264))	('CD14', 'Gene', '929', (271, 275))	('APC', 'Gene', '324', (254, 257))	('CD4', 'Gene', (215, 218))	('CD19', 'Gene', '930', (232, 236))	('HCD56', 'CellLine', 'CVCL:5289', (259, 264))	('CD8', 'Gene', '925', (195, 198))	('CD4', 'Gene', '920', (215, 218))	('FITC', 'Chemical', 'MESH:D016650', (219, 223))	('CD56', 'Gene', '4684', (249, 253))	('CD56', 'Gene', (249, 253))
413630	32746883	These data suggest that PDCD6 has the potential clinical value as a predictive biomarker for disease diagnosis in CRC and the patients with CRC benefit from the elimination of PDCD6.	('elimination', 'Var', (161, 172))	('PDCD6', 'Gene', (24, 29))	('PDCD6', 'Gene', (176, 181))	('patients', 'Species', '9606', (126, 134))	('CRC', 'Disease', (114, 117))
413632	32746883	Proliferation assays and colony formation assays showed that both cell proliferation and the colony formation ability were decreased in PDCD6-KD HCT116 and HCT15 cells compared with cells expressing the vector control (Fig.	('decreased', 'NegReg', (123, 132))	('cell proliferation', 'CPA', (66, 84))	('HCT15', 'CellLine', 'CVCL:0292', (156, 161))	('colony formation ability', 'CPA', (93, 117))	('HCT116', 'Gene', (145, 151))	('HCT116', 'CellLine', 'CVCL:0291', (145, 151))	('PDCD6-KD', 'Var', (136, 144))
413634	32746883	The tumor sizes of the PDCD6-KD group xenografts were markedly smaller than those in the control group (Fig.	('PDCD6-KD group', 'Var', (23, 37))	('tumor', 'Disease', (4, 9))	('smaller', 'NegReg', (63, 70))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('raf', 'Gene', '22882', (43, 46))	('raf', 'Gene', (43, 46))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))
413636	32746883	Accordingly, the weights of tumors originating from PDCD6-KD HCT116 and HCT115 cells decreased more than 2- and 3-fold respectively compared with those originating from the control cells (Fig.	('weights', 'CPA', (17, 24))	('decreased', 'NegReg', (85, 94))	('HCT116', 'CellLine', 'CVCL:0291', (61, 67))	('PDCD6-KD', 'Var', (52, 60))	('tumors', 'Disease', (28, 34))	('tumors', 'Disease', 'MESH:D009369', (28, 34))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('HCT115', 'CellLine', 'CVCL:M747', (72, 78))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('HCT116', 'Gene', (61, 67))
413637	32746883	Collectively, these in vitro and in vivo experiments demonstrate that PDCD6 depletion significantly inhibits tumor cell growth.	('inhibits', 'NegReg', (100, 108))	('PDCD6', 'Gene', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('depletion', 'Var', (76, 85))	('tumor', 'Disease', (109, 114))
413642	32746883	The tumor sizes and weights of the PDCD6-OE group xenografts were significantly greater than those of the vector control xenografts (Fig.	('tumor', 'Disease', (4, 9))	('raf', 'Gene', (126, 129))	('raf', 'Gene', '22882', (55, 58))	('raf', 'Gene', (55, 58))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('greater', 'PosReg', (80, 87))	('raf', 'Gene', '22882', (126, 129))	('PDCD6-OE', 'Var', (35, 43))
413645	32746883	To further investigate the functionally grouped networks in CRC, the ClueGO and the CluePedia plugins of in Cytoscape were used to identify the enriched pathways involved in tumorigenesis and to observe a functionally grouped network between the PDCD6-KD and the control groups.	('tumor', 'Disease', (174, 179))	('PDCD6-KD', 'Var', (246, 254))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))
413661	32746883	Immunoblotting analysis revealed that increased phosphorylation of MEK and ERK in the PDCD6-OE HCT116 cell line was significantly inhibited by RAF709 and Trametinib (Fig.	('ERK', 'Gene', '5594', (75, 78))	('HCT116', 'CellLine', 'CVCL:0291', (95, 101))	('inhibited', 'NegReg', (130, 139))	('ERK', 'Gene', (75, 78))	('RAF709', 'Chemical', 'MESH:C000621808', (143, 149))	('phosphorylation', 'MPA', (48, 63))	('MEK', 'Gene', (67, 70))	('Trametinib', 'Chemical', 'MESH:C560077', (154, 164))	('RAF709', 'Var', (143, 149))	('MEK', 'Gene', '5609', (67, 70))
413662	32746883	Furthermore, we compared the inhibition function by PDCD6-KD and c-Raf KD, and their combination in the MAPK pathway.	('MAPK pathway', 'Pathway', (104, 116))	('PDCD6-KD', 'Var', (52, 60))	('inhibition', 'NegReg', (29, 39))	('c-Raf', 'Gene', '5894', (65, 70))	('c-Raf', 'Gene', (65, 70))
413663	32746883	The results showed the inhibition effect of PDCD6-KD and c-Raf-KD was obviously, in which p- MEK and p-ERK were decreased dramatically.	('ERK', 'Gene', (103, 106))	('PDCD6-KD', 'Var', (44, 52))	('MEK', 'Gene', (93, 96))	('c-Raf', 'Gene', '5894', (57, 62))	('c-Raf', 'Gene', (57, 62))	('MEK', 'Gene', '5609', (93, 96))	('decreased', 'NegReg', (112, 121))	('ERK', 'Gene', '5594', (103, 106))
413667	32746883	RAF709 and Trametinib could also inhibited cell proliferation (Supplementary Fig.	('Trametinib', 'Chemical', 'MESH:C560077', (11, 21))	('RAF709', 'Chemical', 'MESH:C000621808', (0, 6))	('RAF709', 'Var', (0, 6))	('cell proliferation', 'CPA', (43, 61))	('inhibited', 'NegReg', (33, 42))
413671	32746883	Immunohistochemical examination of the tumor xenografts revealed that the phosphorylation of c-Raf/MEK/ERK was markedly suppressed in PDCD6-KD HCT116 cells xenografts, whereas c-Raf/MEK/ERK phosphorylation was markedly enhanced in the PDCD6-OE compared with the vector control cell xenografts.	('phosphorylation', 'MPA', (74, 89))	('ERK', 'Gene', '5594', (186, 189))	('suppressed', 'NegReg', (120, 130))	('MEK', 'Gene', (182, 185))	('c-Raf', 'Gene', (176, 181))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('raf', 'Gene', (50, 53))	('c-Raf', 'Gene', '5894', (93, 98))	('raf', 'Gene', (161, 164))	('MEK', 'Gene', '5609', (99, 102))	('ERK', 'Gene', (186, 189))	('raf', 'Gene', (287, 290))	('ERK', 'Gene', '5594', (103, 106))	('MEK', 'Gene', (99, 102))	('c-Raf', 'Gene', (93, 98))	('HCT116', 'CellLine', 'CVCL:0291', (143, 149))	('raf', 'Gene', '22882', (50, 53))	('raf', 'Gene', '22882', (161, 164))	('tumor', 'Disease', (39, 44))	('PDCD6-KD HCT116', 'Var', (134, 149))	('c-Raf', 'Gene', '5894', (176, 181))	('ERK', 'Gene', (103, 106))	('MEK', 'Gene', '5609', (182, 185))	('enhanced', 'PosReg', (219, 227))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('raf', 'Gene', '22882', (287, 290))
413688	32746883	The functional experiments showed that PDCD6 depletion significantly inhibited colorectal cancer tumorigenesis and PDCD6 overexpression enhanced the proliferation and tumor growth of CRC cells.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('enhanced', 'PosReg', (136, 144))	('colorectal cancer', 'Phenotype', 'HP:0003003', (79, 96))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('colorectal cancer', 'Disease', 'MESH:D015179', (79, 96))	('colorectal cancer', 'Disease', (79, 96))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('proliferation', 'CPA', (149, 162))	('tumor', 'Disease', (97, 102))	('PDCD6', 'Gene', (115, 120))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('inhibited', 'NegReg', (69, 78))	('depletion', 'Var', (45, 54))	('tumor', 'Disease', (167, 172))
413706	32746883	RAF709 and Trametinib, which are effective MAPK pathway effective inhibitors, have been shown to be anticancer agents in multiple tumor types.	('Trametinib', 'Chemical', 'MESH:C560077', (11, 21))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('cancer', 'Disease', (104, 110))	('RAF709', 'Var', (0, 6))	('RAF709', 'Chemical', 'MESH:C000621808', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumor', 'Disease', (130, 135))	('cancer', 'Disease', 'MESH:D009369', (104, 110))
413708	32746883	Moreover, these findings suggest the potential for antagonizing Raf/MEK/ERK signaling as a strategy to inhibit the growth of tumors hyperactivated by PDCD6.	('PDCD6', 'Gene', (150, 155))	('ERK', 'Gene', (72, 75))	('tumors hyperactivated', 'Disease', 'MESH:D011504', (125, 146))	('MEK', 'Gene', '5609', (68, 71))	('Raf', 'Gene', '22882', (64, 67))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('Raf', 'Gene', (64, 67))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('antagonizing', 'Var', (51, 63))	('tumors hyperactivated', 'Disease', (125, 146))	('growth', 'MPA', (115, 121))	('ERK', 'Gene', '5594', (72, 75))	('inhibit', 'NegReg', (103, 110))	('MEK', 'Gene', (68, 71))
413722	32746883	2018YFC1003500), the National Natural Science Foundation of China (81672472, 81672461, and 31725013), the National Key Basic Research Program of China (2015CB943001), the State Key Project on Infection Diseases of China (2017ZX10201021-007-003), and the State Key Laboratory Special fund from the Ministry of Science (2060204).	('81672461', 'Var', (77, 85))	('Infection', 'Disease', (192, 201))	('31725013', 'Var', (91, 99))	('Infection', 'Disease', 'MESH:D007239', (192, 201))	('81672472', 'Var', (67, 75))
413731	32429859	In the multivariable analysis, adjuvant chemotherapy was significantly correlated with DFS and distant metastasis-free survival (DMFS) in patients with high SCC-Ag level.	('SCC', 'Gene', (157, 160))	('DFS', 'Disease', 'None', (87, 90))	('distant metastasis-free survival', 'CPA', (95, 127))	('SCC', 'Gene', '6317', (157, 160))	('correlated', 'Reg', (71, 81))	('DFS', 'Disease', (87, 90))	('high', 'Var', (152, 156))	('patients', 'Species', '9606', (138, 146))
413785	32429859	For patients with high SCC-Ag level, there were 25 cases who died and there were 33 patients who developed recurrence.	('SCC', 'Gene', '6317', (23, 26))	('patients', 'Species', '9606', (84, 92))	('died', 'Disease', (61, 65))	('high', 'Var', (18, 22))	('patients', 'Species', '9606', (4, 12))	('died', 'Disease', 'MESH:D003643', (61, 65))	('SCC', 'Gene', (23, 26))
413789	32429859	For patients with low SCC-Ag level, 23 patients recurred with 15 patents dying of tumor recurrence.	('patients', 'Species', '9606', (39, 47))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('SCC', 'Gene', (22, 25))	('SCC', 'Gene', '6317', (22, 25))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('patients', 'Species', '9606', (4, 12))	('tumor', 'Disease', (82, 87))	('low', 'Var', (18, 21))
413805	32429859	Their data revealed that, among squamous cell carcinoma histology, patients with an Hb level less than 12 g/dl and a SCC-Ag level more than 3 ng/mL had worse oncologic outcomes.	('patients', 'Species', '9606', (67, 75))	('carcinoma', 'Phenotype', 'HP:0030731', (46, 55))	('SCC', 'Gene', (117, 120))	('less than', 'Var', (93, 102))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (32, 55))	('SCC', 'Gene', '6317', (117, 120))	('squamous cell carcinoma', 'Disease', (32, 55))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (32, 55))
413819	32429859	Due to the poor survival in patients with high SCC-Ag level, adjuvant chemotherapy could significantly improve the oncologic outcome.	('SCC', 'Gene', '6317', (47, 50))	('improve', 'PosReg', (103, 110))	('high', 'Var', (42, 46))	('patients', 'Species', '9606', (28, 36))	('SCC', 'Gene', (47, 50))
413820	32429859	However, in patients with low SCC-Ag level, the survival improvement brought by adjuvant chemotherapy may be little and not clinically significant because of the relatively favorable oncologic outcome in these patients who undergone adjuvant radiotherapy alone.	('SCC', 'Gene', '6317', (30, 33))	('patients', 'Species', '9606', (12, 20))	('low', 'Var', (26, 29))	('patients', 'Species', '9606', (210, 218))	('SCC', 'Gene', (30, 33))
413886	31973016	The aHR (95% CI) derived for significant independent prognostic risk factors for poor OS was 1.81 (1.11 to 2.40) for non-treatment compared with CCRT (Table 4).	('aHR', 'Gene', '196', (4, 7))	('poor OS', 'Disease', (81, 88))	('OS', 'Chemical', '-', (86, 88))	('aHR', 'Gene', (4, 7))	('non-treatment', 'Var', (117, 130))
413907	31973016	Moreover, surgery in elderly patients with LA-OCSCC was discovered to be valuable and resulted in lower all-cause mortality than definitive CCRT; this may have been because elderly patients with LA-OCSCC may live to experience disease progression after receiving CCRT instead of surgery.	('patients', 'Species', '9606', (29, 37))	('all-cause', 'MPA', (104, 113))	('LA-OCSCC', 'Var', (195, 203))	('patients', 'Species', '9606', (181, 189))	('lower', 'NegReg', (98, 103))
413938	31973016	; Financial Support, Taipei Medical University (TMU105-AE1-B26); Collection and Assembly of Data, B.-C.S., L.Q., K.-C.L., C.-Y.F., Y.-W.K., L.-L.T.	('C.-Y.F.', 'Var', (122, 129))	('AE1', 'Gene', (55, 58))	('AE1', 'Gene', '6521', (55, 58))
413943	26083936	Deep sequencing, a method of optimizing the high throughput capacity of NGS technologies, allows for the detection of genetic aberrations in small subsets of premalignant and/or tumor cells in noncancerous chronically inflamed tissues.	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('tumor', 'Disease', (178, 183))	('genetic aberrations', 'Var', (118, 137))	('cancerous', 'Disease', 'MESH:D009369', (196, 205))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('cancerous', 'Disease', (196, 205))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))
413947	26083936	In fact, whole-exome sequencing (WES) and whole-genome sequencing (WGS) of various cancers using NGS technologies have led to the identification of many genetic alterations in cancerous tissues.	('cancers', 'Disease', 'MESH:D009369', (83, 90))	('genetic alterations', 'Var', (153, 172))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('cancerous', 'Disease', 'MESH:D009369', (176, 185))	('cancers', 'Phenotype', 'HP:0002664', (83, 90))	('cancerous', 'Disease', (176, 185))	('cancers', 'Disease', (83, 90))
413948	26083936	Most of these genetic alterations might be passenger mutations that do not contribute to carcinogenesis, but some recurrently observed mutations are likely to be oncogenic driver mutations.	('carcinogenesis', 'Disease', 'MESH:D063646', (89, 103))	('genetic alterations', 'Var', (14, 33))	('carcinogenesis', 'Disease', (89, 103))	('mutations', 'Var', (135, 144))
413953	26083936	Hepatocellular carcinomas also have mutations of genes in several pathways, including the p53/RB pathway (TP53 and CDKN2A), WNT pathway (CTNNB1 and AXIN1), and chromatin remodeling complex (ARID1A and ARID2).	('CDKN2A', 'Gene', (115, 121))	('p53', 'Gene', (90, 93))	('ARID2', 'Gene', '196528', (201, 206))	('CTNNB1', 'Gene', '1499', (137, 143))	('Hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (0, 24))	('CDKN2A', 'Gene', '1029', (115, 121))	('carcinomas', 'Phenotype', 'HP:0030731', (15, 25))	('AXIN1', 'Gene', (148, 153))	('carcinoma', 'Phenotype', 'HP:0030731', (15, 24))	('ARID2', 'Gene', (201, 206))	('Hepatocellular carcinomas', 'Phenotype', 'HP:0001402', (0, 25))	('ARID1A', 'Gene', (190, 196))	('TP53', 'Gene', (106, 110))	('CTNNB1', 'Gene', (137, 143))	('ARID1A', 'Gene', '8289', (190, 196))	('Hepatocellular carcinomas', 'Disease', 'MESH:D006528', (0, 25))	('AXIN1', 'Gene', '8312', (148, 153))	('p53', 'Gene', '7157', (90, 93))	('mutations', 'Var', (36, 45))	('WNT pathway', 'Pathway', (124, 135))	('Hepatocellular carcinomas', 'Disease', (0, 25))	('TP53', 'Gene', '7157', (106, 110))
413957	26083936	Identifying somatic mutations contained in noncancerous tissues by such (ultra-) deep sequencing could provide clues to elucidating carcinogenic mechanisms because those mutations might contribute to carcinogenesis at an early stage of tumor development.	('contribute to', 'Reg', (186, 199))	('cancerous', 'Disease', (46, 55))	('mutations', 'Var', (170, 179))	('tumor', 'Disease', 'MESH:D009369', (236, 241))	('cancerous', 'Disease', 'MESH:D009369', (46, 55))	('tumor', 'Phenotype', 'HP:0002664', (236, 241))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('carcinogenic', 'Disease', 'MESH:D063646', (132, 144))	('carcinogenesis', 'Disease', 'MESH:D063646', (200, 214))	('carcinogenic', 'Disease', (132, 144))	('tumor', 'Disease', (236, 241))	('carcinogenesis', 'Disease', (200, 214))
413963	26083936	Germline mutations of some tumor suppressor genes strongly predispose to tumor development, as seen in familial polyposis coli and Li-Fraumeni syndrome.	('Germline mutations', 'Var', (0, 18))	('familial polyposis coli', 'Disease', (103, 126))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('predispose', 'Reg', (59, 69))	('tumor', 'Disease', (27, 32))	('Li-Fraumeni syndrome', 'Disease', 'MESH:D016864', (131, 151))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Disease', (73, 78))	('familial polyposis coli', 'Disease', 'MESH:D011125', (103, 126))	('Li-Fraumeni syndrome', 'Disease', (131, 151))	('tumor', 'Disease', 'MESH:D009369', (27, 32))
413967	26083936	Cancer is a genome disease, and the accumulation of genetic aberrations in tumor-related genes is a critical step in malignant transformation.	('genome disease', 'Disease', (12, 26))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('Cancer', 'Disease', (0, 6))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('genome disease', 'Disease', 'MESH:D042822', (12, 26))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('tumor', 'Disease', (75, 80))	('genetic aberrations', 'Var', (52, 71))
413969	26083936	Thus, it is reasonable to assume that chronically inflamed epithelial cells play a role as the origin of inflammation-associated cancers through the accumulation of genetic alterations.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('cancers', 'Phenotype', 'HP:0002664', (129, 136))	('inflammation-associated cancers', 'Disease', (105, 136))	('epithelia', 'Disease', 'None', (59, 68))	('epithelia', 'Disease', (59, 68))	('inflammation-associated cancers', 'Disease', 'MESH:D007249', (105, 136))	('genetic alterations', 'Var', (165, 184))
413971	26083936	It is possible that mutations latently accumulated in premalignant tissues also include putative driver mutations, which could contribute to the early stage of carcinogenesis.	('contribute', 'Reg', (127, 137))	('carcinogenesis', 'Disease', (160, 174))	('carcinogenesis', 'Disease', 'MESH:D063646', (160, 174))	('mutations', 'Var', (104, 113))
413974	26083936	For example, Barrett's esophagus epithelium represents premalignant lesions of esophageal adenocarcinoma with somatic mutations in TP53 and CDKN2A genes, both of which are key tumor suppressor genes involved in the development of esophageal adenocarcinoma.	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (79, 104))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('mutations', 'Var', (118, 127))	('tumor', 'Disease', (176, 181))	("Barrett's esophagus", 'Disease', (13, 32))	('CDKN2A', 'Gene', (140, 146))	('TP53', 'Gene', '7157', (131, 135))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (13, 32))	('esophageal adenocarcinoma', 'Disease', (230, 255))	('TP53', 'Gene', (131, 135))	('CDKN2A', 'Gene', '1029', (140, 146))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (230, 255))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('esophageal adenocarcinoma', 'Disease', (79, 104))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (230, 255))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (79, 104))	('tumor', 'Disease', 'MESH:D009369', (176, 181))	('carcinoma', 'Phenotype', 'HP:0030731', (246, 255))
413975	26083936	Chronic hepatitis tissues with HCV infection, which predisposes to hepatocellular carcinoma, bear TP53 mutations at frequencies of 4-15 nucleotides per 104 nucleotides.	('mutations', 'Var', (103, 112))	('HCV infection', 'Disease', 'MESH:D006526', (31, 44))	('Chronic hepatitis', 'Disease', 'MESH:D056487', (0, 17))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (67, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('hepatocellular carcinoma', 'Disease', (67, 91))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (67, 91))	('hepatitis', 'Phenotype', 'HP:0012115', (8, 17))	('Chronic hepatitis', 'Disease', (0, 17))	('TP53', 'Gene', '7157', (98, 102))	('HCV infection', 'Disease', (31, 44))	('Chronic hepatitis', 'Phenotype', 'HP:0200123', (0, 17))	('TP53', 'Gene', (98, 102))
413976	26083936	A sequencing study of colon crypts isolated by laser capture microdissection revealed TP53 mutations in both premalignant dysplasia and nondysplastic inflamed colon crypts of patients with ulcerative colitis.	('ulcerative colitis', 'Disease', 'MESH:D003093', (189, 207))	('TP53', 'Gene', '7157', (86, 90))	('premalignant dysplasia and nondysplastic inflamed colon', 'Disease', 'MESH:C531841', (109, 164))	('TP53', 'Gene', (86, 90))	('patients', 'Species', '9606', (175, 183))	('mutations', 'Var', (91, 100))	('ulcerative colitis', 'Phenotype', 'HP:0100279', (189, 207))	('ulcerative colitis', 'Disease', (189, 207))	('colitis', 'Phenotype', 'HP:0002583', (200, 207))
413978	26083936	Because of the low frequencies of cells with mutated genes in noncancerous tissues (Figure 1), however, identifying pro-oncogenic mutations in noncancerous tissues by the Sanger method requires much time and effort, and is still insufficient.	('cancerous', 'Disease', (146, 155))	('insufficient', 'Disease', (229, 241))	('cancerous', 'Disease', 'MESH:D009369', (146, 155))	('cancerous', 'Disease', 'MESH:D009369', (65, 74))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('mutations', 'Var', (130, 139))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('cancerous', 'Disease', (65, 74))	('insufficient', 'Disease', 'MESH:D000309', (229, 241))
413979	26083936	Taking advantage of the high sensitivity of NGS for the detection of low-abundance mutations, recent studies identified somatic mutations of cancer-related genes in noncancerous tissues with chronic inflammation in various organs.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('mutations', 'Var', (128, 137))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('inflammation', 'Disease', (199, 211))	('cancerous', 'Disease', 'MESH:D009369', (168, 177))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('cancer', 'Disease', (168, 174))	('inflammation', 'Disease', 'MESH:D007249', (199, 211))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('cancerous', 'Disease', (168, 177))	('cancer', 'Disease', (141, 147))
413980	26083936	TP53 mutations are most frequently detected in gastric cancer genomes, followed by ARID1A, CTNNB1, and PIK3CA.	('TP53', 'Gene', '7157', (0, 4))	('detected', 'Reg', (35, 43))	('TP53', 'Gene', (0, 4))	('CTNNB1', 'Gene', (91, 97))	('gastric cancer', 'Disease', (47, 61))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('ARID1A', 'Gene', '8289', (83, 89))	('mutations', 'Var', (5, 14))	('PIK3CA', 'Gene', (103, 109))	('ARID1A', 'Gene', (83, 89))	('CTNNB1', 'Gene', '1499', (91, 97))	('gastric cancer', 'Disease', 'MESH:D013274', (47, 61))	('gastric cancer', 'Phenotype', 'HP:0012126', (47, 61))	('PIK3CA', 'Gene', '5290', (103, 109))
413982	26083936	In the gastritis mucosa of 28 patients with gastric cancer, non-synonymous low-abundance mutations in TP53 and ARID1A were detected in 11 cases (39.3%) and four cases (14.3%), respectively.	('TP53', 'Gene', (102, 106))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('gastritis mucosa', 'Disease', (7, 23))	('gastritis', 'Phenotype', 'HP:0005263', (7, 16))	('ARID1A', 'Gene', '8289', (111, 117))	('gastric cancer', 'Disease', (44, 58))	('ARID1A', 'Gene', (111, 117))	('patients', 'Species', '9606', (30, 38))	('detected', 'Reg', (123, 131))	('gastritis mucosa', 'Disease', 'MESH:D005756', (7, 23))	('mutations', 'Var', (89, 98))	('gastric cancer', 'Disease', 'MESH:D013274', (44, 58))	('TP53', 'Gene', '7157', (102, 106))	('gastric cancer', 'Phenotype', 'HP:0012126', (44, 58))
413983	26083936	Interestingly, non-synonymous low-abundance mutations in TP53 and ARID1A were also detected in the gastritis mucosa of patients without gastric cancer.	('gastritis mucosa', 'Disease', (99, 115))	('detected', 'Reg', (83, 91))	('gastritis', 'Phenotype', 'HP:0005263', (99, 108))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('patients', 'Species', '9606', (119, 127))	('low-abundance', 'NegReg', (30, 43))	('gastritis mucosa', 'Disease', 'MESH:D005756', (99, 115))	('gastric cancer', 'Disease', (136, 150))	('ARID1A', 'Gene', (66, 72))	('ARID1A', 'Gene', '8289', (66, 72))	('gastric cancer', 'Disease', 'MESH:D013274', (136, 150))	('mutations', 'Var', (44, 53))	('TP53', 'Gene', '7157', (57, 61))	('TP53', 'Gene', (57, 61))	('gastric cancer', 'Phenotype', 'HP:0012126', (136, 150))
413985	26083936	Consistent with our findings, other recent studies revealed that the majority of recurrent mutations in cancer-related genes detected in esophageal adenocarcinoma were found in Barrett's esophagus.	("Barrett's esophagus", 'Disease', (177, 196))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (177, 196))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('carcinoma', 'Phenotype', 'HP:0030731', (153, 162))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (137, 162))	('esophageal adenocarcinoma', 'Disease', (137, 162))	('mutations', 'Var', (91, 100))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (137, 162))	('found', 'Reg', (168, 173))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))
413988	26083936	Furthermore, the vast majority of detected mutations had similar mutation frequencies among the three disease stages, while TP53 was mutated exclusively in high-grade dysplasia and esophageal adenocarcinoma, but not in never-dysplastic Barrett's esophagus.	('TP53', 'Gene', '7157', (124, 128))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (236, 255))	('TP53', 'Gene', (124, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (197, 206))	('dysplasia', 'Disease', (167, 176))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (181, 206))	('mutations', 'Var', (43, 52))	('esophageal adenocarcinoma', 'Disease', (181, 206))	("dysplastic Barrett's esophagus", 'Disease', (225, 255))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (181, 206))	('dysplasia', 'Disease', 'MESH:D004476', (167, 176))	("dysplastic Barrett's esophagus", 'Disease', 'MESH:D001471', (225, 255))
413989	26083936	Combined with accessional analyses, the TP53 mutation status was found to differentiate never-dysplastic Barrett's esophagus from high-grade dysplasia and esophageal adenocarcinoma.	('dysplasia', 'Disease', (141, 150))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (155, 180))	("dysplastic Barrett's esophagus", 'Disease', 'MESH:D001471', (94, 124))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (105, 124))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (155, 180))	('dysplasia', 'Disease', 'MESH:D004476', (141, 150))	('TP53', 'Gene', '7157', (40, 44))	('mutation', 'Var', (45, 53))	('TP53', 'Gene', (40, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (171, 180))	("dysplastic Barrett's esophagus", 'Disease', (94, 124))	('esophageal adenocarcinoma', 'Disease', (155, 180))
413990	26083936	With regard to hepatobiliary tumors, we demonstrated that many genetic alterations accumulate in the cirrhotic liver following HCV-related chronic hepatitis, a predisposing condition to hepatocellular carcinoma.	('HCV', 'Species', '11103', (127, 130))	('genetic alterations', 'Var', (63, 82))	('hepatitis', 'Phenotype', 'HP:0012115', (147, 156))	('cirrhotic liver', 'Disease', (101, 116))	('carcinoma', 'Phenotype', 'HP:0030731', (201, 210))	('cirrhotic liver', 'Disease', 'MESH:D008103', (101, 116))	('cirrhotic liver', 'Phenotype', 'HP:0001394', (101, 116))	('chronic hepatitis', 'Phenotype', 'HP:0200123', (139, 156))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (186, 210))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('hepatocellular carcinoma', 'Disease', (186, 210))	('hepatobiliary tumors', 'Disease', (15, 35))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (186, 210))	('hepatobiliary tumors', 'Disease', 'MESH:D004066', (15, 35))	('accumulate', 'Reg', (83, 93))	('chronic hepatitis', 'Disease', 'MESH:D056487', (139, 156))	('chronic hepatitis', 'Disease', (139, 156))
413991	26083936	Whole exome sequencing on nontumorous cirrhotic liver tissues led to the identification of nucleotide alterations in a large quantity, comparable to those of hepatocellular carcinoma, while the mutation frequencies in cirrhotic tissues tended to be lower than those in the matched tumor tissues.	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('nucleotide alterations', 'Var', (91, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (173, 182))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('cirrhotic liver', 'Phenotype', 'HP:0001394', (38, 53))	('tumor', 'Disease', 'MESH:D009369', (281, 286))	('cirrhotic liver', 'Disease', (38, 53))	('tumor', 'Disease', (29, 34))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (158, 182))	('tumor', 'Phenotype', 'HP:0002664', (281, 286))	('cirrhotic liver', 'Disease', 'MESH:D008103', (38, 53))	('hepatocellular carcinoma', 'Disease', (158, 182))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (158, 182))	('tumor', 'Disease', (281, 286))
413992	26083936	Although the majority of the mutated genes detected in cirrhotic tissues were thought to be passenger mutations, the leptin receptor gene (LEPR) was identified as a putative cancer-related gene mutated in both cirrhotic tissues and hepatocellular carcinoma.	('LEPR', 'Gene', (139, 143))	('leptin receptor', 'Gene', '3953', (117, 132))	('cancer', 'Disease', (174, 180))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (232, 256))	('carcinoma', 'Phenotype', 'HP:0030731', (247, 256))	('mutated', 'Var', (194, 201))	('hepatocellular carcinoma', 'Disease', (232, 256))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (232, 256))	('leptin receptor', 'Gene', (117, 132))	('LEPR', 'Gene', '3953', (139, 143))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))
413993	26083936	Additional deep sequencing analyses on TP53, CTNNB1, and LEPR genes revealed low-abundance mutations in more than half of the nontumorous cirrhotic tissues analyzed.	('CTNNB1', 'Gene', '1499', (45, 51))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('LEPR', 'Gene', (57, 61))	('CTNNB1', 'Gene', (45, 51))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('mutations', 'Var', (91, 100))	('TP53', 'Gene', '7157', (39, 43))	('LEPR', 'Gene', '3953', (57, 61))	('tumor', 'Disease', (129, 134))	('TP53', 'Gene', (39, 43))
413994	26083936	reported whole exome sequencing on one dysplastic nodule and two hepatocellular carcinomas in the same patient with HBV infection, and, consistent with our results, several mutations were detected in dysplastic nodules as well as tumor tissues, although there was no overlap in the mutations between dysplastic nodules and hepatocellular carcinomas.	('hepatocellular carcinomas', 'Disease', 'MESH:D006528', (65, 90))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (323, 347))	('dysplastic', 'Disease', (200, 210))	('dysplastic', 'Disease', 'MESH:D004416', (39, 49))	('hepatocellular carcinomas', 'Phenotype', 'HP:0001402', (65, 90))	('HBV infection', 'Disease', (116, 129))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('dysplastic nodules', 'Disease', 'MESH:D004416', (300, 318))	('dysplastic', 'Disease', 'MESH:D004416', (300, 310))	('hepatocellular carcinomas', 'Disease', (65, 90))	('carcinomas', 'Phenotype', 'HP:0030731', (80, 90))	('dysplastic', 'Disease', (39, 49))	('patient', 'Species', '9606', (103, 110))	('dysplastic nodules', 'Disease', (200, 218))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (65, 89))	('tumor', 'Disease', (230, 235))	('HBV infection', 'Disease', 'MESH:D006509', (116, 129))	('dysplastic', 'Disease', (300, 310))	('hepatocellular carcinomas', 'Disease', 'MESH:D006528', (323, 348))	('mutations', 'Var', (173, 182))	('tumor', 'Disease', 'MESH:D009369', (230, 235))	('hepatocellular carcinomas', 'Phenotype', 'HP:0001402', (323, 348))	('dysplastic nodules and hepatocellular carcinomas', 'Disease', 'MESH:D006528', (300, 348))	('carcinoma', 'Phenotype', 'HP:0030731', (338, 347))	('carcinomas', 'Phenotype', 'HP:0030731', (338, 348))	('dysplastic nodules', 'Disease', 'MESH:D004416', (200, 218))	('dysplastic', 'Disease', 'MESH:D004416', (200, 210))	('hepatocellular carcinomas', 'Disease', (323, 348))	('detected', 'Reg', (188, 196))	('dysplastic nodules', 'Disease', (300, 318))
413995	26083936	These findings indicate that oncogenic mutations of genes related to hepatocarcinogenesis latently accumulate in cirrhotic livers with viral infection.	('hepatocarcinogenesis latently', 'Disease', (69, 98))	('cirrhotic liver', 'Disease', (113, 128))	('hepatocarcinogenesis latently', 'Disease', 'MESH:D055985', (69, 98))	('mutations', 'Var', (39, 48))	('cirrhotic liver', 'Disease', 'MESH:D008103', (113, 128))	('viral infection', 'Disease', 'MESH:D001102', (135, 150))	('cirrhotic liver', 'Phenotype', 'HP:0001394', (113, 128))	('cirrhotic livers', 'Phenotype', 'HP:0001394', (113, 129))	('accumulate', 'PosReg', (99, 109))	('viral infection', 'Disease', (135, 150))
413996	26083936	Thus, deep sequencing analyses on inflamed noncancerous tissues have elucidated the accumulation of putative pro-oncogenic mutations of cancer-related genes in the noncancerous tissues of various organs during the process of inflammation-associated carcinogenesis.	('carcinogenesis', 'Disease', (249, 263))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('inflammation', 'Disease', 'MESH:D007249', (225, 237))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('cancerous', 'Disease', (46, 55))	('cancer', 'Disease', (46, 52))	('inflammation', 'Disease', (225, 237))	('cancer', 'Disease', (167, 173))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('cancerous', 'Disease', (167, 176))	('cancer', 'Disease', (136, 142))	('cancerous', 'Disease', 'MESH:D009369', (46, 55))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('cancerous', 'Disease', 'MESH:D009369', (167, 176))	('carcinogenesis', 'Disease', 'MESH:D063646', (249, 263))	('mutations', 'Var', (123, 132))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
413998	26083936	Several studies clarified that C:G>T:A transitions at XpCpG trinucleotides (X: any nucleotide, under bar: mutated nucleotide) are the most prominent mutational signature in many types of cancers, particularly gastrointestinal cancers (Figure 2).	('cancers', 'Disease', 'MESH:D009369', (187, 194))	('trinucleotides', 'Chemical', '-', (60, 74))	('cancers', 'Phenotype', 'HP:0002664', (187, 194))	('cancers', 'Disease', (187, 194))	('cancers', 'Phenotype', 'HP:0002664', (226, 233))	('C:G>T', 'Var', (31, 36))	('gastrointestinal cancers', 'Disease', 'MESH:D004067', (209, 233))	('cancers', 'Disease', (226, 233))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('cancers', 'Disease', 'MESH:D009369', (226, 233))	('gastrointestinal cancers', 'Disease', (209, 233))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
414000	26083936	In gastric cancer, C:G>T:A transitions at XpCpG sites as well as GpCpX sites are dominantly observed, and high rates of T:A>G:C transversions at XpTpT sites (specifically at CpTpT sites) were also recently observed in some microsatellite-stable gastric cancers.	('gastric cancers', 'Disease', (245, 260))	('gastric cancers', 'Disease', 'MESH:D013274', (245, 260))	('gastric cancers', 'Phenotype', 'HP:0012126', (245, 260))	('gastric cancer', 'Phenotype', 'HP:0012126', (3, 17))	('cancers', 'Phenotype', 'HP:0002664', (253, 260))	('C:G>T:A', 'Var', (19, 26))	('gastric cancer', 'Disease', 'MESH:D013274', (245, 259))	('T:A>G:C transversions', 'Var', (120, 141))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('XpTpT', 'Gene', (145, 150))	('gastric cancer', 'Phenotype', 'HP:0012126', (245, 259))	('observed', 'Reg', (206, 214))	('gastric cancer', 'Disease', (3, 17))	('gastric cancer', 'Disease', 'MESH:D013274', (3, 17))	('cancer', 'Phenotype', 'HP:0002664', (253, 259))
414003	26083936	While T:A>G:C transversions at XpTpT sites are most frequently observed in esophageal adenocarcinomas similar to some gastric cancers, C:G>T:A transitions at XpCpG trinucleotides are the most predominant patterns in esophageal squamous cell carcinoma, followed by C:G>G:C transversions and C:G>T:A transitions at TpCpX motifs.	('esophageal adenocarcinomas', 'Disease', 'MESH:D004938', (75, 101))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('carcinoma', 'Phenotype', 'HP:0030731', (241, 250))	('C:G>T:A', 'Var', (135, 142))	('trinucleotides', 'Chemical', '-', (164, 178))	('esophageal squamous cell carcinoma', 'Disease', (216, 250))	('gastric cancers', 'Phenotype', 'HP:0012126', (118, 133))	('cancers', 'Phenotype', 'HP:0002664', (126, 133))	('esophageal adenocarcinomas', 'Disease', (75, 101))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (75, 100))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (216, 250))	('gastric cancer', 'Phenotype', 'HP:0012126', (118, 132))	('gastric cancers', 'Disease', (118, 133))	('gastric cancers', 'Disease', 'MESH:D013274', (118, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('observed', 'Reg', (63, 71))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (227, 250))	('carcinomas', 'Phenotype', 'HP:0030731', (91, 101))
414004	26083936	Hepatocellular carcinoma has unique mutational signatures, such as T:A>C:G transitions in ApTpX sequences and T:A>A:T transversions in CpTpG sequences, in addition to C:G>T:A transitions in XpCpG motifs.	('T:A>A:T transversions', 'Var', (110, 131))	('ApTpX', 'Gene', (90, 95))	('Hepatocellular carcinoma', 'Disease', 'MESH:D006528', (0, 24))	('transitions', 'Reg', (75, 86))	('carcinoma', 'Phenotype', 'HP:0030731', (15, 24))	('CpTpG sequences', 'Gene', (135, 150))	('T:A>C:G', 'Var', (67, 74))	('Hepatocellular carcinoma', 'Disease', (0, 24))	('transversions', 'Var', (118, 131))	('CpTpG', 'Chemical', '-', (135, 140))	('Hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (0, 24))
414009	26083936	Tumors with microsatellite instability in many cancer types have numerous substitutions and indels due to defects of mismatch repair function caused by promoter methylation of MLH1 or mutations of MSH2, MSH3, and MSH6.	('mutations', 'Var', (184, 193))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('MSH6', 'Gene', (213, 217))	('cancer', 'Disease', (47, 53))	('MSH6', 'Gene', '2956', (213, 217))	('Tumors', 'Disease', (0, 6))	('MSH3', 'Gene', (203, 207))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('MSH3', 'Gene', '4437', (203, 207))	('MSH2', 'Gene', (197, 201))	('substitutions', 'Var', (74, 87))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('MLH1', 'Gene', (176, 180))	('MSH2', 'Gene', '4436', (197, 201))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('promoter', 'MPA', (152, 160))	('mismatch repair function', 'MPA', (117, 141))	('defects', 'NegReg', (106, 113))	('MLH1', 'Gene', '4292', (176, 180))
414010	26083936	Tumors with mutations in POLE or POLD1 have extreme numbers of mutations due to an impaired proofreading function of DNA polymerases.	('POLE', 'Gene', (25, 29))	('mutations', 'Var', (63, 72))	('POLD1', 'Gene', (33, 38))	('mutations', 'Var', (12, 21))	('POLD1', 'Gene', '5424', (33, 38))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('proofreading function', 'MPA', (92, 113))	('DNA polymerases', 'Enzyme', (117, 132))	('impaired', 'NegReg', (83, 91))
414011	26083936	Some tumors with inactivating mutations of BRCA1 or BRCA2, such as some breast and pancreatic cancers, have substantial numbers of larger deletions (up to 50 bp) with overlapping microhomology at breakpoint junctions.	('BRCA1', 'Gene', (43, 48))	('tumors', 'Disease', (5, 11))	('BRCA2', 'Gene', (52, 57))	('tumors', 'Disease', 'MESH:D009369', (5, 11))	('inactivating mutations', 'Var', (17, 39))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (83, 101))	('breast', 'Disease', (72, 78))	('BRCA2', 'Gene', '675', (52, 57))	('cancers', 'Phenotype', 'HP:0002664', (94, 101))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (83, 100))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('BRCA1', 'Gene', '672', (43, 48))	('pancreatic cancers', 'Disease', 'MESH:D010190', (83, 101))	('pancreatic cancers', 'Disease', (83, 101))	('tumors', 'Phenotype', 'HP:0002664', (5, 11))
414012	26083936	Ultraviolet light, a well-known extrinsic mutagen, mainly induces C:G>T:A transitions in dipyrimidines, and accordingly this mutation pattern is predominant in melanoma and basal cell carcinoma, providing evidence that ultraviolet light is a causative factor in the development of these tumors.	('carcinoma', 'Phenotype', 'HP:0030731', (184, 193))	('dipyrimidines', 'Chemical', '-', (89, 102))	('C:G>T:A transitions', 'Var', (66, 85))	('melanoma', 'Phenotype', 'HP:0002861', (160, 168))	('basal cell carcinoma', 'Disease', (173, 193))	('induces', 'Reg', (58, 65))	('melanoma', 'Disease', (160, 168))	('melanoma', 'Disease', 'MESH:D008545', (160, 168))	('basal cell carcinoma', 'Disease', 'MESH:D002280', (173, 193))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (173, 193))	('tumors', 'Disease', 'MESH:D009369', (287, 293))	('tumors', 'Phenotype', 'HP:0002664', (287, 293))	('tumor', 'Phenotype', 'HP:0002664', (287, 292))	('tumors', 'Disease', (287, 293))
414013	26083936	Benzo[a]pyrene, a convincingly established carcinogen contained in tobacco, is likely to cause C:G>A:T transversions, and this mutation pattern is dominantly observed in lung cancers, especially in those associated with smokers.	('Benzo[a]pyrene', 'Chemical', 'MESH:D001564', (0, 14))	('cause', 'Reg', (89, 94))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('C:G>A:T transversions', 'Var', (95, 116))	('lung cancers', 'Phenotype', 'HP:0100526', (170, 182))	('lung cancers', 'Disease', (170, 182))	('cancers', 'Phenotype', 'HP:0002664', (175, 182))	('lung cancer', 'Phenotype', 'HP:0100526', (170, 181))	('tobacco', 'Species', '4097', (67, 74))	('lung cancers', 'Disease', 'MESH:D008175', (170, 182))
414016	26083936	On the other hand, inflammatory stimulation elicits aberrant AID expression in epithelial cells and overexpressed AID could induce mutations in various non-immunoglobulin genes and trigger inflammation-associated tumorigenesis, including gastric carcinogenesis associated with H. pylori-related gastritis and hepatocarcinogenesis associated with chronic hepatitis C. AID deaminates C to U, resulting in the generation of a U:G mismatch.	('trigger', 'Reg', (181, 188))	('non-immunoglobulin', 'Gene', (152, 170))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('epithelia', 'Disease', (79, 88))	('resulting in', 'Reg', (390, 402))	('inflammation', 'Disease', (189, 201))	('chronic hepatitis C', 'Disease', (346, 365))	('H. pylori', 'Species', '210', (277, 286))	('gastritis', 'Phenotype', 'HP:0005263', (295, 304))	('gastritis and hepatocarcinogenesis', 'Disease', 'MESH:D005756', (295, 329))	('gastric carcinogenesis', 'Disease', (238, 260))	('chronic hepatitis', 'Phenotype', 'HP:0200123', (346, 363))	('gastric carcinogenesis', 'Disease', 'MESH:D063646', (238, 260))	('tumor', 'Disease', (213, 218))	('mutations', 'Var', (131, 140))	('hepatitis', 'Phenotype', 'HP:0012115', (354, 363))	('chronic hepatitis C', 'Disease', 'MESH:D019698', (346, 365))	('U:G mismatch', 'MPA', (423, 435))	('induce', 'Reg', (124, 130))	('inflammation', 'Disease', 'MESH:D007249', (189, 201))	('tumor', 'Disease', 'MESH:D009369', (213, 218))	('epithelia', 'Disease', 'None', (79, 88))
414017	26083936	Such AID-induced mutagenesis is genome-widely confirmed by experimental models in which AID predominantly caused C:G>T:A transitions in the known preferred AID target sequence, i.e., WRCY motifs (W = A or T, R = A or G, and Y = C or T) or RpCpX trinucleotides.	('trinucleotides', 'Chemical', '-', (245, 259))	('caused', 'Reg', (106, 112))	('W = A', 'Var', (196, 201))
414019	26083936	In contrast to AID, APOBEC3B exhibits a strong preference for deaminating C residues flanked by T. Although the function of APOBEC3B in normal conditions is unknown, APOBEC3B expression is correlated with frequencies of C:G>T:A transitions or C:G>G:C transversions in TpCpX motifs in several types of cancer, including breast cancer and lung cancer.	('breast cancer', 'Disease', 'MESH:D001943', (319, 332))	('correlated', 'Reg', (189, 199))	('lung cancer', 'Disease', 'MESH:D008175', (337, 348))	('breast cancer', 'Disease', (319, 332))	('cancer', 'Disease', (342, 348))	('lung cancer', 'Phenotype', 'HP:0100526', (337, 348))	('APOBEC3B', 'Gene', '9582', (124, 132))	('cancer', 'Phenotype', 'HP:0002664', (342, 348))	('TpCpX motifs', 'Gene', (268, 280))	('C:G>T:A transitions', 'Var', (220, 239))	('cancer', 'Disease', (301, 307))	('cancer', 'Disease', (326, 332))	('APOBEC3B', 'Gene', '9582', (20, 28))	('cancer', 'Phenotype', 'HP:0002664', (301, 307))	('APOBEC3B', 'Gene', (166, 174))	('cancer', 'Phenotype', 'HP:0002664', (326, 332))	('cancer', 'Disease', 'MESH:D009369', (342, 348))	('APOBEC3B', 'Gene', (124, 132))	('C:G>G:C transversions', 'Var', (243, 264))	('lung cancer', 'Disease', (337, 348))	('cancer', 'Disease', 'MESH:D009369', (301, 307))	('breast cancer', 'Phenotype', 'HP:0003002', (319, 332))	('cancer', 'Disease', 'MESH:D009369', (326, 332))	('APOBEC3B', 'Gene', (20, 28))	('APOBEC3B', 'Gene', '9582', (166, 174))
414027	26083936	In gastric cancers, the most common mutation is C:G>T:A transitions, more than half of which occur in XpCpG trinucleotides.	('gastric cancer', 'Phenotype', 'HP:0012126', (3, 17))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('gastric cancers', 'Disease', 'MESH:D013274', (3, 18))	('common', 'Reg', (29, 35))	('gastric cancers', 'Disease', (3, 18))	('gastric cancers', 'Phenotype', 'HP:0012126', (3, 18))	('trinucleotides', 'Chemical', '-', (108, 122))	('cancers', 'Phenotype', 'HP:0002664', (11, 18))	('C:G>T:A', 'Var', (48, 55))
414029	26083936	In addition, gastric cancers also have a preponderance of C:G>T:A transitions at non-CpG sites, especially at GpCpX sequences.	('gastric cancer', 'Phenotype', 'HP:0012126', (13, 27))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('gastric cancers', 'Disease', 'MESH:D013274', (13, 28))	('gastric cancers', 'Disease', (13, 28))	('gastric cancers', 'Phenotype', 'HP:0012126', (13, 28))	('cancers', 'Phenotype', 'HP:0002664', (21, 28))	('C:G>T:A', 'Var', (58, 65))
414031	26083936	Moreover, deep sequencing on selected cancer-related genes in nontumorous gastritis mucosa revealed a strong preference for C:G>T:A transitions at GpCpX sequences, similar to those in gastric cancer tissues.	('gastric cancer', 'Disease', 'MESH:D013274', (184, 198))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('nontumorous gastritis mucosa', 'Disease', 'MESH:D005756', (62, 90))	('gastric cancer', 'Phenotype', 'HP:0012126', (184, 198))	('nontumorous gastritis mucosa', 'Disease', (62, 90))	('gastritis', 'Phenotype', 'HP:0005263', (74, 83))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('cancer', 'Disease', (192, 198))	('cancer', 'Disease', 'MESH:D009369', (192, 198))	('cancer', 'Disease', (38, 44))	('gastric cancer', 'Disease', (184, 198))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('C:G>T:A', 'Var', (124, 131))
414033	26083936	In esophageal adenocarcinomas, the predominant mutational signature is T:A>G:C transversions with striking enrichment at the CpTpT site.	('esophageal adenocarcinomas', 'Disease', (3, 29))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (3, 28))	('T:A>G:C transversions', 'Var', (71, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (19, 28))	('esophageal adenocarcinomas', 'Disease', 'MESH:D004938', (3, 29))	('carcinomas', 'Phenotype', 'HP:0030731', (19, 29))
414034	26083936	This mutational signature is relatively rare in other cancers, but some microsatellite-stable gastric cancers exhibit the same pattern.	('cancers', 'Phenotype', 'HP:0002664', (54, 61))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('cancers', 'Disease', (54, 61))	('cancers', 'Disease', 'MESH:D009369', (54, 61))	('microsatellite-stable', 'Var', (72, 93))	('gastric cancer', 'Phenotype', 'HP:0012126', (94, 108))	('cancers', 'Disease', 'MESH:D009369', (102, 109))	('gastric cancers', 'Disease', 'MESH:D013274', (94, 109))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))	('cancers', 'Disease', (102, 109))	('gastric cancers', 'Disease', (94, 109))	('gastric cancers', 'Phenotype', 'HP:0012126', (94, 109))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
414037	26083936	On the other hand, the predominant mutational signature of esophageal squamous cell carcinoma is C:G>T:A transitions at XpCpG and TpCpX sites, followed by C:G>G:C transversions.	('C:G>T:A', 'Var', (97, 104))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (70, 93))	('esophageal squamous cell carcinoma', 'Disease', (59, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (59, 93))
414039	26083936	Interestingly, C:G>A:T transversions, which are dominantly detected in lung squamous cell carcinoma, are not predominant patterns in esophageal squamous cell carcinoma.	('detected', 'Reg', (59, 67))	('esophageal squamous cell carcinoma', 'Disease', (133, 167))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (76, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('lung squamous cell carcinoma', 'Disease', (71, 99))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (71, 99))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (133, 167))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (71, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (158, 167))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (144, 167))	('C:G>A:T transversions', 'Var', (15, 36))
414042	26083936	In addition to C:G>T:A transitions in XpCpG contexts, T:A>C:G transitions in ApTpX contexts and T:A>A:T transversions in CpTpG contexts are characteristic patterns in hepatocellular carcinoma.	('T:A>', 'Var', (54, 58))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (167, 191))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (167, 191))	('carcinoma', 'Phenotype', 'HP:0030731', (182, 191))	('hepatocellular carcinoma', 'Disease', (167, 191))	('CpTpG', 'Chemical', '-', (121, 126))
414043	26083936	While C:G>T:A transitions in XpCpG contexts are commonly observed across all ancestry and sexes, T:A>C:G transitions in ApTpA contexts and T:A>A:T transversions in CpTpG contexts are especially increased in Japanese males and US-Asian cases, respectively.	('T:A>C:G', 'Var', (97, 104))	('CpTpG', 'Chemical', '-', (164, 169))	('T:A>A', 'Var', (139, 144))	('ApTpA', 'Gene', (120, 125))
414047	26083936	For example, in gastric cancers, microsatellite-stable cancers exhibit chromosomal instability and T:A>G:C transversions at the CpTpT site; microsatellite-instable cancers have features of chromosomal stability and a large number of single nucleotide substitutions with relatively high T:A>C:G transition rates; diffuse-type cancers have relatively fewer single nucleotide variants and copy number aberrations.	('cancers', 'Disease', 'MESH:D009369', (55, 62))	('diffuse-type', 'Disease', (312, 324))	('cancers', 'Disease', 'MESH:D009369', (164, 171))	('chromosomal instability', 'Phenotype', 'HP:0040012', (71, 94))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('cancers', 'Phenotype', 'HP:0002664', (325, 332))	('cancers', 'Disease', (325, 332))	('cancer', 'Phenotype', 'HP:0002664', (325, 331))	('cancers', 'Phenotype', 'HP:0002664', (24, 31))	('cancers', 'Phenotype', 'HP:0002664', (55, 62))	('gastric cancers', 'Disease', 'MESH:D013274', (16, 31))	('cancers', 'Disease', (24, 31))	('cancers', 'Disease', (55, 62))	('gastric cancers', 'Disease', (16, 31))	('gastric cancers', 'Phenotype', 'HP:0012126', (16, 31))	('single nucleotide substitutions', 'Var', (233, 264))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('cancers', 'Phenotype', 'HP:0002664', (164, 171))	('cancers', 'Disease', (164, 171))	('gastric cancer', 'Phenotype', 'HP:0012126', (16, 30))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('cancers', 'Disease', 'MESH:D009369', (325, 332))	('cancers', 'Disease', 'MESH:D009369', (24, 31))
414050	26083936	Moreover, mutational signatures determined by NGS also provide the footprints of carcinogenic processes.	('carcinogenic processes', 'Disease', 'MESH:D009385', (81, 103))	('mutational', 'Var', (10, 20))	('carcinogenic processes', 'Disease', (81, 103))
414052	26083936	There are various patterns of mutational signatures observed in human cancers whose mutagenic processes are not yet explained.	('human', 'Species', '9606', (64, 69))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('mutational', 'Var', (30, 40))	('cancers', 'Phenotype', 'HP:0002664', (70, 77))	('cancers', 'Disease', 'MESH:D009369', (70, 77))	('cancers', 'Disease', (70, 77))
414058	33363020	In this study, AUNIP expression was increased in hepatocellular carcinoma (HCC) and lung adenocarcinoma (LUAD) according to data from The Cancer Genome Atlas (TCGA) database, Integrative Molecular Database of Hepatocellular Carcinoma (HCCDB), and Gene Expression Omnibus (GEO) database (GSE45436, GSE102079, GSE10072, GSE31210, and GSE43458).	('hepatocellular carcinoma', 'Disease', (49, 73))	('GSE102079', 'Var', (297, 306))	('Hepatocellular Carcinoma', 'Disease', 'MESH:D006528', (209, 233))	('lung adenocarcinoma', 'Disease', (84, 103))	('AUNIP', 'Gene', '79000', (15, 20))	('AUNIP', 'Gene', (15, 20))	('Cancer', 'Phenotype', 'HP:0002664', (138, 144))	('increased', 'PosReg', (36, 45))	('GSE43458', 'Var', (332, 340))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (84, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))	('Cancer', 'Disease', (138, 144))	('Hepatocellular Carcinoma', 'Phenotype', 'HP:0001402', (209, 233))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (49, 73))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (84, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('HCC', 'Phenotype', 'HP:0001402', (75, 78))	('GSE10072', 'Var', (308, 316))	('HCC', 'Phenotype', 'HP:0001402', (235, 238))	('Carcinoma', 'Phenotype', 'HP:0030731', (224, 233))	('Cancer', 'Disease', 'MESH:D009369', (138, 144))	('GSE31210', 'Var', (318, 326))	('HCCDB', 'Chemical', '-', (235, 240))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (49, 73))	('LUAD', 'Phenotype', 'HP:0030078', (105, 109))	('GSE45436', 'Var', (287, 295))	('Hepatocellular Carcinoma', 'Disease', (209, 233))
414059	33363020	Further, according to copy number variation analysis, AUNIP up-regulation may be associated with copy number variation.	('AUNIP', 'Gene', '79000', (54, 59))	('AUNIP', 'Gene', (54, 59))	('up-regulation', 'PosReg', (60, 73))	('copy number variation', 'Var', (97, 118))
414065	33363020	More specifically, high AUNIP expression was associated with DNA replication, cell cycle, oocyte meiosis, homologous recombination, mismatch repair, the p53 signal transduction pathway, and progesterone-mediated oocyte maturation.	('AUNIP', 'Gene', '79000', (24, 29))	('AUNIP', 'Gene', (24, 29))	('progesterone-mediated oocyte maturation', 'CPA', (190, 229))	('high', 'Var', (19, 23))	('oocyte meiosis', 'CPA', (90, 104))	('progesterone', 'Chemical', 'MESH:D011374', (190, 202))	('associated', 'Reg', (45, 55))	('p53', 'Gene', (153, 156))	('p53', 'Gene', '7157', (153, 156))	('homologous', 'CPA', (106, 116))	('mismatch', 'Disease', (132, 140))	('DNA replication', 'CPA', (61, 76))	('cell cycle', 'CPA', (78, 88))
414094	33363020	From the Gene Expression Omnibus (GEO) database , we selected two HCC datasets GSE45436 and GSE102079 and four LUAD datasets GSE10072, GSE31210, GSE43458, and GSE50081 for bioinformatics analysis (involving analyzing AUNIP expression in cancer tissues relative to non-carcinoma tissues, survival analysis, and analyzing the diagnostic performance of AUNIP).	('GSE45436', 'Var', (79, 87))	('GSE10072', 'Var', (125, 133))	('AUNIP', 'Gene', '79000', (217, 222))	('AUNIP', 'Gene', (217, 222))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('GSE102079', 'Var', (92, 101))	('LUAD', 'Phenotype', 'HP:0030078', (111, 115))	('GSE43458', 'Var', (145, 153))	('non-carcinoma', 'Disease', 'MESH:D009369', (264, 277))	('non-carcinoma', 'Disease', (264, 277))	('cancer', 'Disease', 'MESH:D009369', (237, 243))	('HCC', 'Phenotype', 'HP:0001402', (66, 69))	('cancer', 'Disease', (237, 243))	('AUNIP', 'Gene', '79000', (350, 355))	('AUNIP', 'Gene', (350, 355))	('GSE31210', 'Var', (135, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (268, 277))
414122	33363020	Moreover, an analysis of two HCC cohorts in the GEO database (GSE45436 and GSE102079) showed that AUNIP was highly expressed in HCC in both cohorts ( Figures 3B, C ), while an analysis of three LUAD cohorts in the GEO database (GSE10072, GSE31210, and GSE43458) showed that AUNIP was highly expressed in LUAD in all three cohorts ( Figures 3D-F ).	('AUNIP', 'Gene', (274, 279))	('HCC', 'Phenotype', 'HP:0001402', (128, 131))	('AUNIP', 'Gene', '79000', (274, 279))	('HCC', 'Phenotype', 'HP:0001402', (29, 32))	('GSE102079', 'Var', (75, 84))	('LUAD', 'Phenotype', 'HP:0030078', (304, 308))	('LUAD', 'Phenotype', 'HP:0030078', (194, 198))	('AUNIP', 'Gene', '79000', (98, 103))	('AUNIP', 'Gene', (98, 103))	('HCC', 'Disease', (128, 131))
414124	33363020	Next, as copy number amplification is a genetic mechanism underlying oncogene up-regulation, we analyzed AUNIP mRNA expression (z-scores) and copy number data regarding HCC and LUAD from cBioPortal.	('HCC', 'Phenotype', 'HP:0001402', (169, 172))	('AUNIP', 'Gene', '79000', (105, 110))	('AUNIP', 'Gene', (105, 110))	('LUAD', 'Phenotype', 'HP:0030078', (177, 181))	('copy', 'Var', (9, 13))
414125	33363020	As expected, AUNIP expression increased significantly in the Gain group and was significantly correlated with copy number amplification in both HCC and LUAD ( Figures 3G-J ).	('AUNIP', 'Gene', (13, 18))	('correlated', 'Reg', (94, 104))	('copy number amplification', 'Var', (110, 135))	('LUAD', 'Phenotype', 'HP:0030078', (152, 156))	('increased', 'PosReg', (30, 39))	('HCC', 'Disease', (144, 147))	('AUNIP', 'Gene', '79000', (13, 18))	('HCC', 'Phenotype', 'HP:0001402', (144, 147))
414126	33363020	Therefore, copy number variation may be a primary mechanism underlying AUNIP up-regulation in HCC and LUAD.	('HCC', 'Phenotype', 'HP:0001402', (94, 97))	('AUNIP', 'Gene', '79000', (71, 76))	('up-regulation', 'PosReg', (77, 90))	('copy number variation', 'Var', (11, 32))	('HCC', 'Disease', (94, 97))	('LUAD', 'Disease', (102, 106))	('AUNIP', 'Gene', (71, 76))	('LUAD', 'Phenotype', 'HP:0030078', (102, 106))
414129	33363020	We found that the low AUNIP expression group had better OS for both the HCC cases (ICGC: P<0.001) and the LUAD cases (GSE31210: P<0.001; GSE50081: P<0.001) ( Figures 4A, F, G ).	('HCC', 'Disease', (72, 75))	('GSE31210:', 'Var', (118, 127))	('LUAD', 'Phenotype', 'HP:0030078', (106, 110))	('HCC', 'Phenotype', 'HP:0001402', (72, 75))	('better', 'PosReg', (49, 55))	('AUNIP', 'Gene', '79000', (22, 27))	('AUNIP', 'Gene', (22, 27))
414139	33363020	Meanwhile, GSVA confirmed that the NESs for 7 of these 10 pathways in HCC and LUAD (i.e., cell cycle, DNA replication, homologous recombination, oocyte meiosis, progesterone-mediated oocyte maturation, mismatch repair, and the p53 signaling pathway) were significantly increased in the high expression group of AUNIP ( Figures 6D, E, I, J ).	('p53', 'Gene', (227, 230))	('mismatch repair', 'CPA', (202, 217))	('oocyte meiosis', 'CPA', (145, 159))	('LUAD', 'Phenotype', 'HP:0030078', (78, 82))	('HCC', 'Phenotype', 'HP:0001402', (70, 73))	('LUAD', 'CPA', (78, 82))	('increased', 'PosReg', (269, 278))	('HCC', 'CPA', (70, 73))	('p53', 'Gene', '7157', (227, 230))	('cell cycle', 'CPA', (90, 100))	('AUNIP', 'Gene', '79000', (311, 316))	('homologous recombination', 'CPA', (119, 143))	('high expression', 'Var', (286, 301))	('progesterone-mediated oocyte maturation', 'CPA', (161, 200))	('progesterone', 'Chemical', 'MESH:D011374', (161, 173))	('AUNIP', 'Gene', (311, 316))	('GSVA', 'Chemical', '-', (11, 15))	('DNA replication', 'CPA', (102, 117))
414163	33363020	As the results showed, AUNIP expression significantly increased in the Gain group and AUNIP expression was significantly correlated with copy number amplification in HCC and LUAD ( Figures 3G-J ).	('correlated', 'Reg', (121, 131))	('LUAD', 'Phenotype', 'HP:0030078', (174, 178))	('AUNIP', 'Gene', '79000', (86, 91))	('AUNIP', 'Gene', (86, 91))	('HCC', 'Phenotype', 'HP:0001402', (166, 169))	('increased', 'PosReg', (54, 63))	('AUNIP', 'Gene', '79000', (23, 28))	('AUNIP', 'Gene', (23, 28))	('copy number amplification', 'Var', (137, 162))	('HCC', 'Disease', (166, 169))
414164	33363020	This suggested that copy number amplification might be a mechanism underlying AUNIP up-regulation in HCC and LUAD.	('HCC', 'Disease', (101, 104))	('HCC', 'Phenotype', 'HP:0001402', (101, 104))	('up-regulation', 'PosReg', (84, 97))	('LUAD', 'Phenotype', 'HP:0030078', (109, 113))	('LUAD', 'Disease', (109, 113))	('AUNIP', 'Gene', (78, 83))	('AUNIP', 'Gene', '79000', (78, 83))	('copy number amplification', 'Var', (20, 45))
414166	33363020	TCGA data indicated that high AUNIP expression was related to poorer OS in 10 diverse cancer types, comprising LUAD, LIHC, ACC, KIRC, KIRP, LGG, MESO, PAAD, SARC, and UCEC ( Figure 2 ).	('MESO', 'Disease', (145, 149))	('SARC', 'Phenotype', 'HP:0100242', (157, 161))	('KIRP', 'Disease', (134, 138))	('LUAD', 'Phenotype', 'HP:0030078', (111, 115))	('PAAD', 'Phenotype', 'HP:0006725', (151, 155))	('AUNIP', 'Gene', '79000', (30, 35))	('KIRC', 'Disease', (128, 132))	('AUNIP', 'Gene', (30, 35))	('cancer', 'Disease', (86, 92))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('LUAD', 'Disease', (111, 115))	('PAAD', 'Disease', (151, 155))	('LIHC', 'Disease', (117, 121))	('SARC', 'Disease', (157, 161))	('LGG', 'Disease', (140, 143))	('UCEC', 'Disease', (167, 171))	('poorer', 'NegReg', (62, 68))	('ACC', 'Phenotype', 'HP:0006744', (123, 126))	('high', 'Var', (25, 29))	('ACC', 'Disease', (123, 126))	('cancer', 'Disease', 'MESH:D009369', (86, 92))
414170	33363020	Moreover, GEO and ICGC data confirmed the association of high AUNIP expression with poor OS for HCC and LUAD ( Figures 4A, F, G ).	('AUNIP', 'Gene', '79000', (62, 67))	('LUAD', 'Disease', (104, 108))	('high', 'Var', (57, 61))	('AUNIP', 'Gene', (62, 67))	('LUAD', 'Phenotype', 'HP:0030078', (104, 108))	('HCC', 'Disease', (96, 99))	('HCC', 'Phenotype', 'HP:0001402', (96, 99))
414175	33363020	Aberrant expression of proteins associated with the cell cycle can lead to tumor invasion, metastasis, induce drug resistance, and resist apoptosis.	('lead to', 'Reg', (67, 74))	('Aberrant', 'Var', (0, 8))	('resist apoptosis', 'CPA', (131, 147))	('drug resistance', 'CPA', (110, 125))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('metastasis', 'CPA', (91, 101))	('induce', 'PosReg', (103, 109))	('expression', 'MPA', (9, 19))	('proteins', 'Protein', (23, 31))	('drug resistance', 'Phenotype', 'HP:0020174', (110, 125))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', (75, 80))
414184	33363020	Without prompt and accurate repair, DSB can lead to mutation, genome instability, apoptosis, and even cancer.	('lead to', 'Reg', (44, 51))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('apoptosis', 'CPA', (82, 91))	('DSB', 'Var', (36, 39))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('genome instability', 'CPA', (62, 80))	('mutation', 'CPA', (52, 60))
414185	33363020	Impairments regarding the homologous recombination-related genes can reduce DSB repair and significantly increase the incidence of tumors.	('DSB repair', 'CPA', (76, 86))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('increase', 'PosReg', (105, 113))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('tumors', 'Disease', (131, 137))	('tumors', 'Disease', 'MESH:D009369', (131, 137))	('reduce', 'NegReg', (69, 75))	('Impairments', 'Var', (0, 11))
414207	32068166	STING pathway expression identifies non-small cell lung cancers with an immune-responsive phenotype Although the combination of anti-PD1/PD-L1 with platinum chemotherapy is a standard of care for NSCLC, clinical responses vary.	('small cell lung cancers', 'Phenotype', 'HP:0030357', (40, 63))	('lung cancers', 'Disease', (51, 63))	('anti-PD1/PD-L1', 'Var', (128, 142))	('NSCLC', 'Disease', (196, 201))	('platinum', 'Chemical', 'MESH:D010984', (148, 156))	('NSCLC', 'Disease', 'MESH:D002289', (196, 201))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('lung cancer', 'Phenotype', 'HP:0100526', (51, 62))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (40, 62))	('lung cancers', 'Disease', 'MESH:D008175', (51, 63))	('lung cancers', 'Phenotype', 'HP:0100526', (51, 63))	('NSCLC', 'Phenotype', 'HP:0030358', (196, 201))	('non-small cell lung cancers', 'Phenotype', 'HP:0030358', (36, 63))	('cancers', 'Phenotype', 'HP:0002664', (56, 63))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (36, 62))
414215	32068166	We observed that tumors with lower STING and immune gene expression show higher frequency of STK11 mutations; however, we identified a subset of these tumors that are TP53 co-mutated and display high immune- and STING- related gene expression.	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumors', 'Disease', (17, 23))	('tumors', 'Disease', (151, 157))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('tumors', 'Disease', 'MESH:D009369', (151, 157))	('STK11', 'Gene', (93, 98))	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('co-mutated', 'Var', (172, 182))	('mutations', 'Var', (99, 108))	('TP53', 'Gene', '7157', (167, 171))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('TP53', 'Gene', (167, 171))	('STK11', 'Gene', '6794', (93, 98))
414223	32068166	DNA damage, intrinsic due to tumor genomic instability or increased under the pressure of DNA damaging treatments (radiotherapy, chemotherapy, or inhibitors of DNA damage response (DDR), may stimulate the immune system and enhance tumor response to immunotherapy.	('tumor', 'Disease', 'MESH:D009369', (231, 236))	('inhibitors', 'Var', (146, 156))	('stimulate', 'PosReg', (191, 200))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('enhance', 'PosReg', (223, 230))	('tumor', 'Disease', (231, 236))	('tumor', 'Disease', (29, 34))	('immune system', 'CPA', (205, 218))
414251	32068166	demonstrated that, among KRAS mutated LUAD, tumors with STK11(LKB1) mutations are immunologically "cold" and are intrinsically resistant to anti-PD1/PD-L1 immunotherapy, and they have low expression of immune markers (including PD1, CTLA4, PD-L1, CD8) compared to other LUAD.	('tumors', 'Disease', (44, 50))	('tumors', 'Disease', 'MESH:D009369', (44, 50))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('low', 'NegReg', (184, 187))	('CTLA4', 'Gene', '1493', (233, 238))	('expression', 'MPA', (188, 198))	('LKB1', 'Gene', (62, 66))	('CTLA4', 'Gene', (233, 238))	('CD8', 'Gene', (247, 250))	('CD8', 'Gene', '925', (247, 250))	('LKB1', 'Gene', '6794', (62, 66))	('STK11', 'Gene', (56, 61))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('mutations', 'Var', (68, 77))	('KRAS', 'Gene', (25, 29))	('STK11', 'Gene', '6794', (56, 61))	('KRAS', 'Gene', '3845', (25, 29))
414252	32068166	recently demonstrated that, mechanistically, LKB1 loss inducs a silencing of the STING pathway and impaired response to cytosolic DNA in KRAS/STK11(LKB1) mutant NSCLC models and is associated with downregulation of a type I IFN signature.	('LKB1', 'Gene', (45, 49))	('silencing', 'MPA', (64, 73))	('LKB1', 'Gene', (148, 152))	('KRAS', 'Gene', '3845', (137, 141))	('downregulation', 'NegReg', (197, 211))	('loss', 'NegReg', (50, 54))	('STING pathway', 'Pathway', (81, 94))	('impaired', 'NegReg', (99, 107))	('KRAS', 'Gene', (137, 141))	('NSCLC', 'Disease', 'MESH:D002289', (161, 166))	('LKB1', 'Gene', '6794', (45, 49))	('STK11', 'Gene', (142, 147))	('LKB1', 'Gene', '6794', (148, 152))	('NSCLC', 'Disease', (161, 166))	('inducs', 'Reg', (55, 61))	('response to cytosolic DNA', 'MPA', (108, 133))	('NSCLC', 'Phenotype', 'HP:0030358', (161, 166))	('STK11', 'Gene', '6794', (142, 147))	('mutant', 'Var', (154, 160))
414254	32068166	Consistent with prior findings in KRAS-mutant lung cancers, we also observed that STK11 (LKB1) loss of function mutations were significantly enriched in the STING-low immune group (21% versus 12%, p=0.01) (Supplemental Figure 2A, Figure 2B); similar results were obtained for KRAS mutation (37% versus 28%, p=0.05) (Figure 2B).	('loss of function', 'NegReg', (95, 111))	('STK11', 'Gene', (82, 87))	('KRAS', 'Gene', '3845', (34, 38))	('lung cancers', 'Phenotype', 'HP:0100526', (46, 58))	('KRAS', 'Gene', (276, 280))	('LKB1', 'Gene', (89, 93))	('STK11', 'Gene', '6794', (82, 87))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('LKB1', 'Gene', '6794', (89, 93))	('mutations', 'Var', (112, 121))	('lung cancers', 'Disease', (46, 58))	('KRAS', 'Gene', '3845', (276, 280))	('cancers', 'Phenotype', 'HP:0002664', (51, 58))	('lung cancers', 'Disease', 'MESH:D008175', (46, 58))	('KRAS', 'Gene', (34, 38))	('lung cancer', 'Phenotype', 'HP:0100526', (46, 57))
414255	32068166	Conversely, TP53 mutations were enriched in the high STING-high immune LUAD group (56% versus 35%, p<0.001) (Figure 2B).	('TP53', 'Gene', '7157', (12, 16))	('TP53', 'Gene', (12, 16))	('high STING-high immune LUAD', 'Disease', (48, 75))	('mutations', 'Var', (17, 26))
414256	32068166	As we observed STK11 mutant LUAD in both the STING-high and -low groups, despite these tumors being universally considered to be immunologically cold, we next analyzed only the STK11/LKB1 mutant LUAD tumors (n=73) from the TCGA cohort.	('STK11', 'Gene', '6794', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('LUAD', 'Disease', (28, 32))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('LKB1', 'Gene', '6794', (183, 187))	('tumors', 'Disease', 'MESH:D009369', (200, 206))	('tumors', 'Disease', (87, 93))	('STK11', 'Gene', (177, 182))	('LKB1', 'Gene', (183, 187))	('tumors', 'Phenotype', 'HP:0002664', (200, 206))	('tumors', 'Disease', 'MESH:D009369', (87, 93))	('STK11', 'Gene', (15, 20))	('mutant', 'Var', (188, 194))	('mutant', 'Var', (21, 27))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('STK11', 'Gene', '6794', (177, 182))	('tumors', 'Disease', (200, 206))	('LUAD tumors', 'Disease', 'MESH:D009369', (195, 206))	('LUAD tumors', 'Disease', (195, 206))
414258	32068166	While the majority of STK11/LKB1 mutant tumors were in the STING-low/-intermediate group (n=55) and had low expression of immune related genes, there is a subset in the STING-high group (n=18) with higher levels of targetable immune genes, like CD274, HAVCR2, PDCD1LG2, T-cell infiltration markers, and chemokines (Figure 2C).	('PDCD1LG2', 'Gene', '80380', (260, 268))	('CD274', 'Gene', (245, 250))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('PDCD1LG2', 'Gene', (260, 268))	('STK11', 'Gene', '6794', (22, 27))	('HAVCR2', 'Gene', (252, 258))	('LKB1', 'Gene', (28, 32))	('tumors', 'Disease', 'MESH:D009369', (40, 46))	('HAVCR2', 'Gene', '84868', (252, 258))	('LKB1', 'Gene', '6794', (28, 32))	('levels', 'MPA', (205, 211))	('mutant', 'Var', (33, 39))	('expression', 'MPA', (108, 118))	('CD274', 'Gene', '29126', (245, 250))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumors', 'Disease', (40, 46))	('STK11', 'Gene', (22, 27))	('higher', 'PosReg', (198, 204))
414259	32068166	These STING-high STK11/LKB1 mutant tumors showed an "inflamed" immune phenotype, enriched for immune checkpoints and cytokines expression, which is more similar to a LKB1 wild-type tumor (Figure 2C).	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('mutant', 'Var', (28, 34))	('tumor', 'Disease', (181, 186))	('LKB1', 'Gene', '6794', (23, 27))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('STK11', 'Gene', (17, 22))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('tumor', 'Disease', (35, 40))	('tumors', 'Disease', (35, 41))	('LKB1', 'Gene', (166, 170))	('STK11', 'Gene', '6794', (17, 22))	('tumors', 'Disease', 'MESH:D009369', (35, 41))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('LKB1', 'Gene', '6794', (166, 170))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('LKB1', 'Gene', (23, 27))
414260	32068166	Interestingly, when we compared the mutation profiles of the STING-high STK11/LKB1 mutant group with the other two groups, including low or intermediate expression of these genes (immune "cold" groups), we found that the STING-high group is enriched for TP53 mutations (56% versus 16%, p=0.002) (Figure 2D).	('LKB1', 'Gene', '6794', (78, 82))	('TP53', 'Gene', '7157', (254, 258))	('TP53', 'Gene', (254, 258))	('mutant', 'Var', (83, 89))	('mutations', 'Var', (259, 268))	('STK11', 'Gene', (72, 77))	('STK11', 'Gene', '6794', (72, 77))	('LKB1', 'Gene', (78, 82))
414262	32068166	While several groups have identified STK11 mutations as predictive of poor response to immunotherapy and that STK11/KRAS mutant lung adenocarcinoma have low PD-L1 expression and STING gene silencing, our data suggest that among the STK11 mutant subgroup, there are a range of inflammatory phenotypes defined by the presence of co-mutations.	('STK11', 'Gene', (232, 237))	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('low', 'NegReg', (153, 156))	('mutant', 'Var', (121, 127))	('lung adenocarcinoma', 'Disease', (128, 147))	('STK11', 'Gene', '6794', (37, 42))	('STK11', 'Gene', '6794', (232, 237))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (128, 147))	('poor response to immunotherapy', 'Phenotype', 'HP:0002721', (70, 100))	('mutant', 'Var', (238, 244))	('PD-L1 expression', 'MPA', (157, 173))	('STK11', 'Gene', (110, 115))	('KRAS', 'Gene', (116, 120))	('mutations', 'Var', (43, 52))	('STK11', 'Gene', (37, 42))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (128, 147))	('KRAS', 'Gene', '3845', (116, 120))	('STK11', 'Gene', '6794', (110, 115))
414263	32068166	Specifically, 25% of STK11 mutant tumors have an active STING pathway, immune checkpoint expression, and inflammatory characteristics consistent with other immune "hot" NSCLC subtypes and, among these, 56% are TP53 mutant and KRAS wild-type.	('KRAS', 'Gene', '3845', (226, 230))	('NSCLC', 'Phenotype', 'HP:0030358', (169, 174))	('STING pathway', 'Pathway', (56, 69))	('tumors', 'Disease', (34, 40))	('tumors', 'Disease', 'MESH:D009369', (34, 40))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('TP53', 'Gene', (210, 214))	('mutant', 'Var', (27, 33))	('NSCLC', 'Disease', (169, 174))	('STK11', 'Gene', (21, 26))	('inflammatory', 'CPA', (105, 117))	('immune', 'CPA', (71, 77))	('NSCLC', 'Disease', 'MESH:D002289', (169, 174))	('KRAS', 'Gene', (226, 230))	('STK11', 'Gene', '6794', (21, 26))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('TP53', 'Gene', '7157', (210, 214))
414264	32068166	We investigated the difference in cGAS protein expression by RPPA in our panel of LUAD cell lines, comparing STK11/KRAS mutant cells with STK11/TP53 mutant cells.	('TP53', 'Gene', '7157', (144, 148))	('TP53', 'Gene', (144, 148))	('STK11', 'Gene', (109, 114))	('cGAS', 'Gene', '115004', (34, 38))	('KRAS', 'Gene', (115, 119))	('STK11', 'Gene', (138, 143))	('STK11', 'Gene', '6794', (109, 114))	('KRAS', 'Gene', '3845', (115, 119))	('cGAS', 'Gene', (34, 38))	('STK11', 'Gene', '6794', (138, 143))	('mutant', 'Var', (120, 126))
414265	32068166	Cell lines in the STK11/TP53 mutant group are heterogeneous in their expression of cGAS and include subsets with medium and high cGAS protein expression.	('TP53', 'Gene', (24, 28))	('cGAS', 'Gene', (129, 133))	('mutant', 'Var', (29, 35))	('cGAS', 'Gene', '115004', (83, 87))	('STK11', 'Gene', (18, 23))	('expression', 'MPA', (69, 79))	('expression', 'MPA', (142, 152))	('STK11', 'Gene', '6794', (18, 23))	('cGAS', 'Gene', (83, 87))	('cGAS', 'Gene', '115004', (129, 133))	('TP53', 'Gene', '7157', (24, 28))
414266	32068166	In contrast (but consistent with the patient data), the STK11/KRAS mutant cell lines were all cGAS low (Supplemental Figure 2B).	('KRAS', 'Gene', (62, 66))	('patient', 'Species', '9606', (37, 44))	('low', 'NegReg', (99, 102))	('cGAS', 'Gene', (94, 98))	('KRAS', 'Gene', '3845', (62, 66))	('cGAS', 'Gene', '115004', (94, 98))	('STK11', 'Gene', (56, 61))	('mutant', 'Var', (67, 73))	('STK11', 'Gene', '6794', (56, 61))
414272	32068166	We selected three LUAD NSCLC cell lines representative of three biological profiles: Calu-6 (KRAS/TP53 mutant), HCC827 (EGFR mutant), and H1944 (KRAS/STK11 mutant).	('Calu-6', 'Gene', (85, 91))	('STK11', 'Gene', (150, 155))	('KRAS', 'Gene', (93, 97))	('NSCLC', 'Phenotype', 'HP:0030358', (23, 28))	('KRAS', 'Gene', (145, 149))	('H1944', 'Var', (138, 143))	('STK11', 'Gene', '6794', (150, 155))	('LUAD NSCLC', 'Disease', 'MESH:D002289', (18, 28))	('KRAS', 'Gene', '3845', (93, 97))	('KRAS', 'Gene', '3845', (145, 149))	('TP53', 'Gene', (98, 102))	('LUAD NSCLC', 'Disease', (18, 28))	('TP53', 'Gene', '7157', (98, 102))	('HCC827', 'Gene', (112, 118))	('EGFR', 'Gene', '1956', (120, 124))	('H1944', 'CellLine', 'CVCL:1508', (138, 143))	('HCC827', 'CellLine', 'CVCL:2063', (112, 118))	('EGFR', 'Gene', (120, 124))
414274	32068166	In the KRAS/TP53 mutant LUAD cell line, Calu6, we observed a significant upregulation of multiple STING pathway proteins following cisplatin treatment, including total STING (fold change, FC=2.34, p<0.001), phospho-TBK1 (S172) (FC=1.23, p<0.001) and cGAS (FC=1.86, p=0.002), along with a moderate increase in PD-L1 (FC=1.15, p=0.028) and phospho-H2AX (S139) (FC=1.98, p<0.001), that is a marker of DNA damage, as compared to untreated controls (Figure 3A, B).	('KRAS', 'Gene', '3845', (7, 11))	('cisplatin', 'Chemical', 'MESH:D002945', (131, 140))	('TP53', 'Gene', (12, 16))	('PD-L1', 'MPA', (309, 314))	('TBK1', 'Gene', '29110', (215, 219))	('cGAS', 'Gene', (250, 254))	('increase', 'PosReg', (297, 305))	('STING pathway', 'Pathway', (98, 111))	('Calu6', 'CellLine', 'CVCL:0236', (40, 45))	('TP53', 'Gene', '7157', (12, 16))	('H2AX', 'Gene', '3014', (346, 350))	('H2AX', 'Gene', (346, 350))	('TBK1', 'Gene', (215, 219))	('mutant', 'Var', (17, 23))	('cGAS', 'Gene', '115004', (250, 254))	('KRAS', 'Gene', (7, 11))	('upregulation', 'PosReg', (73, 85))
414277	32068166	Similarly, CXCL10 and CCL5 expression was also increased after cisplatin treatment in two other KRAS/TP53 mutant LUAD cell lines, H1651 (human) and 344SQ (derived from KrasLA1/+p53R172HDeltaG/+ mice) (Figure 3D).	('human', 'Species', '9606', (137, 142))	('mutant', 'Var', (106, 112))	('cisplatin', 'Chemical', 'MESH:D002945', (63, 72))	('KRAS', 'Gene', '3845', (96, 100))	('H1651', 'CellLine', 'CVCL:1484', (130, 135))	('p53', 'Gene', (177, 180))	('p53', 'Gene', '7157', (177, 180))	('TP53', 'Gene', '7157', (101, 105))	('344SQ', 'Var', (148, 153))	('increased', 'PosReg', (47, 56))	('TP53', 'Gene', (101, 105))	('H1651', 'Var', (130, 135))	('mice', 'Species', '10090', (194, 198))	('KRAS', 'Gene', (96, 100))
414278	32068166	Retrospective analysis of immunotherapy clinical trials have shown that EGFR mutant patients do not benefit from immunotherapy.	('EGFR', 'Gene', '1956', (72, 76))	('EGFR', 'Gene', (72, 76))	('mutant', 'Var', (77, 83))	('patients', 'Species', '9606', (84, 92))
414279	32068166	This is thought to be due to their distinct biology, resulting from having a single dominant molecular driver with fewer potential neoantigens, low levels of PD-L1 expression (only 11% of EGFR mutant tumors have PD-L1>50%) and little CD8+ T-cell infiltration.	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('tumors', 'Phenotype', 'HP:0002664', (200, 206))	('CD8', 'Gene', (234, 237))	('mutant', 'Var', (193, 199))	('CD8', 'Gene', '925', (234, 237))	('EGFR', 'Gene', '1956', (188, 192))	('tumors', 'Disease', (200, 206))	('tumors', 'Disease', 'MESH:D009369', (200, 206))	('EGFR', 'Gene', (188, 192))
414280	32068166	Interestingly, in the EGFR mutant-cell line HCC827, we did observe that PD-L1 was modestly increased (similar to other NSCLC models), but cGAS was downregulated post-cisplatin treatment (FC-1.2, p<0.01) without any significant change in other STING markers (Supplemental Figure 3A).	('NSCLC', 'Disease', 'MESH:D002289', (119, 124))	('HCC827', 'CellLine', 'CVCL:2063', (44, 50))	('downregulated', 'NegReg', (147, 160))	('cGAS', 'Gene', '115004', (138, 142))	('cisplatin', 'Chemical', 'MESH:D002945', (166, 175))	('NSCLC', 'Phenotype', 'HP:0030358', (119, 124))	('mutant-cell', 'Var', (27, 38))	('PD-L1', 'MPA', (72, 77))	('EGFR', 'Gene', '1956', (22, 26))	('NSCLC', 'Disease', (119, 124))	('EGFR', 'Gene', (22, 26))	('cGAS', 'Gene', (138, 142))
414283	32068166	Having observed increased expression of STING-related genes in STING-high STK11/TP53 mutant LUAD tumors (Figure 2B) and increased expression of cGAS protein in STK11/TP53 mutant cell lines (Supplemental Figure 2A), we were interested to understand how STK11/TP53 cells respond to cisplatin in terms of production of IFNbeta and inflammatory cytokines, CXCL10 and CCL5.	('STK11', 'Gene', (252, 257))	('expression', 'MPA', (130, 140))	('STK11', 'Gene', '6794', (160, 165))	('IFNbeta', 'Gene', '3438', (316, 323))	('production', 'MPA', (302, 312))	('cGAS', 'Gene', (144, 148))	('STK11', 'Gene', (74, 79))	('expression', 'MPA', (26, 36))	('TP53', 'Gene', (258, 262))	('STK11', 'Gene', '6794', (252, 257))	('TP53', 'Gene', '7157', (166, 170))	('TP53', 'Gene', '7157', (80, 84))	('CXCL10', 'MPA', (352, 358))	('STK11', 'Gene', '6794', (74, 79))	('CCL5', 'MPA', (363, 367))	('mutant', 'Var', (171, 177))	('mutant', 'Var', (85, 91))	('increased', 'PosReg', (120, 129))	('STK11', 'Gene', (160, 165))	('cGAS', 'Gene', '115004', (144, 148))	('TP53', 'Gene', '7157', (258, 262))	('IFNbeta', 'Gene', (316, 323))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('LUAD tumors', 'Disease', 'MESH:D009369', (92, 103))	('inflammatory cytokines', 'MPA', (328, 350))	('TP53', 'Gene', (80, 84))	('cisplatin', 'Chemical', 'MESH:D002945', (280, 289))	('LUAD tumors', 'Disease', (92, 103))	('increased', 'PosReg', (16, 25))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('TP53', 'Gene', (166, 170))
414291	32068166	Mice treated with anti-PD-L1 had inhibition of tumor growth as compared to vehicle (p=0.026, by ANOVA, followed by Tukey's test) (Figure 3E).	('anti-PD-L1', 'Var', (18, 28))	('inhibition', 'NegReg', (33, 43))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('Mice', 'Species', '10090', (0, 4))	('tumor', 'Disease', (47, 52))
414292	32068166	However, combination of anti-PD-L1 with cisplatin, even with submaximal dosing of cisplatin, significantly potentiated the anti-tumor response with tumor growth inhibition as compared to vehicle (p=0.003) and to cisplatin (p=0.026) (Figure 3E).	('potentiated', 'PosReg', (107, 118))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('combination', 'Interaction', (9, 20))	('tumor', 'Disease', (148, 153))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('cisplatin', 'Chemical', 'MESH:D002945', (40, 49))	('cisplatin', 'Chemical', 'MESH:D002945', (82, 91))	('tumor', 'Disease', (128, 133))	('cisplatin', 'Chemical', 'MESH:D002945', (212, 221))	('anti-PD-L1', 'Var', (24, 34))	('tumor', 'Disease', 'MESH:D009369', (148, 153))
414296	32068166	These changes suggest that cisplatin induces changes in T-cell infiltration similar to immunotherapy at a time point where immunotherapy treatment alone inhibits tumor growth.	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('cisplatin', 'Chemical', 'MESH:D002945', (27, 36))	('T-cell infiltration', 'MPA', (56, 75))	('tumor', 'Disease', (162, 167))	('changes', 'Reg', (45, 52))	('cisplatin', 'Var', (27, 36))	('inhibits', 'NegReg', (153, 161))	('tumor', 'Disease', 'MESH:D009369', (162, 167))
414306	32068166	In particular, CXCL10 was increased significantly in combination arm with cisplatin 8 mg/kg (p=0.03 by ANOVA, followed by Tukey's test) and CCL5 was significantly increased by cisplatin 8mg/kg (p=0.01 by ANOVA, followed by Tukey's test), as compared to single agent immunotherapy and in combination arm with cisplatin 4mg/kg (p=0.03 by ANOVA, followed by Tukey's test) as compared to vehicle and single agent immunotherapy.	('cisplatin', 'Chemical', 'MESH:D002945', (176, 185))	('increased', 'PosReg', (163, 172))	('cisplatin', 'MPA', (74, 83))	('cisplatin', 'Chemical', 'MESH:D002945', (308, 317))	('cisplatin', 'Chemical', 'MESH:D002945', (74, 83))	('CCL5', 'MPA', (140, 144))	('increased', 'PosReg', (26, 35))	('CXCL10', 'MPA', (15, 21))	('cisplatin 8mg/kg', 'Var', (176, 192))
414316	32068166	Unlike in LUAD, there were no significant difference in the frequency of TP53 and STK11 mutations between these two groups, as expected considering high frequency of TP53 mutation and almost null frequency of STK11 mutation (81% and 3% respectively).	('STK11', 'Gene', (82, 87))	('TP53', 'Gene', '7157', (73, 77))	('STK11', 'Gene', (209, 214))	('mutation', 'Var', (171, 179))	('STK11', 'Gene', '6794', (82, 87))	('TP53', 'Gene', (73, 77))	('TP53', 'Gene', '7157', (166, 170))	('TP53', 'Gene', (166, 170))	('STK11', 'Gene', '6794', (209, 214))
414322	32068166	When we correlated genomic features of LUAD tumors with STING activation, we found that STK11 (LKB1) mutant tumors have lower expression of immune genes, as compared to other LUAD tumors, as known from previous studies in KRAS/STK11 mutant tumors.	('tumors', 'Disease', 'MESH:D009369', (44, 50))	('LKB1', 'Gene', (95, 99))	('tumors', 'Phenotype', 'HP:0002664', (180, 186))	('STK11', 'Gene', (227, 232))	('tumors', 'Disease', (240, 246))	('expression of immune genes', 'MPA', (126, 152))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('tumors', 'Disease', 'MESH:D009369', (240, 246))	('tumors', 'Disease', (180, 186))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('LUAD tumors', 'Disease', 'MESH:D009369', (175, 186))	('STK11', 'Gene', '6794', (227, 232))	('STK11', 'Gene', (88, 93))	('LUAD tumors', 'Disease', (175, 186))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('lower', 'NegReg', (120, 125))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('LKB1', 'Gene', '6794', (95, 99))	('LUAD tumors', 'Disease', (39, 50))	('LUAD tumors', 'Disease', 'MESH:D009369', (39, 50))	('tumors', 'Disease', 'MESH:D009369', (180, 186))	('tumors', 'Disease', (108, 114))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('KRAS', 'Gene', '3845', (222, 226))	('tumor', 'Phenotype', 'HP:0002664', (240, 245))	('tumors', 'Disease', (44, 50))	('tumors', 'Phenotype', 'HP:0002664', (240, 246))	('STK11', 'Gene', '6794', (88, 93))	('mutant', 'Var', (101, 107))	('KRAS', 'Gene', (222, 226))	('tumors', 'Disease', 'MESH:D009369', (108, 114))
414323	32068166	However, we identified a novel subset of the STK11 patients, characterized by co-mutation in TP53, that show high STING activation and immune genes expression, thus suggesting a subset of STK11 mutant lung adenocarcinoma that may potentially benefit from immunotherapy.	('co-mutation', 'Var', (78, 89))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (201, 220))	('STK11', 'Gene', (188, 193))	('lung adenocarcinoma', 'Disease', (201, 220))	('TP53', 'Gene', '7157', (93, 97))	('TP53', 'Gene', (93, 97))	('mutant', 'Var', (194, 200))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (201, 220))	('carcinoma', 'Phenotype', 'HP:0030731', (211, 220))	('STK11', 'Gene', '6794', (188, 193))	('STK11', 'Gene', (45, 50))	('patients', 'Species', '9606', (51, 59))	('STK11', 'Gene', '6794', (45, 50))
414325	32068166	These findings warrant further investigation in patient samples to investigate the predictive role of each genotype (KRAS/STK11 versus TP53/STK11) for response to chemo-immunotherapy combination and to better understand the molecular features of this subset of STING activated, STK11 (LKB1) mutant NSCLC.	('KRAS', 'Gene', (117, 121))	('NSCLC', 'Disease', 'MESH:D002289', (298, 303))	('STK11', 'Gene', (122, 127))	('STK11', 'Gene', (140, 145))	('LKB1', 'Gene', (285, 289))	('TP53', 'Gene', '7157', (135, 139))	('KRAS', 'Gene', '3845', (117, 121))	('STK11', 'Gene', '6794', (122, 127))	('NSCLC', 'Phenotype', 'HP:0030358', (298, 303))	('STK11', 'Gene', (278, 283))	('LKB1', 'Gene', '6794', (285, 289))	('patient', 'Species', '9606', (48, 55))	('STK11', 'Gene', '6794', (140, 145))	('TP53', 'Gene', (135, 139))	('mutant', 'Var', (291, 297))	('STK11', 'Gene', '6794', (278, 283))	('NSCLC', 'Disease', (298, 303))
414327	32068166	As with TP53 mutations, genetic alterations of DDR machinery genes may explain why many cancer cells have intrinsic levels of DNA damage.	('genetic alterations', 'Var', (24, 43))	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('DDR machinery genes', 'Gene', (47, 66))	('TP53', 'Gene', '7157', (8, 12))	('TP53', 'Gene', (8, 12))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('mutations', 'Var', (13, 22))
414345	31551535	LY-294002, an inhibitor of phosphatidylinositol 3-kinase, inhibited the phosphorylation of Akt and decreased the expression levels of CLDN1 and CLDN11.	('Akt', 'Gene', '207', (91, 94))	('decreased', 'NegReg', (99, 108))	('CLDN1', 'Gene', (134, 139))	('CLDN1', 'Gene', '9076', (144, 149))	('LY-294002', 'Chemical', 'MESH:C085911', (0, 9))	('Akt', 'Gene', (91, 94))	('CLDN1', 'Gene', (144, 149))	('phosphorylation', 'MPA', (72, 87))	('CLDN11', 'Gene', (144, 150))	('LY-294002', 'Var', (0, 9))	('phosphatidylinositol 3-kinase', 'Gene', '5290', (27, 56))	('expression levels', 'MPA', (113, 130))	('phosphatidylinositol 3-kinase', 'Gene', (27, 56))	('inhibited', 'NegReg', (58, 67))	('CLDN1', 'Gene', '9076', (134, 139))	('CLDN11', 'Gene', '5010', (144, 150))
414348	31551535	The knockdown of CLDN1 and CLDN11 using small interfering RNAs increased the transepithelial flux of doxorubicin (DXR), an anthracycline anticancer drug.	('CLDN11', 'Gene', '5010', (27, 33))	('increased', 'PosReg', (63, 72))	('CLDN1', 'Gene', '9076', (17, 22))	('transepithelial flux of doxorubicin', 'MPA', (77, 112))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('CLDN1', 'Gene', '9076', (27, 32))	('CLDN1', 'Gene', (27, 32))	('CLDN1', 'Gene', (17, 22))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('anthracycline', 'Chemical', 'MESH:D018943', (123, 136))	('knockdown', 'Var', (4, 13))	('CLDN11', 'Gene', (27, 33))	('cancer', 'Disease', (141, 147))	('doxorubicin', 'Chemical', 'MESH:D004317', (101, 112))
414349	31551535	Similarly, both chrysin and LY-294002 increased DXR flux.	('LY-294002', 'Var', (28, 37))	('LY-294002', 'Chemical', 'MESH:C085911', (28, 37))	('chrysin', 'Chemical', 'MESH:C043561', (16, 23))	('DXR flux', 'MPA', (48, 56))	('increased', 'PosReg', (38, 47))
414350	31551535	Neither CLDN1 knockdown, CLDN11 knockdown, nor chrysin changed the anticancer drug-induced cytotoxicity in a two-dimensional culture model, whereas they enhanced cytotoxicity in a spheroid culture model.	('chrysin', 'Chemical', 'MESH:C043561', (47, 54))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('CLDN11', 'Gene', '5010', (25, 31))	('cytotoxicity', 'Disease', 'MESH:D064420', (162, 174))	('cancer', 'Disease', (71, 77))	('cytotoxicity', 'Disease', 'MESH:D064420', (91, 103))	('knockdown', 'Var', (14, 23))	('knockdown', 'Var', (32, 41))	('CLDN1', 'Gene', '9076', (25, 30))	('CLDN1', 'Gene', '9076', (8, 13))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('CLDN1', 'Gene', (25, 30))	('CLDN11', 'Gene', (25, 31))	('enhanced', 'PosReg', (153, 161))	('cytotoxicity', 'Disease', (162, 174))	('CLDN1', 'Gene', (8, 13))	('cytotoxicity', 'Disease', (91, 103))
414363	31551535	A variety of mechanisms including mutation in the target molecule of anticancer drugs, induction of drug efflux pumps and drug-metabolizing enzymes, and DNA epigenetic states are involved in the development of drug resistance.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('drug resistance', 'Phenotype', 'HP:0020174', (210, 225))	('involved', 'Reg', (179, 187))	('induction', 'Reg', (87, 96))	('mutation', 'Var', (34, 42))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('drug efflux pumps', 'MPA', (100, 117))
414386	31551535	We examined the effects of CLDN1 and CLDN11 knockdown on anticancer agent-induced cytotoxicity.	('CLDN11', 'Gene', (37, 43))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('cytotoxicity', 'Disease', (82, 94))	('CLDN1', 'Gene', '9076', (27, 32))	('cancer', 'Disease', (61, 67))	('CLDN1', 'Gene', (27, 32))	('CLDN1', 'Gene', '9076', (37, 42))	('CLDN11', 'Gene', '5010', (37, 43))	('knockdown', 'Var', (44, 53))	('cytotoxicity', 'Disease', 'MESH:D064420', (82, 94))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('CLDN1', 'Gene', (37, 42))
414388	31551535	DXR and CDDP increased cytotoxicity in a dose-dependent manner (Fig.	('CDDP', 'Var', (8, 12))	('CDDP', 'Chemical', 'MESH:D002945', (8, 12))	('increased cytotoxicity', 'Disease', 'MESH:D064420', (13, 35))	('increased cytotoxicity', 'Disease', (13, 35))
414389	31551535	Neither CLDN1 nor CLDN11 knockdown significantly changed the sensitivity to DXR and CDDP.	('CLDN11', 'Gene', (18, 24))	('changed', 'Reg', (49, 56))	('CLDN1', 'Gene', '9076', (18, 23))	('CLDN1', 'Gene', (18, 23))	('CLDN11', 'Gene', '5010', (18, 24))	('CDDP', 'Chemical', 'MESH:D002945', (84, 88))	('CLDN1', 'Gene', '9076', (8, 13))	('CLDN1', 'Gene', (8, 13))	('knockdown', 'Var', (25, 34))	('sensitivity to DXR', 'MPA', (61, 79))
414391	31551535	Neither CLDN1 nor CLDN11 knockdown significantly changed the protein levels of ABCB1, ABCC1, or ABCG2 (Fig.	('CLDN11', 'Gene', (18, 24))	('changed', 'Reg', (49, 56))	('ABCG2', 'Gene', (96, 101))	('CLDN1', 'Gene', '9076', (18, 23))	('ABCB1', 'Gene', (79, 84))	('CLDN1', 'Gene', (18, 23))	('protein levels', 'MPA', (61, 75))	('ABCB1', 'Gene', '5243', (79, 84))	('ABCC1', 'Gene', (86, 91))	('ABCG2', 'Gene', '9429', (96, 101))	('CLDN11', 'Gene', '5010', (18, 24))	('CLDN1', 'Gene', '9076', (8, 13))	('CLDN1', 'Gene', (8, 13))	('knockdown', 'Var', (25, 34))	('ABCC1', 'Gene', '4363', (86, 91))
414394	31551535	Both CLDN1 and CLDN11 knockdown increased transepithelial permeability to DXR without changing TER (Fig.	('CLDN1', 'Gene', (5, 10))	('CLDN11', 'Gene', (15, 21))	('knockdown', 'Var', (22, 31))	('transepithelial permeability to DXR', 'MPA', (42, 77))	('CLDN1', 'Gene', '9076', (15, 20))	('increased', 'PosReg', (32, 41))	('CLDN11', 'Gene', '5010', (15, 21))	('CLDN1', 'Gene', '9076', (5, 10))	('CLDN1', 'Gene', (15, 20))
414397	31551535	The accumulation of DXR was significantly enhanced by CLDN1 and CLDN11 knockdown.	('accumulation of DXR', 'MPA', (4, 23))	('CLDN1', 'Gene', (54, 59))	('CLDN1', 'Gene', '9076', (64, 69))	('CLDN1', 'Gene', (64, 69))	('enhanced', 'PosReg', (42, 50))	('knockdown', 'Var', (71, 80))	('CLDN11', 'Gene', (64, 70))	('CLDN1', 'Gene', '9076', (54, 59))	('CLDN11', 'Gene', '5010', (64, 70))
414398	31551535	DXR decreased the viability of spheroid cells in a dose-dependent manner, which was enhanced by CLDN1 and CLDN11 knockdown (Fig.	('CLDN1', 'Gene', '9076', (106, 111))	('decreased', 'NegReg', (4, 13))	('CLDN1', 'Gene', '9076', (96, 101))	('CLDN1', 'Gene', (106, 111))	('CLDN11', 'Gene', (106, 112))	('CLDN1', 'Gene', (96, 101))	('knockdown', 'Var', (113, 122))	('viability of spheroid cells', 'CPA', (18, 45))	('enhanced', 'PosReg', (84, 92))	('CLDN11', 'Gene', '5010', (106, 112))
414411	31551535	LY-294002, an inhibitor of the PI3K/Akt signaling pathway, significantly decreased p-Akt, CLDN1, and CLDN11 levels (Fig.	('CLDN11', 'Gene', (101, 107))	('decreased', 'NegReg', (73, 82))	('Akt', 'Gene', '207', (85, 88))	('LY-294002', 'Chemical', 'MESH:C085911', (0, 9))	('Akt', 'Gene', (36, 39))	('CLDN1', 'Gene', '9076', (90, 95))	('CLDN1', 'Gene', '9076', (101, 106))	('LY-294002', 'Var', (0, 9))	('Akt', 'Gene', (85, 88))	('CLDN11', 'Gene', '5010', (101, 107))	('CLDN1', 'Gene', (101, 106))	('CLDN1', 'Gene', (90, 95))	('Akt', 'Gene', '207', (36, 39))
414412	31551535	In addition, the mRNA levels of CLDN1 and CLDN11 were decreased by LY-294002 (Fig.	('CLDN11', 'Gene', '5010', (42, 48))	('CLDN1', 'Gene', '9076', (42, 47))	('LY-294002', 'Var', (67, 76))	('CLDN1', 'Gene', (42, 47))	('decreased', 'NegReg', (54, 63))	('CLDN1', 'Gene', '9076', (32, 37))	('CLDN11', 'Gene', (42, 48))	('mRNA levels', 'MPA', (17, 28))	('LY-294002', 'Chemical', 'MESH:C085911', (67, 76))	('CLDN1', 'Gene', (32, 37))
414423	31551535	Both chrysin and LY-294002 increased transepithelial permeability to DXR without changing TER (Fig.	('transepithelial permeability to DXR', 'MPA', (37, 72))	('increased', 'PosReg', (27, 36))	('LY-294002', 'Chemical', 'MESH:C085911', (17, 26))	('LY-294002', 'Var', (17, 26))	('chrysin', 'Chemical', 'MESH:C043561', (5, 12))
414434	31551535	However, transepithelial fluxes of lucifer yellow and DXR were increased by the treatment with CA or introduction of siRNA for CLDN1 and CLDN11, suggesting that the cells can form partially functional TJs barrier.	('CLDN11', 'Gene', '5010', (137, 143))	('CLDN1', 'Gene', '9076', (137, 142))	('CLDN1', 'Gene', '9076', (127, 132))	('increased', 'PosReg', (63, 72))	('introduction', 'Var', (101, 113))	('CLDN1', 'Gene', (137, 142))	('CLDN1', 'Gene', (127, 132))	('CLDN11', 'Gene', (137, 143))
414442	31551535	The knockdown of CLDN1 and CLDN11 expression by siRNA increased the transepithelial flux of DXR, but it did not significantly change anticancer drug-induced toxicity or the expression of ABC transporters in a 2D culture model of RERF-LC-AI cells (Figs 2 and 3), suggesting that neither CLDN1 nor CLDN11 are directly involved in chemoresistance against anticancer drugs.	('CLDN1', 'Gene', (27, 32))	('CLDN1', 'Gene', (296, 301))	('cancer', 'Disease', (137, 143))	('CLDN11', 'Gene', (296, 302))	('knockdown', 'Var', (4, 13))	('CLDN11', 'Gene', (27, 33))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('CLDN11', 'Gene', '5010', (27, 33))	('toxicity', 'Disease', 'MESH:D064420', (157, 165))	('CLDN11', 'Gene', '5010', (296, 302))	('CLDN1', 'Gene', (17, 22))	('cancer', 'Disease', (356, 362))	('CLDN1', 'Gene', (286, 291))	('ABC', 'Gene', '10058', (187, 190))	('cancer', 'Phenotype', 'HP:0002664', (356, 362))	('toxicity', 'Disease', (157, 165))	('CLDN1', 'Gene', '9076', (296, 301))	('CLDN1', 'Gene', '9076', (27, 32))	('ABC', 'Gene', (187, 190))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('transepithelial flux of DXR', 'MPA', (68, 95))	('CLDN1', 'Gene', '9076', (17, 22))	('CLDN1', 'Gene', '9076', (286, 291))	('cancer', 'Disease', 'MESH:D009369', (356, 362))	('increased', 'PosReg', (54, 63))
414444	31551535	Both CLDN1 and CLDN11 expression levels were decreased by LY-294002 (Fig.	('CLDN1', 'Gene', (5, 10))	('CLDN11', 'Gene', (15, 21))	('decreased', 'NegReg', (45, 54))	('LY-294002', 'Chemical', 'MESH:C085911', (58, 67))	('CLDN11', 'Gene', '5010', (15, 21))	('CLDN1', 'Gene', '9076', (15, 20))	('expression levels', 'MPA', (22, 39))	('CLDN1', 'Gene', '9076', (5, 10))	('LY-294002', 'Var', (58, 67))	('CLDN1', 'Gene', (15, 20))
414461	31551535	The knockdown of CLDN1 and CLDN11 by siRNA enhances DXR accumulation and DXR-induced toxicity in 3D spheroid cells (Fig.	('CLDN11', 'Gene', '5010', (27, 33))	('toxicity', 'Disease', 'MESH:D064420', (85, 93))	('CLDN1', 'Gene', '9076', (17, 22))	('DXR accumulation', 'MPA', (52, 68))	('toxicity', 'Disease', (85, 93))	('CLDN1', 'Gene', '9076', (27, 32))	('CLDN1', 'Gene', (27, 32))	('enhances', 'PosReg', (43, 51))	('CLDN1', 'Gene', (17, 22))	('knockdown', 'Var', (4, 13))	('CLDN11', 'Gene', (27, 33))
414513	29340250	Six ceRNAs (PLAU, miR-31-5p, miR-455-3p, FAM83A-AS1, MIR31HG, and MIR99AHG) significantly correlated with survival (P < 0.05).	('miR-455-3p', 'Var', (29, 39))	('MIR31HG', 'Gene', (53, 60))	('FAM83A-AS1', 'Gene', '100131726', (41, 51))	('MIR31HG', 'Gene', '554202', (53, 60))	('survival', 'CPA', (106, 114))	('correlated with', 'Reg', (90, 105))	('miR-31', 'Gene', (18, 24))	('MIR99AHG', 'Gene', (66, 74))	('PLAU', 'Gene', (12, 16))	('PLAU', 'Gene', '5328', (12, 16))	('MIR99AHG', 'Gene', '388815', (66, 74))	('miR-31', 'Gene', '407035', (18, 24))	('FAM83A-AS1', 'Gene', (41, 51))
414519	29340250	Multiple studies have confirmed that genes of microRNAs (miRNAs) are deeply involved in the development and metastasis of malignant tumors and perform important functions as oncogenes or tumor suppressor genes.	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('microRNAs', 'Var', (46, 55))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumor', 'Disease', (187, 192))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('tumor', 'Disease', (132, 137))	('involved', 'Reg', (76, 84))	('metastasis of malignant tumors', 'Disease', (108, 138))	('metastasis of malignant tumors', 'Disease', 'MESH:D009362', (108, 138))
414546	29340250	Among the differentially expressed ceRNAs, one mRNA (PLAU), two miRNAs (miR-31-5p and miR-455-3p), and three lncRNAs (FAM83A-AS1, MIR31HG, and MIR99AHG) were found to be associated with the overall survival of patients with LUSC by univariate Cox regression analysis.	('PLAU', 'Gene', '5328', (53, 57))	('LUSC', 'Disease', (224, 228))	('LUSC', 'Phenotype', 'HP:0030359', (224, 228))	('Cox', 'Gene', (243, 246))	('MIR99AHG', 'Gene', (143, 151))	('FAM83A-AS1', 'Gene', (118, 128))	('MIR31HG', 'Gene', (130, 137))	('miR-31', 'Gene', (72, 78))	('MIR31HG', 'Gene', '554202', (130, 137))	('FAM83A-AS1', 'Gene', '100131726', (118, 128))	('MIR99AHG', 'Gene', '388815', (143, 151))	('patients', 'Species', '9606', (210, 218))	('miR-31', 'Gene', '407035', (72, 78))	('associated with', 'Reg', (170, 185))	('miR-455-3p', 'Var', (86, 96))	('Cox', 'Gene', '1351', (243, 246))	('PLAU', 'Gene', (53, 57))
414547	29340250	Kaplan-Meier survival curves indicated that the lncRNA MIR99AHG positively correlated with overall survival, whereas PLAU, miR-31-5p, miR-455-3p, FAM83A-AS1, and MIR31HG were negatively associated with overall survival (Fig.	('MIR31HG', 'Gene', (162, 169))	('miR-31', 'Gene', (123, 129))	('MIR31HG', 'Gene', '554202', (162, 169))	('miR-455-3p', 'Var', (134, 144))	('FAM83A-AS1', 'Gene', (146, 156))	('overall survival', 'MPA', (91, 107))	('miR-31', 'Gene', '407035', (123, 129))	('correlated', 'Reg', (75, 85))	('PLAU', 'Gene', (117, 121))	('MIR99AHG', 'Gene', (55, 63))	('FAM83A-AS1', 'Gene', '100131726', (146, 156))	('PLAU', 'Gene', '5328', (117, 121))	('MIR99AHG', 'Gene', '388815', (55, 63))	('overall survival', 'MPA', (202, 218))
414550	29340250	According to GO analysis, anomalous expression of PLAU is related to aberrant regulation of gene function groups such as pulmonary squamous cell carcinoma, proteolysis, and fibrinolysis (Fig.	('pulmonary squamous cell carcinoma', 'Disease', 'MESH:D002294', (121, 154))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (131, 154))	('carcinoma', 'Phenotype', 'HP:0030731', (145, 154))	('proteolysis', 'MPA', (156, 167))	('gene function', 'MPA', (92, 105))	('anomalous', 'Var', (26, 35))	('related', 'Reg', (58, 65))	('regulation', 'MPA', (78, 88))	('pulmonary squamous cell carcinoma', 'Disease', (121, 154))	('PLAU', 'Gene', (50, 54))	('PLAU', 'Gene', '5328', (50, 54))	('fibrinolysis', 'MPA', (173, 185))
414554	29340250	9D, uPA transcript levels were significantly higher in SK-MES-1 cells than in 16-HBE-T cells (up to 9.99-fold).	('SK-MES-1', 'Var', (55, 63))	('16-HBE-T', 'CellLine', 'CVCL:0112', (78, 86))	('uPA', 'Gene', (4, 7))	('uPA', 'Gene', '5328', (4, 7))	('higher', 'PosReg', (45, 51))	('SK-MES-1', 'CellLine', 'CVCL:0630', (55, 63))	('to 9', 'Species', '1214577', (97, 101))
414556	29340250	As a publicly funded project, TCGA is intended for cataloging and discovery of the major cancer-causing genomic variations to form a comprehensive outline of the cancer genome.	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('cancer', 'Disease', (162, 168))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('cancer', 'Disease', (89, 95))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('variations', 'Var', (112, 122))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
414559	29340250	This observation suggests that aberrant amplification of SOX2 drives the overexpression of TP63 and TP73 as excellent biomarkers contributing to LUSC progression.	('aberrant amplification', 'Var', (31, 53))	('TP73', 'Gene', (100, 104))	('LUSC', 'Phenotype', 'HP:0030359', (145, 149))	('TP63', 'Gene', (91, 95))	('LUSC', 'Disease', (145, 149))	('SOX2', 'Gene', (57, 61))	('TP63', 'Gene', '8626', (91, 95))	('SOX2', 'Gene', '6657', (57, 61))	('overexpression', 'PosReg', (73, 87))	('contributing', 'Reg', (129, 141))	('TP73', 'Gene', '7161', (100, 104))
414561	29340250	also demonstrated that TP63, a member of the p53 gene family, directly activates the Fanconi anemia pathway in LUSC; therefore, targeting TP63 may not only hamper squamous cell carcinomas progression but also sensitize tumors to cisplatin treatment.	('carcinoma', 'Phenotype', 'HP:0030731', (177, 186))	('carcinomas', 'Phenotype', 'HP:0030731', (177, 187))	('sensitize', 'Reg', (209, 218))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (163, 187))	('tumors', 'Phenotype', 'HP:0002664', (219, 225))	('LUSC', 'Phenotype', 'HP:0030359', (111, 115))	('cisplatin', 'Chemical', 'MESH:D002945', (229, 238))	('TP63', 'Gene', (23, 27))	('Fanconi anemia', 'Disease', (85, 99))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (163, 187))	('Fanconi anemia', 'Disease', 'MESH:D005199', (85, 99))	('targeting', 'Var', (128, 137))	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('p53', 'Gene', '7157', (45, 48))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (163, 186))	('tumors', 'Disease', (219, 225))	('TP63', 'Gene', '8626', (23, 27))	('squamous cell carcinomas', 'Disease', (163, 187))	('anemia', 'Phenotype', 'HP:0001903', (93, 99))	('TP63', 'Gene', (138, 142))	('p53', 'Gene', (45, 48))	('tumors', 'Disease', 'MESH:D009369', (219, 225))	('Fanconi anemia', 'Phenotype', 'HP:0001994', (85, 99))	('hamper', 'NegReg', (156, 162))	('TP63', 'Gene', '8626', (138, 142))
414565	29340250	Among the 151 lncRNAs uncovered in this study, lncRNA TUBA4B has been reported as a predictor of poor prognosis and a regulator of cell proliferation in non-small cell lung cancer.	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (153, 179))	('non-small cell lung cancer', 'Disease', (153, 179))	('lung cancer', 'Phenotype', 'HP:0100526', (168, 179))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (157, 179))	('lncRNA', 'Var', (47, 53))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (153, 179))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('TUBA4B', 'Gene', (54, 60))	('TUBA4B', 'Gene', '80086', (54, 60))
414566	29340250	Amplification of PVT-1 is associated with poor prognosis via inhibition of apoptosis in colorectal cancer.	('Amplification', 'Var', (0, 13))	('colorectal cancer', 'Disease', (88, 105))	('colorectal cancer', 'Phenotype', 'HP:0003003', (88, 105))	('apoptosis', 'CPA', (75, 84))	('inhibition', 'NegReg', (61, 71))	('colorectal cancer', 'Disease', 'MESH:D015179', (88, 105))	('PVT-1', 'Gene', '5820', (17, 22))	('PVT-1', 'Gene', (17, 22))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
414577	29340250	MiR-455-3p was found to play a role in acquired temozolomide resistance and may be a novel therapeutic target in recurrent glioblastoma multiforme.	('MiR-455-3p', 'Var', (0, 10))	('glioblastoma multiforme', 'Disease', (123, 146))	('acquired temozolomide resistance', 'MPA', (39, 71))	('glioblastoma', 'Phenotype', 'HP:0012174', (123, 135))	('temozolomide', 'Chemical', 'MESH:D000077204', (48, 60))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (123, 146))
414582	29340250	The anomalous expression of PLAU (uPA) as an oncogeneis associated with tumors encroaching on the extracellular matrix and has been reported to participate in the development and progression of a variety of cancers.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumors encroaching', 'Disease', (72, 90))	('cancers', 'Disease', 'MESH:D009369', (207, 214))	('cancers', 'Phenotype', 'HP:0002664', (207, 214))	('cancers', 'Disease', (207, 214))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('associated', 'Reg', (56, 66))	('uPA', 'Gene', (34, 37))	('anomalous expression', 'Var', (4, 24))	('participate', 'Reg', (144, 155))	('PLAU', 'Gene', (28, 32))	('uPA', 'Gene', '5328', (34, 37))	('PLAU', 'Gene', '5328', (28, 32))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('tumors encroaching', 'Disease', 'MESH:D009369', (72, 90))
414587	29340250	Using these results, we constructed a ceRNA network and studied the significance of the expression pattern of LUSC-specific ceRNAs (PLAU, miR-31-5p, miR-455-3p, FAM83A-AS1, MIR31HG, and MIR99AHG) for overall survival of patients with LUSC.	('MIR31HG', 'Gene', (173, 180))	('FAM83A-AS1', 'Gene', '100131726', (161, 171))	('LUSC', 'Phenotype', 'HP:0030359', (110, 114))	('MIR99AHG', 'Gene', '388815', (186, 194))	('MIR31HG', 'Gene', '554202', (173, 180))	('miR-31', 'Gene', (138, 144))	('patients', 'Species', '9606', (220, 228))	('PLAU', 'Gene', (132, 136))	('PLAU', 'Gene', '5328', (132, 136))	('MIR99AHG', 'Gene', (186, 194))	('FAM83A-AS1', 'Gene', (161, 171))	('miR-31', 'Gene', '407035', (138, 144))	('LUSC', 'Phenotype', 'HP:0030359', (234, 238))	('miR-455-3p', 'Var', (149, 159))
414597	28426276	This work identified the global DNA methylation dysregulation patterns across 14 cancer types showing a higher impact for the non-CpG island areas.	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('cancer', 'Disease', (81, 87))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('dysregulation', 'Var', (48, 61))
414600	28426276	Typically, cancers include hundreds of somatic alterations to DNA, overcoming programs that control replication and apoptosis to allow survival and growth.	('cancers', 'Disease', (11, 18))	('DNA', 'Gene', (62, 65))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('cancers', 'Phenotype', 'HP:0002664', (11, 18))	('alterations', 'Var', (47, 58))	('cancers', 'Disease', 'MESH:D009369', (11, 18))
414604	28426276	Recently, pan-cancer analyses have reported functional mutations, immunogenomic signature, and copy number alterations.	('cancer', 'Disease', (14, 20))	('cancer', 'Disease', 'MESH:D009369', (14, 20))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('copy number alterations', 'Var', (95, 118))
414610	28426276	Diverse methylomes within tumor type have been associated with tumor characteristics and patient prognosis.	('tumor', 'Disease', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('patient', 'Species', '9606', (89, 96))	('methylomes', 'Var', (8, 18))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('associated', 'Reg', (47, 57))
414636	28426276	Extending our assessment to summary measures of genetic somatic alterations, overall copy number alterations:represented by the fraction of the genome altered (FGA):median was 17.4%, though this had a wide IQR (4.75 to 34.3%).	('copy number alterations', 'Var', (85, 108))	('FGA', 'Gene', (160, 163))	('FGA', 'Gene', '2243', (160, 163))
414642	28426276	In contrast, the summary measures of genetic somatic alterations FGA and MCB, also presented in the figure, showed a different order and magnitude across cancer types.	('MCB', 'Gene', (73, 76))	('cancer', 'Disease', (154, 160))	('alterations', 'Var', (53, 64))	('FGA', 'Gene', '2243', (65, 68))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('FGA', 'Gene', (65, 68))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('MCB', 'Chemical', '-', (73, 76))
414646	28426276	Next, we visualized the gcMDI for all samples using unsupervised clustering and for each cancer type set four classes: high dysregulation, high-intermediate dysregulation, low-intermediate dysregulation, and low dysregulation (Fig.	('high dysregulation', 'Var', (119, 137))	('low-intermediate dysregulation', 'Var', (172, 202))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('low', 'Disease', (208, 211))	('cancer', 'Disease', (89, 95))	('high-intermediate dysregulation', 'Var', (139, 170))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
414675	28426276	Several CpG sites were related to long noncoding RNA or antisense genes (OTX2-AS1, LINC00466, TFAP2A-AS1, LHX5-AS1, LOC100507443, LIN28B-AS1, PAUPAR, DKFZp686K1684), transcription and regulatory factors (TFAP2B, USP44), and genes encoding tumor suppressor proteins (TRIM15, CASZ1).	('LINC00466', 'Gene', '199899', (83, 92))	('AS1', 'Gene', (111, 114))	('USP44', 'Gene', (212, 217))	('TRIM15', 'Gene', (266, 272))	('PAUPAR', 'Gene', '103157000', (142, 148))	('LINC00466', 'Gene', (83, 92))	('AS1', 'Gene', (78, 81))	('AS1', 'Gene', '5729', (137, 140))	('LOC100507443', 'Gene', (116, 128))	('CASZ1', 'Gene', (274, 279))	('AS1', 'Gene', (101, 104))	('LHX5-AS1', 'Gene', '104355219;64211;5729', (106, 114))	('CASZ1', 'Gene', '54897', (274, 279))	('tumor', 'Disease', (239, 244))	('TRIM15', 'Gene', '89870', (266, 272))	('USP44', 'Gene', '84101', (212, 217))	('TFAP2A-AS1', 'Gene', '100130275;7020;5729', (94, 104))	('AS1', 'Gene', '5729', (111, 114))	('LIN28B', 'Gene', (130, 136))	('tumor', 'Disease', 'MESH:D009369', (239, 244))	('TFAP2A-AS1', 'Gene', (94, 104))	('antisense', 'Gene', (56, 65))	('TFAP2B', 'Gene', '7021', (204, 210))	('AS1', 'Gene', '5729', (78, 81))	('AS1', 'Gene', (137, 140))	('LHX5-AS1', 'Gene', (106, 114))	('LOC100507443', 'Gene', '100507443', (116, 128))	('OTX2-AS1', 'Gene', (73, 81))	('TFAP2B', 'Gene', (204, 210))	('AS1', 'Gene', '5729', (101, 104))	('PAUPAR', 'Gene', (142, 148))	('OTX2-AS1', 'Gene', '100309464;5015;5729', (73, 81))	('tumor', 'Phenotype', 'HP:0002664', (239, 244))	('LIN28B', 'Gene', '389421', (130, 136))	('DKFZp686K1684', 'Var', (150, 163))
414676	28426276	In addition, several commonly altered CpG sites were located in enhancer elements (cg10903903, cg17754510, cg22797031, cg13539545, cg08443563) and a few were spatially near to the histone related cluster of chromosome 6 (cg10903903-HIST1H2BL, and cg01518607-PRSS16).	('cg22797031', 'Var', (107, 117))	('cg10903903', 'Var', (83, 93))	('cg08443563', 'Var', (131, 141))	('PRSS16', 'Gene', (258, 264))	('enhancer', 'PosReg', (64, 72))	('HIST1H2BL', 'Gene', '8340', (232, 241))	('HIST1H2BL', 'Gene', (232, 241))	('PRSS16', 'Gene', '10279', (258, 264))	('cg17754510', 'Var', (95, 105))	('cg13539545', 'Var', (119, 129))
414682	28426276	This finding was further supported when analyzing the specific loci dysregulation, in which these cancer types cluster together; three of the four showed a pattern of loci dysregulation associated to specific metabolic genes, proto-oncogenes and oncogenes.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('dysregulation', 'Var', (172, 185))	('cancer', 'Disease', (98, 104))	('cancer', 'Disease', 'MESH:D009369', (98, 104))
414684	28426276	In contrast, age was consistently associated with MDI in breast cancer and hepatocellular carcinoma globally and across the different genomic contexts.	('breast cancer', 'Disease', (57, 70))	('associated', 'Reg', (34, 44))	('breast cancer', 'Phenotype', 'HP:0003002', (57, 70))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('hepatocellular carcinoma globally', 'Disease', (75, 108))	('hepatocellular carcinoma globally', 'Disease', 'MESH:D006528', (75, 108))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (75, 99))	('MDI', 'Var', (50, 53))	('breast cancer', 'Disease', 'MESH:D001943', (57, 70))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
414693	28426276	Specific reported mutations associated with differential methylation (CIMP phenotypes) differ by cancer subtype, which precludes an integrative analysis of specific mutation signatures for all the samples.	('mutations', 'Var', (18, 27))	('CIMP', 'Chemical', '-', (70, 74))	('cancer', 'Disease', (97, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('differential methylation', 'MPA', (44, 68))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
414702	28426276	This work contributes to the understanding of the impact of epigenetic alterations from a pan-cancer perspective.	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('epigenetic alterations', 'Var', (60, 82))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
414711	28426276	Although copy number alterations do not bias DNA methylation signals, biologically they are drivers of other cancer alterations which may alter DNA methylation levels, and were therefore included in our models.	('DNA methylation levels', 'MPA', (144, 166))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('cancer', 'Disease', (109, 115))	('alter', 'Reg', (138, 143))	('copy number alterations', 'Var', (9, 32))
414712	28426276	Information on the fraction of the genome with copy number alterations (FGA) and mutation count burden (MCB) were retrieved from cBioportal.	('FGA', 'Gene', (72, 75))	('MCB', 'Chemical', '-', (104, 107))	('FGA', 'Gene', '2243', (72, 75))	('copy number alterations', 'Var', (47, 70))
414713	28426276	FGA was measured using Affymetrix SNP arrays and corresponds to the fraction of the genome affected by copy number alterations, which is equivalent to the number of bases in segments with mean log2 greater than 0.2 or smaller than -0.2 divided by the number of bases in all segments profiled by the array.	('FGA', 'Gene', '2243', (0, 3))	('alterations', 'Var', (115, 126))	('copy number alterations', 'Var', (103, 126))	('affected by', 'Reg', (91, 102))	('FGA', 'Gene', (0, 3))
414779	26928298	As the cohort sizes in this study are less than twice the number of antibodies (2*187 = 374) for 7 of the 11 tumor types (Table 2), it is not surprising that SIMPLEPARCOR has poor performance in these tumor types, hence the poorest overall performance by a margin (Fig 3B).	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('poor', 'NegReg', (175, 179))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('SIMPLEPARCOR', 'Var', (158, 170))	('tumor', 'Disease', (201, 206))	('tumor', 'Disease', (109, 114))
414780	26928298	Indeed, we can observe that the tumor types where SIMPLEPARCOR achieves relatively better ranks are BRCA, OVCA, KIRC, and UCEC, the four tumor types that have cohort size greater than 374 (Fig 3A and 3B and Table 2).	('tumor', 'Disease', (137, 142))	('BRCA', 'Gene', '672', (100, 104))	('KIRC', 'Disease', (112, 116))	('OVCA', 'Disease', (106, 110))	('BRCA', 'Gene', (100, 104))	('SIMPLEPARCOR', 'Var', (50, 62))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('UCEC', 'Disease', (122, 126))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('tumor', 'Disease', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
414799	26928298	These tumors have also been shown to have common DNA-based drivers (mutations and somatic copy number alterations), and hence have been treated as one disease.	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('tumors', 'Disease', (6, 12))	('mutations', 'Var', (68, 77))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))
414818	26928298	Processes such as cell cycle, proliferation, RTK signaling, RAS/MAPK signaling were shared between the modules; but Module 2 antibodies were involved in a greater variety of oncogenic pathways such as AKT/mTOR, Wnt, and NFkappaB signaling.	('RTK', 'Gene', (45, 48))	('AKT', 'Gene', '207', (201, 204))	('mTOR', 'Gene', (205, 209))	('oncogenic pathways', 'Pathway', (174, 192))	('mTOR', 'Gene', '2475', (205, 209))	('NFkappaB', 'Gene', (220, 228))	('AKT', 'Gene', (201, 204))	('RTK', 'Gene', '5979', (45, 48))	('NFkappaB', 'Gene', '4790', (220, 228))	('Wnt', 'Pathway', (211, 214))	('antibodies', 'Var', (125, 135))	('involved in', 'Reg', (141, 152))
414833	26928298	In the Fig 8B heat map, we also tracked the number of significant (consensus rank < 425) interactions that match to each gene list broken down by module or group, and averaged over tumor types (S11 Table).	('broken down', 'Phenotype', 'HP:0001061', (131, 142))	('tumor', 'Disease', (181, 186))	('interactions', 'Var', (89, 101))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))
414884	26465941	Several factors including angiogenesis, lymphangiogenesis, alterations in expression or structure of tumor suppressor genes and oncogenes and their proteins, etc are involved in malignant transformation of potentially malignant oral lesions (PMOLs) to OSCC.	('expression', 'MPA', (74, 84))	('alterations', 'Var', (59, 70))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('malignant oral lesions', 'Disease', 'MESH:D020820', (218, 240))	('oral lesion', 'Phenotype', 'HP:0100649', (228, 239))	('oral lesions', 'Phenotype', 'HP:0100649', (228, 240))	('malignant oral lesions', 'Disease', (218, 240))	('involved', 'Reg', (166, 174))	('structure', 'MPA', (88, 97))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
414932	26465941	FGF-2 positivity was observed in 49.08% (53/108) OSCC cases, 31.95% (23/72) PMOLs and in 26.92% (14/ 52) control cases.	('FGF-2', 'Gene', (0, 5))	('FGF-2', 'Gene', '2247', (0, 5))	('positivity', 'Var', (6, 16))	('OSCC', 'Disease', (49, 53))
414957	26465941	Interestingly, when co-expression of FGF-2 and FGFR-2 was considered as cofactor, the risk of malignant transformation was considerably higher in PMOLs showing co-expression as compared to PMOLS without co-expression of FGF-2and FGFR-2 (OR, 4.19; 95% CI, 1.81-9.71; P < 0.001).	('FGFR-2', 'Gene', '2263', (229, 235))	('FGF-2', 'Gene', (37, 42))	('malignant transformation', 'CPA', (94, 118))	('FGF-2', 'Gene', '2247', (37, 42))	('FGFR-2', 'Gene', '2263', (47, 53))	('higher', 'PosReg', (136, 142))	('FGFR-2', 'Gene', (47, 53))	('FGFR-2', 'Gene', (229, 235))	('FGF-2', 'Gene', (220, 225))	('FGF-2', 'Gene', '2247', (220, 225))	('co-expression', 'Var', (160, 173))
414979	26465941	Inhibition of FGFR-2 signaling in these cells induced apoptosis.	('FGFR-2', 'Gene', (14, 20))	('apoptosis', 'CPA', (54, 63))	('FGFR-2', 'Gene', '2263', (14, 20))	('Inhibition', 'Var', (0, 10))
414980	26465941	Thus, constitutive FGFR-2 signaling due to FGFR-2 overexpression can lead to protection from apoptosis which is one of the hallmarks of cancer.	('FGFR-2', 'Gene', '2263', (43, 49))	('FGFR-2', 'Gene', '2263', (19, 25))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('protection', 'CPA', (77, 87))	('FGFR-2', 'Gene', (43, 49))	('cancer', 'Disease', (136, 142))	('FGFR-2', 'Gene', (19, 25))	('apoptosis', 'CPA', (93, 102))	('overexpression', 'Var', (50, 64))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
414982	26465941	We found FGFR-3 positivity in 75% cases (81/108) of OSCC, 40.28% cases (29/72) of oral PMOLs and 36.54% cases (19/52) of controls.	('FGFR-3', 'Gene', '2261', (9, 15))	('FGFR-3', 'Gene', (9, 15))	('positivity', 'Var', (16, 26))	('OSCC', 'Disease', (52, 56))
414988	26465941	In human bladder cancer, the FGFR-3 mutations were observed to be strongly associated with non invasive, low grade and stage.	('bladder cancer', 'Disease', 'MESH:D001749', (9, 23))	('bladder cancer', 'Disease', (9, 23))	('human', 'Species', '9606', (3, 8))	('FGFR-3', 'Gene', (29, 35))	('stage', 'Disease', (119, 124))	('mutations', 'Var', (36, 45))	('low', 'Disease', (105, 108))	('FGFR-3', 'Gene', '2261', (29, 35))	('non invasive', 'Disease', (91, 103))	('bladder cancer', 'Phenotype', 'HP:0009725', (9, 23))	('associated', 'Reg', (75, 85))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
414990	26465941	The favorable pathway is characterized by mutations in FGFR-3 and a clinically unfavorable pathway characterized by mutations in p53.	('FGFR-3', 'Gene', (55, 61))	('FGFR-3', 'Gene', '2261', (55, 61))	('mutations', 'Var', (116, 125))	('p53', 'Gene', (129, 132))	('p53', 'Gene', '7157', (129, 132))	('mutations', 'Var', (42, 51))
414991	26465941	Further the detection of FGFR-3 mutations in urine from patients with FGFR-3 mutations in primary tumor indicating tumor recurrence has also been reported.	('patients', 'Species', '9606', (56, 64))	('FGFR-3', 'Gene', (25, 31))	('FGFR-3', 'Gene', (70, 76))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('FGFR-3', 'Gene', '2261', (25, 31))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Disease', (115, 120))	('FGFR-3', 'Gene', '2261', (70, 76))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('mutations', 'Var', (32, 41))	('mutations', 'Var', (77, 86))	('tumor', 'Disease', (98, 103))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
414992	26465941	Thus identification of FGFR-3 mutations may be a potential biomarker of prognosis and recurrence.	('mutations', 'Var', (30, 39))	('FGFR-3', 'Gene', '2261', (23, 29))	('FGFR-3', 'Gene', (23, 29))
415002	26465941	Further it is not always clear that the FGFR alterations found in human cancers are "drivers" or "passengers".	('alterations', 'Var', (45, 56))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('human', 'Species', '9606', (66, 71))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('cancers', 'Disease', (72, 79))	('cancers', 'Disease', 'MESH:D009369', (72, 79))	('FGFR', 'Gene', (40, 44))
415003	26465941	Several alterations, most often leading to increased FGFR signaling have been associated with human carcinogenesis and development of a malignant phenotype.	('carcinogenesis', 'Disease', (100, 114))	('associated', 'Reg', (78, 88))	('alterations', 'Var', (8, 19))	('carcinogenesis', 'Disease', 'MESH:D063646', (100, 114))	('human', 'Species', '9606', (94, 99))	('increased', 'PosReg', (43, 52))	('FGFR signaling', 'MPA', (53, 67))
415009	26465941	Imbalanced FGFR signaling could contribute to carcinogenesis and could thus be a potent therapeutic target in several human cancers.	('contribute', 'Reg', (32, 42))	('carcinogenesis', 'Disease', 'MESH:D063646', (46, 60))	('Imbalanced', 'Var', (0, 10))	('carcinogenesis', 'Disease', (46, 60))	('human', 'Species', '9606', (118, 123))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('cancers', 'Phenotype', 'HP:0002664', (124, 131))	('FGFR', 'Protein', (11, 15))	('cancers', 'Disease', (124, 131))	('cancers', 'Disease', 'MESH:D009369', (124, 131))
415066	33633568	The primary antibodies against phospho-NF-kappaB (p-NF-kappaB) p65, p-JAK, phospho-signal transducer and activator of transcription 3 (p-STAT3), peroxisome proliferator-activated receptor gamma (PPARgamma), and beta-actin (1:1,000) were purchased from the Cell Signaling Technology Co., Ltd (Danvers, MA, United States).	('NF-kappaB', 'Gene', '4790', (39, 48))	('STAT3', 'Gene', (137, 142))	('NF-kappaB', 'Gene', (39, 48))	('peroxisome proliferator-activated receptor gamma', 'Gene', '5468', (145, 193))	('NF-kappaB', 'Gene', '4790', (52, 61))	('PPARgamma', 'Gene', (195, 204))	('p-JAK', 'Var', (68, 73))	('p65', 'Gene', (63, 66))	('STAT3', 'Gene', '6774', (137, 142))	('NF-kappaB', 'Gene', (52, 61))	('PPARgamma', 'Gene', '5468', (195, 204))	('p65', 'Gene', '5970', (63, 66))	('signal transducer and activator of transcription 3', 'Gene', '6774', (83, 133))	('peroxisome proliferator-activated receptor gamma', 'Gene', (145, 193))
415117	33633568	Thus, based on the ceRNA network, three key lncRNAs (LINC01504, LINC01783, and THUMPD3-AS1) and miRNAs (has-miR-155-5p, has-miR-7-5p, and has-425-5p) that regulate SOCS1, BTG2, and BTK were identified.	('AS1', 'Gene', '5729', (87, 90))	('AS1', 'Gene', (87, 90))	('THUMPD3', 'Gene', '25917', (79, 86))	('THUMPD3', 'Gene', (79, 86))	('SOCS1', 'Gene', (164, 169))	('LINC01504', 'Gene', '100507540', (53, 62))	('has-425-5p', 'Var', (138, 148))	('miR-7-5p', 'Gene', '407045', (124, 132))	('miR-155', 'Gene', '406947', (108, 115))	('LINC01504', 'Gene', (53, 62))	('BTG2', 'Gene', (171, 175))	('BTK', 'Gene', (181, 184))	('miR-155', 'Gene', (108, 115))	('BTG2', 'Gene', '7832', (171, 175))	('SOCS1', 'Gene', '8651', (164, 169))	('LINC01783', 'Chemical', '-', (64, 73))	('miR-7-5p', 'Gene', (124, 132))	('BTK', 'Gene', '695', (181, 184))
415120	33633568	The expression levels of five mRNAs (i.e., SOCS1, CREBRF, MXD1, BTK, and BTG2) and five lncRNAs (i.e., LINC01504, LUCAT1, LINC01484, THUMPD3-AS1, and LINC01783) were significantly elevated after the SK-MES-1 cells were treated with CA (Figures 10C).	('LUCAT1', 'Gene', '100505994', (114, 120))	('LUCAT1', 'Gene', (114, 120))	('LINC01783', 'Var', (150, 159))	('LINC01504', 'Gene', '100507540', (103, 112))	('MXD1', 'Gene', '4084', (58, 62))	('LINC01484', 'Gene', '101928136', (122, 131))	('CA', 'Gene', '12310', (116, 118))	('LINC01783', 'Chemical', '-', (150, 159))	('CREBRF', 'Gene', '153222', (50, 56))	('BTK', 'Gene', (64, 67))	('BTK', 'Gene', '695', (64, 67))	('SK-MES-1', 'CellLine', 'CVCL:0630', (199, 207))	('THUMPD3', 'Gene', (133, 140))	('BTG2', 'Gene', (73, 77))	('SOCS1', 'Gene', (43, 48))	('AS1', 'Gene', '5729', (141, 144))	('expression levels', 'MPA', (4, 21))	('MXD1', 'Gene', (58, 62))	('CREBRF', 'Gene', (50, 56))	('CA', 'Gene', '12310', (232, 234))	('AS1', 'Gene', (141, 144))	('LINC01484', 'Gene', (122, 131))	('LINC01504', 'Gene', (103, 112))	('BTG2', 'Gene', '7832', (73, 77))	('SOCS1', 'Gene', '8651', (43, 48))	('THUMPD3', 'Gene', '25917', (133, 140))	('elevated', 'PosReg', (180, 188))
415143	33633568	After treatment with CA, LINC01783 and BTG2 in the ceRNA network were upregulated, whereas hsa-miR-7-5p was downregulated.	('BTG2', 'Gene', (39, 43))	('miR-7-5p', 'Gene', (95, 103))	('LINC01783', 'Chemical', '-', (25, 34))	('miR-7-5p', 'Gene', '407045', (95, 103))	('BTG2', 'Gene', '7832', (39, 43))	('upregulated', 'PosReg', (70, 81))	('LINC01783', 'Var', (25, 34))	('CA', 'Gene', '12310', (21, 23))
415147	33633568	Inhibition of miR-7 expression could inhibit migration and proliferation, as well as induce apoptosis in renal cell carcinoma.	('apoptosis', 'CPA', (92, 101))	('migration', 'CPA', (45, 54))	('miR-7', 'Gene', '10859', (14, 19))	('renal cell carcinoma', 'Disease', (105, 125))	('inhibit', 'NegReg', (37, 44))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (105, 125))	('Inhibition', 'Var', (0, 10))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (105, 125))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('miR-7', 'Gene', (14, 19))	('induce', 'Reg', (85, 91))
415156	33633568	The present findings indicate that LINC01504, LINC01783, and THUMPD3-AS1 may play roles as NSCLC suppressors.	('NSCLC', 'Disease', 'MESH:D002289', (91, 96))	('NSCLC', 'Phenotype', 'HP:0030358', (91, 96))	('LINC01783', 'Var', (46, 55))	('LINC01783', 'Chemical', '-', (46, 55))	('LINC01504', 'Gene', '100507540', (35, 44))	('NSCLC', 'Disease', (91, 96))	('THUMPD3', 'Gene', '25917', (61, 68))	('THUMPD3', 'Gene', (61, 68))	('LINC01504', 'Gene', (35, 44))	('AS1', 'Gene', '5729', (69, 72))	('AS1', 'Gene', (69, 72))
415159	33633568	LINC01504, LINC01783, THUMPD3-AS1, has-miR-155-5p, has-miR-425-5p, and has-miR-7-5p may be key ncRNAs in the suppression of malignant phenotypes of NSCLC by CA.	('miR-425', 'Gene', (55, 62))	('miR-7-5p', 'Gene', (75, 83))	('AS1', 'Gene', (30, 33))	('LINC01504', 'Gene', '100507540', (0, 9))	('NSCLC', 'Disease', 'MESH:D002289', (148, 153))	('CA', 'Gene', '12310', (157, 159))	('miR-155', 'Gene', (39, 46))	('NSCLC', 'Disease', (148, 153))	('miR-155', 'Gene', '406947', (39, 46))	('THUMPD3', 'Gene', (22, 29))	('NSCLC', 'Phenotype', 'HP:0030358', (148, 153))	('AS1', 'Gene', '5729', (30, 33))	('LINC01504', 'Gene', (0, 9))	('miR-7-5p', 'Gene', '407045', (75, 83))	('miR-425', 'Gene', '494337', (55, 62))	('LINC01783', 'Var', (11, 20))	('malignant phenotypes', 'CPA', (124, 144))	('LINC01783', 'Chemical', '-', (11, 20))	('THUMPD3', 'Gene', '25917', (22, 29))
415165	31929526	Loss of Yap in T cells results in enhanced T-cell activation, differentiation, and function, which translates in vivo to an improved ability for T cells to infiltrate and repress tumors.	('differentiation', 'CPA', (62, 77))	('enhanced', 'PosReg', (34, 42))	('improved', 'PosReg', (124, 132))	('tumors', 'Phenotype', 'HP:0002664', (179, 185))	('function', 'CPA', (83, 91))	('Yap', 'Gene', (8, 11))	('T-cell activation', 'CPA', (43, 60))	('infiltrate', 'CPA', (156, 166))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('repress tumors', 'Disease', 'MESH:D009369', (171, 185))	('enhanced T-cell activation', 'Phenotype', 'HP:0005419', (34, 60))	('Loss', 'Var', (0, 4))	('repress tumors', 'Disease', (171, 185))
415166	31929526	Gene expression analyses of tumor-infiltrating T cells following Yap deletion implicates Yap as a mediator of global T-cell responses in the tumor microenvironment and as a negative regulator of T-cell tumor infiltration and patient survival in diverse human cancers.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('T-cell tumor infiltration', 'Disease', 'MESH:D018270', (195, 220))	('tumor', 'Disease', (28, 33))	('Yap', 'Gene', (65, 68))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('T-cell tumor infiltration', 'Disease', (195, 220))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumor', 'Disease', (202, 207))	('cancers', 'Disease', 'MESH:D009369', (259, 266))	('deletion', 'Var', (69, 77))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('human', 'Species', '9606', (253, 258))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('cancer', 'Phenotype', 'HP:0002664', (259, 265))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('cancers', 'Phenotype', 'HP:0002664', (259, 266))	('cancers', 'Disease', (259, 266))	('tumor', 'Disease', (141, 146))	('patient', 'Species', '9606', (225, 232))
415178	31929526	Yap controls signals that mediate cell death and survival, proliferation, and cell fate determination, while dysregulated Yap activity contributes to disease, most notably cancer.	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('cell fate determination', 'CPA', (78, 101))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('dysregulated', 'Var', (109, 121))	('cancer', 'Disease', (172, 178))	('contributes', 'Reg', (135, 146))
415181	31929526	Furthermore, an immune-cell-intrinsic role for Yap in CD4+ T cells has also been described, with Yap potentiating transforming growth factor beta (TGFbeta) signaling responses that direct Treg function.	('potentiating', 'PosReg', (101, 113))	('TGFbeta', 'Gene', (147, 154))	('Yap', 'Var', (97, 100))	('TGFbeta', 'Gene', '21802', (147, 154))
415193	31929526	To gain insight into the roles of Yap in T cells, we generated a mouse model in which Yap deletion and enhanced yellow fluorescent protein (EYFP) expression are induced under the control of the CD4 promoter (Yap-locus of X-over P1 [loxP]/loxP; lox-stop-lox [LSL]-EYFP; CD4-Cre, herein referred to as Yap-conditional knockout [cKO]).	('deletion', 'Var', (90, 98))	('enhanced', 'PosReg', (103, 111))	('Yap', 'Gene', (86, 89))	('mouse', 'Species', '10090', (65, 70))
415194	31929526	Yap expression was efficiently reduced in both CD4+ and CD8+ T cells in Yap-cKO mice, which was expected given the activity of this Cre model at the CD4+CD8+ double-positive (DP) stage of T-cell development (S1A and S1B Fig), and cells were also efficiently marked by EYFP expression (S1C and S1D Fig).	('CD8', 'Gene', (153, 156))	('reduced', 'NegReg', (31, 38))	('CD8', 'Gene', '925', (153, 156))	('Yap expression', 'Gene', (0, 14))	('Yap-cKO', 'Var', (72, 79))	('mice', 'Species', '10090', (80, 84))	('CD8', 'Gene', (56, 59))	('CD8', 'Gene', '925', (56, 59))
415199	31929526	CD44 and CD25 in CD4+ and CD8+ T cells exhibited significantly higher expression under all stimulation conditions tested, with CD69 being significantly up-regulated only after stimulation with intermediate anti-CD3 concentrations (0.25 and 0.5 mug/mL for CD8+ T cells, and 0.125 mug/mL for CD4+ T cells).	('CD25', 'Gene', '16184', (9, 13))	('CD69', 'Gene', (127, 131))	('CD8', 'Gene', '925', (26, 29))	('CD8', 'Gene', (255, 258))	('up-regulated', 'PosReg', (152, 164))	('0.125 mug/mL', 'Var', (273, 285))	('CD8', 'Gene', '925', (255, 258))	('expression', 'MPA', (70, 80))	('CD44', 'Gene', '12505', (0, 4))	('CD3', 'Gene', (211, 214))	('CD44', 'Gene', (0, 4))	('higher', 'PosReg', (63, 69))	('CD25', 'Gene', (9, 13))	('CD8', 'Gene', (26, 29))	('CD3', 'Gene', '12501', (211, 214))
415201	31929526	These data indicate that Yap plays an inhibitory role in T-cell activation and that loss of Yap enhances the sensitivity of CD4+ and CD8+ T cells to T cell receptor (TCR) signaling.	('CD8', 'Gene', (133, 136))	('CD8', 'Gene', '925', (133, 136))	('T cell receptor', 'Gene', (149, 164))	('enhances', 'PosReg', (96, 104))	('T cell receptor', 'Gene', '328483', (149, 164))	('loss', 'Var', (84, 88))	('sensitivity', 'MPA', (109, 120))	('Yap', 'Gene', (92, 95))
415220	31929526	There were significantly more Yap-cKO thymocytes in the post-positive-selection stage (TCRbeta+CD69+) compared to WT mice (approximately 1% increase in total cells).	('mice', 'Species', '10090', (117, 121))	('TCRbeta', 'Gene', (87, 94))	('Yap-cKO', 'Var', (30, 37))	('TCRbeta', 'Gene', '21473', (87, 94))
415229	31929526	Our analysis showed no increase in Nur77 expression in Yap-cKO mice compared to WT (Fig 3F), suggesting that Yap-cKO thymocytes do not receive prolonged TCR signaling relative to WT cells.	('Yap-cKO', 'Var', (109, 116))	('Nur77', 'Gene', '15370', (35, 40))	('mice', 'Species', '10090', (63, 67))	('Nur77', 'Gene', (35, 40))
415232	31929526	We observed similar reduced growth of subcutaneous LLC tumors in Yap-cKO mice (Fig 4C and 4D), suggesting a general role for Yap in antitumor T-cell responses.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('reduced', 'NegReg', (20, 27))	('LLC tumors', 'Disease', (51, 61))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('mice', 'Species', '10090', (73, 77))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('tumor', 'Disease', (55, 60))	('growth', 'MPA', (28, 34))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('Yap-cKO', 'Var', (65, 72))	('LLC tumors', 'Disease', 'MESH:D009369', (51, 61))	('tumor', 'Disease', (136, 141))	('subcutaneous', 'Disease', (38, 50))
415234	31929526	Immunofluorescence microscopy analysis revealed that tumors that developed in Yap-cKO mice were significantly more infiltrated with CD8+ T cells at both the tumor center and tumor edge compared to WT mice (Fig 4E).	('tumor', 'Disease', (157, 162))	('tumor', 'Disease', (174, 179))	('Yap-cKO', 'Var', (78, 85))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('more infiltrated', 'PosReg', (110, 126))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('mice', 'Species', '10090', (86, 90))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('mice', 'Species', '10090', (200, 204))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('tumor', 'Disease', (53, 58))	('CD8', 'Gene', (132, 135))	('CD8', 'Gene', '925', (132, 135))	('tumors', 'Disease', (53, 59))
415235	31929526	Flow cytometry analysis revealed more Yap-cKO CD4+ and CD8+ T cells infiltrating tumors compared to WT counterparts (Fig 4F and 4H).	('tumors', 'Disease', (81, 87))	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('Yap-cKO', 'Var', (38, 45))	('CD8', 'Gene', (55, 58))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('CD8', 'Gene', '925', (55, 58))	('4H', 'Chemical', 'MESH:D006859', (128, 130))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))
415239	31929526	Absolute numbers of tdTomato+ (WT) and EYFP+ (Yap-cKO) CD8+ T cells were then measured in tumors after 15 days.	('EYFP+', 'Var', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumors', 'Disease', (90, 96))	('tumors', 'Disease', 'MESH:D009369', (90, 96))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('CD8', 'Gene', (55, 58))	('CD8', 'Gene', '925', (55, 58))
415240	31929526	Yap-cKO CD8+ T cells showed a significantly enhanced capacity to infiltrate tumors (Fig 4J), with nearly 30% of all CD8+ tumor-infiltrating T cells being EYFP+ Yap-cKO T cells compared to almost undetectable numbers of tdTomato+ WT T cells (Fig 4K).	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('CD8', 'Gene', (116, 119))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('tumor', 'Disease', (121, 126))	('tdTomato+ WT T', 'Disease', (219, 233))	('CD8', 'Gene', '925', (116, 119))	('tumors', 'Disease', (76, 82))	('tumor', 'Disease', 'MESH:D009369', (121, 126))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('CD8', 'Gene', (8, 11))	('tdTomato+ WT T', 'Disease', 'MESH:C536751', (219, 233))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('CD8', 'Gene', '925', (8, 11))	('enhanced', 'PosReg', (44, 52))	('EYFP+', 'Var', (154, 159))
415241	31929526	These data are the first to conclusively show that Yap-cKO CD8+ T cells have intrinsically enhanced tumor infiltration capacity.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor infiltration', 'Disease', 'MESH:D017254', (100, 118))	('CD8', 'Gene', (59, 62))	('CD8', 'Gene', '925', (59, 62))	('tumor infiltration', 'Disease', (100, 118))	('Yap-cKO', 'Var', (51, 58))	('enhanced', 'PosReg', (91, 99))
415244	31929526	A large number of genes were differentially expressed in CD4+ and CD8+ TILs isolated from Yap-cKO mice compared to WT mice (Fig 5A and 5B and S2A and S2B Fig).	('CD4+', 'Var', (57, 61))	('CD8', 'Gene', (66, 69))	('CD8', 'Gene', '925', (66, 69))	('mice', 'Species', '10090', (118, 122))	('differentially', 'Reg', (29, 43))	('mice', 'Species', '10090', (98, 102))
415245	31929526	These data are consistent with Yap function being coordinated with T-cell activation and suggest that the enhanced antitumor responses observed in Yap-cKO T cells are mediated by changes in cellular responses to local tumor signals, including TCR signaling and the cytokine milieu.	('tumor', 'Disease', (119, 124))	('enhanced', 'PosReg', (106, 114))	('tumor', 'Disease', 'MESH:D009369', (218, 223))	('Yap-cKO', 'Var', (147, 154))	('TCR signaling', 'MPA', (243, 256))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('changes', 'Reg', (179, 186))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('tumor', 'Disease', (218, 223))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))
415248	31929526	Subset-defining transcription factors and cytokines associated with each of the major CD4+ T-cell phenotypes were all up-regulated in Yap KO CD4+ TILs (S3G and S3H Fig), suggesting that Yap deletion leads to enhanced naive CD4+ T-cell differentiation, consistent with our in vitro observations.	('deletion', 'Var', (190, 198))	('up-regulated', 'PosReg', (118, 130))	('S3H', 'Chemical', 'MESH:C042345', (160, 163))	('naive CD4+ T-cell differentiation', 'CPA', (217, 250))	('Yap', 'Gene', (186, 189))	('enhanced', 'PosReg', (208, 216))
415249	31929526	Using unique up-regulated genes after differentiation to each of the major T helper subsets, our data showed that Yap-cKO CD4+ TILs are more skewed towards a Th2 and Treg phenotype compared to WT CD4+ TILs (S4A-S4D Fig), consistent with prior studies showing that the B16F10 tumor microenvironment enhances these fates.	('Th2', 'Gene', '15111', (158, 161))	('CD4+', 'Var', (122, 126))	('B16F10', 'CellLine', 'CVCL:0159', (268, 274))	('tumor', 'Phenotype', 'HP:0002664', (275, 280))	('tumor', 'Disease', (275, 280))	('Yap-cKO CD4+', 'Var', (114, 126))	('Th2', 'Gene', (158, 161))	('up-regulated', 'PosReg', (13, 25))	('tumor', 'Disease', 'MESH:D009369', (275, 280))
415252	31929526	Comparison of gene expression changes identified in CD4+ and CD8+ Yap-cKO TILs with clinical data from TCGA showed significant correlation of gene signatures with T-cell infiltration across a variety of human cancers (Fig 5I).	('gene', 'MPA', (142, 146))	('human', 'Species', '9606', (203, 208))	('CD8', 'Gene', (61, 64))	('CD8', 'Gene', '925', (61, 64))	('cancers', 'Disease', 'MESH:D009369', (209, 216))	('CD4+', 'Var', (52, 56))	('cancers', 'Phenotype', 'HP:0002664', (209, 216))	('cancers', 'Disease', (209, 216))	('T-cell infiltration', 'CPA', (163, 182))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
415254	31929526	Genes altered in Yap-cKO TILs were also significantly associated with patient survival across several cancers (Fig 4J), as seen most significantly in LUAD for both CD4+ and CD8+ Yap-cKO gene signatures (Fig 4K and 4L).	('CD8', 'Gene', '925', (173, 176))	('LUAD', 'Disease', (150, 154))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('CD4+', 'Var', (164, 168))	('Yap-cKO', 'Gene', (178, 185))	('Yap-cKO', 'Gene', (17, 24))	('patient', 'Species', '9606', (70, 77))	('patient survival', 'CPA', (70, 86))	('cancers', 'Disease', 'MESH:D009369', (102, 109))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))	('CD8', 'Gene', (173, 176))	('cancers', 'Disease', (102, 109))	('associated with', 'Reg', (54, 69))
415257	31929526	We found that disrupting Yap activity leads to enhanced T-cell activation, augmented differentiation, and increased tumor infiltration.	('tumor infiltration', 'Disease', (116, 134))	('enhanced', 'PosReg', (47, 55))	('T-cell activation', 'CPA', (56, 73))	('disrupting', 'Var', (14, 24))	('enhanced T-cell activation', 'Phenotype', 'HP:0005419', (47, 73))	('tumor infiltration', 'Disease', 'MESH:D017254', (116, 134))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('differentiation', 'CPA', (85, 100))	('increased', 'PosReg', (106, 115))	('augmented', 'PosReg', (75, 84))
415259	31929526	Experimental data indicated that CD4+ and CD8+ T cells from Yap-cKO mice were more sensitive to TCR signaling compared to WT cells.	('mice', 'Species', '10090', (68, 72))	('Yap-cKO', 'Var', (60, 67))	('CD8', 'Gene', (42, 45))	('CD8', 'Gene', '925', (42, 45))	('sensitive to TCR signaling', 'MPA', (83, 109))
415263	31929526	RNA-seq analysis of Yap-cKO versus WT TILs revealed that CD3, CD28, CD80, and CD86 receptor molecules, kinases, phosphatases, and scaffold proteins are all up-regulated with Yap deletion, offering a mechanism for enhanced activation of CD4+ and CD8+ T cells.	('CD80', 'Gene', (68, 72))	('CD8', 'Gene', (68, 71))	('Yap', 'Gene', (174, 177))	('enhanced activation', 'PosReg', (213, 232))	('CD8', 'Gene', '925', (245, 248))	('CD86', 'Gene', '12524', (78, 82))	('CD8', 'Gene', '925', (78, 81))	('up-regulated', 'PosReg', (156, 168))	('CD3', 'Gene', (57, 60))	('CD86', 'Gene', (78, 82))	('CD8', 'Gene', '925', (68, 71))	('CD80', 'Gene', '12519', (68, 72))	('deletion', 'Var', (178, 186))	('CD28', 'Gene', (62, 66))	('CD8', 'Gene', (245, 248))	('CD8', 'Gene', (78, 81))	('CD3', 'Gene', '12501', (57, 60))	('CD28', 'Gene', '12487', (62, 66))	('kinases', 'MPA', (103, 110))
415266	31929526	We observed a slight increase in total number of TCRbeta+CD69+ thymocytes in Yap-cKO mice compared to WT mice.	('mice', 'Species', '10090', (85, 89))	('Yap-cKO', 'Var', (77, 84))	('increase', 'PosReg', (21, 29))	('TCRbeta', 'Gene', '21473', (49, 56))	('mice', 'Species', '10090', (105, 109))	('TCRbeta', 'Gene', (49, 56))
415272	31929526	Interestingly, neither Yap deletion nor verteporfin treatment significantly impacted T-cell proliferation.	('Yap', 'Gene', (23, 26))	('T-cell proliferation', 'CPA', (85, 105))	('verteporfin', 'Chemical', 'MESH:C098350', (40, 51))	('deletion', 'Var', (27, 35))	('impacted', 'Reg', (76, 84))
415286	31929526	The significant correlation of CD8+ and CD4+ Yap-cKO gene signatures with tumor T-cell infiltration in TCGA data suggest that Yap represses CD8+ and CD4+ T-cell migration and tumor infiltration in human cancers.	('CD8', 'Gene', (140, 143))	('CD8', 'Gene', '925', (31, 34))	('tumor', 'Disease', (74, 79))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('Yap', 'Var', (126, 129))	('cancers', 'Disease', 'MESH:D009369', (203, 210))	('represses', 'NegReg', (130, 139))	('tumor', 'Disease', (175, 180))	('tumor infiltration', 'Disease', (175, 193))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('CD8', 'Gene', '925', (140, 143))	('CD8', 'Gene', (31, 34))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('human', 'Species', '9606', (197, 202))	('tumor infiltration', 'Disease', 'MESH:D017254', (175, 193))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('cancers', 'Phenotype', 'HP:0002664', (203, 210))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('cancers', 'Disease', (203, 210))
415289	31929526	Collectively, our data show that Yap is an important immunosuppressor and suggest that inhibition of Yap activity in T cells could have important clinical implications in T-cell therapies against cancer and other diseases.	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('cancer', 'Disease', 'MESH:D009369', (196, 202))	('activity', 'MPA', (105, 113))	('cancer', 'Disease', (196, 202))	('inhibition', 'Var', (87, 97))	('Yap', 'Protein', (101, 104))
415308	31929526	Plates were coated with anti-CD3 antibody (Biolegend) at concentrations of 0, 0.125, 0.25, 0.5, and 1 mug/ml at 4 C overnight and were washed twice with PBS before incubation.	('CD3', 'Gene', '12501', (29, 32))	('0.125', 'Var', (78, 83))	('0.5', 'Var', (91, 94))	('0.25', 'Var', (85, 89))	('CD3', 'Gene', (29, 32))
415310	31929526	On days 1 and 3, cells were stained with dead cell dye as well as antibodies recognizing the lineage and activation markers CD3 BUV737 (BD), CD4 BUV395 (BD), CD8 PerCP-Cy5.5 (Biolegend), CD69 PE (Biolegend), CD44 BV650 (Biolegend), and CD25 APC (Biolegend).	('CD44', 'Gene', (208, 212))	('CD25', 'Gene', (236, 240))	('CD8', 'Gene', (158, 161))	('APC', 'Disease', 'MESH:D011125', (241, 244))	('CD8', 'Gene', '925', (158, 161))	('CD25', 'Gene', '16184', (236, 240))	('CD44', 'Gene', '12505', (208, 212))	('CD3', 'Gene', (124, 127))	('CD69 PE', 'Var', (187, 194))	('APC', 'Disease', (241, 244))	('CD3', 'Gene', '12501', (124, 127))	('CD4 BUV395', 'Var', (141, 151))
415318	31929526	Cells were stained with the LIVE/DEAD fixable near-IR dead cell stain kit (Invitrogen); antibodies for surface markers CD3 BUV737 (BD), CD4 BUV395 (BD), CD8 APCFire750 (Biolegend), and CD25 BV510 (Biolegend); antibodies for intracellular cytokines IFNgamma APC (Biolegend) and IL-17 PerCP-Cy5.5 (Biolegend); or antibodies for transcription factors GATA3 PECy7 (Biolegend) and Foxp3 PE (BD), as described earlier.	('IL-17', 'Gene', '16171', (277, 282))	('CD8', 'Gene', '925', (153, 156))	('Foxp3', 'Gene', (376, 381))	('IL-17', 'Gene', (277, 282))	('GATA3', 'Gene', '14462', (348, 353))	('APC', 'Disease', 'MESH:D011125', (157, 160))	('APC', 'Disease', (157, 160))	('CD25', 'Gene', '16184', (185, 189))	('CD25', 'Gene', (185, 189))	('IFNgamma', 'Gene', '15978', (248, 256))	('CD3', 'Gene', (119, 122))	('CD8', 'Gene', (153, 156))	('GATA3', 'Gene', (348, 353))	('APC', 'Disease', 'MESH:D011125', (257, 260))	('Foxp3', 'Gene', '20371', (376, 381))	('APC', 'Disease', (257, 260))	('IFNgamma', 'Gene', (248, 256))	('CD3', 'Gene', '12501', (119, 122))	('CD4 BUV395', 'Var', (136, 146))
415321	31929526	Cells were stained with dead cell dye and antibodies for the following surface markers: CD3 BUV737 (BD), CD4 BUV395 (BD), CD8 PerCP-Cy5.5 (Biolegend), TCRbeta BV510 (Biolegend), CCR7 PECy7 (Biolegend), H-2Kb PE (Biolegend), CD69 BV421 (Biolegend), CD45R/B220 APCFire750 (Biolegend), CD25 APCFire750 (Biolegend), GL3 APCFire750 (Biolegend), and NK1.1 APCFire750 (Biolegend).	('CD25', 'Gene', '16184', (283, 287))	('CD25', 'Gene', (283, 287))	('APC', 'Disease', 'MESH:D011125', (350, 353))	('CD45R', 'Gene', (248, 253))	('APC', 'Disease', 'MESH:D011125', (316, 319))	('CD45R', 'Gene', '19264', (248, 253))	('APC', 'Disease', (350, 353))	('TCRbeta', 'Gene', '21473', (151, 158))	('APC', 'Disease', (316, 319))	('CD8', 'Gene', (122, 125))	('CD3', 'Gene', (88, 91))	('APC', 'Disease', 'MESH:D011125', (259, 262))	('CD69 BV421', 'Var', (224, 234))	('APC', 'Disease', (259, 262))	('APC', 'Disease', 'MESH:D011125', (288, 291))	('CD3', 'Gene', '12501', (88, 91))	('APC', 'Disease', (288, 291))	('CD4 BUV395', 'Var', (105, 115))	('CCR7', 'Gene', (178, 182))	('CD8', 'Gene', '925', (122, 125))	('H-2Kb PE', 'Chemical', 'MESH:C032876', (202, 210))	('CCR7', 'Gene', '12775', (178, 182))	('TCRbeta', 'Gene', (151, 158))
415324	31929526	Cells were treated with ACK red blood cell lysis buffer (Gibco), and tumor single-cell suspensions were prepared for staining and analysis by flow cytometry, using DAPI (Biolegend) and antibodies for CD45 BV510 (Biolegend), CD3 BUV737 (BD), CD4 BUV395 (BD), and CD8 PerCP-Cy5.5 (Biolegend).	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('CD45 BV510', 'Var', (200, 210))	('tumor', 'Disease', (69, 74))	('CD3', 'Gene', (224, 227))	('CD8', 'Gene', (262, 265))	('CD4 BUV395', 'Var', (241, 251))	('CD3', 'Gene', '12501', (224, 227))	('ACK', 'Gene', (24, 27))	('CD8', 'Gene', '925', (262, 265))	('ACK', 'Gene', '107482', (24, 27))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
415328	31929526	On day 15 of tumor growth, tumors were harvested and stained for flow cytometric analysis with dead cell dye, DAPI (Biolegend), and antibodies recognizing CD45 BV510 (Biolegend), CD3 BUV737 (BD), CD4 APC (Biolegend), and CD8 PerCP-Cy5.5 (Biolegend).	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumor', 'Disease', (13, 18))	('CD8', 'Gene', '925', (221, 224))	('APC', 'Disease', (200, 203))	('CD45 BV510', 'Var', (155, 165))	('tumor', 'Disease', (27, 32))	('CD3', 'Gene', (179, 182))	('tumors', 'Disease', (27, 33))	('tumors', 'Disease', 'MESH:D009369', (27, 33))	('CD3', 'Gene', '12501', (179, 182))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('APC', 'Disease', 'MESH:D011125', (200, 203))	('CD8', 'Gene', (221, 224))
415332	31929526	Taqman primers (Life Tech) for mouse Gapdh (4352339E), Yap (Mm01143263_m1), or TEAD1-4 (Mm00493507_m1, Mm00449004_m1, Mm00449013_m1, Mm01189836_m1) were mixed with cDNA and Taqman Universal Master Mix II (Life Tech), and ddCT values were calculated relative to unstimulated controls.	('Mm01189836_m1', 'Var', (133, 146))	('Mm00449004_m1', 'Var', (103, 116))	('4352339E', 'Var', (44, 52))	('mouse', 'Species', '10090', (31, 36))	('Gapdh', 'Gene', '14433', (37, 42))	('Mm00493507_m1', 'Var', (88, 101))	('Gapdh', 'Gene', (37, 42))	('Mm00449013_m1', 'Var', (118, 131))	('TEAD1-4', 'Gene', (79, 86))	('TEAD1-4', 'Gene', '21676;21677;21678;21679', (79, 86))	('Mm01143263_m1', 'Var', (60, 73))	('4352339E', 'Chemical', 'MESH:D017962', (44, 52))
415335	31929526	Tumors cells were subsequently stained with DAPI and antibodies recognizing CD45 V500 (Biolegend), CD3 PE (Biolegend), CD4 APC (Biolegend), CD8 PerCP-Cy5.5 (Biolegend), and CD4+ and CD8+ TILs were sorted from each tumor using a BD FACSAria instrument.	('CD3', 'Gene', (99, 102))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('CD3', 'Gene', '12501', (99, 102))	('APC', 'Disease', 'MESH:D011125', (123, 126))	('APC', 'Disease', (123, 126))	('tumor', 'Disease', 'MESH:D009369', (214, 219))	('CD8', 'Gene', (140, 143))	('CD8', 'Gene', (182, 185))	('CD8', 'Gene', '925', (140, 143))	('CD8', 'Gene', '925', (182, 185))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('CD45 V500', 'Var', (76, 85))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('tumor', 'Disease', (214, 219))
415340	31929526	Differentially expressed genes (DEGs) between Yap-cKO versus WT CD4+ and CD8+ cells were defined as log2(FC) > 1 (up) or log2(FC) < -1 (down) and FDR < 0.05.	('Yap-cKO', 'Var', (46, 53))	('Di', 'Chemical', 'MESH:C076868', (0, 2))	('DEGs', 'Chemical', 'MESH:C062694', (32, 36))	('Differentially', 'Reg', (0, 14))	('CD8', 'Gene', (73, 76))	('CD8', 'Gene', '925', (73, 76))
415346	31929526	Red signifies that an average survival probability is higher for patients with high activity of Yap-regulated signature, whereas dark blue signifies that an average survival probability is higher for patients with low Yap activity.	('patients', 'Species', '9606', (200, 208))	('higher', 'PosReg', (54, 60))	('activity', 'MPA', (84, 92))	('high', 'Var', (79, 83))	('patients', 'Species', '9606', (65, 73))	('survival', 'MPA', (30, 38))
415366	31929526	OT1 TCR and B16-Ova tumor); 2) knocking down Yap in peripheral T cells from WT mice by an shRNA approach; or 3) introducing Yap (i.e.	('introducing', 'Reg', (112, 123))	('Ova tumor', 'Phenotype', 'HP:0100615', (16, 25))	('knocking down', 'Var', (31, 44))	('mice', 'Species', '10090', (79, 83))	('Yap', 'Gene', (45, 48))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('tumor', 'Disease', (20, 25))
415370	31929526	-The authors state that phenotype of "Yap-cKO CD4+ TILs are more skewed towards a Th2 and Treg phenotype compared to WT CD4+ TILs".	('CD4+', 'Var', (46, 50))	('Th2', 'Gene', '15111', (82, 85))	('Th2', 'Gene', (82, 85))
415379	24122460	Genetic variants in TNF-alpha promoter are predictors of recurrence in patients with squamous cell carcinoma of oropharynx after definitive radiotherapy The promoter variants of TNF-alpha, a major regulator of immune and inflammation responses, have been implicated in cancer development and prognosis.	('TNF-alpha', 'Gene', (178, 187))	('inflammation', 'Disease', 'MESH:D007249', (221, 233))	('TNF-alpha', 'Gene', (20, 29))	('inflammation', 'Disease', (221, 233))	('patients', 'Species', '9606', (71, 79))	('cancer', 'Phenotype', 'HP:0002664', (269, 275))	('cancer', 'Disease', (269, 275))	('variants', 'Var', (8, 16))	('TNF-alpha', 'Gene', '7124', (20, 29))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (85, 108))	('variants', 'Var', (166, 174))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (85, 108))	('TNF-alpha', 'Gene', '7124', (178, 187))	('squamous cell carcinoma', 'Disease', (85, 108))	('implicated', 'Reg', (255, 265))	('cancer', 'Disease', 'MESH:D009369', (269, 275))
415380	24122460	Thus, we investigated associations between four TNF-alpha promoter variants and risk of recurrence of squamous cell carcinoma of the oropharynx (SCCOP).	('squamous cell carcinoma', 'Disease', (102, 125))	('TNF-alpha', 'Gene', '7124', (48, 57))	('TNF-alpha', 'Gene', (48, 57))	('investigated', 'Reg', (9, 21))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (102, 125))	('associations', 'Interaction', (22, 34))	('variants', 'Var', (67, 75))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (102, 125))
415384	24122460	Furthermore, among patients with HPV16-positive tumors, those with common homozygous genotypes of the TNF-alpha -308 and -863 polymorphisms had worse disease-free survival (log-rank P = 0.005 and P = 0.007, respectively) and higher recurrence risk than patients with variant genotypes of these polymorphisms (HR, 5.1, 95% CI, 1.4-18.4 and HR, 3.7, 95% CI, 1.5-9.1, respectively), while no such significant associations were found for TNF-alpha -857 or -1031 polymorphisms.	('TNF-alpha', 'Gene', (102, 111))	('higher', 'PosReg', (225, 231))	('disease-free survival', 'CPA', (150, 171))	('patients', 'Species', '9606', (19, 27))	('worse', 'NegReg', (144, 149))	('recurrence', 'CPA', (232, 242))	('TNF-alpha', 'Gene', '7124', (102, 111))	('HPV16-positive tumors', 'Disease', 'MESH:D009369', (33, 54))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('patients', 'Species', '9606', (253, 261))	('polymorphisms', 'Var', (126, 139))	('TNF-alpha', 'Gene', '7124', (434, 443))	('TNF-alpha', 'Gene', (434, 443))	('HPV16-positive tumors', 'Disease', (33, 54))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
415385	24122460	Our findings suggest that TNF-alpha -308 and -863 polymorphisms may modulate the risk of SCCOP recurrence in patients with HPV16-positive tumors.	('patients', 'Species', '9606', (109, 117))	('HPV16-positive tumors', 'Disease', (123, 144))	('polymorphisms', 'Var', (50, 63))	('modulate', 'Reg', (68, 76))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('TNF-alpha', 'Gene', '7124', (26, 35))	('HPV16-positive tumors', 'Disease', 'MESH:D009369', (123, 144))	('SCCOP recurrence', 'Disease', (89, 105))	('TNF-alpha', 'Gene', (26, 35))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
415396	24122460	Genetic variants of TNF- alpha may affect the host immune system and susceptibility to HPV infection and, subsequently, the HPV status and prognosis of patients with SCCOP.	('host immune system', 'CPA', (46, 64))	('affect', 'Reg', (35, 41))	('HPV', 'Species', '10566', (124, 127))	('HPV infection', 'Disease', 'MESH:D030361', (87, 100))	('HPV', 'Species', '10566', (87, 90))	('TNF', 'Gene', '21926', (20, 23))	('HPV infection', 'Disease', (87, 100))	('patients', 'Species', '9606', (152, 160))	('Genetic variants', 'Var', (0, 16))	('TNF', 'Gene', (20, 23))
415397	24122460	Studies have shown that the promoter variants of TNF-alpha may affect its transcription level, cause interindividual variation in immune and inflammation responses, and thus may lead to different susceptibility to HPV-associated SCCOP and different response to treatment of such paients.	('affect', 'Reg', (63, 69))	('inflammation', 'Disease', 'MESH:D007249', (141, 153))	('TNF-alpha', 'Gene', '7124', (49, 58))	('cause', 'Reg', (95, 100))	('lead to', 'Reg', (178, 185))	('inflammation', 'Disease', (141, 153))	('HPV-associated SCCOP', 'Disease', (214, 234))	('transcription level', 'MPA', (74, 93))	('susceptibility', 'Reg', (196, 210))	('TNF-alpha', 'Gene', (49, 58))	('immune', 'CPA', (130, 136))	('HPV', 'Species', '10566', (214, 217))	('variants', 'Var', (37, 45))
415398	24122460	Four single-nucleotide polymorphisms (SNPs) have been found in the promoter region of the TNF-alpha gene: a G to A substitution at position -308 (rs1800629), a C to T substitution at position -857 (rs1799724), a C to A substitution at position -863 (rs1800630), and a T to C substitution at position -1031 (rs1799964).	('rs1800629', 'Var', (146, 155))	('rs1799964', 'Mutation', 'rs1799964', (307, 316))	('TNF-alpha', 'Gene', '7124', (90, 99))	('rs1799964', 'Var', (307, 316))	('rs1799724', 'Var', (198, 207))	('TNF-alpha', 'Gene', (90, 99))	('rs1799724', 'Mutation', 'rs1799724', (198, 207))	('rs1800630', 'Var', (250, 259))	('rs1800629', 'Mutation', 'rs1800629', (146, 155))	('rs1800630', 'Mutation', 'rs1800630', (250, 259))
415399	24122460	It was reported that the G to A substitution at position -308 increased transcriptional activation by approximately eight-fold in vitro, and the variant alleles of the other three SNPs of TNF-alpha, -857, -863, and -1031 have also been associated with high levels of TNF-alpha production.	('substitution', 'Var', (32, 44))	('increased', 'PosReg', (62, 71))	('G to', 'Var', (25, 29))	('TNF-alpha', 'Gene', (188, 197))	('TNF-alpha', 'Gene', '7124', (267, 276))	('associated', 'Reg', (236, 246))	('TNF-alpha', 'Gene', (267, 276))	('transcriptional activation', 'MPA', (72, 98))	('TNF-alpha', 'Gene', '7124', (188, 197))
415400	24122460	In addition, previous studies have reported that TNF-alpha promoter polymorphisms appeared to be biologically functional since these polymorphisms were significantly associated with cancer development, including development of SCCHN.	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('polymorphisms', 'Var', (133, 146))	('TNF-alpha', 'Gene', '7124', (49, 58))	('polymorphisms', 'Var', (68, 81))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('TNF-alpha', 'Gene', (49, 58))	('cancer', 'Disease', (182, 188))	('associated with', 'Reg', (166, 181))
415401	24122460	However, few large studies have examined the association between TNF-alpha promoter polymorphisms and risk of recurrence of SCCOP.	('TNF-alpha', 'Gene', (65, 74))	('TNF-alpha', 'Gene', '7124', (65, 74))	('SCCOP', 'Disease', (124, 129))	('polymorphisms', 'Var', (84, 97))
415402	24122460	In the study reported here, we tested the hypothesis that genetic variations in the TNF-alpha promoter predict the risk of recurrence of SCCOP, particularly HPV16-positive [HPV16(+)] tumors.	('tumors', 'Disease', 'MESH:D009369', (183, 189))	('HPV16', 'Species', '333760', (157, 162))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('SCCOP', 'Disease', (137, 142))	('TNF-alpha', 'Gene', '7124', (84, 93))	('tumors', 'Phenotype', 'HP:0002664', (183, 189))	('tested', 'Reg', (31, 37))	('TNF-alpha', 'Gene', (84, 93))	('tumors', 'Disease', (183, 189))	('genetic variations', 'Var', (58, 76))	('HPV16', 'Species', '333760', (173, 178))
415410	24122460	Associations between TNF-alpha polymorphisms and risk of recurrence were quantified by calculating hazard ratios (HRs) and their 95% CIs.	('polymorphisms', 'Var', (31, 44))	('Associations', 'Interaction', (0, 12))	('TNF-alpha', 'Gene', (21, 30))	('TNF-alpha', 'Gene', '7124', (21, 30))
415424	24122460	Because HPV plays important roles in both the carcinogenesis and prognosis of SCCOP and because TNF-alpha is an important regulator in inflammation response, we further explored the associations between TNF-alpha polymorphisms and risk of recurrence of tumor HPV16(+) patients with SCCOP.	('TNF-alpha', 'Gene', '7124', (203, 212))	('inflammation', 'Disease', 'MESH:D007249', (135, 147))	('HPV16', 'Species', '333760', (259, 264))	('carcinogenesis', 'Disease', 'MESH:D063646', (46, 60))	('TNF-alpha', 'Gene', '7124', (96, 105))	('SCCOP', 'Disease', (78, 83))	('TNF-alpha', 'Gene', (203, 212))	('HPV', 'Species', '10566', (8, 11))	('carcinogenesis', 'Disease', (46, 60))	('inflammation', 'Disease', (135, 147))	('TNF-alpha', 'Gene', (96, 105))	('polymorphisms', 'Var', (213, 226))	('tumor HPV', 'Disease', 'MESH:D030361', (253, 262))	('tumor', 'Phenotype', 'HP:0002664', (253, 258))	('SCCOP', 'Disease', (282, 287))	('tumor HPV', 'Disease', (253, 262))	('HPV', 'Species', '10566', (259, 262))	('patients', 'Species', '9606', (268, 276))
415425	24122460	Since we found that patients with common homozygous genotypes of the TNF-alpha-308 and -863 polymorphisms were approximately twice as likely as patients with the corresponding variant genotypes to have HPV16(+) tumors (OR, 2.3, 95% CI, 1.2-2.4 and OR, 2.0, 95% CI, 1.0-3.9, respectively), we then performed univariate and multivariable analysis to determine the effect of these two TNF-alpha polymorphisms on risk of recurrence among the 158 SCCOP patients with HPV16 (+) tumors.	('TNF-alpha', 'Gene', '7124', (69, 78))	('tumors', 'Disease', 'MESH:D009369', (211, 217))	('HPV16', 'Species', '333760', (462, 467))	('variant', 'Var', (176, 183))	('TNF-alpha', 'Gene', (69, 78))	('TNF-alpha', 'Gene', '7124', (382, 391))	('tumors', 'Phenotype', 'HP:0002664', (472, 478))	('tumor', 'Phenotype', 'HP:0002664', (472, 477))	('patients', 'Species', '9606', (448, 456))	('tumors', 'Phenotype', 'HP:0002664', (211, 217))	('TNF-alpha', 'Gene', (382, 391))	('patients', 'Species', '9606', (144, 152))	('HPV16', 'Species', '333760', (202, 207))	('patients', 'Species', '9606', (20, 28))	('tumors', 'Disease', 'MESH:D009369', (472, 478))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('tumors', 'Disease', (472, 478))	('tumors', 'Disease', (211, 217))
415433	24122460	Although the precise mechanism by which TNF-alpha polymorphisms influence cancer prognosis has not yet been elucidated, it is biologically plausible that genetic variants within the promoter of TNF-alpha result in the altered expression of this gene, thus affecting the regulation of immune and inflammatory responses and subsequently responses of cancer patients to treatment, such as radiotherapy.	('cancer', 'Disease', 'MESH:D009369', (348, 354))	('expression', 'MPA', (226, 236))	('cancer', 'Disease', (74, 80))	('variants', 'Var', (162, 170))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('patients', 'Species', '9606', (355, 363))	('TNF-alpha', 'Gene', '7124', (194, 203))	('influence', 'Reg', (64, 73))	('TNF-alpha', 'Gene', (194, 203))	('cancer', 'Disease', (348, 354))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('polymorphisms', 'Var', (50, 63))	('cancer', 'Phenotype', 'HP:0002664', (348, 354))	('regulation', 'MPA', (270, 280))	('immune', 'CPA', (284, 290))	('affecting', 'Reg', (256, 265))	('altered', 'Reg', (218, 225))	('TNF-alpha', 'Gene', '7124', (40, 49))	('TNF-alpha', 'Gene', (40, 49))
415434	24122460	Therefore, TNF-alpha polymorphisms may serve as predictive biomarkers for clinical outcome of SCCOP, and help physicians individualize treatment, thereby leading to improved prognosis and better quality of life for patients with this disease.	('TNF-alpha', 'Gene', '7124', (11, 20))	('improved', 'PosReg', (165, 173))	('patients', 'Species', '9606', (215, 223))	('prognosis', 'MPA', (174, 183))	('better', 'PosReg', (188, 194))	('TNF-alpha', 'Gene', (11, 20))	('polymorphisms', 'Var', (21, 34))	('SCCOP', 'Disease', (94, 99))
415435	24122460	Associations between TNF-alpha polymorphisms and cancer risk and clinical outcomes have been reported previously; however, few studies have investigated the associations between TNF-alpha polymorphisms and recurrence risk of SCCOP.	('TNF-alpha', 'Gene', (178, 187))	('TNF-alpha', 'Gene', (21, 30))	('polymorphisms', 'Var', (188, 201))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('TNF-alpha', 'Gene', '7124', (21, 30))	('TNF-alpha', 'Gene', '7124', (178, 187))	('cancer', 'Disease', (49, 55))	('associations', 'Interaction', (157, 169))	('SCCOP', 'Disease', (225, 230))
415439	24122460	did not find a significant association of TNF-alpha -308 polymorphism with survival of patients with oral and pharyngeal squamous cell carcinoma, whereas Correa et al.	('TNF-alpha', 'Gene', '7124', (42, 51))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (121, 144))	('pharyngeal squamous cell carcinoma', 'Phenotype', 'HP:0012182', (110, 144))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('squamous cell carcinoma', 'Disease', (121, 144))	('TNF-alpha', 'Gene', (42, 51))	('polymorphism', 'Var', (57, 69))	('patients', 'Species', '9606', (87, 95))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (121, 144))
415442	24122460	The TNF-alpha -857, -863, and -1031 polymorphisms also have been found to affect the transcription activity of TNF-alpha and thus may have biologically functional activities.	('polymorphisms', 'Var', (36, 49))	('TNF-alpha', 'Gene', (4, 13))	('TNF-alpha', 'Gene', '7124', (111, 120))	('TNF-alpha', 'Gene', (111, 120))	('transcription activity', 'MPA', (85, 107))	('affect', 'Reg', (74, 80))	('TNF-alpha', 'Gene', '7124', (4, 13))
415444	24122460	In contrast, in a separate study, no significant association was observed between the TNF-alpha -857 polymorphism and outcome of patients with bladder cancer, which was consistent with the results from the current study.	('TNF-alpha', 'Gene', '7124', (86, 95))	('patients', 'Species', '9606', (129, 137))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('bladder cancer', 'Phenotype', 'HP:0009725', (143, 157))	('TNF-alpha', 'Gene', (86, 95))	('polymorphism', 'Var', (101, 113))	('bladder cancer', 'Disease', 'MESH:D001749', (143, 157))	('bladder cancer', 'Disease', (143, 157))
415447	24122460	The inconsistent results from the aforementioned studies indicate that TNF-alpha promoter polymorphisms may demonstrate different impacts on the prognosis of patients with cancer depending on the cancer site, genetic background, environmental factors, sample size, stage, treatments, adequacy of adjustment for other confounding factors, and specific population studied.	('TNF-alpha', 'Gene', (71, 80))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('impacts', 'Reg', (130, 137))	('cancer', 'Disease', 'MESH:D009369', (196, 202))	('TNF-alpha', 'Gene', '7124', (71, 80))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('cancer', 'Disease', (196, 202))	('cancer', 'Disease', (172, 178))	('patients', 'Species', '9606', (158, 166))	('polymorphisms', 'Var', (90, 103))
415448	24122460	It is also probable that other inflammatory cytokines (e.g., IL-10), other molecular pathways (e.g., cell cycle control), and/or interactions between functional variants of these SNPs and therapeutic agents used also contribute to SCCOP recurrence.	('interactions', 'Interaction', (129, 141))	('variants', 'Var', (161, 169))	('IL-10', 'Gene', (61, 66))	('SNPs', 'Gene', (179, 183))	('SCCOP recurrence', 'Disease', (231, 247))	('contribute', 'Reg', (217, 227))	('IL-10', 'Gene', '3586', (61, 66))
415451	24122460	The HPV(+) SCCOP patients generally lack somatic genetic changes (e.g, intact p53), while HPV(-) SCCOP cases, who are majorly driven by smoking, have the most frequent p53 mutation.	('HPV', 'Species', '10566', (4, 7))	('HPV', 'Species', '10566', (90, 93))	('p53', 'Gene', '7157', (168, 171))	('mutation', 'Var', (172, 180))	('p53', 'Gene', (78, 81))	('patients', 'Species', '9606', (17, 25))	('lack', 'NegReg', (36, 40))	('p53', 'Gene', '7157', (78, 81))	('p53', 'Gene', (168, 171))
415452	24122460	Such p53 mutation seems to correlated with poor response to radiotherapy partially due to inactivation of the p53-mediated apoptotic pathway.	('mutation', 'Var', (9, 17))	('p53', 'Gene', (110, 113))	('p53', 'Gene', '7157', (110, 113))	('p53', 'Gene', '7157', (5, 8))	('p53', 'Gene', (5, 8))	('inactivation', 'NegReg', (90, 102))
415454	24122460	We thus further explored the roles of TNF-alpha polymorphisms in recurrence of SCCOP patients stratified by tumor HPV16 status.	('TNF-alpha', 'Gene', (38, 47))	('tumor HPV', 'Disease', 'MESH:D030361', (108, 117))	('tumor HPV', 'Disease', (108, 117))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('patients', 'Species', '9606', (85, 93))	('polymorphisms', 'Var', (48, 61))	('HPV16', 'Species', '333760', (114, 119))	('TNF-alpha', 'Gene', '7124', (38, 47))
415457	24122460	We expect that the TNF-alpha -308 and -863 variant genotypes may result in increased expression of TNF-alpha, which may confer protective effects against HPV infection among patients with SCOOP.	('expression', 'MPA', (85, 95))	('HPV infection', 'Disease', (154, 167))	('TNF-alpha', 'Gene', '7124', (19, 28))	('patients', 'Species', '9606', (174, 182))	('variant', 'Var', (43, 50))	('TNF-alpha', 'Gene', (19, 28))	('TNF-alpha', 'Gene', '7124', (99, 108))	('increased', 'PosReg', (75, 84))	('HPV infection', 'Disease', 'MESH:D030361', (154, 167))	('TNF-alpha', 'Gene', (99, 108))
415458	24122460	These TNF-alpha variants have been reported to almost double the levels of TNF-alpha in a Japanese study.	('levels', 'MPA', (65, 71))	('TNF-alpha', 'Gene', (75, 84))	('TNF-alpha', 'Gene', (6, 15))	('TNF-alpha', 'Gene', '7124', (75, 84))	('variants', 'Var', (16, 24))	('TNF-alpha', 'Gene', '7124', (6, 15))
415463	24122460	Therefore, the TNF-alpha -308 and -863 variant genotypes may enhance the inflammation and p53-induced apoptotic responses among patients with HPV16(+) tumors, leading to better response to definitive radiotherapy and subsequently lower likelihood of disease recurrence.	('enhance', 'PosReg', (61, 68))	('inflammation', 'Disease', (73, 85))	('p53', 'Gene', (90, 93))	('inflammation', 'Disease', 'MESH:D007249', (73, 85))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('p53', 'Gene', '7157', (90, 93))	('tumors', 'Disease', (151, 157))	('tumors', 'Disease', 'MESH:D009369', (151, 157))	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('variant', 'Var', (39, 46))	('TNF-alpha', 'Gene', '7124', (15, 24))	('HPV16', 'Species', '333760', (142, 147))	('TNF-alpha', 'Gene', (15, 24))	('patients', 'Species', '9606', (128, 136))	('better', 'PosReg', (170, 176))	('HPV16', 'Gene', (142, 147))
415464	24122460	Although the current study reveals some significant associations between TNF-alpha polymorphisms and recurrence risk of SCCOP, it has some limitations.	('polymorphisms', 'Var', (83, 96))	('TNF-alpha', 'Gene', (73, 82))	('TNF-alpha', 'Gene', '7124', (73, 82))	('SCCOP', 'Disease', (120, 125))
415469	24122460	In conclusion, our findings suggest that the TNF-alpha -308 and -863 polymorphisms might modulate the risk of recurrence of SCCOP, especially in patients with HPV16(+) tumors.	('patients', 'Species', '9606', (145, 153))	('TNF-alpha', 'Gene', '7124', (45, 54))	('HPV16', 'Species', '333760', (159, 164))	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('tumors', 'Disease', (168, 174))	('tumors', 'Disease', 'MESH:D009369', (168, 174))	('TNF-alpha', 'Gene', (45, 54))	('polymorphisms', 'Var', (69, 82))	('modulate', 'Reg', (89, 97))	('HPV16(+', 'Var', (159, 166))	('SCCOP', 'Disease', (124, 129))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
415470	24122460	TNF-alpha                tumor necrosis factor-alpha              SCCHN squamous cell carcinoma of the head and neck SCCOP squamous cell carcinoma of the oropharynx HR Hazard ratio CI confidence intervals PCR polymerase chain reaction SNPs single nucleotide polymorphisms TNF-alpha promoter variants modify the risk of SCCOP recurrence, and may be a marker of genetic susceptibility to recurrence of SCCOP, particularly in HPV-positive SCCOP patients.	('variants', 'Var', (291, 299))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (72, 95))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumor necrosis factor-alpha', 'Gene', '7124', (25, 52))	('modify', 'Reg', (300, 306))	('squamous cell carcinoma', 'Disease', (123, 146))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (72, 95))	('SCCOP', 'Disease', (319, 324))	('patients', 'Species', '9606', (442, 450))	('TNF-alpha', 'Gene', '7124', (272, 281))	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('tumor necrosis factor-alpha', 'Gene', (25, 52))	('single nucleotide polymorphisms', 'Var', (240, 271))	('HPV', 'Species', '10566', (423, 426))	('squamous cell carcinoma', 'Disease', (72, 95))	('TNF-alpha', 'Gene', (272, 281))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (123, 146))	('TNF-alpha', 'Gene', '7124', (0, 9))	('carcinoma of the head and neck', 'Phenotype', 'HP:0012288', (86, 116))	('TNF-alpha', 'Gene', (0, 9))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (123, 146))	('SCCOP', 'Disease', (400, 405))
415479	32787801	High miR-448 expression was significantly associated with advanced T stage (P = 0.001), lymph node metastasis (P = 0.007) and higher TNM stage (P = 0.009).	('High', 'Var', (0, 4))	('TNM', 'Gene', (133, 136))	('expression', 'MPA', (13, 23))	('lymph node metastasis', 'CPA', (88, 109))	('miR-448', 'Gene', '554212', (5, 12))	('advanced T stage', 'CPA', (58, 74))	('miR-448', 'Gene', (5, 12))	('TNM', 'Gene', '10178', (133, 136))
415480	32787801	Moreover, Kaplan-Meier and univariate analyses revealed that patients with high expression of miR-448 experienced significantly shorter OS and DFS.	('high expression', 'Var', (75, 90))	('patients', 'Species', '9606', (61, 69))	('miR-448', 'Gene', (94, 101))	('shorter', 'NegReg', (128, 135))	('miR-448', 'Gene', '554212', (94, 101))	('DFS', 'CPA', (143, 146))
415489	32787801	Increasing evidence demonstrates that aberrant regulation of miRNAs plays important roles in various cancers.	('roles', 'Reg', (84, 89))	('aberrant regulation', 'Var', (38, 57))	('cancers', 'Disease', 'MESH:D009369', (101, 108))	('miRNAs', 'Protein', (61, 67))	('cancers', 'Phenotype', 'HP:0002664', (101, 108))	('cancers', 'Disease', (101, 108))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))
415490	32787801	Furthermore, miRNAs may possess oncogenic or tumor suppressor activity according to cellular phenotypes and their target genes.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumor', 'Disease', (45, 50))	('oncogenic', 'CPA', (32, 41))	('miRNAs', 'Var', (13, 19))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
415493	32787801	Aberrant expression of miR-448 is frequent in several cancers, including OSCC.	('Aberrant expression', 'Var', (0, 19))	('cancers', 'Phenotype', 'HP:0002664', (54, 61))	('miR-448', 'Gene', '554212', (23, 30))	('cancers', 'Disease', (54, 61))	('cancers', 'Disease', 'MESH:D009369', (54, 61))	('frequent', 'Reg', (34, 42))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('miR-448', 'Gene', (23, 30))	('OSCC', 'Disease', (73, 77))
415523	32787801	As shown in Table 2, high levels of miR-448 were significantly associated with advanced T stage (P=0.001), lymph node metastasis (P=0.007), and higher TNM stage (P=0.009).	('lymph node metastasis', 'CPA', (107, 128))	('miR-448', 'Gene', '554212', (36, 43))	('TNM', 'Gene', '10178', (151, 154))	('associated', 'Reg', (63, 73))	('advanced T stage', 'CPA', (79, 95))	('high', 'Var', (21, 25))	('TNM', 'Gene', (151, 154))	('miR-448', 'Gene', (36, 43))
415535	32787801	reported that low levels of miR-218, miR-125b, and let-7g are associated with poor survival of patients with OSCC.	('let-7g', 'Gene', '406890', (51, 57))	('OSCC', 'Disease', (109, 113))	('patients', 'Species', '9606', (95, 103))	('miR-218', 'Var', (28, 35))	('poor', 'NegReg', (78, 82))	('let-7g', 'Gene', (51, 57))	('miR-125b', 'Var', (37, 45))
415548	32787801	Moreover, high levels of miR-448 served as an independent predictor of poor prognosis of patients with OSCC.	('OSCC', 'Disease', (103, 107))	('miR-448', 'Gene', (25, 32))	('patients', 'Species', '9606', (89, 97))	('high', 'Var', (10, 14))	('miR-448', 'Gene', '554212', (25, 32))
415559	31651887	Several studies have explored an association between aberrant methylation of MutL homolog-1 (MLH1) promoter and HNSCC risk.	('MutL homolog-1', 'Gene', (77, 91))	('MutL homolog-1', 'Gene', '4292', (77, 91))	('aberrant methylation', 'Var', (53, 73))	('HNSCC', 'Disease', (112, 117))	('HNSCC', 'Phenotype', 'HP:0012288', (112, 117))	('MLH1', 'Gene', '4292', (93, 97))	('MLH1', 'Gene', (93, 97))
415563	31651887	The pooled sensitivity and specificity rates of MLH1 methylation for HNSCC were 0.23 (95% CI = 0.12-0.38) and 0.95 (95% CI, 0.82-0.99), respectively.	('HNSCC', 'Disease', (69, 74))	('HNSCC', 'Phenotype', 'HP:0012288', (69, 74))	('MLH1', 'Gene', '4292', (48, 52))	('MLH1', 'Gene', (48, 52))	('methylation', 'Var', (53, 64))
415564	31651887	The results of this meta-analysis suggested that hypermethylation of MLH1 promoter was associated with HNSCC.	('HNSCC', 'Phenotype', 'HP:0012288', (103, 108))	('HNSCC', 'Disease', (103, 108))	('hypermethylation', 'Var', (49, 65))	('associated', 'Reg', (87, 97))	('MLH1', 'Gene', '4292', (69, 73))	('MLH1', 'Gene', (69, 73))
415565	31651887	Methylated MLH1 could be a potential diagnostic biomarker for diagnose of HNSCC.	('HNSCC', 'Disease', (74, 79))	('HNSCC', 'Phenotype', 'HP:0012288', (74, 79))	('MLH1', 'Gene', '4292', (11, 15))	('MLH1', 'Gene', (11, 15))	('Methylated', 'Var', (0, 10))
415571	31651887	Epigenetic regulation of promoter hypermethylation in tumor-suppressor genes (TSGs) has been emerged as an important cause in human carcinogenesis.	('carcinogenesis', 'Disease', (132, 146))	('human', 'Species', '9606', (126, 131))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('Epigenetic regulation', 'Var', (0, 21))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('TSG', 'Gene', (78, 81))	('carcinogenesis', 'Disease', 'MESH:D063646', (132, 146))	('cause', 'Reg', (117, 122))	('tumor', 'Disease', (54, 59))	('promoter', 'MPA', (25, 33))	('TSG', 'Gene', '57045', (78, 81))
415574	31651887	Researchers have revealed that polymorphism of methylenetetrahydrofolate reductase (MTHFR) affected p16 and MGMT methylation frequency in HNSCC.	('HNSCC', 'Disease', (138, 143))	('methylenetetrahydrofolate reductase', 'Gene', '4524', (47, 82))	('affected', 'Reg', (91, 99))	('polymorphism', 'Var', (31, 43))	('MGMT', 'Gene', (108, 112))	('MTHFR', 'Gene', (84, 89))	('HNSCC', 'Phenotype', 'HP:0012288', (138, 143))	('MGMT', 'Gene', '4255', (108, 112))	('p16', 'Gene', (100, 103))	('MTHFR', 'Gene', '4524', (84, 89))	('methylenetetrahydrofolate reductase', 'Gene', (47, 82))	('p16', 'Gene', '1029', (100, 103))
415576	31651887	Epigenetic silencing of MLH1 promoter methylation can cause mismatch repair (MMR) deficiency, which may cause insertion or deletion mutations in repeated sequences.	('cause', 'Reg', (54, 59))	('mismatch repair (MMR) deficiency', 'Disease', 'MESH:C536928', (60, 92))	('insertion', 'Disease', (110, 119))	('MLH1', 'Gene', '4292', (24, 28))	('MLH1', 'Gene', (24, 28))	('Epigenetic silencing', 'Var', (0, 20))	('cause', 'Reg', (104, 109))	('deletion mutations', 'Var', (123, 141))
415577	31651887	The MLH1 promoter methylation has been reported as a well-established biomarker in several types of cancer, such as esophageal cancer, colorectal cancer, non-small cell lung cancer, gastric cancer, papillary thyroid cancer, and bladder cancer.	('esophageal cancer', 'Disease', 'MESH:D004938', (116, 133))	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (236, 242))	('lung cancer', 'Phenotype', 'HP:0100526', (169, 180))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('cancer', 'Disease', (216, 222))	('non-small cell lung cancer', 'Disease', (154, 180))	('gastric cancer', 'Disease', (182, 196))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('esophageal cancer', 'Disease', (116, 133))	('cancer', 'Disease', (190, 196))	('colorectal cancer', 'Disease', 'MESH:D015179', (135, 152))	('cancer', 'Disease', (174, 180))	('MLH1', 'Gene', (4, 8))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('cancer', 'Disease', (127, 133))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('colorectal cancer', 'Disease', (135, 152))	('gastric cancer', 'Disease', 'MESH:D013274', (182, 196))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (154, 180))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('papillary thyroid cancer', 'Disease', (198, 222))	('bladder cancer', 'Disease', 'MESH:D001749', (228, 242))	('bladder cancer', 'Disease', (228, 242))	('cancer', 'Disease', (236, 242))	('papillary thyroid cancer', 'Disease', 'MESH:C536915', (198, 222))	('MLH1', 'Gene', '4292', (4, 8))	('cancer', 'Disease', 'MESH:D009369', (216, 222))	('cancer', 'Disease', (100, 106))	('bladder cancer', 'Phenotype', 'HP:0009725', (228, 242))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (158, 180))	('cancer', 'Disease', 'MESH:D009369', (190, 196))	('gastric cancer', 'Phenotype', 'HP:0012126', (182, 196))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('papillary thyroid cancer', 'Phenotype', 'HP:0002895', (198, 222))	('thyroid cancer', 'Phenotype', 'HP:0002890', (208, 222))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (154, 180))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('colorectal cancer', 'Phenotype', 'HP:0003003', (135, 152))	('methylation', 'Var', (18, 29))
415578	31651887	To date, several studies have explored an association between aberrant methylation of MLH1 promoter and HNSCC risk.	('HNSCC', 'Disease', (104, 109))	('HNSCC', 'Phenotype', 'HP:0012288', (104, 109))	('MLH1', 'Gene', '4292', (86, 90))	('aberrant methylation', 'Var', (62, 82))	('MLH1', 'Gene', (86, 90))
415582	31651887	The following search terms and key words were used: "MLH1", "hMLH1", "MutL homolog-1", "methylation epigenetic", "head and neck cancer (HNSCC)", "laryngeal squamous cell carcinoma (LSCC)", "squamous cell carcinoma of the tongue (SCCT)", "oral squamous cell carcinoma (OSCC)", and "hypopharyngeal squamous cell carcinoma".	('SCCT', 'Phenotype', 'HP:0030413', (229, 233))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (296, 319))	('hypopharyngeal squamous cell carcinoma', 'Disease', (281, 319))	('squamous cell carcinoma of the tongue', 'Disease', (190, 227))	('squamous cell carcinoma', 'Disease', (156, 179))	('MLH1', 'Gene', (62, 66))	('squamous cell carcinoma', 'Disease', (243, 266))	('MLH1', 'Gene', (53, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (310, 319))	('MutL homolog-1"', 'Gene', '4292', (70, 85))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (190, 213))	('head and neck cancer', 'Phenotype', 'HP:0012288', (114, 134))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('MLH1', 'Gene', '4292', (62, 66))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (243, 266))	('HNSCC', 'Phenotype', 'HP:0012288', (136, 141))	('hMLH1"', 'Gene', '4292', (61, 67))	('carcinoma', 'Phenotype', 'HP:0030731', (204, 213))	('MLH1', 'Gene', '4292', (53, 57))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (156, 179))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (190, 213))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (243, 266))	('hMLH1"', 'Gene', (61, 67))	('head and neck cancer', 'Disease', 'MESH:D006258', (114, 134))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (296, 319))	('carcinoma', 'Phenotype', 'HP:0030731', (170, 179))	('cell carcinoma of the tongue', 'Phenotype', 'HP:0030415', (199, 227))	('squamous cell carcinoma of the tongue', 'Disease', 'MESH:D002294', (190, 227))	('squamous cell carcinoma of the tongue', 'Phenotype', 'HP:0030413', (190, 227))	('carcinoma', 'Phenotype', 'HP:0030731', (257, 266))	('hypopharyngeal squamous cell carcinoma', 'Disease', 'MESH:D002294', (281, 319))	('hypopharyngeal squamous cell carcinoma', 'Phenotype', 'HP:0012182', (281, 319))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (156, 179))	('epigenetic', 'Var', (100, 110))	('MutL homolog-1"', 'Gene', (70, 85))
415583	31651887	The following data were extracted as follows: first author's full-name, year of publication, country, methods for detecting the methylation status, hazard ratio (HR) and the corresponding 95% confidence interval (CI), histology of the sample, sample type in case and control group, sample number of the total people (in the case and control groups), clinicopathological characteristics, and the tumor location.	('tumor', 'Disease', (395, 400))	('people', 'Species', '9606', (309, 315))	('tumor', 'Disease', 'MESH:D009369', (395, 400))	('methylation', 'Var', (128, 139))	('tumor', 'Phenotype', 'HP:0002664', (395, 400))
415584	31651887	The pooled odds ratios (ORs) with 95% CIs were calculated to assess the association between MLH1 promoter methylation and risk of HNSCC, and the association of MLH1 promoter methylation with other clinical features was investigated as well.	('MLH1', 'Gene', (160, 164))	('MLH1', 'Gene', '4292', (92, 96))	('MLH1', 'Gene', (92, 96))	('association', 'Interaction', (72, 83))	('methylation', 'Var', (106, 117))	('HNSCC', 'Disease', (130, 135))	('HNSCC', 'Phenotype', 'HP:0012288', (130, 135))	('MLH1', 'Gene', '4292', (160, 164))
415589	31651887	The frequency of MLH1 promoter methylation in HNSCC was 29.3%, which was significantly higher than that in normal controls (OR = 2.521, 95% CI = 1.327-4.788).	('MLH1', 'Gene', '4292', (17, 21))	('HNSCC', 'Disease', (46, 51))	('MLH1', 'Gene', (17, 21))	('HNSCC', 'Phenotype', 'HP:0012288', (46, 51))	('methylation', 'Var', (31, 42))	('higher', 'PosReg', (87, 93))
415591	31651887	As shown in Table 3, in the control source analyses, the pooled OR for MLH1 methylation in HNSCC compared with heterogeneous controls was 5.349 (95% CI: 0.481-59.496, P = .172), while that was 1.932 (95% CI: 1.363-2.739, P < .001) in the autologous control group.	('HNSCC', 'Phenotype', 'HP:0012288', (91, 96))	('MLH1', 'Gene', '4292', (71, 75))	('methylation', 'Var', (76, 87))	('MLH1', 'Gene', (71, 75))
415592	31651887	Furthermore, subgroup meta-analysis by studies published after 2010 indicated no significant association between MLH1 methylation and risk of HNSCC with pooled OR = 3.505 (95% CI: 0.811-15.142, P = .093).	('MLH1', 'Gene', '4292', (113, 117))	('HNSCC', 'Disease', (142, 147))	('HNSCC', 'Phenotype', 'HP:0012288', (142, 147))	('MLH1', 'Gene', (113, 117))	('methylation', 'Var', (118, 129))
415593	31651887	The results of this subgroup analysis showed that MLH1 hypermethylation was significantly associated with other subgroups (P < .05).	('hypermethylation', 'Var', (55, 71))	('MLH1', 'Gene', (50, 54))	('MLH1', 'Gene', '4292', (50, 54))	('associated', 'Reg', (90, 100))
415597	31651887	The summery sensitivity, summery specificity, and area under the curve (AUC) value of MLH1 promoter methylation in HNSCC patients versus healthy individuals were 0.23, 0.95, and 0.64, respectively.	('HNSCC', 'Disease', (115, 120))	('HNSCC', 'Phenotype', 'HP:0012288', (115, 120))	('methylation', 'Var', (100, 111))	('MLH1', 'Gene', '4292', (86, 90))	('MLH1', 'Gene', (86, 90))	('patients', 'Species', '9606', (121, 129))
415600	31651887	Increasing lines of evidence suggested that MLH1 plays a critical role in genome stability system by correcting replicative DNA polymerase errors or mismatched genes.	('MLH1', 'Gene', (44, 48))	('MLH1', 'Gene', '4292', (44, 48))	('replicative DNA polymerase errors', 'MPA', (112, 145))	('correcting', 'NegReg', (101, 111))	('mismatched genes', 'Var', (149, 165))
415601	31651887	Inactivation of MLH1 increased microsatellite instability.	('increased', 'PosReg', (21, 30))	('MLH1', 'Gene', '4292', (16, 20))	('microsatellite instability', 'MPA', (31, 57))	('MLH1', 'Gene', (16, 20))	('Inactivation', 'Var', (0, 12))
415602	31651887	It has been reported by several scholars that aberrant MLH1 methylation appears as a major mechanism in HNSCC.	('HNSCC', 'Disease', (104, 109))	('HNSCC', 'Phenotype', 'HP:0012288', (104, 109))	('MLH1', 'Gene', '4292', (55, 59))	('MLH1', 'Gene', (55, 59))	('aberrant', 'Var', (46, 54))	('methylation', 'MPA', (60, 71))	('mechanism', 'Reg', (91, 100))
415603	31651887	Promoter methylation is a well-known epigenetic process that has been implicated in various human cancers, that may affect apoptosis, proliferation, and cell adhesion process.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('cancers', 'Phenotype', 'HP:0002664', (98, 105))	('proliferation', 'CPA', (134, 147))	('cell adhesion process', 'CPA', (153, 174))	('affect', 'Reg', (116, 122))	('apoptosis', 'CPA', (123, 132))	('Promoter methylation', 'Var', (0, 20))	('cancers', 'Disease', (98, 105))	('cancers', 'Disease', 'MESH:D009369', (98, 105))	('implicated', 'Reg', (70, 80))	('human', 'Species', '9606', (92, 97))
415604	31651887	It has been reported that MLH1 protein expression was decreased in HNSCC patients compared with normal squamous epithelium due to promoter hypermethylation of MLH1 gene.	('protein', 'Protein', (31, 38))	('MLH1', 'Gene', '4292', (26, 30))	('MLH1', 'Gene', (26, 30))	('promoter hypermethylation', 'Var', (130, 155))	('HNSCC', 'Phenotype', 'HP:0012288', (67, 72))	('decreased', 'NegReg', (54, 63))	('expression', 'MPA', (39, 49))	('MLH1', 'Gene', '4292', (159, 163))	('patients', 'Species', '9606', (73, 81))	('MLH1', 'Gene', (159, 163))
415605	31651887	Promoter hypermethylation of MLH1 was found to be associated with cancer regional lymph node invasion, in laryngeal squamous cell carcinoma.	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (116, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('squamous cell carcinoma', 'Disease', (116, 139))	('Promoter hypermethylation', 'Var', (0, 25))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (116, 139))	('associated', 'Reg', (50, 60))	('MLH1', 'Gene', '4292', (29, 33))	('cancer', 'Disease', (66, 72))	('MLH1', 'Gene', (29, 33))
415608	31651887	Our results indicated that the frequency of methylation of MLH1 promoter was significantly higher in HNSCC patients than in normal controls, which supported hypermethylation of MLH1 associated with an increased risk of HNSCC.	('HNSCC', 'Disease', (219, 224))	('associated', 'Reg', (182, 192))	('MLH1', 'Gene', '4292', (177, 181))	('HNSCC', 'Disease', (101, 106))	('MLH1', 'Gene', (177, 181))	('higher', 'PosReg', (91, 97))	('HNSCC', 'Phenotype', 'HP:0012288', (101, 106))	('MLH1', 'Gene', '4292', (59, 63))	('MLH1', 'Gene', (59, 63))	('hypermethylation', 'Var', (157, 173))	('methylation', 'MPA', (44, 55))	('patients', 'Species', '9606', (107, 115))	('HNSCC', 'Phenotype', 'HP:0012288', (219, 224))
415609	31651887	However, in subgroup analysis of studies used for autologous controls, a more significant association was found between MLH1 methylation and risk of HNSCC with a lower heterogeneity compared with heterogeneous control studies.	('MLH1', 'Gene', '4292', (120, 124))	('MLH1', 'Gene', (120, 124))	('HNSCC', 'Phenotype', 'HP:0012288', (149, 154))	('HNSCC', 'Disease', (149, 154))	('methylation', 'Var', (125, 136))
415610	31651887	On the other hand, the subgroup meta-analysis based on the year of publication revealed that no significant association of MLH1 methylation was available in studies published after 2010, however, those studies published before 2010 presented a significant correlation between hypermethylated MLH1 and HNSCC.	('hypermethylated', 'Var', (276, 291))	('MLH1', 'Gene', '4292', (123, 127))	('MLH1', 'Gene', (123, 127))	('HNSCC', 'Disease', (301, 306))	('MLH1', 'Gene', '4292', (292, 296))	('HNSCC', 'Phenotype', 'HP:0012288', (301, 306))	('MLH1', 'Gene', (292, 296))
415612	31651887	The subgroup analysis by ethnicity showed that Caucasian population had a higher OR than the other population, which suggested that Caucasian population may be more susceptible to MLH1 promoter methylation.	('MLH1', 'Gene', (180, 184))	('methylation', 'Var', (194, 205))	('MLH1', 'Gene', '4292', (180, 184))
415614	31651887	However, no significant association was observed between MLH1 promoter methylation and those clinicopathological features, in which it may be related to the small sample size.	('methylation', 'Var', (71, 82))	('MLH1', 'Gene', '4292', (57, 61))	('MLH1', 'Gene', (57, 61))
415616	31651887	5) indicated that MLH1 hypermethylation yielded an AUC value of 0.64 (95% CI: 0.60-0.68) in distinguishing HNSCC from normal control with a sensitivity of 0.23 and a specificity of 0.95.	('HNSCC', 'Disease', (107, 112))	('HNSCC', 'Phenotype', 'HP:0012288', (107, 112))	('MLH1', 'Gene', '4292', (18, 22))	('hypermethylation', 'Var', (23, 39))	('MLH1', 'Gene', (18, 22))
415617	31651887	Besides, Fagan plots analysis indicated that the probability of HNSCC diagnosis was significantly elevated by the detection of hypermethylation of MLH1.	('detection', 'Reg', (114, 123))	('MLH1', 'Gene', '4292', (147, 151))	('elevated', 'PosReg', (98, 106))	('MLH1', 'Gene', (147, 151))	('HNSCC', 'Phenotype', 'HP:0012288', (64, 69))	('HNSCC', 'Disease', (64, 69))	('hypermethylation', 'Var', (127, 143))
415618	31651887	These results indicated that hypermethylation of MLH1 could be a potential biomarker with low sensitivity for diagnosis of HNSCC.	('HNSCC', 'Phenotype', 'HP:0012288', (123, 128))	('MLH1', 'Gene', '4292', (49, 53))	('hypermethylation', 'Var', (29, 45))	('MLH1', 'Gene', (49, 53))	('HNSCC', 'Disease', (123, 128))
415619	31651887	However, we concluded that MLH1 hypermethylation may be a specific method in diagnosis of HNSCC, which could be used as combined with other methods to improve the diagnostic value of a disease.	('HNSCC', 'Disease', (90, 95))	('HNSCC', 'Phenotype', 'HP:0012288', (90, 95))	('MLH1', 'Gene', '4292', (27, 31))	('MLH1', 'Gene', (27, 31))	('hypermethylation', 'Var', (32, 48))
415620	31651887	First, the studies were from different countries, and population differences were observed regarding the status of MLH1 methylation.	('MLH1', 'Gene', '4292', (115, 119))	('methylation', 'Var', (120, 131))	('MLH1', 'Gene', (115, 119))
415623	31651887	This research indicated that aberrant methylation of MLH1 promoter was significantly associated with tumor progression in HNSCC patients, and it could be a potential tumor-specific biomarker for diagnose of HNSCC.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('aberrant methylation', 'Var', (29, 49))	('MLH1', 'Gene', (53, 57))	('associated with', 'Reg', (85, 100))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('MLH1', 'Gene', '4292', (53, 57))	('HNSCC', 'Phenotype', 'HP:0012288', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('tumor', 'Disease', (166, 171))	('HNSCC', 'Phenotype', 'HP:0012288', (207, 212))	('HNSCC', 'Disease', (122, 127))	('patients', 'Species', '9606', (128, 136))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
415627	31528121	Four cDNA expression profiles GSE19188, GSE101929, GSE18842 and GSE33532 were chosen from GEO database to analyze the differently expressed genes (DEGs) between non-small cell lung cancer (NSCLC) and normal lung tissues.	('GSE33532', 'Var', (64, 72))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (165, 187))	('NSCLC', 'Disease', (189, 194))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (161, 187))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('NSCLC', 'Disease', 'MESH:D002289', (189, 194))	('small cell lung cancer', 'Disease', (165, 187))	('GSE101929', 'Var', (40, 49))	('SCLC', 'Phenotype', 'HP:0030357', (190, 194))	('GSE18842', 'Var', (51, 59))	('NSCLC', 'Phenotype', 'HP:0030358', (189, 194))	('GSE19188', 'Var', (30, 38))	('lung cancer', 'Phenotype', 'HP:0100526', (176, 187))	('small cell lung cancer', 'Disease', 'MESH:D055752', (165, 187))
415644	31528121	Recently, great advance is happening to high-throughput technologies, bringing in tremendous amount of clinical data, which provides a rich source for researchers to better understand the molecular basis of cancer development and to identify disease-causing gene alterations thus exploring potential drug targets for therapeutic intervention.	('cancer', 'Disease', (207, 213))	('cancer', 'Disease', 'MESH:D009369', (207, 213))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('alterations', 'Var', (263, 274))
415683	31528121	We chose four cDNA expression profiles GSE18842, GSE19188, GSE33532 and GSE101929 from GEO database to analyze the DEGs between NSCLC and normal lung tissues.	('NSCLC', 'Phenotype', 'HP:0030358', (128, 133))	('GSE18842', 'Var', (39, 47))	('GSE33532', 'Var', (59, 67))	('NSCLC', 'Disease', (128, 133))	('NSCLC', 'Disease', 'MESH:D002289', (128, 133))	('SCLC', 'Phenotype', 'HP:0030357', (129, 133))	('GSE19188', 'Var', (49, 57))	('GSE101929', 'Var', (72, 81))
415749	31528121	However, above results aren't yet enough to put TOP2A or TPX2 as a drug target in NSCLC, to distinguish gene aberrations that can cause the disease and may serve as drug targets with those only closely linked to the disease and consequently are associated with the disease development, comprehensive and longitudinal experiments, as well as clinical trials are needed to be performed.	('TOP2A', 'Gene', (48, 53))	('cause', 'Reg', (130, 135))	('TPX2', 'Gene', (57, 61))	('NSCLC', 'Phenotype', 'HP:0030358', (82, 87))	('SCLC', 'Phenotype', 'HP:0030357', (83, 87))	('TPX2', 'Gene', '22974', (57, 61))	('aberrations', 'Var', (109, 120))	('NSCLC', 'Disease', (82, 87))	('TOP2A', 'Gene', '7153', (48, 53))	('NSCLC', 'Disease', 'MESH:D002289', (82, 87))
415785	29187211	High nm23 expression is associated with favorable prognosis and may be used to evaluate the risk of recurrence in laryngeal carcinoma.	('laryngeal carcinoma', 'Phenotype', 'HP:0012118', (114, 133))	('nm23', 'Gene', '4830', (5, 9))	('High', 'Var', (0, 4))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('nm23', 'Gene', (5, 9))	('laryngeal carcinoma', 'Disease', (114, 133))	('laryngeal carcinoma', 'Disease', 'MESH:D007827', (114, 133))
415812	29187211	Furthermore, the MLVDs were found to be significantly lower in LSCC patients with positive KAI1 and nm23 expression than those with negative expression (KAI1, 17.1 +- 5.2 vs. 20.9 +- 6.7; nm23, 17.5 +- 5.6 vs. 20.8 +- 6.1, respectively, all P < 0.05) (Table 4).	('positive', 'Var', (82, 90))	('nm23', 'Gene', '4830', (100, 104))	('KAI1', 'Gene', (91, 95))	('SCC', 'Gene', '6317', (64, 67))	('MLVD', 'Disease', 'None', (17, 21))	('nm23', 'Gene', '4830', (188, 192))	('MLVD', 'Disease', (17, 21))	('expression', 'Var', (105, 115))	('nm23', 'Gene', (188, 192))	('KAI1', 'Gene', '3732', (153, 157))	('patients', 'Species', '9606', (68, 76))	('SCC', 'Gene', (64, 67))	('lower', 'NegReg', (54, 59))	('KAI1', 'Gene', (153, 157))	('KAI1', 'Gene', '3732', (91, 95))	('nm23', 'Gene', (100, 104))	('SCC', 'Phenotype', 'HP:0002860', (64, 67))
415849	26933818	Driver mutations have been identified in small percentage of lung squamous cell carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('mutations', 'Var', (7, 16))	('lung squamous cell carcinoma', 'Disease', (61, 89))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (61, 89))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (66, 89))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (61, 89))
415862	26933818	Molecular characterization could be useful in this setting, as shown in a small study in which loss of heterozygosity and TP53 mutation analysis have been successfully used for differential diagnosis.	('mutation', 'Var', (127, 135))	('loss of heterozygosity', 'Var', (95, 117))	('TP53', 'Gene', (122, 126))	('TP53', 'Gene', '7157', (122, 126))
415871	26933818	More than sixty known carcinogens have been detected in cigarette smoke; among these, tobacco-specific N-nitrosamines, polycyclic aromatic hydrocarbons, and aromatic amines are currently recognized as the strongest tumorigenic substances.	('polycyclic aromatic hydrocarbons', 'Chemical', 'MESH:D011084', (119, 151))	('tumor', 'Disease', 'MESH:D009369', (215, 220))	('tobacco', 'Species', '4097', (86, 93))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('aromatic amines', 'Chemical', '-', (157, 172))	('tumor', 'Disease', (215, 220))	('N-nitrosamines', 'Chemical', '-', (103, 117))	('polycyclic aromatic hydrocarbons', 'Var', (119, 151))
415872	26933818	Transitions and transversions at CpG sites are typically found in genes commonly altered in smoking patients, such as KRAS, TP53 and RB.	('transversions', 'Var', (16, 29))	('Transitions', 'Var', (0, 11))	('TP53', 'Gene', '7157', (124, 128))	('KRAS', 'Gene', (118, 122))	('TP53', 'Gene', (124, 128))	('patients', 'Species', '9606', (100, 108))	('KRAS', 'Gene', '3845', (118, 122))
415873	26933818	Interestingly, the pattern of mutations in HNSCC is different according to HPV positivity.	('HPV', 'Species', '10566', (75, 78))	('SCC', 'Gene', (45, 48))	('SCC', 'Phenotype', 'HP:0002860', (45, 48))	('SCC', 'Gene', '6317', (45, 48))	('mutations', 'Var', (30, 39))	('HNSCC', 'Phenotype', 'HP:0012288', (43, 48))
415874	26933818	HPV-negative tumors, where carcinogenesis is mainly smoke-related, show transversions at CpG sites more frequently than HPV-positive tumors, known to be led by virus-mediated carcinogenesis.	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('HPV', 'Species', '10566', (0, 3))	('carcinogenesis', 'Disease', 'MESH:D063646', (175, 189))	('tumors', 'Disease', (13, 19))	('tumors', 'Disease', (133, 139))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Disease', 'MESH:D009369', (133, 139))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('HPV-positive tumors', 'Disease', (120, 139))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('HPV-positive tumors', 'Disease', 'MESH:D030361', (120, 139))	('carcinogenesis', 'Disease', 'MESH:D063646', (27, 41))	('carcinogenesis', 'Disease', (175, 189))	('transversions', 'Var', (72, 85))	('carcinogenesis', 'Disease', (27, 41))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('HPV', 'Species', '10566', (120, 123))
415877	26933818	In addition, nicotine and nitrosamines have been shown to induce cell-cycle progression, by the overexpression of cyclins and decreased levels of cyclin-dependent kinase (Cdk) inhibitors.	('nicotine', 'Var', (13, 21))	('decreased', 'NegReg', (126, 135))	('induce', 'PosReg', (58, 64))	('nitrosamines', 'Chemical', 'MESH:D009602', (26, 38))	('nicotine', 'Chemical', 'MESH:D009538', (13, 21))	('nitrosamines', 'Var', (26, 38))	('cyclins', 'Protein', (114, 121))	('overexpression', 'PosReg', (96, 110))	('cell-cycle progression', 'CPA', (65, 87))
415893	26933818	Moreover, broad amplification of chromosome 3q, widely recognized as associated with SCC, particularly defines the classical subtype and results in the overexpression of three oncogenes: SOX2, TP63 and PIK3CA.	('TP63', 'Gene', (193, 197))	('TP63', 'Gene', '8626', (193, 197))	('overexpression', 'PosReg', (152, 166))	('SCC', 'Gene', '6317', (85, 88))	('SOX2', 'Gene', '6657', (187, 191))	('SOX2', 'Gene', (187, 191))	('PIK3CA', 'Gene', (202, 208))	('associated', 'Reg', (69, 79))	('PIK3CA', 'Gene', '5290', (202, 208))	('results in', 'Reg', (137, 147))	('broad amplification', 'Var', (10, 29))	('SCC', 'Gene', (85, 88))	('SCC', 'Phenotype', 'HP:0002860', (85, 88))
415902	26933818	In different studies about LSCC and HNSCC, mutations and copy number alterations of NRF2 and KEAP1 and/or deletion or mutation of CUL3 have been detected, especially in the classical subtype.	('KEAP1', 'Gene', '9817', (93, 98))	('SCC', 'Gene', (38, 41))	('CUL3', 'Gene', '8452', (130, 134))	('SCC', 'Phenotype', 'HP:0002860', (38, 41))	('SCC', 'Gene', (28, 31))	('CUL3', 'Gene', (130, 134))	('detected', 'Reg', (145, 153))	('NRF2', 'Gene', '4780', (84, 88))	('SCC', 'Phenotype', 'HP:0002860', (28, 31))	('KEAP1', 'Gene', (93, 98))	('mutations', 'Var', (43, 52))	('deletion', 'Var', (106, 114))	('mutation', 'Var', (118, 126))	('SCC', 'Gene', '6317', (28, 31))	('SCC', 'Gene', '6317', (38, 41))	('NRF2', 'Gene', (84, 88))	('HNSCC', 'Phenotype', 'HP:0012288', (36, 41))	('copy number alterations', 'Var', (57, 80))
415906	26933818	Hence, mutations in KEAP1 and CUL3 are mutually exclusive with mutations in NRF2, and each of these leads to a constitutive activation of Nrf2, promoting cancer cell survival.	('mutations', 'Var', (63, 72))	('activation', 'PosReg', (124, 134))	('NRF2', 'Gene', '4780', (76, 80))	('KEAP1', 'Gene', (20, 25))	('Nrf2', 'Gene', '4780', (138, 142))	('CUL3', 'Gene', '8452', (30, 34))	('NRF2', 'Gene', (76, 80))	('CUL3', 'Gene', (30, 34))	('cancer', 'Disease', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('KEAP1', 'Gene', '9817', (20, 25))	('Nrf2', 'Gene', (138, 142))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('promoting', 'PosReg', (144, 153))	('mutations', 'Var', (7, 16))
415908	26933818	Even though the classical subtype can be clearly associated with smoke exposure and genetic alterations associated with tobacco-related damage, the presence of different patterns of genetic alterations does not exclude smoke exposure.	('tobacco', 'Species', '4097', (120, 127))	('genetic alterations', 'Var', (84, 103))	('associated', 'Reg', (49, 59))
415918	26933818	These additional genetic alterations are linked to tobacco-related carcinogens, as confirmed by the presence of KRAS and TP53 mutations.	('tobacco-related carcinogens', 'Disease', (51, 78))	('linked', 'Reg', (41, 47))	('TP53', 'Gene', '7157', (121, 125))	('TP53', 'Gene', (121, 125))	('tobacco', 'Species', '4097', (51, 58))	('KRAS', 'Gene', (112, 116))	('mutations', 'Var', (126, 135))	('KRAS', 'Gene', '3845', (112, 116))
415920	26933818	However, HPV-positive tumors are more enriched in mutations/copy number variations in oncogenes compared to HPV-negative patients.	('HPV-positive tumors', 'Disease', 'MESH:D030361', (9, 28))	('HPV-positive tumors', 'Disease', (9, 28))	('HPV', 'Species', '10566', (108, 111))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('HPV', 'Species', '10566', (9, 12))	('mutations/copy number variations', 'Var', (50, 82))	('tumors', 'Phenotype', 'HP:0002664', (22, 28))	('patients', 'Species', '9606', (121, 129))	('oncogenes', 'Gene', (86, 95))
415922	26933818	The best known element is the overexpression of viral E6-E7 proteins that act as oncoproteins promoting p53 or Rb degradation, activation of hTERT, neutralization of the inhibitory effect by CDK inhibitors on cell cycle; thus, HPV infection activates the process of carcinogenesis by deregulating fundamental cellular pathways.	('p53', 'Gene', (104, 107))	('carcinogenesis', 'Disease', 'MESH:D063646', (266, 280))	('HPV infection', 'Disease', 'MESH:D030361', (227, 240))	('men', 'Species', '9606', (302, 305))	('men', 'Species', '9606', (18, 21))	('hTERT', 'Gene', '7015', (141, 146))	('carcinogenesis', 'Disease', (266, 280))	('promoting', 'PosReg', (94, 103))	('p53', 'Gene', '7157', (104, 107))	('hTERT', 'Gene', (141, 146))	('Rb degradation', 'MPA', (111, 125))	('fundamental cellular pathways', 'Pathway', (297, 326))	('HPV infection', 'Disease', (227, 240))	('E6-E7', 'Var', (54, 59))	('deregulating', 'Reg', (284, 296))	('activates', 'PosReg', (241, 250))
415927	26933818	The effects of viral DNA integration into human genome include disruption of tumor suppressor genes, oncogene amplifications, interchromosomal rearrangements and altered methylation.	('disruption', 'NegReg', (63, 73))	('viral DNA', 'Var', (15, 24))	('oncogene', 'Gene', (101, 109))	('human', 'Species', '9606', (42, 47))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('altered', 'Reg', (162, 169))	('men', 'Species', '9606', (152, 155))	('amplifications', 'Var', (110, 124))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('methylation', 'MPA', (170, 181))	('interchromosomal rearrangements', 'Var', (126, 157))	('tumor', 'Disease', (77, 82))
415928	26933818	Examples of genes altered by viral DNA integration are RAD51B, leading to loss of DNA-repair function, and NR4A2, a nuclear transcription factor which acts as an oncogene, especially by inhibiting apoptosis.	('RAD51B', 'Gene', '5890', (55, 61))	('apoptosis', 'CPA', (197, 206))	('RAD51B', 'Gene', (55, 61))	('DNA-repair function', 'MPA', (82, 101))	('NR4A2', 'Gene', (107, 112))	('loss', 'NegReg', (74, 78))	('NR4A2', 'Gene', '4929', (107, 112))	('inhibiting', 'NegReg', (186, 196))	('viral DNA integration', 'Var', (29, 50))
415931	26933818	Mutations and/or copy number variations of the catalytic domain (PIK3CA) of PI3K are present in about 20-30% of cases, while, more rarely, mutations occur in other genes of the same pathway: PTEN, AKT1, PIK3R1, TSC1, and TSC2, thus making the pathway a potential therapeutic target.	('TSC1', 'Gene', '7248', (211, 215))	('PIK3R1', 'Gene', '5295', (203, 209))	('PIK3R1', 'Gene', (203, 209))	('TSC1', 'Gene', (211, 215))	('PTEN', 'Gene', (191, 195))	('PTEN', 'Gene', '5728', (191, 195))	('TSC2', 'Gene', '7249', (221, 225))	('PIK3CA', 'Gene', (65, 71))	('TSC2', 'Gene', (221, 225))	('Mutations', 'Var', (0, 9))	('PIK3CA', 'Gene', '5290', (65, 71))	('AKT1', 'Gene', '207', (197, 201))	('copy number variations', 'Var', (17, 39))	('AKT1', 'Gene', (197, 201))	('PI3K', 'Gene', (76, 80))
415932	26933818	Other potentially druggable alterations of particular interest are FGFR2/3 mutations occurring in about 25% of HPV-positive cases, while in HPV-negative patients FGFR1 amplifications are more common.	('patients', 'Species', '9606', (153, 161))	('HPV', 'Species', '10566', (111, 114))	('FGFR2', 'Gene', (67, 72))	('FGFR1', 'Gene', (162, 167))	('mutations', 'Var', (75, 84))	('FGFR2', 'Gene', '2263', (67, 72))	('FGFR1', 'Gene', '2260', (162, 167))	('HPV', 'Species', '10566', (140, 143))
415935	26933818	Moreover, wide genome analyses highlighted the higher presence of genetic alterations in immune-related genes (HLA-A and HLA-B) and this point may be directly related to viral tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('HLA-B', 'Gene', '3106', (121, 126))	('HLA-B', 'Gene', (121, 126))	('tumor', 'Disease', (176, 181))	('HLA-A', 'Gene', '3105', (111, 116))	('genetic alterations', 'Var', (66, 85))	('tumor', 'Disease', 'MESH:D009369', (176, 181))	('related', 'Reg', (159, 166))	('HLA-A', 'Gene', (111, 116))
415959	26933818	Consistently, another analysis on 185 Chinese patients confirmed the detection of EGFR mutations among LSCC tumors ranging from 6% to 17%, with high correlation with the absence of smoking exposure.	('EGFR', 'Gene', (82, 86))	('patients', 'Species', '9606', (46, 54))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('SCC', 'Gene', (104, 107))	('SCC', 'Phenotype', 'HP:0002860', (104, 107))	('tumors', 'Disease', (108, 114))	('tumors', 'Disease', 'MESH:D009369', (108, 114))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('SCC', 'Gene', '6317', (104, 107))	('EGFR', 'Gene', '1956', (82, 86))	('mutations', 'Var', (87, 96))
415963	26933818	Only PIK3CA mutations were significantly less common in females, and thus in never smokers, than in males, but the small sample of this study (38 females and 40 males) limits the interpretation of the results.	('PIK3CA', 'Gene', (5, 11))	('mutations', 'Var', (12, 21))	('PIK3CA', 'Gene', '5290', (5, 11))
415971	26933818	Currently, the PI3K pathway is one of the most promising therapeutic targets for both malignancies, on the basis of the high rate of PIK3CA mutations and of the presence of alterations in other genes involved in this pathway.	('PIK3CA', 'Gene', (133, 139))	('PIK3CA', 'Gene', '5290', (133, 139))	('malignancies', 'Disease', 'MESH:D009369', (86, 98))	('mutations', 'Var', (140, 149))	('malignancies', 'Disease', (86, 98))
415973	26933818	Other frequently altered targets in SCC are members of the FGFR family, characterized by the amplification of FGFR1 or mutations of FGFR2/3, which might be targeted by specific agents in development through early phase clinical trials.	('amplification', 'Var', (93, 106))	('SCC', 'Gene', '6317', (36, 39))	('FGFR2', 'Gene', (132, 137))	('SCC', 'Gene', (36, 39))	('men', 'Species', '9606', (194, 197))	('FGFR2', 'Gene', '2263', (132, 137))	('SCC', 'Phenotype', 'HP:0002860', (36, 39))	('mutations', 'Var', (119, 128))	('FGFR1', 'Gene', (110, 115))	('FGFR1', 'Gene', '2260', (110, 115))
415974	26933818	Furthermore, mutations in the DDR2 kinase gene in about 4% of LSCC have been documented; such mutations lead to cellular transformation making this tyrosine kinase gene a promising target.	('DDR2', 'Gene', (30, 34))	('mutations', 'Var', (94, 103))	('cellular transformation', 'CPA', (112, 135))	('SCC', 'Gene', (63, 66))	('SCC', 'Phenotype', 'HP:0002860', (63, 66))	('DDR2', 'Gene', '4921', (30, 34))	('lead to', 'Reg', (104, 111))	('SCC', 'Gene', '6317', (63, 66))	('men', 'Species', '9606', (81, 84))	('mutations', 'Var', (13, 22))
415981	26933818	The rationale for the development of targeted therapy lay on the evidence of tumor cells addicted to one or few genes for maintenance of the malignant phenotype; on the contrary, malignancies characterized by many genetic and epigenetic alterations may potentially benefit from multiple biological agents targeting different drivers.	('malignancies', 'Disease', 'MESH:D009369', (179, 191))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('malignancies', 'Disease', (179, 191))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('men', 'Species', '9606', (29, 32))	('epigenetic alterations', 'Var', (226, 248))	('benefit', 'Reg', (265, 272))	('tumor', 'Disease', (77, 82))
415983	26933818	According to this strategy, a synthetic lethal relationship is seen when a cancer specific gene mutation combined with the therapeutic targeting of another pathway results in the selective killing of mutated cancer cells without affecting the normal ones.	('cancer', 'Disease', (208, 214))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('cancer', 'Disease', (75, 81))	('mutation', 'Var', (96, 104))	('mutated', 'Var', (200, 207))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('cancer', 'Disease', 'MESH:D009369', (208, 214))
415985	26933818	Tumor cells carrying the mutations of the tumor suppressor genes BRCA1 or BRCA2 are defective in homologous recombination, and thus are sensitive to the inhibition of PARP activity, another key pathway involved in DNA repair.	('PARP', 'Gene', (167, 171))	('mutations', 'Var', (25, 34))	('BRCA1', 'Gene', '672', (65, 70))	('sensitive', 'Reg', (136, 145))	('tumor', 'Disease', (42, 47))	('defective', 'NegReg', (84, 93))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('BRCA2', 'Gene', (74, 79))	('BRCA1', 'Gene', (65, 70))	('homologous recombination', 'MPA', (97, 121))	('BRCA2', 'Gene', '675', (74, 79))	('PARP', 'Gene', '142', (167, 171))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
415999	26933818	Molecular predictive markers of sensitivity to immunotherapy are still under investigation; in this trial nivolumab improved survival regardless of PD-L1 expression, while in non-squamous setting the expression of PDL-1, whatever cut-off used, demonstrated to be predictive of benefit from immunotherapy with respect to chemotherapy.	('improved', 'PosReg', (116, 124))	('PDL-1', 'Gene', '29126', (214, 219))	('PDL-1', 'Gene', (214, 219))	('survival', 'MPA', (125, 133))	('nivolumab', 'Chemical', 'MESH:D000077594', (106, 115))	('PD-L1', 'Gene', '29126', (148, 153))	('PD-L1', 'Gene', (148, 153))	('expression', 'Var', (200, 210))
416000	26933818	On the other hand, Herbst and colleagues observed that the responses to the anti-PD-L1 MPDL3280A were associated with high expression of PD-L1 especially by tumor-infiltrating immune cells.	('tumor', 'Disease', (157, 162))	('expression', 'MPA', (123, 133))	('PD-L1', 'Gene', (81, 86))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('MPDL3280A', 'Var', (87, 96))	('PD-L1', 'Gene', (137, 142))	('PD-L1', 'Gene', '29126', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('responses', 'MPA', (59, 68))	('PD-L1', 'Gene', '29126', (137, 142))
416001	26933818	Interestingly, most trials evaluating anti-PD-1 or anti-PD-L1 antibodies suggested that former and current smokers might preferentially benefit from immunotherapy.	('PD-L1', 'Gene', '29126', (56, 61))	('anti-PD-1', 'Var', (38, 47))	('immunotherapy', 'CPA', (149, 162))	('antibodies', 'Var', (62, 72))	('benefit', 'PosReg', (136, 143))	('PD-L1', 'Gene', (56, 61))
416002	26933818	This finding could be related to the higher overall mutational burden in these patients resulting in more tumor neoantigens and increased immunogenicity.	('mutational', 'Var', (52, 62))	('increased', 'PosReg', (128, 137))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('patients', 'Species', '9606', (79, 87))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('immunogenicity', 'MPA', (138, 152))	('more', 'PosReg', (101, 105))	('tumor', 'Disease', (106, 111))
416003	26933818	Recently, whole-exome sequencing of NSCLC cases treated with the anti-PD1 pembrolizumab, revealed that higher non-synonymous mutation burden, higher neoantigen burden, and molecular smoking signature, characterized by high nucleotide transversion rate, molecular smoking signature (high nucleotide transversion rate) were associated with improved objective response, durable clinical benefit and progression-free survival.	('molecular', 'MPA', (253, 262))	('non-synonymous mutation burden', 'MPA', (110, 140))	('neoantigen burden', 'MPA', (149, 166))	('improved', 'PosReg', (338, 346))	('PD1', 'Gene', '5133', (70, 73))	('objective response', 'CPA', (347, 365))	('NSCLC', 'Phenotype', 'HP:0030358', (36, 41))	('PD1', 'Gene', (70, 73))	('high nucleotide transversion rate', 'Var', (218, 251))	('pembrolizumab', 'Chemical', 'MESH:C582435', (74, 87))	('progression-free survival', 'CPA', (396, 421))	('NSCLC', 'Disease', (36, 41))	('higher', 'PosReg', (103, 109))	('molecular', 'MPA', (172, 181))	('NSCLC', 'Disease', 'MESH:D002289', (36, 41))	('higher', 'PosReg', (142, 148))
416004	26933818	Similarly, another study showed that tumors with genetic mismatch repair defects, which are associated with a high degree of mutational burden, respond better to PD-1 inhibitor compared with tumors proficient in mismatch repair.	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('respond', 'MPA', (144, 151))	('tumors', 'Phenotype', 'HP:0002664', (191, 197))	('defects', 'Var', (73, 80))	('tumors', 'Disease', 'MESH:D009369', (191, 197))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('tumors', 'Disease', (37, 43))	('tumors', 'Disease', (191, 197))	('better', 'PosReg', (152, 158))	('tumors', 'Disease', 'MESH:D009369', (37, 43))
416009	26933818	Molecular characterization according to the above discussed subtypes may also have a role in predicting the response to immunotherapy; indeed, the molecular subtypes characterized by alterations in pathways involved in the immune response against cancer (Figure 2) could be suitable for new immunotherapeutic approaches.	('cancer', 'Disease', (247, 253))	('cancer', 'Disease', 'MESH:D009369', (247, 253))	('alterations', 'Var', (183, 194))	('cancer', 'Phenotype', 'HP:0002664', (247, 253))
416022	26168791	In addition, the patients with negative CCR9 expression exhibited a higher overall survival (OS) compared with those with positive CCR9 expression.	('negative', 'NegReg', (31, 39))	('CCR9', 'Gene', (40, 44))	('higher', 'PosReg', (68, 74))	('patients', 'Species', '9606', (17, 25))	('overall survival', 'MPA', (75, 91))	('expression', 'Var', (45, 55))
416036	26168791	Our subsequent study suggested that CCR9-CCL25 interaction supports lung cancer cell survival and up-regulates the anti-apoptotic signaling mediated by the PI3K/Akt survival pathway.	('anti-apoptotic signaling', 'MPA', (115, 139))	('lung cancer', 'Disease', (68, 79))	('lung cancer', 'Phenotype', 'HP:0100526', (68, 79))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('Akt', 'Gene', '207', (161, 164))	('supports', 'PosReg', (59, 67))	('interaction', 'Var', (47, 58))	('lung cancer', 'Disease', 'MESH:D008175', (68, 79))	('Akt', 'Gene', (161, 164))	('up-regulates', 'PosReg', (98, 110))
416069	26168791	OS analysis using the Kaplan-Meier method showed that patients with negative CCR9 expression had higher OS compared with those with positive CCR9 expression (Fig.	('higher', 'PosReg', (97, 103))	('negative', 'NegReg', (68, 76))	('patients', 'Species', '9606', (54, 62))	('expression', 'Var', (82, 92))	('CCR9', 'Gene', (77, 81))
416071	26168791	Moreover, upon the univariate analysis using the cox proportional hazards model, positive lymph node metastasis (HR = 1.71, P = 0.021), advanced TNM stage (HR = 2.184, P = 0.002), postoperative chemotherapy (HR = 0.628, P = 0.044) and positive CCR9 expression (HR = 2.189, P = 0.007) were associated with increased risk of death in the patients with lung adenocarcinoma.	('positive', 'Var', (235, 243))	('TNM', 'Gene', '10178', (145, 148))	('patients', 'Species', '9606', (336, 344))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (350, 369))	('death', 'Disease', 'MESH:D003643', (323, 328))	('death', 'Disease', (323, 328))	('TNM', 'Gene', (145, 148))	('CCR9', 'Gene', (244, 248))	('carcinoma', 'Phenotype', 'HP:0030731', (360, 369))	('lung adenocarcinoma', 'Disease', (350, 369))	('positive lymph node metastasis', 'CPA', (81, 111))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (350, 369))
416072	26168791	In the multivariate analyses, positive CCR9 expression remained predictive for OS after adjustment of lymph node status, TNM stage and chemotherapy as covariates (HR = 1.948, P = 0.028; Table 2).	('expression', 'MPA', (44, 54))	('positive', 'Var', (30, 38))	('men', 'Species', '9606', (94, 97))	('TNM', 'Gene', '10178', (121, 124))	('CCR9', 'Gene', (39, 43))	('TNM', 'Gene', (121, 124))
416077	26168791	The aberrant expression of chemokine receptors has been associated with disease severity, increased invasiveness of cancer cells, and even poor prognosis in various types of malignancies.	('increased', 'PosReg', (90, 99))	('malignancies', 'Disease', (174, 186))	('cancer', 'Disease', (116, 122))	('chemokine receptor', 'Gene', '7852', (27, 45))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('associated', 'Reg', (56, 66))	('aberrant expression', 'Var', (4, 23))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('chemokine receptor', 'Gene', (27, 45))	('malignancies', 'Disease', 'MESH:D009369', (174, 186))
416084	26168791	Previously, we have also shown that over-expressed CCR9 interacts with CCL25 to promote proliferation and suppress apoptosis of NSCLC cells in vitro, and knockdown of CCR9 compromises in vivo tumor growth in a nude mice model.	('NSCLC', 'Phenotype', 'HP:0030358', (128, 133))	('tumor', 'Disease', (192, 197))	('promote', 'PosReg', (80, 87))	('interacts', 'Interaction', (56, 65))	('NSCLC', 'Disease', (128, 133))	('knockdown', 'Var', (154, 163))	('compromises', 'NegReg', (172, 183))	('CCR9', 'Gene', (167, 171))	('NSCLC', 'Disease', 'MESH:D002289', (128, 133))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('proliferation', 'CPA', (88, 101))	('apoptosis', 'CPA', (115, 124))	('suppress', 'NegReg', (106, 114))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('over-expressed', 'PosReg', (36, 50))	('CCR9', 'Gene', (51, 55))	('nude mice', 'Species', '10090', (210, 219))
416090	26168791	Furthermore, the number of lung adenocarcinoma cells that migrated and invaded in response to CCL25 is greater compared with lung squamous cell carcinoma cells.	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (27, 46))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (125, 153))	('carcinoma', 'Phenotype', 'HP:0030731', (37, 46))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (125, 153))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (130, 153))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (27, 46))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('invaded', 'CPA', (71, 78))	('lung squamous cell carcinoma', 'Disease', (125, 153))	('lung adenocarcinoma', 'Disease', (27, 46))	('CCL25', 'Var', (94, 99))
416098	26168791	reported that ectopic expression of CCR9 not only enhances cell proliferation and tumorigenicity in hepatocellular carcinoma cells, but also acts as a novel prognostic marker and therapeutic target for hepatocellular carcinoma.	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (202, 226))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (100, 124))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (100, 124))	('enhances', 'PosReg', (50, 58))	('hepatocellular carcinoma', 'Disease', (202, 226))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('hepatocellular carcinoma', 'Disease', (100, 124))	('CCR9', 'Gene', (36, 40))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('cell proliferation', 'CPA', (59, 77))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('ectopic expression', 'Var', (14, 32))	('tumor', 'Disease', (82, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (217, 226))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (202, 226))
416129	33277589	Mutation and expression of epidermal growth factor receptor (EGFR) and Kirsten rat sarcoma viral oncogene homolog (KRAS) in lung cancer and promoter methylation of O6-methylguanine DNA methyltransferase (MGMT) in glioblastoma (GBM) have been identified to be associated with progressive disease and treatment response.	('O6-methylguanine DNA methyltransferase', 'Gene', (164, 202))	('glioblastoma', 'Disease', (213, 225))	('MGMT', 'Gene', (204, 208))	('glioblastoma', 'Phenotype', 'HP:0012174', (213, 225))	('rat', 'Species', '10116', (79, 82))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('O6-methylguanine DNA methyltransferase', 'Gene', '25332', (164, 202))	('epidermal growth factor receptor', 'Gene', '24329', (27, 59))	('KRAS', 'Gene', (115, 119))	('associated', 'Reg', (259, 269))	('GBM', 'Phenotype', 'HP:0012174', (227, 230))	('lung cancer', 'Disease', (124, 135))	('sarcoma', 'Disease', 'MESH:D012509', (83, 90))	('promoter', 'MPA', (140, 148))	('sarcoma', 'Disease', (83, 90))	('epidermal growth factor receptor', 'Gene', (27, 59))	('lung cancer', 'Disease', 'MESH:D008175', (124, 135))	('expression', 'MPA', (13, 23))	('sarcoma', 'Phenotype', 'HP:0100242', (83, 90))	('Mutation', 'Var', (0, 8))	('glioblastoma', 'Disease', 'MESH:D005909', (213, 225))	('lung cancer', 'Phenotype', 'HP:0100526', (124, 135))	('EGFR', 'Gene', (61, 65))
416133	33277589	demonstrated an insignificant association between promoter methylation of MGMT and progression-free survival in GBM.	('GBM', 'Phenotype', 'HP:0012174', (112, 115))	('promoter methylation', 'Var', (50, 70))	('progression-free survival', 'CPA', (83, 108))	('MGMT', 'Gene', (74, 78))	('rat', 'Species', '10116', (7, 10))	('GBM', 'Disease', (112, 115))
416157	33277589	Raw data from four selected microarray datasets (GSE3141, GSE8894, GSE19188, and GSE30219) were downloaded and pre-processed using robust multiarray averaging for normalization, then compiled to form validation cohorts that include 246 LUAD or 207 LUSC patients, respectively.	('GSE8894', 'Var', (58, 65))	('GSE30219', 'Var', (81, 89))	('GSE8894', 'Chemical', '-', (58, 65))	('patients', 'Species', '9606', (253, 261))	('GSE19188', 'Var', (67, 75))	('LUSC', 'Chemical', '-', (248, 252))	('GSE3141', 'Var', (49, 56))	('GSE3141', 'Chemical', '-', (49, 56))
416167	33277589	Red blood cells were removed using Red Blood Cell Lysis Solution purchased from Miltenyi Biotec Inc. Isolated cells were cultured in DMEM (Life Technologies) supplemented with 15% FBS (Peak Serum, Inc.), streptomycin (100 mug/mL), and penicillin (100 IU/ml), (Life Technologies Corporation).	('penicillin', 'Chemical', 'MESH:D010406', (235, 245))	('rat', 'Species', '10116', (283, 286))	('100', 'Var', (218, 221))	('streptomycin', 'Chemical', 'MESH:D013307', (204, 216))	('100 IU/ml', 'Var', (247, 256))	('DMEM', 'Chemical', '-', (133, 137))
416189	33277589	NSCLC clinical data were processed as follows for cross-study compatibility: (1) Relapsed patients were categorized as "progressed" and non-relapsed patients "disease-free" in GS8894 and GSE30219; (2) Deceased patients were categorized as "progressed" and living patients as "disease-free" in GSE3141 and GSE19188, where relapse incidence data were unavailable.	('GSE3141', 'Chemical', '-', (293, 300))	('NSCLC', 'Disease', 'MESH:D002289', (0, 5))	('patients', 'Species', '9606', (149, 157))	('GS8894', 'Chemical', '-', (176, 182))	('NSCLC', 'Disease', (0, 5))	('patients', 'Species', '9606', (263, 271))	('patients', 'Species', '9606', (210, 218))	('GS8894', 'Var', (176, 182))	('patients', 'Species', '9606', (90, 98))	('GSE30219', 'Var', (187, 195))
416208	33277589	Almost all genes in the NSCLC PGSs were mutated in at least one patient (Supplementary Table S10-S11).	('NSCLC PGSs', 'Disease', 'MESH:D002289', (24, 34))	('mutated', 'Var', (40, 47))	('patient', 'Species', '9606', (64, 71))	('NSCLC PGSs', 'Disease', (24, 34))
416209	33277589	Kaplan-Meier survival analyses revealed that mutations in eukaryotic translation elongation factor 2 (EEF2) in LUAD-PGS or cathepsin B (CTSB) and heat shock protein 90 beta family member 1 (HSP90B1) in LUSC-PGS correlated with shorter disease-free survival (DFS) time (Supplementary Fig.	('EEF2', 'Gene', '1938', (102, 106))	('heat shock protein 90 beta family member 1', 'Gene', (146, 188))	('cathepsin B', 'Gene', (123, 134))	('mutations', 'Var', (45, 54))	('eukaryotic translation elongation factor 2', 'Gene', '1938', (58, 100))	('LUSC-PGS', 'Chemical', '-', (202, 210))	('shock', 'Phenotype', 'HP:0031273', (151, 156))	('EEF2', 'Gene', (102, 106))	('heat shock protein 90 beta family member 1', 'Gene', '7184', (146, 188))	('shorter', 'NegReg', (227, 234))	('cathepsin B', 'Gene', '1508', (123, 134))	('CTSB', 'Gene', '1508', (136, 140))	('eukaryotic translation elongation factor 2', 'Gene', (58, 100))	('HSP90B1', 'Gene', (190, 197))	('disease-free survival', 'CPA', (235, 256))	('HSP90B1', 'Gene', '7184', (190, 197))	('CTSB', 'Gene', (136, 140))
416211	33277589	In GBM-PGS, signature genes were less frequently mutated compared to the NSCLC PGSs (Supplementary Table S12).	('less', 'NegReg', (33, 37))	('PGS', 'Chemical', '-', (7, 10))	('PGS', 'Chemical', '-', (79, 82))	('GBM', 'Phenotype', 'HP:0012174', (3, 6))	('NSCLC PGSs', 'Disease', 'MESH:D002289', (73, 83))	('GBM-PGS', 'Var', (3, 10))	('NSCLC PGSs', 'Disease', (73, 83))
416212	33277589	Despite the low mutation frequency, mutations in amyloid beta precursor protein (APP) and membrane metalloendopeptidase (MME) significantly correlated with shorter DFS time (Supplementary Fig.	('mutations', 'Var', (36, 45))	('MME', 'Gene', (121, 124))	('shorter', 'NegReg', (156, 163))	('APP', 'Gene', (81, 84))	('MME', 'Gene', '4311', (121, 124))	('DFS time', 'MPA', (164, 172))
416223	33277589	We next determined the performance of established biomarkers such as the carcinoembryonic antigen (CEA) family, EGFR, tyrosine-protein kinase Met (MET), neuron-specific enolase (NSE), and KRAS for NSCLC and promoter methylation of MGMT, mutation of isocitrate dehydrogenase 1 (IDH1), EGFR, platelet-derived growth factor receptor alpha (PDGFRA), and cyclin-dependent kinase inhibitor 2A (CDKN2A) for GBM.	('neuron-specific enolase', 'Gene', '2026', (153, 176))	('CEA', 'Gene', (99, 102))	('NSCLC', 'Disease', 'MESH:D002289', (197, 202))	('carcinoembryonic antigen', 'Gene', '1048', (73, 97))	('isocitrate dehydrogenase 1', 'Gene', (249, 275))	('MET', 'Gene', '79811', (147, 150))	('isocitrate dehydrogenase 1', 'Gene', '3417', (249, 275))	('tyrosine-protein kinase Met', 'Gene', (118, 145))	('PDGFRA', 'Gene', (337, 343))	('PDGFRA', 'Gene', '5156', (337, 343))	('IDH1', 'Gene', (277, 281))	('cyclin-dependent kinase inhibitor 2A', 'Gene', '1029', (350, 386))	('NSCLC', 'Disease', (197, 202))	('NSE', 'Gene', '2026', (178, 181))	('GBM', 'Phenotype', 'HP:0012174', (400, 403))	('NSE', 'Gene', (178, 181))	('MGMT', 'Gene', (231, 235))	('CEA', 'Gene', '1048', (99, 102))	('tyrosine-protein kinase Met', 'Gene', '4233', (118, 145))	('cyclin-dependent kinase inhibitor 2A', 'Gene', (350, 386))	('CDKN2A', 'Gene', (388, 394))	('platelet-derived growth factor receptor alpha', 'Gene', '5156', (290, 335))	('IDH1', 'Gene', '3417', (277, 281))	('EGFR', 'Gene', (284, 288))	('carcinoembryonic antigen', 'Gene', (73, 97))	('CDKN2A', 'Gene', '1029', (388, 394))	('MET', 'Gene', (147, 150))	('neuron-specific enolase', 'Gene', (153, 176))	('mutation', 'Var', (237, 245))	('platelet-derived growth factor receptor alpha', 'Gene', (290, 335))
416228	33277589	Interestingly, patients harboring mutations in PGS genes that were prognostically significant were mostly classified as high-risk progression by all PGSs (Supplementary Fig.	('PGS', 'Chemical', '-', (47, 50))	('patients', 'Species', '9606', (15, 23))	('PGSs', 'Disease', 'None', (149, 153))	('PGSs', 'Disease', (149, 153))	('PGS', 'Chemical', '-', (149, 152))	('PGS genes', 'Gene', (47, 56))	('mutations', 'Var', (34, 43))
416238	33277589	Similarly, GBM-PGS was more significantly associated with tumor progression (HR = 3.02) than age or gender (HR = 1.02 or 1.04, respectively).	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('associated with', 'Reg', (42, 57))	('GBM', 'Phenotype', 'HP:0012174', (11, 14))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('PGS', 'Chemical', '-', (15, 18))	('GBM-PGS', 'Var', (11, 18))
416247	33277589	The average DFS times for high-risk progression patients treated with ACT or TMZ was 16.40 (LUAD) or 10.80 (GBM) months compared to 18.18 (LUAD) or 8.44 (GBM) months in patients treated without ACT or TMZ.	('TMZ', 'Var', (77, 80))	('patients', 'Species', '9606', (169, 177))	('TMZ', 'Chemical', 'MESH:D000077204', (201, 204))	('GBM', 'Phenotype', 'HP:0012174', (108, 111))	('GBM', 'Phenotype', 'HP:0012174', (154, 157))	('TMZ', 'Chemical', 'MESH:D000077204', (77, 80))	('patients', 'Species', '9606', (48, 56))	('ACT', 'Var', (70, 73))	('DFS', 'MPA', (12, 15))
416249	33277589	In contrast, DFS times for low-risk progression patients were significantly higher in patients treated with ACT or TMZ (Fig.	('TMZ', 'Var', (115, 118))	('DFS times', 'MPA', (13, 22))	('TMZ', 'Chemical', 'MESH:D000077204', (115, 118))	('higher', 'PosReg', (76, 82))	('patients', 'Species', '9606', (48, 56))	('patients', 'Species', '9606', (86, 94))
416250	33277589	The average DFS times were 23.99 (LUAD), 28.86 (LUSC), and 16.52 (GBM) months in low-risk progression patients treated with ACT or TMZ compared to 12.28 (LUAD), 19.95 (LUSC), and 7.61 (GBM) months in patients treated without ACT or TMZ.	('patients', 'Species', '9606', (200, 208))	('patients', 'Species', '9606', (102, 110))	('TMZ', 'Chemical', 'MESH:D000077204', (131, 134))	('TMZ', 'Chemical', 'MESH:D000077204', (232, 235))	('LUSC', 'Chemical', '-', (168, 172))	('GBM', 'Phenotype', 'HP:0012174', (185, 188))	('GBM', 'Phenotype', 'HP:0012174', (66, 69))	('LUSC', 'Chemical', '-', (48, 52))	('ACT', 'Var', (124, 127))	('DFS', 'MPA', (12, 15))	('low-risk', 'Disease', (81, 89))
416300	33277589	Given the relatively low expression of GLUL in normal tissues, the aberrant activity of GLUL in progressive cancer patients can be an appealing therapeutic target for LUAD and GBM.	('GLUL', 'Gene', '2752', (39, 43))	('GLUL', 'Gene', (39, 43))	('patients', 'Species', '9606', (115, 123))	('cancer', 'Disease', (108, 114))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))	('GBM', 'Phenotype', 'HP:0012174', (176, 179))	('aberrant', 'Var', (67, 75))	('GLUL', 'Gene', '2752', (88, 92))	('GLUL', 'Gene', (88, 92))
416326	32884296	Stromal FAP-alpha expression was significantly associated with poor survival in univariable (HR 2.009; 95% CI 1.259-3.205; p=0.003) and multivariable analysis (HR 1.833; 95% CI 1.144-2.937; p=0.012).	('FAP-alpha', 'Gene', (8, 17))	('FAP-alpha', 'Gene', '2191', (8, 17))	('expression', 'Var', (18, 28))	('poor', 'NegReg', (63, 67))
416341	32884296	FAP-alpha was shown to predict survival, for example, high FAP-alpha being a marker for poor survival in oral squamous cell carcinoma, gastric cancer, and pancreatic ductal adenocarcinoma.	('gastric cancer', 'Disease', (135, 149))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (155, 187))	('gastric cancer', 'Disease', 'MESH:D013274', (135, 149))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (110, 133))	('high', 'Var', (54, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('oral squamous cell carcinoma', 'Disease', (105, 133))	('gastric cancer', 'Phenotype', 'HP:0012126', (135, 149))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (155, 187))	('FAP-alpha', 'Gene', '2191', (0, 9))	('FAP-alpha', 'Gene', '2191', (59, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (178, 187))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (105, 133))	('pancreatic ductal adenocarcinoma', 'Disease', (155, 187))	('FAP-alpha', 'Gene', (0, 9))	('FAP-alpha', 'Gene', (59, 68))
416342	32884296	Subsequently, another study investigated the role of epithelial FAP-alpha in distal cholangiocarcinoma and found that positive of this marker protein correlates with better survival.	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (84, 102))	('cholangiocarcinoma', 'Disease', (84, 102))	('positive', 'Var', (118, 126))	('FAP-alpha', 'Gene', '2191', (64, 73))	('better', 'PosReg', (166, 172))	('FAP-alpha', 'Gene', (64, 73))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (84, 102))
416348	32884296	For this study, the following criteria were required for inclusion: surgery with the radical operation, histopathologically confirmed ESCC, the pathological stage was T3N0-3M0, the degree of differentiation was G2, no history of neoadjuvant treatment, no early (30-d) postoperative mortality, complete clinical information, complete follow-up information, formalin-fixed paraffin-embedded tissue from primary resection available in the archives at the Department of Pathology, First Affiliated Hospital of Bengbu Medical College.	('mortality', 'Disease', (282, 291))	('ESCC', 'Disease', (134, 138))	('T3N0-3M0', 'Var', (167, 175))	('formalin', 'Chemical', 'MESH:D005557', (356, 364))	('mortality', 'Disease', 'MESH:D003643', (282, 291))	('rat', 'Species', '10116', (96, 99))	('rat', 'Species', '10116', (275, 278))	('paraffin', 'Chemical', 'MESH:D010232', (371, 379))
416377	32884296	There was no statistically significant difference between high and low FAP-alpha expression in stromal concerning age, gender, tumor location (Table 1).	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumor', 'Disease', (127, 132))	('FAP-alpha', 'Gene', '2191', (71, 80))	('FAP-alpha', 'Gene', (71, 80))	('high', 'Var', (58, 62))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('low', 'NegReg', (67, 70))
416380	32884296	Multivariate cox regression analyses showed that lymph node metastases and high expression of FAP-alpha remained independent prognostic factors for survival (Table 3).	('FAP-alpha', 'Gene', '2191', (94, 103))	('high', 'Var', (75, 79))	('FAP-alpha', 'Gene', (94, 103))	('metastases', 'Disease', (60, 70))	('metastases', 'Disease', 'MESH:D009362', (60, 70))
416382	32884296	Kaplan-Meier analysis with associated Log rank test showed that the overall survival and disease-free survival of patients with FAP-alpha high expression group were significantly lower than that of FAP-alpha low expression group (mean survival time, 26.5 vs. 52.9 months, P =0.002) (Figure 2A and B).	('lower', 'NegReg', (179, 184))	('disease-free survival', 'CPA', (89, 110))	('FAP-alpha', 'Gene', '2191', (128, 137))	('FAP-alpha', 'Gene', '2191', (198, 207))	('FAP-alpha', 'Gene', (128, 137))	('FAP-alpha', 'Gene', (198, 207))	('overall survival', 'CPA', (68, 84))	('high expression', 'Var', (138, 153))	('patients', 'Species', '9606', (114, 122))
416405	32884296	There are indications that high FAP-alpha expression is associated with higher tumor grade and poorer overall survival rate in most tumors.	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('tumor', 'Disease', (79, 84))	('expression', 'MPA', (42, 52))	('FAP-alpha', 'Gene', '2191', (32, 41))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('rat', 'Species', '10116', (119, 122))	('high', 'Var', (27, 31))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('tumor', 'Disease', (132, 137))	('higher', 'PosReg', (72, 78))	('tumors', 'Disease', (132, 138))	('FAP-alpha', 'Gene', (32, 41))	('overall survival', 'CPA', (102, 118))	('tumors', 'Disease', 'MESH:D009369', (132, 138))	('poorer', 'NegReg', (95, 101))
416406	32884296	A meta-analysis including 9 kinds of solid tumors reported that high FAP-alpha expression is related to poor overall survival.	('FAP-alpha', 'Gene', (69, 78))	('high', 'Var', (64, 68))	('expression', 'MPA', (79, 89))	('FAP-alpha', 'Gene', '2191', (69, 78))	('solid tumors', 'Disease', 'MESH:D009369', (37, 49))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('poor', 'NegReg', (104, 108))	('overall', 'MPA', (109, 116))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('solid tumors', 'Disease', (37, 49))
416407	32884296	In oral squamous cell carcinoma, high FAP-alpha expression correlated to lymph node metastasis and poor overall survival.	('FAP-alpha', 'Gene', (38, 47))	('high', 'Var', (33, 37))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (3, 31))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (8, 31))	('expression', 'MPA', (48, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('oral squamous cell carcinoma', 'Disease', (3, 31))	('FAP-alpha', 'Gene', '2191', (38, 47))	('lymph node metastasis', 'CPA', (73, 94))
416408	32884296	In gastric cancer, high stromal FAP-alpha expression was reported to correlate with adverse clinic-pathological characteristics including higher grade, lymph node, and peritoneal invasion, advanced TNM stage, and worse overall survival.	('peritoneal invasion', 'CPA', (168, 187))	('overall survival', 'CPA', (219, 235))	('high', 'Var', (19, 23))	('higher grade', 'CPA', (138, 150))	('gastric cancer', 'Phenotype', 'HP:0012126', (3, 17))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('TNM', 'Gene', '10178', (198, 201))	('TNM', 'Gene', (198, 201))	('FAP-alpha', 'Gene', '2191', (32, 41))	('gastric cancer', 'Disease', 'MESH:D013274', (3, 17))	('gastric cancer', 'Disease', (3, 17))	('FAP-alpha', 'Gene', (32, 41))	('lymph node', 'CPA', (152, 162))
416410	32884296	In ovarian cancer, high FAP-alpha was significantly associated with shorter disease-free survival.	('FAP-alpha', 'Gene', (24, 33))	('high', 'Var', (19, 23))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('ovarian cancer', 'Phenotype', 'HP:0100615', (3, 17))	('ovarian cancer', 'Disease', 'MESH:D010051', (3, 17))	('ovarian cancer', 'Disease', (3, 17))	('FAP-alpha', 'Gene', '2191', (24, 33))	('disease-free survival', 'CPA', (76, 97))	('shorter', 'NegReg', (68, 75))
416430	32884296	The combination of PT-100 and oxaliplatin can reduce tumor growth and improve survival enhance by enhancing the effect of chemotherapy and reducing CAF markers.	('enhancing', 'PosReg', (98, 107))	('reduce', 'NegReg', (46, 52))	('oxaliplatin', 'Chemical', 'MESH:D000077150', (30, 41))	('PT-100', 'Chemical', 'MESH:C514044', (19, 25))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('effect', 'MPA', (112, 118))	('CAF markers', 'MPA', (148, 159))	('PT-100', 'Var', (19, 25))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('improve', 'PosReg', (70, 77))	('tumor', 'Disease', (53, 58))	('reducing', 'NegReg', (139, 147))	('survival enhance', 'CPA', (78, 94))
416447	32517381	Several studies have indicated that this is caused by defects in the signaling and repair of DNA double-strand breaks (DSBs) in HPV-positive HNSCC cells, largely through the measurement of the DNA damage by neutral comet assays, but also through analysis of surrogate markers, including gammaH2AX, 53BP1 and RAD51 foci.	('53BP1', 'Gene', (298, 303))	('gammaH2AX', 'Var', (287, 296))	('HNSCC', 'Phenotype', 'HP:0012288', (141, 146))	('53BP1', 'Gene', '7158', (298, 303))	('defects', 'NegReg', (54, 61))	('DSBs', 'Chemical', '-', (119, 123))	('signaling', 'MPA', (69, 78))	('DNA', 'Gene', (93, 96))	('RAD51', 'Gene', (308, 313))	('RAD51', 'Gene', '5888', (308, 313))
416452	32517381	For example, the DNA-Pkcs inhibitors KU0060648 and IC87361, and the ATM inhibitor GSK635416A have been demonstrated to increase radiosensitivity of HNSCC cell lines.	('IC87361', 'Var', (51, 58))	('DNA-Pkcs', 'Gene', (17, 25))	('HNSCC', 'Phenotype', 'HP:0012288', (148, 153))	('DNA-Pkcs', 'Gene', '5591', (17, 25))	('radiosensitivity', 'CPA', (128, 144))	('increase radiosensitivity', 'Phenotype', 'HP:0010997', (119, 144))	('increase', 'PosReg', (119, 127))	('KU0060648', 'Chemical', 'MESH:C576809', (37, 46))	('GSK635416A', 'Chemical', '-', (82, 92))	('KU0060648', 'Var', (37, 46))	('IC87361', 'Chemical', '-', (51, 58))
416453	32517381	A number of studies have also focused on ATR as a target to radiosensitise HNSCC cells, through the inhibitors VE821 and AZD6738.	('VE821', 'Var', (111, 116))	('VE821', 'Chemical', 'MESH:C560580', (111, 116))	('inhibitors VE821', 'Var', (100, 116))	('ATR', 'Gene', '545', (41, 44))	('AZD6738', 'Chemical', 'MESH:C000611951', (121, 128))	('AZD6738', 'Var', (121, 128))	('HNSCC', 'Phenotype', 'HP:0012288', (75, 80))	('ATR', 'Gene', (41, 44))	('radiosensitise HNSCC', 'Disease', (60, 80))	('radiosensitise HNSCC', 'Disease', 'MESH:D000077195', (60, 80))
416454	32517381	Whilst the majority of these studies have focused on utilising clonogenic assays as an end-point, the ATR inhibitor AZD6738 was shown to impede the growth of 3D spheroids of hypopharyngeal (FaDu) cells in combination with radiation, which are more representative of the original tumour in vivo.	('AZD6738', 'Chemical', 'MESH:C000611951', (116, 123))	('ATR', 'Gene', '545', (102, 105))	('ATR', 'Gene', (102, 105))	('growth', 'CPA', (148, 154))	('tumour', 'Phenotype', 'HP:0002664', (279, 285))	('impede', 'NegReg', (137, 143))	('tumour', 'Disease', 'MESH:D009369', (279, 285))	('tumour', 'Disease', (279, 285))	('AZD6738', 'Var', (116, 123))
416464	32517381	We report that the clonogenic survival and growth of 3D spheroids of cells derived from HPV-positive and HPV-negative HNSCC can be significantly reduced using inhibitors targeting ATM, ATR, and particularly DNA-Pkcs, in combination with both photon and proton irradiation.	('ATM', 'Gene', (180, 183))	('reduced', 'NegReg', (145, 152))	('HNSCC', 'Phenotype', 'HP:0012288', (118, 123))	('ATR', 'Gene', '545', (185, 188))	('DNA-Pkcs', 'Gene', (207, 215))	('ATR', 'Gene', (185, 188))	('growth', 'CPA', (43, 49))	('DNA-Pkcs', 'Gene', '5591', (207, 215))	('inhibitors', 'Var', (159, 169))	('clonogenic survival', 'CPA', (19, 38))
416469	32517381	The radiosensitivity of the cell lines was generally in the order UMSCC6 > UMSCC74A > UMSCC47 > UPCI-SCC090, and statistical analysis reveals the significantly increased radiosensitivity of UPCI-SCC090 in comparison to UMSCC6 and UMSCC74A (see also Figure S2A,B for linear scale graphs and data fitting).	('UPCI-SCC090', 'Var', (190, 201))	('increased', 'PosReg', (160, 169))	('UMSCC47', 'CellLine', 'CVCL:7759', (86, 93))	('radiosensitivity', 'MPA', (170, 186))	('increased radiosensitivity', 'Phenotype', 'HP:0010997', (160, 186))
416470	32517381	Using clonogenic assays, we first analysed the impact of targeting the major protein kinases involved in DNA DSB repair using specific and characterised inhibitors (ATMi, KU-55933; ATRi, VE-821; DNA-Pkcsi, KU-57788) on the survival of HPV-positive and HPV-negative HNSCC incubated with the inhibitors for 24 h in the absence of radiation, versus a vehicle-only control (DMSO).	('DNA-Pkcs', 'Gene', (195, 203))	('inhibitors', 'Var', (290, 300))	('HNSCC', 'Phenotype', 'HP:0012288', (265, 270))	('ATRi', 'Chemical', '-', (181, 185))	('KU-55933', 'Chemical', 'MESH:C495818', (171, 179))	('KU-57788', 'Chemical', 'MESH:C499693', (206, 214))	('DMSO', 'Chemical', 'MESH:D004121', (370, 374))	('DNA-Pkcs', 'Gene', '5591', (195, 203))	('DSB', 'Chemical', '-', (109, 112))
416491	32517381	In response to proton irradiation, ATRi was not significantly effective at radiosensitising the cells, but the combination of ATMi with protons was able to suppress growth of both A253 and FaDu spheroids by ~3.7-fold.	('growth', 'CPA', (165, 171))	('ATRi', 'Chemical', '-', (35, 39))	('combination', 'Var', (111, 122))	('suppress', 'NegReg', (156, 164))
416500	32517381	This would correlate with studies in HPV-negative HNSCC cells describing downregulation of DNA-Pkcs using siRNA in UTSCC15 and UTSCC45 cells, as well as the DNA-Pkcs inhibitors KU0060648 in HN4 and HN5 cells, and IC87361 in UTSCC54, UTSCC74B and UTSCC76B cells, which were shown to enhance radiosensitisation.	('DNA-Pkcs', 'Gene', '5591', (91, 99))	('downregulation', 'NegReg', (73, 87))	('DNA-Pkcs', 'Gene', (157, 165))	('DNA-Pkcs', 'Gene', '5591', (157, 165))	('enhance', 'PosReg', (282, 289))	('radiosensitisation', 'MPA', (290, 308))	('HN5', 'Gene', '100463289', (198, 201))	('DNA-Pkcs', 'Gene', (91, 99))	('HN5', 'Gene', (198, 201))	('KU0060648', 'Chemical', 'MESH:C576809', (177, 186))	('HN4', 'Gene', '100463285', (190, 193))	('HNSCC', 'Phenotype', 'HP:0012288', (50, 55))	('KU0060648', 'Var', (177, 186))	('IC87361', 'Chemical', '-', (213, 220))	('IC87361', 'Var', (213, 220))	('HN4', 'Gene', (190, 193))
416501	32517381	Only a single study has examined ATM inhibition (GSK635416A) in HNSCC cells, although this demonstrated increased radiosensitivity in five HPV-negative HNSCC cell lines (UTSCC2, UTSCC8, UTSCC24A, UTSCC36 and UTSCC40), which is comparable with our data.	('GSK635416A', 'Chemical', '-', (49, 59))	('increased', 'PosReg', (104, 113))	('HNSCC', 'Phenotype', 'HP:0012288', (152, 157))	('radiosensitivity', 'MPA', (114, 130))	('increased radiosensitivity', 'Phenotype', 'HP:0010997', (104, 130))	('HNSCC', 'Phenotype', 'HP:0012288', (64, 69))	('GSK635416A', 'Var', (49, 59))
416503	32517381	Additionally, the ATR inhibitor VE821 displayed improved radiosensitivity in SQ20B cells, and an alternative inhibitor, AZD6738, showed the same phenotype in Cal27, FaDu, HN4 and HN5 cells.	('HN5', 'Gene', '100463289', (179, 182))	('HN5', 'Gene', (179, 182))	('HN4', 'Gene', (171, 174))	('improved', 'PosReg', (48, 56))	('SQ20B', 'CellLine', 'CVCL:7138', (77, 82))	('VE821', 'Var', (32, 37))	('VE821', 'Chemical', 'MESH:C560580', (32, 37))	('AZD6738', 'Chemical', 'MESH:C000611951', (120, 127))	('ATR', 'Gene', '545', (18, 21))	('ATR', 'Gene', (18, 21))	('HN4', 'Gene', '100463285', (171, 174))	('radiosensitivity', 'MPA', (57, 73))
416512	32517381	Noteworthily, as a monotherapy, the inhibition of ATR alone in the absence of radiation was effective in inhibiting clonogenic survival, but also the growth of HNSCC spheroids (apart from FaDu and A253), which was comparable to the impact caused by a single dose of radiation alone.	('inhibiting', 'NegReg', (105, 115))	('ATR', 'Gene', (50, 53))	('ATR', 'Gene', '545', (50, 53))	('inhibition', 'Var', (36, 46))	('HNSCC spheroids', 'CPA', (160, 175))	('HNSCC', 'Phenotype', 'HP:0012288', (160, 165))	('growth', 'CPA', (150, 156))	('clonogenic survival', 'CPA', (116, 135))
416519	32517381	Consequently, we would advocate that inhibition of NHEJ through DNA-Pkcs is the most promising strategy in optimising the radiosensitisation of HNSCC cells with either photons or protons.	('inhibition', 'Var', (37, 47))	('DNA-Pkcs', 'Gene', '5591', (64, 72))	('DNA-Pkcs', 'Gene', (64, 72))	('HNSCC', 'Phenotype', 'HP:0012288', (144, 149))
416527	32517381	Plating efficiencies for the cells were as followed: UMSCC6 (~10%), UMSCC74A (~10%), UMSCC47 (~10%) and UPCI-SCC090 (~2%).	('UMSCC47', 'CellLine', 'CVCL:7759', (85, 92))	('UMSCC47', 'Var', (85, 92))	('UMSCC74A', 'Var', (68, 76))
416541	32517381	Inhibition of ATM, ATR and DNA-Pkcs increases radiosensitivity of HNSCC cells to photon irradiation; Figure S7.	('DNA-Pkcs', 'Gene', (27, 35))	('HNSCC', 'Phenotype', 'HP:0012288', (66, 71))	('ATR', 'Gene', '545', (19, 22))	('ATR', 'Gene', (19, 22))	('S7', 'Gene', '6264', (108, 110))	('DNA-Pkcs', 'Gene', '5591', (27, 35))	('Inhibition', 'Var', (0, 10))	('increases', 'PosReg', (36, 45))	('increases radiosensitivity', 'Phenotype', 'HP:0010997', (36, 62))	('radiosensitivity', 'MPA', (46, 62))
416542	32517381	Inhibition of ATM, ATR and DNA-Pkcs increases radiosensitivity of HNSCC cells to proton irradiation.	('DNA-Pkcs', 'Gene', (27, 35))	('HNSCC', 'Phenotype', 'HP:0012288', (66, 71))	('ATR', 'Gene', '545', (19, 22))	('ATR', 'Gene', (19, 22))	('DNA-Pkcs', 'Gene', '5591', (27, 35))	('Inhibition', 'Var', (0, 10))	('increases', 'PosReg', (36, 45))	('increases radiosensitivity', 'Phenotype', 'HP:0010997', (36, 62))	('radiosensitivity', 'MPA', (46, 62))
416593	31700218	Overexpression of this surrogate marker is strongly associated with transcriptionally active high-risk HPV.	('high-risk HPV', 'Disease', (93, 106))	('HPV', 'Species', '10566', (103, 106))	('associated', 'Reg', (52, 62))	('Overexpression', 'Var', (0, 14))
416601	31700218	A proto-oncogene is a normal gene that, due to mutations or increased expression, can become a tumor-inducing agent, i.e.	('mutations', 'Var', (47, 56))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('expression', 'MPA', (70, 80))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('increased', 'PosReg', (60, 69))	('tumor', 'Disease', (95, 100))
416602	31700218	A study in India reported the mutation in Rat sarcoma (Ras) gene is related to the development and progression of OSCC.	('sarcoma', 'Disease', 'MESH:D012509', (46, 53))	('OSCC', 'Disease', (114, 118))	('men', 'Species', '9606', (90, 93))	('mutation', 'Var', (30, 38))	('related', 'Reg', (68, 75))	('Rat', 'Species', '10116', (42, 45))	('sarcoma', 'Disease', (46, 53))	('OSCC', 'Disease', 'MESH:D002294', (114, 118))	('sarcoma', 'Phenotype', 'HP:0100242', (46, 53))
416603	31700218	A more recent study reported CT120A gene as possible oncogene for HNSCC and its overexpression is associated with high tumor grades.	('overexpression', 'PosReg', (80, 94))	('tumor', 'Disease', (119, 124))	('HNSCC', 'Disease', (66, 71))	('CT120A gene', 'Var', (29, 40))	('CT120A', 'Mutation', 'c.120CT>A', (29, 35))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('HNSCC', 'Disease', 'MESH:C535575', (66, 71))
416605	31700218	Usually, in combination with other genetic changes, when the tumor suppressor gene mutates leading to a loss or reduction in its function, the cell might progress to cancer.	('function', 'MPA', (129, 137))	('loss', 'NegReg', (104, 108))	('cancer', 'Disease', (166, 172))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('progress', 'PosReg', (154, 162))	('reduction', 'NegReg', (112, 121))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('mutates', 'Var', (83, 90))	('tumor', 'Disease', (61, 66))
416607	31700218	Researchers had indicated that oral cancers may evolve through a series of mutations in tumor suppressor genes, especially p53.	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('cancers', 'Disease', 'MESH:D009369', (36, 43))	('cancers', 'Phenotype', 'HP:0002664', (36, 43))	('cancers', 'Disease', (36, 43))	('evolve', 'Reg', (48, 54))	('p53', 'Gene', (123, 126))	('mutations', 'Var', (75, 84))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('p53', 'Gene', '7157', (123, 126))	('tumor', 'Disease', (88, 93))
416609	31700218	However, at high concentrations, ROS can cause oxidative stress and be hazardous to the body damaging all major cellular components, including DNA, proteins, and cell membranes, and thus they may play a role in the development of cancer and other impaired health conditions.	('cancer', 'Disease', 'MESH:D009369', (230, 236))	('oxidative stress', 'Phenotype', 'HP:0025464', (47, 63))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('proteins', 'Protein', (148, 156))	('DNA', 'MPA', (143, 146))	('play', 'Reg', (196, 200))	('oxidative stress', 'MPA', (47, 63))	('cause', 'Reg', (41, 46))	('cancer', 'Disease', (230, 236))	('men', 'Species', '9606', (222, 225))	('ROS', 'Var', (33, 36))	('role', 'Reg', (203, 207))
416681	31700218	CIS has been reported to cause multiple tissue and organ toxicity due to its unspecificity along with the decrease in antioxidant defense system.	('antioxidant defense system', 'MPA', (118, 144))	('toxicity', 'Disease', (57, 65))	('decrease', 'NegReg', (106, 114))	('CIS', 'Var', (0, 3))	('cause', 'Reg', (25, 30))	('toxicity', 'Disease', 'MESH:D064420', (57, 65))
416694	31700218	However, it is not well understood how the alterations of multiple molecular and cellular pathways could yield the development and especially the recurrence of HNC.	('yield', 'Reg', (105, 110))	('HNC', 'Disease', (160, 163))	('alterations', 'Var', (43, 54))	('men', 'Species', '9606', (122, 125))	('development', 'CPA', (115, 126))
416696	31700218	The stochastic model also known as clonal evolution or clonal genetic model of cancer, is the traditional idea of carcinogenesis, where mutant tumor cells with a growth advantage when compared to the other cells are selected and expanded, considering that cells in the dominant population have a similar potential for recapitulating tumor growth.	('carcinogenesis', 'Disease', (114, 128))	('tumor', 'Disease', (333, 338))	('tumor', 'Phenotype', 'HP:0002664', (333, 338))	('tumor', 'Disease', (143, 148))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('cancer', 'Disease', (79, 85))	('tumor', 'Disease', 'MESH:D009369', (333, 338))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('carcinogenesis', 'Disease', 'MESH:D063646', (114, 128))	('mutant', 'Var', (136, 142))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
416697	31700218	The mutant cell progeny, which attains a proliferative advantage with consequential genomic instability, accumulates more epigenetic and genetic events, causing selection of the more aggressive sub-clones with subsequent tumor evolution.	('mutant', 'Var', (4, 10))	('epigenetic', 'MPA', (122, 132))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('tumor', 'Disease', (221, 226))	('causing', 'Reg', (153, 160))	('tumor', 'Disease', 'MESH:D009369', (221, 226))
416717	31700218	In this study, they found that only CD44+CD24-/low cells have the ability to form a tumor in immunocompromised mice while cells with other phenotypes were unable to form a tumor.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('tumor', 'Disease', (172, 177))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('mice', 'Species', '10090', (111, 115))	('tumor', 'Disease', (84, 89))	('CD44+CD24-/low', 'Var', (36, 50))
416735	31700218	A close relationship between the build-up of genetic alterations and the malignant phenotypic progression of OSCC has been proposed.	('OSCC', 'Disease', 'MESH:D002294', (109, 113))	('genetic alterations', 'Var', (45, 64))	('OSCC', 'Disease', (109, 113))
416738	31700218	Another reason supporting the origin of CSCs to be SCs is the fact that CSCs and normal SCs are endowed with self-renewal capabilities, and dysregulation of the self-renewal process is an early and indispensable step in carcinogenesis.	('dysregulation', 'Var', (140, 153))	('carcinogenesis', 'Disease', (220, 234))	('carcinogenesis', 'Disease', 'MESH:D063646', (220, 234))
416746	31700218	The tumor can sometimes originate from amplifying transitory cells (ATCs) in which their high proliferative rates may boost the risk of genetic mutations, and not exclusively in normal basal SCs.	('tumor', 'Disease', (4, 9))	('boost', 'PosReg', (118, 123))	('genetic mutations', 'Var', (136, 153))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))
416748	31700218	It is proposed that the first set of early transforming mutations could accumulate in the SC compartment, and that the second set of late mutations, which might constitute the ultimate transforming event giving rise to cancer, might accumulate in more mature, downstream progenitors that originated as the progeny of mutated SCs.	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('mutations', 'Var', (56, 65))	('men', 'Species', '9606', (100, 103))	('cancer', 'Disease', 'MESH:D009369', (219, 225))	('cancer', 'Disease', (219, 225))
416749	31700218	In other words, mutated SCs might represent a reservoir population of pre-cancerous cells, whereas fully transformed progenitors might sustain the growth of the full-blown neoplastic mass.	('neoplastic mass', 'Phenotype', 'HP:0002664', (172, 187))	('cancerous', 'Disease', (74, 83))	('mutated', 'Var', (16, 23))	('growth', 'MPA', (147, 153))	('cancerous', 'Disease', 'MESH:D009369', (74, 83))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
416758	31700218	revealed the big difference between both populations to be so remarkable that only 5 x 103 CD44bright cells were capable of regenerating the tumor heterogeneity and demonstrating self-renewal function when transplanted into immunocompromised mice, whereas 5 x 105 CD44dim cells failed to form tumors.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('tumor', 'Disease', 'MESH:D009369', (293, 298))	('tumors', 'Phenotype', 'HP:0002664', (293, 299))	('regenerating', 'CPA', (124, 136))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumor', 'Phenotype', 'HP:0002664', (293, 298))	('tumor', 'Disease', (141, 146))	('tumors', 'Disease', 'MESH:D009369', (293, 299))	('self-renewal function', 'CPA', (179, 200))	('tumor', 'Disease', (293, 298))	('tumors', 'Disease', (293, 299))	('CD44bright', 'Var', (91, 101))	('mice', 'Species', '10090', (242, 246))
416759	31700218	A very interesting study, conducted by proved the intimate correlation between CD44v3, CD44v6, and CD44v10 isoforms and HNC lymph node metastasis with advanced tumor volume status, perineural invasion plus decreased survival, and distant metastasis with the failure of RT, respectively.	('CD44v10', 'Var', (99, 106))	('CD44v6', 'Var', (87, 93))	('decreased', 'NegReg', (206, 215))	('survival', 'CPA', (216, 224))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('distant metastasis', 'CPA', (230, 248))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('CD44v3', 'Var', (79, 85))	('tumor', 'Disease', (160, 165))	('perineural invasion', 'CPA', (181, 200))	('HNC', 'Disease', (120, 123))
416760	31700218	In-vivo studies utilized CD44 to assess the metastatic potential of CSCs in HNC, as they have shown that CD44high cells, rather than CD44low cells, resulted in lung lesions when injected in tails of NOD/SCID mice.	('NOD', 'Gene', (199, 202))	('CD44high cells', 'Var', (105, 119))	('SCID', 'Disease', (203, 207))	('NOD', 'Gene', '1822', (199, 202))	('lung lesions', 'Disease', (160, 172))	('SCID', 'Disease', 'MESH:D053632', (203, 207))	('resulted in', 'Reg', (148, 159))	('mice', 'Species', '10090', (208, 212))	('lung lesions', 'Disease', 'MESH:D008171', (160, 172))
416764	31700218	Patients with favorable responses to induction CCRT did not have a significant CD44v9 expression level in their HNC biopsy specimens, in comparison to CCRT non-responding patients, where CD44v9 positivity was considerably associated with poor prognosis along with advanced lymph nodal metastasis.	('associated with', 'Reg', (222, 237))	('men', 'Species', '9606', (128, 131))	('patients', 'Species', '9606', (171, 179))	('expression', 'MPA', (86, 96))	('CD44v9 positivity', 'Var', (187, 204))	('Patients', 'Species', '9606', (0, 8))	('positivity', 'Var', (194, 204))
416770	31700218	They also showed that, at low cell density, CD166hi HNC cells formed larger tumors than CD166lo cells after implantation in nude mice and were able to reproduce the heterogeneous tumor population, suggesting CSC behavior.	('nude mice', 'Species', '10090', (124, 133))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('tumors', 'Disease', (76, 82))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('CD166hi', 'Var', (44, 51))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('tumor', 'Disease', (179, 184))
416796	31700218	Knocking down BMI-1 and CD44 have led to an enhanced chemo-sensitivity of CSCs in HNC.	('BMI-1', 'Gene', '648', (14, 19))	('Knocking down', 'Var', (0, 13))	('chemo-sensitivity of CSCs', 'MPA', (53, 78))	('CD44', 'Gene', (24, 28))	('HNC', 'Disease', (82, 85))	('BMI-1', 'Gene', (14, 19))	('enhanced', 'PosReg', (44, 52))
416803	31700218	Suboptimal blood flow will decrease the optimal distribution of chemotherapeutic agents to cancer cells as well as lowers the oxygen tension needed for free radical formation in response to radio- or chemo-therapy.	('oxygen', 'Chemical', 'MESH:D010100', (126, 132))	('cancer', 'Disease', (91, 97))	('lowers', 'NegReg', (115, 121))	('decrease', 'NegReg', (27, 35))	('Suboptimal', 'Var', (0, 10))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('distribution of', 'MPA', (48, 63))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('oxygen tension needed for free radical formation', 'MPA', (126, 174))
416809	31700218	New techniques of targeting specific cell membrane growth factor receptors or downstream signaling pathway mutations are currently under investigation, especially in patients with metastatic tumors.	('tumors', 'Phenotype', 'HP:0002664', (191, 197))	('mutations', 'Var', (107, 116))	('tumors', 'Disease', 'MESH:D009369', (191, 197))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('tumors', 'Disease', (191, 197))	('patients', 'Species', '9606', (166, 174))
416837	29538372	Also, DEK overexpression in human keratinocytes, the cell of origin for SCC, was sufficient to cause hyperplasia in 3D organotypic raft cultures that mimic human skin, thus linking high DEK expression in keratinocytes to oncogenic phenotypes.	('cause', 'Reg', (95, 100))	('hyperplasia', 'Disease', (101, 112))	('human', 'Species', '9606', (28, 33))	('expression', 'Species', '29278', (14, 24))	('hyperplasia', 'Disease', 'MESH:D006965', (101, 112))	('SCC', 'Gene', (72, 75))	('expression', 'Species', '29278', (190, 200))	('overexpression', 'PosReg', (10, 24))	('SCC', 'Gene', '6317', (72, 75))	('human', 'Species', '9606', (156, 161))	('DEK', 'Var', (6, 9))
416844	29538372	Furthermore, high Dek expression caused a trend toward esophageal hyperplasia in 4NQO treated mice.	('Dek', 'Gene', (18, 21))	('esophageal hyperplasia', 'Disease', 'MESH:D006965', (55, 77))	('high', 'Var', (13, 17))	('4NQO', 'Chemical', 'MESH:D015112', (81, 85))	('Dek', 'Gene', '110052', (18, 21))	('esophageal hyperplasia', 'Disease', (55, 77))	('mice', 'Species', '10090', (94, 98))	('expression', 'Species', '29278', (22, 32))
416847	29538372	High DEK expression causes cancer related phenotypes such as increased cellular proliferation, migration, and invasion in vitro.	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('cellular proliferation', 'CPA', (71, 93))	('expression', 'Species', '29278', (9, 19))	('increased', 'PosReg', (61, 70))	('cancer', 'Disease', (27, 33))	('High DEK expression', 'Var', (0, 19))	('cancer', 'Disease', 'MESH:D009369', (27, 33))	('invasion', 'CPA', (110, 118))	('migration', 'CPA', (95, 104))
416848	29538372	Despite the well documented link between high DEK expression and cancer, the consequences of Dek overexpression in vivo are poorly understood.	('Dek', 'Gene', (93, 96))	('DEK', 'Protein', (46, 49))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('high', 'Var', (41, 45))	('Dek', 'Gene', '110052', (93, 96))	('expression', 'Species', '29278', (101, 111))	('expression', 'Species', '29278', (50, 60))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))
416856	29538372	Additionally, high DEK expression is associated with poor prognosis in melanoma, gastric, ovarian, breast, prostate, bladder, lung, pancreatic, skin cancer, and head and neck SCC.	('pancreatic', 'Disease', 'MESH:D010195', (132, 142))	('al', 'Chemical', 'MESH:D000535', (8, 10))	('expression', 'Species', '29278', (23, 33))	('gastric', 'Disease', (81, 88))	('bladder', 'Disease', (117, 124))	('skin cancer', 'Disease', (144, 155))	('ovarian', 'Disease', (90, 97))	('pancreatic', 'Disease', (132, 142))	('melanoma', 'Phenotype', 'HP:0002861', (71, 79))	('melanoma', 'Disease', (71, 79))	('DEK', 'Protein', (19, 22))	('high', 'Var', (14, 18))	('ovarian', 'Disease', 'MESH:D010051', (90, 97))	('breast', 'Disease', (99, 105))	('skin cancer', 'Phenotype', 'HP:0008069', (144, 155))	('lung', 'Disease', (126, 130))	('SCC', 'Gene', '6317', (175, 178))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('prostate', 'Disease', (107, 115))	('SCC', 'Gene', (175, 178))	('skin cancer', 'Disease', 'MESH:D012878', (144, 155))	('melanoma', 'Disease', 'MESH:D008545', (71, 79))
416865	29538372	DEK overexpression occurs through various mechanisms including gene amplification, increased transcription, and mutations in microRNAs and ubiquitin ligases responsible for DEK mRNA and protein degradation, respectively.	('increased', 'PosReg', (83, 92))	('microRNAs', 'Gene', (125, 134))	('transcription', 'MPA', (93, 106))	('mutations', 'Var', (112, 121))	('expression', 'Species', '29278', (8, 18))	('protein degradation', 'MPA', (186, 205))	('ubiquitin ligases', 'Enzyme', (139, 156))
416876	29538372	4NQO is a chemical carcinogen that mimics the effects of tobacco smoke by forming DNA adducts and mutations similar to those seen in human HNSCC and ESCC.	('SCC', 'Gene', '6317', (150, 153))	('tobacco', 'Species', '4097', (57, 64))	('SCC', 'Gene', (141, 144))	('4NQO', 'Chemical', 'MESH:D015112', (0, 4))	('DNA adducts', 'MPA', (82, 93))	('mutations', 'Var', (98, 107))	('SCC', 'Gene', '6317', (141, 144))	('SCC', 'Gene', (150, 153))	('al', 'Chemical', 'MESH:D000535', (16, 18))	('human', 'Species', '9606', (133, 138))
416877	29538372	When administered in drinking water, 4NQO stimulates susceptibility to squamous cell carcinomas in the tongue, oral cavity, and esophagus.	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (71, 95))	('4NQO', 'Chemical', 'MESH:D015112', (37, 41))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (71, 94))	('stimulates', 'PosReg', (42, 52))	('drinking water', 'Chemical', 'MESH:D060766', (21, 35))	('carcinomas', 'Phenotype', 'HP:0030731', (85, 95))	('esophagus', 'Disease', (128, 137))	('4NQO', 'Var', (37, 41))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('susceptibility', 'MPA', (53, 67))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (71, 95))	('al', 'Chemical', 'MESH:D000535', (113, 115))	('squamous cell carcinomas', 'Disease', (71, 95))
416928	29538372	Exposure of mice to drinking water containing the soluble quinoline derivative 4NQO promotes the development of oral and/or esophageal cancer.	('4NQO', 'Var', (79, 83))	('esophageal cancer', 'Disease', (124, 141))	('quinoline', 'Chemical', 'MESH:C037219', (58, 67))	('esophageal cancer', 'Disease', 'MESH:D004938', (124, 141))	('drinking water', 'Chemical', 'MESH:D060766', (20, 34))	('al', 'Chemical', 'MESH:D000535', (132, 134))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('4NQO', 'Chemical', 'MESH:D015112', (79, 83))	('al', 'Chemical', 'MESH:D000535', (114, 116))	('mice', 'Species', '10090', (12, 16))	('promotes', 'PosReg', (84, 92))
416965	29538372	Here we demonstrate that Dek overexpression targeted to the epithelium stimulates proliferation specifically in the presence of 4NQO in the tongue and also in the esophagus.	('overexpression', 'PosReg', (29, 43))	('stimulates', 'PosReg', (71, 81))	('4NQO', 'Var', (128, 132))	('al', 'Chemical', 'MESH:D000535', (151, 153))	('al', 'Chemical', 'MESH:D000535', (104, 106))	('Dek', 'Gene', '110052', (25, 28))	('expression', 'Species', '29278', (33, 43))	('4NQO', 'Chemical', 'MESH:D015112', (128, 132))	('proliferation', 'CPA', (82, 95))	('Dek', 'Gene', (25, 28))
416972	29538372	Interestingly, C57BL/6 and FVB/N harbor variations in immune phenotype, raising the intriguing possibility that immune surveillance and/or evasion account at least in part for the differing tumor phenotypes in mice with ubiquitous versus epithelial cell targeted Dek overexpression.	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('mice', 'Species', '10090', (210, 214))	('variations', 'Reg', (40, 50))	('expression', 'Species', '29278', (271, 281))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('Dek', 'Gene', (263, 266))	('tumor', 'Disease', (190, 195))	('al', 'Chemical', 'MESH:D000535', (246, 248))	('C57BL/6', 'Var', (15, 22))	('Dek', 'Gene', '110052', (263, 266))
416977	29538372	The complexity of DEK functions in vivo is exemplified in studies of non-vertebrate organisms For instance, in Arabidopsis, DEK3 overexpression decreases germination efficiency under high salinity conditions, and conversely, plants deficient in DEK3 germinated significantly better compared to wild-type plants suggesting DEK3 levels are crucial for stress tolerance.	('decreases', 'NegReg', (144, 153))	('germination efficiency', 'CPA', (154, 176))	('DEK3', 'Gene', (124, 128))	('deficient', 'Var', (232, 241))	('overexpression', 'PosReg', (129, 143))	('al', 'Chemical', 'MESH:D000535', (189, 191))	('better', 'PosReg', (275, 281))	('DEK3', 'Gene', '828770', (124, 128))	('DEK3', 'Gene', '828770', (322, 326))	('DEK3', 'Gene', (245, 249))	('Arabidopsis', 'Species', '3702', (111, 122))	('DEK3', 'Gene', (322, 326))	('DEK3', 'Gene', '828770', (245, 249))	('germinated', 'CPA', (250, 260))	('al', 'Chemical', 'MESH:D000535', (343, 345))	('expression', 'Species', '29278', (133, 143))
417088	29170406	Although advanced or metastatic (late-stage) NSCLC has routine testing for targets such as epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) rearrangements, there is still lack of validated genetic risk stratification score to select patients who may best benefit from adjuvant chemotherapy (ACT) among early-stage resected NSCLC patients.	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (145, 164))	('EGFR', 'Gene', '1956', (125, 129))	('anaplastic lymphoma kinase', 'Gene', '238', (145, 171))	('NSCLC', 'Disease', 'MESH:D002289', (45, 50))	('NSCLC', 'Disease', 'MESH:D002289', (361, 366))	('anaplastic lymphoma kinase', 'Gene', (145, 171))	('epidermal growth factor receptor', 'Gene', (91, 123))	('epidermal growth factor receptor', 'Gene', '1956', (91, 123))	('NSCLC', 'Disease', (45, 50))	('NSCLC', 'Disease', (361, 366))	('patients', 'Species', '9606', (367, 375))	('patients', 'Species', '9606', (271, 279))	('NSCLC', 'Phenotype', 'HP:0030358', (45, 50))	('lymphoma', 'Phenotype', 'HP:0002665', (156, 164))	('NSCLC', 'Phenotype', 'HP:0030358', (361, 366))	('mutations', 'Var', (131, 140))	('rearrangements', 'Var', (178, 192))	('men', 'Species', '9606', (187, 190))	('ALK', 'Gene', '238', (173, 176))	('EGFR', 'Gene', (125, 129))	('ALK', 'Gene', (173, 176))
417089	29170406	Adjuvant studies that randomized EGFR mutant lung cancer to adjuvant EGFR tyrosine kinase inhibitors or chemotherapy have also demonstrated no survival benefits.	('mutant', 'Var', (38, 44))	('EGFR', 'Gene', '1956', (69, 73))	('lung cancer', 'Disease', 'MESH:D008175', (45, 56))	('EGFR', 'Gene', (69, 73))	('lung cancer', 'Disease', (45, 56))	('EGFR', 'Gene', '1956', (33, 37))	('lung cancer', 'Phenotype', 'HP:0100526', (45, 56))	('EGFR', 'Gene', (33, 37))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))
417093	29170406	Whereas cancer has been previously examined for genetic or epigenetic mutations in epithelial cells, it is now clear that the extracellular cues in tumor microenvironment (TME) also regulate cancer development and metastasis.	('cancer', 'Disease', (191, 197))	('cancer', 'Disease', 'MESH:D009369', (191, 197))	('cancer', 'Disease', (8, 14))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('metastasis', 'CPA', (214, 224))	('tumor', 'Disease', (148, 153))	('men', 'Species', '9606', (166, 169))	('men', 'Species', '9606', (205, 208))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('regulate', 'Reg', (182, 190))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('epigenetic mutations', 'Var', (59, 79))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('cancer', 'Disease', 'MESH:D009369', (8, 14))
417120	29170406	The histology profiles of the samples included two studies comprising exclusively of lung adenocarcinomas (GSE68465, TCGA), and one of squamous cell carcinoma (GSE4573), and six of mixed histological types (GSE3141, GSE37745, GSE30219, GSE42127, GSE41271, and GSE11969).	('GSE4573', 'Chemical', '-', (160, 167))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (135, 158))	('carcinoma', 'Phenotype', 'HP:0030731', (149, 158))	('GSE3141', 'Var', (207, 214))	('GSE3141', 'Chemical', '-', (207, 214))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (135, 158))	('GSE42127', 'Var', (236, 244))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (85, 104))	('GSE30219', 'Var', (226, 234))	('squamous cell carcinoma', 'Disease', (135, 158))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('carcinomas', 'Phenotype', 'HP:0030731', (95, 105))	('GSE41271', 'Var', (246, 254))	('GSE37745', 'Var', (216, 224))	('GSE11969', 'Var', (260, 268))	('lung adenocarcinomas', 'Disease', (85, 105))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (85, 105))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (85, 105))
417131	29170406	Although EPPI model also shows statistically significance in the other two data sets, histology and tumor staging shows better performance in GSE30219 and TCGA, respectively.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Disease', (100, 105))	('GSE30219', 'Var', (142, 150))	('TCGA', 'Disease', (155, 159))	('tumor', 'Disease', 'MESH:D009369', (100, 105))
417139	29170406	We further tested the therapeutic predictive utility of the EPPI signature in an independent validation cohort, hypothesizing that the high-risk group would likely benefit from the ACT: 144 tumors from GSE42127 comprising 35 patients who received ACT and 109 patients who did not receive ACT.	('tumors', 'Disease', (190, 196))	('patients', 'Species', '9606', (225, 233))	('patients', 'Species', '9606', (259, 267))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('tested', 'Reg', (11, 17))	('tumors', 'Disease', 'MESH:D009369', (190, 196))	('GSE42127', 'Var', (202, 210))	('tumors', 'Phenotype', 'HP:0002664', (190, 196))
417211	29170406	Data for all the bioinformatics analyses using open-source R packages have been described throughout the text and are available under accession codes GSE10245, GSE10445, GSE10799, GSE12667, GSE18842, GSE19188, GSE28571, GSE31210, GSE33356, GSE50081, GSE3141, GSE37745, GSE30219, GSE68465, GSE4573, GSE42127, GSE41271, and GSE11969 from the National Center for Biotechnology Information Gene Expression Omnibus (GEO).	('GSE18842', 'Var', (190, 198))	('GSE4573', 'Var', (289, 296))	('GSE37745', 'Var', (259, 267))	('GSE68465', 'Var', (279, 287))	('GSE19188', 'Var', (200, 208))	('GSE3141', 'Var', (250, 257))	('GSE33356', 'Var', (230, 238))	('GSE4573', 'Chemical', '-', (289, 296))	('GSE42127', 'Var', (298, 306))	('GSE50081', 'Var', (240, 248))	('GSE3141', 'Chemical', '-', (250, 257))	('GSE10245', 'Var', (150, 158))	('GSE30219', 'Var', (269, 277))	('GSE28571', 'Var', (210, 218))
417283	32675385	Patients with NSCLC, advanced nonsquamous NSCLC, and squamous cell histology were suggested to test for EGFR mutations, ALK rearrangements, and ROS1 fusions.	('NSCLC', 'Disease', (42, 47))	('NSCLC', 'Disease', (14, 19))	('EGFR', 'Gene', '1956', (104, 108))	('EGFR', 'Gene', (104, 108))	('NSCLC', 'Disease', 'MESH:D002289', (14, 19))	('NSCLC', 'Disease', 'MESH:D002289', (42, 47))	('ROS1', 'Gene', (144, 148))	('ALK', 'Gene', (120, 123))	('rearrangements', 'Var', (124, 138))	('Patients', 'Species', '9606', (0, 8))	('ROS1', 'Gene', '6098', (144, 148))	('SCLC', 'Phenotype', 'HP:0030357', (15, 19))	('mutations', 'Var', (109, 118))	('NSCLC', 'Phenotype', 'HP:0030358', (14, 19))	('NSCLC', 'Phenotype', 'HP:0030358', (42, 47))	('ALK', 'Gene', '238', (120, 123))	('SCLC', 'Phenotype', 'HP:0030357', (43, 47))	('test', 'Reg', (95, 99))
417295	32675385	Patient information from the downloaded datasets are summarized in Table 1 and Figure 1: (a) GSE18842 (Affymetrix), (b) GSE19188 (Affymetrix), (c) GSE70880 (Agilent), and (d) TCGA.	('GSE19188', 'Var', (120, 128))	('GSE18842', 'Var', (93, 101))	('GSE70880', 'Var', (147, 155))	('Patient', 'Species', '9606', (0, 7))
417302	32675385	This process revealed the most related 20 lncRNAs which were: AC008268.1-201, AC027288.3-203, AC146944.4-201, ADAMTS9-AS2-203, AL109741.1-201, AP000866.2-201, CARD8-AS1-201, GATA6-AS1-202, HHIP-AS1-201, HHIP-AS1-203, HSPC324-201, LINC00261-202, LINC01614-201, LINC01852-201, LINC01936-201, LINC02555-201, MAFG-AS1-201, SBF2-AS1-201, TBX5-AS1-201, and TMPO-AS1-202.	('ADAMTS9-AS2-203', 'CellLine', 'CVCL:1Y40', (110, 125))	('AS1', 'Gene', (324, 327))	('AS1', 'Gene', (310, 313))	('LINC00261', 'Gene', (230, 239))	('AS1', 'Gene', '5729', (194, 197))	('GATA6', 'Gene', '2627', (174, 179))	('AS1', 'Gene', (356, 359))	('HHIP-AS1-201', 'CellLine', 'CVCL:V460', (189, 201))	('AS1', 'Gene', (165, 168))	('AS1', 'Gene', (338, 341))	('LINC01614', 'Gene', (245, 254))	('LINC00261', 'Gene', '140828', (230, 239))	('AS1', 'Gene', (180, 183))	('LINC02555', 'Chemical', '-', (290, 299))	('ncRNA', 'Gene', (43, 48))	('AS1', 'Gene', '5729', (208, 211))	('TBX5', 'Gene', '6910', (333, 337))	('ncRNA', 'Gene', '54719', (43, 48))	('LINC01614', 'Gene', '105373869', (245, 254))	('AS1', 'Gene', '5729', (324, 327))	('AS1', 'Gene', '5729', (310, 313))	('AS1', 'Gene', (194, 197))	('GATA6', 'Gene', (174, 179))	('LINC02555-201', 'Var', (290, 303))	('TBX5', 'Gene', (333, 337))	('AS1', 'Gene', '5729', (356, 359))	('AS1', 'Gene', '5729', (165, 168))	('LINC01852-201', 'Var', (260, 273))	('AS1', 'Gene', '5729', (338, 341))	('AS1', 'Gene', '5729', (180, 183))	('AS1', 'Gene', (208, 211))	('LINC01936-201', 'Var', (275, 288))
417303	32675385	Here, two-sample t-test and Correlation Attribute Eval feature selection method revealed the following top 20 lncRNAs: AC004947.1-201, AC007128.1-201, AC008268.1-201, AC023509.2-201, AC087521.1-201, AC107959.1-202, ADAMTS9-AS2-201, ADAMTS9-AS2-203, AP000866.2-201, AP001189.1-201, DDX11-AS1-201, GATA6-AS1-202, HSPC324-201, LINC00163-201, LINC00656-201, LINC01936-201, LINC02016-201, LINC02555-201, TBX5-AS1-201, and VPS9D1-AS1-202.	('AS1', 'Gene', (302, 305))	('TBX5', 'Gene', '6910', (399, 403))	('ADAMTS9-AS2-201', 'CellLine', 'CVCL:V460', (215, 230))	('LINC00163-201', 'Var', (324, 337))	('AS1', 'Gene', (404, 407))	('AS1', 'Gene', '5729', (424, 427))	('LINC02016-201', 'Var', (369, 382))	('GATA6', 'Gene', (296, 301))	('LINC02555', 'Chemical', '-', (384, 393))	('TBX5', 'Gene', (399, 403))	('VPS9D1', 'Gene', '9605', (417, 423))	('AS1', 'Gene', '5729', (287, 290))	('LINC00656', 'Gene', (339, 348))	('AS1', 'Gene', '5729', (302, 305))	('HSPC324-201', 'Var', (311, 322))	('AS1', 'Gene', '5729', (404, 407))	('AS1', 'Gene', (424, 427))	('LINC01936-201', 'Var', (354, 367))	('ADAMTS9-AS2-203', 'CellLine', 'CVCL:1Y40', (232, 247))	('AP001189.1-201', 'Var', (265, 279))	('GATA6', 'Gene', '2627', (296, 301))	('ncRNA', 'Gene', (111, 116))	('ncRNA', 'Gene', '54719', (111, 116))	('AC023509.2-201', 'Var', (167, 181))	('AS1', 'Gene', (287, 290))	('VPS9D1', 'Gene', (417, 423))	('LINC02555-201', 'Var', (384, 397))	('LINC00656', 'Gene', '200261', (339, 348))
417353	32675385	Based on this design, we downloaded three lung cancer microarray datasets, GSE19188, GSE18842 and GSE70880, with a total of 287 samples, from the GEO repository, and 216 RNA-Seq samples from TCGA (http://cancergenome.nih.gov/).	('cancer', 'Disease', (204, 210))	('cancer', 'Disease', 'MESH:D009369', (204, 210))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('cancer', 'Disease', (47, 53))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('GSE18842', 'Var', (85, 93))	('GSE70880', 'Var', (98, 106))	('lung cancer', 'Disease', (42, 53))	('lung cancer', 'Phenotype', 'HP:0100526', (42, 53))	('GSE19188', 'Var', (75, 83))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('lung cancer', 'Disease', 'MESH:D008175', (42, 53))
417365	32675385	GSE19188 and GSE18842 contain NSCLC samples but the lung cancer types in GSE70880 are unknown.	('NSCLC', 'Disease', 'MESH:D002289', (30, 35))	('lung cancer', 'Disease', 'MESH:D008175', (52, 63))	('GSE18842', 'Var', (13, 21))	('SCLC', 'Phenotype', 'HP:0030357', (31, 35))	('NSCLC', 'Phenotype', 'HP:0030358', (30, 35))	('lung cancer', 'Disease', (52, 63))	('lung cancer', 'Phenotype', 'HP:0100526', (52, 63))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('NSCLC', 'Disease', (30, 35))	('GSE70880', 'Var', (73, 81))
417367	32675385	First, we used per sample every sample median value across all the lncRNAs in GSE19188, GSE70880, and GSE18842 datasets.	('GSE70880', 'Var', (88, 96))	('GSE18842', 'Var', (102, 110))	('ncRNA', 'Gene', (68, 73))	('GSE19188', 'Var', (78, 86))	('ncRNA', 'Gene', '54719', (68, 73))
417394	31867319	Some of these differential methylation sites were associated with cancer survival.	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('methylation', 'Var', (27, 38))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('associated', 'Reg', (50, 60))	('cancer', 'Disease', (66, 72))
417401	31867319	DNA methylation could modulate gene expression during development and cancer progression (Wang et al.,; Zhang et al.,).	('development', 'CPA', (54, 65))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('modulate', 'Reg', (22, 30))	('methylation', 'Var', (4, 15))	('gene expression', 'MPA', (31, 46))	('men', 'Species', '9606', (61, 64))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))
417410	31867319	Methylation of SLFN11 is a biomarker for poor prognosis in colorectal cancer and methylations of SLIT1, SLIT2, and SLIT3 are abnormal in gastric cancer.	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('SLIT2', 'Gene', (104, 109))	('SLIT3', 'Gene', '6586', (115, 120))	('SLIT3', 'Gene', (115, 120))	('gastric cancer', 'Disease', 'MESH:D013274', (137, 151))	('methylations', 'MPA', (81, 93))	('colorectal cancer', 'Phenotype', 'HP:0003003', (59, 76))	('Methylation', 'Var', (0, 11))	('SLIT2', 'Gene', '9353', (104, 109))	('abnormal', 'Reg', (125, 133))	('SLIT1', 'Gene', (97, 102))	('gastric cancer', 'Phenotype', 'HP:0012126', (137, 151))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('SLFN11', 'Gene', (15, 21))	('SLIT1', 'Gene', '6585', (97, 102))	('colorectal cancer', 'Disease', 'MESH:D015179', (59, 76))	('colorectal cancer', 'Disease', (59, 76))	('gastric cancer', 'Disease', (137, 151))	('SLFN11', 'Gene', '91607', (15, 21))
417411	31867319	F2RL3 methylation is recently identified as a biomarker closely reflecting both current and past smoking exposure, causing lung cancer (Yan et al.,; Kim et al.,; He et al.,).	('lung cancer', 'Disease', (123, 134))	('lung cancer', 'Phenotype', 'HP:0100526', (123, 134))	('F2RL3', 'Gene', (0, 5))	('causing', 'Reg', (115, 122))	('lung cancer', 'Disease', 'MESH:D008175', (123, 134))	('methylation', 'Var', (6, 17))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('F2RL3', 'Gene', '9002', (0, 5))
417418	31867319	For each cancer type, we detected a series of methylation sites, which could influence m-age compared to healthy samples.	('cancer', 'Disease', (9, 15))	('influence', 'Reg', (77, 86))	('m-age', 'CPA', (87, 92))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('methylation sites', 'Var', (46, 63))
417447	31867319	According to the least Mean-Squared Error (MSE, reflect the degree of difference between the estimator and true value, the smaller the MSE, the better the model fit) of LASSO linear regression model, we found that the value beta0 of the model was 34.63 when the adjustment parameter was 0.1419941 (Figure 2C).	('MSE', 'Gene', (135, 138))	('MSE', 'Gene', '101180900', (135, 138))	('0.1419941', 'Var', (287, 296))	('men', 'Species', '9606', (268, 271))	('MSE', 'Gene', (43, 46))	('MSE', 'Gene', '101180900', (43, 46))
417448	31867319	Among the 282 methylation characteristics in the construction of model, the levels of cg08461576, cg05923914, cg27641628, cg13221458, cg05632420, and cg07103722 were significantly and negatively correlated with sample age, and the linear model coefficients of the six sites above were negative as well (Figure 2D).	('cg27641628', 'Var', (110, 120))	('cg13221458', 'Var', (122, 132))	('cg08461576', 'Chemical', '-', (86, 96))	('negatively', 'NegReg', (184, 194))	('cg05632420', 'Chemical', '-', (134, 144))	('cg05923914', 'Chemical', '-', (98, 108))	('cg27641628', 'Chemical', '-', (110, 120))	('cg08461576', 'Var', (86, 96))	('cg05923914', 'Var', (98, 108))	('cg07103722', 'Var', (150, 160))	('cg05632420', 'Var', (134, 144))	('cg13221458', 'Chemical', '-', (122, 132))
417449	31867319	Gene Ontology (GO) analysis of the genes for the 282 model characteristics revealed that these genes were associated with some GO terms such as "lysine catabolic process" (GO:0006554) and "lysine metabolic process" (GO:0006553) (Figure 3A).	('GO:0006553', 'Var', (216, 226))	('lysine', 'Chemical', 'MESH:D008239', (189, 195))	('lysine', 'Chemical', 'MESH:D008239', (145, 151))	('associated', 'Reg', (106, 116))	('metabolic process', 'MPA', (196, 213))
417450	31867319	These results indicated that age-related methylation sites could alter many important biology processes (Supplementary Table S5).	('sites', 'Var', (53, 58))	('methylation sites', 'Var', (41, 58))	('alter', 'Reg', (65, 70))	('men', 'Species', '9606', (111, 114))
417452	31867319	In addition, we found that most methylation sites were enriched in human acute leukemia [-log10 (p) > 50] (Figure 3C, Supplementary Table S6).	('men', 'Species', '9606', (124, 127))	('methylation sites', 'Var', (32, 49))	('acute leukemia', 'Disease', (73, 87))	('acute leukemia', 'Phenotype', 'HP:0002488', (73, 87))	('leukemia', 'Phenotype', 'HP:0001909', (79, 87))	('sites', 'Var', (44, 49))	('acute leukemia', 'Disease', 'MESH:D015470', (73, 87))	('human', 'Species', '9606', (67, 72))
417467	31867319	It is suggested that hyper-methylation of these age-related differences may lead to changes in m-age and cancer development.	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('lead to changes', 'Reg', (76, 91))	('men', 'Species', '9606', (119, 122))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('hyper-methylation', 'Var', (21, 38))	('m-age', 'CPA', (95, 100))
417471	31867319	In most cancer types, these differential methylation sites in age-related samples were associated with survival (Figure 5).	('survival', 'MPA', (103, 111))	('differential methylation', 'Var', (28, 52))	('cancer', 'Disease', (8, 14))	('methylation', 'Var', (41, 52))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('associated with', 'Reg', (87, 102))	('cancer', 'Disease', 'MESH:D009369', (8, 14))
417473	31867319	The results indicated that differential methylation sites of age-related samples maybe could be an effective prognostic biomarker for cancers.	('cancers', 'Disease', 'MESH:D009369', (134, 141))	('cancers', 'Phenotype', 'HP:0002664', (134, 141))	('differential methylation sites', 'Var', (27, 57))	('cancers', 'Disease', (134, 141))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
417483	31867319	Previous study also showed that epigenetic age acceleration is associated with colorectal cancer molecular characteristics and can be a significant predictor of overall survival, as well as age and tumor stage (Zheng et al.,).	('epigenetic age', 'Var', (32, 46))	('colorectal cancer', 'Phenotype', 'HP:0003003', (79, 96))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('associated', 'Reg', (63, 73))	('colorectal cancer', 'Disease', (79, 96))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('acceleration', 'PosReg', (47, 59))	('tumor', 'Disease', (198, 203))	('colorectal cancer', 'Disease', 'MESH:D015179', (79, 96))
417492	31867319	We further discovered the differential methylation sites between age-related cancer samples and normal samples.	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('methylation', 'Var', (39, 50))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))
417493	31867319	These differential methylation sites were associated with survival in cancers.	('methylation sites', 'Var', (19, 36))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('associated with', 'Reg', (42, 57))	('cancers', 'Disease', 'MESH:D009369', (70, 77))	('cancers', 'Phenotype', 'HP:0002664', (70, 77))	('cancers', 'Disease', (70, 77))
417498	31781300	Determination of SIRT1 rs12778366, FGFR2 rs2981582, STAT3 rs744166, and RAGE rs1800625 Single Gene Polymorphisms in Patients with Laryngeal Squamous Cell Carcinoma To determine the frequency of the genotype of signal transducer and activator of transcription protein 3 (STAT3) rs744166, sirtuin (SIRT1) rs12778366, fibroblast growth factor (FGFR2) rs2981582, and advanced glycosylation end product-specific receptor (RAGE) rs1800625 gene polymorphisms in patients with laryngeal squamous cell carcinoma (LSCC).	('patient', 'Species', '9606', (455, 462))	('LSCC', 'Disease', (504, 508))	('rs744166', 'DBSNP_MENTION', 'None', (277, 285))	('rs1800625', 'Var', (77, 86))	('rs744166', 'Var', (58, 66))	('rs12778366', 'Mutation', 'rs12778366', (23, 33))	('carcinoma', 'Phenotype', 'HP:0030731', (493, 502))	('RAGE', 'Gene', '177', (417, 421))	('STAT3', 'Gene', (270, 275))	('SIRT1', 'Gene', '23411', (296, 301))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (479, 502))	('rs744166', 'Mutation', 'rs744166', (277, 285))	('carcinoma', 'Disease', (493, 502))	('rs2981582', 'Mutation', 'rs2981582', (348, 357))	('rs12778366', 'DBSNP_MENTION', 'None', (23, 33))	('rs1800625', 'Mutation', 'rs1800625', (423, 432))	('rs2981582', 'DBSNP_MENTION', 'None', (41, 50))	('rs2981582', 'Var', (41, 50))	('Laryngeal Squamous Cell Carcinoma', 'Disease', (130, 163))	('FGFR2', 'Gene', (35, 40))	('STAT3', 'Gene', '6774', (270, 275))	('laryngeal squamous cell carcinoma', 'Disease', 'MESH:D002294', (469, 502))	('rs1800625', 'DBSNP_MENTION', 'None', (77, 86))	('SIRT1', 'Gene', '23411', (17, 22))	('rs12778366', 'Var', (303, 313))	('rs1800625', 'Var', (423, 432))	('SIRT1', 'Gene', (296, 301))	('rs744166', 'Var', (277, 285))	('patients', 'Species', '9606', (455, 463))	('STAT3', 'Gene', (52, 57))	('Carcinoma', 'Phenotype', 'HP:0030731', (154, 163))	('FGFR2', 'Gene', (341, 346))	('FGFR2', 'Gene', '2263', (35, 40))	('carcinoma', 'Disease', 'MESH:D002277', (493, 502))	('rs2981582', 'Var', (348, 357))	('rs744166', 'DBSNP_MENTION', 'None', (58, 66))	('rs2981582', 'DBSNP_MENTION', 'None', (348, 357))	('SIRT1', 'Gene', (17, 22))	('signal transducer and activator of transcription protein 3', 'Gene', '6774', (210, 268))	('Laryngeal Squamous Cell Carcinoma', 'Disease', 'MESH:D002294', (130, 163))	('RAGE', 'Gene', (72, 76))	('rs1800625', 'DBSNP_MENTION', 'None', (423, 432))	('STAT3', 'Gene', '6774', (52, 57))	('rs744166', 'Mutation', 'rs744166', (58, 66))	('rs12778366', 'Mutation', 'rs12778366', (303, 313))	('rs12778366', 'Var', (23, 33))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (140, 163))	('FGFR2', 'Gene', '2263', (341, 346))	('LSCC', 'Disease', 'MESH:D002294', (504, 508))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (479, 502))	('Patients', 'Species', '9606', (116, 124))	('RAGE', 'Gene', '177', (72, 76))	('rs2981582', 'Mutation', 'rs2981582', (41, 50))	('rs12778366', 'DBSNP_MENTION', 'None', (303, 313))	('rs1800625', 'Mutation', 'rs1800625', (77, 86))	('RAGE', 'Gene', (417, 421))	('laryngeal squamous cell carcinoma', 'Disease', (469, 502))
417499	31781300	The genotyping of STAT3 rs744166, SIRT1 rs12778366, FGFR2 rs2981582, and RAGE rs1800625 was carried out using the RT-PCR.	('rs2981582', 'Var', (58, 67))	('rs1800625', 'Var', (78, 87))	('STAT3', 'Gene', (18, 23))	('FGFR2', 'Gene', (52, 57))	('rs12778366', 'Var', (40, 50))	('rs2981582', 'DBSNP_MENTION', 'None', (58, 67))	('rs744166', 'Var', (24, 32))	('rs1800625', 'DBSNP_MENTION', 'None', (78, 87))	('rs744166', 'DBSNP_MENTION', 'None', (24, 32))	('SIRT1', 'Gene', (34, 39))	('rs12778366', 'DBSNP_MENTION', 'None', (40, 50))
417500	31781300	The analysis of STAT3 rs744166, SIRT1 rs12778366, and FGFR2 rs2981582 gene polymorphisms did not reveal any differences in genotype distribution between the patients with LSCC and the control subjects.	('rs12778366', 'DBSNP_MENTION', 'None', (38, 48))	('rs12778366', 'Var', (38, 48))	('LSCC', 'Disease', (171, 175))	('rs2981582', 'DBSNP_MENTION', 'None', (60, 69))	('rs744166', 'DBSNP_MENTION', 'None', (22, 30))	('FGFR2', 'Gene', (54, 59))	('rs2981582', 'Var', (60, 69))	('rs744166', 'Var', (22, 30))
417503	31781300	RAGE rs1800625 gene polymorphism may play a significant role in laryngeal squamous cell carcinoma development.	('laryngeal squamous cell carcinoma', 'Disease', (64, 97))	('rs1800625', 'Var', (5, 14))	('play', 'Reg', (37, 41))	('rs1800625', 'DBSNP_MENTION', 'None', (5, 14))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('men', 'Species', '9606', (105, 108))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (74, 97))
417509	31781300	Aberrant expression and constitutive activation of STAT3 are involved in a broad range of human malignancies, including gastric, breast, prostate, and non-small-cell lung cancers.	('gastric', 'Disease', (120, 127))	('Aberrant expression', 'Var', (0, 19))	('malignancies', 'Disease', 'MESH:D009369', (96, 108))	('STAT3', 'Gene', (51, 56))	('involved', 'Reg', (61, 69))	('activation', 'PosReg', (37, 47))	('prostate', 'Disease', (137, 145))	('non-small-cell lung cancer', 'Disease', 'MESH:D002289', (151, 177))	('lung cancer', 'Disease', 'MESH:D008175', (166, 177))	('malignancies', 'Disease', (96, 108))	('cancers', 'Phenotype', 'HP:0002664', (171, 178))	('non-small-cell lung cancers', 'Disease', (151, 178))	('lung cancers', 'Phenotype', 'HP:0100526', (166, 178))	('lung cancer', 'Phenotype', 'HP:0100526', (166, 177))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('non-small-cell lung cancers', 'Disease', 'MESH:D002289', (151, 178))	('breast', 'Disease', (129, 135))
417521	31781300	Our study results showed that genotypes (AA, AG, and GG) of rs1800625 in RAGE gene were distributed statistically significantly differently between patients and controls (61.1%, 30.6%, and 8.3% vs. 72.5%, 25.8%, and 1.8%, respectively; p < 0.001) and allele G at rs1800625 was more frequently observed in the patient group than in controls (23.6% vs. 14.6%; p < 0.001) (Table 3).	('rs1800625', 'DBSNP_MENTION', 'None', (263, 272))	('rs1800625', 'DBSNP_MENTION', 'None', (60, 69))	('rs1800625', 'Var', (60, 69))	('rs1800625', 'Var', (263, 272))
417525	31781300	It was found that Rs12778366 polymorphism of SIRT1 gene is associated with breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('breast cancer', 'Disease', (75, 88))	('breast cancer', 'Phenotype', 'HP:0003002', (75, 88))	('associated', 'Reg', (59, 69))	('Rs12778366 polymorphism', 'Var', (18, 41))	('Rs12778366', 'Mutation', 'Rs12778366', (18, 28))	('SIRT1', 'Gene', (45, 50))
417526	31781300	revealed that SIRT1 rs12778366 TT genotypes were more frequent in CC and CT genotypes and were associated with histological grade of cancer and lymph node status.	('rs12778366', 'DBSNP_MENTION', 'None', (20, 30))	('frequent', 'Reg', (54, 62))	('rs12778366', 'Var', (20, 30))	('SIRT1', 'Gene', (14, 19))	('associated', 'Reg', (95, 105))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
417527	31781300	SIRT1 rs12778366 TT genotype also correlated with negative estrogen receptor and progesterone receptor statuses.	('rs12778366', 'DBSNP_MENTION', 'None', (6, 16))	('rs12778366', 'Var', (6, 16))	('SIRT1', 'Gene', (0, 5))	('progesterone receptor', 'Gene', '5241', (81, 102))	('estrogen', 'Chemical', 'MESH:D004967', (59, 67))	('progesterone receptor', 'Gene', (81, 102))	('negative', 'NegReg', (50, 58))
417530	31781300	The importance of FGFR2 rs2981582 gene polymorphism was studied in breast and prostate cancer.	('breast and prostate cancer', 'Disease', 'MESH:D001943', (67, 93))	('FGFR2', 'Gene', (18, 23))	('prostate cancer', 'Phenotype', 'HP:0012125', (78, 93))	('rs2981582', 'DBSNP_MENTION', 'None', (24, 33))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('rs2981582', 'Var', (24, 33))
417531	31781300	A study in Tunisian population reported that subjects with AA genotype of FGFR2 rs2981582 had increased risk of breast cancer.	('breast cancer', 'Phenotype', 'HP:0003002', (112, 125))	('breast cancer', 'Disease', (112, 125))	('rs2981582', 'Var', (80, 89))	('rs2981582', 'DBSNP_MENTION', 'None', (80, 89))	('FGFR2', 'Gene', (74, 79))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
417532	31781300	in their cohort study in Swedish population confirmed the association between AA genotypes of FGFR2 rs2981582 and increased breast cancer risk.	('rs2981582', 'Var', (100, 109))	('FGFR2', 'Gene', (94, 99))	('increased', 'PosReg', (114, 123))	('rs2981582', 'DBSNP_MENTION', 'None', (100, 109))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('breast cancer', 'Phenotype', 'HP:0003002', (124, 137))	('breast cancer', 'Disease', (124, 137))
417533	31781300	in their study revealed that GA and AA genotypes of FGFR2 rs2981582 appear to be associated with lower mammographic density and reduced breast cancer risk.	('rs2981582', 'Var', (58, 67))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('FGFR2', 'Gene', (52, 57))	('rs2981582', 'DBSNP_MENTION', 'None', (58, 67))	('mammographic density', 'CPA', (103, 123))	('reduced', 'NegReg', (128, 135))	('breast cancer', 'Disease', (136, 149))	('breast cancer', 'Phenotype', 'HP:0003002', (136, 149))	('lower', 'NegReg', (97, 102))
417534	31781300	The current study also evaluates the importance of FGFR2 rs2981582 gene polymorphism in LSCC.	('FGFR2', 'Gene', (51, 56))	('rs2981582', 'Var', (57, 66))	('rs2981582', 'DBSNP_MENTION', 'None', (57, 66))	('LSCC', 'Disease', (88, 92))
417535	31781300	This analysis revealed that there was no statistically significant difference between FGFR2 rs2981582 gene polymorphism in LSCC and that in the control groups.	('LSCC', 'Disease', (123, 127))	('rs2981582', 'DBSNP_MENTION', 'None', (92, 101))	('FGFR2', 'Gene', (86, 91))	('rs2981582', 'Var', (92, 101))
417539	31781300	A literature search for information on STAT3 rs744166 polymorphism has yielded few studies on gastric, colon, and lung cancer.	('rs744166', 'Var', (45, 53))	('gastric', 'Disease', (94, 101))	('colon', 'Disease', (103, 108))	('rs744166', 'DBSNP_MENTION', 'None', (45, 53))	('STAT3', 'Gene', (39, 44))	('lung cancer', 'Disease', (114, 125))	('lung cancer', 'Phenotype', 'HP:0100526', (114, 125))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
417540	31781300	showed that rs744166 polymorphism of the STAT3 gene, along with environmental factors, might be associated with the development of gastric cancer.	('gastric cancer', 'Disease', 'MESH:D013274', (131, 145))	('STAT3', 'Gene', (41, 46))	('associated with', 'Reg', (96, 111))	('gastric cancer', 'Phenotype', 'HP:0012126', (131, 145))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('rs744166', 'Var', (12, 20))	('rs744166', 'DBSNP_MENTION', 'None', (12, 20))	('gastric cancer', 'Disease', (131, 145))
417541	31781300	provided the evidence that STAT3 rs744166 G allele is an independent risk factor for gastric cancer.	('gastric cancer', 'Disease', (85, 99))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('gastric cancer', 'Phenotype', 'HP:0012126', (85, 99))	('rs744166', 'DBSNP_MENTION', 'None', (33, 41))	('rs744166', 'Var', (33, 41))
417542	31781300	found that rs744166 in STAT3 was associated with a colon cancer risk, while Jiang et al.	('colon cancer', 'Disease', (51, 63))	('rs744166', 'Var', (11, 19))	('STAT3', 'Gene', (23, 28))	('rs744166', 'DBSNP_MENTION', 'None', (11, 19))	('colon cancer', 'Phenotype', 'HP:0003003', (51, 63))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('associated with', 'Reg', (33, 48))
417543	31781300	determined that carriers of STAT3 rs744166 have a significantly decreased risk of non-small-cell lung cancer.	('STAT3', 'Gene', (28, 33))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('rs744166', 'DBSNP_MENTION', 'None', (34, 42))	('rs744166', 'Var', (34, 42))	('non-small-cell lung cancer', 'Disease', (82, 108))	('lung cancer', 'Phenotype', 'HP:0100526', (97, 108))	('decreased', 'NegReg', (64, 73))
417544	31781300	In the study reported here, association between STAT3 rs744166 and LSCC risk was not determined.	('LSCC', 'Disease', (67, 71))	('rs744166', 'Var', (54, 62))	('rs744166', 'DBSNP_MENTION', 'None', (54, 62))
417545	31781300	Statistical analysis showed that genotypes (AA, AG, and GG) of rs744166 in STAT3 gene were not distributed significantly different between patients and controls (32.6%, 47.2%, and 20.1% vs. 35.4%, 45.4%, and 19.2%, respectively; p = 0.818).	('rs744166', 'Var', (63, 71))	('STAT3', 'Gene', (75, 80))	('rs744166', 'DBSNP_MENTION', 'None', (63, 71))
417548	31781300	Genetic variations in gene sequence have a potential to alter the function or of RAGE, leading to changes in its final bioavailability and, thus, the carcinogenesis.	('final bioavailability', 'MPA', (113, 134))	('carcinogenesis', 'Disease', 'MESH:D063646', (150, 164))	('changes', 'Reg', (98, 105))	('carcinogenesis', 'Disease', (150, 164))	('function', 'MPA', (66, 74))	('alter', 'Reg', (56, 61))	('Genetic variations', 'Var', (0, 18))
417549	31781300	It should be noted that the polymorphisms of RAGE, in particular the -429T/C (rs1800625) and 2184A/G (rs2070600) polymorphisms, were associated with the genesis and progression of lung cancer.	('2184A/G', 'Mutation', 'rs2070600', (93, 100))	('rs1800625', 'Var', (78, 87))	('rs2070600', 'Mutation', 'rs2070600', (102, 111))	('associated with', 'Reg', (133, 148))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('rs1800625', 'DBSNP_MENTION', 'None', (78, 87))	('-429T/C', 'Mutation', 'rs1800625', (69, 76))	('lung cancer', 'Disease', (180, 191))	('lung cancer', 'Phenotype', 'HP:0100526', (180, 191))	('rs2070600', 'Var', (102, 111))
417550	31781300	study showed that RAGE rs1800625 is associated with the risk and/or progression of oral squamous cell carcinoma.	('rs1800625', 'Var', (23, 32))	('rs1800625', 'DBSNP_MENTION', 'None', (23, 32))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (83, 111))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (88, 111))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('oral squamous cell carcinoma', 'Disease', (83, 111))	('associated', 'Reg', (36, 46))
417551	31781300	Moreover, a study revealed that the RAGE gene polymorphism rs1800625 not only conferred an increased risk of oral cancer but also was associated with late-stage and large-size tumors.	('associated', 'Reg', (134, 144))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('oral cancer', 'Disease', (109, 120))	('rs1800625', 'Var', (59, 68))	('tumors', 'Phenotype', 'HP:0002664', (176, 182))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('rs1800625', 'DBSNP_MENTION', 'None', (59, 68))
417552	31781300	This study also found that individuals who carry at least 1 polymorphic allele of rs1800625, smoke, and chew betel nuts are more susceptible to oral cancer.	('rs1800625', 'Var', (82, 91))	('oral cancer', 'Disease', (144, 155))	('rs1800625', 'DBSNP_MENTION', 'None', (82, 91))	('susceptible', 'Reg', (129, 140))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))
417553	31781300	Our study was the first to assess the association between RAGE rs1800625 and LSCC.	('rs1800625', 'Var', (63, 72))	('LSCC', 'Disease', (77, 81))	('rs1800625', 'DBSNP_MENTION', 'None', (63, 72))
417555	31781300	Moreover, RAGE rs1800625 analysis revealed that there were significant variables in the codominant (OR = 8.377; 95% CI: 2.880-24.368; p < 0.001), recessive (OR = 7.623; 95% CI: 2.643-21.989; p < 0.001) and additive (OR = 1.844; 95% CI: 1.301-2.613; p = 0.001) models of the patients with LSCC and the control group.	('rs1800625', 'DBSNP_MENTION', 'None', (15, 24))	('rs1800625', 'Var', (15, 24))	('LSCC', 'Disease', (288, 292))
417556	31781300	In conclusion, RAGE rs1800625 gene polymorphism might play a significant role in laryngeal squamous cell carcinoma development.	('laryngeal squamous cell carcinoma', 'Disease', (81, 114))	('play', 'Reg', (54, 58))	('rs1800625', 'Var', (20, 29))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (91, 114))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('rs1800625', 'DBSNP_MENTION', 'None', (20, 29))	('role', 'Reg', (73, 77))
417622	30643941	Fourteen epidermal growth factor receptor (EGFR)-mutant LSCC patients treated with first-line EGFR-tyrosine kinase inhibitor (TKI) therapy were enrolled for validation dataset.	('epidermal growth factor receptor', 'Gene', '1956', (9, 41))	('EGFR', 'Gene', '1956', (94, 98))	('patients', 'Species', '9606', (61, 69))	('EGFR', 'Gene', (94, 98))	('EGFR', 'Gene', '1956', (43, 47))	('LSCC', 'Disease', (56, 60))	('-mutant', 'Var', (48, 55))	('epidermal growth factor receptor', 'Gene', (9, 41))	('EGFR', 'Gene', (43, 47))	('LSCC', 'Phenotype', 'HP:0030359', (56, 60))
417650	30643941	The effectiveness of PIM was validated by a cohort of stage III-IV epidermal growth factor receptor (EGFR)-mutant LSCC patients who only received first-line EGFR-tyrosine kinase inhibitor (TKI) therapy.	('epidermal growth factor receptor', 'Gene', '1956', (67, 99))	('EGFR', 'Gene', (157, 161))	('LSCC', 'Phenotype', 'HP:0030359', (114, 118))	('-mutant', 'Var', (106, 113))	('EGFR', 'Gene', '1956', (101, 105))	('EGFR', 'Gene', (101, 105))	('patients', 'Species', '9606', (119, 127))	('epidermal growth factor receptor', 'Gene', (67, 99))	('EGFR', 'Gene', '1956', (157, 161))	('LSCC', 'Disease', (114, 118))
417653	30643941	Finally, 96 stage III-IV LSCC patients received first-line chemotherapy, and 14 stage III-IV LSCC patients with confirmed EGFR-positive mutation who received first-line EGFR-TKI were eligible in this study.	('mutation', 'Var', (136, 144))	('EGFR', 'Gene', '1956', (169, 173))	('patients', 'Species', '9606', (98, 106))	('LSCC', 'Phenotype', 'HP:0030359', (25, 29))	('patients', 'Species', '9606', (30, 38))	('EGFR', 'Gene', (169, 173))	('LSCC', 'Phenotype', 'HP:0030359', (93, 97))	('EGFR', 'Gene', '1956', (122, 126))	('EGFR', 'Gene', (122, 126))
417689	30643941	In patients with a score lower than the cut-off value, his/her TTP benefit tended to be better (median TTP = 6.7 months), and these patients had higher scores indicating faster progression (median TTP = 3.2 months) in this study (HR = 2.45, 95% CI = 1.44-4.23, p < 0.0001), as presented in Fig.	('lower', 'NegReg', (25, 30))	('score', 'Var', (19, 24))	('patients', 'Species', '9606', (3, 11))	('faster', 'PosReg', (170, 176))	('better', 'PosReg', (88, 94))	('patients', 'Species', '9606', (132, 140))	('TTP', 'MPA', (63, 66))
417717	30643941	As the observed incidence of EGFR mutations was only 2.7% in patients with LSCC, EGFR mutations were not applicable to routine testing of all LSCC tumor specimens.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('LSCC', 'Disease', (75, 79))	('LSCC', 'Phenotype', 'HP:0030359', (75, 79))	('LSCC', 'Phenotype', 'HP:0030359', (142, 146))	('patients', 'Species', '9606', (61, 69))	('EGFR', 'Gene', '1956', (81, 85))	('EGFR', 'Gene', '1956', (29, 33))	('EGFR', 'Gene', (29, 33))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('mutations', 'Var', (34, 43))	('EGFR', 'Gene', (81, 85))
417729	30643941	Thus, we suspected that the abnormality in AST in patients with stage III-IV LSCC potentially indicated liver metastasis.	('AST', 'Gene', '26503', (43, 46))	('patients', 'Species', '9606', (50, 58))	('LSCC', 'Phenotype', 'HP:0030359', (77, 81))	('liver metastasis', 'Disease', 'MESH:D009362', (104, 120))	('liver metastasis', 'Disease', (104, 120))	('abnormality', 'Var', (28, 39))	('AST', 'Gene', (43, 46))	('indicated', 'Reg', (94, 103))
417736	30643941	Since the low incidence of the stage IIII-IV LSCC patients (only 20~30% in NSCLC) and the natural characteristics of EGFR mutation in this kind of population (only 2.7% in LSCC), the small number of patients in the validation dataset is another limitation.	('patients', 'Species', '9606', (50, 58))	('NSCLC', 'Phenotype', 'HP:0030358', (75, 80))	('EGFR', 'Gene', '1956', (117, 121))	('mutation', 'Var', (122, 130))	('EGFR', 'Gene', (117, 121))	('LSCC', 'Phenotype', 'HP:0030359', (45, 49))	('NSCLC', 'Disease', (75, 80))	('patients', 'Species', '9606', (199, 207))	('LSCC', 'Phenotype', 'HP:0030359', (172, 176))	('NSCLC', 'Disease', 'MESH:D002289', (75, 80))
417745	33450833	Several different somatic genetic and epigenetic processes contribute to the development of cancer, including copy number alterations, deletions, rearrangements or translocations of certain genes, somatic point mutations, and hypermethylation of promoters.	('point mutations', 'Var', (205, 220))	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('copy number alterations', 'Var', (110, 133))	('rearrangements', 'Var', (146, 160))	('translocations', 'Var', (164, 178))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('contribute', 'Reg', (59, 69))	('deletions', 'Var', (135, 144))	('hypermethylation', 'Var', (226, 242))
417747	33450833	In general, there are two types of LOH, (1) LOH with copy number losses (CNL-LOH), with a typical example of being losing the wildtype allele of a tumor suppressor, and (2) copy number neutral LOH (CNN-LOH), exemplified by the presence of two mutant alleles of WT1 (11p), FLT3 (13q), CEBPA (19q) and RUNX1 (21q) which resulted in a growth advantage in tumors, such as in leukemia.	('RUNX1', 'Gene', (300, 305))	('RUNX1', 'Gene', '861', (300, 305))	('growth', 'MPA', (332, 338))	('tumors', 'Disease', 'MESH:D009369', (352, 358))	('19q', 'Var', (291, 294))	('leukemia', 'Phenotype', 'HP:0001909', (371, 379))	('tumor', 'Disease', (147, 152))	('tumor', 'Disease', (352, 357))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('leukemia', 'Disease', 'MESH:D007938', (371, 379))	('losses', 'NegReg', (65, 71))	('copy number', 'Var', (53, 64))	('tumor', 'Disease', 'MESH:D009369', (352, 357))	('FLT3', 'Gene', (272, 276))	('leukemia', 'Disease', (371, 379))	('CEBPA', 'Gene', '1050', (284, 289))	('WT1', 'Gene', (261, 264))	('tumors', 'Phenotype', 'HP:0002664', (352, 358))	('FLT3', 'Gene', '2322', (272, 276))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('CEBPA', 'Gene', (284, 289))	('WT1', 'Gene', '7490', (261, 264))	('tumor', 'Phenotype', 'HP:0002664', (352, 357))	('tumors', 'Disease', (352, 358))
417748	33450833	A complete or partial deletion of a chromosome leads to CNL-LOH, while CNN-LOH is mainly caused by acquired uniparental disomy (UPD) and gene conversion, and occurs without net change in the copy number (Figure 1).	('caused', 'Reg', (89, 95))	('leads to', 'Reg', (47, 55))	('partial deletion', 'Var', (14, 30))	('uniparental disomy', 'Disease', (108, 126))	('CNL-LOH', 'Disease', (56, 63))	('uniparental disomy', 'Disease', 'MESH:D024182', (108, 126))
417749	33450833	This review will primarily focus on LOH with copy number loss (CNL-LOH), as it is a common phenomenon in cancer and more thoroughly investigated in comparison to copy number neutral LOH.	('copy number loss', 'Var', (45, 61))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))
417751	33450833	Thus, LOH decreases the level of heterozygosity in cancer cells and creates significantly distinct genetic characters between tumor and normal cells.	('decreases', 'NegReg', (10, 19))	('LOH', 'Var', (6, 9))	('level', 'MPA', (24, 29))	('creates', 'Reg', (68, 75))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('cancer', 'Disease', (51, 57))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('distinct', 'Reg', (90, 98))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('tumor', 'Disease', (126, 131))
417754	33450833	Following this finding, numerous candidate tumor suppressors were discovered by characterizing sites of prevalent LOH in human cancers.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('human', 'Species', '9606', (121, 126))	('cancers', 'Disease', 'MESH:D009369', (127, 134))	('cancers', 'Phenotype', 'HP:0002664', (127, 134))	('LOH', 'Var', (114, 117))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('cancers', 'Disease', (127, 134))	('tumor', 'Disease', (43, 48))
417755	33450833	For example, as a consequence of LOH, the tumor suppressor gene TP53 is inactivated, contributing to the development of many cancer types such as breast, lung and stomach as well as chronic lymphocytic leukemia.	('LOH', 'Var', (33, 36))	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (182, 210))	('tumor', 'Disease', (42, 47))	('lung', 'Disease', (154, 158))	('contributing to', 'Reg', (85, 100))	('stomach', 'Disease', (163, 170))	('leukemia', 'Phenotype', 'HP:0001909', (202, 210))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('lymphocytic leukemia', 'Disease', (190, 210))	('breast', 'Disease', (146, 152))	('TP53', 'Gene', '7157', (64, 68))	('lymphocytic leukemia', 'Disease', 'MESH:D007945', (190, 210))	('TP53', 'Gene', (64, 68))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
417757	33450833	Further, there are inherited cancer predisposition syndromes which have germline mutations in tumor suppressor genes under LOH, such as BRCA1 at 17q21.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('cancer', 'Disease', (29, 35))	('BRCA1', 'Gene', (136, 141))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('tumor', 'Disease', (94, 99))	('cancer', 'Disease', 'MESH:D009369', (29, 35))	('germline mutations', 'Var', (72, 90))	('BRCA1', 'Gene', '672', (136, 141))
417758	33450833	Women carrying germline LOH at BRCA1 have an 85% lifetime risk of developing breast cancer and a greatly elevated risk of ovarian cancer.	('breast cancer', 'Disease', (77, 90))	('Women', 'Species', '9606', (0, 5))	('breast cancer', 'Phenotype', 'HP:0003002', (77, 90))	('ovarian cancer', 'Disease', 'MESH:D010051', (122, 136))	('BRCA1', 'Gene', '672', (31, 36))	('germline LOH at', 'Var', (15, 30))	('ovarian cancer', 'Disease', (122, 136))	('BRCA1', 'Gene', (31, 36))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('breast cancer', 'Disease', 'MESH:D001943', (77, 90))	('ovarian cancer', 'Phenotype', 'HP:0100615', (122, 136))
417768	33450833	Together, these and other studies demonstrate that LOH in cancer genomes is not only affecting tumor suppressor genes but also numerous non-driver genes.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('affecting', 'Reg', (85, 94))	('LOH', 'Var', (51, 54))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('cancer', 'Disease', (58, 64))	('tumor', 'Disease', (95, 100))
417769	33450833	When one allele of an essential non-driver gene undergoes LOH in cancer cells, cancer cells should not be able to survive if the remaining allele is further lost or inhibited, whereas normal cells will be able to survive relying solely on the remaining allele, leading to an unique vulnerability in cancer cells.	('lost', 'NegReg', (157, 161))	('LOH', 'Var', (58, 61))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('cancer', 'Disease', (65, 71))	('inhibited', 'NegReg', (165, 174))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('cancer', 'Phenotype', 'HP:0002664', (299, 305))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('cancer', 'Disease', (299, 305))	('cancer', 'Disease', 'MESH:D009369', (299, 305))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (65, 71))
417773	33450833	Oct1 promotes glycolytic metabolism and mitotic stability and plays important roles in stress responses, and loss of one or both Oct1 alleles has been associated with an upregulation of oxidative metabolism and increased levels of reactive oxygen species (ROS), thus inducing a coordinate metabolic shift and hypersensitive to oxidative stress.	('hypersensitive', 'Disease', (309, 323))	('metabolic shift', 'MPA', (289, 304))	('loss', 'Var', (109, 113))	('promotes', 'PosReg', (5, 13))	('oxidative metabolism', 'MPA', (186, 206))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (231, 254))	('increased', 'PosReg', (211, 220))	('glycolytic metabolism', 'MPA', (14, 35))	('hypersensitive', 'Disease', 'MESH:D004342', (309, 323))	('increased levels of reactive oxygen species', 'Phenotype', 'HP:0025464', (211, 254))	('Oct1', 'Gene', (129, 133))	('Oct1', 'Gene', '5451', (129, 133))	('upregulation', 'PosReg', (170, 182))	('inducing', 'PosReg', (267, 275))	('mitotic stability', 'CPA', (40, 57))	('oxidative stress', 'Phenotype', 'HP:0025464', (327, 343))	('ROS', 'Chemical', 'MESH:D017382', (256, 259))	('levels of reactive oxygen species', 'MPA', (221, 254))	('Oct1', 'Gene', (0, 4))	('Oct1', 'Gene', '5451', (0, 4))
417777	33450833	Clinical investigations have revealed that LOH of non-driver genes could engender unique vulnerabilities in rare cancer types.	('cancer', 'Disease', (113, 119))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('LOH', 'Var', (43, 46))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
417778	33450833	Pheochromocytomas and paragangliomas are rare neuroendocrine tumors, and ~40% of tumors arise in patients with germline LOH of the succinate dehydrogenase (SDHx) genes.	('SDHx', 'Gene', (156, 160))	('tumors', 'Disease', (81, 87))	('glioma', 'Phenotype', 'HP:0009733', (29, 35))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('neuroendocrine tumors', 'Disease', (46, 67))	('Pheochromocytomas', 'Disease', 'MESH:D010673', (0, 17))	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('LOH', 'Var', (120, 123))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('paragangliomas', 'Disease', 'MESH:D010235', (22, 36))	('paragangliomas', 'Phenotype', 'HP:0002668', (22, 36))	('tumors', 'Disease', (61, 67))	('arise', 'Reg', (88, 93))	('Pheochromocytomas', 'Disease', (0, 17))	('neuroendocrine tumors', 'Disease', 'MESH:D018358', (46, 67))	('Pheochromocytomas', 'Phenotype', 'HP:0002666', (0, 17))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('patients', 'Species', '9606', (97, 105))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (46, 67))	('paragangliomas', 'Disease', (22, 36))
417780	33450833	Taken together, loss of non-driver genes by LOH can cause unique vulnerabilities in cancer cells and thereby provide a novel class of therapeutic targets for cancer drug discovery and personalized medicine.	('LOH', 'Var', (44, 47))	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('cancer', 'Disease', (84, 90))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('vulnerabilities', 'MPA', (65, 80))	('loss', 'NegReg', (16, 20))	('cancer', 'Disease', (158, 164))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
417782	33450833	Targets include oncogenes which are activated by mutation, tumor suppressor genes which are inactivated by mutation, or perturbed cell signaling in the maintenance of genome integrity or regular cellular metabolism.	('tumor', 'Disease', (59, 64))	('oncogenes', 'Gene', (16, 25))	('activated', 'PosReg', (36, 45))	('mutation', 'Var', (49, 57))	('perturbed', 'Reg', (120, 129))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('mutation', 'Var', (107, 115))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
417785	33450833	Among the 393 amino acids of P53, sequences at positions 5-28 have p53 transcription activity and pathogenic mutations are enriched at R248Q, R273H, and R282W which affect DNA binding, or in R175H, Y220C, G245S, and R249S which are called conformational mutations.	('DNA binding', 'Interaction', (172, 183))	('R273H', 'Var', (142, 147))	('R282W', 'Var', (153, 158))	('R249S', 'Mutation', 'rs28934571', (216, 221))	('affect', 'Reg', (165, 171))	('Y220C', 'Var', (198, 203))	('R282W', 'Mutation', 'rs28934574', (153, 158))	('R249S', 'Var', (216, 221))	('R248Q', 'Mutation', 'rs11540652', (135, 140))	('P53', 'Gene', (29, 32))	('G245S', 'Mutation', 'rs28934575', (205, 210))	('transcription activity', 'MPA', (71, 93))	('p53', 'Gene', '7157', (67, 70))	('R248Q', 'Var', (135, 140))	('G245S', 'Var', (205, 210))	('Y220C', 'Mutation', 'rs121912666', (198, 203))	('R273H', 'Mutation', 'rs28934576', (142, 147))	('P53', 'Gene', '7157', (29, 32))	('p53', 'Gene', (67, 70))	('R175H', 'Mutation', 'rs28934578', (191, 196))	('R175H', 'Var', (191, 196))
417787	33450833	Nevertheless, there is still no drug targeting p53 available in the clinic, mainly due to the lack of a good binding site to serve as a direct target in the mutant p53 structure.	('mutant', 'Var', (157, 163))	('p53', 'Gene', (164, 167))	('p53', 'Gene', (47, 50))	('binding', 'Interaction', (109, 116))	('p53', 'Gene', '7157', (47, 50))	('p53', 'Gene', '7157', (164, 167))
417789	33450833	Currently, several MYC inhibitors have been identified from phenotypic screens, including 10058-F4, atorvastatin and the recently discovered Omomyc, however, all of them still have a long way to go from bench to clinic.	('10058-F4', 'Var', (90, 98))	('MYC', 'Gene', (19, 22))	('atorvastatin', 'Chemical', 'MESH:D000069059', (100, 112))	('MYC', 'Gene', '4609', (19, 22))
417792	33450833	RPA70 undergoes LOH in 44% of colon cancers, 58% of ovarian cancers, 20% of breast cancers, and 27% of non-small cell lung carcinomas.	('colon cancers', 'Disease', 'MESH:D015179', (30, 43))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('breast cancers', 'Disease', 'MESH:D001943', (76, 90))	('breast cancers', 'Disease', (76, 90))	('colon cancers', 'Disease', (30, 43))	('ovarian cancers', 'Phenotype', 'HP:0100615', (52, 67))	('LOH', 'Var', (16, 19))	('RPA70', 'Gene', '6117', (0, 5))	('ovarian cancer', 'Phenotype', 'HP:0100615', (52, 66))	('breast cancers', 'Phenotype', 'HP:0003002', (76, 90))	('breast cancer', 'Phenotype', 'HP:0003002', (76, 89))	('lung carcinomas', 'Disease', 'MESH:D008175', (118, 133))	('lung carcinomas', 'Disease', (118, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('RPA70', 'Gene', (0, 5))	('colon cancers', 'Phenotype', 'HP:0003003', (30, 43))	('small cell lung carcinomas', 'Phenotype', 'HP:0030357', (107, 133))	('ovarian cancers', 'Disease', (52, 67))	('ovarian cancers', 'Disease', 'MESH:D010051', (52, 67))	('cancers', 'Phenotype', 'HP:0002664', (60, 67))	('cancers', 'Phenotype', 'HP:0002664', (36, 43))	('non-small cell lung carcinomas', 'Phenotype', 'HP:0030358', (103, 133))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('cancers', 'Phenotype', 'HP:0002664', (83, 90))	('carcinomas', 'Phenotype', 'HP:0030731', (123, 133))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
417793	33450833	The oligonucleotide ISIS 1278 targeting segments of RPA70 mRNA containing variants effectively inhibited survival of cells expressing only the RPA70 mRNA with the exact complementary sequence, but was less effective in cells expressing the mismatched target, suggesting that developing anticancer agents based on normal genetic variation under LOH in essential genes is a feasible strategy for anticancer therapy.	('RPA70', 'Gene', (143, 148))	('RPA70', 'Gene', (52, 57))	('RPA70', 'Gene', '6117', (52, 57))	('cancer', 'Disease', 'MESH:D009369', (290, 296))	('oligonucleotide', 'Chemical', 'MESH:D009841', (4, 19))	('cancer', 'Phenotype', 'HP:0002664', (398, 404))	('variants', 'Var', (74, 82))	('inhibited', 'NegReg', (95, 104))	('cancer', 'Disease', (290, 296))	('cancer', 'Disease', (398, 404))	('cancer', 'Disease', 'MESH:D009369', (398, 404))	('cancer', 'Phenotype', 'HP:0002664', (290, 296))	('survival', 'CPA', (105, 113))	('RPA70', 'Gene', '6117', (143, 148))
417794	33450833	Recently, the Beroukhim group have identified 5664 variants in 1278 essential genes that undergo LOH in cancer and pointed out that allele-specific inactivation of either of two essential genes (PRIM1 and EXOSC8), which have been rigorously validated as genetic dependencies in cancer, is lethal in cancer cells.	('EXOSC8', 'Gene', '11340', (205, 211))	('cancer', 'Phenotype', 'HP:0002664', (278, 284))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (299, 305))	('variants', 'Var', (51, 59))	('cancer', 'Phenotype', 'HP:0002664', (299, 305))	('PRIM1', 'Gene', (195, 200))	('cancer', 'Disease', 'MESH:D009369', (278, 284))	('EXOSC8', 'Gene', (205, 211))	('inactivation', 'Var', (148, 160))	('cancer', 'Disease', (299, 305))	('genetic dependencies', 'Disease', (254, 274))	('cancer', 'Disease', (278, 284))	('PRIM1', 'Gene', '5557', (195, 200))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('genetic dependencies', 'Disease', 'MESH:D030342', (254, 274))
417795	33450833	PRIM1 encodes the catalytic subunit of DNA primase and contains two common SNPs, of which one (rs2277339) undergoes frequent LOH across 33 different cancer types, occurring in 21% of lung adenocarcinomas, 18% of ovarian cancers, and 17% of pancreatic cancers.	('carcinoma', 'Phenotype', 'HP:0030731', (193, 202))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (183, 203))	('PRIM1', 'Gene', '5557', (0, 5))	('cancer', 'Disease', 'MESH:D009369', (220, 226))	('cancer', 'Disease', 'MESH:D009369', (251, 257))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (240, 257))	('carcinomas', 'Phenotype', 'HP:0030731', (193, 203))	('ovarian cancer', 'Phenotype', 'HP:0100615', (212, 226))	('lung adenocarcinomas', 'Disease', (183, 203))	('rs2277339', 'Var', (95, 104))	('ovarian cancers', 'Disease', (212, 227))	('rs2277339', 'Mutation', 'rs2277339', (95, 104))	('ovarian cancers', 'Disease', 'MESH:D010051', (212, 227))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (240, 258))	('cancer', 'Disease', (149, 155))	('cancers', 'Phenotype', 'HP:0002664', (251, 258))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('cancers', 'Phenotype', 'HP:0002664', (220, 227))	('pancreatic cancers', 'Disease', (240, 258))	('cancer', 'Disease', (220, 226))	('cancer', 'Disease', (251, 257))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (183, 203))	('ovarian cancers', 'Phenotype', 'HP:0100615', (212, 227))	('pancreatic cancers', 'Disease', 'MESH:D010190', (240, 258))	('PRIM1', 'Gene', (0, 5))	('cancer', 'Disease', 'MESH:D009369', (149, 155))	('occurring', 'Reg', (163, 172))
417797	33450833	The position of rs117135638 in EXOSC8 undergoes LOH in 29% of cancers, including 72% of lung squamous cell carcinomas, 62% of ovarian cancers, 46% of lung adenocarcinomas, and 40% of breast cancers.	('ovarian cancer', 'Phenotype', 'HP:0100615', (126, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (160, 169))	('cancers', 'Disease', 'MESH:D009369', (190, 197))	('lung squamous cell carcinomas', 'Disease', (88, 117))	('EXOSC8', 'Gene', '11340', (31, 37))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (150, 170))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (88, 116))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (93, 117))	('cancers', 'Phenotype', 'HP:0002664', (134, 141))	('lung adenocarcinomas', 'Disease', (150, 170))	('cancers', 'Disease', (134, 141))	('ovarian cancers', 'Disease', (126, 141))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('cancers', 'Phenotype', 'HP:0002664', (62, 69))	('carcinomas', 'Phenotype', 'HP:0030731', (160, 170))	('ovarian cancers', 'Disease', 'MESH:D010051', (126, 141))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('cancers', 'Disease', (62, 69))	('cancers', 'Phenotype', 'HP:0002664', (190, 197))	('EXOSC8', 'Gene', (31, 37))	('cancers', 'Disease', (190, 197))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (93, 116))	('breast cancers', 'Disease', 'MESH:D001943', (183, 197))	('rs117135638', 'Var', (16, 27))	('breast cancers', 'Disease', (183, 197))	('lung squamous cell carcinomas', 'Disease', 'MESH:D002294', (88, 117))	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('carcinomas', 'Phenotype', 'HP:0030731', (107, 117))	('cancers', 'Disease', 'MESH:D009369', (134, 141))	('ovarian cancers', 'Phenotype', 'HP:0100615', (126, 141))	('breast cancers', 'Phenotype', 'HP:0003002', (183, 197))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (150, 170))	('cancers', 'Disease', 'MESH:D009369', (62, 69))	('rs117135638', 'Mutation', 'rs117135638', (16, 27))	('breast cancer', 'Phenotype', 'HP:0003002', (183, 196))
417798	33450833	Allele-specific disruption using sgRNA targeting rs2277339 in PRIM1 and rs117135638 in EXOSC8 strongly reduces the growth in cells containing targeted LOH allele of rs2277339 or rs117135638, while cells harboring the non-targeted allele remain intact.	('PRIM1', 'Gene', '5557', (62, 67))	('rs2277339', 'Mutation', 'rs2277339', (49, 58))	('rs117135638', 'Var', (178, 189))	('PRIM1', 'Gene', (62, 67))	('rs117135638', 'Var', (72, 83))	('rs117135638', 'Mutation', 'rs117135638', (178, 189))	('reduces', 'NegReg', (103, 110))	('rs2277339', 'Var', (165, 174))	('EXOSC8', 'Gene', (87, 93))	('rs117135638', 'Mutation', 'rs117135638', (72, 83))	('rs2277339', 'Mutation', 'rs2277339', (165, 174))	('EXOSC8', 'Gene', '11340', (87, 93))	('growth', 'MPA', (115, 121))	('rs2277339', 'Var', (49, 58))
417799	33450833	Although there were no followed drug screens by targeting the products of the two essential genes, the authors discussed the possibility of developing allele-specific small molecule inhibitors using the canSAR protein annotation tool which provides a prioritization of targets based on general drugability, suggesting that cancer vulnerabilities generating from LOH represent viable targets for novel anticancer drug development.	('cancer', 'Disease', 'MESH:D009369', (323, 329))	('cancer', 'Disease', (323, 329))	('cancer', 'Disease', 'MESH:D009369', (405, 411))	('cancer', 'Disease', (405, 411))	('cancer', 'Phenotype', 'HP:0002664', (323, 329))	('LOH', 'Var', (362, 365))	('cancer', 'Phenotype', 'HP:0002664', (405, 411))
417802	33450833	It is worth noting that, the following proof of concept experiments suggested that NAT2 harboring mutant allele (NAT2*6A, rs1799930) has a 10-fold reduced activity comparing with the wild type allele (NAT2*13A).	('activity', 'MPA', (155, 163))	('NAT2', 'Gene', '10', (83, 87))	('NAT2', 'Gene', (113, 117))	('NAT2', 'Gene', (83, 87))	('NAT2', 'Gene', '10', (201, 205))	('rs1799930', 'Mutation', 'rs1799930', (122, 131))	('NAT2', 'Gene', '10', (113, 117))	('rs1799930', 'Var', (122, 131))	('reduced', 'NegReg', (147, 154))	('NAT2', 'Gene', (201, 205))
417803	33450833	From a total of 189,018 compounds, we identified 6-(4-aminophenyl)-N-(3,4,5-trimethoxyphenyl) pyrazin-2-amine (APA) which preferentially kills cells expressing slow NAT2 (NAT2*6A, rs1799930).	('NAT2', 'Gene', '10', (165, 169))	('rs1799930', 'Mutation', 'rs1799930', (180, 189))	('rs1799930', 'Var', (180, 189))	('NAT2', 'Gene', (165, 169))	('NAT2', 'Gene', (171, 175))	('APA', 'Chemical', '-', (111, 114))	('preferentially', 'PosReg', (122, 136))	('NAT2', 'Gene', '10', (171, 175))	('6-(4-aminophenyl)-N-(3,4,5-trimethoxyphenyl) pyrazin-2-amine', 'Chemical', '-', (49, 109))
417806	33450833	Loss of heterozygosity is a common genetic event in the development of many cancer types and occurs in every step of tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('Loss of heterozygosity', 'Var', (0, 22))	('tumor', 'Disease', (117, 122))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('cancer', 'Disease', (76, 82))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
417807	33450833	At the same time, several studies have demonstrated that LOH at a specific gene locus could be used as biomarkers of cancer risk or the prediction of clinical outcomes in certain types of tumors.	('LOH', 'Var', (57, 60))	('tumors', 'Disease', (188, 194))	('tumors', 'Disease', 'MESH:D009369', (188, 194))	('tumors', 'Phenotype', 'HP:0002664', (188, 194))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('cancer', 'Disease', (117, 123))
417809	33450833	In primary neuroblastoma, loss of heterozygosity on 1p36 has been reported in 23-35% of patients, and was shown to be significantly associated with prognostic markers of aggressive neuroblastoma when patients are diagnosed.	('neuroblastoma', 'Phenotype', 'HP:0003006', (181, 194))	('loss of heterozygosity', 'Var', (26, 48))	('patients', 'Species', '9606', (200, 208))	('neuroblastoma', 'Phenotype', 'HP:0003006', (11, 24))	('aggressive neuroblastoma', 'Disease', (170, 194))	('patients', 'Species', '9606', (88, 96))	('neuroblastoma', 'Disease', 'MESH:D009447', (181, 194))	('aggressive neuroblastoma', 'Disease', 'MESH:D009447', (170, 194))	('neuroblastoma', 'Disease', 'MESH:D009447', (11, 24))	('neuroblastoma', 'Disease', (181, 194))	('1p36', 'Protein', (52, 56))	('neuroblastoma', 'Disease', (11, 24))
417810	33450833	The underlying driver gene mutation is unknown, but may involve one or more neuroblastoma tumor suppressor genes and loss of 1p36 could promote tumor growth and favor the effects from the MYCN oncogene.	('tumor', 'Disease', (144, 149))	('promote', 'PosReg', (136, 143))	('effects', 'MPA', (171, 178))	('neuroblastoma', 'Phenotype', 'HP:0003006', (76, 89))	('loss', 'Var', (117, 121))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('neuroblastoma tumor', 'Disease', (76, 95))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('neuroblastoma tumor', 'Disease', 'MESH:D009447', (76, 95))	('1p36', 'Gene', (125, 129))	('favor', 'PosReg', (161, 166))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('MYCN', 'Gene', (188, 192))	('MYCN', 'Gene', '4613', (188, 192))
417811	33450833	FRA3B locating on chromosome 3p14.2, is one of the most active common fragile sites in the human genome and has been reported to incur deletions or translocation breakpoints in many types of cancers including lung cancers.	('FRA3B', 'Gene', '2272', (0, 5))	('lung cancer', 'Phenotype', 'HP:0100526', (209, 220))	('cancers', 'Disease', 'MESH:D009369', (214, 221))	('translocation', 'Var', (148, 161))	('incur', 'Reg', (129, 134))	('lung cancers', 'Disease', 'MESH:D008175', (209, 221))	('lung cancers', 'Disease', (209, 221))	('cancers', 'Phenotype', 'HP:0002664', (191, 198))	('fragile', 'Disease', 'MESH:D005600', (70, 77))	('cancers', 'Disease', (191, 198))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('lung cancers', 'Phenotype', 'HP:0100526', (209, 221))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('cancers', 'Phenotype', 'HP:0002664', (214, 221))	('fragile', 'Disease', (70, 77))	('cancers', 'Disease', (214, 221))	('FRA3B', 'Gene', (0, 5))	('deletions', 'Var', (135, 144))	('cancers', 'Disease', 'MESH:D009369', (191, 198))	('human', 'Species', '9606', (91, 96))
417815	33450833	There are two commonly SNP sites undergoing LOH (rs589281, rs6797113) at 3p21 which have been reported to associate with poor clinical outcome in esophageal cancer.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('rs589281', 'Var', (49, 57))	('rs6797113', 'Mutation', 'rs6797113', (59, 68))	('esophageal cancer', 'Disease', (146, 163))	('esophageal cancer', 'Disease', 'MESH:D004938', (146, 163))	('rs589281', 'Mutation', 'rs589281', (49, 57))	('rs6797113', 'Var', (59, 68))
417817	33450833	LOH at two loci (rs1642742 and rs1642743) of VHL gene results in a loss of VHL protein function, has been proposed as a candidate predictive biomarker for clinical outcome in clear-cell renal-cell carcinoma (ccRCC) patients.	('VHL', 'Gene', '7428', (45, 48))	('patients', 'Species', '9606', (215, 223))	('VHL', 'Gene', (75, 78))	('clear-cell renal-cell carcinoma', 'Disease', 'MESH:C538614', (175, 206))	('VHL', 'Gene', '7428', (75, 78))	('rs1642743', 'Var', (31, 40))	('carcinoma', 'Phenotype', 'HP:0030731', (197, 206))	('clear-cell renal-cell carcinoma', 'Phenotype', 'HP:0006770', (175, 206))	('loss', 'NegReg', (67, 71))	('rs1642742', 'Var', (17, 26))	('function', 'MPA', (87, 95))	('rs1642742', 'Mutation', 'rs1642742', (17, 26))	('rs1642743', 'Mutation', 'rs1642743', (31, 40))	('VHL', 'Gene', (45, 48))	('renal-cell carcinoma', 'Phenotype', 'HP:0005584', (186, 206))	('clear-cell renal-cell carcinoma', 'Disease', (175, 206))
417819	33450833	Similarly, LOH at HLA-A02 has been proposed as a predictive biomarker for synovial sarcoma and is prognostic of poor outcome.	('synovial sarcoma', 'Disease', (74, 90))	('LOH at HLA-A02', 'Var', (11, 25))	('sarcoma', 'Phenotype', 'HP:0100242', (83, 90))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (74, 90))	('synovial sarcoma', 'Disease', 'MESH:D013584', (74, 90))
417825	33450833	However, more than 30% of tumors that responded to CTL019 therapy eventually recurred which was found to be caused by frameshift mutations leading to a truncated protein with a nonfunctional or absent transmembrane domain and consequently to a loss of surface antigen.	('surface antigen', 'MPA', (252, 267))	('truncated protein', 'MPA', (152, 169))	('frameshift mutations', 'Var', (118, 138))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('absent', 'NegReg', (194, 200))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('nonfunctional', 'MPA', (177, 190))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('loss', 'NegReg', (244, 248))	('tumors', 'Disease', (26, 32))
417828	33450833	These TP53 gene exons are also mutational hotspots in cancer and >80% of TP53 mutations occur within this region.	('TP53', 'Gene', '7157', (73, 77))	('TP53', 'Gene', '7157', (6, 10))	('TP53', 'Gene', (6, 10))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('TP53', 'Gene', (73, 77))	('cancer', 'Disease', (54, 60))	('mutations', 'Var', (78, 87))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
417830	33450833	Further, LOH at 17p13.1 is one of the most frequent genetic alterations leading to human cancers.	('LOH at 17p13.1', 'Var', (9, 23))	('cancers', 'Phenotype', 'HP:0002664', (89, 96))	('human', 'Species', '9606', (83, 88))	('cancers', 'Disease', 'MESH:D009369', (89, 96))	('cancers', 'Disease', (89, 96))	('leading', 'Reg', (72, 79))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
417831	33450833	Analysis of TP53 mutations from 1,420 tumor samples revealed that loss of one TP53 allele may be a sufficient driver in breast cancers of the luminal B subtype as a higher fraction of wild-type tumors with LOH is noticed.	('tumor', 'Disease', (194, 199))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('cancers', 'Phenotype', 'HP:0002664', (127, 134))	('tumors', 'Phenotype', 'HP:0002664', (194, 200))	('TP53', 'Gene', '7157', (78, 82))	('TP53', 'Gene', (12, 16))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('breast cancers', 'Disease', 'MESH:D001943', (120, 134))	('breast cancers', 'Disease', (120, 134))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('breast cancers', 'Phenotype', 'HP:0003002', (120, 134))	('tumors', 'Disease', (194, 200))	('tumor', 'Disease', (38, 43))	('loss', 'Var', (66, 70))	('breast cancer', 'Phenotype', 'HP:0003002', (120, 133))	('luminal', 'Chemical', 'MESH:D010634', (142, 149))	('TP53', 'Gene', '7157', (12, 16))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('TP53', 'Gene', (78, 82))	('tumors', 'Disease', 'MESH:D009369', (194, 200))
417832	33450833	Codon 72 of the TP53 gene contains a well-known polymorphic site with the two alleles arginine and proline (Arg72Pro).	('Arg72Pro', 'Var', (108, 116))	('proline', 'Chemical', 'MESH:D011392', (99, 106))	('TP53', 'Gene', '7157', (16, 20))	('Arg72Pro', 'Mutation', 'rs1042522', (108, 116))	('arginine', 'Chemical', 'MESH:D001120', (86, 94))	('TP53', 'Gene', (16, 20))
417833	33450833	Analysis of TP53 mutations from 204 Danish women and revealed that heterozygous patients losing either the Arg72 or Pro72 variant in the TP53 gene because of LOH had a reduction in disease-free survival compared with patients retaining the polymorphism (Arg72Pro).	('Arg72', 'Chemical', '-', (254, 259))	('Arg72', 'Chemical', '-', (107, 112))	('patients', 'Species', '9606', (80, 88))	('Arg72', 'Var', (107, 112))	('patients', 'Species', '9606', (217, 225))	('disease-free survival', 'CPA', (181, 202))	('women', 'Species', '9606', (43, 48))	('losing', 'NegReg', (89, 95))	('TP53', 'Gene', '7157', (12, 16))	('Arg72Pro', 'Mutation', 'rs1042522', (254, 262))	('TP53', 'Gene', '7157', (137, 141))	('TP53', 'Gene', (12, 16))	('reduction', 'NegReg', (168, 177))	('Pro72', 'Var', (116, 121))	('TP53', 'Gene', (137, 141))
417834	33450833	Another analysis revealed that patients with homozygous deletion under LOH or both del17p and TP53 mutation had a significantly worse outcome, comparing with patients who had only del17p or TP53 mutation (3-year overall survival 84% versus 29% (p = 0.02) and 3-year progression-free survival 73% versus 29% (p = 0.04), respectively).	('del17p', 'Mutation', 'c.del17', (180, 186))	('del17p', 'Mutation', 'c.del17', (83, 89))	('del17p', 'Gene', (83, 89))	('TP53', 'Gene', '7157', (94, 98))	('mutation', 'Var', (99, 107))	('TP53', 'Gene', (94, 98))	('TP53', 'Gene', '7157', (190, 194))	('TP53', 'Gene', (190, 194))	('patients', 'Species', '9606', (31, 39))	('patients', 'Species', '9606', (158, 166))
417835	33450833	Loss of heterozygosity at 9p was observed to be significantly associated with poorer prognosis of glioma patients.	('patients', 'Species', '9606', (105, 113))	('Loss of heterozygosity', 'Var', (0, 22))	('glioma', 'Disease', 'MESH:D005910', (98, 104))	('glioma', 'Phenotype', 'HP:0009733', (98, 104))	('glioma', 'Disease', (98, 104))
417836	33450833	Another study reported that LOH at 9p13 was associated with poor survival in squamous cell carcinoma/adenocarcinoma patients who had surgical resection.	('adenocarcinoma', 'Disease', 'MESH:D000230', (101, 115))	('poor', 'NegReg', (60, 64))	('patients', 'Species', '9606', (116, 124))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (77, 100))	('LOH at 9p13', 'Var', (28, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (77, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('squamous cell carcinoma', 'Disease', (77, 100))	('adenocarcinoma', 'Disease', (101, 115))
417839	33450833	A number of studies have revealed that colorectal cancer patients at stage III with LOH at SMAD4 at 18q showed a poorer overall 5-year survival rate comparing with patients harboring non-18q LOH.	('poorer', 'NegReg', (113, 119))	('patients', 'Species', '9606', (57, 65))	('SMAD4', 'Gene', (91, 96))	('colorectal cancer', 'Disease', 'MESH:D015179', (39, 56))	('colorectal cancer', 'Phenotype', 'HP:0003003', (39, 56))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('patients', 'Species', '9606', (164, 172))	('SMAD4', 'Gene', '4089', (91, 96))	('LOH', 'Var', (84, 87))	('colorectal cancer', 'Disease', (39, 56))
417840	33450833	A meta-analysis of data from 27 studies and 2189 patients extended this finding, showing that LOH on chromosome 18q could assist in predicting the clinical outcome after therapies in stage III colorectal cancer (CRC).	('colorectal cancer', 'Disease', (193, 210))	('CRC', 'Disease', 'MESH:D015179', (212, 215))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('colorectal cancer', 'Disease', 'MESH:D015179', (193, 210))	('assist', 'Reg', (122, 128))	('patients', 'Species', '9606', (49, 57))	('CRC', 'Disease', (212, 215))	('colorectal cancer', 'Phenotype', 'HP:0003003', (193, 210))	('LOH on chromosome', 'Var', (94, 111))
417842	33450833	Here, last but not the least, studies of loss of heterozygosity in tumors also provides up-and-coming possibilities to understand the underlying mechanism of cancer evolution which surpasses the scheme of targeting point mutations in tumorigenesis and focuses on the contribution of losses and gains of genetic material through whole chromosomes or chromosome arms.	('loss', 'Var', (41, 45))	('tumor', 'Disease', (234, 239))	('tumors', 'Disease', 'MESH:D009369', (67, 73))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('cancer', 'Disease', (158, 164))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('tumor', 'Disease', 'MESH:D009369', (234, 239))	('tumor', 'Disease', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('tumors', 'Disease', (67, 73))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
417843	33450833	A very recent study relating to non-small cell lung cancer (NSCLC) has observed a significant enrichment for whole-genome doubling (WGD) which is coordinated with an extensive loss of heterozygosity, indicating that loss of heterozygosity and whole-genome doubling are common events.	('loss', 'Var', (216, 220))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('lung cancer', 'Disease', (47, 58))	('lung cancer', 'Phenotype', 'HP:0100526', (47, 58))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (36, 58))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (32, 58))	('lung cancer', 'Disease', 'MESH:D008175', (47, 58))	('NSCLC', 'Disease', (60, 65))	('NSCLC', 'Disease', 'MESH:D002289', (60, 65))
417844	33450833	Then they pursue to understand the effects of natural selection on LOH and WGD during cancer evolution by comparing the early (pre-WGD) and late (post-WGD) mutations within segments of LOH based on their modified dN/dS ratio.	('mutations', 'Var', (156, 165))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('dS', 'Chemical', 'MESH:D003903', (216, 218))	('dN', 'Chemical', 'MESH:C022306', (213, 215))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('cancer', 'Disease', (86, 92))
417847	33450833	Firstly, using their method for calculating dN/dS ratio and a series of strict filtration, the two well-established tumor suppressor genes TP53 and PTEN were discovered with a dN/dS ratio > 50 in lung squamous cell carcinoma (LUSC), indicating the reliability of their analysis method.	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (196, 224))	('dN/dS', 'Var', (176, 181))	('PTEN', 'Gene', (148, 152))	('dN', 'Chemical', 'MESH:C022306', (176, 178))	('PTEN', 'Gene', '5728', (148, 152))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (201, 224))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (196, 224))	('lung squamous cell carcinoma', 'Disease', (196, 224))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('TP53', 'Gene', '7157', (139, 143))	('dS', 'Chemical', 'MESH:D003903', (47, 49))	('dS', 'Chemical', 'MESH:D003903', (179, 181))	('carcinoma', 'Phenotype', 'HP:0030731', (215, 224))	('dN', 'Chemical', 'MESH:C022306', (44, 46))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('TP53', 'Gene', (139, 143))	('tumor', 'Disease', (116, 121))
417854	33450833	Further investigation into the ~25% CNAs of the genome revealed that the most common type of allele-specific CNAs identified by CHISEL are copy-neutral LOHs and contains several genes which have been reported in the previous 560 breast cancer database, such as ARID1B and ESR1 on chromosome 6q, PTEN on chromosome 10q, BRCA2 and RB1 on chromosome 13, It is worth noting that all the genes undergoing copy-neutral LOHs have been reported in almost all type of tumor cells, indicating that these copy-neutral LOHs mutations may take an important role at an early stage during the tumor evolution.	('tumor', 'Disease', 'MESH:D009369', (578, 583))	('tumor', 'Phenotype', 'HP:0002664', (459, 464))	('BRCA2', 'Gene', (319, 324))	('breast cancer', 'Disease', 'MESH:D001943', (229, 242))	('breast cancer', 'Disease', (229, 242))	('ARID1B', 'Gene', (261, 267))	('tumor', 'Phenotype', 'HP:0002664', (578, 583))	('ARID1B', 'Gene', '57492', (261, 267))	('RB1', 'Gene', (329, 332))	('ESR1', 'Gene', '2099', (272, 276))	('BRCA2', 'Gene', '675', (319, 324))	('ESR1', 'Gene', (272, 276))	('PTEN', 'Gene', (295, 299))	('tumor', 'Disease', (459, 464))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('mutations', 'Var', (512, 521))	('RB1', 'Gene', '5925', (329, 332))	('tumor', 'Disease', 'MESH:D009369', (459, 464))	('tumor', 'Disease', (578, 583))	('PTEN', 'Gene', '5728', (295, 299))	('breast cancer', 'Phenotype', 'HP:0003002', (229, 242))
417865	33450833	Moreover, emerging studies have shown that findings on loss of heterozygosity shed a light on understanding the mechanism underlying tumor immune evasion during tumor evolution.	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('loss of heterozygosity', 'Var', (55, 77))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('tumor', 'Disease', (133, 138))	('tumor', 'Disease', (161, 166))
417871	33450833	Another study relating to lung cancer accelerated the study about the relationship of loss of heterozygosity at HLA and immune escape in evolution of lung cancer.	('lung cancer', 'Phenotype', 'HP:0100526', (150, 161))	('lung cancer', 'Disease', (150, 161))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('lung cancer', 'Disease', 'MESH:D008175', (26, 37))	('lung cancer', 'Disease', 'MESH:D008175', (150, 161))	('loss of heterozygosity', 'Var', (86, 108))	('immune escape', 'CPA', (120, 133))	('HLA', 'Protein', (112, 115))	('lung cancer', 'Disease', (26, 37))	('lung cancer', 'Phenotype', 'HP:0100526', (26, 37))
417877	33450833	Loss of heterozygosity (LOH) is a common genetic event in the development of cancer and is known to play an essential role in the somatic loss of wild-type alleles in cancers.	('Loss of heterozygosity', 'Var', (0, 22))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('cancer', 'Disease', (167, 173))	('cancers', 'Phenotype', 'HP:0002664', (167, 174))	('cancers', 'Disease', (167, 174))	('cancers', 'Disease', 'MESH:D009369', (167, 174))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))
417880	33450833	Here, we have reviewed and summarized mutations associated with LOH on chromosomes which have been shown to be promising biomarkers of cancer risk or predictive of clinical outcomes in certain types of tumors.	('cancer', 'Disease', (135, 141))	('tumors', 'Phenotype', 'HP:0002664', (202, 208))	('tumors', 'Disease', (202, 208))	('tumors', 'Disease', 'MESH:D009369', (202, 208))	('LOH', 'Gene', (64, 67))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('mutations', 'Var', (38, 47))	('cancer', 'Disease', 'MESH:D009369', (135, 141))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))
417882	33450833	As loss of heterozygosity is a common genetic event in cancer genomes, analysis of LOH could in addition provide a therapeutic option for precision medicine.	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('cancer', 'Disease', (55, 61))	('loss of heterozygosity', 'Var', (3, 25))
417901	33171596	In 2017, pembrolizumab, an anti-PD-1 antibody, was granted the first agnostic indication by the U.S.A's FDA for patients with microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR) solid tumors.	('pembrolizumab', 'Chemical', 'MESH:C582435', (9, 22))	('MSI-H', 'Chemical', '-', (159, 164))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('patients', 'Species', '9606', (112, 120))	('deficient mismatch repair', 'Var', (169, 194))	('tumors', 'Disease', (208, 214))	('tumors', 'Phenotype', 'HP:0002664', (208, 214))	('tumors', 'Disease', 'MESH:D009369', (208, 214))	('microsatellite instability-high', 'Var', (126, 157))
417910	33171596	CIN involves intratumor heterogenicity, cancer evaluation, host immunity, and gene mutation, which can be immunogenic, as well as increased immune evasion.	('gene mutation', 'Var', (78, 91))	('tumor', 'Disease', (18, 23))	('CIN', 'Disease', (0, 3))	('immune evasion', 'MPA', (140, 154))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('cancer', 'Disease', (40, 46))	('CIN', 'Disease', 'MESH:D007674', (0, 3))	('increased', 'PosReg', (130, 139))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('CIN', 'Phenotype', 'HP:0040012', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
417924	33171596	TMB-H and a high CIN70 were associated with a poor progression-free survival (PFS) and overall survival (OS); in contrast, MSI-H was marginally associated with a favorable PFS, but not OS (Figure 2D-I).	('poor', 'NegReg', (46, 50))	('high', 'Var', (12, 16))	('overall survival', 'CPA', (87, 103))	('progression-free survival', 'CPA', (51, 76))	('CIN', 'Disease', (17, 20))	('CIN', 'Disease', 'MESH:D007674', (17, 20))	('TMB-H', 'Chemical', '-', (0, 5))	('CIN', 'Phenotype', 'HP:0040012', (17, 20))	('MSI-H', 'Chemical', '-', (123, 128))
417929	33171596	Among the 25 cancer types with MSI-H samples, the CIN70 scores were significantly higher in the MSI-H group than non-MSI-H group within only three cancer types (breast invasive carcinoma (BRCA), colon adenocarcinoma (COAD), and stomach adenocarcinoma (STAD); Figure 3, Supplementary Figure S2).	('carcinoma', 'Phenotype', 'HP:0030731', (241, 250))	('MSI-H', 'Chemical', '-', (117, 122))	('MSI-H', 'Chemical', '-', (31, 36))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('CIN', 'Disease', 'MESH:D007674', (50, 53))	('MSI-H', 'Var', (96, 101))	('carcinoma', 'Phenotype', 'HP:0030731', (177, 186))	('cancer', 'Disease', 'MESH:D009369', (13, 19))	('stomach adenocarcinoma', 'Disease', 'MESH:D000230', (228, 250))	('breast invasive carcinoma', 'Phenotype', 'HP:0003002', (161, 186))	('colon adenocarcinoma', 'Disease', 'MESH:D003110', (195, 215))	('stomach adenocarcinoma', 'Disease', (228, 250))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('CIN', 'Disease', (50, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (206, 215))	('cancer', 'Disease', (13, 19))	('colon adenocarcinoma', 'Disease', (195, 215))	('breast invasive carcinoma', 'Disease', (161, 186))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('MSI-H', 'Chemical', '-', (96, 101))	('higher', 'PosReg', (82, 88))	('CIN', 'Phenotype', 'HP:0040012', (50, 53))	('breast invasive carcinoma', 'Disease', 'MESH:D001943', (161, 186))	('cancer', 'Disease', (147, 153))
417931	33171596	Regarding PFS, TMB is significantly associated with a PFS difference in 9 out of 32 cancer types (Figure 3, Supplementary Figure S4; Supplementary Table S1).	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('PFS difference', 'Var', (54, 68))	('cancer', 'Disease', (84, 90))	('TMB', 'Disease', (15, 18))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('TMB', 'Chemical', '-', (15, 18))	('associated', 'Reg', (36, 46))	('difference', 'Var', (58, 68))
417932	33171596	In most cancer types, patients with TMB-H had a significantly shorter PFS than patients without TMB-H, indicating TMB-H is an unfavorable prognostic factor in such cancers.	('TMB-H', 'Chemical', '-', (96, 101))	('shorter', 'NegReg', (62, 69))	('cancer', 'Disease', (8, 14))	('TMB-H', 'Chemical', '-', (114, 119))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('patients', 'Species', '9606', (22, 30))	('cancers', 'Phenotype', 'HP:0002664', (164, 171))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('cancer', 'Disease', (164, 170))	('cancers', 'Disease', (164, 171))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('patients', 'Species', '9606', (79, 87))	('TMB-H', 'Var', (36, 41))	('PFS', 'MPA', (70, 73))	('TMB-H', 'Chemical', '-', (36, 41))	('cancers', 'Disease', 'MESH:D009369', (164, 171))	('cancer', 'Disease', 'MESH:D009369', (8, 14))
417933	33171596	However, patients with TMB-H had a significantly longer PFS than the patients without TMB-H in three cancer types (bladder urothelial carcinoma (BLCA), STAD, and uterine corpus endometrial carcinoma (UCEC); Supplementary Figure S4).	('patients', 'Species', '9606', (9, 17))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (177, 198))	('cancer', 'Disease', (101, 107))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (115, 143))	('TMB-H', 'Chemical', '-', (23, 28))	('bladder urothelial carcinoma', 'Disease', (115, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (177, 198))	('TMB-H', 'Var', (23, 28))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('longer', 'PosReg', (49, 55))	('PFS', 'MPA', (56, 59))	('patients', 'Species', '9606', (69, 77))	('endometrial carcinoma', 'Disease', (177, 198))	('carcinoma', 'Phenotype', 'HP:0030731', (189, 198))	('TMB-H', 'Chemical', '-', (86, 91))
417936	33171596	Using the median of CIN70, we performed the survival analysis, comparing the high CIN70 and low CIN70 patients in each cancer type.	('CIN', 'Disease', (82, 85))	('high', 'Var', (77, 81))	('CIN', 'Disease', (20, 23))	('patients', 'Species', '9606', (102, 110))	('CIN', 'Disease', (96, 99))	('CIN', 'Disease', 'MESH:D007674', (82, 85))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('cancer', 'Disease', (119, 125))	('CIN', 'Disease', 'MESH:D007674', (20, 23))	('CIN', 'Disease', 'MESH:D007674', (96, 99))	('CIN', 'Phenotype', 'HP:0040012', (20, 23))	('CIN', 'Phenotype', 'HP:0040012', (82, 85))	('CIN', 'Phenotype', 'HP:0040012', (96, 99))
417941	33171596	On the other hand, patients with TMB-H had a longer OS than those without TMB-H in four cancers (BLCA, ovarian serous cystadenocarcinoma (OV), skin cutaneous melanoma (SKCM), and testicular germ cell tumors (TGCT); Supplementary Figure S7).	('TMB-H', 'Chemical', '-', (33, 38))	('ovarian serous cystadenocarcinoma', 'Phenotype', 'HP:0012887', (103, 136))	('tumors', 'Disease', 'MESH:D009369', (200, 206))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (143, 166))	('skin cutaneous melanoma', 'Disease', (143, 166))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('cancers', 'Disease', (88, 95))	('germ cell tumors', 'Phenotype', 'HP:0100728', (190, 206))	('ovarian serous cystadenocarcinoma', 'Disease', (103, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('melanoma', 'Phenotype', 'HP:0002861', (158, 166))	('patients', 'Species', '9606', (19, 27))	('ovarian serous cystadenocarcinoma', 'Disease', 'MESH:D018284', (103, 136))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (148, 166))	('tumors', 'Phenotype', 'HP:0002664', (200, 206))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('TMB-H', 'Chemical', '-', (74, 79))	('cancers', 'Disease', 'MESH:D009369', (88, 95))	('TMB-H', 'Var', (33, 38))	('tumors', 'Disease', (200, 206))
417942	33171596	In 25 cancer types with MSI-H samples, MSI status was significantly associated with OS in three cancer types (Figure 3, Supplementary Figure S8; Supplementary Table S2).	('MSI status', 'Var', (39, 49))	('MSI-H', 'Chemical', '-', (24, 29))	('associated with', 'Reg', (68, 83))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('cancer', 'Disease', 'MESH:D009369', (6, 12))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Disease', (6, 12))	('cancer', 'Disease', (96, 102))
417944	33171596	However, MSI-H patients had a longer OS than the non-MSI-H patients in UCEC (Supplementary Figure S8).	('patients', 'Species', '9606', (15, 23))	('UCEC', 'Disease', (71, 75))	('MSI-H', 'Chemical', '-', (9, 14))	('MSI-H', 'Chemical', '-', (53, 58))	('MSI-H', 'Var', (9, 14))	('patients', 'Species', '9606', (59, 67))
417947	33171596	However, unlike the prognostic value of CIN70, PFS showing CIN70 is a universally poor prognostic factor, and patients with a high CIN70 had a favorable OS in two cancer types (cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC) and THYM; Supplementary Figure S9).	('CIN', 'Disease', 'MESH:D007674', (131, 134))	('carcinoma', 'Phenotype', 'HP:0030731', (200, 209))	('THYM', 'Disease', (253, 257))	('CIN', 'Phenotype', 'HP:0040012', (40, 43))	('carcinoma', 'Phenotype', 'HP:0030731', (232, 241))	('cancer', 'Disease', 'MESH:D009369', (163, 169))	('CIN', 'Disease', 'MESH:D007674', (40, 43))	('CIN', 'Disease', (59, 62))	('high', 'Var', (126, 130))	('CIN', 'Disease', (131, 134))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (186, 209))	('cancer', 'Disease', (163, 169))	('CIN', 'Disease', (40, 43))	('cervical squamous cell carcinoma and endocervical adenocarcinoma', 'Disease', 'MESH:D002294', (177, 241))	('CIN', 'Phenotype', 'HP:0040012', (59, 62))	('CIN', 'Phenotype', 'HP:0040012', (131, 134))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('CIN', 'Disease', 'MESH:D007674', (59, 62))	('patients', 'Species', '9606', (110, 118))
417956	33171596	Multiple genetic alterations contribute to CIN, such as genes involving DNA damage and repair, mitotic checkpoint, chromosome condensation and segregation from mutational inactivation of STAG2, and possibly sister chromatid cohesion (hSecurin).	('contribute', 'Reg', (29, 39))	('segregation', 'CPA', (143, 154))	('mutational inactivation', 'Var', (160, 183))	('mitotic checkpoint', 'CPA', (95, 113))	('CIN', 'Disease', (43, 46))	('hSecurin', 'Gene', '9232', (234, 242))	('CIN', 'Disease', 'MESH:D007674', (43, 46))	('STAG2', 'Gene', (187, 192))	('STAG2', 'Gene', '10735', (187, 192))	('CIN', 'Phenotype', 'HP:0040012', (43, 46))	('chromosome condensation', 'CPA', (115, 138))	('hSecurin', 'Gene', (234, 242))
417988	33171596	Therefore, TMB was determined by counting the number of mutations in the TCGA MC3 data.	('TMB', 'Chemical', '-', (11, 14))	('mutations', 'Var', (56, 65))	('TCGA MC3', 'Gene', (73, 81))
417995	33171596	), the Ministry of Science and Technology (105-2314-B-182A-041-MY2 and 107-2314-B-182A-134-MY3 to C.-N.Y., 106-2221-E-010-019-MY3 and 109-2221-E-010-013-MY3 to Y.-C.W., 109-2314-B-182A-148 -MY3 to C.-E.W., and 104-2314-B-075-064-MY2 to M.-H.C.), and the Taipei Veterans General Hospital (V109C-028 to M.-H.C.).	('104-2314-B-075-064-MY2 to', 'Var', (210, 235))	('V109C', 'Mutation', 'p.V109C', (288, 293))	('109-2314-B-182A-148 -MY3', 'Var', (169, 193))
417998	31188922	We identified significant, novel recurrent mutations in ASNS (asparagine synthetase) that may affect substrate binding, and variants in driver genes including TP53, PIK3CA, FGFR2, ARID2, MLL3, MYC and ALK.	('PIK3CA', 'Gene', (165, 171))	('affect', 'Reg', (94, 100))	('MLL3', 'Gene', '58508', (187, 191))	('FGFR2', 'Gene', '2263', (173, 178))	('MYC', 'Gene', (193, 196))	('ASNS', 'Gene', '440', (56, 60))	('asparagine synthetase', 'Gene', (62, 83))	('ALK', 'Gene', '238', (201, 204))	('TP53', 'Gene', '7157', (159, 163))	('substrate binding', 'Interaction', (101, 118))	('ALK', 'Gene', (201, 204))	('ASNS', 'Gene', (56, 60))	('MLL3', 'Gene', (187, 191))	('MYC', 'Gene', '4609', (193, 196))	('ARID2', 'Gene', '196528', (180, 185))	('PIK3CA', 'Gene', '5290', (165, 171))	('asparagine synthetase', 'Gene', '440', (62, 83))	('ARID2', 'Gene', (180, 185))	('variants', 'Var', (124, 132))	('FGFR2', 'Gene', (173, 178))	('TP53', 'Gene', (159, 163))	('mutations', 'Var', (43, 52))
418025	31188922	All somatic missense mutations were analysed for their likely tumourigenic impact based on CHASM (Cancer-specific High-throughput Annotation of Somatic Mutations)  and the IntOGen-mutations platform.	('missense mutations', 'Var', (12, 30))	('tumour', 'Phenotype', 'HP:0002664', (62, 68))	('Cancer', 'Phenotype', 'HP:0002664', (98, 104))	('Cancer', 'Disease', (98, 104))	('tumour', 'Disease', 'MESH:D009369', (62, 68))	('Cancer', 'Disease', 'MESH:D009369', (98, 104))	('tumour', 'Disease', (62, 68))
418026	31188922	The annotation ranked the SNVs for somatic driver mutations for specific cancer tissue types, predicted protein functional impact, allele frequencies from the 1000 Genomes Project and ESP6500 populations, and previous cancer association of the gene harbouring the variants.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (218, 224))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('variants', 'Var', (264, 272))	('cancer', 'Disease', (218, 224))	('protein', 'Protein', (104, 111))	('mutations', 'Var', (50, 59))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))
418027	31188922	CHASM training set is composed of a positive class of driver mutations from the COSMIC database and VEST training set comprising a positive class of disease mutations from the Human Gene Mutation Database 66 and a negative class of variants detected in the ESP6500 population and 1000 Genomes Project cohort with an allele frequency of >1%.	('mutations', 'Var', (157, 166))	('mutations', 'Var', (61, 70))	('Human', 'Species', '9606', (176, 181))
418036	31188922	Filtering for driver and other significant variants using CHASM revealed alterations in genes that have been implicated in HNSCC or other cancers (Figure 2, middle panel; Table 4).	('alterations', 'Reg', (73, 84))	('genes', 'Gene', (88, 93))	('HNSCC', 'Phenotype', 'HP:0012288', (123, 128))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('cancers', 'Phenotype', 'HP:0002664', (138, 145))	('variants', 'Var', (43, 51))	('cancers', 'Disease', (138, 145))	('cancers', 'Disease', 'MESH:D009369', (138, 145))	('HNSCC', 'Disease', (123, 128))
418037	31188922	Driver missense mutations in FGFR2 (Fibroblast Growth Factor Receptor 2), SETBP1 (SET Binding Protein 1), PIK3CA (Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit Alpha), IGF2BP3 (Insulin Like Growth Factor 2 MRNA Binding Protein 3), TP53 (Tumour Protein P53), PTPN11 (Protein Tyrosine Phosphatase, Non-Receptor Type 11) and NF2 (Neurofibromin 2) were identified.	('PTPN11', 'Gene', (277, 283))	('IGF2BP3', 'Gene', '10643', (187, 194))	('PIK3CA', 'Gene', '5290', (106, 112))	('FGFR2', 'Gene', '2263', (29, 34))	('SETBP1', 'Gene', '26040', (74, 80))	('PTPN11', 'Gene', '5781', (277, 283))	('NF2', 'Gene', '4771', (341, 344))	('Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit Alpha', 'Gene', '5290', (114, 184))	('Tumour Protein P53', 'Gene', (256, 274))	('SETBP1', 'Gene', (74, 80))	('NF2', 'Gene', (341, 344))	('missense mutations', 'Var', (7, 25))	('TP53', 'Gene', (250, 254))	('Fibroblast Growth Factor Receptor 2', 'Gene', (36, 71))	('Neurofibromin 2', 'Gene', '4771', (346, 361))	('PIK3CA', 'Gene', (106, 112))	('Neurofibromin 2', 'Gene', (346, 361))	('SET Binding Protein 1', 'Gene', (82, 103))	('Tumour', 'Phenotype', 'HP:0002664', (256, 262))	('Insulin Like Growth Factor 2 MRNA Binding Protein 3', 'Gene', '10643', (196, 247))	('FGFR2', 'Gene', (29, 34))	('TP53', 'Gene', '7157', (250, 254))	('Tumour Protein P53', 'Gene', '7157', (256, 274))	('Fibroblast Growth Factor Receptor 2', 'Gene', '2263', (36, 71))	('IGF2BP3', 'Gene', (187, 194))	('SET Binding Protein 1', 'Gene', '26040', (82, 103))
418038	31188922	Significant missense mutations were also identified in ASNS (Asparagine Synthetase (Glutamine-Hydrolyzing)) in four of the seven samples.	('missense mutations', 'Var', (12, 30))	('Asparagine Synthetase', 'Gene', (61, 82))	('ASNS', 'Gene', '440', (55, 59))	('Glu', 'Chemical', 'MESH:D018698', (84, 87))	('ASNS', 'Gene', (55, 59))	('Asparagine Synthetase', 'Gene', '440', (61, 82))
418039	31188922	Other genes that exhibited recurrent mutations included the CLMN (Calmin) gene (5/7), CHEK2 (Checkpoint Kinase 2) (3/7), and DRD5 (Dopamine Receptor D5) and PAK2 (P21 (RAC1) Activated Kinase 2) (2/7) (Table 3).	('DRD5', 'Gene', (125, 129))	('P21 (RAC1) Activated Kinase 2', 'Gene', (163, 192))	('CHEK2', 'Gene', '11200', (86, 91))	('PAK2', 'Gene', (157, 161))	('Checkpoint Kinase 2', 'Gene', '11200', (93, 112))	('PAK2', 'Gene', '5062', (157, 161))	('CHEK2', 'Gene', (86, 91))	('DRD5', 'Gene', '1816', (125, 129))	('CLMN', 'Gene', '79789', (60, 64))	('Dopamine Receptor D5', 'Gene', '1816', (131, 151))	('mutations', 'Var', (37, 46))	('CLMN', 'Gene', (60, 64))	('Calmin', 'Gene', '79789', (66, 72))	('Dopamine Receptor D5', 'Gene', (131, 151))	('Calmin', 'Gene', (66, 72))	('P21 (RAC1) Activated Kinase 2', 'Gene', '644914', (163, 192))	('Checkpoint Kinase 2', 'Gene', (93, 112))
418040	31188922	Synonymous variants in previously identified driver genes ARID2 (AT-Rich Interaction Domain 2), ALK (Anaplastic Lymphoma Receptor Tyrosine Kinase), MLL3 [Myeloid/Lymphoid Or Mixed-Lineage Leukemia 3, also known as KMT2C (Lysine Methyltransferase 2C)] and MYC (V-Myc Avian Myelocytomatosis Viral Oncogene Homolog), were also identified (Figure 2, middle panel; Table 4).	('AT-Rich Interaction Domain 2', 'Gene', (65, 93))	('Avian Myelocytomatosis Viral Oncogene Homolog', 'Gene', '4609', (266, 311))	('Lymphoid Or Mixed-Lineage Leukemia', 'Phenotype', 'HP:0005531', (162, 196))	('Leukemia', 'Disease', (188, 196))	('MLL3', 'Gene', '58508', (148, 152))	('Myc', 'Gene', (262, 265))	('AT-Rich Interaction Domain 2', 'Gene', '196528', (65, 93))	('MYC', 'Gene', (255, 258))	('ARID2', 'Gene', (58, 63))	('variants', 'Var', (11, 19))	('Lymphoma', 'Phenotype', 'HP:0002665', (112, 120))	('MLL3', 'Gene', (148, 152))	('Anaplastic Lymphoma', 'Phenotype', 'HP:0012193', (101, 120))	('ALK', 'Gene', '238', (96, 99))	('KMT2C', 'Gene', '58508', (214, 219))	('KMT2C', 'Gene', (214, 219))	('Myc', 'Gene', '4609', (262, 265))	('Leukemia', 'Phenotype', 'HP:0001909', (188, 196))	('MYC', 'Gene', '4609', (255, 258))	('ALK', 'Gene', (96, 99))	('Anaplastic Lymphoma Receptor Tyrosine Kinase', 'Gene', '238', (101, 145))	('Leukemia', 'Disease', 'MESH:D007938', (188, 196))	('Anaplastic Lymphoma Receptor Tyrosine Kinase', 'Gene', (101, 145))	('ARID2', 'Gene', '196528', (58, 63))	('Avian Myelocytomatosis Viral Oncogene Homolog', 'Gene', (266, 311))
418043	31188922	In the 3'UTR region, mutations in IGF1R (Insulin Like Growth Factor 1 Receptor) and ERBB4 (Erb-B2 Receptor Tyrosine Kinase 4) were identified as significant.	('ERBB4', 'Gene', (84, 89))	('Insulin Like Growth Factor 1 Receptor', 'Gene', '3480', (41, 78))	('Erb-B2 Receptor Tyrosine Kinase 4', 'Gene', (91, 124))	('IGF1R', 'Gene', (34, 39))	('Insulin Like Growth Factor 1 Receptor', 'Gene', (41, 78))	('ERBB4', 'Gene', '2066', (84, 89))	('Erb-B2 Receptor Tyrosine Kinase 4', 'Gene', '2066', (91, 124))	('IGF1R', 'Gene', '3480', (34, 39))	('mutations', 'Var', (21, 30))
418046	31188922	Genes with driver mutations implicated in multiple pathways included FGFR2, PIK3CA, and TP53.	('FGFR2', 'Gene', (69, 74))	('FGFR2', 'Gene', '2263', (69, 74))	('PIK3CA', 'Gene', (76, 82))	('TP53', 'Gene', '7157', (88, 92))	('TP53', 'Gene', (88, 92))	('PIK3CA', 'Gene', '5290', (76, 82))	('mutations', 'Var', (18, 27))
418048	31188922	Protein modeling of the effect of the three novel, recurrent mutations in ASNS identified in this cohort revealed that the mutated amino acids (p.A13T, p.A25V and p.M22T) are located in the vicinity (within 10 A distance) of the glutamine binding pocket (Figure 4).	('ASNS', 'Gene', '440', (74, 78))	('p.A25V', 'Var', (152, 158))	('ASNS', 'Gene', (74, 78))	('glutamine', 'Chemical', 'MESH:D005973', (229, 238))	('p.A25V', 'Mutation', 'rs1244803625', (152, 158))	('p.M22T', 'Mutation', 'rs1437603777', (163, 169))	('p.A13T', 'Mutation', 'p.A13T', (144, 150))	('p.A13T', 'Var', (144, 150))	('p.M22T', 'Var', (163, 169))
418051	31188922	Previous studies have reported greater number of mutations in HPV-negative as compared to HPV-positive HNSCC tumours.	('HNSCC', 'Phenotype', 'HP:0012288', (103, 108))	('HNSCC tumours', 'Disease', (103, 116))	('tumours', 'Phenotype', 'HP:0002664', (109, 116))	('tumour', 'Phenotype', 'HP:0002664', (109, 115))	('HPV', 'Species', '10566', (90, 93))	('mutations', 'Var', (49, 58))	('HNSCC tumours', 'Disease', 'MESH:D000077195', (103, 116))	('HPV', 'Species', '10566', (62, 65))
418053	31188922	Several variants were found in more than one sample and in genes that have been previously identified to play a role in HNSCC carcinogenesis.	('HNSCC carcinogenesis', 'Disease', 'MESH:D000077195', (120, 140))	('HNSCC carcinogenesis', 'Disease', (120, 140))	('HNSCC', 'Phenotype', 'HP:0012288', (120, 125))	('variants', 'Var', (8, 16))
418054	31188922	Next generation sequencing studies in other populations have identified mutations in the tumour suppressor gene TP53, which is associated with smoking-related disease, and the oncogene PIK3CA, at a mutation rate of 40-60% and 6-8%, respectively.	('mutations', 'Var', (72, 81))	('associated', 'Reg', (127, 137))	('tumour', 'Phenotype', 'HP:0002664', (89, 95))	('tumour', 'Disease', 'MESH:D009369', (89, 95))	('tumour', 'Disease', (89, 95))	('PIK3CA', 'Gene', (185, 191))	('TP53', 'Gene', '7157', (112, 116))	('PIK3CA', 'Gene', '5290', (185, 191))	('TP53', 'Gene', (112, 116))
418055	31188922	The TCGA study, with the largest cohort to date, reported a TP53 mutation rate of 72% and PIK3CA mutation rate of 18-21%.	('PIK3CA', 'Gene', (90, 96))	('TP53', 'Gene', '7157', (60, 64))	('mutation', 'Var', (65, 73))	('TP53', 'Gene', (60, 64))	('PIK3CA', 'Gene', '5290', (90, 96))
418056	31188922	Mutations in TP53 gene were detected in two of the seven cases in the current study, and in PIK3CA in one patient.	('TP53', 'Gene', (13, 17))	('detected', 'Reg', (28, 36))	('PIK3CA', 'Gene', '5290', (92, 98))	('patient', 'Species', '9606', (106, 113))	('Mutations', 'Var', (0, 9))	('TP53', 'Gene', '7157', (13, 17))	('PIK3CA', 'Gene', (92, 98))
418057	31188922	In a comparative genomic analysis of HPV-positive and HPV-negative tumours, the former showed mutations in FGFR2 and MLL3, among others.	('tumour', 'Phenotype', 'HP:0002664', (67, 73))	('FGFR2', 'Gene', (107, 112))	('mutations', 'Var', (94, 103))	('FGFR2', 'Gene', '2263', (107, 112))	('MLL3', 'Gene', '58508', (117, 121))	('HPV-negative tumours', 'Disease', 'MESH:D030361', (54, 74))	('HPV', 'Species', '10566', (54, 57))	('MLL3', 'Gene', (117, 121))	('HPV-negative tumours', 'Disease', (54, 74))	('HPV', 'Species', '10566', (37, 40))	('tumours', 'Phenotype', 'HP:0002664', (67, 74))
418058	31188922	The mutational spectrum in HPV-negative tumours closely resembled lung and esophageal squamous cell carcinomas, with mutations identified in genes including TP53, MLL2/3, NOTCH1, PIK3CA and DDR2.	('TP53', 'Gene', (157, 161))	('lung', 'Disease', (66, 70))	('esophageal squamous cell carcinomas', 'Disease', (75, 110))	('esophageal squamous cell carcinomas', 'Disease', 'MESH:D000077277', (75, 110))	('DDR2', 'Gene', '4921', (190, 194))	('HPV-negative tumours', 'Disease', (27, 47))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (86, 109))	('MLL2/3', 'Gene', '9757;58508', (163, 169))	('NOTCH1', 'Gene', (171, 177))	('PIK3CA', 'Gene', (179, 185))	('HPV-negative tumours', 'Disease', 'MESH:D030361', (27, 47))	('tumours', 'Phenotype', 'HP:0002664', (40, 47))	('TP53', 'Gene', '7157', (157, 161))	('mutations', 'Var', (117, 126))	('DDR2', 'Gene', (190, 194))	('NOTCH1', 'Gene', '4851', (171, 177))	('tumour', 'Phenotype', 'HP:0002664', (40, 46))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('carcinomas', 'Phenotype', 'HP:0030731', (100, 110))	('MLL2/3', 'Gene', (163, 169))	('PIK3CA', 'Gene', '5290', (179, 185))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (86, 110))
418059	31188922	The HPV-negative cohort in the current study exhibited a nonsense variant (p.Y223X) in DDR2 in a single sample.	('HPV', 'Species', '10566', (4, 7))	('p.Y223X', 'Var', (75, 82))	('DDR2', 'Gene', '4921', (87, 91))	('DDR2', 'Gene', (87, 91))	('p.Y223X', 'Mutation', 'p.Y223X', (75, 82))
418060	31188922	A different nonsense mutation (p.R709X) and missense mutations (p.I474M; p.I724M) have been previously identified exclusively in HNSCC recurrences .	('p.R709X', 'Mutation', 'rs1056323839', (31, 38))	('p.I474M', 'Mutation', 'rs764592717', (64, 71))	('p.I724M', 'Mutation', 'p.I724M', (73, 80))	('HNSCC', 'Phenotype', 'HP:0012288', (129, 134))	('p.R709X', 'Var', (31, 38))	('HNSCC', 'Disease', (129, 134))	('p.I724M', 'Var', (73, 80))	('p.I474M; p.I724M', 'Var', (64, 80))
418062	31188922	In addition, an SNV was identified in MLL3 in a sample that also exhibited an SNV in the driver gene MYC.	('MLL3', 'Gene', '58508', (38, 42))	('SNV', 'Var', (78, 81))	('MYC', 'Gene', '4609', (101, 104))	('MYC', 'Gene', (101, 104))	('MLL3', 'Gene', (38, 42))
418064	31188922	Recurrent mutations in MLL genes have been identified in several other cancers, including lung squamous cell carcinoma, and been associated with poor clinical outcomes.	('associated', 'Reg', (129, 139))	('MLL', 'Gene', (23, 26))	('cancers', 'Disease', 'MESH:D009369', (71, 78))	('cancers', 'Phenotype', 'HP:0002664', (71, 78))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (90, 118))	('cancers', 'Disease', (71, 78))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (95, 118))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (90, 118))	('lung squamous cell carcinoma', 'Disease', (90, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('identified', 'Reg', (43, 53))	('mutations', 'Var', (10, 19))	('MLL', 'Gene', '4297', (23, 26))
418066	31188922	Additionally, we discovered recurrent significant missense mutations in ASNS (asparagine synthetase) gene in 4 out of 7 samples.	('missense mutations', 'Var', (50, 68))	('asparagine synthetase', 'Gene', '440', (78, 99))	('asparagine synthetase', 'Gene', (78, 99))	('ASNS', 'Gene', (72, 76))	('ASNS', 'Gene', '440', (72, 76))
418069	31188922	The active site responsible for the binding and hydrolysis of glutamine is situated between these layers and important, evolutionarily conserved side chains involved in glutamine binding within the substrate binding pocket include Arg 49, Asn 74, Glu 76, and Asp 98.	('Glu', 'Chemical', 'MESH:D018698', (247, 250))	('glutamine', 'Chemical', 'MESH:D005973', (169, 178))	('Arg', 'Chemical', 'MESH:D001120', (231, 234))	('Arg 49', 'Var', (231, 237))	('Asn 74', 'Var', (239, 245))	('Asp', 'Chemical', 'MESH:D001224', (259, 262))	('Asn', 'Chemical', 'MESH:D001216', (239, 242))	('glutamine', 'Chemical', 'MESH:D005973', (62, 71))	('Asp 98', 'Var', (259, 265))	('Glu 76', 'Var', (247, 253))
418070	31188922	While the amino acids mutated as a result of the novel and recurrent mutations in ASNS identified in this cohort are not part of the glutamine binding pocket, protein modeling revealed their proximity to the region.	('mutations', 'Var', (69, 78))	('glutamine', 'Chemical', 'MESH:D005973', (133, 142))	('ASNS', 'Gene', (82, 86))	('ASNS', 'Gene', '440', (82, 86))
418071	31188922	Therefore, these mutations may affect glutamine binding during catalysis.	('affect', 'Reg', (31, 37))	('glutamine binding', 'MPA', (38, 55))	('glutamine', 'Chemical', 'MESH:D005973', (38, 47))	('mutations', 'Var', (17, 26))
418079	31188922	While KRAS mutations are uncommon in HNSCC, particularly as compared to HRAS, mutations in ASNS could effectively have the same functional consequences.	('KRAS', 'Gene', '3845', (6, 10))	('HRAS', 'Gene', '3265', (72, 76))	('ASNS', 'Gene', '440', (91, 95))	('HNSCC', 'Disease', (37, 42))	('ASNS', 'Gene', (91, 95))	('mutations', 'Var', (78, 87))	('HRAS', 'Gene', (72, 76))	('HNSCC', 'Phenotype', 'HP:0012288', (37, 42))	('KRAS', 'Gene', (6, 10))
418081	31188922	The current analysis also revealed significant low-frequency driver mutations in SETBP1, IGF2BP3, PTPN11 and NF2.	('PTPN11', 'Gene', '5781', (98, 104))	('IGF2BP3', 'Gene', '10643', (89, 96))	('IGF2BP3', 'Gene', (89, 96))	('NF2', 'Gene', '4771', (109, 112))	('PTPN11', 'Gene', (98, 104))	('SETBP1', 'Gene', '26040', (81, 87))	('NF2', 'Gene', (109, 112))	('mutations', 'Var', (68, 77))	('SETBP1', 'Gene', (81, 87))
418084	31188922	Mutations in SETBP1 resulting in overexpression or gain of function have been documented previously in hematological malignancies.	('overexpression', 'PosReg', (33, 47))	('SETBP1', 'Gene', (13, 19))	('malignancies', 'Disease', 'MESH:D009369', (117, 129))	('Mutations', 'Var', (0, 9))	('gain of function', 'PosReg', (51, 67))	('SETBP1', 'Gene', '26040', (13, 19))	('malignancies', 'Disease', (117, 129))	('hematological malignancies', 'Phenotype', 'HP:0004377', (103, 129))
418085	31188922	An IGF2BP3 mutation was found in a sample that also had driver mutations in PIK3CA and TP53.	('mutations', 'Var', (63, 72))	('TP53', 'Gene', '7157', (87, 91))	('IGF2BP3', 'Gene', '10643', (3, 10))	('IGF2BP3', 'Gene', (3, 10))	('TP53', 'Gene', (87, 91))	('PIK3CA', 'Gene', (76, 82))	('PIK3CA', 'Gene', '5290', (76, 82))
418087	31188922	IGF2BP3 mutations and copy number variations have been reported previously in HNSCC, and its role in cell invasiveness and metastasis in several other cancers has been documented in the literature.	('IGF2BP3', 'Gene', '10643', (0, 7))	('IGF2BP3', 'Gene', (0, 7))	('reported', 'Reg', (55, 63))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('copy number variations', 'Var', (22, 44))	('mutations', 'Var', (8, 17))	('HNSCC', 'Disease', (78, 83))	('HNSCC', 'Phenotype', 'HP:0012288', (78, 83))	('cancers', 'Disease', 'MESH:D009369', (151, 158))	('cancers', 'Phenotype', 'HP:0002664', (151, 158))	('cell invasiveness', 'CPA', (101, 118))	('cancers', 'Disease', (151, 158))
418088	31188922	Mutations in PTPN11 and NF2 genes were found in the same sample.	('PTPN11', 'Gene', '5781', (13, 19))	('NF2', 'Gene', (24, 27))	('PTPN11', 'Gene', (13, 19))	('NF2', 'Gene', '4771', (24, 27))	('Mutations', 'Var', (0, 9))
418090	31188922	Somatic PTPN11 mutations have been detected in juvenile myelomonocytic leukemia, myelodysplastic syndromes and acute myeloid leukemia.	('myeloid leukemia', 'Phenotype', 'HP:0012324', (117, 133))	('detected', 'Reg', (35, 43))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (111, 133))	('juvenile myelomonocytic leukemia', 'Disease', 'MESH:D054429', (47, 79))	('leukemia', 'Phenotype', 'HP:0001909', (71, 79))	('myelodysplastic syndromes', 'Phenotype', 'HP:0002863', (81, 106))	('mutations', 'Var', (15, 24))	('myelodysplastic syndromes', 'Disease', 'MESH:D009190', (81, 106))	('PTPN11', 'Gene', '5781', (8, 14))	('myelodysplastic syndromes', 'Disease', (81, 106))	('juvenile myelomonocytic leukemia', 'Disease', (47, 79))	('leukemia', 'Phenotype', 'HP:0001909', (125, 133))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (111, 133))	('PTPN11', 'Gene', (8, 14))	('acute myeloid leukemia', 'Disease', (111, 133))	('juvenile myelomonocytic leukemia', 'Phenotype', 'HP:0012209', (47, 79))
418091	31188922	While PTPN11 mutations have not been reported previously in HNSCC, this gene has been identified as a target of the tumour-suppressive microRNA miR-489.	('tumour', 'Disease', 'MESH:D009369', (116, 122))	('PTPN11', 'Gene', '5781', (6, 12))	('tumour', 'Disease', (116, 122))	('PTPN11', 'Gene', (6, 12))	('HNSCC', 'Phenotype', 'HP:0012288', (60, 65))	('mutations', 'Var', (13, 22))	('tumour', 'Phenotype', 'HP:0002664', (116, 122))
418094	31188922	Somatic NF2 mutations have been reported in a number of different cancers.	('mutations', 'Var', (12, 21))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('NF2', 'Gene', (8, 11))	('cancers', 'Phenotype', 'HP:0002664', (66, 73))	('reported', 'Reg', (32, 40))	('cancers', 'Disease', (66, 73))	('cancers', 'Disease', 'MESH:D009369', (66, 73))	('NF2', 'Gene', '4771', (8, 11))
418096	31188922	In addition to non-synonymous mutations, synonymous mutations are known to frequently act as driver mutations in cancers.	('synonymous mutations', 'Var', (41, 61))	('cancers', 'Phenotype', 'HP:0002664', (113, 120))	('cancers', 'Disease', 'MESH:D009369', (113, 120))	('cancers', 'Disease', (113, 120))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
418098	31188922	Mutations in MLL and ARID gene families have been previously documented for HNSCC .	('MLL', 'Gene', '4297', (13, 16))	('HNSCC', 'Disease', (76, 81))	('MLL', 'Gene', (13, 16))	('ARID', 'Disease', (21, 25))	('HNSCC', 'Phenotype', 'HP:0012288', (76, 81))	('ARID', 'Disease', 'None', (21, 25))	('Mutations', 'Var', (0, 9))
418104	31188922	The small sample size is a limitation of this study, which may explain low frequency of commonly mutated genes and why some of the commonly occurring HNSCC mutations such as NOTCH1 and HRAS were not identified in this small cohort.	('HRAS', 'Gene', (185, 189))	('mutations', 'Var', (156, 165))	('HNSCC', 'Gene', (150, 155))	('NOTCH1', 'Gene', '4851', (174, 180))	('NOTCH1', 'Gene', (174, 180))	('HNSCC', 'Phenotype', 'HP:0012288', (150, 155))	('HRAS', 'Gene', '3265', (185, 189))
418109	31188922	In addition to reporting known HNSCC mutations, we have identified novel, recurrent mutations in ASNS and other genes in the Pakistani population.	('HNSCC', 'Phenotype', 'HP:0012288', (31, 36))	('mutations', 'Var', (84, 93))	('HNSCC', 'Gene', (31, 36))	('ASNS', 'Gene', (97, 101))	('ASNS', 'Gene', '440', (97, 101))
418113	31405379	There is growing evidence to suggest that environmental factors due to epigenetic changes can be involved in the OSCC pathogenesis.	('SCC', 'Gene', '6317', (114, 117))	('SCC', 'Gene', (114, 117))	('epigenetic changes', 'Var', (71, 89))	('involved', 'Reg', (97, 105))
418114	31405379	Although tumor suppressor genes (TSGs) are commonly inactivated by promoter hypermethylation in human cancers, the epigenetic changes and the mechanism of TSGs in human OSCC remain unclear.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('TSG', 'Gene', '57045', (155, 158))	('human', 'Species', '9606', (96, 101))	('promoter hypermethylation', 'Var', (67, 92))	('inactivated', 'NegReg', (52, 63))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('TSG', 'Gene', (33, 36))	('tumor', 'Disease', (9, 14))	('SCC', 'Gene', (170, 173))	('human', 'Species', '9606', (163, 168))	('cancers', 'Disease', 'MESH:D009369', (102, 109))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))	('cancers', 'Disease', (102, 109))	('SCC', 'Gene', '6317', (170, 173))	('TSG', 'Gene', (155, 158))	('TSG', 'Gene', '57045', (33, 36))
418115	31405379	We therefore assessed the methylation status of the TSGs, which are associated with epigenetic silencing in human cancers, OSCC cell lines, primary tumors, and normal oral mucosa.	('primary tumors', 'Disease', (140, 154))	('cancers', 'Disease', 'MESH:D009369', (114, 121))	('TSG', 'Gene', (52, 55))	('cancers', 'Phenotype', 'HP:0002664', (114, 121))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('cancers', 'Disease', (114, 121))	('primary tumors', 'Disease', 'MESH:D009369', (140, 154))	('SCC', 'Gene', (124, 127))	('TSG', 'Gene', '57045', (52, 55))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('human', 'Species', '9606', (108, 113))	('epigenetic silencing', 'Var', (84, 104))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('SCC', 'Gene', '6317', (124, 127))	('assessed', 'Reg', (13, 21))
418121	31405379	Bisulfite sequencing analysis confirmed the cancer-specific methylation of the TFPI2, SOX17, and GATA4 promoters in the OSCC cell lines and tumors but not in the normal oral mucosa samples.	('GATA4', 'Gene', '2626', (97, 102))	('tumors', 'Disease', (140, 146))	('tumors', 'Disease', 'MESH:D009369', (140, 146))	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('GATA4', 'Gene', (97, 102))	('methylation', 'Var', (60, 71))	('SOX17', 'Gene', (86, 91))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('TFPI2', 'Gene', (79, 84))	('SCC', 'Gene', (121, 124))	('TFPI2', 'Gene', '7980', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('SCC', 'Gene', '6317', (121, 124))	('SOX17', 'Gene', '64321', (86, 91))	('Bisulfite', 'Chemical', 'MESH:C042345', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
418122	31405379	More importantly, the methylation status of TFPI2, GATA4, and SOX17 was significantly associated with OSCC patients' overall survival through TCGA DNA methylation database.	('patients', 'Species', '9606', (107, 115))	('TFPI2', 'Gene', (44, 49))	('TFPI2', 'Gene', '7980', (44, 49))	('SOX17', 'Gene', (62, 67))	('GATA4', 'Gene', (51, 56))	('SCC', 'Gene', (103, 106))	('associated with', 'Reg', (86, 101))	('methylation status', 'Var', (22, 40))	('SCC', 'Gene', '6317', (103, 106))	('SOX17', 'Gene', '64321', (62, 67))	('GATA4', 'Gene', '2626', (51, 56))
418123	31405379	We identified that TFPI2, SOX17, and GATA4 are frequently hypermethylated in human OSCC cells in a cancer-specific manner and that the transcriptional expression of these genes is regulated by promoter hypermethylation in OSCC.	('SCC', 'Gene', '6317', (84, 87))	('regulated', 'Reg', (180, 189))	('transcriptional expression', 'MPA', (135, 161))	('SOX17', 'Gene', '64321', (26, 31))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('SCC', 'Gene', (223, 226))	('GATA4', 'Gene', '2626', (37, 42))	('promoter hypermethylation', 'Var', (193, 218))	('cancer', 'Disease', (99, 105))	('GATA4', 'Gene', (37, 42))	('hypermethylated', 'Var', (58, 73))	('SCC', 'Gene', '6317', (223, 226))	('SCC', 'Gene', (84, 87))	('SOX17', 'Gene', (26, 31))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('TFPI2', 'Gene', (19, 24))	('human', 'Species', '9606', (77, 82))	('TFPI2', 'Gene', '7980', (19, 24))
418125	31405379	DNA methylation is the primary and most studied epigenetic modification and plays an important role in normal mammalian development, but aberrant methylation patterns are correlated with several differentiation-related diseases, including many types of human cancers.	('cancers', 'Disease', 'MESH:D009369', (259, 266))	('mammalian', 'Species', '9606', (110, 119))	('cancers', 'Phenotype', 'HP:0002664', (259, 266))	('methylation', 'MPA', (146, 157))	('cancers', 'Disease', (259, 266))	('differentiation-related diseases', 'Disease', (195, 227))	('correlated', 'Reg', (171, 181))	('cancer', 'Phenotype', 'HP:0002664', (259, 265))	('human', 'Species', '9606', (253, 258))	('aberrant', 'Var', (137, 145))
418127	31405379	Aberrant DNA methylation is a common phenomenon in malignancies, and the methylation profiles are altered in various tumors, which might be associated with clinical outcomes.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('associated', 'Reg', (140, 150))	('Aberrant', 'Var', (0, 8))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('malignancies', 'Disease', 'MESH:D009369', (51, 63))	('methylation', 'MPA', (73, 84))	('DNA', 'Protein', (9, 12))	('tumors', 'Disease', (117, 123))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('malignancies', 'Disease', (51, 63))	('altered', 'Reg', (98, 105))
418128	31405379	We and others have reported that the transcriptional silencing of tumor suppressor candidate genes is regulated by promoter hypermethylation in colorectal cancer.	('colorectal cancer', 'Phenotype', 'HP:0003003', (144, 161))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('promoter hypermethylation', 'Var', (115, 140))	('tumor', 'Disease', (66, 71))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('colorectal cancer', 'Disease', (144, 161))	('transcriptional', 'MPA', (37, 52))	('colorectal cancer', 'Disease', 'MESH:D015179', (144, 161))	('tumor', 'Disease', 'MESH:D009369', (66, 71))
418137	31405379	Remarkably, we found that most of the genes are silenced by promoter hypermethylation in OSCC cell lines.	('promoter hypermethylation', 'Var', (60, 85))	('SCC', 'Gene', '6317', (90, 93))	('SCC', 'Gene', (90, 93))	('silenced', 'NegReg', (48, 56))
418138	31405379	Among these genes, TFPI2, SOX17, and GATA4 were frequently hypermethylated in both OSCC and oral cancer patient samples in a cancer-specific manner, suggesting that these genes may play a role as tumor suppressors in OSCC.	('SCC', 'Gene', '6317', (84, 87))	('tumor', 'Disease', (196, 201))	('patient', 'Species', '9606', (104, 111))	('hypermethylated', 'Var', (59, 74))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('SCC', 'Gene', (84, 87))	('SOX17', 'Gene', (26, 31))	('oral cancer', 'Disease', 'MESH:D009062', (92, 103))	('TFPI2', 'Gene', (19, 24))	('SCC', 'Gene', '6317', (218, 221))	('oral cancer', 'Disease', (92, 103))	('cancer', 'Disease', (97, 103))	('GATA4', 'Gene', '2626', (37, 42))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('play', 'Reg', (181, 185))	('cancer', 'Disease', (125, 131))	('SCC', 'Gene', (218, 221))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('TFPI2', 'Gene', '7980', (19, 24))	('cancer', 'Disease', 'MESH:D009369', (97, 103))	('SOX17', 'Gene', '64321', (26, 31))	('GATA4', 'Gene', (37, 42))	('cancer', 'Disease', 'MESH:D009369', (125, 131))
418146	31405379	1a (Additional file 1: Figure S1) with the following three categories: (1) genes are silenced by promoter hypermethylation with re-expression by 5-aza-dC treatment, (2) genes are silenced by promoter hypermethylation without re-expression by 5-aza-dC treatment, and (3) gene expression is not correlated with promoter methylation.	('promoter hypermethylation', 'Var', (191, 216))	('5-aza-dC', 'Chemical', 'MESH:D000077209', (145, 153))	('5-aza-dC', 'Chemical', 'MESH:D000077209', (242, 250))	('silenced', 'NegReg', (179, 187))	('silenced', 'NegReg', (85, 93))
418150	31405379	We found that the transcriptional silencing of 9 genes (MGMT, HIC1, sFRP4, Timp3, TFPI2, SOX17, GATA4, FBN2, and TCERG1L) out of 14 genes by promoter hypermethylation was correlated with gene re-expression by 5-aza-dC treatment in 2 or more OSCC cell lines.	('FBN2', 'Gene', '2201', (103, 107))	('transcriptional', 'MPA', (18, 33))	('5-aza-dC', 'Chemical', 'MESH:D000077209', (209, 217))	('SCC', 'Gene', (242, 245))	('SOX17', 'Gene', (89, 94))	('TFPI2', 'Gene', (82, 87))	('Timp3', 'Gene', (75, 80))	('MGMT', 'Gene', '4255', (56, 60))	('silencing', 'NegReg', (34, 43))	('Timp3', 'Gene', '7078', (75, 80))	('promoter hypermethylation', 'Var', (141, 166))	('GATA4', 'Gene', (96, 101))	('HIC1', 'Gene', (62, 66))	('TCERG1L', 'Gene', '256536', (113, 120))	('TFPI2', 'Gene', '7980', (82, 87))	('MGMT', 'Gene', (56, 60))	('FBN2', 'Gene', (103, 107))	('TCERG1L', 'Gene', (113, 120))	('sFRP4', 'Gene', '6424', (68, 73))	('SOX17', 'Gene', '64321', (89, 94))	('HIC1', 'Gene', '3090', (62, 66))	('sFRP4', 'Gene', (68, 73))	('SCC', 'Gene', '6317', (242, 245))	('GATA4', 'Gene', '2626', (96, 101))
418155	31405379	Overall, we identified four TSGs (TFPI2, SOX17, GATA4, and FBN2) that are regulated by promoter hypermethylation associated with transcriptional silencing in OSCC cell lines.	('promoter hypermethylation', 'Var', (87, 112))	('GATA4', 'Gene', (48, 53))	('FBN2', 'Gene', (59, 63))	('SOX17', 'Gene', (41, 46))	('SCC', 'Gene', (159, 162))	('TFPI2', 'Gene', (34, 39))	('TSG', 'Gene', '57045', (28, 31))	('TFPI2', 'Gene', '7980', (34, 39))	('transcriptional', 'MPA', (129, 144))	('SCC', 'Gene', '6317', (159, 162))	('GATA4', 'Gene', '2626', (48, 53))	('SOX17', 'Gene', '64321', (41, 46))	('FBN2', 'Gene', '2201', (59, 63))	('TSG', 'Gene', (28, 31))
418159	31405379	3a), and frequent methylation in primary OSCC tumor samples (Fig.	('OSCC tumor', 'Disease', (41, 51))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('OSCC tumor', 'Disease', 'MESH:D009369', (41, 51))	('methylation', 'Var', (18, 29))
418164	31405379	The methylation status of the TFPI2 promoter region in OSCC cells and primary tissues showed that most of the CpG sites (> 99%) we sequenced were methylated compared to those in the normal oral mucosal tissues (< 11%).	('TFPI2', 'Gene', '7980', (30, 35))	('TFPI2', 'Gene', (30, 35))	('SCC', 'Gene', (56, 59))	('SCC', 'Gene', '6317', (56, 59))	('methylated', 'Var', (146, 156))
418175	31405379	For example, Kaplan-Meier survival curves for GATA4 and SOX17, individually, show that DNA methylation of each is associated with decreased survival but no significant statistical results for TFPI2 alone (Fig.	('methylation', 'Var', (91, 102))	('TFPI2', 'Gene', (192, 197))	('GATA4', 'Gene', (46, 51))	('SOX17', 'Gene', (56, 61))	('TFPI2', 'Gene', '7980', (192, 197))	('SOX17', 'Gene', '64321', (56, 61))	('survival', 'MPA', (140, 148))	('decreased', 'NegReg', (130, 139))	('GATA4', 'Gene', '2626', (46, 51))
418176	31405379	6a, p = 0.016 for GATA4, p = 0.0066 for SOX17), even though TPFI2 gene was frequently hypermethylated in both OSCC cells and OSCC primary tumors.	('TPFI2', 'Gene', (60, 65))	('SCC', 'Gene', '6317', (126, 129))	('OSCC primary tumors', 'Disease', 'MESH:D009369', (125, 144))	('SOX17', 'Gene', '64321', (40, 45))	('OSCC primary tumors', 'Disease', (125, 144))	('SCC', 'Gene', (111, 114))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('GATA4', 'Gene', '2626', (18, 23))	('SOX17', 'Gene', (40, 45))	('hypermethylated', 'Var', (86, 101))	('SCC', 'Gene', '6317', (111, 114))	('GATA4', 'Gene', (18, 23))	('SCC', 'Gene', (126, 129))
418177	31405379	Very interestingly, combination of two-gene (SOX17 and GATA4) methylation is associated with significantly worse survival (Fig.	('GATA4', 'Gene', '2626', (55, 60))	('GATA4', 'Gene', (55, 60))	('worse', 'NegReg', (107, 112))	('SOX17', 'Gene', (45, 50))	('methylation', 'Var', (62, 73))	('survival', 'MPA', (113, 121))	('SOX17', 'Gene', '64321', (45, 50))
418178	31405379	In addition, SOX17 combination of TFPI2 gene methylation is associated with worse survival as well (Fig, 6)b, p = 0.019, but there are no statistically significant results for combination of GATA4 and TFPI2 genes.	('TFPI2', 'Gene', '7980', (201, 206))	('SOX17', 'Gene', (13, 18))	('TFPI2', 'Gene', (34, 39))	('GATA4', 'Gene', '2626', (191, 196))	('TFPI2', 'Gene', '7980', (34, 39))	('worse', 'NegReg', (76, 81))	('GATA4', 'Gene', (191, 196))	('methylation', 'Var', (45, 56))	('SOX17', 'Gene', '64321', (13, 18))	('TFPI2', 'Gene', (201, 206))
418181	31405379	The aberrant promoter hypermethylation in the adjacent of transcription start sites (TSSs) often leads to alterations in gene function and abnormal cellular pathway in human cancer.	('cellular pathway', 'CPA', (148, 164))	('human', 'Species', '9606', (168, 173))	('gene function', 'MPA', (121, 134))	('aberrant', 'Var', (4, 12))	('cancer', 'Disease', (174, 180))	('leads to alterations', 'Reg', (97, 117))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('promoter', 'MPA', (13, 21))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('abnormal', 'Reg', (139, 147))
418182	31405379	Epigenetic events linked to TSG inactivation through promoter methylation are as frequent as somatic mutations in cancer and contribute to drive tumor initiation and progression.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('cancer', 'Disease', (114, 120))	('TSG', 'Gene', '57045', (28, 31))	('tumor', 'Disease', (145, 150))	('Epigenetic', 'Var', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('drive', 'PosReg', (139, 144))	('inactivation', 'Var', (32, 44))	('promoter', 'MPA', (53, 61))	('progression', 'CPA', (166, 177))	('TSG', 'Gene', (28, 31))
418184	31405379	Recently, it has been demonstrated that OSCC involves genetic alterations and epigenetic mechanisms play crucial roles.	('SCC', 'Gene', (41, 44))	('genetic alterations', 'Var', (54, 73))	('SCC', 'Gene', '6317', (41, 44))
418194	31405379	TFPI2 methylation frequently existed in CRC patients' sera and stool samples.	('patients', 'Species', '9606', (44, 52))	('TFPI2', 'Gene', (0, 5))	('TFPI2', 'Gene', '7980', (0, 5))	('methylation', 'Var', (6, 17))	('existed', 'Reg', (29, 36))	('CRC', 'Phenotype', 'HP:0003003', (40, 43))
418195	31405379	Moreover, hypermethylated TFPI2 was associated with recurrence and early-stage CRC, and TFPI2 was significant in CRC patients' sera with large, poorly differentiated carcinoma, deep invasion, lymph node metastasis, or distant metastasis.	('carcinoma', 'Disease', 'MESH:D002277', (166, 175))	('TFPI2', 'Gene', (88, 93))	('early-stage', 'CPA', (67, 78))	('TFPI2', 'Gene', '7980', (88, 93))	('CRC', 'Phenotype', 'HP:0003003', (79, 82))	('TFPI2', 'Gene', (26, 31))	('distant metastasis', 'CPA', (218, 236))	('recurrence', 'Disease', (52, 62))	('TFPI2', 'Gene', '7980', (26, 31))	('CRC', 'Phenotype', 'HP:0003003', (113, 116))	('carcinoma', 'Phenotype', 'HP:0030731', (166, 175))	('carcinoma', 'Disease', (166, 175))	('patients', 'Species', '9606', (117, 125))	('lymph node metastasis', 'CPA', (192, 213))	('deep invasion', 'CPA', (177, 190))	('hypermethylated', 'Var', (10, 25))	('associated', 'Reg', (36, 46))
418197	31405379	In this study, we validated that TFPI2 is frequently methylated in a panel of OSCC primary tumor samples in a cancer-specific manner and that TFPI2 is transcriptionally regulated by promoter hypermethylation in OSCC cells.	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('cancer', 'Disease', (110, 116))	('SCC', 'Gene', (212, 215))	('SCC', 'Gene', (79, 82))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('SCC', 'Gene', '6317', (212, 215))	('SCC', 'Gene', '6317', (79, 82))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('TFPI2', 'Gene', '7980', (142, 147))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('TFPI2', 'Gene', (142, 147))	('promoter hypermethylation', 'Var', (182, 207))	('tumor', 'Disease', (91, 96))	('TFPI2', 'Gene', (33, 38))	('TFPI2', 'Gene', '7980', (33, 38))
418198	31405379	Our study thus highlights the finding that TFPI2 is hypermethylated in most OSCC tumor samples we tested in this study, suggesting that TFPI2 may be a useful biomarker for screening OSCC patients.	('hypermethylated', 'Var', (52, 67))	('TFPI2', 'Gene', (43, 48))	('patients', 'Species', '9606', (187, 195))	('TFPI2', 'Gene', '7980', (43, 48))	('OSCC tumor', 'Disease', (76, 86))	('TFPI2', 'Gene', '7980', (136, 141))	('TFPI2', 'Gene', (136, 141))	('SCC', 'Gene', (183, 186))	('OSCC tumor', 'Disease', 'MESH:D009369', (76, 86))	('SCC', 'Gene', (77, 80))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('SCC', 'Gene', '6317', (183, 186))	('SCC', 'Gene', '6317', (77, 80))
418202	31405379	Additionally, epigenetically regulated SOX17 may contribute to the abnormal activation of the Wnt signaling pathway in human cancer.	('SOX17', 'Gene', '64321', (39, 44))	('cancer', 'Disease', (125, 131))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('SOX17', 'Gene', (39, 44))	('contribute', 'Reg', (49, 59))	('Wnt signaling pathway', 'Pathway', (94, 115))	('epigenetically regulated', 'Var', (14, 38))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('activation', 'PosReg', (76, 86))	('human', 'Species', '9606', (119, 124))
418203	31405379	The high frequency of SOX17 methylation in 50% of non-small-cell lung cancers and nearly 90% of esophageal squamous cancers strongly supports this possibility and is consistent with the known role of the aberrant activation of Wnt signaling during tumorigenesis for multiple cancer types.	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('lung cancers', 'Disease', 'MESH:D008175', (65, 77))	('cancer', 'Disease', 'MESH:D009369', (275, 281))	('tumor', 'Disease', (248, 253))	('lung cancers', 'Disease', (65, 77))	('SOX17', 'Gene', '64321', (22, 27))	('esophageal squamous cancers', 'Disease', (96, 123))	('lung cancer', 'Phenotype', 'HP:0100526', (65, 76))	('esophageal squamous cancers', 'Disease', 'MESH:D004938', (96, 123))	('tumor', 'Disease', 'MESH:D009369', (248, 253))	('cancers', 'Phenotype', 'HP:0002664', (70, 77))	('lung cancers', 'Phenotype', 'HP:0100526', (65, 77))	('cancer', 'Disease', (70, 76))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('cancer', 'Disease', (116, 122))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('SOX17', 'Gene', (22, 27))	('methylation', 'Var', (28, 39))	('tumor', 'Phenotype', 'HP:0002664', (248, 253))	('cancer', 'Disease', (275, 281))	('cancer', 'Phenotype', 'HP:0002664', (275, 281))	('cancers', 'Phenotype', 'HP:0002664', (116, 123))	('cancer', 'Disease', 'MESH:D009369', (70, 76))
418207	31405379	The loss of GATA4 expression due to promoter hypermethylation has been reported in primary colorectal, gastric, esophageal, lung, and ovarian cancers.	('colorectal', 'Disease', 'MESH:D015179', (91, 101))	('promoter hypermethylation', 'Var', (36, 61))	('ovarian cancers', 'Phenotype', 'HP:0100615', (134, 149))	('ovarian cancers', 'Disease', (134, 149))	('GATA4', 'Gene', '2626', (12, 17))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('lung', 'Disease', (124, 128))	('gastric', 'Disease', (103, 110))	('colorectal', 'Disease', (91, 101))	('GATA4', 'Gene', (12, 17))	('esophageal', 'Disease', 'MESH:D004941', (112, 122))	('ovarian cancers', 'Disease', 'MESH:D010051', (134, 149))	('expression', 'MPA', (18, 28))	('cancers', 'Phenotype', 'HP:0002664', (142, 149))	('loss', 'NegReg', (4, 8))	('esophageal', 'Disease', (112, 122))
418209	31405379	Epigenetic alterations of specific genes have recently emerged as potential candidate biomarkers for the early detection of cancer.	('Epigenetic alterations', 'Var', (0, 22))	('cancer', 'Disease', (124, 130))	('cancer', 'Disease', 'MESH:D009369', (124, 130))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))
418212	31405379	Recently, several studies have reported that early DNA promoter methylation alterations are associated with histological changes during oral tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('alterations', 'Var', (76, 87))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('early DNA promoter', 'Protein', (45, 63))	('tumor', 'Disease', (141, 146))	('associated', 'Reg', (92, 102))
418214	31405379	According to our KM analysis for patients with OSCC from TCGA data, we found a statistically significant increased risk for mortality when either individual genes or combination of genes were methylated.	('SCC', 'Gene', (48, 51))	('patients', 'Species', '9606', (33, 41))	('SCC', 'Gene', '6317', (48, 51))	('methylated', 'Var', (192, 202))
418216	31405379	Promoter methylation of TFPI2 is detected in most of tumors (over 90% tested cancer patients samples) with OSCC and other cancer types as well which explained TFPI2 methylation can be useful for early detection biomarker rather than prognostic biomarkers.	('SCC', 'Gene', (108, 111))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('TFPI2', 'Gene', '7980', (24, 29))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('TFPI2', 'Gene', '7980', (159, 164))	('patients', 'Species', '9606', (84, 92))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('methylation', 'Var', (165, 176))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumors', 'Disease', (53, 59))	('cancer', 'Disease', (77, 83))	('TFPI2', 'Gene', (24, 29))	('detected', 'Reg', (33, 41))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('TFPI2', 'Gene', (159, 164))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('cancer', 'Disease', (122, 128))	('SCC', 'Gene', '6317', (108, 111))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))
418220	31405379	Based on our data, the dysregulation of the TFPI2, SOX17, and GATA4 genes regulated by epigenetic changes may explain a main mechanism linked to OSCC development, and these three-gene panels could serve as synergistic prognostic biomarkers in OSCC treatment.	('dysregulation', 'Var', (23, 36))	('GATA4', 'Gene', (62, 67))	('TFPI2', 'Gene', (44, 49))	('TFPI2', 'Gene', '7980', (44, 49))	('SCC', 'Gene', (244, 247))	('SOX17', 'Gene', (51, 56))	('linked', 'Reg', (135, 141))	('SCC', 'Gene', (146, 149))	('SCC', 'Gene', '6317', (244, 247))	('epigenetic changes', 'Var', (87, 105))	('SCC', 'Gene', '6317', (146, 149))	('SOX17', 'Gene', '64321', (51, 56))	('GATA4', 'Gene', '2626', (62, 67))
418223	31405379	We identified the transcriptional expression of 9 genes regulated by promoter hypermethylation in OSCC and finally provided 3 genes (TFPI2, SOX17, and GATA4) that were frequently hypermethylated in primary OSCC tumors in a cancer-specific manner.	('SOX17', 'Gene', (140, 145))	('GATA4', 'Gene', (151, 156))	('TFPI2', 'Gene', (133, 138))	('SCC', 'Gene', '6317', (99, 102))	('TFPI2', 'Gene', '7980', (133, 138))	('SCC', 'Gene', '6317', (207, 210))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('tumors', 'Phenotype', 'HP:0002664', (211, 217))	('GATA4', 'Gene', '2626', (151, 156))	('SOX17', 'Gene', '64321', (140, 145))	('SCC', 'Gene', (207, 210))	('cancer', 'Disease', 'MESH:D009369', (223, 229))	('primary OSCC tumors', 'Disease', 'MESH:D009369', (198, 217))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('cancer', 'Disease', (223, 229))	('SCC', 'Gene', (99, 102))	('promoter hypermethylation', 'Var', (69, 94))	('primary OSCC tumors', 'Disease', (198, 217))
418225	31405379	Our study thus highlights the finding that the dysregulation of TFPI2, SOX17, and GATA4 genes regulated by epigenetic changes may explain a main mechanism linked to OSCC development, and this three-gene panel has a potential to be used as a synergistic biomarker set capable of improving the prognosis and treatment for patients with OSCC.	('SCC', 'Gene', '6317', (335, 338))	('dysregulation', 'Var', (47, 60))	('linked', 'Reg', (155, 161))	('SOX17', 'Gene', '64321', (71, 76))	('TFPI2', 'Gene', (64, 69))	('GATA4', 'Gene', '2626', (82, 87))	('TFPI2', 'Gene', '7980', (64, 69))	('SCC', 'Gene', (166, 169))	('GATA4', 'Gene', (82, 87))	('epigenetic changes', 'Var', (107, 125))	('SCC', 'Gene', '6317', (166, 169))	('SCC', 'Gene', (335, 338))	('SOX17', 'Gene', (71, 76))	('patients', 'Species', '9606', (320, 328))
418273	29440175	The Cancer Genome Atlas (TCGA), a large-scale effort to comprehensively characterize over 10,000 human cancers at the molecular level, provides a common platform for the study of diverse cancer types, with multiple levels of data including mRNA, miRNA, protein, DNA methylation, copy number, and mutation.	('cancers', 'Disease', 'MESH:D009369', (103, 110))	('human', 'Species', '9606', (97, 102))	('Cancer', 'Phenotype', 'HP:0002664', (4, 10))	('mRNA', 'MPA', (240, 244))	('cancer', 'Disease', (103, 109))	('copy number', 'Var', (279, 290))	('cancer', 'Disease', 'MESH:D009369', (187, 193))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('Cancer', 'Disease', (4, 10))	('DNA', 'MPA', (262, 265))	('cancers', 'Phenotype', 'HP:0002664', (103, 110))	('protein', 'Protein', (253, 260))	('mutation', 'Var', (296, 304))	('cancers', 'Disease', (103, 110))	('Cancer', 'Disease', 'MESH:D009369', (4, 10))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('cancer', 'Disease', (187, 193))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('miRNA', 'MPA', (246, 251))
418316	29440175	A number of pathway-level or individual gene-level alterations surveyed were highly represented within specific cancer types or pan-cancer classes (Supplementary Figures 8B and 9B).	('alterations', 'Var', (51, 62))	('cancer', 'Disease', (132, 138))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (132, 138))
418317	29440175	In particular, TP53 mutations were highly represented within both c4 and c5 tumors, and MYC amplifications were highly represented in c5 tumors (Supplementary Figures 8B and 9B).	('tumors', 'Disease', (137, 143))	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('MYC', 'Gene', '4609', (88, 91))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('tumors', 'Disease', (76, 82))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('TP53', 'Gene', (15, 19))	('TP53', 'Gene', '7157', (15, 19))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('MYC', 'Gene', (88, 91))	('mutations', 'Var', (20, 29))
418319	29440175	Some of the somatic mutation associations observed might be attributable to cancer type- or mutation rate-specific patterns (Supplementary Figures 10 and 11); for example, TP53 and chromatin modifier mutations being enriched within c4 tumors would reflect in part the types of cancers more highly represented within c4 (BLCA, CESC, HNSC, LUSC, etc.).	('mutations', 'Var', (200, 209))	('cancers', 'Disease', 'MESH:D009369', (277, 284))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('LUSC', 'Disease', (338, 342))	('cancer', 'Disease', (277, 283))	('TP53', 'Gene', (172, 176))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('CESC', 'Disease', (326, 330))	('cancer', 'Phenotype', 'HP:0002664', (277, 283))	('tumors', 'Phenotype', 'HP:0002664', (235, 241))	('cancers', 'Phenotype', 'HP:0002664', (277, 284))	('cancers', 'Disease', (277, 284))	('cancer', 'Disease', (76, 82))	('HNSC', 'Disease', (332, 336))	('tumors', 'Disease', (235, 241))	('TP53', 'Gene', '7157', (172, 176))	('cancer', 'Disease', 'MESH:D009369', (277, 283))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('tumors', 'Disease', 'MESH:D009369', (235, 241))
418321	29440175	p53-related alterations were associated with decreased levels of p53 transcriptional targets, and MTOR-related alterations were associated with increased MTOR proteomic signaling)(Supplementary Figure 8C).	('p53', 'Gene', (0, 3))	('p53', 'Gene', '7157', (0, 3))	('p53', 'Gene', (65, 68))	('p53', 'Gene', '7157', (65, 68))	('MTOR', 'Gene', '2475', (154, 158))	('alterations', 'Reg', (111, 122))	('alterations', 'Var', (12, 23))	('MTOR', 'Gene', (98, 102))	('decreased', 'NegReg', (45, 54))	('MTOR', 'Gene', (154, 158))	('MTOR', 'Gene', '2475', (98, 102))	('increased', 'PosReg', (144, 153))
418357	29440175	Deregulated pathways were also reflective of tumor microenvironmental effects at work in distinct subsets of cancers.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('Deregulated', 'Var', (0, 11))	('cancers', 'Disease', 'MESH:D009369', (109, 116))	('cancers', 'Phenotype', 'HP:0002664', (109, 116))	('tumor', 'Disease', (45, 50))	('cancers', 'Disease', (109, 116))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
418379	29440175	For example, mutations in VHL or in RTK genes may accelerate processes of hypoxia or RTK signaling, respectively, or microenvironmental conditions such as lack of oxygen or availabilty of growth factors could conceivably achieve the same respective results.	('accelerate', 'PosReg', (50, 60))	('processes', 'MPA', (61, 70))	('VHL', 'Disease', (26, 29))	('RTK signaling', 'MPA', (85, 98))	('hypoxia', 'Disease', 'MESH:D000860', (74, 81))	('RTK genes', 'Gene', (36, 45))	('hypoxia', 'Disease', (74, 81))	('oxygen', 'Chemical', 'MESH:D010100', (163, 169))	('mutations', 'Var', (13, 22))	('VHL', 'Disease', 'MESH:D006623', (26, 29))
418405	29731995	We found EGFR expression is higher in the squamous cell carcinomas than in adenocarcinomas (p=0.043), and that nuclear p53 staining correlated with lower differentiated squamous tumors (p=0.034).	('squamous cell carcinomas', 'Disease', (42, 66))	('adenocarcinomas', 'Disease', 'MESH:D000230', (75, 90))	('carcinoma', 'Phenotype', 'HP:0030731', (56, 65))	('adenocarcinomas', 'Disease', (75, 90))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('carcinomas', 'Phenotype', 'HP:0030731', (56, 66))	('carcinomas', 'Phenotype', 'HP:0030731', (80, 90))	('higher', 'PosReg', (28, 34))	('EGFR', 'Gene', (9, 13))	('nuclear', 'Var', (111, 118))	('tumors', 'Phenotype', 'HP:0002664', (178, 184))	('squamous tumor', 'Phenotype', 'HP:0002860', (169, 183))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (42, 66))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (42, 65))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('squamous tumors', 'Disease', (169, 184))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (42, 66))	('lower', 'NegReg', (148, 153))	('expression', 'MPA', (14, 24))	('squamous tumors', 'Disease', 'MESH:D002294', (169, 184))	('EGFR', 'Gene', '1956', (9, 13))
418416	29731995	In this sense, lung cancer patients harboring EGFR mutations are sensitive to EGFR tyrosine kinase inhibitors (TKIs).	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('mutations', 'Var', (51, 60))	('EGFR', 'Gene', '1956', (46, 50))	('sensitive', 'Reg', (65, 74))	('lung cancer', 'Disease', 'MESH:D008175', (15, 26))	('patients', 'Species', '9606', (27, 35))	('EGFR', 'Gene', (46, 50))	('EGFR', 'Gene', '1956', (78, 82))	('EGFR', 'Gene', (78, 82))	('lung cancer', 'Disease', (15, 26))	('lung cancer', 'Phenotype', 'HP:0100526', (15, 26))
418417	29731995	Although these mutations are characteristic of adenocarcinoma tumors, it has been recently shown that some squamous cell carcinoma patients respond to anti-EGFR therapy and that high EGFR expression levels correlate with better responses in these patients, highlighting the therapeutic relevance of EGFR in this setting.	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (107, 130))	('expression levels', 'MPA', (188, 205))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('EGFR', 'Gene', '1956', (299, 303))	('EGFR', 'Gene', (183, 187))	('EGFR', 'Gene', '1956', (156, 160))	('mutations', 'Var', (15, 24))	('squamous cell carcinoma', 'Disease', (107, 130))	('patients', 'Species', '9606', (131, 139))	('respond', 'Reg', (140, 147))	('adenocarcinoma tumors', 'Disease', 'MESH:D000230', (47, 68))	('patients', 'Species', '9606', (247, 255))	('adenocarcinoma tumors', 'Disease', (47, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (52, 61))	('EGFR', 'Gene', (299, 303))	('EGFR', 'Gene', '1956', (183, 187))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (107, 130))	('EGFR', 'Gene', (156, 160))	('responses', 'MPA', (228, 237))
418418	29731995	Alterations in EGFR, as well as in other genes such as KRAS mutations or ALK translocations, are frequent in lung adenocarcinoma; all these changes have been involved in the activation of signaling pathways critical in lung tumorigenesis, such as MAPK and PI3K/AKT pathways.	('AKT', 'Gene', (261, 264))	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('Alterations', 'Var', (0, 11))	('lung tumor', 'Disease', 'MESH:D008175', (219, 229))	('EGFR', 'Gene', '1956', (15, 19))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (109, 128))	('frequent', 'Reg', (97, 105))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (109, 128))	('changes', 'Var', (140, 147))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('AKT', 'Gene', '207', (261, 264))	('signaling pathways', 'Pathway', (188, 206))	('ALK', 'Gene', '238', (73, 76))	('KRAS', 'Gene', '3845', (55, 59))	('involved', 'Reg', (158, 166))	('lung tumor', 'Disease', (219, 229))	('EGFR', 'Gene', (15, 19))	('activation', 'PosReg', (174, 184))	('ALK', 'Gene', (73, 76))	('KRAS', 'Gene', (55, 59))	('lung tumor', 'Phenotype', 'HP:0100526', (219, 229))	('lung adenocarcinoma', 'Disease', (109, 128))
418423	29731995	However, mutant p53 is unable to bind DNA and can no longer prevent cell cycle continuation, which contributes to cancer progression.	('prevent', 'NegReg', (60, 67))	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('contributes', 'Reg', (99, 110))	('mutant', 'Var', (9, 15))	('p53', 'Gene', (16, 19))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('cell cycle continuation', 'CPA', (68, 91))	('cancer', 'Disease', (114, 120))
418449	29731995	However, in the squamous cell carcinoma patients, a clear association was found between higher nuclear p53 percentage and worse progression-free survival (p=0.031), with a median progression-free survival of 35.4 [22.7-48.1] months for patients with high nuclear p53 staining, while the median survival value was not reached in the group of patients with low nuclear p53 protein levels.	('higher', 'PosReg', (88, 94))	('nuclear p53', 'MPA', (95, 106))	('patients', 'Species', '9606', (341, 349))	('high', 'Var', (250, 254))	('patients', 'Species', '9606', (40, 48))	('patients', 'Species', '9606', (236, 244))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (16, 39))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (16, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (30, 39))	('squamous cell carcinoma', 'Disease', (16, 39))
418456	29731995	By incorporating the expression levels of the previously assessed proteins into chemotherapy treatment information, we identified a trend demonstrating that patients with high nuclear pAKT expression could benefit from adjuvant chemotherapy; however, this therapeutic approach may not be a good choice for patients whose tumors show low expression of this marker (Supplementary Figure 3A).	('AKT', 'Gene', (185, 188))	('men', 'Species', '9606', (370, 373))	('tumors', 'Disease', 'MESH:D009369', (321, 327))	('high', 'Var', (171, 175))	('patients', 'Species', '9606', (157, 165))	('tumor', 'Phenotype', 'HP:0002664', (321, 326))	('tumors', 'Phenotype', 'HP:0002664', (321, 327))	('AKT', 'Gene', '207', (185, 188))	('men', 'Species', '9606', (98, 101))	('tumors', 'Disease', (321, 327))	('patients', 'Species', '9606', (306, 314))
418460	29731995	In this study, we report a prognostic role for pERK levels in lung adenocarcinoma, and we demonstrate that nuclear p53 expression is a potential prognostic biomarker in lung squamous cell carcinoma patients, where it is associated with poorer tumor differentiation.	('pERK', 'Gene', '9451', (47, 51))	('pERK', 'Gene', (47, 51))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (62, 81))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('patients', 'Species', '9606', (198, 206))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (169, 197))	('lung adenocarcinoma', 'Disease', (62, 81))	('nuclear p53', 'Var', (107, 118))	('tumor', 'Disease', 'MESH:D009369', (243, 248))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (169, 197))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (62, 81))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (174, 197))	('lung squamous cell carcinoma', 'Disease', (169, 197))	('carcinoma', 'Phenotype', 'HP:0030731', (188, 197))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))	('tumor', 'Disease', (243, 248))
418468	29731995	EGFR has been primarily linked to adenocarcinoma, where alterations in this gene represent a cancer-driving force, and anti-EGFR therapy is approved for patients with these alterations.	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('EGFR', 'Gene', (0, 4))	('EGFR', 'Gene', '1956', (124, 128))	('adenocarcinoma', 'Disease', (34, 48))	('alterations', 'Var', (56, 67))	('patients', 'Species', '9606', (153, 161))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('EGFR', 'Gene', (124, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (39, 48))	('adenocarcinoma', 'Disease', 'MESH:D000230', (34, 48))	('linked', 'Reg', (24, 30))	('EGFR', 'Gene', '1956', (0, 4))
418473	29731995	In several retrospective studies involving NSCLC patients, high pERK levels were reported as a prognostic factor for overall survival and for recurrence-free survival.	('pERK', 'Gene', '9451', (64, 68))	('overall survival', 'CPA', (117, 133))	('high', 'Var', (59, 63))	('patients', 'Species', '9606', (49, 57))	('NSCLC', 'Disease', (43, 48))	('pERK', 'Gene', (64, 68))	('recurrence-free survival', 'CPA', (142, 166))	('NSCLC', 'Disease', 'MESH:D002289', (43, 48))
418478	29731995	The most incident molecular alterations in lung adenocarcinoma, namely, KRAS mutations, EGFR mutations and ALK translocations, have been linked to MAPK activation.	('activation', 'PosReg', (152, 162))	('mutations', 'Var', (93, 102))	('KRAS', 'Gene', (72, 76))	('MAPK', 'Gene', (147, 151))	('ALK', 'Gene', '238', (107, 110))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (43, 62))	('KRAS', 'Gene', '3845', (72, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (53, 62))	('mutations', 'Var', (77, 86))	('EGFR', 'Gene', '1956', (88, 92))	('lung adenocarcinoma', 'Disease', (43, 62))	('ALK', 'Gene', (107, 110))	('EGFR', 'Gene', (88, 92))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (43, 62))
418479	29731995	Mutations in these three genes alone represent the driving alteration in approximately half of adenocarcinoma tumors, which is in accordance with the prognostic role of pERK observed in our adenocarcinoma cohort.	('adenocarcinoma tumors', 'Disease', (95, 116))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('adenocarcinoma tumors', 'Disease', 'MESH:D000230', (95, 116))	('Mutations', 'Var', (0, 9))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('adenocarcinoma cohort', 'Disease', 'MESH:D000230', (190, 211))	('pERK', 'Gene', '9451', (169, 173))	('pERK', 'Gene', (169, 173))	('adenocarcinoma cohort', 'Disease', (190, 211))	('carcinoma', 'Phenotype', 'HP:0030731', (195, 204))
418484	29731995	In contrast to the previously cited studies, another study correlated p53 IHC and poorer survival in NSCLC.	('p53 IHC', 'Var', (70, 77))	('poorer', 'NegReg', (82, 88))	('NSCLC', 'Disease', (101, 106))	('NSCLC', 'Disease', 'MESH:D002289', (101, 106))	('survival', 'MPA', (89, 97))
418485	29731995	This study evaluated p53 IHC not only in primary lung tumor samples but also in metastatic tumors, and most samples were obtained from advanced-stage tumors (III-IV).	('tumors', 'Disease', (91, 97))	('tumors', 'Disease', (150, 156))	('tumors', 'Disease', 'MESH:D009369', (91, 97))	('tumors', 'Disease', 'MESH:D009369', (150, 156))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('tumors', 'Phenotype', 'HP:0002664', (150, 156))	('evaluated', 'Reg', (11, 20))	('lung tumor', 'Phenotype', 'HP:0100526', (49, 59))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('lung tumor', 'Disease', 'MESH:D008175', (49, 59))	('lung tumor', 'Disease', (49, 59))	('p53 IHC', 'Var', (21, 28))
418490	29731995	In accordance with our results, a study involving stage I lung squamous cell carcinoma patients reported that high p53 IHC correlates with lower overall survival.	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (58, 86))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (63, 86))	('overall survival', 'MPA', (145, 161))	('I lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (56, 86))	('I lung squamous cell carcinoma', 'Disease', (56, 86))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('high p53', 'Var', (110, 118))	('lower', 'NegReg', (139, 144))	('patients', 'Species', '9606', (87, 95))
418491	29731995	Our results in a higher number of patients, are in line with this prognostic role for p53 IHC in lung squamous cell carcinoma and extend it to early-stage patients, and not only to stage I patients, with this subtype of NSCLC.	('p53 IHC', 'Var', (86, 93))	('NSCLC', 'Disease', (220, 225))	('NSCLC', 'Disease', 'MESH:D002289', (220, 225))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (97, 125))	('IHC', 'Var', (90, 93))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (97, 125))	('patients', 'Species', '9606', (34, 42))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('patients', 'Species', '9606', (155, 163))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (102, 125))	('patients', 'Species', '9606', (189, 197))	('lung squamous cell carcinoma', 'Disease', (97, 125))
418493	29731995	p53 IHC staining has been previously related to poor differentiation in NSCLC.	('NSCLC', 'Disease', (72, 77))	('p53', 'Var', (0, 3))	('NSCLC', 'Disease', 'MESH:D002289', (72, 77))
418495	29731995	Furthermore, mutant p53 has been shown to exert differentiation-blocking effects, affecting normal cellular maturation and generating highly proliferative lethal tumors and to facilitate reprogramming efficiency of somatic cells.	('mutant', 'Var', (13, 19))	('p53', 'Gene', (20, 23))	('affecting', 'Reg', (82, 91))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('normal cellular maturation', 'CPA', (92, 118))	('facilitate', 'PosReg', (176, 186))	('reprogramming efficiency', 'CPA', (187, 211))	('tumors', 'Disease', (162, 168))	('tumors', 'Disease', 'MESH:D009369', (162, 168))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))	('generating', 'Reg', (123, 133))
418497	29731995	Regarding the potential therapeutic relevance of these findings, although limited therapies addressing p53 alterations have been approved for use in patients, several approaches to target p53 are being evaluated.	('alterations', 'Var', (107, 118))	('patients', 'Species', '9606', (149, 157))	('p53', 'Gene', (103, 106))
418519	29731995	Immune detection was performed with the pAKT (Ser473, #736E11, Cell Signaling), pERK (Thr202/Tyr204, #9101 CST), FLEX p53 (#GA616, Dako) and EGFR (#NCL-L-EGFR-384, Leica) antibodies.	('EGFR', 'Gene', (154, 158))	('Thr202/Tyr204', 'Var', (86, 99))	('EGFR', 'Gene', '1956', (141, 145))	('#GA616', 'Var', (123, 129))	('Ser473', 'Var', (46, 52))	('Ser473', 'Chemical', '-', (46, 52))	('EGFR', 'Gene', (141, 145))	('pERK', 'Gene', '9451', (80, 84))	('#9101 CST', 'Var', (101, 110))	('Thr202', 'Chemical', '-', (86, 92))	('pERK', 'Gene', (80, 84))	('AKT', 'Gene', '207', (41, 44))	('Tyr204', 'Chemical', '-', (93, 99))	('EGFR', 'Gene', '1956', (154, 158))	('AKT', 'Gene', (41, 44))
418521	29125844	Significant associations between driver gene mutations and DNA methylation alterations across many cancer types Recent evidence shows that mutations in several driver genes can cause aberrant methylation patterns, a hallmark of cancer.	('hallmark of cancer', 'Disease', (216, 234))	('cancer', 'Disease', (228, 234))	('mutations', 'Var', (139, 148))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('hallmark of cancer', 'Disease', 'MESH:D009369', (216, 234))	('cancer', 'Disease', (99, 105))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('aberrant methylation patterns', 'MPA', (183, 212))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('cause', 'Reg', (177, 182))	('cancer', 'Disease', 'MESH:D009369', (228, 234))
418523	29125844	We found that a few mutated driver genes were associated with genome-wide patterns of aberrant hypomethylation or CpG island hypermethylation in specific cancer types.	('CpG island hypermethylation', 'Var', (114, 141))	('aberrant hypomethylation', 'Var', (86, 110))	('cancer', 'Disease', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('associated', 'Reg', (46, 56))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))
418524	29125844	Moreover, using these mutation-methylation associations, we were able to distinguish between two uterine and two thyroid cancer subtypes.	('uterine', 'Disease', (97, 104))	('mutation-methylation', 'Var', (22, 42))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('thyroid cancer', 'Phenotype', 'HP:0002890', (113, 127))	('thyroid cancer', 'Disease', (113, 127))	('distinguish', 'Reg', (73, 84))	('thyroid cancer', 'Disease', 'MESH:D013964', (113, 127))
418525	29125844	The driver gene mutation-associated methylation differences between the thyroid cancer subtypes were linked to differential gene expression in JAK-STAT signaling, NADPH oxidation, and other cancer-related pathways.	('cancer', 'Disease', (190, 196))	('cancer', 'Disease', 'MESH:D009369', (190, 196))	('thyroid cancer', 'Phenotype', 'HP:0002890', (72, 86))	('mutation-associated', 'Reg', (16, 35))	('differences', 'Var', (48, 59))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('JAK-STAT signaling', 'MPA', (143, 161))	('methylation differences', 'Var', (36, 59))	('thyroid cancer', 'Disease', 'MESH:D013964', (72, 86))	('linked', 'Reg', (101, 107))	('NADPH', 'Chemical', 'MESH:D009249', (163, 168))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('thyroid cancer', 'Disease', (72, 86))	('cancer', 'Disease', (80, 86))
418527	29125844	Mutations that alter the function of driver genes by changing DNA nucleotides have been recognized as key players in cancer progression.	('DNA nucleotides', 'MPA', (62, 77))	('function', 'MPA', (25, 33))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('Mutations', 'Var', (0, 9))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('cancer', 'Disease', (117, 123))
418528	29125844	However, recent evidence has shown that DNA methylation, which can control gene expression, is also highly dysregulated in cancer and contributes to carcinogenesis.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('gene expression', 'MPA', (75, 90))	('methylation', 'Var', (44, 55))	('carcinogenesis', 'Disease', (149, 163))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('cancer', 'Disease', (123, 129))	('contributes to', 'Reg', (134, 148))	('carcinogenesis', 'Disease', 'MESH:D063646', (149, 163))
418529	29125844	Whether methylation alterations correspond to mutated driver genes in cancer remains unclear.	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('methylation', 'Var', (8, 19))
418530	29125844	In this study, we analyzed 4,302 tumors from 18 cancer types and demonstrated that driver gene mutations are inherently connected with the aberrant DNA methylation landscape in cancer.	('cancer', 'Disease', (177, 183))	('cancer', 'Disease', 'MESH:D009369', (177, 183))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('mutations', 'Var', (95, 104))	('tumors', 'Disease', 'MESH:D009369', (33, 39))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('tumors', 'Disease', (33, 39))
418531	29125844	We showed that driver gene-associated methylation patterns can classify heterogeneous tumors within a cancer type into homogeneous subtypes and have the potential to influence genes that contribute to tumor growth.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('methylation patterns', 'Var', (38, 58))	('tumor', 'Disease', (86, 91))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('tumors', 'Disease', (86, 92))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('tumor', 'Disease', (201, 206))	('genes', 'Gene', (176, 181))	('influence', 'Reg', (166, 175))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
418532	29125844	This finding could help us better understand the fundamental connection between driver gene mutations and DNA methylation alterations in cancer, and to further improve cancer treatment.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('mutations', 'Var', (92, 101))	('cancer', 'Disease', (137, 143))	('cancer', 'Disease', (168, 174))
418533	29125844	DNA methylation (DNAm) is highly dysregulated in cancers from many organs, displaying aberrant CpG island (CGI) hypermethylation and long-range blocks of hypomethylation.	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('hypermethylation', 'Var', (112, 128))	('cancers', 'Disease', 'MESH:D009369', (49, 56))	('cancers', 'Phenotype', 'HP:0002664', (49, 56))	('cancers', 'Disease', (49, 56))
418540	29125844	Because tumors of the same molecular subtype often harbor both dysregulated DNAm at particular locations in the genome and mutations in driver genes, we decided to investigate the connection between somatic mutations and specific aberrant DNAm patterns.	('dysregulated', 'Var', (63, 75))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('tumors', 'Phenotype', 'HP:0002664', (8, 14))	('tumors', 'Disease', 'MESH:D009369', (8, 14))	('tumors', 'Disease', (8, 14))
418542	29125844	For example, mutations in SETD2, the H3K36me3 writer, lead to ectopic H3K36me3, coinciding with DNA hypermethylation in renal cell carcinomas.	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('lead', 'Reg', (54, 58))	('carcinomas', 'Phenotype', 'HP:0030731', (131, 141))	('SETD2', 'Gene', '29072', (26, 31))	('renal cell carcinomas', 'Disease', 'MESH:C538614', (120, 141))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (120, 141))	('SETD2', 'Gene', (26, 31))	('ectopic H3K36me3', 'MPA', (62, 78))	('mutations', 'Var', (13, 22))	('renal cell carcinomas', 'Disease', (120, 141))
418543	29125844	For example, in glioblastoma, mutated IDH1 produces abnormal 2-hydroxyglutarate.	('IDH1', 'Gene', '3417', (38, 42))	('glioblastoma', 'Phenotype', 'HP:0012174', (16, 28))	('2-hydroxyglutarate', 'MPA', (61, 79))	('mutated', 'Var', (30, 37))	('abnormal 2-hydroxyglutarate', 'Phenotype', 'HP:0012401', (52, 79))	('IDH1', 'Gene', (38, 42))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (61, 79))	('glioblastoma', 'Disease', (16, 28))	('glioblastoma', 'Disease', 'MESH:D005909', (16, 28))
418546	29125844	Finally, the KRAS G13D mutation upregulates another transcriptional repressor, ZNF304, to establish a CIMP-intermediate pattern in colorectal cancer.	('ZNF304', 'Gene', (79, 85))	('mutation', 'Var', (23, 31))	('upregulates', 'PosReg', (32, 43))	('G13D', 'Mutation', 'rs112445441', (18, 22))	('colorectal cancer', 'Disease', 'MESH:D015179', (131, 148))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('KRAS', 'Gene', (13, 17))	('colorectal cancer', 'Phenotype', 'HP:0003003', (131, 148))	('CIMP', 'Chemical', '-', (102, 106))	('ZNF304', 'Gene', '57343', (79, 85))	('colorectal cancer', 'Disease', (131, 148))	('KRAS', 'Gene', '3845', (13, 17))
418548	29125844	In head and neck squamous cell carcinomas (HNSCs), for instance, an atypical CIMP subtype was recently identified in association with CASP8 mutations, which are not known to have a functional link to the epigenome.	('head and neck squamous cell carcinomas', 'Phenotype', 'HP:0012288', (3, 41))	('CASP8', 'Gene', (134, 139))	('CASP8', 'Gene', '841', (134, 139))	('carcinomas', 'Phenotype', 'HP:0030731', (31, 41))	('HNSC', 'Phenotype', 'HP:0012288', (43, 47))	('neck squamous cell carcinomas', 'Disease', 'MESH:D000077195', (12, 41))	('CIMP', 'Chemical', '-', (77, 81))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (17, 41))	('association', 'Reg', (117, 128))	('neck squamous cell carcinomas', 'Disease', (12, 41))	('mutations', 'Var', (140, 149))	('HNSCs', 'Phenotype', 'HP:0012288', (43, 48))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (3, 40))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (17, 40))	('carcinoma', 'Phenotype', 'HP:0030731', (31, 40))
418549	29125844	And in gastric cancer, PIK3CA mutations co-occur with CIMP, which is thought to be caused by Epstein-Barr virus (EBV) infection.	('gastric cancer', 'Phenotype', 'HP:0012126', (7, 21))	('PIK3CA', 'Gene', (23, 29))	('CIMP', 'Chemical', '-', (54, 58))	('Epstein-Barr virus (EBV) infection', 'Disease', 'MESH:D020031', (93, 127))	('PIK3CA', 'Gene', '5290', (23, 29))	('gastric cancer', 'Disease', (7, 21))	('mutations', 'Var', (30, 39))	('gastric cancer', 'Disease', 'MESH:D013274', (7, 21))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('CIMP', 'Disease', (54, 58))
418550	29125844	In this type of cancer, TP53 mutations are largely mutually exclusive with PIK3CA mutations.	('PIK3CA', 'Gene', (75, 81))	('cancer', 'Disease', 'MESH:D009369', (16, 22))	('PIK3CA', 'Gene', '5290', (75, 81))	('TP53', 'Gene', (24, 28))	('cancer', 'Disease', (16, 22))	('mutations', 'Var', (29, 38))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('TP53', 'Gene', '7157', (24, 28))
418551	29125844	Thus, we would also expect TP53 mutations to be associated with non-CIMP tumors.	('TP53', 'Gene', '7157', (27, 31))	('TP53', 'Gene', (27, 31))	('associated', 'Reg', (48, 58))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('CIMP', 'Chemical', '-', (68, 72))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('mutations', 'Var', (32, 41))	('tumors', 'Disease', (73, 79))	('tumors', 'Disease', 'MESH:D009369', (73, 79))
418552	29125844	Based on these findings, we hypothesized that tumor genomic and epigenetic landscapes are stable and interdependent, and that specific driver mutations are associated with specific DNAm patterns.	('mutations', 'Var', (142, 151))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Disease', (46, 51))	('associated', 'Reg', (156, 166))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
418553	29125844	Thus, in this study, we systematically evaluated mutation-methylation associations across 4,302 tumors from 18 cancer types, along with 727 normal tissue samples from The Cancer Genome Atlas (TCGA).	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('Cancer', 'Phenotype', 'HP:0002664', (171, 177))	('Cancer Genome Atlas', 'Disease', (171, 190))	('tumors', 'Disease', (96, 102))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (171, 190))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('mutation-methylation', 'Var', (49, 69))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))
418554	29125844	By investigating DNAm alterations associated with mutated driver genes on both a genome-wide scale and a site-specific scale, we were able to show that (i) mutated driver genes are tightly associated with DNAm variation in cancer; (ii) some driver gene associations are present across cancer types; for example, TP53 mutations predominantly correspond to hypomethylation across cancer types; (iii) other associations are cancer type-specific; and (iv) these associations can be used to classify tumors into molecular subtypes and gain insight into functional alterations.	('cancer', 'Disease', 'MESH:D009369', (378, 384))	('tumors', 'Disease', 'MESH:D009369', (495, 501))	('cancer', 'Disease', (223, 229))	('mutations', 'Var', (317, 326))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('cancer', 'Disease', (421, 427))	('cancer', 'Phenotype', 'HP:0002664', (421, 427))	('cancer', 'Disease', (285, 291))	('TP53', 'Gene', (312, 316))	('tumors', 'Phenotype', 'HP:0002664', (495, 501))	('cancer', 'Phenotype', 'HP:0002664', (285, 291))	('cancer', 'Disease', (378, 384))	('cancer', 'Disease', 'MESH:D009369', (223, 229))	('cancer', 'Disease', 'MESH:D009369', (421, 427))	('cancer', 'Phenotype', 'HP:0002664', (378, 384))	('tumor', 'Phenotype', 'HP:0002664', (495, 500))	('tumors', 'Disease', (495, 501))	('hypomethylation', 'Var', (355, 370))	('TP53', 'Gene', '7157', (312, 316))	('cancer', 'Disease', 'MESH:D009369', (285, 291))
418555	29125844	Together, these results establish that driver mutations and DNAm alterations are tightly coupled in tumor cells, and that this coupling may affect important regulatory networks related to oncogenesis.	('regulatory networks', 'MPA', (157, 176))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('mutations', 'Var', (46, 55))	('tumor', 'Disease', (100, 105))	('affect', 'Reg', (140, 146))	('DNAm', 'MPA', (60, 64))	('tumor', 'Disease', 'MESH:D009369', (100, 105))
418558	29125844	For each cancer type, a driver gene was considered to be associated with a PC if samples in which the gene was mutated (any synonymous/non-synonymous mutation reported in TCGA level 2 exome-sequencing data) were unevenly distributed toward the positive or negative extremes of that PC (q<0.05; two-sided Wilcoxon rank-sum test).	('mutated', 'Var', (111, 118))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('cancer', 'Disease', (9, 15))
418563	29125844	For each cancer type, the full list of driver genes associated with methylation PCs can be found in S1 Table, and the full list of MutSigCV-reported driver genes can be found in S2 Table.	('methylation', 'Var', (68, 79))	('cancer', 'Disease', (9, 15))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))
418565	29125844	Thus, the frequent driver gene-PC associations in almost every cancer type suggest a tight connection between driver gene mutations and DNA methylation alterations in cancer.	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('cancer', 'Disease', (167, 173))	('mutations', 'Var', (122, 131))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('cancer', 'Disease', (63, 69))
418569	29125844	In total, 14 of 18 cancer types harbored significant associations between driver gene mutations and the top five methylation PCs at CGIs, 14 of 18 at SSs, and 15 of 18 in open sea regions.	('mutations', 'Var', (86, 95))	('cancer', 'Disease', 'MESH:D009369', (19, 25))	('cancer', 'Disease', (19, 25))	('SSs', 'Chemical', '-', (150, 153))	('driver gene', 'Gene', (74, 85))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))
418571	29125844	Some researchers have recently proposed that aberrant DNAm in cancer is driven by cell proliferation and developed a DNAm-based mitotic index (derived from the average methylation level across 385 CpG sites).	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('aberrant', 'Var', (45, 53))	('cell proliferation', 'CPA', (82, 100))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))
418573	29125844	However, after removing probes correlated with the DNAm-based mitotic index (p<0.05; Pearson correlation), methylation PC-driver gene associations remained for 11 cancer types (S3 Fig), indicating that mutation-methylation associations cannot be totally explained by the DNAm-based mitotic index.	('methylation', 'Var', (107, 118))	('cancer', 'Disease', (163, 169))	('cancer', 'Disease', 'MESH:D009369', (163, 169))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))
418575	29125844	We next asked whether driver gene-associated methylation alterations correspond to genome-wide methylation patterns characteristic of cancer: i.e., widespread CGI hypermethylation and huge hypomethylated blocks, primarily in open sea regions.	('hypermethylation', 'Var', (163, 179))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('alterations', 'Var', (57, 68))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
418576	29125844	A high HyperZ index indicates that aberrant hypermethylation exists in many CGIs for a given sample, whereas a high HypoZ index indicates that extensive open sea hypomethylation is present.	('open sea hypomethylation', 'Disease', 'MESH:D009041', (153, 177))	('aberrant', 'Var', (35, 43))	('open sea hypomethylation', 'Disease', (153, 177))
418578	29125844	For example, a high HyperZ index was associated with BRAF in COAD and IDH1 in glioblastoma (GBM); both genes are linked to CIMP in cancer.	('high', 'Var', (15, 19))	('cancer', 'Disease', (131, 137))	('COAD', 'Disease', (61, 65))	('glioblastoma', 'Disease', (78, 90))	('BRAF', 'Gene', '673', (53, 57))	('glioblastoma', 'Disease', 'MESH:D005909', (78, 90))	('GBM', 'Phenotype', 'HP:0012174', (92, 95))	('BRAF', 'Gene', (53, 57))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('COAD', 'Disease', 'MESH:D029424', (61, 65))	('IDH1', 'Gene', '3417', (70, 74))	('glioblastoma', 'Phenotype', 'HP:0012174', (78, 90))	('CIMP', 'Chemical', '-', (123, 127))	('associated', 'Reg', (37, 47))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('linked', 'Reg', (113, 119))	('IDH1', 'Gene', (70, 74))
418580	29125844	The associations we detected in most cancer types underscore the relationship between driver gene mutations and the genome-wide methylation alterations commonly observed in cancer.	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('cancer', 'Disease', (173, 179))	('cancer', 'Disease', (37, 43))	('mutations', 'Var', (98, 107))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))
418582	29125844	Next, we investigated whether the connection between driver gene mutations and methylation alterations was methylation site-specific in each cancer type.	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('methylation', 'MPA', (79, 90))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('cancer', 'Disease', (141, 147))	('mutations', 'Var', (65, 74))
418583	29125844	To do so, we calculated the associations between every driver gene and every methylation array probe for all 18 cancer types, testing whether the presence of mutations in a driver gene was associated with high or low methylation levels at a given probe site (q<0.05; Wilcoxon rank-sum test).	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('methylation levels', 'MPA', (217, 235))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('low', 'NegReg', (213, 216))	('mutations', 'Var', (158, 167))
418585	29125844	An example of the chromosomal distribution of driver gene-associated methylation probes present in kidney renal clear cell carcinoma (KIRC) is shown in S4A Fig.	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('kidney renal clear cell carcinoma', 'Disease', (99, 132))	('kidney renal clear cell carcinoma', 'Disease', 'MESH:C538614', (99, 132))	('methylation', 'Var', (69, 80))
418586	29125844	A heat map illustrates mutations in these 14 genes in KIRC (S4B Fig), showing some co-occurrence between SETD2 mutations and PBRM1 mutations, and between BAP1 mutations and PBRM1 mutations, whereas SETD2 mutations and BAP1 mutations are almost mutually exclusive.	('PBRM1', 'Gene', (173, 178))	('mutations', 'Var', (111, 120))	('mutations', 'Var', (131, 140))	('SETD2', 'Gene', '29072', (105, 110))	('PBRM1', 'Gene', '55193', (173, 178))	('SETD2', 'Gene', (198, 203))	('BAP1', 'Gene', (154, 158))	('SETD2', 'Gene', (105, 110))	('mutations', 'Var', (159, 168))	('PBRM1', 'Gene', '55193', (125, 130))	('BAP1', 'Gene', '8314', (218, 222))	('co-occurrence', 'Interaction', (83, 96))	('mutations', 'Var', (179, 188))	('PBRM1', 'Gene', (125, 130))	('BAP1', 'Gene', (218, 222))	('BAP1', 'Gene', '8314', (154, 158))	('SETD2', 'Gene', '29072', (198, 203))
418590	29125844	By definition, positive associations indicate higher methylation levels among tumor samples in the presence of driver gene mutations, whereas negative associations indicate lower methylation levels.	('methylation', 'MPA', (179, 190))	('mutations', 'Var', (123, 132))	('higher', 'PosReg', (46, 52))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('driver gene', 'Gene', (111, 122))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('lower', 'NegReg', (173, 178))	('tumor', 'Disease', (78, 83))	('methylation levels', 'MPA', (53, 71))
418597	29125844	Genomic distribution analysis on RNF43-associated probes revealed that positively associated probes were enriched in gene promoters, whereas negatively associated probes were enriched in gene bodies, suggesting that they may have different functional impacts (S5 Fig).	('RNF43', 'Gene', '54894', (33, 38))	('probes', 'Var', (93, 99))	('RNF43', 'Gene', (33, 38))
418598	29125844	In short, a few driver genes were linked to genome-wide patterns of CGI hypermethylation and open sea hypomethylation in particular cancer types, whereas many more driver genes were linked to a few probe sites aberrantly methylated in cancer (S2 Table).	('cancer', 'Disease', (132, 138))	('cancer', 'Disease', (235, 241))	('cancer', 'Disease', 'MESH:D009369', (235, 241))	('open sea hypomethylation in particular cancer', 'Disease', 'MESH:D009369', (93, 138))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('hypermethylation', 'Var', (72, 88))	('open sea hypomethylation in particular cancer', 'Disease', (93, 138))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('linked', 'Reg', (34, 40))
418604	29125844	These genes were selected because they were associated with extensive methylation alterations (more than 1,000 probe associations per driver gene) in at least two cancer types.	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('cancer', 'Disease', (163, 169))	('cancer', 'Disease', 'MESH:D009369', (163, 169))	('methylation alterations', 'Var', (70, 93))
418606	29125844	This suggests a tight connection between TP53 mutations and open sea hypomethylation across multiple cancer types.	('TP53', 'Gene', '7157', (41, 45))	('TP53', 'Gene', (41, 45))	('mutations', 'Var', (46, 55))	('open sea hypomethylation across multiple cancer', 'Disease', (60, 107))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('open sea hypomethylation across multiple cancer', 'Disease', 'MESH:D009369', (60, 107))
418609	29125844	By contrast, IDH1 strongly favored positive associations in two cancer types, GBM and SKCM, consistent with reports that mutated IDH1 downregulates TET-dependent demethylation, resulting in aberrant CGI hypermethylation.	('SKCM', 'Disease', (86, 90))	('IDH1', 'Gene', (129, 133))	('GBM', 'Phenotype', 'HP:0012174', (78, 81))	('downregulates', 'NegReg', (134, 147))	('CGI hypermethylation', 'MPA', (199, 219))	('TET-dependent demethylation', 'MPA', (148, 175))	('cancer', 'Disease', (64, 70))	('mutated', 'Var', (121, 128))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('IDH1', 'Gene', (13, 17))	('IDH1', 'Gene', '3417', (129, 133))	('IDH1', 'Gene', '3417', (13, 17))	('TET', 'Chemical', 'MESH:C010349', (148, 151))	('GBM', 'Disease', (78, 81))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
418619	29125844	For each cancer type, we then identified genes whose expression levels were correlated with TP53-associated probes (q<0.05; Spearman correlation) in gene promoters or bodies exhibiting aberrant methylation changes (magnitude of median difference in beta values between TP53-mutated tumors and normal samples >0.1).	('cancer', 'Disease', (9, 15))	('tumor', 'Phenotype', 'HP:0002664', (282, 287))	('tumors', 'Disease', (282, 288))	('tumors', 'Disease', 'MESH:D009369', (282, 288))	('TP53', 'Gene', '7157', (269, 273))	('tumors', 'Phenotype', 'HP:0002664', (282, 288))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('TP53', 'Gene', (92, 96))	('TP53', 'Gene', (269, 273))	('TP53', 'Gene', '7157', (92, 96))	('expression', 'MPA', (53, 63))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('methylation changes', 'Var', (194, 213))
418623	29125844	The enriched pathways/gene sets remained largely the same when repeating the analysis restricted to genes corresponding to TP53-negatively associated probes, whereas no enriched pathways/gene sets were found for genes corresponding to TP53-positively associated probes.	('probes', 'Var', (150, 156))	('TP53', 'Gene', '7157', (235, 239))	('TP53', 'Gene', '7157', (123, 127))	('TP53', 'Gene', (235, 239))	('TP53', 'Gene', (123, 127))
418628	29125844	And in UCEC, mutations in TP53 were nearly mutually exclusive with PTEN and CTNNB1 mutations, which co-occurred in many tumor samples.	('TP53', 'Gene', (26, 30))	('mutations', 'Var', (83, 92))	('CTNNB1', 'Gene', '1499', (76, 82))	('TP53', 'Gene', '7157', (26, 30))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('PTEN', 'Gene', (67, 71))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('CTNNB1', 'Gene', (76, 82))	('mutations', 'Var', (13, 22))	('PTEN', 'Gene', '5728', (67, 71))	('tumor', 'Disease', (120, 125))
418629	29125844	For both cancer types, we performed hierarchical clustering on the union of the 500 methylation probes most significantly associated with mutations in each of the top three genes (Fig 4).	('associated', 'Reg', (122, 132))	('cancer', 'Disease', (9, 15))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('mutations', 'Var', (138, 147))
418631	29125844	SS and open sea regions); BRAF mutants displayed hypomethylation in open sea and some SS regions, whereas NRAS and HRAS mutants displayed methylation levels similar to normal samples in open sea and SS regions, with little hypermethylation.	('mutants', 'Var', (31, 38))	('BRAF', 'Gene', '673', (26, 30))	('HRAS', 'Gene', '3265', (115, 119))	('BRAF', 'Gene', (26, 30))	('NRAS', 'Gene', (106, 110))	('HRAS', 'Gene', (115, 119))	('hypomethylation', 'MPA', (49, 64))	('methylation levels', 'MPA', (138, 156))	('NRAS', 'Gene', '4893', (106, 110))
418635	29125844	Two methylation subtypes were also identified in UCEC, this time corresponding to TP53 vs. PTEN mutations, consistent with the serous vs. endometrioid histological subtypes of UCEC, respectively (Fig 4B).	('TP53', 'Gene', '7157', (82, 86))	('TP53', 'Gene', (82, 86))	('UCEC', 'Disease', (49, 53))	('PTEN', 'Gene', (91, 95))	('PTEN', 'Gene', '5728', (91, 95))	('mutations', 'Var', (96, 105))
418637	29125844	Most UCEC samples with mutations in both PTEN and CTNNB1 displayed greater levels of open sea hypomethylation than samples with PTEN mutations alone, a finding which has not been previously reported.	('CTNNB1', 'Gene', (50, 56))	('PTEN', 'Gene', (128, 132))	('PTEN', 'Gene', '5728', (128, 132))	('CTNNB1', 'Gene', '1499', (50, 56))	('mutations', 'Var', (23, 32))	('greater', 'PosReg', (67, 74))	('PTEN', 'Gene', (41, 45))	('PTEN', 'Gene', '5728', (41, 45))	('open sea hypomethylation', 'Disease', 'MESH:D009041', (85, 109))	('open sea hypomethylation', 'Disease', (85, 109))
418641	29125844	We focused on CpG sites in promoter regions and gene bodies in NRAS and HRAS mutants (the NRAS-HRAS group) vs. BRAF mutants (the BRAF group).	('NRAS', 'Gene', '4893', (63, 67))	('HRAS', 'Gene', (95, 99))	('NRAS', 'Gene', (90, 94))	('BRAF', 'Gene', (129, 133))	('HRAS', 'Gene', '3265', (72, 76))	('BRAF', 'Gene', '673', (129, 133))	('NRAS', 'Gene', '4893', (90, 94))	('NRAS-HRAS group', 'Gene', '4893', (90, 105))	('HRAS', 'Gene', (72, 76))	('mutants', 'Var', (77, 84))	('NRAS-HRAS group', 'Gene', (90, 105))	('BRAF', 'Gene', '673', (111, 115))	('HRAS', 'Gene', '3265', (95, 99))	('NRAS', 'Gene', (63, 67))	('BRAF', 'Gene', (111, 115))
418652	29125844	We did not find a substantial proportion of differentially methylated genes implicated in tumor progression among the top differentially expressed genes (defined by median difference in expression between NRAS-HRAS mutants and normal samples).	('NRAS-HRAS', 'Gene', (205, 214))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('mutants', 'Var', (215, 222))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
418653	29125844	However, when we considered the top 17 differentially expressed, highly transcribed genes (median expression level in mutants > 10 log2 RSEM; median difference > 1 log2 RSEM; highlighted in S6 Table in bold), 6 out of 17 were implicated in tumorigenesis.	('tumor', 'Disease', (240, 245))	('mutants', 'Var', (118, 125))	('tumor', 'Disease', 'MESH:D009369', (240, 245))	('expression level', 'MPA', (98, 114))	('implicated', 'Reg', (226, 236))	('tumor', 'Phenotype', 'HP:0002664', (240, 245))
418658	29125844	This result demonstrates that methylation changes are indeed associated with differential gene expression between BRAF-mutated and NRAS- and HRAS-mutated samples in THCA.	('methylation changes', 'Var', (30, 49))	('BRAF', 'Gene', (114, 118))	('HRAS', 'Gene', '3265', (141, 145))	('BRAF', 'Gene', '673', (114, 118))	('THCA', 'Phenotype', 'HP:0002890', (165, 169))	('HRAS', 'Gene', (141, 145))	('NRAS-', 'Gene', '4893', (131, 136))	('differential gene expression', 'MPA', (77, 105))	('NRAS-', 'Gene', (131, 136))	('associated', 'Reg', (61, 71))
418659	29125844	In this study, we demonstrated that driver gene mutations are tightly tied to the DNAm landscape in multiple types of cancer.	('cancer', 'Disease', (118, 124))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('mutations', 'Var', (48, 57))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))
418660	29125844	In each cancer type, a few driver genes dominate the site-specific associations, and some potentially contribute to CGI hypermethylation and extensive hypomethylation, i.e., the hallmarks of cancer.	('cancer', 'Disease', (191, 197))	('cancer', 'Disease', 'MESH:D009369', (191, 197))	('cancer', 'Disease', (8, 14))	('contribute', 'Reg', (102, 112))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('extensive hypomethylation', 'MPA', (141, 166))	('hypermethylation', 'Var', (120, 136))	('cancer', 'Disease', 'MESH:D009369', (8, 14))	('CGI', 'MPA', (116, 119))
418662	29125844	Several driver genes that displayed primarily positive or negative associations with methylation probes in this study have been previously linked to CGI hypermethylation or open sea hypomethylation, respectively.	('methylation', 'Var', (85, 96))	('open sea hypomethylation', 'Disease', 'MESH:D009041', (173, 197))	('open sea hypomethylation', 'Disease', (173, 197))	('linked', 'Reg', (139, 145))	('CGI', 'Disease', (149, 152))	('negative', 'NegReg', (58, 66))	('associations', 'Interaction', (67, 79))
418665	29125844	In addition to these examples, we identified novel driver genes that may contribute to CGI hypermethylation, such as BAP1 in KIRC, or to open sea hypomethylation, such as CTNNB1 in LIHC.	('contribute', 'Reg', (73, 83))	('CTNNB1', 'Gene', (171, 177))	('BAP1', 'Gene', '8314', (117, 121))	('CGI', 'MPA', (87, 90))	('BAP1', 'Gene', (117, 121))	('hypermethylation', 'Var', (91, 107))	('CTNNB1', 'Gene', '1499', (171, 177))	('open sea hypomethylation', 'Disease', 'MESH:D009041', (137, 161))	('open sea hypomethylation', 'Disease', (137, 161))
418666	29125844	By illuminating the driver genes associated with widespread DNAm alterations, as well as driver genes associated with more limited DNAm alterations, our comprehensive analysis provides a detailed mutation-methylation map for many types of cancer.	('cancer', 'Disease', (239, 245))	('cancer', 'Disease', 'MESH:D009369', (239, 245))	('alterations', 'Var', (65, 76))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))
418667	29125844	Several mutated driver genes displayed consistent and widespread positive or negative associations across cancers, corresponding to extensive DNAm alterations.	('negative', 'NegReg', (77, 85))	('associations', 'Interaction', (86, 98))	('mutated', 'Var', (8, 15))	('cancers', 'Phenotype', 'HP:0002664', (106, 113))	('positive', 'PosReg', (65, 73))	('cancers', 'Disease', (106, 113))	('cancers', 'Disease', 'MESH:D009369', (106, 113))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
418669	29125844	For example, mutations in IDH1 and SETD2 directly affect the epigenetic landscape by inhibiting TET-dependent demethylation and disturbing DNA methyltransferase targeting, respectively.	('epigenetic landscape', 'MPA', (61, 81))	('inhibiting', 'NegReg', (85, 95))	('disturbing', 'Reg', (128, 138))	('IDH1', 'Gene', (26, 30))	('TET', 'Chemical', 'MESH:C010349', (96, 99))	('affect', 'Reg', (50, 56))	('SETD2', 'Gene', '29072', (35, 40))	('TET-dependent demethylation', 'MPA', (96, 123))	('mutations', 'Var', (13, 22))	('IDH1', 'Gene', '3417', (26, 30))	('SETD2', 'Gene', (35, 40))	('DNA methyltransferase targeting', 'MPA', (139, 170))
418670	29125844	BRAF mutations, by contrast, displayed inconsistent methylation patterns between cancer types in this study.	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('cancer', 'Disease', (81, 87))	('mutations', 'Var', (5, 14))	('BRAF', 'Gene', '673', (0, 4))	('BRAF', 'Gene', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))
418671	29125844	In COAD, BRAF-mutated samples mutations displayed widespread CGI hypermethylation.	('BRAF', 'Gene', (9, 13))	('BRAF', 'Gene', '673', (9, 13))	('COAD', 'Disease', (3, 7))	('mutations', 'Var', (30, 39))	('COAD', 'Disease', 'MESH:D029424', (3, 7))	('CGI hypermethylation', 'MPA', (61, 81))
418673	29125844	However, in THCA, BRAF-mutated samples (260/266 of which harbored the V600E mutation) largely displayed hypomethylation.	('THCA', 'Phenotype', 'HP:0002890', (12, 16))	('V600E', 'Var', (70, 75))	('displayed', 'Reg', (94, 103))	('BRAF', 'Gene', '673', (18, 22))	('hypomethylation', 'MPA', (104, 119))	('V600E', 'Mutation', 'rs113488022', (70, 75))	('BRAF', 'Gene', (18, 22))
418674	29125844	Although no mechanistic explanation for this observation is yet available, it is possible that the mutation does not upregulate MAFG in THCA.	('THCA', 'Phenotype', 'HP:0002890', (136, 140))	('THCA', 'Disease', (136, 140))	('MAFG', 'Gene', (128, 132))	('mutation', 'Var', (99, 107))	('MAFG', 'Gene', '4097', (128, 132))
418676	29125844	Several mechanisms have been documented to support the consistent hypomethylation we observed in association with TP53 mutations, across cancer types.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('TP53', 'Gene', '7157', (114, 118))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('association', 'Interaction', (97, 108))	('cancer', 'Disease', (137, 143))	('TP53', 'Gene', (114, 118))	('mutations', 'Var', (119, 128))
418677	29125844	For example, in hepatocellular carcinoma, loss-of-function mutations in TP53 allow pre-malignant cells to bypass senescence induced by global hypomethylation, which could explain the connection between TP53 mutations and hypomethylation.	('TP53', 'Gene', (202, 206))	('TP53', 'Gene', '7157', (72, 76))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (16, 40))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (16, 40))	('TP53', 'Gene', (72, 76))	('hepatocellular carcinoma', 'Disease', (16, 40))	('loss-of-function', 'NegReg', (42, 58))	('mutations', 'Var', (59, 68))	('global', 'MPA', (135, 141))	('carcinoma', 'Phenotype', 'HP:0030731', (31, 40))	('TP53', 'Gene', '7157', (202, 206))
418678	29125844	In this study, we found that hypomethylated sites associated with TP53 mutation are shared across cancer types and correspond to upregulated E2F-targets and genes involved in cell cycle regulation.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('hypomethylated sites', 'Var', (29, 49))	('TP53', 'Gene', '7157', (66, 70))	('mutation', 'Var', (71, 79))	('TP53', 'Gene', (66, 70))	('upregulated', 'PosReg', (129, 140))	('E2F-targets', 'MPA', (141, 152))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('cancer', 'Disease', (98, 104))
418680	29125844	Moreover, CpG methylation regulates E2F activity by preventing E2F family members from binding target promoters, supporting the correlation between TP53-associated hypomethylation at E2F targets and their upregulation.	('regulates', 'Reg', (26, 35))	('preventing', 'NegReg', (52, 62))	('upregulation', 'PosReg', (205, 217))	('TP53', 'Gene', '7157', (148, 152))	('TP53', 'Gene', (148, 152))	('binding', 'Interaction', (87, 94))	('E2F', 'Protein', (63, 66))	('methylation', 'Var', (14, 25))	('activity', 'MPA', (40, 48))
418681	29125844	Upregulated E2F activity may promote cell proliferation, consistent with the association between TP53 mutations and a high expression-based mitotic index in 9 cancer types found in this study (S3 Table).	('cancer', 'Disease', (159, 165))	('promote', 'PosReg', (29, 36))	('TP53', 'Gene', '7157', (97, 101))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('TP53', 'Gene', (97, 101))	('mutations', 'Var', (102, 111))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('E2F', 'Protein', (12, 15))	('activity', 'MPA', (16, 24))	('Upregulated', 'PosReg', (0, 11))	('cell proliferation', 'CPA', (37, 55))
418682	29125844	Therefore, the hypomethylation at E2F targets could regulate E2F activity or could simply represent the footprint of upregulated E2F activity due to TP53 loss, yielding the association between TP53 mutations and DNAm changes at E2F targets.	('TP53', 'Gene', '7157', (193, 197))	('E2F activity', 'MPA', (61, 73))	('TP53', 'Gene', '7157', (149, 153))	('mutations', 'Var', (198, 207))	('association', 'Interaction', (173, 184))	('TP53', 'Gene', (193, 197))	('TP53', 'Gene', (149, 153))	('loss', 'NegReg', (154, 158))	('regulate', 'Reg', (52, 60))
418684	29125844	Future research is needed to elucidate the role of hypomethylation in TP53-mutated tumors.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('TP53', 'Gene', '7157', (70, 74))	('hypomethylation', 'Var', (51, 66))	('tumors', 'Disease', (83, 89))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('TP53', 'Gene', (70, 74))	('tumors', 'Disease', 'MESH:D009369', (83, 89))
418685	29125844	However, the DNAm landscape can be affected by mutations in epigenetic modifying enzymes such as SETD2, the H3K36me3 writer.	('H3K36me3 writer', 'Var', (108, 123))	('mutations', 'Var', (47, 56))	('affected', 'Reg', (35, 43))	('SETD2', 'Gene', '29072', (97, 102))	('DNAm landscape', 'MPA', (13, 27))	('SETD2', 'Gene', (97, 102))
418688	29125844	The TP53-associated hypomethylation at E2F targets found in this study may also be explained in this way.	('hypomethylation', 'Var', (20, 35))	('TP53', 'Gene', '7157', (4, 8))	('TP53', 'Gene', (4, 8))
418690	29125844	Conversely, changes in DNAm can cause mutations in cancer.	('DNAm', 'Gene', (23, 27))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('mutations', 'Var', (38, 47))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('cause', 'Reg', (32, 37))	('changes', 'Var', (12, 19))
418693	29125844	The associations observed may simply reflect the presence of specific DNAm patterns in the same tumor subtypes in which particular driver gene mutations are enriched or depleted.	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('tumor', 'Disease', (96, 101))	('mutations', 'Var', (143, 152))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))
418694	29125844	In the previously mentioned example, DNA hypomethylation triggers TP53-mediated senescence, and hepatocellular carcinoma emerges when senescence is bypassed due to later TP53 loss.	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('hepatocellular carcinoma', 'Disease', (96, 120))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (96, 120))	('TP53', 'Gene', '7157', (66, 70))	('TP53', 'Gene', (66, 70))	('triggers', 'Reg', (57, 65))	('TP53', 'Gene', '7157', (170, 174))	('TP53', 'Gene', (170, 174))	('DNA hypomethylation', 'Var', (37, 56))	('loss', 'NegReg', (175, 179))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (96, 120))
418695	29125844	In this manner, positive selection for both the gene level and the DNAm level alterations could mechanistically link two non-causal events during tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('alterations', 'Var', (78, 89))	('tumor', 'Disease', (146, 151))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
418696	29125844	Because mutation-methylation patterns may reflect important oncogenic characteristics, using these patterns to separate tumors into molecular subtypes could potentially aid treatment selection.	('tumors', 'Disease', 'MESH:D009369', (120, 126))	('tumors', 'Disease', (120, 126))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('aid', 'Reg', (169, 172))	('mutation-methylation patterns', 'Var', (8, 37))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))
418698	29125844	Likewise, the two UCEC subtypes characterized by PTEN and TP53 mutations corresponded to the endometrioid-like and serous-like subtypes identified in TCGA analysis, respectively (Fig 4B).	('mutations', 'Var', (63, 72))	('PTEN', 'Gene', '5728', (49, 53))	('TP53', 'Gene', '7157', (58, 62))	('TP53', 'Gene', (58, 62))	('endometrioid-like', 'Disease', (93, 110))	('PTEN', 'Gene', (49, 53))
418699	29125844	Moreover, TCGA classification indicated that the endometrioid-like subtype could be further subdivided into a microsatellite instability subtype (with a low frequency of CTNNB1 mutations) and a low-copy-number subtype (with a high frequency of CTNNB1 mutations).	('CTNNB1', 'Gene', '1499', (244, 250))	('microsatellite instability', 'MPA', (110, 136))	('mutations', 'Var', (177, 186))	('CTNNB1', 'Gene', '1499', (170, 176))	('endometrioid-like', 'Disease', (49, 66))	('CTNNB1', 'Gene', (244, 250))	('CTNNB1', 'Gene', (170, 176))
418700	29125844	Consistent with this finding, in our study tumors with co-occurring PTEN and CTNNB1 mutations displayed more hypomethylation (corresponding to the low-copy-number subtype) than tumors with PTEN mutations alone.	('hypomethylation', 'MPA', (109, 124))	('PTEN', 'Gene', (189, 193))	('PTEN', 'Gene', '5728', (189, 193))	('tumors', 'Phenotype', 'HP:0002664', (177, 183))	('CTNNB1', 'Gene', (77, 83))	('tumors', 'Disease', 'MESH:D009369', (177, 183))	('PTEN', 'Gene', (68, 72))	('mutations', 'Var', (84, 93))	('CTNNB1', 'Gene', '1499', (77, 83))	('PTEN', 'Gene', '5728', (68, 72))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('tumors', 'Disease', (43, 49))	('tumors', 'Disease', (177, 183))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('tumors', 'Disease', 'MESH:D009369', (43, 49))
418702	29125844	The mutual exclusivity of the NRAS, HRAS, and BRAF mutations in THCA tumors has been interpreted to mean that these mutations must have interchangeable effects on MAPK signaling activation, the main cancer-driving event in papillary thyroid carcinomas.	('carcinoma', 'Phenotype', 'HP:0030731', (241, 250))	('carcinomas', 'Phenotype', 'HP:0030731', (241, 251))	('mutations', 'Var', (51, 60))	('papillary thyroid carcinoma', 'Phenotype', 'HP:0002895', (223, 250))	('HRAS', 'Gene', '3265', (36, 40))	('papillary thyroid carcinomas', 'Disease', 'MESH:D000077273', (223, 251))	('activation', 'PosReg', (178, 188))	('HRAS', 'Gene', (36, 40))	('cancer', 'Disease', (199, 205))	('BRAF', 'Gene', (46, 50))	('BRAF', 'Gene', '673', (46, 50))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('NRAS', 'Gene', '4893', (30, 34))	('THCA', 'Disease', (64, 68))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('tumors', 'Disease', (69, 75))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (233, 250))	('THCA', 'Phenotype', 'HP:0002890', (64, 68))	('papillary thyroid carcinomas', 'Disease', (223, 251))	('papillary thyroid carcinomas', 'Phenotype', 'HP:0002895', (223, 251))	('MAPK', 'MPA', (163, 167))	('thyroid carcinomas', 'Phenotype', 'HP:0002890', (233, 251))	('NRAS', 'Gene', (30, 34))	('tumors', 'Disease', 'MESH:D009369', (69, 75))
418703	29125844	Our analysis, however, highlights substantial differences in DNAm between BRAF-mutated vs. NRAS- and HRAS-mutated THCA tumors; moreover, the differences in DNAm appear to profoundly shape gene expression profiles, which may contribute to thyroid tumorigenesis.	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('HRAS', 'Gene', '3265', (101, 105))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('HRAS', 'Gene', (101, 105))	('thyroid tumor', 'Disease', 'MESH:D013959', (238, 251))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('shape', 'Reg', (182, 187))	('differences', 'Var', (141, 152))	('tumors', 'Disease', (119, 125))	('thyroid tumor', 'Disease', (238, 251))	('gene expression profiles', 'MPA', (188, 212))	('tumors', 'Disease', 'MESH:D009369', (119, 125))	('NRAS-', 'Gene', '4893', (91, 96))	('contribute', 'Reg', (224, 234))	('THCA', 'Phenotype', 'HP:0002890', (114, 118))	('NRAS-', 'Gene', (91, 96))	('BRAF', 'Gene', (74, 78))	('BRAF', 'Gene', '673', (74, 78))	('thyroid tumor', 'Phenotype', 'HP:0100031', (238, 251))
418704	29125844	In this study, differential DNAm in six JAK and STAT family genes were found to correlate with their upregulation in BRAF-mutated tumors.	('tumors', 'Disease', (130, 136))	('tumors', 'Disease', 'MESH:D009369', (130, 136))	('upregulation', 'PosReg', (101, 113))	('JAK', 'Gene', (40, 43))	('differential DNAm', 'Var', (15, 32))	('STAT family genes', 'Gene', (48, 65))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('BRAF', 'Gene', '673', (117, 121))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('BRAF', 'Gene', (117, 121))
418708	29125844	Paired with the aggressiveness of BRAF vs. RAS mutation-positive thyroid tumors, our results support a connection between BRAF mutations, JAK-STAT signaling upregulation (including STAT3 activation), and THCA metastasis, suggesting the role of STAT3 and other JAK-STAT family genes in oncogenesis in THCA.	('THCA', 'Disease', (204, 208))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('THCA', 'Phenotype', 'HP:0002890', (300, 304))	('STAT3', 'Gene', (181, 186))	('THCA', 'Phenotype', 'HP:0002890', (204, 208))	('JAK-STAT signaling', 'MPA', (138, 156))	('STAT3', 'Gene', (244, 249))	('STAT3', 'Gene', '6774', (181, 186))	('upregulation', 'PosReg', (157, 169))	('STAT3', 'Gene', '6774', (244, 249))	('thyroid tumors', 'Disease', 'MESH:D013959', (65, 79))	('mutations', 'Var', (127, 136))	('aggressiveness', 'Disease', (16, 30))	('aggressiveness', 'Phenotype', 'HP:0000718', (16, 30))	('thyroid tumor', 'Phenotype', 'HP:0100031', (65, 78))	('aggressiveness', 'Disease', 'MESH:D001523', (16, 30))	('BRAF', 'Gene', '673', (122, 126))	('thyroid tumors', 'Disease', (65, 79))	('BRAF', 'Gene', (122, 126))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('BRAF', 'Gene', '673', (34, 38))	('BRAF', 'Gene', (34, 38))
418710	29125844	These differences in the molecular processes linked to different driver gene mutations may contribute to distinct pathways of tumorigenesis, yielding different prognoses and clinical phenotypes.	('contribute', 'Reg', (91, 101))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('mutations', 'Var', (77, 86))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumor', 'Disease', (126, 131))
418711	29125844	For example, although the majority of BRAF-mutated samples carried the V600E mutation (25 out of 34 BRAF-mutated tumors carried BRAF V600E in COAD, 167/195 in SKCM, and 260/266 in THCA), this group also included a few non-V600E mutations.	('COAD', 'Disease', 'MESH:D029424', (142, 146))	('BRAF', 'Gene', '673', (128, 132))	('tumors', 'Disease', (113, 119))	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('V600E', 'Mutation', 'rs113488022', (71, 76))	('V600E', 'Mutation', 'rs113488022', (222, 227))	('V600E', 'Mutation', 'rs113488022', (133, 138))	('BRAF', 'Gene', '673', (38, 42))	('COAD', 'Disease', (142, 146))	('BRAF', 'Gene', '673', (100, 104))	('V600E', 'Var', (71, 76))	('BRAF', 'Gene', (38, 42))	('V600E', 'Var', (133, 138))	('BRAF', 'Gene', (100, 104))	('THCA', 'Phenotype', 'HP:0002890', (180, 184))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('BRAF', 'Gene', (128, 132))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
418712	29125844	However, combinatorial effects of driver gene mutations on methylation could exist, as several driver gene mutations typically co-occur in a given tumor.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('mutations', 'Var', (107, 116))
418713	29125844	Although MutSigCV is one of the most reliable driver gene-detection tools available, limitations associated with the detection algorithm:paired with limitations imposed by the number of tumor samples available in TCGA:may have led us to miss methylation-altering mutations that occurred in unknown driver genes.	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('mutations', 'Var', (263, 272))	('tumor', 'Disease', (186, 191))	('methylation-altering', 'MPA', (242, 262))
418719	29125844	In addition, in the future, further analysis of methylation and expression data may identify driver gene mutation-induced methylation alterations that dysregulate genes/pathways that promote tumor growth.	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('mutation-induced', 'Reg', (105, 121))	('dysregulate', 'Reg', (151, 162))	('methylation alterations', 'Var', (122, 145))	('genes/pathways', 'Pathway', (163, 177))	('alterations', 'Var', (134, 145))	('tumor', 'Disease', (191, 196))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('promote', 'PosReg', (183, 190))
418721	29125844	Demethylating agents such as 5-aza-2'-deoxycytidine, for example, have been used to reactivate epigenetically silenced tumor suppressor genes and also to decrease overexpression of oncogenes.	('tumor', 'Disease', (119, 124))	('overexpression', 'MPA', (163, 177))	('reactivate epigenetically silenced', 'Var', (84, 118))	("5-aza-2'-deoxycytidine", 'Chemical', 'MESH:D000077209', (29, 51))	('decrease', 'NegReg', (154, 162))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('oncogenes', 'Protein', (181, 190))
418722	29125844	By contrast, the methyl donor S-adenosylmethionine has been shown to downregulate the oncogenes c-MYC and HRAS, inhibiting cancer cell growth.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('c-MYC', 'Gene', (96, 101))	('HRAS', 'Gene', (106, 110))	('S-adenosylmethionine', 'Chemical', 'MESH:D012436', (30, 50))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('cancer', 'Disease', (123, 129))	('downregulate', 'NegReg', (69, 81))	('c-MYC', 'Gene', '4609', (96, 101))	('HRAS', 'Gene', '3265', (106, 110))	('donor', 'Species', '9606', (24, 29))	('S-adenosylmethionine', 'Var', (30, 50))	('inhibiting', 'NegReg', (112, 122))
418723	29125844	In summary, in light of the connection between driver gene mutations and DNA methylation shown here, it will be important to further study how coordinated genomic and epigenomic alterations result in the hallmarks of cancer.	('result in', 'Reg', (190, 199))	('cancer', 'Disease', (217, 223))	('cancer', 'Disease', 'MESH:D009369', (217, 223))	('mutations', 'Var', (59, 68))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))
418731	29125844	The following types of probes were removed from the analysis: (i) probes on the X and Y chromosomes, (ii) cross-reactive probes, (iii) probes near single nucleotide polymorphisms (SNPs), and (iv) probes with missing rates >=90% across all samples for a given cancer type.	('cancer', 'Disease', 'MESH:D009369', (259, 265))	('single nucleotide polymorphisms', 'Var', (147, 178))	('probes', 'Var', (135, 141))	('cancer', 'Phenotype', 'HP:0002664', (259, 265))	('cancer', 'Disease', (259, 265))
418744	29125844	A driver gene was classified as either mutated (any mutations) or not mutated (no mutations) for each tumor sample.	('mutations', 'Var', (52, 61))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('tumor', 'Disease', 'MESH:D009369', (102, 107))
418745	29125844	Finally, we performed the same association test for every driver gene and the HyperZ and HypoZ indices, to identify driver genes potentially associated with genome-wide CGI hypermethylation and open sea hypomethylation.	('associated', 'Reg', (141, 151))	('open sea hypomethylation', 'Disease', 'MESH:D009041', (194, 218))	('hypermethylation', 'Var', (173, 189))	('open sea hypomethylation', 'Disease', (194, 218))
418748	29125844	First, we visually identified two THCA molecular subtypes based on driver gene mutations and DNA methylation patterns (Fig 4A): (i) BRAF-mutated tumors (the BRAF group) and (ii) NRAS- and HRAS-mutated tumors (the NRAS-HRAS group).	('HRAS', 'Gene', (188, 192))	('NRAS-HRAS group', 'Gene', '4893', (213, 228))	('tumors', 'Disease', 'MESH:D009369', (145, 151))	('tumors', 'Disease', 'MESH:D009369', (201, 207))	('mutations', 'Var', (79, 88))	('NRAS-', 'Gene', (213, 218))	('NRAS-', 'Gene', '4893', (213, 218))	('BRAF', 'Gene', '673', (157, 161))	('HRAS', 'Gene', '3265', (218, 222))	('BRAF', 'Gene', (157, 161))	('HRAS', 'Gene', (218, 222))	('BRAF', 'Gene', '673', (132, 136))	('BRAF', 'Gene', (132, 136))	('THCA', 'Phenotype', 'HP:0002890', (34, 38))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('tumors', 'Phenotype', 'HP:0002664', (201, 207))	('NRAS-', 'Gene', '4893', (178, 183))	('NRAS-', 'Gene', (178, 183))	('NRAS-HRAS group', 'Gene', (213, 228))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumors', 'Disease', (145, 151))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('HRAS', 'Gene', '3265', (188, 192))	('tumors', 'Disease', (201, 207))
418749	29125844	The search was restricted to genes whose aberrant expression levels coincided with hyper- or hypomethylated probes associated with BRAF, HRAS, and NRAS mutations (see section below).	('BRAF', 'Gene', '673', (131, 135))	('BRAF', 'Gene', (131, 135))	('mutations', 'Var', (152, 161))	('expression levels', 'MPA', (50, 67))	('NRAS', 'Gene', (147, 151))	('HRAS', 'Gene', '3265', (137, 141))	('NRAS', 'Gene', '4893', (147, 151))	('HRAS', 'Gene', (137, 141))
418750	29125844	We sought genes whose aberrant expression was correlated with aberrant methylation in the presence of BRAF, HRAS, or NRAS mutations.	('NRAS', 'Gene', (117, 121))	('HRAS', 'Gene', '3265', (108, 112))	('BRAF', 'Gene', '673', (102, 106))	('NRAS', 'Gene', '4893', (117, 121))	('BRAF', 'Gene', (102, 106))	('aberrant', 'Var', (62, 70))	('HRAS', 'Gene', (108, 112))	('methylation', 'MPA', (71, 82))	('mutations', 'Var', (122, 131))
418752	29125844	Third, we integrated the results from the first and second steps to identify aberrantly methylated probes whose methylation levels were significantly correlated with the expression levels of their corresponding genes for each group of BRAF-, HRAS-, and NRAS- mutated samples.	('BRAF', 'Gene', '673', (235, 239))	('methylation levels', 'MPA', (112, 130))	('BRAF', 'Gene', (235, 239))	('HRAS', 'Gene', '3265', (242, 246))	('expression levels', 'MPA', (170, 187))	('NRAS-', 'Gene', '4893', (253, 258))	('HRAS', 'Gene', (242, 246))	('correlated', 'Reg', (150, 160))	('NRAS-', 'Gene', (253, 258))	('aberrantly methylated probes', 'Var', (77, 105))
418753	29125844	For example, when we looked for genes that were upregulated in BRAF-mutated samples but exhibited no change or were downregulated in HRAS- and NRAS-mutated samples, we restricted the search to genes that were hyper- (or hypo-) methylated in BRAF-mutated samples but exhibited no change or were hypo- (or hyper-) methylated in HRAS- and NRAS-mutated samples in the third step.	('HRAS', 'Gene', (133, 137))	('NRAS-', 'Gene', '4893', (143, 148))	('hypo-', 'Var', (220, 225))	('NRAS-', 'Gene', (143, 148))	('hyper-', 'Var', (209, 215))	('BRAF', 'Gene', '673', (241, 245))	('HRAS', 'Gene', '3265', (133, 137))	('HRAS', 'Gene', '3265', (326, 330))	('BRAF', 'Gene', '673', (63, 67))	('upregulated', 'PosReg', (48, 59))	('BRAF', 'Gene', (241, 245))	('BRAF', 'Gene', (63, 67))	('HRAS', 'Gene', (326, 330))	('NRAS-', 'Gene', (336, 341))	('NRAS-', 'Gene', '4893', (336, 341))
418757	29142209	Consistent with a substrate relationship, Fxr1 is overexpressed in Fbxo4 knockout cells, tissues and in human cancer cells, harbouring inactivating Fbxo4 mutations.	('inactivating', 'NegReg', (135, 147))	('cancer', 'Disease', (110, 116))	('Fbxo4', 'Gene', (148, 153))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('human', 'Species', '9606', (104, 109))	('mutations', 'Var', (154, 163))	('Fbxo4', 'Gene', (67, 72))	('cancer', 'Disease', 'MESH:D009369', (110, 116))
418761	29142209	Protein ubiquitylation controls protein stability, endocytosis, trafficking, DNA damage repair and cell signalling depending on the lysine residue (K6, K11, K27, K29, K33, K48 and K63) within the ubiquitin molecules that is modified.	('endocytosis', 'MPA', (51, 62))	('Protein ubiquitylation', 'MPA', (0, 22))	('K63', 'Var', (180, 183))	('DNA', 'MPA', (77, 80))	('K33', 'Var', (167, 170))	('K11', 'Var', (152, 155))	('K48', 'Var', (172, 175))	('cell signalling', 'CPA', (99, 114))	('lysine', 'Chemical', 'MESH:D008239', (132, 138))	('K27', 'Gene', '342574', (157, 160))	('K27', 'Gene', (157, 160))	('K6', 'Var', (148, 150))	('protein stability', 'MPA', (32, 49))	('trafficking', 'MPA', (64, 75))	('K29', 'Var', (162, 165))
418765	29142209	Fbxo4 missense mutations occur with a frequency of ~14% in human oesophageal squamous cell carcinoma (ESCC) and 10% in melanoma, accounting for cyclin D1 accumulation and tumorigenesis.	('human', 'Species', '9606', (59, 64))	('accumulation', 'PosReg', (154, 166))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (77, 100))	('missense mutations', 'Var', (6, 24))	('oesophageal squamous cell carcinoma', 'Disease', (65, 100))	('melanoma', 'Phenotype', 'HP:0002861', (119, 127))	('cyclin D1', 'Gene', '595', (144, 153))	('melanoma', 'Disease', (119, 127))	('melanoma', 'Disease', 'MESH:D008545', (119, 127))	('cyclin D1', 'Gene', (144, 153))	('oesophageal squamous cell carcinoma', 'Disease', 'MESH:D002294', (65, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('Fbxo4', 'Gene', (0, 5))
418772	29142209	Herein, we demonstrate that SCFFbxo4 ubiquitylates and targets Fxr1 for proteasome degradation.	('Fxr1', 'Gene', (63, 67))	('proteasome degradation', 'MPA', (72, 94))	('SCFFbxo4', 'Var', (28, 36))	('SCFFbxo4', 'Chemical', '-', (28, 36))	('targets', 'Reg', (55, 62))	('ubiquitylates', 'MPA', (37, 50))
418774	29142209	To identify substrates of the SCFFbxo4 E3 ligase, Fbxo4-/- MEFs reconstituted with Flag-Fbxo4 or Flag-Fbxo4DeltaF, which binds to substrates without recruiting E1 or E2 enzymes, were treated + /- MG-132 for 6 h, and subjected to immuno-affinity purification.	('Flag-Fbxo4', 'Var', (83, 93))	('SCFFbxo4', 'Chemical', '-', (30, 38))	('MEFs', 'CellLine', 'CVCL:9115', (59, 63))	('Flag-Fbxo4DeltaF', 'Chemical', '-', (97, 113))	('MG-132', 'Chemical', 'MESH:C072553', (196, 202))	('Flag-Fbxo4DeltaF', 'Var', (97, 113))
418784	29142209	One area of high similarity was identified corresponding to S104-I123 in Trf1 and A173-I192 in Fxr1 (Supplementary Fig.	('A173-I192', 'Var', (82, 91))	('S104-I123', 'Var', (60, 69))	('Trf1', 'Gene', '7013', (73, 77))	('Fxr1', 'Gene', (95, 99))	('Trf1', 'Gene', (73, 77))
418785	29142209	Of particular interest was the existence of four hydrophobic interactions (I109, L115, L120 and I123 in Trf1) found in the Fbxo4:Trf1-interacting model, corresponding to V178, L184, L189 and I192 in Fxr1 (Fig.	('I192', 'Var', (191, 195))	('L189', 'Var', (182, 186))	('Trf1', 'Gene', (129, 133))	('Trf1', 'Gene', '7013', (104, 108))	('I123', 'Var', (96, 100))	('L115', 'Var', (81, 85))	('L184', 'Var', (176, 180))	('Trf1', 'Gene', (104, 108))	('V178', 'Var', (170, 174))	('L120', 'Var', (87, 91))	('Trf1', 'Gene', '7013', (129, 133))
418789	29142209	These data suggest the interaction of Fbxo4 with either Trf1 or Fxr1 uses, in part, a similar interface driven by the hydrophobic residues in C-terminal amphipathic helix.	('Trf1', 'Gene', (56, 60))	('hydrophobic', 'Var', (118, 129))	('Fxr1', 'Gene', (64, 68))	('Trf1', 'Gene', '7013', (56, 60))	('interaction', 'Interaction', (23, 34))
418790	29142209	Of the Fbxo4 mutants evaluated (DeltaN, DeltaF, DeltaC2 and DeltaC3; Supplementary Fig.	('Fbxo4', 'Gene', (7, 12))	('DeltaC3', 'Var', (60, 67))	('DeltaC3', 'DELETION', 'None', (60, 67))	('DeltaC2', 'Var', (48, 55))	('DeltaC2', 'DELETION', 'None', (48, 55))	('mutants', 'Var', (13, 20))	('DeltaN', 'Var', (32, 38))
418791	29142209	4a), Fbxo4DeltaN, DeltaC2 and DeltaC3 were defecting in binding (Supplementary Fig.	('defecting', 'NegReg', (43, 52))	('DeltaC3', 'Var', (30, 37))	('DeltaC3', 'DELETION', 'None', (30, 37))	('DeltaC2', 'Var', (18, 25))	('DeltaC2', 'DELETION', 'None', (18, 25))	('binding', 'Interaction', (56, 63))
418792	29142209	According to the model structure, E379 and E380 within the DeltaC3 region should make direct contact with Fxr1 (Fig.	('DeltaC3', 'Var', (59, 66))	('E380', 'Var', (43, 47))	('DeltaC3', 'DELETION', 'None', (59, 66))	('E379', 'Var', (34, 38))
418793	29142209	Alanine substitution at these residues disrupted Fbxo4 and Fxr1 binding, while the double mutation of C341W/A354R residues that mediate Trf1 interaction failed to disrupt their binding (Fig.	('binding', 'Interaction', (64, 71))	('C341W', 'Var', (102, 107))	('Alanine substitution', 'Var', (0, 20))	('disrupted', 'NegReg', (39, 48))	('Fxr1', 'Enzyme', (59, 63))	('Alanine', 'Chemical', 'MESH:D000409', (0, 7))	('C341W', 'SUBSTITUTION', 'None', (102, 107))	('Trf1', 'Gene', '7013', (136, 140))	('Trf1', 'Gene', (136, 140))	('A354R', 'Mutation', 'p.A354R', (108, 113))	('Fbxo4', 'Enzyme', (49, 54))
418794	29142209	Additionally, a cancer-derived Fbxo4 mutant, I377M, was assessed for Fxr1 binding.	('cancer', 'Disease', 'MESH:D009369', (16, 22))	('cancer', 'Disease', (16, 22))	('Fbxo4', 'Gene', (31, 36))	('I377M', 'Mutation', 'rs149145775', (45, 50))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('I377M', 'Var', (45, 50))	('binding', 'Interaction', (74, 81))
418795	29142209	Fbxo4I377M, which does not bind cyclin D1, was defective in Fxr1 binding (Fig.	('defective', 'NegReg', (47, 56))	('Fbxo4I377M', 'Var', (0, 10))	('Fxr1', 'Protein', (60, 64))	('binding', 'Interaction', (65, 72))	('cyclin D1', 'Gene', '595', (32, 41))	('cyclin D1', 'Gene', (32, 41))	('I377M', 'Mutation', 'rs149145775', (5, 10))
418798	29142209	Mutational analysis revealed that a V178A mutation disrupted binding while, strikingy, a L189A mutation facilitated binding (Fig.	('binding', 'Interaction', (116, 123))	('V178A', 'Var', (36, 41))	('V178A', 'Mutation', 'p.V178A', (36, 41))	('L189A', 'Var', (89, 94))	('L189A', 'Mutation', 'p.L189A', (89, 94))	('disrupted', 'NegReg', (51, 60))	('facilitated', 'PosReg', (104, 115))	('binding', 'Interaction', (61, 68))
418799	29142209	Of note, V178R also enhanced their binding (Supplementary Fig.	('binding', 'Interaction', (35, 42))	('V178R', 'Mutation', 'p.V178R', (9, 14))	('V178R', 'Var', (9, 14))	('enhanced', 'PosReg', (20, 28))
418803	29142209	Indeed, Fxr1 knockdown reduced FMRP co-precipitation (Supplementary Fig.	('Fxr1', 'Gene', (8, 12))	('FMRP', 'Gene', '2332', (31, 35))	('reduced', 'NegReg', (23, 30))	('knockdown', 'Var', (13, 22))	('FMRP', 'Gene', (31, 35))
418805	29142209	Fxr1 levels were elevated in Fbxo4-/- MEFs relative to WT counterparts (Fig.	('Fbxo4-/- MEFs', 'Var', (29, 42))	('MEFs', 'CellLine', 'CVCL:9115', (38, 42))	('elevated', 'PosReg', (17, 25))	('Fxr1 levels', 'MPA', (0, 11))
418813	29142209	As an additional control, dominant negative Fbxo4DeltaF was used; SCFFbxo4DeltaF did not increase Fxr1 ubiquitylation above background (Fig.	('SCFFbxo4DeltaF', 'Var', (66, 80))	('SCFFbxo4', 'Chemical', '-', (66, 74))	('Fxr1 ubiquitylation', 'MPA', (98, 117))
418818	29142209	Expression of phospho-mimetic Fbxo4S12E increased Fxr1 ubiquitylation, while an S12A mutant decreased polyubiquitylation (Fig.	('Fxr1 ubiquitylation', 'MPA', (50, 69))	('polyubiquitylation', 'MPA', (102, 120))	('increased', 'PosReg', (40, 49))	('Fbxo4S12E', 'Var', (30, 39))	('decreased', 'NegReg', (92, 101))	('S12A', 'Var', (80, 84))	('S12A', 'SUBSTITUTION', 'None', (80, 84))
418819	29142209	Fbxo4 E379A, E380A and I377M mutants were also assessed for ubiquitylation of Fxr1 to ensure the direct interaction was required.	('I377M', 'Var', (23, 28))	('E379A', 'Var', (6, 11))	('E379A', 'Mutation', 'rs1339191438', (6, 11))	('ubiquitylation', 'MPA', (60, 74))	('E380A', 'Mutation', 'p.E380A', (13, 18))	('E380A', 'Var', (13, 18))	('I377M', 'Mutation', 'rs149145775', (23, 28))	('Fbxo4', 'Gene', (0, 5))
418820	29142209	Taken together, the biochemical data support SCFFbxo4 can directly ubiquitylate and degrade Fxr1 in a manner that depends upon GSK3beta-mediated Fbxo4 phosphorylation.	('SCFFbxo4', 'Var', (45, 53))	('SCFFbxo4', 'Chemical', '-', (45, 53))	('ubiquitylate', 'MPA', (67, 79))	('GSK3beta', 'Gene', (127, 135))	('Fxr1', 'MPA', (92, 96))	('GSK3beta', 'Gene', '2932', (127, 135))	('degrade', 'NegReg', (84, 91))
418821	29142209	While inactivation of FMRP family proteins contributes to fragile X syndrome and mental retardation, mining of the data deposited in Oncomine specifically revealed elevated Fxr1 in human cancers (Fig.	('human', 'Species', '9606', (181, 186))	('cancers', 'Disease', 'MESH:D009369', (187, 194))	('contributes', 'Reg', (43, 54))	('FMRP', 'Gene', '2332', (22, 26))	('cancers', 'Phenotype', 'HP:0002664', (187, 194))	('cancers', 'Disease', (187, 194))	('inactivation', 'Var', (6, 18))	('fragile X syndrome', 'Disease', (58, 76))	('mental retardation', 'Phenotype', 'HP:0001249', (81, 99))	('fragile X syndrome', 'Disease', 'MESH:D005600', (58, 76))	('Fxr1', 'Gene', (173, 177))	('FMRP', 'Gene', (22, 26))	('mental retardation', 'Disease', (81, 99))	('mental retardation', 'Disease', 'MESH:D008607', (81, 99))	('Oncomine', 'Chemical', '-', (133, 141))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('elevated', 'PosReg', (164, 172))
418827	29142209	Consistent with ubiquitylation assay, inhibition of GSK3beta kinase activity rescues Fxr1 downregulation-mediated by Fbxo4 (Supplementary Fig.	('GSK3beta', 'Gene', (52, 60))	('GSK3beta', 'Gene', '2932', (52, 60))	('downregulation-mediated', 'NegReg', (90, 113))	('inhibition', 'Var', (38, 48))	('Fxr1', 'Gene', (85, 89))
418828	29142209	To further corroborate the ubiquitylation findings, S12A, S12E, E379A, and I377M Fbxo4 were expressed in HNSCC cells.	('S12A', 'SUBSTITUTION', 'None', (52, 56))	('E379A', 'Var', (64, 69))	('I377M', 'Var', (75, 80))	('E379A', 'Mutation', 'rs1339191438', (64, 69))	('S12E', 'Var', (58, 62))	('S12E', 'Mutation', 'p.S12E', (58, 62))	('HNSCC', 'Phenotype', 'HP:0012288', (105, 110))	('Fbxo4', 'Gene', (81, 86))	('S12A', 'Var', (52, 56))	('I377M', 'Mutation', 'rs149145775', (75, 80))
418829	29142209	Only WT and S12E Fbxo4 but not inactive mutants effectively suppressed Fxr1 expression (Supplementary Fig.	('suppressed', 'NegReg', (60, 70))	('expression', 'MPA', (76, 86))	('Fxr1', 'Gene', (71, 75))	('S12E', 'Mutation', 'p.S12E', (12, 16))	('S12E', 'Var', (12, 16))
418832	29142209	Consistently, Fbxo4 expression increased SA-beta-Gal staining to a similar degree as Fxr1 knockdown (Fig.	('Fbxo4', 'Gene', (14, 19))	('SA-beta-Gal staining', 'MPA', (41, 61))	('increased', 'PosReg', (31, 40))	('SA', 'Chemical', 'MESH:C012546', (41, 43))	('expression', 'Var', (20, 30))	('beta-Gal', 'Chemical', '-', (44, 52))
418833	29142209	Fbxo4 overexpression or Fxr1 knockdown resulted in increased expression of both p21Cip1 and p27Kip1 (Fig.	('knockdown', 'Var', (29, 38))	('p27Kip1', 'Gene', (92, 99))	('increased', 'PosReg', (51, 60))	('p21Cip1', 'Gene', (80, 87))	('overexpression', 'PosReg', (6, 20))	('p27Kip1', 'Gene', '1027', (92, 99))	('Fxr1', 'Gene', (24, 28))	('expression', 'MPA', (61, 71))	('Fbxo4', 'Gene', (0, 5))	('p21Cip1', 'Gene', '1026', (80, 87))
418837	29142209	9g, h), consistent with the compensatory upregulation of p21 Cip1 by p27 Kip1 knockdown (Fig.	('p27 Kip1', 'Gene', (69, 77))	('knockdown', 'Var', (78, 87))	('p21 Cip1', 'Gene', (57, 65))	('p21 Cip1', 'Gene', '1026', (57, 65))	('upregulation', 'PosReg', (41, 53))	('p27 Kip1', 'Gene', '1027', (69, 77))
418838	29142209	Fxr1-mediated p21 Cip1 mRNA degradation has been clearly demonstrated; Fxr1 knockdown resulted in increased mRNA and protein levels of p27 Kip1, while no mRNA binding was detected by RNA-binding protein immunoprecipitation (RIP), suggesting indirect regulation.	('knockdown', 'Var', (76, 85))	('RIP', 'Gene', '3267', (224, 227))	('p27 Kip1', 'Gene', '1027', (135, 143))	('p27 Kip1', 'Gene', (135, 143))	('Fxr1', 'Gene', (71, 75))	('increased', 'PosReg', (98, 107))	('p21 Cip1', 'Gene', (14, 22))	('RIP', 'Gene', (224, 227))	('p21 Cip1', 'Gene', '1026', (14, 22))
418843	29142209	To corroborate the dysregulation of Fbxo4-Fxr1 axis, both ESCC and melanoma cells were utilised due to the presence of Fbxo4 mutations in these cancers.	('mutations', 'Var', (125, 134))	('melanoma', 'Phenotype', 'HP:0002861', (67, 75))	('melanoma', 'Disease', (67, 75))	('presence', 'Reg', (107, 115))	('melanoma', 'Disease', 'MESH:D008545', (67, 75))	('cancers', 'Phenotype', 'HP:0002664', (144, 151))	('cancers', 'Disease', (144, 151))	('cancers', 'Disease', 'MESH:D009369', (144, 151))	('Fbxo4', 'Gene', (119, 124))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
418844	29142209	Fxr1 was elevated in TE10 cells, a cell line that harbours an S8R mutation that disrupts Fbxo4 dimerisation (Supplementary Fig.	('TE10', 'CellLine', 'CVCL:1760', (21, 25))	('S8R', 'Mutation', 'rs762437813', (62, 65))	('Fbxo4 dimerisation', 'MPA', (89, 107))	('mutation', 'Var', (66, 74))	('S8R', 'Gene', (62, 65))	('disrupts', 'NegReg', (80, 88))
418847	29142209	To further assess Fbxo4-Fxr1 regulation in tumorigenesis, tumours that developed in Fbxo4 + / + , + /- and -/- mice, treated with N-nitrosomethylbenzylamine (NMBA) to trigger SCC, were subjected to IHC staining.	('tumours', 'Phenotype', 'HP:0002664', (58, 65))	('tumour', 'Phenotype', 'HP:0002664', (58, 64))	('Fbxo4 + / +', 'Var', (84, 95))	('N-nitrosomethylbenzylamine', 'Chemical', 'MESH:C014707', (130, 156))	('NMBA', 'Chemical', 'MESH:C014707', (158, 162))	('mice', 'Species', '10090', (111, 115))	('tumours', 'Disease', 'MESH:D009369', (58, 65))	('tumours', 'Disease', (58, 65))
418848	29142209	As reported, high papilloma incidence was observed in Fbxo4 + /-(27/32, 84.4%) and -/- mice (20 out of 22, 90.9%) compared with + / + mice (6 out of 21, 28.6%), p < 0.01 (chi 2 test).	('papilloma', 'Disease', (18, 27))	('mice', 'Species', '10090', (134, 138))	('papilloma', 'Disease', 'MESH:D010212', (18, 27))	('mice', 'Species', '10090', (87, 91))	('papilloma', 'Phenotype', 'HP:0012740', (18, 27))	('Fbxo4 + /-', 'Var', (54, 64))
418851	29142209	These data demonstrate that Fbxo4 regulates Fxr1 accumulation in vivo and that loss of Fbxo4 leads to Fxr1 overexpression in both normal and tumour tissues.	('loss', 'Var', (79, 83))	('Fbxo4', 'Gene', (87, 92))	('tumour', 'Phenotype', 'HP:0002664', (141, 147))	('Fxr1 accumulation', 'MPA', (44, 61))	('tumour', 'Disease', 'MESH:D009369', (141, 147))	('overexpression', 'PosReg', (107, 121))	('tumour', 'Disease', (141, 147))	('Fxr1', 'MPA', (102, 106))
418852	29142209	Although Fbxo4 mutations have been found in human ESCC and melanoma, additional mutations are only rarely observed in other human cancers (Supplementary Fig.	('human', 'Species', '9606', (44, 49))	('cancers', 'Phenotype', 'HP:0002664', (130, 137))	('cancers', 'Disease', (130, 137))	('mutations', 'Var', (15, 24))	('Fbxo4', 'Gene', (9, 14))	('cancers', 'Disease', 'MESH:D009369', (130, 137))	('human', 'Species', '9606', (124, 129))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('melanoma', 'Disease', 'MESH:D008545', (59, 67))	('melanoma', 'Phenotype', 'HP:0002861', (59, 67))	('melanoma', 'Disease', (59, 67))	('ESCC', 'Disease', (50, 54))	('found', 'Reg', (35, 40))
418859	29142209	Fbxw7 directs proteolysis of key pro-neoplastic proteins, including c-Myc, Notch and cyclin E. Mutations in the gene encoding Fbxw7 occur in a number of malignancies and Fbxw7-deficient mice are tumour prone, demonstrating its tumour suppressive function.	('c-Myc', 'Gene', (68, 73))	('Fbxw7', 'Gene', (126, 131))	('malignancies and Fbxw7-deficient', 'Disease', 'MESH:D009369', (153, 185))	('tumour', 'Disease', 'MESH:D009369', (195, 201))	('tumour', 'Phenotype', 'HP:0002664', (227, 233))	('Mutations', 'Var', (95, 104))	('occur', 'Reg', (132, 137))	('tumour', 'Disease', (195, 201))	('tumour', 'Disease', 'MESH:D009369', (227, 233))	('c-Myc', 'Gene', '4609', (68, 73))	('mice', 'Species', '10090', (186, 190))	('tumour', 'Disease', (227, 233))	('tumour', 'Phenotype', 'HP:0002664', (195, 201))
418861	29142209	Fbxo4 is subject to both inactivating mutations and reduced expression in cancers.	('expression', 'MPA', (60, 70))	('inactivating mutations', 'Var', (25, 47))	('reduced', 'NegReg', (52, 59))	('cancers', 'Disease', 'MESH:D009369', (74, 81))	('cancers', 'Phenotype', 'HP:0002664', (74, 81))	('cancers', 'Disease', (74, 81))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('Fbxo4', 'Gene', (0, 5))
418885	29142209	Although gene amplification contributes to Fxr1 overexpression in cancers, we now demonstrate that post-translational regulation of Fxr1 is also a contributing factor.	('Fxr1', 'Gene', (132, 136))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('gene amplification', 'Var', (9, 27))	('Fxr1', 'Gene', (43, 47))	('post-translational regulation', 'MPA', (99, 128))	('cancers', 'Phenotype', 'HP:0002664', (66, 73))	('overexpression', 'PosReg', (48, 62))	('cancers', 'Disease', (66, 73))	('cancers', 'Disease', 'MESH:D009369', (66, 73))
418886	29142209	Loss of Fbxo4 directly contributes to Fxr1 overexpression in both normal and cancer cells; likewise, re-introduction of Fbxo4 into HNSCC cells triggers Fxr1-dependent senescence, demonstrating the importance of this regulatory loop.	('HNSCC', 'Phenotype', 'HP:0012288', (131, 136))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('re-introduction', 'Var', (101, 116))	('triggers', 'Reg', (143, 151))	('Fbxo4', 'Gene', (8, 13))	('Fxr1-dependent senescence', 'MPA', (152, 177))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('Fbxo4', 'Gene', (120, 125))	('Loss', 'Var', (0, 4))
418887	29142209	Rescue experiments support the importance of both p21Cip1 and p27Kip1 as downstream factors that control cell senescence and proliferation upon Fxr1 knockdown or Fbxo4 overexpression.	('p21Cip1', 'Gene', '1026', (50, 57))	('control', 'Reg', (97, 104))	('knockdown', 'Var', (149, 158))	('p27Kip1', 'Gene', '1027', (62, 69))	('Fbxo4', 'Gene', (162, 167))	('proliferation', 'CPA', (125, 138))	('cell senescence', 'CPA', (105, 120))	('p27Kip1', 'Gene', (62, 69))	('p21Cip1', 'Gene', (50, 57))	('Fxr1', 'Gene', (144, 148))
418889	29142209	Although Fbxo4 is subjected to mutations in ESCC, the mutation frequency is much lower than that with protein loss or reduction in primary HNSCC (Supplementary Fig.	('mutations', 'Var', (31, 40))	('ESCC', 'Gene', (44, 48))	('HNSCC', 'Phenotype', 'HP:0012288', (139, 144))	('protein loss', 'Disease', (102, 114))	('protein loss', 'Disease', 'MESH:D011488', (102, 114))
418908	29142209	451Lu, WM88, WM983B, WM3918, 1205Lu and WM793B melanoma cells were propagated in Tu2% medium: 80% MCDB153, 20% Leibovitz's L-15, 2% FBS, 4 mM Glutamine, and 1.68 mM CaCl2.	('Tu2', 'Chemical', '-', (81, 84))	('WM793B', 'Var', (40, 46))	('L-15', 'Chemical', '-', (123, 127))	('FBS', 'Disease', (132, 135))	('Glutamine', 'Chemical', 'MESH:D005973', (142, 151))	('CaCl2', 'Chemical', 'MESH:D002122', (165, 170))	('melanoma', 'Phenotype', 'HP:0002861', (47, 55))	('FBS', 'Disease', 'MESH:D005198', (132, 135))	('melanoma', 'Disease', (47, 55))	('melanoma', 'Disease', 'MESH:D008545', (47, 55))	('MCDB153', 'Chemical', 'MESH:C112696', (98, 105))	('WM793B', 'CellLine', 'CVCL:8787', (40, 46))
418953	26136768	Amplification of several genomic regions at 3q26-qter chromosome is associated with multiple human cancers.	('Amplification', 'Var', (0, 13))	('associated', 'Reg', (68, 78))	('human', 'Species', '9606', (93, 98))	('cancers', 'Disease', 'MESH:D009369', (99, 106))	('cancers', 'Phenotype', 'HP:0002664', (99, 106))	('cancers', 'Disease', (99, 106))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
418966	26136768	In addition to the experimentally approved novel transcripts, human EST database (dbEST) also provided some ESTs with GenBank accession numbers BX423294.2, BX442540.2, BX459910.2, DA268964.1, and DA282731.1 which are related to the novel sequence of exon 3-exon five junction in SOX2OT-S1, and DA308672.1 which is related to the novel sequence of exon 2-exon five junction in SOX2OT-S2 variant.	('BX442540.2', 'Var', (156, 166))	('GenBank', 'Var', (118, 125))	('human', 'Species', '9606', (62, 67))	('DA308672.1', 'Var', (294, 304))	('BX459910.2', 'Var', (168, 178))	('DA268964.1', 'Var', (180, 190))	('BX423294.2', 'Var', (144, 154))	('DA282731.1', 'Var', (196, 206))
418976	26136768	The expression pattern of SOX2OT variants was similar to those of SOX2 and OCT4, and downregulated upon the induction of neural differentiation.	('downregulated', 'NegReg', (85, 98))	('expression', 'MPA', (4, 14))	('OCT4', 'Gene', '5460', (75, 79))	('OCT4', 'Gene', (75, 79))	('SOX2OT', 'Gene', (26, 32))	('variants', 'Var', (33, 41))
418977	26136768	However, in contrast to a complete shut-down of SOX2 and OCT4 expression, a low expression of SOX2OT and its variants is persisted in later time points of differentiation.	('SOX2OT', 'Gene', (94, 100))	('OCT4', 'Gene', '5460', (57, 61))	('OCT4', 'Gene', (57, 61))	('variants', 'Var', (109, 117))
418993	26136768	Transcription factor SOX2 regulates the expression of more than one thousand genes in stem cells where small changes of its expression strikingly alter the self-renewal and pluripotency properties; hence SOX2 acts role as a molecular rheostat in those cells.	('changes', 'Var', (109, 116))	('self-renewal', 'MPA', (156, 168))	('pluripotency', 'Disease', (173, 185))	('pluripotency', 'Disease', 'None', (173, 185))	('alter', 'Reg', (146, 151))
418994	26136768	Recent evidences have demonstrated that gene amplification and/or aberrant expression level of SOX2 play a role in the development and tumorigenesis of many types of cancer including pancreatic carcinoma, prostate, breast, lung, gastric, and esophagus cancers.	('cancer', 'Disease', 'MESH:D009369', (252, 258))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('pancreatic carcinoma', 'Disease', 'MESH:C562463', (183, 203))	('aberrant', 'Var', (66, 74))	('gene amplification', 'Var', (40, 58))	('prostate', 'Disease', (205, 213))	('pancreatic carcinoma', 'Disease', (183, 203))	('lung', 'Disease', (223, 227))	('cancer', 'Disease', (166, 172))	('cancers', 'Phenotype', 'HP:0002664', (252, 259))	('role', 'Reg', (107, 111))	('cancer', 'Disease', (252, 258))	('tumor', 'Disease', (135, 140))	('esophagus cancers', 'Disease', (242, 259))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('SOX2', 'Gene', (95, 99))	('gastric', 'Disease', (229, 236))	('tumor', 'Disease', 'MESH:D009369', (135, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (194, 203))	('expression level', 'MPA', (75, 91))	('breast', 'Disease', (215, 221))	('esophagus cancers', 'Disease', 'MESH:D004938', (242, 259))
418998	26136768	This hypothesis is more approved by several experimental approaches obtained from gene expression alteration during stem cell differentiation or carcinogenesis, and also by manipulation of SOX2OT expression in vitro.	('alteration', 'Var', (98, 108))	('manipulation', 'Reg', (173, 185))	('SOX2OT', 'Gene', (189, 195))	('carcinogenesis', 'Disease', 'MESH:D063646', (145, 159))	('carcinogenesis', 'Disease', (145, 159))
418999	26136768	Using the RNA interference strategy, our group performed a functional assay on SOX2OT, where the data supported our hypothesis on the existence of a positive regulation of SOX2 and OCT4 by SOX2OT.	('SOX2', 'Gene', (172, 176))	('positive regulation', 'PosReg', (149, 168))	('SOX2OT', 'Var', (189, 195))	('OCT4', 'Gene', '5460', (181, 185))	('OCT4', 'Gene', (181, 185))
419003	26136768	The knocking down of SOX2OT caused induction of G2/M arrest, prohibition of S phase entry and inhibited cell proliferation which correlated with reduced protein levels of Cyclin B1 and Cdc2 in human lung cancer cell lines.	('knocking down', 'Var', (4, 17))	('lung cancer', 'Disease', 'MESH:D008175', (199, 210))	('S phase entry', 'CPA', (76, 89))	('reduced', 'NegReg', (145, 152))	('G2/M arrest', 'CPA', (48, 59))	('SOX2OT', 'Gene', (21, 27))	('Cdc2', 'Gene', (185, 189))	('induction', 'Reg', (35, 44))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('cell proliferation', 'CPA', (104, 122))	('lung cancer', 'Disease', (199, 210))	('lung cancer', 'Phenotype', 'HP:0100526', (199, 210))	('Cyclin B1', 'Gene', '891', (171, 180))	('human', 'Species', '9606', (193, 198))	('Cdc2', 'Gene', '983', (185, 189))	('inhibited', 'NegReg', (94, 103))	('prohibition', 'NegReg', (61, 72))	('Cyclin B1', 'Gene', (171, 180))
419021	26136768	This observation along with the observed correlations between the expression of SOX2OT variants with that of key genes promoting those events, all suggested a key role for SOX2OT in pluripotency and tumorigenesis.	('tumor', 'Disease', (199, 204))	('pluripotency', 'Disease', 'None', (182, 194))	('variants', 'Var', (87, 95))	('SOX2OT', 'Gene', (80, 86))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('pluripotency', 'Disease', (182, 194))
419022	26136768	Furthermore, the expression patterns of its variants and their emerging roles in stem cell biology and tumorigenesis is discussed.	('tumor', 'Disease', (103, 108))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('variants', 'Var', (44, 52))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))
419217	24693428	The process of tumorigenesis requires multistep initiation of cellular and molecular pathways leading to a series of mutations resulting in the acquisition of replication and growth factor independence, resistance to growth-inhibitory signals, tissue invasion, and metastasis.	('metastasis', 'CPA', (265, 275))	('mutations', 'Var', (117, 126))	('resistance to growth-inhibitory signals', 'MPA', (203, 242))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('replication and', 'MPA', (159, 174))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('acquisition', 'PosReg', (144, 155))	('tumor', 'Disease', (15, 20))	('tissue invasion', 'CPA', (244, 259))
419222	24693428	The CSC hypothesis postulates that tumor heterogeneity with regard to initiation, progression, response to therapy, and metastasis is the result of mutations which either render a normal somatic tissue stem cell cancerous or cause a cancer cell to become stem cell-like.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('mutations', 'Var', (148, 157))	('cancerous', 'Disease', 'MESH:D009369', (212, 221))	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumor', 'Disease', (35, 40))	('cancer', 'Disease', (233, 239))	('cancerous', 'Disease', (212, 221))	('cancer', 'Disease', 'MESH:D009369', (233, 239))	('cancer', 'Disease', (212, 218))	('cancer', 'Disease', 'MESH:D009369', (212, 218))	('cause', 'Reg', (225, 230))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))
419271	24693428	As already known, the activated fibroblasts (myofibroblasts) inside the tumor stroma stimulate the transformed keratinocytes, thus influencing stem cell division patterns and with further genetic alterations of these keratinocytes leads to evolution of more invasive clones.	('stem cell division patterns', 'CPA', (143, 170))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('invasive clones', 'CPA', (258, 273))	('influencing', 'Reg', (131, 142))	('leads to', 'Reg', (231, 239))	('genetic alterations', 'Var', (188, 207))	('tumor stroma', 'Disease', 'MESH:D009369', (72, 84))	('tumor stroma', 'Disease', (72, 84))
419307	32856880	Many previous studies have shown that fucoidan enhances antioxidant (Wang et al., 2008), anti-coagulant (Cumashi et al., 2007), anti-inflammatory (Cumashi et al., 2007; Matsumoto et al., 2004), anti-viral (Hayashi et al., 2008), anti-bacterial (Zapopozhets et al., 1995) and immunomodulatory effects (Choi et al., 2005).	('anti-viral', 'CPA', (194, 204))	('fucoidan', 'Chemical', 'MESH:C007789', (38, 46))	('anti-inflammatory', 'CPA', (128, 145))	('immunomodulatory effects', 'CPA', (275, 299))	('anti-bacterial', 'CPA', (229, 243))	('fucoidan', 'Var', (38, 46))	('antioxidant', 'MPA', (56, 67))	('enhances', 'PosReg', (47, 55))	('anti-coagulant', 'MPA', (89, 103))
419311	32856880	Previous in vivo studies reported that fucoidan suppressed the growth of Ehrlich ascites carcinoma (Zhuang et al., 1995), Lewis lung adenocarcinoma (Alekseyenko et al., 2007), 13762 MAT rat mammary adenocarcinoma (Coombe et al., 1987) and reduced the angiogenesis of breast cancer (Xue et al., 2012).	('suppressed', 'NegReg', (48, 58))	('fucoidan', 'Chemical', 'MESH:C007789', (39, 47))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('breast cancer', 'Phenotype', 'HP:0003002', (267, 280))	('adenocarcinoma', 'Disease', 'MESH:D000230', (198, 212))	('adenocarcinoma', 'Disease', (133, 147))	('reduced', 'NegReg', (239, 246))	('breast cancer', 'Disease', 'MESH:D001943', (267, 280))	('Ehrlich ascites carcinoma', 'Disease', 'MESH:D002286', (73, 98))	('breast cancer', 'Disease', (267, 280))	('lung adenocarcinoma', 'Disease', (128, 147))	('angiogenesis', 'CPA', (251, 263))	('adenocarcinoma', 'Disease', 'MESH:D000230', (133, 147))	('Ehrlich ascites carcinoma', 'Disease', (73, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (203, 212))	('13762 MAT', 'Var', (176, 185))	('ascites', 'Phenotype', 'HP:0001541', (81, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('rat', 'Species', '10116', (186, 189))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (128, 147))	('adenocarcinoma', 'Disease', (198, 212))	('growth', 'MPA', (63, 69))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (128, 147))	('cancer', 'Phenotype', 'HP:0002664', (274, 280))
419331	32856880	Briefly, 1 x 105 harvested cells were incubated with FITC Annexin V and PI in the binding buffer and incubate for 15 min at room temperature in the dark.	('Annexin V', 'Gene', '308', (58, 67))	('FITC', 'Chemical', 'MESH:D016650', (53, 57))	('Annexin V', 'Gene', (58, 67))	('rat', 'Species', '10116', (134, 137))	('FITC', 'Var', (53, 57))
419387	32856880	The present study revealed that fucoidan could induce apoptosis in HSC-3 cells as shown in the decrease of Bcl-2 but increase of Bax levels.	('decrease', 'NegReg', (95, 103))	('Bcl-2', 'Gene', (107, 112))	('increase', 'PosReg', (117, 125))	('Bcl-2', 'Gene', '596', (107, 112))	('fucoidan', 'Var', (32, 40))	('HSC-3', 'Gene', (67, 72))	('fucoidan', 'Chemical', 'MESH:C007789', (32, 40))	('Bax', 'Gene', (129, 132))	('HSC-3', 'Gene', '150353', (67, 72))	('Bax', 'Gene', '581', (129, 132))
419393	32856880	In the intrinsic pathway, alterations in the mitochondrial membrane potential due to various stimuli result in releasing cytochrome c to the cytosol that further activates caspase-9 (Brenner and Mak, 2009).	('activates', 'PosReg', (162, 171))	('Mak', 'Gene', (195, 198))	('cytochrome c', 'Gene', (121, 133))	('caspase-9', 'Gene', '842', (172, 181))	('alterations', 'Var', (26, 37))	('rat', 'Species', '10116', (30, 33))	('cytochrome c', 'Gene', '54205', (121, 133))	('intrinsic pathway', 'Pathway', (7, 24))	('caspase-9', 'Gene', (172, 181))	('mitochondrial membrane potential', 'MPA', (45, 77))	('Mak', 'Gene', '4117', (195, 198))
419397	32856880	For mitochondria, interruption of mitochondrial membrane potential (DeltaPsim) by increasing the permeability of the outer mitochondrial membrane can lead the cell to apoptosis (Green and Reed, 1998; Philchenkov, 2004).	('DeltaPsim', 'Disease', 'None', (68, 77))	('apoptosis', 'CPA', (167, 176))	('interruption', 'Var', (18, 30))	('lead', 'Reg', (150, 154))	('DeltaPsim', 'Disease', (68, 77))	('increasing', 'PosReg', (82, 92))	('permeability of the outer mitochondrial membrane', 'MPA', (97, 145))
419398	32856880	Previous studies suggested that fucoidan induced apoptosis in cancer cells by DeltaPsim alteration (Kim et al., 2010; Narayani et al., 2019; Park et al., 2011).	('DeltaPsim', 'Disease', 'None', (78, 87))	('DeltaPsim', 'Disease', (78, 87))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('fucoidan', 'Chemical', 'MESH:C007789', (32, 40))	('rat', 'Species', '10116', (92, 95))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('apoptosis', 'CPA', (49, 58))	('alteration', 'Var', (88, 98))
419403	32856880	However, in the previous study, arrest in S/G2 phase was observed in head and neck squamous cell carcinoma H103 and FaDu cell lines treated with fucoidan (Blaszczak et al., 2018).	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (78, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (83, 106))	('fucoidan', 'Chemical', 'MESH:C007789', (145, 153))	('arrest', 'Disease', 'MESH:D006323', (32, 38))	('neck squamous cell carcinoma', 'Disease', (78, 106))	('arrest', 'Disease', (32, 38))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (69, 106))	('S/G2', 'Var', (42, 46))	('S/G2', 'SUBSTITUTION', 'None', (42, 46))
419422	29884408	Whole exome sequencing data recently revealed an abundance of genetic and expression alterations in a family of enzymes known as protein methyltransferases in a variety of cancer types, including squamous cell carcinoma of the head and neck.	('carcinoma', 'Phenotype', 'HP:0030731', (210, 219))	('squamous cell carcinoma', 'Disease', (196, 219))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (196, 219))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('carcinoma of the head and neck', 'Phenotype', 'HP:0012288', (210, 240))	('alterations', 'Var', (85, 96))	('cancer', 'Disease', (172, 178))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (196, 219))
419427	29884408	More specifically, 95% of patients with SCCHN in the TCGA database carry genetic or expression alterations in any of the protein methyltransferases (PMTs).	('expression', 'MPA', (84, 94))	('SCCHN', 'Disease', (40, 45))	('genetic', 'Var', (73, 80))	('patients', 'Species', '9606', (26, 34))
419428	29884408	Interestingly, while PMTs are mostly known to regulate epigenetic and transcriptional events through histone methylation, preclinical studies have also revealed a number of non-histone protein substrates that are methylated either at lysine or arginine residues.	('methylated', 'Var', (213, 223))	('arginine', 'Var', (244, 252))	('arginine', 'Chemical', 'MESH:D001120', (244, 252))	('lysine', 'Chemical', 'MESH:D008239', (234, 240))
419436	29884408	As a clarification, although the top five PMTs with the highest frequency of genetic and expression alterations in SCCHN are MLL2 (KMT2D, 20%), SUV420H1 (KMT5B, 18%), SETD3 (18%), NSD1 (17%) and NSD3 (17%), we found literature with mechanistic insight pertaining to SCCHN only on NSD1 and NSD3, as well as NSD2, EHMT2, EZH2, PRMT1 and PRMT5.	('PRMT5', 'Gene', '10419', (335, 340))	('KMT2D', 'Gene', '8085', (131, 136))	('NSD3', 'Gene', '54904', (195, 199))	('NSD3', 'Gene', '54904', (289, 293))	('SETD3', 'Gene', (167, 172))	('MLL2', 'Gene', '8085', (125, 129))	('SUV420H1', 'Gene', (144, 152))	('PRMT1', 'Gene', '3276', (325, 330))	('MLL2', 'Gene', (125, 129))	('PRMT1', 'Gene', (325, 330))	('SUV420H1', 'Gene', '51111', (144, 152))	('PRMT5', 'Gene', (335, 340))	('NSD2', 'Gene', (306, 310))	('KMT5B', 'Gene', (154, 159))	('KMT2D', 'Gene', (131, 136))	('EHMT2', 'Gene', (312, 317))	('KMT5B', 'Gene', '51111', (154, 159))	('NSD2', 'Gene', '7468', (306, 310))	('EHMT2', 'Gene', '10919', (312, 317))	('NSD3', 'Gene', (195, 199))	('NSD3', 'Gene', (289, 293))	('SETD3', 'Gene', '84193', (167, 172))	('alterations', 'Var', (100, 111))
419437	29884408	The NSD (nuclear SET-Suppressor of variegation 3-9, Enhancer of zeste and Trithorax-domain) family of PKMTs consisting of NSD1, NSD2 (MMSET/WHSC1, Wolf-Hirschhorn Syndrome Candidate 1) and NSD3 (WHSC1L1, Wolf-Hirschhorn Syndrome Candidate 1-Like 1) is a group of chromatin modifiers known to catalyze the deposition of mono- and di-methyl groups on lysine 36 of histone H3 (H3K36mel, H3K36me2), marks which induce active gene expression.	('Wolf-Hirschhorn', 'Disease', 'MESH:D054877', (204, 219))	('NSD3', 'Gene', '54904', (189, 193))	('H3K36me2', 'Var', (384, 392))	('NSD2', 'Gene', '7468', (128, 132))	('NSD', 'Disease', 'MESH:D029461', (189, 192))	('WHSC1L1', 'Gene', '54904', (195, 202))	('induce', 'PosReg', (407, 413))	('NSD', 'Disease', (189, 192))	('WHSC1', 'Gene', (140, 145))	('WHSC1', 'Gene', (195, 200))	('Wolf-Hirschhorn', 'Disease', (147, 162))	('WHSC1L1', 'Gene', (195, 202))	('NSD', 'Disease', 'MESH:D029461', (4, 7))	('NSD', 'Disease', (4, 7))	('Wolf-Hirschhorn', 'Disease', 'MESH:D054877', (147, 162))	('NSD', 'Disease', 'MESH:D029461', (122, 125))	('NSD', 'Disease', 'MESH:D029461', (128, 131))	('NSD', 'Disease', (122, 125))	('NSD3', 'Gene', (189, 193))	('NSD', 'Disease', (128, 131))	('MMSET', 'Gene', (134, 139))	('NSD2', 'Gene', (128, 132))	('lysine', 'Chemical', 'MESH:D008239', (349, 355))	('WHSC1', 'Gene', '7468', (140, 145))	('MMSET', 'Gene', '7468', (134, 139))	('Wolf-Hirschhorn', 'Disease', (204, 219))	('active gene expression', 'MPA', (414, 436))	('WHSC1', 'Gene', '7468', (195, 200))
419439	29884408	Per TCGA, 17% of patients with SCCHN have genetic and expression alterations in NSD1 (Table 1).	('expression', 'MPA', (54, 64))	('genetic', 'Var', (42, 49))	('SCCHN', 'Disease', (31, 36))	('patients', 'Species', '9606', (17, 25))	('NSD1', 'Gene', (80, 84))
419440	29884408	A recent study reported a subset of HPV-negative SCCHN cases with impaired methylation of H3K36 which was attributed to NSD1 inactivating mutations or recurrent histone 3 lysine 36 (H3K36M) mutations, indicating that loss of H3K36 methylation contributes to SCCHN oncogenesis.	('H3K36M', 'Gene', (182, 188))	('contributes', 'Reg', (243, 254))	('impaired', 'NegReg', (66, 74))	('oncogenesis', 'Disease', (264, 275))	('SCCHN oncogenesis', 'Disease', (258, 275))	('SCCHN', 'Disease', (49, 54))	('mutations', 'Var', (190, 199))	('HPV', 'Species', '10566', (36, 39))	('lysine', 'Chemical', 'MESH:D008239', (171, 177))	('methylation', 'MPA', (75, 86))	('H3K36', 'Protein', (90, 95))	('K36M', 'Mutation', 'p.K36M', (184, 188))
419441	29884408	Interrogation of other genes known to be involved in H3K36 methylation showed that 16% (10 out of 61) of the DNA hypomethylation samples had K36M mutations in histone H3 variant genes (H3.1, H3.2, H3.3), while other H3K36 methyltransferase genes, such as SETD2 and NSD2, were only rarely mutated.	('K36M mutations', 'Var', (141, 155))	('H3.2', 'CellLine', 'CVCL:F498', (191, 195))	('NSD2', 'Gene', '7468', (265, 269))	('SETD2', 'Gene', '29072', (255, 260))	('NSD2', 'Gene', (265, 269))	('K36M', 'Mutation', 'p.K36M', (141, 145))	('SETD2', 'Gene', (255, 260))
419443	29884408	NSD1-mutant tumors were noted to be significantly hypermutated and localized mostly in the larynx, whereas H3K36M-mutant tumors had similar number of mutations compared to the other DNA methylation clusters and were all localized in the oral cavity.	('K36M', 'Mutation', 'p.K36M', (109, 113))	('hypermutated', 'PosReg', (50, 62))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('localized in the oral cavity', 'Phenotype', 'HP:0100649', (220, 248))	('tumors', 'Disease', (121, 127))	('H3K36M-mutant', 'Var', (107, 120))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('tumors', 'Disease', 'MESH:D009369', (121, 127))	('NSD1-mutant', 'Gene', (0, 11))	('tumors', 'Disease', (12, 18))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('tumors', 'Disease', 'MESH:D009369', (12, 18))
419444	29884408	The authors also detected the mutant H3K36M protein by immunohistochemical staining at a frequency of 2% in a tissue microarray of 158 oropharyngeal squamous cell carcinomas.	('H3K36M', 'Protein', (37, 43))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (149, 173))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (149, 172))	('carcinoma', 'Phenotype', 'HP:0030731', (163, 172))	('carcinomas', 'Phenotype', 'HP:0030731', (163, 173))	('K36M', 'Mutation', 'p.K36M', (39, 43))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (149, 173))	('oropharyngeal squamous cell carcinomas', 'Phenotype', 'HP:0012182', (135, 173))	('detected', 'Reg', (17, 25))	('mutant', 'Var', (30, 36))	('squamous cell carcinomas', 'Disease', (149, 173))
419446	29884408	Accordingly, SCCHN cell lines with mutant NSD1 showed decreased levels of H3K36me2, eventhough the levels of NSD2 and NSD3 were normal, signifying a non-redundant role of NSD 1 in the production of H3K36me2 in SCCHN.	('NSD3', 'Gene', (118, 122))	('NSD1', 'Gene', (42, 46))	('mutant', 'Var', (35, 41))	('NSD 1', 'Gene', '64324', (171, 176))	('NSD 1', 'Gene', (171, 176))	('levels', 'MPA', (64, 70))	('NSD2', 'Gene', '7468', (109, 113))	('decreased', 'NegReg', (54, 63))	('H3K36me2', 'MPA', (74, 82))	('NSD3', 'Gene', '54904', (118, 122))	('NSD2', 'Gene', (109, 113))
419447	29884408	Interestingly, ectopic expression of H3K36M in SCCHN cells lines with wild-type NSD1 also lead to decreased levels of H3K36me2, implying a dominant function and that H3K36M may operate as a "trap" for H3K36 methyltransferases in SCCHN.	('H3K36M', 'Var', (166, 172))	('H3K36M', 'Var', (37, 43))	('K36M', 'Mutation', 'p.K36M', (39, 43))	('levels of H3K36me2', 'MPA', (108, 126))	('K36M', 'Mutation', 'p.K36M', (168, 172))	('decreased', 'NegReg', (98, 107))
419449	29884408	In another report, inactivating NSD1 and NSD2 mutations were found to stratify patients with laryngeal cancer in two prognostically distinct subtypes, with patients with NSD1 or NSD2 mutations having a favorable prognosis.	('patients', 'Species', '9606', (156, 164))	('mutations', 'Var', (46, 55))	('mutations', 'Var', (183, 192))	('NSD2', 'Gene', '7468', (41, 45))	('NSD2', 'Gene', (41, 45))	('NSD2', 'Gene', '7468', (178, 182))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('laryngeal cancer', 'Disease', (93, 109))	('inactivating', 'Var', (19, 31))	('laryngeal cancer', 'Phenotype', 'HP:0012118', (93, 109))	('NSD1', 'Gene', (170, 174))	('NSD2', 'Gene', (178, 182))	('NSD1', 'Gene', (32, 36))	('patients', 'Species', '9606', (79, 87))	('stratify', 'Reg', (70, 78))	('laryngeal cancer', 'Disease', 'MESH:D007822', (93, 109))
419452	29884408	Also, NSD1 and/or NSD2 inactivating mutations in laryngeal cancer patients with more advanced stages (III, IV) rendered a more pronounced OS and PFS advantage.	('NSD1', 'Gene', (6, 10))	('laryngeal cancer', 'Disease', (49, 65))	('laryngeal cancer', 'Phenotype', 'HP:0012118', (49, 65))	('NSD2', 'Gene', '7468', (18, 22))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('inactivating mutations', 'Var', (23, 45))	('NSD2', 'Gene', (18, 22))	('laryngeal cancer', 'Disease', 'MESH:D007822', (49, 65))	('patients', 'Species', '9606', (66, 74))
419454	29884408	Interestingly, lower NSD1 mRNA levels were not associated with better survival outcomes, despite the fact that the majority of the NSD1 mutations in the cluster with the favorable prognosis in the TCGA database seemed to be truncating, rather than missense, Selected protein lysine and arginine methyltransferases (PMTs): frequency of genetic/expression alterations per TCGA and clinicopathologic significance in SCCHN.	('lysine', 'Chemical', 'MESH:D008239', (275, 281))	('mutations', 'Var', (136, 145))	('SCCHN', 'Disease', (413, 418))	('NSD1', 'Gene', (131, 135))	('TCGA', 'Gene', (370, 374))	('arginine', 'Chemical', 'MESH:D001120', (286, 294))
419457	29884408	Another important point in this study is that missense or truncating NSD1 mutations are identified as a favorable prognostic factor in laryngeal cancers but not other head and neck cancers.	('head and neck cancer', 'Phenotype', 'HP:0012288', (167, 187))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('NSD1', 'Gene', (69, 73))	('laryngeal cancers', 'Disease', (135, 152))	('head and neck cancers', 'Phenotype', 'HP:0012288', (167, 188))	('mutations', 'Var', (74, 83))	('missense or truncating', 'Var', (46, 68))	('neck cancers', 'Disease', (176, 188))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('neck cancers', 'Disease', 'MESH:D006258', (176, 188))	('cancers', 'Phenotype', 'HP:0002664', (181, 188))	('laryngeal cancer', 'Phenotype', 'HP:0012118', (135, 151))	('laryngeal cancers', 'Phenotype', 'HP:0012118', (135, 152))	('cancers', 'Phenotype', 'HP:0002664', (145, 152))	('laryngeal cancers', 'Disease', 'MESH:D007822', (135, 152))
419459	29884408	Although NSD1 has been characterized to function as an oncogene in pediatric acute myeloid leukemias with recurrent NUP98-NSD1 translocations, it has also been reported as a putative tumor suppressor in neuroblastoma.	('myeloid leukemias', 'Phenotype', 'HP:0012324', (83, 100))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('NUP98', 'Gene', (116, 121))	('NUP98', 'Gene', '4928', (116, 121))	('acute myeloid leukemias', 'Phenotype', 'HP:0004808', (77, 100))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('leukemias', 'Phenotype', 'HP:0001909', (91, 100))	('myeloid leukemias', 'Disease', 'MESH:D007951', (83, 100))	('tumor', 'Disease', (183, 188))	('neuroblastoma', 'Disease', 'MESH:D009447', (203, 216))	('NSD1', 'Gene', (9, 13))	('myeloid leukemias', 'Disease', (83, 100))	('translocations', 'Var', (127, 141))	('neuroblastoma', 'Disease', (203, 216))	('neuroblastoma', 'Phenotype', 'HP:0003006', (203, 216))
419460	29884408	More specifically, the authors found that NSD1-mutant SCCHN demonstrated the lowest tumor associated leukocyte levels, including Ml macrophages, CD8+ and CD4+ memory T-cells.	('lowest', 'NegReg', (77, 83))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('Ml macrophages', 'MPA', (129, 143))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('NSD1-mutant', 'Var', (42, 53))	('CD8', 'Gene', (145, 148))	('SCCHN', 'Gene', (54, 59))	('tumor', 'Disease', (84, 89))	('CD8', 'Gene', '925', (145, 148))	('CD4', 'Gene', (154, 157))	('CD4', 'Gene', '920', (154, 157))
419462	29884408	Additionally, the authors showed that NSD1 mRNA expression is positively correlated with T-cell infiltration and that knockdown of NSD1 in three SCCHN cell lines led to significant downregulation of the mRNA expression levels of a panel of multiple chemokines involved in immune cell recruitment, such as CXCL1 and CXCL3.	('correlated', 'Reg', (73, 83))	('NSD1', 'Gene', (38, 42))	('knockdown', 'Var', (118, 127))	('CXCL1', 'Gene', (305, 310))	('downregulation', 'NegReg', (181, 195))	('T-cell infiltration', 'CPA', (89, 108))	('CXCL3', 'Gene', (315, 320))	('NSD1', 'Gene', (131, 135))	('CXCL3', 'Gene', '2921', (315, 320))	('CXCL1', 'Gene', '2919', (305, 310))
419463	29884408	This finding was corroborated by a mouse model of NOD-scid IL2Rgammanu11 (NSG) mice with flank subcutaneous SCCHN tumors treated with control versus NSD1 shRNAs, where after the infusion of human peripheral blood mononuclear cells, NSD1 knockdown tumors had decreased CD8+ T-cell infiltration compared to the control tumors.	('tumor', 'Phenotype', 'HP:0002664', (247, 252))	('tumor', 'Phenotype', 'HP:0002664', (317, 322))	('tumors', 'Disease', (247, 253))	('tumors', 'Phenotype', 'HP:0002664', (317, 323))	('tumors', 'Disease', 'MESH:D009369', (114, 120))	('tumors', 'Disease', 'MESH:D009369', (247, 253))	('tumors', 'Disease', (317, 323))	('human', 'Species', '9606', (190, 195))	('knockdown', 'Var', (237, 246))	('CD8', 'Gene', '925', (268, 271))	('decreased CD8+ T', 'Phenotype', 'HP:0005415', (258, 274))	('flank subcutaneous SCCHN tumors', 'Disease', (89, 120))	('tumors', 'Disease', 'MESH:D009369', (317, 323))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('NSD1', 'Gene', (232, 236))	('tumors', 'Phenotype', 'HP:0002664', (247, 253))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('decreased', 'NegReg', (258, 267))	('mice', 'Species', '10090', (79, 83))	('mouse', 'Species', '10090', (35, 40))	('tumors', 'Disease', (114, 120))	('CD8', 'Gene', (268, 271))	('flank subcutaneous SCCHN tumors', 'Disease', 'MESH:D021501', (89, 120))
419464	29884408	It is interesting to note that the Peri study showed that NSD1-mutant laryngeal SCCHN tumors are associated with better survival outcomes, even though NSD1 inactivation seems to induce an immune cold phenotype in SCCHN tumors.	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('immune cold', 'MPA', (188, 199))	('induce', 'Reg', (178, 184))	('better', 'PosReg', (113, 119))	('SCCHN tumors', 'Disease', 'MESH:D009369', (213, 225))	('tumors', 'Phenotype', 'HP:0002664', (219, 225))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('SCCHN tumors', 'Disease', (213, 225))	('laryngeal SCCHN tumors', 'Disease', (70, 92))	('NSD1-mutant', 'Gene', (58, 69))	('laryngeal SCCHN tumors', 'Disease', 'MESH:D007822', (70, 92))	('SCCHN tumors', 'Disease', 'MESH:D009369', (80, 92))	('inactivation', 'Var', (156, 168))
419469	29884408	While most of these alterations are deletions or missense mutations, a study published by our group found that NSD2 is moderately or strongly overexpressed in 73% of SCCHN patients with locoregionally advanced disease and that this overexpression was significantly higher compared to normal squamous epithelium.	('alterations', 'Var', (20, 31))	('missense', 'Var', (49, 57))	('SCCHN', 'Disease', (166, 171))	('overexpressed', 'PosReg', (142, 155))	('NSD2', 'Gene', '7468', (111, 115))	('NSD2', 'Gene', (111, 115))	('patients', 'Species', '9606', (172, 180))	('higher', 'PosReg', (265, 271))
419473	29884408	Furthermore, NSD2 directly regulated the transcription of NIMA-related-kinase-7 (NEK7), a cell cycle regulator necessary for progression into cytokinesis and mitotic spindle formation, and, accordingly, its knockdown delayed the cell-cycle progression of SCCHN cells.	('NIMA-related-kinase-7', 'Gene', (58, 79))	('NSD2', 'Gene', (13, 17))	('transcription', 'MPA', (41, 54))	('cell-cycle progression of', 'CPA', (229, 254))	('delayed', 'NegReg', (217, 224))	('knockdown', 'Var', (207, 216))	('NIMA-related-kinase-7', 'Gene', '140609', (58, 79))	('NEK7', 'Gene', '140609', (81, 85))	('NEK7', 'Gene', (81, 85))	('regulated', 'Reg', (27, 36))	('NSD2', 'Gene', '7468', (13, 17))
419480	29884408	NSD3 knockdown caused a significant decrease in the cell viability of both HPV-positive and HPV-negative SCCHN cell lines, accompanied by a decrease in the global levels of H3K36 di-methylation.	('HPV', 'Species', '10566', (75, 78))	('H3K36', 'Protein', (173, 178))	('NSD3', 'Gene', '54904', (0, 4))	('global levels', 'MPA', (156, 169))	('cell viability', 'CPA', (52, 66))	('knockdown', 'Var', (5, 14))	('decrease', 'NegReg', (140, 148))	('NSD3', 'Gene', (0, 4))	('HPV', 'Species', '10566', (92, 95))	('decrease', 'NegReg', (36, 44))
419482	29884408	Mechanistically, this study showed that NSD3 is necessary for the transition of SCCHN cells from the G1 to the S phase through induction of H3K36 di-methylation in the gene body regions of two critical cell cycle regulators, cell division cycle 6 (CDC6) and cyclin-dependent kinase 2 (CDK2), and subsequent activation of their transcription.	('CDC6', 'Gene', (248, 252))	('NSD3', 'Gene', (40, 44))	('activation', 'PosReg', (307, 317))	('cyclin-dependent kinase 2', 'Gene', '1017', (258, 283))	('CDK2', 'Gene', (285, 289))	('transcription', 'MPA', (327, 340))	('H3K36', 'Protein', (140, 145))	('NSD3', 'Gene', '54904', (40, 44))	('di-methylation', 'Var', (146, 160))	('CDK2', 'Gene', '1017', (285, 289))	('CDC6', 'Gene', '990', (248, 252))	('cyclin-dependent kinase 2', 'Gene', (258, 283))
419484	29884408	More specifically, we reported that NSD3 mono-methylated EGFR at lysine K721, which is located within the tyrosine kinase domain of EGFR, and that this methylation enhances the activating phosphorylation marks of serine 845, 1148 and 1173, and activating the downstream ERK cascade.	('lysine', 'Chemical', 'MESH:D008239', (65, 71))	('serine', 'Chemical', 'MESH:D012694', (213, 219))	('EGFR', 'Gene', '1956', (132, 136))	('NSD3', 'Gene', (36, 40))	('activating', 'Reg', (244, 254))	('ERK', 'Gene', (270, 273))	('activating phosphorylation marks of serine 845', 'MPA', (177, 223))	('EGFR', 'Gene', (132, 136))	('lysine K721', 'Var', (65, 76))	('ERK', 'Gene', '2048', (270, 273))	('EGFR', 'Gene', '1956', (57, 61))	('NSD3', 'Gene', '54904', (36, 40))	('enhances', 'PosReg', (164, 172))	('EGFR', 'Gene', (57, 61))
419487	29884408	K721 mono-methylation of nuclear EGFR potentiated its interaction with proliferating cell nuclear antigen (PCNA), stabilized PCNA and led to enhanced DNA replication in SCCHN cells.	('PCNA', 'Gene', '5111', (125, 129))	('proliferating cell nuclear antigen', 'Gene', '5111', (71, 105))	('PCNA', 'Gene', '5111', (107, 111))	('DNA replication', 'MPA', (150, 165))	('EGFR', 'Gene', '1956', (33, 37))	('potentiated', 'PosReg', (38, 49))	('PCNA', 'Gene', (125, 129))	('EGFR', 'Gene', (33, 37))	('enhanced', 'PosReg', (141, 149))	('PCNA', 'Gene', (107, 111))	('proliferating cell nuclear antigen', 'Gene', (71, 105))	('interaction', 'Interaction', (54, 65))	('K721 mono-methylation', 'Var', (0, 21))	('mono-methylation', 'Var', (5, 21))
419488	29884408	We hypothesized that a fraction of the K721 mono-methylated EGFR remains in the nucleus to exert its function through stabilization of PCNA, while another fraction translocates back to the cytoplasm and activates the membrane/cytoplasmic EGFR cascade.	('PCNA', 'Gene', (135, 139))	('stabilization', 'MPA', (118, 131))	('PCNA', 'Gene', '5111', (135, 139))	('K721 mono-methylated', 'Var', (39, 59))	('EGFR', 'Gene', '1956', (238, 242))	('EGFR', 'Gene', '1956', (60, 64))	('EGFR', 'Gene', (238, 242))	('translocates', 'MPA', (164, 176))	('activates', 'PosReg', (203, 212))	('EGFR', 'Gene', (60, 64))
419489	29884408	Furthermore, we showed that knockdown of NSD3 sensitizes SCCHN cells to Erlotinib.	('sensitizes', 'Reg', (46, 56))	('Erlotinib', 'Chemical', 'MESH:D000069347', (72, 81))	('NSD3', 'Gene', (41, 45))	('knockdown', 'Var', (28, 37))	('SCCHN', 'Disease', (57, 62))	('NSD3', 'Gene', '54904', (41, 45))
419490	29884408	This indicates that methylation of lysine K721 of EGFR may allosterically enhance the affinity of the ATP-binding site of EGFR with ATP and thus decrease its affinity to Erlotinib, rendering resistance to this drug.	('ATP-binding site', 'Interaction', (102, 118))	('affinity', 'Interaction', (86, 94))	('lysine', 'Chemical', 'MESH:D008239', (35, 41))	('lysine K721', 'Var', (35, 46))	('ATP', 'Chemical', 'MESH:D000255', (102, 105))	('resistance', 'MPA', (191, 201))	('EGFR', 'Gene', '1956', (50, 54))	('Erlotinib', 'Chemical', 'MESH:D000069347', (170, 179))	('methylation', 'Var', (20, 31))	('affinity', 'MPA', (158, 166))	('rendering', 'Reg', (181, 190))	('EGFR', 'Gene', (50, 54))	('decrease', 'NegReg', (145, 153))	('ATP', 'Chemical', 'MESH:D000255', (132, 135))	('EGFR', 'Gene', (122, 126))	('EGFR', 'Gene', '1956', (122, 126))	('enhance', 'PosReg', (74, 81))
419491	29884408	Alternatively, NSD3-mediated methylation of nuclear EGFR may be responsible for resistance to EGFR inhibition through the potentiation of the functions of nuclear EGFR which is known confer resistance to EGFR inhibitors and cetuximab.	('cetuximab', 'Chemical', 'MESH:D000068818', (224, 233))	('methylation', 'Var', (29, 40))	('NSD3', 'Gene', (15, 19))	('functions', 'MPA', (142, 151))	('EGFR', 'Gene', '1956', (94, 98))	('EGFR', 'Gene', '1956', (52, 56))	('EGFR', 'Gene', (52, 56))	('potentiation', 'PosReg', (122, 134))	('EGFR', 'Gene', '1956', (163, 167))	('EGFR', 'Gene', (94, 98))	('EGFR', 'Gene', '1956', (204, 208))	('EGFR', 'Gene', (163, 167))	('NSD3', 'Gene', '54904', (15, 19))	('EGFR', 'Gene', (204, 208))
419499	29884408	Per TCGA, 9% of patients with SCCHN have genetic or expression alterations in this enzyme (Table 1).	('expression', 'MPA', (52, 62))	('genetic', 'Var', (41, 48))	('patients', 'Species', '9606', (16, 24))	('SCCHN', 'Disease', (30, 35))
419500	29884408	found that G9a interacts with Snail in a metastatic SCCHN cell line derived from lymph-node metastasis (HN12) and suppresses the expression of E-cadherin through H3K9 promoter di-methylation in these cells, but not the non-metastatic parental cell line (HN4).	('Snail', 'Gene', '6615', (30, 35))	('Snail', 'Gene', (30, 35))	('expression', 'MPA', (129, 139))	('HN12', 'CellLine', 'CVCL:5518', (104, 108))	('HN4', 'CellLine', 'CVCL:5515', (254, 257))	('interacts', 'Reg', (15, 24))	('G9a', 'Var', (11, 14))	('H3K9', 'Protein', (162, 166))	('E-cadherin', 'Gene', (143, 153))	('E-cadherin', 'Gene', '999', (143, 153))	('suppresses', 'NegReg', (114, 124))
419501	29884408	Additionally, the authors showed that TGF-beta-induced epithelial-mesenchymal transition (EMT) of the HN4 cells was reversed by BIX01294, a G9a inhibitor, and decreased the levels of di-methylated H3K9 at the E-cadherin promoter, suggesting that G9a is essential for the EMT of the HN4 cells.	('HN4', 'CellLine', 'CVCL:5515', (102, 105))	('TGF-beta', 'Gene', (38, 46))	('BIX01294', 'Chemical', 'MESH:C518299', (128, 136))	('BIX01294', 'Var', (128, 136))	('E-cadherin', 'Gene', (209, 219))	('epithelial-mesenchymal transition', 'CPA', (55, 88))	('levels of di-methylated H3K9', 'MPA', (173, 201))	('decreased', 'NegReg', (159, 168))	('HN4', 'CellLine', 'CVCL:5515', (282, 285))	('E-cadherin', 'Gene', '999', (209, 219))	('TGF-beta', 'Gene', '7040', (38, 46))
419503	29884408	Furthermore, BIX01294 treatment of HN4 cells suppressed TGF-beta-induced tumorsphere formation and CD44 protein expression, both markers of cancer sternness in SCCHN cells.	('tumors', 'Disease', 'MESH:D009369', (73, 79))	('TGF-beta', 'Gene', '7040', (56, 64))	('HN4', 'CellLine', 'CVCL:5515', (35, 38))	('CD44', 'Gene', '960', (99, 103))	('BIX01294', 'Chemical', 'MESH:C518299', (13, 21))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('cancer sternness', 'Disease', 'MESH:D009369', (140, 156))	('TGF-beta', 'Gene', (56, 64))	('suppressed', 'NegReg', (45, 55))	('cancer sternness', 'Disease', (140, 156))	('CD44', 'Gene', (99, 103))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('tumors', 'Disease', (73, 79))	('BIX01294', 'Var', (13, 21))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('expression', 'MPA', (112, 122))
419504	29884408	Accordingly, knockdown of G9a in HN12 cells led to abolishment of these cancer sternness features, supporting that G9a promotes cancer sternness in SCCHN.	('promotes', 'PosReg', (119, 127))	('cancer sternness', 'Disease', (72, 88))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('SCCHN', 'Disease', (148, 153))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('cancer sternness', 'Disease', 'MESH:D009369', (128, 144))	('HN12', 'CellLine', 'CVCL:5518', (33, 37))	('cancer sternness', 'Disease', (128, 144))	('cancer sternness', 'Disease', 'MESH:D009369', (72, 88))	('G9a', 'Var', (115, 118))
419506	29884408	In another study by Li et al., high protein levels of G9a were found to be associated with worse survival in patients with SCCHN.	('SCCHN', 'Disease', (123, 128))	('patients', 'Species', '9606', (109, 117))	('G9a', 'Protein', (54, 57))	('high', 'Var', (31, 35))	('worse', 'NegReg', (91, 96))
419507	29884408	Knockdown of G9a by shRNAs or BIX01294 led to decreased cell proliferation and colony formation, and this was mediated through induction of autophagy.	('induction', 'Reg', (127, 136))	('colony formation', 'CPA', (79, 95))	('cell proliferation', 'CPA', (56, 74))	('decreased', 'NegReg', (46, 55))	('BIX01294', 'Chemical', 'MESH:C518299', (30, 38))	('BIX01294', 'Var', (30, 38))	('autophagy', 'CPA', (140, 149))
419510	29884408	Similar results demonstrating both autophagy and induction of apoptosis with BIX01294 in oral squamous cell carcinoma cell lines were obtained by a different group.	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (94, 117))	('oral squamous cell carcinoma', 'Disease', (89, 117))	('BIX01294', 'Chemical', 'MESH:C518299', (77, 85))	('BIX01294', 'Var', (77, 85))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (89, 117))
419511	29884408	A recently published study also showed that G9a promotes cisplatin resistance and is associated with poor disease-free survival in patients with locoregionally advanced SCCHN.	('patients', 'Species', '9606', (131, 139))	('G9a', 'Var', (44, 47))	('poor', 'NegReg', (101, 105))	('disease-free survival', 'CPA', (106, 127))	('promotes', 'PosReg', (48, 56))	('cisplatin', 'Chemical', 'MESH:D002945', (57, 66))	('cisplatin resistance', 'MPA', (57, 77))
419513	29884408	G9a knockdown or treatment with the G9a inhibitor UNC0638 led to sensitization of resistant SCCHN and sphere forming SCCHN cells to cisplatin.	('knockdown', 'Var', (4, 13))	('sensitization', 'MPA', (65, 78))	('UNC0638', 'Gene', (50, 57))	('cisplatin', 'Chemical', 'MESH:D002945', (132, 141))
419514	29884408	Mechanistically, the cisplatin resistance was attributed to G9a-mediated H3K9 mono-methylation and subsequent transcriptional upregulation of the glutamate-cysteine ligase catalytic subunit which promotes glutathione biosynthesis.	('cisplatin', 'Chemical', 'MESH:D002945', (21, 30))	('cisplatin resistance', 'MPA', (21, 41))	('G9a-mediated', 'Var', (60, 72))	('glutamate-cysteine', 'Protein', (146, 164))	('glutathione', 'Chemical', 'MESH:D005978', (205, 216))	('glutathione biosynthesis', 'MPA', (205, 229))	('H3K9', 'Protein', (73, 77))	('mono-methylation', 'MPA', (78, 94))	('upregulation', 'PosReg', (126, 138))
419518	29884408	5% of SCCHN patients in the TCGA database carry genetic or expression alterations in this PKMT (Table 1).	('patients', 'Species', '9606', (12, 20))	('SCCHN', 'Disease', (6, 11))	('expression', 'MPA', (59, 69))	('genetic', 'Var', (48, 55))
419526	29884408	showed that knockdown of EZH2 led to a decrease in the proliferation rate and invasive potential of two SCCHN cell lines, and that higher EZH2 protein levels were significantly associated with the presence of perineural invasion, and worse overall survival in multivariate analysis of a cohort of 117 SCCHN patients with locoregionally advanced disease.	('worse', 'NegReg', (234, 239))	('decrease', 'NegReg', (39, 47))	('invasive potential of two SCCHN cell lines', 'CPA', (78, 120))	('EZH2', 'Gene', (25, 29))	('knockdown', 'Var', (12, 21))	('EZH2', 'Gene', (138, 142))	('perineural invasion', 'CPA', (209, 228))	('associated', 'Reg', (177, 187))	('patients', 'Species', '9606', (307, 315))	('protein levels', 'MPA', (143, 157))	('higher', 'PosReg', (131, 137))	('overall survival', 'CPA', (240, 256))
419527	29884408	The prognostic significance of EZH2 in SCCHN was also shown in another study where high protein levels of EZH2 were associated with poor overall survival in a cohort of 209 nasopharyngeal cancer patients with locoregionally advanced disease independently of other known risk factors.	('nasopharyngeal cancer', 'Phenotype', 'HP:0100630', (173, 194))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('EZH2', 'Gene', (106, 110))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('overall survival', 'MPA', (137, 153))	('SCCHN', 'Disease', (39, 44))	('patients', 'Species', '9606', (195, 203))	('cancer', 'Disease', (188, 194))	('high', 'Var', (83, 87))	('poor', 'NegReg', (132, 136))
419528	29884408	Furthermore, this study supported that shRNA-mediated knockdown of EZH2 decreased the invasive potential of NPC cell lines and the metastatic burden of an in vivo tumor model of CNE2 nasopharyngeal cancer cells.	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('knockdown', 'Var', (54, 63))	('cancer', 'Disease', (198, 204))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('invasive potential of NPC cell lines', 'CPA', (86, 122))	('decreased', 'NegReg', (72, 81))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('tumor', 'Disease', (163, 168))	('nasopharyngeal cancer', 'Phenotype', 'HP:0100630', (183, 204))	('CNE2', 'CellLine', 'CVCL:6889', (178, 182))	('EZH2', 'Gene', (67, 71))	('NPC', 'Phenotype', 'HP:0100630', (108, 111))
419529	29884408	Mechanistically, this was explained by the repression of E-cadherin, a cell adhesive molecule, by EZH2-mediated H3K27 tri-methylation, which enhanced the metastatic potential of CNE2 cells.	('tri-methylation', 'Var', (118, 133))	('metastatic potential of CNE2 cells', 'CPA', (154, 188))	('repression', 'NegReg', (43, 53))	('E-cadherin', 'Gene', (57, 67))	('E-cadherin', 'Gene', '999', (57, 67))	('H3K27', 'Protein', (112, 117))	('enhanced', 'PosReg', (141, 149))	('CNE2', 'CellLine', 'CVCL:6889', (178, 182))
419532	29884408	Con-cordantly, they showed that ectopic expression of EZH2 reduced E-cadherin expression and enhanced the invasive potential in oral tongue SCCHN cell lines.	('EZH2', 'Gene', (54, 58))	('reduced', 'NegReg', (59, 66))	('E-cadherin', 'Gene', (67, 77))	('E-cadherin', 'Gene', '999', (67, 77))	('ectopic expression', 'Var', (32, 50))	('invasive potential in oral tongue SCCHN cell lines', 'CPA', (106, 156))	('enhanced', 'PosReg', (93, 101))
419536	29884408	Protein levels of EZH2 and H3K27 tri-methylation were evaluated in a tissue microarray of 59 patients with SCCHN (and 12 normal oral epithelial tissue sections).	('SCCHN', 'Disease', (107, 112))	('patients', 'Species', '9606', (93, 101))	('H3K27', 'Var', (27, 32))
419539	29884408	The authors also found that inhibition of EZH2-mediated H3K27 tri-methylation by EZH2-specific siRNAs or DZNep, an EZH2 inhibitor, increased the expression of squamous differentiation markers in SCCHN cell lines and induced cell cytotoxicity both in vitro and in in vivo xenograft mouse models.	('cytotoxicity', 'Disease', (229, 241))	('H3K27 tri-methylation', 'Protein', (56, 77))	('increased', 'PosReg', (131, 140))	('inhibition', 'Var', (28, 38))	('cytotoxicity', 'Disease', 'MESH:D064420', (229, 241))	('expression', 'MPA', (145, 155))	('induced', 'Reg', (216, 223))	('mouse', 'Species', '10090', (281, 286))
419542	29884408	Per TCGA, 6% of SCCHN patients have genetic or expression alterations in this gene (Table 1).	('SCCHN', 'Disease', (16, 21))	('genetic', 'Var', (36, 43))	('patients', 'Species', '9606', (22, 30))	('expression', 'MPA', (47, 57))
419543	29884408	Recently, PRMT1 was found to mono-methylate arginine R198 and R200 of the extracellular domain of the epidermal growth factor receptor (EGFR), enhancing EGF binding and subsequent EGFR dimerization and EGFR downstream activation.	('EGFR', 'Gene', (202, 206))	('epidermal growth factor receptor', 'Gene', (102, 134))	('binding', 'Interaction', (157, 164))	('PRMT1', 'Gene', '3276', (10, 15))	('arginine', 'Chemical', 'MESH:D001120', (44, 52))	('R200', 'Var', (62, 66))	('enhancing', 'PosReg', (143, 152))	('activation', 'PosReg', (218, 228))	('EGF', 'Protein', (153, 156))	('downstream', 'MPA', (207, 217))	('epidermal growth factor receptor', 'Gene', '1956', (102, 134))	('PRMT1', 'Gene', (10, 15))	('EGFR', 'Gene', '1956', (180, 184))	('EGFR', 'Gene', (180, 184))	('EGFR', 'Gene', '1956', (136, 140))	('EGFR', 'Gene', '1956', (202, 206))	('dimerization', 'MPA', (185, 197))	('EGFR', 'Gene', (136, 140))
419544	29884408	Furthermore, PRMT1-mediated methylation of EGFR rendered colon cancer cells resistant to Cetuximab treatment and was associated with significantly higher recurrence rates and decreased overall survival in metastatic colon cancer patients treated with cetuximab.	('patients', 'Species', '9606', (229, 237))	('colon cancer', 'Phenotype', 'HP:0003003', (216, 228))	('EGFR', 'Gene', (43, 47))	('decreased', 'NegReg', (175, 184))	('associated', 'Reg', (117, 127))	('colon cancer', 'Phenotype', 'HP:0003003', (57, 69))	('colon cancer', 'Disease', 'MESH:D015179', (216, 228))	('Cetuximab', 'Chemical', 'MESH:D000068818', (89, 98))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('cetuximab', 'Chemical', 'MESH:D000068818', (251, 260))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('colon cancer', 'Disease', 'MESH:D015179', (57, 69))	('EGFR', 'Gene', '1956', (43, 47))	('higher', 'PosReg', (147, 153))	('methylation', 'Var', (28, 39))	('colon cancer', 'Disease', (216, 228))	('overall survival', 'CPA', (185, 201))	('PRMT1', 'Gene', '3276', (13, 18))	('PRMT1', 'Gene', (13, 18))	('recurrence rates', 'CPA', (154, 170))	('colon cancer', 'Disease', (57, 69))
419546	29884408	investigated mechanisms of Cetuximab resistance in SCCHN, beyond mutations in EGFR, RAS, PIK3CA and ERBB2 amplification that are known to be culprits for Cetuximab resistance, and found that Cetuximab resistant SCCHN cell lines upregulated Snail and that this transcription factor directly bound to the promoter and increased the transcription of lymphotoxin-beta which induced EMT transition.	('bound', 'Interaction', (290, 295))	('Cetuximab', 'Chemical', 'MESH:D000068818', (27, 36))	('PIK3CA', 'Gene', (89, 95))	('increased', 'PosReg', (316, 325))	('Cetuximab', 'Chemical', 'MESH:D000068818', (154, 163))	('transcription', 'MPA', (330, 343))	('Snail', 'Gene', (240, 245))	('lymphotoxin-beta', 'Gene', (347, 363))	('Cetuximab', 'Chemical', 'MESH:D000068818', (191, 200))	('PIK3CA', 'Gene', '5290', (89, 95))	('Snail', 'Gene', '6615', (240, 245))	('ERBB2', 'Gene', '2064', (100, 105))	('EGFR', 'Gene', '1956', (78, 82))	('EGFR', 'Gene', (78, 82))	('ERBB2', 'Gene', (100, 105))	('lymphotoxin-beta', 'Gene', '4050', (347, 363))	('upregulated', 'PosReg', (228, 239))	('mutations', 'Var', (65, 74))
419547	29884408	The authors also described that lymphotoxin-beta directly and preferentially bound to R198/R200 methylated EGFR and that PRMT1, which induces this methylation, is directly upregulated by Snail.	('Snail', 'Gene', '6615', (187, 192))	('preferentially', 'PosReg', (62, 76))	('R198/R200 methylated', 'Var', (86, 106))	('EGFR', 'Gene', '1956', (107, 111))	('PRMT1', 'Gene', '3276', (121, 126))	('EGFR', 'Gene', (107, 111))	('upregulated', 'PosReg', (172, 183))	('methylated', 'Var', (96, 106))	('PRMT1', 'Gene', (121, 126))	('lymphotoxin-beta', 'Gene', (32, 48))	('Snail', 'Gene', (187, 192))	('lymphotoxin-beta', 'Gene', '4050', (32, 48))	('bound', 'Interaction', (77, 82))
419552	29884408	14% of SCCHN patients in the TCGA database have genetic or expression alterations in this gene (Table 1).	('expression', 'MPA', (59, 69))	('patients', 'Species', '9606', (13, 21))	('SCCHN', 'Disease', (7, 12))	('genetic', 'Var', (48, 55))
419553	29884408	analyzed the protein expression levels in a tissue microarray of 112 patients with NPC at various stages and found that high nuclear PRMT5 protein levels were associated with more advanced clinical and lymph node stage, and poor overall survival.	('PRMT5', 'Gene', (133, 138))	('high', 'Var', (120, 124))	('associated', 'Reg', (159, 169))	('PRMT5', 'Gene', '10419', (133, 138))	('overall survival', 'CPA', (229, 245))	('patients', 'Species', '9606', (69, 77))	('NPC', 'Phenotype', 'HP:0100630', (83, 86))
419564	29884408	Tazemetostat demonstrated an acceptable safety profile, and objective responses were observed in 9 out of 15 evaluable patients with both wild-type and mutant EZH2 relapsed/refractory B-cell NHL, as well as in INI1 (integrase interactor 1)- or SMARCA4 (SWI/SNF Related, Matrix Associated, Actin Dependent Regulator Of Chromatin, Subfamily A, Member 4)-negative tumors.	('tumor', 'Phenotype', 'HP:0002664', (361, 366))	('NHL', 'Phenotype', 'HP:0012539', (191, 194))	('Tazemetostat', 'Chemical', 'MESH:C000593333', (0, 12))	('patients', 'Species', '9606', (119, 127))	('SMARCA4', 'Gene', (244, 251))	('integrase interactor 1', 'Gene', '6598', (216, 238))	('SMARCA4', 'Gene', '6597', (244, 251))	('INI1', 'Gene', (210, 214))	('tumors', 'Disease', (361, 367))	('mutant', 'Var', (152, 158))	('integrase interactor 1', 'Gene', (216, 238))	('EZH2', 'Gene', (159, 163))	('tumors', 'Disease', 'MESH:D009369', (361, 367))	('INI1', 'Gene', '6598', (210, 214))	('tumors', 'Phenotype', 'HP:0002664', (361, 367))	('SWI/SNF Related, Matrix Associated, Actin Dependent Regulator Of Chromatin, Subfamily A, Member 4', 'Gene', '6597', (253, 350))
419567	29884408	Furthermore, Tazemetostat is being further investigated in phase II trials for pediatric or adult relapsed/refractory or INI-negative synovial sarcoma, in advanced solid tumors and NHL with EZH2 or SMARC4 mutations and in malignant mesothelioma.	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (222, 244))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (134, 150))	('relapsed/refractory', 'Disease', (98, 117))	('sarcoma', 'Phenotype', 'HP:0100242', (143, 150))	('solid tumors', 'Disease', (164, 176))	('malignant mesothelioma', 'Disease', (222, 244))	('SMARC4', 'Gene', (198, 204))	('EZH2', 'Gene', (190, 194))	('INI', 'Gene', (121, 124))	('malignant mesothelioma', 'Disease', 'MESH:C562839', (222, 244))	('INI', 'Gene', '84844', (121, 124))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('mutations', 'Var', (205, 214))	('synovial sarcoma', 'Disease', (134, 150))	('tumors', 'Phenotype', 'HP:0002664', (170, 176))	('solid tumors', 'Disease', 'MESH:D009369', (164, 176))	('synovial sarcoma', 'Disease', 'MESH:D013584', (134, 150))	('Tazemetostat', 'Chemical', 'MESH:C000593333', (13, 25))	('NHL', 'Phenotype', 'HP:0012539', (181, 184))
419577	28045090	Some miRNAs differ between sexes with respect to concentration, and miR-137 promoter methylation is a female-associated molecule.	('miR-137', 'Gene', (68, 75))	('methylation', 'Var', (85, 96))	('promoter', 'PosReg', (76, 84))	('miR-137', 'Gene', '406928', (68, 75))
419586	28045090	Specifically, CRISP3 was up-regulated in PRAD-male group and down-regulated in other groups.	('up-regulated', 'PosReg', (25, 37))	('CRISP3', 'Gene', '10321', (14, 20))	('CRISP3', 'Gene', (14, 20))	('PRAD-male', 'Var', (41, 50))	('down-regulated', 'NegReg', (61, 75))
419593	28045090	miR-34a was up-regulated in PRAD-male group, and was not abnormally expressed in the other groups; miR-34b and miR-34c had inconsistent expression across different groups (Fig.	('miR-34c', 'Gene', '407042', (111, 118))	('miR-34c', 'Gene', (111, 118))	('up-regulated', 'PosReg', (12, 24))	('miR-34b', 'Gene', (99, 106))	('miR-34b', 'Gene', '407041', (99, 106))	('PRAD-male', 'Var', (28, 37))	('miR-34a', 'Gene', '407040', (0, 7))	('miR-34a', 'Gene', (0, 7))
419603	28045090	Functional analyses using deregulated RNA molecules indicate relevant cancer hallmark network, suggesting their crucial roles in pathological process.	('deregulated', 'Var', (26, 37))	('RNA molecules', 'Protein', (38, 51))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))
419625	33676554	Our findings reveal that METTL3 positively regulates FBXW7 expression and confirm the tumor-suppressive role of m6A-modified FBXW7, thus providing insight into its epigenetic regulatory mechanisms in LUAD initiation and development.	('FBXW7', 'Gene', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('regulates', 'Reg', (43, 52))	('tumor', 'Disease', (86, 91))	('LUAD initiation', 'Disease', 'MESH:D007319', (200, 215))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('LUAD', 'Phenotype', 'HP:0030078', (200, 204))	('expression', 'MPA', (59, 69))	('FBXW7', 'Gene', (125, 130))	('LUAD initiation', 'Disease', (200, 215))	('m6A-modified', 'Var', (112, 124))
419630	33676554	High FBXW7 expression is independently associated with a favorable prognosis in patients with NSCLC, as it plays a negative role in NSCLC pathogenesis.	('FBXW7', 'Gene', (5, 10))	('NSCLC', 'Phenotype', 'HP:0030358', (94, 99))	('patients', 'Species', '9606', (80, 88))	('High', 'Var', (0, 4))	('NSCLC', 'Phenotype', 'HP:0030358', (132, 137))	('NSCLC', 'Disease', (94, 99))	('NSCLC', 'Disease', (132, 137))	('NSCLC', 'Disease', 'MESH:D002289', (94, 99))	('NSCLC', 'Disease', 'MESH:D002289', (132, 137))
419631	33676554	Accumulating studies have shown that FBXW7 dysregulation by point mutation, genomic deletion, or promoter hypermethylation leads to various cancers and that Fbxw7+/- mice are more prone to radiation-induced tumorigenesis.	('point mutation', 'Var', (60, 74))	('FBXW7', 'Gene', (37, 42))	('dysregulation', 'Var', (43, 56))	('Fbxw7', 'Gene', (157, 162))	('prone', 'Reg', (180, 185))	('promoter hypermethylation', 'Var', (97, 122))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('cancers', 'Phenotype', 'HP:0002664', (140, 147))	('Fbxw7', 'Gene', '50754', (157, 162))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('cancers', 'Disease', (140, 147))	('mice', 'Species', '10090', (166, 170))	('cancers', 'Disease', 'MESH:D009369', (140, 147))	('tumor', 'Disease', (207, 212))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('genomic deletion', 'Var', (76, 92))	('leads to', 'Reg', (123, 131))
419634	33676554	Identification of cancer-related epigenetic modifications is a rapidly expanding field of study within molecular biological mechanisms, and research has indicated that RNA-targeted modifications are biologically crucial in tumorigenesis.	('cancer', 'Disease', (18, 24))	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('tumor', 'Disease', (223, 228))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('tumor', 'Disease', 'MESH:D009369', (223, 228))	('modifications', 'Var', (181, 194))	('epigenetic modifications', 'Var', (33, 57))	('cancer', 'Disease', 'MESH:D009369', (18, 24))
419635	33676554	Among the more than 170 known RNA modifications, N6-methyladenosine (m6A) is the most abundant internal mRNA modification and reportedly mediates various biological processes, including tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('tumor', 'Disease', (186, 191))	('N6-methyladenosine', 'Chemical', 'MESH:C010223', (49, 67))	('mediates', 'Reg', (137, 145))	('N6-methyladenosine', 'Var', (49, 67))
419636	33676554	The m6A methyltransferase complex contains several enzymes (namely METTL3, METTL14, and WTAP), which are known as "writers," of which METTL3 (methyltransferase-like 3) is the most important because of its pivotal roles in regulating gene expression by influencing RNA stability, mRNA degradation, and translation.	('METTL3', 'Var', (134, 140))	('translation', 'MPA', (301, 312))	('methyltransferase-like 3', 'Gene', (142, 166))	('mRNA degradation', 'MPA', (279, 295))	('WTAP', 'Gene', '9589', (88, 92))	('influencing', 'Reg', (252, 263))	('METTL14', 'Gene', '57721', (75, 82))	('METTL14', 'Gene', (75, 82))	('methyltransferase-like 3', 'Gene', '56339', (142, 166))	('RNA stability', 'MPA', (264, 277))	('WTAP', 'Gene', (88, 92))
419637	33676554	In contrast, FTO (alpha-ketoglutarate-dependent dioxygenase) and ALKBH5 (AlkB homolog 5, RNA demethylase) have the potential to remove m6A from mRNA by functioning as "erasers".	('ALKBH5', 'Gene', (65, 71))	('AlkB homolog 5, RNA demethylase', 'Gene', '54890', (73, 104))	('FTO', 'Gene', (13, 16))	('m6A', 'Var', (135, 138))	('remove', 'NegReg', (128, 134))	('ALKBH5', 'Gene', '54890', (65, 71))	('FTO', 'Gene', '79068', (13, 16))
419639	33676554	Emerging evidence has illustrated that abnormal m6A mRNA methylation is intimately involved in the onset and progression of human cancers, including leukemia, brain cancer, breast cancer, liver cancer, and endometrial cancer.	('brain cancer', 'Disease', (159, 171))	('liver cancer', 'Disease', (188, 200))	('mRNA', 'Protein', (52, 56))	('endometrial cancer', 'Phenotype', 'HP:0012114', (206, 224))	('abnormal', 'Var', (39, 47))	('endometrial cancer', 'Disease', (206, 224))	('breast cancer', 'Phenotype', 'HP:0003002', (173, 186))	('cancers', 'Disease', 'MESH:D009369', (130, 137))	('endometrial cancer', 'Disease', 'MESH:D016889', (206, 224))	('brain cancer', 'Phenotype', 'HP:0030692', (159, 171))	('leukemia', 'Phenotype', 'HP:0001909', (149, 157))	('breast cancer', 'Disease', 'MESH:D001943', (173, 186))	('breast cancer', 'Disease', (173, 186))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('brain cancer', 'Disease', 'MESH:D001932', (159, 171))	('leukemia', 'Disease', (149, 157))	('leukemia', 'Disease', 'MESH:D007938', (149, 157))	('liver cancer', 'Disease', 'MESH:D006528', (188, 200))	('cancers', 'Phenotype', 'HP:0002664', (130, 137))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('cancers', 'Disease', (130, 137))	('m6A mRNA', 'Protein', (48, 56))	('involved', 'Reg', (83, 91))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('human', 'Species', '9606', (124, 129))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('liver cancer', 'Phenotype', 'HP:0002896', (188, 200))
419640	33676554	Additionally, multiple m6A-regulated proteins and their target mRNAs display varying expression profiles in cancers, suggesting that m6A modification plays an oncogenic or tumor-suppressive role under different genomic backgrounds or in different tumor subtypes.	('tumor', 'Phenotype', 'HP:0002664', (247, 252))	('expression', 'MPA', (85, 95))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('tumor', 'Disease', (247, 252))	('tumor', 'Disease', (172, 177))	('modification', 'Var', (137, 149))	('cancers', 'Phenotype', 'HP:0002664', (108, 115))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('m6A', 'Gene', (133, 136))	('cancers', 'Disease', 'MESH:D009369', (108, 115))	('tumor', 'Disease', 'MESH:D009369', (247, 252))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('cancers', 'Disease', (108, 115))
419643	33676554	FBXW7 reactivation reduced Mcl-1 expression, in turn, increasing the tumor metastatic, invasive, and drug-resistant capacities of lung cancer by depredating specific substrates.	('lung cancer', 'Phenotype', 'HP:0100526', (130, 141))	('invasive', 'CPA', (87, 95))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('drug-resistant capacities', 'CPA', (101, 126))	('Mcl-1', 'Gene', '4170', (27, 32))	('increasing', 'PosReg', (54, 64))	('tumor', 'Disease', (69, 74))	('reduced Mcl', 'Phenotype', 'HP:0025066', (19, 30))	('FBXW7', 'Gene', (0, 5))	('depredating', 'NegReg', (145, 156))	('lung cancer', 'Disease', 'MESH:D008175', (130, 141))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('Mcl-1', 'Gene', (27, 32))	('reduced', 'NegReg', (19, 26))	('reactivation', 'Var', (6, 18))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('lung cancer', 'Disease', (130, 141))	('specific substrates', 'MPA', (157, 176))
419645	33676554	Our results reveal an anticancer role and novel regulatory mechanisms for m6A-modified FBXW7 in LUAD, which may be applicable for molecular diagnosis and targeted therapy.	('m6A-modified', 'Var', (74, 86))	('LUAD', 'Phenotype', 'HP:0030078', (96, 100))	('LUAD', 'Disease', (96, 100))	('cancer', 'Disease', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('regulatory', 'MPA', (48, 58))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('FBXW7', 'Gene', (87, 92))
419650	33676554	After endogenous peroxidase activity had been quenched with 3% H2O2 dH2O and nonspecific binding had been blocked with 1% bovine serum albumin buffer, the sections were incubated overnight at 4  C with anti-METTL3 (ab195352, 1:1000, Abcam, Cambridge, UK) or anti-FBW7alpha (A301-720, 1:1000, Bethyl Laboratories, Montgomery, TX, USA) antibodies.	('dH2O', 'Chemical', '-', (68, 72))	('FBW7', 'Gene', '55294', (263, 267))	('ab195352', 'Var', (215, 223))	('serum albumin', 'Gene', '213', (129, 142))	('FBW7', 'Gene', (263, 267))	('serum albumin', 'Gene', (129, 142))	('quenched', 'NegReg', (46, 54))	('A301-720', 'Var', (274, 282))	('H2O2', 'Chemical', 'MESH:D006861', (63, 67))
419679	33676554	Recent studies have suggested that the m6A modification of many proteins plays a critical role in the development of various cancers; however, the role of METTL3 in LUAD remained unclear.	('cancers', 'Disease', 'MESH:D009369', (125, 132))	('LUAD', 'Phenotype', 'HP:0030078', (165, 169))	('cancers', 'Phenotype', 'HP:0002664', (125, 132))	('cancers', 'Disease', (125, 132))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('m6A', 'Var', (39, 42))	('proteins', 'Protein', (64, 72))
419680	33676554	To identify direct targets of METTL3, we investigated changes in protein expression following METTL3 overexpression or knockdown in HCC827 and PC9 cells.	('overexpression', 'PosReg', (101, 115))	('protein expression', 'MPA', (65, 83))	('PC9', 'CellLine', 'CVCL:B260', (143, 146))	('knockdown', 'Var', (119, 128))	('METTL3', 'Gene', (94, 100))	('HCC827', 'CellLine', 'CVCL:2063', (132, 138))
419681	33676554	We found that METTL3 overexpression increased the protein levels of apoptosis molecules (cleaved caspase 3 and Bax) and decreased the protein levels of Mcl-1 and c-Myc, which are classical FBXW7 target genes.	('decreased', 'NegReg', (120, 129))	('overexpression', 'Var', (21, 35))	('Bax', 'Gene', (111, 114))	('Mcl-1', 'Gene', '4170', (152, 157))	('c-Myc', 'Gene', (162, 167))	('METTL3', 'Gene', (14, 20))	('increased', 'PosReg', (36, 45))	('Bax', 'Gene', '581', (111, 114))	('Mcl-1', 'Gene', (152, 157))	('c-Myc', 'Gene', '4609', (162, 167))
419684	33676554	Although METTL3 depletion reduced apoptosis and promoted HCC827 and PC9 cell proliferation (Fig.	('METTL3', 'Gene', (9, 15))	('depletion', 'Var', (16, 25))	('PC9 cell proliferation', 'CPA', (68, 90))	('PC9', 'CellLine', 'CVCL:B260', (68, 71))	('apoptosis', 'CPA', (34, 43))	('reduced', 'NegReg', (26, 33))	('promoted', 'PosReg', (48, 56))	('HCC827', 'CPA', (57, 63))	('HCC827', 'CellLine', 'CVCL:2063', (57, 63))
419691	33676554	S3B) to determine whether FBXW7 overexpression could rescue the effects of METTL3 knockdown on the biological behavior of HCC827 or PC9 cells.	('HCC827', 'CellLine', 'CVCL:2063', (122, 128))	('METTL3', 'Gene', (75, 81))	('knockdown', 'Var', (82, 91))	('biological behavior', 'MPA', (99, 118))	('PC9', 'CellLine', 'CVCL:B260', (132, 135))
419693	33676554	Collectively, these results indicate that FBXW7 overexpression rescues the impaired anti-tumor phenotype caused by METTL3 knockdown.	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('knockdown', 'Var', (122, 131))	('METTL3', 'Gene', (115, 121))	('rescues', 'PosReg', (63, 70))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
419697	33676554	S4A); however, no notable discrepancy was observed in the subcellular localization of FBXW7 mRNA between METTL3 knockdown and control HCC827 cells (Fig.	('HCC827', 'CellLine', 'CVCL:2063', (134, 140))	('knockdown', 'Var', (112, 121))	('FBXW7', 'Gene', (86, 91))	('METTL3', 'Gene', (105, 111))
419698	33676554	Similarly, no dramatic differences in the half-life of FBXW7 mRNA were detected in METTL3 knockdown and control HCC827 cells, as measured using actinomycin D (Fig.	('METTL3', 'Gene', (83, 89))	('actinomycin D', 'Chemical', 'MESH:D003609', (144, 157))	('HCC827', 'CellLine', 'CVCL:2063', (112, 118))	('knockdown', 'Var', (90, 99))
419701	33676554	To assess the potential effects of METTL3 on FBXW7 protein stability, we blocked translation using CHX and measured FBXW7 degradation in METTL3 knockdown and control HCC827 cells.	('METTL3', 'Gene', (137, 143))	('FBXW7', 'Gene', (116, 121))	('translation', 'MPA', (81, 92))	('CHX', 'Chemical', 'MESH:D003513', (99, 102))	('HCC827', 'CellLine', 'CVCL:2063', (166, 172))	('knockdown', 'Var', (144, 153))	('degradation', 'MPA', (122, 133))	('blocked', 'NegReg', (73, 80))
419702	33676554	The western blot analysis results revealed that the half-life of FBXW7 proteins was similar in METTL3 knockdown and control HCC827 cells (Fig.	('FBXW7', 'Gene', (65, 70))	('METTL3', 'Gene', (95, 101))	('HCC827', 'CellLine', 'CVCL:2063', (124, 130))	('knockdown', 'Var', (102, 111))
419707	33676554	Accordingly, decreased m6A enrichment was observed in the FBXW7 CDS in shMETTL3 cells, indicating that m6A modification is more dynamic in the CDS than in the 3'UTR region.	('decreased', 'NegReg', (13, 22))	('UTR', 'Gene', '2837', (161, 164))	('m6A enrichment', 'MPA', (23, 37))	('FBXW7', 'Var', (58, 63))	('UTR', 'Gene', (161, 164))
419710	33676554	Subsequently, we identified sites #11, #16, and #23 in cells transfected with the indicated mutant plasmids (RRACH   RRCCH) using MeRIP (Additional file 1: Fig.	('RIP', 'Gene', (132, 135))	('RIP', 'Gene', '3267', (132, 135))	('mutant', 'Var', (92, 98))
419725	33676554	Taken together, these data suggest that the METTL3-FBXW7 axis contributes to inhibition of tumor growth in vivo and that targeting m6A-modified FBXW7 is a promising strategy for overcoming tumorigenesis in LUAD.	('overcoming', 'PosReg', (178, 188))	('tumor', 'Disease', (189, 194))	('LUAD', 'Disease', (206, 210))	('LUAD', 'Phenotype', 'HP:0030078', (206, 210))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('FBXW7', 'Gene', (144, 149))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('inhibition', 'NegReg', (77, 87))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('m6A-modified', 'Var', (131, 143))	('tumor', 'Disease', (91, 96))
419727	33676554	Several studies have shown that the loss-of-function mutation of FBXW7 is most often found in human cancers among the ~ 70 F-box genes identified in the human genome, meaning that approximately 6% of all cancers contain FBXW7 mutations and supporting the role of FBXW7 as a tumor suppressor.	('cancers', 'Phenotype', 'HP:0002664', (204, 211))	('mutation', 'Var', (53, 61))	('cancers', 'Phenotype', 'HP:0002664', (100, 107))	('cancers', 'Disease', (204, 211))	('cancers', 'Disease', 'MESH:D009369', (204, 211))	('tumor', 'Disease', 'MESH:D009369', (274, 279))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('FBXW7', 'Gene', (65, 70))	('human', 'Species', '9606', (94, 99))	('FBXW7', 'Gene', (220, 225))	('human', 'Species', '9606', (153, 158))	('mutations', 'Var', (226, 235))	('tumor', 'Phenotype', 'HP:0002664', (274, 279))	('loss-of-function', 'NegReg', (36, 52))	('tumor', 'Disease', (274, 279))	('cancers', 'Disease', 'MESH:D009369', (100, 107))	('cancers', 'Disease', (100, 107))
419729	33676554	Similarly, EZH2 (enhancer of zeste homolog 2 polycomb repressive complex 2) is a histone methyltransferase that can silence FBXW7 function by trimethylating histone H3 at Lys27 (H3K27me3).	('function', 'MPA', (130, 138))	('trimethylating', 'Var', (142, 156))	('silence', 'NegReg', (116, 123))	('enhancer of zeste homolog 2', 'Gene', (17, 44))	('histone H3', 'Protein', (157, 167))	('EZH2', 'Gene', (11, 15))	('EZH2', 'Gene', '2146', (11, 15))	('enhancer of zeste homolog 2', 'Gene', '2146', (17, 44))	('FBXW7', 'Gene', (124, 129))	('Lys27', 'Chemical', '-', (171, 176))
419732	33676554	Moreover, the m6A methylation of several associated proteins has been closely related to tumorigenesis in a broad range of cancer types.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('proteins', 'Protein', (52, 60))	('related', 'Reg', (78, 85))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('tumor', 'Disease', (89, 94))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('cancer', 'Disease', (123, 129))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('m6A methylation', 'Var', (14, 29))
419735	33676554	confirmed that METTL3 depletion suppresses CRC tumorigenesis and metastasis.	('METTL3', 'Gene', (15, 21))	('suppresses', 'NegReg', (32, 42))	('depletion', 'Var', (22, 31))	('CRC', 'Disease', (43, 46))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor', 'Disease', (47, 52))
419740	33676554	found that METTL3 plays an oncogenic role in NSCLC by enhancing YAP translation and promoting YAP activity via miR-19143p to stimulate drug resistance and metastasis in NSCLC cells (A549 and H1299).	('NSCLC', 'Phenotype', 'HP:0030358', (169, 174))	('YAP', 'Gene', (94, 97))	('miR-19143p', 'Var', (111, 121))	('H1299', 'CellLine', 'CVCL:0060', (191, 196))	('promoting', 'PosReg', (84, 93))	('enhancing', 'PosReg', (54, 63))	('YAP', 'Gene', '10413', (64, 67))	('NSCLC', 'Disease', 'MESH:D002289', (45, 50))	('drug resistance', 'CPA', (135, 150))	('stimulate', 'PosReg', (125, 134))	('YAP', 'Gene', '10413', (94, 97))	('metastasis', 'CPA', (155, 165))	('A549', 'CellLine', 'CVCL:0023', (182, 186))	('NSCLC', 'Disease', (45, 50))	('METTL3', 'Gene', (11, 17))	('NSCLC', 'Disease', 'MESH:D002289', (169, 174))	('NSCLC', 'Phenotype', 'HP:0030358', (45, 50))	('NSCLC', 'Disease', (169, 174))	('drug resistance', 'Phenotype', 'HP:0020174', (135, 150))	('YAP', 'Gene', (64, 67))
419743	33676554	Importantly, we found drastic differences when comparing our results with previously published METTL3 target proteins in other cancer cell lines, illustrating the high target specificity of m6A-modified proteins and rationality of the observed inconsistencies.	('m6A-modified', 'Var', (190, 202))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('cancer', 'Disease', (127, 133))
419746	33676554	Moreover, we identified abnormally m6A-modified FBXW7 as a vulnerability of LUAD malignancies and provided a molecular basis for m6A modification agonists of FBXW7 mRNA for future use in clinical research (Fig.	('m6A-modified', 'Var', (35, 47))	('FBXW7', 'Gene', (48, 53))	('LUAD', 'Phenotype', 'HP:0030078', (76, 80))	('abnormally m6A-modified', 'Var', (24, 47))	('LUAD malignancies', 'Disease', (76, 93))	('LUAD malignancies', 'Disease', 'MESH:D009369', (76, 93))
419758	32099380	Hoechst 33258 staining and flow cytometry analysis revealed that apoptosis was more pronounced in the VitK3-UVB group compared to the VitK3 and UVB groups.	('Hoechst 33258', 'Chemical', 'MESH:D006690', (0, 13))	('VitK3-UVB', 'Var', (102, 111))	('apoptosis', 'CPA', (65, 74))
419760	32099380	The VitK3-UVB group exhibited a significantly lower tumor growth rate in mouse xenograft models.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('VitK3-UVB', 'Var', (4, 13))	('tumor', 'Disease', (52, 57))	('lower', 'NegReg', (46, 51))	('mouse', 'Species', '10090', (73, 78))	('tumor', 'Disease', 'MESH:D009369', (52, 57))
419766	32099380	For already diagnosed patients, the main treatments modalities for cSCC include surgery, radiotherapy, local and systemic chemotherapy, laser therapy, photodynamic therapy (PDT), gene therapy, and liquid nitrogen cryotherapy.	('nitrogen', 'Chemical', 'MESH:D009584', (204, 212))	('gene', 'Var', (179, 183))	('patients', 'Species', '9606', (22, 30))	('cSCC', 'Disease', (67, 71))	('cSCC', 'Disease', 'MESH:D002294', (67, 71))
419771	32099380	Following PDT, the endothelial cells of the tumor blood vessels are damaged, and their mechanical repair may lead to vascular stenosis, embolism, and further reduction or inhibition of blood supply to the tumor cells; 3) in the process of killing tumor cells, PDT increases the expression and presentation of tumor antigens, which enhance the immune response and induce immunity to tumor cells; 4) there are also other several mechanisms with combined effects that cause tumor killing.	('tumor', 'Phenotype', 'HP:0002664', (247, 252))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('vascular stenosis', 'Disease', 'MESH:D003251', (117, 134))	('tumor', 'Disease', (44, 49))	('expression', 'MPA', (278, 288))	('increases', 'PosReg', (264, 273))	('tumor', 'Disease', (471, 476))	('tumor', 'Disease', (382, 387))	('immune response', 'CPA', (343, 358))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('vascular stenosis', 'Phenotype', 'HP:0100545', (117, 134))	('embolism', 'Disease', 'MESH:D004617', (136, 144))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('enhance', 'PosReg', (331, 338))	('tumor', 'Disease', 'MESH:D009369', (382, 387))	('tumor', 'Disease', 'MESH:D009369', (471, 476))	('tumor', 'Disease', (309, 314))	('tumor', 'Disease', (247, 252))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumor', 'Disease', 'MESH:D009369', (309, 314))	('vascular stenosis', 'Disease', (117, 134))	('tumor', 'Disease', 'MESH:D009369', (247, 252))	('tumor', 'Phenotype', 'HP:0002664', (382, 387))	('embolism', 'Disease', (136, 144))	('presentation', 'MPA', (293, 305))	('tumor', 'Disease', (205, 210))	('tumor', 'Phenotype', 'HP:0002664', (309, 314))	('PDT', 'Var', (260, 263))
419838	32099380	Further, there was a statistically significant difference in the expression of anti-apoptotic protein:Bcl-2 which was weaker in the VitK3-UVB treatment group compared with the control, VitK3, and UVB groups.	('weaker', 'NegReg', (118, 124))	('expression', 'MPA', (65, 75))	('Bcl-2', 'Gene', (102, 107))	('VitK3-UVB', 'Var', (132, 141))	('Bcl-2', 'Gene', '12043', (102, 107))
419839	32099380	In addition, the expression of Caspase-9 was significantly higher in VitK3 group than in the UVB group, while the expression of Cytc was significantly higher in the UVB group than in VitK3.	('Caspase-9', 'Gene', '12371', (31, 40))	('expression', 'MPA', (17, 27))	('higher', 'PosReg', (151, 157))	('expression', 'MPA', (114, 124))	('higher', 'PosReg', (59, 65))	('VitK3', 'Var', (69, 74))	('Caspase-9', 'Gene', (31, 40))
419845	32099380	Immunohistochemical staining revealed that the level of Caspase-3, Caspase-9, Bax, and Cytc expression was significantly increased and level of Bcl-2 expression was decreased in the VitK3-UVB group when compared with the control, VitK3, and UVB groups (Figure 6G).	('decreased', 'NegReg', (165, 174))	('Bcl-2', 'Gene', '12043', (144, 149))	('Caspase-9', 'Gene', (67, 76))	('Caspase-3', 'Gene', (56, 65))	('increased', 'PosReg', (121, 130))	('Bax', 'Gene', (78, 81))	('VitK3-UVB', 'Var', (182, 191))	('Caspase-9', 'Gene', '12371', (67, 76))	('Caspase-3', 'Gene', '12367', (56, 65))	('Cytc expression', 'MPA', (87, 102))	('Bax', 'Gene', '12028', (78, 81))	('level', 'MPA', (47, 52))	('Bcl-2', 'Gene', (144, 149))
419865	32099380	The antitumor effect of VitK3 can be achieved by the following three mechanisms: 1) generation of active oxygen through a redox cycle and a type II photoreaction; 2) conjugation of VitK3 with the thiol groups of proteins leading to the depletion of glutathione and changes in the intracellular Ca2+ concentrations; and 3) VitK3 arylation directly activates transcription factors and other proteins.	('Ca2+', 'Chemical', 'MESH:D000069285', (294, 298))	('proteins', 'Protein', (389, 397))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('glutathione', 'MPA', (249, 260))	('redox', 'MPA', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('oxygen', 'Chemical', 'MESH:D010100', (105, 111))	('depletion', 'MPA', (236, 245))	('thiol', 'Chemical', 'MESH:D013438', (196, 201))	('intracellular Ca2+ concentrations', 'MPA', (280, 313))	('tumor', 'Disease', (8, 13))	('changes', 'Reg', (265, 272))	('conjugation', 'Var', (166, 177))	('transcription', 'Protein', (357, 370))	('glutathione', 'Chemical', 'MESH:D005978', (249, 260))	('activates', 'PosReg', (347, 356))
419869	32099380	Hoechst33258 staining and observation of the A431 cells under a fluorescence microscope revealed typical changes in apoptosis which were more pronounced in the VitK3-UVB group.	('apoptosis', 'CPA', (116, 125))	('VitK3-UVB', 'Var', (160, 169))	('Hoechst33258', 'Chemical', 'MESH:D006690', (0, 12))	('A431', 'CellLine', 'CVCL:0037', (45, 49))
419877	32099380	This study found that the levels of ROS and MMP depolarization in the VitK3-UVB group was significantly higher than individual treatment groups.	('MMP depolarization', 'MPA', (44, 62))	('ROS', 'MPA', (36, 39))	('levels', 'MPA', (26, 32))	('VitK3-UVB', 'Var', (70, 79))	('ROS', 'Chemical', 'MESH:D017382', (36, 39))	('higher', 'PosReg', (104, 110))
419878	32099380	That is to say, VitK3-UVB induces apoptosis in A431 cells by increasing ROS and altering MMP.	('ROS', 'MPA', (72, 75))	('increasing', 'PosReg', (61, 71))	('ROS', 'Chemical', 'MESH:D017382', (72, 75))	('altering', 'Reg', (80, 88))	('MMP', 'MPA', (89, 92))	('VitK3-UVB', 'Var', (16, 25))	('A431', 'CellLine', 'CVCL:0037', (47, 51))
419886	32099380	In vivo experiments revealed that mice treated with VitK3-UVB inhibited tumor growth and increased the tumor inhibitory rate.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('mice', 'Species', '10090', (34, 38))	('tumor', 'Disease', (72, 77))	('tumor', 'Disease', (103, 108))	('VitK3-UVB', 'Var', (52, 61))	('inhibited', 'NegReg', (62, 71))	('increased', 'PosReg', (89, 98))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
419891	28585546	A molecular portrait of microsatellite instability across multiple cancers Microsatellite instability (MSI) refers to the hypermutability of short repetitive sequences in the genome caused by impaired DNA mismatch repair.	('cancers', 'Phenotype', 'HP:0002664', (67, 74))	('cancers', 'Disease', (67, 74))	('impaired', 'Var', (192, 200))	('cancers', 'Disease', 'MESH:D009369', (67, 74))	('Microsatellite instability', 'Disease', (75, 101))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))
419896	28585546	Here the authors analyse twenty three cancer types at the exome and whole-genome level, and identify loci with recurrent microsatellite instability that could be used to identify patients who would benefit from immunotherapy.	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('microsatellite instability', 'Var', (121, 147))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('patients', 'Species', '9606', (179, 187))	('cancer', 'Disease', (38, 44))
419898	28585546	Microsatellite instability (MSI) is a hypermutator phenotype that occurs in tumours with impaired DNA mismatch repair (MMR) and is characterized by widespread length polymorphisms of MS repeats due to DNA polymerase slippage as well as by elevated frequency of single-nucleotide variants (SNVs).	('tumours', 'Disease', 'MESH:D009369', (76, 83))	('tumours', 'Disease', (76, 83))	('tumour', 'Phenotype', 'HP:0002664', (76, 82))	('Microsatellite instability', 'Disease', (0, 26))	('single-nucleotide variants', 'Var', (261, 287))	('tumours', 'Phenotype', 'HP:0002664', (76, 83))
419899	28585546	MSI in sporadic cases is caused by inactivation of MMR genes (for example, MLH1, MSH2, MSH3, MSH6 and PMS2) through somatic mutations, with increased risk of cancer for those with inherited germline mutations (that is, Lynch syndrome).	('PMS2', 'Gene', (102, 106))	('MSH6', 'Gene', (93, 97))	('Lynch syndrome', 'Disease', 'MESH:D003123', (219, 233))	('MLH1', 'Gene', '4292', (75, 79))	('PMS2', 'Gene', '5395', (102, 106))	('MSH2', 'Gene', (81, 85))	('MLH1', 'Gene', (75, 79))	('inactivation', 'Var', (35, 47))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('MSH2', 'Gene', '4436', (81, 85))	('MSI', 'Disease', (0, 3))	('cancer', 'Disease', (158, 164))	('MSH3', 'Gene', (87, 91))	('MSH6', 'Gene', '2956', (93, 97))	('MMR genes', 'Gene', (51, 60))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('MSH3', 'Gene', '4437', (87, 91))	('Lynch syndrome', 'Disease', (219, 233))
419900	28585546	MSI also occurs by hypermethylation of the MLH1 promoter (for example, associated with the somatic BRAF V600E mutation), epigenetic inactivation of MSH2 (ref.	('V600E', 'Mutation', 'rs113488022', (104, 109))	('MLH1', 'Gene', '4292', (43, 47))	('MLH1', 'Gene', (43, 47))	('BRAF', 'Gene', (99, 103))	('epigenetic inactivation', 'Var', (121, 144))	('BRAF', 'Gene', '673', (99, 103))	('hypermethylation', 'Var', (19, 35))	('MSH2', 'Gene', (148, 152))	('MSH2', 'Gene', '4436', (148, 152))	('associated', 'Reg', (71, 81))
419902	28585546	In clinical settings, detection of MSI is customarily performed by immunohistochemical analysis of MMR proteins or by profiling the Bethesda markers, which often include two mononucleotide (BAT25 and BAT26) and three dinucleotide (D5S346, D2S123 and D17S250) MS loci.	('D17S250', 'Var', (250, 257))	('BAT25', 'Var', (190, 195))	('dinucleotide', 'Chemical', 'MESH:D015226', (217, 229))	('mononucleotide', 'Chemical', '-', (174, 188))	('D5S346', 'Var', (231, 237))	('D2S123', 'Var', (239, 245))	('BAT26', 'Var', (200, 205))
419904	28585546	It was conjectured more than two decades ago that the less aggressive nature of MSI tumours may be due to their high incidence of somatic mutations, which results in a greater likelihood of having mutated genes whose products elicit antitumour immune responses.	('genes', 'Gene', (205, 210))	('tumour', 'Disease', (84, 90))	('MSI tumours', 'Disease', 'MESH:D009369', (80, 91))	('tumour', 'Phenotype', 'HP:0002664', (237, 243))	('elicit', 'Reg', (226, 232))	('MSI tumours', 'Disease', (80, 91))	('mutated', 'Var', (197, 204))	('tumour', 'Disease', 'MESH:D009369', (237, 243))	('tumour', 'Phenotype', 'HP:0002664', (84, 90))	('tumour', 'Disease', (237, 243))	('tumours', 'Phenotype', 'HP:0002664', (84, 91))	('tumour', 'Disease', 'MESH:D009369', (84, 90))
419910	28585546	These analyses uncover new genes harbouring frameshift MSI events with varying degrees of cancer-type specificity and generate the most comprehensive catalogue to date of MS loci selectively subject to DNA slippage events in MSI-H tumours.	('tumours', 'Phenotype', 'HP:0002664', (231, 238))	('MSI-H tumours', 'Disease', (225, 238))	('frameshift MSI', 'Var', (44, 58))	('cancer-type', 'Disease', (90, 101))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('MSI-H tumours', 'Disease', 'MESH:D009369', (225, 238))	('cancer-type', 'Disease', 'MESH:D009369', (90, 101))	('tumour', 'Phenotype', 'HP:0002664', (231, 237))
419920	28585546	Pathway analysis reveals that transmembrane/TGFbeta, response to cellular stress/DNA damage and chromosome/M-phase-related molecular functions are significantly enriched in genes harbouring recurrent MSI in COAD, STAD and UCEC cases, respectively (Supplementary Data 2; P<0.01).	('STAD', 'Disease', (213, 217))	('COAD', 'Disease', 'MESH:D029424', (207, 211))	('TGFbeta', 'Gene', (44, 51))	('MSI', 'Var', (200, 203))	('UCEC', 'Disease', (222, 226))	('COAD', 'Disease', (207, 211))	('TGFbeta', 'Gene', '7040', (44, 51))
419921	28585546	The rates of deleterious mutations (for example, missense, nonsense and splicing site SNVs, and frameshift indels) and frameshift MSI events for MLH1, MLH3, MSH2, MSH3, MSH6, PMS1, PMS2, POLE, POLD1, PRKDC, APC and BRAF (p.V600E) are shown in Fig.	('PMS1', 'Gene', '5378', (175, 179))	('APC', 'Disease', (207, 210))	('PMS2', 'Gene', (181, 185))	('BRAF', 'Gene', (215, 219))	('PRKDC', 'Gene', '5591', (200, 205))	('PRKDC', 'Gene', (200, 205))	('mutations', 'Var', (25, 34))	('MSH2', 'Gene', (157, 161))	('missense', 'Var', (49, 57))	('frameshift MSI', 'Var', (119, 133))	('MLH3', 'Gene', '27030', (151, 155))	('MLH3', 'Gene', (151, 155))	('POLD1', 'Gene', (193, 198))	('p.V600E', 'Mutation', 'rs113488022', (221, 228))	('frameshift', 'Var', (96, 106))	('MSH3', 'Gene', (163, 167))	('MSH3', 'Gene', '4437', (163, 167))	('PMS2', 'Gene', '5395', (181, 185))	('MSH2', 'Gene', '4436', (157, 161))	('MLH1', 'Gene', (145, 149))	('MSH6', 'Gene', (169, 173))	('POLD1', 'Gene', '5424', (193, 198))	('APC', 'Disease', 'MESH:D011125', (207, 210))	('MLH1', 'Gene', '4292', (145, 149))	('MSH6', 'Gene', '2956', (169, 173))	('PMS1', 'Gene', (175, 179))	('BRAF', 'Gene', '673', (215, 219))
419922	28585546	Among these genes (selected on the basis of their association with MSI, DNA repair and colorectal cancer), MSI frameshift events represent a major source for the inactivation of MSH3 and MSH6.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('colorectal cancer', 'Disease', 'MESH:D015179', (87, 104))	('MSH6', 'Gene', (187, 191))	('inactivation', 'NegReg', (162, 174))	('frameshift events', 'Var', (111, 128))	('colorectal cancer', 'Phenotype', 'HP:0003003', (87, 104))	('MSH3', 'Gene', (178, 182))	('MSH6', 'Gene', '2956', (187, 191))	('colorectal cancer', 'Disease', (87, 104))	('MSH3', 'Gene', '4437', (178, 182))
419923	28585546	In contrast, deleterious SNV mutations more frequently contribute to the loss of function of POLD1 and POLE (27 and 23% of cases, respectively).	('POLD1', 'Gene', (93, 98))	('POLD1', 'Gene', '5424', (93, 98))	('SNV', 'Gene', (25, 28))	('mutations', 'Var', (29, 38))	('loss of function', 'NegReg', (73, 89))
419924	28585546	We next examined the patterns of frameshift MSI events across MSI-prone tumours.	('MSI-prone tumours', 'Disease', (62, 79))	('tumour', 'Phenotype', 'HP:0002664', (72, 78))	('tumours', 'Phenotype', 'HP:0002664', (72, 79))	('frameshift MSI', 'Var', (33, 47))	('MSI-prone tumours', 'Disease', 'MESH:D003922', (62, 79))
419930	28585546	We observe that 4 COAD (9%), 4 UCEC (5%) and 2 STAD (3%) patients harbour deleterious germline mutations in MMR genes.	('MMR', 'Gene', (108, 111))	('patients', 'Species', '9606', (57, 65))	('COAD', 'Disease', (18, 22))	('germline mutations', 'Var', (86, 104))	('COAD', 'Disease', 'MESH:D029424', (18, 22))
419931	28585546	Of these, at least five patients may have acquired the MSI-H phenotypes due to biallelic inactivation of MMR genes, where the inherited germline mutations of MMR genes are complemented with somatically acquired mutations of the corresponding genes.	('due', 'Reg', (72, 75))	('biallelic inactivation', 'Var', (79, 101))	('MSI-H', 'Disease', 'MESH:D000848', (55, 60))	('acquired', 'Reg', (42, 50))	('MMR genes', 'Gene', (105, 114))	('patients', 'Species', '9606', (24, 32))	('MSI-H', 'Disease', (55, 60))
419933	28585546	Overall, germline mutations in MMR genes, POLE and POLD1 are consistently more prevalent in MSI-H patients compared to MSS cases (Fig.	('POLD1', 'Gene', '5424', (51, 56))	('MSI-H', 'Disease', (92, 97))	('POLD1', 'Gene', (51, 56))	('POLE', 'Gene', (42, 46))	('MSS', 'Gene', (119, 122))	('MSI-H', 'Disease', 'MESH:D000848', (92, 97))	('patients', 'Species', '9606', (98, 106))	('MSS', 'Gene', '64374', (119, 122))	('MMR genes', 'Gene', (31, 40))	('prevalent', 'Reg', (79, 88))	('germline mutations', 'Var', (9, 27))
419934	28585546	These frequencies of germline mutation carriers in MMR genes are likely to be under-estimates, since we have applied stringent filtering criteria for our germline calls (see Methods) to account for the uncertain pathogenicity of missense mutations, as well as the technical challenges in identifying mutations in PMS2, which has multiple copies of its pseudogenes in the genome.	('PMS2', 'Gene', '5395', (313, 317))	('PMS2', 'Gene', (313, 317))	('mutations', 'Var', (300, 309))
419935	28585546	Although it is difficult to pinpoint the genomic events initiating MMR deficiency, it is likely that truncating mutations in various MMR genes in addition to the hypermethylation of MLH1 shape the MSI-H genomes, leading to further accumulation of mutations in the DNA repair pathway.	('truncating mutations', 'Var', (101, 121))	('MSI-H', 'Disease', (197, 202))	('MMR deficiency', 'Disease', (67, 81))	('MMR deficiency', 'Disease', 'MESH:C536143', (67, 81))	('MLH1', 'Gene', '4292', (182, 186))	('MMR', 'Gene', (133, 136))	('MLH1', 'Gene', (182, 186))	('MSI-H', 'Disease', 'MESH:D000848', (197, 202))	('accumulation', 'PosReg', (231, 243))	('mutations', 'Var', (247, 256))	('DNA repair pathway', 'Pathway', (264, 282))
419937	28585546	Other than MLH1, the most common genomic events that show association with gene expression (P<0.05; Mann-Whitney test) are the truncating SNVs and frameshift MSI events (MLH3, MSH2, MSH3, MSH6, PMS1 and POLD1), suggesting that these somatic events are responsible for the under-expression of these genes.	('POLD1', 'Gene', '5424', (203, 208))	('MSH6', 'Gene', '2956', (188, 192))	('PMS1', 'Gene', '5378', (194, 198))	('frameshift MSI events', 'Var', (147, 168))	('MSH6', 'Gene', (188, 192))	('MLH1', 'Gene', '4292', (11, 15))	('MSH3', 'Gene', (182, 186))	('MLH1', 'Gene', (11, 15))	('PMS1', 'Gene', (194, 198))	('MSH2', 'Gene', (176, 180))	('MSH2', 'Gene', '4436', (176, 180))	('MLH3', 'Gene', '27030', (170, 174))	('MLH3', 'Gene', (170, 174))	('POLD1', 'Gene', (203, 208))	('SNVs', 'Var', (138, 142))	('MSH3', 'Gene', '4437', (182, 186))
419940	28585546	We investigated the frequency of frameshift MSI events in 130 cancer-related genes across the MSI-prone tumours.	('frameshift MSI events', 'Var', (33, 54))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('MSI-prone tumours', 'Disease', 'MESH:D003922', (94, 111))	('MSI-prone tumours', 'Disease', (94, 111))	('tumour', 'Phenotype', 'HP:0002664', (104, 110))	('tumours', 'Phenotype', 'HP:0002664', (104, 111))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))
419941	28585546	Tumour-type specificity of frameshift MSI is evident for some well-known targets of MSI, such as ACVR2A (52% of MSI-H tumours) and TGFBR2 (44%) (enriched in both COAD and STAD; P<0.05, one-tailed Fisher's exact test) as well as RPL22 (31%), RNF43 (31%), MLL3 (27%), PRDM2 (21%), JAK1 (16%) and APC (3%) (Supplementary Fig.	('APC', 'Disease', 'MESH:D011125', (294, 297))	('ACVR2A', 'Gene', (97, 103))	('APC', 'Disease', (294, 297))	('TGFBR2', 'Gene', (131, 137))	('MLL3', 'Gene', (254, 258))	('Tumour', 'Phenotype', 'HP:0002664', (0, 6))	('RNF43', 'Gene', (241, 246))	('MSI-H tumours', 'Disease', 'MESH:D009369', (112, 125))	('PRDM2', 'Gene', (266, 271))	('PRDM2', 'Gene', '7799', (266, 271))	('RPL22', 'Gene', '6146', (228, 233))	('COAD', 'Disease', 'MESH:D029424', (162, 166))	('JAK1', 'Gene', '3716', (279, 283))	('RPL22', 'Gene', (228, 233))	('tumours', 'Phenotype', 'HP:0002664', (118, 125))	('RNF43', 'Gene', '54894', (241, 246))	('TGFBR2', 'Gene', '7048', (131, 137))	('MLL3', 'Gene', '58508', (254, 258))	('frameshift MSI', 'Var', (27, 41))	('MSI-H tumours', 'Disease', (112, 125))	('COAD', 'Disease', (162, 166))	('tumour', 'Phenotype', 'HP:0002664', (118, 124))	('JAK1', 'Gene', (279, 283))	('ACVR2A', 'Gene', '92', (97, 103))
419942	28585546	For instance, frameshift MSI events are present in TGFBR2 for 26/45 (58%) of COAD and 51/64 (80%) of STAD but only in 4/75 (5%) of UCEC cases, suggesting that certain tumour types or tumour environments are favourable to the occurrence of particular MSI events.	('tumour', 'Disease', 'MESH:D009369', (167, 173))	('tumour', 'Disease', (183, 189))	('tumour', 'Disease', (167, 173))	('tumour type', 'Disease', (167, 178))	('TGFBR2', 'Gene', (51, 57))	('COAD', 'Disease', 'MESH:D029424', (77, 81))	('tumour type', 'Disease', 'MESH:D009369', (167, 178))	('frameshift MSI', 'Var', (14, 28))	('tumour', 'Disease', 'MESH:D009369', (183, 189))	('tumour', 'Phenotype', 'HP:0002664', (167, 173))	('TGFBR2', 'Gene', '7048', (51, 57))	('tumour', 'Phenotype', 'HP:0002664', (183, 189))	('COAD', 'Disease', (77, 81))
419943	28585546	Given the inactivating nature of frameshift MSI events in coding regions, the absence of MSI in known oncogenes such as BRAF likely represents the pressures of negative selection in the context of the MSI-H phenotype.	('MSI-H', 'Disease', (201, 206))	('frameshift', 'Var', (33, 43))	('BRAF', 'Gene', '673', (120, 124))	('MSI-H', 'Disease', 'MESH:D000848', (201, 206))	('BRAF', 'Gene', (120, 124))
419945	28585546	To uncover other MS loci frequently targeted by frameshift MSI mutations, we first ranked MS loci by the recurrence level of frameshift MSI events in COAD, STAD and UCEC MSI-H tumours.	('COAD', 'Disease', (150, 154))	('frameshift', 'Var', (125, 135))	('MSI-H tumours', 'Disease', (170, 183))	('tumour', 'Phenotype', 'HP:0002664', (176, 182))	('COAD', 'Disease', 'MESH:D029424', (150, 154))	('tumours', 'Phenotype', 'HP:0002664', (176, 183))	('MSI-H tumours', 'Disease', 'MESH:D009369', (170, 183))
419946	28585546	The most recurrent frameshift MSI events are found in ACVR2A (51.6% of the tumours), KIAA2018 (51%), SLC22A9 (50%), ASTE1 (45%), TGFBR2 (44%), NDUFC2 (36%), LTN1 (36%) and SEC31A (36%).	('LTN1', 'Gene', '26046', (157, 161))	('tumours', 'Disease', 'MESH:D009369', (75, 82))	('TGFBR2', 'Gene', '7048', (129, 135))	('KIAA2018', 'Gene', '205717', (85, 93))	('ASTE1', 'Gene', '28990', (116, 121))	('NDUFC2', 'Gene', '4718', (143, 149))	('ACVR2A', 'Gene', '92', (54, 60))	('tumour', 'Phenotype', 'HP:0002664', (75, 81))	('NDUFC2', 'Gene', (143, 149))	('ASTE1', 'Gene', (116, 121))	('ACVR2A', 'Gene', (54, 60))	('SEC31A', 'Gene', (172, 178))	('SEC31A', 'Gene', '22872', (172, 178))	('TGFBR2', 'Gene', (129, 135))	('frameshift MSI events', 'Var', (19, 40))	('KIAA2018', 'Gene', (85, 93))	('SLC22A9', 'Gene', (101, 108))	('SLC22A9', 'Gene', '114571', (101, 108))	('LTN1', 'Gene', (157, 161))	('tumours', 'Disease', (75, 82))	('tumours', 'Phenotype', 'HP:0002664', (75, 82))
419947	28585546	Frameshift MSI events often display significant tumour-type specificity, for example, MLL3, PRDM2, C9orf114, BAX and OR7E24 are enriched in STAD, JAK1, TFAM and SMC6 are enriched in UCEC, whereas SEC31A, C18orf34, NDUFC2, KIAA1919, CCDC168 and others, are enriched in COAD (P<0.05, one-tailed Fisher's exact test).	('PRDM2', 'Gene', (92, 97))	('PRDM2', 'Gene', '7799', (92, 97))	('MLL3', 'Gene', '58508', (86, 90))	('NDUFC2', 'Gene', '4718', (214, 220))	('Frameshift MSI', 'Var', (0, 14))	('NDUFC2', 'Gene', (214, 220))	('SMC6', 'Gene', '79677', (161, 165))	('COAD', 'Disease', 'MESH:D029424', (268, 272))	('OR7E24', 'Gene', (117, 123))	('JAK1', 'Gene', '3716', (146, 150))	('SMC6', 'Gene', (161, 165))	('SEC31A', 'Gene', (196, 202))	('SEC31A', 'Gene', '22872', (196, 202))	('KIAA1919', 'Gene', '91749', (222, 230))	('OR7E24', 'Gene', '26648', (117, 123))	('TFAM', 'Gene', '7019', (152, 156))	('MLL3', 'Gene', (86, 90))	('BAX', 'Gene', '581', (109, 112))	('C18orf34', 'Gene', '374864', (204, 212))	('BAX', 'Gene', (109, 112))	('CCDC168', 'Gene', (232, 239))	('C9orf114', 'Gene', (99, 107))	('CCDC168', 'Gene', '643677', (232, 239))	('tumour', 'Phenotype', 'HP:0002664', (48, 54))	('COAD', 'Disease', (268, 272))	('tumour', 'Disease', 'MESH:D009369', (48, 54))	('KIAA1919', 'Gene', (222, 230))	('C9orf114', 'Gene', '51490', (99, 107))	('tumour', 'Disease', (48, 54))	('JAK1', 'Gene', (146, 150))	('C18orf34', 'Gene', (204, 212))	('TFAM', 'Gene', (152, 156))
419948	28585546	Among low-frequency MSI events, SMAP1, CCDC168 and SPINK5 harbour frameshift mutations in COAD and UCEC but not in STAD tumours.	('tumour', 'Phenotype', 'HP:0002664', (120, 126))	('COAD', 'Disease', 'MESH:D029424', (90, 94))	('SPINK5', 'Gene', '11005', (51, 57))	('tumours', 'Phenotype', 'HP:0002664', (120, 127))	('CCDC168', 'Gene', (39, 46))	('CCDC168', 'Gene', '643677', (39, 46))	('frameshift mutations', 'Var', (66, 86))	('SMAP1', 'Gene', '60682', (32, 37))	('UCEC', 'Disease', (99, 103))	('COAD', 'Disease', (90, 94))	('STAD tumours', 'Disease', (115, 127))	('STAD tumours', 'Disease', 'MESH:D009369', (115, 127))	('SPINK5', 'Gene', (51, 57))	('SMAP1', 'Gene', (32, 37))
419951	28585546	Supplementary Data 8 reports the enrichment of frameshift, 3' and 5' UTR MSI events in COAD, STAD and UCEC.	('COAD', 'Disease', (87, 91))	('frameshift', 'Var', (47, 57))	('STAD', 'Disease', (93, 97))	('UCEC', 'Disease', (102, 106))	('COAD', 'Disease', 'MESH:D029424', (87, 91))
419954	28585546	For instance, FAM129A, GMIP and NEK3 are altered in 107 (12%), 93 (10%) and 53 (6%) BRCA (breast cancer) tumours, respectively; ABT1 and SLC22A24 are altered in 19.6 and 14% of ACC (adrenocortical carcinoma) tumours; and ALPK2 and DPYSL2 are altered by frameshift MSI in 73 (17%) and 59 (14%) OV (ovarian serous cystadenocarcinoma) patients, respectively, but only in 62 of the remaining samples.	('NEK3', 'Gene', '4752', (32, 36))	('ABT1', 'Gene', (128, 132))	('ovarian serous cystadenocarcinoma', 'Disease', (297, 330))	('altered', 'Reg', (41, 48))	('tumours', 'Disease', (105, 112))	('patients', 'Species', '9606', (332, 340))	('BRCA', 'Gene', '672', (84, 88))	('altered', 'Reg', (150, 157))	('ovarian serous cystadenocarcinoma', 'Disease', 'MESH:D018284', (297, 330))	('tumours', 'Phenotype', 'HP:0002664', (105, 112))	('frameshift MSI', 'Var', (253, 267))	('tumours', 'Disease', 'MESH:D009369', (105, 112))	('tumours', 'Disease', (208, 215))	('DPYSL2', 'Gene', (231, 237))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('tumour', 'Phenotype', 'HP:0002664', (208, 214))	('BRCA', 'Gene', (84, 88))	('FAM129A', 'Gene', '116496', (14, 21))	('tumour', 'Phenotype', 'HP:0002664', (105, 111))	('ALPK2', 'Gene', (221, 226))	('tumours', 'Phenotype', 'HP:0002664', (208, 215))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (182, 206))	('ABT1', 'Gene', '29777', (128, 132))	('tumours', 'Disease', 'MESH:D009369', (208, 215))	('altered', 'Reg', (242, 249))	('carcinoma', 'Phenotype', 'HP:0030731', (197, 206))	('FAM129A', 'Gene', (14, 21))	('SLC22A24', 'Gene', '283238', (137, 145))	('GMIP', 'Gene', '51291', (23, 27))	('breast cancer', 'Phenotype', 'HP:0003002', (90, 103))	('serous cystadenocarcinoma', 'Phenotype', 'HP:0012887', (305, 330))	('DPYSL2', 'Gene', '1808', (231, 237))	('breast cancer', 'Disease', 'MESH:D001943', (90, 103))	('SLC22A24', 'Gene', (137, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (321, 330))	('breast cancer', 'Disease', (90, 103))	('NEK3', 'Gene', (32, 36))	('ALPK2', 'Gene', '115701', (221, 226))	('adrenocortical carcinoma) tumours', 'Disease', 'MESH:D018268', (182, 215))	('GMIP', 'Gene', (23, 27))
419963	28585546	In MSS tumours, only 3 out of 105 (3%) show enrichment of MSI in 3' UTR regions, whereas 42 (46%) show depletion of MSI events in coding regions (P<0.05; one-tailed Fisher's exact test).	('MSS tumours', 'Disease', (3, 14))	('tumour', 'Phenotype', 'HP:0002664', (7, 13))	('tumours', 'Phenotype', 'HP:0002664', (7, 14))	('MSI', 'Var', (58, 61))	('MSS tumours', 'Disease', 'MESH:D013132', (3, 14))
419965	28585546	The shortening of 3' UTRs in cancer cells is known to increase the stability of transcripts and thus the translational level of oncogenes.	('cancer', 'Disease', (29, 35))	('shortening', 'Var', (4, 14))	('increase', 'PosReg', (54, 62))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('translational level', 'MPA', (105, 124))	('stability of transcripts', 'MPA', (67, 91))	('cancer', 'Disease', 'MESH:D009369', (29, 35))
419976	28585546	The most recurrent MSI event is observed in DQ582201, a polyC mononucleotide repeat (115 MSI events, 37% of tumours); the second most recurrent event is on the exon regions of AF079515 (15 MSI events, 5% of tumours).	('tumours', 'Disease', (108, 115))	('tumours', 'Disease', 'MESH:D009369', (207, 214))	('tumours', 'Disease', (207, 214))	('polyC mononucleotide', 'Chemical', '-', (56, 76))	('tumour', 'Phenotype', 'HP:0002664', (108, 114))	('tumour', 'Phenotype', 'HP:0002664', (207, 213))	('tumours', 'Phenotype', 'HP:0002664', (108, 115))	('tumours', 'Disease', 'MESH:D009369', (108, 115))	('DQ582201', 'Var', (44, 52))	('tumours', 'Phenotype', 'HP:0002664', (207, 214))
419977	28585546	The instability of DQ582201 has been reported in several cancer types.	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('cancer', 'Disease', (57, 63))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('reported', 'Reg', (37, 45))	('DQ582201', 'Var', (19, 27))
419980	28585546	We focused on frameshift MSI events earlier to understand the functional impact of coding MSI in MSI-prone tumours.	('MSI-prone tumours', 'Disease', 'MESH:D003922', (97, 114))	('MSI-prone tumours', 'Disease', (97, 114))	('tumour', 'Phenotype', 'HP:0002664', (107, 113))	('frameshift MSI', 'Var', (14, 28))	('tumours', 'Phenotype', 'HP:0002664', (107, 114))
419984	28585546	We find that several of these MS loci lie within genes prone to frameshift MSI events, such as KIAA2018, ACVR2A or ASTE1 (ref.).	('KIAA2018', 'Gene', '205717', (95, 103))	('ASTE1', 'Gene', '28990', (115, 120))	('ACVR2A', 'Gene', (105, 111))	('KIAA2018', 'Gene', (95, 103))	('frameshift', 'Var', (64, 74))	('ASTE1', 'Gene', (115, 120))	('ACVR2A', 'Gene', '92', (105, 111))
419991	28585546	The total numbers of MSI and frameshift MSI events are significantly higher in MSI-H tumours than in MSI-L or MSS tumours (P<10-15; Kolmogorov-Smirnov test; Fig.	('MSI', 'MPA', (21, 24))	('tumours', 'Phenotype', 'HP:0002664', (85, 92))	('MSI-L or MSS tumours', 'Disease', (101, 121))	('MSI-L or MSS tumours', 'Disease', 'MESH:D013132', (101, 121))	('MSI-H tumours', 'Disease', 'MESH:D009369', (79, 92))	('tumour', 'Phenotype', 'HP:0002664', (114, 120))	('tumours', 'Phenotype', 'HP:0002664', (114, 121))	('frameshift MSI', 'Var', (29, 43))	('tumour', 'Phenotype', 'HP:0002664', (85, 91))	('higher', 'PosReg', (69, 75))	('MSI-H tumours', 'Disease', (79, 92))
420008	28585546	We detected 1,365 frameshift MSI events in the tumours predicted as MSI-H, with the most frequent incidences in DPYSL2 (12 cases), OR11G2 (9), SLC22A9 (9) and KIAA2018 (8), suggesting that the MSI events that recur in MSI-H cases (cf.	('SLC22A9', 'Gene', '114571', (143, 150))	('KIAA2018', 'Gene', (159, 167))	('MSI-H', 'Disease', (218, 223))	('frameshift', 'Var', (18, 28))	('DPYSL2', 'Gene', '1808', (112, 118))	('OR11G2', 'Gene', '390439', (131, 137))	('tumours', 'Phenotype', 'HP:0002664', (47, 54))	('MSI-H', 'Disease', (68, 73))	('DPYSL2', 'Gene', (112, 118))	('SLC22A9', 'Gene', (143, 150))	('MSI-H', 'Disease', 'MESH:D000848', (218, 223))	('tumours', 'Disease', 'MESH:D009369', (47, 54))	('KIAA2018', 'Gene', '205717', (159, 167))	('tumours', 'Disease', (47, 54))	('OR11G2', 'Gene', (131, 137))	('MSI-H', 'Disease', 'MESH:D000848', (68, 73))	('tumour', 'Phenotype', 'HP:0002664', (47, 53))
420009	28585546	We find that 31 patients display somatic mutations in MMR genes, and 1 CESC (TCGA-EA-A410) and 2 LIHC (TCGA-WQ-A9G7 and TCGA-EP-A12J) cases harbour germline mutations in MSH2, MSH6 and MLH3, respectively.	('mutations', 'Var', (41, 50))	('LIHC', 'Disease', (97, 101))	('LIHC', 'Disease', 'None', (97, 101))	('MSH6', 'Gene', (176, 180))	('CESC', 'Disease', (71, 75))	('patients', 'Species', '9606', (16, 24))	('A12J', 'SUBSTITUTION', 'None', (128, 132))	('MLH3', 'Gene', '27030', (185, 189))	('MLH3', 'Gene', (185, 189))	('MSH6', 'Gene', '2956', (176, 180))	('MSH2', 'Gene', (170, 174))	('MSH2', 'Gene', '4436', (170, 174))	('MMR genes', 'Gene', (54, 63))	('A12J', 'Var', (128, 132))
420010	28585546	In addition, we observe that 1 BRCA patient (TCGA-BH-A18G) harbours a missense germline mutation predicted to be pathogenic with high confidence (Methods) and a somatic frameshift event in MSH3.	('A18G', 'Mutation', 'c.18A>G', (53, 57))	('BRCA', 'Gene', '672', (31, 35))	('BRCA', 'Gene', (31, 35))	('missense', 'Var', (70, 78))	('MSH3', 'Gene', (189, 193))	('MSH3', 'Gene', '4437', (189, 193))	('patient', 'Species', '9606', (36, 43))
420012	28585546	For the 91 MSI-H predicted cases, we confirm the mutation signatures characteristic of MSI-H cases, for example, C>T transitions in (A/C/G)pCpN sequence contexts and C>A transversions at an CpCpN context, suggesting that the mutation signatures of predicted MSI-H cases are largely concordant with those of known MSI-H cases.	('MSI-H', 'Disease', 'MESH:D000848', (87, 92))	('MSI-H', 'Disease', 'MESH:D000848', (313, 318))	('MSI-H', 'Disease', (313, 318))	('C>T transitions', 'Var', (113, 128))	('MSI-H', 'Disease', (258, 263))	('MSI-H', 'Disease', (11, 16))	('MSI-H', 'Disease', (87, 92))	('MSI-H', 'Disease', 'MESH:D000848', (258, 263))	('MSI-H', 'Disease', 'MESH:D000848', (11, 16))	('C>A transversions', 'Var', (166, 183))
420013	28585546	Our joint analysis of MSI-H tumours from multiple cancer types has revealed that several DNA repair pathways other than MMR, including ATR, BER, HR and NHEJ, are altered by single-nucleotide and MS mutations.	('MSI-H tumours', 'Disease', 'MESH:D009369', (22, 35))	('tumour', 'Phenotype', 'HP:0002664', (28, 34))	('MSI-H tumours', 'Disease', (22, 35))	('altered', 'Reg', (162, 169))	('EJ', 'CellLine', 'CVCL:7039', (154, 156))	('multiple cancer', 'Disease', (41, 56))	('tumours', 'Phenotype', 'HP:0002664', (28, 35))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('MS mutations', 'Var', (195, 207))	('DNA repair pathways', 'Pathway', (89, 108))	('multiple cancer', 'Disease', 'MESH:D009369', (41, 56))	('ATR', 'Gene', '545', (135, 138))	('single-nucleotide', 'Var', (173, 190))	('ATR', 'Gene', (135, 138))
420014	28585546	Moreover, we have uncovered new genes affected by frameshift MSI events in MSI-prone tumours as well as in tumour types not frequently affected by MSI (for example, FAM129A, GMIP and NEK3 in BRCA, and DPYSL2 and ALPK2 in OV).	('frameshift MSI', 'Var', (50, 64))	('GMIP', 'Gene', (174, 178))	('DPYSL2', 'Gene', (201, 207))	('ALPK2', 'Gene', '115701', (212, 217))	('tumour', 'Phenotype', 'HP:0002664', (107, 113))	('tumour type', 'Disease', (107, 118))	('FAM129A', 'Gene', '116496', (165, 172))	('DPYSL2', 'Gene', '1808', (201, 207))	('FAM129A', 'Gene', (165, 172))	('ALPK2', 'Gene', (212, 217))	('BRCA', 'Gene', '672', (191, 195))	('MSI-prone tumours', 'Disease', 'MESH:D003922', (75, 92))	('GMIP', 'Gene', '51291', (174, 178))	('tumours', 'Phenotype', 'HP:0002664', (85, 92))	('NEK3', 'Gene', (183, 187))	('BRCA', 'Gene', (191, 195))	('MSI-prone tumours', 'Disease', (75, 92))	('NEK3', 'Gene', '4752', (183, 187))	('tumour', 'Phenotype', 'HP:0002664', (85, 91))	('tumour type', 'Disease', 'MESH:D009369', (107, 118))
420026	28585546	MSI status was evaluated by the TCGA consortium for COAD, READ, ESCA, STAD and UCEC tumours using a panel of four mononucleotide repeats (BAT25, BAT26, BAT40 and TGFBRII) and three dinucleotide repeats (D2S123, D5S346 and D17S250), except for a subset of COAD/READ genomes evaluated by five mononucleotide markers (BAT25, BAT26, NR21, NR24 and MONO27).	('dinucleotide', 'Chemical', 'MESH:D015226', (181, 193))	('COAD', 'Disease', (255, 259))	('D5S346', 'Var', (211, 217))	('UCEC tumours', 'Disease', (79, 91))	('D2S123', 'Var', (203, 209))	('mononucleotide', 'Chemical', '-', (114, 128))	('BAT40', 'Var', (152, 157))	('BAT26', 'Var', (322, 327))	('UCEC tumours', 'Disease', 'MESH:D009369', (79, 91))	('COAD', 'Disease', 'MESH:D029424', (52, 56))	('COAD', 'Disease', 'MESH:D029424', (255, 259))	('mononucleotide', 'Chemical', '-', (291, 305))	('COAD', 'Disease', (52, 56))	('BAT26', 'Var', (145, 150))	('BAT25', 'Var', (315, 320))	('D17S250', 'Var', (222, 229))	('tumour', 'Phenotype', 'HP:0002664', (84, 90))	('BAT25', 'Var', (138, 143))	('tumours', 'Phenotype', 'HP:0002664', (84, 91))
420030	28585546	The final reference set of exonic MS sites comprised 386,396 loci (112,896 mono-, 63,162 di-, 132,117 tri- and 78,221 tetranucleotides).	('di-', 'Var', (89, 92))	('tetranucleotides', 'Chemical', '-', (118, 134))	('mono-', 'Var', (75, 80))	('tri-', 'Var', (102, 106))
420031	28585546	This MS set encompasses 7,404,614 mono-, 3,686,129, di-, 3,750,887 tri- and 4,197,813 tetranucleotides.	('tetranucleotides', 'Chemical', '-', (86, 102))	('di-', 'Var', (52, 55))	('tri-', 'Var', (67, 71))
420044	28585546	We downloaded the coordinates of the 25-state chromatin state map defined using 12 marks (H3K4me1, H3K4me2, H3K4me3, H3K9ac, H3K27ac, H4K20me1, H3K79me2, H3K36me3, H3K9me3, H3K27me3, H2A.Z and DNase) across 127 reference epigenomes from the Epigenome Roadmap project.	('H4K20me1', 'Var', (134, 142))	('H3K27me3', 'Var', (173, 181))	('H3K4me1', 'Var', (90, 97))	('H3K9me3', 'Var', (164, 171))	('H3K4me2', 'Var', (99, 106))	('H3K36me3', 'Var', (154, 162))	('H2A.Z', 'Gene', (183, 188))	('H3K79me2', 'Var', (144, 152))	('H3K9ac', 'Var', (117, 123))	('H3K27ac', 'Var', (125, 132))	('H3K4me3', 'Var', (108, 115))	('H2A.Z', 'Gene', '3015', (183, 188))
420046	28585546	We used the chromatin state maps defined using the epigenomes E092, E094, E0110 and E0111 for STAD, E117 for UCEC, E076, E106 and E075 for COAD, E086 for KICH, E027, E028 and E199 for BRCA, E053, E054, E067, E068, E069, E070, E071, E072, E073, E074, E081, E082 and E0125 for GBM, E097 for OV, E088, E096, E114 and E128 for LUSC, E055, E056, E057, E059, E061, E126, E127 and E058 for HNSC and E086 for KIRP.	('E070', 'Var', (220, 224))	('E096', 'Var', (299, 303))	('E0125', 'Var', (265, 270))	('HNSC', 'Disease', 'None', (383, 387))	('E086', 'Var', (392, 396))	('E073', 'Var', (238, 242))	('E127', 'Var', (365, 369))	('E082', 'Var', (256, 260))	('E126', 'Var', (359, 363))	('E088', 'Var', (293, 297))	('E071', 'Var', (226, 230))	('E057', 'Var', (341, 345))	('E074', 'Var', (244, 248))	('HNSC', 'Disease', (383, 387))	('KICH', 'Disease', 'None', (154, 158))	('E069', 'Var', (214, 218))	('E199', 'Var', (175, 179))	('E055', 'Var', (329, 333))	('E056', 'Var', (335, 339))	('E072', 'Var', (232, 236))	('E053', 'Var', (190, 194))	('COAD', 'Disease', 'MESH:D029424', (139, 143))	('BRCA', 'Gene', '672', (184, 188))	('E061', 'Var', (353, 357))	('KICH', 'Disease', (154, 158))	('E128', 'Var', (314, 318))	('E054', 'Var', (196, 200))	('E059', 'Var', (347, 351))	('E114', 'Var', (305, 309))	('E081', 'Var', (250, 254))	('E068', 'Var', (208, 212))	('E058', 'Var', (374, 378))	('E067', 'Var', (202, 206))	('BRCA', 'Gene', (184, 188))	('COAD', 'Disease', (139, 143))	('E097', 'Var', (280, 284))
420053	28585546	A molecular portrait of microsatellite instability across multiple cancers.	('cancers', 'Phenotype', 'HP:0002664', (67, 74))	('cancers', 'Disease', (67, 74))	('cancers', 'Disease', 'MESH:D009369', (67, 74))	('multiple cancer', 'Disease', (58, 73))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('multiple cancer', 'Disease', 'MESH:D009369', (58, 73))	('microsatellite', 'Var', (24, 38))
420065	27809842	Among high risk HPV types, type 16 and type 18 are the most common and carcinogenic.	('type 16', 'Var', (27, 34))	('carcinogenic', 'Disease', 'MESH:D063646', (71, 83))	('carcinogenic', 'Disease', (71, 83))	('HPV', 'Species', '10566', (16, 19))	('common', 'Reg', (60, 66))
420077	27809842	This process often leads to the deletion of many early (E1, E2, E4, and E5) and late (L1 and L2) genes.	('deletion', 'Var', (32, 40))	('leads to', 'Reg', (19, 27))	('E1, E2, E4, and E5', 'Gene', '6080', (56, 74))	('L1 and L2', 'Gene', '25479185', (86, 95))
420078	27809842	The deletion of L1 and L2 during the integration process is what renders prophylactic vaccines useless against HPV-associated cancers.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('cancers', 'Phenotype', 'HP:0002664', (126, 133))	('HPV', 'Species', '10566', (111, 114))	('L1 and L2', 'Gene', '25479185', (16, 25))	('cancers', 'Disease', (126, 133))	('deletion', 'Var', (4, 12))	('cancers', 'Disease', 'MESH:D009369', (126, 133))
420080	27809842	The deletion of E2 during integration leads to elevated expression of E6 and E7 and is thought to contribute to the carcinogenesis of HPV-associated lesions (for review see).	('carcinogenesis', 'Disease', 'MESH:D063646', (116, 130))	('contribute', 'Reg', (98, 108))	('carcinogenesis', 'Disease', (116, 130))	('elevated', 'PosReg', (47, 55))	('expression', 'MPA', (56, 66))	('E6 and E7', 'Gene', '25479186', (70, 79))	('deletion', 'Var', (4, 12))	('HPV', 'Species', '10566', (134, 137))
420109	27809842	Peripheral blood mononuclear cells (PBMCs) were collected from patients and tested, showing an increase in E7-specific IFNgamma + T cells in three patients after vaccination.	('IFNgamma', 'Gene', (119, 127))	('increase', 'PosReg', (95, 103))	('IFNgamma', 'Gene', '3458', (119, 127))	('patients', 'Species', '9606', (147, 155))	('E7-specific', 'Var', (107, 118))	('patients', 'Species', '9606', (63, 71))
420111	27809842	The therapeutic potential demonstrated by the Lm-LLo-E7 vaccine has prompt the scientists to plan and design additional clinical trials to further determine the efficacy of this vaccine, including a phase II trial in patients with persistent, recurrent, loco-regional or metastatic anal cancer or HPV+ squamous cell carcinoma of the rectum (NCT02399813), a phase II trial in patients with HPV+ OPC before resection (NCT02002182), a phase I/II trial in patients with locally advanced or metastatic cervical or HPV+ head and neck cancer with or without MED14736 chemobile treatment (NCT02291055), and a phase II trial in patients with persistent or recurrent squamous or non squamous cell carcinoma of the cervix (NCT01266460).	('cancer', 'Phenotype', 'HP:0002664', (528, 534))	('neck cancer', 'Disease', 'MESH:D006258', (523, 534))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (302, 325))	('neck cancer', 'Disease', (523, 534))	('cancer', 'Disease', (287, 293))	('patients', 'Species', '9606', (619, 627))	('patients', 'Species', '9606', (452, 460))	('HPV', 'Species', '10566', (297, 300))	('squamous cell carcinoma', 'Disease', (673, 696))	('cancer', 'Phenotype', 'HP:0002664', (287, 293))	('HPV+ squamous cell carcinoma of the rectum', 'Disease', 'MESH:D002294', (297, 339))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (302, 325))	('cancer', 'Disease', 'MESH:D009369', (528, 534))	('carcinoma', 'Phenotype', 'HP:0030731', (316, 325))	('HPV', 'Species', '10566', (509, 512))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (673, 696))	('cancer', 'Disease', 'MESH:D009369', (287, 293))	('HPV', 'Species', '10566', (389, 392))	('NCT02399813', 'Var', (341, 352))	('patients', 'Species', '9606', (217, 225))	('carcinoma', 'Phenotype', 'HP:0030731', (687, 696))	('patients', 'Species', '9606', (375, 383))	('anal cancer', 'Phenotype', 'HP:0032186', (282, 293))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (673, 696))	('cancer', 'Disease', (528, 534))	('HPV+ squamous cell carcinoma of the rectum', 'Disease', (297, 339))	('head and neck cancer', 'Phenotype', 'HP:0012288', (514, 534))
420112	27809842	A recent study tested the efficacy and safety of oral administration of GLBL101c, a bacterial vector-based therapeutic HPV vaccine.	('GLBL101c', 'Var', (72, 80))	('tested', 'Reg', (15, 21))	('HPV', 'Species', '10566', (119, 122))
420114	27809842	GLBL101c is generated from a recombinant L. casei that expresses a modified HPV16-E7 antigen, which is no longer carcinogenic.	('carcinogenic', 'Disease', (113, 125))	('modified', 'Var', (67, 75))	('L. casei', 'Species', '1582', (41, 49))	('HPV16-E7', 'Gene', (76, 84))	('carcinogenic', 'Disease', 'MESH:D063646', (113, 125))	('HPV16', 'Species', '333760', (76, 81))
420124	27809842	TG4001 is a suspension of MVATG8042 particles consisting of attenuated recombinant MVA including sequences encoding modified HPV16 E6/E7 and human IL-2.	('MVATG8042', 'Chemical', '-', (26, 35))	('IL-2', 'Gene', (147, 151))	('modified', 'Var', (116, 124))	('HPV16', 'Species', '333760', (125, 130))	('human', 'Species', '9606', (141, 146))	('TG4001', 'Chemical', '-', (0, 6))	('E6/E7', 'Gene', '25479186', (131, 136))	('E6/E7', 'Gene', (131, 136))	('HPV16', 'Gene', (125, 130))	('IL-2', 'Gene', '3558', (147, 151))
420130	27809842	The vaccine utilize the knowledge that E2 protein serve as inhibitor for the expression of E6 and E7 oncoproteins, and that the introduction of E2 into the host may suppress the activity of E6 and E7 in HPV-infected host, and subsequently reduce the transforming ability of the infected cells and the survivability of the malignant, HPV-associated tumor cells.	('transforming ability', 'CPA', (250, 270))	('E6 and E7', 'Gene', '25479186', (190, 199))	('introduction', 'Var', (128, 140))	('E6 and E7', 'Gene', '25479186', (91, 100))	('HPV', 'Species', '10566', (203, 206))	('HPV', 'Species', '10566', (333, 336))	('tumor', 'Disease', 'MESH:D009369', (348, 353))	('HPV-infected host', 'Disease', (203, 220))	('reduce', 'NegReg', (239, 245))	('survivability of the malignant', 'CPA', (301, 331))	('HPV-infected host', 'Disease', 'MESH:D030361', (203, 220))	('tumor', 'Phenotype', 'HP:0002664', (348, 353))	('tumor', 'Disease', (348, 353))	('activity', 'MPA', (178, 186))	('E2 protein', 'Gene', '7320', (39, 49))	('suppress', 'NegReg', (165, 173))	('E2 protein', 'Gene', (39, 49))
420143	27809842	Another clinical trial administered TA-HPV to 12 patients with HPV16+ vulval intraepithelial neoplasia (VIN) grade III and one patient with HPV16+ vaginal intraepithelial neoplasia (VAIN) grade II.	('vulval intraepithelial neoplasia', 'Disease', (70, 102))	('HPV16', 'Species', '333760', (140, 145))	('patient', 'Species', '9606', (49, 56))	('HPV', 'Species', '10566', (140, 143))	('patient', 'Species', '9606', (127, 134))	('vulval intraepithelial neoplasia', 'Disease', 'MESH:D019048', (70, 102))	('HPV16', 'Species', '333760', (63, 68))	('intraepithelial neoplasia', 'Phenotype', 'HP:0032187', (77, 102))	('HPV16+', 'Var', (63, 69))	('patients', 'Species', '9606', (49, 57))	('vaginal intraepithelial neoplasia', 'Disease', (147, 180))	('vaginal intraepithelial neoplasia', 'Disease', 'MESH:D019048', (147, 180))	('vulval intraepithelial neoplasia', 'Phenotype', 'HP:0032202', (70, 102))	('intraepithelial neoplasia', 'Phenotype', 'HP:0032187', (155, 180))	('neoplasia', 'Phenotype', 'HP:0002664', (93, 102))	('HPV', 'Species', '10566', (63, 66))	('VIN', 'Phenotype', 'HP:0032202', (104, 107))	('HPV', 'Species', '10566', (39, 42))	('neoplasia', 'Phenotype', 'HP:0002664', (171, 180))
420146	27809842	This issue was partially addressed by a former study, which showed that cyclooxygenase 2 (COX-2) inhibitors may prevent the production of neutralizing antibodies to vaccinia virus.	('prevent', 'NegReg', (112, 119))	('COX-2', 'Gene', (90, 95))	('production', 'MPA', (124, 134))	('vaccinia virus', 'Species', '10245', (165, 179))	('vaccinia virus', 'Protein', (165, 179))	('neutralizing antibodies', 'MPA', (138, 161))	('inhibitors', 'Var', (97, 107))
420155	27809842	In this study 50 patients were randomly assigned to receive HPV16-SLP vaccination or placebo, followed by a vaccine or placebo booster one year later.	('patients', 'Species', '9606', (17, 25))	('vaccination', 'Var', (70, 81))	('HPV16', 'Species', '333760', (60, 65))	('HPV16-SLP', 'Gene', (60, 69))
420182	27809842	Four patients (80 %) with HPV16+ RM SCCHN generated T cell and antibody responses.	('HPV16+ RM', 'Var', (26, 35))	('HPV16', 'Species', '333760', (26, 31))	('patients', 'Species', '9606', (5, 13))	('antibody responses', 'CPA', (63, 81))
420184	27809842	This trial demonstrated that GL-0810 is able to elicit an immune response and is well tolerated by patients with late stage SCCHN.	('patients', 'Species', '9606', (99, 107))	('immune response', 'CPA', (58, 73))	('elicit', 'Reg', (48, 54))	('GL-0810', 'Chemical', '-', (29, 36))	('GL-0810', 'Var', (29, 36))
420185	27809842	In addition to the vaccine candidates described above, a Phase I clinical trial has also been planned to evaluate the safety and therapeutic effect of PDS0101, a new therapeutic HPV vaccine candidate consist of Peptides from HPV-16 E6 and E7 as antigen and R-enantiomer of 1,2-dioleoyl-3-trimethylammonium-propane chloride as adjuvant, in female patients with high risk HPV infection or CIN1 (NCT02065973).	('E6 and E7', 'Gene', '25479186', (232, 241))	('HPV', 'Species', '10566', (370, 373))	('PDS0101', 'Chemical', '-', (151, 158))	('HPV-16', 'Species', '333760', (225, 231))	('NCT02065973', 'Var', (393, 404))	('CIN', 'Disease', (387, 390))	('HPV infection', 'Disease', (370, 383))	('patients', 'Species', '9606', (346, 354))	('CIN', 'Disease', 'MESH:D007674', (387, 390))	('HPV', 'Species', '10566', (225, 228))	('1,2-dioleoyl', 'Chemical', '-', (273, 285))	('PDS0101', 'Gene', (151, 158))	('HPV infection', 'Disease', 'MESH:D030361', (370, 383))	('CIN', 'Phenotype', 'HP:0032242', (387, 390))	('HPV', 'Species', '10566', (178, 181))	('trimethylammonium-propane chloride', 'Chemical', '-', (288, 322))
420204	27809842	Each patient was administered either 100ug or 600ug of GTL001 with imiquimod.	('GTL001', 'Gene', (55, 61))	('patient', 'Species', '9606', (5, 12))	('100ug', 'Var', (37, 42))	('600ug', 'Var', (46, 51))	('imiquimod', 'Chemical', 'MESH:D000077271', (67, 76))
420207	27809842	Patients in cohort 4 (n = 9) who received 600ug GTL001 powder + imiquimod experienced the highest HPV16/18 clearance rate.	('600ug', 'Var', (42, 47))	('HPV16', 'Species', '333760', (98, 103))	('imiquimod', 'Chemical', 'MESH:D000077271', (64, 73))	('Patients', 'Species', '9606', (0, 8))	('GTL001', 'Gene', (48, 54))	('HPV16/18 clearance', 'MPA', (98, 116))
420215	27809842	DCs play an important role in presenting the antigen to naive CD8+ cytotoxic T cells and do so through either phagocytosis and present exogenous antigen release from transfected myocytes on MHC class I through cross presentation, or direct transfection of DCs by vaccination leading to direct presentation to CD8+ T cells.	('CD8', 'Gene', (62, 65))	('MHC', 'Gene', (190, 193))	('CD8', 'Gene', '925', (62, 65))	('CD8', 'Gene', (309, 312))	('transfection', 'Var', (240, 252))	('CD8', 'Gene', '925', (309, 312))	('MHC', 'Gene', '3107', (190, 193))
420218	27809842	The DNA vaccine used in this study was pNGVL4a-sig/E7(detox)/HSP70, a plasmid encoding mutated form of HPV16-E7 linked to signal peptide and heat shock protein 70. pNGVL4a-sig/E7(detox)/HSP70 DNA vaccine was previously shown to enhance the HPV-16 E7 antigen-specific T cell mediated immune responses in a preclinical model.	('shock', 'Phenotype', 'HP:0031273', (146, 151))	('HSP70', 'Gene', '3308', (186, 191))	('HPV-16', 'Gene', (240, 246))	('HSP70', 'Gene', '3308', (61, 66))	('HSP70', 'Gene', (186, 191))	('enhance', 'PosReg', (228, 235))	('pNGVL4a-sig/E7', 'Var', (164, 178))	('HSP70', 'Gene', (61, 66))	('HPV16', 'Species', '333760', (103, 108))	('heat shock', 'Disease', 'MESH:D012769', (141, 151))	('HPV-16', 'Species', '333760', (240, 246))	('heat shock', 'Disease', (141, 151))
420231	27809842	Nine patients were administered GX-188E through intramuscular injection followed by electroporation to enhance immunogenicity.	('GX-188E', 'Var', (32, 39))	('immunogenicity', 'MPA', (111, 125))	('patients', 'Species', '9606', (5, 13))	('enhance', 'PosReg', (103, 110))
420245	27809842	This formulation is being tested in a phase I/IIA trial in patients with HPV associated head and neck squamous cell carcinoma (NCT02163057), a phase I/IIA trial in female patients with new, recurrent, or persistent cervical cancer (NCT02172911), as well as a phase II trial in patients with locally advanced cervical cancer who received standard of care chemoradiation (NCT02501278).	('cervical cancer', 'Disease', (215, 230))	('cervical cancer', 'Disease', 'MESH:D002583', (215, 230))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('HPV', 'Species', '10566', (73, 76))	('NCT02172911', 'Var', (232, 243))	('cervical cancer', 'Disease', (308, 323))	('HPV', 'Gene', (73, 76))	('neck squamous cell carcinoma', 'Disease', (97, 125))	('NCT02163057', 'Var', (127, 138))	('patients', 'Species', '9606', (171, 179))	('patients', 'Species', '9606', (277, 285))	('patients', 'Species', '9606', (59, 67))	('cervical cancer', 'Disease', 'MESH:D002583', (308, 323))	('cancer', 'Phenotype', 'HP:0002664', (317, 323))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (102, 125))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (97, 125))
420247	27809842	One example is the inclusion of genes encoding anti-apoptotic protein into 'suicidal DNA' to enhance survival of transfected APCs.	('genes', 'Var', (32, 37))	('enhance', 'PosReg', (93, 100))	('APC', 'Disease', 'MESH:D011125', (125, 128))	('survival', 'CPA', (101, 109))	('APC', 'Disease', (125, 128))
420289	27136592	These changes ultimately resulted in isolated tumor cells showing a uniform phenotype, irrespective of the differentiation of the main tumor mass (i.e., differentiated or undifferentiated carcinomas).	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('differentiated', 'Disease', (153, 167))	('tumor', 'Disease', (46, 51))	('tumor', 'Disease', (135, 140))	('undifferentiated carcinomas', 'Disease', 'MESH:D002277', (171, 198))	('changes', 'Var', (6, 13))	('tumor', 'Disease', 'MESH:D009369', (135, 140))	('undifferentiated carcinomas', 'Disease', (171, 198))	('resulted', 'Reg', (25, 33))	('carcinoma', 'Phenotype', 'HP:0030731', (188, 197))	('carcinomas', 'Phenotype', 'HP:0030731', (188, 198))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
420342	27136592	In CRC, high budding correlated with lower 5-year overall survival (OS) (, although see), 10-year OS, 5-year CSS, and 10-year CSS.	('high', 'Var', (8, 12))	('lower', 'NegReg', (37, 42))	('overall survival', 'MPA', (50, 66))	('OS', 'Chemical', '-', (98, 100))	('OS', 'Chemical', '-', (68, 70))
420348	27136592	In colon cancer, high budding correlated with lower 5-year recurrence-free survival (RFS), 5-year OS (although see), 10-year OS, and 5-year CSS.	('OS', 'Chemical', '-', (125, 127))	('high', 'Var', (17, 21))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('recurrence-free survival', 'CPA', (59, 83))	('lower', 'NegReg', (46, 51))	('colon cancer', 'Phenotype', 'HP:0003003', (3, 15))	('colon cancer', 'Disease', 'MESH:D015179', (3, 15))	('OS', 'Chemical', '-', (98, 100))	('colon cancer', 'Disease', (3, 15))
420349	27136592	In RC, high budding correlated with recurrence, both local and distant (most notably liver metastases) and consequently, with lower 5-year DFS.	('lower', 'NegReg', (126, 131))	('liver', 'Disease', (85, 90))	('metastases', 'Disease', (91, 101))	('high', 'Var', (7, 11))	('recurrence', 'Disease', (36, 46))	('metastases', 'Disease', 'MESH:D009362', (91, 101))	('DFS', 'MPA', (139, 142))
420350	27136592	High budding also correlated with lower 5-year OS and 10-year OS.	('OS', 'Chemical', '-', (62, 64))	('High', 'Var', (0, 4))	('5-year OS', 'CPA', (40, 49))	('lower', 'NegReg', (34, 39))	('OS', 'Chemical', '-', (47, 49))
420352	27136592	In CRC patients, high budding correlated with higher overall stage, higher T stage (but see), higher N stage, higher Dukes stage, tumor dedifferentiation, infiltrating growth pattern, lymphatic invasion, venous invasion, lymphovascular invasion, perineural invasion, nodal metastasis, and distant metastasis (but see).	('Dukes', 'MPA', (117, 122))	('patients', 'Species', '9606', (7, 15))	('lymphatic invasion', 'CPA', (184, 202))	('higher', 'PosReg', (46, 52))	('venous invasion', 'CPA', (204, 219))	('higher T stage', 'CPA', (68, 82))	('perineural invasion', 'CPA', (246, 265))	('high', 'Var', (17, 21))	('lymphovascular invasion', 'CPA', (221, 244))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('overall stage', 'CPA', (53, 66))	('nodal metastasis', 'CPA', (267, 283))	('tumor', 'Disease', (130, 135))	('infiltrating growth pattern', 'CPA', (155, 182))	('distant metastasis', 'CPA', (289, 307))
420373	27136592	High budding correlated with lower 5-year DFS, lower 3-year OS and 5-year OS.	('lower', 'NegReg', (47, 52))	('High', 'Var', (0, 4))	('3-year OS', 'MPA', (53, 62))	('DFS', 'MPA', (42, 45))	('lower', 'NegReg', (29, 34))	('OS', 'Chemical', '-', (74, 76))	('OS', 'Chemical', '-', (60, 62))
420379	27136592	Despite this weaker prognostic correlation for adenocarcinoma, one study, which included both patients with squamous cell carcinoma and patients with adenocarcinoma, found that high budding correlated with higher grade, higher T stage, higher overall stage, nodal metastasis, lower inflammatory response, incomplete excision of the tumor, and lower OS.	('adenocarcinoma', 'Disease', (150, 164))	('nodal metastasis', 'CPA', (258, 274))	('high', 'Var', (177, 181))	('squamous cell carcinoma', 'Disease', (108, 131))	('tumor', 'Phenotype', 'HP:0002664', (332, 337))	('patients', 'Species', '9606', (94, 102))	('adenocarcinoma', 'Disease', 'MESH:D000230', (150, 164))	('adenocarcinoma', 'Disease', 'MESH:D000230', (47, 61))	('higher overall stage', 'CPA', (236, 256))	('higher grade', 'CPA', (206, 218))	('OS', 'Chemical', '-', (349, 351))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (108, 131))	('higher T stage', 'CPA', (220, 234))	('lower', 'NegReg', (276, 281))	('tumor', 'Disease', (332, 337))	('lower inflammatory response', 'Phenotype', 'HP:0012648', (276, 303))	('carcinoma', 'Phenotype', 'HP:0030731', (155, 164))	('carcinoma', 'Phenotype', 'HP:0030731', (52, 61))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (108, 131))	('lower OS', 'CPA', (343, 351))	('tumor', 'Disease', 'MESH:D009369', (332, 337))	('patients', 'Species', '9606', (136, 144))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('adenocarcinoma', 'Disease', (47, 61))
420385	27136592	High budding also correlated with lower 3-year OS and 5-year OS.	('lower', 'NegReg', (34, 39))	('OS', 'Chemical', '-', (47, 49))	('OS', 'Chemical', '-', (61, 63))	('High', 'Var', (0, 4))
420395	27136592	High budding also correlated with lower 5-year OS and lower CSS (reviewed in).	('High', 'Var', (0, 4))	('5-year OS', 'CPA', (40, 49))	('lower', 'NegReg', (34, 39))	('CSS', 'CPA', (60, 63))	('OS', 'Chemical', '-', (47, 49))	('lower', 'NegReg', (54, 59))
420396	27136592	In nasopharyngeal carcinoma, high budding correlated with higher T stage, higher overall clinical stage, lymphatic invasion, vascular invasion, and nodal metastases.	('high', 'Var', (29, 33))	('carcinoma', 'Phenotype', 'HP:0030731', (18, 27))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (3, 27))	('nasopharyngeal carcinoma', 'Disease', (3, 27))	('vascular invasion', 'CPA', (125, 142))	('nodal metastases', 'Disease', (148, 164))	('lymphatic invasion', 'CPA', (105, 123))	('T stage', 'CPA', (65, 72))	('nodal metastases', 'Disease', 'MESH:D009362', (148, 164))	('higher', 'PosReg', (58, 64))	('nasopharyngeal carcinoma', 'Disease', 'MESH:D000077274', (3, 27))
420398	27136592	In laryngeal carcinoma, high budding correlated with lower metastatic DFS.	('laryngeal carcinoma', 'Disease', (3, 22))	('laryngeal carcinoma', 'Disease', 'MESH:D007827', (3, 22))	('high', 'Var', (24, 28))	('metastatic DFS', 'CPA', (59, 73))	('laryngeal carcinoma', 'Phenotype', 'HP:0012118', (3, 22))	('carcinoma', 'Phenotype', 'HP:0030731', (13, 22))	('lower', 'NegReg', (53, 58))
420401	27136592	In lung adenocarcinoma, budding correlated with higher overall pathologic stage, infiltrating growth pattern, schirrhous (i.e., rich in dense connective tissue) stromal type, lymphatic invasion, vascular invasion, pleural invasion, and nodal metastases.	('budding', 'Var', (24, 31))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (3, 22))	('schirrhous', 'CPA', (110, 120))	('dense connective tissue', 'Phenotype', 'HP:0009025', (136, 159))	('nodal metastases', 'Disease', 'MESH:D009362', (236, 252))	('carcinoma', 'Phenotype', 'HP:0030731', (13, 22))	('lymphatic invasion', 'CPA', (175, 193))	('pleural invasion', 'Disease', 'MESH:D010995', (214, 230))	('infiltrating growth pattern', 'CPA', (81, 108))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (3, 22))	('higher', 'PosReg', (48, 54))	('pleural invasion', 'Disease', (214, 230))	('vascular invasion', 'CPA', (195, 212))	('pathologic stage', 'CPA', (63, 79))	('nodal metastases', 'Disease', (236, 252))	('lung adenocarcinoma', 'Disease', (3, 22))
420402	27136592	Budding correlated with lower OS, including lower 5-year OS.	('lower', 'NegReg', (44, 49))	('lower', 'Disease', (24, 29))	('Budding', 'Var', (0, 7))	('OS', 'Chemical', '-', (57, 59))	('OS', 'Chemical', '-', (30, 32))
420404	27136592	Budding also correlated with lower 5-year OS and 5-year CSS.	('Budding', 'Var', (0, 7))	('lower', 'NegReg', (29, 34))	('OS', 'Chemical', '-', (42, 44))
420407	27136592	High budding also correlated with lower 5-year OS and shorter CSS.	('High', 'Var', (0, 4))	('5-year OS', 'CPA', (40, 49))	('lower', 'NegReg', (34, 39))	('shorter', 'NegReg', (54, 61))	('OS', 'Chemical', '-', (47, 49))
420411	27136592	In endometrial cancer, high budding correlated with advanced overall stage (III + IV) and deep invasion of the myometrium (>=50%).	('endometrial cancer', 'Phenotype', 'HP:0012114', (3, 21))	('high', 'Var', (23, 27))	('endometrial cancer', 'Disease', 'MESH:D016889', (3, 21))	('endometrial cancer', 'Disease', (3, 21))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))
420412	27136592	High budding also correlated with lower 5-year OS.	('5-year OS', 'CPA', (40, 49))	('lower', 'NegReg', (34, 39))	('OS', 'Chemical', '-', (47, 49))	('High', 'Var', (0, 4))
420441	27136592	Aberrant activation of EMT is considered to be a hallmark of cancer metastasis (reviewed in).	('hallmark of cancer metastasis', 'Disease', (49, 78))	('Aberrant', 'Var', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('EMT', 'CPA', (23, 26))	('hallmark of cancer metastasis', 'Disease', 'MESH:D009362', (49, 78))
420506	31387622	Depleting PTOV1 sensitizes non-small cell lung cancer cells to chemotherapy through attenuating cancer stem cell traits Prostate tumor over expressed gene 1 (PTOV1) has been reported as an oncogene in several human cancers.	('human', 'Species', '9606', (209, 214))	('Depleting', 'Var', (0, 9))	('Prostate tumor', 'Phenotype', 'HP:0100787', (120, 134))	('PTOV1', 'Gene', '53635', (158, 163))	('cancer', 'Disease', (96, 102))	('PTOV1', 'Gene', (158, 163))	('cancer', 'Disease', (215, 221))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('cancers', 'Phenotype', 'HP:0002664', (215, 222))	('sensitizes', 'Reg', (16, 26))	('cancer', 'Disease', (47, 53))	('cancers', 'Disease', (215, 222))	('lung cancer', 'Phenotype', 'HP:0100526', (42, 53))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('Prostate tumor', 'Disease', (120, 134))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (27, 53))	('attenuating', 'NegReg', (84, 95))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('PTOV1', 'Gene', '53635', (10, 15))	('PTOV1', 'Gene', (10, 15))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (31, 53))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('cancer', 'Disease', 'MESH:D009369', (215, 221))	('cancers', 'Disease', 'MESH:D009369', (215, 222))	('Prostate tumor', 'Disease', 'MESH:D011471', (120, 134))
420513	31387622	Depleting PTOV1 increased sensitivity to chemotherapy drugs cisplatin and docetaxel by increasing cell apoptosis, inhibiting cell migration and invasion.	('cell apoptosis', 'CPA', (98, 112))	('Depleting', 'Var', (0, 9))	('increased', 'PosReg', (16, 25))	('docetaxel', 'Chemical', 'MESH:D000077143', (74, 83))	('inhibiting', 'NegReg', (114, 124))	('cisplatin', 'Chemical', 'MESH:D002945', (60, 69))	('PTOV1', 'Gene', '53635', (10, 15))	('increasing', 'PosReg', (87, 97))	('PTOV1', 'Gene', (10, 15))	('sensitivity', 'MPA', (26, 37))
420514	31387622	Our study verified that depleting PTOV1 attenuated cancer stem cell traits through impairing DKK1/beta-catenin signaling to enhance chemosensitivity of NSCLC cells.	('impairing', 'NegReg', (83, 92))	('depleting', 'Var', (24, 33))	('chemosensitivity of', 'CPA', (132, 151))	('NSCLC', 'Phenotype', 'HP:0030358', (152, 157))	('enhance', 'PosReg', (124, 131))	('NSCLC', 'Disease', (152, 157))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('NSCLC', 'Disease', 'MESH:D002289', (152, 157))	('PTOV1', 'Gene', '53635', (34, 39))	('DKK1', 'Gene', '22943', (93, 97))	('beta-catenin', 'Gene', (98, 110))	('DKK1', 'Gene', (93, 97))	('PTOV1', 'Gene', (34, 39))	('attenuated', 'NegReg', (40, 50))	('cancer', 'Disease', (51, 57))	('beta-catenin', 'Gene', '1499', (98, 110))
420532	31387622	Overexpression of PTOV1 has been found in multiple cancers such as prostate cancer, breast cancer, and liver cancer.	('prostate cancer', 'Disease', (67, 82))	('multiple cancers', 'Disease', 'MESH:D009369', (42, 58))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('Overexpression', 'Var', (0, 14))	('breast cancer', 'Phenotype', 'HP:0003002', (84, 97))	('found', 'Reg', (33, 38))	('breast cancer', 'Disease', 'MESH:D001943', (84, 97))	('breast cancer', 'Disease', (84, 97))	('multiple cancers', 'Disease', (42, 58))	('liver cancer', 'Disease', 'MESH:D006528', (103, 115))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('PTOV1', 'Gene', '53635', (18, 23))	('PTOV1', 'Gene', (18, 23))	('liver cancer', 'Phenotype', 'HP:0002896', (103, 115))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('prostate cancer', 'Disease', 'MESH:D011471', (67, 82))	('liver cancer', 'Disease', (103, 115))	('prostate cancer', 'Phenotype', 'HP:0012125', (67, 82))	('cancers', 'Phenotype', 'HP:0002664', (51, 58))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))
420538	31387622	Additionally, our results showed that depleting PTOV1 sensitizes lung cancer cell lines to chemotherapeutic drugs, cisplatin and docetaxel in vitro and in vivo, through attenuating cancer stem cell traits.	('attenuating', 'NegReg', (169, 180))	('PTOV1', 'Gene', (48, 53))	('lung cancer', 'Disease', 'MESH:D008175', (65, 76))	('depleting', 'Var', (38, 47))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('cisplatin', 'Chemical', 'MESH:D002945', (115, 124))	('lung cancer', 'Disease', (65, 76))	('sensitizes', 'Reg', (54, 64))	('lung cancer', 'Phenotype', 'HP:0100526', (65, 76))	('docetaxel', 'Chemical', 'MESH:D000077143', (129, 138))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('cancer', 'Disease', (181, 187))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('PTOV1', 'Gene', '53635', (48, 53))
420558	31387622	The primary antibodies against PTOV1 (SAB1301047, Sigma), GAPDH (sc-365,062, Santa Cruz), beta-catenin (610,153, BD Biosciences), Caspase-3 (#9662), Cleaved-caspase-3 (#9661), Bcl-2 (#2876, Cell Signaling Technology), LaminB1 (YM3036, Immunoway) and DKK1 (21112-1-AP, Proteintech) were used.	('LaminB1', 'Gene', (218, 225))	('GAPDH', 'Gene', '2597', (58, 63))	('PTOV1', 'Gene', '53635', (31, 36))	('GAPDH', 'Gene', (58, 63))	('DKK1', 'Gene', '22943', (250, 254))	('DKK1', 'Gene', (250, 254))	('Bcl-2', 'Gene', (176, 181))	('PTOV1', 'Gene', (31, 36))	('Caspase-3', 'Gene', '836', (130, 139))	('Bcl-2', 'Gene', '596', (176, 181))	('beta-catenin', 'Gene', (90, 102))	('LaminB1', 'Gene', '4001', (218, 225))	('caspase-3', 'Gene', (157, 166))	('beta-catenin', 'Gene', '1499', (90, 102))	('caspase-3', 'Gene', '836', (157, 166))	('YM3036', 'Var', (227, 233))	('Caspase-3', 'Gene', (130, 139))
420572	31387622	The proportion of tumor cells was graded as follows: 0 (no positive tumor cells), 1 (< 10% positive tumor cells), 2 (10-50% positive tumor cells), 3 (50-75% positive tumor cells), and 4 (> 75% positive tumor cells).	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('tumor', 'Disease', (100, 105))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('tumor', 'Disease', (68, 73))	('tumor', 'Disease', (202, 207))	('tumor', 'Disease', (18, 23))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('50-75', 'Var', (150, 155))	('tumor', 'Disease', (166, 171))	('tumor', 'Disease', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('10-50', 'Var', (117, 122))
420591	31387622	Kaplan-Meier survival analyses showed that NSCLC patients with high PTOV1 had a shorter overall survival time than the ones with low PTOV1 in both all patients and the subgroup received chemotherapy (Fig.	('PTOV1', 'Gene', '53635', (133, 138))	('overall survival', 'MPA', (88, 104))	('patients', 'Species', '9606', (151, 159))	('NSCLC', 'Phenotype', 'HP:0030358', (43, 48))	('PTOV1', 'Gene', (133, 138))	('shorter', 'NegReg', (80, 87))	('high', 'Var', (63, 67))	('patients', 'Species', '9606', (49, 57))	('NSCLC', 'Disease', (43, 48))	('PTOV1', 'Gene', '53635', (68, 73))	('PTOV1', 'Gene', (68, 73))	('NSCLC', 'Disease', 'MESH:D002289', (43, 48))
420594	31387622	Additionally, PTOV1 high expression also associated with poor first progression survival time of LUAD patients from the Kaplan-Meier Plotter database (Additional file 2: Figure S1C).	('poor', 'NegReg', (57, 61))	('patients', 'Species', '9606', (102, 110))	('LUAD', 'Phenotype', 'HP:0030078', (97, 101))	('high expression', 'Var', (20, 35))	('first progression survival time', 'CPA', (62, 93))	('PTOV1', 'Gene', '53635', (14, 19))	('PTOV1', 'Gene', (14, 19))
420596	31387622	As high expression of PTOV1 predicting poor prognosis in NSCLC and the reported oncogenic roles of PTOV1 in types of cancer, we presumed that depletion of PTOV1 might benefit NSCLC treatment.	('benefit', 'PosReg', (167, 174))	('NSCLC', 'Disease', 'MESH:D002289', (175, 180))	('NSCLC', 'Disease', (57, 62))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('PTOV1', 'Gene', (155, 160))	('NSCLC', 'Phenotype', 'HP:0030358', (57, 62))	('PTOV1', 'Gene', '53635', (22, 27))	('NSCLC', 'Phenotype', 'HP:0030358', (175, 180))	('PTOV1', 'Gene', (22, 27))	('PTOV1', 'Gene', '53635', (99, 104))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('PTOV1', 'Gene', (99, 104))	('expression', 'MPA', (8, 18))	('depletion', 'Var', (142, 151))	('cancer', 'Disease', (117, 123))	('NSCLC', 'Disease', (175, 180))	('PTOV1', 'Gene', '53635', (155, 160))	('NSCLC', 'Disease', 'MESH:D002289', (57, 62))
420604	31387622	These data indicated that inhibiting the expression of PTOV1 increases chemosensitivities of NSCLC cells.	('chemosensitivities', 'MPA', (71, 89))	('PTOV1', 'Gene', (55, 60))	('NSCLC', 'Disease', (93, 98))	('expression', 'MPA', (41, 51))	('NSCLC', 'Disease', 'MESH:D002289', (93, 98))	('increases', 'PosReg', (61, 70))	('NSCLC', 'Phenotype', 'HP:0030358', (93, 98))	('inhibiting', 'Var', (26, 36))	('PTOV1', 'Gene', '53635', (55, 60))
420606	31387622	Depletion of PTOV1 slowed down the closure of a "wound" scratched into a confluent epithelial monolayer (Fig.	('slowed down', 'NegReg', (19, 30))	('closure of a "wound" scratched', 'CPA', (35, 65))	('Depletion', 'Var', (0, 9))	('PTOV1', 'Gene', '53635', (13, 18))	('PTOV1', 'Gene', (13, 18))
420607	31387622	Trans-well assay showed that both the migratory and invasive abilities of H460 and Calu3 cells with silenced PTOV1 expression was significantly reduced, as there were less cells migrated (Additional file 3: Figure S2A and B) or invaded (Fig.	('reduced', 'NegReg', (144, 151))	('cells migrated', 'CPA', (172, 186))	('silenced', 'Var', (100, 108))	('less', 'NegReg', (167, 171))	('migratory', 'CPA', (38, 47))	('invaded', 'CPA', (228, 235))	('PTOV1', 'Gene', '53635', (109, 114))	('H460', 'CellLine', 'CVCL:0459', (74, 78))	('PTOV1', 'Gene', (109, 114))	('invasive abilities', 'CPA', (52, 70))	('expression', 'Var', (115, 125))
420610	31387622	Flow cytometry assay revealed that there were much more Annexin V positive cells, indicating apoptotic cells, in PTOV1 knockout cells after drug treatment (Fig.	('Annexin V', 'Gene', '308', (56, 65))	('knockout', 'Var', (119, 127))	('PTOV1', 'Gene', '53635', (113, 118))	('Annexin V', 'Gene', (56, 65))	('PTOV1', 'Gene', (113, 118))
420613	31387622	These findings proved that depletion of PTOV1 promoted chemotherapy-induced cell apoptosis.	('promoted', 'PosReg', (46, 54))	('chemotherapy-induced cell apoptosis', 'CPA', (55, 90))	('PTOV1', 'Gene', '53635', (40, 45))	('PTOV1', 'Gene', (40, 45))	('depletion', 'Var', (27, 36))
420614	31387622	Additionally, overexpressing PTOV1 in lung bronchus epithelial cell line BEAS-2B decreased the percentage of apoptotic cells induced by cisplatin and docetaxel analyzed by Annexin V/PI staining, which indicted decreased chemosensitivity of BEAS-2B/PTOV1 cells (Additional file 5: Figure S4A-C).	('decreased', 'NegReg', (81, 90))	('Annexin V', 'Gene', '308', (172, 181))	('PTOV1', 'Gene', '53635', (29, 34))	('docetaxel', 'Chemical', 'MESH:D000077143', (150, 159))	('PTOV1', 'Gene', (29, 34))	('decreased', 'NegReg', (210, 219))	('Annexin V', 'Gene', (172, 181))	('BEAS-2B', 'CellLine', 'CVCL:0168', (240, 247))	('BEAS-2B', 'CellLine', 'CVCL:0168', (73, 80))	('cisplatin', 'Chemical', 'MESH:D002945', (136, 145))	('BEAS-2B/PTOV1', 'CellLine', 'CVCL:0168', (240, 253))	('PTOV1', 'Gene', '53635', (248, 253))	('overexpressing', 'Var', (14, 28))	('PTOV1', 'Gene', (248, 253))
420620	31387622	Here we found that high PTOV1 level correlated with poor survival of NSCLC patients who received chemotherapy (Fig.	('high', 'Var', (19, 23))	('NSCLC', 'Disease', (69, 74))	('patients', 'Species', '9606', (75, 83))	('NSCLC', 'Disease', 'MESH:D002289', (69, 74))	('survival', 'MPA', (57, 65))	('PTOV1', 'Gene', '53635', (24, 29))	('NSCLC', 'Phenotype', 'HP:0030358', (69, 74))	('PTOV1', 'Gene', (24, 29))	('poor', 'NegReg', (52, 56))
420626	31387622	Tumor sphere formation assays showed that depleting PTOV1 significantly reduced the size and number of spheres than that formed by the vector cells (Fig.	('reduced', 'NegReg', (72, 79))	('PTOV1', 'Gene', (52, 57))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('depleting', 'Var', (42, 51))	('PTOV1', 'Gene', '53635', (52, 57))
420627	31387622	Flow cytometry analysis of the CSCs marker CD133 showed that silencing PTOV1 decreased CD133+ cell populations comparing to the vector control (Fig.	('CD133', 'Gene', (87, 92))	('CD133', 'Gene', '8842', (87, 92))	('PTOV1', 'Gene', '53635', (71, 76))	('silencing', 'Var', (61, 70))	('CD133', 'Gene', (43, 48))	('PTOV1', 'Gene', (71, 76))	('CD133', 'Gene', '8842', (43, 48))	('decreased', 'NegReg', (77, 86))
420629	31387622	Moreover, the mRNA expression levels of pluripotency factors, including SOX2, ABCG2, NANOG and OCT4, were also dramatically decreased in PTOV1 knockout cells (Fig.	('pluripotency factors', 'MPA', (40, 60))	('SOX2', 'Gene', '6657', (72, 76))	('NANOG', 'Gene', '79923', (85, 90))	('SOX2', 'Gene', (72, 76))	('NANOG', 'Gene', (85, 90))	('decreased', 'NegReg', (124, 133))	('ABCG2', 'Gene', (78, 83))	('knockout', 'Var', (143, 151))	('mRNA expression levels', 'MPA', (14, 36))	('OCT4', 'Gene', '5460', (95, 99))	('PTOV1', 'Gene', '53635', (137, 142))	('OCT4', 'Gene', (95, 99))	('PTOV1', 'Gene', (137, 142))	('ABCG2', 'Gene', '9429', (78, 83))
420637	31387622	Immunofluorescence staining and nuclear protein extraction showed that depleting PTOV1 decreased nuclear localization of beta-catenin protein (Fig.	('decreased', 'NegReg', (87, 96))	('beta-catenin', 'Gene', (121, 133))	('PTOV1', 'Gene', '53635', (81, 86))	('beta-catenin', 'Gene', '1499', (121, 133))	('PTOV1', 'Gene', (81, 86))	('nuclear localization of', 'MPA', (97, 120))	('depleting', 'Var', (71, 80))
420638	31387622	The expression of LEF1, AXIN2 and MMP9, the putative downstream genes of beta-catenin, were also inhibited after silencing PTOV1 expression (Fig.	('PTOV1', 'Gene', (123, 128))	('MMP9', 'Gene', '4318', (34, 38))	('MMP9', 'Gene', (34, 38))	('beta-catenin', 'Gene', (73, 85))	('expression', 'MPA', (129, 139))	('AXIN2', 'Gene', (24, 29))	('AXIN2', 'Gene', '8313', (24, 29))	('expression', 'MPA', (4, 14))	('LEF1', 'Gene', '51176', (18, 22))	('beta-catenin', 'Gene', '1499', (73, 85))	('PTOV1', 'Gene', '53635', (123, 128))	('inhibited', 'NegReg', (97, 106))	('LEF1', 'Gene', (18, 22))	('silencing', 'Var', (113, 122))
420639	31387622	These data proved that depleting PTOV1 impaired beta-catenin.	('beta-catenin', 'Gene', (48, 60))	('PTOV1', 'Gene', '53635', (33, 38))	('impaired', 'NegReg', (39, 47))	('beta-catenin', 'Gene', '1499', (48, 60))	('PTOV1', 'Gene', (33, 38))	('depleting', 'Var', (23, 32))
420645	31387622	6f and Additional file 7: Figure S6D), which proved that inhibiting DKK1 restored stemness of PTOV1-depleted cells.	('DKK1', 'Gene', '22943', (68, 72))	('DKK1', 'Gene', (68, 72))	('PTOV1', 'Gene', '53635', (94, 99))	('stemness', 'CPA', (82, 90))	('PTOV1', 'Gene', (94, 99))	('restored', 'PosReg', (73, 81))	('inhibiting', 'Var', (57, 67))
420646	31387622	Overall, we conclude that depleting PTOV1 upregulates DKK1, which further leads to impaired beta-catenin signaling and stemness of NSCLC cells.	('DKK1', 'Gene', '22943', (54, 58))	('DKK1', 'Gene', (54, 58))	('NSCLC', 'Disease', (131, 136))	('PTOV1', 'Gene', '53635', (36, 41))	('NSCLC', 'Disease', 'MESH:D002289', (131, 136))	('PTOV1', 'Gene', (36, 41))	('beta-catenin', 'Gene', (92, 104))	('impaired', 'NegReg', (83, 91))	('beta-catenin', 'Gene', '1499', (92, 104))	('NSCLC', 'Phenotype', 'HP:0030358', (131, 136))	('depleting', 'Var', (26, 35))	('upregulates', 'PosReg', (42, 53))
420647	31387622	These results suggested that depleting PTOV1 attenuated stem cell-like properties of NSCLC cells by inhibiting beta-catenin signaling activation.	('NSCLC', 'Disease', (85, 90))	('NSCLC', 'Disease', 'MESH:D002289', (85, 90))	('PTOV1', 'Gene', '53635', (39, 44))	('beta-catenin', 'Gene', (111, 123))	('attenuated', 'NegReg', (45, 55))	('NSCLC', 'Phenotype', 'HP:0030358', (85, 90))	('inhibiting', 'NegReg', (100, 110))	('PTOV1', 'Gene', (39, 44))	('beta-catenin', 'Gene', '1499', (111, 123))	('depleting', 'Var', (29, 38))
420649	31387622	Depleting PTOV1 only slightly inhibited tumor growth as indicated by the tumor volume and weight when receiving no treatment (Fig.	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('Depleting', 'Var', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('inhibited', 'NegReg', (30, 39))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Disease', (73, 78))	('PTOV1', 'Gene', '53635', (10, 15))	('tumor', 'Disease', (40, 45))	('PTOV1', 'Gene', (10, 15))
420650	31387622	However, when treated with docetaxel, depleting PTOV1 significantly reduced tumor growth compared with the vector group (Fig.	('PTOV1', 'Gene', (48, 53))	('depleting', 'Var', (38, 47))	('docetaxel', 'Chemical', 'MESH:D000077143', (27, 36))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('reduced', 'NegReg', (68, 75))	('PTOV1', 'Gene', '53635', (48, 53))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
420651	31387622	Furthermore, IHC staining showed that depleting PTOV1 significantly repressed expression of Ki-67, inhibited of beta-catenin nuclear localization and increased expression of cleaved caspase-3 (Fig.	('PTOV1', 'Gene', (48, 53))	('expression', 'MPA', (160, 170))	('caspase-3', 'Gene', (182, 191))	('expression', 'MPA', (78, 88))	('depleting', 'Var', (38, 47))	('PTOV1', 'Gene', '53635', (48, 53))	('inhibited', 'NegReg', (99, 108))	('caspase-3', 'Gene', '836', (182, 191))	('Ki-67', 'Gene', (92, 97))	('beta-catenin', 'Gene', (112, 124))	('increased', 'PosReg', (150, 159))	('repressed', 'NegReg', (68, 77))	('beta-catenin', 'Gene', '1499', (112, 124))
420652	31387622	Taken together, these results indicated that depleting PTOV1 inhibited cell proliferation, promoted cell apoptosis and sensitized NSCLC to chemotherapy in vivo.	('NSCLC', 'Disease', 'MESH:D002289', (130, 135))	('promoted', 'PosReg', (91, 99))	('PTOV1', 'Gene', (55, 60))	('inhibited', 'NegReg', (61, 70))	('sensitized', 'NegReg', (119, 129))	('NSCLC', 'Phenotype', 'HP:0030358', (130, 135))	('depleting', 'Var', (45, 54))	('cell apoptosis', 'CPA', (100, 114))	('NSCLC', 'Disease', (130, 135))	('cell proliferation', 'CPA', (71, 89))	('PTOV1', 'Gene', '53635', (55, 60))
420654	31387622	Later, it was found that high levels of PTOV1 correlated with poor prognosis of prostate cancer, breast cancer, urothelial carcinoma and so on.	('high levels', 'Var', (25, 36))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('prostate cancer', 'Disease', 'MESH:D011471', (80, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('correlated', 'Reg', (46, 56))	('prostate cancer', 'Phenotype', 'HP:0012125', (80, 95))	('urothelial carcinoma', 'Disease', (112, 132))	('breast cancer', 'Disease', 'MESH:D001943', (97, 110))	('PTOV1', 'Gene', '53635', (40, 45))	('breast cancer', 'Phenotype', 'HP:0003002', (97, 110))	('PTOV1', 'Gene', (40, 45))	('breast cancer', 'Disease', (97, 110))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('prostate cancer', 'Disease', (80, 95))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (112, 132))
420662	31387622	reported that transduction of PTOV1 in Du145 and PC3 cells significantly increased cell survival after docetaxel exposure and induced docetaxel-resistance genes expression.	('increased', 'PosReg', (73, 82))	('induced', 'PosReg', (126, 133))	('docetaxel', 'Chemical', 'MESH:D000077143', (103, 112))	('cell survival', 'CPA', (83, 96))	('docetaxel-resistance genes expression', 'MPA', (134, 171))	('docetaxel', 'Chemical', 'MESH:D000077143', (134, 143))	('transduction', 'Var', (14, 26))	('PTOV1', 'Gene', '53635', (30, 35))	('PC3', 'CellLine', 'CVCL:0035', (49, 52))	('PTOV1', 'Gene', (30, 35))
420666	31387622	By analyzing the subgroup NSCLC patients who received chemotherapy, we found that high PTOV1 also associated with short survival time.	('PTOV1', 'Gene', (87, 92))	('patients', 'Species', '9606', (32, 40))	('high', 'Var', (82, 86))	('NSCLC', 'Phenotype', 'HP:0030358', (26, 31))	('PTOV1', 'Gene', '53635', (87, 92))	('short survival time', 'CPA', (114, 133))	('NSCLC', 'Disease', (26, 31))	('associated', 'Reg', (98, 108))	('NSCLC', 'Disease', 'MESH:D002289', (26, 31))
420667	31387622	Surprisingly, the hazard ratio of high PTOV1 in NSCLC patients received chemotherapy is much higher than that in the pooled all patients, which indicated that PTOV1 could not only be a prognosis marker for NSCLC patients but also be better in predicting outcome to chemotherapy.	('higher', 'PosReg', (93, 99))	('PTOV1', 'Gene', '53635', (159, 164))	('NSCLC', 'Disease', (48, 53))	('PTOV1', 'Gene', (159, 164))	('PTOV1', 'Gene', '53635', (39, 44))	('NSCLC', 'Disease', (206, 211))	('NSCLC', 'Disease', 'MESH:D002289', (48, 53))	('patients', 'Species', '9606', (54, 62))	('patients', 'Species', '9606', (212, 220))	('NSCLC', 'Disease', 'MESH:D002289', (206, 211))	('high', 'Var', (34, 38))	('PTOV1', 'Gene', (39, 44))	('NSCLC', 'Phenotype', 'HP:0030358', (206, 211))	('NSCLC', 'Phenotype', 'HP:0030358', (48, 53))	('patients', 'Species', '9606', (128, 136))
420669	31387622	Together, these findings suggest that PTOV1 regulates chemosensitivity in malignant tumors and depleting PTOV1 chemosensitizes NSCLC cells.	('NSCLC', 'Disease', (127, 132))	('depleting', 'Var', (95, 104))	('chemosensitivity', 'MPA', (54, 70))	('malignant tumors', 'Disease', (74, 90))	('NSCLC', 'Disease', 'MESH:D002289', (127, 132))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('PTOV1', 'Gene', '53635', (105, 110))	('malignant tumors', 'Disease', 'MESH:D018198', (74, 90))	('regulates', 'Reg', (44, 53))	('PTOV1', 'Gene', (105, 110))	('NSCLC', 'Phenotype', 'HP:0030358', (127, 132))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('PTOV1', 'Gene', '53635', (38, 43))	('PTOV1', 'Gene', (38, 43))
420671	31387622	In prostate cancer cells, transduction of PTOV1 induced prostatospheres formation and self-renewal genes expression.	('transduction', 'Var', (26, 38))	('prostate cancer', 'Phenotype', 'HP:0012125', (3, 18))	('PTOV1', 'Gene', '53635', (42, 47))	('prostate cancer', 'Disease', 'MESH:D011471', (3, 18))	('prostate cancer', 'Disease', (3, 18))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('self-renewal genes', 'CPA', (86, 104))	('expression', 'MPA', (105, 115))	('induced', 'Reg', (48, 55))	('PTOV1', 'Gene', (42, 47))	('prostatospheres formation', 'CPA', (56, 81))
420674	31387622	Depleting PTOV1 impaired tumor sphere formation, reduced CD133+ cell population and decreased the expression of pluripotency factors of NSCLC cells.	('NSCLC', 'Disease', 'MESH:D002289', (136, 141))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('impaired tumor', 'Disease', 'MESH:D015417', (16, 30))	('Depleting', 'Var', (0, 9))	('reduced', 'NegReg', (49, 56))	('CD133', 'Gene', '8842', (57, 62))	('impaired tumor', 'Disease', (16, 30))	('NSCLC', 'Phenotype', 'HP:0030358', (136, 141))	('CD133', 'Gene', (57, 62))	('PTOV1', 'Gene', (10, 15))	('PTOV1', 'Gene', '53635', (10, 15))	('decreased', 'NegReg', (84, 93))	('NSCLC', 'Disease', (136, 141))	('expression of pluripotency factors', 'MPA', (98, 132))
420679	31387622	In conclusion, this study revealed PTOV1 as a poor prognosis factor for NSCLC patients, and targeting PTOV1 can be a strategy to increase chemosensitivity in NSCLC.	('NSCLC', 'Disease', (158, 163))	('PTOV1', 'Gene', (35, 40))	('targeting', 'Var', (92, 101))	('NSCLC', 'Disease', 'MESH:D002289', (158, 163))	('NSCLC', 'Disease', (72, 77))	('patients', 'Species', '9606', (78, 86))	('NSCLC', 'Disease', 'MESH:D002289', (72, 77))	('PTOV1', 'Gene', '53635', (102, 107))	('NSCLC', 'Phenotype', 'HP:0030358', (158, 163))	('PTOV1', 'Gene', (102, 107))	('NSCLC', 'Phenotype', 'HP:0030358', (72, 77))	('PTOV1', 'Gene', '53635', (35, 40))
420681	31387622	Our study provides compelling evidence that depleting PTOV1 can increase cell apoptosis, inhibit invasion, migration, stemness and tumorigenicity and chemosensitize NSCLC cells.	('cell apoptosis', 'CPA', (73, 87))	('depleting', 'Var', (44, 53))	('migration', 'CPA', (107, 116))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('NSCLC', 'Disease', 'MESH:D002289', (165, 170))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('PTOV1', 'Gene', '53635', (54, 59))	('tumor', 'Disease', (131, 136))	('increase', 'PosReg', (64, 72))	('stemness', 'CPA', (118, 126))	('PTOV1', 'Gene', (54, 59))	('inhibit', 'NegReg', (89, 96))	('NSCLC', 'Phenotype', 'HP:0030358', (165, 170))	('invasion', 'CPA', (97, 105))	('NSCLC', 'Disease', (165, 170))
420697	31360238	The cancer hallmark includes tumor-promoting inflammation, enabling replicative immortality, avoiding immune destruction, evading growth suppressors, sustaining proliferative signaling, deregulating cellular energetics, resisting cell death, genome instability and mutation, inducing angiogenesis, and activating invasion and metastasis.	('genome instability', 'CPA', (242, 260))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('activating', 'PosReg', (302, 312))	('replicative immortality', 'CPA', (68, 91))	('mutation', 'Var', (265, 273))	('inflammation', 'Disease', (45, 57))	('proliferative signaling', 'MPA', (161, 184))	('enabling', 'PosReg', (59, 67))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('cancer', 'Disease', 'MESH:D009369', (4, 10))	('resisting', 'NegReg', (220, 229))	('angiogenesis', 'CPA', (284, 296))	('cell death', 'CPA', (230, 240))	('cellular energetics', 'MPA', (199, 218))	('inducing', 'PosReg', (275, 283))	('sustaining', 'PosReg', (150, 160))	('tumor', 'Disease', (29, 34))	('deregulating', 'NegReg', (186, 198))	('inflammation', 'Disease', 'MESH:D007249', (45, 57))	('cancer', 'Disease', (4, 10))
420702	31360238	Disruption of the balance between the activities of MMPs and TIMPs during carcinogenesis may affect invasion and metastasis and may worsen patient outcomes.	('MMPs', 'Gene', '4312;4313;17390;4314;4316;4318;17395;81687;4323;4325;4327;10893;10893;10893', (52, 56))	('worsen', 'NegReg', (132, 138))	('carcinogenesis', 'Disease', 'MESH:D063646', (74, 88))	('affect', 'Reg', (93, 99))	('TIMP', 'Gene', '7076', (61, 65))	('carcinogenesis', 'Disease', (74, 88))	('MMPs', 'Gene', (52, 56))	('TIMP', 'Gene', (61, 65))	('patient outcomes', 'CPA', (139, 155))	('patient', 'Species', '9606', (139, 146))	('Disruption', 'Var', (0, 10))
420704	31360238	Knockout of the TIMP-3 gene in mice resulted in increased MMP, a disintegrin and MMPs with thrombospondin motifs (ADAMTS) activity, and cartilage degradation, suggesting that reduced TIMP-3 levels may cause osteoarthritis.	('cartilage degradation', 'Disease', 'MESH:D002357', (136, 157))	('increased', 'PosReg', (48, 57))	('cause', 'Reg', (201, 206))	('reduced', 'Var', (175, 182))	('reduced TIMP-3 levels', 'Phenotype', 'HP:0031037', (175, 196))	('osteoarthritis', 'Phenotype', 'HP:0002758', (207, 221))	('MMPs', 'Gene', (81, 85))	('MMP', 'CPA', (58, 61))	('osteoarthritis', 'Disease', (207, 221))	('mice', 'Species', '10090', (31, 35))	('Knockout', 'Var', (0, 8))	('osteoarthritis', 'Disease', 'MESH:D010003', (207, 221))	('MMPs', 'Gene', '4312;4313;17390;4314;4316;4318;17395;81687;4323;4325;4327;10893;10893;10893', (81, 85))	('cartilage degradation', 'Disease', (136, 157))	('TIMP-3', 'Gene', (16, 22))
420705	31360238	In addition, the absence of TIMP-3 leads to poor cardiac remodeling and has been associated with myocardial infarction or hypertension.	('hypertension', 'Disease', 'MESH:D006973', (122, 134))	('TIMP-3', 'Gene', (28, 34))	('hypertension', 'Disease', (122, 134))	('absence', 'Var', (17, 24))	('myocardial infarction', 'Disease', (97, 118))	('hypertension', 'Phenotype', 'HP:0000822', (122, 134))	('myocardial infarction', 'Disease', 'MESH:D009203', (97, 118))	('cardiac remodeling', 'Disease', (49, 67))	('cardiac remodeling', 'Disease', 'MESH:D020257', (49, 67))	('associated', 'Reg', (81, 91))	('myocardial infarction', 'Phenotype', 'HP:0001658', (97, 118))
420709	31360238	Moreover, TIMP-3 can inhibit cancer cell migration, invasion, and metastasis in vitro and in vivo.	('cancer', 'Disease', (29, 35))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('inhibit', 'NegReg', (21, 28))	('invasion', 'CPA', (52, 60))	('cancer', 'Disease', 'MESH:D009369', (29, 35))	('metastasis', 'CPA', (66, 76))	('TIMP-3', 'Var', (10, 16))
420710	31360238	Clinical studies have reported reduced TIMP-3 expression in cases of several cancer types compared with normal controls; the loss of TIMP-3 may lead to poor outcomes, including large tumor size, high tumor stage, and metastasis.	('TIMP-3', 'Gene', (133, 139))	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('loss', 'Var', (125, 129))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('lead', 'Reg', (144, 148))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('tumor', 'Disease', (200, 205))	('tumor', 'Disease', (183, 188))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('metastasis', 'CPA', (217, 227))
420730	31360238	The enhancer of zeste homolog 2 (EZH2), which has histone methyltransferase activity, is known to reduced TIMP-3 expression by catalyzing H3K27me3.	('expression', 'MPA', (113, 123))	('TIMP-3', 'Gene', (106, 112))	('enhancer of zeste homolog 2', 'Gene', (4, 31))	('EZH2', 'Gene', '2146', (33, 37))	('reduced', 'NegReg', (98, 105))	('enhancer of zeste homolog 2', 'Gene', '2146', (4, 31))	('EZH2', 'Gene', (33, 37))	('H3K27me3', 'Var', (138, 146))
420737	31360238	Knockout of TIMP-3 in cell promoted activation of pro-MMP-2 mediated by MT1-MMP.	('MT1-MMP', 'Gene', (72, 79))	('activation', 'PosReg', (36, 46))	('MT1-MMP', 'Gene', '4323', (72, 79))	('pro-MMP-2', 'Protein', (50, 59))	('Knockout', 'Var', (0, 8))	('TIMP-3', 'Gene', (12, 18))
420739	31360238	For instance, the ECM protein-degrading activity of ADAM12 can only be blocked by TIMP-3, but not by TIMP-1, TIMP-2, and TIMP-4.	('ADAM12', 'Gene', '8038', (52, 58))	('TIMP-2', 'Gene', (109, 115))	('ADAM12', 'Gene', (52, 58))	('TIMP-4', 'Gene', '7079', (121, 127))	('TIMP-4', 'Gene', (121, 127))	('TIMP-1', 'Gene', (101, 107))	('TIMP-2', 'Gene', '7077', (109, 115))	('TIMP-1', 'Gene', '7076', (101, 107))	('TIMP-3', 'Var', (82, 88))	('ECM protein-degrading activity', 'MPA', (18, 48))
420742	31360238	For example, high TIMP-1 expression has been reported to be associated with poor prognosis in most cancers.	('TIMP-1', 'Gene', (18, 24))	('TIMP-1', 'Gene', '7076', (18, 24))	('high', 'Var', (13, 17))	('expression', 'MPA', (25, 35))	('cancers', 'Disease', 'MESH:D009369', (99, 106))	('cancers', 'Phenotype', 'HP:0002664', (99, 106))	('cancers', 'Disease', (99, 106))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
420744	31360238	Clinical studies have shown that a high level of TIMP-1 is associated with a shortened relapse-free and cancer-specific survival in endometrial carcinoma and poor overall survival in laryngeal squamous cell carcinoma.	('laryngeal squamous cell carcinoma', 'Disease', 'MESH:D002294', (183, 216))	('high level', 'Var', (35, 45))	('TIMP-1', 'Gene', (49, 55))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('TIMP-1', 'Gene', '7076', (49, 55))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (193, 216))	('relapse-free', 'CPA', (87, 99))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (132, 153))	('carcinoma', 'Phenotype', 'HP:0030731', (207, 216))	('endometrial carcinoma', 'Disease', (132, 153))	('laryngeal squamous cell carcinoma', 'Disease', (183, 216))	('poor', 'NegReg', (158, 162))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (132, 153))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('shortened', 'NegReg', (77, 86))
420746	31360238	Overexpression of TIMP-2 has been reported to increase proliferation of choriocarcinoma cells.	('increase', 'PosReg', (46, 54))	('choriocarcinoma', 'Disease', (72, 87))	('choriocarcinoma', 'Phenotype', 'HP:0100768', (72, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('Overexpression', 'Var', (0, 14))	('TIMP-2', 'Gene', (18, 24))	('choriocarcinoma', 'Disease', 'MESH:D002822', (72, 87))	('TIMP-2', 'Gene', '7077', (18, 24))
420751	31360238	In an in vitro study, TIMP-3 expression was observed to induce cancer cell apoptosis in cervical cancer, fibrosarcoma, and breast cancer cell lines.	('cervical cancer', 'Disease', (88, 103))	('cervical cancer', 'Disease', 'MESH:D002583', (88, 103))	('fibrosarcoma', 'Disease', 'MESH:D005354', (105, 117))	('fibrosarcoma', 'Disease', (105, 117))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('cancer', 'Disease', (97, 103))	('TIMP-3 expression', 'Var', (22, 39))	('induce', 'PosReg', (56, 62))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('cancer', 'Disease', (63, 69))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('breast cancer', 'Phenotype', 'HP:0003002', (123, 136))	('cancer', 'Disease', 'MESH:D009369', (97, 103))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (105, 117))	('breast cancer', 'Disease', 'MESH:D001943', (123, 136))	('cancer', 'Disease', (130, 136))	('breast cancer', 'Disease', (123, 136))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('cancer', 'Disease', 'MESH:D009369', (63, 69))
420753	31360238	Moreover, TIMP-3 can inhibit the migration and invasiveness of cancer cells in vitro.	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('inhibit', 'NegReg', (21, 28))	('invasiveness of cancer', 'Disease', (47, 69))	('invasiveness of cancer', 'Disease', 'MESH:D009362', (47, 69))	('TIMP-3', 'Var', (10, 16))
420759	31360238	Polymorphisms of TIMP-3 have been reported in many cancers including adenocarcinoma, bladder cancer, breast cancer, hepatocellular carcinoma, oral cancer, and prostate cancer.	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (116, 140))	('breast cancer', 'Phenotype', 'HP:0003002', (101, 114))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('TIMP-3', 'Gene', (17, 23))	('reported', 'Reg', (34, 42))	('Polymorphisms', 'Var', (0, 13))	('prostate cancer', 'Disease', 'MESH:D011471', (159, 174))	('prostate cancer', 'Phenotype', 'HP:0012125', (159, 174))	('breast cancer', 'Disease', 'MESH:D001943', (101, 114))	('prostate cancer', 'Disease', (159, 174))	('adenocarcinoma', 'Disease', (69, 83))	('breast cancer', 'Disease', (101, 114))	('cancers', 'Disease', 'MESH:D009369', (51, 58))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (116, 140))	('bladder cancer', 'Disease', 'MESH:D001749', (85, 99))	('bladder cancer', 'Disease', (85, 99))	('adenocarcinoma', 'Disease', 'MESH:D000230', (69, 83))	('hepatocellular carcinoma', 'Disease', (116, 140))	('bladder cancer', 'Phenotype', 'HP:0009725', (85, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('oral cancer', 'Disease', 'MESH:D009062', (142, 153))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('cancers', 'Phenotype', 'HP:0002664', (51, 58))	('oral cancer', 'Disease', (142, 153))	('cancers', 'Disease', (51, 58))
420760	31360238	The TIMP-3 polymorphic rs9862 allele is associated with increased plasma levels of TIMP-3 and higher risk of oral cancer than with the wild-type allele.	('oral cancer', 'Disease', (109, 120))	('increased', 'PosReg', (56, 65))	('TIMP-3', 'Gene', (4, 10))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('rs9862', 'Mutation', 'rs9862', (23, 29))	('rs9862', 'Var', (23, 29))	('plasma levels of TIMP-3', 'MPA', (66, 89))	('oral cancer', 'Disease', 'MESH:D009062', (109, 120))
420761	31360238	In adenocarcinoma of the gastroesophageal junction, polymorphisms (rs130274, rs715572, rs1962223, and rs5754312) in TIMP-3 and polymorphism rs9862 in the TIMP-3 promoter are associated with survival.	('adenocarcinoma of the gastroesophageal junction', 'Disease', 'MESH:D008309', (3, 50))	('rs5754312', 'Mutation', 'rs5754312', (102, 111))	('associated with', 'Reg', (174, 189))	('rs715572', 'Var', (77, 85))	('TIMP-3', 'Gene', (154, 160))	('rs130274', 'Var', (67, 75))	('carcinoma', 'Phenotype', 'HP:0030731', (8, 17))	('rs130274', 'Mutation', 'rs130274', (67, 75))	('rs1962223', 'Mutation', 'rs1962223', (87, 96))	('rs1962223', 'Var', (87, 96))	('rs9862', 'Mutation', 'rs9862', (140, 146))	('TIMP-3', 'Gene', (116, 122))	('adenocarcinoma of the gastroesophageal junction', 'Disease', (3, 50))	('rs715572', 'Mutation', 'rs715572', (77, 85))	('rs5754312', 'Var', (102, 111))
420762	31360238	Moreover, rs8136803 (TT) is associated with decreased disease-free survival in breast cancer patients.	('breast cancer', 'Disease', 'MESH:D001943', (79, 92))	('rs8136803', 'Var', (10, 19))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('breast cancer', 'Disease', (79, 92))	('breast cancer', 'Phenotype', 'HP:0003002', (79, 92))	('rs8136803', 'Mutation', 'rs8136803', (10, 19))	('disease-free survival', 'CPA', (54, 75))	('patients', 'Species', '9606', (93, 101))	('decreased', 'NegReg', (44, 53))
420764	31360238	TIMP-3 methylation in the sp1 binding site and the TATA box of the promoter are associated with low expression of TIMP-3 protein in gastric cancer cell lines.	('gastric cancer', 'Disease', (132, 146))	('TIMP-3', 'Gene', (0, 6))	('gastric cancer', 'Disease', 'MESH:D013274', (132, 146))	('methylation', 'Var', (7, 18))	('expression', 'MPA', (100, 110))	('low', 'NegReg', (96, 99))	('gastric cancer', 'Phenotype', 'HP:0012126', (132, 146))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))
420765	31360238	DNA methyltransferases (DNMTs) are key enzymes causing gene methylation, and dysregulation of DNMTs has been reported in tumorigenesis.	('dysregulation', 'Var', (77, 90))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('N', 'Chemical', 'MESH:D009584', (95, 96))	('tumor', 'Disease', (121, 126))	('N', 'Chemical', 'MESH:D009584', (25, 26))	('reported', 'Reg', (109, 117))	('N', 'Chemical', 'MESH:D009584', (1, 2))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
420769	31360238	Loss of TIMP-3 expression can also be regulated by histone H3K27 methylation via upregulation of the EZH2 in non-small cell lung cancer (NSCLC).	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (109, 135))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('NSCLC', 'Disease', (137, 142))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (109, 135))	('NSCLC', 'Disease', 'MESH:D002289', (137, 142))	('histone H3K27', 'Protein', (51, 64))	('Loss', 'NegReg', (0, 4))	('upregulation', 'PosReg', (81, 93))	('EZH2', 'Gene', (101, 105))	('expression', 'MPA', (15, 25))	('methylation', 'Var', (65, 76))	('TIMP-3', 'Gene', (8, 14))	('non-small cell lung cancer', 'Disease', (109, 135))	('EZH2', 'Gene', '2146', (101, 105))	('NSCLC', 'Phenotype', 'HP:0030358', (137, 142))	('lung cancer', 'Phenotype', 'HP:0100526', (124, 135))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (113, 135))
420773	31360238	MiRNAs involved in the post-transcriptional regulation of TIMP-3.	('MiRNAs', 'Var', (0, 6))	('N', 'Chemical', 'MESH:D009584', (3, 4))	('TIMP-3', 'Gene', (58, 64))
420774	31360238	The mechanism of MicroRNA to suppress gene expression is by controlling mRNA stability and translation through base pairing to the 3' untranslated region (3'-UTR).	('N', 'Chemical', 'MESH:D009584', (23, 24))	('N', 'Chemical', 'MESH:D009584', (74, 75))	('translation', 'MPA', (91, 102))	('mRNA stability', 'MPA', (72, 86))	('gene expression', 'MPA', (38, 53))	('base', 'Var', (111, 115))
420785	31360238	Accumulating evidence indicates that lncRNAs play critical roles in tumorigenesis through various mechanisms such as transcriptional, post-transcriptional, and epigenetic regulation.	('tumor', 'Disease', (68, 73))	('epigenetic regulation', 'Var', (160, 181))	('N', 'Chemical', 'MESH:D009584', (41, 42))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))
420787	31360238	The lncRNA DANCR suppresses TIMP-3 expression by increasing the binding ability of EZH2 and H3K27me3 to the TIMP-3 promoter in prostate cancer.	('binding', 'Interaction', (64, 71))	('prostate cancer', 'Disease', 'MESH:D011471', (127, 142))	('DANCR', 'Gene', (11, 16))	('prostate cancer', 'Phenotype', 'HP:0012125', (127, 142))	('TIMP-3', 'Gene', (28, 34))	('EZH2', 'Gene', '2146', (83, 87))	('DANCR', 'Gene', '57291', (11, 16))	('H3K27me3', 'Var', (92, 100))	('prostate cancer', 'Disease', (127, 142))	('EZH2', 'Gene', (83, 87))	('suppresses', 'NegReg', (17, 27))	('N', 'Chemical', 'MESH:D009584', (13, 14))	('increasing', 'PosReg', (49, 59))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('N', 'Chemical', 'MESH:D009584', (8, 9))
420794	31360238	In addition, TIMP-3 can enhance the sensitivity of cancer cells to apoptosis by stabilizing the death receptor.	('stabilizing', 'MPA', (80, 91))	('death', 'Protein', (96, 101))	('enhance', 'PosReg', (24, 31))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('TIMP-3', 'Var', (13, 19))	('sensitivity', 'MPA', (36, 47))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))
420797	31360238	Notably, TIMP-3 can also promote death of nonadherent small-cell lung carcinoma cells even if the cells do not present cell surface death receptors or caspase-8.	('lung carcinoma', 'Disease', (65, 79))	('TIMP-3', 'Var', (9, 15))	('caspase-8', 'Gene', (151, 160))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('N', 'Chemical', 'MESH:D009584', (0, 1))	('death', 'CPA', (33, 38))	('caspase-8', 'Gene', '841', (151, 160))	('promote', 'PosReg', (25, 32))	('lung carcinoma', 'Disease', 'MESH:D008175', (65, 79))
420803	31360238	In leukemia cells, TIMP-3 can inhibit the proliferation and migration of human umbilical vein endothelial cells (HUVECs) and reduce VEGF-mediated MMP-2 and MMP-9 expression.	('MMP-9', 'Protein', (156, 161))	('VEGF', 'Gene', (132, 136))	('leukemia', 'Phenotype', 'HP:0001909', (3, 11))	('proliferation', 'CPA', (42, 55))	('leukemia', 'Disease', 'MESH:D007938', (3, 11))	('inhibit', 'NegReg', (30, 37))	('TIMP-3', 'Var', (19, 25))	('leukemia', 'Disease', (3, 11))	('human', 'Species', '9606', (73, 78))	('reduce', 'NegReg', (125, 131))	('expression', 'MPA', (162, 172))	('VEGF', 'Gene', '7422', (132, 136))
420806	31360238	suggested that TIMP-3 may induce apoptosis of endothelial cells by triggering a FAK/Paxillin cell survival pathway but not a caspase-dependent cell death pathway.	('triggering', 'Reg', (67, 77))	('apoptosis', 'CPA', (33, 42))	('FAK', 'Gene', (80, 83))	('Paxillin', 'Gene', (84, 92))	('FAK', 'Gene', '5747', (80, 83))	('TIMP-3', 'Var', (15, 21))	('Paxillin', 'Gene', '5829', (84, 92))	('induce', 'PosReg', (26, 32))
420808	31360238	In an in vivo study, TIMP-3 knockout in nude mice but not in the tumor showed enhanced growth of tumor and increased angiogenesis.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('TIMP-3', 'Gene', (21, 27))	('tumor', 'Disease', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('increased', 'PosReg', (107, 116))	('nude mice', 'Species', '10090', (40, 49))	('tumor', 'Disease', (97, 102))	('knockout', 'Var', (28, 36))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('angiogenesis', 'CPA', (117, 129))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('enhanced', 'PosReg', (78, 86))
420815	31360238	Inhibition of the invasive activity of melanoma cells is more pronounced in the case of TIMP-3 overexpression compared with TIMP-1 and TIMP-2 overexpression.	('TIMP-1', 'Gene', '7076', (124, 130))	('melanoma', 'Phenotype', 'HP:0002861', (39, 47))	('TIMP-1', 'Gene', (124, 130))	('melanoma', 'Disease', (39, 47))	('melanoma', 'Disease', 'MESH:D008545', (39, 47))	('TIMP-3', 'Gene', (88, 94))	('TIMP-2', 'Gene', (135, 141))	('overexpression', 'Var', (95, 109))	('TIMP-2', 'Gene', '7077', (135, 141))
420816	31360238	Loss of TIMP-3 promotes NSCLC cell invasion via TNF-mediated IL-6 production.	('NSCLC', 'Disease', (24, 29))	('TNF', 'Gene', (48, 51))	('NSCLC', 'Disease', 'MESH:D002289', (24, 29))	('TNF', 'Gene', '7124', (48, 51))	('IL-6', 'Gene', (61, 65))	('NSCLC', 'Phenotype', 'HP:0030358', (24, 29))	('TIMP-3', 'Gene', (8, 14))	('IL-6', 'Gene', '3569', (61, 65))	('Loss', 'Var', (0, 4))	('promotes', 'PosReg', (15, 23))
420818	31360238	In an animal study, melanoma and lymphoma cells in TIMP-3-/- mice were observed to have higher metastatic ability, metastasizing to multiple organs, and lung tissues from TIMP-3-/- mice showed higher MMP-2 and MMP-9 enzyme activity than did those from wide-type mice.	('higher', 'PosReg', (88, 94))	('mice', 'Species', '10090', (181, 185))	('mice', 'Species', '10090', (61, 65))	('lymphoma', 'Phenotype', 'HP:0002665', (33, 41))	('TIMP-3-/-', 'Var', (51, 60))	('activity', 'MPA', (223, 231))	('MMP-9 enzyme', 'Enzyme', (210, 222))	('mice', 'Species', '10090', (262, 266))	('metastatic ability', 'CPA', (95, 113))	('melanoma and lymphoma', 'Disease', 'MESH:D008545', (20, 41))	('metastasizing to multiple organs', 'CPA', (115, 147))	('melanoma', 'Phenotype', 'HP:0002861', (20, 28))	('TIMP-3-/-', 'Var', (171, 180))	('MMP-2', 'Enzyme', (200, 205))	('higher', 'PosReg', (193, 199))
420830	31360238	TIMP-3 polymorphism rs9862 has been associated with an increased risk of developing a tumor of size >T2 among betel quid chewers with oral cancer.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('oral cancer', 'Disease', (134, 145))	('TIMP-3', 'Gene', (0, 6))	('tumor', 'Disease', (86, 91))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('rs9862', 'Var', (20, 26))	('rs9862', 'Mutation', 'rs9862', (20, 26))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('oral cancer', 'Disease', 'MESH:D009062', (134, 145))
420831	31360238	A study revealed that TIMP-3 hypermethylation in patients with esophageal squamous cell carcinoma is associated with poorer prognosis for both disease-free and overall survival than that of patients without TIMP-3 methylation.	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (63, 97))	('patients', 'Species', '9606', (190, 198))	('poorer', 'NegReg', (117, 123))	('esophageal squamous cell carcinoma', 'Disease', (63, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (74, 97))	('hypermethylation', 'Var', (29, 45))	('patients', 'Species', '9606', (49, 57))	('TIMP-3', 'Gene', (22, 28))
420832	31360238	Patients with AML harboring methylation of TIMP-3 show higher frequency of adverse cytogenetic prognosis than those with a favorable or intermediate prognosis.	('AML', 'Phenotype', 'HP:0004808', (14, 17))	('AML', 'Disease', (14, 17))	('Patients', 'Species', '9606', (0, 8))	('TIMP-3', 'Gene', (43, 49))	('methylation', 'Var', (28, 39))	('AML', 'Disease', 'MESH:D015470', (14, 17))
420834	31360238	Methylation of the TIMP-3 promoter identified from body fluids has been reported to be a useful biomarker for predicting tumor size, differentiation, T stage, lymph node metastasis, distant metastasis, and clinical stage in patients with gastric cancer (Table 2).	('T stage', 'CPA', (150, 157))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('gastric cancer', 'Disease', (238, 252))	('lymph node metastasis', 'CPA', (159, 180))	('Methylation', 'Var', (0, 11))	('gastric cancer', 'Disease', 'MESH:D013274', (238, 252))	('tumor', 'Disease', (121, 126))	('gastric cancer', 'Phenotype', 'HP:0012126', (238, 252))	('distant metastasis', 'CPA', (182, 200))	('patients', 'Species', '9606', (224, 232))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))	('differentiation', 'CPA', (133, 148))	('TIMP-3', 'Gene', (19, 25))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
420837	31360238	In prostate cancer, adenovirus-mediated expression of TIMP-3 highly sensitizes prostate cancer cells to the chemotherapeutic drug paclitaxel (Taxol) and promotes synergistic enhancement in cell death.	('prostate cancer', 'Phenotype', 'HP:0012125', (3, 18))	('prostate cancer', 'Disease', 'MESH:D011471', (79, 94))	('expression', 'Var', (40, 50))	('prostate cancer', 'Phenotype', 'HP:0012125', (79, 94))	('prostate cancer', 'Disease', 'MESH:D011471', (3, 18))	('cell death', 'CPA', (189, 199))	('prostate cancer', 'Disease', (3, 18))	('enhancement', 'PosReg', (174, 185))	('paclitaxel', 'Chemical', 'MESH:D017239', (130, 140))	('sensitizes', 'Reg', (68, 78))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('Taxol', 'Chemical', 'MESH:D017239', (142, 147))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('prostate cancer', 'Disease', (79, 94))	('promotes', 'PosReg', (153, 161))	('TIMP-3', 'Gene', (54, 60))
420851	31360238	The synthetic peptide p700, which is derived from the N-terminal domain of TIMP-3, inhibits VEGF-family receptors, angiogenesis, and tumor growth.	('p700', 'Var', (22, 26))	('angiogenesis', 'CPA', (115, 127))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('N', 'Chemical', 'MESH:D009584', (54, 55))	('inhibits', 'NegReg', (83, 91))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('VEGF', 'Gene', (92, 96))	('tumor', 'Disease', (133, 138))	('TIMP-3', 'Gene', (75, 81))	('VEGF', 'Gene', '7422', (92, 96))
420855	31360238	In addition, they claimed that treatment with SGI-1027 facilitates re-expression of the tumor suppressor genes MLH1, P16, and TIMP-3 in cancer cell lines.	('SGI-1027', 'Var', (46, 54))	('MLH1', 'Gene', '17350', (111, 115))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('facilitates', 'PosReg', (55, 66))	('P16', 'Gene', (117, 120))	('P16', 'Gene', '12578', (117, 120))	('cancer', 'Disease', (136, 142))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor', 'Disease', (88, 93))	('MLH1', 'Gene', (111, 115))	('TIMP-3', 'Gene', (126, 132))	('re-expression', 'MPA', (67, 80))
420856	31360238	MPT0G013, a HDAC inhibitor, has been reported to induce TIMP-3 expression and further inhibit angiogenesis and tumor growth in vivo.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('DAC', 'Gene', '6468', (13, 16))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('TIMP-3', 'Gene', (56, 62))	('expression', 'MPA', (63, 73))	('tumor', 'Disease', (111, 116))	('induce', 'PosReg', (49, 55))	('inhibit', 'NegReg', (86, 93))	('DAC', 'Gene', (13, 16))	('MPT0G013', 'Var', (0, 8))
420861	31360238	Moreover, DNA hypomethylation may cause some autoimmune diseases such as systemic lupus erythematosus (SLE), and may also activate some cancer metastasis genes such as u-PA to accelerate cancer metastasis.	('systemic lupus erythematosus', 'Disease', (73, 101))	('u-PA', 'Gene', (168, 172))	('cancer metastasis', 'Disease', (187, 204))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('systemic lupus erythematosus', 'Phenotype', 'HP:0002725', (73, 101))	('N', 'Chemical', 'MESH:D009584', (11, 12))	('u-PA', 'Gene', '5328', (168, 172))	('systemic lupus erythematosus', 'Disease', 'MESH:D008180', (73, 101))	('cancer metastasis', 'Disease', 'MESH:D009362', (187, 204))	('cancer metastasis', 'Disease', (136, 153))	('activate', 'PosReg', (122, 130))	('DNA hypomethylation', 'Var', (10, 29))	('autoimmune diseases', 'Disease', 'MESH:D001327', (45, 64))	('SLE', 'Disease', 'MESH:D008180', (103, 106))	('SLE', 'Disease', (103, 106))	('SLE', 'Phenotype', 'HP:0002725', (103, 106))	('autoimmune diseases', 'Disease', (45, 64))	('autoimmune diseases', 'Phenotype', 'HP:0002960', (45, 64))	('cancer metastasis', 'Disease', 'MESH:D009362', (136, 153))	('accelerate', 'PosReg', (176, 186))	('cause', 'Reg', (34, 39))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))
420863	31360238	In addition, TIMP-3 can inhibit not only MMPs but also a wide range of ADAMs and ADAMTSs.	('ADAMs', 'Disease', (71, 76))	('MMPs', 'Gene', (41, 45))	('ADAMTSs', 'Disease', (81, 88))	('TIMP-3', 'Var', (13, 19))	('MMPs', 'Gene', '4312;4313;17390;4314;4316;4318;17395;81687;4323;4325;4327;10893;10893;10893', (41, 45))	('inhibit', 'NegReg', (24, 31))
420865	31360238	However, TIMP-3 expression is downregulated by genetic and epigenetic alternation in most cancers.	('cancers', 'Disease', (90, 97))	('downregulated', 'NegReg', (30, 43))	('epigenetic alternation', 'Var', (59, 81))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('TIMP-3', 'Gene', (9, 15))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('expression', 'MPA', (16, 26))	('cancers', 'Disease', 'MESH:D009369', (90, 97))
420948	26323893	Finally the cDNA was amplified by quantitative real-time PCR (qRT-PCR) using the included TaqMan Gene Expression Master Mix and the specific TaqMan primer/probe assay designed for the investigated genes: ALDH1A1 (Hs00946916_m1), NANOG (Hs02387400_g1), OCT4 (Hs03005111_g1), SOX2 (Hs01053049_s1) and GAPDH (Hs99999905_m1), (Applied Biosystems, Tokyo, Japan).	('NANOG', 'Gene', (229, 234))	('ALDH1A1', 'Gene', '216', (204, 211))	('GAPDH', 'Gene', '2597', (299, 304))	('Hs00946916_m1', 'Var', (213, 226))	('GAPDH', 'Gene', (299, 304))	('Hs01053049_s1', 'Var', (280, 293))	('Hs03005111_g1', 'Var', (258, 271))	('Hs02387400_g1', 'Var', (236, 249))	('ALDH1A1', 'Gene', (204, 211))	('OCT4', 'Gene', '5460', (252, 256))	('OCT4', 'Gene', (252, 256))	('SOX2', 'Gene', (274, 278))	('SOX2', 'Gene', '6657', (274, 278))	('NANOG', 'Gene', '79923', (229, 234))	('Mix', 'Gene', (120, 123))	('Hs99999905_m1', 'Var', (306, 319))	('Mix', 'Gene', '83881', (120, 123))
420951	26323893	Finally the cDNA of each mature microRNA was amplified separately by qRT-PCR using the TaqMan Universal Master Mix and the specific primer and probe mix included in predesigned TaqMan MicroRNA assays: hsa-miR-424; ID: 000604, hsa-miR-4730; ID: 462061_mat, hsa-miR-6836-5p; ID: 467207_mat, hsa-miR-6873-5p; ID: 467097_mat, hsa-miR-7152-3; ID: 466958_mat, hsa-hsa-let-7a; ID: 000377, hsa-miR-147b; ID: 002262, hsa-miR-3622a-3p; ID: 464955_mat, hsa-miR- miR-1976; ID: 121207_mat (Applied Biosystems).	('ID: 464955_mat', 'Var', (426, 440))	('miR', 'Gene', (205, 208))	('miR', 'Gene', (260, 263))	('Mix', 'Gene', (111, 114))	('miR-7152', 'Gene', '102465689', (326, 334))	('ID: 002262', 'Var', (396, 406))	('miR-6873', 'Gene', (293, 301))	('miR', 'Gene', '220972', (386, 389))	('miR-6873', 'Gene', '102466754', (293, 301))	('miR', 'Gene', (386, 389))	('ID: 466958_mat', 'Var', (338, 352))	('miR', 'Gene', '220972', (446, 449))	('miR-4730', 'Gene', '100616359', (230, 238))	('miR-1976', 'Gene', '100302190', (451, 459))	('miR-6836', 'Gene', (260, 268))	('mix', 'Gene', '83881', (149, 152))	('mix', 'Gene', (149, 152))	('miR-1976', 'Gene', (451, 459))	('miR-147b', 'Gene', '100126311', (386, 394))	('hsa-miR-424', 'Gene', (201, 212))	('miR', 'Gene', '220972', (412, 415))	('miR', 'Gene', '220972', (326, 329))	('miR', 'Gene', '220972', (230, 233))	('miR-147b', 'Gene', (386, 394))	('miR-7152', 'Gene', (326, 334))	('miR', 'Gene', (446, 449))	('miR', 'Gene', '220972', (293, 296))	('miR', 'Gene', '220972', (451, 454))	('miR', 'Gene', '220972', (205, 208))	('ID: 121207_mat', 'Var', (461, 475))	('miR-4730', 'Gene', (230, 238))	('miR', 'Gene', '220972', (260, 263))	('miR-6836', 'Gene', '102465503', (260, 268))	('miR', 'Gene', (412, 415))	('miR', 'Gene', (326, 329))	('miR', 'Gene', (230, 233))	('ID: 000377', 'Var', (370, 380))	('hsa-miR-424', 'Gene', '494336', (201, 212))	('Mix', 'Gene', '83881', (111, 114))	('miR', 'Gene', (293, 296))	('miR', 'Gene', (451, 454))	('ID: 467207_mat', 'Var', (273, 287))
420960	26323893	mRNA expression of ALDH1 was significantly higher in ALDH1high cells as compared to ALDH1low in both UTSCC-9 and UTSCC-90 cells (Fig.	('higher', 'PosReg', (43, 49))	('ALDH1', 'Gene', (19, 24))	('mRNA expression', 'MPA', (0, 15))	('ALDH1high', 'Var', (53, 62))	('UTSCC-90', 'CellLine', 'CVCL:7869', (113, 121))
420969	26323893	In UTSCC-90 group, ALDH1high cells produced tumors in all four mice, while ALDH1low cells did not produce any tumor.	('tumors', 'Disease', (44, 50))	('tumors', 'Disease', 'MESH:D009369', (44, 50))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('UTSCC-90', 'CellLine', 'CVCL:7869', (3, 11))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('mice', 'Species', '10090', (63, 67))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('ALDH1high', 'Var', (19, 28))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumor', 'Disease', (44, 49))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
420970	26323893	Similarly, tumor formation was observed in 2 of the 3 mice for ALDH1high cells, whereas no tumor occurred in sites injected with ALDH1low cells in UTSCC-9 group (Fig.	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('ALDH1high cells', 'Var', (63, 78))	('tumor', 'Disease', (11, 16))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('mice', 'Species', '10090', (54, 58))	('tumor', 'Disease', (91, 96))	('tumor', 'Disease', 'MESH:D009369', (11, 16))
420972	26323893	These results confirmed higher tumor-initiating ability of ALDH1high cells compared to ALDH1low cells in vivo.	('ALDH1high', 'Var', (59, 68))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumor', 'Disease', (31, 36))	('higher', 'PosReg', (24, 30))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
420976	26323893	In ALDH1high cells, six out of nine miRNAs, including miR-424, let-7a, miR-4730, miR-6836, miR-6873, miR-7152 were significantly downregulated, while three miRNAs including miR-147b, miR-3622a-3p and miR-1976 were significantly upregulated.	('downregulated', 'NegReg', (129, 142))	('miR-7152', 'Gene', (101, 109))	('miR', 'Gene', (54, 57))	('miR', 'Gene', '220972', (101, 104))	('miR-1976', 'Gene', '100302190', (200, 208))	('miR', 'Gene', (36, 39))	('miR', 'Gene', (156, 159))	('miR-1976', 'Gene', (200, 208))	('miR', 'Gene', (101, 104))	('miR', 'Gene', (91, 94))	('miR', 'Gene', '220972', (81, 84))	('miR-6836', 'Gene', '102465503', (81, 89))	('miR', 'Gene', '220972', (36, 39))	('miR', 'Gene', '220972', (183, 186))	('miR-6873', 'Gene', (91, 99))	('miR-6873', 'Gene', '102466754', (91, 99))	('miR', 'Gene', '220972', (71, 74))	('miR', 'Gene', '220972', (200, 203))	('miR', 'Gene', (81, 84))	('miR-147b', 'Gene', '100126311', (173, 181))	('miR-7152', 'Gene', '102465689', (101, 109))	('miR-4730', 'Gene', '100616359', (71, 79))	('miR-147b', 'Gene', (173, 181))	('miR', 'Gene', '220972', (156, 159))	('miR', 'Gene', (183, 186))	('miR', 'Gene', '220972', (173, 176))	('miR', 'Gene', (71, 74))	('miR', 'Gene', (200, 203))	('miR', 'Gene', '220972', (91, 94))	('miR', 'Gene', '220972', (54, 57))	('miR-424', 'Gene', (54, 61))	('miR-6836', 'Gene', (81, 89))	('miR-4730', 'Gene', (71, 79))	('upregulated', 'PosReg', (228, 239))	('miR-424', 'Gene', '494336', (54, 61))	('miR', 'Gene', (173, 176))	('let-7a', 'Var', (63, 69))
420996	26323893	The results of microarray analysis in the cell lines of HNSCC showed that nine miRNAs were differentially expressed in ALDH1high HNSCC cells compared to ALDH1low cells.	('ALDH1high', 'Var', (119, 128))	('HNSCC', 'Phenotype', 'HP:0012288', (56, 61))	('HNSCC', 'Phenotype', 'HP:0012288', (129, 134))	('miR', 'Gene', '220972', (79, 82))	('miR', 'Gene', (79, 82))
421029	33691026	Immunohistochemistry in tumor biopsies from 294 patients with lung cancer showed that high protein expression of KRT8 is a prognostic marker of poor survival (HR = 1.73, p = 0.01).	('lung cancer', 'Disease', 'MESH:D008175', (62, 73))	('KRT8', 'Gene', (113, 117))	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumor', 'Disease', (24, 29))	('lung cancer', 'Phenotype', 'HP:0100526', (62, 73))	('KRT8', 'Gene', '3856', (113, 117))	('lung cancer', 'Disease', (62, 73))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('patients', 'Species', '9606', (48, 56))	('high', 'Var', (86, 90))
421039	33691026	Others have documented the prognostic ability of other epigenetic signatures in colon, lung, and pancreatic cancer.	('lung', 'Disease', (87, 91))	('pancreatic cancer', 'Disease', 'MESH:D010190', (97, 114))	('epigenetic signatures', 'Var', (55, 76))	('pancreatic cancer', 'Disease', (97, 114))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('colon', 'Disease', (80, 85))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (97, 114))
421041	33691026	In this study, we performed a pan-cancer analysis of TCGA DNA methylation data from 9855 tissue samples across 23 cancers to inform subsequent gene expression, proteomic, and clinical outcome analyses.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('cancers', 'Disease', 'MESH:D009369', (114, 121))	('cancers', 'Phenotype', 'HP:0002664', (114, 121))	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('cancers', 'Disease', (114, 121))	('methylation', 'Var', (62, 73))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('TCGA DNA', 'Gene', (53, 61))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('cancer', 'Disease', (34, 40))	('cancer', 'Disease', (114, 120))
421081	33691026	We identified 23 cancers that had methylation data and at least two healthy controls per cancer from TCGA.	('methylation', 'Var', (34, 45))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('cancers', 'Phenotype', 'HP:0002664', (17, 24))	('cancers', 'Disease', (17, 24))	('cancer', 'Disease', (17, 23))	('cancer', 'Disease', (89, 95))	('cancers', 'Disease', 'MESH:D009369', (17, 24))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
421084	33691026	We hypothesized that the resulting set of methylation sites, irrespective of the set of cancers analyzed, would constitute a robust methylation signature across cancers.	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('cancers', 'Disease', 'MESH:D009369', (88, 95))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('cancers', 'Disease', (88, 95))	('methylation sites', 'Var', (42, 59))	('cancers', 'Disease', 'MESH:D009369', (161, 168))	('cancers', 'Phenotype', 'HP:0002664', (161, 168))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('cancers', 'Disease', (161, 168))
421087	33691026	In the validation cohorts, which used Illumina 450 platform, we found 1083 out of 1,801 sites were differentially methylated across all cancers (FDR < 5%; Figure 1B and Supplementary Figure 1B).	('cancers', 'Phenotype', 'HP:0002664', (136, 143))	('cancers', 'Disease', (136, 143))	('cancers', 'Disease', 'MESH:D009369', (136, 143))	('Illumina', 'Chemical', '-', (38, 46))	('methylated', 'Var', (114, 124))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
421089	33691026	KRT8 was the most statistically significant hypomethylated gene after multiple hypothesis correction (discovery ES = -1.71, p = 3.2e-7, FDR=9.15e-6; Figure 2A), but was unchanged in renal clear cell carcinoma.	('renal clear cell carcinoma', 'Disease', 'MESH:C538614', (182, 208))	('KRT8', 'Gene', (0, 4))	('renal clear cell carcinoma', 'Disease', (182, 208))	('hypomethylated', 'Var', (44, 58))	('KRT8', 'Gene', '3856', (0, 4))	('carcinoma', 'Phenotype', 'HP:0030731', (199, 208))
421090	33691026	KRT8 was also hypomethylated in the validation cohorts across all cancers except pheochromatoma/paraganglioma and melanoma (validation ES=-0.69, p = 3.3e-15, FDR = 4.0e-14; Figure 2B) (Figure 2).	('hypomethylated', 'Var', (14, 28))	('pheochromatoma/paraganglioma and melanoma', 'Disease', 'MESH:D008545', (81, 122))	('KRT8', 'Gene', '3856', (0, 4))	('KRT8', 'Gene', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('paraganglioma', 'Phenotype', 'HP:0002668', (96, 109))	('cancers', 'Phenotype', 'HP:0002664', (66, 73))	('cancers', 'Disease', (66, 73))	('cancers', 'Disease', 'MESH:D009369', (66, 73))	('melanoma', 'Phenotype', 'HP:0002861', (114, 122))
421091	33691026	Therefore, we hypothesized that hypo- or hyper-methylated genes across multiple cancers will be over- or under-expressed across multiple cancer compared to control samples.	('under-expressed', 'NegReg', (105, 120))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('cancers', 'Disease', 'MESH:D009369', (80, 87))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancers', 'Disease', (80, 87))	('hyper-methylated genes', 'Var', (41, 63))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('over-', 'PosReg', (96, 101))	('cancer', 'Disease', (137, 143))	('hypo-', 'Var', (32, 37))	('cancer', 'Disease', (80, 86))	('cancers', 'Phenotype', 'HP:0002664', (80, 87))
421095	33691026	Finally, we found that hypomethylation of KRT8 led to overexpression in multiple cancers compared to healthy samples (ES=1.05, p=2.8e-27, FDR=2.0e-24; Figure 3).	('cancers', 'Phenotype', 'HP:0002664', (81, 88))	('overexpression', 'PosReg', (54, 68))	('cancers', 'Disease', (81, 88))	('cancers', 'Disease', 'MESH:D009369', (81, 88))	('KRT8', 'Gene', (42, 46))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('KRT8', 'Gene', '3856', (42, 46))	('hypomethylation', 'Var', (23, 38))
421116	33691026	Given robust hypomethylation of KRT8 across 9,855 samples from 23 cancers, over-expression across 6,781 biopsies from 5 cancers, strong association with chemo-resistance, and sustained correlation with p53-regulated genes both at single-cell and sample levels, we investigated whether KRT8 is also expressed at protein-level in tumor biopsies, and whether it is associated with survival in patients with either lung adenocarcinoma or lung squamous cell carcinoma.	('lung squamous cell carcinoma', 'Disease', (434, 462))	('lung adenocarcinoma', 'Disease', (411, 430))	('hypomethylation', 'Var', (13, 28))	('KRT8', 'Gene', '3856', (32, 36))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('KRT8', 'Gene', (32, 36))	('carcinoma', 'Phenotype', 'HP:0030731', (453, 462))	('tumor', 'Disease', (328, 333))	('KRT8', 'Gene', '3856', (285, 289))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (411, 430))	('carcinoma', 'Phenotype', 'HP:0030731', (421, 430))	('tumor', 'Disease', 'MESH:D009369', (328, 333))	('cancers', 'Phenotype', 'HP:0002664', (120, 127))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (411, 430))	('cancers', 'Disease', (120, 127))	('KRT8', 'Gene', (285, 289))	('cancers', 'Disease', 'MESH:D009369', (66, 73))	('associated', 'Reg', (362, 372))	('tumor', 'Phenotype', 'HP:0002664', (328, 333))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (434, 462))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (439, 462))	('p53', 'Gene', '7157', (202, 205))	('patients', 'Species', '9606', (390, 398))	('cancers', 'Phenotype', 'HP:0002664', (66, 73))	('cancers', 'Disease', 'MESH:D009369', (120, 127))	('cancers', 'Disease', (66, 73))	('p53', 'Gene', (202, 205))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (434, 462))
421135	33691026	KRT8 was significantly hypomethlyated in both platforms, suggesting it is robust to platform bias.	('hypomethlyated', 'Var', (23, 37))	('KRT8', 'Gene', (0, 4))	('KRT8', 'Gene', '3856', (0, 4))
421202	33219024	RT-qPCR and Western blotting analysis confirmed that the mRNA and protein expression levels of PD-L1-A549 cells were substantially higher than those of vector-A549 cells (Fig.	('PD-L1-A549', 'Var', (95, 105))	('A549', 'CellLine', 'CVCL:0023', (159, 163))	('A549', 'CellLine', 'CVCL:0023', (101, 105))	('higher', 'PosReg', (131, 137))
421204	33219024	EVs from PD-L1-A549 cells showed a significantly increased expression of PD-L1 mRNA and protein in comparison with vector-A549 cells.	('A549', 'CellLine', 'CVCL:0023', (122, 126))	('increased', 'PosReg', (49, 58))	('expression', 'MPA', (59, 69))	('A549', 'CellLine', 'CVCL:0023', (15, 19))	('PD-L1-A549', 'Var', (9, 19))	('PD-L1', 'Gene', (73, 78))
421215	33219024	In a similar trend, we found that the PD-L1 protein expression levels of EVs derived from patients with LUAD (4.81 x 106 +- 4.93 x 106) were significantly higher than those from healthy donors (0.84 x 106 +- 0.66 x 106) (Fig.	('LUAD', 'Phenotype', 'HP:0030078', (104, 108))	('LUAD', 'Var', (104, 108))	('higher', 'PosReg', (155, 161))	('PD-L1 protein expression levels', 'MPA', (38, 69))	('patients', 'Species', '9606', (90, 98))
421220	33219024	We first used CD63 exosome capture beads to isolated EVs in plasma from healthy donors and patients with LUAD and then stained EVs with CD63-AF488 and PD-L1-AF647 fluorescent antibodies and analyzed the signals using two-color FCM.	('CD63', 'Gene', (136, 140))	('patients', 'Species', '9606', (91, 99))	('CD63', 'Gene', (14, 18))	('PD-L1-AF647', 'Var', (151, 162))	('CD63', 'Gene', '967', (136, 140))	('LUAD', 'Phenotype', 'HP:0030078', (105, 109))	('CD63', 'Gene', '967', (14, 18))
421262	33219024	In this study, we quantitated the fraction of CD63+ and PD-L1+ EV subpopulation in the entire EV population from both cell supernatant and from human plasma and found that about 27% EVs were both CD63+ and PD-L1+ in the EV population from cell supernatant and about 47% from human plasma (Fig.	('CD63', 'Gene', '967', (46, 50))	('human', 'Species', '9606', (144, 149))	('human', 'Species', '9606', (275, 280))	('CD63', 'Gene', (46, 50))	('CD63', 'Gene', '967', (196, 200))	('PD-L1+', 'Var', (206, 212))	('CD63', 'Gene', (196, 200))
421340	32038997	We chose the top 25% most variant mRNAs (4,938 mRNAs) and the top 25% most variant lncRNAs (3,712 genes) for constructing networks, while we did not do pretreatment for miRNA expression profile due to the small number of miRNAs (1,881 miRNAs).	('miR', 'Gene', '220972', (235, 238))	('miR', 'Gene', (235, 238))	('variant', 'Var', (26, 33))	('miR', 'Gene', '220972', (169, 172))	('miR', 'Gene', (169, 172))	('miR', 'Gene', '220972', (221, 224))	('miR', 'Gene', (221, 224))
421361	32038997	Then, the common candidate miRNAs with  MM  > 0.4 in hub modules and prediction by TargetScan was defined as real hub miRNAs.	('hub', 'Gene', (53, 56))	('miR', 'Gene', '220972', (27, 30))	('miR', 'Gene', (27, 30))	('hub', 'Gene', '1993', (114, 117))	('MM  > 0.4', 'Var', (40, 49))	('miR', 'Gene', '220972', (118, 121))	('miR', 'Gene', (118, 121))	('hub', 'Gene', '1993', (53, 56))	('hub', 'Gene', (114, 117))
421398	32038997	Based on the MM of lncRNA co-expression network and the prediction by LncBase (Table 3), 21 lncRNAs (RP11-275I4.2, RP11-327F22.6, LINC01355, CTD-3018O17.3, RP11-504P24.8, RP11-2H3.6, AC016735.1, PSMG3-AS1, C1orf213, RP5-1054A22.4, AC141928.1, XIST, RP11-332H14.2, CTD-2023N9.1, RP5-1125A11.7, RP3-470B24.5, AC226118.1, RP5-1184F4.5, RP11-440L14.1, ETV5-AS1, and RP5-1029K10.2) were considered as hub lncRNAs.	('AS1', 'Gene', '5729', (201, 204))	('RP11', 'Gene', (101, 105))	('RP11', 'Gene', (156, 160))	('CTD', 'Gene', (264, 267))	('ETV5', 'Gene', (348, 352))	('RP11', 'Gene', (171, 175))	('RP5-1184F4.5', 'Var', (319, 331))	('RP5-1125A11.7', 'Var', (278, 291))	('C1orf213', 'Gene', '148898', (206, 214))	('hub', 'Gene', (396, 399))	('XIST', 'Gene', (243, 247))	('RP11', 'Gene', (115, 119))	('RP11', 'Gene', (249, 253))	('C1orf213', 'Gene', (206, 214))	('CTD', 'Gene', (141, 144))	('AS1', 'Gene', (353, 356))	('hub', 'Gene', '1993', (396, 399))	('AS1', 'Gene', (201, 204))	('ETV5', 'Gene', '2119', (348, 352))	('CTD', 'Gene', '1283', (264, 267))	('XIST', 'Gene', '7503', (243, 247))	('RP11', 'Gene', '26121', (333, 337))	('PSMG3', 'Gene', (195, 200))	('RP3', 'Gene', (293, 296))	('RP11', 'Gene', '26121', (156, 160))	('RP11', 'Gene', '26121', (101, 105))	('RP11', 'Gene', '26121', (171, 175))	('LINC01355', 'Gene', (130, 139))	('PSMG3', 'Gene', '84262', (195, 200))	('CTD', 'Gene', '1283', (141, 144))	('LINC01355', 'Gene', '100996511', (130, 139))	('RP11', 'Gene', '26121', (115, 119))	('AS1', 'Gene', '5729', (353, 356))	('RP3', 'Gene', '6990', (293, 296))	('RP11', 'Gene', '26121', (249, 253))	('RP11', 'Gene', (333, 337))
421400	32038997	Eight genes (SPI1, RNASE6, C1QB, C1QC, CSF1R, C1QA, TBC1D2, and ATP6V0E1), seven miRNAs (hsa-miR-519e-5p, hsa-miR-519d-5p, hsa-miR-515-5p, hsa-miR-6756-5p, hsa-miR-6769b-5p, hsa-miR-4707-3p, and hsa-miR-650), and 21 lncRNAs (RP11-275I4.2, RP11-327F22.6, LINC01355, CTD-3018O17.3, RP11-504P24.8, RP11-2H3.6, AC016735.1, PSMG3-AS1, C1orf213, RP5-1054A22.4, AC141928.1, XIST, RP11-332H14.2, CTD-2023N9.1, RP5-1125A11.7, RP3-470B24.5, AC226118.1, RP5-1184F4.5, RP11-440L14.1, ETV5-AS1, and RP5-1029K10.2) were involved in this interaction network.	('SPI1', 'Gene', '6688', (13, 17))	('PSMG3', 'Gene', (319, 324))	('C1QB', 'Gene', (27, 31))	('LINC01355', 'Gene', (254, 263))	('miR', 'Gene', '220972', (178, 181))	('LINC01355', 'Gene', '100996511', (254, 263))	('TBC1D2', 'Gene', (52, 58))	('miR', 'Gene', (93, 96))	('RP11', 'Gene', '26121', (239, 243))	('AS1', 'Gene', '5729', (477, 480))	('RP11', 'Gene', '26121', (373, 377))	('RP3', 'Gene', '6990', (417, 420))	('ATP6V0E1', 'Gene', (64, 72))	('RP11', 'Gene', '26121', (295, 299))	('miR', 'Gene', '220972', (81, 84))	('RP11', 'Gene', (457, 461))	('C1QB', 'Gene', '713', (27, 31))	('PSMG3', 'Gene', '84262', (319, 324))	('CTD', 'Gene', '1283', (265, 268))	('CTD', 'Gene', (388, 391))	('miR', 'Gene', (178, 181))	('AS1', 'Gene', '5729', (325, 328))	('RP11', 'Gene', (280, 284))	('RP11', 'Gene', (225, 229))	('C1QC', 'Gene', '714', (33, 37))	('ETV5', 'Gene', (472, 476))	('C1QC', 'Gene', (33, 37))	('hsa-miR-650', 'Gene', '723778', (195, 206))	('miR', 'Gene', '220972', (160, 163))	('miR', 'Gene', (81, 84))	('TBC1D2', 'Gene', '55357', (52, 58))	('RNASE6', 'Gene', '6039', (19, 25))	('C1orf213', 'Gene', '148898', (330, 338))	('miR', 'Gene', '220972', (143, 146))	('miR', 'Gene', '220972', (127, 130))	('XIST', 'Gene', (367, 371))	('RP11', 'Gene', (239, 243))	('C1orf213', 'Gene', (330, 338))	('SPI1', 'Gene', (13, 17))	('hsa-miR-650', 'Gene', (195, 206))	('miR', 'Gene', '220972', (199, 202))	('RP11', 'Gene', (295, 299))	('RP11', 'Gene', (373, 377))	('CTD', 'Gene', '1283', (388, 391))	('miR', 'Gene', '220972', (110, 113))	('CSF1R', 'Gene', '1436', (39, 44))	('AS1', 'Gene', (477, 480))	('RP5-1125A11.7', 'Var', (402, 415))	('miR', 'Gene', (160, 163))	('ATP6V0E1', 'Gene', '8992', (64, 72))	('XIST', 'Gene', '7503', (367, 371))	('CSF1R', 'Gene', (39, 44))	('RP11', 'Gene', '26121', (457, 461))	('AS1', 'Gene', (325, 328))	('RNASE6', 'Gene', (19, 25))	('miR', 'Gene', (143, 146))	('miR', 'Gene', (127, 130))	('RP3', 'Gene', (417, 420))	('CTD', 'Gene', (265, 268))	('RP11', 'Gene', '26121', (280, 284))	('ETV5', 'Gene', '2119', (472, 476))	('miR', 'Gene', (199, 202))	('RP11', 'Gene', '26121', (225, 229))	('miR', 'Gene', '220972', (93, 96))	('C1QA', 'Gene', '712', (46, 50))	('miR', 'Gene', (110, 113))	('C1QA', 'Gene', (46, 50))
421444	32038997	A recent study demonstrated the abnormal expression of XIST could contribute to esophageal cancer via miR-494/CDK6 axis.	('expression', 'MPA', (41, 51))	('miR-494', 'Gene', (102, 109))	('esophageal cancer', 'Disease', (80, 97))	('CDK6', 'Gene', (110, 114))	('abnormal', 'Var', (32, 40))	('CDK6', 'Gene', '1021', (110, 114))	('esophageal cancer', 'Disease', 'MESH:D004938', (80, 97))	('XIST', 'Gene', '7503', (55, 59))	('contribute', 'Reg', (66, 76))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('XIST', 'Gene', (55, 59))	('miR-494', 'Gene', '574452', (102, 109))
421454	32038997	A lot of cancer-promoting errors may occur during cell division, such as DNA mutations and epigenetic mistakes, chromosome aberrations occurring, and the wrong distribution of cell-fate determinants between the daughter cells.	('cancer', 'Disease', (9, 15))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('chromosome aberrations', 'CPA', (112, 134))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('DNA', 'Disease', (73, 76))	('epigenetic mistakes', 'Var', (91, 110))
421458	32038997	For example, the high expression of EGFR causes the abnormal differentiation of ESCC cells and the decrease in adhesion between cells, and the tumor is prone to lymphatic and distant metastasis.	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('prone', 'Reg', (152, 157))	('tumor', 'Disease', (143, 148))	('high expression', 'Var', (17, 32))	('decrease', 'NegReg', (99, 107))	('ESCC', 'Disease', 'MESH:C562729', (80, 84))	('EGFR', 'Gene', '1956', (36, 40))	('adhesion between cells', 'CPA', (111, 133))	('EGFR', 'Gene', (36, 40))	('ESCC', 'Disease', (80, 84))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
421469	31271844	We propose a novel method to effectively explore the landscape of genetic mutations and aggregate them to predict cancer type.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('mutations', 'Var', (74, 83))	('cancer', 'Disease', (114, 120))
421471	31271844	Mutations were identified from multiple cancers and scored using SIFT, PP2, and CADD, and collapsed at the individual gene level.	('cancers', 'Phenotype', 'HP:0002664', (40, 47))	('multiple cancers', 'Disease', 'MESH:D009369', (31, 47))	('Mutations', 'Var', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('multiple cancers', 'Disease', (31, 47))
421482	31271844	Despite the fact that mutations in many genes have been identified in cancer, it is not yet understood how these genes cumulatively interact in the development and progression of cancer.	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('mutations', 'Var', (22, 31))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', (179, 185))	('cancer', 'Disease', 'MESH:D009369', (70, 76))
421483	31271844	With the aim to uncover the genetic complexity behind cancer development, and to identify mutations that directly affect processes involved with oncogenesis, we propose a framework utilizing NMF.	('mutations', 'Var', (90, 99))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('affect', 'Reg', (114, 120))	('cancer', 'Disease', (54, 60))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
421493	31271844	To set up baselines for comparison, the mutation frequency and the collapsed scores were used as independent predictors to fit SVM models and penalized logistic regression models were used to predict cancer types.	('cancer', 'Disease', 'MESH:D009369', (200, 206))	('mutation', 'Var', (40, 48))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('cancer', 'Disease', (200, 206))
421495	31271844	A number of models have been developed for cancer classification utilizing somatic mutation profiles, including variations of CADD scores, logistical regression on L1-regularised terms, and SVM-RFE.	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('cancer', 'Disease', (43, 49))	('CADD scores', 'Gene', (126, 137))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('variations', 'Var', (112, 122))
421519	31271844	We acknowledge that non-protein-coding genes, including mutations in intronic areas, long non-coding RNAs, mi-RNAs are also important for cancer development.	('cancer', 'Disease', (138, 144))	('mutations', 'Var', (56, 65))	('mi-RNAs', 'Gene', (107, 114))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('long', 'Protein', (85, 89))	('cancer', 'Disease', 'MESH:D009369', (138, 144))
421536	30012580	In this regard, genetic ablation of senescent cells delays and ameliorates some aging-associated diseases, reverts long-term degenerative processes associated with chemotherapy, and extends longevity (Baker et al, 2016; Childs et al, 2016; Demaria et al, 2017).	('reverts', 'NegReg', (107, 114))	('rat', 'Species', '10116', (131, 134))	('delays', 'NegReg', (52, 58))	('aging-associated diseases', 'Disease', (80, 105))	('long-term degenerative processes', 'MPA', (115, 147))	('longevity', 'CPA', (190, 199))	('ameliorates', 'PosReg', (63, 74))	('genetic ablation', 'Var', (16, 32))	('rat', 'Species', '10116', (69, 72))	('extends', 'PosReg', (182, 189))
421539	30012580	Similarly, inactivation of the transcription factor FOXA4 with a peptide derivative preferentially eliminates senescent cells over non-senescent ones (Baar et al, 2017).	('senescent cells', 'CPA', (110, 125))	('eliminates', 'NegReg', (99, 109))	('inactivation', 'Var', (11, 23))	('FOXA4', 'Gene', (52, 57))	('Si', 'Chemical', 'MESH:D012825', (0, 2))
421554	30012580	Of note, the three cell lines used, SK-MEL-103, NCI-H226, and UT-SCC-42B, have an active retinoblastoma pathway (RB1-proficient; Ikediobi et al, 2006; Giefing et al, 2011; Massaro et al, 2017) and undergo senescence upon treatment with palbociclib (Fig 1B and Appendix Fig S1F).	('SK-MEL-103', 'Var', (36, 46))	('retinoblastoma', 'Phenotype', 'HP:0009919', (89, 103))	('SK-MEL-103', 'CellLine', 'CVCL:6069', (36, 46))	('retinoblastoma', 'Disease', 'MESH:D012175', (89, 103))	('retinoblastoma', 'Disease', (89, 103))	('UT-SCC-42B', 'CellLine', 'CVCL:7848', (62, 72))	('senescence', 'MPA', (205, 215))	('palbociclib', 'Chemical', 'MESH:C500026', (236, 247))	('UT-SCC-42B', 'Var', (62, 72))	('undergo', 'Reg', (197, 204))	('NCI-H226', 'CellLine', 'CVCL:1544', (48, 56))
421559	30012580	Upon tumor formation, mice were treated daily with palbociclib for 7 days, and this resulted in high levels of intratumoral senescence, as inferred from elevated SAbetaGal activity, absence of the proliferative marker Ki67, and reduction in phosphorylated Rb (Fig 1C).	('phosphorylated', 'MPA', (241, 255))	('reduction', 'NegReg', (228, 237))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('absence', 'NegReg', (182, 189))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('Ki67', 'Gene', '17345', (218, 222))	('mice', 'Species', '10090', (22, 26))	('palbociclib', 'Chemical', 'MESH:C500026', (51, 62))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('SAbetaGal activity', 'MPA', (162, 180))	('elevated', 'PosReg', (153, 161))	('rat', 'Species', '10116', (204, 207))	('SAbetaGal', 'Chemical', '-', (162, 171))	('rat', 'Species', '10116', (114, 117))	('Ki67', 'Gene', (218, 222))	('tumor', 'Disease', (5, 10))	('tumor', 'Disease', (116, 121))	('palbociclib', 'Var', (51, 62))
421562	30012580	Importantly, however, rhodamine was detectable above background in mice treated with GalNP(rho), and the signal attributed to rhodamine was higher in tumors treated with palbociclib compared to non-treated tumors (Fig 1D).	('palbociclib', 'Var', (170, 181))	('tumors', 'Disease', (150, 156))	('tumors', 'Disease', 'MESH:D009369', (150, 156))	('tumors', 'Phenotype', 'HP:0002664', (150, 156))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('signal', 'MPA', (105, 111))	('rhodamine', 'Chemical', 'MESH:D012235', (22, 31))	('tumors', 'Phenotype', 'HP:0002664', (206, 212))	('higher', 'PosReg', (140, 146))	('tumors', 'Disease', (206, 212))	('tumors', 'Disease', 'MESH:D009369', (206, 212))	('rhodamine', 'Chemical', 'MESH:D012235', (126, 135))	('palbociclib', 'Chemical', 'MESH:C500026', (170, 181))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('mice', 'Species', '10090', (67, 71))
421584	30012580	However, the relative levels of Rho+ macrophages were reduced in bleomycin-treated lungs, and the same trend was observed in the other cell types (Appendix Fig S2E-G).	('bleomycin', 'Chemical', 'MESH:D001761', (65, 74))	('reduced', 'NegReg', (54, 61))	('bleomycin-treated', 'Var', (65, 82))	('Rho+ macrophages', 'MPA', (32, 48))
421602	30012580	It is known that modified forms of doxorubicin with lysosomal tropism efficiently induce apoptosis (Nair et al, 2015; Sheng et al, 2015).	('modified', 'Var', (17, 25))	('apoptosis', 'CPA', (89, 98))	('induce', 'Reg', (82, 88))	('doxorubicin', 'Chemical', 'MESH:D004317', (35, 46))
421614	30012580	Cardiotoxicity is the most serious side effect of doxorubicin (Chatterjee et al, 2010), whereas thrombocytopenia is the main toxicity of navitoclax (Kile, 2014).	('doxorubicin', 'Chemical', 'MESH:D004317', (50, 61))	('thrombocytopenia', 'Disease', (96, 112))	('doxorubicin', 'Var', (50, 61))	('toxicity of navitoclax', 'Disease', (125, 147))	('Cardiotoxicity', 'Disease', 'MESH:D066126', (0, 14))	('Cardiotoxicity', 'Disease', (0, 14))	('toxicity of navitoclax', 'Disease', 'MESH:D064420', (125, 147))	('thrombocytopenia', 'Disease', 'MESH:D013921', (96, 112))	('thrombocytopenia', 'Phenotype', 'HP:0001873', (96, 112))
421623	30012580	We first confirmed that GalNP(dox) efficiently released doxorubicin in lungs from bleomycin-treated mice, but not in healthy lungs, as determined by total fluorescence (Appendix Fig S4A).	('GalNP', 'Chemical', '-', (24, 29))	('mice', 'Species', '10090', (100, 104))	('dox', 'Chemical', 'MESH:D004317', (56, 59))	('dox', 'Chemical', 'MESH:D004317', (30, 33))	('released doxorubicin', 'MPA', (47, 67))	('bleomycin', 'Chemical', 'MESH:D001761', (82, 91))	('doxorubicin', 'Chemical', 'MESH:D004317', (56, 67))	('bleomycin-treated', 'Var', (82, 99))
421626	30012580	Importantly, at the end of the treatment, mice treated with GalNP(dox), but not with free doxorubicin, presented LR/Cdyn values similar to those of healthy controls (Fig 4B and Appendix Fig S4B).	('dox', 'Chemical', 'MESH:D004317', (66, 69))	('LR/Cdyn values', 'MPA', (113, 127))	('dox', 'Chemical', 'MESH:D004317', (90, 93))	('mice', 'Species', '10090', (42, 46))	('Cdyn', 'Chemical', '-', (116, 120))	('GalNP', 'Var', (60, 65))	('GalNP', 'Chemical', '-', (60, 65))	('doxorubicin', 'Chemical', 'MESH:D004317', (90, 101))
421659	30012580	Upon administration of GalNP(dox), doxorubicin-derived fluorescence was higher in bleomycin-treated lungs compared to control lungs.	('dox', 'Chemical', 'MESH:D004317', (35, 38))	('doxorubicin-derived fluorescence', 'MPA', (35, 67))	('GalNP', 'Chemical', '-', (23, 28))	('rat', 'Species', '10116', (13, 16))	('dox', 'Chemical', 'MESH:D004317', (29, 32))	('higher', 'PosReg', (72, 78))	('doxorubicin', 'Chemical', 'MESH:D004317', (35, 46))	('bleomycin', 'Chemical', 'MESH:D001761', (82, 91))	('bleomycin-treated', 'Var', (82, 99))
421737	30012580	Antigen retrieval was first performed with high pH buffer (CC1m, Roche), endogenous peroxidase was blocked, and slides were then incubated with the appropriate primary antibodies as detailed: Ki67 (Master Diagnostica, #0003110QD), phosphorylated Rb (Ser807/811) (Cell Signalling Technology, #9308).	('phosphorylated', 'Var', (231, 245))	('Si', 'Chemical', 'MESH:D012825', (268, 270))	('Ser807', 'Chemical', '-', (250, 256))	('Ki67', 'Gene', (192, 196))	('Ki67', 'Gene', '17345', (192, 196))
421762	30012580	The following rat monoclonal conjugated antibodies were used: anti-CD31 APC (1:400, BD Biosciences; #551260), anti-CD45 APC (1:200, BD Biosciences, #559864), anti-CD326 (EpCAM) AF488 (1:200, Biolegend, #118210), anti-CD45.2 APC-Cy7 (1:100, Biolegend, #109824), anti-F4/80 BV421 (1:50, Biolegend, 123131), anti-CD11b PE-Cy7 (1:200, BD Biosciences #552850).	('CD326', 'Gene', '17075', (163, 168))	('CD31', 'Gene', '18613', (67, 71))	('CD45', 'Gene', (115, 119))	('EpCAM', 'Gene', (170, 175))	('CD45', 'Gene', '19264', (115, 119))	('CD31', 'Gene', (67, 71))	('EpCAM', 'Gene', '17075', (170, 175))	('CD11b', 'Gene', (310, 315))	('CD11b', 'Gene', '16409', (310, 315))	('anti-F4/80', 'Var', (261, 271))	('AF', 'Disease', 'MESH:D001281', (177, 179))	('CD45', 'Gene', '19264', (217, 221))	('CD326', 'Gene', (163, 168))	('rat', 'Species', '10116', (14, 17))	('CD45', 'Gene', (217, 221))
421837	27788497	(S,R)-3-(4-hydroxyphenyl)-4,5-dihydro-5- isoxazole acetic acid methyl ester (ISO-1), an inhibitor of DDT, could decrease wild-type or mutant MIF activity in human and murine mononuclear cells.	('ISO-1', 'Gene', (77, 82))	('murine', 'Species', '10090', (167, 173))	('decrease', 'NegReg', (112, 120))	('human', 'Species', '9606', (157, 162))	('activity', 'MPA', (145, 153))	('(S,R)-3-(4-hydroxyphenyl)-4,5-dihydro-5-', 'Chemical', '-', (0, 40))	('ISO-1', 'Gene', '10209', (77, 82))	('isoxazole acetic acid methyl ester', 'Chemical', '-', (41, 75))	('MIF', 'Enzyme', (141, 144))	('DDT', 'Chemical', '-', (101, 104))	('mutant', 'Var', (134, 140))
421839	27788497	Knockdown of CD74 could slow down the proliferation and invasiveness of a squamous carcinoma cell line SCCVII as well as negatively affected the growth of orthotopic tumors generated by SCCVII cell inoculation.	('negatively', 'NegReg', (121, 131))	('squamous carcinoma', 'Disease', (74, 92))	('slow down', 'NegReg', (24, 33))	('Knockdown', 'Var', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('invasiveness', 'CPA', (56, 68))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (74, 92))	('growth', 'CPA', (145, 151))	('orthotopic tumors', 'Disease', 'MESH:D009369', (155, 172))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))	('affected', 'Reg', (132, 140))	('orthotopic tumors', 'Disease', (155, 172))	('CD74', 'Gene', (13, 17))	('squamous carcinoma', 'Disease', 'MESH:D002294', (74, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))
421850	27788497	In the non-small cell lung cancer cell lines, the dissociation of MIF- ribosomal protein S3 complex induced by ionizing radiation sequentially activated NF-kappaB and made the expression of target genes of this factor, which promoted tumor metastatic conversion.	('lung cancer', 'Phenotype', 'HP:0100526', (22, 33))	('promoted', 'PosReg', (225, 233))	('tumor', 'Disease', (234, 239))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (7, 33))	('expression', 'MPA', (176, 186))	('activated', 'PosReg', (143, 152))	('dissociation', 'Var', (50, 62))	('cancer', 'Disease', (27, 33))	('cancer', 'Disease', 'MESH:D009369', (27, 33))	('NF-kappaB', 'Gene', '4790', (153, 162))	('tumor', 'Disease', 'MESH:D009369', (234, 239))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (11, 33))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('NF-kappaB', 'Gene', (153, 162))
421866	27788497	With observations that the high-expression of MIF and IL-8 was significantly associated with increased lymph node metastasis in NPC patients and exogenous MIF treatment alone could upregulate IL-8 secretion in CNE-1 and CNE-2 NPC cells in vitro, Liao et al.	('lymph node metastasis', 'CPA', (103, 124))	('NPC', 'Phenotype', 'HP:0100630', (128, 131))	('secretion', 'MPA', (197, 206))	('IL-8', 'Gene', '3576', (192, 196))	('MIF', 'Gene', (46, 49))	('increased', 'PosReg', (93, 102))	('IL-8', 'Gene', (54, 58))	('IL-8', 'Gene', (192, 196))	('upregulate', 'PosReg', (181, 191))	('CNE-2 NPC', 'CellLine', 'CVCL:6889', (220, 229))	('high-expression', 'Var', (27, 42))	('CNE-1', 'CellLine', 'CVCL:6888', (210, 215))	('NPC', 'Phenotype', 'HP:0100630', (226, 229))	('patients', 'Species', '9606', (132, 140))	('IL-8', 'Gene', '3576', (54, 58))
421867	27788497	inferred that MIF contributed to lymph node metastasis by upregulating IL-8 expression.	('IL-8', 'Gene', '3576', (71, 75))	('MIF', 'Var', (14, 17))	('upregulating', 'PosReg', (58, 70))	('IL-8', 'Gene', (71, 75))	('lymph node metastasis', 'CPA', (33, 54))	('expression', 'MPA', (76, 86))
421882	27788497	Conversely, MIF also contributed to stabilize HIF-1.	('MIF', 'Var', (12, 15))	('stabilize', 'MPA', (36, 45))	('HIF-1', 'Gene', (46, 51))	('HIF-1', 'Gene', '3091', (46, 51))
421895	27788497	This result suggested that the antitumor effect caused by anti-MIF resulted from MIF suppression on angiogenesis.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumor', 'Disease', (35, 40))	('anti-MIF', 'Var', (58, 66))	('MIF', 'Gene', (81, 84))	('angiogenesis', 'CPA', (100, 112))	('suppression', 'NegReg', (85, 96))
421901	27788497	inferred that MIF contributed to lymph node metastasis by inducing angiogenesis through the way of upregulating IL-8 expression.	('IL-8', 'Gene', '3576', (112, 116))	('inducing', 'PosReg', (58, 66))	('MIF', 'Var', (14, 17))	('angiogenesis', 'CPA', (67, 79))	('expression', 'MPA', (117, 127))	('lymph node metastasis', 'CPA', (33, 54))	('IL-8', 'Gene', (112, 116))	('upregulating', 'PosReg', (99, 111))
421911	27788497	utilized small siRNA to knock down the expression of MIF which inhibited the proliferation, migration, and colony formation of oral squamous cell carcinoma (OSCC) cells.	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('colony formation', 'CPA', (107, 123))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (127, 155))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (132, 155))	('oral squamous cell carcinoma', 'Disease', (127, 155))	('MIF', 'Gene', (53, 56))	('migration', 'CPA', (92, 101))	('knock down', 'Var', (24, 34))	('inhibited', 'NegReg', (63, 72))	('proliferation', 'CPA', (77, 90))
421912	27788497	They also found that Twist1, the transcriptional factor of the EMT, downregulated concomitantly in the MIF-knockdown (KD) OSCC cells.	('downregulated', 'NegReg', (68, 81))	('Twist1', 'Gene', '7291', (21, 27))	('MIF-knockdown', 'Var', (103, 116))	('Twist1', 'Gene', (21, 27))
421914	27788497	Conversely, the expression of snail, vimentin and twist could be decreased by the MIF knockdown.	('snail', 'Gene', '6615', (30, 35))	('knockdown', 'Var', (86, 95))	('twist', 'Protein', (50, 55))	('decreased', 'NegReg', (65, 74))	('vimentin', 'Gene', '7431', (37, 45))	('vimentin', 'Gene', (37, 45))	('snail', 'Gene', (30, 35))	('MIF', 'Gene', (82, 85))	('expression', 'MPA', (16, 26))
421916	27788497	Both the cyclin D1 and p27Kip contributed to regulate cell cycle progression from G1 to S phase.	('p27Kip', 'Var', (23, 29))	('cyclin D1', 'Gene', '595', (9, 18))	('cyclin D1', 'Gene', (9, 18))	('regulate', 'Reg', (45, 53))	('cell cycle progression', 'CPA', (54, 76))
421921	27788497	CPSI-1306, MIF antagonist, could enhance keratinocyte apoptosis and inhibit the UVB-induced epidermal proliferation by promoting p53 degradation, which antagonized UVB-induced squamous carcinogenesis.	('squamous carcinogenesis', 'Disease', (176, 199))	('CPSI-1306', 'Chemical', 'MESH:C000598334', (0, 9))	('CPSI-1306', 'Var', (0, 9))	('inhibit', 'NegReg', (68, 75))	('squamous carcinogenesis', 'Disease', 'MESH:D063646', (176, 199))	('p53', 'Gene', (129, 132))	('keratinocyte apoptosis', 'CPA', (41, 63))	('p53', 'Gene', '7157', (129, 132))	('degradation', 'MPA', (133, 144))	('enhance', 'PosReg', (33, 40))	('promoting', 'PosReg', (119, 128))
421926	27788497	The results demonstrated that in MIF deficient cells, the positive regulators of G1/S cell cycle progression, Cyclin, CDK, CAK and APC/C were downregulated.	('APC', 'Disease', (131, 134))	('G1/S', 'Gene', (81, 85))	('deficient', 'Var', (37, 46))	('Cyclin', 'Gene', (110, 116))	('CAK', 'Gene', (123, 126))	('CAK', 'Gene', '780', (123, 126))	('cell cycle progression', 'CPA', (86, 108))	('CDK', 'MPA', (118, 121))	('downregulated', 'NegReg', (142, 155))	('MIF', 'Var', (33, 36))	('Cyclin', 'Gene', '5111', (110, 116))	('APC', 'Disease', 'MESH:D011125', (131, 134))
421931	27788497	Then, activated p53 results in a variety of genes activation and transcription which play important roles in cell cycle arrest, senescence, apoptosis, and differentiation.	('activated', 'Var', (6, 15))	('differentiation', 'CPA', (155, 170))	('senescence', 'CPA', (128, 138))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (109, 126))	('genes', 'Gene', (44, 49))	('p53', 'Gene', (16, 19))	('apoptosis', 'CPA', (140, 149))	('transcription', 'MPA', (65, 78))	('activation', 'PosReg', (50, 60))	('p53', 'Gene', '7157', (16, 19))	('cell cycle arrest', 'CPA', (109, 126))
421935	27788497	Subsequently, considerable studies identified MIF as an effective p53 antagonist by inhibiting p53-dependent apoptosis and tumor suppressor role.	('tumor', 'Disease', (123, 128))	('p53', 'Gene', '7157', (66, 69))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('MIF', 'Var', (46, 49))	('p53', 'Gene', (95, 98))	('p53', 'Gene', '7157', (95, 98))	('inhibiting', 'NegReg', (84, 94))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('p53', 'Gene', (66, 69))
421945	27788497	On the other hand, recent studies have discovered that defective autophagy links to increased tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('autophagy', 'CPA', (65, 74))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Disease', (94, 99))	('defective', 'Var', (55, 64))	('increased', 'PosReg', (84, 93))
421946	27788497	The loss of the essential autophagy gene beclin1 induced hepatocellular carcinoma, lung adenocarcinoma, mammary hyperplasia, and lymphoma in the mice.	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('lymphoma', 'Disease', (129, 137))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('hyperplasia', 'Disease', 'MESH:D006965', (112, 123))	('lymphoma', 'Disease', 'MESH:D008223', (129, 137))	('lymphoma', 'Phenotype', 'HP:0002665', (129, 137))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (57, 81))	('lung adenocarcinoma', 'Disease', (83, 102))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (83, 102))	('mammary hyperplasia', 'Phenotype', 'HP:0010313', (104, 123))	('induced', 'Reg', (49, 56))	('hyperplasia', 'Disease', (112, 123))	('beclin1', 'Gene', (41, 48))	('mice', 'Species', '10090', (145, 149))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (57, 81))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (83, 102))	('hepatocellular carcinoma', 'Disease', (57, 81))	('loss', 'Var', (4, 8))
421947	27788497	The constitutive activation of PI3k/Akt pathway by mutations might stimulate the process.	('Akt', 'Gene', '207', (36, 39))	('activation', 'PosReg', (17, 27))	('mutations', 'Var', (51, 60))	('Akt', 'Gene', (36, 39))
421951	27788497	found that MIF could induce autophagy in hepatocytes through ROS generation.	('MIF', 'Var', (11, 14))	('ROS', 'Protein', (61, 64))	('autophagy in', 'CPA', (28, 40))	('induce', 'Reg', (21, 27))	('ROS', 'Chemical', 'MESH:D017382', (61, 64))
421964	27788497	High MIF expression in tumor cells were significantly associated with worse prognosis of NPC patients.	('High', 'Var', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('MIF', 'Protein', (5, 8))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('expression', 'MPA', (9, 19))	('NPC', 'Phenotype', 'HP:0100630', (89, 92))	('tumor', 'Disease', (23, 28))	('patients', 'Species', '9606', (93, 101))	('associated', 'Reg', (54, 64))	('NPC', 'Disease', (89, 92))
421980	27788497	They found that the knockdown of CD74 or using anti-CD74 mAb could achieve the similar results in gastric cancer.	('gastric cancer', 'Disease', (98, 112))	('gastric cancer', 'Disease', 'MESH:D013274', (98, 112))	('CD74', 'Gene', (33, 37))	('knockdown', 'Var', (20, 29))	('gastric cancer', 'Phenotype', 'HP:0012126', (98, 112))	('anti-CD74', 'Var', (47, 56))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
421998	30785474	Immunohistochemistry revealed tumor cells with strong positivity to vimentin and P53 (Figures 3A and 3B), positivity to alpha-smooth muscle actin (alpha-SMA) (Figure 3C) and focal positivity for epithelial membrane antigen (EMA) and P63.	('EMA', 'Disease', (224, 227))	('P53', 'Gene', (81, 84))	('EMA', 'Disease', 'MESH:D054069', (224, 227))	('positivity', 'Var', (106, 116))	('P53', 'Gene', '7157', (81, 84))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('positivity', 'MPA', (54, 64))	('vimentin', 'Gene', '7431', (68, 76))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('P63', 'Gene', (233, 236))	('tumor', 'Disease', (30, 35))	('vimentin', 'Gene', (68, 76))	('P63', 'Gene', '8626', (233, 236))
422030	28671973	This rare subtype of lung cancer is thought to be more resistant to chemotherapy, and a small subset of them seems to exhibit targetable mutations.	('lung cancer', 'Disease', (21, 32))	('lung cancer', 'Phenotype', 'HP:0100526', (21, 32))	('mutations', 'Var', (137, 146))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('lung cancer', 'Disease', 'MESH:D008175', (21, 32))
422071	28671973	A search through pubmed search engine has been performed on the 20th of January 2017 with the following search terms: ("antigens, cd274"[MeSH Terms] OR ("antigens"[All Fields] AND "cd274"[All Fields]) OR "cd274 antigens"[All Fields] OR ("pd"[All Fields] AND "l1"[All Fields]) OR "pd l1"[All Fields]) AND ("carcinoma"[MeSH Terms] OR "carcinoma"[All Fields] OR ("sarcomatoid"[All Fields] AND "carcinoma"[All Fields]) OR "sarcomatoid carcinoma"[All Fields]) AND ("lung"[MeSH Terms] OR "lung"[All Fields]) PD-L1 was negative for 9 (25%) patients, and was found positive for 27 (75%) of patients (Fig 1).	('sarcomatoid', 'Disease', 'MESH:C538614', (361, 372))	('PD-L1', 'Gene', '29126', (502, 507))	('pd l1', 'Gene', (280, 285))	('cd274', 'Gene', (181, 186))	('carcinoma', 'Phenotype', 'HP:0030731', (431, 440))	('cd274', 'Gene', '29126', (181, 186))	('sarcomatoid carcinoma', 'Disease', (419, 440))	('sarcomatoid carcinoma', 'Disease', 'MESH:C538614', (419, 440))	('pd l1', 'Gene', '29126', (280, 285))	('"carcinoma', 'Disease', 'MESH:D002277', (332, 342))	('cd274', 'Gene', (205, 210))	('"carcinoma', 'Disease', (390, 400))	('sarcomatoid', 'Disease', (419, 430))	('"pd"[All Fields] AND "l1', 'Var', (237, 261))	('cd274', 'Gene', '29126', (205, 210))	('"carcinoma', 'Disease', 'MESH:D002277', (305, 315))	('carcinoma', 'Phenotype', 'HP:0030731', (333, 342))	('cd274', 'Gene', '29126', (130, 135))	('"carcinoma', 'Disease', (332, 342))	('cd274', 'Gene', (130, 135))	('sarcomatoid', 'Disease', (361, 372))	('sarcomatoid carcinoma', 'Phenotype', 'HP:0100242', (419, 440))	('sarcomatoid', 'Disease', 'MESH:C538614', (419, 430))	('patients', 'Species', '9606', (533, 541))	('carcinoma', 'Phenotype', 'HP:0030731', (306, 315))	('"carcinoma', 'Disease', (305, 315))	('patients', 'Species', '9606', (582, 590))	('carcinoma', 'Phenotype', 'HP:0030731', (391, 400))	('"carcinoma', 'Disease', 'MESH:D002277', (390, 400))	('PD-L1', 'Gene', (502, 507))
422074	28671973	PD-L1 positivity was related to p40 expression (p = 0.013) and to TTF-1 and or Napsin expression (p = 0.039) in PSCGC carcinoma (Table 1).	('TTF-1', 'Gene', (66, 71))	('carcinoma', 'Disease', 'MESH:D002277', (118, 127))	('positivity', 'Var', (6, 16))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('PD-L1', 'Gene', (0, 5))	('TTF-1', 'Gene', '7270', (66, 71))	('SC', 'Phenotype', 'HP:0100242', (113, 115))	('carcinoma', 'Disease', (118, 127))	('PD-L1', 'Gene', '29126', (0, 5))	('p40', 'Gene', (32, 35))	('p40', 'Gene', '3578', (32, 35))
422080	28671973	Patients with PSCGCC with an expression of PD-L1 had a worse prognosis than patients with PSCGCC without PD-L1 expression (mean = 9 vs 37 months) (p = 0.045, Fig 2).	('patients', 'Species', '9606', (76, 84))	('expression', 'Var', (29, 39))	('PD-L1', 'Gene', (105, 110))	('PD-L1', 'Gene', (43, 48))	('PSCGCC', 'Disease', (14, 20))	('SC', 'Phenotype', 'HP:0100242', (91, 93))	('Patients', 'Species', '9606', (0, 8))	('PD-L1', 'Gene', '29126', (105, 110))	('SC', 'Phenotype', 'HP:0100242', (15, 17))	('PD-L1', 'Gene', '29126', (43, 48))
422085	28671973	A subset of SC harbors targetable mutations such as EGFR mutations, ALK or ROS 1 rearrangement.	('EGFR', 'Gene', '1956', (52, 56))	('ROS 1', 'Gene', (75, 80))	('EGFR', 'Gene', (52, 56))	('ALK', 'Gene', (68, 71))	('SC', 'Phenotype', 'HP:0100242', (12, 14))	('mutations', 'Var', (57, 66))	('ALK', 'Gene', '238', (68, 71))	('rearrangement', 'Var', (81, 94))	('ROS 1', 'Gene', '6098', (75, 80))
422094	28671973	A recent study on SC found that TTF-1 positivity is associated with PD-L1 expression.	('expression', 'MPA', (74, 84))	('SC', 'Phenotype', 'HP:0100242', (18, 20))	('positivity', 'Var', (38, 48))	('associated', 'Reg', (52, 62))	('PD-L1', 'Gene', (68, 73))	('TTF-1', 'Gene', (32, 37))	('TTF-1', 'Gene', '7270', (32, 37))	('PD-L1', 'Gene', '29126', (68, 73))
422097	28671973	Our study finds a shorter overall survival in PSCGC carcinoma which is in accordance with another study in this rare subtype, nervertheless this results in our study should be interpreted with caution because the stage of patients in PD-L1 positive group is more progressive than that of PD-L1 negative group.	('PD-L1', 'Gene', '29126', (288, 293))	('carcinoma', 'Phenotype', 'HP:0030731', (52, 61))	('carcinoma', 'Disease', (52, 61))	('patients', 'Species', '9606', (222, 230))	('positive', 'Var', (240, 248))	('PD-L1', 'Gene', (288, 293))	('shorter', 'NegReg', (18, 25))	('SC', 'Phenotype', 'HP:0100242', (47, 49))	('PD-L1', 'Gene', (234, 239))	('overall', 'MPA', (26, 33))	('carcinoma', 'Disease', 'MESH:D002277', (52, 61))	('PD-L1', 'Gene', '29126', (234, 239))
422098	28671973	In lung adenocarcinoma, the presence of KRAS or the absence of targetable mutation are associated with PD-L1 expression, whereas EGFR or other common mutated adenocarcinoma rarely express PD-L1.	('adenocarcinoma', 'Disease', (158, 172))	('PD-L1', 'Gene', (103, 108))	('EGFR', 'Gene', (129, 133))	('lung adenocarcinoma', 'Disease', (3, 22))	('PD-L1', 'Gene', '29126', (103, 108))	('adenocarcinoma', 'Disease', 'MESH:D000230', (8, 22))	('associated', 'Reg', (87, 97))	('adenocarcinoma', 'Disease', 'MESH:D000230', (158, 172))	('KRAS', 'Gene', '3845', (40, 44))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (3, 22))	('KRAS', 'Gene', (40, 44))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (3, 22))	('EGFR', 'Gene', '1956', (129, 133))	('PD-L1', 'Gene', (188, 193))	('carcinoma', 'Phenotype', 'HP:0030731', (13, 22))	('PD-L1', 'Gene', '29126', (188, 193))	('presence', 'Var', (28, 36))	('expression', 'MPA', (109, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (163, 172))	('adenocarcinoma', 'Disease', (8, 22))
422099	28671973	A study in SC found that KRAS mutations are associated with PD-L1 expression, probably because these mutations are more likely to occur in smokers.	('associated', 'Reg', (44, 54))	('PD-L1', 'Gene', (60, 65))	('expression', 'MPA', (66, 76))	('mutations', 'Var', (30, 39))	('PD-L1', 'Gene', '29126', (60, 65))	('KRAS', 'Gene', (25, 29))	('SC', 'Phenotype', 'HP:0100242', (11, 13))	('KRAS', 'Gene', '3845', (25, 29))
422105	28671973	A study on pleomorphic carcinoma found that the amount of CD8+ or PD-1+ TILs and the ratio of PD-1+/CD8+ TILs in PC were higher in males, smokers and older patients.	('patients', 'Species', '9606', (156, 164))	('CD8+', 'Var', (58, 62))	('PD-1+', 'Chemical', '-', (66, 71))	('pleomorphic carcinoma', 'Disease', 'MESH:D008228', (11, 32))	('pleomorphic carcinoma', 'Disease', (11, 32))	('PD-1+', 'Chemical', '-', (94, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (23, 32))	('PD-1+', 'Var', (66, 71))	('higher', 'PosReg', (121, 127))
422113	28671973	Another hope for patients with lung SC is the relatively higher frequency in this subtype of exon 14 skipping of MET (hepatocyte growth factor receptor gene).	('MET', 'Gene', (113, 116))	('hepatocyte growth factor receptor', 'Gene', '4233', (118, 151))	('SC', 'Phenotype', 'HP:0100242', (36, 38))	('lung SC', 'Disease', (31, 38))	('hepatocyte growth factor receptor', 'Gene', (118, 151))	('skipping', 'Var', (101, 109))	('exon 14 skipping', 'Var', (93, 109))	('patients', 'Species', '9606', (17, 25))
422129	24860692	Studies have shown that several immunohistochemical (IHC) markers are highly expressed in CC including Annexin A1 (94.1%), CK19 (89%), MOC31 (88.2%), CK7 (83.4%), CD133 (79%), claudin4 (69.2%), high mobility group A1 (HMGA1) (31.5%) and S100P, while others has no or very low expression in CC such as glypican 3 (GPC3) (7%) and biglycan (7%).	('HMGA1', 'Gene', (218, 223))	('GPC3', 'Gene', '2719', (313, 317))	('high mobility group A1', 'Gene', (194, 216))	('S100P', 'Var', (237, 242))	('claudin4', 'Gene', '1364', (176, 184))	('glypican 3', 'Gene', (301, 311))	('CK7', 'Gene', (150, 153))	('CC', 'Phenotype', 'HP:0030153', (290, 292))	('CK19', 'Gene', (123, 127))	('CK19', 'Gene', '3880', (123, 127))	('CC', 'Phenotype', 'HP:0030153', (90, 92))	('Annexin A1', 'Gene', '301', (103, 113))	('MOC31', 'Var', (135, 140))	('CK7', 'Gene', '3855', (150, 153))	('Annexin A1', 'Gene', (103, 113))	('HMGA1', 'Gene', '3159', (218, 223))	('high mobility group A1', 'Gene', '3159', (194, 216))	('CD133', 'Gene', (163, 168))	('GPC3', 'Gene', (313, 317))	('claudin4', 'Gene', (176, 184))	('S100P', 'SUBSTITUTION', 'None', (237, 242))	('CD133', 'Gene', '8842', (163, 168))	('glypican 3', 'Gene', '2719', (301, 311))
422161	24860692	In contrast, CK19 positivity does not discriminate CC and non-cancerous NBD, and should be used only for confirmation of a bile duct (biliary) lineage.	('CC', 'Phenotype', 'HP:0030153', (51, 53))	('non-cancerous NBD', 'Disease', (58, 75))	('non-cancerous NBD', 'Disease', 'MESH:D009369', (58, 75))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('positivity', 'Var', (18, 28))	('CK19', 'Gene', (13, 17))	('CK19', 'Gene', '3880', (13, 17))
422207	33211709	High infiltrates of CD3+ and CD8+ cells in CT was associated with significantly improved survival.	('CD8', 'Gene', '925', (29, 32))	('survival', 'CPA', (89, 97))	('improved', 'PosReg', (80, 88))	('CD3+', 'Var', (20, 24))	('CD8', 'Gene', (29, 32))
422221	33211709	Hot immune tumors have high infiltration of CD3+ and CD8+ T cells in the invasive margin (IM) and center of tumor (CT), while in cold tumors, there is the absence of T cell infiltrates within the IM and CT.	('CD8', 'Gene', (53, 56))	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('CD3+', 'Var', (44, 48))	('tumor', 'Disease', (108, 113))	('tumors', 'Disease', 'MESH:D009369', (11, 17))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('cold tumors', 'Disease', (129, 140))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('tumors', 'Disease', (134, 140))	('tumor', 'Disease', (11, 16))	('cold tumors', 'Disease', 'MESH:D000067390', (129, 140))	('tumor', 'Disease', 'MESH:D009369', (11, 16))	('tumors', 'Disease', 'MESH:D009369', (134, 140))	('CD8', 'Gene', '925', (53, 56))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('tumors', 'Phenotype', 'HP:0002664', (11, 17))	('tumor', 'Disease', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('tumors', 'Disease', (11, 17))	('tumor', 'Disease', 'MESH:D009369', (134, 139))
422229	33211709	Communication between cancer cells with various stromal cells of the TME also promotes metastasis.	('promotes', 'PosReg', (78, 86))	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('metastasis', 'CPA', (87, 97))	('Communication', 'Var', (0, 13))	('cancer', 'Disease', (22, 28))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))
422260	33211709	Mann-Whitney U test was performed to compare the expression level of immune cell marker between node-positive vs negative groups and tumor size T1-T2 vs T3-T4 groups.	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('expression', 'MPA', (49, 59))	('T1-T2', 'Var', (144, 149))	('tumor', 'Disease', (133, 138))
422272	33211709	The presence of a high percentage of CD3+cells both in IM (p = 0.006 95% CI) and CT (p = 0.003 95% CI) was associated with small tumor size (T1 & T2).	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('small tumor', 'Disease', 'MESH:D058405', (123, 134))	('CD3+cells', 'Var', (37, 46))	('small tumor', 'Disease', (123, 134))
422273	33211709	No statistically significant difference (P>0.05) in the expression CD15, CD14, and CD56 were observed between the T1&T2 and T3&T4 groups (S2 Fig).	('CD56', 'Gene', '4684', (83, 87))	('CD15', 'Gene', '2526', (67, 71))	('CD15', 'Gene', (67, 71))	('T1&', 'Var', (114, 117))	('CD56', 'Gene', (83, 87))	('CD14', 'Gene', (73, 77))	('CD14', 'Gene', '929', (73, 77))
422274	33211709	However, there were significant differences in the expression of Granzyme B between T1-T2 vs T3-T4 in both IM (P = 0.003 95%CI) and CT (P = 0.018 95% CI).	('Granzyme B', 'Gene', (65, 75))	('differences', 'Reg', (32, 43))	('T3-T4', 'Var', (93, 98))	('expression', 'MPA', (51, 61))	('Granzyme B', 'Gene', '3002', (65, 75))	('T1-T2', 'Var', (84, 89))
422275	33211709	We also observed significant differences in expression of Neutrophil Elastase and Arginase1 (P = 0.003 95%CI) in IM between T1-T2 vs T3-T4 (P = 0.047 95%CI).	('differences', 'Reg', (29, 40))	('expression', 'MPA', (44, 54))	('Arginase1', 'Gene', (82, 91))	('Neutrophil Elastase', 'Gene', '1991', (58, 77))	('T1-T2', 'Var', (124, 129))	('Arginase1', 'Gene', '383', (82, 91))	('Neutrophil Elastase', 'Gene', (58, 77))
422278	33211709	Patients with high percentages of CD3+, CD8+, and CD68+ cells at the IM and CT, had fewer lymph node metastasis.	('lymph node metastasis', 'CPA', (90, 111))	('CD8', 'Gene', '925', (40, 43))	('fewer', 'NegReg', (84, 89))	('CD68', 'Gene', (50, 54))	('CD68', 'Gene', '968', (50, 54))	('Patients', 'Species', '9606', (0, 8))	('CD3+', 'Var', (34, 38))	('CD8', 'Gene', (40, 43))
422293	33211709	High counts of CD3 + and CD68+ cells at the IM and CT were associated with smaller tumor size.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('CD3 +', 'Var', (15, 20))	('tumor', 'Disease', (83, 88))	('smaller', 'NegReg', (75, 82))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('CD68', 'Gene', (25, 29))	('CD68', 'Gene', '968', (25, 29))
422295	33211709	There is evidence that presence of high numbers of CD3+ T cells are associated with good prognosis and increased survival in oral squamous cell carcinoma.	('survival', 'CPA', (113, 121))	('CD3+ T cells', 'Var', (51, 63))	('increased', 'PosReg', (103, 112))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (125, 153))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (130, 153))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('oral squamous cell carcinoma', 'Disease', (125, 153))
422320	33211709	High immunoscores based on quantification of densities of CD3+ and CD8+ in IM and CT in primary tumors has been shown to be associated with lower metastases in colon cancer patients.	('metastases in colon cancer', 'Disease', (146, 172))	('lower', 'NegReg', (140, 145))	('colon cancer', 'Phenotype', 'HP:0003003', (160, 172))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('patients', 'Species', '9606', (173, 181))	('metastases in colon cancer', 'Disease', 'MESH:D009362', (146, 172))	('tumors', 'Disease', (96, 102))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('CD3+', 'Var', (58, 62))	('CD8', 'Gene', (67, 70))	('CD8', 'Gene', '925', (67, 70))
422326	33211709	In our study, high CD68 density had association with lymph node negative disease.	('CD68', 'Gene', (19, 23))	('high', 'Var', (14, 18))	('CD68', 'Gene', '968', (19, 23))	('lymph node negative disease', 'Disease', 'MESH:D000072717', (53, 80))	('association', 'Interaction', (36, 47))	('lymph node negative disease', 'Disease', (53, 80))
422358	33211709	The title is intricate and should be rephrased (Density of CD3+ and CD8+ cells in gingiva-buccal oral squamous cell carcinoma is associated with lymph node metastases and survival).	('gingiva-buccal oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (82, 125))	('associated with', 'Reg', (129, 144))	('survival', 'CPA', (171, 179))	('CD8', 'Gene', (68, 71))	('metastases', 'Disease', (156, 166))	('CD8', 'Gene', '925', (68, 71))	('gingiva-buccal oral squamous cell carcinoma', 'Disease', (82, 125))	('metastases', 'Disease', 'MESH:D009362', (156, 166))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('CD3+', 'Var', (59, 63))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (102, 125))
422360	33211709	"Furthermore, high densities of CD3+ and CD8+ cells in CT resulted in a significantly longer patient survival" should be revised as the term "resulted in" suggests a causal relationship that cannot be determined based on this type of study.	('CD3+', 'Var', (32, 36))	('CD8', 'Gene', (41, 44))	('longer', 'PosReg', (86, 92))	('patient survival', 'CPA', (93, 109))	('CD8', 'Gene', '925', (41, 44))	('patient', 'Species', '9606', (93, 100))
422387	33211709	The statement that CD68 cannot be considered a marker of significance is not supported by many recent studies, that have found that high CD68 expression is frequently associated with better survival and response to (immune)therapies.	('expression', 'MPA', (142, 152))	('CD68', 'Gene', (19, 23))	('CD68', 'Gene', '968', (19, 23))	('CD68', 'Gene', (137, 141))	('CD68', 'Gene', '968', (137, 141))	('high', 'Var', (132, 136))	('better', 'PosReg', (183, 189))
422391	33211709	Remove of Page 8: 'Patients with high percentages of CD3+, CD8+ and CD68 + cells at the tumor centers and invasive margins were more frequently lymph node metastasis negative.'	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('CD3+', 'Var', (53, 57))	('Patients', 'Species', '9606', (19, 27))	('CD8', 'Gene', (59, 62))	('lymph node metastasis negative', 'CPA', (144, 174))	('CD68', 'Gene', (68, 72))	('CD8', 'Gene', '925', (59, 62))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('CD68', 'Gene', '968', (68, 72))	('tumor', 'Disease', (88, 93))
422407	33176591	Silencing ubiquitin resulted in the suppression of cell growth, chemoresistance, colony formation and cell migration in esophageal squamous cell carcinoma cells.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (131, 154))	('cell growth', 'CPA', (51, 62))	('carcinoma', 'Phenotype', 'HP:0030731', (145, 154))	('ubiquitin', 'Protein', (10, 19))	('esophageal squamous cell carcinoma', 'Disease', (120, 154))	('chemoresistance', 'CPA', (64, 79))	('colony formation', 'CPA', (81, 97))	('suppression', 'NegReg', (36, 47))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (120, 154))	('Silencing', 'Var', (0, 9))	('cell migration', 'CPA', (102, 116))
422408	33176591	Proteomic analysis in esophageal squamous cell carcinoma cells showed that knockdown of ubiquitin coding genes deregulated the expression of 159 proteins (92 were upregulated and 67 were downregulated) involved in multiple pathways.	('downregulated', 'NegReg', (187, 200))	('deregulated', 'NegReg', (111, 122))	('esophageal squamous cell carcinoma', 'Disease', (22, 56))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (33, 56))	('ubiquitin coding genes', 'Gene', (88, 110))	('proteins', 'Protein', (145, 153))	('expression of', 'MPA', (127, 140))	('knockdown', 'Var', (75, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (47, 56))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (22, 56))	('upregulated', 'PosReg', (163, 174))
422423	33176591	The UBA52 and RPS27A genes encode the fusion ribosomal proteins L40 and S27a, respectively, and are thought to be essential for protein synthesis.	('RPS27A', 'Gene', '6233', (14, 20))	('UBA52', 'Gene', '7311', (4, 9))	('RPS27A', 'Gene', (14, 20))	('UBA52', 'Gene', (4, 9))	('S27a', 'Var', (72, 76))
422428	33176591	We have previously reported that ubiquitin expression was significantly upregulated in human lung cancer cells and that silencing ubiquitin genes inhibited the proliferation and radioresistance of H1299 xenografts by promoting apoptosis.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('radioresistance', 'CPA', (178, 193))	('lung cancer', 'Disease', 'MESH:D008175', (93, 104))	('human', 'Species', '9606', (87, 92))	('lung cancer', 'Phenotype', 'HP:0100526', (93, 104))	('H1299', 'CellLine', 'CVCL:0060', (197, 202))	('ubiquitin genes', 'Gene', (130, 145))	('apoptosis', 'CPA', (227, 236))	('silencing', 'Var', (120, 129))	('lung cancer', 'Disease', (93, 104))	('inhibited', 'NegReg', (146, 155))	('ubiquitin expression', 'MPA', (33, 53))	('upregulated', 'PosReg', (72, 83))	('promoting', 'PosReg', (217, 226))
422484	33176591	Carbamidomethyl on Cys, TMT-6plex (N-term), and TMT-6plex (K) were specified as fixed modifications, and oxidation on Met was specified as a variable modification.	('Carbamidomethyl', 'Chemical', '-', (0, 15))	('Cys', 'Chemical', 'MESH:D003545', (19, 22))	('TMT-6plex', 'Var', (24, 33))	('TMT-6plex', 'Var', (48, 57))	('Carbamidomethyl', 'Var', (0, 15))
422497	33176591	As measured by real-time PCR analysis, the most effective shRNAs for the knockdown of UBB and UBC were shRNA-1 and shRNA-2, respectively, in both Eca-109 and TE-1 cells (Figures 2B and C).	('UBC', 'Gene', '7316', (94, 97))	('UBC', 'Gene', (94, 97))	('UBB', 'Gene', (86, 89))	('shRNA-2', 'Gene', (115, 122))	('shRNA-1', 'Gene', (103, 110))	('UBB', 'Gene', '7314', (86, 89))	('knockdown', 'Var', (73, 82))
422499	33176591	As shown in the MTT assay (Figure 3A and B), knockdown of UBB/UBC appeared to suppress the cell viability of Eca-109 and TE-1 cells with or without cisplatin.	('cisplatin', 'Chemical', 'MESH:D002945', (148, 157))	('suppress', 'NegReg', (78, 86))	('UBB/UBC', 'Gene', '7314;7316', (58, 65))	('UBB/UBC', 'Gene', (58, 65))	('cell viability', 'CPA', (91, 105))	('knockdown', 'Var', (45, 54))	('MTT', 'Chemical', 'MESH:C070243', (16, 19))
422500	33176591	The combined knockdown of UBB and UBC also significantly decreased the migration and invasion of Eca-109 and TE-1 cells (Figure 3D).	('UBB', 'Gene', (26, 29))	('UBB', 'Gene', '7314', (26, 29))	('migration', 'CPA', (71, 80))	('decreased', 'NegReg', (57, 66))	('UBC', 'Gene', '7316', (34, 37))	('knockdown', 'Var', (13, 22))	('UBC', 'Gene', (34, 37))
422501	33176591	These results indicated that silencing of ubiquitin coding genes (UBB and UBC) abrogated the aggressive phenotypes of ESCC cells.	('ESCC', 'Disease', (118, 122))	('silencing', 'Var', (29, 38))	('UBB', 'Gene', (66, 69))	('UBC', 'Gene', '7316', (74, 77))	('aggressive phenotypes', 'CPA', (93, 114))	('UBC', 'Gene', (74, 77))	('UBB', 'Gene', '7314', (66, 69))	('abrogated', 'NegReg', (79, 88))
422505	33176591	Dysfunction of ubiquitin has been implicated in a vast array of human diseases, including cancer.	('human', 'Species', '9606', (64, 69))	('Dysfunction', 'Var', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('ubiquitin', 'Protein', (15, 24))	('implicated', 'Reg', (34, 44))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))
422514	33176591	Silencing ubiquitin induces apoptotic cell death, indicating that ubiquitin might be a potential target for cancer treatment.	('death', 'Disease', 'MESH:D003643', (43, 48))	('death', 'Disease', (43, 48))	('ubiquitin', 'Protein', (10, 19))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('Silencing', 'Var', (0, 9))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
422515	33176591	Consistent with previous studies, we found that knock-down of UBB/UBC resulted in decreased ESCC cell growth, colony formation and migration, suggesting that ubiquitin may be a potent inhibitor in esophageal cancer progression.	('UBB/UBC', 'Gene', (62, 69))	('esophageal cancer', 'Disease', 'MESH:D004938', (197, 214))	('ESCC', 'Disease', (92, 96))	('migration', 'CPA', (131, 140))	('knock-down', 'Var', (48, 58))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('decreased ESCC', 'Phenotype', 'HP:0025022', (82, 96))	('UBB/UBC', 'Gene', '7314;7316', (62, 69))	('esophageal cancer', 'Disease', (197, 214))	('colony formation', 'CPA', (110, 126))	('decreased', 'NegReg', (82, 91))
422517	33176591	In this study, we revealed that silencing UBB/UBC contributed to decreased chemoresistance.	('decreased', 'NegReg', (65, 74))	('silencing', 'Var', (32, 41))	('chemoresistance', 'CPA', (75, 90))	('UBB/UBC', 'Gene', '7314;7316', (42, 49))	('UBB/UBC', 'Gene', (42, 49))
422529	33176591	In previous studies, we found that silencing ubiquitin genes inhibited the expression of anti-apoptotic protein Bcl-2 in lung cancer H1299 cells, and silencing ubiquitin genes suppressed the proliferation and radioresistance of H1299 transplanted xenografts by promoting apoptosis.	('lung cancer', 'Disease', 'MESH:D008175', (121, 132))	('inhibited', 'NegReg', (61, 70))	('promoting', 'PosReg', (261, 270))	('silencing', 'Var', (150, 159))	('H1299', 'CellLine', 'CVCL:0060', (133, 138))	('lung cancer', 'Phenotype', 'HP:0100526', (121, 132))	('proliferation', 'CPA', (191, 204))	('H1299', 'CellLine', 'CVCL:0060', (228, 233))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('ubiquitin genes', 'Gene', (45, 60))	('lung cancer', 'Disease', (121, 132))	('Bcl-2', 'Gene', (112, 117))	('silencing', 'Var', (35, 44))	('radioresistance', 'CPA', (209, 224))	('ubiquitin', 'Gene', (160, 169))	('suppressed', 'NegReg', (176, 186))	('Bcl-2', 'Gene', '596', (112, 117))	('apoptosis', 'CPA', (271, 280))	('expression', 'MPA', (75, 85))
422549	33092626	Our patient, who had been staged T4N3M1(TNM classification), had also lost his vision more than a month earlier.	('TNM', 'Gene', (40, 43))	('vision', 'MPA', (79, 85))	('patient', 'Species', '9606', (4, 11))	('lost', 'NegReg', (70, 74))	('T4N3M1', 'Var', (33, 39))	('TNM', 'Gene', '10178', (40, 43))
422578	33092626	The MRI scan of our patient's orbit showed a fusiform mass that presented as hyperintense on T1-weighted images and hypointense on T2-weighted images, in contrast to results from previous studies.	('T1-weighted images', 'MPA', (93, 111))	('patient', 'Species', '9606', (20, 27))	('hypointense', 'Var', (116, 127))
422605	32467987	CAFs and cancer cells have been revealed to have the ability to release exosomal microRNAs (miRNAs) to exert effects over each other, and the extracellular vesicles (EVs) can be categorized into three types, on the basis of biogenesis and size: Exosomes (30-100 nm); microvesicles (100-1000 nm); and oncosomes (1-10 mum).	('100-1000 nm', 'Var', (282, 293))	('cancer', 'Disease', (9, 15))	('30-100 nm', 'Var', (255, 264))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('CAF', 'Gene', (0, 3))	('mum', 'Gene', '56925', (316, 319))	('CAF', 'Gene', '8850', (0, 3))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('mum', 'Gene', (316, 319))
422610	32467987	Glomus cells with inactivated NF1 exhibited elevated Ras-mitogen-activated protein kinase (MAPK) signals.	('MAPK', 'Gene', (91, 95))	('elevated', 'PosReg', (44, 52))	('NF1', 'Gene', (30, 33))	('MAPK', 'Gene', '5604', (91, 95))	('inactivated', 'Var', (18, 29))
422612	32467987	In addition, NF1 deficiency facilities murine Kirsten rat sarcoma viral oncogene homolog gene-driven tumorigenesis of lung adenocarcinomas, which may validate the functional activity of NF1 mutations in NSCLC and the efficacy of targeted suppression of downstream Ras signaling pathway.	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (118, 138))	('murine', 'Species', '10090', (39, 45))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (118, 137))	('NSCLC', 'Disease', 'MESH:D002289', (203, 208))	('mutations', 'Var', (190, 199))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('rat', 'Species', '10116', (54, 57))	('NF1', 'Gene', (13, 16))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (118, 138))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('sarcoma', 'Disease', 'MESH:D012509', (58, 65))	('sarcoma', 'Disease', (58, 65))	('NSCLC', 'Disease', (203, 208))	('lung adenocarcinomas', 'Disease', (118, 138))	('NSCLC', 'Phenotype', 'HP:0030358', (203, 208))	('sarcoma', 'Phenotype', 'HP:0100242', (58, 65))	('NF1', 'Gene', (186, 189))	('tumor', 'Disease', (101, 106))	('deficiency', 'Var', (17, 27))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
422655	32467987	The sequences of the primers used were as follows: miR-369 forward, 5'-GGGACCCAGTTCAAGTAATTCAGG-3'; miR-369 reverse, 5'-TTTGGCACTAGCACATT-3'; U6 forward, 5'-CTCGCTTCGGCAGCACA-3'; and U6 reverse 5'-AACGCTTCACGAATTTGCGT-3'.	('miR-369', 'Gene', (100, 107))	('miR-369', 'Gene', '442914', (100, 107))	('U6 reverse', 'Var', (183, 193))	('miR-369', 'Gene', '442914', (51, 58))	('miR-369', 'Gene', (51, 58))	('U6 forward', 'Var', (142, 152))
422679	32467987	StarBase (http://starbase.sysu.edu.cn/), a bioinformatic software, was chosen to predict the binding sequence of miR-369 and NF1-3' untranslated region (UTR).	('NF1-3', 'Var', (125, 130))	('miR-369', 'Gene', (113, 120))	('miR-369', 'Gene', '442914', (113, 120))	('binding', 'Interaction', (93, 100))
422691	32467987	The tumor tissues from each group were paraffin-embedded, dewaxed (in xylene I and xylene II for 20 min, respectively) and hydrated (twice in anhydrous ethanol, once in 95% ethanol and once in 80% ethanol; 5 min each time).	('tumor', 'Disease', (4, 9))	('ethanol', 'Chemical', 'MESH:D000431', (173, 180))	('ethanol', 'Chemical', 'MESH:D000431', (152, 159))	('xylene I', 'Chemical', '-', (83, 91))	('xylene', 'Var', (83, 89))	('xylene I', 'Chemical', '-', (70, 78))	('ethanol', 'Chemical', 'MESH:D000431', (197, 204))	('xylene II', 'Chemical', '-', (83, 92))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('paraffin', 'Chemical', 'MESH:D010232', (39, 47))	('rat', 'Species', '10116', (126, 129))
422716	32467987	The expression levels of miR-369 in H520 and SK-MES-1 cells were then detected by RT-qPCR, which was enhanced by treatment with EVs (Fig.	('expression levels', 'MPA', (4, 21))	('RT-qPCR', 'Var', (82, 89))	('enhanced', 'PosReg', (101, 109))	('miR-369', 'Gene', '442914', (25, 32))	('miR-369', 'Gene', (25, 32))	('detected', 'MPA', (70, 78))	('SK-MES-1', 'CellLine', 'CVCL:0630', (45, 53))
422724	32467987	It was reported previously that the NF1 mutation could promote or lead to the occurrence of lung adenocarcinomas.	('mutation', 'Var', (40, 48))	('NF1', 'Gene', (36, 39))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (92, 111))	('lung adenocarcinomas', 'Disease', (92, 112))	('lead to', 'Reg', (66, 73))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (92, 112))	('promote', 'PosReg', (55, 62))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (92, 112))
422732	32467987	Furthermore, in the in vivo metastasis model, it was identified that the number of liver metastases and lung metastases increased significantly following EVs treatment (Fig.	('lung metastases', 'Disease', (104, 119))	('lung metastases', 'Disease', 'MESH:D009362', (104, 119))	('liver metastases', 'Disease', (83, 99))	('EVs', 'Var', (154, 157))	('liver metastases', 'Disease', 'MESH:D009362', (83, 99))	('increased', 'PosReg', (120, 129))
422737	32467987	These results suggest that the dysregulation of miR-369 may serve a paramount role in accelerating tumorigenesis and metastases in LUSC.	('tumor', 'Disease', (99, 104))	('miR-369', 'Gene', (48, 55))	('metastases', 'Disease', 'MESH:D009362', (117, 127))	('LUSC', 'Phenotype', 'HP:0030359', (131, 135))	('rat', 'Species', '10116', (92, 95))	('accelerating', 'PosReg', (86, 98))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('dysregulation', 'Var', (31, 44))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('metastases', 'Disease', (117, 127))	('miR-369', 'Gene', '442914', (48, 55))
422745	32467987	Aberrations in NF1 contribute to the dysregulation of the RAS/MAPK signaling pathway, culminating in disfunction of cell growth and proliferation.	('NF1', 'Gene', (15, 18))	('rat', 'Species', '10116', (139, 142))	('dysregulation', 'MPA', (37, 50))	('MAPK', 'Gene', (62, 66))	('MAPK', 'Gene', '5604', (62, 66))	('rat', 'Species', '10116', (4, 7))	('Aberrations', 'Var', (0, 11))	('disfunction', 'MPA', (101, 112))
422751	32467987	Notably, CAFs-EVs exhibited stimulatory effects on the growth of the H520 and SK-MES-1 cell lines in vivo, suggesting that the inhibition of CAFs-EVs may be a potential therapeutic strategy in LUSC.	('rat', 'Species', '10116', (183, 186))	('LUSC', 'Phenotype', 'HP:0030359', (193, 197))	('growth', 'CPA', (55, 61))	('LUSC', 'Disease', (193, 197))	('SK-MES-1', 'CellLine', 'CVCL:0630', (78, 86))	('inhibition', 'Var', (127, 137))	('CAFs-EVs', 'Chemical', '-', (141, 149))	('CAFs-EVs', 'Chemical', '-', (9, 17))
422763	30400878	Some studies also suggest that CDG mutations contribute to cancer-associated epigenomic and transcriptomic alterations across many cancer types.	('cancer', 'Disease', (131, 137))	('epigenomic', 'MPA', (77, 87))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('transcriptomic alterations', 'MPA', (92, 118))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('cancer', 'Disease', (59, 65))	('CDG', 'Gene', (31, 34))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('contribute', 'Reg', (45, 55))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('CDG', 'Chemical', '-', (31, 34))	('mutations', 'Var', (35, 44))
422764	30400878	Here we aim to improve our understanding of the connections between CDG mutations and altered cancer cell epigenomes and transcriptomes on pan-cancer level and how these connections contribute to the known association between epigenome and transcriptome.	('mutations', 'Var', (72, 81))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('CDG', 'Gene', (68, 71))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('CDG', 'Chemical', '-', (68, 71))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
422770	30400878	Cancer arises through accumulation of somatically acquired genetic and epigenetic aberrations that lead to malignant transformation.	('epigenetic aberrations', 'Var', (71, 93))	('lead to', 'Reg', (99, 106))	('malignant transformation', 'CPA', (107, 131))	('genetic', 'Var', (59, 66))	('Cancer', 'Disease', (0, 6))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))
422771	30400878	Comprehensive characterization of somatic mutations in cancer genomes using next-generation sequencing technology has led to discoveries of cancer driver genes (CDGs) in human cancers.	('cancers', 'Disease', (176, 183))	('cancers', 'Disease', 'MESH:D009369', (176, 183))	('CDGs', 'Chemical', '-', (161, 165))	('cancers', 'Phenotype', 'HP:0002664', (176, 183))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('human', 'Species', '9606', (170, 175))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('cancer', 'Disease', (176, 182))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('mutations', 'Var', (42, 51))	('cancer', 'Disease', (55, 61))
422772	30400878	Specifically, genome-wide change of DNA methylation was observed in patients with mutations in epigenetic regulators, affecting both the global levels of 5-methyl-cytosine (5mC) and the precise DNA methylation patterns in diverse regulatory sequences across the genome.	('affecting', 'Reg', (118, 127))	('5mC', 'Chemical', 'MESH:D044503', (173, 176))	('5-methyl-cytosine', 'Chemical', 'MESH:D044503', (154, 171))	('patients', 'Species', '9606', (68, 76))	('DNA methylation patterns', 'MPA', (194, 218))	('mutations', 'Var', (82, 91))	('change', 'Reg', (26, 32))
422773	30400878	A recent study investigated associations between driver gene mutations and DNA methylation alterations across many cancer types, and identified associations between mutated driver genes and site-specific methylation changes as well as some genome-wide trends in specific cancer types.	('associations', 'Interaction', (144, 156))	('cancer', 'Disease', (115, 121))	('associations', 'Interaction', (28, 40))	('cancer', 'Phenotype', 'HP:0002664', (271, 277))	('mutations', 'Var', (61, 70))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('cancer', 'Disease', 'MESH:D009369', (271, 277))	('DNA', 'Gene', (75, 78))	('cancer', 'Disease', (271, 277))	('cancer', 'Disease', 'MESH:D009369', (115, 121))
422775	30400878	However, it remains largely unknown how the CDG mutations contribute to changes in cancer cell epigenomes on a pan-cancer level.	('cancer', 'Disease', (115, 121))	('CDG', 'Gene', (44, 47))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('CDG', 'Chemical', '-', (44, 47))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('changes', 'Reg', (72, 79))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('mutations', 'Var', (48, 57))	('cancer', 'Disease', (83, 89))
422776	30400878	A better understanding of the connections between CDGs and altered cancer cell epigenomes is an important goal, particularly since mutations in epigenetic regulators could be novel targets for anti-cancer therapies.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('mutations', 'Var', (131, 140))	('cancer', 'Disease', (67, 73))	('cancer', 'Disease', (198, 204))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('CDGs', 'Chemical', '-', (50, 54))
422778	30400878	An integrative analysis of DNA methylation data and gene expression data of various cancer types identified pan-cancer hypo- and hyper-methylated genes that are predictive of transcription as well as methylation-driven subgroups with clinical implications.	('hypo-', 'Var', (119, 124))	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('cancer', 'Disease', (84, 90))	('hyper-methylated', 'Var', (129, 145))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))
422780	30400878	Here we aim to improve our understanding of the connections between CDGs and altered cancer cell epigenomes and altered cancer cell transcriptome on pan-cancer level, and how these connections contribute to the known association between cancer epigenome and transcriptome.	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('cancer', 'Disease', (153, 159))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('CDGs', 'Chemical', '-', (68, 72))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('cancer', 'Disease', (85, 91))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('CDGs', 'Var', (68, 72))	('cancer', 'Disease', 'MESH:D009369', (237, 243))	('cancer', 'Disease', (237, 243))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
422781	30400878	We used somatic mutation, DNA methylation, and gene expression data of 20 cancer types from The Cancer Genome Atlas (TCGA) project to identify CDGs that, when mutated, have strong associations with genome-wide methylation or expression changes across cancer types, which we refer as methylation driver genes (MDGs) or expression driver genes (EDGs).	('CDGs', 'Chemical', '-', (143, 147))	('expression changes', 'MPA', (225, 243))	('mutated', 'Var', (159, 166))	('methylation', 'MPA', (210, 221))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('CDGs', 'Gene', (143, 147))	('MDG', 'Gene', (309, 312))	('associations', 'Interaction', (180, 192))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('EDG', 'Chemical', '-', (343, 346))	('MDG', 'Gene', '4350', (309, 312))	('cancer', 'Disease', (74, 80))	('Cancer Genome Atlas', 'Disease', (96, 115))	('Cancer', 'Phenotype', 'HP:0002664', (96, 102))	('cancer', 'Disease', 'MESH:D009369', (251, 257))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (96, 115))	('cancer', 'Disease', (251, 257))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
422784	30400878	This finding shows that dysregulation of chromatin regulators is potentially an important mechanism that induces global change of DNA methylation and gene expression in tumor development.	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('DNA methylation', 'MPA', (130, 145))	('gene expression', 'MPA', (150, 165))	('dysregulation', 'Var', (24, 37))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('tumor', 'Disease', (169, 174))
422787	30400878	We then corrected for the type I/II probe bias using the BMIQ algorithm  We obtained level 2 somatic mutation data of the above-mentioned 20 tumor types from Broad Institute TCGA Genome Data Analysis Center Firehose and selected candidate CDGs using the MutSIG algorithm that tests how frequently a gene is mutated in a tumor type comparing to the background mutation rate.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('tumor', 'Disease', 'MESH:D009369', (320, 325))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumor', 'Phenotype', 'HP:0002664', (320, 325))	('mutated', 'Var', (307, 314))	('tumor', 'Disease', (141, 146))	('tumor', 'Disease', (320, 325))	('CDGs', 'Chemical', '-', (239, 243))
422792	30400878	To conduct pan-cancer analysis associating mutation and methylation/expression, within a tumor type, we selected CDGs that have mutations in at least 5 samples with matched methylation data or expression data in order to have not-too-sparse numbers in the mutated group.	('CDGs', 'Gene', (113, 117))	('mutations', 'Var', (128, 137))	('cancer', 'Disease', (15, 21))	('cancer', 'Disease', 'MESH:D009369', (15, 21))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('CDGs', 'Chemical', '-', (113, 117))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))
422799	30400878	For the 422 CDGs, the number of tumor types in which a CDG is mutated in at least five samples varies from 1 to 14 (Additional file 2: Table S2), where TP53 and PTEN were mutated in 14 tumor types.	('tumor', 'Disease', (185, 190))	('TP53', 'Gene', '7157', (152, 156))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('CDGs', 'Chemical', '-', (12, 16))	('mutated', 'Var', (171, 178))	('CDG i', 'Chemical', '-', (55, 60))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('TP53', 'Gene', (152, 156))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('PTEN', 'Gene', (161, 165))	('tumor', 'Disease', (32, 37))	('PTEN', 'Gene', '5728', (161, 165))
422802	30400878	We then determine the hyper- or hypo-methylation status per CpG site by the mutation status of CDG i using the nonparametric Wilcoxon test.	('mutation', 'Var', (76, 84))	('CDG i', 'Gene', (95, 100))	('CDG i', 'Chemical', '-', (95, 100))
422805	30400878	To determine if mutation status of CDG i is significantly associated with genome-wide methylation changes in cancer type k, we calculate the p-value pi,k, which is the probability of observing the number of differentially (hyper- or hypo-) methylated sites  or more that are associated with the mutation status of CDG i in cancer type k under the null hypothesis that the mutation status of CDG i is not associated with genome-wide methylation changes.	('cancer', 'Disease', 'MESH:D009369', (323, 329))	('mutation', 'Var', (16, 24))	('cancer', 'Disease', (323, 329))	('CDG i', 'Chemical', '-', (391, 396))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('mutation', 'Var', (295, 303))	('cancer', 'Disease', (109, 115))	('CDG i', 'Chemical', '-', (35, 40))	('cancer', 'Phenotype', 'HP:0002664', (323, 329))	('CDG i', 'Chemical', '-', (314, 319))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('CDG i', 'Gene', (314, 319))
422816	30400878	We classify the effect of CDG i on genome-wide methylation in tumor type k as: To calculate the p-value, pi, testing if CDG i is significantly associated with genome-wide methylation changes across multiple cancer types, we compare , the observed total number of differentially methylated sites associated with CDG i summed over Ai cancer types, to B resampled values generated from the "methylation null pool" where we set B=one million.	('differentially', 'Var', (263, 277))	('CDG i', 'Chemical', '-', (311, 316))	('cancer', 'Disease', 'MESH:D009369', (207, 213))	('cancer', 'Phenotype', 'HP:0002664', (332, 338))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('cancer', 'Disease', (207, 213))	('CDG i', 'Gene', (311, 316))	('tumor', 'Disease', (62, 67))	('cancer', 'Disease', 'MESH:D009369', (332, 338))	('cancer', 'Disease', (332, 338))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('CDG i', 'Chemical', '-', (120, 125))	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('CDG i', 'Chemical', '-', (26, 31))
422826	30400878	We first tested whether mutations in a CDG are significantly associated with changes in genome-wide methylation patterns in one cancer type.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('changes', 'Reg', (77, 84))	('genome-wide methylation patterns', 'MPA', (88, 120))	('CDG', 'Gene', (39, 42))	('CDG', 'Chemical', '-', (39, 42))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('mutations', 'Var', (24, 33))	('associated', 'Reg', (61, 71))	('cancer', 'Disease', (128, 134))
422828	30400878	We then used the number of genome-wide differentially methylated sites as the test statistic to measure degree of genome-wide methylation changes associated with the mutation status of a CDG for one cancer type.	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('CDG', 'Chemical', '-', (187, 190))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('cancer', 'Disease', (199, 205))	('CDG', 'Gene', (187, 190))	('mutation', 'Var', (166, 174))
422829	30400878	To assess the significance of the genome-wide methylation changes by a CDG in one cancer type, we first generated an empirical null distribution with numbers of genome-wide differentially methylated sites by mutations of non-CDGs and then calculated the p-value pi,k for CDG i in cancer type k by comparing the number of genome-wide differentially methylated sites by the mutation of CDG i in cancer type k with the empirical null distribution.	('cancer', 'Disease', (393, 399))	('CDG i', 'Chemical', '-', (384, 389))	('cancer', 'Disease', 'MESH:D009369', (280, 286))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('cancer', 'Disease', (280, 286))	('CDG i', 'Chemical', '-', (271, 276))	('cancer', 'Phenotype', 'HP:0002664', (393, 399))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('CDG i', 'Gene', (384, 389))	('mutation', 'Var', (372, 380))	('CDGs', 'Chemical', '-', (225, 229))	('cancer', 'Phenotype', 'HP:0002664', (280, 286))	('CDG i', 'Chemical', '-', (71, 76))	('cancer', 'Disease', 'MESH:D009369', (393, 399))
422830	30400878	We then classify the effect of CDG i in tumor type k as hyper-methylated if pi,k<0.05 and the number of genome-wide hyper-methylated sites is greater than that of hypo-methylated sites or hypo-methylated if pi,k<0.05 and the number of genome-wide hypo-methylated sites is greater than that of hyper-methylated sites.	('k<0.05', 'Var', (79, 85))	('CDG i', 'Gene', (31, 36))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('CDG i', 'Chemical', '-', (31, 36))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))
422837	30400878	For the complete list of CDGs whose mutation states were significantly associated with genome-wide methylation changes within each cancer type (gene i with pi,k<0.05 in the cancer type k), see Additional file 5: Table S4.	('cancer', 'Disease', (131, 137))	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('CDGs', 'Chemical', '-', (25, 29))	('cancer', 'Disease', (173, 179))	('mutation', 'Var', (36, 44))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('CDGs', 'Gene', (25, 29))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('methylation changes', 'MPA', (99, 118))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('associated', 'Reg', (71, 81))
422839	30400878	They used Principal Component Analysis (PCA) to identify driver genes whose mutations are associated with the top five PCs within each cancer.	('cancer', 'Disease', (135, 141))	('mutations', 'Var', (76, 85))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('associated', 'Reg', (90, 100))	('cancer', 'Disease', 'MESH:D009369', (135, 141))
422840	30400878	The 32 MDGs were mutated with different frequencies in each cancer types (Additional file 6: Figure S1) and the mutation status of the 32 MDGs is associated with different genome-wide number of hyper- and hypo-methylated sites (Fig.	('mutation', 'Var', (112, 120))	('MDG', 'Gene', (7, 10))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('MDG', 'Gene', '4350', (7, 10))	('MDG', 'Gene', (138, 141))	('cancer', 'Disease', (60, 66))	('MDG', 'Gene', '4350', (138, 141))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
422843	30400878	In CESC, LUSC, PAAD, and SARC tumor types, genome-wide methylation patterns were not significantly affected by mutations of any of the identified 32 MDGs, potentially due to small sample sizes or fewer number of CDGs.	('mutations', 'Var', (111, 120))	('SARC tumor', 'Disease', (25, 35))	('PAAD', 'Disease', (15, 19))	('CDGs', 'Chemical', '-', (212, 216))	('SARC tumor', 'Phenotype', 'HP:0100242', (25, 35))	('MDG', 'Gene', (149, 152))	('SARC tumor', 'Disease', 'MESH:D009369', (25, 35))	('MDG', 'Gene', '4350', (149, 152))	('LUSC', 'Disease', (9, 13))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('methylation patterns', 'MPA', (55, 75))	('CESC', 'Disease', (3, 7))
422844	30400878	TP53 mutations are associated with significant genome-wide methylation changes in 8 out of the 15 tumor types in which it was mutated in more than 5 samples (Table 1).	('TP53', 'Gene', '7157', (0, 4))	('methylation changes', 'MPA', (59, 78))	('TP53', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('15 tumor', 'Disease', (95, 103))	('15 tumor', 'Disease', 'MESH:C567447', (95, 103))
422845	30400878	Among these 8 tumor types, more CpG sites were hypo-methylated in all but LGG.	('hypo-methylated', 'Var', (47, 62))	('tumor', 'Disease', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('tumor', 'Disease', 'MESH:D009369', (14, 19))
422846	30400878	Instead, in LGG, TP53 mutations are associated with more hyper-methylated CpG sites.	('hyper-methylated', 'MPA', (57, 73))	('mutations', 'Var', (22, 31))	('more', 'PosReg', (52, 56))	('TP53', 'Gene', '7157', (17, 21))	('TP53', 'Gene', (17, 21))
422847	30400878	However, almost all LGG tumors with TP53 mutations also have IDH1 mutations (Additional file 6: Figure S1), which are known to lead to hyper-methylation in LGG.	('mutations', 'Var', (66, 75))	('LGG tumors', 'Disease', (20, 30))	('mutations', 'Var', (41, 50))	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('LGG tumors', 'Disease', 'MESH:D009369', (20, 30))	('IDH1', 'Gene', '3417', (61, 65))	('TP53', 'Gene', '7157', (36, 40))	('IDH1', 'Gene', (61, 65))	('TP53', 'Gene', (36, 40))	('hyper-methylation', 'MPA', (135, 152))
422849	30400878	Given the prominent role of IDH1 in LGG, we stratified LGG tumor samples by the IDH1 mutation status and further examined the effect of the other 31 MDGs within the IDH1 mutation stratum and the IDH1 wild-type stratum and found that TP53 mutations are now significantly associated with more hypo-methylation genome-wide in each stratum (Additional file 3: Text S1).	('LGG tumor', 'Disease', 'MESH:D009369', (55, 64))	('IDH1', 'Gene', '3417', (28, 32))	('hypo-methylation', 'MPA', (291, 307))	('IDH1', 'Gene', '3417', (195, 199))	('associated', 'Reg', (270, 280))	('IDH1', 'Gene', (80, 84))	('mutations', 'Var', (238, 247))	('IDH1', 'Gene', (165, 169))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('more', 'PosReg', (286, 290))	('TP53', 'Gene', (233, 237))	('IDH1', 'Gene', '3417', (80, 84))	('MDG', 'Gene', (149, 152))	('IDH1', 'Gene', (195, 199))	('IDH1', 'Gene', '3417', (165, 169))	('IDH1', 'Gene', (28, 32))	('MDG', 'Gene', '4350', (149, 152))	('LGG tumor', 'Disease', (55, 64))	('TP53', 'Gene', '7157', (233, 237))
422850	30400878	Similar stratified analyses were conducted in all other tumor types whose genome-wide methylation patterns were significantly associated with mutations of the identified MDGs.	('mutations', 'Var', (142, 151))	('associated', 'Reg', (126, 136))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Disease', (56, 61))	('MDG', 'Gene', (170, 173))	('MDG', 'Gene', '4350', (170, 173))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
422853	30400878	To test this hypothesis, we examined whether mutations of these 24 MDGs are associated with the expression changes of known epigenomic regulator genes across the 20 tumor types, where we used the exon level RNA-Seq data of the 20 tumor tissue types from TCGA.	('tumor', 'Disease', (230, 235))	('mutations', 'Var', (45, 54))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))	('expression', 'MPA', (96, 106))	('associated', 'Reg', (76, 86))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('tumor', 'Disease', 'MESH:D009369', (230, 235))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('MDG', 'Gene', (67, 70))	('MDG', 'Gene', '4350', (67, 70))	('tumor', 'Disease', (165, 170))
422858	30400878	For each of these 12 genes, we first identified genome-wide target genes whose expression levels were dysregulated by the mutation status commonly across tumor types.	('expression', 'MPA', (79, 89))	('mutation', 'Var', (122, 130))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('tumor', 'Disease', (154, 159))
422865	30400878	For example, TP53 mutations are associated with upregulated KDM1A expression levels across all tumor types whose genome-wide methylation patterns are also significantly associated with TP53 mutations.	('TP53', 'Gene', (13, 17))	('TP53', 'Gene', (185, 189))	('expression levels', 'MPA', (66, 83))	('mutations', 'Var', (190, 199))	('KDM1A', 'Gene', '23028', (60, 65))	('TP53', 'Gene', '7157', (185, 189))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('KDM1A', 'Gene', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('upregulated', 'PosReg', (48, 59))	('TP53', 'Gene', '7157', (13, 17))	('tumor', 'Disease', (95, 100))	('mutations', 'Var', (18, 27))
422866	30400878	KDM1A is known to physically interact with TP53 and it demethylates histone lysine residues 9 of histone 3, which in turn leads to extensive hypo-methylation in that region.	('lysine', 'Chemical', 'MESH:D008239', (76, 82))	('hypo-methylation', 'MPA', (141, 157))	('leads to', 'Reg', (122, 130))	('TP53', 'Gene', '7157', (43, 47))	('KDM1A', 'Gene', '23028', (0, 5))	('demethylates', 'Var', (55, 67))	('KDM1A', 'Gene', (0, 5))	('TP53', 'Gene', (43, 47))
422867	30400878	This analysis suggests that KDM1A may play a role in the association between TP53 mutations and genome-wide hypo-methylation changes across tumor types.	('KDM1A', 'Gene', (28, 33))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('mutations', 'Var', (82, 91))	('KDM1A', 'Gene', '23028', (28, 33))	('association', 'Interaction', (57, 68))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('TP53', 'Gene', '7157', (77, 81))	('TP53', 'Gene', (77, 81))	('tumor', 'Disease', (140, 145))
422873	30400878	We found only a small fraction of genes in list B whose expression and methylation levels are both associated with the mutation status of the MDGs (Table 2), which suggests that the differential expression of these target genes may be directly associated with mutations of these MDGs instead of being indirectly associated through changes in their methylation patterns.	('expression', 'MPA', (195, 205))	('MDG', 'Gene', (279, 282))	('MDG', 'Gene', '4350', (279, 282))	('expression', 'MPA', (56, 66))	('associated', 'Reg', (244, 254))	('MDG', 'Gene', (142, 145))	('MDG', 'Gene', '4350', (142, 145))	('mutations', 'Var', (260, 269))	('associated', 'Reg', (99, 109))
422874	30400878	We further investigated mutation status of genes in list B to examine if the mutations affect their expression or methylation levels directly and found that the majority of genes in list B were rarely mutated across tumor types (Additional file 8: Table S6).	('tumor', 'Disease', (216, 221))	('affect', 'Reg', (87, 93))	('list B', 'Gene', (182, 188))	('expression', 'MPA', (100, 110))	('mutations', 'Var', (77, 86))	('tumor', 'Disease', 'MESH:D009369', (216, 221))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('methylation levels', 'MPA', (114, 132))
422875	30400878	Although CIC was not included in the above analyses since it was mutated only in LGG, due to its important role in LGG tumors, we examined how CIC regulates expressions of target genes and found that chromatin remodeling genes in list A were significantly enriched among dysregulated target genes, in both full LGG tumor samples and in stratified samples by IDH1 mutation status (Additional file 9: Table S7).	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('LGG tumor', 'Disease', 'MESH:D009369', (115, 124))	('CIC', 'Gene', '23152', (9, 12))	('mutation', 'Var', (363, 371))	('LGG tumor', 'Disease', (311, 320))	('IDH1', 'Gene', '3417', (358, 362))	('LGG tumors', 'Disease', (115, 125))	('CIC', 'Gene', (9, 12))	('LGG tumor', 'Disease', 'MESH:D009369', (311, 320))	('CIC', 'Gene', '23152', (143, 146))	('LGG tumors', 'Disease', 'MESH:D009369', (115, 125))	('tumor', 'Phenotype', 'HP:0002664', (315, 320))	('CIC', 'Gene', (143, 146))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('IDH1', 'Gene', (358, 362))
422878	30400878	The mutation status of these 29 EDGs is associated with different genome-wide number of up- and down-regulated genes (Fig.	('EDG', 'Chemical', '-', (32, 35))	('down-regulated', 'NegReg', (96, 110))	('up-', 'PosReg', (88, 91))	('mutation', 'Var', (4, 12))
422879	30400878	For the complete list of CDGs whose mutation states were significantly associated with genome-wide expression changes within each cancer type, see Additional file 10: Table S8.	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('CDGs', 'Chemical', '-', (25, 29))	('cancer', 'Disease', (130, 136))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('associated', 'Reg', (71, 81))	('mutation', 'Var', (36, 44))
422881	30400878	To understand this high rate of overlap, within each cancer type, we examined the overlap between CDGs that are significantly associated with genome-wide methylation changes and CDGs that are significantly associated with genome-wide expression changes, and found they overlap highly.	('associated', 'Reg', (126, 136))	('CDGs', 'Disease', (98, 102))	('cancer', 'Disease', (53, 59))	('methylation changes', 'Var', (154, 173))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('CDGs', 'Chemical', '-', (178, 182))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('CDGs', 'Chemical', '-', (98, 102))
422884	30400878	A specific example of a target gene that is hypo-methylated and up-regulated by the mutation of TP53 is HSF1 gene.	('TP53', 'Gene', (96, 100))	('HSF1', 'Gene', (104, 108))	('HSF1', 'Gene', '3297', (104, 108))	('up-regulated', 'PosReg', (64, 76))	('TP53', 'Gene', '7157', (96, 100))	('mutation', 'Var', (84, 92))
422885	30400878	It is hypo-methylated and up-regulated by TP53 mutations across 9 tumor types.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('TP53', 'Gene', '7157', (42, 46))	('tumor', 'Disease', (66, 71))	('TP53', 'Gene', (42, 46))	('mutations', 'Var', (47, 56))	('up-regulated', 'PosReg', (26, 38))	('tumor', 'Disease', 'MESH:D009369', (66, 71))
422887	30400878	For each CDG, for every pair of tumor types in which it is mutated in more than five samples, we tested using a hypergeometric distribution if the number of overlapping target genes that are differentially methylated by the mutation of the CDG is larger than expected.	('tested', 'Reg', (97, 103))	('CDG', 'Chemical', '-', (240, 243))	('CDG', 'Chemical', '-', (9, 12))	('CDG i', 'Chemical', '-', (240, 245))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('mutation', 'Var', (224, 232))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('CDG', 'Gene', (240, 243))	('tumor', 'Disease', (32, 37))
422891	30400878	Our findings on how CDG mutations contribute to pan-cancer-associated epigenomic alterations and transcriptomic alterations suggest that there are potentially three mechanisms (Fig.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('contribute', 'Reg', (34, 44))	('CDG', 'Gene', (20, 23))	('epigenomic alterations', 'MPA', (70, 92))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('mutations', 'Var', (24, 33))	('CDG', 'Chemical', '-', (20, 23))
422892	30400878	We conducted a pan-cancer analysis to identify CDGs whose somatic mutations are associated with genome-wide methylation/expression changes across multiple cancer types.	('mutations', 'Var', (66, 75))	('methylation/expression', 'MPA', (108, 130))	('cancer', 'Disease', 'MESH:D009369', (19, 25))	('CDGs', 'Gene', (47, 51))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('cancer', 'Disease', (19, 25))	('CDGs', 'Chemical', '-', (47, 51))	('associated', 'Reg', (80, 90))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('cancer', 'Disease', (155, 161))	('cancer', 'Disease', 'MESH:D009369', (155, 161))
422893	30400878	We used a straightforward method to compare methylation/expression levels between mutated and non-mutated groups of each CDG.	('methylation/expression', 'MPA', (44, 66))	('mutated', 'Var', (82, 89))	('CDG', 'Chemical', '-', (121, 124))
422900	30400878	However, as Table 2 shows, the deregulation of the 18 master regulators in list B are correlated with the mutation status of the MDGs.	('MDG', 'Gene', (129, 132))	('MDG', 'Gene', '4350', (129, 132))	('mutation', 'Var', (106, 114))	('deregulation', 'MPA', (31, 43))
422905	30400878	To identify TERT-independent TL regulation, they associated somatic alterations of 196 telomere-associated genes to TL ratio between matching tumor and normal samples and found alterations of ATRX, IDH1, TP53, BCOR, and RB1 were significantly associated with relative TL elongation under FDR<0.05.	('RB1', 'Gene', (220, 223))	('associated with', 'Reg', (243, 258))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('relative TL elongation', 'CPA', (259, 281))	('BCOR', 'Gene', (210, 214))	('BCOR', 'Gene', '54880', (210, 214))	('ATRX', 'Gene', (192, 196))	('TERT', 'Gene', '7015', (12, 16))	('RB1', 'Gene', '5925', (220, 223))	('alterations', 'Var', (177, 188))	('tumor', 'Disease', (142, 147))	('IDH1', 'Gene', (198, 202))	('ATRX', 'Gene', '546', (192, 196))	('TP53', 'Gene', '7157', (204, 208))	('IDH1', 'Gene', '3417', (198, 202))	('TP53', 'Gene', (204, 208))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('TERT', 'Gene', (12, 16))
422907	30400878	In a recent review by Feinberg et al., an epigenetic functional classification system was introduced that classifies epigenetic genes into three categories 1) "epigenetic mediators", which correspond to tumor progenitor genes that are targets of epigenetic modification; 2) "epigenetic modifiers", which modify DNA methylation or chromatin structure; and 3) "epigenetic modulators", which influence activities of epigenetic modifiers to destabilize epigenetic states.	('DNA', 'MPA', (311, 314))	('tumor', 'Disease', (203, 208))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('epigenetic states', 'MPA', (449, 466))	('modifiers', 'Var', (286, 295))	('modulators', 'Var', (370, 380))	('modify', 'Reg', (304, 310))	('activities', 'MPA', (399, 409))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('influence', 'Reg', (389, 398))
422909	30400878	Further analysis that examined whether mutations of 12 MDGs out of these 24 MDGs are associated with the expression of known epigenetic modifiers across cancer types supports our mechanistic hypothesis that some of these MDGs are the ones that regulate expression of chromatin regulators.	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('expression', 'MPA', (253, 263))	('cancer', 'Disease', (153, 159))	('mutations', 'Var', (39, 48))	('MDG', 'Gene', (55, 58))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('regulate', 'Reg', (244, 252))	('MDG', 'Gene', (76, 79))	('MDG', 'Gene', '4350', (55, 58))	('MDG', 'Gene', '4350', (76, 79))	('MDG', 'Gene', '4350', (221, 224))	('MDG', 'Gene', (221, 224))	('associated', 'Reg', (85, 95))
422912	30400878	BRAF mutation is known to be tightly associated with a CpG island methylator phenotype (CIMP) and alteration of SWI/SNF chromatin remodeling pathway.	('SWI/SNF chromatin remodeling pathway', 'Pathway', (112, 148))	('BRAF', 'Gene', '673', (0, 4))	('alteration', 'Reg', (98, 108))	('associated', 'Reg', (37, 47))	('BRAF', 'Gene', (0, 4))	('mutation', 'Var', (5, 13))
422924	30400878	Note that CIC mutations are associated with hyper-methylation in LGG both among IDH1 wild-type tumors and IDH1 mutated tumors.	('CIC', 'Gene', (10, 13))	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('IDH1', 'Gene', (80, 84))	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('tumors', 'Disease', (119, 125))	('hyper-methylation', 'MPA', (44, 61))	('tumors', 'Disease', (95, 101))	('tumors', 'Disease', 'MESH:D009369', (119, 125))	('IDH1', 'Gene', '3417', (80, 84))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('IDH1', 'Gene', (106, 110))	('CIC', 'Gene', '23152', (10, 13))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('IDH1', 'Gene', '3417', (106, 110))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('mutations', 'Var', (14, 23))	('LGG', 'Gene', (65, 68))
422925	30400878	Further studies are needed to investigate if the observed clinical and biological impact of CIC mutations in LGG is through hyper-methylation of the epigenome.	('LGG', 'Gene', (109, 112))	('CIC', 'Gene', '23152', (92, 95))	('CIC', 'Gene', (92, 95))	('mutations', 'Var', (96, 105))
422926	30400878	In this study, we identified CDGs whose somatic mutations are associated with pan-cancer genome-wide methylation/expression changes by using a simple and straightforward method to compare methylation or expression levels between mutated and non-mutated groups of each CDG.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('CDG', 'Chemical', '-', (268, 271))	('associated', 'Reg', (62, 72))	('expression', 'MPA', (203, 213))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('CDG', 'Chemical', '-', (29, 32))	('CDGs', 'Chemical', '-', (29, 33))	('mutations', 'Var', (48, 57))
422928	30400878	Our pan-cancer analysis examining connections between somatic mutation and DNA methylation/gene expression identified CDGs (32 MDGs and 29 EDGs) whose somatic mutations are associated with genome-wide methylation/expression changes across multiple cancer types.	('cancer', 'Disease', (248, 254))	('cancer', 'Disease', 'MESH:D009369', (248, 254))	('MDG', 'Gene', (127, 130))	('cancer', 'Disease', (8, 14))	('MDG', 'Gene', '4350', (127, 130))	('mutations', 'Var', (159, 168))	('EDG', 'Chemical', '-', (139, 142))	('cancer', 'Phenotype', 'HP:0002664', (248, 254))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('CDGs', 'Chemical', '-', (118, 122))	('cancer', 'Disease', 'MESH:D009369', (8, 14))
422931	30400878	These findings highlight that the dysregulation of chromatin regulation is an important mechanism that amplifies the impact of mutations in CDGs by global methylation and gene expression changes.	('CDGs', 'Chemical', '-', (140, 144))	('gene expression', 'MPA', (171, 186))	('CDGs', 'Gene', (140, 144))	('mutations', 'Var', (127, 136))	('changes', 'Reg', (187, 194))
422968	31772147	Further, subgroup analysis was performed (Figure 5) and the survival outcome revealed that significantly shorter RFS was founded in cavitary adenocarcinoma patients with stage T1a (P=0.002) and T1b (P<0.001) but not stage T1c (P=0.962) and T2a (P=0.364).	('patients', 'Species', '9606', (156, 164))	('cavitary adenocarcinoma', 'Disease', 'MESH:D000230', (132, 155))	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('cavitary adenocarcinoma', 'Disease', (132, 155))	('RFS', 'MPA', (113, 116))	('shorter', 'NegReg', (105, 112))	('T1b', 'Var', (194, 197))
422976	31772147	We found that in the group with a maximum cavitation diameter/tumor diameter ratio of <=15, the cavity was more likely to be in a multiple state (P<0.001), the ratio might not fully describe the actual situation of the cavity.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', (62, 67))	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('<=15', 'Var', (86, 90))
422993	31772147	The subgroup analysis of T stage revealed that significantly shorter RFS was founded in cavitary adenocarcinoma patients with stage T1a and T1b but not stage T1c and T2a.	('shorter', 'NegReg', (61, 68))	('RFS', 'MPA', (69, 72))	('cavitary adenocarcinoma', 'Disease', 'MESH:D000230', (88, 111))	('T1b', 'Var', (140, 143))	('cavitary adenocarcinoma', 'Disease', (88, 111))	('patients', 'Species', '9606', (112, 120))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))
423002	30590044	Mutations in an Innate Immunity Pathway Are Associated with Poor Overall Survival Outcomes and Hypoxic Signaling in Cancer Complement-mediated cytotoxicity may act as a selective pressure for tumor overexpression of complement regulators.	('tumor', 'Disease', (192, 197))	('Cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cytotoxicity', 'Disease', (143, 155))	('Mutations', 'Var', (0, 9))	('Hypoxic Signaling in Cancer', 'Disease', 'MESH:C566796', (95, 122))	('cytotoxicity', 'Disease', 'MESH:D064420', (143, 155))	('Hypoxic Signaling in Cancer', 'Disease', (95, 122))	('Innate Immunity Pathway', 'Pathway', (16, 39))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))
423004	30590044	We find that, when analyzed as a pathway, mutations in complement genes occur at a relatively high frequency and are associated with changes in overall survival across a number of cancer types.	('associated', 'Reg', (117, 127))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('changes', 'Reg', (133, 140))	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('overall survival', 'MPA', (144, 160))	('mutations', 'Var', (42, 51))	('cancer', 'Disease', (180, 186))	('complement genes', 'Gene', (55, 71))
423005	30590044	Analysis of pathways expressed in patients with complement mutations that are associated with poor overall survival reveals crosstalk between complement and hypoxia in colorectal cancer.	('colorectal cancer', 'Phenotype', 'HP:0003003', (168, 185))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('hypoxia', 'Disease', 'MESH:D000860', (157, 164))	('colorectal cancer', 'Disease', (168, 185))	('hypoxia', 'Disease', (157, 164))	('crosstalk', 'Reg', (124, 133))	('patients', 'Species', '9606', (34, 42))	('mutations', 'Var', (59, 68))	('colorectal cancer', 'Disease', 'MESH:D015179', (168, 185))
423006	30590044	The importance of this crosstalk is highlighted by two key findings: hypoxic signaling is increased in tumors harboring complement mutations, and hypoxic tumor cells are resistant to complement-mediated cytotoxicity due, in part, to hypoxia-induced expression of complement regulator CD55.	('mutations', 'Var', (131, 140))	('complement', 'Gene', (120, 130))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('increased', 'PosReg', (90, 99))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('hypoxia', 'Disease', 'MESH:D000860', (233, 240))	('hypoxic tumor', 'Disease', 'MESH:D009369', (146, 159))	('tumors', 'Disease', (103, 109))	('tumors', 'Disease', 'MESH:D009369', (103, 109))	('cytotoxicity', 'Disease', (203, 215))	('hypoxia', 'Disease', (233, 240))	('hypoxic signaling', 'MPA', (69, 86))	('cytotoxicity', 'Disease', 'MESH:D064420', (203, 215))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('CD55', 'Gene', (284, 288))	('hypoxic tumor', 'Disease', (146, 159))
423008	30590044	Mutations in the complement system are prevalent across cancers.	('cancers', 'Disease', (56, 63))	('cancers', 'Disease', 'MESH:D009369', (56, 63))	('prevalent', 'Reg', (39, 48))	('cancers', 'Phenotype', 'HP:0002664', (56, 63))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('Mutations', 'Var', (0, 9))	('complement system', 'Gene', (17, 34))
423009	30590044	find that colorectal cancers with complement component mutations are associated with increased hypoxic signaling and poor overall survival outcomes.	('increased hypoxic', 'Disease', (85, 102))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('colorectal cancer', 'Phenotype', 'HP:0003003', (10, 27))	('colorectal cancers', 'Disease', 'MESH:D015179', (10, 28))	('mutations', 'Var', (55, 64))	('colorectal cancers', 'Disease', (10, 28))	('cancers', 'Phenotype', 'HP:0002664', (21, 28))	('increased hypoxic', 'Disease', 'MESH:D000860', (85, 102))
423011	30590044	Since uncontrolled activation of the complement system is associated with cell lysis/cytotoxicity and can result in normal tissue toxicity, the pathway is tightly controlled by membrane-bound regulators such as CD35 (complement receptor type 1), CD46 (membrane cofactor protein), CD55 (complement decay accelerating factor), and CD59 (protectin).	('complement receptor type 1', 'Gene', (217, 243))	('complement decay accelerating factor', 'Gene', '1604', (286, 322))	('membrane cofactor protein', 'Gene', (252, 277))	('toxicity', 'Disease', 'MESH:D064420', (130, 138))	('toxicity', 'Disease', (130, 138))	('toxicity', 'Disease', 'MESH:D064420', (89, 97))	('toxicity', 'Disease', (89, 97))	('result', 'Reg', (106, 112))	('cytotoxicity', 'Disease', (85, 97))	('CD35', 'Gene', '1378', (211, 215))	('complement decay accelerating factor', 'Gene', (286, 322))	('CD46', 'Gene', '4179', (246, 250))	('CD46', 'Gene', (246, 250))	('complement receptor type 1', 'Gene', '1378', (217, 243))	('CD55', 'Var', (280, 284))	('membrane cofactor protein', 'Gene', '4179', (252, 277))	('cytotoxicity', 'Disease', 'MESH:D064420', (85, 97))	('CD35', 'Gene', (211, 215))
423016	30590044	The existence of complement mutations across cancer types could provide additional evidence to support a role for complement in tumor progression.	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('complement', 'Gene', (17, 27))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('tumor', 'Disease', (128, 133))	('cancer', 'Disease', (45, 51))	('mutations', 'Var', (28, 37))
423018	30590044	As the complement system is a complex set of over 50 proteins converging on functional networks, interrogation of mutations across cancer types and within the whole pathway is likely to yield the most insights about the relevance of any potential alterations.	('cancer', 'Disease', (131, 137))	('mutations', 'Var', (114, 123))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('rat', 'Species', '10116', (251, 254))	('cancer', 'Disease', 'MESH:D009369', (131, 137))
423020	30590044	Exome sequencing efforts, including TCGA datasets, have also recently proved useful in finding patient-specific tumor-derived antigens (neoantigens) arising as a consequence of tumor-specific mutations.	('mutations', 'Var', (192, 201))	('patient', 'Species', '9606', (95, 102))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('tumor', 'Disease', (112, 117))	('tumor', 'Disease', (177, 182))
423023	30590044	Our analysis of pathways expressed in patients with complement mutations associated with poor prognostic outcomes reveals crosstalk between the complement system and hypoxia.	('mutations', 'Var', (63, 72))	('crosstalk', 'Reg', (122, 131))	('associated', 'Reg', (73, 83))	('patients', 'Species', '9606', (38, 46))	('hypoxia', 'Disease', 'MESH:D000860', (166, 173))	('hypoxia', 'Disease', (166, 173))
423032	30590044	Importantly, those tumors with dysregulated complement through either protein or genetic alterations are associated with the worse prognostic outcome, highlighting the clinical relevance of these findings.	('dysregulated', 'Var', (31, 43))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('tumors', 'Disease', (19, 25))	('complement', 'Protein', (44, 54))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('genetic alterations', 'Var', (81, 100))	('clinical', 'Species', '191496', (168, 176))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('rat', 'Species', '10116', (93, 96))
423033	30590044	Using TCGA, we found that mutations and copy number alterations (CNAs) in complement system genes occurred in all tumor types queried (Figure 1A).	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('rat', 'Species', '10116', (56, 59))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumor', 'Disease', (114, 119))	('complement system genes', 'Gene', (74, 97))	('mutations', 'Var', (26, 35))	('occurred', 'Reg', (98, 106))	('copy number alterations', 'Var', (40, 63))
423037	30590044	Furthermore, methylation changes of 40 complement genes are also significantly correlated with mRNA expression changes (correlation coefficients ranging from :0.5562 to 0.3180), suggesting that methylation and CNA could alter complement pathway activation through mechanisms independent of alterations in protein structure.	('methylation', 'Var', (194, 205))	('rat', 'Species', '10116', (294, 297))	('mRNA', 'MPA', (95, 99))	('activation', 'MPA', (245, 255))	('alter', 'Reg', (220, 225))	('complement pathway', 'Pathway', (226, 244))
423039	30590044	KS test analysis revealed that mutations in complement system genes, as a group, occurred at a rate above background in 8 of the cancers analyzed (Figure 1B; Table S1C).	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('mutations', 'Var', (31, 40))	('cancers', 'Disease', 'MESH:D009369', (129, 136))	('rat', 'Species', '10116', (95, 98))	('cancers', 'Phenotype', 'HP:0002664', (129, 136))	('cancers', 'Disease', (129, 136))	('complement system genes', 'Gene', (44, 67))	('occurred', 'Reg', (81, 89))	('KS', 'Chemical', '-', (0, 2))
423040	30590044	A pan-cancer meta-analysis of the KS test results maintained significance even without melanoma, which had an individually high rate of complement mutations (Figure 1C; Table S1C).	('melanoma', 'Disease', (87, 95))	('mutations', 'Var', (147, 156))	('melanoma', 'Disease', 'MESH:D008545', (87, 95))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('KS', 'Chemical', '-', (34, 36))	('cancer', 'Disease', 'MESH:D009369', (6, 12))	('cancer', 'Disease', (6, 12))	('rat', 'Species', '10116', (128, 131))	('melanoma', 'Phenotype', 'HP:0002861', (87, 95))
423043	30590044	Interestingly, we found that, across a number of cancer types, several complement mutations scored as significant (Figure 1D; Table S1D).	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('mutations', 'Var', (82, 91))	('significant', 'Reg', (102, 113))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('complement', 'Gene', (71, 81))	('cancer', 'Disease', (49, 55))
423044	30590044	Given the rising interest in the role of T cell-mediated responses mounted to tumor-derived antigens, we asked whether any of the mutations predicted to be drivers by MutSig2CV analysis could also give rise to neoantigens with sufficiently strong predicted binding affinities (<500 nM) by NetMHCpan.	('binding', 'Interaction', (257, 264))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('give rise', 'Reg', (197, 206))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('NetMHCpan', 'Chemical', '-', (289, 298))	('mutations', 'Var', (130, 139))	('tumor', 'Disease', (78, 83))	('neoantigens', 'MPA', (210, 221))
423045	30590044	To assess the relevance of the predicted binding affinities for complement mutation-derived neoantigens in comparison with frequently mutated cancer drivers, we analyzed an equivalent number of peptides derived from mutations in three driver genes in colorectal cancer as assessed by MutSig2CV (APC, TP53, and ARID1A).	('cancer', 'Disease', (262, 268))	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('APC', 'Disease', 'MESH:D011125', (295, 298))	('TP53', 'Gene', '7157', (300, 304))	('colorectal cancer', 'Phenotype', 'HP:0003003', (251, 268))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('APC', 'Disease', (295, 298))	('cancer', 'Phenotype', 'HP:0002664', (262, 268))	('TP53', 'Gene', (300, 304))	('ARID1A', 'Gene', '8289', (310, 316))	('colorectal cancer', 'Disease', (251, 268))	('ARID1A', 'Gene', (310, 316))	('mutations', 'Var', (216, 225))	('cancer', 'Disease', 'MESH:D009369', (262, 268))	('colorectal cancer', 'Disease', 'MESH:D015179', (251, 268))	('cancer', 'Disease', (142, 148))
423048	30590044	Given the prevalence of complement mutation-derived neoantigens with high binding affinities, we asked whether any of the complement mutations predicted to be drivers would also be expected to result in changes in immune infiltrates.	('rat', 'Species', '10116', (227, 230))	('immune infiltrates', 'MPA', (214, 232))	('mutations', 'Var', (133, 142))	('changes', 'Reg', (203, 210))	('binding', 'Interaction', (74, 81))
423049	30590044	Interestingly, several of these mutations were associated with significant increased cytolytic activity, CD8+ T cells, and cytotoxic lymphocyte infiltration (Figures S1C-S1I).	('CD8', 'Gene', (105, 108))	('CD8', 'Gene', '925', (105, 108))	('cytolytic activity', 'CPA', (85, 103))	('rat', 'Species', '10116', (150, 153))	('cytotoxic lymphocyte infiltration', 'CPA', (123, 156))	('mutations', 'Var', (32, 41))	('increased', 'PosReg', (75, 84))
423052	30590044	This analysis confirmed that complement mutations occur at a global level, with 79.7% of datasets analyzed (including 34 different cancer types) containing at least one complement network and several datasets containing more than one mutated complement network (Figure 2A; Table S2A).	('cancer', 'Disease', (131, 137))	('containing', 'Reg', (145, 155))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('mutations', 'Var', (40, 49))	('cancer', 'Disease', 'MESH:D009369', (131, 137))
423053	30590044	These data support the hypothesis that mutations in complement genes may be cooperative in nature, with genes working within functional networks.	('rat', 'Species', '10116', (81, 84))	('complement genes', 'Gene', (52, 68))	('mutations', 'Var', (39, 48))
423054	30590044	We hypothesized that grouping mutations into subsets based on known gene function, and then performing downstream analysis, could provide information about the functional relevance of these mutations and their possible cooperation in cancer.	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('mutations', 'Var', (190, 199))	('cancer', 'Disease', 'MESH:D009369', (234, 240))	('mutations', 'Var', (30, 39))	('rat', 'Species', '10116', (224, 227))	('cancer', 'Disease', (234, 240))
423056	30590044	Interestingly, when performing these analyses, we found that several groups of mutations and CNAs were associated with changes in overall survival outcome across different cancer types (Figures 2B-2G; Tables S2C-S2N).	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('changes', 'Reg', (119, 126))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('overall survival', 'MPA', (130, 146))	('cancer', 'Disease', (172, 178))	('CNAs', 'Gene', (93, 97))	('mutations', 'Var', (79, 88))
423057	30590044	The association between component mutations in colorectal cancer and poor overall survival outcome is noteworthy (Figures 2B and2C).	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('colorectal cancer', 'Disease', (47, 64))	('colorectal cancer', 'Disease', 'MESH:D015179', (47, 64))	('colorectal cancer', 'Phenotype', 'HP:0003003', (47, 64))	('mutations', 'Var', (34, 43))
423058	30590044	In addition, there is a strong association between poor overall survival and amplifications in components in skin cutaneous melanoma (SKCM) and deletions in regulators in LGG (Figures 2D-2G).	('skin cutaneous melanoma', 'Disease', (109, 132))	('amplifications', 'Var', (77, 91))	('melanoma', 'Phenotype', 'HP:0002861', (124, 132))	('overall survival', 'MPA', (56, 72))	('deletions', 'Var', (144, 153))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (114, 132))	('LGG', 'Gene', (171, 174))	('poor', 'NegReg', (51, 55))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (109, 132))
423061	30590044	Similarly to what we had observed from our multivariate analysis, we found that multiple complement gene mutations and CNA were significantly associated with poor overall survival outcomes (e.g., mutations in components in COADREAD, p value = 0.00273).	('poor', 'NegReg', (158, 162))	('complement gene', 'Gene', (89, 104))	('associated', 'Reg', (142, 152))	('mutations', 'Var', (105, 114))	('COADREAD', 'Disease', 'None', (223, 231))	('CNA', 'Gene', (119, 122))	('COADREAD', 'Disease', (223, 231))	('mutations', 'Var', (196, 205))
423064	30590044	These analyses showed significant correlations with overall survival for certain groups of genes (e.g., protease and receptor mutations, q < 0.05), as well as for individual genes (e.g., mutations and deletions in C1QA, p < 0.05), even when performing stage, age, and cancer-type corrections (Tables S2O-S2T).	('C1QA', 'Gene', (214, 218))	('cancer-type', 'Disease', 'MESH:D009369', (268, 279))	('C1QA', 'Gene', '712', (214, 218))	('deletions', 'Var', (201, 210))	('cancer', 'Phenotype', 'HP:0002664', (268, 274))	('cancer-type', 'Disease', (268, 279))	('mutations', 'Var', (187, 196))	('mutations', 'Var', (126, 135))	('correlations', 'Reg', (34, 46))
423065	30590044	Overall, these analyses demonstrate that certain complement mutations and CNAs (either analyzed at the individual gene level or in gene subsets) are associated with changes in overall survival, both in specific cancer types as well as when analyzed at the pan-cancer level.	('CNAs', 'Gene', (74, 78))	('overall survival', 'MPA', (176, 192))	('cancer', 'Disease', 'MESH:D009369', (211, 217))	('cancer', 'Disease', 'MESH:D009369', (260, 266))	('cancer', 'Disease', (211, 217))	('complement', 'Gene', (49, 59))	('cancer', 'Disease', (260, 266))	('changes', 'Reg', (165, 172))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('mutations', 'Var', (60, 69))	('cancer', 'Phenotype', 'HP:0002664', (260, 266))	('rat', 'Species', '10116', (31, 34))
423070	30590044	Overall, hypoxia gene sets as a whole were enriched in patients with complement mutations (p value = 0.0005, GSEA-squared), with two of the four additional hypoxia signatures nominally enriched (p < 0.05) in these two groups of patients (Figures S2C and S2D; Tables S3A, S3D, and S3E).	('hypoxia', 'Disease', (156, 163))	('hypoxia', 'Disease', (9, 16))	('hypoxia', 'Disease', 'MESH:D000860', (156, 163))	('mutations', 'Var', (80, 89))	('patients', 'Species', '9606', (228, 236))	('GSEA', 'Chemical', '-', (109, 113))	('patients', 'Species', '9606', (55, 63))	('hypoxia', 'Disease', 'MESH:D000860', (9, 16))
423072	30590044	We then refined the analysis by asking whether hypoxia signatures were also enriched specifically in patients with component mutations in colorectal cancer, where a strong association between these mutations and poor overall survival had been observed.	('mutations', 'Var', (125, 134))	('patients', 'Species', '9606', (101, 109))	('colorectal cancer', 'Phenotype', 'HP:0003003', (138, 155))	('hypoxia', 'Disease', 'MESH:D000860', (47, 54))	('hypoxia', 'Disease', (47, 54))	('colorectal cancer', 'Disease', (138, 155))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('colorectal cancer', 'Disease', 'MESH:D015179', (138, 155))
423073	30590044	Overall, hypoxia signatures as a whole were enriched in patients with component mutations (p value = 0.0008, GSEA-squared) with four of five signatures being nominally enriched (p < 0.05) (Figures 3B-3E; Tables S3B-S3E and S3G-S3I).	('patients', 'Species', '9606', (56, 64))	('hypoxia', 'Disease', (9, 16))	('mutations', 'Var', (80, 89))	('GSEA', 'Chemical', '-', (109, 113))	('S3G-S3I', 'Var', (223, 230))	('hypoxia', 'Disease', 'MESH:D000860', (9, 16))
423075	30590044	To assess the specificity of the association between hypoxia and complement mutations in colorectal cancer, we asked whether component mutations were also associated with hypoxia signatures in SKCM, another cancer type where this group of mutations was associated with poor outcome.	('hypoxia', 'Disease', (53, 60))	('hypoxia', 'Disease', 'MESH:D000860', (53, 60))	('cancer', 'Disease', 'MESH:D009369', (207, 213))	('colorectal cancer', 'Phenotype', 'HP:0003003', (89, 106))	('SKCM', 'Disease', (193, 197))	('cancer', 'Disease', (207, 213))	('hypoxia', 'Disease', 'MESH:D000860', (171, 178))	('associated', 'Reg', (155, 165))	('colorectal cancer', 'Disease', (89, 106))	('mutations', 'Var', (135, 144))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('hypoxia', 'Disease', (171, 178))	('colorectal cancer', 'Disease', 'MESH:D015179', (89, 106))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))
423076	30590044	Interestingly, no significant association was found between component mutations in SKCM and hypoxia signatures in this group (Figure S2G; Table S3J).	('hypoxia', 'Disease', 'MESH:D000860', (92, 99))	('SKCM', 'Gene', (83, 87))	('mutations', 'Var', (70, 79))	('hypoxia', 'Disease', (92, 99))
423077	30590044	To extend these analyses, we also asked whether hypoxia signatures would be enriched in patients with mutations in a different group of complement genes, the regulators, also associated with poor overall survival in LGG, and once again observed no significant association (Figure S2H; Table S3K).	('LGG', 'Disease', (216, 219))	('poor', 'NegReg', (191, 195))	('associated with', 'Reg', (175, 190))	('patients', 'Species', '9606', (88, 96))	('mutations', 'Var', (102, 111))	('hypoxia', 'Disease', 'MESH:D000860', (48, 55))	('hypoxia', 'Disease', (48, 55))
423078	30590044	These data suggest certain specificity in the association between component mutations and hypoxia in colorectal cancer, and therefore we decided to focus on colorectal cancer for our subsequent experiments.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('colorectal cancer', 'Disease', 'MESH:D015179', (101, 118))	('mutations', 'Var', (76, 85))	('colorectal cancer', 'Disease', (157, 174))	('colorectal cancer', 'Disease', 'MESH:D015179', (157, 174))	('colorectal cancer', 'Phenotype', 'HP:0003003', (101, 118))	('association', 'Interaction', (46, 57))	('hypoxia', 'Disease', (90, 97))	('hypoxia', 'Disease', 'MESH:D000860', (90, 97))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('colorectal cancer', 'Disease', (101, 118))	('colorectal cancer', 'Phenotype', 'HP:0003003', (157, 174))
423079	30590044	Furthermore, these data suggest that colorectal cancer patients with component mutations have tumors associated with high expression of hypoxia signatures, and therefore may have more hypoxic tumors, providing one potential explanation for the poor overall survival observed in this patient population.	('expression', 'MPA', (122, 132))	('hypoxia', 'Disease', (136, 143))	('tumors', 'Disease', (192, 198))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('colorectal cancer', 'Phenotype', 'HP:0003003', (37, 54))	('hypoxic tumors', 'Disease', (184, 198))	('mutations', 'Var', (79, 88))	('hypoxia', 'Disease', 'MESH:D000860', (136, 143))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('tumors', 'Disease', 'MESH:D009369', (192, 198))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumors', 'Disease', (94, 100))	('patient', 'Species', '9606', (55, 62))	('patient', 'Species', '9606', (283, 290))	('colorectal cancer', 'Disease', 'MESH:D015179', (37, 54))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('colorectal cancer', 'Disease', (37, 54))	('tumors', 'Phenotype', 'HP:0002664', (192, 198))	('patients', 'Species', '9606', (55, 63))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('hypoxic tumors', 'Disease', 'MESH:D009369', (184, 198))
423083	30590044	Notably, the murine colorectal cancer cells tested, CT26, have a mutation in central complement component C3 (pV254I).	('colorectal cancer', 'Phenotype', 'HP:0003003', (20, 37))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('complement component C3', 'Disease', (85, 108))	('complement component C3', 'Disease', 'MESH:C565169', (85, 108))	('colorectal cancer', 'Disease', (20, 37))	('CT26', 'CellLine', 'CVCL:7254', (52, 56))	('murine', 'Species', '10090', (13, 19))	('mutation', 'Var', (65, 73))	('colorectal cancer', 'Disease', 'MESH:D015179', (20, 37))	('pV254I', 'Gene', (110, 116))
423084	30590044	The human colorectal cancer cells tested, HCT116 also harbor a C3 mutation, but in this case the C3 mutation is silent, and therefore should not alter amino acid sequence.	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('human', 'Species', '9606', (4, 9))	('colorectal cancer', 'Phenotype', 'HP:0003003', (10, 27))	('HCT116', 'CellLine', 'CVCL:0291', (42, 48))	('colorectal cancer', 'Disease', (10, 27))	('mutation', 'Var', (66, 74))	('colorectal cancer', 'Disease', 'MESH:D015179', (10, 27))
423086	30590044	On one hand, complement component mutations are highly associated with hypoxia signatures and therefore hypoxia-induced gene expression changes.	('hypoxia', 'Disease', (71, 78))	('hypoxia', 'Disease', 'MESH:D000860', (71, 78))	('associated', 'Reg', (55, 65))	('complement component', 'Gene', (13, 33))	('expression', 'MPA', (125, 135))	('hypoxia', 'Disease', (104, 111))	('hypoxia', 'Disease', 'MESH:D000860', (104, 111))	('mutations', 'Var', (34, 43))
423087	30590044	On the other, we note that hypoxia itself can also regulate the terminal consequence of complement system activation by making cancer cells (including those with complement component mutations) more resistant to CMC.	('resistant', 'CPA', (199, 208))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('mutations', 'Var', (183, 192))	('CMC', 'Chemical', '-', (212, 215))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('hypoxia', 'Disease', (27, 34))	('hypoxia', 'Disease', 'MESH:D000860', (27, 34))	('cancer', 'Disease', (127, 133))
423092	30590044	We asked whether increased mRNA levels of either of these regulators was associated with a hypoxia signature (same as was used in Figure 3A) and found that there was a positive and significant correlation between CD55 mRNA expression and the hypoxia signature tested in colorectal cancer TCGA patient samples (Figure 4B).	('hypoxia', 'Disease', (242, 249))	('increased', 'PosReg', (17, 26))	('hypoxia', 'Disease', 'MESH:D000860', (242, 249))	('colorectal cancer', 'Disease', (270, 287))	('hypoxia', 'Disease', (91, 98))	('CD55', 'Var', (213, 217))	('patient', 'Species', '9606', (293, 300))	('colorectal cancer', 'Disease', 'MESH:D015179', (270, 287))	('cancer', 'Phenotype', 'HP:0002664', (281, 287))	('colorectal cancer', 'Phenotype', 'HP:0003003', (270, 287))	('mRNA levels', 'MPA', (27, 38))	('hypoxia', 'Disease', 'MESH:D000860', (91, 98))
423097	30590044	Notably, CD55 mRNA expression in colorectal cancer correlates with poor patient prognosis (Figure 4C).	('CD55 mRNA', 'Var', (9, 18))	('colorectal cancer', 'Disease', 'MESH:D015179', (33, 50))	('patient', 'Species', '9606', (72, 79))	('colorectal cancer', 'Phenotype', 'HP:0003003', (33, 50))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('colorectal cancer', 'Disease', (33, 50))
423103	30590044	These data suggested that both HIF1alpha and HIF2alpha contribute to the regulation of CD55 under hypoxic conditions (Figures S3G and S3H).	('hypoxic conditions', 'Disease', 'MESH:D009135', (98, 116))	('regulation', 'MPA', (73, 83))	('CD55', 'Gene', (87, 91))	('hypoxic conditions', 'Disease', (98, 116))	('S3H', 'Var', (134, 137))
423104	30590044	Since the greatest decrease in CD55 expression was observed following depletion of the dimerization HIFa partner, HIF1beta, these data indicate that the hypoxia-inducible expression of CD55 is likely dependent on both HIF1alpha and HIF2alpha (since loss of HIF1beta leads to loss of HIF1alpha- and HIF2alpha-dependent transcriptional activation).	('decrease', 'NegReg', (19, 27))	('CD55', 'Gene', (185, 189))	('hypoxia', 'Disease', 'MESH:D000860', (153, 160))	('HIF1beta', 'Gene', '405', (257, 265))	('CD55', 'Gene', (31, 35))	('loss', 'Var', (249, 253))	('HIF1beta', 'Gene', '405', (114, 122))	('hypoxia', 'Disease', (153, 160))	('HIF1beta', 'Gene', (257, 265))	('expression', 'MPA', (36, 46))	('HIF1beta', 'Gene', (114, 122))
423115	30590044	Pathway-level mutational analysis revealed that complement pathway mutations are widespread across many cancer types.	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('complement pathway', 'Pathway', (48, 66))	('mutations', 'Var', (67, 76))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))
423116	30590044	Additionally, KS test analysis revealed that mutations in complement genes, as a group, occur at a rate above background in a number of the cancers analyzed.	('mutations', 'Var', (45, 54))	('rat', 'Species', '10116', (99, 102))	('cancers', 'Phenotype', 'HP:0002664', (140, 147))	('cancers', 'Disease', (140, 147))	('cancers', 'Disease', 'MESH:D009369', (140, 147))	('occur', 'Reg', (88, 93))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('KS', 'Chemical', '-', (14, 16))	('complement genes', 'Gene', (58, 74))
423118	30590044	This is due to the fact that specific groups of mutations in these cancer types could still be clinically significant if not analyzed as a block.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('cancer', 'Disease', (67, 73))	('clinical', 'Species', '191496', (95, 103))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('mutations', 'Var', (48, 57))
423119	30590044	Indeed, analysis of immune infiltration differences between patients with and without CD55 mutations (one of the mutations giving rise to neoantigens) correlates with altered immune infiltrates including increased cytotoxic T cell responses.	('cytotoxic T cell responses', 'CPA', (214, 240))	('patients', 'Species', '9606', (60, 68))	('increased', 'PosReg', (204, 213))	('CD55', 'Gene', (86, 90))	('rat', 'Species', '10116', (33, 36))	('mutations', 'Var', (91, 100))	('rat', 'Species', '10116', (188, 191))	('altered', 'Reg', (167, 174))
423123	30590044	A closer look at the CD55 mutations identified in colorectal cancer suggests that these mutations occur across different short consensus repeat (SCR) domains, suggesting that they are likely to be loss of function.	('colorectal cancer', 'Disease', 'MESH:D015179', (50, 67))	('CD55', 'Gene', (21, 25))	('short consensus repeat', 'Disease', 'MESH:D000647', (121, 143))	('short consensus repeat', 'Disease', (121, 143))	('mutations', 'Var', (26, 35))	('colorectal cancer', 'Phenotype', 'HP:0003003', (50, 67))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('colorectal cancer', 'Disease', (50, 67))
423124	30590044	However, to our knowledge, none of the CD55 mutations we report here overlap with variants identified in other diseases such as Cromer Inab phenotype (lack of all Cromer complex blood group antigens) or even those variants that have been associated with lung cancer or gastric cancer risk.	('lung cancer', 'Disease', 'MESH:D008175', (254, 265))	('gastric cancer', 'Disease', (269, 283))	('gastric cancer', 'Disease', 'MESH:D013274', (269, 283))	('lung cancer', 'Disease', (254, 265))	('gastric cancer', 'Phenotype', 'HP:0012126', (269, 283))	('lung cancer', 'Phenotype', 'HP:0100526', (254, 265))	('cancer', 'Phenotype', 'HP:0002664', (259, 265))	('mutations', 'Var', (44, 53))	('variants', 'Var', (214, 222))	('associated', 'Reg', (238, 248))	('cancer', 'Phenotype', 'HP:0002664', (277, 283))	('CD55', 'Gene', (39, 43))
423125	30590044	Interestingly, showed that missense mutation L205F (present in a colon adenocarcinoma patient) results in 50% reduced CD55 function compared to wild-type CD55.	('colon adenocarcinoma', 'Disease', 'MESH:D003110', (65, 85))	('reduced', 'NegReg', (110, 117))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('L205F', 'Mutation', 'p.L205F', (45, 50))	('patient', 'Species', '9606', (86, 93))	('CD55', 'Protein', (118, 122))	('L205F', 'Var', (45, 50))	('colon adenocarcinoma', 'Disease', (65, 85))
423126	30590044	We note, however, that CD55 mutations are not associated with changes in overall survival in colorectal cancer patients.	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('colorectal cancer', 'Phenotype', 'HP:0003003', (93, 110))	('CD55', 'Gene', (23, 27))	('colorectal cancer', 'Disease', (93, 110))	('mutations', 'Var', (28, 37))	('colorectal cancer', 'Disease', 'MESH:D015179', (93, 110))	('patients', 'Species', '9606', (111, 119))
423127	30590044	In contrast, we report that high CD55 mRNA expression is significantly associated with decreased disease-free survival in colorectal cancer.	('colorectal cancer', 'Phenotype', 'HP:0003003', (122, 139))	('decreased', 'NegReg', (87, 96))	('colorectal cancer', 'Disease', (122, 139))	('CD55', 'Protein', (33, 37))	('colorectal cancer', 'Disease', 'MESH:D015179', (122, 139))	('disease-free survival', 'CPA', (97, 118))	('high', 'Var', (28, 32))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
423146	30590044	However, while apoptosis programs may also be triggered in hypoxic tumors (especially in a p53 wild-type tumor), it is common for tumors to evade such apoptosis through mechanisms including p53 mutations.	('tumors', 'Disease', 'MESH:D009369', (130, 136))	('hypoxic tumors', 'Disease', (59, 73))	('tumor', 'Disease', (67, 72))	('tumor', 'Disease', (130, 135))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('p53', 'Gene', '7157', (190, 193))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('tumor', 'Disease', (105, 110))	('apoptosis programs', 'CPA', (15, 33))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('p53', 'Gene', (190, 193))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('p53', 'Gene', '7157', (91, 94))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumors', 'Disease', (67, 73))	('tumors', 'Disease', (130, 136))	('mutations', 'Var', (194, 203))	('p53', 'Gene', (91, 94))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('hypoxic tumors', 'Disease', 'MESH:D009369', (59, 73))	('evade', 'NegReg', (140, 145))	('tumors', 'Disease', 'MESH:D009369', (67, 73))
423180	30590044	To determine the enrichment of complement mutations in each TCGA cancer, a modified Kolmogorov-Smirnov (KS) test using the method of GSEA (kt.test2; https://github.com/franapoli/signed-ks-test) was performed on "mutation ranks."	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('GSEA', 'Chemical', '-', (133, 137))	('cancer', 'Disease', (65, 71))	('mutations', 'Var', (42, 51))	('KS', 'Chemical', '-', (104, 106))
423201	30590044	The list of variants predicted as "cancer drivers" by Mutsig2CV was used for neoantigen prediction (following removal of synonymous mutations), Genes, mutations, neoantigens and predicted binding affinities (IC50) are shown in Tables S1E-S1I).	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('variants', 'Var', (12, 20))	('cancer', 'Disease', (35, 41))	('cancer', 'Disease', 'MESH:D009369', (35, 41))
423202	30590044	The term neoantigen refers to tumor specific DNA alterations that give rise to novel peptide sequences, usually entirely absent from the normal human genome.	('alterations', 'Var', (49, 60))	('human', 'Species', '9606', (144, 149))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('rat', 'Species', '10116', (53, 56))	('give rise to', 'Reg', (66, 78))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('tumor', 'Disease', (30, 35))
423203	30590044	The list of variants and the list of HLA alleles was fed into the NetMHCpan (v3) via topiary tool (https://github.com/openvax/topiary) to calculate predicted binding affinities of predicted true neoantigens.	('variants', 'Var', (12, 20))	('NetMHCpan', 'Chemical', '-', (66, 75))	('binding', 'Interaction', (158, 165))
423227	30590044	An additional covariate of mutational load which is the sum of all non-silent mutations in a cancer sample was used (variable: corrected.for.load.wal.pval; Tables S2C, S2E, S2G, S2I, S2K, and S2M) to control for genomic instability and as a proxy for MSI.	('S2K', 'Var', (183, 186))	('S2M', 'Var', (192, 195))	('cancer', 'Disease', (93, 99))	('MSI', 'Disease', 'None', (251, 254))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('MSI', 'Disease', (251, 254))	('S2I', 'Var', (178, 181))	('S2M', 'Mutation', 'p.S2M', (192, 195))	('S2E', 'Var', (168, 171))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('S2G', 'Var', (173, 176))
423228	30590044	These data represent Benjamani Hochberg corrected Log q-values of the model including age, stage, gender, and in the cases of COADREAD, ESCA, STAD and UCEC also mutational load correction.	('COADREAD', 'Disease', 'None', (126, 134))	('ESCA', 'Disease', (136, 140))	('mutational load correction', 'Var', (161, 187))	('COADREAD', 'Disease', (126, 134))
423234	30590044	Complement mutations occur at a significantly higher rate than background mutations Complement component mutations are associated with poor overall survival Tumors with complement component mutations harbor increased hypoxic signaling Hypoxic colorectal cancer cells are resistant to complement-mediated cytotoxicity	('Hypoxic colorectal cancer', 'Disease', (235, 260))	('cancer', 'Phenotype', 'HP:0002664', (254, 260))	('complement component', 'Gene', (169, 189))	('cytotoxicity', 'Disease', (304, 316))	('mutations', 'Var', (190, 199))	('Hypoxic colorectal cancer', 'Disease', 'MESH:D015179', (235, 260))	('increased hypoxic', 'Disease', 'MESH:D000860', (207, 224))	('Tumors', 'Disease', (157, 163))	('Tumors', 'Disease', 'MESH:D009369', (157, 163))	('Tumors', 'Phenotype', 'HP:0002664', (157, 163))	('rat', 'Species', '10116', (53, 56))	('increased hypoxic', 'Disease', (207, 224))	('cytotoxicity', 'Disease', 'MESH:D064420', (304, 316))	('colorectal cancer', 'Phenotype', 'HP:0003003', (243, 260))	('Tumor', 'Phenotype', 'HP:0002664', (157, 162))
423297	25056374	HPV-negative tumors showed a mutational spectrum concordant with published lung squamous cell carcinoma analyses with enrichment for mutations in TP53, CDKN2A, MLL2, CUL3, NSD1, PIK3CA and NOTCH genes.	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (75, 103))	('lung squamous cell carcinoma', 'Disease', (75, 103))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (80, 103))	('NOTCH genes', 'Gene', (189, 200))	('MLL2', 'Gene', (160, 164))	('CUL3', 'Gene', '8452', (166, 170))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('NSD1', 'Gene', (172, 176))	('PIK3CA', 'Gene', (178, 184))	('TP53', 'Gene', (146, 150))	('mutations', 'Var', (133, 142))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('CDKN2A', 'Gene', (152, 158))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('tumors', 'Disease', (13, 19))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (75, 103))	('MLL2', 'Gene', '9757', (160, 164))	('NSD1', 'Gene', '64324', (172, 176))	('CUL3', 'Gene', (166, 170))	('HPV', 'Species', '10566', (0, 3))	('TP53', 'Gene', '7157', (146, 150))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('CDKN2A', 'Gene', '1029', (152, 158))	('PIK3CA', 'Gene', '5290', (178, 184))
423298	25056374	HPV-positive tumors showed unique mutations in DDX3X, FGFR2/3 and aberrations in PIK3CA, KRAS, MLL2/3 and NOTCH1 were enriched in HPV-positive tumors.	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('PIK3CA', 'Gene', '5290', (81, 87))	('DDX3X', 'Gene', (47, 52))	('MLL2', 'Gene', '9757', (95, 99))	('HPV-positive tumors', 'Disease', (130, 149))	('NOTCH1', 'Gene', '4851', (106, 112))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('HPV-positive tumors', 'Disease', 'MESH:D030361', (130, 149))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('MLL2', 'Gene', (95, 99))	('DDX3X', 'Gene', '1654', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('KRAS', 'Gene', '3845', (89, 93))	('PIK3CA', 'Gene', (81, 87))	('HPV-positive tumors', 'Disease', (0, 19))	('KRAS', 'Gene', (89, 93))	('aberrations', 'Var', (66, 77))	('FGFR2/3', 'Gene', (54, 61))	('HPV-positive tumors', 'Disease', 'MESH:D030361', (0, 19))	('NOTCH1', 'Gene', (106, 112))	('mutations', 'Var', (34, 43))
423300	25056374	EGFR, CCND1, and FGFR1 amplifications occurred in HPV-negative tumors, while 17.6% of HPV-positive tumors harbored mutations in Fibroblast Growth Factor Receptor genes (FGFR2/3) including six recurrent FGFR3 S249C mutations.	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('FGFR1', 'Gene', (17, 22))	('FGFR2/3', 'Gene', (169, 176))	('tumors', 'Disease', (63, 69))	('HPV', 'Species', '10566', (50, 53))	('CCND1', 'Gene', '595', (6, 11))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))	('EGFR', 'Gene', (0, 4))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('FGFR3', 'Gene', (202, 207))	('S249C', 'Var', (208, 213))	('CCND1', 'Gene', (6, 11))	('FGFR1', 'Gene', '2260', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('HPV-positive tumors', 'Disease', (86, 105))	('tumors', 'Disease', (99, 105))	('HPV', 'Species', '10566', (86, 89))	('mutations', 'Var', (115, 124))	('FGFR3', 'Gene', '2261', (202, 207))	('HPV-positive tumors', 'Disease', 'MESH:D030361', (86, 105))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('S249C', 'Mutation', 'rs121913483', (208, 213))	('EGFR', 'Gene', '1956', (0, 4))	('tumors', 'Disease', 'MESH:D009369', (99, 105))
423301	25056374	HPV-positive tumors showed a 5.8% incidence of KRAS mutations, and DNA repair gene aberrations including 7.8% BRCA1/2 mutations were identified.	('BRCA1/2', 'Gene', (110, 117))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('mutations', 'Var', (118, 127))	('HPV-positive tumors', 'Disease', 'MESH:D030361', (0, 19))	('KRAS', 'Gene', (47, 51))	('HPV-positive tumors', 'Disease', (0, 19))	('KRAS', 'Gene', '3845', (47, 51))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
423314	25056374	Previous studies have demonstrated frequent mutations of several genes in cohorts of largely HPV-negative HNSCC, most notably TP53, PIK3CA, CDKN2A, the TERT promoter, and NOTCH pathway gene alterations.	('TERT', 'Gene', '7015', (152, 156))	('TP53', 'Gene', (126, 130))	('NOTCH pathway', 'Gene', (171, 184))	('CDKN2A', 'Gene', (140, 146))	('HPV', 'Species', '10566', (93, 96))	('alterations', 'Var', (190, 201))	('HNSCC', 'Disease', (106, 111))	('CDKN2A', 'Gene', '1029', (140, 146))	('mutations', 'Var', (44, 53))	('PIK3CA', 'Gene', (132, 138))	('TERT', 'Gene', (152, 156))	('PIK3CA', 'Gene', '5290', (132, 138))	('TP53', 'Gene', '7157', (126, 130))
423321	25056374	Results were corroborated by additional tests to increase accuracy including an E6/E7 DNA based multiplex PCR for five high-risk HPV types as well as p16/CDKN2A expression, and TP53 mutations.	('p16', 'Gene', (150, 153))	('CDKN2A', 'Gene', (154, 160))	('p16', 'Gene', '1029', (150, 153))	('CDKN2A', 'Gene', '1029', (154, 160))	('TP53', 'Gene', '7157', (177, 181))	('E6/E7 DNA', 'Var', (80, 89))	('HPV', 'Species', '10566', (129, 132))	('TP53', 'Gene', (177, 181))	('mutations', 'Var', (182, 191))
423324	25056374	Furthermore we used VarWalker to determine potentially relevant genetic aberrations (mutations and copy number aberrations) using prioritization via a protein-protein interaction network focusing on frequently mutated and cancer gene census genes  We used an established machine learning based approach - Cancer-Specific High-Throughput Annotation of Somatic Mutations (CHASM) - to predict and prioritize missense mutations leading to functional changes and thus likely driving tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (478, 483))	('leading to', 'Reg', (424, 434))	('cancer', 'Disease', 'MESH:D009369', (222, 228))	('Cancer', 'Phenotype', 'HP:0002664', (305, 311))	('missense mutations', 'Var', (405, 423))	('tumor', 'Disease', (478, 483))	('cancer', 'Disease', (222, 228))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('tumor', 'Disease', 'MESH:D009369', (478, 483))	('functional changes', 'MPA', (435, 453))
423330	25056374	Analysis of targeted hybrid capture sequencing data identified a total of 5476 point mutations and 4562 insertion/deletion (indel) events across 120 tumor/normal pairs in targeted 617 genes (Supplementary Table S1A).	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('point mutations', 'Var', (79, 94))	('tumor', 'Disease', (149, 154))	('insertion/deletion', 'Reg', (104, 122))
423331	25056374	Among non-synonymous substitutions, transitions and transversions at CpG sites, which are typically associated with tobacco exposure, were the most commonly observed mutational context with a rate of 21/Mb.	('CpG sites', 'Gene', (69, 78))	('tobacco', 'Species', '4097', (116, 123))	('transitions', 'Var', (36, 47))	('associated', 'Reg', (100, 110))	('transversions', 'Var', (52, 65))	('non-synonymous', 'Var', (6, 20))
423332	25056374	Mutations at Tp*Cp(A/C/T) sites, a substitution type commonly associated with virally induced cancers, were the second most commonly observed context at 13/Mb and enriched in the HPV-positive patients.	('cancers', 'Disease', 'MESH:D009369', (94, 101))	('HPV', 'Species', '10566', (179, 182))	('patients', 'Species', '9606', (192, 200))	('Tp*Cp', 'Gene', (13, 18))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('Mutations', 'Var', (0, 9))	('cancers', 'Phenotype', 'HP:0002664', (94, 101))	('cancers', 'Disease', (94, 101))
423334	25056374	We applied the MutSig method to identify cancer-relevant genes demonstrating evidence of statistical selection for mutations in our cohort.	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('mutations', 'Var', (115, 124))	('cancer', 'Disease', (41, 47))
423335	25056374	MutSig identified11 genes displaying significant enrichment for mutations as defined by a q-value of <0.1 in the overall cohort (Supplementary Figure S2): TP53, CDKN2A, PIK3CA, MLL2, TPRX1, CUL3, FLG, NSD1, DDX3X, RPIK4 and HRAS.	('TPRX1', 'Gene', '284355', (183, 188))	('DDX3X', 'Gene', (207, 212))	('FLG', 'Gene', (196, 199))	('MLL2', 'Gene', (177, 181))	('CUL3', 'Gene', '8452', (190, 194))	('FLG', 'Gene', '2312', (196, 199))	('TP53', 'Gene', (155, 159))	('NSD1', 'Gene', (201, 205))	('mutations', 'Var', (64, 73))	('CDKN2A', 'Gene', (161, 167))	('DDX3X', 'Gene', '1654', (207, 212))	('PIK3CA', 'Gene', (169, 175))	('HRAS', 'Gene', '3265', (224, 228))	('HRAS', 'Gene', (224, 228))	('CUL3', 'Gene', (190, 194))	('CDKN2A', 'Gene', '1029', (161, 167))	('MLL2', 'Gene', '9757', (177, 181))	('NSD1', 'Gene', '64324', (201, 205))	('TP53', 'Gene', '7157', (155, 159))	('TPRX1', 'Gene', (183, 188))	('PIK3CA', 'Gene', '5290', (169, 175))
423339	25056374	Analysis of mutated genes displaying enrichment in the HPV-negative cohorts demonstrated statistical enrichment for mutations of TP53, CDKN2A, MLL2/3, NOTCH1, PIK3CA, NSD1, FBXW7, DDR2 and CUL3, in the HPV-negative samples (Figure 1A).	('NSD1', 'Gene', '64324', (167, 171))	('MLL2', 'Gene', (143, 147))	('NOTCH1', 'Gene', (151, 157))	('PIK3CA', 'Gene', '5290', (159, 165))	('HPV', 'Species', '10566', (202, 205))	('CUL3', 'Gene', '8452', (189, 193))	('NOTCH1', 'Gene', '4851', (151, 157))	('TP53', 'Gene', (129, 133))	('DDR2', 'Gene', '4921', (180, 184))	('CDKN2A', 'Gene', (135, 141))	('FBXW7', 'Gene', (173, 178))	('mutations', 'Var', (116, 125))	('PIK3CA', 'Gene', (159, 165))	('NSD1', 'Gene', (167, 171))	('CDKN2A', 'Gene', '1029', (135, 141))	('DDR2', 'Gene', (180, 184))	('MLL2', 'Gene', '9757', (143, 147))	('HPV', 'Species', '10566', (55, 58))	('TP53', 'Gene', '7157', (129, 133))	('CUL3', 'Gene', (189, 193))	('FBXW7', 'Gene', '55294', (173, 178))
423341	25056374	Copy number analysis demonstrated many previously demonstrated regions of amplification and deletion including focal gains of EGFR, REL, BCL6, PIK3CA, TP63, CCDN1 and MDM2 and losses of ATM, CDKN2A, RB1, NOTCH1 and NF1 (Figures 1C, 1D).	('ATM', 'Gene', (186, 189))	('NF1', 'Gene', (215, 218))	('BCL6', 'Gene', '604', (137, 141))	('TP63', 'Gene', (151, 155))	('gains', 'PosReg', (117, 122))	('EGFR', 'Gene', '1956', (126, 130))	('NOTCH1', 'Gene', (204, 210))	('losses', 'NegReg', (176, 182))	('CCDN1', 'Gene', (157, 162))	('RB1', 'Gene', '5925', (199, 202))	('REL', 'Gene', (132, 135))	('TP63', 'Gene', '8626', (151, 155))	('PIK3CA', 'Gene', '5290', (143, 149))	('NOTCH1', 'Gene', '4851', (204, 210))	('CDKN2A', 'Gene', (191, 197))	('MDM2', 'Gene', (167, 171))	('deletion', 'Var', (92, 100))	('ATM', 'Gene', '472', (186, 189))	('BCL6', 'Gene', (137, 141))	('MDM2', 'Gene', '4193', (167, 171))	('EGFR', 'Gene', (126, 130))	('CDKN2A', 'Gene', '1029', (191, 197))	('NF1', 'Gene', '4763', (215, 218))	('PIK3CA', 'Gene', (143, 149))	('RB1', 'Gene', (199, 202))
423342	25056374	Significantly amplified regions that occurred primarily in HPV-negative tumors were amplifications of 11q13 likely targeting CCND1, 7p11 (EGFR) (Figure 2A).	('CCND1', 'Gene', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('amplified', 'PosReg', (14, 23))	('HPV', 'Species', '10566', (59, 62))	('EGFR', 'Gene', '1956', (138, 142))	('CCND1', 'Gene', '595', (125, 130))	('tumors', 'Disease', (72, 78))	('EGFR', 'Gene', (138, 142))	('11q13', 'Gene', (102, 107))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('amplifications', 'Var', (84, 98))
423344	25056374	3p loss and CDKN2A deletions (Figure 2C) occurred primarily in HPV-negative tumors while ATM deletions occurred primarily in HPV-positive tumors (Figure 2D).	('CDKN2A', 'Gene', (12, 18))	('HPV', 'Species', '10566', (63, 66))	('ATM', 'Gene', (89, 92))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('CDKN2A', 'Gene', '1029', (12, 18))	('HPV', 'Species', '10566', (125, 128))	('tumors', 'Disease', (76, 82))	('tumors', 'Disease', (138, 144))	('deletions', 'Var', (19, 28))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('tumors', 'Disease', 'MESH:D009369', (138, 144))	('HPV-positive tumors', 'Disease', 'MESH:D030361', (125, 144))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('ATM', 'Gene', '472', (89, 92))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('HPV-positive tumors', 'Disease', (125, 144))	('loss', 'NegReg', (3, 7))
423353	25056374	FGFR2 mutations included N569D and N569K (both in HPV-positive), and FGFR3 mutations included six S249C mutations, which were validated by Sanger Sequencing (all in HPV-positive), as well as a K413N somatic mutation (Figures 4A, 4B).	('N569K', 'Mutation', 'rs121913476', (35, 40))	('S249C', 'Mutation', 'rs121913483', (98, 103))	('FGFR3', 'Gene', '2261', (69, 74))	('HPV', 'Species', '10566', (165, 168))	('K413N', 'Mutation', 'rs140898926', (193, 198))	('N569K', 'Var', (35, 40))	('N569D', 'Mutation', 'p.N569D', (25, 30))	('FGFR3', 'Gene', (69, 74))	('mutations', 'Var', (75, 84))	('FGFR2', 'Gene', (0, 5))	('S249C', 'Var', (98, 103))	('HPV', 'Species', '10566', (50, 53))	('FGFR2', 'Gene', '2263', (0, 5))	('mutations', 'Var', (6, 15))	('N569D', 'Var', (25, 30))	('K413N', 'Var', (193, 198))
423354	25056374	Both FGFR2 N569K and FGFR3 S249C have been described in several cancer types and showed low CHASM scores suggestive of oncogenic driver character (Figures 4A/B).	('4A/B', 'Var', (155, 159))	('FGFR3', 'Gene', '2261', (21, 26))	('low', 'NegReg', (88, 91))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('FGFR3', 'Gene', (21, 26))	('S249C', 'Mutation', 'rs121913483', (27, 32))	('FGFR2', 'Gene', (5, 10))	('FGFR2', 'Gene', '2263', (5, 10))	('4A/B', 'SUBSTITUTION', 'None', (155, 159))	('N569K', 'Mutation', 'rs121913476', (11, 16))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
423355	25056374	Importantly the FGFR3 S249C mutation was identified recurrently in six HPV-positive tumors.	('S249C', 'Mutation', 'rs121913483', (22, 27))	('FGFR3', 'Gene', (16, 21))	('HPV-positive tumors', 'Disease', 'MESH:D030361', (71, 90))	('HPV-positive tumors', 'Disease', (71, 90))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('S249C', 'Var', (22, 27))	('FGFR3', 'Gene', '2261', (16, 21))
423356	25056374	S249C has been reported in one HPV-positive tumor in the TCGA HNSCC cohort and in the TCGA lung squamous cell and bladder carcinoma cohorts.	('S249C', 'Var', (0, 5))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (114, 131))	('S249C', 'Mutation', 'rs121913483', (0, 5))	('HPV-positive tumor', 'Disease', (31, 49))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('HPV-positive tumor', 'Disease', 'MESH:D030361', (31, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('bladder carcinoma', 'Disease', (114, 131))	('bladder carcinoma', 'Disease', 'MESH:D001749', (114, 131))
423357	25056374	A fraction of DDR2 and EPHA2 mutations also showed low CHASM scores, but were not recurrent, and did not cluster in any domain (Figures 4A, 4B).	('EPHA2', 'Gene', (23, 28))	('CHASM scores', 'MPA', (55, 67))	('mutations', 'Var', (29, 38))	('low', 'NegReg', (51, 54))	('EPHA2', 'Gene', '1969', (23, 28))	('DDR2', 'Gene', '4921', (14, 18))	('DDR2', 'Gene', (14, 18))
423358	25056374	PIK3CA was the most commonly altered oncogene including a number of established canonical mutations (E542K, E545K, H1047R) (Figures 4A, 4B).	('E542K', 'Var', (101, 106))	('PIK3CA', 'Gene', (0, 6))	('H1047R', 'Mutation', 'rs121913279', (115, 121))	('E542K', 'Mutation', 'rs121913273', (101, 106))	('PIK3CA', 'Gene', '5290', (0, 6))	('E545K', 'Mutation', 'rs104886003', (108, 113))	('E545K', 'Var', (108, 113))	('H1047R', 'Var', (115, 121))
423359	25056374	Other PI3K pathway mutations included somatic events in PIK3R1, PTEN, TSC1 and TSC2, all of which have been reported to harbor mutations in other tumor types (Figure 4A).	('included', 'Reg', (29, 37))	('TSC2', 'Gene', '7249', (79, 83))	('TSC1', 'Gene', (70, 74))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('PIK3R1', 'Gene', '5295', (56, 62))	('TSC2', 'Gene', (79, 83))	('tumor', 'Disease', (146, 151))	('mutations', 'Var', (19, 28))	('PIK3R1', 'Gene', (56, 62))	('PTEN', 'Gene', (64, 68))	('PTEN', 'Gene', '5728', (64, 68))	('TSC1', 'Gene', '7248', (70, 74))	('PI3K pathway', 'Pathway', (6, 18))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
423360	25056374	PIK3CA mutations were more commonly observed in HPV-positive individuals though the difference was not statistically significant in our cohort (p=0.20).	('observed', 'Reg', (36, 44))	('HPV', 'Species', '10566', (48, 51))	('HPV-positive', 'Gene', (48, 60))	('PIK3CA', 'Gene', (0, 6))	('PIK3CA', 'Gene', '5290', (0, 6))	('mutations', 'Var', (7, 16))
423361	25056374	Mutations in the MAPK pathway genes included seven canonical HRAS (G13V, Q61L, K117N), KRAS (G12D, G13D, L19F) and NRAS (Q61R) events (incidence 5.8%), as well as multiple mutations of unclear significance in the tumor suppressor NF1 (Figure 4A, 4B).	('NRAS', 'Gene', (115, 119))	('G13D', 'Var', (99, 103))	('NF1', 'Gene', (230, 233))	('HRAS', 'Gene', '3265', (61, 65))	('K117N', 'Mutation', 'rs770248150', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('Q61L', 'Mutation', 'rs121913233', (73, 77))	('HRAS', 'Gene', (61, 65))	('Q61R', 'Mutation', 'rs11554290', (121, 125))	('L19F', 'Var', (105, 109))	('Mutations', 'Var', (0, 9))	('Q61L', 'Var', (73, 77))	('KRAS', 'Gene', '3845', (87, 91))	('MAPK pathway', 'Gene', (17, 29))	('NRAS', 'Gene', '4893', (115, 119))	('K117N', 'Var', (79, 84))	('tumor', 'Disease', (213, 218))	('L19F', 'Mutation', 'rs121913538', (105, 109))	('G12D', 'Mutation', 'rs121913529', (93, 97))	('KRAS', 'Gene', (87, 91))	('G13V', 'Mutation', 'rs104894226', (67, 71))	('tumor', 'Disease', 'MESH:D009369', (213, 218))	('NF1', 'Gene', '4763', (230, 233))	('G13D', 'Mutation', 'rs112445441', (99, 103))
423363	25056374	We noted a significant association among smoking and mutations in TP53 (p = 0.0009), CSMD3 (p = 0.0062), RB1CC1 (p = 0.0161), THSD7A (p = 0.0319).	('RB1CC1', 'Gene', '9821', (105, 111))	('TP53', 'Gene', '7157', (66, 70))	('CSMD3', 'Gene', '114788', (85, 90))	('TP53', 'Gene', (66, 70))	('THSD7A', 'Gene', '221981', (126, 132))	('mutations', 'Var', (53, 62))	('THSD7A', 'Gene', (126, 132))	('CSMD3', 'Gene', (85, 90))	('RB1CC1', 'Gene', (105, 111))
423364	25056374	Mutations in ZFHX4 (p = 0.0167, Fisher's exact test) and TRRAP (p = 0.0392, Fisher's exact test) were significantly enriched in smokers compared to non-smokers.	('ZFHX4', 'Gene', '79776', (13, 18))	('TRRAP', 'Gene', (57, 62))	('TRRAP', 'Gene', '8295', (57, 62))	('Mutations', 'Var', (0, 9))	('ZFHX4', 'Gene', (13, 18))
423367	25056374	As expected HPV positive patients had significantly better prognosis that HPV negative patients for both OS (p = 0.015) and PFS (p = 0.013), and this holds true for the overall cohort as well as oropharyngeal cancers (OS: p=4e-05, PFS: p = 0.0001) (Supplementary Figure S3A).	('positive', 'Var', (16, 24))	('oropharyngeal cancers', 'Disease', (195, 216))	('better', 'PosReg', (52, 58))	('cancers', 'Phenotype', 'HP:0002664', (209, 216))	('oropharyngeal cancers', 'Disease', 'MESH:D009959', (195, 216))	('patients', 'Species', '9606', (25, 33))	('HPV', 'Species', '10566', (12, 15))	('HPV', 'Species', '10566', (74, 77))	('patients', 'Species', '9606', (87, 95))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
423368	25056374	In the smaller sub-cohorts of HPV-positive and HPV-negative tumors most associations were not significant, though we did identify in HPV-negative tumors a possible correlation of PIK3CA mutations (OS: p = 0.017, PFS: p = 0.004)(Supplementary Figure S3B), as well as TP53 wildtype status with poor prognosis (OS: p = 0.262, PFS: p = 0.017) (Supplementary Figure S3C).	('tumors', 'Phenotype', 'HP:0002664', (146, 152))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('correlation', 'Interaction', (164, 175))	('mutations', 'Var', (186, 195))	('TP53', 'Gene', '7157', (266, 270))	('tumors', 'Disease', 'MESH:D009369', (146, 152))	('tumors', 'Disease', 'MESH:D009369', (60, 66))	('PIK3CA', 'Gene', (179, 185))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('TP53', 'Gene', (266, 270))	('PIK3CA', 'Gene', '5290', (179, 185))	('HPV', 'Species', '10566', (30, 33))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('tumors', 'Disease', (146, 152))	('HPV', 'Species', '10566', (133, 136))	('HPV', 'Species', '10566', (47, 50))	('tumors', 'Disease', (60, 66))
423374	25056374	We identify targetable genetic aberrations including both HPV-positive and HPV-negative tumors including frequent FGFR2/3 aberrations in later group.	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('FGFR2/3', 'Gene', (114, 121))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumors', 'Disease', (88, 94))	('HPV', 'Species', '10566', (75, 78))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('aberrations', 'Var', (122, 133))	('HPV', 'Species', '10566', (58, 61))
423376	25056374	The mutational spectrum in HPV-negative HNSCC is very similar to lung and esophageal squamous cell carcinomas with enrichment for mutations in TP53, CDKN2A, MLL2, CUL3, NSD1, PIK3CA and NOTCH genes, and copy number increases in EGFR, CCND1and FGFR1.	('CDKN2A', 'Gene', '1029', (149, 155))	('lung', 'Disease', (65, 69))	('copy', 'MPA', (203, 207))	('NSD1', 'Gene', '64324', (169, 173))	('PIK3CA', 'Gene', '5290', (175, 181))	('MLL2', 'Gene', '9757', (157, 161))	('TP53', 'Gene', '7157', (143, 147))	('CUL3', 'Gene', (163, 167))	('HPV', 'Species', '10566', (27, 30))	('NOTCH genes', 'Gene', (186, 197))	('EGFR', 'Gene', '1956', (228, 232))	('FGFR1', 'Gene', '2260', (243, 248))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (85, 108))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (85, 109))	('MLL2', 'Gene', (157, 161))	('esophageal squamous cell carcinomas', 'Disease', (74, 109))	('esophageal squamous cell carcinomas', 'Disease', 'MESH:D000077277', (74, 109))	('PIK3CA', 'Gene', (175, 181))	('NSD1', 'Gene', (169, 173))	('increases', 'PosReg', (215, 224))	('CDKN2A', 'Gene', (149, 155))	('CUL3', 'Gene', '8452', (163, 167))	('TP53', 'Gene', (143, 147))	('CCND1', 'Gene', '595', (234, 239))	('FGFR1', 'Gene', (243, 248))	('mutations', 'Var', (130, 139))	('CCND1', 'Gene', (234, 239))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('carcinomas', 'Phenotype', 'HP:0030731', (99, 109))	('EGFR', 'Gene', (228, 232))
423378	25056374	In contrast HPV-positive tumors show a distinct genetic profile with unique mutations in DDX3X, CYLD and FGFR and enrichment for PI3K pathway alterations and rarer KRAS mutations.	('FGFR', 'Gene', (105, 109))	('DDX3X', 'Gene', '1654', (89, 94))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('mutations', 'Var', (76, 85))	('KRAS', 'Gene', '3845', (164, 168))	('HPV-positive tumors', 'Disease', (12, 31))	('alterations', 'Reg', (142, 153))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('CYLD', 'Gene', (96, 100))	('PI3K pathway', 'Pathway', (129, 141))	('DDX3X', 'Gene', (89, 94))	('KRAS', 'Gene', (164, 168))	('HPV-positive tumors', 'Disease', 'MESH:D030361', (12, 31))
423379	25056374	Somatic aberrations in DNA-repair genes (BRCA1/2, Fanconi anemia genes, and ATM) may contribute to chemo- and/or radiosensitivity of HPV-positive tumors, and interestingly occurred in HPV-positive tumors in non-/light smokers.	('ATM', 'Gene', (76, 79))	('HPV-positive tumors', 'Disease', 'MESH:D030361', (133, 152))	('aberrations', 'Var', (8, 19))	('contribute', 'Reg', (85, 95))	('tumors', 'Phenotype', 'HP:0002664', (197, 203))	('BRCA1/2', 'Gene', (41, 48))	('Fanconi anemia', 'Phenotype', 'HP:0001994', (50, 64))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('HPV-positive tumors', 'Disease', (184, 203))	('ATM', 'Gene', '472', (76, 79))	('chemo-', 'CPA', (99, 105))	('tumors', 'Phenotype', 'HP:0002664', (146, 152))	('HPV-positive tumors', 'Disease', 'MESH:D030361', (184, 203))	('anemia', 'Phenotype', 'HP:0001903', (58, 64))	('Fanconi anemia', 'Disease', (50, 64))	('HPV-positive tumors', 'Disease', (133, 152))	('radiosensitivity', 'CPA', (113, 129))	('Fanconi anemia', 'Disease', 'MESH:D005199', (50, 64))
423380	25056374	Both tobacco smoke and defects in DNA repair are known to induce a large number of genetic aberrations, and may be distinct ways to accumulate genetic aberrations required for the emergence of cancer.	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('tobacco', 'Species', '4097', (5, 12))	('induce', 'Reg', (58, 64))	('cancer', 'Disease', (193, 199))	('defects', 'Var', (23, 30))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('DNA repair', 'Gene', (34, 44))	('genetic aberrations', 'MPA', (83, 102))
423382	25056374	FGFR2/3 mutations are of particular interest as they occurred in 17.6% of HPV-positive tumors, most commonly the S249C mutation, which has been shown to be an oncogenic driven in bladder cancer.	('bladder cancer', 'Phenotype', 'HP:0009725', (179, 193))	('S249C', 'Var', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('HPV-positive tumors', 'Disease', 'MESH:D030361', (74, 93))	('S249C', 'Mutation', 'rs121913483', (113, 118))	('occurred', 'Reg', (53, 61))	('HPV-positive tumors', 'Disease', (74, 93))	('mutations', 'Var', (8, 17))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('bladder cancer', 'Disease', 'MESH:D001749', (179, 193))	('bladder cancer', 'Disease', (179, 193))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('FGFR2/3', 'Gene', (0, 7))
423383	25056374	One HPV-negative tumor harbored amplification of FGFR1, which is being explored clinically for lung squamous cell carcinomas.	('HPV', 'Species', '10566', (4, 7))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (100, 123))	('lung squamous cell carcinomas', 'Disease', 'MESH:D002294', (95, 124))	('tumor', 'Disease', (17, 22))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (100, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('carcinomas', 'Phenotype', 'HP:0030731', (114, 124))	('amplification', 'Var', (32, 45))	('lung squamous cell carcinomas', 'Disease', (95, 124))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('FGFR1', 'Gene', (49, 54))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (95, 123))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('FGFR1', 'Gene', '2260', (49, 54))
423384	25056374	Furthermore oncogenic FGFR3-TACC3 fusions were recently reported in HPV-positive HNC supporting a prominent role for oncogenic FGFR signaling for HPV-positive HNC while other kinases are genetically unaltered.	('TACC3', 'Gene', '10460', (28, 33))	('FGFR3', 'Gene', (22, 27))	('TACC3', 'Gene', (28, 33))	('reported', 'Reg', (56, 64))	('HPV', 'Species', '10566', (146, 149))	('FGFR3', 'Gene', '2261', (22, 27))	('HPV-positive HNC', 'Disease', (68, 84))	('HNC', 'Disease', (81, 84))	('HPV', 'Species', '10566', (68, 71))	('fusions', 'Var', (34, 41))
423387	25056374	While the number of KRAS (N=3) and TP53 (N=2) mutations in HPV-positive oropharyngeal tumors was small, they occurred in patients with significant tobacco history, and showed 4-6-fold higher average mutational burden (NS).	('KRAS', 'Gene', '3845', (20, 24))	('HPV-positive oropharyngeal tumors', 'Disease', 'MESH:D030361', (59, 92))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('mutations', 'Var', (46, 55))	('HPV-positive oropharyngeal tumors', 'Disease', (59, 92))	('tobacco', 'Species', '4097', (147, 154))	('TP53', 'Gene', '7157', (35, 39))	('occurred', 'Reg', (109, 117))	('mutational burden', 'MPA', (199, 216))	('TP53', 'Gene', (35, 39))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('oropharyngeal tumors', 'Phenotype', 'HP:0100638', (72, 92))	('higher', 'PosReg', (184, 190))	('KRAS', 'Gene', (20, 24))	('patients', 'Species', '9606', (121, 129))
423388	25056374	Interestingly the two TP53 mutations (H179R, G361fs) co-occurred with KRAS (G12D, L19F) and one PIK3CA mutation (F872L) suggesting multiple oncogenic drivers in highly mutational altered HPV-positive tumors.	('G361fs', 'Var', (45, 51))	('G361fs', 'Mutation', 'p.G361fsX', (45, 51))	('HPV-positive tumors', 'Disease', 'MESH:D030361', (187, 206))	('HPV-positive tumors', 'Disease', (187, 206))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('G12D', 'Mutation', 'rs121913529', (76, 80))	('KRAS', 'Gene', (70, 74))	('L19F', 'Mutation', 'rs121913538', (82, 86))	('KRAS', 'Gene', '3845', (70, 74))	('L19F', 'Var', (82, 86))	('tumors', 'Phenotype', 'HP:0002664', (200, 206))	('PIK3CA', 'Gene', (96, 102))	('TP53', 'Gene', '7157', (22, 26))	('PIK3CA', 'Gene', '5290', (96, 102))	('F872L', 'Mutation', 'p.F872L', (113, 118))	('H179R', 'Mutation', 'rs1057519991', (38, 43))	('TP53', 'Gene', (22, 26))	('H179R', 'Var', (38, 43))
423391	25056374	RAS mutations have been associated with poor outcome in other cancer types (e.g.	('RAS', 'Gene', (0, 3))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('mutations', 'Var', (4, 13))
423393	25056374	Further study in HNC will be important, especially regarding the implications of KRAS mutations in otherwise good-prognosis HPV-positive tumors, which were present in 5.8% of HPV-positive tumors.	('KRAS', 'Gene', '3845', (81, 85))	('mutations', 'Var', (86, 95))	('HPV-positive tumors', 'Disease', (124, 143))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('tumors', 'Phenotype', 'HP:0002664', (188, 194))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('HPV-positive tumors', 'Disease', 'MESH:D030361', (175, 194))	('KRAS', 'Gene', (81, 85))	('HPV-positive tumors', 'Disease', (175, 194))	('HPV-positive tumors', 'Disease', 'MESH:D030361', (124, 143))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
423394	25056374	One additional case of a canonical KRAS mutation in an HPV-positive tumor was previously reported.	('mutation', 'Var', (40, 48))	('KRAS', 'Gene', (35, 39))	('KRAS', 'Gene', '3845', (35, 39))	('HPV-positive tumor', 'Disease', (55, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('HPV-positive tumor', 'Disease', 'MESH:D030361', (55, 73))
423396	25056374	The lack of targeted therapies for squamous cell tumors remains challenging: In addition to FGFRs we identify multiple potentially targetable genomic alterations including mutations in the DDR2, EPHA2 kinases, PIK3CA and PI3K pathway genes (e.g.	('squamous cell tumors', 'Disease', (35, 55))	('mutations', 'Var', (172, 181))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('EPHA2', 'Gene', (195, 200))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('squamous cell tumors', 'Phenotype', 'HP:0002860', (35, 55))	('PIK3CA', 'Gene', (210, 216))	('DDR2', 'Gene', '4921', (189, 193))	('PIK3CA', 'Gene', '5290', (210, 216))	('squamous cell tumors', 'Disease', 'MESH:D002294', (35, 55))	('DDR2', 'Gene', (189, 193))	('EPHA2', 'Gene', '1969', (195, 200))
423398	25056374	The lack of EGFR aberrations in HPV-positive tumors is consistent with prior reports, and clinical data.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('HPV-positive tumors', 'Disease', (32, 51))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('EGFR', 'Gene', '1956', (12, 16))	('EGFR', 'Gene', (12, 16))	('aberrations', 'Var', (17, 28))	('HPV-positive tumors', 'Disease', 'MESH:D030361', (32, 51))
423402	25056374	2) CUL3, NFE2L2 and KEAP1mediate cellular responses to oxidative stress and are a frequent target for mutations in lung squamous cell carcinomas as well as the HPV-negative HNSCC cohort.	('lung squamous cell carcinomas', 'Disease', 'MESH:D002294', (115, 144))	('KEAP1', 'Gene', (20, 25))	('lung squamous cell carcinomas', 'Disease', (115, 144))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (115, 143))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (120, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('CUL3', 'Gene', '8452', (3, 7))	('mutations', 'Var', (102, 111))	('cellular responses to oxidative stress', 'MPA', (33, 71))	('CUL3', 'Gene', (3, 7))	('NFE2L2', 'Gene', '4780', (9, 15))	('HPV', 'Species', '10566', (160, 163))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (120, 144))	('oxidative stress', 'Phenotype', 'HP:0025464', (55, 71))	('carcinomas', 'Phenotype', 'HP:0030731', (134, 144))	('KEAP1', 'Gene', '9817', (20, 25))	('NFE2L2', 'Gene', (9, 15))
423404	25056374	Mutations are typically associated with heavy tobacco exposure, and distributed across the gene, which is suggestive of loss of function mutations.	('tobacco', 'Species', '4097', (46, 53))	('Mutations', 'Var', (0, 9))	('associated', 'Reg', (24, 34))
423407	25056374	It has been described to be significantly mutated in medulloblastomas, and can potentiate beta-catenin activity by promoter transactivation.4) In addition, HPV-positive tumors harbor mutations in CYLD, a gene that has not been implicated as a hotspot for mutations, but is well known for its' role in HPV-positive cervical cancer: CYLD is involved in differentiation and NFkappaB signaling and in response to hypoxia activates pro-oncogenic processes (Supplementary Figure S4).5) Lastly, UBR5 mutations are involved in DNA damage and apoptosis signaling, and in addition to our discovery in HPV-positive and negative tumors, UBR5 is recurrently mutated in mantle cell lymphomas (Supplementary Figure S4).	('HPV-positive cervical cancer', 'Disease', (301, 329))	('medulloblastomas', 'Disease', (53, 69))	('UBR5', 'Gene', '51366', (625, 629))	('HPV-positive tumors', 'Disease', (156, 175))	('hypoxia', 'Disease', 'MESH:D000860', (409, 416))	('HPV', 'Species', '10566', (156, 159))	('tumor', 'Phenotype', 'HP:0002664', (617, 622))	('tumors', 'Disease', 'MESH:D009369', (169, 175))	('HPV-positive tumors', 'Disease', 'MESH:D030361', (156, 175))	('tumors', 'Phenotype', 'HP:0002664', (617, 623))	('UBR5', 'Gene', '51366', (488, 492))	('HPV', 'Species', '10566', (591, 594))	('UBR5', 'Gene', (625, 629))	('medulloblastomas', 'Disease', 'MESH:D008527', (53, 69))	('mantle cell lymphomas', 'Disease', (656, 677))	('tumors', 'Disease', (617, 623))	('HPV', 'Species', '10566', (301, 304))	('tumors', 'Phenotype', 'HP:0002664', (169, 175))	('lymphomas', 'Phenotype', 'HP:0002665', (668, 677))	('HPV-positive cervical cancer', 'Disease', 'MESH:D030361', (301, 329))	('mutated', 'Var', (645, 652))	('mantle cell lymphomas', 'Disease', 'MESH:D020522', (656, 677))	('UBR5', 'Gene', (488, 492))	('tumors', 'Disease', 'MESH:D009369', (617, 623))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('cancer', 'Phenotype', 'HP:0002664', (323, 329))	('hypoxia', 'Disease', (409, 416))	('tumors', 'Disease', (169, 175))
423416	25056374	We discover multiple, novel therapeutic targets with predicted driver character that are of high translational relevance: EGFR, CCND1, and FGFR1 amplifications occurred in HPV-negative tumors, while 17.6% of HPV-positive tumors harbored mutations in Fibroblast Growth Factor Receptor genes (FGFR2/3).	('HPV', 'Species', '10566', (172, 175))	('tumors', 'Disease', (185, 191))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('FGFR2/3', 'Gene', (291, 298))	('tumors', 'Phenotype', 'HP:0002664', (221, 227))	('EGFR', 'Gene', (122, 126))	('FGFR1', 'Gene', '2260', (139, 144))	('HPV-positive tumors', 'Disease', (208, 227))	('CCND1', 'Gene', '595', (128, 133))	('tumors', 'Disease', 'MESH:D009369', (185, 191))	('tumors', 'Disease', (221, 227))	('mutations', 'Var', (237, 246))	('HPV-positive tumors', 'Disease', 'MESH:D030361', (208, 227))	('CCND1', 'Gene', (128, 133))	('HPV', 'Species', '10566', (208, 211))	('tumors', 'Disease', 'MESH:D009369', (221, 227))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('EGFR', 'Gene', '1956', (122, 126))	('harbored', 'Reg', (228, 236))	('FGFR1', 'Gene', (139, 144))	('tumors', 'Phenotype', 'HP:0002664', (185, 191))
423447	33640903	Genetic and epigenetic modifications, tyrosine kinases and their inhibitors (TKIs), and CSCs-like properties play a vital role in the treatment of OSCC.	('of', 'Gene', '6688', (144, 146))	('tyrosine', 'Var', (38, 46))	('Genetic', 'Var', (0, 7))	('men', 'Species', '9606', (139, 142))	('OSCC', 'Disease', (147, 151))	('epigenetic modifications', 'Var', (12, 36))
423457	33640903	High-BTK expression in hematopoietic tissues plays a critical role in the differentiation of blood cells; especially, mutations in the BTK gene result in X-linked agammaglobulinemia in humans and X-linked immunodeficiency in mice.	('BTK', 'Gene', (135, 138))	('X-linked agammaglobulinemia', 'Disease', 'MESH:C537409', (154, 181))	('X-linked agammaglobulinemia', 'Disease', (154, 181))	('immunodeficiency', 'Phenotype', 'HP:0002721', (205, 221))	('mutations', 'Var', (118, 127))	('X-linked immunodeficiency', 'Disease', (196, 221))	('of', 'Gene', '6688', (90, 92))	('result in', 'Reg', (144, 153))	('mice', 'Species', '10090', (225, 229))	('X-linked immunodeficiency', 'Disease', 'MESH:D053632', (196, 221))	('agammaglobulinemia', 'Phenotype', 'HP:0004432', (163, 181))	('humans', 'Species', '9606', (185, 191))
423462	33640903	In this study, we investigated the feasibility of the BTK-mediated attenuation of OSCC cell viability, suppression of OSCC-CSCs-like attributes and associated pluripotency, deregulation of the constitutive CSCs-EMT loop in OSCC, and enhancement of OSCC cell sensitivity to concurrent chemoradiotherapy.	('attenuation', 'NegReg', (67, 78))	('men', 'Species', '9606', (240, 243))	('suppression', 'NegReg', (103, 114))	('of', 'Gene', '6688', (79, 81))	('OSCC', 'Disease', (82, 86))	('OSCC-CSCs-like', 'Protein', (118, 132))	('deregulation', 'Var', (173, 185))	('pluripotency', 'MPA', (159, 171))	('enhancement', 'PosReg', (233, 244))	('of', 'Gene', '6688', (186, 188))	('of', 'Gene', '6688', (115, 117))	('of', 'Gene', '6688', (245, 247))	('of', 'Gene', '6688', (47, 49))
423533	33640903	To explore the role of BTK in resistance OSCC, using our local TSGH OSCC cohort (n = 70); first, we demonstrated that high-BTK expression was associated with higher 5-year survival in the general TSGH OSCC cohort (Fig.	('of', 'Gene', '6688', (20, 22))	('5-year survival', 'MPA', (165, 180))	('high-BTK expression', 'Var', (118, 137))	('higher', 'PosReg', (158, 164))
423537	33640903	Moreover, consistent with our local cohort results, in the general TCGA OSCC cohort, patients with high-BTK expression exhibited higher overall survival than those with low BTK expression (Fig.	('patients', 'Species', '9606', (85, 93))	('higher', 'PosReg', (129, 135))	('overall survival', 'MPA', (136, 152))	('high-BTK expression', 'Var', (99, 118))
423539	33640903	TCGA OSCC patients with high-BTK expression who had not received any CCRT exhibited higher 5-year survival than those with low BTK expression (Fig.	('high-BTK expression', 'Var', (24, 43))	('5-year survival', 'CPA', (91, 106))	('higher', 'PosReg', (84, 90))	('patients', 'Species', '9606', (10, 18))
423540	33640903	Conversely, high-BTK expression in TCGA patients with OSCC who had received CCRT was associated with significantly worse prognosis (p = 0.034) (Fig.	('OSCC', 'Disease', (54, 58))	('high-BTK expression', 'Var', (12, 31))	('patients', 'Species', '9606', (40, 48))
423551	33640903	We further examined the effects of shBTK on these SAS-derived tumorspheres using immunofluorescence analysis, and the results demonstrated that compared with wild-type cells, shBTK significantly decreased the immunoreactivity of the stemness makers TIM-3, CD133, and KLF4 (Fig.	('shBTK', 'Var', (175, 180))	('KLF4', 'Gene', (267, 271))	('KLF4', 'Gene', '9314', (267, 271))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('of', 'Gene', '6688', (226, 228))	('tumors', 'Disease', (62, 68))	('tumors', 'Disease', 'MESH:D009369', (62, 68))	('of', 'Gene', '6688', (86, 88))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('stemness', 'CPA', (233, 241))	('TIM-3', 'Gene', (249, 254))	('CD133', 'Gene', (256, 261))	('TIM-3', 'Gene', '84868', (249, 254))	('immunoreactivity', 'MPA', (209, 225))	('of', 'Gene', '6688', (32, 34))	('CD133', 'Gene', '8842', (256, 261))	('decreased', 'NegReg', (195, 204))
423554	33640903	The results of the SRB assay revealed that shBTK significantly improved chemosensitization and inhibited the viability of SAS-IR or TW2.6-IR cells treated with 0-20 muM cisplatin for 48 h (Fig.	('improved', 'PosReg', (63, 71))	('viability', 'CPA', (109, 118))	('of', 'Gene', '6688', (119, 121))	('inhibited', 'NegReg', (95, 104))	('cisplatin', 'Chemical', '-', (169, 178))	('of', 'Gene', '6688', (12, 14))	('chemosensitization', 'CPA', (72, 90))	('SRB', 'Gene', '10575', (19, 22))	('shBTK', 'Var', (43, 48))	('SRB', 'Gene', (19, 22))
423558	33640903	Furthermore, using the immunofluorescence assay, we demonstrated that concomitant with decreased BTK expression, shBTK caused a significant increase in E-cadherin (Fig.	('E-cadherin', 'Gene', (152, 162))	('BTK', 'Protein', (97, 100))	('decreased', 'NegReg', (87, 96))	('E-cadherin', 'Gene', '999', (152, 162))	('of', 'Gene', '6688', (28, 30))	('expression', 'MPA', (101, 111))	('increase', 'PosReg', (140, 148))	('shBTK', 'Var', (113, 118))
423564	33640903	Moreover, we examined the probable effect of ibrutinib on the self-renewal ability of OSCC-CSCs using primary and secondary SAS or TW2.6 tumorspheres, and the results demonstrated that ibrutinib caused significant quantitative and qualitative inhibition of both primary (SAS: 60% reduction, p < 0.05; TW2.6: 64% reduction, p < 0.05) and secondary (SAS: 71% reduction, p < 0.05; TW2.6: 60% reduction, p < 0.05) tumorsphere formation compared with their control counterparts (Fig.	('tumors', 'Disease', (137, 143))	('reduction', 'NegReg', (280, 289))	('tumors', 'Disease', 'MESH:D009369', (137, 143))	('ibrutinib', 'Chemical', 'MESH:C551803', (45, 54))	('of', 'Gene', '6688', (42, 44))	('tumors', 'Phenotype', 'HP:0002664', (137, 143))	('tumors', 'Disease', 'MESH:D009369', (410, 416))	('tumor', 'Phenotype', 'HP:0002664', (410, 415))	('ibrutinib', 'Var', (185, 194))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('reduction', 'NegReg', (312, 321))	('of', 'Gene', '6688', (254, 256))	('of', 'Gene', '6688', (83, 85))	('secondary', 'CPA', (337, 346))	('inhibition', 'NegReg', (243, 253))	('ibrutinib', 'Chemical', 'MESH:C551803', (185, 194))	('tumors', 'Disease', (410, 416))	('tumors', 'Phenotype', 'HP:0002664', (410, 416))
423578	33640903	Consistent with in vitro findings, we found that cisplatin, ibrutinib, and ibrutinib/cisplatin combination caused mild, moderate, and strong suppression of tumor growth, respectively, as evidenced by a 0.04 cm3, 0.47 cm3 (p < 0.01), and 0.72 cm3 (p < 0.001) reduction in the average volume of tumors grown in mice, respectively, by week 5 (Fig.	('of', 'Gene', '6688', (290, 292))	('tumor', 'Disease', 'MESH:D009369', (293, 298))	('cisplatin', 'Chemical', '-', (85, 94))	('of', 'Gene', '6688', (153, 155))	('ibrutinib', 'Chemical', 'MESH:C551803', (75, 84))	('tumors', 'Phenotype', 'HP:0002664', (293, 299))	('tumor', 'Disease', (156, 161))	('ibrutinib', 'Chemical', 'MESH:C551803', (60, 69))	('cisplatin', 'Var', (49, 58))	('reduction', 'NegReg', (258, 267))	('suppression', 'NegReg', (141, 152))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('tumor', 'Phenotype', 'HP:0002664', (293, 298))	('tumors', 'Disease', (293, 299))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumors', 'Disease', 'MESH:D009369', (293, 299))	('ibrutinib/cisplatin', 'Var', (75, 94))	('cisplatin', 'Chemical', '-', (49, 58))	('mice', 'Species', '10090', (309, 313))	('tumor', 'Disease', (293, 298))
423579	33640903	Moreover, although no apparent change in the average body weight was noted in the control, ibrutinib alone, or ibrutinib/cisplatin combination groups, cisplatin-treated mice exhibited an average body weight loss of 4.15 g, (Fig.	('ibrutinib', 'Chemical', 'MESH:C551803', (111, 120))	('cisplatin-treated', 'Var', (151, 168))	('loss', 'NegReg', (207, 211))	('of', 'Gene', '6688', (212, 214))	('body weight', 'CPA', (195, 206))	('cisplatin', 'Chemical', '-', (151, 160))	('cisplatin', 'Chemical', '-', (121, 130))	('mice', 'Species', '10090', (169, 173))	('ibrutinib', 'Chemical', 'MESH:C551803', (91, 100))	('weight loss', 'Phenotype', 'HP:0001824', (200, 211))
423597	33640903	Overexpression of ALDH activity in CSCs is significantly correlated with poor clinical outcomes in breast and ovarian cancers.	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('ALDH', 'Protein', (18, 22))	('Overexpression', 'Var', (0, 14))	('breast and ovarian cancers', 'Disease', 'MESH:D001943', (99, 125))	('ovarian cancers', 'Phenotype', 'HP:0100615', (110, 125))	('of', 'Gene', '6688', (15, 17))	('cancers', 'Phenotype', 'HP:0002664', (118, 125))
423622	33640903	We also established a link between high-BTK expression and the CSCs-like and cisplatin resistance phenotype of OSCC (SAS and TW2.6) cells compared with parental cells (Fig.	('cisplatin', 'Chemical', '-', (77, 86))	('cisplatin resistance phenotype', 'MPA', (77, 107))	('high-BTK', 'Var', (35, 43))	('of', 'Gene', '6688', (108, 110))	('CSCs-like', 'MPA', (63, 72))
423624	33640903	BTK knockdown reduced the number of colony/tumorsphere formation, stemness of OSCC cells, and the EMT markers:E-cadherin and vimentin (Fig.	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('reduced', 'NegReg', (14, 21))	('vimentin', 'Gene', '7431', (125, 133))	('E-cadherin', 'Gene', '999', (110, 120))	('vimentin', 'Gene', (125, 133))	('BTK', 'Gene', (0, 3))	('of', 'Gene', '6688', (33, 35))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumors', 'Disease', (43, 49))	('of', 'Gene', '6688', (75, 77))	('knockdown', 'Var', (4, 13))	('E-cadherin', 'Gene', (110, 120))	('tumors', 'Disease', 'MESH:D009369', (43, 49))
423626	33640903	According to GenBank, BTK has five isoforms: isoform 1 (NP_000052), isoform 2 (NP_001274274), isoform 3 (NP_001274273), BTK truncate form (KF241986) and P65BTK with corresponding molecular weight of 76, 57, 80, 65.5, and 65 kDa.	('NP_001274274', 'Var', (79, 91))	('NP_000052', 'Var', (56, 65))	('of', 'Gene', '6688', (196, 198))	('of', 'Gene', '6688', (96, 98))	('of', 'Gene', '6688', (70, 72))	('P65BTK', 'Var', (153, 159))	('KF241986', 'Var', (139, 147))	('NP_001274273', 'Var', (105, 117))	('of', 'Gene', '6688', (37, 39))	('of', 'Gene', '6688', (47, 49))
423638	33640903	Several preclinical findings indicate that ibrutinib induces apoptosis and impairs cancer cell proliferation.	('impairs cancer', 'Disease', (75, 89))	('apoptosis', 'CPA', (61, 70))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('impairs cancer', 'Disease', 'MESH:D009369', (75, 89))	('induces', 'PosReg', (53, 60))	('ibrutinib', 'Chemical', 'MESH:C551803', (43, 52))	('ibrutinib', 'Var', (43, 52))
423653	33640903	This is essential because TIM-3 is selectively expressed on CD4+ T helper 1 and CD8+ T cytotoxic cells, and its expression on T cells activates myeloid-derived suppressor cells, which subsequently suppress intratumoral immune responses.	('TIM-3', 'Gene', '84868', (26, 31))	('CD8', 'Gene', '925', (80, 83))	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('expression', 'Var', (112, 122))	('TIM-3', 'Gene', (26, 31))	('suppress', 'NegReg', (197, 205))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('activates', 'PosReg', (134, 143))	('CD4', 'Gene', (60, 63))	('tumor', 'Disease', (211, 216))	('CD8', 'Gene', (80, 83))	('myeloid-derived suppressor cells', 'CPA', (144, 176))	('CD4', 'Gene', '920', (60, 63))
423654	33640903	Taken together, these findings indicate that silencing BTK at least partly promotes cancer immune response by targeting TIM-3 signaling.	('silencing', 'Var', (45, 54))	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('cancer', 'Disease', (84, 90))	('promotes', 'PosReg', (75, 83))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('BTK', 'Gene', (55, 58))	('targeting', 'Reg', (110, 119))	('TIM-3', 'Gene', '84868', (120, 125))	('TIM-3', 'Gene', (120, 125))
423657	33640903	Importantly, we provide the first preclinical evidence that the suppression of the integrin-associated signal transducer BTK enhanced radio- or chemosensitivity by downregulating CSC-associated pluripotency factors TIM-3, Nanog, and KLF4 and by deactivating EMT in OSCC (Fig.	('CSC-associated pluripotency factors', 'MPA', (179, 214))	('downregulating', 'NegReg', (164, 178))	('radio- or chemosensitivity', 'CPA', (134, 160))	('deactivating', 'NegReg', (245, 257))	('TIM-3', 'Gene', '84868', (215, 220))	('KLF4', 'Gene', '9314', (233, 237))	('Nanog', 'Gene', '79923', (222, 227))	('suppression', 'Var', (64, 75))	('of', 'Gene', '6688', (76, 78))	('Nanog', 'Gene', (222, 227))	('KLF4', 'Gene', (233, 237))	('enhanced', 'PosReg', (125, 133))	('TIM-3', 'Gene', (215, 220))	('BTK', 'Gene', (121, 124))
423677	32957442	The protein products of individual CGB genes show amino acid differences at position 117.	('amino acid differences', 'Var', (50, 72))	('CGB', 'Gene', (35, 38))	('CGB', 'Gene', '93659', (35, 38))
423684	32957442	The insertion led to the deletion of a 52-base long segment of the proximal promoter, as well as the entire 5' untranslated region (5'UTR) region of the CGB gene.	(', as', 'Gene', '112935892', (84, 88))	('CGB', 'Gene', (153, 156))	('to', 'Gene', '6999', (18, 20))	('deletion', 'Var', (25, 33))	('CGB', 'Gene', '93659', (153, 156))
423685	32957442	The consequence of this mutation was the creation of a new promoter sequence for CGB1 and CGB2, a new 5'UTR region with an alternative start codon, and a new first exon.	('CGB2', 'Gene', (90, 94))	('CGB1', 'Gene', (81, 85))	('CGB1', 'Gene', '114335', (81, 85))	('mutation', 'Var', (24, 32))	('CGB2', 'Gene', '114336', (90, 94))
423719	32957442	It was also demonstrated that specific targeting of CGB1 and CGB2 with siRNA was much more effective in reducing cancer cell numbers than silencing other CGB genes.	('CGB', 'Gene', '93659', (154, 157))	('CGB', 'Gene', (52, 55))	('targeting', 'Var', (39, 48))	('CGB2', 'Gene', '114336', (61, 65))	('CGB', 'Gene', '93659', (61, 64))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('CGB', 'Gene', (154, 157))	('cancer', 'Disease', (113, 119))	('reducing', 'NegReg', (104, 112))	('CGB', 'Gene', (61, 64))	('CGB', 'Gene', '93659', (52, 55))	('CGB2', 'Gene', (61, 65))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('CGB1', 'Gene', (52, 56))	('CGB1', 'Gene', '114335', (52, 56))
423742	32025007	Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously.	('tumour', 'Disease', 'MESH:D009369', (130, 136))	('acral melanoma', 'Disease', (151, 165))	('cancer', 'Disease', 'MESH:D009369', (249, 255))	('variants', 'Var', (51, 59))	('tumour', 'Disease', (130, 136))	('acral melanoma', 'Disease', 'MESH:D008545', (151, 165))	('cancer', 'Disease', (249, 255))	('melanoma', 'Phenotype', 'HP:0002861', (157, 165))	('Chromothripsis', 'Disease', (0, 14))	('acral melanoma', 'Phenotype', 'HP:0012060', (151, 165))	('cancer', 'Phenotype', 'HP:0002664', (249, 255))	('tumour', 'Phenotype', 'HP:0002664', (130, 136))	('affect', 'Reg', (234, 240))
423744	32025007	A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter; identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation; analyses timings and patterns of tumour evolution; describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity; and evaluates a range of more-specialized features of cancer genomes.	('mutational', 'Var', (162, 172))	('deletions', 'Var', (235, 244))	('mutations', 'Var', (70, 79))	('tumour', 'Disease', 'MESH:D009369', (304, 310))	('drive', 'Reg', (85, 90))	('base substitutions', 'Var', (194, 212))	('tumour', 'Phenotype', 'HP:0002664', (304, 310))	('cancer', 'Disease', (91, 97))	('cause', 'Reg', (188, 193))	('mutation', 'Var', (384, 392))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('cancer', 'Phenotype', 'HP:0002664', (515, 521))	('tumour', 'Disease', (304, 310))	('structural', 'Var', (249, 259))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (515, 521))	('cancer', 'Disease', (515, 521))
423749	32025007	Initial studies using massively parallel sequencing demonstrated the feasibility of identifying every somatic point mutation, copy-number change and structural variant (SV) in a given cancer.	('cancer', 'Disease', (184, 190))	('point mutation', 'Var', (110, 124))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('structural variant', 'Var', (149, 167))	('copy-number change', 'Var', (126, 144))	('cancer', 'Disease', 'MESH:D009369', (184, 190))
423762	32025007	Germline variants identified by the three separate pipelines included single-nucleotide polymorphisms, indels, SVs and mobile-element insertions (Supplementary Table 2).	('single-nucleotide polymorphisms', 'Var', (70, 101))	('men', 'Species', '9606', (152, 155))	('mobile-element insertions', 'Var', (119, 144))	('SVs', 'Var', (111, 114))	('men', 'Species', '9606', (129, 132))	('indels', 'Var', (103, 109))
423770	32025007	UCSC Xena  UCSC Xena (https://pcawg.xenahubs.net) visualizes all PCAWG primary results, including copy-number, gene-expression, gene-fusion and promoter-usage alterations, simple somatic mutations, large somatic structural variations, mutational signatures and phenotypic data.	('gene-fusion', 'Var', (128, 139))	('alterations', 'Var', (159, 170))	('structural variations', 'Disease', (212, 233))	('copy-number', 'Var', (98, 109))	('structural variations', 'Disease', 'MESH:D020914', (212, 233))
423777	32025007	The improvement in calling accuracy from combining different pipelines was most noticeable in variants with low variant allele fractions, which probably originate from tumour subclones (Fig.	('tumour', 'Phenotype', 'HP:0002664', (168, 174))	('tumour', 'Disease', 'MESH:D009369', (168, 174))	('calling', 'MPA', (19, 26))	('variants', 'Var', (94, 102))	('tumour', 'Disease', (168, 174))	('men', 'Species', '9606', (11, 14))
423779	32025007	The uniformly generated, high-quality set of variant calls across more than 2,500 donors provided the springboard for a series of scientific working groups to explore the biology of cancer.	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('donor', 'Species', '9606', (82, 87))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('variant calls', 'Var', (45, 58))	('cancer', 'Disease', (182, 188))
423780	32025007	Across the 2,583 white-listed PCAWG donors, we called 43,778,859 somatic SNVs, 410,123 somatic multinucleotide variants, 2,418,247 somatic indels, 288,416 somatic SVs, 19,166 somatic retrotransposition events and 8,185 de novo mitochondrial DNA mutations (Supplementary Table 1).	('men', 'Species', '9606', (262, 265))	('mitochondrial DNA', 'Gene', (227, 244))	('donor', 'Species', '9606', (36, 41))	('variants', 'Var', (111, 119))	('multinucleotide', 'Chemical', '-', (95, 110))
423796	32025007	For probable pathogenic germline variants, we identified all truncating germline point mutations and SVs that affect high-penetrance germline cancer-associated genes.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('point mutations', 'Var', (81, 96))	('affect', 'Reg', (110, 116))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('high-penetrance', 'MPA', (117, 132))	('cancer', 'Disease', (142, 148))
423797	32025007	This analysis defined a set of mutations that we could confidently assert, based on current knowledge, drove tumorigenesis in the more than 2,500 tumours of PCAWG.	('tumours', 'Disease', 'MESH:D009369', (146, 153))	('mutations', 'Var', (31, 40))	('tumours', 'Disease', (146, 153))	('tumorigenesis', 'CPA', (109, 122))	('tumour', 'Phenotype', 'HP:0002664', (146, 152))	('drove', 'Reg', (103, 108))	('tumours', 'Phenotype', 'HP:0002664', (146, 153))
423800	32025007	Nonetheless, 25% of PCAWG tumours bear at least one putative non-coding driver point mutation, and one third (237 out of 785) affected the TERT promoter (9% of PCAWG tumours).	('tumours', 'Disease', (166, 173))	('TERT promoter', 'MPA', (139, 152))	('tumours', 'Disease', 'MESH:D009369', (26, 33))	('tumours', 'Disease', (26, 33))	('affected', 'Reg', (126, 134))	('mutation', 'Var', (85, 93))	('PCAWG', 'Disease', (20, 25))	('tumour', 'Phenotype', 'HP:0002664', (166, 172))	('tumours', 'Phenotype', 'HP:0002664', (166, 173))	('tumour', 'Phenotype', 'HP:0002664', (26, 32))	('tumours', 'Disease', 'MESH:D009369', (166, 173))	('tumours', 'Phenotype', 'HP:0002664', (26, 33))
423801	32025007	Across tumour types, SVs and point mutations have different relative contributions to tumorigenesis.	('tumour', 'Phenotype', 'HP:0002664', (7, 13))	('tumour type', 'Disease', 'MESH:D009369', (7, 18))	('tumour type', 'Disease', (7, 18))	('tumorigenesis', 'CPA', (86, 99))	('point mutations', 'Var', (29, 44))
423804	32025007	Across tumour types, there are differences in which classes of mutation affect a given genomic element (Fig.	('affect', 'Reg', (72, 78))	('tumour', 'Phenotype', 'HP:0002664', (7, 13))	('mutation', 'Var', (63, 71))	('tumour type', 'Disease', 'MESH:D009369', (7, 18))	('genomic element', 'MPA', (87, 102))	('tumour type', 'Disease', (7, 18))	('men', 'Species', '9606', (98, 101))
423805	32025007	We confirmed that many driver mutations that affect tumour-suppressor genes are two-hit inactivation events (Fig.	('tumour', 'Disease', (52, 58))	('mutations', 'Var', (30, 39))	('tumour', 'Disease', 'MESH:D009369', (52, 58))	('tumour', 'Phenotype', 'HP:0002664', (52, 58))
423806	32025007	For example, of the 954 tumours in the cohort with driver mutations in TP53, 736 (77%) had both alleles mutated, 96% of which (707 out of 736) combined a somatic point mutation that affected one allele with somatic deletion of the other allele.	('tumours', 'Disease', (24, 31))	('mutations', 'Var', (58, 67))	('tumour', 'Phenotype', 'HP:0002664', (24, 30))	('tumours', 'Phenotype', 'HP:0002664', (24, 31))	('tumours', 'Disease', 'MESH:D009369', (24, 31))	('TP53', 'Gene', '7157', (71, 75))	('TP53', 'Gene', (71, 75))
423808	32025007	Biallelic inactivation due to somatic alteration on top of a germline PTV was observed in 4.5% of patients overall, with 81% of these affecting known cancer-predisposition genes (such as BRCA1, BRCA2 and ATM).	('affecting', 'Reg', (134, 143))	('BRCA2', 'Gene', (194, 199))	('ATM', 'Gene', (204, 207))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('BRCA1', 'Gene', '672', (187, 192))	('patients', 'Species', '9606', (98, 106))	('Biallelic inactivation', 'Var', (0, 22))	('BRCA2', 'Gene', '675', (194, 199))	('cancer', 'Disease', (150, 156))	('ATM', 'Gene', '472', (204, 207))	('BRCA1', 'Gene', (187, 192))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
423812	32025007	Using an algorithm designed to correct for this contamination, we identified previously missed mutations in genes relevant to the respective cancer types.	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('cancer', 'Disease', (141, 147))	('mutations', 'Var', (95, 104))	('cancer', 'Disease', 'MESH:D009369', (141, 147))
423814	32025007	Most tumours with no known drivers had an average power to detect mutations close to 100%; however, a few had power in the 70-90% range (Fig.	('mutations', 'Var', (66, 75))	('tumours', 'Phenotype', 'HP:0002664', (5, 12))	('tumours', 'Disease', 'MESH:D009369', (5, 12))	('tumours', 'Disease', (5, 12))	('tumour', 'Phenotype', 'HP:0002664', (5, 11))
423815	32025007	For example, only around 50% of PCAWG tumours had sufficient coverage to call a mutation (>=90% power) at the two TERT promoter hotspots, probably because the high GC content of this region causes biased coverage (Fig.	('tumours', 'Disease', (38, 45))	('tumour', 'Phenotype', 'HP:0002664', (38, 44))	('tumours', 'Phenotype', 'HP:0002664', (38, 45))	('tumours', 'Disease', 'MESH:D009369', (38, 45))	('mutation', 'Var', (80, 88))
423818	32025007	With regard to biological causes, tumours may be driven by mutations in cancer-associated genes that are not yet described for that tumour type.	('tumour', 'Phenotype', 'HP:0002664', (34, 40))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('tumours', 'Phenotype', 'HP:0002664', (34, 41))	('driven by', 'Reg', (49, 58))	('tumours', 'Disease', 'MESH:D009369', (34, 41))	('tumour', 'Phenotype', 'HP:0002664', (132, 138))	('mutations', 'Var', (59, 68))	('tumour type', 'Disease', 'MESH:D009369', (132, 143))	('tumour type', 'Disease', (132, 143))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('tumours', 'Disease', (34, 41))	('cancer', 'Disease', (72, 78))
423822	32025007	Inactivation of SETD2 in medulloblastoma significantly decreased gene expression (P = 0.002)(Extended Data Fig.	('SETD2', 'Gene', '29072', (16, 21))	('SETD2', 'Gene', (16, 21))	('medulloblastoma', 'Disease', 'MESH:D008527', (25, 40))	('decreased', 'NegReg', (55, 64))	('gene expression', 'MPA', (65, 80))	('medulloblastoma', 'Phenotype', 'HP:0002885', (25, 40))	('medulloblastoma', 'Disease', (25, 40))	('Inactivation', 'Var', (0, 12))
423823	32025007	Notably, SETD2 mutations occurred exclusively in medulloblastoma group-4 tumours (P < 1 x 10-4).	('SETD2', 'Gene', (9, 14))	('mutations', 'Var', (15, 24))	('tumour', 'Phenotype', 'HP:0002664', (73, 79))	('medulloblastoma', 'Phenotype', 'HP:0002885', (49, 64))	('medulloblastoma group-4 tumours', 'Disease', 'MESH:D008527', (49, 80))	('tumours', 'Phenotype', 'HP:0002664', (73, 80))	('SETD2', 'Gene', '29072', (9, 14))	('occurred', 'Reg', (25, 33))	('medulloblastoma group-4 tumours', 'Disease', (49, 80))
423827	32025007	The absence of other identified driver mutations in these patients raises the possibility that certain combinations of whole-chromosome gains and losses may be sufficient to initiate a cancer in the absence of more-targeted driver events such as point mutations or fusion genes of focal CNAs.	('patients', 'Species', '9606', (58, 66))	('fusion genes', 'Var', (265, 277))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('losses', 'NegReg', (146, 152))	('gains', 'PosReg', (136, 141))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('initiate', 'Reg', (174, 182))	('cancer', 'Disease', (185, 191))	('point mutations', 'Var', (246, 261))
423835	32025007	Different genomic loci were recurrently rearranged by chromoplexy across the three tumour types, mediated by positive selection for particular fusion genes or enhancer-hijacking events.	('tumour', 'Phenotype', 'HP:0002664', (83, 89))	('tumour type', 'Disease', 'MESH:D009369', (83, 94))	('tumour type', 'Disease', (83, 94))	('fusion', 'Var', (143, 149))
423836	32025007	Of 13 fusion genes or enhancer hijacking events in 48 thyroid adenocarcinomas, at least 4 (31%) were caused by chromoplexy, with a further 4 (31%) part of complexes that contained chromoplexy footprints (Extended Data Fig.	('thyroid adenocarcinomas', 'Disease', (54, 77))	('thyroid adenocarcinoma', 'Phenotype', 'HP:0002890', (54, 76))	('thyroid adenocarcinomas', 'Disease', 'MESH:D013959', (54, 77))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('fusion', 'Var', (6, 12))	('carcinomas', 'Phenotype', 'HP:0030731', (67, 77))	('enhancer hijacking', 'PosReg', (22, 40))	('caused by', 'Reg', (101, 110))
423837	32025007	These events generated fusion genes that involved RET (two cases) and NTRK3 (one case), and the juxtaposition of the oncogene IGF2BP3 with regulatory elements from highly expressed genes (five cases).	('RET', 'Gene', (50, 53))	('fusion', 'Var', (23, 29))	('IGF2BP3', 'Gene', '10643', (126, 133))	('IGF2BP3', 'Gene', (126, 133))	('NTRK3', 'Gene', (70, 75))	('men', 'Species', '9606', (153, 156))	('RET', 'Gene', '5979', (50, 53))	('NTRK3', 'Gene', '4916', (70, 75))
423843	32025007	Deletions and complex rearrangements were most-strongly associated with kataegis, whereas tandem duplications and other simple SV classes were only infrequently associated (Supplementary Fig.	('men', 'Species', '9606', (179, 182))	('kataegis', 'Disease', (72, 80))	('men', 'Species', '9606', (31, 34))	('associated', 'Reg', (56, 66))	('Deletions', 'Var', (0, 9))
423844	32025007	Kataegis inducing predominantly T > N mutations in CpTpT context was enriched near deletions, specifically those in the 10-25-kilobase (kb) range (Supplementary Fig.	('men', 'Species', '9606', (153, 156))	('T > N mutations', 'Var', (32, 47))	('CpTpT context', 'Gene', (51, 64))
423848	32025007	Chromothripsis increased with whole-genome duplications in most cancer types (Extended Data Fig.	('Chromothripsis', 'MPA', (0, 14))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('increased', 'PosReg', (15, 24))	('whole-genome', 'Var', (30, 42))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
423856	32025007	Acral melanomas frequently exhibited CCND1 amplification, and lung squamous cell carcinomas SOX2 amplifications.	('lung squamous cell carcinomas', 'Disease', (62, 91))	('Acral melanomas', 'Disease', (0, 15))	('exhibited', 'Reg', (27, 36))	('CCND1', 'Gene', (37, 42))	('amplification', 'Var', (43, 56))	('Acral melanomas', 'Disease', 'MESH:D008545', (0, 15))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (67, 90))	('SOX2', 'Gene', (92, 96))	('lung squamous cell carcinomas', 'Disease', 'MESH:D002294', (62, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('CCND1', 'Gene', '595', (37, 42))	('SOX2', 'Gene', '6657', (92, 96))	('Acral melanomas', 'Phenotype', 'HP:0012060', (0, 15))	('carcinomas', 'Phenotype', 'HP:0030731', (81, 91))	('melanoma', 'Phenotype', 'HP:0002861', (6, 14))	('melanomas', 'Phenotype', 'HP:0002861', (6, 15))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (67, 91))
423857	32025007	In both cases, these drivers were more-frequently altered by chromothripsis compared with other drivers in the same cancer type and to other cancer types for the same driver (Fig.	('chromothripsis', 'Var', (61, 75))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('altered', 'Reg', (50, 57))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('cancer', 'Disease', (141, 147))
423871	32025007	Notably, in cancer types in which the mutational load was sufficiently high, we could detect a larger-than-expected number of SNVs on an intermediate number of DNA copies, suggesting that they appeared during the amplification process (Supplementary Fig.	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('SNVs', 'Gene', (126, 130))	('cancer', 'Disease', (12, 18))	('men', 'Species', '9606', (242, 245))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('mutational', 'Var', (38, 48))
423874	32025007	However, a locus at 22q13.1 predicted an APOBEC3B-like mutagenesis at the pan-cancer level (Fig.	('mutagenesis', 'Var', (55, 66))	('APOBEC3B', 'Gene', (41, 49))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('APOBEC3B', 'Gene', '9582', (41, 49))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))
423875	32025007	The strongest signal at 22q13.1 was driven by rs12628403, and the minor (non-reference) allele was protective against APOBEC3B-like mutagenesis (beta = -0.43, P = 5.6 x 10-9, MAF = 8.2%, n = 1,201 donors)(Extended Data Fig.	('mutagenesis', 'Var', (132, 143))	('rs12628403', 'Mutation', 'rs12628403', (46, 56))	('donor', 'Species', '9606', (197, 202))	('APOBEC3B', 'Gene', (118, 126))	('rs12628403', 'Var', (46, 56))	('APOBEC3B', 'Gene', '9582', (118, 126))
423876	32025007	This variant tags a common, approximately 30-kb germline SV that deletes the APOBEC3B coding sequence and fuses the APOBEC3B 3' untranslated region with the coding sequence of APOBEC3A.	('APOBEC3A', 'Gene', (176, 184))	('APOBEC3B', 'Gene', (77, 85))	('APOBEC3B', 'Gene', (116, 124))	('APOBEC3B', 'Gene', '9582', (77, 85))	('variant', 'Var', (5, 12))	('APOBEC3B', 'Gene', '9582', (116, 124))	('deletes', 'NegReg', (65, 72))	('APOBEC3A', 'Gene', '200315', (176, 184))	('fuses', 'NegReg', (106, 111))
423877	32025007	The deletion is known to increase breast cancer risk and APOBEC mutagenesis in breast cancer genomes.	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('breast cancer', 'Disease', 'MESH:D001943', (34, 47))	('APOBEC', 'Gene', (57, 63))	('breast cancer', 'Disease', 'MESH:D001943', (79, 92))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('breast cancer', 'Disease', (34, 47))	('breast cancer', 'Disease', (79, 92))	('breast cancer', 'Phenotype', 'HP:0003002', (34, 47))	('breast cancer', 'Phenotype', 'HP:0003002', (79, 92))	('deletion', 'Var', (4, 12))	('increase', 'PosReg', (25, 33))	('mutagenesis', 'Var', (64, 75))
423878	32025007	Here, we found that rs12628403 reduces APOBEC3B-like mutagenesis specifically in cancer types with low levels of APOBEC mutagenesis (betalow = -0.50, Plow = 1 x 10-8; betahigh = 0.17, Phigh = 0.2), and increases APOBEC3A-like mutagenesis in cancer types with high levels of APOBEC mutagenesis (betahigh = 0.44, Phigh = 8 x 10-4; betalow = -0.21, Plow = 0.02).	('APOBEC3A', 'Gene', '200315', (212, 220))	('rs12628403', 'Var', (20, 30))	('APOBEC3B', 'Gene', (39, 47))	('increases', 'PosReg', (202, 211))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('reduces', 'NegReg', (31, 38))	('APOBEC3B', 'Gene', '9582', (39, 47))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('cancer', 'Disease', (81, 87))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('cancer', 'Disease', (241, 247))	('cancer', 'Disease', 'MESH:D009369', (241, 247))	('APOBEC3A', 'Gene', (212, 220))	('rs12628403', 'Mutation', 'rs12628403', (20, 30))
423879	32025007	Moreover, we identified a second, novel locus at 22q13.1 that was associated with APOBEC3B-like mutagenesis across cancer types (rs2142833, beta = 0.23, P = 1.3 x 10-8).	('cancer', 'Disease', (115, 121))	('mutagenesis', 'Var', (96, 107))	('APOBEC3B', 'Gene', (82, 90))	('APOBEC3B', 'Gene', '9582', (82, 90))	('associated', 'Reg', (66, 76))	('rs2142833', 'Var', (129, 138))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('rs2142833', 'Mutation', 'rs2142833', (129, 138))
423880	32025007	We independently validated the association between both loci and APOBEC3B-like mutagenesis using East Asian individuals from Asian cancer genome projects (betars12628403 = 0.57, Prs12628403 = 4.2 x 10-12; betars2142833 = 0.58, Prs2142833 = 8 x 10-15) (Extended Data Fig.	('cancer', 'Disease', (131, 137))	('rs12628403', 'Mutation', 'rs12628403', (159, 169))	('betars2142833 =', 'Var', (205, 220))	('Prs2142833', 'Var', (227, 237))	('Prs12628403', 'Var', (178, 189))	('rs2142833', 'Mutation', 'rs2142833', (209, 218))	('betars12628403', 'Var', (155, 169))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('APOBEC3B', 'Gene', (65, 73))	('rs12628403', 'Mutation', 'rs12628403', (179, 189))	('APOBEC3B', 'Gene', '9582', (65, 73))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('rs2142833', 'Mutation', 'rs2142833', (228, 237))
423881	32025007	Notably, in a conditional analysis that accounted for rs12628403, we found that rs2142833 and rs12628403 are inherited independently in Europeans (r2<0.1), and rs2142833 remained significantly associated with APOBEC3B-like mutagenesis in Europeans (betaEUR = 0.17, PEUR = 3 x 10-5) and East Asians (betaASN = 0.25, PASN = 2 x 10-3) (Extended Data Fig.	('rs2142833', 'Var', (80, 89))	('rs12628403', 'Mutation', 'rs12628403', (94, 104))	('rs2142833', 'Var', (160, 169))	('APOBEC3B', 'Gene', (209, 217))	('rs12628403', 'Mutation', 'rs12628403', (54, 64))	('APOBEC3B', 'Gene', '9582', (209, 217))	('rs12628403', 'Var', (94, 104))	('rs2142833', 'Mutation', 'rs2142833', (160, 169))	('rs2142833', 'Mutation', 'rs2142833', (80, 89))	('associated', 'Reg', (193, 203))
423882	32025007	Analysis of donor-matched expression data further suggests that rs2142833 is a cis-expression quantitative trait locus (eQTL) for APOBEC3B at the pan-cancer level (beta = 0.19, P = 2 x 10-6)(Extended Data Fig.	('rs2142833', 'Mutation', 'rs2142833', (64, 73))	('APOBEC3B', 'Gene', (130, 138))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('donor', 'Species', '9606', (12, 17))	('rs2142833', 'Var', (64, 73))	('cancer', 'Disease', (150, 156))	('APOBEC3B', 'Gene', '9582', (130, 138))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
423884	32025007	Germline BRCA2 and BRCA1 PTVs were associated with an increased burden of small (less than 10 kb) somatic SV deletions (P = 1 x 10-8) and tandem duplications (P = 6 x 10-13), respectively, corroborating recent studies in breast and ovarian cancer.	('breast and ovarian cancer', 'Disease', 'MESH:D061325', (221, 246))	('BRCA2', 'Gene', (9, 14))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('BRCA2', 'Gene', '675', (9, 14))	('BRCA1', 'Gene', '672', (19, 24))	('ovarian cancer', 'Phenotype', 'HP:0100615', (232, 246))	('BRCA1', 'Gene', (19, 24))	('tandem duplications', 'Var', (138, 157))
423885	32025007	In PCAWG data, this pattern also extends to other tumour types, including adenocarcinomas of the prostate and pancreas, typically in the setting of biallelic inactivation.	('tumour type', 'Disease', (50, 61))	('adenocarcinomas of the prostate', 'Disease', (74, 105))	('tumour type', 'Disease', 'MESH:D009369', (50, 61))	('adenocarcinomas of the prostate', 'Disease', 'MESH:D011471', (74, 105))	('biallelic inactivation', 'Var', (148, 170))	('pancreas', 'Disease', (110, 118))	('tumour', 'Phenotype', 'HP:0002664', (50, 56))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('carcinomas', 'Phenotype', 'HP:0030731', (79, 89))
423886	32025007	In addition, tumours with high levels of small SV tandem duplications frequently exhibited a novel and distinct class of SVs termed 'cycles of templated insertions'.	('tumour', 'Phenotype', 'HP:0002664', (13, 19))	('tumours', 'Phenotype', 'HP:0002664', (13, 20))	('small', 'Var', (41, 46))	('tumours', 'Disease', 'MESH:D009369', (13, 20))	('tumours', 'Disease', (13, 20))	('exhibited', 'Reg', (81, 90))
423887	32025007	We found a significant association between germline BRCA1 PTVs and templated insertions at the pan-cancer level (P = 4 x 10-15)(Extended Data Fig.	('germline', 'Var', (43, 51))	('BRCA1', 'Gene', '672', (52, 57))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('BRCA1', 'Gene', (52, 57))	('cancer', 'Disease', (99, 105))	('templated insertions', 'Disease', (67, 87))	('PTVs', 'Var', (58, 62))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
423888	32025007	Whole-genome long-read sequencing data generated for a BRCA1-deficient PCAWG prostate tumour verified the small tandem-duplication and templated-insertion SV phenotypes (Fig.	('BRCA1-deficient PCAWG prostate tumour', 'Disease', (55, 92))	('deficient PCAWG prostate', 'Phenotype', 'HP:0008687', (61, 85))	('tumour', 'Phenotype', 'HP:0002664', (86, 92))	('small tandem-duplication', 'Var', (106, 130))	('BRCA1-deficient PCAWG prostate tumour', 'Disease', 'MESH:C537243', (55, 92))	('prostate tumour', 'Phenotype', 'HP:0100787', (77, 92))
423890	32025007	Together, these data suggest that biallelic inactivation of BRCA1 is a driver of the templated-insertion SV phenotype.	('BRCA1', 'Gene', (60, 65))	('biallelic inactivation', 'Var', (34, 56))	('BRCA1', 'Gene', '672', (60, 65))
423891	32025007	Third, rare-variant association analysis revealed that patients with germline MBD4 PTVs had increased rates of somatic C > T mutation rates at CpG dinucleotides (P < 2.5 x 10-6)(Fig.	('CpG dinucleotides', 'Chemical', 'MESH:C015772', (143, 160))	('MBD4', 'Gene', '8930', (78, 82))	('MBD4', 'Gene', (78, 82))	('C >', 'Var', (119, 122))	('patients', 'Species', '9606', (55, 63))
423892	32025007	Analysis of previously published whole-exome sequencing samples from the TCGA (n = 8,134) replicated the association between germline MBD4 PTVs and increased somatic CpG mutagenesis at the pan-cancer level (P = 7.1 x 10-4)(Extended Data Fig.	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('increased', 'PosReg', (148, 157))	('cancer', 'Disease', (193, 199))	('MBD4', 'Gene', '8930', (134, 138))	('mutagenesis', 'Var', (170, 181))	('MBD4', 'Gene', (134, 138))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('germline', 'Var', (125, 133))
423894	32025007	MBD4 encodes a DNA-repair gene that removes thymidines from T:G mismatches within methylated CpG sites, a functionality that would be consistent with a CpG mutational signature in cancer.	('thymidines', 'MPA', (44, 54))	('T:G mismatches', 'Var', (60, 74))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('removes', 'NegReg', (36, 43))	('MBD4', 'Gene', '8930', (0, 4))	('MBD4', 'Gene', (0, 4))	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('mismatches', 'Var', (64, 74))	('cancer', 'Disease', (180, 186))	('thymidines', 'Chemical', 'MESH:D013936', (44, 54))
423908	32025007	This can be achieved through point mutations in the promoter that lead to de novo transcription factor binding; hitching TERT to highly active regulatory elements elsewhere in the genome; insertions of viral enhancers upstream of the gene; and increased dosage through chromosomal amplification, as we have seen in melanoma (Fig.	('dosage', 'Var', (254, 260))	('insertions', 'Var', (188, 198))	('binding', 'Interaction', (103, 110))	('men', 'Species', '9606', (157, 160))	('melanoma', 'Disease', 'MESH:D008545', (315, 323))	('melanoma', 'Phenotype', 'HP:0002861', (315, 323))	('melanoma', 'Disease', (315, 323))	('increased', 'PosReg', (244, 253))	('point mutations', 'Var', (29, 44))
423909	32025007	In addition, there is an 'alternative lengthening of telomeres' (ALT) pathway, in which telomeres are lengthened through homologous recombination, mediated by loss-of-function mutations in the ATRX and DAXX genes.	('mutations', 'Var', (176, 185))	('DAXX', 'Gene', (202, 206))	('loss-of-function', 'NegReg', (159, 175))	('DAXX', 'Gene', '1616', (202, 206))	('ATRX', 'Gene', (193, 197))
423910	32025007	As reported in a companion paper, 16% of tumours in the PCAWG dataset exhibited somatic mutations in at least one of ATRX, DAXX and TERT.	('DAXX', 'Gene', (123, 127))	('tumour', 'Phenotype', 'HP:0002664', (41, 47))	('exhibited', 'Reg', (70, 79))	('mutations', 'Var', (88, 97))	('tumours', 'Phenotype', 'HP:0002664', (41, 48))	('DAXX', 'Gene', '1616', (123, 127))	('ATRX', 'Gene', (117, 121))	('tumours', 'Disease', 'MESH:D009369', (41, 48))	('tumours', 'Disease', (41, 48))
423912	32025007	These included counts of nine variants of the core hexameric sequence, the number of ectopic telomere-like insertions within the genome, the number of genomic breakpoints and telomere length as a ratio between tumour and normal.	('tumour', 'Phenotype', 'HP:0002664', (210, 216))	('variants', 'Var', (30, 38))	('tumour', 'Disease', 'MESH:D009369', (210, 216))	('tumour', 'Disease', (210, 216))
423915	32025007	Clusters C1 (47 tumours) and C2 (42 tumours) were enriched for traits of the ALT pathway:having longer telomeres, more genomic breakpoints, more ectopic telomere insertions and variant telomere sequence motifs (Supplementary Fig.	('tumours', 'Phenotype', 'HP:0002664', (36, 43))	('men', 'Species', '9606', (217, 220))	('tumours', 'Disease', 'MESH:D009369', (16, 23))	('variant', 'Var', (177, 184))	('tumours', 'Disease', (16, 23))	('tumours', 'Disease', 'MESH:D009369', (36, 43))	('tumours', 'Phenotype', 'HP:0002664', (16, 23))	('tumours', 'Disease', (36, 43))	('longer', 'PosReg', (96, 102))	('tumour', 'Phenotype', 'HP:0002664', (16, 22))	('tumour', 'Phenotype', 'HP:0002664', (36, 42))	('genomic breakpoints', 'CPA', (119, 138))	('ectopic', 'CPA', (145, 152))	('telomere', 'Protein', (185, 193))	('more', 'PosReg', (114, 118))
423916	32025007	C1 and C2 were distinguished from one another by the latter having a considerable increase in the number of TTCGGG and TGAGGG variant motifs among the telomeric hexamers.	('C1 and C2', 'Gene', '6966;717', (0, 9))	('variant motifs', 'Var', (126, 140))	('TTCGGG', 'Gene', (108, 114))	('TGAGGG', 'Gene', (119, 125))
423920	32025007	C1 tumours were enriched for RB1 mutations or SVs (P = 3 x 10-5), as well as frequent SVs that affected ATRX (P = 6 x 10-14), but not DAXX.	('ATRX', 'Disease', (104, 108))	('tumour', 'Phenotype', 'HP:0002664', (3, 9))	('DAXX', 'Gene', (134, 138))	('C1 tumours', 'Disease', (0, 10))	('tumours', 'Phenotype', 'HP:0002664', (3, 10))	('mutations', 'Var', (33, 42))	('RB1', 'Gene', (29, 32))	('C1 tumours', 'Disease', 'MESH:C565170', (0, 10))	('DAXX', 'Gene', '1616', (134, 138))	('affected', 'Reg', (95, 103))
423922	32025007	The enrichment of RB1 mutations in C1 remained significant when only leiomyosarcomas and osteosarcomas were considered, confirming that this enrichment is not merely a consequence of the different distribution of tumour types across clusters.	('tumour', 'Phenotype', 'HP:0002664', (213, 219))	('men', 'Species', '9606', (10, 13))	('RB1', 'Gene', (18, 21))	('osteosarcomas', 'Disease', (89, 102))	('osteosarcomas', 'Phenotype', 'HP:0002669', (89, 102))	('osteosarcoma', 'Phenotype', 'HP:0002669', (89, 101))	('osteosarcomas', 'Disease', 'MESH:D012516', (89, 102))	('sarcoma', 'Phenotype', 'HP:0100242', (94, 101))	('tumour type', 'Disease', (213, 224))	('tumour type', 'Disease', 'MESH:D009369', (213, 224))	('sarcomas', 'Phenotype', 'HP:0100242', (76, 84))	('leiomyosarcomas', 'Phenotype', 'HP:0100243', (69, 84))	('sarcomas', 'Phenotype', 'HP:0100242', (94, 102))	('leiomyosarcomas', 'Disease', 'MESH:D007890', (69, 84))	('mutations', 'Var', (22, 31))	('sarcoma', 'Phenotype', 'HP:0100242', (76, 83))	('leiomyosarcomas', 'Disease', (69, 84))	('men', 'Species', '9606', (147, 150))
423923	32025007	Previous research has shown that RB1 mutations are associated with long telomeres in the absence of TERT mutations and ATRX inactivation, and studies using mouse models have shown that knockout of Rb-family proteins causes elongated telomeres.	('associated', 'Reg', (51, 61))	('mutations', 'Var', (37, 46))	('long telomeres', 'CPA', (67, 81))	('RB1', 'Gene', (33, 36))	('mouse', 'Species', '10090', (156, 161))	('elongated telomeres', 'CPA', (223, 242))
423924	32025007	The association with the C1 cluster here suggests that RB1 mutations can represent another route to activating the ALT pathway, which has subtly different properties of telomeric sequence compared with the inactivation of DAXX:these fall almost exclusively in cluster C2.	('ALT pathway', 'Pathway', (115, 126))	('RB1', 'Gene', (55, 58))	('activating', 'MPA', (100, 110))	('fall', 'Phenotype', 'HP:0002527', (233, 237))	('DAXX', 'Gene', '1616', (222, 226))	('mutations', 'Var', (59, 68))	('DAXX', 'Gene', (222, 226))
423926	32025007	The resource reported in this paper and its companion papers has yielded insights into the nature and timing of the many mutational processes that shape large- and small-scale somatic variation in the cancer genome; the patterns of selection that act on these variations; the widespread effect of somatic variants on transcription; the complementary roles of the coding and non-coding genome for both germline and somatic mutations; the ubiquity of intratumoral heterogeneity; and the distinctive evolutionary trajectory of each cancer type.	('variants', 'Var', (305, 313))	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('cancer', 'Disease', (201, 207))	('cancer', 'Phenotype', 'HP:0002664', (529, 535))	('effect', 'Reg', (287, 293))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('men', 'Species', '9606', (342, 345))	('cancer', 'Disease', 'MESH:D009369', (529, 535))	('variations', 'Var', (260, 270))	('cancer', 'Disease', (529, 535))
423956	32025007	Calls of common (>=1% frequency in PCAWG) and rare (<1%) germline variants including single-nucleotide polymorphisms, indels, SVs and mobile-element insertions (MEIs) were generated using a population-scale genetic polymorphism-detection approach.	('single-nucleotide polymorphisms', 'Var', (85, 116))	('indels', 'Var', (118, 124))	('men', 'Species', '9606', (144, 147))
423958	32025007	Using this strategy, we identified 80.1 million germline single-nucleotide polymorphisms, 5.9 million germline indels, 1.8 million multi-allelic short (<50 bp) germline variants, as well as germline SVs >= 50 bp in size including 29,492 biallelic deletions and 27,254 MEIs (Supplementary Table 2).	('variants', 'Var', (169, 177))	('biallelic deletions', 'Var', (237, 256))	('men', 'Species', '9606', (280, 283))	('MEIs', 'Var', (268, 272))
423960	32025007	The requirement to uniformly realign and call variants on nearly 5,800 whole genomes (tumour plus normal) presented considerable computational challenges, and raised ethical issues owing to the use of data from different jurisdictions (Extended Data Table 2).	('tumour plus normal', 'Disease', 'MESH:D009369', (86, 104))	('tumour', 'Phenotype', 'HP:0002664', (86, 92))	('variants', 'Var', (46, 54))	('tumour plus normal', 'Disease', (86, 104))	('men', 'Species', '9606', (11, 14))
423971	32025007	The improvement in calling accuracy from combining different pipelines was most noticeable in variants that had low variant allele fractions, which are likely to originate from subclonal populations of the tumour (Fig.	('tumour', 'Phenotype', 'HP:0002664', (206, 212))	('calling', 'MPA', (19, 26))	('tumour', 'Disease', 'MESH:D009369', (206, 212))	('variants', 'Var', (94, 102))	('tumour', 'Disease', (206, 212))	('men', 'Species', '9606', (11, 14))
423978	32025007	Panorama of driver mutations in human cancer: led by Radhakrishnan Sabarinathan, Oriol Pich, Abel Gonzalez-Perez.	('cancer', 'Disease', (38, 44))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('mutations', 'Var', (19, 28))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('human', 'Species', '9606', (32, 37))
424003	32025007	In addition, to access somatic single nucleotide variants derived from TCGA donors, researchers will also need to obtain dbGaP authorisation.	('donor', 'Species', '9606', (76, 81))	('single nucleotide variants', 'Var', (31, 57))	('TCGA', 'Gene', (71, 75))
424006	32025007	The datasets encompass: clinical data from each patient including demographics, tumour stage and vital status (syn10389158); harmonised tumour histopathology annotations using a standardised hierarchical ontology (syn1038916); inferred purity and ploidy values for each tumour sample (syn8272483); driver mutations for each patient from their cancer genome spanning all classes of variant, and coding versus non-coding drivers (syn11639581); mutational signatures inferred from PCAWG donors (syn11804065), including APOBEC mutagenesis (syn7437313); and transcriptional data from RNA-sequencing, including gene expression levels (syn5553985, syn5553991, syn8105922) and gene fusions (syn10003873, syn7221157).	('syn10003873', 'Var', (683, 694))	('cancer', 'Disease', (343, 349))	('cancer', 'Phenotype', 'HP:0002664', (343, 349))	('syn8105922', 'Var', (653, 663))	('patient', 'Species', '9606', (48, 55))	('patient', 'Species', '9606', (324, 331))	('donor', 'Species', '9606', (484, 489))	('tumour', 'Phenotype', 'HP:0002664', (136, 142))	('syn5553991', 'Var', (641, 651))	('tumour', 'Disease', 'MESH:D009369', (136, 142))	('tumour', 'Disease', (136, 142))	('cancer', 'Disease', 'MESH:D009369', (343, 349))	('tumour', 'Phenotype', 'HP:0002664', (80, 86))	('tumour', 'Disease', 'MESH:D009369', (80, 86))	('tumour', 'Phenotype', 'HP:0002664', (270, 276))	('tumour', 'Disease', (80, 86))	('tumour', 'Disease', 'MESH:D009369', (270, 276))	('tumour', 'Disease', (270, 276))	('syn5553985', 'Var', (629, 639))	('syn7221157', 'Var', (696, 706))
424020	31894334	In addition, niclosamide inhibited cell proliferation as determined by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay and soft agar colony forming assay, and induced cell apoptosis as determined by Annexin V and PI staining.	('soft agar colony forming assay', 'CPA', (237, 267))	('Annexin V', 'Gene', '308', (313, 322))	('cell apoptosis', 'CPA', (281, 295))	('niclosamide', 'Var', (13, 24))	('Annexin V', 'Gene', (313, 322))	('cell proliferation', 'CPA', (35, 53))	('inhibited', 'NegReg', (25, 34))	('niclosamide', 'Chemical', 'MESH:D009534', (13, 24))
424023	31894334	To confirm the results using an apoptosis assay, the apoptotic enhancement of niclosamide was only demonstrated in CE48T cells co-treated with 5-FU, cisplatin, or paclitaxel, and in BE3 cells co-treated with paclitaxel, but not in CE81T cells.	('5-FU', 'Chemical', 'MESH:D005472', (143, 147))	('enhancement', 'PosReg', (63, 74))	('cisplatin', 'Var', (149, 158))	('paclitaxel', 'Chemical', 'MESH:D017239', (208, 218))	('men', 'Species', '9606', (70, 73))	('paclitaxel', 'Chemical', 'MESH:D017239', (163, 173))	('BE3', 'CellLine', 'CVCL:L992', (182, 185))	('cisplatin', 'Chemical', 'MESH:D002945', (149, 158))	('paclitaxel', 'Var', (163, 173))	('niclosamide', 'Chemical', 'MESH:D009534', (78, 89))	('apoptotic', 'CPA', (53, 62))	('5-FU', 'Var', (143, 147))
424042	31894334	The molecular mechanisms underlying the antineoplastic effect of niclosamide have been explored in many human malignant cancers, indicating that niclosamide exhibits anticancer activity by suppressing many oncogenic signaling pathways concurrently.	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('oncogenic signaling pathways', 'Pathway', (206, 234))	('niclosamide', 'Chemical', 'MESH:D009534', (145, 156))	('cancer', 'Disease', (170, 176))	('niclosamide', 'Chemical', 'MESH:D009534', (65, 76))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('cancers', 'Phenotype', 'HP:0002664', (120, 127))	('human', 'Species', '9606', (104, 109))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('cancers', 'Disease', (120, 127))	('niclosamide', 'Var', (145, 156))	('suppressing', 'NegReg', (189, 200))	('cancers', 'Disease', 'MESH:D009369', (120, 127))
424044	31894334	In ovarian cancer, niclosamide significantly decreased the expression of proteins in the wingless/integrated (Wnt), mammalian target of rapamycin (mTOR) and STAT3 pathways and caused significant inhibition of proliferation of cells.	('niclosamide', 'Var', (19, 30))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('ovarian cancer', 'Phenotype', 'HP:0100615', (3, 17))	('expression of proteins', 'MPA', (59, 81))	('mammalian target of rapamycin', 'Gene', '2475', (116, 145))	('mammalian target of rapamycin', 'Gene', (116, 145))	('decreased', 'NegReg', (45, 54))	('ovarian cancer', 'Disease', 'MESH:D010051', (3, 17))	('STAT3', 'Gene', '6774', (157, 162))	('inhibition', 'NegReg', (195, 205))	('ovarian cancer', 'Disease', (3, 17))	('STAT3', 'Gene', (157, 162))	('niclosamide', 'Chemical', 'MESH:D009534', (19, 30))	('mTOR', 'Gene', '2475', (147, 151))	('proliferation of cells', 'CPA', (209, 231))	('mTOR', 'Gene', (147, 151))
424045	31894334	In acute myeloid leukemia, niclosamide could induce apoptosis of AML blast cells through inhibition of the nuclear factor-kappaB (NF-kappaB) pathway and increasing the production of reactive oxygen species.	('AML', 'Disease', (65, 68))	('niclosamide', 'Chemical', 'MESH:D009534', (27, 38))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (9, 25))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (3, 25))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (3, 25))	('leukemia', 'Phenotype', 'HP:0001909', (17, 25))	('niclosamide', 'Var', (27, 38))	('inhibition', 'NegReg', (89, 99))	('acute myeloid leukemia', 'Disease', (3, 25))	('apoptosis', 'CPA', (52, 61))	('oxygen', 'Chemical', 'MESH:D010100', (191, 197))	('AML', 'Disease', 'MESH:D015470', (65, 68))	('production of reactive oxygen species', 'MPA', (168, 205))	('increasing', 'PosReg', (153, 163))
424048	31894334	In the present study, the antineoplastic effects of niclosamide on esophageal cancer cells were investigated and it was revealed that niclosamide suppressed the STAT3 signaling pathway and inhibited cell proliferation in esophageal cancer cells.	('niclosamide', 'Var', (134, 145))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('niclosamide', 'Chemical', 'MESH:D009534', (52, 63))	('cell proliferation', 'CPA', (199, 217))	('niclosamide', 'Chemical', 'MESH:D009534', (134, 145))	('esophageal cancer', 'Disease', (221, 238))	('inhibited', 'NegReg', (189, 198))	('STAT3', 'Gene', '6774', (161, 166))	('esophageal cancer', 'Disease', (67, 84))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('STAT3', 'Gene', (161, 166))	('esophageal cancer', 'Disease', 'MESH:D004938', (221, 238))	('esophageal cancer', 'Disease', 'MESH:D004938', (67, 84))	('suppressed', 'NegReg', (146, 156))
424054	31894334	F6627), cisplatin (P4394), and paclitaxel (T7402) were purchased from Sigma-Aldrich (Merk KGaA).	('paclitaxel', 'Chemical', 'MESH:D017239', (31, 41))	('P4394', 'Var', (19, 24))	('T7402', 'Var', (43, 48))	('F6627', 'Var', (0, 5))	('P4394', 'Chemical', 'MESH:D010695', (19, 24))	('cisplatin', 'Chemical', 'MESH:D002945', (8, 17))	('F6627', 'Chemical', 'MESH:D005461', (0, 5))	('T7402', 'CellLine', 'CVCL:5492', (43, 48))
424057	31894334	Esophageal cancer cell lines, BE3 (adenocarcinoma), CE48T/VGH and CE81T/VGH (squamous cell carcinoma) were courtesy of Dr Yen and Dr Lee, respectively.	('Esophageal cancer', 'Disease', 'MESH:D004938', (0, 17))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('BE3', 'CellLine', 'CVCL:L992', (30, 33))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (77, 100))	('adenocarcinoma', 'Disease', (35, 49))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (77, 100))	('CE81T/VGH', 'Var', (66, 75))	('carcinoma', 'Phenotype', 'HP:0030731', (40, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('squamous cell carcinoma', 'Disease', (77, 100))	('Esophageal cancer', 'Disease', (0, 17))	('adenocarcinoma', 'Disease', 'MESH:D000230', (35, 49))	('CE48T/VGH', 'Var', (52, 61))
424075	31894334	The protein levels of endogenous beta-catenin could only be detected in CE48T and CE81T cells, but not in BE3 cells.	('BE3', 'CellLine', 'CVCL:L992', (106, 109))	('CE81T', 'Var', (82, 87))	('beta-catenin', 'Gene', (33, 45))	('CE48T', 'Var', (72, 77))	('beta-catenin', 'Gene', '1499', (33, 45))
424080	31894334	The IC50 concentrations of niclosamide were 2.8, 11.3, and 5.1 microM for CE48T, CE81T and BE3, respectively.	('CE81T', 'Var', (81, 86))	('CE48T', 'Var', (74, 79))	('niclosamide', 'Chemical', 'MESH:D009534', (27, 38))	('BE3', 'CellLine', 'CVCL:L992', (91, 94))
424088	31894334	The results indicated that the reduction of cell viabilities of CE48T and BE3 cells was mainly caused by niclosamide-induced cell apoptosis, but was partial to that of CE81T cells.	('reduction', 'NegReg', (31, 40))	('BE3', 'CellLine', 'CVCL:L992', (74, 77))	('CE48T', 'Var', (64, 69))	('niclosamide-induced', 'MPA', (105, 124))	('cell viabilities', 'CPA', (44, 60))	('niclosamide', 'Chemical', 'MESH:D009534', (105, 116))
424093	31894334	The proportion of sub-G1 cells was increased in a time-dependent manner in CE48T and BE3 cells after 48 and 72 h treatment.	('increased', 'PosReg', (35, 44))	('CE48T', 'Var', (75, 80))	('BE3', 'CellLine', 'CVCL:L992', (85, 88))	('men', 'Species', '9606', (118, 121))
424098	31894334	The protein levels of various cyclins in CE48T, CE81T and BE3 cells were assessed by western blot assay, and it was revealed that all of the expression levels of cyclin D1, E, A and B1 were almost completely lost in CE81T cells treated with niclosamide for 48 h (Fig.	('niclosamide', 'Chemical', 'MESH:D009534', (241, 252))	('cyclin', 'Gene', (162, 168))	('cyclin', 'Gene', '5111', (30, 36))	('BE3', 'CellLine', 'CVCL:L992', (58, 61))	('cyclin', 'Gene', (30, 36))	('expression', 'MPA', (141, 151))	('cyclin D1, E, A and B1', 'Gene', '595;890;891', (162, 184))	('lost', 'NegReg', (208, 212))	('CE81T', 'Var', (216, 221))	('cyclin', 'Gene', '5111', (162, 168))
424111	31894334	Moreover, the combination of niclosamide and cisplatin (10 microM) resulted in a higher proportion of apoptotic cells than cisplatin treatment alone (56.68+-1.82% vs. 25.57+-8.81%; P<0.05), as well as the combination of niclosamide and paclitaxel (10 nM) which induced a higher proportion of apoptotic cells than paclitaxel treatment alone (28.69+-1.75% vs. 12.54+-1.12%; P<0.005).	('apoptotic cells', 'CPA', (102, 117))	('cisplatin', 'Chemical', 'MESH:D002945', (123, 132))	('niclosamide', 'Chemical', 'MESH:D009534', (220, 231))	('paclitaxel', 'Chemical', 'MESH:D017239', (313, 323))	('cisplatin', 'Chemical', 'MESH:D002945', (45, 54))	('men', 'Species', '9606', (138, 141))	('paclitaxel', 'Chemical', 'MESH:D017239', (236, 246))	('niclosamide', 'Chemical', 'MESH:D009534', (29, 40))	('men', 'Species', '9606', (329, 332))	('niclosamide', 'Var', (29, 40))
424113	31894334	In BE3 cells, the combination of niclosamide and paclitaxel induced a higher proportion of apoptotic cells than paclitaxel treatment alone (39.88+-6.83% vs. 21.26+-3.26%; P<0.05) (as revealed in Fig.	('niclosamide', 'Var', (33, 44))	('paclitaxel', 'Chemical', 'MESH:D017239', (49, 59))	('men', 'Species', '9606', (128, 131))	('BE3', 'CellLine', 'CVCL:L992', (3, 6))	('niclosamide', 'Chemical', 'MESH:D009534', (33, 44))	('paclitaxel', 'Chemical', 'MESH:D017239', (112, 122))	('apoptotic cells', 'CPA', (91, 106))
424120	31894334	In addition to its role in STAT3 inhibition, niclosamide has also been revealed to concurrently inhibit multiple intracellular signaling pathways, including the Wnt, Notch 1, mTOR and NF-kappaB signaling cascades.	('Wnt', 'Pathway', (161, 164))	('STAT3', 'Gene', (27, 32))	('Notch 1', 'Gene', '4851', (166, 173))	('Notch 1', 'Gene', (166, 173))	('intracellular signaling pathways', 'Pathway', (113, 145))	('STAT3', 'Gene', '6774', (27, 32))	('niclosamide', 'Var', (45, 56))	('mTOR', 'Gene', '2475', (175, 179))	('inhibit', 'NegReg', (96, 103))	('NF-kappaB signaling cascades', 'Pathway', (184, 212))	('mTOR', 'Gene', (175, 179))	('niclosamide', 'Chemical', 'MESH:D009534', (45, 56))
424125	31894334	Moreover, STAT3 activated HET-1A cells to form tumors in vivo, suggesting that aberrant STAT3 expression plays a crucial role in esophageal carcinogenesis.	('tumors', 'Disease', (47, 53))	('esophageal carcinogenesis', 'Disease', (129, 154))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('STAT3', 'Gene', '6774', (88, 93))	('aberrant', 'Var', (79, 87))	('STAT3', 'Gene', (88, 93))	('STAT3', 'Gene', '6774', (10, 15))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (129, 154))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))	('STAT3', 'Gene', (10, 15))
424126	31894334	Conversely, STAT3 knockdown significantly reduced cell proliferation of OE21 (ESCC) and OE33 (EAC) cells, and a reduced STAT3 level was revealed to be associated with significant downregulation of cell cycle genes in both cell lines, indicating that STAT3 plays a pivotal role in cell proliferation of esophageal cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (313, 319))	('STAT3', 'Gene', '6774', (120, 125))	('cell proliferation', 'CPA', (50, 68))	('reduced', 'NegReg', (42, 49))	('downregulation', 'NegReg', (179, 193))	('reduced', 'NegReg', (112, 119))	('ESCC', 'Disease', 'MESH:C562729', (78, 82))	('knockdown', 'Var', (18, 27))	('EAC', 'Disease', (94, 97))	('EAC', 'Disease', 'MESH:D004941', (94, 97))	('STAT3', 'Gene', (12, 17))	('esophageal cancer', 'Disease', 'MESH:D004938', (302, 319))	('STAT3', 'Gene', (250, 255))	('ESCC', 'Disease', (78, 82))	('STAT3', 'Gene', '6774', (12, 17))	('STAT3', 'Gene', '6774', (250, 255))	('esophageal cancer', 'Disease', (302, 319))	('cell cycle genes', 'Gene', (197, 213))	('STAT3', 'Gene', (120, 125))
424128	31894334	In addition, niclosamide treatment did not only markedly suppress the phosphorylation of Y705 of STAT3, but also slightly decreased the total protein levels of STAT3.	('STAT3', 'Gene', (97, 102))	('STAT3', 'Gene', '6774', (160, 165))	('suppress', 'NegReg', (57, 65))	('phosphorylation', 'MPA', (70, 85))	('STAT3', 'Gene', (160, 165))	('men', 'Species', '9606', (30, 33))	('niclosamide', 'Chemical', 'MESH:D009534', (13, 24))	('Y705', 'Var', (89, 93))	('STAT3', 'Gene', '6774', (97, 102))	('decreased', 'NegReg', (122, 131))
424132	31894334	Notably, ESCC CE81T cells were more resistant than ESCC CE48T cells to niclosamide.	('ESCC', 'Disease', (9, 13))	('ESCC', 'Disease', 'MESH:C562729', (51, 55))	('niclosamide', 'Chemical', 'MESH:D009534', (71, 82))	('resistant', 'MPA', (36, 45))	('ESCC', 'Disease', (51, 55))	('ESCC', 'Disease', 'MESH:C562729', (9, 13))	('CE81T', 'Var', (14, 19))
424133	31894334	Similar resistant responses were revealed in a previous study in which CE81T cells were resistant to photofrin-induced inhibition of EGFR as well as to photofrin-mediated dark toxicity, compared with CE48T cells.	('photofrin', 'Chemical', 'MESH:D017323', (101, 110))	('toxicity', 'Disease', 'MESH:D064420', (176, 184))	('EGFR', 'Gene', '1956', (133, 137))	('CE81T', 'Var', (71, 76))	('toxicity', 'Disease', (176, 184))	('photofrin', 'Chemical', 'MESH:D017323', (152, 161))	('EGFR', 'Gene', (133, 137))
424137	31894334	By contrast, in esophageal squamous cell carcinoma cell lines, niclosamide significantly (P<0.05) increased the proportion of early apoptotic cells in both CE48T and CE81T cells, however only significantly increased the proportion of dead cells in CE48T (P<0.005), but not in CE81T cells.	('early apoptotic cells', 'CPA', (126, 147))	('esophageal squamous cell carcinoma', 'Disease', (16, 50))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:C562729', (16, 50))	('CE48T', 'Var', (156, 161))	('carcinoma', 'Phenotype', 'HP:0030731', (41, 50))	('CE81T', 'Var', (166, 171))	('niclosamide', 'Chemical', 'MESH:D009534', (63, 74))	('CE48T', 'Var', (248, 253))	('increased', 'PosReg', (98, 107))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (27, 50))
424138	31894334	After 48 h of treatment of niclosamide, only a small proportion of Annexin V-positive cells were detected in CE81T, compared with CE48T and BE3 cells.	('niclosamide', 'Chemical', 'MESH:D009534', (27, 38))	('BE3', 'CellLine', 'CVCL:L992', (140, 143))	('Annexin V', 'Gene', '308', (67, 76))	('men', 'Species', '9606', (19, 22))	('CE81T', 'Var', (109, 114))	('Annexin V', 'Gene', (67, 76))
424140	31894334	Previous studies in oral squamous cell carcinoma, adrenocortical carcinoma and head and neck cancer and osteosarcoma revealed that niclosamide could induce G1-phase arrest of the cell cycle.	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('head and neck cancer', 'Phenotype', 'HP:0012288', (79, 99))	('adrenocortical carcinoma', 'Disease', (50, 74))	('osteosarcoma', 'Disease', (104, 116))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (20, 48))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('osteosarcoma', 'Phenotype', 'HP:0002669', (104, 116))	('induce', 'Reg', (149, 155))	('niclosamide', 'Chemical', 'MESH:D009534', (131, 142))	('osteosarcoma', 'Disease', 'MESH:D012516', (104, 116))	('oral squamous cell carcinoma', 'Disease', (20, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (39, 48))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (50, 74))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (50, 74))	('G1-phase arrest of the cell cycle', 'CPA', (156, 189))	('head and neck cancer', 'Disease', 'MESH:D006258', (79, 99))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (25, 48))	('niclosamide', 'Var', (131, 142))
424141	31894334	Through flow cytometric analysis using DNA dye PI staining, it was revealed that a high proportion of sub-G1 cells were detected in CE48T and BE3 cells after 10 microM niclosamide treatment for 72 h, while only a small proportion of sub-G1 was detected in CE81T cells.	('CE48T', 'Var', (132, 137))	('niclosamide', 'Chemical', 'MESH:D009534', (168, 179))	('men', 'Species', '9606', (185, 188))	('sub-G1', 'Gene', (102, 108))	('detected', 'Reg', (120, 128))	('BE3', 'CellLine', 'CVCL:L992', (142, 145))
424187	30881502	Studies have reported that the detection of high CTCs by the CellSearch  system in metastatic breast cancer is associated with poor overall survival.	('high CTCs', 'Var', (44, 53))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('breast cancer', 'Disease', 'MESH:D001943', (94, 107))	('breast cancer', 'Phenotype', 'HP:0003002', (94, 107))	('breast cancer', 'Disease', (94, 107))
424263	30881502	Kaganoi et al used RT-qPCR to detect cancer cells using specific mRNAs; patients who were positive for the mRNA encoding squamous cell carcinoma antigen (SCCA mRNA) had a higher recurrence rate compared with those who were negative for the antigen.	('mRNA', 'Var', (107, 111))	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (121, 144))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('squamous cell carcinoma', 'Disease', (121, 144))	('cancer', 'Disease', (37, 43))	('recurrence rate', 'CPA', (178, 193))	('higher', 'PosReg', (171, 177))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('rat', 'Species', '10116', (189, 192))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (121, 144))	('patients', 'Species', '9606', (72, 80))
424268	30881502	Notably, a single patient who accepted the left thoracotomy surgery approach, was CTC positive, with postoperative pathological staging of T1bN0M0, IB, while another patient, who accepted the thoracoscopic and laparoscopic approach with thoracic anastomosis (Ivor-Lewis), was CTM-positive with the same postoperative pathological stage.	('thoracic anastomosis', 'Disease', 'MESH:D013896', (237, 257))	('rat', 'Species', '10116', (108, 111))	('rat', 'Species', '10116', (310, 313))	('patient', 'Species', '9606', (166, 173))	('patient', 'Species', '9606', (18, 25))	('CTM', 'Chemical', '-', (276, 279))	('T1bN0M0', 'Var', (139, 146))	('thoracic anastomosis', 'Disease', (237, 257))
424280	30881502	One study of esophageal cancer illustrated that LODDS predicts survival more accurately compared with the present system of LNMs, and may serve as another indicator of the LNR.	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('esophageal cancer', 'Disease', 'MESH:D004938', (13, 30))	('rat', 'Species', '10116', (81, 84))	('rat', 'Species', '10116', (37, 40))	('LODDS', 'Var', (48, 53))	('LODDS', 'Chemical', '-', (48, 53))	('survival', 'MPA', (63, 71))	('esophageal cancer', 'Disease', (13, 30))
424322	28883082	In lung cancer and colorectal cancer, high levels of CXCL8 expression suggested an increased risk of cancer and unfavorable prognosis.	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('cancer', 'Disease', (8, 14))	('lung cancer', 'Disease', (3, 14))	('cancer', 'Disease', (101, 107))	('lung cancer', 'Phenotype', 'HP:0100526', (3, 14))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('cancer', 'Disease', (30, 36))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('colorectal cancer', 'Disease', 'MESH:D015179', (19, 36))	('high', 'Var', (38, 42))	('lung cancer', 'Disease', 'MESH:D008175', (3, 14))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('colorectal cancer', 'Phenotype', 'HP:0003003', (19, 36))	('CXCL8', 'Gene', '3576', (53, 58))	('CXCL8', 'Gene', (53, 58))	('colorectal cancer', 'Disease', (19, 36))	('cancer', 'Disease', 'MESH:D009369', (8, 14))
424365	28883082	Kaplan-Meier survival analysis indicated that cervical cancer patients with CXCL8 protein's high expression had shorter overall survival compared in patients with CXCL8 protein low expression (P<0.001, Figure 3A).	('cervical cancer', 'Disease', 'MESH:D002583', (46, 61))	('patients', 'Species', '9606', (149, 157))	('cervical cancer', 'Disease', (46, 61))	('high expression', 'Var', (92, 107))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('CXCL8', 'Gene', '3576', (76, 81))	('CXCL8', 'Gene', '3576', (163, 168))	('CXCL8', 'Gene', (76, 81))	('CXCL8', 'Gene', (163, 168))	('overall survival', 'MPA', (120, 136))	('patients', 'Species', '9606', (62, 70))	('shorter', 'NegReg', (112, 119))
424398	28883082	Furthermore, we analyzed a cohort that included 246 cervical cancer patients from The Cancer Genome Atlas database, and found that patients with high level of CXCL8 had shorter overall survival compared with patients with low level of CXCL8, which was consistent with our result.	('patients', 'Species', '9606', (131, 139))	('cervical cancer', 'Disease', (52, 67))	('patients', 'Species', '9606', (208, 216))	('high level', 'Var', (145, 155))	('cervical cancer', 'Disease', 'MESH:D002583', (52, 67))	('CXCL8', 'Gene', '3576', (159, 164))	('overall survival', 'MPA', (177, 193))	('patients', 'Species', '9606', (68, 76))	('CXCL8', 'Gene', (159, 164))	('shorter', 'NegReg', (169, 176))	('CXCL8', 'Gene', '3576', (235, 240))	('Cancer', 'Phenotype', 'HP:0002664', (86, 92))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('CXCL8', 'Gene', (235, 240))
424405	28883082	Moreover, HuMab10F8 (also known as HuMax-CXCL8), a specific antibody, blocks CXCL8 signaling by neutralizing CXCL8.	('CXCL8', 'Gene', (109, 114))	('HuMab10F8', 'Var', (10, 19))	('CXCL8', 'Gene', '3576', (41, 46))	('CXCL8', 'Gene', (41, 46))	('blocks', 'NegReg', (70, 76))	('CXCL8', 'Gene', '3576', (77, 82))	('CXCL8', 'Gene', (77, 82))	('CXCL8', 'Gene', '3576', (109, 114))
424410	26785143	Transcriptome profiling in oral cavity and esophagus tissues from (S)-N'-nitrosonornicotine-treated rats reveals candidate genes involved in human oral cavity and esophageal carcinogenesis Recently, we have shown that (S)-N'-Nitrosonornicotine [(S)-NNN], the major form of NNN in tobacco products, is a potent oral cavity and esophageal carcinogen in rats.	('tobacco', 'Species', '4097', (280, 287))	('rats', 'Species', '10116', (100, 104))	("(S)-N'-Nitrosonornicotine", 'Chemical', 'MESH:C008655', (218, 243))	('NNN', 'Chemical', 'MESH:C008655', (249, 252))	('human', 'Species', '9606', (141, 146))	("S)-N'-Nitrosonornicotine", 'Var', (219, 243))	('rats', 'Species', '10116', (351, 355))	('NNN', 'Chemical', 'MESH:C008655', (273, 276))	('esophageal carcinogenesis', 'Disease', (163, 188))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (163, 188))	('(S)-NNN', 'Chemical', 'MESH:C008655', (245, 252))	("(S)-N'-nitrosonornicotine", 'Chemical', 'MESH:C008655', (66, 91))
424418	26785143	NNN causes esophageal, oral cavity, and nasal cavity tumors in rats, nasal cavity tumors in mink, and respiratory tract tumors in mice and hamsters.	('tumors', 'Disease', (120, 126))	('tumors', 'Disease', (82, 88))	('respiratory tract tumors', 'Disease', (102, 126))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('tumors', 'Disease', 'MESH:D009369', (120, 126))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumors', 'Disease', (53, 59))	('mice', 'Species', '10090', (130, 134))	('rats', 'Species', '10116', (63, 67))	('esophageal', 'Disease', (11, 21))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('oral cavity', 'Disease', (23, 34))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('NNN', 'Var', (0, 3))	('mink', 'Species', '9666', (92, 96))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('causes', 'Reg', (4, 10))	('respiratory tract tumors', 'Phenotype', 'HP:0100606', (102, 126))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('NNN', 'Chemical', 'MESH:C008655', (0, 3))	('respiratory tract tumors', 'Disease', 'MESH:D012140', (102, 126))
424426	26785143	Indeed, in our recent studies with male F-344 rats treated chronically with 14 ppm (S)-NNN in the drinking water, we showed that (S)-NNN is a strong oral cavity carcinogen, whereas the opposite enantiomer (R)-NNN was inactive, but synergistically enhanced the carcinogenicity of (S)-NNN [2].	('(S)-NNN', 'Chemical', 'MESH:C008655', (279, 286))	('drinking water', 'Chemical', 'MESH:D060766', (98, 112))	('enhanced', 'PosReg', (247, 255))	('(S)-NNN', 'Chemical', 'MESH:C008655', (83, 90))	('carcinogenic', 'Disease', 'MESH:D063646', (260, 272))	('S)-NNN', 'Var', (130, 136))	('(R)-NNN', 'Chemical', '-', (205, 212))	('carcinogenic', 'Disease', (260, 272))	('(S)-NNN', 'Chemical', 'MESH:C008655', (129, 136))	('rats', 'Species', '10116', (46, 50))
424427	26785143	Although (S)-NNN is a potent esophageal and oral cavity carcinogen in rats, the molecular mechanisms responsible for its carcinogenicity and its higher potency as compared to (R)-NNN are not known.	('(S)-NNN', 'Chemical', 'MESH:C008655', (9, 16))	('rats', 'Species', '10116', (70, 74))	('carcinogenic', 'Disease', 'MESH:D063646', (121, 133))	('(R)-NNN', 'Chemical', '-', (175, 182))	('carcinogenic', 'Disease', (121, 133))	('S)-NNN', 'Var', (10, 16))
424454	26785143	The concentration (A260) and purity (A260/A280 and A260/A230) of RNA were determined using NanoDrop 1000 spectrophotometry.	('rat', 'Species', '10116', (11, 14))	('A260/A230', 'Var', (51, 60))	('A260/A280', 'Var', (37, 46))
424480	26785143	The broader list of genes upregulated and downregulated by (S)-NNN in the esophageal mucosa of rats at a less stringent p-value < 0.01 is included in Supplementary Tables 2 and 3, respectively.	('(S)-NNN', 'Chemical', 'MESH:C008655', (59, 66))	('upregulated', 'PosReg', (26, 37))	('rats', 'Species', '10116', (95, 99))	('downregulated', 'NegReg', (42, 55))	('S)-NNN', 'Var', (60, 66))
424486	26785143	At a p-value between 0.005 and < 0.05, five additional genes (ADIPOQ, B3GNT5, EMB, GPR171, and RTP4) showed increased copy numbers in 10 - 21% of esophageal carcinoma cases (Supplementary Figure 1).	('EMB', 'Gene', (78, 81))	('RTP4', 'Gene', '360733', (95, 99))	('ADIPOQ', 'Gene', (62, 68))	('increased', 'PosReg', (108, 117))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (146, 166))	('GPR171', 'Gene', '688737', (83, 89))	('ADIPOQ', 'Gene', '246253', (62, 68))	('esophageal carcinoma', 'Disease', (146, 166))	('B3GNT5', 'Gene', '116740', (70, 76))	('EMB', 'Gene', '114511', (78, 81))	('carcinoma', 'Phenotype', 'HP:0030731', (157, 166))	('B3GNT5', 'Gene', (70, 76))	('RTP4', 'Gene', (95, 99))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (146, 166))	('copy numbers', 'Var', (118, 130))	('GPR171', 'Gene', (83, 89))
424487	26785143	In addition to copy number amplifications, ATP13A5, LY6E, NR1D1, B3GNT5, EMB, and RTP4 all showed mRNA upregulation in ESCA in comparison to the adjacent normal tissues (Table 1a).	('ESCA', 'Disease', (119, 123))	('EMB', 'Gene', '114511', (73, 76))	('RTP4', 'Gene', '360733', (82, 86))	('upregulation', 'PosReg', (103, 115))	('NR1D1', 'Gene', (58, 63))	('EMB', 'Gene', (73, 76))	('mRNA', 'MPA', (98, 102))	('B3GNT5', 'Gene', '116740', (65, 71))	('LY6E', 'Var', (52, 56))	('ATP13A5', 'Var', (43, 50))	('B3GNT5', 'Gene', (65, 71))	('NR1D1', 'Gene', '252917', (58, 63))	('RTP4', 'Gene', (82, 86))
424521	26785143	Similarly, Ctla-4 inhibits T cell activation by competing with CD28, a protein that provides co-stimulatory signals required for T cell activation and survival, for binding to leucocyte surface molecules CD80 and CD86, and thereby dampening of T-cell activation and proliferation.	('dampening', 'NegReg', (231, 240))	('T cell activation', 'CPA', (27, 44))	('binding', 'Interaction', (165, 172))	('inhibits', 'NegReg', (18, 26))	('CD86', 'Gene', '56822', (213, 217))	('dampening of T-cell activation', 'Phenotype', 'HP:0005419', (231, 261))	('CD86', 'Gene', (213, 217))	('CD28', 'Gene', (63, 67))	('CD28', 'Gene', '25660', (63, 67))	('CD80', 'Var', (204, 208))	('rat', 'Species', '10116', (273, 276))	('T-cell activation', 'CPA', (244, 261))	('Ctla-4', 'Gene', (11, 17))	('Ctla-4', 'Gene', '63835', (11, 17))
424529	26785143	Overexpression of CDKN2A has been reported in several benign and pre-malignant lesions and this phenomenon is believed to control cell proliferation in response to oncogenic stimuli, thereby protecting cells from malignant transformation.	('reported', 'Reg', (34, 42))	('control', 'Reg', (122, 129))	('Overexpression', 'Var', (0, 14))	('CDKN2A', 'Gene', (18, 24))	('rat', 'Species', '10116', (142, 145))	('cell proliferation', 'CPA', (130, 148))
424532	26785143	Therefore, inhibition of sEH could suppress chronic inflammation-associated cancers.	('sEH', 'Gene', (25, 28))	('inflammation-associated cancers', 'Disease', (52, 83))	('cancers', 'Phenotype', 'HP:0002664', (76, 83))	('inflammation-associated cancers', 'Disease', 'MESH:D007249', (52, 83))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('inhibition', 'Var', (11, 21))	('sEH', 'Gene', '65030', (25, 28))	('suppress', 'NegReg', (35, 43))
424533	26785143	Indeed, in one recent study, genetic knockout of sEH inhibited dextran sulfate sodium-induced colitis, inflammatory cytokines and chemokines, pre-cancerous dysplastic lesions and colon tumor incidence and tumor size.	('inhibited', 'NegReg', (53, 62))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('inflammatory cytokines', 'MPA', (103, 125))	('tumor', 'Disease', (185, 190))	('cancerous dysplastic lesions', 'Disease', (146, 174))	('colitis', 'Disease', (94, 101))	('sEH', 'Gene', (49, 52))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('cancerous dysplastic lesions', 'Disease', 'MESH:D009062', (146, 174))	('colitis', 'Disease', 'MESH:D003092', (94, 101))	('dextran sulfate sodium-induced', 'MPA', (63, 93))	('colon tumor', 'Disease', 'MESH:D015179', (179, 190))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('colon tumor', 'Phenotype', 'HP:0100273', (179, 190))	('genetic knockout', 'Var', (29, 45))	('colon tumor', 'Disease', (179, 190))	('tumor', 'Disease', (205, 210))	('colitis', 'Phenotype', 'HP:0002583', (94, 101))	('dextran sulfate sodium', 'Chemical', 'MESH:D016264', (63, 85))	('sEH', 'Gene', '65030', (49, 52))
424537	26785143	Thus, it appears that induction of sEH plays a role in the promotion and progression of inflammation-associated cancers such as oral and esophageal cancer and thus could serve as a biomarker for the early detection of these diseases and as a target for chemopreventive and therapeutic agents.	('induction', 'Var', (22, 31))	('esophageal cancer', 'Disease', 'MESH:D004938', (137, 154))	('cancers', 'Phenotype', 'HP:0002664', (112, 119))	('sEH', 'Gene', (35, 38))	('inflammation-associated cancers', 'Disease', (88, 119))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('inflammation-associated cancers', 'Disease', 'MESH:D007249', (88, 119))	('sEH', 'Gene', '65030', (35, 38))	('esophageal cancer', 'Disease', (137, 154))	('promotion', 'PosReg', (59, 68))
424542	26785143	LCK is a member of the Src family nonreceptor protein-tyrosine kinase and aberrant LCK expression and kinase activity have been implicated in the pathogenesis of both lymphoid and nonlymphoid malignancies.	('implicated', 'Reg', (128, 138))	('LCK', 'Gene', (83, 86))	('lymphoid and nonlymphoid malignancies', 'Disease', 'MESH:D008223', (167, 204))	('kinase activity', 'MPA', (102, 117))	('aberrant', 'Var', (74, 82))
424547	26785143	In addition to copy number amplification, both ATP13A5 and LY6E showed mRNA upregulation in human ESCA, suggesting their potential roles in early onset and maintenance of tumorigenesis as a result of increases in genetic activities.	('upregulation', 'PosReg', (76, 88))	('LY6E', 'Var', (59, 63))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('mRNA', 'MPA', (71, 75))	('ATP13A5', 'Var', (47, 54))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', (171, 176))	('human', 'Species', '9606', (92, 97))	('ESCA', 'Disease', (98, 102))
424658	31067990	The histology codes were grouped into the following 5 categories: small-cell lung carcinoma (ICDO-3 codes 8041-8045), squamous cell lung carcinoma (8050-8082), adenocarcinoma (8140-8191, 8201-8221, 8250-8300, 8312-8420, 8440-8550), and other/unspecified (most of the "other" cases were malignant neoplasms and carcinomas not otherwise specified).	('8201-8221', 'Var', (187, 196))	('unspecified', 'Species', '32644', (242, 253))	('8140-8191', 'Var', (176, 185))	('small-cell lung carcinoma', 'Phenotype', 'HP:0030357', (66, 91))	('squamous cell lung carcinoma', 'Disease', (118, 146))	('8050-8082', 'Var', (148, 157))	('small-cell lung carcinoma', 'Disease', (66, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (310, 319))	('adenocarcinoma', 'Disease', 'MESH:D000230', (160, 174))	('8312-8420', 'Var', (209, 218))	('carcinomas', 'Phenotype', 'HP:0030731', (310, 320))	('carcinomas', 'Disease', 'MESH:D002277', (310, 320))	('squamous cell lung carcinoma', 'Disease', 'MESH:D002294', (118, 146))	('neoplasms', 'Phenotype', 'HP:0002664', (296, 305))	('carcinoma', 'Phenotype', 'HP:0030731', (165, 174))	('8250-8300', 'Var', (198, 207))	('malignant neoplasms', 'Disease', 'MESH:D009369', (286, 305))	('8440-8550', 'Var', (220, 229))	('malignant neoplasms', 'Disease', (286, 305))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('squamous cell lung carcinoma', 'Phenotype', 'HP:0030359', (118, 146))	('carcinomas', 'Disease', (310, 320))	('small-cell lung carcinoma', 'Disease', 'MESH:D055752', (66, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('adenocarcinoma', 'Disease', (160, 174))
424660	31067990	TNM classification-based information reported to the cancer registry was grouped into 4 categories: (1) localized cancer:T1-2/N0/M0; (2) locally advanced cancer:T3-4/N0/M0; (3) cancer with regional metastasis:any T/N+/M0; and (4) advanced cancer:any T/any N/M+.	('cancer', 'Disease', (177, 183))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('T/N+/M0', 'Var', (213, 220))	('T3-4/N0/M0', 'Var', (161, 171))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('cancer', 'Disease', (239, 245))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('cancer', 'Disease', 'MESH:D009369', (177, 183))	('cancer', 'Disease', (53, 59))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('TNM', 'Gene', '10178', (0, 3))	('cancer', 'Disease', 'MESH:D009369', (239, 245))	('cancer', 'Disease', (154, 160))	('TNM', 'Gene', (0, 3))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('cancer', 'Disease', (114, 120))
424733	30102398	FACER: comprehensive molecular and functional characterization of epigenetic chromatin regulators Epigenetic alterations, a well-recognized cancer hallmark, are driven by chromatin regulators (CRs).	('CRs', 'Chemical', '-', (193, 196))	('cancer hallmark', 'Disease', (140, 155))	('cancer hallmark', 'Disease', 'MESH:D009369', (140, 155))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('Epigenetic alterations', 'Var', (98, 120))
424734	30102398	However, little is known about the extent of CR deregulation in cancer, and less is known about their common and specialized roles across various cancers.	('cancers', 'Disease', (146, 153))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('cancer', 'Disease', (146, 152))	('cancers', 'Disease', 'MESH:D009369', (146, 153))	('CR', 'Chemical', '-', (45, 47))	('cancer', 'Disease', (64, 70))	('deregulation', 'Var', (48, 60))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('cancers', 'Phenotype', 'HP:0002664', (146, 153))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
424745	30102398	DNA methylators and histone modifiers can code and decode various modifications on cytosine and histone residues and are usually further divided into readers, writers, and erasers.	('cytosine', 'MPA', (83, 91))	('modifications', 'Var', (66, 79))	('cytosine', 'Chemical', 'MESH:D003596', (83, 91))	('histone', 'Protein', (96, 103))
424748	30102398	Chromatin remodelers are a special type of CRs that can disrupt the contact between nucleosomes and DNA, shuffle nucleosomes around, replace them or remove them from the chromatin, and cause abnormal epigenetic modifications.	('contact', 'Interaction', (68, 75))	('epigenetic modifications', 'MPA', (200, 224))	('cause', 'Reg', (185, 190))	('replace', 'Reg', (133, 140))	('disrupt', 'NegReg', (56, 63))	('CRs', 'Chemical', '-', (43, 46))	('shuffle', 'Var', (105, 112))	('remove', 'NegReg', (149, 155))
424749	30102398	The alteration of epigenetic marks is a prevalent feature in cancer.	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('cancer', 'Disease', (61, 67))	('alteration', 'Var', (4, 14))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('epigenetic marks', 'Var', (18, 34))
424751	30102398	For example, it is widely accepted that mutations can perturb CR functions.	('CR functions', 'CPA', (62, 74))	('mutations', 'Var', (40, 49))	('perturb', 'NegReg', (54, 61))	('CR', 'Chemical', '-', (62, 64))
424752	30102398	have found that genetic alteration of DNMT3A (a DNA methylation transferase) can induce genome-wide alterations of DNA methylation and gene expression.	('alterations', 'Reg', (100, 111))	('gene expression', 'MPA', (135, 150))	('genetic alteration', 'Var', (16, 34))	('DNMT3A', 'Gene', (38, 44))	('DNMT3A', 'Gene', '1788', (38, 44))	('DNA methylation', 'MPA', (115, 130))
424753	30102398	Moreover, patients with DNMT3A mutations have poor prognosis compared with those without such mutations.	('DNMT3A', 'Gene', (24, 30))	('DNMT3A', 'Gene', '1788', (24, 30))	('mutations', 'Var', (31, 40))	('patients', 'Species', '9606', (10, 18))
424756	30102398	They found that dysregulation of these CRs results in structural abnormalities in chromatins and epigenetic alterations of numerous cancer-associated genes, which finally lead to increased tumor volume, extracapsular extension, and metastases in prostate cancer patients.	('numerous cancer', 'Disease', 'MESH:D009369', (123, 138))	('structural abnormalities', 'Disease', (54, 78))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('increased', 'PosReg', (179, 188))	('structural abnormalities', 'Disease', 'MESH:C566527', (54, 78))	('cancer', 'Phenotype', 'HP:0002664', (255, 261))	('metastases in prostate cancer', 'Disease', 'MESH:D009362', (232, 261))	('chromatins', 'Protein', (82, 92))	('metastases in prostate cancer', 'Disease', (232, 261))	('prostate cancer', 'Phenotype', 'HP:0012125', (246, 261))	('numerous cancer', 'Disease', (123, 138))	('epigenetic alterations', 'Var', (97, 119))	('extracapsular extension', 'CPA', (203, 226))	('dysregulation', 'Var', (16, 29))	('tumor', 'Disease', (189, 194))	('CRs', 'Chemical', '-', (39, 42))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('patients', 'Species', '9606', (262, 270))
424787	30102398	To evaluate the global regulatory effect of a given CR on the DNA hypermethylation (or hypomethylation) in a specific cancer type, we computed the significance of Pearson correlation (P value) between CR expression and aberrant hypermethylation (or hypomethylation) of tumor samples.	('tumor', 'Disease', 'MESH:D009369', (269, 274))	('CR', 'Chemical', '-', (52, 54))	('cancer', 'Disease', (118, 124))	('tumor', 'Phenotype', 'HP:0002664', (269, 274))	('aberrant', 'Var', (219, 227))	('tumor', 'Disease', (269, 274))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('CR', 'Chemical', '-', (201, 203))	('cancer', 'Disease', 'MESH:D009369', (118, 124))
424863	30102398	Mutation frequency and centrality in PPIN were found to be the top two recurrent features (Figure 2I), which were involved in 25 and 29 cancer types, respectively.	('Mutation frequency', 'Var', (0, 18))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('PPIN', 'Gene', (37, 41))	('cancer', 'Disease', (136, 142))	('involved', 'Reg', (114, 122))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
424874	30102398	Moreover, we found that DNA methylation readers and histone modification writers were the most common functional CRs across all 33 cancer types (Figure 3A).	('cancer', 'Disease', (131, 137))	('DNA methylation readers', 'Var', (24, 47))	('histone modification writers', 'Var', (52, 80))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('CRs', 'Chemical', '-', (113, 116))	('cancer', 'Disease', 'MESH:D009369', (131, 137))
424877	30102398	Moreover, histone modification readers and writers as well as chromatin remodelers played important roles across cancer types compared with DNA methylation erasers and histone modification erasers (Figure 3B, bottom).	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('histone', 'Var', (10, 17))	('cancer', 'Disease', (113, 119))	('played', 'Reg', (83, 89))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
424883	30102398	Functional enrichment analysis showed that DNA methylators, histone modifiers and chromatin remodelers were all enriched in at least one cancer hallmark, especially in the hallmark 'genome instability and mutation', highlighting the extent of genome alternations in cancer (Supplementary Figure S8 and Supplementary Table S5).	("mutation'", 'Var', (205, 214))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('cancer', 'Disease', 'MESH:D009369', (266, 272))	('Supplementary Figure S8', 'Disease', (274, 297))	('cancer', 'Disease', (266, 272))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('cancer hallmark', 'Disease', (137, 152))	('cancer', 'Disease', (137, 143))	('cancer hallmark', 'Disease', 'MESH:D009369', (137, 152))	('cancer', 'Phenotype', 'HP:0002664', (266, 272))	('Supplementary Figure S8', 'Disease', 'MESH:D017034', (274, 297))
424885	30102398	Functional histone modifiers in almost all cancer types were enriched in the functions 'evading apoptosis', 'genome instability and mutation', 'insensitivity to antigrowth signals', and 'self-sufficiency in growth signals'.	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('cancer', 'Disease', (43, 49))	("'evading", 'Disease', (87, 95))	('sufficiency in growth', 'Phenotype', 'HP:0001510', (192, 213))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	("mutation'", 'Var', (132, 141))
424897	30102398	For example, we found that PHF19, a writer for H3K36me3 as a component of polycomb repressive complex 2 (PRC2), was prioritized as a breast invasive carcinoma (BRCA) related CR in our analyses.	('carcinoma', 'Phenotype', 'HP:0030731', (149, 158))	('H3K36me3', 'Var', (47, 55))	('PHF19', 'Gene', '26147', (27, 32))	('BRCA', 'Phenotype', 'HP:0003002', (160, 164))	('BRCA', 'Gene', '672', (160, 164))	('PHF19', 'Gene', (27, 32))	('BRCA', 'Gene', (160, 164))	('breast invasive carcinoma', 'Disease', 'MESH:D018270', (133, 158))	('CR', 'Chemical', '-', (174, 176))	('breast invasive carcinoma', 'Phenotype', 'HP:0003002', (133, 158))	('breast invasive carcinoma', 'Disease', (133, 158))
424900	30102398	Moreover, the genome-wide H3K36me3 marks showed an obvious increase in cancer.	('H3K36me3 marks', 'Var', (26, 40))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('cancer', 'Disease', (71, 77))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('increase', 'PosReg', (59, 67))
424915	30102398	Among these CRs, 14 were up-regulated in cancer, and 1 was down-regulated (Supplementary Figure S11A).	('up-regulated', 'PosReg', (25, 37))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('CRs', 'Chemical', '-', (12, 15))	('S11A', 'Var', (96, 100))	('down-regulated', 'NegReg', (59, 73))	('S11A', 'SUBSTITUTION', 'None', (96, 100))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (41, 47))
424916	30102398	Interestingly, 11 of these 15 CRs showed consistent deregulation across cancer types compared with the corresponding adjacent normal samples (Supplementary Figure S11B).	('deregulation', 'MPA', (52, 64))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('CRs', 'Chemical', '-', (30, 33))	('S11B', 'Var', (163, 167))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('S11B', 'SUBSTITUTION', 'None', (163, 167))	('cancer', 'Disease', (72, 78))
424923	30102398	For cancer-specific CRs, we found that these CRs included 36% of the DNA methylation erasers and 35% of the histone modification erasers.	('CRs', 'Chemical', '-', (45, 48))	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('cancer', 'Disease', (4, 10))	('histone modification', 'MPA', (108, 128))	('methylation', 'Var', (73, 84))	('DNA', 'MPA', (69, 72))	('cancer', 'Disease', 'MESH:D009369', (4, 10))	('CRs', 'Chemical', '-', (20, 23))
424931	30102398	KMT2C showed a higher mutation frequency in KIRP patients, whereas the aberrant regulation of miRNAs and its regulation of DNA methylation over open sea regions were additional features in KICH patients.	('mutation', 'Var', (22, 30))	('KICH', 'Disease', (189, 193))	('patients', 'Species', '9606', (194, 202))	('DNA methylation', 'MPA', (123, 138))	('KMT2C', 'Gene', '58508', (0, 5))	('KMT2C', 'Gene', (0, 5))	('KICH', 'Disease', 'None', (189, 193))	('patients', 'Species', '9606', (49, 57))
424937	30102398	We found that common CRs in cancer had higher values for all seven features compared with specific CRs, especially in four functional features (all P < 0.05, Wilcoxon rank-sum test), including mutation frequency, differential expression, degree in PPIN, and regulation of genome hypermethylation (Figure 5C, top, and Supplementary Table S8).	('higher', 'PosReg', (39, 45))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('mutation frequency', 'Var', (193, 211))	('CRs', 'Chemical', '-', (99, 102))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('CRs', 'Chemical', '-', (21, 24))	('PPIN', 'Protein', (248, 252))	('cancer', 'Disease', (28, 34))	('differential expression', 'MPA', (213, 236))
424963	30102398	Patients in subtype 1 of ACC showed the highest mutation frequency of TP53 and CGI methylation, while patients in subtype 3 showed high mutation of KDM6B and the lowest open sea methylation.	('TP53', 'Gene', '7157', (70, 74))	('patients', 'Species', '9606', (102, 110))	('KDM6B', 'Gene', '23135', (148, 153))	('Patients', 'Species', '9606', (0, 8))	('TP53', 'Gene', (70, 74))	('mutation', 'Var', (48, 56))	('ACC', 'Phenotype', 'HP:0006744', (25, 28))	('KDM6B', 'Gene', (148, 153))	('methylation', 'Var', (83, 94))	('CGI', 'Protein', (79, 82))
424988	30102398	Analysis of the functional features revealed recurrent multi-omics effects of functional CRs across 33 cancer types.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('effects', 'Reg', (67, 74))	('CRs', 'Chemical', '-', (89, 92))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('functional', 'Var', (78, 88))
424993	30102398	By comparison between common, specific and mixed CRs as well as DNA methylators, histone modifiers and chromatin remodelers, we found that DNA methylation readers as well as histone modification readers and writers were with more common CRs, suggesting that these three categories of CRs tend to be aberrant across cancer types.	('methylation', 'Var', (143, 154))	('cancer', 'Disease', 'MESH:D009369', (315, 321))	('DNA', 'Var', (139, 142))	('cancer', 'Disease', (315, 321))	('CRs', 'Chemical', '-', (284, 287))	('cancer', 'Phenotype', 'HP:0002664', (315, 321))	('CRs', 'Chemical', '-', (237, 240))	('CRs', 'Chemical', '-', (49, 52))
424994	30102398	We also found that DNA methylation erasers and histone modification erasers tend to be dysregulated in specific cancer type.	('DNA', 'MPA', (19, 22))	('histone modification', 'MPA', (47, 67))	('methylation', 'Var', (23, 34))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('cancer', 'Disease', (112, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))
425000	30102398	Moreover, we found that DNA methylators and histone modifiers can induce the development of cancer by regulation of DNA methylation and histone modifications, such as DNMT1, DNMT3A and PHF19.	('PHF19', 'Gene', '26147', (185, 190))	('histone', 'Protein', (136, 143))	('cancer', 'Disease', (92, 98))	('development of', 'CPA', (77, 91))	('PHF19', 'Gene', (185, 190))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('DNMT3A', 'Gene', (174, 180))	('DNMT3A', 'Gene', '1788', (174, 180))	('induce', 'PosReg', (66, 72))	('DNA', 'MPA', (116, 119))	('DNMT1', 'Gene', (167, 172))	('DNMT1', 'Gene', '1786', (167, 172))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('modifications', 'Var', (144, 157))
425022	28678605	Furthermore, the large genomic regions affected by these patterns of hypomethylation encompass genes involved in pathways related to epithelial-mesenchymal transition, immune response, and inflammation.	('inflammation', 'Disease', (189, 201))	('inflammation', 'Disease', 'MESH:D007249', (189, 201))	('hypomethylation', 'Var', (69, 84))
425029	28678605	Studies on DNA methylation in cancer cells and placental cells have highlighted similarities in their epigenetic landscapes, which are characterized by a widespread hypomethylation throughout the genome and focal hypermethylation at CpG islands, including at promoters of tumor suppressor genes.	('tumor', 'Phenotype', 'HP:0002664', (272, 277))	('tumor', 'Disease', (272, 277))	('cancer', 'Disease', (30, 36))	('hypomethylation', 'Var', (165, 180))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('tumor', 'Disease', 'MESH:D009369', (272, 277))	('placental', 'Species', '9347', (47, 56))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
425030	28678605	A recent study also linked the observation of genes specifically expressed in both the placenta and various tumors to hypomethylation.	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('hypomethylation', 'Var', (118, 133))	('tumors', 'Disease', 'MESH:D009369', (108, 114))	('tumors', 'Disease', (108, 114))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))
425032	28678605	We hypothesized that there may be parallels between the patterns of methylation that distinguish the early pregnancy placenta from the late pregnancy placenta and those that distinguish tumors from corresponding normal tissues, and that such similar epigenetic patterns may contribute to the regulation of shared cancer/placenta phenotypes.	('late pregnancy', 'Phenotype', 'HP:0001622', (135, 149))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('methylation', 'Var', (68, 79))	('contribute', 'Reg', (274, 284))	('tumors', 'Phenotype', 'HP:0002664', (186, 192))	('cancer', 'Phenotype', 'HP:0002664', (313, 319))	('early pregnancy', 'Phenotype', 'HP:0001622', (101, 116))	('tumors', 'Disease', (186, 192))	('tumors', 'Disease', 'MESH:D009369', (186, 192))	('cancer', 'Disease', (313, 319))	('cancer', 'Disease', 'MESH:D009369', (313, 319))
425033	28678605	Therefore, we conducted a genome-wide comparison of DNA methylation changes in placental tissues during pregnancy and in 13 types of tumor tissues during neoplastic transformation.	('placental', 'Species', '9347', (79, 88))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('DNA', 'Gene', (52, 55))	('tumor', 'Disease', (133, 138))	('methylation', 'Var', (56, 67))
425045	28678605	Given the similarities between the patterns of hypomethylation in first trimester placental chorionic villi and cancers, we sought to further characterize the genomic regions involved.	('hypomethylation', 'Var', (47, 62))	('cancers', 'Phenotype', 'HP:0002664', (112, 119))	('cancers', 'Disease', 'MESH:D009369', (112, 119))	('cancers', 'Disease', (112, 119))	('placental', 'Species', '9347', (82, 91))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))
425046	28678605	Methylomes of solid tumors have been shown to display hypomethylated blocks, defined as large regions within which the average methylation is reduced compared with normal tissues.	('methylation', 'MPA', (127, 138))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('reduced', 'NegReg', (142, 149))	('solid tumors', 'Disease', (14, 26))	('hypomethylated', 'Var', (54, 68))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('solid tumors', 'Disease', 'MESH:D009369', (14, 26))
425054	28678605	Taken together, these observations reveal that the patterns of hypomethylation that distinguish first from third trimester placental tissues are similar in structure, size and location to those that distinguish tumors from matched normal tissues.	('tumors', 'Disease', 'MESH:D009369', (211, 217))	('placental', 'Species', '9347', (123, 132))	('tumors', 'Phenotype', 'HP:0002664', (211, 217))	('hypomethylation', 'Var', (63, 78))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('tumors', 'Disease', (211, 217))
425066	28678605	More recently, independent studies in cancer biology and placenta biology have suggested similarities between epigenetic patterns in placental and cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('epigenetic patterns', 'Var', (110, 129))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('cancer', 'Disease', (38, 44))	('cancer', 'Disease', (147, 153))	('placental', 'Species', '9347', (133, 142))
425068	28678605	We report here that epigenetic similarities between cancer and placenta are most striking in early pregnancy placenta, and that the similarities are partially erased as pregnancy progresses.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('epigenetic similarities', 'Var', (20, 43))	('early pregnancy', 'Phenotype', 'HP:0001622', (93, 108))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))
425069	28678605	We also find that these shared epigenetic patterns relate to pivotal genes in both placentogenesis and carcinogenesis.	('placentogenesis', 'Disease', (83, 98))	('carcinogenesis', 'Disease', 'MESH:D063646', (103, 117))	('relate', 'Reg', (51, 57))	('carcinogenesis', 'Disease', (103, 117))	('epigenetic', 'Var', (31, 41))
425075	28678605	Hypomethylated blocks have initially been described in cancers using whole-genome bisulfite sequencing.	('cancers', 'Disease', 'MESH:D009369', (55, 62))	('bisulfite', 'Chemical', 'MESH:C042345', (82, 91))	('Hypomethylated', 'Var', (0, 14))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('cancers', 'Phenotype', 'HP:0002664', (55, 62))	('cancers', 'Disease', (55, 62))
425078	28678605	These studies have thus established hypomethylated blocks as a universal defining epigenetic alteration in human solid tumors.	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('human', 'Species', '9606', (107, 112))	('solid tumors', 'Disease', 'MESH:D009369', (113, 125))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('hypomethylated blocks', 'Var', (36, 57))	('solid tumors', 'Disease', (113, 125))
425079	28678605	Using TCGA data for 13 cancer types, we also observed hypomethylated blocks in breast, colon, lung, pancreas and thyroid cancers, as well as described such hypomethylation patterns for the first time in liver, head and neck, bladder, uterus, esophageal and prostate cancers.	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('breast', 'Disease', (79, 85))	('prostate cancers', 'Phenotype', 'HP:0012125', (257, 273))	('cancer', 'Disease', 'MESH:D009369', (23, 29))	('pancreas and thyroid cancers', 'Disease', 'MESH:D010190', (100, 128))	('cancers', 'Phenotype', 'HP:0002664', (121, 128))	('cancer', 'Disease', 'MESH:D009369', (266, 272))	('uterus', 'Disease', (234, 240))	('hypomethylated', 'Var', (54, 68))	('liver', 'Disease', (203, 208))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('bladder', 'Disease', (225, 232))	('lung', 'Disease', (94, 98))	('cancer', 'Disease', (23, 29))	('colon', 'Disease', (87, 92))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('cancers', 'Phenotype', 'HP:0002664', (266, 273))	('cancer', 'Disease', (266, 272))	('thyroid cancer', 'Phenotype', 'HP:0002890', (113, 127))	('cancer', 'Phenotype', 'HP:0002664', (266, 272))	('cancer', 'Disease', (121, 127))	('esophageal and prostate cancers', 'Disease', 'MESH:D011471', (242, 273))
425083	28678605	Moreover, we also observed that hypomethylated blocks distinguish villous cytotrophoblasts before and after they first come into contact with maternal blood (weeks 10-12), providing the first non-cancer evidence of large-scale hypomethylated blocks in a purified cell type.	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('hypomethylated', 'Var', (32, 46))	('cancer', 'Disease', (196, 202))	('cancer', 'Disease', 'MESH:D009369', (196, 202))
425096	28678605	Further analyses of these patterns could eventually lead to the identification of critical epigenetic switches that prevent healthy placentas from degenerating into tumors, and whose failure allows tumor development.	('epigenetic switches', 'Var', (91, 110))	('failure allows tumor', 'Disease', 'MESH:D009369', (183, 203))	('tumors', 'Disease', (165, 171))	('tumors', 'Disease', 'MESH:D009369', (165, 171))	('tumors', 'Phenotype', 'HP:0002664', (165, 171))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('failure allows tumor', 'Disease', (183, 203))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('lead to', 'Reg', (52, 59))
425120	32128997	Inhibition of USP28 destabilises DeltaNp63 protein abundance and enables therapeutic targeting of squamous tumours of various origins, such as head and neck, lung, cervix and pancreas.	('lung', 'Disease', (158, 162))	('squamous tumours of various origins', 'Phenotype', 'HP:0002860', (98, 133))	('pancreas', 'Disease', (175, 183))	('USP28', 'Gene', (14, 19))	('tumour', 'Phenotype', 'HP:0002664', (107, 113))	('destabilises', 'NegReg', (20, 32))	('Inhibition', 'Var', (0, 10))	('DeltaNp63', 'Gene', (33, 42))	('tumours', 'Phenotype', 'HP:0002664', (107, 114))	('cervix', 'Disease', (164, 170))	('squamous tumours', 'Disease', 'MESH:D002294', (98, 114))	('squamous tumours', 'Disease', (98, 114))	('Np63', 'Chemical', '-', (38, 42))
425127	32128997	Depletion of USP28 in human tumour cell lines affected proliferation and epithelial cell identity of SCC cells.	('tumour', 'Phenotype', 'HP:0002664', (28, 34))	('USP28', 'Gene', (13, 18))	('proliferation', 'CPA', (55, 68))	('epithelial cell identity of', 'CPA', (73, 100))	('Depletion', 'Var', (0, 9))	('tumour', 'Disease', 'MESH:D009369', (28, 34))	('SCC', 'Gene', (101, 104))	('SCC', 'Phenotype', 'HP:0002860', (101, 104))	('tumour', 'Disease', (28, 34))	('human', 'Species', '9606', (22, 27))	('affected', 'Reg', (46, 54))	('SCC', 'Gene', '6317', (101, 104))
425131	32128997	In vivo, we could demonstrate that in a mouse model of lung SCC, loss of Usp28 during tumour initiation abolished SCC formation entirely.	('loss', 'Var', (65, 69))	('SCC', 'Gene', '6317', (60, 63))	('tumour initiation', 'Disease', 'MESH:D009369', (86, 103))	('SCC', 'Gene', (114, 117))	('tumour', 'Phenotype', 'HP:0002664', (86, 92))	('abolished', 'NegReg', (104, 113))	('tumour initiation', 'Disease', (86, 103))	('SCC', 'Phenotype', 'HP:0002860', (114, 117))	('SCC', 'Gene', '6317', (114, 117))	('Usp28', 'Gene', (73, 78))	('mouse', 'Species', '10090', (40, 45))	('SCC', 'Gene', (60, 63))	('SCC', 'Phenotype', 'HP:0002860', (60, 63))
425132	32128997	Similar effects could be demonstrated in an orthotopic lung SCC transplant model, where knock-down or inhibition of Usp28 was sufficient to hinder tumour growth.	('hinder', 'NegReg', (140, 146))	('SCC', 'Gene', '6317', (60, 63))	('tumour', 'Phenotype', 'HP:0002664', (147, 153))	('inhibition', 'Var', (102, 112))	('tumour', 'Disease', 'MESH:D009369', (147, 153))	('knock-down', 'Var', (88, 98))	('tumour', 'Disease', (147, 153))	('SCC', 'Gene', (60, 63))	('SCC', 'Phenotype', 'HP:0002860', (60, 63))	('Usp28', 'Gene', (116, 121))
425135	32128997	USP28 is druggable, and its modulation, in vitro and in vivo, negatively affected SCC in a  Np63-dependent manner; hence, USP28 can function as a druggable surrogate target for  Np63 in SCC.	('SCC', 'Gene', '6317', (186, 189))	('USP28', 'Gene', (122, 127))	('SCC', 'Phenotype', 'HP:0002860', (82, 85))	('modulation', 'Var', (28, 38))	('SCC', 'Gene', '6317', (82, 85))	('negatively', 'NegReg', (62, 72))	('Np63', 'Chemical', '-', (92, 96))	('SCC', 'Gene', (186, 189))	('SCC', 'Phenotype', 'HP:0002860', (186, 189))	('SCC', 'Gene', (82, 85))	('Np63', 'Chemical', '-', (178, 182))
425137	32128997	If proved safe and efficient in humans, USP28 inhibitors could expand the current limited available portfolio of applicable SCC therapeutic agents.	('inhibitors', 'Var', (46, 56))	('humans', 'Species', '9606', (32, 38))	('SCC', 'Gene', (124, 127))	('SCC', 'Phenotype', 'HP:0002860', (124, 127))	('SCC', 'Gene', '6317', (124, 127))	('USP28', 'Gene', (40, 45))
425143	32128997	Np63 is highly expressed in lung SCC as well as in SCCs of the skin, head and neck, and oesophagus, in part due to gene amplification (Hibi et al, 2000, Tonon et al, 2005; Cancer Genome Atlas Research N, 2012).	('SCC', 'Gene', '6317', (33, 36))	('SCC', 'Gene', (51, 54))	('Np63', 'Gene', (0, 4))	('gene amplification', 'Var', (115, 133))	('SCCs', 'Phenotype', 'HP:0002860', (51, 55))	('SCC', 'Phenotype', 'HP:0002860', (51, 54))	('Cancer', 'Disease', (172, 178))	('SCC', 'Gene', '6317', (51, 54))	('Cancer', 'Phenotype', 'HP:0002664', (172, 178))	('Cancer', 'Disease', 'MESH:D009369', (172, 178))	('SCC', 'Gene', (33, 36))	('SCC', 'Phenotype', 'HP:0002860', (33, 36))	('Np63', 'Chemical', '-', (0, 4))
425150	32128997	FBXW7 is frequently mutated or deleted in SCC tumours (cervix 13.15%, HNSC 7.55%, lung 6.4% and oesophagus 7.29%; cBioPortal, Galli et al, 2010; Ruiz et al, 2019).	('FBXW7', 'Gene', '55294', (0, 5))	('SCC tumours', 'Disease', (42, 53))	('deleted', 'Var', (31, 38))	('SCC', 'Phenotype', 'HP:0002860', (42, 45))	('FBXW7', 'Gene', (0, 5))	('tumour', 'Phenotype', 'HP:0002664', (46, 52))	('SCC tumours', 'Disease', 'MESH:D009369', (42, 53))	('tumours', 'Phenotype', 'HP:0002664', (46, 53))
425154	32128997	Loss of USP28 counteracts the loss of Fbxw7 in a murine colon tumour model (Diefenbacher et al, 2015; Cremona et al, 2016), and acute deletion of USP28 in established tumours increases survival in the APCmin /+ colorectal tumour model (Diefenbacher et al, 2014), while not affecting tissue homeostasis in non-transformed cells (Schulein-Volk et al, 2014).	('tumour', 'Phenotype', 'HP:0002664', (62, 68))	('colorectal tumour', 'Disease', 'MESH:D015179', (211, 228))	('tumours', 'Phenotype', 'HP:0002664', (167, 174))	('survival', 'CPA', (185, 193))	('colon tumour', 'Disease', (56, 68))	('colorectal tumour', 'Disease', (211, 228))	('USP28', 'Gene', (146, 151))	('tumours', 'Disease', 'MESH:D009369', (167, 174))	('tumour', 'Phenotype', 'HP:0002664', (222, 228))	('colon tumour', 'Disease', 'MESH:D003110', (56, 68))	('tumours', 'Disease', (167, 174))	('tumour', 'Phenotype', 'HP:0002664', (167, 173))	('Loss', 'Var', (0, 4))	('increases', 'PosReg', (175, 184))	('murine', 'Species', '10090', (49, 55))	('colon tumour', 'Phenotype', 'HP:0100273', (56, 68))
425155	32128997	Together, these data argue that targeting USP28 may destabilize  Np63 and suggest that this strategy may have therapeutic efficacy in SCC.	('Np63', 'Chemical', '-', (65, 69))	('targeting', 'Var', (32, 41))	('SCC', 'Phenotype', 'HP:0002860', (134, 137))	('SCC', 'Gene', '6317', (134, 137))	('Np63', 'Protein', (65, 69))	('USP28', 'Gene', (42, 47))	('destabilize', 'NegReg', (52, 63))	('SCC', 'Gene', (134, 137))
425165	32128997	Finally, we noted that 3% of lung SCC patients display mutations in USP28 or a deletion of USP28, and those showed a much better disease-free survival compared to USP28 wild-type patients (Fig EV1D).	('disease-free survival', 'CPA', (129, 150))	('better', 'PosReg', (122, 128))	('SCC', 'Gene', (34, 37))	('USP28', 'Gene', (68, 73))	('mutations', 'Var', (55, 64))	('EV1', 'Gene', '11322', (193, 196))	('SCC', 'Phenotype', 'HP:0002860', (34, 37))	('EV1', 'Gene', (193, 196))	('SCC', 'Gene', '6317', (34, 37))	('patients', 'Species', '9606', (179, 187))	('patients', 'Species', '9606', (38, 46))	('USP28', 'Gene', (91, 96))	('deletion', 'Var', (79, 87))
425173	32128997	Upon His-ubiquitin pulldown, K48- as well as K63-linked poly-ubiquitin chains could be detected on  Np63, as previously reported (Galli et al, 2010; Peschiaroli et al, 2010; Fig 2C).	('K63-linked', 'Var', (45, 55))	('detected', 'Reg', (87, 95))	('K48-', 'Var', (29, 33))	('Np63', 'Gene', (100, 104))	('Np63', 'Chemical', '-', (100, 104))
425174	32128997	Upon overexpression of USP28, only K48-linked ubiquitin chains were removed from  Np63, whereas K63-linked chains were resistant to USP28 (Fig 2C).	('Np63', 'Chemical', '-', (82, 86))	('ubiquitin chains', 'Protein', (46, 62))	('K48-linked', 'Var', (35, 45))
425176	32128997	Immunoprecipitation of transfected cells using an  Np63-specific antibody revealed that USP28C171A was able to bind to  Np63 (Fig 2D).	('Np63', 'Gene', (120, 124))	('USP28C171A', 'Var', (88, 98))	('Np63', 'Chemical', '-', (51, 55))	('bind', 'Interaction', (111, 115))	('Np63', 'Chemical', '-', (120, 124))
425179	32128997	To do so, we co-expressed  Np63 with either wild-type USP28 or USP28C171A in HEK293 cells.	('HEK293', 'CellLine', 'CVCL:0045', (77, 83))	('Np63', 'Var', (27, 31))	('C171A', 'Mutation', 'c.171C>A', (68, 73))	('USP28C171A', 'Var', (63, 73))	('Np63', 'Chemical', '-', (27, 31))
425181	32128997	Co-expression of wild-type USP28, but not of the catalytically inactive mutant, strongly stabilized  Np63 protein (Fig 2F).	('Np63', 'Chemical', '-', (101, 105))	('stabilized', 'PosReg', (89, 99))	('Np63', 'Gene', (101, 105))	('USP28', 'Var', (27, 32))
425182	32128997	As  Np63 protein stability was enhanced by USP28, but not via the catalytic inactive C171A mutant, we tested whether a pharmacologic inhibitor of DUBs, PR-619, would also affect overall protein abundance of  Np63.	('protein abundance', 'MPA', (186, 203))	('enhanced', 'PosReg', (31, 39))	('USP28', 'Var', (43, 48))	('Np63', 'Gene', (4, 8))	('PR-619', 'Chemical', 'MESH:C570894', (152, 158))	('protein', 'Protein', (9, 16))	('C171A', 'Mutation', 'c.171C>A', (85, 90))	('Np63', 'Chemical', '-', (208, 212))	('tested', 'Reg', (102, 108))	('affect', 'Reg', (171, 177))	('Np63', 'Chemical', '-', (4, 8))
425189	32128997	To investigate whether USP28 interacts with  Np63 in a FBXW7-dependent fashion and whether the phosphodegron motive is required to facilitate the interaction, we made use of a  Np63 point mutant,  Np63S383A, which is not phosphorylated by GSK3beta and abolishes binding to FBXW7 (Galli et al, 2010).	('Np63', 'Chemical', '-', (45, 49))	('FBXW7', 'Gene', (273, 278))	('GSK3beta', 'Gene', (239, 247))	('binding', 'Interaction', (262, 269))	('abolishes', 'NegReg', (252, 261))	('FBXW7', 'Gene', '55294', (55, 60))	('Np63', 'Chemical', '-', (177, 181))	('Np63', 'Chemical', '-', (197, 201))	('GSK3beta', 'Gene', '2931', (239, 247))	('Np63S383A', 'Var', (197, 206))	('FBXW7', 'Gene', (55, 60))	('FBXW7', 'Gene', '55294', (273, 278))	('Np63', 'Gene', (177, 181))
425190	32128997	Ectopic expression of USP28 and  Np63S383A in HEK293 cells showed that USP28 was able to increase  Np63S383A abundance (Appendix Fig S1C).	('HEK293', 'CellLine', 'CVCL:0045', (46, 52))	('USP28', 'Var', (71, 76))	('Np63', 'Chemical', '-', (33, 37))	('abundance', 'MPA', (109, 118))	('Np63S383A', 'Var', (99, 108))	('Np63', 'Chemical', '-', (99, 103))	('increase', 'PosReg', (89, 97))
425191	32128997	Furthermore, by co-immunoprecipitation experiments with exogenous USP28 and  Np63S383A in HEK293 cells, we were able to detect that USP28 binds to  Np63S383A (Appendix Fig S1D), This interaction resulted in a decreased ubiquitylation of  Np63S383A (Appendix Fig S1E).	('binds', 'Interaction', (138, 143))	('men', 'Species', '9606', (45, 48))	('Np63', 'Chemical', '-', (148, 152))	('Np63S383A', 'Var', (148, 157))	('Np63', 'Chemical', '-', (238, 242))	('Np63S383A', 'Var', (238, 247))	('ubiquitylation', 'MPA', (219, 233))	('HEK293', 'CellLine', 'CVCL:0045', (90, 96))	('Np63', 'Chemical', '-', (77, 81))	('decreased', 'NegReg', (209, 218))
425192	32128997	Furthermore, overexpression of USP28 was able to increase protein half-life (Appendix Fig S1F) and treatment of cells with PR-619 affected  Np63S383A protein stability, albeit to a somewhat lesser extent compared to wild-type  Np63 (Appendix Fig S1G).	('increase', 'PosReg', (49, 57))	('stability', 'MPA', (158, 167))	('Np63', 'Chemical', '-', (227, 231))	('protein half-life', 'MPA', (58, 75))	('men', 'Species', '9606', (104, 107))	('affected', 'Reg', (130, 138))	('USP28', 'Gene', (31, 36))	('PR-619', 'Chemical', 'MESH:C570894', (123, 129))	('Np63', 'Chemical', '-', (140, 144))	('PR-619', 'Var', (123, 129))	('Np63S383A', 'Var', (140, 149))
425194	32128997	These cells are homozygous for the S462Y mutation in FBXW7, which is thought to inactivate substrate recognition (Appendix Fig S2C and D; Yeh et al, 2016).	('FBXW7', 'Gene', (53, 58))	('substrate recognition', 'MPA', (91, 112))	('FBXW7', 'Gene', '55294', (53, 58))	('S462Y', 'Var', (35, 40))	('S462Y', 'Mutation', 'p.S462Y', (35, 40))
425202	32128997	This degradation was mediated via the 26s proteasome, as addition of MG132 restored protein levels of  Np63 and USP28 (Appendix Fig S2G).	('restored', 'PosReg', (75, 83))	('Np63', 'Chemical', '-', (103, 107))	('protein levels', 'MPA', (84, 98))	('MG132', 'Chemical', 'MESH:C072553', (69, 74))	('MG132', 'Var', (69, 74))	('USP28', 'MPA', (112, 117))	('Np63', 'MPA', (103, 107))
425203	32128997	To investigate whether USP28 regulates  Np63 protein stability in A-431 cells, we generated cell lines expressing either a doxycycline-inducible or constitutive shRNA targeting USP28 (Figs 3B and EV2D, Appendix Fig S2H) and investigated the effects of acute USP28 depletion on  Np63 protein.	('Np63', 'Chemical', '-', (278, 282))	('targeting', 'Var', (167, 176))	('EV2', 'Gene', '147138', (196, 199))	('EV2', 'Gene', (196, 199))	('Np63', 'Chemical', '-', (40, 44))	('doxycycline', 'Chemical', 'MESH:D004318', (123, 134))	('USP28', 'Gene', (177, 182))	('A-431', 'CellLine', 'CVCL:0037', (66, 71))
425205	32128997	Notably, depletion of USP28 also reduced  Np63 mRNA levels, consistent with previous observations that  Np63 activates the expression of its own mRNA (Antonini et al, 2006) (Fig 3B).	('Np63', 'Chemical', '-', (104, 108))	('mRNA', 'MPA', (145, 149))	('expression', 'MPA', (123, 133))	('Np63', 'Chemical', '-', (42, 46))	('Np63 mRNA levels', 'MPA', (42, 58))	('Np63', 'Gene', (104, 108))	('reduced', 'NegReg', (33, 40))	('activates', 'PosReg', (109, 118))	('USP28', 'Gene', (22, 27))	('depletion', 'Var', (9, 18))
425209	32128997	Next, we asked whether acute loss of USP28 affects  Np63 protein half-life.	('USP28', 'Gene', (37, 42))	('loss', 'Var', (29, 33))	('Np63', 'Chemical', '-', (52, 56))	('Np63 protein', 'Protein', (52, 64))
425216	32128997	Conversely, overexpression of the catalytic inactive USP28C171A in A-431 failed to stabilize endogenous  Np63 (Appendix Fig S2J) and instead resulted in an increase in  Np63 ubiquitylation, as measured by TUBE assay (Appendix Fig S2K).	('Np63 ubiquitylation', 'MPA', (169, 188))	('stabilize endogenous  Np63', 'MPA', (83, 109))	('USP28C171A', 'Var', (53, 63))	('increase', 'PosReg', (156, 164))	('A-431', 'CellLine', 'CVCL:0037', (67, 72))	('Np63', 'Chemical', '-', (105, 109))	('Np63', 'Chemical', '-', (169, 173))	('C171A', 'Mutation', 'c.171C>A', (58, 63))
425227	32128997	Depletion of  Np63 decreased SCC proliferation (Fig EV2B) and cell cycle profiling indicated a mild accumulation of cells in S-phase (Fig EV2C), consistent with previous reports (Wang et al, 2019).	('SCC', 'Gene', '6317', (29, 32))	('cells in S-phase', 'CPA', (116, 132))	('Np63', 'Gene', (14, 18))	('Depletion', 'Var', (0, 9))	('EV2', 'Gene', '147138', (138, 141))	('EV2', 'Gene', '147138', (52, 55))	('cell cycle profiling', 'CPA', (62, 82))	('EV2', 'Gene', (138, 141))	('EV2', 'Gene', (52, 55))	('decreased', 'NegReg', (19, 28))	('SCC', 'Gene', (29, 32))	('SCC', 'Phenotype', 'HP:0002860', (29, 32))	('Np63', 'Chemical', '-', (14, 18))
425229	32128997	To investigate whether USP28, like  Np63, is required to maintain the characteristic gene expression pattern of SCC cells, RNA expression profiles of A-431 cells stably expressing shRNAs targeting either USP28 or  Np63 were compared to cells expressing a non-targeting control shRNA.	('SCC', 'Phenotype', 'HP:0002860', (112, 115))	('USP28', 'Var', (204, 209))	('Np63', 'Var', (214, 218))	('targeting', 'Var', (187, 196))	('SCC', 'Gene', '6317', (112, 115))	('Np63', 'Chemical', '-', (36, 40))	('Np63', 'Chemical', '-', (214, 218))	('A-431', 'CellLine', 'CVCL:0037', (150, 155))	('SCC', 'Gene', (112, 115))
425235	32128997	These data indicate that depletion of USP28 affected cellular proliferation in SCC via reducing  Np63 levels.	('affected', 'Reg', (44, 52))	('SCC', 'Gene', (79, 82))	('USP28', 'Gene', (38, 43))	('cellular proliferation', 'CPA', (53, 75))	('Np63', 'Chemical', '-', (97, 101))	('Np63 levels', 'MPA', (97, 108))	('SCC', 'Phenotype', 'HP:0002860', (79, 82))	('reducing', 'NegReg', (87, 95))	('SCC', 'Gene', '6317', (79, 82))	('depletion', 'Var', (25, 34))
425238	32128997	In contrast to SCC-associated cytokeratins, KRT10, which is a marker of differentiation (Saladi et al, 2017), was upregulated in  Np63- and USP28-depleted A-431 (Fig 4K).	('A-431', 'CellLine', 'CVCL:0037', (155, 160))	('KRT10', 'Gene', '3858', (44, 49))	('Np63-', 'Var', (130, 135))	('SCC', 'Gene', (15, 18))	('Np63', 'Chemical', '-', (130, 134))	('SCC', 'Phenotype', 'HP:0002860', (15, 18))	('upregulated', 'PosReg', (114, 125))	('SCC', 'Gene', '6317', (15, 18))	('KRT10', 'Gene', (44, 49))
425239	32128997	Similar responses were observed for the putative tumour suppressor GPRC5A (Saladi et al, 2017); loss of either protein resulted in an increased expression (Fig 4K), thereby contributing to cellular differentiation and suppression of colony formation.	('GPRC5A', 'Gene', '9052', (67, 73))	('cellular differentiation', 'CPA', (189, 213))	('loss', 'Var', (96, 100))	('expression', 'MPA', (144, 154))	('colony formation', 'CPA', (233, 249))	('tumour', 'Phenotype', 'HP:0002664', (49, 55))	('tumour', 'Disease', 'MESH:D009369', (49, 55))	('contributing', 'Reg', (173, 185))	('increased', 'PosReg', (134, 143))	('suppression', 'NegReg', (218, 229))	('GPRC5A', 'Gene', (67, 73))	('tumour', 'Disease', (49, 55))
425240	32128997	Hence, loss of USP28 or  Np63 changes the cellular fate and signature of SCC tumour cells.	('loss', 'Var', (7, 11))	('Np63', 'Gene', (25, 29))	('changes', 'Reg', (30, 37))	('SCC', 'Phenotype', 'HP:0002860', (73, 76))	('cellular fate', 'CPA', (42, 55))	('USP28', 'Gene', (15, 20))	('SCC tumour', 'Disease', 'MESH:D009369', (73, 83))	('tumour', 'Phenotype', 'HP:0002664', (77, 83))	('SCC tumour', 'Disease', (73, 83))	('Np63', 'Chemical', '-', (25, 29))
425244	32128997	We analysed the expression of these genes in control,  Np63 and USP28 knock-down A-431 cells.	('A-431', 'CellLine', 'CVCL:0037', (81, 86))	('USP28', 'Gene', (64, 69))	('Np63', 'Chemical', '-', (55, 59))	('knock-down', 'Var', (70, 80))
425249	32128997	In neither case, a significant downregulation, as seen for  Np63 (Fig 4D), could be observed, indicating that the biological effects observed on SCC cell identity are specific to the regulation of  Np63 by USP28.	('SCC', 'Gene', (145, 148))	('SCC', 'Phenotype', 'HP:0002860', (145, 148))	('Np63', 'Chemical', '-', (60, 64))	('Np63', 'Chemical', '-', (198, 202))	('SCC', 'Gene', '6317', (145, 148))	('Np63', 'Var', (198, 202))
425250	32128997	Additionally, no compensatory gene expression mechanism was observed in  Np63-silenced cells (Fig EV2K), demonstrating that  Np63 is a vulnerability of SCC.	('Np63', 'Chemical', '-', (73, 77))	('EV2', 'Gene', '147138', (98, 101))	('Np63', 'Chemical', '-', (125, 129))	('EV2', 'Gene', (98, 101))	('SCC', 'Gene', (152, 155))	('Np63', 'Var', (125, 129))	('SCC', 'Phenotype', 'HP:0002860', (152, 155))	('SCC', 'Gene', '6317', (152, 155))
425256	32128997	To ablate USP28 during tumour initiation, we used CRISPR/Cas9-mediated gene targeting.	('tumour', 'Phenotype', 'HP:0002664', (23, 29))	('USP28', 'Gene', (10, 15))	('PR', 'Chemical', 'MESH:D011221', (54, 56))	('tumour initiation', 'Disease', 'MESH:D009369', (23, 40))	('ablate', 'Var', (3, 9))	('tumour initiation', 'Disease', (23, 40))
425257	32128997	To induce primary lesions in the lungs of mice, we used a constitutive Rosa26 Sor -CAGG-Cas9-IRES-GFP transgenic mouse strain and intratracheally infected these mice at 8 weeks of age with adeno-associated virus (AAV) virions containing sgRNA cassettes targeting sequences that inactivate Tp53 (p53  ) and Stk11/Lkb1 (Lkb1   ) and introduce the oncogenic mutation G12D, via a repair template, into the KRas locus.	('mice', 'Species', '10090', (161, 165))	('p53', 'Gene', '7157', (295, 298))	('AAV', 'Gene', '17', (213, 216))	('mice', 'Species', '10090', (42, 46))	('infected', 'Disease', (146, 154))	('trachea', 'Disease', (135, 142))	('G12D', 'Var', (364, 368))	('inactivate', 'NegReg', (278, 288))	('adeno-associated virus', 'Species', '272636', (189, 211))	('p53', 'Gene', (290, 293))	('p53', 'Gene', '7157', (290, 293))	('infected', 'Disease', 'MESH:D007239', (146, 154))	('trachea', 'Disease', 'MESH:C557675', (135, 142))	('p53', 'Gene', (295, 298))	('mouse', 'Species', '10090', (113, 118))	('AAV', 'Gene', (213, 216))	('Stk11/Lkb1', 'Gene', (306, 316))	('G12D', 'Mutation', 'rs121913529', (364, 368))
425261	32128997	Loss of Stk11/Lkb1 in KPL mice dramatically increased tumour area and shortened overall survival compared to that of KP mice (Fig EV3D and E).	('Stk11/Lkb1', 'Gene', (8, 18))	('mice', 'Species', '10090', (120, 124))	('tumour', 'Disease', 'MESH:D009369', (54, 60))	('overall survival', 'CPA', (80, 96))	('tumour', 'Disease', (54, 60))	('shortened', 'NegReg', (70, 79))	('increased', 'PosReg', (44, 53))	('tumour', 'Phenotype', 'HP:0002664', (54, 60))	('Loss', 'Var', (0, 4))	('mice', 'Species', '10090', (26, 30))
425263	32128997	To test the role of USP28 in tumour induction, we included two sgRNA cassettes targeting USP28 into the experimental cohort of KPL mice (USP28  , referred to as KPLU).	('USP28', 'Gene', (89, 94))	('tumour', 'Disease', (29, 35))	('men', 'Species', '9606', (110, 113))	('tumour', 'Phenotype', 'HP:0002664', (29, 35))	('mice', 'Species', '10090', (131, 135))	('tumour', 'Disease', 'MESH:D009369', (29, 35))	('cassettes', 'Var', (69, 78))
425264	32128997	Concomitant targeting of USP28 at the time of tumour induction significantly affected NSCLC formation (Fig 5B).	('targeting', 'Var', (12, 21))	('tumour', 'Phenotype', 'HP:0002664', (46, 52))	('NSCLC', 'Disease', (86, 91))	('affected', 'Reg', (77, 85))	('SCLC', 'Phenotype', 'HP:0030357', (87, 91))	('tumour', 'Disease', (46, 52))	('NSCLC', 'Disease', 'MESH:D002289', (86, 91))	('USP28', 'Gene', (25, 30))	('NSCLC', 'Phenotype', 'HP:0030358', (86, 91))	('tumour', 'Disease', 'MESH:D009369', (46, 52))
425265	32128997	Both total tumour area and tumour number per animal were significantly reduced in KPLU compared to KPL mice (Fig 5D and E).	('KPLU', 'Var', (82, 86))	('mice', 'Species', '10090', (103, 107))	('tumour', 'Phenotype', 'HP:0002664', (27, 33))	('tumour', 'Phenotype', 'HP:0002664', (11, 17))	('reduced', 'NegReg', (71, 78))	('tumour area and tumour', 'Disease', 'MESH:D009369', (11, 33))
425266	32128997	Analysis of present tumour types using IHC staining for marker proteins of ADC and SCC revealed that loss of USP28 completely abolished the presence of SCC and negatively affected the abundance of ADC in KPLU mice (Figs 5C and EV3F).	('abolished', 'NegReg', (126, 135))	('mice', 'Species', '10090', (209, 213))	('ADC', 'MPA', (197, 200))	('affected', 'Reg', (171, 179))	('abundance', 'MPA', (184, 193))	('SCC', 'Gene', (83, 86))	('loss', 'Var', (101, 105))	('tumour', 'Disease', 'MESH:D009369', (20, 26))	('SCC', 'Gene', (152, 155))	('tumour', 'Disease', (20, 26))	('presence', 'MPA', (140, 148))	('SCC', 'Phenotype', 'HP:0002860', (83, 86))	('SCC', 'Gene', '6317', (83, 86))	('negatively', 'NegReg', (160, 170))	('SCC', 'Phenotype', 'HP:0002860', (152, 155))	('SCC', 'Gene', '6317', (152, 155))	('USP28', 'Gene', (109, 114))	('tumour', 'Phenotype', 'HP:0002664', (20, 26))
425267	32128997	Tumours developing in KPL mice showed expression of USP28 and  Np63, while USP28 was strongly reduced in isolated tumours from KPLU mice and  Np63 was not detectable (Fig 5C).	('Np63', 'Chemical', '-', (63, 67))	('Np63', 'Chemical', '-', (142, 146))	('Np63', 'Var', (63, 67))	('isolated tumours', 'Disease', (105, 121))	('tumour', 'Phenotype', 'HP:0002664', (114, 120))	('mice', 'Species', '10090', (132, 136))	('tumours', 'Phenotype', 'HP:0002664', (114, 121))	('Tumour', 'Phenotype', 'HP:0002664', (0, 6))	('Tumours', 'Phenotype', 'HP:0002664', (0, 7))	('isolated tumours', 'Disease', 'MESH:D009369', (105, 121))	('USP28', 'Var', (52, 57))	('mice', 'Species', '10090', (26, 30))
425270	32128997	However, active NOTCH1 was reduced, in protein abundance and IHC staining intensity upon targeting of USP28 (Figs 5G and EV3G).	('IHC staining intensity', 'MPA', (61, 83))	('USP28', 'Gene', (102, 107))	('reduced', 'NegReg', (27, 34))	('NOTCH1', 'Gene', '4851', (16, 22))	('protein abundance', 'MPA', (39, 56))	('NOTCH1', 'Gene', (16, 22))	('targeting', 'Var', (89, 98))
425272	32128997	Consistent with this effect, the survival of KPLU mice was significantly prolonged compared to KPL mice (Fig 5H).	('mice', 'Species', '10090', (99, 103))	('survival', 'CPA', (33, 41))	('KPLU', 'Var', (45, 49))	('prolonged', 'PosReg', (73, 82))	('mice', 'Species', '10090', (50, 54))
425290	32128997	Chromosomal amplification and increased gene expression of  Np63 are very common in lung SCC when compared to cervix, head-and-neck, oesophagus or pancreatic tumours (Fig 6A).	('tumour', 'Phenotype', 'HP:0002664', (158, 164))	('gene expression', 'MPA', (40, 55))	('tumours', 'Phenotype', 'HP:0002664', (158, 165))	('SCC', 'Gene', '6317', (89, 92))	('pancreatic tumours', 'Disease', (147, 165))	('Chromosomal amplification', 'Var', (0, 25))	('Np63', 'Chemical', '-', (60, 64))	('pancreatic tumours', 'Disease', 'MESH:D010190', (147, 165))	('increased', 'PosReg', (30, 39))	('SCC', 'Gene', (89, 92))	('common', 'Reg', (74, 80))	('Np63', 'Gene', (60, 64))	('SCC', 'Phenotype', 'HP:0002860', (89, 92))
425294	32128997	Patients with an increased expression of USP28 showed a significantly shortened overall survival in cervix and head-and-neck tumours, while expression of  Np63 significantly shortened life expectancy in pancreatic cancer (Appendix Fig S3B).	('cervix', 'Disease', (100, 106))	('shortened', 'NegReg', (174, 183))	('shortened', 'NegReg', (70, 79))	('head-and-neck tumours', 'Disease', (111, 132))	('pancreatic cancer', 'Disease', 'MESH:D010190', (203, 220))	('overall survival', 'MPA', (80, 96))	('head-and-neck tumours', 'Disease', 'MESH:D006258', (111, 132))	('life', 'MPA', (184, 188))	('Patients', 'Species', '9606', (0, 8))	('Np63', 'Var', (155, 159))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('expression', 'Var', (27, 37))	('pancreatic cancer', 'Disease', (203, 220))	('Np63', 'Chemical', '-', (155, 159))	('increased', 'PosReg', (17, 26))	('tumour', 'Phenotype', 'HP:0002664', (125, 131))	('USP28', 'Gene', (41, 46))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (203, 220))	('tumours', 'Phenotype', 'HP:0002664', (125, 132))
425306	32128997	While SCC cell lines infected with a non-targeting control shRNA expressed  Np63 and the downstream target KRT14, knock-down of USP28 reduced  Np63 protein levels, along with the SCC marker KRT14 (Fig 6E and Appendix Fig S3E), consistent with observed USP28 effects in A-431 cells (Fig EV2).	('infected', 'Disease', 'MESH:D007239', (21, 29))	('SCC', 'Gene', (6, 9))	('infected', 'Disease', (21, 29))	('SCC', 'Gene', '6317', (179, 182))	('KRT14', 'Gene', '3861', (107, 112))	('Np63 protein levels', 'MPA', (143, 162))	('A-431', 'CellLine', 'CVCL:0037', (269, 274))	('KRT14', 'Gene', (107, 112))	('SCC', 'Gene', (179, 182))	('reduced', 'NegReg', (134, 141))	('SCC', 'Phenotype', 'HP:0002860', (6, 9))	('Np63', 'Chemical', '-', (76, 80))	('knock-down', 'Var', (114, 124))	('EV2', 'Gene', (286, 289))	('KRT14', 'Gene', '3861', (190, 195))	('SCC', 'Phenotype', 'HP:0002860', (179, 182))	('KRT14', 'Gene', (190, 195))	('SCC', 'Gene', '6317', (6, 9))	('EV2', 'Gene', '147138', (286, 289))	('Np63', 'Chemical', '-', (143, 147))	('USP28', 'Gene', (128, 133))
425307	32128997	SCC is uniquely dependent on the expression of  Np63; therefore, we next analysed the effect of USP28 knock-down on ADC and SCC cell line proliferation (Fig 6F and G, Appendix Fig S3F and G).	('knock-down', 'Var', (102, 112))	('SCC', 'Gene', (0, 3))	('SCC', 'Phenotype', 'HP:0002860', (0, 3))	('Np63', 'Chemical', '-', (48, 52))	('USP28', 'Gene', (96, 101))	('SCC', 'Gene', (124, 127))	('SCC', 'Gene', '6317', (0, 3))	('SCC', 'Phenotype', 'HP:0002860', (124, 127))	('SCC', 'Gene', '6317', (124, 127))
425310	32128997	Cells of SCC origin, which maintained expression of  Np63 (Ca Ski, BXPC3, Detroit 562 and LUDLU-1adh), demonstrated a growth disadvantage upon knock-down of USP28 by shRNA (Fig 6F and G, Appendix Fig S3F).	('Np63', 'Gene', (53, 57))	('knock-down', 'Var', (143, 153))	('Ca Ski', 'CellLine', 'CVCL:1100', (59, 65))	('adh', 'Chemical', 'MESH:C010011', (97, 100))	('SCC', 'Gene', (9, 12))	('Np63', 'Chemical', '-', (53, 57))	('growth disadvantage', 'CPA', (118, 137))	('SCC', 'Phenotype', 'HP:0002860', (9, 12))	('SCC', 'Gene', '6317', (9, 12))	('USP28', 'Gene', (157, 162))
425322	32128997	Therefore, we designed constructs, in which all 21 lysine residues were either mutated to arginine ( Np63KtoR) or depleted ( Np63Kless; Fig EV4A).	('lysine', 'Protein', (51, 57))	('lysine', 'Chemical', 'MESH:D008239', (51, 57))	('arginine', 'MPA', (90, 98))	('Np63', 'Chemical', '-', (125, 129))	('mutated', 'Var', (79, 86))	('Np63', 'Chemical', '-', (101, 105))	('depleted', 'NegReg', (114, 122))	('arginine', 'Chemical', 'MESH:D001120', (90, 98))
425323	32128997	While FLAG-tagged  Np63 was sensitive to USP28 inhibition via AZ1 treatment, neither FLAG- Np63KtoR nor  Np63Kless showed decrease in protein stability upon treatment with AZ1 (Fig EV4B).	('protein stability', 'MPA', (134, 151))	('decrease', 'NegReg', (122, 130))	('men', 'Species', '9606', (162, 165))	('men', 'Species', '9606', (71, 74))	('Np63', 'Chemical', '-', (105, 109))	('Np63', 'Chemical', '-', (19, 23))	('FLAG- Np63KtoR', 'Var', (85, 99))	('Np63', 'Chemical', '-', (91, 95))
425328	32128997	Upon addition of MG132, USP28 and  Np63 protein levels were restored, but lower than in control cells (Fig 7D).	('USP28', 'MPA', (24, 29))	('Np63 protein levels', 'MPA', (35, 54))	('MG132', 'Var', (17, 22))	('Np63', 'Chemical', '-', (35, 39))	('MG132', 'Chemical', 'MESH:C072553', (17, 22))	('lower', 'NegReg', (74, 79))
425330	32128997	As SCC cells require  Np63 to maintain proliferation (Abraham et al, 2018) and genetic depletion of USP28 by shRNA affected proliferation of human SCC cells (Fig 6), we investigated the ability of AZ1 to hinder growth in A-431.	('A-431', 'CellLine', 'CVCL:0037', (221, 226))	('SCC', 'Gene', (147, 150))	('SCC', 'Phenotype', 'HP:0002860', (147, 150))	('SCC', 'Phenotype', 'HP:0002860', (3, 6))	('SCC', 'Gene', '6317', (3, 6))	('genetic depletion', 'Var', (79, 96))	('proliferation', 'CPA', (124, 137))	('SCC', 'Gene', '6317', (147, 150))	('USP28', 'Gene', (100, 105))	('human', 'Species', '9606', (141, 146))	('Np63', 'Chemical', '-', (22, 26))	('affected', 'Reg', (115, 123))	('SCC', 'Gene', (3, 6))
425338	32128997	Np63 expressing SCC cells LUDLU-1adh and Ca Ski, as well as Detroit 562 and BXPC3, demonstrated a growth disadvantage at significantly lower concentrations (Figs 7G and H, and EV4E and F).	('growth disadvantage', 'CPA', (98, 117))	('adh', 'Chemical', 'MESH:C010011', (33, 36))	('Ca Ski', 'CellLine', 'CVCL:1100', (41, 47))	('SCC', 'Gene', (16, 19))	('LUDLU-1adh', 'Var', (26, 36))	('Detroit', 'Var', (60, 67))	('SCC', 'Gene', '6317', (16, 19))	('SCC', 'Phenotype', 'HP:0002860', (16, 19))	('Np63', 'Chemical', '-', (0, 4))
425339	32128997	AZ1 selectively sensitizes SCC cells, in particular when compared to ADC, of various origins.	('AZ1', 'Var', (0, 3))	('SCC', 'Gene', (27, 30))	('SCC', 'Phenotype', 'HP:0002860', (27, 30))	('sensitizes', 'Reg', (16, 26))	('SCC', 'Gene', '6317', (27, 30))
425340	32128997	These data demonstrate that AZ1 blocks USP28-dependent stabilization of  Np63 and induces its proteasomal degradation.	('Np63', 'Chemical', '-', (73, 77))	('induces', 'Reg', (82, 89))	('blocks', 'NegReg', (32, 38))	('AZ1', 'Var', (28, 31))	('proteasomal degradation', 'MPA', (94, 117))	('Np63', 'Gene', (73, 77))	('USP28-dependent', 'Protein', (39, 54))	('stabilization', 'MPA', (55, 68))
425341	32128997	Since  Np63 expressing SCC cells showed a selective, anti-proliferative response to AZ1 treatment, we wondered if in vivo tumour maintenance could be affected.	('tumour', 'Disease', 'MESH:D009369', (122, 128))	('Np63', 'Chemical', '-', (7, 11))	('SCC', 'Gene', '6317', (23, 26))	('men', 'Species', '9606', (93, 96))	('Np63', 'Var', (7, 11))	('tumour', 'Disease', (122, 128))	('SCC', 'Phenotype', 'HP:0002860', (23, 26))	('SCC', 'Gene', (23, 26))	('anti-proliferative response', 'MPA', (53, 80))	('tumour', 'Phenotype', 'HP:0002664', (122, 128))
425347	32128997	While control solvent-treated mice showed large tumour lesions at endpoint, treatment with AZ1 for the indicated time points resulted in a reduced tumour burden, in a dose-dependent manner (Fig 8D and E).	('mice', 'Species', '10090', (30, 34))	('tumour', 'Phenotype', 'HP:0002664', (48, 54))	('tumour', 'Phenotype', 'HP:0002664', (147, 153))	('tumour lesions', 'Disease', (48, 62))	('tumour lesions', 'Disease', 'MESH:D009369', (48, 62))	('tumour', 'Disease', 'MESH:D009369', (147, 153))	('tumour', 'Disease', 'MESH:D009369', (48, 54))	('men', 'Species', '9606', (81, 84))	('reduced', 'NegReg', (139, 146))	('tumour', 'Disease', (48, 54))	('AZ1', 'Var', (91, 94))	('tumour', 'Disease', (147, 153))
425351	32128997	As a consequence, while tumours of control-treated mice showed a strong staining against  Np63, mice treated with AZ1 showed a reduction in  Np63 abundance (Fig 8E and F).	('tumours', 'Disease', (24, 31))	('tumour', 'Phenotype', 'HP:0002664', (24, 30))	('mice', 'Species', '10090', (51, 55))	('mice', 'Species', '10090', (96, 100))	('Np63', 'Chemical', '-', (90, 94))	('Np63', 'Chemical', '-', (141, 145))	('AZ1', 'Var', (114, 117))	('Np63', 'Protein', (90, 94))	('Np63 abundance', 'MPA', (141, 155))	('tumours', 'Phenotype', 'HP:0002664', (24, 31))	('tumours', 'Disease', 'MESH:D009369', (24, 31))	('reduction', 'NegReg', (127, 136))	('staining', 'MPA', (72, 80))
425355	32128997	Driver mutations can vary widely, ranging from activating mutations in members of the MAPK pathway, the PI3K pathway or RTKs, to gene amplifications in several loci, including  Np63 (Cancer Genome Atlas Research N, 2012).	('Cancer', 'Disease', 'MESH:D009369', (183, 189))	('MAPK pathway', 'Pathway', (86, 98))	('Np63', 'Chemical', '-', (177, 181))	('gene amplifications', 'Var', (129, 148))	('Cancer', 'Phenotype', 'HP:0002664', (183, 189))	('Cancer', 'Disease', (183, 189))	('activating', 'PosReg', (47, 57))	('PI3K pathway', 'Pathway', (104, 116))
425366	32128997	Loss of USP28 reduced SCC cell proliferation in a  Np63-dependent manner and interfered with the expression of marker genes that define the SCC lineage to a similar extent as targeting  Np63 directly.	('Np63', 'Chemical', '-', (51, 55))	('reduced', 'NegReg', (14, 21))	('SCC', 'Phenotype', 'HP:0002860', (140, 143))	('SCC', 'Gene', '6317', (140, 143))	('Np63', 'Chemical', '-', (186, 190))	('SCC', 'Gene', (22, 25))	('interfered', 'NegReg', (77, 87))	('USP28', 'Gene', (8, 13))	('SCC', 'Phenotype', 'HP:0002860', (22, 25))	('SCC', 'Gene', '6317', (22, 25))	('Loss', 'Var', (0, 4))	('expression', 'MPA', (97, 107))	('SCC', 'Gene', (140, 143))
425369	32128997	In vivo, however, using a whole-body acute depletion model, in control and intestinal tumour-bearing animals, loss of Usp28 did not result in changes of endogenous Tp53 nor in its activation (Diefenbacher et al, 2014).	('loss', 'Var', (110, 114))	('intestinal tumour', 'Disease', 'MESH:D007414', (75, 92))	('tumour', 'Phenotype', 'HP:0002664', (86, 92))	('Tp53', 'Protein', (164, 168))	('endogenous', 'MPA', (153, 163))	('activation', 'MPA', (180, 190))	('Usp28', 'Gene', (118, 123))	('intestinal tumour', 'Disease', (75, 92))
425370	32128997	This observation argues that the observed effects upon interference with USP28 on cell proliferation in SCC are independent of TP53.	('cell proliferation', 'CPA', (82, 100))	('SCC', 'Gene', (104, 107))	('SCC', 'Phenotype', 'HP:0002860', (104, 107))	('USP28', 'Gene', (73, 78))	('SCC', 'Gene', '6317', (104, 107))	('interference', 'Var', (55, 67))	('TP53', 'Gene', '7157', (127, 131))	('TP53', 'Gene', (127, 131))
425371	32128997	This is in particularly relevant as the majority of patients diagnosed with lung squamous cell carcinoma harbour inactivating mutations within TP53.	('TP53', 'Gene', (143, 147))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (76, 104))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (76, 104))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (81, 104))	('TP53', 'Gene', '7157', (143, 147))	('inactivating mutations', 'Var', (113, 135))	('lung squamous cell carcinoma', 'Disease', (76, 104))	('patients', 'Species', '9606', (52, 60))
425372	32128997	The depletion of USP28 partially phenocopied the effect of  Np63 ablation.	('USP28', 'Gene', (17, 22))	('Np63', 'Chemical', '-', (60, 64))	('depletion', 'MPA', (4, 13))	('ablation', 'Var', (65, 73))	('Np63', 'Gene', (60, 64))
425374	32128997	USP28, however, regulates additional proto-oncogenes, and we detected changes in NOTCH signalling in USP28 shRNA cells, while JUN/AP-1 and MYC were not affected.	('USP28', 'Var', (101, 106))	('regulates', 'Reg', (16, 25))	('AP-1', 'Gene', (130, 134))	('MYC', 'Gene', '4609', (139, 142))	('AP-1', 'Gene', '3725', (130, 134))	('proto-oncogenes', 'MPA', (37, 52))	('changes', 'Reg', (70, 77))	('MYC', 'Gene', (139, 142))	('NOTCH signalling', 'MPA', (81, 97))
425377	32128997	In strong support of this notion, targeting USP28 in a model of lung SCC ("KPL mice") using the CRISPR/Cas9 system reduced the total number of tumours and, specifically, abrogated the formation of the SCC subtype.	('USP28', 'Gene', (44, 49))	('PR', 'Chemical', 'MESH:D011221', (100, 102))	('tumour', 'Phenotype', 'HP:0002664', (143, 149))	('abrogated', 'NegReg', (170, 179))	('SCC', 'Gene', (69, 72))	('SCC', 'Gene', (201, 204))	('reduced', 'NegReg', (115, 122))	('mice', 'Species', '10090', (79, 83))	('tumours', 'Phenotype', 'HP:0002664', (143, 150))	('tumours', 'Disease', 'MESH:D009369', (143, 150))	('SCC', 'Phenotype', 'HP:0002860', (69, 72))	('targeting', 'Var', (34, 43))	('SCC', 'Gene', '6317', (69, 72))	('SCC', 'Phenotype', 'HP:0002860', (201, 204))	('SCC', 'Gene', '6317', (201, 204))	('tumours', 'Disease', (143, 150))
425378	32128997	While KPL mice developed both NSCLC entities, ADC and SCC, loss of USP28 strongly affected overall tumour induction and blocked SCC formation.	('NSCLC', 'Disease', 'MESH:D002289', (30, 35))	('SCC', 'Gene', '6317', (54, 57))	('tumour', 'Disease', 'MESH:D009369', (99, 105))	('mice', 'Species', '10090', (10, 14))	('affected', 'Reg', (82, 90))	('SCLC', 'Phenotype', 'HP:0030357', (31, 35))	('SCC', 'Gene', (128, 131))	('loss', 'Var', (59, 63))	('tumour', 'Disease', (99, 105))	('NSCLC', 'Phenotype', 'HP:0030358', (30, 35))	('blocked', 'NegReg', (120, 127))	('SCC', 'Phenotype', 'HP:0002860', (128, 131))	('SCC', 'Phenotype', 'HP:0002860', (54, 57))	('SCC', 'Gene', '6317', (128, 131))	('SCC', 'Gene', (54, 57))	('NSCLC', 'Disease', (30, 35))	('tumour', 'Phenotype', 'HP:0002664', (99, 105))	('USP28', 'Gene', (67, 72))
425382	32128997	Mutation of this cysteine residue strongly reduced the ability of USP28 to deubiquitylate  Np63.	('Mutation', 'Var', (0, 8))	('Np63', 'Chemical', '-', (91, 95))	('reduced', 'NegReg', (43, 50))	('ability', 'MPA', (55, 62))	('deubiquitylate  Np63', 'MPA', (75, 95))	('cysteine', 'Chemical', 'MESH:D003545', (17, 25))
425385	32128997	SCC cells exposed to the pan-inhibitor PR-619 showed a strong decrease in  Np63 levels.	('SCC', 'Gene', (0, 3))	('SCC', 'Phenotype', 'HP:0002860', (0, 3))	('SCC', 'Gene', '6317', (0, 3))	('PR-619', 'Var', (39, 45))	('PR-619', 'Chemical', 'MESH:C570894', (39, 45))	('decrease', 'NegReg', (62, 70))	('Np63', 'Chemical', '-', (75, 79))	('Np63 levels', 'MPA', (75, 86))
425387	32128997	This was further confirmed by observing the ability of AZ1 to reduce tumour burden in a  Np63-expressing transplant lung cancer model system in vivo.	('tumour', 'Disease', (69, 75))	('lung cancer', 'Disease', (116, 127))	('AZ1', 'Var', (55, 58))	('lung cancer', 'Phenotype', 'HP:0100526', (116, 127))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('reduce', 'NegReg', (62, 68))	('tumour', 'Phenotype', 'HP:0002664', (69, 75))	('tumour', 'Disease', 'MESH:D009369', (69, 75))	('lung cancer', 'Disease', 'MESH:D008175', (116, 127))	('Np63', 'Chemical', '-', (89, 93))
425389	32128997	In addition to  Np63, targeting of USP28 reduced NOTCH signature gene expression and NOTCH1 protein abundance, consistent with previous data (Popov et al, 2007a; Diefenbacher et al, 2014, 2015; Schulein-Volk et al, 2014).	('reduced', 'NegReg', (41, 48))	('NOTCH1', 'Gene', '4851', (85, 91))	('targeting', 'Var', (22, 31))	('USP28', 'Gene', (35, 40))	('NOTCH1', 'Gene', (85, 91))	('Np63', 'Chemical', '-', (16, 20))	('protein', 'Protein', (92, 99))	('NOTCH signature gene', 'Gene', (49, 69))
425390	32128997	As NOTCH signalling plays an important role in KRas-induced tumour formation in the lung (Xu et al, 2014b; Sosa Iglesias et al, 2018), loss of USP28 reduced overall tumour burden and, while blocking SCC formation, also reduced ADC tumour burden in the lung.	('USP28', 'Gene', (143, 148))	('tumour', 'Phenotype', 'HP:0002664', (165, 171))	('tumour', 'Disease', 'MESH:D009369', (165, 171))	('loss', 'Var', (135, 139))	('tumour', 'Disease', (165, 171))	('tumour', 'Phenotype', 'HP:0002664', (60, 66))	('tumour', 'Disease', 'MESH:D009369', (60, 66))	('SCC', 'Phenotype', 'HP:0002860', (199, 202))	('tumour', 'Disease', (60, 66))	('reduced', 'NegReg', (149, 156))	('SCC', 'Gene', '6317', (199, 202))	('blocking', 'NegReg', (190, 198))	('Sosa Iglesias', 'Disease', 'None', (107, 120))	('tumour', 'Phenotype', 'HP:0002664', (231, 237))	('Sosa Iglesias', 'Disease', (107, 120))	('reduced', 'NegReg', (219, 226))	('tumour', 'Disease', 'MESH:D009369', (231, 237))	('SCC', 'Gene', (199, 202))	('tumour', 'Disease', (231, 237))
425439	32128997	Briefly, cells/tissues were lysed in buffer containing 20 mM Na2HPO4, 20 mM NaH2PO4, 1% (v/v) NP-40 and 2 mM EDTA and supplemented with 5 mM NEM, and complete protease inhibitor cocktail (Bimake).	('NP-40 and 2', 'Gene', '8828', (94, 105))	('men', 'Species', '9606', (124, 127))	('Na2HPO4', 'Chemical', '-', (61, 68))	('EDTA', 'Chemical', 'MESH:D004492', (109, 113))	('NaH2PO4', 'Chemical', '-', (76, 83))	('NaH2PO4', 'Var', (76, 83))	('Na2HPO4', 'Var', (61, 68))
425453	32128997	For AAV production, cells (70% confluence) were transfected with the plasmid of interest (10 mug), pHelper (15 mug) and pAAV-DJ or pAAV-2/8 (10 mug) using PEI (70 mug).	('AAV', 'Gene', (4, 7))	('AAV', 'Gene', '17', (4, 7))	('AAV', 'Gene', (132, 135))	('AAV', 'Gene', (121, 124))	('AAV', 'Gene', '17', (132, 135))	('AAV', 'Gene', '17', (121, 124))	('10 mug', 'Var', (90, 96))
425459	32128997	For lentivirus production, HEK293 cells (70% confluence) were transfected with the plasmid of interest (15 mug), pPAX (10 mug) and pPMD2 (10 mug) using PEI (70 mug).	('HEK293', 'CellLine', 'CVCL:0045', (27, 33))	('pPMD2 (10 mug', 'Var', (131, 144))	('15 mug', 'Var', (104, 110))	('lentivirus', 'MPA', (4, 14))
425492	32128997	For the survival analysis of USP28-altered samples (mutation or deep deletion), cBioPortal was used to calculate disease-free survival using the dataset "Lung Squamous Cell Carcinoma (LUSC-TCGA, Provisional)" (Fig EV1).	('Carcinoma', 'Phenotype', 'HP:0030731', (173, 182))	('Lung Squamous Cell Carcinoma', 'Disease', (154, 182))	('Lung Squamous Cell Carcinoma', 'Disease', 'MESH:D002294', (154, 182))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (159, 182))	('deep deletion', 'Var', (64, 77))	('EV1', 'Gene', '11322', (214, 217))	('mutation', 'Var', (52, 60))	('EV1', 'Gene', (214, 217))	('Lung Squamous Cell Carcinoma', 'Phenotype', 'HP:0030359', (154, 182))
425562	30002503	8 differentially expressed IncRNA, including ABCA9-AS1, AL163952.1, AL356056.1, ANO1-AS2, AP002478.1, HOTTIP, LINC00052, and LINC00460, were negatively correlated with overall survival (P < 0.05).	('HOTTIP', 'Gene', (102, 108))	('AL356056.1', 'Var', (68, 78))	('overall survival', 'CPA', (168, 184))	('LINC00052', 'Gene', (110, 119))	('negatively', 'NegReg', (141, 151))	('ANO1', 'Gene', (80, 84))	('AP002478.1', 'Var', (90, 100))	('AL163952.1', 'Var', (56, 66))	('ABCA9', 'Gene', '10350', (45, 50))	('HOTTIP', 'Gene', '100316868', (102, 108))	('LINC00460', 'Gene', (125, 134))	('LINC00460', 'Gene', '728192', (125, 134))	('ABCA9', 'Gene', (45, 50))	('AS1', 'Gene', '5729', (51, 54))	('AS1', 'Gene', (51, 54))	('ANO1', 'Gene', '55107', (80, 84))	('LINC00052', 'Gene', '145978', (110, 119))
425563	30002503	On the contrary, 5 differentially expressed IncRNA, including AL161645.1, HCG22, MIAT, MUC19, and ZFY-AS1, were positively correlated with overall survival time (P < 0.05).	('MUC19', 'Gene', '283463', (87, 92))	('overall survival time', 'CPA', (139, 160))	('AL161645.1', 'Var', (62, 72))	('MIAT', 'Gene', '440823', (81, 85))	('MUC19', 'Gene', (87, 92))	('HCG22', 'Gene', '285834', (74, 79))	('MIAT', 'Gene', (81, 85))	('HCG22', 'Gene', (74, 79))	('correlated', 'Reg', (123, 133))	('ZFY-AS1', 'Gene', '107987337', (98, 105))	('ZFY-AS1', 'Gene', (98, 105))
425568	30002503	Accumulative evidence shows that long-chain non-coding RNAs play a very important regulatory role in tumorigenesis and tumor progression.	('tumor', 'Disease', (119, 124))	('long-chain non-coding', 'Var', (33, 54))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
425582	30002503	Considering all the identified lncRNAs, HOTTIP's abnormal expression had the most significant impact on the survival of patients (P = 6.241e-04).	('HOTTIP', 'Gene', '100316868', (40, 46))	('abnormal expression', 'Var', (49, 68))	('patients', 'Species', '9606', (120, 128))	('survival', 'CPA', (108, 116))	('HOTTIP', 'Gene', (40, 46))	('impact', 'Reg', (94, 100))
425601	27637100	Our study shows that high expression of FAK is associated with a worse OS in patients with carcinomas, but the association between FAK and prognosis varies according to cancer type.	('worse OS', 'Disease', (65, 73))	('carcinomas', 'Disease', 'MESH:D002277', (91, 101))	('cancer', 'Disease', (169, 175))	('FAK', 'Gene', '5747', (131, 134))	('FAK', 'Gene', (40, 43))	('FAK', 'Gene', '5747', (40, 43))	('cancer', 'Disease', 'MESH:D009369', (169, 175))	('patients', 'Species', '9606', (77, 85))	('high expression', 'Var', (21, 36))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('carcinomas', 'Phenotype', 'HP:0030731', (91, 101))	('carcinomas', 'Disease', (91, 101))	('associated', 'Reg', (47, 57))	('FAK', 'Gene', (131, 134))
425607	27637100	Dysregulation of FAK leads to the development of malignancies, including initiation of invasion, metastasis and neoangiogenesis.	('leads to', 'Reg', (21, 29))	('initiation of invasion', 'CPA', (73, 95))	('neoangiogenesis', 'CPA', (112, 127))	('Dysregulation', 'Var', (0, 13))	('metastasis', 'CPA', (97, 107))	('malignancies', 'Disease', 'MESH:D009369', (49, 61))	('FAK', 'Gene', (17, 20))	('FAK', 'Gene', '5747', (17, 20))	('malignancies', 'Disease', (49, 61))
425655	27637100	At least six tyrosine residues (Y397, Y407, Y576, Y577, Y861, and Y925) have been identified as phosphorylation sites.	('Y577', 'Var', (50, 54))	('Y397', 'Var', (32, 36))	('Y925', 'Var', (66, 70))	('Y861', 'Var', (56, 60))	('Y576', 'Var', (44, 48))	('Y407', 'Var', (38, 42))	('tyrosine', 'Chemical', 'MESH:D014443', (13, 21))
425656	27637100	These above results suggest that high expression of both FAK and phosphorylation status may be a target for cancer therapeutics and may have an impact on survival.	('high expression', 'Var', (33, 48))	('survival', 'CPA', (154, 162))	('impact', 'Reg', (144, 150))	('have', 'Reg', (136, 140))	('FAK', 'Gene', (57, 60))	('FAK', 'Gene', '5747', (57, 60))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
425665	27637100	In human colorectal cancer, nuclear expression of phosphorylated FAK is associated with poor prognosis.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('phosphorylated', 'Var', (50, 64))	('colorectal cancer', 'Disease', (9, 26))	('human', 'Species', '9606', (3, 8))	('colorectal cancer', 'Disease', 'MESH:D015179', (9, 26))	('nuclear', 'MPA', (28, 35))	('colorectal cancer', 'Phenotype', 'HP:0003003', (9, 26))	('FAK', 'Gene', '5747', (65, 68))	('FAK', 'Gene', (65, 68))
425675	31680452	MicroRNA-29b-3p suppresses oral squamous cell carcinoma cell migration and invasion via IL32/AKT signalling pathway Oral squamous cell carcinoma (OSCC) is aggressive accompanied with poor prognosis.	('MicroRNA-29b-3p', 'Var', (0, 15))	('IL32', 'Gene', '9235', (88, 92))	('suppresses', 'NegReg', (16, 26))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (121, 144))	('Oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (116, 144))	('invasion', 'CPA', (75, 83))	('AKT', 'Gene', (93, 96))	('oral squamous cell carcinoma cell migration', 'Disease', (27, 70))	('Oral squamous cell carcinoma', 'Disease', (116, 144))	('IL32', 'Gene', (88, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('carcinoma', 'Phenotype', 'HP:0030731', (46, 55))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (32, 55))	('oral squamous cell carcinoma cell migration', 'Disease', 'MESH:D002294', (27, 70))	('AKT', 'Gene', '207', (93, 96))
425677	31680452	Here, we verified the miR-29b-3p as a guarder that suppressed migration and invasion of OSCC cells and was down-regulated in the most invasive cells.	('miR-29b-3p', 'Chemical', '-', (22, 32))	('suppressed', 'NegReg', (51, 61))	('down-regulated', 'NegReg', (107, 121))	('miR-29b-3p', 'Var', (22, 32))
425678	31680452	Besides that, the invasion suppression role of miR-29b-3p was achieved through the IL32/AKT pathway.	('miR-29b-3p', 'Chemical', '-', (47, 57))	('AKT', 'Gene', '207', (88, 91))	('AKT', 'Gene', (88, 91))	('IL32', 'Gene', '9235', (83, 87))	('miR-29b-3p', 'Var', (47, 57))	('IL32', 'Gene', (83, 87))	('invasion', 'CPA', (18, 26))
425684	31680452	These invasion tumour front-like cells serve as a good model for exploring the underlying mechanism for OSCC invasion behaviour.4  MicroRNAs (miRNAs) participate in many aspects of tumour properties by regulating gene expression post-transcriptionally.5, 6 Recent studies have shown that miRNAs play an essential role in the transformation of oral leukoplakia to OSCC and can serve as biomarkers for this process.7 They also regulate essential genes involved in OSCC invasion and metastasis at the post-transcriptional level.8, 9 We explored miRNA profile in OSCC cell lines in our previous work and characterized some miRNAs with differential expression between the cell lines with high and low invasion ability.4 Among these miRNAs, miR-29b-3p is significantly down-regulated in highly invasive OSCC cell line.	('oral leukoplakia', 'Phenotype', 'HP:0002745', (343, 359))	('invasion tumour', 'Disease', 'MESH:D009361', (6, 21))	('oral leukoplakia', 'Disease', 'MESH:D007972', (343, 359))	('tumour', 'Phenotype', 'HP:0002664', (181, 187))	('tumour', 'Disease', 'MESH:D009369', (15, 21))	('miR-29b-3p', 'Var', (735, 745))	('tumour', 'Disease', (15, 21))	('tumour', 'Disease', 'MESH:D009369', (181, 187))	('oral leukoplakia', 'Disease', (343, 359))	('tumour', 'Disease', (181, 187))	('miR-29b-3p', 'Chemical', '-', (735, 745))	('invasion tumour', 'Disease', (6, 21))	('down-regulated', 'NegReg', (763, 777))	('tumour', 'Phenotype', 'HP:0002664', (15, 21))
425686	31680452	In the present study, we show that miR-29b-3p is down-regulated in OSCC invasive cells and inhibits OSCC cell migration and invasion by suppressing the interleukin (IL) 32/AKT pathway.	('suppressing', 'NegReg', (136, 147))	('OSCC cell migration', 'CPA', (100, 119))	('AKT', 'Gene', (172, 175))	('miR-29b-3p', 'Var', (35, 45))	('OSCC', 'Disease', (67, 71))	('down-regulated', 'NegReg', (49, 63))	('miR-29b-3p', 'Chemical', '-', (35, 45))	('AKT', 'Gene', '207', (172, 175))	('inhibits', 'NegReg', (91, 99))	('invasion', 'CPA', (124, 132))
425694	31680452	Plasmids pcDNA6 and pLKO-tet-on were used to overexpressing and knocking down the IL32, respectively.	('tet', 'Chemical', 'MESH:C010349', (25, 28))	('knocking down', 'Var', (64, 77))	('IL32', 'Gene', (82, 86))	('IL32', 'Gene', '9235', (82, 86))
425702	31680452	The invasion tumour front-like cells, which we named UM-SCC6-M, exhibited mesenchymal properties and enhanced invasiveness.4 The UM-SCC6 cells were interconnected and exhibited a cobblestone organization, whereas UM-SCC6-M cells were spindle-shaped and loosely connected (Figure S1A).	('UM-SCC6-M', 'CellLine', 'CVCL:7773', (53, 62))	('cobblestone organization', 'CPA', (179, 203))	('UM-SCC6', 'CellLine', 'CVCL:7773', (129, 136))	('tumour', 'Phenotype', 'HP:0002664', (13, 19))	('UM-SCC6', 'Var', (129, 136))	('UM-SCC6', 'CellLine', 'CVCL:7773', (213, 220))	('UM-SCC6-M', 'CellLine', 'CVCL:7773', (213, 222))	('exhibited', 'Reg', (167, 176))	('invasion tumour', 'Disease', (4, 19))	('UM-SCC6', 'CellLine', 'CVCL:7773', (53, 60))	('invasion tumour', 'Disease', 'MESH:D009361', (4, 19))
425705	31680452	The small RNA sequencing data from our previous work showed that miR-29b-3p was significantly down-regulated in UM-SCC6-M cells, which was supported by qPCR (Figure 1C).	('UM-SCC6-M', 'CellLine', 'CVCL:7773', (112, 121))	('miR-29b-3p', 'Var', (65, 75))	('down-regulated', 'NegReg', (94, 108))	('miR-29b-3p', 'Chemical', '-', (65, 75))
425710	31680452	Meanwhile, MK-2206 attenuated the migrating and invading stimulatory effect of miR-29b-3p inhibitor in UM-SCC6 cells (Figure 3C,D).	('invading', 'CPA', (48, 56))	('MK-2206', 'Chemical', 'MESH:C548887', (11, 18))	('MK-2206', 'Var', (11, 18))	('miR-29b-3p', 'Chemical', '-', (79, 89))	('miR-29b-3p', 'Gene', (79, 89))	('UM-SCC6', 'CellLine', 'CVCL:7773', (103, 110))	('attenuated', 'NegReg', (19, 29))
425711	31680452	These results demonstrate that AKT signalling mediates the migration and invasion of OSCC cells and may be a downstream effector of miR-29b-3p.	('AKT', 'Gene', (31, 34))	('mediates', 'Reg', (46, 54))	('miR-29b-3p', 'Var', (132, 142))	('invasion', 'CPA', (73, 81))	('migration', 'CPA', (59, 68))	('AKT', 'Gene', '207', (31, 34))	('miR-29b-3p', 'Chemical', '-', (132, 142))
425716	31680452	The 402 up-regulated genes in UM-SCC6-M cells transfected with miR-29b-3p mimic were enriched in tumour-related and metabolic pathways (FC > 1.5) (Figure S4E), whereas the 319 down-regulated genes were enriched in tumour metastasis-related pathways (FC > 1.5) (Figure S4F), including those associated with the extracellular matrix, cytoskeleton and cell adhesion, which was consistent with the results of the functional assays.	('tumour', 'Disease', (97, 103))	('tumour', 'Disease', (214, 220))	('UM-SCC6-M', 'CellLine', 'CVCL:7773', (30, 39))	('up-regulated', 'PosReg', (8, 20))	('miR-29b-3p mimic', 'Var', (63, 79))	('miR-29b-3p', 'Chemical', '-', (63, 73))	('metabolic pathways', 'Pathway', (116, 134))	('tumour', 'Disease', 'MESH:D009369', (97, 103))	('tumour', 'Phenotype', 'HP:0002664', (214, 220))	('tumour', 'Disease', 'MESH:D009369', (214, 220))	('tumour', 'Phenotype', 'HP:0002664', (97, 103))
425718	31680452	Since miR-29b-3p was down-regulated in UM-SCC6-M cells and miRNAs typically act as negative regulators of gene expression, we focused on the 30 genes which were both enriched in UM-SCC6-M compared with UM-SCC6 and decreased by miR-29b-3p mimic infection (Figure 4A).	('UM-SCC6-M', 'CellLine', 'CVCL:7773', (39, 48))	('UM-SCC6', 'CellLine', 'CVCL:7773', (39, 46))	('miR-29b-3p', 'Var', (227, 237))	('infection', 'Disease', (244, 253))	('UM-SCC6', 'CellLine', 'CVCL:7773', (178, 185))	('UM-SCC6', 'CellLine', 'CVCL:7773', (202, 209))	('UM-SCC6-M', 'CellLine', 'CVCL:7773', (178, 187))	('down-regulated', 'NegReg', (21, 35))	('miR-29b-3p', 'Chemical', '-', (6, 16))	('infection', 'Disease', 'MESH:D007239', (244, 253))	('miR-29b-3p', 'Chemical', '-', (227, 237))	('decreased', 'NegReg', (214, 223))	('UM-SCC6-M', 'Var', (178, 187))
425723	31680452	More importantly, it has been reported that miR-29b regulated IL32 via direct binding to the 3' untranslated region of the IL-32 transcript.15 Furthermore, by transfecting UM-SCC6 and UM-SCC6-M cells with the miR-29b-3p inhibitor and mimic, respectively, we found that IL32 was under the negative regulation by miR-29b-3p at the post-transcriptional level (Figures 4E and S5).	('IL32', 'Gene', (269, 273))	('IL-32', 'Gene', '9235', (123, 128))	('miR-29b-3p', 'Chemical', '-', (209, 219))	('UM-SCC6', 'CellLine', 'CVCL:7773', (172, 179))	('IL-32', 'Gene', (123, 128))	('IL32', 'Gene', '9235', (62, 66))	('miR-29b-3p', 'Var', (311, 321))	('IL32', 'Gene', '9235', (269, 273))	('IL32', 'Gene', (62, 66))	('UM-SCC6-M', 'CellLine', 'CVCL:7773', (184, 193))	('UM-SCC6', 'CellLine', 'CVCL:7773', (184, 191))	('miR-29b-3p', 'Chemical', '-', (311, 321))
425725	31680452	On the contrary, migration and invasion of UM-SCC6-M cells were suppressed by IL32 knockdown (Figure S6A-C).	('UM-SCC6-M', 'CellLine', 'CVCL:7773', (43, 52))	('suppressed', 'NegReg', (64, 74))	('IL32', 'Gene', (78, 82))	('knockdown', 'Var', (83, 92))	('IL32', 'Gene', '9235', (78, 82))
425727	31680452	As expected, overexpression and knockdown of IL32 altered AKT phosphorylation (Figure 5C).	('IL32', 'Gene', '9235', (45, 49))	('knockdown', 'Var', (32, 41))	('IL32', 'Gene', (45, 49))	('altered', 'Reg', (50, 57))	('AKT', 'Gene', '207', (58, 61))	('AKT', 'Gene', (58, 61))
425729	31680452	The above results implied that IL32 mediated the effects of miR-29b-3p on AKT signalling.	('miR-29b-3p', 'Chemical', '-', (60, 70))	('AKT', 'Gene', '207', (74, 77))	('IL32', 'Gene', '9235', (31, 35))	('AKT', 'Gene', (74, 77))	('miR-29b-3p', 'Var', (60, 70))	('IL32', 'Gene', (31, 35))
425730	31680452	Indeed, miR-29b-3p mimic interfered with the migration and invasion of UM-SCC6-M cells, overexpression of IL32 abrogated its effects and restored the migratory and invasive potentials of the cells (Figure 6A,B).	('interfered', 'NegReg', (25, 35))	('UM-SCC6-M', 'CellLine', 'CVCL:7773', (71, 80))	('overexpression', 'PosReg', (88, 102))	('IL32', 'Gene', '9235', (106, 110))	('migration', 'CPA', (45, 54))	('abrogated', 'NegReg', (111, 120))	('IL32', 'Gene', (106, 110))	('invasive potentials of the cells', 'CPA', (164, 196))	('miR-29b-3p mimic', 'Var', (8, 24))	('miR-29b-3p', 'Chemical', '-', (8, 18))	('restored', 'PosReg', (137, 145))
425731	31680452	Conversely, knockdown of IL32 reversed the effect of the miR-29b-3p inhibitor on migration and invasion of UM-SCC6 cells (Figure S7A,B).	('IL32', 'Gene', '9235', (25, 29))	('knockdown', 'Var', (12, 21))	('IL32', 'Gene', (25, 29))	('miR-29b-3p', 'Gene', (57, 67))	('invasion of UM-SCC6', 'CPA', (95, 114))	('UM-SCC6', 'CellLine', 'CVCL:7773', (107, 114))	('migration', 'CPA', (81, 90))	('miR-29b-3p', 'Chemical', '-', (57, 67))
425733	31680452	As expected, the AKT inhibitor MK-2206 suppressed the migration and invasion of UM-SCC6 cells transfected with the miR-29b-3p mimic and IL32 overexpression plasmid (Figure S7C,D).	('AKT', 'Gene', (17, 20))	('IL32', 'Gene', '9235', (136, 140))	('MK-2206', 'Chemical', 'MESH:C548887', (31, 38))	('MK-2206', 'Var', (31, 38))	('invasion', 'CPA', (68, 76))	('migration', 'CPA', (54, 63))	('IL32', 'Gene', (136, 140))	('AKT', 'Gene', '207', (17, 20))	('miR-29b-3p', 'Chemical', '-', (115, 125))	('UM-SCC6', 'CellLine', 'CVCL:7773', (80, 87))	('miR-29b-3p mimic', 'Var', (115, 131))	('suppressed', 'NegReg', (39, 49))
425734	31680452	Taken together, miR-29b-3p suppresses migration and invasion of OSCC via the IL32/AKT axis.	('IL32', 'Gene', '9235', (77, 81))	('IL32', 'Gene', (77, 81))	('AKT', 'Gene', '207', (82, 85))	('miR-29b-3p', 'Var', (16, 26))	('suppresses', 'NegReg', (27, 37))	('invasion of OSCC', 'CPA', (52, 68))	('AKT', 'Gene', (82, 85))	('migration', 'CPA', (38, 47))	('miR-29b-3p', 'Chemical', '-', (16, 26))
425737	31680452	We deeply explored the function and mechanism of miR-29b-3p, which is significantly down-regulated in UM-SCC6-M cells in our previous miRNA sequencing data.	('miR-29b-3p', 'Chemical', '-', (49, 59))	('miR-29b-3p', 'Var', (49, 59))	('UM-SCC6-M', 'CellLine', 'CVCL:7773', (102, 111))	('down-regulated', 'NegReg', (84, 98))
425738	31680452	And we found that miR-29b-3p suppresses migration and invasion of OSCC via the IL32/AKT axis.	('suppresses', 'NegReg', (29, 39))	('invasion of OSCC', 'CPA', (54, 70))	('AKT', 'Gene', '207', (84, 87))	('IL32', 'Gene', '9235', (79, 83))	('miR-29b-3p', 'Var', (18, 28))	('AKT', 'Gene', (84, 87))	('migration', 'CPA', (40, 49))	('miR-29b-3p', 'Chemical', '-', (18, 28))	('IL32', 'Gene', (79, 83))
425739	31680452	MiR-29b is known to be a critical suppressor in tumour progression, regulating epigenetics, proliferation, apoptosis, differentiation, metastasis and chemosensitivity.20 MiR-29b-3p is a member of the miR-29 family, it has been reported as an antitumour effector in colorectal cancer,21 glioblastoma,12 gastric cancer,22 breast cancer23 and tongue squamous cell carcinoma,13 and our present study provided new evidence of the important role of miR-29b-3p in OSCC invasion.	('colorectal cancer', 'Disease', 'MESH:D015179', (265, 282))	('colorectal cancer', 'Disease', (265, 282))	('MiR-29b', 'Gene', (0, 7))	('gastric cancer', 'Disease', 'MESH:D013274', (302, 316))	('tongue squamous cell carcinoma', 'Disease', (340, 370))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (347, 370))	('MiR-29b', 'Gene', '407024', (0, 7))	('cancer', 'Phenotype', 'HP:0002664', (310, 316))	('cancer', 'Phenotype', 'HP:0002664', (327, 333))	('miR-29b-3p', 'Var', (443, 453))	('tumour', 'Phenotype', 'HP:0002664', (48, 54))	('gastric cancer', 'Phenotype', 'HP:0012126', (302, 316))	('tongue squamous cell carcinoma', 'Phenotype', 'HP:0030413', (340, 370))	('MiR-29b', 'Gene', '407024', (170, 177))	('tumour', 'Disease', 'MESH:D009369', (48, 54))	('cancer', 'Phenotype', 'HP:0002664', (276, 282))	('tumour', 'Disease', (48, 54))	('breast cancer', 'Phenotype', 'HP:0003002', (320, 333))	('tumour', 'Phenotype', 'HP:0002664', (246, 252))	('glioblastoma', 'Disease', 'MESH:D005909', (286, 298))	('tumour', 'Disease', 'MESH:D009369', (246, 252))	('OSCC', 'Disease', (457, 461))	('carcinoma', 'Phenotype', 'HP:0030731', (361, 370))	('miR-29b-3p', 'Chemical', '-', (443, 453))	('tumour', 'Disease', (246, 252))	('MiR-29b', 'Gene', (170, 177))	('breast cancer', 'Disease', 'MESH:D001943', (320, 333))	('glioblastoma', 'Disease', (286, 298))	('tongue squamous cell carcinoma', 'Disease', 'MESH:D002294', (340, 370))	('breast cancer', 'Disease', (320, 333))	('gastric cancer', 'Disease', (302, 316))	('glioblastoma', 'Phenotype', 'HP:0012174', (286, 298))
425740	31680452	By transcription profiling and miRNA targets analysis, we found out IL32, as a downstream target of miR-29b-3p.	('IL32', 'Gene', '9235', (68, 72))	('miR-29b-3p', 'Var', (100, 110))	('miR-29b-3p', 'Chemical', '-', (100, 110))	('IL32', 'Gene', (68, 72))
425742	31680452	This is also supported by the observation that IL32 induces the expression of AKT in osteoclasts30 and gastric cancer.18  In conclusion, the present study demonstrated that miR-29b-3p played an antitumour role in the migration and invasion of OSCC cells via suppressing the IL32/AKT signalling axis.	('IL32', 'Gene', (47, 51))	('gastric cancer', 'Disease', 'MESH:D013274', (103, 117))	('AKT', 'Gene', (78, 81))	('AKT', 'Gene', '207', (279, 282))	('IL32', 'Gene', (274, 278))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('suppressing', 'NegReg', (258, 269))	('invasion', 'CPA', (231, 239))	('IL32', 'Gene', '9235', (47, 51))	('gastric cancer', 'Phenotype', 'HP:0012126', (103, 117))	('AKT', 'Gene', '207', (78, 81))	('miR-29b-3p', 'Var', (173, 183))	('tumour', 'Phenotype', 'HP:0002664', (198, 204))	('tumour', 'Disease', 'MESH:D009369', (198, 204))	('migration', 'CPA', (217, 226))	('IL32', 'Gene', '9235', (274, 278))	('tumour', 'Disease', (198, 204))	('AKT', 'Gene', (279, 282))	('gastric cancer', 'Disease', (103, 117))	('miR-29b-3p', 'Chemical', '-', (173, 183))
425743	31680452	These findings provide new insight into the mechanistic basis for OSCC metastasis and suggest that miR-29b-3p-based treatment may enable promising new strategies to overcome OSCC metastasis.	('miR-29b-3p-based', 'Var', (99, 115))	('OSCC', 'Disease', (174, 178))	('OSCC', 'Disease', (66, 70))	('miR-29b-3p', 'Chemical', '-', (99, 109))
425751	29192647	This review summarizes the key components of the tumor microenvironment, presents an overview of and the challenges with PD-L1 antibodies and assays, and addresses newer candidate biomarkers, such as CD8+ cell density and mutational load.	('PD-L1', 'Gene', (121, 126))	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('CD8', 'Gene', '925', (200, 203))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('men', 'Species', '9606', (67, 70))	('tumor', 'Disease', (49, 54))	('mutational', 'Var', (222, 232))	('CD8', 'Gene', (200, 203))
425835	29192647	Whole-exome sequencing revealed that patients with high mutational load showed an increased likelihood of response to immune checkpoint inhibitors, based on the concept that more mutations resulted in more neoantigens, which increased the likelihood of checkpoint-mediated immune inhibition.	('resulted in', 'Reg', (189, 200))	('patients', 'Species', '9606', (37, 45))	('response', 'MPA', (106, 114))	('more', 'PosReg', (201, 205))	('mutations', 'Var', (179, 188))	('high mutational load', 'Var', (51, 71))	('neoantigens', 'MPA', (206, 217))
425836	29192647	However, this predictive method has been limited by the fact that some patients with low mutational load also respond to PD-1 axis therapies.	('patients', 'Species', '9606', (71, 79))	('respond', 'Reg', (110, 117))	('PD-1', 'Gene', (121, 125))	('PD-1', 'Gene', '5133', (121, 125))	('mutational load', 'Var', (89, 104))
425862	29192647	Specific genetic resistance mechanisms to anti-PD-1 have also been identified in patients with melanoma, including JAK1/2 mutations, influencing the response to IFN-gamma, and B2 microglobulin loss, leading to a lack of MHC class I expression.	('PD-1', 'Gene', (47, 51))	('PD-1', 'Gene', '5133', (47, 51))	('lack', 'NegReg', (212, 216))	('loss', 'NegReg', (193, 197))	('melanoma', 'Disease', 'MESH:D008545', (95, 103))	('JAK1/2', 'Gene', '3716;3717', (115, 121))	('melanoma', 'Phenotype', 'HP:0002861', (95, 103))	('melanoma', 'Disease', (95, 103))	('patients', 'Species', '9606', (81, 89))	('B2 microglobulin', 'Gene', '3135', (176, 192))	('JAK1/2', 'Gene', (115, 121))	('mutations', 'Var', (122, 131))	('B2 microglobulin', 'Gene', (176, 192))	('expression', 'MPA', (232, 242))	('MHC class I', 'Protein', (220, 231))	('response to IFN-gamma', 'MPA', (149, 170))
425863	29192647	Most recently, an increase in copy number alteration has been associated with decreased immune infiltration and a more resistant phenotype to sequential antiCTLA-4, anti-PD-1 blockade.	('CTLA-4', 'Gene', (157, 163))	('resistant phenotype', 'MPA', (119, 138))	('CTLA-4', 'Gene', '1493', (157, 163))	('immune infiltration', 'CPA', (88, 107))	('PD-1', 'Gene', (170, 174))	('PD-1', 'Gene', '5133', (170, 174))	('decreased', 'NegReg', (78, 87))	('copy number alteration', 'Var', (30, 52))
425865	29192647	Patients with Merkel cell carcinoma have shown response rates of 56 and 32% to anti-PD-1 and anti-PD-L1, respectively, the latter of which is now FDA approved.	('anti-PD-L1', 'Var', (93, 103))	('FDA', 'Chemical', '-', (146, 149))	('Merkel cell carcinoma', 'Disease', 'MESH:D015266', (14, 35))	('Patients', 'Species', '9606', (0, 8))	('carcinoma', 'Phenotype', 'HP:0030731', (26, 35))	('Merkel cell carcinoma', 'Disease', (14, 35))	('PD-1', 'Gene', (84, 88))	('PD-1', 'Gene', '5133', (84, 88))
425869	29192647	Incremental gains in lung cancer survival have been driven by the use of combined platinum and pemetrexed chemotherapies, as well as identification and directed therapy of oncogenic alterations in EGFR, ALK, and ROS1 using tyrosine kinase inhibitors.	('Incremental gains in lung cancer', 'Disease', (0, 32))	('pemetrexed', 'Chemical', 'MESH:D000068437', (95, 105))	('ROS1', 'Gene', (212, 216))	('lung cancer', 'Phenotype', 'HP:0100526', (21, 32))	('ROS1', 'Gene', '6098', (212, 216))	('ALK', 'Gene', (203, 206))	('EGFR', 'Gene', '1956', (197, 201))	('Incremental gains in lung cancer', 'Disease', 'MESH:D008175', (0, 32))	('platinum', 'Chemical', 'MESH:D010984', (82, 90))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('alterations', 'Var', (182, 193))	('EGFR', 'Gene', (197, 201))	('ALK', 'Gene', '238', (203, 206))
425873	29192647	As of May 2017, three immune checkpoint blockade inhibitors have been approved by the FDA for use in non-small-cell lung carcinoma, the anti-PD-1 antibodies pembrolizumab (first- and second-line setting) and nivolumab (second line) and the anti-PD-L1 antibody atezolizumab (second line).	('FDA', 'Chemical', '-', (86, 89))	('antibodies', 'Var', (146, 156))	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('nivolumab', 'Chemical', 'MESH:D000077594', (208, 217))	('small-cell lung carcinoma', 'Phenotype', 'HP:0030357', (105, 130))	('atezolizumab', 'Chemical', 'MESH:C000594389', (260, 272))	('lung carcinoma', 'Disease', 'MESH:D008175', (116, 130))	('PD-1', 'Gene', (141, 145))	('lung carcinoma', 'Disease', (116, 130))	('PD-1', 'Gene', '5133', (141, 145))	('pembrolizumab', 'Chemical', 'MESH:C582435', (157, 170))
425878	29192647	Correlative biomarker analyses in the phase 1, KEYNOTE-001 trial (which included both untreated and previously treated patients) demonstrated that patients with PD-L1 labeling in at least 50% of tumor cells had a higher likelihood of response to pembrolizumab and longer progressionfree and overall survival than those whose tumors had lower levels of PD-L1 expression.	('tumors', 'Disease', (325, 331))	('tumors', 'Disease', 'MESH:D009369', (325, 331))	('PD-L1 labeling in', 'Var', (161, 178))	('tumors', 'Phenotype', 'HP:0002664', (325, 331))	('tumor', 'Disease', (195, 200))	('tumor', 'Disease', (325, 330))	('patients', 'Species', '9606', (119, 127))	('higher', 'PosReg', (213, 219))	('tumor', 'Disease', 'MESH:D009369', (325, 330))	('pembrolizumab', 'Chemical', 'MESH:C582435', (246, 259))	('patients', 'Species', '9606', (147, 155))	('response', 'MPA', (234, 242))	('longer', 'PosReg', (264, 270))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('tumor', 'Phenotype', 'HP:0002664', (325, 330))	('overall survival', 'CPA', (291, 307))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))
425880	29192647	Indeed, subsequent phase 2 and 3 trials found that PD-L1 labeling in 1% of tumor cells also predicted improved survival with second-line pembrolizumab compared with standard-of-care chemotherapy in previously treated patients.	('survival', 'MPA', (111, 119))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('pembrolizumab', 'Chemical', 'MESH:C582435', (137, 150))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('patients', 'Species', '9606', (217, 225))	('labeling', 'Var', (57, 65))	('tumor', 'Disease', (75, 80))	('improved', 'PosReg', (102, 110))	('PD-L1', 'Gene', (51, 56))
425884	29192647	It is also important to note that patients with EGFR mutations and ALK rearrangements do not appear to benefit from immune checkpoint blockade and were excluded from trials in the first-line setting.	('EGFR', 'Gene', '1956', (48, 52))	('ALK', 'Gene', '238', (67, 70))	('EGFR', 'Gene', (48, 52))	('mutations', 'Var', (53, 62))	('men', 'Species', '9606', (80, 83))	('patients', 'Species', '9606', (34, 42))	('ALK', 'Gene', (67, 70))
425885	29192647	As a result, patients with a new diagnosis of advanced-stage lung adenocarcinoma should undergo testing for EGFR mutations, ALK and ROS1 rearrangements, and PD-L1 protein expression to determine eligibility for tyrosine kinase inhibitors and pembrolizumab therapy, respectively.	('advanced-stage lung adenocarcinoma', 'Disease', (46, 80))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (61, 80))	('EGFR', 'Gene', '1956', (108, 112))	('ALK', 'Gene', '238', (124, 127))	('EGFR', 'Gene', (108, 112))	('patients', 'Species', '9606', (13, 21))	('PD-L1', 'Gene', (157, 162))	('advanced-stage lung adenocarcinoma', 'Disease', 'MESH:D000077192', (46, 80))	('men', 'Species', '9606', (146, 149))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('ROS1', 'Gene', (132, 136))	('mutations', 'Var', (113, 122))	('pembrolizumab', 'Chemical', 'MESH:C582435', (242, 255))	('ALK', 'Gene', (124, 127))	('ROS1', 'Gene', '6098', (132, 136))
425889	29192647	Mechanistically, smoking-related transversion mutations in non-small-cell lung carcinoma contribute to neoantigen formation with resulting T-cell recruitment.	('transversion mutations', 'Var', (33, 55))	('contribute', 'Reg', (89, 99))	('neoantigen formation', 'MPA', (103, 123))	('lung carcinoma', 'Disease', (74, 88))	('lung carcinoma', 'Disease', 'MESH:D008175', (74, 88))	('men', 'Species', '9606', (153, 156))	('small-cell lung carcinoma', 'Phenotype', 'HP:0030357', (63, 88))	('T-cell', 'CPA', (139, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))
425891	29192647	PD-1 inhibitors may be effective in unleashing the immune system in this scenario; however, a number of other tumor-specific factors are likely to influence the efficacy of this therapeutic strategy.	('PD-1', 'Gene', (0, 4))	('PD-1', 'Gene', '5133', (0, 4))	('inhibitors', 'Var', (5, 15))	('tumor', 'Disease', (110, 115))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('influence', 'Reg', (147, 156))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
425895	29192647	Some studies have failed to identify a correlation between tumor genotype and immunoprofile, while others have suggested that KRAS/TP53 mutation status predicts for tumor adaptive immune resistance that may be amenable to PD-1 pathway blockade.	('KRAS', 'Gene', '3845', (126, 130))	('tumor', 'Disease', (165, 170))	('PD-1', 'Gene', '5133', (222, 226))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('tumor', 'Disease', (59, 64))	('predicts', 'Reg', (152, 160))	('mutation', 'Var', (136, 144))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('TP53', 'Gene', '7157', (131, 135))	('men', 'Species', '9606', (211, 214))	('TP53', 'Gene', (131, 135))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('KRAS', 'Gene', (126, 130))	('PD-1', 'Gene', (222, 226))
425896	29192647	STK11 loss-of-function mutations, which occur in 10-15% of lung adenocarcinomas, tend to co-occur with KRAS mutations, appear to promote recruitment of neutrophils to the tumor and exclude T-cell infiltrates, and thus may confer relative resistance to immune checkpoint blockade.	('promote', 'PosReg', (129, 136))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('mutations', 'Var', (23, 32))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))	('men', 'Species', '9606', (144, 147))	('STK11', 'Gene', (0, 5))	('KRAS', 'Gene', '3845', (103, 107))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (59, 79))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (59, 78))	('recruitment', 'MPA', (137, 148))	('KRAS', 'Gene', (103, 107))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (59, 79))	('carcinomas', 'Phenotype', 'HP:0030731', (69, 79))	('mutations', 'Var', (108, 117))	('loss-of-function', 'NegReg', (6, 22))	('STK11', 'Gene', '6794', (0, 5))	('tumor', 'Disease', (171, 176))	('lung adenocarcinomas', 'Disease', (59, 79))
425926	29192647	In primary mediastinal large B-cell lymphoma, amplification of 9p24.1 also has been associated with increased PD-L2 expression by immunohistochemistry.	('PD-L2', 'Gene', (110, 115))	('PD-L2', 'Gene', '80380', (110, 115))	('expression', 'MPA', (116, 126))	('9p24.1', 'Gene', (63, 69))	('increased', 'PosReg', (100, 109))	('lymphoma', 'Phenotype', 'HP:0002665', (36, 44))	('cell lymphoma', 'Phenotype', 'HP:0012191', (31, 44))	('increased PD', 'Phenotype', 'HP:0008151', (100, 112))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (29, 44))	('lymphoma', 'Disease', (36, 44))	('lymphoma', 'Disease', 'MESH:D008223', (36, 44))	('amplification of', 'Var', (46, 62))
425927	29192647	Interestingly, certain extranodal large B-cell lymphomas, including primary central nervous system lymphomas and primary testicular lymphomas, also harbor 9p24.1/PD-L1/PD-L2 copy number alterations.	('lymphoma', 'Phenotype', 'HP:0002665', (99, 107))	('lymphomas', 'Disease', 'MESH:D008223', (132, 141))	('primary testicular lymphomas', 'Disease', 'MESH:D013736', (113, 141))	('primary central nervous system lymphomas', 'Phenotype', 'HP:0030069', (68, 108))	('central nervous system lymphomas', 'Disease', 'MESH:D002493', (76, 108))	('central nervous system lymphomas', 'Disease', (76, 108))	('lymphomas', 'Disease', (47, 56))	('lymphomas', 'Disease', 'MESH:D008223', (99, 108))	('PD-L2', 'Gene', '80380', (168, 173))	('lymphomas', 'Phenotype', 'HP:0002665', (132, 141))	('lymphomas', 'Phenotype', 'HP:0002665', (99, 108))	('copy number alterations', 'Var', (174, 197))	('harbor', 'Reg', (148, 154))	('cell lymphoma', 'Phenotype', 'HP:0012191', (42, 55))	('B-cell lymphomas', 'Phenotype', 'HP:0012191', (40, 56))	('primary testicular lymphomas', 'Disease', (113, 141))	('lymphoma', 'Phenotype', 'HP:0002665', (47, 55))	('PD-L2', 'Gene', (168, 173))	('lymphoma', 'Phenotype', 'HP:0002665', (132, 140))	('lymphomas', 'Disease', (132, 141))	('lymphomas', 'Disease', 'MESH:D008223', (47, 56))	('lymphomas', 'Disease', (99, 108))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (40, 55))	('lymphomas', 'Phenotype', 'HP:0002665', (47, 56))
425932	29192647	In this cohort, 97% of cases showed concordant alterations of PD-L1 and PD-L2 loci, with copy gain and amplification identified in 56 and 36% of cases, respectively; PD-L1 protein expression by immunohistochemistry correlated with copy number alterations.	('protein', 'Protein', (172, 179))	('PD-L1', 'Gene', (62, 67))	('alterations', 'Var', (47, 58))	('PD-L1', 'Gene', (166, 171))	('PD-L2', 'Gene', (72, 77))	('PD-L2', 'Gene', '80380', (72, 77))	('copy number alterations', 'Var', (231, 254))
425933	29192647	Most importantly, patients whose tumors showed 9p24.1 amplification were more likely to have advanced-stage disease and were associated with worse progression-free survival following standard induction therapy.	('amplification', 'Var', (54, 67))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('9p24.1 amplification', 'Var', (47, 67))	('tumors', 'Disease', 'MESH:D009369', (33, 39))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('patients', 'Species', '9606', (18, 26))	('tumors', 'Disease', (33, 39))	('advanced-stage disease', 'CPA', (93, 115))
425936	29192647	In a subgroup of 10 patients with available pretreatment tissue biopsies, all tumors showed PD-L1 and PD-L2 copy number gains or amplifications by fluorescence in situ hybridization and membranous protein expression by immunohistochemistry on the Hodgkin Reed-Sternberg cells.	('tumors', 'Disease', (78, 84))	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('amplifications', 'Var', (129, 143))	('PD-L2 copy number gains', 'Disease', (102, 125))	('PD-L2 copy number gains', 'Disease', 'MESH:D010300', (102, 125))	('men', 'Species', '9606', (52, 55))	('PD-L1', 'Gene', (92, 97))	('membranous', 'MPA', (186, 196))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('patients', 'Species', '9606', (20, 28))
425941	29192647	The efficacy of PD-1 blockade in classical Hodgkin lymphoma and select other lymphoma types appears to be a direct result of 9p24.1 copy number alterations, whereas the majority of non-Hodgkin lymphomas have shown reduced clinical response rates, perhaps as a result of lacking these same chromosomal aberrations.	('lymphoma', 'Phenotype', 'HP:0002665', (193, 201))	('PD-1 blockade in classical Hodgkin lymphoma', 'Disease', (16, 59))	('Hodgkin lymphoma', 'Phenotype', 'HP:0012189', (43, 59))	('Hodgkin lymphoma', 'Phenotype', 'HP:0012189', (185, 201))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (289, 312))	('non-Hodgkin lymphomas', 'Phenotype', 'HP:0012539', (181, 202))	('lymphoma', 'Disease', (77, 85))	('lymphoma', 'Disease', 'MESH:D008223', (77, 85))	('non-Hodgkin lymphomas', 'Disease', 'MESH:D008228', (181, 202))	('lymphoma', 'Disease', (51, 59))	('lymphoma', 'Disease', 'MESH:D008223', (51, 59))	('lymphoma', 'Disease', (193, 201))	('PD-1 blockade in classical Hodgkin lymphoma', 'Disease', 'MESH:D010300', (16, 59))	('lymphoma', 'Disease', 'MESH:D008223', (193, 201))	('lymphomas', 'Phenotype', 'HP:0002665', (193, 202))	('Hodgkin lymphomas', 'Phenotype', 'HP:0012189', (185, 202))	('non-Hodgkin lymphomas', 'Disease', (181, 202))	('9p24.1', 'Gene', (125, 131))	('lymphoma', 'Phenotype', 'HP:0002665', (77, 85))	('copy number alterations', 'Var', (132, 155))	('lymphoma', 'Phenotype', 'HP:0002665', (51, 59))
425946	29192647	The HPV-negative tumors tend to be associated with field cancerization and a higher mutational density, which may be attributable to their association with carcinogens and resultant p53 mutations.	('HPV', 'Species', '10566', (4, 7))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('mutations', 'Var', (186, 195))	('higher', 'PosReg', (77, 83))	('tumors', 'Disease', (17, 23))	('HPV-negative', 'Gene', (4, 16))	('cancer', 'Disease', (57, 63))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('HPV-negative', 'NegReg', (4, 16))	('mutational density', 'MPA', (84, 102))	('p53', 'Gene', (182, 185))
425950	29192647	Numerous phase III trials are ongoing, many of which are assessing the efficacy of combinatorial PD-1/PD-L1 blockade with either CTLA-4 inhibition or chemotherapy and/or radiation.	('CTLA-4', 'Gene', '1493', (129, 135))	('PD-1', 'Gene', (97, 101))	('PD-1', 'Gene', '5133', (97, 101))	('blockade', 'Var', (108, 116))	('CTLA-4', 'Gene', (129, 135))
425964	29192647	Finally, half of microsatellite-unstable colorectal carcinomas show the expression of PD-L1 in the tumor microenvironment, either on carcinoma or immune cells.	('tumor', 'Disease', (99, 104))	('carcinoma', 'Phenotype', 'HP:0030731', (52, 61))	('carcinomas', 'Phenotype', 'HP:0030731', (52, 62))	('carcinoma', 'Disease', (52, 61))	('men', 'Species', '9606', (117, 120))	('carcinoma', 'Disease', 'MESH:D002277', (133, 142))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('microsatellite-unstable', 'Var', (17, 40))	('colorectal carcinomas', 'Disease', (41, 62))	('colorectal carcinomas', 'Disease', 'MESH:D015179', (41, 62))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('carcinoma', 'Disease', 'MESH:D002277', (52, 61))	('PD-L1', 'Gene', (86, 91))	('carcinoma', 'Disease', (133, 142))
425974	29192647	Triple-negative breast carcinomas (TNBC) and those with amplification of the human epidermal growth factor receptor-2 (HER-2) oncogene appear to be more immunogenic than luminal type, or estrogen receptor (ER) positive, breast carcinomas, both on the basis of higher degree of tumor-infiltrating lymphocytes and increased immune gene signatures in the former tumor types.	('immune gene signatures', 'MPA', (322, 344))	('HER-2', 'Gene', '2064', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (277, 282))	('HER-2', 'Gene', (119, 124))	('ER', 'Gene', '2099', (206, 208))	('carcinoma', 'Phenotype', 'HP:0030731', (23, 32))	('tumor', 'Disease', (359, 364))	('increased', 'PosReg', (312, 321))	('estrogen receptor', 'Gene', (187, 204))	('immunogenic', 'CPA', (153, 164))	('epidermal growth factor receptor-2', 'Gene', (83, 117))	('breast carcinomas', 'Disease', 'MESH:D001943', (16, 33))	('breast carcinomas', 'Disease', (16, 33))	('epidermal growth factor receptor-2', 'Gene', '2064', (83, 117))	('tumor', 'Disease', 'MESH:D009369', (359, 364))	('breast carcinomas', 'Disease', 'MESH:D001943', (220, 237))	('breast carcinomas', 'Disease', (220, 237))	('breast carcinoma', 'Phenotype', 'HP:0003002', (16, 32))	('more', 'PosReg', (148, 152))	('tumor', 'Disease', (277, 282))	('carcinomas', 'Phenotype', 'HP:0030731', (23, 33))	('amplification', 'Var', (56, 69))	('human', 'Species', '9606', (77, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (227, 236))	('carcinomas', 'Phenotype', 'HP:0030731', (227, 237))	('breast carcinomas', 'Phenotype', 'HP:0003002', (16, 33))	('tumor', 'Phenotype', 'HP:0002664', (359, 364))	('tumor', 'Disease', 'MESH:D009369', (277, 282))	('breast carcinomas', 'Phenotype', 'HP:0003002', (220, 237))	('ER', 'Gene', '2099', (120, 122))	('estrogen receptor', 'Gene', '2099', (187, 204))	('breast carcinoma', 'Phenotype', 'HP:0003002', (220, 236))
426079	32570879	Rare Tumor-Normal Matched Whole Exome Sequencing Identifies Novel Genomic Pathogenic Germline and Somatic Aberrations Whole exome sequencing (WES) of matched tumor-normal pairs in rare tumors has the potential to identify genome-wide mutations and copy number alterations (CNAs).	('tumor', 'Disease', (185, 190))	('tumor', 'Disease', (158, 163))	('tumors', 'Disease', (185, 191))	('tumors', 'Phenotype', 'HP:0002664', (185, 191))	('identify', 'Reg', (213, 221))	('copy number alterations', 'Var', (248, 271))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('tumors', 'Disease', 'MESH:D009369', (185, 191))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('Tumor', 'Phenotype', 'HP:0002664', (5, 10))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('mutations', 'Var', (234, 243))
426081	32570879	Our goal was to: 1) identify known and novel variants and CNAs in rare cancers with comparison to common cancers; 2) examine differences between germline and somatic variants and how that functionally impacts rare tumors; 3) detect and characterize alleles in biologically relevant genes-pathways that may be of clinical importance but not represented in classical cancer genes.	('cancers', 'Phenotype', 'HP:0002664', (105, 112))	('cancer', 'Disease', (105, 111))	('cancers', 'Disease', (105, 112))	('genes-pathways', 'Pathway', (282, 296))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('tumors', 'Disease', (214, 220))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('impacts', 'Reg', (201, 208))	('cancer', 'Disease', (365, 371))	('cancers', 'Phenotype', 'HP:0002664', (71, 78))	('cancers', 'Disease', (71, 78))	('cancer', 'Disease', (71, 77))	('cancer', 'Phenotype', 'HP:0002664', (365, 371))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('tumors', 'Disease', 'MESH:D009369', (214, 220))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('cancers', 'Disease', 'MESH:D009369', (105, 112))	('cancer', 'Disease', 'MESH:D009369', (365, 371))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('cancers', 'Disease', 'MESH:D009369', (71, 78))	('variants', 'Var', (45, 53))	('tumors', 'Phenotype', 'HP:0002664', (214, 220))
426082	32570879	We identified 3343 germline single nucleotide variants (SNVs) and small indel variants:1670 in oncogenes and 1673 in tumor suppressor genes:generating an average of 124 germline variants/case.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('variants:1670', 'Var', (78, 91))	('tumor', 'Disease', (117, 122))	('single nucleotide variants', 'Var', (28, 54))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
426086	32570879	Genomic analysis of tumors has dramatically reshaped cancer treatment through the identification of genetic variants that provide diagnostic and prognostic information and that aid in therapeutic selection.	('tumors', 'Disease', (20, 26))	('tumors', 'Disease', 'MESH:D009369', (20, 26))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('aid', 'Gene', '57379', (177, 180))	('variants', 'Var', (108, 116))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('aid', 'Gene', (177, 180))	('reshaped', 'Reg', (44, 52))
426093	32570879	A recent precision medicine study focused on molecular characterization of rare cancers identified actionable variants over 92% of the time, with 52% receiving a matched therapy.	('cancers', 'Disease', 'MESH:D009369', (80, 87))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancers', 'Disease', (80, 87))	('variants', 'Var', (110, 118))	('cancers', 'Phenotype', 'HP:0002664', (80, 87))
426106	32570879	Variants were then further categorized as either a passenger mutation or a functional driver mutation using the Cancer Genome Interpreter tool .	('Cancer', 'Phenotype', 'HP:0002664', (112, 118))	('Variants', 'Var', (0, 8))	('Cancer', 'Disease', 'MESH:D009369', (112, 118))	('Cancer', 'Disease', (112, 118))
426107	32570879	From germline variants found to be in cancer predisposition genes, six (all heterozygous) were identified to be pathogenic or likely pathogenic by the more stringent ACMG guidelines: BRCA2-Q2859Kfs (gray zone lymphoma), SDHA-R75* (spindle cell breast cancer), SDHC-A3Rfs (gastrointestinal stromal tumor), RUNX1-M151L (glioblastoma), FANCC-c.456+4A>T splice site/exon skipping (anaplastic astrocytoma), and MUTYH-G396D (alveolar soft part sarcoma) (Table 2).	('R75*', 'Var', (225, 229))	('FANCC', 'Gene', '2176', (333, 338))	('cell breast cancer', 'Disease', 'MESH:D001943', (239, 257))	('gastrointestinal stromal tumor', 'Phenotype', 'HP:0100723', (272, 302))	('breast cancer', 'Phenotype', 'HP:0003002', (244, 257))	('lymphoma', 'Phenotype', 'HP:0002665', (209, 217))	('cancer', 'Disease', 'MESH:D009369', (251, 257))	('sarcoma', 'Phenotype', 'HP:0100242', (438, 445))	('MUTYH', 'Gene', '4595', (406, 411))	('R75*', 'SUBSTITUTION', 'None', (225, 229))	('gastrointestinal stromal tumor', 'Disease', 'MESH:D046152', (272, 302))	('SDHC', 'Gene', (260, 264))	('BRCA2', 'Gene', (183, 188))	('anaplastic astrocytoma', 'Disease', 'MESH:D001254', (377, 399))	('c.456+4A>T', 'Mutation', 'rs104886456', (339, 349))	('FANCC', 'Gene', (333, 338))	('RUNX1', 'Gene', (305, 310))	('RUNX1', 'Gene', '861', (305, 310))	('cancer', 'Disease', (38, 44))	('gastrointestinal stromal tumor', 'Disease', (272, 302))	('M151L', 'Mutation', 'p.M151L', (311, 316))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('astrocytoma', 'Phenotype', 'HP:0009592', (388, 399))	('lymphoma', 'Disease', (209, 217))	('SDHA', 'Gene', (220, 224))	('glioblastoma', 'Disease', 'MESH:D005909', (318, 330))	('lymphoma', 'Disease', 'MESH:D008223', (209, 217))	('BRCA2', 'Gene', '675', (183, 188))	('G396D', 'Mutation', 'rs36053993', (412, 417))	('tumor', 'Phenotype', 'HP:0002664', (297, 302))	('cancer', 'Disease', (251, 257))	('cell breast cancer', 'Disease', (239, 257))	('SDHA', 'Gene', '6389', (220, 224))	('glioblastoma', 'Disease', (318, 330))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('variants', 'Var', (14, 22))	('SDHC', 'Gene', '6391', (260, 264))	('sarcoma', 'Disease', 'MESH:D012509', (438, 445))	('alveolar soft part sarcoma', 'Phenotype', 'HP:0012218', (419, 445))	('glioblastoma', 'Phenotype', 'HP:0012174', (318, 330))	('soft part sarcoma', 'Phenotype', 'HP:0030448', (428, 445))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('sarcoma', 'Disease', (438, 445))	('MUTYH', 'Gene', (406, 411))	('anaplastic astrocytoma', 'Disease', (377, 399))
426111	32570879	Interestingly the SPEN-Q3621* nonsense variant that was identified in this tumor likely truncates the protein product (a hormone inducible transcriptional repressor), resulting in loss of a portion of a domain that is necessary for interactions with other nuclear co-repressors.	('interactions', 'Interaction', (232, 244))	('domain', 'MPA', (203, 209))	('Q3621*', 'SUBSTITUTION', 'None', (23, 29))	('loss', 'NegReg', (180, 184))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('SPEN', 'Gene', '23013', (18, 22))	('truncates', 'NegReg', (88, 97))	('protein product', 'MPA', (102, 117))	('Q3621*', 'Var', (23, 29))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('SPEN', 'Gene', (18, 22))	('tumor', 'Disease', (75, 80))
426112	32570879	While SPEN mutations are reported in 8% (8/97) of MCC samples in COSMIC, this variant is not functionally characterized and its effect on protein function is unknown.	('SPEN', 'Gene', (6, 10))	('amp', 'Chemical', 'MESH:D000249', (55, 58))	('SPEN', 'Gene', '23013', (6, 10))	('mutations', 'Var', (11, 20))
426113	32570879	Actionable variants found in the patient cohort were classified in the four categories: FDA-approved for rare cancer type, FDA-approved for different cancer type, clinical trial for rare cancer type, clinical trial for different cancer type.	('cancer', 'Disease', 'MESH:D009369', (187, 193))	('cancer', 'Disease', (110, 116))	('patient', 'Species', '9606', (33, 40))	('cancer', 'Disease', (187, 193))	('cancer', 'Disease', (229, 235))	('variants', 'Var', (11, 19))	('cancer', 'Disease', 'MESH:D009369', (229, 235))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('cancer', 'Disease', (150, 156))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
426115	32570879	In fact, only one patient had a variant with an FDA approved therapy, and three had a variant with a clinical trial for their tumor type (Figure 2).	('variant', 'Var', (32, 39))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('patient', 'Species', '9606', (18, 25))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumor', 'Disease', (126, 131))
426118	32570879	When comparing our WES tumor/germline with tumor only analysis, there was general concordance in the classification of known pathogenic variants and VUS.	('variants', 'Var', (136, 144))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Disease', (23, 28))	('tumor', 'Disease', (43, 48))
426119	32570879	However, while most of the pathogenic/likely pathogenic variants where found to be somatic using both assays, the vast majority (~80%) of the clinically reported VUS turn out to be inherited when using the tumor/germline analysis (Figure 3).	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('VUS', 'Disease', (162, 165))	('tumor', 'Disease', (206, 211))	('variants', 'Var', (56, 64))	('tumor', 'Disease', 'MESH:D009369', (206, 211))
426121	32570879	Additionally, our tumor/germline approach identified a single pathogenic variant that turned out to be germline in origin.	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('variant', 'Var', (73, 80))	('tumor', 'Disease', (18, 23))
426122	32570879	This frameshift variant (A3fs) in the C subunit of the succinate dehydrogenase (SDH) gene was found in a patient with gastrointestinal stromal tumor (GIST).	('found', 'Reg', (94, 99))	('patient', 'Species', '9606', (105, 112))	('gastrointestinal stromal tumor', 'Disease', (118, 148))	('A3fs', 'Var', (25, 29))	('succinate dehydrogenase', 'Gene', '6390', (55, 78))	('gastrointestinal stromal tumor', 'Disease', 'MESH:D046152', (118, 148))	('SDH', 'Gene', '6390', (80, 83))	('A3fs', 'FRAMESHIFT', 'None', (25, 29))	('succinate dehydrogenase', 'Gene', (55, 78))	('SDH', 'Gene', (80, 83))	('gastrointestinal stromal tumor', 'Phenotype', 'HP:0100723', (118, 148))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
426126	32570879	The percentage of cases harboring an inherited pathogenic variant appears to differ between rare vs. common (i.e., lung, breast, colon, rectal, and prostate) cancers (Table 3).	('breast', 'Disease', (121, 127))	('cancers', 'Phenotype', 'HP:0002664', (158, 165))	('cancers', 'Disease', (158, 165))	('lung', 'Disease', (115, 119))	('cancers', 'Disease', 'MESH:D009369', (158, 165))	('variant', 'Var', (58, 65))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('colon', 'Disease', (129, 134))	('rectal', 'Disease', (136, 142))
426128	32570879	In contrast, common cancers taken from 3451 combined cases in TCGA, showed 7.9% of variants as germline pathogenic or likely pathogenic.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('variants', 'Var', (83, 91))	('cancers', 'Phenotype', 'HP:0002664', (20, 27))	('cancers', 'Disease', (20, 27))	('cancers', 'Disease', 'MESH:D009369', (20, 27))
426129	32570879	This increased rate of inherited pathogenic variants in rare cancer was found to be statistically significant using the Fisher exact test (p = 0.01800).	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('variants', 'Var', (44, 52))	('cancer', 'Disease', (61, 67))	('cancer', 'Disease', 'MESH:D009369', (61, 67))
426131	32570879	There is a consistent yet slight increase in the overall percentage of germline variants detected in rare tumors in our cohort when compared to the other rare tumor cohorts (Table 4).	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('tumors', 'Disease', (106, 112))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('increase', 'PosReg', (33, 41))	('tumor', 'Disease', (159, 164))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('germline variants', 'Var', (71, 88))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('tumor', 'Disease', (106, 111))
426132	32570879	Copy number analysis (CNA) performed using Sequenza on all WES cases and analyzed using the GISTIC2 pipeline, produced a heatmap of the overall amplification and deletion scores across all chromosomes to compare cases (Figure 4A).	('deletion', 'Var', (162, 170))	('amplification', 'MPA', (144, 157))	('amp', 'Chemical', 'MESH:D000249', (144, 147))
426134	32570879	As shown the total number of amplified oncogenes and deletions of tumor suppressor genes in our cohort was widely variable from case to case (Table S4).	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('deletions', 'Var', (53, 62))	('amp', 'Chemical', 'MESH:D000249', (29, 32))	('tumor', 'Disease', (66, 71))	('tumor', 'Disease', 'MESH:D009369', (66, 71))
426135	32570879	Nine of the 27 cases contained at least one amplification of an oncogenic gene or loss of a TSG.	('oncogenic gene', 'Gene', (64, 78))	('amp', 'Chemical', 'MESH:D000249', (44, 47))	('amplification', 'Var', (44, 57))	('TSG', 'Gene', (92, 95))	('loss', 'NegReg', (82, 86))
426136	32570879	Of the cases containing amplification of oncogenic genes (~50% cases), the average was eight oncogenes/case (min 3, max 56).	('amplification', 'Var', (24, 37))	('min 3', 'Gene', '966', (109, 114))	('min 3', 'Gene', (109, 114))	('amp', 'Chemical', 'MESH:D000249', (24, 27))	('oncogenic genes', 'Gene', (41, 56))
426144	32570879	We used the TCGA containing 3149 common and 2120 rare cancers showed amplifications are more prevalent than deletions: rare (2.25-fold) and common cancers (3-fold) (Figure S1A).	('cancers', 'Phenotype', 'HP:0002664', (54, 61))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('cancers', 'Disease', (54, 61))	('cancers', 'Disease', 'MESH:D009369', (54, 61))	('cancers', 'Disease', 'MESH:D009369', (147, 154))	('cancers', 'Phenotype', 'HP:0002664', (147, 154))	('amplifications', 'Var', (69, 83))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('cancers', 'Disease', (147, 154))	('amp', 'Chemical', 'MESH:D000249', (69, 72))
426145	32570879	Common cancers have an overall greater number of amplifications (2.8-fold) and deletions (2.2-fold) than rare cancers.	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('cancers', 'Disease', (110, 117))	('amplifications', 'MPA', (49, 63))	('deletions', 'Var', (79, 88))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('cancers', 'Disease', 'MESH:D009369', (7, 14))	('cancers', 'Phenotype', 'HP:0002664', (7, 14))	('cancers', 'Disease', (7, 14))	('cancers', 'Phenotype', 'HP:0002664', (110, 117))	('amp', 'Chemical', 'MESH:D000249', (49, 52))	('cancers', 'Disease', 'MESH:D009369', (110, 117))
426146	32570879	When this analysis is limited only to per sample amplifications of oncogenes and deletions of tumor suppressor genes, the same trend is seen (Figure S1B,C).	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('deletions', 'Var', (81, 90))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('amp', 'Chemical', 'MESH:D000249', (43, 46))	('tumor', 'Disease', (94, 99))	('amp', 'Chemical', 'MESH:D000249', (49, 52))
426147	32570879	Whether these differences could be attributed to a specific cancer type, we graphed the total number of amplifications and deletions per sample for all protein coding genes across all of the rare and common cancer types individually (Figure S2A).	('cancer', 'Disease', 'MESH:D009369', (207, 213))	('cancer', 'Disease', (207, 213))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('deletions', 'Var', (123, 132))	('cancer', 'Disease', (60, 66))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('amp', 'Chemical', 'MESH:D000249', (104, 107))	('amp', 'Chemical', 'MESH:D000249', (138, 141))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
426148	32570879	To determine the alteration frequencies of pathways known to be involved in cancer, we mapped all variants to genes in 11 canonical signaling pathways.	('canonical signaling pathways', 'Pathway', (122, 150))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('variants', 'Var', (98, 106))
426152	32570879	Interestingly, all 27 cases had germline variants detected in the RTK-RAS pathway key to cell survival (CS) (101 total variants), Hippo (138) and Notch pathways (238), and 24 of 27 cases showed a variant in the WNT pathway (75 total) which, excluding the RTK-RAS pathway, are all largely comprised of TSGs.	('variants', 'Var', (41, 49))	('Hippo', 'Pathway', (130, 135))	('Notch', 'Gene', (146, 151))	('detected', 'Reg', (50, 58))	('WNT pathway', 'Pathway', (211, 222))	('variant', 'Var', (196, 203))	('RTK-RAS pathway', 'Pathway', (66, 81))	('variants', 'Var', (119, 127))	('Notch', 'Gene', '4853', (146, 151))
426153	32570879	When looking at somatic variants, 20 cases had at least one variant in the Notch pathway (36 total), while eight cases had a variant in the WNT pathway (11 total), both CF determinants.	('WNT pathway', 'Pathway', (140, 151))	('variant', 'Var', (60, 67))	('Notch', 'Gene', (75, 80))	('Notch', 'Gene', '4853', (75, 80))
426155	32570879	The number total of cases showing a predicted germline driver mutation was limited to 23, with (n = 5) cases each showing variants in WNT, Notch (n = 4) cases and each in RTK-RAS and TP53 (n = 3) in Hippo.	('variants', 'Var', (122, 130))	('WNT', 'Gene', (134, 137))	('TP53', 'Gene', '7157', (183, 187))	('Notch', 'Gene', '4853', (139, 144))	('TP53', 'Gene', (183, 187))	('RTK-RAS', 'Gene', (171, 178))	('Notch', 'Gene', (139, 144))
426156	32570879	Of the somatic variants, the predicted drivers clustered around the Notch and p53 pathways with four and five respectively, with one case showing a double hit in TP53.	('Notch', 'Gene', (68, 73))	('TP53', 'Gene', '7157', (162, 166))	('TP53', 'Gene', (162, 166))	('p53', 'Gene', (78, 81))	('Notch', 'Gene', '4853', (68, 73))	('variants', 'Var', (15, 23))	('p53', 'Gene', '7157', (78, 81))
426158	32570879	The most severe of these likely to have a functional effect was found in the anaplastic astrocytoma case, which saw both a driver mutation (rs149840192, p.A289V) and an amplification of at least five extra copies of the EGFR.	('rs149840192', 'Var', (140, 151))	('amp', 'Chemical', 'MESH:D000249', (169, 172))	('anaplastic astrocytoma', 'Disease', 'MESH:D001254', (77, 99))	('p.A289V', 'Mutation', 'rs149840192', (153, 160))	('EGFR', 'Gene', (220, 224))	('amplification', 'MPA', (169, 182))	('anaplastic astrocytoma', 'Disease', (77, 99))	('rs149840192', 'Mutation', 'rs149840192', (140, 151))	('EGFR', 'Gene', '1956', (220, 224))	('astrocytoma', 'Phenotype', 'HP:0009592', (88, 99))	('p.A289V', 'Var', (153, 160))
426159	32570879	This was of particular interest as both amplifications and mutations in EGFR have been shown to be drivers in many cancer types and may confer efficacy of treatment with tyrosine kinase inhibitors.	('cancer', 'Disease', (115, 121))	('amp', 'Chemical', 'MESH:D000249', (40, 43))	('EGFR', 'Gene', '1956', (72, 76))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('EGFR', 'Gene', (72, 76))	('confer', 'Reg', (136, 142))	('mutations', 'Var', (59, 68))	('drivers', 'Reg', (99, 106))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('efficacy', 'PosReg', (143, 151))	('amplifications', 'Var', (40, 54))
426160	32570879	With respect to TSG double hits we identified only one case, metastatic chondrosarcoma, that contained both a driver mutation and a CNA.	('chondrosarcoma', 'Disease', 'MESH:D002813', (72, 86))	('sarcoma', 'Phenotype', 'HP:0100242', (79, 86))	('chondrosarcoma', 'Disease', (72, 86))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (72, 86))	('mutation', 'Var', (117, 125))
426163	32570879	Tumor-only NGS fails to provide a complete picture since germline sequencing is absent which can generate false positive biomarkers, that may lead to targeting of a variant unrelated to cancer development and/or not be present on the panel.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('variant', 'Var', (165, 172))	('lead to', 'Reg', (142, 149))	('cancer', 'Disease', (186, 192))	('cancer', 'Disease', 'MESH:D009369', (186, 192))
426168	32570879	For example, in a patient with glioblastoma, tumor-normal match pair WES identified a germline variant RUNX1-M151L deemed likely pathogenic (ACMG guidelines) but not reported with tumor-only NGS (Caris Life Sciences) as it was not included in their panel.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('RUNX1', 'Gene', '861', (103, 108))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('variant', 'Var', (95, 102))	('tumor', 'Disease', (45, 50))	('tumor', 'Disease', (180, 185))	('glioblastoma', 'Disease', (31, 43))	('glioblastoma', 'Phenotype', 'HP:0012174', (31, 43))	('glioblastoma', 'Disease', 'MESH:D005909', (31, 43))	('patient', 'Species', '9606', (18, 25))	('pathogenic', 'Reg', (129, 139))	('amp', 'Chemical', 'MESH:D000249', (6, 9))	('M151L', 'Mutation', 'p.M151L', (109, 114))	('RUNX1', 'Gene', (103, 108))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
426170	32570879	Over-expression of RUNX1 in U87 GBM cells inhibited tumor growth by extensive down-regulation of target genes and deregulation of key developmental pathways.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('U87', 'Gene', '641648', (28, 31))	('RUNX1', 'Gene', (19, 24))	('tumor', 'Disease', (52, 57))	('RUNX1', 'Gene', '861', (19, 24))	('inhibited', 'NegReg', (42, 51))	('down-regulation', 'NegReg', (78, 93))	('deregulation', 'Reg', (114, 126))	('key developmental pathways', 'Pathway', (130, 156))	('Over-expression', 'Var', (0, 15))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('U87', 'Gene', (28, 31))
426174	32570879	We identified IDH1 and PIK3CA gene variants which occurred at the same site.	('PIK3CA', 'Gene', (23, 29))	('variants', 'Var', (35, 43))	('PIK3CA', 'Gene', '5290', (23, 29))	('IDH1', 'Gene', (14, 18))	('IDH1', 'Gene', '3417', (14, 18))
426175	32570879	The IDH1 variant occurred at amino acid 132 in the IDH1 gene in two sarcoma cases; chondrosarcoma R132C and pleiomorphic sarcoma R132G substitution respectively.	('IDH1', 'Gene', '3417', (51, 55))	('IDH1', 'Gene', '3417', (4, 8))	('sarcoma', 'Phenotype', 'HP:0100242', (121, 128))	('occurred', 'Reg', (17, 25))	('sarcoma', 'Disease', 'MESH:D012509', (68, 75))	('sarcoma', 'Disease', (68, 75))	('R132G', 'Mutation', 'rs121913499', (129, 134))	('sarcoma', 'Disease', 'MESH:D012509', (90, 97))	('R132G substitution', 'Var', (129, 147))	('chondrosarcoma', 'Disease', (83, 97))	('sarcoma', 'Disease', (90, 97))	('chondrosarcoma', 'Disease', 'MESH:D002813', (83, 97))	('IDH1', 'Gene', (4, 8))	('IDH1', 'Gene', (51, 55))	('sarcoma', 'Phenotype', 'HP:0100242', (68, 75))	('R132C', 'Mutation', 'rs121913499', (98, 103))	('sarcoma', 'Disease', 'MESH:D012509', (121, 128))	('pleiomorphic sarcoma', 'Disease', 'MESH:D012509', (108, 128))	('pleiomorphic sarcoma', 'Disease', (108, 128))	('sarcoma', 'Phenotype', 'HP:0100242', (90, 97))	('sarcoma', 'Disease', (121, 128))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (83, 97))
426176	32570879	The pleomorphic sarcoma with a concurrent IDH1 R132G mutation and a SUFU splice site mutation may indicate that the Hedgehog (Hh) pathway is operant in these cells independent of SHH ligand expression since SUFU is a negative regulator of Hh signaling.	('R132G', 'Mutation', 'rs121913499', (47, 52))	('SHH', 'Gene', (179, 182))	('IDH1', 'Gene', '3417', (42, 46))	('pleomorphic sarcoma', 'Disease', (4, 23))	('R132G', 'Var', (47, 52))	('sarcoma', 'Phenotype', 'HP:0100242', (16, 23))	('SHH', 'Gene', '6469', (179, 182))	('SUFU', 'Gene', (207, 211))	('IDH1', 'Gene', (42, 46))	('SUFU', 'Gene', '51684', (207, 211))	('SUFU', 'Gene', (68, 72))	('pleomorphic sarcoma', 'Disease', 'MESH:D012509', (4, 23))	('SUFU', 'Gene', '51684', (68, 72))
426177	32570879	Further, a frameshift mutation in SUFU was found in our metastatic mucoepidermoid sarcoma patient indicative of active Hh signaling amenable for therapeutic intervention.	('frameshift mutation', 'Var', (11, 30))	('SUFU', 'Gene', (34, 38))	('SUFU', 'Gene', '51684', (34, 38))	('sarcoma', 'Disease', 'MESH:D012509', (82, 89))	('patient', 'Species', '9606', (90, 97))	('sarcoma', 'Disease', (82, 89))	('sarcoma', 'Phenotype', 'HP:0100242', (82, 89))
426178	32570879	The mutant IDH1 makes it a highly promising candidate for the IDH1 small molecule inhibitor ivosidenib approved for AML.	('mutant', 'Var', (4, 10))	('IDH1', 'Gene', '3417', (11, 15))	('IDH1', 'Gene', '3417', (62, 66))	('AML', 'Disease', 'MESH:D015470', (116, 119))	('ivosidenib', 'Chemical', 'MESH:C000627630', (92, 102))	('IDH1', 'Gene', (62, 66))	('AML', 'Disease', (116, 119))	('IDH1', 'Gene', (11, 15))
426179	32570879	The PIK3CA variant occurred at amino acid E542K in two rare salivary gland tumors, myoepithelioma and mucoepidermoid tumor.	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('myoepithelioma', 'Disease', (83, 97))	('mucoepidermoid tumor', 'Disease', 'MESH:D018298', (102, 122))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('E542K', 'Mutation', 'rs121913273', (42, 47))	('PIK3CA', 'Gene', (4, 10))	('occurred', 'Reg', (19, 27))	('salivary gland tumors', 'Phenotype', 'HP:0100684', (60, 81))	('myoepithelioma', 'Disease', 'MESH:D009208', (83, 97))	('amino acid E542K', 'Var', (31, 47))	('PIK3CA', 'Gene', '5290', (4, 10))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('mucoepidermoid tumor', 'Disease', (102, 122))	('tumors', 'Disease', (75, 81))
426180	32570879	A concurrent HRAS mutation identified in salivary mucoepidermoid tumor patient will most likely not respond to a PI3KCA inhibitor, however, the myoepithelioma patient could benefit from off-label therapy.	('HRAS', 'Gene', (13, 17))	('myoepithelioma', 'Disease', 'MESH:D009208', (144, 158))	('mucoepidermoid tumor', 'Disease', (50, 70))	('mutation', 'Var', (18, 26))	('mucoepidermoid tumor', 'Disease', 'MESH:D018298', (50, 70))	('patient', 'Species', '9606', (159, 166))	('HRAS', 'Gene', '3265', (13, 17))	('myoepithelioma', 'Disease', (144, 158))	('patient', 'Species', '9606', (71, 78))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
426182	32570879	TP53 is the most common gene to carry pathogenic variants in common cancers with an average of 44.4%.	('TP53', 'Gene', '7157', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('TP53', 'Gene', (0, 4))	('variants', 'Var', (49, 57))	('cancers', 'Phenotype', 'HP:0002664', (68, 75))	('cancers', 'Disease', (68, 75))	('cancers', 'Disease', 'MESH:D009369', (68, 75))	('pathogenic', 'Reg', (38, 48))
426185	32570879	Both ARID1A and CDKN2A mutations are context dependent tumor suppressor genes that may be targetable in a synthetic lethal pair such as with a EGLN (prolyl hydroxylase) inhibitor (targeting HIF1alpha) or MTAP deletions with a PRMT5 (arginine N-methyltransferase 5) inhibitor dependent tumors respectively.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('ARID1A', 'Gene', (5, 11))	('PRMT5', 'Gene', (226, 231))	('tumors', 'Phenotype', 'HP:0002664', (285, 291))	('ARID1A', 'Gene', '8289', (5, 11))	('tumor', 'Phenotype', 'HP:0002664', (285, 290))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('deletions', 'Var', (209, 218))	('mutations', 'Var', (23, 32))	('tumors', 'Disease', (285, 291))	('HIF1alpha', 'Gene', '3091', (190, 199))	('CDKN2A', 'Gene', (16, 22))	('tumors', 'Disease', 'MESH:D009369', (285, 291))	('PRMT5', 'Gene', '10419', (226, 231))	('HIF1alpha', 'Gene', (190, 199))	('MTAP', 'Gene', (204, 208))	('CDKN2A', 'Gene', '1029', (16, 22))	('tumor', 'Disease', (285, 290))	('tumor', 'Disease', (55, 60))	('MTAP', 'Gene', '4507', (204, 208))	('tumor', 'Disease', 'MESH:D009369', (285, 290))
426188	32570879	FOXL2 mutations was found in Granulosa cell ovarian cancer case, ~5% of ovarian cancer, which functions as a DNA binding forkhead transcription factor required for granulosa cell differentiation.	('Granulosa cell ovarian cancer', 'Disease', 'MESH:D006106', (29, 58))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('ovarian cancer', 'Disease', 'MESH:D010051', (44, 58))	('ovarian cancer', 'Phenotype', 'HP:0100615', (44, 58))	('FOXL2', 'Gene', '668', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('ovarian cancer', 'Phenotype', 'HP:0100615', (72, 86))	('ovarian cancer', 'Disease', 'MESH:D010051', (72, 86))	('Granulosa cell ovarian cancer', 'Disease', (29, 58))	('found', 'Reg', (20, 25))	('FOXL2', 'Gene', (0, 5))	('ovarian cancer', 'Disease', (72, 86))	('mutations', 'Var', (6, 15))
426189	32570879	The Cys134Trp mutation in FOXL2 is associated increased cell cycling and downregulation of genes associated with apoptosis.	('cell cycling', 'CPA', (56, 68))	('FOXL2', 'Gene', '668', (26, 31))	('Cys134Trp', 'Chemical', '-', (4, 13))	('increased', 'PosReg', (46, 55))	('Cys134Trp', 'Var', (4, 13))	('FOXL2', 'Gene', (26, 31))	('downregulation', 'NegReg', (73, 87))
426190	32570879	The tumor suppressor-oncogene pair TNFAIP3 and CHD1L both have a frameshift deletion respectively is found in our gray zone lymphoma patient.	('CHD1L', 'Gene', (47, 52))	('tumor', 'Disease', (4, 9))	('frameshift deletion', 'Var', (65, 84))	('CHD1L', 'Gene', '9557', (47, 52))	('TNFAIP3', 'Gene', (35, 42))	('lymphoma', 'Disease', 'MESH:D008223', (124, 132))	('patient', 'Species', '9606', (133, 140))	('lymphoma', 'Disease', (124, 132))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('TNFAIP3', 'Gene', '7128', (35, 42))	('lymphoma', 'Phenotype', 'HP:0002665', (124, 132))
426195	32570879	Oncogenic KIT mutations (e.g., non-frameshift deletions) are well established in GIST.	('non-frameshift deletions', 'Var', (31, 55))	('KIT', 'Gene', '3815', (10, 13))	('KIT', 'Gene', (10, 13))
426196	32570879	We are the first to document a concurrent loss of CTCF and a KIT activating mutation in GIST, however, in SDH-deficient GIST, CTCF may be epigenetically silenced.	('CTCF', 'Gene', (126, 130))	('CTCF', 'Gene', '10664', (50, 54))	('KIT', 'Gene', '3815', (61, 64))	('GIST', 'Gene', (88, 92))	('CTCF', 'Gene', '10664', (126, 130))	('CTCF', 'Gene', (50, 54))	('SDH-deficient GIST', 'Disease', 'MESH:D046152', (106, 124))	('KIT', 'Gene', (61, 64))	('SDH-deficient GIST', 'Disease', (106, 124))	('mutation', 'Var', (76, 84))	('loss', 'NegReg', (42, 46))
426197	32570879	Copy number alterations (CNAs) play a role in cancer type (e.g., breast, colorectal), tumor progression, overall prognosis, and response to therapy.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('cancer', 'Disease', (46, 52))	('tumor', 'Disease', (86, 91))	('breast', 'Disease', (65, 71))	('Copy number alterations', 'Var', (0, 23))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
426199	32570879	Deletion frequencies were generally lower in the rare tumor cohort with the exception of sarcomas, which showed a number of per-sample deletions (133/case) that was higher than any other rare tumor types and higher than all common cancers save prostate (180/case) (Figure S1B,C).	('tumor', 'Disease', (192, 197))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('cancers', 'Disease', 'MESH:D009369', (231, 238))	('cancers', 'Phenotype', 'HP:0002664', (231, 238))	('sarcomas', 'Disease', (89, 97))	('sarcomas', 'Disease', 'MESH:D012509', (89, 97))	('amp', 'Chemical', 'MESH:D000249', (129, 132))	('cancers', 'Disease', (231, 238))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('sarcoma', 'Phenotype', 'HP:0100242', (89, 96))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('deletions', 'Var', (135, 144))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('tumor', 'Disease', (54, 59))	('prostate', 'Disease', (244, 252))	('sarcomas', 'Phenotype', 'HP:0100242', (89, 97))
426202	32570879	Further, sarcomas showed an increased frequency of deletions of tumor suppressor genes (Figure S2C).	('tumor', 'Disease', (64, 69))	('sarcomas', 'Disease', 'MESH:D012509', (9, 17))	('deletions', 'Var', (51, 60))	('sarcomas', 'Phenotype', 'HP:0100242', (9, 17))	('sarcoma', 'Phenotype', 'HP:0100242', (9, 16))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('sarcomas', 'Disease', (9, 17))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
426207	32570879	This limitation did not allow us to assess many important questions concerning the overall stability of some genomic regions compared to others in rare cancer, any impacts of epigenetic regulation, etc.	('cancer', 'Disease', (152, 158))	('epigenetic regulation', 'Var', (175, 196))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))
426221	32570879	For MuTect2 results, variants were filtered based on the MuTect2-assigned filter flag, quality score, and read depth (FILTER = PASS, QUAL > 20 and DP > 20).	('DP > 20', 'Var', (147, 154))	('MuTect2-assigned', 'Gene', (57, 73))	('DP', 'Chemical', 'MESH:D004176', (147, 149))
426225	32570879	Using vcftools, the remaining variants were restricted to either known oncosignaling genes for pathway analysis or known oncogenes and tumor suppressor genes for the double hit analysis.	('variants', 'Var', (30, 38))	('tumor', 'Disease', (135, 140))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
426226	32570879	Mutations in these gene sets were assessed for driver status using the Cancer Genome Interpreter (CGI).	('Cancer', 'Disease', (71, 77))	('Mutations', 'Var', (0, 9))	('Cancer', 'Disease', 'MESH:D009369', (71, 77))	('Cancer', 'Phenotype', 'HP:0002664', (71, 77))
426227	32570879	Heat maps showing the frequency of amplifications/deletions in 2.5 Mbp windows along the chromosomes were generated using the R package chromoMap v0.2.	('Mbp', 'Gene', (67, 70))	('amp', 'Chemical', 'MESH:D000249', (35, 38))	('Mbp', 'Gene', '4155', (67, 70))	('amplifications/deletions', 'Var', (35, 59))
426236	32570879	The following are available online at , Figure S1: CNA gene counts from TCGA rare and common cancer cohorts; Figure S2: CNA gene counts from TCGA rare and common cancer cohorts, broken down by cancer type; Table S1: 1670 were found in oncogenes and 1673 were in tumor suppressor genes, generating an average of 124 germline variants per case; Table S2: The number of somatic SNVs and small indels detected in all cases totaled 523, with 306 in oncogenes and 217 in tumor suppressor genes; Table S3: Classification of oncogenic genes (OG) and tumor suppressor genes (TSG) was defined by the Oncogene; Table S4: Total number of amplified oncogenes and deletions of tumor suppressor genes in the cohort rare cancer cases; Table S5: Drivers genes with additional copy number variation:Double Hits; Table S6: GO Enrichment analysis.	('tumor', 'Phenotype', 'HP:0002664', (262, 267))	('tumor', 'Disease', (663, 668))	('cancer', 'Disease', (162, 168))	('cancer', 'Disease', (193, 199))	('tumor', 'Disease', 'MESH:D009369', (465, 470))	('broken down', 'Phenotype', 'HP:0001061', (178, 189))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('broken', 'Disease', (178, 184))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('tumor', 'Disease', 'MESH:D009369', (663, 668))	('broken', 'Disease', 'MESH:D050723', (178, 184))	('tumor', 'Disease', (542, 547))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('tumor', 'Disease', 'MESH:D009369', (542, 547))	('tumor', 'Phenotype', 'HP:0002664', (465, 470))	('cancer', 'Disease', (705, 711))	('tumor', 'Phenotype', 'HP:0002664', (663, 668))	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('tumor', 'Disease', (262, 267))	('cancer', 'Phenotype', 'HP:0002664', (705, 711))	('tumor', 'Phenotype', 'HP:0002664', (542, 547))	('deletions', 'Var', (650, 659))	('tumor', 'Disease', 'MESH:D009369', (262, 267))	('amp', 'Chemical', 'MESH:D000249', (626, 629))	('cancer', 'Disease', (93, 99))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('tumor', 'Disease', (465, 470))	('cancer', 'Disease', 'MESH:D009369', (705, 711))
426319	31829526	Data on BRAF/MEK inhibitors are limited by the fact that fewer vulvar melanomas carry a BRAF mutation, but in those with a BRAF V600 mutation this provides a good option 52, 67.	('MEK', 'Gene', '5609', (13, 16))	('BRAF', 'Gene', '673', (8, 12))	('BRAF', 'Gene', (88, 92))	('BRAF', 'Gene', '673', (88, 92))	('BRAF', 'Gene', (8, 12))	('melanomas', 'Phenotype', 'HP:0002861', (70, 79))	('BRAF', 'Gene', (123, 127))	('V600 mutation', 'Var', (128, 141))	('BRAF', 'Gene', '673', (123, 127))	('vulvar melanomas', 'Phenotype', 'HP:0030418', (63, 79))	('vulvar melanomas', 'Disease', 'MESH:D008545', (63, 79))	('vulvar melanoma', 'Phenotype', 'HP:0030418', (63, 78))	('vulvar melanomas', 'Disease', (63, 79))	('mutation', 'Var', (93, 101))	('melanoma', 'Phenotype', 'HP:0002861', (70, 78))	('MEK', 'Gene', (13, 16))
426320	31829526	Due to the relatively high number of KIT mutations in vulvovaginal melanoma, tyrosine kinase inhibitors may be a treatment option in the future.	('mutations', 'Var', (41, 50))	('KIT', 'Gene', '3815', (37, 40))	('vulvovaginal melanoma', 'Disease', 'MESH:D014848', (54, 75))	('melanoma', 'Phenotype', 'HP:0002861', (67, 75))	('tyrosine', 'Chemical', 'None', (77, 85))	('vulvovaginal melanoma', 'Phenotype', 'HP:0030418', (54, 75))	('KIT', 'Gene', (37, 40))	('vulvovaginal melanoma', 'Disease', (54, 75))
426412	30410599	High expression of CDK5 was associated with shorter overall survival (OS) in lung cancer.	('lung cancer', 'Phenotype', 'HP:0100526', (77, 88))	('overall survival', 'MPA', (52, 68))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('CDK5', 'Gene', (19, 23))	('OS', 'Chemical', '-', (70, 72))	('High', 'Var', (0, 4))	('lung cancer', 'Disease', 'MESH:D008175', (77, 88))	('shorter', 'NegReg', (44, 51))	('lung cancer', 'Disease', (77, 88))
426414	30410599	Inhibited CDK5 decreases CAP1 phosphorylation.	('CAP1', 'Gene', '10487', (25, 29))	('CAP1', 'Gene', (25, 29))	('decreases', 'NegReg', (15, 24))	('Inhibited', 'Var', (0, 9))	('CDK5', 'Protein', (10, 14))
426419	30410599	Deregulation of cell cycle is a fundamental process that underlies cancer proliferation.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('cancer', 'Disease', (67, 73))	('Deregulation', 'Var', (0, 12))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('cell cycle', 'CPA', (16, 26))
426446	30410599	The following primary antibodies were used by CAP1 (1:2000; Santa Cruz, USA), pCAP1 (1:500, donated by Professor Field), CDK5 (1:1000, Cell Signaling Technology, USA), beta-Actin (1:1000, Sigma, USA) and GAPDH (1:2000, Bioworld, USA).	('beta-Actin', 'Gene', '728378', (168, 178))	('CAP1', 'Gene', '10487', (79, 83))	('1:1000', 'Var', (180, 186))	('CAP1', 'Gene', '10487', (46, 50))	('CAP1', 'Gene', (79, 83))	('CAP1', 'Gene', (46, 50))	('beta-Actin', 'Gene', (168, 178))
426461	30410599	The result of analysis revealed that cancers with statistical significance regarding OS were lung, skin and blood cancers, the p-value was 0.000846, 0.004384, 0.001214 and 0.015104 respectively (Table 2).	('cancers', 'Disease', 'MESH:D009369', (114, 121))	('cancers', 'Phenotype', 'HP:0002664', (114, 121))	('cancers', 'Disease', (114, 121))	('cancers', 'Phenotype', 'HP:0002664', (37, 44))	('lung', 'Disease', (93, 97))	('0.004384', 'Var', (149, 157))	('cancers', 'Disease', (37, 44))	('0.015104', 'Var', (172, 180))	('cancers', 'Disease', 'MESH:D009369', (37, 44))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('skin', 'Disease', (99, 103))	('0.001214', 'Var', (159, 167))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('blood cancers', 'Disease', 'MESH:D009369', (108, 121))	('blood cancers', 'Phenotype', 'HP:0001909', (108, 121))	('blood cancers', 'Disease', (108, 121))	('OS', 'Chemical', '-', (85, 87))	('blood cancer', 'Phenotype', 'HP:0001909', (108, 120))
426474	30410599	Genetic alterations in cancer mainly include mutation, amplification, deletion and multiple alterations.	('deletion', 'Var', (70, 78))	('amplification', 'Var', (55, 68))	('cancer', 'Disease', (23, 29))	('cancer', 'Disease', 'MESH:D009369', (23, 29))	('mutation', 'Var', (45, 53))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))
426477	30410599	Five datasets including lung squamous cell carcinoma (lung squ), non-small cell lung cancer (NSCLC) and lung adenocarcinoma (lung adeno) samples showed gene alteration rates were varied from 5.7% to 7.9%.	('small cell lung cancer', 'Phenotype', 'HP:0030357', (69, 91))	('lung adeno', 'Phenotype', 'HP:0030078', (125, 135))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('NSCLC', 'Disease', 'MESH:D002289', (93, 98))	('non-small cell lung cancer', 'Disease', (65, 91))	('NSCLC', 'Disease', (93, 98))	('to 7', 'Species', '1214577', (196, 200))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (29, 52))	('lung cancer', 'Phenotype', 'HP:0100526', (80, 91))	('NSCLC', 'Phenotype', 'HP:0030358', (93, 98))	('lung adenocarcinoma', 'Disease', (104, 123))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (65, 91))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (24, 52))	('lung squamous cell carcinoma', 'Disease', (24, 52))	('gene alteration', 'Var', (152, 167))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (104, 123))	('lung adeno', 'Phenotype', 'HP:0030078', (104, 114))	('carcinoma', 'Phenotype', 'HP:0030731', (43, 52))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (65, 91))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (104, 123))
426488	30410599	Experiments showed that S2 interference effect was better than S1, without specific notification CDK5 siRNA means S2.MTT assay showed that after down-regulated the expression of CDK5 by CDK5 siRNA significantly inhibited the proliferation (Fig.7B, Fig.S1A).	('inhibited', 'NegReg', (211, 220))	('CDK5', 'Var', (186, 190))	('expression', 'MPA', (164, 174))	('down-regulated', 'NegReg', (145, 159))	('proliferation', 'CPA', (225, 238))	('MTT', 'Chemical', 'MESH:C070243', (117, 120))	('CDK5', 'Gene', (178, 182))
426492	30410599	A549 and PC9 cells were transfected with CDK5 siRNA or treated with CDK5 specific inhibitor roscovitine then performed transwell invasion and wound healing assay respectively in indicated time.	('roscovitine', 'Chemical', 'MESH:D000077546', (92, 103))	('A549', 'CellLine', 'CVCL:0023', (0, 4))	('wound healing assay', 'CPA', (142, 161))	('PC9', 'Gene', '255738', (9, 12))	('CDK5', 'Var', (41, 45))	('transwell invasion', 'CPA', (119, 137))	('PC9', 'Gene', (9, 12))	('performed', 'Reg', (109, 118))
426493	30410599	The results showed that transfected lung cancer cells by CDK5 siRNA will inhibit cells migration (Fig.8A, Fig.S2A).	('CDK5 siRNA', 'Var', (57, 67))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('cells migration', 'CPA', (81, 96))	('transfected lung cancer', 'Disease', (24, 47))	('inhibit', 'NegReg', (73, 80))	('lung cancer', 'Phenotype', 'HP:0100526', (36, 47))	('transfected lung cancer', 'Disease', 'MESH:D008175', (24, 47))
426495	30410599	Recent findings suggested CDK5 as a kinase that phosphorylates the S307/S309 regulatory site on cyclase-associated protein 1 (CAP1; H. Zhang & G.L.	('CAP1', 'Gene', '10487', (126, 130))	('CAP1', 'Gene', (126, 130))	('cyclase-associated protein 1', 'Gene', (96, 124))	('cyclase-associated protein 1', 'Gene', '10487', (96, 124))	('S307/S309', 'Var', (67, 76))
426497	30410599	We found that phosphorylated CAP1 (pCAP1) was decreased after treatment with CDK5 inhibitor roscovitine and knockdown CDK5 by siRNA in lung cancer cell (Fig.	('CDK5', 'Gene', (118, 122))	('roscovitine', 'Chemical', 'MESH:D000077546', (92, 103))	('knockdown', 'Var', (108, 117))	('CAP1', 'Gene', (29, 33))	('phosphorylated', 'MPA', (14, 28))	('lung cancer', 'Phenotype', 'HP:0100526', (135, 146))	('lung cancer', 'Disease', 'MESH:D008175', (135, 146))	('CAP1', 'Gene', '10487', (29, 33))	('decreased', 'NegReg', (46, 55))	('CAP1', 'Gene', '10487', (36, 40))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('lung cancer', 'Disease', (135, 146))	('CAP1', 'Gene', (36, 40))
426509	30410599	The inhibition or knockdown of CDK5 has been proven to play an anti-cancer role through various mechanisms, and can synergize the killing effect of chemotherapeutics.	('knockdown', 'Var', (18, 27))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('cancer', 'Disease', (68, 74))	('CDK5', 'Gene', (31, 35))	('inhibition', 'NegReg', (4, 14))
426516	30410599	found that copy number alterations (CNAs) uncover all gene expression, which could be a critical element in the tumor development.	('gene expression', 'MPA', (54, 69))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('copy number alterations', 'Var', (11, 34))	('uncover', 'Reg', (42, 49))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumor', 'Disease', (112, 117))
426517	30410599	The present study aimed to determine if the CNAs of the CDK5 correlate with aggressive cancer sub-types, based on the cBioPortal.	('aggressive cancer', 'Disease', 'MESH:D009369', (76, 93))	('correlate', 'Reg', (61, 70))	('aggressive cancer', 'Disease', (76, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('CNAs', 'Var', (44, 48))	('CDK5', 'Gene', (56, 60))
426518	30410599	The mutations alteration (2.8-3.4%) was the most common gene alteration in lung squamous cell carcinoma, while in lung adenocarcinoma patients amplifications (3.9%) were the most common gene alteration.	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (75, 103))	('lung squamous cell carcinoma', 'Disease', (75, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('lung adenocarcinoma', 'Disease', (114, 133))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (80, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (114, 133))	('patients', 'Species', '9606', (134, 142))	('lung adeno', 'Phenotype', 'HP:0030078', (114, 124))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (114, 133))	('mutations alteration', 'Var', (4, 24))
426530	30410599	In addition, we also found that knockdown of CDK5 inhibited lung cancer cells proliferation and migration (Fig.	('migration', 'CPA', (96, 105))	('lung cancer', 'Disease', (60, 71))	('lung cancer', 'Phenotype', 'HP:0100526', (60, 71))	('knockdown', 'Var', (32, 41))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('lung cancer', 'Disease', 'MESH:D008175', (60, 71))	('CDK5', 'Gene', (45, 49))	('inhibited', 'NegReg', (50, 59))
426538	30410599	found that there were 9 CAP1 phosphorylation sites; one of the phosphorylation sites S309 of CAP1 can recognize the sequence of CDKs (S/T-P-X-K/R/H).	('S309', 'Var', (85, 89))	('CAP1', 'Gene', '10487', (24, 28))	('CAP1', 'Gene', '10487', (93, 97))	('CAP1', 'Gene', (24, 28))	('CDKs', 'Gene', (128, 132))	('CDKs', 'Gene', '983;1020;12568;8621', (128, 132))	('CAP1', 'Gene', (93, 97))
426564	30221720	The dysregulation of lncRNAs has been demonstrated to have specific roles in a variety of cancer types, including bladder, prostate and kidney cancer.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('kidney cancer', 'Phenotype', 'HP:0009726', (136, 149))	('bladder', 'Disease', (114, 121))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('dysregulation', 'Var', (4, 17))	('lncRNAs', 'Protein', (21, 28))	('roles', 'Reg', (68, 73))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('cancer', 'Disease', (90, 96))	('prostate and kidney cancer', 'Disease', 'MESH:D011471', (123, 149))
426568	30221720	However, to the best of our knowledge, whether lncRNA FTH1P3 expression is dysregulated and involved in glioma development by sequestering miR-224-5p has not yet been reported.	('involved', 'Reg', (92, 100))	('si', 'Chemical', 'MESH:D012825', (67, 69))	('miR-224', 'Gene', '407009', (139, 146))	('miR-224', 'Gene', (139, 146))	('glioma', 'Disease', 'MESH:D005910', (104, 110))	('glioma', 'Phenotype', 'HP:0009733', (104, 110))	('FTH1P3', 'Gene', (54, 60))	('lncRNA', 'Var', (47, 53))	('FTH1P3', 'Gene', '2498', (54, 60))	('5p', 'Chemical', '-', (147, 149))	('glioma', 'Disease', (104, 110))
426628	30221720	2C, the results demonstrated that the expression of miR-224-5p was significantly increased by transfection with miR-224-5p mimic, indicating a high transfection efficiency (P<0.01).	('miR-224', 'Gene', '407009', (52, 59))	('si', 'Chemical', 'MESH:D012825', (67, 69))	('expression', 'MPA', (38, 48))	('5p', 'Chemical', '-', (120, 122))	('miR-224', 'Gene', (112, 119))	('5p', 'Chemical', '-', (60, 62))	('si', 'Chemical', 'MESH:D012825', (44, 46))	('miR-224', 'Gene', '407009', (112, 119))	('increased', 'PosReg', (81, 90))	('transfection', 'Var', (94, 106))	('miR-224', 'Gene', (52, 59))
426642	30221720	Finally, miR-224-5p mimic transfection significantly induced cellular apoptosis and increased the expression of BAX/BCL2 in U251 cells, which was significantly reversed following co-transfection of miR-224-5p and TPD52 (P<0.01; Fig.	('si', 'Chemical', 'MESH:D012825', (146, 148))	('transfection', 'Var', (26, 38))	('miR-224', 'Gene', '407009', (198, 205))	('miR-224', 'Gene', (198, 205))	('increased', 'PosReg', (84, 93))	('TPD52', 'Gene', '7163', (213, 218))	('si', 'Chemical', 'MESH:D012825', (104, 106))	('BCL2', 'Gene', (116, 120))	('BAX', 'Gene', (112, 115))	('si', 'Chemical', 'MESH:D012825', (39, 41))	('BAX', 'Gene', '581', (112, 115))	('induced', 'PosReg', (53, 60))	('5p', 'Chemical', '-', (17, 19))	('TPD52', 'Gene', (213, 218))	('si', 'Chemical', 'MESH:D012825', (76, 78))	('miR-224', 'Gene', '407009', (9, 16))	('miR-224', 'Gene', (9, 16))	('cellular apoptosis', 'CPA', (61, 79))	('U251', 'CellLine', 'CVCL:0021', (124, 128))	('BCL2', 'Gene', '596', (116, 120))	('5p', 'Chemical', '-', (206, 208))	('expression', 'MPA', (98, 108))
426651	30221720	Aberrant expression of miR-224 has been associated with the development of numerous cancer types.	('numerous cancer', 'Disease', 'MESH:D009369', (75, 90))	('Aberrant expression', 'Var', (0, 19))	('miR-224', 'Gene', '407009', (23, 30))	('si', 'Chemical', 'MESH:D012825', (15, 17))	('miR-224', 'Gene', (23, 30))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('numerous cancer', 'Disease', (75, 90))	('associated', 'Reg', (40, 50))
426654	30221720	In addition, dysregulation of miR-224-5p is correlated with cisplatin resistance in ovarian papillary serous carcinoma.	('miR-224', 'Gene', '407009', (30, 37))	('dysregulation', 'Var', (13, 26))	('miR-224', 'Gene', (30, 37))	('ovarian papillary serous carcinoma', 'Disease', 'MESH:D002291', (84, 118))	('correlated', 'Reg', (44, 54))	('cisplatin', 'Chemical', 'MESH:D002945', (60, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('ovarian papillary serous carcinoma', 'Disease', (84, 118))	('5p', 'Chemical', '-', (38, 40))	('si', 'Chemical', 'MESH:D012825', (72, 74))	('cisplatin resistance', 'MPA', (60, 80))
426687	27446358	Ezhkova et al reported that EZH2 regulates the proliferative capacity of epidermal progenitor cells by suppressing the Ink4A-Ink4B locus, and moderates their differentiation by preventing the early recruitment of the jun proto-oncogene transcriptional activator to the structural genes required for epidermal differentiation.	('regulates', 'Reg', (33, 42))	('EZH2', 'Var', (28, 32))	('differentiation', 'MPA', (158, 173))	('Ink4A', 'Gene', (119, 124))	('Ink4A', 'Gene', '1029', (119, 124))	('Ink4B', 'Gene', (125, 130))	('proliferative capacity', 'CPA', (47, 69))	('recruitment', 'MPA', (198, 209))	('preventing', 'NegReg', (177, 187))	('Ink4B', 'Gene', '1030', (125, 130))	('moderates', 'NegReg', (142, 151))	('suppressing', 'NegReg', (103, 114))
426746	27446358	In particular, the proliferative capacity of the transfected cells was significantly greater compared with the AMC-HN-8 cells between the fifth (P=0.012) to the seventh (P=0.004) of culture (Table II), suggesting that EZH2 overexpression enhanced the proliferative capacity of the AMC-HN-8 cells.	('proliferative capacity', 'CPA', (19, 41))	('transfected', 'Var', (49, 60))	('overexpression enhanced', 'PosReg', (223, 246))	('AMC-HN-8', 'CellLine', 'CVCL:5966', (111, 119))	('proliferative capacity', 'CPA', (251, 273))	('AMC-HN-8', 'CellLine', 'CVCL:5966', (281, 289))	('greater', 'PosReg', (85, 92))	('EZH2', 'Gene', (218, 222))
426751	27446358	The rate of inhibition of the growth of the transfected tumor cells was significantly decreased compared with the control AMC-HN-8 cells, and the statistical analysis showed that the rates were significantly different in the 3 microg/ml (P=0.027) and 6 microg/ml (P=0.006) groups (Table III).	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('AMC-HN-8', 'CellLine', 'CVCL:5966', (122, 130))	('inhibition', 'NegReg', (12, 22))	('tumor', 'Disease', (56, 61))	('decreased', 'NegReg', (86, 95))	('growth of', 'CPA', (30, 39))	('transfected', 'Var', (44, 55))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
426758	27446358	6C shows that the tumors derived from the EZH2-overexpressing cells were significantly larger compared with those derived from the AMC-HN-8 cells.	('larger', 'PosReg', (87, 93))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('tumors', 'Disease', (18, 24))	('AMC-HN-8', 'CellLine', 'CVCL:5966', (131, 139))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('EZH2-overexpressing', 'Var', (42, 61))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
426759	27446358	The mean tumor weight in the transfected group was greater compared with the AMC-HN-8 group, with values of 0.2157+-0.0256 and 0.0780+-0.0303 g for tumors derived from EZH2-overexpressing cells and the control AMC-HN-8 cells (P=0.001), respectively.	('0.0780+-0.0303 g', 'Var', (127, 143))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('AMC-HN-8', 'CellLine', 'CVCL:5966', (77, 85))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('AMC-HN-8', 'CellLine', 'CVCL:5966', (210, 218))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumor', 'Disease', (148, 153))	('greater', 'PosReg', (51, 58))	('tumor', 'Disease', (9, 14))	('tumors', 'Disease', (148, 154))	('tumors', 'Disease', 'MESH:D009369', (148, 154))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('tumor', 'Disease', 'MESH:D009369', (148, 153))
426767	27446358	Kidani et al reported that high-level EZH2 expression is associated with a poor prognosis of oral squamous cell cancers.	('oral squamous cell cancers', 'Disease', (93, 119))	('cancers', 'Phenotype', 'HP:0002664', (112, 119))	('high-level', 'Var', (27, 37))	('oral squamous cell cancers', 'Disease', 'MESH:D002294', (93, 119))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('EZH2', 'Gene', (38, 42))	('squamous cell cancers', 'Phenotype', 'HP:0002860', (98, 119))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (98, 118))
426781	27446358	In contrast, the knockdown of EZH2 expression suppresses the proliferation of cancer cells in numerous malignancy models, including prostate cancer, breast cancer and lymphoma.	('prostate cancer', 'Disease', (132, 147))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('breast cancer', 'Phenotype', 'HP:0003002', (149, 162))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('lymphoma', 'Phenotype', 'HP:0002665', (167, 175))	('breast cancer', 'Disease', 'MESH:D001943', (149, 162))	('proliferation', 'CPA', (61, 74))	('breast cancer', 'Disease', (149, 162))	('cancer', 'Disease', (141, 147))	('numerous malignancy', 'Disease', (94, 113))	('numerous malignancy', 'Disease', 'MESH:D009369', (94, 113))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('cancer', 'Disease', (78, 84))	('knockdown', 'Var', (17, 26))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('lymphoma', 'Disease', (167, 175))	('suppresses', 'NegReg', (46, 56))	('cancer', 'Disease', (156, 162))	('EZH2', 'Gene', (30, 34))	('lymphoma', 'Disease', 'MESH:D008223', (167, 175))	('prostate cancer', 'Disease', 'MESH:D011471', (132, 147))	('prostate cancer', 'Phenotype', 'HP:0012125', (132, 147))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('cancer', 'Disease', 'MESH:D009369', (141, 147))
426782	27446358	However, certain studies have reported that the knockdown of EZH2 and BMI1 expression does not prevent osteosarcoma cell proliferation.	('EZH2', 'Gene', (61, 65))	('osteosarcoma', 'Phenotype', 'HP:0002669', (103, 115))	('osteosarcoma', 'Disease', (103, 115))	('osteosarcoma', 'Disease', 'MESH:D012516', (103, 115))	('BMI1', 'Gene', '648', (70, 74))	('BMI1', 'Gene', (70, 74))	('knockdown', 'Var', (48, 57))
426796	27446358	Consistent with the results of previous studies, the present findings showed that EZH2 had a similar effect on the drug resistance of laryngeal squamous cancer cells, indicating that EZH2 can enhance the drug resistance of cancer cells.	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('enhance', 'PosReg', (192, 199))	('cancer', 'Disease', (153, 159))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('laryngeal squamous cancer', 'Phenotype', 'HP:0012118', (134, 159))	('squamous cancer', 'Phenotype', 'HP:0002860', (144, 159))	('laryngeal squamous cancer', 'Disease', (134, 159))	('drug resistance', 'CPA', (204, 219))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('drug', 'MPA', (115, 119))	('cancer', 'Disease', 'MESH:D009369', (223, 229))	('laryngeal squamous cancer', 'Disease', 'MESH:D007822', (134, 159))	('drug resistance', 'Phenotype', 'HP:0020174', (115, 130))	('drug resistance', 'Phenotype', 'HP:0020174', (204, 219))	('cancer', 'Disease', (223, 229))	('EZH2', 'Var', (183, 187))
426802	27446358	Thus, EZH2 could increase the invasive ability of laryngeal cancer cells, and high-level expression may result in a poor outcome for laryngeal cancer patients.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('laryngeal cancer', 'Disease', 'MESH:D007822', (50, 66))	('laryngeal cancer', 'Disease', (50, 66))	('laryngeal cancer', 'Disease', 'MESH:D007822', (133, 149))	('laryngeal cancer', 'Phenotype', 'HP:0012118', (50, 66))	('patients', 'Species', '9606', (150, 158))	('result', 'Reg', (104, 110))	('increase', 'PosReg', (17, 25))	('laryngeal cancer', 'Disease', (133, 149))	('EZH2', 'Var', (6, 10))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('laryngeal cancer', 'Phenotype', 'HP:0012118', (133, 149))
426812	25580324	A 55-year-old male presenting with progressive dyspnea and hoarseness was found to have Stage IVA T4aN2cM0 laryngeal cancer and eventually underwent total laryngectomy.	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('dyspnea', 'Phenotype', 'HP:0002094', (47, 54))	('hoarseness', 'Disease', (59, 69))	('laryngeal cancer', 'Disease', (107, 123))	('laryngeal cancer', 'Phenotype', 'HP:0012118', (107, 123))	('IVA', 'Disease', (94, 97))	('dyspnea', 'Disease', (47, 54))	('T4aN2cM0', 'Var', (98, 106))	('IVA', 'Disease', 'MESH:C538167', (94, 97))	('hoarseness', 'Phenotype', 'HP:0001609', (59, 69))	('dyspnea', 'Disease', 'MESH:D004417', (47, 54))	('laryngeal cancer', 'Disease', 'MESH:D007822', (107, 123))
426864	25013497	Upon admission, the patient was diagnosed with poorly-differentiated T2N2M0 squamous cell carcinoma of the nasopharynx, secondary pulmonary tuberculosis (type III), and gout.	('pulmonary tuberculosis', 'Disease', (130, 152))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (76, 99))	('gout', 'Disease', (169, 173))	('squamous cell carcinoma', 'Disease', (76, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (76, 99))	('T2N2M0', 'Var', (69, 75))	('pulmonary tuberculosis', 'Disease', 'MESH:D014397', (130, 152))	('patient', 'Species', '9606', (20, 27))	('gout', 'Disease', 'MESH:D006073', (169, 173))	('pulmonary tuberculosis', 'Phenotype', 'HP:0032262', (130, 152))	('gout', 'Phenotype', 'HP:0001997', (169, 173))
426898	25013497	A number of clinical trials have demonstrated that cisplatin can enhance radiosensitivity.	('enhance radiosensitivity', 'Phenotype', 'HP:0010997', (65, 89))	('radiosensitivity', 'CPA', (73, 89))	('cisplatin', 'Chemical', 'MESH:D002945', (51, 60))	('enhance', 'PosReg', (65, 72))	('cisplatin', 'Var', (51, 60))
426927	31625289	CD137L mRNA was widely expressed in lung cancer cell lines whereas levels of protein expression were generally low.	('lung cancer', 'Disease', (36, 47))	('CD137L', 'Var', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('lung cancer', 'Disease', 'MESH:D008175', (36, 47))	('lung cancer', 'Phenotype', 'HP:0100526', (36, 47))
426934	31625289	CD137, a representative costimulatory molecule belong to TNF-receptor superfamily, is an important target for tumor immunotherapy.20 Its gene expression is inducible in activated T cells.21 In early reports, monoclonal antibodies (mAbs) against CD137 have been shown to preferentially induce CD8 T cell proliferation compared to CD4 T cells and to eradicate established tumors in a mouse model.21, 22 Stimulating CD137 in vivo was found to alter the trafficking of CD8+ T lymphocytes and elevate the production of IFN-gamma and TNF-alpha.	('CD8', 'Gene', (465, 468))	('tumor', 'Disease', 'MESH:D009369', (370, 375))	('CD8', 'Gene', '925', (292, 295))	('alter', 'Reg', (440, 445))	('model.21', 'Var', (388, 396))	('TNF', 'Gene', '7124', (528, 531))	('tumors', 'Phenotype', 'HP:0002664', (370, 376))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Phenotype', 'HP:0002664', (370, 375))	('TNF', 'Gene', (57, 60))	('tumors', 'Disease', (370, 376))	('trafficking', 'MPA', (450, 461))	('Stimulating', 'PosReg', (401, 412))	('CD8', 'Gene', '925', (465, 468))	('CD8', 'Gene', (292, 295))	('elevate', 'PosReg', (488, 495))	('tumors', 'Disease', 'MESH:D009369', (370, 376))	('TNF', 'Gene', '7124', (57, 60))	('CD137', 'Gene', (413, 418))	('production of IFN-gamma', 'MPA', (500, 523))	('mouse', 'Species', '10090', (382, 387))	('tumor', 'Disease', (110, 115))	('TNF', 'Gene', (528, 531))	('tumor', 'Disease', (370, 375))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
426986	31625289	Cocultures of HCC-827 cells with T cells supplemented with anti-CD3 mAb induced significant increases in the levels of IFN-gamma (28.65 +- 4.41 pg/mL) (P < 0.05) compared to absence of anti-CD3 mAb or HCC-827.	('levels of IFN-gamma', 'MPA', (109, 128))	('anti-CD3', 'Var', (59, 67))	('HCC-827', 'CellLine', 'CVCL:2063', (14, 21))	('HCC-827', 'CellLine', 'CVCL:2063', (201, 208))	('increases', 'PosReg', (92, 101))
426987	31625289	In the presence of anti-CD137 mAb and anti-CD3 mAb, T cells cocultured with HCC-827 cells produced extremely low levels of IFN-gamma (3.52 +- 0.71 pg/mL) (P < 0.05) (Fig 5(a)).	('HCC-827', 'CellLine', 'CVCL:2063', (76, 83))	('anti-CD3', 'Var', (38, 46))	('anti-CD137', 'Var', (19, 29))
426988	31625289	Flow cytometry analysis of PD-L1 expression in each group containing HCC-827 showed that HCC-827 cells cocultured with T cells and antihuman CD3 mAb had the highest PD-L1 expression (MFI 719), which was significantly higher than that of containing T cells only group (MFI 581) and containing anti-CD3 mAb only group (MFI 474) (Fig 5(b)).	('expression', 'MPA', (171, 181))	('HCC-827', 'Var', (89, 96))	('HCC-827', 'CellLine', 'CVCL:2063', (69, 76))	('higher', 'PosReg', (217, 223))	('human', 'Species', '9606', (135, 140))	('PD-L1', 'Gene', (165, 170))	('HCC-827', 'CellLine', 'CVCL:2063', (89, 96))	('PD-L1', 'Gene', (27, 32))
426989	31625289	Interestingly, anti-CD137 mAb also induced PD-L1 expression in lung cancer cells and led to a synergistic increase when added with IFN-gamma (data not shown).	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('lung cancer', 'Disease', 'MESH:D008175', (63, 74))	('PD-L1', 'Gene', (43, 48))	('expression', 'MPA', (49, 59))	('anti-CD137 mAb', 'Var', (15, 29))	('lung cancer', 'Disease', (63, 74))	('induced', 'Reg', (35, 42))	('lung cancer', 'Phenotype', 'HP:0100526', (63, 74))	('increase', 'PosReg', (106, 114))
426992	31625289	Furthermore, 293FT* cells produced more IFN-gamma than the 293FT cells (P < 0.01).	('293FT', 'CellLine', 'CVCL:6911', (13, 18))	('293FT', 'CellLine', 'CVCL:6911', (59, 64))	('IFN-gamma', 'MPA', (40, 49))	('293FT*', 'Var', (13, 19))	('more', 'PosReg', (35, 39))
426993	31625289	However, in the presence of anti-CD137 mAb and anti-CD3 mAb, T cells cocultured with 293FT* cells produced extremely low levels of IFN-gamma (8.95 +- 2.03 pg/mL) (Fig 5(c)).	('293FT', 'CellLine', 'CVCL:6911', (85, 90))	('anti-CD3', 'Var', (47, 55))	('anti-CD137 mAb', 'Var', (28, 42))
426994	31625289	Many suppressive mechanisms have been recognized, such as the functional impairment or deletion of tumor-reactive T lymphocytes to suppress T cell function.	('suppress T cell function', 'Phenotype', 'HP:0005435', (131, 155))	('tumor', 'Disease', (99, 104))	('suppress', 'NegReg', (131, 139))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('deletion', 'Var', (87, 95))
427009	31625289	An IFN-induced upregulation of PD-L1 expression in carcinoma cell lines was first reported by Dong et al.41 and tumor cell-associated PD-L1 expression was later found to increase the apoptosis of antigen-specific T lymphocytes in vitro.	('PD-L1', 'Gene', (134, 139))	('increase', 'PosReg', (170, 178))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('upregulation', 'PosReg', (15, 27))	('carcinoma', 'Disease', (51, 60))	('expression', 'Var', (140, 150))	('IFN', 'Gene', '3439', (3, 6))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('IFN', 'Gene', (3, 6))	('carcinoma', 'Disease', 'MESH:D002277', (51, 60))	('tumor', 'Disease', (112, 117))	('apoptosis', 'CPA', (183, 192))	('PD-L1', 'Gene', (31, 36))	('carcinoma', 'Phenotype', 'HP:0030731', (51, 60))
427018	31625289	The HCC-827, in which the CD137L expression is low at the protein level, had an improved PD-L1 expression following coculture with T cells, most likely mediated by IFN-gamma.	('HCC-827', 'CellLine', 'CVCL:2063', (4, 11))	('PD-L1', 'Gene', (89, 94))	('improved', 'PosReg', (80, 88))	('CD137L', 'Var', (26, 32))	('expression', 'MPA', (95, 105))
427019	31625289	Additionally, the CD137L expression on HCC-827 cells significantly induced IFN-gamma production because this could be completely inhibited by treatment with anti-CD137 mAb.	('IFN-gamma production', 'MPA', (75, 95))	('CD137L', 'Gene', (18, 24))	('induced', 'PosReg', (67, 74))	('expression', 'Var', (25, 35))	('HCC-827', 'CellLine', 'CVCL:2063', (39, 46))
427020	31625289	More interestingly, we found that anti-CD137 mAb can also induce the expression of PD-L1 in lung cancer cells and synergize with IFN-gamma.	('lung cancer', 'Disease', (92, 103))	('lung cancer', 'Phenotype', 'HP:0100526', (92, 103))	('induce', 'PosReg', (58, 64))	('expression', 'MPA', (69, 79))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('lung cancer', 'Disease', 'MESH:D008175', (92, 103))	('PD-L1', 'Gene', (83, 88))	('anti-CD137 mAb', 'Var', (34, 48))
427021	31625289	Based on our findings, we propose that CD137L could upregulate PD-L1 expression on lung cancer via a feedback loop involving IFN-gamma production by T cells.	('lung cancer', 'Disease', 'MESH:D008175', (83, 94))	('expression', 'MPA', (69, 79))	('CD137L', 'Var', (39, 45))	('lung cancer', 'Disease', (83, 94))	('PD-L1', 'Gene', (63, 68))	('lung cancer', 'Phenotype', 'HP:0100526', (83, 94))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('upregulate', 'PosReg', (52, 62))
427024	31625289	From this point of view, our results may support the combined therapeutic value of anti-CD137 mAb and anti-PD-1/PD-L1 mAb, which, in addition to being assessed in several preclinical studies, has been investigated in clinical trials.20  In conclusion, we found that CD137L mRNA was widely expressed in lung cancer cell lines whereas levels of protein expression were generally low.	('lung cancer', 'Disease', 'MESH:D008175', (302, 313))	('cancer', 'Phenotype', 'HP:0002664', (307, 313))	('lung cancer', 'Disease', (302, 313))	('lung cancer', 'Phenotype', 'HP:0100526', (302, 313))	('CD137L', 'Var', (266, 272))
427025	30760522	NRF2 activation in cancer: from DNA to protein The Cancer Genome Atlas (TCGA) catalogued alterations in the Kelch-like ECH-associated protein 1 (KEAP1) and nuclear factor erythroid 2-related factor 2 (NRF2) signaling pathway in 6.3% of patient samples across 226 studies, with significant enrichment in lung and upper airway cancers.	('NRF2', 'Gene', '4780', (201, 205))	('cancer', 'Disease', (19, 25))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('Cancer', 'Phenotype', 'HP:0002664', (51, 57))	('Kelch-like ECH-associated protein 1', 'Gene', '9817', (108, 143))	('nuclear factor erythroid 2-related factor 2', 'Gene', '4780', (156, 199))	('cancers', 'Phenotype', 'HP:0002664', (325, 332))	('cancer', 'Disease', (325, 331))	('NRF2', 'Gene', (201, 205))	('cancer', 'Phenotype', 'HP:0002664', (325, 331))	('Kelch-like ECH-associated protein 1', 'Gene', (108, 143))	('NRF2', 'Gene', '4780', (0, 4))	('alterations', 'Var', (89, 100))	('patient', 'Species', '9606', (236, 243))	('cancer', 'Disease', 'MESH:D009369', (19, 25))	('lung and upper airway cancers', 'Disease', 'MESH:D008175', (303, 332))	('NRF2', 'Gene', (0, 4))	('cancer', 'Disease', 'MESH:D009369', (325, 331))	('nuclear factor erythroid 2-related factor 2', 'Gene', (156, 199))
427026	30760522	These alterations constitutively activate NRF2-dependent gene transcription to promote many of the cancer hallmarks, including cellular resistance to oxidative stress, xenobiotic efflux, proliferation, and metabolic reprogramming.	('cancer hallmarks', 'Disease', 'MESH:D009369', (99, 115))	('alterations', 'Var', (6, 17))	('oxidative stress', 'Phenotype', 'HP:0025464', (150, 166))	('NRF2-dependent gene transcription', 'Gene', (42, 75))	('xenobiotic efflux', 'MPA', (168, 185))	('metabolic reprogramming', 'CPA', (206, 229))	('proliferation', 'CPA', (187, 200))	('promote', 'PosReg', (79, 86))	('cellular resistance to oxidative stress', 'MPA', (127, 166))	('cancer hallmarks', 'Disease', (99, 115))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('activate', 'PosReg', (33, 41))
427040	30760522	Looking across all organ systems, 226 TCGA studies have catalogued genetic mutations and copy-number alterations to the KEAP1-NRF2 signaling pathway, most notably lung (LUSC and LUAD; 31.4% and 24%, respectively), uterine (20.6%), head and neck (17.4%), esophageal (19.8%), and bladder carcinomas (14.8%).	('carcinoma', 'Phenotype', 'HP:0030731', (286, 295))	('genetic mutations', 'Var', (67, 84))	('carcinomas', 'Phenotype', 'HP:0030731', (286, 296))	('copy-number alterations', 'Var', (89, 112))	('bladder carcinomas', 'Disease', (278, 296))	('LUAD', 'Disease', (178, 182))	('esophageal', 'Disease', (254, 264))	('bladder carcinomas', 'Disease', 'MESH:D001749', (278, 296))	('LUAD', 'Disease', 'MESH:C538231', (178, 182))	('uterine', 'Disease', (214, 221))	('LUSC', 'Disease', (169, 173))	('LUSC', 'Disease', 'MESH:D002294', (169, 173))	('lung', 'Disease', (163, 167))	('KEAP1-NRF2 signaling pathway', 'Pathway', (120, 148))	('bladder carcinomas', 'Phenotype', 'HP:0002862', (278, 296))
427046	30760522	Of the 1,735,350 new cases of diagnosed cancer predicted by the American Cancer Society for the US population in 2018, 5% or more of these cases are estimated to be NRF2 pathway mutant and hyperactive.	('mutant', 'Var', (178, 184))	('NRF2 pathway', 'Pathway', (165, 177))	('hyperactive', 'PosReg', (189, 200))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('cancer', 'Disease', (40, 46))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('Cancer', 'Phenotype', 'HP:0002664', (73, 79))
427047	30760522	These mutational rates likely underrepresent the true number of NRF2 hyperactive tumors, given the various non-genomic mechanisms of NRF2 activation discussed in this review.	('mutational', 'Var', (6, 16))	('tumors', 'Disease', (81, 87))	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('underrepresent', 'NegReg', (30, 44))	('hyperactive', 'PosReg', (69, 80))	('NRF2', 'Gene', (64, 68))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))
427050	30760522	Consequently, cells with low levels of NRF2 and elevated ROS are at risk for neurodegeneration, cardiovascular disease, and chronic inflammation.	('inflammation', 'Disease', 'MESH:D007249', (132, 144))	('ROS', 'Chemical', 'MESH:D017382', (57, 60))	('ROS', 'Protein', (57, 60))	('cardiovascular disease', 'Disease', (96, 118))	('low levels', 'Var', (25, 35))	('inflammation', 'Disease', (132, 144))	('neurodegeneration', 'Phenotype', 'HP:0002180', (77, 94))	('cardiovascular disease', 'Phenotype', 'HP:0001626', (96, 118))	('neurodegeneration', 'Disease', (77, 94))	('cardiovascular disease', 'Disease', 'MESH:D002318', (96, 118))	('neurodegeneration', 'Disease', 'MESH:D019636', (77, 94))	('elevated', 'PosReg', (48, 56))	('NRF2', 'Protein', (39, 43))
427051	30760522	In contrast, high NRF2 activity leads to cellular resiliency in the face of various stressors, including ROS, genotoxic stress, and metabolic stress.	('cellular resiliency', 'MPA', (41, 60))	('NRF2', 'Gene', (18, 22))	('high', 'Var', (13, 17))	('activity', 'MPA', (23, 31))	('ROS', 'Chemical', 'MESH:D017382', (105, 108))	('leads to', 'Reg', (32, 40))
427052	30760522	Thus, mutations and alterations that increase NRF2 activity contribute to cancer progression and the development of chemo- and radio-resistance.	('alterations', 'Var', (20, 31))	('activity', 'MPA', (51, 59))	('contribute', 'Reg', (60, 70))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Disease', (74, 80))	('increase', 'PosReg', (37, 45))	('NRF2', 'Protein', (46, 50))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('mutations', 'Var', (6, 15))
427054	30760522	Upon exposure to oxidative stress or xenobiotic challenge, reactive cysteine residues within KEAP1 are modified leading to a conformational change in KEAP1 structure that prevents the degradation of NRF2.	('leading to', 'Reg', (112, 122))	('oxidative stress', 'Phenotype', 'HP:0025464', (17, 33))	('degradation', 'MPA', (184, 195))	('prevents', 'NegReg', (171, 179))	('NRF2', 'Protein', (199, 203))	('conformational change', 'MPA', (125, 146))	('structure', 'MPA', (156, 165))	('cysteine', 'Chemical', 'MESH:D003545', (68, 76))	('modified', 'Var', (103, 111))
427059	30760522	Alterations to NFE2L2, CUL3, and KEAP1 frequently occur at the genomic level, resulting in enhanced NRF2 protein expression and transactivation activity.	('NRF2 protein', 'Protein', (100, 112))	('expression', 'MPA', (113, 123))	('NFE2L2', 'Gene', (15, 21))	('transactivation activity', 'MPA', (128, 152))	('Alterations', 'Var', (0, 11))	('NFE2L2', 'Gene', '4780', (15, 21))	('enhanced', 'PosReg', (91, 99))
427060	30760522	NFE2L2, located on a copy-number-amplified region of chromosome 2q31.2, can be genetically modified through promoter demethylation, copy-number amplifications (CNA), oncogene-induced transcription of NRF2 via cMYCERT2, BRAFV619E, and KRASG12D, or by gain-of-function (GOF) somatic mutations in the DLG or ETGE motifs required for KEAP1 association (Fig.	('KRAS', 'Gene', '3845', (234, 238))	('NFE2L2', 'Gene', '4780', (0, 6))	('NRF2', 'Gene', (200, 204))	('copy-number', 'Var', (132, 143))	('DLG', 'Gene', (298, 301))	('NFE2L2', 'Gene', (0, 6))	('KRAS', 'Gene', (234, 238))	('gain-of-function', 'PosReg', (250, 266))
427062	30760522	Demethylation of the NFE2L2 promoter frequently occurs in lung and colorectal cancers (CRC); in contrast, CNA of NFE2L2 appears most prominently in ovarian and head and neck tumors.	('CRC', 'Disease', (87, 90))	('ovarian and head and neck tumors', 'Disease', 'MESH:D010051', (148, 180))	('colorectal cancers', 'Disease', (67, 85))	('NFE2L2', 'Gene', '4780', (113, 119))	('head and neck tumors', 'Phenotype', 'HP:0012288', (160, 180))	('lung', 'Disease', (58, 62))	('NFE2L2', 'Gene', '4780', (21, 27))	('NFE2L2', 'Gene', (113, 119))	('cancers', 'Phenotype', 'HP:0002664', (78, 85))	('Demethylation', 'Var', (0, 13))	('occurs', 'Reg', (48, 54))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('NFE2L2', 'Gene', (21, 27))	('CRC', 'Disease', 'MESH:D015179', (87, 90))	('colorectal cancers', 'Disease', 'MESH:D015179', (67, 85))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('tumors', 'Phenotype', 'HP:0002664', (174, 180))
427064	30760522	For example, NFE2L2 mutations within the DLG and ETGE motifs required for KEAP1 association frequently occur in LUSC; however NFE2L2 mutations rarely appear in LUAD.	('NFE2L2', 'Gene', '4780', (126, 132))	('NFE2L2', 'Gene', '4780', (13, 19))	('NFE2L2', 'Gene', (126, 132))	('NFE2L2', 'Gene', (13, 19))	('occur', 'Reg', (103, 108))	('LUAD', 'Disease', (160, 164))	('LUAD', 'Disease', 'MESH:C538231', (160, 164))	('LUSC', 'Disease', 'MESH:D002294', (112, 116))	('LUSC', 'Disease', (112, 116))	('mutations', 'Var', (20, 29))
427066	30760522	CUL3 deletions arise most frequently in bladder and head and neck tumors, whereas uterine (7.75%) and LUSC (7%) cancers generally possess CUL3 mutations.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('arise', 'Reg', (15, 20))	('cancers', 'Phenotype', 'HP:0002664', (112, 119))	('neck tumors', 'Disease', 'MESH:D006258', (61, 72))	('bladder', 'Disease', (40, 47))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('CUL3', 'Gene', (0, 4))	('cancers', 'Disease', 'MESH:D009369', (112, 119))	('neck tumors', 'Disease', (61, 72))	('cancers', 'Disease', (112, 119))	('head and neck tumors', 'Phenotype', 'HP:0012288', (52, 72))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('LUSC', 'Disease', 'MESH:D002294', (102, 106))	('LUSC', 'Disease', (102, 106))	('deletions', 'Var', (5, 14))
427067	30760522	In contrast to the comprehensive analyses of NFE2L2 or KEAP1 mutations, the functional consequences of patient-derived CUL3 mutations remains understudied.	('mutations', 'Var', (124, 133))	('CUL3', 'Gene', (119, 123))	('NFE2L2', 'Gene', '4780', (45, 51))	('NFE2L2', 'Gene', (45, 51))	('patient', 'Species', '9606', (103, 110))
427068	30760522	In comparison to KEAP1 and NFE2L2, mutations in CUL3 occur less frequently, perhaps reflecting the critical role of CUL3 as an E3 ligase for a family of broad complex, bric-a-brac, tramtrack (BTB)-containing proteins beyond just KEAP1.	('NFE2L2', 'Gene', '4780', (27, 33))	('NFE2L2', 'Gene', (27, 33))	('CUL3', 'Gene', (48, 52))	('mutations', 'Var', (35, 44))
427072	30760522	In fact, KEAP1 ubiquitylates proteins involved in cell cycle regulation such as MCM3, although the biological function of this interaction remains understudied.	('KEAP1', 'Var', (9, 14))	('MCM3', 'Gene', (80, 84))	('MCM3', 'Gene', '4172', (80, 84))	('proteins', 'Protein', (29, 37))	('ubiquitylates', 'MPA', (15, 28))
427073	30760522	KEAP1 mutations occur most frequently in LUAD and LUSC tumors.	('LUAD', 'Disease', (41, 45))	('LUAD', 'Disease', 'MESH:C538231', (41, 45))	('KEAP1', 'Gene', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('LUSC', 'Disease', 'MESH:D002294', (50, 54))	('LUSC', 'Disease', (50, 54))	('tumors', 'Disease', (55, 61))	('tumors', 'Disease', 'MESH:D009369', (55, 61))	('occur', 'Reg', (16, 21))	('mutations', 'Var', (6, 15))
427074	30760522	Previous studies estimate that 75% of KEAP1 LUSC and 92% of KEAP1 LUAD somatic missense mutations abrogate KEAP1 protein function.	('LUAD', 'Disease', (66, 70))	('LUAD', 'Disease', 'MESH:C538231', (66, 70))	('missense mutations', 'Var', (79, 97))	('KEAP1', 'Gene', (107, 112))	('abrogate', 'NegReg', (98, 106))	('LUSC', 'Disease', 'MESH:D002294', (44, 48))	('LUSC', 'Disease', (44, 48))
427076	30760522	NRF2 transcript levels in cancer are regulated by miRNAs and alternative splicing of exon 2 or the combination of exons 2 and 3.	('NRF2', 'Gene', (0, 4))	('regulated', 'Reg', (37, 46))	('cancer', 'Disease', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('transcript levels', 'MPA', (5, 22))	('alternative splicing', 'Var', (61, 81))	('miRNAs', 'MPA', (50, 56))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))
427077	30760522	For example, a miRNA library screen using the ARE reporter assay identified four miRNAs that regulate NRF2: miR-507, -634, -450a, and 129-5p whose downregulation was observed in patient samples with esophageal squamous cell carcinoma (ESCC).	('miR-507', 'Gene', (108, 115))	('ESCC', 'Disease', (235, 239))	('miR-507', 'Gene', '574512', (108, 115))	('carcinoma', 'Phenotype', 'HP:0030731', (224, 233))	('patient', 'Species', '9606', (178, 185))	('esophageal squamous cell carcinoma', 'Disease', (199, 233))	('downregulation', 'NegReg', (147, 161))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:C562729', (199, 233))	('ESCC', 'Disease', 'MESH:C562729', (235, 239))	('NRF2', 'Gene', (102, 106))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (210, 233))	('129-5p', 'Var', (134, 140))
427081	30760522	A 2017 analysis of RNA-seq transcript variants from patient samples with elevated NRF2 activity in the absence of KEAP1 or NFE2L2 mutations identified alternatively spliced transcripts of NRF2 lacking exon 2 or both exons 2 and 3.	('NRF2', 'Enzyme', (82, 86))	('variants', 'Var', (38, 46))	('activity', 'MPA', (87, 95))	('NFE2L2', 'Gene', '4780', (123, 129))	('NRF2', 'Gene', (188, 192))	('exon 2', 'MPA', (201, 207))	('NFE2L2', 'Gene', (123, 129))	('mutations', 'Var', (130, 139))	('patient', 'Species', '9606', (52, 59))	('lacking', 'NegReg', (193, 200))	('elevated', 'PosReg', (73, 81))
427082	30760522	Currently, this alternative splicing event has only been detected in LUSC and head and neck squamous cell carcinomas (HNSCC); however, additional studies of other tumor types may identify additional instances of NFE2L2 alternative splicing.	('carcinomas', 'Phenotype', 'HP:0030731', (106, 116))	('LUSC', 'Disease', 'MESH:D002294', (69, 73))	('LUSC', 'Disease', (69, 73))	('NFE2L2', 'Gene', '4780', (212, 218))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('neck squamous cell carcinomas', 'Disease', (87, 116))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (92, 116))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('NFE2L2', 'Gene', (212, 218))	('neck squamous cell carcinomas', 'Disease', 'MESH:C535575', (87, 116))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('tumor', 'Disease', (163, 168))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (92, 115))	('alternative splicing', 'Var', (219, 239))
427083	30760522	Of the few reports describing miRNAs that regulate CUL3, only miR-101 and miR-455 have been shown to target CUL3 and activate NRF2 signaling (Fig.	('miR-455', 'Gene', '619556', (74, 81))	('NRF2 signaling', 'Pathway', (126, 140))	('activate', 'PosReg', (117, 125))	('CUL3', 'Gene', (108, 112))	('miR-455', 'Gene', (74, 81))	('miR-101', 'Chemical', '-', (62, 69))	('miR-101', 'Var', (62, 69))
427097	30760522	The Neh2 domain also contains serine 40 (S40) that is phosphorylated by protein kinase C (PKC).	('PKC', 'Gene', (90, 93))	('PKC', 'Gene', '112476', (90, 93))	('protein kinase C', 'Gene', '112476', (72, 88))	('serine', 'Var', (30, 36))	('protein kinase C', 'Gene', (72, 88))	('serine', 'Chemical', 'MESH:D012694', (30, 36))
427099	30760522	Unexpectedly, NRF2 target gene expression is not significantly altered by PKC-dependent S40 phosphorylation of NRF2.	('PKC', 'Gene', (74, 77))	('S40 phosphorylation', 'Var', (88, 107))	('PKC', 'Gene', '112476', (74, 77))	('NRF2', 'Gene', (111, 115))
427100	30760522	The Neh6 domain contains two beta-transducin repeat-containing E3 ubiquitin protein ligase (BTrCP; hereafter BTRC) degron motifs: 343DSGIS347 and 382DSAPGS387 for human NRF2.	('BTRC', 'Gene', '8945', (109, 113))	('BTRC', 'Gene', (109, 113))	('BTrCP', 'Gene', (92, 97))	('human', 'Species', '9606', (163, 168))	('382DSAPGS387', 'Var', (146, 158))	('NRF2', 'Gene', (169, 173))	('BTrCP', 'Gene', '8945', (92, 97))
427103	30760522	Whether BTRC alterations contribute to NRF2 activity in cancer has not been reported, but given the lack of NRF2 mutations in the DSGIS motif, it likely does not play a major role.	('BTRC', 'Gene', '8945', (8, 12))	('NRF2', 'Gene', (108, 112))	('BTRC', 'Gene', (8, 12))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('activity', 'MPA', (44, 52))	('mutations', 'Var', (113, 122))	('alterations', 'Var', (13, 24))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))
427106	30760522	Neddylation of CUL3 by the Nedd-8 activating enzyme (NAE) is required for ubiquitylation activity, and small molecule NAE inhibitors such as MLN4924 result in stabilization of CUL3 substrates, including robust NRF2 transcriptional activation.	('MLN4924', 'Var', (141, 148))	('NRF2', 'Gene', (210, 214))	('NAE', 'Chemical', '-', (53, 56))	('activation', 'PosReg', (231, 241))	('transcriptional', 'MPA', (215, 230))	('Nedd-8', 'Gene', '4738', (27, 33))	('NAE', 'Chemical', '-', (118, 121))	('Nedd-8', 'Gene', (27, 33))	('MLN4924', 'Chemical', 'MESH:C539933', (141, 148))	('CUL3', 'Gene', (176, 180))	('stabilization', 'MPA', (159, 172))
427107	30760522	Current clinical trials are testing the efficacy of MLN4924 in patients with hematologic malignancies.	('MLN4924', 'Chemical', 'MESH:C539933', (52, 59))	('hematologic malignancies', 'Disease', 'MESH:D019337', (77, 101))	('MLN4924', 'Var', (52, 59))	('hematologic malignancies', 'Disease', (77, 101))	('patients', 'Species', '9606', (63, 71))
427108	30760522	Whether NRF2 activation impacts the efficacy of MLN4924 treatment, either as a single agent or in combination with conventional chemotherapies, remains untested.	('MLN4924', 'Chemical', 'MESH:C539933', (48, 55))	('NRF2', 'Gene', (8, 12))	('efficacy', 'MPA', (36, 44))	('MLN4924 treatment', 'Var', (48, 65))
427111	30760522	Modifications to specific amino acid residues alter KEAP1 homodimerization, CUL3 or NRF2 association, or KEAP1 redox sensing via one or more of its reactive cysteines.	('reactive cysteines', 'MPA', (148, 166))	('homodimerization', 'MPA', (58, 74))	('cysteines', 'Chemical', 'MESH:D003545', (157, 166))	('Modifications', 'Var', (0, 13))	('NRF2', 'Gene', (84, 88))	('redox sensing', 'MPA', (111, 124))	('alter', 'Reg', (46, 51))	('CUL3', 'Gene', (76, 80))	('association', 'Interaction', (89, 100))
427112	30760522	Mutations which disrupt these essential functions of KEAP1 protein result in NRF2 stabilization and increased transcriptional activity in cancer.	('cancer', 'Disease', (138, 144))	('increased', 'PosReg', (100, 109))	('stabilization', 'MPA', (82, 95))	('transcriptional activity', 'MPA', (110, 134))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('Mutations', 'Var', (0, 9))	('NRF2', 'Gene', (77, 81))	('cancer', 'Disease', 'MESH:D009369', (138, 144))
427113	30760522	In general, predicting the effects of KEAP1 mutations found in tumors upon NRF2 signaling remains difficult and thus requires the use of biochemical and functional assays.	('KEAP1', 'Gene', (38, 43))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('tumors', 'Disease', (63, 69))	('mutations', 'Var', (44, 53))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
427120	30760522	Although changes in RBM45 expression in tumors has not been extensively studied, recent proteomic studies examining reactive cysteines in KEAP1-mutant NSCLC cancer cell lines revealed protein-protein interactions between the cysteine-reactive nuclear factor receptor subfamily 0 group B member 1 (NR0B1), and RBM45.	('NR0B1', 'Gene', '190', (297, 302))	('RBM45', 'Gene', '129831', (20, 25))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('RBM45', 'Gene', '129831', (309, 314))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('NSCLC cancer', 'Disease', 'MESH:D009369', (151, 163))	('cysteine', 'Chemical', 'MESH:D003545', (125, 133))	('tumors', 'Disease', 'MESH:D009369', (40, 46))	('KEAP1-mutant', 'Var', (138, 150))	('cysteine', 'Chemical', 'MESH:D003545', (225, 233))	('protein-protein interactions', 'MPA', (184, 212))	('cysteines', 'Chemical', 'MESH:D003545', (125, 134))	('NR0B1', 'Gene', (297, 302))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('RBM45', 'Gene', (309, 314))	('RBM45', 'Gene', (20, 25))	('tumors', 'Disease', (40, 46))	('NSCLC cancer', 'Disease', (151, 163))
427122	30760522	KEAP1 ubiquitylation results in p62-dependent autophagic degradation of KEAP1.	('autophagic degradation', 'CPA', (46, 68))	('p62', 'Gene', '8878', (32, 35))	('results in', 'Reg', (21, 31))	('p62', 'Gene', (32, 35))	('ubiquitylation', 'Var', (6, 20))
427124	30760522	The loss of FH results in the formation of S-(2-succinyl) adducts (2SC) on C151 and C288 that may increase NRF2 transcriptional activity by modifying KEAP1 structure (Fig.	('succinyl', 'Chemical', '-', (48, 56))	('C288', 'Var', (84, 88))	('NRF2', 'Gene', (107, 111))	('FH', 'Gene', '2271', (12, 14))	('increase', 'PosReg', (98, 106))	('loss', 'NegReg', (4, 8))	('modifying', 'Reg', (140, 149))	('transcriptional activity', 'MPA', (112, 136))	('KEAP1', 'MPA', (150, 155))
427126	30760522	Additionally, it was recently reported that the mitochondrial metabolite itaconate activates NRF2-dependent transcription through alkylation of KEAP1 on C151, C257, C273, C288 and C297.	('activates', 'PosReg', (83, 92))	('C273', 'Var', (165, 169))	('alkylation', 'MPA', (130, 140))	('C151', 'Var', (153, 157))	('itaconate', 'Chemical', 'MESH:C005229', (73, 82))	('C257', 'Var', (159, 163))	('C297', 'Var', (180, 184))	('C288', 'Var', (171, 175))	('transcription', 'MPA', (108, 121))	('NRF2-dependent', 'Gene', (93, 107))
427140	30760522	Examples of class IV-reactive cysteines include C226 and C613 which are responsive to transition metal ions (i.e.	('metal', 'Chemical', 'MESH:D008670', (97, 102))	('C613', 'Var', (57, 61))	('C226', 'Var', (48, 52))	('cysteines', 'Chemical', 'MESH:D003545', (30, 39))
427141	30760522	As3+, Cd2+, Se4+, and Zn2+), and are capable of forming a disulfide bridge following exposure to hydrogen peroxide or hydrogen sulfide.	('disulfide', 'Chemical', 'MESH:D004220', (58, 67))	('Cd2+', 'Var', (6, 10))	('disulfide bridge', 'MPA', (58, 74))	('As3+', 'Chemical', '-', (0, 4))	('Se4+', 'Chemical', '-', (12, 16))	('hydrogen peroxide', 'Chemical', 'MESH:D006861', (97, 114))	('Se4+', 'Var', (12, 16))	('hydrogen sulfide', 'Chemical', 'MESH:D006862', (118, 134))	('forming', 'Reg', (48, 55))	('Zn2+', 'Chemical', 'MESH:D015032', (22, 26))
427143	30760522	Although not assigned to a specific class, the NEDD8-activating enzyme inhibitor (NAE1; hereafter, MLN4924) and the CYP450 inhibitor oltipraz also induce NRF2 activation.	('NEDD8', 'Gene', (47, 52))	('activation', 'PosReg', (159, 169))	('MLN4924', 'Var', (99, 106))	('NEDD8', 'Gene', '4738', (47, 52))	('NRF2', 'Protein', (154, 158))	('MLN4924', 'Chemical', 'MESH:C539933', (99, 106))	('oltipraz', 'Chemical', 'MESH:C026209', (133, 141))	('NAE1', 'Gene', '8883', (82, 86))	('NAE1', 'Gene', (82, 86))
427145	30760522	Multiple reports have established that hyperactivation of NRF2 is detrimental for survival in cancer patients.	('patients', 'Species', '9606', (101, 109))	('survival', 'CPA', (82, 90))	('NRF2', 'Gene', (58, 62))	('hyperactivation', 'Var', (39, 54))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('detrimental', 'NegReg', (66, 77))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
427148	30760522	ML385 disrupts NRF2-sMAF heterodimerization via direct association with the Neh1 domain of NRF2.	('ML385', 'Var', (0, 5))	('sMAF', 'Disease', (20, 24))	('disrupts', 'NegReg', (6, 14))	('sMAF', 'Disease', 'MESH:D005354', (20, 24))	('association', 'Interaction', (55, 66))	('heterodimerization', 'MPA', (25, 43))	('NRF2', 'Gene', (91, 95))
427150	30760522	Although both ML385 and CP were effective in preclinical studies using cellular-based assays and animal models of cancer, they remain untested in clinical trials for patients with NRF2-hyperactive tumors.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('ML385', 'Var', (14, 19))	('tumors', 'Disease', 'MESH:D009369', (197, 203))	('tumors', 'Phenotype', 'HP:0002664', (197, 203))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('tumors', 'Disease', (197, 203))	('patients', 'Species', '9606', (166, 174))	('cancer', 'Disease', (114, 120))
427160	29864749	We also demonstrate that only 30 unique cancer-specific mutations overlap the three subtypes from COSMIC and that this is fewer than overlapping mutations chosen at random.	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('mutations', 'Var', (56, 65))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('cancer', 'Disease', (40, 46))
427175	29864749	15) representing three cytobands (6p22.1, 6p21.32, 15q25.1) were associated with the three most frequent lung cancer histologic groups, i.e.	('lung cancer', 'Phenotype', 'HP:0100526', (105, 116))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('6p22.1', 'Var', (34, 40))	('lung cancer', 'Disease', 'MESH:D008175', (105, 116))	('associated', 'Reg', (65, 75))	('lung cancer', 'Disease', (105, 116))
427181	29864749	For example, a recent GWAS for lung cancer in African Americans found two significant SNPs near CHRNA5 and TERT where one of the SNPs, rs2853677, near the TERT gene was only significant in LUAD but not in LUSC.	('lung cancer', 'Disease', 'MESH:D008175', (31, 42))	('rs2853677', 'Var', (135, 144))	('LUAD', 'Phenotype', 'HP:0030078', (189, 193))	('LUSC', 'Phenotype', 'HP:0030359', (205, 209))	('LUAD', 'Disease', (189, 193))	('CHRNA5', 'Gene', '1138', (96, 102))	('lung cancer', 'Disease', (31, 42))	('lung cancer', 'Phenotype', 'HP:0100526', (31, 42))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('TERT', 'Gene', (107, 111))	('TERT', 'Gene', (155, 159))	('TERT', 'Gene', '7015', (107, 111))	('TERT', 'Gene', '7015', (155, 159))	('CHRNA5', 'Gene', (96, 102))	('rs2853677', 'Mutation', 'rs2853677', (135, 144))
427184	29864749	For these six SNPs, two (rs2736100 and rs448809) were significantly different per subtype using LUAD, LUSC, and SCLC.	('rs448809', 'Mutation', 'rs448809', (39, 47))	('LUAD', 'Phenotype', 'HP:0030078', (96, 100))	('rs2736100', 'Var', (25, 34))	('SCLC', 'Disease', 'MESH:D018288', (112, 116))	('SCLC', 'Disease', (112, 116))	('rs2736100', 'Mutation', 'rs2736100', (25, 34))	('LUSC', 'Phenotype', 'HP:0030359', (102, 106))	('rs448809', 'Var', (39, 47))	('SCLC', 'Phenotype', 'HP:0030357', (112, 116))
427187	29864749	They discovered that rs9387478 and rs2395185 were only associated with LUAD while rs7086803 showed a stronger effect in LUSC than LUAD.	('rs2395185', 'Var', (35, 44))	('rs2395185', 'Mutation', 'rs2395185', (35, 44))	('rs9387478', 'Var', (21, 30))	('associated', 'Reg', (55, 65))	('rs9387478', 'Mutation', 'rs9387478', (21, 30))	('LUSC', 'Phenotype', 'HP:0030359', (120, 124))	('LUAD', 'Phenotype', 'HP:0030078', (71, 75))	('LUSC', 'Disease', (120, 124))	('LUAD', 'Disease', (71, 75))	('rs7086803', 'Mutation', 'rs7086803', (82, 91))	('rs7086803', 'Var', (82, 91))	('LUAD', 'Phenotype', 'HP:0030078', (130, 134))
427190	29864749	We obtained all COSMIC somatic mutations from genome-wide screens, that do not target any specific genes, and removed mutations identified in cell lines, non-primary tumors, and silent mutations.	('mutations', 'Var', (31, 40))	('tumors', 'Disease', 'MESH:D009369', (166, 172))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('tumors', 'Disease', (166, 172))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))
427192	29864749	These 37 mutations represent 10 different genes, and the majority of the mutations (> 70%) are in the well-known tumor suppressor gene TP53 that is mutated in many cancer types.	('tumor', 'Disease', (113, 118))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('mutations', 'Var', (9, 18))	('TP53', 'Gene', '7157', (135, 139))	('cancer', 'Disease', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('TP53', 'Gene', (135, 139))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('mutations', 'Var', (73, 82))
427193	29864749	However, these genes that contain the exact same mutations may still be passenger genes that do not lead to cancer.	('cancer', 'Disease', (108, 114))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('mutations', 'Var', (49, 58))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
427194	29864749	To identify relevant cancer-related driver genes that are in each subtype, we additionally filtered the mutations to include genes identified in the Cancer Gene Census (CGC), a list of genes causally implicated in cancer.	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('mutations', 'Var', (104, 113))	('cancer', 'Disease', (214, 220))	('Cancer', 'Phenotype', 'HP:0002664', (149, 155))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('cancer', 'Disease', (21, 27))	('cancer', 'Disease', 'MESH:D009369', (21, 27))	('Cancer', 'Disease', 'MESH:D009369', (149, 155))	('Cancer', 'Disease', (149, 155))	('cancer', 'Disease', 'MESH:D009369', (214, 220))
427195	29864749	After filtering for CGC genes, we found only 30 unique mutations that overlap LUAD, LUSC, and SCLC and these mutations were all found within three genes: TP53, BRAF, and PIK3CA (Fig.	('PIK3CA', 'Gene', '5290', (170, 176))	('BRAF', 'Gene', (160, 164))	('SCLC', 'Disease', (94, 98))	('BRAF', 'Gene', '673', (160, 164))	('SCLC', 'Disease', 'MESH:D018288', (94, 98))	('TP53', 'Gene', (154, 158))	('mutations', 'Var', (55, 64))	('SCLC', 'Phenotype', 'HP:0030357', (94, 98))	('LUSC', 'Phenotype', 'HP:0030359', (84, 88))	('LUAD', 'Disease', (78, 82))	('LUAD', 'Phenotype', 'HP:0030078', (78, 82))	('PIK3CA', 'Gene', (170, 176))	('TP53', 'Gene', '7157', (154, 158))
427196	29864749	This finding suggests that the 30 shared mutations in LUAD, LUSC, and SCLC may not be due to any shared biology and are the result of random chance.	('mutations', 'Var', (41, 50))	('SCLC', 'Disease', 'MESH:D018288', (70, 74))	('SCLC', 'Phenotype', 'HP:0030357', (70, 74))	('LUSC', 'Phenotype', 'HP:0030359', (60, 64))	('LUSC', 'Disease', (60, 64))	('LUAD', 'Phenotype', 'HP:0030078', (54, 58))	('LUAD', 'Disease', (54, 58))	('SCLC', 'Disease', (70, 74))
427197	29864749	In confirmation of the COSMIC data, the authors show that TP53, BRAF, and PIK3CA have evidence for mutation in LUAD and LUSC; albeit at different frequencies (authors did not report statistics for SCLC).	('BRAF', 'Gene', '673', (64, 68))	('TP53', 'Gene', '7157', (58, 62))	('SCLC', 'Disease', (197, 201))	('TP53', 'Gene', (58, 62))	('PIK3CA', 'Gene', '5290', (74, 80))	('BRAF', 'Gene', (64, 68))	('SCLC', 'Disease', 'MESH:D018288', (197, 201))	('LUAD', 'Phenotype', 'HP:0030078', (111, 115))	('mutation', 'Var', (99, 107))	('LUSC', 'Phenotype', 'HP:0030359', (120, 124))	('SCLC', 'Phenotype', 'HP:0030357', (197, 201))	('PIK3CA', 'Gene', (74, 80))
427198	29864749	ATM and FGFR1) are only uniquely mutated in LUAD or LUSC in confirmation of the genetic differences between lung cancer subtypes at the somatic level.	('LUSC', 'Phenotype', 'HP:0030359', (52, 56))	('lung cancer', 'Disease', 'MESH:D008175', (108, 119))	('FGFR1', 'Gene', '2260', (8, 13))	('mutated', 'Var', (33, 40))	('ATM', 'Gene', (0, 3))	('lung cancer', 'Disease', (108, 119))	('lung cancer', 'Phenotype', 'HP:0100526', (108, 119))	('LUAD', 'Phenotype', 'HP:0030078', (44, 48))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('ATM', 'Gene', '472', (0, 3))	('FGFR1', 'Gene', (8, 13))
427200	29864749	Somatic mutational signatures are unique patterns of mutations and can be used to gain an understanding of the mutational processes as well as environmental exposures of a cancer sample.	('cancer', 'Disease', (172, 178))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('mutational', 'Var', (8, 18))
427219	27877079	Amplification of 11q13 resulting in overexpression of CTTN/CCND1 was the most prominent finding, which was observed in 13 of 19 ESCC cases.	('SCC', 'Phenotype', 'HP:0002860', (129, 132))	('Amplification', 'Var', (0, 13))	('overexpression', 'PosReg', (36, 50))	('CTTN', 'Gene', (54, 58))	('CCND1', 'Gene', (59, 64))	('CTTN', 'Gene', '2017', (54, 58))	('ESCC', 'Disease', (128, 132))	('CCND1', 'Gene', '595', (59, 64))
427223	27877079	Regions with such high incidence of ESCC (15150/100,000) are referred to as the famous ''Asian Esophageal Cancer Belt,'' which includes the countries of the Caspian littoral region, the central Asian republics, Mongolia and north-western China, which have a 10-100 fold greater chance of being affected by esophageal cancer compared to other countries.	('Esophageal Cancer', 'Disease', (95, 112))	('ESCC', 'Disease', (36, 40))	('esophageal cancer', 'Disease', (306, 323))	('15150/100,000', 'Var', (42, 55))	('Cancer', 'Phenotype', 'HP:0002664', (106, 112))	('cancer', 'Phenotype', 'HP:0002664', (317, 323))	('esophageal cancer', 'Disease', 'MESH:D004938', (306, 323))	('SCC', 'Phenotype', 'HP:0002860', (37, 40))	('Esophageal Cancer', 'Disease', 'MESH:D004938', (95, 112))
427226	27877079	Regardless of the ethnic origin of the patients and the etiological factors, genetic instabilities such as microsatellite instability and chromosomal instability are associated with tumorigenesis of ESCC.	('chromosomal', 'MPA', (138, 149))	('SCC', 'Phenotype', 'HP:0002860', (200, 203))	('microsatellite instability', 'Var', (107, 133))	('tumor', 'Disease', (182, 187))	('patients', 'Species', '9606', (39, 47))	('chromosomal instability', 'Phenotype', 'HP:0040012', (138, 161))	('ESCC', 'Disease', (199, 203))	('associated with', 'Reg', (166, 181))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))
427245	27877079	The most frequent genomic imbalances detected in more than 8 out of 19 ESCC cases (> 42%) were gains of 1q21.1-qter, 3q13.11-qter, 5pter-p11, 7pter-p15.3, 7p12.1-p11.2, 7q11-q11.2, 8p12-qter, 11q13.2-q13.3, 12pter-p13.3, 17q24.2, 20q11.21-qter, and 22q11.21-q11.22; and losses of 3pter-p11.1, 4pter-p12, 4q28.3-q31.22, 4q31.3-q32.1, 9pter-p12, 11q22.3-qter, and 13q12.11-q22.1 (Table 2).	('p13', 'Gene', '440926', (214, 217))	('p12', 'Gene', '56655', (339, 342))	('imbalance', 'Phenotype', 'HP:0002172', (26, 35))	('p12', 'Gene', '56655', (299, 302))	('p12', 'Gene', '56655', (156, 159))	('p12', 'Gene', (182, 185))	('p11', 'Gene', '6281', (162, 165))	('4q28.3-q31.22', 'Var', (304, 317))	('SCC', 'Phenotype', 'HP:0002860', (72, 75))	('p11', 'Gene', '6281', (137, 140))	('p11', 'Gene', (162, 165))	('p12', 'Gene', (339, 342))	('p11', 'Gene', (137, 140))	('p12', 'Gene', (299, 302))	('losses', 'NegReg', (270, 276))	('3q13.11-qter', 'Var', (117, 129))	('p12', 'Gene', (156, 159))	('p15', 'Gene', (148, 151))	('p13', 'Gene', (214, 217))	('imbalances', 'Phenotype', 'HP:0002172', (26, 36))	('p11', 'Gene', '6281', (286, 289))	('ESCC', 'Disease', (71, 75))	('1q21.1-qter', 'Var', (104, 115))	('4q31.3-q32.1', 'Var', (319, 331))	('p12', 'Gene', '56655', (182, 185))	('p11', 'Gene', (286, 289))	('p15', 'Gene', '1030', (148, 151))
427260	27877079	Especially, the isochromosome 3q was visualized in lung cancer, squamous cell carcinomas of the vulva, oral, and the head and neck, as well as in the ESCC cell line KYSE 410-4,, suggesting that isochromosome 3q formation is a mechanism of somatic chromosomal aberrations, resulting in reciprocal loss of 3p and gain of 3q during epithelial cell carcinogenesis.	('loss', 'NegReg', (296, 300))	('lung cancer', 'Disease', 'MESH:D008175', (51, 62))	('carcinomas of the vulva', 'Phenotype', 'HP:0030416', (78, 101))	('squamous cell carcinomas of the vulva', 'Phenotype', 'HP:0030417', (64, 101))	('SCC', 'Phenotype', 'HP:0002860', (151, 154))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (64, 88))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (247, 270))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('lung cancer', 'Disease', (51, 62))	('gain of', 'PosReg', (311, 318))	('lung cancer', 'Phenotype', 'HP:0100526', (51, 62))	('squamous cell carcinomas of the vulva', 'Disease', (64, 101))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (64, 87))	('squamous cell carcinomas of the vulva', 'Disease', 'MESH:D002294', (64, 101))	('carcinomas', 'Phenotype', 'HP:0030731', (78, 88))	('isochromosome', 'Var', (194, 207))
427261	27877079	Amplifications were observed in 41 segmental regions, of which 7p11.2 and 11q13.3 were the most repeatedly involved interesting regions (Table S1).	('p11', 'Gene', '6281', (64, 67))	('Amplifications', 'Var', (0, 14))	('p11', 'Gene', (64, 67))
427264	27877079	In the present study, subsequent examination of CCND1 and CTTN protein expression levels confirmed that genomic amplification status parallels the increased protein level.	('CTTN', 'Gene', '2017', (58, 62))	('CCND1', 'Gene', '595', (48, 53))	('genomic amplification status', 'Var', (104, 132))	('CTTN', 'Gene', (58, 62))	('CCND1', 'Gene', (48, 53))
427270	27877079	Amplification and overexpression of EGFR has been reported in ESCC and was significantly associated with a poor prognosis in ESCC patients indicating that it may play an important role in ESCC progression.	('associated', 'Reg', (89, 99))	('Amplification', 'Var', (0, 13))	('SCC', 'Phenotype', 'HP:0002860', (126, 129))	('ESCC', 'Disease', (188, 192))	('SCC', 'Phenotype', 'HP:0002860', (63, 66))	('SCC', 'Phenotype', 'HP:0002860', (189, 192))	('EGFR', 'Gene', '1956', (36, 40))	('patients', 'Species', '9606', (130, 138))	('EGFR', 'Gene', (36, 40))	('ESCC', 'Disease', (62, 66))	('play', 'Reg', (162, 166))	('overexpression', 'PosReg', (18, 32))
427272	27877079	Additional sequencing analysis of CDK2NA revealed a somatic mutation in exon 2 (c.31_32dupCC;p.S12Lfs*15) leading to a stop codon, in one tumor case (TL 0122) of 19 (Fig S2) without the mutation in adjacent normal tissues.	('CDK2', 'Gene', (34, 38))	('c.31_32dupCC;p.S12Lfs*15', 'Var', (80, 104))	('c.31_32dupCC', 'Mutation', 'c.31_32dupCC', (80, 92))	('p.S12Lfs*15', 'Var', (93, 104))	('tumor', 'Disease', (138, 143))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('CDK2', 'Gene', '1017', (34, 38))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('p.S12Lfs*15', 'Mutation', 'p.S12LfsX15', (93, 104))
427273	27877079	FHIT and CDKN2A are virtually known as the most frequently affected genes after TP53 in the context of homozygous deletion, promoter hypermethylation, loss of heterozygosity (LOH), and point mutations in various human cancers including ESCC.	('promoter hypermethylation', 'Var', (124, 149))	('human', 'Species', '9606', (212, 217))	('CDKN2A', 'Gene', '1029', (9, 15))	('SCC', 'Phenotype', 'HP:0002860', (237, 240))	('loss of heterozygosity', 'Var', (151, 173))	('cancers', 'Disease', 'MESH:D009369', (218, 225))	('ESCC', 'Disease', (236, 240))	('cancers', 'Phenotype', 'HP:0002664', (218, 225))	('TP53', 'Gene', '7157', (80, 84))	('cancers', 'Disease', (218, 225))	('TP53', 'Gene', (80, 84))	('point mutations', 'Var', (185, 200))	('FHIT', 'Gene', (0, 4))	('affected', 'Reg', (59, 67))	('FHIT', 'Gene', '2272', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('CDKN2A', 'Gene', (9, 15))
427282	33407724	RNA immunoprecipitation and Dual-luciferase reporter assays were used to assess the interaction between lnc-GAN1 and miR-26a-5p in lung cancer cells.	('GAN1', 'Gene', (108, 112))	('lung cancer', 'Disease', 'MESH:D008175', (131, 142))	('GAN1', 'Gene', '8139', (108, 112))	('miR-26a-5p', 'Var', (117, 127))	('lung cancer', 'Disease', (131, 142))	('interaction', 'Interaction', (84, 95))	('miR-26a-5p', 'Chemical', '-', (117, 127))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('lung cancer', 'Phenotype', 'HP:0100526', (131, 142))
427283	33407724	lnc-GAN1 is downregulated in HCC tissues and associated with larger tumor size and poor overall survival and disease-free survival; its ectopic expression suppresses cell proliferation, colony formation, and cell cycle progression and induces apoptosis in NSCLC cells; it also inhibits tumor growth in the NSCLC xenograft model.	('tumor', 'Phenotype', 'HP:0002664', (286, 291))	('inhibits', 'NegReg', (277, 285))	('tumor', 'Disease', (68, 73))	('apoptosis', 'CPA', (243, 252))	('cell proliferation', 'CPA', (166, 184))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('GAN1', 'Gene', '8139', (4, 8))	('NSCLC', 'Disease', 'MESH:D002289', (306, 311))	('induces', 'Reg', (235, 242))	('colony formation', 'CPA', (186, 202))	('tumor', 'Disease', (286, 291))	('ectopic expression', 'Var', (136, 154))	('NSCLC', 'Disease', (306, 311))	('cell cycle progression', 'CPA', (208, 230))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('tumor', 'Disease', 'MESH:D009369', (286, 291))	('NSCLC', 'Disease', 'MESH:D002289', (256, 261))	('GAN1', 'Gene', (4, 8))	('suppresses', 'NegReg', (155, 165))	('NSCLC', 'Disease', (256, 261))
427300	33407724	Conversely, loss of GAS5-AS1 has been found to contribute to metastasis in lung cancer, and pan-histone deacetylase (HDAC) inhibitors inhibit NSCLC cell metastasis by increasing GAS5-AS1 expression.	('lung cancer', 'Disease', (75, 86))	('lung cancer', 'Phenotype', 'HP:0100526', (75, 86))	('GAS5-AS1', 'Gene', '100506046', (178, 186))	('contribute', 'Reg', (47, 57))	('increasing', 'PosReg', (167, 177))	('NSCLC', 'Disease', (142, 147))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('inhibit', 'NegReg', (134, 141))	('GAS5-AS1', 'Gene', '100506046', (20, 28))	('loss', 'NegReg', (12, 16))	('inhibitors', 'Var', (123, 133))	('NSCLC', 'Disease', 'MESH:D002289', (142, 147))	('metastasis', 'CPA', (61, 71))	('lung cancer', 'Disease', 'MESH:D008175', (75, 86))	('expression', 'MPA', (187, 197))	('GAS5-AS1', 'Gene', (178, 186))	('GAS5-AS1', 'Gene', (20, 28))
427321	33407724	The efficiency of lnc-GAN1 overexpression or knockdown was verified by qRT-PCR.	('overexpression', 'PosReg', (27, 41))	('GAN1', 'Gene', (22, 26))	('knockdown', 'Var', (45, 54))	('GAN1', 'Gene', '8139', (22, 26))
427343	33407724	The H1299 or H1650 cells were seeded in a 10-cm Petri dish and collected according to the manufacturer's instructions.	('H1650', 'Var', (13, 18))	('H1299', 'CellLine', 'CVCL:0060', (4, 9))	('H1650', 'CellLine', 'CVCL:1483', (13, 18))	('H1299', 'Var', (4, 9))
427350	33407724	Lnc-GAN1 with mutated complementary sequence for miR-26a-5p seed sequence was generated by PCR.	('miR-26a-5p', 'Chemical', '-', (49, 59))	('GAN1', 'Gene', '8139', (4, 8))	('mutated', 'Var', (14, 21))	('GAN1', 'Gene', (4, 8))
427368	33407724	We find that the patients with low lnc-GAN1 expression have significantly poorer overall survival (OS) and disease-free survival (DFS) than those with high lnc-GAN1 expression (Fig.	('GAN1', 'Gene', '8139', (160, 164))	('poorer', 'NegReg', (74, 80))	('GAN1', 'Gene', '8139', (39, 43))	('GAN1', 'Gene', (160, 164))	('expression', 'Var', (44, 54))	('GAN1', 'Gene', (39, 43))	('disease-free survival', 'CPA', (107, 128))	('patients', 'Species', '9606', (17, 25))	('low', 'NegReg', (31, 34))	('overall survival', 'CPA', (81, 97))
427379	33407724	S1d); meanwhile, overexpressed lnc-GAN1 significantly increased the apoptosis in H460 and A549 cells whereas downregulated lnc-GAN1 decreased the apoptosis in H1299 and H1650 cells (Fig.	('overexpressed', 'Var', (17, 30))	('GAN1', 'Gene', (35, 39))	('downregulated', 'NegReg', (109, 122))	('H460', 'CellLine', 'CVCL:0459', (81, 85))	('GAN1', 'Gene', '8139', (127, 131))	('H1299', 'CellLine', 'CVCL:0060', (159, 164))	('apoptosis', 'CPA', (68, 77))	('A549', 'CellLine', 'CVCL:0023', (90, 94))	('increased', 'PosReg', (54, 63))	('GAN1', 'Gene', '8139', (35, 39))	('GAN1', 'Gene', (127, 131))	('decreased', 'NegReg', (132, 141))	('H1650', 'CellLine', 'CVCL:1483', (169, 174))
427385	33407724	In addition, IHC staining reveals significantly lower Ki-67 expression (growth index) in the tumors derived from the cells with high lnc-GAN1 expression than in tumors derived from the control cells (Fig.	('expression', 'Var', (142, 152))	('expression', 'MPA', (60, 70))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumors', 'Disease', (161, 167))	('tumors', 'Phenotype', 'HP:0002664', (161, 167))	('lower', 'NegReg', (48, 53))	('GAN1', 'Gene', '8139', (137, 141))	('tumors', 'Disease', 'MESH:D009369', (93, 99))	('tumors', 'Disease', 'MESH:D009369', (161, 167))	('GAN1', 'Gene', (137, 141))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('high', 'Var', (128, 132))	('tumors', 'Disease', (93, 99))	('Ki-67', 'Gene', (54, 59))
427402	33407724	The results show a much higher amount of PCR product from H1650 cells with endogenous high lnc-GAN1 expression compared with that from A549 cells with endogenous low lnc-GAN1 expression (Fig.	('GAN1', 'Gene', (170, 174))	('GAN1', 'Gene', '8139', (95, 99))	('higher', 'PosReg', (24, 30))	('GAN1', 'Gene', (95, 99))	('PCR', 'MPA', (41, 44))	('H1650', 'CellLine', 'CVCL:1483', (58, 63))	('A549', 'CellLine', 'CVCL:0023', (135, 139))	('expression', 'Var', (100, 110))	('high', 'Var', (86, 90))	('GAN1', 'Gene', '8139', (170, 174))
427415	33407724	5b), including miR-26a-5p, mir-1297 and mir-26b-5p.	('miR-26a-5p', 'Var', (15, 25))	('-5p', 'Chemical', '-', (47, 50))	('miR-26a-5p', 'Chemical', '-', (15, 25))	('mir-1297', 'Gene', (27, 35))	('-5p', 'Chemical', '-', (22, 25))	('mir-26b-5p', 'Var', (40, 50))	('mir-1297', 'Gene', '100302187', (27, 35))
427417	33407724	The result shows that only miR-26a-5p has a negative correlation with lnc-GAN1 (R2 = - 0.45, P < 0.05, Fig.	('GAN1', 'Gene', '8139', (74, 78))	('GAN1', 'Gene', (74, 78))	('miR-26a-5p', 'Chemical', '-', (27, 37))	('miR-26a-5p', 'Var', (27, 37))	('negative', 'NegReg', (44, 52))
427419	33407724	Not unexpectedly, overexpressed miR-26a-5p significantly attenuates the expression of lnc-GAN1 in H1299 and H1650 cells (Fig.	('miR-26a-5p', 'Var', (32, 42))	('GAN1', 'Gene', (90, 94))	('miR-26a-5p', 'Chemical', '-', (32, 42))	('H1299', 'CellLine', 'CVCL:0060', (98, 103))	('expression', 'MPA', (72, 82))	('GAN1', 'Gene', '8139', (90, 94))	('H1650', 'CellLine', 'CVCL:1483', (108, 113))	('attenuates', 'NegReg', (57, 67))
427424	33407724	To confirm this point, we constructed lnc-GAN1 luciferase reporters that contained the putative wild-type or mutant miR-26a-5p binding sites (Fig.	('miR-26a-5p', 'Gene', (116, 126))	('miR-26a-5p', 'Chemical', '-', (116, 126))	('mutant', 'Var', (109, 115))	('GAN1', 'Gene', '8139', (42, 46))	('GAN1', 'Gene', (42, 46))
427425	33407724	As expected, miR-26a-5p overexpression significantly decreases the luciferase activity of the wild-type lnc-GAN1 reporter in H1299 and H1650 cells but did not affect that of the mutant lnc-GAN1 reporter (Fig.	('GAN1', 'Gene', (108, 112))	('luciferase', 'Enzyme', (67, 77))	('H1299', 'CellLine', 'CVCL:0060', (125, 130))	('miR-26a-5p', 'Var', (13, 23))	('H1650', 'CellLine', 'CVCL:1483', (135, 140))	('GAN1', 'Gene', '8139', (189, 193))	('miR-26a-5p', 'Chemical', '-', (13, 23))	('GAN1', 'Gene', '8139', (108, 112))	('decreases', 'NegReg', (53, 62))	('activity', 'MPA', (78, 86))	('GAN1', 'Gene', (189, 193))
427431	33407724	Finally, we want to know what role miR-26a-5p plays in NSCLC.	('miR-26a-5p', 'Chemical', '-', (35, 45))	('miR-26a-5p', 'Var', (35, 45))	('NSCLC', 'Disease', 'MESH:D002289', (55, 60))	('NSCLC', 'Disease', (55, 60))
427432	33407724	To this purpose, we overexpressed miR-26a-5p in H1299 and H1650 cells and observed the change in cell proliferation, cell cycle, and apoptosis.	('apoptosis', 'CPA', (133, 142))	('miR-26a-5p', 'Var', (34, 44))	('cell cycle', 'CPA', (117, 127))	('H1650', 'CellLine', 'CVCL:1483', (58, 63))	('miR-26a-5p', 'Chemical', '-', (34, 44))	('change', 'Reg', (87, 93))	('cell proliferation', 'CPA', (97, 115))	('H1299', 'CellLine', 'CVCL:0060', (48, 53))
427433	33407724	The results show that miR-26a-5p overexpression promotes the proliferation and G2 phase progression and decreases apoptosis in both H1299 and H1650 cells (Fig.	('miR-26a-5p', 'Var', (22, 32))	('G2 phase progression', 'CPA', (79, 99))	('miR-26a-5p', 'Chemical', '-', (22, 32))	('decreases', 'NegReg', (104, 113))	('H1299', 'CellLine', 'CVCL:0060', (132, 137))	('promotes', 'PosReg', (48, 56))	('H1650', 'CellLine', 'CVCL:1483', (142, 147))	('proliferation', 'CPA', (61, 74))	('apoptosis', 'CPA', (114, 123))
427434	33407724	S4b-e), suggesting that miR-26a-5p plays a oncogenic role in lung cancer cells.	('lung cancer', 'Disease', (61, 72))	('lung cancer', 'Phenotype', 'HP:0100526', (61, 72))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('miR-26a-5p', 'Var', (24, 34))	('lung cancer', 'Disease', 'MESH:D008175', (61, 72))	('miR-26a-5p', 'Chemical', '-', (24, 34))
427436	33407724	We also found that miR-26a-5p was highly expressed in the 30 NSCLC tissues compared with the matched normal lung tissues (Additional file 2: Fig.	('miR-26a-5p', 'Var', (19, 29))	('NSCLC', 'Disease', 'MESH:D002289', (61, 66))	('NSCLC', 'Disease', (61, 66))	('miR-26a-5p', 'Chemical', '-', (19, 29))
427441	33407724	Therefore, we want to know which target gene(s) of miR-26a-5p mediates the tumor suppressor role of lnc-GAN1 in lung cancer.	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('lung cancer', 'Disease', (112, 123))	('lung cancer', 'Phenotype', 'HP:0100526', (112, 123))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('GAN1', 'Gene', '8139', (104, 108))	('lung cancer', 'Disease', 'MESH:D008175', (112, 123))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('GAN1', 'Gene', (104, 108))	('miR-26a-5p', 'Var', (51, 61))	('tumor', 'Disease', (75, 80))	('miR-26a-5p', 'Chemical', '-', (51, 61))
427444	33407724	Of the three upregulated genes, CDK8 and PTGS2 have been reported to be oncogenic gene, which cannot mediate the tumor-suppressor role; PTEN is one of the most important tumor suppressor genes in cancers, and meets both requirements: a direct target of miR-26a-5p and a possible indirect downstream gene of the tumor-suppressive lnc-GAN1.	('CDK8', 'Gene', (32, 36))	('upregulated', 'PosReg', (13, 24))	('GAN1', 'Gene', '8139', (333, 337))	('tumor', 'Disease', (170, 175))	('cancers', 'Disease', 'MESH:D009369', (196, 203))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('CDK8', 'Gene', '1024', (32, 36))	('PTGS2', 'Gene', (41, 46))	('tumor', 'Disease', (311, 316))	('tumor', 'Disease', (113, 118))	('miR-26a-5p', 'Var', (253, 263))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('tumor', 'Disease', 'MESH:D009369', (311, 316))	('cancers', 'Phenotype', 'HP:0002664', (196, 203))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('cancers', 'Disease', (196, 203))	('GAN1', 'Gene', (333, 337))	('PTEN', 'Gene', (136, 140))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('PTGS2', 'Gene', '5743', (41, 46))	('miR-26a-5p', 'Chemical', '-', (253, 263))	('tumor', 'Phenotype', 'HP:0002664', (311, 316))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('PTEN', 'Gene', '5728', (136, 140))
427445	33407724	To verified which gene(s) can be targeted by miR-26a-5p, we overexpressed miR-26a-5p in H1299 cells and found that only PTEN expression was decreased and CDK8 and PTGS2 expression did not change in H1299 cells (Additional file 2: Fig.	('CDK8', 'Gene', '1024', (154, 158))	('decreased', 'NegReg', (140, 149))	('miR-26a-5p', 'Var', (74, 84))	('miR-26a-5p', 'Chemical', '-', (45, 55))	('miR-26a-5p', 'Chemical', '-', (74, 84))	('H1299', 'CellLine', 'CVCL:0060', (198, 203))	('expression', 'MPA', (125, 135))	('H1299', 'CellLine', 'CVCL:0060', (88, 93))	('PTEN', 'Gene', (120, 124))	('PTGS2', 'Gene', (163, 168))	('PTEN', 'Gene', '5728', (120, 124))	('PTGS2', 'Gene', '5743', (163, 168))	('CDK8', 'Gene', (154, 158))
427446	33407724	S5a), implying that only PTEN may be a target of miR-26a-5p in lung cancer.	('miR-26a-5p', 'Chemical', '-', (49, 59))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('lung cancer', 'Disease', 'MESH:D008175', (63, 74))	('lung cancer', 'Disease', (63, 74))	('S5a', 'Gene', '5710', (0, 3))	('S5a', 'Gene', (0, 3))	('lung cancer', 'Phenotype', 'HP:0100526', (63, 74))	('PTEN', 'Gene', (25, 29))	('miR-26a-5p', 'Var', (49, 59))	('PTEN', 'Gene', '5728', (25, 29))
427448	33407724	Then, we want to verify that PTEN is a direct target of miR-26a-5p.	('miR-26a-5p', 'Var', (56, 66))	('PTEN', 'Gene', (29, 33))	('PTEN', 'Gene', '5728', (29, 33))	('miR-26a-5p', 'Chemical', '-', (56, 66))
427450	33407724	The result indicates that ectopic expression of miR-26a-5p indeed downregulated PTEN mRNA and protein levels in H1299 and H1650 cells (Fig.	('ectopic expression', 'MPA', (26, 44))	('PTEN', 'Gene', (80, 84))	('H1650', 'CellLine', 'CVCL:1483', (122, 127))	('PTEN', 'Gene', '5728', (80, 84))	('H1299', 'CellLine', 'CVCL:0060', (112, 117))	('downregulated', 'NegReg', (66, 79))	('miR-26a-5p', 'Var', (48, 58))	('miR-26a-5p', 'Chemical', '-', (48, 58))
427451	33407724	We next attempt to determine whether PTEN could be directly bound by miR-26a-5p.	('PTEN', 'Gene', '5728', (37, 41))	('miR-26a-5p', 'Chemical', '-', (69, 79))	('miR-26a-5p', 'Var', (69, 79))	('PTEN', 'Gene', (37, 41))
427452	33407724	Thus, we inserted wild-type or mutant PTEN 3'UTR sequence (Fig.	('PTEN', 'Gene', '5728', (38, 42))	('mutant', 'Var', (31, 37))	('PTEN', 'Gene', (38, 42))
427454	33407724	As expected, miR-26a-5p overexpression reduced the luciferase activity of the wild-type PTEN 3'UTR reporter, but had no effect on the mutant reporter in the two cell lines (Fig.	('activity', 'MPA', (62, 70))	('miR-26a-5p', 'Var', (13, 23))	('PTEN', 'Gene', (88, 92))	('PTEN', 'Gene', '5728', (88, 92))	('miR-26a-5p', 'Chemical', '-', (13, 23))	('reduced', 'NegReg', (39, 46))	('luciferase', 'Enzyme', (51, 61))
427455	33407724	6c lower-panel), indicating that miR-26a-5p can directly bind to 3'UTR of PTEN gene.	('miR-26a-5p', 'Var', (33, 43))	('miR-26a-5p', 'Chemical', '-', (33, 43))	('PTEN', 'Gene', (74, 78))	('bind', 'Interaction', (57, 61))	('PTEN', 'Gene', '5728', (74, 78))
427458	33407724	The results demonstrate that ectopic lnc-GAN1 expression upregulates PTEN mRNA and downregulates mir-26a-5p in A549 cells (Fig.	('ectopic', 'Var', (29, 36))	('PTEN', 'Gene', '5728', (69, 73))	('upregulates', 'PosReg', (57, 68))	('-5p', 'Chemical', '-', (104, 107))	('GAN1', 'Gene', '8139', (41, 45))	('A549', 'CellLine', 'CVCL:0023', (111, 115))	('GAN1', 'Gene', (41, 45))	('downregulates', 'NegReg', (83, 96))	('mir-26a-5p', 'MPA', (97, 107))	('PTEN', 'Gene', (69, 73))
427459	33407724	6d upper-penal), while lnc-GAN1 knockdown exerted the opposite effects in H1299 cells (Fig.	('H1299', 'CellLine', 'CVCL:0060', (74, 79))	('GAN1', 'Gene', (27, 31))	('knockdown', 'Var', (32, 41))	('GAN1', 'Gene', '8139', (27, 31))
427462	33407724	The results suggest that miR-26a-5p overexpression can not only reduce endogenous PTEN protein but also reverse the upregulation of PTEN protein induced by lnc-GAN1 in A549 cells (Fig.	('GAN1', 'Gene', '8139', (160, 164))	('PTEN', 'Gene', (132, 136))	('GAN1', 'Gene', (160, 164))	('PTEN', 'Gene', '5728', (82, 86))	('reduce', 'NegReg', (64, 70))	('PTEN', 'Gene', '5728', (132, 136))	('A549', 'CellLine', 'CVCL:0023', (168, 172))	('reverse', 'NegReg', (104, 111))	('miR-26a-5p', 'Var', (25, 35))	('upregulation', 'PosReg', (116, 128))	('miR-26a-5p', 'Chemical', '-', (25, 35))	('PTEN', 'Gene', (82, 86))	('endogenous', 'MPA', (71, 81))
427463	33407724	6e); CCK8 and cell cycle assays revealed that miR-26a-5p overexpression can not only promote cell proliferation and G1-phase cell cycle progression but also restore the cell proliferation and G1-phase cell cycle progression that are inhibited by lnc-GAN1 in A549 and H1650 cells (Fig.	('miR-26a-5p', 'Var', (46, 56))	('H1650', 'CellLine', 'CVCL:1483', (267, 272))	('restore', 'PosReg', (157, 164))	('miR-26a-5p', 'Chemical', '-', (46, 56))	('GAN1', 'Gene', '8139', (250, 254))	('promote', 'PosReg', (85, 92))	('A549', 'CellLine', 'CVCL:0023', (258, 262))	('GAN1', 'Gene', (250, 254))	('cell proliferation', 'CPA', (93, 111))	('G1-phase cell cycle progression', 'CPA', (116, 147))	('G1-phase cell cycle progression', 'CPA', (192, 223))	('cell proliferation', 'CPA', (169, 187))
427469	33407724	7d, R2 = - 0.46, P < 0.05), indicating that PTEN is a target gene of miR-26a-5p and mediates the tumor-suppressor role of lnc-GAN1 in NSCLC.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('NSCLC', 'Disease', 'MESH:D002289', (134, 139))	('miR-26a-5p', 'Chemical', '-', (69, 79))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumor', 'Disease', (97, 102))	('GAN1', 'Gene', '8139', (126, 130))	('PTEN', 'Gene', (44, 48))	('GAN1', 'Gene', (126, 130))	('PTEN', 'Gene', '5728', (44, 48))	('miR-26a-5p', 'Var', (69, 79))	('NSCLC', 'Disease', (134, 139))
427481	33407724	S5f), which is consistent with the reported findings that the activated PTEN induces G1-phase cell cycle arrest; we also confirmed the G1-phase arrest caused by activated lnc-GAN1/miR-26-5p/PTEN axis in the above experiment.	('PTEN', 'Gene', (72, 76))	('PTEN', 'Gene', (190, 194))	('activated', 'Var', (62, 71))	('PTEN', 'Gene', '5728', (72, 76))	('PTEN', 'Gene', '5728', (190, 194))	('arrest', 'Disease', 'MESH:D006323', (105, 111))	('GAN1', 'Gene', '8139', (175, 179))	('GAN1', 'Gene', (175, 179))	('arrest', 'Disease', 'MESH:D006323', (144, 150))	('arrest', 'Disease', (144, 150))	('-5p', 'Chemical', '-', (186, 189))	('induces', 'Reg', (77, 84))	('arrest', 'Disease', (105, 111))
427495	33407724	In this study, we demonstrate for the first time that lnc-GAN1 functions as an endogenous sponge for miR-26a-5p to upregulate PTEN expression and thereby exert tumor-suppressive effects in NSCLC.	('NSCLC', 'Disease', (189, 194))	('miR-26a-5p', 'Var', (101, 111))	('NSCLC', 'Disease', 'MESH:D002289', (189, 194))	('miR-26a-5p', 'Chemical', '-', (101, 111))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('expression', 'MPA', (131, 141))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('GAN1', 'Gene', '8139', (58, 62))	('GAN1', 'Gene', (58, 62))	('tumor', 'Disease', (160, 165))	('PTEN', 'Gene', (126, 130))	('upregulate', 'PosReg', (115, 125))	('PTEN', 'Gene', '5728', (126, 130))
427502	33407724	Bioinformatics analysis showed that there are two predicted binding sites for miR-26a-5p in lnc-GAN1 sequence.	('miR-26a-5p', 'Var', (78, 88))	('miR-26a-5p', 'Chemical', '-', (78, 88))	('GAN1', 'Gene', '8139', (96, 100))	('GAN1', 'Gene', (96, 100))	('binding', 'Interaction', (60, 67))
427505	33407724	MiR-26a-5p has previously been reported to promote cell proliferation, accelerate G1/S cell cycle transition, and enhance cancer metastasis.	('promote', 'PosReg', (43, 50))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('G1/S cell cycle transition', 'CPA', (82, 108))	('enhance', 'PosReg', (114, 121))	('cell proliferation', 'CPA', (51, 69))	('MiR-26a-5p', 'Chemical', '-', (0, 10))	('MiR-26a-5p', 'Var', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('accelerate', 'PosReg', (71, 81))
427506	33407724	Moreover, miR-26a-5p upregulation predicts poor prognosis in lung cancer and has been proposed to be used as a potential prognostic biomarker.	('lung cancer', 'Disease', (61, 72))	('miR-26a-5p', 'Chemical', '-', (10, 20))	('lung cancer', 'Phenotype', 'HP:0100526', (61, 72))	('poor', 'NegReg', (43, 47))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('lung cancer', 'Disease', 'MESH:D008175', (61, 72))	('upregulation', 'PosReg', (21, 33))	('miR-26a-5p', 'Var', (10, 20))
427508	33407724	In vitro experiment shows that miR-26a-5p overexpression promotes NSCLC cell proliferation and inhibits apoptosis, thereby directly opposing the effects of lnc-GAN1.	('GAN1', 'Gene', '8139', (160, 164))	('GAN1', 'Gene', (160, 164))	('NSCLC', 'Disease', (66, 71))	('NSCLC', 'Disease', 'MESH:D002289', (66, 71))	('miR-26a-5p', 'Var', (31, 41))	('apoptosis', 'CPA', (104, 113))	('inhibits', 'NegReg', (95, 103))	('miR-26a-5p', 'Chemical', '-', (31, 41))	('promotes', 'PosReg', (57, 65))
427510	33407724	Previous studies have validated PTEN as a direct target of miR-26a-5p and showed that miR-26a-5p promotes cancer progression by down-regulating PTEN and subsequently activating the downstream PI3K/AKT pathway.	('down-regulating', 'NegReg', (128, 143))	('AKT', 'Gene', '207', (197, 200))	('PTEN', 'Gene', '5728', (144, 148))	('PTEN', 'Gene', (32, 36))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('PTEN', 'Gene', '5728', (32, 36))	('AKT', 'Gene', (197, 200))	('cancer', 'Disease', (106, 112))	('promotes', 'PosReg', (97, 105))	('miR-26a-5p', 'Var', (86, 96))	('PTEN', 'Gene', (144, 148))	('activating', 'PosReg', (166, 176))	('miR-26a-5p', 'Chemical', '-', (86, 96))	('miR-26a-5p', 'Chemical', '-', (59, 69))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
427511	33407724	We confirm the negative correlation between mir-26a-5p and PTEN levels in NSCLC clinical samples in this study and find that miR-26a-5p overexpression reduces the mRNA and protein levels of PTEN in NSCLC cell lines.	('miR-26a-5p', 'Chemical', '-', (125, 135))	('reduces', 'NegReg', (151, 158))	('PTEN', 'Gene', (190, 194))	('-5p', 'Chemical', '-', (51, 54))	('PTEN', 'Gene', '5728', (190, 194))	('overexpression', 'PosReg', (136, 150))	('-5p', 'Chemical', '-', (132, 135))	('NSCLC', 'Disease', (74, 79))	('miR-26a-5p', 'Var', (125, 135))	('NSCLC', 'Disease', (198, 203))	('NSCLC', 'Disease', 'MESH:D002289', (74, 79))	('PTEN', 'Gene', (59, 63))	('NSCLC', 'Disease', 'MESH:D002289', (198, 203))	('PTEN', 'Gene', '5728', (59, 63))
427512	33407724	Dual-luciferase reporter assays further revealed that miR-26a-5p can specifically bind to the 3'UTR region of PTEN.	('PTEN', 'Gene', '5728', (110, 114))	('miR-26a-5p', 'Var', (54, 64))	('miR-26a-5p', 'Chemical', '-', (54, 64))	('bind', 'Interaction', (82, 86))	('PTEN', 'Gene', (110, 114))
427519	33407724	For instance, lncRNA-AC078883.3 has been reported to regulate the PTEN/AKT signaling pathway by sponging miR-19a, thus suppressing the development of cisplatin chemoresistance in lung cancer.	('development', 'CPA', (135, 146))	('cisplatin', 'Chemical', 'MESH:D002945', (150, 159))	('sponging', 'Var', (96, 104))	('regulate', 'Reg', (53, 61))	('PTEN', 'Gene', (66, 70))	('AKT', 'Gene', '207', (71, 74))	('suppressing', 'NegReg', (119, 130))	('lung cancer', 'Disease', (179, 190))	('lncRNA-AC078883.3', 'Var', (14, 31))	('PTEN', 'Gene', '5728', (66, 70))	('miR-19a', 'Gene', '406979', (105, 112))	('lung cancer', 'Phenotype', 'HP:0100526', (179, 190))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('AKT', 'Gene', (71, 74))	('miR-19a', 'Gene', (105, 112))	('lung cancer', 'Disease', 'MESH:D008175', (179, 190))
427524	33407724	In addition, miR-26a-5p overexpression could rescue the effects of lnc-GAN1 overexpression on cell proliferation and cell cycle.	('GAN1', 'Gene', '8139', (71, 75))	('GAN1', 'Gene', (71, 75))	('cell cycle', 'CPA', (117, 127))	('miR-26a-5p', 'Var', (13, 23))	('miR-26a-5p', 'Chemical', '-', (13, 23))	('cell proliferation', 'CPA', (94, 112))	('overexpression', 'PosReg', (76, 90))
427536	33298066	The intraoperative bleeding volume of modified reverse-puncture anastomotic technique group was 157.3 +- 107.4 ml, while it was 191.9 +- 123.6 ml in traditional technique group (P = 0.14).	('intraoperative bleeding', 'Disease', (4, 27))	('modified', 'Var', (38, 46))	('intraoperative bleeding', 'Disease', 'MESH:D016063', (4, 27))
427645	33396658	Notably, it was observed that CXT efficiently induces mitochondrial dysfunction at the molecular level and poisoning at the physiological level.	('poisoning', 'MPA', (107, 116))	('CXT', 'Chemical', 'MESH:C003853', (30, 33))	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (54, 79))	('mitochondrial dysfunction', 'Disease', 'MESH:D028361', (54, 79))	('induces', 'Reg', (46, 53))	('CXT', 'Var', (30, 33))	('mitochondrial dysfunction', 'Disease', (54, 79))
427655	33396658	HK2 and CaKi-1 cells were maintained in high glucose Dulbecco's Modified Eagle's Medium (DMEM) with sodium pyruvate and stable glutamine (Euroclone, ECL0103L, Pero, Milan, Italy), supplemented with 10% Fetal Bovine Serum (FBS, Euroclone ECS0180L, Pero, Milan, Italy), and 1% penicillin-streptomycin (Euroclone, ECM0010, Pero, Milan, Italy).	('DMEM', 'Chemical', '-', (89, 93))	('HK2', 'Gene', '3099', (0, 3))	('streptomycin', 'Chemical', 'MESH:D013307', (286, 298))	('sodium pyruvate', 'Chemical', '-', (100, 115))	('CaKi-1', 'CellLine', 'CVCL:0234', (8, 14))	("Dulbecco's Modified Eagle's Medium", 'Chemical', '-', (53, 87))	('glutamine', 'Chemical', 'MESH:D005973', (127, 136))	('Bovine', 'Species', '9913', (208, 214))	('ECS0180L', 'Var', (237, 245))	('high glucose', 'Phenotype', 'HP:0003074', (40, 52))	('penicillin', 'Chemical', 'MESH:D010406', (275, 285))	('HK2', 'Gene', (0, 3))	('glucose', 'Chemical', 'MESH:D005947', (45, 52))
427675	33396658	The following day, membranes were washed in 0.5% Tween20-TBS (P9416 and T5912, Sigma, St. Louis, MO, USA) under shaking and incubated for 1 h at room temperature with appropriate peroxidase-conjugated secondary antibodies (Santa Cruz Biotechnology, Santa Cruz, CA, USA; 1:30,000 dilution).	('T5912', 'Chemical', '-', (72, 77))	('P9416', 'Chemical', '-', (62, 67))	('P9416', 'Var', (62, 67))	('Tween20-TBS', 'Chemical', '-', (49, 60))	('T5912', 'Var', (72, 77))
427737	33396658	The differential expression of AACs in the different cited cancer/non-cancer tissue pairs should reflect specific metabolic adaptations in response to specific cancer driver mutations or gene expression alterations, as already observed in cell-based assays.	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('cancer', 'Disease', (160, 166))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('alterations', 'Var', (203, 214))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('mutations', 'Var', (174, 183))	('cancer', 'Disease', (59, 65))	('non-cancer', 'Disease', (66, 76))	('cancer', 'Disease', (70, 76))	('non-cancer', 'Disease', 'MESH:D009369', (66, 76))	('AACs', 'Gene', (31, 35))
427757	31285545	Aberrant activation of this signaling network is an early driver of many sporadic human cancers.	('activation', 'PosReg', (9, 19))	('Aberrant', 'Var', (0, 8))	('cancers', 'Disease', 'MESH:D009369', (88, 95))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('cancers', 'Disease', (88, 95))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('human', 'Species', '9606', (82, 87))
427764	31285545	Recurrent PI3K/AKT/mTORC1 alterations, particularly activating hotspot PIK3CA mutations (E545K and H1047R) or inactivating PTEN mutations, occur in 30% of human sporadic tumors.	('E545K', 'Var', (89, 94))	('PTEN', 'Gene', (123, 127))	('AKT', 'Gene', (15, 18))	('inactivating', 'NegReg', (110, 122))	('tumors', 'Disease', 'MESH:D009369', (170, 176))	('PIK3CA', 'Gene', '5290', (71, 77))	('H1047R', 'Var', (99, 105))	('mTORC1', 'Gene', (19, 25))	('PTEN', 'Gene', '5728', (123, 127))	('mTORC1', 'Gene', '382056', (19, 25))	('H1047R', 'Mutation', 'rs121913279', (99, 105))	('AKT', 'Gene', '207', (15, 18))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('activating', 'PosReg', (52, 62))	('tumors', 'Phenotype', 'HP:0002664', (170, 176))	('PIK3CA', 'Gene', (71, 77))	('E545K', 'Mutation', 'rs104886003', (89, 94))	('human', 'Species', '9606', (155, 160))	('tumors', 'Disease', (170, 176))
427765	31285545	Some (1.4-8%) breast, colorectal, and ovarian cancers display an AKT-E17K mutation conferring constitutive activation.	('mutation', 'Var', (74, 82))	('E17K', 'Mutation', 'rs121434592', (69, 73))	('cancers', 'Phenotype', 'HP:0002664', (46, 53))	('colorectal', 'Disease', (22, 32))	('AKT', 'Gene', (65, 68))	('breast', 'Disease', (14, 20))	('ovarian cancers', 'Phenotype', 'HP:0100615', (38, 53))	('ovarian cancers', 'Disease', (38, 53))	('ovarian cancers', 'Disease', 'MESH:D010051', (38, 53))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('AKT', 'Gene', '207', (65, 68))
427771	31285545	However, additional genetic and epigenetic perturbations can reverse OIS to promote cancer development.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('epigenetic perturbations', 'Var', (32, 56))	('promote', 'PosReg', (76, 83))	('perturbations', 'Var', (43, 56))	('cancer', 'Disease', (84, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))
427772	31285545	Lymphocytes in Emicro-Nras mice display strong SA-ssGal activity; however, loss of the histone methyltransferase Suv39h1 impairs SA-ssGal activity and causes T-cell lymphoma.	('SA-ssGal activity', 'CPA', (129, 146))	('SA-ssGal', 'Chemical', '-', (47, 55))	('impairs', 'NegReg', (121, 128))	('Nras', 'Gene', (22, 26))	('Suv39h1', 'Gene', (113, 120))	('mice', 'Species', '10090', (27, 31))	('Suv39h1', 'Gene', '20937', (113, 120))	('T-cell lymphoma', 'Phenotype', 'HP:0012190', (158, 173))	('Nras', 'Gene', '18176', (22, 26))	('causes', 'Reg', (151, 157))	('T-cell lymphoma', 'Disease', (158, 173))	('T-cell lymphoma', 'Disease', 'MESH:D016399', (158, 173))	('lymphoma', 'Phenotype', 'HP:0002665', (165, 173))	('cell lymphoma', 'Phenotype', 'HP:0012191', (160, 173))	('loss', 'Var', (75, 79))	('SA-ssGal', 'Chemical', '-', (129, 137))
427773	31285545	Constitutively active BrafV600E promotes senescence in melanocytic nevi, but Pten depletion drives melanomagenesis.	('melanomagenesis', 'Disease', (99, 114))	('melanocytic nevi', 'Phenotype', 'HP:0000995', (55, 71))	('melanomagenesis', 'Disease', 'None', (99, 114))	('Pten depletion', 'MPA', (77, 91))	('senescence', 'MPA', (41, 51))	('BrafV600E', 'Var', (22, 31))	('BrafV600E', 'Mutation', 'rs113488022', (22, 31))	('nevi', 'Phenotype', 'HP:0003764', (67, 71))	('melanoma', 'Phenotype', 'HP:0002861', (99, 107))	('promotes', 'PosReg', (32, 40))	('melanocytic nevi', 'Disease', (55, 71))
427774	31285545	Neurofibromin 1 (NF1) deficiency overcame BrafV600E-induced senescence and conferred BRAF inhibitor resistance in melanoma.	('senescence', 'MPA', (60, 70))	('overcame', 'PosReg', (33, 41))	('melanoma', 'Disease', 'MESH:D008545', (114, 122))	('deficiency', 'Var', (22, 32))	('Neurofibromin 1', 'Gene', '4763', (0, 15))	('BrafV600E-induced', 'Var', (42, 59))	('BRAF', 'Gene', (85, 89))	('BRAF', 'Gene', '673', (85, 89))	('NF1', 'Gene', (17, 20))	('Neurofibromin 1', 'Gene', (0, 15))	('BrafV600E', 'Mutation', 'rs113488022', (42, 51))	('conferred', 'Reg', (75, 84))	('NF1', 'Gene', '4763', (17, 20))	('melanoma', 'Phenotype', 'HP:0002861', (114, 122))	('melanoma', 'Disease', (114, 122))
427775	31285545	We and others have demonstrated chronic PI3K/AKT/mTORC1 pathway activation promotes an OIS-like phenotype, termed AKT-induced senescence (AIS), with PIK3CA mutants, PTEN knockdown, and constitutively active AKT triggering AIS.	('AKT', 'Gene', '207', (114, 117))	('AKT', 'Gene', '207', (207, 210))	('AKT', 'Gene', '207', (45, 48))	('activation promotes', 'PosReg', (64, 83))	('AKT', 'Gene', (45, 48))	('AKT', 'Gene', (114, 117))	('mTORC1', 'Gene', '382056', (49, 55))	('OIS-like', 'Disease', (87, 95))	('mutants', 'Var', (156, 163))	('AKT', 'Gene', (207, 210))	('PIK3CA', 'Gene', (149, 155))	('PIK3CA', 'Gene', '5290', (149, 155))	('PTEN', 'Gene', (165, 169))	('mTORC1', 'Gene', (49, 55))	('PTEN', 'Gene', '5728', (165, 169))
427778	31285545	Similarly, activated Akt or Pten knockout in murine prostate epithelium promoted intraepithelial neoplasia and senescence marker expression, while subsequent Cdkn1b or Trp53 loss facilitated adenocarcinoma progression and senescence marker loss.	('Trp53', 'Gene', (168, 173))	('intraepithelial neoplasia', 'Phenotype', 'HP:0032187', (81, 106))	('facilitated', 'PosReg', (179, 190))	('Pten', 'Gene', (28, 32))	('Akt', 'Gene', (21, 24))	('promoted', 'PosReg', (72, 80))	('adenocarcinoma', 'Disease', 'MESH:D000230', (191, 205))	('neoplasia', 'Phenotype', 'HP:0002664', (97, 106))	('senescence marker', 'CPA', (222, 239))	('Akt', 'Gene', '11651', (21, 24))	('Cdkn1b', 'Gene', '12576', (158, 164))	('murine', 'Species', '10090', (45, 51))	('loss', 'NegReg', (240, 244))	('knockout', 'Var', (33, 41))	('carcinoma', 'Phenotype', 'HP:0030731', (196, 205))	('senescence marker expression', 'MPA', (111, 139))	('Trp53', 'Gene', '22059', (168, 173))	('neoplasia', 'Disease', 'MESH:D009369', (97, 106))	('Cdkn1b', 'Gene', (158, 164))	('loss', 'NegReg', (174, 178))	('adenocarcinoma', 'Disease', (191, 205))	('neoplasia', 'Disease', (97, 106))
427779	31285545	We hypothesize that, like OIS, AIS is a reversible tumor-suppressive mechanism, and understanding how it is overcome will identify mechanisms of tumorigenesis and therapeutic resistance in the 38% of human solid cancers with deregulated PI3K/AKT/mTORC1 activity.	('AKT', 'Gene', '207', (242, 245))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('deregulated', 'Var', (225, 236))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('mTORC1', 'Gene', (246, 252))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumor', 'Disease', (51, 56))	('cancers', 'Phenotype', 'HP:0002664', (212, 219))	('tumor', 'Disease', (145, 150))	('AKT', 'Gene', (242, 245))	('human', 'Species', '9606', (200, 205))	('cancers', 'Disease', 'MESH:D009369', (212, 219))	('mTORC1', 'Gene', '382056', (246, 252))	('cancers', 'Disease', (212, 219))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))
427788	31285545	BJ-TERT cells were cultured in Dulbecco's Modified Eagle's Medium (DMEM) (Gibco  #11965084) +20 mM HEPES, 17% Medium 199 (Gibco  #11150067), 15% fetal bovine serum (FBS), and 1% GlutaMAX  l-alanyl-l-glutamine dipeptide (Gibco  #35050061).	('dipeptide', 'Chemical', 'MESH:D004151', (209, 218))	("Dulbecco's Modified Eagle's Medium", 'Chemical', '-', (31, 65))	('Gibco', 'Var', (74, 79))	('HEPES', 'Chemical', 'MESH:D006531', (99, 104))	('Gibco', 'Var', (122, 127))	('GlutaMAX  l-alanyl-l-glutamine', 'Chemical', '-', (178, 208))	('DMEM', 'Chemical', '-', (67, 71))	('BJ-TERT', 'CellLine', 'CVCL:6573', (0, 7))
427802	31285545	The REBIR plasmid was modified to generate an inducible overexpression construct RT3-puro by excising the dsRed2/mirE cassette and replacing EBFP2 with the puromycin resistance gene.	('EBFP2', 'Gene', (141, 146))	('puromycin', 'Chemical', 'MESH:D011691', (156, 165))	('dsRed2/mirE', 'Gene', (106, 117))	('excising', 'NegReg', (93, 101))	('replacing', 'Var', (131, 140))
427811	31285545	BJ-TERT cells were retrovirally transduced with myristoylated AKT1 (myrAKT1), establishing a senescent cell population, as we utilized for RNA-sequencing (RNA-seq) analysis.	('AKT1', 'Gene', '207', (62, 66))	('AKT1', 'Gene', (62, 66))	('myristoylated', 'Var', (48, 61))	('AKT1', 'Gene', '207', (71, 75))	('AKT1', 'Gene', (71, 75))	('BJ-TERT', 'CellLine', 'CVCL:6573', (0, 7))
427842	31285545	Spheroids were then embedded in a 20 microL droplet of Matrigel  Growth Factor Reduced Basement Membrane Matrix (Corning  #356231) in a 48-well flat-bottom polystyrene tissue culture plate (Corning  #3548).	('Corning', 'Var', (113, 120))	('polystyrene', 'Chemical', 'MESH:D011137', (156, 167))	('Reduced', 'NegReg', (79, 86))	('Basement', 'Protein', (87, 95))
427853	31285545	In REVOLVER, an alteration could be of any type, including single-nucleotide variants, copy-number alterations, or epigenomics events.	('ER', 'Gene', '2099', (9, 11))	('copy-number alterations', 'Var', (87, 110))	('single-nucleotide variants', 'Var', (59, 85))
427856	31285545	We obtained the clonality of mutations of lung (TRACERx) cohorts, where patient-level trees capturing the evolution of the cancer were derived based on multiregion sequencing using machine learning based on a transfer learning method.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('ER', 'Gene', '2099', (52, 54))	('mutations', 'Var', (29, 38))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('patient', 'Species', '9606', (72, 79))	('cancer', 'Disease', (123, 129))
427857	31285545	We only considered the 36 AIS escape screen genes with mutations in >=3 patients and were clonal or subclonal in >=1 patient.	('mutations', 'Var', (55, 64))	('patient', 'Species', '9606', (72, 79))	('patient', 'Species', '9606', (117, 124))	('AIS escape screen genes', 'Gene', (26, 49))	('patients', 'Species', '9606', (72, 80))
427860	31285545	Of these samples, 19 patients had cell cycle and apoptosis regulator 1 (CCAR1) mutations, 5 had Fas-associated protein with death domain (FADD) mutations, and 21 had NF1 mutations.	('NF1', 'Gene', (166, 169))	('CCAR1', 'Gene', '55749', (72, 77))	('NF1', 'Gene', '4763', (166, 169))	('FADD', 'Gene', '8772', (138, 142))	('patients', 'Species', '9606', (21, 29))	('cell cycle and apoptosis regulator 1', 'Gene', '55749', (34, 70))	('FADD', 'Gene', (138, 142))	('CCAR1', 'Gene', (72, 77))	('death', 'Disease', 'MESH:D003643', (124, 129))	('death', 'Disease', (124, 129))	('mutations', 'Var', (79, 88))
427861	31285545	Two LUSC patients had CCAR1 mutations and three had NF1 mutations.	('NF1', 'Gene', (52, 55))	('CCAR1', 'Gene', (22, 27))	('patients', 'Species', '9606', (9, 17))	('NF1', 'Gene', '4763', (52, 55))	('CCAR1', 'Gene', '55749', (22, 27))	('mutations', 'Var', (28, 37))
427862	31285545	In the LUSC with CCAR1 or NF1 mutations, we calculated the level of expression of the AIS escape signature in individual patients using ssGSEA from the GSVA R package on the RNA-seq data.	('GSEA', 'Chemical', '-', (138, 142))	('NF1', 'Gene', (26, 29))	('CCAR1', 'Gene', (17, 22))	('NF1', 'Gene', '4763', (26, 29))	('mutations', 'Var', (30, 39))	('patients', 'Species', '9606', (121, 129))	('CCAR1', 'Gene', '55749', (17, 22))
427863	31285545	For the reference group, we only considered patients with mutation, copy-number aberration, and gene expression data to ensure the group excluded patients with alterations in CCAR1, FADD, or NF1.	('patients', 'Species', '9606', (44, 52))	('NF1', 'Gene', (191, 194))	('CCAR1', 'Gene', (175, 180))	('FADD', 'Gene', (182, 186))	('NF1', 'Gene', '4763', (191, 194))	('FADD', 'Gene', '8772', (182, 186))	('alterations', 'Var', (160, 171))	('CCAR1', 'Gene', '55749', (175, 180))	('patients', 'Species', '9606', (146, 154))
427883	31285545	RNA-seq analysis also revealed RAS/ERK pathway inhibitor upregulation during AIS: the Sprouty-related genes SPRED1, SPRED2, and SPRED3; Sproutys SPRY1, SPRY2, SPRY3, and SPRY4; and the ERK-inactivating dual specificity phosphatases DUSP4 and DUSP6 (Fig.	('SPRED3', 'Gene', (128, 134))	('Sproutys', 'Var', (136, 144))	('SPRY1', 'Gene', (145, 150))	('SPRY2', 'Gene', '10253', (152, 157))	('DUSP6', 'Gene', '1848', (242, 247))	('upregulation', 'PosReg', (57, 69))	('ERK', 'Gene', '5594', (185, 188))	('SPRED1', 'Gene', (108, 114))	('ERK', 'Gene', (35, 38))	('SPRED2', 'Gene', '200734', (116, 122))	('SPRY2', 'Gene', (152, 157))	('SPRY3', 'Gene', (159, 164))	('DUSP4', 'Gene', (232, 237))	('DUSP6', 'Gene', (242, 247))	('SPRY4', 'Gene', (170, 175))	('ERK', 'Gene', (185, 188))	('SPRED3', 'Gene', '399473', (128, 134))	('SPRY3', 'Gene', '10251', (159, 164))	('SPRED2', 'Gene', (116, 122))	('SPRY1', 'Gene', '10252', (145, 150))	('SPRY4', 'Gene', '81848', (170, 175))	('SPRED1', 'Gene', '161742', (108, 114))	('DUSP4', 'Gene', '1846', (232, 237))	('ERK', 'Gene', '5594', (35, 38))
427906	31285545	Mutations were classified as clonal (present in all cells), occurring early during tumor evolution, or subclonal (present in a subset), occurring later.	('tumor', 'Disease', (83, 88))	('Mutations', 'Var', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))
427910	31285545	To test this, we generated BJ-TERT cell lines expressing inducible shRNAs (Fig.	('shRNAs', 'Gene', (67, 73))	('BJ-TERT', 'CellLine', 'CVCL:6573', (27, 34))	('inducible', 'Var', (57, 66))
427913	31285545	S3b) and confirmed p65 knockdown (Fig.	('p65', 'Gene', '5970', (19, 22))	('knockdown', 'Var', (23, 32))	('p65', 'Gene', (19, 22))
427915	31285545	While cells during AIS or OIS were EdU-negative and SA-ssGal positive, RELA knockdown decreased SA-ssGal-positive and increased EdU-positive cells, indicating cell cycle re-entry (Fig.	('RELA', 'Gene', (71, 75))	('SA-ssGal', 'Chemical', '-', (96, 104))	('RELA', 'Gene', '5970', (71, 75))	('knockdown', 'Var', (76, 85))	('SA-ssGal', 'Chemical', '-', (52, 60))	('increased', 'PosReg', (118, 127))	('decreased', 'NegReg', (86, 95))	('cell cycle re-entry', 'CPA', (159, 178))	('EdU', 'Chemical', 'MESH:C022811', (35, 38))	('EdU', 'Chemical', 'MESH:C022811', (128, 131))	('SA-ssGal-positive', 'MPA', (96, 113))
427917	31285545	To test RELA knockdown's impact on the SASP, we examined conditioned medium on cytokine membrane arrays (Fig.	('RELA', 'Gene', '5970', (8, 12))	('knockdown', 'Var', (13, 22))	('SA', 'Chemical', 'MESH:C012546', (39, 41))	('RELA', 'Gene', (8, 12))
427925	31285545	Depleting TP53, CCAR1, FADD, and NF1 showed decreased SA-ssGal-positive and increased EdU-positive cells compared to control, indicating significant AIS disengagement.	('FADD', 'Gene', '8772', (23, 27))	('CCAR1', 'Gene', (16, 21))	('Depleting', 'Var', (0, 9))	('TP53', 'Gene', (10, 14))	('NF1', 'Gene', (33, 36))	('increased', 'PosReg', (76, 85))	('NF1', 'Gene', '4763', (33, 36))	('EdU-positive cells', 'CPA', (86, 104))	('FADD', 'Gene', (23, 27))	('CCAR1', 'Gene', '55749', (16, 21))	('EdU', 'Chemical', 'MESH:C022811', (86, 89))	('SA-ssGal', 'Chemical', '-', (54, 62))	('SA-ssGal-positive', 'CPA', (54, 71))	('decreased', 'NegReg', (44, 53))	('TP53', 'Gene', '7157', (10, 14))
427928	31285545	TP53 knockdown increased phosphorylation of Rb, lamin B1, and cyclin A, and decreased p21 during AIS, indicating cell cycle re-entry/senescence escape.	('lamin B1', 'Gene', (48, 56))	('p21', 'Gene', '1026', (86, 89))	('TP53', 'Gene', '7157', (0, 4))	('p21', 'Gene', (86, 89))	('TP53', 'Gene', (0, 4))	('phosphorylation', 'MPA', (25, 40))	('knockdown', 'Var', (5, 14))	('cell cycle re-entry/senescence escape', 'CPA', (113, 150))	('decreased', 'NegReg', (76, 85))	('increased', 'PosReg', (15, 24))	('cyclin A', 'Gene', (62, 70))	('lamin B1', 'Gene', '4001', (48, 56))	('cyclin A', 'Gene', '890', (62, 70))
427929	31285545	HRASV12-expressing cells with TP53 knockdown also showed increased phosphorylated Rb and cyclin A, and decreased p21 but unlike myrAKT1-expressing cells, did not display increased lamin B1.	('knockdown', 'Var', (35, 44))	('TP53', 'Gene', (30, 34))	('TP53', 'Gene', '7157', (30, 34))	('lamin B1', 'Gene', (180, 188))	('decreased', 'NegReg', (103, 112))	('cyclin A', 'Gene', (89, 97))	('AKT1', 'Gene', '207', (131, 135))	('p21', 'Gene', '1026', (113, 116))	('lamin B1', 'Gene', '4001', (180, 188))	('phosphorylated', 'MPA', (67, 81))	('cyclin A', 'Gene', '890', (89, 97))	('increased', 'PosReg', (57, 66))	('AKT1', 'Gene', (131, 135))	('p21', 'Gene', (113, 116))
427930	31285545	CCAR1 depletion increased phosphorylated Rb, lamin B1, and cyclin A in myrAKT1-expressing cells and markedly in HRASV12-expressing cells, suggesting it is a common mediator.	('lamin B1', 'Gene', (45, 53))	('CCAR1', 'Gene', (0, 5))	('lamin B1', 'Gene', '4001', (45, 53))	('cyclin A', 'Gene', (59, 67))	('increased', 'PosReg', (16, 25))	('depletion', 'Var', (6, 15))	('cyclin A', 'Gene', '890', (59, 67))	('phosphorylated', 'MPA', (26, 40))	('CCAR1', 'Gene', '55749', (0, 5))	('AKT1', 'Gene', '207', (74, 78))	('AKT1', 'Gene', (74, 78))
427931	31285545	FADD knockdown in myrAKT1-expressing cells increased phosphorylated Rb but not in HRASV12-expressing cells.	('knockdown', 'Var', (5, 14))	('AKT1', 'Gene', (21, 25))	('FADD', 'Gene', (0, 4))	('FADD', 'Gene', '8772', (0, 4))	('phosphorylated', 'MPA', (53, 67))	('increased', 'PosReg', (43, 52))	('AKT1', 'Gene', '207', (21, 25))
427932	31285545	Intriguingly, NF1 depletion robustly increased phosphorylation of Rb, lamin B1, and cyclin A only in myrAKT1-expressing cells, indicating specificity for NF1 during AIS.	('cyclin A', 'Gene', (84, 92))	('NF1', 'Gene', '4763', (14, 17))	('AKT1', 'Gene', '207', (104, 108))	('lamin B1', 'Gene', (70, 78))	('cyclin A', 'Gene', '890', (84, 92))	('phosphorylation', 'MPA', (47, 62))	('NF1', 'Gene', (154, 157))	('AKT1', 'Gene', (104, 108))	('NF1', 'Gene', '4763', (154, 157))	('depletion', 'Var', (18, 27))	('increased', 'PosReg', (37, 46))	('lamin B1', 'Gene', '4001', (70, 78))	('NF1', 'Gene', (14, 17))
427935	31285545	Colony formation was increased with knockdown of these genes upon constitutive RAS/ERK activation, albeit less robust than observed for AIS, even for TP53, indicating the mediators tested play a more significant role in regulating AIS than OIS.	('TP53', 'Gene', (150, 154))	('increased', 'PosReg', (21, 30))	('ERK', 'Gene', (83, 86))	('knockdown', 'Var', (36, 45))	('Colony formation', 'CPA', (0, 16))	('TP53', 'Gene', '7157', (150, 154))	('ERK', 'Gene', '5594', (83, 86))
427937	31285545	IMR-90 cells undergoing AIS following myrAKT1 transduction stained strongly with SA-ssGal and were EdU-negative.	('AKT1', 'Gene', '207', (41, 45))	('stained', 'Reg', (59, 66))	('EdU', 'Chemical', 'MESH:C022811', (99, 102))	('AKT1', 'Gene', (41, 45))	('SA-ssGal', 'Chemical', '-', (81, 89))	('IMR-90', 'CellLine', 'CVCL:0347', (0, 6))	('transduction', 'Var', (46, 58))	('SA-ssGal', 'Protein', (81, 89))
427938	31285545	Depleting TP53, CCAR1, FADD, or NF1 in myrAKT1-expressing cells showed reduced SA-ssGal-positive and increased EdU-positive cells.	('FADD', 'Gene', '8772', (23, 27))	('CCAR1', 'Gene', (16, 21))	('SA-ssGal', 'Chemical', '-', (79, 87))	('SA-ssGal-positive', 'CPA', (79, 96))	('NF1', 'Gene', (32, 35))	('Depleting', 'Var', (0, 9))	('TP53', 'Gene', (10, 14))	('increased', 'PosReg', (101, 110))	('AKT1', 'Gene', '207', (42, 46))	('NF1', 'Gene', '4763', (32, 35))	('AKT1', 'Gene', (42, 46))	('EdU-positive cells', 'CPA', (111, 129))	('CCAR1', 'Gene', '55749', (16, 21))	('reduced', 'NegReg', (71, 78))	('EdU', 'Chemical', 'MESH:C022811', (111, 114))	('FADD', 'Gene', (23, 27))	('TP53', 'Gene', '7157', (10, 14))
427941	31285545	To further ascertain clinical relevance, we selected TCGA patients with mutations/copy number alterations in NF1, FADD, and/or CCAR1 using cBioportal.	('TCGA', 'Disease', (53, 57))	('NF1', 'Gene', (109, 112))	('CCAR1', 'Gene', (127, 132))	('NF1', 'Gene', '4763', (109, 112))	('mutations/copy number alterations', 'Var', (72, 105))	('FADD', 'Gene', '8772', (114, 118))	('patients', 'Species', '9606', (58, 66))	('CCAR1', 'Gene', '55749', (127, 132))	('FADD', 'Gene', (114, 118))
427943	31285545	While no patients had FADD alterations in LUSC, when we compared patients with mutations in NF1 (n = 3) or CCAR1 (n = 2) versus those without, the AIS escape signature was enriched (P = 0.03) of (Fig.	('CCAR1', 'Gene', '55749', (107, 112))	('patients', 'Species', '9606', (9, 17))	('FADD', 'Gene', (22, 26))	('FADD', 'Gene', '8772', (22, 26))	('NF1', 'Gene', (92, 95))	('CCAR1', 'Gene', (107, 112))	('patients', 'Species', '9606', (65, 73))	('NF1', 'Gene', '4763', (92, 95))	('mutations', 'Var', (79, 88))
427944	31285545	These data demonstrate some patients with mutations in AIS mediators also have gene expression changes associated with AIS escape mechanisms.	('AIS mediators', 'Gene', (55, 68))	('gene expression changes', 'MPA', (79, 102))	('AIS escape mechanisms', 'Disease', (119, 140))	('patients', 'Species', '9606', (28, 36))	('mutations', 'Var', (42, 51))
427954	31285545	BJ-TERT cells coexpressing doxycycline-inducible NF1 shRNA and 4-OHT-inducible NF1-GRD were made senescent upon myrAKT1 transduction, and were treated without or with doxycycline to induce NF1 knockdown and AIS escape.	('knockdown', 'Var', (193, 202))	('4-OHT', 'Chemical', 'MESH:C032278', (63, 68))	('BJ-TERT', 'CellLine', 'CVCL:6573', (0, 7))	('AKT1', 'Gene', '207', (115, 119))	('doxycycline', 'Chemical', 'MESH:D004318', (167, 178))	('NF1', 'Gene', (189, 192))	('AKT1', 'Gene', (115, 119))	('NF1', 'Gene', '4763', (189, 192))	('NF1', 'Gene', (79, 82))	('NF1', 'Gene', (49, 52))	('NF1', 'Gene', '4763', (79, 82))	('doxycycline', 'Chemical', 'MESH:D004318', (27, 38))	('NF1', 'Gene', '4763', (49, 52))
427956	31285545	While NF1 depletion caused AIS escape, cells with NF1 knockdown and simultaneous NF1-GRD induction remained senescent (Fig.	('knockdown', 'Var', (54, 63))	('NF1', 'Gene', (50, 53))	('NF1', 'Gene', (81, 84))	('depletion', 'Var', (10, 19))	('NF1', 'Gene', '4763', (50, 53))	('NF1', 'Gene', '4763', (81, 84))	('NF1', 'Gene', (6, 9))	('NF1', 'Gene', '4763', (6, 9))
427958	31285545	Given 50% of cancers harbor p53-inactivating alterations we investigated whether we could exploit the screen candidates to reinstate AIS in cells with hyperactive AKT and p53 deficiency.	('p53', 'Gene', (28, 31))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('deficiency', 'Var', (175, 185))	('p53', 'Gene', '7157', (28, 31))	('hyperactive AKT', 'Disease', 'MESH:D006948', (151, 166))	('cancers', 'Disease', 'MESH:D009369', (13, 20))	('cancers', 'Phenotype', 'HP:0002664', (13, 20))	('hyperactive AKT', 'Disease', (151, 166))	('cancers', 'Disease', (13, 20))	('p53', 'Gene', (171, 174))	('p53', 'Gene', '7157', (171, 174))
427959	31285545	The fallopian tube secretory epithelial cell line FT282 models the premalignant precursor to high-grade serous ovarian cancers (HGSOC), of which 96% harbor TP53 mutations and >35% display constitutive PI3K/AKT/mTORC1 pathway activation.	('AKT', 'Gene', (206, 209))	('serous ovarian cancers', 'Disease', 'MESH:D018284', (104, 126))	('ovarian cancers', 'Phenotype', 'HP:0100615', (111, 126))	('activation', 'PosReg', (225, 235))	('mTORC1', 'Gene', '382056', (210, 216))	('cancers', 'Phenotype', 'HP:0002664', (119, 126))	('serous ovarian cancers', 'Disease', (104, 126))	('TP53', 'Gene', '7157', (156, 160))	('TP53', 'Gene', (156, 160))	('mutations', 'Var', (161, 170))	('AKT', 'Gene', '207', (206, 209))	('mTORC1', 'Gene', (210, 216))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
427964	31285545	However, NF1 loss increased soft agar colony formation in FT282 myrAKT1-expressing cells, indicating cooperation with PI3K/AKT/mTORC1 activation and mutant p53 to drive transformation (Fig.	('AKT1', 'Gene', (67, 71))	('AKT', 'Gene', '207', (67, 70))	('increased', 'PosReg', (18, 27))	('NF1', 'Gene', (9, 12))	('mTORC1', 'Gene', '382056', (127, 133))	('NF1', 'Gene', '4763', (9, 12))	('mutant', 'Var', (149, 155))	('AKT', 'Gene', (67, 70))	('p53', 'Gene', (156, 159))	('AKT', 'Gene', '207', (123, 126))	('p53', 'Gene', '7157', (156, 159))	('AKT1', 'Gene', '207', (67, 71))	('loss', 'NegReg', (13, 17))	('mTORC1', 'Gene', (127, 133))	('agar', 'Chemical', 'MESH:D000362', (33, 37))	('AKT', 'Gene', (123, 126))	('soft agar colony formation', 'CPA', (28, 54))
427978	31285545	Our finding that depleting NF1 caused AIS escape reinforces mutually exclusive senescence induction mechanisms.	('depleting', 'Var', (17, 26))	('NF1', 'Gene', '4763', (27, 30))	('AIS escape', 'MPA', (38, 48))	('NF1', 'Gene', (27, 30))
427986	31285545	As NF1 deficiency mediated escape from BRAF-driven OIS and BRAF inhibitor resistance in melanoma, which could be combatted with MEK inhibitors, we hypothesize NF1 loss may be a key targetable mechanism of resistance to PI3K/AKT/mTORC1 inhibitors.	('melanoma', 'Phenotype', 'HP:0002861', (88, 96))	('melanoma', 'Disease', (88, 96))	('deficiency', 'Var', (7, 17))	('AKT', 'Gene', '207', (224, 227))	('BRAF', 'Gene', '673', (39, 43))	('BRAF', 'Gene', (39, 43))	('NF1', 'Gene', '4763', (3, 6))	('melanoma', 'Disease', 'MESH:D008545', (88, 96))	('NF1', 'Gene', (3, 6))	('MEK', 'Gene', '5609', (128, 131))	('BRAF', 'Gene', (59, 63))	('BRAF', 'Gene', '673', (59, 63))	('NF1', 'Gene', '4763', (159, 162))	('mTORC1', 'Gene', (228, 234))	('AKT', 'Gene', (224, 227))	('escape', 'PosReg', (27, 33))	('MEK', 'Gene', (128, 131))	('mTORC1', 'Gene', '382056', (228, 234))	('NF1', 'Gene', (159, 162))
427989	31285545	Inhibiting MEK could reinstate AIS in cancers with deregulated PI3K/AKT/mTORC1 signaling and NF1 loss.	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('Inhibiting', 'Var', (0, 10))	('loss', 'NegReg', (97, 101))	('NF1', 'Gene', '4763', (93, 96))	('MEK', 'Gene', (11, 14))	('MEK', 'Gene', '5609', (11, 14))	('AKT', 'Gene', (68, 71))	('mTORC1', 'Gene', '382056', (72, 78))	('cancers', 'Phenotype', 'HP:0002664', (38, 45))	('AKT', 'Gene', '207', (68, 71))	('mTORC1', 'Gene', (72, 78))	('cancers', 'Disease', 'MESH:D009369', (38, 45))	('cancers', 'Disease', (38, 45))	('NF1', 'Gene', (93, 96))
427995	31285545	This approach succeeded in a study of melanocytes expressing BRAFV600E, which undergo OIS and suppress the mitochondrial gatekeeper enzyme pyruvate dehydrogenase kinase 1 (PDK1).	('mitochondrial', 'MPA', (107, 120))	('suppress', 'NegReg', (94, 102))	('PDK1', 'Gene', (172, 176))	('BRAFV600E', 'Var', (61, 70))	('BRAFV600E', 'Mutation', 'rs113488022', (61, 70))	('gatekeeper', 'Species', '111938', (121, 131))
427996	31285545	Inhibiting PDK1 caused BRAFV600E inhibitor-resistant melanoma regression.	('Inhibiting', 'NegReg', (0, 10))	('melanoma', 'Phenotype', 'HP:0002861', (53, 61))	('melanoma', 'Disease', (53, 61))	('melanoma', 'Disease', 'MESH:D008545', (53, 61))	('BRAFV600E', 'Var', (23, 32))	('BRAFV600E', 'Mutation', 'rs113488022', (23, 32))	('PDK1', 'Gene', (11, 15))
428002	31285545	Disrupting key pathways in the network can drive AIS escape, providing insight into tumor development and targeted therapy resistance mechanisms, which can potentially be harnessed to reinstate senescence or drive PI3K/AKT/mTORC1-driven cancers toward death.	('death', 'Disease', 'MESH:D003643', (252, 257))	('AKT', 'Gene', (219, 222))	('death', 'Disease', (252, 257))	('senescence', 'CPA', (194, 204))	('reinstate', 'PosReg', (184, 193))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('mTORC1', 'Gene', '382056', (223, 229))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('cancers', 'Phenotype', 'HP:0002664', (237, 244))	('tumor', 'Disease', (84, 89))	('Disrupting', 'Var', (0, 10))	('cancers', 'Disease', (237, 244))	('cancers', 'Disease', 'MESH:D009369', (237, 244))	('AKT', 'Gene', '207', (219, 222))	('mTORC1', 'Gene', (223, 229))	('drive', 'Reg', (43, 48))
428018	31401438	Numerous genetic alterations have been described in SCC sub-types, although the molecular mechanisms contributing to tumor initiation and progression are still being studied.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumor initiation', 'Disease', 'MESH:D009369', (117, 133))	('genetic alterations', 'Var', (9, 28))	('SCC', 'Gene', (52, 55))	('SCC', 'Phenotype', 'HP:0002860', (52, 55))	('tumor initiation', 'Disease', (117, 133))	('SCC', 'Gene', '6317', (52, 55))
428118	29572294	Systematic characterization of pan-cancer mutation clusters Cancer genome sequencing has shown that driver genes can often be distinguished not only by the elevated mutation frequency but also by specific nucleotide positions that accumulate changes at a high rate.	('Cancer', 'Phenotype', 'HP:0002664', (60, 66))	('Cancer', 'Disease', (60, 66))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('Cancer', 'Disease', 'MESH:D009369', (60, 66))	('mutation', 'Var', (42, 50))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('cancer', 'Disease', (35, 41))
428121	29572294	We find that such mutations (i) are more prominent in proteins that can exist in the on and off state, (ii) reflect the identity of a tumor of origin, and (iii) often localize within interfaces which mediate interactions with other proteins or ligands.	('localize', 'Reg', (167, 175))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('proteins', 'Protein', (54, 62))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('interactions', 'Interaction', (208, 220))	('tumor', 'Disease', (134, 139))	('mutations', 'Var', (18, 27))
428122	29572294	Following, we further examine structural data for human protein complexes and identify a number of additional protein interfaces that accumulate cancer mutations at a high rate.	('cancer', 'Disease', (145, 151))	('mutations', 'Var', (152, 161))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('human', 'Species', '9606', (50, 55))	('cancer', 'Disease', 'MESH:D009369', (145, 151))
428123	29572294	Jointly, these analyses suggest that disruption and dysregulation of protein interactions can be instrumental in switching functions of cancer proteins and activating downstream changes.	('switching', 'Reg', (113, 122))	('functions', 'MPA', (123, 132))	('disruption', 'Var', (37, 47))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('protein interactions', 'Protein', (69, 89))	('cancer', 'Disease', (136, 142))	('dysregulation', 'Var', (52, 65))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
428126	29572294	Analysis of different cancer genomics datasets has further underscored a high degree of heterogeneity in the mutation frequency and spectrum among different cancer types (Garraway & Lander, 2013; Lawrence et al, 2013) and uncovered a long tail of low-frequency driver mutations (Garraway & Lander, 2013).	('driver', 'Var', (261, 267))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('cancer', 'Disease', (22, 28))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('cancer', 'Disease', (157, 163))	('long tail', 'Phenotype', 'HP:0002831', (234, 243))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))
428129	29572294	Large-scale cancer genome initiatives, specifically The Cancer Genome Atlas (TCGA, https://cancergenome.nih.gov/) and International Cancer Genome Consortium (International Cancer Genome et al, 2010; ICGC, http://icgc.org/), have increased statistical power in the analyses of cancer mutations and have driven the development of innovative approaches for the study of patient data (Dees et al, 2012; Hofree et al, 2013; Kandoth et al, 2013; Lawrence et al, 2013, 2014; Chen et al, 2014; Sanchez-Garcia et al, 2014).	('Sanchez-Garcia', 'Disease', (486, 500))	('cancer', 'Disease', 'MESH:D009369', (276, 282))	('patient', 'Species', '9606', (367, 374))	('Cancer', 'Disease', (172, 178))	('Cancer', 'Disease', (132, 138))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (56, 75))	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('statistical', 'MPA', (239, 250))	('Sanchez-Garcia', 'Disease', 'MESH:C536767', (486, 500))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('Cancer', 'Disease', 'MESH:D009369', (172, 178))	('Cancer', 'Phenotype', 'HP:0002664', (56, 62))	('Cancer Genome Atlas', 'Disease', (56, 75))	('Cancer', 'Disease', 'MESH:D009369', (132, 138))	('cancer', 'Disease', (276, 282))	('mutations', 'Var', (283, 292))	('Cancer', 'Disease', (56, 62))	('cancer', 'Phenotype', 'HP:0002664', (276, 282))	('cancer', 'Disease', (12, 18))	('cancer', 'Disease', (91, 97))	('increased', 'PosReg', (229, 238))	('Cancer', 'Phenotype', 'HP:0002664', (172, 178))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('Cancer', 'Disease', 'MESH:D009369', (56, 62))	('Cancer', 'Phenotype', 'HP:0002664', (132, 138))
428132	29572294	Many of the individual cancer mutations are not well studied in terms of how they influence the properties of proteins (Cancer Genome Atlas Research et al, 2013).	('influence', 'Reg', (82, 91))	('Cancer', 'Phenotype', 'HP:0002664', (120, 126))	('properties of proteins', 'MPA', (96, 118))	('Cancer Genome Atlas', 'Disease', (120, 139))	('cancer', 'Disease', (23, 29))	('cancer', 'Disease', 'MESH:D009369', (23, 29))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (120, 139))	('mutations', 'Var', (30, 39))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))
428134	29572294	In this study, we applied the tool to 40 cancer types with the TCGA or ICGC sequencing data and identified 180 hotspot mutation residues in 160 genes that had a likely functional impact.	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('cancer', 'Disease', (41, 47))	('mutation residues', 'Var', (119, 136))
428135	29572294	These mutations alone had the power to cluster tumors based on the cell type of origin, and many of the hotspots were found within proteins, for example, enzymes, that are known to exist in the active and inactive states.	('cluster tumors', 'Disease', 'MESH:D003027', (39, 53))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('cluster tumors', 'Disease', (39, 53))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))	('mutations', 'Var', (6, 15))
428139	29572294	We mapped protein interfaces in these and based on the presence of mutation clusters within the mapped interfaces, we were able to identify 87 proteins in which cancer mutations were likely to affect protein interactions.	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('mutation', 'Var', (67, 75))	('affect', 'Reg', (193, 199))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('protein', 'Protein', (200, 207))	('cancer', 'Disease', (161, 167))	('mutations', 'Var', (168, 177))
428142	29572294	Overall, characterization of the recurrent functional mutations suggests that a disruption and dysregulation of protein interactions could be an important molecular mechanism for switching functions of cancer proteins.	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('interactions', 'Interaction', (120, 132))	('mutations', 'Var', (54, 63))	('cancer', 'Disease', 'MESH:D009369', (202, 208))	('dysregulation', 'MPA', (95, 108))	('cancer', 'Disease', (202, 208))	('protein', 'Protein', (112, 119))
428143	29572294	Collectively, the data encompassed 40 different cancer types from 22 tissues, with the sequencing information from ~10,000 tumor samples, including ~1,300,000 mutations within coding sequences (see Materials and Methods).	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('mutations', 'Var', (159, 168))	('000 tumor', 'Disease', 'MESH:D009369', (119, 128))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('000 tumor', 'Disease', (119, 128))
428145	29572294	The tool identifies and characterizes individual hotspot protein residues that accumulate mutations at a significantly higher rate than their surrounding protein sequence (Figs 1 and EV1).	('EV1', 'Gene', (183, 186))	('mutations', 'Var', (90, 99))	('EV1', 'Gene', '11322', (183, 186))
428148	29572294	Simulations of randomly re-assigned mutations within titin, that is, a gene with the highest overall mutation burden, did not report any hotspot residues (1,000 repetitions).	('titin', 'Gene', (53, 58))	('titin', 'Gene', '7273', (53, 58))	('mutations', 'Var', (36, 45))
428149	29572294	Using the approach introduced here, we applied the DominoEffect tool to the pan-cancer data and identified both known instances of hotspot driver mutations as well as residues that were as yet not annotated as such.	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('mutations', 'Var', (146, 155))	('cancer', 'Disease', (80, 86))
428150	29572294	In total, we identified 180 hotspots within 160 genes (Dataset EV1) for which the reported mutations were categorized as deleterious by the PolyPhen-2.	('EV1', 'Gene', '11322', (63, 66))	('EV1', 'Gene', (63, 66))	('mutations', 'Var', (91, 100))
428153	29572294	Of note, on average, 88% of tumor allele changes assigned as hotspot mutations were reported as heterozygotic in the TCGA dataset.	('mutations', 'Var', (69, 78))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('tumor', 'Disease', (28, 33))	('tumor', 'Disease', 'MESH:D009369', (28, 33))
428156	29572294	Independently of the hotspot analysis, we additionally searched for cancer mutation clusters in known and modeled protein interaction interfaces (Fig 1).	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('mutation', 'Var', (75, 83))	('cancer', 'Disease', (68, 74))
428157	29572294	Strikingly, 36% (3,679/10,118) of the analyzed cancer genomes had at least one of the 180 hotspot residues mutated (Fig 2A).	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('cancer', 'Disease', (47, 53))	('mutated', 'Var', (107, 114))	('cancer', 'Disease', 'MESH:D009369', (47, 53))
428158	29572294	For a comparison, the same size randomly selected gene set that contained any of the protein positions with five or more pan-cancer mutations was on average mutated in 14% of the patients (P < 6 x 10-12, distance from the observed distribution of 1,000 random values).	('mutations', 'Var', (132, 141))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('patients', 'Species', '9606', (179, 187))	('cancer', 'Disease', (125, 131))	('mutated', 'Var', (157, 164))
428159	29572294	The major contributors to the highly prevalent mutations were the well-studied oncogenes KRAS, BRAF, IDH1, PIK3CA, NRAS, SF3B1, CTNNB1, and PTEN: More than one-quarter (i.e., 27%) of all patients had a hotspot mutation in at least one of these genes.	('NRAS', 'Gene', (115, 119))	('PIK3CA', 'Gene', (107, 113))	('SF3B1', 'Gene', (121, 126))	('PTEN', 'Gene', (140, 144))	('patients', 'Species', '9606', (187, 195))	('CTNNB1', 'Gene', '1499', (128, 134))	('BRAF', 'Gene', '673', (95, 99))	('mutations', 'Var', (47, 56))	('BRAF', 'Gene', (95, 99))	('KRAS', 'Gene', '3845', (89, 93))	('IDH1', 'Gene', (101, 105))	('SF3B1', 'Gene', '23451', (121, 126))	('PTEN', 'Gene', '5728', (140, 144))	('NRAS', 'Gene', '4893', (115, 119))	('PIK3CA', 'Gene', '5290', (107, 113))	('KRAS', 'Gene', (89, 93))	('CTNNB1', 'Gene', (128, 134))	('IDH1', 'Gene', '3417', (101, 105))	('hotspot', 'PosReg', (202, 209))
428164	29572294	The obtained extensive set of known and candidate cancer-associated genes with hotspot mutations provides an opportunity to define gene and protein characteristics associated with such residues.	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('mutations', 'Var', (87, 96))	('cancer', 'Disease', (50, 56))
428166	29572294	Among the most prominent examples of cancer drivers with hotspot residues are kinases and Ras proteins where the hotspot mutations frequently act by switching the proteins to a constantly active state.	('residues', 'Var', (65, 73))	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('mutations', 'Var', (121, 130))	('cancer', 'Disease', (37, 43))	('proteins', 'MPA', (163, 171))	('Ras', 'Protein', (90, 93))	('switching', 'Reg', (149, 158))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))
428170	29572294	Moreover, the fraction of enzymes was even two times higher among the here-identified genes with hotspot residues than among the genes in the Cancer Gene Census that were involved in translocations (P < 0.0003).	('higher', 'PosReg', (53, 59))	('residues', 'Var', (105, 113))	('Cancer', 'Phenotype', 'HP:0002664', (142, 148))	('enzymes', 'MPA', (26, 33))	('Cancer', 'Disease', (142, 148))	('fraction', 'MPA', (14, 22))	('Cancer', 'Disease', 'MESH:D009369', (142, 148))
428179	29572294	Overall, this shows that many of the genes with hotspot residues relate to cancer-associated processes and that jointly more than a third of them encode proteins that are known to exist in an active and inactive state.	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('encode', 'Reg', (146, 152))	('residues', 'Var', (56, 64))	('cancer', 'Disease', (75, 81))	('proteins', 'Protein', (153, 161))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('relate', 'Reg', (65, 71))
428181	29572294	We found that domains which were targets of hotspot mutations in two or more proteins were often associated with enzymatic activities, or with binding to proteins, nucleic acids, or lipids (Fig 2E and Dataset EV1).	('proteins', 'Protein', (154, 162))	('mutations', 'Var', (52, 61))	('binding', 'Interaction', (143, 150))	('lipids', 'Chemical', 'MESH:D008055', (182, 188))	('enzymatic activities', 'MPA', (113, 133))	('EV1', 'Gene', '11322', (209, 212))	('domains', 'MPA', (14, 21))	('EV1', 'Gene', (209, 212))	('associated', 'Reg', (97, 107))
428185	29572294	A hotspot residue within this protein mapped to the KH domain that has a role in nucleic acid recognition and is also a target of a hotspot mutation in the known cancer driver FUBP1.	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('cancer', 'Disease', (162, 168))	('FUBP1', 'Gene', '8880', (176, 181))	('mutation', 'Var', (140, 148))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('FUBP1', 'Gene', (176, 181))	('role', 'Reg', (73, 77))
428187	29572294	As a following step, we analyzed the PDB structures of proteins with the identified hotspot mutations (Berman et al, 2000; www.rcsb.org).	('PDB', 'Gene', (37, 40))	('PDB', 'Gene', '5131', (37, 40))	('mutations', 'Var', (92, 101))
428188	29572294	When structural data were available, we aligned the segments with hotspot mutations onto the corresponding PDB sequences (see Materials and Methods).	('mutations', 'Var', (74, 83))	('PDB', 'Gene', '5131', (107, 110))	('PDB', 'Gene', (107, 110))
428193	29572294	The observed hotspot mutations in CARM1 and METTL4 could thus have an effect on the interactions between the CARM1 proteins that together form a complex, or on the METTL4 binding to its interactor protein METTL3.	('METTL4', 'Gene', '64863', (164, 170))	('binding', 'Interaction', (171, 178))	('CARM1', 'Gene', '10498', (34, 39))	('effect', 'Reg', (70, 76))	('METTL4', 'Gene', (44, 50))	('proteins', 'Protein', (115, 123))	('METTL4', 'Gene', (164, 170))	('METTL3', 'Gene', '56339', (205, 211))	('interactions', 'Interaction', (84, 96))	('METTL4', 'Gene', '64863', (44, 50))	('CARM1', 'Gene', (109, 114))	('complex', 'Interaction', (145, 152))	('CARM1', 'Gene', (34, 39))	('METTL3', 'Gene', (205, 211))	('CARM1', 'Gene', '10498', (109, 114))	('have', 'Reg', (62, 66))	('mutations', 'Var', (21, 30))
428195	29572294	Finally, hotspot residues in the PBX2 and MAX proteins mapped to their conserved DNA interfaces, suggesting abolished or altered transcriptional regulation.	('PBX2', 'Gene', (33, 37))	('transcriptional regulation', 'MPA', (129, 155))	('altered', 'Reg', (121, 128))	('residues', 'Var', (17, 25))	('PBX2', 'Gene', '5089', (33, 37))
428196	29572294	In the case of the PTEN (Papa et al, 2014), FBXW7 (Welcker & Clurman, 2008) and SMAD4 (Miyaki & Kuroki, 2003) genes, as well as several other tumor suppressors (de Vries et al, 2002; Hanel et al, 2013), a frequent mechanism of inactivation is through point mutations that reoccur at the defined residues and act dominantly on the molecular level.	('FBXW7', 'Gene', '55294', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('mechanism', 'NegReg', (214, 223))	('FBXW7', 'Gene', (44, 49))	('tumor', 'Disease', (142, 147))	('PTEN', 'Gene', (19, 23))	('SMAD4', 'Gene', '4089', (80, 85))	('PTEN', 'Gene', '5728', (19, 23))	('is through', 'Var', (240, 250))	('Papa', 'Gene', '5069', (25, 29))	('and', 'Gene', (76, 79))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('Papa', 'Gene', (25, 29))	('SMAD4', 'Gene', (80, 85))
428197	29572294	In the cancer genomics studies, mutational clustering is often used as a signature that is associated with oncogenes (Davoli et al, 2013; Vogelstein et al, 2013).	('mutational', 'Var', (32, 42))	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('cancer', 'Disease', (7, 13))	('cancer', 'Disease', 'MESH:D009369', (7, 13))
428199	29572294	In order to categorize hotspot mutations that could function by inactivating tumor suppressors, we analyzed which of the here-identified genes were categorized as tumor suppressors in the Cancer Gene Census, or were predicted to be suppressors based on mutation signatures in an independent study (Davoli et al, 2013).	('mutations', 'Var', (31, 40))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('inactivating', 'NegReg', (64, 76))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('Cancer', 'Disease', (188, 194))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('Cancer', 'Phenotype', 'HP:0002664', (188, 194))	('Cancer', 'Disease', 'MESH:D009369', (188, 194))	('tumor', 'Disease', (163, 168))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Disease', (77, 82))
428200	29572294	In addition, to further expand the set of tumor suppressor candidates, we assessed the frequency of deleterious mutations within the here-defined set of hotspot genes using the mutation data from the above-described TCGA and ICGC datasets.	('mutations', 'Var', (112, 121))	('tumor', 'Disease', (42, 47))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
428201	29572294	Using a conservative threshold that required an overrepresentation of deleterious over neutral changes within a protein, we found that 15 genes with a hotspot mutation also exhibited mutation patterns typical of tumor suppressors (Dataset EV5).	('tumor', 'Disease', 'MESH:D009369', (212, 217))	('mutation', 'Var', (159, 167))	('tumor', 'Disease', (212, 217))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))
428206	29572294	Furthermore, to gain additional insights into the distribution of functional effects of hotspot mutations, we classified genes in which hotspot residues were mutated in 10 or more tumor samples into the following three categories: (i) instances where mutations occurred within a tumor suppressor and were likely inactivating, (ii) instances where mutations affected protein binding properties and were likely activating, and (iii) all other instances (Fig 3B and Dataset EV6).	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('mutations', 'Var', (251, 260))	('activating', 'MPA', (409, 419))	('tumor', 'Phenotype', 'HP:0002664', (279, 284))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('inactivating', 'NegReg', (312, 324))	('tumor', 'Disease', (279, 284))	('affected', 'Reg', (357, 365))	('tumor', 'Disease', (180, 185))	('protein', 'Protein', (366, 373))	('tumor', 'Disease', 'MESH:D009369', (279, 284))	('mutations', 'Var', (96, 105))	('mutations', 'Var', (347, 356))
428207	29572294	These more frequently mutated instances encompassed in total 53 genes and included the experimentally characterized hotspots within the PTEN, FBXW7, SMAD4, EP300, and CREBBP tumor suppressors.	('tumor', 'Disease', (174, 179))	('EP300', 'Gene', (156, 161))	('EP300', 'Gene', '2033', (156, 161))	('CREBBP', 'Gene', (167, 173))	('SMAD4', 'Gene', (149, 154))	('encompassed', 'Reg', (40, 51))	('mutated', 'Var', (22, 29))	('FBXW7', 'Gene', '55294', (142, 147))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('CREBBP', 'Gene', '1387', (167, 173))	('FBXW7', 'Gene', (142, 147))	('SMAD4', 'Gene', '4089', (149, 154))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('PTEN', 'Gene', (136, 140))	('PTEN', 'Gene', '5728', (136, 140))
428208	29572294	In the set of proteins with more frequently mutated and better-characterized hotspots, 32% (i.e.,17 of 53) were tumor suppressor, 51% (i.e., 27 of 53) represented instances where hotspot mutations were likely to affect protein binding properties, and 17% (i.e., 9 of 53) were proteins in which the impacts of hotspot mutations could not be readily classified.	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('mutated', 'Var', (44, 51))	('mutations', 'Var', (187, 196))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumor', 'Disease', (112, 117))	('affect', 'Reg', (212, 218))	('protein', 'Protein', (219, 226))
428211	29572294	Using a complementary approach, we compared the presence of iPfam domains (Wang et al, 2012; Finn et al, 2014), that is, Pfam domains that can mediate protein-protein interactions, in the protein sets that we established above: (i) proteins that contain hotspot mutations, (ii) other proteins encoded by the Cancer Gene Census (described above), and (iii) all other human proteins.	('Finn', 'Species', '1754191', (93, 97))	('Cancer', 'Disease', (308, 314))	('Cancer', 'Phenotype', 'HP:0002664', (308, 314))	('Cancer', 'Disease', 'MESH:D009369', (308, 314))	('mutations', 'Var', (262, 271))	('human', 'Species', '9606', (366, 371))
428217	29572294	Individually, 20 (i.e., 19%) of these 106 proteins had interaction neighborhoods strongly enriched in the known cancer drivers (adjusted P < 0.05, Dataset EV7), and these clusters often included other proteins with hotspot mutations (Dataset EV7).	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('interaction', 'Interaction', (55, 66))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('mutations', 'Var', (223, 232))	('included', 'Reg', (186, 194))
428220	29572294	Additionally, 27 interaction pairs in which one partner was a candidate with a hotspot mutation and the other partner was a Cancer Gene Census protein were also supported with a PDB structure or a homology-based structural model that indicated a stable interaction between the proteins (see Materials and Methods).	('Cancer', 'Disease', 'MESH:D009369', (124, 130))	('PDB', 'Gene', '5131', (178, 181))	('Cancer', 'Disease', (124, 130))	('interaction', 'Interaction', (253, 264))	('Cancer', 'Phenotype', 'HP:0002664', (124, 130))	('mutation', 'Var', (87, 95))	('PDB', 'Gene', (178, 181))
428222	29572294	The hotspot mutation in this gene was originally reported in the TCGA study of bladder cancer (Cancer Genome Atlas Research, 2014a), but its impact has as yet not been characterized.	('Cancer', 'Phenotype', 'HP:0002664', (95, 101))	('bladder cancer', 'Phenotype', 'HP:0009725', (79, 93))	('Cancer Genome Atlas', 'Disease', (95, 114))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (95, 114))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('bladder cancer', 'Disease', 'MESH:D001749', (79, 93))	('mutation', 'Var', (12, 20))	('bladder cancer', 'Disease', (79, 93))
428223	29572294	The observation that a number of the candidates with hotspot mutations were physically associated with each other or with known cancer drivers suggests their possible connections to interaction networks relevant in disease development.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('interaction', 'Interaction', (182, 193))	('connections', 'Interaction', (167, 178))	('mutations', 'Var', (61, 70))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('associated', 'Interaction', (87, 97))	('cancer', 'Disease', (128, 134))
428226	29572294	We found that 35 out of 180 hotspot residues were largely associated with one tumor type, that is, more than 75% of the mutations on these 35 positions were reported in a single tumor type (Dataset EV8).	('tumor', 'Disease', (178, 183))	('associated', 'Reg', (58, 68))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('mutations', 'Var', (120, 129))	('tumor', 'Disease', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))
428229	29572294	For instance, for 89 hotspot positions, a single tumor type never contributed to 50% or more of the mutations (Dataset EV8).	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('mutations', 'Var', (100, 109))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor', 'Disease', (49, 54))
428230	29572294	Next, we performed a hierarchical clustering of the analyzed tumor types, based on the percentage of patients that had a mutation in each of the identified hotspots.	('patients', 'Species', '9606', (101, 109))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('mutation', 'Var', (121, 129))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Disease', (61, 66))
428231	29572294	Patterns of hotspot mutations could also point to the shared and cell-type-specific pathways in cancer.	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('point', 'Reg', (41, 46))	('cancer', 'Disease', (96, 102))	('mutations', 'Var', (20, 29))
428238	29572294	Blood tumors were largely defined by the scarcity of point mutations, and skin cutaneous melanoma and thyroid cancer were clustered together based on a high frequency of the BRAF hotspot mutation.	('thyroid cancer', 'Disease', 'MESH:D013964', (102, 116))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (79, 97))	('skin cutaneous melanoma', 'Disease', (74, 97))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('BRAF', 'Gene', '673', (174, 178))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('tumors', 'Disease', (6, 12))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('BRAF', 'Gene', (174, 178))	('thyroid cancer', 'Disease', (102, 116))	('thyroid cancer', 'Phenotype', 'HP:0002890', (102, 116))	('melanoma', 'Phenotype', 'HP:0002861', (89, 97))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (74, 97))	('mutation', 'Var', (187, 195))	('Blood tumors', 'Phenotype', 'HP:0004377', (0, 12))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))
428240	29572294	Overall, this analysis showed a strong power of hotspot mutations to reflect the identity of a tumor of origin.	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('mutations', 'Var', (56, 65))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Disease', (95, 100))
428242	29572294	Proteins in which the mutation clusters were identified with the most significant P-values were cancer drivers for which it was previously shown that mutations in their interfaces can lead to disease development by disrupting interactions with regulatory proteins (PIK3CA and PPP2R1A) or by preventing GTP hydrolysis (KRAS, HRAS, and GNAS); Dataset EV9, 87 proteins in total.	('mutation', 'Var', (22, 30))	('GNAS', 'Gene', '2778', (334, 338))	('interactions', 'Interaction', (226, 238))	('HRAS', 'Gene', '3265', (324, 328))	('preventing', 'NegReg', (291, 301))	('HRAS', 'Gene', (324, 328))	('cancer', 'Disease', (96, 102))	('disrupting', 'NegReg', (215, 225))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('PIK3CA', 'Gene', (265, 271))	('PPP2R1A', 'Gene', '5518', (276, 283))	('mutations', 'Var', (150, 159))	('KRAS', 'Gene', '3845', (318, 322))	('disease', 'Disease', (192, 199))	('KRAS', 'Gene', (318, 322))	('GTP', 'Chemical', 'MESH:D006160', (302, 305))	('PPP2R1A', 'Gene', (276, 283))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('lead to', 'Reg', (184, 191))	('GTP hydrolysis', 'MPA', (302, 316))	('GNAS', 'Gene', (334, 338))	('PIK3CA', 'Gene', '5290', (265, 271))
428248	29572294	Of interest, both CUL1 and CUL4B had a mutation cluster at one of the interface contacts with the regulator protein CAND1 (Fig 6C).	('mutation', 'Var', (39, 47))	('CUL4B', 'Gene', '8450', (27, 32))	('CUL1', 'Gene', (18, 22))	('CAND1', 'Gene', (116, 121))	('CAND1', 'Gene', '55832', (116, 121))	('CUL1', 'Gene', '8454', (18, 22))	('CUL4B', 'Gene', (27, 32))
428249	29572294	In addition, we used annotations of protein complexes from the ConsensusPathDB (Kamburov et al, 2013) and found a number of protein complexes relevant in cancer that would be affected through these mutations (Dataset EV10).	('EV1', 'Gene', (217, 220))	('EV1', 'Gene', '11322', (217, 220))	('affected', 'Reg', (175, 183))	('protein', 'Protein', (124, 131))	('cancer', 'Disease', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('mutations', 'Var', (198, 207))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))
428251	29572294	Of relevance, mutations in the GNB1 protein interface were recently shown to promote cellular growth and transformation, as well as kinase inhibitor resistance (Yoda et al, 2015).	('GNB1', 'Gene', '2782', (31, 35))	('promote', 'PosReg', (77, 84))	('cellular growth', 'CPA', (85, 100))	('GNB1', 'Gene', (31, 35))	('transformation', 'CPA', (105, 119))	('protein', 'Protein', (36, 43))	('kinase inhibitor resistance', 'MPA', (132, 159))	('mutations', 'Var', (14, 23))
428254	29572294	In addition to finding mutation clusters within protein-protein interfaces, the analysis identified a mutation cluster at the interface of the PAX5 transcription factor with DNA, as well as a number of contacts with small ligands, most commonly ATP and GTP.	('PAX5', 'Gene', '5079', (143, 147))	('mutation', 'Var', (102, 110))	('PAX5', 'Gene', (143, 147))	('GTP', 'Chemical', 'MESH:D006160', (253, 256))	('ATP', 'Chemical', 'MESH:D000255', (245, 248))
428255	29572294	PAX5 is a known tumor suppressor with a highly conserved DNA-binding motif (Garvie et al, 2001) that is often involved in leukemia development, however, most frequently through translocations.	('leukemia', 'Disease', (122, 130))	('leukemia', 'Phenotype', 'HP:0001909', (122, 130))	('leukemia', 'Disease', 'MESH:D007938', (122, 130))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('PAX5', 'Gene', (0, 4))	('translocations', 'Var', (177, 191))	('PAX5', 'Gene', '5079', (0, 4))	('involved', 'Reg', (110, 118))	('tumor', 'Disease', (16, 21))
428256	29572294	Overall, mutation clusters in structural interfaces were able to highlight additional cancer-relevant proteins and protein regions, which can mediate a switch in protein activity and function.	('mutation', 'Var', (9, 17))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('activity', 'MPA', (170, 178))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('cancer', 'Disease', (86, 92))
428259	29572294	Here, based on the sequencing data for more than 10,000 cancer genomes, we composed a set of most common hotspot mutations with a likely functional effect and characterized these using available structural and interaction data, as well as protein sequence features and residue annotations.	('000 cancer', 'Disease', (52, 62))	('mutations', 'Var', (113, 122))	('000 cancer', 'Disease', 'MESH:D009369', (52, 62))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))
428263	29572294	Mechanistically, these mutations tend to disrupt the original protein function, exemplified by the disrupted substrate binding in CREBBP and EP300, or to prevent the activation of a tumor suppressor, exemplified by mutations within the SMAD4 interface or CHEK2 activation loop (Dataset EV5).	('CREBBP', 'Gene', (130, 136))	('disrupted', 'NegReg', (99, 108))	('EP300', 'Gene', (141, 146))	('activation', 'MPA', (166, 176))	('substrate', 'MPA', (109, 118))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))	('protein', 'Protein', (62, 69))	('SMAD4', 'Gene', (236, 241))	('mutations', 'Var', (215, 224))	('mutations', 'Var', (23, 32))	('CREBBP', 'Gene', '1387', (130, 136))	('disrupt', 'NegReg', (41, 48))	('prevent', 'NegReg', (154, 161))	('CHEK2', 'Gene', (255, 260))	('SMAD4', 'Gene', '4089', (236, 241))	('CHEK2', 'Gene', '11200', (255, 260))	('original', 'MPA', (53, 61))	('tumor', 'Disease', (182, 187))	('EP300', 'Gene', '2033', (141, 146))	('tumor', 'Disease', 'MESH:D009369', (182, 187))
428264	29572294	Alternatively, these mutations can interfere with the oncogene regulation, exemplified by the PIK3R1 interface to PIK3CA.	('PIK3CA', 'Gene', '5290', (114, 120))	('oncogene regulation', 'MPA', (54, 73))	('interfere', 'Reg', (35, 44))	('PIK3R1', 'Gene', '5295', (94, 100))	('PIK3R1', 'Gene', (94, 100))	('PIK3CA', 'Gene', (114, 120))	('mutations', 'Var', (21, 30))
428267	29572294	As more cancer genomes get sequenced, we expect that the list of genes with hotspot mutations will expand.	('mutations', 'Var', (84, 93))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('cancer', 'Disease', (8, 14))	('cancer', 'Disease', 'MESH:D009369', (8, 14))
428271	29572294	Cancer classification based on molecular data, which include point mutations, copy number variations, and mRNA and protein expression, has proven to be able to recapitulate pathological subtypes and suggest finer subclasses within tumor types (Hoadley et al, 2014).	('point mutations', 'Var', (61, 76))	('tumor', 'Disease', 'MESH:D009369', (231, 236))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('copy number variations', 'Var', (78, 100))	('tumor', 'Disease', (231, 236))	('Cancer', 'Disease', (0, 6))	('mRNA', 'MPA', (106, 110))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))
428272	29572294	Remarkably, here we observed that clustering of tumor types based on a small number of functional hotspot mutations was able to largely mimic the behavior of much more complex molecular datasets.	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('tumor', 'Disease', (48, 53))	('mutations', 'Var', (106, 115))	('tumor', 'Disease', 'MESH:D009369', (48, 53))
428277	29572294	Of relevance, many (i.e., 45) of the proteins with hotspot mutations are classified as druggable (Dataset EV12).	('EV1', 'Gene', (106, 109))	('EV1', 'Gene', '11322', (106, 109))	('mutations', 'Var', (59, 68))
428281	29572294	In this way, we detect a number of additional interaction interfaces that are significantly affected by cancer mutations.	('mutations', 'Var', (111, 120))	('affected', 'Reg', (92, 100))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('interaction', 'Interaction', (46, 57))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))
428285	29572294	Eventually, a larger catalog of cancer-associated mutations further characterized in vitro and in model organisms would be invaluable for understanding different routes of disease emergence and for identifying therapeutic opportunities.	('mutations', 'Var', (50, 59))	('cancer', 'Disease', (32, 38))	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))
428288	29572294	In this study, we used the package on the Pan-cancer data, but with more permissive thresholds, it can also be used for finding hotspot mutations relevant for individual tumor types.	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('cancer', 'Disease', (46, 52))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('tumor', 'Disease', (170, 175))	('mutations', 'Var', (136, 145))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))
428297	29572294	Jointly, the analyzed TCGA and ICGC mutation datasets covered 40 different tumor types which spanned 23 tissues of origin.	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('TCGA', 'Gene', (22, 26))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('ICGC', 'Gene', (31, 35))	('tumor', 'Disease', (75, 80))	('mutation', 'Var', (36, 44))
428299	29572294	A major source of false positives in the set of the identified hotspot mutations is due to common variants that, incorrectly, were not detected in the paired healthy tissue from the same patient.	('patient', 'Species', '9606', (187, 194))	('mutations', 'Var', (71, 80))	('variants', 'Var', (98, 106))
428302	29572294	Based on this catalogue, we classified the genes with the identified hotspot mutations as known or candidate cancer driver genes.	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('mutations', 'Var', (77, 86))	('cancer', 'Disease', (109, 115))	('cancer', 'Disease', 'MESH:D009369', (109, 115))
428303	29572294	Next, through the Ensembl BioMart service (Kinsella et al, 2011), we retrieved predictions for all human genes that are homologous to those with hotspot mutations, and assessed which of these were in the cancer Gene Census or had a hotspot mutation themselves.	('cancer', 'Disease', (204, 210))	('cancer', 'Disease', 'MESH:D009369', (204, 210))	('mutations', 'Var', (153, 162))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('human', 'Species', '9606', (99, 104))
428304	29572294	We composed two other sets of genes to which we compared those with hotspot mutations: (i) all other genes in the Cancer Gene Census, that is, excluding those with hotspots and paralogs of genes with hotspot mutations (based on the Ensembl homology assignments) and (ii) all other protein coding genes in the UniProtKB reference set of human proteins (release 2016_06, July 2016), that is, excluding all Cancer Gene Census genes or genes with hotspot mutations.	('Cancer', 'Phenotype', 'HP:0002664', (404, 410))	('mutations', 'Var', (76, 85))	('Cancer', 'Disease', (404, 410))	('Cancer', 'Disease', 'MESH:D009369', (404, 410))	('mutations', 'Var', (208, 217))	('Cancer', 'Disease', (114, 120))	('Cancer', 'Phenotype', 'HP:0002664', (114, 120))	('Cancer', 'Disease', 'MESH:D009369', (114, 120))	('human', 'Species', '9606', (336, 341))
428309	29572294	For all proteins with hotspot mutations, for which X-ray structural data were available, we obtained a representative PDB structure.	('mutations', 'Var', (30, 39))	('PDB', 'Gene', (118, 121))	('PDB', 'Gene', '5131', (118, 121))
428316	29572294	Genes with a high number of the reported deleterious changes (at least 25) and large contribution of these changes to the overall mutation load (the ratio of deleterious over synonymous changes was higher than 0.7) were considered as tumor suppressor candidates.	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('changes', 'Var', (53, 60))	('tumor', 'Disease', (234, 239))	('tumor', 'Disease', 'MESH:D009369', (234, 239))
428317	29572294	To address whether a mechanism of action for any of the mutations was interference with the activation of tumor suppressors through phosphorylation, we obtained positions of phosphosites in these proteins using the PhosphoSitePlus resource (Hornbeck et al, 2012).	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('mutations', 'Var', (56, 65))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Disease', (106, 111))
428318	29572294	To compare a fraction of domains that mediate protein interactions among the previously composed sets of genes (genes with hotspot mutations, other genes in the Cancer Gene Census and background human proteins), we obtained domain annotations from the iPfam 1.0 (June 2013) and used chi-squared test in R. Further, we used a Functional Annotation service from the ConsensusPathDB-human database compendium (Kamburov et al, 2013).	('human', 'Species', '9606', (195, 200))	('mutations', 'Var', (131, 140))	('Cancer', 'Phenotype', 'HP:0002664', (161, 167))	('Cancer', 'Disease', (161, 167))	('Cancer', 'Disease', 'MESH:D009369', (161, 167))	('human', 'Species', '9606', (380, 385))
428325	29572294	For each of the identified hotspot mutations, we looked at the individual tumor types and calculated a fraction of patients which had this residue mutated.	('patients', 'Species', '9606', (115, 123))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor', 'Disease', (74, 79))	('mutations', 'Var', (35, 44))
428326	29572294	We next drew a heatmap plot where the clustering of tissue types was defined with the pvclust results and where, for the clarity, we reduced the number of the visualized hotspots by including only those mutated in one-third or more of the patients in at least one tumor type.	('tumor', 'Phenotype', 'HP:0002664', (264, 269))	('mutated', 'Var', (203, 210))	('tumor', 'Disease', (264, 269))	('patients', 'Species', '9606', (239, 247))	('tumor', 'Disease', 'MESH:D009369', (264, 269))
428332	29572294	It was initially developed to identify phosphosites that had a mutation pattern which significantly differed from the gene background mutation rate, while accounting for the differences in mutation rates between structured and disordered protein regions.	('disordered protein', 'Disease', (227, 245))	('disordered protein', 'Disease', 'MESH:D001796', (227, 245))	('mutation', 'Var', (63, 71))
428333	29572294	For the required mutation data, we provided the amino acid changes reported in the above-described TCGA and ICGC datasets, and we specified intrinsically disordered protein regions by using the IUPred tool (Dosztanyi et al, 2005; version 1.0) with the settings for short disorder and a residue disorder prediction threshold of 0.5.	('short disorder', 'Disease', 'MESH:C537327', (265, 279))	('disordered protein', 'Disease', 'MESH:D001796', (154, 172))	('mutation', 'Var', (17, 25))	('short disorder', 'Disease', (265, 279))	('disordered protein', 'Disease', (154, 172))
428336	29572294	Using as thresholds CNV values > 1 and mRNA z-scores > 2, we looked at the percentages of patients in each tumor type that had the "hotspot genes" amplified and/or overexpressed.	('amplified', 'Var', (147, 156))	('overexpressed', 'PosReg', (164, 177))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('patients', 'Species', '9606', (90, 98))
428408	24587773	Recently, epidemiological and molecular data have suggested HPV, especially type 16, to be an independent risk factor in the development of HNSCC.	('SCC', 'Gene', (142, 145))	('men', 'Species', '9606', (132, 135))	('SCC', 'Phenotype', 'HP:0002860', (142, 145))	('SCC', 'Gene', '6317', (142, 145))	('type 16', 'Var', (76, 83))	('HPV', 'Species', '10566', (60, 63))	('HNSCC', 'Phenotype', 'HP:0012288', (140, 145))	('HPV', 'Var', (60, 63))
428411	24587773	A strong association between HPV-16 positivity and oropharyngeal primary cancers was reported by Gillison et al.	('HPV-16', 'Species', '333760', (29, 35))	('primary cancers', 'Disease', (65, 80))	('primary cancers', 'Disease', 'MESH:D009369', (65, 80))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('HPV-16', 'Gene', (29, 35))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('positivity', 'Var', (36, 46))
428421	24587773	On the contrary, typical for tobacco/ alcohol-associated head and neck cancers are downregulation of p16 protein, p53 gene mutation and overexpression of pRb and cyclin D1.	('tobacco', 'Species', '4097', (29, 36))	('cancers', 'Phenotype', 'HP:0002664', (71, 78))	('mutation', 'Var', (123, 131))	('p53', 'Gene', (114, 117))	('p16', 'Gene', '1029', (101, 104))	('p53', 'Gene', '7157', (114, 117))	('head and neck cancers', 'Phenotype', 'HP:0012288', (57, 78))	('neck cancers', 'Disease', (66, 78))	('overexpression', 'PosReg', (136, 150))	('alcohol', 'Chemical', 'MESH:D000438', (38, 45))	('pRb', 'Gene', '5925', (154, 157))	('downregulation', 'NegReg', (83, 97))	('pRb', 'Gene', (154, 157))	('Rb', 'Phenotype', 'HP:0009919', (155, 157))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('neck cancers', 'Disease', 'MESH:D006258', (66, 78))	('head and neck cancer', 'Phenotype', 'HP:0012288', (57, 77))	('p16', 'Gene', (101, 104))
428449	24587773	Additionally, Fanconi anaemia, an autosomal recessive syndrome caused by defects in DNA repair, is associated with a high risk of developing malignancy at a young age (the incidence of HNSCC in this population is estimated to be 14% by age 40).	('defects', 'Var', (73, 80))	('autosomal recessive syndrome', 'Disease', 'MESH:D030342', (34, 62))	('Fanconi anaemia', 'Disease', (14, 29))	('malignancy', 'Disease', 'MESH:D009369', (141, 151))	('SCC', 'Gene', (187, 190))	('anaemia', 'Phenotype', 'HP:0001903', (22, 29))	('malignancy', 'Disease', (141, 151))	('Fanconi anaemia', 'Phenotype', 'HP:0001994', (14, 29))	('DNA repair', 'Gene', (84, 94))	('SCC', 'Phenotype', 'HP:0002860', (187, 190))	('Fanconi anaemia', 'Disease', 'MESH:D005199', (14, 29))	('SCC', 'Gene', '6317', (187, 190))	('autosomal recessive syndrome', 'Disease', (34, 62))	('caused by', 'Reg', (63, 72))	('HNSCC', 'Phenotype', 'HP:0012288', (185, 190))
428484	24587773	P16 positivity has been shown to be connected with improved outcomes, regardless of HPV infection status.	('outcomes', 'MPA', (60, 68))	('improved', 'PosReg', (51, 59))	('P16', 'Gene', (0, 3))	('positivity', 'Var', (4, 14))	('HPV infection', 'Disease', 'MESH:D030361', (84, 97))	('P16', 'Gene', '1029', (0, 3))	('HPV infection', 'Disease', (84, 97))
428485	24587773	Therefore, p16 positivity has been proposed to be a more reliable and reproducible prognostic marker in HNSCC.	('SCC', 'Phenotype', 'HP:0002860', (106, 109))	('SCC', 'Gene', '6317', (106, 109))	('HNSCC', 'Phenotype', 'HP:0012288', (104, 109))	('p16', 'Gene', (11, 14))	('positivity', 'Var', (15, 25))	('p16', 'Gene', '1029', (11, 14))	('SCC', 'Gene', (106, 109))
428488	24587773	HPV-positive HNSCC patients are consistently proved to have an improved prognosis when comparing to those with HPV-negative tumours.	('improved', 'PosReg', (63, 71))	('tumours', 'Disease', 'MESH:D009369', (124, 131))	('tumours', 'Disease', (124, 131))	('HPV', 'Species', '10566', (0, 3))	('patients', 'Species', '9606', (19, 27))	('tumour', 'Phenotype', 'HP:0002664', (124, 130))	('HPV', 'Species', '10566', (111, 114))	('tumours', 'Phenotype', 'HP:0002664', (124, 131))	('SCC', 'Gene', (15, 18))	('SCC', 'Phenotype', 'HP:0002860', (15, 18))	('SCC', 'Gene', '6317', (15, 18))	('HNSCC', 'Phenotype', 'HP:0012288', (13, 18))	('HPV-positive', 'Var', (0, 12))
428490	24587773	identified group of patients, characterized by T1-3 and N0-2b HPV-positive oropharyngeal SCCs (in case of N2b disease, patients should be nonsmokers/minimal smokers) that would not necessarily need intensive chemoradiation and are candidates for treatment de-escalation clinical trials.	('HPV-positive', 'Gene', (62, 74))	('SCC', 'Gene', '6317', (89, 92))	('T1-3', 'Var', (47, 51))	('patients', 'Species', '9606', (119, 127))	('HPV', 'Species', '10566', (62, 65))	('SCC', 'Phenotype', 'HP:0002860', (89, 92))	('patients', 'Species', '9606', (20, 28))	('N0-2b', 'Var', (56, 61))	('SCC', 'Gene', (89, 92))	('men', 'Species', '9606', (251, 254))
428493	24587773	who showed that transfection of the E6 transcript in HPV-negative SCC cell lines resulted in sensitization to radiation-induced cell death.	('SCC', 'Gene', (66, 69))	('SCC', 'Phenotype', 'HP:0002860', (66, 69))	('SCC', 'Gene', '6317', (66, 69))	('sensitization', 'Reg', (93, 106))	('HPV', 'Species', '10566', (53, 56))	('transfection', 'Var', (16, 28))
428542	33641495	The biopsy results identified dysplastic squamous epithelium, which was positive for immunostaining for P40, P63, CK19, and CK5/6 (Figure 3).	('dysplastic squamous epithelium', 'Disease', (30, 60))	('dysplastic squamous epithelium', 'Disease', 'MESH:D002294', (30, 60))	('CK5/6', 'Var', (124, 129))	('CK19', 'Gene', (114, 118))	('P63', 'Gene', (109, 112))	('P40', 'Gene', (104, 107))	('P63', 'Gene', '8626', (109, 112))	('CK19', 'Gene', '3880', (114, 118))	('P40', 'Gene', '3578', (104, 107))
428554	33641495	Final histological examination of the completely resected specimen revealed squamous cell carcinoma with necrosis arising from the pancreas, and immunostaining showed positivity for P40, P63, CK19, and CK5/6 (Figure 5).	('necrosis', 'Disease', 'MESH:D009336', (105, 113))	('men', 'Species', '9606', (63, 66))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (76, 99))	('CK5/6', 'Var', (202, 207))	('P40', 'Gene', (182, 185))	('squamous cell carcinoma', 'Disease', (76, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (76, 99))	('P40', 'Gene', '3578', (182, 185))	('P63', 'Gene', '8626', (187, 190))	('necrosis', 'Disease', (105, 113))	('CK19', 'Gene', (192, 196))	('CK19', 'Gene', '3880', (192, 196))	('P63', 'Gene', (187, 190))
428573	33641495	Only one case report described the MRI features of the tumor as hypointense on T1WI and hyperintense on T2WI (Table 2).	('hypointense', 'Var', (64, 75))	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Disease', (55, 60))	('hyperintense', 'Var', (88, 100))
428605	32799825	In the tumor microenvironment, S1P exhibits multiple functions: (a) it increases the survival of macrophages; (b) it serves as the "come-and-get-me" signal of dead cells, attracting and enhancing macrophage migration by combining with S1PR1; (c) it stimulates the polarization of TAM/M2 macrophages by activating S1PR1/2/4.	('polarization', 'CPA', (264, 276))	('S1PR1/2/4', 'Gene', (313, 322))	('S1P', 'Chemical', 'MESH:C060506', (313, 316))	('activating', 'PosReg', (302, 312))	('survival of macrophages', 'CPA', (85, 108))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))	('stimulates', 'PosReg', (249, 259))	('S1PR1', 'Gene', '1901', (235, 240))	('S1PR1', 'Gene', (235, 240))	('S1PR1', 'Gene', '1901', (313, 318))	('S1PR1/2/4', 'Gene', '1901;9294;8698', (313, 322))	('S1P', 'Chemical', 'MESH:C060506', (31, 34))	('S1PR1', 'Gene', (313, 318))	('combining', 'Interaction', (220, 229))	('increases', 'PosReg', (71, 80))	('enhancing', 'PosReg', (186, 195))	('macrophage migration', 'CPA', (196, 216))	('S1P', 'Var', (31, 34))	('tumor', 'Disease', (7, 12))	('S1P', 'Chemical', 'MESH:C060506', (235, 238))	('tumor', 'Disease', 'MESH:D009369', (7, 12))
428644	32799825	Two probes (204642_at and 239401_at) matching S1PR1 were detected.	('S1PR1', 'Gene', '1901', (46, 51))	('S1PR1', 'Gene', (46, 51))	('204642_at', 'Var', (12, 21))	('239401_at', 'Var', (26, 35))
428645	32799825	Notably, in three breast cancer cohorts (GSE1456-GPL96, GSE7378, and GSE12276), low S1PR1 expression was significantly associated with a poorer prognosis breast cancer (Fig.	('breast cancer', 'Disease', 'MESH:D001943', (154, 167))	('low', 'NegReg', (80, 83))	('S1PR1', 'Gene', '1901', (84, 89))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('breast cancer', 'Disease', (154, 167))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('GSE12276', 'Var', (69, 77))	('breast cancer', 'Disease', 'MESH:D001943', (18, 31))	('breast cancer', 'Phenotype', 'HP:0003002', (154, 167))	('breast cancer', 'Disease', (18, 31))	('S1PR1', 'Gene', (84, 89))	('breast cancer', 'Phenotype', 'HP:0003002', (18, 31))	('expression', 'MPA', (90, 100))	('GSE1456-GPL96', 'Var', (41, 54))
428649	32799825	In addition, low S1PR1 expression was also related to poor prognosis in two cohorts of patients with lung cancer (GSE31210 and GSE8894), as determined using two probes (204642_at and 239401_at) (Fig.	('S1PR1', 'Gene', (17, 22))	('low', 'NegReg', (13, 16))	('lung cancer', 'Disease', 'MESH:D008175', (101, 112))	('poor', 'NegReg', (54, 58))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('lung cancer', 'Phenotype', 'HP:0100526', (101, 112))	('204642_at', 'Var', (169, 178))	('239401_at', 'Var', (183, 192))	('S1PR1', 'Gene', '1901', (17, 22))	('patients', 'Species', '9606', (87, 95))	('lung cancer', 'Disease', (101, 112))	('expression', 'MPA', (23, 33))
428650	32799825	Kaplan-Meier plotter database also showed that low expression of S1PR1 was an independent risk factor for poor prognosis of lung cancer (overall survival, HR = 0.7, P = 6.9e-08; recurrence-free survival, HR = 0.71, P = 0.00035), but not related to post-progression survival in lung cancer (HR = 0.82, P = 0.14) (Fig.	('low expression', 'Var', (47, 61))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('lung cancer', 'Disease', 'MESH:D008175', (124, 135))	('lung cancer', 'Disease', (277, 288))	('lung cancer', 'Phenotype', 'HP:0100526', (277, 288))	('S1PR1', 'Gene', (65, 70))	('cancer', 'Phenotype', 'HP:0002664', (282, 288))	('lung cancer', 'Phenotype', 'HP:0100526', (124, 135))	('lung cancer', 'Disease', 'MESH:D008175', (277, 288))	('lung cancer', 'Disease', (124, 135))	('S1PR1', 'Gene', '1901', (65, 70))
428662	32799825	Taken together, high expression of S1PR1 could be considered a good prognostic indictor for breast and lung cancers depending on the clinical characteristics.	('S1PR1', 'Gene', '1901', (35, 40))	('high', 'Var', (16, 20))	('S1PR1', 'Gene', (35, 40))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('lung cancer', 'Phenotype', 'HP:0100526', (103, 114))	('lung cancers', 'Phenotype', 'HP:0100526', (103, 115))	('cancers', 'Phenotype', 'HP:0002664', (108, 115))	('breast and lung cancers', 'Disease', 'MESH:D001943', (92, 115))
428676	32799825	cBioPortal database was used to determine the types and frequencies of S1PR1 alterations in BRCA, LUAD, and LUSC.	('LUSC', 'Phenotype', 'HP:0030359', (108, 112))	('S1PR1', 'Gene', '1901', (71, 76))	('BRCA', 'Phenotype', 'HP:0003002', (92, 96))	('alterations', 'Var', (77, 88))	('BRCA', 'Gene', '672', (92, 96))	('LUAD', 'Phenotype', 'HP:0030078', (98, 102))	('BRCA', 'Gene', (92, 96))	('S1PR1', 'Gene', (71, 76))
428678	32799825	S1PR1 was altered in 6% of patients with LUAD and 2.3% of patients with LUSC, including mRNA missense mutations, truncating mutations, amplifications, and deletions (Fig.	('LUAD', 'Disease', (41, 45))	('altered', 'Reg', (10, 17))	('LUAD', 'Phenotype', 'HP:0030078', (41, 45))	('LUSC', 'Phenotype', 'HP:0030359', (72, 76))	('S1PR1', 'Gene', '1901', (0, 5))	('patients', 'Species', '9606', (27, 35))	('truncating', 'MPA', (113, 123))	('missense mutations', 'Var', (93, 111))	('deletions', 'Var', (155, 164))	('amplifications', 'Var', (135, 149))	('patients', 'Species', '9606', (58, 66))	('S1PR1', 'Gene', (0, 5))
428680	32799825	These results suggest that mutations in S1PR1 are associated with prognosis in LUAD.	('mutations', 'Var', (27, 36))	('LUAD', 'Disease', (79, 83))	('LUAD', 'Phenotype', 'HP:0030078', (79, 83))	('S1PR1', 'Gene', '1901', (40, 45))	('S1PR1', 'Gene', (40, 45))	('associated', 'Reg', (50, 60))
428702	32799825	This further confirms that S1PR1 is significantly related to immune infiltrating cells in lung and breast cancer, suggesting that high levels of S1PR1 could induce immune activity in the lung and breast cancer microenvironment.	('breast cancer', 'Disease', 'MESH:D001943', (99, 112))	('S1PR1', 'Gene', '1901', (145, 150))	('breast cancer', 'Disease', 'MESH:D001943', (196, 209))	('breast cancer', 'Disease', (99, 112))	('S1PR1', 'Gene', (27, 32))	('S1PR1', 'Gene', (145, 150))	('breast cancer', 'Phenotype', 'HP:0003002', (99, 112))	('induce', 'PosReg', (157, 163))	('breast cancer', 'Disease', (196, 209))	('breast cancer', 'Phenotype', 'HP:0003002', (196, 209))	('high levels', 'Var', (130, 141))	('immune activity', 'CPA', (164, 179))	('S1PR1', 'Gene', '1901', (27, 32))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
428706	32799825	Prognostic data from Kaplan-Meier plotter showed that low levels of S1PR1 are significantly related to poor prognosis in breast cancer and lung cancer.	('lung cancer', 'Disease', (139, 150))	('S1PR1', 'Gene', (68, 73))	('lung cancer', 'Disease', 'MESH:D008175', (139, 150))	('breast cancer', 'Disease', 'MESH:D001943', (121, 134))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('S1PR1', 'Gene', '1901', (68, 73))	('breast cancer', 'Disease', (121, 134))	('breast cancer', 'Phenotype', 'HP:0003002', (121, 134))	('lung cancer', 'Phenotype', 'HP:0100526', (139, 150))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('low levels', 'Var', (54, 64))
428716	32799825	These studies support our findings that high expression of S1PR1 is beneficial for tumor survival.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('high expression', 'Var', (40, 55))	('S1PR1', 'Gene', (59, 64))	('tumor', 'Disease', (83, 88))	('S1PR1', 'Gene', '1901', (59, 64))	('beneficial', 'PosReg', (68, 78))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
428725	32799825	As shown in recently reports, endothelial loss of S1PR1 led to a reduction in CD45+ cells, macrophages, and DCs, which influences tumor growth and metastasis.	('influences', 'Reg', (119, 129))	('loss', 'Var', (42, 46))	('CD45', 'Gene', '5788', (78, 82))	('DCs', 'MPA', (108, 111))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('S1PR1', 'Gene', '1901', (50, 55))	('CD45', 'Gene', (78, 82))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('S1PR1', 'Gene', (50, 55))	('tumor', 'Disease', (130, 135))	('reduction', 'NegReg', (65, 74))	('metastasis', 'CPA', (147, 157))
428726	32799825	In addition, S1P is involved in enhancing endocytosis and migration of mature dendritic cells through S1PR3, an event that may increase the immune response to cancer cells.	('cancer', 'Disease', (159, 165))	('enhancing', 'PosReg', (32, 41))	('endocytosis', 'MPA', (42, 53))	('S1PR3', 'Gene', '1903', (102, 107))	('S1PR3', 'Gene', (102, 107))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('increase', 'PosReg', (127, 135))	('S1P', 'Chemical', 'MESH:C060506', (102, 105))	('S1P', 'Chemical', 'MESH:C060506', (13, 16))	('S1P', 'Var', (13, 16))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('migration', 'CPA', (58, 67))
428735	32799825	This shows that S1PR1 defects promote the occurrence of VM, and the knockout of S1PR1 in breast cancer cells increases the number of VMs.	('S1PR1', 'Gene', '1901', (80, 85))	('promote', 'PosReg', (30, 37))	('breast cancer', 'Disease', 'MESH:D001943', (89, 102))	('S1PR1', 'Gene', '1901', (16, 21))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('knockout', 'Var', (68, 76))	('breast cancer', 'Disease', (89, 102))	('defects', 'Var', (22, 29))	('S1PR1', 'Gene', (80, 85))	('breast cancer', 'Phenotype', 'HP:0003002', (89, 102))	('S1PR1', 'Gene', (16, 21))	('increases', 'PosReg', (109, 118))	('VMs', 'Disease', (133, 136))
428736	32799825	More importantly, tumor cells with low S1PR1 expression receive nutrition through VM, and accelerate tumor growth in animal models.	('tumor', 'Disease', (18, 23))	('S1PR1', 'Gene', '1901', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('accelerate', 'PosReg', (90, 100))	('S1PR1', 'Gene', (39, 44))	('low', 'Var', (35, 38))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
428745	27072585	Predictive and prognostic value of preoperative serum tumor markers is EGFR mutation-specific in resectable non-small-cell lung cancer The predictive and prognostic value of carcinoembryonic antigen (CEA), cytokeratin-19 fragments (Cyfra21-1), squamous cell carcinoma antigen (SCCA) and neuron-specific enolase (NSE) has been investigated in non-small-cell lung cancer (NSCLC) patients.	('neuron-specific enolase', 'Gene', '2026', (287, 310))	('lung cancer', 'Disease', (357, 368))	('squamous cell carcinoma', 'Disease', (244, 267))	('lung cancer', 'Phenotype', 'HP:0100526', (123, 134))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('EGFR', 'Gene', '1956', (71, 75))	('cytokeratin-19', 'Gene', '3880', (206, 220))	('NSCLC', 'Disease', 'MESH:D002289', (370, 375))	('carcinoembryonic antigen', 'Gene', '1084', (174, 198))	('patients', 'Species', '9606', (377, 385))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (108, 134))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('lung cancer', 'Disease', 'MESH:D008175', (357, 368))	('NSCLC', 'Disease', (370, 375))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (244, 267))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (346, 368))	('lung cancer', 'Disease', (123, 134))	('lung cancer', 'Phenotype', 'HP:0100526', (357, 368))	('CEA', 'Gene', (200, 203))	('NSCLC', 'Phenotype', 'HP:0030358', (370, 375))	('EGFR', 'Gene', (71, 75))	('carcinoma', 'Phenotype', 'HP:0030731', (258, 267))	('NSE', 'Gene', '2026', (312, 315))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (342, 368))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (244, 267))	('NSE', 'Gene', (312, 315))	('cancer', 'Phenotype', 'HP:0002664', (362, 368))	('lung cancer', 'Disease', 'MESH:D008175', (123, 134))	('carcinoembryonic antigen', 'Gene', (174, 198))	('CEA', 'Gene', '1084', (200, 203))	('cytokeratin-19', 'Gene', (206, 220))	('neuron-specific enolase', 'Gene', (287, 310))	('tumor', 'Disease', (54, 59))	('mutation-specific', 'Var', (76, 93))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (112, 134))
428748	27072585	Correlations between serum tumor marker levels and EGFR mutations and survival parameters were analyzed and prognostic factors were identified.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('mutations', 'Var', (56, 65))	('EGFR', 'Gene', (51, 55))	('tumor', 'Disease', (27, 32))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('EGFR', 'Gene', '1956', (51, 55))
428751	27072585	Further stratification analysis revealed that in EGFR exon 19 deletion adenocarcinomas, elevated Cyfra21-1 was an independent prognostic factor (P = 0.002).	('EGFR', 'Gene', '1956', (49, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('carcinomas', 'Phenotype', 'HP:0030731', (76, 86))	('EGFR', 'Gene', (49, 53))	('elevated', 'PosReg', (88, 96))	('exon', 'Var', (54, 58))	('adenocarcinomas', 'Disease', 'MESH:D000230', (71, 86))	('deletion', 'Var', (62, 70))	('adenocarcinomas', 'Disease', (71, 86))	('Cyfra21-1', 'MPA', (97, 106))
428752	27072585	Within the Leu858Arg substitution subgroup, increased CEA (P = 0.005) and clinical stage were predictive factors of DFS, while elevated CEA (P = 0.005) and Cyfra21-1 (P = 0.027) were independent prognostic factors.	('CEA', 'Gene', '1084', (136, 139))	('Leu858Arg', 'Var', (11, 20))	('Leu858Arg', 'Chemical', '-', (11, 20))	('CEA', 'Gene', (54, 57))	('DFS', 'Disease', (116, 119))	('increased CEA', 'Phenotype', 'HP:0031029', (44, 57))	('CEA', 'Gene', '1084', (54, 57))	('elevated CEA', 'Phenotype', 'HP:0031029', (127, 139))	('increased', 'PosReg', (44, 53))	('CEA', 'Gene', (136, 139))
428754	27072585	The prognostic impact of preoperative serum tumor markers should be evaluated together with EGFR mutation status.	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('EGFR', 'Gene', '1956', (92, 96))	('mutation', 'Var', (97, 105))	('EGFR', 'Gene', (92, 96))	('tumor', 'Disease', (44, 49))
428757	27072585	Recent advancements in molecular targeted therapy have exploited the discovery of distinct cancer subsets with epidermal growth factor receptor (EGFR) mutations and led to a major paradigm shift in the treatment of NSCLC.	('EGFR', 'Gene', '1956', (145, 149))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('NSCLC', 'Phenotype', 'HP:0030358', (215, 220))	('epidermal growth factor receptor', 'Gene', (111, 143))	('EGFR', 'Gene', (145, 149))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('NSCLC', 'Disease', (215, 220))	('NSCLC', 'Disease', 'MESH:D002289', (215, 220))	('mutations', 'Var', (151, 160))	('epidermal growth factor receptor', 'Gene', '1956', (111, 143))
428758	27072585	EGFR exon 19 deletion (del19) and exon 21 Leu858Arg substitution (L858R) make up around 90% of all EGFR mutation-positive lung adenocarcinomas, and are strongly associated with robust responses and improved progression-free survival (PFS) to EGFR tyrosine kinase inhibitors (EGFR-TKIs).	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (122, 142))	('EGFR', 'Gene', (242, 246))	('lung adenocarcinomas', 'Disease', (122, 142))	('EGFR', 'Gene', '1956', (275, 279))	('EGFR', 'Gene', (99, 103))	('mutation-positive', 'Reg', (104, 121))	('improved', 'PosReg', (198, 206))	('L858R', 'Mutation', 'rs121434568', (66, 71))	('Leu858Arg', 'Chemical', '-', (42, 51))	('Leu858Arg', 'Var', (42, 51))	('EGFR', 'Gene', (0, 4))	('progression-free survival', 'CPA', (207, 232))	('EGFR', 'Gene', '1956', (242, 246))	('EGFR', 'Gene', '1956', (99, 103))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (122, 142))	('EGFR', 'Gene', (275, 279))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('carcinomas', 'Phenotype', 'HP:0030731', (132, 142))	('del19', 'Mutation', 'c.del19', (23, 28))	('EGFR', 'Gene', '1956', (0, 4))
428760	27072585	Preclinical studies have shown that EGFR del19 and L858R mutants have distinct biochemical properties that affect response to EGFR-TKIs, thus likely belong to different molecular subsets and should be studied independently.	('response', 'MPA', (114, 122))	('affect', 'Reg', (107, 113))	('EGFR', 'Gene', (126, 130))	('del19', 'Mutation', 'c.del19', (41, 46))	('L858R', 'Var', (51, 56))	('EGFR', 'Gene', '1956', (36, 40))	('L858R', 'Mutation', 'rs121434568', (51, 56))	('EGFR', 'Gene', (36, 40))	('EGFR', 'Gene', '1956', (126, 130))
428761	27072585	EGFR mutations are most common in Asian populations, nonsmokers, females and those with adenocarcinoma histology.	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('EGFR', 'Gene', (0, 4))	('adenocarcinoma', 'Disease', 'MESH:D000230', (88, 102))	('mutations', 'Var', (5, 14))	('common', 'Reg', (24, 30))	('EGFR', 'Gene', '1956', (0, 4))	('adenocarcinoma', 'Disease', (88, 102))
428762	27072585	The EGFR mutation rate in squamous cell carcinoma is reported to be approximately 5%, therefore, most squamous cell carcinoma patients do not benefit from EGFR targeted therapy.	('mutation', 'Var', (9, 17))	('squamous cell carcinoma', 'Disease', (102, 125))	('EGFR', 'Gene', '1956', (155, 159))	('EGFR', 'Gene', (4, 8))	('EGFR', 'Gene', (155, 159))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (26, 49))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (102, 125))	('carcinoma', 'Phenotype', 'HP:0030731', (40, 49))	('squamous cell carcinoma', 'Disease', (26, 49))	('patients', 'Species', '9606', (126, 134))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (26, 49))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (102, 125))	('EGFR', 'Gene', '1956', (4, 8))
428765	27072585	Several studies have shown that serum tumor markers were associated with EGFR mutation status and capable of predicting the efficacy of EGFR-TKI therapy in advanced NSCLC.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('EGFR', 'Gene', '1956', (73, 77))	('NSCLC', 'Disease', 'MESH:D002289', (165, 170))	('NSCLC', 'Disease', (165, 170))	('EGFR', 'Gene', (73, 77))	('NSCLC', 'Phenotype', 'HP:0030358', (165, 170))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('mutation status', 'Var', (78, 93))	('EGFR', 'Gene', '1956', (136, 140))	('EGFR', 'Gene', (136, 140))	('associated', 'Reg', (57, 67))
428766	27072585	Higher serum CEA level has been associated with higher EGFR mutation rate, higher disease control rate (DCR) and longer survival time in advanced adenocarcinoma patients treated with EGFR-TKI.	('disease', 'MPA', (82, 89))	('EGFR', 'Gene', '1956', (55, 59))	('mutation', 'Var', (60, 68))	('adenocarcinoma', 'Disease', 'MESH:D000230', (146, 160))	('Higher serum CEA level', 'Phenotype', 'HP:0031029', (0, 22))	('EGFR', 'Gene', '1956', (183, 187))	('EGFR', 'Gene', (183, 187))	('higher', 'PosReg', (75, 81))	('EGFR', 'Gene', (55, 59))	('higher', 'PosReg', (48, 54))	('CEA', 'Gene', (13, 16))	('patients', 'Species', '9606', (161, 169))	('CEA', 'Gene', '1084', (13, 16))	('adenocarcinoma', 'Disease', (146, 160))	('carcinoma', 'Phenotype', 'HP:0030731', (151, 160))
428769	27072585	reported that high pre-treatment levels of CEA and/or Cyfra21-1 were associated with poor outcome for advanced NSCLC patients treated with erlotinib.	('Cyfra21-1', 'Var', (54, 63))	('erlotinib', 'Chemical', 'MESH:D000069347', (139, 148))	('NSCLC', 'Disease', (111, 116))	('NSCLC', 'Disease', 'MESH:D002289', (111, 116))	('CEA', 'Gene', (43, 46))	('CEA', 'Gene', '1084', (43, 46))	('patients', 'Species', '9606', (117, 125))	('NSCLC', 'Phenotype', 'HP:0030358', (111, 116))
428771	27072585	Therefore, prognostic significance of CEA and Cyfra21-1 in EGFR mutated NSCLC remains largely unknown.	('CEA', 'Gene', (38, 41))	('CEA', 'Gene', '1084', (38, 41))	('EGFR', 'Gene', (59, 63))	('NSCLC', 'Disease', (72, 77))	('NSCLC', 'Disease', 'MESH:D002289', (72, 77))	('mutated', 'Var', (64, 71))	('NSCLC', 'Phenotype', 'HP:0030358', (72, 77))	('EGFR', 'Gene', '1956', (59, 63))
428774	27072585	Particularly we addressed the impact of respective tumor markers in patients with EGFR mutations as potential prognostic factors.	('EGFR', 'Gene', (82, 86))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor', 'Disease', (51, 56))	('patients', 'Species', '9606', (68, 76))	('EGFR', 'Gene', '1956', (82, 86))	('mutations', 'Var', (87, 96))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
428779	27072585	EGFR Mutations were detected in 38.5% (218/566) adenocarcinoma cases, 4.3% (15/352) squamous cell carcinoma, 42.1% (8/19) adenosquamous carcinoma and 9.5% (4/42) large cell lung carcinoma.	('detected', 'Reg', (20, 28))	('Mutations', 'Var', (5, 14))	('EGFR', 'Gene', (0, 4))	('cell lung carcinoma', 'Disease', (168, 187))	('adenosquamous carcinoma', 'Disease', 'MESH:D018196', (122, 145))	('adenosquamous carcinoma', 'Disease', (122, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('adenocarcinoma', 'Disease', (48, 62))	('cell lung carcinoma', 'Disease', 'MESH:D055752', (168, 187))	('large cell lung carcinoma', 'Phenotype', 'HP:0030360', (162, 187))	('carcinoma', 'Phenotype', 'HP:0030731', (53, 62))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (84, 107))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (84, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (178, 187))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('squamous cell carcinoma', 'Disease', (84, 107))	('adenocarcinoma', 'Disease', 'MESH:D000230', (48, 62))	('EGFR', 'Gene', '1956', (0, 4))
428780	27072585	Among the 245 EGFR mutations, 123 were del19, and 122 were L858R.	('EGFR', 'Gene', '1956', (14, 18))	('EGFR', 'Gene', (14, 18))	('L858R', 'Var', (59, 64))	('del19', 'Var', (39, 44))	('mutations', 'Var', (19, 28))	('L858R', 'Mutation', 'rs121434568', (59, 64))	('del19', 'Mutation', 'c.del19', (39, 44))
428789	27072585	Median levels and positive rates for CEA, Cyfra21-1 or SCCA were similar regardless of EGFR mutation status in adenocarcinoma patients (Table 2).	('EGFR', 'Gene', '1956', (87, 91))	('mutation', 'Var', (92, 100))	('EGFR', 'Gene', (87, 91))	('CEA', 'Gene', (37, 40))	('adenocarcinoma', 'Disease', (111, 125))	('patients', 'Species', '9606', (126, 134))	('CEA', 'Gene', '1084', (37, 40))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('SCCA', 'MPA', (55, 59))	('adenocarcinoma', 'Disease', 'MESH:D000230', (111, 125))
428790	27072585	Similarly, no differences were found in those marker levels between del19 and L858R adenocarcinoma patient subgroups.	('patient', 'Species', '9606', (99, 106))	('del19', 'Mutation', 'c.del19', (68, 73))	('L858R', 'Mutation', 'rs121434568', (78, 83))	('del19', 'Var', (68, 73))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('L858R', 'Var', (78, 83))	('adenocarcinoma', 'Disease', (84, 98))	('adenocarcinoma', 'Disease', 'MESH:D000230', (84, 98))
428791	27072585	However, median NSE levels in patients with EGFR mutations were higher than those with wild-type EGFR (median: 14.27 versus 13.25 ng/ml, P = 0.007).	('NSE', 'Gene', (16, 19))	('mutations', 'Var', (49, 58))	('EGFR', 'Gene', '1956', (97, 101))	('higher', 'PosReg', (64, 70))	('EGFR', 'Gene', (97, 101))	('patients', 'Species', '9606', (30, 38))	('EGFR', 'Gene', '1956', (44, 48))	('NSE', 'Gene', '2026', (16, 19))	('EGFR', 'Gene', (44, 48))
428792	27072585	In addition, elevated NSE was observed in 32.1% EGFR mutated patients compared to 24.4% in EGFR wild-type patients (chi2 = 3.981, P = 0.046).	('EGFR', 'Gene', (91, 95))	('EGFR', 'Gene', '1956', (48, 52))	('NSE', 'Gene', (22, 25))	('elevated', 'PosReg', (13, 21))	('patients', 'Species', '9606', (61, 69))	('EGFR', 'Gene', (48, 52))	('mutated', 'Var', (53, 60))	('patients', 'Species', '9606', (106, 114))	('NSE', 'Gene', '2026', (22, 25))	('EGFR', 'Gene', '1956', (91, 95))
428793	27072585	No difference was found in median levels and positive rates of NSE between del19 and L858R adenocarcinoma subgroups.	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('L858R', 'Var', (85, 90))	('del19', 'Var', (75, 80))	('NSE', 'Gene', '2026', (63, 66))	('adenocarcinoma subgroups', 'Disease', 'MESH:D000230', (91, 115))	('L858R', 'Mutation', 'rs121434568', (85, 90))	('adenocarcinoma subgroups', 'Disease', (91, 115))	('NSE', 'Gene', (63, 66))	('del19', 'Mutation', 'c.del19', (75, 80))
428797	27072585	Patients with high SCCA had significantly shorter DFS (22.0 versus 36.0 months, log-rank chi2 = 4.542, P = 0.033), but this was not associated with an effect on OS (53.8 versus 59.8 months, log-rank chi2 = 1.665, P = 0.197).	('OS', 'Chemical', '-', (161, 163))	('shorter', 'NegReg', (42, 49))	('Patients', 'Species', '9606', (0, 8))	('DFS', 'MPA', (50, 53))	('high SCCA', 'Var', (14, 23))
428802	27072585	EGFR was mutated in 218 adenocarcinoma patients, and among them CEA, Cyfra21-1, SCCA, and NSE increased in 86, 68, 12, and 70 patients, respectively.	('CEA', 'Gene', '1084', (64, 67))	('EGFR', 'Gene', (0, 4))	('patients', 'Species', '9606', (39, 47))	('carcinoma', 'Phenotype', 'HP:0030731', (29, 38))	('adenocarcinoma', 'Disease', (24, 38))	('mutated', 'Var', (9, 16))	('NSE', 'Gene', '2026', (90, 93))	('patients', 'Species', '9606', (126, 134))	('CEA', 'Gene', (64, 67))	('adenocarcinoma', 'Disease', 'MESH:D000230', (24, 38))	('NSE', 'Gene', (90, 93))	('EGFR', 'Gene', '1956', (0, 4))
428804	27072585	EGFR-mutated adenocarcinoma patients with either elevated CEA or Cyfra21-1 exhibited both shorter DFS and OS (CEA: 25.0 versus 46.4 months, log-rank chi2 = 21.977, P < 0.001 for DFS, Figure 1A; 48.6 months versus NR, log-rank chi2 = 16.315, P < 0.001 for OS, Figure 1B; Cyfra21-1: 24.0 versus 50.8 months, log-rank chi2 = 12.820, P < 0.001 for DFS, Figure 1C; 42.6 months versus NR, log-rank chi2 = 23.537, P < 0.001 for OS, Figure 1D).	('OS', 'Chemical', '-', (255, 257))	('CEA', 'Gene', '1084', (58, 61))	('carcinoma', 'Phenotype', 'HP:0030731', (18, 27))	('EGFR', 'Gene', (0, 4))	('CEA', 'Gene', (110, 113))	('elevated CEA', 'Phenotype', 'HP:0031029', (49, 61))	('adenocarcinoma', 'Disease', (13, 27))	('shorter', 'NegReg', (90, 97))	('CEA', 'Gene', '1084', (110, 113))	('OS', 'Chemical', '-', (421, 423))	('Cyfra21-1', 'Var', (65, 74))	('adenocarcinoma', 'Disease', 'MESH:D000230', (13, 27))	('elevated', 'PosReg', (49, 57))	('patients', 'Species', '9606', (28, 36))	('CEA', 'Gene', (58, 61))	('EGFR', 'Gene', '1956', (0, 4))	('OS', 'Chemical', '-', (106, 108))
428807	27072585	Similar to EGFR-mutated patients, both CEA and Cyfra21-1 increases were associated with worse DFS and OS (CEA: 15.0 versus 47.7 months, log-rank chi2 = 40.887, P < 0.001 for DFS; Figure 1E; 33.5 versus 56.3 months, log-rank chi2 = 22.726, P < 0.001 for OS, Figure 1F; Cyfra21-1: 23.3 versus 37.5 months, log-rank chi2 = 10.155, P = 0.001 for DFS, Figure 1G; 39.0 versus 54.7 months, log-rank chi2 = 10.399, P = 0.001 for OS, Figure 1H).	('OS', 'Chemical', '-', (102, 104))	('EGFR', 'Gene', '1956', (11, 15))	('Cyfra21-1', 'Var', (47, 56))	('EGFR', 'Gene', (11, 15))	('CEA', 'Gene', (39, 42))	('OS', 'Chemical', '-', (421, 423))	('DFS', 'Disease', (94, 97))	('increases', 'PosReg', (57, 66))	('CEA', 'Gene', '1084', (39, 42))	('CEA', 'Gene', (106, 109))	('patients', 'Species', '9606', (24, 32))	('CEA', 'Gene', '1084', (106, 109))	('OS', 'Chemical', '-', (253, 255))
428809	27072585	Among the 218 patients with EGFR mutations, 105 patients possessed the del19 mutation.	('EGFR', 'Gene', '1956', (28, 32))	('del19', 'Mutation', 'c.del19', (71, 76))	('del19', 'Var', (71, 76))	('EGFR', 'Gene', (28, 32))	('mutations', 'Var', (33, 42))	('patients', 'Species', '9606', (14, 22))	('patients', 'Species', '9606', (48, 56))
428811	27072585	Interestingly, there was no association in DFS with elevated levels of any of the 3 markers (P = 0.081 for CEA, Figure 2A; P = 0.076 for Cyfra21-1, Figure 2C; P = 0.849 for NSE).	('NSE', 'Gene', (173, 176))	('CEA', 'Gene', (107, 110))	('CEA', 'Gene', '1084', (107, 110))	('Cyfra21-1', 'Var', (137, 146))	('NSE', 'Gene', '2026', (173, 176))
428812	27072585	In addition, there was no effect on OS for increased CEA (P = 0.071; Figure 2B) or NSE (P = 0.958) patients, but elevated Cyfra21-1 was associated with shorter OS (48.6 months versus NR, log-rank chi2 = 10.267, P = 0.001; Figure 2D).	('NSE', 'Gene', '2026', (83, 86))	('increased CEA', 'Phenotype', 'HP:0031029', (43, 56))	('CEA', 'Gene', (53, 56))	('patients', 'Species', '9606', (99, 107))	('Cyfra21-1', 'Var', (122, 131))	('shorter', 'NegReg', (152, 159))	('OS', 'Chemical', '-', (160, 162))	('CEA', 'Gene', '1084', (53, 56))	('OS', 'Chemical', '-', (36, 38))	('NSE', 'Gene', (83, 86))
428813	27072585	The remaining EGFR-mutated patients harbored L858R, of which 45 had increased CEA, 38 increased Cyfra21-1 and 33 increased NSE.	('EGFR', 'Gene', '1956', (14, 18))	('increased', 'PosReg', (86, 95))	('EGFR', 'Gene', (14, 18))	('L858R', 'Var', (45, 50))	('NSE', 'Gene', (123, 126))	('patients', 'Species', '9606', (27, 35))	('increased CEA', 'Phenotype', 'HP:0031029', (68, 81))	('CEA', 'Gene', (78, 81))	('increased', 'PosReg', (113, 122))	('L858R', 'Mutation', 'rs121434568', (45, 50))	('Cyfra21-1', 'MPA', (96, 105))	('CEA', 'Gene', '1084', (78, 81))	('increased', 'PosReg', (68, 77))	('NSE', 'Gene', '2026', (123, 126))
428816	27072585	By univariate analysis, adenocarcinoma patients harboring EGFR mutations had DFS and OS significantly associated with clinical stage, tumor size, regional lymph node (LN) metastasis, adjuvant treatment, CEA, and Cyfra21-1 (Table 3).	('mutations', 'Var', (63, 72))	('EGFR', 'Gene', '1956', (58, 62))	('CEA', 'Gene', '1084', (203, 206))	('associated', 'Reg', (102, 112))	('patients', 'Species', '9606', (39, 47))	('carcinoma', 'Phenotype', 'HP:0030731', (29, 38))	('EGFR', 'Gene', (58, 62))	('adenocarcinoma', 'Disease', (24, 38))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('DFS', 'CPA', (77, 80))	('adenocarcinoma', 'Disease', 'MESH:D000230', (24, 38))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('OS', 'Chemical', '-', (85, 87))	('CEA', 'Gene', (203, 206))	('tumor', 'Disease', (134, 139))
428817	27072585	When stratifying EGFR-mutated cases into del19 (105 cases) and L858R (113 cases) subgroups, we found that DFS and OS were longer in the Cyfra21-1 normal group than in the elevated Cyfra21-1 group for both subgroups.	('longer', 'PosReg', (122, 128))	('del19', 'Mutation', 'c.del19', (41, 46))	('Cyfra21-1', 'Var', (136, 145))	('OS', 'Chemical', '-', (114, 116))	('L858R', 'Mutation', 'rs121434568', (63, 68))	('EGFR', 'Gene', '1956', (17, 21))	('DFS', 'CPA', (106, 109))	('EGFR', 'Gene', (17, 21))
428818	27072585	However, elevated CEA level was associated with shorter DFS and OS only in L858R patients.	('L858R', 'Mutation', 'rs121434568', (75, 80))	('CEA', 'Gene', '1084', (18, 21))	('patients', 'Species', '9606', (81, 89))	('elevated CEA', 'Phenotype', 'HP:0031029', (9, 21))	('shorter', 'NegReg', (48, 55))	('OS', 'Chemical', '-', (64, 66))	('DFS', 'MPA', (56, 59))	('L858R', 'Var', (75, 80))	('CEA', 'Gene', (18, 21))
428821	27072585	Further stratification analysis revealed that Cyfra21-1 (HR = 2.713, P = 0.002) was an independent prognostic factor for EGFR del19 adenocarcinoma patients.	('del19 adenocarcinoma', 'Disease', 'MESH:D000230', (126, 146))	('Cyfra21-1', 'Var', (46, 55))	('EGFR', 'Gene', '1956', (121, 125))	('del19 adenocarcinoma', 'Disease', (126, 146))	('EGFR', 'Gene', (121, 125))	('patients', 'Species', '9606', (147, 155))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))
428822	27072585	In L858R subgroup, CEA (HR = 2.259, P = 0.005) and clinical stage (HR = 2.234, P = 0.007) were predictive factors of DFS, while CEA (HR = 2.515, P = 0.005) and Cyfra21-1 (HR = 2.068, P = 0.027) were independent prognostic factors for OS (Table 4).	('CEA', 'Gene', (128, 131))	('OS', 'Chemical', '-', (234, 236))	('CEA', 'Gene', '1084', (128, 131))	('L858R', 'Var', (3, 8))	('CEA', 'Gene', (19, 22))	('L858R', 'Mutation', 'rs121434568', (3, 8))	('CEA', 'Gene', '1084', (19, 22))	('DFS', 'Disease', (117, 120))
428824	27072585	Over 25% (139/549) of recurrent patients harbored EGFR mutations, 54 of which received EGFR-TKI therapy (30 del19 and 24 L858R cases), either gefitinib 250 mg/d or erlotinib 150 mg/d.	('30 del19', 'Mutation', 'c.30del19', (105, 113))	('patients', 'Species', '9606', (32, 40))	('EGFR', 'Gene', '1956', (87, 91))	('mutations', 'Var', (55, 64))	('gefitinib', 'Chemical', 'MESH:D000077156', (142, 151))	('harbored', 'Reg', (41, 49))	('EGFR', 'Gene', (87, 91))	('EGFR', 'Gene', '1956', (50, 54))	('erlotinib', 'Chemical', 'MESH:D000069347', (164, 173))	('EGFR', 'Gene', (50, 54))	('L858R', 'Mutation', 'rs121434568', (121, 126))
428827	27072585	It is noteworthy that serum CEA or NSE could not predict PRS for patients treated with EGFR-TKIs, while elevated Cyfra21-1 conferred shorter PRS (log-rank chi2 = 8.110, P = 0.004).	('shorter', 'NegReg', (133, 140))	('CEA', 'Gene', (28, 31))	('EGFR', 'Gene', '1956', (87, 91))	('PRS', 'Disease', (57, 60))	('NSE', 'Gene', '2026', (35, 38))	('CEA', 'Gene', '1084', (28, 31))	('EGFR', 'Gene', (87, 91))	('Cyfra21-1', 'Var', (113, 122))	('patients', 'Species', '9606', (65, 73))	('NSE', 'Gene', (35, 38))	('elevated', 'PosReg', (104, 112))	('PRS', 'MPA', (141, 144))
428828	27072585	Among non-adenocarcinoma patients, EGFR mutations were detected in 15 squamous cell carcinomas, 8 adenosquamous carcinomas 8 and 4 large cell lung carcinomas (Table 5).	('cell lung carcinomas', 'Disease', 'MESH:D055752', (137, 157))	('large cell lung carcinoma', 'Phenotype', 'HP:0030360', (131, 156))	('cell lung carcinomas', 'Disease', (137, 157))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('carcinomas', 'Phenotype', 'HP:0030731', (112, 122))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (70, 94))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (70, 93))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (70, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (15, 24))	('EGFR', 'Gene', (35, 39))	('mutations', 'Var', (40, 49))	('large cell lung carcinomas', 'Phenotype', 'HP:0030360', (131, 157))	('adenosquamous carcinomas', 'Disease', (98, 122))	('non-adenocarcinoma', 'Disease', 'MESH:D000230', (6, 24))	('non-adenocarcinoma', 'Disease', (6, 24))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('carcinomas', 'Phenotype', 'HP:0030731', (84, 94))	('patients', 'Species', '9606', (25, 33))	('squamous cell carcinomas', 'Disease', (70, 94))	('adenosquamous carcinomas', 'Disease', 'MESH:D018196', (98, 122))	('detected', 'Reg', (55, 63))	('EGFR', 'Gene', '1956', (35, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (147, 156))	('carcinomas', 'Phenotype', 'HP:0030731', (147, 157))
428829	27072585	Non-adenocarcinoma patients harboring EGFR mutations had significantly shorter DFS and OS compared to EGFR-mutated adenocarcinoma patients (15.0 versus 39.0 months, log-rank chi2 = 15.075, P < 0.001 for DFS; 30.1 versus 62.6 months, log-rank chi2 = 32.665, P < 0.001 for OS).	('carcinoma', 'Phenotype', 'HP:0030731', (9, 18))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('EGFR', 'Gene', '1956', (102, 106))	('Non-adenocarcinoma', 'Disease', 'MESH:D000230', (0, 18))	('EGFR', 'Gene', '1956', (38, 42))	('OS', 'Chemical', '-', (271, 273))	('Non-adenocarcinoma', 'Disease', (0, 18))	('adenocarcinoma', 'Disease', (115, 129))	('patients', 'Species', '9606', (19, 27))	('OS', 'Chemical', '-', (87, 89))	('adenocarcinoma', 'Disease', (4, 18))	('patients', 'Species', '9606', (130, 138))	('shorter', 'NegReg', (71, 78))	('adenocarcinoma', 'Disease', 'MESH:D000230', (115, 129))	('EGFR', 'Gene', (102, 106))	('DFS', 'CPA', (79, 82))	('EGFR', 'Gene', (38, 42))	('mutations', 'Var', (43, 52))	('adenocarcinoma', 'Disease', 'MESH:D000230', (4, 18))
428832	27072585	Among the non-adenocarcinoma patients, those with elevated Cyfra21-1 had shorter DFS and OS compared to normal Cyfra21-1 cases (median DFS, 13.2 versus 22.0 months; median OS, 23.4 versus 39.6 months), especially among the 15 squamous cell carcinoma patients, 9 cases with elevated Cyfra21-1 had shorter DFS and OS compared to those with normal Cyfra21-1 levels (median DFS, 13.2 versus 24.0 months; median OS, 18.3 versus 43.7 months).	('DFS', 'MPA', (81, 84))	('DFS', 'MPA', (304, 307))	('OS', 'Chemical', '-', (172, 174))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (226, 249))	('shorter', 'NegReg', (296, 303))	('non-adenocarcinoma', 'Disease', 'MESH:D000230', (10, 28))	('patients', 'Species', '9606', (29, 37))	('carcinoma', 'Phenotype', 'HP:0030731', (19, 28))	('patients', 'Species', '9606', (250, 258))	('non-adenocarcinoma', 'Disease', (10, 28))	('shorter', 'NegReg', (73, 80))	('OS', 'Chemical', '-', (407, 409))	('Cyfra21-1', 'Var', (59, 68))	('OS', 'Chemical', '-', (89, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (240, 249))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (226, 249))	('OS', 'Chemical', '-', (312, 314))	('squamous cell carcinoma', 'Disease', (226, 249))
428833	27072585	Serum SCCA levels were not different between squamous cell carcinoma patients with or without EGFR mutations, nor did it have a relationship with DFS or OS.	('squamous cell carcinoma', 'Disease', (45, 68))	('EGFR', 'Gene', '1956', (94, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (59, 68))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (45, 68))	('OS', 'Chemical', '-', (153, 155))	('patients', 'Species', '9606', (69, 77))	('EGFR', 'Gene', (94, 98))	('mutations', 'Var', (99, 108))	('DFS', 'Disease', (146, 149))	('Serum SCCA levels', 'MPA', (0, 17))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (45, 68))	('relationship', 'Reg', (128, 140))
428836	27072585	Moreover, several serum tumor markers have been shown to be associated with EGFR mutation status and efficacy of EGFR-TKI treatment.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumor', 'Disease', (24, 29))	('EGFR', 'Gene', '1956', (76, 80))	('mutation', 'Var', (81, 89))	('EGFR', 'Gene', '1956', (113, 117))	('EGFR', 'Gene', (76, 80))	('EGFR', 'Gene', (113, 117))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('associated', 'Reg', (60, 70))
428837	27072585	In addition, their association with EGFR mutation subtypes (del19 and L858R) remains largely unknown.	('del19', 'Var', (60, 65))	('L858R', 'Var', (70, 75))	('EGFR', 'Gene', '1956', (36, 40))	('L858R', 'Mutation', 'rs121434568', (70, 75))	('EGFR', 'Gene', (36, 40))	('del19', 'Mutation', 'c.del19', (60, 65))
428838	27072585	In this study, we demonstrated that elevated Cyfra21-1 and advanced clinical stage were independently associated with shorter DFS and OS in EGFR-mutated adenocarcinoma patients, while increased CEA and advanced clinical stage were independently associated with worse DFS and OS in wild-type adenocarcinoma patients.	('elevated', 'PosReg', (36, 44))	('EGFR', 'Gene', (140, 144))	('adenocarcinoma', 'Disease', (291, 305))	('CEA', 'Gene', (194, 197))	('carcinoma', 'Phenotype', 'HP:0030731', (158, 167))	('OS', 'Chemical', '-', (134, 136))	('EGFR', 'Gene', '1956', (140, 144))	('patients', 'Species', '9606', (306, 314))	('increased CEA', 'Phenotype', 'HP:0031029', (184, 197))	('adenocarcinoma', 'Disease', 'MESH:D000230', (291, 305))	('CEA', 'Gene', '1084', (194, 197))	('Cyfra21-1', 'Var', (45, 54))	('adenocarcinoma', 'Disease', (153, 167))	('OS', 'Chemical', '-', (275, 277))	('shorter', 'NegReg', (118, 125))	('patients', 'Species', '9606', (168, 176))	('DFS', 'CPA', (126, 129))	('adenocarcinoma', 'Disease', 'MESH:D000230', (153, 167))	('carcinoma', 'Phenotype', 'HP:0030731', (296, 305))
428840	27072585	However in L858R group, CEA and clinical stage were significantly associated with DFS, while elevated CEA and Cyfra21-1 were significantly unfavorable prognostic factors.	('CEA', 'Gene', (24, 27))	('CEA', 'Gene', '1084', (24, 27))	('elevated CEA', 'Phenotype', 'HP:0031029', (93, 105))	('DFS', 'Disease', (82, 85))	('associated', 'Reg', (66, 76))	('L858R', 'Var', (11, 16))	('clinical stage', 'CPA', (32, 46))	('CEA', 'Gene', (102, 105))	('L858R', 'Mutation', 'rs121434568', (11, 16))	('CEA', 'Gene', '1084', (102, 105))
428843	27072585	Preoperative CEA may not be predictive or prognostic for patients with EGFR mutations due to the high sensitivity to EGFR-TKI and platinum-based doublet chemotherapy.	('mutations', 'Var', (76, 85))	('EGFR', 'Gene', '1956', (117, 121))	('patients', 'Species', '9606', (57, 65))	('EGFR', 'Gene', (117, 121))	('EGFR', 'Gene', '1956', (71, 75))	('CEA', 'Gene', (13, 16))	('platinum', 'Chemical', 'MESH:D010984', (130, 138))	('CEA', 'Gene', '1084', (13, 16))	('EGFR', 'Gene', (71, 75))
428846	27072585	Cyfra21-1 was previously shown to be useful for predicting clinical outcome of NSCLC patients, especially those with EGFR mutations.	('NSCLC', 'Disease', 'MESH:D002289', (79, 84))	('EGFR', 'Gene', '1956', (117, 121))	('EGFR', 'Gene', (117, 121))	('patients', 'Species', '9606', (85, 93))	('NSCLC', 'Phenotype', 'HP:0030358', (79, 84))	('mutations', 'Var', (122, 131))	('NSCLC', 'Disease', (79, 84))
428849	27072585	We observed squamous cell carcinoma patients had significantly shorter DFS and OS than those with adenocarcinomas, especially in the context of EGFR mutations, consistent with previous reports.	('EGFR', 'Gene', (144, 148))	('DFS', 'MPA', (71, 74))	('mutations', 'Var', (149, 158))	('adenocarcinomas', 'Disease', 'MESH:D000230', (98, 113))	('adenocarcinomas', 'Disease', (98, 113))	('OS', 'Chemical', '-', (79, 81))	('patients', 'Species', '9606', (36, 44))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (12, 35))	('carcinomas', 'Phenotype', 'HP:0030731', (103, 113))	('shorter', 'NegReg', (63, 70))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (12, 35))	('carcinoma', 'Phenotype', 'HP:0030731', (26, 35))	('squamous cell carcinoma', 'Disease', (12, 35))	('EGFR', 'Gene', '1956', (144, 148))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))
428851	27072585	Previous studies have linked EGFR mutation status to elevated CEA levels.	('elevated', 'PosReg', (53, 61))	('EGFR', 'Gene', '1956', (29, 33))	('EGFR', 'Gene', (29, 33))	('elevated CEA', 'Phenotype', 'HP:0031029', (53, 65))	('CEA', 'Gene', (62, 65))	('mutation status', 'Var', (34, 49))	('CEA', 'Gene', '1084', (62, 65))
428853	27072585	To our knowledge, the association between serum tumor markers and EGFR mutation subtypes (del19 and L858R) has not been reported.	('tumor', 'Disease', (48, 53))	('EGFR', 'Gene', '1956', (66, 70))	('EGFR', 'Gene', (66, 70))	('L858R', 'Var', (100, 105))	('del19', 'Mutation', 'c.del19', (90, 95))	('L858R', 'Mutation', 'rs121434568', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('del19', 'Var', (90, 95))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
428855	27072585	This suggests that EGFR del19 and L858R NSCLC possess different biochemical properties and belong to distinct molecular subsets.	('del19', 'Mutation', 'c.del19', (24, 29))	('L858R', 'Var', (34, 39))	('NSCLC', 'Phenotype', 'HP:0030358', (40, 45))	('EGFR', 'Gene', '1956', (19, 23))	('L858R', 'Mutation', 'rs121434568', (34, 39))	('EGFR', 'Gene', (19, 23))	('NSCLC', 'Disease', (40, 45))	('NSCLC', 'Disease', 'MESH:D002289', (40, 45))
428856	27072585	Our findings are consistent with this notion as only Cyfra21-1 in correlated with shorter OS in the EGFR del19 group while both CEA and Cyfra21-1 were prognostic in L858R group.	('shorter OS', 'MPA', (82, 92))	('CEA', 'Gene', (128, 131))	('EGFR', 'Gene', '1956', (100, 104))	('OS', 'Chemical', '-', (90, 92))	('CEA', 'Gene', '1084', (128, 131))	('EGFR', 'Gene', (100, 104))	('Cyfra21-1', 'Var', (53, 62))	('L858R', 'Mutation', 'rs121434568', (165, 170))	('del19', 'Mutation', 'c.del19', (105, 110))
428860	27072585	Within these patients, SCCA levels did not vary depending on EGFR mutation status.	('patients', 'Species', '9606', (13, 21))	('mutation', 'Var', (66, 74))	('SCCA levels', 'MPA', (23, 34))	('EGFR', 'Gene', '1956', (61, 65))	('EGFR', 'Gene', (61, 65))
428867	27072585	It should be noted that treatment after recurrence clearly had an impact on overall survival, especially the use of EGFR-TKI for patients harboring EGFR mutations.	('mutations', 'Var', (153, 162))	('patients', 'Species', '9606', (129, 137))	('EGFR', 'Gene', '1956', (148, 152))	('EGFR', 'Gene', (148, 152))	('overall', 'MPA', (76, 83))	('impact', 'Reg', (66, 72))	('EGFR', 'Gene', '1956', (116, 120))	('EGFR', 'Gene', (116, 120))
428869	27072585	However, recurrent patients treated with EGFR-TKI were evenly distributed into EGFR del19 and L858R subgroups.	('EGFR', 'Gene', (41, 45))	('patients', 'Species', '9606', (19, 27))	('EGFR', 'Gene', '1956', (79, 83))	('EGFR', 'Gene', (79, 83))	('L858R', 'Var', (94, 99))	('del19', 'Mutation', 'c.del19', (84, 89))	('EGFR', 'Gene', '1956', (41, 45))	('L858R', 'Mutation', 'rs121434568', (94, 99))
428870	27072585	Secondly, only EGFR del19 and L858R were examined in this study; therefore, uncommon EGFR mutations might have been miscategorized during analysis.	('EGFR', 'Gene', (85, 89))	('L858R', 'Mutation', 'rs121434568', (30, 35))	('EGFR', 'Gene', '1956', (15, 19))	('EGFR', 'Gene', (15, 19))	('EGFR', 'Gene', '1956', (85, 89))	('L858R', 'Var', (30, 35))	('del19', 'Mutation', 'c.del19', (20, 25))
428873	27072585	In conclusion, Cyfra21-1 is a predictive and prognostic marker in resectable adenocarcinoma patients harboring EGFR mutations, and a prognostic factor in EGFR del19 or L858R group.	('EGFR', 'Gene', (154, 158))	('L858R', 'Var', (168, 173))	('EGFR', 'Gene', '1956', (111, 115))	('adenocarcinoma', 'Disease', 'MESH:D000230', (77, 91))	('del19', 'Mutation', 'c.del19', (159, 164))	('patients', 'Species', '9606', (92, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('EGFR', 'Gene', (111, 115))	('L858R', 'Mutation', 'rs121434568', (168, 173))	('mutations', 'Var', (116, 125))	('adenocarcinoma', 'Disease', (77, 91))	('EGFR', 'Gene', '1956', (154, 158))
428874	27072585	However, CEA was an independent predictive and prognostic factor only for EGFR wild-type adenocarcinoma patients and EGFR L858R adenocarcinoma patients.	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('L858R', 'Var', (122, 127))	('adenocarcinoma', 'Disease', 'MESH:D000230', (128, 142))	('adenocarcinoma', 'Disease', (89, 103))	('L858R', 'Mutation', 'rs121434568', (122, 127))	('EGFR', 'Gene', '1956', (117, 121))	('CEA', 'Gene', (9, 12))	('EGFR', 'Gene', (117, 121))	('adenocarcinoma', 'Disease', 'MESH:D000230', (89, 103))	('patients', 'Species', '9606', (143, 151))	('patients', 'Species', '9606', (104, 112))	('CEA', 'Gene', '1084', (9, 12))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('EGFR', 'Gene', '1956', (74, 78))	('adenocarcinoma', 'Disease', (128, 142))	('EGFR', 'Gene', (74, 78))
428887	27072585	Based on manufacturer recommendation, the following cut-offs for serum marker levels were used: CEA 5.0 ng/ml, NSE 15.2 ng/ml, SCCA 1.5 ng/ml, and Cyfra21-1 3.3 ng/ml.	('CEA', 'Gene', '1084', (96, 99))	('NSE', 'Gene', '2026', (111, 114))	('SCCA 1', 'Gene', '6317', (127, 133))	('SCCA 1', 'Gene', (127, 133))	('Cyfra21-1', 'Var', (147, 156))	('NSE', 'Gene', (111, 114))	('CEA', 'Gene', (96, 99))
428888	27072585	EGFR mutations (del19 and L858R) were identified by real-time PCR or DNA sequencing as previously described.	('L858R', 'Var', (26, 31))	('L858R', 'Mutation', 'rs121434568', (26, 31))	('del19', 'Var', (16, 21))	('EGFR', 'Gene', (0, 4))	('del19', 'Mutation', 'c.del19', (16, 21))	('EGFR', 'Gene', '1956', (0, 4))
428902	27018053	In recent years, brain metastasis are increasingly seen in adenocarcinomas with epidermal growth factor receptor (EGFR) mutations and EML4ALK1 rearrangement, whereas squamous cell carcinomas in many cases have a tendency to locally invade the thoracic wall.	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (166, 190))	('mutations', 'Var', (120, 129))	('epidermal growth factor receptor', 'Gene', (80, 112))	('epidermal growth factor receptor', 'Gene', '1956', (80, 112))	('brain metastasis', 'CPA', (17, 33))	('seen', 'Reg', (51, 55))	('EML4ALK1', 'Gene', (134, 142))	('adenocarcinomas', 'Disease', 'MESH:D000230', (59, 74))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (166, 189))	('adenocarcinomas', 'Disease', (59, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))	('EGFR', 'Gene', (114, 118))	('carcinomas', 'Phenotype', 'HP:0030731', (64, 74))	('squamous cell carcinomas', 'Disease', (166, 190))	('rearrangement', 'Var', (143, 156))	('carcinoma', 'Phenotype', 'HP:0030731', (180, 189))	('carcinomas', 'Phenotype', 'HP:0030731', (180, 190))	('EGFR', 'Gene', '1956', (114, 118))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (166, 190))
428913	27018053	The differentiation of naive macrophages into either M1 or M2 types is facilitated by NOTCH, where low Notch via SOCS3 drives macrophages into M2 types.	('NOTCH', 'Var', (86, 91))	('SOCS3', 'Gene', (113, 118))	('SOCS3', 'Gene', '9021', (113, 118))
428915	27018053	Notably, mutation and inactivation of Notch are found in neuroendocrine carcinomas, whereas activation in other non-small-cell carcinomas, which questions the function of this gene as either oncogene or tumor suppressor.	('tumor', 'Disease', (203, 208))	('carcinomas', 'Disease', (127, 137))	('small-cell carcinoma', 'Disease', 'MESH:D018288', (116, 136))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('inactivation', 'Var', (22, 34))	('small-cell carcinoma', 'Disease', (116, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('carcinomas', 'Phenotype', 'HP:0030731', (72, 82))	('carcinomas', 'Disease', 'MESH:D002277', (72, 82))	('neuroendocrine carcinomas', 'Phenotype', 'HP:0100634', (57, 82))	('neuroendocrine carcinomas', 'Disease', (57, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('carcinomas', 'Phenotype', 'HP:0030731', (127, 137))	('mutation', 'Var', (9, 17))	('carcinomas', 'Disease', 'MESH:D002277', (127, 137))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('neuroendocrine carcinoma', 'Phenotype', 'HP:0100634', (57, 81))	('Notch', 'Gene', (38, 43))	('carcinomas', 'Disease', (72, 82))	('neuroendocrine carcinomas', 'Disease', 'MESH:D018278', (57, 82))
428922	27018053	In mouse models of lung adenocarcinomas driven by the mutated RAS oncogene, invasion was exclusively seen starting in areas of necrosis and hypoxia  (Fig.	('mouse', 'Species', '10090', (3, 8))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (19, 38))	('necrosis', 'Disease', 'MESH:D009336', (127, 135))	('carcinoma', 'Phenotype', 'HP:0030731', (29, 38))	('lung adenocarcinomas', 'Disease', (19, 39))	('hypoxia', 'Disease', (140, 147))	('hypoxia', 'Disease', 'MESH:D000860', (140, 147))	('carcinomas', 'Phenotype', 'HP:0030731', (29, 39))	('mutated', 'Var', (54, 61))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (19, 39))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (19, 39))	('necrosis', 'Disease', (127, 135))	('RAS', 'Gene', (62, 65))
428934	27018053	Serine protease fibroblast activation protein (FAP) promotes tumor growth in an endogenous mouse model of lung cancer driven by the K-rasG12D mutant.	('K-rasG12D', 'Var', (132, 141))	('lung cancer', 'Disease', (106, 117))	('lung cancer', 'Phenotype', 'HP:0100526', (106, 117))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('fibroblast activation protein', 'Gene', '14089', (16, 45))	('promotes', 'PosReg', (52, 60))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('lung cancer', 'Disease', 'MESH:D008175', (106, 117))	('fibroblast activation protein', 'Gene', (16, 45))	('mouse', 'Species', '10090', (91, 96))	('tumor', 'Disease', (61, 66))
428935	27018053	On the contrary, FAP depletion inhibits tumor cell proliferation indirectly by increasing collagen accumulation, decreasing myofibroblasts in number, and decreasing blood vessel density in tumors.	('tumor', 'Disease', (189, 194))	('inhibits', 'NegReg', (31, 39))	('decreasing', 'NegReg', (154, 164))	('decreasing', 'NegReg', (113, 123))	('myofibroblasts in number', 'CPA', (124, 148))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('increasing', 'PosReg', (79, 89))	('FAP', 'Gene', (17, 20))	('tumors', 'Disease', (189, 195))	('blood vessel density', 'CPA', (165, 185))	('tumors', 'Disease', 'MESH:D009369', (189, 195))	('collagen accumulation', 'MPA', (90, 111))	('depletion', 'Var', (21, 30))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('tumors', 'Phenotype', 'HP:0002664', (189, 195))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))
428942	27018053	Adhesion to ECM proteins stimulated protein tyrosine kinase (PTK) activity in both untreated and etoposide-treated cells.	('activity', 'MPA', (66, 74))	('Adhesion', 'Var', (0, 8))	('stimulated', 'PosReg', (25, 35))	('etoposide', 'Chemical', 'MESH:D005047', (97, 106))
428950	27018053	Loss of RBM5 causes upregulation of Rac1, beta-catenin, collagen, and laminin, which in turn increase cell movement.	('RBM5', 'Gene', '10181', (8, 12))	('Rac1', 'Gene', '5879', (36, 40))	('beta-catenin', 'Gene', (42, 54))	('increase', 'PosReg', (93, 101))	('beta-catenin', 'Gene', '1499', (42, 54))	('laminin', 'Protein', (70, 77))	('cell movement', 'CPA', (102, 115))	('RBM5', 'Gene', (8, 12))	('upregulation', 'PosReg', (20, 32))	('Loss', 'Var', (0, 4))	('collagen', 'Protein', (56, 64))	('Rac1', 'Gene', (36, 40))
428956	27018053	Usually, tumor cells produce many modified proteins, which are recognized as foreign by dendritic cells and lymphocytes.	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('modified', 'Var', (34, 42))	('tumor', 'Disease', (9, 14))	('proteins', 'Protein', (43, 51))
428969	27018053	It may be that variants of IL-17 (IL-17E) induce a helper 2 type of immune response, which in turn by the release of IL-4 and IL-5 causes tissue eosinophilia.	('IL-17', 'Gene', (34, 39))	('IL-17', 'Gene', (27, 32))	('helper 2 type of immune response', 'CPA', (51, 83))	('IL-5', 'Gene', '3567', (126, 130))	('induce', 'Reg', (42, 48))	('IL-5', 'Gene', (126, 130))	('eosinophilia', 'Phenotype', 'HP:0001880', (145, 157))	('eosinophilia', 'Disease', 'MESH:D004802', (145, 157))	('IL-17E', 'Gene', '64806', (34, 40))	('IL-17', 'Gene', '64806', (34, 39))	('IL-17', 'Gene', '64806', (27, 32))	('release', 'MPA', (106, 113))	('eosinophilia', 'Disease', (145, 157))	('IL-4', 'Gene', (117, 121))	('variants', 'Var', (15, 23))	('causes', 'Reg', (131, 137))	('IL-17E', 'Gene', (34, 40))	('IL-4', 'Gene', '3565', (117, 121))
428986	27018053	If CPNE3 was knocked down, the metastatic abilities were inhibited in a mouse model.	('inhibited', 'NegReg', (57, 66))	('knocked down', 'Var', (13, 25))	('mouse', 'Species', '10090', (72, 77))	('CPNE3', 'Gene', (3, 8))	('metastatic abilities', 'CPA', (31, 51))
428996	27018053	Twist expressed in lung adenocarcinoma cell lines with EGFR mutation showed increased cell mobility.	('EGFR', 'Gene', '1956', (55, 59))	('mutation', 'Var', (60, 68))	('Twist', 'Gene', '7291', (0, 5))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (19, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (29, 38))	('increased', 'PosReg', (76, 85))	('Twist', 'Gene', (0, 5))	('EGFR', 'Gene', (55, 59))	('cell mobility', 'CPA', (86, 99))	('lung adenocarcinoma', 'Disease', (19, 38))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (19, 38))
429012	27018053	The study by Shen showed that increased levels of long non-coding RNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) promotes lung cancer brain metastasis by EMT, whereas silencing of MALAT1 inhibits lung cancer cell migration and metastasis in the brain.	('MALAT1', 'Gene', (126, 132))	('lung cancer brain metastasis', 'Disease', 'MESH:D009362', (143, 171))	('lung cancer', 'Disease', (217, 228))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (92, 111))	('lung cancer', 'Phenotype', 'HP:0100526', (217, 228))	('promotes', 'PosReg', (134, 142))	('lung cancer', 'Phenotype', 'HP:0100526', (143, 154))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('metastasis-associated lung adenocarcinoma transcript 1', 'Gene', '378938', (70, 124))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('MALAT1', 'Gene', (201, 207))	('lung cancer', 'Disease', 'MESH:D008175', (143, 154))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('inhibits', 'NegReg', (208, 216))	('lung cancer', 'Disease', 'MESH:D008175', (217, 228))	('lung cancer brain metastasis', 'Disease', (143, 171))	('silencing', 'Var', (188, 197))
429029	27018053	Impairment of macrophage function decreased tumor cell survival without altering clot formation, demonstrating that the recruitment of functional macrophages was essential for tumor cell survival.	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('decreased', 'NegReg', (34, 43))	('tumor', 'Disease', (176, 181))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('Impairment', 'Var', (0, 10))	('tumor', 'Disease', (44, 49))	('tumor', 'Disease', 'MESH:D009369', (176, 181))
429046	27018053	Loss of caveolin increases endothelial permeability and tumor growth.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('increases', 'PosReg', (17, 26))	('caveolin', 'Protein', (8, 16))	('tumor', 'Disease', (56, 61))	('endothelial permeability', 'MPA', (27, 51))	('Loss', 'Var', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
429114	27018053	Similar to tumor dentritic cell interaction, bacterial lipopolysacharide shifts tumor-educated microglia into a classical M1 phenotype, reduces their proinvasive function, and unmasks inflammatory and Wnt signaling as the most strongly regulated pathways.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('lipopolysacharide', 'Chemical', '-', (55, 72))	('unmasks', 'Reg', (176, 183))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumor', 'Disease', (11, 16))	('proinvasive function', 'CPA', (150, 170))	('tumor', 'Disease', (80, 85))	('bacterial lipopolysacharide', 'Var', (45, 72))	('reduces', 'NegReg', (136, 143))	('tumor', 'Disease', 'MESH:D009369', (11, 16))
429125	27018053	Interestingly, when looking up adenocarcinomas with ALK1 rearrangement, FGFR1 gene amplification correlated significantly with brain metastases.	('correlated', 'Reg', (97, 107))	('adenocarcinomas', 'Disease', 'MESH:D000230', (31, 46))	('carcinoma', 'Phenotype', 'HP:0030731', (36, 45))	('carcinomas', 'Phenotype', 'HP:0030731', (36, 46))	('adenocarcinomas', 'Disease', (31, 46))	('ALK1', 'Gene', (52, 56))	('FGFR1', 'Gene', (72, 77))	('FGFR1', 'Gene', '2260', (72, 77))	('brain metastases', 'Disease', 'MESH:D009362', (127, 143))	('amplification', 'Var', (83, 96))	('brain metastases', 'Disease', (127, 143))	('ALK1', 'Gene', '94', (52, 56))
429126	27018053	Although in these cases there were also higher numbers of visceral metastases, FGFR1 amplifications in brain metastases of adenocarcinomas were fivefold more frequent than in the primary tumors.	('metastases of adenocarcinomas', 'Disease', (109, 138))	('primary tumors', 'Disease', (179, 193))	('amplifications', 'Var', (85, 99))	('brain metastases', 'Disease', (103, 119))	('primary tumors', 'Disease', 'MESH:D009369', (179, 193))	('brain metastases', 'Disease', 'MESH:D009362', (103, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('carcinomas', 'Phenotype', 'HP:0030731', (128, 138))	('visceral metastases', 'Disease', (58, 77))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('FGFR1', 'Gene', (79, 84))	('metastases of adenocarcinomas', 'Disease', 'MESH:D009362', (109, 138))	('tumors', 'Phenotype', 'HP:0002664', (187, 193))	('FGFR1', 'Gene', '2260', (79, 84))	('visceral metastases', 'Disease', 'MESH:D009362', (58, 77))
429134	27018053	The downregulation of ADAM9 upregulated SLIT2 and miR-218, which together downregulated CDH2 expression.	('miR', 'Gene', '220972', (50, 53))	('SLIT2', 'Gene', '9353', (40, 45))	('miR', 'Gene', (50, 53))	('CDH2', 'Gene', (88, 92))	('CDH2', 'Gene', '1000', (88, 92))	('downregulation', 'Var', (4, 18))	('expression', 'MPA', (93, 103))	('ADAM9', 'Gene', '8754', (22, 27))	('upregulated', 'PosReg', (28, 39))	('ADAM9', 'Gene', (22, 27))	('SLIT2', 'Gene', (40, 45))	('downregulated', 'NegReg', (74, 87))
429138	27018053	Genes with amplified copy numbers in primary and metastatic tumors were related to DNA replication and mismatch repair.	('mismatch repair', 'Disease', (103, 118))	('tumors', 'Disease', 'MESH:D009369', (60, 66))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('amplified copy numbers', 'Var', (11, 33))	('DNA', 'CPA', (83, 86))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('related', 'Reg', (72, 79))	('tumors', 'Disease', (60, 66))
429151	27018053	In the study by Li et al., genotypes for AKT1 and PI3K were associated with brain metastasis risk (AKT1 rs2498804, AKT1 rs2494732, and PIK3CA rs2699887).	('AKT1', 'Gene', '207', (41, 45))	('PI3K', 'Gene', (50, 54))	('AKT1', 'Gene', (99, 103))	('AKT1', 'Gene', (41, 45))	('brain metastasis', 'CPA', (76, 92))	('AKT1', 'Gene', '207', (115, 119))	('PIK3CA', 'Gene', (135, 141))	('rs2699887', 'Mutation', 'rs2699887', (142, 151))	('AKT1', 'Gene', (115, 119))	('rs2494732', 'Var', (120, 129))	('rs2498804', 'Var', (104, 113))	('rs2494732', 'Mutation', 'rs2494732', (120, 129))	('rs2498804', 'Mutation', 'rs2498804', (104, 113))	('PIK3CA', 'Gene', '5290', (135, 141))	('associated', 'Reg', (60, 70))	('AKT1', 'Gene', '207', (99, 103))
429152	27018053	In another study by Li, genotype variations for SMAD6 (rs12913975) and INHBC (rs4760259) were associated with risk of brain metastasis.	('rs12913975', 'Mutation', 'rs12913975', (55, 65))	('rs4760259', 'Var', (78, 87))	('INHBC', 'Gene', '3626', (71, 76))	('SMAD6', 'Gene', '4091', (48, 53))	('brain metastasis', 'CPA', (118, 134))	('SMAD6', 'Gene', (48, 53))	('associated', 'Reg', (94, 104))	('rs12913975', 'Var', (55, 65))	('genotype variations', 'Var', (24, 43))	('rs4760259', 'Mutation', 'rs4760259', (78, 87))	('INHBC', 'Gene', (71, 76))
429164	27018053	Pretreatment of mice with sunitinib before intracardiac inoculation of A549M1 or H460M5 cells caused marked inhibition of tumor cells homing to bone, whereas no effect was found when tumor cells were pretreated before inoculation.	('sunitinib', 'Chemical', 'MESH:D000077210', (26, 35))	('inhibition', 'NegReg', (108, 118))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('A549M1', 'Var', (71, 77))	('mice', 'Species', '10090', (16, 20))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('H460M5', 'Var', (81, 87))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumor', 'Disease', (183, 188))	('A549', 'CellLine', 'CVCL:0023', (71, 75))	('tumor', 'Disease', (122, 127))
429175	27018053	Gene silencing of RHOB prevented metastatic activity in a systemic murine model of bone metastasis.	('murine', 'Species', '10090', (67, 73))	('RHOB', 'Gene', (18, 22))	('metastatic activity', 'CPA', (33, 52))	('Gene silencing', 'Var', (0, 14))	('prevented', 'NegReg', (23, 32))
429196	27018053	Interestingly, when comparing adenocarcinomas with known driver mutation, it is evident that adenocarcinomas with EML4-ALK1 rearrangement have a higher propensity for pleura metastasis and malignant effusion.	('carcinoma', 'Phenotype', 'HP:0030731', (35, 44))	('adenocarcinomas', 'Disease', (30, 45))	('EML4', 'Gene', '27436', (114, 118))	('malignant effusion', 'Disease', 'MESH:D016066', (189, 207))	('carcinomas', 'Phenotype', 'HP:0030731', (35, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('ALK1', 'Gene', (119, 123))	('pleura metastasis', 'Disease', 'MESH:D009362', (167, 184))	('rearrangement', 'Var', (124, 137))	('ALK1', 'Gene', '94', (119, 123))	('adenocarcinomas', 'Disease', 'MESH:D000230', (93, 108))	('malignant effusion', 'Disease', (189, 207))	('adenocarcinomas', 'Disease', (93, 108))	('carcinomas', 'Phenotype', 'HP:0030731', (98, 108))	('pleura metastasis', 'Disease', (167, 184))	('adenocarcinomas', 'Disease', 'MESH:D000230', (30, 45))	('EML4', 'Gene', (114, 118))
429197	27018053	In one study, it was proposed that the 216G/T polymorphism of the EGF receptor may play a role in pleural metastasis by overexpressing the protein.	('pleural metastasis', 'Disease', 'MESH:D009362', (98, 116))	('216G/T', 'Mutation', 'rs712829', (39, 45))	('216G/T', 'Var', (39, 45))	('role', 'Reg', (90, 94))	('pleural metastasis', 'Disease', (98, 116))	('protein', 'Protein', (139, 146))	('overexpressing', 'PosReg', (120, 134))	('play', 'Reg', (83, 87))	('EGF receptor', 'Gene', '1956', (66, 78))	('EGF receptor', 'Gene', (66, 78))
429201	27018053	It was shown that hypoxia induced HIF-1alpha and HIF-2alpha expression, which upregulated CCR7; inhibiting HIF-1alpha or HIF-2alpha resulted in decreased CCR7 expression and furthermore in inhibition of tumor cell migration and invasion.	('tumor', 'Disease', (203, 208))	('CCR7', 'Gene', '1236', (154, 158))	('inhibiting', 'Var', (96, 106))	('HIF-2alpha', 'Gene', '2034', (121, 131))	('HIF-1alpha', 'Gene', '3091', (34, 44))	('CCR7', 'Gene', '1236', (90, 94))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('hypoxia', 'Disease', (18, 25))	('HIF-1alpha', 'Gene', (107, 117))	('decreased', 'NegReg', (144, 153))	('HIF-2alpha', 'Gene', '2034', (49, 59))	('expression', 'MPA', (159, 169))	('hypoxia', 'Disease', 'MESH:D000860', (18, 25))	('HIF-1alpha', 'Gene', (34, 44))	('inhibition', 'NegReg', (189, 199))	('HIF-2alpha', 'Gene', (121, 131))	('HIF-1alpha and HIF-2alpha', 'Disease', 'None', (34, 59))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('HIF-2alpha', 'Gene', (49, 59))	('CCR7', 'Gene', (154, 158))	('CCR7', 'Gene', (90, 94))	('HIF-1alpha', 'Gene', '3091', (107, 117))
429202	27018053	Gains at 7q36, 8p12, 10q22, and 12p12; loss at 4p14; and the homozygous deletions at 4q occurred significantly more frequent in SCC from patients with lymph node metastases only.	('Gains', 'Var', (0, 5))	('SCC', 'Gene', (128, 131))	('lymph node metastases', 'Disease', 'MESH:D009362', (151, 172))	('patients', 'Species', '9606', (137, 145))	('loss', 'NegReg', (39, 43))	('SCC', 'Phenotype', 'HP:0002860', (128, 131))	('SCC', 'Gene', '6317', (128, 131))	('4p14', 'Gene', (47, 51))	('lymph node metastases', 'Disease', (151, 172))
429222	25519684	Recent studies have shown that the overexpression of USP7 in prostate cancer correlates with tumor aggressiveness and that the inhibition of USP7 can induce the apoptosis of multiple myeloma (MM) cells resistant to conventional and bortezomib therapies.	('induce', 'PosReg', (150, 156))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('USP7', 'Gene', (53, 57))	('prostate cancer', 'Disease', (61, 76))	('multiple myeloma', 'Phenotype', 'HP:0006775', (174, 190))	('tumor aggressiveness', 'Disease', (93, 113))	('apoptosis', 'CPA', (161, 170))	('aggressiveness', 'Phenotype', 'HP:0000718', (99, 113))	('inhibition', 'Var', (127, 137))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (93, 113))	('prostate cancer', 'Disease', 'MESH:D011471', (61, 76))	('overexpression', 'PosReg', (35, 49))	('USP7', 'Gene', (141, 145))	('prostate cancer', 'Phenotype', 'HP:0012125', (61, 76))	('multiple myeloma', 'Disease', 'MESH:D009101', (174, 190))	('multiple myeloma', 'Disease', (174, 190))	('bortezomib', 'Chemical', 'MESH:D000069286', (232, 242))
429223	25519684	Thus, contrary to initial reports, high levels of USP7 may promote tumor progression.	('USP7', 'Gene', (50, 54))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('high levels', 'Var', (35, 46))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('promote', 'PosReg', (59, 66))	('tumor', 'Disease', (67, 72))
429224	25519684	USP7 knockout mice die during early embryonic development compared to wild-type mice, and USP7 knockout embryos show p53 activation and cell growth arrest.	('cell growth arrest', 'CPA', (136, 154))	('p53', 'Gene', (117, 120))	('knockout', 'Var', (95, 103))	('mice', 'Species', '10090', (14, 18))	('growth arrest', 'Phenotype', 'HP:0001510', (141, 154))	('mice', 'Species', '10090', (80, 84))	('activation', 'PosReg', (121, 131))	('USP7', 'Gene', (90, 94))
429230	25519684	The knockdown of USP7 in NSCLC cells impaired cell invasion and motility, and tumor formation, and induced cell apoptosis.	('induced', 'Reg', (99, 106))	('NSCLC', 'Disease', (25, 30))	('USP7', 'Gene', (17, 21))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('impaired', 'NegReg', (37, 45))	('NSCLC', 'Disease', 'MESH:D002289', (25, 30))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('cell invasion', 'CPA', (46, 59))	('tumor', 'Disease', (78, 83))	('knockdown', 'Var', (4, 13))	('cell apoptosis', 'CPA', (107, 121))	('NSCLC', 'Phenotype', 'HP:0030358', (25, 30))
429263	25519684	NSCLC cells expressed high levels of USP7 compared with immortalized lung epithelial cells (Fig.	('NSCLC', 'Phenotype', 'HP:0030358', (0, 5))	('NSCLC', 'Disease', 'MESH:D002289', (0, 5))	('NSCLC', 'Disease', (0, 5))	('USP7', 'Var', (37, 41))
429267	25519684	Univariate analysis revealed that tumor size (>=3 cm, p < 0.001), lymph node metastasis (p < 0.001), advanced tumor stage (p < 0.001), and high USP7 expression (p < 0.001) were associated with OS (Table 2).	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('tumor', 'Disease', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('OS', 'Chemical', '-', (193, 195))	('expression', 'MPA', (149, 159))	('USP7', 'Gene', (144, 148))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('associated', 'Reg', (177, 187))	('high', 'Var', (139, 143))	('lymph node metastasis', 'CPA', (66, 87))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
429270	25519684	The multivariate Cox proportional hazards model was used for further analysis and high USP7 expression was an independent prognostic predictor for OS (p = 0.007) (Table 2, Fig.	('OS', 'Chemical', '-', (147, 149))	('Cox', 'Gene', '1351', (17, 20))	('high', 'Var', (82, 86))	('Cox', 'Gene', (17, 20))	('USP7', 'Gene', (87, 91))	('expression', 'MPA', (92, 102))
429279	25519684	We found that the levels of Bcl-2, Bcl-xL, and phosphorylated Bad were significantly downregulated after USP7 expression was knocked down (Fig.	('Bcl-2', 'Gene', (28, 33))	('downregulated', 'NegReg', (85, 98))	('Bcl-2', 'Gene', '596', (28, 33))	('USP7', 'Gene', (105, 109))	('Bcl-xL', 'Gene', '598', (35, 41))	('expression', 'MPA', (110, 120))	('knocked down', 'Var', (125, 137))	('Bcl-xL', 'Gene', (35, 41))	('phosphorylated Bad', 'MPA', (47, 65))
429286	25519684	Consistently, we observed an upregulation in E-cadherin protein levels, but a downregulation in Vimentin and N-cadherin proteins levels, after USP7 knockdown by shRNAs (Fig.	('Vimentin', 'Gene', (96, 104))	('Vimentin', 'Gene', '7431', (96, 104))	('downregulation', 'NegReg', (78, 92))	('upregulation', 'PosReg', (29, 41))	('N-cadherin', 'Gene', '1000', (109, 119))	('E-cadherin', 'Gene', (45, 55))	('E-cadherin', 'Gene', '999', (45, 55))	('knockdown', 'Var', (148, 157))	('N-cadherin', 'Gene', (109, 119))
429290	25519684	Here, our results indicate that lung squamous cell carcinoma and large cell carcinoma tumors and NSCLC cell lines express high levels of USP7 compared with corresponding non-tumorous tissues or immortalized normal lung cell lines.	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (32, 60))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('USP7', 'Var', (137, 141))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (37, 60))	('cell carcinoma tumors', 'Disease', (71, 92))	('NSCLC', 'Phenotype', 'HP:0030358', (97, 102))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (32, 60))	('lung squamous cell carcinoma', 'Disease', (32, 60))	('cell carcinoma tumors', 'Disease', 'MESH:D009369', (71, 92))	('NSCLC', 'Disease', 'MESH:D002289', (97, 102))	('tumor', 'Disease', (174, 179))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('large cell carcinoma', 'Phenotype', 'HP:0030360', (65, 85))	('NSCLC', 'Disease', (97, 102))	('tumor', 'Disease', (86, 91))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (51, 60))
429292	25519684	Furthermore, Kaplan-Meier analysis revealed that the patients with high USP7 levels had significantly shorter overall survival than those with low USP7 expression in 110 squamous cell carcinoma and large cell carcinoma patients.	('overall survival', 'MPA', (110, 126))	('shorter', 'NegReg', (102, 109))	('high', 'Var', (67, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (184, 193))	('patients', 'Species', '9606', (53, 61))	('cell carcinoma', 'Disease', 'MESH:C538614', (204, 218))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (170, 193))	('squamous cell carcinoma', 'Disease', (170, 193))	('large cell carcinoma', 'Phenotype', 'HP:0030360', (198, 218))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (170, 193))	('patients', 'Species', '9606', (219, 227))	('cell carcinoma', 'Disease', (204, 218))	('carcinoma', 'Phenotype', 'HP:0030731', (209, 218))	('USP7', 'Gene', (72, 76))	('cell carcinoma', 'Disease', 'MESH:C538614', (179, 193))
429294	25519684	Thus, we showed that high USP7 levels promote squamous cell carcinoma and large cell carcinoma progression.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (46, 69))	('USP7', 'Gene', (26, 30))	('cell carcinoma', 'Disease', 'MESH:C538614', (55, 69))	('high', 'Var', (21, 25))	('cell carcinoma', 'Disease', 'MESH:C538614', (80, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (60, 69))	('squamous cell carcinoma', 'Disease', (46, 69))	('promote', 'PosReg', (38, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (46, 69))	('large cell carcinoma', 'Phenotype', 'HP:0030360', (74, 94))	('cell carcinoma', 'Disease', (80, 94))
429295	25519684	In the mitochondrial apoptotic pathway, Bcl-2 family apoptotic-modulating proteins are closely regulated by p53.	('mitochondrial apoptotic pathway', 'Pathway', (7, 38))	('regulated', 'Reg', (95, 104))	('Bcl-2', 'Gene', (40, 45))	('Bcl-2', 'Gene', '596', (40, 45))	('p53', 'Var', (108, 111))
429296	25519684	Our data showed that the knockdown of USP7 is associated with the downregulation of Bcl-2 and Bcl-xL anti-apoptotic proteins.	('Bcl-2', 'Gene', (84, 89))	('Bcl-2', 'Gene', '596', (84, 89))	('Bcl-xL', 'Gene', '598', (94, 100))	('USP7', 'Gene', (38, 42))	('downregulation', 'NegReg', (66, 80))	('Bcl-xL', 'Gene', (94, 100))	('knockdown', 'Var', (25, 34))
429297	25519684	As p53 can antagonize the anti-apoptotic effects of Bcl-2 and Bcl-xL, USP7 may inhibit the Bcl-2 and Bcl-xL anti-apoptotic effect by negatively regulating p53.	('inhibit', 'NegReg', (79, 86))	('Bcl-xL', 'Gene', (101, 107))	('Bcl-2', 'Gene', (52, 57))	('Bcl-xL', 'Gene', '598', (62, 68))	('Bcl-2', 'Gene', '596', (52, 57))	('p53', 'MPA', (155, 158))	('Bcl-xL', 'Gene', (62, 68))	('negatively regulating', 'NegReg', (133, 154))	('USP7', 'Var', (70, 74))	('Bcl-2', 'Gene', '596', (91, 96))	('Bcl-2', 'Gene', (91, 96))	('Bcl-xL', 'Gene', '598', (101, 107))
429298	25519684	Interestingly, the level of phosphorylated Bad was also downregulated by USP7 knockdown, and dephosphorylated Bad can interact with Bcl-2 and Bcl-xL in mitochondria, thereby inactivating these anti-apoptotic proteins and inducing apoptosis.	('knockdown', 'Var', (78, 87))	('dephosphorylated', 'Var', (93, 109))	('interact', 'Interaction', (118, 126))	('inactivating', 'NegReg', (174, 186))	('apoptosis', 'CPA', (230, 239))	('Bcl-2', 'Gene', (132, 137))	('Bcl-xL', 'Gene', '598', (142, 148))	('Bcl-2', 'Gene', '596', (132, 137))	('inducing', 'Reg', (221, 229))	('downregulated', 'NegReg', (56, 69))	('anti-apoptotic proteins', 'Protein', (193, 216))	('USP7', 'Gene', (73, 77))	('Bcl-xL', 'Gene', (142, 148))
429300	25519684	Therefore, as ERK and p38-MAPK phosphorylation levels did not significantly change after USP7 knockdown in NSCLC cells, USP7 may directly affect the phosphorylation status of Bad.	('ERK', 'Gene', (14, 17))	('knockdown', 'Var', (94, 103))	('p38-MAPK', 'Gene', (22, 30))	('USP7', 'Var', (120, 124))	('NSCLC', 'Disease', (107, 112))	('affect', 'Reg', (138, 144))	('p38-MAPK', 'Gene', '1432', (22, 30))	('phosphorylation status', 'MPA', (149, 171))	('NSCLC', 'Disease', 'MESH:D002289', (107, 112))	('USP7', 'Gene', (89, 93))	('ERK', 'Gene', '5594', (14, 17))	('NSCLC', 'Phenotype', 'HP:0030358', (107, 112))
429301	25519684	Furthermore, upregulation in E-cadherin protein levels, but downregulation in Vimentin and N-cadherin proteins levels, was found after the knockdown in USP7 levels.	('N-cadherin', 'Gene', '1000', (91, 101))	('E-cadherin', 'Gene', (29, 39))	('E-cadherin', 'Gene', '999', (29, 39))	('downregulation', 'NegReg', (60, 74))	('knockdown', 'Var', (139, 148))	('Vimentin', 'Gene', (78, 86))	('upregulation', 'PosReg', (13, 25))	('N-cadherin', 'Gene', (91, 101))	('Vimentin', 'Gene', '7431', (78, 86))
429323	26195293	The HER family of receptors, which includes EGFR, HER2, HER3, and HER4, has drawn much clinical interest, owing primarily to the frequently observed overexpression, mutation, or gene amplification of EGFR and HER2 in human epithelial malignancies.	('human', 'Species', '9606', (217, 222))	('HER3', 'Gene', '2065', (56, 60))	('HER2', 'Gene', (50, 54))	('epithelial malignancies', 'Phenotype', 'HP:0031492', (223, 246))	('EGFR', 'Gene', (200, 204))	('HER4', 'Gene', (66, 70))	('epithelial malignancies', 'Disease', 'MESH:D002277', (223, 246))	('HER2', 'Gene', (209, 213))	('EGFR', 'Gene', '1956', (44, 48))	('HER3', 'Gene', (56, 60))	('gene amplification', 'Var', (178, 196))	('epithelial malignancies', 'Disease', (223, 246))	('HER2', 'Gene', '2064', (50, 54))	('mutation', 'Var', (165, 173))	('EGFR', 'Gene', '1956', (200, 204))	('HER4', 'Gene', '2066', (66, 70))	('EGFR', 'Gene', (44, 48))	('HER2', 'Gene', '2064', (209, 213))	('overexpression', 'PosReg', (149, 163))
429325	26195293	Their levels as well as mutation status have also been linked to patient outcome.	('levels', 'MPA', (6, 12))	('linked', 'Reg', (55, 61))	('patient', 'Species', '9606', (65, 72))	('mutation', 'Var', (24, 32))
429399	26195293	The results showed that high heregulin was an independent prognostic factor for OS (HR(95%CI): 8.48(2.17-33.17), P = 0.002, Table 1), after adjusting for age, gender, race, p16 status, smoking, node metastasis, differentiation, stage, tumor stage, and the measured protein levels of HER3, HER2, and EGFR.	('heregulin', 'Protein', (29, 38))	('tumor', 'Disease', 'MESH:D009369', (235, 240))	('EGFR', 'Gene', '1956', (299, 303))	('EGFR', 'Gene', (299, 303))	('p16', 'Gene', '1029', (173, 176))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('HER3', 'Gene', (283, 287))	('tumor', 'Disease', (235, 240))	('high', 'Var', (24, 28))	('HER3', 'Gene', '2065', (283, 287))	('p16', 'Gene', (173, 176))	('HER2', 'Gene', (289, 293))	('HER2', 'Gene', '2064', (289, 293))
429426	26195293	In our study, high HER3 expression independently correlated with poor OS, consistent with two previous studies reporting that HER3 gene copy number  and protein levels (IHC)  were significant prognostic factors of poor OS in recurrent or metastatic HNSCC.	('HER3', 'Gene', '2065', (126, 130))	('correlated', 'Reg', (49, 59))	('poor OS', 'Disease', (65, 72))	('expression', 'MPA', (24, 34))	('HNSCC', 'Phenotype', 'HP:0012288', (249, 254))	('high', 'Var', (14, 18))	('HER3', 'Gene', (19, 23))	('HER3', 'Gene', '2065', (19, 23))	('metastatic HNSCC', 'Disease', (238, 254))	('HER3', 'Gene', (126, 130))
429427	26195293	Our findings are also supported by a recent meta-analysis showing that high HER3 expression is prognostic in various solid tumors, including HNSCC.	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('high', 'Var', (71, 75))	('HNSCC', 'Disease', (141, 146))	('HER3', 'Gene', (76, 80))	('HNSCC', 'Phenotype', 'HP:0012288', (141, 146))	('HER3', 'Gene', '2065', (76, 80))	('prognostic', 'Reg', (95, 105))	('solid tumors', 'Disease', (117, 129))	('solid tumors', 'Disease', 'MESH:D009369', (117, 129))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('expression', 'MPA', (81, 91))
429444	26195293	Our previously reported findings that HER3 inhibition potentiates the anti-tumor effects of cetuximab in preclinical models of HNSCC suggest that a combination therapy approach may be most appropriate.	('HER3', 'Gene', '2065', (38, 42))	('inhibition', 'Var', (43, 53))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('potentiates', 'PosReg', (54, 65))	('cetuximab', 'Chemical', 'MESH:D000068818', (92, 101))	('HNSCC', 'Phenotype', 'HP:0012288', (127, 132))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('HER3', 'Gene', (38, 42))	('tumor', 'Disease', (75, 80))
429445	26195293	The lack of reliable predictive or prognostic molecular markers in HNSCC beyond HPV/p16 status render our findings particularly interesting, as they are also consistent with recent findings in other tumor types indicating that heregulin expression is predictive of poor response to standard therapy as well as benefit from HER3 inhibition.	('poor response', 'CPA', (265, 278))	('tumor', 'Disease', (199, 204))	('HER3', 'Gene', (323, 327))	('HER3', 'Gene', '2065', (323, 327))	('p16', 'Gene', '1029', (84, 87))	('benefit', 'PosReg', (310, 317))	('HPV', 'Species', '10566', (80, 83))	('HNSCC', 'Disease', (67, 72))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('expression', 'Var', (237, 247))	('HNSCC', 'Phenotype', 'HP:0012288', (67, 72))	('heregulin', 'Protein', (227, 236))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('p16', 'Gene', (84, 87))
429465	24410957	Evidence suggests that miRNAs can be functionally classified as proto-oncogenes or tumor suppressor genes and aberrantly expressed in different cancer types Dysregulation of these cancerous miRNAs is involved in tumor initiation and progression by facilitating an inappropriate cellular program that promotes uncontrolled cell proliferation, favors survival, inhibits differentiation, or induces invasive behavior.	('cancerous', 'Disease', (180, 189))	('aberrantly', 'Var', (110, 120))	('survival', 'CPA', (349, 357))	('miR', 'Gene', (23, 26))	('uncontrolled', 'MPA', (309, 321))	('induces', 'Reg', (388, 395))	('tumor', 'Disease', (83, 88))	('cancer', 'Disease', (144, 150))	('promotes', 'PosReg', (300, 308))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('involved', 'Reg', (200, 208))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('invasive behavior', 'CPA', (396, 413))	('Dysregulation', 'Var', (157, 170))	('differentiation', 'CPA', (368, 383))	('favors', 'PosReg', (342, 348))	('cancer', 'Disease', (180, 186))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('cancerous', 'Disease', 'MESH:D009369', (180, 189))	('miR', 'Gene', '220972', (190, 193))	('tumor', 'Disease', (212, 217))	('miR', 'Gene', '220972', (23, 26))	('tumor', 'Disease', 'MESH:D009369', (212, 217))	('inhibits', 'NegReg', (359, 367))	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('miR', 'Gene', (190, 193))
429482	24410957	We also used qRT-PCR to examine the expression of miR-99a in 16 OSCC cell lines, observing reduced levels of miR-99a in all OSCC cell lines when compared with normal human oral keratinocytes (HOK) (Figure 1D).	('miR-99a', 'Var', (109, 116))	('C', 'Chemical', 'MESH:D002244', (18, 19))	('C', 'Chemical', 'MESH:D002244', (66, 67))	('human', 'Species', '9606', (166, 171))	('C', 'Chemical', 'MESH:D002244', (67, 68))	('reduced', 'NegReg', (91, 98))	('levels', 'MPA', (99, 105))	('16 OSCC', 'CellLine', 'CVCL:L894', (61, 68))	('C', 'Chemical', 'MESH:D002244', (126, 127))	('C', 'Chemical', 'MESH:D002244', (127, 128))
429487	24410957	Results indicated that ectopic miR-99a expression in OEC-M1 and CGHNC9 cells, established from Taiwan OSCC patients, led to increased miR-99a expression (Figure 2A) and insignificant reductions in cell growth (Figures 2B and 2C) when compared with their corresponding controls.	('reductions', 'NegReg', (183, 193))	('patients', 'Species', '9606', (107, 115))	('miR-99a', 'Gene', (134, 141))	('ectopic', 'Var', (23, 30))	('increased', 'PosReg', (124, 133))	('C', 'Chemical', 'MESH:D002244', (104, 105))	('C', 'Chemical', 'MESH:D002244', (55, 56))	('cell growth', 'CPA', (197, 208))	('C', 'Chemical', 'MESH:D002244', (226, 227))	('miR-99a', 'Gene', (31, 38))	('expression', 'MPA', (142, 152))	('C', 'Chemical', 'MESH:D002244', (64, 65))	('C', 'Chemical', 'MESH:D002244', (105, 106))	('C', 'Chemical', 'MESH:D002244', (68, 69))
429488	24410957	Using transwell assay, we then identified that migration and invasion activities were reduced significantly in the OEC-M1 cells with ectopic miR-99a expression when compared with their corresponding controls (Figure 2D).	('reduced', 'NegReg', (86, 93))	('ectopic', 'Var', (133, 140))	('C', 'Chemical', 'MESH:D002244', (117, 118))	('miR-99a', 'Gene', (141, 148))
429493	24410957	Analysis of cell morphology using light microscopy and fluorescent confocal microscope by phalloidin staining and immunoflurescence with anti-alpha-tubulin, E-cadherin and focal adhesion kinase (FAK) did not reveal any gross differences between miR-99a expressing cells and vector controls (Figure 3A and Additional file 2: Figure S1).	('focal adhesion kinase', 'Gene', '5747', (172, 193))	('alpha-tubulin', 'Gene', (142, 155))	('phalloidin', 'Chemical', 'MESH:D010590', (90, 100))	('miR-99a expressing', 'Var', (245, 263))	('alpha-tubulin', 'Gene', '10376', (142, 155))	('FAK', 'Gene', (195, 198))	('focal adhesion kinase', 'Gene', (172, 193))	('FAK', 'Gene', '5747', (195, 198))	('E-cadherin', 'Gene', (157, 167))	('E-cadherin', 'Gene', '999', (157, 167))
429494	24410957	Furthermore, results from immunoblot analysis showed that ectopic miR-99a expression slightly increased the expression of alpha-catenin, an epithelial protein in OEC-M1 cells, and reduced the expression of N-cadherin, a mesenchymal marker in CGHNC9 cells (Figure 3B).	('expression', 'MPA', (192, 202))	('ectopic', 'Var', (58, 65))	('N-cadherin', 'Gene', (206, 216))	('reduced', 'NegReg', (180, 187))	('increased', 'PosReg', (94, 103))	('C', 'Chemical', 'MESH:D002244', (246, 247))	('miR-99a', 'Gene', (66, 73))	('C', 'Chemical', 'MESH:D002244', (242, 243))	('N-cadherin', 'Gene', '1000', (206, 216))	('alpha-catenin', 'Protein', (122, 135))	('expression', 'MPA', (108, 118))	('C', 'Chemical', 'MESH:D002244', (164, 165))
429496	24410957	The expression of metalloproteinase 2 (MMP2) and 9 (MMP9) did not show a markedly reduction in cells with ectopic miR-99a expression (Figure 3D).	('miR-99a', 'Gene', (114, 121))	('MMP9', 'Gene', (52, 56))	('MMP9', 'Gene', '4318', (52, 56))	('ectopic', 'Var', (106, 113))	('metalloproteinase 2 (MMP2) and 9', 'Gene', '4313;4318', (18, 50))
429498	24410957	Results excluded this possibility and indicated that the components of the IGF1R signaling pathway, including mTOR and IGF1R, could be the potential targets of miR-99a (Additional file 1: Table S2).	('mTOR', 'Gene', (110, 114))	('mTOR', 'Gene', '2475', (110, 114))	('IGF1R', 'Gene', (75, 80))	('IGF1R', 'Gene', (119, 124))	('miR-99a', 'Var', (160, 167))
429505	24410957	Results from Western blot analysis further showed that ectopic miR-99a expression decreased IGF1R expression, but not mTOR expression in OSCC cells (Figure 4D).	('IGF1R', 'Gene', (92, 97))	('mTOR', 'Gene', (118, 122))	('mTOR', 'Gene', '2475', (118, 122))	('miR-99a', 'Gene', (63, 70))	('ectopic', 'Var', (55, 62))	('decreased', 'NegReg', (82, 91))	('expression', 'MPA', (98, 108))
429506	24410957	To determine whether IGF1R mRNA is the specific binding target of miR-99a, we used the clones of the human IGF1R 3'UTR fragment containing the wild type or mutant miR-99a binding sequence in the region downstream of the Renilla luciferase reporter gene.	('IGF1R', 'Gene', (107, 112))	('human', 'Species', '9606', (101, 106))	('miR-99a', 'Gene', (163, 170))	('mutant', 'Var', (156, 162))
429507	24410957	In OEC-M1 cells with ectopic miR-99a expression, the luciferase activity of cells expressing wild type IGF1R 3'UTR was reduced 0.75 +- 0.03-fold in comparison with cells expressing the mutant seed region of miR-99a in the IGF1R 3'UTR (Figure 4E).	('luciferase', 'Enzyme', (53, 63))	('miR-99a', 'Gene', (29, 36))	('ectopic', 'Var', (21, 28))	('C', 'Chemical', 'MESH:D002244', (5, 6))	('activity', 'MPA', (64, 72))	('reduced', 'NegReg', (119, 126))
429508	24410957	However, in OEC-M1 control cells with low miR-99a expression, the luciferase activity of cells expressing wild type or mutant IGF1R 3'UTR remained unchanged.	('C', 'Chemical', 'MESH:D002244', (14, 15))	('IGF1R', 'Gene', (126, 131))	('activity', 'MPA', (77, 85))	('mutant', 'Var', (119, 125))	('luciferase', 'Enzyme', (66, 76))
429510	24410957	We observed that the migration and invasion activities were rescued by ectopic IGF1R expression in miR-99a expressing OEC-M1 cells, indicating that IGF1R was involved in miR-99a-mediated reduction of migration and invasion (Additional file 5: Figure S4B).	('ectopic', 'Var', (71, 78))	('reduction', 'NegReg', (187, 196))	('IGF1R', 'Gene', (79, 84))	('C', 'Chemical', 'MESH:D002244', (120, 121))	('migration', 'CPA', (21, 30))
429511	24410957	To elucidate the mechanisms underlying the downregulation of miR-99a, we first investigated the possibility of genetic methylation, which typically occurs at CpG sites and inactivates gene transcription.	('downregulation', 'NegReg', (43, 57))	('methylation', 'Var', (119, 130))	('miR-99a', 'Gene', (61, 68))	('gene transcription', 'MPA', (184, 202))	('genetic methylation', 'Var', (111, 130))	('inactivates', 'NegReg', (172, 183))	('C', 'Chemical', 'MESH:D002244', (158, 159))
429520	24410957	To verify whether the regulation of miR-99a is mediated by activation of IGF1R signaling pathway, the data showed that cells displayed the decreased phosphorylation levels of AKT and MAPK upon treatment with the LY294002 and PD98059 inhibitors for downstream of IGF1R signaling pathways, PI3K and MAPK kinase, respectively (Additional file 6: Figure S5).	('MAPK', 'MPA', (183, 187))	('AKT', 'Gene', (175, 178))	('LY294002', 'Chemical', 'MESH:C085911', (212, 220))	('decreased', 'NegReg', (139, 148))	('AKT', 'Gene', '207', (175, 178))	('PD98059', 'Chemical', 'MESH:C093973', (225, 232))	('PD98059', 'Var', (225, 232))	('LY294002', 'Var', (212, 220))	('phosphorylation levels', 'MPA', (149, 171))
429521	24410957	We found that the inhibitors LY294002 and PD98059 eliminated IGF1-induced downregulation of miR-99a in a dose-dependent manner (Figures 6C and 6D).	('LY294002', 'Chemical', 'MESH:C085911', (29, 37))	('eliminated', 'NegReg', (50, 60))	('downregulation', 'NegReg', (74, 88))	('PD98059', 'Var', (42, 49))	('IGF1', 'Gene', (61, 65))	('LY294002', 'Var', (29, 37))	('PD98059', 'Chemical', 'MESH:C093973', (42, 49))	('IGF1', 'Gene', '3479', (61, 65))	('miR-99a', 'Protein', (92, 99))	('C', 'Chemical', 'MESH:D002244', (137, 138))
429524	24410957	Their findings suggested the dysregulation of miRNAs in the initiation and progression of oral cancers.	('miR', 'Gene', (46, 49))	('oral cancers', 'Disease', 'MESH:D009062', (90, 102))	('cancers', 'Phenotype', 'HP:0002664', (95, 102))	('oral cancers', 'Disease', (90, 102))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('dysregulation', 'Var', (29, 42))	('miR', 'Gene', '220972', (46, 49))
429528	24410957	Previous studies described that ectopic miR-99a expression slowed keratinocyte growth and liver cancer cell growth by blocking the cell cycle at the G1/S transition.	('blocking', 'NegReg', (118, 126))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('miR-99a', 'Gene', (40, 47))	('liver cancer', 'Phenotype', 'HP:0002896', (90, 102))	('liver cancer', 'Disease', 'MESH:D006528', (90, 102))	('slowed', 'NegReg', (59, 65))	('cell cycle at the G1/S transition', 'CPA', (131, 164))	('keratinocyte growth', 'CPA', (66, 85))	('ectopic', 'Var', (32, 39))	('liver cancer', 'Disease', (90, 102))
429529	24410957	In OEC-M1 and CGHNC9 cells, ectopic miR-99a expression had no significant effects on cell growth (Figures 2B and C), cell cycle (Additional file 7: Figure S6A) and cell morphology (Figure 3A and Additional file 2: Figure S1) even though ectopic expression of miR-99a did subtly affect the expression of cell cycle-related molecules (Additional file 7: Figure S6B) and EMT-related proteins (Figure 3).	('C', 'Chemical', 'MESH:D002244', (14, 15))	('C', 'Chemical', 'MESH:D002244', (18, 19))	('miR-99a', 'Gene', (36, 43))	('EMT-related proteins', 'CPA', (368, 388))	('cell morphology', 'CPA', (164, 179))	('cell cycle', 'CPA', (117, 127))	('cell cycle-related', 'CPA', (303, 321))	('cell growth', 'CPA', (85, 96))	('C', 'Chemical', 'MESH:D002244', (5, 6))	('ectopic', 'Var', (28, 35))	('expression', 'MPA', (289, 299))	('C', 'Chemical', 'MESH:D002244', (113, 114))	('affect', 'Reg', (278, 284))
429533	24410957	However, it remains possible that miR-99a might functionally target mTOR in other cell types or in different biological systems.	('target', 'Reg', (61, 67))	('mTOR', 'Gene', (68, 72))	('miR-99a', 'Var', (34, 41))	('mTOR', 'Gene', '2475', (68, 72))
429539	24410957	As previously reported, epigenetic mechanisms, including DNA methylation and histone modification, chromosome deficiency, and transcriptional regulation can influence the downregulation of miRNA.	('chromosome deficiency', 'Disease', 'MESH:D002869', (99, 120))	('DNA methylation', 'Var', (57, 72))	('histone', 'Reg', (77, 84))	('influence', 'Reg', (157, 166))	('miR', 'Gene', '220972', (189, 192))	('miR', 'Gene', (189, 192))	('chromosome deficiency', 'Disease', (99, 120))	('downregulation', 'MPA', (171, 185))
429546	24410957	Due to tumor heterogeneity, however, our results indicated a reciprocal regulation that mutually regulates the levels of miR-99a and IGF1R in a part of OSCC cells.	('levels', 'MPA', (111, 117))	('tumor', 'Disease', (7, 12))	('IGF1R', 'Gene', (133, 138))	('miR-99a', 'Var', (121, 128))	('tumor', 'Disease', 'MESH:D009369', (7, 12))	('regulates', 'Reg', (97, 106))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
429567	24410957	Primary antibodies were used as followed: anti-E-cadherin (610182, BD, San Jose, CA, USA), anti-alpha-catenin (610193, BD), anti-N-cadherin (610920, BD), anti-Vimentin (MS-129-P0, Thermo Scientific, Cheshire, UK), anti-Twist (sc-15393, Santa Cruz, Santa Cruz, CA, USA), anti-Snail (3895, Cell Signaling, Danvers, MA, USA), anti-Slug (AP2053a, Abgent, San Diego, CA, USA), anti-MMP2 (#4022, Cell Signaling), anti-MMP9 (#2551-1, Epitomics, Burlingame, CA, USA), anti-phospho-mTOR (Ser2448) (#5536, Cell Signaling), anti-mTOR (#2972, Cell Signaling), anti-phospho-IGF1 Receptor beta (Tyr980) (#4568, Cell Signaling), anti-IGF1 Receptor beta (#3018, Cell Signaling), anti-p21 (#2946, Cell Signaling), anti-p27 (#2552, Cell Signaling), anti-cyclin D1 (#2926, Cell Signaling), anti-cyclin E (sc-247, Santa Cruz), anti-beta-actin (sc-1615, Santa Cruz) and anti-alpha-tubulin (MS-581-P0, Thermo Scientific).	('C', 'Chemical', 'MESH:D002244', (680, 681))	('C', 'Chemical', 'MESH:D002244', (450, 451))	('beta-actin', 'Gene', '728378', (812, 822))	('MMP2', 'Gene', (377, 381))	('C', 'Chemical', 'MESH:D002244', (362, 363))	('Snail', 'Gene', (275, 280))	('#2926', 'Var', (747, 752))	('mTOR', 'Gene', (518, 522))	('sc-1615', 'Var', (824, 831))	('IGF1', 'Gene', '3479', (619, 623))	('p21', 'Gene', (668, 671))	('mTOR', 'Gene', '2475', (473, 477))	('alpha-tubulin', 'Gene', '10376', (854, 867))	('C', 'Chemical', 'MESH:D002244', (242, 243))	('C', 'Chemical', 'MESH:D002244', (496, 497))	('Slug', 'Gene', '6591', (328, 332))	('C', 'Chemical', 'MESH:D002244', (646, 647))	('p21', 'Gene', '644914', (668, 671))	('MMP9', 'Gene', '4318', (412, 416))	('MMP9', 'Gene', (412, 416))	('MMP2', 'Gene', '4313', (377, 381))	('IGF1', 'Gene', '3479', (561, 565))	('C', 'Chemical', 'MESH:D002244', (81, 82))	('p27', 'Gene', '3429', (702, 705))	('C', 'Chemical', 'MESH:D002244', (288, 289))	('mTOR', 'Gene', '2475', (518, 522))	('p27', 'Gene', (702, 705))	('C', 'Chemical', 'MESH:D002244', (597, 598))	('C', 'Chemical', 'MESH:D002244', (199, 200))	('IGF1', 'Gene', (619, 623))	('N-cadherin', 'Gene', (129, 139))	('C', 'Chemical', 'MESH:D002244', (254, 255))	('C', 'Chemical', 'MESH:D002244', (714, 715))	('cyclin D1', 'Gene', (736, 745))	('beta-actin', 'Gene', (812, 822))	('N-cadherin', 'Gene', '1000', (129, 139))	('C', 'Chemical', 'MESH:D002244', (531, 532))	('alpha-tubulin', 'Gene', (854, 867))	('C', 'Chemical', 'MESH:D002244', (390, 391))	('Snail', 'Gene', '6615', (275, 280))	('IGF1', 'Gene', (561, 565))	('C', 'Chemical', 'MESH:D002244', (800, 801))	('C', 'Chemical', 'MESH:D002244', (754, 755))	('cyclin D1', 'Gene', '595', (736, 745))	('Slug', 'Gene', (328, 332))	('E-cadherin', 'Gene', (47, 57))	('Vimentin', 'Gene', '7431', (159, 167))	('C', 'Chemical', 'MESH:D002244', (839, 840))	('E-cadherin', 'Gene', '999', (47, 57))	('C', 'Chemical', 'MESH:D002244', (260, 261))	('mTOR', 'Gene', (473, 477))	('Vimentin', 'Gene', (159, 167))
429581	24410957	After incubation with Alexa Fluro 488 phalloidin (1:200, Molecular Probes, Ungene, OR, USA), anti-beta-tubulin (MS-581-P0, Thermo Scientific), anti-E-cadherin (610182, BD) and anti-FAK (sc-557, Santa Cruz), the slips were mounted with antifade onto the slides and viewed under a fluorescence confocal microscope.	('E-cadherin', 'Gene', (148, 158))	('Alexa Fluro 488', 'Chemical', '-', (22, 37))	('E-cadherin', 'Gene', '999', (148, 158))	('C', 'Chemical', 'MESH:D002244', (200, 201))	('FAK', 'Gene', (181, 184))	('FAK', 'Gene', '5747', (181, 184))	('610182', 'Var', (160, 166))	('phalloidin', 'Chemical', 'MESH:D010590', (38, 48))
429591	24410957	For experiments involving inhibition of signaling pathways, cells were cultured in the presence of PD98059 (Sigma) or LY294002 (Sigma), specific inhibitors of MAPK kinase and PI3K, respectively, for 1 hour prior to IGF1 stimulation.	('PD98059', 'Var', (99, 106))	('LY294002', 'Var', (118, 126))	('PD98059', 'Chemical', 'MESH:C093973', (99, 106))	('IGF1', 'Gene', '3479', (215, 219))	('LY294002', 'Chemical', 'MESH:C085911', (118, 126))	('IGF1', 'Gene', (215, 219))
429611	29890775	The Univariate cox regression analysis revealed that a positive pSTAT3 in SCC was adversely associated with survival (Hazard ratio (HR) 6.382, 95% CI 1.266-32.184), while a protective effect was demonstrated with the higher pSTAT3 levels in OAC epithelium (HR 0.74, 95% CI 0.574-0.953).	('associated with', 'Reg', (92, 107))	('STAT3', 'Gene', '6774', (225, 230))	('cox', 'Gene', '1351', (15, 18))	('STAT3', 'Gene', (225, 230))	('cox', 'Gene', (15, 18))	('positive', 'Var', (55, 63))	('STAT3', 'Gene', '6774', (65, 70))	('SCC', 'Gene', (74, 77))	('survival', 'CPA', (108, 116))	('STAT3', 'Gene', (65, 70))	('SCC', 'Phenotype', 'HP:0002860', (74, 77))	('SCC', 'Gene', '6317', (74, 77))
429615	29890775	The pSTAT3 expression was associated with adverse survival in SCC, but not in the OAC patients.	('SCC', 'Phenotype', 'HP:0002860', (62, 65))	('SCC', 'Gene', '6317', (62, 65))	('STAT3', 'Gene', '6774', (5, 10))	('SCC', 'Gene', (62, 65))	('STAT3', 'Gene', (5, 10))	('expression', 'Var', (11, 21))	('associated', 'Reg', (26, 36))	('patients', 'Species', '9606', (86, 94))
429642	29890775	However, on the univariate cox regression analysis, the positive tumour pSTAT3 stromal staining in core SCC samples was associated with death (HR 6.382, 95% CI 1.266-32.184).	('death', 'Disease', 'MESH:D003643', (136, 141))	('death', 'Disease', (136, 141))	('associated with', 'Reg', (120, 135))	('SCC', 'Gene', (104, 107))	('STAT3', 'Gene', (73, 78))	('cox', 'Gene', '1351', (27, 30))	('SCC', 'Phenotype', 'HP:0002860', (104, 107))	('tumour', 'Phenotype', 'HP:0002664', (65, 71))	('positive', 'Var', (56, 64))	('SCC', 'Gene', '6317', (104, 107))	('tumour', 'Disease', 'MESH:D009369', (65, 71))	('cox', 'Gene', (27, 30))	('tumour', 'Disease', (65, 71))	('STAT3', 'Gene', '6774', (73, 78))
429652	29890775	Notably, the association between the IL-6R expressions was examined and a high IL-6R was associated with an adverse survival in the stroma of the OAC core specimens (Supplementary Table S1).	('IL-6R', 'Gene', (79, 84))	('high', 'Var', (74, 78))	('IL-6R', 'Gene', '3570', (37, 42))	('IL-6R', 'Gene', (37, 42))	('IL-6R', 'Gene', '3570', (79, 84))
429679	29890775	examined the expression of the total STAT3 and pSTAT3 in OAC and SCC, and found differential expression across the subtypes, with more frequent nuclear pSTAT3 positivity in the nucleus of the SCC samples.	('STAT3', 'Gene', (48, 53))	('STAT3', 'Gene', '6774', (153, 158))	('SCC', 'Phenotype', 'HP:0002860', (192, 195))	('OAC', 'Disease', (57, 60))	('SCC', 'Gene', (65, 68))	('SCC', 'Gene', '6317', (192, 195))	('STAT3', 'Gene', '6774', (37, 42))	('STAT3', 'Gene', (153, 158))	('STAT3', 'Gene', (37, 42))	('SCC', 'Phenotype', 'HP:0002860', (65, 68))	('positivity', 'Var', (159, 169))	('SCC', 'Gene', '6317', (65, 68))	('STAT3', 'Gene', '6774', (48, 53))	('SCC', 'Gene', (192, 195))
429696	29890775	Following the treatment of KYSE150 and KYSE450 cell lines with STAT3-PLK-1-AKT signalling blocker plumbagin, there was a reduction in the proliferation and an induction of apoptosis in the SCC cells via the abrogation of STAT3-PLK-1-AKT signalling.	('SCC', 'Gene', (189, 192))	('STAT3', 'Gene', (221, 226))	('STAT3', 'Gene', '6774', (63, 68))	('PLK-1', 'Gene', '5347', (69, 74))	('STAT3', 'Gene', '6774', (221, 226))	('induction', 'Reg', (159, 168))	('abrogation', 'NegReg', (207, 217))	('AKT', 'Gene', (75, 78))	('apoptosis', 'CPA', (172, 181))	('PLK-1', 'Gene', '5347', (227, 232))	('reduction', 'NegReg', (121, 130))	('AKT', 'Gene', (233, 236))	('KYSE450', 'CellLine', 'CVCL:1353', (39, 46))	('proliferation', 'CPA', (138, 151))	('SCC', 'Phenotype', 'HP:0002860', (189, 192))	('PLK-1', 'Gene', (69, 74))	('KYSE450', 'Var', (39, 46))	('AKT', 'Gene', '207', (75, 78))	('SCC', 'Gene', '6317', (189, 192))	('AKT', 'Gene', '207', (233, 236))	('PLK-1', 'Gene', (227, 232))	('STAT3', 'Gene', (63, 68))
429697	29890775	Interestingly, the authors also found that constitutively activated mutant STAT3C reinstated the plumbagin blockade of signalling.	('STAT3', 'Gene', '6774', (75, 80))	('plumbagin blockade of signalling', 'MPA', (97, 129))	('STAT3', 'Gene', (75, 80))	('reinstated', 'PosReg', (82, 92))	('mutant', 'Var', (68, 74))
429701	29890775	Timme et al., examined the functional effects of STAT3 knockdown in both OAC and SCC, and demonstrated reduced cell migration in both of the cancer subtypes.	('knockdown', 'Var', (55, 64))	('STAT3', 'Gene', (49, 54))	('SCC', 'Gene', '6317', (81, 84))	('OAC', 'Disease', (73, 76))	('cell migration', 'CPA', (111, 125))	('reduced', 'NegReg', (103, 110))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('SCC', 'Gene', (81, 84))	('SCC', 'Phenotype', 'HP:0002860', (81, 84))	('STAT3', 'Gene', '6774', (49, 54))	('cancer', 'Disease', (141, 147))
429778	25539663	The results also showed that high PTHrP level was associated with poor pathologic differentiation (P = 0.0001) and poor prognosis (P = 0.0003) in patients with HNSCC.	('high', 'Var', (29, 33))	('PTHrP', 'Gene', (34, 39))	('poor pathologic differentiation', 'CPA', (66, 97))	('PTHrP', 'Gene', '5744', (34, 39))	('HNSCC', 'Disease', (160, 165))	('HNSCC', 'Phenotype', 'HP:0012288', (160, 165))	('high PTHrP level', 'Phenotype', 'HP:0003165', (29, 45))	('patients', 'Species', '9606', (146, 154))
429802	25539663	Thus, PTHrP imbalance is implicated in the pathogenesis of cancer.	('PTHrP', 'Gene', (6, 11))	('imbalance', 'Var', (12, 21))	('PTHrP', 'Gene', '5744', (6, 11))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('imbalance', 'Phenotype', 'HP:0002172', (12, 21))	('implicated', 'Reg', (25, 35))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))
429805	25539663	The biological function of PTHLH/PTHrP in OSCC was observed by knocking down PTHLH/PTHrP expression in the WSU-HN6, HN13 and CAL-27 cell lines.	('PTHLH', 'Gene', (77, 82))	('knocking', 'Var', (63, 71))	('expression', 'MPA', (89, 99))	('HN6', 'Gene', (111, 114))	('PTHLH', 'Gene', '5744', (77, 82))	('PTHrP', 'Gene', (83, 88))	('PTHLH', 'Gene', (27, 32))	('HN6', 'Gene', '100463482', (111, 114))	('CAL-27', 'CellLine', 'CVCL:1107', (125, 131))	('HN13', 'Gene', (116, 120))	('PTHrP', 'Gene', '5744', (83, 88))	('PTHLH', 'Gene', '5744', (27, 32))	('PTHrP', 'Gene', (33, 38))	('HN13', 'Gene', '100463500', (116, 120))	('OSCC', 'Disease', (42, 46))	('PTHrP', 'Gene', '5744', (33, 38))
429860	25539663	Three cell lines, WSU-HN6, HN13 and CAL-27, were transiently transfected with siRNAs (Figure 2A), and the results showed that the growth of cells transfected with P-si was obviously reduced compared to that of cells transfected with scrambled siRNA (Figure 2B).	('HN13', 'Gene', '100463500', (27, 31))	('HN6', 'Gene', (22, 25))	('HN6', 'Gene', '100463482', (22, 25))	('CAL-27', 'CellLine', 'CVCL:1107', (36, 42))	('P-si', 'Var', (163, 167))	('growth', 'CPA', (130, 136))	('HN13', 'Gene', (27, 31))	('reduced', 'NegReg', (182, 189))
429865	25539663	The results showed that the fractions of P-si transfected WSU-HN6, HN13 and CAL-27 cells in G1 phase were increased to 49.55%, 55.80% and 53.19%, respectively compared to the corresponding cells transfected with scrambled siRNA (39.22%, 38.40% and 39.80%, respectively) (P < 0.05) (Figure 3A).	('HN6', 'Gene', '100463482', (62, 65))	('P-si', 'Var', (41, 45))	('G1 phase', 'CPA', (92, 100))	('HN13', 'Gene', (67, 71))	('HN13', 'Gene', '100463500', (67, 71))	('HN6', 'Gene', (62, 65))	('CAL-27', 'CellLine', 'CVCL:1107', (76, 82))	('increased', 'PosReg', (106, 115))	('CAL-27 cells', 'CPA', (76, 88))
429886	25539663	These data were consistent with the results that HPV16/18 was an important etiologic factor especially for oropharyngeal SCC, and HPV-related HNSCC was more frequent in younger patients with no exposure of tobacco and alcohol.	('oropharyngeal SCC', 'Disease', (107, 124))	('HPV-related HNSCC', 'Disease', (130, 147))	('HPV16/18', 'Var', (49, 57))	('etiologic', 'Reg', (75, 84))	('HPV', 'Species', '10566', (49, 52))	('alcohol', 'Chemical', 'MESH:D000438', (218, 225))	('patients', 'Species', '9606', (177, 185))	('HNSCC', 'Phenotype', 'HP:0012288', (142, 147))	('tobacco', 'Species', '4097', (206, 213))	('HPV16', 'Species', '333760', (49, 54))	('HPV', 'Species', '10566', (130, 133))
429915	25539663	In addition, overall survival analysis revealed that high PTHrP expression was associated with poor prognosis, and patients with high PTHrP expression had a significantly low survival.	('patients', 'Species', '9606', (115, 123))	('expression', 'MPA', (64, 74))	('high', 'Var', (53, 57))	('PTHrP', 'Gene', '5744', (134, 139))	('PTHrP', 'Gene', (58, 63))	('PTHrP', 'Gene', '5744', (58, 63))	('low', 'NegReg', (171, 174))	('PTHrP', 'Gene', (134, 139))
429917	25539663	The results of the univariate and multivariate Cox proportional hazards analyses both illustrated that PTHrP expression could be used as an independent indicator of prognosis for patients with HNSCC, which was in accordance with reports showing that high PTHrP expression was an adverse prognostic indicator of gastroesophageal carcinoma and predicted poor survival for patients with early breast cancer.	('Cox', 'Gene', '1351', (47, 50))	('high', 'Var', (250, 254))	('PTHrP', 'Gene', (103, 108))	('Cox', 'Gene', (47, 50))	('PTHrP', 'Gene', (255, 260))	('gastroesophageal carcinoma', 'Disease', 'MESH:D005764', (311, 337))	('gastroesophageal carcinoma', 'Disease', (311, 337))	('PTHrP', 'Gene', '5744', (255, 260))	('patients', 'Species', '9606', (370, 378))	('HNSCC', 'Disease', (193, 198))	('PTHrP', 'Gene', '5744', (103, 108))	('patients', 'Species', '9606', (179, 187))	('HNSCC', 'Phenotype', 'HP:0012288', (193, 198))	('cancer', 'Phenotype', 'HP:0002664', (397, 403))	('carcinoma', 'Phenotype', 'HP:0030731', (328, 337))	('breast cancer', 'Disease', 'MESH:D001943', (390, 403))	('breast cancer', 'Phenotype', 'HP:0003002', (390, 403))	('breast cancer', 'Disease', (390, 403))
429921	25539663	Recently, it had been found that HPV was a major etiologic factor for head and neck squamous cell carcinoma especially for oropharyngeal squamous cell carcinoma (OPSCC), and patients with positive HPV show significant better overall survival than those with negative HPV in those cancers.	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (70, 107))	('OPSCC', 'Phenotype', 'HP:0012182', (162, 167))	('cancers', 'Phenotype', 'HP:0002664', (280, 287))	('cancers', 'Disease', (280, 287))	('overall', 'MPA', (225, 232))	('cancer', 'Phenotype', 'HP:0002664', (280, 286))	('HPV', 'Species', '10566', (267, 270))	('HPV', 'Gene', (197, 200))	('better', 'PosReg', (218, 224))	('neck squamous cell carcinoma', 'Disease', (79, 107))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (79, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (151, 160))	('positive', 'Var', (188, 196))	('cancers', 'Disease', 'MESH:D009369', (280, 287))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (84, 107))	('HPV', 'Species', '10566', (33, 36))	('oropharyngeal squamous cell carcinoma', 'Disease', (123, 160))	('oropharyngeal squamous cell carcinoma', 'Phenotype', 'HP:0012182', (123, 160))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('oropharyngeal squamous cell carcinoma', 'Disease', 'MESH:D002294', (123, 160))	('HPV', 'Species', '10566', (197, 200))	('patients', 'Species', '9606', (174, 182))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (137, 160))
429938	25539663	In this study, Kaplan-Meier analysis showed that the HNSCC patients with low PTHrP expression still had better overall survival than those of the patients with high PTHrP expression after adjusting the HPV infectious factor.	('HPV', 'Species', '10566', (202, 205))	('PTHrP', 'Gene', '5744', (77, 82))	('PTHrP', 'Gene', (165, 170))	('PTHrP', 'Gene', '5744', (165, 170))	('low PTHrP', 'Phenotype', 'HP:0031817', (73, 82))	('overall', 'MPA', (111, 118))	('HNSCC', 'Phenotype', 'HP:0012288', (53, 58))	('better', 'PosReg', (104, 110))	('patients', 'Species', '9606', (59, 67))	('patients', 'Species', '9606', (146, 154))	('PTHrP', 'Gene', (77, 82))	('low', 'Var', (73, 76))
429944	33863325	Silencing SHMT2 inhibits the progression of tongue squamous cell carcinoma through cell cycle regulation Serine hydroxymethyltransferase 2 (SHMT2) is a vital metabolic enzyme in one carbon metabolism catalyzing the conversion of serine to glycine, which has been reported to play a crucial role in the progression of tumors.	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('tumor', 'Phenotype', 'HP:0002664', (317, 322))	('SHMT2', 'Gene', (10, 15))	('carbon', 'Chemical', 'MESH:D002244', (182, 188))	('tongue squamous cell carcinoma', 'Phenotype', 'HP:0030413', (44, 74))	('tumors', 'Phenotype', 'HP:0002664', (317, 323))	('inhibits', 'NegReg', (16, 24))	('Silencing', 'Var', (0, 9))	('SHMT2', 'Gene', '6472', (140, 145))	('tongue squamous cell carcinoma', 'Disease', 'MESH:D002294', (44, 74))	('tumors', 'Disease', (317, 323))	('glycine', 'Chemical', 'MESH:D005998', (239, 246))	('Serine hydroxymethyltransferase 2', 'Gene', (105, 138))	('cell cycle regulation', 'CPA', (83, 104))	('SHMT2', 'Gene', '6472', (10, 15))	('tumors', 'Disease', 'MESH:D009369', (317, 323))	('tongue squamous cell carcinoma', 'Disease', (44, 74))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (51, 74))	('SHMT2', 'Gene', (140, 145))	('progression', 'CPA', (29, 40))	('Serine hydroxymethyltransferase 2', 'Gene', '6472', (105, 138))	('serine', 'Chemical', 'MESH:D012694', (229, 235))
429948	33863325	The expression of SHMT2 was up-regulated in TSCC tissues and cell lines compared with normal groups, and highly expressed SHMT2 significantly indicated a poorer clinical outcome for TSCC patients.	('patients', 'Species', '9606', (187, 195))	('up-regulated', 'PosReg', (28, 40))	('TSCC', 'Disease', (182, 186))	('SHMT2', 'Gene', (18, 23))	('expression', 'MPA', (4, 14))	('highly expressed', 'Var', (105, 121))	('indicated', 'Reg', (142, 151))	('SHMT2', 'Gene', (122, 127))	('poorer', 'NegReg', (154, 160))
429949	33863325	Furthermore, western blot showed that cell cycle-related regulators such as cyclin-dependent kinase 4 (CDK4) and cyclinD1 expression levels were decreased, while the expression levels of the cyclin-dependent kinase inhibitors p21Cip1 and p27Kip1 were increased after SHMT2 knockdown.	('increased', 'PosReg', (251, 260))	('cyclin-dependent kinase 4', 'Gene', '1019', (76, 101))	('cyclin-dependent kinase 4', 'Gene', (76, 101))	('expression levels', 'MPA', (166, 183))	('knockdown', 'Var', (273, 282))	('cell', 'MPA', (38, 42))	('p27Kip1', 'Var', (238, 245))	('decreased', 'NegReg', (145, 154))	('cyclinD1', 'Gene', (113, 121))	('SHMT2', 'Gene', (267, 272))	('expression levels', 'MPA', (122, 139))	('cyclinD1', 'Gene', '595', (113, 121))
429950	33863325	Silencing SHMT2 in the HN6 cell line using short hairpin RNA also impeded tumor growth in vivo.	('SHMT2', 'Gene', (10, 15))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('HN6', 'CellLine', 'CVCL:5516', (23, 26))	('impeded', 'NegReg', (66, 73))	('tumor', 'Disease', (74, 79))	('Silencing', 'Var', (0, 9))
429968	33863325	Another 9 normal oral tissues were selected from oral cancer tissue chip (HOraC080PG01, Shanghai Outdo Biotech Co, Shanghai, China).	('oral cancer', 'Disease', 'MESH:D009369', (49, 60))	('oral cancer', 'Disease', (49, 60))	('HOraC080PG01', 'CellLine', 'CVCL:C045', (74, 86))	('HOraC080PG01', 'Var', (74, 86))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
429990	33863325	Then the blots were incubated with the primary antibodies against SHMT2 (1:1,000, GTX125939, GeneTex), E-cadherin (1:1,000, 24E10, Cell Signaling), ZO1 (1:1000, D7D12, Cell Signaling), N-cadherin (1:1,000, D4R1H, Cell Signaling), Vimentin (1:1,000,D21H3,Cell Signaling, beta-catenin (1:1,000, D10A8, Cell Signaling), p21Cip1 (1:1000, 12D1, Cell Signaling), p27Kip1 (1:1000, D69C12, Cell Signaling), Cyclin D1(1:1000, E3P5S, Cell Signaling), CDK4(1:1000, D9G3E, Cell Signaling), beta-actin (1:1000,13E5, Cell Signaling), and GAPAH (1:1,000,D16H11, Cell Signaling) at 4 C overnight.	('ZO1', 'Gene', (148, 151))	('CDK4', 'Gene', (441, 445))	('Cyclin D1', 'Gene', (399, 408))	('N-cadherin', 'Gene', (185, 195))	('1:1000,13E5', 'Var', (490, 501))	('Cyclin D1', 'Gene', '449028', (399, 408))	('N-cadherin', 'Gene', '1000', (185, 195))	('ZO1', 'Gene', '403752', (148, 151))	('beta-actin', 'Protein', (478, 488))
430014	33863325	Survival analysis showed that high expression of SHMT2 was statistically significant, with lower overall survival rate (P = 0.003), shorter disease free survival (P = 0.018), and worse disease specific survival (P = 0.009) in OSCC patients (Fig.	('lower', 'NegReg', (91, 96))	('worse', 'NegReg', (179, 184))	('patients', 'Species', '9606', (231, 239))	('high expression', 'Var', (30, 45))	('SHMT2', 'Gene', (49, 54))	('overall', 'MPA', (97, 104))	('shorter', 'NegReg', (132, 139))	('OSCC', 'Disease', (226, 230))	('disease free survival', 'CPA', (140, 161))
430017	33863325	Analysis of the relationships among a series of clinicopathological features revealed that expression of SHMT2 was significantly associated with age (P = 0.03), pathologic tumor stage (P = 0.016), pathologic lymph node metastasis (P = 0.039) and clinical stage (P = 0.004), alcohol history (P = 0.005) and margin status (P = 0.045).	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('associated', 'Reg', (129, 139))	('tumor', 'Disease', (172, 177))	('alcohol', 'Chemical', 'MESH:D000438', (274, 281))	('expression', 'Var', (91, 101))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('SHMT2', 'Gene', (105, 110))
430024	33863325	We selected two sequences with a good silencing effect, si-SHMT2-2 and si-SHMT2-3, for subsequent experiments.	('SHMT2-2', 'Gene', (59, 66))	('SHMT2-2', 'Gene', '6472', (59, 66))	('si-SHMT2-3', 'Var', (71, 81))	('silencing', 'MPA', (38, 47))
430025	33863325	CCK-8 assay results demonstrated that SHMT2 knockdown suppressed the cell viability of HN6 and HSC3 cell lines compared with the control group (Fig.	('HN6', 'CellLine', 'CVCL:5516', (87, 90))	('SHMT2', 'Gene', (38, 43))	('suppressed', 'NegReg', (54, 64))	('HSC3', 'Gene', '150353', (95, 99))	('HSC3', 'Gene', (95, 99))	('knockdown', 'Var', (44, 53))	('CCK-8', 'Chemical', '-', (0, 5))
430028	33863325	As shown in western blot analyze, the protein levels of the cell cycle inhibitors p21Cip1 and p27Kip1 increased by SHMT2 knockdown in HN6 and HSC3.	('knockdown', 'Var', (121, 130))	('protein levels', 'MPA', (38, 52))	('cell cycle inhibitors', 'MPA', (60, 81))	('p27Kip1', 'Var', (94, 101))	('SHMT2', 'Gene', (115, 120))	('HN6', 'CellLine', 'CVCL:5516', (134, 137))	('HSC3', 'Gene', '150353', (142, 146))	('HSC3', 'Gene', (142, 146))	('increased', 'PosReg', (102, 111))	('p21Cip1', 'Var', (82, 89))
430029	33863325	Conversely, the protein levels of the cell cycle promoters cyclinD1 and CDK4 decreased in SHMT2 silenced cells (Fig.	('silenced', 'Var', (96, 104))	('cyclinD1', 'Gene', '595', (59, 67))	('CDK4', 'MPA', (72, 76))	('protein levels', 'MPA', (16, 30))	('SHMT2', 'Gene', (90, 95))	('decreased', 'NegReg', (77, 86))	('cyclinD1', 'Gene', (59, 67))
430030	33863325	Consistently, RT-qPCR results revealed that after si-SHMT2 transfection, the mRNA level of CDKN1A and CDKN1B were upregulated, while the mRNA level of CCDN1 and CDK4 were downregulated in HN6 and HSC3 (Fig.	('si-SHMT2', 'Gene', (50, 58))	('HSC3', 'Gene', '150353', (196, 200))	('CDKN1B', 'Gene', (102, 108))	('downregulated', 'NegReg', (171, 184))	('HSC3', 'Gene', (196, 200))	('HN6', 'CellLine', 'CVCL:5516', (188, 191))	('transfection', 'Var', (59, 71))	('CDKN1A', 'MPA', (91, 97))	('mRNA', 'MPA', (137, 141))	('mRNA level', 'MPA', (77, 87))	('upregulated', 'PosReg', (114, 125))
430033	33863325	We found that mesenchymal phenotype markers including N-cadherin, beta-catenin, and Vimentin were downregulated, whereas epithelial phenotype markers such as ZO-1 and E-cadherin were up-regulated after SHMT2 knockdown (Fig.	('downregulated', 'NegReg', (98, 111))	('N-cadherin', 'Gene', (54, 64))	('beta-catenin', 'Protein', (66, 78))	('up-regulated', 'PosReg', (183, 195))	('mesenchymal phenotype', 'CPA', (14, 35))	('knockdown', 'Var', (208, 217))	('SHMT2', 'Gene', (202, 207))	('N-cadherin', 'Gene', '1000', (54, 64))	('ZO-1', 'Gene', (158, 162))	('Vimentin', 'Protein', (84, 92))	('E-cadherin', 'CPA', (167, 177))	('ZO-1', 'Gene', '7082', (158, 162))
430034	33863325	Unexpectedly, compared with control group, E-cad expression in HN6 treated cells showed negligible change and N-cad level in si-SHMT2-3 of HSC3 cells increased abnormally, which may be led by complex protein expression regulatory network.	('E-cad', 'Gene', '999', (43, 48))	('N-cad', 'Gene', (110, 115))	('HSC3', 'Gene', (139, 143))	('si-SHMT2-3', 'Var', (125, 135))	('E-cad', 'Gene', (43, 48))	('expression', 'MPA', (49, 59))	('increased', 'PosReg', (150, 159))	('HSC3', 'Gene', '150353', (139, 143))	('HN6', 'CellLine', 'CVCL:5516', (63, 66))	('N-cad', 'Gene', '1000', (110, 115))
430036	33863325	The results of CCK-8 assays showed that silencing SHMT2 could inhibit the viability of OSCC cells (Fig.	('viability of OSCC cells', 'CPA', (74, 97))	('CCK-8', 'Chemical', '-', (15, 20))	('silencing', 'Var', (40, 49))	('SHMT2', 'Gene', (50, 55))	('inhibit', 'NegReg', (62, 69))
430038	33863325	Western blot analysis of the expression of EMT-associated proteins indicated that SHMT2 silencing in HN6 and HSC3 significantly down-regulated mesenchymal phenotypic markers such as N-cadherin, beta-catenin and Vimentin, while epithelial phenotypic markers including ZO-1, E-cadherin were significantly up-regulated (Fig.	('HSC3', 'Gene', (109, 113))	('ZO-1', 'Gene', (267, 271))	('N-cadherin', 'Gene', (182, 192))	('mesenchymal phenotypic markers', 'CPA', (143, 173))	('beta-catenin', 'Protein', (194, 206))	('up-regulated', 'PosReg', (303, 315))	('HN6', 'CellLine', 'CVCL:5516', (101, 104))	('N-cadherin', 'Gene', '1000', (182, 192))	('silencing', 'Var', (88, 97))	('Vimentin', 'CPA', (211, 219))	('ZO-1', 'Gene', '7082', (267, 271))	('down-regulated', 'NegReg', (128, 142))	('HSC3', 'Gene', '150353', (109, 113))	('SHMT2', 'Gene', (82, 87))
430039	33863325	Wound healing results showed that SHMT2 silencing remarkably reduced the healing area of HN6 and HSC3 cells (Fig.	('SHMT2', 'Gene', (34, 39))	('HN6', 'CellLine', 'CVCL:5516', (89, 92))	('HSC3', 'Gene', (97, 101))	('HSC3', 'Gene', '150353', (97, 101))	('silencing', 'Var', (40, 49))	('reduced', 'NegReg', (61, 68))
430043	33863325	The SHMT2 expression level was significantly reduced in tumors from the sh-SHMT2 mice group compared with that from the control group.	('SHMT2', 'Gene', (4, 9))	('expression level', 'MPA', (10, 26))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('reduced', 'NegReg', (45, 52))	('mice', 'Species', '10090', (81, 85))	('sh-SHMT2', 'Var', (72, 80))	('tumors', 'Disease', (56, 62))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))
430045	33863325	Immunohistochemistry analysis of tumors from mice showed that SHMT2 and Ki-67 protein expression levels were downregulated in the sh-SHTM2 group (Fig.	('mice', 'Species', '10090', (45, 49))	('downregulated', 'NegReg', (109, 122))	('SHMT2', 'Gene', (62, 67))	('protein expression levels', 'MPA', (78, 103))	('Ki-67', 'Gene', (72, 77))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('sh-SHTM2', 'Var', (130, 138))	('tumors', 'Disease', 'MESH:D009369', (33, 39))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('tumors', 'Disease', (33, 39))	('Ki-67', 'Gene', '17345', (72, 77))
430047	33863325	These findings supported the hypothesis that SHMT2 deletion inhibited TSCC cell proliferation and tumor growth in vivo.	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('TSCC cell proliferation', 'CPA', (70, 93))	('SHMT2', 'Gene', (45, 50))	('inhibited', 'NegReg', (60, 69))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumor', 'Disease', (98, 103))	('deletion', 'Var', (51, 59))
430055	33863325	These findings suggested that abnormal expression of SHMT2 protein exerts a profound influence on tumors progression.	('abnormal', 'Var', (30, 38))	('tumors', 'Disease', (98, 104))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('protein', 'Protein', (59, 66))	('tumors', 'Disease', 'MESH:D009369', (98, 104))	('influence', 'Reg', (85, 94))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('expression', 'MPA', (39, 49))	('SHMT2', 'Gene', (53, 58))
430056	33863325	Moreover, clinical significance analysis revealed that high expression of SHMT2 was significantly correlated with advanced pathologic tumor stage, lymph node metastasis and advanced clinic stage.	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('correlated', 'Reg', (98, 108))	('SHMT2', 'Gene', (74, 79))	('high', 'Var', (55, 59))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('lymph node metastasis', 'CPA', (147, 168))	('tumor', 'Disease', (134, 139))
430058	33863325	In gliomas, overexpression of SHMT2 was found to enhance the proliferation and invasion of tumor cells.	('glioma', 'Phenotype', 'HP:0009733', (3, 9))	('enhance', 'PosReg', (49, 56))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('gliomas', 'Disease', 'MESH:D005910', (3, 10))	('overexpression', 'Var', (12, 26))	('gliomas', 'Disease', (3, 10))	('proliferation', 'CPA', (61, 74))	('gliomas', 'Phenotype', 'HP:0009733', (3, 10))	('tumor', 'Disease', (91, 96))	('SHMT2', 'Gene', (30, 35))
430061	33863325	Notably, one study has reported that silencing the SHMT2 gene and depleting extracellular glycine prolonged the G1 phase of the cell cycle, thereby slowing down the proliferation of HeLa cells.	('prolonged', 'PosReg', (98, 107))	('SHMT2', 'Gene', (51, 56))	('glycine', 'Chemical', 'MESH:D005998', (90, 97))	('silencing', 'Var', (37, 46))	('HeLa', 'CellLine', 'CVCL:0030', (182, 186))	('G1 phase of the cell cycle', 'CPA', (112, 138))	('proliferation', 'CPA', (165, 178))	('depleting extracellular glycine', 'MPA', (66, 97))	('slowing down', 'NegReg', (148, 160))
430063	33863325	For GSEA, we found that SHMT2 high-expression group was more remarkably correlated with cell cycle, cell cycle checkpoint, positive regulation of cell cycle transition and cell cycle G1/S transition signal pathways when compared with SHMT2 low-expression group.	('cell cycle G1/S transition signal pathways', 'Pathway', (172, 214))	('SHMT2', 'Gene', (24, 29))	('correlated', 'Reg', (72, 82))	('high-expression', 'Var', (30, 45))	('cell cycle transition', 'CPA', (146, 167))	('cell cycle checkpoint', 'CPA', (100, 121))	('cell cycle', 'CPA', (88, 98))	('positive regulation', 'PosReg', (123, 142))	('GSEA', 'Chemical', '-', (4, 8))
430064	33863325	To validate the findings of bioinformatic analysis, we further measured the proliferation of HN6 and HSC3 cells after silencing SHMT2 by CCK-8 and Edu staining.	('HN6', 'CellLine', 'CVCL:5516', (93, 96))	('CCK-8', 'Chemical', '-', (137, 142))	('proliferation', 'CPA', (76, 89))	('silencing', 'Var', (118, 127))	('SHMT2', 'Gene', (128, 133))	('Edu', 'Chemical', '-', (147, 150))	('HSC3', 'Gene', '150353', (101, 105))	('HSC3', 'Gene', (101, 105))
430065	33863325	Western blot analysis showed that p21Cip1 and p27Kip1 protein level elevated, while cyclinD1 and CDK4 protein expression reduced by SHMT2 knockdown.	('knockdown', 'Var', (138, 147))	('CDK4 protein expression', 'MPA', (97, 120))	('reduced', 'NegReg', (121, 128))	('elevated', 'PosReg', (68, 76))	('cyclinD1', 'Gene', (84, 92))	('SHMT2', 'Gene', (132, 137))	('cyclinD1', 'Gene', '595', (84, 92))	('p27Kip1', 'Var', (46, 53))	('p21Cip1', 'MPA', (34, 41))
430067	33863325	Likewise, silencing SHMT2 effectively impeded the tumor growth in vivo.	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('impeded', 'NegReg', (38, 45))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Disease', (50, 55))	('silencing', 'Var', (10, 19))	('SHMT2', 'Gene', (20, 25))
430075	33863325	In vivo, SHMT2 inhibition also reduced breast cancer growth of primary and metastatic sites.	('breast cancer', 'Phenotype', 'HP:0003002', (39, 52))	('reduced', 'NegReg', (31, 38))	('SHMT2', 'Gene', (9, 14))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('breast cancer', 'Disease', 'MESH:D001943', (39, 52))	('inhibition', 'Var', (15, 25))	('breast cancer', 'Disease', (39, 52))
430087	32793196	Comparison of a Novel Bisphosphonate Prodrug and Zoledronic Acid in the Induction of Cytotoxicity in Human Vgamma2Vdelta2 T Cells Increasing attention has been paid to human gammadelta T cells expressing Vgamma2Vdelta2 T cell receptor (also termed Vgamma9Vdelta2) in the field of cancer immunotherapy.	('Vgamma2Vdelta2', 'Var', (204, 218))	('cancer', 'Disease', 'MESH:D009369', (280, 286))	('human', 'Species', '9606', (168, 173))	('Vgamma2Vdelta2 T', 'CellLine', 'CVCL:0042', (107, 123))	('Vgamma2Vdelta2 T', 'CellLine', 'CVCL:0042', (204, 220))	('Cytotoxicity', 'Disease', (85, 97))	('cancer', 'Disease', (280, 286))	('Zoledronic Acid', 'Chemical', 'MESH:D000077211', (49, 64))	('Bisphosphonate', 'Chemical', 'MESH:D004164', (22, 36))	('cancer', 'Phenotype', 'HP:0002664', (280, 286))	('Human', 'Species', '9606', (101, 106))	('Cytotoxicity', 'Disease', 'MESH:D064420', (85, 97))
430092	32793196	We next analyzed TCR-independent cytotoxicity of Vgamma2Vdelta2 T cells.	('cytotoxicity', 'Disease', (33, 45))	('TCR', 'Gene', '6962', (17, 20))	('cytotoxicity', 'Disease', 'MESH:D064420', (33, 45))	('TCR', 'Gene', (17, 20))	('Vgamma2Vdelta2 T', 'CellLine', 'CVCL:0042', (49, 65))	('Vgamma2Vdelta2', 'Var', (49, 63))
430093	32793196	When human lung cancer cell lines were challenged by Vgamma2Vdelta2 T cells, no detectable cytotoxicity was observed in 40 min.	('Vgamma2Vdelta2 T', 'Var', (53, 69))	('cytotoxicity', 'Disease', 'MESH:D064420', (91, 103))	('lung cancer', 'Disease', (11, 22))	('Vgamma2Vdelta2 T', 'CellLine', 'CVCL:0042', (53, 69))	('lung cancer', 'Phenotype', 'HP:0100526', (11, 22))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('human', 'Species', '9606', (5, 10))	('cytotoxicity', 'Disease', (91, 103))	('lung cancer', 'Disease', 'MESH:D008175', (11, 22))
430094	32793196	The lung cancer cell lines were, however, significantly killed by Vgamma2Vdelta2 T cells after 4-16 h in an effector-to-target ratio-dependent manner, demonstrating that Vgamma2Vdelta2 T cell-based cell therapy required a large number of cells and longer time when tumor cells were not sensitized.	('tumor', 'Phenotype', 'HP:0002664', (265, 270))	('Vgamma2Vdelta2 T', 'CellLine', 'CVCL:0042', (170, 186))	('tumor', 'Disease', (265, 270))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('lung cancer', 'Disease', (4, 15))	('Vgamma2Vdelta2 T', 'Var', (66, 82))	('lung cancer', 'Phenotype', 'HP:0100526', (4, 15))	('lung cancer', 'Disease', 'MESH:D008175', (4, 15))	('tumor', 'Disease', 'MESH:D009369', (265, 270))	('Vgamma2Vdelta2 T', 'CellLine', 'CVCL:0042', (66, 82))
430097	32793196	In addition, Vgamma2Vdelta2 T cells secreted interferon-gamma (IFN-gamma) when challenged by lung cancer cell lines pulsed with PTA in a dose-dependent manner.	('IFN-gamma', 'Gene', (63, 72))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('PTA', 'Chemical', 'MESH:C000621092', (128, 131))	('lung cancer', 'Disease', 'MESH:D008175', (93, 104))	('secreted', 'MPA', (36, 44))	('Vgamma2Vdelta2 T', 'CellLine', 'CVCL:0042', (13, 29))	('IFN-gamma', 'Gene', '3458', (63, 72))	('lung cancer', 'Disease', (93, 104))	('interferon-gamma', 'Gene', '3458', (45, 61))	('lung cancer', 'Phenotype', 'HP:0100526', (93, 104))	('Vgamma2Vdelta2', 'Var', (13, 27))	('interferon-gamma', 'Gene', (45, 61))
430106	32793196	In humans, most circulating gammadelta T cells express Vgamma2Vdelta2 (also termed Vgamma9Vdelta2) and recognize foreign phosphoantigens (pAgs) like (E)-4-hydroxy-3-methylbut-2-enyl diphosphate (HMBPP) derived from pathogenic microbes and self pAgs like isopentenyl diphosphate (IPP).	('phosphoantigens', 'Chemical', '-', (121, 136))	('pAgs', 'Chemical', '-', (244, 248))	('E)-4', 'Gene', (150, 154))	('Vgamma2Vdelta2', 'Var', (55, 69))	('HMBPP', 'Chemical', '-', (195, 200))	('(E)-4', 'Gene', '9354', (149, 154))	('pAgs', 'Chemical', '-', (138, 142))	('IPP', 'Chemical', 'MESH:C004809', (279, 282))	('humans', 'Species', '9606', (3, 9))	('isopentenyl diphosphate', 'Chemical', 'MESH:C004809', (254, 277))	('isopentenyl diphosphate', 'MPA', (254, 277))
430108	32793196	However, the precise mode of recognition by Vgamma2Vdelta2 T cells of the BTN complex has not been fully elucidated.	('BTN', 'Gene', (74, 77))	('Vgamma2Vdelta2 T', 'CellLine', 'CVCL:0042', (44, 60))	('Vgamma2Vdelta2', 'Var', (44, 58))	('BTN', 'Gene', '696', (74, 77))
430187	32793196	As illustrated in the left panel of Figure 2C, both IPP and DMAPP accumulated in the cells in a PTA dose-dependent manner: 0.010 +- 0.001 nmole at 0 nM, 0.084 +- 0.003 nmole at 10 nM, 0.152 +- 0.012 nmole at 30 nM, 0.222 +- 0.005 nmole at 100 nM for IPP and 0.000 +- 0.000 nmole at 0 nM, 0193 +- 0.011 nmole at 10 nM, 0.352 +- 0.020 nmole at 30 nM, 0.485 +- 0.022 nmole at 100 nM for DMAPP.	('0.222 +- 0.005 nmole', 'Var', (215, 235))	('0.485 +- 0.022 nmole', 'Var', (349, 369))	('0.084 +- 0.003 nmole', 'Var', (153, 173))	('DMAPP', 'Chemical', 'MESH:C043060', (60, 65))	('DMAPP', 'Chemical', 'MESH:C043060', (384, 389))	('0.352 +- 0.020 nmole', 'Var', (318, 338))	('0.152 +- 0.012 nmole', 'Var', (184, 204))	('IPP', 'Chemical', 'MESH:C004809', (52, 55))	('0.010 +- 0.001 nmole', 'Var', (123, 143))	('PTA', 'Chemical', 'MESH:C000621092', (96, 99))	('IPP', 'Chemical', 'MESH:C004809', (250, 253))
430188	32793196	The concentrations of DMAPP in Raji cells were consistently higher than those of IPP at any concentrations of PTA.	('PTA', 'Chemical', 'MESH:C000621092', (110, 113))	('DMAPP', 'Chemical', 'MESH:C043060', (22, 27))	('concentrations', 'MPA', (4, 18))	('higher', 'PosReg', (60, 66))	('Raji', 'CellLine', 'CVCL:0511', (31, 35))	('DMAPP', 'Var', (22, 27))	('IPP', 'Chemical', 'MESH:C004809', (81, 84))
430189	32793196	When the P31/FUJ monocytic cell line was examined for IPP and DMAPP accumulation, essentially the same results were obtained: 0.009 +- 0.000 nmole at 0 nM, 0.072 +- 0.004 nmole at 10 nM, 0.158 +- 0.006 nmole at 30 nM, 0.222 +- 0.007 nmole at 100 nM for IPP, and 0.000 +- 0.000 nmole at 0 nM, 0.115 +- 0.006 nmole at 10 nM, 0.226 +- 0.002 nmole at 30 nM, 0.330 +- 0.014 nmole at 100 nM for DMAPP as depicted in the right panel of Figure 2C.	('IPP', 'Chemical', 'MESH:C004809', (54, 57))	('IPP', 'Chemical', 'MESH:C004809', (253, 256))	('0.009', 'Var', (126, 131))	('0.330 +- 0.014 nmole at', 'Var', (354, 377))	('0.226 +- 0.002 nmole', 'Var', (323, 343))	('DMAPP', 'Chemical', 'MESH:C043060', (62, 67))	('DMAPP', 'Chemical', 'MESH:C043060', (389, 394))	('0.158', 'Var', (187, 192))
430192	32793196	Although only a low level of DMAPP was observed in Raji cells after ZOL treatment for 2 h, the accumulation was dependent on ZOL concentrations: 0.000 +- 0.000 nmole at 0 muM, 0.001 +- 0.000 nmole at 100 muM, 0.002 +- 0.000 nmole at 300 muM, 0.07 +- 0.000 nmole at 1,000 muM.	('DMAPP', 'Chemical', 'MESH:C043060', (29, 34))	('muM', 'Gene', '56925', (271, 274))	('muM', 'Gene', '56925', (237, 240))	('muM', 'Gene', (171, 174))	('ZOL', 'Chemical', 'MESH:D000077211', (68, 71))	('Raji', 'CellLine', 'CVCL:0511', (51, 55))	('muM', 'Gene', (237, 240))	('muM', 'Gene', (271, 274))	('0.000 +- 0.000 nmole at', 'Var', (145, 168))	('0.002 +- 0.000 nmole', 'Var', (209, 229))	('muM', 'Gene', '56925', (204, 207))	('0.001 +- 0.000 nmole at', 'Var', (176, 199))	('muM', 'Gene', '56925', (171, 174))	('ZOL', 'Chemical', 'MESH:D000077211', (125, 128))	('muM', 'Gene', (204, 207))
430198	32793196	Regarding the initial phase of stimulation, RPMI1640 medium induced more pronounced responses in PBMC than Yssel's medium.	("Yssel's medium", 'Chemical', '-', (107, 121))	('RPMI1640', 'Var', (44, 52))	('RPMI1640 medium', 'Chemical', '-', (44, 59))	('responses', 'MPA', (84, 93))
430208	32793196	As shown in Figure 3B, the proportions of Vgamma2Vdelta2 T cells on day 8 were 3.87, 12.6, 54.5, and 70.1% when stimulated with 0, 156.25 nM, 1.25 muM, and 5 muM of ZOL, and 69.6, 86.7, and 94.8% with 31.25, 125 nM, and 1 muM of PTA, respectively, demonstrating that PTA induced the specific expansion of Vgamma2Vdelta2 T cells to a greater degree than ZOL.	('Vgamma2Vdelta2 T', 'CellLine', 'CVCL:0042', (42, 58))	('muM', 'Gene', (222, 225))	('muM', 'Gene', (158, 161))	('muM', 'Gene', (147, 150))	('ZOL', 'Chemical', 'MESH:D000077211', (353, 356))	('PTA', 'Chemical', 'MESH:C000621092', (229, 232))	('muM', 'Gene', '56925', (147, 150))	('PTA', 'Chemical', 'MESH:C000621092', (267, 270))	('Vgamma2Vdelta2', 'Var', (305, 319))	('ZOL', 'Chemical', 'MESH:D000077211', (165, 168))	('muM', 'Gene', '56925', (222, 225))	('Vgamma2Vdelta2 T', 'CellLine', 'CVCL:0042', (305, 321))	('muM', 'Gene', '56925', (158, 161))
430213	32793196	We then examined the effect of PTA on the expansion of Vgamma2Vdelta2 T cells in lung cancer patients (Figure 3E).	('lung cancer', 'Disease', (81, 92))	('lung cancer', 'Phenotype', 'HP:0100526', (81, 92))	('Vgamma2Vdelta2', 'Var', (55, 69))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('lung cancer', 'Disease', 'MESH:D008175', (81, 92))	('patients', 'Species', '9606', (93, 101))	('PTA', 'Chemical', 'MESH:C000621092', (31, 34))	('Vgamma2Vdelta2 T', 'CellLine', 'CVCL:0042', (55, 71))
430217	32793196	The results demonstrated that Vgamma2Vdelta2 T cells of lung cancer patients could be efficiently expanded by PTA, which might be used for adoptive transfer therapy.	('PTA', 'Chemical', 'MESH:C000621092', (110, 113))	('lung cancer', 'Disease', 'MESH:D008175', (56, 67))	('Vgamma2Vdelta2', 'Var', (30, 44))	('patients', 'Species', '9606', (68, 76))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('Vgamma2Vdelta2 T', 'CellLine', 'CVCL:0042', (30, 46))	('lung cancer', 'Disease', (56, 67))	('lung cancer', 'Phenotype', 'HP:0100526', (56, 67))
430218	32793196	Human Vgamma2Vdelta2 T cells exhibit at least three types of cellular cytotoxicity, TCR-independent, TCR-dependent, and antibody-dependent cytotoxicity.	('Human', 'Species', '9606', (0, 5))	('TCR', 'Gene', '6962', (84, 87))	('cytotoxicity', 'Disease', 'MESH:D064420', (70, 82))	('TCR', 'Gene', (101, 104))	('cytotoxicity', 'Disease', 'MESH:D064420', (139, 151))	('TCR', 'Gene', (84, 87))	('cytotoxicity', 'Disease', (70, 82))	('Vgamma2Vdelta2 T', 'CellLine', 'CVCL:0042', (6, 22))	('Vgamma2Vdelta2', 'Var', (6, 20))	('TCR', 'Gene', '6962', (101, 104))	('cytotoxicity', 'Disease', (139, 151))
430220	32793196	As shown in Figure S2, the purity of Vgamma2Vdelta2 T cells after expansion with PTA and IL-2 for 11 days was 99.2 and 98.5% in healthy adult volunteers HD01 and HD02, respectively.	('IL-2', 'Gene', (89, 93))	('IL-2', 'Gene', '3558', (89, 93))	('Vgamma2Vdelta2', 'Var', (37, 51))	('PTA', 'Chemical', 'MESH:C000621092', (81, 84))	('Vgamma2Vdelta2 T', 'CellLine', 'CVCL:0042', (37, 53))	('HD01', 'CellLine', 'CVCL:A241', (153, 157))
430221	32793196	Most of the PTA-expanded Vgamma2Vdelta2 T cells exhibited a CD45RA-CD27+ phenotype and were categorized into effector memory cells.	('CD45', 'Gene', '5788', (60, 64))	('exhibited', 'Reg', (48, 57))	('PTA', 'Chemical', 'MESH:C000621092', (12, 15))	('CD27', 'Gene', '939', (67, 71))	('CD27', 'Gene', (67, 71))	('CD45', 'Gene', (60, 64))	('Vgamma2Vdelta2 T', 'CellLine', 'CVCL:0042', (25, 41))	('Vgamma2Vdelta2', 'Var', (25, 39))
430230	32793196	It is thus likely that Vgamma2Vdelta2 T cells require relatively long time to kill lung cancer cells when TCR is not involved in the recognition.	('lung cancer', 'Disease', 'MESH:D008175', (83, 94))	('TCR', 'Gene', '6962', (106, 109))	('Vgamma2Vdelta2', 'Var', (23, 37))	('Vgamma2Vdelta2 T', 'CellLine', 'CVCL:0042', (23, 39))	('lung cancer', 'Disease', (83, 94))	('lung cancer', 'Phenotype', 'HP:0100526', (83, 94))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('TCR', 'Gene', (106, 109))
430231	32793196	We next compared PTA and ZOL in the TCR-dependent killing of lung cancer cells by Vgamma2Vdelta2 T cells.	('lung cancer', 'Disease', (61, 72))	('lung cancer', 'Phenotype', 'HP:0100526', (61, 72))	('Vgamma2Vdelta2 T', 'Var', (82, 98))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('TCR', 'Gene', (36, 39))	('Vgamma2Vdelta2 T', 'CellLine', 'CVCL:0042', (82, 98))	('ZOL', 'Chemical', 'MESH:D000077211', (25, 28))	('lung cancer', 'Disease', 'MESH:D008175', (61, 72))	('PTA', 'Chemical', 'MESH:C000621092', (17, 20))	('TCR', 'Gene', '6962', (36, 39))
430232	32793196	When PTA- or ZOL-pulsed lung cancer cell lines were challenged by Vgamma2Vdelta2 T cells for 40 min at an E/T ratio of 80:1, the specific lysis rate attained to around 30% in all the lung cancer cell lines as shown in the middle panels of Figure 4.	('Vgamma2Vdelta2', 'Var', (66, 80))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('ZOL', 'Chemical', 'MESH:D000077211', (13, 16))	('lung cancer', 'Disease', 'MESH:D008175', (183, 194))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('PTA', 'Chemical', 'MESH:C000621092', (5, 8))	('lung cancer', 'Disease', (24, 35))	('lung cancer', 'Phenotype', 'HP:0100526', (24, 35))	('specific lysis', 'MPA', (129, 143))	('lung cancer', 'Disease', (183, 194))	('lung cancer', 'Phenotype', 'HP:0100526', (183, 194))	('lung cancer', 'Disease', 'MESH:D008175', (24, 35))	('Vgamma2Vdelta2 T', 'CellLine', 'CVCL:0042', (66, 82))
430234	32793196	When the incubation was extended to 4 h, more than 50% of PTA- or ZOL-pulsed lung cancer cells were killed by Vgamma2Vdelta2 T cells at an E/T ratio of 15:1, with the drug concentrations required for the half-maximal specific lysis rates being essentially the same as those for 40 min as shown in the right panels of Figure 4.	('lung cancer', 'Phenotype', 'HP:0100526', (77, 88))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('ZOL', 'Chemical', 'MESH:D000077211', (66, 69))	('lung cancer', 'Disease', 'MESH:D008175', (77, 88))	('Vgamma2Vdelta2 T', 'Var', (110, 126))	('PTA', 'Chemical', 'MESH:C000621092', (58, 61))	('Vgamma2Vdelta2 T', 'CellLine', 'CVCL:0042', (110, 126))	('lung cancer', 'Disease', (77, 88))
430237	32793196	The secretion of IFN-gamma from Vgamma2Vdelta2 T cells was confirmed by intracellular staining of IFN-gamma as shown in Figure 5B, in which the amount of IFN-gamma secreted from Vgamma2Vdelta2 T cells in response to PTA-pulsed lung cancer cells was more than that to ZOL-pulsed target cells.	('IFN-gamma', 'Gene', '3458', (17, 26))	('IFN-gamma', 'Gene', (17, 26))	('ZOL', 'Chemical', 'MESH:D000077211', (267, 270))	('lung cancer', 'Disease', (227, 238))	('Vgamma2Vdelta2 T', 'CellLine', 'CVCL:0042', (32, 48))	('lung cancer', 'Phenotype', 'HP:0100526', (227, 238))	('IFN-gamma', 'Gene', '3458', (98, 107))	('Vgamma2Vdelta2 T', 'CellLine', 'CVCL:0042', (178, 194))	('Vgamma2Vdelta2', 'Var', (178, 192))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('IFN-gamma', 'Gene', (98, 107))	('PTA', 'Chemical', 'MESH:C000621092', (216, 219))	('lung cancer', 'Disease', 'MESH:D008175', (227, 238))	('IFN-gamma', 'Gene', '3458', (154, 163))	('IFN-gamma', 'Gene', (154, 163))
430262	32793196	It was previously shown that negatively-charged N-BPs taken up by monocytes or dendritic cells through fluid-phase endocytosis inhibited FDPS, resulting in the depletion of the downstream metabolites including geranylgeranyl diphosphate.	('negatively-charged', 'Var', (29, 47))	('FDPS', 'Gene', (137, 141))	('FDPS', 'Gene', '2224', (137, 141))	('depletion of', 'MPA', (160, 172))	('inhibited', 'NegReg', (127, 136))	('geranylgeranyl diphosphate', 'MPA', (210, 236))	('geranylgeranyl diphosphate', 'Chemical', 'MESH:C002963', (210, 236))	('N-BPs', 'Chemical', '-', (48, 53))
430269	32793196	The present study indicates that Yssel's medium somehow prevents the inflammation caused by IL-1beta/IL-18/IFN-gamma and APPPI and sustains the specific expansion of Vgamma2Vdelta2 T cells triggered by accumulation of IPP and DMAPP in a BTN2A1/3A1-dependent manner.	('APPPI', 'Chemical', '-', (121, 126))	('IL-18', 'Gene', '3606', (101, 106))	('IFN-gamma', 'Gene', '3458', (107, 116))	('IFN-gamma', 'Gene', (107, 116))	('IL-1beta', 'Gene', (92, 100))	('Vgamma2Vdelta2', 'Var', (166, 180))	('IL-18', 'Gene', (101, 106))	('inflammation', 'Disease', (69, 81))	('Vgamma2Vdelta2 T', 'CellLine', 'CVCL:0042', (166, 182))	('BTN2A1/3A1', 'Gene', '11120;11119', (237, 247))	('BTN2A1/3A1', 'Gene', (237, 247))	('DMAPP', 'Chemical', 'MESH:C043060', (226, 231))	("Yssel's medium", 'Chemical', '-', (33, 47))	('IL-1beta', 'Gene', '3552', (92, 100))	('inflammation', 'Disease', 'MESH:D007249', (69, 81))	('IPP', 'Chemical', 'MESH:C004809', (218, 221))
430276	32793196	As previously reported, antigen-presenting cell-related molecules such as CD86, HLA-DQ, and HLA-DR were also expressed, suggesting that Vgamma2Vdelta2 T cells might serve as antigen-presenting cells as well as immune effector cells.	('CD86', 'Gene', (74, 78))	('Vgamma2Vdelta2', 'Var', (136, 150))	('Vgamma2Vdelta2 T', 'CellLine', 'CVCL:0042', (136, 152))	('CD86', 'Gene', '942', (74, 78))
430278	32793196	In this study, we examined the TCR-independent, NK-like cellular cytotoxicity of Vgamma2Vdelta2 T cells against lung cancer cell lines.	('TCR', 'Gene', (31, 34))	('cytotoxicity', 'Disease', 'MESH:D064420', (65, 77))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('lung cancer', 'Disease', (112, 123))	('lung cancer', 'Phenotype', 'HP:0100526', (112, 123))	('Vgamma2Vdelta2', 'Var', (81, 95))	('TCR', 'Gene', '6962', (31, 34))	('lung cancer', 'Disease', 'MESH:D008175', (112, 123))	('Vgamma2Vdelta2 T', 'CellLine', 'CVCL:0042', (81, 97))	('cytotoxicity', 'Disease', (65, 77))
430280	32793196	Based on the time-resolved fluorescence assay, the lung cancer cell lines were resistant to NK-like activity of Vgamma2Vdelta2 T cells in a relatively short period of incubation.	('lung cancer', 'Disease', 'MESH:D008175', (51, 62))	('Vgamma2Vdelta2', 'Var', (112, 126))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('lung cancer', 'Disease', (51, 62))	('lung cancer', 'Phenotype', 'HP:0100526', (51, 62))	('Vgamma2Vdelta2 T', 'CellLine', 'CVCL:0042', (112, 128))
430281	32793196	Vgamma2Vdelta2 T cells-mediated NK-like cytotoxicity against lung cancer cells became apparent after 4 h of incubation at an E/T ratio of 80:1, based on luminescence-based assay.	('lung cancer', 'Disease', (61, 72))	('cytotoxicity', 'Disease', (40, 52))	('lung cancer', 'Phenotype', 'HP:0100526', (61, 72))	('Vgamma2Vdelta2 T', 'Var', (0, 16))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('cytotoxicity', 'Disease', 'MESH:D064420', (40, 52))	('lung cancer', 'Disease', 'MESH:D008175', (61, 72))	('Vgamma2Vdelta2 T', 'CellLine', 'CVCL:0042', (0, 16))
430282	32793196	These results demonstrate that Vgamma2Vdelta2 T cells can kill lung cancer cells in an NK-like manner, whereas a higher E/T ratio and a longer incubation time are required for the manifestation of the Vgamma2Vdelta2 TCR-independent, NK-like cellular cytotoxicity, compared to those for conventional human NK cells against K562 cells.	('Vgamma2Vdelta2 T', 'CellLine', 'CVCL:0042', (31, 47))	('lung cancer', 'Disease', 'MESH:D008175', (63, 74))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('Vgamma2Vdelta2 T', 'CellLine', 'CVCL:0042', (201, 217))	('Vgamma2Vdelta2', 'Var', (201, 215))	('human', 'Species', '9606', (299, 304))	('TCR', 'Gene', '6962', (216, 219))	('cytotoxicity', 'Disease', 'MESH:D064420', (250, 262))	('lung cancer', 'Disease', (63, 74))	('lung cancer', 'Phenotype', 'HP:0100526', (63, 74))	('K562', 'CellLine', 'CVCL:0004', (322, 326))	('TCR', 'Gene', (216, 219))	('Vgamma2Vdelta2', 'Var', (31, 45))	('cytotoxicity', 'Disease', (250, 262))
430284	32793196	In this assay system, N-BP-sensitized tumor cells were killed by Vgamma2Vdelta2 T cells in a TCR-dependent manner.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('TCR', 'Gene', (93, 96))	('Vgamma2Vdelta2 T', 'Var', (65, 81))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('TCR', 'Gene', '6962', (93, 96))	('Vgamma2Vdelta2 T', 'CellLine', 'CVCL:0042', (65, 81))	('N-BP', 'Chemical', '-', (22, 26))
430288	32793196	It is worthy of note that 100-300 muM of ZOL is required for the sensitization of lung cancer cells for Vgamma2Vdelta2 T cells, which is much higher than the plasma concentration (1-2 muM) after infusion of 4 mg of ZOL.	('muM', 'Gene', '56925', (34, 37))	('Vgamma2Vdelta2', 'Var', (104, 118))	('lung cancer', 'Phenotype', 'HP:0100526', (82, 93))	('lung cancer', 'Disease', (82, 93))	('muM', 'Gene', (34, 37))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('ZOL', 'Chemical', 'MESH:D000077211', (41, 44))	('muM', 'Gene', '56925', (184, 187))	('lung cancer', 'Disease', 'MESH:D008175', (82, 93))	('Vgamma2Vdelta2 T', 'CellLine', 'CVCL:0042', (104, 120))	('muM', 'Gene', (184, 187))	('ZOL', 'Chemical', 'MESH:D000077211', (215, 218))
430292	32793196	It is thus prerequisite to develop N-BP prodrugs for successful Vgamma2Vdelta2 T cell-based immunotherapy for lung cancer.	('lung cancer', 'Disease', 'MESH:D008175', (110, 121))	('Vgamma2Vdelta2 T', 'CellLine', 'CVCL:0042', (64, 80))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('lung cancer', 'Disease', (110, 121))	('N-BP', 'Chemical', '-', (35, 39))	('lung cancer', 'Phenotype', 'HP:0100526', (110, 121))	('Vgamma2Vdelta2', 'Var', (64, 78))
430305	31059559	Immunohistochemistry (IHC)-based immunoscores, which quantify the number of CD8+ cytotoxic T lymphocytes and CD45RO+ memory T cells, show better prognostic potential than conventional pathological methods in colon cancer patients.	('patients', 'Species', '9606', (221, 229))	('colon cancer', 'Phenotype', 'HP:0003003', (208, 220))	('colon cancer', 'Disease', 'MESH:D015179', (208, 220))	('colon cancer', 'Disease', (208, 220))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('CD45RO+', 'Var', (109, 116))	('CD8', 'Gene', (76, 79))	('CD8', 'Gene', '925', (76, 79))
430322	31059559	Similarly, we update  through  where  x  means the ceiling of , alpha1   (0, 1) is used to obtain a lower bound for N in the first step, alpha2 > 1 guarantees the monotonicity of , and the min operator guarantees  is smaller than .	('monotonicity', 'MPA', (163, 175))	('alpha2 > 1', 'Var', (137, 147))	('alpha1', 'Gene', '146', (64, 70))	('alpha1', 'Gene', (64, 70))
430340	31059559	The mixture file was constructed from the four immune cell lines data, as mentioned in the previous section, and a colon cancer cell line HCT116 (average of GSM269529 and GSM269530 in GSE10650).	('GSM269529', 'Var', (157, 166))	('colon cancer', 'Disease', (115, 127))	('GSM269530', 'Var', (171, 180))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('GSM269530', 'Chemical', '-', (171, 180))	('GSM269529', 'Chemical', '-', (157, 166))	('HCT116', 'CellLine', 'CVCL:0291', (138, 144))	('colon cancer', 'Phenotype', 'HP:0003003', (115, 127))	('colon cancer', 'Disease', 'MESH:D015179', (115, 127))
430344	31059559	Furthermore, as shown in S4 Table, FARDEEP detected gene CD79A and BCL2A1 as outliers for most samples in case (i) of GSE65135.	('CD79A', 'Gene', '973', (57, 62))	('GSE65135', 'Var', (118, 126))	('CD79A', 'Gene', (57, 62))	('BCL2A1', 'Gene', (67, 73))	('BCL2A1', 'Gene', '597', (67, 73))
430348	31059559	We applied CIBERSORT and FARDEEP using signature matrix quanTIseq to peripheral blood mononuclear cell (PBMC) mixtures (GSE64655) generated by Hoek et al., and lymph node bulk samples of 4 melanoma patients from GSE93722.	('patients', 'Species', '9606', (198, 206))	('melanoma', 'Phenotype', 'HP:0002861', (189, 197))	('GSE93722', 'Var', (212, 220))	('melanoma', 'Disease', (189, 197))	('melanoma', 'Disease', 'MESH:D008545', (189, 197))
430412	28807841	Among Asians, variants in genes involved in alcohol metabolism confer increased risk of SCC.	('alcohol', 'Chemical', 'MESH:D000438', (44, 51))	('variants', 'Var', (14, 22))	('SCC', 'Gene', (88, 91))	('risk', 'Reg', (80, 84))	('SCC', 'Gene', '6317', (88, 91))
430415	28807841	A number of genome-wide association studies (GWAS) of esophageal SCC have been performed in Asian populations and identified functional variants in alcohol metabolizing genes, ALDH2 and ADH1B, that, when combined with lifestyle factors, significantly increase risk of SCC.	('ADH1B', 'Gene', (186, 191))	('variants', 'Var', (136, 144))	('SCC', 'Gene', (65, 68))	('alcohol', 'Chemical', 'MESH:D000438', (148, 155))	('ADH1B', 'Gene', '125', (186, 191))	('SCC', 'Gene', (268, 271))	('ALDH2', 'Gene', '217', (176, 181))	('SCC', 'Gene', '6317', (65, 68))	('esophageal SCC', 'Disease', (54, 68))	('SCC', 'Gene', '6317', (268, 271))	('increase', 'PosReg', (251, 259))	('esophageal SCC', 'Disease', 'MESH:D004941', (54, 68))	('ALDH2', 'Gene', (176, 181))
430416	28807841	Moreover, variants in PLCE1 were associated with SCC in 2 GWAS evaluations, and the allele frequencies of these variants are similar across populations, but have not been studied as risk factors in non-Asian populations.	('variants', 'Var', (10, 18))	('SCC', 'Gene', (49, 52))	('PLCE1', 'Gene', (22, 27))	('PLCE1', 'Gene', '51196', (22, 27))	('SCC', 'Gene', '6317', (49, 52))	('associated', 'Reg', (33, 43))
430421	28807841	GWAS for Barrett's esophagus and esophageal adenocarcinoma in individuals of European descent have identified a number of genetic variants in CRTC1, BARX1, FOXP1, GDF7, TBX5 and HLA.	('variants', 'Var', (130, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('TBX5', 'Gene', (169, 173))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (9, 28))	('esophageal adenocarcinoma', 'Disease', (33, 58))	('TBX5', 'Gene', '6910', (169, 173))	('FOXP1', 'Gene', (156, 161))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (33, 58))	('BARX1', 'Gene', (149, 154))	('GDF7', 'Gene', (163, 167))	('CRTC1', 'Gene', (142, 147))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (33, 58))	('GDF7', 'Gene', '151449', (163, 167))	('CRTC1', 'Gene', '23373', (142, 147))	('BARX1', 'Gene', '56033', (149, 154))	('FOXP1', 'Gene', '27086', (156, 161))
430422	28807841	The risk variant in CRTC1 has 30% higher allele frequency in European Americans compared with Blacks; however, the other GWAS variants do not have large allele frequency differences or have higher frequency of the risk allele in Blacks and would not explain differences in risk between populations.	('variant', 'Var', (9, 16))	('CRTC1', 'Gene', (20, 25))	('allele', 'MPA', (41, 47))	('higher', 'PosReg', (34, 40))	('CRTC1', 'Gene', '23373', (20, 25))
430423	28807841	Additional work is needed to understand the contribution of genetic variants in addition to known environmental risk factors for adenocarcinoma in Whites compared with other US populations.	('variants', 'Var', (68, 76))	('adenocarcinoma', 'Disease', (129, 143))	('adenocarcinoma', 'Disease', 'MESH:D000230', (129, 143))	('men', 'Species', '9606', (105, 108))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))
430437	28807841	While many studies have advocated eradication of H. pylori to reduce non-cardia gastric cancer incidence, strong evidence for this approach is still lacking.	('eradication', 'Var', (34, 45))	('non-cardia gastric cancer', 'Disease', 'MESH:D013274', (69, 94))	('H. pylori', 'Gene', (49, 58))	('reduce', 'NegReg', (62, 68))	('gastric cancer', 'Phenotype', 'HP:0012126', (80, 94))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('H. pylori', 'Species', '210', (49, 58))	('non-cardia gastric cancer', 'Disease', (69, 94))
430441	28807841	Among Asians, low penetrance genetic variants in PSCA, PLCE1, PRKAA1 and MUC1 increase risk for gastric cancer and among Europeans, loss of function of ATM increases gastric cancer risk.	('gastric cancer', 'Disease', (166, 180))	('PRKAA1', 'Gene', (62, 68))	('gastric cancer', 'Disease', 'MESH:D013274', (96, 110))	('increase', 'Reg', (78, 86))	('PLCE1', 'Gene', (55, 60))	('ATM', 'Gene', (152, 155))	('PLCE1', 'Gene', '51196', (55, 60))	('gastric cancer', 'Disease', 'MESH:D013274', (166, 180))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('loss', 'Var', (132, 136))	('PSCA', 'Gene', (49, 53))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('PSCA', 'Gene', '8000', (49, 53))	('PRKAA1', 'Gene', '5562', (62, 68))	('gastric cancer', 'Phenotype', 'HP:0012126', (96, 110))	('gastric cancer', 'Phenotype', 'HP:0012126', (166, 180))	('increase risk for gastric cancer', 'Phenotype', 'HP:0006753', (78, 110))	('increases gastric cancer', 'Phenotype', 'HP:0006753', (156, 180))	('MUC1', 'Gene', (73, 77))	('MUC1', 'Gene', '4582', (73, 77))	('ATM', 'Gene', '472', (152, 155))	('increases', 'PosReg', (156, 165))	('variants', 'Var', (37, 45))	('gastric cancer', 'Disease', (96, 110))
430442	28807841	Inactivating mutations in the E-Cadherin gene (CDH1) leads to hereditary diffuse gastric cancer syndrome in a small fraction of individuals.	('CDH1', 'Gene', '999', (47, 51))	('E-Cadherin', 'Gene', (30, 40))	('Inactivating mutations', 'Var', (0, 22))	('hereditary diffuse gastric cancer syndrome', 'Disease', (62, 104))	('E-Cadherin', 'Gene', '999', (30, 40))	('hereditary diffuse gastric cancer syndrome', 'Disease', 'MESH:D013274', (62, 104))	('CDH1', 'Gene', (47, 51))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('leads to', 'Reg', (53, 61))	('gastric cancer', 'Phenotype', 'HP:0012126', (81, 95))
430443	28807841	This same gene is the target of inactivation through methylation in the presence of H. pylori infection.	('H. pylori infection', 'Phenotype', 'HP:0005202', (84, 103))	('infection', 'Disease', (94, 103))	('infection', 'Disease', 'MESH:D007239', (94, 103))	('H. pylori', 'Species', '210', (84, 93))	('H. pylori', 'Disease', (84, 93))	('methylation', 'Var', (53, 64))
430456	28807841	Hereditary syndromes (such as those due to germline mutations in STK11, BRCA1/2, PALB2, CDKN2A, and DNA repair genes) significantly increase pancreatic cancer risk, especially with family history of pancreatic cancer in a first-degree relative.	('pancreatic cancer', 'Disease', (199, 216))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('PALB2', 'Gene', '79728', (81, 86))	('pancreatic cancer', 'Disease', 'MESH:D010190', (141, 158))	('CDKN2A', 'Gene', (88, 94))	('BRCA1/2', 'Gene', (72, 79))	('increase', 'PosReg', (132, 140))	('STK11', 'Gene', (65, 70))	('pancreatic cancer', 'Disease', (141, 158))	('increase pancreatic cancer', 'Phenotype', 'HP:0002894', (132, 158))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (199, 216))	('germline mutations', 'Var', (43, 61))	('CDKN2A', 'Gene', '1029', (88, 94))	('BRCA1/2', 'Gene', '672;675', (72, 79))	('STK11', 'Gene', '6794', (65, 70))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (141, 158))	('pancreatic cancer', 'Disease', 'MESH:D010190', (199, 216))	('PALB2', 'Gene', (81, 86))
430477	28807841	For small bowel neuroendocrine tumors, GWAS evaluations have identified risk variants upstream of ELK3, though the impact of these variants by race is not known.	('variants', 'Var', (77, 85))	('small bowel neuroendocrine tumors', 'Disease', 'MESH:D018358', (4, 37))	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (16, 37))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('small bowel neuroendocrine tumors', 'Disease', (4, 37))	('ELK3', 'Gene', (98, 102))	('ELK3', 'Gene', '2004', (98, 102))
430500	28807841	With Lynch syndrome, the cumulative risk for CRC in Blacks and NHWs with a germline mismatch repair mutation was nearly identical; however, the mutational spectrum of the mismatch repair genes was different, likely reflecting the genetic diversity of the Black population.	('CRC', 'Disease', (45, 48))	('Lynch syndrome', 'Disease', 'MESH:D003123', (5, 19))	('Lynch syndrome', 'Disease', (5, 19))	('mutation', 'Var', (100, 108))
430510	28807841	Black patients display a higher frequency of KRAS mutations in tumors, increasing the aggressiveness of the CRC.	('KRAS', 'Gene', '3845', (45, 49))	('aggressiveness', 'Phenotype', 'HP:0000718', (86, 100))	('increasing', 'PosReg', (71, 81))	('mutations', 'Var', (50, 59))	('aggressiveness', 'Disease', 'MESH:D001523', (86, 100))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('aggressiveness', 'Disease', (86, 100))	('tumors', 'Disease', (63, 69))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('patients', 'Species', '9606', (6, 14))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('KRAS', 'Gene', (45, 49))
430511	28807841	Mutations in the driver genes EPHA6 and FLCN were found exclusively in Black CRCs, suggesting a unique behavior modifying role for these CRCs.	('EPHA6', 'Gene', (30, 35))	('FLCN', 'Gene', '201163', (40, 44))	('EPHA6', 'Gene', '285220', (30, 35))	('Mutations', 'Var', (0, 9))	('FLCN', 'Gene', (40, 44))
430512	28807841	Another study identified novel somatic alterations in well-known CRC genes (APC, BRAF, KRAS, and PIK3CA) among Blacks.	('KRAS', 'Gene', (87, 91))	('PIK3CA', 'Gene', (97, 103))	('KRAS', 'Gene', '3845', (87, 91))	('BRAF', 'Gene', '673', (81, 85))	('BRAF', 'Gene', (81, 85))	('alterations', 'Var', (39, 50))	('CRC genes', 'Gene', (65, 74))	('APC', 'Disease', 'MESH:D011125', (76, 79))	('APC', 'Disease', (76, 79))	('PIK3CA', 'Gene', '5290', (97, 103))
430513	28807841	Microsatellite instability (MSI), a good prognostic biomarker caused by the hypermethylation of the DNA mismatch repair gene MLH1, shows a lower frequency among Blacks, although a meta-analysis did not reach statistical significance to show a difference.	('Microsatellite instability', 'Disease', 'MESH:D053842', (0, 26))	('MSI', 'Disease', 'None', (28, 31))	('hypermethylation', 'Var', (76, 92))	('Microsatellite instability', 'Disease', (0, 26))	('MSI', 'Disease', (28, 31))	('caused by', 'Reg', (62, 71))	('MLH1', 'Gene', '4292', (125, 129))	('MLH1', 'Gene', (125, 129))
430516	28807841	Somatic epigenetic differences have not been adequately studied between races; insulin and TGFbeta pathway genes (GAS7, BMP3, GPR75) were observed epigenetically inactivated among Blacks, but without comparison with their NHW counterparts.	('GAS7', 'Gene', (114, 118))	('GPR75', 'Gene', '10936', (126, 131))	('BMP3', 'Gene', (120, 124))	('epigenetically', 'Var', (147, 161))	('insulin', 'Gene', (79, 86))	('GAS7', 'Gene', '8522', (114, 118))	('insulin', 'Gene', '3630', (79, 86))	('GPR75', 'Gene', (126, 131))	('BMP3', 'Gene', '651', (120, 124))
430543	28807841	Variants for NAFLD risk exist in single nucleotide polymorphisms in or near PNPLA3 and PPP1R3B genes in Hispanic Americans and PNPLA3, NCAN, GCKR, and PPP1R3B genes in Blacks.	('PNPLA3', 'Gene', (76, 82))	('GCKR', 'Gene', (141, 145))	('Variants', 'Var', (0, 8))	('PNPLA3', 'Gene', '80339', (127, 133))	('NCAN', 'Gene', (135, 139))	('PPP1R3B', 'Gene', '79660', (151, 158))	('PNPLA3', 'Gene', '80339', (76, 82))	('NAFLD', 'Gene', (13, 18))	('PPP1R3B', 'Gene', (151, 158))	('GCKR', 'Gene', '2646', (141, 145))	('PPP1R3B', 'Gene', '79660', (87, 94))	('PPP1R3B', 'Gene', (87, 94))	('PNPLA3', 'Gene', (127, 133))	('NCAN', 'Gene', '1463', (135, 139))
430584	28107179	Taken together, our results demonstrate for the first time that nuclear PRMT5 expression is associated with poor clinical outcome in OPSCC patients and IL-6 plays a role in the nuclear translocation of PRMT5.	('IL-6', 'Gene', (152, 156))	('patients', 'Species', '9606', (139, 147))	('IL-6', 'Gene', '3569', (152, 156))	('PRMT5', 'Gene', '10419', (72, 77))	('nuclear', 'Var', (64, 71))	('PRMT5', 'Gene', '10419', (202, 207))	('OPSCC', 'Phenotype', 'HP:0012182', (133, 138))	('associated', 'Reg', (92, 102))	('PRMT5', 'Gene', (202, 207))	('PRMT5', 'Gene', (72, 77))	('OPSCC', 'Disease', (133, 138))
430632	28107179	In addition, amplification of cyclin D1 gene and overexpression of cyclin D1 protein has been reported in HNSCC.	('cyclin D1', 'Gene', '595', (67, 76))	('HNSCC', 'Disease', (106, 111))	('cyclin D1', 'Gene', '595', (30, 39))	('cyclin D1', 'Gene', (67, 76))	('amplification', 'Var', (13, 26))	('cyclin D1', 'Gene', (30, 39))	('overexpression', 'PosReg', (49, 63))	('HNSCC', 'Phenotype', 'HP:0012288', (106, 111))
430642	28107179	Overexpression of IL-6 was significantly associated with worse overall survival of patients with OPSCC (p < 0.001).	('IL-6', 'Gene', '3569', (18, 22))	('overall survival', 'MPA', (63, 79))	('OPSCC', 'Phenotype', 'HP:0012182', (97, 102))	('patients', 'Species', '9606', (83, 91))	('Overexpression', 'Var', (0, 14))	('OPSCC', 'Disease', (97, 102))	('IL-6', 'Gene', (18, 22))	('worse', 'NegReg', (57, 62))
430644	28107179	This poorer prognosis of patients with tumors expressing higher IL-6 was maintained after adjustments for age, T stage, N stage, AJCC stage, gender and smoking status (p < 0.0001; HR 4.089 95% CI: 2.390-6.995).	('higher', 'Var', (57, 63))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('IL-6', 'Gene', (64, 68))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('IL-6', 'Gene', '3569', (64, 68))	('patients', 'Species', '9606', (25, 33))	('tumors', 'Disease', (39, 45))
430648	28107179	Our results from this study show that nuclear localization of PRMT5 was directly associated with poor clinical outcome in OPSCC patients.	('PRMT5', 'Gene', '10419', (62, 67))	('OPSCC', 'Disease', (122, 127))	('nuclear localization', 'Var', (38, 58))	('OPSCC', 'Phenotype', 'HP:0012182', (122, 127))	('patients', 'Species', '9606', (128, 136))	('associated', 'Reg', (81, 91))	('PRMT5', 'Gene', (62, 67))
430659	28107179	In contrast, cytoplasmic PRMT5 expression was recently shown to be directly correlated with poor prognosis in lung adenocarcinoma.	('PRMT5', 'Gene', '10419', (25, 30))	('lung adenocarcinoma', 'Disease', (110, 129))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (110, 129))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('cytoplasmic', 'Var', (13, 24))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (110, 129))	('PRMT5', 'Gene', (25, 30))
430714	25767599	Association between CYP1A1 Ile462Val Polymorphism and Oral Squamous Cell Carcinoma Susceptibility: Evidence from 13 Investigations CYP1A1 Ile462Val polymorphism might play a key role in pathogenesis of oral squamous cell carcinoma (OSCC).	('CYP1A1', 'Gene', '1543', (20, 26))	('CYP1A1', 'Gene', (131, 137))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (59, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (221, 230))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (202, 230))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (207, 230))	('Ile462Val', 'Var', (138, 147))	('CYP1A1', 'Gene', '1543', (131, 137))	('Oral Squamous Cell Carcinoma', 'Disease', 'MESH:D002294', (54, 82))	('oral squamous cell carcinoma', 'Disease', (202, 230))	('Ile462Val', 'Chemical', '-', (138, 147))	('Ile462Val', 'Chemical', '-', (27, 36))	('Carcinoma', 'Phenotype', 'HP:0030731', (73, 82))	('Oral Squamous Cell Carcinoma', 'Disease', (54, 82))	('CYP1A1', 'Gene', (20, 26))
430715	25767599	Many case-control studies have investigated the association between CYP1A1 Ile462Val polymorphism and OSCC susceptibility.	('CYP1A1', 'Gene', '1543', (68, 74))	('Ile462Val', 'Chemical', '-', (75, 84))	('Ile462Val', 'Var', (75, 84))	('OSCC', 'Disease', (102, 106))	('CYP1A1', 'Gene', (68, 74))
430716	25767599	To aim a convincible conclusion, we carried out a meta-analysis to systematically evaluate the association of CYP1A1 Ile462Val polymorphism with OSCC susceptibility.	('association', 'Interaction', (95, 106))	('polymorphism', 'Var', (127, 139))	('CYP1A1', 'Gene', (110, 116))	('OSCC', 'Disease', (145, 149))	('CYP1A1', 'Gene', '1543', (110, 116))	('Ile462Val polymorphism', 'Var', (117, 139))	('Ile462Val', 'Chemical', '-', (117, 126))
430717	25767599	Our results suggest that the homozygous variant of CYP1A1 Ile462Val might be a risk factor of OSCC.	('OSCC', 'Disease', (94, 98))	('CYP1A1', 'Gene', (51, 57))	('Ile462Val', 'Var', (58, 67))	('homozygous', 'Var', (29, 39))	('Ile462Val', 'Chemical', '-', (58, 67))	('CYP1A1', 'Gene', '1543', (51, 57))	('risk', 'Reg', (79, 83))
430724	25767599	Currently, the published evidences showed that there were significant associations of gene polymorphisms with the susceptibility of many cancers, such as Glutathione S-transferase (GSTs) and Cytochrome P4501 A1 (CYP1A1) gene polymorphisms with lung of squamous cell carcinoma, polymorphism of 8q24 rsl3281615 with risk of breast cancer, CYP1A1 and GSTs gene polymorphisms with head and neck cancer.	('lung of squamous cell carcinoma', 'Disease', 'MESH:D002294', (244, 275))	('cancer', 'Phenotype', 'HP:0002664', (329, 335))	('GSTs', 'Gene', (348, 352))	('cancers', 'Phenotype', 'HP:0002664', (137, 144))	('Glutathione S-transferase', 'Gene', (154, 179))	('cancers', 'Disease', (137, 144))	('Cytochrome P4501 A1', 'Gene', (191, 210))	('head and neck cancer', 'Phenotype', 'HP:0012288', (377, 397))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('cancer', 'Phenotype', 'HP:0002664', (391, 397))	('breast cancer', 'Phenotype', 'HP:0003002', (322, 335))	('neck cancer', 'Disease', 'MESH:D006258', (386, 397))	('neck cancer', 'Disease', (386, 397))	('GSTs', 'Gene', '373156', (181, 185))	('Glutathione S-transferase', 'Gene', '373156', (154, 179))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (252, 275))	('CYP1A1', 'Gene', (212, 218))	('breast cancer', 'Disease', 'MESH:D001943', (322, 335))	('CYP1A1', 'Gene', (337, 343))	('GSTs', 'Gene', '373156', (348, 352))	('breast cancer', 'Disease', (322, 335))	('cancers', 'Disease', 'MESH:D009369', (137, 144))	('Cytochrome P4501 A1', 'Gene', '1543', (191, 210))	('8q24', 'Gene', (293, 297))	('CYP1A1', 'Gene', '1543', (212, 218))	('polymorphism', 'Var', (277, 289))	('CYP1A1', 'Gene', '1543', (337, 343))	('associations', 'Interaction', (70, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (266, 275))	('lung of squamous cell carcinoma', 'Disease', (244, 275))	('GSTs', 'Gene', (181, 185))	('polymorphisms', 'Var', (225, 238))
430725	25767599	However, the associations of CYP1A1 Ile462Val variant with OSCC risks are inconsistent.	('Ile462Val', 'Chemical', '-', (36, 45))	('CYP1A1', 'Gene', (29, 35))	('CYP1A1', 'Gene', '1543', (29, 35))	('OSCC', 'Disease', (59, 63))	('Ile462Val', 'Var', (36, 45))
430730	25767599	The CYP1A1*2C or CYP1A1 exon7 or Ile462Val is one of the most common polymorphisms, which is a transition from valine to isoleucine at codon 462 in the exon7 region resulting in the introduction of an BsrDI restriction site and associating with increase in enzyme activity and hence affecting the risks of carcinoma.	('CYP1A1', 'Gene', (4, 10))	('introduction', 'PosReg', (182, 194))	('affecting', 'Reg', (283, 292))	('carcinoma', 'Disease', 'MESH:D002277', (306, 315))	('valine to isoleucine at codon 462', 'Mutation', 'rs1048943', (111, 144))	('CYP1A1', 'Gene', '1543', (17, 23))	('carcinoma', 'Phenotype', 'HP:0030731', (306, 315))	('CYP1A1', 'Gene', '1543', (4, 10))	('increase', 'PosReg', (245, 253))	('carcinoma', 'Disease', (306, 315))	('Ile462Val', 'Var', (33, 42))	('CYP1A1', 'Gene', (17, 23))	('Ile462Val', 'Chemical', '-', (33, 42))	('enzyme activity', 'MPA', (257, 272))	('BsrDI restriction site', 'MPA', (201, 223))
430732	25767599	Considering the significance of CYP1A1 Ile462Val polymorphism in the occurrence and development of malignancies including OSCC, we systematically evaluated the association between CYP1A1 Ile462Val polymorphism and OSCC susceptibility through a meta-analysis.	('CYP1A1', 'Gene', (180, 186))	('Ile462Val', 'Chemical', '-', (39, 48))	('malignancies', 'Disease', (99, 111))	('CYP1A1', 'Gene', '1543', (180, 186))	('OSCC', 'Disease', (214, 218))	('CYP1A1', 'Gene', (32, 38))	('association', 'Interaction', (160, 171))	('Ile462Val', 'Var', (187, 196))	('CYP1A1', 'Gene', '1543', (32, 38))	('Ile462Val', 'Chemical', '-', (187, 196))	('malignancies', 'Disease', 'MESH:D009369', (99, 111))
430733	25767599	The search process was designed to find primarily all relevant articles and the search strategies were listed as follows: (1) Cytochrome P450 1A1 or P450 1A1 or CYP1A1 or CYP1A1*2C or exon7 or Ile462Val; and (2) genotype or polymorphism or allele or variant; and (3) oral squamous cell carcinoma or OSCC or mouth neoplasm or oral cancer or oral carcinoma or oral tumor.	('oral carcinoma', 'Disease', 'MESH:D020820', (340, 354))	('tumor', 'Phenotype', 'HP:0002664', (363, 368))	('Ile462Val', 'Var', (193, 202))	('oral tumor', 'Phenotype', 'HP:0100649', (358, 368))	('carcinoma', 'Phenotype', 'HP:0030731', (286, 295))	('CYP1A1', 'Gene', '1543', (161, 167))	('oral tumor', 'Disease', 'MESH:D020820', (358, 368))	('neoplasm', 'Phenotype', 'HP:0002664', (313, 321))	('CYP1A1', 'Gene', (171, 177))	('mouth neoplasm', 'Phenotype', 'HP:0012290', (307, 321))	('oral tumor', 'Disease', (358, 368))	('squamous cell carcinoma or OSCC or mouth neoplasm or oral cancer', 'Disease', 'MESH:D002294', (272, 336))	('oral carcinoma', 'Disease', (340, 354))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (272, 295))	('Ile462Val', 'Chemical', '-', (193, 202))	('CYP1A1', 'Gene', '1543', (171, 177))	('Cytochrome P450 1A1', 'Gene', (126, 145))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (267, 295))	('Cytochrome P450 1A1', 'Gene', '1543', (126, 145))	('variant', 'Var', (250, 257))	('cancer', 'Phenotype', 'HP:0002664', (330, 336))	('carcinoma', 'Phenotype', 'HP:0030731', (345, 354))	('oral squamous cell carcinoma', 'Disease', (267, 295))	('CYP1A1', 'Gene', (161, 167))
430736	25767599	The odds ratios (ORs) with corresponding 95% confidence intervals (CIs) were used to estimate the association between CYP1A1 Ile462Val polymorphism and OSCC risk.	('association', 'Interaction', (98, 109))	('OSCC', 'Disease', (152, 156))	('CYP1A1', 'Gene', (118, 124))	('CYP1A1', 'Gene', '1543', (118, 124))	('polymorphism', 'Var', (135, 147))	('Ile462Val', 'Chemical', '-', (125, 134))	('Ile462Val polymorphism', 'Var', (125, 147))
430739	25767599	Of which, 290 studies were excluded as being irrelevant to CYP1A1 Ile462Val or OSCC or genetic polymorphism or not human studies.	('Ile462Val', 'Var', (66, 75))	('CYP1A1', 'Gene', (59, 65))	('CYP1A1', 'Gene', '1543', (59, 65))	('human', 'Species', '9606', (115, 120))	('Ile462Val', 'Chemical', '-', (66, 75))
430742	25767599	Finally, 13 papers were conformed to the inclusion criteria and they were eligible for the meta-analysis of CYP1A1 Ile462Val polymorphism.	('CYP1A1', 'Gene', (108, 114))	('CYP1A1', 'Gene', '1543', (108, 114))	('polymorphism', 'Var', (125, 137))	('Ile462Val polymorphism', 'Var', (115, 137))	('Ile462Val', 'Chemical', '-', (115, 124))
430743	25767599	The frequency of the CYP1A1 Ile462Val homozygous variant allele (Val/Val) in cases group varied from 0-13.4%, and the controls group were present in 0-6.2%.	('Val', 'Chemical', 'MESH:D014633', (34, 37))	('Ile462Val', 'Var', (28, 37))	('Val', 'Chemical', 'MESH:D014633', (65, 68))	('CYP1A1', 'Gene', '1543', (21, 27))	('Val', 'Chemical', 'MESH:D014633', (69, 72))	('Ile462Val', 'Chemical', '-', (28, 37))	('CYP1A1', 'Gene', (21, 27))
430745	25767599	The overall results in recessive model suggested that individuals carrying homozygous variant (Val/Val) might have an increased risk of OSCC when compared with those who carried the homozygous Ile allele (OR=1.64, 95% CI=1.08-2.49).	('Val', 'Chemical', 'MESH:D014633', (95, 98))	('OSCC', 'Disease', (136, 140))	('variant', 'Var', (86, 93))	('Val', 'Chemical', 'MESH:D014633', (99, 102))
430746	25767599	However, results in dominant model, homozygous model failed to obvious association of CYP1A1 Ile462Val with risks of OSCC.	('OSCC', 'Disease', (117, 121))	('CYP1A1', 'Gene', (86, 92))	('Ile462Val', 'Var', (93, 102))	('CYP1A1', 'Gene', '1543', (86, 92))	('Ile462Val', 'Chemical', '-', (93, 102))
430747	25767599	Thirteen trials (3651 subjects) were used to investigate the association between CYP1A1 Ile462Val polymorphism and OSCC risk.	('OSCC', 'Disease', (115, 119))	('CYP1A1', 'Gene', (81, 87))	('CYP1A1', 'Gene', '1543', (81, 87))	('Ile462Val polymorphism', 'Var', (88, 110))	('Ile462Val', 'Chemical', '-', (88, 97))	('association', 'Interaction', (61, 72))
430751	25767599	Different histopathologic types of cancers might have different genetic susceptibilities, for example, CYP1A1 Ile462Val polymorphism is a risk factor of squamous cell carcinoma of lung, but the associations vary in different histological types of lung cancer.	('risk factor', 'Reg', (138, 149))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('carcinoma', 'Phenotype', 'HP:0030731', (167, 176))	('lung cancer', 'Disease', 'MESH:D008175', (247, 258))	('Ile462Val', 'Chemical', '-', (110, 119))	('CYP1A1', 'Gene', (103, 109))	('CYP1A1', 'Gene', '1543', (103, 109))	('lung cancer', 'Phenotype', 'HP:0100526', (247, 258))	('squamous cell carcinoma of lung', 'Phenotype', 'HP:0030359', (153, 184))	('Ile462Val polymorphism', 'Var', (110, 132))	('cancers', 'Disease', 'MESH:D009369', (35, 42))	('squamous cell carcinoma of lung', 'Disease', (153, 184))	('carcinoma of lung', 'Phenotype', 'HP:0100526', (167, 184))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('polymorphism', 'Var', (120, 132))	('lung cancer', 'Disease', (247, 258))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (153, 176))	('squamous cell carcinoma of lung', 'Disease', 'MESH:D002294', (153, 184))	('cancers', 'Phenotype', 'HP:0002664', (35, 42))	('cancers', 'Disease', (35, 42))
430753	25767599	To our knowledge, this is the first meta-analysis to assess the association between CYP1A1 Ile462Val polymorphism and OSCC risk.	('Ile462Val polymorphism', 'Var', (91, 113))	('Ile462Val', 'Chemical', '-', (91, 100))	('OSCC', 'Disease', (118, 122))	('CYP1A1', 'Gene', (84, 90))	('polymorphism', 'Var', (101, 113))	('CYP1A1', 'Gene', '1543', (84, 90))	('association', 'Interaction', (64, 75))
430754	25767599	Although there were two previous meta-analyses concerning of CYP1A1 Ile462Val polymorphism and risks of oral cancer, the results did not involve in single histopathologic type and therefore they failed to be on behalf of the association of CYP1A1 Ile462Val polymorphism with OSCC risk.	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('Ile462Val', 'Var', (247, 256))	('CYP1A1', 'Gene', '1543', (240, 246))	('Ile462Val', 'Chemical', '-', (68, 77))	('Ile462Val', 'Chemical', '-', (247, 256))	('oral cancer', 'Disease', 'MESH:D009062', (104, 115))	('CYP1A1', 'Gene', (61, 67))	('oral cancer', 'Disease', (104, 115))	('association', 'Interaction', (225, 236))	('OSCC', 'Disease', (275, 279))	('CYP1A1', 'Gene', '1543', (61, 67))	('CYP1A1', 'Gene', (240, 246))
430755	25767599	found no association between CYP1A1 Ile462Val polymorphism and oral cancer risk.	('Ile462Val', 'Chemical', '-', (36, 45))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('CYP1A1', 'Gene', (29, 35))	('oral cancer', 'Disease', 'MESH:D009062', (63, 74))	('CYP1A1', 'Gene', '1543', (29, 35))	('oral cancer', 'Disease', (63, 74))	('Ile462Val polymorphism', 'Var', (36, 58))
430757	25767599	Thus, the results might fail to be on behalf of the association of OSCC and CYP1A1 Ile462Val polymorphism.	('CYP1A1', 'Gene', (76, 82))	('Ile462Val', 'Var', (83, 92))	('CYP1A1', 'Gene', '1543', (76, 82))	('Ile462Val', 'Chemical', '-', (83, 92))	('OSCC', 'Disease', (67, 71))
430758	25767599	Based on what mentioned above and for obtaining a powerful conclusion concerning about risks of OSCC and CYP1A1 Ile462Val polymorphism, we performed this systematical meta-analysis to evaluate it.	('Ile462Val', 'Chemical', '-', (112, 121))	('CYP1A1', 'Gene', (105, 111))	('CYP1A1', 'Gene', '1543', (105, 111))	('OSCC', 'Disease', (96, 100))	('Ile462Val polymorphism', 'Var', (112, 134))
430761	25767599	As for the other three models (homozygous model, dominant model and allele comparing model), they failed to show obvious association between CYP1A1 Ile462Val polymorphism and OSCC risk, and the heterogeneities among studies were observed in them, respectively.	('polymorphism', 'Var', (158, 170))	('CYP1A1', 'Gene', (141, 147))	('CYP1A1', 'Gene', '1543', (141, 147))	('OSCC', 'Disease', (175, 179))	('Ile462Val', 'Chemical', '-', (148, 157))	('Ile462Val polymorphism', 'Var', (148, 170))
430764	25767599	And future studies focusing on CYP1A1 Ile462Val polymorphism containing large sample sizes and well-designed criteria are necessary to make the conclusions more credible.	('Ile462Val', 'Chemical', '-', (38, 47))	('CYP1A1', 'Gene', '1543', (31, 37))	('CYP1A1', 'Gene', (31, 37))	('Ile462Val polymorphism', 'Var', (38, 60))
430765	25767599	OSCC oral squamous cell carcinomas HGP human genome project SNP single nucleotide polymorphisms GST Glutathione S-transferase CYP1A1 Cytochrome P4501 A1 AHH aryl hydrocarbon hydrolase PAH polycyclic aromatic hydrocarbon HWE Hardy-Weinberg Equilibrium NOS Newcastle-Ottawa Scale OR odds ratio CI confidence interval TSA trial sequential analysis.	('Cytochrome P4501 A1', 'Gene', '1543', (133, 152))	('oral squamous cell carcinomas', 'Disease', 'MESH:D002294', (5, 34))	('PAH', 'Chemical', 'MESH:D011084', (184, 187))	('CYP1A1', 'Gene', (126, 132))	('carcinoma', 'Phenotype', 'HP:0030731', (24, 33))	('aryl hydrocarbon hydrolase', 'Gene', '1543', (157, 183))	('carcinomas', 'Phenotype', 'HP:0030731', (24, 34))	('AHH', 'Gene', (153, 156))	('AHH', 'Gene', '1543', (153, 156))	('oral squamous cell carcinomas', 'Disease', (5, 34))	('aryl hydrocarbon hydrolase', 'Gene', (157, 183))	('human', 'Species', '9606', (39, 44))	('CYP1A1', 'Gene', '1543', (126, 132))	('Cytochrome P4501 A1', 'Gene', (133, 152))	('polycyclic aromatic hydrocarbon', 'Chemical', 'MESH:D011084', (188, 219))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (10, 34))	('Glutathione S-transferase', 'Gene', (100, 125))	('single nucleotide polymorphisms', 'Var', (64, 95))	('TSA', 'Chemical', '-', (315, 318))	('Glutathione S-transferase', 'Gene', '373156', (100, 125))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (10, 33))
430780	27600345	These studies have used a variety of genomic, transcriptomic and proteomic methods and have identified, copy number variation, mutation and DNA methylation as well as changes in gene expression as differentiating between healthy lung tissue and tumors.	('tumors', 'Phenotype', 'HP:0002664', (245, 251))	('gene expression', 'MPA', (178, 193))	('mutation', 'Var', (127, 135))	('changes', 'Reg', (167, 174))	('tumors', 'Disease', 'MESH:D009369', (245, 251))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('copy number variation', 'Var', (104, 125))	('tumors', 'Disease', (245, 251))
430794	27600345	The overlapping pathways between the E-GEOD-18842 and E-GEOD-19188 contain many of the usual suspects, such as the control of mitosis and control of the cell cycle including checkpoints.	('E-GEOD-18842', 'Var', (37, 49))	('mitosis', 'Disease', (126, 133))	('mitosis', 'Disease', 'None', (126, 133))	('E-GEOD-19188', 'Var', (54, 66))
430799	27600345	Three datasets have a comparison between normal lung tissue and adenocarcinoma: E-GEOD-6044, E-GEOD-40725 and E-GEOD-43458.	('adenocarcinoma', 'Disease', (64, 78))	('E-GEOD-43458', 'Var', (110, 122))	('adenocarcinoma', 'Disease', 'MESH:D000230', (64, 78))	('E-GEOD-6044', 'Var', (80, 91))	('E-GEOD-40725', 'Var', (93, 105))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))
430807	27600345	These include a number of cancer specific pathways involving mutants and also a group of pathways involved in mRNA regulation and processing (Figure 5).	('cancer', 'Disease', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('mutants', 'Var', (61, 68))
430813	27600345	Two datasets are available to compare the transcriptomes of normal lung tissue and squamous cell carcinoma, E-GEOD-6044 and E-GEOD-40275.	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (83, 106))	('squamous cell carcinoma', 'Disease', (83, 106))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (83, 106))	('E-GEOD-40275', 'Var', (124, 136))	('E-GEOD-6044', 'Var', (108, 119))
430814	27600345	The E-GEOD-6044 data shows a similar profile to the normal-adenocarcinoma pathway profile for E-GEOD-40275 including the TCF dependent signaling in response to Wnt (Supplementary Figures S2-S4).	('TCF', 'Gene', (121, 124))	('response to Wnt', 'MPA', (148, 163))	('TCF', 'Gene', '3172', (121, 124))	('adenocarcinoma', 'Disease', (59, 73))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))	('adenocarcinoma', 'Disease', 'MESH:D000230', (59, 73))	('E-GEOD-40275', 'Var', (94, 106))
430820	27600345	There are three datasets that allow direct comparison between the transcriptomes of the two NSCLC sub-types, E-GEOD-6044, E-GEOD-40275 and E-GEOD-50081 (this dataset was specifically created to compare gene expression between cancer sub-types).	('E-GEOD-6044', 'Var', (109, 120))	('E-GEOD-40275', 'Var', (122, 134))	('NSCLC', 'Phenotype', 'HP:0030358', (92, 97))	('cancer', 'Disease', (226, 232))	('cancer', 'Disease', 'MESH:D009369', (226, 232))	('E-GEOD-50081', 'Var', (139, 151))	('NSCLC', 'Disease', (92, 97))	('NSCLC', 'Disease', 'MESH:D002289', (92, 97))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
430873	33614703	In terms of the described effects of CKAP4 on the architecture of the ER and microtubule networks, there are predicted phosphorylation sites of serine 3, 17, and 19 on CKAP4 (Figure 1), which have shown negatively regulated microtubule and induced collapse of the ER around the nucleus.	('ER', 'Gene', '2069', (264, 266))	('serine', 'Chemical', 'MESH:D012694', (144, 150))	('CKAP4', 'Var', (168, 173))	('collapse', 'MPA', (248, 256))	('regulated microtubule', 'MPA', (214, 235))	('ER', 'Gene', '2069', (70, 72))	('negatively', 'NegReg', (203, 213))
430879	33614703	Palmitoyl acyltransferase DHHC2, which is a putative tumor suppressor, modifies Cys100 of CKAP4 and contributes to the localization of CKAP4 on the plasma membrane.	('Cys100', 'Chemical', '-', (80, 86))	('DHHC2', 'Gene', (26, 31))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('localization', 'MPA', (119, 131))	('modifies', 'Var', (71, 79))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('contributes', 'Reg', (100, 111))	('tumor', 'Disease', (53, 58))	('Cys100', 'MPA', (80, 86))	('DHHC2', 'Gene', '51201', (26, 31))	('CKAP4', 'Gene', (90, 95))
430880	33614703	In the extracellular region, CKAP4 contains three coiled-coil regions, two shorter regions (AA 130-214 and AA 533-602) and one longer one (AA 256-460), and a leucine zipper (LZ) domain (AA 468-503) (Figure 1).	('leucine', 'Chemical', 'MESH:D007930', (158, 165))	('CKAP4', 'Gene', (29, 34))	('AA 533-602', 'Var', (107, 117))	('coiled-coil regions', 'MPA', (50, 69))	('AA 130-214', 'Var', (92, 102))
430895	33614703	Transfection of the mutant's COS-1 cells led to an increase in tPA-catalyzed plasminogen activation, which confirmed the role of cell surface CKAP4 in tPA binding.	('increase', 'PosReg', (51, 59))	('tPA', 'Gene', (63, 66))	('tPA', 'Gene', '100128998', (63, 66))	('tPA', 'Gene', (151, 154))	('tPA', 'Gene', '100128998', (151, 154))	('mutant', 'Var', (20, 26))	('COS-1', 'CellLine', 'CVCL:0223', (29, 34))
430921	33614703	CKAP4 knockdown or CRD-1 deletion mutants of DKKs inhibited MDCK cellular proliferation (14).	('MDCK cellular proliferation', 'CPA', (60, 87))	('MDCK', 'CellLine', 'CVCL:0422', (60, 64))	('inhibited', 'NegReg', (50, 59))	('deletion mutants', 'Var', (25, 41))	('CRD-1', 'Gene', '1319', (19, 24))	('CRD-1', 'Gene', (19, 24))	('DKK', 'Gene', '22943', (45, 48))	('DKK', 'Gene', (45, 48))
430928	33614703	Following CKAP4 knockdown, the inhibition effect of APF on T24 cell proliferation was eliminated, indicating the important role of the receptor in mediating the antiproliferation activity of APF in bladder cancer cells.	('APF', 'Chemical', '-', (191, 194))	('bladder cancer', 'Disease', 'MESH:D001749', (198, 212))	('T24 cell proliferation', 'CPA', (59, 81))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('bladder cancer', 'Disease', (198, 212))	('knockdown', 'Var', (16, 25))	('eliminated', 'NegReg', (86, 96))	('CKAP4', 'Gene', (10, 15))	('bladder cancer', 'Phenotype', 'HP:0009725', (198, 212))	('APF', 'Chemical', '-', (52, 55))
430932	33614703	When CKAP4 was reduced with siRNA or anti-CKAP4 antibody, the upregulation of CCN2 during APF treatment was inhibited.	('CCN2', 'Gene', '1490', (78, 82))	('anti-CKAP4', 'Gene', (37, 47))	('reduced', 'NegReg', (15, 22))	('APF', 'Chemical', '-', (90, 93))	('anti-CKAP4 antibody', 'Var', (37, 56))	('CCN2', 'Gene', (78, 82))	('inhibited', 'NegReg', (108, 117))
430938	33614703	Further research demonstrated that CKAP4 phosphorylation of N-terminal serine residues (S3, S17, and S19) is necessary for translocation from the plasma membrane to the nucleus in Hela cell (Figure 2).	('S19', 'Var', (101, 104))	('translocation', 'MPA', (123, 136))	('S17', 'Gene', '6218', (92, 95))	('S3', 'Var', (88, 90))	('Hela cell', 'CellLine', 'CVCL:0030', (180, 189))	('serine', 'Chemical', 'MESH:D012694', (71, 77))	('S17', 'Gene', (92, 95))
430940	33614703	CKAP4 of palmitoylation site mutant (C100S) or phosphorylation site mutant does not cause relocalization and has APF-like activity inhibiting cell proliferation.	('APF', 'Chemical', '-', (113, 116))	('APF-like activity', 'MPA', (113, 130))	('cell proliferation', 'CPA', (142, 160))	('inhibiting', 'NegReg', (131, 141))	('C100S', 'Mutation', 'p.C100S', (37, 42))	('C100S', 'Var', (37, 42))
430941	33614703	It suggests that the mutation of CKAP4 could be used to treat excessive proliferation diseases such as tumor.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('CKAP4', 'Gene', (33, 38))	('proliferation diseases', 'Disease', (72, 94))	('tumor', 'Disease', (103, 108))	('proliferation diseases', 'Disease', 'MESH:C565054', (72, 94))	('mutation', 'Var', (21, 29))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
430943	33614703	Moreover, high expression of CKAP4 inhibited the growth of xenograft tumor and the metastatic potential of HCC in nude mice.	('HCC', 'Phenotype', 'HP:0001402', (107, 110))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('CKAP4', 'Gene', (29, 34))	('tumor', 'Disease', (69, 74))	('nude mice', 'Species', '10090', (114, 123))	('metastatic potential of HCC', 'CPA', (83, 110))	('high expression', 'Var', (10, 25))	('inhibited', 'NegReg', (35, 44))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
430952	33614703	Furthermore, in vivo experiments also showed that the low CKAP4 expression cells formed much smaller xenograft tumors than the control group.	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('low', 'Var', (54, 57))	('tumors', 'Disease', 'MESH:D009369', (111, 117))	('tumors', 'Disease', (111, 117))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('smaller', 'NegReg', (93, 100))	('CKAP4', 'Gene', (58, 63))
430954	33614703	It is worth noting that knockdown of CKAP4 did not influence cell proliferation in cells with insufficient DKK1 and/or DKK3.	('CKAP4', 'Gene', (37, 42))	('DKK1', 'Var', (107, 111))	('DKK3', 'Gene', '27122', (119, 123))	('knockdown', 'Var', (24, 33))	('DKK3', 'Gene', (119, 123))	('cell proliferation', 'CPA', (61, 79))
430962	33614703	It was noted that CKAP4 was not directly involved in alpha5beta1 integrin endocytosis but inhibited its recycling.	('beta1 integrin', 'Gene', '3688', (59, 73))	('beta1 integrin', 'Gene', (59, 73))	('CKAP4', 'Var', (18, 23))	('inhibited', 'NegReg', (90, 99))	('recycling', 'MPA', (104, 113))
430978	33614703	Prognosis was favorable in patients with high CKAP4 or high DHHC2 expression compared with those with low CKAP4 or low DHHC2 expression.	('DHHC2', 'Gene', '51201', (119, 124))	('DHHC2', 'Gene', (60, 65))	('high CKAP4', 'Var', (41, 51))	('DHHC2', 'Gene', (119, 124))	('expression', 'MPA', (66, 76))	('patients', 'Species', '9606', (27, 35))	('high', 'Var', (55, 59))	('DHHC2', 'Gene', '51201', (60, 65))
430983	33614703	Prognostic values of CKAP4 expression showed that the high-CKAP4 patients had a much longer overall survival and lower recurrence rate than the low-CKAP4 patients, and CKAP4 is an independent predictor for overall survival in ICC patients.	('longer', 'PosReg', (85, 91))	('lower', 'NegReg', (113, 118))	('recurrence rate', 'CPA', (119, 134))	('patients', 'Species', '9606', (154, 162))	('patients', 'Species', '9606', (230, 238))	('IC', 'Disease', 'MESH:C566126', (226, 228))	('patients', 'Species', '9606', (65, 73))	('overall survival', 'CPA', (92, 108))	('high-CKAP4', 'Var', (54, 64))
430988	33614703	The positive rates of CKAP4 and DKK1in lung adenocarcinoma were 74.6 and 79.1%, respectively, and in squamous cell carcinoma were 74.6 and 73.8%, respectively (Table 2).	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('CKAP4', 'Var', (22, 27))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (39, 58))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (101, 124))	('DKK1in', 'Var', (32, 38))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (101, 124))	('squamous cell carcinoma', 'Disease', (101, 124))	('lung adenocarcinoma', 'Disease', (39, 58))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (39, 58))
430989	33614703	Patients positive for both CKAP4 and DKK1 showed a more shorter relapse-free survival than patients positive for either CKAP4 or DKK1 or negative for both (Table 2).	('DKK1', 'Var', (37, 41))	('patients', 'Species', '9606', (91, 99))	('relapse-free survival', 'CPA', (64, 85))	('CKAP4', 'Var', (27, 32))	('shorter', 'NegReg', (56, 63))	('Patients', 'Species', '9606', (0, 8))
430994	33614703	analyzed 119 cases and 72 cases of esophageal squamous cell carcinoma (ESCC) and showed that expression of CKAP4, along with DKK1 and/or DKK3, in ESCC was associated with poor prognosis (Table 2).	('DKK3', 'Gene', (137, 141))	('expression', 'Var', (93, 103))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (35, 69))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (46, 69))	('associated', 'Reg', (155, 165))	('esophageal squamous cell carcinoma', 'Disease', (35, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (60, 69))	('CKAP4', 'Gene', (107, 112))	('DKK3', 'Gene', '27122', (137, 141))
431001	33614703	Patients positive for both CKAP4 and ligands (DKK1 and/or DKK3) showed unfavorable prognosis and shortened relapse-free survival than do patients positive for either CKAP4 or DKK1/DKK3 or negative for CKAP4 and DKK1/DKK3 (Table 2).	('relapse-free survival', 'CPA', (107, 128))	('DKK3', 'Gene', (216, 220))	('DKK3', 'Gene', '27122', (58, 62))	('DKK3', 'Gene', (58, 62))	('CKAP4', 'Var', (27, 32))	('patients', 'Species', '9606', (137, 145))	('Patients', 'Species', '9606', (0, 8))	('shortened', 'NegReg', (97, 106))	('DKK3', 'Gene', '27122', (180, 184))	('DKK3', 'Gene', (180, 184))	('DKK3', 'Gene', '27122', (216, 220))	('DKK1', 'Var', (46, 50))
431008	33614703	In the cells with high CKAP4 but with little ligands, DKKs, CKAP4 did not affect cellular proliferation.	('DKK', 'Gene', '22943', (54, 57))	('DKK', 'Gene', (54, 57))	('high CKAP4', 'Var', (18, 28))	('CKAP4', 'Var', (23, 28))
431009	33614703	On the other hand, patients positive for both CKAP4 and DKKs show unfavorable prognosis and shorter relapse-free survival in pancreatic, lung, and esophageal tumors.	('DKK', 'Gene', '22943', (56, 59))	('tumors', 'Phenotype', 'HP:0002664', (158, 164))	('pancreatic', 'Disease', (125, 135))	('relapse-free survival', 'CPA', (100, 121))	('patients', 'Species', '9606', (19, 27))	('esophageal tumors', 'Disease', 'MESH:D004938', (147, 164))	('DKK', 'Gene', (56, 59))	('esophageal tumors', 'Disease', (147, 164))	('esophageal tumors', 'Phenotype', 'HP:0100751', (147, 164))	('CKAP4', 'Var', (46, 51))	('pancreatic', 'Disease', 'MESH:D010195', (125, 135))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('shorter', 'NegReg', (92, 99))	('lung', 'Disease', (137, 141))
431010	33614703	However, high expression of CKAP4 showed a favorable overall survival and longer disease-free survival in HCC and ICC.	('high expression', 'Var', (9, 24))	('HCC', 'Disease', (106, 109))	('CKAP4', 'Gene', (28, 33))	('HCC', 'Phenotype', 'HP:0001402', (106, 109))	('IC', 'Disease', 'MESH:C566126', (114, 116))
431013	33614703	Palmitoylated CKAP4 translocates to the nucleus and then binds to CCN2 gene, which inhibits cell proliferation, adhesion, migration, differentiation, and survival.	('inhibits', 'NegReg', (83, 91))	('survival', 'CPA', (154, 162))	('CCN2', 'Gene', (66, 70))	('Palmitoylated', 'Var', (0, 13))	('differentiation', 'CPA', (133, 148))	('adhesion', 'CPA', (112, 120))	('migration', 'CPA', (122, 131))	('cell proliferation', 'CPA', (92, 110))	('CCN2', 'Gene', '1490', (66, 70))	('binds', 'Interaction', (57, 62))
431029	33614703	The results showed that the sensitivity of the serum CKAP4 is 70% and the specificity is 67.5%, and detection of serum CKAP4 increased the diagnostic efficacy especially in HCC patients with low or negative alpha-fetoprotein (AFP).	('low', 'NegReg', (191, 194))	('HCC', 'Disease', (173, 176))	('serum CKAP4', 'Var', (113, 124))	('increased', 'PosReg', (125, 134))	('HCC', 'Phenotype', 'HP:0001402', (173, 176))	('patients', 'Species', '9606', (177, 185))	('alpha-fetoprotein', 'Gene', '174', (207, 224))	('AFP', 'Gene', (226, 229))	('AFP', 'Gene', '174', (226, 229))	('alpha-fetoprotein', 'Gene', (207, 224))	('negative', 'NegReg', (198, 206))
431031	33614703	The sensitivity and specificity for HCC diagnosis of CKAP4 alone had no advantage compared with AFP, but combined CKAP4 and AFP showed a better diagnostic accuracy (sensitivity = 0.8, specificity = 0.963), even in early HCC (sensitivity = 0.762, specificity = 0.963), which was similar to our results (Table 3).	('AFP', 'Gene', '174', (124, 127))	('AFP', 'Gene', '174', (96, 99))	('HCC', 'Phenotype', 'HP:0001402', (36, 39))	('AFP', 'Gene', (96, 99))	('CKAP4', 'Var', (114, 119))	('HCC', 'Phenotype', 'HP:0001402', (220, 223))	('AFP', 'Gene', (124, 127))	('early HCC', 'Disease', (214, 223))
431050	33614703	Furthermore, an anti-CKAP4 polyclonal antibody (pAb) can significantly reduce xenograft tumor volume and weight caused by these cancer cell lines, suggesting that CAKP4 represents a novel molecular target for cancer therapy.	('anti-CKAP4', 'Var', (16, 26))	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('reduce', 'NegReg', (71, 77))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('cancer', 'Disease', 'MESH:D009369', (209, 215))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('cancer', 'Disease', (209, 215))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('anti-CKAP4', 'Gene', (16, 26))	('tumor', 'Disease', (88, 93))	('cancer', 'Disease', (128, 134))
431063	33614703	Mechanistically, TGF-beta was revealed to induce CKAP4 expression, and inhibition of CKAP4 increased the expression of markers for activated fibroblasts under TGF-beta treatment.	('TGF-beta', 'Gene', (17, 25))	('CKAP4', 'Gene', (49, 54))	('inhibition', 'Var', (71, 81))	('TGF-beta', 'Gene', (159, 167))	('TGF-beta', 'Gene', '7039', (17, 25))	('induce', 'PosReg', (42, 48))	('expression', 'MPA', (55, 65))	('CKAP4', 'Gene', (85, 90))	('TGF-beta', 'Gene', '7039', (159, 167))	('increased', 'PosReg', (91, 100))	('expression of', 'MPA', (105, 118))
431065	33614703	Another research showed that it is possible to establish a noninvasion diagnostic method for IC/PBS because the special domains of CKAP4 (AA127-360, AA361-524) could enhance the binding activity to APF, increasing detection efficiency to APF concentrations in urine.	('APF', 'Protein', (198, 201))	('APF concentrations', 'MPA', (238, 256))	('IC', 'Disease', 'MESH:C566126', (93, 95))	('AA127-360', 'Var', (138, 147))	('APF', 'Chemical', '-', (198, 201))	('detection efficiency', 'MPA', (214, 234))	('PBS', 'Chemical', 'MESH:D007854', (96, 99))	('increasing', 'PosReg', (203, 213))	('enhance', 'PosReg', (166, 173))	('AA361-524', 'Var', (149, 158))	('APF', 'Chemical', '-', (238, 241))	('CKAP4', 'Gene', (131, 136))	('binding', 'Interaction', (178, 185))
431081	33614703	81600593, 81770763, and 81500583), the State Key Project for Liver Cancer (2017ZX10203,2017ZX10203206), and the National Key Research and Development Program (2017YFC0906900).	('81770763', 'Var', (10, 18))	('Cancer', 'Phenotype', 'HP:0002664', (67, 73))	('Liver Cancer', 'Disease', 'MESH:D006528', (61, 73))	('Liver Cancer', 'Phenotype', 'HP:0002896', (61, 73))	('2017ZX10203,2017ZX10203206', 'Var', (75, 101))	('Liver Cancer', 'Disease', (61, 73))	('81500583', 'Var', (24, 32))	('81600593', 'Var', (0, 8))
431098	33173620	Mounting dysregulated lncRNAs may also play a role as tumor suppressors or oncogenes in multiple tumors, including NSCLCs.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('lncRNAs', 'Protein', (22, 29))	('NSCLCs', 'Disease', (115, 121))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('dysregulated', 'Var', (9, 21))	('tumor', 'Disease', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumors', 'Disease', (97, 103))	('NSCLCs', 'Disease', 'MESH:D002289', (115, 121))	('NSCLCs', 'Phenotype', 'HP:0030358', (115, 121))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('tumor', 'Disease', (54, 59))	('tumors', 'Disease', 'MESH:D009369', (97, 103))
431139	33173620	We found that the primary antibodies included PDL1 (E1L3N), JAK2 (D2E12), phospho-STAT3 (Tyr705; D3A7), STAT3 (79D7), phospho-AKT (Ser473; D9E), AKT (40D4; all purchased from Cell Signaling Technology, Boston, MA, USA), and ZFPM2 (OriGene).	('PDL1', 'Gene', (46, 50))	('Ser473', 'Chemical', '-', (131, 137))	('STAT3', 'Gene', (104, 109))	('ZFPM2', 'Gene', '23414', (224, 229))	('ZFPM2', 'Gene', (224, 229))	('PDL1', 'Gene', '29126', (46, 50))	('79D7', 'Var', (111, 115))	('D2E12', 'Var', (66, 71))	('STAT3', 'Gene', '6774', (104, 109))	('AKT', 'Gene', (126, 129))	('Ser473; D9E', 'Var', (131, 142))	('Tyr705; D3A7', 'Var', (89, 101))	('JAK2', 'Gene', '3717', (60, 64))	('AKT', 'Gene', (145, 148))	('STAT3', 'Gene', (82, 87))	('AKT', 'Gene', '207', (126, 129))	('Tyr705', 'Chemical', '-', (89, 95))	('JAK2', 'Gene', (60, 64))	('STAT3', 'Gene', '6774', (82, 87))	('AKT', 'Gene', '207', (145, 148))
431158	33173620	Subsequently, we used an MTT assay to show any cell proliferation caused by ZFPM2-AS1 silencing or overexpression.	('silencing', 'Var', (86, 95))	('ZFPM2-AS1', 'Gene', '102723356', (76, 85))	('ZFPM2-AS1', 'Gene', (76, 85))	('overexpression', 'PosReg', (99, 113))	('MTT', 'Chemical', 'MESH:C070243', (25, 28))	('cell proliferation', 'CPA', (47, 65))
431161	33173620	In the A549 cells, the proliferation rate was significantly lower when silencing ZFPM2-AS1 after 72 h without IFN-gamma, and after 96-120 h with IFN-gamma (Fig.	('IFN-gamma', 'Gene', '3458', (145, 154))	('IFN-gamma', 'Gene', (145, 154))	('A549', 'CellLine', 'CVCL:0023', (7, 11))	('IFN-gamma', 'Gene', '3458', (110, 119))	('IFN-gamma', 'Gene', (110, 119))	('silencing', 'Var', (71, 80))	('proliferation rate', 'CPA', (23, 41))	('ZFPM2-AS1', 'Gene', '102723356', (81, 90))	('ZFPM2-AS1', 'Gene', (81, 90))	('lower', 'NegReg', (60, 65))
431162	33173620	We obtained similar results when performing colony forming assays, confirming that ZFPM2-AS1 knockdown distinctly inhibited colony forming in both A549 and H460 cells (Figs.	('knockdown', 'Var', (93, 102))	('A549', 'CellLine', 'CVCL:0023', (147, 151))	('ZFPM2-AS1', 'Gene', (83, 92))	('ZFPM2-AS1', 'Gene', '102723356', (83, 92))	('colony forming', 'CPA', (124, 138))	('H460', 'CellLine', 'CVCL:0459', (156, 160))	('inhibited', 'NegReg', (114, 123))
431165	33173620	The results of the wound healing assay indicated that ZFPM2-AS1 knockdown significantly inhibited A549 and H460 cell motility when compared to the control group (Figs.	('A549', 'CellLine', 'CVCL:0023', (98, 102))	('inhibited', 'NegReg', (88, 97))	('ZFPM2-AS1', 'Gene', '102723356', (54, 63))	('ZFPM2-AS1', 'Gene', (54, 63))	('H460', 'CellLine', 'CVCL:0459', (107, 111))	('knockdown', 'Var', (64, 73))
431167	33173620	We found that the siRNA-mediated ZFPM2-AS1 knockdown significantly inhibited the invasion capacities of both A549 and H460 cells (Figs.	('inhibited', 'NegReg', (67, 76))	('ZFPM2-AS1', 'Gene', (33, 42))	('knockdown', 'Var', (43, 52))	('ZFPM2-AS1', 'Gene', '102723356', (33, 42))	('invasion capacities of', 'CPA', (81, 103))	('A549', 'CellLine', 'CVCL:0023', (109, 113))	('H460', 'CellLine', 'CVCL:0459', (118, 122))
431168	33173620	The silencing of ZFPM2-AS1 distinctly impeded the invasion and migration capabilities of A549 cells, in both the presence and absence of IFN-gamma (Figs.	('ZFPM2-AS1', 'Gene', (17, 26))	('A549', 'CellLine', 'CVCL:0023', (89, 93))	('impeded', 'NegReg', (38, 45))	('IFN-gamma', 'Gene', '3458', (137, 146))	('IFN-gamma', 'Gene', (137, 146))	('silencing', 'Var', (4, 13))	('ZFPM2-AS1', 'Gene', '102723356', (17, 26))
431177	33173620	However, ZFPM2-AS1 silencing and overexpression did not significantly affect the A549 cell cycle (Figs.	('A549 cell cycle', 'CPA', (81, 96))	('silencing', 'Var', (19, 28))	('ZFPM2-AS1', 'Gene', '102723356', (9, 18))	('ZFPM2-AS1', 'Gene', (9, 18))	('A549', 'CellLine', 'CVCL:0023', (81, 85))
431192	33173620	We found that in both the presence and absence of IFN-gamma, ZFPM2-AS1 knockdown significantly upregulated ZFPM2 expression and downregulated JAK2, p-STAT3, and p-AKT expression.	('JAK2', 'Gene', '3717', (142, 146))	('STAT3', 'Gene', (150, 155))	('expression', 'MPA', (167, 177))	('expression', 'MPA', (113, 123))	('AKT', 'Gene', (163, 166))	('STAT3', 'Gene', '6774', (150, 155))	('downregulated', 'NegReg', (128, 141))	('ZFPM2', 'Gene', '23414', (61, 66))	('ZFPM2', 'Gene', (61, 66))	('JAK2', 'Gene', (142, 146))	('ZFPM2', 'Gene', '23414', (107, 112))	('ZFPM2', 'Gene', (107, 112))	('IFN-gamma', 'Gene', (50, 59))	('IFN-gamma', 'Gene', '3458', (50, 59))	('ZFPM2-AS1', 'Gene', (61, 70))	('AKT', 'Gene', '207', (163, 166))	('upregulated', 'PosReg', (95, 106))	('knockdown', 'Var', (71, 80))	('ZFPM2-AS1', 'Gene', '102723356', (61, 70))
431213	33173620	Notably, our study confirmed that ZFPM2-AS1 knockdown decreased PD-L1 expression in the presence of IFN-gamma, suggesting that ZFPM2-AS1 may be a potential target during PD-L1 immunotherapy.	('ZFPM2-AS1', 'Gene', '102723356', (34, 43))	('decreased PD', 'Phenotype', 'HP:0032198', (54, 66))	('PD-L1', 'Gene', (170, 175))	('IFN-gamma', 'Gene', '3458', (100, 109))	('IFN-gamma', 'Gene', (100, 109))	('PD-L1', 'Gene', '29126', (170, 175))	('PD-L1', 'Gene', (64, 69))	('expression', 'MPA', (70, 80))	('decreased', 'NegReg', (54, 63))	('knockdown', 'Var', (44, 53))	('ZFPM2-AS1', 'Gene', (34, 43))	('PD-L1', 'Gene', '29126', (64, 69))	('ZFPM2-AS1', 'Gene', '102723356', (127, 136))	('ZFPM2-AS1', 'Gene', (127, 136))
431223	30979011	Here, we established a method to identify and isolate CSCs in ESCC using fluorescence-activated cell sorting with combined surface biomarkers including CD71, CD271, and CD338.	('CD271', 'Gene', '4804', (158, 163))	('CD338', 'Gene', (169, 174))	('CD271', 'Gene', (158, 163))	('CD71', 'Var', (152, 156))	('CD338', 'Gene', '9429', (169, 174))	('ESCC', 'Disease', (62, 66))
431240	30979011	In this study, various combinations of CD71, CD338, CD271, and CD49f have been considered and tested in ECa9706, ECa109, KYSE50, and CAES17.	('tested', 'Reg', (94, 100))	('CD49f', 'Gene', '3655', (63, 68))	('CD338', 'Gene', (45, 50))	('CD271', 'Gene', '4804', (52, 57))	('CD49f', 'Gene', (63, 68))	('CD338', 'Gene', '9429', (45, 50))	('ECa9706', 'CellLine', 'CVCL:E307', (104, 111))	('CD71', 'Var', (39, 43))	('CD271', 'Gene', (52, 57))
431246	30979011	Through a literature review, four candidate stem surface markers (CD49f, CD71, CD338, and CD271) were selected for CSC sorting in ECa9706, ECa109, CAES17, and KYSE150.	('CD71', 'Gene', (73, 77))	('ECa9706', 'CellLine', 'CVCL:E307', (130, 137))	('ECa109', 'Var', (139, 145))	('CD49f', 'Gene', '3655', (66, 71))	('CD338', 'Gene', '9429', (79, 84))	('CD271', 'Gene', '4804', (90, 95))	('CD49f', 'Gene', (66, 71))	('CD338', 'Gene', (79, 84))	('CD271', 'Gene', (90, 95))	('ECa9706', 'Var', (130, 137))
431247	30979011	We firstly detected CD49f, CD71, CD338, and CD271 when stained individually; CD49f and CD71 were detected with high positive rates, and CD338 and CD271 were expressed with low positive rates (Figure 1A).	('CD338', 'Gene', '9429', (33, 38))	('CD71', 'Var', (87, 91))	('CD338', 'Gene', '9429', (136, 141))	('CD271', 'Gene', (44, 49))	('CD49f', 'Gene', (77, 82))	('CD338', 'Gene', (33, 38))	('CD271', 'Gene', '4804', (146, 151))	('CD49f', 'Gene', (20, 25))	('CD338', 'Gene', (136, 141))	('CD271', 'Gene', (146, 151))	('CD49f', 'Gene', '3655', (77, 82))	('CD49f', 'Gene', '3655', (20, 25))	('CD271', 'Gene', '4804', (44, 49))
431252	30979011	In EC9706, the rates for positive (CD71-/CD271+/CD338+) and negative (CD71+/CD271-/CD338-) subpopulations were 0.86% and 90.0%, respectively.	('CD338', 'Gene', (83, 88))	('EC9706', 'CellLine', 'CVCL:E307', (3, 9))	('CD271', 'Gene', '4804', (41, 46))	('CD338', 'Gene', '9429', (48, 53))	('CD338', 'Gene', '9429', (83, 88))	('CD271', 'Gene', '4804', (76, 81))	('CD271', 'Gene', (41, 46))	('EC9706', 'Var', (3, 9))	('CD338', 'Gene', (48, 53))	('CD271', 'Gene', (76, 81))
431264	30979011	We detected growth inhibition in SSM with 1 microg/mL of DDP.	('growth', 'MPA', (12, 18))	('DDP', 'Var', (57, 60))	('DDP', 'Chemical', 'MESH:D002945', (57, 60))
431266	30979011	When cultured with 0.1 microg/mL, 0.5 microg/mL, and 1.0 microg/mL DDP for 120 h, both positive and negative cells were inhibited, and the inhibitory effect gradually increased with increasing concentrations, where the negative subpopulation cells were more sensitive to DPP treatment (Figure 3K).	('DDP', 'Chemical', 'MESH:D002945', (67, 70))	('inhibited', 'NegReg', (120, 129))	('DPP', 'Chemical', 'MESH:C038694', (271, 274))	('DDP', 'Var', (67, 70))
431275	30979011	Thirty-nine up-regulated miRNAs, including hsa-miR-18a-5p, hsa-miR-18b-5p, hsa-miR-29b-3p, hsa-miR-29c-3p, and hsa-let-7b were identified (Figure 4C).	('miRNAs', 'MPA', (25, 31))	('hsa-miR-18a', 'Gene', (43, 54))	('hsa-let-7b', 'Gene', '406884', (111, 121))	('hsa-miR-18b', 'Gene', '574033', (59, 70))	('hsa-miR-18b', 'Gene', (59, 70))	('up-regulated', 'PosReg', (12, 24))	('hsa-miR-29b-3p', 'Var', (75, 89))	('hsa-miR-18a', 'Gene', '406953', (43, 54))	('hsa-miR-29c', 'Gene', (91, 102))	('hsa-miR-29c', 'Gene', '407026', (91, 102))	('hsa-let-7b', 'Gene', (111, 121))
431292	30979011	The relative luciferase activity was significantly reduced (nearly 80.0%) by hsa-miR-21-3p when the reporter plasmid carried the wild type TRAF4 3'UTR, but no significant suppression was observed in the negative control plasmid; for cells transfected with mutant plasmid, only 25.6% of the relative luciferase activity was reduced (Figure 6G), which suggested miR-21-3p bound directly to the predicted TRAF4 3'UTR and negatively regulated TRAF4 expression.	('activity', 'MPA', (24, 32))	('reduced', 'NegReg', (51, 58))	('TRAF4', 'Gene', (439, 444))	('activity', 'MPA', (310, 318))	('miR-21-3p', 'Gene', (81, 90))	('miR-21-3p', 'Gene', '406995', (81, 90))	('miR-21-3p', 'Gene', '406995', (360, 369))	('TRAF4', 'Gene', (402, 407))	('hsa-miR-21-3p', 'Gene', '406995', (77, 90))	('mutant', 'Var', (256, 262))	('miR-21-3p', 'Gene', (360, 369))	('negatively regulated', 'NegReg', (418, 438))	('expression', 'MPA', (445, 455))	('hsa-miR-21-3p', 'Gene', (77, 90))	('bound', 'Interaction', (370, 375))
431293	30979011	We further confirmed that down-regulation of TRAF4 could partly rescue the functional changes in proliferation, cell cycle, and apoptosis in EC9706 (Figure 6B-D).	('EC9706', 'CellLine', 'CVCL:E307', (141, 147))	('down-regulation', 'NegReg', (26, 41))	('TRAF4', 'Gene', (45, 50))	('cell cycle', 'CPA', (112, 122))	('apoptosis', 'CPA', (128, 137))	('EC9706', 'Var', (141, 147))
431311	30979011	In ESCC, CD71 is reported to be correlated with tumorigenic properties.	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('CD71', 'Var', (9, 13))	('tumor', 'Disease', (48, 53))	('tumor', 'Disease', 'MESH:D009369', (48, 53))
431315	30979011	miR-135a can inhibit the development of Cancer Stem Cell-Driven Medulloblastoma by repressing Arhgef6 Expression.	('miR-135a', 'Var', (0, 8))	('Cancer', 'Phenotype', 'HP:0002664', (40, 46))	('Expression', 'MPA', (102, 112))	('repressing', 'NegReg', (83, 93))	('miR-135a', 'Chemical', '-', (0, 8))	('Medulloblastoma', 'Phenotype', 'HP:0002885', (64, 79))	('Cancer Stem Cell-Driven Medulloblastoma', 'Disease', 'MESH:D008527', (40, 79))	('Arhgef6', 'Gene', '9459', (94, 101))	('Arhgef6', 'Gene', (94, 101))	('inhibit', 'NegReg', (13, 20))	('Cancer Stem Cell-Driven Medulloblastoma', 'Disease', (40, 79))
431317	30979011	discovered that miRNA-148b suppressed CSCs by targeting neuropilin-1 in hepatocellular carcinoma.	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (72, 96))	('suppressed', 'NegReg', (27, 37))	('miRNA-148b', 'Var', (16, 26))	('hepatocellular carcinoma', 'Disease', (72, 96))	('neuropilin-1', 'Gene', (56, 68))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (72, 96))	('neuropilin-1', 'Gene', '8829', (56, 68))	('targeting', 'Reg', (46, 55))	('CSCs', 'MPA', (38, 42))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))
431397	29225480	Other studies have identified HER4 mutations in lung SqCCs, and another one demonstrated that genomic aberrations in neuregulin 1 (NRG1), one of the similar ligands of the ErbB family receptors, are a recurrent feature of lung SqCCs.	('neuregulin 1', 'Gene', '3084', (117, 129))	('SqCC', 'Phenotype', 'HP:0002860', (53, 57))	('lung SqCCs', 'Disease', (48, 58))	('HER4', 'Gene', '2066', (30, 34))	('NRG1', 'Gene', '3084', (131, 135))	('HER4', 'Gene', (30, 34))	('SqCCs', 'Phenotype', 'HP:0002860', (227, 232))	('SqCCs', 'Phenotype', 'HP:0002860', (53, 58))	('SqCC', 'Phenotype', 'HP:0002860', (227, 231))	('lung SqCCs', 'Disease', (222, 232))	('neuregulin 1', 'Gene', (117, 129))	('ErbB', 'Gene', '1956', (172, 176))	('NRG1', 'Gene', (131, 135))	('ErbB', 'Gene', (172, 176))	('mutations', 'Var', (35, 44))
431403	29225480	Mutations activating EGFR signaling pathway, like L858R mutation in exon 21 and exon 19 deletions, are used as biomarkers to preferentially identify NSCLC patients suitable for EGFR TKI therapy, but clinical responses in NSCLC patients with lack of EGFR mutations have been described in retrospective trials suggesting that a mutation-independent mechanism could potentially contribute to the observed efficacy of EGFR TKI therapies.	('NSCLC', 'Disease', (221, 226))	('activating', 'PosReg', (10, 20))	('EGFR', 'Gene', (249, 253))	('patients', 'Species', '9606', (155, 163))	('NSCLC', 'Disease', 'MESH:D002289', (149, 154))	('mutations', 'Var', (254, 263))	('EGFR', 'Gene', '1956', (21, 25))	('NSCLC', 'Disease', (149, 154))	('EGFR', 'Gene', (414, 418))	('EGFR', 'Gene', (177, 181))	('patients', 'Species', '9606', (227, 235))	('deletions', 'Var', (88, 97))	('L858R', 'Mutation', 'rs121434568', (50, 55))	('EGFR', 'Gene', '1956', (249, 253))	('EGFR', 'Gene', (21, 25))	('EGFR', 'Gene', '1956', (414, 418))	('NSCLC', 'Disease', 'MESH:D002289', (221, 226))	('EGFR', 'Gene', '1956', (177, 181))	('L858R', 'Var', (50, 55))
431441	29225480	It was originally developed with the aim to improve clinical outcomes versus first-generation EGFR inhibitors as, in preclinical studies, it was evidenced to be more effective in suppressing tyrosine kinase activity of both wild-type and activated EGFR or HER2 mutants in lung cancer cell lines; these afatinib-sensitive cancer cell lines contained erlotinib-resistant isoforms, wild-type EGFR, L858R/T790M double mutation, or HER2 overexpression and paved the way for Phase I studies.	('HER2', 'Gene', (427, 431))	('EGFR', 'Gene', '1956', (389, 393))	('afatinib', 'Chemical', 'MESH:D000077716', (302, 310))	('HER2', 'Gene', '2064', (256, 260))	('L858R', 'SUBSTITUTION', 'None', (395, 400))	('lung cancer', 'Disease', 'MESH:D008175', (272, 283))	('L858R', 'Var', (395, 400))	('EGFR', 'Gene', '1956', (94, 98))	('cancer', 'Disease', 'MESH:D009369', (321, 327))	('cancer', 'Disease', (277, 283))	('EGFR', 'Gene', (248, 252))	('suppressing', 'NegReg', (179, 190))	('T790M', 'Var', (401, 406))	('lung cancer', 'Phenotype', 'HP:0100526', (272, 283))	('overexpression', 'PosReg', (432, 446))	('cancer', 'Phenotype', 'HP:0002664', (277, 283))	('tyrosine kinase activity', 'MPA', (191, 215))	('HER2', 'Gene', (256, 260))	('HER2', 'Gene', '2064', (427, 431))	('EGFR', 'Gene', (389, 393))	('erlotinib', 'Chemical', 'MESH:D000069347', (349, 358))	('mutants', 'Var', (261, 268))	('EGFR', 'Gene', '1956', (248, 252))	('T790M', 'SUBSTITUTION', 'None', (401, 406))	('cancer', 'Disease', 'MESH:D009369', (277, 283))	('cancer', 'Disease', (321, 327))	('EGFR', 'Gene', (94, 98))	('lung cancer', 'Disease', (272, 283))	('cancer', 'Phenotype', 'HP:0002664', (321, 327))
431446	29225480	This trial did not require EGFR mutations; however, they were present in 96 (68%) patients.	('patients', 'Species', '9606', (82, 90))	('EGFR', 'Gene', '1956', (27, 31))	('mutations', 'Var', (32, 41))	('EGFR', 'Gene', (27, 31))
431449	29225480	The lack of a significant difference in OS between the two groups was hypothesized to be the result of subsequent different treatments; in fact, 257 (68%) patients in the afatinib group and 153 (79%) patients in the placebo group underwent further therapies.	('afatinib', 'Chemical', 'MESH:D000077716', (171, 179))	('patients', 'Species', '9606', (200, 208))	('OS', 'Chemical', '-', (40, 42))	('patients', 'Species', '9606', (155, 163))	('underwent', 'Reg', (230, 239))	('afatinib', 'Var', (171, 179))
431452	29225480	LUX-Lung 2 was a Phase II single-arm study enrolling 129 stage IIIB/IV EGFR mutated patients with adenocarcinoma histology who were inhibitor naive and had no more than one previous chemotherapy regimen for advanced disease.	('adenocarcinoma', 'Disease', (98, 112))	('adenocarcinoma', 'Disease', 'MESH:D000230', (98, 112))	('patients', 'Species', '9606', (84, 92))	('mutated', 'Var', (76, 83))	('EGFR', 'Gene', '1956', (71, 75))	('EGFR', 'Gene', (71, 75))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))
431458	29225480	Even if no differences were found in terms of response rates between the two dosing groups, the most common toxicities of afatinib were higher in those patients who received 50 mg daily: 22, 22% of 99 patients receiving afatinib 50 mg as starting dose, presented diarrhea grade 3 and 28, 28% of 99 patients, had rash or acne, while two, 7% of 30 patients receiving afatinib 40 mg as starting dose, evidenced both diarrhea and rash or acne, grade 3.	('diarrhea', 'Disease', 'MESH:D003967', (263, 271))	('rash or acne', 'Disease', 'MESH:D005076', (426, 438))	('toxicities', 'Disease', (108, 118))	('diarrhea and rash', 'Disease', 'MESH:D005076', (413, 430))	('rash', 'Phenotype', 'HP:0000988', (312, 316))	('afatinib', 'Chemical', 'MESH:D000077716', (365, 373))	('afatinib', 'Chemical', 'MESH:D000077716', (220, 228))	('patients', 'Species', '9606', (298, 306))	('patients', 'Species', '9606', (346, 354))	('diarrhea', 'Phenotype', 'HP:0002014', (413, 421))	('rash or acne', 'Disease', (312, 324))	('acne', 'Phenotype', 'HP:0001061', (320, 324))	('diarrhea', 'Phenotype', 'HP:0002014', (263, 271))	('rash or acne', 'Disease', 'MESH:D005076', (312, 324))	('patients', 'Species', '9606', (201, 209))	('rash', 'Phenotype', 'HP:0000988', (426, 430))	('diarrhea', 'Disease', (413, 421))	('diarrhea', 'Disease', (263, 271))	('patients', 'Species', '9606', (152, 160))	('afatinib', 'Chemical', 'MESH:D000077716', (122, 130))	('afatinib 50 mg', 'Var', (220, 234))	('higher', 'PosReg', (136, 142))	('diarrhea', 'Disease', 'MESH:D003967', (413, 421))	('toxicities', 'Disease', 'MESH:D064420', (108, 118))	('rash or acne', 'Disease', (426, 438))	('acne', 'Phenotype', 'HP:0001061', (434, 438))
431468	29225480	EGFR mutation in their primary tumor was positive in 45 (72.6%) of 62 treated patients, according to local and/or central laboratory analyses, and 51 patients (82.3%) presented acquired resistance to erlotinib and/or gefitinib.	('resistance', 'MPA', (186, 196))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('gefitinib', 'Chemical', 'MESH:D000077156', (217, 226))	('erlotinib', 'Chemical', 'MESH:D000069347', (200, 209))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('EGFR', 'Gene', (0, 4))	('tumor', 'Disease', (31, 36))	('positive', 'Reg', (41, 49))	('patients', 'Species', '9606', (78, 86))	('patients', 'Species', '9606', (150, 158))	('EGFR', 'Gene', '1956', (0, 4))	('mutation', 'Var', (5, 13))
431486	29225480	Prespecified subgroup analyses showed similar OS trends in the afatinib versus gefitinib group; particularly, they showed 30.7 versus 26.4 months (HR 0.83, 95% CI 0.58-1.17, P=0.284) in patients with exon 19 deletion, in the two arms, respectively, and 25 versus 21.2 months (HR 0.91, 95% CI 0.62-1.36, P=0.658) in patients with L858R mutations.	('gefitinib', 'Chemical', 'MESH:D000077156', (79, 88))	('L858R', 'Mutation', 'rs121434568', (329, 334))	('afatinib', 'Chemical', 'MESH:D000077716', (63, 71))	('OS', 'Chemical', '-', (46, 48))	('patients', 'Species', '9606', (315, 323))	('exon 19 deletion', 'Var', (200, 216))	('patients', 'Species', '9606', (186, 194))	('L858R', 'Var', (329, 334))
431494	29225480	The rationale was based on the hypothesis that even if EGFR mutations are rarely found in lung SqCC, the inhibition of disease progression by TKIs may not be performed exclusively by mutated EGFRs but through different molecular mechanisms, since overexpression levels of wild-type EGFR are higher in this histology.	('lung SqCC', 'Disease', (90, 99))	('EGFR', 'Gene', '1956', (55, 59))	('SqCC', 'Phenotype', 'HP:0002860', (95, 99))	('EGFR', 'Gene', '1956', (282, 286))	('higher', 'PosReg', (291, 297))	('overexpression levels', 'MPA', (247, 268))	('EGFR', 'Gene', (55, 59))	('EGFR', 'Gene', (282, 286))	('EGFR', 'Gene', '1956', (191, 195))	('EGFR', 'Gene', (191, 195))	('mutations', 'Var', (60, 69))
431503	29225480	To date, two studies illustrated afatinib activity in advanced NSCLC patients who were lacking EGFR mutations but presented an increased EGFR gene copy number by amplification or polysomy.	('EGFR', 'Gene', (137, 141))	('NSCLC', 'Disease', (63, 68))	('amplification', 'Var', (162, 175))	('activity', 'MPA', (42, 50))	('NSCLC', 'Disease', 'MESH:D002289', (63, 68))	('polysomy', 'Var', (179, 187))	('EGFR', 'Gene', '1956', (95, 99))	('EGFR', 'Gene', '1956', (137, 141))	('patients', 'Species', '9606', (69, 77))	('afatinib', 'Chemical', 'MESH:D000077716', (33, 41))	('increased', 'PosReg', (127, 136))	('EGFR', 'Gene', (95, 99))
431504	29225480	Specifically, Cappuzzo et al investigated the activity and safety of afatinib in advanced NSCLC with increased EGFR gene copy number and/or gene amplification by fluorescence in situ hybridization (FISH), with or without EGFR mutation in a Phase II study.	('increased', 'PosReg', (101, 110))	('EGFR', 'Gene', '1956', (111, 115))	('NSCLC', 'Disease', (90, 95))	('afatinib', 'Chemical', 'MESH:D000077716', (69, 77))	('EGFR', 'Gene', '1956', (221, 225))	('EGFR', 'Gene', (111, 115))	('NSCLC', 'Disease', 'MESH:D002289', (90, 95))	('EGFR', 'Gene', (221, 225))	('gene amplification', 'Var', (140, 158))
431507	29225480	Higher ORRs were observed in patients with gene amplification (20%; n=5/25 patients) and in those with EGFR mutation-positive tumors (25%; n=3/12 patients).	('EGFR', 'Gene', '1956', (103, 107))	('patients', 'Species', '9606', (29, 37))	('tumors', 'Disease', (126, 132))	('tumors', 'Disease', 'MESH:D009369', (126, 132))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('EGFR', 'Gene', (103, 107))	('patients', 'Species', '9606', (75, 83))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('gene amplification', 'Var', (43, 61))	('patients', 'Species', '9606', (146, 154))
431508	29225480	DCR was 50.7% overall (n=35/69 patients; median duration: 24.9 weeks) with higher DCRs evidenced in those subjects with gene amplification, 64% (n=16/25 patients), and in those with EGFR mutation-positive tumors, 66.7% (n=8/12 patients).	('tumors', 'Disease', 'MESH:D009369', (205, 211))	('EGFR', 'Gene', '1956', (182, 186))	('patients', 'Species', '9606', (153, 161))	('DCRs', 'MPA', (82, 86))	('EGFR', 'Gene', (182, 186))	('tumors', 'Phenotype', 'HP:0002664', (205, 211))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('patients', 'Species', '9606', (31, 39))	('tumors', 'Disease', (205, 211))	('patients', 'Species', '9606', (227, 235))	('gene amplification', 'Var', (120, 138))
431510	29225480	The percentage of EGFR mutated patients was low (14, 6%) and only 15 patients had EGFR amplification (6%, nine in the afatinib group and six in the erlotinib group).	('EGFR', 'Gene', (82, 86))	('EGFR', 'Gene', '1956', (18, 22))	('EGFR', 'Gene', (18, 22))	('afatinib', 'Chemical', 'MESH:D000077716', (118, 126))	('mutated', 'Var', (23, 30))	('patients', 'Species', '9606', (31, 39))	('patients', 'Species', '9606', (69, 77))	('EGFR', 'Gene', '1956', (82, 86))	('erlotinib', 'Chemical', 'MESH:D000069347', (148, 157))
431514	29225480	Another possible mechanism of afatinib was evidenced in H358 and H441 NSCLC cell lines, which lack EGFR mutations.	('EGFR', 'Gene', (99, 103))	('mutations', 'Var', (104, 113))	('NSCLC', 'Disease', (70, 75))	('NSCLC', 'Disease', 'MESH:D002289', (70, 75))	('H358', 'CellLine', 'CVCL:1559', (56, 60))	('EGFR', 'Gene', '1956', (99, 103))	('afatinib', 'Chemical', 'MESH:D000077716', (30, 38))
431519	29225480	Overall, targeting CIP2A is likely a potential mechanism of afatinib able to limit the progression of lung SqCC.	('targeting', 'Var', (9, 18))	('lung SqCC', 'Disease', (102, 111))	('SqCC', 'Phenotype', 'HP:0002860', (107, 111))	('afatinib', 'Chemical', 'MESH:D000077716', (60, 68))	('CIP2A', 'Gene', (19, 24))	('CIP2A', 'Gene', '57650', (19, 24))
431521	29225480	In those patients treated with an EGFR TKI, it was evidenced that VS-G status was associated with better OS than VS-P status.	('patients', 'Species', '9606', (9, 17))	('VS-G status', 'Var', (66, 77))	('EGFR', 'Gene', (34, 38))	('OS', 'Chemical', '-', (105, 107))	('EGFR', 'Gene', '1956', (34, 38))
431536	29225480	Grade >3 AEs, such as diarrhea (10.4 versus 2.6%) and stomatitis (4.1 versus 0%), were more frequent with afatinib than erlotinib while treatment-related grade 3 rash or acne was more frequent with erlotinib (10.4%) than afatinib (5.9%).	('afatinib', 'Chemical', 'MESH:D000077716', (106, 114))	('diarrhea', 'Disease', 'MESH:D003967', (22, 30))	('stomatitis', 'Phenotype', 'HP:0010280', (54, 64))	('AEs', 'Chemical', 'MESH:C045560', (9, 12))	('rash or acne', 'Disease', (162, 174))	('erlotinib', 'Chemical', 'MESH:D000069347', (198, 207))	('afatinib', 'Var', (106, 114))	('erlotinib', 'Chemical', 'MESH:D000069347', (120, 129))	('rash or acne', 'Disease', 'MESH:D005076', (162, 174))	('acne', 'Phenotype', 'HP:0001061', (170, 174))	('afatinib', 'Chemical', 'MESH:D000077716', (221, 229))	('stomatitis', 'Disease', 'MESH:D013280', (54, 64))	('diarrhea', 'Phenotype', 'HP:0002014', (22, 30))	('rash', 'Phenotype', 'HP:0000988', (162, 166))	('stomatitis', 'Disease', (54, 64))	('diarrhea', 'Disease', (22, 30))
431547	29225480	However, as already stated before, particularly for afatinib, diarrhea was the most impacting toxicity: in LUX-Lung 8, the frequency of treatment-related grade 3/4 diarrhea was higher with afatinib, although discontinuations because of diarrhea were low for both treatment arms (4.1% with afatinib and 1.5% with erlotinib).	('diarrhea', 'Phenotype', 'HP:0002014', (236, 244))	('diarrhea', 'Disease', 'MESH:D003967', (236, 244))	('afatinib', 'Var', (189, 197))	('diarrhea', 'Disease', (236, 244))	('afatinib', 'Chemical', 'MESH:D000077716', (189, 197))	('diarrhea', 'Phenotype', 'HP:0002014', (164, 172))	('diarrhea', 'Phenotype', 'HP:0002014', (62, 70))	('afatinib', 'Chemical', 'MESH:D000077716', (52, 60))	('diarrhea', 'Disease', (164, 172))	('afatinib', 'Chemical', 'MESH:D000077716', (289, 297))	('diarrhea', 'Disease', (62, 70))	('diarrhea', 'Disease', 'MESH:D003967', (164, 172))	('erlotinib', 'Chemical', 'MESH:D000069347', (312, 321))	('diarrhea', 'Disease', 'MESH:D003967', (62, 70))	('toxicity', 'Disease', 'MESH:D064420', (94, 102))	('toxicity', 'Disease', (94, 102))
431570	31807166	Abnormal expression and mutations of genes are involved in the development and progression of ES.	('genes', 'Gene', (37, 42))	('ES', 'Phenotype', 'HP:0012254', (94, 96))	('involved', 'Reg', (47, 55))	('ES', 'Disease', 'MESH:D012512', (94, 96))	('mutations', 'Var', (24, 33))
431574	31807166	Stromal antigen 2 mutation occurs in 20% of ES cases and is associated with distant metastasis, although whether it may be considered a prognostic marker for ES remains controversial.	('distant metastasis', 'CPA', (76, 94))	('Stromal antigen 2', 'Gene', (0, 17))	('Stromal antigen 2', 'Gene', '10735', (0, 17))	('mutation', 'Var', (18, 26))	('ES', 'Phenotype', 'HP:0012254', (158, 160))	('ES', 'Phenotype', 'HP:0012254', (44, 46))	('ES', 'Disease', 'MESH:D012512', (158, 160))	('ES', 'Disease', 'MESH:D012512', (44, 46))	('associated', 'Reg', (60, 70))
431575	31807166	Other molecular genetic alterations associated with ES include abnormal expression of platelet-derived growth factor receptor beta and mammalian target of rapamycin, as well as CDKN2A and TP53 mutations.	('CDKN2A', 'Gene', (177, 183))	('ES', 'Disease', 'MESH:D012512', (52, 54))	('CDKN2A', 'Gene', '1029', (177, 183))	('platelet-derived growth factor receptor beta', 'Gene', '5159', (86, 130))	('mutations', 'Var', (193, 202))	('ES', 'Phenotype', 'HP:0012254', (52, 54))	('TP53', 'Gene', '7157', (188, 192))	('TP53', 'Gene', (188, 192))	('platelet-derived growth factor receptor beta', 'Gene', (86, 130))	('mammalian target of rapamycin', 'Gene', '2475', (135, 164))	('mammalian target of rapamycin', 'Gene', (135, 164))
431588	31807166	Following standardization of the chip results, 1,133, 1,290 and 768 DEGs between ES and healthy tissues were extracted from the GSE17674, GSE17679 and GSE45544 mRNA expression profile data sets, respectively.	('GSE17674', 'Var', (128, 136))	('ES', 'Phenotype', 'HP:0012254', (81, 83))	('GSE45544', 'Var', (151, 159))	('ES', 'Disease', 'MESH:D012512', (81, 83))
431618	31807166	Microinjections of tropomyosin into epithelial cells can induce rapid cell migration; TNNT1 may contribute to the interaction between actin and tropomyosin, thus regulating cell migration and invasion.	('TNNT1', 'Gene', (86, 91))	('TNNT1', 'Gene', '7138', (86, 91))	('rapid cell migration', 'CPA', (64, 84))	('Microinjections', 'Var', (0, 15))	('invasion', 'CPA', (192, 200))	('interaction', 'Interaction', (114, 125))	('cell migration', 'CPA', (173, 187))	('regulating', 'Reg', (162, 172))	('contribute', 'Reg', (96, 106))	('induce', 'Reg', (57, 63))
431628	31807166	The results of the analysis in the present study demonstrated that high expression of TNNT1 was significantly associated with poor OS in patients with ES, consistent with the above findings.	('ES', 'Phenotype', 'HP:0012254', (151, 153))	('ES', 'Disease', 'MESH:D012512', (151, 153))	('TNNT1', 'Gene', (86, 91))	('poor OS', 'Disease', (126, 133))	('TNNT1', 'Gene', '7138', (86, 91))	('patients', 'Species', '9606', (137, 145))	('associated', 'Reg', (110, 120))	('high expression', 'Var', (67, 82))
431634	31807166	Whole exome sequence data have been previously used to estimate the gene mutation rate of TTN, which identified TTN mutations in colorectal cancer, suggesting that TTN mutations may serve a specific role in the occurrence or progression of colorectal cancer.	('colorectal cancer', 'Disease', (129, 146))	('TTN', 'Gene', (164, 167))	('colorectal cancer', 'Phenotype', 'HP:0003003', (240, 257))	('TTN', 'Gene', (112, 115))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('TTN', 'Gene', '7273', (112, 115))	('colorectal cancer', 'Disease', (240, 257))	('TTN', 'Gene', '7273', (164, 167))	('colorectal cancer', 'Disease', 'MESH:D015179', (129, 146))	('mutations', 'Var', (116, 125))	('TTN', 'Gene', (90, 93))	('colorectal cancer', 'Phenotype', 'HP:0003003', (129, 146))	('TTN', 'Gene', '7273', (90, 93))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('colorectal cancer', 'Disease', 'MESH:D015179', (240, 257))	('mutations', 'Var', (168, 177))
431637	31807166	The Cancer Genome Atlas-based aggregation analysis revealed that the missense mutation of TTN was associated with good prognosis in lung squamous cell carcinoma.	('missense mutation', 'Var', (69, 86))	('Cancer', 'Phenotype', 'HP:0002664', (4, 10))	('TTN', 'Gene', (90, 93))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (137, 160))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (132, 160))	('lung squamous cell carcinoma', 'Disease', (132, 160))	('TTN', 'Gene', '7273', (90, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (151, 160))
431638	31807166	However, no studies are currently available on TTN in ES, but the LASSO COX regression and OS analysis results of the present study demonstrated that high expression of TTN was associated with poor prognosis of patients with ES and may serve an important role in the development of ES.	('ES', 'Phenotype', 'HP:0012254', (282, 284))	('TTN', 'Gene', (47, 50))	('ES', 'Disease', 'MESH:D012512', (282, 284))	('patients', 'Species', '9606', (211, 219))	('high expression', 'Var', (150, 165))	('TTN', 'Gene', '7273', (169, 172))	('TTN', 'Gene', '7273', (47, 50))	('ES', 'Phenotype', 'HP:0012254', (54, 56))	('ES', 'Phenotype', 'HP:0012254', (225, 227))	('TTN', 'Gene', (169, 172))	('ES', 'Disease', 'MESH:D012512', (225, 227))	('ES', 'Disease', 'MESH:D012512', (54, 56))	('LASSO', 'Chemical', 'MESH:C000188', (66, 71))
431645	31807166	The results of the present study demonstrated that a high expression of MYL3 was associated with poor prognosis in patients with ES, and this result may help explain the molecular mechanism of ES.	('patients', 'Species', '9606', (115, 123))	('MYL3', 'Gene', '4634', (72, 76))	('high', 'Var', (53, 57))	('ES', 'Phenotype', 'HP:0012254', (193, 195))	('ES', 'Disease', 'MESH:D012512', (193, 195))	('ES', 'Phenotype', 'HP:0012254', (129, 131))	('MYL3', 'Gene', (72, 76))	('ES', 'Disease', 'MESH:D012512', (129, 131))
431647	31807166	High expression of TMOD1 is a key biomarker for poor prognosis in patients with oral squamous cell carcinoma.	('oral squamous cell carcinoma', 'Disease', (80, 108))	('High', 'Var', (0, 4))	('TMOD1', 'Gene', '7111', (19, 24))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (85, 108))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (80, 108))	('TMOD1', 'Gene', (19, 24))	('patients', 'Species', '9606', (66, 74))
431652	31807166	High expression of TNNT1 is a prognostic biomarker for a variety of cancers.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('High', 'Var', (0, 4))	('cancers', 'Phenotype', 'HP:0002664', (68, 75))	('cancers', 'Disease', (68, 75))	('cancers', 'Disease', 'MESH:D009369', (68, 75))	('TNNT1', 'Gene', (19, 24))	('TNNT1', 'Gene', '7138', (19, 24))
431673	30744164	There is also a concern that e-cig use may lead to nicotine addiction and smoking, especially among youth.	('smoking', 'Disease', (74, 81))	('lead to', 'Reg', (43, 50))	('e-cig', 'Var', (29, 34))	('nicotine', 'Chemical', 'MESH:D009538', (51, 59))	('nicotine', 'Disease', (51, 59))
431679	30744164	Human cancer is characterized by deregulation of genes involved in crucial cellular functions, such as growth control and differentiation.	('differentiation', 'CPA', (122, 137))	('Human', 'Species', '9606', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('cancer', 'Disease', 'MESH:D009369', (6, 12))	('deregulation', 'Var', (33, 45))	('cancer', 'Disease', (6, 12))	('growth control', 'CPA', (103, 117))
431681	30744164	Consistent with tobacco smoking being a major risk factor for various types of human cancer, deregulation of cancer-related genes and disruption of associated pathways and networks have been demonstrated in target and relevant surrogate tissues of cigarette smokers.	('human', 'Species', '9606', (79, 84))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('cancer', 'Disease', (109, 115))	('deregulation', 'Var', (93, 105))	('cancer', 'Disease', (85, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('disruption', 'Reg', (134, 144))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('tobacco', 'Species', '4097', (16, 23))
431685	30744164	We found that the most affected pathway in e-cig users was the "Wnt/Ca+ pathway" (P = 4.7 x 10-5), while in smokers the "integrin signaling pathway" was primarily impacted (P = 1.42 x 10-8) (Figure 2).	('integrin signaling pathway', 'Pathway', (121, 147))	('e-cig', 'Var', (43, 48))	('Wnt', 'Chemical', '-', (64, 67))	('affected', 'Reg', (23, 31))
431705	30744164	As shown in Figure 2, "cancer" was the top disease associated with the deregulated genes in both e-cig users and smokers (~62 versus 79%).	('deregulated', 'Var', (71, 82))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('cancer', 'Disease', (23, 29))	('cancer', 'Disease', 'MESH:D009369', (23, 29))
431712	30744164	In the present study, the WNT5A gene and the frizzled receptor FDZ7 gene were down-regulated in e-cig users, most likely causing inhibition of downstream effectors of the cascade (Table S1).	('down-regulated', 'NegReg', (78, 92))	('WNT5A', 'Gene', '7474', (26, 31))	('FDZ7', 'Gene', (63, 67))	('inhibition', 'NegReg', (129, 139))	('e-cig', 'Var', (96, 101))	('WNT5A', 'Gene', (26, 31))
431713	30744164	When deregulated, this pathway can promote tumor invasion and metastasis.	('deregulated', 'Var', (5, 16))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('promote', 'PosReg', (35, 42))	('tumor', 'Disease', (43, 48))
431722	30744164	Reduced expression of NOTCH1 has been detected by immunohistochemistry not only in oral squamous cell carcinoma but also in oral epithelial dysplasia, suggesting that deregulation of NOTCH1 is an early event in the disease.	('NOTCH1', 'Gene', '4851', (183, 189))	('NOTCH1', 'Gene', (183, 189))	('NOTCH1', 'Gene', '4851', (22, 28))	('NOTCH1', 'Gene', (22, 28))	('oral epithelial dysplasia', 'Disease', 'MESH:D017573', (124, 149))	('Reduced', 'NegReg', (0, 7))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (83, 111))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (88, 111))	('oral epithelial dysplasia', 'Disease', (124, 149))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('expression', 'MPA', (8, 18))	('oral squamous cell carcinoma', 'Disease', (83, 111))	('deregulation', 'Var', (167, 179))
431723	30744164	Of relevance, loss-of-function mutations of the NOTCH1 gene have been detected in about 10% of head and neck squamous cell carcinoma (HNSCC), making it one of the most mutated genes in squamous cell carcinoma, which is highly associated with smoking.	('mutations', 'Var', (31, 40))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (185, 208))	('squamous cell carcinoma', 'Disease', (185, 208))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (95, 132))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (185, 208))	('neck squamous cell carcinoma', 'Disease', (104, 132))	('loss-of-function', 'NegReg', (14, 30))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (109, 132))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (104, 132))	('NOTCH1', 'Gene', '4851', (48, 54))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('NOTCH1', 'Gene', (48, 54))	('carcinoma', 'Phenotype', 'HP:0030731', (199, 208))	('HNSCC', 'Phenotype', 'HP:0012288', (134, 139))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (109, 132))
431728	30744164	Depletion of HERC2 has been shown to up-regulate cell growth and increase focus formation.	('increase', 'PosReg', (65, 73))	('HERC2', 'Gene', (13, 18))	('Depletion', 'Var', (0, 9))	('focus formation', 'CPA', (74, 89))	('HERC2', 'Gene', '8924', (13, 18))	('up-regulate', 'PosReg', (37, 48))	('cell growth', 'CPA', (49, 60))
431729	30744164	Frameshift mutations of HERC2 have been reported in gastric and colorectal cancer with microsatellite instability.	('colorectal cancer', 'Disease', (64, 81))	('colorectal cancer', 'Disease', 'MESH:D015179', (64, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('gastric', 'Disease', (52, 59))	('HERC2', 'Gene', (24, 29))	('Frameshift mutations', 'Var', (0, 20))	('HERC2', 'Gene', '8924', (24, 29))	('reported', 'Reg', (40, 48))	('colorectal cancer', 'Phenotype', 'HP:0003003', (64, 81))
431737	30744164	Malfunction of these inhibitor proteins has been linked to a variety of diseases, including cancer and cardiovascular disease.	('cardiovascular disease', 'Disease', (103, 125))	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('linked', 'Reg', (49, 55))	('cardiovascular disease', 'Phenotype', 'HP:0001626', (103, 125))	('Malfunction', 'Var', (0, 11))	('cardiovascular disease', 'Disease', 'MESH:D002318', (103, 125))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
431740	30744164	To our knowledge, this is the first report to demonstrate that e-cig users have significant deregulation of critically important genes and associated molecular pathways in the oral epithelium, which is a major target tissue for smoking-associated cancer.	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('molecular pathways', 'Pathway', (150, 168))	('cancer', 'Disease', (247, 253))	('e-cig', 'Var', (63, 68))	('deregulation', 'MPA', (92, 104))	('critically important genes', 'Gene', (108, 134))	('cancer', 'Disease', 'MESH:D009369', (247, 253))
431744	30744164	Health indicators for exclusion were oral infection or inflammation, gum disease, dental decay, immune system disorders, diabetes, respiratory diseases (e.g., asthma), kidney diseases, body mass index <18 kg/m2 or >40 kg/m2, or any medical disorder/medication that could affect the subject's safety or study results.	('diabetes', 'Disease', (121, 129))	('gum disease', 'Disease', (69, 80))	('immune system disorders', 'Phenotype', 'HP:0002715', (96, 119))	('kidney diseases', 'Phenotype', 'HP:0000112', (168, 183))	('respiratory diseases', 'Disease', (131, 151))	('system disorders', 'Disease', (103, 119))	('<18 kg/m2', 'Var', (201, 210))	('disorder', 'Disease', (240, 248))	('oral infection', 'Disease', (37, 51))	('asthma', 'Disease', 'MESH:D001249', (159, 165))	('disorder', 'Disease', 'MESH:D030342', (240, 248))	('kidney diseases', 'Disease', (168, 183))	('diabetes', 'Disease', 'MESH:D003920', (121, 129))	('dental decay', 'Disease', (82, 94))	('kidney diseases', 'Disease', 'MESH:D007674', (168, 183))	('oral infection', 'Disease', 'MESH:D020820', (37, 51))	('inflammation', 'Disease', 'MESH:D007249', (55, 67))	('disorder', 'Disease', (110, 118))	('asthma', 'Phenotype', 'HP:0002099', (159, 165))	('dental decay', 'Phenotype', 'HP:0000670', (82, 94))	('>40 kg/m2', 'Var', (214, 223))	('asthma', 'Disease', (159, 165))	('disorder', 'Disease', 'MESH:D030342', (110, 118))	('respiratory diseases', 'Disease', 'MESH:D012131', (131, 151))	('gum disease', 'Phenotype', 'HP:0000704', (69, 80))	('system disorders', 'Disease', 'MESH:D007154', (103, 119))	('inflammation', 'Disease', (55, 67))
431794	26445240	The M code is 8560/3 for ASC, 8140/3 for AC, and 8070/3 for SCC.	('8140/3', 'Var', (30, 36))	('SCC', 'Gene', '6317', (60, 63))	('8070/3', 'Var', (49, 55))	('ASC', 'Disease', (25, 28))	('SCC', 'Gene', (60, 63))	('SCC', 'Phenotype', 'HP:0002860', (60, 63))
431804	26445240	With regard to the TNM stage, ASCs in the alimentary system were associated with more advanced TNM stage (stage III and IV) compared with respiratory and female reproductive systems (74.5% vs. 67.4% vs. 48.2%, P = 0.004).	('TNM', 'Gene', (95, 98))	('men', 'Species', '9606', (45, 48))	('TNM', 'Gene', (19, 22))	('TNM', 'Gene', '10178', (95, 98))	('ASCs', 'Var', (30, 34))	('TNM', 'Gene', '10178', (19, 22))
431843	26445240	In lung ASC, the frequency of EGFR mutations was reported to be 33.3% in tumor specimens and which were significantly more frequent in women than men (44.4% vs. 25%) and in never-smokers than smokers (40% vs. 16.7%).	('lung', 'Disease', (3, 7))	('EGFR', 'Gene', (30, 34))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('men', 'Species', '9606', (146, 149))	('tumor', 'Disease', (73, 78))	('mutations', 'Var', (35, 44))	('men', 'Species', '9606', (84, 87))	('men', 'Species', '9606', (137, 140))	('EGFR', 'Gene', '1956', (30, 34))	('women', 'Species', '9606', (135, 140))
431852	26445240	ASC pancreatic tumors have somatic mutations in Up-frameshift 1 (UPF1), which encodes an RNA helicase essential for a highly conserved RNA degradation pathway called nonsense-mediated RNA decay.	('Up-frameshift 1', 'Gene', '5976', (48, 63))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('Up-frameshift 1', 'Gene', (48, 63))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('ASC', 'Disease', (0, 3))	('pancreatic tumors', 'Phenotype', 'HP:0002894', (4, 21))	('UPF1', 'Gene', (65, 69))	('pancreatic tumors', 'Disease', (4, 21))	('pancreatic tumors', 'Disease', 'MESH:D010190', (4, 21))	('UPF1', 'Gene', '5976', (65, 69))	('mutations', 'Var', (35, 44))
431854	26445240	In addition, the frequency of EGFR mutations in lung ASC was reported to be 13.1%-33.3%, and KRAS mutations in pulmonary adenocarcinomas are resistant to EGFR tyrosine kinase inhibitor therapy.	('EGFR', 'Gene', (154, 158))	('carcinomas', 'Phenotype', 'HP:0030731', (126, 136))	('EGFR', 'Gene', (30, 34))	('KRAS', 'Gene', (93, 97))	('KRAS', 'Gene', '3845', (93, 97))	('mutations', 'Var', (98, 107))	('lung ASC', 'Disease', (48, 56))	('pulmonary adenocarcinomas', 'Disease', 'MESH:D008175', (111, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('EGFR', 'Gene', '1956', (30, 34))	('pulmonary adenocarcinomas', 'Disease', (111, 136))	('EGFR', 'Gene', '1956', (154, 158))	('mutations', 'Var', (35, 44))
431881	25826333	The invasiveness of MCF-7/6 is decreased either by knockdown of MYH9 or treatment with blebbistatin, which inhibits the function of MYH9, indicating the involvement of MYH9 in the migration and invasion of cancer cells.	('MCF-7/6', 'CellLine', 'CVCL:W972', (20, 27))	('MYH9', 'Gene', '4627', (132, 136))	('involvement', 'Reg', (153, 164))	('MYH9', 'Gene', (132, 136))	('function', 'MPA', (120, 128))	('blebbistatin', 'Chemical', 'MESH:C472645', (87, 99))	('men', 'Species', '9606', (160, 163))	('cancer', 'Disease', (206, 212))	('knockdown', 'Var', (51, 60))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('decreased', 'NegReg', (31, 40))	('inhibits', 'NegReg', (107, 115))	('men', 'Species', '9606', (77, 80))	('MYH9', 'Gene', '4627', (64, 68))	('MYH9', 'Gene', '4627', (168, 172))	('MYH9', 'Gene', (64, 68))	('MYH9', 'Gene', (168, 172))	('cancer', 'Disease', 'MESH:D009369', (206, 212))	('invasiveness', 'CPA', (4, 16))
431942	25826333	The immunoglobulin isotype of KU-Lu-6 antibody was determined as IgM, k. By the antibody absorption test, the stainability of KU-Lu-6 antibody was gradually reduced depending on the concentration of MYH9 protein.	('MYH9', 'Gene', '4627', (199, 203))	('reduced', 'NegReg', (157, 164))	('KU-Lu-6', 'Var', (126, 133))	('MYH9', 'Gene', (199, 203))	('stainability', 'MPA', (110, 122))
431964	25826333	In further analyses, MYH9 expression was significantly correlated with poorer survival in patients with either adenocarcinoma (P = 0.007) (Fig.	('MYH9', 'Gene', '4627', (21, 25))	('expression', 'Var', (26, 36))	('adenocarcinoma', 'Disease', (111, 125))	('MYH9', 'Gene', (21, 25))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('poorer', 'NegReg', (71, 77))	('patients', 'Species', '9606', (90, 98))	('adenocarcinoma', 'Disease', 'MESH:D000230', (111, 125))
431970	25826333	The results indicated that MYH9 expression was a significantly independent predictor of a poorer survival (HR, 2.15; 95%CI, 1.17-3.92; P = 0.01) (Table 3).	('MYH9', 'Gene', '4627', (27, 31))	('expression', 'Var', (32, 42))	('poorer', 'NegReg', (90, 96))	('MYH9', 'Gene', (27, 31))	('survival', 'CPA', (97, 105))
431982	25826333	Thus, MYH9 expression may be associated with the acquisition of migration and invasion capabilities of tumor cells, which subsequently results in highly intratumoral lymphovascular invasion, and poorer prognoses in the present study.	('tumor', 'Disease', (158, 163))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('MYH9', 'Gene', '4627', (6, 10))	('invasion capabilities', 'CPA', (78, 99))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('tumor', 'Disease', (103, 108))	('MYH9', 'Gene', (6, 10))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('associated', 'Reg', (29, 39))	('migration', 'CPA', (64, 73))	('expression', 'Var', (11, 21))	('acquisition', 'PosReg', (49, 60))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('results in', 'Reg', (135, 145))
431990	24465228	Genomic Profiling of Liver Cancer Development of liver cancers is driven largely by genomic alterations that deregulate signaling pathways, influencing growth and survival of cancer cells.	('signaling pathways', 'Pathway', (120, 138))	('cancer', 'Disease', (175, 181))	('alterations', 'Var', (92, 103))	('Cancer', 'Phenotype', 'HP:0002664', (27, 33))	('Liver Cancer', 'Disease', (21, 33))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('liver cancers', 'Disease', 'MESH:D006528', (49, 62))	('growth', 'CPA', (152, 158))	('cancers', 'Phenotype', 'HP:0002664', (55, 62))	('cancer', 'Disease', (55, 61))	('liver cancer', 'Phenotype', 'HP:0002896', (49, 61))	('deregulate', 'Reg', (109, 119))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('Liver Cancer', 'Disease', 'MESH:D006528', (21, 33))	('liver cancers', 'Phenotype', 'HP:0002896', (49, 62))	('Liver Cancer', 'Phenotype', 'HP:0002896', (21, 33))	('liver cancers', 'Disease', (49, 62))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('influencing', 'Reg', (140, 151))
432002	24465228	Due to the complex nature of cancers that are initiated by activation of many different oncogenes or inactivation of different tumor suppressor genes and progress by additional genetic or epigenetic alterations, conventional gene-by-gene approaches are likely to deliver only a limited understanding of the biological and pathological characteristics of cancer cells.	('cancer', 'Disease', (354, 360))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('cancer', 'Disease', (29, 35))	('cancers', 'Phenotype', 'HP:0002664', (29, 36))	('epigenetic alterations', 'Var', (188, 210))	('tumor', 'Disease', (127, 132))	('oncogenes', 'Gene', (88, 97))	('cancers', 'Disease', 'MESH:D009369', (29, 36))	('cancer', 'Phenotype', 'HP:0002664', (354, 360))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('cancers', 'Disease', (29, 36))	('inactivation', 'Var', (101, 113))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('genetic', 'Var', (177, 184))	('cancer', 'Disease', 'MESH:D009369', (354, 360))	('activation', 'PosReg', (59, 69))	('cancer', 'Disease', 'MESH:D009369', (29, 35))
432004	24465228	This information promises to improve our understanding of the genetic and epigenetic alterations driving the development of liver cancer, as well as ultimately provide guidance on personalized treatment of patients.	('epigenetic alterations', 'Var', (74, 96))	('liver cancer', 'Phenotype', 'HP:0002896', (124, 136))	('liver cancer', 'Disease', 'MESH:D006528', (124, 136))	('liver cancer', 'Disease', (124, 136))	('patients', 'Species', '9606', (206, 214))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))
432006	24465228	Since the discovery of frequent genetic rearrangements and copy number aberrations in the cancer genome, cytogenetic methods have been used widely to find the genetic changes in cancer genomes.	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('cancer', 'Disease', (178, 184))	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('copy number aberrations', 'Var', (59, 82))
432008	24465228	Increased or decreased regions of copy number are believed to have either oncogenes or tumor suppressor genes.	('decreased', 'NegReg', (13, 22))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Disease', (87, 92))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('regions', 'Var', (23, 30))
432010	24465228	Multiple studies have reported amplification of the 8q24 loci, in which MYC is located.	('MYC', 'Gene', '4609', (72, 75))	('8q24', 'Gene', (52, 56))	('MYC', 'Gene', (72, 75))	('amplification', 'Var', (31, 44))
432013	24465228	Use of microarray technology is not restricted to genome-wide gene expression profiling of cells or tissues but expands to uncovering single-nucleotide polymorphisms associated with cancer risk, methylation status of gene promoters, DNA copy number alterations, protein expression profiling, and re-sequencing of cancer genomes.	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('copy number alterations', 'Var', (237, 260))	('cancer', 'Phenotype', 'HP:0002664', (313, 319))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('single-nucleotide polymorphisms', 'Var', (134, 165))	('cancer', 'Disease', (182, 188))	('associated', 'Reg', (166, 176))	('cancer', 'Disease', (313, 319))	('cancer', 'Disease', 'MESH:D009369', (313, 319))
432017	24465228	These new technologies have been used to identify potential driver mutations in the development of liver cancer through whole-genome and -exome sequencing.	('liver cancer', 'Disease', (99, 111))	('mutations', 'Var', (67, 76))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('liver cancer', 'Phenotype', 'HP:0002896', (99, 111))	('liver cancer', 'Disease', 'MESH:D006528', (99, 111))
432019	24465228	Following studies showed that the CTNNB1, TP53, and EGFR genes were frequently mutated in liver cancer.	('TP53', 'Gene', '7157', (42, 46))	('mutated', 'Var', (79, 86))	('EGFR', 'Gene', '1956', (52, 56))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('CTNNB1', 'Gene', (34, 40))	('EGFR', 'Gene', (52, 56))	('TP53', 'Gene', (42, 46))	('liver cancer', 'Phenotype', 'HP:0002896', (90, 102))	('liver cancer', 'Disease', 'MESH:D006528', (90, 102))	('CTNNB1', 'Gene', '1499', (34, 40))	('liver cancer', 'Disease', (90, 102))
432020	24465228	Additionally, the ARID family, including ARID1A, ARID1B, and ARID2, was mutated in about half of all tumors, suggesting a potential role of them in the development of liver cancer.	('liver cancer', 'Disease', 'MESH:D006528', (167, 179))	('mutated', 'Var', (72, 79))	('tumors', 'Disease', 'MESH:D009369', (101, 107))	('liver cancer', 'Disease', (167, 179))	('ARID1B', 'Gene', (49, 55))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('ARID1A', 'Gene', '8289', (41, 47))	('ARID2', 'Gene', '196528', (61, 66))	('ARID1A', 'Gene', (41, 47))	('ARID2', 'Gene', (61, 66))	('ARID1B', 'Gene', '57492', (49, 55))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('liver cancer', 'Phenotype', 'HP:0002896', (167, 179))	('tumors', 'Disease', (101, 107))
432028	24465228	As discussed earlier, CGH analyses have identified many recurrent candidate loci of DNA copy number changes in liver cancer.	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('liver cancer', 'Phenotype', 'HP:0002896', (111, 123))	('copy number changes', 'Var', (88, 107))	('liver cancer', 'Disease', 'MESH:D006528', (111, 123))	('liver cancer', 'Disease', (111, 123))	('DNA', 'Gene', (84, 87))
432032	24465228	Integrative analysis of copy number alteration data and gene expression further identified 50 driver candidates whose activation was triggered by copy number amplifications of genes and also significantly associated with aggressive tumor phenotypes in liver cancer.	('activation', 'PosReg', (118, 128))	('liver cancer', 'Disease', (252, 264))	('cancer', 'Phenotype', 'HP:0002664', (258, 264))	('liver cancer', 'Phenotype', 'HP:0002896', (252, 264))	('aggressive tumor', 'Disease', 'MESH:D001523', (221, 237))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('associated with', 'Reg', (205, 220))	('copy number amplifications', 'Var', (146, 172))	('aggressive tumor', 'Disease', (221, 237))	('liver cancer', 'Disease', 'MESH:D006528', (252, 264))
432033	24465228	Alterations in DNA copy number and expression patterns of thousands of genes are important characteristics of many cancer cells.	('cancer', 'Disease', (115, 121))	('Alterations', 'Var', (0, 11))	('expression', 'MPA', (35, 45))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('DNA', 'Gene', (15, 18))	('cancer', 'Disease', 'MESH:D009369', (115, 121))
432041	24465228	In lung squamous cell cancer, while KRAS and EGFR mutations, the most commonly activated oncogenes in lung adenocarcinoma, are extremely rare, alterations in the FGFR kinase family are common.	('lung squamous cell cancer', 'Disease', 'MESH:D002294', (3, 28))	('EGFR', 'Gene', (45, 49))	('mutations', 'Var', (50, 59))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (8, 28))	('lung squamous cell cancer', 'Disease', (3, 28))	('KRAS', 'Gene', (36, 40))	('KRAS', 'Gene', '3845', (36, 40))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (102, 121))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('lung adenocarcinoma', 'Disease', (102, 121))	('EGFR', 'Gene', '1956', (45, 49))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (102, 121))
432048	33387960	Aberrant expression of CBX4 has been implicated in several human malignancies.	('Aberrant expression', 'Var', (0, 19))	('human', 'Species', '9606', (59, 64))	('implicated', 'Reg', (37, 47))	('malignancies', 'Disease', 'MESH:D009369', (65, 77))	('malignancies', 'Disease', (65, 77))	('CBX4', 'Gene', (23, 27))
432051	33387960	Importantly, genetic ablation of CBX4 greatly dampened lung tumor formation and improved survival in the KrasG12D/P53L/L (KP) autochthonous mouse model of LUAD.	('mouse', 'Species', '10090', (140, 145))	('P53L', 'SUBSTITUTION', 'None', (114, 118))	('P53L', 'Var', (114, 118))	('genetic ablation', 'Var', (13, 29))	('survival', 'CPA', (89, 97))	('LUAD', 'Phenotype', 'HP:0030078', (155, 159))	('lung tumor', 'Phenotype', 'HP:0100526', (55, 65))	('improved', 'PosReg', (80, 88))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('CBX4', 'Gene', (33, 37))	('lung tumor', 'Disease', (55, 65))	('dampened', 'NegReg', (46, 54))	('lung tumor', 'Disease', 'MESH:D008175', (55, 65))
432052	33387960	In addition, CBX4 depletion significantly inhibited proliferation and anchorage-independent growth of KP mouse embryonic fibroblasts.	('proliferation', 'CPA', (52, 65))	('mouse', 'Species', '10090', (105, 110))	('inhibited', 'NegReg', (42, 51))	('anchorage-independent growth', 'CPA', (70, 98))	('depletion', 'Var', (18, 27))	('CBX4', 'Gene', (13, 17))
432053	33387960	Moreover, ectopic CBX4 expression clearly promoted proliferation and anchorage-independent growth in both human and mouse LUAD cells, whereas silencing of CBX4 exerted opposite effects.	('human', 'Species', '9606', (106, 111))	('CBX4', 'Gene', (18, 22))	('CBX4', 'Gene', (155, 159))	('proliferation', 'CPA', (51, 64))	('anchorage-independent growth', 'CPA', (69, 97))	('ectopic', 'Var', (10, 17))	('promoted', 'PosReg', (42, 50))	('mouse', 'Species', '10090', (116, 121))	('LUAD', 'Phenotype', 'HP:0030078', (122, 126))
432060	33387960	For instance, pharmacologic inhibition of EZH2, the catalytic subunit of PRC2, has been demonstrated to be a promising treatment in various types of cancer including lung cancer.	('cancer', 'Disease', (149, 155))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('EZH2', 'Gene', '14056', (42, 46))	('lung cancer', 'Disease', 'MESH:D008175', (166, 177))	('cancer', 'Disease', (171, 177))	('pharmacologic', 'Var', (14, 27))	('EZH2', 'Gene', (42, 46))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('lung cancer', 'Disease', (166, 177))	('lung cancer', 'Phenotype', 'HP:0100526', (166, 177))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('cancer', 'Disease', 'MESH:D009369', (149, 155))
432074	33387960	The KrasG12D and P53L/L mice were originally generously provided by Dr. Tyler Jacks, Dr. Kwok-Kin Wong, and Dr. Ronald A. DePinho, respectively.	('P53L', 'SUBSTITUTION', 'None', (17, 21))	('KrasG12D', 'Var', (4, 12))	('P53L', 'Var', (17, 21))	('mice', 'Species', '10090', (24, 28))
432077	33387960	At an age of 8 weeks, KrasG12D/P53L/L (KP) and KrasG12D/P53L/L/Cbx4L/L (KPC) mice were treated with 2  x 106 PFU Adeno-Cre by nasal inhalation as previously described.	('P53L', 'Var', (56, 60))	('mice', 'Species', '10090', (77, 81))	('Cbx4', 'Gene', (63, 67))	('Cbx4', 'Gene', '12418', (63, 67))	('P53L', 'SUBSTITUTION', 'None', (31, 35))	('P53L', 'Var', (31, 35))	('P53L', 'SUBSTITUTION', 'None', (56, 60))
432098	33387960	Western blot analysis was performed using the following antibodies: CBX4 from Santa Cruz (1:500, SC-199929); beta-catenin from Proteintech (1:1000, 51067-2-AP); c-MYC from Abclonal (1:1000, A17332); CyclinD1 from CST (1:1000, #2926); Tublin from DSHB (1:1000, E7); and Actin from Sigma-Aldrich (1:1000, A1978).	('CST', 'Gene', '12854', (213, 216))	('CST', 'Gene', (213, 216))	('Actin', 'Protein', (269, 274))	('Tublin', 'Protein', (234, 240))	('beta-catenin', 'Protein', (109, 121))	('CyclinD1', 'Gene', (199, 207))	('c-MYC', 'Protein', (161, 166))	('1:1000', 'Var', (252, 258))	('CyclinD1', 'Gene', '12443', (199, 207))	('CBX4', 'Gene', (68, 72))
432113	33387960	CBX4 antibody for IHC was generated by Dr. Guoliang Xu and described previously; KI67 (1:1000, SC-23900); Cleaved caspase-3 (1:200, CST #9661); beta-catenin (1:2000, Proteintech-51067-2-AP); and VEGFR2 (CST #55B11).	('VEGFR2', 'Gene', (195, 201))	('Cleaved', 'Var', (106, 113))	('caspase-3', 'Gene', (114, 123))	('CST', 'Gene', '12854', (203, 206))	('CST', 'Gene', (203, 206))	('VEGFR2', 'Gene', '16542', (195, 201))	('CST', 'Gene', '12854', (132, 135))	('KI67', 'Gene', (81, 85))	('CST', 'Gene', (132, 135))	('caspase-3', 'Gene', '12367', (114, 123))	('KI67', 'Gene', '17345', (81, 85))
432117	33387960	The median IRS value (IRS = 4) of intratumoral CBX4 expression was chosen as the cut-off for differentiating between high and low CBX4 expression.	('CBX4', 'Gene', (47, 51))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('IRS = 4', 'Gene', '16370', (22, 29))	('IRS = 4', 'Gene', (22, 29))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('low', 'NegReg', (126, 129))	('expression', 'MPA', (135, 145))	('tumor', 'Disease', (39, 44))	('high', 'Var', (117, 121))	('CBX4', 'Gene', (130, 134))
432118	33387960	An IRS of >=4 was used to define tumors with high CBX4 expression and an IRS of <4 was used to indicate tumors with low CBX4 expression.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('expression', 'MPA', (55, 65))	('tumors', 'Disease', (104, 110))	('CBX4', 'Gene', (50, 54))	('high', 'Var', (45, 49))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('tumors', 'Disease', 'MESH:D009369', (33, 39))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('tumors', 'Disease', (33, 39))
432126	33387960	Importantly, survival analysis of the 72 LUAD patients revealed that patients with high intratumoral CBX4 expression had a significantly shorter survival time than those with low CBX4 expression (Figure 1E).	('patients', 'Species', '9606', (46, 54))	('shorter', 'NegReg', (137, 144))	('LUAD', 'Phenotype', 'HP:0030078', (41, 45))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Disease', (93, 98))	('CBX4', 'Gene', (101, 105))	('survival time', 'CPA', (145, 158))	('high', 'Var', (83, 87))	('patients', 'Species', '9606', (69, 77))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
432128	33387960	While, no significant survival difference were observed between high and low CBX4 expression in patients with lung squamous cell carcinoma (LUSC) (Figure S1).	('high', 'Var', (64, 68))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (110, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (110, 138))	('lung squamous cell carcinoma', 'Disease', (110, 138))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (115, 138))	('patients', 'Species', '9606', (96, 104))	('low', 'NegReg', (73, 76))	('LUSC', 'Phenotype', 'HP:0030359', (140, 144))	('CBX4', 'Gene', (77, 81))
432129	33387960	The KrasG12D/P53L/L (KP) mouse model is a well-established autochthonous model for the study of LUAD tumorigenesis.	('LUAD', 'Phenotype', 'HP:0030078', (96, 100))	('mouse', 'Species', '10090', (25, 30))	('tumor', 'Disease', (101, 106))	('P53L', 'SUBSTITUTION', 'None', (13, 17))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('P53L', 'Var', (13, 17))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
432132	33387960	To determine the role of CBX4 in LUAD tumorigenesis in vivo, we crossed Cbx4L/L mice with KP mice to generate the KrasG12D/P53L/L/Cbx4L/L (KPC) mice.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('Cbx4', 'Gene', '12418', (130, 134))	('mice', 'Species', '10090', (144, 148))	('P53L', 'SUBSTITUTION', 'None', (123, 127))	('P53L', 'Var', (123, 127))	('LUAD', 'Phenotype', 'HP:0030078', (33, 37))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('Cbx4', 'Gene', (72, 76))	('mice', 'Species', '10090', (93, 97))	('mice', 'Species', '10090', (80, 84))	('Cbx4', 'Gene', '12418', (72, 76))	('Cbx4', 'Gene', (130, 134))
432136	33387960	Importantly, deletion of CBX4 significantly prolonged the survival of KP mice (median survival times: 16.9 weeks in KPC mice vs 8.3 weeks in KP mice, P < 0.001; Figure 2D).	('prolonged', 'PosReg', (44, 53))	('CBX4', 'Gene', (25, 29))	('mice', 'Species', '10090', (120, 124))	('mice', 'Species', '10090', (144, 148))	('mice', 'Species', '10090', (73, 77))	('deletion', 'Var', (13, 21))	('survival', 'MPA', (58, 66))
432138	33387960	Quantitative analysis confirmed that both tumor number and the tumor area were dramatically reduced in KPCvs KP mice (Figure 2F,G).	('tumor', 'Disease', (63, 68))	('tumor', 'Disease', (42, 47))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('mice', 'Species', '10090', (112, 116))	('reduced', 'NegReg', (92, 99))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('KPCvs KP', 'Var', (103, 111))
432140	33387960	Further IHC analysis revealed that deletion of CBX4 greatly suppressed the proliferation of cancer cells, as indicated by decreased Ki67 staining in KPC mice compared with KP mice (Figure 2I,J).	('mice', 'Species', '10090', (175, 179))	('cancer', 'Disease', (92, 98))	('suppressed', 'NegReg', (60, 70))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('Ki67', 'Gene', '17345', (132, 136))	('deletion', 'Var', (35, 43))	('CBX4', 'Gene', (47, 51))	('mice', 'Species', '10090', (153, 157))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('Ki67', 'Gene', (132, 136))	('decreased', 'NegReg', (122, 131))
432144	33387960	The MEFs were infected with Adeno-Cre to activate KrasG12D with concurrent knockout P53 and Cbx4 at the genomic DNA level.	('P53', 'Gene', '22059', (84, 87))	('infected', 'Disease', 'MESH:D007239', (14, 22))	('knockout', 'Var', (75, 83))	('MEFs', 'CellLine', 'CVCL:9115', (4, 8))	('infected', 'Disease', (14, 22))	('Cbx4', 'Gene', (92, 96))	('Cbx4', 'Gene', '12418', (92, 96))	('P53', 'Gene', (84, 87))
432148	33387960	MTT assay showed that knockout of CBX4 suppressed the increased cell growth in KP MEFs (Figure 3E).	('cell growth in', 'CPA', (64, 78))	('CBX4', 'Gene', (34, 38))	('MEFs', 'CellLine', 'CVCL:9115', (82, 86))	('MTT', 'Chemical', 'MESH:C070243', (0, 3))	('knockout', 'Var', (22, 30))	('suppressed', 'NegReg', (39, 49))
432153	33387960	Consistently, ectopic expression of CBX4 promoted cell growth and also colony formation in soft agar in each cell line (Figure 4D-F).	('agar', 'Chemical', 'MESH:D000362', (96, 100))	('cell growth', 'CPA', (50, 61))	('promoted', 'PosReg', (41, 49))	('CBX4', 'Gene', (36, 40))	('colony formation in soft agar', 'CPA', (71, 100))	('ectopic expression', 'Var', (14, 32))
432156	33387960	Not surprisingly, knockdown of CBX4 resulted in reduced cell growth and soft agar colony formation capacity in both cell lines (Figure 5C-E).	('knockdown', 'Var', (18, 27))	('cell growth', 'CPA', (56, 67))	('reduced', 'NegReg', (48, 55))	('CBX4', 'Gene', (31, 35))	('soft agar colony formation capacity', 'CPA', (72, 107))	('agar', 'Chemical', 'MESH:D000362', (77, 81))
432163	33387960	Interestingly, we found that protein levels of beta-catenin were greatly reduced in the tumors from KPC mice vs KP mice (Figure 6A), indicating that the Wnt/beta-catenin pathway might be involved in mediating the CBX4's action.	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('protein levels of beta-catenin', 'MPA', (29, 59))	('mice', 'Species', '10090', (115, 119))	('reduced', 'NegReg', (73, 80))	('mice', 'Species', '10090', (104, 108))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('KPC', 'Var', (100, 103))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('tumors', 'Disease', (88, 94))
432164	33387960	To test this hypothesis, we evaluated the levels of beta-catenin and found that knockdown of CBX4 in A549 cells greatly reduced beta-catenin expression at both RNA and protein levels (Figure 6B-D).	('knockdown', 'Var', (80, 89))	('beta-catenin', 'Protein', (128, 140))	('A549', 'CellLine', 'CVCL:0023', (101, 105))	('CBX4', 'Gene', (93, 97))	('expression', 'MPA', (141, 151))	('reduced', 'NegReg', (120, 127))
432166	33387960	Conversely, ectopic CBX4 expression clearly up-regulated the levels of beta-catenin as well as its downstream targets c-Myc and cyclinD1 in A549 cells (Figure 6E-G).	('A549', 'CellLine', 'CVCL:0023', (140, 144))	('cyclinD1', 'Gene', '12443', (128, 136))	('cyclinD1', 'Gene', (128, 136))	('CBX4', 'Gene', (20, 24))	('c-Myc', 'MPA', (118, 123))	('up-regulated', 'PosReg', (44, 56))	('expression', 'Var', (25, 35))	('ectopic', 'Var', (12, 19))	('levels of beta-catenin', 'MPA', (61, 83))
432167	33387960	More important, knockdown of beta-catenin through siRNA not only markedly inhibited the expression of beta-catenin as well as its downstream targets c-Myc and cyclinD1 (Figure 6H-I), but also abrogated the effects of CBX4 on cell growth and colony formation in soft agar (Figure 6J-L).	('inhibited', 'NegReg', (74, 83))	('colony formation in soft agar', 'CPA', (241, 270))	('cyclinD1', 'Gene', '12443', (159, 167))	('cyclinD1', 'Gene', (159, 167))	('cell growth', 'CPA', (225, 236))	('beta-catenin', 'Protein', (29, 41))	('expression', 'MPA', (88, 98))	('knockdown', 'Var', (16, 25))	('beta-catenin', 'Protein', (102, 114))	('agar', 'Chemical', 'MESH:D000362', (266, 270))	('abrogated', 'NegReg', (192, 201))
432171	33387960	Dysregulation of PcG proteins has been linked to tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('Dysregulation', 'Var', (0, 13))	('PcG proteins', 'Protein', (17, 29))	('tumor', 'Disease', (49, 54))	('linked', 'Reg', (39, 45))
432184	33387960	To address this, we employ the well-established KP mouse model and demonstrate that genetic ablation of Cbx4 profoundly attenuated lung tumor formation and improved survival in mice.	('lung tumor', 'Disease', 'MESH:D008175', (131, 141))	('Cbx4', 'Gene', (104, 108))	('survival', 'CPA', (165, 173))	('ablation', 'Var', (92, 100))	('improved', 'PosReg', (156, 164))	('mouse', 'Species', '10090', (51, 56))	('Cbx4', 'Gene', '12418', (104, 108))	('lung tumor', 'Phenotype', 'HP:0100526', (131, 141))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('mice', 'Species', '10090', (177, 181))	('lung tumor', 'Disease', (131, 141))	('attenuated', 'NegReg', (120, 130))
432189	33387960	Besides, we did not observe an obvious up-regulation of CBX4 in tumors from KrasG12D mice compared with adjacent normal tissues (Figure S4).	('mice', 'Species', '10090', (85, 89))	('tumors', 'Disease', (64, 70))	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('CBX4', 'Gene', (56, 60))	('KrasG12D', 'Var', (76, 84))	('up-regulation', 'PosReg', (39, 52))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
432190	33387960	These results indicate that mutant KRAS may not be responsible for the CBX4 up-regulation in KP mice.	('mutant', 'Var', (28, 34))	('up-regulation', 'PosReg', (76, 89))	('KRAS', 'Gene', (35, 39))	('mice', 'Species', '10090', (96, 100))	('KRAS', 'Gene', '16653', (35, 39))	('CBX4', 'Gene', (71, 75))
432201	33387960	In addition, knockdown of CBX4 markedly inhibited beta-catenin and its downstream targets c-Myc and cyclinD1 both at mRNA and protein levels, whereas ectopic expression of CBX4 did the opposite.	('inhibited', 'NegReg', (40, 49))	('c-Myc', 'MPA', (90, 95))	('cyclinD1', 'Gene', '12443', (100, 108))	('beta-catenin', 'MPA', (50, 62))	('CBX4', 'Gene', (26, 30))	('knockdown', 'Var', (13, 22))	('cyclinD1', 'Gene', (100, 108))
432212	33387960	), the  CAS to Z.W.,  (19ZR1466300 to Z.W.	('CAS', 'Gene', '12388', (8, 11))	('CAS', 'Gene', (8, 11))	('19ZR1466300', 'Var', (23, 34))
432348	30444080	The antibodies used were as follows: anti-Capn4 (1:1000), anti-beta-catenin (Abcam, Cambridge, MA, USA); anti-ZEB1 (1:1000, Cell Signaling Technology, Danvers, MA, USA); and anti-GAPDH (1:1000, Santa Cruz, Biotechnology Inc., Santa Cruz, CA, USA).	('beta-catenin', 'Gene', (63, 75))	('GAPDH', 'Gene', (179, 184))	('beta-catenin', 'Gene', '1499', (63, 75))	('anti-ZEB1', 'Var', (105, 114))	('anti-Capn4', 'Var', (37, 47))	('GAPDH', 'Gene', '2597', (179, 184))
432352	30444080	Esophageal squamous cell carcinoma cells overexpressing or silencing Capn4 were transplanted into SCID beige mice via tail vein injection.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (11, 34))	('Esophageal squamous cell carcinoma', 'Disease', (0, 34))	('SCID', 'Disease', 'MESH:D053632', (98, 102))	('carcinoma', 'Phenotype', 'HP:0030731', (25, 34))	('SCID', 'Disease', (98, 102))	('Capn4', 'Gene', (69, 74))	('mice', 'Species', '10090', (109, 113))	('silencing', 'Var', (59, 68))	('Esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (0, 34))
432359	30444080	qRT-PCR and Western blotting results showed that knockdown of Capn4 reduced ZEB1 mRNA and protein levels in the ECA109 and TE7 cells (Fig 2b-d).	('knockdown', 'Var', (49, 58))	('Capn4', 'Gene', (62, 67))	('TE7', 'CellLine', 'CVCL:9972', (123, 126))	('reduced', 'NegReg', (68, 75))
432366	30444080	Meanwhile, in a TOP-Flash reporter luciferase assay, silencing of Capn4 in ECA109 cells decreased the transcriptional activity of TCF4 compared to the control groups (Fig 4b).	('transcriptional activity', 'MPA', (102, 126))	('silencing', 'Var', (53, 62))	('Capn4', 'Gene', (66, 71))	('decreased', 'NegReg', (88, 97))	('TCF4', 'Gene', (130, 134))	('TCF4', 'Gene', '6925', (130, 134))
432367	30444080	In addition, we found that upregulation of beta-catenin reversed the effects of decreased ZEB1 expression and cell migration and invasion induced by Capn4 knockdown (Fig.	('Capn4', 'Gene', (149, 154))	('expression', 'MPA', (95, 105))	('knockdown', 'Var', (155, 164))	('beta-catenin', 'Gene', '1499', (43, 55))	('cell migration', 'CPA', (110, 124))	('decreased', 'NegReg', (80, 89))	('upregulation', 'PosReg', (27, 39))	('beta-catenin', 'Gene', (43, 55))	('ZEB1', 'Protein', (90, 94))
432379	30444080	Second, Capn4 knockdown led to the recovery of ZEB1 protein levels in cells overexpressing beta-catenin.	('Capn4', 'Gene', (8, 13))	('ZEB1', 'Protein', (47, 51))	('beta-catenin', 'Gene', (91, 103))	('recovery', 'MPA', (35, 43))	('knockdown', 'Var', (14, 23))	('beta-catenin', 'Gene', '1499', (91, 103))
432380	30444080	Third, Capn4 upregulation decreased ZEB1 in cells silencing beta-catenin.	('silencing', 'Var', (50, 59))	('ZEB1', 'MPA', (36, 40))	('beta-catenin', 'Gene', (60, 72))	('Capn4', 'Gene', (7, 12))	('upregulation', 'PosReg', (13, 25))	('beta-catenin', 'Gene', '1499', (60, 72))	('decreased', 'NegReg', (26, 35))
432386	30410362	The results showed that cytokine secretion increased significantly after EGFR-CAR T-cells were incubated with target cells, and EGFR-CAR T-cells has higher cytotoxic effect on target cells than the CART-control group.	('EGFR-CAR', 'Var', (128, 136))	('CART', 'Gene', '9607', (198, 202))	('cytokine secretion', 'MPA', (24, 42))	('CART', 'Gene', (198, 202))	('increased', 'PosReg', (43, 52))	('cytotoxic effect', 'CPA', (156, 172))	('higher', 'PosReg', (149, 155))
432410	30410362	The CART (effect cells) were treated in the same way, and the cell density was finally adjusted to 2x106/mL, 1x106/mL, 0.5x106/mL, 0.25x106/mL, and 0.125x106/mL.	('0.5x106/mL', 'Var', (119, 129))	('0.125x106/mL', 'Var', (148, 160))	('0.25x106/mL', 'Var', (131, 142))	('CART', 'Gene', '9607', (4, 8))	('CART', 'Gene', (4, 8))
432414	30410362	The infection rate of EGFR-CAR T-cells was approximately 67.13%, and the infection rate of the CART-control group was approximately 67.46%.	('EGFR-CAR', 'Var', (22, 30))	('infection', 'CPA', (4, 13))	('CART', 'Gene', (95, 99))	('CART', 'Gene', '9607', (95, 99))
432431	30410362	Moreover, many target cells were lysed under the action of EGFR-CAR T-cells, indicating that EGFR-CAR T-cells have a strong tumor killing effect.	('EGFR-CAR', 'Var', (93, 101))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('tumor', 'Disease', (124, 129))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
432432	30410362	Overall, it was shown that EGFR-CAR T-cells were activated and produced an antitumor effect through targeting EGFR in hypopharyngeal squamous cell carcinoma.	('hypopharyngeal squamous cell carcinoma', 'Disease', (118, 156))	('carcinoma', 'Phenotype', 'HP:0030731', (147, 156))	('tumor', 'Disease', (79, 84))	('EGFR', 'Gene', (110, 114))	('hypopharyngeal squamous cell carcinoma', 'Phenotype', 'HP:0012182', (118, 156))	('hypopharyngeal squamous cell carcinoma', 'Disease', 'MESH:D002294', (118, 156))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (133, 156))	('targeting', 'Var', (100, 109))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
432451	30410362	In a Phase I clinical trial in the treatment of GD2+ neuroblastoma, GD2-CAR T-cell therapy showed stronger antitumor effects and few side effects, only presenting as mild fever and mild to moderate pain due to tumor necrosis.	('stronger', 'PosReg', (98, 106))	('pain due to tumor necrosis', 'Phenotype', 'HP:0010885', (198, 224))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('fever', 'Disease', 'MESH:D005334', (171, 176))	('fever', 'Disease', (171, 176))	('tumor', 'Disease', (210, 215))	('pain', 'Disease', (198, 202))	('mild fever', 'Phenotype', 'HP:0011134', (166, 176))	('tumor', 'Disease', 'MESH:D009369', (210, 215))	('tumor necrosis', 'Disease', 'MESH:D009336', (210, 224))	('pain', 'Phenotype', 'HP:0012531', (198, 202))	('tumor', 'Disease', (111, 116))	('neuroblastoma', 'Disease', (53, 66))	('fever', 'Phenotype', 'HP:0001945', (171, 176))	('GD2-CAR', 'Var', (68, 75))	('tumor necrosis', 'Disease', (210, 224))	('neuroblastoma', 'Phenotype', 'HP:0003006', (53, 66))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('neuroblastoma', 'Disease', 'MESH:D009447', (53, 66))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('pain', 'Disease', 'MESH:D010146', (198, 202))
432456	30410362	Therefore, cancer therapy targeting EGFR and its mutants is widely studied.	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('mutants', 'Var', (49, 56))	('cancer', 'Disease', 'MESH:D009369', (11, 17))	('EGFR', 'Gene', (36, 40))	('cancer', 'Disease', (11, 17))
432472	30181806	We hypothesize that a higher sensitivity to smoking-related damages and the enrichment of defective DNA MMR related mutations may contribute to the higher mutational burden of younger patients.	('mutations', 'Var', (116, 125))	('DNA MMR related', 'Gene', (100, 115))	('patients', 'Species', '9606', (184, 192))
432481	30181806	Signature 1 (SI1) characterized by C>T transitions at CpG sites due to the deamination of 5-methylcytosine was associated to mutational processes related to the ageing.	('deamination of 5-methylcytosine', 'MPA', (75, 106))	('5-methylcytosine', 'Chemical', 'MESH:D044503', (90, 106))	('C', 'Chemical', 'MESH:D002244', (35, 36))	('associated', 'Reg', (111, 121))	('C', 'Chemical', 'MESH:D002244', (54, 55))	('C>T transitions', 'Var', (35, 50))
432482	30181806	While Signature 4 (SI4) associated with C>A transversions was found in cancers in which tobacco smoking increases risk and mainly in those derived from cells directly exposed to the tobacco smoke.	('cancers', 'Disease', 'MESH:D009369', (71, 78))	('cancers', 'Phenotype', 'HP:0002664', (71, 78))	('tobacco', 'Species', '4097', (88, 95))	('cancers', 'Disease', (71, 78))	('C>A transversions', 'Var', (40, 57))	('tobacco', 'Species', '4097', (182, 189))	('C', 'Chemical', 'MESH:D002244', (40, 41))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))
432484	30181806	Past studies hypothesized that chemicals of tobacco smoke increases the speed with which these mutations accumulate.	('tobacco', 'Species', '4097', (44, 51))	('increases', 'PosReg', (58, 67))	('mutations', 'Var', (95, 104))
432487	30181806	Therefore the hypothesis of the "mutator phenotype", which is a tumor harboring mutations in DNA polymerases and DNA repair genes, has to be taken into account.	('tumor', 'Disease', (64, 69))	('mutations', 'Var', (80, 89))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('DNA polymerases', 'Gene', (93, 108))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
432488	30181806	Furthermore, Copy Number Variations (CNVs) play also important roles in the development of cancer showing an association with ageing in terms of longevity, healthy aging, and aging-related pathologies.	('Copy Number Variations', 'Var', (13, 35))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('C', 'Chemical', 'MESH:D002244', (37, 38))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('C', 'Chemical', 'MESH:D002244', (13, 14))
432490	30181806	Moreover, epigenomic alteration is now increasingly recognized as part of aging and its associated pathologic phenotypes as cancer.	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('cancer', 'Disease', (124, 130))	('cancer', 'Disease', 'MESH:D009369', (124, 130))	('epigenomic alteration', 'Var', (10, 31))
432492	30181806	The epimutation rate appears to be almost 100,000 times the mutation rate and aberrant DNA methylation can predispose to malignancy.	('predispose', 'Reg', (107, 117))	('malignancy', 'Disease', 'MESH:D009369', (121, 131))	('malignancy', 'Disease', (121, 131))	('aberrant DNA methylation', 'Var', (78, 102))	('epimutation', 'Var', (4, 15))
432498	30181806	Genome-wide mutations and epigenomic changes are expected to varying among tumor subtypes showing a different distribution across age.	('mutations', 'Var', (12, 21))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('epigenomic changes', 'Var', (26, 44))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', (75, 80))
432505	30181806	The analysis of sub-cohort with a high mutational load (i.e., transversion-high status) showed a negative correlation between the SNPs load and patient age while no correlations were detected in the low mutational load sub-cohort (i.e., transversion low status) (Table 1).	('high mutational load', 'Var', (34, 54))	('negative', 'NegReg', (97, 105))	('patient', 'Species', '9606', (144, 151))	('SNPs load', 'MPA', (130, 139))
432511	30181806	In order to explore the hypothesis of possible mutator phenotypes contributing to the high mutational rate detected among younger patients, we analyzed whether mutations harboring on the top 20 frequently mutated DNA repair genes in lung cancer might have a significant impact on the SNPs load.	('mutations', 'Var', (160, 169))	('impact', 'Reg', (270, 276))	('lung cancer', 'Phenotype', 'HP:0100526', (233, 244))	('lung cancer', 'Disease', (233, 244))	('DNA repair genes', 'Gene', (213, 229))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('patients', 'Species', '9606', (130, 138))	('lung cancer', 'Disease', 'MESH:D008175', (233, 244))	('SNPs load', 'MPA', (284, 293))
432517	30181806	The defective DNA mismatch repair (MMR)-related signature 6 (SI6) was negatively correlated (rho=-0.13, p=0.004, FDR=0.12) with the patient age (Figure 2A) while the signature 26 (SI26) as well associated with defective DNA MMR, was positively correlated (rho=0.11, p=0.013, FDR=0.20) with the patient age (Figure 2B).	('patient', 'Species', '9606', (294, 301))	('defective', 'Var', (4, 13))	('SI26', 'Var', (180, 184))	('SI26', 'Chemical', '-', (180, 184))	('patient', 'Species', '9606', (132, 139))
432518	30181806	The smoking-related SI4 was negatively correlated (rho=-0.11, p=0.02, FDR=0.21) with patient age (Figure 2C), showing higher values in the <=50 and 51-60 age groups (Supplementary Table 7).	('patient', 'Species', '9606', (85, 92))	('C', 'Chemical', 'MESH:D002244', (106, 107))	('higher values', 'PosReg', (118, 131))	('SI4', 'Var', (20, 23))
432519	30181806	In order to study the patient sub-cohorts, which predominantly exhibit SI26 and SI6, we divided the overall LUSC cohort into four subgroups using the mean values of SI6 and SI26 as threshold (Figure 2D): high-SI6/high-SI26 (77/480=16.0%), low-SI6/high-SI26 (55/480=11.0%), high-SI6/low-SI26 (223/480=45.8%), and low-SI6/low-SI26 (130/480=27.1%).	('SI26', 'Chemical', '-', (173, 177))	('high-SI6/high-SI26', 'Var', (204, 222))	('SI26', 'Chemical', '-', (218, 222))	('SI26', 'Chemical', '-', (252, 256))	('SI26', 'Chemical', '-', (71, 75))	('C', 'Chemical', 'MESH:D002244', (111, 112))	('low-SI6/low-SI26', 'Disease', 'MESH:D009800', (312, 328))	('SI26', 'Chemical', '-', (286, 290))	('low-SI6/high-SI26', 'Var', (239, 256))	('SI6 and SI26', 'Disease', 'None', (165, 177))	('SI26', 'Chemical', '-', (324, 328))	('patient', 'Species', '9606', (22, 29))	('low-SI6/low-SI26', 'Disease', (312, 328))	('high-SI6/low-SI26', 'Var', (273, 290))
432521	30181806	The patients age of the low-SI6/high-SI26 cohort was significantly higher than the high-SI6/low-SI26 cohort (Wilcoxon Rank-Sum test: p=0.005).	('SI26', 'Chemical', '-', (37, 41))	('higher', 'PosReg', (67, 73))	('low-SI6/high-SI26', 'Var', (24, 41))	('SI26', 'Chemical', '-', (96, 100))	('patients', 'Species', '9606', (4, 12))
432523	30181806	To study the molecular effects of these signatures independently, we projected the SNPs, CNVs and DNA methylation values from the high-SI6/low-SI26 and low-SI6/high-SI26 subtypes into the space of the 186 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways by means of single-sample gene set enrichment analysis (ssGSEA) (Supplementary Table 9).	('GSEA', 'Chemical', '-', (319, 323))	('high-SI6/low-SI26', 'Var', (130, 147))	('SI26', 'Chemical', '-', (143, 147))	('SI26', 'Chemical', '-', (165, 169))	('low-SI6/high-SI26', 'Var', (152, 169))	('C', 'Chemical', 'MESH:D002244', (89, 90))
432525	30181806	The Regulation of Autophagy pathway (p=0.0006, FDR=0.06) showed an enrichment of SNPs in low-SI6/high-SI26 patient sub-cohort.	('SI26', 'Chemical', '-', (102, 106))	('patient', 'Species', '9606', (107, 114))	('Autophagy pathway', 'CPA', (18, 35))	('low-SI6/high-SI26', 'Var', (89, 106))
432527	30181806	In Figure 3, the GSEA values of "ECM-Receptor Interaction" pathway were reported for both (Figure 3A) high-SI6/low-SI26 and (Figure 3B) low-SI6/high-SI26 patient sub-cohorts in order to visualize the different trends.	('low-SI6/high-SI26', 'Var', (136, 153))	('patient', 'Species', '9606', (154, 161))	('SI26', 'Chemical', '-', (149, 153))	('GSEA', 'Chemical', '-', (17, 21))	('C', 'Chemical', 'MESH:D002244', (34, 35))	('SI26', 'Chemical', '-', (115, 119))	('high-SI6/low-SI26', 'Var', (102, 119))
432536	30181806	Age-dependent hypermethylation at CpGs was observed to be enriched with DNA binding factors and transcription factors, therefore the dysregulation can simultaneously affect several biological processes.	('affect', 'Reg', (166, 172))	('C', 'Chemical', 'MESH:D002244', (34, 35))	('hypermethylation', 'Var', (14, 30))
432543	30181806	Therefore NOTCH1 aberrations might be involved in the peculiar higher mutational burden of younger LUSC patients.	('C', 'Chemical', 'MESH:D002244', (102, 103))	('involved', 'Reg', (38, 46))	('NOTCH1', 'Gene', '4851', (10, 16))	('aberrations', 'Var', (17, 28))	('mutational burden', 'MPA', (70, 87))	('NOTCH1', 'Gene', (10, 16))	('patients', 'Species', '9606', (104, 112))	('C', 'Chemical', 'MESH:D002244', (13, 14))
432549	30181806	Past studies described a similar scenario showing that despite maintained carcinogen exposure, tumors from smokers showed a relative decrease in smoking-related mutations over time.	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('decrease', 'NegReg', (133, 141))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('smoking-related', 'MPA', (145, 160))	('mutations', 'Var', (161, 170))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumors', 'Disease', (95, 101))
432550	30181806	Therefore, younger patients may develop higher sensitivity to smoking-related mutations.	('sensitivity', 'MPA', (47, 58))	('patients', 'Species', '9606', (19, 27))	('mutations', 'Var', (78, 87))
432554	30181806	Both SI6 and SI26 are found in microsatellite unstable tumors with high numbers of small (shorter than 3bp) insertions and deletions at mono/polynucleotide repeats.	('microsatellite unstable tumors', 'Disease', (31, 61))	('microsatellite unstable tumors', 'Disease', 'MESH:D053842', (31, 61))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('deletions', 'Var', (123, 132))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('SI6 and SI26', 'Disease', 'None', (5, 17))	('insertions', 'Var', (108, 118))	('mono', 'Chemical', 'MESH:C106553', (136, 140))	('polynucleotide', 'Chemical', 'MESH:D011119', (141, 155))
432559	30181806	We identified the SNPs enrichment in ECM-Receptor Interaction pathway among younger patients of high-SI6/low-SI26 sub-cohort.	('SI26', 'Chemical', '-', (109, 113))	('patients', 'Species', '9606', (84, 92))	('ECM-Receptor Interaction pathway', 'Pathway', (37, 69))	('high-SI6/low-SI26', 'Var', (96, 113))	('C', 'Chemical', 'MESH:D002244', (38, 39))
432561	30181806	Aberrant ECM may promote genetic instability and might compromise DNA repair pathways necessary to prevent malignant transformation.	('genetic instability', 'CPA', (25, 44))	('Aberrant', 'Var', (0, 8))	('DNA repair pathways', 'Pathway', (66, 85))	('promote', 'PosReg', (17, 24))	('compromise', 'NegReg', (55, 65))	('C', 'Chemical', 'MESH:D002244', (10, 11))
432562	30181806	Furthermore, we identified an enrichment of CNVs in Nucleotide Excision Repair (NER) pathway in high-SI6/low-SI26 sub-cohort.	('SI26', 'Chemical', '-', (109, 113))	('C', 'Chemical', 'MESH:D002244', (44, 45))	('CNVs', 'Var', (44, 48))	('high-SI6/low-SI26', 'Var', (96, 113))
432563	30181806	Since the NER system is primarily responsible for detecting and removing bulky DNA lesions induced by tobacco smoke in the respiratory tract, SNPs in NER protein-encoding genes may contribute to the higher sensitivity to smoking consumption detected in younger patients.	('patients', 'Species', '9606', (261, 269))	('tobacco', 'Species', '4097', (102, 109))	('NER', 'Gene', (150, 153))	('SNPs', 'Var', (142, 146))
432565	30181806	The low-SI6/high-SI26 sub-cohort was enriched in SNPs disruptions of Regulation of Autophagy pathway involved in lysosome-dependent degradation processes.	('low-SI6/high-SI26', 'Var', (4, 21))	('Regulation', 'MPA', (69, 79))	('SI26', 'Chemical', '-', (17, 21))	('disruptions', 'Var', (54, 65))	('SNPs', 'Gene', (49, 53))	('Autophagy pathway', 'Pathway', (83, 100))
432566	30181806	Therefore, disruption of Regulation of Autophagy pathway might contribute to the defective DNA MMR system in low-SI6/high-SI26 patient sub-cohort.	('SI26', 'Chemical', '-', (122, 126))	('patient', 'Species', '9606', (127, 134))	('defective', 'NegReg', (81, 90))	('low-SI6/high-SI26', 'Var', (109, 126))	('Regulation', 'MPA', (25, 35))	('Autophagy pathway', 'CPA', (39, 56))	('disruption', 'Reg', (11, 21))
432574	30181806	While the defective DNA MMR SI26 showed increasing tendency along patient ageing.	('DNA MMR SI26', 'Gene', (20, 32))	('SI26', 'Gene', (28, 32))	('defective', 'Var', (10, 19))	('patient', 'Species', '9606', (66, 73))	('SI26', 'Chemical', '-', (28, 32))
432589	30181806	The signature profile was evaluated using the six subtype: C>A, C>G, C>T, T>A, T>C, and T>G (all substitutions were referred to by the pyrimidine of the mutated Watson-Crick base pair).	('C', 'Chemical', 'MESH:D002244', (168, 169))	('T>C', 'Var', (79, 82))	('C', 'Chemical', 'MESH:D002244', (69, 70))	('C>G', 'Var', (64, 67))	('pyrimidine', 'Chemical', 'MESH:C030986', (135, 145))	('C>T', 'Var', (69, 72))	('T>A', 'Var', (74, 77))	('C', 'Chemical', 'MESH:D002244', (81, 82))	('C>A', 'Var', (59, 62))	('C', 'Chemical', 'MESH:D002244', (64, 65))	('C', 'Chemical', 'MESH:D002244', (59, 60))
432600	29029509	Establishment of oral squamous cell carcinoma cell line and magnetic bead-based isolation and characterization of its CD90/CD44 subpopulations In this study, we describe the establishment of the human papillomavirus 18-positive, stage II, grade 1, T2N0M0 head and neck tumor primary cell line derived from oral squamous cell carcinoma of a non-smoking patient by using two different protocols.	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (17, 45))	('human papillomavirus 18', 'Species', '337042', (195, 218))	('neck tumor', 'Disease', (264, 274))	('oral squamous cell carcinoma', 'Disease', (17, 45))	('neck tumor', 'Disease', 'MESH:D006258', (264, 274))	('CD90', 'Gene', (118, 122))	('head and neck tumor', 'Phenotype', 'HP:0012288', (255, 274))	('tumor', 'Phenotype', 'HP:0002664', (269, 274))	('CD90', 'Gene', '7070', (118, 122))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (22, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (325, 334))	('CD44', 'Gene', '960', (123, 127))	('T2N0M0', 'Var', (248, 254))	('CD44', 'Gene', (123, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (36, 45))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (311, 334))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (306, 334))	('patient', 'Species', '9606', (352, 359))	('oral squamous cell carcinoma', 'Disease', (306, 334))
432605	29029509	Based on the wound-healing assay, CD44+ cells exhibited stronger migratory capacity than CD44- subpopulations.	('rat', 'Species', '10116', (68, 71))	('CD44+', 'Var', (34, 39))	('stronger', 'PosReg', (56, 64))	('migratory capacity', 'CPA', (65, 83))
432606	29029509	CD44+ subpopulations had also significantly higher expression of BIRC5 and SOX2, lower expression of FLT1 and IL6, and higher levels of basal autophagy compared to CD44- subpopulations.	('lower', 'NegReg', (81, 86))	('basal autophagy', 'CPA', (136, 151))	('higher', 'PosReg', (44, 50))	('FLT1', 'Gene', (101, 105))	('FLT1', 'Gene', '2321', (101, 105))	('IL6', 'Gene', '3569', (110, 113))	('higher', 'PosReg', (119, 125))	('expression', 'MPA', (87, 97))	('expression', 'MPA', (51, 61))	('BIRC5', 'Gene', '332', (65, 70))	('BIRC5', 'Gene', (65, 70))	('SOX2', 'Gene', (75, 79))	('IL6', 'Gene', (110, 113))	('SOX2', 'Gene', '6657', (75, 79))	('CD44+', 'Var', (0, 5))
432617	29029509	The CD44+ phenotype is associated with head and neck, prostate, pancreatic, and breast cancer-initiator cells.	('prostate', 'Disease', (54, 62))	('pancreatic', 'Disease', 'MESH:D010195', (64, 74))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('breast cancer', 'Disease', 'MESH:D001943', (80, 93))	('pancreatic', 'Disease', (64, 74))	('breast cancer', 'Disease', (80, 93))	('breast cancer', 'Phenotype', 'HP:0003002', (80, 93))	('associated', 'Reg', (23, 33))	('CD44+', 'Var', (4, 9))
432661	29029509	Subpopulation expressing CD44 had significantly higher expression of BIRC5 and SOX2 (CD44+/CD90+ vs. CD44-/CD90+ p=0.002 resp.	('BIRC5', 'Gene', (69, 74))	('SOX2', 'Gene', '6657', (79, 83))	('CD90', 'Gene', '7070', (107, 111))	('CD44', 'Var', (25, 29))	('CD44-/CD90+', 'Gene', (101, 112))	('CD90', 'Gene', (107, 111))	('expression', 'MPA', (55, 65))	('CD44-/CD90+', 'Gene', '960;7070', (101, 112))	('higher', 'PosReg', (48, 54))	('CD90', 'Gene', '7070', (91, 95))	('CD90', 'Gene', (91, 95))	('BIRC5', 'Gene', '332', (69, 74))	('SOX2', 'Gene', (79, 83))
432668	29029509	Nearness of CD44+ subpopulations in gene expression is clearly highlighted, while CD90 status did not affect the overall expression pattern substantially.	('CD90', 'Gene', (82, 86))	('CD90', 'Gene', '7070', (82, 86))	('CD44+', 'Var', (12, 17))
432669	29029509	Based on this interactome network, it was revealed that biological processes relating to proliferation, migration, stemness, and angiogenesis were significantly affected by differentially expressed set of genes, (e.g GoMiner GO.0030335, GO.0050678, GO.0001525, GO.0022402, GO.0048646, GO.0016477).	('proliferation', 'CPA', (89, 102))	('GO.0048646', 'Var', (273, 283))	('GO.0022402', 'Var', (261, 271))	('GO.0050678', 'Var', (237, 247))	('GO.0016477', 'Var', (285, 295))	('migration', 'CPA', (104, 113))	('GO.0001525', 'Var', (249, 259))	('affected', 'Reg', (161, 169))	('angiogenesis', 'CPA', (129, 141))	('GO.0030335', 'Var', (225, 235))	('rat', 'Species', '10116', (96, 99))	('biological processes', 'CPA', (56, 76))	('stemness', 'Disease', 'MESH:D020295', (115, 123))	('stemness', 'Disease', (115, 123))	('rat', 'Species', '10116', (107, 110))
432706	29029509	Based on this interactome network, it was revealed that biological processes relating to the cell division, cell cycle, and cellular response to interleukin-6 were significantly affected by differentially expressed set of genes, (e.g GoMiner GO.0051301, GO.0022402, GO.0071354).	('cellular', 'CPA', (124, 132))	('interleukin-6', 'Gene', '3569', (145, 158))	('GO.0071354', 'Var', (266, 276))	('affected', 'Reg', (178, 186))	('GO.0051301', 'Var', (242, 252))	('cell cycle', 'CPA', (108, 118))	('interleukin-6', 'Gene', (145, 158))	('GO.0022402', 'Var', (254, 264))	('biological processes', 'CPA', (56, 76))	('cell division', 'CPA', (93, 106))
432713	29029509	Primary cell line prepared by using trypsin proteolysis was more viable than the one prepared by using collagenase (verified also in further primary cell lines preparations; unpublished results).	('rat', 'Species', '10116', (165, 168))	('more', 'PosReg', (60, 64))	('trypsin', 'Var', (36, 43))
432719	29029509	findings suggest that the phenotype of cells expressing high levels of CD90 is more tumor-promoting than the phenotype of cells expressing low CD90.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumor', 'Disease', (84, 89))	('CD90', 'Gene', '7070', (143, 147))	('high levels', 'Var', (56, 67))	('CD90', 'Gene', '7070', (71, 75))	('CD90', 'Gene', (143, 147))	('CD90', 'Gene', (71, 75))
432733	29029509	Dufour et al showed that transfection of COS-1 cells with MMP-9, MMP-2, or even with a proteolytically inactive mutant of MMP-9 increases cell migration.	('MMP-2', 'Gene', (65, 70))	('rat', 'Species', '10116', (146, 149))	('cell migration', 'CPA', (138, 152))	('transfection', 'Var', (25, 37))	('increases', 'PosReg', (128, 137))	('COS-1', 'CellLine', 'CVCL:0223', (41, 46))	('MMP-2', 'Gene', '4313', (65, 70))	('MMP-9', 'Gene', (122, 127))
432747	29029509	have recently showed that POU5F-induced plasticity in human fibroblasts results in a capability of responding to changes in the extracellular environment that could ultimately lead to the alteration of cell fate.	('POU5F', 'Chemical', '-', (26, 31))	('cell fate', 'CPA', (202, 211))	('rat', 'Species', '10116', (192, 195))	('alteration', 'Reg', (188, 198))	('plasticity', 'Var', (40, 50))	('human', 'Species', '9606', (54, 59))	('lead to', 'Reg', (176, 183))
432822	29029509	The EGFR antibodies were raised against the L25-S645 region of EGFR.	('EGFR', 'Gene', '1956', (63, 67))	('EGFR', 'Gene', (4, 8))	('EGFR', 'Gene', (63, 67))	('L25-S645', 'Var', (44, 52))	('EGFR', 'Gene', '1956', (4, 8))
432826	29029509	The primer and probe sets for ACTB (assay ID: Hs99999903_m1), MT2A (Hs02379661_g1), MT1A (Hs00831826_s1), TP53 (Hs01034249_m1), BAX (Hs00180269_m1), BCL2 (Hs00608023_m1), VEGFA (Hs00900055_m1), FLT1 (Hs01052961_m1), MMP2 (Hs01548727_m1), FOS (Hs00170630_m1), JUN (Hs00277190_s1), MKI67 (Hs00606991_m1), EGF (Hs01099999_m1), EGFR (Hs01076078_m1), SOX2 (Hs01053049_s1), NFkB1 (Hs00765730_m1), BECN1 (Hs00186838_m1), HIF1A (Hs00153153_m1), MAP1LC3B (Hs00797944_s1), NANOG (Hs04260366_g1), CAV1 (Hs00971716_m1), MTOR (Hs00234508_m1), CCL2 (Hs00907239_m1), ZIP1 (also known as SLC39A1) (Hs00205358_m1), BIRC5 (Hs00153353_m1), IL6 (Hs00985639_m1), IL6R (Hs01075666_m1), and POU5F1 (Hs04260367_gH) were selected from TaqMan gene expression assays (Life Technologies, USA).	('FLT1', 'Gene', '2321', (194, 198))	('IL6', 'Gene', '3569', (621, 624))	('VEGFA', 'Gene', '7422', (171, 176))	('CAV1', 'Gene', (486, 490))	('MAP1LC3B', 'Gene', '81631', (437, 445))	('FOS', 'Gene', (238, 241))	('ZIP1', 'Gene', '27173', (552, 556))	('MT2A', 'Gene', '4502', (62, 66))	('CCL2', 'Gene', (530, 534))	('BAX', 'Gene', '581', (128, 131))	('EGF', 'Gene', (324, 327))	('BAX', 'Gene', (128, 131))	('Hs00153353_m1', 'Var', (605, 618))	('FOS', 'Gene', '2353', (238, 241))	('MT1A', 'Gene', (84, 88))	('BCL2', 'Gene', (149, 153))	('BECN1', 'Gene', '8678', (391, 396))	('MMP2', 'Gene', (216, 220))	('Hs00205358_m1', 'Var', (582, 595))	('MAP1LC3B', 'Gene', (437, 445))	('POU5F1', 'Gene', (668, 674))	('IL6', 'Gene', (621, 624))	('IL6', 'Gene', '3569', (642, 645))	('EGFR', 'Gene', '1956', (324, 328))	('NANOG', 'Gene', '79923', (463, 468))	('MT2A', 'Gene', (62, 66))	('NANOG', 'Gene', (463, 468))	('BECN1', 'Gene', (391, 396))	('EGF', 'Gene', (172, 175))	('HIF1A', 'Gene', '3091', (414, 419))	('Hs00985639_m1', 'Var', (626, 639))	('MTOR', 'Gene', (508, 512))	('TP53', 'Gene', (106, 110))	('SLC39A1', 'Gene', (572, 579))	('ZIP1', 'Gene', (552, 556))	('NFkB1', 'Gene', (368, 373))	('SLC39A1', 'Gene', '27173', (572, 579))	('CCL2', 'Gene', '6347', (530, 534))	('EGF', 'Gene', '1950', (303, 306))	('MTOR', 'Gene', '2475', (508, 512))	('BIRC5', 'Gene', '332', (598, 603))	('IL6', 'Gene', (642, 645))	('BIRC5', 'Gene', (598, 603))	('Hs04260367_gH', 'Var', (676, 689))	('IL6R', 'Gene', (642, 646))	('MMP2', 'Gene', '4313', (216, 220))	('VEGFA', 'Gene', (171, 176))	('CAV1', 'Gene', '857', (486, 490))	('EGF', 'Gene', '1950', (324, 327))	('MKI67', 'Gene', (280, 285))	('NFkB1', 'Gene', '4790', (368, 373))	('POU5F1', 'Gene', '5460', (668, 674))	('MKI67', 'Gene', '4288', (280, 285))	('BCL2', 'Gene', '596', (149, 153))	('ACTB', 'Gene', '60', (30, 34))	('FLT1', 'Gene', (194, 198))	('EGFR', 'Gene', (324, 328))	('ACTB', 'Gene', (30, 34))	('HIF1A', 'Gene', (414, 419))	('EGF', 'Gene', (303, 306))	('SOX2', 'Gene', (346, 350))	('SOX2', 'Gene', '6657', (346, 350))	('MT1A', 'Gene', '4489', (84, 88))	('IL6R', 'Gene', '3570', (642, 646))	('TP53', 'Gene', '7157', (106, 110))	('EGF', 'Gene', '1950', (172, 175))
432841	24533074	 PIK3CA Mutations Frequently Coexist with EGFR/KRAS Mutations in Non-Small Cell Lung Cancer and Suggest Poor Prognosis in EGFR/KRAS Wildtype Subgroup PIK3CA gene encoding a catalytic subunit of the phosphatidylinositol-3-kinase (PI3K) is mutated and/or amplified in various neoplasia, including lung cancer.	('lung cancer', 'Disease', (295, 306))	('Non-Small Cell Lung Cancer', 'Disease', (65, 91))	('neoplasia', 'Phenotype', 'HP:0002664', (274, 283))	('Non-Small Cell Lung Cancer', 'Phenotype', 'HP:0030358', (65, 91))	('EGFR', 'Gene', (122, 126))	('PIK3CA', 'Gene', '5290', (1, 7))	('EGFR', 'Gene', (42, 46))	('PIK3CA', 'Gene', '5290', (150, 156))	('lung cancer', 'Disease', 'MESH:D008175', (295, 306))	('KRAS', 'Gene', '3845', (127, 131))	('Small Cell Lung Cancer', 'Phenotype', 'HP:0030357', (69, 91))	('Mutations', 'Var', (8, 17))	('Coexist', 'Reg', (29, 36))	('lung cancer', 'Phenotype', 'HP:0100526', (295, 306))	('cancer', 'Phenotype', 'HP:0002664', (300, 306))	('KRAS', 'Gene', (127, 131))	('KRAS', 'Gene', '3845', (47, 51))	('Non-Small Cell Lung Cancer', 'Disease', 'MESH:D002289', (65, 91))	('EGFR', 'Gene', '1956', (122, 126))	('PIK3CA', 'Gene', (1, 7))	('PIK3CA', 'Gene', (150, 156))	('neoplasia', 'Disease', 'MESH:D009369', (274, 283))	('EGFR', 'Gene', '1956', (42, 46))	('Cancer', 'Phenotype', 'HP:0002664', (85, 91))	('neoplasia', 'Disease', (274, 283))	('KRAS', 'Gene', (47, 51))	('Lung Cancer', 'Phenotype', 'HP:0100526', (80, 91))
432842	24533074	Here we investigated PIK3CA gene alterations, the expression of core components of PI3K pathway, and evaluated their clinical importance in non-small cell lung cancer (NSCLC).	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (140, 166))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (140, 166))	('NSCLC', 'Disease', 'MESH:D002289', (168, 173))	('PIK3CA', 'Gene', (21, 27))	('non-small cell lung cancer', 'Disease', (140, 166))	('alterations', 'Var', (33, 44))	('lung cancer', 'Phenotype', 'HP:0100526', (155, 166))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (144, 166))	('NSCLC', 'Disease', (168, 173))
432843	24533074	Oncogenic mutations/rearrangements in PIK3CA, EGFR, KRAS, HER2, BRAF, AKT1 and ALK genes were detected in tumors from 1117 patients with NSCLC.	('BRAF', 'Gene', '673', (64, 68))	('tumors', 'Disease', (106, 112))	('detected', 'Reg', (94, 102))	('BRAF', 'Gene', (64, 68))	('AKT1', 'Gene', '207', (70, 74))	('tumor', 'Disease', (106, 111))	('KRAS', 'Gene', (52, 56))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('AKT', 'Gene', (70, 73))	('mutations/rearrangements', 'Var', (10, 34))	('patients', 'Species', '9606', (123, 131))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('AKT1', 'Gene', (70, 74))	('HER2', 'Gene', (58, 62))	('EGFR', 'Gene', (46, 50))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('ALK', 'Gene', '238', (79, 82))	('AKT', 'Gene', '207', (70, 73))	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('patient', 'Species', '9606', (123, 130))	('PIK3CA', 'Gene', (38, 44))	('ALK', 'Gene', (79, 82))	('men', 'Species', '9606', (29, 32))	('HER2', 'Gene', '2064', (58, 62))
432844	24533074	PIK3CA gene copy number was examined by fluorescent in situ hybridization and the expression of PI3K p110 subunit alpha (PI3K p110alpha), p-Akt, mTOR, PTEN was determined by immunohistochemistry in PIK3CA mutant cases and 108 patients without PIK3CA mutation.	('mutant', 'Var', (205, 211))	('Akt', 'Gene', '207', (140, 143))	('Akt', 'Gene', (140, 143))	('PIK3CA', 'Gene', (198, 204))
432845	24533074	PIK3CA mutation was found in 3.9% of squamous cell carcinoma and 2.7% of adenocarcinoma.	('adenocarcinoma', 'Disease', 'MESH:D000230', (73, 87))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (37, 60))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('PIK3CA', 'Gene', (0, 6))	('cell carcinoma', 'Disease', 'MESH:C538614', (46, 60))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (37, 60))	('squamous cell carcinoma', 'Disease', (37, 60))	('adenocarcinoma', 'Disease', (73, 87))	('mutation', 'Var', (7, 15))	('found', 'Reg', (20, 25))	('carcinoma', 'Phenotype', 'HP:0030731', (51, 60))
432846	24533074	Patients with single PIK3CA mutation had shorter overall survival than those with PIK3CA-EGFR/KRAS co-mutation or wildtype PIK3CA (p = 0.004).	('overall survival', 'MPA', (49, 65))	('shorter', 'NegReg', (41, 48))	('PIK3CA', 'Gene', (21, 27))	('Patients', 'Species', '9606', (0, 8))	('mutation', 'Var', (28, 36))
432848	24533074	PI3K-dependent activity is frequently elevated due to mutation of PIK3CA, a gene encoding the p110alpha catalytic subunit of PI3K (PI3K p110alpha), and the absence of the phosphatase and tensin homolog(PTEN) protein, a tumor suppressor with an important role in regulating the PI3K antiapoptotic and survival pathway.	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('mutation', 'Var', (54, 62))	('PI3K-dependent activity', 'MPA', (0, 23))	('PIK3CA, a', 'Gene', '5290;133584', (66, 75))	('PTEN', 'Gene', (202, 206))	('elevated', 'PosReg', (38, 46))	('absence', 'NegReg', (156, 163))
432849	24533074	Aberrations in the components of the PI3K signaling pathway have been reported in many solid tumors, including lung cancer.	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('reported', 'Reg', (70, 78))	('solid tumors', 'Disease', (87, 99))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('PI3K signaling pathway', 'Pathway', (37, 59))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('lung cancer', 'Disease', (111, 122))	('Aberrations', 'Var', (0, 11))	('lung cancer', 'Phenotype', 'HP:0100526', (111, 122))	('solid tumors', 'Disease', 'MESH:D009369', (87, 99))
432851	24533074	In our previous study, we reported that 90% of 52 lung adenocarcinoma samples from East Asian never smokers harbored driver mutations in just EGFR, KRAS, HER2 and ALK genes.	('KRAS', 'Gene', (148, 152))	('mutations', 'Var', (124, 133))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (50, 69))	('EGFR', 'Gene', (142, 146))	('lung adenocarcinoma', 'Disease', (50, 69))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (50, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (60, 69))	('HER2', 'Protein', (154, 158))	('ALK', 'Gene', (163, 166))
432852	24533074	The frequency of EGFR, KRAS, HER2 mutations and EML4-ALK fusion were 75.3%, 2%, 5.9% and 5%, separately, in recent analysis of 202 lung adenocarcinoma samples from Chinese patients who never smoked.	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('lung adenocarcinoma', 'Disease', (131, 150))	('HER2', 'Gene', (29, 33))	('KRAS', 'Gene', (23, 27))	('EML4', 'Gene', (48, 52))	('EML4', 'Gene', '27436', (48, 52))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (131, 150))	('mutations', 'Var', (34, 43))	('EGFR', 'Gene', (17, 21))
432853	24533074	In the present study, we examined PIK3CA gene mutation, PIK3CA amplification as well as the expression of PI3K p110alpha, p-Akt, mTOR and PTEN which lie in the PI3K pathway in a consecutive collection of NSCLC tumor samples.	('p110alpha', 'Var', (111, 120))	('PIK3CA', 'Gene', (34, 40))	('PTEN', 'Gene', (138, 142))	('NSCLC tumor', 'Disease', 'MESH:D009369', (204, 215))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('PI3K', 'Gene', (106, 110))	('p-Akt', 'Gene', (122, 127))	('NSCLC tumor', 'Disease', (204, 215))	('PIK3CA', 'Gene', (56, 62))	('mTOR', 'Gene', (129, 133))
432868	24533074	3.0% (34/1117) patients harbored mutations in PIK3CA, accounting for 2.7% (22/807) of lung adenocarcinomas, and 3.9% (12/310) of squamous cell carcinomas.	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (86, 106))	('squamous cell carcinomas', 'Disease', (129, 153))	('carcinomas', 'Disease', (143, 153))	('mutations', 'Var', (33, 42))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (86, 105))	('adenocarcinomas', 'Disease', 'MESH:D000230', (91, 106))	('adenocarcinomas', 'Disease', (91, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (86, 106))	('carcinomas', 'Phenotype', 'HP:0030731', (96, 106))	('carcinomas', 'Disease', 'MESH:D002277', (96, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (143, 152))	('lung adenocarcinomas', 'Disease', (86, 106))	('carcinomas', 'Phenotype', 'HP:0030731', (143, 153))	('carcinomas', 'Disease', 'MESH:D002277', (143, 153))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (129, 153))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (129, 153))	('carcinomas', 'Disease', (96, 106))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (129, 152))	('PIK3CA', 'Gene', (46, 52))
432869	24533074	Mutations in exon 9 encoding for the helical domain (E545K, E545Q, E545G, E545A, Q546R, E542K, T536I) were found in 21 patients.	('E545Q', 'Var', (60, 65))	('E545A', 'Var', (74, 79))	('E545A', 'Mutation', 'rs121913274', (74, 79))	('E545Q', 'Mutation', 'rs104886003', (60, 65))	('T536I', 'Mutation', 'rs750585255', (95, 100))	('E542K', 'Var', (88, 93))	('Q546R', 'Var', (81, 86))	('E545G', 'Var', (67, 72))	('Q546R', 'Mutation', 'rs397517201', (81, 86))	('E545G', 'Mutation', 'rs121913274', (67, 72))	('E545K', 'Mutation', 'rs104886003', (53, 58))	('E542K', 'Mutation', 'rs121913273', (88, 93))	('E545K', 'Var', (53, 58))	('T536I', 'Var', (95, 100))
432870	24533074	Exon 20 mutations coding for the kinase domain (H1047R, H1047L, M1043L, G1007R, Y1021C) were found in 13 patients.	('G1007R', 'Mutation', 'p.G1007R', (72, 78))	('H1047L', 'Mutation', 'rs121913279', (56, 62))	('H1047R', 'Mutation', 'rs121913279', (48, 54))	('H1047L', 'Var', (56, 62))	('G1007R', 'Var', (72, 78))	('Y1021C', 'Var', (80, 86))	('M1043L', 'Var', (64, 70))	('Y1021C', 'Mutation', 'rs121913288', (80, 86))	('H1047R', 'Var', (48, 54))	('M1043L', 'Mutation', 'rs1057519936', (64, 70))
432871	24533074	The most frequent mutations were E545K and H1047R occurring in 16(47.1%, 16/34) of 34 patients with PIK3CA mutations ( Figure 1 ,  Table 2 ).	('E545K', 'Var', (33, 38))	('H1047R', 'SUBSTITUTION', 'None', (43, 49))	('H1047R', 'Var', (43, 49))	('E545K', 'SUBSTITUTION', 'None', (33, 38))	('PIK3CA', 'Gene', (100, 106))
432873	24533074	In PIK3CA mutant group, high PI3K p110alpha expression was associated with stage II to IV disease.	('IV disease', 'Disease', 'MESH:D020432', (87, 97))	('PIK3CA', 'Gene', (3, 9))	('high PI3K p110alpha expression', 'Var', (24, 54))	('IV disease', 'Disease', (87, 97))	('associated', 'Reg', (59, 69))
432874	24533074	Of these, 2 patients, with L858R and 746-deletion separately, were treated with gefitinib after operation.	('L858R', 'Var', (27, 32))	('L858R', 'Mutation', 'rs121434568', (27, 32))	('746-deletion', 'Var', (37, 49))	('gefitinib', 'Chemical', 'MESH:D000077156', (80, 89))
432875	24533074	We observed that the presence PIK3CA mutation was associated with high expression of PI3K p110alpha, p-Akt, mTOR in NSCLC, similar to the results from ovarian clear cell carcinoma.	('expression', 'MPA', (71, 81))	('PI3K p110alpha', 'Var', (85, 99))	('PIK3CA', 'Gene', (30, 36))	('carcinoma', 'Phenotype', 'HP:0030731', (170, 179))	('mutation', 'Var', (37, 45))	('ovarian clear cell carcinoma', 'Disease', (151, 179))	('p-Akt', 'Protein', (101, 106))	('ovarian clear cell carcinoma', 'Disease', 'MESH:D008649', (151, 179))
432876	24533074	Nonetheless, one recent research on colorectal cancer reported PIK3CA mutation was not in accordance with the expression of PI3K p110alpha protein, indicating that PIK3CA mutations might not be the unique cause leading to high expression of PI3K p110alpha and might play diverse roles on the activity of PI3K pathway in distinct types of carcinomas.	('play', 'Reg', (266, 270))	('colorectal cancer', 'Disease', (36, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (338, 347))	('PIK3CA', 'Gene', (164, 170))	('carcinomas', 'Phenotype', 'HP:0030731', (338, 348))	('PI3K', 'Var', (241, 245))	('expression', 'MPA', (227, 237))	('PI3K pathway', 'Pathway', (304, 316))	('colorectal cancer', 'Disease', 'MESH:D015179', (36, 53))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('mutations', 'Var', (171, 180))	('colorectal cancer', 'Phenotype', 'HP:0003003', (36, 53))
432877	24533074	The expression of PI3K p110alpha was also found to be correlated with primary and metastatic lesions, suggesting that PI3K p110alpha might be involved in tumor progression and metastases.	('metastases', 'Disease', 'MESH:D009362', (176, 186))	('tumor', 'CPA', (154, 159))	('PI3K', 'Var', (18, 22))	('correlated', 'Reg', (54, 64))	('involved', 'Reg', (142, 150))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('PI3K p110alpha', 'Var', (118, 132))	('metastases', 'Disease', (176, 186))
432878	24533074	Some investigators reported better prognosis in certain cancers such as breast cancer with PIK3CA mutations, whereas others suggested that PIK3CA mutations indicated a worse prognosis in colorectal cancer, endometrial cancer and NSCLC.	('PIK3CA', 'Gene', (91, 97))	('colorectal cancer', 'Disease', (187, 204))	('endometrial cancer', 'Disease', (206, 224))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('better', 'PosReg', (28, 34))	('endometrial cancer', 'Phenotype', 'HP:0012114', (206, 224))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('mutations', 'Var', (98, 107))	('NSCLC', 'Disease', (229, 234))	('breast cancer', 'Disease', 'MESH:D001943', (72, 85))	('endometrial cancer', 'Disease', 'MESH:D016889', (206, 224))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('colorectal cancer', 'Phenotype', 'HP:0003003', (187, 204))	('breast cancer', 'Disease', (72, 85))	('breast cancer', 'Phenotype', 'HP:0003002', (72, 85))	('cancers', 'Phenotype', 'HP:0002664', (56, 63))
432879	24533074	In addition, as patients in E20 group had a longer OS and RFS than those in E9 group, studies in breast cancer had found clinical significance between patients with mutations in helical (exon 9) and kinase (exon 20) domain with inferior overall survival in those with mutation in the helical domain.These observations are also supported by findings in soft tissue sarcoma in which downstream activation level of PI3K is higher in tumors with helical domain mutations than those with kinase domain mutation.	('sarcoma', 'Disease', (364, 371))	('sarcoma', 'Phenotype', 'HP:0100242', (364, 371))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('helical domain mutations', 'Var', (442, 466))	('tumors', 'Phenotype', 'HP:0002664', (430, 436))	('breast cancer', 'Phenotype', 'HP:0003002', (97, 110))	('soft tissue sarcoma', 'Phenotype', 'HP:0030448', (352, 371))	('sarcoma', 'Disease', 'MESH:D012509', (364, 371))	('higher', 'PosReg', (420, 426))	('tumor', 'Phenotype', 'HP:0002664', (430, 435))	('activation', 'PosReg', (392, 402))
432880	31891239	Aortic dissection in a patient treated with anlotinib for metastatic lung squamous cell carcinoma Anlotinib is an anti-angiogenic drug that targets vascular endothelial growth factor receptor, platelet-derived growth factor receptor, fibroblast growth factor receptor, c-Kit, and other kinases and has been approved for the treatment of advanced non-small cell lung cancer (NSCLC).	('c-Kit', 'Gene', '3815', (269, 274))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('NSCLC', 'Phenotype', 'HP:0030358', (374, 379))	('c-Kit', 'Gene', (269, 274))	('cancer', 'Phenotype', 'HP:0002664', (366, 372))	('Anlotinib', 'Chemical', 'None', (98, 107))	('lung cancer', 'Phenotype', 'HP:0100526', (361, 372))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (346, 372))	('vascular endothelial growth factor receptor', 'Gene', (148, 191))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (350, 372))	('vascular endothelial growth factor receptor', 'Gene', '3791', (148, 191))	('patient', 'Species', '9606', (23, 30))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (346, 372))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (69, 97))	('anlotinib', 'Chemical', 'None', (44, 53))	('Aortic dissection', 'Phenotype', 'HP:0002647', (0, 17))	('Anlotinib', 'Var', (98, 107))	('NSCLC', 'Disease', 'MESH:D002289', (374, 379))	('NSCLC', 'Disease', (374, 379))	('non-small cell lung cancer', 'Disease', (346, 372))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (74, 97))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (69, 97))	('lung squamous cell carcinoma', 'Disease', (69, 97))	('metastatic', 'Disease', (58, 68))	('platelet-derived growth factor receptor', 'Gene', '5159', (193, 232))	('platelet-derived growth factor receptor', 'Gene', (193, 232))
432894	31891239	Next-generation sequencing (NGS) of lung cancer tissues did not show EGFR, ALK, ROS1, MET, BRAF V600E or NTRK gene mutation.	('lung cancer', 'Disease', (36, 47))	('EGFR', 'Gene', '1956', (69, 73))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('ALK', 'Gene', (75, 78))	('V600E', 'Var', (96, 101))	('NTRK', 'Gene', (105, 109))	('BRAF', 'Gene', '673', (91, 95))	('EGFR', 'Gene', (69, 73))	('lung cancer', 'Disease', 'MESH:D008175', (36, 47))	('BRAF', 'Gene', (91, 95))	('ALK', 'Gene', '238', (75, 78))	('ROS1', 'Gene', (80, 84))	('lung cancer', 'Phenotype', 'HP:0100526', (36, 47))	('V600E', 'Mutation', 'rs113488022', (96, 101))	('ROS1', 'Gene', '6098', (80, 84))
432922	31417642	To evaluate the effects of aberrant ENKUR expression on cellular biology of LAD cells in vitro and tumor growth in vivo, ENKUR-overexpressed and -silenced LAD cell lines were constructed using lentiviral vectors.	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumor', 'Disease', (99, 104))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('aberrant', 'Var', (27, 35))
432923	31417642	Silencing of ENKUR in LAD cells also promoted tumorigenesis in nude mice model and caused epithelial to mesenchymal transition (EMT).	('ENKUR', 'Gene', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('promoted', 'PosReg', (37, 45))	('caused', 'Reg', (83, 89))	('Silencing', 'Var', (0, 9))	('nude mice', 'Species', '10090', (63, 72))	('tumor', 'Disease', (46, 51))	('epithelial to mesenchymal transition', 'CPA', (90, 126))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
432935	31417642	We also investigated the effects of aberrant ENKUR expression on the biological behavior and tumor-forming ability of LAD cells and revealed potential involvement of ENKUR in the MAPK/ERK and PI3K/Akt signaling pathways.	('Akt', 'Gene', '207', (197, 200))	('ERK', 'Gene', '5594', (184, 187))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('biological behavior', 'CPA', (69, 88))	('ERK', 'Gene', (184, 187))	('ENKUR', 'Gene', (45, 50))	('ENKUR', 'Gene', (166, 171))	('investigated', 'Reg', (8, 20))	('tumor', 'Disease', (93, 98))	('Akt', 'Gene', (197, 200))	('involvement', 'Reg', (151, 162))	('aberrant', 'Var', (36, 44))	('men', 'Species', '9606', (158, 161))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
432956	31417642	After treatment with 5% non-fat dry milk in Tris-buffered saline, the membranes were immunoblotted with the following antibodies: PI3 Kinase p85 (1:1000, #4292, Cell Signaling, Danvers, MA, USA); Akt (1: 1000, #9272, Cell Signaling, Danvers, MA, USA); pAkt (1: 2000, #4060, Cell Signaling, Danvers, MA, USA); E-cadherin (1:500, #SAB4503751; Sigma Aldrich, St. Louis, MO, USA); N-cadherin (1:5000, # SAB2702400; Sigma Aldrich, St. Louis, MO, USA); vimentin (1:200, #V6630; Sigma Aldrich, St. Louis, MO, USA); ERK1/2(1: 1000, #sc-16981-R, Santa Cruz Biotechnology, Santa Cruz, CA, USA); pERK1/2 (1: 1000, #sc-7383, Santa Cruz Biotechnology, Santa Cruz, CA, USA); ENKUR (1:200, #HPA161503; Sigma Aldrich, St. Louis, MO, USA); beta-ACTIN (1: 5000, #A5441, Sigma Aldrich, St. Louis, MO, USA).	('Akt', 'Gene', (253, 256))	('vimentin', 'Gene', '7431', (447, 455))	('Akt', 'Gene', (196, 199))	('ERK1/2', 'Gene', (508, 514))	('vimentin', 'Gene', (447, 455))	('ERK1/2', 'Gene', '5595;5594', (508, 514))	('Akt', 'Gene', '207', (253, 256))	('N-cadherin', 'Gene', (377, 387))	('Akt', 'Gene', '207', (196, 199))	('N-cadherin', 'Gene', '1000', (377, 387))	('ERK1/2', 'Gene', '5595;5594', (586, 592))	('ERK1/2', 'Gene', (586, 592))	('p85', 'Gene', '5295', (141, 144))	('E-cadherin', 'Gene', (309, 319))	('E-cadherin', 'Gene', '999', (309, 319))	('beta-ACTIN', 'Gene', '728378', (723, 733))	('1: 5000', 'Var', (735, 742))	('beta-ACTIN', 'Gene', (723, 733))	('p85', 'Gene', (141, 144))	('men', 'Species', '9606', (449, 452))	('men', 'Species', '9606', (11, 14))
432995	31417642	Consistent with this effect, in vivo xenograft assay showed that tumors formed of A549-shRNA cells grew more rapidly than tumors generated from the control cells (p<0.05; Figure 6).	('tumors', 'Disease', (122, 128))	('tumors', 'Disease', 'MESH:D009369', (122, 128))	('A549-shRNA', 'Var', (82, 92))	('tumors', 'Disease', (65, 71))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('grew', 'CPA', (99, 103))	('tumors', 'Phenotype', 'HP:0002664', (122, 128))	('A549', 'CellLine', 'CVCL:0023', (82, 86))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
432997	31417642	Comparison between the A549-shRNA cells and control cells showed that silencing of ENKUR caused switch from non-invasive epithelial cells to mesenchymal, spindle cells (Figure 7A).	('silencing', 'Var', (70, 79))	('A549', 'CellLine', 'CVCL:0023', (23, 27))	('ENKUR', 'Gene', (83, 88))
432998	31417642	Western blot analyses showed that silencing of ENKUR significantly decreased E-cadherin expression and increased N-cadherin and vimentin expression (Figure 7B).	('vimentin', 'Gene', '7431', (128, 136))	('N-cadherin', 'Gene', (113, 123))	('expression', 'MPA', (137, 147))	('vimentin', 'Gene', (128, 136))	('increased', 'PosReg', (103, 112))	('N-cadherin', 'Gene', '1000', (113, 123))	('E-cadherin', 'Gene', (77, 87))	('expression', 'MPA', (88, 98))	('E-cadherin', 'Gene', '999', (77, 87))	('decreased', 'NegReg', (67, 76))	('silencing', 'Var', (34, 43))	('ENKUR', 'Gene', (47, 52))
433001	31417642	In contrast, silencing of ENKUR resulted in evidently increased phosphorylation levels of Akt and ERK1/2 as compared with the control group (Figure 7C).	('ERK1/2', 'Gene', '5595;5594', (98, 104))	('Akt', 'Gene', (90, 93))	('Akt', 'Gene', '207', (90, 93))	('phosphorylation levels', 'MPA', (64, 86))	('increased', 'PosReg', (54, 63))	('ERK1/2', 'Gene', (98, 104))	('ENKUR', 'Gene', (26, 31))	('silencing', 'Var', (13, 22))
433011	31417642	Moreover, silencing of ENKUR increased cell proliferative, migratory, and invasive properties in vitro and promoted tumor growth in vivo (Figures 4, 5, 6).	('invasive properties', 'CPA', (74, 93))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('increased', 'PosReg', (29, 38))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('ENKUR', 'Gene', (23, 28))	('cell proliferative', 'CPA', (39, 57))	('promoted', 'PosReg', (107, 115))	('tumor', 'Disease', (116, 121))	('silencing', 'Var', (10, 19))
433018	31417642	By contrast, silencing of ENKUR led to increased activities of PI3K/Akt and MAPK/ERK signaling (Figure 7C).	('Akt', 'Gene', '207', (68, 71))	('activities', 'MPA', (49, 59))	('ERK', 'Gene', '5594', (81, 84))	('ERK', 'Gene', (81, 84))	('increased', 'PosReg', (39, 48))	('Akt', 'Gene', (68, 71))	('ENKUR', 'Gene', (26, 31))	('silencing', 'Var', (13, 22))
433028	30647837	CDK4/6 inhibition stabilizes disease in patients with p16-null non-small cell lung cancer and is synergistic with mTOR inhibition Aberrant activation of CDK4/6 kinase is the most common somatic event in non-small cell lung cancer (NSCLC).	('NSCLC', 'Phenotype', 'HP:0030358', (231, 236))	('activation', 'PosReg', (139, 149))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (67, 89))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('disease', 'Disease', (29, 36))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (63, 89))	('CDK4/6', 'Gene', '1019;1021', (153, 159))	('CDK4/6', 'Gene', (0, 6))	('cancer', 'Disease', (223, 229))	('lung cancer', 'Phenotype', 'HP:0100526', (218, 229))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (203, 229))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('mTOR', 'Gene', (114, 118))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('non-small cell lung cancer', 'Disease', (63, 89))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (207, 229))	('mTOR', 'Gene', '2475', (114, 118))	('CDK4/6', 'Gene', '1019;1021', (0, 6))	('inhibition', 'Var', (7, 17))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (203, 229))	('cancer', 'Disease', 'MESH:D009369', (223, 229))	('NSCLC', 'Disease', 'MESH:D002289', (231, 236))	('SCLC', 'Phenotype', 'HP:0030357', (232, 236))	('p16', 'Gene', (54, 57))	('lung cancer', 'Phenotype', 'HP:0100526', (78, 89))	('CDK4/6', 'Gene', (153, 159))	('patients', 'Species', '9606', (40, 48))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (63, 89))	('p16', 'Gene', '1029', (54, 57))	('NSCLC', 'Disease', (231, 236))	('non-small cell lung cancer', 'Disease', (203, 229))	('cancer', 'Disease', (83, 89))
433038	30647837	Only the combination of palbociclib and mTOR inhibitors resulted in synergistic growth inhibition, particularly in tumors carrying RAS mutations.	('palbociclib', 'Chemical', 'MESH:C500026', (24, 35))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('mutations', 'Var', (135, 144))	('mTOR', 'Gene', (40, 44))	('mTOR', 'Gene', '2475', (40, 44))	('tumors', 'Disease', (115, 121))	('RAS', 'Gene', (131, 134))	('tumors', 'Disease', 'MESH:D009369', (115, 121))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))
433039	30647837	Our findings warrant further clinical investigation of the combination of palbociclib and mTOR inhibitors, especially in patients carrying activated RAS mutations.	('activated RAS', 'Protein', (139, 152))	('mTOR', 'Gene', (90, 94))	('mutations', 'Var', (153, 162))	('mTOR', 'Gene', '2475', (90, 94))	('palbociclib', 'Chemical', 'MESH:C500026', (74, 85))	('patients', 'Species', '9606', (121, 129))
433041	30647837	The epistatic retinoblastoma (RB: CDK4/6: Cyclin D: CDKN2a/p16) signaling pathway is targeted for somatic or epigenetic alterations in essentially 100% of lung cancer samples.	('p16', 'Gene', '1029', (59, 62))	('RB', 'Phenotype', 'HP:0009919', (30, 32))	('epistatic retinoblastoma', 'Disease', 'MESH:D012175', (4, 28))	('RB', 'Chemical', 'MESH:D012413', (30, 32))	('Cyclin', 'Gene', '5111', (42, 48))	('CDKN2a', 'Gene', (52, 58))	('epigenetic alterations', 'Var', (109, 131))	('lung cancer', 'Disease', (155, 166))	('p16', 'Gene', (59, 62))	('lung cancer', 'Phenotype', 'HP:0100526', (155, 166))	('retinoblastoma', 'Phenotype', 'HP:0009919', (14, 28))	('epistatic retinoblastoma', 'Disease', (4, 28))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('CDKN2a', 'Gene', '1029', (52, 58))	('Cyclin', 'Gene', (42, 48))	('lung cancer', 'Disease', 'MESH:D008175', (155, 166))
433042	30647837	In the case of small cell lung cancer (SCLC), almost 90% of tumors specifically target the RB gene with loss-of-function somatic mutations, and the remaining tumors show genetic or epigenetic alterations in either CDKN2a/p16 or other cryptic gene loci within the RB tumor suppressor pathway.	('tumors', 'Phenotype', 'HP:0002664', (158, 164))	('RB', 'Phenotype', 'HP:0009919', (91, 93))	('small cell lung cancer', 'Disease', 'MESH:D055752', (15, 37))	('CDKN2a', 'Gene', '1029', (214, 220))	('small cell lung cancer', 'Disease', (15, 37))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('RB', 'Phenotype', 'HP:0009919', (263, 265))	('RB tumor', 'Disease', 'MESH:D012175', (263, 271))	('lung cancer', 'Phenotype', 'HP:0100526', (26, 37))	('tumors', 'Disease', (158, 164))	('RB', 'Chemical', 'MESH:D012413', (91, 93))	('SCLC', 'Disease', 'MESH:D018288', (39, 43))	('loss-of-function', 'NegReg', (104, 120))	('RB', 'Chemical', 'MESH:D012413', (263, 265))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (15, 37))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('tumors', 'Disease', 'MESH:D009369', (158, 164))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('CDKN2a', 'Gene', (214, 220))	('RB tumor', 'Disease', (263, 271))	('tumor', 'Phenotype', 'HP:0002664', (266, 271))	('p16', 'Gene', (221, 224))	('tumors', 'Disease', (60, 66))	('SCLC', 'Disease', (39, 43))	('mutations', 'Var', (129, 138))	('p16', 'Gene', '1029', (221, 224))	('epigenetic alterations', 'Var', (181, 203))	('RB gene', 'Gene', (91, 98))	('SCLC', 'Phenotype', 'HP:0030357', (39, 43))	('tumors', 'Disease', 'MESH:D009369', (60, 66))
433044	30647837	Studies from different research groups worldwide have shown that the majority of NSCLC tumors preferentially target the CDKN2a/p16 locus for mutational or epigenetic loss of function.	('epigenetic', 'Var', (155, 165))	('CDKN2a', 'Gene', (120, 126))	('mutational', 'Var', (141, 151))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('p16', 'Gene', (127, 130))	('NSCLC', 'Phenotype', 'HP:0030358', (81, 86))	('NSCLC tumors', 'Disease', 'MESH:D009369', (81, 93))	('SCLC', 'Phenotype', 'HP:0030357', (82, 86))	('CDKN2a', 'Gene', '1029', (120, 126))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('p16', 'Gene', '1029', (127, 130))	('NSCLC tumors', 'Disease', (81, 93))
433061	30647837	Patients were required to have a CDK4 mutation or cyclin gene family CCND1, D2 or D3 amplification.	('cyclin', 'Gene', '5111', (50, 56))	('D3 amplification', 'Var', (82, 98))	('CDK4', 'Gene', (33, 37))	('CCND1', 'Gene', '595', (69, 74))	('cyclin', 'Gene', (50, 56))	('Patients', 'Species', '9606', (0, 8))	('CCND1', 'Gene', (69, 74))
433063	30647837	However, the DCR was 44%, where 12 patients treated with palbociclib had stable disease and 2 patients with a documented partial response had a CCND1 abnormality.	('abnormality', 'Var', (150, 161))	('CCND1', 'Gene', '595', (144, 149))	('patients', 'Species', '9606', (94, 102))	('palbociclib', 'Chemical', 'MESH:C500026', (57, 68))	('patients', 'Species', '9606', (35, 43))	('CCND1', 'Gene', (144, 149))
433084	30647837	We were able to extract DNA and perform an exploratory analysis of the cancer gene mutational status on archival biopsy samples from 11 of 16 patients and did not detect EGFR, KRAS or ALK gene alterations in any cases (Table 2, Supplementary Table 2).	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('mutational', 'Var', (83, 93))	('EGFR', 'Gene', '1956', (170, 174))	('cancer', 'Disease', (71, 77))	('ALK', 'Gene', '238', (184, 187))	('EGFR', 'Gene', (170, 174))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('patients', 'Species', '9606', (142, 150))	('ALK', 'Gene', (184, 187))
433085	30647837	Therefore, we could not assess the potential preferential benefit of palbociclib in patients with KRAS mutant lung cancer.	('lung cancer', 'Disease', 'MESH:D008175', (110, 121))	('patients', 'Species', '9606', (84, 92))	('palbociclib', 'Chemical', 'MESH:C500026', (69, 80))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('lung cancer', 'Disease', (110, 121))	('lung cancer', 'Phenotype', 'HP:0100526', (110, 121))	('KRAS', 'Var', (98, 102))
433088	30647837	In summary, we observed a high rate of disease stability consistent with preclinical data and reports from other clinical trials which demonstrate that palbociclib alone acts predominantly as a cytostatic agent and induces senescence but not apoptosis.	('induces', 'Reg', (215, 222))	('palbociclib', 'Chemical', 'MESH:C500026', (152, 163))	('senescence', 'MPA', (223, 233))	('palbociclib', 'Var', (152, 163))
433093	30647837	We observed that p16-null lung tumor cells with the lowest IC50 typically had KRAS, NRAS or HRAS mutations, suggesting enhanced palbociclib sensitivity in the presence of a RAS mutation and absence of p16 expression as previously proposed.	('mutations', 'Var', (97, 106))	('palbociclib sensitivity', 'MPA', (128, 151))	('lung tumor', 'Disease', (26, 36))	('HRAS', 'Gene', '3265', (92, 96))	('p16', 'Gene', (201, 204))	('lung tumor', 'Phenotype', 'HP:0100526', (26, 36))	('enhanced', 'PosReg', (119, 127))	('HRAS', 'Gene', (92, 96))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('p16', 'Gene', '1029', (201, 204))	('p16', 'Gene', (17, 20))	('NRAS', 'Gene', '4893', (84, 88))	('p16', 'Gene', '1029', (17, 20))	('mutation', 'Var', (177, 185))	('KRAS', 'Disease', (78, 82))	('palbociclib', 'Chemical', 'MESH:C500026', (128, 139))	('lung tumor', 'Disease', 'MESH:D008175', (26, 36))	('expression', 'MPA', (205, 215))	('NRAS', 'Gene', (84, 88))
433098	30647837	A second class of palbociclib non-responders comprise tumor samples with RB wildtype/p16 null status and concurrent wildtype RAS, however a mechanism underlying this palbociclib-resistance subset has not been defined.	('p16', 'Gene', (85, 88))	('palbociclib', 'Chemical', 'MESH:C500026', (18, 29))	('null status', 'Var', (89, 100))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('palbociclib', 'Chemical', 'MESH:C500026', (166, 177))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('p16', 'Gene', '1029', (85, 88))	('tumor', 'Disease', (54, 59))	('RB', 'Phenotype', 'HP:0009919', (73, 75))	('RB', 'Chemical', 'MESH:D012413', (73, 75))
433102	30647837	First, since hypermethylation of CDKN2A with loss of p16 expression is the common mechanism to activate CDK4/6 in NSCLC, we tested decitabine, a potent demethylating agent that can efficiently induce p16 protein expression to block CDK4/6 activity independently of exposure to palbociclib.	('palbociclib', 'Chemical', 'MESH:C500026', (277, 288))	('NSCLC', 'Phenotype', 'HP:0030358', (114, 119))	('CDKN2A', 'Gene', (33, 39))	('p16', 'Gene', (53, 56))	('decitabine', 'Chemical', 'MESH:D000077209', (131, 141))	('CDKN2A', 'Gene', '1029', (33, 39))	('p16', 'Gene', '1029', (200, 203))	('p16', 'Gene', (200, 203))	('NSCLC', 'Disease', (114, 119))	('SCLC', 'Phenotype', 'HP:0030357', (115, 119))	('p16', 'Gene', '1029', (53, 56))	('NSCLC', 'Disease', 'MESH:D002289', (114, 119))	('activate', 'PosReg', (95, 103))	('loss', 'NegReg', (45, 49))	('hypermethylation', 'Var', (13, 29))	('CDK4/6', 'Gene', (104, 110))
433103	30647837	Therefore, we anticipated that the combination of demethylating the CDKN2A locus to reactivate p16-mediated CDK4/6 inhibition with palbociclib-mediated CDK4/6 inhibition would target dual independent mechanisms to block cell growth more effectively than palbociclib alone, particularly in cell lines with hypermethylated CDKN2A.	('hypermethylated', 'Var', (305, 320))	('palbociclib', 'Chemical', 'MESH:C500026', (254, 265))	('CDKN2A', 'Gene', (321, 327))	('CDKN2A', 'Gene', (68, 74))	('CDKN2A', 'Gene', '1029', (321, 327))	('p16', 'Gene', '1029', (95, 98))	('palbociclib', 'Chemical', 'MESH:C500026', (131, 142))	('block', 'NegReg', (214, 219))	('CDKN2A', 'Gene', '1029', (68, 74))	('demethylating', 'Var', (50, 63))	('cell growth', 'CPA', (220, 231))	('p16', 'Gene', (95, 98))
433104	30647837	Second, we anticipated that combining MEK and CDK4/6 inhibition would enhance tumor cell cytotoxicity in vitro and we studied these combinations in cell lines with either wildtype or mutant RAS.	('inhibition', 'NegReg', (53, 63))	('enhance', 'PosReg', (70, 77))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('MEK', 'Gene', (38, 41))	('cytotoxicity', 'Disease', (89, 101))	('mutant', 'Var', (183, 189))	('CDK4/6', 'Protein', (46, 52))	('MEK', 'Gene', '5609', (38, 41))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Disease', (78, 83))	('cytotoxicity', 'Disease', 'MESH:D064420', (89, 101))
433112	30647837	These data are consistent with the hypothesis that palbociclib induces senescence which limits the cytotoxic activity of cancer agents that rely on cell proliferation.	('palbociclib', 'Chemical', 'MESH:C500026', (51, 62))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('induces', 'Reg', (63, 70))	('cancer', 'Disease', (121, 127))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('senescence', 'MPA', (71, 81))	('palbociclib', 'Var', (51, 62))
433113	30647837	We also studied palbociclib combinations with the EGFR inhibitors erlotinib and dacomitinib (a pan-EGFR inhibitor), and the mTOR inhibitors rapamycin, everolimus and PF04691502 (a dual PI3K/mTOR inhibitor) (Table 4).	('PF04691502', 'Var', (166, 176))	('PF04691502', 'Chemical', 'MESH:C570662', (166, 176))	('EGFR', 'Gene', (99, 103))	('mTOR', 'Gene', '2475', (124, 128))	('mTOR', 'Gene', '2475', (190, 194))	('mTOR', 'Gene', (124, 128))	('mTOR', 'Gene', (190, 194))	('EGFR', 'Gene', '1956', (50, 54))	('palbociclib', 'Chemical', 'MESH:C500026', (16, 27))	('rapamycin', 'Chemical', 'MESH:D020123', (140, 149))	('dacomitinib', 'Chemical', 'MESH:C525726', (80, 91))	('EGFR', 'Gene', (50, 54))	('EGFR', 'Gene', '1956', (99, 103))	('erlotinib', 'Chemical', 'MESH:D000069347', (66, 75))	('everolimus', 'Chemical', 'MESH:D000068338', (151, 161))
433114	30647837	We observed the greatest degree of cell growth inhibition with each of the mTOR inhibitors, rapamycin, everolimus and PF 04691502.	('rapamycin', 'Chemical', 'MESH:D020123', (92, 101))	('mTOR', 'Gene', '2475', (75, 79))	('mTOR', 'Gene', (75, 79))	('cell growth inhibition', 'CPA', (35, 57))	('PF 04691502', 'Var', (118, 129))	('everolimus', 'Chemical', 'MESH:D000068338', (103, 113))
433115	30647837	To validate the detection of enhanced growth inhibition observed with palbociclib in combination with mTOR pathway inhibitors, we studied the combination of palbociclib with everolimus, rapamycin and PF04691502 in three additional p16-null lung tumor cell lines and confirmed synergy (Figure 2A and 2B, Supplementary Figures 2 and 3).	('palbociclib', 'Chemical', 'MESH:C500026', (157, 168))	('lung tumor', 'Disease', 'MESH:D008175', (240, 250))	('PF04691502', 'Chemical', 'MESH:C570662', (200, 210))	('rapamycin', 'Chemical', 'MESH:D020123', (186, 195))	('palbociclib', 'Chemical', 'MESH:C500026', (70, 81))	('p16', 'Gene', '1029', (231, 234))	('lung tumor', 'Phenotype', 'HP:0100526', (240, 250))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('mTOR', 'Gene', (102, 106))	('mTOR', 'Gene', '2475', (102, 106))	('everolimus', 'Chemical', 'MESH:D000068338', (174, 184))	('PF04691502', 'Var', (200, 210))	('p16', 'Gene', (231, 234))	('lung tumor', 'Disease', (240, 250))
433118	30647837	In both cell lines, palbociclib significantly increased senescence over control cells.	('senescence', 'CPA', (56, 66))	('increased', 'PosReg', (46, 55))	('palbociclib', 'Var', (20, 31))	('palbociclib', 'Chemical', 'MESH:C500026', (20, 31))
433141	30647837	First, loss of CDKN2A/p16 is the most common somatic genetic or epigenetic event in NSCLC and is mutually exclusive with loss of RB function in lung cancer.	('loss of RB function in lung cancer', 'Disease', 'MESH:D012175', (121, 155))	('NSCLC', 'Phenotype', 'HP:0030358', (84, 89))	('CDKN2A', 'Gene', (15, 21))	('loss', 'Var', (7, 11))	('lung cancer', 'Phenotype', 'HP:0100526', (144, 155))	('RB', 'Phenotype', 'HP:0009919', (129, 131))	('p16', 'Gene', '1029', (22, 25))	('CDKN2A', 'Gene', '1029', (15, 21))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('NSCLC', 'Disease', (84, 89))	('NSCLC', 'Disease', 'MESH:D002289', (84, 89))	('loss of RB function in lung cancer', 'Disease', (121, 155))	('p16', 'Gene', (22, 25))	('SCLC', 'Phenotype', 'HP:0030357', (85, 89))
433143	30647837	Further, rare RB missense mutations or integration of DNA tumor viral sequences can occasionally inactivate RB protein function without affecting steady-state levels.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('function', 'MPA', (119, 127))	('inactivate', 'NegReg', (97, 107))	('RB protein', 'Protein', (108, 118))	('missense mutations', 'Var', (17, 35))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('RB', 'Chemical', 'MESH:D012413', (14, 16))	('RB', 'Phenotype', 'HP:0009919', (108, 110))	('RB', 'Phenotype', 'HP:0009919', (14, 16))	('RB', 'Chemical', 'MESH:D012413', (108, 110))
433146	30647837	In the Lung-MAP clinical trial, patients with advanced lung squamous cell carcinoma with CDK4 or CCND1/2/3 amplifications, which are molecularly similar to the p16-null state, were randomized to palbociclib or docetaxel.	('p16', 'Gene', (160, 163))	('patients', 'Species', '9606', (32, 40))	('CCND1/2/3', 'Gene', (97, 106))	('docetaxel', 'Chemical', 'MESH:D000077143', (210, 219))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (55, 83))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('CCND1/2/3', 'Gene', '595;894;896', (97, 106))	('p16', 'Gene', '1029', (160, 163))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (55, 83))	('amplifications', 'Var', (107, 121))	('lung squamous cell carcinoma', 'Disease', (55, 83))	('CDK4', 'Gene', (89, 93))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (60, 83))	('palbociclib', 'Chemical', 'MESH:C500026', (195, 206))
433149	30647837	A potential molecular biomarker for palbociclib response is mutant KRAS status, first suggested through in vitro and in vivo work in tumor cell lines and mice where synthetic lethality was observed following CDK4 inhibition.	('mice', 'Species', '10090', (154, 158))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('KRAS', 'Gene', (67, 71))	('palbociclib', 'Chemical', 'MESH:C500026', (36, 47))	('tumor', 'Disease', (133, 138))	('mutant', 'Var', (60, 66))
433150	30647837	In addition, the DCR was reported to be higher in the subset of patients with KRAS mutation (DCR 54%) compared to KRAS wildtype (DCR 37%) in the phase 1 clinical trial of abemaciclib in previously-treated, molecularly unselected patients with advanced NSCLC.	('patients', 'Species', '9606', (229, 237))	('higher', 'PosReg', (40, 46))	('patients', 'Species', '9606', (64, 72))	('NSCLC', 'Phenotype', 'HP:0030358', (252, 257))	('KRAS', 'Gene', (78, 82))	('mutation', 'Var', (83, 91))	('SCLC', 'Phenotype', 'HP:0030357', (253, 257))	('NSCLC', 'Disease', (252, 257))	('DCR', 'MPA', (17, 20))	('NSCLC', 'Disease', 'MESH:D002289', (252, 257))
433151	30647837	Based on these results, the phase 3 JUNIPER clinical trial was designed, in which previously-treated patients with advanced NSCLC with a KRAS mutation in codon 12 or 13 were randomized to receive either abemaciclib or erlotinib as second-line treatment in patients with NSCLC with a KRAS mutation.	('NSCLC', 'Disease', 'MESH:D002289', (270, 275))	('patients', 'Species', '9606', (101, 109))	('NSCLC', 'Phenotype', 'HP:0030358', (270, 275))	('JUNIPER', 'Species', '58039', (36, 43))	('NSCLC', 'Disease', (124, 129))	('erlotinib', 'Chemical', 'MESH:D000069347', (218, 227))	('patients', 'Species', '9606', (256, 264))	('NSCLC', 'Phenotype', 'HP:0030358', (124, 129))	('SCLC', 'Phenotype', 'HP:0030357', (125, 129))	('NSCLC', 'Disease', 'MESH:D002289', (124, 129))	('KRAS', 'Gene', (137, 141))	('NSCLC', 'Disease', (270, 275))	('SCLC', 'Phenotype', 'HP:0030357', (271, 275))	('mutation in', 'Var', (142, 153))
433154	30647837	However, we did note that cell lines with RAS mutations (KRAS, HRAS or NRAS) were more sensitive to inhibition by palbociclib, with lower IC50 values (Figure 3B).	('mutations', 'Var', (46, 55))	('HRAS', 'Gene', (63, 67))	('RAS', 'Gene', (42, 45))	('NRAS', 'Gene', (71, 75))	('palbociclib', 'Chemical', 'MESH:C500026', (114, 125))	('IC50 values', 'MPA', (138, 149))	('NRAS', 'Gene', '4893', (71, 75))	('sensitive', 'MPA', (87, 96))	('lower', 'NegReg', (132, 137))	('HRAS', 'Gene', '3265', (63, 67))
433175	30647837	Human NSCLC cell lines H125 (adenocarcinoma), H226 (squamous cell carcinoma), H358 (adenocarcinoma in situ), H441 (adenocarcinoma), H520 (squamous cell carcinoma), H1299 (NSCLC not otherwise specified), H1650 (adenocarcinoma), H1703 (squamous cell carcinoma), H1734 (adenocarcinoma), H1792 (adenocarcinoma), H2009 (adenocarcinoma), H2347 (adenocarcinoma) and H2882 (squamous cell carcinoma) were initially isolated by the NCI-Navy Oncology Branch.	('Human', 'Species', '9606', (0, 5))	('carcinoma', 'Phenotype', 'HP:0030731', (152, 161))	('squamous cell carcinoma', 'Disease', (52, 75))	('H358', 'CellLine', 'CVCL:1559', (78, 82))	('NSCLC', 'Disease', 'MESH:D002289', (6, 11))	('SCLC', 'Phenotype', 'HP:0030357', (7, 11))	('carcinoma', 'Phenotype', 'HP:0030731', (66, 75))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (234, 257))	('H2882', 'Var', (359, 364))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (138, 161))	('H125', 'CellLine', 'CVCL:3968', (23, 27))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (366, 389))	('H1703', 'Var', (227, 232))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('adenocarcinoma', 'Disease', (84, 98))	('H2009', 'Var', (308, 313))	('adenocarcinoma', 'Disease', (29, 43))	('NSCLC', 'Disease', (6, 11))	('H1734', 'Var', (260, 265))	('adenocarcinoma', 'Disease', (267, 281))	('H226', 'CellLine', 'CVCL:J621', (46, 50))	('NSCLC', 'Disease', 'MESH:D002289', (171, 176))	('adenocarcinoma', 'Disease', (291, 305))	('squamous cell carcinoma', 'Disease', (234, 257))	('adenocarcinoma', 'Disease', (315, 329))	('SCLC', 'Phenotype', 'HP:0030357', (172, 176))	('adenocarcinoma', 'Disease', (339, 353))	('squamous cell carcinoma', 'Disease', (138, 161))	('NSCLC', 'Phenotype', 'HP:0030358', (6, 11))	('adenocarcinoma', 'Disease', (115, 129))	('H1734', 'CellLine', 'CVCL:1491', (260, 265))	('NSCLC', 'Disease', (171, 176))	('H1299', 'CellLine', 'CVCL:0060', (164, 169))	('squamous cell carcinoma', 'Disease', (366, 389))	('adenocarcinoma', 'Disease', 'MESH:D000230', (84, 98))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (52, 75))	('adenocarcinoma', 'Disease', 'MESH:D000230', (29, 43))	('carcinoma', 'Phenotype', 'HP:0030731', (34, 43))	('adenocarcinoma', 'Disease', 'MESH:D000230', (267, 281))	('adenocarcinoma', 'Disease', 'MESH:D000230', (291, 305))	('NSCLC', 'Phenotype', 'HP:0030358', (171, 176))	('adenocarcinoma', 'Disease', 'MESH:D000230', (315, 329))	('H1792', 'Var', (284, 289))	('adenocarcinoma', 'Disease', 'MESH:D000230', (339, 353))	('adenocarcinoma', 'Disease', (210, 224))	('adenocarcinoma', 'Disease', 'MESH:D000230', (115, 129))	('H2882', 'CellLine', 'CVCL:5158', (359, 364))	('H2347', 'Var', (332, 337))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (234, 257))	('Oncology', 'Phenotype', 'HP:0002664', (431, 439))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (138, 161))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (52, 75))	('H1703', 'CellLine', 'CVCL:1490', (227, 232))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (366, 389))	('H2347', 'CellLine', 'CVCL:1550', (332, 337))	('adenocarcinoma', 'Disease', 'MESH:D000230', (210, 224))
433179	30647837	Antibodies purchased from Cell Signaling Technology (Beverly, MA) included: total RB (clone 4H1, Catalog #9309), phospho-RB (Ser608) (#2181), phospho-AKT (Ser473) (#4060), cyclin D1 (#9309), PARP-1 (#9542), caspase 3 (#9665), caspase 9 (#9502), and phospho-p70 S6K (Thr389, #9205).	('Ser473', 'Chemical', '-', (155, 161))	('PARP-1', 'Gene', (191, 197))	('caspase 9', 'Gene', '842', (226, 235))	('RB', 'Phenotype', 'HP:0009919', (121, 123))	('#9542', 'Var', (199, 204))	('RB', 'Phenotype', 'HP:0009919', (82, 84))	('AKT', 'Gene', '207', (150, 153))	('p70 S6K', 'Gene', '6198', (257, 264))	('caspase 3', 'Gene', (207, 216))	('RB', 'Chemical', 'MESH:D012413', (121, 123))	('caspase 3', 'Gene', '836', (207, 216))	('p70 S6K', 'Gene', (257, 264))	('#9665', 'Var', (218, 223))	('Thr389', 'Chemical', '-', (266, 272))	('RB', 'Chemical', 'MESH:D012413', (82, 84))	('Ser608', 'Chemical', '-', (125, 131))	('PARP-1', 'Gene', '142', (191, 197))	('#9502', 'Var', (237, 242))	('cyclin D1', 'Gene', (172, 181))	('#2181', 'Var', (134, 139))	('caspase 9', 'Gene', (226, 235))	('#4060', 'Var', (164, 169))	('#9309', 'Var', (183, 188))	('cyclin D1', 'Gene', '595', (172, 181))	('AKT', 'Gene', (150, 153))	('Ser473', 'Var', (155, 161))
433184	30647837	Selumetinib, flavopiridol, sunitinib, AZD5438, ponatinib, AZD4547, erlotinib, pazopanib, imatinib, PF-04691502, dacomitinib and rapamycin were purchased from Selleck Chemicals (Boston, MA).	('flavopiridol', 'Chemical', 'MESH:C077990', (13, 25))	('AZD5438', 'Chemical', 'MESH:C521840', (38, 45))	('dacomitinib', 'Chemical', 'MESH:C525726', (112, 123))	('AZD4547', 'Chemical', 'MESH:C572463', (58, 65))	('rapamycin', 'Chemical', 'MESH:D020123', (128, 137))	('sunitinib', 'Chemical', 'MESH:D000077210', (27, 36))	('erlotinib', 'Chemical', 'MESH:D000069347', (67, 76))	('ponatinib', 'Chemical', 'MESH:C545373', (47, 56))	('Selumetinib', 'Chemical', 'MESH:C517975', (0, 11))	('PF-04691502', 'Var', (99, 110))	('AZD4547', 'Var', (58, 65))	('imatinib', 'Chemical', 'MESH:D000068877', (89, 97))	('PF-04691502', 'Chemical', 'MESH:C570662', (99, 110))	('pazopanib', 'Chemical', 'MESH:C516667', (78, 87))
433194	30647837	The positive control for PARP-1 was a lysate of BON cells treated for 72 hours with 10uM of PF-04554878.	('PARP-1', 'Gene', '142', (25, 31))	('BON', 'CellLine', 'CVCL:3985', (48, 51))	('PF-04554878', 'Var', (92, 103))	('PARP-1', 'Gene', (25, 31))
433210	29667751	Furthermore, shRNA-mediated SUZ12 knock-down significantly inhibited cell proliferation, migration and invasion in HNSCC cells, and resulted in compromised tumour growth in vivo.	('compromised', 'NegReg', (144, 155))	('SUZ12', 'Chemical', '-', (28, 33))	('knock-down', 'Var', (34, 44))	('tumour', 'Disease', (156, 162))	('SCC', 'Gene', (117, 120))	('inhibited', 'NegReg', (59, 68))	('SUZ12', 'Gene', (28, 33))	('cell proliferation', 'CPA', (69, 87))	('SCC', 'Gene', '6317', (117, 120))	('tumour', 'Phenotype', 'HP:0002664', (156, 162))	('migration', 'CPA', (89, 98))	('tumour', 'Disease', 'MESH:D009369', (156, 162))
433267	29667751	As shown in Figure 1A-F, data mining and interrogation from Oncomine database indicated significant higher expression of SUZ12 mRNA in HNSCC samples from several independent patient cohorts as compared to normal counterparts, respectively, except the Cromer's cohort.27, 28, 29, 30, 31, 32, 33 Data integration and analyses from TCGA-HNSCC cohort (502 cases) using cBioPortal platform indicated that total frequency of SUZ12 genetic alterations in HNSCC samples was less than 2.5%.	('SCC', 'Gene', (450, 453))	('SCC', 'Gene', (336, 339))	('patient', 'Species', '9606', (174, 181))	('SUZ12', 'Gene', (419, 424))	('SCC', 'Gene', '6317', (137, 140))	('SUZ12', 'Chemical', '-', (419, 424))	('SCC', 'Gene', '6317', (450, 453))	('SCC', 'Gene', '6317', (336, 339))	('Oncomine', 'Chemical', '-', (60, 68))	('SUZ12', 'Chemical', '-', (121, 126))	('genetic alterations', 'Var', (425, 444))	('SCC', 'Gene', (137, 140))
433278	29667751	In agreement with this, the abundance of the epigenetic marker H3K27me3 as surrogate marker of SUZ12-associated PRC2 activity was also significantly increased in HSNCC relative to normal counterparts (Figure S3).	('abundance', 'MPA', (28, 37))	('SUZ12', 'Chemical', '-', (95, 100))	('HSNCC', 'Disease', (162, 167))	('increased', 'PosReg', (149, 158))	('H3K27me3', 'Var', (63, 71))
433290	29667751	The Kaplan-Meier survival analyses revealed that high SUZ12 expression in HNSCC significantly associated with shorter overall survival and disease-free survival in comparison with its low counterparts (log-rank test, P = .0117, .0125, Figure 3).	('overall survival', 'CPA', (118, 134))	('shorter', 'NegReg', (110, 117))	('SCC', 'Gene', (76, 79))	('high SUZ12 expression', 'Var', (49, 70))	('SCC', 'Gene', '6317', (76, 79))	('disease-free survival', 'CPA', (139, 160))	('SUZ12', 'Chemical', '-', (54, 59))
433301	29667751	Results from MTT assay indicated that cell proliferation was potently inhibited in both cells upon SUZ12 knock-down (Figure 5B).	('SUZ12', 'Gene', (99, 104))	('cell proliferation', 'CPA', (38, 56))	('SUZ12', 'Chemical', '-', (99, 104))	('MTT', 'Chemical', 'MESH:C070243', (13, 16))	('inhibited', 'NegReg', (70, 79))	('knock-down', 'Var', (105, 115))
433302	29667751	Interestingly, we treated stable shSUZ12 cells with 5-FU, a common chemotherapeutic agent for HNSCC and found that cells with SUZ12 silencing had enhanced chemosensitivity to 5-FU as evidenced by significant lower OD values in shSUZ12 cell treated with 5-FU as compared with shSUZ12 cells or cells treated with 5-FU alone (Figure 5C,D).	('SUZ12', 'Gene', (126, 131))	('SUZ12', 'Chemical', '-', (126, 131))	('5-FU', 'Chemical', 'MESH:D005472', (311, 315))	('5-FU', 'Chemical', 'MESH:D005472', (175, 179))	('SCC', 'Gene', (96, 99))	('silencing', 'Var', (132, 141))	('OD values', 'MPA', (214, 223))	('5-FU', 'Chemical', 'MESH:D005472', (52, 56))	('SUZ12', 'Chemical', '-', (277, 282))	('SCC', 'Gene', '6317', (96, 99))	('SUZ12', 'Chemical', '-', (35, 40))	('enhanced', 'PosReg', (146, 154))	('SUZ12', 'Chemical', '-', (229, 234))	('chemosensitivity to 5-FU', 'MPA', (155, 179))	('lower', 'NegReg', (208, 213))	('5-FU', 'Chemical', 'MESH:D005472', (253, 257))
433303	29667751	However, the ratios of cells undergoing apoptosis upon SUZ12 knock-down were comparable to control cells without significant difference (data not shown).	('knock-down', 'Var', (61, 71))	('SUZ12', 'Chemical', '-', (55, 60))	('SUZ12', 'Gene', (55, 60))
433304	29667751	Moreover, the migratory and invasive potentials of cell following SUZ12 knock-down were also measured using wound-healing and transwell assays, respectively.	('SUZ12', 'Chemical', '-', (66, 71))	('invasive potentials of cell', 'CPA', (28, 55))	('SUZ12', 'Gene', (66, 71))	('knock-down', 'Var', (72, 82))	('migratory', 'CPA', (14, 23))
433305	29667751	As shown in Figure 5E,F, SUZ12 knock-down significantly reduced both migratory and invasive properties of cells in vitro.	('reduced', 'NegReg', (56, 63))	('SUZ12', 'Chemical', '-', (25, 30))	('knock-down', 'Var', (31, 41))	('SUZ12', 'Gene', (25, 30))	('invasive properties of cells in vitro', 'CPA', (83, 120))
433306	29667751	In agreement with these observed phenotypical changes following SUZ12 depletion, the expression of cell proliferation marker cyclin D1 was markedly reduced in SUZ12 knock-down cells, while the EMT/metastasis-associated marker Vimentin was down-regulated concomitant with E-cadherin up-regulation (Figure 5G).	('expression', 'MPA', (85, 95))	('down-regulated', 'NegReg', (239, 253))	('cell proliferation', 'CPA', (99, 117))	('cyclin D1', 'Gene', (125, 134))	('up-regulation', 'PosReg', (282, 295))	('Vimentin', 'Gene', '7431', (226, 234))	('SUZ12', 'Chemical', '-', (64, 69))	('reduced', 'NegReg', (148, 155))	('EMT', 'Gene', (193, 196))	('knock-down', 'Var', (165, 175))	('EMT', 'Gene', '3702', (193, 196))	('SUZ12', 'Gene', (159, 164))	('SUZ12', 'Chemical', '-', (159, 164))	('E-cadherin', 'Gene', (271, 281))	('E-cadherin', 'Gene', '999', (271, 281))	('Vimentin', 'Gene', (226, 234))	('cyclin D1', 'Gene', '595', (125, 134))
433316	29667751	To substantiate the oncogenic roles of SUZ12 in HNSCC, we developed a HNSCC xenograft model in which stable SUZ12 knock-down cells were inoculated into left flanks of nude mice.	('SCC', 'Gene', '6317', (50, 53))	('SUZ12', 'Chemical', '-', (39, 44))	('nude mice', 'Species', '10090', (167, 176))	('SUZ12', 'Gene', (108, 113))	('SCC', 'Gene', (72, 75))	('SUZ12', 'Chemical', '-', (108, 113))	('knock-down', 'Var', (114, 124))	('SCC', 'Gene', (50, 53))	('SCC', 'Gene', '6317', (72, 75))
433319	29667751	Nevertheless, the incidence of tumour masses formed was comparable in SUZ12 knock-down cells and control cells at two weeks after cell transplantation.	('SUZ12', 'Gene', (70, 75))	('tumour', 'Phenotype', 'HP:0002664', (31, 37))	('SUZ12', 'Chemical', '-', (70, 75))	('knock-down', 'Var', (76, 86))	('tumour', 'Disease', 'MESH:D009369', (31, 37))	('tumour', 'Disease', (31, 37))
433320	29667751	Immunohistochemical staining of tumour samples revealed significantly reduced H3K27me3 staining, a surrogate marker of SUZ12 expression and function, in samples from SUZ12 knock-down cells in comparisons with controls (Figure 7E,F).	('reduced', 'NegReg', (70, 77))	('SUZ12', 'Chemical', '-', (119, 124))	('H3K27me3 staining', 'Protein', (78, 95))	('tumour', 'Disease', (32, 38))	('knock-down', 'Var', (172, 182))	('SUZ12', 'Gene', (166, 171))	('SUZ12', 'Chemical', '-', (166, 171))	('tumour', 'Phenotype', 'HP:0002664', (32, 38))	('tumour', 'Disease', 'MESH:D009369', (32, 38))
433321	29667751	Moreover, the number of Ki67-positive cells was significantly reduced in tumour samples from SUZ12 knock-down cells as compared to samples formed from control cells (Figure 7E,F).	('tumour', 'Disease', (73, 79))	('knock-down', 'Var', (99, 109))	('SUZ12', 'Gene', (93, 98))	('SUZ12', 'Chemical', '-', (93, 98))	('tumour', 'Phenotype', 'HP:0002664', (73, 79))	('tumour', 'Disease', 'MESH:D009369', (73, 79))	('reduced', 'NegReg', (62, 69))
433322	29667751	Together, these findings revealed that SUZ12 knock-down impaired tumour growth of HNSCC in vivo, suggesting that SUZ12 might be required for HNSCC growth.	('SCC', 'Gene', (143, 146))	('SCC', 'Gene', '6317', (84, 87))	('SUZ12', 'Chemical', '-', (113, 118))	('SCC', 'Gene', '6317', (143, 146))	('tumour', 'Phenotype', 'HP:0002664', (65, 71))	('knock-down', 'Var', (45, 55))	('impaired tumour growth', 'Disease', (56, 78))	('SUZ12', 'Gene', (39, 44))	('SUZ12', 'Chemical', '-', (39, 44))	('SCC', 'Gene', (84, 87))	('impaired tumour growth', 'Disease', 'MESH:D006130', (56, 78))
433332	29667751	Accumulating evidence has indicated that SUZ12 is critically involved in tumorigenesis by promoting cell proliferation, migration and suppressing apoptosis.14, 15, 17, 19 In line with this, our findings from in vitro loss-of-function assay reveal that loss of SUZ12 resulted in reduced proliferation, migration and invasion in HNSCC cells.	('SUZ12', 'Gene', (260, 265))	('SCC', 'Gene', '6317', (329, 332))	('SUZ12', 'Chemical', '-', (260, 265))	('reduced', 'NegReg', (278, 285))	('proliferation', 'CPA', (286, 299))	('SUZ12', 'Chemical', '-', (41, 46))	('invasion', 'CPA', (315, 323))	('migration', 'CPA', (301, 310))	('SCC', 'Gene', (329, 332))	('loss', 'Var', (252, 256))
433333	29667751	These findings were also further substantiated by the facts such as reduced xenograft tumour growth upon SUZ12 depletion and positive association between SUZ expression and cervical node metastasis in patient cohort.	('reduced xenograft tumour', 'Disease', (68, 92))	('reduced xenograft tumour', 'Disease', 'MESH:D015354', (68, 92))	('SUZ expression', 'Gene', (154, 168))	('tumour', 'Phenotype', 'HP:0002664', (86, 92))	('cervical node metastasis', 'Phenotype', 'HP:0025289', (173, 197))	('cervical node metastasis', 'CPA', (173, 197))	('patient', 'Species', '9606', (201, 208))	('depletion', 'Var', (111, 120))	('SUZ12', 'Chemical', '-', (105, 110))
433336	29667751	In conclusion, our findings reveal aberrantly overexpressed SUZ12 in a significant subset of HNSCC and unravel its oncogenic roles to promote initiation and progression of HNSCC.	('SCC', 'Gene', (174, 177))	('SUZ12', 'Gene', (60, 65))	('SCC', 'Gene', '6317', (95, 98))	('promote', 'PosReg', (134, 141))	('SCC', 'Gene', '6317', (174, 177))	('aberrantly overexpressed', 'Var', (35, 59))	('SCC', 'Gene', (95, 98))	('SUZ12', 'Chemical', '-', (60, 65))
433339	27581340	 FGFR gene alterations in lung squamous cell carcinoma are potential targets for the multikinase inhibitor nintedanib Fibroblast growth factor receptor (FGFR) gene alterations are relatively frequent in lung squamous cell carcinoma (LSCC) and are a potential targets for therapy with FGFR inhibitors.	('frequent', 'Reg', (191, 199))	('nintedanib', 'Chemical', 'MESH:C530716', (107, 117))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (31, 54))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (203, 231))	('lung squamous cell carcinoma', 'Disease', (26, 54))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (203, 231))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (208, 231))	('carcinoma', 'Phenotype', 'HP:0030731', (222, 231))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (26, 54))	('lung squamous cell carcinoma', 'Disease', (203, 231))	('alterations', 'Var', (164, 175))	('FGFR', 'Gene', (153, 157))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (26, 54))	('carcinoma', 'Phenotype', 'HP:0030731', (45, 54))
433341	27581340	We have now applied next-generation sequencing (NGS) to characterize FGFR alterations in LSCC patients as well as examined the antitumor activity of nintedanib in LSCC cell lines positive for FGFR1 copy number gain (CNG).	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('copy number', 'Var', (198, 209))	('patients', 'Species', '9606', (94, 102))	('nintedanib', 'Chemical', 'MESH:C530716', (149, 159))	('gain', 'PosReg', (210, 214))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('FGFR1', 'Gene', (192, 197))	('FGFR', 'Gene', (69, 73))	('LSCC', 'Disease', (89, 93))	('tumor', 'Disease', (131, 136))	('alterations', 'Var', (74, 85))
433344	27581340	FGFR1  CNG (10.7%), FGFR1 mutation (2.7%), FGFR2 mutation (2.7%), FGFR4 mutation (5.3%), and FGFR3 fusion (1.3%) were detected in LSCC specimens by NGS.	('FGFR4', 'Gene', '2264', (66, 71))	('FGFR4', 'Gene', (66, 71))	('LSCC', 'Disease', (130, 134))	('mutation', 'Var', (26, 34))	('FGFR3', 'Gene', '2261', (93, 98))	('FGFR1', 'Gene', (20, 25))	('mutation', 'Var', (49, 57))	('FGFR3', 'Gene', (93, 98))	('FGFR2', 'Gene', (43, 48))	('mutation', 'Var', (72, 80))	('FGFR2', 'Gene', '2263', (43, 48))
433345	27581340	Clinicopathologic features did not differ between LSCC patients positive or negative for FGFR alterations.	('positive', 'Reg', (64, 72))	('alterations', 'Var', (94, 105))	('FGFR', 'Gene', (89, 93))	('patients', 'Species', '9606', (55, 63))	('LSCC', 'Disease', (50, 54))
433346	27581340	However, among the 36 patients with disease recurrence after surgery, prognosis was significantly worse for those harboring FGFR alterations.	('FGFR', 'Gene', (124, 128))	('patients', 'Species', '9606', (22, 30))	('alterations', 'Var', (129, 140))
433347	27581340	Screening for FGFR alterations by NGS warrants further study as a means to identify patients with LSCC recurrence after surgery who might benefit from nintedanib therapy.	('LSCC', 'Disease', (98, 102))	('nintedanib', 'Chemical', 'MESH:C530716', (151, 161))	('patients', 'Species', '9606', (84, 92))	('FGFR', 'Gene', (14, 18))	('alterations', 'Var', (19, 30))
433351	27581340	FGFR gene alterations such as mutations and amplification were found to be most common in bladder carcinoma, uterine cancer, and LSCC.16 Gene amplification and overexpression of FGFR1 or FGFR2 have also been identified in breast17 and gastric18 cancer, respectively, and mutation of FGFR3 or FGFR4 has been detected in bladder cancer19 and rhabdomyosarcoma,20 respectively.	('cancer', 'Disease', 'MESH:D009369', (245, 251))	('detected', 'Reg', (307, 315))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (90, 107))	('FGFR2', 'Gene', (187, 192))	('bladder carcinoma', 'Disease', 'MESH:D001749', (90, 107))	('gastric18 cancer', 'Phenotype', 'HP:0012126', (235, 251))	('breast17', 'Disease', (222, 230))	('cancer', 'Disease', (327, 333))	('FGFR3', 'Gene', (283, 288))	('mutation', 'Var', (271, 279))	('FGFR2', 'Gene', '2263', (187, 192))	('cancer', 'Phenotype', 'HP:0002664', (327, 333))	('bladder carcinoma', 'Disease', (90, 107))	('FGFR gene', 'Gene', (0, 9))	('FGFR3', 'Gene', '2261', (283, 288))	('cancer', 'Disease', (117, 123))	('FGFR4', 'Gene', '2264', (292, 297))	('alterations', 'Var', (10, 21))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('cancer', 'Disease', (245, 251))	('bladder cancer19 and rhabdomyosarcoma', 'Disease', 'MESH:D012208', (319, 356))	('mutations', 'Var', (30, 39))	('uterine cancer', 'Phenotype', 'HP:0010784', (109, 123))	('cancer', 'Phenotype', 'HP:0002664', (245, 251))	('cancer', 'Disease', 'MESH:D009369', (327, 333))	('overexpression', 'PosReg', (160, 174))	('FGFR4', 'Gene', (292, 297))	('common', 'Reg', (80, 86))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('FGFR1', 'Gene', (178, 183))	('amplification', 'PosReg', (142, 155))	('cancer', 'Disease', 'MESH:D009369', (117, 123))
433352	27581340	However, the consequences of FGFR genetic alterations for nintedanib treatment in LSCC patients after surgery remain unclear.	('LSCC', 'Disease', (82, 86))	('genetic alterations', 'Var', (34, 53))	('patients', 'Species', '9606', (87, 95))	('nintedanib', 'Chemical', 'MESH:C530716', (58, 68))	('FGFR', 'Gene', (29, 33))
433353	27581340	We have now characterized FGFR alterations in LSCC patients as well as evaluated the clinicopathologic features of patients positive for such gene alterations and the impact of the genetic changes on patient survival after disease recurrence.	('alterations', 'Var', (31, 42))	('patients', 'Species', '9606', (115, 123))	('FGFR', 'Gene', (26, 30))	('patient', 'Species', '9606', (51, 58))	('patients', 'Species', '9606', (51, 59))	('LSCC', 'Disease', (46, 50))	('patient', 'Species', '9606', (115, 122))	('patient', 'Species', '9606', (200, 207))
433360	27581340	Lysates were fractionated by SDS-PAGE, transferred onto a nitrocellulose membrane, blocked with 5% skim milk, and incubated overnight at 4 C with primary antibodies including: p-FGFR, ERK, AKT, and p-AKT (Cell Signaling Technology); FGFR and p-ERK (Santa Cruz Biotechnology, Santa Cruz, CA, USA); and beta-actin (Sigma).	('ERK', 'Gene', (244, 247))	('beta-actin (Sigma', 'Gene', (301, 318))	('SDS', 'Chemical', 'MESH:D012967', (29, 32))	('San', 'Gene', '80218', (249, 252))	('ERK', 'Gene', '2048', (244, 247))	('AKT', 'Gene', (189, 192))	('AKT', 'Gene', '207', (200, 203))	('San', 'Gene', (275, 278))	('ERK', 'Gene', (184, 187))	('AKT', 'Gene', '207', (189, 192))	('San', 'Gene', '80218', (275, 278))	('ERK', 'Gene', '2048', (184, 187))	('FGFR', 'Gene', (233, 237))	('San', 'Gene', (249, 252))	('p-FGFR', 'Var', (176, 182))	('p-ERK', 'Gene', '9451', (242, 247))	('AKT', 'Gene', (200, 203))	('p-ERK', 'Gene', (242, 247))	('beta-actin (Sigma)', 'Gene', '728378', (301, 319))
433366	27581340	For immunohistochemistry, FFPE tissue sections were steamed in Dako antigen retrieval solution (Dako North America, Carpinteria, CA, USA) and incubated overnight with the following antibodies: p-FGFR (Cell Signaling Technology), CD31 (BD Biosciences San Jose, CA, USA) and Ki-67 (Thermo Fisher Scientific, Waltham, MA, USA).	('CD31', 'Gene', (229, 233))	('San', 'Gene', (250, 253))	('CD31', 'Gene', '5175', (229, 233))	('San', 'Gene', '80218', (250, 253))	('p-FGFR', 'Var', (193, 199))
433379	27581340	Nucleotide and amino acid numbers refer to the following GenBank accession numbers: FGFR1, NM_023110 or NM_001174067; FGFR2, NM_000141; FGFR3, NM_000142; and FGFR4, NM_022963.	('FGFR3', 'Gene', '2261', (136, 141))	('NM_023110', 'Var', (91, 100))	('FGFR3', 'Gene', (136, 141))	('NM_001174067', 'Var', (104, 116))	('FGFR4', 'Gene', '2264', (158, 163))	('FGFR2', 'Gene', (118, 123))	('FGFR2', 'Gene', '2263', (118, 123))	('NM_000141', 'Var', (125, 134))	('NM_000142', 'Var', (143, 152))	('NM_022963', 'Var', (165, 174))	('FGFR4', 'Gene', (158, 163))
433382	27581340	DNA copy numbers for FGFR1, FGFR2, FGFR3, and FGFR4 were determined with the use of TaqMan Copy Number Assays (Applied Biosystems, Foster City, CA, USA) and primers Hs02164585_cn, Hs05208783_cn, Hs00113109_cn, and Hs01949336_cn, respectively.	('FGFR2', 'Gene', (28, 33))	('Hs01949336_cn', 'Var', (214, 227))	('FGFR2', 'Gene', '2263', (28, 33))	('Hs02164585_cn', 'Var', (165, 178))	('Hs05208783_cn', 'Var', (180, 193))	('FGFR4', 'Gene', '2264', (46, 51))	('FGFR4', 'Gene', (46, 51))	('FGFR3', 'Gene', '2261', (35, 40))	('Hs00113109_cn', 'Var', (195, 208))	('FGFR1', 'Gene', (21, 26))	('FGFR3', 'Gene', (35, 40))
433387	27581340	To investigate the antitumor activity of nintedanib for NSCLC cells harboring FGFR alterations, we examined two human LSCC cell lines (LK-2 and H520) and one large-cell carcinoma cell line (H1581).	('nintedanib', 'Chemical', 'MESH:C530716', (41, 51))	('alterations', 'Var', (83, 94))	('carcinoma', 'Disease', 'MESH:D002277', (169, 178))	('carcinoma', 'Phenotype', 'HP:0030731', (169, 178))	('NSCLC', 'Disease', (56, 61))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('large-cell carcinoma', 'Phenotype', 'HP:0030360', (158, 178))	('carcinoma', 'Disease', (169, 178))	('NSCLC', 'Disease', 'MESH:D002289', (56, 61))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('tumor', 'Disease', (23, 28))	('human', 'Species', '9606', (112, 117))
433389	27581340	Immunoblot analysis revealed increased levels of both FGFR1 and p-FGFR1 in H520, H1581, and LK-2 cells compared with H1299, A549, and PC-9 (Fig.	('H1299', 'CellLine', 'CVCL:0060', (117, 122))	('PC-9', 'Gene', (134, 138))	('p-FGFR1', 'Var', (64, 71))	('A549', 'CellLine', 'CVCL:0023', (124, 128))	('FGFR1', 'Gene', (54, 59))	('increased', 'PosReg', (29, 38))	('PC-9', 'Gene', '255738', (134, 138))
433396	27581340	We examined the preclinical efficacy of nintedanib treatment on H520 and LK-2 LSCC cells harboring FGFR1 alterations.	('alterations', 'Var', (105, 116))	('FGFR1', 'Gene', (99, 104))	('nintedanib', 'Chemical', 'MESH:C530716', (40, 50))	('LK-2 LSCC', 'CellLine', 'CVCL:1377', (73, 82))
433409	27581340	However, in LK-2 tumors, p-FGFR1 was detected in the mouse stromal/vascular cells but not the LK-2 cells.	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('tumors', 'Disease', (17, 23))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('p-FGFR1', 'Var', (25, 32))	('mouse', 'Species', '10090', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
433425	27581340	Matched specimens for all eight tumors found to be positive for FGFR1 copy number gain by NGS were also judged to be positive for FGFR1 CNG by FISH (Fig.	('FGFR1', 'Gene', (64, 69))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumors', 'Disease', (32, 38))	('copy number', 'Var', (70, 81))	('gain', 'PosReg', (82, 86))	('tumors', 'Disease', 'MESH:D009369', (32, 38))
433426	27581340	Somatic missense mutations in the coding regions of FGFR1, FGFR2, FGFR3, and FGFR4 were detected in 2/75 (2.7%), 2/75 (2.7%), 0/75 (0%), and 4/75 (5.3%) specimens, respectively, with one tumor showing missense mutations of both FGFR1 and FGFR2.	('FGFR2', 'Gene', (59, 64))	('FGFR2', 'Gene', '2263', (59, 64))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('FGFR3', 'Gene', '2261', (66, 71))	('FGFR1', 'Gene', (228, 233))	('detected', 'Reg', (88, 96))	('FGFR2', 'Gene', (238, 243))	('tumor', 'Disease', (187, 192))	('FGFR2', 'Gene', '2263', (238, 243))	('FGFR4', 'Gene', '2264', (77, 82))	('FGFR3', 'Gene', (66, 71))	('FGFR4', 'Gene', (77, 82))	('FGFR1', 'Gene', (52, 57))	('missense mutations', 'Var', (8, 26))	('missense mutations', 'Var', (201, 219))
433429	27581340	Among all patients, there was no significant difference in age, sex, smoking status, clinical stage, or recurrence between patients classified as FGFR alteration-positive or -negative by NGS.	('FGFR', 'Gene', (146, 150))	('alteration-positive', 'Var', (151, 170))	('patients', 'Species', '9606', (123, 131))	('patients', 'Species', '9606', (10, 18))
433430	27581340	The OS rates of the FGFR alteration-positive and -negative patients were investigated.	('FGFR', 'Gene', (20, 24))	('OS', 'Chemical', 'MESH:D009992', (4, 6))	('patients', 'Species', '9606', (59, 67))	('alteration-positive', 'Var', (25, 44))
433431	27581340	We further analyzed the association between FGFR alteration status and survival in the subgroup of patients with recurrence.	('alteration', 'Var', (49, 59))	('FGFR', 'Gene', (44, 48))	('analyzed', 'Reg', (11, 19))	('patients', 'Species', '9606', (99, 107))
433437	27581340	Subset analysis of these 36 patients revealed that the FGFR alteration-positive group had a shorter median OS than did the FGFR alteration-negative group (17.5 vs 37.7 months, P = 0.0025) (Fig.	('OS', 'Chemical', 'MESH:D009992', (107, 109))	('alteration-positive', 'Var', (60, 79))	('FGFR', 'Gene', (55, 59))	('patients', 'Species', '9606', (28, 36))	('shorter', 'NegReg', (92, 99))	('median OS', 'MPA', (100, 109))
433438	27581340	FGFR alteration-positive patients tended to have shorter recurrence-free survival compared with the alteration-negative patients (6.7 vs 7.1 months, P = 0.1393) (Fig.	('FGFR', 'Gene', (0, 4))	('alteration-positive', 'Var', (5, 24))	('shorter', 'NegReg', (49, 56))	('recurrence-free survival', 'CPA', (57, 81))	('patients', 'Species', '9606', (25, 33))	('patients', 'Species', '9606', (120, 128))
433439	27581340	These results suggest that FGFR alteration might be a prognostic marker for LSCC patients with recurrence after surgery.	('patients', 'Species', '9606', (81, 89))	('alteration', 'Var', (32, 42))	('FGFR', 'Gene', (27, 31))	('LSCC', 'Disease', (76, 80))
433440	27581340	Among the relapsed patients in this study, the OS time in FGFR alteration-positive patients was significantly shorter than that in negative patients.	('patients', 'Species', '9606', (19, 27))	('patients', 'Species', '9606', (83, 91))	('shorter', 'NegReg', (110, 117))	('FGFR', 'Gene', (58, 62))	('alteration-positive', 'Var', (63, 82))	('patients', 'Species', '9606', (140, 148))	('OS time', 'MPA', (47, 54))	('OS', 'Chemical', 'MESH:D009992', (47, 49))
433442	27581340	The screening for FGFR alteration in order to select patients whose tumors may be sensitive to nintedanib thus warrants further investigation as a potential new therapeutic approach for LSCC.	('tumors', 'Disease', (68, 74))	('patients', 'Species', '9606', (53, 61))	('tumors', 'Disease', 'MESH:D009369', (68, 74))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('alteration', 'Var', (23, 33))	('FGFR', 'Gene', (18, 22))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('nintedanib', 'Chemical', 'MESH:C530716', (95, 105))	('LSCC', 'Disease', (186, 190))
433449	27581340	In essence, our findings showed that inhibition of the FGFR1 signal pathway targets both cancer and vascular cells in tumors and provided preclinical evidence that supports the targeting of FGFR1 with nintedanib in LSCC tumors with FGFR1 alterations.	('targeting', 'Reg', (177, 186))	('FGFR1', 'Gene', (232, 237))	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('tumors', 'Phenotype', 'HP:0002664', (220, 226))	('alterations', 'Var', (238, 249))	('nintedanib', 'Chemical', 'MESH:C530716', (201, 211))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('tumors', 'Disease', (220, 226))	('tumors', 'Disease', 'MESH:D009369', (220, 226))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('cancer', 'Disease', (89, 95))	('tumors', 'Disease', (118, 124))	('FGFR1', 'Gene', (190, 195))	('tumors', 'Disease', 'MESH:D009369', (118, 124))
433454	27581340	We detected FGFR1, FGFR2, and FGFR4 mutations in 2.7%, 2.7%, and 5.3% of LSCC specimens.	('FGFR1', 'Gene', (12, 17))	('mutations', 'Var', (36, 45))	('LSCC', 'Disease', (73, 77))	('FGFR2', 'Gene', (19, 24))	('FGFR2', 'Gene', '2263', (19, 24))	('FGFR4', 'Gene', '2264', (30, 35))	('FGFR4', 'Gene', (30, 35))	('detected', 'Reg', (3, 11))
433455	27581340	These mutations included: (i) G70R located in the Ig-like domain of FGFR1 (NM_023110), which has previously been detected in lung adenocarcinoma;34 (ii) P582S located in the tyrosine kinase domain of FGFR2, with mutations at this site also having been detected in cancer cell lines;35 and (iii) T27I of FGFR1 (NM_001174067), T14I of FGFR2, as well as E381K, S382L, and G408S of FGFR4, all of which are located in alternative exons and have not been previously reported.	('G70R', 'Mutation', 'rs140254426', (30, 34))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (125, 144))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (125, 144))	('FGFR1', 'Gene', (303, 308))	('P582S', 'Var', (153, 158))	('cancer', 'Disease', (264, 270))	('S382L', 'Var', (358, 363))	('S382L', 'Mutation', 'rs1436734443', (358, 363))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('cancer', 'Phenotype', 'HP:0002664', (264, 270))	('FGFR2', 'Gene', (200, 205))	('T14I', 'Mutation', 'rs753987054', (325, 329))	('NM_001174067', 'Var', (310, 322))	('G408S', 'Var', (369, 374))	('G70R', 'Var', (30, 34))	('E381K', 'Var', (351, 356))	('T27I', 'Mutation', 'p.T27I', (295, 299))	('T27I', 'Var', (295, 299))	('E381K', 'Mutation', 'rs777668601', (351, 356))	('FGFR2', 'Gene', '2263', (200, 205))	('FGFR4', 'Gene', '2264', (378, 383))	('FGFR2', 'Gene', (333, 338))	('G408S', 'Mutation', 'rs145635664', (369, 374))	('cancer', 'Disease', 'MESH:D009369', (264, 270))	('lung adenocarcinoma', 'Disease', (125, 144))	('T14I', 'Var', (325, 329))	('P582S', 'Mutation', 'p.P582S', (153, 158))	('FGFR2', 'Gene', '2263', (333, 338))	('FGFR4', 'Gene', (378, 383))
433457	27581340	The association between the nintedanib and other FGFR gene alterations, other than FGFR1 CNG, remains unclear and should be clarified in future studies.	('alterations', 'Var', (59, 70))	('nintedanib', 'Chemical', 'MESH:C530716', (28, 38))	('FGFR gene', 'Gene', (49, 58))
433458	27581340	However, there are some reports regarding FGFR kinase or multikinase inhibitors against cancers with other FGFR gene alterations.	('alterations', 'Var', (117, 128))	('cancers', 'Disease', 'MESH:D009369', (88, 95))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('cancers', 'Disease', (88, 95))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('FGFR gene', 'Gene', (107, 116))
433459	27581340	AZD4547, a selective inhibitor of FGFR1, FGFR2, and FGFR3, has shown potent antitumor activity against an FGFR2 amplified xenograft model.39 Tumors, including LSCC harboring FGFR2, FGFR3, or FGFR4 mutations, were found to be sensitive to the FGFR selective inhibitor BGJ398 and a multikinase inhibitor (ponatinib) in vitro and in vivo.40, 41 Tumors harboring FGFR fusions also showed increased sensitivity to the FGFR selective inhibitor JNJ-42756493 and the multikinase inhibitor pazopanib.42, 43 Thus, FGFR gene alterations other than FGFR1 CNG are considered to be a potential targets for cancer therapy.	('Tumors', 'Disease', (342, 348))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('FGFR3', 'Gene', (181, 186))	('Tumors', 'Phenotype', 'HP:0002664', (141, 147))	('FGFR gene', 'Gene', (504, 513))	('FGFR2', 'Gene', (106, 111))	('FGFR3', 'Gene', '2261', (181, 186))	('Tumors', 'Disease', 'MESH:D009369', (342, 348))	('cancer', 'Disease', 'MESH:D009369', (592, 598))	('Tumor', 'Phenotype', 'HP:0002664', (141, 146))	('Tumors', 'Disease', (141, 147))	('FGFR3', 'Gene', (52, 57))	('FGFR4', 'Gene', '2264', (191, 196))	('FGFR2', 'Gene', '2263', (106, 111))	('FGFR2', 'Gene', (41, 46))	('FGFR3', 'Gene', '2261', (52, 57))	('tumor', 'Disease', (80, 85))	('FGFR4', 'Gene', (191, 196))	('Tumors', 'Disease', 'MESH:D009369', (141, 147))	('FGFR1', 'Gene', (537, 542))	('FGFR2', 'Gene', (174, 179))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('cancer', 'Disease', (592, 598))	('FGFR2', 'Gene', '2263', (41, 46))	('Tumors', 'Phenotype', 'HP:0002664', (342, 348))	('cancer', 'Phenotype', 'HP:0002664', (592, 598))	('alterations', 'Var', (514, 525))	('Tumor', 'Phenotype', 'HP:0002664', (342, 347))	('FGFR2', 'Gene', '2263', (174, 179))
433461	27581340	No difference in relapse frequency was apparent between patients whose tumors were positive or negative for FGFR alteration, suggesting that FGFR alteration is not a risk factor for recurrence.	('patients', 'Species', '9606', (56, 64))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('FGFR', 'Gene', (108, 112))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('tumors', 'Disease', (71, 77))	('alteration', 'Var', (146, 156))	('tumors', 'Disease', 'MESH:D009369', (71, 77))
433463	27581340	Among the relapsed patients in the present study, the OS time of those positive for FGFR alterations was significantly shorter than in those without such genetic changes.	('shorter', 'NegReg', (119, 126))	('positive', 'Reg', (71, 79))	('patients', 'Species', '9606', (19, 27))	('OS', 'Chemical', 'MESH:D009992', (54, 56))	('OS time', 'MPA', (54, 61))	('alterations', 'Var', (89, 100))	('FGFR', 'Gene', (84, 88))
433464	27581340	The presence of FGFR aberrations as detected by NGS was associated with a significantly worse prognosis among patients with disease recurrence after surgery.	('FGFR', 'Gene', (16, 20))	('presence', 'Var', (4, 12))	('patients', 'Species', '9606', (110, 118))	('aberrations', 'Var', (21, 32))
433468	27581340	AKT protein kinase B CNG copy number gain FGFR fibroblast growth factor receptor IC50 half maximal (50%) inhibitory concentration LSCC lung squamous cell carcinoma NGS next-generation sequencing NSCLC non-small cell lung cancer OS overall survival p- phosphorylated PDGFR platelet-derived growth factor receptor VEGF vascular endothelial growth factor VEGFR VEGF receptor	('AKT', 'Gene', (0, 3))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (201, 227))	('NSCLC', 'Disease', 'MESH:D002289', (195, 200))	('VEGF', 'Gene', '7422', (312, 316))	('non-small cell lung cancer', 'Disease', (201, 227))	('lung cancer', 'Phenotype', 'HP:0100526', (216, 227))	('VEGF', 'Gene', '7422', (358, 362))	('AKT', 'Gene', '207', (0, 3))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (135, 163))	('VEGF', 'Gene', (312, 316))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (140, 163))	('NSCLC', 'Disease', (195, 200))	('VEGF', 'Gene', '7422', (352, 356))	('VEGF', 'Gene', (358, 362))	('OS', 'Chemical', 'MESH:D009992', (228, 230))	('copy', 'Var', (25, 29))	('VEGF', 'Gene', (352, 356))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('VEGFR', 'Gene', '3791', (352, 357))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (201, 227))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (135, 163))	('lung squamous cell carcinoma', 'Disease', (135, 163))	('VEGFR', 'Gene', (352, 357))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (205, 227))	('PDGFR', 'Gene', (266, 271))	('PDGFR', 'Gene', '5159', (266, 271))	('carcinoma', 'Phenotype', 'HP:0030731', (154, 163))
433469	25797617	The Association of GSTM1 Deletion Polymorphism with Lung Cancer Risk in Chinese Population: Evidence from an Updated Meta-analysis Previous studies have reported the association of glutathione S-transferase M1 (GSTM1) deletion polymorphism with genetic susceptibility of lung cancer in Chinese population.	('Cancer', 'Disease', (57, 63))	('GSTM1', 'Gene', '2944', (19, 24))	('deletion polymorphism', 'Var', (218, 239))	('glutathione S-transferase M1', 'Gene', (181, 209))	('Cancer', 'Disease', 'MESH:D009369', (57, 63))	('GSTM1', 'Gene', '2944', (211, 216))	('lung cancer', 'Phenotype', 'HP:0100526', (271, 282))	('GSTM1', 'Gene', (19, 24))	('lung cancer', 'Disease', (271, 282))	('GSTM1', 'Gene', (211, 216))	('cancer', 'Phenotype', 'HP:0002664', (276, 282))	('glutathione S-transferase M1', 'Gene', '2944', (181, 209))	('lung cancer', 'Disease', 'MESH:D008175', (271, 282))	('Deletion Polymorphism', 'Var', (25, 46))	('Lung Cancer', 'Phenotype', 'HP:0100526', (52, 63))	('Cancer', 'Phenotype', 'HP:0002664', (57, 63))
433470	25797617	The aim of this study was to clarify the association of GSTM1 deletion polymorphism with lung cancer risk in Chinese population.	('GSTM1', 'Gene', (56, 61))	('lung cancer', 'Disease', (89, 100))	('lung cancer', 'Phenotype', 'HP:0100526', (89, 100))	('association', 'Interaction', (41, 52))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('deletion polymorphism', 'Var', (62, 83))	('lung cancer', 'Disease', 'MESH:D008175', (89, 100))	('GSTM1', 'Gene', '2944', (56, 61))
433471	25797617	Overall, we observed an association of GSTM1 deletion polymorphism with increased lung cancer risk in Chinese population (odds ratio (OR) = 1.46, 95% confidence interval (95%CI): 1.32-1.66 for null genotype vs. present genotype) based on 53 studies including 7,833 cases and 10,353 controls.	('GSTM1', 'Gene', '2944', (39, 44))	('lung cancer', 'Phenotype', 'HP:0100526', (82, 93))	('lung cancer', 'Disease', (82, 93))	('GSTM1', 'Gene', (39, 44))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('deletion polymorphism', 'Var', (45, 66))	('lung cancer', 'Disease', 'MESH:D008175', (82, 93))
433472	25797617	We also observed an increased risk of GSTM1 null genotype for lung cancer in stratified analyses by source of control, smoking status and histological type.	('lung cancer', 'Phenotype', 'HP:0100526', (62, 73))	('null genotype', 'Var', (44, 57))	('lung cancer', 'Disease', (62, 73))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('GSTM1', 'Gene', '2944', (38, 43))	('lung cancer', 'Disease', 'MESH:D008175', (62, 73))	('GSTM1', 'Gene', (38, 43))
433473	25797617	The findings suggest that GSTM1 deletion polymorphism may contribute to lung cancer risk in Chinese population.	('deletion polymorphism', 'Var', (32, 53))	('GSTM1', 'Gene', '2944', (26, 31))	('contribute', 'Reg', (58, 68))	('lung cancer', 'Disease', (72, 83))	('lung cancer', 'Phenotype', 'HP:0100526', (72, 83))	('GSTM1', 'Gene', (26, 31))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('lung cancer', 'Disease', 'MESH:D008175', (72, 83))
433480	25797617	Recently, increasing evidence has been accumulated to support the hypothesis that common genetic variations of drug-metabolizing enzyme genes may be of importance in determining an individual's sensitivity to develop lung cancer.	('lung cancer', 'Disease', (217, 228))	('lung cancer', 'Phenotype', 'HP:0100526', (217, 228))	('importance', 'Reg', (152, 162))	('common genetic variations', 'Var', (82, 107))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('lung cancer', 'Disease', 'MESH:D008175', (217, 228))
433483	25797617	GSTM1 deletion polymorphism has been shown to result in the elimination of the activity of GSTM1 enzymes and modulate lung cancer risk.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('activity', 'MPA', (79, 87))	('GSTM1', 'Gene', '2944', (91, 96))	('modulate', 'Reg', (109, 117))	('lung cancer', 'Disease', 'MESH:D008175', (118, 129))	('lung cancer', 'Phenotype', 'HP:0100526', (118, 129))	('GSTM1', 'Gene', '2944', (0, 5))	('GSTM1', 'Gene', (91, 96))	('deletion polymorphism', 'Var', (6, 27))	('GSTM1', 'Gene', (0, 5))	('lung cancer', 'Disease', (118, 129))	('elimination', 'NegReg', (60, 71))
433484	25797617	To date, results from epidemiological studies on the association between GSTM1 deletion polymorphism and lung cancer risk in Chinese population have been mixed.	('lung cancer', 'Phenotype', 'HP:0100526', (105, 116))	('GSTM1', 'Gene', '2944', (73, 78))	('GSTM1', 'Gene', (73, 78))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('lung cancer', 'Disease', 'MESH:D008175', (105, 116))	('association', 'Interaction', (53, 64))	('deletion polymorphism', 'Var', (79, 100))	('lung cancer', 'Disease', (105, 116))
433485	25797617	Recently, two meta-analyses have reported the association of GSTM1 deletion polymorphism with increased lung cancer risk in Chinese population.	('lung cancer', 'Disease', 'MESH:D008175', (104, 115))	('GSTM1', 'Gene', '2944', (61, 66))	('deletion polymorphism', 'Var', (67, 88))	('lung cancer', 'Disease', (104, 115))	('lung cancer', 'Phenotype', 'HP:0100526', (104, 115))	('GSTM1', 'Gene', (61, 66))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))
433486	25797617	In order to obtain a more precise estimation of this relationship, a meta-analysis including a total of 53 studies was conducted, which may provide more comprehensive evidence for the association of GSTM1 deletion polymorphism with lung cancer risk in Chinese population.	('deletion polymorphism', 'Var', (205, 226))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('lung cancer', 'Disease', 'MESH:D008175', (232, 243))	('GSTM1', 'Gene', '2944', (199, 204))	('GSTM1', 'Gene', (199, 204))	('association', 'Interaction', (184, 195))	('lung cancer', 'Disease', (232, 243))	('lung cancer', 'Phenotype', 'HP:0100526', (232, 243))
433488	25797617	Criteria of literature inclusion were (a) the subjects of literature must be Chinese; (b) the papers should evaluate the association of GSTM1 deletion polymorphism with lung cancer risk; (c) case-control studies or cohort studies; (d) studies should have sufficient data for estimating odds ratio (OR) with 95% confidence intervals (CI).	('lung cancer', 'Disease', 'MESH:D008175', (169, 180))	('association', 'Interaction', (121, 132))	('GSTM1', 'Gene', '2944', (136, 141))	('GSTM1', 'Gene', (136, 141))	('lung cancer', 'Phenotype', 'HP:0100526', (169, 180))	('lung cancer', 'Disease', (169, 180))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('deletion polymorphism', 'Var', (142, 163))
433489	25797617	In total, ninety eight published articles were identified with the association of GSTM1 deletion polymorphism with lung cancer risk in Chinese population.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('GSTM1', 'Gene', '2944', (82, 87))	('deletion polymorphism', 'Var', (88, 109))	('lung cancer', 'Disease', 'MESH:D008175', (115, 126))	('GSTM1', 'Gene', (82, 87))	('association', 'Interaction', (67, 78))	('lung cancer', 'Disease', (115, 126))	('lung cancer', 'Phenotype', 'HP:0100526', (115, 126))
433490	25797617	At last, fifty three original articles that focused on the association between GSTM1 deletion polymorphism and lung cancer risk in Chinese population were determined to be eligible to enter our study (Fig.	('association', 'Interaction', (59, 70))	('lung cancer', 'Disease', 'MESH:D008175', (111, 122))	('deletion polymorphism', 'Var', (85, 106))	('GSTM1', 'Gene', '2944', (79, 84))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('lung cancer', 'Disease', (111, 122))	('lung cancer', 'Phenotype', 'HP:0100526', (111, 122))	('GSTM1', 'Gene', (79, 84))
433491	25797617	The strength of the association between GSTM1 deletion polymorphism and lung cancer risk was measured by OR with 95%CI.	('deletion polymorphism', 'Var', (46, 67))	('GSTM1', 'Gene', '2944', (40, 45))	('GSTM1', 'Gene', (40, 45))	('lung cancer', 'Disease', (72, 83))	('lung cancer', 'Phenotype', 'HP:0100526', (72, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('lung cancer', 'Disease', 'MESH:D008175', (72, 83))
433492	25797617	There were a total of 53 studies with 7,833 cases and 10,353 controls concerning the GSTM1 deletion polymorphism related to lung cancer risk.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('lung cancer', 'Disease', 'MESH:D008175', (124, 135))	('related', 'Reg', (113, 120))	('deletion polymorphism', 'Var', (91, 112))	('GSTM1', 'Gene', '2944', (85, 90))	('lung cancer', 'Disease', (124, 135))	('GSTM1', 'Gene', (85, 90))	('lung cancer', 'Phenotype', 'HP:0100526', (124, 135))
433495	25797617	The results showed that GSTM1 null genotype vs. present genotype for squamous cell carcinoma, hospitalized patients-based control, smokers and nonsmokers had no heterogeneity with a P value >=0.05.	('null', 'Var', (30, 34))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (69, 92))	('squamous cell carcinoma', 'Disease', (69, 92))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (69, 92))	('GSTM1', 'Gene', '2944', (24, 29))	('patients', 'Species', '9606', (107, 115))	('GSTM1', 'Gene', (24, 29))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))
433496	25797617	Table 2 listed the summary ORs of GSTM1 deletion polymorphism related to lung cancer risk in Chinese population on the basis of 7,833 cases and 10,353 controls.	('lung cancer', 'Disease', 'MESH:D008175', (73, 84))	('deletion polymorphism', 'Var', (40, 61))	('GSTM1', 'Gene', '2944', (34, 39))	('related', 'Reg', (62, 69))	('lung cancer', 'Disease', (73, 84))	('lung cancer', 'Phenotype', 'HP:0100526', (73, 84))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('GSTM1', 'Gene', (34, 39))
433497	25797617	We observed an association of GSTM1 deletion polymorphism with increased lung cancer risk in the total population (OR = 1.46, 95%CI: 1.32-1.61 for null vs. present) (Fig.	('lung cancer', 'Disease', 'MESH:D008175', (73, 84))	('deletion polymorphism', 'Var', (36, 57))	('GSTM1', 'Gene', '2944', (30, 35))	('GSTM1', 'Gene', (30, 35))	('lung cancer', 'Disease', (73, 84))	('lung cancer', 'Phenotype', 'HP:0100526', (73, 84))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))
433499	25797617	We also observed an increased risk of GSTM1 null genotype for lung cancer stratified by smoking status (OR = 1.60, 95%CI: 1.41-1.81 for smokers and OR = 1.79, 95%CI: 1.54-2.08 for nonsmokers, respectively).	('lung cancer', 'Phenotype', 'HP:0100526', (62, 73))	('lung cancer', 'Disease', (62, 73))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('GSTM1', 'Gene', '2944', (38, 43))	('null', 'Var', (44, 48))	('lung cancer', 'Disease', 'MESH:D008175', (62, 73))	('GSTM1', 'Gene', (38, 43))
433500	25797617	We observed an association between GSTM1 null genotype and increased lung cancer risk in stratified analysis by histological type (OR = 1.50, 95%CI: 1.31-1.72 for squamous cell carcinoma and OR = 1.36, 95%CI: 1.08-1.70 for adenocarcinoma, respectively) (Table 2).	('GSTM1', 'Gene', (35, 40))	('lung cancer', 'Disease', 'MESH:D008175', (69, 80))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (163, 186))	('carcinoma', 'Phenotype', 'HP:0030731', (228, 237))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (163, 186))	('adenocarcinoma', 'Disease', (223, 237))	('carcinoma', 'Phenotype', 'HP:0030731', (177, 186))	('squamous cell carcinoma', 'Disease', (163, 186))	('lung cancer', 'Disease', (69, 80))	('null genotype', 'Var', (41, 54))	('adenocarcinoma', 'Disease', 'MESH:D000230', (223, 237))	('lung cancer', 'Phenotype', 'HP:0100526', (69, 80))	('GSTM1', 'Gene', '2944', (35, 40))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
433505	25797617	In addition, GSTM1 null/present polymorphisms could predict the treatment response of the platinum-based chemotherapy in NSCLC patients, especially in East-Asian patients.	('polymorphisms', 'Var', (32, 45))	('patients', 'Species', '9606', (162, 170))	('predict', 'Reg', (52, 59))	('platinum', 'Chemical', 'MESH:D010984', (90, 98))	('NSCLC', 'Disease', (121, 126))	('treatment response', 'CPA', (64, 82))	('patients', 'Species', '9606', (127, 135))	('NSCLC', 'Disease', 'MESH:D002289', (121, 126))	('GSTM1', 'Gene', '2944', (13, 18))	('GSTM1', 'Gene', (13, 18))
433506	25797617	Some meta-analyses explored the association of GSTM1 null genotype with the development of several kinds of cancers in Chinese population.	('null genotype', 'Var', (53, 66))	('cancers', 'Phenotype', 'HP:0002664', (108, 115))	('GSTM1', 'Gene', '2944', (47, 52))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('GSTM1', 'Gene', (47, 52))	('cancers', 'Disease', 'MESH:D009369', (108, 115))	('association', 'Interaction', (32, 43))	('cancers', 'Disease', (108, 115))
433507	25797617	In this paper, we performed a systematic literature review to comprehensively evaluate the association of GSTM1 deletion polymorphism with lung cancer risk in Chinese population.	('lung cancer', 'Disease', (139, 150))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('lung cancer', 'Disease', 'MESH:D008175', (139, 150))	('deletion polymorphism', 'Var', (112, 133))	('GSTM1', 'Gene', '2944', (106, 111))	('GSTM1', 'Gene', (106, 111))	('lung cancer', 'Phenotype', 'HP:0100526', (139, 150))	('association', 'Interaction', (91, 102))
433510	25797617	In summary, we observed an increased lung cancer risk in subjects with GSTM1 null genotype.	('lung cancer', 'Disease', (37, 48))	('lung cancer', 'Phenotype', 'HP:0100526', (37, 48))	('GSTM1', 'Gene', '2944', (71, 76))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('GSTM1', 'Gene', (71, 76))	('lung cancer', 'Disease', 'MESH:D008175', (37, 48))	('null', 'Var', (77, 81))
433511	25797617	Two previous meta-analyses have reported the association of GSTM1 deletion polymorphism with increased lung cancer risk in Chinese population.	('lung cancer', 'Disease', 'MESH:D008175', (103, 114))	('GSTM1', 'Gene', '2944', (60, 65))	('GSTM1', 'Gene', (60, 65))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('lung cancer', 'Disease', (103, 114))	('lung cancer', 'Phenotype', 'HP:0100526', (103, 114))	('deletion polymorphism', 'Var', (66, 87))
433512	25797617	The present meta-analysis of 53 published studies including 7,833 cases and 10,353 controls might present a precise estimation of the association of GSTM1 deletion polymorphism with lung cancer risk in Chinese population, owing to including the updated data.	('association', 'Interaction', (134, 145))	('GSTM1', 'Gene', '2944', (149, 154))	('lung cancer', 'Disease', (182, 193))	('GSTM1', 'Gene', (149, 154))	('lung cancer', 'Phenotype', 'HP:0100526', (182, 193))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('deletion polymorphism', 'Var', (155, 176))	('lung cancer', 'Disease', 'MESH:D008175', (182, 193))
433514	25797617	After being stratified by smoking status, the GSTM1 null genotype was associated with an increased risk of lung cancer in both smokers and nonsmokers.	('GSTM1', 'Gene', '2944', (46, 51))	('GSTM1', 'Gene', (46, 51))	('null', 'Var', (52, 56))	('lung cancer', 'Disease', 'MESH:D008175', (107, 118))	('lung cancer', 'Disease', (107, 118))	('lung cancer', 'Phenotype', 'HP:0100526', (107, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))
433517	25797617	We observed significant associations of GSTM1 deletion polymorphism with the increased risk of both squamous cell carcinoma and adenocarcinoma.	('deletion polymorphism', 'Var', (46, 67))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (100, 123))	('associations', 'Reg', (24, 36))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('GSTM1', 'Gene', '2944', (40, 45))	('squamous cell carcinoma and adenocarcinoma', 'Disease', 'MESH:D002294', (100, 142))	('GSTM1', 'Gene', (40, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))
433518	25797617	When subgroup analysis was performed by source of control, we observed an association between GSTM1 deletion polymorphism and increased lung cancer risk in both healthy subjects-based control and hospitalized patients-based control.	('lung cancer', 'Phenotype', 'HP:0100526', (136, 147))	('GSTM1', 'Gene', '2944', (94, 99))	('GSTM1', 'Gene', (94, 99))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('lung cancer', 'Disease', 'MESH:D008175', (136, 147))	('patients', 'Species', '9606', (209, 217))	('increased', 'PosReg', (126, 135))	('deletion polymorphism', 'Var', (100, 121))	('lung cancer', 'Disease', (136, 147))
433519	25797617	In conclusion, this comprehensive review demonstrates that GSTM1 null genotype might be a risk factor for lung cancer in the Chinese population.	('risk factor', 'Reg', (90, 101))	('lung cancer', 'Disease', (106, 117))	('lung cancer', 'Phenotype', 'HP:0100526', (106, 117))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('GSTM1', 'Gene', '2944', (59, 64))	('null genotype', 'Var', (65, 78))	('lung cancer', 'Disease', 'MESH:D008175', (106, 117))	('GSTM1', 'Gene', (59, 64))
433528	33931024	UBE2W was abnormally expressed and significantly correlated with mismatch repair (MMR) gene mutation levels, DNA methyltransferase, and BRCA1/2 expression in breast cancer.	('correlated', 'Reg', (49, 59))	('breast cancer', 'Disease', 'MESH:D001943', (158, 171))	('mutation', 'Var', (92, 100))	('DNA', 'MPA', (109, 112))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('expression', 'MPA', (144, 154))	('breast cancer', 'Disease', (158, 171))	('UBE2W', 'Gene', (0, 5))	('breast cancer', 'Phenotype', 'HP:0003002', (158, 171))	('UBE2W', 'Gene', '55284', (0, 5))	('BRCA1/2', 'Gene', (136, 143))	('BRCA', 'Phenotype', 'HP:0003002', (136, 140))	('MMR', 'Gene', (82, 85))	('N', 'Chemical', 'MESH:D009584', (110, 111))	('BRCA1/2', 'Gene', '672;675', (136, 143))
433534	33931024	Over the last few decades, the various molecular mechanism of carcinogenesis has been identified, including gene mutation and epigenetic modification.	('epigenetic modification', 'Var', (126, 149))	('carcinogenesis', 'Disease', (62, 76))	('gene mutation', 'Var', (108, 121))	('carcinogenesis', 'Disease', 'MESH:D063646', (62, 76))
433541	33931024	A few recent studies disclosed that loss of ubiquitin E2 UBE2W rescues hypersensitivity of Rnf4 mutant cells to DNA damage.	('mutant', 'Var', (96, 102))	('ubiquitin E2', 'Protein', (44, 56))	('UBE2W', 'Gene', (57, 62))	('N', 'Chemical', 'MESH:D009584', (113, 114))	('loss', 'Var', (36, 40))	('UBE2W', 'Gene', '55284', (57, 62))	('hypersensitivity', 'Disease', 'MESH:D004342', (71, 87))	('rescues', 'PosReg', (63, 70))	('Rnf4', 'Gene', '6047', (91, 95))	('hypersensitivity', 'Disease', (71, 87))	('Rnf4', 'Gene', (91, 95))
433563	33931024	Besides, the association between the CNV alteration of UBE2W with survival was also displayed.	('N', 'Chemical', 'MESH:D009584', (38, 39))	('alteration', 'Var', (41, 51))	('association', 'Reg', (13, 24))	('UBE2W', 'Gene', (55, 60))	('UBE2W', 'Gene', '55284', (55, 60))
433593	33931024	Survival analysis further verified the high expression UBE2W was correlated with poor distant metastasis-free survival (Fig.	('high expression', 'Var', (39, 54))	('poor', 'NegReg', (81, 85))	('distant metastasis-free survival', 'CPA', (86, 118))	('UBE2W', 'Gene', (55, 60))	('UBE2W', 'Gene', '55284', (55, 60))
433599	33931024	The above results indicate that high UBE2W expression could promote tumor metastasis and cause resistance to endocrine therapy in breast cancer.	('UBE2W', 'Gene', (37, 42))	('high', 'Var', (32, 36))	('breast cancer', 'Disease', (130, 143))	('promote', 'PosReg', (60, 67))	('tumor metastasis', 'Disease', (68, 84))	('resistance to endocrine therapy', 'MPA', (95, 126))	('tumor metastasis', 'Disease', 'MESH:D009362', (68, 84))	('cause', 'Reg', (89, 94))	('UBE2W', 'Gene', '55284', (37, 42))	('breast cancer', 'Phenotype', 'HP:0003002', (130, 143))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('breast cancer', 'Disease', 'MESH:D001943', (130, 143))
433602	33931024	DNA methyltransferase could affect the expression of tumor-suppressing genes by the means of epigenetic modification.	('affect', 'Reg', (28, 34))	('expression', 'MPA', (39, 49))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Disease', (53, 58))	('epigenetic modification', 'Var', (93, 116))	('N', 'Chemical', 'MESH:D009584', (1, 2))
433632	33931024	The loss of UBE2W could sensitized cells to the DNA damage agents with the absence of Rnf4.	('UBE2W', 'Gene', (12, 17))	('Rnf4', 'Gene', '6047', (86, 90))	('sensitized', 'Reg', (24, 34))	('UBE2W', 'Gene', '55284', (12, 17))	('Rnf4', 'Gene', (86, 90))	('N', 'Chemical', 'MESH:D009584', (49, 50))	('loss', 'Var', (4, 8))
433651	33931024	Finally, the genomic analysis revealed that higher UBE2W mRNA expression was related to the copy number amplification in BRCA.	('mRNA expression', 'MPA', (57, 72))	('UBE2W', 'Gene', '55284', (51, 56))	('BRCA', 'Phenotype', 'HP:0003002', (121, 125))	('BRCA', 'Gene', '672', (121, 125))	('higher', 'PosReg', (44, 50))	('N', 'Chemical', 'MESH:D009584', (59, 60))	('BRCA', 'Gene', (121, 125))	('copy number amplification', 'Var', (92, 117))	('UBE2W', 'Gene', (51, 56))
433658	33931024	Combined co-expression analysis and survival analysis, we found RBX1 was a gene co-expression with UBE2W and high RBX1 expression was correlated with the poor survival in BRCA.	('expression', 'MPA', (119, 129))	('BRCA', 'Gene', (171, 175))	('high', 'Var', (109, 113))	('RBX1', 'Gene', (64, 68))	('UBE2W', 'Gene', (99, 104))	('UBE2W', 'Gene', '55284', (99, 104))	('RBX1', 'Gene', '9978', (114, 118))	('RBX1', 'Gene', '9978', (64, 68))	('BRCA', 'Phenotype', 'HP:0003002', (171, 175))	('BRCA', 'Gene', '672', (171, 175))	('RBX1', 'Gene', (114, 118))	('correlated with', 'Reg', (134, 149))
433661	33931024	Dysregulation of DNA damage repair (DDR) genes was reported to be a factor that promoting endocrine therapy resistance.	('Dysregulation', 'Var', (0, 13))	('promoting', 'PosReg', (80, 89))	('endocrine therapy resistance', 'MPA', (90, 118))	('N', 'Chemical', 'MESH:D009584', (18, 19))	('DDR) genes', 'Gene', (36, 46))
433663	33931024	A novel resistance mechanism with re-express BRCA1 causes the acquisition of therapy resistance.	('acquisition', 'MPA', (62, 73))	('BRCA1', 'Gene', '672', (45, 50))	('therapy resistance', 'MPA', (77, 95))	('BRCA1', 'Gene', (45, 50))	('re-express', 'Var', (34, 44))	('BRCA', 'Phenotype', 'HP:0003002', (45, 49))
433664	33931024	And BRCA2 mutation was associated with disease progression in breast cancer.	('BRCA', 'Phenotype', 'HP:0003002', (4, 8))	('associated with', 'Reg', (23, 38))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('breast cancer', 'Disease', 'MESH:D001943', (62, 75))	('mutation', 'Var', (10, 18))	('breast cancer', 'Phenotype', 'HP:0003002', (62, 75))	('breast cancer', 'Disease', (62, 75))	('BRCA2', 'Gene', (4, 9))	('BRCA2', 'Gene', '675', (4, 9))
433666	33931024	And the function loss of those genes brings about a mutator phenotype which causes an increasing tumor risk.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('function', 'Var', (8, 16))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumor', 'Disease', (97, 102))	('causes', 'Reg', (76, 82))	('loss', 'NegReg', (17, 21))	('mutator', 'MPA', (52, 59))
433713	32927716	The authors attribute the SERS peaks of discrimination to phenylalanine, tyrosine, tryptophan, proline, certain proteins, collagen, phospholipids, and Amide I (Table 2).	('tryptophan', 'MPA', (83, 93))	('proline', 'Chemical', 'MESH:D011392', (95, 102))	('phenylalanine', 'Chemical', 'MESH:D010649', (58, 71))	('Amide', 'Chemical', 'MESH:D000577', (151, 156))	('tyrosine', 'Chemical', 'MESH:D014443', (73, 81))	('tryptophan', 'Chemical', 'MESH:D014364', (83, 93))	('phospholipids', 'Chemical', 'MESH:D010743', (132, 145))	('SERS', 'Chemical', '-', (26, 30))	('proline', 'MPA', (95, 102))	('tyrosine', 'MPA', (73, 81))	('proteins', 'Protein', (112, 120))	('phenylalanine', 'Var', (58, 71))	('collagen', 'MPA', (122, 130))
433719	32927716	Specific SERS peaks were also identified between cancer and control groups, particularly corresponding to phenylalanine, proline, valine, proteins, and collagens (see Table 2).	('proteins', 'Protein', (138, 146))	('proline', 'MPA', (121, 128))	('valine', 'MPA', (130, 136))	('SERS', 'Chemical', '-', (9, 13))	('valine', 'Chemical', 'MESH:D014633', (130, 136))	('phenylalanine', 'Var', (106, 119))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('proline', 'Chemical', 'MESH:D011392', (121, 128))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('phenylalanine', 'Chemical', 'MESH:D010649', (106, 119))	('cancer', 'Disease', (49, 55))
433851	31799620	The microRNA-33b (miR-33b), a member of miR-33 family, is reported to function as a tumor suppressor in various cancers.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('miR-33', 'Gene', '723897', (18, 24))	('cancers', 'Phenotype', 'HP:0002664', (112, 119))	('miR-33', 'Gene', (18, 24))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('microRNA-33b', 'Var', (4, 16))	('miR-33b', 'Gene', '693120', (18, 25))	('cancers', 'Disease', 'MESH:D009369', (112, 119))	('tumor', 'Disease', (84, 89))	('N', 'Chemical', 'MESH:D009584', (10, 11))	('cancers', 'Disease', (112, 119))	('miR-33', 'Gene', '723897', (40, 46))	('miR-33b', 'Gene', (18, 25))	('miR-33', 'Gene', (40, 46))
433857	31799620	The miR-33b up-regulation or CROCC silencing was observed to increase the level of E-cadherin but decrease the levels of N-cadherin and Vimentin, corresponding to impeded cell proliferation, migration, invasion, EMT, and tumor growth.	('CROCC', 'Gene', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('migration', 'CPA', (191, 200))	('invasion', 'CPA', (202, 210))	('level', 'MPA', (74, 79))	('Vimentin', 'Gene', (136, 144))	('EMT', 'CPA', (212, 215))	('Vimentin', 'Gene', '22352', (136, 144))	('miR-33b', 'Gene', '693120', (4, 11))	('N-cadherin', 'Gene', (121, 131))	('miR-33b', 'Gene', (4, 11))	('increase', 'PosReg', (61, 69))	('si', 'Chemical', 'MESH:D012825', (206, 208))	('E-cadherin', 'Gene', (83, 93))	('decrease', 'NegReg', (98, 106))	('N-cadherin', 'Gene', '12558', (121, 131))	('tumor', 'Disease', (221, 226))	('impeded', 'NegReg', (163, 170))	('tumor', 'Disease', 'MESH:D009369', (221, 226))	('E-cadherin', 'Gene', '12550', (83, 93))	('cell proliferation', 'CPA', (171, 189))	('CROCC', 'Gene', '230872', (29, 34))	('silencing', 'Var', (35, 44))	('up-regulation', 'PosReg', (12, 25))	('si', 'Chemical', 'MESH:D012825', (35, 37))
433877	31799620	The GBC-related miRNA microarray database GSE104165 was retrieved from the Gene Expression Omnibus (GEO) database (https://www.ncbi.nlm.nih.gov/) and the database with GBC tissues (n = 40) and adjacent normal tissues (n = 8) were then subjected to differential expression analysis with  log2FC  > 1, P value < 0.05 as threshold.	('si', 'Chemical', 'MESH:D012825', (267, 269))	('GSE104165', 'Var', (42, 51))	('GBC', 'Disease', 'MESH:D005706', (4, 7))	('si', 'Chemical', 'MESH:D012825', (277, 279))	('GBC', 'Disease', (168, 171))	('si', 'Chemical', 'MESH:D012825', (86, 88))	('GBC', 'Disease', 'MESH:D005706', (168, 171))	('GBC', 'Disease', (4, 7))
433883	31799620	The sequence confirmed that the luciferase reporter plasmids WT and mutant type (MUT) were co-transfected with the miR-33b mimic respectively into HEK-293T cells (Shanghai Institute of Life Sciences, Shanghai Academy of Sciences Cell Resource Center, Shanghai, China).	('luciferase', 'Enzyme', (32, 42))	('miR-33b', 'Gene', '693120', (115, 122))	('miR-33b', 'Gene', (115, 122))	('HEK-293T', 'CellLine', 'CVCL:0063', (147, 155))	('mutant', 'Var', (68, 74))
433884	31799620	Next, the dual luciferase reporter assay system kit (Promega, U.S.A.) was employed to detect the luciferase activity of HEK-293T cells using a Luminometer TD-20/20 detector (E5311, Promega, U.S.A.).	('luciferase', 'Enzyme', (97, 107))	('E5311', 'Var', (174, 179))	('si', 'Chemical', 'MESH:D012825', (136, 138))	('N', 'Chemical', 'MESH:D009584', (0, 1))	('HEK-293T', 'CellLine', 'CVCL:0063', (120, 128))
433899	31799620	Subsequently, immunostaining primary antibody diluent was added to dilute E-Cadherin (1:3000; ab15148; Abcam Inc., Cambridge, MA, U.S.A.), N-Cadherin (1:1000; ab18203; Abcam Inc., Cambridge, MA, U.S.A.), Vimentin (1:1000; ab45939; Abcam Inc., Cambridge, MA, U.S.A.), followed by incubation at 4 C overnight.	('1:1000; ab45939;', 'Var', (214, 230))	('E-Cadherin', 'Gene', (74, 84))	('Vimentin', 'Gene', (204, 212))	('E-Cadherin', 'Gene', '12550', (74, 84))	('Vimentin', 'Gene', '22352', (204, 212))	('N-Cadherin', 'Gene', (139, 149))	('N-Cadherin', 'Gene', '12558', (139, 149))
433983	31799620	Tumor growth rate was the fastest with an augmented tumor size (P < 0.05) in the miR-33b inhibitor group compared with the inhibitor NC group.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('inhibitor', 'Var', (89, 98))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumor', 'Disease', (52, 57))	('fastest', 'PosReg', (26, 33))	('miR-33b', 'Gene', (81, 88))	('augmented', 'PosReg', (42, 51))	('N', 'Chemical', 'MESH:D009584', (133, 134))	('Tumor growth rate', 'CPA', (0, 17))	('si', 'Chemical', 'MESH:D012825', (58, 60))	('miR-33b', 'Gene', '693120', (81, 88))	('tumor', 'Disease', 'MESH:D009369', (52, 57))
433993	31799620	The aberrant expression of certain miRs has been demonstrated to be functionally involved in GBC progression through regulation of various cellular processes such as cell proliferation, migration, invasion, and apoptosis.	('invasion', 'CPA', (197, 205))	('apoptosis', 'CPA', (211, 220))	('GBC', 'Disease', (93, 96))	('si', 'Chemical', 'MESH:D012825', (201, 203))	('involved', 'Reg', (81, 89))	('migration', 'CPA', (186, 195))	('GBC', 'Disease', 'MESH:D005706', (93, 96))	('si', 'Chemical', 'MESH:D012825', (19, 21))	('cell proliferation', 'CPA', (166, 184))	('aberrant expression', 'Var', (4, 23))	('si', 'Chemical', 'MESH:D012825', (217, 219))	('miR', 'Gene', '735281', (35, 38))	('miR', 'Gene', (35, 38))	('si', 'Chemical', 'MESH:D012825', (104, 106))
434006	31799620	Moreover, restoration of miR-33b expression inhibited lung adenocarcinoma cell proliferation, migration, and invasion and tumor cell EMT in vitro, which conformed to a previous study supporting the functionality of an altered miR expression to be vital in cancer metastasis.	('cancer', 'Disease', (256, 262))	('si', 'Chemical', 'MESH:D012825', (113, 115))	('expression', 'MPA', (33, 43))	('cancer', 'Phenotype', 'HP:0002664', (256, 262))	('tumor', 'Disease', (122, 127))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (54, 73))	('si', 'Chemical', 'MESH:D012825', (39, 41))	('inhibited', 'NegReg', (44, 53))	('migration', 'CPA', (94, 103))	('si', 'Chemical', 'MESH:D012825', (270, 272))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('miR', 'Gene', (226, 229))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))	('miR-33b', 'Gene', '693120', (25, 32))	('cancer', 'Disease', 'MESH:D009369', (256, 262))	('restoration', 'Var', (10, 21))	('miR', 'Gene', '735281', (226, 229))	('si', 'Chemical', 'MESH:D012825', (236, 238))	('miR', 'Gene', (25, 28))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('miR-33b', 'Gene', (25, 32))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (54, 73))	('miR', 'Gene', '735281', (25, 28))	('lung adenocarcinoma', 'Disease', (54, 73))
434014	31799620	CROCC has also been demonstrated to be of critical functionality with dual motives in regulating both tumorigenicity and aberrant centrosome duplication.	('CROCC', 'Gene', '230872', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('CROCC', 'Gene', (0, 5))	('aberrant', 'Var', (121, 129))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))
434039	31533612	miRNAs also act on several cellular processes, such as cell differentiation, cell cycle progression, and apoptosis.	('apoptosis', 'CPA', (105, 114))	('cell differentiation', 'CPA', (55, 75))	('act', 'Reg', (12, 15))	('cellular processes', 'CPA', (27, 45))	('N', 'Chemical', 'MESH:D009584', (3, 4))	('cell cycle progression', 'CPA', (77, 99))	('miRNAs', 'Var', (0, 6))
434040	31533612	Additionally, in tumors, some miRNAs can function as oncogenes, while others suppress tumors.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('N', 'Chemical', 'MESH:D009584', (33, 34))	('tumors', 'Disease', (17, 23))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('tumors', 'Disease', (86, 92))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('miRNAs', 'Var', (30, 36))	('suppress', 'NegReg', (77, 85))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
434042	31533612	Since ectopic modulation of specific miRNAs compromise the hallmarks of cancer, several efforts have been spent to generate scaffold-mediated miRNA-based delivery systems trying to demonstrate the potential of miRNA-mediated therapies.	('compromise', 'NegReg', (44, 54))	('N', 'Chemical', 'MESH:D009584', (40, 41))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('hallmarks of cancer', 'Disease', 'MESH:D009369', (59, 78))	('N', 'Chemical', 'MESH:D009584', (213, 214))	('N', 'Chemical', 'MESH:D009584', (145, 146))	('ectopic modulation', 'Var', (6, 24))	('hallmarks of cancer', 'Disease', (59, 78))
434047	31533612	For example, the expression levels of miRNA hsa-miR-21 change for different cancer types such as: squamous cell lung carcinoma, astrocytoma, breast cancer, and gastric cancer.	('expression levels', 'MPA', (17, 34))	('gastric cancer', 'Disease', (160, 174))	('change', 'Reg', (55, 61))	('cancer', 'Disease', (168, 174))	('breast cancer', 'Phenotype', 'HP:0003002', (141, 154))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('miRNA', 'Var', (38, 43))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('hsa-miR-21', 'Gene', (44, 54))	('gastric cancer', 'Disease', 'MESH:D013274', (160, 174))	('breast cancer', 'Disease', 'MESH:D001943', (141, 154))	('astrocytoma', 'Phenotype', 'HP:0009592', (128, 139))	('breast cancer', 'Disease', (141, 154))	('hsa-miR-21', 'Gene', '406991', (44, 54))	('squamous cell lung carcinoma', 'Phenotype', 'HP:0030359', (98, 126))	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('gastric cancer', 'Phenotype', 'HP:0012126', (160, 174))	('N', 'Chemical', 'MESH:D009584', (41, 42))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', (148, 154))	('squamous cell lung carcinoma', 'Disease', (98, 126))	('astrocytoma', 'Disease', 'MESH:D001254', (128, 139))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('astrocytoma', 'Disease', (128, 139))	('squamous cell lung carcinoma', 'Disease', 'MESH:D002294', (98, 126))
434078	31533612	For EFS-CLA, we use percentage of reduction E=20%, 40 as SVM calls per step, and k =100.	('CLA', 'Gene', '6404', (8, 11))	('CLA', 'Gene', (8, 11))	('E=20', 'Var', (44, 48))
434083	31533612	GSE86277,GSE86278 and GSE86281, deal with different molecular subtypes of BRCA, that could explain some of the performance issues.	('GSE86277', 'Var', (0, 8))	('GSE86281', 'Var', (22, 30))	('GSE86278', 'Var', (9, 17))	('deal', 'Reg', (32, 36))	('BRCA', 'Gene', '672', (74, 78))	('BRCA', 'Gene', (74, 78))
434095	31533612	We create a single dataset composed of 4 series (GSE86281, GSE86277, GSE86278, GSE46823), with 2 classes: TNBC, featuring 139 samples, and all other molecular subtypes (LumA, LumB, and Her2), with 32 samples in total.	('GSE86277', 'Var', (59, 67))	('GSE86278', 'Var', (69, 77))	('GSE46823', 'Var', (79, 87))	('GSE86281', 'Var', (49, 57))	('LumB', 'Chemical', 'MESH:D010634', (175, 179))	('Her2', 'Gene', '2064', (185, 189))	('LumA', 'Gene', (169, 173))	('LumA', 'Gene', '79188', (169, 173))	('N', 'Chemical', 'MESH:D009584', (107, 108))	('Her2', 'Gene', (185, 189))	('TNBC', 'Disease', (106, 110))
434112	31533612	23 miRNAs in the signature do not appear in the surveys, but they are mentioned in recent research papers, as promising research leads whose role may need further corroboration (we put the mature sequence as they appear in the study): miR-211, miR-135a, miR-3678-3p, miR-204, miR-1228, miR-374b, miR-424 miR-217-5p miR-3613-5p, miR-124, miR-1277-5p miR-190, miR-934, miR-490, miR-1247, miR-199b, miR-135a, miR-503, miR-584, miR-137-3p, and miR-103.	('miR-204', 'Gene', '406987', (267, 274))	('miR-503', 'Gene', (406, 413))	('miR-199b', 'Gene', (386, 394))	('miR-1247', 'Gene', '100302145', (376, 384))	('miR-934', 'Gene', (358, 365))	('miR-503', 'Gene', '574506', (406, 413))	('miR-3613', 'Gene', (315, 323))	('miR-3678-3p', 'Var', (254, 265))	('217-5p', 'Chemical', 'MESH:C002187', (308, 314))	('miR-490', 'Gene', '574443', (367, 374))	('miR-490', 'Gene', (367, 374))	('miR-199b', 'Gene', '406978', (386, 394))	('miR-584', 'Gene', '693169', (415, 422))	('miR-1247', 'Gene', (376, 384))	('miR-137-3p', 'Var', (424, 434))	('miR-211', 'Gene', '406993', (235, 242))	('miR-190', 'Gene', (349, 356))	('miR-584', 'Gene', (415, 422))	('miR-1228', 'Gene', (276, 284))	('miR-204', 'Gene', (267, 274))	('miR-103', 'Var', (440, 447))	('miR-3613', 'Gene', '100500908', (315, 323))	('miR-374b', 'Gene', (286, 294))	('miR-135a', 'Var', (396, 404))	('miR-1277', 'Gene', '100302214', (337, 345))	('miR-1228', 'Gene', '100302201', (276, 284))	('miR-934', 'Gene', '100126324', (358, 365))	('miR-190', 'Gene', '406965', (349, 356))	('miR-124', 'Var', (328, 335))	('miR-135a', 'Var', (244, 252))	('N', 'Chemical', 'MESH:D009584', (6, 7))	('miR-211', 'Gene', (235, 242))	('miR-374b', 'Gene', '100126317', (286, 294))	('miR-1277', 'Gene', (337, 345))
434118	31533612	For example, by ectopic expression of hsa-miR-944 which decreases malignant features in gastric, colorectal and endometrial cancers.	('hsa-miR-944', 'Gene', (38, 49))	('colorectal and endometrial cancers', 'Disease', 'MESH:D016889', (97, 131))	('malignant features', 'CPA', (66, 84))	('decreases', 'NegReg', (56, 65))	('ectopic expression', 'Var', (16, 34))	('hsa-miR-944', 'Gene', '100126340', (38, 49))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('cancers', 'Phenotype', 'HP:0002664', (124, 131))	('gastric', 'Disease', (88, 95))
434122	31533612	Alterations in miRNA expression profiles are associated with several diseases, such as cancer.	('cancer', 'Disease', (87, 93))	('Alterations', 'Var', (0, 11))	('miRNA', 'Protein', (15, 20))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('associated', 'Reg', (45, 55))	('N', 'Chemical', 'MESH:D009584', (18, 19))	('cancer', 'Disease', 'MESH:D009369', (87, 93))
434145	31533612	For GPL10850 we use the MatLab function agferead from the Bioinformatics Toolbox and use the value of gTotalGeneSignal as value for each of the probes and calculate the contributions and  as for GPL8786.	('GPL10850', 'Var', (4, 12))	('gTotalGeneSignal', 'Disease', 'None', (102, 118))	('gTotalGeneSignal', 'Disease', (102, 118))
434203	27994665	Aberrant methylation of CDH13 can be a diagnostic biomarker for lung adenocarcinoma Background: Aberrant methylation of CpG islands in tumor cells in promoter regions is a critical event in non-small cell lung carcinoma (NSCLC) tumorigenesis and can be a potential diagnostic biomarker for NSCLC patients.	('carcinoma', 'Phenotype', 'HP:0030731', (210, 219))	('small cell lung carcinoma', 'Phenotype', 'HP:0030357', (194, 219))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (64, 83))	('tumor', 'Disease', 'MESH:D009369', (228, 233))	('NSCLC', 'Disease', (221, 226))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('CDH13', 'Gene', (24, 29))	('Aberrant methylation', 'Var', (96, 116))	('cell lung carcinoma', 'Disease', (200, 219))	('NSCLC', 'Disease', 'MESH:D002289', (290, 295))	('cell lung carcinoma', 'Disease', 'MESH:D055752', (200, 219))	('tumor', 'Disease', (135, 140))	('NSCLC', 'Disease', (290, 295))	('lung adenocarcinoma', 'Disease', (64, 83))	('patients', 'Species', '9606', (296, 304))	('tumor', 'Disease', 'MESH:D009369', (135, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('non-small cell lung carcinoma', 'Phenotype', 'HP:0030358', (190, 219))	('NSCLC', 'Disease', 'MESH:D002289', (221, 226))	('tumor', 'Disease', (228, 233))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (64, 83))	('CDH13', 'Gene', '1012', (24, 29))
434204	27994665	The present study systemically and quantitatively reviewed the diagnostic ability of CDH13 methylation in NSCLC as well as in its subsets.	('NSCLC', 'Disease', 'MESH:D002289', (106, 111))	('methylation', 'Var', (91, 102))	('CDH13', 'Gene', (85, 90))	('CDH13', 'Gene', '1012', (85, 90))	('NSCLC', 'Disease', (106, 111))
434210	27994665	Conclusion: The pooled data showed that the methylation status of the CDH13 promoter is strongly associated with lung adenocarcinoma.	('CDH13', 'Gene', '1012', (70, 75))	('associated', 'Reg', (97, 107))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (113, 132))	('lung adenocarcinoma', 'Disease', (113, 132))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (113, 132))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('methylation status', 'Var', (44, 62))	('CDH13', 'Gene', (70, 75))
434211	27994665	The CDH13 methylation status could be a promising diagnostic biomarker for diagnosis of lung adenocarcinoma.	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (88, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('CDH13', 'Gene', (4, 9))	('lung adenocarcinoma', 'Disease', (88, 107))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (88, 107))	('CDH13', 'Gene', '1012', (4, 9))	('methylation status', 'Var', (10, 28))
434212	27994665	Lung cancer is a complicated disease involving genetic and epigenetic variation, and is the leading cause of cancer death all over the world.	('cancer death', 'Disease', (109, 121))	('Lung cancer', 'Phenotype', 'HP:0100526', (0, 11))	('cancer death', 'Disease', 'MESH:D003643', (109, 121))	('Lung cancer', 'Disease', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('Lung cancer', 'Disease', 'MESH:D008175', (0, 11))	('epigenetic variation', 'Var', (59, 79))
434217	27994665	Moreover, with the advantages of stable chemical property, detection ability in remote patient media, quantitative signal, relatively low cost in detection, DNA methylation has been regarded as a promising non-invasive biomarker for the early detection of lung cancer.	('lung cancer', 'Disease', (256, 267))	('lung cancer', 'Phenotype', 'HP:0100526', (256, 267))	('cancer', 'Phenotype', 'HP:0002664', (261, 267))	('lung cancer', 'Disease', 'MESH:D008175', (256, 267))	('methylation', 'Var', (161, 172))	('patient', 'Species', '9606', (87, 94))	('DNA methylation', 'Var', (157, 172))
434221	27994665	It was shown that the expression of CDH13 could be down-regulated through hypermethylation of gene promoter region.	('CDH13', 'Gene', (36, 41))	('down-regulated', 'NegReg', (51, 65))	('hypermethylation', 'Var', (74, 90))	('CDH13', 'Gene', '1012', (36, 41))	('expression', 'MPA', (22, 32))
434222	27994665	Alterations, like promoter hypermethylation and loss of function of CDH13 gene have been detected in breast cancer and lung cancer, in pituitary adenoma, diffuse large B cell lymphoma, and nasopharyngeal carcinoma.	('lung cancer', 'Disease', (119, 130))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (189, 213))	('pituitary adenoma', 'Disease', 'MESH:D010911', (135, 152))	('CDH13', 'Gene', (68, 73))	('pituitary adenoma', 'Phenotype', 'HP:0002893', (135, 152))	('breast cancer', 'Phenotype', 'HP:0003002', (101, 114))	('pituitary adenoma', 'Disease', (135, 152))	('B cell lymphoma', 'Phenotype', 'HP:0012191', (168, 183))	('lymphoma', 'Phenotype', 'HP:0002665', (175, 183))	('diffuse large B cell lymphoma', 'Disease', (154, 183))	('breast cancer', 'Disease', 'MESH:D001943', (101, 114))	('lung cancer', 'Disease', 'MESH:D008175', (119, 130))	('breast cancer', 'Disease', (101, 114))	('large B cell', 'Phenotype', 'HP:0005404', (162, 174))	('carcinoma', 'Phenotype', 'HP:0030731', (204, 213))	('lung cancer', 'Phenotype', 'HP:0100526', (119, 130))	('nasopharyngeal carcinoma', 'Disease', (189, 213))	('loss of function', 'NegReg', (48, 64))	('CDH13', 'Gene', '1012', (68, 73))	('detected', 'Reg', (89, 97))	('nasopharyngeal carcinoma', 'Disease', 'MESH:D000077274', (189, 213))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('promoter hypermethylation', 'Var', (18, 43))
434233	27994665	The pooled ORs for CDH13 methylation in cancer samples compared with that in normal controls were 6.47 (95% CI: 4.58 to 9.14, z = 10.59, P < 0.00001) in random effects model using DerSimonian and Laird method, and 7.41 (95% CI: 5.34 to 10.29, z = 11.96, P < 0.0001) in fixed effects model using Mantel-Haenszel method, demonstrating a statistically significant increase in likelihood of methylation in lung cancer tissues comparing to controls.	('cancer', 'Disease', 'MESH:D009369', (407, 413))	('methylation', 'MPA', (387, 398))	('cancer', 'Disease', (407, 413))	('increase', 'PosReg', (361, 369))	('lung cancer', 'Disease', (402, 413))	('CDH13', 'Gene', (19, 24))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('lung cancer', 'Phenotype', 'HP:0100526', (402, 413))	('cancer', 'Disease', (40, 46))	('methylation', 'Var', (25, 36))	('cancer', 'Phenotype', 'HP:0002664', (407, 413))	('CDH13', 'Gene', '1012', (19, 24))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('lung cancer', 'Disease', 'MESH:D008175', (402, 413))	('to 9', 'Species', '1214577', (117, 121))
434236	27994665	Both tissue and serum subgroups showed significant association between CDH13 methylation and NSCLC (OR = 6.75 and 9.07, respectively; P = 0.48) (Figure 2B) which suggested that CDH13 methylation can be taken as a potential biomarker for NSCLC diagnosis using either tissue or serum samples.	('NSCLC', 'Disease', (237, 242))	('methylation', 'Var', (77, 88))	('NSCLC', 'Disease', (93, 98))	('CDH13', 'Gene', (177, 182))	('NSCLC', 'Disease', 'MESH:D002289', (237, 242))	('NSCLC', 'Disease', 'MESH:D002289', (93, 98))	('CDH13', 'Gene', (71, 76))	('CDH13', 'Gene', '1012', (177, 182))	('CDH13', 'Gene', '1012', (71, 76))	('methylation', 'Var', (183, 194))
434242	27994665	Both results demonstrated a significantly positive association between CDH13 hypermethylation and NSCLC (Figure S2).	('CDH13', 'Gene', (71, 76))	('positive', 'PosReg', (42, 50))	('NSCLC', 'Disease', (98, 103))	('CDH13', 'Gene', '1012', (71, 76))	('hypermethylation', 'Var', (77, 93))	('NSCLC', 'Disease', 'MESH:D002289', (98, 103))
434249	27994665	Moreover, another independent GEO dataset GSE56044 with 83 lung adenocarcinomas and 23 lung squamous cell carcinoma tissues and 12 adjacent normal tissues, was also downloaded for further validation (Figure S5).	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (59, 79))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (59, 79))	('GSE56044', 'Var', (42, 50))	('carcinomas', 'Phenotype', 'HP:0030731', (69, 79))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (87, 115))	('lung squamous cell carcinoma tissues', 'Disease', (87, 123))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (92, 115))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (59, 78))	('lung adenocarcinomas', 'Disease', (59, 79))	('lung squamous cell carcinoma tissues', 'Disease', 'MESH:D002294', (87, 123))
434250	27994665	Further, we then combined the TCGA and GEO datasets for evaluation of the diagnosis ability of CDH13 methylation status.	('methylation status', 'Var', (101, 119))	('CDH13', 'Gene', (95, 100))	('CDH13', 'Gene', '1012', (95, 100))
434251	27994665	The AUCs of logistic regression models based on the CpG sites were 0.83-0.94 for Ads and 0.60-0.75 for SqCs, showing that the diagnostic ability of CDH13 methylation status is much better in Ads than in SqCs (Table S4).	('CDH13', 'Gene', '1012', (148, 153))	('Ads', 'Disease', (191, 194))	('better', 'Reg', (181, 187))	('methylation status', 'Var', (154, 172))	('CDH13', 'Gene', (148, 153))
434255	27994665	In this study, we performed an integrated analysis to quantify the ability for the CDH13 promoter methylation test in NSCLC diagnosis, and a significant association was identified between CDH13 methylation and NSCLC (OR = 7.41, 95% CI: 5.34 to 10.29, P < 0.0001).	('methylation', 'Var', (194, 205))	('CDH13', 'Gene', '1012', (83, 88))	('NSCLC', 'Disease', (210, 215))	('NSCLC', 'Disease', (118, 123))	('CDH13', 'Gene', (188, 193))	('NSCLC', 'Disease', 'MESH:D002289', (210, 215))	('NSCLC', 'Disease', 'MESH:D002289', (118, 123))	('CDH13', 'Gene', (83, 88))	('CDH13', 'Gene', '1012', (188, 193))
434260	27994665	Furthermore, we also conducted logistic regression model to evaluate the diagnosis ability of CDH13 methylation status in the lung adenocarcinoma and lung squamous cell tissues as well.	('CDH13', 'Gene', (94, 99))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (126, 145))	('CDH13', 'Gene', '1012', (94, 99))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (126, 145))	('methylation', 'Var', (100, 111))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('lung adenocarcinoma', 'Disease', (126, 145))
434267	27994665	This integrated analysis of the pooled data provides strong evidence that the methylation status of the CDH13 promoter is significantly associated with lung adenocarcinoma.	('associated', 'Reg', (136, 146))	('carcinoma', 'Phenotype', 'HP:0030731', (162, 171))	('CDH13', 'Gene', '1012', (104, 109))	('lung adenocarcinoma', 'Disease', (152, 171))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (152, 171))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (152, 171))	('methylation status', 'Var', (78, 96))	('CDH13', 'Gene', (104, 109))
434268	27994665	The aberrant CDH13 methylation could be a promising diagnostic biomarker for non-invasive lung adenocarcinoma detection.	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('lung adenocarcinoma', 'Disease', (90, 109))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (90, 109))	('aberrant', 'Var', (4, 12))	('CDH13', 'Gene', (13, 18))	('methylation', 'MPA', (19, 30))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (90, 109))	('CDH13', 'Gene', '1012', (13, 18))
434270	27994665	The study used a subject and text word strategy with (CDH13 OR CDHH OR P105 OR H-cadherin OR Cdht OR T-cadherin OR Tcad OR CH211-122A20.1 OR BOS_16969 OR cdhh) AND (lung or non-small) as the primary search terms.	('CDHH', 'Gene', (63, 67))	('cadherin', 'Gene', (103, 111))	('CDHH', 'Gene', '1012', (63, 67))	('cadherin', 'Gene', '999;1012', (103, 111))	('cdhh', 'Gene', '1012', (154, 158))	('CDH13', 'Gene', (54, 59))	('P105', 'Var', (71, 75))	('cadherin', 'Gene', (81, 89))	('cdhh', 'Gene', (154, 158))	('CDH13', 'Gene', '1012', (54, 59))	('cadherin', 'Gene', '999;1012', (81, 89))
434274	27994665	The SROC curve showed the performance of the diagnostic ability of CDH13 methylation to NSCLC.	('CDH13', 'Gene', (67, 72))	('methylation', 'Var', (73, 84))	('NSCLC', 'Disease', (88, 93))	('CDH13', 'Gene', '1012', (67, 72))	('NSCLC', 'Disease', 'MESH:D002289', (88, 93))
434276	27994665	And GEO datasets including GSE39279 and GSE52401 and GSE56044 were downloaded from Gene Expression Omnibus [http://www.ncbi.nlm.nih.gov/geo/], including a sum of 568 NSCLC tissues and 256 adjacent or normal lung tissues.	('GSE52401', 'Var', (40, 48))	('NSCLC', 'Disease', (166, 171))	('GSE56044', 'Var', (53, 61))	('NSCLC', 'Disease', 'MESH:D002289', (166, 171))	('GSE39279', 'Var', (27, 35))
434303	32884340	Several studies on cancer cells showed that raised ENO1 can result in the promotion of cell proliferation.	('cancer', 'Disease', 'MESH:D009369', (19, 25))	('cancer', 'Disease', (19, 25))	('cell proliferation', 'CPA', (87, 105))	('promotion', 'PosReg', (74, 83))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('raised', 'Var', (44, 50))	('ENO1', 'Gene', (51, 55))
434323	32884340	At the same time, researchers have constructed the transcriptome expression profile of the OLP-OSCC disease process, and suggested that noncoding RNAs could play an important role in this disease process.	('SCC', 'Phenotype', 'HP:0002860', (96, 99))	('OLP-OSCC disease', 'Disease', 'MESH:D003141', (91, 107))	('OLP-OSCC disease', 'Disease', (91, 107))	('noncoding RNAs', 'Var', (136, 150))
434329	32884340	There were 69 binding miRNAs towards circ-AMOTL1 and 45 towards ENO1, and among the intersection factors, several miRNAs were included: hsa-miR-22-3p, hsa-miR-1294, hsa-miR-330-3p, hsa-miR-485-5p, and hsa-miR-193a-5p, etc.	('hsa-miR-485', 'Gene', (181, 192))	('hsa-miR-193a', 'Gene', (201, 213))	('hsa-miR-1294', 'Gene', (151, 163))	('hsa-miR-22-3p', 'Gene', (136, 149))	('AMOTL1', 'Gene', (42, 48))	('hsa-miR-330-3p', 'Var', (165, 179))	('hsa-miR-1294', 'Gene', '100302181', (151, 163))	('AMOTL1', 'Gene', '154810', (42, 48))	('hsa-miR-22-3p', 'Gene', '407008', (136, 149))	('hsa-miR-485', 'Gene', '574436', (181, 192))	('hsa-miR-193a', 'Gene', '406968', (201, 213))
434333	32884340	In the OLP cell model, we found that the knocking down of circ-AMOTL1 caused a reduction of ENO1 in the mRNA level (Figure 3D and E).	('mRNA level', 'MPA', (104, 114))	('AMOTL1', 'Gene', (63, 69))	('ENO1', 'Gene', (92, 96))	('AMOTL1', 'Gene', '154810', (63, 69))	('knocking down', 'Var', (41, 54))	('reduction', 'NegReg', (79, 88))
434352	32884340	Generally, most studies support the idea that ENO1 expression is elevated and promotes the Warburg effect and cancer proliferation and invasion; ENO1 overexpression and modifications have diagnostic and prognostic value.	('promotes', 'PosReg', (78, 86))	('cancer', 'Disease', (110, 116))	('ENO1', 'Gene', (145, 149))	('Warburg effect', 'CPA', (91, 105))	('ENO1', 'Gene', (46, 50))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('modifications', 'Var', (169, 182))	('expression', 'MPA', (51, 61))	('elevated', 'PosReg', (65, 73))	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('invasion', 'CPA', (135, 143))
434372	32884340	Underlying its procarcinogenic effects, different mechanisms have been proposed, including increasing the affinity of c-myc binding to a number of promoters and serving as a sponge for binding miR-193a-5p and relieving miR-193a-5p repression of some oncogene clusters.	('relieving', 'NegReg', (209, 218))	('miR-193a-5p repression', 'MPA', (219, 241))	('increasing', 'PosReg', (91, 101))	('binding', 'Interaction', (185, 192))	('affinity', 'MPA', (106, 114))	('binding', 'Interaction', (124, 131))	('oncogene', 'Gene', (250, 258))	('miR-193a-5p', 'Var', (193, 204))	('c-myc', 'Gene', '4609', (118, 123))	('c-myc', 'Gene', (118, 123))
434440	32194796	Inhibition of DDX39 by siRNA could significantly enhance the sensitivity of MCF-7 to doxorubicin.	('doxorubicin', 'Chemical', 'MESH:D004317', (85, 96))	('enhance', 'PosReg', (49, 56))	('DDX39', 'Gene', (14, 19))	('Inhibition', 'Var', (0, 10))	('sensitivity', 'MPA', (61, 72))	('DDX39', 'Gene', '10212', (14, 19))
434447	32194796	Overexpression of DDX39 inhibits the invasion of bladder cancer cells, and prognoses better outcome in bladder cancer.	('bladder cancer', 'Disease', (49, 63))	('inhibits', 'NegReg', (24, 32))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('DDX39', 'Gene', (18, 23))	('bladder cancer', 'Phenotype', 'HP:0009725', (103, 117))	('bladder cancer', 'Phenotype', 'HP:0009725', (49, 63))	('Overexpression', 'Var', (0, 14))	('bladder cancer', 'Disease', 'MESH:D001749', (103, 117))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('DDX39', 'Gene', '10212', (18, 23))	('bladder cancer', 'Disease', 'MESH:D001749', (49, 63))	('bladder cancer', 'Disease', (103, 117))
434485	32194796	GSE10885, GSE12093, GSE2034, GSE20624, GSE22226, GSE25066, GSE3143, GSE6532, GSE7390, GSE70947 and GSE7849 were collected from North America.	('GSE7849', 'Chemical', '-', (99, 106))	('GSE6532', 'Var', (68, 75))	('GSE2034', 'Var', (20, 27))	('GSE25066', 'Var', (49, 57))	('GSE7390', 'Var', (77, 84))	('GSE3143', 'Var', (59, 66))	('GSE7390', 'Chemical', '-', (77, 84))	('GSE22226', 'Var', (39, 47))	('GSE20624', 'Var', (29, 37))	('GSE3143', 'Chemical', '-', (59, 66))	('GSE70947', 'Var', (86, 94))	('GSE6532', 'Chemical', '-', (68, 75))	('GSE12093', 'Var', (10, 18))	('GSE2034', 'Chemical', '-', (20, 27))
434487	32194796	All others including GSE11121, GSE12276, GSE1456, GSE21653, GSE22220, GSE24450, GSE42568, GSE4922, GSE53031, GSE58812 and NKI were collected from Europe.	('GSE53031', 'Var', (99, 107))	('GSE1456', 'Var', (41, 48))	('GSE12276', 'Var', (31, 39))	('GSE1456', 'Chemical', '-', (41, 48))	('GSE21653', 'Var', (50, 58))	('GSE4922', 'Var', (90, 97))	('GSE22220', 'Var', (60, 68))	('GSE58812', 'Var', (109, 117))	('GSE42568', 'Var', (80, 88))	('GSE4922', 'Chemical', '-', (90, 97))	('GSE24450', 'Var', (70, 78))	('GSE11121', 'Var', (21, 29))
434501	32194796	1B, the Western blot showed that E-cadherin, an indicator of differentiation, dramatically increased in si-DDX39 (#2) transfectant in the MDA-MB-231 cell.	('transfectant', 'Var', (118, 130))	('E-cadherin', 'Gene', (33, 43))	('E-cadherin', 'Gene', '999', (33, 43))	('DDX39', 'Gene', (107, 112))	('increased', 'PosReg', (91, 100))	('DDX39', 'Gene', '10212', (107, 112))
434511	32194796	These findings suggested that inhibition of DDX39 by siRNA could reduce the growth and invasion capability of cancer cells, especially in ER-positive BC cells (MCF-7 and ZR-75).	('DDX39', 'Gene', (44, 49))	('BC', 'Phenotype', 'HP:0003002', (150, 152))	('cancer', 'Disease', (110, 116))	('inhibition', 'Var', (30, 40))	('ER', 'Gene', '2099', (138, 140))	('BC', 'Disease', 'MESH:D001943', (150, 152))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('DDX39', 'Gene', '10212', (44, 49))	('reduce', 'NegReg', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (110, 116))
434512	32194796	Inhibition of DDX39 might affect the growth, but not the invasion, of MDA-MB-231 (ER-negative) cells.	('growth', 'MPA', (37, 43))	('affect', 'Reg', (26, 32))	('DDX39', 'Gene', (14, 19))	('Inhibition', 'Var', (0, 10))	('DDX39', 'Gene', '10212', (14, 19))	('ER', 'Gene', '2099', (82, 84))
434533	32194796	In pooled GEO datasets, DDX39 expression was significantly associated with inferior OS in both ER-positive and ER-negative subtypes (data not shown).	('expression', 'Var', (30, 40))	('DDX39', 'Gene', (24, 29))	('associated with', 'Reg', (59, 74))	('ER', 'Gene', '2099', (111, 113))	('OS', 'Chemical', '-', (84, 86))	('DDX39', 'Gene', '10212', (24, 29))	('ER', 'Gene', '2099', (95, 97))	('inferior OS', 'Disease', (75, 86))
434539	32194796	S2A and S2B, the DDX39 showed better predictive ability in ER-positive BC than that of the TNM stage in the NKI dataset.	('BC', 'Phenotype', 'HP:0003002', (71, 73))	('TNM', 'Gene', (91, 94))	('ER', 'Gene', '2099', (59, 61))	('DDX39', 'Gene', (17, 22))	('S2B', 'Var', (8, 11))	('BC', 'Disease', 'MESH:D001943', (71, 73))	('TNM', 'Gene', '10178', (91, 94))	('DDX39', 'Gene', '10212', (17, 22))
434548	32194796	Results revealed that inhibition of DDX39 significantly enhanced the cytotoxicity to doxorubicin in MCF-7 (Fig.	('inhibition', 'Var', (22, 32))	('DDX39', 'Gene', (36, 41))	('cytotoxicity', 'Disease', 'MESH:D064420', (69, 81))	('doxorubicin', 'Chemical', 'MESH:D004317', (85, 96))	('DDX39', 'Gene', '10212', (36, 41))	('enhanced', 'PosReg', (56, 64))	('cytotoxicity', 'Disease', (69, 81))
434572	32194796	The expression of DDX39 promotes cell growth and invasion ability, which had been reported in many research teams.	('cell growth', 'CPA', (33, 44))	('DDX39', 'Gene', (18, 23))	('invasion ability', 'CPA', (49, 65))	('promotes', 'PosReg', (24, 32))	('expression', 'Var', (4, 14))	('DDX39', 'Gene', '10212', (18, 23))
434575	32194796	Our experiments demonstrated that inhibition of DDX39 by siRNA significantly increased the E-Cadherin and up-regulated p-AKT protein expression levels in MCF-7 and MDA-MB-231 cells (Fig.	('E-Cadherin', 'Gene', (91, 101))	('inhibition', 'Var', (34, 44))	('AKT', 'Gene', (121, 124))	('DDX39', 'Gene', (48, 53))	('E-Cadherin', 'Gene', '999', (91, 101))	('increased', 'PosReg', (77, 86))	('up-regulated', 'PosReg', (106, 118))	('AKT', 'Gene', '207', (121, 124))	('DDX39', 'Gene', '10212', (48, 53))
434598	32194796	Inhibition of DDX39 could significantly enhance the sensitivity to doxorubicin in the MCF7 cell, but not MDA-MB-231 cell.	('doxorubicin', 'Chemical', 'MESH:D004317', (67, 78))	('DDX39', 'Gene', (14, 19))	('Inhibition', 'Var', (0, 10))	('enhance', 'PosReg', (40, 47))	('sensitivity to doxorubicin', 'MPA', (52, 78))	('DDX39', 'Gene', '10212', (14, 19))
434608	32194796	Inhibition of DDX39 only could enhance the drug sensitivity to chemotherapy in ER-positive BC (Fig.	('drug sensitivity to chemotherapy', 'MPA', (43, 75))	('BC', 'Phenotype', 'HP:0003002', (91, 93))	('enhance', 'PosReg', (31, 38))	('ER', 'Gene', '2099', (79, 81))	('BC', 'Disease', 'MESH:D001943', (91, 93))	('drug sensitivity', 'Phenotype', 'HP:0020174', (43, 59))	('DDX39', 'Gene', (14, 19))	('Inhibition', 'Var', (0, 10))	('DDX39', 'Gene', '10212', (14, 19))
434625	31490704	PTK7 knockdown not only reduced ligand-free and fibroblast growth factor (FGF)-induced phosphorylation of FGFR1 but also the interaction of signaling adaptor proteins with FGFR1 and activation of downstream signaling proteins in TE-10 cells.	('PTK7', 'Gene', (0, 4))	('FGFR1', 'Gene', (106, 111))	('knockdown', 'Var', (5, 14))	('reduced', 'NegReg', (24, 31))	('interaction', 'Interaction', (125, 136))	('ligand-free', 'MPA', (32, 43))	('FGFR1', 'Gene', '2260', (106, 111))	('TE', 'Chemical', 'MESH:D013691', (229, 231))	('FGFR1', 'Gene', (172, 177))	('activation', 'PosReg', (182, 192))	('phosphorylation', 'MPA', (87, 102))	('FGFR1', 'Gene', '2260', (172, 177))
434640	31490704	However, at higher molar ratios, PTK7 encloses KDR molecules and prevents activation of KDR.	('encloses', 'Reg', (38, 46))	('KDR', 'Gene', '3791', (88, 91))	('PTK7', 'Var', (33, 37))	('KDR', 'Gene', '3791', (47, 50))	('prevents', 'NegReg', (65, 73))	('KDR', 'Gene', (88, 91))	('KDR', 'Gene', (47, 50))	('activation', 'MPA', (74, 84))
434642	31490704	In ESCC cells, PTK7 transactivates matrix metallopeptidase 9 (MMP-9) expression via activation of activator protein 1 (AP-1) and NF-kappaB.	('AP-1', 'Gene', '3726', (119, 123))	('AP-1', 'Gene', (119, 123))	('activation', 'PosReg', (84, 94))	('NF-kappaB', 'Gene', (129, 138))	('MMP-9', 'Gene', (62, 67))	('MMP-9', 'Gene', '4318', (62, 67))	('expression', 'Species', '29278', (69, 79))	('expression', 'MPA', (69, 79))	('PTK7', 'Var', (15, 19))	('NF-kappaB', 'Gene', '4790', (129, 138))
434659	31490704	The pcDNA3-PTK7-Ext-TM-FLAG encoding the human PTK7 extracellular domain and TM domain (residues 34-725) with a C-terminal FLAG-tag was constructed by deleting nucleotides encoding residues 726-1070 of PTK7 (GenBank U40271) from pcDNA3-hPTK7-FLAG.	('hPTK7', 'Gene', '5754', (236, 241))	('PTK7', 'Gene', (202, 206))	('human', 'Species', '9606', (41, 46))	('deleting', 'Var', (151, 159))	('hPTK7', 'Gene', (236, 241))
434664	31490704	The pLKO.1-shRNA-PTK7-6433 and -6434 constructs for human PTK7 knockdown and the pLKO.1-control (MilliporeSigma) were previously described by Shin et al..	('knockdown', 'Var', (63, 72))	('PTK7', 'Gene', (58, 62))	('human', 'Species', '9606', (52, 57))
434706	31490704	Specific binding of PTK7 to the FGFR1 extracellular domain was further supported by the finding that knockout of FGFR1 abolished the interaction of sPTK7-His with FGFR1 in TE-10 cells (Supplemental Fig.	('interaction', 'Interaction', (133, 144))	('abolished', 'NegReg', (119, 128))	('FGFR1', 'Gene', (32, 37))	('knockout', 'Var', (101, 109))	('TE', 'Chemical', 'MESH:D013691', (172, 174))	('sPTK7-His', 'Protein', (148, 157))	('FGFR1', 'Gene', '2260', (163, 168))	('FGFR1', 'Gene', (113, 118))	('FGFR1', 'Gene', '2260', (32, 37))	('FGFR1', 'Gene', '2260', (113, 118))	('FGFR1', 'Gene', (163, 168))
434707	31490704	To observe whether PTK7 colocalizes with FGFR1 on the cell surface, we analyzed the subcellular localization of PTK7 and FGFR1 in HEK293 cells coexpressing PTK7-FLAG and FGFR1-HA using confocal microscopy.	('FGFR1', 'Gene', '2260', (170, 175))	('HEK293', 'CellLine', 'CVCL:0045', (130, 136))	('FGFR1', 'Gene', '2260', (121, 126))	('FGFR1', 'Gene', (121, 126))	('FGFR1', 'Gene', (41, 46))	('FGFR1', 'Gene', '2260', (41, 46))	('FGFR1', 'Gene', (170, 175))	('PTK7-FLAG', 'Var', (156, 165))
434715	31490704	The presence of full-length PTK7 significantly increased FGFR1 phosphorylation under both ligand-free and aFGF-stimulated conditions in HEK293 cells (Fig.	('FGFR1', 'Gene', (57, 62))	('HEK293', 'CellLine', 'CVCL:0045', (136, 142))	('aFGF', 'Gene', '2246', (106, 110))	('FGFR1', 'Gene', '2260', (57, 62))	('PTK7', 'Gene', (28, 32))	('increased FGFR1', 'Phenotype', 'HP:0030269', (47, 62))	('increased', 'PosReg', (47, 56))	('phosphorylation', 'MPA', (63, 78))	('presence', 'Var', (4, 12))	('aFGF', 'Gene', (106, 110))
434718	31490704	Consistently, PTK7 knockdown in TE-10 cells reduced tyrosine phosphorylation of FGFR1 and cellular proteins independent of aFGF stimulation (Fig.	('FGFR1', 'Gene', '2260', (80, 85))	('PTK7', 'Gene', (14, 18))	('knockdown', 'Var', (19, 28))	('tyrosine', 'Chemical', 'MESH:D014443', (52, 60))	('aFGF', 'Gene', '2246', (123, 127))	('tyrosine phosphorylation', 'MPA', (52, 76))	('cellular', 'Protein', (90, 98))	('reduced', 'NegReg', (44, 51))	('TE', 'Chemical', 'MESH:D013691', (32, 34))	('FGFR1', 'Gene', (80, 85))	('aFGF', 'Gene', (123, 127))
434720	31490704	Thus, PTK7 enhances FGFR1 activation by interaction of their extracellular domains independent of the presence of a cognate ligand but is not phosphorylated by activated FGFR1.	('FGFR1', 'Gene', '2260', (170, 175))	('activation', 'MPA', (26, 36))	('FGFR1', 'Gene', (20, 25))	('FGFR1', 'Gene', '2260', (20, 25))	('interaction', 'Interaction', (40, 51))	('FGFR1', 'Gene', (170, 175))	('PTK7', 'Var', (6, 10))	('enhances', 'PosReg', (11, 19))
434723	31490704	PTK7 knockdown also decreased aFGF-induced association of FGFR1 with FGFR1-interacting proteins such as FRS2, Src, Grb2, p85 PI3-kinase, and Shc (Fig.	('FRS2', 'Gene', (104, 108))	('aFGF', 'Gene', (30, 34))	('association', 'Interaction', (43, 54))	('decreased', 'NegReg', (20, 29))	('PTK7', 'Gene', (0, 4))	('knockdown', 'Var', (5, 14))	('Shc', 'Gene', '6464', (141, 144))	('aFGF', 'Gene', '2246', (30, 34))	('FGFR1', 'Gene', (58, 63))	('FGFR1', 'Gene', (69, 74))	('Grb2', 'Gene', (115, 119))	('FGFR1', 'Gene', '2260', (58, 63))	('FRS2', 'Gene', '10818', (104, 108))	('Shc', 'Gene', (141, 144))	('FGFR1', 'Gene', '2260', (69, 74))	('Grb2', 'Gene', '2885', (115, 119))
434724	31490704	Decreased FGFR1 binding with interacting proteins by PTK7 knockdown was also detected in the absence of aFGF stimulation but to a much weaker extent (Fig.	('knockdown', 'Var', (58, 67))	('aFGF', 'Gene', (104, 108))	('Decreased', 'NegReg', (0, 9))	('FGFR1', 'Gene', (10, 15))	('aFGF', 'Gene', '2246', (104, 108))	('binding', 'Interaction', (16, 23))	('FGFR1', 'Gene', '2260', (10, 15))	('PTK7', 'Gene', (53, 57))	('proteins', 'Protein', (41, 49))
434733	31490704	In these cells, PTK7 knockdown decreased fibroblast growth factor (FGF)-induced proliferation to the same extent as FGFR1 knockout (Fig.	('FGFR1', 'Gene', (116, 121))	('FGFR1', 'Gene', '2260', (116, 121))	('decreased', 'NegReg', (31, 40))	('knockdown', 'Var', (21, 30))	('PTK7', 'Gene', (16, 20))
434735	31490704	In ESCC TE-6, TE-9, TE-10, and TE-11 cells, knockdown of PTK7 reduced phosphorylation of FGFR1 independent of aFGF and decreased binding to FGFR1 (Fig.	('TE', 'Chemical', 'MESH:D013691', (20, 22))	('decreased', 'NegReg', (119, 128))	('TE', 'Chemical', 'MESH:D013691', (31, 33))	('FGFR1', 'Gene', (140, 145))	('aFGF', 'Gene', (110, 114))	('TE', 'Chemical', 'MESH:D013691', (14, 16))	('FGFR1', 'Gene', (89, 94))	('FGFR1', 'Gene', '2260', (89, 94))	('FGFR1', 'Gene', '2260', (140, 145))	('phosphorylation', 'MPA', (70, 85))	('aFGF', 'Gene', '2246', (110, 114))	('TE', 'Chemical', 'MESH:D013691', (8, 10))	('knockdown', 'Var', (44, 53))	('binding', 'Interaction', (129, 136))	('PTK7', 'Gene', (57, 61))	('reduced', 'NegReg', (62, 69))
434736	31490704	PTK7 knockdown also inhibited aFGF- and bFGF-induced proliferation in the ESCC cells (Fig.	('aFGF', 'Gene', (30, 34))	('bFGF', 'Gene', (40, 44))	('PTK7', 'Gene', (0, 4))	('knockdown', 'Var', (5, 14))	('aFGF', 'Gene', '2246', (30, 34))	('inhibited', 'NegReg', (20, 29))	('proliferation', 'CPA', (53, 66))	('bFGF', 'Gene', '2247', (40, 44))
434740	31490704	FGFR1 is associated with poor survival of patients with ESCC, and inhibition of FGFR1 activity reduces ESCC tumor growth in vivo.	('ESCC', 'Disease', (56, 60))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('FGFR1', 'Gene', '2260', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('FGFR1', 'Gene', (0, 5))	('FGFR1', 'Gene', '2260', (0, 5))	('tumor', 'Disease', (108, 113))	('inhibition', 'Var', (66, 76))	('ESCC', 'Disease', (103, 107))	('FGFR1', 'Gene', (80, 85))	('patients', 'Species', '9606', (42, 50))	('reduces', 'NegReg', (95, 102))
434749	31490704	Similarly, PTK7 might promote ligand-independent oligomerization of FGFR1 and increase phosphorylation of FGFR1.	('promote', 'PosReg', (22, 29))	('PTK7', 'Var', (11, 15))	('FGFR1', 'Gene', (106, 111))	('FGFR1', 'Gene', (68, 73))	('FGFR1', 'Gene', '2260', (106, 111))	('increase', 'PosReg', (78, 86))	('FGFR1', 'Gene', '2260', (68, 73))	('ligand-independent oligomerization', 'MPA', (30, 64))	('phosphorylation', 'MPA', (87, 102))
434751	31490704	Similarly, the PTK7 extracellular domain or a truncated PTK7 mutant lacking the Cyt domain is sufficient to bind to and activate KDR or tyrosine-protein kinase transmembrane receptor 2 (ROR2) as much as the intact PTK7 does.	('bind', 'Interaction', (108, 112))	('activate', 'PosReg', (120, 128))	('KDR', 'Gene', '3791', (129, 132))	('mutant', 'Var', (61, 67))	('PTK7', 'Gene', (56, 60))	('KDR', 'Gene', (129, 132))	('ROR2', 'Gene', '4920', (186, 190))	('ROR2', 'Gene', (186, 190))	('tyrosine', 'Chemical', 'MESH:D014443', (136, 144))
434757	31490704	Ligand-independent activation of FGFR1 often occurs in the presence of FGFR1 mutations within the TM domain, such as Y373C, which induce dimerization of FGFR1.	('FGFR1', 'Gene', (153, 158))	('FGFR1', 'Gene', '2260', (153, 158))	('FGFR1', 'Gene', (71, 76))	('Y373C', 'Var', (117, 122))	('FGFR1', 'Gene', '2260', (33, 38))	('FGFR1', 'Gene', '2260', (71, 76))	('activation', 'PosReg', (19, 29))	('dimerization', 'MPA', (137, 149))	('Y373C', 'SUBSTITUTION', 'None', (117, 122))	('FGFR1', 'Gene', (33, 38))
434760	31490704	Here, we have shown that PTK7 activates FGFR1 in the absence of FGF and enhances FGFR1 activity in the presence of FGF.	('FGFR1', 'Gene', (81, 86))	('activity', 'MPA', (87, 95))	('FGFR1', 'Gene', (40, 45))	('FGFR1', 'Gene', '2260', (40, 45))	('FGFR1', 'Gene', '2260', (81, 86))	('activates', 'PosReg', (30, 39))	('PTK7', 'Var', (25, 29))	('enhances', 'PosReg', (72, 80))
434764	31490704	Overexpression of PTK7 increases proliferation, migration, and invasion in PTK7-low (TE-5 and TE-14) cells but decreases them in PTK7-high (TE-6 and TE-10) cells.	('migration', 'CPA', (48, 57))	('TE', 'Chemical', 'MESH:D013691', (140, 142))	('PTK7-low', 'Var', (75, 83))	('expression', 'Species', '29278', (4, 14))	('TE', 'Chemical', 'MESH:D013691', (94, 96))	('decreases', 'NegReg', (111, 120))	('TE', 'Chemical', 'MESH:D013691', (149, 151))	('PTK7', 'Gene', (18, 22))	('proliferation', 'CPA', (33, 46))	('invasion', 'CPA', (63, 71))	('increases', 'PosReg', (23, 32))	('TE', 'Chemical', 'MESH:D013691', (85, 87))
434766	31490704	Previously, we showed that low expression of PTK7 oligomerizes and activates KDR molecules, but high levels of PTK7 surround and inhibit KDR molecules in endothelial cells.	('oligomerizes', 'MPA', (50, 62))	('KDR', 'Gene', '3791', (77, 80))	('PTK7', 'Var', (111, 115))	('PTK7', 'Gene', (45, 49))	('inhibit', 'NegReg', (129, 136))	('expression', 'Species', '29278', (31, 41))	('activates', 'PosReg', (67, 76))	('KDR', 'Gene', '3791', (137, 140))	('KDR', 'Gene', (77, 80))	('KDR', 'Gene', (137, 140))
434786	30881377	suggested a strategy including the large-scale screening of potential RGs from RNA-Seq data with further validation by qPCR and applied it for breast cancer (Tilli et al.,).	('breast cancer', 'Disease', 'MESH:D001943', (143, 156))	('breast cancer', 'Disease', (143, 156))	('breast cancer', 'Phenotype', 'HP:0003002', (143, 156))	('RGs', 'Var', (70, 73))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
434824	30881377	For this purpose, we calculated the pan-cancer score as follows: where: where M = 12 (a number of cancer types analyzed); k = -0.4 (negative k value implies that the pan-cancer score is a harmonic mean of individual scores); CA = 12 (a constant add).	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('cancer', 'Disease', (170, 176))	('k = -0.4', 'Var', (122, 130))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('cancer', 'Disease', (40, 46))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('cancer', 'Disease', (98, 104))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))
434871	30881377	The presence of pseudogenes is a weakness of such widely used RGs as GAPDH and ACTB (67 and 64, respectively) (Sun et al.,), or genes encoding ribosomal proteins, including RPL13A and RPS17 (Tonner et al.,).	('RPS17', 'Gene', (184, 189))	('GAPDH', 'Gene', '2597', (69, 74))	('RPS17', 'Gene', '6218', (184, 189))	('GAPDH', 'Gene', (69, 74))	('RPL13A', 'Gene', (173, 179))	('ACTB', 'Gene', (79, 83))	('pseudogenes', 'Var', (16, 27))	('ACTB', 'Gene', '60', (79, 83))	('RPL13A', 'Gene', '23521', (173, 179))
434875	30881377	Aberrant splicing in cancer provides a way to generate alternatively spliced transcripts encoding proteins with distinct functions (Ghigna et al.,).	('Aberrant splicing', 'Var', (0, 17))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('cancer', 'Disease', (21, 27))	('cancer', 'Disease', 'MESH:D009369', (21, 27))
434876	30881377	There are at least two ways resulting in splicing aberrations in cancer: mutations in the affected genes, e.g., in their splice sites (cis-effect), and altered expression and/or activity of the elements of splicing machinery (trans-effect).	('expression', 'MPA', (160, 170))	('splice', 'MPA', (121, 127))	('splicing', 'MPA', (41, 49))	('cancer', 'Disease', (65, 71))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('altered', 'Reg', (152, 159))	('activity', 'MPA', (178, 186))	('resulting', 'Reg', (28, 37))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('mutations', 'Var', (73, 82))
434877	30881377	Some of the splicing factors are known to be deregulated in cancer, by means of mRNA level alterations, mutations or posttranslational modifications (Stickeler et al.,; Blaustein et al.,; Ghigna et al.,).	('mutations', 'Var', (104, 113))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('mRNA level', 'MPA', (80, 90))	('cancer', 'Disease', (60, 66))	('alterations', 'Reg', (91, 102))	('deregulated', 'PosReg', (45, 56))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
434925	28209200	For patients with advanced tumor stage (T3 or T4), lymph node ECS, tumor depth >=10 mm, or poor differentiation, postoperative radiotherapy or concomitant chemoradiotherapy would be suggested.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('lymph', 'Disease', (51, 56))	('poor', 'Var', (91, 95))	('tumor', 'Disease', (27, 32))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('patients', 'Species', '9606', (4, 12))	('tumor', 'Disease', (67, 72))	('tumor', 'Disease', 'MESH:D009369', (27, 32))
434949	28209200	We analyzed the influence of CRP on survival according to different subsites: the HR for CRP in tongue cancer DFS 1.785 (95% CI 0.848-3.757); OS 1.535 (95% CI 0.630-3.741); the HR for CRP in buccal cancer, DFS 2.293 (95% CI 1.309-4.017); OS 3.610 (95% CI 1.732-7.526); the HR for CRP in other cancer subsites, DFS 1.577 (95% CI 0.721-3.449), OS 1.252 (95% CI 0.403-3.885).	('buccal cancer', 'Disease', 'MESH:D009369', (191, 204))	('cancer', 'Disease', 'MESH:D009369', (293, 299))	('CRP', 'Gene', '1401', (280, 283))	('CRP', 'Gene', '1401', (89, 92))	('tongue cancer', 'Disease', (96, 109))	('OS', 'Chemical', '-', (342, 344))	('cancer', 'Disease', (103, 109))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('cancer', 'Disease', (198, 204))	('CRP', 'Gene', '1401', (184, 187))	('OS', 'Chemical', '-', (238, 240))	('CRP', 'Gene', (29, 32))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('tongue cancer', 'Disease', 'MESH:D014062', (96, 109))	('buccal cancer', 'Disease', (191, 204))	('cancer', 'Disease', (293, 299))	('CRP', 'Gene', (280, 283))	('OS', 'Chemical', '-', (142, 144))	('DFS', 'Var', (310, 313))	('CRP', 'Gene', (89, 92))	('cancer', 'Phenotype', 'HP:0002664', (293, 299))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('CRP', 'Gene', (184, 187))	('CRP', 'Gene', '1401', (29, 32))
435011	25885699	Nicotine also can upregulate nAChR expression, thus shifting ACh signaling in lung cells toward the nicotinic vs. muscarinic physiological signaling pathways.	('upregulate', 'PosReg', (18, 28))	('Nicotine', 'Chemical', 'MESH:D009538', (0, 8))	('Nicotine', 'Var', (0, 8))	('ACh', 'Chemical', 'MESH:D000109', (61, 64))	('shifting', 'Reg', (52, 60))	('ACh signaling', 'MPA', (61, 74))	('ACh', 'Chemical', 'MESH:D000109', (30, 33))	('nAChR', 'Gene', '1137', (29, 34))	('nAChR', 'Gene', (29, 34))
435016	25885699	Silencing of the expression of nAChR subunits and treatment with nAChR antagonists produce anti-tumor effects both in vitro and in vivo.	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('nAChR', 'Gene', '1137', (65, 70))	('tumor', 'Disease', (96, 101))	('nAChR', 'Gene', '1137', (31, 36))	('nAChR', 'Gene', (65, 70))	('nAChR', 'Gene', (31, 36))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('Silencing', 'Var', (0, 9))
435022	25885699	Additionally, modulation of functional electron transport in mitochondria has been recently found to play an important role in implementing the nicotine action interfering with chemotherapy-induced apoptosis.	('chemotherapy-induced apoptosis', 'CPA', (177, 207))	('modulation', 'Var', (14, 24))	('nicotine', 'Chemical', 'MESH:D009538', (144, 152))	('interfering', 'NegReg', (160, 171))	('functional electron transport', 'MPA', (28, 57))
435025	25885699	mPTP opening causes massive swelling of mitochondria, rupture of outer membrane and release of intermembrane components that induce intrinsic apoptosis, such as cytochrome c (CytC).	('cytochrome c', 'Gene', '54205', (161, 173))	('mitochondria', 'MPA', (40, 52))	('opening', 'Var', (5, 12))	('mPTP', 'Gene', (0, 4))	('induce', 'Reg', (125, 131))	('CytC', 'Gene', '54205', (175, 179))	('release of intermembrane components', 'MPA', (84, 119))	('rupture', 'CPA', (54, 61))	('CytC', 'Gene', (175, 179))	('massive swelling of mitochondria', 'Phenotype', 'HP:0030774', (20, 52))	('cytochrome c', 'Gene', (161, 173))	('intrinsic apoptosis', 'CPA', (132, 151))
435066	25885699	The involvement of a particular cm-nAChR subtype in the binary interaction with GFRs was determined based on disappearance of the additive (synergistic) effect upon functional inactivation of the cm-nAChR in question by transfection with anti-receptor shRNAs, but not shRNA-NC.	('disappearance', 'NegReg', (109, 122))	('GFR', 'Gene', (80, 83))	('inactivation', 'NegReg', (176, 188))	('nAChR', 'Gene', '1137', (199, 204))	('nAChR', 'Gene', (199, 204))	('additive', 'MPA', (130, 138))	('nAChR', 'Gene', '1137', (35, 40))	('GFR', 'Gene', '9771', (80, 83))	('nAChR', 'Gene', (35, 40))	('anti-receptor', 'Var', (238, 251))
435067	25885699	In keeping with results obtained with pharmacological nAChR antagonists (Figure 1), silencing of the alpha7 gene selectively inhibited synergy of nicotine with EGF (Figure 2).	('EGF', 'Gene', (160, 163))	('nAChR', 'Gene', '1137', (54, 59))	('nicotine', 'Chemical', 'MESH:D009538', (146, 154))	('nAChR', 'Gene', (54, 59))	('alpha7', 'Gene', '16404', (101, 107))	('silencing', 'Var', (84, 93))	('EGF', 'Gene', '1950', (160, 163))	('alpha7', 'Gene', (101, 107))	('inhibited', 'NegReg', (125, 134))
435069	25885699	Interestingly, abolishing signaling by alpha9 nAChRs significantly (p < 0.05) decreased the additive effect of nicotine to that of each tested GF (Figure 2).	('abolishing', 'Var', (15, 25))	('nicotine', 'Chemical', 'MESH:D009538', (111, 119))	('signaling', 'MPA', (26, 35))	('nAChRs', 'Chemical', '-', (46, 52))	('alpha9 nAChRs', 'Protein', (39, 52))	('additive effect of nicotine', 'MPA', (92, 119))	('decreased', 'NegReg', (78, 87))
435076	25885699	By the former technique, we determined specific binding of the preferred radioligands of alpha7 and non-alpha7 nAChRs, [3H] alphaBtx and [3H] epibatidine, respectively.	('alpha7', 'Gene', (104, 110))	('[3H] epibatidine', 'Chemical', '-', (137, 153))	('alpha7', 'Gene', '16404', (104, 110))	('binding', 'Interaction', (48, 55))	('[3H] alphaBtx', 'Chemical', '-', (119, 132))	('alpha7', 'Gene', '16404', (89, 95))	('[3H] alphaBtx', 'Var', (119, 132))	('[3H', 'Var', (137, 140))	('alpha7', 'Gene', (89, 95))	('nAChRs', 'Chemical', '-', (111, 117))
435094	25885699	The additive oncogenic effect of nicotine is best illustrated in the lung cancer model in A/J mice, wherein nicotine increases both the numbers and the size of tobacco nitrosamine-initiated lung tumors, and decreases survival probability.	('nicotine', 'Chemical', 'MESH:D009538', (108, 116))	('tobacco', 'Species', '4097', (160, 167))	('tumors', 'Phenotype', 'HP:0002664', (195, 201))	('lung tumors', 'Disease', (190, 201))	('nitrosamine', 'Chemical', 'MESH:D009602', (168, 179))	('lung cancer', 'Disease', 'MESH:D008175', (69, 80))	('lung tumors', 'Phenotype', 'HP:0100526', (190, 201))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('increases', 'PosReg', (117, 126))	('nicotine', 'Chemical', 'MESH:D009538', (33, 41))	('nicotine', 'Var', (108, 116))	('lung cancer', 'Disease', (69, 80))	('lung tumors', 'Disease', 'MESH:D008175', (190, 201))	('lung cancer', 'Phenotype', 'HP:0100526', (69, 80))	('mice', 'Species', '10090', (94, 98))	('decreases', 'NegReg', (207, 216))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('survival probability', 'CPA', (217, 237))
435095	25885699	Furthermore, while smoking is an independent predictive factor of chemoresistance of lung cancer, silencing of nAChRs in the non-small-cell lung carcinoma cell lines suppresses nicotine-dependent chemoresistance.	('suppresses', 'NegReg', (166, 176))	('nicotine-dependent chemoresistance', 'CPA', (177, 211))	('lung cancer', 'Disease', (85, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (145, 154))	('lung cancer', 'Phenotype', 'HP:0100526', (85, 96))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('small-cell lung carcinoma', 'Phenotype', 'HP:0030357', (129, 154))	('nicotine', 'Chemical', 'MESH:D009538', (177, 185))	('silencing', 'Var', (98, 107))	('lung cancer', 'Disease', 'MESH:D008175', (85, 96))	('nAChRs', 'Gene', (111, 117))	('lung carcinoma', 'Disease', (140, 154))	('lung carcinoma', 'Disease', 'MESH:D008175', (140, 154))	('non-small-cell lung carcinoma', 'Phenotype', 'HP:0030358', (125, 154))	('nAChRs', 'Chemical', '-', (111, 117))
435098	25885699	Altogether, the downstream signaling from cm-nAChRs has been shown to activate protein kinase C isoforms, Ca2+/calmodulin-dependent protein-kinase II, Jak2, phosphatidylinositol-3-kinase, JNK, phospholipase C, EGFR kinase, Rac, Rho, p38 and p44/42 MAPK, as well as the Ras-Raf1-MEK-ERK pathway.	('Rac', 'Enzyme', (223, 226))	('cm-nAChRs', 'Var', (42, 51))	('EGFR', 'Gene', (210, 214))	('Ca2+/calmodulin-dependent', 'MPA', (106, 131))	('phosphatidylinositol-3-kinase', 'MPA', (157, 186))	('p44', 'Gene', (241, 244))	('activate', 'PosReg', (70, 78))	('p38', 'Gene', (233, 236))	('p44', 'Gene', '10561', (241, 244))	('protein kinase C isoforms', 'Enzyme', (79, 104))	('phospholipase C', 'Enzyme', (193, 208))	('nAChRs', 'Chemical', '-', (45, 51))	('Ca2+', 'Chemical', 'MESH:D000069285', (106, 110))	('ERK', 'Gene', (282, 285))	('JNK', 'Gene', (188, 191))	('MAPK', 'Gene', (248, 252))	('JNK', 'Gene', '5599', (188, 191))	('EGFR', 'Gene', '1956', (210, 214))	('Raf1', 'Gene', '5894', (273, 277))	('MAPK', 'Gene', '5594', (248, 252))	('Rho', 'Enzyme', (228, 231))	('p38', 'Gene', '1432', (233, 236))	('Raf1', 'Gene', (273, 277))	('Jak2', 'Gene', (151, 155))	('Jak2', 'Gene', '3717', (151, 155))	('ERK', 'Gene', '5594', (282, 285))
435102	25885699	For instance, it is well-documented that nicotine accelerates wound healing by synergizing with and mimicking the effects of various GFs.	('nicotine', 'Var', (41, 49))	('nicotine', 'Chemical', 'MESH:D009538', (41, 49))	('wound healing', 'CPA', (62, 75))	('accelerates', 'PosReg', (50, 61))
435128	25885699	Noteworthily, inhibition of nAChR expression has been shown to attenuate nicotine- or tobacco nitrosamine-induced cell proliferation in vitro and/or in vivo (reviewed in).	('nicotine-', 'MPA', (73, 82))	('attenuate', 'NegReg', (63, 72))	('nitrosamine', 'Chemical', 'MESH:D009602', (94, 105))	('nAChR', 'Gene', '1137', (28, 33))	('nAChR', 'Gene', (28, 33))	('tobacco', 'Species', '4097', (86, 93))	('inhibition', 'Var', (14, 24))	('nicotine', 'Chemical', 'MESH:D009538', (73, 81))
435133	33725812	Here, we describe 2 cases of renal metastases with chromosome duplications in urine exfoliated cells.	('renal metastases', 'Disease', 'MESH:D009362', (29, 45))	('renal metastases', 'Disease', (29, 45))	('chromosome duplications', 'Var', (51, 74))
435216	33725812	Chromosomal aberrations are a prominent feature of human malignancies.	('Chromosomal aberrations', 'Var', (0, 23))	('malignancies', 'Disease', (57, 69))	('Chromosomal aberrations', 'Phenotype', 'HP:0040012', (0, 23))	('human', 'Species', '9606', (51, 56))	('malignancies', 'Disease', 'MESH:D009369', (57, 69))
435221	33725812	The main chromosomal structural aberrations that occurred were 1q+, 1p+, 6q-, 8q+, 14q+, 18p+, 18q+, and 2p21-p23.	('18p+', 'Var', (89, 93))	('1q+', 'Var', (63, 66))	('14q+', 'Var', (83, 87))	('8q+', 'Var', (78, 81))	('p23', 'Gene', '8851', (110, 113))	('6q-', 'Var', (73, 76))	('18q+', 'Var', (95, 99))	('1p+', 'Var', (68, 71))	('p23', 'Gene', (110, 113))
435225	33725812	The immunohistochemistry results of patient 2 indicated positivity for BCL-2 and BCL-6, which implied that the prognosis was poor.	('BCL-2', 'Gene', (71, 76))	('BCL', 'Phenotype', 'HP:0012191', (71, 74))	('BCL-6', 'Gene', (81, 86))	('positivity', 'Var', (56, 66))	('BCL', 'Phenotype', 'HP:0012191', (81, 84))	('BCL-6', 'Gene', '604', (81, 86))	('BCL-2', 'Gene', '596', (71, 76))	('patient', 'Species', '9606', (36, 43))
435226	33725812	The data from these studies indicate that tumor cells of esophageal squamous cell carcinoma and NHL have possible chromosome 3, 7, and 17 aberrations and/or deletion or amplification of the p16 gene locus on chromosome 9.	('esophageal squamous cell carcinoma', 'Disease', (57, 91))	('tumor', 'Disease', (42, 47))	('amplification', 'Var', (169, 182))	('aberrations', 'Var', (138, 149))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('deletion', 'Var', (157, 165))	('p16', 'Gene', '1029', (190, 193))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (57, 91))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (68, 91))	('NHL', 'Phenotype', 'HP:0012539', (96, 99))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('p16', 'Gene', (190, 193))
435238	33725812	The FISH test results of the primary esophageal cancer tissue and the renal metastatic tumor tissue in patient 1 showed aberrations in chromosome 3, 7, and 17, which were consistent with the urine FISH results.	('renal metastatic tumor', 'Disease', (70, 92))	('renal metastatic tumor', 'Disease', 'MESH:C538445', (70, 92))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('esophageal cancer', 'Disease', (37, 54))	('patient', 'Species', '9606', (103, 110))	('aberrations', 'Var', (120, 131))	('esophageal cancer', 'Disease', 'MESH:D004938', (37, 54))
435250	33311458	Patterns for TP53 mutations can also be detected, with WSI self- and cross-tissue AUCs ranging from 0.65-0.80.	('TP53', 'Gene', '7157', (13, 17))	('TP53', 'Gene', (13, 17))	('mutations', 'Var', (18, 27))
435262	33311458	trained ResNet-50 CNNs to predict SPOP mutations using WSIs from 177 prostate cancer patients, achieving AUC = 0.74 in cross-validation and AUC = 0.64 on an independent set.	('SPOP', 'Gene', '8405', (34, 38))	('SPOP', 'Gene', (34, 38))	('prostate cancer', 'Disease', 'MESH:D011471', (69, 84))	('prostate cancer', 'Phenotype', 'HP:0012125', (69, 84))	('mutations', 'Var', (39, 48))	('patients', 'Species', '9606', (85, 93))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('prostate cancer', 'Disease', (69, 84))
435265	33311458	Further, their models were able to predict mutations in ten genes in LUAD with AUCs 0.64-0.86, and subsequently mutations in BRAF (AUC ~0.75) or NRAS (AUC ~0.77) melanomas.	('NRAS', 'Gene', (145, 149))	('LUAD', 'Phenotype', 'HP:0030078', (69, 73))	('melanomas', 'Disease', 'MESH:D008545', (162, 171))	('LUAD', 'Disease', (69, 73))	('mutations', 'Var', (112, 121))	('NRAS', 'Gene', '4893', (145, 149))	('mutations', 'Var', (43, 52))	('BRAF', 'Gene', '673', (125, 129))	('melanomas', 'Disease', (162, 171))	('melanomas', 'Phenotype', 'HP:0002861', (162, 171))	('BRAF', 'Gene', (125, 129))	('predict', 'Reg', (35, 42))
435344	33311458	To investigate how images can be used to distinguish cancer drivers, we tested the accuracy of CNNs for classifying TP53 mutation status in five TCGA cancer types, namely BRCA, LUAD, STAD, COAD, and BLCA.	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('LUAD', 'Phenotype', 'HP:0030078', (177, 181))	('COAD', 'Disease', 'MESH:D029424', (189, 193))	('BRCA', 'Gene', '672', (171, 175))	('TP53', 'Gene', (116, 120))	('BLCA', 'Chemical', '-', (199, 203))	('STAD', 'Disease', (183, 187))	('cancer', 'Disease', (150, 156))	('mutation', 'Var', (121, 129))	('LUAD', 'Disease', (177, 181))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('BRCA', 'Gene', (171, 175))	('cancer', 'Disease', (53, 59))	('COAD', 'Disease', (189, 193))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('TP53', 'Gene', '7157', (116, 120))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('BLCA', 'Disease', (199, 203))	('tested', 'Reg', (72, 78))
435348	33311458	The CNNs achieved a higher AUC compared with a random forest using tumor purity and stage for TP53 mutation prediction (see Supplementary Fig.	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('TP53', 'Gene', '7157', (94, 98))	('mutation', 'Var', (99, 107))	('TP53', 'Gene', (94, 98))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Disease', (67, 72))	('AUC', 'MPA', (27, 30))
435349	33311458	We also observed that CNNs were able to more accurately identify tumors with TP53 mutations when the allele frequency of the mutation was higher, suggesting that prediction is easier when the tumor is more homogeneous (Supplementary Fig.	('tumor', 'Disease', (192, 197))	('tumor', 'Disease', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('tumors', 'Disease', (65, 71))	('mutations', 'Var', (82, 91))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('TP53', 'Gene', '7157', (77, 81))	('TP53', 'Gene', (77, 81))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
435353	33311458	Figure 8 shows TP53 mutational heatmaps of one LUAD slide known to be mutant and one LUAD slide known to be wild type from the sequencing data.	('mutant', 'Var', (70, 76))	('TP53', 'Gene', '7157', (15, 19))	('TP53', 'Gene', (15, 19))	('LUAD', 'Phenotype', 'HP:0030078', (47, 51))	('mutational', 'Var', (20, 30))	('LUAD', 'Phenotype', 'HP:0030078', (85, 89))
435357	33311458	Analogously, the BRCA-trained TP53 mutation status model predicts patterns similar to the LUAD-trained model.	('BRCA', 'Gene', (17, 21))	('TP53', 'Gene', (30, 34))	('predicts', 'Reg', (57, 65))	('LUAD', 'Phenotype', 'HP:0030078', (90, 94))	('patterns', 'MPA', (66, 74))	('mutation', 'Var', (35, 43))	('BRCA', 'Gene', '672', (17, 21))	('TP53', 'Gene', '7157', (30, 34))
435376	33311458	Using this framework, we were able to train extremely accurate slide-based tumor/normal classifiers in nearly all cancer types, and we also were able to classify subtypes and TP53 mutation status with significant though less extreme accuracy.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('TP53', 'Gene', (175, 179))	('mutation status', 'Var', (180, 195))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('TP53', 'Gene', '7157', (175, 179))	('tumor', 'Disease', (75, 80))	('cancer', 'Disease', (114, 120))
435392	33311458	For example, for the TP53 mutation studies we had enough data to identify significant cross-correlations and spatial structures within images, but such analysis will be more challenging for rarer drivers.	('TP53', 'Gene', (21, 25))	('TP53', 'Gene', '7157', (21, 25))	('mutation', 'Var', (26, 34))
435393	33311458	While we have observed that transfer-learning networks excel at tumor/normal classification, they have lower accuracy for cancer subtype and TP53 mutation status predictions.	('tumor', 'Disease', (64, 69))	('cancer', 'Disease', (122, 128))	('TP53', 'Gene', '7157', (141, 145))	('mutation status', 'Var', (146, 161))	('TP53', 'Gene', (141, 145))	('lower', 'NegReg', (103, 108))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
435394	33311458	reported that TP53 mutation status is associated with the pixel intensity distribution in the cytoplasm and specific texture features within tumor nuclei, and it is possible that such textures are not in ImageNet while tumor/normal classification may be more related to cell shape and size, which are simpler variables more likely to have analogs within ImageNet.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('TP53', 'Gene', '7157', (14, 18))	('TP53', 'Gene', (14, 18))	('mutation', 'Var', (19, 27))	('associated', 'Reg', (38, 48))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumor', 'Disease', (219, 224))	('tumor', 'Disease', (141, 146))	('pixel intensity distribution', 'MPA', (58, 86))	('tumor', 'Disease', 'MESH:D009369', (219, 224))
435427	33311458	Impactful TP53 mutations were determined using masked somatic mutations maf files called by MuTect2.	('TP53', 'Gene', (10, 14))	('mutations', 'Var', (15, 24))	('TP53', 'Gene', '7157', (10, 14))
435429	33311458	Table 1 shows the number of wild-type and mutated slides in each cancer type.	('cancer', 'Disease', (65, 71))	('mutated', 'Var', (42, 49))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))
435430	33311458	We utilized the Inception v3 architecture to predict TP53-associated mutations in BRCA, LUAD, and STAD sets.	('mutations', 'Var', (69, 78))	('BRCA', 'Gene', (82, 86))	('TP53', 'Gene', '7157', (53, 57))	('LUAD', 'Phenotype', 'HP:0030078', (88, 92))	('BRCA', 'Gene', '672', (82, 86))	('TP53', 'Gene', (53, 57))
435434	33311458	To predict mutations in the TP53 gene, we trained two-way classifiers, assigning 70% of the images in each tissue to training and the remaining 30% to the test set.	('mutations', 'Var', (11, 20))	('TP53', 'Gene', (28, 32))	('TP53', 'Gene', '7157', (28, 32))
435466	31500519	We showed that microRNA-299-3p expression was significantly reduced in oral squamous cell carcinoma cell lines.	('oral squamous cell carcinoma', 'Disease', (71, 99))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (76, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('expression', 'Species', '29278', (31, 41))	('microRNA-299-3p', 'Var', (15, 30))	('reduced', 'NegReg', (60, 67))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (71, 99))
435467	31500519	Next, overexpression of microRNA-299-3p was found to inhibit oral squamous cell carcinoma cell proliferation and migration but promote apoptosis.	('apoptosis', 'CPA', (135, 144))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('inhibit', 'NegReg', (53, 60))	('microRNA-299-3p', 'Var', (24, 39))	('promote', 'PosReg', (127, 134))	('oral squamous cell carcinoma', 'Disease', (61, 89))	('expression', 'Species', '29278', (10, 20))	('overexpression', 'PosReg', (6, 20))	('migration', 'CPA', (113, 122))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (61, 89))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (66, 89))
435474	31500519	MicroRNA-299-3p was documented to have dual roles in regulating human cancer proliferation, migration, and invasion.	('human', 'Species', '9606', (64, 69))	('MicroRNA-299-3p', 'Var', (0, 15))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('migration', 'CPA', (92, 101))	('invasion', 'CPA', (107, 115))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))
435475	31500519	MicroRNA-299-3p was reported as oncogenic miRNA in ovarian cancer and acute promyelocytic leukemia.	('acute promyelocytic leukemia', 'Phenotype', 'HP:0004836', (70, 98))	('MicroRNA-299-3p', 'Var', (0, 15))	('acute promyelocytic leukemia', 'Disease', 'MESH:D015473', (70, 98))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('ovarian cancer', 'Phenotype', 'HP:0100615', (51, 65))	('miR', 'Gene', '220972', (42, 45))	('ovarian cancer', 'Disease', 'MESH:D010051', (51, 65))	('miR', 'Gene', (42, 45))	('leukemia', 'Phenotype', 'HP:0001909', (90, 98))	('acute promyelocytic leukemia', 'Disease', (70, 98))	('ovarian cancer', 'Disease', (51, 65))
435476	31500519	MicroRNA-299-3p expression was significantly upregulated in ovarian cancer and its overexpression promotes cell proliferation, migration, invasion, and at the same time inhibits apoptosis through targeting OCT4.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('ovarian cancer', 'Phenotype', 'HP:0100615', (60, 74))	('MicroRNA-299-3p expression', 'Var', (0, 26))	('ovarian cancer', 'Disease', 'MESH:D010051', (60, 74))	('expression', 'Species', '29278', (87, 97))	('cell proliferation', 'CPA', (107, 125))	('upregulated', 'PosReg', (45, 56))	('apoptosis', 'CPA', (178, 187))	('ovarian cancer', 'Disease', (60, 74))	('overexpression promotes', 'PosReg', (83, 106))	('expression', 'Species', '29278', (16, 26))	('inhibits', 'NegReg', (169, 177))	('OCT4', 'Protein', (206, 210))	('invasion', 'CPA', (138, 146))	('migration', 'CPA', (127, 136))
435505	31500519	The wild type (wt) or mutate type (mt) of FOXP4 3'-UTR was built based on pmiRGLO vector (Promega, Madison, Wisconsin) and named as wt-FOXP4 or mt-FOXP4.	('miR', 'Gene', '220972', (75, 78))	('FOXP4', 'Gene', (147, 152))	('miR', 'Gene', (75, 78))	('FOXP4', 'Gene', (42, 47))	('mutate', 'Var', (22, 28))	('FOXP4', 'Gene', '116113', (135, 140))	('FOXP4', 'Gene', (135, 140))	('FOXP4', 'Gene', '116113', (147, 152))	('FOXP4', 'Gene', '116113', (42, 47))
435516	31500519	When synthetic miRNAs were transfected into OSCC cell lines, it was found miR-299-3p mimic transfection significantly increased the expression levels of miR-299-3p (Figure 3A).	('miR', 'Gene', (74, 77))	('transfection', 'Var', (91, 103))	('miR', 'Gene', '220972', (153, 156))	('miR', 'Gene', (153, 156))	('miR', 'Gene', '220972', (74, 77))	('miR-299', 'Gene', '407023', (153, 160))	('expression levels', 'MPA', (132, 149))	('miR-299', 'Gene', (74, 81))	('increased', 'PosReg', (118, 127))	('miR', 'Gene', '220972', (15, 18))	('expression', 'Species', '29278', (132, 142))	('miR-299', 'Gene', '407023', (74, 81))	('miR-299', 'Gene', (153, 160))	('miR', 'Gene', (15, 18))
435528	31500519	The overexpression of miR-1297 or silencing of PTEN inhibited OSCC cell growth, indicating miR-1297 may drive OSCC progression through targeting PTEN.	('miR', 'Gene', (91, 94))	('miR', 'Gene', '220972', (22, 25))	('PTEN', 'Gene', (145, 149))	('expression', 'Species', '29278', (8, 18))	('OSCC cell growth', 'CPA', (62, 78))	('PTEN', 'Gene', (47, 51))	('inhibited', 'NegReg', (52, 61))	('overexpression', 'PosReg', (4, 18))	('drive', 'PosReg', (104, 109))	('silencing', 'Var', (34, 43))	('miR', 'Gene', (22, 25))	('OSCC', 'Disease', (110, 114))	('miR', 'Gene', '220972', (91, 94))
435546	31500519	Upregulation of FOXP4 has been identified in non-small cell lung cancer, and knockdown of FOXP4 by specific short hairpin RNA (shRNA) significantly decreased cancer cell growth, invasion, and at the same time arrested cell cycle.	('non-small cell lung cancer', 'Disease', (45, 71))	('lung cancer', 'Phenotype', 'HP:0100526', (60, 71))	('arrested', 'NegReg', (209, 217))	('knockdown', 'Var', (77, 86))	('invasion', 'CPA', (178, 186))	('cancer', 'Disease', (65, 71))	('FOXP4', 'Gene', '116113', (90, 95))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (45, 71))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('cancer', 'Disease', (158, 164))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (49, 71))	('FOXP4', 'Gene', (90, 95))	('decreased', 'NegReg', (148, 157))	('FOXP4', 'Gene', '116113', (16, 21))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (45, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('Upregulation', 'PosReg', (0, 12))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('FOXP4', 'Gene', (16, 21))	('cell cycle', 'CPA', (218, 228))
435554	26224133	FGFR germline mutations (activating) can cause skeletal disorders, primarily dwarfism (generally mutations in FGFR3), and craniofacial malformation syndromes (usually mutations in FGFR1 and FGFR2); intriguingly, some of these activating FGFR mutations are also seen in human cancers.	('mutations', 'Var', (97, 106))	('dwarfism', 'Phenotype', 'HP:0003510', (77, 85))	('FGFR', 'Gene', (0, 4))	('craniofacial malformation syndromes', 'Disease', 'MESH:D019465', (122, 157))	('mutations', 'Var', (167, 176))	('cause', 'Reg', (41, 46))	('skeletal disorders', 'Phenotype', 'HP:0000924', (47, 65))	('cancers', 'Disease', 'MESH:D009369', (275, 282))	('FGFR3', 'Gene', (110, 115))	('FGFR1', 'Gene', (180, 185))	('skeletal disorders', 'Disease', 'MESH:C538496', (47, 65))	('craniofacial malformation', 'Phenotype', 'HP:0004484', (122, 147))	('FGFR2', 'Gene', (190, 195))	('dwarfism', 'Disease', (77, 85))	('human', 'Species', '9606', (269, 274))	('cancers', 'Phenotype', 'HP:0002664', (275, 282))	('craniofacial malformation syndromes', 'Disease', (122, 157))	('cancers', 'Disease', (275, 282))	('skeletal disorders', 'Disease', (47, 65))	('cancer', 'Phenotype', 'HP:0002664', (275, 281))
435555	26224133	FGF/FGFR aberrations reported in cancers are mainly thought to be gain-of-function changes, and several cancers have high frequencies of FGFR alterations, including breast, bladder, or squamous cell carcinomas (lung and head and neck).	('bladder', 'Disease', (173, 180))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (185, 208))	('squamous cell carcinomas', 'Disease', (185, 209))	('FGF', 'Gene', (0, 3))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('cancers', 'Phenotype', 'HP:0002664', (104, 111))	('carcinoma', 'Phenotype', 'HP:0030731', (199, 208))	('FGF', 'Gene', '42356', (4, 7))	('cancers', 'Disease', (104, 111))	('carcinomas', 'Phenotype', 'HP:0030731', (199, 209))	('breast', 'Disease', (165, 171))	('cancers', 'Phenotype', 'HP:0002664', (33, 40))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('cancers', 'Disease', (33, 40))	('FGF', 'Gene', '42356', (137, 140))	('FGF', 'Gene', (4, 7))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (185, 209))	('FGF', 'Gene', '42356', (0, 3))	('cancers', 'Disease', 'MESH:D009369', (104, 111))	('alterations', 'Var', (142, 153))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (185, 209))	('FGF', 'Gene', (137, 140))	('cancers', 'Disease', 'MESH:D009369', (33, 40))
435556	26224133	FGF ligand aberrations (predominantly gene amplifications) are also frequently seen in cancers, in contrast to hereditary syndromes.	('cancers', 'Disease', (87, 94))	('seen', 'Reg', (79, 83))	('aberrations', 'Var', (11, 22))	('hereditary syndromes', 'Disease', 'MESH:D009386', (111, 131))	('hereditary syndromes', 'Disease', (111, 131))	('cancers', 'Phenotype', 'HP:0002664', (87, 94))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('FGF', 'Gene', (0, 3))	('gene amplifications', 'Var', (38, 57))	('FGF', 'Gene', '42356', (0, 3))	('cancers', 'Disease', 'MESH:D009369', (87, 94))
435560	26224133	The development of potent inhibitors targeting FGF/FGFR may provide new tools against disorders caused by FGF/FGFR alterations.	('FGF', 'Gene', '42356', (51, 54))	('FGF', 'Gene', '42356', (110, 113))	('FGF', 'Gene', (47, 50))	('alterations', 'Var', (115, 126))	('FGF', 'Gene', (106, 109))	('FGF', 'Gene', (51, 54))	('FGF', 'Gene', '42356', (47, 50))	('FGF', 'Gene', '42356', (106, 109))	('FGF', 'Gene', (110, 113))
435561	26224133	One of the most important advances in tumor biology is the recognition that cancer is frequently driven by inherited or acquired alterations in specific gene(s) or their products.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('driven', 'Reg', (97, 103))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('alterations', 'Var', (129, 140))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))
435563	26224133	A literature review suggests that over 1 % of human genes can be implicated as cancer drivers when they are mutated, with protein kinases comprising the largest subgroup of genes altered.	('mutated', 'Var', (108, 115))	('human genes', 'Gene', (46, 57))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('human', 'Species', '9606', (46, 51))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))
435564	26224133	Among human signaling pathways, fibroblast growth factor (FGF)/fibroblast growth factor receptor (FGFR) is one of the pathways most enriched in non-synonymous mutations, including several candidate driver mutations.	('human', 'Species', '9606', (6, 11))	('non-synonymous mutations', 'Var', (144, 168))	('mutations', 'Var', (159, 168))	('FGF', 'Gene', (98, 101))	('FGF', 'Gene', (58, 61))	('FGF', 'Gene', '42356', (98, 101))	('FGF', 'Gene', '42356', (58, 61))	('fibroblast growth factor receptor', 'Gene', (63, 96))	('fibroblast growth factor receptor', 'Gene', '2260', (63, 96))
435565	26224133	A computational method designed to identify driver mutations within protein kinase datasets successfully identified multiple aberrations in the FGF/FGFR machinery.	('mutations', 'Var', (51, 60))	('FGF', 'Gene', '42356', (148, 151))	('FGF', 'Gene', (144, 147))	('FGF', 'Gene', '42356', (144, 147))	('FGF', 'Gene', (148, 151))
435567	26224133	Indeed, FGFR aberrations have been identified in both hereditary and neoplastic human diseases.	('hereditary', 'Disease', (54, 64))	('identified', 'Reg', (35, 45))	('neoplastic human diseases', 'Disease', 'MESH:D001943', (69, 94))	('aberrations', 'Var', (13, 24))	('FGFR', 'Gene', (8, 12))	('neoplastic human diseases', 'Disease', (69, 94))
435568	26224133	Most of the reported FGFR mutations that cause heritable human diseases are activating mutations which increase receptor signaling.	('increase', 'PosReg', (103, 111))	('FGFR', 'Gene', (21, 25))	('mutations', 'Var', (26, 35))	('receptor signaling', 'MPA', (112, 130))	('human', 'Species', '9606', (57, 62))
435570	26224133	The only reported inherited condition caused by loss of FGFR function is an autosomal dominant form of hereditary hypogonatotrophic hypogonadism 2 with or without anosmia, which is caused by loss of function of FGFR1 or a missense mutation in FGF8.	('FGFR function', 'Gene', (56, 69))	('loss', 'NegReg', (48, 52))	('missense mutation', 'Var', (222, 239))	('anosmia', 'Disease', (163, 170))	('anosmia', 'Phenotype', 'HP:0000458', (163, 170))	('FGFR1', 'Gene', (211, 216))	('hypogonatotrophic hypogonadism', 'Phenotype', 'HP:0000044', (114, 144))	('hereditary hypogonatotrophic hypogonadism', 'Disease', 'MESH:D007006', (103, 144))	('anosmia', 'Disease', 'MESH:D000857', (163, 170))	('loss of function', 'NegReg', (191, 207))	('hereditary hypogonatotrophic hypogonadism', 'Disease', (103, 144))	('FGF8', 'Gene', (243, 247))	('hypogonadism', 'Phenotype', 'HP:0000135', (132, 144))
435571	26224133	Intriguingly, some of the same activating FGFR mutations seen in inherited syndromes are also seen in human cancers.	('cancers', 'Phenotype', 'HP:0002664', (108, 115))	('mutations', 'Var', (47, 56))	('FGFR', 'Gene', (42, 46))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('activating', 'PosReg', (31, 41))	('cancers', 'Disease', 'MESH:D009369', (108, 115))	('cancers', 'Disease', (108, 115))	('human', 'Species', '9606', (102, 107))
435572	26224133	Furthermore, FGF/FGFR aberrations reported in cancers are overwhelmingly thought to be gain-of-function changes, including gene amplifications and gene rearrangements.	('cancers', 'Disease', 'MESH:D009369', (46, 53))	('cancers', 'Phenotype', 'HP:0002664', (46, 53))	('FGF', 'Gene', (13, 16))	('cancers', 'Disease', (46, 53))	('FGF', 'Gene', (17, 20))	('aberrations', 'Var', (22, 33))	('gain-of-function', 'PosReg', (87, 103))	('FGF', 'Gene', '42356', (13, 16))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('FGF', 'Gene', '42356', (17, 20))
435573	26224133	The goal of identification and characterization of driver mutations in cancer is, ultimately, to create successful anti-cancer therapies with which to prosecute these tumors; several such therapies already exist, demonstrating proof of principle.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('mutations', 'Var', (58, 67))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('tumors', 'Disease', 'MESH:D009369', (167, 173))	('cancer', 'Disease', (71, 77))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('tumors', 'Disease', (167, 173))	('tumors', 'Phenotype', 'HP:0002664', (167, 173))
435574	26224133	Furthermore, for some gene targets, drugs may impact the course of cancer as well as non-malignant conditions that are driven by abnormalities in the cognate signal.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('impact', 'Reg', (46, 52))	('drugs', 'Var', (36, 41))	('cancer', 'Disease', (67, 73))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('course', 'Disease', (57, 63))
435575	26224133	JAK2 aberrations, for instance, are found in myelofibrosis, and JAK2 inhibitors such as ruxolitinib provide significant benefit in such patients.	('benefit', 'PosReg', (120, 127))	('myelofibrosis', 'Disease', 'MESH:D055728', (45, 58))	('JAK2', 'Gene', '3717', (0, 4))	('JAK2', 'Gene', (64, 68))	('found', 'Reg', (36, 41))	('myelofibrosis', 'Phenotype', 'HP:0011974', (45, 58))	('JAK2', 'Gene', '3717', (64, 68))	('patients', 'Species', '9606', (136, 144))	('JAK2', 'Gene', (0, 4))	('aberrations', 'Var', (5, 16))	('myelofibrosis', 'Disease', (45, 58))	('ruxolitinib', 'Chemical', 'MESH:C540383', (88, 99))
435578	26224133	Herein, we discuss the landscape of diseases that are driven by aberrant FGF/FGFR machinery.	('FGF', 'Gene', (77, 80))	('FGF', 'Gene', '42356', (73, 76))	('FGF', 'Gene', '42356', (77, 80))	('FGF', 'Gene', (73, 76))	('aberrant', 'Var', (64, 72))
435600	26224133	Mice heterozygous for FGFR knockout mutations develop normally, so haplo-insufficiency is not likely to be a factor.	('FGFR', 'Gene', (22, 26))	('mutations', 'Var', (36, 45))	('insufficiency', 'Disease', 'MESH:D000309', (73, 86))	('develop', 'CPA', (46, 53))	('Mice', 'Species', '10090', (0, 4))	('insufficiency', 'Disease', (73, 86))
435601	26224133	However, mice homozygous for FGFR1 or FGFR2 null mutations die in utero, and FGFR3-null mice develop normally other than overgrowth of cancellous bones and deafness.	('mutations', 'Var', (49, 58))	('deafness', 'Disease', 'MESH:D003638', (156, 164))	('overgrowth', 'Phenotype', 'HP:0001548', (121, 131))	('deafness', 'Phenotype', 'HP:0000365', (156, 164))	('deafness', 'Disease', (156, 164))	('mice', 'Species', '10090', (9, 13))	('mice', 'Species', '10090', (88, 92))	('FGFR1', 'Gene', (29, 34))	('FGFR2', 'Gene', (38, 43))
435616	26224133	FGFRL1-null mice die in infancy with diaphragmatic defects and renal agenesis, and there are case reports of FGFRL1 mutations in human disease: craniosynostosis and ovarian cancer.	('craniosynostosis and ovarian cancer', 'Disease', 'MESH:D010051', (144, 179))	('mice', 'Species', '10090', (12, 16))	('ovarian cancer', 'Phenotype', 'HP:0100615', (165, 179))	('mutations', 'Var', (116, 125))	('diaphragmatic', 'Disease', (37, 50))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('human', 'Species', '9606', (129, 134))	('renal agenesis', 'Disease', 'MESH:D007674', (63, 77))	('FGFRL1', 'Gene', (109, 115))	('craniosynostosis', 'Phenotype', 'HP:0001363', (144, 160))	('diaphragmatic defects', 'Phenotype', 'HP:0000775', (37, 58))	('renal agenesis', 'Phenotype', 'HP:0000104', (63, 77))	('renal agenesis', 'Disease', (63, 77))
435617	26224133	These include craniosynostosis syndromes and achondroplasia, mainly due to gain-of-function mutations, as well as loss-of-function anomalies associated with congenital hypogonadotropic hypogonadism (Table 1).	('craniosynostosis syndromes and achondroplasia', 'Disease', 'MESH:D000130', (14, 59))	('anomalies', 'Disease', (131, 140))	('gain-of-function', 'PosReg', (75, 91))	('congenital hypogonadotropic hypogonadism', 'Disease', 'MESH:D007006', (157, 197))	('mutations', 'Var', (92, 101))	('congenital hypogonadotropic hypogonadism', 'Disease', (157, 197))	('hypogonadotropic hypogonadism', 'Phenotype', 'HP:0000044', (168, 197))	('hypogonadism', 'Phenotype', 'HP:0000135', (185, 197))	('anomalies', 'Disease', 'MESH:D000014', (131, 140))	('craniosynostosis', 'Phenotype', 'HP:0001363', (14, 30))
435621	26224133	Somatic or acquired mutations in FGFR3 have been observed in benign skin conditions like seborrheic keratosis and epidermal nevi.	('seborrheic keratosis', 'Phenotype', 'HP:0031287', (89, 109))	('nevi', 'Phenotype', 'HP:0003764', (124, 128))	('seborrheic keratosis', 'Disease', 'MESH:D017492', (89, 109))	('epidermal nevi', 'Disease', (114, 128))	('epidermal nevi', 'Phenotype', 'HP:0010816', (114, 128))	('observed', 'Reg', (49, 57))	('mutations', 'Var', (20, 29))	('FGFR3', 'Gene', (33, 38))	('seborrheic keratosis', 'Disease', (89, 109))
435623	26224133	Aberrations in FGFR and its ligands are common in malignancy (Tables 2, 3, and 4 and Figs.	('common', 'Reg', (40, 46))	('malignancy', 'Disease', 'MESH:D009369', (50, 60))	('Aberrations', 'Var', (0, 11))	('malignancy', 'Disease', (50, 60))	('FGFR', 'Gene', (15, 19))
435629	26224133	More commonly, however, mutations in FGFR3 characterize bladder carcinoma.	('FGFR3', 'Gene', (37, 42))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (56, 73))	('characterize', 'Reg', (43, 55))	('bladder carcinoma', 'Disease', 'MESH:D001749', (56, 73))	('bladder carcinoma', 'Disease', (56, 73))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))	('mutations', 'Var', (24, 33))
435631	26224133	In muscle-invasive disease, FGFR3 mutations are found in 20 % of tumors, but overexpression of FGFR3 is observed in about half of cases.	('tumors', 'Disease', (65, 71))	('FGFR3', 'Gene', (28, 33))	('muscle-invasive disease', 'Disease', 'MESH:D009135', (3, 26))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('found', 'Reg', (48, 53))	('muscle-invasive disease', 'Disease', (3, 26))	('mutations', 'Var', (34, 43))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
435632	26224133	Loss-of-function alterations are relatively uncommon in cancer (a pattern that is also seen in hereditary disorders).	('Loss-of-function', 'NegReg', (0, 16))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('hereditary disorders', 'Disease', 'MESH:D030342', (95, 115))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('alterations', 'Var', (17, 28))	('hereditary disorders', 'Disease', (95, 115))	('cancer', 'Disease', (56, 62))
435634	26224133	FGFR1 amplification is prevalent in both squamous cell carcinoma of the lung and of the head and neck, suggesting a possible common underlying mechanism of carcinogenesis in these smoking-related carcinomas.	('carcinogenesis', 'Disease', 'MESH:D063646', (156, 170))	('carcinomas', 'Phenotype', 'HP:0030731', (196, 206))	('carcinomas', 'Disease', (196, 206))	('carcinomas', 'Disease', 'MESH:D002277', (196, 206))	('carcinogenesis', 'Disease', (156, 170))	('squamous cell carcinoma of the lung', 'Disease', 'MESH:D002294', (41, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (55, 64))	('FGFR1', 'Gene', (0, 5))	('prevalent', 'Reg', (23, 32))	('amplification', 'Var', (6, 19))	('squamous cell carcinoma of the lung', 'Disease', (41, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (196, 205))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (41, 64))
435635	26224133	Perhaps more importantly, development of FGFR1 inhibitors represents a viable targeted therapy for use in squamous cell lung cancers.	('cancers', 'Phenotype', 'HP:0002664', (125, 132))	('inhibitors', 'Var', (47, 57))	('lung cancer', 'Phenotype', 'HP:0100526', (120, 131))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('lung cancers', 'Phenotype', 'HP:0100526', (120, 132))	('squamous cell lung cancers', 'Disease', 'MESH:D002294', (106, 132))	('squamous cell lung cancers', 'Disease', (106, 132))	('FGFR1', 'Gene', (41, 46))
435636	26224133	FGF abnormalities are for the most part amplifications (Fig.	('FGF', 'Gene', '42356', (0, 3))	('FGF', 'Gene', (0, 3))	('abnormalities', 'Var', (4, 17))
435644	26224133	The efficacy results demonstrated a 54 % major cytogenetic response (MCyR) rate in patients with CP-CML, and seventy percent of patients with CP-CML with the T315I mutation in BCR-ABL achieved MCyR.	('CP-CML', 'Disease', 'MESH:D015464', (142, 148))	('major cytogenetic response', 'MPA', (41, 67))	('T315I', 'Var', (158, 163))	('CP-CML', 'Disease', 'MESH:D015464', (97, 103))	('T315I', 'Mutation', 'rs121913459', (158, 163))	('BCR-ABL', 'Gene', '25', (176, 183))	('CML', 'Phenotype', 'HP:0005506', (100, 103))	('CML', 'Phenotype', 'HP:0005506', (145, 148))	('patients', 'Species', '9606', (83, 91))	('patients', 'Species', '9606', (128, 136))	('CP-CML', 'Disease', (97, 103))	('CP-CML', 'Disease', (142, 148))	('BCR-ABL', 'Gene', (176, 183))
435659	26224133	A recent study demonstrated that Debio 1347 (a selective orally available FGFR1-3 inhibitor) displayed preferential anti-tumor activity against cells with FGFR genetic alterations in a panel of 327 cancer cell lines and xenograft models.	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('cancer', 'Disease', (198, 204))	('genetic alterations', 'Var', (160, 179))	('tumor', 'Disease', (121, 126))	('FGFR', 'Gene', (155, 159))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('Debio 1347', 'Chemical', 'MESH:C000602562', (33, 43))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
435660	26224133	Debio 1347 is currently under investigation for the treatment of patients harboring FGFR genetic alterations.	('Debio 1347', 'Chemical', 'MESH:C000602562', (0, 10))	('FGFR', 'Gene', (84, 88))	('patients', 'Species', '9606', (65, 73))	('genetic alterations', 'Var', (89, 108))
435661	26224133	As an example, FP-1039 is a soluble fusion protein, consisting of the extracellular domains of human FGFR1 linked to the Fc region of the human immunoglobulin G1; it is designed to bind multiple FGF ligands (TRAP molecule).	('FGF', 'Gene', (101, 104))	('human', 'Species', '9606', (95, 100))	('FGF', 'Gene', '42356', (101, 104))	('FP-1039', 'Var', (15, 22))	('human', 'Species', '9606', (138, 143))	('FGF', 'Gene', (195, 198))	('bind', 'Interaction', (181, 185))	('FGF', 'Gene', '42356', (195, 198))
435664	26224133	reported that resistance mutations at the "gatekeeper" residue may arise (FGFR1 V561M mutation confers a 38-fold increase in autophosphorylation and significant resistance to lucitanib), leading to tumor progression and explaining the non-durable responses.	('gatekeeper', 'Species', '111938', (43, 53))	('leading to', 'Reg', (187, 197))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('lucitanib', 'Chemical', 'MESH:C000595232', (175, 184))	('V561M', 'Mutation', 'p.V561M', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('autophosphorylation', 'MPA', (125, 144))	('increase', 'PosReg', (113, 121))	('tumor', 'Disease', (198, 203))	('FGFR1', 'Gene', (74, 79))	('V561M', 'Var', (80, 85))
435665	26224133	For instance, it has also been shown that the heterozygous gatekeeper mutation FGFR3 V555M appeared as a mechanism of acquired resistance to selective FGFR inhibitors.	('acquired resistance', 'MPA', (118, 137))	('FGFR3', 'Gene', (79, 84))	('V555M', 'Mutation', 'rs199544087', (85, 90))	('V555M', 'Var', (85, 90))	('gatekeeper', 'Species', '111938', (59, 69))
435666	26224133	Several other activating mutations were identified in FGFR2-expressing cells treated with high concentrations of dovitinib, and the multi-kinase inhibitor ponatinib inhibitory activity was affected by the V565I gatekeeper mutation.	('FGFR2-expressing', 'Gene', (54, 70))	('inhibitory activity', 'MPA', (165, 184))	('V565I', 'Var', (205, 210))	('gatekeeper', 'Species', '111938', (211, 221))	('dovitinib', 'Chemical', 'MESH:C500007', (113, 122))	('affected', 'Reg', (189, 197))	('multi-kinase inhibitor', 'MPA', (132, 154))	('V565I', 'Mutation', 'rs1057519797', (205, 210))	('ponatinib', 'Chemical', 'MESH:C545373', (155, 164))
435667	26224133	In addition, a previously undescribed FGFR3 variant was identified as a key contributor to resistance in the MGH156-1A cell line derived from a patient with acquired resistance to EGFR TKIs, and follow-up studies clearly indicated that FGFR inhibitors re-sensitized these cells to EGFR inhibitors.	('variant', 'Var', (44, 51))	('EGFR', 'Gene', '1956', (180, 184))	('FGFR3', 'Gene', (38, 43))	('EGFR', 'Gene', (180, 184))	('patient', 'Species', '9606', (144, 151))	('contributor', 'Reg', (76, 87))	('EGFR', 'Gene', '1956', (281, 285))	('EGFR', 'Gene', (281, 285))
435670	26224133	Furthermore, signaling crosstalk between KIT and FGFR3 activated the MAPK pathway to promote resistance to imatinib.	('imatinib', 'Chemical', 'MESH:D000068877', (107, 115))	('MAPK pathway', 'Pathway', (69, 81))	('resistance to imatinib', 'MPA', (93, 115))	('promote', 'PosReg', (85, 92))	('signaling crosstalk', 'Var', (13, 32))	('FGFR3', 'Gene', (49, 54))	('KIT', 'Gene', (41, 44))	('activated', 'PosReg', (55, 64))
435671	26224133	FGFR amplification and overexpression have also been related to poor prognosis and endocrine resistance in breast cancer.	('overexpression', 'PosReg', (23, 37))	('endocrine resistance', 'CPA', (83, 103))	('FGFR', 'Gene', (0, 4))	('amplification', 'Var', (5, 18))	('breast cancer', 'Disease', 'MESH:D001943', (107, 120))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('breast cancer', 'Disease', (107, 120))	('breast cancer', 'Phenotype', 'HP:0003002', (107, 120))	('poor prognosis', 'CPA', (64, 78))
435677	26224133	FGFR germline mutations (activating) can cause skeletal disorders, primarily dwarfism (generally mutations in FGFR3) and craniofacial malformation syndromes (usually mutations in FGFR1 and FGFR2).	('mutations', 'Var', (97, 106))	('skeletal disorders', 'Disease', 'MESH:C538496', (47, 65))	('dwarfism', 'Phenotype', 'HP:0003510', (77, 85))	('skeletal disorders', 'Disease', (47, 65))	('craniofacial malformation syndromes', 'Disease', (121, 156))	('mutations', 'Var', (166, 175))	('FGFR1', 'Gene', (179, 184))	('FGFR', 'Gene', (0, 4))	('dwarfism', 'Disease', (77, 85))	('cause', 'Reg', (41, 46))	('craniofacial malformation syndromes', 'Disease', 'MESH:D019465', (121, 156))	('skeletal disorders', 'Phenotype', 'HP:0000924', (47, 65))	('craniofacial malformation', 'Phenotype', 'HP:0004484', (121, 146))	('FGFR3', 'Gene', (110, 115))	('FGFR2', 'Gene', (189, 194))
435678	26224133	Loss-of-function mutations in FGF signaling are seen in congenital hypogonadotropic hypogonadism (including the Kallman syndrome variant with anosmia).	('Loss-of-function', 'NegReg', (0, 16))	('hypogonadotropic hypogonadism', 'Phenotype', 'HP:0000044', (67, 96))	('anosmia', 'Phenotype', 'HP:0000458', (142, 149))	('anosmia', 'Disease', (142, 149))	('hypogonadism', 'Phenotype', 'HP:0000135', (84, 96))	('FGF', 'Gene', (30, 33))	('anosmia', 'Disease', 'MESH:D000857', (142, 149))	('FGF', 'Gene', '42356', (30, 33))	('Kallman syndrome', 'Disease', (112, 128))	('congenital hypogonadotropic hypogonadism', 'Disease', 'MESH:D007006', (56, 96))	('congenital hypogonadotropic hypogonadism', 'Disease', (56, 96))	('mutations', 'Var', (17, 26))	('Kallman syndrome', 'Disease', 'MESH:D013577', (112, 128))
435680	26224133	The most common abnormalities in malignancies are gene amplifications of FGFR1-3 or of the FGF ligands.	('FGF', 'Gene', (91, 94))	('malignancies', 'Disease', (33, 45))	('FGF', 'Gene', '42356', (73, 76))	('gene amplifications', 'Var', (50, 69))	('common', 'Reg', (9, 15))	('malignancies', 'Disease', 'MESH:D009369', (33, 45))	('FGF', 'Gene', '42356', (91, 94))	('FGF', 'Gene', (73, 76))
435682	26224133	Point mutations are seen in all FGFRs but are less frequent in FGFs.	('seen', 'Reg', (20, 24))	('FGF', 'Gene', (32, 35))	('FGF', 'Gene', '42356', (32, 35))	('FGF', 'Gene', (63, 66))	('Point mutations', 'Var', (0, 15))	('FGF', 'Gene', '42356', (63, 66))
435683	26224133	For instance, mutations in FGFR3 are frequent in bladder carcinoma, and FGFR2 mutations in endometrial cancer, melanoma, and gastric tumors (Tables 2 and 3).	('bladder carcinoma', 'Disease', 'MESH:D001749', (49, 66))	('carcinoma', 'Phenotype', 'HP:0030731', (57, 66))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('melanoma', 'Phenotype', 'HP:0002861', (111, 119))	('melanoma', 'Disease', (111, 119))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('bladder carcinoma', 'Disease', (49, 66))	('mutations', 'Var', (78, 87))	('gastric tumors', 'Disease', 'MESH:D013274', (125, 139))	('mutations', 'Var', (14, 23))	('endometrial cancer', 'Phenotype', 'HP:0012114', (91, 109))	('gastric tumors', 'Phenotype', 'HP:0006753', (125, 139))	('FGFR2', 'Gene', (72, 77))	('FGFR3', 'Gene', (27, 32))	('endometrial cancer', 'Disease', (91, 109))	('melanoma', 'Disease', 'MESH:D008545', (111, 119))	('endometrial cancer', 'Disease', 'MESH:D016889', (91, 109))	('frequent', 'Reg', (37, 45))	('gastric tumors', 'Disease', (125, 139))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (49, 66))
435685	26224133	FGFR rearrangements are also observed in certain cancers and characterize certain myeloproliferative disorders (Table 2).	('myeloproliferative disorders', 'Disease', (82, 110))	('observed', 'Reg', (29, 37))	('FGFR', 'Gene', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('myeloproliferative disorders', 'Phenotype', 'HP:0005547', (82, 110))	('myeloproliferative disorders', 'Disease', 'MESH:D009196', (82, 110))	('cancers', 'Disease', 'MESH:D009369', (49, 56))	('cancers', 'Phenotype', 'HP:0002664', (49, 56))	('cancers', 'Disease', (49, 56))	('rearrangements', 'Var', (5, 19))
435690	26224133	injected ia mouse model of achondroplasia with a soluble form of human FGFR3 (acting as a decoy receptor and preventing FGF from binding to mutant FGFR3), and effective maturation of growth plate chondrocytes was restored in the bones of treated mice.	('FGF', 'Gene', (71, 74))	('human', 'Species', '9606', (65, 70))	('maturation', 'CPA', (169, 179))	('achondroplasia', 'Disease', (27, 41))	('FGF', 'Gene', '42356', (71, 74))	('FGF', 'Gene', (147, 150))	('FGF', 'Gene', (120, 123))	('mouse', 'Species', '10090', (12, 17))	('mice', 'Species', '10090', (246, 250))	('FGF', 'Gene', '42356', (147, 150))	('FGF', 'Gene', '42356', (120, 123))	('binding', 'Interaction', (129, 136))	('mutant', 'Var', (140, 146))	('achondroplasia', 'Disease', 'MESH:D000130', (27, 41))
435691	26224133	Of interest in this regard, individuals afflicted with the inherited disorders associated with FGFR aberrations, such as dwarfism, do not have an increased incidence of cancer, despite having mutations that are often identical to those somatic FGFR aberrations that characterize certain tumors.	('aberrations', 'Var', (100, 111))	('dwarfism', 'Disease', (121, 129))	('cancer', 'Disease', (169, 175))	('inherited disorders', 'Disease', 'MESH:D030342', (59, 78))	('FGFR', 'Gene', (95, 99))	('dwarfism', 'Phenotype', 'HP:0003510', (121, 129))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('tumors', 'Disease', 'MESH:D009369', (287, 293))	('tumors', 'Phenotype', 'HP:0002664', (287, 293))	('tumor', 'Phenotype', 'HP:0002664', (287, 292))	('inherited disorders', 'Disease', (59, 78))	('tumors', 'Disease', (287, 293))	('cancer', 'Disease', 'MESH:D009369', (169, 175))
435693	26224133	Whether or not treating them at an early age with FGFR inhibitors would increase the later risk of cancer if the inhibitors were withdrawn would need to be considered.	('increase', 'PosReg', (72, 80))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('cancer', 'Disease', (99, 105))	('inhibitors', 'Var', (55, 65))	('FGFR', 'Gene', (50, 54))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
435694	26224133	In summary, perturbations in the FGF/FGFR machinery appear to underlie a variety of inherited syndromes, as well as benign and malignant disorders.	('underlie', 'Reg', (62, 70))	('FGF', 'Gene', (37, 40))	('perturbations', 'Var', (12, 25))	('FGF', 'Gene', (33, 36))	('FGF', 'Gene', '42356', (37, 40))	('malignant disorders', 'Disease', (127, 146))	('FGF', 'Gene', '42356', (33, 36))	('inherited syndromes', 'Disease', (84, 103))	('malignant disorders', 'Disease', 'MESH:D009369', (127, 146))
435695	26224133	The advent of potent FGFR inhibitors provides important new agents in the armamentarium against diseases caused by FGF/FGFR abnormalities.	('FGF', 'Gene', (115, 118))	('abnormalities', 'Var', (124, 137))	('FGF', 'Gene', '42356', (115, 118))	('FGF', 'Gene', (119, 122))	('FGF', 'Gene', (21, 24))	('FGF', 'Gene', '42356', (119, 122))	('FGF', 'Gene', '42356', (21, 24))
435700	33842305	In addition, the expression levels of AKT pS473, PCK1 pS90, INSIG1 pS207/INSIG2 pS151, and nuclear SREBP1 are higher in 451 analyzed human NSCLC specimens than in their adjacent normal tissues and positively correlated with each other in the tumor specimens.	('NSCLC', 'Phenotype', 'HP:0030358', (139, 144))	('expression levels', 'MPA', (17, 34))	('AKT', 'Gene', (38, 41))	('tumor', 'Disease', 'MESH:D009369', (242, 247))	('INSIG2', 'Gene', '51141', (73, 79))	('tumor', 'Phenotype', 'HP:0002664', (242, 247))	('NSCLC', 'Disease', (139, 144))	('pS473', 'Var', (42, 47))	('INSIG1', 'Gene', (60, 66))	('INSIG1', 'Gene', '3638', (60, 66))	('NSCLC', 'Disease', 'MESH:D002289', (139, 144))	('tumor', 'Disease', (242, 247))	('higher', 'PosReg', (110, 116))	('human', 'Species', '9606', (133, 138))	('PCK1', 'Gene', (49, 53))	('INSIG2', 'Gene', (73, 79))
435702	33842305	Importantly, levels of PCK1 pS90 or INSIG1 pS207/INSIG2 pS151 are positively correlated with poor prognosis in NSCLC patients, and the combined expression value of the PCK1 and INSIG1/2 phosphorylation has a better prognostic value than that of each individual protein phosphorylation value and is an independent prognostic marker for NSCLC.	('PCK1 pS90', 'Var', (23, 32))	('INSIG1', 'Gene', (177, 183))	('NSCLC', 'Disease', 'MESH:D002289', (335, 340))	('NSCLC', 'Disease', (111, 116))	('INSIG2', 'Gene', '51141', (49, 55))	('INSIG1', 'Gene', '3638', (177, 183))	('INSIG1', 'Gene', (36, 42))	('INSIG1', 'Gene', '3638', (36, 42))	('NSCLC', 'Disease', 'MESH:D002289', (111, 116))	('NSCLC', 'Phenotype', 'HP:0030358', (335, 340))	('NSCLC', 'Phenotype', 'HP:0030358', (111, 116))	('patients', 'Species', '9606', (117, 125))	('INSIG2', 'Gene', (49, 55))	('NSCLC', 'Disease', (335, 340))
435711	33842305	Our recent studies demonstrated that AKT activation in response to activation of growth factor receptors, including insulin-like growth factor 1 receptor (IGF1R), epidermal growth factor receptor (EGFR), and platelet-derived growth factor receptor (PDGFR), and active K-RAS mutations, results in the binding of AKT to PCK1 and AKT-mediated phosphorylation of PCK1 at S90.	('platelet-derived growth factor receptor', 'Gene', (208, 247))	('AKT', 'Pathway', (37, 40))	('activation', 'PosReg', (67, 77))	('PCK1', 'Protein', (359, 363))	('insulin-like growth factor 1 receptor', 'Gene', (116, 153))	('PCK1', 'Protein', (318, 322))	('platelet-derived growth factor receptor', 'Gene', '5159', (208, 247))	('epidermal growth factor receptor', 'Gene', (163, 195))	('AKT', 'Protein', (311, 314))	('EGFR', 'Gene', '1956', (197, 201))	('activation', 'PosReg', (41, 51))	('epidermal growth factor receptor', 'Gene', '1956', (163, 195))	('AKT-mediated phosphorylation', 'MPA', (327, 355))	('K-RAS', 'Gene', (268, 273))	('insulin-like growth factor 1 receptor', 'Gene', '3480', (116, 153))	('IGF1R', 'Gene', '3480', (155, 160))	('K-RAS', 'Gene', '3845', (268, 273))	('PDGFR', 'Gene', (249, 254))	('binding', 'Interaction', (300, 307))	('PDGFR', 'Gene', '5159', (249, 254))	('mutations', 'Var', (274, 283))	('IGF1R', 'Gene', (155, 160))	('EGFR', 'Gene', (197, 201))
435715	33842305	Although the role of PCK1-dependent lipogenesis in HCC cell proliferation was revealed, whether AKT-phosphorylated PCK1 pS90, INSIG1 pS207/INSIG2 pS151, or nuclear SREBP1 expression is associated with progression and prognosis in NSCLC patients is unknown.	('pS90', 'Var', (120, 124))	('HCC', 'Phenotype', 'HP:0001402', (51, 54))	('associated', 'Reg', (185, 195))	('PCK1', 'Gene', (115, 119))	('NSCLC', 'Disease', 'MESH:D002289', (230, 235))	('INSIG2', 'Gene', '51141', (139, 145))	('patients', 'Species', '9606', (236, 244))	('NSCLC', 'Phenotype', 'HP:0030358', (230, 235))	('INSIG1', 'Gene', (126, 132))	('INSIG1', 'Gene', '3638', (126, 132))	('NSCLC', 'Disease', (230, 235))	('INSIG2', 'Gene', (139, 145))
435717	33842305	In addition, the levels of AKT pS473, AKT-dependent PCK1 pS90, PCK1-mediated INSIG1 pS207/INSIG2 pS151, and nuclear SREBP1 expression were higher in human NSCLC specimens than in their adjacent normal tissues.	('expression', 'MPA', (123, 133))	('INSIG2', 'Gene', '51141', (90, 96))	('INSIG1', 'Gene', (77, 83))	('NSCLC', 'Disease', (155, 160))	('human', 'Species', '9606', (149, 154))	('INSIG1', 'Gene', '3638', (77, 83))	('NSCLC', 'Disease', 'MESH:D002289', (155, 160))	('pS473', 'Var', (31, 36))	('NSCLC', 'Phenotype', 'HP:0030358', (155, 160))	('INSIG2', 'Gene', (90, 96))	('higher', 'PosReg', (139, 145))
435719	33842305	H1395, H226, A549, H358, H460, H1299, H1993, and H322M NSCLC cells were from ATCC.	('H1993', 'CellLine', 'CVCL:1512', (38, 43))	('H1299', 'CellLine', 'CVCL:0060', (31, 36))	('H358', 'CellLine', 'CVCL:1559', (19, 23))	('H460', 'CellLine', 'CVCL:0459', (25, 29))	('NSCLC', 'Disease', (55, 60))	('H1993', 'Var', (38, 43))	('NSCLC', 'Disease', 'MESH:D002289', (55, 60))	('H226', 'CellLine', 'CVCL:J621', (7, 11))	('H1299', 'Var', (31, 36))	('NSCLC', 'Phenotype', 'HP:0030358', (55, 60))	('A549', 'CellLine', 'CVCL:0023', (13, 17))	('H322M', 'Var', (49, 54))
435726	33842305	One million H1395 cells with expression of rPCK1, rPCK1 S90A, rINSIG1/INSIG2 or rINSIG1 S207A/rINSIG2 S151 double mutants were collected in 20 mul DMEM with 33% matrigel and subcutaneously injected into 6-week-old female BALB/c athymic nude mice.	('DMEM', 'Chemical', '-', (147, 151))	('rINSIG2', 'Gene', '288985', (94, 101))	('rPCK1', 'Gene', (43, 48))	('rPCK1', 'Gene', '362282', (43, 48))	('S90A', 'Mutation', 'p.S90A', (56, 60))	('rPCK1', 'Gene', '362282', (50, 55))	('rINSIG2', 'Gene', (94, 101))	('rPCK1', 'Gene', (50, 55))	('INSIG2', 'Gene', '51141', (95, 101))	('INSIG2', 'Gene', '51141', (70, 76))	('S207A', 'Mutation', 'p.S207A', (88, 93))	('nude mice', 'Species', '10090', (236, 245))	('rINSIG1', 'Gene', '64194', (62, 69))	('S90A', 'Var', (56, 60))	('rINSIG1', 'Gene', (62, 69))	('rINSIG1', 'Gene', '64194', (80, 87))	('INSIG2', 'Gene', (95, 101))	('rINSIG1', 'Gene', (80, 87))	('INSIG2', 'Gene', (70, 76))
435743	33842305	The expression levels of AKT pS473, PCK1 pS90, INSIG1 pS207/INSIG2 pS151, and nuclear SREBP1 in tumor and normal tissues were compared using the independent variable t test.	('PCK1 pS90', 'Var', (36, 45))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('INSIG1', 'Gene', (47, 53))	('tumor', 'Disease', (96, 101))	('INSIG2', 'Gene', (60, 66))	('INSIG1', 'Gene', '3638', (47, 53))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('INSIG2', 'Gene', '51141', (60, 66))
435747	33842305	We treated human NSCLC cells with epidermal growth factor (EGF) and found that EGFR activation induced a substantial increase of phosphorylation levels of AKT S473, PCK1 S90, INSIG1 S207 and INSIG2 S151, and the cleavage of SREBP1 in H1395 lung adenocarcinoma (LUAD) cells and H226 lung squamous cell carcinoma (LUSC) cells.	('epidermal growth factor', 'Gene', (34, 57))	('NSCLC', 'Disease', (17, 22))	('epidermal growth factor', 'Gene', '1950', (34, 57))	('EGFR', 'Gene', '1956', (79, 83))	('human', 'Species', '9606', (11, 16))	('EGF', 'Gene', (79, 82))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (282, 310))	('lung squamous cell carcinoma', 'Disease', (282, 310))	('NSCLC', 'Phenotype', 'HP:0030358', (17, 22))	('EGF', 'Gene', '1950', (59, 62))	('increase', 'PosReg', (117, 125))	('SREBP1', 'Gene', (224, 230))	('H226', 'CellLine', 'CVCL:J621', (277, 281))	('INSIG1', 'Gene', (175, 181))	('INSIG2', 'Gene', '51141', (191, 197))	('carcinoma', 'Phenotype', 'HP:0030731', (301, 310))	('INSIG1', 'Gene', '3638', (175, 181))	('lung adenocarcinoma', 'Disease', (240, 259))	('EGFR', 'Gene', (79, 83))	('S473', 'Var', (159, 163))	('LUAD', 'Phenotype', 'HP:0030078', (261, 265))	('phosphorylation levels', 'MPA', (129, 151))	('EGF', 'Gene', (59, 62))	('INSIG2', 'Gene', (191, 197))	('EGF', 'Gene', '1950', (79, 82))	('cleavage', 'MPA', (212, 220))	('NSCLC', 'Disease', 'MESH:D002289', (17, 22))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (240, 259))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (282, 310))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (287, 310))	('carcinoma', 'Phenotype', 'HP:0030731', (250, 259))	('PCK1 S90', 'Var', (165, 173))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (240, 259))	('LUSC', 'Phenotype', 'HP:0030359', (312, 316))	('AKT', 'Protein', (155, 158))
435748	33842305	Expression of PCK1 S90A mutant inhibited EGF-induced INSIG1/2 phosphorylation and SREBP1 cleavage ( Figure 1A ).	('inhibited', 'NegReg', (31, 40))	('S90A mutant', 'Var', (19, 30))	('INSIG1/2', 'Protein', (53, 61))	('EGF', 'Gene', (41, 44))	('S90A', 'Mutation', 'p.S90A', (19, 23))	('PCK1', 'Gene', (14, 18))	('SREBP1 cleavage', 'MPA', (82, 97))	('EGF', 'Gene', '1950', (41, 44))
435749	33842305	In addition, we examined a panel of NSCLC cell lines, including A549, H358, H460, H1299, H1395, H1993, H322M, and H226, and showed that PCK1 pS90, INSIG1 pS207/INSIG2 pS151, and nuclear SREBP1 accumulation were correlated with each other ( Figure 1B ).	('H226', 'CellLine', 'CVCL:J621', (114, 118))	('H1993', 'CellLine', 'CVCL:1512', (96, 101))	('INSIG1', 'Gene', '3638', (147, 153))	('INSIG2', 'Gene', (160, 166))	('NSCLC', 'Phenotype', 'HP:0030358', (36, 41))	('PCK1', 'Var', (136, 140))	('H1299', 'CellLine', 'CVCL:0060', (82, 87))	('H460', 'CellLine', 'CVCL:0459', (76, 80))	('NSCLC', 'Disease', (36, 41))	('INSIG2', 'Gene', '51141', (160, 166))	('H358', 'CellLine', 'CVCL:1559', (70, 74))	('A549', 'CellLine', 'CVCL:0023', (64, 68))	('INSIG1', 'Gene', (147, 153))	('NSCLC', 'Disease', 'MESH:D002289', (36, 41))
435750	33842305	These results indicated that EGFR activation activates the AKT pS473-PCK1 pS90-INSIG1 pS207/INSIG2 pS151-activated SREBP1 cascade in NSCLC cells.	('activates', 'PosReg', (45, 54))	('INSIG1', 'Gene', '3638', (79, 85))	('INSIG2', 'Gene', '51141', (92, 98))	('NSCLC', 'Phenotype', 'HP:0030358', (133, 138))	('INSIG2', 'Gene', (92, 98))	('EGFR', 'Gene', '1956', (29, 33))	('EGFR', 'Gene', (29, 33))	('NSCLC', 'Disease', (133, 138))	('pS473-PCK1', 'Var', (63, 73))	('AKT', 'Pathway', (59, 62))	('NSCLC', 'Disease', 'MESH:D002289', (133, 138))	('INSIG1', 'Gene', (79, 85))
435752	33842305	Expression of these mutant proteins substantially inhibited tumor growth in the mice ( Figures 1C, D  ).	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('mice', 'Species', '10090', (80, 84))	('tumor', 'Disease', (60, 65))	('proteins', 'Protein', (27, 35))	('mutant', 'Var', (20, 26))	('inhibited', 'NegReg', (50, 59))
435756	33842305	To determine whether the AKT-PCK1-INSIG1/2-SREBP cascade is activated in NSCLC tissues, we analyzed the correlation of expression levels of these biomarkers and showed that AKT pS473, PCK1 pS90, INSIG1 pS207/INSIG2 pS151, and nuclear SREBP1 expression levels were positively and significantly correlated with each other in LUAD specimens ( Figure 3A ).	('pS473', 'Var', (177, 182))	('INSIG2', 'Gene', (208, 214))	('LUAD', 'Phenotype', 'HP:0030078', (323, 327))	('INSIG1', 'Gene', (195, 201))	('expression', 'MPA', (241, 251))	('INSIG2', 'Gene', '51141', (208, 214))	('NSCLC', 'Disease', (73, 78))	('INSIG1', 'Gene', '3638', (195, 201))	('INSIG1', 'Gene', (34, 40))	('INSIG1', 'Gene', '3638', (34, 40))	('NSCLC', 'Disease', 'MESH:D002289', (73, 78))	('NSCLC', 'Phenotype', 'HP:0030358', (73, 78))
435758	33842305	These results indicated that the levels of AKT pS473, PCK1 pS90, INSIG1 pS207/INSIG2 pS151, and nuclear SREBP1 expression are positively correlated with each other in LUAD specimens and that the correlation of INSIG1 pS207/INSIG2 pS151 with PCK1 pS90 and nuclear SREBP1 expression is significant in LUSC.	('LUSC', 'Phenotype', 'HP:0030359', (299, 303))	('INSIG1', 'Gene', '3638', (210, 216))	('INSIG1', 'Gene', '3638', (65, 71))	('INSIG2', 'Gene', '51141', (223, 229))	('pS473', 'Var', (47, 52))	('INSIG2', 'Gene', (78, 84))	('INSIG2', 'Gene', '51141', (78, 84))	('INSIG2', 'Gene', (223, 229))	('LUAD', 'Phenotype', 'HP:0030078', (167, 171))	('INSIG1', 'Gene', (65, 71))	('INSIG1', 'Gene', (210, 216))
435761	33842305	However, in LUSC, the expression levels of PCK1 pS90, INSIG1 pS207/INSIG2 pS151, and nuclear SREBP1, but not the expression levels of AKT pS473, were associated with these clinical characteristics ( Table 1 ).	('associated', 'Reg', (150, 160))	('PCK1 pS90', 'Var', (43, 52))	('INSIG2', 'Gene', (67, 73))	('LUSC', 'Phenotype', 'HP:0030359', (12, 16))	('INSIG1', 'Gene', (54, 60))	('INSIG1', 'Gene', '3638', (54, 60))	('INSIG2', 'Gene', '51141', (67, 73))	('expression', 'MPA', (22, 32))
435763	33842305	To further determine the clinical significance of AKT pS473, PCK1 pS90, INSIG1 pS207/INSIG2 pS151, and nuclear SREBP1 expression levels, we determined their relationship with NSCLC patient survival time.	('INSIG1', 'Gene', (72, 78))	('INSIG1', 'Gene', '3638', (72, 78))	('NSCLC', 'Disease', 'MESH:D002289', (175, 180))	('pS473', 'Var', (54, 59))	('patient', 'Species', '9606', (181, 188))	('INSIG2', 'Gene', '51141', (85, 91))	('INSIG2', 'Gene', (85, 91))	('NSCLC', 'Phenotype', 'HP:0030358', (175, 180))	('NSCLC', 'Disease', (175, 180))
435765	33842305	In addition, the combined expression values of PCK1 pS90 and INSIG1 pS207/INSIG2 pS151 and the combined expression values of all four markers were positively correlated with poor prognosis of both LUAD ( Figure 4A ) and LUSC ( Figure 4B ).	('expression', 'MPA', (26, 36))	('INSIG2', 'Gene', '51141', (74, 80))	('PCK1 pS90', 'Var', (47, 56))	('INSIG1', 'Gene', (61, 67))	('INSIG2', 'Gene', (74, 80))	('INSIG1', 'Gene', '3638', (61, 67))	('correlated', 'Reg', (158, 168))	('LUAD', 'Phenotype', 'HP:0030078', (197, 201))	('LUSC', 'Phenotype', 'HP:0030359', (220, 224))	('LUAD', 'Disease', (197, 201))	('LUSC', 'Disease', (220, 224))
435766	33842305	These results indicated that increased levels of PCK1 pS90 and INSIG1 pS207/INSIG2 pS151 are positively correlated with poor prognosis in NSCLC patients.	('INSIG1', 'Gene', '3638', (63, 69))	('NSCLC', 'Disease', (138, 143))	('INSIG2', 'Gene', '51141', (76, 82))	('NSCLC', 'Disease', 'MESH:D002289', (138, 143))	('increased', 'PosReg', (29, 38))	('patients', 'Species', '9606', (144, 152))	('NSCLC', 'Phenotype', 'HP:0030358', (138, 143))	('INSIG2', 'Gene', (76, 82))	('PCK1 pS90', 'Var', (49, 58))	('INSIG1', 'Gene', (63, 69))
435767	33842305	To further determine the prognostic values of PCK1 pS90 and INSIG1 pS207/INSIG2 pS151 in NSCLC, we performed univariate and multivariate Cox regression analyses.	('NSCLC', 'Disease', 'MESH:D002289', (89, 94))	('INSIG2', 'Gene', '51141', (73, 79))	('NSCLC', 'Phenotype', 'HP:0030358', (89, 94))	('INSIG1', 'Gene', (60, 66))	('INSIG1', 'Gene', '3638', (60, 66))	('PCK1 pS90', 'Var', (46, 55))	('NSCLC', 'Disease', (89, 94))	('INSIG2', 'Gene', (73, 79))
435768	33842305	Univariate analysis revealed that advanced age (p < 0.05), TNM stage (p < 0.05), high expression of PCK1 pS90 (p < 0.05) or INSIG1 pS207/INSIG2 pS151 (p < 0.05), and high combined expression value of PCK1 pS90 and INSIG1 pS207/INSIG2 pS151 (p < 0.01) were associated with shorter overall survival time of both LUAD and LUSC ( Table 2 ) patients.	('INSIG1', 'Gene', (124, 130))	('INSIG1', 'Gene', '3638', (124, 130))	('INSIG1', 'Gene', (214, 220))	('TNM', 'Gene', '10178', (59, 62))	('INSIG2', 'Gene', '51141', (227, 233))	('INSIG1', 'Gene', '3638', (214, 220))	('shorter', 'NegReg', (272, 279))	('LUAD', 'Phenotype', 'HP:0030078', (310, 314))	('overall', 'MPA', (280, 287))	('LUAD', 'Disease', (310, 314))	('INSIG2', 'Gene', (137, 143))	('INSIG2', 'Gene', (227, 233))	('PCK1', 'Gene', (100, 104))	('patients', 'Species', '9606', (336, 344))	('TNM', 'Gene', (59, 62))	('LUSC', 'Phenotype', 'HP:0030359', (319, 323))	('PCK1 pS90', 'Var', (200, 209))	('INSIG2', 'Gene', '51141', (137, 143))
435771	33842305	Multivariate analysis of patients with NSCLC demonstrated that, in addition to age (p < 0.05) and TNM stage (p < 0.05), combined expression values of PCK1 pS90 and INSIG1 pS207/INSIG2 pS151 were an independent poor prognostic factor in LUAD (HR, 1.365; 95% CI, 0.777-2.154; p = 0.040) and LUSC (HR, 1.443; 95% CI, 0.935-2.156; p = 0.033) ( Table 2 ).	('INSIG2', 'Gene', (177, 183))	('NSCLC', 'Phenotype', 'HP:0030358', (39, 44))	('LUSC', 'Disease', (289, 293))	('LUSC', 'Phenotype', 'HP:0030359', (289, 293))	('PCK1 pS90', 'Var', (150, 159))	('TNM', 'Gene', (98, 101))	('INSIG1', 'Gene', (164, 170))	('patients', 'Species', '9606', (25, 33))	('INSIG2', 'Gene', '51141', (177, 183))	('NSCLC', 'Disease', (39, 44))	('LUAD', 'Phenotype', 'HP:0030078', (236, 240))	('INSIG1', 'Gene', '3638', (164, 170))	('LUAD', 'Disease', (236, 240))	('NSCLC', 'Disease', 'MESH:D002289', (39, 44))	('TNM', 'Gene', '10178', (98, 101))
435773	33842305	These results indicated that combined expression values of PCK1 pS90 and INSIG1 pS207/INSIG2 pS151 is an independent prognostic factor for NSCLC patients.	('patients', 'Species', '9606', (145, 153))	('INSIG1', 'Gene', (73, 79))	('INSIG1', 'Gene', '3638', (73, 79))	('NSCLC', 'Phenotype', 'HP:0030358', (139, 144))	('INSIG2', 'Gene', '51141', (86, 92))	('PCK1 pS90', 'Var', (59, 68))	('NSCLC', 'Disease', (139, 144))	('NSCLC', 'Disease', 'MESH:D002289', (139, 144))	('INSIG2', 'Gene', (86, 92))
435776	33842305	We recently demonstrated that PCK1, a gluconeogenesis enzyme, is phosphorylated at S90 by AKT, which is activated by active IGF1R, EGFR, and PDGFR and K-RAS mutations and promotes tumor progression.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('IGF1R', 'Gene', '3480', (124, 129))	('PDGFR', 'Gene', (141, 146))	('promotes', 'PosReg', (171, 179))	('K-RAS', 'Gene', '3845', (151, 156))	('PDGFR', 'Gene', '5159', (141, 146))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('AKT', 'Gene', (90, 93))	('K-RAS', 'Gene', (151, 156))	('tumor', 'Disease', (180, 185))	('EGFR', 'Gene', '1956', (131, 135))	('mutations', 'Var', (157, 166))	('EGFR', 'Gene', (131, 135))	('activated', 'PosReg', (104, 113))	('IGF1R', 'Gene', (124, 129))
435784	33842305	In addition, expression of PCK1 S90A and the INSIG1/2 phosphorylation-dead mutant inhibited the growth of tumor in mice derived from human NSCLC cells.	('NSCLC', 'Phenotype', 'HP:0030358', (139, 144))	('inhibited', 'NegReg', (82, 91))	('NSCLC', 'Disease', (139, 144))	('human', 'Species', '9606', (133, 138))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('S90A', 'Mutation', 'p.S90A', (32, 36))	('PCK1', 'Gene', (27, 31))	('mutant', 'Var', (75, 81))	('NSCLC', 'Disease', 'MESH:D002289', (139, 144))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('mice', 'Species', '10090', (115, 119))	('INSIG1/2', 'Gene', (45, 53))	('tumor', 'Disease', (106, 111))
435786	33842305	Our results showed that AKT pS473, PCK1 pS90, INSIG1 pS207/INSIG2 pS151 and nuclear SREBP1 expression levels were positively and significantly correlated with each other in LUAD specimens.	('expression', 'MPA', (91, 101))	('INSIG2', 'Gene', '51141', (59, 65))	('INSIG1', 'Gene', (46, 52))	('INSIG1', 'Gene', '3638', (46, 52))	('pS473', 'Var', (28, 33))	('LUAD', 'Phenotype', 'HP:0030078', (173, 177))	('INSIG2', 'Gene', (59, 65))	('correlated', 'Reg', (143, 153))
435789	33842305	Our work demonstrated that the expression levels of AKT pS473, PCK1 pS90, INSIG1 pS207/INSIG2 pS151, and nuclear SREBP1 were higher in tumor specimens than in their adjacent normal tissues.	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('expression levels', 'MPA', (31, 48))	('AKT', 'Gene', (52, 55))	('tumor', 'Disease', (135, 140))	('tumor', 'Disease', 'MESH:D009369', (135, 140))	('INSIG2', 'Gene', '51141', (87, 93))	('INSIG1', 'Gene', (74, 80))	('INSIG1', 'Gene', '3638', (74, 80))	('higher', 'PosReg', (125, 131))	('pS473', 'Var', (56, 61))	('PCK1', 'Gene', (63, 67))	('INSIG2', 'Gene', (87, 93))
435792	33842305	We found that the expression levels of PCK1 pS90 or INSIG1 pS207/INSIG2 pS151 are positively correlated with poor prognosis in NSCLC patients and that the combined expression value of PCK1 pS90 and INSIG1 pS207/INSIG2 pS151 exhibits a better prognostic value than that of each individual expression level.	('NSCLC', 'Disease', (127, 132))	('INSIG1', 'Gene', (52, 58))	('INSIG1', 'Gene', '3638', (52, 58))	('PCK1 pS90', 'Var', (39, 48))	('NSCLC', 'Disease', 'MESH:D002289', (127, 132))	('expression levels', 'MPA', (18, 35))	('INSIG1', 'Gene', (198, 204))	('INSIG2', 'Gene', (211, 217))	('INSIG1', 'Gene', '3638', (198, 204))	('patients', 'Species', '9606', (133, 141))	('INSIG2', 'Gene', '51141', (65, 71))	('NSCLC', 'Phenotype', 'HP:0030358', (127, 132))	('INSIG2', 'Gene', '51141', (211, 217))	('PCK1 pS90', 'Var', (184, 193))	('INSIG2', 'Gene', (65, 71))
435794	33842305	These findings shed light on the potential for the application of PCK1-mediated INSIG1/2 phosphorylation as a biomarker of NSCLC patient progression and prognosis and highlight the inhibition of the protein kinase activity of PCK1 as a treatment strategy against human NSCLC.	('NSCLC', 'Phenotype', 'HP:0030358', (269, 274))	('NSCLC', 'Disease', (123, 128))	('INSIG1/2', 'Gene', (80, 88))	('NSCLC', 'Disease', 'MESH:D002289', (123, 128))	('NSCLC', 'Disease', (269, 274))	('inhibition', 'Var', (181, 191))	('PCK1', 'Gene', (226, 230))	('NSCLC', 'Phenotype', 'HP:0030358', (123, 128))	('NSCLC', 'Disease', 'MESH:D002289', (269, 274))	('PCK1-mediated', 'Gene', (66, 79))	('human', 'Species', '9606', (263, 268))	('patient', 'Species', '9606', (129, 136))
435802	33842305	ZL owns shares in Signalway Biotechnology (Pearland, TX), which supplied rabbit antibodies that recognize PCK1 pS90, INSIG1 pS207 and INSIG2 pS151.	('PCK1 pS90', 'Var', (106, 115))	('INSIG1', 'Gene', (117, 123))	('INSIG2', 'Gene', (134, 140))	('INSIG2', 'Gene', '51141', (134, 140))	('INSIG1', 'Gene', '3638', (117, 123))
435805	32359397	We found that RMC was characterized by high replication stress and an abundance of focal copy number alterations associated with activation of the stimulator of the cyclic GMP-AMP synthase interferon genes (cGAS-STING) innate immune pathway.	('RMC', 'Disease', (14, 17))	('cGAS-STING', 'Gene', (207, 217))	('alterations', 'Var', (101, 112))	('RMC', 'Chemical', '-', (14, 17))	('activation', 'PosReg', (129, 139))
435808	32359397	These tumors harbor SMARCB1 mutations leading to high MYC expression and replicative stress that sensitize RMC cells to PARP inhibitors.	('high MYC expression', 'MPA', (49, 68))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('RMC', 'Chemical', '-', (107, 110))	('tumors', 'Disease', (6, 12))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('leading to', 'Reg', (38, 48))	('SMARCB1', 'Gene', (20, 27))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('mutations', 'Var', (28, 37))
435817	32359397	Inactivation of SMARCB1 deregulates the activity of SWI/SNF, resulting in aggressive tumors.	('resulting in', 'Reg', (61, 73))	('aggressive tumors', 'Disease', 'MESH:D001523', (74, 91))	('deregulates', 'Reg', (24, 35))	('SMARCB1', 'Gene', (16, 23))	('aggressive tumors', 'Disease', (74, 91))	('activity', 'MPA', (40, 48))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('Inactivation', 'Var', (0, 12))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))
435818	32359397	In addition to RMC, inactivation of SMARCB1 occurs in the majority of malignant rhabdoid tumors (MRT), atypical teratoid/rhabdoid tumors (ATRT), and epithelioid sarcomas (ES).	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('sarcoma', 'Phenotype', 'HP:0100242', (161, 168))	('occurs', 'Reg', (44, 50))	('sarcomas', 'Disease', (161, 169))	('inactivation', 'Var', (20, 32))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('malignant rhabdoid tumors', 'Disease', (70, 95))	('SMARCB1', 'Gene', (36, 43))	('rhabdoid tumors', 'Disease', (121, 136))	('rhabdoid tumors', 'Disease', 'MESH:D018335', (121, 136))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('sarcomas', 'Disease', 'MESH:D012509', (161, 169))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('RMC', 'Chemical', '-', (15, 18))	('rhabdoid tumors', 'Disease', 'MESH:D018335', (80, 95))	('sarcomas', 'Phenotype', 'HP:0100242', (161, 169))	('malignant rhabdoid tumors', 'Disease', 'MESH:D018335', (70, 95))
435823	32359397	Overall, rates of single nucleotide variants (SNVs) and insertion and deletion mutations (inDels) were very low for RMC.	('deletion mutations', 'Var', (70, 88))	('RMC', 'Chemical', '-', (116, 119))	('insertion', 'Var', (56, 65))	('RMC', 'Disease', (116, 119))	('single nucleotide variants', 'Var', (18, 44))
435825	32359397	A total of 1332 SNVs and inDels in 1165 genes were identified by WES, with a median of 24 per patient (Figure 1 and Supplementary Table 1).	('inDels', 'Var', (25, 31))	('SNVs', 'Var', (16, 20))	('men', 'Species', '9606', (122, 125))	('patient', 'Species', '9606', (94, 101))
435826	32359397	Clinical targeted next-generation sequencing of 5/31 untreated primary tumor samples (Figure 1) did not detect additional SNVs and inDels.	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('inDels', 'Var', (131, 137))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('SNVs', 'Var', (122, 126))	('tumor', 'Disease', (71, 76))
435829	32359397	Of the 1165 genes mutated in untreated primary RMC tumors from a total of 31 patients, only 22 were known tumor suppressors or oncogenes listed in the Catalogue of Somatic Mutations in Cancer (COSMIC) database (Figure S1B and Supplementary Table 1).	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('mutated', 'Var', (18, 25))	('tumor', 'Disease', (51, 56))	('men', 'Species', '9606', (232, 235))	('RMC tumors', 'Disease', 'MESH:D009369', (47, 57))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('patients', 'Species', '9606', (77, 85))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('Cancer', 'Disease', (185, 191))	('Cancer', 'Phenotype', 'HP:0002664', (185, 191))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('Cancer', 'Disease', 'MESH:D009369', (185, 191))	('tumor', 'Disease', (106, 111))	('RMC tumors', 'Disease', (47, 57))
435833	32359397	SETD2 was mutated in 2/31 (6.5%) of RMC tumors and was the only established gene driver of other renal cell carcinomas to be altered in RMC (Figure 1 and Supplementary Table 1).	('mutated', 'Var', (10, 17))	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (97, 117))	('RMC', 'Chemical', '-', (136, 139))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('renal cell carcinomas', 'Disease', (97, 118))	('SETD2', 'Gene', '29072', (0, 5))	('RMC tumors', 'Disease', 'MESH:D009369', (36, 46))	('carcinomas', 'Phenotype', 'HP:0030731', (108, 118))	('SETD2', 'Gene', (0, 5))	('men', 'Species', '9606', (160, 163))	('RMC', 'Chemical', '-', (36, 39))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (97, 118))	('renal cell carcinomas', 'Disease', 'MESH:C538614', (97, 118))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('RMC tumors', 'Disease', (36, 46))
435835	32359397	Whereas other SMARCB1-deficient malignancies, such as the rhabdoid tumors MRT and ATRT, harbor a simple genome with very few CNAs other than 22q11.23 loss (Figure S1E), RMC had recurrent focal chromosomal amplifications and deletions in addition to 22q11.23 loss (Figures 2C, 2D, and S2).	('loss', 'NegReg', (258, 262))	('rhabdoid tumors MRT', 'Disease', (58, 77))	('deletions', 'Var', (224, 233))	('deficient malignancies', 'Disease', 'MESH:D009369', (22, 44))	('RMC', 'Chemical', '-', (169, 172))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('rhabdoid tumors MRT', 'Disease', 'MESH:D018335', (58, 77))	('deficient malignancies', 'Disease', (22, 44))
435843	32359397	The most common focal deletion in both RMC and rhabdoid tumors was in the SMARCB1 locus 22q11.23 found in 9/15 (60%) RMC tumors and in 28/35 (80%) rhabdoid tumors.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('deletion', 'Var', (22, 30))	('RMC tumors', 'Disease', (117, 127))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('rhabdoid tumors', 'Disease', (147, 162))	('rhabdoid tumors', 'Disease', (47, 62))	('rhabdoid tumors', 'Disease', 'MESH:D018335', (47, 62))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('SMARCB1', 'Gene', (74, 81))	('RMC', 'Chemical', '-', (117, 120))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('rhabdoid tumors', 'Disease', 'MESH:D018335', (147, 162))	('RMC tumors', 'Disease', 'MESH:D009369', (117, 127))	('RMC', 'Chemical', '-', (39, 42))
435846	32359397	Furthermore, we found amplification of NOTCH2 in 6/15 (40%) RMC tumors, with 4/15 (26.7%) demonstrating concurrent deletion of NOTCH1 and NOTCH3 and amplification of NOTCH2, a distinct pattern also found in the basal subtype of bladder urothelial carcinoma (BLCA) and associated with increased cell-cycle progression and epithelial-mesenchymal transition (EMT).	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('RMC tumors', 'Disease', (60, 70))	('amplification', 'Var', (149, 162))	('NOTCH2', 'Gene', (166, 172))	('amplification', 'Var', (22, 35))	('NOTCH1', 'Gene', (127, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (247, 256))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('RMC tumors', 'Disease', 'MESH:D009369', (60, 70))	('bladder urothelial carcinoma', 'Disease', (228, 256))	('NOTCH1', 'Gene', '4851', (127, 133))	('NOTCH3', 'Gene', '4854', (138, 144))	('NOTCH2', 'Gene', '4853', (39, 45))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (228, 256))	('NOTCH3', 'Gene', (138, 144))	('deletion', 'Var', (115, 123))	('NOTCH2', 'Gene', '4853', (166, 172))	('cell-cycle progression', 'CPA', (294, 316))	('NOTCH2', 'Gene', (39, 45))	('increased', 'PosReg', (284, 293))	('epithelial-mesenchymal transition', 'CPA', (321, 354))
435848	32359397	By integrating our genomic and RNA-seq data we identified 341 genes (Supplementary Table 2) in areas of recurrent focal copy number gain or loss that were significantly (FDR < 0.1) upregulated or downregulated, respectively, in RMC tumors compared with adjacent normal kidney.	('focal copy number', 'Var', (114, 131))	('RMC tumors', 'Disease', 'MESH:D009369', (228, 238))	('downregulated', 'NegReg', (196, 209))	('gain', 'PosReg', (132, 136))	('upregulated', 'PosReg', (181, 192))	('men', 'Species', '9606', (75, 78))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('tumors', 'Phenotype', 'HP:0002664', (232, 238))	('RMC tumors', 'Disease', (228, 238))	('loss', 'NegReg', (140, 144))
435849	32359397	The reliability of our CNA analyses of WES data was confirmed in sample MED1T by array CGH (Figure 3A), which detected the presence of the focal amplification on chromosome 2p, large amplification of chromosome 8, monosomy of chromosomes 4 and 22, large deletions of chromosomes 15 and 16, and a focal deletion of chromosome 17p13.1 (TP53 gene region), which were also found by WES (Figure S2).	('MED1', 'Gene', '5469', (72, 76))	('MED1', 'Gene', (72, 76))	('monosomy', 'Var', (214, 222))
435852	32359397	Less frequent were deletion of both SMARCB1 alleles (6/38 patients; 15.8%), deletion of one SMARCB1 allele and inDel of the second SMARCB1 allele (5/38 patients; 13.2%), and deletion of one SMARCB1 allele and truncating nonsense mutation of the second SMARCB1 allele (1/38 patients; 2.6%).	('deletion', 'Var', (76, 84))	('patients', 'Species', '9606', (273, 281))	('SMARCB1', 'Gene', (190, 197))	('deletion', 'Var', (19, 27))	('SMARCB1', 'Gene', (252, 259))	('truncating nonsense mutation', 'Var', (209, 237))	('SMARCB1', 'Gene', (36, 43))	('deletion', 'Var', (174, 182))	('SMARCB1', 'Gene', (92, 99))	('patients', 'Species', '9606', (58, 66))	('patients', 'Species', '9606', (152, 160))
435854	32359397	In addition, we determined that this pattern for SMARCB1 inactivation (inactivating translocation combined with hemizygous deletion) occurred not only in primary tumors but also in lymph node and liver mestastases of patients RMC38 and RMC32, respectively.	('inactivation', 'NegReg', (57, 69))	('liver mestastases', 'Disease', (196, 213))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('RMC', 'Chemical', '-', (226, 229))	('patients', 'Species', '9606', (217, 225))	('RMC', 'Chemical', '-', (236, 239))	('tumors', 'Disease', (162, 168))	('tumors', 'Disease', 'MESH:D009369', (162, 168))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))	('RMC38', 'Var', (226, 231))	('liver mestastases', 'Disease', 'MESH:D017093', (196, 213))	('SMARCB1', 'Gene', (49, 56))
435855	32359397	Sanger sequencing confirmed that both the primary kidney tumor and the liver metastasis of patient RMC32 harbored the same translocation between the SMARCB1 and MYOM1 genes (Figures 3E and 3F).	('translocation', 'Var', (123, 136))	('kidney tumor', 'Disease', 'MESH:D007680', (50, 62))	('SMARCB1', 'Gene', (149, 156))	('kidney tumor', 'Phenotype', 'HP:0009726', (50, 62))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('kidney tumor', 'Disease', (50, 62))	('MYOM1', 'Gene', (161, 166))	('patient', 'Species', '9606', (91, 98))	('RMC', 'Chemical', '-', (99, 102))	('MYOM1', 'Gene', '8736', (161, 166))
435858	32359397	RNA-seq (see below) of 5 samples (RMC32T, RMC36T1, MED1T, MED2T, MED5T) that harbored inactivating translocations identified SMARCB1 fusion transcripts in 2/5 cases (RMC32T and MED1T) as shown in Figure 3E.	('RMC36T1', 'CellLine', 'CVCL:5354', (42, 49))	('MED1', 'Gene', '5469', (177, 181))	('SMARCB1', 'Gene', (125, 132))	('MED1', 'Gene', (177, 181))	('RMC', 'Chemical', '-', (34, 37))	('RMC', 'Chemical', '-', (42, 45))	('MED1', 'Gene', '5469', (51, 55))	('RMC32T', 'Var', (166, 172))	('RMC', 'Chemical', '-', (166, 169))	('MED5T', 'CellLine', 'CVCL:M137', (65, 70))	('MED1', 'Gene', (51, 55))	('inactivating translocations', 'Var', (86, 113))
435862	32359397	The RMC36T1 sample that clustered within the CDC samples in our unsupervised analysis of protein-coding gene expression (Figure 4A) was confirmed to be RMC as the patient had sickle cell trait by hemoglobin electrophoresis (Figure 1) and the tumor was negative for SMARCB1 by immunohistochemistry (Figure S1A).	('sickle cell trait', 'Disease', (175, 192))	('RMC36T1', 'CellLine', 'CVCL:5354', (4, 11))	('tumor', 'Disease', 'MESH:D009369', (242, 247))	('RMC', 'Chemical', '-', (4, 7))	('tumor', 'Phenotype', 'HP:0002664', (242, 247))	('patient', 'Species', '9606', (163, 170))	('tumor', 'Disease', (242, 247))	('RMC', 'Chemical', '-', (152, 155))	('RMC36T1', 'Var', (4, 11))
435865	32359397	The distinct gene expression profiles of RMC compared with kidney MRT, despite their common renal origin and shared etiology of SMARCB1 inactivation, led us to explore the nephron site of origin of these malignancies.	('malignancies', 'Disease', (204, 216))	('inactivation', 'Var', (136, 148))	('SMARCB1', 'Gene', (128, 135))	('RMC', 'Chemical', '-', (41, 44))	('malignancies', 'Disease', 'MESH:D009369', (204, 216))	('RMC', 'Disease', (41, 44))
435899	32359397	In the mutational landscape of RMC we noted that the most common substitutions in most RMC tumors were C > T transitions (Figure 1), which are linked to the process of cytosine deamination often associated with age or DNA replication stress.	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('RMC tumors', 'Disease', 'MESH:D009369', (87, 97))	('C > T transitions', 'Var', (103, 120))	('RMC', 'Chemical', '-', (31, 34))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('RMC tumors', 'Disease', (87, 97))	('RMC', 'Chemical', '-', (87, 90))	('cytosine', 'Chemical', 'MESH:D003596', (168, 176))
435900	32359397	However, patient age did not strongly correlate with the number of C > T mutations (Spearman rank correlation = 0.395, p = 0.145), suggesting that they are instead caused by replication stress in the setting of high cell turnover.	('patient', 'Species', '9606', (9, 16))	('caused by', 'Reg', (164, 173))	('C > T mutations', 'Var', (67, 82))
435901	32359397	Furthermore, the predominant mutational signature pattern in RMC tumors was Signature 1 (Figure S1C), which consists mainly of C > T transitions at CpG dinucleotide motifs and is known to be associated with age and/or high number of mitoses.	('RMC tumors', 'Disease', 'MESH:D009369', (61, 71))	('C > T transitions', 'Var', (127, 144))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('dinucleotide', 'Chemical', 'MESH:D015226', (152, 164))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('RMC tumors', 'Disease', (61, 71))
435908	32359397	We additionally used a previously established established RMC cell line (RMC219), which is also negative for inactivating SMARCB1 translocations and harbors centromeric deletions of both SMARCB1 alleles (Supplementary Table 3 and Figure S6H).	('men', 'Species', '9606', (210, 213))	('RMC', 'Chemical', '-', (58, 61))	('SMARCB1', 'Gene', (187, 194))	('RMC219', 'Chemical', '-', (73, 79))	('RMC', 'Chemical', '-', (73, 76))	('translocations', 'Var', (130, 144))	('SMARCB1', 'Gene', (122, 129))
435912	32359397	As shown using our two RMC cell lines and two other SMARCB1-negative cell lines (MRT line G401 and epitheliod sarcoma line VA-ES-BJ) in Figure 6D, high c-MYC levels correlated with expression of the DNA damage marker gammaH2AX, expression of DNA damage repair enzymes Poly-(ADP-ribose) polymerase (PARP) and ataxia-telangiectasia and Rad3-related (ATR), ATR activation via phosphorylation at serine 428, upregulation and phosphorylation at serines 4 and 8 of the RPA32 subunit of human replication protein A (a marker of DNA damage response), upregulation of FANCD2 (which protects cells from replication stress), phosphorylation of CDK1 at tyrosine 15 (which regulates the G2-M checkpoint), as well as phosphorylation of TP53 at serine 15, a marker specific to DNA damage response and not to other stimuli such as hyper-proliferation.	('sarcoma', 'Disease', 'MESH:D012509', (110, 117))	('ataxia', 'Phenotype', 'HP:0001251', (308, 314))	('sarcoma', 'Disease', (110, 117))	('CDK1', 'Gene', (633, 637))	('phosphorylation', 'Var', (614, 629))	('ataxia-telangiectasia and Rad3-related', 'Gene', '685055', (308, 346))	('FANCD2', 'Gene', (559, 565))	('Poly-(ADP-ribose) polymerase', 'Gene', '25591', (268, 296))	('sarcoma', 'Phenotype', 'HP:0100242', (110, 117))	('serine', 'Chemical', 'MESH:D012694', (440, 446))	('serine', 'Chemical', 'MESH:D012694', (392, 398))	('RPA32', 'Gene', '108689', (463, 468))	('RMC', 'Chemical', '-', (23, 26))	('gammaH2AX', 'Gene', (217, 226))	('RPA32', 'Gene', (463, 468))	('BJ', 'CellLine', 'CVCL:6573', (129, 131))	('Poly-(ADP-ribose) polymerase', 'Gene', (268, 296))	('telangiectasia', 'Phenotype', 'HP:0001009', (315, 329))	('upregulation', 'PosReg', (543, 555))	('serine', 'Chemical', 'MESH:D012694', (730, 736))	('phosphorylation', 'MPA', (703, 718))	('TP53', 'Gene', (722, 726))	('gammaH2AX', 'Gene', '15270', (217, 226))	('human', 'Species', '9606', (480, 485))
435913	32359397	Conversely, SMARCB1 knockout by CRISPR/Cas9 in human embryonic kidney (HEK-293FT) cells increased c-MYC and the resulting replication stress (Figures S7B and S7C).	('S7C', 'Mutation', 'p.S7C', (158, 161))	('embryonic kidney', 'Disease', 'MESH:D007674', (53, 69))	('SMARCB1', 'Gene', (12, 19))	('replication', 'MPA', (122, 133))	('increased', 'PosReg', (88, 97))	('HEK-293FT', 'CellLine', 'CVCL:6911', (71, 80))	('knockout', 'Var', (20, 28))	('human', 'Species', '9606', (47, 52))	('embryonic kidney', 'Disease', (53, 69))	('c-MYC', 'MPA', (98, 103))
435922	32359397	We also found that SMARCB1-negative cell lines are sensitive to the ATR inhibitors VX970 and AZD6738 and to the WEE1 inhibitor adavosertib (Figure 7B).	('AZD6738', 'Var', (93, 100))	('ATR', 'Gene', (68, 71))	('sensitive', 'Reg', (51, 60))	('AZD6738', 'Chemical', 'MESH:C000611951', (93, 100))	('VX970', 'Var', (83, 88))	('WEE1', 'Gene', (112, 116))	('WEE1', 'Gene', '7465', (112, 116))	('adavosertib', 'Chemical', 'MESH:C549567', (127, 138))
435928	32359397	Mice harboring RMC2X tumors (n = 5 per group; average tumor volume of 158 mm3 at treatment initiation) were randomly assigned to receive niraparib, AZD6738, the combination of niraparib with AZD6738, or vehicle control for a total of 25 days.	('men', 'Species', '9606', (86, 89))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('tumor', 'Disease', (21, 26))	('AZD6738', 'Chemical', 'MESH:C000611951', (148, 155))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumors', 'Disease', (21, 27))	('AZD6738', 'Chemical', 'MESH:C000611951', (191, 198))	('AZD6738', 'Var', (148, 155))	('tumors', 'Disease', 'MESH:D009369', (21, 27))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('niraparib', 'Chemical', 'MESH:C545685', (137, 146))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('Mice', 'Species', '10090', (0, 4))	('tumor', 'Disease', (54, 59))	('RMC', 'Chemical', '-', (15, 18))	('niraparib', 'Chemical', 'MESH:C545685', (176, 185))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
435931	32359397	Conversely, treatment with AZD6738 did not significantly reduce tumor volume compared with vehicle control (p = 0.54), and its combination with niraparib did not produce a stronger antitumor effect compared with niraparib alone (p = 0.868).	('tumor', 'Disease', (185, 190))	('AZD6738', 'Chemical', 'MESH:C000611951', (27, 34))	('tumor', 'Disease', (64, 69))	('AZD6738', 'Var', (27, 34))	('combination', 'Interaction', (127, 138))	('niraparib', 'Chemical', 'MESH:C545685', (212, 221))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('niraparib', 'Chemical', 'MESH:C545685', (144, 153))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('men', 'Species', '9606', (17, 20))
435941	32359397	CNAs in chromosomal fragile sites such as those noted in RMC can be both a source and a consequence of DNA replication stress in cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('RMC', 'Chemical', '-', (57, 60))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('chromosomal fragile sites', 'Phenotype', 'HP:0040012', (8, 33))	('CNAs', 'Var', (0, 4))
435992	32359397	Thus, although our WES had high sensitivity to detect dominant clonal or subclonal RMC tumor mutations, it would be less likely to detect more rare subclonal alterations.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('RMC tumor', 'Disease', (83, 92))	('RMC tumor', 'Disease', 'MESH:D009369', (83, 92))	('mutations', 'Var', (93, 102))
435999	32359397	The somatic status of a specific SNV/inDel was reported once the matched germline had wild allele-based homozygous genotype and the tumor had heterozygous or mutant allele-based homozygous genotype with a certain cutoff of genotype likelihood/p value of 0.99.	('mutant', 'Var', (158, 164))	('tumor', 'Disease', (132, 137))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))
436014	32359397	DNA was labeled by random priming with CY5-dCTPs (tumor DNA) and CY3-dCTPs (control DNA), and was hybridized to 4x180K whole-genome Agilent arrays (G4448A).	('CY3-dCTPs', 'Var', (65, 74))	('CY3-dCTPs', 'Chemical', '-', (65, 74))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('CY5-dCTPs', 'Var', (39, 48))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('G4448A', 'Mutation', 'rs1249266779', (148, 154))	('CY5-dCTPs', 'Chemical', 'MESH:C544355', (39, 48))	('tumor', 'Disease', (50, 55))
436040	32359397	Samples with break-apart in >= 15% of tumor nuclei were considered positive for SMARCB1 translocation.	('positive', 'Reg', (67, 75))	('tumor', 'Disease', (38, 43))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('SMARCB1', 'Gene', (80, 87))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('translocation', 'Var', (88, 101))
436041	32359397	Partial SMARCB1 deletion was defined as loss of either green or orange probes in >= 15% of tumor nuclei.	('SMARCB1', 'Gene', (8, 15))	('orange probes', 'MPA', (64, 77))	('deletion', 'Var', (16, 24))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('loss', 'NegReg', (40, 44))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor', 'Disease', (91, 96))	('green', 'MPA', (55, 60))	('Partial', 'Var', (0, 7))
436155	31015447	In the TCGA LUSC tumors, the LUSC-Classical subtype was associated with alterations and over expression of KEAP1 and NFE2L2 as well as amplification of 3q26 with over expression of SOX2, TP63, and PIK3CA.	('PIK3CA', 'Gene', (197, 203))	('over expression', 'PosReg', (88, 103))	('tumors', 'Disease', (17, 23))	('NFE2L2', 'Gene', (117, 123))	('3q26', 'Gene', (152, 156))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('LUSC-Classical', 'Disease', (29, 43))	('TP63', 'Gene', (187, 191))	('PIK3CA', 'Gene', '5290', (197, 203))	('SOX2', 'Gene', '6657', (181, 185))	('over expression', 'PosReg', (162, 177))	('SOX2', 'Gene', (181, 185))	('TP63', 'Gene', '8626', (187, 191))	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('KEAP1', 'Gene', '9817', (107, 112))	('amplification', 'Var', (135, 148))	('NFE2L2', 'Gene', '4780', (117, 123))	('KEAP1', 'Gene', (107, 112))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
436212	31015447	Telomere shortening and maintenance and loss of heterozygosity in regions frequently deleted in lung cancer (3p, 5q, 9p, 13q, 17p) has been observed in early hyperplasia/metaplasia lesions and found to increase in frequency and size in higher-grade dysplasia.	('hyperplasia', 'Disease', 'MESH:D006965', (158, 169))	('lung cancer', 'Disease', 'MESH:D008175', (96, 107))	('Telomere shortening', 'Phenotype', 'HP:0031413', (0, 19))	('3p', 'Var', (109, 111))	('dysplasia', 'Disease', (249, 258))	('loss', 'NegReg', (40, 44))	('lung cancer', 'Disease', (96, 107))	('observed', 'Reg', (140, 148))	('hyperplasia', 'Disease', (158, 169))	('metaplasia lesions', 'Disease', (170, 188))	('dysplasia', 'Disease', 'MESH:D004476', (249, 258))	('lung cancer', 'Phenotype', 'HP:0100526', (96, 107))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('metaplasia lesions', 'Disease', 'MESH:D008679', (170, 188))	('increase', 'PosReg', (202, 210))
436213	31015447	Genomic gains in loci containing SOX2, TP63, EGFR, MYC, CEP3, and CEP5 are also associated with progression of high-grade dysplasia.	('CEP5', 'Gene', (66, 70))	('CEP5', 'Gene', '148170', (66, 70))	('EGFR', 'Gene', (45, 49))	('gains', 'PosReg', (8, 13))	('MYC', 'Gene', (51, 54))	('SOX2', 'Gene', '6657', (33, 37))	('TP63', 'Gene', (39, 43))	('TP63', 'Gene', '8626', (39, 43))	('SOX2', 'Gene', (33, 37))	('associated', 'Reg', (80, 90))	('CEP3', 'Gene', '10602', (56, 60))	('CEP3', 'Gene', (56, 60))	('dysplasia', 'Disease', (122, 131))	('MYC', 'Gene', '4609', (51, 54))	('Genomic', 'Var', (0, 7))	('dysplasia', 'Disease', 'MESH:D004476', (122, 131))	('EGFR', 'Gene', '1956', (45, 49))
436224	31015447	Interestingly, IL1B is part of this inflammation-related gene module, and inhibition of IL1B has recently been shown to reduce lung cancer incidence.	('lung cancer', 'Disease', (127, 138))	('inhibition', 'Var', (74, 84))	('inflammation', 'Disease', 'MESH:D007249', (36, 48))	('reduce', 'NegReg', (120, 126))	('lung cancer', 'Phenotype', 'HP:0100526', (127, 138))	('inflammation', 'Disease', (36, 48))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('IL1B', 'Gene', (15, 19))	('IL1B', 'Gene', (88, 92))	('IL1B', 'Gene', '3553', (15, 19))	('IL1B', 'Gene', '3553', (88, 92))	('lung cancer', 'Disease', 'MESH:D008175', (127, 138))
436225	31015447	In the current study, we have both normal-appearing bronchial brushes and endobronchial biopsies collected during the same procedure, allowing us to identify gene expression differences in brushings, which indicate the presence of Proliferative subtype PMLs.	('gene expression', 'MPA', (158, 173))	('PML', 'Gene', (253, 256))	('PML', 'Gene', '5371', (253, 256))	('differences', 'Var', (174, 185))
436231	31015447	By immunofluorescent staining of formalin-fixed paraformaldehyde-embedded (FFPE) biopsy sections we confirmed that the progressive/persistent Proliferative lesions with low Module 9 GSVA scores had fewer CD163+ macrophages and CD8+ T cells and the CD8+T cells had a distinct localization pattern.	('formalin', 'Chemical', 'MESH:D005557', (33, 41))	('GSVA', 'Gene', (182, 186))	('fewer', 'NegReg', (198, 203))	('CD8', 'Gene', (248, 251))	('low Module 9', 'Var', (169, 181))	('CD8', 'Gene', (227, 230))	('CD163', 'Gene', '9332', (204, 209))	('CD8', 'Gene', '925', (227, 230))	('CD8', 'Gene', '925', (248, 251))	('GSVA', 'Chemical', '-', (182, 186))	('paraformaldehyde', 'Chemical', 'MESH:C003043', (48, 64))	('CD163', 'Gene', (204, 209))	('Proliferative lesions', 'CPA', (142, 163))
436241	31015447	Future DNA sequencing data on the PMLs profiled here may indicate heterozygous or homozygous loss of B2M or mutations in other genes in the interferon and antigen processing and presentation pathways; however, even in the case of acquired resistance, mutations and copy number changes could not explain the down regulation of these pathways across all subjects, suggesting that other epigenetic alterations or signaling pathways may have a role.	('mutations', 'Var', (108, 117))	('loss', 'NegReg', (93, 97))	('PML', 'Gene', '5371', (34, 37))	('PML', 'Gene', (34, 37))	('B2M', 'Gene', (101, 104))	('B2M', 'Gene', '567', (101, 104))
436280	31015447	The models were used across samples from the Proliferative subtype and across samples from the Proliferative subtype where the biopsy outcome (progressive/persistent versus regressive) agreed with the Module 9 GSVA score (scores < 0 are associated with progression/persistence and scores greater than 0 are associated with regression).	('scores < 0', 'Var', (222, 232))	('GSVA', 'Chemical', '-', (210, 214))	('progression/persistence', 'Disease', (253, 276))
436311	30524946	In addition, previous studies demonstrated that the Wnt/beta-catenin signaling pathway also participated during cancer cell EMT 26, 27, accompanied by downregulated epithelial markers, E-cadherin and keratin, and upregulated mesenchymal markers such as N-cadherin and vimentin, while tankyrase 2 (TNKS2) plays an important role in tumor cell migration and invasion 28 and TNKS2 inhibition was able to downregulate activity of the Wnt/beta-catenin signaling pathway and thereby reduce tumor cell growth 29.	('tumor', 'Disease', 'MESH:D009369', (331, 336))	('tankyrase 2', 'Gene', (284, 295))	('cancer', 'Disease', (112, 118))	('tumor', 'Phenotype', 'HP:0002664', (484, 489))	('TNKS2', 'Gene', (372, 377))	('activity', 'MPA', (414, 422))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('tankyrase 2', 'Gene', '80351', (284, 295))	('tumor', 'Phenotype', 'HP:0002664', (331, 336))	('downregulate', 'NegReg', (401, 413))	('tumor', 'Disease', (484, 489))	('Wnt/beta-catenin signaling pathway', 'Pathway', (430, 464))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('downregulated', 'NegReg', (151, 164))	('tumor', 'Disease', 'MESH:D009369', (484, 489))	('vimentin', 'Gene', '7431', (268, 276))	('vimentin', 'Gene', (268, 276))	('mesenchymal', 'CPA', (225, 236))	('inhibition', 'Var', (378, 388))	('upregulated', 'PosReg', (213, 224))	('tumor', 'Disease', (331, 336))	('reduce', 'NegReg', (477, 483))	('E-cadherin', 'Protein', (185, 195))
436334	30524946	In this study, CRL1623 cells were grown and stably transfected with pcDNA3.1(+)-IL-18 and pcDNA3.1, respectively, using Lipofectamine 2000 reagent (Invitrogen) and then stabilized in G418 (Invitrogen)-containing medium using single cell cloning and expansion.	('CRL', 'Gene', '133396', (15, 18))	('Lipofectamine 2000', 'Chemical', 'MESH:C086724', (120, 138))	('G418', 'Chemical', 'MESH:C010680', (183, 187))	('pcDNA3.1', 'Gene', (68, 76))	('pcDNA3.1', 'Var', (90, 98))	('CRL', 'Gene', (15, 18))
436336	30524946	Stable CRL1623 sublines were grown in the full cell culture medium containing G418 and re-seeded into the upper chamber (400 muL for 10 000 cells per chamber), while the bottom chambers were filled with 600 muL of the growth medium containing 10% fetal bovine serum.	('G418', 'Chemical', 'MESH:C010680', (78, 82))	('bovine', 'Species', '9913', (253, 259))	('CRL', 'Gene', (7, 10))	('G418', 'Var', (78, 82))	('CRL', 'Gene', '133396', (7, 10))
436359	30524946	Furthermore, although our in vitro data showed that IL-18 promoted TSCC cell migration and invasion, our nude mouse assay revealed that IL-18 suppressed growth of nude mouse xenografts.	('invasion', 'CPA', (91, 99))	('mouse', 'Species', '10090', (168, 173))	('growth', 'CPA', (153, 159))	('mouse', 'Species', '10090', (110, 115))	('promoted', 'PosReg', (58, 66))	('TSCC cell migration', 'CPA', (67, 86))	('IL-18', 'Var', (136, 141))	('suppressed', 'NegReg', (142, 152))
436367	30524946	41 discovered that IL-18 expression was able to induce gastric cancer cell immune evasion by upregulation of CD44 and vascular endothelial growth factor in nude mouse gastric cancer xenografts, while Li et al.	('upregulation', 'PosReg', (93, 105))	('gastric cancer', 'Disease', (55, 69))	('gastric cancer', 'Disease', 'MESH:D013274', (55, 69))	('CD44', 'Gene', '12505', (109, 113))	('CD44', 'Gene', (109, 113))	('gastric cancer', 'Disease', (167, 181))	('induce', 'PosReg', (48, 54))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('gastric cancer', 'Disease', 'MESH:D013274', (167, 181))	('gastric cancer', 'Phenotype', 'HP:0012126', (55, 69))	('IL-18', 'Gene', (19, 24))	('vascular endothelial growth factor', 'MPA', (118, 152))	('gastric cancer', 'Phenotype', 'HP:0012126', (167, 181))	('expression', 'Var', (25, 35))	('mouse', 'Species', '10090', (161, 166))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
436434	28204826	For example, the four KEGG pathways such as adherens junction (hsa04520), regulation of actin cytoskeleton (hsa04810), cell cycle (hsa04110) and pathway in cancer (hsa05200) were consistently upregulated in the ARLC-SCC patients compared with the average level of gene expression in all the NARLC-SCC patients.	('SCC', 'Gene', (216, 219))	('cell', 'CPA', (119, 123))	('hsa04110', 'Var', (131, 139))	('hsa04810', 'Var', (108, 116))	('cancer', 'Disease', (156, 162))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('hsa05200', 'Var', (164, 172))	('SCC', 'Gene', '6317', (216, 219))	('patients', 'Species', '9606', (301, 309))	('SCC', 'Gene', (297, 300))	('pathway', 'Pathway', (145, 152))	('adherens', 'MPA', (44, 52))	('regulation', 'MPA', (74, 84))	('upregulated', 'PosReg', (192, 203))	('patients', 'Species', '9606', (220, 228))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('KEGG pathways', 'Pathway', (22, 35))	('SCC', 'Gene', '6317', (297, 300))
436442	28204826	In the study of Wright et al, 6 candidate genes (CARD18, MS4A1, ABHD12, API5, ANKRD20A3 and LOC402117) were identified as being differentially expressed between ARLC-SCC and NARLC-SCC cases, while subsequent validations failed to support any of them as markers of asbestos etiology.	('ABHD12', 'Gene', (64, 70))	('CARD18', 'Gene', (49, 55))	('MS4A1', 'Gene', '931', (57, 62))	('API5', 'Gene', '8539', (72, 76))	('asbestos', 'Chemical', 'MESH:D001194', (264, 272))	('CARD18', 'Gene', '59082', (49, 55))	('MS4A1', 'Gene', (57, 62))	('ANKRD20A3', 'Gene', '441425', (78, 87))	('LOC402117', 'Var', (92, 101))	('SCC', 'Gene', (180, 183))	('SCC', 'Gene', (166, 169))	('API5', 'Gene', (72, 76))	('ANKRD20A3', 'Gene', (78, 87))	('SCC', 'Gene', '6317', (166, 169))	('SCC', 'Gene', '6317', (180, 183))	('ABHD12', 'Gene', '26090', (64, 70))	('differentially', 'Reg', (128, 142))
436452	28204826	Abnormal regulation or functioning in cytoskeletal components is often a cause of many diseases including cancers.	('Abnormal regulation', 'Var', (0, 19))	('functioning', 'MPA', (23, 34))	('cancers', 'Phenotype', 'HP:0002664', (106, 113))	('cancers', 'Disease', (106, 113))	('cancers', 'Disease', 'MESH:D009369', (106, 113))	('cause', 'Reg', (73, 78))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
436469	27158780	Lung ADCs lacking receptor tyrosine kinase/Ras/Raf alterations revealed mutations in SOS1, VAV1, RASA1, and ARHGAP35.	('mutations', 'Var', (72, 81))	('RASA1', 'Gene', '5921', (97, 102))	('ARHGAP35', 'Gene', (108, 116))	('Raf', 'Gene', '22882', (47, 50))	('RASA1', 'Gene', (97, 102))	('Raf', 'Gene', (47, 50))	('receptor tyrosine kinase', 'Gene', (18, 42))	('receptor tyrosine kinase', 'Gene', '5979', (18, 42))	('SOS1', 'Gene', (85, 89))	('VAV1', 'Gene', '7409', (91, 95))	('ARHGAP35', 'Gene', '2909', (108, 116))	('SOS1', 'Gene', '6654', (85, 89))	('VAV1', 'Gene', (91, 95))
436475	27158780	Molecularly targeted therapies directed against receptor tyrosine kinases (RTKs) lead to dramatic responses in subsets of patients with lung ADCs harboring activating genomic alterations in the corresponding kinase genes, including EGFR, ALK, and ROS1.	('ROS1', 'Gene', (247, 251))	('receptor tyrosine kinase', 'Gene', (48, 72))	('ALK', 'Gene', '238', (238, 241))	('receptor tyrosine kinase', 'Gene', '5979', (48, 72))	('ROS1', 'Gene', '6098', (247, 251))	('RTK', 'Gene', '5979', (75, 78))	('RTK', 'Gene', (75, 78))	('patients', 'Species', '9606', (122, 130))	('lung ADCs', 'Disease', (136, 145))	('EGFR', 'Gene', '1956', (232, 236))	('EGFR', 'Gene', (232, 236))	('ALK', 'Gene', (238, 241))	('alterations', 'Var', (175, 186))
436478	27158780	Identifying novel cancer genes can be challenging due to the large number of passenger mutations that can accumulate from prolonged exposure to tobacco carcinogens and from inherent mutagenic processes such as those caused by the aberrant activity of APOBEC cytidine deaminases.	('APOBEC', 'Gene', (251, 257))	('tobacco', 'Species', '4097', (144, 151))	('aberrant activity', 'Var', (230, 247))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('cancer', 'Disease', (18, 24))	('cancer', 'Disease', 'MESH:D009369', (18, 24))
436479	27158780	Profiling larger numbers of samples within a tumor type and combining samples across tumor types can help overcome this problem, by providing the additional statistical power necessary to distinguish important genes mutated at a lower frequency from other genes with passenger mutations.	('tumor', 'Disease', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumor', 'Disease', (45, 50))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('mutated', 'Var', (216, 223))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
436482	27158780	Only 6 genes, TP53, RB1, ARID1A, CDKN2A, PIK3CA, and NF1, were significantly mutated in both tumor types and of these, the frequency of TP53, CDKN2A, and PIK3CA mutation was significantly higher in SqCC tumors (p < 0.01; Fisher's exact test; Figure 1a).	('tumor', 'Disease', (203, 208))	('TP53', 'Gene', (14, 18))	('CDKN2A', 'Gene', '1029', (142, 148))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('higher', 'Reg', (188, 194))	('PIK3CA', 'Gene', '5290', (41, 47))	('TP53', 'Gene', '7157', (136, 140))	('CDKN2A', 'Gene', (33, 39))	('PIK3CA', 'Gene', (154, 160))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumors', 'Phenotype', 'HP:0002664', (203, 209))	('mutation', 'Var', (161, 169))	('ARID1A', 'Gene', (25, 31))	('NF1', 'Gene', '4763', (53, 56))	('RB1', 'Gene', (20, 23))	('TP53', 'Gene', '7157', (14, 18))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('tumors', 'Disease', (203, 209))	('NF1', 'Gene', (53, 56))	('CDKN2A', 'Gene', '1029', (33, 39))	('ARID1A', 'Gene', '8289', (25, 31))	('PIK3CA', 'Gene', (41, 47))	('TP53', 'Gene', (136, 140))	('CDKN2A', 'Gene', (142, 148))	('RB1', 'Gene', '5925', (20, 23))	('tumors', 'Disease', 'MESH:D009369', (203, 209))	('tumor', 'Disease', (93, 98))	('PIK3CA', 'Gene', '5290', (154, 160))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
436490	27158780	Various carcinogenic and cancer-related processes contribute to the mutational patterns observed in tumors.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('tumors', 'Disease', (100, 106))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (25, 31))	('mutational', 'Var', (68, 78))	('cancer', 'Disease', (25, 31))	('carcinogenic', 'Disease', 'MESH:D063646', (8, 20))	('carcinogenic', 'Disease', (8, 20))
436492	27158780	These included a UV-related signature of C>T at TpCpC or CpCpC (COSMIC Signature 7, abbreviated SI7), a smoking-related signature of C>A transversions (SI4), a mismatch repair (MMR) signature of C>T at GpCpG (SI15/SI6), two APOBEC-related signatures of C>G or C>T at TpCpT or TpCpA (SI13 and SI2), and a final signature with a moderate correlation to COSMIC signature 5 (SI5) with putative "molecular clock" properties (Supplementary Fig.	('C>T', 'Var', (41, 44))	('SI15/SI6', 'Disease', 'None', (209, 217))	('SI13 and SI2', 'Disease', 'None', (283, 295))	('SI15/SI6', 'Disease', (209, 217))
436494	27158780	Furthermore, the rate of SI4 mutations per Mb was able to classify tumors into those from never vs. ever smokers substantially better in lung ADCs (AUC=0.87; Supplementary Fig.	('better', 'PosReg', (127, 133))	('tumors', 'Disease', 'MESH:D009369', (67, 73))	('mutations', 'Var', (29, 38))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('lung ADCs', 'Disease', (137, 146))	('SI4', 'Gene', (25, 28))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('tumors', 'Disease', (67, 73))
436496	27158780	Within each tumor, we also derived the fraction of estimated mutations for a signature by dividing the number of estimated mutations for that signature by the sum of estimated mutations from all signatures.	('tumor', 'Disease', (12, 17))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('mutations', 'Var', (61, 70))
436498	27158780	The mutational profiles of three lung SqCCs (~1% of lung SqCCs) exhibited a pattern of UV-related mutations (SI7) commonly observed in melanoma and displayed a significantly higher mutation rate of somatic single nucleotide variants (SSNVs) and somatic dinucleotide polymorphisms (DNPs) compared to the other lung tumors (p < 0.01) but not higher rates of indels (p > 0.05; Figure 2d).	('single nucleotide variants', 'Var', (206, 232))	('melanoma', 'Disease', 'MESH:D008545', (135, 143))	('melanoma', 'Phenotype', 'HP:0002861', (135, 143))	('tumor', 'Phenotype', 'HP:0002664', (314, 319))	('melanoma', 'Disease', (135, 143))	('lung tumors', 'Disease', 'MESH:D008175', (309, 320))	('higher', 'PosReg', (174, 180))	('mutations', 'Var', (98, 107))	('observed', 'Reg', (123, 131))	('dinucleotide', 'Chemical', 'MESH:D015226', (253, 265))	('tumors', 'Phenotype', 'HP:0002664', (314, 320))	('lung tumors', 'Phenotype', 'HP:0100526', (309, 320))	('lung tumors', 'Disease', (309, 320))
436502	27158780	These tumors had significantly higher rates of both SSNVs and short indels (p < 0.00).	('short indels', 'Var', (62, 74))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('SSNVs', 'Disease', (52, 57))	('tumors', 'Disease', (6, 12))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))
436504	27158780	Comparing the significantly mutated genes to other tumor types from the TCGA Pan-Cancer study revealed that there were several genes significantly mutated exclusively in lung ADC including STK11, RBM10, KEAP1, RAF1, RIT1, and MET (MutSig2CV q-value < 0.1; Figure 3a; Supplementary Table 5).	('KEAP1', 'Gene', '9817', (203, 208))	('Cancer', 'Phenotype', 'HP:0002664', (81, 87))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('Pan-Cancer', 'Disease', (77, 87))	('RBM10', 'Gene', (196, 201))	('STK11', 'Gene', (189, 194))	('tumor', 'Disease', (51, 56))	('KEAP1', 'Gene', (203, 208))	('RIT1', 'Gene', '6016', (216, 220))	('RIT1', 'Gene', (216, 220))	('RAF1', 'Gene', (210, 214))	('RAF1', 'Gene', '5894', (210, 214))	('STK11', 'Gene', '6794', (189, 194))	('Pan-Cancer', 'Disease', 'MESH:C537931', (77, 87))	('lung ADC', 'Disease', (170, 178))	('mutated', 'Var', (147, 154))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('RBM10', 'Gene', '8241', (196, 201))
436505	27158780	NFE2L2, KDM6A, RASA1, NOTCH1, and HRAS were significantly mutated in lung SqCC but not in other cancer types (excluding HNSC and BLCA) (Figure 3b; Supplementary Table 6).	('KDM6A', 'Gene', '7403', (8, 13))	('NOTCH1', 'Gene', '4851', (22, 28))	('HRAS', 'Gene', (34, 38))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('NOTCH1', 'Gene', (22, 28))	('RASA1', 'Gene', '5921', (15, 20))	('NFE2L2', 'Gene', '4780', (0, 6))	('cancer', 'Disease', (96, 102))	('RASA1', 'Gene', (15, 20))	('lung SqCC', 'Disease', (69, 78))	('NFE2L2', 'Gene', (0, 6))	('KDM6A', 'Gene', (8, 13))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('HRAS', 'Gene', '3265', (34, 38))	('mutated', 'Var', (58, 65))
436506	27158780	Genes that reached modest statistical significance in lung ADC that have been observed previously in lung cancer or in other tumor types include AKT1 with a recurrent mutation at p.E17K, CDK4 with a recurrent mutation at p.R24L, and DNMT3A (p < 0.005; Supplementary Table 5).	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('CDK4', 'Gene', (187, 191))	('p.E17K', 'Var', (179, 185))	('lung cancer', 'Disease', (101, 112))	('lung cancer', 'Disease', 'MESH:D008175', (101, 112))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('CDK4', 'Gene', '1019', (187, 191))	('p.E17K', 'Mutation', 'rs121434592', (179, 185))	('DNMT3A', 'Gene', (233, 239))	('DNMT3A', 'Gene', '1788', (233, 239))	('AKT1', 'Gene', '207', (145, 149))	('tumor', 'Disease', (125, 130))	('p.R24L', 'Mutation', 'rs104894340', (221, 227))	('lung cancer', 'Phenotype', 'HP:0100526', (101, 112))	('AKT1', 'Gene', (145, 149))	('lung ADC', 'Disease', (54, 62))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
436507	27158780	Novel significantly mutated genes exclusive to lung ADC and which are absent in other tumor types include PPP3CA, which is the catalytic subunit for the calcium-dependent phosphatase, calcineurin.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('lung ADC', 'Disease', (47, 55))	('tumor', 'Disease', (86, 91))	('PPP3CA', 'Gene', '5530', (106, 112))	('PPP3CA', 'Gene', (106, 112))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('mutated', 'Var', (20, 27))
436508	27158780	The mutations in PPP3CA clustered in the autoinhibitory domain near the C-terminus suggesting they may be gain-of-fuction alterations (Figure 4a).	('mutations', 'Var', (4, 13))	('PPP3CA', 'Gene', '5530', (17, 23))	('PPP3CA', 'Gene', (17, 23))	('gain-of-fuction', 'PosReg', (106, 121))
436509	27158780	In addition, mutations in the autoinhibitory domain also tended to co-occur with activating KRAS mutations (p = 0.033) suggesting a potential relationship between K-Ras and calcineurin signaling pathways.	('mutations', 'Var', (97, 106))	('relationship', 'Interaction', (142, 154))	('KRAS', 'Gene', (92, 96))	('KRAS', 'Gene', '3845', (92, 96))	('mutations', 'Var', (13, 22))	('K-Ras', 'Gene', '3845', (163, 168))	('activating', 'PosReg', (81, 91))	('K-Ras', 'Gene', (163, 168))
436510	27158780	Significantly mutated methyltransferase genes included MLL3 (KMT2C) and SETD2.	('MLL3', 'Gene', '58508', (55, 59))	('mutated', 'Var', (14, 21))	('KMT2C', 'Gene', (61, 66))	('methyltransferase', 'Enzyme', (22, 39))	('KMT2C', 'Gene', '58508', (61, 66))	('MLL3', 'Gene', (55, 59))	('SETD2', 'Gene', '29072', (72, 77))	('SETD2', 'Gene', (72, 77))
436511	27158780	A novel gene in this class was the H3K79 methyltransferase DOT1L, which was mutated in 3% of lung adenocarcinomas with enrichment for truncating mutations (Figure 4a).	('lung adenocarcinomas', 'Disease', (93, 113))	('carcinomas', 'Phenotype', 'HP:0030731', (103, 113))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (93, 113))	('H3K79 methyltransferase', 'Enzyme', (35, 58))	('mutated', 'Var', (76, 83))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (93, 113))	('DOT1L', 'Gene', (59, 64))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('DOT1L', 'Gene', '84444', (59, 64))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (93, 112))
436512	27158780	Recurrent mutations in lung adenocarcinoma have been previously reported in splicing factors such as U2AF1 and loss of function mutations in the RNA binding protein RBM108.	('U2AF1', 'Gene', '7307', (101, 106))	('mutations', 'Var', (128, 137))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (23, 42))	('RBM10', 'Gene', '8241', (165, 170))	('carcinoma', 'Phenotype', 'HP:0030731', (33, 42))	('U2AF1', 'Gene', (101, 106))	('lung adenocarcinoma', 'Disease', (23, 42))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (23, 42))	('loss of function', 'NegReg', (111, 127))	('mutations', 'Var', (10, 19))	('RBM10', 'Gene', (165, 170))
436513	27158780	In the current dataset, a cap methyltransferase, FTSJD1 (also known as CMTR2), was significantly mutated and enriched for frame shift mutations (Figure 4a).	('FTSJD1', 'Gene', (49, 55))	('CMTR2', 'Gene', (71, 76))	('mutated', 'Var', (97, 104))	('CMTR2', 'Gene', '55783', (71, 76))	('FTSJD1', 'Gene', '55783', (49, 55))	('frame shift mutations', 'Var', (122, 143))
436514	27158780	We also examined genes for other known proteins in this class and found recurrent mutations in SF3B1 and SNRPD3 (Supplementary Fig.	('SF3B1', 'Gene', (95, 100))	('SF3B1', 'Gene', '23451', (95, 100))	('mutations', 'Var', (82, 91))	('SNRPD3', 'Gene', (105, 111))	('SNRPD3', 'Gene', '6634', (105, 111))
436515	27158780	EGFR mutations were enriched in females, and SMARCA4 mutations were enriched in males (FDR q-value < 0.1; Supplementary Table 8).	('EGFR', 'Gene', (0, 4))	('SMARCA4', 'Gene', (45, 52))	('SMARCA4', 'Gene', '6597', (45, 52))	('mutations', 'Var', (5, 14))	('mutations', 'Var', (53, 62))	('EGFR', 'Gene', '1956', (0, 4))
436516	27158780	RBM10 mutations were modestly enriched in males as previously reported (q-value = 0.219).	('RBM10', 'Gene', (0, 5))	('mutations', 'Var', (6, 15))	('RBM10', 'Gene', '8241', (0, 5))
436517	27158780	Novel significantly mutated genes in lung SqCC that were enriched for frame shift mutations (p < 0.001) included RASA1, whose protein product is p120GAP (Figure 4b).	('p120GAP', 'Gene', '5921', (145, 152))	('frame shift mutations', 'Var', (70, 91))	('mutated', 'Reg', (20, 27))	('p120GAP', 'Gene', (145, 152))	('lung SqCC', 'Gene', (37, 46))	('RASA1', 'Gene', '5921', (113, 118))	('RASA1', 'Gene', (113, 118))
436519	27158780	RB1 mutations were enriched in females, whereas PASK mutations were exclusive to males (FDR q-value < 0.1; Supplementary Table 9).	('RB1', 'Gene', '5925', (0, 3))	('mutations', 'Var', (4, 13))	('RB1', 'Gene', (0, 3))	('PASK', 'Gene', (48, 52))	('PASK', 'Gene', '23178', (48, 52))
436526	27158780	KLF5, a transcription factor critical for lung development contained a novel recurrent mutation in the zinc finger domain, which was observed in both ADCs and SqCCs (Figure 4c).	('mutation in the', 'Var', (87, 102))	('KLF5', 'Gene', (0, 4))	('KLF5', 'Gene', '688', (0, 4))
436527	27158780	A regulator of KLF5, the E3 ubiquitin ligase FBXW7, was also significantly mutated in the lung SqCC and Pan-Lung cohorts but did not co-occur with KLF5 mutations.	('KLF5', 'Gene', (147, 151))	('KLF5', 'Gene', '688', (147, 151))	('mutated', 'Var', (75, 82))	('FBXW7', 'Gene', '55294', (45, 50))	('KLF5', 'Gene', (15, 19))	('KLF5', 'Gene', '688', (15, 19))	('FBXW7', 'Gene', (45, 50))	('E3 ubiquitin ligase', 'Enzyme', (25, 44))
436528	27158780	A super-enhancer duplication associated with increased KLF5 expression has also been recently reported in HNSC by our group.	('expression', 'MPA', (60, 70))	('increased', 'PosReg', (45, 54))	('KLF5', 'Gene', (55, 59))	('duplication', 'Var', (17, 28))	('KLF5', 'Gene', '688', (55, 59))	('HNSC', 'Disease', (106, 110))
436536	27158780	Expression of MIR205 has been used to distinguish lung squamous cell carcinomas from other NSCLC types suggesting that amplification of this microRNA may represent a lineage specific alteration similar to that of SOX2 amplification.	('SOX2', 'Gene', (213, 217))	('NSCLC', 'Disease', 'MESH:D002289', (91, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))	('carcinomas', 'Phenotype', 'HP:0030731', (69, 79))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (55, 78))	('MIR205', 'Gene', '406988', (14, 20))	('lung squamous cell carcinomas', 'Disease', (50, 79))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (50, 78))	('MIR205', 'Gene', (14, 20))	('amplification', 'Var', (119, 132))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (55, 79))	('NSCLC', 'Disease', (91, 96))	('lung squamous cell carcinomas', 'Disease', 'MESH:D002294', (50, 79))	('SOX2', 'Gene', '6657', (213, 217))
436539	27158780	Novel lung SqCC focal deletions observed in other tumor types included ZMYND11, CREBBP, ROBO1, USP22, and KDM6A (Supplementary Fig.	('KDM6A', 'Gene', (106, 111))	('ROBO1', 'Gene', '6091', (88, 93))	('USP22', 'Gene', '23326', (95, 100))	('ROBO1', 'Gene', (88, 93))	('deletions', 'Var', (22, 31))	('USP22', 'Gene', (95, 100))	('KDM6A', 'Gene', '7403', (106, 111))	('CREBBP', 'Gene', '1387', (80, 86))	('ZMYND11', 'Gene', '10771', (71, 78))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('ZMYND11', 'Gene', (71, 78))	('lung SqCC focal', 'Gene', (6, 21))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Disease', (50, 55))	('CREBBP', 'Gene', (80, 86))
436540	27158780	B2M (Beta2-microglobulin), a component of the MHC complex, was focally deleted in both tumor types, enriched for loss-of-function mutations in both tumor types (p < 0.01), and was significantly mutated in the Pan-Lung analysis (FDR q-value = 0.006).	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Disease', (148, 153))	('tumor', 'Disease', (87, 92))	('MHC', 'Gene', (46, 49))	('B2M', 'Gene', (0, 3))	('B2M', 'Gene', '567', (0, 3))	('deleted', 'NegReg', (71, 78))	('MHC', 'Gene', '3107', (46, 49))	('Beta2-microglobulin', 'Gene', (5, 24))	('mutations', 'Var', (130, 139))	('Beta2-microglobulin', 'Gene', '567', (5, 24))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('loss-of-function', 'NegReg', (113, 129))	('tumor', 'Disease', 'MESH:D009369', (148, 153))
436541	27158780	Combined Pan-Lung copy number analysis revealed another focal deletion peak around TRAF3 (Supplementary Table 20), which was also reported in HNSC.	('TRAF3', 'Gene', '7187', (83, 88))	('deletion', 'Var', (62, 70))	('TRAF3', 'Gene', (83, 88))
436544	27158780	These alterations are of particular interest because of the dramatic responses that have been observed in response to RTK inhibitors in clinical trials such as those for lung ADC patients harboring EGFR mutation or ALK or ROS1 translocations.	('ALK', 'Gene', (215, 218))	('ROS1', 'Gene', '6098', (222, 226))	('RTK', 'Gene', (118, 121))	('ALK', 'Gene', '238', (215, 218))	('EGFR', 'Gene', '1956', (198, 202))	('mutation', 'Var', (203, 211))	('patients', 'Species', '9606', (179, 187))	('RTK', 'Gene', '5979', (118, 121))	('EGFR', 'Gene', (198, 202))	('lung ADC', 'Disease', (170, 178))	('ROS1', 'Gene', (222, 226))
436545	27158780	Novel alterations in known pathway genes included a recurrent in-frame-insertion in MAP2K1 and a fusion of MET with its neighboring gene, CAPZA2 (Figure 6; Supplementary Table 21).	('fusion', 'Interaction', (97, 103))	('in-frame-insertion', 'Var', (62, 80))	('CAPZA2', 'Gene', '830', (138, 144))	('CAPZA2', 'Gene', (138, 144))	('MAP2K1', 'Gene', (84, 90))	('MAP2K1', 'Gene', '5604', (84, 90))
436546	27158780	Previously reported TRIM24-NTRK2 and KIF5B-MET fusions were observed in tumors without other known activating alterations.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('NTRK2', 'Gene', '4915', (27, 32))	('KIF5B', 'Gene', '3799', (37, 42))	('observed', 'Reg', (60, 68))	('tumors', 'Disease', (72, 78))	('TRIM24', 'Gene', '8805', (20, 26))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('fusions', 'Var', (47, 54))	('NTRK2', 'Gene', (27, 32))	('TRIM24', 'Gene', (20, 26))	('KIF5B', 'Gene', (37, 42))
436548	27158780	As observed previously, high MET and ERBB2 amplifications were enriched in tumors without other known activating alterations in this pathway (p < 0.01; Supplementary Fig.	('amplifications', 'Var', (43, 57))	('ERBB2', 'Gene', (37, 42))	('MET', 'Gene', (29, 32))	('ERBB2', 'Gene', '2064', (37, 42))	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumors', 'Disease', (75, 81))
436550	27158780	By manual review, we found additional canonical mutations in KRAS, EGFR, or ERBB2 in 17 tumors and complex indels in EGFR or MET in 11 tumors, some of which have been previously reported (Supplementary Table 22).	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('ERBB2', 'Gene', '2064', (76, 81))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('EGFR', 'Gene', '1956', (117, 121))	('EGFR', 'Gene', (117, 121))	('MET', 'Gene', (125, 128))	('tumors', 'Disease', (135, 141))	('tumors', 'Disease', 'MESH:D009369', (135, 141))	('KRAS', 'Gene', (61, 65))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))	('EGFR', 'Gene', '1956', (67, 71))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('EGFR', 'Gene', (67, 71))	('tumors', 'Disease', (88, 94))	('ERBB2', 'Gene', (76, 81))	('mutations', 'Var', (48, 57))	('KRAS', 'Gene', '3845', (61, 65))
436551	27158780	Lung ADCs that had an activating SSNV, indel, amplification or gene fusion in a known RTK/Ras/Raf driver were designated "oncogene positive" (n=418) while the remaining lung ADCs were considered "oncogene negative" (n=242).	('RTK', 'Gene', (86, 89))	('amplification', 'Var', (46, 59))	('Raf', 'Gene', '22882', (94, 97))	('gene fusion', 'Var', (63, 74))	('RTK', 'Gene', '5979', (86, 89))	('indel', 'Var', (39, 44))	('Raf', 'Gene', (94, 97))	('activating', 'PosReg', (22, 32))
436555	27158780	Recurrent p.N233Y mutations were observed in the autoinhibitory domain (DH) of SOS1 in 4 lung ADCs and the mutation p.D309Y in the same region has been reported in Noonan syndrome (Supplementary Fig.	('p.N233Y', 'Var', (10, 17))	('SOS1', 'Gene', '6654', (79, 83))	('Noonan syndrome', 'Disease', (164, 179))	('p.N233Y', 'Mutation', 'rs1057519963', (10, 17))	('p.D309Y', 'Var', (116, 123))	('p.D309Y', 'Mutation', 'rs397517180', (116, 123))	('Noonan syndrome', 'Disease', 'MESH:D009634', (164, 179))	('SOS1', 'Gene', (79, 83))
436557	27158780	The p.S67Y mutation is located near the interface of the CH, Ac and PH domains and mutagenesis at this site has been shown to increase overall GEF activity (Supplementary Fig.	('mutagenesis', 'Var', (83, 94))	('increase', 'PosReg', (126, 134))	('p.S67Y', 'Mutation', 'p.S67Y', (4, 10))	('GEF', 'Gene', '6654', (143, 146))	('p.S67Y', 'Var', (4, 10))	('GEF', 'Gene', (143, 146))
436562	27158780	Novel co-occurrences included MET amplifications and NF1 mutations (p = 0.019; Supplementary Figure 16).	('NF1', 'Gene', (53, 56))	('mutations', 'Var', (57, 66))	('NF1', 'Gene', '4763', (53, 56))	('MET amplifications', 'Var', (30, 48))
436563	27158780	Additionally, high EGFR amplification significantly overlapped with activating EGFR mutations (p = 1.9 x 10-8) and STK11 mutations significantly overlapped with activating KRAS mutations (p = 1.1 x 10-6; Figure 7c).	('KRAS', 'Gene', (172, 176))	('KRAS', 'Gene', '3845', (172, 176))	('mutations', 'Var', (121, 130))	('EGFR', 'Gene', '1956', (79, 83))	('EGFR', 'Gene', (79, 83))	('EGFR', 'Gene', '1956', (19, 23))	('mutations', 'Var', (84, 93))	('STK11', 'Gene', (115, 120))	('EGFR', 'Gene', (19, 23))	('STK11', 'Gene', '6794', (115, 120))
436564	27158780	Furthermore, 28 lung ADCs that remain oncogene-negative for the RTK/Ras/Raf pathway harbor STK11 mutations (Figure 7c), suggesting the possibility of an additional hitherto-unrecognized KRAS-related genome alteration complementary to STK11 mutation in these cancer samples.	('mutations', 'Var', (97, 106))	('STK11', 'Gene', (91, 96))	('RTK', 'Gene', '5979', (64, 67))	('cancer', 'Phenotype', 'HP:0002664', (258, 264))	('KRAS', 'Gene', (186, 190))	('STK11', 'Gene', (234, 239))	('STK11', 'Gene', '6794', (91, 96))	('Raf', 'Gene', '22882', (72, 75))	('cancer', 'Disease', 'MESH:D009369', (258, 264))	('KRAS', 'Gene', '3845', (186, 190))	('RTK', 'Gene', (64, 67))	('STK11', 'Gene', '6794', (234, 239))	('cancer', 'Disease', (258, 264))	('Raf', 'Gene', (72, 75))
436568	27158780	Mutations predicted to be neoepitopes in at least 4 tumors included PIK3CA p.E542K, NFE2L2 p.E79Q, BRAF p.G466V, and EGFR p.G719A and several mutations in TP53, including p.V157F, p.G154V, p.R175G, and p.P278A (Figure 8c).	('p.E79Q', 'Var', (91, 97))	('p.G719A', 'Mutation', 'rs121913428', (122, 129))	('p.G719A', 'Var', (122, 129))	('NFE2L2', 'Gene', (84, 90))	('PIK3CA', 'Gene', (68, 74))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('p.V157F', 'Var', (171, 178))	('EGFR', 'Gene', '1956', (117, 121))	('p.E79Q', 'Mutation', 'rs1057519922', (91, 97))	('TP53', 'Gene', (155, 159))	('p.R175G', 'Mutation', 'rs138729528', (189, 196))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('p.G466V', 'Mutation', 'rs121913351', (104, 111))	('p.P278A', 'Mutation', 'rs17849781', (202, 209))	('tumors', 'Disease', (52, 58))	('p.P278A', 'Var', (202, 209))	('p.E542K', 'Mutation', 'rs121913273', (75, 82))	('p.V157F', 'Mutation', 'rs121912654', (171, 178))	('p.G154V', 'Var', (180, 187))	('TP53', 'Gene', '7157', (155, 159))	('EGFR', 'Gene', (117, 121))	('p.G154V', 'Mutation', 'rs762846821', (180, 187))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('BRAF', 'Gene', (99, 103))	('BRAF', 'Gene', '673', (99, 103))	('p.E542K', 'Var', (75, 82))	('PIK3CA', 'Gene', '5290', (68, 74))	('p.R175G', 'Var', (189, 196))	('NFE2L2', 'Gene', '4780', (84, 90))	('p.G466V', 'Var', (104, 111))
436569	27158780	A gene not previously implicated in lung cancer, C3orf59 (also known as MB21D2), contained a recurrent mutation at p.Q311E with predicted neoepitope properties (Figure 8c).	('p.Q311E', 'Var', (115, 122))	('lung cancer', 'Disease', (36, 47))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('MB21D2', 'Gene', (72, 78))	('p.Q311E', 'Mutation', 'rs988241015', (115, 122))	('lung cancer', 'Disease', 'MESH:D008175', (36, 47))	('neoepitope properties', 'MPA', (138, 159))	('C3orf59', 'Gene', '151963', (49, 56))	('MB21D2', 'Gene', '151963', (72, 78))	('lung cancer', 'Phenotype', 'HP:0100526', (36, 47))	('C3orf59', 'Gene', (49, 56))
436579	27158780	Our study has uncovered multiple significantly mutated genes in the RTK/Ras/Raf pathway, including newly identified genes such as RASA1, SOS1, and VAV1.	('VAV1', 'Gene', (147, 151))	('RTK', 'Gene', '5979', (68, 71))	('SOS1', 'Gene', (137, 141))	('Raf', 'Gene', '22882', (76, 79))	('SOS1', 'Gene', '6654', (137, 141))	('RASA1', 'Gene', '5921', (130, 135))	('mutated', 'Var', (47, 54))	('RTK', 'Gene', (68, 71))	('RASA1', 'Gene', (130, 135))	('VAV1', 'Gene', '7409', (147, 151))	('Raf', 'Gene', (76, 79))
436580	27158780	Previous studies examining smaller numbers of lung tumors were not able to detect recurrent mutations in SOS1.	('lung tumors', 'Phenotype', 'HP:0100526', (46, 57))	('lung tumors', 'Disease', (46, 57))	('SOS1', 'Gene', (105, 109))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('mutations', 'Var', (92, 101))	('SOS1', 'Gene', '6654', (105, 109))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('lung tumors', 'Disease', 'MESH:D008175', (46, 57))
436581	27158780	Since we did not have matching RNA-seq data for every tumor, we may be underestimating the rates of oncogenic fusions or MET exon 14 skipping events.	('tumor', 'Disease', (54, 59))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('MET exon 14', 'Var', (121, 132))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))
436582	27158780	As 15% to 25% of lung ADCs still do not contain a known detectable alteration in the RTK/Ras/Raf pathway, we may yet be underpowered to find additional rare recurrent mutations in known and novel pathway members.	('Raf', 'Gene', '22882', (93, 96))	('mutations', 'Var', (167, 176))	('RTK', 'Gene', (85, 88))	('Raf', 'Gene', (93, 96))	('lung ADCs', 'Disease', (17, 26))	('RTK', 'Gene', '5979', (85, 88))
436583	27158780	For example, we identified new epigenetic modifier mutations in CREBBP and EP300, previously shown in small cell lung cancer.	('EP300', 'Gene', (75, 80))	('EP300', 'Gene', '2033', (75, 80))	('lung cancer', 'Phenotype', 'HP:0100526', (113, 124))	('CREBBP', 'Gene', (64, 70))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (102, 124))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('small cell lung cancer', 'Disease', 'MESH:D055752', (102, 124))	('CREBBP', 'Gene', '1387', (64, 70))	('epigenetic modifier mutations', 'Var', (31, 60))	('small cell lung cancer', 'Disease', (102, 124))
436590	27158780	Somatic single nucleotide variants (SSNVs) and indels were called using MuTect and Indelocator (www.broadinstitute.org/cancer/cga/indelocator), respectively.	('cga', 'Gene', (126, 129))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('cancer', 'Disease', (119, 125))	('single nucleotide', 'Var', (8, 25))	('cga', 'Gene', '1113', (126, 129))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
436592	27158780	Significantly mutated genes were identified using MutSig2CV which combines p-values from tests for high mutational frequency relative to the background mutation rate (pCV), clustering of mutations within the gene (pCL), and enrichment of mutations within evolutionarily conserved sites (pFN).	('mutations', 'Var', (187, 196))	('pCL', 'Gene', '5252', (214, 217))	('pCV', 'Species', '28355', (167, 170))	('pCL', 'Gene', (214, 217))
436593	27158780	For 660 lung adenocarcinomas, we had 100% power to detect genes mutated in 10% of patients and 73% power for genes mutated in 5% of patients assuming a mutation rate of 8.7/Mb.	('lung adenocarcinomas', 'Disease', (8, 28))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (8, 27))	('carcinoma', 'Phenotype', 'HP:0030731', (18, 27))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (8, 28))	('patients', 'Species', '9606', (82, 90))	('carcinomas', 'Phenotype', 'HP:0030731', (18, 28))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (8, 28))	('mutated', 'Var', (64, 71))	('patients', 'Species', '9606', (132, 140))
436594	27158780	For 484 lung squamous cell carcinomas, we had 100% power to detect genes mutated in 10% of patients and 41% power for genes mutated in 5% of patients assuming a mutation rate of 9.7/Mb.	('carcinoma', 'Phenotype', 'HP:0030731', (27, 36))	('patients', 'Species', '9606', (91, 99))	('mutated', 'Var', (73, 80))	('lung squamous cell carcinomas', 'Disease', (8, 37))	('carcinomas', 'Phenotype', 'HP:0030731', (27, 37))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (13, 37))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (8, 36))	('lung squamous cell carcinomas', 'Disease', 'MESH:D002294', (8, 37))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (13, 36))	('patients', 'Species', '9606', (141, 149))
436597	27158780	One gene, TRERF1, was excluded from the final results as closer inspection of its mutations revealed a recurrent frameshift deletion that was likely a false positive as all of these mutations had low allelic fractions (<1.5%) and had no supporting reads in matching RNA-seq data.	('TRERF1', 'Gene', '55809', (10, 16))	('TRERF1', 'Gene', (10, 16))	('frameshift deletion', 'Var', (113, 132))
436604	27158780	Transcript annotations used for this analysis included ENST00000397752 for MET, ENST00000361183 for CAPZA2, ENST00000302418 for KIF5B, ENST00000323115 for NTRK2, ENST00000343526 for TRIM24, and ENST00000354600 for TP63.	('CAPZA2', 'Gene', '830', (100, 106))	('KIF5B', 'Gene', '3799', (128, 133))	('CAPZA2', 'Gene', (100, 106))	('TP63', 'Gene', '8626', (214, 218))	('ENST00000343526', 'Var', (162, 177))	('NTRK2', 'Gene', '4915', (155, 160))	('TP63', 'Gene', (214, 218))	('KIF5B', 'Gene', (128, 133))	('ENST00000354600', 'Var', (194, 209))	('ENST00000397752', 'Var', (55, 70))	('ENST00000323115', 'Var', (135, 150))	('TRIM24', 'Gene', '8805', (182, 188))	('ENST00000302418', 'Var', (108, 123))	('TRIM24', 'Gene', (182, 188))	('ENST00000361183', 'Var', (80, 95))	('NTRK2', 'Gene', (155, 160))
436609	27158780	Separate lists were made consisting of wildtype and mutant peptides of length 8, 9, 10 and 11 amino acids since these are the possible peptide lengths known to be presented by human MHC class I molecules.	('MHC', 'Gene', (182, 185))	('human', 'Species', '9606', (176, 181))	('MHC', 'Gene', '3107', (182, 185))	('mutant', 'Var', (52, 58))
436612	27158780	Peptide pairs were further considered if the mutant peptide displayed a processing score >=0.7, a median affinity value >=0.01, a neoepitope ratio >=1, and the mRNA transcript of the gene was expressed in the RNA-seq data for that tumor (top 15,000 expressed genes within each tumor).	('tumor', 'Disease', 'MESH:D009369', (231, 236))	('mutant', 'Var', (45, 51))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('tumor', 'Disease', 'MESH:D009369', (277, 282))	('neoepitope ratio', 'MPA', (130, 146))	('tumor', 'Disease', (231, 236))	('tumor', 'Phenotype', 'HP:0002664', (277, 282))	('tumor', 'Disease', (277, 282))
436637	32509772	Inhibiting coinhibitory checkpoints using ICBT has been regarded as a promising method for controlling tumors, and many studies have demonstrated its efficacy.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('Inhibiting', 'Var', (0, 10))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('tumors', 'Disease', 'MESH:D009369', (103, 109))	('tumors', 'Disease', (103, 109))
436647	32509772	Specifically, 101 and 72 pairs of normal and matched cancer samples were obtained from GSE40435 and GSE53757, respectively.	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('GSE53757', 'Var', (100, 108))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('GSE40435', 'Var', (87, 95))
436678	32509772	Patients with high HHLA2 expression had a significantly longer survival time than those patients with low expression.	('patients', 'Species', '9606', (88, 96))	('survival time', 'CPA', (63, 76))	('HHLA2', 'Gene', '11148', (19, 24))	('high', 'Var', (14, 18))	('longer', 'PosReg', (56, 62))	('Patients', 'Species', '9606', (0, 8))	('HHLA2', 'Gene', (19, 24))
436690	32509772	Copy number alterations (CNAs) are an important mechanism of oncogene activation in cancer.	('Copy number alterations', 'Var', (0, 23))	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('cancer', 'Disease', (84, 90))
436694	32509772	The proportion of single copy deletions showed the opposite trend, with 41.4 and 11.4% in the HHLA2-low and high groups, respectively (Figures 3A,B).	('HHLA2', 'Gene', (94, 99))	('HHLA2', 'Gene', '11148', (94, 99))	('single copy deletions', 'Var', (18, 39))
436696	32509772	Only seven CpG sites had associated data; among them, five CpG sites, including cg02059214, cg02124498, cg08817540, cg10431989, and cg11326415, showed a negative correlation with HHLA2 expression; the other two sites were positively correlated with HHLA2 (Figure 3C).	('HHLA2', 'Gene', (249, 254))	('expression', 'MPA', (185, 195))	('HHLA2', 'Gene', '11148', (249, 254))	('HHLA2', 'Gene', (179, 184))	('cg02124498', 'Var', (92, 102))	('HHLA2', 'Gene', '11148', (179, 184))	('cg10431989', 'Var', (116, 126))	('cg11326415', 'Var', (132, 142))	('cg08817540', 'Var', (104, 114))	('negative', 'NegReg', (153, 161))	('cg02059214', 'Var', (80, 90))
436757	32509772	Patients with high HHLA2 showed longer survival rates, contradicting previous studies.	('longer', 'PosReg', (32, 38))	('survival rates', 'CPA', (39, 53))	('HHLA2', 'Gene', '11148', (19, 24))	('high', 'Var', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('HHLA2', 'Gene', (19, 24))
436776	32509772	Taking these findings into consideration, immunotherapy based on HHLA2 expression may further improve the prognosis of patients with high HHLA2 expression.	('high', 'Var', (133, 137))	('patients', 'Species', '9606', (119, 127))	('HHLA2', 'Gene', (65, 70))	('HHLA2', 'Gene', (138, 143))	('improve', 'PosReg', (94, 101))	('HHLA2', 'Gene', '11148', (65, 70))	('HHLA2', 'Gene', '11148', (138, 143))
436793	29312626	Furthermore, these miRNAs may contribute to tumor progression primarily through inhibiting the expression of some key downstream target genes.	('miRNAs', 'Var', (19, 25))	('contribute', 'Reg', (30, 40))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('inhibiting', 'NegReg', (80, 90))	('tumor', 'Disease', (44, 49))	('expression', 'MPA', (95, 105))
436799	29312626	Some progress in this area has been made, for example, epigenetic silencing of the tumor suppressor miR-124a confers a poor prognosis in acute lymphoblastic leukemia by regulating CDK6 expression.	('CDK6', 'Gene', '1021', (180, 184))	('leukemia', 'Phenotype', 'HP:0001909', (157, 165))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('acute lymphoblastic leukemia', 'Disease', (137, 165))	('miR-124a', 'Gene', (100, 108))	('epigenetic silencing', 'Var', (55, 75))	('expression', 'MPA', (185, 195))	('tumor', 'Disease', (83, 88))	('acute lymphoblastic leukemia', 'Disease', 'MESH:D054198', (137, 165))	('miR-124a', 'Gene', '406907', (100, 108))	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (137, 165))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (143, 165))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('CDK6', 'Gene', (180, 184))	('regulating', 'Reg', (169, 179))
436814	29312626	The analysis identified a total of 11 hub miRNAs including miR-20a, miR-221, miR-17, miR-137, miR-21, miR-130b, miR-15b, miR-9, miR-106b, miR-93 and miR-155 shared by at least two cancer types (Figure 2C).	('miR-20a', 'Gene', (59, 66))	('miR-93', 'Gene', '407051', (138, 144))	('miR-21', 'Gene', (94, 100))	('miR-20a', 'Gene', '406982', (59, 66))	('miR-155', 'Gene', (149, 156))	('miR-137', 'Gene', (85, 92))	('miR-137', 'Gene', '406928', (85, 92))	('miR-155', 'Gene', '406947', (149, 156))	('miR-17', 'Gene', '406952', (77, 83))	('cancer', 'Disease', (180, 186))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('miR-221', 'Gene', (68, 75))	('miR-130b', 'Gene', (102, 110))	('miR-130b', 'Gene', '406920', (102, 110))	('miR-106b', 'Gene', '406900', (128, 136))	('miR-21', 'Gene', '406991', (94, 100))	('miR-15b', 'Gene', '406949', (112, 119))	('miR-221', 'Gene', '407006', (68, 75))	('miR-106b', 'Gene', (128, 136))	('miR-17', 'Gene', (77, 83))	('miR-93', 'Gene', (138, 144))	('miR-15b', 'Gene', (112, 119))	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('miR-9', 'Var', (121, 126))
436817	29312626	For example, activation of MFAP3L can promote colorectal cancer cell invasion and metastasis.	('MFAP3L', 'Gene', '9848', (27, 33))	('activation', 'Var', (13, 23))	('colorectal cancer', 'Disease', 'MESH:D015179', (46, 63))	('colorectal cancer', 'Phenotype', 'HP:0003003', (46, 63))	('MFAP3L', 'Gene', (27, 33))	('metastasis', 'CPA', (82, 92))	('colorectal cancer', 'Disease', (46, 63))	('promote', 'PosReg', (38, 45))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))
436846	29312626	Additionally, three additional data sets containing mRNA expression, miRNA expression and clinical information of 60 GBM samples (CGCA), 65 COAD samples (GSE29623) and 32 LUAD samples (GSE63805 and GSE63459) were used to further confirm the clinical benefit of key miRNA-target interactions.	('GSE63805', 'Var', (185, 193))	('COAD', 'Disease', (140, 144))	('interactions', 'Interaction', (278, 290))	('COAD', 'Disease', 'MESH:D029424', (140, 144))	('GSE63459', 'Var', (198, 206))	('GBM', 'Phenotype', 'HP:0012174', (117, 120))	('LUAD', 'Phenotype', 'HP:0030078', (171, 175))
436871	29312626	The miRNATarget allows users to retrieve data on the basis of cancer type, miRNA name, or Entrez gene ID of interest, and a report page gives a quick overview of the prognosis-related key miRNA-target interactions, the associated cancer types and Kaplan-Meier survival curves (Figure 6B).	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('cancer', 'Disease', (230, 236))	('cancer', 'Disease', 'MESH:D009369', (230, 236))	('interactions', 'Var', (201, 213))
436872	29312626	MiRNAs prove to be associated with cancer progression and prognosis by regulating key target genes.	('associated', 'Reg', (19, 29))	('MiRNAs', 'Var', (0, 6))	('regulating', 'Reg', (71, 81))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('cancer', 'Disease', (35, 41))
436890	29312626	More importantly, cancer type-specific key miRNA-target signatures may provide a robust approach towards personalized medicine in cancer prognosis and treatment and reduce the incidence of side effects.	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('cancer', 'Disease', (130, 136))	('reduce', 'NegReg', (165, 171))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('miRNA-target', 'Var', (43, 55))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('cancer', 'Disease', (18, 24))	('cancer', 'Disease', 'MESH:D009369', (18, 24))
436905	29312626	The first group consisted of patients with a high-expressed miRNA regulating its low-expressed target and the second group of patients with a low-expressed miRNA regulating its high-expressed target.	('miRNA', 'Var', (60, 65))	('patients', 'Species', '9606', (29, 37))	('low-expressed target', 'MPA', (81, 101))	('patients', 'Species', '9606', (126, 134))
436908	29312626	Human KEGG pathways from Synapse (syn1741407) which shows the semantic similarity score >0.3 with a hallmark-associated GO term using R package 'GOSemSim', are considered to be associated with hallmarks of cancer.	('Human', 'Species', '9606', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('hallmarks of cancer', 'Disease', (193, 212))	('syn1741407', 'Var', (34, 44))	('associated', 'Reg', (177, 187))	('hallmarks of cancer', 'Disease', 'MESH:D009369', (193, 212))
436910	29312626	To investigate the significance of impact of prognosis-related key miRNA-target interactions on a specific hallmark of cancer, we perturbed the PPI network for 1,000 times by rewiring every edge (keeping the degree distribution of the original network).	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('perturbed', 'Reg', (130, 139))	('cancer', 'Disease', (119, 125))	('rewiring', 'Var', (175, 183))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
436921	25917195	In cancers, the dysregulation of miRNAs has been proven to be involved in oncogenesis (reviewed in), tumor progression, and clinical outcomes, such as patient survival.	('oncogenesis', 'CPA', (74, 85))	('clinical', 'Species', '191496', (124, 132))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('patient', 'Species', '9606', (151, 158))	('cancers', 'Phenotype', 'HP:0002664', (3, 10))	('involved', 'Reg', (62, 70))	('cancers', 'Disease', (3, 10))	('cancers', 'Disease', 'MESH:D009369', (3, 10))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))	('miRNAs', 'Protein', (33, 39))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('dysregulation', 'Var', (16, 29))
436959	33731118	Role of m6A methyltransferase component VIRMA in multiple human cancers (Review) N6-Methyladenosine (m6A) modification is one of the most widely distributed RNA modifications in eukaryotes.	('human', 'Species', '9606', (58, 63))	('cancers', 'Disease', 'MESH:D009369', (64, 71))	('m6A', 'Chemical', '-', (8, 11))	('cancers', 'Phenotype', 'HP:0002664', (64, 71))	('m6A', 'Chemical', '-', (101, 104))	('cancers', 'Disease', (64, 71))	('N6-Methyladenosine', 'Var', (81, 99))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('N6-Methyladenosine', 'Chemical', 'MESH:C010223', (81, 99))
436968	33731118	m6A modification refers to methylation occurring at the sixth position of nitrogen atoms of adenosine at the post-transcriptional level, with S-adenosylmethionine serving as the methyl donor for m6A formation.	('nitrogen', 'Chemical', 'MESH:D009584', (74, 82))	('m6A', 'Chemical', '-', (195, 198))	('m6A', 'Chemical', '-', (0, 3))	('methylation', 'MPA', (27, 38))	('adenosine', 'Chemical', 'MESH:D000241', (92, 101))	('S-adenosylmethionine', 'Chemical', 'MESH:D012436', (142, 162))	('m6A', 'Var', (0, 3))
436969	33731118	m6A modification exists in mammalian mRNAs, long-noncoding RNAs, and microRNAs, and participates in various RNA functions such as mRNA stability, splicing, transport, translation, primary microRNA processing and RNA-protein interactions.	('m6A', 'Chemical', '-', (0, 3))	('transport', 'MPA', (156, 165))	('m6A modification', 'Var', (0, 16))	('mammalian', 'Species', '9606', (27, 36))	('interactions', 'Interaction', (224, 236))	('participates in', 'Reg', (84, 99))	('modification', 'Var', (4, 16))	('translation', 'MPA', (167, 178))	('primary microRNA processing', 'MPA', (180, 207))	('splicing', 'MPA', (146, 154))	('mRNA stability', 'MPA', (130, 144))
436972	33731118	Studies have shown that m6A modification plays a vital role in tissue development, stem cell formation and differentiation, heat shock response control and circadian clock control, particularly during tumor development.	('m6A', 'Gene', (24, 27))	('tissue development', 'CPA', (63, 81))	('m6A', 'Chemical', '-', (24, 27))	('differentiation', 'CPA', (107, 122))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('shock', 'Phenotype', 'HP:0031273', (129, 134))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('stem cell formation', 'CPA', (83, 102))	('modification', 'Var', (28, 40))	('tumor', 'Disease', (201, 206))
436980	33731118	It was reported that in human HeLa cells, VIRMA could recruit the m6A methyltransferase components METTL3/METTL14/WTAP to guide region-selective methylations, suggesting that VIRMA plays a significant role in m6A modification.	('METTL3', 'Gene', (99, 105))	('methylations', 'Var', (145, 157))	('METTL14', 'Gene', '57721', (106, 113))	('human', 'Species', '9606', (24, 29))	('METTL14', 'Gene', (106, 113))	('m6A', 'Chemical', '-', (66, 69))	('WTAP', 'Gene', '9589', (114, 118))	('HeLa', 'CellLine', 'CVCL:0030', (30, 34))	('METTL3', 'Gene', '56339', (99, 105))	('WTAP', 'Gene', (114, 118))	('m6A', 'Chemical', '-', (209, 212))
436983	33731118	Studies have demonstrated that the abnormal expression of RBPs could lead to the upregulation of certain oncogenes or the downregulation of certain tumor suppressor genes.	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('RBP', 'Gene', (58, 61))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('abnormal', 'Var', (35, 43))	('downregulation', 'NegReg', (122, 136))	('tumor', 'Disease', (148, 153))	('oncogenes', 'Gene', (105, 114))	('upregulation', 'PosReg', (81, 93))	('RBP', 'Gene', '27303', (58, 61))
436985	33731118	found that hsa_circ_0084922 (also named circ_KIAA1429), coming from VIRMA, was upregulated in hepatocellular carcinoma (HCC), which may promote cancer progression.	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (94, 118))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (94, 118))	('hsa_circ_0084922', 'Var', (11, 27))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('hepatocellular carcinoma', 'Disease', (94, 118))	('cancer', 'Disease', (144, 150))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('KIAA1429', 'Gene', (45, 53))	('upregulated', 'PosReg', (79, 90))	('HCC', 'Phenotype', 'HP:0001402', (120, 123))	('KIAA1429', 'Gene', '25962', (45, 53))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
436994	33731118	The overall copy number variation (CNV) amplification frequency of VIRMA in cancer was 1.40-78%, with a high frequency in most tumors, such as uveal melanoma (UVM), TGCT, and low frequency in THCA, PCPG (Fig.	('copy number variation', 'Var', (12, 33))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('THCA', 'Phenotype', 'HP:0002890', (192, 196))	('tumors', 'Disease', (127, 133))	('TGCT', 'Disease', (165, 169))	('melanoma', 'Phenotype', 'HP:0002861', (149, 157))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('tumors', 'Disease', 'MESH:D009369', (127, 133))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('UVM', 'Phenotype', 'HP:0007716', (159, 162))	('uveal melanoma', 'Disease', 'MESH:C536494', (143, 157))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('uveal melanoma', 'Phenotype', 'HP:0007716', (143, 157))	('uveal melanoma', 'Disease', (143, 157))
437003	33731118	Knockdown of VIRMA could inhibit cancer cell proliferation and metastasis in vitro.	('cancer', 'Disease', (33, 39))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('Knockdown', 'Var', (0, 9))	('VIRMA', 'Gene', (13, 18))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('inhibit', 'NegReg', (25, 32))
437008	33731118	The knockdown of VIRMA could inhibit gastric cancer cell proliferation by arresting the cell cycle in vivo and in vitro.	('gastric cancer', 'Disease', (37, 51))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('gastric cancer', 'Disease', 'MESH:D013274', (37, 51))	('VIRMA', 'Gene', (17, 22))	('inhibit', 'NegReg', (29, 36))	('arresting', 'NegReg', (74, 83))	('gastric cancer', 'Phenotype', 'HP:0012126', (37, 51))	('cell cycle', 'CPA', (88, 98))	('knockdown', 'Var', (4, 13))
437022	33731118	revealed that knockdown of VIRMA could suppress osteosarcoma cancer cell migration, invasion, and proliferation in vitro, as well as suppress tumor growth in vivo.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('invasion', 'CPA', (84, 92))	('VIRMA', 'Gene', (27, 32))	('osteosarcoma cancer', 'Disease', 'MESH:D009369', (48, 67))	('tumor', 'Disease', (142, 147))	('osteosarcoma', 'Phenotype', 'HP:0002669', (48, 60))	('suppress', 'NegReg', (133, 141))	('suppress', 'NegReg', (39, 47))	('sarcoma', 'Phenotype', 'HP:0100242', (53, 60))	('knockdown', 'Var', (14, 23))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('proliferation', 'CPA', (98, 111))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('osteosarcoma cancer', 'Disease', (48, 67))
437037	33731118	The expression of VIRMA may also be regulated by miR-143-3p in cancer cells.	('VIRMA', 'Gene', (18, 23))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('miR-143-3p', 'Var', (49, 59))	('regulated', 'Reg', (36, 45))	('expression', 'MPA', (4, 14))	('miR-143-3p', 'Chemical', '-', (49, 59))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('cancer', 'Disease', (63, 69))
437038	33731118	In the VIRMA-depleted cell lines, m6A modification around the 3'-UTR and near the stop codon significantly disappeared, indicating that VIRMA can exert its effects by mediating mRNA m6A methylation in 3'UTR and near stop codon region.	('mRNA m6A', 'Var', (177, 185))	('m6A', 'Chemical', '-', (34, 37))	('modification', 'MPA', (38, 50))	('methylation', 'MPA', (186, 197))	('disappeared', 'NegReg', (107, 118))	('m6A', 'Gene', (34, 37))	('m6A', 'Chemical', '-', (182, 185))
437040	33731118	VIRMA promoted cell migration and invasion in liver cancer by increasing the m6A modification of ID2 mRNA, which then led to the decrease in ID2 expression.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('decrease', 'NegReg', (129, 137))	('m6A', 'Var', (77, 80))	('invasion', 'CPA', (34, 42))	('expression', 'MPA', (145, 155))	('promoted', 'PosReg', (6, 14))	('cell migration', 'CPA', (15, 29))	('increasing', 'PosReg', (62, 72))	('m6A', 'Chemical', '-', (77, 80))	('ID2', 'Gene', '3398', (141, 144))	('liver cancer', 'Disease', (46, 58))	('liver cancer', 'Disease', 'MESH:D006528', (46, 58))	('liver cancer', 'Phenotype', 'HP:0002896', (46, 58))	('ID2', 'Gene', '3398', (97, 100))	('ID2', 'Gene', (141, 144))	('ID2', 'Gene', (97, 100))
437043	33731118	VIRMA regulated the migration and invasion of liver cancer by regulating the m6A modification of ID2.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('ID2', 'Gene', '3398', (97, 100))	('m6A', 'Var', (77, 80))	('invasion', 'CPA', (34, 42))	('liver cancer', 'Phenotype', 'HP:0002896', (46, 58))	('liver cancer', 'Disease', 'MESH:D006528', (46, 58))	('m6A', 'Chemical', '-', (77, 80))	('liver cancer', 'Disease', (46, 58))	('migration', 'CPA', (20, 29))	('ID2', 'Gene', (97, 100))
437044	33731118	GATA3 was identified as the direct downstream target of VIRMA-mediated m6A modification in liver cancer through the combination of immunoprecipitation sequencing (RIP-seq), and high-throughput methylated RNA immunoprecipitation sequencing (MeRIP-seq).	('GATA3', 'Gene', '2625', (0, 5))	('modification', 'Var', (75, 87))	('m6A', 'Gene', (71, 74))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('liver cancer', 'Phenotype', 'HP:0002896', (91, 103))	('m6A', 'Chemical', '-', (71, 74))	('GATA3', 'Gene', (0, 5))	('liver cancer', 'Disease', 'MESH:D006528', (91, 103))	('liver cancer', 'Disease', (91, 103))
437050	33731118	VIRMA knockdown could decrease the m6A levels and stability of CCAT1 and CCAT2 lncRNA in prostate cancer.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('prostate cancer', 'Phenotype', 'HP:0012125', (89, 104))	('decrease', 'NegReg', (22, 30))	('m6A', 'Chemical', '-', (35, 38))	('CCAT2', 'Gene', '101805488', (73, 78))	('prostate cancer', 'Disease', (89, 104))	('stability', 'MPA', (50, 59))	('m6A levels', 'MPA', (35, 45))	('CCAT2', 'Gene', (73, 78))	('CCAT1', 'Gene', '100507056', (63, 68))	('prostate cancer', 'Disease', 'MESH:D011471', (89, 104))	('knockdown', 'Var', (6, 15))	('CCAT1', 'Gene', (63, 68))
437053	33731118	hypothesized that stabilization of lncRNAs CCAT1/2 by m6A modification amplified the effect of MYC expression levels in cancer cells by 2 separate mechanisms: (i) directly, both lncRNAs acted as super-enhancers for positive regulation of MYC mRNA; (ii) indirectly, CCAT1/2 actedas microRNA sponges for MYC-targeting microRNAs let-7A and miR-145, respectively.	('CCAT1/2', 'Gene', '100507056;101805488', (265, 272))	('cancer', 'Disease', (120, 126))	('CCAT1/2', 'Gene', '100507056;101805488', (43, 50))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('MYC', 'Gene', (238, 241))	('m6A', 'Gene', (54, 57))	('modification', 'Var', (58, 70))	('MYC', 'Gene', (95, 98))	('CCAT1/2', 'Gene', (265, 272))	('miR-145', 'Gene', '406937', (337, 344))	('MYC', 'Gene', (302, 305))	('effect', 'MPA', (85, 91))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('CCAT1/2', 'Gene', (43, 50))	('MYC', 'Gene', '4609', (238, 241))	('MYC', 'Gene', '4609', (95, 98))	('miR-145', 'Gene', (337, 344))	('amplified', 'PosReg', (71, 80))	('m6A', 'Chemical', '-', (54, 57))	('MYC', 'Gene', '4609', (302, 305))
437065	33731118	METTL3 knockdown could decrease CDK1 mRNAs with m6A modification, while VIRMA knockdown did not change the level of m6A modification in CDK1 mRNAs, indicating that m6A modification did not disturb the interaction between VIRMA and CDK1 in cancer cells.	('CDK1', 'Gene', (32, 36))	('decrease', 'NegReg', (23, 31))	('m6A', 'Chemical', '-', (116, 119))	('CDK1', 'Gene', (231, 235))	('CDK1', 'Gene', '983', (32, 36))	('CDK1', 'Gene', '983', (231, 235))	('METTL3', 'Gene', '56339', (0, 6))	('m6A', 'Chemical', '-', (48, 51))	('cancer', 'Disease', 'MESH:D009369', (239, 245))	('m6A modification', 'Var', (48, 64))	('CDK1', 'Gene', '983', (136, 140))	('CDK1', 'Gene', (136, 140))	('interaction', 'Interaction', (201, 212))	('METTL3', 'Gene', (0, 6))	('cancer', 'Disease', (239, 245))	('m6A', 'Chemical', '-', (164, 167))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))
437070	33731118	As the regulation of CDK1 mRNA in breast cancer, no significant difference was observed in luciferase activity between the reporter carrying mutant m6A site of 3'-UTR in c-Jun and that carrying the non-mutant m6A site.	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('mutant', 'Var', (141, 147))	('breast cancer', 'Disease', 'MESH:D001943', (34, 47))	('luciferase', 'Enzyme', (91, 101))	('m6A', 'Gene', (148, 151))	('breast cancer', 'Disease', (34, 47))	('c-Jun', 'Gene', (170, 175))	('breast cancer', 'Phenotype', 'HP:0003002', (34, 47))	('CDK1', 'Gene', '983', (21, 25))	('m6A', 'Chemical', '-', (148, 151))	('CDK1', 'Gene', (21, 25))	('activity', 'MPA', (102, 110))	('c-Jun', 'Gene', '3725', (170, 175))	('m6A', 'Chemical', '-', (209, 212))
437079	33731118	revealed that VIRMA and miR-143-3p were negatively correlated in osteosarcoma samples.	('sarcoma', 'Phenotype', 'HP:0100242', (70, 77))	('osteosarcoma', 'Phenotype', 'HP:0002669', (65, 77))	('osteosarcoma', 'Disease', (65, 77))	('osteosarcoma', 'Disease', 'MESH:D012516', (65, 77))	('miR-143-3p', 'Chemical', '-', (24, 34))	('negatively', 'NegReg', (40, 50))	('VIRMA', 'MPA', (14, 19))	('miR-143-3p', 'Var', (24, 34))
437080	33731118	The overexpression of miR-143-3p could inhibit VIRMA expression in osteosarcoma cells.	('miR-143-3p', 'Chemical', '-', (22, 32))	('osteosarcoma', 'Disease', 'MESH:D012516', (67, 79))	('sarcoma', 'Phenotype', 'HP:0100242', (72, 79))	('inhibit', 'NegReg', (39, 46))	('miR-143-3p', 'Var', (22, 32))	('overexpression', 'PosReg', (4, 18))	('VIRMA expression', 'MPA', (47, 63))	('osteosarcoma', 'Disease', (67, 79))	('osteosarcoma', 'Phenotype', 'HP:0002669', (67, 79))
437081	33731118	The overexpression of VIRMA could reverse the anti-proliferation caused by miR-143-3p.	('anti-proliferation', 'CPA', (46, 64))	('miR-143-3p', 'Chemical', '-', (75, 85))	('miR-143-3p', 'Var', (75, 85))
437082	33731118	It was proven that miR-143-3p could suppress VIRMA expression by directly targeting its 3'-UTR region in osteosarcoma cells.	('targeting', 'Reg', (74, 83))	('miR-143-3p', 'Chemical', '-', (19, 29))	('VIRMA expression', 'MPA', (45, 61))	('sarcoma', 'Phenotype', 'HP:0100242', (110, 117))	('suppress', 'NegReg', (36, 44))	('osteosarcoma', 'Phenotype', 'HP:0002669', (105, 117))	('miR-143-3p', 'Var', (19, 29))	('osteosarcoma', 'Disease', (105, 117))	('osteosarcoma', 'Disease', 'MESH:D012516', (105, 117))
437083	33731118	While the roles of m6A modifications in cancers have been extensively reviewed elsewhere, the crucial functions of VIRMA in various types of cancer, as well as the potential targeting of VIRMA as cancer treatment, have not yet been highlighted.	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('cancers', 'Phenotype', 'HP:0002664', (40, 47))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('cancers', 'Disease', 'MESH:D009369', (40, 47))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('cancers', 'Disease', (40, 47))	('cancer', 'Disease', (40, 46))	('cancer', 'Disease', 'MESH:D009369', (196, 202))	('modifications', 'Var', (23, 36))	('cancer', 'Disease', (196, 202))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('m6A', 'Chemical', '-', (19, 22))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('cancer', 'Disease', (141, 147))
437085	33731118	High expression of VIRMA has been verified to predict poor survival in multiple cancers, such as breast cancer, liver cancer, kidney cancer and prostate cancer.	('cancers', 'Disease', 'MESH:D009369', (80, 87))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('VIRMA', 'Gene', (19, 24))	('prostate cancer', 'Disease', 'MESH:D011471', (144, 159))	('prostate cancer', 'Phenotype', 'HP:0012125', (144, 159))	('High expression', 'Var', (0, 15))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('prostate cancer', 'Disease', (144, 159))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('liver cancer', 'Disease', 'MESH:D006528', (112, 124))	('cancers', 'Phenotype', 'HP:0002664', (80, 87))	('kidney cancer', 'Disease', 'MESH:D007680', (126, 139))	('cancers', 'Disease', (80, 87))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('breast cancer', 'Phenotype', 'HP:0003002', (97, 110))	('liver cancer', 'Phenotype', 'HP:0002896', (112, 124))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('kidney cancer', 'Phenotype', 'HP:0009726', (126, 139))	('liver cancer', 'Disease', (112, 124))	('kidney cancer', 'Disease', (126, 139))	('poor', 'NegReg', (54, 58))	('breast cancer', 'Disease', 'MESH:D001943', (97, 110))	('breast cancer', 'Disease', (97, 110))
437086	33731118	Inhibiting these downstream targets could reverse the oncogenic effect of VIRMA in cancer progression.	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('Inhibiting', 'Var', (0, 10))	('cancer', 'Disease', (83, 89))
437095	33731118	m6A modification has been shown to act by influencing RNA transcript, splicing, processing, translation and decay, and to participate in the development of various cancer types.	('m6A', 'Chemical', '-', (0, 3))	('decay', 'MPA', (108, 113))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('translation', 'MPA', (92, 103))	('influencing', 'Reg', (42, 53))	('splicing', 'MPA', (70, 78))	('modification', 'Var', (4, 16))	('participate', 'Reg', (122, 133))	('cancer', 'Disease', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('RNA transcript', 'MPA', (54, 68))	('m6A', 'Gene', (0, 3))	('processing', 'MPA', (80, 90))
437118	33690683	At the molecular level, recent studies have revealed that approximately 59-93% of patients with ESCC harbor mutations in tumor protein p53.	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('mutations', 'Var', (108, 117))	('patients', 'Species', '9606', (82, 90))	('tumor', 'Disease', (121, 126))	('p53', 'Gene', (135, 138))	('p53', 'Gene', '7157', (135, 138))	('ESCC', 'Disease', (96, 100))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
437148	33690683	The AUC was 0.912 (sensitivity 91.7%, specificity 76.0%) for serum miR-1246, 0.823 (sensitivity 90.3%, specificity 62.0%) for urine miR-1246, and 0.802 (sensitivity 83.3%, specificity 66.0%) for saliva miR-1246.	('miR-1246', 'Gene', '100302142', (67, 75))	('miR-1246', 'Gene', (132, 140))	('0.802', 'Var', (146, 151))	('miR-1246', 'Gene', '100302142', (202, 210))	('0.823', 'Var', (77, 82))	('miR-1246', 'Gene', (67, 75))	('urine', 'MPA', (126, 131))	('miR-1246', 'Gene', (202, 210))	('miR-1246', 'Gene', '100302142', (132, 140))
437159	33690683	The prognosis of the group with high serum miR-1246 expression was significantly worse than that of the group with low serum miR-1246 expression (p = 0.035), consistent with our previous report.	('high', 'Var', (32, 36))	('miR-1246', 'Gene', '100302142', (43, 51))	('miR-1246', 'Gene', (43, 51))	('miR-1246', 'Gene', '100302142', (125, 133))	('worse', 'NegReg', (81, 86))	('miR-1246', 'Gene', (125, 133))
437177	33690683	Mechanistically, inhibition of miR-1246 expression reduces stemness and epithelial-mesenchymal transition in non-small cell lung cancer, in addition to suppressing proliferation, sphere formation, colony formation, and invasion of tumor cells.	('colony formation', 'CPA', (197, 213))	('reduces', 'NegReg', (51, 58))	('miR-1246', 'Gene', '100302142', (31, 39))	('stemness', 'Disease', 'MESH:D020295', (59, 67))	('stemness', 'Disease', (59, 67))	('sphere formation', 'CPA', (179, 195))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (109, 135))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('inhibition', 'Var', (17, 27))	('tumor', 'Disease', (231, 236))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (113, 135))	('lung cancer', 'Disease', (124, 135))	('tumor', 'Disease', 'MESH:D009369', (231, 236))	('proliferation', 'CPA', (164, 177))	('miR-1246', 'Gene', (31, 39))	('suppressing', 'NegReg', (152, 163))	('lung cancer', 'Disease', 'MESH:D008175', (124, 135))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('lung cancer', 'Phenotype', 'HP:0100526', (124, 135))
437181	33690683	To date, 18 salivary miRs (miR-1246, miR-4644, miR-21, miR-34a, mir-155, miR-200b, miR-376a, miR-23a, miR-23b, miR-29c, miR-210, miR-216, miR -940, miR-3679-5p, miR-17, miR-18b, miR-18a, and miR-196a) have been studied in gastrointestinal cancers and pancreatic cancer, regardless of tumor progression.	('miR-376a', 'Var', (83, 91))	('miR-29c', 'Gene', '407026', (111, 118))	('miR-17', 'Gene', '406952', (161, 167))	('miR -940', 'Gene', '100126328', (138, 146))	('tumor', 'Disease', 'MESH:D009369', (284, 289))	('miR-1246', 'Gene', (27, 35))	('miR-18b', 'Gene', (169, 176))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (251, 268))	('miR-18a', 'Gene', (178, 185))	('miR-29c', 'Gene', (111, 118))	('miR-23b', 'Gene', '407011', (102, 109))	('miR-18b', 'Gene', '574033', (169, 176))	('miR -940', 'Gene', (138, 146))	('mir-155', 'Gene', (64, 71))	('miR-4644', 'Gene', '100616430', (37, 45))	('pancreatic cancer', 'Disease', 'MESH:D010190', (251, 268))	('cancers', 'Phenotype', 'HP:0002664', (239, 246))	('miR-21', 'Gene', '406991', (120, 126))	('miR-21', 'Gene', '406991', (129, 135))	('mir-155', 'Gene', '406947', (64, 71))	('miR-200b', 'Gene', '406984', (73, 81))	('tumor', 'Phenotype', 'HP:0002664', (284, 289))	('miR-4644', 'Gene', (37, 45))	('miR-17', 'Gene', (161, 167))	('miR-3679', 'Gene', (148, 156))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))	('pancreatic cancer', 'Disease', (251, 268))	('gastrointestinal cancers', 'Disease', 'MESH:D004067', (222, 246))	('miR-18a', 'Gene', '406953', (178, 185))	('miR-23b', 'Gene', (102, 109))	('miR-21', 'Gene', '406991', (47, 53))	('miR-1246', 'Gene', '100302142', (27, 35))	('cancer', 'Phenotype', 'HP:0002664', (262, 268))	('miR-216', 'Gene', (129, 136))	('miR-23a', 'Gene', '407010', (93, 100))	('miR-210', 'Gene', '406992', (120, 127))	('miR-216', 'Gene', '406998', (129, 136))	('miR-23a', 'Gene', (93, 100))	('miR-21', 'Gene', (120, 126))	('miR-21', 'Gene', (129, 135))	('miR-3679', 'Gene', '100500878', (148, 156))	('miR-34a', 'Gene', (55, 62))	('gastrointestinal cancers', 'Disease', (222, 246))	('miR-210', 'Gene', (120, 127))	('miR-200b', 'Gene', (73, 81))	('tumor', 'Disease', (284, 289))	('miR-34a', 'Gene', '407040', (55, 62))	('miR-21', 'Gene', (47, 53))
437188	33138076	We hypothesize that in individual samples, the disruption of transcription homeostasis can influence the occurrence, development, and metastasis of tumors and has implications for patient survival outcomes.	('transcription homeostasis', 'MPA', (61, 86))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('implications', 'Reg', (163, 175))	('disruption', 'Var', (47, 57))	('influence', 'Reg', (91, 100))	('occurrence', 'CPA', (105, 115))	('metastasis of tumors', 'Disease', 'MESH:D009362', (134, 154))	('development', 'CPA', (117, 128))	('metastasis of tumors', 'Disease', (134, 154))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('patient', 'Species', '9606', (180, 187))
437201	33138076	Several commercialized gene signatures have been approved for risk prediction in clinical practice, such as PAM50 for breast cancer, Mammaprint , a set of 70 genes for low- or high-risk prediction in breast cancer, and OncoType DX  panels for tumor profiling in breast, prostate, and colon cancers.	('prostate', 'Disease', (270, 278))	('breast', 'Disease', (262, 268))	('breast cancer', 'Phenotype', 'HP:0003002', (118, 131))	('tumor', 'Disease', (243, 248))	('colon cancers', 'Phenotype', 'HP:0003003', (284, 297))	('tumor', 'Disease', 'MESH:D009369', (243, 248))	('breast cancer', 'Disease', 'MESH:D001943', (118, 131))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('breast cancer', 'Disease', (118, 131))	('colon cancer', 'Phenotype', 'HP:0003003', (284, 296))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('colon cancers', 'Disease', 'MESH:D015179', (284, 297))	('breast cancer', 'Phenotype', 'HP:0003002', (200, 213))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))	('PAM50', 'Var', (108, 113))	('colon cancers', 'Disease', (284, 297))	('cancers', 'Phenotype', 'HP:0002664', (290, 297))	('breast cancer', 'Disease', 'MESH:D001943', (200, 213))	('breast cancer', 'Disease', (200, 213))	('cancer', 'Phenotype', 'HP:0002664', (290, 296))
437229	33138076	And a differential pathway was defined as a prognosis-related pathway if perturbed-strong samples had worse prognosis than perturbed-week samples for a given cancer type with a significant log-rank p-value < 0.005.	('worse', 'NegReg', (102, 107))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('perturbed-strong', 'Var', (73, 89))	('cancer', 'Disease', (158, 164))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
437256	33138076	We found some prognosis-related pathways of breast cancer, such as the regulation of insulin-like growth factor (IGF) transport and uptake by insulin-like growth factor binding proteins (IGFBPs), the PI3K/Akt signal transduction pathway, signaling by PDGF, Toll-like receptor cascades, DAP12 interactions, and constitutive signaling by aberrant PI3K in cancer.	('uptake', 'MPA', (132, 138))	('Akt', 'Gene', '207', (205, 208))	('breast cancer', 'Disease', 'MESH:D001943', (44, 57))	('breast cancer', 'Phenotype', 'HP:0003002', (44, 57))	('aberrant PI3K', 'Var', (336, 349))	('breast cancer', 'Disease', (44, 57))	('cancer', 'Disease', 'MESH:D009369', (353, 359))	('Akt', 'Gene', (205, 208))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('cancer', 'Disease', (353, 359))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('PI3K', 'Var', (345, 349))	('DAP12', 'Gene', '7305', (286, 291))	('cancer', 'Disease', (51, 57))	('DAP12', 'Gene', (286, 291))	('cancer', 'Phenotype', 'HP:0002664', (353, 359))
437262	33138076	studied the relationship between DAP12 expression in breast cancer cells and disease progression and found that breast cancer patients with high DAP12 expression had poor prognosis, high recurrence rates and short survival times due to liver metastasis (Figure 5).	('breast cancer', 'Disease', 'MESH:D001943', (112, 125))	('breast cancer', 'Disease', (112, 125))	('patients', 'Species', '9606', (126, 134))	('liver metastasis', 'Disease', (236, 252))	('breast cancer', 'Phenotype', 'HP:0003002', (53, 66))	('breast cancer', 'Disease', 'MESH:D001943', (53, 66))	('recurrence rates', 'CPA', (187, 203))	('DAP12', 'Gene', '7305', (145, 150))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('DAP12', 'Gene', (145, 150))	('breast cancer', 'Disease', (53, 66))	('DAP12', 'Gene', (33, 38))	('DAP12', 'Gene', '7305', (33, 38))	('high', 'Var', (140, 144))	('expression', 'MPA', (151, 161))	('liver metastasis', 'Disease', 'MESH:D009362', (236, 252))	('breast cancer', 'Phenotype', 'HP:0003002', (112, 125))	('poor', 'NegReg', (166, 170))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
437267	33138076	In stomach cancer (STAD), constitutive signaling by aberrant PI3K in cancer, PTEN loss of function in cancer (Figure S2a), deadenylation-dependent mRNA decay (Figure S2b), and transcriptional regulation of pluripotent stem cells (Figure S2c) are pathways that are well known to play important roles in the tumorigenesis and development of STAD.	('PTEN loss of function', 'Disease', (77, 98))	('PTEN loss of function', 'Disease', 'MESH:D006223', (77, 98))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('deadenylation-dependent mRNA decay', 'MPA', (123, 157))	('tumor', 'Disease', (306, 311))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('constitutive signaling', 'MPA', (26, 48))	('tumor', 'Disease', 'MESH:D009369', (306, 311))	('stomach cancer', 'Disease', (3, 17))	('cancer', 'Disease', 'MESH:D009369', (11, 17))	('tumor', 'Phenotype', 'HP:0002664', (306, 311))	('cancer', 'Disease', (102, 108))	('stomach cancer', 'Disease', 'MESH:D013274', (3, 17))	('cancer', 'Disease', (69, 75))	('stomach cancer', 'Phenotype', 'HP:0012126', (3, 17))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('PI3K', 'Gene', (61, 65))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('aberrant', 'Var', (52, 60))	('cancer', 'Disease', (11, 17))
437276	33138076	showed that mutations in CDKN1B had effects on the survival of breast cancer (BRCA) patients.	('CDKN1B', 'Gene', (25, 31))	('BRCA', 'Disease', (78, 82))	('patients', 'Species', '9606', (84, 92))	('breast cancer', 'Disease', 'MESH:D001943', (63, 76))	('mutations', 'Var', (12, 21))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('breast cancer', 'Disease', (63, 76))	('survival', 'CPA', (51, 59))	('breast cancer', 'Phenotype', 'HP:0003002', (63, 76))	('effects', 'Reg', (36, 43))	('CDKN1B', 'Gene', '1027', (25, 31))	('BRCA', 'Disease', 'MESH:C562694', (78, 82))
437290	33138076	The abnormal expression of TRAF6 is closely related to carcinogenesis by participating in the regulation of tumor cell apoptosis, growth, and invasion through different signaling pathways.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('TRAF6', 'Gene', (27, 32))	('TRAF6', 'Gene', '7189', (27, 32))	('abnormal', 'Var', (4, 12))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('expression', 'MPA', (13, 23))	('related', 'Reg', (44, 51))	('participating', 'Reg', (73, 86))	('tumor', 'Disease', (108, 113))	('growth', 'CPA', (130, 136))	('carcinogenesis', 'Disease', 'MESH:D063646', (55, 69))	('invasion', 'CPA', (142, 150))	('carcinogenesis', 'Disease', (55, 69))
437304	33138076	In the breast cancer (BRCA) and REACTOME pathways, PIP3 activates AKT signaling and was identified by iPS as a prognosis-related pathway.	('PIP3', 'Var', (51, 55))	('activates', 'PosReg', (56, 65))	('AKT', 'Gene', (66, 69))	('iPS', 'Disease', (102, 105))	('breast cancer', 'Disease', 'MESH:D001943', (7, 20))	('iPS', 'Disease', 'OMIM:613661', (102, 105))	('BRCA', 'Disease', (22, 26))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('breast cancer', 'Disease', (7, 20))	('REACTOME pathways', 'Pathway', (32, 49))	('breast cancer', 'Phenotype', 'HP:0003002', (7, 20))	('PIP3', 'Chemical', '-', (51, 55))	('AKT', 'Gene', '207', (66, 69))	('BRCA', 'Disease', 'MESH:C562694', (22, 26))
437320	33138076	The following are available online at , Figure S1: Significant survival differences for the mutation frequency of Notch4 by iPS in HNSC.	('mutation', 'Var', (92, 100))	('iPS', 'Disease', (124, 127))	('Notch4', 'Gene', '4855', (114, 120))	('iPS', 'Disease', 'OMIM:613661', (124, 127))	('Notch4', 'Gene', (114, 120))
437322	33138076	(a) Constitutive Signaling by Aberrant PI3K in Cancer and PTEN Loss of Function in Cancer, (b) Deadenylation-dependent mRNA decay, (c) Transcriptional regulation of pluripotent stem cells pathways.	('Deadenylation-dependent mRNA decay', 'MPA', (95, 129))	('Aberrant PI3K', 'Var', (30, 43))	('Cancer', 'Disease', (47, 53))	('pluripotent stem cells pathways', 'Pathway', (165, 196))	('PTEN Loss of Function in Cancer', 'Disease', (58, 89))	('Cancer', 'Disease', 'MESH:D009369', (47, 53))	('PTEN Loss of Function in Cancer', 'Disease', 'MESH:D006223', (58, 89))	('Cancer', 'Phenotype', 'HP:0002664', (47, 53))	('Constitutive Signaling', 'MPA', (4, 26))	('Cancer', 'Phenotype', 'HP:0002664', (83, 89))	('Cancer', 'Disease', (83, 89))	('Cancer', 'Disease', 'MESH:D009369', (83, 89))	('PI3K', 'Var', (39, 43))
437407	31802898	Clinicopathological Characteristics And EGFR-TKIs Efficacies In Lung Squamous Cell Carcinoma Patients Harboring An EGFR Sensitizing Mutation This study analyzed the relationship between the clinicopathological features and epidermal growth factor receptor (EGFR) mutation status of squamous cell lung cancer (SqCLC) patients.	('Squamous Cell Carcinoma', 'Disease', (69, 92))	('EGFR', 'Gene', (257, 261))	('lung cancer', 'Phenotype', 'HP:0100526', (296, 307))	('EGFR', 'Gene', (115, 119))	('Lung Squamous Cell Carcinoma', 'Phenotype', 'HP:0030359', (64, 92))	('patients', 'Species', '9606', (316, 324))	('Mutation', 'Var', (132, 140))	('Carcinoma', 'Phenotype', 'HP:0030731', (83, 92))	('EGFR', 'Gene', (40, 44))	('SqCLC', 'Disease', (309, 314))	('cancer', 'Phenotype', 'HP:0002664', (301, 307))	('EGFR', 'Gene', '1956', (257, 261))	('EGFR', 'Gene', '1956', (115, 119))	('SqCLC', 'Phenotype', 'HP:0030359', (309, 314))	('squamous cell lung cancer', 'Phenotype', 'HP:0030359', (282, 307))	('Squamous Cell Carcinoma', 'Disease', 'MESH:D002294', (69, 92))	('Patients', 'Species', '9606', (93, 101))	('epidermal growth factor receptor', 'Gene', (223, 255))	('squamous cell lung cancer', 'Disease', (282, 307))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (69, 92))	('EGFR', 'Gene', '1956', (40, 44))	('epidermal growth factor receptor', 'Gene', '1956', (223, 255))	('SqCLC', 'Disease', 'MESH:D018307', (309, 314))	('squamous cell lung cancer', 'Disease', 'MESH:D018307', (282, 307))
437410	31802898	The EGFR mutations in tumor tissues were identified by ARMS-PCR and NGS.	('EGFR', 'Gene', (4, 8))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('mutations', 'Var', (9, 18))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('tumor', 'Disease', (22, 27))	('EGFR', 'Gene', '1956', (4, 8))
437413	31802898	Among the 292 SqCLC patients, 24 (8.2%) were identified to have an EGFR-sensitizing mutation.	('SqCLC', 'Disease', (14, 19))	('patients', 'Species', '9606', (20, 28))	('EGFR', 'Gene', '1956', (67, 71))	('SqCLC', 'Disease', 'MESH:D018307', (14, 19))	('EGFR', 'Gene', (67, 71))	('SqCLC', 'Phenotype', 'HP:0030359', (14, 19))	('mutation', 'Var', (84, 92))
437414	31802898	Both ARMS-PCR and NGS were equally effective in detecting EGFR mutations.	('mutations', 'Var', (63, 72))	('EGFR', 'Gene', '1956', (58, 62))	('EGFR', 'Gene', (58, 62))
437415	31802898	Females and non-smokers had higher EGFR mutation rates than males and smokers (22.1% vs. 5.1%, P = 0.007 and 16.7% vs. 4.5%, P = 0.001, respectively).	('mutation', 'Var', (40, 48))	('higher', 'PosReg', (28, 34))	('EGFR', 'Gene', '1956', (35, 39))	('EGFR', 'Gene', (35, 39))
437416	31802898	EGFR mutation was unrelated to the degree of differentiation, clinical stage, specimen type and level of serum carcino-embryonic antigen (CEA) and squamous cell carcinoma antigen (SCC) (P > 0.05).	('squamous cell carcinoma', 'Disease', (147, 170))	('EGFR', 'Gene', (0, 4))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (147, 170))	('carcino-embryonic antigen', 'Gene', (111, 136))	('SCC', 'Gene', (180, 183))	('CEA', 'Gene', '1048', (138, 141))	('carcino-embryonic antigen', 'Gene', '1048', (111, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (161, 170))	('SCC', 'Gene', '6317', (180, 183))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (147, 170))	('EGFR', 'Gene', '1956', (0, 4))	('mutation', 'Var', (5, 13))	('CEA', 'Gene', (138, 141))
437417	31802898	In the 14 EGFR mutant cases treated with EGFR-TKIs, the objective response rate (ORR) and disease control rate (DCR) were 28.6% and 78.6%, respectively.	('EGFR', 'Gene', '1956', (10, 14))	('EGFR', 'Gene', (41, 45))	('EGFR', 'Gene', (10, 14))	('objective response', 'CPA', (56, 74))	('mutant', 'Var', (15, 21))	('EGFR', 'Gene', '1956', (41, 45))
437419	31802898	EGFR-sensitizing mutations are rare in SqCLC patients with females and non-smokers having a higher risk of harboring them.	('EGFR', 'Gene', (0, 4))	('SqCLC', 'Phenotype', 'HP:0030359', (39, 44))	('SqCLC', 'Disease', (39, 44))	('SqCLC', 'Disease', 'MESH:D018307', (39, 44))	('patients', 'Species', '9606', (45, 53))	('mutations', 'Var', (17, 26))	('EGFR', 'Gene', '1956', (0, 4))
437421	31802898	EGFR-TKIs showed modest efficacies and low toxicity profiles in EGFR mutant cases.	('toxicity', 'Disease', (43, 51))	('EGFR', 'Gene', (0, 4))	('mutant', 'Var', (69, 75))	('EGFR', 'Gene', '1956', (64, 68))	('EGFR', 'Gene', (64, 68))	('EGFR', 'Gene', '1956', (0, 4))	('toxicity', 'Disease', 'MESH:D064420', (43, 51))
437424	31802898	In the past decade, epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), as a primary example of targeted therapy, have achieved unprecedented advancement in the treatment of NSCLC patients harboring EGFR-sensitizing mutations.	('patients', 'Species', '9606', (201, 209))	('NSCLC', 'Disease', 'MESH:D002289', (195, 200))	('EGFR', 'Gene', (220, 224))	('epidermal growth factor receptor', 'Gene', (20, 52))	('EGFR', 'Gene', '1956', (220, 224))	('tyrosine', 'Chemical', 'None', (53, 61))	('NSCLC', 'Disease', (195, 200))	('NSCLC', 'Phenotype', 'HP:0030358', (195, 200))	('epidermal growth factor receptor', 'Gene', '1956', (20, 52))	('advancement', 'PosReg', (163, 174))	('mutations', 'Var', (237, 246))	('EGFR', 'Gene', '1956', (81, 85))	('EGFR', 'Gene', (81, 85))
437425	31802898	A substantial amount of data has demonstrated that a variety of demographic and clinicopathological features, such as gender, ethnicity, smoking history and histological type, are closely related to EGFR mutation status.	('EGFR', 'Gene', (199, 203))	('EGFR', 'Gene', '1956', (199, 203))	('related', 'Reg', (188, 195))	('mutation status', 'Var', (204, 219))
437426	31802898	For Caucasians, the frequency of EGFR mutations in NSCLC patients is 12%, whereas in China, the frequency is substantially higher at 50.2%.	('patients', 'Species', '9606', (57, 65))	('NSCLC', 'Disease', (51, 56))	('EGFR', 'Gene', '1956', (33, 37))	('NSCLC', 'Disease', 'MESH:D002289', (51, 56))	('EGFR', 'Gene', (33, 37))	('mutations', 'Var', (38, 47))	('NSCLC', 'Phenotype', 'HP:0030358', (51, 56))
437427	31802898	Due to the higher efficacies, lower classic toxicities and well tolerability, the EGFR-TKIs have become an optimal choice as the first-line of therapy in EGFR mutant NSCLC patients as opposed to chemotherapy.	('EGFR', 'Gene', (154, 158))	('EGFR', 'Gene', (82, 86))	('NSCLC', 'Phenotype', 'HP:0030358', (166, 171))	('efficacies', 'MPA', (18, 28))	('toxicities', 'Disease', 'MESH:D064420', (44, 54))	('mutant', 'Var', (159, 165))	('NSCLC', 'Disease', (166, 171))	('NSCLC', 'Disease', 'MESH:D002289', (166, 171))	('toxicities', 'Disease', (44, 54))	('higher', 'PosReg', (11, 17))	('patients', 'Species', '9606', (172, 180))	('EGFR', 'Gene', '1956', (82, 86))	('EGFR', 'Gene', '1956', (154, 158))
437432	31802898	However, knowledge about the frequency of EGFR mutations in SqCLC, its predominance in a population that is more likely to harbor EGFR mutation in adenocarcinoma patients, and the efficacies of EGFR-TKIs in this subgroup of patients are not yet available.	('patients', 'Species', '9606', (162, 170))	('carcinoma', 'Phenotype', 'HP:0030731', (152, 161))	('EGFR', 'Gene', '1956', (42, 46))	('adenocarcinoma', 'Disease', (147, 161))	('EGFR', 'Gene', (42, 46))	('adenocarcinoma', 'Disease', 'MESH:D000230', (147, 161))	('mutations', 'Var', (47, 56))	('SqCLC', 'Phenotype', 'HP:0030359', (60, 65))	('SqCLC', 'Disease', (60, 65))	('SqCLC', 'Disease', 'MESH:D018307', (60, 65))	('EGFR', 'Gene', (194, 198))	('patients', 'Species', '9606', (224, 232))	('EGFR', 'Gene', '1956', (194, 198))	('EGFR', 'Gene', '1956', (130, 134))	('mutation', 'Var', (135, 143))	('EGFR', 'Gene', (130, 134))
437433	31802898	Very few studies have reported the frequency of EGFR mutation in SqCLC.	('EGFR', 'Gene', '1956', (48, 52))	('mutation', 'Var', (53, 61))	('SqCLC', 'Disease', (65, 70))	('EGFR', 'Gene', (48, 52))	('SqCLC', 'Phenotype', 'HP:0030359', (65, 70))	('SqCLC', 'Disease', 'MESH:D018307', (65, 70))
437434	31802898	Thus, the aim of this study was to analyze the relationship between the clinicopathological features and EGFR mutation status in patients with SqCLC and to observe the efficacies of EGFR-TKIs in these patients to provide clinical information that might be helpful for determining the treatment strategy for such cases.	('patients', 'Species', '9606', (201, 209))	('EGFR', 'Gene', '1956', (182, 186))	('EGFR', 'Gene', (182, 186))	('patients', 'Species', '9606', (129, 137))	('EGFR', 'Gene', '1956', (105, 109))	('SqCLC', 'Phenotype', 'HP:0030359', (143, 148))	('SqCLC', 'Disease', 'MESH:D018307', (143, 148))	('mutation', 'Var', (110, 118))	('EGFR', 'Gene', (105, 109))	('SqCLC', 'Disease', (143, 148))
437435	31802898	A total of 272 NSCLC patients admitted to Guangxi Medical University Affiliated Tumor Hospital and subjected to detection of EGFR mutations from December 2013 to December 2018 were selected for the study, which was reviewed and approved by the Institutional Ethics Committee of the hospital.	('NSCLC', 'Phenotype', 'HP:0030358', (15, 20))	('EGFR', 'Gene', '1956', (125, 129))	('Tumor', 'Phenotype', 'HP:0002664', (80, 85))	('patients', 'Species', '9606', (21, 29))	('EGFR', 'Gene', (125, 129))	('NSCLC', 'Disease', (15, 20))	('mutations', 'Var', (130, 139))	('NSCLC', 'Disease', 'MESH:D002289', (15, 20))
437439	31802898	(3) Detection of EGFR mutation prior to adjuvant or salvage treatment, including chemotherapy or targeted therapy.	('mutation', 'Var', (22, 30))	('EGFR', 'Gene', '1956', (17, 21))	('EGFR', 'Gene', (17, 21))
437443	31802898	Amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) and next-generation sequencing technology (NGS) were used to define the EGFR mutation status of tissue samples in our institute.	('EGFR', 'Gene', '1956', (150, 154))	('EGFR', 'Gene', (150, 154))	('mutation', 'Var', (155, 163))
437444	31802898	ARMS-PCR, a PCR-based method that can detect previously predefined point mutations, was used to define EGFR gene mutations.	('mutations', 'Var', (113, 122))	('EGFR', 'Gene', (103, 107))	('EGFR', 'Gene', '1956', (103, 107))
437445	31802898	The ADx EGFR29 Mutation Kit (Amoy Diagnostics, Xiamen, China) covers 29 point mutations of EGFR including exon 18 G719X (G719A, G719, G719C), exon 19 deletions, exon 20 insertions (three types of insertions), exon 20 T790M and S768I, and exon 21 L858R and L861Q mutation, etc.	('EGFR', 'Gene', '1956', (8, 12))	('G719C', 'Mutation', 'rs28929495', (134, 139))	('S768I', 'SUBSTITUTION', 'None', (227, 232))	('L858R', 'Var', (246, 251))	('EGFR', 'Gene', (91, 95))	('G719C', 'Var', (134, 139))	('T790M', 'Mutation', 'rs121434569', (217, 222))	('S768I', 'Var', (227, 232))	('insertions', 'Var', (169, 179))	('G719A', 'Mutation', 'rs121913428', (121, 126))	('L861Q mutation', 'Var', (256, 270))	('EGFR', 'Gene', (8, 12))	('T790M', 'Var', (217, 222))	('EGFR', 'Gene', '1956', (91, 95))	('deletions', 'Var', (150, 159))	('L858R', 'Mutation', 'rs121434568', (246, 251))	('L861Q', 'Mutation', 'rs121913444', (256, 261))	('G719X', 'Mutation', 'p.G719X', (114, 119))	('G719', 'Var', (128, 132))
437447	31802898	EGFR-sensitizing activation mutations were defined according to National Comprehensive Cancer Network (NCCN) guidelines, including common exon 19 del and exon 21 L858R mutations and rare exon 18 G719X, exon 20 S768I, exon 20 insertion variant A763_Y764insFQEA and exon 21 L861Q mutations.	('A763_Y764insFQEA', 'Mutation', 'c.763,764insFQEA', (243, 259))	('EGFR', 'Gene', (0, 4))	('L858R', 'Mutation', 'rs121434568', (162, 167))	('G719X', 'Mutation', 'p.G719X', (195, 200))	('L858R', 'Var', (162, 167))	('G719X', 'Var', (195, 200))	('L861Q mutations', 'Var', (272, 287))	('L861Q', 'Mutation', 'rs121913444', (272, 277))	('S768I', 'SUBSTITUTION', 'None', (210, 215))	('A763_Y764insFQEA', 'Var', (243, 259))	('S768I', 'Var', (210, 215))	('EGFR', 'Gene', '1956', (0, 4))	('Cancer', 'Phenotype', 'HP:0002664', (87, 93))
437448	31802898	Patients with SqCLC harboring EGFR mutation were treated with Icotinib 125 mg three times daily or gefitinib 250 mg, erlotinib 150 mg, or afatinib 40 mg once daily until the manifestation of disease progression or intolerable side-effects.	('EGFR', 'Gene', (30, 34))	('erlotinib', 'Chemical', 'MESH:C400278', (117, 126))	('Patients', 'Species', '9606', (0, 8))	('SqCLC', 'Disease', (14, 19))	('afatinib', 'Chemical', 'MESH:C522924', (138, 146))	('mutation', 'Var', (35, 43))	('SqCLC', 'Disease', 'MESH:D018307', (14, 19))	('SqCLC', 'Phenotype', 'HP:0030359', (14, 19))	('EGFR', 'Gene', '1956', (30, 34))	('Icotinib', 'Chemical', 'MESH:C531470', (62, 70))	('gefitinib', 'Chemical', 'MESH:C419708', (99, 108))
437457	31802898	Twenty-four out of 292 SqCLC patients were identified to have an EGEF activating mutation with a mutation rate of 8.2% (24/292), out of which 14 patients were verified to have an exon 19 del (14/292, 4.8%) (Figure 1), 9 were verified to have an exon 21 L858R mutation (9/292,3.1%) (Figure 2), and one was verified to have an L861Q mutation (1/292, 0.3%).	('patients', 'Species', '9606', (145, 153))	('L858R', 'Mutation', 'rs121434568', (253, 258))	('patients', 'Species', '9606', (29, 37))	('SqCLC', 'Phenotype', 'HP:0030359', (23, 28))	('exon 21 L858R', 'Var', (245, 258))	('activating', 'PosReg', (70, 80))	('mutation', 'Var', (81, 89))	('SqCLC', 'Disease', (23, 28))	('SqCLC', 'Disease', 'MESH:D018307', (23, 28))	('EGEF', 'Gene', (65, 69))	('L861Q', 'Mutation', 'rs121913444', (325, 330))	('L858R', 'Var', (253, 258))
437458	31802898	There were no EGFR concurrent mutations, and the rest of the enrolled patients were found to possess the wild type EGFR gene (267/292, 91.8%).	('patients', 'Species', '9606', (70, 78))	('EGFR', 'Gene', '1956', (14, 18))	('EGFR', 'Gene', (14, 18))	('EGFR', 'Gene', '1956', (115, 119))	('EGFR', 'Gene', (115, 119))	('mutations', 'Var', (30, 39))
437459	31802898	The results for EGFR mutation rate were 8.7% (19/219) for ARMS-PCR and 7.3% (5/73) for NGS method, respectively.	('ARMS-PCR', 'Disease', (58, 66))	('EGFR', 'Gene', '1956', (16, 20))	('EGFR', 'Gene', (16, 20))	('mutation', 'Var', (21, 29))
437460	31802898	Analysis of 24 EGFR positive SqCLC patients revealed that the frequencies of EGFR mutations were significantly higher in patients who had no history of smoking (14.3% vs. 4.8%) and whose gender was female (18.1% vs. 5%) with P = 0.007 and P = 0.001, respectively.	('SqCLC', 'Phenotype', 'HP:0030359', (29, 34))	('SqCLC', 'Disease', (29, 34))	('SqCLC', 'Disease', 'MESH:D018307', (29, 34))	('mutations', 'Var', (82, 91))	('EGFR', 'Gene', '1956', (15, 19))	('EGFR', 'Gene', (15, 19))	('EGFR', 'Gene', '1956', (77, 81))	('higher', 'PosReg', (111, 117))	('patients', 'Species', '9606', (35, 43))	('EGFR', 'Gene', (77, 81))	('patients', 'Species', '9606', (121, 129))
437461	31802898	However, parameters such as age, degree of differentiation, clinical stages, sample types, values of serum CEA and SCC were not correlated with EGFR mutation status (P > 0.05).	('EGFR', 'Gene', (144, 148))	('CEA', 'Gene', (107, 110))	('mutation status', 'Var', (149, 164))	('SCC', 'Gene', (115, 118))	('EGFR', 'Gene', '1956', (144, 148))	('SCC', 'Gene', '6317', (115, 118))	('CEA', 'Gene', '1048', (107, 110))
437462	31802898	The relationship between EGFR mutations and the clinicopathological features is summarized in Table 1.	('mutations', 'Var', (30, 39))	('EGFR', 'Gene', (25, 29))	('EGFR', 'Gene', '1956', (25, 29))
437471	31802898	The necessity of detecting EGFR mutations and the application of EGFR-TKI therapy in SqCLC patients remains controversial.	('EGFR', 'Gene', '1956', (27, 31))	('EGFR', 'Gene', (27, 31))	('patients', 'Species', '9606', (91, 99))	('EGFR', 'Gene', '1956', (65, 69))	('EGFR', 'Gene', (65, 69))	('SqCLC', 'Phenotype', 'HP:0030359', (85, 90))	('mutations', 'Var', (32, 41))	('SqCLC', 'Disease', (85, 90))	('SqCLC', 'Disease', 'MESH:D018307', (85, 90))
437472	31802898	Guidelines from the European Society for Medical Oncology (ESMO) recommend that EGFR mutations should be detected in cases of non-squamous carcinoma, while the NCCN recommends the detection of EGFR mutations in SqCLC only in cases of non-smokers, small specimen type, or mixed histological types.	('non-squamous carcinoma', 'Disease', (126, 148))	('SqCLC', 'Phenotype', 'HP:0030359', (211, 216))	('carcinoma', 'Phenotype', 'HP:0030731', (139, 148))	('EGFR', 'Gene', '1956', (193, 197))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (130, 148))	('EGFR', 'Gene', '1956', (80, 84))	('SqCLC', 'Disease', (211, 216))	('EGFR', 'Gene', (80, 84))	('detected', 'Reg', (105, 113))	('mutations', 'Var', (85, 94))	('SqCLC', 'Disease', 'MESH:D018307', (211, 216))	('EGFR', 'Gene', (193, 197))	('Oncology', 'Phenotype', 'HP:0002664', (49, 57))	('non-squamous carcinoma', 'Disease', 'MESH:D002294', (126, 148))
437473	31802898	The Chinese Society of Clinical Oncology (CSCO) is mostly in accordance with the NCCN on this topic, but certainly points out that patients with squamous carcinoma mixed with adenocarcinoma should undergo EGFR mutation detection.	('patients', 'Species', '9606', (131, 139))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (145, 163))	('mutation detection', 'Var', (210, 228))	('adenocarcinoma', 'Disease', (175, 189))	('carcinoma', 'Phenotype', 'HP:0030731', (180, 189))	('EGFR', 'Gene', '1956', (205, 209))	('carcinoma', 'Phenotype', 'HP:0030731', (154, 163))	('EGFR', 'Gene', (205, 209))	('adenocarcinoma', 'Disease', 'MESH:D000230', (175, 189))	('squamous carcinoma', 'Disease', 'MESH:D002294', (145, 163))	('squamous carcinoma', 'Disease', (145, 163))	('Oncology', 'Phenotype', 'HP:0002664', (32, 40))
437475	31802898	Additionally, varying frequencies of EGFR mutations in SqCLC patients are reported from different institutes, testing platforms and ethnic groups.	('SqCLC', 'Disease', 'MESH:D018307', (55, 60))	('SqCLC', 'Disease', (55, 60))	('SqCLC', 'Phenotype', 'HP:0030359', (55, 60))	('patients', 'Species', '9606', (61, 69))	('EGFR', 'Gene', '1956', (37, 41))	('EGFR', 'Gene', (37, 41))	('mutations', 'Var', (42, 51))
437476	31802898	Yohei Miyamae et al have reported that the EGFR gene mutation rate is 3.4% (3/87) in Japanese SqCLC patients upon detecting 87 such patients by direct sequencing.	('SqCLC', 'Phenotype', 'HP:0030359', (94, 99))	('SqCLC', 'Disease', 'MESH:D018307', (94, 99))	('SqCLC', 'Disease', (94, 99))	('mutation', 'Var', (53, 61))	('EGFR', 'Gene', '1956', (43, 47))	('patients', 'Species', '9606', (100, 108))	('EGFR', 'Gene', (43, 47))	('patients', 'Species', '9606', (132, 140))
437477	31802898	Another study on Korean SqCLC patients, using the same method, demonstrated an EGFR mutation rate of 8.4% (21/250).	('EGFR', 'Gene', '1956', (79, 83))	('EGFR', 'Gene', (79, 83))	('patients', 'Species', '9606', (30, 38))	('SqCLC', 'Phenotype', 'HP:0030359', (24, 29))	('SqCLC', 'Disease', (24, 29))	('SqCLC', 'Disease', 'MESH:D018307', (24, 29))	('mutation', 'Var', (84, 92))
437478	31802898	Akito Hata et al used peptide nucleic acid-locked nucleic acid (PNA-LNA) to detect 249 SqCLC patients, 33 of whom were identified to harbor EGFR mutations with a mutation rate of 13.3%.	('EGFR', 'Gene', (140, 144))	('mutations', 'Var', (145, 154))	('SqCLC', 'Phenotype', 'HP:0030359', (87, 92))	('SqCLC', 'Disease', 'MESH:D018307', (87, 92))	('patients', 'Species', '9606', (93, 101))	('EGFR', 'Gene', '1956', (140, 144))	('SqCLC', 'Disease', (87, 92))
437479	31802898	Furthermore, Amit Joshi et al used TaqMan probe real-time fluorescent quantitative PCR in 639 SqCLC patients and found the EGFR mutation rate to be 4.5% (29/639).	('EGFR', 'Gene', (123, 127))	('SqCLC', 'Phenotype', 'HP:0030359', (94, 99))	('SqCLC', 'Disease', (94, 99))	('SqCLC', 'Disease', 'MESH:D018307', (94, 99))	('patients', 'Species', '9606', (100, 108))	('EGFR', 'Gene', '1956', (123, 127))	('mutation', 'Var', (128, 136))
437480	31802898	Interestingly, we noted that the EGFR mutation rate mentioned above ranged from 3.4% to 13.3% and the studies were mainly done in Asian patients.	('EGFR', 'Gene', '1956', (33, 37))	('patients', 'Species', '9606', (136, 144))	('mutation', 'Var', (38, 46))	('EGFR', 'Gene', (33, 37))
437481	31802898	However, all these studies failed to further distinguish predominant subgroups that are more likely to harbor EGFR mutations.	('EGFR', 'Gene', (110, 114))	('mutations', 'Var', (115, 124))	('EGFR', 'Gene', '1956', (110, 114))
437482	31802898	A study from Zhang et al revealed that female sex and non-smokers are correlated with higher EGFR mutations by detecting 28 positive cases among a total of 163 SqCLC patients using the ARMS-PCR method.	('EGFR', 'Gene', '1956', (93, 97))	('SqCLC', 'Phenotype', 'HP:0030359', (160, 165))	('SqCLC', 'Disease', 'MESH:D018307', (160, 165))	('EGFR', 'Gene', (93, 97))	('SqCLC', 'Disease', (160, 165))	('mutations', 'Var', (98, 107))	('higher', 'PosReg', (86, 92))	('patients', 'Species', '9606', (166, 174))
437483	31802898	Meanwhile, the study also confirmed that age and pathological differentiation seem to be unrelated to EGFR mutations.	('EGFR', 'Gene', '1956', (102, 106))	('EGFR', 'Gene', (102, 106))	('mutations', 'Var', (107, 116))
437485	31802898	Another study from Zhang TT et al identified that the proportion of poor and moderate differentiations was lower in EGFR mutation harboring SqCLC patients compared to wild type patients.	('patients', 'Species', '9606', (177, 185))	('lower', 'NegReg', (107, 112))	('patients', 'Species', '9606', (146, 154))	('SqCLC', 'Phenotype', 'HP:0030359', (140, 145))	('SqCLC', 'Disease', (140, 145))	('SqCLC', 'Disease', 'MESH:D018307', (140, 145))	('mutation', 'Var', (121, 129))	('EGFR', 'Gene', '1956', (116, 120))	('EGFR', 'Gene', (116, 120))
437486	31802898	Our study identified the EGFR mutation rate to be 8.2% in 292 SqCLC patients using the ARMS-PCR method, whose documented sensitivity is 1% and specificity can reach 100%.	('EGFR', 'Gene', (25, 29))	('mutation', 'Var', (30, 38))	('patients', 'Species', '9606', (68, 76))	('SqCLC', 'Disease', 'MESH:D018307', (62, 67))	('SqCLC', 'Phenotype', 'HP:0030359', (62, 67))	('EGFR', 'Gene', '1956', (25, 29))	('SqCLC', 'Disease', (62, 67))
437487	31802898	Besides different methods, the different sample sizes and a potential mix-up of SqCLC with adenocarcinoma patients can be attributed, in part, to the reporting of various EGFR mutation detection rates.	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('EGFR', 'Gene', (171, 175))	('SqCLC', 'Disease', (80, 85))	('SqCLC', 'Disease', 'MESH:D018307', (80, 85))	('SqCLC', 'Phenotype', 'HP:0030359', (80, 85))	('adenocarcinoma', 'Disease', 'MESH:D000230', (91, 105))	('patients', 'Species', '9606', (106, 114))	('EGFR', 'Gene', '1956', (171, 175))	('mutation', 'Var', (176, 184))	('adenocarcinoma', 'Disease', (91, 105))
437488	31802898	We also noted that, in our study, the detection rate of the EGFR mutation was 7.3% using NGS.	('EGFR', 'Gene', (60, 64))	('EGFR', 'Gene', '1956', (60, 64))	('mutation', 'Var', (65, 73))
437490	31802898	Mutated and wide-type cells generally co-exist in one solid tumor.	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Disease', (60, 65))	('Mutated', 'Var', (0, 7))	('tumor', 'Disease', 'MESH:D009369', (60, 65))
437491	31802898	(2) The small sample size combined with low frequency of EGFR mutation in this study, which may contribute to the discrepancy in the detection rate between the two methods.	('EGFR', 'Gene', '1956', (57, 61))	('mutation', 'Var', (62, 70))	('EGFR', 'Gene', (57, 61))
437492	31802898	Another finding from our study demonstrated that SqCLC patients harboring EGFR mutations may share the same clinicopathological characteristics with adenocarcinoma of lung - higher frequency in females and non-smokers.	('SqCLC', 'Disease', (49, 54))	('SqCLC', 'Disease', 'MESH:D018307', (49, 54))	('adenocarcinoma', 'Disease', 'MESH:D000230', (149, 163))	('carcinoma', 'Phenotype', 'HP:0030731', (154, 163))	('EGFR', 'Gene', '1956', (74, 78))	('adenocarcinoma', 'Disease', (149, 163))	('patients', 'Species', '9606', (55, 63))	('SqCLC', 'Phenotype', 'HP:0030359', (49, 54))	('EGFR', 'Gene', (74, 78))	('mutations', 'Var', (79, 88))
437493	31802898	At the same time, differentiation, staging, specimen type, serum CEA, and SCC levels were unrelated to EGFR mutations, which are consistent with several other studies.	('EGFR', 'Gene', '1956', (103, 107))	('SCC', 'Gene', '6317', (74, 77))	('CEA', 'Gene', '1048', (65, 68))	('mutations', 'Var', (108, 117))	('EGFR', 'Gene', (103, 107))	('SCC', 'Gene', (74, 77))	('CEA', 'Gene', (65, 68))
437497	31802898	In summary, we strongly recommend that SqCLC patients should be routinely subjected to the detection of an EGFR mutation, especially when patients are female and non-smokers.	('EGFR', 'Gene', '1956', (107, 111))	('mutation', 'Var', (112, 120))	('SqCLC', 'Phenotype', 'HP:0030359', (39, 44))	('SqCLC', 'Disease', (39, 44))	('SqCLC', 'Disease', 'MESH:D018307', (39, 44))	('EGFR', 'Gene', (107, 111))	('patients', 'Species', '9606', (45, 53))	('patients', 'Species', '9606', (138, 146))
437511	31802898	First, only 25% (73/292) of patients underwent NGS detection, which is capable of simultaneous detection of mutations, indels, copy number variations, and genomic rearrangements.	('indels', 'Var', (119, 125))	('copy number variations', 'Var', (127, 149))	('patients', 'Species', '9606', (28, 36))	('mutations', 'Var', (108, 117))
437512	31802898	ARMS-PCR detected only 29 previously identified point mutations in the EGFR gene and may have missed valuable information related to concurrent or accompanying mutations deemed important to broaden insights into the mechanisms of acquired resistance.	('EGFR', 'Gene', '1956', (71, 75))	('EGFR', 'Gene', (71, 75))	('point mutations', 'Var', (48, 63))
437513	31802898	Second, the frequency rate of the EGFR mutation in SqCLC is quite low and hinders adequate statistical significance to arrive at conclusions due to the small number of patients with mutations.	('mutation', 'Var', (39, 47))	('EGFR', 'Gene', (34, 38))	('SqCLC', 'Disease', 'MESH:D018307', (51, 56))	('low', 'NegReg', (66, 69))	('patients', 'Species', '9606', (168, 176))	('EGFR', 'Gene', '1956', (34, 38))	('SqCLC', 'Phenotype', 'HP:0030359', (51, 56))	('SqCLC', 'Disease', (51, 56))
437515	31802898	Last but not the least, it has been well established that mutations in PI3KCA, FGFR1, PETN, DDR2, IGF-1R, BRAF, and FGFR2 and amplification of PI3KCA and PDGFRA may be involved in the initialization and development of SqCLC.	('mutations', 'Var', (58, 67))	('SqCLC', 'Disease', (218, 223))	('PETN', 'Gene', (86, 90))	('FGFR1', 'Gene', (79, 84))	('IGF-1R', 'Gene', '3480', (98, 104))	('IGF-1R', 'Gene', (98, 104))	('FGFR2', 'Gene', '2263', (116, 121))	('SqCLC', 'Phenotype', 'HP:0030359', (218, 223))	('involved', 'Reg', (168, 176))	('PDGFRA', 'Gene', (154, 160))	('PDGFRA', 'Gene', '5156', (154, 160))	('DDR2', 'Gene', '4921', (92, 96))	('SqCLC', 'Disease', 'MESH:D018307', (218, 223))	('FGFR1', 'Gene', '2260', (79, 84))	('PI3KCA', 'Gene', (71, 77))	('PI3KCA', 'Gene', (143, 149))	('BRAF', 'Gene', '673', (106, 110))	('DDR2', 'Gene', (92, 96))	('BRAF', 'Gene', (106, 110))	('amplification', 'Var', (126, 139))	('FGFR2', 'Gene', (116, 121))
437517	31802898	Finally, with the widespread application of NGS in clinical practices and the increasing number of clinical trials, more driver mutations and drugs in SqCLC beyond EGFR and EGFR-TKIs are to be verified, with potential breakthroughs in this field possible in the near future.	('SqCLC', 'Disease', 'MESH:D018307', (151, 156))	('EGFR', 'Gene', (164, 168))	('mutations', 'Var', (128, 137))	('EGFR', 'Gene', '1956', (173, 177))	('SqCLC', 'Phenotype', 'HP:0030359', (151, 156))	('EGFR', 'Gene', (173, 177))	('EGFR', 'Gene', '1956', (164, 168))	('SqCLC', 'Disease', (151, 156))
437518	31802898	According to our study, we have confirmed that EGFR-sensitizing mutations remain a rare event in SqCLC patients.	('SqCLC', 'Disease', (97, 102))	('SqCLC', 'Disease', 'MESH:D018307', (97, 102))	('mutations', 'Var', (64, 73))	('EGFR', 'Gene', '1956', (47, 51))	('patients', 'Species', '9606', (103, 111))	('SqCLC', 'Phenotype', 'HP:0030359', (97, 102))	('EGFR', 'Gene', (47, 51))
437519	31802898	Both ARMS-PCR and NGS methods showed no difference in the detection of EGFR mutations.	('EGFR', 'Gene', '1956', (71, 75))	('EGFR', 'Gene', (71, 75))	('mutations', 'Var', (76, 85))
437520	31802898	Detection of EGFR mutations is recommended especially in female patients or those patients who have no history of smoking.	('patients', 'Species', '9606', (64, 72))	('patients', 'Species', '9606', (82, 90))	('EGFR', 'Gene', '1956', (13, 17))	('EGFR', 'Gene', (13, 17))	('mutations', 'Var', (18, 27))
437521	31802898	EGFR-TKIs show modest efficacies and low toxicity profiles in EGFR mutant cases.	('EGFR', 'Gene', '1956', (62, 66))	('EGFR', 'Gene', (0, 4))	('toxicity', 'Disease', 'MESH:D064420', (41, 49))	('toxicity', 'Disease', (41, 49))	('EGFR', 'Gene', (62, 66))	('mutant', 'Var', (67, 73))	('EGFR', 'Gene', '1956', (0, 4))
437528	31637211	Such cancer-omics data resources include the Catalog of Somatic Mutations in Cancer (COSMIC), the Cancer Genome Atlas (TCGA), the International Cancer Genome Consortium (ICGC), and the Cancer Proteome Atlas (TCPA).	('cancer', 'Disease', 'MESH:D009369', (5, 11))	('Cancer', 'Phenotype', 'HP:0002664', (144, 150))	('Cancer', 'Phenotype', 'HP:0002664', (77, 83))	('Cancer', 'Phenotype', 'HP:0002664', (98, 104))	('cancer', 'Disease', (5, 11))	('Mutations', 'Var', (64, 73))	('Cancer', 'Phenotype', 'HP:0002664', (185, 191))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))
437598	31637211	This was consistent with the subcellular localization observed in an immunofluorescent study of three cancer cell lines (A-431, U-2 OS and U-251 MG) in HPA (Figure S2).	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('U-251 MG', 'Var', (139, 147))
437630	31637211	In human cancers, the mutation rates of RRM1, RRM2, and RRM2B are all below 0.5%, based on the data from COSMIC and cBioPortal (Table S4).	('cancers', 'Disease', 'MESH:D009369', (9, 16))	('RRM2B', 'Gene', '50484', (56, 61))	('mutation', 'Var', (22, 30))	('cancers', 'Phenotype', 'HP:0002664', (9, 16))	('cancers', 'Disease', (9, 16))	('human', 'Species', '9606', (3, 8))	('RRM2', 'Gene', '6241', (56, 60))	('RRM2', 'Gene', (56, 60))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('RRM2', 'Gene', (46, 50))	('RRM1', 'Gene', '6240', (40, 44))	('RRM2B', 'Gene', (56, 61))	('RRM1', 'Gene', (40, 44))	('RRM2', 'Gene', '6241', (46, 50))
437645	31637211	Consistent with the role of RR in DNA replication and repair, a high RRM1 expression is known to be associated with a poor response to the DNA-damaging platinum drugs and to the RRM1-targeting drug gemcitabine, and thus led to poor outcomes in these cancer patients.	('expression', 'MPA', (74, 84))	('high', 'Var', (64, 68))	('cancer', 'Disease', 'MESH:D009369', (250, 256))	('RRM1', 'Gene', '6240', (69, 73))	('RRM1', 'Gene', '6240', (178, 182))	('platinum', 'Chemical', 'MESH:D010984', (152, 160))	('cancer', 'Disease', (250, 256))	('RRM1', 'Gene', (178, 182))	('RRM1', 'Gene', (69, 73))	('patients', 'Species', '9606', (257, 265))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))	('gemcitabine', 'Chemical', 'MESH:C056507', (198, 209))
437646	31637211	However, several studies have also shown that a highly expressed RRM1 might be associated with a better outcome for some cancer patients, suggestive of a suppressor role of tumor initiation, invasion and metastasis.	('associated', 'Reg', (79, 89))	('RRM1', 'Gene', '6240', (65, 69))	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('highly expressed', 'Var', (48, 64))	('RRM1', 'Gene', (65, 69))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumor', 'Disease', (173, 178))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('patients', 'Species', '9606', (128, 136))	('cancer', 'Disease', (121, 127))
437659	31637211	For RRM1, some studies showed that high RRM1 expression was associated with better survival in early stage NSCLC or had poor prognosis in advanced NSCLC or lung adenocarcinoma, while another study showed that RRM1 protein expression had no significant predictive value for early NSCLC patients.	('RRM1', 'Gene', '6240', (4, 8))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (156, 175))	('SCLC', 'Phenotype', 'HP:0030357', (108, 112))	('SCLC', 'Phenotype', 'HP:0030357', (148, 152))	('NSCLC', 'Disease', (279, 284))	('lung adenocarcinoma', 'Disease', (156, 175))	('better', 'PosReg', (76, 82))	('RRM1', 'Gene', '6240', (209, 213))	('carcinoma', 'Phenotype', 'HP:0030731', (166, 175))	('NSCLC', 'Disease', 'MESH:D002289', (107, 112))	('RRM1', 'Gene', '6240', (40, 44))	('SCLC', 'Phenotype', 'HP:0030357', (280, 284))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (156, 175))	('NSCLC', 'Disease', (107, 112))	('NSCLC', 'Disease', 'MESH:D002289', (147, 152))	('RRM1', 'Gene', (4, 8))	('NSCLC', 'Disease', (147, 152))	('RRM1', 'Gene', (209, 213))	('NSCLC', 'Disease', 'MESH:D002289', (279, 284))	('expression', 'MPA', (45, 55))	('RRM1', 'Gene', (40, 44))	('patients', 'Species', '9606', (285, 293))	('high', 'Var', (35, 39))
437660	31637211	For RRM2, some studies suggested that high expression of RRM2 prognosticated a shorter overall survival for NSCLC patients, while the others did not find any predictive value.	('RRM2', 'Gene', (4, 8))	('RRM2', 'Gene', '6241', (4, 8))	('shorter', 'NegReg', (79, 86))	('high expression', 'Var', (38, 53))	('NSCLC', 'Disease', (108, 113))	('NSCLC', 'Disease', 'MESH:D002289', (108, 113))	('SCLC', 'Phenotype', 'HP:0030357', (109, 113))	('patients', 'Species', '9606', (114, 122))	('RRM2', 'Gene', '6241', (57, 61))	('RRM2', 'Gene', (57, 61))	('overall survival', 'MPA', (87, 103))
437675	31637211	By contrast, RRM2 expression was significantly associated with cell cycle-progression (Figure 7B), consistent with its role as a RR subunit to promote cancer cell proliferation.	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('promote', 'PosReg', (143, 150))	('RRM2', 'Gene', (13, 17))	('cell cycle-progression', 'CPA', (63, 85))	('cancer', 'Disease', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('associated', 'Reg', (47, 57))	('RRM2', 'Gene', '6241', (13, 17))	('expression', 'Var', (18, 28))
437760	24615328	reported there were differences in specific genetic alterations detected in small cell lung cancer compared with non-small cell lung cancers, and the smoking-damaged bronchial epithelium of patients with small cell lung cancer showed considerably more genetic damage:in terms of allele loss and microsatellite alterations:than that of patients with non-small cell lung cancers.	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (349, 375))	('non-small cell lung cancers', 'Phenotype', 'HP:0030358', (349, 376))	('cancers', 'Phenotype', 'HP:0002664', (369, 376))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (76, 98))	('genetic damage', 'Disease', (252, 266))	('patients', 'Species', '9606', (190, 198))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (353, 375))	('small cell lung cancer', 'Disease', 'MESH:D055752', (117, 139))	('non-small cell lung cancers', 'Disease', 'MESH:D002289', (113, 140))	('microsatellite alterations', 'Var', (295, 321))	('small cell lung cancer', 'Disease', 'MESH:D055752', (204, 226))	('small cell lung cancers', 'Phenotype', 'HP:0030357', (353, 376))	('small cell lung cancer', 'Disease', (204, 226))	('lung cancer', 'Phenotype', 'HP:0100526', (128, 139))	('non-small cell lung cancers', 'Disease', 'MESH:D002289', (349, 376))	('lung cancer', 'Phenotype', 'HP:0100526', (215, 226))	('lung cancers', 'Phenotype', 'HP:0100526', (128, 140))	('small cell lung cancer', 'Disease', 'MESH:D055752', (76, 98))	('cancers', 'Phenotype', 'HP:0002664', (133, 140))	('small cell lung cancer', 'Disease', (76, 98))	('non-small cell lung cancers', 'Disease', (113, 140))	('lung cancer', 'Phenotype', 'HP:0100526', (87, 98))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('small cell lung cancer', 'Disease', 'MESH:D055752', (353, 375))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (117, 139))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (113, 139))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('non-small cell lung cancers', 'Phenotype', 'HP:0030358', (113, 140))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('genetic damage', 'Disease', 'MESH:D030342', (252, 266))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (204, 226))	('lung cancer', 'Phenotype', 'HP:0100526', (364, 375))	('cancer', 'Phenotype', 'HP:0002664', (369, 375))	('non-small cell lung cancers', 'Disease', (349, 376))	('small cell lung cancers', 'Phenotype', 'HP:0030357', (117, 140))	('patients', 'Species', '9606', (335, 343))	('lung cancers', 'Phenotype', 'HP:0100526', (364, 376))
437761	24615328	Rb and p53 mutations, which occur in up to 90% of human small cell lung cancers, are examples of genetic damage caused by smoking.	('mutations', 'Var', (11, 20))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (56, 78))	('genetic damage', 'Disease', (97, 111))	('genetic damage', 'Disease', 'MESH:D030342', (97, 111))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('lung cancers', 'Phenotype', 'HP:0100526', (67, 79))	('small cell lung cancers', 'Disease', 'MESH:D055752', (56, 79))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('small cell lung cancers', 'Phenotype', 'HP:0030357', (56, 79))	('small cell lung cancers', 'Disease', (56, 79))	('human', 'Species', '9606', (50, 55))	('lung cancer', 'Phenotype', 'HP:0100526', (67, 78))	('p53', 'Gene', (7, 10))
437780	33362860	Identification of Potential Long Non-coding RNA Expression Quantitative Trait Methylations in Lung Adenocarcinoma and Lung Squamous Carcinoma There are associations between DNA methylation and the expression of long non-coding RNA (lncRNA), also known as lncRNA expression quantitative trait methylations (lnc-eQTMs).	('Carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('associations', 'Interaction', (152, 164))	('Methylations', 'Var', (78, 90))	('Squamous Carcinoma', 'Phenotype', 'HP:0002860', (123, 141))	('Lung Adenocarcinoma and Lung Squamous Carcinoma', 'Disease', 'MESH:D000077192', (94, 141))	('expression', 'MPA', (197, 207))	('Lung Adenocarcinoma', 'Phenotype', 'HP:0030078', (94, 113))	('Lung Squamous Carcinoma', 'Phenotype', 'HP:0030359', (118, 141))
437791	33362860	Targeted drugs are available for a certain number of patients with NSCLC harboring gene alterations.	('patients', 'Species', '9606', (53, 61))	('NSCLC', 'Phenotype', 'HP:0030358', (67, 72))	('NSCLC', 'Disease', (67, 72))	('gene alterations', 'Var', (83, 99))	('NSCLC', 'Disease', 'MESH:D002289', (67, 72))
437800	33362860	For instance, methylation of H3K36 activates NOTCH signaling to drive breast tumor initiation and metastatic progression.	('H3K36', 'Protein', (29, 34))	('breast tumor', 'Disease', 'MESH:D001943', (70, 82))	('activates', 'PosReg', (35, 44))	('drive', 'PosReg', (64, 69))	('breast tumor', 'Disease', (70, 82))	('methylation', 'Var', (14, 25))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('NOTCH signaling', 'MPA', (45, 60))	('breast tumor', 'Phenotype', 'HP:0100013', (70, 82))	('metastatic progression', 'CPA', (98, 120))
437801	33362860	For example, knockdown of lncRNA HOTAIR has been carried out in multidrug-resistant lung cancer cell lines (H69AR and H446AR) to assess its influence on chemoresistance.	('H69', 'CellLine', 'CVCL:8121', (108, 111))	('lung cancer', 'Phenotype', 'HP:0100526', (84, 95))	('multidrug-resistant lung cancer', 'Disease', (64, 95))	('HOTAIR', 'Gene', (33, 39))	('HOTAIR', 'Gene', '100124700', (33, 39))	('multidrug-resistant lung cancer', 'Disease', 'MESH:D008175', (64, 95))	('H446AR', 'Mutation', 'p.H446AR', (118, 124))	('knockdown', 'Var', (13, 22))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
437804	33362860	Functional analyses showed that these DMSmlncRNAs were associated with cancer-related functions, such as lung epithelium development and vasculogenesis.	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('cancer', 'Disease', (71, 77))	('vasculogenesis', 'CPA', (137, 151))	('associated', 'Reg', (55, 65))	('lung epithelium development', 'CPA', (105, 132))	('DMSmlncRNAs', 'Var', (38, 49))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))
437818	33362860	For these DLX6-AS1-centric lnc-eQTMs, DMS cg21945930 showed the strongest correlation difference with DLX6-AS1 in LUSC (PCC = 0.14) and normal tissues (PCC = 0.83, PCC difference = 0.69).	('DLX6-AS1', 'Gene', (102, 110))	('DMS cg21945930', 'Var', (38, 52))	('DLX6-AS1', 'Gene', (10, 18))	('LUSC', 'Phenotype', 'HP:0030359', (114, 118))	('cg21945930', 'Chemical', '-', (42, 52))	('DLX6-AS1', 'Gene', '285987', (102, 110))	('cg21945930', 'Var', (42, 52))	('correlation', 'Interaction', (74, 85))	('DLX6-AS1', 'Gene', '285987', (10, 18))
437819	33362860	The correlation between cg21945930 and DLX6-AS1 showed a strong change in LUSC compared with normal tissues.	('change', 'Reg', (64, 70))	('DLX6-AS1', 'Gene', (39, 47))	('correlation', 'Interaction', (4, 15))	('cg21945930', 'Chemical', '-', (24, 34))	('DLX6-AS1', 'Gene', '285987', (39, 47))	('LUSC', 'Phenotype', 'HP:0030359', (74, 78))	('cg21945930', 'Var', (24, 34))	('LUSC', 'CPA', (74, 78))
437827	33362860	For example, lnc-eQTM AC005082.12 was significantly related with survival in LUAD patients (P = 0.032, Figure 4C).	('patients', 'Species', '9606', (82, 90))	('AC005082.12', 'Var', (22, 33))	('LUAD', 'Phenotype', 'HP:0030078', (77, 81))	('lnc-eQTM AC005082.12', 'Var', (13, 33))	('related with', 'Reg', (52, 64))
437838	33362860	The associations between epigenetic modifications, such as aberrant DNA methylation and histone modifications, and lncRNA expression play a role in many kinds of diseases, including cancer.	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('aberrant', 'Var', (59, 67))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('cancer', 'Disease', (182, 188))	('DNA', 'Protein', (68, 71))	('role', 'Reg', (140, 144))	('histone', 'MPA', (88, 95))	('associations', 'Interaction', (4, 16))	('lncRNA expression', 'MPA', (115, 132))
437842	33362860	PRC2 is involved in trimethylation of specific lysine residues (K9 and K27) in histone H3 (H3K9me3 and H3K27me3).	('K27', 'Gene', '342574', (71, 74))	('K27', 'Gene', (71, 74))	('K9', 'Var', (64, 66))	('K27', 'Gene', (105, 108))	('H3K9me3', 'Var', (91, 98))	('lysine', 'Chemical', 'MESH:D008239', (47, 53))	('involved', 'Reg', (8, 16))	('PRC2', 'Gene', (0, 4))	('K27', 'Gene', '342574', (105, 108))
437843	33362860	Several studies have suggested that lncRNAs could be regulated by DNA methylation in cancers.	('cancers', 'Phenotype', 'HP:0002664', (85, 92))	('cancers', 'Disease', 'MESH:D009369', (85, 92))	('cancers', 'Disease', (85, 92))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('DNA', 'Var', (66, 69))
437844	33362860	For instance, the expression level of lncRNA CTC-276P9.1 was associated with the aberrant hypermethylation of regions around the transcription start site in esophageal cancer.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('expression level', 'MPA', (18, 34))	('CTC-276P9.1', 'Gene', (45, 56))	('aberrant', 'MPA', (81, 89))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('CTC-276P9.1', 'Gene', '101927953', (45, 56))	('cancer', 'Disease', (168, 174))	('associated', 'Reg', (61, 71))	('lncRNA', 'Var', (38, 44))
437858	33039710	The CUP-AI-Dx molecular subtype was also independently tested on independent ovarian and breast cancer microarray datasets CUP-AI-Dx identifies the primary site with an overall top-1-accuracy of 98.54% in cross-validation and 96.70% on a test dataset.	('breast cancer', 'Disease', 'MESH:D001943', (89, 102))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('breast cancer', 'Disease', (89, 102))	('breast cancer', 'Phenotype', 'HP:0003002', (89, 102))	('CUP-AI-Dx', 'Var', (123, 132))	('ovarian', 'Disease', 'MESH:D010049', (77, 84))	('ovarian', 'Disease', (77, 84))
437874	33039710	The paradigm of precision oncology involving detection of therapeutically actionable mutations may be of benefit for some CUP patients; however, access to these drugs can be limited, especially outside of clinical trials or through compassionate access, as with few exceptions such treatments are approved for specific tumour type indications.	('tumour', 'Phenotype', 'HP:0002664', (319, 325))	('tumour', 'Disease', 'MESH:D009369', (319, 325))	('oncology', 'Phenotype', 'HP:0002664', (26, 34))	('mutations', 'Var', (85, 94))	('tumour', 'Disease', (319, 325))	('patients', 'Species', '9606', (126, 134))
437951	33039710	show that there are five distinct molecular subtypes shared among hypermutated ESCA, STAD, COAD, and READ tumours.	('COAD', 'Disease', (91, 95))	('tumour', 'Phenotype', 'HP:0002664', (106, 112))	('tumours', 'Phenotype', 'HP:0002664', (106, 113))	('READ tumours', 'Disease', 'MESH:D009369', (101, 113))	('COAD', 'Disease', 'MESH:D029424', (91, 95))	('hypermutated', 'Var', (66, 78))	('READ tumours', 'Disease', (101, 113))	('STAD', 'Disease', (85, 89))
438043	31819775	The targeting ability of 125I-anti-CD93 mAb enabled its rapid, continuous and highly specific accumulation in CD93-expressing tumors in vivo.	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('tumors', 'Disease', (126, 132))	('tumors', 'Disease', 'MESH:D009369', (126, 132))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('125I-anti-CD93', 'Var', (25, 39))	('125I', 'Chemical', 'MESH:C492712', (25, 29))
438044	31819775	These results revealed the potential applicability of 125I-anti-CD93 mAb for non-invasive imaging diagnosis of CD93-positive NSCLC.	('NSCLC', 'Disease', (125, 130))	('NSCLC', 'Disease', 'MESH:D002289', (125, 130))	('125I-anti-CD93', 'Var', (54, 68))	('125I', 'Chemical', 'MESH:C492712', (54, 58))	('125I-anti-CD93', 'Gene', (54, 68))	('NSCLC', 'Phenotype', 'HP:0030358', (125, 130))
438046	31819775	Non-small cell lung cancer (NSCLC) accounts for 15% of all cases of lung cancer with multiple toxin-associated mutations, including epidermal growth factor, KRAS, PI3K subunit alpha (PIK3CA) and AKT1 mutations and PIK3CA amplification.	('lung cancer', 'Phenotype', 'HP:0100526', (68, 79))	('mutations', 'Var', (200, 209))	('Non-small cell lung cancer', 'Disease', 'MESH:D002289', (0, 26))	('PIK3CA', 'Gene', '5290', (183, 189))	('PIK3CA', 'Gene', '5290', (214, 220))	('AKT1', 'Gene', '207', (195, 199))	('NSCLC', 'Disease', 'MESH:D002289', (28, 33))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('Non-small cell lung cancer', 'Disease', (0, 26))	('NSCLC', 'Disease', (28, 33))	('lung cancer', 'Disease', (68, 79))	('AKT1', 'Gene', (195, 199))	('lung cancer', 'Disease', 'MESH:D008175', (15, 26))	('Non-small cell lung cancer', 'Phenotype', 'HP:0030358', (0, 26))	('NSCLC', 'Phenotype', 'HP:0030358', (28, 33))	('PIK3CA', 'Gene', (183, 189))	('PIK3CA', 'Gene', (214, 220))	('lung cancer', 'Phenotype', 'HP:0100526', (15, 26))	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('KRAS', 'Gene', '3845', (157, 161))	('amplification', 'Var', (221, 234))	('epidermal growth factor', 'Gene', (132, 155))	('lung cancer', 'Disease', 'MESH:D008175', (68, 79))	('KRAS', 'Gene', (157, 161))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (4, 26))
438112	31819775	The ratio of CD93 to GAPDH was obtained by normalizing the band intensities of CD93 to those of GAPDH at the protein level.	('GAPDH', 'Gene', '2597', (96, 101))	('GAPDH', 'Gene', (96, 101))	('GAPDH', 'Gene', (21, 26))	('CD93', 'Var', (79, 83))	('GAPDH', 'Gene', '2597', (21, 26))
438114	31819775	Labeling of the anti-CD93 mAb with 125I resulted in a labeling yield of 91.37+-2.21%, whereas labeling of the IgG yielded 90.24+-1.58% 125I-IgG.	('labeling', 'MPA', (54, 62))	('125I', 'Var', (35, 39))	('125I', 'Chemical', 'MESH:C492712', (135, 139))	('125I', 'Chemical', 'MESH:C492712', (35, 39))
438118	31819775	The cell-binding studies indicated that the Kd of 125I-anti-CD93 mAb was ~27.09+-1.81 nM for A549 cells and 40.31+-3.55 nM for SK-MES-1 cells (Fig.	('A549', 'CellLine', 'CVCL:0023', (93, 97))	('125I-anti-CD93', 'Var', (50, 64))	('125I', 'Chemical', 'MESH:C492712', (50, 54))	('SK-MES-1', 'CellLine', 'CVCL:0630', (127, 135))	('125I-anti-CD93', 'Gene', (50, 64))
438119	31819775	4A), demonstrating that 125I-anti-CD93 mAb had a higher binding affinity for A549 cells than for SK-MES-1 cells.	('125I', 'Chemical', 'MESH:C492712', (24, 28))	('SK-MES-1', 'CellLine', 'CVCL:0630', (97, 105))	('binding affinity', 'Interaction', (56, 72))	('125I-anti-CD93', 'Var', (24, 38))	('higher', 'PosReg', (49, 55))	('A549', 'CellLine', 'CVCL:0023', (77, 81))
438121	31819775	Whole-body phosphor autoradiography was performed at 24, 48 and 72 h after injection of the 125I-anti-CD93 mAb into the A549 and SK-MES-1 tumor-bearing mice.	('tumor', 'Disease', (138, 143))	('125I-anti-CD93', 'Var', (92, 106))	('125I', 'Chemical', 'MESH:C492712', (92, 96))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('SK-MES-1', 'CellLine', 'CVCL:0630', (129, 137))	('mice', 'Species', '10090', (152, 156))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('A549', 'CellLine', 'CVCL:0023', (120, 124))
438122	31819775	The uptake of 125I-anti-CD93 mAb in A549 tumor bearing mice increased from 24 h and declined at 72 h (Fig.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('125I-anti-CD93', 'Var', (14, 28))	('125I', 'Chemical', 'MESH:C492712', (14, 18))	('tumor', 'Disease', (41, 46))	('declined', 'NegReg', (84, 92))	('mice', 'Species', '10090', (55, 59))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('A549', 'CellLine', 'CVCL:0023', (36, 40))	('uptake', 'MPA', (4, 10))	('increased', 'PosReg', (60, 69))
438128	31819775	5), suggesting that there was a specific accumulation of 125I-anti-CD93 mAb in the CD93-positive tumors only.	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('accumulation', 'PosReg', (41, 53))	('125I-anti-CD93', 'Var', (57, 71))	('125I', 'Chemical', 'MESH:C492712', (57, 61))	('tumors', 'Disease', (97, 103))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('125I-anti-CD93', 'Gene', (57, 71))	('tumors', 'Disease', 'MESH:D009369', (97, 103))
438130	31819775	As presented in Table I, 125I-anti-CD93 mAb exhibited favorable blood clearance efficiency in A549 tumor xenograft models, comparable with the non-tumor-bearing mice (Table II).	('tumor', 'Disease', (99, 104))	('tumor', 'Disease', (147, 152))	('mice', 'Species', '10090', (161, 165))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('A549', 'CellLine', 'CVCL:0023', (94, 98))	('blood clearance', 'CPA', (64, 79))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('125I-anti-CD93', 'Var', (25, 39))	('125I', 'Chemical', 'MESH:C492712', (25, 29))
438131	31819775	The uptake of 125I-anti-CD93 mAb by A549 tumors was 7.81+-0.80, 6.42+-0.71 and 3.51+-0.44% ID/g, with T/NT ratios of 2.42+-0.14, 4.45+-0.86 and 2.69+-0.13 at 24, 48 and 72 h post injection, respectively.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('125I-anti-CD93', 'Var', (14, 28))	('125I', 'Chemical', 'MESH:C492712', (14, 18))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('tumors', 'Disease', 'MESH:D009369', (41, 47))	('tumors', 'Disease', (41, 47))	('A549', 'CellLine', 'CVCL:0023', (36, 40))	('uptake', 'MPA', (4, 10))
438132	31819775	By contrast, the T/NT ratios of 125I-anti-CD93 mAb in SK-MES-1 tumors were 1.67+-0.27, 1.97+-0.07 and 2.02+-0.18 at 24, 48 and 72 h post injection, respectively, which were significantly lower than those in A549 tumors (Fig.	('SK-MES-1', 'Disease', (54, 62))	('tumors', 'Disease', (212, 218))	('tumors', 'Disease', 'MESH:D009369', (212, 218))	('125I-anti-CD93', 'Var', (32, 46))	('SK-MES-1', 'CellLine', 'CVCL:0630', (54, 62))	('125I', 'Chemical', 'MESH:C492712', (32, 36))	('A549', 'CellLine', 'CVCL:0023', (207, 211))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('tumors', 'Phenotype', 'HP:0002664', (212, 218))	('tumors', 'Disease', (63, 69))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
438140	31819775	Tumor angiogenesis occurs through the regulation of genes, including inhibitors of DNA binding-1, endothelial tyrosine kinase and CD34, that orchestrate endothelial sprouting and vessel maturation, including the deposition of a vessel-associated extracellular matrix.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('CD34', 'Gene', (130, 134))	('endothelial tyrosine kinase', 'Gene', '7010', (98, 125))	('CD34', 'Gene', '947', (130, 134))	('endothelial tyrosine kinase', 'Gene', (98, 125))	('Tumor angiogenesis', 'CPA', (0, 18))	('inhibitors', 'Var', (69, 79))
438142	31819775	Langenkamp et al reported that high expression of CD93 promoted angiogenesis and reduced survival of patients with high-grade astrocytic gliomas.	('glioma', 'Phenotype', 'HP:0009733', (137, 143))	('patients', 'Species', '9606', (101, 109))	('gliomas', 'Phenotype', 'HP:0009733', (137, 144))	('survival', 'CPA', (89, 97))	('angiogenesis', 'CPA', (64, 76))	('high expression', 'Var', (31, 46))	('reduced', 'NegReg', (81, 88))	('promoted', 'PosReg', (55, 63))	('CD93', 'Gene', (50, 54))	('astrocytic gliomas', 'Disease', 'MESH:D001254', (126, 144))	('astrocytic gliomas', 'Disease', (126, 144))
438147	31819775	Thus, 125I-anti-CD93 mAb could be used in these NSCLC models, which is more clinically relevant compared with conventional tumor imaging agents.	('NSCLC', 'Disease', (48, 53))	('tumor', 'Disease', (123, 128))	('NSCLC', 'Phenotype', 'HP:0030358', (48, 53))	('NSCLC', 'Disease', 'MESH:D002289', (48, 53))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('125I-anti-CD93', 'Var', (6, 20))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('125I', 'Chemical', 'MESH:C492712', (6, 10))
438149	31819775	However, an unexpectedly high uptake (6.06+-0.83% ID/g) in the spleen was observed 24 h after 125I-anti-CD93 mAb administration.	('125I-anti-CD93', 'Var', (94, 108))	('uptake', 'MPA', (30, 36))	('125I', 'Chemical', 'MESH:C492712', (94, 98))
438150	31819775	This may be due to the spleen being blood-rich and the biggest immune organ, which contained more CD93-positive immunocytes, so 125I-anti-CD93 mAb in the blood may have more chances of binding to these immunocytes, leading to the relatively higher radioactivity retention.	('125I-anti-CD93 mAb', 'Var', (128, 146))	('binding', 'Interaction', (185, 192))	('125I', 'Chemical', 'MESH:C492712', (128, 132))	('higher', 'PosReg', (241, 247))	('radioactivity retention', 'MPA', (248, 271))
438154	31819775	These cell-specific and favorable non-target clearance features of 125I-anti-CD93 mAb make it a promising radiotracer for imaging NSCLC.	('NSCLC', 'Disease', 'MESH:D002289', (130, 135))	('NSCLC', 'Phenotype', 'HP:0030358', (130, 135))	('125I-anti-CD93', 'Var', (67, 81))	('125I-anti-CD93', 'Gene', (67, 81))	('125I', 'Chemical', 'MESH:C492712', (67, 71))	('NSCLC', 'Disease', (130, 135))
438162	31819775	The specificity of a targeted probe based on CD93 expression in the two different NSCLC xenograft models was evaluated, and 125I-anti-CD93 mAb revealed a higher rate of radiotracer retention in A549 tumors compared with that in SK-MES-1 tumors at all time points.	('tumors', 'Disease', (199, 205))	('tumors', 'Disease', 'MESH:D009369', (199, 205))	('125I', 'Chemical', 'MESH:C492712', (124, 128))	('NSCLC', 'Phenotype', 'HP:0030358', (82, 87))	('tumors', 'Disease', (237, 243))	('tumors', 'Disease', 'MESH:D009369', (237, 243))	('tumors', 'Phenotype', 'HP:0002664', (237, 243))	('higher', 'PosReg', (154, 160))	('tumors', 'Phenotype', 'HP:0002664', (199, 205))	('radiotracer retention', 'MPA', (169, 190))	('SK-MES-1', 'CellLine', 'CVCL:0630', (228, 236))	('A549', 'CellLine', 'CVCL:0023', (194, 198))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('NSCLC', 'Disease', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))	('A549', 'Var', (194, 198))	('NSCLC', 'Disease', 'MESH:D002289', (82, 87))
438171	29095550	Downregulation of CD24 suppresses bone metastasis of lung cancer Suppression of bone metastasis can improve patient quality of life.	('bone metastasis of lung cancer', 'Disease', 'MESH:D009362', (34, 64))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('suppresses', 'NegReg', (23, 33))	('Downregulation', 'Var', (0, 14))	('bone metastasis of lung cancer', 'Disease', (34, 64))	('CD24', 'Gene', '100133941', (18, 22))	('patient', 'Species', '9606', (108, 115))	('lung cancer', 'Phenotype', 'HP:0100526', (53, 64))	('CD24', 'Gene', (18, 22))
438179	29095550	Our findings indicate that iRFP720 is effective for in vivo imaging analysis of bone metastasis and that downregulation of CD24 suppresses bone metastasis of lung cancer cells.	('iRFP', 'Gene', '100038882', (27, 31))	('iRFP', 'Gene', (27, 31))	('lung cancer', 'Phenotype', 'HP:0100526', (158, 169))	('CD24', 'Gene', (123, 127))	('bone metastasis of lung cancer', 'Disease', 'MESH:D009362', (139, 169))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('suppresses', 'NegReg', (128, 138))	('downregulation', 'Var', (105, 119))	('bone metastasis of lung cancer', 'Disease', (139, 169))
438204	29095550	Each cell solution (100 muL) was incubated with 5 muL anti-CD24 antibody (Miltenyi Biotec, Bergisch Gladbach, Germany) or 0.5 muL isotype control (Miltenyi Biotec) for 30 minutes at 4 C. After washing with FACS buffer, samples were analyzed using MACS Quant (Miltenyi Biotec).	('anti-CD24', 'Gene', (54, 63))	('anti-CD24', 'Var', (54, 63))	('Biotec', 'Chemical', '-', (83, 89))	('Biotec', 'Chemical', '-', (268, 274))	('Biotec', 'Chemical', '-', (156, 162))
438223	29095550	Previous studies have shown that CD24 is associated with poor prognosis of several cancers.4, 16, 17 Consistent with this, meta-analysis data indicate that the overall survival rate of patients with high CD24 expression is lower than that for those with low CD24 expression for breast, bladder, and lung cancer (Figure 1).	('cancers', 'Disease', 'MESH:D009369', (83, 90))	('bladder', 'Disease', (286, 293))	('lung cancer', 'Disease', 'MESH:D008175', (299, 310))	('expression', 'MPA', (209, 219))	('CD24', 'Gene', (204, 208))	('breast', 'Disease', (278, 284))	('lower', 'NegReg', (223, 228))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('cancer', 'Phenotype', 'HP:0002664', (304, 310))	('lung cancer', 'Disease', (299, 310))	('lung cancer', 'Phenotype', 'HP:0100526', (299, 310))	('high', 'Var', (199, 203))	('patients', 'Species', '9606', (185, 193))	('cancers', 'Phenotype', 'HP:0002664', (83, 90))	('survival', 'MPA', (168, 176))	('cancers', 'Disease', (83, 90))
438255	29095550	These results indicate that knockdown of CD24 markedly reduces bone metastasis of HARA-B4 cells in vivo.	('HARA-B4', 'CellLine', 'CVCL:4W91', (82, 89))	('reduces', 'NegReg', (55, 62))	('knockdown', 'Var', (28, 37))	('CD24', 'Gene', (41, 45))	('bone metastasis of', 'CPA', (63, 81))
438267	29095550	The role of CD-24 in bone metastasis was further validated in our in vivo findings; mice inoculated with shCD24 cells showed decreased bone metastasis, which was reversed in mice inoculated with resistant cells, revealing CD24-specific effects.	('mice', 'Species', '10090', (174, 178))	('decreased', 'NegReg', (125, 134))	('shCD24', 'Var', (105, 111))	('bone metastasis', 'CPA', (135, 150))	('mice', 'Species', '10090', (84, 88))
438284	29095550	Importantly, inhibition of CD24 by mAbs and siRNAs have been reported to reduce primary tumor growth and metastasis of colon, pancreas, and bladder cancers,29, 30 suggesting that bone metastasis of lung cancer can be suppressed by drugs targeting CD24.	('bladder cancers', 'Disease', 'MESH:D001749', (140, 155))	('cancers', 'Phenotype', 'HP:0002664', (148, 155))	('lung cancer', 'Phenotype', 'HP:0100526', (198, 209))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('inhibition', 'Var', (13, 23))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('bladder cancers', 'Disease', (140, 155))	('bone metastasis of lung cancer', 'Disease', (179, 209))	('metastasis of colon, pancreas', 'Disease', 'MESH:D009362', (105, 134))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor', 'Disease', (88, 93))	('CD24', 'Gene', (27, 31))	('reduce', 'NegReg', (73, 79))	('bone metastasis of lung cancer', 'Disease', 'MESH:D009362', (179, 209))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))
438285	29095550	In conclusion, we have shown that CD24 is highly expressed in a bone metastatic lung cancer cell line, promotes anchorage-independent growth and adhesion in vitro, and that CD24-knockdown suppressed bone metastasis of lung cancer cells in vivo.	('lung cancer', 'Phenotype', 'HP:0100526', (218, 229))	('bone metastasis of lung cancer', 'Disease', 'MESH:D009362', (199, 229))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('anchorage-independent growth', 'CPA', (112, 140))	('suppressed', 'NegReg', (188, 198))	('adhesion', 'CPA', (145, 153))	('CD24-knockdown', 'Var', (173, 187))	('bone metastatic lung cancer', 'Disease', (64, 91))	('bone metastatic lung cancer', 'Disease', 'MESH:D001859', (64, 91))	('CD24', 'Gene', (34, 38))	('lung cancer', 'Phenotype', 'HP:0100526', (80, 91))	('bone metastasis of lung cancer', 'Disease', (199, 229))	('promotes', 'PosReg', (103, 111))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
438336	28727543	Interestingly, this group of NSCLC was enriched in cases with EGF receptor mutations (P < .0001, Wilcoxon rank-sum test).	('NSCLC', 'Phenotype', 'HP:0030358', (29, 34))	('NSCLC', 'Disease', (29, 34))	('mutations', 'Var', (75, 84))	('EGF receptor', 'Gene', '1956', (62, 74))	('NSCLC', 'Disease', 'MESH:D002289', (29, 34))	('EGF receptor', 'Gene', (62, 74))
438345	28727543	When these tumors are enriched in mutations in EGF receptor, thereby severing the inhibitory link with LRIG1, downstream activation of KRAS and PIK3CA pathways again occur but manifest with a different phenotype at CT as cancers with markedly irregular or poorly defined margins, most likely caused by the presence of ground-glass opacity.	('cancers', 'Disease', 'MESH:D009369', (221, 228))	('LRIG1', 'Gene', '26018', (103, 108))	('severing', 'NegReg', (69, 77))	('PIK3CA', 'Gene', '5290', (144, 150))	('tumors', 'Disease', 'MESH:D009369', (11, 17))	('activation', 'PosReg', (121, 131))	('cancers', 'Phenotype', 'HP:0002664', (221, 228))	('PIK3CA', 'Gene', (144, 150))	('inhibitory link', 'MPA', (82, 97))	('cancers', 'Disease', (221, 228))	('EGF receptor', 'Gene', '1956', (47, 59))	('tumors', 'Phenotype', 'HP:0002664', (11, 17))	('KRAS', 'Gene', '3845', (135, 139))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('ground-glass opacity', 'Phenotype', 'HP:0025179', (318, 338))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('KRAS', 'Gene', (135, 139))	('EGF receptor', 'Gene', (47, 59))	('tumors', 'Disease', (11, 17))	('mutations', 'Var', (34, 43))	('LRIG1', 'Gene', (103, 108))
438368	25184138	These changes could affect cancer development by modulating downstream signal transduction pathways such as the well-known AKT signaling pathway.	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('AKT', 'Gene', '207', (123, 126))	('modulating', 'Reg', (49, 59))	('changes', 'Var', (6, 13))	('cancer', 'Disease', (27, 33))	('cancer', 'Disease', 'MESH:D009369', (27, 33))	('affect', 'Reg', (20, 26))	('AKT', 'Gene', (123, 126))
438404	25184138	We created 3 corresponding mutant constructs by mutating the seed regions of the miR-375 binding sites: PsiCHECKUM-mut1 plasmid contains mutated binding site at position 2276-2282, PsiCHECKUM-mut2 plasmid contains mutated binding site at position 2993-2999, and PsiCHECKUM-mut3 plasmid contains mutated binding sites at both positions as mentioned above.	('mutating', 'Var', (48, 56))	('miR-375', 'Gene', '494324', (81, 88))	('binding', 'Interaction', (222, 229))	('miR-375', 'Gene', (81, 88))
438420	25184138	miR-375 was found to be downregulated in LSCC tissues by qRT-PCR, implicating its potential role in regulating LSCC cells' biological behaviors.	('miR-375', 'Gene', (0, 7))	('downregulated', 'NegReg', (24, 37))	('miR-375', 'Gene', '494324', (0, 7))	('regulating', 'Reg', (100, 110))	('qRT-PCR', 'Var', (57, 64))
438424	25184138	The percentage of apoptotic cells was significantly increased in response to miR-375 overexpression compared with miR-NC overexpression in SNU46 cells.	('miR', 'Gene', (77, 80))	('miR-375', 'Gene', '494324', (77, 84))	('increased', 'PosReg', (52, 61))	('miR', 'Gene', '220972', (77, 80))	('SNU46', 'CellLine', 'CVCL:5063', (139, 144))	('apoptotic cells', 'CPA', (18, 33))	('miR-375', 'Gene', (77, 84))	('miR', 'Gene', '220972', (114, 117))	('miR', 'Gene', (114, 117))	('overexpression', 'Var', (85, 99))
438425	25184138	In SNU899 cells, an increase in apoptotic cells was observed with miR-375 overexpression compared with miR-NC overexpression.	('miR-375', 'Gene', (66, 73))	('miR', 'Gene', (66, 69))	('miR-375', 'Gene', '494324', (66, 73))	('apoptotic cells', 'CPA', (32, 47))	('miR', 'Gene', '220972', (66, 69))	('miR', 'Gene', '220972', (103, 106))	('miR', 'Gene', (103, 106))	('overexpression', 'Var', (74, 88))
438432	25184138	Two potential miR-375 targeting sites were identified at position 2276 and 2993, respectively, in IGF1R 3'-UTR (Figure 6(a)).	('miR-375', 'Gene', (14, 21))	('IGF1R', 'Gene', (98, 103))	('IGF1R', 'Gene', '3480', (98, 103))	('2993', 'Var', (75, 79))	('miR-375', 'Gene', '494324', (14, 21))
438433	25184138	To confirm the target relationship, four luciferase reporter plasmids were generated, including the psiCHECK-2-wild-IGF1R-3'UTR reporter plasmid (wt) with the wild-type IGF1R target sequence and the psiCHECK-2-mutant-IGF1R-3'UTR reporter plasmids (mut1, mut2, and mut3) in which the conserved target sequence at position 2276 and/or 2993 was mutated.	('IGF1R', 'Gene', (169, 174))	('IGF1R', 'Gene', '3480', (217, 222))	('IGF1R', 'Gene', '3480', (169, 174))	('IGF1R', 'Gene', (116, 121))	('IGF1R', 'Gene', '3480', (116, 121))	('IGF1R', 'Gene', (217, 222))	('mutated', 'Var', (342, 349))
438436	25184138	In contrast, the luciferase activity was not affected by plasmid mut3 (Figure 6(e)), probably due to the mutation of both miR-375 binding sites in IGF1R 3'UTR.	('mutation', 'Var', (105, 113))	('miR-375', 'Gene', '494324', (122, 129))	('luciferase', 'Enzyme', (17, 27))	('IGF1R', 'Gene', (147, 152))	('miR-375', 'Gene', (122, 129))	('binding', 'Interaction', (130, 137))	('IGF1R', 'Gene', '3480', (147, 152))
438443	25184138	In recent years, with the development of microarrays and PCR, many studies have suggested that dysregulation of miRNAs is closely related with tumor development.	('tumor', 'Disease', (143, 148))	('dysregulation', 'Var', (95, 108))	('related', 'Reg', (130, 137))	('miR', 'Gene', '220972', (112, 115))	('miR', 'Gene', (112, 115))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
438526	33752762	Otolaryngologists were at a high risk because of aerosol-generating procedures, as in the SARS-CoV-1 pandemic in 2003.	('SARS-CoV-1', 'Disease', (90, 100))	('aerosol-generating', 'Var', (49, 67))	('SARS-CoV', 'Species', '694009', (90, 98))
438592	30956762	Whilst the less immunogenic and less favorably surviving LUAD patients showed elevated enrichment of both Th1 and Th2 cells, this result is in line with a previous study using different methods (e.g., flow cytometry) to show that high levels of Th1 in the TME is associated with worse prognosis in NSCLC.	('Th1', 'Gene', (106, 109))	('NSCLC', 'Disease', 'MESH:D002289', (298, 303))	('Th1', 'Gene', '51497', (245, 248))	('high levels', 'Var', (230, 241))	('elevated', 'PosReg', (78, 86))	('NSCLC', 'Phenotype', 'HP:0030358', (298, 303))	('Th1', 'Gene', (245, 248))	('Th1', 'Gene', '51497', (106, 109))	('LUAD', 'Phenotype', 'HP:0030078', (57, 61))	('enrichment', 'MPA', (87, 97))	('patients', 'Species', '9606', (62, 70))	('NSCLC', 'Disease', (298, 303))
438626	25901368	Little is known about the molecular mechanisms of carcinogenesis of PeCa; mutations in p53 and ras, and dysregulation of proteins such as cyclin D1 (CD1), E-cadherin and matrix metalloproteinase (MMP) 9 have been identified as factors involved in PeCa.	('E-cadherin', 'Gene', '999', (155, 165))	('cyclin D1', 'Gene', (138, 147))	('PeCa', 'Disease', (247, 251))	('p53', 'Gene', (87, 90))	('cyclin D1', 'Gene', '595', (138, 147))	('p53', 'Gene', '7157', (87, 90))	('mutations', 'Var', (74, 83))	('ras', 'Gene', (95, 98))	('carcinogenesis of PeCa', 'Disease', (50, 72))	('matrix metalloproteinase (MMP) 9', 'Gene', '4318', (170, 202))	('CD1', 'Gene', '595', (149, 152))	('carcinogenesis of PeCa', 'Disease', 'MESH:D063646', (50, 72))	('dysregulation', 'Var', (104, 117))	('CD1', 'Gene', (149, 152))	('involved', 'Reg', (235, 243))	('E-cadherin', 'Gene', (155, 165))
438631	25901368	Consequently, dysregulation in Wnt signaling, because of mutations or via temporal and kinetic defects in function, are causative or associated with a variety of diseases, including cancers.	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('dysregulation', 'Var', (14, 27))	('cancers', 'Phenotype', 'HP:0002664', (182, 189))	('mutations', 'Var', (57, 66))	('Wnt signaling', 'Pathway', (31, 44))	('cancers', 'Disease', (182, 189))	('kinetic defects', 'Disease', 'MESH:D020240', (87, 102))	('cancers', 'Disease', 'MESH:D009369', (182, 189))	('kinetic defects', 'Disease', (87, 102))	('associated', 'Reg', (133, 143))
438658	25901368	Two tissue array slides (PE241 and PE801) were stained in two separate experiments; all tissue array slides used for signal and co-localization quantitation were stained at the same time and under identical conditions.	('PE241', 'Var', (25, 30))	('PE801', 'Var', (35, 40))	('men', 'Species', '9606', (77, 80))
438659	25901368	The imaging was performed on both slides (PE241 and PE801 plus the other TMA samples) on the same day with identical image acquisition settings.	('PE801', 'Var', (52, 57))	('TMA', 'Chemical', 'MESH:C071868', (73, 76))	('PE241', 'Var', (42, 47))
438665	25901368	Deconvolved images were saved as Huygens specific (HDF5) files for each channel (excitation/emission (nm) Alexa Fluor-405 405 / 415-480, FITC = 488 / 500-550, Cy3 = 559 / 575-620, Cy5 = 635 / 645-740).	('Cy5', 'Chemical', 'MESH:C085321', (180, 183))	('Cy3 = 559 / 575-620', 'Var', (159, 178))	('Cy5 = 635 / 645-740', 'Var', (180, 199))	('FITC', 'Chemical', 'MESH:D016650', (137, 141))	('Alexa Fluor-405', 'Chemical', '-', (106, 121))	('Cy3', 'Chemical', '-', (159, 162))
438677	25901368	These results indicate that, in addition to increased expression (Figs 1 and 2), alterations in co-localization of CD1 could also be a disease biomarker for PeCa and perhaps as a molecular discriminator for the grade of cancer.	('expression', 'MPA', (54, 64))	('CD1', 'Gene', (115, 118))	('PeCa', 'Disease', (157, 161))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('co-localization', 'MPA', (96, 111))	('cancer', 'Disease', 'MESH:D009369', (220, 226))	('alterations', 'Var', (81, 92))	('increased', 'PosReg', (44, 53))	('cancer', 'Disease', (220, 226))	('CD1', 'Gene', '595', (115, 118))
438711	31942182	This study aimed to evaluate the effect of HOXA11-AS polymorphisms (rs17427875 and rs11564004) on lung cancer susceptibility and its interaction with smoking exposure.	('HOXA11-AS', 'Gene', (43, 52))	('HOXA11-AS', 'Gene', '221883', (43, 52))	('rs17427875', 'DBSNP_MENTION', 'None', (68, 78))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('lung cancer', 'Disease', (98, 109))	('lung cancer', 'Phenotype', 'HP:0100526', (98, 109))	('rs11564004', 'Var', (83, 93))	('rs17427875', 'Var', (68, 78))	('rs11564004', 'DBSNP_MENTION', 'None', (83, 93))	('lung cancer', 'Disease', 'MESH:D008175', (98, 109))
438712	31942182	The results demonstrated that HOXA11AS-rs17427875 polymorphisms were correlated with the susceptibility of lung adenocarcinoma.	('HOXA11AS', 'Gene', (30, 38))	('rs17427875', 'Var', (39, 49))	('correlated', 'Reg', (69, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('lung adenocarcinoma', 'Disease', (107, 126))	('rs17427875', 'DBSNP_MENTION', 'None', (39, 49))	('HOXA11AS', 'Gene', '221883', (30, 38))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (107, 126))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (107, 126))	('polymorphisms', 'Var', (50, 63))
438713	31942182	T alleles of rs17427875 played a portal role in increasing lung adenocarcinoma risk.	('rs17427875', 'Var', (13, 23))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (59, 78))	('increasing', 'PosReg', (48, 58))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (59, 78))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))	('lung adenocarcinoma', 'Disease', (59, 78))	('rs17427875', 'DBSNP_MENTION', 'None', (13, 23))
438714	31942182	HOXA11AS-rs11564004 polymorphisms had the significant association with lung cancer risks, as well as its subtypes like non-small cell lung cancer, adenocarcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (152, 161))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (123, 145))	('association', 'Interaction', (54, 65))	('lung cancer', 'Disease', 'MESH:D008175', (71, 82))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (119, 145))	('rs11564004', 'Var', (9, 19))	('lung cancer', 'Disease', 'MESH:D008175', (134, 145))	('rs11564004', 'DBSNP_MENTION', 'None', (9, 19))	('lung cancer', 'Phenotype', 'HP:0100526', (71, 82))	('lung cancer', 'Phenotype', 'HP:0100526', (134, 145))	('lung cancer', 'Disease', (71, 82))	('adenocarcinoma', 'Disease', (147, 161))	('non-small cell lung cancer', 'Disease', (119, 145))	('HOXA11AS', 'Gene', '221883', (0, 8))	('HOXA11AS', 'Gene', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('polymorphisms', 'Var', (20, 33))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('adenocarcinoma', 'Disease', 'MESH:D000230', (147, 161))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (119, 145))
438715	31942182	The allele G of rs11564004 acted as a protective factor for lung cancer.	('lung cancer', 'Disease', (60, 71))	('lung cancer', 'Phenotype', 'HP:0100526', (60, 71))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('lung cancer', 'Disease', 'MESH:D008175', (60, 71))	('rs11564004', 'Var', (16, 26))	('rs11564004', 'DBSNP_MENTION', 'None', (16, 26))
438717	31942182	Nevertheless, interaction analysis of the additive and multiplicative model scales showed no statistical significance between HOXA11-AS polymorphisms and smoking exposure in the development of lung cancer.	('HOXA11-AS', 'Gene', (126, 135))	('HOXA11-AS', 'Gene', '221883', (126, 135))	('lung cancer', 'Disease', 'MESH:D008175', (193, 204))	('polymorphisms', 'Var', (136, 149))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('lung cancer', 'Disease', (193, 204))	('lung cancer', 'Phenotype', 'HP:0100526', (193, 204))
438727	31942182	With the in-depth exploration of genome-wide association studies (GWAS), a variety of studies have emerged for genetic risk factors, which have a potential association between single nucleotide polymorphisms (SNPs) in LncRNA and various cancer types.	('association', 'Reg', (156, 167))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('single nucleotide polymorphisms', 'Var', (176, 207))	('cancer', 'Disease', 'MESH:D009369', (237, 243))	('LncRNA', 'Gene', (218, 224))	('cancer', 'Disease', (237, 243))
438732	31942182	At present, whether gene mutation caused the ectopic expression of HOXA11-AS has not been clearly elucidated.	('mutation', 'Var', (25, 33))	('ectopic expression', 'MPA', (45, 63))	('caused', 'Reg', (34, 40))	('HOXA11-AS', 'Gene', (67, 76))	('HOXA11-AS', 'Gene', '221883', (67, 76))
438734	31942182	studied the association between HOXA11AS-rs17427875 and serous ovarian cancer (EOC) by GWAS.	('rs17427875', 'DBSNP_MENTION', 'None', (41, 51))	('HOXA11AS', 'Gene', '221883', (32, 40))	('ovarian cancer', 'Phenotype', 'HP:0100615', (63, 77))	('rs17427875', 'Var', (41, 51))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('ovarian cancer', 'Disease', 'MESH:D010051', (63, 77))	('HOXA11AS', 'Gene', (32, 40))	('ovarian cancer', 'Disease', (63, 77))
438747	31942182	The genotyping details of the SNPs were listed in Table 2 and Table 3, the allelic mutation of rs17427875 showed remarkable significance in lung adenocarcinoma population.	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (140, 159))	('rs17427875', 'Var', (95, 105))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (140, 159))	('carcinoma', 'Phenotype', 'HP:0030731', (150, 159))	('lung adenocarcinoma', 'Disease', (140, 159))	('rs17427875', 'DBSNP_MENTION', 'None', (95, 105))
438748	31942182	As shown in Table 3, mutant allele T played a risky role in LUAD susceptibility (adjusted OR=1.937, P=0.005).	('LUAD', 'Disease', (60, 64))	('LUAD', 'Disease', 'MESH:C538231', (60, 64))	('LUAD', 'Phenotype', 'HP:0030078', (60, 64))	('mutant', 'Var', (21, 27))
438750	31942182	The dominant model also showed relationship between SNPs and the risk of LUAD (adjusted OR=1.883, P=0.013).	('LUAD', 'Disease', (73, 77))	('SNPs', 'Var', (52, 56))	('LUAD', 'Disease', 'MESH:C538231', (73, 77))	('LUAD', 'Phenotype', 'HP:0030078', (73, 77))
438751	31942182	As for rs11564004, the allelic mutation showed no statistical significance in lung cancer.	('lung cancer', 'Disease', (78, 89))	('lung cancer', 'Phenotype', 'HP:0100526', (78, 89))	('rs11564004', 'Var', (7, 17))	('rs11564004', 'DBSNP_MENTION', 'None', (7, 17))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('lung cancer', 'Disease', 'MESH:D008175', (78, 89))
438754	31942182	According to the statistical results, we preliminarily indicated that the mutant allele G of rs11564004 may act as a protective factor in the risk of lung cancer.	('lung cancer', 'Phenotype', 'HP:0100526', (150, 161))	('lung cancer', 'Disease', (150, 161))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('rs11564004', 'Var', (93, 103))	('lung cancer', 'Disease', 'MESH:D008175', (150, 161))	('rs11564004', 'DBSNP_MENTION', 'None', (93, 103))
438755	31942182	To validate the possible function of tagSNP HOXA11AS-rs17427875 in cancers, two in silico analysis were utilized to predict the potential functions.	('cancers', 'Phenotype', 'HP:0002664', (67, 74))	('rs17427875', 'Var', (53, 63))	('cancers', 'Disease', (67, 74))	('cancers', 'Disease', 'MESH:D009369', (67, 74))	('HOXA11AS', 'Gene', '221883', (44, 52))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('rs17427875', 'DBSNP_MENTION', 'None', (53, 63))	('HOXA11AS', 'Gene', (44, 52))
438756	31942182	A "3a" rank was got in RegulomeDB, which meant that HOXA11-AS rs17427875 SNP may be likely to affect binding transcription factors, motifs or DNase peak.	('rs17427875', 'DBSNP_MENTION', 'None', (62, 72))	('affect', 'Reg', (94, 100))	('HOXA11-AS', 'Gene', (52, 61))	('HOXA11-AS', 'Gene', '221883', (52, 61))	('DNase', 'MPA', (142, 147))	('motifs', 'MPA', (132, 138))	('binding', 'Interaction', (101, 108))	('rs17427875', 'Var', (62, 72))
438757	31942182	SNPinfo also predicted rs17427875 acting as a binding site for several transcription factors.	('rs17427875', 'Var', (23, 33))	('rs17427875', 'DBSNP_MENTION', 'None', (23, 33))	('binding', 'Interaction', (46, 53))
438758	31942182	Next, we analyzed cumulative effects of variant alleles rs17427875-T, rs11564004-T on lung cancer and its subtypes susceptibility (Table 4 and Table 5).	('rs11564004', 'Var', (70, 80))	('rs17427875', 'DBSNP_MENTION', 'None', (56, 66))	('rs11564004', 'DBSNP_MENTION', 'None', (70, 80))	('lung cancer', 'Phenotype', 'HP:0100526', (86, 97))	('lung cancer', 'Disease', (86, 97))	('rs17427875', 'Var', (56, 66))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('lung cancer', 'Disease', 'MESH:D008175', (86, 97))
438759	31942182	The results elucidated that the increasing number of rs17427875-T, rs11564004-T and lung cancer susceptibility existed linear relationship, acting similarly with dose-dependent manner (LC: P=0.033, NSCLC: P=0.015, LUAD: P=0.025).	('lung cancer', 'Disease', (84, 95))	('rs17427875', 'Var', (53, 63))	('lung cancer', 'Phenotype', 'HP:0100526', (84, 95))	('NSCLC', 'Phenotype', 'HP:0030358', (198, 203))	('SCLC', 'Phenotype', 'HP:0030357', (199, 203))	('LUAD', 'Disease', 'MESH:C538231', (214, 218))	('rs11564004', 'Var', (67, 77))	('LUAD', 'Disease', (214, 218))	('NSCLC', 'Disease', (198, 203))	('rs17427875', 'DBSNP_MENTION', 'None', (53, 63))	('rs11564004', 'DBSNP_MENTION', 'None', (67, 77))	('NSCLC', 'Disease', 'MESH:D002289', (198, 203))	('LUAD', 'Phenotype', 'HP:0030078', (214, 218))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
438760	31942182	We suggested that AA genotype carriers and AT+TT genotype carriers with smoking exposure were significantly connected with lung cancer (rs17427875: P=0.001; rs11564004: P=0.001).	('rs17427875', 'DBSNP_MENTION', 'None', (136, 146))	('rs11564004', 'Var', (157, 167))	('lung cancer', 'Disease', (123, 134))	('rs11564004', 'DBSNP_MENTION', 'None', (157, 167))	('lung cancer', 'Phenotype', 'HP:0100526', (123, 134))	('rs17427875', 'Var', (136, 146))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('lung cancer', 'Disease', 'MESH:D008175', (123, 134))	('connected', 'Reg', (108, 117))
438761	31942182	However, the parameters of additive and multiplicative interaction model presented that rs17427875 and rs11564004 polymorphisms had no remarkable interaction results with smoking exposure (showed in Table 7 and Table 8).	('rs11564004', 'Var', (103, 113))	('rs17427875', 'DBSNP_MENTION', 'None', (88, 98))	('rs11564004', 'DBSNP_MENTION', 'None', (103, 113))	('rs17427875', 'Var', (88, 98))
438776	31942182	elucidated that HOXA11AS rs17427875-T was marginally associated with reduced EOC susceptibility in European ancestry population and the inhibitory effect was enhanced by alleles T. Our study explored the association between HOXA11-AS polymorphisms and the risk of lung cancer in Northeastern Chinese population.	('lung cancer', 'Disease', 'MESH:D008175', (264, 275))	('reduced', 'NegReg', (69, 76))	('rs17427875', 'DBSNP_MENTION', 'None', (25, 35))	('HOXA11-AS', 'Gene', '221883', (224, 233))	('cancer', 'Phenotype', 'HP:0002664', (269, 275))	('HOXA11-AS', 'Gene', (224, 233))	('lung cancer', 'Disease', (264, 275))	('HOXA11AS', 'Gene', '221883', (16, 24))	('rs17427875', 'Var', (25, 35))	('lung cancer', 'Phenotype', 'HP:0100526', (264, 275))	('HOXA11AS', 'Gene', (16, 24))	('EOC susceptibility', 'MPA', (77, 95))
438777	31942182	The results demonstrated that rs17427875-T, rs11564004-T were correlated with the increasing lung cancer risks.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('lung cancer', 'Disease', 'MESH:D008175', (93, 104))	('rs17427875', 'Var', (30, 40))	('rs11564004', 'DBSNP_MENTION', 'None', (44, 54))	('lung cancer', 'Disease', (93, 104))	('lung cancer', 'Phenotype', 'HP:0100526', (93, 104))	('rs11564004', 'Var', (44, 54))	('rs17427875', 'DBSNP_MENTION', 'None', (30, 40))
438778	31942182	Binding in silico analysis, it can be inferred that SNPs may inhibit or promote the occurrence and development of lung cancer by associating with the transcription factors related to lung cancer.	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('occurrence', 'CPA', (84, 94))	('lung cancer', 'Disease', 'MESH:D008175', (114, 125))	('development', 'CPA', (99, 110))	('lung cancer', 'Disease', 'MESH:D008175', (183, 194))	('inhibit', 'NegReg', (61, 68))	('promote', 'PosReg', (72, 79))	('lung cancer', 'Disease', (114, 125))	('associating', 'Reg', (129, 140))	('lung cancer', 'Phenotype', 'HP:0100526', (114, 125))	('lung cancer', 'Disease', (183, 194))	('lung cancer', 'Phenotype', 'HP:0100526', (183, 194))	('SNPs', 'Var', (52, 56))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
438782	31942182	HOXA11AS-rs17427875 and rs11564004 were correlated with the risk of lung cancer as well as its subtypes.	('lung cancer', 'Disease', (68, 79))	('lung cancer', 'Phenotype', 'HP:0100526', (68, 79))	('HOXA11AS', 'Gene', (0, 8))	('rs11564004', 'DBSNP_MENTION', 'None', (24, 34))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('rs17427875', 'DBSNP_MENTION', 'None', (9, 19))	('correlated', 'Reg', (40, 50))	('lung cancer', 'Disease', 'MESH:D008175', (68, 79))	('HOXA11AS', 'Gene', '221883', (0, 8))	('rs17427875', 'Var', (9, 19))	('rs11564004', 'Var', (24, 34))
438783	31942182	And meanwhile, there were dose-response effect between the increasing number of rs1727875-T and rs11564004-T with lung cancer procedure.	('rs11564004', 'Var', (96, 106))	('lung cancer', 'Disease', 'MESH:D008175', (114, 125))	('rs11564004', 'DBSNP_MENTION', 'None', (96, 106))	('lung cancer', 'Disease', (114, 125))	('lung cancer', 'Phenotype', 'HP:0100526', (114, 125))	('rs1727875', 'DBSNP_MENTION', 'None', (80, 89))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('rs1727875', 'Var', (80, 89))
438786	30197682	Using SRVS, a gene vector was selected from each dataset, resulting in significantly higher classification accuracy (CR), compared with randomly selected genes (For datasets GSE18842 and GSE1987, CR=100 and 100% and permutation P=5.0x10-4 and 1.8x10-3, respectively).	('classification', 'MPA', (92, 106))	('CR', 'Chemical', '-', (117, 119))	('higher', 'PosReg', (85, 91))	('GSE18842', 'Var', (174, 182))	('GSE1987', 'Var', (187, 194))	('GSE1987', 'Chemical', '-', (187, 194))	('CR', 'Chemical', '-', (196, 198))
438792	30197682	Mutations of a number of risk genes have been frequently reported in LSCC, such as tumor protein P53 (TP53); however, these genes may also be biomarkers for multiple other diseases.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('TP53', 'Gene', (102, 106))	('P53', 'Gene', '7157', (97, 100))	('tumor', 'Disease', (83, 88))	('Mutations', 'Var', (0, 9))	('LSCC', 'Disease', (69, 73))	('P53', 'Gene', (97, 100))	('P53', 'Gene', (103, 106))	('TP53', 'Gene', '7157', (102, 106))	('reported', 'Reg', (57, 65))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('P53', 'Gene', '7157', (103, 106))
438821	30197682	Additionally, as displayed in Table II, the SRVS method outperformed ANOVA method in terms of CR in all datasets (5.0x10-4 vs. 4.9x10-2 and 1.8x10-3 vs. 2.0x10-3 for GSE18842 and GSE1987, respectively).	('GSE1987', 'Chemical', '-', (179, 186))	('GSE18842', 'Var', (166, 174))	('GSE1987', 'Var', (179, 186))	('CR', 'Chemical', '-', (94, 96))
438822	30197682	For the ANOVA method, the two dataset (GSE18842 and GSE1987) demonstrated 91.67 and 0% unique genes, respectively [Table II Unique genes from all datasets (%)].	('GSE1987', 'Chemical', '-', (52, 59))	('GSE18842', 'Var', (39, 47))	('GSE1987', 'Var', (52, 59))
438826	30197682	For instance, focal FGFR1 amplification occurs in up to 22% of LSCC cases.	('LSCC', 'Disease', (63, 67))	('amplification', 'Var', (26, 39))	('FGFR1', 'Gene', (20, 25))	('FGFR1', 'Gene', '2260', (20, 25))
438833	30197682	For instance, AZD4547, a FGFR inhibitor, is a key drug in the treatment of LSCC.	('AZD4547', 'Var', (14, 21))	('AZD4547', 'Chemical', 'MESH:C572463', (14, 21))	('LSCC', 'Disease', (75, 79))
438834	30197682	This may be explained due to AZD4547 exhibiting a highly selective profile across a lung cell line panel, potently inhibiting cell growth only in those lines harboring amplified FGFR1.	('cell growth only', 'CPA', (126, 142))	('FGFR1', 'Gene', (178, 183))	('AZD4547', 'Var', (29, 36))	('inhibiting', 'NegReg', (115, 125))	('FGFR1', 'Gene', '2260', (178, 183))	('AZD4547', 'Chemical', 'MESH:C572463', (29, 36))	('amplified', 'Var', (168, 177))
438836	30197682	The basic theory for gene selection is that mutations of these 260 genes will not be exhibited in a number of patients with LSCC, and therefore are not effective as biomarkers for all patients.	('LSCC', 'Disease', (124, 128))	('mutations', 'Var', (44, 53))	('patients', 'Species', '9606', (110, 118))	('patients', 'Species', '9606', (184, 192))
438837	30197682	Compared with randomly selected genes, those selected by SRVS and ANOVA generated significantly higher predication power (permutation P<1.8x10-3 for SRVS, and P<5.0x10-2 for ANOVA), with improved high classification accuracy (SRVS vs. ANOVA: 100% vs. 98.9%, and 100% vs. 96.15%, for datasets GSE18842 and GSE1987, respectively), as depicted in Table II.	('predication', 'MPA', (103, 114))	('improved', 'PosReg', (187, 195))	('GSE1987', 'Chemical', '-', (305, 312))	('GSE18842', 'Var', (292, 300))	('higher', 'PosReg', (96, 102))	('GSE1987', 'Var', (305, 312))
438847	25351873	ADAM17 mRNA expression in esophageal squamous cell carcinoma was correlated with lymph node metastasis (P<0.01) and tumor, node and metastasis (TNM) staging (P<0.05), however, it was not correlated with gender, age or histological grade (P>0.05).	('esophageal squamous cell carcinoma', 'Disease', (26, 60))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (37, 60))	('ADAM17', 'Gene', (0, 6))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (51, 60))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('lymph node metastasis', 'CPA', (81, 102))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (26, 60))	('tumor', 'Disease', (116, 121))	('mRNA', 'Var', (7, 11))	('correlated', 'Reg', (65, 75))
438891	25351873	Statistical analysis showed that the EGFR positive expression rate in the ADAM17 positive expression group was significantly higher than the of the ADAM17 negative expression group (P<0.01).	('positive expression', 'Var', (81, 100))	('EGFR', 'Gene', '1956', (37, 41))	('ADAM17', 'Gene', (74, 80))	('higher', 'PosReg', (125, 131))	('EGFR', 'Gene', (37, 41))
438907	25351873	Le et al found that in ADAM17 deficient mice, T cells lost almost all of their ability to release tumor necrosis factor-alpha.	('tumor necrosis factor-alpha', 'Gene', (98, 125))	('deficient', 'Var', (30, 39))	('tumor necrosis factor-alpha', 'Gene', '21926', (98, 125))	('ADAM17', 'Gene', (23, 29))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('ability', 'MPA', (79, 86))	('mice', 'Species', '10090', (40, 44))	('lost', 'NegReg', (54, 58))
438913	25351873	It proved that the ADAM17 mRNA was involved in breast carcinogenesis and progression, the high expression of ADAM17 will increase the invasiveness and spreading ability of MCF-7 breast cancer cells in vitro.	('spreading ability', 'CPA', (151, 168))	('breast carcinogenesis', 'Disease', (47, 68))	('increase', 'PosReg', (121, 129))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('breast carcinogenesis', 'Disease', 'MESH:D063646', (47, 68))	('breast cancer', 'Phenotype', 'HP:0003002', (178, 191))	('ADAM17', 'Gene', (109, 115))	('MCF-7 breast cancer', 'Disease', 'MESH:D001943', (172, 191))	('MCF-7 breast cancer', 'Disease', (172, 191))	('invasiveness', 'CPA', (134, 146))	('high expression', 'Var', (90, 105))
438914	25351873	ADAM17 can shed amphiregulin, transforming growth factor alpha and other EGFR ligands, it can also activate the EGFR to thereby improve the lung cancer cell proliferation and cell motility capacity.	('EGFR', 'Gene', (112, 116))	('cell motility capacity', 'CPA', (175, 197))	('lung cancer', 'Disease', (140, 151))	('transforming growth factor alpha', 'Gene', (30, 62))	('EGFR', 'Gene', '1956', (73, 77))	('lung cancer', 'Phenotype', 'HP:0100526', (140, 151))	('activate', 'PosReg', (99, 107))	('transforming growth factor alpha', 'Gene', '7124', (30, 62))	('shed', 'MPA', (11, 15))	('EGFR', 'Gene', (73, 77))	('amphiregulin', 'Gene', (16, 28))	('ADAM17', 'Var', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('lung cancer', 'Disease', 'MESH:D008175', (140, 151))	('improve', 'PosReg', (128, 135))	('EGFR', 'Gene', '1956', (112, 116))	('amphiregulin', 'Gene', '374', (16, 28))
438918	25351873	Kornfeld et al reported that ADAM17 can activate the EGFR through the release of regulatory proteins in two ways to thereby enhance the proliferation and invasion of head and neck squamous cell carcinoma.	('neck squamous cell carcinoma', 'Disease', (175, 203))	('ADAM17', 'Var', (29, 35))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (180, 203))	('carcinoma', 'Phenotype', 'HP:0030731', (194, 203))	('enhance', 'PosReg', (124, 131))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (175, 203))	('invasion', 'CPA', (154, 162))	('release of', 'MPA', (70, 80))	('EGFR', 'Gene', '1956', (53, 57))	('EGFR', 'Gene', (53, 57))	('activate', 'PosReg', (40, 48))	('proliferation', 'CPA', (136, 149))
438926	25351873	ADAMl7 mRNA and protein overexpression suggested gene mutation occurs in the process of esophageal carcinoma.	('mutation', 'Var', (54, 62))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (88, 108))	('occurs', 'Reg', (63, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('esophageal carcinoma', 'Disease', (88, 108))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (88, 108))
438933	25351873	This indicated that high ADAMl7 mRNA and protein expression may become an marker for metastasis and prognosis in esophageal squamous cell carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (124, 147))	('esophageal squamous cell carcinoma', 'Disease', (113, 147))	('ADAMl7', 'Gene', (25, 31))	('high', 'Var', (20, 24))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (113, 147))
438943	32195172	The expression of FAM83A in lung cancer cells was enhanced by gene transfection or knocked down by small interfering RNA interference.	('FAM83A', 'Gene', '84985', (18, 24))	('lung cancer', 'Disease', 'MESH:D008175', (28, 39))	('expression', 'MPA', (4, 14))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('lung cancer', 'Disease', (28, 39))	('lung cancer', 'Phenotype', 'HP:0100526', (28, 39))	('enhanced', 'PosReg', (50, 58))	('gene transfection', 'Var', (62, 79))	('FAM83A', 'Gene', (18, 24))
438950	32195172	On knocking down the expression of FAM83A, we obtained the opposite results.	('knocking', 'Var', (3, 11))	('expression', 'MPA', (21, 31))	('FAM83A', 'Gene', '84985', (35, 41))	('FAM83A', 'Gene', (35, 41))
438958	32195172	It consists of 434 amino acids, including DUF1669, serine-rich, and protein-rich domains, and the DUF1669 domain at its N-terminus is thought to be involved in tumor progression.	('DUF1669', 'Var', (42, 49))	('serine-rich', 'MPA', (51, 62))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('serine', 'Chemical', 'MESH:D012694', (51, 57))	('DUF1669 domain', 'Var', (98, 112))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('involved', 'Reg', (148, 156))	('tumor', 'Disease', (160, 165))
438962	32195172	Meanwhile, silencing FAM83A significantly reduces the ability of breast cancer cells to proliferate in vitro and in vivo and to grow and invade independently of anchoring.	('silencing', 'Var', (11, 20))	('breast cancer', 'Disease', 'MESH:D001943', (65, 78))	('reduces', 'NegReg', (42, 49))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('breast cancer', 'Disease', (65, 78))	('breast cancer', 'Phenotype', 'HP:0003002', (65, 78))	('grow', 'CPA', (128, 132))	('FAM83A', 'Gene', '84985', (21, 27))	('FAM83A', 'Gene', (21, 27))
438990	32195172	The expression level of FAM83A was upregulated by FAM83A gene transfection in H1299 (H1299-FAM83A) and A549 (A549-FAM83A) cells (Figures 2A,B).	('expression level', 'MPA', (4, 20))	('FAM83A', 'Gene', (114, 120))	('FAM83A', 'Gene', (50, 56))	('FAM83A', 'Gene', '84985', (114, 120))	('FAM83A', 'Gene', '84985', (91, 97))	('FAM83A', 'Gene', (91, 97))	('FAM83A', 'Gene', '84985', (50, 56))	('gene transfection', 'Var', (57, 74))	('FAM83A', 'Gene', (24, 30))	('upregulated', 'PosReg', (35, 46))	('FAM83A', 'Gene', '84985', (24, 30))	('transfection', 'Var', (62, 74))
438994	32195172	Meanwhile, knocking down the expression of FAM83A inhibited the invasive ability of H1299-SiFAM83A (P < 0.001) and A549-SiFAM83A (P = 0.0016) cells compared to those of control cells (Figures 2J,K).	('FAM83A', 'Gene', (92, 98))	('FAM83A', 'Gene', '84985', (43, 49))	('FAM83A', 'Gene', (43, 49))	('FAM83A', 'Gene', '84985', (122, 128))	('FAM83A', 'Gene', (122, 128))	('invasive ability', 'CPA', (64, 80))	('knocking', 'Var', (11, 19))	('FAM83A', 'Gene', '84985', (92, 98))	('A549-SiFAM83A', 'CellLine', 'CVCL:0023;0.05220797413250369', (115, 128))	('inhibited', 'NegReg', (50, 59))
439001	32195172	On the contrary, in H1299-SiFAM83A and A549-SiFAM83A cells, the expressions of Twist, Snail, and vimentin were decreased, whereas the expression of E-cadherin was increased (Figures 3D-F).	('E-cadherin', 'Gene', (148, 158))	('H1299-SiFAM83A', 'Var', (20, 34))	('expressions', 'MPA', (64, 75))	('expression', 'MPA', (134, 144))	('Twist', 'Protein', (79, 84))	('A549-SiFAM83A', 'Var', (39, 52))	('vimentin', 'Gene', '7431', (97, 105))	('increased', 'PosReg', (163, 172))	('E-cadherin', 'Gene', '999', (148, 158))	('decreased', 'NegReg', (111, 120))	('vimentin', 'Gene', (97, 105))	('Snail', 'Gene', '6615', (86, 91))	('Snail', 'Gene', (86, 91))	('A549-SiFAM83A', 'CellLine', 'CVCL:0023;0.05220797413250369', (39, 52))
439007	32195172	Compared with H1299-FAM83A cells treated with DMSO, the proliferation rate (P < 0.001) and number of colony formations (P < 0.001) of H1299-FAM83A cells treated with XAV-939 were significantly decreased (Figures 5A-C).	('DMSO', 'Chemical', 'MESH:D004121', (46, 50))	('XAV-939', 'Chemical', 'MESH:C544261', (166, 173))	('decreased', 'NegReg', (193, 202))	('H1299-FAM83A', 'Var', (134, 146))
439008	32195172	Similarly, the Matrigel invasion assay showed that H1299-FAM83A cells treated with XAV-939 had a reduced invasion capacity compared to the H1299-FAM83A with DMSO group (P < 0.001) (Figures 5D,E).	('Matrigel invasion assay', 'CPA', (15, 38))	('XAV-939', 'Chemical', 'MESH:C544261', (83, 90))	('DMSO', 'Chemical', 'MESH:D004121', (157, 161))	('reduced', 'NegReg', (97, 104))	('invasion capacity', 'CPA', (105, 122))	('XAV-939', 'Var', (83, 90))
439010	32195172	The expression level of YAP was upregulated in H1299-FAM83A cells but was reversed when XAV-939 was added.	('H1299-FAM83A', 'Var', (47, 59))	('YAP', 'Gene', (24, 27))	('expression', 'MPA', (4, 14))	('YAP', 'Gene', '10413', (24, 27))	('XAV-939', 'Chemical', 'MESH:C544261', (88, 95))	('upregulated', 'PosReg', (32, 43))
439011	32195172	The expressions of cyclin E and CTGF, the downstream targets of YAP, were upregulated in H1299-FAM83A cells but were also downregulated after the addition of XAV-939 (Figures 6A,B).	('downregulated', 'NegReg', (122, 135))	('upregulated', 'PosReg', (74, 85))	('CTGF', 'Gene', '1490', (32, 36))	('H1299-FAM83A', 'Var', (89, 101))	('expressions', 'MPA', (4, 15))	('YAP', 'Gene', '10413', (64, 67))	('cyclin E', 'Gene', (19, 27))	('CTGF', 'Gene', (32, 36))	('YAP', 'Gene', (64, 67))	('XAV-939', 'Chemical', 'MESH:C544261', (158, 165))
439025	32195172	Similar to our results, it has been reported previously that the Wnt signaling pathway is significantly inhibited after the silencing of FAM83A in pancreatic cancer cells.	('pancreatic cancer', 'Disease', 'MESH:D010190', (147, 164))	('silencing', 'Var', (124, 133))	('FAM83A', 'Gene', (137, 143))	('Wnt signaling pathway', 'Pathway', (65, 86))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (147, 164))	('FAM83A', 'Gene', '84985', (137, 143))	('inhibited', 'NegReg', (104, 113))	('pancreatic cancer', 'Disease', (147, 164))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
439061	26115045	With multivariate analysis, lymph node status was an independent predictor for DFS, and lymph node status and EGFR overexpression/gene amplification were independent predictors for OS.	('OS', 'Chemical', 'MESH:D009992', (181, 183))	('EGFR', 'Gene', '1956', (110, 114))	('EGFR', 'Gene', (110, 114))	('overexpression/gene amplification', 'Var', (115, 148))	('DFS', 'Disease', (79, 82))
439079	26115045	Family history of breast cancer or BRCA gene mutation was noted in 4 of the patients.	('patients', 'Species', '9606', (76, 84))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('breast cancer', 'Disease', 'MESH:D001943', (18, 31))	('breast cancer', 'Disease', (18, 31))	('BRCA', 'Gene', (35, 39))	('BRCA', 'Gene', '672', (35, 39))	('breast cancer', 'Phenotype', 'HP:0003002', (18, 31))	('mutation', 'Var', (45, 53))
439086	26115045	Immunohistochemistry (IHC) was performed on selected tumor sections using the avidin-biotin-immunoperoxidase technique for ER, PR, HER2, Ki-67, p53, CK5/6 and EGFR.	('CK5/6', 'Gene', '3852', (149, 154))	('Ki-67', 'Var', (137, 142))	('p53', 'Gene', '7157', (144, 147))	('HER2', 'Gene', (131, 135))	('EGFR', 'Gene', '1956', (159, 163))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('HER2', 'Gene', '2064', (131, 135))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('CK5/6', 'Gene', (149, 154))	('EGFR', 'Gene', (159, 163))	('tumor', 'Disease', (53, 58))	('p53', 'Gene', (144, 147))
439129	26115045	Of these 14 cases, 5 (35.7%) showed increased EGFR copy number and 9 (64.3%) displayed high aneusomy.	('increased', 'PosReg', (36, 45))	('EGFR', 'Gene', '1956', (46, 50))	('EGFR', 'Gene', (46, 50))	('copy number', 'Var', (51, 62))
439165	26115045	Rakha et al, in their recent study of 405 MBC patients from a large international multicenter series, found that lymph node stage, lymphovascular invasion, histologic subtype, and chemotherapy were associated with lower breast cancer-specific survival and/or disease free interval.	('patients', 'Species', '9606', (46, 54))	('MBC', 'Disease', (42, 45))	('breast cancer', 'Disease', 'MESH:D001943', (220, 233))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('breast cancer', 'Disease', (220, 233))	('breast cancer', 'Phenotype', 'HP:0003002', (220, 233))	('disease free interval', 'CPA', (259, 280))	('MBC', 'Disease', 'MESH:D001943', (42, 45))	('lower', 'NegReg', (214, 219))	('lymphovascular invasion', 'CPA', (131, 154))	('lymph', 'Var', (113, 118))
439174	26115045	Aberrant signaling through EGFR overexpression is associated with neoplastic cell proliferation, migration, stromal invasion, resistance to apoptosis, and angiogenesis.	('EGFR', 'Gene', '1956', (27, 31))	('EGFR', 'Gene', (27, 31))	('overexpression', 'PosReg', (32, 46))	('migration', 'CPA', (97, 106))	('Aberrant', 'Var', (0, 8))	('associated', 'Reg', (50, 60))	('neoplastic cell proliferation', 'CPA', (66, 95))	('signaling', 'MPA', (9, 18))	('angiogenesis', 'CPA', (155, 167))	('stromal invasion', 'CPA', (108, 124))	('resistance to apoptosis', 'CPA', (126, 149))
439181	26115045	These results beg the question of whether MBC patients with EGFR overexpression and/or gene amplification might benefit from EGFR tyrosine kinase inhibitor and EGFR monoclonal antibody (cetuximab) therapies.	('patients', 'Species', '9606', (46, 54))	('MBC', 'Disease', (42, 45))	('EGFR', 'Gene', '1956', (125, 129))	('cetuximab', 'Chemical', 'MESH:D000068818', (186, 195))	('gene amplification', 'Var', (87, 105))	('EGFR', 'Gene', '1956', (160, 164))	('EGFR', 'Gene', (125, 129))	('EGFR', 'Gene', '1956', (60, 64))	('EGFR', 'Gene', (160, 164))	('overexpression', 'PosReg', (65, 79))	('MBC', 'Disease', 'MESH:D001943', (42, 45))	('benefit', 'PosReg', (112, 119))	('EGFR', 'Gene', (60, 64))
439186	26115045	LNM is identified as an independent predictive factor for unfavorable DFS, and LNM and EGFR overexpression/gene amplification are independent predictive factors for decreased OS.	('decreased', 'NegReg', (165, 174))	('EGFR', 'Gene', '1956', (87, 91))	('EGFR', 'Gene', (87, 91))	('overexpression/gene amplification', 'Var', (92, 125))	('LNM', 'Gene', (79, 82))	('OS', 'Chemical', 'MESH:D009992', (175, 177))
439188	26115045	New therapy targeting EGFR in tumors with overexpression and/or gene amplification of EGFR is worthy of further exploration.	('tumors', 'Disease', (30, 36))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('EGFR', 'Gene', '1956', (86, 90))	('EGFR', 'Gene', (86, 90))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('EGFR', 'Gene', '1956', (22, 26))	('gene amplification', 'Var', (64, 82))	('EGFR', 'Gene', (22, 26))
439207	33376346	For example, in patients with osimertinib-resistant NSCLC, the level of circ_0002130 in serum exosomes is upregulated.	('circ_0002130', 'Var', (72, 84))	('osimertinib-resistant NSCLC', 'Disease', 'MESH:D060467', (30, 57))	('level', 'MPA', (63, 68))	('upregulated', 'PosReg', (106, 117))	('patients', 'Species', '9606', (16, 24))	('osimertinib-resistant NSCLC', 'Disease', (30, 57))
439208	33376346	Further, circ_0002130 regulates the osimertinib resistance of NSCLC cells through targeting miR-498.	('targeting', 'Reg', (82, 91))	('circ_0002130', 'Var', (9, 21))	('NSCLC', 'Disease', (62, 67))	('regulates', 'Reg', (22, 31))	('osimertinib resistance', 'MPA', (36, 58))	('NSCLC', 'Disease', 'MESH:D002289', (62, 67))	('miR-498', 'Gene', '574460', (92, 99))	('osimertinib', 'Chemical', '-', (36, 47))	('miR-498', 'Gene', (92, 99))
439209	33376346	In LUAD cancer cells, circRNA_0002178 enhances PD-L1 expression by sponging miR-34.	('LUAD cancer', 'Disease', (3, 14))	('LUAD', 'Phenotype', 'HP:0030078', (3, 7))	('miR-34', 'Gene', '407040', (76, 82))	('PD-L1', 'Gene', (47, 52))	('circRNA_0002178', 'Var', (22, 37))	('sponging', 'NegReg', (67, 75))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('LUAD cancer', 'Disease', 'MESH:D009369', (3, 14))	('PD-L1', 'Gene', '29126', (47, 52))	('expression', 'MPA', (53, 63))	('enhances', 'PosReg', (38, 46))	('miR-34', 'Gene', (76, 82))
439214	33376346	We found that circ_0102537 inhibited the migration and invasion of H1299 cells in vitro.	('invasion of H1299 cells in vitro', 'CPA', (55, 87))	('inhibited', 'NegReg', (27, 36))	('H1299', 'CellLine', 'CVCL:0060', (67, 72))	('circ_0102537', 'Var', (14, 26))
439242	33376346	H1299 cells (5 x 102) were transfected with si-NC or si-circ_0102537 and then added to the wells of 6-well plates.	('si-NC', 'Var', (44, 49))	('si-circ_0102537', 'Var', (53, 68))	('H1299', 'CellLine', 'CVCL:0060', (0, 5))
439254	33376346	Circ_0102537 was upregulated the most in H1299 cells (Figure 6A).	('Circ_0102537', 'Var', (0, 12))	('upregulated', 'PosReg', (17, 28))	('H1299', 'CellLine', 'CVCL:0060', (41, 46))
439270	33376346	For example, plasma circ_0013958 distinguished LUAD patients from healthy controls with an area under the receiver operating characteristic (AUC) of 0.794 (95% CI = 0.703-0.912; P < 0.001).	('LUAD', 'Phenotype', 'HP:0030078', (47, 51))	('patients', 'Species', '9606', (52, 60))	('LUAD', 'Disease', (47, 51))	('plasma circ_0013958', 'Var', (13, 32))
439277	33376346	Novel drugs that target VEGF, including anti-VEGF antibodies, anti-VEGF receptor antibodies, and small-molecule tyrosine kinase inhibitors, are already available and approved for the treatment of various tumors, including lung cancer.	('tumors', 'Disease', 'MESH:D009369', (204, 210))	('antibodies', 'Var', (50, 60))	('lung cancer', 'Disease', (222, 233))	('lung cancer', 'Phenotype', 'HP:0100526', (222, 233))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('VEGF', 'Gene', '7422', (45, 49))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('VEGF', 'Gene', '7422', (24, 28))	('VEGF', 'Gene', (67, 71))	('tumors', 'Disease', (204, 210))	('tumors', 'Phenotype', 'HP:0002664', (204, 210))	('VEGF', 'Gene', (24, 28))	('lung cancer', 'Disease', 'MESH:D008175', (222, 233))	('VEGF', 'Gene', '7422', (67, 71))	('VEGF', 'Gene', (45, 49))
439283	33376346	For example, miR-181a-5p inhibits A549 cell proliferation and invasion by targeting Kras.	('targeting', 'Reg', (74, 83))	('Kras', 'Gene', (84, 88))	('inhibits', 'NegReg', (25, 33))	('A549', 'CellLine', 'CVCL:0023', (34, 38))	('Kras', 'Gene', '3845', (84, 88))	('invasion', 'CPA', (62, 70))	('miR-181a-5p', 'Chemical', '-', (13, 24))	('miR-181a-5p', 'Var', (13, 24))
439285	33376346	Further, mir-450b-5p, mir-330-3p, and mir-335-3p are determined to be prominent in tumorigenesis and progression.	('mir-450b-5p', 'Var', (9, 20))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumor', 'Disease', (83, 88))	('mir-335-3p', 'Var', (38, 48))	('mir-330-3p', 'Var', (22, 32))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('progression', 'CPA', (101, 112))
439287	33376346	We have also analyzed hsa_circ_0102537 involvement in two cancer-related signaling pathways, fluid shear stress, and PI3K-Akt signaling pathway.	('hsa_circ_0102537', 'Var', (22, 38))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('involvement', 'Reg', (39, 50))	('Akt', 'Gene', '207', (122, 125))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('cancer', 'Disease', (58, 64))	('Akt', 'Gene', (122, 125))
439290	33376346	Further experiments showed that circ_0102537 functioned as a tumor suppressor by inhibiting the migration and invasion of LUAD cells in vitro, albeit through an unknown mechanism.	('inhibiting', 'NegReg', (81, 91))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('circ_0102537', 'Var', (32, 44))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Disease', (61, 66))	('LUAD', 'Phenotype', 'HP:0030078', (122, 126))
439292	31432113	MicroRNA-208a directly targets Src kinase signaling inhibitor 1 to facilitate cell proliferation and invasion in non-small cell lung cancer The abnormal expression of microRNAs (miRNAs/miRs) has a critical function in the formation and progression of non-small cell lung cancer (NSCLC).	('abnormal', 'Var', (144, 152))	('NSCLC', 'Disease', (279, 284))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (113, 139))	('NSCLC', 'Phenotype', 'HP:0030358', (279, 284))	('Src kinase signaling inhibitor 1', 'Gene', (31, 63))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (251, 277))	('cancer', 'Phenotype', 'HP:0002664', (271, 277))	('non-small cell lung cancer', 'Disease', (113, 139))	('microRNAs', 'Var', (167, 176))	('lung cancer', 'Phenotype', 'HP:0100526', (128, 139))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (255, 277))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (251, 277))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (117, 139))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (113, 139))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('function', 'Reg', (206, 214))	('NSCLC', 'Disease', 'MESH:D002289', (279, 284))	('Src kinase signaling inhibitor 1', 'Gene', '80725', (31, 63))	('non-small cell lung cancer', 'Disease', (251, 277))	('lung cancer', 'Phenotype', 'HP:0100526', (266, 277))
439298	31432113	miR-208a silencing decreased the proliferative and invasive capacities of NSCLC cells.	('NSCLC', 'Phenotype', 'HP:0030358', (74, 79))	('silencing', 'Var', (9, 18))	('miR-208a', 'Gene', (0, 8))	('miR-208a', 'Gene', '406990', (0, 8))	('NSCLC', 'Disease', (74, 79))	('decreased', 'NegReg', (19, 28))	('NSCLC', 'Disease', 'MESH:D002289', (74, 79))
439301	31432113	In addition to this, silencing miR-208a expression inhibited the extracellular regulated kinase (ERK) signaling pathway in NSCLC.	('NSCLC', 'Disease', (123, 128))	('NSCLC', 'Disease', 'MESH:D002289', (123, 128))	('miR-208a', 'Gene', (31, 39))	('NSCLC', 'Phenotype', 'HP:0030358', (123, 128))	('miR-208a', 'Gene', '406990', (31, 39))	('inhibited', 'NegReg', (51, 60))	('silencing', 'Var', (21, 30))
439313	31432113	miRNAs may modulate over one half of all gene expression of human proteins and may participate in the modulation of numerous cellular biological behaviors, including cell proliferation, survival, apoptosis, differentiation, metabolism and metastasis.	('participate', 'Reg', (83, 94))	('modulate', 'Reg', (11, 19))	('cellular biological behaviors', 'CPA', (125, 154))	('metabolism', 'CPA', (224, 234))	('proteins', 'Protein', (66, 74))	('modulation', 'Reg', (102, 112))	('gene expression', 'MPA', (41, 56))	('cell proliferation', 'CPA', (166, 184))	('differentiation', 'CPA', (207, 222))	('metastasis', 'CPA', (239, 249))	('apoptosis', 'CPA', (196, 205))	('miRNAs', 'Var', (0, 6))	('survival', 'CPA', (186, 194))	('human', 'Species', '9606', (60, 65))
439314	31432113	Numerous deregulated miRNAs have been identified in various disorders, including human malignancies.	('deregulated', 'Var', (9, 20))	('miRNAs', 'Protein', (21, 27))	('malignancies', 'Disease', 'MESH:D009369', (87, 99))	('human', 'Species', '9606', (81, 86))	('malignancies', 'Disease', (87, 99))
439315	31432113	The aberrant expression of miRNAs is strongly associated with the tumorigenesis and tumor development.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('tumor', 'Disease', (66, 71))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('aberrant expression', 'Var', (4, 23))	('tumor', 'Disease', (84, 89))	('miRNAs', 'Gene', (27, 33))	('associated', 'Reg', (46, 56))	('tumor', 'Disease', 'MESH:D009369', (66, 71))
439316	31432113	miRNAs may function as tumor-suppressing or tumor-promoting miRNAs in different types of human cancer, depending on the biological functions of their target genes.	('human', 'Species', '9606', (89, 94))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('cancer', 'Disease', (95, 101))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('miRNAs', 'Var', (0, 6))	('tumor', 'Disease', (23, 28))	('tumor', 'Disease', (44, 49))
439347	31432113	The 3'-UTR segments of the SRCIN1 gene containing the wild-type or mutant miR-208a binding sites were inserted into pMIR-GLO  luciferase vector to generate the wild-type luciferase plasmid (pMIR-SRCIN1-Wt-3'-UTR) or mutant luciferase plasmid (pMIR-SRCIN1-Mut-3'-UTR).	('SRCIN1', 'Gene', (248, 254))	('SRCIN1', 'Gene', '80725', (27, 33))	('SRCIN1', 'Gene', '80725', (248, 254))	('miR-208a', 'Gene', '406990', (74, 82))	('SRCIN1', 'Gene', (195, 201))	('mutant', 'Var', (67, 73))	('SRCIN1', 'Gene', '80725', (195, 201))	('SRCIN1', 'Gene', (27, 33))	('miR-208a', 'Gene', (74, 82))
439362	31432113	As presented in Table I, high miR-208a expression was significantly associated with Tumor-Node-Metastasis (TNM) stage (P=0.026) and lymph node metastasis (P=0.012).	('lymph node metastasis', 'CPA', (132, 153))	('associated', 'Reg', (68, 78))	('miR-208a', 'Gene', (30, 38))	('miR-208a', 'Gene', '406990', (30, 38))	('high', 'Var', (25, 29))	('Tumor', 'Phenotype', 'HP:0002664', (84, 89))	('expression', 'MPA', (39, 49))
439365	31432113	miR-208a revealed a significant decrease in H460 and A549 cells following miR-208a knockdown compared with the NC inhibitor group (P<0.05; Fig.	('miR-208a', 'Gene', '406990', (74, 82))	('miR-208a', 'Gene', (0, 8))	('decrease', 'NegReg', (32, 40))	('miR-208a', 'Gene', '406990', (0, 8))	('knockdown', 'Var', (83, 92))	('miR-208a', 'Gene', (74, 82))
439367	31432113	As expected, cell proliferation in H460 and A549 cells was significantly decreased with miR-208a inhibitor transfection compared with the NC inhibitor group (P<0.05; Fig.	('miR-208a', 'Gene', '406990', (88, 96))	('transfection', 'Var', (107, 119))	('miR-208a', 'Gene', (88, 96))	('decreased', 'NegReg', (73, 82))
439368	31432113	The effect of silencing miR-208a expression on cell invasion capacity in NSCLC was evaluated using a Matrigel invasion assay.	('silencing', 'Var', (14, 23))	('miR-208a', 'Gene', (24, 32))	('NSCLC', 'Disease', (73, 78))	('miR-208a', 'Gene', '406990', (24, 32))	('NSCLC', 'Disease', 'MESH:D002289', (73, 78))	('NSCLC', 'Phenotype', 'HP:0030358', (73, 78))
439377	31432113	The expression levels of SRCIN1 mRNA (P<0.05) and protein (P<0.05) in miR-208a inhibitor-transfected H460 and A549 cells were significantly upregulated in comparison with those in NC inhibitor-transfected cells (Fig.	('expression levels', 'MPA', (4, 21))	('protein', 'MPA', (50, 57))	('mRNA', 'MPA', (32, 36))	('upregulated', 'PosReg', (140, 151))	('inhibitor-transfected', 'Var', (79, 100))	('miR-208a', 'Gene', (70, 78))	('SRCIN1', 'Gene', (25, 31))	('miR-208a', 'Gene', '406990', (70, 78))	('SRCIN1', 'Gene', '80725', (25, 31))
439401	31432113	Silencing SRCIN1 expression partially reversed the oncogenic effects of miR-208a on NSCLC cell proliferation and invasion.	('SRCIN1', 'Gene', '80725', (10, 16))	('NSCLC', 'Phenotype', 'HP:0030358', (84, 89))	('SRCIN1', 'Gene', (10, 16))	('invasion', 'CPA', (113, 121))	('NSCLC', 'Disease', (84, 89))	('NSCLC', 'Disease', 'MESH:D002289', (84, 89))	('miR-208a', 'Gene', (72, 80))	('Silencing', 'Var', (0, 9))	('miR-208a', 'Gene', '406990', (72, 80))
439420	31432113	Ectopic expression of SRCIN1 in cutaneous squamous cell carcinoma suppressed the proliferative and migratory abilities of the cells.	('SRCIN1', 'Gene', (22, 28))	('cutaneous squamous cell carcinoma', 'Disease', (32, 65))	('Ectopic expression', 'Var', (0, 18))	('SRCIN1', 'Gene', '80725', (22, 28))	('suppressed', 'NegReg', (66, 76))	('cutaneous squamous cell carcinoma', 'Disease', 'MESH:D002294', (32, 65))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (42, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (56, 65))
439421	31432113	In the present study, it was demonstrated that miR-208a silencing deactivated the ERK signaling pathway via the regulation of SRCIN1.	('silencing', 'Var', (56, 65))	('deactivated', 'NegReg', (66, 77))	('miR-208a', 'Gene', (47, 55))	('ERK signaling pathway', 'Pathway', (82, 103))	('miR-208a', 'Gene', '406990', (47, 55))	('SRCIN1', 'Gene', (126, 132))	('SRCIN1', 'Gene', '80725', (126, 132))
439455	29541383	Moreover, a previous report demonstrated that exogenous TRIM71 expression promotes the formation of inducible pluripotent stem cells (iPSCs), whereas knockdown of endogenous TRIM71 expression inhibits reprogramming.	('promotes', 'PosReg', (74, 82))	('TRIM71', 'Gene', '131405', (56, 62))	('exogenous', 'Var', (46, 55))	('reprogramming', 'CPA', (201, 214))	('TRIM71', 'Gene', (56, 62))	('inhibits', 'NegReg', (192, 200))	('TRIM71', 'Gene', '131405', (174, 180))	('formation of inducible pluripotent stem cells', 'MPA', (87, 132))	('TRIM71', 'Gene', (174, 180))
439471	29541383	Moreover, Kaplan-Meier survival analysis of TRIM71-negative and -positive cases in 89 patients with complete follow-up data showed that high levels of TRIM71 were significantly associated with poor patient outcomes (p < 0.05; Figure 1B).	('TRIM71', 'Gene', '131405', (151, 157))	('TRIM71', 'Gene', (151, 157))	('patient', 'Species', '9606', (198, 205))	('patient', 'Species', '9606', (86, 93))	('TRIM71', 'Gene', '131405', (44, 50))	('associated', 'Reg', (177, 187))	('TRIM71', 'Gene', (44, 50))	('high levels', 'Var', (136, 147))	('patients', 'Species', '9606', (86, 94))
439478	29541383	On the basis of the above findings, we next aimed to further determine the role of high TRIM71 protein expression in NSCLC.	('NSCLC', 'Disease', (117, 122))	('TRIM71', 'Gene', '131405', (88, 94))	('NSCLC', 'Disease', 'MESH:D002289', (117, 122))	('TRIM71', 'Gene', (88, 94))	('NSCLC', 'Phenotype', 'HP:0030358', (117, 122))	('high', 'Var', (83, 87))	('protein', 'Protein', (95, 102))
439507	29541383	We also transfected cells with the RING domain-deleted pcmv-flag TRIM71 DeltaR plasmid and found that when the RING domain was deleted, the effects of TRIM71 on IkappaB-alpha were reversed, and IkappaB-alpha protein levels were not decreased.	('deleted', 'Var', (127, 134))	('TRIM71', 'Gene', (151, 157))	('IkappaB-alpha', 'Gene', '4792', (161, 174))	('TRIM71', 'Gene', '131405', (65, 71))	('TRIM71', 'Gene', (65, 71))	('IkappaB-alpha', 'Gene', (194, 207))	('IkappaB-alpha', 'Gene', '4792', (194, 207))	('IkappaB-alpha', 'Gene', (161, 174))	('TRIM71', 'Gene', '131405', (151, 157))
439509	29541383	TRIM71 did not reduce the expression of IkappaB-alpha or increase the ubiquitination level of IkappaB-alpha after deletion of the RING domain (Figure 5B).	('expression', 'MPA', (26, 36))	('IkappaB-alpha', 'Gene', '4792', (40, 53))	('TRIM71', 'Gene', '131405', (0, 6))	('TRIM71', 'Gene', (0, 6))	('IkappaB-alpha', 'Gene', (94, 107))	('ubiquitination level', 'MPA', (70, 90))	('increase', 'PosReg', (57, 65))	('IkappaB-alpha', 'Gene', '4792', (94, 107))	('IkappaB-alpha', 'Gene', (40, 53))	('deletion', 'Var', (114, 122))
439577	29282042	Recent reports have indicated that the expressions of EMMPRIN correlate with poor clinical factors and outcomes in lung cancer but some studies have inconsistent conclusions.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('expressions', 'Var', (39, 50))	('lung cancer', 'Disease', 'MESH:D008175', (115, 126))	('EMMPRIN', 'Gene', '682', (54, 61))	('lung cancer', 'Disease', (115, 126))	('EMMPRIN', 'Gene', (54, 61))	('lung cancer', 'Phenotype', 'HP:0100526', (115, 126))
439605	29282042	In addition, the serum level of EMMPRIN in NSCLC patients with N0-N1 of lymph node metastasis was 91.78+-9.97 pg/mL, which is lower than those lung cancer patients with N2-N3 of lymph node metastasis (107.66+-14.39 pg/mL) (p < 0.001).	('lower', 'NegReg', (126, 131))	('lung cancer', 'Disease', (143, 154))	('serum level', 'MPA', (17, 28))	('lung cancer', 'Phenotype', 'HP:0100526', (143, 154))	('NSCLC', 'Phenotype', 'HP:0030358', (43, 48))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('patients', 'Species', '9606', (155, 163))	('lung cancer', 'Disease', 'MESH:D008175', (143, 154))	('EMMPRIN', 'Gene', '682', (32, 39))	('patients', 'Species', '9606', (49, 57))	('EMMPRIN', 'Gene', (32, 39))	('NSCLC', 'Disease', (43, 48))	('N0-N1', 'Var', (63, 68))	('NSCLC', 'Disease', 'MESH:D002289', (43, 48))
439620	29282042	The results showed that subjects with higher EMMPRIN expression in serum and tissues implied a higher risk for NSCLC possibility (risk ratio =1.56 and 1.1) compared with subjects with lower EMMPRIN expression, and the RR of EMMPRIN expression in serum is greater than in tissues.	('EMMPRIN', 'Gene', '682', (45, 52))	('expression', 'Var', (53, 63))	('EMMPRIN', 'Gene', (45, 52))	('NSCLC', 'Disease', (111, 116))	('EMMPRIN', 'Gene', (224, 231))	('EMMPRIN', 'Gene', '682', (224, 231))	('NSCLC', 'Disease', 'MESH:D002289', (111, 116))	('higher', 'PosReg', (38, 44))	('EMMPRIN', 'Gene', '682', (190, 197))	('NSCLC', 'Phenotype', 'HP:0030358', (111, 116))	('EMMPRIN', 'Gene', (190, 197))
439673	26304537	Dysregulation of miRNA activity has been shown to play an important role in tumor initiation and progression.	('Dysregulation', 'Var', (0, 13))	('miR', 'Gene', '220972', (17, 20))	('miR', 'Gene', (17, 20))	('tumor initiation', 'Disease', 'MESH:D009369', (76, 92))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor initiation', 'Disease', (76, 92))
439720	26304537	Depending on the total number of functional miR-binding sites that they share with a target, ceRNA modulators can decrease the number of free miR molecules available to repress other target genes.	('miR', 'Gene', '220972', (44, 47))	('miR', 'Gene', (44, 47))	('modulators', 'Var', (99, 109))	('repress', 'MPA', (169, 176))	('miR', 'Gene', '220972', (142, 145))	('miR', 'Gene', (142, 145))	('decrease', 'NegReg', (114, 122))
439837	26304537	And the dysregulation of miRNAs has been demonstrated to play critical roles in cancer through regulating the genes inappropriately.	('dysregulation', 'Var', (8, 21))	('regulating', 'Reg', (95, 105))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('miR', 'Gene', '220972', (25, 28))	('miR', 'Gene', (25, 28))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('genes', 'Gene', (110, 115))	('cancer', 'Disease', (80, 86))
439840	26304537	Evidences have demonstrated that cancers develop from the accumulation of mutations and epigenetic changes, such as changes in DNA copy number, translocation as well as gene fusions.	('DNA', 'Gene', (127, 130))	('translocation', 'CPA', (144, 157))	('cancers', 'Phenotype', 'HP:0002664', (33, 40))	('cancers', 'Disease', (33, 40))	('mutations', 'Var', (74, 83))	('cancers', 'Disease', 'MESH:D009369', (33, 40))	('changes', 'Reg', (116, 123))	('gene fusions', 'Var', (169, 181))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('epigenetic changes', 'Var', (88, 106))
439841	26304537	Changes of the genes impact the MREs and further alter the capacity of a proper mRNA to attach or titrate miRNAs.	('genes', 'Gene', (15, 20))	('capacity', 'MPA', (59, 67))	('miR', 'Gene', (106, 109))	('miR', 'Gene', '220972', (106, 109))	('Changes', 'Var', (0, 7))	('impact', 'Reg', (21, 27))	('alter', 'Reg', (49, 54))	('MREs', 'CPA', (32, 36))
439855	26304537	MiRNAs have been shown to regulate PTEN and thus contribute to cell transformation mediated by aberrant activation of the PI3K/AKT pathway.	('cell transformation', 'CPA', (63, 82))	('activation', 'PosReg', (104, 114))	('MiRNAs', 'Var', (0, 6))	('PTEN', 'Gene', (35, 39))	('regulate', 'Reg', (26, 34))	('PTEN', 'Gene', '5728', (35, 39))	('contribute', 'Reg', (49, 59))	('PI3K/AKT pathway', 'Pathway', (122, 138))
439860	26304537	siRNA silencing of these miR-mediated PTEN regulators had been shown to be sufficient to downregulate PTEN in a 3' UTR-dependent manner and to increase tumor cell growth rates.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('PTEN', 'Gene', '5728', (38, 42))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('tumor', 'Disease', (152, 157))	('miR', 'Gene', '220972', (25, 28))	('miR', 'Gene', (25, 28))	('downregulate', 'NegReg', (89, 101))	('PTEN', 'Gene', (102, 106))	('increase', 'PosReg', (143, 151))	('silencing', 'Var', (6, 15))	('PTEN', 'Gene', '5728', (102, 106))	('PTEN', 'Gene', (38, 42))
439883	26304537	The multivariate linear model could measure the expression association between a miRNA and a mRNA, that also factors in variation (noise) in mRNA expression induced by changes in DNA copy number and promoter methylation at the mRNA gene locus.	('changes', 'Var', (168, 175))	('mRNA expression', 'MPA', (141, 156))	('miR', 'Gene', (81, 84))	('miR', 'Gene', '220972', (81, 84))
439902	32350633	CYP4F2 and CYP3A5 gene polymorphisms and lung cancer in Chinese Han population This study aimed to explore whether the polymorphisms of CYP4F2 and CYP3A5 are correlated with the risk of lung cancer development.	('lung cancer', 'Disease', 'MESH:D008175', (186, 197))	('Chinese', 'Species', '10029', (56, 63))	('lung cancer', 'Phenotype', 'HP:0100526', (186, 197))	('CYP4F2', 'Gene', '8529', (0, 6))	('lung cancer', 'Disease', 'MESH:D008175', (41, 52))	('CYP4F2', 'Gene', (0, 6))	('CYP3A5', 'Gene', '1577', (147, 153))	('lung cancer', 'Phenotype', 'HP:0100526', (41, 52))	('CYP3A5', 'Gene', '1577', (11, 17))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('CYP3A5', 'Gene', (147, 153))	('CYP3A5', 'Gene', (11, 17))	('polymorphisms', 'Var', (119, 132))	('men', 'Species', '9606', (205, 208))	('correlated', 'Reg', (158, 168))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('lung cancer', 'Disease', (186, 197))	('lung cancer', 'Disease', (41, 52))	('CYP4F2', 'Gene', '8529', (136, 142))	('CYP4F2', 'Gene', (136, 142))
439905	32350633	Stratified analysis found that the rs3093105 and rs3093106 loci of CYP4F2 gene were significantly associated with lower risk of lung cancer (P = 0.012, OR 0.64, 95% CI 0.45-0.91).	('lung cancer', 'Disease', 'MESH:D008175', (128, 139))	('rs3093105', 'Mutation', 'rs3093105', (35, 44))	('CYP4F2', 'Gene', '8529', (67, 73))	('CYP4F2', 'Gene', (67, 73))	('rs3093106', 'Var', (49, 58))	('lung cancer', 'Disease', (128, 139))	('lower', 'NegReg', (114, 119))	('lung cancer', 'Phenotype', 'HP:0100526', (128, 139))	('rs3093106', 'Mutation', 'rs3093106', (49, 58))	('rs3093105', 'Var', (35, 44))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
439907	32350633	Similarly, the rs10242455 loci of CYP3A5 gene showed a statistical significance between the case group and the control group (P = 0.018, OR 0.71, 95% CI 0.53-0.94), which also was associated with reduced risk of squamous cell lung cancer in the dominant and additive models (dominant: OR 0.66, 95% CI 0.46-0.94, P = 0.021; additive: OR 0.71, 95% CI 0.53-0.95, P = 0.023).	('CYP3A5', 'Gene', '1577', (34, 40))	('rs10242455', 'Mutation', 'rs10242455', (15, 25))	('lung cancer', 'Phenotype', 'HP:0100526', (226, 237))	('squamous cell lung cancer', 'Disease', 'MESH:D002294', (212, 237))	('squamous cell lung cancer', 'Phenotype', 'HP:0030359', (212, 237))	('rs10242455', 'Var', (15, 25))	('CYP3A5', 'Gene', (34, 40))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('squamous cell lung cancer', 'Disease', (212, 237))	('reduced', 'NegReg', (196, 203))
439915	32350633	In addition, many studies have shown that the development, metastasis, and prognosis of lung cancer are related to many gene mutations, such as EGFR, KRAS, and BRAF.	('metastasis', 'CPA', (59, 69))	('mutations', 'Var', (125, 134))	('BRAF', 'Gene', (160, 164))	('EGFR', 'Gene', (144, 148))	('lung cancer', 'Disease', (88, 99))	('BRAF', 'Gene', '673', (160, 164))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('lung cancer', 'Disease', 'MESH:D008175', (88, 99))	('EGFR', 'Gene', '1956', (144, 148))	('men', 'Species', '9606', (53, 56))	('related', 'Reg', (104, 111))	('KRAS', 'Gene', (150, 154))	('KRAS', 'Gene', '3845', (150, 154))	('lung cancer', 'Phenotype', 'HP:0100526', (88, 99))
439925	32350633	Therefore, in this study, four SNP locus in CYP4F2 and CYP3A5 genes were analyzed to explore the association between the polymorphisms of CYP4F2 and CYP3A5 genes and the risk for lung cancer.	('CYP4F2', 'Gene', '8529', (138, 144))	('CYP3A5', 'Gene', (55, 61))	('CYP3A5', 'Gene', (149, 155))	('CYP4F2', 'Gene', (138, 144))	('lung cancer', 'Disease', (179, 190))	('lung cancer', 'Phenotype', 'HP:0100526', (179, 190))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('CYP4F2', 'Gene', '8529', (44, 50))	('CYP4F2', 'Gene', (44, 50))	('CYP3A5', 'Gene', '1577', (149, 155))	('polymorphisms', 'Var', (121, 134))	('CYP3A5', 'Gene', '1577', (55, 61))	('lung cancer', 'Disease', 'MESH:D008175', (179, 190))
439941	32350633	Stratified analysis found that three of the four selected SNP loci were significantly associated with lowered risk of lung cancer in allele model, namely rs3093106 (CYP4F2), rs3093105 (CYP4F2), and rs10242455 (CYP3A5), among which rs3093106 and rs3093105 were significantly different between the two groups in the subjects of older than 58 years old (rs3093105: P = 0.023, OR 0.59, 95% CI 0.37-0.93; rs3093106: P = 0.029, OR 0.60, 95% CI 0.38-0.94), lung adenocarcinoma (rs3093105, P = 0.023, OR 0.59, 95% CI 0.37-0.93; rs3093106: P = 0.025; OR 0.60, 95% CI 0.38-0.94) and male patients (rs3093105, P = 0.017, OR 0.68, 95% CI 0.49-0.93; rs3093106: P = 0.020, OR 0.68, 95% CI 0.50-0.94).	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('lung adenocarcinoma', 'Disease', (450, 469))	('CYP4F2', 'Gene', (185, 191))	('rs3093105', 'Var', (588, 597))	('rs3093105', 'Mutation', 'rs3093105', (471, 480))	('rs3093105', 'Mutation', 'rs3093105', (351, 360))	('rs10242455', 'Mutation', 'rs10242455', (198, 208))	('rs3093106', 'Mutation', 'rs3093106', (154, 163))	('rs3093105', 'Var', (174, 183))	('lung cancer', 'Disease', (118, 129))	('carcinoma', 'Phenotype', 'HP:0030731', (460, 469))	('rs3093106', 'Mutation', 'rs3093106', (637, 646))	('rs3093106', 'Var', (154, 163))	('rs3093106', 'Mutation', 'rs3093106', (231, 240))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (450, 469))	('CYP3A5', 'Gene', '1577', (210, 216))	('rs3093106', 'Var', (231, 240))	('rs3093105', 'Mutation', 'rs3093105', (245, 254))	('rs3093105', 'Mutation', 'rs3093105', (588, 597))	('rs3093106', 'Var', (637, 646))	('CYP4F2', 'Gene', '8529', (165, 171))	('CYP4F2', 'Gene', (165, 171))	('rs10242455', 'Var', (198, 208))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (450, 469))	('CYP3A5', 'Gene', (210, 216))	('rs3093105', 'Mutation', 'rs3093105', (174, 183))	('lung cancer', 'Disease', 'MESH:D008175', (118, 129))	('lung cancer', 'Phenotype', 'HP:0100526', (118, 129))	('rs3093105', 'Var', (471, 480))	('rs3093106', 'Mutation', 'rs3093106', (520, 529))	('lowered', 'NegReg', (102, 109))	('CYP4F2', 'Gene', '8529', (185, 191))	('patients', 'Species', '9606', (578, 586))	('rs3093106', 'Mutation', 'rs3093106', (400, 409))
439942	32350633	Rs10242455 in CYP3A5 gene showed significant difference between the two groups in lung squamous cell carcinoma (rs10242455: P = 0.018, OR 0.71, 95% CI 0.53-0.94) (Tables 3, 4).	('Rs10242455', 'Mutation', 'Rs10242455', (0, 10))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (87, 110))	('CYP3A5', 'Gene', (14, 20))	('lung squamous cell carcinoma', 'Disease', (82, 110))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (82, 110))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('Rs10242455', 'Var', (0, 10))	('difference', 'Reg', (45, 55))	('CYP3A5', 'Gene', '1577', (14, 20))	('rs10242455', 'Mutation', 'rs10242455', (112, 122))	('rs10242455:', 'Var', (112, 123))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (82, 110))
439943	32350633	The results showed that the rs3093105 and rs3093106 were linked with reduced risk of lung cancer in the dominant model and additive model of lung adenocarcinoma, male patients and patients older than 58 years old.	('lung adenocarcinoma', 'Disease', (141, 160))	('lung cancer', 'Disease', (85, 96))	('rs3093106', 'Var', (42, 51))	('rs3093105', 'Mutation', 'rs3093105', (28, 37))	('lung cancer', 'Phenotype', 'HP:0100526', (85, 96))	('reduced', 'NegReg', (69, 76))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (141, 160))	('patients', 'Species', '9606', (167, 175))	('lung cancer', 'Disease', 'MESH:D008175', (85, 96))	('rs3093106', 'Mutation', 'rs3093106', (42, 51))	('rs3093105', 'Var', (28, 37))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (141, 160))	('patients', 'Species', '9606', (180, 188))	('carcinoma', 'Phenotype', 'HP:0030731', (151, 160))
439944	32350633	The rs10242455 was associated with lowered risk of lung squamous cell carcinoma in the dominant model and additive model; after adjusting for age and gender, the correlation was still observed (Table 4).	('rs10242455', 'Mutation', 'rs10242455', (4, 14))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (56, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (51, 79))	('rs10242455', 'Var', (4, 14))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (51, 79))	('lung squamous cell carcinoma', 'Disease', (51, 79))	('lowered', 'NegReg', (35, 42))
439954	32350633	Our study has been the first to report that there is a significant correlation between CYP4F2 gene polymorphisms and lung cancer in Chinese Han population, and this is associated with lowered risk of lung cancer in people older than 58 years old, lung adenocarcinoma and men.	('lung cancer', 'Disease', 'MESH:D008175', (200, 211))	('polymorphisms', 'Var', (99, 112))	('lung cancer', 'Disease', (117, 128))	('lung cancer', 'Phenotype', 'HP:0100526', (200, 211))	('men', 'Species', '9606', (271, 274))	('CYP4F2', 'Gene', '8529', (87, 93))	('CYP4F2', 'Gene', (87, 93))	('people', 'Species', '9606', (215, 221))	('correlation', 'Interaction', (67, 78))	('Chinese', 'Species', '10029', (132, 139))	('lung adenocarcinoma', 'Disease', (247, 266))	('lowered', 'NegReg', (184, 191))	('lung cancer', 'Disease', 'MESH:D008175', (117, 128))	('lung cancer', 'Phenotype', 'HP:0100526', (117, 128))	('lung cancer', 'Disease', (200, 211))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (247, 266))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (247, 266))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (257, 266))
439959	32350633	Similarly, two studies have demonstrated that HET0016 (20-HETE antagonist) can inhibit the growth of tumors in non-small cell lung cancer cell lines and of human glioma.	('inhibit', 'NegReg', (79, 86))	('20-HETE', 'Chemical', 'MESH:C055987', (55, 62))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (115, 137))	('tumors', 'Disease', 'MESH:D009369', (101, 107))	('glioma', 'Disease', (162, 168))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (111, 137))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('lung cancer', 'Disease', (126, 137))	('lung cancer', 'Phenotype', 'HP:0100526', (126, 137))	('HET0016', 'Var', (46, 53))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('growth', 'CPA', (91, 97))	('glioma', 'Disease', 'MESH:D005910', (162, 168))	('lung cancer', 'Disease', 'MESH:D008175', (126, 137))	('human', 'Species', '9606', (156, 161))	('glioma', 'Phenotype', 'HP:0009733', (162, 168))	('tumors', 'Disease', (101, 107))
439960	32350633	We hypothesize that the effect of CYP4F2 gene polymorphisms on the risk for lung cancer may be related to the metabolism of 20-HETE and then affect the growth of cancer cells by regulating the signal pathway of vascular endothelial growth factor.	('affect', 'Reg', (141, 147))	('cancer', 'Disease', (162, 168))	('cancer', 'Disease', (81, 87))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('lung cancer', 'Disease', (76, 87))	('growth', 'CPA', (152, 158))	('polymorphisms', 'Var', (46, 59))	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('vascular endothelial growth factor', 'Gene', '7422', (211, 245))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('metabolism of 20-HETE', 'MPA', (110, 131))	('regulating', 'Reg', (178, 188))	('CYP4F2', 'Gene', '8529', (34, 40))	('CYP4F2', 'Gene', (34, 40))	('vascular endothelial growth factor', 'Gene', (211, 245))	('lung cancer', 'Disease', 'MESH:D008175', (76, 87))	('related', 'Reg', (95, 102))	('lung cancer', 'Phenotype', 'HP:0100526', (76, 87))	('20-HETE', 'Chemical', 'MESH:C055987', (124, 131))
439969	32350633	Research has found that a SNP within intron-3 (CYP3A5*3) results in aberrant mRNA splicing and a pronounced reduction in protein synthesis.	('CYP3A5', 'Gene', '1577', (47, 53))	('mRNA splicing', 'MPA', (77, 90))	('CYP3A5', 'Gene', (47, 53))	('SNP', 'Var', (26, 29))	('protein synthesis', 'MPA', (121, 138))	('reduction', 'NegReg', (108, 117))
439970	32350633	Likewise, rs10242455 belongs to intron variants in CYP3A5 gene.	('rs10242455', 'Var', (10, 20))	('CYP3A5', 'Gene', '1577', (51, 57))	('rs10242455', 'Mutation', 'rs10242455', (10, 20))	('CYP3A5', 'Gene', (51, 57))
439983	32350633	The purpose of this study was to investigate the relationship between CYP450 gene polymorphism and lung cancer susceptibility.	('lung cancer', 'Disease', (99, 110))	('CYP450', 'Gene', (70, 76))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('lung cancer', 'Disease', 'MESH:D008175', (99, 110))	('CYP450', 'Gene', '4051', (70, 76))	('polymorphism', 'Var', (82, 94))	('lung cancer', 'Phenotype', 'HP:0100526', (99, 110))
440030	29858064	The striking unanimity of cancer-related studies gives us the impression that expression differentiation between cancer and adjacent normal tissues might be helpful in the identification of prognostic molecules; molecules upregulated in cancer might only shorten patient's survival, while downregulated ones might have the opposite effect.	('patient', 'Species', '9606', (263, 270))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('upregulated', 'PosReg', (222, 233))	('cancer', 'Disease', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('cancer', 'Disease', (113, 119))	('shorten', 'NegReg', (255, 262))	('cancer', 'Disease', (237, 243))	('cancer', 'Disease', 'MESH:D009369', (237, 243))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('molecules', 'Var', (212, 221))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
440045	29858064	However, the result of our study indicated that the direction of DEG's survival correlation was actually independent of its expression differentiation (Figure 3), that is, overexpression of upregulated genes could shorten or prolong patient's survival randomly, and vice versa.	('shorten', 'NegReg', (214, 221))	('patient', 'Species', '9606', (233, 240))	('prolong', 'PosReg', (225, 232))	('overexpression', 'PosReg', (172, 186))	('genes', 'Var', (202, 207))	('upregulated', 'PosReg', (190, 201))
440071	27507904	Integrated Genomic Analysis of Recurrence-Associated Small Non-coding RNAs in Oesophageal Cancer Oesophageal squamous cell carcinoma (ESCC) is a heterogeneous disease with variable outcomes that are challenging to predict.	('Cancer', 'Phenotype', 'HP:0002664', (90, 96))	('Oesophageal Cancer', 'Disease', 'MESH:D009369', (78, 96))	('Oesophageal Cancer', 'Disease', (78, 96))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (109, 132))	('Oesophageal squamous cell carcinoma', 'Disease', (97, 132))	('Oesophageal squamous cell carcinoma', 'Disease', 'MESH:D002294', (97, 132))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('Small Non-coding RNAs', 'Var', (53, 74))
440111	27507904	We next developed a recurrence risk assessment model with Cox regression coefficients and the expression level of each sncRNA measured with qRT-PCR: Raw Risk Assessment Score for Recurrence (RASraw)=(-0.084xexpression value of nc886)+(-0.227xexpression value of miR-223)+(0.137xexpression value of miR-1269a).	('miR-223', 'Gene', '407008', (262, 269))	('Cox', 'Gene', '1351', (58, 61))	('Cox', 'Gene', (58, 61))	('miR-1269a', 'Gene', (298, 307))	('miR-1269a', 'Gene', '100302177', (298, 307))	('-0.084xexpression', 'Var', (200, 217))	('nc886', 'Gene', (227, 232))	('miR-223', 'Gene', (262, 269))	('nc886', 'Gene', '100126299', (227, 232))
440119	27507904	Enrichment analysis of these genes through gene ontology revealed that genes related to cell mitosis, chromatin remodeling, histone modification, and DNA repair were significantly activated in the high-RAS group, but genes related to cell-to-cell cytokine signaling were dominant in the low-RAS group.	('cell mitosis', 'Disease', (88, 100))	('cell mitosis', 'Disease', 'MESH:C538614', (88, 100))	('histone modification', 'MPA', (124, 144))	('high-RAS', 'Var', (197, 205))	('activated', 'PosReg', (180, 189))
440125	27507904	TAp63alpha, beta, and gamma with a transcription activation (TA) domain have tumor suppressive activity, but DeltaNp63 alpha, beta, and gamma without a TA domain have oncogenic activity, as they serve as competitive inhibitors of TAp63alpha, beta, and gamma.	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('oncogenic activity', 'CPA', (167, 185))	('DeltaNp63', 'Var', (109, 118))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Disease', (77, 82))
440126	27507904	As a result, the expression of oncogenic isoforms, DeltaNp63beta and gamma were significantly higher in the high-RAS group of both ESCA and LUSC cohorts (figure 4B-C), suggesting that the tumor suppressive activity of TP63 is blocked by its oncogenic isoforms in this group.	('tumor', 'Disease', (188, 193))	('TP63', 'Gene', (218, 222))	('TP63', 'Gene', '8626', (218, 222))	('expression', 'MPA', (17, 27))	('DeltaNp63beta', 'Var', (51, 64))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('LUSC', 'Phenotype', 'HP:0030359', (140, 144))	('higher', 'PosReg', (94, 100))
440127	27507904	Interestingly, higher expression of DeltaNp63beta and gamma correlated with amplification of TP63, further suggesting that the activation of alternative promoters and alternative splicing of TP63 is a major mechanism in the regulation of TP63 in squamous cell carcinoma.	('TP63', 'Gene', (93, 97))	('TP63', 'Gene', (191, 195))	('TP63', 'Gene', '8626', (238, 242))	('higher', 'PosReg', (15, 21))	('TP63', 'Gene', '8626', (93, 97))	('TP63', 'Gene', (238, 242))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (246, 269))	('carcinoma', 'Phenotype', 'HP:0030731', (260, 269))	('squamous cell carcinoma', 'Disease', (246, 269))	('amplification', 'MPA', (76, 89))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (246, 269))	('DeltaNp63beta', 'Var', (36, 49))	('expression', 'MPA', (22, 32))	('TP63', 'Gene', '8626', (191, 195))
440128	27507904	Additionally, TP53 mutation and PIK3CA amplification are significantly higher in the high-RAS group (figure 4C).	('higher', 'PosReg', (71, 77))	('amplification', 'MPA', (39, 52))	('TP53', 'Gene', '7157', (14, 18))	('PIK3CA', 'Gene', '5290', (32, 38))	('mutation', 'Var', (19, 27))	('TP53', 'Gene', (14, 18))	('high-RAS', 'Disease', (85, 93))	('PIK3CA', 'Gene', (32, 38))
440134	27507904	Furthermore, the apoptosis assay of risk-stratified ESCC cell lines for three HDAC inhibitors (Panobisnotat, Dacinostat (LAQ824), and Vorinostat), two PLK inhibitors (BI2536 and BI6727 [Volasertib]), and two mTOR inhibitors (BEZ235 [Dactolisib] and Tacrolimus [FK506]) demonstrated that TE-8 high-risk cell line had dominant signals of the apoptosis compared with Het-1a and TE-1 cell lines with lower risk (figure 5B).	('apoptosis', 'CPA', (340, 349))	('BI6727', 'Var', (178, 184))	('HDAC', 'Gene', (78, 82))	('HDAC', 'Gene', '9734', (78, 82))
440141	27507904	Furthermore, PD-L1 was markedly expressed in dendritic cells in a tumor microenvironment with TE-1 but not with TE-8 (figure 6B and supplementary figure S14).	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Disease', (66, 71))	('TE-1', 'Var', (94, 98))	('PD-L1', 'Gene', (13, 18))	('tumor', 'Disease', 'MESH:D009369', (66, 71))
440152	27507904	Recently, we reported that nc886 knockdown induced oncogenes MYC and FOS.	('FOS', 'Gene', (69, 72))	('knockdown', 'Var', (33, 42))	('MYC', 'Gene', '4609', (61, 64))	('nc886', 'Gene', (27, 32))	('FOS', 'Gene', '2353', (69, 72))	('nc886', 'Gene', '100126299', (27, 32))	('MYC', 'Gene', (61, 64))	('induced', 'PosReg', (43, 50))
440157	27507904	In our study, the low-risk group presented a tumor microenvironment in which immune cells coexisted with tumor cells expressing PD-L1, which suppressed cytotoxic T cell functions.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('PD-L1', 'Var', (128, 133))	('tumor', 'Disease', (45, 50))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('cytotoxic T cell functions', 'CPA', (152, 178))	('suppressed', 'NegReg', (141, 151))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumor', 'Disease', (105, 110))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
440169	27507904	The expression of oncogenic isoforms DeltaNp63 was significantly higher in the high-RAS group, and, interestingly, this higher expression correlated with amplification of TP63, further suggesting that the activation of alternative promoters and alternative splicing of TP63 are major mechanisms for the regulation of TP63 in squamous carcinoma.	('TP63', 'Gene', '8626', (317, 321))	('DeltaNp63', 'Gene', (37, 46))	('squamous carcinoma', 'Disease', (325, 343))	('TP63', 'Gene', (269, 273))	('TP63', 'Gene', '8626', (269, 273))	('carcinoma', 'Phenotype', 'HP:0030731', (334, 343))	('squamous carcinoma', 'Disease', 'MESH:D002294', (325, 343))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (325, 343))	('high-RAS', 'Var', (79, 87))	('expression', 'MPA', (4, 14))	('TP63', 'Gene', '8626', (171, 175))	('TP63', 'Gene', (171, 175))	('higher', 'PosReg', (65, 71))	('TP63', 'Gene', (317, 321))
440176	27322142	Our approach revealed several dysregulated L-FFL motifs common across different cancers or specific to particular cancers.	('cancers', 'Disease', 'MESH:D009369', (114, 121))	('cancers', 'Phenotype', 'HP:0002664', (114, 121))	('motifs', 'Var', (49, 55))	('cancers', 'Disease', (114, 121))	('cancers', 'Disease', 'MESH:D009369', (80, 87))	('L-FFL', 'Chemical', '-', (43, 48))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancers', 'Disease', (80, 87))	('L-FFL', 'Gene', (43, 48))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('particular cancers', 'Disease', (103, 121))	('particular cancers', 'Disease', 'MESH:D009369', (103, 121))	('cancers', 'Phenotype', 'HP:0002664', (80, 87))
440177	27322142	We also found that L-FFL motifs can take part in other types of regulatory networks, such as mRNA-mediated FFLs and ceRNA networks, and form the more complex networks in human cancers.	('L-FFL', 'Var', (19, 24))	('cancers', 'Disease', (176, 183))	('cancers', 'Disease', 'MESH:D009369', (176, 183))	('cancers', 'Phenotype', 'HP:0002664', (176, 183))	('take', 'Reg', (36, 40))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('regulatory', 'MPA', (64, 74))	('human', 'Species', '9606', (170, 175))	('L-FFL', 'Chemical', '-', (19, 24))	('form', 'Reg', (136, 140))
440180	27322142	Long non-coding RNAs (lncRNAs, > 200 nucleotides in length) are pervasive across the genome and dysregulation of their expression is associated with many human diseases, including cancer.	('expression', 'MPA', (119, 129))	('human', 'Species', '9606', (154, 159))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('Long', 'Protein', (0, 4))	('dysregulation', 'Var', (96, 109))	('cancer', 'Disease', (180, 186))	('associated', 'Reg', (133, 143))
440196	27322142	More importantly, we found that some L-FFL motifs provide novel information on cancer regulation.	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('L-FFL', 'Gene', (37, 42))	('motifs', 'Var', (43, 49))	('information', 'Reg', (64, 75))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('L-FFL', 'Chemical', '-', (37, 42))
440201	27322142	Our L-FFL network is composed of L-FFL motifs in lung cancer, which may represent a new mechanism in cancer (Figure 1F).	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('lung cancer', 'Disease', 'MESH:D008175', (49, 60))	('cancer', 'Disease', (101, 107))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('L-FFL', 'Chemical', '-', (4, 9))	('cancer', 'Disease', (54, 60))	('lung cancer', 'Disease', (49, 60))	('lung cancer', 'Phenotype', 'HP:0100526', (49, 60))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('L-FFL', 'Chemical', '-', (33, 38))	('L-FFL motifs', 'Var', (33, 45))
440215	27322142	Here, L-FFL motifs dysregulated in at least two cancer types are designated as "common", while those dysregulated in only one cancer type are considered "specific".	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('L-FFL', 'Chemical', '-', (6, 11))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('motifs', 'Var', (12, 18))	('cancer', 'Disease', (48, 54))	('L-FFL', 'Gene', (6, 11))	('cancer', 'Disease', 'MESH:D009369', (48, 54))
440232	27322142	These results suggest that L-FFL motifs may serve as prognostic biomarkers for different cancers.	('cancers', 'Phenotype', 'HP:0002664', (89, 96))	('L-FFL', 'Chemical', '-', (27, 32))	('motifs', 'Var', (33, 39))	('cancers', 'Disease', 'MESH:D009369', (89, 96))	('cancers', 'Disease', (89, 96))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
440234	27322142	First, we identified dysregulated mRNA-mediated FFL (M-FFL) motifs in different types of cancers by following the same pipeline as with the L-FFL motif identification.	('L-FFL', 'Chemical', '-', (140, 145))	('cancers', 'Phenotype', 'HP:0002664', (89, 96))	('cancers', 'Disease', 'MESH:D009369', (89, 96))	('cancers', 'Disease', (89, 96))	('mRNA-mediated', 'MPA', (34, 47))	('motifs', 'Var', (60, 66))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
440236	27322142	For example, we found that an L-FFL motif constituted by SNHG12, E2F1, and miR-16, and an M-FFL motif constituted by E2F1, miR-16 and AURKB could form a complex regulation motif by sharing common TF E2F1 and miRNA miR-16, which were highly dysregulated in breast and bladder cancers (Figure 5A, Supplementary Table S6).	('E2F1', 'Gene', (65, 69))	('miR-16', 'Gene', '51573', (214, 220))	('E2F1', 'Gene', '1869', (65, 69))	('E2F1', 'Gene', (199, 203))	('breast and bladder cancers', 'Disease', 'MESH:D001749', (256, 282))	('miR-16', 'Gene', (75, 81))	('E2F1', 'Gene', '1869', (199, 203))	('miR-16', 'Gene', (123, 129))	('AURKB', 'Gene', (134, 139))	('E2F1', 'Gene', (117, 121))	('L-FFL', 'Chemical', '-', (30, 35))	('SNHG12', 'Gene', (57, 63))	('cancers', 'Phenotype', 'HP:0002664', (275, 282))	('E2F1', 'Gene', '1869', (117, 121))	('miR-16', 'Gene', '51573', (75, 81))	('bladder cancer', 'Phenotype', 'HP:0009725', (267, 281))	('miR-16', 'Gene', '51573', (123, 129))	('cancer', 'Phenotype', 'HP:0002664', (275, 281))	('miR-16', 'Gene', (214, 220))	('miRNA', 'Var', (208, 213))	('SNHG12', 'Gene', '85028', (57, 63))	('bladder cancers', 'Phenotype', 'HP:0009725', (267, 282))	('AURKB', 'Gene', '9212', (134, 139))
440251	27322142	In this study, we also identified dysregulated L-FFL motifs that were common and specific to several cancers, consistent with previous studies on the tissue specificity of miRNA and lncRNA.	('dysregulated', 'Var', (34, 46))	('L-FFL', 'Chemical', '-', (47, 52))	('cancers', 'Disease', 'MESH:D009369', (101, 108))	('cancers', 'Phenotype', 'HP:0002664', (101, 108))	('cancers', 'Disease', (101, 108))	('L-FFL', 'Gene', (47, 52))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))
440253	27322142	Our functional and survival analyses suggest that L-FFL motifs may serve as prognostic biomarkers for cancer.	('motifs', 'Var', (56, 62))	('L-FFL', 'Chemical', '-', (50, 55))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('L-FFL', 'Protein', (50, 55))
440303	26318035	Our previous studies demonstrate that TNF-alpha is an essential inflammatory mediator for cell neoplastic transformation upon B[a]P/B[a]PDE exposure.	('PDE', 'Gene', (136, 139))	('PDE', 'Gene', '501', (136, 139))	('B[a]P/B[a', 'Var', (126, 135))	('B[a]P', 'Chemical', 'MESH:D001564', (132, 137))	('cell neoplastic transformation', 'CPA', (90, 120))	('B[a]P', 'Chemical', 'MESH:D001564', (126, 131))
440320	26318035	The SIRT1 protein level was also induced by B[a]P in a time-dependent manner and reached its peak at 48 h as shown by immunoblotting (Figure 2C).	('protein', 'Protein', (10, 17))	('induced', 'Reg', (33, 40))	('SIRT1', 'Gene', (4, 9))	('B[a]P', 'Var', (44, 49))	('B[a]P', 'Chemical', 'MESH:D001564', (44, 49))
440327	26318035	It showed that B[a]P induced SIRT1 expression at transcriptional level (Figure 2I).	('B[a]P', 'Var', (15, 20))	('B[a]P', 'Chemical', 'MESH:D001564', (15, 20))	('SIRT1', 'Gene', (29, 34))	('expression', 'MPA', (35, 45))
440328	26318035	Taken together, our data strongly demonstrated that B[a]P could up-regulate SIRT1 expression in vitro and in vivo.	('up-regulate', 'PosReg', (64, 75))	('B[a]P', 'Var', (52, 57))	('expression', 'MPA', (82, 92))	('B[a]P', 'Chemical', 'MESH:D001564', (52, 57))	('SIRT1', 'Gene', (76, 81))
440341	26318035	Our results showed that SIRT1 overexpression enhanced the expression of NF-kappaB and COX-2, whereas silencing SIRT1 reduced the levels of NF-kappaB and COX-2 in BEAS-2B cells by Western blotting (Figure 4A).	('SIRT1', 'Gene', (111, 116))	('COX-2', 'Gene', (86, 91))	('NF-kappaB', 'Gene', (139, 148))	('expression', 'MPA', (58, 68))	('silencing', 'Var', (101, 110))	('reduced', 'NegReg', (117, 124))	('enhanced', 'PosReg', (45, 53))	('NF-kappaB', 'Gene', '4790', (72, 81))	('SIRT1', 'Gene', (24, 29))	('COX-2', 'MPA', (153, 158))	('levels', 'MPA', (129, 135))	('NF-kappaB', 'Gene', (72, 81))	('NF-kappaB', 'Gene', '4790', (139, 148))	('BEAS-2B', 'CellLine', 'CVCL:0168', (162, 169))
440344	26318035	TNF-alpha transcriptional activity were elevated in the SIRT1 overexpressing cells upon B[a]P treatment, but reduced in the SIRT1 silencing cells (Figure 4E).	('TNF-alpha', 'Gene', (0, 9))	('elevated', 'PosReg', (40, 48))	('transcriptional activity', 'MPA', (10, 34))	('B[a]P', 'Chemical', 'MESH:D001564', (88, 93))	('reduced', 'NegReg', (109, 116))	('B[a]P treatment', 'Var', (88, 103))
440346	26318035	TNF-alpha silencing could eliminate the effects of SIRT1 on the invasion ability of BEAS-2B cells (Figure 5D).	('BEAS-2B', 'CellLine', 'CVCL:0168', (84, 91))	('invasion ability of BEAS-2B cells', 'CPA', (64, 97))	('TNF-alpha', 'Protein', (0, 9))	('eliminate', 'NegReg', (26, 35))	('silencing', 'Var', (10, 19))	('SIRT1', 'Gene', (51, 56))
440347	26318035	Furthermore, we compared the difference among control cells, SIRT1 overexpressed cells with or without B[a]P treatment by wound healing assay under the conditions of silencing TNF-alpha.	('B[a]P', 'Chemical', 'MESH:D001564', (103, 108))	('silencing', 'Var', (166, 175))	('TNF-alpha', 'Protein', (176, 185))
440349	26318035	As shown in Figure 6A, we found that SIRT1 silencing did not reduce the mRNA levels of RAC1/CDC42/CFL2/XIAP, except beta-catenin, upon B[a]P exposure.	('XIAP', 'Gene', (103, 107))	('RAC1', 'Gene', (87, 91))	('mRNA levels', 'MPA', (72, 83))	('SIRT1', 'Gene', (37, 42))	('XIAP', 'Gene', '331', (103, 107))	('B[a]P', 'Chemical', 'MESH:D001564', (135, 140))	('silencing', 'Var', (43, 52))	('RAC1', 'Gene', '5879', (87, 91))	('CFL2', 'Gene', '1073', (98, 102))	('CFL2', 'Gene', (98, 102))	('CDC42', 'Gene', '998', (92, 97))	('CDC42', 'Gene', (92, 97))
440351	26318035	TNF-alpha silencing could reverse the effects of SIRT1 on the beta-catenin protein expression in BEAS-2B cells upon B[a]P exposure (Figure 7A).	('SIRT1', 'Gene', (49, 54))	('TNF-alpha', 'Gene', (0, 9))	('BEAS-2B', 'CellLine', 'CVCL:0168', (97, 104))	('B[a]P', 'Chemical', 'MESH:D001564', (116, 121))	('beta-catenin protein', 'Protein', (62, 82))	('silencing', 'Var', (10, 19))
440352	26318035	On the other hand, the mRNA level of TNF-alpha decreased under XAV939 treatment (Figure 7B).	('XAV939 treatment', 'Var', (63, 79))	('TNF-alpha', 'Protein', (37, 46))	('XAV939', 'Chemical', 'MESH:C544261', (63, 69))	('mRNA level', 'MPA', (23, 33))	('decreased', 'NegReg', (47, 56))
440369	26318035	SIRT1 transgenic mice exhibit reduced susceptibility to carcinogen-induced liver cancer.	('susceptibility', 'MPA', (38, 52))	('liver cancer', 'Disease', (75, 87))	('SIRT1', 'Gene', (0, 5))	('reduced', 'NegReg', (30, 37))	('transgenic mice', 'Species', '10090', (6, 21))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('liver cancer', 'Phenotype', 'HP:0002896', (75, 87))	('liver cancer', 'Disease', 'MESH:D006528', (75, 87))	('transgenic', 'Var', (6, 16))
440386	26318035	We also found that knock-down of TNF-alpha could eliminate the effect of SIRT1 on invasive and migratory ability of BEAS-2B cells.	('SIRT1', 'Gene', (73, 78))	('TNF-alpha', 'Protein', (33, 42))	('eliminate', 'NegReg', (49, 58))	('BEAS-2B', 'CellLine', 'CVCL:0168', (116, 123))	('knock-down', 'Var', (19, 29))
440389	26318035	XAV939, a Wnt/beta-catenin specifice inhibitor, reduced the mRNA levels of TNF-alpha, while beta-catenin stimulated the promotor activity of TNF-alpha.	('promotor activity', 'MPA', (120, 137))	('XAV939', 'Var', (0, 6))	('reduced', 'NegReg', (48, 55))	('TNF-alpha', 'MPA', (75, 84))	('stimulated', 'PosReg', (105, 115))	('XAV939', 'Chemical', 'MESH:C544261', (0, 6))	('mRNA levels', 'MPA', (60, 71))
440397	26318035	B[a]P exposure: BEAS-2B cells were treated with 8 muM B[a]P (Sigma-Aldrich, USA).	('B[a]P', 'Chemical', 'MESH:D001564', (54, 59))	('muM', 'Gene', '56925', (50, 53))	('B[a]P', 'Var', (54, 59))	('BEAS-2B', 'CellLine', 'CVCL:0168', (16, 23))	('muM', 'Gene', (50, 53))	('B[a]P', 'Chemical', 'MESH:D001564', (0, 5))
440398	26318035	Wnt/beta-catenin specific inhibitor: BEAS-2B cells were treated with 1 muM XAV939 (Sigma-Aldrich, USA) for 24 h. To overexpress and knock down SIRT1 in BEAS-2B cells, the cells were transfected with pcDNA3.1/SIRT1 plasmid or pcDNA3.1 vector as a control, and pGPU6/shSIRT1 plasmid or pGPU6 vector as a control (GenePharma, China), respectively, using Lipofectamine 2000 as manufacturer instructed (Invitrogen, USA).	('muM', 'Gene', (71, 74))	('BEAS-2B', 'CellLine', 'CVCL:0168', (37, 44))	('overexpress', 'PosReg', (116, 127))	('XAV939', 'Chemical', 'MESH:C544261', (75, 81))	('knock down', 'Var', (132, 142))	('muM', 'Gene', '56925', (71, 74))	('Lipofectamine 2000', 'Chemical', 'MESH:C086724', (351, 369))	('BEAS-2B', 'CellLine', 'CVCL:0168', (152, 159))	('SIRT1', 'Gene', (143, 148))
440423	26318035	The concentrations and timings of the intratracheal instillation of B[a]P were chosen based upon lung tumor induction by B[a]P in previous studies, and were adjusted, if necessary, to cause maximal induction of SIRT1 expression with minimal observed toxicity to mice.	('B[a]P', 'Chemical', 'MESH:D001564', (68, 73))	('toxicity', 'Disease', 'MESH:D064420', (250, 258))	('toxicity', 'Disease', (250, 258))	('lung tumor', 'Disease', 'MESH:D008175', (97, 107))	('SIRT1', 'Gene', (211, 216))	('lung tumor', 'Disease', (97, 107))	('expression', 'MPA', (217, 227))	('B[a]P', 'Var', (121, 126))	('mice', 'Species', '10090', (262, 266))	('B[a]P', 'Chemical', 'MESH:D001564', (121, 126))	('lung tumor', 'Phenotype', 'HP:0100526', (97, 107))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('induction', 'MPA', (198, 207))
440442	26678909	In The Cancer Genome Atlas data sets, the PAM50 gene set was prognostic in both adenocarcinoma and squamous cell carcinoma, whereas the seven-gene panel was prognostic only in squamous cell carcinoma.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (176, 199))	('carcinoma', 'Phenotype', 'HP:0030731', (190, 199))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (176, 199))	('Cancer', 'Disease', (7, 13))	('squamous cell carcinoma', 'Disease', (176, 199))	('prognostic', 'Reg', (61, 71))	('adenocarcinoma and squamous cell carcinoma', 'Disease', 'MESH:D002294', (80, 122))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (99, 122))	('PAM50 gene', 'Var', (42, 52))	('Cancer', 'Disease', 'MESH:D009369', (7, 13))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('Cancer', 'Phenotype', 'HP:0002664', (7, 13))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (99, 122))	('squamous cell carcinoma', 'Disease', (99, 122))
440505	26678909	These included R5020 (a progestin; activation score of 1.96), trastuzumab (a neutralizing antibody for HER2), HOXB4 (a homeobox transcription factor that regulates MYC and PGR), NRG-1 (a ligand for HER3/HER4; activation score of 1.98), the ER letrozole (an aromatase inhibitor), and beta-estradiol (activation score of 2.14).	('PGR', 'Gene', '5241', (172, 175))	('trastuzumab', 'Chemical', 'MESH:D000068878', (62, 73))	('ER', 'Gene', '2099', (240, 242))	('ER', 'Gene', '2099', (104, 106))	('HER4', 'Gene', (203, 207))	('MYC', 'Gene', '4609', (164, 167))	('beta-estradiol', 'Chemical', '-', (283, 297))	('HER3', 'Gene', '2065', (198, 202))	('HER2', 'Gene', '2064', (103, 107))	('aromatase', 'Gene', (257, 266))	('ER', 'Gene', '2099', (204, 206))	('PGR', 'Gene', (172, 175))	('HOXB4', 'Gene', (110, 115))	('HER4', 'Gene', '2066', (203, 207))	('HER3', 'Gene', (198, 202))	('NRG-1', 'Gene', '3084', (178, 183))	('HOXB4', 'Gene', '3214', (110, 115))	('HER2', 'Gene', (103, 107))	('beta-estradiol', 'MPA', (283, 297))	('MYC', 'Gene', (164, 167))	('R5020', 'Var', (15, 20))	('aromatase', 'Gene', '1588', (257, 266))	('NRG-1', 'Gene', (178, 183))	('ER', 'Gene', '2099', (199, 201))
440558	26678909	Low PGR was associated with more aggressive breast cancers that were driven by HER signaling (28), a mechanism that could also be operative in lung cancer.	('PGR', 'Gene', '5241', (4, 7))	('breast cancer', 'Phenotype', 'HP:0003002', (44, 57))	('lung cancer', 'Disease', (143, 154))	('lung cancer', 'Phenotype', 'HP:0100526', (143, 154))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('aggressive breast cancers', 'Disease', (33, 58))	('ER', 'Gene', '2099', (80, 82))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('lung cancer', 'Disease', 'MESH:D008175', (143, 154))	('aggressive breast cancers', 'Disease', 'MESH:D001943', (33, 58))	('cancers', 'Phenotype', 'HP:0002664', (51, 58))	('PGR', 'Gene', (4, 7))	('breast cancers', 'Phenotype', 'HP:0003002', (44, 58))	('Low', 'Var', (0, 3))
440565	26678909	In TCGA data, the proportion of lung adenocarcinomas and squamous cell carcinomas overexpressing genes in the seven-gene signature was similar, as was the proportion of tumors displaying amplified, mutated, or overexpressed ERBB2/HER2, HER3, and NRG1.	('carcinomas', 'Phenotype', 'HP:0030731', (42, 52))	('mutated', 'Var', (198, 205))	('amplified', 'Var', (187, 196))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (32, 52))	('tumors', 'Disease', 'MESH:D009369', (169, 175))	('ERBB2', 'Gene', (224, 229))	('HER2', 'Gene', '2064', (230, 234))	('squamous cell carcinomas', 'Disease', (57, 81))	('lung adenocarcinomas', 'Disease', (32, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('overexpressed', 'PosReg', (210, 223))	('carcinomas', 'Phenotype', 'HP:0030731', (71, 81))	('ERBB2', 'Gene', '2064', (224, 229))	('HER3', 'Gene', '2065', (236, 240))	('NRG1', 'Gene', (246, 250))	('NRG1', 'Gene', '3084', (246, 250))	('tumors', 'Phenotype', 'HP:0002664', (169, 175))	('HER2', 'Gene', (230, 234))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (57, 80))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (32, 52))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (57, 81))	('overexpressing', 'PosReg', (82, 96))	('HER3', 'Gene', (236, 240))	('tumors', 'Disease', (169, 175))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (57, 81))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (32, 51))	('carcinoma', 'Phenotype', 'HP:0030731', (42, 51))
440584	25500544	The landscape and therapeutic relevance of cancer-associated transcript fusions Transcript fusions as a result of chromosomal rearrangements have been a focus of attention in cancer as they provide attractive therapeutic targets.	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('cancer', 'Disease', (43, 49))	('cancer', 'Disease', (175, 181))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('chromosomal rearrangements', 'Var', (114, 140))	('focus of attention', 'Phenotype', 'HP:0000736', (153, 171))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
440590	25500544	In-frame fusion transcripts involving histone methyltransferase or histone demethylase genes were detected in 111 samples (2.5%) and may additionally be considered as therapeutic targets.	('histone methyltransferase', 'Gene', (38, 63))	('detected', 'Reg', (98, 106))	('histone methyltransferase', 'Gene', '56979', (38, 63))	('fusion transcripts', 'Var', (9, 27))	('histone demethylase genes', 'Gene', (67, 92))
440593	25500544	Transcript fusions resulting from chromosomal rearrangements are an important class of cancer-contributing somatic alteration.	('chromosomal rearrangements', 'Var', (34, 60))	('cancer', 'Disease', (87, 93))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))
440596	25500544	Recent advances in sequencing technology have enabled the comprehensive detection of rearrangements in the cancer genome and transcriptome.	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('rearrangements', 'Var', (85, 99))	('cancer', 'Disease', (107, 113))	('cancer', 'Disease', 'MESH:D009369', (107, 113))
440597	25500544	For example, transcriptome sequencing has identified FGFR3-TACC3 fusions in glioblastoma, bladder cancer and head and neck, lung squamous cell carcinoma, and cell lines expression FGFR3 chimeras were found to be sensitive to the FGFR inhibitors.	('bladder cancer', 'Disease', (90, 104))	('TACC3', 'Gene', '10460', (59, 64))	('TACC3', 'Gene', (59, 64))	('bladder cancer', 'Phenotype', 'HP:0009725', (90, 104))	('FGFR3', 'Gene', (180, 185))	('FGFR3', 'Gene', (53, 58))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('glioblastoma', 'Disease', 'MESH:D005909', (76, 88))	('FGFR3', 'Gene', '2261', (180, 185))	('FGFR3', 'Gene', '2261', (53, 58))	('glioblastoma', 'Disease', (76, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (143, 152))	('glioblastoma', 'Phenotype', 'HP:0012174', (76, 88))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (124, 152))	('fusions', 'Var', (65, 72))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (129, 152))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (124, 152))	('lung squamous cell carcinoma', 'Disease', (124, 152))	('bladder cancer', 'Disease', 'MESH:D001749', (90, 104))
440601	25500544	We assessed the significance of fusions per cancer type and evaluated their potential as molecular therapeutic targets by integrating mRNA exon/gene expression, somatic mutations, copy number gains and losses, and protein kinase annotation.	('copy number', 'Var', (180, 191))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('losses', 'NegReg', (202, 208))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
440609	25500544	As a result, high or medium confidence structural variants were found to support 78 of 79 fusion transcripts detected in 48 glioma samples within 1Mb from the predicted junction points (Supplementary Table 2).	('glioma', 'Phenotype', 'HP:0009733', (124, 130))	('glioma', 'Disease', 'MESH:D005910', (124, 130))	('glioma', 'Disease', (124, 130))	('variants', 'Var', (50, 58))
440612	25500544	Determining how fusion transcripts promote cancer in various tumor types is an important goal.	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('cancer', 'Disease', (43, 49))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('promote', 'PosReg', (35, 42))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('fusion', 'Var', (16, 22))	('tumor', 'Disease', (61, 66))
440613	25500544	We categorized fusion transcripts into eight categories based on (i) distance between the two fusion gene partners and (ii) the presence of copy number alterations in proximity to the fusion junction, and examined the distribution of each category for each tumor type.	('copy number alterations', 'Var', (140, 163))	('tumor', 'Phenotype', 'HP:0002664', (257, 262))	('tumor', 'Disease', (257, 262))	('tumor', 'Disease', 'MESH:D009369', (257, 262))
440616	25500544	In nine of ten remaining tumor types, the exception being prostate adenocarcinoma, more than 80% of fusion transcripts were associated with DNA amplification or deletion events (Supplementary Figure 3).	('deletion events', 'Var', (161, 176))	('prostate adenocarcinoma', 'Disease', (58, 81))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('prostate adenocarcinoma', 'Disease', 'MESH:D011471', (58, 81))	('tumor', 'Disease', (25, 30))	('associated', 'Reg', (124, 134))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('DNA amplification', 'Var', (140, 157))
440617	25500544	Acute myeloid leukemia and thyroid carcinoma demonstrated a relatively high frequency of copy-neutral interchromosomal fusions (Figure 1C), suggesting the frequent occurrence of balanced genomic rearrangements.	('thyroid carcinoma', 'Disease', (27, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (35, 44))	('Acute myeloid leukemia', 'Disease', 'MESH:D015470', (0, 22))	('leukemia', 'Phenotype', 'HP:0001909', (14, 22))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (6, 22))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (27, 44))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (27, 44))	('Acute myeloid leukemia', 'Disease', (0, 22))	('Acute myeloid leukemia', 'Phenotype', 'HP:0004808', (0, 22))	('copy-neutral interchromosomal fusions', 'Var', (89, 126))
440618	25500544	Fusion transcripts originating from genes within 1 Megabase of each other were dominant in ovarian cancer, which might be related to the high frequency of copy number alteration in ovarian cancer.	('Fusion', 'Var', (0, 6))	('ovarian cancer', 'Disease', 'MESH:D010051', (91, 105))	('ovarian cancer', 'Phenotype', 'HP:0100615', (181, 195))	('ovarian cancer', 'Disease', 'MESH:D010051', (181, 195))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('ovarian cancer', 'Disease', (91, 105))	('dominant', 'Reg', (79, 87))	('ovarian cancer', 'Disease', (181, 195))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('ovarian cancer', 'Phenotype', 'HP:0100615', (91, 105))
440619	25500544	Next, we generated a summary of recurrent fusion transcripts across 13 tumor types (Supplementary Table 3) which included 263 fusions occurring at least twice.	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Disease', (71, 76))	('fusion', 'Var', (42, 48))	('tumor', 'Disease', 'MESH:D009369', (71, 76))
440621	25500544	We identified 16 ESR1 associated fusions in breast cancer, which represents 1.5%) of the entire breast cancer cohort.	('breast cancer', 'Disease', 'MESH:D001943', (44, 57))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('breast cancer', 'Phenotype', 'HP:0003002', (44, 57))	('breast cancer', 'Disease', (44, 57))	('fusions', 'Var', (33, 40))	('breast cancer', 'Disease', 'MESH:D001943', (96, 109))	('ESR1', 'Gene', '2099', (17, 21))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('breast cancer', 'Disease', (96, 109))	('breast cancer', 'Phenotype', 'HP:0003002', (96, 109))	('associated', 'Reg', (22, 32))	('ESR1', 'Gene', (17, 21))
440622	25500544	On the basis of this result, we extracted 221 fusions involving a tumor suppressor gene (TSG) that have a potential to result in loss of function (Supplementary Table 5).	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('loss of function', 'NegReg', (129, 145))	('tumor', 'Disease', (66, 71))	('fusions', 'Var', (46, 53))	('TSG', 'Gene', (89, 92))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('TSG', 'Gene', '57045', (89, 92))
440623	25500544	All samples harboring TSG fusions were called wild type except one low grade glioma sample.	('fusions', 'Var', (26, 33))	('TSG', 'Gene', (22, 25))	('glioma', 'Disease', (77, 83))	('TSG', 'Gene', '57045', (22, 25))	('glioma', 'Disease', 'MESH:D005910', (77, 83))	('glioma', 'Phenotype', 'HP:0009733', (77, 83))
440624	25500544	Approximately 36% of detected fusion transcripts were predicted to be in-frame and thus may result in a functional protein, with acute myeloid leukemia and thyroid carcinoma showing relatively high fractions of in-frame fusions (78.5% and 70.3%) compared to other tumor types (Supplementary Figure 5A).	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (129, 151))	('leukemia', 'Phenotype', 'HP:0001909', (143, 151))	('fusion', 'Var', (30, 36))	('tumor', 'Phenotype', 'HP:0002664', (264, 269))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (156, 173))	('result in', 'Reg', (92, 101))	('tumor', 'Disease', (264, 269))	('thyroid carcinoma', 'Disease', (156, 173))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (129, 151))	('protein', 'Protein', (115, 122))	('acute myeloid leukemia', 'Disease', (129, 151))	('functional', 'MPA', (104, 114))	('carcinoma', 'Phenotype', 'HP:0030731', (164, 173))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (156, 173))	('tumor', 'Disease', 'MESH:D009369', (264, 269))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (135, 151))
440627	25500544	The difference was statistically significant in bladder carcinoma, breast cancer, head and neck squamous cell carcinoma, clear cell renal cell carcinoma, acute myeloid leukemia, and thyroid cancer (Welch's t-test, P = 0.0067, 0.022, 0.030, 0.063, 4.8-e15, and 8.3e-88, respectively), suggesting that fusions in these cancer types could be functioning as incidental cancer driving events (Supplementary Figure 6).	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (154, 176))	('thyroid cancer', 'Disease', 'MESH:D013964', (182, 196))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (132, 152))	('leukemia', 'Phenotype', 'HP:0001909', (168, 176))	('cancer', 'Disease', (74, 80))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (48, 65))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (56, 65))	('thyroid cancer', 'Phenotype', 'HP:0002890', (182, 196))	('cancer', 'Disease', (365, 371))	('cancer', 'Disease', (190, 196))	('cancer', 'Phenotype', 'HP:0002664', (365, 371))	('bladder carcinoma', 'Disease', 'MESH:D001749', (48, 65))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (121, 152))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (82, 119))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('carcinoma', 'Phenotype', 'HP:0030731', (143, 152))	('cancer', 'Disease', (317, 323))	('breast cancer', 'Phenotype', 'HP:0003002', (67, 80))	('head and neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (82, 119))	('fusions', 'Var', (300, 307))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('bladder carcinoma', 'Disease', (48, 65))	('acute myeloid leukemia', 'Disease', (154, 176))	('cancer', 'Phenotype', 'HP:0002664', (317, 323))	('breast cancer', 'Disease', 'MESH:D001943', (67, 80))	('thyroid cancer', 'Disease', (182, 196))	('cancer', 'Disease', 'MESH:D009369', (365, 371))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (121, 152))	('breast cancer', 'Disease', (67, 80))	('cancer', 'Disease', 'MESH:D009369', (190, 196))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (160, 176))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (154, 176))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (96, 119))	('clear cell renal cell carcinoma', 'Disease', (121, 152))	('cancer', 'Disease', 'MESH:D009369', (317, 323))
440630	25500544	The majority of in frame kinase fusions belonged to the tyrosine kinase family (36.1%), the AGC serine/threonine protein kinases (14.8%) and the tyrosine kinase-like serine/threonine protein kinase group (10.1%) (Supplementary Table 9).	('tyrosine kinase', 'Gene', (56, 71))	('fusions', 'Var', (32, 39))	('tyrosine kinase', 'Gene', '7294', (145, 160))	('tyrosine kinase', 'Gene', '7294', (56, 71))	('kinase fusions', 'Var', (25, 39))	('tyrosine kinase', 'Gene', (145, 160))
440632	25500544	BRAF fusions were also detected in two prostate adenocarcinoma, two melanoma and one low grade glioma samples (Supplementary Table 10).	('glioma', 'Phenotype', 'HP:0009733', (95, 101))	('fusions', 'Var', (5, 12))	('melanoma', 'Phenotype', 'HP:0002861', (68, 76))	('glioma', 'Disease', (95, 101))	('melanoma', 'Disease', (68, 76))	('prostate adenocarcinoma', 'Disease', (39, 62))	('BRAF', 'Gene', '673', (0, 4))	('melanoma', 'Disease', 'MESH:D008545', (68, 76))	('detected', 'Reg', (23, 31))	('prostate adenocarcinoma', 'Disease', 'MESH:D011471', (39, 62))	('carcinoma', 'Phenotype', 'HP:0030731', (53, 62))	('BRAF', 'Gene', (0, 4))	('glioma', 'Disease', 'MESH:D005910', (95, 101))
440633	25500544	BRAF fusions are notable because of mutually exclusivity with BRAF mutation (Figure 4) as well as the life-prolonging effects of RAF and MEK inhibitors for patients with melanoma harboring BRAF V600E mutations.	('RAF', 'Gene', '22882', (1, 4))	('BRAF', 'Gene', '673', (0, 4))	('BRAF', 'Gene', (0, 4))	('RAF', 'Gene', (129, 132))	('patients', 'Species', '9606', (156, 164))	('V600E mutations', 'Var', (194, 209))	('mutation', 'Var', (67, 75))	('V600E', 'Mutation', 'rs113488022', (194, 199))	('RAF', 'Gene', '22882', (63, 66))	('melanoma', 'Disease', 'MESH:D008545', (170, 178))	('RAF', 'Gene', '22882', (190, 193))	('RAF', 'Gene', (1, 4))	('BRAF', 'Gene', (189, 193))	('BRAF', 'Gene', '673', (189, 193))	('BRAF', 'Gene', '673', (62, 66))	('BRAF', 'Gene', (62, 66))	('MEK', 'Gene', '5609', (137, 140))	('RAF', 'Gene', (63, 66))	('RAF', 'Gene', (190, 193))	('MEK', 'Gene', (137, 140))	('melanoma', 'Phenotype', 'HP:0002861', (170, 178))	('melanoma', 'Disease', (170, 178))	('RAF', 'Gene', '22882', (129, 132))
440634	25500544	RET is frequently activated by mutations in medullary thyroid cancer and inhibitors of multiple tyrosine kinases including RET has been approved for medullary thyroid cancer by the Food and Drug Administration (FDA), while treatment of NTRK1 fusion positive lung cancer cells with a kinase inhibitor led to suppression of cell growth.	('lung cancer', 'Disease', 'MESH:D008175', (258, 269))	('RET', 'Gene', (123, 126))	('thyroid cancer', 'Phenotype', 'HP:0002890', (159, 173))	('lung cancer', 'Phenotype', 'HP:0100526', (258, 269))	('cancer', 'Phenotype', 'HP:0002664', (263, 269))	('medullary thyroid cancer', 'Phenotype', 'HP:0002865', (149, 173))	('medullary thyroid cancer', 'Phenotype', 'HP:0002865', (44, 68))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('thyroid cancer', 'Disease', 'MESH:D013964', (54, 68))	('RET', 'Gene', '5979', (0, 3))	('thyroid cancer', 'Phenotype', 'HP:0002890', (54, 68))	('activated', 'PosReg', (18, 27))	('mutations', 'Var', (31, 40))	('thyroid cancer', 'Disease', (159, 173))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('suppression', 'NegReg', (307, 318))	('RET', 'Gene', (0, 3))	('lung cancer', 'Disease', (258, 269))	('RET', 'Gene', '5979', (123, 126))	('tyrosine kinase', 'Gene', (96, 111))	('tyrosine kinase', 'Gene', '7294', (96, 111))	('thyroid cancer', 'Disease', (54, 68))	('NTRK1', 'Gene', '4914', (236, 241))	('thyroid cancer', 'Disease', 'MESH:D013964', (159, 173))	('cell growth', 'CPA', (322, 333))	('NTRK1', 'Gene', (236, 241))
440638	25500544	We detected ALK fusions in lung adenocarcinoma (0.8%), bladder (0.8%), melanoma (1,3%), and thyroid cancer (0.6%), suggesting that ALK fusions are rare but occur across different tumor lineages.	('bladder', 'Disease', (55, 62))	('ALK', 'Gene', '238', (12, 15))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('thyroid cancer', 'Disease', 'MESH:D013964', (92, 106))	('lung adenocarcinoma', 'Disease', (27, 46))	('ALK', 'Gene', (12, 15))	('ALK', 'Gene', '238', (131, 134))	('melanoma', 'Phenotype', 'HP:0002861', (71, 79))	('melanoma', 'Disease', (71, 79))	('thyroid cancer', 'Phenotype', 'HP:0002890', (92, 106))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('ALK', 'Gene', (131, 134))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (27, 46))	('carcinoma', 'Phenotype', 'HP:0030731', (37, 46))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (27, 46))	('fusions', 'Var', (16, 23))	('thyroid cancer', 'Disease', (92, 106))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('melanoma', 'Disease', 'MESH:D008545', (71, 79))	('tumor', 'Disease', (179, 184))
440640	25500544	Inhibitors of DNA methylation and histone deacetylates (HDAC) show antitumor activity, and have been approved for the treatment of myelodysplastic syndrome and cutaneous T cell lymphoma by the FDA.	('cutaneous T cell lymphoma', 'Disease', (160, 185))	('cell lymphoma', 'Phenotype', 'HP:0012191', (172, 185))	('cutaneous T cell lymphoma', 'Disease', 'MESH:D016410', (160, 185))	('myelodysplastic syndrome', 'Phenotype', 'HP:0002863', (131, 155))	('lymphoma', 'Phenotype', 'HP:0002665', (177, 185))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('Inhibitors', 'Var', (0, 10))	('cutaneous T cell lymphoma', 'Phenotype', 'HP:0012192', (160, 185))	('myelodysplastic syndrome', 'Disease', (131, 155))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('T cell lymphoma', 'Phenotype', 'HP:0012190', (170, 185))	('myelodysplastic syndrome', 'Disease', 'MESH:D009190', (131, 155))	('tumor', 'Disease', (71, 76))
440642	25500544	Although there were only seven recurrent chromatin modifier fusions across 13 tumor types (Figure 5B), fusions related to histone methyltransferases and demethylase families with potential as a target for anticancer therapy were detected in 48 (1.1%) of 4,366 samples (Figure 5C).	('fusions', 'Var', (103, 110))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('cancer', 'Disease', 'MESH:D009369', (209, 215))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('cancer', 'Disease', (209, 215))	('histone methyltransferase', 'Gene', '56979', (122, 147))	('tumor', 'Disease', (78, 83))	('histone methyltransferase', 'Gene', (122, 147))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
440649	25500544	Importantly, we showed that in-frame and potentially activating NTRK1, and ALK rearrangements are not limited to breast, thyroid, and lung cancer respectively, but can be detected across cancer at low frequency.	('NTRK1', 'Gene', (64, 69))	('breast', 'Disease', (113, 119))	('lung cancer', 'Disease', (134, 145))	('cancer', 'Disease', 'MESH:D009369', (187, 193))	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('ALK', 'Gene', (75, 78))	('lung cancer', 'Phenotype', 'HP:0100526', (134, 145))	('cancer', 'Disease', (187, 193))	('rearrangements', 'Var', (79, 93))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('thyroid', 'Disease', (121, 128))	('in-frame', 'Var', (28, 36))	('ALK', 'Gene', '238', (75, 78))	('lung cancer', 'Disease', 'MESH:D008175', (134, 145))	('NTRK1', 'Gene', '4914', (64, 69))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('activating', 'PosReg', (53, 63))	('cancer', 'Disease', (139, 145))
440650	25500544	Similarly, FGFR related fusions with therapeutic potential have been reported across tumor types, which was confirmed by our study.	('tumor', 'Disease', (85, 90))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('FGFR', 'Gene', (11, 15))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('fusions', 'Var', (24, 31))
440652	25500544	have reported that suppressing HDAC4 causes chromosome segregation defects in p53-deficient tumor cells and one lung adenocarcinoma sample harboring HDAC4-SNX18 fusion showed HDAC4 mRNA overexpression and TP53 somatic mutation, suggesting a possible beneficial effect of HDAC inhibitors.	('HDAC4', 'Gene', (175, 180))	('chromosome segregation defects', 'CPA', (44, 74))	('SNX18', 'Gene', '112574', (155, 160))	('HDAC4', 'Gene', '9759', (31, 36))	('overexpression', 'PosReg', (186, 200))	('HDAC4', 'Gene', '9759', (149, 154))	('TP53', 'Gene', '7157', (205, 209))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('lung adenocarcinoma', 'Disease', (112, 131))	('HDAC4', 'Gene', (31, 36))	('HDAC4', 'Gene', (149, 154))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (112, 131))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (112, 131))	('SNX18', 'Gene', (155, 160))	('TP53', 'Gene', (205, 209))	('p53-deficient tumor', 'Disease', 'MESH:D009369', (78, 97))	('p53-deficient tumor', 'Disease', (78, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('HDAC4', 'Gene', '9759', (175, 180))	('suppressing', 'Var', (19, 30))
440653	25500544	We observed a significant anti-correlation between the presence of a transcript fusion and significant gene mutations in most tumor types, which suggested that driver genome and transcriptome rearrangements may occur infrequently but with high relevance to the tumor in which they are detected.	('mutations', 'Var', (108, 117))	('tumor', 'Disease', (261, 266))	('tumor', 'Phenotype', 'HP:0002664', (261, 266))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumor', 'Disease', 'MESH:D009369', (261, 266))	('tumor', 'Disease', (126, 131))
440703	24598405	The overexpression of certain CD44 splice variants has been found to be involved in cancer progression, and CD44v6 in particular has been suggested to play a role in tumour formation, invasion, and metastasis formation.	('tumour', 'Disease', 'MESH:D009369', (166, 172))	('CD44v6', 'Var', (108, 114))	('metastasis formation', 'CPA', (198, 218))	('invasion', 'CPA', (184, 192))	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('tumour', 'Disease', (166, 172))	('cancer', 'Disease', (84, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('involved', 'Reg', (72, 80))	('CD44', 'Gene', (30, 34))	('play', 'Reg', (151, 155))	('overexpression', 'PosReg', (4, 18))	('tumour', 'Phenotype', 'HP:0002664', (166, 172))	('role', 'Reg', (158, 162))
440713	24598405	To our knowledge, this study generated the first and most thoroughly characterized fully human Fab fragment specific for CD44v6.	('CD44v6', 'Var', (121, 127))	('human', 'Species', '9606', (89, 94))	('Fab', 'Gene', '2187', (95, 98))	('Fab', 'Gene', (95, 98))
440741	24598405	The chelator CHX-A''-DTPA used for 111In labelling exhibits high affinity for several isotopes that are suitable for either diagnostic or therapeutic purposes, including 111In, 86Y, 90Y and 177Lu.	('111In', 'Var', (170, 175))	('177Lu', 'MPA', (190, 195))	('90Y', 'Var', (182, 185))	('111In', 'Chemical', 'MESH:C000615551', (35, 40))	('111In', 'Chemical', 'MESH:C000615551', (170, 175))	('86Y', 'Var', (177, 180))
440745	24598405	111In-labelled AbD15179 is referred to as 111In-Fab in this paper.	('111In', 'Chemical', 'MESH:C000615551', (42, 47))	('Fab', 'Gene', '2187', (48, 51))	('AbD15179', 'Var', (15, 23))	('Fab', 'Gene', (48, 51))	('111In', 'Chemical', 'MESH:C000615551', (0, 5))
440770	24598405	The Fab fragment AbD15179 bound strongly to the human v6 peptide, whereas no binding was detected for the murine form of the target (Figure 1).	('human v6', 'Protein', (48, 56))	('AbD15179', 'Var', (17, 25))	('human', 'Species', '9606', (48, 53))	('Fab', 'Gene', '2187', (4, 7))	('murine', 'Species', '10090', (106, 112))	('Fab', 'Gene', (4, 7))	('bound', 'Interaction', (26, 31))
440784	24598405	The specificity of AbD15179 was assessed in vivo by comparing the uptake of 125I-Fab in CD44v6-negative (MDA-MB-231) and CD44v6-positive (A431) tumours 24 h p.i.	('tumour', 'Phenotype', 'HP:0002664', (144, 150))	('125I', 'Chemical', 'MESH:C000614960', (76, 80))	('CD44v6-positive', 'Var', (121, 136))	('tumours', 'Phenotype', 'HP:0002664', (144, 151))	('Fab', 'Gene', (81, 84))	('A431', 'CellLine', 'CVCL:0037', (138, 142))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (105, 115))	('tumours', 'Disease', 'MESH:D009369', (144, 151))	('tumours', 'Disease', (144, 151))	('uptake', 'MPA', (66, 72))	('Fab', 'Gene', '2187', (81, 84))
440789	24598405	Tumour uptake differed significantly between the CD44v6-negative and CD44v6-positive tumours, with the CD44v6-positive A431 tumours displaying more than two times higher uptake than the CD44v6-negative MDA-MB-231 tumours (0.66 +- 0.13 (%ID/g +- SD) and 1.34 +- 0.26 %ID/g for MDA-MB-231 and A431 tumours, respectively).	('A431', 'CellLine', 'CVCL:0037', (291, 295))	('tumour', 'Phenotype', 'HP:0002664', (124, 130))	('tumours', 'Phenotype', 'HP:0002664', (296, 303))	('tumours', 'Disease', 'MESH:D009369', (296, 303))	('Tumour', 'Phenotype', 'HP:0002664', (0, 6))	('uptake', 'MPA', (170, 176))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (202, 212))	('Tumour uptake', 'MPA', (0, 13))	('tumour', 'Phenotype', 'HP:0002664', (296, 302))	('CD44v6-positive', 'Var', (103, 118))	('tumours', 'Disease', (213, 220))	('higher', 'PosReg', (163, 169))	('A431', 'CellLine', 'CVCL:0037', (119, 123))	('tumours', 'Phenotype', 'HP:0002664', (213, 220))	('tumours', 'Disease', 'MESH:D009369', (213, 220))	('tumours', 'Disease', (85, 92))	('tumours', 'Disease', (124, 131))	('tumour', 'Phenotype', 'HP:0002664', (213, 219))	('tumours', 'Phenotype', 'HP:0002664', (85, 92))	('tumours', 'Disease', 'MESH:D009369', (85, 92))	('tumours', 'Phenotype', 'HP:0002664', (124, 131))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (276, 286))	('tumour', 'Phenotype', 'HP:0002664', (85, 91))	('tumours', 'Disease', 'MESH:D009369', (124, 131))	('tumours', 'Disease', (296, 303))
440790	24598405	The biodistribution of AbD15179 was assessed in vivo by comparing the uptake of 125I-Fab and 111In-Fab in mice bearing both CD44v6-moderate (H314) and CD44v6-positive (A431) tumours.	('CD44v6-moderate', 'Var', (124, 139))	('125I', 'Chemical', 'MESH:C000614960', (80, 84))	('tumour', 'Phenotype', 'HP:0002664', (174, 180))	('mice', 'Species', '10090', (106, 110))	('111In', 'Chemical', 'MESH:C000615551', (93, 98))	('tumours', 'Phenotype', 'HP:0002664', (174, 181))	('Fab', 'Gene', '2187', (99, 102))	('CD44v6-positive', 'Var', (151, 166))	('Fab', 'Gene', '2187', (85, 88))	('A431', 'CellLine', 'CVCL:0037', (168, 172))	('H314', 'Chemical', '-', (141, 145))	('tumours', 'Disease', 'MESH:D009369', (174, 181))	('Fab', 'Gene', (99, 102))	('tumours', 'Disease', (174, 181))	('Fab', 'Gene', (85, 88))
440797	24598405	At 6 h p.i., the percentage of the injected dose per gram of 111In-Fab in the moderate-CD44v6-expressing H314 tumours was 2.4 +- 1.1 (SD) and remained at this level.	('Fab', 'Gene', (67, 70))	('moderate-CD44v6-expressing', 'Var', (78, 104))	('tumour', 'Phenotype', 'HP:0002664', (110, 116))	('H314 tumours', 'Disease', 'MESH:D009369', (105, 117))	('H314 tumours', 'Disease', (105, 117))	('tumours', 'Phenotype', 'HP:0002664', (110, 117))	('111In', 'Chemical', 'MESH:C000615551', (61, 66))	('Fab', 'Gene', '2187', (67, 70))
440798	24598405	The uptake in the high-CD44v6-expressing A431 tumours was significantly higher, being 4.6 +- 1.9 %ID/g at 6 h p.i., with a slight, although not significant, decrease over time to 3.2 +- 0.2 %ID/g at 72 h p.i.	('high-CD44v6-expressing', 'Var', (18, 40))	('tumours', 'Disease', 'MESH:D009369', (46, 53))	('A431', 'CellLine', 'CVCL:0037', (41, 45))	('tumours', 'Disease', (46, 53))	('higher', 'PosReg', (72, 78))	('uptake', 'MPA', (4, 10))	('tumour', 'Phenotype', 'HP:0002664', (46, 52))	('tumours', 'Phenotype', 'HP:0002664', (46, 53))
440801	24598405	At 6, 24, and 48 h p.i., 125I-Fab displayed a difference in tumour uptake between the high- and moderate-CD44v6-expressing tumours, although not as pronounced as for 111In-Fab, ranging between 1.3 and 1.4 times higher for the high-CD44v6-expressing A431 tumours compared to the medium-CD44v6-expressing H314 tumours.	('tumour', 'Disease', 'MESH:D009369', (308, 314))	('tumours', 'Phenotype', 'HP:0002664', (123, 130))	('tumour', 'Disease', (308, 314))	('Fab', 'Gene', (30, 33))	('tumours', 'Disease', 'MESH:D009369', (123, 130))	('A431', 'CellLine', 'CVCL:0037', (249, 253))	('125I', 'Chemical', 'MESH:C000614960', (25, 29))	('Fab', 'Gene', (172, 175))	('high-CD44v6-expressing', 'Var', (226, 248))	('tumour', 'Phenotype', 'HP:0002664', (60, 66))	('tumour', 'Phenotype', 'HP:0002664', (123, 129))	('tumour', 'Disease', 'MESH:D009369', (60, 66))	('tumour', 'Disease', 'MESH:D009369', (123, 129))	('tumour', 'Disease', (60, 66))	('H314 tumours', 'Disease', (303, 315))	('111In', 'Chemical', 'MESH:C000615551', (166, 171))	('tumour', 'Disease', (123, 129))	('tumours', 'Disease', (254, 261))	('tumour', 'Phenotype', 'HP:0002664', (254, 260))	('higher', 'PosReg', (211, 217))	('H314 tumours', 'Disease', 'MESH:D009369', (303, 315))	('tumour', 'Disease', 'MESH:D009369', (254, 260))	('tumour', 'Disease', (254, 260))	('tumours', 'Phenotype', 'HP:0002664', (254, 261))	('tumours', 'Disease', (308, 315))	('tumours', 'Disease', 'MESH:D009369', (254, 261))	('Fab', 'Gene', '2187', (30, 33))	('tumours', 'Phenotype', 'HP:0002664', (308, 315))	('tumours', 'Disease', 'MESH:D009369', (308, 315))	('Fab', 'Gene', '2187', (172, 175))	('tumours', 'Disease', (123, 130))	('tumour', 'Phenotype', 'HP:0002664', (308, 314))
440805	24598405	In high-CD44v6-expressing A431 tumours, this decrease was also significant between 48 and 72 h p.i.	('A431', 'CellLine', 'CVCL:0037', (26, 30))	('tumour', 'Phenotype', 'HP:0002664', (31, 37))	('tumours', 'Phenotype', 'HP:0002664', (31, 38))	('tumours', 'Disease', 'MESH:D009369', (31, 38))	('tumours', 'Disease', (31, 38))	('high-CD44v6-expressing', 'Var', (3, 25))
440807	24598405	In the high-CD44v6-expressing A431 tumours, the activity of 125I-Fab was 1.6 +- 0.1 %ID/g at 6 h, decreasing to 0.22 +- 0.03 %ID/g at 72 h p.i.	('tumours', 'Disease', (35, 42))	('high-CD44v6-expressing', 'Var', (7, 29))	('A431', 'CellLine', 'CVCL:0037', (30, 34))	('125I', 'Chemical', 'MESH:C000614960', (60, 64))	('activity', 'MPA', (48, 56))	('tumour', 'Phenotype', 'HP:0002664', (35, 41))	('Fab', 'Gene', '2187', (65, 68))	('tumours', 'Phenotype', 'HP:0002664', (35, 42))	('tumours', 'Disease', 'MESH:D009369', (35, 42))	('Fab', 'Gene', (65, 68))
440809	24598405	In order to assess the selectivity of tumour targeting for the 111In-Fab and 125I-Fab conjugates, tumour-to-normal tissue ratios were calculated based on the high-CD44v6-expressing A431 tumours (Figure 4), and tumour-to-blood ratios were calculated for both tumour types (Figure 4, insets).	('tumours', 'Disease', (186, 193))	('tumour', 'Phenotype', 'HP:0002664', (258, 264))	('tumour', 'Disease', 'MESH:D009369', (258, 264))	('tumour', 'Phenotype', 'HP:0002664', (186, 192))	('tumour', 'Disease', 'MESH:D009369', (186, 192))	('tumour', 'Disease', (258, 264))	('tumours', 'Phenotype', 'HP:0002664', (186, 193))	('Fab', 'Gene', (69, 72))	('tumour', 'Disease', (186, 192))	('111In', 'Chemical', 'MESH:C000615551', (63, 68))	('tumours', 'Disease', 'MESH:D009369', (186, 193))	('Fab', 'Gene', '2187', (82, 85))	('tumour', 'Phenotype', 'HP:0002664', (210, 216))	('tumour', 'Disease', 'MESH:D009369', (210, 216))	('tumour', 'Disease', (210, 216))	('tumour-to-blood', 'Disease', (210, 225))	('tumour', 'Phenotype', 'HP:0002664', (98, 104))	('tumour', 'Disease', 'MESH:D009369', (98, 104))	('tumour', 'Disease', (98, 104))	('Fab', 'Gene', (82, 85))	('A431', 'CellLine', 'CVCL:0037', (181, 185))	('tumour', 'Phenotype', 'HP:0002664', (38, 44))	('tumour', 'Disease', 'MESH:D009369', (38, 44))	('125I', 'Chemical', 'MESH:C000614960', (77, 81))	('Fab', 'Gene', '2187', (69, 72))	('tumour', 'Disease', (38, 44))	('tumour-to-blood', 'Disease', 'MESH:D009369', (210, 225))	('high-CD44v6-expressing', 'Var', (158, 180))
440811	24598405	The tumour-to-blood ratios for both A431 and H314 tumours increased over time with a ratio of over 10 for A431 tumours at 72 h p.i.	('A431', 'CellLine', 'CVCL:0037', (106, 110))	('H314 tumours', 'Disease', (45, 57))	('tumours', 'Disease', 'MESH:D009369', (111, 118))	('tumours', 'Phenotype', 'HP:0002664', (50, 57))	('increased', 'PosReg', (58, 67))	('tumour-to-blood', 'Disease', (4, 19))	('tumours', 'Disease', 'MESH:D009369', (50, 57))	('tumours', 'Disease', (111, 118))	('tumour', 'Phenotype', 'HP:0002664', (4, 10))	('tumour', 'Phenotype', 'HP:0002664', (111, 117))	('A431', 'Var', (106, 110))	('tumours', 'Disease', (50, 57))	('tumour-to-blood', 'Disease', 'MESH:D009369', (4, 19))	('tumour', 'Phenotype', 'HP:0002664', (50, 56))	('A431', 'CellLine', 'CVCL:0037', (36, 40))	('tumours', 'Phenotype', 'HP:0002664', (111, 118))	('H314 tumours', 'Disease', 'MESH:D009369', (45, 57))
440826	24598405	The lack of binding of AbD15179 to the murine v6 peptide was expected, since 9 of the 16 residues in the peptides differ between the murine and human variants.	('variants', 'Var', (150, 158))	('human', 'Species', '9606', (144, 149))	('murine', 'Species', '10090', (39, 45))	('differ', 'Reg', (114, 120))	('murine', 'Species', '10090', (133, 139))
440831	24598405	In vivo, we first demonstrated a CD44v6-dependent tumour uptake for AbD15179, with a markedly higher tumour uptake of 125I-Fab in high-CD44v6-expressing tumours compared to the CD44v6-negative tumours, establishing the specificity of the conjugate also in vivo.	('tumours', 'Disease', (153, 160))	('Fab', 'Gene', '2187', (123, 126))	('tumours', 'Disease', (193, 200))	('AbD15179', 'Gene', (68, 76))	('tumours', 'Phenotype', 'HP:0002664', (153, 160))	('tumour', 'Phenotype', 'HP:0002664', (101, 107))	('higher', 'PosReg', (94, 100))	('tumour', 'Disease', 'MESH:D009369', (101, 107))	('tumours', 'Phenotype', 'HP:0002664', (193, 200))	('tumours', 'Disease', 'MESH:D009369', (153, 160))	('tumours', 'Disease', 'MESH:D009369', (193, 200))	('tumour', 'Disease', (101, 107))	('Fab', 'Gene', (123, 126))	('tumour', 'Phenotype', 'HP:0002664', (153, 159))	('tumour', 'Phenotype', 'HP:0002664', (193, 199))	('high-CD44v6-expressing', 'Var', (130, 152))	('tumour', 'Phenotype', 'HP:0002664', (50, 56))	('tumour', 'Disease', 'MESH:D009369', (153, 159))	('tumour', 'Disease', 'MESH:D009369', (193, 199))	('tumour', 'Disease', (153, 159))	('tumour', 'Disease', 'MESH:D009369', (50, 56))	('tumour', 'Disease', (193, 199))	('tumour', 'Disease', (50, 56))	('125I', 'Chemical', 'MESH:C000614960', (118, 122))	('CD44v6-dependent', 'MPA', (33, 49))
440832	24598405	Tumour uptake (%ID/g) differed significantly between the CD44v6-negative and CD44v6-positive tumours, with the CD44v6-positive A431 tumours displaying more than two times higher uptake than the CD44v6-negative MDA-MB-231 tumours.	('tumours', 'Disease', 'MESH:D009369', (132, 139))	('tumour', 'Phenotype', 'HP:0002664', (132, 138))	('tumour', 'Phenotype', 'HP:0002664', (93, 99))	('Tumour', 'Phenotype', 'HP:0002664', (0, 6))	('uptake', 'MPA', (178, 184))	('tumours', 'Phenotype', 'HP:0002664', (132, 139))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (210, 220))	('Tumour uptake', 'MPA', (0, 13))	('higher', 'PosReg', (171, 177))	('CD44v6-positive', 'Var', (111, 126))	('A431', 'CellLine', 'CVCL:0037', (127, 131))	('tumours', 'Disease', (221, 228))	('tumours', 'Phenotype', 'HP:0002664', (221, 228))	('tumours', 'Disease', 'MESH:D009369', (221, 228))	('tumours', 'Disease', (93, 100))	('tumours', 'Disease', (132, 139))	('tumour', 'Phenotype', 'HP:0002664', (221, 227))	('tumours', 'Phenotype', 'HP:0002664', (93, 100))	('tumours', 'Disease', 'MESH:D009369', (93, 100))
440833	24598405	in the subsequent biodistribution study in this paper, in which high-CD44v6-expressing A431 tumour uptake of 125I-Fab was approximately 1.3 times higher than the uptake in the moderate-CD44v6-expressing H314 tumours.	('higher', 'PosReg', (146, 152))	('Fab', 'Gene', (114, 117))	('tumours', 'Phenotype', 'HP:0002664', (208, 215))	('tumour', 'Disease', 'MESH:D009369', (92, 98))	('H314 tumours', 'Disease', 'MESH:D009369', (203, 215))	('tumour', 'Disease', (208, 214))	('H314 tumours', 'Disease', (203, 215))	('tumour', 'Disease', (92, 98))	('125I', 'Chemical', 'MESH:C000614960', (109, 113))	('A431', 'CellLine', 'CVCL:0037', (87, 91))	('tumour', 'Phenotype', 'HP:0002664', (208, 214))	('Fab', 'Gene', '2187', (114, 117))	('high-CD44v6-expressing', 'Var', (64, 86))	('tumour', 'Disease', 'MESH:D009369', (208, 214))	('tumour', 'Phenotype', 'HP:0002664', (92, 98))
440834	24598405	However, at later time points, the difference in tumour uptake between moderate- and high-CD44v6-expressing tumours was diminished for 125I-Fab, whereas 111In-Fab displayed a clear difference in tumour uptake between the moderate- and high-CD44v6-expressing tumours, ranging between 1.5 to 2 times higher for the high-CD44v6-expressing tumours throughout the study.	('tumours', 'Disease', (258, 265))	('tumour', 'Disease', 'MESH:D009369', (195, 201))	('tumour', 'Phenotype', 'HP:0002664', (258, 264))	('Fab', 'Gene', '2187', (140, 143))	('tumour', 'Disease', 'MESH:D009369', (258, 264))	('tumour', 'Disease', (195, 201))	('111In', 'Chemical', 'MESH:C000615551', (153, 158))	('tumour', 'Phenotype', 'HP:0002664', (108, 114))	('tumours', 'Phenotype', 'HP:0002664', (258, 265))	('tumours', 'Disease', 'MESH:D009369', (258, 265))	('tumour', 'Disease', (258, 264))	('tumours', 'Disease', (336, 343))	('tumour', 'Disease', 'MESH:D009369', (108, 114))	('high-CD44v6-expressing', 'Var', (85, 107))	('tumour', 'Disease', (108, 114))	('diminished', 'NegReg', (120, 130))	('tumours', 'Phenotype', 'HP:0002664', (336, 343))	('Fab', 'Gene', '2187', (159, 162))	('tumours', 'Disease', 'MESH:D009369', (336, 343))	('Fab', 'Gene', (140, 143))	('125I', 'Chemical', 'MESH:C000614960', (135, 139))	('tumour', 'Phenotype', 'HP:0002664', (336, 342))	('tumour', 'Disease', 'MESH:D009369', (336, 342))	('tumour', 'Phenotype', 'HP:0002664', (49, 55))	('higher', 'PosReg', (298, 304))	('tumour', 'Disease', 'MESH:D009369', (49, 55))	('tumour', 'Disease', (336, 342))	('Fab', 'Gene', (159, 162))	('tumour', 'Disease', (49, 55))	('tumours', 'Disease', (108, 115))	('tumours', 'Phenotype', 'HP:0002664', (108, 115))	('tumours', 'Disease', 'MESH:D009369', (108, 115))	('tumour', 'Phenotype', 'HP:0002664', (195, 201))
440865	24598405	125I was used as a surrogate for radionuclides more suitable for imaging such as 124I, or 131I for therapy.	('124I', 'Var', (81, 85))	('radionuclide', 'Chemical', 'MESH:D011868', (33, 45))	('131I', 'Chemical', 'MESH:C000614965', (90, 94))	('125I', 'Chemical', 'MESH:C000614960', (0, 4))	('131I', 'Var', (90, 94))	('124I', 'Chemical', 'MESH:C000614959', (81, 85))
440880	24598405	However, since AbD15179 was selected from a large number of fragments due to its high affinity and very slow dissociation from tumour cells, one hypothesis for the superior targeting qualities of 125I-Fab compared to those of 125I-U36-Fab may be the desirable kinetic properties of 125I-Fab.	('Fab', 'Gene', '2187', (235, 238))	('Fab', 'Gene', (201, 204))	('Fab', 'Gene', '2187', (287, 290))	('Fab', 'Gene', '2187', (201, 204))	('U36', 'Gene', '26842', (231, 234))	('tumour', 'Phenotype', 'HP:0002664', (127, 133))	('tumour', 'Disease', 'MESH:D009369', (127, 133))	('Fab', 'Gene', (235, 238))	('125I', 'Chemical', 'MESH:C000614960', (226, 230))	('125I', 'Chemical', 'MESH:C000614960', (196, 200))	('Fab', 'Gene', (287, 290))	('targeting', 'MPA', (173, 182))	('125I', 'Chemical', 'MESH:C000614960', (282, 286))	('AbD15179', 'Var', (15, 23))	('tumour', 'Disease', (127, 133))	('superior', 'PosReg', (164, 172))	('U36', 'Gene', (231, 234))
440882	24598405	We have, for the first time, evaluated the in vivo properties of the AbD15179 Fab fragment targeted against CD44v6 labelled with 111In or 125I and assessed its utility as a targeting agent for radio-immunotargeting of HNSCC.	('CD44v6', 'Var', (108, 114))	('SCC', 'Gene', (220, 223))	('Fab', 'Gene', '2187', (78, 81))	('SCC', 'Phenotype', 'HP:0002860', (220, 223))	('Fab', 'Gene', (78, 81))	('SCC', 'Gene', '6317', (220, 223))	('111In', 'Chemical', 'MESH:C000615551', (129, 134))	('AbD15179', 'Gene', (69, 77))	('125I', 'Chemical', 'MESH:C000614960', (138, 142))
440900	33632211	A lung cancer cohort study (GSE31210) showed that high SLC7A7 expression was associated with poor overall survival (OS) and relapse-free survival (RFS).	('lung cancer', 'Phenotype', 'HP:0100526', (2, 13))	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('SLC7A7', 'Gene', '9056', (55, 61))	('SLC7A7', 'Gene', (55, 61))	('lung cancer', 'Disease', 'MESH:D008175', (2, 13))	('expression', 'MPA', (62, 72))	('overall survival', 'CPA', (98, 114))	('relapse-free survival', 'CPA', (124, 145))	('poor', 'NegReg', (93, 97))	('high', 'Var', (50, 54))	('lung cancer', 'Disease', (2, 13))
440915	33632211	In addition, mutations in SLC7A7 causing cation transporter dysfunction are associated with a variety of clinical symptoms.	('associated', 'Reg', (76, 86))	('SLC7A7', 'Gene', '9056', (26, 32))	('SLC7A7', 'Gene', (26, 32))	('causing', 'Reg', (33, 40))	('mutations', 'Var', (13, 22))	('cation transporter dysfunction', 'MPA', (41, 71))
440916	33632211	Overexpression of SLC7A7 is correlated with poor RFS and OS in patients with glioblastoma.	('SLC7A7', 'Gene', '9056', (18, 24))	('RFS', 'MPA', (49, 52))	('SLC7A7', 'Gene', (18, 24))	('glioblastoma', 'Disease', (77, 89))	('glioblastoma', 'Disease', 'MESH:D005909', (77, 89))	('poor', 'NegReg', (44, 48))	('glioblastoma', 'Phenotype', 'HP:0012174', (77, 89))	('Overexpression', 'Var', (0, 14))	('patients', 'Species', '9606', (63, 71))
440974	33632211	Interestingly, one cohort (GSE19615) including 115 samples showed that high SLC7A7 expression was associated with a better prognosis in breast cancer (distant metastasis-free survival [DMFS]; HR = 0.19, 95% CI 0.06-0.68, P = 0.0103).	('better', 'PosReg', (116, 122))	('distant metastasis-free', 'CPA', (151, 174))	('SLC7A7', 'Gene', '9056', (76, 82))	('breast cancer', 'Disease', 'MESH:D001943', (136, 149))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('SLC7A7', 'Gene', (76, 82))	('high', 'Var', (71, 75))	('breast cancer', 'Disease', (136, 149))	('breast cancer', 'Phenotype', 'HP:0003002', (136, 149))	('expression', 'MPA', (83, 93))
441003	33632211	DCs can promote tumor metastasis by increasing Treg cells and attenuating CD8 + T cell cytotoxicity.	('DCs', 'Var', (0, 3))	('CD8', 'Gene', '925', (74, 77))	('increasing', 'PosReg', (36, 46))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('Treg cells', 'CPA', (47, 57))	('tumor', 'Disease', (16, 21))	('attenuating', 'NegReg', (62, 73))	('promote', 'PosReg', (8, 15))	('CD8', 'Gene', (74, 77))
441016	33632211	Herein, variations in SLC7A7 expression levels were found to be correlated with prognosis in different types of cancer.	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('SLC7A7', 'Gene', (22, 28))	('SLC7A7', 'Gene', '9056', (22, 28))	('expression levels', 'MPA', (29, 46))	('variations', 'Var', (8, 18))	('correlated', 'Reg', (64, 74))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))
441028	33632211	Multiple myeloma and breast cancer were exceptions where high SLC7A7 expression showed a better prognosis.	('Multiple myeloma', 'Phenotype', 'HP:0006775', (0, 16))	('Multiple myeloma and breast cancer', 'Disease', 'MESH:D001943', (0, 34))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('high', 'Var', (57, 61))	('expression', 'MPA', (69, 79))	('breast cancer', 'Phenotype', 'HP:0003002', (21, 34))	('SLC7A7', 'Gene', '9056', (62, 68))	('SLC7A7', 'Gene', (62, 68))
441029	33632211	In one dataset of PrognoScan, high SLC7A7 expression could be used as an independent risk factor for poor prognosis in NSCLC (Fig.	('NSCLC', 'Disease', 'MESH:D002289', (119, 124))	('SLC7A7', 'Gene', '9056', (35, 41))	('SLC7A7', 'Gene', (35, 41))	('expression', 'MPA', (42, 52))	('high', 'Var', (30, 34))	('NSCLC', 'Disease', (119, 124))
441049	33632211	The microenvironment deprivation of L-arginine in turn leads to the suppression of T-cell activation, proliferation, differentiation and function.	('differentiation', 'CPA', (117, 132))	('L-arginine', 'Chemical', 'MESH:D001120', (36, 46))	('suppression', 'NegReg', (68, 79))	('L-arginine', 'Var', (36, 46))	('T-cell activation', 'CPA', (83, 100))	('function', 'CPA', (137, 145))
441066	32024216	Overall, we did not find an increased risk of lung cancer with higher exposure to PM10 or NO2.	('PM10', 'Var', (82, 86))	('PM10', 'Chemical', '-', (82, 86))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('lung cancer', 'Disease', 'MESH:D008175', (46, 57))	('NO2', 'Var', (90, 93))	('NO2', 'Chemical', 'MESH:D009585', (90, 93))	('lung cancer', 'Disease', (46, 57))	('lung cancer', 'Phenotype', 'HP:0100526', (46, 57))
441067	32024216	However, high exposure to PM10 was associated with increased risk of adenocarcinoma in comparison with lower exposure in males and current smokers (HR, 1.14; 95% CI, 1.03-1.25).	('high exposure', 'Var', (9, 22))	('PM10', 'Var', (26, 30))	('PM10', 'Chemical', '-', (26, 30))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('adenocarcinoma', 'Disease', (69, 83))	('adenocarcinoma', 'Disease', 'MESH:D000230', (69, 83))
441092	32024216	Cox proportional hazards models were used to estimate the hazard ratio (HR) of lung cancer incidence in total and by histologic type at diagnosis for PM10 and NO2.	('lung cancer', 'Disease', 'MESH:D008175', (79, 90))	('PM10', 'Var', (150, 154))	('lung cancer', 'Disease', (79, 90))	('lung cancer', 'Phenotype', 'HP:0100526', (79, 90))	('NO2', 'Var', (159, 162))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('PM10', 'Chemical', '-', (150, 154))	('NO2', 'Chemical', 'MESH:D009585', (159, 162))
441096	32024216	Cancers defined morphologically as adenocarcinoma (8140/3), squamous cell carcinoma (8070/3), large cell carcinoma (8012/3, 8072/3, 8013/3, 8071/3, 8014/3, 8046/3) and small cell carcinoma (8041/3) and not specified (8250/3).	('8041/3', 'Var', (190, 196))	('Cancers', 'Disease', (0, 7))	('Cancers', 'Phenotype', 'HP:0002664', (0, 7))	('large cell carcinoma', 'Phenotype', 'HP:0030360', (94, 114))	('small cell carcinoma', 'Phenotype', 'HP:0030357', (168, 188))	('cell carcinoma', 'Disease', 'MESH:D002292', (69, 83))	('cell carcinoma', 'Disease', 'MESH:D002292', (100, 114))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('squamous cell carcinoma', 'Disease', (60, 83))	('8012/3', 'Var', (116, 122))	('8140/3', 'Var', (51, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (40, 49))	('small cell carcinoma', 'Disease', (168, 188))	('small cell carcinoma', 'Disease', 'MESH:D018288', (168, 188))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('adenocarcinoma', 'Disease', (35, 49))	('Cancers', 'Disease', 'MESH:D009369', (0, 7))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (60, 83))	('carcinoma', 'Phenotype', 'HP:0030731', (179, 188))	('8070/3', 'Var', (85, 91))	('cell carcinoma', 'Disease', 'MESH:D002292', (174, 188))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('not specified', 'Species', '32644', (202, 215))	('cell carcinoma', 'Disease', (100, 114))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (60, 83))	('adenocarcinoma', 'Disease', 'MESH:D000230', (35, 49))
441101	32024216	It was 55.8 mcg/m3 (Min to Max; 37.99 to 75.95), and 23.9 ppm (Min to Max; 4.16 to 42.66), for PM10 and NO2.	('NO2', 'Chemical', 'MESH:D009585', (104, 107))	('NO2', 'Var', (104, 107))	('PM10', 'Var', (95, 99))	('PM10', 'Chemical', '-', (95, 99))
441121	32024216	We did not observe an increased risk associated with PM10 or NO2 exposure.	('PM10', 'Chemical', '-', (53, 57))	('NO2', 'Chemical', 'MESH:D009585', (61, 64))	('NO2', 'Var', (61, 64))	('PM10', 'Var', (53, 57))
441123	32024216	In the final model, adjusting for other influencing factors, the highest exposure to PM10 in the top 25% percentile was significantly associated with increased risk of adenocarcinoma in comparison with lower exposure in the bottom 75% percentile (HR, 1.14; 95% CI, 1.03-1.25) in male smokers.	('carcinoma', 'Phenotype', 'HP:0030731', (173, 182))	('adenocarcinoma', 'Disease', (168, 182))	('PM10', 'Var', (85, 89))	('PM10', 'Chemical', '-', (85, 89))	('adenocarcinoma', 'Disease', 'MESH:D000230', (168, 182))
441132	32024216	However, in sub-analysis, there was a significant association between high exposure to PM10 and increased risk of adenocarcinoma in male and current smokers (HR, 1.14; 95% CI, 1.03-1.25).	('adenocarcinoma', 'Disease', 'MESH:D000230', (114, 128))	('PM10', 'Gene', (87, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('PM10', 'Chemical', '-', (87, 91))	('adenocarcinoma', 'Disease', (114, 128))	('high exposure', 'Var', (70, 83))
441148	32024216	The ESCAPE study found ORs for adenocarcinoma (based on 663 cases) and squamous cell carcinoma (322 cases), respectively, of 1.51 (95% CI: 1.10-2.08) and 0.84 (95% CI: 0.50-1.40) per 10 mug/m3 of PM10.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (71, 94))	('PM10', 'Var', (196, 200))	('carcinoma', 'Phenotype', 'HP:0030731', (36, 45))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (71, 94))	('PM10', 'Chemical', '-', (196, 200))	('adenocarcinoma', 'Disease', (31, 45))	('squamous cell carcinoma', 'Disease', (71, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('adenocarcinoma', 'Disease', 'MESH:D000230', (31, 45))
441151	32024216	The International Agency for Research on Cancer (IARC)'s systemic review and meta-analysis showed the lung cancer risk associated with exposure to PM in outdoor air, specifically PM2.5 and PM10.	('PM2.5', 'Var', (179, 184))	('lung cancer', 'Phenotype', 'HP:0100526', (102, 113))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('lung cancer', 'Disease', (102, 113))	('PM', 'Chemical', 'MESH:D011399', (179, 181))	('PM', 'Chemical', 'MESH:D011399', (189, 191))	('PM', 'Chemical', 'MESH:D011399', (147, 149))	('PM10', 'Var', (189, 193))	('PM10', 'Chemical', '-', (189, 193))	('Cancer', 'Phenotype', 'HP:0002664', (41, 47))	('lung cancer', 'Disease', 'MESH:D008175', (102, 113))
441152	32024216	The meta-estimates for adenocarcinoma associated with PM2.5 and PM10 were 1.40 (95% CI: 1.07, 1.83) and 1.29 (95% CI: 1.02, 1.63), respectively.	('PM', 'Chemical', 'MESH:D011399', (64, 66))	('PM10', 'Var', (64, 68))	('adenocarcinoma', 'Disease', 'MESH:D000230', (23, 37))	('PM10', 'Chemical', '-', (64, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (28, 37))	('PM2.5', 'Var', (54, 59))	('adenocarcinoma', 'Disease', (23, 37))	('PM', 'Chemical', 'MESH:D011399', (54, 56))
441155	32024216	This study has found an increased risk of lung cancer incidence with residential exposure to ambient PM10 and NO2 in particular squamous cell carcinoma and small cell carcinoma in Korea.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (128, 151))	('small cell carcinoma', 'Disease', (156, 176))	('particular squamous cell carcinoma', 'Disease', 'MESH:D002294', (117, 151))	('NO2', 'Chemical', 'MESH:D009585', (110, 113))	('small cell carcinoma', 'Phenotype', 'HP:0030357', (156, 176))	('small cell carcinoma', 'Disease', 'MESH:D018288', (156, 176))	('carcinoma', 'Phenotype', 'HP:0030731', (142, 151))	('carcinoma', 'Phenotype', 'HP:0030731', (167, 176))	('lung cancer', 'Disease', (42, 53))	('NO2', 'Var', (110, 113))	('lung cancer', 'Phenotype', 'HP:0100526', (42, 53))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('particular squamous cell carcinoma', 'Disease', (117, 151))	('PM10', 'Chemical', '-', (101, 105))	('lung cancer', 'Disease', 'MESH:D008175', (42, 53))
441165	32024216	One study showed that PM10 and NO2 exposures were associated with an increased risk of lung cancer.	('lung cancer', 'Disease', 'MESH:D008175', (87, 98))	('NO2 exposures', 'Var', (31, 44))	('PM10', 'Var', (22, 26))	('PM10', 'Chemical', '-', (22, 26))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('lung cancer', 'Disease', (87, 98))	('lung cancer', 'Phenotype', 'HP:0100526', (87, 98))	('NO2', 'Chemical', 'MESH:D009585', (31, 34))
441226	30932358	Moreover, according to Kaplan-Meier analysis, patients with high expression levels of PHF5A had a shorter OS than those with low PHF5A expression in LUAD (Figure 2E) but not in LUSC (Figure 2F), which was concordant with the results obtained using TCGA database.	('PHF5A', 'Gene', '84844', (86, 91))	('patients', 'Species', '9606', (46, 54))	('high', 'Var', (60, 64))	('LUSC', 'Phenotype', 'HP:0030359', (177, 181))	('LUAD', 'Phenotype', 'HP:0030078', (149, 153))	('PHF5A', 'Gene', '84844', (129, 134))	('expression', 'MPA', (65, 75))	('PHF5A', 'Gene', (86, 91))	('shorter', 'NegReg', (98, 105))	('PHF5A', 'Gene', (129, 134))
441246	30932358	Because the in vitro experiments also demonstrated that knockdown of PHF5A inhibited LUAD cell proliferation partially by inducing G0/G1 cell cycle arrest and promoting cell apoptosis, we focused on cell cycle and apoptosis pathways to elucidate the underlying molecular mechanisms of PHF5A.	('PHF5A', 'Gene', '84844', (69, 74))	('PHF5A', 'Gene', '84844', (285, 290))	('arrest', 'Disease', 'MESH:D006323', (148, 154))	('inhibited', 'NegReg', (75, 84))	('promoting', 'PosReg', (159, 168))	('LUAD cell proliferation', 'CPA', (85, 108))	('PHF5A', 'Gene', (69, 74))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (137, 154))	('arrest', 'Disease', (148, 154))	('PHF5A', 'Gene', (285, 290))	('LUAD', 'Phenotype', 'HP:0030078', (85, 89))	('cell apoptosis', 'CPA', (169, 183))	('inducing', 'NegReg', (122, 130))	('knockdown', 'Var', (56, 65))
441253	30932358	More importantly, we found that pladienolide induced AS events similarly to PHF5A knockdown in a dose-dependent manner, including splicing of ANAPC10, ATR, MECP2, MITD1, MLLT10, MRPS12, SMC3, KDM6A, API5 and BCL2L13 (Figure 6D-E).	('MRPS12', 'Gene', (178, 184))	('PHF5A', 'Gene', '84844', (76, 81))	('ATR', 'Gene', (151, 154))	('BCL2L13', 'Gene', '23786', (208, 215))	('MRPS12', 'Gene', '6183', (178, 184))	('ANAPC10', 'Gene', (142, 149))	('SMC3', 'Gene', '9126', (186, 190))	('KDM6A', 'Gene', (192, 197))	('API5', 'Gene', (199, 203))	('MITD1', 'Gene', (163, 168))	('knockdown', 'Var', (82, 91))	('MITD1', 'Gene', '129531', (163, 168))	('MLLT10', 'Gene', '8028', (170, 176))	('BCL2L13', 'Gene', (208, 215))	('API5', 'Gene', '8539', (199, 203))	('ANAPC10', 'Gene', '10393', (142, 149))	('pladienolide', 'Chemical', '-', (32, 44))	('ATR', 'Gene', '545', (151, 154))	('splicing', 'Var', (130, 138))	('MLLT10', 'Gene', (170, 176))	('SMC3', 'Gene', (186, 190))	('MECP2', 'Gene', '4204', (156, 161))	('pladienolide', 'Gene', (32, 44))	('KDM6A', 'Gene', '7403', (192, 197))	('MECP2', 'Gene', (156, 161))	('PHF5A', 'Gene', (76, 81))
441268	30932358	In addition, high expression of PHF5A mRNA was significantly correlated with shorter OS in LUAD patients but not in LUSC patients, as shown in the Kaplan-Meier plotter.	('high', 'Var', (13, 17))	('PHF5A', 'Gene', '84844', (32, 37))	('LUSC', 'Phenotype', 'HP:0030359', (116, 120))	('patients', 'Species', '9606', (96, 104))	('LUAD', 'Disease', (91, 95))	('shorter', 'Disease', (77, 84))	('patients', 'Species', '9606', (121, 129))	('LUAD', 'Phenotype', 'HP:0030078', (91, 95))	('PHF5A', 'Gene', (32, 37))
441272	30932358	Knockdown of PHF5A in H1299 and A549 significantly inhibited cell proliferation, clone formation ability, migration and invasion ability; promoted G0/G1 cell cycle arrest; and induced cisplatin-induced apoptosis in vitro.	('inhibited', 'NegReg', (51, 60))	('cisplatin-induced apoptosis', 'CPA', (184, 211))	('arrest', 'Disease', (164, 170))	('invasion ability', 'CPA', (120, 136))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (153, 170))	('A549', 'Var', (32, 36))	('PHF5A', 'Gene', (13, 18))	('cisplatin', 'Chemical', 'MESH:D002945', (184, 193))	('H1299', 'CellLine', 'CVCL:0060', (22, 27))	('promoted', 'PosReg', (138, 146))	('A549', 'CellLine', 'CVCL:0023', (32, 36))	('clone formation ability', 'CPA', (81, 104))	('PHF5A', 'Gene', '84844', (13, 18))	('migration', 'CPA', (106, 115))	('induced', 'Reg', (176, 183))	('arrest', 'Disease', 'MESH:D006323', (164, 170))	('cell proliferation', 'CPA', (61, 79))
441274	30932358	To further evaluate the underlying molecular mechanisms of PHF5A, we conducted next-generation sequencing using RNA extracted from H1299 and A549 cell lines transfected with PHF5A targeting siRNA-1 and control siRNA-NC.	('siRNA-1', 'MPA', (190, 197))	('H1299', 'CellLine', 'CVCL:0060', (131, 136))	('PHF5A', 'Gene', (59, 64))	('PHF5A', 'Gene', (174, 179))	('A549', 'CellLine', 'CVCL:0023', (141, 145))	('targeting', 'Var', (180, 189))	('PHF5A', 'Gene', '84844', (59, 64))	('PHF5A', 'Gene', '84844', (174, 179))
441281	30932358	Second, Yang et al just studied the biological effect of PHF5A knockdown in H1299 and H1975, whereas we additionally completed functional experiments of PHF5A overexpression and further confirmed the oncogenic role of PHF5A in LUAD.	('PHF5A', 'Gene', (57, 62))	('H1975', 'CellLine', 'CVCL:1511', (86, 91))	('H1299', 'CellLine', 'CVCL:0060', (76, 81))	('LUAD', 'Phenotype', 'HP:0030078', (227, 231))	('LUAD', 'Disease', (227, 231))	('PHF5A', 'Gene', '84844', (153, 158))	('PHF5A', 'Gene', '84844', (218, 223))	('PHF5A', 'Gene', '84844', (57, 62))	('knockdown', 'Var', (63, 72))	('PHF5A', 'Gene', (153, 158))	('PHF5A', 'Gene', (218, 223))
441386	32252671	When comparing the highest with the lowest categories, dietary folate intake was associated with a reduced risk of esophageal cancer-specific mortality in patients with esophageal squamous cell carcinoma (HR: 0.41, 95% CI: 0.25-0.69), with low heterogeneity (I2 = 0%, P = 0.788).	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('dietary', 'Var', (55, 62))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (180, 203))	('carcinoma', 'Phenotype', 'HP:0030731', (194, 203))	('folate', 'Chemical', 'MESH:D005492', (63, 69))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (169, 203))	('esophageal cancer', 'Disease', (115, 132))	('mortality', 'Disease', 'MESH:D003643', (142, 151))	('esophageal cancer', 'Disease', 'MESH:D004938', (115, 132))	('patients', 'Species', '9606', (155, 163))	('reduced', 'NegReg', (99, 106))	('esophageal squamous cell carcinoma', 'Disease', (169, 203))	('mortality', 'Disease', (142, 151))
441387	32252671	When comparing the highest with the lowest categories of alcohol consumption, alcohol consumption was associated with an increased risk of all-cause mortality in patients with esophageal squamous cell carcinoma (HR: 1.29, 95% CI: 1.07-1.55; heterogeneity: I2 = 53%, P = 0.030), but this increased risk was not significant in patients with esophageal adenocarcinoma (HR = 1.05, 95% CI: 0.84-1.32).	('carcinoma', 'Phenotype', 'HP:0030731', (355, 364))	('patients', 'Species', '9606', (162, 170))	('patients', 'Species', '9606', (325, 333))	('carcinoma', 'Phenotype', 'HP:0030731', (201, 210))	('alcohol', 'Chemical', 'MESH:D000438', (78, 85))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (187, 210))	('mortality', 'Disease', (149, 158))	('esophageal adenocarcinoma', 'Disease', 'MESH:D000230', (339, 364))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (176, 210))	('alcohol', 'Chemical', 'MESH:D000438', (57, 64))	('alcohol consumption', 'Var', (78, 97))	('esophageal adenocarcinoma', 'Disease', (339, 364))	('esophageal squamous cell carcinoma', 'Disease', (176, 210))	('mortality', 'Disease', 'MESH:D003643', (149, 158))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (339, 364))
441388	32252671	This review with pre-diagnostic dietary exposure showed that dietary folate intake was associated with a reduced risk of mortality of esophageal squamous cell carcinoma, whereas alcohol consumption was associated with an increased risk.	('mortality', 'Disease', (121, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (159, 168))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (145, 168))	('esophageal squamous cell carcinoma', 'Disease', (134, 168))	('alcohol', 'Chemical', 'MESH:D000438', (178, 185))	('folate', 'Chemical', 'MESH:D005492', (69, 75))	('reduced', 'NegReg', (105, 112))	('mortality', 'Disease', 'MESH:D003643', (121, 130))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (134, 168))	('dietary', 'Var', (61, 68))
441427	32252671	The pooled results in our study showed that pre-diagnostic alcohol consumption could increase risk of mortality among EC and ESCC patients by 48 and 29% respectively; however, this effect was not found in EAC patients.	('mortality', 'Disease', 'MESH:D003643', (102, 111))	('mortality', 'Disease', (102, 111))	('patients', 'Species', '9606', (130, 138))	('patients', 'Species', '9606', (209, 217))	('alcohol', 'Chemical', 'MESH:D000438', (59, 66))	('pre-diagnostic', 'Var', (44, 58))	('EAC', 'Phenotype', 'HP:0011459', (205, 208))	('ESCC', 'Disease', (125, 129))
441447	32252671	In summary, this review with limited evidence suggested that folate intake was associated with a reduced risk of esophageal cancer-specific mortality for ESCC, whereas alcohol consumption was associated with increased risk of mortality for ESCC.	('esophageal cancer', 'Disease', 'MESH:D004938', (113, 130))	('mortality', 'Disease', 'MESH:D003643', (226, 235))	('mortality', 'Disease', 'MESH:D003643', (140, 149))	('ESCC', 'Disease', (154, 158))	('reduced', 'NegReg', (97, 104))	('alcohol', 'Chemical', 'MESH:D000438', (168, 175))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('mortality', 'Disease', (226, 235))	('mortality', 'Disease', (140, 149))	('folate', 'Var', (61, 67))	('esophageal cancer', 'Disease', (113, 130))	('folate', 'Chemical', 'MESH:D005492', (61, 67))
441456	30214552	Results demonstrated significant associations between OS and MTVPET volume computerized assisted reporting (PETVCAR), MTV2.5, MTV25%, MTV42% and TLGPETVCAR; however, no significant associations were identified between OS and MTV50%, MTV75%, TLG2.5, all SUV and SUL.	('MTV', 'Chemical', '-', (126, 129))	('SUL', 'Chemical', 'MESH:D013444', (261, 264))	('MTV50%', 'Var', (225, 231))	('MTV75%', 'Var', (233, 239))	('MTV42', 'Chemical', '-', (134, 139))	('MTV50', 'Chemical', '-', (225, 230))	('MTV', 'Chemical', '-', (118, 121))	('TLG', 'Chemical', '-', (241, 244))	('MTV', 'Chemical', '-', (225, 228))	('OS', 'Chemical', '-', (54, 56))	('OS', 'Chemical', '-', (218, 220))	('TLG2.5', 'Gene', (241, 247))	('MTV25', 'Chemical', '-', (126, 131))	('TLG', 'Chemical', '-', (145, 148))	('MTV', 'Chemical', '-', (233, 236))	('MTV', 'Chemical', '-', (61, 64))	('MTV', 'Chemical', '-', (134, 137))
441457	30214552	Subgroup analyses according to pathology demonstrated that there were statistically significant associations between OS and stage (P<0.001), MTV50% (P=0.002) and MTV42% (P=0.004) in the adenocarcinoma group, and SULmean (P=0.010), MTV25% (P=0.005) and MTV42% (P=0.001) in the squamous cell carcinoma group; however, no significant differences were identified between any other group.	('MTV42%', 'Var', (162, 168))	('OS', 'Chemical', '-', (117, 119))	('MTV42%', 'Var', (252, 258))	('carcinoma', 'Phenotype', 'HP:0030731', (290, 299))	('MTV25', 'Chemical', '-', (231, 236))	('MTV42', 'Chemical', '-', (252, 257))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (276, 299))	('MTV50', 'Chemical', '-', (141, 146))	('carcinoma', 'Phenotype', 'HP:0030731', (191, 200))	('MTV25%', 'Var', (231, 237))	('squamous cell carcinoma', 'Disease', (276, 299))	('MTV42', 'Chemical', '-', (162, 167))	('MTV50%', 'Var', (141, 147))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (276, 299))	('adenocarcinoma', 'Disease', (186, 200))	('adenocarcinoma', 'Disease', 'MESH:D000230', (186, 200))	('SUL', 'Chemical', 'MESH:D013444', (212, 215))
441458	30214552	Furthermore, there was a significant association between OS and MTV42% (P=0.02) and MTV50% (P=0.04) in the early-stage group; however, no significant differences were identified in the advanced-stage group.	('MTV42', 'Chemical', '-', (64, 69))	('MTV42%', 'Var', (64, 70))	('OS', 'Chemical', '-', (57, 59))	('MTV50', 'Chemical', '-', (84, 89))	('MTV50%', 'Var', (84, 90))
441488	30214552	Once segmentation had reached the maximum percentage threshold, PETVCAR was used to calculate several parameters for lung cancer VOI, including MTV25, MTV42, MTV50 and MTV75%, which were defined as tumor volume with an absolute threshold of 25, 42, 50 and 75% of the histogram of SUVmax, respectively.	('MTV', 'Chemical', '-', (151, 154))	('lung cancer VOI', 'Disease', 'MESH:D008175', (117, 132))	('MTV25', 'Var', (144, 149))	('MTV', 'Chemical', '-', (144, 147))	('lung cancer VOI', 'Disease', (117, 132))	('MTV75%', 'Var', (168, 174))	('MTV50', 'Var', (158, 163))	('MTV50', 'Chemical', '-', (158, 163))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('MTV25', 'Chemical', '-', (144, 149))	('lung cancer', 'Phenotype', 'HP:0100526', (117, 128))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('MTV42', 'Var', (151, 156))	('MTV42', 'Chemical', '-', (151, 156))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('tumor', 'Disease', (198, 203))	('MTV', 'Chemical', '-', (168, 171))	('MTV', 'Chemical', '-', (158, 161))
441507	30214552	Results presented little difference between OR values and survival rates, which suggests that the influence of various parameters on survival rates are similar; however, no significant associations were identified between OS and MTV50, MTV75%, TLG2.5, all SUV and/or SUL.	('MTV75%', 'Var', (236, 242))	('MTV', 'Chemical', '-', (236, 239))	('MTV50', 'Gene', (229, 234))	('TLG', 'Chemical', '-', (244, 247))	('MTV', 'Chemical', '-', (229, 232))	('TLG2.5', 'Gene', (244, 250))	('SUL', 'Chemical', 'MESH:D013444', (267, 270))	('SUV', 'Disease', (256, 259))	('OS', 'Chemical', '-', (222, 224))	('MTV50', 'Chemical', '-', (229, 234))
441510	30214552	Results obtained from the adenocarcinoma group demonstrated significant associations between OS and stage (P<0.001), MTV50% (P=0.002) and MTV42% (P=0.004).	('adenocarcinoma', 'Disease', (26, 40))	('adenocarcinoma', 'Disease', 'MESH:D000230', (26, 40))	('MTV50', 'Chemical', '-', (117, 122))	('OS', 'Chemical', '-', (93, 95))	('MTV42', 'Chemical', '-', (138, 143))	('MTV50%', 'Var', (117, 123))	('stage', 'Disease', (100, 105))	('carcinoma', 'Phenotype', 'HP:0030731', (31, 40))	('MTV42%', 'Var', (138, 144))
441511	30214552	Results obtained from the squamous cell carcinoma group demonstrated significant associations between OS and SULmean (P=0.010), MTV25% (P=0.005) and MTV42% (P=0.001).	('OS', 'Chemical', '-', (102, 104))	('MTV25%', 'Var', (128, 134))	('SULmean', 'Disease', (109, 116))	('MTV25', 'Chemical', '-', (128, 133))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (26, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (40, 49))	('squamous cell carcinoma', 'Disease', (26, 49))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (26, 49))	('SUL', 'Chemical', 'MESH:D013444', (109, 112))	('MTV42', 'Chemical', '-', (149, 154))	('MTV42%', 'Var', (149, 155))
441515	30214552	Results from the early-stage group demonstrated significant associations between OS, MTV42% (P=0.02; OR=1.572) and MTV50% (P=0.04; OR=0.871).	('MTV42', 'Chemical', '-', (85, 90))	('MTV42%', 'Var', (85, 91))	('MTV50', 'Chemical', '-', (115, 120))	('OS', 'Chemical', '-', (81, 83))	('MTV50%', 'Var', (115, 121))
441537	30214552	Results from subgroup data with regard to pathology analysis demonstrated that patients with adenocarcinoma exhibited a significant association between OS and stage, MTV50% or MTV42%; patients with squamous cell carcinoma exhibited significant associations between OS and SULmean, MTV25% or MTV42%; patients assigned to the others group did not exhibit any significant associations.	('MTV42', 'Chemical', '-', (291, 296))	('OS', 'Chemical', '-', (265, 267))	('patients', 'Species', '9606', (299, 307))	('SULmean', 'Disease', (272, 279))	('SUL', 'Chemical', 'MESH:D013444', (272, 275))	('OS', 'Chemical', '-', (152, 154))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (198, 221))	('MTV50', 'Chemical', '-', (166, 171))	('carcinoma', 'Phenotype', 'HP:0030731', (212, 221))	('MTV42', 'Chemical', '-', (176, 181))	('adenocarcinoma', 'Disease', (93, 107))	('MTV25', 'Chemical', '-', (281, 286))	('MTV25%', 'Var', (281, 287))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (198, 221))	('adenocarcinoma', 'Disease', 'MESH:D000230', (93, 107))	('associations', 'Interaction', (244, 256))	('patients', 'Species', '9606', (184, 192))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('patients', 'Species', '9606', (79, 87))	('squamous cell carcinoma', 'Disease', (198, 221))
441538	30214552	Early stage Cox's multivariate analyses demonstrated significant associations between OS and MTV42% or MTV50%; however, no significant differences were identified in late-stage Cox's multivariate analyses.	('MTV42%', 'Var', (93, 99))	('OS', 'Chemical', '-', (86, 88))	('MTV50', 'Chemical', '-', (103, 108))	('MTV50%', 'Var', (103, 109))	('Cox', 'Gene', '1351', (177, 180))	('MTV42', 'Chemical', '-', (93, 98))	('Cox', 'Gene', '1351', (12, 15))	('Cox', 'Gene', (12, 15))	('Cox', 'Gene', (177, 180))
441539	30214552	Therefore, MTV50% and/or MTV42% in adenocarcinoma or early stage, and MTV25% and/or MTV42% in squamous cell carcinoma may provide an improved prediction of prognosis compared with other metabolic indexes (SUVmean, SUVmax, SULmean, SULmax, SULpeak, MTVPETVCAR, MTV2.5, MTV75%, TLGPETVCAR, TLG2.5 and SD) for patients with NSCLC.	('MTV42', 'Chemical', '-', (84, 89))	('MTV25', 'Chemical', '-', (70, 75))	('MTV50', 'Chemical', '-', (11, 16))	('MTV', 'Chemical', '-', (70, 73))	('MTV', 'Chemical', '-', (268, 271))	('MTV', 'Chemical', '-', (84, 87))	('patients', 'Species', '9606', (307, 315))	('MTV', 'Chemical', '-', (11, 14))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (94, 117))	('TLG', 'Chemical', '-', (288, 291))	('MTV25', 'Var', (70, 75))	('SUL', 'Chemical', 'MESH:D013444', (231, 234))	('carcinoma', 'Phenotype', 'HP:0030731', (40, 49))	('SUL', 'Chemical', 'MESH:D013444', (239, 242))	('NSCLC', 'Disease', 'MESH:D002289', (321, 326))	('MTV', 'Chemical', '-', (25, 28))	('MTV', 'Chemical', '-', (248, 251))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (94, 117))	('adenocarcinoma', 'Disease', (35, 49))	('MTV50', 'Var', (11, 16))	('MTV42', 'Chemical', '-', (25, 30))	('SUL', 'Chemical', 'MESH:D013444', (222, 225))	('NSCLC', 'Disease', (321, 326))	('MTV42', 'Var', (84, 89))	('TLG', 'Chemical', '-', (276, 279))	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('squamous cell carcinoma', 'Disease', (94, 117))	('MTV', 'Chemical', '-', (260, 263))	('adenocarcinoma', 'Disease', 'MESH:D000230', (35, 49))
441562	33946045	Multivariate analysis showed that the expression of ZBTB7C was an independent prognostic factor in COAD and MESO.	('COAD', 'Disease', (99, 103))	('expression', 'Var', (38, 48))	('COAD', 'Disease', 'MESH:D029424', (99, 103))	('ZBTB7C', 'Gene', (52, 58))	('MESO', 'Disease', (108, 112))
441576	33946045	However, ZBTB7C in clear cell renal cancer cells can function as a proto-oncogene to stimulate the rapid proliferation of tumor cells.	('renal cancer', 'Phenotype', 'HP:0009726', (30, 42))	('stimulate', 'PosReg', (85, 94))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('clear cell renal cancer', 'Phenotype', 'HP:0006770', (19, 42))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('clear cell renal cancer', 'Disease', 'MESH:C538614', (19, 42))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('ZBTB7C', 'Var', (9, 15))	('tumor', 'Disease', (122, 127))	('clear cell renal cancer', 'Disease', (19, 42))
441588	33946045	As shown in Figure 2A-2D, the expression of ZBTB7C was significantly correlated with the overall survival (OS) of 4 cancers: COAD (P = 0.006), DLBC (P = 0.001), ESCA (P = 0.031) and MESO (P = 0.001).	('COAD', 'Disease', 'MESH:D029424', (125, 129))	('ESCA', 'Disease', (161, 165))	('expression', 'Var', (30, 40))	('COAD', 'Disease', (125, 129))	('correlated with', 'Reg', (69, 84))	('ZBTB7C', 'Gene', (44, 50))	('cancers', 'Disease', 'MESH:D009369', (116, 123))	('cancers', 'Phenotype', 'HP:0002664', (116, 123))	('overall', 'MPA', (89, 96))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cancers', 'Disease', (116, 123))	('MESO', 'Disease', (182, 186))	('DLBC', 'Disease', (143, 147))
441602	33946045	Finally, we found that the expression of ZBTB7C in the TP53 mutant group was decreased (Figure 5K).	('TP53', 'Gene', '7157', (55, 59))	('TP53', 'Gene', (55, 59))	('decreased', 'NegReg', (77, 86))	('expression', 'MPA', (27, 37))	('mutant', 'Var', (60, 66))	('ZBTB7C', 'Gene', (41, 47))
441607	33946045	At both the mRNA level (Figure 6C) and the protein level (Figure 7; Supplementary Table 3), the levels of ZBTB7C, TPSB2, MS4A2, CD19, and MS4A1 in CRC tissues were lower than those in normal tissues adjacent to the cancer.	('levels', 'MPA', (96, 102))	('cancer', 'Disease', (215, 221))	('lower', 'NegReg', (164, 169))	('TPSB2', 'Gene', (114, 119))	('cancer', 'Disease', 'MESH:D009369', (215, 221))	('ZBTB7C', 'Gene', (106, 112))	('CD19', 'MPA', (128, 132))	('CRC', 'Disease', (147, 150))	('MS4A1', 'Var', (138, 143))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('MS4A2', 'Var', (121, 126))
441616	33946045	ZBTB7C was also shown to be a protective factor in COAD, DLBC, ESCA and MESO, in which its overexpression was related to superior prognosis.	('superior', 'PosReg', (121, 129))	('COAD', 'Disease', (51, 55))	('overexpression', 'PosReg', (91, 105))	('MESO', 'Disease', (72, 76))	('ESCA', 'Disease', (63, 67))	('ZBTB7C', 'Var', (0, 6))	('COAD', 'Disease', 'MESH:D029424', (51, 55))	('DLBC', 'Disease', (57, 61))
441618	33946045	TMB is an emerging independent biomarker that detects the total number of mutations in the coding region of tumor genes and can be used to stratify the response of patients to immune checkpoint inhibitors (ICPIs).	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('TMB', 'Chemical', '-', (0, 3))	('mutations', 'Var', (74, 83))	('tumor', 'Disease', (108, 113))	('patients', 'Species', '9606', (164, 172))
441623	33946045	Considering the correlation coefficients  and P values comprehensively, ZBTB7C had the strongest correlation with TMB and MSI in COAD.	('TMB', 'Disease', (114, 117))	('COAD', 'Disease', 'MESH:D029424', (129, 133))	('TMB', 'Chemical', '-', (114, 117))	('MSI', 'Gene', (122, 125))	('COAD', 'Disease', (129, 133))	('correlation', 'Interaction', (97, 108))	('MSI', 'Gene', '5928', (122, 125))	('ZBTB7C', 'Var', (72, 78))
441624	33946045	The strong positive correlation in COAD shows that ZBTB7C can be used as a potential biomarker for the efficacy of immunotherapy, supplementing and validating the conclusion of the abovementioned multivariate Cox regression analysis.	('COAD', 'Disease', (35, 39))	('COAD', 'Disease', 'MESH:D029424', (35, 39))	('ZBTB7C', 'Var', (51, 57))
441638	33946045	More importantly, ZBTB7C can also regulate tumor glutamine metabolism by affecting the transcription of glutaminase (GLS1).	('GLS1', 'Gene', '2744', (117, 121))	('glutaminase', 'Gene', '2744', (104, 115))	('glutamine', 'Chemical', 'MESH:D005973', (49, 58))	('transcription', 'MPA', (87, 100))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('regulate', 'Reg', (34, 42))	('affecting', 'Reg', (73, 82))	('GLS1', 'Gene', (117, 121))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('ZBTB7C', 'Var', (18, 24))	('glutaminase', 'Gene', (104, 115))	('tumor', 'Disease', (43, 48))
441641	33946045	Considering these findings and our data, ZBTB7C may inhibit Myc and then inhibit tumor cell glutamine metabolism, resulting in a relative excess of glutamine in the microenvironment, promoting the proliferation of immune cells (especially mast cells and B cells), and ultimately inhibiting the proliferation of CRC cells to achieve a tumor suppressor effect.	('tumor', 'Phenotype', 'HP:0002664', (334, 339))	('glutamine in', 'MPA', (148, 160))	('ZBTB7C', 'Var', (41, 47))	('proliferation', 'CPA', (197, 210))	('tumor', 'Disease', (81, 86))	('Myc', 'Gene', (60, 63))	('excess', 'MPA', (138, 144))	('tumor', 'Disease', (334, 339))	('inhibiting', 'NegReg', (279, 289))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('excess of glutamine', 'Phenotype', 'HP:0003217', (138, 157))	('inhibit', 'NegReg', (52, 59))	('tumor', 'Disease', 'MESH:D009369', (334, 339))	('glutamine', 'Chemical', 'MESH:D005973', (148, 157))	('glutamine', 'Chemical', 'MESH:D005973', (92, 101))	('promoting', 'PosReg', (183, 192))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('proliferation', 'CPA', (294, 307))	('Myc', 'Gene', '4609', (60, 63))	('inhibit', 'NegReg', (73, 80))
441646	33946045	This study found for the first time that ZBTB7C is widely underexpressed and is related to prognosis across cancers; in addition, ZBTB7C is related to TMB, MSI and immune infiltration, especially in COAD.	('MSI', 'Gene', (156, 159))	('ZBTB7C', 'Var', (130, 136))	('TMB', 'Chemical', '-', (151, 154))	('COAD', 'Disease', (199, 203))	('MSI', 'Gene', '5928', (156, 159))	('cancers', 'Phenotype', 'HP:0002664', (108, 115))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('related', 'Reg', (140, 147))	('immune infiltration', 'CPA', (164, 183))	('COAD', 'Disease', 'MESH:D029424', (199, 203))	('cancers', 'Disease', 'MESH:D009369', (108, 115))	('TMB', 'Disease', (151, 154))	('cancers', 'Disease', (108, 115))
441714	32385277	Patients with high tS2 signature gene expression showed worse overall survival (two-sided log-rank test p < 0.01) than those with low expression (Fig.	('tS2', 'Gene', '110292', (19, 22))	('tS2', 'Gene', (19, 22))	('high', 'Var', (14, 18))	('worse', 'NegReg', (56, 61))	('Patients', 'Species', '9606', (0, 8))	('overall survival', 'MPA', (62, 78))
441803	32385277	These alterations in stromal and immune populations cooperatively transformed immune-competent tissues into an immune-suppressive tumor microenvironment.	('alterations', 'Var', (6, 17))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('transformed', 'Reg', (66, 77))	('tumor', 'Disease', (130, 135))
441822	32385277	Sequencing libraries were constructed for the HiSeq2500 system (Illumina, San Diego, CA, USA) and sequenced using the 100-bp paired-end mode of the Hiseq PE Cluster kit v4 (PE-401-4001, Illumina, San Diego, CA, USA), and the Hiseq SBS kit v4 (PE-401-4003, Illumina, San Diego, CA, USA).	('kit', 'Gene', (165, 168))	('PE-401-4001', 'Var', (173, 184))	('kit', 'Gene', '3815', (165, 168))	('PE-401-4003', 'Var', (243, 254))	('kit', 'Gene', (235, 238))	('kit', 'Gene', '3815', (235, 238))
441831	32385277	The pDC populations in lung tissues were identified using anti-CD45-BV421 (368521, BioLegend) and anti-Human 4-Color Dendritic Value Bundle (340565, BD).	('pDC', 'Gene', (4, 7))	('368521', 'Var', (75, 81))	('4-Color Dendritic Value Bundle', 'Disease', 'MESH:D003117', (109, 139))	('Human', 'Species', '9606', (103, 108))	('CD45', 'Gene', '5788', (63, 67))	('340565', 'Var', (141, 147))	('pDC', 'Gene', '5132', (4, 7))	('4-Color Dendritic Value Bundle', 'Disease', (109, 139))	('CD45', 'Gene', (63, 67))
441833	32385277	In order to examine NK, T, and regulatory T cells, we stained cells with FITC-conjugated anti-human CD56 (CD56-FITC, Cat# 318303), CD3-PerCP (300428), CD4-APC/Cy7 (317417), CD8-BV421 (344747), and CD25-PE (302605) antibodies.	('CD25', 'Gene', (197, 201))	('CD4', 'Gene', (151, 154))	('CD56', 'Gene', '4684', (100, 104))	('CD4', 'Gene', '920', (151, 154))	('FITC', 'Chemical', 'MESH:D016650', (111, 115))	('CD8', 'Gene', '925', (173, 176))	('300428', 'Var', (142, 148))	('CD56', 'Gene', (106, 110))	('FITC', 'Chemical', 'MESH:D016650', (73, 77))	('CD56', 'Gene', (100, 104))	('CD25', 'Gene', '3559', (197, 201))	('human', 'Species', '9606', (94, 99))	('CD8', 'Gene', (173, 176))	('344747', 'Var', (184, 190))	('CD56', 'Gene', '4684', (106, 110))
441834	32385277	CD3-PerCP (300428), CD8a-PE (300908), CD16-FITC (360715), and PD-1-BV421 (329920) antibodies were used together to label cytotoxic or exhausted T cells.	('300908', 'Var', (29, 35))	('CD8a', 'Gene', (20, 24))	('FITC', 'Chemical', 'MESH:D016650', (43, 47))	('CD16', 'Gene', '2214', (38, 42))	('CD8a', 'Gene', '925', (20, 24))	('CD16', 'Gene', (38, 42))
441842	32385277	Cancer cells showing perturbation in their CNV signal (>0.02 mean squares or >0.2 CNV correlation) were classified as malignant.	('CNV signal', 'MPA', (43, 53))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('perturbation', 'Var', (21, 33))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))
441901	24653651	Pleural fluid analysis was done, which showed 80 cells, P60 L40, sugar - 7 mg%, proteins - 3.6 gm%, and Adenosine Deaminase (ADA) - 34.	('sugar', 'Chemical', 'MESH:D000073893', (65, 70))	('ADA', 'Gene', '100', (125, 128))	('Adenosine Deaminase', 'Gene', (104, 123))	('P60 L40', 'Var', (56, 63))	('Pleural fluid', 'Phenotype', 'HP:0002202', (0, 13))	('Adenosine Deaminase', 'Gene', '100', (104, 123))	('ADA', 'Gene', (125, 128))
441939	32587774	The aberrant expression of CUL4 has been reported in breast cancer and hepatocellular cancer.	('CUL4', 'Gene', (27, 31))	('reported', 'Reg', (41, 49))	('hepatocellular cancer', 'Disease', 'MESH:D006528', (71, 92))	('breast cancer', 'Phenotype', 'HP:0003002', (53, 66))	('hepatocellular cancer', 'Disease', (71, 92))	('CUL4', 'Chemical', '-', (27, 31))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('aberrant expression', 'Var', (4, 23))	('hepatocellular cancer', 'Phenotype', 'HP:0001402', (71, 92))	('breast cancer', 'Disease', 'MESH:D001943', (53, 66))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('breast cancer', 'Disease', (53, 66))
441941	32587774	Our previous study showed that high expression of CUL4A and CUL4B was significantly associated with worse clinicopathological characteristics, including lymph node metastasis, higher tumor node metastasis stage, distant metastasis, and a larger tumor size in different subtypes of lung cancer, including squamous cell carcinoma (SCC), adenocarcinoma, large cell carcinoma, and small cell lung carcinoma (SCLC).	('SCC', 'Gene', '6317', (329, 332))	('larger', 'PosReg', (238, 244))	('lymph node metastasis', 'CPA', (153, 174))	('carcinoma', 'Phenotype', 'HP:0030731', (318, 327))	('adenocarcinoma', 'Disease', 'MESH:D000230', (335, 349))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('SCC', 'Gene', (329, 332))	('lung cancer', 'Disease', 'MESH:D008175', (281, 292))	('carcinoma', 'Disease', (318, 327))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (304, 327))	('CUL4A', 'Gene', '8451', (50, 55))	('carcinoma', 'Disease', 'MESH:D009369', (362, 371))	('carcinoma', 'Disease', 'MESH:D009369', (393, 402))	('SCLC', 'Disease', 'MESH:D018288', (404, 408))	('lung cancer', 'Phenotype', 'HP:0100526', (281, 292))	('cancer', 'Phenotype', 'HP:0002664', (286, 292))	('small cell lung carcinoma', 'Disease', 'MESH:D055752', (377, 402))	('associated', 'Reg', (84, 94))	('CUL4A', 'Gene', (50, 55))	('carcinoma', 'Phenotype', 'HP:0030731', (340, 349))	('squamous cell carcinoma', 'Disease', (304, 327))	('carcinoma', 'Disease', (340, 349))	('carcinoma', 'Disease', 'MESH:D009369', (318, 327))	('tumor', 'Disease', (183, 188))	('high expression', 'Var', (31, 46))	('tumor', 'Disease', (245, 250))	('small cell lung carcinoma', 'Disease', (377, 402))	('distant metastasis', 'CPA', (212, 230))	('SCC', 'Phenotype', 'HP:0002860', (329, 332))	('carcinoma', 'Phenotype', 'HP:0030731', (393, 402))	('lung cancer', 'Disease', (281, 292))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('adenocarcinoma', 'Disease', (335, 349))	('tumor', 'Disease', 'MESH:D009369', (245, 250))	('carcinoma', 'Phenotype', 'HP:0030731', (362, 371))	('SCLC', 'Disease', (404, 408))	('small cell lung carcinoma', 'Phenotype', 'HP:0030357', (377, 402))	('carcinoma', 'Disease', 'MESH:D009369', (340, 349))	('large cell carcinoma', 'Phenotype', 'HP:0030360', (351, 371))	('CUL4B', 'Gene', (60, 65))	('carcinoma', 'Disease', (362, 371))	('carcinoma', 'Disease', (393, 402))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (304, 327))	('SCLC', 'Phenotype', 'HP:0030357', (404, 408))	('CUL4B', 'Gene', '8450', (60, 65))
441943	32587774	In particular, we observed a strong association of high CUL4 levels with tobacco smoking risk in SCLC and SCC, the two smoking-related lung cancer subtypes.	('SCLC', 'Disease', (97, 101))	('SCLC', 'Disease', 'MESH:D018288', (97, 101))	('SCC', 'Phenotype', 'HP:0002860', (106, 109))	('SCC', 'Gene', '6317', (106, 109))	('tobacco smoking', 'MPA', (73, 88))	('CUL4', 'Gene', (56, 60))	('SCLC', 'Phenotype', 'HP:0030357', (97, 101))	('lung cancer', 'Disease', 'MESH:D008175', (135, 146))	('high', 'Var', (51, 55))	('CUL4', 'Chemical', '-', (56, 60))	('tobacco', 'Species', '4097', (73, 80))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('lung cancer', 'Disease', (135, 146))	('SCC', 'Gene', (106, 109))	('lung cancer', 'Phenotype', 'HP:0100526', (135, 146))
441957	32587774	MG132, MLN4924, and PD98059 were purchased from Selleck Chemicals (Houston, TX, USA).	('MG132', 'Var', (0, 5))	('MG132', 'Chemical', 'MESH:C072553', (0, 5))	('PD98059', 'Var', (20, 27))	('MLN4924', 'Chemical', 'MESH:C539933', (7, 14))	('PD98059', 'Chemical', 'MESH:C093973', (20, 27))	('MLN4924', 'Var', (7, 14))
441959	32587774	ShRNA plasmids for knocking down CUL4A and CUL4B were described previously.	('CUL4A', 'Gene', (33, 38))	('CUL4B', 'Gene', (43, 48))	('CUL4A', 'Gene', '8451', (33, 38))	('CUL4B', 'Gene', '8450', (43, 48))	('knocking down', 'Var', (19, 32))
441963	32587774	Infected NCI-H520 and SK-MES-1 cells were selected in RPMI-1640 medium (Gibco, Thermo Fisher Scientific, Waltham, MA, USA), NCI-H2227 in Dulbecco's Modified Eagle Medium:F12 (Gibco, Thermo Fisher Scientific), and DMS114 in Waymouth Medium (Gibco) containing 4 mug/mL puromycin dihydrochloride (Sigma-Aldrich, Buchs, Switzerland).	('Waymouth Medium', 'Chemical', '-', (223, 238))	('RPMI-1640 medium', 'Chemical', '-', (54, 70))	('puromycin dihydrochloride', 'Chemical', 'MESH:D011691', (267, 292))	('SK-MES-1', 'CellLine', 'CVCL:0630', (22, 30))	('DMS114', 'Chemical', '-', (213, 219))	('NCI-H2227', 'Var', (124, 133))	('Infected', 'Disease', (0, 8))	("Dulbecco's Modified Eagle Medium", 'Chemical', '-', (137, 169))	('Infected', 'Disease', 'MESH:D007239', (0, 8))	('NCI-H2227', 'CellLine', 'CVCL:1542', (124, 133))
441991	32587774	Moreover, the apoptotic percentage data showed that depletion of CUL4B led to a significant increase in the apoptotic percentages of SCC and SCLC cells, whereas depletion of CUL4A did not (Figure 3A).	('apoptotic percentages', 'CPA', (108, 129))	('SCLC', 'Disease', (141, 145))	('CUL4B', 'Gene', '8450', (65, 70))	('SCLC', 'Disease', 'MESH:D018288', (141, 145))	('SCC', 'Gene', '6317', (133, 136))	('CUL4A', 'Gene', '8451', (174, 179))	('SCLC', 'Phenotype', 'HP:0030357', (141, 145))	('increase', 'PosReg', (92, 100))	('depletion', 'Var', (52, 61))	('CUL4B', 'Gene', (65, 70))	('CUL4A', 'Gene', (174, 179))	('SCC', 'Gene', (133, 136))	('SCC', 'Phenotype', 'HP:0002860', (133, 136))
441999	32587774	With the depletion of both CUL4A and P21, G1 phase arrest was attenuated, and cyclin E1 expression was recovered (Figure 4).	('cyclin E1', 'Gene', '898', (78, 87))	('CUL4A', 'Gene', (27, 32))	('P21', 'Gene', '644914', (37, 40))	('recovered', 'PosReg', (103, 112))	('attenuated', 'NegReg', (62, 72))	('arrest', 'Disease', 'MESH:D006323', (51, 57))	('CUL4A', 'Gene', '8451', (27, 32))	('cyclin E1', 'Gene', (78, 87))	('arrest', 'Disease', (51, 57))	('P21', 'Gene', (37, 40))	('depletion', 'Var', (9, 18))
442005	32587774	FOXO3A knockdown in CUL4B-depleted cells resulted in a significant decrease in the percentage of apoptotic cells (Figure 5B).	('CUL4B', 'Gene', '8450', (20, 25))	('decrease', 'NegReg', (67, 75))	('CUL4B', 'Gene', (20, 25))	('FOXO3A', 'Gene', (0, 6))	('knockdown', 'Var', (7, 16))	('FOXO3A', 'Gene', '2309', (0, 6))
442006	32587774	The expression levels of cleaved caspase-3, BAX, and BCL-2 were recovered after FOXO3A knockdown (Figure 5C).	('expression levels', 'MPA', (4, 21))	('BAX', 'Gene', (44, 47))	('BCL-2', 'Gene', (53, 58))	('FOXO3A', 'Gene', '2309', (80, 86))	('caspase-3', 'Gene', (33, 42))	('caspase-3', 'Gene', '836', (33, 42))	('cleaved', 'MPA', (25, 32))	('recovered', 'MPA', (64, 73))	('BCL-2', 'Gene', '596', (53, 58))	('FOXO3A', 'Gene', (80, 86))	('BAX', 'Gene', '581', (44, 47))	('knockdown', 'Var', (87, 96))
442014	32587774	ERK phosphorylates FOXO3A at Ser 294, and p-FOXO3A (Ser 294) increases the FOXO3A-MDM2 interaction and enhances FOXO3A degradation via an MDM2-dependent ubiquitin-proteasome pathway.	('p-FOXO3A', 'Gene', (42, 50))	('interaction', 'Interaction', (87, 98))	('FOXO3A', 'Gene', '2309', (19, 25))	('FOXO3A', 'Gene', '2309', (112, 118))	('Ser', 'Chemical', 'MESH:D012694', (29, 32))	('MDM2', 'Gene', (138, 142))	('Ser 294', 'Var', (52, 59))	('FOXO3A', 'Gene', (44, 50))	('FOXO3A', 'Gene', (75, 81))	('MDM2', 'Gene', (82, 86))	('Ser', 'Chemical', 'MESH:D012694', (52, 55))	('MDM2', 'Gene', '4193', (138, 142))	('ERK', 'Gene', '5594', (0, 3))	('enhances', 'PosReg', (103, 111))	('FOXO3A', 'Gene', (112, 118))	('MDM2', 'Gene', '4193', (82, 86))	('FOXO3A', 'Gene', (19, 25))	('ERK', 'Gene', (0, 3))	('FOXO3A', 'Gene', '2309', (75, 81))	('FOXO3A', 'Gene', '2309', (44, 50))	('p-FOXO3A', 'Gene', '2309', (42, 50))	('increases', 'PosReg', (61, 70))	('degradation', 'MPA', (119, 130))
442015	32587774	MDM2 expression is required in CUL4-mediated p53 polyubiquitination.	('p53', 'Gene', (45, 48))	('p53', 'Gene', '7157', (45, 48))	('polyubiquitination', 'Var', (49, 67))	('MDM2', 'Gene', '4193', (0, 4))	('CUL4', 'Chemical', '-', (31, 35))	('MDM2', 'Gene', (0, 4))
442017	32587774	To test this hypothesis, we first determined if the activity of ERK was affected by CUL4B knockdown, if total ERK and p-ERK (an MAPK pathway target) were detected, and if PD98059 (an inhibitor of ERK kinases) could be used to inhibit ERK activity in CUL4Bknockdown cells.	('activity', 'MPA', (238, 246))	('PD98059', 'Chemical', 'MESH:C093973', (171, 178))	('affected', 'Reg', (72, 80))	('ERK', 'Gene', (234, 237))	('ERK', 'Gene', '5594', (64, 67))	('ERK', 'Gene', '5594', (120, 123))	('ERK', 'Gene', '5594', (110, 113))	('knockdown', 'Var', (90, 99))	('CUL4B', 'Gene', (84, 89))	('CUL4B', 'Gene', '8450', (84, 89))	('inhibit', 'NegReg', (226, 233))	('ERK', 'Gene', (64, 67))	('ERK', 'Gene', '5594', (196, 199))	('ERK', 'Gene', (120, 123))	('ERK', 'Gene', (110, 113))	('activity', 'MPA', (52, 60))	('CUL4B', 'Gene', (250, 255))	('ERK', 'Gene', '5594', (234, 237))	('CUL4B', 'Gene', '8450', (250, 255))	('ERK', 'Gene', (196, 199))
442024	32587774	As further confirmation, MLN4924 (a NEDD8-activating enzyme inhibitor) was used to inhibit CUL4B activity.	('NEDD8', 'Gene', (36, 41))	('MLN4924', 'Var', (25, 32))	('NEDD8', 'Gene', '4738', (36, 41))	('activity', 'MPA', (97, 105))	('CUL4B', 'Gene', (91, 96))	('MLN4924', 'Chemical', 'MESH:C539933', (25, 32))	('CUL4B', 'Gene', '8450', (91, 96))	('inhibit', 'NegReg', (83, 90))
442027	32587774	As expected, the cellular levels of p-FOXO3A were reduced in control siRNA-treated cells, while the neddylation pathway was blocked by the depletion of UBC12 (a NEDD8 E2-conjugating enzyme) (Figure 7C and D).	('UBC12', 'Gene', (152, 157))	('p-FOXO3A', 'Gene', '2309', (36, 44))	('NEDD8', 'Gene', '4738', (161, 166))	('NEDD8', 'Gene', (161, 166))	('cellular levels', 'MPA', (17, 32))	('UBC12', 'Gene', '9040', (152, 157))	('p-FOXO3A', 'Gene', (36, 44))	('reduced', 'NegReg', (50, 57))	('blocked', 'NegReg', (124, 131))	('neddylation pathway', 'Pathway', (100, 119))	('depletion', 'Var', (139, 148))
442028	32587774	These results indicated that the inactivation of CUL4B blocked the degradation of p-FOXO3A.	('p-FOXO3A', 'Gene', (82, 90))	('CUL4B', 'Gene', '8450', (49, 54))	('p-FOXO3A', 'Gene', '2309', (82, 90))	('degradation', 'MPA', (67, 78))	('inactivation', 'Var', (33, 45))	('blocked', 'NegReg', (55, 62))	('CUL4B', 'Gene', (49, 54))
442034	32587774	The aberrant expression of CUL4 in breast cancer and other malignant tumors compared to normal tissues supports its potential role in cancer development.	('CUL4', 'Gene', (27, 31))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('CUL4', 'Chemical', '-', (27, 31))	('aberrant', 'Var', (4, 12))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('breast cancer', 'Disease', 'MESH:D001943', (35, 48))	('malignant tumors', 'Disease', (59, 75))	('malignant tumors', 'Disease', 'MESH:D009369', (59, 75))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('breast cancer', 'Disease', (35, 48))	('breast cancer', 'Phenotype', 'HP:0003002', (35, 48))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
442044	32587774	Cytology experiments were then conducted, which showed that G1 phase arrest induced by CUL4A depletion was prevented in P21-CUL4A dual knockout cells.	('arrest', 'Disease', 'MESH:D006323', (69, 75))	('CUL4A', 'Gene', (87, 92))	('CUL4A', 'Gene', (124, 129))	('CUL4A', 'Gene', '8451', (87, 92))	('P21', 'Gene', '644914', (120, 123))	('prevented', 'NegReg', (107, 116))	('arrest', 'Disease', (69, 75))	('CUL4A', 'Gene', '8451', (124, 129))	('P21', 'Gene', (120, 123))	('depletion', 'Var', (93, 102))
442048	32587774	First, we confirmed that FOXO3A was a crucial factor in CUL4B knockdown-induced cell apoptosis.	('CUL4B', 'Gene', (56, 61))	('knockdown-induced', 'Var', (62, 79))	('CUL4B', 'Gene', '8450', (56, 61))	('FOXO3A', 'Gene', (25, 31))	('FOXO3A', 'Gene', '2309', (25, 31))
442063	31569614	miRNAs influence multiple biologic processes, including ones that constitute the hallmarks of cancer, such as proliferative signaling, cell death, and metastasis.	('metastasis', 'CPA', (151, 161))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('influence', 'Reg', (7, 16))	('cell death', 'CPA', (135, 145))	('cancer', 'Disease', 'MESH:D009369', (94, 100))	('miRNAs', 'Var', (0, 6))	('cancer', 'Disease', (94, 100))	('proliferative signaling', 'CPA', (110, 133))
442129	31569614	found that salivary miRNAs, including miR-122, miR-124, miR-205, and miR-146a, are downregulated in HPV-associated HNSCC and have the potential to differentiate between HPV+ and HPV- cancers.	('HNSCC', 'Disease', 'MESH:C535575', (115, 120))	('HPV', 'Species', '10566', (100, 103))	('cancers', 'Disease', (183, 190))	('HNSCC', 'Disease', (115, 120))	('miR-146a', 'Var', (69, 77))	('miR-124', 'Var', (47, 54))	('HPV', 'Species', '10566', (169, 172))	('HPV+', 'Disease', (169, 173))	('downregulated', 'NegReg', (83, 96))	('miR-205', 'Var', (56, 63))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('differentiate', 'Reg', (147, 160))	('cancers', 'Phenotype', 'HP:0002664', (183, 190))	('miR-122', 'Var', (38, 45))	('HPV', 'Species', '10566', (178, 181))	('cancers', 'Disease', 'MESH:D009369', (183, 190))
442130	31569614	compared salivary miRNA expression between HPV-positive and HPV-negative HNSCC patients and found that a panel consisting of miR-9, miR-134, miR-196b, miR-210 and miR-455 could discriminate HPV-positive HNSCC from HPV-negative HNSCC.	('miR-134', 'Gene', (132, 139))	('HPV', 'Species', '10566', (60, 63))	('HNSCC', 'Disease', 'MESH:C535575', (203, 208))	('HNSCC', 'Disease', 'MESH:C535575', (227, 232))	('miR-134', 'Gene', '406924', (132, 139))	('miR-196b', 'Gene', (141, 149))	('HNSCC', 'Disease', (73, 78))	('miR-455', 'Gene', (163, 170))	('HPV', 'Species', '10566', (43, 46))	('miR-9', 'Var', (125, 130))	('discriminate', 'Reg', (177, 189))	('miR-210', 'Gene', '406992', (151, 158))	('HNSCC', 'Disease', (203, 208))	('HNSCC', 'Disease', (227, 232))	('HNSCC', 'Disease', 'MESH:C535575', (73, 78))	('miR-196b', 'Gene', '442920', (141, 149))	('HPV', 'Species', '10566', (190, 193))	('miR-455', 'Gene', '619556', (163, 170))	('patients', 'Species', '9606', (79, 87))	('HPV', 'Species', '10566', (214, 217))	('miR-210', 'Gene', (151, 158))
442132	31569614	evaluated the miRNA expression profile of small extracellular vesicles (EVs) released by HPV(+) and HPV(-) OPSCC cell lines.	('SCC', 'Gene', '6317', (109, 112))	('HPV', 'Species', '10566', (100, 103))	('HPV', 'Var', (100, 103))	('miRNA expression', 'MPA', (14, 30))	('HPV', 'Species', '10566', (89, 92))	('SCC', 'Gene', (109, 112))
442145	31569614	They found that six miRNAs (miR-425-5p, miR-21-5p, miR-106b-5p, miR-590-5p, miR-574-3p, miR-885-3p) were downregulated after two days of treatment, pointing to their potential use as radiation-responsive biomarkers.	('miR-425', 'Gene', (28, 35))	('miR-574-3p', 'Gene', (76, 86))	('miR-574-3p', 'Gene', '693159', (76, 86))	('miR-106b-5p', 'Var', (51, 62))	('miR-590-5p', 'Var', (64, 74))	('miR-425', 'Gene', '494337', (28, 35))	('miR-885-3p', 'Var', (88, 98))	('miR-21-5p', 'Gene', (40, 49))	('miR-21-5p', 'Gene', '406997', (40, 49))	('downregulated', 'NegReg', (105, 118))
442149	31569614	They found that high plasma levels of miR-186-5p, miR-374b-5p, and miR-574-3p prior to treatment were associated with shorter progression-free or overall survival and that high plasma levels of miR-28-3p, miR-142-3p, miR-191-5p, miR-195-5p, miR-425-5p, and miR-574-3p after treatment were associated with a worse prognosis.	('progression-free', 'CPA', (126, 142))	('miR-425', 'Gene', '494337', (241, 248))	('miR-374b', 'Gene', (50, 58))	('miR-28', 'Gene', (194, 200))	('miR-142', 'Gene', '406934', (205, 212))	('miR-374b', 'Gene', '100126317', (50, 58))	('miR-425', 'Gene', (241, 248))	('miR-191-5p', 'Var', (217, 227))	('overall survival', 'CPA', (146, 162))	('miR-574-3p', 'Gene', '693159', (67, 77))	('miR-195', 'Gene', '406971', (229, 236))	('miR-186', 'Gene', '406962', (38, 45))	('miR-574-3p', 'Gene', '693159', (257, 267))	('miR-186', 'Gene', (38, 45))	('miR-28', 'Gene', '407020', (194, 200))	('miR-574-3p', 'Gene', (67, 77))	('shorter', 'NegReg', (118, 125))	('miR-142', 'Gene', (205, 212))	('miR-195', 'Gene', (229, 236))	('miR-574-3p', 'Gene', (257, 267))
442192	30046394	Conversely, disrupting integrin-ligand interactions can induce apoptosis via integrin-mediated death (IMD), which is mediated by recruiting and activating caspase-8.	('caspase-8', 'Gene', (155, 164))	('activating', 'PosReg', (144, 154))	('integrin-mediated death', 'Disease', (77, 100))	('integrin-ligand', 'Protein', (23, 38))	('induce', 'PosReg', (56, 62))	('caspase-8', 'Gene', '841', (155, 164))	('apoptosis', 'CPA', (63, 72))	('disrupting', 'Var', (12, 22))	('interactions', 'Interaction', (39, 51))
442269	30046394	The overexpression of alphav integrins (alphavbeta3, alphavbeta5, alphavbeta6) serves as key prognostic, and therapeutic targets in stomach cancers.	('stomach cancers', 'Disease', 'MESH:D013274', (132, 147))	('stomach cancers', 'Disease', (132, 147))	('stomach cancers', 'Phenotype', 'HP:0012126', (132, 147))	('stomach cancer', 'Phenotype', 'HP:0012126', (132, 146))	('cancers', 'Phenotype', 'HP:0002664', (140, 147))	('alphavbeta6', 'Var', (66, 77))	('overexpression', 'PosReg', (4, 18))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('alphav integrins', 'Protein', (22, 38))
442273	30046394	Inhibition of individual subunits is expected to disrupt cellular signaling and acts to halt tumor metastatic processes, angiogenesis and growth.	('tumor', 'Disease', 'MESH:D009369', (93, 98))	('disrupt', 'NegReg', (49, 56))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('growth', 'CPA', (138, 144))	('tumor', 'Disease', (93, 98))	('cellular signaling', 'MPA', (57, 75))	('Inhibition', 'Var', (0, 10))	('halt', 'NegReg', (88, 92))	('angiogenesis', 'CPA', (121, 133))
442285	30046394	Using this relaxed criteria, three plausible targets emerge for BLCA: alpha3beta1, alphavb6, and alpha6b4 (Figure 8A).	('beta1', 'Gene', '10678', (76, 81))	('alpha6b4', 'Var', (97, 105))	('beta1', 'Gene', (76, 81))	('BLCA', 'Chemical', '-', (64, 68))
442303	30046394	Results for each cancer type included, for each of the 27 integrin subunit genes, a log 2 value of expression difference between cancer and normal, a p-value, and a false discovery rate (FDR) adjusted according to the Benjamini-Hochberg method (Supplementary Table 2).	('expression', 'MPA', (99, 109))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('p-value', 'Var', (150, 157))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('cancer', 'Disease', (17, 23))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
442321	26920496	CTL activity to at least one peptide at the time of the third and sixth vaccination increased in 2 and 3 of 6 (10 mg), 2 of 8 and 4 of 6 (20 mg), or 2 and 1 of 6 (30 mg) patients, respectively.	('10', 'Var', (111, 113))	('CTL activity to at least one peptide', 'MPA', (0, 36))	('increased', 'PosReg', (84, 93))	('patients', 'Species', '9606', (170, 178))
442322	26920496	IgG levels, at the third and sixth vaccination, were also increased in 1 and 1 of 6 (10 mg), 2 of 8 and 4 of 6 (20 mg), or 1 and 3 of 6 (30 mg) patients, respectively.	('patients', 'Species', '9606', (144, 152))	('10 mg', 'Var', (85, 90))	('increased', 'PosReg', (58, 67))	('IgG levels', 'MPA', (0, 10))
442328	26920496	Patients were required to have a life expectancy of at least 3 months, an Eastern Cooperative Oncology Group performance status of 0-1, the ability to eat, and adequate organ function as assessed by a platelet (>=75 000/mm3) count, an absolute lymphocyte (>=1000/mm3) count, serum total bilirubin (<=2.0 mg/dL), serum creatinine (<=1.5 mg/dL) and alanine aminotransferase and aspartate aminotransferase (<=100 IU/L, or <=200 IU/L in patients with hepatic metastasis) levels.	('aspartate aminotransferase', 'MPA', (376, 402))	('Oncology', 'Phenotype', 'HP:0002664', (94, 102))	('<=200 IU/L', 'Var', (419, 429))	('Patients', 'Species', '9606', (0, 8))	('alanine aminotransferase', 'Gene', (347, 371))	('hepatic metastasis', 'Disease', (447, 465))	('patients', 'Species', '9606', (433, 441))	('serum creatinine', 'MPA', (312, 328))	('hepatic metastasis', 'Disease', 'MESH:D009362', (447, 465))	('bilirubin', 'Chemical', 'MESH:D001663', (287, 296))	('alanine aminotransferase', 'Gene', '2875', (347, 371))
442356	26920496	HLA-class IA types determined by genotyping were A24 (n = 10), A2 (9), A31 (6), A26 (4), A33 (3), A11 (2) and A3 (1).	('A33', 'Gene', '10223', (89, 92))	('A24', 'Gene', (49, 52))	('A24', 'Gene', '28924', (49, 52))	('A26', 'Gene', (80, 83))	('A33', 'Gene', (89, 92))	('A11', 'Gene', (98, 101))	('A31', 'Var', (71, 74))	('A11', 'Gene', '8248', (98, 101))	('A26', 'Gene', '28906', (80, 83))
442363	26920496	However, CTL activity to at least one peptide at the third and sixth vaccination increased in 2 and 3 of 6 (10 mg), 2 of 8 and 4 of 6 (20 mg), or 2 and 1 of 6 (30 mg) patients, respectively.	('10', 'Var', (108, 110))	('increased', 'PosReg', (81, 90))	('patients', 'Species', '9606', (167, 175))	('CTL activity to at least one peptide', 'MPA', (9, 45))
442379	26920496	However, of note, the 10-mg group was dominated by advanced esophageal cancer patients, whereas the other groups were dominated by colorectal cancer patients.	('10-mg', 'Var', (22, 27))	('patients', 'Species', '9606', (149, 157))	('colorectal cancer', 'Disease', 'MESH:D015179', (131, 148))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('patients', 'Species', '9606', (78, 86))	('colorectal cancer', 'Phenotype', 'HP:0003003', (131, 148))	('esophageal cancer', 'Disease', (60, 77))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('colorectal cancer', 'Disease', (131, 148))	('esophageal cancer', 'Disease', 'MESH:D004938', (60, 77))
442404	30066858	The results revealed that the HOXA3 expression levels in NSCLC, LUAD and lung squamous cell carcinoma (LUSC) were 0.1130+-0.1398, 0.1295+-0.16890 and 0.0906+-0.0846, respectively.	('LUSC', 'Phenotype', 'HP:0030359', (103, 107))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (73, 101))	('SCLC', 'Phenotype', 'HP:0030357', (58, 62))	('0.1295+-0.16890', 'Var', (130, 145))	('LUAD', 'Phenotype', 'HP:0030078', (64, 68))	('NSCLC', 'Phenotype', 'HP:0030358', (57, 62))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (73, 101))	('HOXA3', 'Gene', (30, 35))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (78, 101))	('lung squamous cell carcinoma', 'Disease', (73, 101))	('0.0906+-0.0846', 'Var', (150, 164))	('NSCLC', 'Disease', (57, 62))	('HOXA3', 'Gene', '3200', (30, 35))	('0.1130+-0.1398', 'Var', (114, 128))	('NSCLC', 'Disease', 'MESH:D002289', (57, 62))
442500	30066858	Patients with NSCLC with a low HOXA3 expression exhibited a better OS [HR (high), 1.3; P=0.0035] (Fig.	('HOXA3', 'Gene', (31, 36))	('NSCLC', 'Disease', (14, 19))	('NSCLC', 'Disease', 'MESH:D002289', (14, 19))	('HOXA3', 'Gene', '3200', (31, 36))	('Patients', 'Species', '9606', (0, 8))	('low', 'Var', (27, 30))	('SCLC', 'Phenotype', 'HP:0030357', (15, 19))	('NSCLC', 'Phenotype', 'HP:0030358', (14, 19))	('OS [', 'MPA', (67, 71))
442504	30066858	4A, panel b), suggesting that a high HOXA3 level may be a risk factor for the prognosis of LUAD.	('high', 'Var', (32, 36))	('HOXA3', 'Gene', (37, 42))	('HOXA3', 'Gene', '3200', (37, 42))	('LUAD', 'Disease', (91, 95))	('LUAD', 'Phenotype', 'HP:0030078', (91, 95))
442507	30066858	Furthermore, based on the microarray and RNA sequencing technologies, the sequencing results of 520 patients with LUAD revealed that the genetic alteration rates of HOXA3 were 5% (24/520) and 11% (59/520).	('genetic alteration', 'Var', (137, 155))	('patients', 'Species', '9606', (100, 108))	('LUAD', 'Phenotype', 'HP:0030078', (114, 118))	('HOXA3', 'Gene', (165, 170))	('HOXA3', 'Gene', '3200', (165, 170))
442508	30066858	In addition, the sequencing results of 504 patients LUSC suggested that the genetic alteration rates of HOXA3 were 5% (25/504), 7% (35/504) and 4% (18/504).	('LUSC', 'Phenotype', 'HP:0030359', (52, 56))	('HOXA3', 'Gene', (104, 109))	('patients', 'Species', '9606', (43, 51))	('HOXA3', 'Gene', '3200', (104, 109))	('genetic alteration', 'Var', (76, 94))
442551	30066858	The investigation of the association between HOXA3 and tumour progression has demonstrated that a high HOXA3 expression is associated with low survival rates in colon cancer.	('tumour', 'Disease', (55, 61))	('HOXA3', 'Gene', (103, 108))	('HOXA3', 'Gene', (45, 50))	('low', 'NegReg', (139, 142))	('expression', 'MPA', (109, 119))	('HOXA3', 'Gene', '3200', (103, 108))	('HOXA3', 'Gene', '3200', (45, 50))	('high', 'Var', (98, 102))	('colon cancer', 'Disease', 'MESH:D015179', (161, 173))	('colon cancer', 'Phenotype', 'HP:0003003', (161, 173))	('tumour', 'Phenotype', 'HP:0002664', (55, 61))	('tumour', 'Disease', 'MESH:D009369', (55, 61))	('survival', 'MPA', (143, 151))	('colon cancer', 'Disease', (161, 173))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))
442555	30066858	The survival analyses demonstrated that patients LUAD with a low HOXA3 expression had a better OS.	('LUAD', 'Phenotype', 'HP:0030078', (49, 53))	('HOXA3', 'Gene', '3200', (65, 70))	('patients', 'Species', '9606', (40, 48))	('low', 'Var', (61, 64))	('HOXA3', 'Gene', (65, 70))
442621	28574843	This 'Immunoscore' is based on the quantification of CD3+ and CD8+ TILs in the tumor core (CT) and the invasive margin (IM) and has proven to be a strong prognostic tool in colorectal cancer.	('colorectal cancer', 'Disease', (173, 190))	('tumor', 'Disease', (79, 84))	('colorectal cancer', 'Disease', 'MESH:D015179', (173, 190))	('CD3+', 'Var', (53, 57))	('CD8', 'Gene', (62, 65))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('CD8', 'Gene', '925', (62, 65))	('colorectal cancer', 'Phenotype', 'HP:0003003', (173, 190))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
442623	28574843	Furthermore, high MHC class I expression on tumor cells is associated with improved disease-free survival (DFS) in patients with HPV negative tonsillar squamous cell carcinoma compared to low MHC class I expression.	('improved', 'PosReg', (75, 83))	('patients', 'Species', '9606', (115, 123))	('high', 'Var', (13, 17))	('carcinoma', 'Phenotype', 'HP:0030731', (166, 175))	('tonsillar squamous cell carcinoma', 'Disease', 'MESH:D002294', (142, 175))	('tonsillar squamous cell carcinoma', 'Disease', (142, 175))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (152, 175))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('high MHC', 'Phenotype', 'HP:0025548', (13, 21))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('disease-free', 'Disease', (84, 96))	('HPV', 'Species', '10566', (129, 132))	('tumor', 'Disease', (44, 49))	('MHC class I', 'Gene', (18, 29))
442634	28574843	However, the percentage of CD4+ T cells was significantly decreased in tumor samples (54.7 +- 19.6%) and mucosa (45.3 +- 28.6%) compared to PBMC HNSCC (66.6 +- 15.9%; p < 0.05; Figure 1B, middle plot).	('HNSCC', 'Phenotype', 'HP:0012288', (145, 150))	('CD4+', 'Var', (27, 31))	('decreased', 'NegReg', (58, 67))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Disease', (71, 76))
442663	28574843	The probability for high MHC I expression in tumor cells was significantly increased in the 'Immunoscore high' compared to the 'Immunoscore low' group (p < 0.05; Figure 2G).	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumor', 'Disease', (45, 50))	("'Immunoscore high'", 'Var', (92, 110))	('expression', 'MPA', (31, 41))	('increased', 'PosReg', (75, 84))	('high MHC', 'Phenotype', 'HP:0025548', (20, 28))	('MHC I', 'Gene', (25, 30))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
442673	28574843	Non-cancerous mucosa (14.2 +- 15.1%) and tumor tissue (21.9 +- 12.4%) showed similar percentages of CD4+ T cells in the PD-L1+ fraction.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Disease', (41, 46))	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('CD4+', 'Var', (100, 104))	('Non-cancerous mucosa', 'Disease', (0, 20))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('Non-cancerous mucosa', 'Disease', 'MESH:D009369', (0, 20))
442679	28574843	The proportion of CD4+ cells among CTLA-4+ T cells in non-cancerous mucosa was decreased compared to PBMC HNSCC (51.0 +- 18.8% vs. 69.3 +- 14.6%; p < 0.05), but not compared to tumor tissue.	('HNSCC', 'Phenotype', 'HP:0012288', (106, 111))	('non-cancerous mucosa', 'Disease', (54, 74))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('decreased', 'NegReg', (79, 88))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('CD4+', 'Var', (18, 22))	('non-cancerous mucosa', 'Disease', 'MESH:D009369', (54, 74))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('CTLA-4+', 'Gene', (35, 42))	('tumor', 'Disease', (177, 182))
442716	28574843	In a recent study evaluating PD-L1 expression by immunohistochemistry in oral squamous cell carcinoma, high PD-L1 levels were associated with metastasis and poor prognosis.	('associated with', 'Reg', (126, 141))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('metastasis', 'CPA', (142, 152))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (73, 101))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (78, 101))	('high', 'Var', (103, 107))	('PD-L1 levels', 'MPA', (108, 120))	('oral squamous cell carcinoma', 'Disease', (73, 101))
442775	28574843	Using the median CD3+ or CD8+ cell density of all analyzed samples as cut-off value, samples were classified as CD3high or CD3low and CD8high or CD8low, respectively.	('CD8', 'Gene', (25, 28))	('CD8', 'Gene', (134, 137))	('CD8', 'Gene', '925', (134, 137))	('CD3low', 'Var', (123, 129))	('CD8', 'Gene', (145, 148))	('CD8', 'Gene', '925', (25, 28))	('CD8', 'Gene', '925', (145, 148))	('CD3high', 'Var', (112, 119))
442803	26943418	The clinical diagnosis was esophageal cancer (T3N0M1 stage IV according to the 7th edition of the Union for International Cancer Control classification) and synchronous right breast cancer (T1cN0M0 stage I).	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('Cancer', 'Disease', (122, 128))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('synchronous right breast cancer', 'Disease', (157, 188))	('esophageal cancer', 'Disease', (27, 44))	('breast cancer', 'Phenotype', 'HP:0003002', (175, 188))	('Cancer', 'Disease', 'MESH:D009369', (122, 128))	('Cancer', 'Phenotype', 'HP:0002664', (122, 128))	('esophageal cancer', 'Disease', 'MESH:D004938', (27, 44))	('T1cN0M0', 'Var', (190, 197))	('synchronous right breast cancer', 'Disease', 'MESH:D001943', (157, 188))
442924	32128433	Molecular markers have been reported to have an important role in detecting occult neoplastic cells in resection margins after head and neck excision47 Genomic, transcriptomic, and protein alterations in laryngeal cancer progression are key areas when aiming at investigation of possible targets for classification and prognostication purposes.48 PCR and cloning can identify a single malignant cell among 10 000 normal cells when the primary tumor contains a p53 mutation.	('p53', 'Gene', '7157', (460, 463))	('tumor', 'Disease', (443, 448))	('laryngeal cancer', 'Disease', 'MESH:D007822', (204, 220))	('mutation', 'Var', (464, 472))	('laryngeal cancer', 'Disease', (204, 220))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('laryngeal cancer', 'Phenotype', 'HP:0012118', (204, 220))	('tumor', 'Disease', 'MESH:D009369', (443, 448))	('p53', 'Gene', (460, 463))	('tumor', 'Phenotype', 'HP:0002664', (443, 448))
442926	32128433	They also noted that there was a "lack of response to primary radiation therapy in patients whose tumors harbor a p53 mutation" and suggested that alternative and more aggressive therapy might be more appropriate in this instance.	('tumors', 'Disease', (98, 104))	('lack', 'NegReg', (34, 38))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('p53', 'Gene', (114, 117))	('p53', 'Gene', '7157', (114, 117))	('tumors', 'Disease', 'MESH:D009369', (98, 104))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('mutation', 'Var', (118, 126))	('patients', 'Species', '9606', (83, 91))
442937	32128433	In addition, tumors that overexpressed cyclin D1 were more likely to have mutated p53.	('tumors', 'Disease', (13, 19))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('overexpressed', 'PosReg', (25, 38))	('cyclin D1', 'Gene', '595', (39, 48))	('cyclin D1', 'Gene', (39, 48))	('mutated', 'Var', (74, 81))	('p53', 'Gene', (82, 85))	('p53', 'Gene', '7157', (82, 85))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
442938	32128433	The incidence of p16INK4a/HPV positivity in LSCC is generally low and the average of reported observations in the four meta-analyses vary between 16% and 28%.59, 60, 61, 62 Furthermore, there is a large geographical variation.	('LSCC', 'Disease', (44, 48))	('positivity', 'Var', (30, 40))	('low', 'NegReg', (62, 65))	('p16INK4a', 'Gene', (17, 25))	('LSCC', 'Disease', 'MESH:D002294', (44, 48))	('p16INK4a', 'Gene', '1029', (17, 25))
442976	26318634	In order to generate comprehensive molecular profiles for each tumor type, different technologies were employed by TCGA, such as whole genome and exon sequencing, SNP genotyping, copy number variation profiling using microarrays (i.e.	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('tumor', 'Disease', (63, 68))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('copy number variation', 'Var', (179, 200))
442993	26318634	The increased focus on driver mutations in tumorigenesis provided critical insight for personalized therapeutics in the treatment of NSCLCs.	('NSCLC', 'Phenotype', 'HP:0030358', (133, 138))	('NSCLC', 'Disease', 'MESH:D002289', (133, 138))	('men', 'Species', '9606', (125, 128))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('mutations', 'Var', (30, 39))	('NSCLC', 'Disease', (133, 138))	('tumor', 'Disease', (43, 48))	('SCLC', 'Phenotype', 'HP:0030357', (134, 138))
442994	26318634	Research into the mutations of the epidermal growth factor receptor (EGFR) and the translocation of anaplastic lymphoma kinase (ALK) have been fertile ground for the treatment of NSCLCs.	('EGFR', 'Gene', '1956', (69, 73))	('NSCLC', 'Disease', 'MESH:D002289', (179, 184))	('ALK', 'Gene', '238', (128, 131))	('lymphoma', 'Phenotype', 'HP:0002665', (111, 119))	('epidermal growth factor receptor', 'Gene', (35, 67))	('EGFR', 'Gene', (69, 73))	('anaplastic lymphoma kinase', 'Gene', '238', (100, 126))	('SCLC', 'Phenotype', 'HP:0030357', (180, 184))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (100, 119))	('NSCLC', 'Phenotype', 'HP:0030358', (179, 184))	('epidermal growth factor receptor', 'Gene', '1956', (35, 67))	('ALK', 'Gene', (128, 131))	('men', 'Species', '9606', (171, 174))	('anaplastic lymphoma kinase', 'Gene', (100, 126))	('NSCLC', 'Disease', (179, 184))	('mutations', 'Var', (18, 27))
442995	26318634	Targeted therapies for the active oncogenic EGFR mutation have significantly improved treatment outcomes, especially for LUAD since this NSCLC type is the most likely to contain EGFR aberrations.	('EGFR', 'Gene', '1956', (178, 182))	('NSCLC', 'Disease', (137, 142))	('LUAD', 'Phenotype', 'HP:0030078', (121, 125))	('NSCLC', 'Disease', 'MESH:D002289', (137, 142))	('EGFR', 'Gene', (178, 182))	('LUAD', 'Disease', (121, 125))	('SCLC', 'Phenotype', 'HP:0030357', (138, 142))	('mutation', 'Var', (49, 57))	('men', 'Species', '9606', (91, 94))	('NSCLC', 'Phenotype', 'HP:0030358', (137, 142))	('EGFR', 'Gene', '1956', (44, 48))	('EGFR', 'Gene', (44, 48))	('treatment outcomes', 'MPA', (86, 104))	('improved', 'PosReg', (77, 85))
442996	26318634	Despite the effective use of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) drugs such as gefitinib to treat EGFR-mutated cancers, drug resistance from mutations such as the threonine-790 to methionine (T790M) point mutation are major obstacles in the treatment of NSCLCs.	('cancers', 'Disease', (145, 152))	('NSCLC', 'Phenotype', 'HP:0030358', (288, 293))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('T790M', 'Mutation', 'rs121434569', (226, 231))	('T790M) point mutation', 'Var', (226, 247))	('men', 'Species', '9606', (280, 283))	('drug resistance', 'Phenotype', 'HP:0020174', (154, 169))	('EGFR', 'Gene', '1956', (132, 136))	('SCLC', 'Phenotype', 'HP:0030357', (289, 293))	('cancers', 'Disease', 'MESH:D009369', (145, 152))	('epidermal growth factor receptor', 'Gene', (29, 61))	('epidermal growth factor receptor', 'Gene', '1956', (29, 61))	('EGFR', 'Gene', (89, 93))	('threonine-790 to methionine', 'Mutation', 'rs121434569', (197, 224))	('NSCLC', 'Disease', 'MESH:D002289', (288, 293))	('EGFR', 'Gene', (132, 136))	('cancers', 'Phenotype', 'HP:0002664', (145, 152))	('EGFR', 'Gene', '1956', (89, 93))	('gefitinib', 'Chemical', 'MESH:D000077156', (113, 122))	('NSCLC', 'Disease', (288, 293))
443006	26318634	Mutations in TP53 were the most common abnormality, occurring in 81% of samples, but this figure could have been as high as 90% if it were not for suboptimal coverage or poor sample purity.	('TP53', 'Gene', '7157', (13, 17))	('TP53', 'Gene', (13, 17))	('Mutations', 'Var', (0, 9))
443007	26318634	A surprise find was that alterations in NOTCH1, NOTCH2, and ASCL4 were mutually exclusive with TP63 and/or SOX2 alterations.	('alterations', 'Var', (25, 36))	('ASCL4', 'Gene', '121549', (60, 65))	('NOTCH2', 'Gene', (48, 54))	('SOX2', 'Gene', (107, 111))	('SOX2', 'Gene', '6657', (107, 111))	('NOTCH1', 'Gene', '4851', (40, 46))	('NOTCH1', 'Gene', (40, 46))	('TP63', 'Gene', '8626', (95, 99))	('ASCL4', 'Gene', (60, 65))	('NOTCH2', 'Gene', '4853', (48, 54))	('TP63', 'Gene', (95, 99))
443008	26318634	Given that 7% of the LUSC cases possessed amplifications of EGFR, the TCGA study suggested that some forms of LUSC may respond to EGFR-TKIs such as erlotinib and gefitinib.	('LUSC', 'Phenotype', 'HP:0030359', (110, 114))	('EGFR', 'Gene', (60, 64))	('gefitinib', 'Chemical', 'MESH:D000077156', (162, 171))	('amplifications', 'Var', (42, 56))	('EGFR', 'Gene', '1956', (60, 64))	('EGFR', 'Gene', '1956', (130, 134))	('LUSC', 'Phenotype', 'HP:0030359', (21, 25))	('EGFR', 'Gene', (130, 134))	('respond', 'Reg', (119, 126))	('erlotinib', 'Chemical', 'MESH:D000069347', (148, 157))
443009	26318634	Ten tumors had somatic MET DNA alterations with MET exon 14 skipping in RNA.	('MET exon 14 skipping', 'Var', (48, 68))	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('tumors', 'Disease', (4, 10))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('MET DNA', 'Var', (23, 30))
443012	26318634	For important pathways, TCGA found that 76% (175/230) of LUAD tumors contained known activating mutations in driver oncogenes that precipitated the RTK/RAS/RAF pathway.	('activating', 'PosReg', (85, 95))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('LUAD tumors', 'Disease', 'MESH:D009369', (57, 68))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('LUAD tumors', 'Disease', (57, 68))	('RAF', 'Gene', '22882', (156, 159))	('RAF', 'Gene', (156, 159))	('LUAD', 'Phenotype', 'HP:0030078', (57, 61))	('mutations', 'Var', (96, 105))
443013	26318634	The low transversion cohort was associated with mutations in EGFR, as well as PIK3CA and RB1.	('RB1', 'Gene', '5925', (89, 92))	('PIK3CA', 'Gene', (78, 84))	('PIK3CA', 'Gene', '5290', (78, 84))	('RB1', 'Gene', (89, 92))	('EGFR', 'Gene', '1956', (61, 65))	('mutations', 'Var', (48, 57))	('EGFR', 'Gene', (61, 65))
443019	26318634	Mutation in KRAS is not an independent mutation that singularly drives carcinogenesis, but is often associated with mutations in the CDKN2AB locus as well.	('CDKN2AB', 'Gene', (133, 140))	('carcinogenesis', 'Disease', (71, 85))	('Mutation', 'Var', (0, 8))	('associated', 'Reg', (100, 110))	('KRAS', 'Gene', (12, 16))	('mutations', 'Var', (116, 125))	('carcinogenesis', 'Disease', 'MESH:D063646', (71, 85))
443022	26318634	With the use of two genetically-engineered mouse models that contain KRAS mutations of the respiratory epithelium and human lung cancer cell lines, the featured study found that mutant KRAS mice conditionally deficient in the entire CDKN2AB locus experienced higher lung cancer mediated mortality.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('mutant', 'Var', (178, 184))	('higher', 'PosReg', (259, 265))	('lung cancer', 'Disease', 'MESH:D008175', (124, 135))	('CDKN2AB', 'Gene', (233, 240))	('cancer', 'Phenotype', 'HP:0002664', (271, 277))	('deficient', 'NegReg', (209, 218))	('human', 'Species', '9606', (118, 123))	('lung cancer', 'Disease', 'MESH:D008175', (266, 277))	('lung cancer', 'Disease', (124, 135))	('mice', 'Species', '10090', (190, 194))	('lung cancer', 'Phenotype', 'HP:0100526', (124, 135))	('mouse', 'Species', '10090', (43, 48))	('lung cancer', 'Disease', (266, 277))	('lung cancer', 'Phenotype', 'HP:0100526', (266, 277))
443023	26318634	Deficiency of the entire CDKN2AB gene promoted the development of high-grade tumors as KRAS mutant mouse displayed an increased number of tumors and increased tumor burden.	('tumor', 'Disease', (138, 143))	('increased', 'PosReg', (149, 158))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('increased', 'PosReg', (118, 127))	('tumors', 'Disease', 'MESH:D009369', (138, 144))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('Deficiency', 'Var', (0, 10))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('promoted', 'PosReg', (38, 46))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('tumors', 'Disease', (77, 83))	('CDKN2AB', 'Gene', (25, 32))	('tumor', 'Disease', (159, 164))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('tumors', 'Disease', 'MESH:D009369', (77, 83))	('mouse', 'Species', '10090', (99, 104))	('tumors', 'Disease', (138, 144))	('development', 'CPA', (51, 62))	('tumor', 'Disease', (77, 82))	('men', 'Species', '9606', (58, 61))
443026	26318634	Patients with CDKN2A inactivation experienced poorer overall survival (OS) than the average patient with KRAS- mutated LUAD.	('inactivation', 'Var', (21, 33))	('patient', 'Species', '9606', (92, 99))	('overall survival', 'MPA', (53, 69))	('Patients', 'Species', '9606', (0, 8))	('OS', 'Chemical', '-', (71, 73))	('LUAD', 'Phenotype', 'HP:0030078', (119, 123))	('poorer', 'NegReg', (46, 52))	('CDKN2A', 'Gene', (14, 20))
443027	26318634	While patients with the additional deficiency of CDKN2B tended to have even poorer OS, the results were not statistically significant.	('CDKN2B', 'Gene', '1030', (49, 55))	('OS', 'Chemical', '-', (83, 85))	('deficiency', 'Var', (35, 45))	('patients', 'Species', '9606', (6, 14))	('CDKN2B', 'Gene', (49, 55))
443032	26318634	Using methylated CpG island amplification microarray (MCAM) analysis for a set of 41 LUAD samples received from various hospitals in Japan, the study identified six markers for CIMP in LUAD: CCNA1, ACAN, GFRA1, EDARADD, MGC45800 and p16 (CDKN2A).	('ACAN', 'Gene', (198, 202))	('LUAD', 'Phenotype', 'HP:0030078', (185, 189))	('EDARADD', 'Gene', (211, 218))	('EDARADD', 'Gene', '128178', (211, 218))	('p16', 'Gene', (233, 236))	('ACAN', 'Gene', '176', (198, 202))	('CIMP', 'Chemical', '-', (177, 181))	('MGC45800', 'Var', (220, 228))	('CCNA1', 'Gene', (191, 196))	('GFRA1', 'Gene', (204, 209))	('p16', 'Gene', '1029', (233, 236))	('LUAD', 'Phenotype', 'HP:0030078', (85, 89))	('CCNA1', 'Gene', '8900', (191, 196))	('GFRA1', 'Gene', '2674', (204, 209))
443033	26318634	The study evaluated three markers- ACAN, CCNA1 and GFRA1- on the 85 TCGA samples and found that no single sample was methylated in all three CIMP markers, 4 (4.7%) were methylated in two CIMP markers, 14 (16.5%) were methylated for one CIMP marker, and 67 (78.8%) demonstrated no methylation for any of the three markers.	('CIMP', 'Chemical', '-', (141, 145))	('ACAN', 'Gene', '176', (35, 39))	('CIMP', 'Chemical', '-', (187, 191))	('CCNA1', 'Gene', (41, 46))	('GFRA1', 'Gene', '2674', (51, 56))	('GFRA1', 'Gene', (51, 56))	('CIMP', 'Chemical', '-', (236, 240))	('CCNA1', 'Gene', '8900', (41, 46))	('ACAN', 'Gene', (35, 39))	('methylated', 'Var', (169, 179))
443038	26318634	CIMP-H was found to be a poor prognostic factor regardless of the presence of the EGFR mutation.	('EGFR', 'Gene', (82, 86))	('EGFR', 'Gene', '1956', (82, 86))	('mutation', 'Var', (87, 95))	('CIMP-H', 'Chemical', '-', (0, 6))
443046	26318634	These two genes were observed to be altered in 46.4% of 179 TCGA LUSC samples, and the findings of the study may possess future promise in improving the diagnostic efficiency for LUSCs as SOX2 alterations are common for LUSC.	('LUSC', 'Phenotype', 'HP:0030359', (65, 69))	('alterations', 'Var', (193, 204))	('SOX2', 'Gene', (188, 192))	('LUSCs', 'Disease', (179, 184))	('SOX2', 'Gene', '6657', (188, 192))	('LUSC', 'Phenotype', 'HP:0030359', (179, 183))	('LUSC', 'Phenotype', 'HP:0030359', (220, 224))
443050	26318634	The SOX2 gene has been implicated to be vital for the maintenance of cancer stem cells, and the gene PRKC1 is a known oncogene found to be overexpressed in LUSC cells due to the amplification of 3q26 in some LUSCs.	('SOX2', 'Gene', (4, 8))	('PRKC1', 'Gene', (101, 106))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('LUSC', 'Phenotype', 'HP:0030359', (156, 160))	('LUSC', 'Phenotype', 'HP:0030359', (208, 212))	('overexpressed', 'PosReg', (139, 152))	('amplification', 'Var', (178, 191))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('SOX2', 'Gene', '6657', (4, 8))	('cancer', 'Disease', (69, 75))
443051	26318634	The featured study first isolated stem-like cells from five human lung cancer cell lines that contain 3q26 copy number gains (H1299, H1703, ChagoK1, H520 and H1869).	('H1703', 'Var', (133, 138))	('3q26', 'Gene', (102, 106))	('H520', 'Var', (149, 153))	('lung cancer', 'Disease', (66, 77))	('H1299', 'Var', (126, 131))	('lung cancer', 'Phenotype', 'HP:0100526', (66, 77))	('H1869', 'Var', (158, 163))	('H1299', 'CellLine', 'CVCL:0060', (126, 131))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('H1703', 'CellLine', 'CVCL:1490', (133, 138))	('lung cancer', 'Disease', 'MESH:D008175', (66, 77))	('human', 'Species', '9606', (60, 65))
443062	26318634	To demonstrate that SOX2 and PRKCI regulated HHAT and GLI1, the study used tumor cell lines from LUSC patients and performed either RNAi for the two genes or HHAT knock-down (KD).	('SOX2', 'Gene', '6657', (20, 24))	('patients', 'Species', '9606', (102, 110))	('LUSC', 'Phenotype', 'HP:0030359', (97, 101))	('HHAT', 'Gene', (158, 162))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('knock-down', 'Var', (163, 173))	('tumor', 'Disease', (75, 80))	('SOX2', 'Gene', (20, 24))
443100	26318634	miR-31 was found to be upregulated in the N1+ cohort through a comparison of the qPCR miR expression of the N1+ and N0 groups, which was consistent with other previous studies that observed miR-31 up-regulation in metastatic colon cancer.	('miR-31', 'Gene', '407035', (190, 196))	('upregulated', 'PosReg', (23, 34))	('miR-31', 'Gene', (0, 6))	('colon cancer', 'Disease', (225, 237))	('miR', 'Gene', '220972', (86, 89))	('miR', 'Gene', '220972', (0, 3))	('miR', 'Gene', (86, 89))	('miR', 'Gene', (0, 3))	('miR-31', 'Gene', '407035', (0, 6))	('miR-31', 'Gene', (190, 196))	('up-regulation', 'PosReg', (197, 210))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('colon cancer', 'Phenotype', 'HP:0003003', (225, 237))	('N1+', 'Var', (42, 45))	('miR', 'Gene', '220972', (190, 193))	('miR', 'Gene', (190, 193))	('colon cancer', 'Disease', 'MESH:D015179', (225, 237))
443105	26318634	To gain a functional understanding of miR-31 expression, three LUAD cell lines (H23, H2228, and H1573) were tested in vitro for migration, invasion, and proliferation with the modulation of miR-31 expression level.	('invasion', 'CPA', (139, 147))	('miR-31', 'Gene', (38, 44))	('modulation', 'Var', (176, 186))	('miR-31', 'Gene', '407035', (190, 196))	('LUAD', 'Phenotype', 'HP:0030078', (63, 67))	('H23', 'CellLine', 'CVCL:1547', (80, 83))	('migration', 'CPA', (128, 137))	('miR-31', 'Gene', '407035', (38, 44))	('H2228', 'CellLine', 'CVCL:1543', (85, 90))	('proliferation', 'CPA', (153, 166))	('miR-31', 'Gene', (190, 196))
443113	26318634	Another study evaluated a wide range of novel cancer drivers for LUSC and found that patients with high expression of the ARHGDIB gene had good prognoses while patients with high expression of the HOXD3 gene had poor prognoses.	('LUSC', 'Phenotype', 'HP:0030359', (65, 69))	('ARHGDIB', 'Gene', (122, 129))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('high expression', 'Var', (99, 114))	('patients', 'Species', '9606', (160, 168))	('cancer', 'Disease', (46, 52))	('ARHGDIB', 'Gene', '397', (122, 129))	('patients', 'Species', '9606', (85, 93))	('HOXD3', 'Gene', '3232', (197, 202))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('HOXD3', 'Gene', (197, 202))
443116	26318634	Previous research has demonstrated that STAT3 is an integration point of common cancer drivers such as the EGFR mutation, making the STAT3 pathway a promising therapeutic target for cancer treatment.	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('EGFR', 'Gene', '1956', (107, 111))	('mutation', 'Var', (112, 120))	('STAT3', 'Gene', '6774', (133, 138))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('STAT3', 'Gene', '6774', (40, 45))	('EGFR', 'Gene', (107, 111))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('men', 'Species', '9606', (194, 197))	('STAT3', 'Gene', (133, 138))	('cancer', 'Disease', (182, 188))	('STAT3', 'Gene', (40, 45))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('cancer', 'Disease', (80, 86))
443121	26318634	To explore the potential clinical impact of low PIAS3 expression for LUSC, TCGA mRNA transcripts and patient survival data for 133 individuals were correlated.	('LUSC', 'Phenotype', 'HP:0030359', (69, 73))	('low', 'Var', (44, 47))	('PIAS3', 'Gene', (48, 53))	('patient', 'Species', '9606', (101, 108))	('PIAS3', 'Gene', '10401', (48, 53))
443122	26318634	The cohort of patients with the highest level of PIAS3 expression (<75%) demonstrated the highest OS of any group while the cohort with the lowest level of expression (<25%) demonstrated the lowest OS.	('OS', 'Chemical', '-', (98, 100))	('<75%', 'Var', (67, 71))	('PIAS3', 'Gene', (49, 54))	('OS', 'Chemical', '-', (198, 200))	('patients', 'Species', '9606', (14, 22))	('PIAS3', 'Gene', '10401', (49, 54))
443163	26318634	It was also noted that nearly twice as many TTP-low LUAD patients had Stage 3 or Stage 4 tumors (27% combined) than TTP-high patients (14% combined).	('TTP-low LUAD', 'Var', (44, 56))	('tumors', 'Disease', (89, 95))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('patients', 'Species', '9606', (57, 65))	('LUAD', 'Phenotype', 'HP:0030078', (52, 56))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('Stage 3', 'CPA', (70, 77))	('patients', 'Species', '9606', (125, 133))
443165	26318634	Although CREB expression was not significantly altered between the TTP-high and TTP-low cohorts, Activating Transcription Factor 3 (ATF3) was significantly reduced in TTP-low LUAD.	('CREB', 'Gene', '1385', (9, 13))	('ATF3', 'Gene', (132, 136))	('TTP-low', 'Var', (167, 174))	('Transcription Factor 3', 'Gene', '6929', (108, 130))	('reduced', 'NegReg', (156, 163))	('Transcription Factor 3', 'Gene', (108, 130))	('CREB', 'Gene', (9, 13))	('ATF3', 'Gene', '467', (132, 136))	('LUAD', 'Phenotype', 'HP:0030078', (175, 179))
443173	26318634	The goal of personalized medicine requires not only an understanding of the molecular subtypes of different cancers, but also an extensive knowledge of how genetic variations affect drug response and toxicity for individuals.	('cancers', 'Phenotype', 'HP:0002664', (108, 115))	('genetic variations', 'Var', (156, 174))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('drug response', 'CPA', (182, 195))	('affect', 'Reg', (175, 181))	('cancers', 'Disease', 'MESH:D009369', (108, 115))	('toxicity', 'Disease', 'MESH:D064420', (200, 208))	('toxicity', 'Disease', (200, 208))	('cancers', 'Disease', (108, 115))
443177	26318634	With these values, LUSC demonstrated the highest number of gene losses, additions, and amplifications among the four cancers studied.	('gene', 'Var', (59, 63))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('amplifications', 'Var', (87, 101))	('additions', 'Var', (72, 81))	('LUSC', 'Phenotype', 'HP:0030359', (19, 23))	('cancers', 'Phenotype', 'HP:0002664', (117, 124))	('cancers', 'Disease', 'MESH:D009369', (117, 124))	('cancers', 'Disease', (117, 124))
443179	26318634	The FHIT gene ranked the highest in frequency for gene loss (27.49%) and CDKN2A ranked highest in frequency for gene deletion in LUSC (12.13%).	('FHIT', 'Gene', (4, 8))	('LUSC', 'Phenotype', 'HP:0030359', (129, 133))	('FHIT', 'Gene', '2272', (4, 8))	('gene deletion', 'Var', (112, 125))	('CDKN2A', 'Gene', (73, 79))
443181	26318634	CNVs in drug transporters such as SLC19A1 and SLC28A1 were also found in all four of the cancers.	('SLC28A1', 'Gene', '9154', (46, 53))	('SLC19A1', 'Gene', '6573', (34, 41))	('cancers', 'Phenotype', 'HP:0002664', (89, 96))	('SLC19A1', 'Gene', (34, 41))	('drug transporters', 'MPA', (8, 25))	('cancers', 'Disease', 'MESH:D009369', (89, 96))	('cancers', 'Disease', (89, 96))	('found', 'Reg', (64, 69))	('CNVs', 'Var', (0, 4))	('SLC28A1', 'Gene', (46, 53))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
443182	26318634	The CNVs for these pharmacogenes may potentially affect patients' drug sensitivity, resistance and toxicity as well as act as a barrier to effective treatment for LUSC.	('patients', 'Species', '9606', (56, 64))	('resistance', 'MPA', (84, 94))	('affect', 'Reg', (49, 55))	('drug sensitivity', 'MPA', (66, 82))	('toxicity', 'Disease', 'MESH:D064420', (99, 107))	('toxicity', 'Disease', (99, 107))	('LUSC', 'Disease', (163, 167))	('LUSC', 'Phenotype', 'HP:0030359', (163, 167))	('men', 'Species', '9606', (154, 157))	('drug sensitivity', 'Phenotype', 'HP:0020174', (66, 82))	('CNVs', 'Var', (4, 8))
443202	26318634	While many mutation calling algorithms have focused on comparing the DNA from normal tissue to tumor tissue of the same individual, the introduction of vast amounts of RNA-seq data from TCGA has created a new avenue to detect mutations and to characterize the cancer genome.	('cancer', 'Disease', 'MESH:D009369', (260, 266))	('TCGA', 'Gene', (186, 190))	('cancer', 'Disease', (260, 266))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('mutations', 'Var', (226, 235))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('cancer', 'Phenotype', 'HP:0002664', (260, 266))	('tumor', 'Disease', (95, 100))
443205	26318634	RADIA detected two non-synonymous TP53 mutations that were below the detection threshold of other mutation calling algorithms used by TCGA.	('TP53', 'Gene', '7157', (34, 38))	('TP53', 'Gene', (34, 38))	('mutations', 'Var', (39, 48))
443206	26318634	One of these mutations (G266E) was confirmed by another lung cancer study and appears to play a role in other cancers such as prostate, pancreas, urinary tract, and hematopoietic and lymphoid cancer.	('lymphoid cancer', 'Disease', 'MESH:D009369', (183, 198))	('play', 'Reg', (89, 93))	('lung cancer', 'Disease', (56, 67))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('prostate', 'Disease', (126, 134))	('cancers', 'Phenotype', 'HP:0002664', (110, 117))	('cancers', 'Disease', (110, 117))	('lymphoid cancer', 'Phenotype', 'HP:0002665', (183, 198))	('lung cancer', 'Disease', 'MESH:D008175', (56, 67))	('lymphoid cancer', 'Disease', (183, 198))	('G266E', 'Var', (24, 29))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('lung cancer', 'Phenotype', 'HP:0100526', (56, 67))	('G266E', 'Mutation', 'rs193920774', (24, 29))	('role', 'Reg', (96, 100))	('pancreas', 'Disease', (136, 144))	('urinary tract', 'Disease', (146, 159))	('cancers', 'Disease', 'MESH:D009369', (110, 117))
443207	26318634	The other TP53 mutation (G199V) is a known anti-apoptotic gain-of-function mutation through the STAT3 pathway.	('STAT3', 'Gene', (96, 101))	('TP53', 'Gene', (10, 14))	('G199V', 'Mutation', 'rs1292996434', (25, 30))	('anti-apoptotic', 'MPA', (43, 57))	('gain-of-function', 'PosReg', (58, 74))	('STAT3', 'Gene', '6774', (96, 101))	('G199V', 'Var', (25, 30))	('TP53', 'Gene', '7157', (10, 14))
443208	26318634	The study also found a nonsense mutation (W239*) that was below the detection threshold of other mutation calling algorithms in the STK11 gene, which is a tumor suppressor gene.	('W239*', 'Var', (42, 47))	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('STK11', 'Gene', '6794', (132, 137))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('tumor', 'Disease', (155, 160))	('W239*', 'SUBSTITUTION', 'None', (42, 47))	('STK11', 'Gene', (132, 137))
443210	26318634	The discovery of an effective therapeutic target for LUSC has remained elusive with no equivalent to the discovery of TKI-sensitivity for EGFR and ALK mutations for LUAD.	('LUAD', 'Phenotype', 'HP:0030078', (165, 169))	('EGFR', 'Gene', '1956', (138, 142))	('ALK', 'Gene', (147, 150))	('EGFR', 'Gene', (138, 142))	('LUSC', 'Phenotype', 'HP:0030359', (53, 57))	('mutations', 'Var', (151, 160))	('ALK', 'Gene', '238', (147, 150))
443213	26318634	The importance of transcriptional events such as alternative splicing has increased in recent years as these events appear to contribute to tumorigenesis.	('alternative splicing', 'Var', (49, 69))	('contribute', 'Reg', (126, 136))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('tumor', 'Disease', (140, 145))
443331	26264462	According to this study, miR-210 stable expression mimics hypoxia-induced metabolic changes associated with a slight but significant stabilization of HIF-1alpha, and this information, combined with a strong reduction of radioresistance following HIF-1 silencing, reinforces the central role of HIF-1 in the resistance to radiotherapy.	('HIF-1alpha', 'Gene', '3091', (150, 160))	('reduction', 'NegReg', (207, 216))	('stabilization', 'MPA', (133, 146))	('hypoxia', 'Disease', (58, 65))	('HIF-1', 'Gene', '3091', (246, 251))	('hypoxia', 'Disease', 'MESH:D000860', (58, 65))	('radioresistance', 'CPA', (220, 235))	('silencing', 'Var', (252, 261))	('HIF-1', 'Gene', '3091', (150, 155))	('HIF-1', 'Gene', '3091', (294, 299))	('miR-210', 'Gene', (25, 32))	('miR-210', 'Gene', '406992', (25, 32))	('HIF-1', 'Gene', (246, 251))	('HIF-1alpha', 'Gene', (150, 160))	('HIF-1', 'Gene', (150, 155))	('HIF-1', 'Gene', (294, 299))
443337	26264462	Furthermore, these authors also demonstrated that esophageal tumors with high expression of miR-296-5p had a worse prognosis compared with those with low expression.	('esophageal tumors', 'Disease', (50, 67))	('esophageal tumors', 'Phenotype', 'HP:0100751', (50, 67))	('miR-296', 'Gene', '407022', (92, 99))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('high expression', 'Var', (73, 88))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('esophageal tumors', 'Disease', 'MESH:D004938', (50, 67))	('miR-296', 'Gene', (92, 99))
443346	30531839	Cell type-dependent function of LATS1/2 in cancer cell growth The Hippo pathway controls organ size and tissue homeostasis, and its dysregulation often contributes to tumorigenesis.	('LATS1/2', 'Gene', (32, 39))	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('cancer', 'Disease', (43, 49))	('contributes to', 'Reg', (152, 166))	('organ size', 'CPA', (89, 99))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('LATS1/2', 'Gene', '16798;50523', (32, 39))	('Hippo pathway', 'Pathway', (66, 79))	('controls', 'Reg', (80, 88))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('tumor', 'Disease', (167, 172))	('dysregulation', 'Var', (132, 145))
443348	30531839	As expected, loss of LATS1/2 promotes cancer cell growth in most cell lines.	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('LATS1/2', 'Gene', (21, 28))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('cancer', 'Disease', (38, 44))	('loss', 'Var', (13, 17))	('promotes', 'PosReg', (29, 37))
443349	30531839	Surprisingly, however, LATS1/2 deletion inhibits the growth of murine MC38 colon cancer cells, especially under detachment conditions.	('growth', 'MPA', (53, 59))	('LATS1/2', 'Gene', (23, 30))	('colon cancer', 'Phenotype', 'HP:0003003', (75, 87))	('colon cancer', 'Disease', 'MESH:D015179', (75, 87))	('colon cancer', 'Disease', (75, 87))	('deletion', 'Var', (31, 39))	('inhibits', 'NegReg', (40, 48))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('murine', 'Species', '10090', (63, 69))
443350	30531839	This growth inhibitory effect caused by LATS1/2 deletion is due to uncontrolled activation of Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ), the key downstream transcriptional coactivators inhibited by LATS1/2.	('LATS1/2', 'Gene', (40, 47))	('growth inhibitory effect', 'MPA', (5, 29))	('Yes-associated protein', 'Gene', (94, 116))	('Yes-associated protein', 'Gene', '22601', (94, 116))	('deletion', 'Var', (48, 56))	('activation', 'PosReg', (80, 90))
443352	30531839	Furthermore, deletion of WISP2 and CCDC80 prevents the growth inhibitory effect of LATS1/2 loss in MC38 cells.	('WISP2', 'Gene', '22403', (25, 30))	('growth inhibitory effect', 'MPA', (55, 79))	('WISP2', 'Gene', (25, 30))	('deletion', 'Var', (13, 21))	('CCDC80', 'Gene', (35, 41))	('LATS1/2', 'Gene', (83, 90))	('loss', 'NegReg', (91, 95))	('prevents', 'NegReg', (42, 50))
443356	30531839	Aberrant expression or dysregulation of the Hippo pathway has been linked to human cancers.	('cancers', 'Disease', 'MESH:D009369', (83, 90))	('Aberrant expression', 'Var', (0, 19))	('dysregulation', 'Var', (23, 36))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('Hippo pathway', 'Pathway', (44, 57))	('linked', 'Reg', (67, 73))	('cancers', 'Phenotype', 'HP:0002664', (83, 90))	('cancers', 'Disease', (83, 90))	('human', 'Species', '9606', (77, 82))
443361	30531839	Many studies in mouse models show that loss of Hippo signaling or overexpression of YAP is sufficient to promote tumor formation.	('tumor', 'Disease', (113, 118))	('promote', 'PosReg', (105, 112))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('Hippo signaling', 'Protein', (47, 62))	('loss', 'Var', (39, 43))	('YAP', 'Gene', (84, 87))	('mouse', 'Species', '10090', (16, 21))	('overexpression', 'PosReg', (66, 80))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))
443363	30531839	Loss-of function mutations of the Hippo pathway upstream component NF2 contributes to schwannoma and meningioma with high activation of YAP/TAZ.	('YAP/TAZ', 'MPA', (136, 143))	('meningioma', 'Phenotype', 'HP:0002858', (101, 111))	('schwannoma and meningioma', 'Disease', 'MESH:D009442', (86, 111))	('NF2', 'Gene', (67, 70))	('activation', 'PosReg', (122, 132))	('Loss-of function', 'NegReg', (0, 16))	('schwannoma', 'Phenotype', 'HP:0100008', (86, 96))	('NF2', 'Gene', '18016', (67, 70))	('mutations', 'Var', (17, 26))
443364	30531839	Furthermore, deletion of LATS2 is associated with malignant mesothelioma.	('malignant mesothelioma', 'Disease', 'MESH:C562839', (50, 72))	('associated', 'Reg', (34, 44))	('LATS2', 'Gene', '50523', (25, 30))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (50, 72))	('deletion', 'Var', (13, 21))	('malignant mesothelioma', 'Disease', (50, 72))	('LATS2', 'Gene', (25, 30))
443366	30531839	In this study, we examined the effect of LATS1/2 deletion in 8 mouse cancer cell lines and found that in most cell lines LATS1/2 deletion moderately or dramatically enhanced anchorage independent cell growth.	('mouse', 'Species', '10090', (63, 68))	('enhanced', 'PosReg', (165, 173))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('anchorage independent cell growth', 'CPA', (174, 207))	('deletion', 'Var', (129, 137))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('LATS1/2', 'Gene', (121, 128))	('cancer', 'Disease', (69, 75))
443367	30531839	Interestingly, MC38 colon cancer cells are addicted to LATS1/2 as cell growth inversely correlates with the degree of LATS1/2 deletion.	('colon cancer', 'Phenotype', 'HP:0003003', (20, 32))	('colon cancer', 'Disease', 'MESH:D015179', (20, 32))	('deletion', 'Var', (126, 134))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('cell growth', 'CPA', (66, 77))	('colon cancer', 'Disease', (20, 32))	('LATS1/2', 'Gene', (118, 125))
443368	30531839	Cells with complete LATS1/2 deletion display severe growth retardation and senescent phenotypes.	('growth retardation', 'Phenotype', 'HP:0001510', (52, 70))	('growth retardation', 'Disease', 'MESH:D006130', (52, 70))	('LATS1/2', 'Gene', (20, 27))	('growth retardation', 'Disease', (52, 70))	('severe growth retardation', 'Phenotype', 'HP:0008850', (45, 70))	('deletion', 'Var', (28, 36))	('senescent phenotypes', 'CPA', (75, 95))
443370	30531839	We had previously observed that deletion of LATS1/2 in mouse cancer cell lines B16, SCC7, and 4T1 enhanced immunogenicity of the cancer cells, leading to a tumor growth suppression of the LATS1/2 knockout (KO) cells in syngeneic immune competent mice.	('enhanced', 'PosReg', (98, 106))	('B16', 'CellLine', 'CVCL:N540', (79, 82))	('deletion', 'Var', (32, 40))	('LATS1/2', 'Gene', (44, 51))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('SCC7', 'Gene', (84, 88))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('cancer', 'Disease', (61, 67))	('SCC7', 'Gene', '109433', (84, 88))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('mouse', 'Species', '10090', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('tumor', 'Disease', (156, 161))	('immunogenicity', 'MPA', (107, 121))	('mice', 'Species', '10090', (246, 250))
443371	30531839	In an effort to expand this discovery, we deleted LATS1/2 in many mouse cancer cell lines, including MC38 and CT26 colon cancer cells, Panc02 pancreatic cancer cells, MB49 bladder cancer cells, GL261 glioma cancer cells, MyC-CaP prostate cancer cells, and 168FARN and 67NR breast cancer cells, using CRISPR/Cas9 technology.	('cancer', 'Disease', (153, 159))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('cancer', 'Disease', (280, 286))	('pancreatic cancer', 'Disease', (142, 159))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('GL261', 'CellLine', 'CVCL:Y003', (194, 199))	('colon cancer', 'Disease', 'MESH:D015179', (115, 127))	('cancer', 'Disease', (72, 78))	('cancer', 'Disease', (238, 244))	('glioma cancer', 'Disease', 'MESH:D005910', (200, 213))	('cancer', 'Disease', (207, 213))	('deleted', 'Var', (42, 49))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('MB49 bladder cancer', 'Disease', 'MESH:D001749', (167, 186))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('MB49 bladder cancer', 'Disease', (167, 186))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (142, 159))	('cancer', 'Disease', (180, 186))	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('breast cancer', 'Phenotype', 'HP:0003002', (273, 286))	('MyC-CaP prostate cancer', 'Disease', 'MESH:D011471', (221, 244))	('cancer', 'Disease', 'MESH:D009369', (280, 286))	('LATS1/2', 'Gene', (50, 57))	('colon cancer', 'Disease', (115, 127))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('CT26', 'CellLine', 'CVCL:7254', (110, 114))	('glioma', 'Phenotype', 'HP:0009733', (200, 206))	('prostate cancer', 'Phenotype', 'HP:0012125', (229, 244))	('breast cancer', 'Disease', 'MESH:D001943', (273, 286))	('Panc02', 'CellLine', 'CVCL:D627', (135, 141))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('glioma cancer', 'Disease', (200, 213))	('breast cancer', 'Disease', (273, 286))	('MyC-CaP prostate cancer', 'Disease', (221, 244))	('cancer', 'Disease', 'MESH:D009369', (207, 213))	('cancer', 'Disease', 'MESH:D009369', (238, 244))	('mouse', 'Species', '10090', (66, 71))	('bladder cancer', 'Phenotype', 'HP:0009725', (172, 186))	('pancreatic cancer', 'Disease', 'MESH:D010190', (142, 159))	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('colon cancer', 'Phenotype', 'HP:0003003', (115, 127))	('cancer', 'Disease', (121, 127))
443377	30531839	LATS1/2 deletion strongly increased anchorage independent growth in pancreatic cancer Panc02, prostate cancer MyC-CaP, breast cancer 168FARN and 67NR cells.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (68, 85))	('breast cancer', 'Phenotype', 'HP:0003002', (119, 132))	('prostate cancer', 'Phenotype', 'HP:0012125', (94, 109))	('anchorage independent growth', 'MPA', (36, 64))	('LATS1/2', 'Gene', (0, 7))	('increased', 'PosReg', (26, 35))	('pancreatic cancer Panc02, prostate cancer MyC-CaP, breast cancer', 'Disease', 'MESH:D009369', (68, 132))	('deletion', 'Var', (8, 16))
443378	30531839	LATS1/2 deletion also increased growth of colon cancer CT26, glioma GL261, and bladder cancer MB49 (Figs.	('glioma', 'Phenotype', 'HP:0009733', (61, 67))	('growth', 'MPA', (32, 38))	('bladder cancer MB49', 'Disease', 'MESH:D001749', (79, 98))	('bladder cancer MB49', 'Disease', (79, 98))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('bladder cancer', 'Phenotype', 'HP:0009725', (79, 93))	('GL261', 'CellLine', 'CVCL:Y003', (68, 73))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('glioma', 'Disease', (61, 67))	('CT26', 'CellLine', 'CVCL:7254', (55, 59))	('LATS1/2', 'Gene', (0, 7))	('increased', 'PosReg', (22, 31))	('colon cancer', 'Phenotype', 'HP:0003003', (42, 54))	('colon cancer', 'Disease', 'MESH:D015179', (42, 54))	('glioma', 'Disease', 'MESH:D005910', (61, 67))	('deletion', 'Var', (8, 16))	('colon cancer', 'Disease', (42, 54))
443382	30531839	Either energy starvation by 2-DG (2-deoxyglucose) or disruption of F-actin by LatB (Latrunculin B) induced YAP phosphorylation in wild type MC38 as determined by both phospho-YAP antibody and phos-tag gel (Fig.	('disruption', 'Var', (53, 63))	('2-deoxyglucose', 'Chemical', 'MESH:D003847', (34, 48))	('YAP phosphorylation', 'MPA', (107, 126))	('2-DG', 'Chemical', 'MESH:D003847', (28, 32))
443383	30531839	Partial deletion of LATS1/2 (clone #5) showed a significant reduction in YAP phosphorylation while complete LATS1/2 deletion (clone #8 and 14) abolished YAP phosphorylation upon treatment with either 2-DG or LatB (Fig.	('2-DG', 'Chemical', 'MESH:D003847', (200, 204))	('YAP phosphorylation', 'MPA', (73, 92))	('abolished', 'NegReg', (143, 152))	('deletion', 'Var', (116, 124))	('reduction', 'NegReg', (60, 69))	('LATS1/2', 'Gene', (20, 27))	('LATS1/2', 'Gene', (108, 115))
443386	30531839	Notably, Panc02 LATS1/2 KO cells showed a significantly stronger growth potential than WT cells in suspension (Fig.	('LATS1/2 KO', 'Gene', (16, 26))	('Panc02', 'Var', (9, 15))	('growth potential', 'CPA', (65, 81))	('stronger', 'PosReg', (56, 64))	('Panc02', 'CellLine', 'CVCL:D627', (9, 15))	('LATS1/2 KO', 'Gene', '16798', (16, 26))
443387	30531839	In contrast, LATS1/2 partial deletion inhibited MC38 clone #5 growth in soft agar (Fig.	('partial deletion', 'Var', (21, 37))	('inhibited', 'NegReg', (38, 47))	('growth', 'MPA', (62, 68))	('MC38', 'Gene', (48, 52))	('agar', 'Chemical', 'MESH:D000362', (77, 81))
443393	30531839	LATS1/2 deletion abolished YAP/TAZ phosphorylation in Panc02 while partial LATS1/2 deletion in MC38 clone #5 reduced YAP/TAZ phosphorylation (Figs.	('YAP/TAZ phosphorylation', 'MPA', (27, 50))	('YAP/TAZ phosphorylation', 'MPA', (117, 140))	('abolished', 'NegReg', (17, 26))	('LATS1/2', 'Gene', (75, 82))	('Panc02', 'CellLine', 'CVCL:D627', (54, 60))	('deletion', 'Var', (83, 91))	('reduced', 'NegReg', (109, 116))	('deletion', 'Var', (8, 16))
443394	30531839	Consistent with the functional importance of YAP/TAZ phosphorylation, LATS1/2 deletion also increased the expression of YAP/TAZ target genes Ctgf and Amotl2 in both MC38 and Panc02 cells (Fig.	('Ctgf', 'Gene', '14219', (141, 145))	('Panc02', 'CellLine', 'CVCL:D627', (174, 180))	('expression', 'MPA', (106, 116))	('deletion', 'Var', (78, 86))	('Amotl2', 'Gene', '56332', (150, 156))	('Ctgf', 'Gene', (141, 145))	('LATS1/2', 'Gene', (70, 77))	('increased', 'PosReg', (92, 101))	('Amotl2', 'Gene', (150, 156))
443397	30531839	We found that LATS1/2 deficient cell pools decreased colony formation in soft agar.	('agar', 'Chemical', 'MESH:D000362', (78, 82))	('deficient', 'Var', (22, 31))	('colony formation in soft agar', 'CPA', (53, 82))	('LATS1/2', 'Gene', (14, 21))	('decreased', 'NegReg', (43, 52))
443401	30531839	YAP/TAZ are the major physiological targets of LATS1/2 and activation of YAP/TAZ is generally believed to promote cell growth and tumorigenesis.	('cell growth', 'CPA', (114, 125))	('promote', 'PosReg', (106, 113))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('activation', 'Var', (59, 69))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumor', 'Disease', (130, 135))	('YAP/TAZ', 'Gene', (73, 80))
443403	30531839	Overexpression of YAP5SA, but not the inactive YAP5SA/S94A, inhibited cell growth of MC38 cells under soft agar, 2D surface, and suspension conditions (Fig.	('inhibited', 'NegReg', (60, 69))	('S94A', 'Mutation', 'rs751418145', (54, 58))	('YAP5SA', 'Var', (18, 24))	('agar', 'Chemical', 'MESH:D000362', (107, 111))	('cell growth', 'CPA', (70, 81))
443404	30531839	As expected, expressions of YAP target genes Ctgf and Amotl2 were reduced by YAP/TAZ deletion in MC38 clone #5 (Supplementary Fig.	('reduced', 'NegReg', (66, 73))	('YAP/TAZ', 'Gene', (77, 84))	('Ctgf', 'Gene', (45, 49))	('expressions', 'MPA', (13, 24))	('Amotl2', 'Gene', '56332', (54, 60))	('Amotl2', 'Gene', (54, 60))	('deletion', 'Var', (85, 93))	('Ctgf', 'Gene', '14219', (45, 49))	('MC38', 'Gene', (97, 101))
443406	30531839	However, more complete LATS1/2 deletion, as in clone #8, severely retarded cell growth even under attachment and cells showed an enlarged morphology, similar to senescent cells.	('LATS1/2', 'Gene', (23, 30))	('retarded', 'Disease', (66, 74))	('cell growth even under attachment', 'CPA', (75, 108))	('deletion', 'Var', (31, 39))	('retarded', 'Disease', 'MESH:D008607', (66, 74))
443412	30531839	LATS1/2 deficient cells grew tumors slower than the control MC38 WT group (Figs.	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('LATS1/2', 'Gene', (0, 7))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('tumors', 'Disease', 'MESH:D009369', (29, 35))	('tumors', 'Disease', (29, 35))	('slower', 'NegReg', (36, 42))	('deficient', 'Var', (8, 17))
443416	30531839	It has recently been reported that YAP hyperactivation induces reactive oxygen species (ROS) accumulation and suppresses lung squamous cell carcinoma growth .	('suppresses', 'NegReg', (110, 120))	('lung squamous cell carcinoma growth', 'Disease', (121, 156))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (121, 149))	('lung squamous cell carcinoma growth', 'Disease', 'MESH:D002294', (121, 156))	('hyperactivation', 'Var', (39, 54))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (126, 149))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (63, 86))	('ROS', 'Chemical', 'MESH:D017382', (88, 91))
443417	30531839	This led us to investigate if LATS1/2 deletion increased ROS levels in MC38 cells.	('LATS1/2', 'Gene', (30, 37))	('ROS', 'Chemical', 'MESH:D017382', (57, 60))	('increased', 'PosReg', (47, 56))	('ROS levels', 'MPA', (57, 67))	('deletion', 'Var', (38, 46))	('increased ROS levels', 'Phenotype', 'HP:0025464', (47, 67))
443422	30531839	LATS1/2 deletion specifically inhibits anchorage independent growth in MC38 cells, but not in Panc02 or other cell lines (Fig.1).	('LATS1/2', 'Gene', (0, 7))	('deletion', 'Var', (8, 16))	('Panc02', 'CellLine', 'CVCL:D627', (94, 100))	('inhibits', 'NegReg', (30, 38))	('anchorage independent growth', 'CPA', (39, 67))
443424	30531839	Actually, these three genes were repressed by LATS1/2 deletion in Panc02 cells (Fig.	('deletion', 'Var', (54, 62))	('LATS1/2', 'Gene', (46, 53))	('Panc02', 'CellLine', 'CVCL:D627', (66, 72))
443425	30531839	In contrast, other genes, such as Ctgf, Gpc3, Alcam and Spp1, were similarly altered by LATS1/2 deletion in both MC38 and Panc02 cells (Fig.	('Panc02', 'CellLine', 'CVCL:D627', (122, 128))	('Alcam', 'Gene', (46, 51))	('Ctgf', 'Gene', (34, 38))	('LATS1/2', 'Gene', (88, 95))	('Gpc3', 'Gene', '14734', (40, 44))	('altered', 'Reg', (77, 84))	('Spp1', 'Gene', (56, 60))	('Gpc3', 'Gene', (40, 44))	('Alcam', 'Gene', '11658', (46, 51))	('deletion', 'Var', (96, 104))	('Ctgf', 'Gene', '14219', (34, 38))	('Spp1', 'Gene', '20750', (56, 60))
443426	30531839	Furthermore, Wisp2 and Ccdc80 were only weakly altered by LATS1/2 deletion in CT26 and 168FARN cells whereas Scara5 was strongly increased (Fig.	('Ccdc80', 'Gene', '67896', (23, 29))	('Ccdc80', 'Gene', (23, 29))	('Scara5', 'Gene', '71145', (109, 115))	('Scara5', 'Gene', (109, 115))	('Wisp2', 'Gene', '22403', (13, 18))	('increased', 'PosReg', (129, 138))	('LATS1/2', 'Gene', (58, 65))	('Wisp2', 'Gene', (13, 18))	('altered', 'Reg', (47, 54))	('deletion', 'Var', (66, 74))	('CT26', 'CellLine', 'CVCL:7254', (78, 82))
443427	30531839	Thus, WISP2 and CCDC80 are selectively induced by LATS1/2 deletion in MC38 cells.	('LATS1/2', 'Gene', (50, 57))	('CCDC80', 'Disease', (16, 22))	('induced', 'Reg', (39, 46))	('deletion', 'Var', (58, 66))	('WISP2', 'Gene', '22403', (6, 11))	('WISP2', 'Gene', (6, 11))
443429	30531839	We found that deletion of WISP2, CCDC80 partially restored the anchorage independent growth of MC38 clone #5 (Fig.7f).	('restored', 'PosReg', (50, 58))	('anchorage independent growth', 'CPA', (63, 91))	('WISP2', 'Gene', '22403', (26, 31))	('deletion', 'Var', (14, 22))	('WISP2', 'Gene', (26, 31))	('CCDC80', 'Gene', (33, 39))
443430	30531839	Deletion of Wisp2 produced more significant effect.	('Wisp2', 'Gene', (12, 17))	('Wisp2', 'Gene', '22403', (12, 17))	('Deletion', 'Var', (0, 8))
443431	30531839	In contrast, deletion of SCARA5 had little effect (Fig.	('deletion', 'Var', (13, 21))	('SCARA5', 'Gene', (25, 31))	('SCARA5', 'Gene', '71145', (25, 31))
443432	30531839	We also found that deletion of WISP2 and CCDC80 in clone #5 partially, but significantly, rescued cell growth defects in suspension (Fig.7g and Supplementary Fig.	('WISP2', 'Gene', '22403', (31, 36))	('deletion', 'Var', (19, 27))	('WISP2', 'Gene', (31, 36))	('CCDC80', 'Gene', (41, 47))	('rescued', 'PosReg', (90, 97))	('cell growth defects', 'CPA', (98, 117))
443444	30531839	This growth inhibitory effect is specific to MC38 possibly because WISP2 and CCDC80 are selectively induced by LATS1/2 deletion in MC38 cells.	('MC38', 'Gene', (131, 135))	('CCDC80', 'Gene', (77, 83))	('deletion', 'Var', (119, 127))	('WISP2', 'Gene', '22403', (67, 72))	('induced', 'Reg', (100, 107))	('WISP2', 'Gene', (67, 72))	('LATS1/2', 'Gene', (111, 118))
443446	30531839	LATS1/2 deletion promotes cell growth (particularly anchorage independent growth) in most cancer cell lines, but inhibits MC38 colon cancer cell growth.	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('cell growth', 'CPA', (26, 37))	('promotes', 'PosReg', (17, 25))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('colon cancer', 'Disease', 'MESH:D015179', (127, 139))	('colon cancer', 'Phenotype', 'HP:0003003', (127, 139))	('LATS1/2', 'Gene', (0, 7))	('cancer', 'Disease', (133, 139))	('colon cancer', 'Disease', (127, 139))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('inhibits', 'NegReg', (113, 121))	('deletion', 'Var', (8, 16))
443447	30531839	For example, LATS1/2 deletion has a minor effect on Pan02 under 2D culture, but strongly promotes growth both in soft agar and suspension (Fig.1 and Fig.	('promotes', 'PosReg', (89, 97))	('growth', 'MPA', (98, 104))	('LATS1/2', 'Gene', (13, 20))	('deletion', 'Var', (21, 29))	('agar', 'Chemical', 'MESH:D000362', (118, 122))
443448	30531839	Partial deletion of LATS1/2 in MC38 cells (#5 clone: LATS1-/-/+;LATS2-/-/+) can maintain cell growth in the attachment condition, but their growth is severely retarded in detachment condition or soft agar.	('Partial deletion', 'Var', (0, 16))	('retarded in detachment condition', 'Disease', (159, 191))	('agar', 'Chemical', 'MESH:D000362', (200, 204))	('LATS2', 'Gene', (64, 69))	('growth', 'MPA', (140, 146))	('retarded in detachment condition', 'Disease', 'MESH:D012163', (159, 191))	('LATS1/2', 'Gene', (20, 27))	('cell growth', 'CPA', (89, 100))	('attachment condition', 'CPA', (108, 128))	('LATS2', 'Gene', '50523', (64, 69))
443449	30531839	In addition, re-expression of LATS1/2 as well as deletion of YAP/TAZ in MC38 LATS1/2 KO clone #5 showed only a partial rescue of anchorage independent cell growth.	('LATS1/2 KO', 'Gene', '16798', (77, 87))	('anchorage independent cell growth', 'CPA', (129, 162))	('LATS1/2 KO', 'Gene', (77, 87))	('YAP/TAZ', 'Gene', (61, 68))	('deletion', 'Var', (49, 57))
443454	30531839	Mechanistic investigations reveal that WISP2 and CCDC80 induction by LATS1/2 deletion in MC38 contributes to inhibition of anchorage independent growth.	('anchorage independent growth', 'CPA', (123, 151))	('MC38', 'Gene', (89, 93))	('WISP2', 'Gene', '22403', (39, 44))	('deletion', 'Var', (77, 85))	('WISP2', 'Gene', (39, 44))	('inhibition', 'NegReg', (109, 119))	('CCDC80', 'Gene', (49, 55))	('LATS1/2', 'Gene', (69, 76))
443460	30531839	In addition, CCDC80 can suppress anchorage independent growth and sensitize cells to anoikis and CD95-induced apoptosis .	('sensitize', 'Reg', (66, 75))	('CD95', 'Gene', '14102', (97, 101))	('CCDC80', 'Var', (13, 19))	('suppress', 'NegReg', (24, 32))	('CD95', 'Gene', (97, 101))	('anchorage independent growth', 'CPA', (33, 61))	('anoikis', 'CPA', (85, 92))
443481	30531839	MC38 cells stably expressing empty vector, YAP5SA or YAP5SA/S94A were generated by retroviral infection.	('YAP5SA', 'Var', (43, 49))	('S94A', 'Mutation', 'rs751418145', (60, 64))	('YAP5SA/S94A', 'Var', (53, 64))
443537	30181543	The other two independent GBM datasets (GSE4412 and GSE4271) were downloaded from the Gene Expression Omnibus database.	('GSE4412', 'Var', (40, 47))	('GSE4271', 'Var', (52, 59))	('GSE4271', 'Chemical', '-', (52, 59))	('GSE4412', 'Chemical', '-', (40, 47))
443586	30181543	The C-indices were significantly larger for RRSF than RSF at levels 6-12 on the GSE4412 (median C-index: 0.5779 vs 0.5429, Wilcoxon signed rank test, P = 6.02 x 10-15; 0.5778 vs 0.5651, P = 2.70 x 10-6; 0.5893 vs 0.5774, P = 8.59 x 10-3; and 0.5966 vs 0.5856, P = 1.74 x 10-2, respectively), and the GSE4271 (median C-index: 0.5709 vs 0.5582, Wilcoxon signed rank test, P = 4.73 x 10-4; 0.5876 vs 0.5744, P = 2.76 x 10-6; 0.6051 vs 0.5771, P = 6.17 x 10-11; and 0.6107 vs 0.5871, P = 1.08 x 10-10, respectively).	('RSF', 'Chemical', '-', (45, 48))	('0.6107', 'Var', (462, 468))	('GSE4412', 'Chemical', '-', (80, 87))	('GSE4271', 'Chemical', '-', (300, 307))	('larger', 'PosReg', (33, 39))	('0.6051', 'Var', (422, 428))	('RSF', 'Chemical', '-', (54, 57))	('C-indices', 'MPA', (4, 13))
443633	30181543	To identify biomarkers for ESCC, we also started from the 10 lncRNAs identified by RRSF at the 10-gene level, where RRSF obtained a favorable predictive performance (Fig.	('ESCC', 'Disease', (27, 31))	('RSF', 'Chemical', '-', (84, 87))	('RRSF', 'Var', (116, 120))	('RSF', 'Chemical', '-', (117, 120))
443644	30181543	After collecting the neighbors for each lncRNA, four were found to be highly connective lncRNAs (AC117500.2, AP003108.1, AC005546.1, and LINC00840, Fig.	('LINC00840', 'Gene', (137, 146))	('AP003108.1', 'Var', (109, 119))	('LINC00840', 'Gene', '100506835', (137, 146))	('AC117500.2', 'Var', (97, 107))	('AC005546.1', 'Var', (121, 131))
443656	30181543	MAMDC2-AS1, and AC146944.4 had node degrees of 3, and 5, respectively.	('MAMDC2', 'Gene', '256691', (0, 6))	('MAMDC2', 'Gene', (0, 6))	('AS1', 'Gene', '5729', (7, 10))	('AS1', 'Gene', (7, 10))	('AC146944.4', 'Var', (16, 26))
443745	28903437	The complete list of potential drugs acting in proteins regulated by the microRNAs in head and neck cancer and their function is presented in Supplementary Table 3.	('head and neck cancer', 'Phenotype', 'HP:0012288', (86, 106))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('neck cancer', 'Disease', 'MESH:D006258', (95, 106))	('neck cancer', 'Disease', (95, 106))	('microRNAs', 'Var', (73, 82))
443767	28903437	Deregulation of the miR-222-ABCG2 in tongue squamous cells carcinoma was correlated with cisplatin resistance and enhanced migratory/invasive potential.	('carcinoma', 'Disease', (59, 68))	('cisplatin resistance', 'MPA', (89, 109))	('Deregulation', 'Var', (0, 12))	('ABCG2', 'Gene', '9429', (28, 33))	('miR-222', 'Gene', '407007', (20, 27))	('enhanced', 'PosReg', (114, 122))	('carcinoma', 'Disease', 'MESH:D002277', (59, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (59, 68))	('cisplatin', 'Chemical', 'MESH:D002945', (89, 98))	('miR-222', 'Gene', (20, 27))	('squamous cells carcinoma', 'Phenotype', 'HP:0002860', (44, 68))	('migratory/invasive potential', 'CPA', (123, 151))	('ABCG2', 'Gene', (28, 33))	('tongue squamous cells carcinoma', 'Phenotype', 'HP:0030413', (37, 68))
443781	28903437	Likewise, restoration of miR-99a level by miR mimic transfection markedly suppressed proliferation and induced apoptosis of oral cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('suppressed', 'NegReg', (74, 84))	('apoptosis of oral cancer', 'Disease', (111, 135))	('miR-99a', 'Gene', '407055', (25, 32))	('miR', 'Gene', '220972', (25, 28))	('apoptosis of oral cancer', 'Disease', 'MESH:D009062', (111, 135))	('miR', 'Gene', (25, 28))	('miR-99a', 'Gene', (25, 32))	('transfection', 'Var', (52, 64))	('miR', 'Gene', '220972', (42, 45))	('miR', 'Gene', (42, 45))	('induced', 'Reg', (103, 110))	('proliferation', 'CPA', (85, 98))
443790	28903437	Further, restoration of miR-100 to the HNSCC cell lines enhanced apoptosis and thus suppressed cell proliferation and migration.	('miR-100', 'Gene', (24, 31))	('restoration', 'Var', (9, 20))	('enhanced', 'PosReg', (56, 64))	('apoptosis', 'CPA', (65, 74))	('miR-100', 'Gene', '406892', (24, 31))	('suppressed', 'NegReg', (84, 94))
443841	28248963	Anti-SOX2 (AM2048a, ABGENT) was used at 500-times dilution and anti-beta-Actin antibody (A2228, Sigma-Aldrich) was used at 2000-times dilution.	('SOX2', 'Gene', (5, 9))	('SOX2', 'Gene', '6657', (5, 9))	('AM2048a', 'Var', (11, 18))	('beta-Actin', 'Gene', (68, 78))	('beta-Actin', 'Gene', '728378', (68, 78))
443915	33314711	Furthermore, three miRNAs, hsa-mir-190a-5p, hsa-mir-195-5p, and hsa-mir-490-3p, were identified to be potentially involved in the regulation of EXT1.	('EXT1', 'Gene', (144, 148))	('involved', 'Reg', (114, 122))	('hsa-mir-195', 'Gene', (44, 55))	('hsa-mir-190a', 'Gene', '406965', (27, 39))	('hsa-mir-195', 'Gene', '406971', (44, 55))	('hsa-mir-490-3p', 'Var', (64, 78))	('hsa-mir-190a', 'Gene', (27, 39))	('EXT1', 'Gene', '2131', (144, 148))
443925	33314711	9   Mutations in the EXT2 gene, located on chromosome 11, cause the type II form of multiple exostoses.	('type II form of multiple exostoses', 'Disease', (68, 102))	('cause', 'Reg', (58, 63))	('multiple exostoses', 'Phenotype', 'HP:0002762', (84, 102))	('EXT2', 'Gene', '2132', (21, 25))	('exostoses', 'Phenotype', 'HP:0100777', (93, 102))	('EXT2', 'Gene', (21, 25))	('Mutations', 'Var', (4, 13))
443933	33314711	Furthermore, we identified three regulatory miRNAs of EXT1, hsa-mir-190a-5p, hsa-mir-195-5p, and hsa-mir-490-3p, which could potentially be involved in molecular mechanisms underlying of the disease.	('involved', 'Reg', (140, 148))	('EXT1', 'Gene', (54, 58))	('hsa-mir-190a', 'Gene', '406965', (60, 72))	('hsa-mir-490-3p', 'Var', (97, 111))	('EXT1', 'Gene', '2131', (54, 58))	('hsa-mir-195', 'Gene', (77, 88))	('hsa-mir-190a', 'Gene', (60, 72))	('hsa-mir-195', 'Gene', '406971', (77, 88))
443982	33314711	Three miRNAs (hsa-miR-190a-5p, hsa-miR-195-5p, and hsa-miR-490-3p) were found to be significantly downregulated in LUSC samples (Figure 9A-C).	('downregulated', 'NegReg', (98, 111))	('hsa-miR-190a', 'Gene', '406965', (14, 26))	('hsa-miR-195', 'Gene', (31, 42))	('LUSC', 'Phenotype', 'HP:0030359', (115, 119))	('hsa-miR-190a', 'Gene', (14, 26))	('hsa-miR-195', 'Gene', '406971', (31, 42))	('hsa-miR-490-3p', 'Var', (51, 65))
443985	33314711	Dysregulation of the EXT1 gene has been reported in many cancers, including multiple osteochondroma (MO), 30  breast cancer, 7  ALL 31  and HCC.	('osteochondroma', 'Phenotype', 'HP:0030431', (85, 99))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('Dysregulation', 'Var', (0, 13))	('cancers', 'Phenotype', 'HP:0002664', (57, 64))	('cancers', 'Disease', (57, 64))	('cancers', 'Disease', 'MESH:D009369', (57, 64))	('EXT1', 'Gene', (21, 25))	('osteochondroma', 'Disease', 'MESH:D015831', (85, 99))	('breast cancer', 'Disease', 'MESH:D001943', (110, 123))	('HCC', 'Disease', (140, 143))	('breast cancer', 'Phenotype', 'HP:0003002', (110, 123))	('ALL', 'Phenotype', 'HP:0006721', (128, 131))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('reported', 'Reg', (40, 48))	('breast cancer', 'Disease', (110, 123))	('HCC', 'Phenotype', 'HP:0001402', (140, 143))	('osteochondroma', 'Disease', (85, 99))	('EXT1', 'Gene', '2131', (21, 25))
443989	33314711	It is reported that 70% to 90% MO cases are caused by pathogenic mutations in the EXT1 or EXT2 genes, and EXT1 is more frequently mutated than the EXT2 gene.	('EXT2', 'Gene', '2132', (90, 94))	('EXT1', 'Gene', (82, 86))	('EXT2', 'Gene', (147, 151))	('EXT1', 'Gene', (106, 110))	('caused by', 'Reg', (44, 53))	('EXT2', 'Gene', '2132', (147, 151))	('EXT1', 'Gene', '2131', (82, 86))	('EXT1', 'Gene', '2131', (106, 110))	('EXT2', 'Gene', (90, 94))	('mutations', 'Var', (65, 74))
443996	33314711	Survival analysis showed that patients with high EXT1 expression had unfavorable OS prognosis.	('EXT1', 'Gene', (49, 53))	('patients', 'Species', '9606', (30, 38))	('high', 'Var', (44, 48))	('EXT1', 'Gene', '2131', (49, 53))
444005	33314711	37 ,  38 ,  39  We identified three significantly down-regulated miRNAs, hsa-miR-190a-5p, hsa-miR-195-5p, and hsa-miR-490-3p, with good prognostic value.	('hsa-miR-195', 'Gene', '406971', (90, 101))	('hsa-miR-190a', 'Gene', '406965', (73, 85))	('hsa-miR-195', 'Gene', (90, 101))	('hsa-miR-190a', 'Gene', (73, 85))	('down-regulated', 'NegReg', (50, 64))	('hsa-miR-490-3p', 'Var', (110, 124))
444007	33314711	miR-190a-5p expression levels are significantly decreased in the cancer group compared with the normal group, and overexpression of miR-190a-5p inhibits cell proliferation and invasion and promotes apoptosis in cancers such as cervical cancer, neuroblastoma, and breast tumors.	('inhibits', 'NegReg', (144, 152))	('apoptosis', 'CPA', (198, 207))	('cancer', 'Disease', 'MESH:D009369', (236, 242))	('breast tumors', 'Disease', (263, 276))	('breast tumors', 'Disease', 'MESH:D001943', (263, 276))	('promotes', 'PosReg', (189, 197))	('cell proliferation', 'CPA', (153, 171))	('tumor', 'Phenotype', 'HP:0002664', (270, 275))	('cancer', 'Disease', (65, 71))	('breast tumors', 'Phenotype', 'HP:0100013', (263, 276))	('cancer', 'Disease', 'MESH:D009369', (211, 217))	('cancers', 'Disease', 'MESH:D009369', (211, 218))	('decreased', 'NegReg', (48, 57))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('cervical cancer', 'Disease', (227, 242))	('cervical cancer', 'Disease', 'MESH:D002583', (227, 242))	('neuroblastoma', 'Disease', (244, 257))	('invasion', 'CPA', (176, 184))	('overexpression', 'PosReg', (114, 128))	('neuroblastoma', 'Phenotype', 'HP:0003006', (244, 257))	('cancer', 'Disease', (236, 242))	('miR-190a-5p', 'Var', (132, 143))	('neuroblastoma', 'Disease', 'MESH:D009447', (244, 257))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('expression levels', 'MPA', (12, 29))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('cancers', 'Phenotype', 'HP:0002664', (211, 218))	('cancer', 'Disease', (211, 217))	('cancers', 'Disease', (211, 218))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('tumors', 'Phenotype', 'HP:0002664', (270, 276))
444008	33314711	40 ,  41 ,  42  A recent study showed that smoking-induced dysregulation of hsa-miR-190a-5p was significantly associated with epithelial-mesenchymal transition (EMT) and carcinogenesis.	('carcinogenesis', 'Disease', (170, 184))	('hsa-miR-190a', 'Gene', (76, 88))	('epithelial-mesenchymal transition', 'CPA', (126, 159))	('dysregulation', 'Var', (59, 72))	('associated', 'Reg', (110, 120))	('hsa-miR-190a', 'Gene', '406965', (76, 88))	('carcinogenesis', 'Disease', 'MESH:D063646', (170, 184))
444013	33314711	Overall, our findings are consistent with previous studies and indicate that the three miRNAs identified in this study, hsa-miR-190a-5p, hsa-miR-195-5p and hsa-miR-490-3p, play an important role in the inhibition of malignant tumors.	('tumors', 'Phenotype', 'HP:0002664', (226, 232))	('hsa-miR-195', 'Gene', (137, 148))	('hsa-miR-490-3p', 'Var', (156, 170))	('malignant tumors', 'Disease', (216, 232))	('hsa-miR-190a', 'Gene', (120, 132))	('hsa-miR-195', 'Gene', '406971', (137, 148))	('malignant tumors', 'Disease', 'MESH:D009369', (216, 232))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('hsa-miR-190a', 'Gene', '406965', (120, 132))
444055	31666716	In our own preliminary clinical study in locally advanced breast cancers, the presence of EMT before neoadjuvant chemotherapy was associated with improved survival outcomes, whereas its presence after neoadjuvant chemotherapy was associated with poorer survival, indicating that EMT does not automatically correlate with clinically significant metastasis.	('breast cancers', 'Phenotype', 'HP:0003002', (58, 72))	('survival outcomes', 'CPA', (155, 172))	('EMT', 'Gene', (90, 93))	('breast cancers', 'Disease', 'MESH:D001943', (58, 72))	('breast cancers', 'Disease', (58, 72))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('improved', 'PosReg', (146, 154))	('breast cancer', 'Phenotype', 'HP:0003002', (58, 71))	('cancers', 'Phenotype', 'HP:0002664', (65, 72))	('presence', 'Var', (78, 86))
444064	31666716	In particular, knockdown of PRRX1, which encodes an EMT inducer, reversed EMT and promoted metastasis in breast cancer cells; however, the carcinoma cells resulting from the MET retained elements of stemness.	('breast cancer', 'Phenotype', 'HP:0003002', (105, 118))	('knockdown', 'Var', (15, 24))	('promoted', 'PosReg', (82, 90))	('carcinoma', 'Phenotype', 'HP:0030731', (139, 148))	('metastasis', 'CPA', (91, 101))	('EMT', 'CPA', (74, 77))	('carcinoma', 'Disease', (139, 148))	('reversed', 'NegReg', (65, 73))	('PRRX1', 'Gene', (28, 33))	('breast cancer', 'Disease', 'MESH:D001943', (105, 118))	('PRRX1', 'Gene', '5396', (28, 33))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('breast cancer', 'Disease', (105, 118))	('carcinoma', 'Disease', 'MESH:D009369', (139, 148))
444075	31666716	However, mutations in genes encoding EMT-TFs are not sufficient to drive ab initio tumorigenesis in mice, despite causing a range of developmental defects.	('developmental defects', 'Disease', 'MESH:D000014', (133, 154))	('drive', 'Reg', (67, 72))	('mice', 'Species', '10090', (100, 104))	('mutations', 'Var', (9, 18))	('EMT-TFs', 'Gene', (37, 44))	('causing', 'Reg', (114, 121))	('tumorigenesis', 'CPA', (83, 96))	('developmental defects', 'Disease', (133, 154))
444096	31666716	Studies using xenografts of the LM2 variant of MDA-MB-231 human breast cancer cells have shown that CTC clusters are oligoclonal and have a more robust metastatic capacity than single CTCs, consistent with their association with poor prognosis in breast and prostate cancer, and have implicated the epithelial cell junction component plakoglobin (JUP) in CTC cluster formation.	('junction component plakoglobin', 'Gene', '3728', (315, 345))	('breast cancer', 'Phenotype', 'HP:0003002', (64, 77))	('human', 'Species', '9606', (58, 63))	('variant', 'Var', (36, 43))	('JUP', 'Gene', (347, 350))	('more', 'PosReg', (140, 144))	('breast and prostate cancer', 'Disease', 'MESH:D001943', (247, 273))	('prostate cancer', 'Phenotype', 'HP:0012125', (258, 273))	('cancer', 'Phenotype', 'HP:0002664', (267, 273))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('LM2 variant', 'CellLine', 'CVCL:7204', (32, 43))	('JUP', 'Gene', '3728', (347, 350))	('breast cancer', 'Disease', 'MESH:D001943', (64, 77))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (47, 57))	('junction component plakoglobin', 'Gene', (315, 345))	('metastatic capacity', 'CPA', (152, 171))	('breast cancer', 'Disease', (64, 77))
444097	31666716	Furthermore, a single-cell RNA-sequencing study of CTCs in a mouse model of pancreatic cancer showed an overall loss of expression of the epithelial markers Chd1 (which encodes E-cadherin) and Muc1 (which encodes mucin-1) in CTCs compared with the primary xenograft tumours, with mixed and heterogeneous expression of mesenchymal markers in the same cells.	('mucin-1', 'Gene', '17829', (213, 220))	('Muc1', 'Gene', (193, 197))	('expression', 'MPA', (120, 130))	('Chd1', 'Gene', (157, 161))	('Muc1', 'Gene', '17829', (193, 197))	('mucin-1', 'Gene', (213, 220))	('tumours', 'Disease', 'MESH:D009369', (266, 273))	('pancreatic cancer', 'Disease', (76, 93))	('tumours', 'Disease', (266, 273))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('pancreatic cancer', 'Disease', 'MESH:D010190', (76, 93))	('Chd1', 'Gene', '12648', (157, 161))	('loss', 'NegReg', (112, 116))	('tumour', 'Phenotype', 'HP:0002664', (266, 272))	('mouse', 'Species', '10090', (61, 66))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (76, 93))	('CTCs', 'Var', (225, 229))	('tumours', 'Phenotype', 'HP:0002664', (266, 273))
444103	31666716	showed that inducible knockdown of CDH1 expression reduced the proliferation and survival of tumour cells as well as CTC numbers.	('proliferation', 'CPA', (63, 76))	('tumour', 'Disease', (93, 99))	('reduced', 'NegReg', (51, 58))	('rat', 'Species', '10116', (70, 73))	('CDH1', 'Gene', (35, 39))	('knockdown', 'Var', (22, 31))	('CDH1', 'Gene', '999', (35, 39))	('tumour', 'Phenotype', 'HP:0002664', (93, 99))	('tumour', 'Disease', 'MESH:D009369', (93, 99))	('CTC numbers', 'CPA', (117, 128))
444104	31666716	Furthermore, our group has also reported reduced proliferation, both in vitro and in vivo, in MDA-MB-468 breast cancer cells after CDH1 knockdown.	('reduced', 'NegReg', (41, 48))	('rat', 'Species', '10116', (56, 59))	('proliferation', 'CPA', (49, 62))	('CDH1', 'Gene', (131, 135))	('knockdown', 'Var', (136, 145))	('breast cancer', 'Disease', 'MESH:D001943', (105, 118))	('CDH1', 'Gene', '999', (131, 135))	('MDA-MB-468', 'CellLine', 'CVCL:0419', (94, 104))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('breast cancer', 'Disease', (105, 118))	('breast cancer', 'Phenotype', 'HP:0003002', (105, 118))
444123	31666716	Similarly, only cells with an epithelial phenotype (E-cadherinhigh, CK18high) gave rise to lung and liver metastases following orthotopic inoculation in a panel of isogenic mouse breast cancer (4T1-derived) cell lines.	('liver metastases', 'Disease', (100, 116))	('breast cancer', 'Disease', 'MESH:D001943', (179, 192))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('CK18', 'Gene', '16668', (68, 72))	('breast cancer', 'Disease', (179, 192))	('E-cadherinhigh', 'Var', (52, 66))	('liver metastases', 'Disease', 'MESH:D009362', (100, 116))	('breast cancer', 'Phenotype', 'HP:0003002', (179, 192))	('mouse', 'Species', '10090', (173, 178))	('CK18', 'Gene', (68, 72))
444151	31666716	In mice, genetic knockout of Snail1 or Twist1 did not alter the emergence, dissemination or liver metastasis of invasive pancreatic cancer, yet a similar approach of tissue-specific Zeb1 silencing resulted in a marked reduction in metastasis.	('Zeb1', 'Gene', '21417', (182, 186))	('liver metastasis of invasive pancreatic cancer', 'Disease', (92, 138))	('liver metastasis of invasive pancreatic cancer', 'Disease', 'MESH:D009362', (92, 138))	('Zeb1', 'Gene', (182, 186))	('reduction', 'NegReg', (218, 227))	('mice', 'Species', '10090', (3, 7))	('Twist1', 'Gene', '22160', (39, 45))	('silencing', 'Var', (187, 196))	('Twist1', 'Gene', (39, 45))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('metastasis', 'CPA', (231, 241))	('Snail1', 'Gene', (29, 35))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (121, 138))
444152	31666716	Moreover, breast tumour cell-specific knockout of Twist1 impaired lung metastasis formation in a mouse model.	('breast tumour', 'Phenotype', 'HP:0100013', (10, 23))	('lung metastasis formation', 'CPA', (66, 91))	('breast tumour', 'Disease', (10, 23))	('tumour', 'Phenotype', 'HP:0002664', (17, 23))	('Twist1', 'Gene', '22160', (50, 56))	('impaired', 'NegReg', (57, 65))	('mouse', 'Species', '10090', (97, 102))	('breast tumour', 'Disease', 'MESH:D001943', (10, 23))	('Twist1', 'Gene', (50, 56))	('knockout', 'Var', (38, 46))
444153	31666716	However, inhibiting EMT by overexpression of miR-200s, which directly target ZEB1 and ZEB2, did not impair lung metastasis formation in an orthotopic breast tumour GEMM.	('breast tumour', 'Disease', (150, 163))	('EMT', 'CPA', (20, 23))	('ZEB2', 'Gene', (86, 90))	('breast tumour', 'Phenotype', 'HP:0100013', (150, 163))	('miR-200s', 'Var', (45, 53))	('lung metastasis formation', 'CPA', (107, 132))	('miR-200', 'Chemical', '-', (45, 52))	('tumour', 'Phenotype', 'HP:0002664', (157, 163))	('breast tumour', 'Disease', 'MESH:D001943', (150, 163))	('impair', 'NegReg', (100, 106))	('ZEB2', 'Gene', '9839', (86, 90))	('inhibiting', 'NegReg', (9, 19))	('overexpression', 'PosReg', (27, 41))
444208	31666716	Specifically, multivariate analysis revealed that low CDH1 expression was predictive of reduced time to prostate-specific antigen relapse and high ZEB1 expression correlated with rapid radiological progression.	('low', 'NegReg', (50, 53))	('high', 'Var', (142, 146))	('prostate-specific antigen', 'Gene', '354', (104, 129))	('expression', 'MPA', (59, 69))	('ZEB1', 'Gene', (147, 151))	('CDH1', 'Gene', (54, 58))	('prostate-specific antigen', 'Gene', (104, 129))	('CDH1', 'Gene', '999', (54, 58))	('reduced', 'NegReg', (88, 95))	('expression', 'MPA', (152, 162))
444244	31666716	Extensive laboratory studies support the therapeutic potential of EMT-TF inhibition to increase treatment response across a range of therapeutic scenarios, including hormonal therapy for breast cancer, chemotherapy for ovarian malignancy and targeted therapy for lung cancer.	('ovarian malignancy', 'Disease', 'MESH:D010049', (219, 237))	('breast cancer', 'Phenotype', 'HP:0003002', (187, 200))	('lung cancer', 'Disease', (263, 274))	('lung cancer', 'Phenotype', 'HP:0100526', (263, 274))	('increase', 'PosReg', (87, 95))	('ovarian malignancy', 'Phenotype', 'HP:0100615', (219, 237))	('cancer', 'Phenotype', 'HP:0002664', (268, 274))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('EMT-TF', 'Gene', (66, 72))	('lung cancer', 'Disease', 'MESH:D008175', (263, 274))	('ovarian malignancy', 'Disease', (219, 237))	('treatment response', 'CPA', (96, 114))	('breast cancer', 'Disease', 'MESH:D001943', (187, 200))	('inhibition', 'Var', (73, 83))	('rat', 'Species', '10116', (14, 17))	('breast cancer', 'Disease', (187, 200))
444251	31666716	In a co-culture model, antibody-mediated neutralization of neutrophil-produced IL-17a reversed neutrophil-induced EMT changes in gastric cancer cells and inhibited their migration and invasion.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('rat', 'Species', '10116', (173, 176))	('gastric cancer', 'Disease', (129, 143))	('inhibited', 'NegReg', (154, 163))	('EMT changes', 'MPA', (114, 125))	('gastric cancer', 'Disease', 'MESH:D013274', (129, 143))	('gastric cancer', 'Phenotype', 'HP:0012126', (129, 143))	('IL-17a', 'Gene', (79, 85))	('neutralization', 'Var', (41, 55))	('IL-17a', 'Gene', '3605', (79, 85))
444252	31666716	Depletion of CAFs using a fibroblast-targeted immunotoxin inhibited TGFbeta signalling, reduced tumour progression and enhanced chemosensitivity in the syngeneic 4T1 breast cancer mouse model, which is consistent with inhibition of EMT, although the process was not directly assessed.	('TGFbeta', 'Protein', (68, 75))	('chemosensitivity', 'CPA', (128, 144))	('tumour', 'Phenotype', 'HP:0002664', (96, 102))	('Depletion', 'Var', (0, 9))	('breast cancer', 'Disease', 'MESH:D001943', (166, 179))	('mouse', 'Species', '10090', (180, 185))	('tumour', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('breast cancer', 'Disease', (166, 179))	('inhibited', 'NegReg', (58, 67))	('breast cancer', 'Phenotype', 'HP:0003002', (166, 179))	('reduced', 'NegReg', (88, 95))	('enhanced', 'PosReg', (119, 127))	('tumour', 'Disease', (96, 102))
444253	31666716	Furthermore, knockout of the gene encoding collagen VIII was reported to reduce EMT in renal cells in the context of experimental diabetic nephropathy, although such studies have not been performed in cancer models.	('diabetic nephropathy', 'Disease', (130, 150))	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('EMT in renal cells', 'CPA', (80, 98))	('diabetic nephropathy', 'Disease', 'MESH:D003928', (130, 150))	('cancer', 'Disease', (201, 207))	('knockout', 'Var', (13, 21))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('nephropathy', 'Phenotype', 'HP:0000112', (139, 150))	('reduce EMT', 'Phenotype', 'HP:0032198', (73, 83))	('reduce', 'NegReg', (73, 79))	('collagen', 'Gene', (43, 51))
444287	31666716	In a PC-3 prostate cancer tumour xenograft mouse model, co-inoculation of mesenchymal PC-3 variants promoted metastasis of epithelial PC-3 variants.	('PC-3', 'CellLine', 'CVCL:0035', (86, 90))	('PC-3 prostate cancer tumour', 'Disease', (5, 32))	('PC-3', 'CellLine', 'CVCL:0035', (5, 9))	('prostate cancer', 'Phenotype', 'HP:0012125', (10, 25))	('promoted', 'PosReg', (100, 108))	('metastasis', 'CPA', (109, 119))	('variants', 'Var', (91, 99))	('PC-3 prostate cancer tumour', 'Disease', 'MESH:D011471', (5, 32))	('variants', 'Var', (139, 147))	('PC-3', 'CellLine', 'CVCL:0035', (134, 138))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('tumour', 'Phenotype', 'HP:0002664', (26, 32))	('PC-3', 'Gene', (86, 90))	('mouse', 'Species', '10090', (43, 48))
444299	31666716	In mouse and human melanoma cells, EMT induction through SNAIL1 expression caused progression by enhancing both invasion and immunosuppression; regulatory T cells were induced and dendritic cells were inhibited, with increased CTLA-4 and PD-1 expression.	('PD-1', 'Gene', '5133', (238, 242))	('CTLA-4', 'Gene', (227, 233))	('SNAIL1', 'Gene', (57, 63))	('mouse', 'Species', '10090', (3, 8))	('expression', 'MPA', (243, 253))	('human', 'Species', '9606', (13, 18))	('immunosuppression; regulatory T cells', 'CPA', (125, 162))	('melanoma', 'Phenotype', 'HP:0002861', (19, 27))	('invasion', 'CPA', (112, 120))	('melanoma', 'Disease', (19, 27))	('melanoma', 'Disease', 'MESH:D008545', (19, 27))	('enhancing', 'PosReg', (97, 106))	('expression', 'Var', (64, 74))	('CTLA-4', 'Gene', '1493', (227, 233))	('PD-1', 'Gene', (238, 242))	('increased', 'PosReg', (217, 226))
444301	31666716	In oesophageal squamous cell carcinoma cell lines, inhibition of the known EMT suppressor GSK3beta induced EMT and upregulated PD-L1 expression; EMT-positive tumour cells could induce T cell apoptosis.	('expression', 'MPA', (133, 143))	('GSK3beta', 'Gene', (90, 98))	('GSK3beta', 'Gene', '2931', (90, 98))	('tumour', 'Phenotype', 'HP:0002664', (158, 164))	('carcinoma', 'Phenotype', 'HP:0030731', (29, 38))	('tumour', 'Disease', 'MESH:D009369', (158, 164))	('EMT', 'CPA', (107, 110))	('oesophageal squamous cell carcinoma', 'Disease', 'MESH:D002294', (3, 38))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (15, 38))	('T cell apoptosis', 'CPA', (184, 200))	('tumour', 'Disease', (158, 164))	('PD-L1', 'Gene', (127, 132))	('inhibition', 'Var', (51, 61))	('induce', 'Reg', (177, 183))	('upregulated', 'PosReg', (115, 126))	('oesophageal squamous cell carcinoma', 'Disease', (3, 38))
444315	31666716	Although epidermal growth factor receptor (EGFR) stimulation in salivary adenoid cystic carcinoma cells induced both EMT and PD-L1 expression, EMT was suppressible by SNAI1 knockdown and PD-L1 by MYC knockdown, but not the reverse.	('epidermal growth factor receptor', 'Gene', '1956', (9, 41))	('MYC', 'Gene', (196, 199))	('EMT', 'CPA', (117, 120))	('knockdown', 'Var', (173, 182))	('SNAI1', 'Gene', (167, 172))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('salivary adenoid cystic carcinoma', 'Disease', (64, 97))	('expression', 'MPA', (131, 141))	('EGFR', 'Gene', '1956', (43, 47))	('MYC', 'Gene', '4609', (196, 199))	('epidermal growth factor receptor', 'Gene', (9, 41))	('EGFR', 'Gene', (43, 47))	('PD-L1', 'Gene', (125, 130))	('salivary adenoid cystic carcinoma', 'Disease', 'MESH:D003528', (64, 97))
444393	30755230	The following study investigates the role of miR-223-3p in LSCC growth and metastasis and its underlying mechanism.	('3p', 'Chemical', '-', (53, 55))	('miR-223-3p', 'Var', (45, 55))	('SCC', 'Gene', (60, 63))	('SCC', 'Gene', '6317', (60, 63))
444395	30755230	RT-PCR and in situ hybridization (ISH) was performed to evaluate the expression of miR-223-3p in 12 paired adjacent normal tissues and LSCC specimens.	('SCC', 'Gene', '6317', (136, 139))	('SCC', 'Gene', (136, 139))	('3p', 'Chemical', '-', (91, 93))	('miR-223-3p', 'Var', (83, 93))
444398	30755230	Bioinformatics analysis, Dual-luciferase reporter assays, Chromatin immunoprecipitation (ChIP) assay and Western blot analysis were used to identify the direct target of miR-223-3p and its interactions.	('interactions', 'Interaction', (189, 201))	('3p', 'Chemical', '-', (178, 180))	('miR-223-3p', 'Var', (170, 180))
444400	30755230	Gain- and loss-of function experiments showed that miR-223-3p inhibited proliferation and migration in vitro.	('3p', 'Chemical', '-', (59, 61))	('miR-223-3p', 'Var', (51, 61))	('inhibited', 'NegReg', (62, 71))
444401	30755230	More importantly, miR-223-3p overexpression greatly suppressed tumor growth in vivo.	('tumor', 'Disease', (63, 68))	('miR-223-3p', 'Var', (18, 28))	('overexpression', 'PosReg', (29, 43))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('suppressed', 'NegReg', (52, 62))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('3p', 'Chemical', '-', (26, 28))
444402	30755230	Mechanistically, we found that mutant p53 bound to the promoter region of miR-223 and reduced its transcription.	('miR-223', 'Gene', (74, 81))	('reduced', 'NegReg', (86, 93))	('mutant', 'Var', (31, 37))	('p53', 'Gene', (38, 41))	('p53', 'Gene', '7157', (38, 41))	('bound', 'Interaction', (42, 47))	('transcription', 'MPA', (98, 111))
444403	30755230	Meanwhile, p53 is a direct target of miR-223-3p.	('p53', 'Gene', (11, 14))	('miR-223-3p', 'Var', (37, 47))	('p53', 'Gene', '7157', (11, 14))	('3p', 'Chemical', '-', (45, 47))
444404	30755230	Thus, miR-223-3p regulated mutant p53 expression in a feedback loop that inhibited cell proliferation and migration.	('p53', 'Gene', (34, 37))	('p53', 'Gene', '7157', (34, 37))	('mutant', 'Var', (27, 33))	('expression', 'MPA', (38, 48))	('3p', 'Chemical', '-', (14, 16))	('inhibited', 'NegReg', (73, 82))
444405	30755230	Our study identified miR-223-3p, as a tumor suppressor gene, markedly inhibited cell proliferation and migration via miR-223-3p-mutant p53 feedback loop, which suggested miR-223-3p might be a new therapeutic target in LSCC bearing p53 mutations.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('miR-223-3p-mutant', 'Var', (117, 134))	('SCC', 'Gene', (219, 222))	('3p', 'Chemical', '-', (125, 127))	('mutations', 'Var', (235, 244))	('p53', 'Gene', (231, 234))	('3p', 'Chemical', '-', (29, 31))	('p53', 'Gene', (135, 138))	('p53', 'Gene', '7157', (135, 138))	('SCC', 'Gene', '6317', (219, 222))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('p53', 'Gene', '7157', (231, 234))	('inhibited', 'NegReg', (70, 79))	('3p', 'Chemical', '-', (178, 180))	('miR-223-3p', 'Var', (21, 31))
444421	30755230	Importantly, miR-223-3p overexpression greatly suppressed tumor growth in vivo.	('3p', 'Chemical', '-', (21, 23))	('suppressed', 'NegReg', (47, 57))	('tumor', 'Disease', (58, 63))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('overexpression', 'PosReg', (24, 38))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('miR-223-3p', 'Var', (13, 23))
444422	30755230	Our results further demonstrated that mutant p53 bound to the promoter region of miR-223 and reduced its transcription in LSCC bearing p53 mutations.	('mutant', 'Var', (38, 44))	('p53', 'Gene', (45, 48))	('p53', 'Gene', '7157', (45, 48))	('mutations', 'Var', (139, 148))	('SCC', 'Gene', '6317', (123, 126))	('reduced', 'NegReg', (93, 100))	('p53', 'Gene', (135, 138))	('bound', 'Interaction', (49, 54))	('p53', 'Gene', '7157', (135, 138))	('transcription', 'MPA', (105, 118))	('miR-223', 'Gene', (81, 88))	('SCC', 'Gene', (123, 126))
444423	30755230	Meanwhile, we provide evidence that miR-223-3p directly targets mutant p53, to suppress cell proliferation and migration.	('p53', 'Gene', (71, 74))	('p53', 'Gene', '7157', (71, 74))	('suppress', 'NegReg', (79, 87))	('mutant', 'Var', (64, 70))	('3p', 'Chemical', '-', (44, 46))
444424	30755230	Collectively, the results of this study provide an explanation for the aggressiveness of LSCC and this is a mutual regulation between miR-223-3p and mutant p53.	('aggressiveness', 'Disease', (71, 85))	('aggressiveness', 'Phenotype', 'HP:0000718', (71, 85))	('mutant', 'Var', (149, 155))	('p53', 'Gene', (156, 159))	('SCC', 'Gene', (90, 93))	('p53', 'Gene', '7157', (156, 159))	('3p', 'Chemical', '-', (142, 144))	('miR-223-3p', 'Var', (134, 144))	('aggressiveness', 'Disease', 'MESH:D001523', (71, 85))	('SCC', 'Gene', '6317', (90, 93))
444425	30755230	Our results also suggest that miR-223-3p might be a new therapeutic target in LSCC bearing p53 mutations.	('3p', 'Chemical', '-', (38, 40))	('SCC', 'Gene', (79, 82))	('SCC', 'Gene', '6317', (79, 82))	('p53', 'Gene', '7157', (91, 94))	('p53', 'Gene', (91, 94))	('mutations', 'Var', (95, 104))
444466	30755230	Since p53 mutations occur throughout the gene in human cancer, the p53 coding sequence was screened for mutations using Sanger sequencing.	('p53', 'Gene', (6, 9))	('p53', 'Gene', '7157', (6, 9))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('human', 'Species', '9606', (49, 54))	('p53', 'Gene', (67, 70))	('p53', 'Gene', '7157', (67, 70))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('mutations', 'Var', (10, 19))	('cancer', 'Disease', (55, 61))
444475	30755230	Among these miRNAs, miR-451a, miR-222, miR-223, and miR-200a-3p were highly involved in the regulation of tumor growth and migration.	('miR-451a', 'Gene', '574411', (20, 28))	('miR-451a', 'Gene', (20, 28))	('miR-222', 'Gene', (30, 37))	('miR-223', 'Var', (39, 46))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('3p', 'Chemical', '-', (61, 63))	('miR-200a-3p', 'Var', (52, 63))	('involved', 'Reg', (76, 84))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('miR-222', 'Gene', '407007', (30, 37))	('tumor', 'Disease', (106, 111))
444476	30755230	Paradoxically, miR-223 was revealed to function as a tumor suppressor in Lewis lung carcinoma cells while miR-223 may function as an oncogene in lung adenocarcinoma A549 cells.	('carcinoma', 'Phenotype', 'HP:0030731', (155, 164))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('Lewis lung carcinoma', 'Disease', (73, 93))	('Lewis lung carcinoma', 'Disease', 'MESH:D018827', (73, 93))	('tumor', 'Disease', (53, 58))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (145, 164))	('miR-223', 'Var', (106, 113))	('miR-223', 'Gene', (15, 22))	('lung adenocarcinoma A549', 'Disease', 'MESH:D000077192', (145, 169))	('lung adenocarcinoma A549', 'Disease', (145, 169))
444479	30755230	RT-PCR results showed that the miR-223-3p expression was down-regulated in the LSCC tissues compared with that in the normal lung tissues (Fig.	('down-regulated', 'NegReg', (57, 71))	('SCC', 'Gene', '6317', (80, 83))	('miR-223-3p', 'Var', (31, 41))	('3p', 'Chemical', '-', (39, 41))	('SCC', 'Gene', (80, 83))
444483	30755230	Among them, 5 of 6 patients harboring p53 mutations were successfully formed xenografts.	('mutations', 'Var', (42, 51))	('p53', 'Gene', (38, 41))	('patients', 'Species', '9606', (19, 27))	('p53', 'Gene', '7157', (38, 41))
444484	30755230	However, 5 of 6 patients harboring wild-type p53 were failed to form xenografts (no-XG).	('p53', 'Gene', (45, 48))	('patients', 'Species', '9606', (16, 24))	('p53', 'Gene', '7157', (45, 48))	('wild-type', 'Var', (35, 44))
444485	30755230	Furthermore, 4 of 5 patients harboring p53215C > G missence mutation were successfully formed xenografts.	('missence', 'Gene', (51, 59))	('patients', 'Species', '9606', (20, 28))	('p53215C > G', 'Var', (39, 50))
444487	30755230	Altogether, these results revealed the potential possibilities of miR-223-3p and p53 mutations in tumor formation.	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('mutations', 'Var', (85, 94))	('p53', 'Gene', (81, 84))	('p53', 'Gene', '7157', (81, 84))	('tumor', 'Disease', (98, 103))	('3p', 'Chemical', '-', (74, 76))	('miR-223-3p', 'Var', (66, 76))
444489	30755230	Furthermore, CCK-8 assays were performed to measure the effect of miR-223-3p on cell proliferation; significantly suppressed cell viability was observed in SK-MES-1 and NCI-H520 cells transfected with miR-223-3p mimics compared with NC (Fig.	('CCK-8', 'Chemical', '-', (13, 18))	('SK-MES-1', 'CellLine', 'CVCL:0630', (156, 164))	('cell viability', 'CPA', (125, 139))	('miR-223-3p mimics', 'Var', (201, 218))	('suppressed', 'NegReg', (114, 124))	('NCI-H520', 'CellLine', 'CVCL:1566', (169, 177))	('3p', 'Chemical', '-', (74, 76))	('3p', 'Chemical', '-', (209, 211))
444490	30755230	Similarly, miR-223-3p mimics were identified to exhibit a significantly inhibited colony-forming ability, as demonstrated by the decrease in colony numbers (Fig.	('colony-forming ability', 'CPA', (82, 104))	('decrease', 'NegReg', (129, 137))	('miR-223-3p mimics', 'Var', (11, 28))	('colony numbers', 'CPA', (141, 155))	('inhibited', 'NegReg', (72, 81))	('3p', 'Chemical', '-', (19, 21))
444492	30755230	In addition, flow cytometry (FCM) indicated that miR-223-3p mimics significantly promoted cell apoptosis (Fig.	('cell apoptosis', 'CPA', (90, 104))	('promoted', 'PosReg', (81, 89))	('3p', 'Chemical', '-', (57, 59))	('miR-223-3p mimics', 'Var', (49, 66))
444493	30755230	To further study whether the migration ability of LSCC cells was affected by miR-223-3p, Transwell assays were performed.	('SCC', 'Gene', '6317', (51, 54))	('miR-223-3p', 'Var', (77, 87))	('3p', 'Chemical', '-', (85, 87))	('SCC', 'Gene', (51, 54))
444494	30755230	The results indicated that miR-223-3p mimics could significantly inhibit the migration of SK-MES-1 and NCI-H520 cells (Fig.	('SK-MES-1', 'CellLine', 'CVCL:0630', (90, 98))	('3p', 'Chemical', '-', (35, 37))	('NCI-H520', 'CellLine', 'CVCL:1566', (103, 111))	('migration of SK-MES-1', 'CPA', (77, 98))	('inhibit', 'NegReg', (65, 72))	('miR-223-3p', 'Var', (27, 37))
444496	30755230	Taken together, these results suggest that miR-223-3p harbors the ability to suppress the proliferation and migration of LSCC cells in vitro.	('SCC', 'Gene', (122, 125))	('migration', 'CPA', (108, 117))	('3p', 'Chemical', '-', (51, 53))	('proliferation', 'CPA', (90, 103))	('miR-223-3p', 'Var', (43, 53))	('SCC', 'Gene', '6317', (122, 125))	('suppress', 'NegReg', (77, 85))
444498	30755230	reported that mutant p53 proteins down-regulated miR-223 expression in breast and colon cancer cell lines by binding miR-223 promoter and reducing its transcriptional activity.	('expression', 'MPA', (57, 67))	('breast and colon cancer', 'Disease', 'MESH:D001943', (71, 94))	('transcriptional activity', 'MPA', (151, 175))	('miR-223', 'Gene', (49, 56))	('mutant', 'Var', (14, 20))	('colon cancer', 'Phenotype', 'HP:0003003', (82, 94))	('down-regulated', 'NegReg', (34, 48))	('p53', 'Gene', '7157', (21, 24))	('miR-223', 'Gene', (117, 124))	('reducing', 'NegReg', (138, 146))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('binding', 'Interaction', (109, 116))	('p53', 'Gene', (21, 24))	('proteins', 'Protein', (25, 33))
444499	30755230	Experiments were carried out to explore whether downregulation of miR-223-3p expression in LSCC could be modulated by mutant p53.	('expression', 'MPA', (77, 87))	('SCC', 'Gene', '6317', (92, 95))	('p53', 'Gene', (125, 128))	('p53', 'Gene', '7157', (125, 128))	('mutant', 'Var', (118, 124))	('downregulation', 'NegReg', (48, 62))	('3p', 'Chemical', '-', (74, 76))	('miR-223-3p', 'Gene', (66, 76))	('SCC', 'Gene', (92, 95))
444501	30755230	The p53 sequence analysis found that SK-MES-1 cells had missense (215C > G) and nonsense (892G > T) mutations, and that NCI-H520 cells had missense (215C > G) mutation (Fig.	('892G > T', 'Var', (90, 98))	('p53', 'Gene', '7157', (4, 7))	('SK-MES-1', 'CellLine', 'CVCL:0630', (37, 45))	('215C > G', 'Mutation', 'rs1042522', (66, 74))	('892G > T', 'Mutation', 'rs201744589', (90, 98))	('missense (215C > G', 'Var', (139, 157))	('p53', 'Gene', (4, 7))	('215C > G', 'Mutation', 'rs1042522', (149, 157))	('NCI-H520', 'CellLine', 'CVCL:1566', (120, 128))
444502	30755230	ChIP assay revealed that mutant p53 directly binds to the miR-223 promoter in SK-MES-1 and NCI-H520 cells (Fig.	('mutant', 'Var', (25, 31))	('binds', 'Interaction', (45, 50))	('p53', 'Gene', (32, 35))	('SK-MES-1', 'CellLine', 'CVCL:0630', (78, 86))	('p53', 'Gene', '7157', (32, 35))	('NCI-H520', 'CellLine', 'CVCL:1566', (91, 99))
444503	30755230	We thus silenced mutant p53 in the SK-MES-1 and NCI-H520 by siRNA, and then evaluated miR-223-3p expression.	('p53', 'Gene', (24, 27))	('p53', 'Gene', '7157', (24, 27))	('NCI-H520', 'CellLine', 'CVCL:1566', (48, 56))	('3p', 'Chemical', '-', (94, 96))	('SK-MES-1', 'CellLine', 'CVCL:0630', (35, 43))	('mutant', 'Var', (17, 23))
444504	30755230	MiR-223-3p was up-regulated upon transient silence of mutant p53.	('silence', 'NegReg', (43, 50))	('MiR-223', 'Gene', (0, 7))	('3p', 'Chemical', '-', (8, 10))	('up-regulated', 'PosReg', (15, 27))	('MiR-223', 'Gene', '407008', (0, 7))	('p53', 'Gene', '7157', (61, 64))	('mutant', 'Var', (54, 60))	('p53', 'Gene', (61, 64))
444506	30755230	In addition, compared to the LSCC tissues with wild-type p53, the relative expression level of miR-223-3p did significantly decrease in the LSCC tissue samples with mutant p53 (Fig.	('SCC', 'Gene', '6317', (30, 33))	('mutant', 'Var', (165, 171))	('3p', 'Chemical', '-', (103, 105))	('SCC', 'Gene', (141, 144))	('p53', 'Gene', '7157', (172, 175))	('SCC', 'Gene', '6317', (141, 144))	('p53', 'Gene', (57, 60))	('SCC', 'Gene', (30, 33))	('expression level', 'MPA', (75, 91))	('decrease', 'NegReg', (124, 132))	('p53', 'Gene', '7157', (57, 60))	('p53', 'Gene', (172, 175))
444507	30755230	Moreover, miR-223-3p was significantly down-regulated upon mutant p53215C > G upregulation in the SK-MES-1 (Fig.	('mutant p53215C > G', 'Var', (59, 77))	('3p', 'Chemical', '-', (18, 20))	('upregulation', 'PosReg', (78, 90))	('SK-MES-1', 'CellLine', 'CVCL:0630', (98, 106))	('SK-MES-1', 'Gene', (98, 106))	('miR-223-3p', 'Gene', (10, 20))	('down-regulated', 'NegReg', (39, 53))
444508	30755230	These observations indicated that miR-223-3p was regulated by mutant p53 at the transcriptional level.	('regulated', 'Reg', (49, 58))	('mutant', 'Var', (62, 68))	('3p', 'Chemical', '-', (42, 44))	('p53', 'Gene', (69, 72))	('p53', 'Gene', '7157', (69, 72))	('miR-223-3p', 'MPA', (34, 44))
444509	30755230	To elucidate how miR-223-3p inhibits cell proliferation and migration in LSCC harboring p53 mutant.	('3p', 'Chemical', '-', (25, 27))	('inhibits', 'NegReg', (28, 36))	('p53', 'Gene', (88, 91))	('p53', 'Gene', '7157', (88, 91))	('SCC', 'Gene', (74, 77))	('mutant', 'Var', (92, 98))	('cell proliferation', 'CPA', (37, 55))	('miR-223-3p', 'Var', (17, 27))	('SCC', 'Gene', '6317', (74, 77))
444510	30755230	MiRNA target-predicted database (http://www.targetscan.org) showed that p53 is a direct target of miR-223-3p.	('p53', 'Gene', '7157', (72, 75))	('p53', 'Gene', (72, 75))	('3p', 'Chemical', '-', (106, 108))	('miR-223-3p', 'Var', (98, 108))
444511	30755230	Then, we performed a luciferase reporter assay to confirm that miR-223-3p directly binds to the 3' untranslated region (UTR) of p53.	('p53', 'Gene', '7157', (128, 131))	('p53', 'Gene', (128, 131))	('binds', 'Interaction', (83, 88))	('3p', 'Chemical', '-', (71, 73))	('miR-223-3p', 'Var', (63, 73))
444512	30755230	Our results showed that overexpression of miR-223-3p significantly reduced luciferase activity of the reporter gene in wild type, but not in mutant type, indicating that miR-223-3p directly targeted the p53 3'-UTR (Fig.4a).	('luciferase', 'Enzyme', (75, 85))	('activity of the reporter gene', 'MPA', (86, 115))	('miR-223-3p', 'Var', (170, 180))	('reduced', 'NegReg', (67, 74))	('3p', 'Chemical', '-', (50, 52))	('p53', 'Gene', '7157', (203, 206))	('miR-223-3p', 'Var', (42, 52))	('3p', 'Chemical', '-', (178, 180))	('p53', 'Gene', (203, 206))
444513	30755230	Consistent with the results of the reporter assay, transfection with miR-223-3p mimics resulted in a significant decrease in p53 protein level in SK-MES-1 and NCI-H520 by western blot.	('decrease', 'NegReg', (113, 121))	('NCI-H520', 'CellLine', 'CVCL:1566', (159, 167))	('SK-MES-1', 'CellLine', 'CVCL:0630', (146, 154))	('miR-223-3p mimics', 'Var', (69, 86))	('p53', 'Gene', (125, 128))	('p53', 'Gene', '7157', (125, 128))	('3p', 'Chemical', '-', (77, 79))
444514	30755230	Furthermore, p53 expression was significantly increased by transfection with miR-223-3p inhibitor (Fig.	('increased', 'PosReg', (46, 55))	('p53', 'Gene', (13, 16))	('expression', 'MPA', (17, 27))	('miR-223-3p inhibitor', 'Var', (77, 97))	('p53', 'Gene', '7157', (13, 16))	('3p', 'Chemical', '-', (85, 87))
444516	30755230	These results indicate that miR-223-3p inhibits cell proliferation and migration by targeting and suppressing mutant p53 in LSCC.	('p53', 'Gene', (117, 120))	('p53', 'Gene', '7157', (117, 120))	('suppressing', 'NegReg', (98, 109))	('mutant', 'Var', (110, 116))	('cell proliferation', 'CPA', (48, 66))	('SCC', 'Gene', (125, 128))	('3p', 'Chemical', '-', (36, 38))	('inhibits', 'NegReg', (39, 47))	('SCC', 'Gene', '6317', (125, 128))
444517	30755230	All together, the aforementioned observations indicated that miR-223-3p and p53 were reciprocally linked in a feedback loop in LSCC bearing p53 mutations.	('p53', 'Gene', (76, 79))	('p53', 'Gene', '7157', (76, 79))	('SCC', 'Gene', (128, 131))	('3p', 'Chemical', '-', (69, 71))	('SCC', 'Gene', '6317', (128, 131))	('mutations', 'Var', (144, 153))	('p53', 'Gene', (140, 143))	('p53', 'Gene', '7157', (140, 143))
444518	30755230	To explore whether the expression level of miR-223-3p affects tumorigenesis, immunodeficient female BALB/c mice were subcutaneously injected with LSCC patient-derived tumor tissues.	('SCC', 'Gene', (147, 150))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('affects', 'Reg', (54, 61))	('3p', 'Chemical', '-', (51, 53))	('miR-223-3p', 'Var', (43, 53))	('tumor', 'Disease', (62, 67))	('patient', 'Species', '9606', (151, 158))	('SCC', 'Gene', '6317', (147, 150))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('mice', 'Species', '10090', (107, 111))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('tumor', 'Disease', (167, 172))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
444519	30755230	When the tumor volume reached 50-100 mm3, the mice were treated with an intratumoral injection of miR-223-3p agomir or agomir control twice a week for 3 weeks.	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('miR-223-3p', 'Var', (98, 108))	('tumor', 'Disease', (9, 14))	('mice', 'Species', '10090', (46, 50))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Disease', (77, 82))	('3p', 'Chemical', '-', (106, 108))
444520	30755230	During the whole-tumor growth period, tumors from miR-223-3p agomir treatment group grew slower in comparison with the control group (Fig.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('3p', 'Chemical', '-', (58, 60))	('tumor', 'Disease', (17, 22))	('tumors', 'Disease', (38, 44))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('slower', 'NegReg', (89, 95))	('miR-223-3p', 'Var', (50, 60))	('tumors', 'Disease', 'MESH:D009369', (38, 44))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
444521	30755230	After three weeks treatment, the average weight of tumors from miR-223-3p agomir treatment group was significantly smaller than that of control mice (Fig.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('mice', 'Species', '10090', (144, 148))	('tumors', 'Disease', 'MESH:D009369', (51, 57))	('tumors', 'Disease', (51, 57))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('smaller', 'NegReg', (115, 122))	('3p', 'Chemical', '-', (71, 73))	('miR-223-3p', 'Var', (63, 73))
444523	30755230	5c and d, the expression level of miR-223-3p in miR-223-3p agomir treatment group was significantly higher than that in control group.	('miR-223-3p agomir treatment', 'Var', (48, 75))	('3p', 'Chemical', '-', (56, 58))	('3p', 'Chemical', '-', (42, 44))	('miR-223-3p', 'Var', (34, 44))	('higher', 'PosReg', (100, 106))	('expression level', 'MPA', (14, 30))
444524	30755230	Furthermore, immunohistochemical staining of Ki-67 to assess tumor cell proliferation revealed a reverse correlation between the miR-223-3p levels and the expression of p53 protein and cell proliferation (Fig.	('cell proliferation', 'CPA', (185, 203))	('p53', 'Gene', (169, 172))	('p53', 'Gene', '7157', (169, 172))	('expression', 'MPA', (155, 165))	('protein', 'Protein', (173, 180))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('miR-223-3p', 'Var', (129, 139))	('tumor', 'Disease', (61, 66))	('3p', 'Chemical', '-', (137, 139))
444526	30755230	Together, these results indicated that miR-223-3p may exert a significant inhibitory effect on tumorigenesis by repressing mutant p53 in vivo.	('inhibitory', 'NegReg', (74, 84))	('repressing', 'PosReg', (112, 122))	('miR-223-3p', 'Var', (39, 49))	('p53', 'Gene', '7157', (130, 133))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('3p', 'Chemical', '-', (47, 49))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('p53', 'Gene', (130, 133))	('mutant', 'Var', (123, 129))	('tumor', 'Disease', (95, 100))
444528	30755230	Our findings demonstrated a tumor suppressive role of miR-223-3p in LSCC bearing mutant p53 in vitro and vivo.	('tumor', 'Disease', (28, 33))	('3p', 'Chemical', '-', (62, 64))	('SCC', 'Gene', (69, 72))	('p53', 'Gene', (88, 91))	('miR-223-3p', 'Var', (54, 64))	('p53', 'Gene', '7157', (88, 91))	('SCC', 'Gene', '6317', (69, 72))	('mutant', 'Var', (81, 87))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
444529	30755230	MiR-223-3p could be regulated by mutant p53 at the transcriptional level.	('p53', 'Gene', (40, 43))	('3p', 'Chemical', '-', (8, 10))	('MiR-223', 'Gene', '407008', (0, 7))	('regulated', 'Reg', (20, 29))	('mutant', 'Var', (33, 39))	('p53', 'Gene', '7157', (40, 43))	('MiR-223', 'Gene', (0, 7))
444530	30755230	Meanwhile, p53 is a direct target gene of miR-223-3p, suggesting miR-223-3p and mutant p53 were reciprocally linked in a feedback loop affect LSCC proliferation and metastasis.	('p53', 'Gene', (11, 14))	('SCC', 'Gene', (143, 146))	('metastasis', 'CPA', (165, 175))	('p53', 'Gene', '7157', (11, 14))	('mutant', 'Var', (80, 86))	('p53', 'Gene', (87, 90))	('affect', 'Reg', (135, 141))	('SCC', 'Gene', '6317', (143, 146))	('p53', 'Gene', '7157', (87, 90))	('3p', 'Chemical', '-', (73, 75))	('3p', 'Chemical', '-', (50, 52))
444536	30755230	As patient tumors that successfully form xenografts represented more aggressive, therefore, aberrantly expressed miRNAs between successful engraft tumors and failed engraft tumors may possess greatest potential to affect tumor proliferation and metastasis.	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('aberrantly', 'Var', (92, 102))	('tumors', 'Disease', 'MESH:D009369', (147, 153))	('tumors', 'Disease', 'MESH:D009369', (11, 17))	('tumors', 'Phenotype', 'HP:0002664', (173, 179))	('engraft tumors', 'Disease', (165, 179))	('tumor', 'Disease', (147, 152))	('engraft tumors', 'Disease', (139, 153))	('tumor', 'Disease', (11, 16))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('tumors', 'Disease', (173, 179))	('tumor', 'Disease', 'MESH:D009369', (11, 16))	('tumors', 'Phenotype', 'HP:0002664', (147, 153))	('tumors', 'Phenotype', 'HP:0002664', (11, 17))	('tumor', 'Disease', (221, 226))	('tumors', 'Disease', 'MESH:D009369', (173, 179))	('engraft tumors', 'Disease', 'MESH:D009369', (165, 179))	('tumor', 'Disease', 'MESH:D009369', (221, 226))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('engraft tumors', 'Disease', 'MESH:D009369', (139, 153))	('tumors', 'Disease', (147, 153))	('affect', 'Reg', (214, 220))	('patient', 'Species', '9606', (3, 10))	('tumors', 'Disease', (11, 17))	('tumor', 'Disease', (173, 178))
444541	30755230	Therefore, this study focused on determining whether miR-223-3p functioned as a tumor suppressor in LSCC through in vitro and in vivo experiments; it was down-regulated in successfully engrafted tumors (Fig.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumors', 'Disease', (195, 201))	('tumors', 'Disease', 'MESH:D009369', (195, 201))	('tumor', 'Disease', (195, 200))	('down-regulated', 'NegReg', (154, 168))	('tumors', 'Phenotype', 'HP:0002664', (195, 201))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('miR-223-3p', 'Var', (53, 63))	('tumor', 'Disease', (80, 85))	('SCC', 'Gene', (101, 104))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('3p', 'Chemical', '-', (61, 63))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('SCC', 'Gene', '6317', (101, 104))
444543	30755230	Moreover, exogenous miR-223-3p could significantly affect the growth and migration of LSCC cells in vitro (Fig.	('affect', 'Reg', (51, 57))	('3p', 'Chemical', '-', (28, 30))	('SCC', 'Gene', (87, 90))	('miR-223-3p', 'Var', (20, 30))	('SCC', 'Gene', '6317', (87, 90))	('exogenous', 'Var', (10, 19))
444544	30755230	At the same time, the present study also found that miR-223-3p expression repressed tumorigenesis in vivo (Fig.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('miR-223-3p expression', 'Var', (52, 73))	('tumor', 'Disease', (84, 89))	('3p', 'Chemical', '-', (60, 62))
444545	30755230	These results suggested that the downregulation of miR-223-3p might be associated with cellular mechanisms related to LSCC development.	('miR-223-3p', 'Var', (51, 61))	('3p', 'Chemical', '-', (59, 61))	('SCC', 'Gene', '6317', (119, 122))	('SCC', 'Gene', (119, 122))	('downregulation', 'NegReg', (33, 47))
444546	30755230	Mutant p53 proteins are expressed at a high frequency in human tumors and are associated with cell proliferation and migration.	('associated', 'Reg', (78, 88))	('proteins', 'Protein', (11, 19))	('migration', 'CPA', (117, 126))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('p53', 'Gene', '7157', (7, 10))	('tumors', 'Disease', (63, 69))	('Mutant', 'Var', (0, 6))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('cell proliferation', 'CPA', (94, 112))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('p53', 'Gene', (7, 10))	('human', 'Species', '9606', (57, 62))
444548	30755230	Among them, 6 of 12 patients harbored p53 mutations.	('p53', 'Gene', (38, 41))	('p53', 'Gene', '7157', (38, 41))	('patients', 'Species', '9606', (20, 28))	('harbored', 'Reg', (29, 37))	('mutations', 'Var', (42, 51))
444549	30755230	Moreover, 5 of 6 patients harboring p53 mutations were successfully formed xenografts.	('mutations', 'Var', (40, 49))	('patients', 'Species', '9606', (17, 25))	('p53', 'Gene', (36, 39))	('p53', 'Gene', '7157', (36, 39))
444552	30755230	Previous studies have shown that mutant p53 protein downregulates miR-223 expression in breast and colon cancer cell lines by binding miR-223 promoter and by reducing its transcriptional activity.	('expression', 'MPA', (74, 84))	('colon cancer', 'Phenotype', 'HP:0003003', (99, 111))	('breast and colon cancer', 'Disease', 'MESH:D001943', (88, 111))	('binding', 'Interaction', (126, 133))	('miR-223', 'Gene', (66, 73))	('transcriptional activity', 'MPA', (171, 195))	('reducing', 'NegReg', (158, 166))	('p53', 'Gene', (40, 43))	('downregulates', 'NegReg', (52, 65))	('mutant', 'Var', (33, 39))	('p53', 'Gene', '7157', (40, 43))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('protein', 'Protein', (44, 51))	('miR-223', 'Gene', (134, 141))
444553	30755230	Our results also confirmed that mutant p53 directly binds to the miR-223 promoter by ChIP assay (Fig.	('binds', 'Interaction', (52, 57))	('miR-223', 'Gene', (65, 72))	('mutant', 'Var', (32, 38))	('p53', 'Gene', (39, 42))	('p53', 'Gene', '7157', (39, 42))
444555	30755230	Down-regulation of mutant p53 in the SK-MES-1 and NCI-H520, miR-223-3p expression was up-regulated (Fig.	('up-regulated', 'PosReg', (86, 98))	('SK-MES-1', 'CellLine', 'CVCL:0630', (37, 45))	('miR-223-3p expression', 'MPA', (60, 81))	('p53', 'Gene', (26, 29))	('Down-regulation', 'NegReg', (0, 15))	('NCI-H520', 'CellLine', 'CVCL:1566', (50, 58))	('mutant', 'Var', (19, 25))	('p53', 'Gene', '7157', (26, 29))	('3p', 'Chemical', '-', (68, 70))
444556	30755230	In addition, the relative expression level of miR-223-3p significantly decreased in the LSCC tissue samples with mutant p53 (Fig.	('p53', 'Gene', '7157', (120, 123))	('SCC', 'Gene', '6317', (89, 92))	('expression level', 'MPA', (26, 42))	('miR-223-3p', 'Protein', (46, 56))	('3p', 'Chemical', '-', (54, 56))	('mutant', 'Var', (113, 119))	('p53', 'Gene', (120, 123))	('decreased', 'NegReg', (71, 80))	('SCC', 'Gene', (89, 92))
444557	30755230	These observations indicated that miR-223-3p was also regulated by mutant p53 at the transcriptional level in LSCC.	('regulated', 'Reg', (54, 63))	('3p', 'Chemical', '-', (42, 44))	('miR-223-3p', 'MPA', (34, 44))	('SCC', 'Gene', (111, 114))	('p53', 'Gene', (74, 77))	('mutant', 'Var', (67, 73))	('p53', 'Gene', '7157', (74, 77))	('SCC', 'Gene', '6317', (111, 114))
444559	30755230	Luciferase reporter, Western blot and IHC assay confirmed that the p53 gene was regulated by miR-223-3p in LSCC (Fig.	('SCC', 'Gene', (108, 111))	('miR-223-3p', 'Var', (93, 103))	('p53', 'Gene', (67, 70))	('p53', 'Gene', '7157', (67, 70))	('SCC', 'Gene', '6317', (108, 111))	('3p', 'Chemical', '-', (101, 103))	('regulated', 'Reg', (80, 89))
444560	30755230	In addition, we inhibited mutant p53 expression by RNA interference and found that the inhibition of p53 could significantly inhibit proliferation and migration in LSCC cells (Fig.	('inhibition', 'NegReg', (87, 97))	('inhibited', 'NegReg', (16, 25))	('inhibit', 'NegReg', (125, 132))	('SCC', 'Gene', (165, 168))	('p53', 'Gene', (101, 104))	('p53', 'Gene', '7157', (101, 104))	('SCC', 'Gene', '6317', (165, 168))	('p53', 'Gene', (33, 36))	('p53', 'Gene', '7157', (33, 36))	('mutant', 'Var', (26, 32))	('RNA interference', 'MPA', (51, 67))
444561	30755230	Thus, it was concluded that downregulation of mutant p53 might be a mechanism by which miR-223-3p exerts its tumor suppressor functions.	('miR-223-3p', 'Var', (87, 97))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('downregulation', 'NegReg', (28, 42))	('p53', 'Gene', (53, 56))	('mutant', 'Var', (46, 52))	('p53', 'Gene', '7157', (53, 56))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('3p', 'Chemical', '-', (95, 97))	('tumor', 'Disease', (109, 114))
444562	30755230	All together, these data indicated the existence of a regulatory network between miR-223-3p and mutant p53 proteins in LSCC cells to affect tumor proliferation and metastasis.	('mutant', 'Var', (96, 102))	('p53', 'Gene', (103, 106))	('proteins', 'Protein', (107, 115))	('SCC', 'Gene', '6317', (120, 123))	('p53', 'Gene', '7157', (103, 106))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('miR-223-3p', 'Var', (81, 91))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('affect', 'Reg', (133, 139))	('3p', 'Chemical', '-', (89, 91))	('SCC', 'Gene', (120, 123))	('tumor', 'Disease', (140, 145))
444563	30755230	Although we have shed a new light on the molecular mechanism responsible for miR-223-3p in LSCC progression, the other targets of miR-223-3p require further investigation.	('SCC', 'Gene', '6317', (92, 95))	('3p', 'Chemical', '-', (138, 140))	('miR-223-3p', 'Var', (77, 87))	('3p', 'Chemical', '-', (85, 87))	('SCC', 'Gene', (92, 95))
444564	30755230	On the other hand, the other detailed mechanisms by which miR-223-3p is downregulated, such as through DNA promoter methylation, interaction with long noncoding RNA or inflammation cytokines (such as IL-1beta, TNF-alpha) induction, still need to be elucidated in future studies.	('3p', 'Chemical', '-', (66, 68))	('TNF-alpha', 'Gene', '7124', (210, 219))	('IL-1beta', 'Gene', '3553', (200, 208))	('long', 'Protein', (146, 150))	('TNF-alpha', 'Gene', (210, 219))	('downregulated', 'NegReg', (72, 85))	('miR-223-3p', 'Var', (58, 68))	('inflammation', 'Disease', 'MESH:D007249', (168, 180))	('inflammation', 'Disease', (168, 180))	('interaction', 'Interaction', (129, 140))	('IL-1beta', 'Gene', (200, 208))
444565	30755230	Our study reported the altered miRNA expression pattern between LSCC tissues that were successfully engrafted into immunocompromised mice (XG) and those that did not engraft (no-XG) showing that miR-223-3p was significantly down-regulated in the XG group.	('mice', 'Species', '10090', (133, 137))	('3p', 'Chemical', '-', (203, 205))	('SCC', 'Gene', (65, 68))	('SCC', 'Gene', '6317', (65, 68))	('down-regulated', 'NegReg', (224, 238))	('miR-223-3p', 'Var', (195, 205))	('altered', 'Reg', (23, 30))	('miRNA expression pattern', 'MPA', (31, 55))
444566	30755230	Our findings demonstrated a tumor suppressor role of miR-223-3p in LSCC bearing p53 mutations in vitro and vivo.	('tumor', 'Disease', (28, 33))	('SCC', 'Gene', '6317', (68, 71))	('p53', 'Gene', (80, 83))	('miR-223-3p', 'Var', (53, 63))	('mutations', 'Var', (84, 93))	('p53', 'Gene', '7157', (80, 83))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('3p', 'Chemical', '-', (61, 63))	('SCC', 'Gene', (68, 71))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
444567	30755230	In addition, we demonstrated that a regulatory network existed between miR-223-3p and mutant p53 proteins in LSCC cells; mutant p53/miR-223-3p feedback loop regulated the proliferation and migration of LSCC cell lines.	('3p', 'Chemical', '-', (140, 142))	('SCC', 'Gene', (203, 206))	('mutant', 'Var', (121, 127))	('p53', 'Gene', (128, 131))	('p53', 'Gene', '7157', (128, 131))	('mutant', 'Var', (86, 92))	('p53', 'Gene', (93, 96))	('proteins', 'Protein', (97, 105))	('p53', 'Gene', '7157', (93, 96))	('3p', 'Chemical', '-', (79, 81))	('regulated', 'Reg', (157, 166))	('SCC', 'Gene', (110, 113))	('SCC', 'Gene', '6317', (203, 206))	('SCC', 'Gene', '6317', (110, 113))	('proliferation', 'CPA', (171, 184))	('migration', 'CPA', (189, 198))
444568	30755230	The present experimental data suggested that miR-223-3p plus mutant p53 may serve as an improved prognostic biomarker useful for prediction of prognosis in patients with LSCC.	('SCC', 'Gene', (171, 174))	('patients', 'Species', '9606', (156, 164))	('miR-223-3p plus mutant', 'Var', (45, 67))	('SCC', 'Gene', '6317', (171, 174))	('mutant', 'Var', (61, 67))	('p53', 'Gene', (68, 71))	('p53', 'Gene', '7157', (68, 71))	('3p', 'Chemical', '-', (53, 55))
444569	30755230	These data may also provide a novel strategy for treatment of patients with LSCC bearing p53 mutations.	('mutations', 'Var', (93, 102))	('p53', 'Gene', (89, 92))	('SCC', 'Gene', (77, 80))	('p53', 'Gene', '7157', (89, 92))	('patients', 'Species', '9606', (62, 70))	('SCC', 'Gene', '6317', (77, 80))
444575	26146661	Ten candidate SNPs previously associated with non-melanoma skin cancer in the general population were significantly associated with cSCC in transplant recipients.	('cSCC', 'Disease', (132, 136))	('skin cancer', 'Phenotype', 'HP:0008069', (59, 70))	('melanoma', 'Phenotype', 'HP:0002861', (50, 58))	('non-melanoma skin cancer', 'Disease', 'MESH:D012878', (46, 70))	('SNPs', 'Var', (14, 18))	('non-melanoma skin cancer', 'Disease', (46, 70))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('associated', 'Reg', (116, 126))
444576	26146661	Genome wide association analysis implicated SNPs in genes previously associated with malignancy, CSMD1 (OR 3.14 [1.90-5.20]) and CACNA1D (OR 2.67 [1.73-4.10]).	('malignancy', 'Disease', (85, 95))	('CSMD1', 'Gene', (97, 102))	('CSMD1', 'Gene', '64478', (97, 102))	('SNPs', 'Var', (44, 48))	('CACNA1D', 'Gene', (129, 136))	('CACNA1D', 'Gene', '776', (129, 136))	('malignancy', 'Disease', 'MESH:D009369', (85, 95))
444584	26146661	The heart transplant population was similarly identified by searching the SD for ICD9 (V42.1 - heart transplantation) and CPT (33935 and 33945 - heart transplant) codes resulting in 137 adult individuals.	('33935', 'Var', (127, 132))	('CPT', 'Gene', (122, 125))	('ICD', 'Gene', (81, 84))	('ICD', 'Gene', '79158', (81, 84))
444586	26146661	Cases of cSCC were identified by ICD9 codes (173.xx group - squamous cell carcinoma) and keyword(s) search ("squamous cell carcinoma", "SCC", "skin cancer").	('skin cancer', 'Phenotype', 'HP:0008069', (143, 154))	('skin cancer', 'Disease', (143, 154))	('cSCC', 'Disease', (9, 13))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (109, 132))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (109, 132))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('skin cancer', 'Disease', 'MESH:D012878', (143, 154))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (60, 83))	('ICD', 'Gene', '79158', (33, 36))	('173.xx', 'Var', (45, 51))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (60, 83))	('squamous cell carcinoma', 'Disease', (109, 132))	('ICD', 'Gene', (33, 36))	('squamous cell carcinoma', 'Disease', (60, 83))
444601	26146661	Prior azathioprine exposure was also significantly associated with cSCC development with individuals exposed to azathioprine having an increased odds for cSCC development compared to controls without prior exposure (OR 8.64 [3.92-19.03], p<0.001).	('cSCC development', 'Disease', (67, 83))	('associated', 'Reg', (51, 61))	('azathioprine', 'Chemical', 'MESH:D001379', (112, 124))	('azathioprine', 'Var', (112, 124))	('azathioprine', 'Chemical', 'MESH:D001379', (6, 18))
444603	26146661	Our replication included rs12203592 (OR 2.08 [1.23-3.53], p=0.007), an intronic SNP in interferon regulatory factor 4 (IRF4), which is the most significant SNP-NMSC association in both the PheWAS (Table 4) and NHGRI (OR 4.76 [3.70-6.67], p=7x10-14) catalogs.	('interferon regulatory factor 4', 'Gene', '3662', (87, 117))	('interferon regulatory factor 4', 'Gene', (87, 117))	('rs12203592', 'Var', (25, 35))	('IRF4', 'Gene', '3662', (119, 123))	('IRF4', 'Gene', (119, 123))	('rs12203592', 'Mutation', 'rs12203592', (25, 35))
444604	26146661	These associations included several polymorphisms in LINC00882 (long intergenic non-protein coding RNA 882) and the genes CACNA1D (calcium channel, voltage-dependent, L-type, alpha 1D subunit) and CSMD1 (CUB and Sushi multiple domains 1).	('LINC00882', 'Gene', (53, 62))	('polymorphisms', 'Var', (36, 49))	('associations', 'Interaction', (6, 18))	('CUB and Sushi multiple domains 1', 'Gene', '64478', (204, 236))	('CSMD1', 'Gene', (197, 202))	('CSMD1', 'Gene', '64478', (197, 202))	('LINC00882', 'Gene', '100302640', (53, 62))	('CACNA1D', 'Gene', '776', (122, 129))	('CACNA1D', 'Gene', (122, 129))
444608	26146661	Though we did not find any genome-wide associations, our results did replicate 10 candidate SNPs previously associated with skin cancer risk in the general population.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('SNPs', 'Var', (92, 96))	('skin cancer', 'Phenotype', 'HP:0008069', (124, 135))	('associated', 'Reg', (108, 118))	('skin cancer', 'Disease', (124, 135))	('skin cancer', 'Disease', 'MESH:D012878', (124, 135))
444621	26146661	The IRF4 SNP, rs12203592, replicated in our study of 88 cases was previously discovered (p=7.2x10-14) and replicated (6.7x10-7) in a much larger population GWAS for pigmentation traits and NMSC development with 10,183 European Americans in the discovery set and an additional 4,504 European Americans in the replication set.	('IRF4', 'Gene', '3662', (4, 8))	('rs12203592', 'Mutation', 'rs12203592', (14, 24))	('IRF4', 'Gene', (4, 8))	('pigmentation traits', 'Disease', (165, 184))	('rs12203592', 'Var', (14, 24))	('pigmentation traits', 'Disease', 'MESH:D010859', (165, 184))
444622	26146661	The EXOC2 SNP, rs12210050, also replicated in our study was previously identified from a case-control study examining SNP-cSCC association in 783 incident cSCC cases and 2,026 controls and demonstrated a significant increase in the odds of cSCC development for white individuals with this SNP (OR 1.35, p=7.6x10-5).	('EXOC2', 'Gene', '55770', (4, 9))	('cSCC development', 'CPA', (240, 256))	('rs12210050', 'Var', (15, 25))	('EXOC2', 'Gene', (4, 9))	('rs12210050', 'Mutation', 'rs12210050', (15, 25))	('increase', 'PosReg', (216, 224))
444623	26146661	In addition, four of our replicated SNPs (intergenic rs1540771, rs12203592 in IRF4, rs12210050 in EXOC2, and rs258322 in CDK10) have also previously been associated with freckling, tanning, eye and hair color and variations in each of these characteristics has also been linked to increased NMSC risk.	('freckling', 'Disease', (170, 179))	('eye and hair color', 'Disease', 'MESH:D003117', (190, 208))	('rs12203592', 'Var', (64, 74))	('rs1540771', 'Mutation', 'rs1540771', (53, 62))	('NMSC', 'Disease', (291, 295))	('rs258322', 'Var', (109, 117))	('EXOC2', 'Gene', '55770', (98, 103))	('linked', 'Reg', (271, 277))	('CDK10', 'Gene', '8558', (121, 126))	('CDK10', 'Gene', (121, 126))	('rs12210050', 'Var', (84, 94))	('variations', 'Var', (213, 223))	('EXOC2', 'Gene', (98, 103))	('IRF4', 'Gene', '3662', (78, 82))	('rs12210050', 'Mutation', 'rs12210050', (84, 94))	('freckling', 'Phenotype', 'HP:0001480', (170, 179))	('associated', 'Reg', (154, 164))	('tanning', 'Disease', (181, 188))	('IRF4', 'Gene', (78, 82))	('rs12203592', 'Mutation', 'rs12203592', (64, 74))	('rs1540771', 'Var', (53, 62))	('rs258322', 'Mutation', 'rs258322', (109, 117))
444625	26146661	The GWAS did not produce any SNP-cSCC associations that were genome-wide significant (p<5x10-8) likely due to the relatively small number of cSCC cases, but SNPs associated with the biologically plausible genes CSMD1 and CACNA1D that could play a role in cSCC development were suggested.	('CACNA1D', 'Gene', '776', (221, 228))	('CACNA1D', 'Gene', (221, 228))	('SNPs', 'Var', (157, 161))	('CSMD1', 'Gene', (211, 216))	('CSMD1', 'Gene', '64478', (211, 216))	('cSCC', 'Disease', (255, 259))
444634	26146661	Future multi-center prospective studies are warranted to identify genetic variation associated with post-transplant cSCC in order to enhance the long-term care of the transplant patient.	('enhance', 'PosReg', (133, 140))	('genetic variation', 'Var', (66, 83))	('patient', 'Species', '9606', (178, 185))	('associated', 'Reg', (84, 94))	('cSCC', 'Disease', (116, 120))
444635	26146661	AIM Ancestry Informative Markers CPT Current Procedural Terminology cSCC cutaneous Squamous Cell Carcinoma eMERGE Electronic Medical Records and Genomics EMR electronic medical record GWAS Genome Wide Association Study IBD Identity By Descent ICD International Classification of Disease NHGRI National Human Genome Research Institute NMSC non-melanoma skin cancer OR Odds Ratio PC Principal Component PheWAS Phenome Wide Association Study QC Quality Control SD Synthetic Derivative SNP Single Nucleotide Polymorphisms VUMC Vanderbilt University Medical Center	('VUMC', 'Chemical', '-', (518, 522))	('cancer', 'Phenotype', 'HP:0002664', (357, 363))	('non-melanoma skin cancer', 'Disease', (339, 363))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (83, 106))	('melanoma', 'Phenotype', 'HP:0002861', (343, 351))	('cutaneous Squamous Cell Carcinoma', 'Disease', 'MESH:D002294', (73, 106))	('cutaneous Squamous Cell Carcinoma', 'Phenotype', 'HP:0006739', (73, 106))	('ICD', 'Gene', '79158', (243, 246))	('Human', 'Species', '9606', (302, 307))	('skin cancer', 'Phenotype', 'HP:0008069', (352, 363))	('cutaneous Squamous Cell Carcinoma', 'Disease', (73, 106))	('Carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('Single Nucleotide Polymorphisms', 'Var', (486, 517))	('ICD', 'Gene', (243, 246))	('non-melanoma skin cancer', 'Disease', 'MESH:D012878', (339, 363))
444716	31239782	Deletion of the GPHN gene in mice revealed that gephyrin regulates molybdenum cofactor biosynthesis, implying that the main functions of gephyrin in neurons are linked to the control of inhibitory neurotransmission.	('regulates', 'Reg', (57, 66))	('molybdenum cofactor biosynthesis', 'MPA', (67, 99))	('mice', 'Species', '10090', (29, 33))	('GPHN', 'Gene', (16, 20))	('Deletion', 'Var', (0, 8))
444719	31239782	Here, we report that gephyrin expression was lower in human NSCLC specimens than in the surrounding non-tumorous tissues, and gephyrin suppressed LUSC development via reduction of the mTOR pathway.	('expression', 'MPA', (30, 40))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('gephyrin', 'Protein', (21, 29))	('suppressed', 'NegReg', (135, 145))	('mTOR', 'Gene', '2475', (184, 188))	('mTOR', 'Gene', (184, 188))	('tumor', 'Disease', (104, 109))	('reduction', 'NegReg', (167, 176))	('lower', 'NegReg', (45, 50))	('NSCLC', 'Disease', (60, 65))	('LUSC development', 'CPA', (146, 162))	('gephyrin', 'Var', (126, 134))	('human', 'Species', '9606', (54, 59))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('NSCLC', 'Disease', 'MESH:D002289', (60, 65))
444756	31239782	The proliferation marker PCNA was also suppressed by gephyrin in H520 (Figure 2E) and SK-MES-1 (Figure 2F) cells.	('SK-MES-1', 'CellLine', 'CVCL:0630', (86, 94))	('PCNA', 'Gene', (25, 29))	('gephyrin', 'Var', (53, 61))	('PCNA', 'Gene', '5111', (25, 29))	('suppressed', 'NegReg', (39, 49))
444757	31239782	In addition, knockdown of gephyrin by siRNA promoted H520 (Figure 2G) and SK-MES-1 (Figure 2H) cell growth.	('H520', 'CPA', (53, 57))	('promoted', 'PosReg', (44, 52))	('gephyrin', 'Gene', (26, 34))	('SK-MES-1', 'CellLine', 'CVCL:0630', (74, 82))	('knockdown', 'Var', (13, 22))
444770	31239782	Gephyrin significantly reduced the stability of mTOR (half-life [t1/2]=1.9 hours in the gephyrin overexpression group and t1/2=11.2 hours in the control group) (Figure 4B).	('overexpression', 'PosReg', (97, 111))	('mTOR', 'Gene', '2475', (48, 52))	('mTOR', 'Gene', (48, 52))	('Gephyrin', 'Gene', '10243', (0, 8))	('stability', 'MPA', (35, 44))	('gephyrin', 'Var', (88, 96))	('reduced', 'NegReg', (23, 30))	('Gephyrin', 'Gene', (0, 8))
444785	31239782	GPHN mutations may cause some neurological diseases (eg, molybdenum cofactor deficiency, stiff-person syndrome, and hyperekplexia).	('cause', 'Reg', (19, 24))	('hyperekplexia', 'Disease', (116, 129))	('GPHN', 'Gene', (0, 4))	('neurological diseases', 'Disease', (30, 51))	('molybdenum cofactor deficiency', 'Disease', 'MESH:C535811', (57, 87))	('stiff-person syndrome', 'Disease', 'MESH:D016750', (89, 110))	('mutations', 'Var', (5, 14))	('molybdenum cofactor deficiency', 'Disease', (57, 87))	('hyperekplexia', 'Disease', 'MESH:D000071017', (116, 129))	('hyperekplexia', 'Phenotype', 'HP:0002267', (116, 129))	('molybdenum cofactor deficiency', 'Phenotype', 'HP:0003570', (57, 87))	('stiff-person syndrome', 'Disease', (89, 110))	('neurological diseases', 'Disease', 'MESH:D019636', (30, 51))
444789	31239782	The target of rapamycin (TOR) was originally identified by mutations which confer resistance to the growth-inhibitory properties of rapamycin.	('rapamycin', 'Chemical', 'MESH:D020123', (132, 141))	('resistance', 'MPA', (82, 92))	('mutations', 'Var', (59, 68))	('rapamycin', 'Chemical', 'MESH:D020123', (14, 23))	('growth-inhibitory properties of rapamycin', 'MPA', (100, 141))
444792	31239782	Targeted inhibition of the mTOR pathway can prevent tumor progression.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumor', 'Disease', (52, 57))	('mTOR', 'Gene', (27, 31))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('inhibition', 'Var', (9, 19))	('mTOR', 'Gene', '2475', (27, 31))
444804	30073324	We also calculated the metastatic rate using an updated dataset of uveal melanoma patients with known mutations in BAP1, SF3B1 and EIF1AX provided by the Rotterdam Ocular Melanoma Study Group.	('Melanoma', 'Phenotype', 'HP:0002861', (171, 179))	('melanoma', 'Phenotype', 'HP:0002861', (73, 81))	('EIF1AX', 'Gene', '1964', (131, 137))	('EIF1AX', 'Gene', (131, 137))	('Ocular Melanoma', 'Phenotype', 'HP:0007716', (164, 179))	('Rotterdam Ocular Melanoma', 'Disease', 'MESH:D008545', (154, 179))	('BAP1', 'Gene', '8314', (115, 119))	('patients', 'Species', '9606', (82, 90))	('uveal melanoma', 'Phenotype', 'HP:0007716', (67, 81))	('uveal melanoma', 'Disease', (67, 81))	('uveal melanoma', 'Disease', 'MESH:C536494', (67, 81))	('mutations', 'Var', (102, 111))	('BAP1', 'Gene', (115, 119))	('SF3B1', 'Gene', (121, 126))	('Rotterdam Ocular Melanoma', 'Disease', (154, 179))	('SF3B1', 'Gene', '23451', (121, 126))
444807	30073324	EIF1AX mutations were not exclusive of other mutations as two cases with EIF1AX mutations and metastasis also had BAP1 mutations.	('EIF1AX', 'Gene', '1964', (73, 79))	('EIF1AX', 'Gene', (73, 79))	('mutations', 'Var', (80, 89))	('BAP1', 'Gene', '8314', (114, 118))	('BAP1', 'Gene', (114, 118))	('mutations', 'Var', (119, 128))	('EIF1AX', 'Gene', '1964', (0, 6))	('EIF1AX', 'Gene', (0, 6))
444808	30073324	None of the tumors with only an EIF1AX mutation metastasized.	('mutation', 'Var', (39, 47))	('EIF1AX', 'Gene', (32, 38))	('EIF1AX', 'Gene', '1964', (32, 38))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('tumors', 'Disease', (12, 18))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('tumors', 'Disease', 'MESH:D009369', (12, 18))
444809	30073324	After plotting the yearly metastatic rate versus time after treatment, we observed a small peak at 1 year and a large peak at 3.5 years after treatment for BAP1 mutations, with peaks between 2 and 3 years and at 7 years for SF3B1 mutations.	('BAP1', 'Gene', '8314', (156, 160))	('mutations', 'Var', (230, 239))	('SF3B1', 'Gene', (224, 229))	('mutations', 'Var', (161, 170))	('BAP1', 'Gene', (156, 160))	('SF3B1', 'Gene', '23451', (224, 229))
444834	30073324	The Rotterdam Ocular Melanoma Study Group provided a large dataset of uveal melanoma patients with mutation analysis for BAP1, SF3B1 and EIF1AX.	('Rotterdam Ocular Melanoma', 'Disease', (4, 29))	('Melanoma', 'Phenotype', 'HP:0002861', (21, 29))	('BAP1', 'Gene', '8314', (121, 125))	('uveal melanoma', 'Disease', (70, 84))	('uveal melanoma', 'Disease', 'MESH:C536494', (70, 84))	('uveal melanoma', 'Phenotype', 'HP:0007716', (70, 84))	('SF3B1', 'Gene', (127, 132))	('Rotterdam Ocular Melanoma', 'Disease', 'MESH:D008545', (4, 29))	('Ocular Melanoma', 'Phenotype', 'HP:0007716', (14, 29))	('BAP1', 'Gene', (121, 125))	('patients', 'Species', '9606', (85, 93))	('mutation analysis', 'Var', (99, 116))	('EIF1AX', 'Gene', (137, 143))	('EIF1AX', 'Gene', '1964', (137, 143))	('SF3B1', 'Gene', '23451', (127, 132))	('melanoma', 'Phenotype', 'HP:0002861', (76, 84))
444843	30073324	The Rotterdam Ocular Melanoma Study Group investigated the mutation status for BAP1, SF3B1 and EIF1AX in uveal melanoma and compared this with survival.	('Rotterdam Ocular Melanoma', 'Disease', (4, 29))	('Melanoma', 'Phenotype', 'HP:0002861', (21, 29))	('BAP1', 'Gene', '8314', (79, 83))	('melanoma', 'Phenotype', 'HP:0002861', (111, 119))	('SF3B1', 'Gene', (85, 90))	('Rotterdam Ocular Melanoma', 'Disease', 'MESH:D008545', (4, 29))	('EIF1AX', 'Gene', (95, 101))	('Ocular Melanoma', 'Phenotype', 'HP:0007716', (14, 29))	('BAP1', 'Gene', (79, 83))	('EIF1AX', 'Gene', '1964', (95, 101))	('mutation', 'Var', (59, 67))	('uveal melanoma', 'Disease', (105, 119))	('uveal melanoma', 'Disease', 'MESH:C536494', (105, 119))	('SF3B1', 'Gene', '23451', (85, 90))	('uveal melanoma', 'Phenotype', 'HP:0007716', (105, 119))
444844	30073324	In that study, there were 255 subjects, of which 162 had BAP1 mutations, 43 had SF3B1 mutations, 21 had EIF1AX mutations and 29 had no mutation.	('EIF1AX', 'Gene', (104, 110))	('mutations', 'Var', (86, 95))	('SF3B1', 'Gene', '23451', (80, 85))	('BAP1', 'Gene', '8314', (57, 61))	('SF3B1', 'Gene', (80, 85))	('BAP1', 'Gene', (57, 61))	('mutations', 'Var', (62, 71))	('EIF1AX', 'Gene', '1964', (104, 110))
444848	30073324	Ninety-one subjects harbored BAP1 mutations, 31 had GNAQ mutations, 31 had GNA11 mutations, 2 had EIF1AX mutations and 12 had SF3B1 mutations.	('SF3B1', 'Gene', (126, 131))	('GNAQ', 'Gene', '2776', (52, 56))	('GNA11', 'Gene', '2767', (75, 80))	('GNA11', 'Gene', (75, 80))	('BAP1', 'Gene', '8314', (29, 33))	('EIF1AX', 'Gene', '1964', (98, 104))	('EIF1AX', 'Gene', (98, 104))	('SF3B1', 'Gene', '23451', (126, 131))	('GNAQ', 'Gene', (52, 56))	('BAP1', 'Gene', (29, 33))	('mutations', 'Var', (34, 43))
444849	30073324	Two patients with metastatic uveal melanoma and mutated EIF1AX were excluded because they harbored a BAP1 mutation.	('mutated', 'Var', (48, 55))	('BAP1', 'Gene', '8314', (101, 105))	('uveal melanoma', 'Phenotype', 'HP:0007716', (29, 43))	('uveal melanoma', 'Disease', (29, 43))	('mutation', 'Var', (106, 114))	('uveal melanoma', 'Disease', 'MESH:C536494', (29, 43))	('harbored', 'Reg', (90, 98))	('BAP1', 'Gene', (101, 105))	('patients', 'Species', '9606', (4, 12))	('melanoma', 'Phenotype', 'HP:0002861', (35, 43))	('EIF1AX', 'Gene', '1964', (56, 62))	('EIF1AX', 'Gene', (56, 62))
444851	30073324	Twenty-five patients with mutated GNAQ harbored BAP1 mutations, and 5 with GNAQ mutations had SF3B1 mutations.	('SF3B1', 'Gene', '23451', (94, 99))	('patients', 'Species', '9606', (12, 20))	('BAP1', 'Gene', '8314', (48, 52))	('GNAQ', 'Gene', (75, 79))	('BAP1', 'Gene', (48, 52))	('mutations', 'Var', (53, 62))	('mutated', 'Var', (26, 33))	('GNAQ', 'Gene', (34, 38))	('SF3B1', 'Gene', (94, 99))	('GNAQ', 'Gene', '2776', (75, 79))	('GNAQ', 'Gene', '2776', (34, 38))
444852	30073324	24 of subjects with GNA11 mutations harbored BAP1 mutations and 4 of them had SF3B1 mutations.	('BAP1', 'Gene', (45, 49))	('mutations', 'Var', (50, 59))	('SF3B1', 'Gene', '23451', (78, 83))	('GNA11', 'Gene', (20, 25))	('mutations', 'Var', (26, 35))	('GNA11', 'Gene', '2767', (20, 25))	('harbored', 'Reg', (36, 44))	('BAP1', 'Gene', '8314', (45, 49))	('SF3B1', 'Gene', (78, 83))
444853	30073324	After plotting yearly metastatic rate against the time after treatment for the different mutations, we observed a small peak in metastases at 1 year after treatment and a large peak at 3.5 years for BAP1 mutations, with an early peak between 2 and 3 years and a late peak at 7 years for SF3B1 mutations (Figure 1B).	('metastases', 'Disease', (128, 138))	('BAP1', 'Gene', (199, 203))	('SF3B1', 'Gene', '23451', (287, 292))	('mutations', 'Var', (204, 213))	('mutations', 'Var', (293, 302))	('metastases', 'Disease', 'MESH:D009362', (128, 138))	('BAP1', 'Gene', '8314', (199, 203))	('SF3B1', 'Gene', (287, 292))
444854	30073324	There was a lack of metastases in patients with tumors that harbored EIF1AX mutations.	('EIF1AX', 'Gene', '1964', (69, 75))	('EIF1AX', 'Gene', (69, 75))	('mutations', 'Var', (76, 85))	('tumors', 'Disease', (48, 54))	('tumors', 'Disease', 'MESH:D009369', (48, 54))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('patients', 'Species', '9606', (34, 42))	('metastases', 'Disease', (20, 30))	('metastases', 'Disease', 'MESH:D009362', (20, 30))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
444875	30073324	Our results support the hypothesis that for uveal melanoma, tumor size correlating with metastatic rate can largely be explained by the number of neutral mutations in the tumors, consistent with the notion that tumor heterogeneity arises from subclonal accumulation of mutations.	('tumors', 'Disease', 'MESH:D009369', (171, 177))	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('melanoma', 'Phenotype', 'HP:0002861', (50, 58))	('metastatic', 'CPA', (88, 98))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('uveal melanoma', 'Phenotype', 'HP:0007716', (44, 58))	('tumor', 'Disease', (211, 216))	('uveal melanoma', 'Disease', 'MESH:C536494', (44, 58))	('mutations', 'Var', (154, 163))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', (171, 176))	('tumor', 'Disease', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('uveal melanoma', 'Disease', (44, 58))	('tumors', 'Disease', (171, 177))	('tumors', 'Phenotype', 'HP:0002664', (171, 177))
444882	30073324	Williams et al highlighted that mutation rate and mutational timeline are the most important characteristics of tumors possessing neutral growth, whereas selection and the microenvironment may play a key role for non-neutral cancer types.	('cancer', 'Disease', 'MESH:D009369', (225, 231))	('cancer', 'Disease', (225, 231))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('mutational', 'Var', (50, 60))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('tumors', 'Disease', 'MESH:D009369', (112, 118))	('mutation', 'Var', (32, 40))	('tumors', 'Disease', (112, 118))
444890	30073324	Mutations in GNAQ and GNA11 occur early in tumor formation while BAP1, SF3B1, and EIF1AX mutations likely occur later in tumor progression.	('SF3B1', 'Gene', (71, 76))	('BAP1', 'Gene', '8314', (65, 69))	('GNA11', 'Gene', (22, 27))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('GNAQ', 'Gene', (13, 17))	('GNA11', 'Gene', '2767', (22, 27))	('SF3B1', 'Gene', '23451', (71, 76))	('tumor', 'Disease', (121, 126))	('BAP1', 'Gene', (65, 69))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('Mutations', 'Var', (0, 9))	('EIF1AX', 'Gene', '1964', (82, 88))	('EIF1AX', 'Gene', (82, 88))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Disease', (43, 48))	('GNAQ', 'Gene', '2776', (13, 17))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
444891	30073324	Mutation in EIF1AX is an indicator of good prognosis, whereas mutations in SF3B1 and BAP1 are associated with intermediate and poor prognosis.	('BAP1', 'Gene', (85, 89))	('EIF1AX', 'Gene', (12, 18))	('mutations', 'Var', (62, 71))	('Mutation', 'Var', (0, 8))	('EIF1AX', 'Gene', '1964', (12, 18))	('SF3B1', 'Gene', '23451', (75, 80))	('BAP1', 'Gene', '8314', (85, 89))	('SF3B1', 'Gene', (75, 80))
444892	30073324	GNAQ and GNA11 have recently shown to be mutated in choroidal nevi and they have not been proved to be associated with metastasis and survival in uveal melanoma.	('GNA11', 'Gene', (9, 14))	('melanoma', 'Phenotype', 'HP:0002861', (152, 160))	('mutated', 'Var', (41, 48))	('nevi', 'Phenotype', 'HP:0003764', (62, 66))	('uveal melanoma', 'Disease', 'MESH:C536494', (146, 160))	('GNAQ', 'Gene', '2776', (0, 4))	('associated', 'Reg', (103, 113))	('uveal melanoma', 'Phenotype', 'HP:0007716', (146, 160))	('uveal melanoma', 'Disease', (146, 160))	('choroidal nevi', 'Phenotype', 'HP:0025314', (52, 66))	('GNAQ', 'Gene', (0, 4))	('choroidal nevi', 'Disease', (52, 66))	('GNA11', 'Gene', '2767', (9, 14))
444895	30073324	The Rotterdam Ocular Melanoma Study Group investigated the association of EIF1AX, SF3B1 and BAP1 mutation with disease-free survival and metastatic risk of patients with uveal melanoma.	('patients', 'Species', '9606', (156, 164))	('Rotterdam Ocular Melanoma', 'Disease', (4, 29))	('SF3B1', 'Gene', (82, 87))	('uveal melanoma', 'Disease', 'MESH:C536494', (170, 184))	('Melanoma', 'Phenotype', 'HP:0002861', (21, 29))	('melanoma', 'Phenotype', 'HP:0002861', (176, 184))	('association', 'Interaction', (59, 70))	('Rotterdam Ocular Melanoma', 'Disease', 'MESH:D008545', (4, 29))	('uveal melanoma', 'Disease', (170, 184))	('uveal melanoma', 'Phenotype', 'HP:0007716', (170, 184))	('SF3B1', 'Gene', '23451', (82, 87))	('EIF1AX', 'Gene', '1964', (74, 80))	('EIF1AX', 'Gene', (74, 80))	('Ocular Melanoma', 'Phenotype', 'HP:0007716', (14, 29))	('BAP1', 'Gene', '8314', (92, 96))	('mutation', 'Var', (97, 105))	('metastatic', 'CPA', (137, 147))	('BAP1', 'Gene', (92, 96))
444896	30073324	Three slopes on survival curves of patients treated for uveal melanoma could be identified, the first slope being at 3 years on the BAP1 mutation curve, the second slope being at 7-8 years on the SF3B1 mutation curve and the third slope being at 8 years on the EIF1AX mutation curve.	('BAP1', 'Gene', '8314', (132, 136))	('uveal melanoma', 'Disease', (56, 70))	('uveal melanoma', 'Phenotype', 'HP:0007716', (56, 70))	('mutation', 'Var', (137, 145))	('SF3B1', 'Gene', (196, 201))	('BAP1', 'Gene', (132, 136))	('patients', 'Species', '9606', (35, 43))	('SF3B1', 'Gene', '23451', (196, 201))	('EIF1AX', 'Gene', '1964', (261, 267))	('EIF1AX', 'Gene', (261, 267))	('uveal melanoma', 'Disease', 'MESH:C536494', (56, 70))	('melanoma', 'Phenotype', 'HP:0002861', (62, 70))
444900	30073324	The third peak may coincide with the SF3B1 mutation effects on the metastasis and survival probability.	('SF3B1', 'Gene', '23451', (37, 42))	('mutation', 'Var', (43, 51))	('metastasis', 'CPA', (67, 77))	('effects', 'Reg', (52, 59))	('survival probability', 'CPA', (82, 102))	('SF3B1', 'Gene', (37, 42))
444902	30073324	In the original article, 24% of patients harbored an SF3B1 mutations and 21% of patients had an EIF1AX mutations.	('EIF1AX', 'Gene', '1964', (96, 102))	('patients', 'Species', '9606', (32, 40))	('patients', 'Species', '9606', (80, 88))	('SF3B1', 'Gene', '23451', (53, 58))	('mutations', 'Var', (59, 68))	('EIF1AX', 'Gene', (96, 102))	('SF3B1', 'Gene', (53, 58))
444904	30073324	Decatur et al reported a prevalence of BAP1 mutations in 45%, SF3B1 mutations in 24%, and EIF1AX mutations in 17% of uveal melanomas.	('EIF1AX', 'Gene', (90, 96))	('mutations', 'Var', (97, 106))	('EIF1AX', 'Gene', '1964', (90, 96))	('uveal melanomas', 'Disease', (117, 132))	('uveal melanomas', 'Phenotype', 'HP:0007716', (117, 132))	('melanoma', 'Phenotype', 'HP:0002861', (123, 131))	('SF3B1', 'Gene', (62, 67))	('mutations', 'Var', (44, 53))	('BAP1', 'Gene', '8314', (39, 43))	('uveal melanomas', 'Disease', 'MESH:C536494', (117, 132))	('mutations', 'Var', (68, 77))	('melanomas', 'Phenotype', 'HP:0002861', (123, 132))	('uveal melanoma', 'Phenotype', 'HP:0007716', (117, 131))	('SF3B1', 'Gene', '23451', (62, 67))	('BAP1', 'Gene', (39, 43))
444905	30073324	They found that BAP1, SF3B1, and EIF1AX mutations were usually mutually exclusive from one another.	('SF3B1', 'Gene', (22, 27))	('SF3B1', 'Gene', '23451', (22, 27))	('EIF1AX', 'Gene', '1964', (33, 39))	('EIF1AX', 'Gene', (33, 39))	('mutations', 'Var', (40, 49))	('BAP1', 'Gene', '8314', (16, 20))	('BAP1', 'Gene', (16, 20))
444906	30073324	After performing a meta-analysis of the Rotterdam data, we observed a peak of metastasis at 3.5 years for BAP1 mutations and a peak between 2 and 3 years and a late peak at 7 years for SF3B1 mutation after treatment for the primary uveal melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (238, 246))	('mutations', 'Var', (111, 120))	('BAP1', 'Gene', (106, 110))	('SF3B1', 'Gene', (185, 190))	('uveal melanoma', 'Phenotype', 'HP:0007716', (232, 246))	('uveal melanoma', 'Disease', 'MESH:C536494', (232, 246))	('uveal melanoma', 'Disease', (232, 246))	('SF3B1', 'Gene', '23451', (185, 190))	('BAP1', 'Gene', '8314', (106, 110))	('metastasis', 'CPA', (78, 88))
444907	30073324	SF3B1 mutations have been found to be associated with Preferentially Expressed Antigen in Melanoma (PRAME) expression.	('SF3B1', 'Gene', (0, 5))	('associated', 'Reg', (38, 48))	('PRAME', 'Gene', '23532', (100, 105))	('Preferentially Expressed Antigen in Melanoma', 'Gene', '23532', (54, 98))	('PRAME', 'Gene', (100, 105))	('Melanoma', 'Phenotype', 'HP:0002861', (90, 98))	('SF3B1', 'Gene', '23451', (0, 5))	('Preferentially Expressed Antigen in Melanoma', 'Gene', (54, 98))	('mutations', 'Var', (6, 15))
444908	30073324	Since PRAME is an independent risk factor for the development of metastasis in disomy 3 tumors, PRAME expression might have an influence on the SF3B1 mutation related survival curve.	('PRAME', 'Gene', '23532', (96, 101))	('metastasis in disomy 3 tumors', 'Disease', (65, 94))	('PRAME', 'Gene', (6, 11))	('SF3B1', 'Gene', (144, 149))	('mutation', 'Var', (150, 158))	('PRAME', 'Gene', (96, 101))	('metastasis in disomy 3 tumors', 'Disease', 'MESH:D009362', (65, 94))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('influence', 'Reg', (127, 136))	('SF3B1', 'Gene', '23451', (144, 149))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('PRAME', 'Gene', '23532', (6, 11))
444912	30073324	Disease-free survival of uveal melanoma patients with BAP1 and SF3B1 mutation may be influenced by the follow-up as survival is more favorable for patients with SF3B1 mutation in the earlier stages.	('uveal melanoma', 'Phenotype', 'HP:0007716', (25, 39))	('uveal melanoma', 'Disease', (25, 39))	('SF3B1', 'Gene', (161, 166))	('SF3B1', 'Gene', (63, 68))	('patients', 'Species', '9606', (40, 48))	('SF3B1', 'Gene', '23451', (161, 166))	('mutation', 'Var', (69, 77))	('BAP1', 'Gene', '8314', (54, 58))	('patients', 'Species', '9606', (147, 155))	('SF3B1', 'Gene', '23451', (63, 68))	('melanoma', 'Phenotype', 'HP:0002861', (31, 39))	('BAP1', 'Gene', (54, 58))	('uveal melanoma', 'Disease', 'MESH:C536494', (25, 39))
444916	30073324	Regarding time to clinically detected metastasis, the first two peaks appear to coincide with BAP1-mutated tumors and the late peak appears to coincide with the SF3B1 mutated tumors.	('tumors', 'Disease', (175, 181))	('tumors', 'Disease', 'MESH:D009369', (175, 181))	('SF3B1', 'Gene', (161, 166))	('tumors', 'Phenotype', 'HP:0002664', (175, 181))	('BAP1', 'Gene', '8314', (94, 98))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumors', 'Disease', (107, 113))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('SF3B1', 'Gene', '23451', (161, 166))	('tumors', 'Disease', 'MESH:D009369', (107, 113))	('mutated', 'Var', (167, 174))	('BAP1', 'Gene', (94, 98))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))
444921	25909164	In surgically resected human SCLC specimens, the frequency of Geminin-positive cancer cells was significantly higher in the cases with PDPN-positive CAFs than in the cases with PDPN-negative CAFs.	('CAFs', 'Gene', '6899', (149, 153))	('CAFs', 'Gene', '6899', (191, 195))	('Geminin', 'Gene', '51053', (62, 69))	('Geminin', 'Gene', (62, 69))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('SCLC', 'Gene', '7864', (29, 33))	('CAFs', 'Gene', (191, 195))	('SCLC', 'Gene', (29, 33))	('SCLC', 'Phenotype', 'HP:0030357', (29, 33))	('human', 'Species', '9606', (23, 28))	('CAFs', 'Gene', (149, 153))	('higher', 'PosReg', (110, 116))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('PDPN-positive', 'Var', (135, 148))
444929	25909164	reported that AKT2 phosphorylation in CAFs can induce epithelial cell invasion.	('AKT2', 'Gene', '208', (14, 18))	('induce', 'PosReg', (47, 53))	('CAFs', 'Gene', (38, 42))	('epithelial cell invasion', 'CPA', (54, 78))	('phosphorylation', 'Var', (19, 34))	('CAFs', 'Gene', '6899', (38, 42))	('AKT2', 'Gene', (14, 18))
444939	25909164	We previously reported that PDPN-positive CAFs were found in some cases of lung cancer and that the presence of PDPN-positive CAFs predicted a poor outcome among patients with adenocarcinoma and squamous cell carcinoma.	('lung cancer', 'Disease', (75, 86))	('patients', 'Species', '9606', (162, 170))	('lung cancer', 'Phenotype', 'HP:0100526', (75, 86))	('CAFs', 'Gene', (126, 130))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('CAFs', 'Gene', (42, 46))	('lung cancer', 'Disease', 'MESH:D008175', (75, 86))	('adenocarcinoma and squamous cell carcinoma', 'Disease', 'MESH:D002294', (176, 218))	('CAFs', 'Gene', '6899', (126, 130))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (195, 218))	('carcinoma', 'Phenotype', 'HP:0030731', (181, 190))	('CAFs', 'Gene', '6899', (42, 46))	('carcinoma', 'Phenotype', 'HP:0030731', (209, 218))	('presence', 'Var', (100, 108))
444943	25909164	Therefore, the extrinsic role of PDPN-positive CAFs in the SCLC progression process is likely to differ from that in adenocarcinoma and squamous cell carcinoma, with PDPN-positive CAFs possibly having a tumor suppressive effect in SCLC.	('tumor', 'Disease', (203, 208))	('PDPN-positive', 'Var', (33, 46))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('PDPN-positive', 'Var', (166, 179))	('CAFs', 'Gene', (47, 51))	('SCLC', 'Phenotype', 'HP:0030357', (59, 63))	('CAFs', 'Gene', '6899', (47, 51))	('carcinoma', 'Phenotype', 'HP:0030731', (150, 159))	('CAFs', 'Gene', (180, 184))	('SCLC', 'Gene', (59, 63))	('SCLC', 'Gene', '7864', (59, 63))	('CAFs', 'Gene', '6899', (180, 184))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('adenocarcinoma and squamous cell carcinoma', 'Disease', 'MESH:D002294', (117, 159))	('SCLC', 'Phenotype', 'HP:0030357', (231, 235))	('SCLC', 'Gene', (231, 235))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (136, 159))	('SCLC', 'Gene', '7864', (231, 235))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))
444971	25909164	We also examined the frequency of Geminin-positive cancer cells of invasive lung adenocarcinoma with a tumor size of 2-3 cm in diameter (Cases with PDPN-positive CAFs vs Cases with PDPN-negative CAFs, n = 20, each).	('CAFs', 'Gene', '6899', (162, 166))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('Geminin', 'Gene', (34, 41))	('CAFs', 'Gene', (195, 199))	('tumor', 'Disease', (103, 108))	('Geminin', 'Gene', '51053', (34, 41))	('CAFs', 'Gene', (162, 166))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('invasive lung adenocarcinoma', 'Disease', (67, 95))	('invasive lung adenocarcinoma', 'Disease', 'MESH:D000077192', (67, 95))	('CAFs', 'Gene', '6899', (195, 199))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (76, 95))	('cancer', 'Disease', (51, 57))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('PDPN-positive', 'Var', (148, 161))
444992	25909164	Adenocarcinoma cells in the cases with PDPN-positive cases showed significant higher positive ratio for Geminin than in the cases with PDPN-negative CAFs (9.2% vs 2.5%, p < 0.01) (Figure 5C).	('Adenocarcinoma', 'Disease', (0, 14))	('CAFs', 'Gene', '6899', (149, 153))	('Adenocarcinoma', 'Disease', 'MESH:D000230', (0, 14))	('Geminin', 'Gene', (104, 111))	('PDPN-positive', 'Var', (39, 52))	('higher', 'PosReg', (78, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (5, 14))	('Geminin', 'Gene', '51053', (104, 111))	('CAFs', 'Gene', (149, 153))
444995	25909164	We have reported that the presence of CAFs expressing PDPN is a predictor of a poor prognosis among patients with lung adenocarcinoma and squamous cell carcinoma of the lung, and PDPN itself has been shown to exert tumor-promoting effects using in vitro and in vivo models.	('carcinoma', 'Phenotype', 'HP:0030731', (152, 161))	('lung adenocarcinoma', 'Disease', (114, 133))	('squamous cell carcinoma of the lung', 'Disease', (138, 173))	('CAFs', 'Gene', (38, 42))	('adenocarcinoma and squamous cell carcinoma', 'Disease', 'MESH:D002294', (119, 161))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (138, 161))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('tumor', 'Disease', 'MESH:D009369', (215, 220))	('carcinoma of the lung', 'Phenotype', 'HP:0100526', (152, 173))	('squamous cell carcinoma of the lung', 'Disease', 'MESH:D002294', (138, 173))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (114, 133))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('patients', 'Species', '9606', (100, 108))	('PDPN', 'Gene', (54, 58))	('CAFs', 'Gene', '6899', (38, 42))	('tumor', 'Disease', (215, 220))	('presence', 'Var', (26, 34))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (114, 133))
445028	25531467	Transcriptome Meta-Analysis of Lung Cancer Reveals Recurrent Aberrations in NRG1 and Hippo Pathway Genes Lung cancer is emerging as a paradigm for disease molecular subtyping, facilitating targeted therapy based on driving somatic alterations.	('Cancer', 'Phenotype', 'HP:0002664', (36, 42))	('Lung cancer', 'Disease', (105, 116))	('NRG1', 'Gene', '3084', (76, 80))	('Lung cancer', 'Disease', 'MESH:D008175', (105, 116))	('Aberrations', 'Var', (61, 72))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('Hippo Pathway Genes', 'Gene', (85, 104))	('Lung Cancer', 'Phenotype', 'HP:0100526', (31, 42))	('Lung cancer', 'Phenotype', 'HP:0100526', (105, 116))	('NRG1', 'Gene', (76, 80))
445031	25531467	We show that higher numbers of gene fusions is an independent prognostic factor for poor survival in lung cancer.	('lung cancer', 'Disease', 'MESH:D008175', (101, 112))	('gene fusions', 'Var', (31, 43))	('lung cancer', 'Phenotype', 'HP:0100526', (101, 112))	('lung cancer', 'Disease', (101, 112))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
445032	25531467	Our analysis confirms the recently reported CD74-NRG1 fusion and suggests that NRG1, NF1 and Hippo pathway fusions may play important roles in tumors without known driver mutations.	('fusion', 'Var', (54, 60))	('CD74', 'Gene', '972', (44, 48))	('NRG1', 'Gene', '3084', (49, 53))	('fusions', 'Var', (107, 114))	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('Hippo pathway', 'Gene', (93, 106))	('tumors', 'Disease', (143, 149))	('play', 'Reg', (119, 123))	('NF1', 'Gene', (85, 88))	('roles', 'Reg', (134, 139))	('tumors', 'Disease', 'MESH:D009369', (143, 149))	('NRG1', 'Gene', (79, 83))	('NF1', 'Gene', '4763', (85, 88))	('NRG1', 'Gene', (49, 53))	('CD74', 'Gene', (44, 48))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('NRG1', 'Gene', '3084', (79, 83))
445038	25531467	Genomic analyses of LUAD have revealed mutations in many known oncogenes and tumor suppressor genes including KRAS, EGFR, TP53, CDKN2A, and STK11.	('TP53', 'Gene', (122, 126))	('CDKN2A', 'Gene', '1029', (128, 134))	('EGFR', 'Gene', '1956', (116, 120))	('STK11', 'Gene', (140, 145))	('revealed', 'Reg', (30, 38))	('KRAS', 'Gene', '3845', (110, 114))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('mutations', 'Var', (39, 48))	('STK11', 'Gene', '6794', (140, 145))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('TP53', 'Gene', '7157', (122, 126))	('tumor', 'Disease', (77, 82))	('EGFR', 'Gene', (116, 120))	('CDKN2A', 'Gene', (128, 134))	('KRAS', 'Gene', (110, 114))
445040	25531467	Alterations in oncogenes such as KRAS, EGFR, ALK and MET influence tumor formation and maintenance and are considered "drivers" in a subset of NSCLCs yet in a substantial patient population the driver aberrations are yet to be identified (i.e., "driver mutation unknown").	('ALK', 'Gene', '238', (45, 48))	('NSCLC', 'Disease', (143, 148))	('influence', 'Reg', (57, 66))	('patient', 'Species', '9606', (171, 178))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('Alterations', 'Var', (0, 11))	('NSCLC', 'Disease', 'MESH:D002289', (143, 148))	('KRAS', 'Gene', (33, 37))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('KRAS', 'Gene', '3845', (33, 37))	('ALK', 'Gene', (45, 48))	('EGFR', 'Gene', '1956', (39, 43))	('tumor', 'Disease', (67, 72))	('EGFR', 'Gene', (39, 43))	('maintenance', 'CPA', (87, 98))	('MET', 'Gene', (53, 56))
445041	25531467	Recent analyses by The Cancer Genome Atlas (TCGA) of both LUSC and LUAD revealed recurrent mutations and recurrent copy number alterations in genes that present in both subtypes and also specific to each.	('Cancer Genome Atlas', 'Disease', (23, 42))	('Cancer', 'Phenotype', 'HP:0002664', (23, 29))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (23, 42))	('mutations', 'Var', (91, 100))	('genes', 'Gene', (142, 147))	('copy number alterations', 'Var', (115, 138))
445043	25531467	Patients with EGFR mutations show responsiveness to EGFR inhibitors which are often not durable.	('EGFR', 'Gene', '1956', (14, 18))	('EGFR', 'Gene', (14, 18))	('EGFR', 'Gene', '1956', (52, 56))	('EGFR', 'Gene', (52, 56))	('mutations', 'Var', (19, 28))	('Patients', 'Species', '9606', (0, 8))
445046	25531467	The EML4-ALK translocation is mutually exclusive with EGFR and KRAS mutations, an indicator of therapeutic responsiveness to ALK inhibitors, and tumors with this translocation also have fewer TP53 gene mutations.	('ALK', 'Gene', (9, 12))	('KRAS', 'Gene', '3845', (63, 67))	('TP53', 'Gene', '7157', (192, 196))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('fewer', 'NegReg', (186, 191))	('EML4', 'Gene', (4, 8))	('ALK', 'Gene', '238', (9, 12))	('ALK', 'Gene', '238', (125, 128))	('tumors', 'Disease', (145, 151))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('EGFR', 'Gene', '1956', (54, 58))	('EML4', 'Gene', '27436', (4, 8))	('tumors', 'Disease', 'MESH:D009369', (145, 151))	('mutations', 'Var', (68, 77))	('EGFR', 'Gene', (54, 58))	('TP53', 'Gene', (192, 196))	('ALK', 'Gene', (125, 128))	('KRAS', 'Gene', (63, 67))
445061	25531467	KRAS was mutated in 30.1% and 1.6% of LUAD and LUSC respectively; EGFR in 13% and 1.6 of LUAD and LUSC; BRAF in 8% and 3.2% of LUAD and LUSC and PIK3CA in 7.6% and 13.5% of LUAD and LUSC respectively.	('PIK3CA', 'Gene', '5290', (145, 151))	('EGFR', 'Gene', '1956', (66, 70))	('EGFR', 'Gene', (66, 70))	('mutated', 'Var', (9, 16))	('BRAF', 'Gene', '673', (104, 108))	('PIK3CA', 'Gene', (145, 151))	('BRAF', 'Gene', (104, 108))	('KRAS', 'Gene', (0, 4))	('KRAS', 'Gene', '3845', (0, 4))
445062	25531467	As previously reported, TP53 mutations are common in both LUAD and LUSC patients, 50.3% and 65.7% respectively (Fig.	('TP53', 'Gene', (24, 28))	('LUAD', 'Disease', (58, 62))	('mutations', 'Var', (29, 38))	('TP53', 'Gene', '7157', (24, 28))	('common', 'Reg', (43, 49))	('patients', 'Species', '9606', (72, 80))
445064	25531467	In LCLC we found 1 sample with KRAS activating mutation, 3 with TP53 missense mutations and 4 without mutations in known lung cancer genes (Supplementary Table 2).	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('KRAS', 'Gene', (31, 35))	('lung cancer', 'Disease', 'MESH:D008175', (121, 132))	('KRAS', 'Gene', '3845', (31, 35))	('lung cancer', 'Disease', (121, 132))	('lung cancer', 'Phenotype', 'HP:0100526', (121, 132))	('TP53', 'Gene', '7157', (64, 68))	('missense mutations', 'Var', (69, 87))	('TP53', 'Gene', (64, 68))
445065	25531467	In LACC, despite the small sample size, we observed a higher frequency of RAS/RAF pathway mutations (72%, 8/11) compared to the major NSCLC subtypes (Supplementary Table 2).	('NSCLC', 'Disease', 'MESH:D002289', (134, 139))	('mutations', 'Var', (90, 99))	('RAF', 'Gene', (78, 81))	('RAF', 'Gene', '22882', (78, 81))	('NSCLC', 'Disease', (134, 139))
445066	25531467	The mutations were mutually exclusive, where five samples with KRAS mutations had KRASG12C, G12V, G13C, G12D, Q61H variants respectively, while BRAFV600E, HRASQ61L, and NRASQ61R were observed in three independent samples.	('KRAS', 'Gene', (82, 86))	('KRAS', 'Gene', '3845', (63, 67))	('HRAS', 'Gene', '3265', (155, 159))	('NRAS', 'Gene', (169, 173))	('G13C', 'Var', (98, 102))	('G12V', 'Var', (92, 96))	('Q61H', 'Var', (110, 114))	('Q61H', 'Mutation', 'rs17851045', (110, 114))	('HRAS', 'Gene', (155, 159))	('NRAS', 'Gene', '4893', (169, 173))	('G12V', 'Mutation', 'rs121913529', (92, 96))	('G12D', 'Var', (104, 108))	('G13C', 'Mutation', 'rs121913535', (98, 102))	('mutations', 'Var', (68, 77))	('G12D', 'Mutation', 'rs121913529', (104, 108))	('KRAS', 'Gene', '3845', (82, 86))	('BRAFV600E', 'Mutation', 'rs113488022', (144, 153))	('KRAS', 'Gene', (63, 67))
445067	25531467	Interestingly, the samples with NRASQ61R and KRASG13C also had mutations in TP53R141C, R141L and KITM537L.	('mutations', 'Var', (63, 72))	('KITM537L', 'Var', (97, 105))	('NRAS', 'Gene', (32, 36))	('TP53', 'Gene', '7157', (76, 80))	('KRASG13C', 'Var', (45, 53))	('NRAS', 'Gene', '4893', (32, 36))	('TP53', 'Gene', (76, 80))	('R141L', 'Mutation', 'rs28934576', (87, 92))	('R141L', 'Var', (87, 92))
445068	25531467	METT1010I variation was also observed in the NRAS mutated sample.	('METT1010I', 'Var', (0, 9))	('NRAS', 'Gene', '4893', (45, 49))	('NRAS', 'Gene', (45, 49))
445069	25531467	Interestingly, MYB-NF1 gene fusions were absent in the lung ACC, unlike the salivary gland-ACC where it occurs in 57% of cases.	('absent', 'NegReg', (41, 47))	('MYB', 'Gene', '4602', (15, 18))	('NF1', 'Gene', (19, 22))	('NF1', 'Gene', '4763', (19, 22))	('MYB', 'Gene', (15, 18))	('fusions', 'Var', (28, 35))	('lung ACC', 'Disease', (55, 63))
445070	25531467	Likewise, KRAS mutations were common in LACC, but none were detected in the 60 salivary-ACCs sequenced recently.	('KRAS', 'Gene', '3845', (10, 14))	('mutations', 'Var', (15, 24))	('KRAS', 'Gene', (10, 14))
445071	25531467	However, in the salivary-ACC cohort a potential driver HRAS non-synonymous mutation was noted to be mutually exclusive with MYB gene fusion.	('HRAS', 'Gene', '3265', (55, 59))	('non-synonymous mutation', 'Var', (60, 83))	('MYB', 'Gene', '4602', (124, 127))	('HRAS', 'Gene', (55, 59))	('MYB', 'Gene', (124, 127))
445072	25531467	Another recent study identified activating BRAF and HRAS mutations in breast adenoid cystic carcinoma (BACC) samples that were a distinct subset of triple negative breast cancers.	('HRAS', 'Gene', '3265', (52, 56))	('BRAF', 'Gene', '673', (43, 47))	('breast cancers', 'Disease', 'MESH:D001943', (164, 178))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('breast cancers', 'Disease', (164, 178))	('breast cancer', 'Phenotype', 'HP:0003002', (164, 177))	('HRAS', 'Gene', (52, 56))	('BRAF', 'Gene', (43, 47))	('cancers', 'Phenotype', 'HP:0002664', (171, 178))	('mutations', 'Var', (57, 66))	('breast adenoid cystic carcinoma', 'Disease', (70, 101))	('activating', 'PosReg', (32, 42))	('breast adenoid cystic carcinoma', 'Disease', 'MESH:D003528', (70, 101))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('breast cancers', 'Phenotype', 'HP:0003002', (164, 178))
445073	25531467	Hence the previous report on BACC and our results here on LACC have identified distinct ACC subsets that harbor activating RAS/RAF mutations but lack MYB fusions that are primarily found in head and neck ACC, revealing differences in underlying molecular events despite histological similarities.	('mutations', 'Var', (131, 140))	('ACC', 'Disease', (88, 91))	('lack', 'NegReg', (145, 149))	('MYB', 'Gene', '4602', (150, 153))	('MYB', 'Gene', (150, 153))	('RAF', 'Gene', '22882', (127, 130))	('RAF', 'Gene', (127, 130))	('activating', 'PosReg', (112, 122))
445074	25531467	We detected 6,348 unique fusions among the 733 samples for an average of 13 fusions per tumor sample (range: 0-67).	('fusions', 'Var', (25, 32))	('tumor', 'Disease', (88, 93))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))
445076	25531467	Tumors with missense or nonsense mutations in TP53 showed greater average number of fusions compared to samples with wild-type TP53 (Supplementary Fig.	('nonsense mutations', 'Var', (24, 42))	('TP53', 'Gene', '7157', (46, 50))	('missense', 'Var', (12, 20))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('TP53', 'Gene', (46, 50))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('TP53', 'Gene', '7157', (127, 131))	('TP53', 'Gene', (127, 131))	('fusions', 'MPA', (84, 91))
445079	25531467	We could not determine whether a similar correlation exists in LUSC due to the low incidence of mutations in KRAS, EGFR or other oncogenes in the samples.	('EGFR', 'Gene', '1956', (115, 119))	('KRAS', 'Gene', (109, 113))	('KRAS', 'Gene', '3845', (109, 113))	('EGFR', 'Gene', (115, 119))	('mutations', 'Var', (96, 105))
445082	25531467	Patients with high number of fusions had significantly shorter median overall survival (35.6, 95% confidence interval (CI) 27.2-43.9) compared to patients with intermediate (49.5, 95% CI 23.9-75.1) or low number of fusions (62.3, 95% CI 44.6-80.1; Likelihood ratio test P=0.008 Fig.	('overall survival', 'MPA', (70, 86))	('fusions', 'Var', (29, 36))	('shorter', 'NegReg', (55, 62))	('Patients', 'Species', '9606', (0, 8))	('patients', 'Species', '9606', (146, 154))
445083	25531467	When TP53, KRAS and EGFR mutation status or smoking status was included in the multivariate analysis, the number of fusions remained independently associated with poor outcome (Supplementary Table 6).	('KRAS', 'Gene', (11, 15))	('associated', 'Reg', (147, 157))	('EGFR', 'Gene', (20, 24))	('mutation', 'Var', (25, 33))	('KRAS', 'Gene', '3845', (11, 15))	('TP53', 'Gene', '7157', (5, 9))	('TP53', 'Gene', (5, 9))	('EGFR', 'Gene', '1956', (20, 24))
445084	25531467	Sixty-four out of 422 fusions (15%) involved kinases (either as 3' or 5'-partner) including the known ROS1, RET and ALK fusions: 52 fusions involved oncogenes and 63 involved tumor suppressors (Supplementary Data 4).	('tumor', 'Disease', (175, 180))	('ROS1', 'Gene', (102, 106))	('RET', 'Gene', '5979', (108, 111))	('involved', 'Reg', (140, 148))	('oncogenes', 'Protein', (149, 158))	('ROS1', 'Gene', '6098', (102, 106))	('fusions', 'Var', (22, 29))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('ALK', 'Gene', (116, 119))	('RET', 'Gene', (108, 111))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('involved', 'Reg', (166, 174))	('involved', 'Reg', (36, 44))	('ALK', 'Gene', '238', (116, 119))
445085	25531467	In the KRAS mutant population, a large NSCLC molecular subtype where chemotherapy is the only approved treatment we identified additional private fusions (Supplementary Data 4).	('KRAS', 'Gene', '3845', (7, 11))	('mutant', 'Var', (12, 18))	('NSCLC', 'Disease', (39, 44))	('NSCLC', 'Disease', 'MESH:D002289', (39, 44))	('KRAS', 'Gene', (7, 11))
445087	25531467	While the TRAF interacting protein-Inositol Hexakisphosphate Kinase (TRAIP-IP6K1) fusion results in loss of function of both partners, the SLC12A7-TERT fusion produces an in-frame ORF where, the telomerase domain of TERT is retained and could serve as a potential combinatorial drug target.	('RAF', 'Gene', '22882', (11, 14))	('SLC12A7', 'Gene', (139, 146))	('SLC12A7', 'Gene', '10723', (139, 146))	('RAF', 'Gene', (11, 14))	('TERT', 'Gene', (147, 151))	('fusion', 'Var', (82, 88))	('TERT', 'Gene', (216, 220))	('TERT', 'Gene', '7015', (216, 220))	('function', 'MPA', (108, 116))	('TERT', 'Gene', '7015', (147, 151))	('loss', 'NegReg', (100, 104))
445088	25531467	In another sample, pt_lung_A63, that harbored KRASG12D, TP53P72R and ATME2423K mutations, in addition has a TSC1-SMARCA4 fusion.	('TSC1', 'Gene', (108, 112))	('SMARCA4', 'Gene', '6597', (113, 120))	('ATME2423K', 'Var', (69, 78))	('TP53', 'Gene', '7157', (56, 60))	('TP53', 'Gene', (56, 60))	('TSC1', 'Gene', '7248', (108, 112))	('KRASG12D', 'Var', (46, 54))	('SMARCA4', 'Gene', (113, 120))
445093	25531467	Interestingly, in tumors with known driver fusions the number of "classified" fusions is lower than those without driver fusions (Student t-test t = 2.7588, df =5.023, P=0.01985) suggesting their functional importance.	('lower', 'NegReg', (89, 94))	('fusions', 'Var', (43, 50))	('tumors', 'Disease', (18, 24))	('tumors', 'Disease', 'MESH:D009369', (18, 24))	('tumors', 'Phenotype', 'HP:0002664', (18, 24))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
445102	25531467	We observed novel recurrent NF2 fusions, where retention of only the first exon of NF2, in both NF2-OSBP2 and NF2-MORC2 fusions result in loss of function of this tumor suppressor gene (Fig.	('OSBP2', 'Gene', '23762', (100, 105))	('OSBP2', 'Gene', (100, 105))	('fusions', 'Var', (32, 39))	('NF2', 'Gene', (110, 113))	('NF2', 'Gene', (96, 99))	('NF2', 'Gene', (83, 86))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('NF2', 'Gene', (28, 31))	('MORC2', 'Gene', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('loss of function', 'NegReg', (138, 154))	('NF2', 'Gene', '4771', (96, 99))	('NF2', 'Gene', '4771', (83, 86))	('tumor', 'Disease', (163, 168))	('fusions', 'Var', (120, 127))	('NF2', 'Gene', '4771', (28, 31))	('NF2', 'Gene', '4771', (110, 113))	('MORC2', 'Gene', '22880', (114, 119))
445104	25531467	We also identified fusions in associate members of the Hippo pathway including, HIPK2, TAOK1, TAOK3, FAT1, DCHS2 and PTPN14 (Fig.	('FAT1', 'Gene', '2195', (101, 105))	('TAOK1', 'Gene', '57551', (87, 92))	('TAOK1', 'Gene', (87, 92))	('PTPN14', 'Gene', (117, 123))	('FAT1', 'Gene', (101, 105))	('DCHS2', 'Gene', '54798', (107, 112))	('fusions', 'Var', (19, 26))	('DCHS2', 'Gene', (107, 112))	('PTPN14', 'Gene', '5784', (117, 123))	('HIPK2', 'Gene', (80, 85))	('HIPK2', 'Gene', '28996', (80, 85))	('TAOK3', 'Gene', (94, 99))	('Hippo pathway', 'Pathway', (55, 68))	('TAOK3', 'Gene', '51347', (94, 99))
445106	25531467	However, fusions involving oncogenic proteins in the Hippo pathway such as WWTR1, YAP1 and HIPK2 retained their crucial functional domains Fig.	('HIPK2', 'Gene', '28996', (91, 96))	('Hippo pathway', 'Pathway', (53, 66))	('YAP1', 'Gene', '10413', (82, 86))	('fusions', 'Var', (9, 16))	('HIPK2', 'Gene', (91, 96))	('WWTR1', 'Gene', (75, 80))	('WWTR1', 'Gene', '25937', (75, 80))	('YAP1', 'Gene', (82, 86))
445107	25531467	Using cbioportal (http://www.cbioportal.org) we discovered copy number loss and associated low mRNA expression of FAT1 in the index fusion sample (Supplementary Fig S6A) and copy gain and elevated expression of YAP1 in the sample harboring YAP1 fusion (Supplementary Fig S6B).	('gain', 'PosReg', (179, 183))	('low', 'NegReg', (91, 94))	('mRNA expression', 'MPA', (95, 110))	('FAT1', 'Gene', '2195', (114, 118))	('YAP1', 'Gene', (240, 244))	('YAP1', 'Gene', '10413', (240, 244))	('FAT1', 'Gene', (114, 118))	('YAP1', 'Gene', '10413', (211, 215))	('copy', 'Var', (174, 178))	('elevated', 'PosReg', (188, 196))	('copy number', 'Var', (59, 70))	('loss', 'NegReg', (71, 75))	('YAP1', 'Gene', (211, 215))	('expression', 'MPA', (197, 207))
445109	25531467	Despite this heterogeneity, gene fusions could still be functionally relevant in lung cancers by affecting several members of common pathways such as those of the Hippo signaling cascade we observed here.	('lung cancer', 'Phenotype', 'HP:0100526', (81, 92))	('gene fusions', 'Var', (28, 40))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('lung cancers', 'Disease', 'MESH:D008175', (81, 93))	('lung cancers', 'Phenotype', 'HP:0100526', (81, 93))	('cancers', 'Phenotype', 'HP:0002664', (86, 93))	('affecting', 'Reg', (97, 106))	('lung cancers', 'Disease', (81, 93))
445110	25531467	Next, our integrative analysis combining fusion and mutation status revealed a total of 33 samples with aberrations in NF1 gene such as truncating fusions: GOSR1-NF1, NLK-NF1 and NF1-PSMD11 or deleterious mutations: non-sense, frame shift or splice site (Fig.	('PSMD11', 'Gene', (183, 189))	('NF1', 'Gene', (162, 165))	('non-sense', 'Var', (216, 225))	('NLK', 'Gene', '51701', (167, 170))	('NF1', 'Gene', '4763', (162, 165))	('NLK', 'Gene', (167, 170))	('PSMD11', 'Gene', '5717', (183, 189))	('NF1', 'Gene', (119, 122))	('NF1', 'Gene', (171, 174))	('NF1', 'Gene', '4763', (119, 122))	('NF1', 'Gene', '4763', (171, 174))	('NF1', 'Gene', (179, 182))	('frame shift', 'Var', (227, 238))	('GOSR1', 'Gene', (156, 161))	('NF1', 'Gene', '4763', (179, 182))	('GOSR1', 'Gene', '9527', (156, 161))	('truncating fusions', 'Var', (136, 154))
445111	25531467	Loss of NF1 promotes cell proliferation by de-repressing the mTOR pathway in a RAS-, PI3K-dependent fashion.	('NF1', 'Gene', (8, 11))	('NF1', 'Gene', '4763', (8, 11))	('cell proliferation', 'CPA', (21, 39))	('de-repressing', 'NegReg', (43, 56))	('mTOR', 'Gene', (61, 65))	('promotes', 'PosReg', (12, 20))	('mTOR', 'Gene', '2475', (61, 65))	('Loss', 'Var', (0, 4))
445115	25531467	The read evidence suggests genomic deletion as the mechanism for the NF1 fusions except in sample LS2 where centromeric inversion may be the underlying aberration (Fig.	('NF1', 'Gene', '4763', (69, 72))	('fusions', 'Var', (73, 80))	('LS2', 'Gene', (98, 101))	('LS2', 'Gene', '3053', (98, 101))	('NF1', 'Gene', (69, 72))
445116	25531467	Importantly, 20 out 29 mutated NF1 samples and all NF1 truncating fusions were observed in samples without known drivers, accounting for 6.2% (24/386) of this subpopulation.	('mutated', 'Var', (23, 30))	('NF1', 'Gene', (31, 34))	('NF1', 'Gene', (51, 54))	('NF1', 'Gene', '4763', (31, 34))	('NF1', 'Gene', '4763', (51, 54))
445117	25531467	Interestingly, two samples had fusions accompanying somatic mutations in NF1 potentially altering both the alleles of this tumor suppressor gene (Supplementary Table 7).	('NF1', 'Gene', '4763', (73, 76))	('tumor', 'Disease', (123, 128))	('altering', 'Reg', (89, 97))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('fusions', 'Var', (31, 38))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('NF1', 'Gene', (73, 76))
445118	25531467	Recently, a significant percent of driver unknown lung cancer samples have been shown to harbor fusions involving ALK, ROS1, RET kinases and an activating exon skipping in the c-MET oncogene.	('c-MET', 'Gene', (176, 181))	('ROS1', 'Gene', '6098', (119, 123))	('ALK', 'Gene', '238', (114, 117))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('RET', 'Gene', '5979', (125, 128))	('activating exon', 'PosReg', (144, 159))	('c-MET', 'Gene', '4233', (176, 181))	('lung cancer', 'Phenotype', 'HP:0100526', (50, 61))	('fusions', 'Var', (96, 103))	('ALK', 'Gene', (114, 117))	('driver unknown lung cancer', 'Disease', (35, 61))	('RET', 'Gene', (125, 128))	('driver unknown lung cancer', 'Disease', 'MESH:D008175', (35, 61))	('ROS1', 'Gene', (119, 123))
445119	25531467	Our analysis revealed that 1.3, 0.52 and 0.26 percent fusions involving ROS1, RET and ALK respectively among LUAD and LUSC with unknown driver.	('ALK', 'Gene', '238', (86, 89))	('RET', 'Gene', (78, 81))	('fusions', 'Var', (54, 61))	('ALK', 'Gene', (86, 89))	('ROS1', 'Gene', (72, 76))	('ROS1', 'Gene', '6098', (72, 76))	('RET', 'Gene', '5979', (78, 81))
445120	25531467	We detected c-MET exon-14 skipping in 15 samples, 14 of which occurred in driver unknown samples, a 3.6% (14/386) recurrence rate in this subpopulation (Fig.	('skipping', 'Var', (26, 34))	('c-MET', 'Gene', '4233', (12, 17))	('c-MET', 'Gene', (12, 17))
445121	25531467	Importantly, in 5 out 15 samples the skipping of c-MET exon-14 is likely caused by a mutation affecting the splice donor site adjacent to the amino acid position D1010 as previously described.	('c-MET', 'Gene', (49, 54))	('donor', 'Species', '9606', (115, 120))	('mutation', 'Var', (85, 93))	('c-MET', 'Gene', '4233', (49, 54))	('caused by', 'Reg', (73, 82))	('skipping', 'Var', (37, 45))
445130	25531467	While CD74-NRG1, SDC4-NRG1 and RBPMS-NRG1 fusion events resulted in the production of chimeric proteins, the WRN-NRG1 fusion results in the overexpression of full length NRG1 regulated by the WRN gene promoter.	('resulted in', 'Reg', (56, 67))	('RBPMS-NRG1', 'Gene', '11030;3084', (31, 41))	('NRG1', 'Gene', (113, 117))	('NRG1', 'Gene', '3084', (170, 174))	('NRG1', 'Gene', '3084', (113, 117))	('overexpression', 'PosReg', (140, 154))	('WRN', 'Gene', (109, 112))	('WRN', 'Gene', '7486', (109, 112))	('NRG1', 'Gene', (11, 15))	('SDC4', 'Gene', '6385', (17, 21))	('RBPMS-NRG1', 'Gene', (31, 41))	('SDC4', 'Gene', (17, 21))	('NRG1', 'Gene', '3084', (11, 15))	('fusion', 'Var', (42, 48))	('CD74', 'Gene', '972', (6, 10))	('WRN-NRG1', 'Gene', (109, 117))	('production of chimeric proteins', 'MPA', (72, 103))	('WRN', 'Gene', (192, 195))	('WRN', 'Gene', '7486', (192, 195))	('CD74', 'Gene', (6, 10))	('NRG1', 'Gene', (37, 41))	('NRG1', 'Gene', (22, 26))	('NRG1', 'Gene', '3084', (37, 41))	('NRG1', 'Gene', '3084', (22, 26))	('fusion', 'Var', (118, 124))	('NRG1', 'Gene', (170, 174))	('WRN-NRG1', 'Gene', '7486;3084', (109, 117))
445133	25531467	Notably the EGF domain is essential for receptor interaction and preserved in all the NRG1 fusions identified (Fig.	('NRG1', 'Gene', '3084', (86, 90))	('fusions', 'Var', (91, 98))	('interaction', 'Interaction', (49, 60))	('NRG1', 'Gene', (86, 90))
445137	25531467	At 70% knock down with two independent NRG1 siRNAs (Fig.	('NRG1', 'Gene', '3084', (39, 43))	('NRG1', 'Gene', (39, 43))	('knock down', 'Var', (7, 17))
445140	25531467	CD74-NRG1 overexpression induces epithelial to mesenchymal transition (EMT) as evidenced by increased VIM and SNAIL protein expression and decreased CDH1 level by Western blot analysis (Supplementary Fig.	('SNAIL', 'Gene', '6615', (110, 115))	('NRG1', 'Gene', (5, 9))	('SNAIL', 'Gene', (110, 115))	('VIM', 'Gene', '7431', (102, 105))	('epithelial to mesenchymal transition', 'CPA', (33, 69))	('overexpression', 'Var', (10, 24))	('CDH1', 'Gene', (149, 153))	('NRG1', 'Gene', '3084', (5, 9))	('CD74', 'Gene', '972', (0, 4))	('decreased', 'NegReg', (139, 148))	('increased', 'PosReg', (92, 101))	('VIM', 'Gene', (102, 105))	('CDH1', 'Gene', '999', (149, 153))	('CD74', 'Gene', (0, 4))
445153	25531467	Altogether, NRG1 is perturbed (NRG1 fusions and/or outlier expression) in 3.9% (15/386) of driver unknown samples, supporting a causal role for NRG1 in this lung cancer patient subpopulation.	('NRG1', 'Gene', '3084', (31, 35))	('NRG1', 'Gene', (12, 16))	('lung cancer', 'Disease', 'MESH:D008175', (157, 168))	('lung cancer', 'Disease', (157, 168))	('lung cancer', 'Phenotype', 'HP:0100526', (157, 168))	('fusions', 'Var', (36, 43))	('NRG1', 'Gene', (144, 148))	('perturbed', 'Reg', (20, 29))	('NRG1', 'Gene', '3084', (12, 16))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('patient', 'Species', '9606', (169, 176))	('NRG1', 'Gene', (31, 35))	('NRG1', 'Gene', '3084', (144, 148))
445155	25531467	For example, EGFR activating mutations in exons 18, 19 and 21 are now routinely assessed in tumor biopsies prior to treatment with gefitinib or erlotinib; the response rate is nearly 70% in mutation-positive advanced NSCLC.	('NSCLC', 'Disease', (217, 222))	('NSCLC', 'Disease', 'MESH:D002289', (217, 222))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('mutations', 'Var', (29, 38))	('gefitinib', 'Chemical', 'MESH:D000077156', (131, 140))	('mutation-positive', 'Reg', (190, 207))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('activating', 'PosReg', (18, 28))	('erlotinib', 'Chemical', 'MESH:D000069347', (144, 153))	('tumor', 'Disease', (92, 97))	('EGFR', 'Gene', '1956', (13, 17))	('EGFR', 'Gene', (13, 17))
445156	25531467	Further, fusions involving ROS1, ALK and RET tyrosine kinases are identified primarily in younger patients with LUAD and without known driver mutations or significant smoking history.	('ALK', 'Gene', (33, 36))	('fusions', 'Var', (9, 16))	('ROS1', 'Gene', (27, 31))	('RET', 'Gene', (41, 44))	('patients', 'Species', '9606', (98, 106))	('ROS1', 'Gene', '6098', (27, 31))	('ALK', 'Gene', '238', (33, 36))	('LUAD', 'Disease', (112, 116))	('RET', 'Gene', '5979', (41, 44))
445157	25531467	Despite the low fusion frequency, clinical trials for ALK-positive lung cancer patients have shown higher response rate and longer progression-free survival when treated with crizotinib, a drug targeting ALK, relative to chemotherapy.	('ALK', 'Gene', (204, 207))	('ALK', 'Gene', (54, 57))	('higher', 'PosReg', (99, 105))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('lung cancer', 'Disease', 'MESH:D008175', (67, 78))	('ALK', 'Gene', '238', (204, 207))	('crizotinib', 'Chemical', 'MESH:D000077547', (175, 185))	('progression-free survival', 'CPA', (131, 156))	('response', 'MPA', (106, 114))	('ALK', 'Gene', '238', (54, 57))	('patients', 'Species', '9606', (79, 87))	('crizotinib', 'Var', (175, 185))	('lung cancer', 'Disease', (67, 78))	('longer', 'PosReg', (124, 130))	('lung cancer', 'Phenotype', 'HP:0100526', (67, 78))
445161	25531467	As RNA sequencing becomes widely adopted for profiling transcript expression and gene fusion detection, our results suggest that the number of fusions could also be used as an independent prognostic marker in lung cancers.	('number', 'Var', (133, 139))	('lung cancers', 'Disease', (209, 221))	('cancers', 'Phenotype', 'HP:0002664', (214, 221))	('lung cancer', 'Phenotype', 'HP:0100526', (209, 220))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('lung cancers', 'Disease', 'MESH:D008175', (209, 221))	('lung cancers', 'Phenotype', 'HP:0100526', (209, 221))	('fusions', 'Var', (143, 150))
445163	25531467	Functional studies conducted in mouse models showed that knock down of tumor suppressor or overexpression of oncogene members of the pathway induced tumor formation.	('overexpression', 'PosReg', (91, 105))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('induced', 'Reg', (141, 148))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('knock down', 'Var', (57, 67))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Disease', (149, 154))	('mouse', 'Species', '10090', (32, 37))	('tumor', 'Disease', (71, 76))
445164	25531467	Furthermore, two recent reports identified recurrent fusions involving WWTR1, an oncogene member of the Hippo pathway and CAMTA1 in epithelioid hemangioendothelioma.	('epithelioid hemangioendothelioma', 'Disease', (132, 164))	('CAMTA1', 'Gene', (122, 128))	('fusions', 'Var', (53, 60))	('epithelioid hemangioendothelioma', 'Phenotype', 'HP:0032060', (132, 164))	('WWTR1', 'Gene', (71, 76))	('epithelioid hemangioendothelioma', 'Disease', 'MESH:D018323', (132, 164))	('CAMTA1', 'Gene', '23261', (122, 128))	('WWTR1', 'Gene', '25937', (71, 76))
445170	25531467	This discovery now vastly expands the incidence of Hippo pathway aberration in lung cancers.	('lung cancers', 'Disease', (79, 91))	('cancers', 'Phenotype', 'HP:0002664', (84, 91))	('lung cancer', 'Phenotype', 'HP:0100526', (79, 90))	('aberration', 'Var', (65, 75))	('Hippo', 'Gene', (51, 56))	('lung cancers', 'Disease', 'MESH:D008175', (79, 91))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('lung cancers', 'Phenotype', 'HP:0100526', (79, 91))
445176	25531467	While CD74-NRG1 and WRN-NRG1 fusions contain the signal peptide and type II transmembrane domain required for NRG1 localization to the plasma membrane, cellular location of RAB2IL1-NRG1 and RBPMS-NRG1 fusion proteins is uncertain.	('RBPMS-NRG1', 'Gene', (190, 200))	('NRG1', 'Gene', (11, 15))	('NRG1', 'Gene', '3084', (11, 15))	('fusions', 'Var', (29, 36))	('RAB2IL1-NRG1', 'Gene', (173, 185))	('WRN-NRG1', 'Gene', '7486;3084', (20, 28))	('CD74', 'Gene', '972', (6, 10))	('NRG1', 'Gene', (110, 114))	('NRG1', 'Gene', (24, 28))	('NRG1', 'Gene', '3084', (110, 114))	('NRG1', 'Gene', '3084', (24, 28))	('NRG1', 'Gene', (196, 200))	('NRG1', 'Gene', (181, 185))	('NRG1', 'Gene', '3084', (196, 200))	('NRG1', 'Gene', '3084', (181, 185))	('CD74', 'Gene', (6, 10))	('WRN-NRG1', 'Gene', (20, 28))	('RBPMS-NRG1', 'Gene', '11030;3084', (190, 200))	('RAB2IL1-NRG1', 'Gene', '3084', (173, 185))
445177	25531467	However, of the 20 NRG transcript variants (transcribed from NRG1-4) reported, several lack the N-terminal signal sequence required for membrane localization and transport to the extracellular space.	('NRG', 'Gene', (19, 22))	('N-terminal signal sequence', 'MPA', (96, 122))	('variants', 'Var', (34, 42))	('lack', 'NegReg', (87, 91))	('NRG1-4', 'Gene', (61, 67))	('NRG1-4', 'Gene', '3084;9542;10718;145957', (61, 67))	('transport to the extracellular space', 'MPA', (162, 198))
445178	25531467	Additionally, we identified a novel SDC4-NRG1 fusion in two samples added to the TCGA cohort after our data freeze.	('NRG1', 'Gene', (41, 45))	('SDC4', 'Gene', '6385', (36, 40))	('SDC4', 'Gene', (36, 40))	('fusion', 'Var', (46, 52))	('NRG1', 'Gene', '3084', (41, 45))
445180	25531467	This observation suggests that incidence of NRG1 aberrations in lung cancer is likely to increase as more samples are characterized.	('lung cancer', 'Disease', (64, 75))	('NRG1', 'Gene', (44, 48))	('lung cancer', 'Phenotype', 'HP:0100526', (64, 75))	('aberrations', 'Var', (49, 60))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('NRG1', 'Gene', '3084', (44, 48))	('lung cancer', 'Disease', 'MESH:D008175', (64, 75))
445181	25531467	Remarkably, NRG1 fusions are present in tumors without known driver events (Fig.	('NRG1', 'Gene', (12, 16))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('NRG1', 'Gene', '3084', (12, 16))	('fusions', 'Var', (17, 24))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumors', 'Disease', (40, 46))	('tumors', 'Disease', 'MESH:D009369', (40, 46))
445185	25531467	We demonstrated that abrogating NRG1 expression affects cell proliferation (Fig.	('NRG1', 'Gene', (32, 36))	('abrogating', 'Var', (21, 31))	('NRG1', 'Gene', '3084', (32, 36))	('cell proliferation', 'CPA', (56, 74))	('expression', 'MPA', (37, 47))
445187	25531467	Three independent studies have very recently associated CD74-NRG1 fusions with mucinous LUAD subtype.	('NRG1', 'Gene', (61, 65))	('CD74', 'Gene', (56, 60))	('mucinous LUAD subtype', 'Disease', 'MESH:D002288', (79, 100))	('CD74', 'Gene', '972', (56, 60))	('mucinous LUAD subtype', 'Disease', (79, 100))	('NRG1', 'Gene', '3084', (61, 65))	('fusions', 'Var', (66, 73))
445188	25531467	We further examined our samples and discovered that HNF4A, a recently characterized biomarker for mucinous LUAD, showed highest expression in our CD74-NRG1 index case, providing independent support for association of NRG1 gene fusions with mucinous LUAD.	('HNF4A', 'Gene', '3172', (52, 57))	('CD74', 'Gene', (146, 150))	('association', 'Interaction', (202, 213))	('HNF4A', 'Gene', (52, 57))	('mucinous LUAD', 'Disease', (240, 253))	('highest', 'PosReg', (120, 127))	('NRG1', 'Gene', (151, 155))	('NRG1', 'Gene', (217, 221))	('expression', 'MPA', (128, 138))	('NRG1', 'Gene', '3084', (151, 155))	('NRG1', 'Gene', '3084', (217, 221))	('fusions', 'Var', (227, 234))	('CD74', 'Gene', '972', (146, 150))
445189	25531467	Interestingly, the SDC4-NRG1 index sample with the highest NRG1 outlier expression (Fig 6B, NRG1 expression: 380FPKM, higher than the cell line H1793) did not show high HNF4A expression, suggesting that NRG1 fusions with partners other than CD74 are perhaps more prevalent in non-mucinous LUAD.	('NRG1', 'Gene', '3084', (24, 28))	('H1793', 'CellLine', 'CVCL:1496', (144, 149))	('NRG1', 'Gene', (92, 96))	('HNF4A', 'Gene', '3172', (169, 174))	('CD74', 'Gene', (241, 245))	('fusions', 'Var', (208, 215))	('non-mucinous LUAD', 'Disease', (276, 293))	('SDC4', 'Gene', '6385', (19, 23))	('NRG1', 'Gene', '3084', (92, 96))	('NRG1', 'Gene', (59, 63))	('CD74', 'Gene', '972', (241, 245))	('NRG1', 'Gene', (24, 28))	('NRG1', 'Gene', (203, 207))	('HNF4A', 'Gene', (169, 174))	('SDC4', 'Gene', (19, 23))	('NRG1', 'Gene', '3084', (203, 207))	('NRG1', 'Gene', '3084', (59, 63))
445190	25531467	NRG1 rearrangements have also been detected using FISH in breast cancer cell lines.	('breast cancer', 'Disease', 'MESH:D001943', (58, 71))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('NRG1', 'Gene', (0, 4))	('breast cancer', 'Disease', (58, 71))	('breast cancer', 'Phenotype', 'HP:0003002', (58, 71))	('NRG1', 'Gene', '3084', (0, 4))	('rearrangements', 'Var', (5, 19))
445192	25531467	These observations together with our results from lung and ovarian cancers suggest that NRG1 rearrangements are recurrent and likely drivers of various cancers types.	('drivers', 'Reg', (133, 140))	('cancers', 'Phenotype', 'HP:0002664', (67, 74))	('cancers', 'Disease', (152, 159))	('cancers', 'Disease', 'MESH:D009369', (152, 159))	('cancers', 'Disease', (67, 74))	('NRG1', 'Gene', (88, 92))	('lung and ovarian cancers', 'Disease', 'MESH:D010051', (50, 74))	('cancers', 'Disease', 'MESH:D009369', (67, 74))	('ovarian cancer', 'Phenotype', 'HP:0100615', (59, 73))	('NRG1', 'Gene', '3084', (88, 92))	('rearrangements', 'Var', (93, 107))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('ovarian cancers', 'Phenotype', 'HP:0100615', (59, 74))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('cancers', 'Phenotype', 'HP:0002664', (152, 159))
445194	25531467	Therefore, the characterization of all NRG1 fusions presented in this study, as well as the common signaling pathways activated in both fusion and outlier expression index samples could further elucidate NRG1 mechanism of action and reveal further therapeutic opportunities.	('NRG1', 'Gene', (204, 208))	('NRG1', 'Gene', (39, 43))	('NRG1', 'Gene', '3084', (204, 208))	('fusions', 'Var', (44, 51))	('NRG1', 'Gene', '3084', (39, 43))
445195	25531467	Our integrative analysis combining mutation and fusion status extended previous observations of c-MET exon skipping and NF1 truncating mutations.	('c-MET', 'Gene', (96, 101))	('c-MET', 'Gene', '4233', (96, 101))	('NF1', 'Gene', (120, 123))	('NF1', 'Gene', '4763', (120, 123))	('truncating mutations', 'Var', (124, 144))
445196	25531467	We detect novel truncating fusions involving several tumor suppressor genes such as NF1, NF2, TP53 (data not shown), LATS1, DCHS2, FAT1, SMARCA4, TAOK1 and TAOK3 among others.	('TAOK3', 'Gene', (156, 161))	('SMARCA4', 'Gene', (137, 144))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('TP53', 'Gene', (94, 98))	('truncating fusions', 'Var', (16, 34))	('TAOK3', 'Gene', '51347', (156, 161))	('FAT1', 'Gene', (131, 135))	('NF1', 'Gene', '4763', (84, 87))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('SMARCA4', 'Gene', '6597', (137, 144))	('NF1', 'Gene', (84, 87))	('TAOK1', 'Gene', (146, 151))	('TP53', 'Gene', '7157', (94, 98))	('DCHS2', 'Gene', '54798', (124, 129))	('LATS1', 'Gene', (117, 122))	('LATS1', 'Gene', '9113', (117, 122))	('FAT1', 'Gene', '2195', (131, 135))	('NF2', 'Gene', '4771', (89, 92))	('TAOK1', 'Gene', '57551', (146, 151))	('DCHS2', 'Gene', (124, 129))	('tumor', 'Disease', (53, 58))	('NF2', 'Gene', (89, 92))
445197	25531467	These results highlight gene fusions as potentially common and a previously underappreciated mechanism for loss of function of many tumor suppressor genes.	('gene fusions', 'Var', (24, 36))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumor', 'Disease', (132, 137))	('tumor', 'Disease', 'MESH:D009369', (132, 137))
445198	25531467	In summary, Hippo pathway fusions (2.6%), NRG1 fusion/outlier expression (3.9%), NF1 truncating mutations/fusions (6.2%) and c-MET exon skipping (3.6%) account for ~16% of driver-unknown lung cancer cases, and expanding the repertoire of lung cancer molecular subtypes.	('NRG1', 'Gene', (42, 46))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('NRG1', 'Gene', '3084', (42, 46))	('lung cancer', 'Disease', 'MESH:D008175', (238, 249))	('c-MET', 'Gene', '4233', (125, 130))	('lung cancer', 'Phenotype', 'HP:0100526', (238, 249))	('fusion/outlier', 'Var', (47, 61))	('lung cancer', 'Disease', (187, 198))	('c-MET', 'Gene', (125, 130))	('fusions', 'Var', (26, 33))	('mutations/fusions', 'Var', (96, 113))	('NF1', 'Gene', '4763', (81, 84))	('lung cancer', 'Disease', 'MESH:D008175', (187, 198))	('truncating mutations/fusions', 'Var', (85, 113))	('NF1', 'Gene', (81, 84))	('lung cancer', 'Disease', (238, 249))	('cancer', 'Phenotype', 'HP:0002664', (243, 249))	('lung cancer', 'Phenotype', 'HP:0100526', (187, 198))	('Hippo', 'Gene', (12, 17))
445210	25531467	Overexpression of the 3'-partner as consequence of gene fusions has been observed in well-known fusions such as TMPRSS2-ERG and others.	('TMPRSS2', 'Gene', (112, 119))	('ERG', 'Gene', (120, 123))	('gene fusions', 'Var', (51, 63))	('TMPRSS2', 'Gene', '7113', (112, 119))	('ERG', 'Gene', '2078', (120, 123))
445249	24278362	These results indicated that V-ATPase inhibitors have the potential to increase the tumor sensitivity to chemotherapeutic drugs.	('V-ATPase', 'Protein', (29, 37))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumor', 'Disease', (84, 89))	('inhibitors', 'Var', (38, 48))	('increase', 'PosReg', (71, 79))
445287	24278362	Antibodies for phospho-p38 MAPK (pT180/pY182), p38alpha(SAPK2a), phospho-STAT3 (pY705, pS727) and total STAT3 were purchased from BD Biosciences (Franklin Lakes, NJ, USA).	('STAT3', 'Gene', '6774', (104, 109))	('p38', 'Gene', '1432', (23, 26))	('SAPK2a', 'Gene', '1432', (56, 62))	('p38', 'Gene', '1432', (47, 50))	('STAT3', 'Gene', (104, 109))	('pT180/pY182', 'Var', (33, 44))	('STAT3', 'Gene', (73, 78))	('p38alpha', 'Gene', '1432', (47, 55))	('p38', 'Gene', (23, 26))	('SAPK2a', 'Gene', (56, 62))	('p38', 'Gene', (47, 50))	('p38alpha', 'Gene', (47, 55))	('STAT3', 'Gene', '6774', (73, 78))
445299	24278362	1A), indicating that CMA inhibited the acidification of vesicular organelles in the OSCC cells.	('inhibited', 'NegReg', (25, 34))	('CMA', 'Var', (21, 24))	('CMA', 'Chemical', '-', (21, 24))	('acidification of vesicular organelles', 'MPA', (39, 76))
445371	24278362	The induction of apoptosis by CMA involved the phosphorylation of p38, similar to the effects observed in human colon adenocarcinoma cells treated with bafilomycin A1, another V-ATPase inhibitor.	('human', 'Species', '9606', (106, 111))	('phosphorylation', 'MPA', (47, 62))	('CMA', 'Var', (30, 33))	('apoptosis', 'CPA', (17, 26))	('p38', 'Gene', '1432', (66, 69))	('CMA', 'Chemical', '-', (30, 33))	('colon adenocarcinoma', 'Disease', 'MESH:D003110', (112, 132))	('colon adenocarcinoma', 'Disease', (112, 132))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('bafilomycin A1', 'Chemical', 'MESH:C040929', (152, 166))	('p38', 'Gene', (66, 69))
445377	24278362	reported that the induction of apoptosis in cancer cells by synthetic analogues of the concanamycins corresponds with the V-ATPase inhibitory activity of the analogues.	('analogues', 'Var', (70, 79))	('V-ATPase inhibitory activity', 'MPA', (122, 150))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('concanamycins', 'Gene', (87, 100))	('concanamycins', 'Chemical', '-', (87, 100))	('apoptosis', 'CPA', (31, 40))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
445385	24278362	Our results also indicated that the phosphorylation of p38 is involved in the CMA-induced apoptosis in CMA-sensitive OSCC cells.	('phosphorylation', 'Var', (36, 51))	('CMA', 'Chemical', '-', (103, 106))	('involved', 'Reg', (62, 70))	('p38', 'Gene', '1432', (55, 58))	('CMA', 'Chemical', '-', (78, 81))	('apoptosis', 'CPA', (90, 99))	('CMA-induced', 'Disease', (78, 89))	('p38', 'Gene', (55, 58))
445392	24278362	Because CMA did lead to limited anti-tumor effects on the SQUU-B cells, such as the disappearance of the orange fluorescence and a decrease in cell mobility (shown in Figs.	('CMA', 'Var', (8, 11))	('cell mobility', 'CPA', (143, 156))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('CMA', 'Chemical', '-', (8, 11))	('orange fluorescence', 'MPA', (105, 124))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('decrease', 'NegReg', (131, 139))	('disappearance', 'NegReg', (84, 97))
445398	24278362	Therefore, SAHA, one of the HDACi, was used in the combination treatment with CMA in this study, because accumulated evidence has demonstrated that SAHA was capable of causing drug-induced apoptosis in OSCC cells, including carcinoma cells with resistance to antitumor drugs.	('HDAC', 'Gene', (28, 32))	('carcinoma', 'Disease', (224, 233))	('SAHA', 'Var', (148, 152))	('HDAC', 'Gene', '9734', (28, 32))	('tumor', 'Disease', 'MESH:D009369', (263, 268))	('tumor', 'Phenotype', 'HP:0002664', (263, 268))	('tumor', 'Disease', (263, 268))	('CMA', 'Chemical', '-', (78, 81))	('carcinoma', 'Disease', 'MESH:D002277', (224, 233))	('carcinoma', 'Phenotype', 'HP:0030731', (224, 233))	('SAHA', 'Chemical', 'MESH:D000077337', (11, 15))	('SAHA', 'Chemical', 'MESH:D000077337', (148, 152))
445415	24278362	In other studies, SAHA (vorinostat) reduced the pY705-STAT3, and the inhibition of pY705-STAT3 suppressed the Bcl-2 expression and enhanced the cytotoxicity of chemotherapeutic drugs to induce apoptosis in human cancer cell lines.	('suppressed', 'NegReg', (95, 105))	('enhanced', 'PosReg', (131, 139))	('human', 'Species', '9606', (206, 211))	('vorinostat', 'Chemical', 'MESH:D000077337', (24, 34))	('Bcl-2', 'Gene', (110, 115))	('Bcl-2', 'Gene', '596', (110, 115))	('STAT3', 'Gene', '6774', (54, 59))	('cytotoxicity', 'Disease', (144, 156))	('STAT3', 'Gene', (89, 94))	('cancer', 'Disease', (212, 218))	('STAT3', 'Gene', '6774', (89, 94))	('STAT3', 'Gene', (54, 59))	('reduced', 'NegReg', (36, 43))	('cancer', 'Disease', 'MESH:D009369', (212, 218))	('SAHA', 'Chemical', 'MESH:D000077337', (18, 22))	('inhibition', 'Var', (69, 79))	('cytotoxicity', 'Disease', 'MESH:D064420', (144, 156))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))
445419	24278362	The negative interaction between the pS727 and pY705 of STAT3 may be involved in the reduction of the Bcl-2 expression.	('pS727', 'Var', (37, 42))	('pY705', 'Var', (47, 52))	('STAT3', 'Gene', (56, 61))	('negative', 'NegReg', (4, 12))	('reduction', 'NegReg', (85, 94))	('STAT3', 'Gene', '6774', (56, 61))	('Bcl-2', 'Gene', (102, 107))	('Bcl-2', 'Gene', '596', (102, 107))	('interaction', 'Interaction', (13, 24))
445422	24278362	It is conceivable that the decrease of Bcl-2 expression induced by the change in the STAT3 phosphorylation can sensitize the cells to apoptotic injury.	('sensitize', 'Reg', (111, 120))	('apoptotic injury', 'CPA', (134, 150))	('decrease', 'NegReg', (27, 35))	('Bcl-2', 'Gene', '596', (39, 44))	('STAT3', 'Gene', '6774', (85, 90))	('expression', 'MPA', (45, 55))	('Bcl-2', 'Gene', (39, 44))	('STAT3', 'Gene', (85, 90))	('change', 'Var', (71, 77))
445423	24278362	However, Choi and Han showed that the activation of STAT3 (pS727) increased the Bcl-2 expression in HeLa cells overexpressing phospholipase D, which was different from our results concerning the Bcl-2 expression following STAT3 activation.	('STAT3', 'Gene', (52, 57))	('increased', 'PosReg', (66, 75))	('STAT3', 'Gene', '6774', (222, 227))	('Bcl-2', 'Gene', (80, 85))	('Bcl-2', 'Gene', '596', (80, 85))	('STAT3', 'Gene', (222, 227))	('pS727', 'Var', (59, 64))	('HeLa', 'CellLine', 'CVCL:0030', (100, 104))	('Bcl-2', 'Gene', (195, 200))	('Bcl-2', 'Gene', '596', (195, 200))	('STAT3', 'Gene', '6774', (52, 57))
445435	24278362	A decrease in Bcl-2 expression resulting from the changes in STAT3 phosphorylation, such as a decrease of pY705 and an increase of pS727, is at least partially responsible for inducing the increased susceptibility of SQUU-B cells to CMA.	('Bcl-2', 'Gene', (14, 19))	('Bcl-2', 'Gene', '596', (14, 19))	('pS727', 'MPA', (131, 136))	('decrease', 'NegReg', (2, 10))	('expression', 'MPA', (20, 30))	('changes', 'Reg', (50, 57))	('pY705', 'Var', (106, 111))	('STAT3', 'Gene', '6774', (61, 66))	('STAT3', 'Gene', (61, 66))	('increase', 'PosReg', (119, 127))	('CMA', 'Chemical', '-', (233, 236))	('decrease', 'NegReg', (94, 102))
445440	33495411	We found that ACK1 gene amplification was associated with mRNA levels in The Cancer Genome Atlas (TCGA) lung cancer cohort.	('Cancer', 'Disease', (77, 83))	('lung cancer', 'Disease', 'MESH:D008175', (104, 115))	('Cancer', 'Disease', 'MESH:D009369', (77, 83))	('associated', 'Reg', (42, 52))	('Cancer', 'Phenotype', 'HP:0002664', (77, 83))	('ACK1', 'Gene', '10188', (14, 18))	('lung cancer', 'Disease', (104, 115))	('ACK1', 'Gene', (14, 18))	('lung cancer', 'Phenotype', 'HP:0100526', (104, 115))	('amplification', 'Var', (24, 37))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('mRNA levels', 'MPA', (58, 69))
445443	33495411	RNA-sequencing results demonstrated that an ACK1 deficiency in A549 cells affected the MAPK, PI3K/AKT, and Wnt pathways.	('ACK1', 'Gene', (44, 48))	('MAPK', 'Pathway', (87, 91))	('affected', 'Reg', (74, 82))	('A549', 'CellLine', 'CVCL:0023', (63, 67))	('AKT', 'Gene', '207', (98, 101))	('deficiency', 'Var', (49, 59))	('Wnt pathways', 'Pathway', (107, 119))	('AKT', 'Gene', (98, 101))	('ACK1', 'Gene', '10188', (44, 48))
445460	33495411	ACK1 gene alterations (i.e., amplification, deletion, and mutation) have been detected in various human cancers, ranging from 4% to 27%.	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('deletion', 'Var', (44, 52))	('ACK1', 'Gene', '10188', (0, 4))	('ACK1', 'Gene', (0, 4))	('mutation', 'Var', (58, 66))	('cancers', 'Disease', 'MESH:D009369', (104, 111))	('cancers', 'Phenotype', 'HP:0002664', (104, 111))	('detected', 'Reg', (78, 86))	('cancers', 'Disease', (104, 111))	('human', 'Species', '9606', (98, 103))	('amplification', 'MPA', (29, 42))
445462	33495411	ACK1 may phosphorylate AKT at an evolutionarily conserved tyrosine residue at the 176th position (Tyr176) to induce PI3K-independent AKT activation.	('tyrosine', 'Chemical', 'MESH:D014443', (58, 66))	('Tyr176', 'Chemical', '-', (98, 104))	('AKT', 'Gene', '207', (23, 26))	('AKT', 'Gene', '207', (133, 136))	('ACK1', 'Gene', '10188', (0, 4))	('Tyr176', 'Var', (98, 104))	('ACK1', 'Gene', (0, 4))	('AKT', 'Gene', (23, 26))	('activation', 'PosReg', (137, 147))	('AKT', 'Gene', (133, 136))	('induce', 'PosReg', (109, 115))
445463	33495411	Moreover, ACK1 phosphorylates androgen receptor (AR) at Tyr267 and Try363 to stimulate the progression of prostate cancers.	('prostate cancer', 'Phenotype', 'HP:0012125', (106, 121))	('cancers', 'Phenotype', 'HP:0002664', (115, 122))	('stimulate', 'PosReg', (77, 86))	('androgen receptor', 'Gene', '367', (30, 47))	('Try363', 'Var', (67, 73))	('ACK1', 'Gene', '10188', (10, 14))	('prostate cancers', 'Phenotype', 'HP:0012125', (106, 122))	('ACK1', 'Gene', (10, 14))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('prostate cancers', 'Disease', (106, 122))	('androgen receptor', 'Gene', (30, 47))	('Try363', 'Chemical', '-', (67, 73))	('Tyr267', 'Chemical', '-', (56, 62))	('prostate cancers', 'Disease', 'MESH:D011471', (106, 122))	('AR', 'Gene', '367', (49, 51))
445469	33495411	The genetic alterations of ACK1 are displayed in Figure 1A, and ACK1 amplification was significantly associated with its transcription levels in TCGA lung cancer cohorts (Figure 1B).	('lung cancer', 'Phenotype', 'HP:0100526', (150, 161))	('ACK1', 'Gene', (64, 68))	('lung cancer', 'Disease', (150, 161))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('ACK1', 'Gene', '10188', (27, 31))	('ACK1', 'Gene', (27, 31))	('lung cancer', 'Disease', 'MESH:D008175', (150, 161))	('associated', 'Reg', (101, 111))	('transcription levels', 'MPA', (121, 141))	('amplification', 'Var', (69, 82))	('ACK1', 'Gene', '10188', (64, 68))
445475	33495411	However, the synergistic inhibition of cell proliferation was observed to a lesser extent for dasatinib and MK-2206 (AKT inhibitor) in the A549 cells (Figure 2A).	('AKT', 'Gene', '207', (117, 120))	('MK-2206', 'Var', (108, 115))	('MK-2206', 'Chemical', 'MESH:C548887', (108, 115))	('AKT', 'Gene', (117, 120))	('A549', 'CellLine', 'CVCL:0023', (139, 143))	('dasatinib', 'Chemical', 'MESH:D000069439', (94, 103))	('cell proliferation', 'CPA', (39, 57))
445477	33495411	Results from other teams and ours have shown the suppression of NSCLC cell proliferation by diverse ACK1 inhibitors.	('NSCLC', 'Disease', 'MESH:D002289', (64, 69))	('inhibitors', 'Var', (105, 115))	('suppression', 'NegReg', (49, 60))	('ACK1', 'Gene', '10188', (100, 104))	('ACK1', 'Gene', (100, 104))	('NSCLC', 'Phenotype', 'HP:0030358', (64, 69))	('NSCLC', 'Disease', (64, 69))
445479	33495411	In this study, we knocked down the ACK1 gene in A549 cells with the lentivirus delivery system (Figure 3A) and checked the affected downstream signaling pathways.	('knocked', 'Var', (18, 25))	('A549', 'CellLine', 'CVCL:0023', (48, 52))	('ACK1', 'Gene', '10188', (35, 39))	('ACK1', 'Gene', (35, 39))	('checked', 'Reg', (111, 118))
445483	33495411	Using the CytoHubba Cytoscape plug-in, we identified 219 hub genes with degrees >=10, 107 genes with degrees >=15, and 57 genes with degrees >=20.	('degrees >=10', 'Var', (72, 84))	('hub', 'Gene', '1993', (57, 60))	('hub', 'Gene', (57, 60))	('Hub', 'Gene', '1993', (14, 17))	('Hub', 'Gene', (14, 17))
445504	33495411	ACK1 is a nonreceptor tyrosine kinase, the deregulation of which may drive hallmarks of cancer, including cell proliferation, migration/metastasis, and EMT.	('cell proliferation', 'CPA', (106, 124))	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('EMT', 'CPA', (152, 155))	('migration/metastasis', 'CPA', (126, 146))	('ACK1', 'Gene', '10188', (0, 4))	('ACK1', 'Gene', (0, 4))	('tyrosine', 'Chemical', 'MESH:D014443', (22, 30))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('deregulation', 'Var', (43, 55))
445507	33495411	A relatively high frequency of ACK1 amplification in primary lung cancer was observed, coincident with augmented ACK1 mRNA levels.	('ACK1', 'Gene', (113, 117))	('lung cancer', 'Disease', (61, 72))	('lung cancer', 'Phenotype', 'HP:0100526', (61, 72))	('mRNA levels', 'MPA', (118, 129))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('augmented', 'PosReg', (103, 112))	('amplification', 'Var', (36, 49))	('lung cancer', 'Disease', 'MESH:D008175', (61, 72))	('ACK1', 'Gene', '10188', (31, 35))	('ACK1', 'Gene', (31, 35))	('ACK1', 'Gene', '10188', (113, 117))
445510	33495411	In this study, we validated ACK1 amplification and the association between ACK1 mRNA expression and copy number variation.	('ACK1', 'Gene', '10188', (75, 79))	('ACK1', 'Gene', (75, 79))	('ACK1', 'Gene', (28, 32))	('association', 'Interaction', (55, 66))	('ACK1', 'Gene', '10188', (28, 32))	('copy number variation', 'Var', (100, 121))	('mRNA expression', 'MPA', (80, 95))
445520	33495411	Inhibition of ACK1 reduced the migration and invasion of KRAS mutant lung adenocarcinoma.	('migration', 'CPA', (31, 40))	('lung adenocarcinoma', 'Disease', (69, 88))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (69, 88))	('ACK1', 'Gene', '10188', (14, 18))	('ACK1', 'Gene', (14, 18))	('KRAS', 'Gene', (57, 61))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('reduced', 'NegReg', (19, 26))	('Inhibition', 'Var', (0, 10))	('invasion', 'CPA', (45, 53))	('KRAS', 'Gene', '3845', (57, 61))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (69, 88))
445521	33495411	Moreover, ACK1 stabilizes EGFR, and knockdown of ACK1 increases the sensitivity of renal carcinoma cells to gefitinib.	('EGFR', 'Gene', (26, 30))	('ACK1', 'Gene', '10188', (10, 14))	('renal carcinoma', 'Phenotype', 'HP:0005584', (83, 98))	('gefitinib', 'Chemical', 'MESH:D000077156', (108, 117))	('ACK1', 'Gene', (10, 14))	('renal carcinoma', 'Disease', 'MESH:C538614', (83, 98))	('stabilizes', 'MPA', (15, 25))	('knockdown', 'Var', (36, 45))	('ACK1', 'Gene', '10188', (49, 53))	('increases', 'PosReg', (54, 63))	('ACK1', 'Gene', (49, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('EGFR', 'Gene', '1956', (26, 30))	('renal carcinoma', 'Disease', (83, 98))	('sensitivity', 'MPA', (68, 79))
445527	33495411	We next attempted to scrutinize the signaling pathways impacted by the silencing of ACK1 in A549 cells using RNA-seq.	('silencing', 'Var', (71, 80))	('ACK1', 'Gene', '10188', (84, 88))	('A549', 'CellLine', 'CVCL:0023', (92, 96))	('ACK1', 'Gene', (84, 88))
445530	33495411	Consistent with our finding, silencing of ACK1 inhibited the phosphorylation of ERK and AKT (Ser473), as well as the proliferation of renal cancer-derived cells, and reversed the EMT.	('reversed', 'PosReg', (166, 174))	('EMT', 'CPA', (179, 182))	('phosphorylation', 'MPA', (61, 76))	('inhibited', 'NegReg', (47, 56))	('ERK', 'Gene', '5594', (80, 83))	('proliferation', 'CPA', (117, 130))	('renal cancer', 'Disease', 'MESH:D007680', (134, 146))	('silencing', 'Var', (29, 38))	('renal cancer', 'Phenotype', 'HP:0009726', (134, 146))	('ERK', 'Gene', (80, 83))	('AKT', 'Gene', '207', (88, 91))	('Ser473', 'Chemical', '-', (93, 99))	('ACK1', 'Gene', (42, 46))	('ACK1', 'Gene', '10188', (42, 46))	('AKT', 'Gene', (88, 91))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('renal cancer', 'Disease', (134, 146))
445531	33495411	In mouse embryonic fibroblasts (MEFs), normal prostate cells, and MCF-7 cells, in response to EGF stimuli, ACK1 directly interacted with AKT and phosphorylated the latter at Tyr176 in the kinase domain.	('interacted', 'Interaction', (121, 131))	('EGF', 'Gene', '1950', (94, 97))	('mouse', 'Species', '10090', (3, 8))	('phosphorylated', 'MPA', (145, 159))	('Tyr176', 'Chemical', '-', (174, 180))	('Tyr176', 'Var', (174, 180))	('MCF-7', 'CellLine', 'CVCL:0031', (66, 71))	('AKT', 'Gene', '207', (137, 140))	('response', 'MPA', (82, 90))	('ACK1', 'Gene', '10188', (107, 111))	('EGF', 'Gene', (94, 97))	('ACK1', 'Gene', (107, 111))	('AKT', 'Gene', (137, 140))	('MEFs', 'CellLine', 'CVCL:9115', (32, 36))
445533	33495411	Conversely, knockdown of ACK1 resulted in a decreased Ser473 phosphorylation of AKT.	('AKT', 'Gene', '207', (80, 83))	('ACK1', 'Gene', (25, 29))	('knockdown', 'Var', (12, 21))	('ACK1', 'Gene', '10188', (25, 29))	('Ser473', 'Chemical', '-', (54, 60))	('AKT', 'Gene', (80, 83))	('decreased', 'NegReg', (44, 53))	('Ser473 phosphorylation', 'MPA', (54, 76))
445536	33495411	Breast cancer patients with high expression levels of Tyr176-phosphorylated AKT and Tyr284-phosphorylated ACK1 were significantly more likely to have unfavorable outcomes.	('unfavorable outcomes', 'CPA', (150, 170))	('Tyr176', 'Chemical', '-', (54, 60))	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('AKT', 'Gene', '207', (76, 79))	('ACK1', 'Gene', '10188', (106, 110))	('Breast cancer', 'Phenotype', 'HP:0003002', (0, 13))	('ACK1', 'Gene', (106, 110))	('Breast cancer', 'Disease', 'MESH:D001943', (0, 13))	('Tyr284-phosphorylated', 'Var', (84, 105))	('AKT', 'Gene', (76, 79))	('expression', 'MPA', (33, 43))	('Tyr284', 'Chemical', '-', (84, 90))	('Breast cancer', 'Disease', (0, 13))	('Tyr176-phosphorylated', 'Var', (54, 75))	('patients', 'Species', '9606', (14, 22))
445549	33495411	reported that the high expression level of ACK1 was significantly associated with poor survival in NSCLC.	('ACK1', 'Gene', '10188', (43, 47))	('ACK1', 'Gene', (43, 47))	('associated', 'Reg', (66, 76))	('NSCLC', 'Phenotype', 'HP:0030358', (99, 104))	('poor', 'NegReg', (82, 86))	('high', 'Var', (18, 22))	('NSCLC', 'Disease', (99, 104))	('NSCLC', 'Disease', 'MESH:D002289', (99, 104))
445711	32915772	Previous studies have shown that at the time of diagnosis, high-level TILs correlate with better outcomes in patients with nonmetastatic, basal-like cancer treated with standard therapeutic regimens.	('basal-like cancer', 'Phenotype', 'HP:0002671', (138, 155))	('cancer', 'Disease', (149, 155))	('patients', 'Species', '9606', (109, 117))	('high-level', 'Var', (59, 69))	('nonmetastatic', 'Disease', (123, 136))	('TIL', 'Gene', '7096', (70, 73))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('better', 'PosReg', (90, 96))	('TIL', 'Gene', (70, 73))	('cancer', 'Disease', 'MESH:D009369', (149, 155))
445800	32915772	Clinical trial results have shown that TIL enrichment is a predictive response to the PD-1 antibody pembrolizumab, both in patients with HER2-positive BC (NCT02129556) or TNBC (KEYNOTE-086).	('PD-1 antibody pembrolizumab', 'Disease', (86, 113))	('TIL', 'Gene', (39, 42))	('NCT02129556', 'Var', (155, 166))	('PD-1 antibody pembrolizumab', 'Disease', 'MESH:D010300', (86, 113))	('patients', 'Species', '9606', (123, 131))	('HER2', 'Gene', (137, 141))	('BC', 'Phenotype', 'HP:0003002', (151, 153))	('HER2', 'Gene', '2064', (137, 141))	('TIL', 'Gene', '7096', (39, 42))	('BC', 'Phenotype', 'HP:0003002', (173, 175))
445801	32915772	Multifactorial markers incorporating PD-L1 expression, mutational load, intratumoral CD8+ T cells, and other variables may enhance predictive power contrast to individual tests for ICB agents.	('enhance', 'PosReg', (123, 130))	('PD-L1', 'Gene', (37, 42))	('CD8', 'Gene', (85, 88))	('CD8', 'Gene', '925', (85, 88))	('predictive', 'MPA', (131, 141))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('mutational load', 'Var', (55, 70))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Disease', (77, 82))
445827	28178311	As a result, we found that genes that show a methylation change larger than 32.2% may influence cancer-related genes via fewer interaction steps and with much higher percentages compared with genes showing a methylation change less than 32.2%.	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('fewer', 'NegReg', (121, 126))	('cancer', 'Disease', (96, 102))	('methylation', 'Var', (45, 56))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('influence', 'Reg', (86, 95))	('interaction', 'Interaction', (127, 138))
445834	28178311	It is well established that hypermethylation in promoter regions leads to inactivation, whereas hypomethylation is associated with genomic instability and loss of imprinting, in addition to contributing to cell transformation and the progression of lesions, which may be the key factors in the reproduction and metastasis of cancer cells.	('loss', 'NegReg', (155, 159))	('hypermethylation', 'Var', (28, 44))	('cell transformation', 'CPA', (206, 225))	('hypomethylation', 'Var', (96, 111))	('associated', 'Reg', (115, 125))	('metastasis of cancer', 'Disease', (311, 331))	('genomic', 'MPA', (131, 138))	('inactivation', 'MPA', (74, 86))	('contributing', 'Reg', (190, 202))	('imprinting', 'Protein', (163, 173))	('metastasis of cancer', 'Disease', 'MESH:D009362', (311, 331))	('cancer', 'Phenotype', 'HP:0002664', (325, 331))
445835	28178311	Indeed, both hyper- and hypomethylation have previously been associated with a variety of cancers, including kidney, colon, pancreas, liver and lung cancers.	('kidney', 'Disease', (109, 115))	('cancers', 'Disease', (90, 97))	('cancers', 'Disease', (149, 156))	('cancers', 'Phenotype', 'HP:0002664', (149, 156))	('lung cancer', 'Phenotype', 'HP:0100526', (144, 155))	('colon, pancreas, liver and lung cancers', 'Disease', 'MESH:D008175', (117, 156))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('hypomethylation', 'Var', (24, 39))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('hyper-', 'Var', (13, 19))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('lung cancers', 'Phenotype', 'HP:0100526', (144, 156))	('associated', 'Reg', (61, 71))	('cancers', 'Disease', 'MESH:D009369', (90, 97))	('cancers', 'Disease', 'MESH:D009369', (149, 156))
445836	28178311	Additionally, gene silencing via the hypermethylation of tumor-suppressing genes and activation of tumor-promoting genes via hypomethylation has been demonstrated to favor oncogenesis.	('tumor', 'Disease', (99, 104))	('favor', 'PosReg', (166, 171))	('gene', 'Var', (14, 18))	('oncogenesis', 'CPA', (172, 183))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('hypomethylation', 'Var', (125, 140))	('activation', 'PosReg', (85, 95))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('hypermethylation', 'Var', (37, 53))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumor', 'Disease', (57, 62))
445863	28178311	In this work, we focused on identifying methylation-affected patterns that could potentially result in a cancer state.	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('methylation-affected', 'Var', (40, 60))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('result in', 'Reg', (93, 102))
445869	28178311	More specifically, renal papillary cell carcinoma exhibited the greatest number of differentially methylated genes (FDR<0.1), while the number of differentially expressed genes was highest for cholangiocarcinoma, and the thyroid cancer dataset contained the minimum numbers of genes regarding both differential expression and differential methylation.	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (193, 211))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (193, 211))	('renal papillary cell carcinoma', 'Phenotype', 'HP:0006766', (19, 49))	('renal papillary cell carcinoma', 'Disease', 'MESH:C538614', (19, 49))	('thyroid cancer', 'Disease', (221, 235))	('thyroid cancer', 'Phenotype', 'HP:0002890', (221, 235))	('differentially', 'Var', (83, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (202, 211))	('carcinoma', 'Phenotype', 'HP:0030731', (40, 49))	('renal papillary cell carcinoma', 'Disease', (19, 49))	('thyroid cancer', 'Disease', 'MESH:D013964', (221, 235))	('cholangiocarcinoma', 'Disease', (193, 211))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))
445870	28178311	The numbers of genes showing methylation changes exceeding 15% and 32.2% for each cancer type are illustrated in Table 2.	('methylation', 'Var', (29, 40))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('changes', 'Reg', (41, 48))
445874	28178311	To address these issues, we adopted a graph-based approach and calculated the distances between large methylation changes and potentially cancer-causing driver genes by considering pairwise protein-protein interactions.	('methylation changes', 'Var', (102, 121))	('cancer', 'Disease', (138, 144))	('cancer', 'Disease', 'MESH:D009369', (138, 144))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))
445875	28178311	The results revealed that the genes with large methylation changes affected driver genes in fewer steps, except for thyroid cancer.	('thyroid cancer', 'Disease', 'MESH:D013964', (116, 130))	('methylation changes', 'Var', (47, 66))	('thyroid cancer', 'Disease', (116, 130))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('thyroid cancer', 'Phenotype', 'HP:0002890', (116, 130))
445888	28178311	Focusing on the affected genes that were observed only in a single cancer type revealed that the RET gene was affected by high methylation in thyroid cancer (shown in cornflower blue).	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('cancer', 'Disease', (67, 73))	('thyroid cancer', 'Phenotype', 'HP:0002890', (142, 156))	('thyroid cancer', 'Disease', (142, 156))	('high methylation', 'Var', (122, 138))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('RET', 'Gene', '5979', (97, 100))	('cancer', 'Disease', (150, 156))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('affected', 'Reg', (110, 118))	('thyroid cancer', 'Disease', 'MESH:D013964', (142, 156))	('RET', 'Gene', (97, 100))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
445890	28178311	Examining cholangiocarcinoma, we observed that the HRAS, KIT, ZBTB16, FAS and NCOA4 genes were altered by high methylation (shown in light sea green).	('cholangiocarcinoma', 'Disease', (10, 28))	('NCOA4', 'Gene', '8031', (78, 83))	('HRAS', 'Gene', (51, 55))	('ZBTB16', 'Gene', (62, 68))	('FAS', 'Gene', (70, 73))	('carcinoma', 'Phenotype', 'HP:0030731', (19, 28))	('high methylation', 'Var', (106, 122))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (10, 28))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (10, 28))	('altered', 'Reg', (95, 102))	('KIT', 'Gene', (57, 60))	('HRAS', 'Gene', '3265', (51, 55))	('NCOA4', 'Gene', (78, 83))	('ZBTB16', 'Gene', '7704', (62, 68))
445892	28178311	The ZBTB16 gene is active in the blocking of differentiation; thus, methylation-driven abnormalities in ZBTB16 may lead to cholangiocarcinoma.	('ZBTB16', 'Gene', '7704', (4, 10))	('abnormalities', 'Var', (87, 100))	('cholangiocarcinoma', 'Disease', (123, 141))	('ZBTB16', 'Gene', '7704', (104, 110))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (123, 141))	('ZBTB16', 'Gene', (104, 110))	('ZBTB16', 'Gene', (4, 10))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (123, 141))	('methylation-driven', 'Var', (68, 86))	('lead to', 'Reg', (115, 122))
445895	28178311	In lung squamous cell carcinoma, we detected 15 genes that were altered by high methylation, and six of these genes were observed to be affected only in this type of cancer (shown in magenta).	('cancer', 'Disease', (166, 172))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (8, 31))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (3, 31))	('lung squamous cell carcinoma', 'Disease', (3, 31))	('high methylation', 'Var', (75, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('altered', 'Reg', (64, 71))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (3, 31))
445900	28178311	Additionally, in the thyroid cancer dataset, copy number analysis of the RET gene revealed decreases in 5 of the 46 samples, while no sample exhibited an increase in the RET copy number.	('RET', 'Gene', (170, 173))	('thyroid cancer', 'Disease', 'MESH:D013964', (21, 35))	('RET', 'Gene', '5979', (73, 76))	('RET', 'Gene', '5979', (170, 173))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('copy', 'Var', (45, 49))	('thyroid cancer', 'Disease', (21, 35))	('RET', 'Gene', (73, 76))	('thyroid cancer', 'Phenotype', 'HP:0002890', (21, 35))	('decreases', 'NegReg', (91, 100))
445909	28178311	Additionally, based on the idea that large methylation changes might exhibit more rapid effects on the mechanisms leading to cancer states, we defined a large methylation change threshold.	('methylation changes', 'Var', (43, 62))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('changes', 'Var', (55, 62))
445910	28178311	Subsequently, we continued our analysis of the effects of methylation-driven changes on cancer-related genes (driver genes).	('changes', 'Reg', (77, 84))	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('methylation-driven', 'Var', (58, 76))
445912	28178311	We found that large methylation changes exerted a major influence on the expression of driver genes in fewer steps (1.95 vs. 2.09, except for thyroid cancer) and at a higher proportion (7.83% vs. 3.00%), although these results varied among different cancer types.	('cancer', 'Disease', 'MESH:D009369', (250, 256))	('thyroid cancer', 'Phenotype', 'HP:0002890', (142, 156))	('thyroid cancer', 'Disease', (142, 156))	('cancer', 'Disease', (250, 256))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))	('cancer', 'Disease', (150, 156))	('methylation changes', 'Var', (20, 39))	('expression', 'MPA', (73, 83))	('thyroid cancer', 'Disease', 'MESH:D013964', (142, 156))	('influence', 'Reg', (56, 65))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('changes', 'Var', (32, 39))
445920	28178311	In the present study, AGTR1 was found to exhibit a decreased expression level; hence, in a maximum of three steps, we identified genes that were altered by large methylation changes that signaled decreases in the expression level of AGTR1.	('expression level', 'MPA', (213, 229))	('decreases', 'NegReg', (196, 205))	('altered', 'Reg', (145, 152))	('AGTR1', 'Gene', (233, 238))	('changes', 'Var', (174, 181))	('AGTR1', 'Gene', '185', (233, 238))	('methylation', 'MPA', (162, 173))	('expression level', 'MPA', (61, 77))	('AGTR1', 'Gene', (22, 27))	('AGTR1', 'Gene', '185', (22, 27))
445922	28178311	In summary, our findings suggest that both AGTR1 and IGF1 are frequently observed as changed in variety of cancers and experimentally validating the hits that we find with our method linking large methylation alteration to these changes may reveal their potentially crucial role on overall cancer progression.	('AGTR1', 'Gene', '185', (43, 48))	('cancers', 'Disease', (107, 114))	('IGF1', 'Gene', (53, 57))	('cancers', 'Disease', 'MESH:D009369', (107, 114))	('cancer', 'Disease', 'MESH:D009369', (290, 296))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('cancer', 'Disease', (290, 296))	('IGF1', 'Gene', '3479', (53, 57))	('changed', 'Reg', (85, 92))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('methylation alteration', 'Var', (197, 219))	('cancer', 'Phenotype', 'HP:0002664', (290, 296))	('AGTR1', 'Gene', (43, 48))	('cancer', 'Disease', (107, 113))	('cancers', 'Phenotype', 'HP:0002664', (107, 114))
445927	28178311	Moreover, increased methylation-driven expression of the important oncogene SRC was identified in cholangiocarcinoma, hepatocellular carcinoma and colon adenocarcinoma, and SRC has previously been demonstrated to be active in cancer progression.	('SRC', 'Gene', (76, 79))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (98, 116))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (118, 142))	('methylation-driven', 'Var', (20, 38))	('cholangiocarcinoma', 'Disease', (98, 116))	('SRC', 'Gene', '6714', (173, 176))	('colon adenocarcinoma', 'Disease', 'MESH:D003110', (147, 167))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (98, 116))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('hepatocellular carcinoma', 'Disease', (118, 142))	('cancer', 'Disease', 'MESH:D009369', (226, 232))	('carcinoma', 'Phenotype', 'HP:0030731', (158, 167))	('expression', 'MPA', (39, 49))	('increased', 'PosReg', (10, 19))	('SRC', 'Gene', (173, 176))	('colon adenocarcinoma', 'Disease', (147, 167))	('SRC', 'Gene', '6714', (76, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (118, 142))	('cancer', 'Disease', (226, 232))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
445931	28178311	Both of these genes were found to be differentially altered by high methylation in colon cancer in our analysis.	('colon cancer', 'Disease', (83, 95))	('altered', 'Reg', (52, 59))	('colon cancer', 'Phenotype', 'HP:0003003', (83, 95))	('high methylation', 'Var', (63, 79))	('colon cancer', 'Disease', 'MESH:D015179', (83, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
445940	28178311	Additionally, changes in EGFR have been associated with lung cancer, and this gene has been recommended as a drug target.	('lung cancer', 'Phenotype', 'HP:0100526', (56, 67))	('EGFR', 'Gene', (25, 29))	('lung cancer', 'Disease', 'MESH:D008175', (56, 67))	('changes', 'Var', (14, 21))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('lung cancer', 'Disease', (56, 67))	('EGFR', 'Gene', '1956', (25, 29))	('associated', 'Reg', (40, 50))
445941	28178311	Alterations of AXIN2 have been demonstrated to contribute to carcinogenesis, specifically in lung cancer, and the downregulation of this suppressor via a large methylation change was successfully detected by our method.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('contribute', 'Reg', (47, 57))	('lung cancer', 'Disease', 'MESH:D008175', (93, 104))	('Alterations', 'Var', (0, 11))	('carcinogenesis', 'Disease', (61, 75))	('AXIN2', 'Gene', (15, 20))	('lung cancer', 'Disease', (93, 104))	('lung cancer', 'Phenotype', 'HP:0100526', (93, 104))	('methylation change', 'Var', (160, 178))	('AXIN2', 'Gene', '8313', (15, 20))	('downregulation', 'NegReg', (114, 128))	('carcinogenesis', 'Disease', 'MESH:D063646', (61, 75))
445946	28178311	Because an increase in copy number is generally associated with greater expression, our findings suggest that large methylation changes were the predominant factors underlying the downregulation of these tumor suppressors, which was supported by copy number analyses.	('methylation', 'MPA', (116, 127))	('increase', 'PosReg', (11, 19))	('greater', 'PosReg', (64, 71))	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('copy number', 'Var', (23, 34))	('expression', 'MPA', (72, 82))	('tumor', 'Disease', (204, 209))	('downregulation', 'NegReg', (180, 194))
445956	28178311	Although our method reveals important and previously unexplored information about possible methylation-driven changes in different cancer types, whether a large methylation change effectively leads to predicted change in corresponding driver gene in vitro and in vivo remains unknown.	('cancer', 'Disease', (131, 137))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('change', 'Var', (173, 179))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))
445979	26435481	Recent whole-exome sequencing studies provided evidence of HER2 activation by somatic mutation, amplification, and human papilloma virus (HPV) integration in cervical cancer, warranting investigation of the effects of HER2 inhibitors.	('amplification', 'Var', (96, 109))	('HPV', 'Species', '10566', (138, 141))	('HER2', 'Gene', (218, 222))	('HER2', 'Gene', '2064', (218, 222))	('cervical cancer', 'Disease', (158, 173))	('cervical cancer', 'Disease', 'MESH:D002583', (158, 173))	('activation', 'PosReg', (64, 74))	('HER2', 'Gene', (59, 63))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('HER2', 'Gene', '2064', (59, 63))	('papilloma', 'Phenotype', 'HP:0012740', (121, 130))	('human papilloma virus', 'Species', '10566', (115, 136))
445982	26435481	In addition, when analyzing patient's tumors and PDXs, we found a single case with aberrant HER2 amplification and expression.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('amplification', 'Var', (97, 110))	('tumors', 'Disease', (38, 44))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('HER2', 'Gene', '2064', (92, 96))	('tumors', 'Disease', 'MESH:D009369', (38, 44))	('HER2', 'Gene', (92, 96))	('patient', 'Species', '9606', (28, 35))	('expression', 'MPA', (115, 125))
446000	26435481	In CX14 PDX tumor (adenocarcinoma), tumor glands were more irregular in shape and situated back to back closely with little intervening stroma.	('CX14', 'Var', (3, 7))	('adenocarcinoma', 'Disease', 'MESH:D000230', (19, 33))	('back to back', 'Disease', (91, 103))	('back to back', 'Disease', 'MESH:D001416', (91, 103))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('adenocarcinoma', 'Disease', (19, 33))	('tumor', 'Disease', (12, 17))	('carcinoma', 'Phenotype', 'HP:0030731', (24, 33))	('tumor', 'Disease', (36, 41))
446003	26435481	The STR profiles of 7 PDX counterparts (i.e., CX4-M1, CX8-M1, CX10-M1, CX11-M1, CX13-M1, CX15-M1, and CX17-M1) were identical to their respective original human tumors at all STR loci (Supplementary Table S2).	('CX4-M1', 'Var', (46, 52))	('CX11-M1', 'Var', (71, 78))	('CX17-M1', 'Var', (102, 109))	('tumors', 'Disease', (161, 167))	('tumors', 'Phenotype', 'HP:0002664', (161, 167))	('CX8-M1', 'Var', (54, 60))	('human', 'Species', '9606', (155, 160))	('CX10-M1', 'Var', (62, 69))	('tumors', 'Disease', 'MESH:D009369', (161, 167))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('CX13-M1', 'Var', (80, 87))	('CX15-M1', 'Var', (89, 96))
446007	26435481	Interestingly, the Cancer Panel revealed a single case with HER2 amplification (Supplementary Table S3).	('HER2', 'Gene', '2064', (60, 64))	('amplification', 'Var', (65, 78))	('HER2', 'Gene', (60, 64))	('Cancer', 'Phenotype', 'HP:0002664', (19, 25))
446015	26435481	Only the CX17 patient's tumor but not the cervical cancer cell lines exhibited a high HER2 copy number (Supplementary Figure S2).	('HER2', 'Gene', (86, 90))	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('HER2', 'Gene', '2064', (86, 90))	('tumor', 'Disease', (24, 29))	('copy number', 'Var', (91, 102))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('cervical cancer', 'Disease', (42, 57))	('cervical cancer', 'Disease', 'MESH:D002583', (42, 57))	('patient', 'Species', '9606', (14, 21))	('tumor', 'Disease', 'MESH:D009369', (24, 29))
446017	26435481	In the CX17 sample which exhibited HER2 amplification in the genomic study, the tumor was histologically defined as a stage IIB squamous cell carcinoma.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('HER2', 'Gene', (35, 39))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (128, 151))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('HER2', 'Gene', '2064', (35, 39))	('squamous cell carcinoma', 'Disease', (128, 151))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (128, 151))	('tumor', 'Disease', (80, 85))	('amplification', 'Var', (40, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (142, 151))
446035	26435481	Moreover, trastuzumab and lapatinib combination decreased the phosphorylation of mitogen-activated protein kinase (Phospho-p42/44 MAPK [Thr202/Tyr204]) and STAT3 (Phospho-Stat3 [Tyr705]), but not AKT (Phospho-AKT [Ser473]) in the CX17 PDX (Figure 5D).	('Tyr204', 'Chemical', '-', (143, 149))	('combination', 'Var', (36, 47))	('AKT', 'Gene', (196, 199))	('p42', 'Gene', (123, 126))	('phosphorylation', 'MPA', (62, 77))	('decreased', 'NegReg', (48, 57))	('AKT', 'Gene', (209, 212))	('Tyr705', 'Chemical', '-', (178, 184))	('Ser473', 'Chemical', '-', (214, 220))	('Stat3', 'Gene', (171, 176))	('p42', 'Gene', '2038', (123, 126))	('STAT3', 'Gene', (156, 161))	('AKT', 'Gene', '207', (196, 199))	('lapatinib', 'Chemical', 'MESH:D000077341', (26, 35))	('mitogen-activated', 'MPA', (81, 98))	('Thr202', 'Chemical', '-', (136, 142))	('trastuzumab', 'Chemical', 'MESH:D000068878', (10, 21))	('STAT3', 'Gene', '6774', (156, 161))	('AKT', 'Gene', '207', (209, 212))	('Stat3', 'Gene', '6774', (171, 176))
446036	26435481	In this study, we established histopathologically and genomically homologous PDX models for human cervical cancer and found a single case with aberrant HER2 amplification and expression.	('expression', 'MPA', (175, 185))	('aberrant', 'Var', (143, 151))	('HER2', 'Gene', (152, 156))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('HER2', 'Gene', '2064', (152, 156))	('cervical cancer', 'Disease', 'MESH:D002583', (98, 113))	('cervical cancer', 'Disease', (98, 113))	('amplification', 'Var', (157, 170))	('human', 'Species', '9606', (92, 97))
446052	26435481	These results are supported by work recently published by Ojesina et al., who observed HER2 amplification in a small percentage of cervical cancer patients and evidence of HER2 activation by somatic mutation, amplification, and human papilloma virus (HPV) integration in cervical cancer.	('amplification', 'MPA', (92, 105))	('HER2', 'Gene', '2064', (87, 91))	('human papilloma virus', 'Species', '10566', (228, 249))	('HPV', 'Species', '10566', (251, 254))	('activation', 'PosReg', (177, 187))	('HER2', 'Gene', '2064', (172, 176))	('papilloma', 'Phenotype', 'HP:0012740', (234, 243))	('cervical cancer', 'Disease', (271, 286))	('cervical cancer', 'Disease', 'MESH:D002583', (271, 286))	('patients', 'Species', '9606', (147, 155))	('cancer', 'Phenotype', 'HP:0002664', (280, 286))	('amplification', 'Var', (209, 222))	('cervical cancer', 'Disease', 'MESH:D002583', (131, 146))	('HER2', 'Gene', (172, 176))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('HER2', 'Gene', (87, 91))	('cervical cancer', 'Disease', (131, 146))
446054	26435481	Although absolute numbers remain small, it is evident that some cases with HER2 amplification either in cervical cancer PDXs or in patients will not respond to chemo-radiation.	('patients', 'Species', '9606', (131, 139))	('amplification', 'Var', (80, 93))	('HER2', 'Gene', (75, 79))	('HER2', 'Gene', '2064', (75, 79))	('cervical cancer', 'Disease', (104, 119))	('cervical cancer', 'Disease', 'MESH:D002583', (104, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
446098	26435481	Tumor and control DNA were labeled with Cy5-dCTP and Cy3-dCTP, respectively, followed by DNA hybridization to a microarray.	('Cy5-dCTP', 'Var', (40, 48))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('Cy3-dCTP', 'Chemical', '-', (53, 61))	('Cy3-dCTP', 'Var', (53, 61))	('Cy5-dCTP', 'Chemical', 'MESH:C544355', (40, 48))
446146	32703928	There are many genes in this network that are significantly associated with survival of patients with 2 types of cancer (Figure 5).	('genes', 'Var', (15, 20))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('patients', 'Species', '9606', (88, 96))	('cancer', 'Disease', (113, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('associated with', 'Reg', (60, 75))
446156	32703928	For example, lncRNA PVT1 regulates expression of HIF1alpha via functioning as ceRNA for miR-199a-5p in non-small cell lung cancer under hypoxia.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('hypoxia', 'Disease', (136, 143))	('hypoxia', 'Disease', 'MESH:D000860', (136, 143))	('PVT1', 'Gene', (20, 24))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (103, 129))	('PVT1', 'Gene', '5820', (20, 24))	('expression', 'MPA', (35, 45))	('HIF1alpha', 'Gene', (49, 58))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (103, 129))	('regulates', 'Reg', (25, 34))	('lung cancer', 'Phenotype', 'HP:0100526', (118, 129))	('non-small cell lung cancer', 'Disease', (103, 129))	('miR-199a-5p', 'Var', (88, 99))	('HIF1alpha', 'Gene', '3091', (49, 58))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (107, 129))
446181	32195170	At the molecular level, it was found that HK2 alteration drove metabolic reprogramming toward OxPhos and modulated oncogenic Akt and mutant TP53-mediated signals in HNSCC cells.	('alteration', 'Var', (46, 56))	('Akt', 'Gene', '207', (125, 128))	('TP53', 'Gene', (140, 144))	('drove', 'Reg', (57, 62))	('Akt', 'Gene', (125, 128))	('modulated', 'Reg', (105, 114))	('metabolic reprogramming', 'CPA', (63, 86))	('HK2', 'Gene', (42, 45))	('mutant', 'Var', (133, 139))	('HNSCC', 'Phenotype', 'HP:0012288', (165, 170))	('TP53', 'Gene', '7157', (140, 144))
446214	32195170	Furthermore, immunohistochemical analysis showed that HK2 is strongly detected in 4-NQO-induced mouse tongue neoplastic lesions compared with normal oral epithelium (Figure 1G), as well as human oral squamous cell carcinoma (Figure 1H).	('detected', 'Reg', (70, 78))	('HK2', 'Gene', (54, 57))	('4-NQO-induced', 'Var', (82, 95))	('human', 'Species', '9606', (189, 194))	('squamous cell carcinoma', 'Disease', (200, 223))	('mouse', 'Species', '10090', (96, 101))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (200, 223))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (200, 223))	('neoplastic lesions', 'Disease', (109, 127))	('neoplastic lesions', 'Disease', 'MESH:D051437', (109, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (214, 223))	('tongue neoplastic lesions', 'Phenotype', 'HP:0100648', (102, 127))	('4-NQO', 'Chemical', 'MESH:D015112', (82, 87))	('neoplastic lesions', 'Phenotype', 'HP:0002664', (109, 127))
446217	32195170	As shRNA-mediated HK2-deficient HNSCC cells were successfully established without apparent morphological change (Figures 2B,C and Supplementary Figure 3), it was demonstrated that, by using both trypan blue exclusion (Figure 2D) and MTT (Figure 2E) assays, HK2-silencing resulted in decreased cell growth in HNSCC cells.	('cell growth in HNSCC cells', 'CPA', (293, 319))	('MTT', 'Chemical', 'MESH:C070243', (233, 236))	('HK2-silencing', 'Var', (257, 270))	('HNSCC', 'Phenotype', 'HP:0012288', (32, 37))	('HNSCC', 'Phenotype', 'HP:0012288', (308, 313))	('trypan blue', 'Chemical', 'MESH:D014343', (195, 206))	('decreased', 'NegReg', (283, 292))
446219	32195170	The results indicated that HK2 deficiency led to significant decrease of cell migration and invasion in OECM-1 and HSC3 clones (Figures 3A,B).	('decrease', 'NegReg', (61, 69))	('cell migration', 'CPA', (73, 87))	('invasion in OECM-1', 'CPA', (92, 110))	('deficiency', 'Var', (31, 41))	('HSC3', 'Gene', '150353', (115, 119))	('HK2', 'Gene', (27, 30))	('HSC3', 'Gene', (115, 119))
446230	32195170	Consistent with this notion, stemness indicators Nanog and Oct4 mRNA (Figure 4C) and ALDH activity (Figure 4D) were downregulated in HK2-silencing HNSCC cells.	('stemness', 'CPA', (29, 37))	('HK2-silencing', 'Var', (133, 146))	('Nanog', 'Gene', (49, 54))	('downregulated', 'NegReg', (116, 129))	('Oct4', 'Gene', (59, 63))	('ALDH activity', 'CPA', (85, 98))	('Oct4', 'Gene', '5460', (59, 63))	('Nanog', 'Gene', '79923', (49, 54))	('HNSCC', 'Phenotype', 'HP:0012288', (147, 152))
446234	32195170	This statement could be further supported by the results showing a greater extracellular acidification rate (ECAR) upon addition of ATPase inhibitor oligomycin (Figure 5C) and increased PDH activity (Figure 5D) in HK2-silencing HNSCC cells.	('increased', 'PosReg', (176, 185))	('activity', 'MPA', (190, 198))	('PDH', 'Gene', '54704', (186, 189))	('ATPase', 'Gene', '1769', (132, 138))	('extracellular acidification rate', 'MPA', (75, 107))	('HNSCC', 'Phenotype', 'HP:0012288', (228, 233))	('greater', 'PosReg', (67, 74))	('ATPase', 'Gene', (132, 138))	('oligomycin', 'Chemical', 'MESH:D009840', (149, 159))	('HK2-silencing', 'Var', (214, 227))	('PDH', 'Gene', (186, 189))
446235	32195170	Unexpectedly, HK2 deficiency-mediated decreased cell growth did not result from reduction of cellular ATP level (Figure 5E), suggesting that bioenergetics could be dispensable for metabolism-mediated cell growth.	('ATP', 'Gene', (102, 105))	('cell growth', 'CPA', (48, 59))	('decreased', 'NegReg', (38, 47))	('ATP', 'Gene', '51761', (102, 105))	('deficiency-mediated', 'Var', (18, 37))	('HK2', 'Gene', (14, 17))
446236	32195170	Using a high-throughput human protein array, it was discovered that Akt (S473), TP53 (S15, S46, and S392), and p27 (T198) proteins were downregulated in HK2-silencing OECM-1 cells (Figure 5F).	('S473', 'Var', (73, 77))	('downregulated', 'NegReg', (136, 149))	('human', 'Species', '9606', (24, 29))	('Akt', 'Gene', '207', (68, 71))	('TP53', 'Gene', '7157', (80, 84))	('TP53', 'Gene', (80, 84))	('S392', 'Var', (100, 104))	('p27', 'Gene', '3429', (111, 114))	('Akt', 'Gene', (68, 71))	('S15', 'Var', (86, 89))	('p27', 'Gene', (111, 114))	('HK2-silencing', 'Var', (153, 166))	('proteins', 'Protein', (122, 130))
446242	32195170	Based on protein array analysis, HK2 loss resulted in decreased phosphorylated TP53 at transactivation domain (S15 and S46) and C-terminal domain (S392) in OECM-1 cells.	('TP53', 'Gene', '7157', (79, 83))	('TP53', 'Gene', (79, 83))	('HK2', 'Gene', (33, 36))	('S392', 'Var', (147, 151))	('S46', 'Var', (119, 122))	('loss', 'NegReg', (37, 41))	('decreased', 'NegReg', (54, 63))	('phosphorylated', 'MPA', (64, 78))	('S15', 'Var', (111, 114))
446243	32195170	While previous sequencing analysis for TP53 gene in OECM-1 cells showed that OECM-1 cells carry mutant TP53 (P139R/V239L), phosphorylation on S15, S46, and S392 of TP53 could be oncogenic in OECM-1 cells.	('P139R', 'SUBSTITUTION', 'None', (109, 114))	('TP53', 'Gene', '7157', (164, 168))	('TP53', 'Gene', '7157', (103, 107))	('TP53', 'Gene', (164, 168))	('TP53', 'Gene', (39, 43))	('TP53', 'Gene', (103, 107))	('P139R', 'Var', (109, 114))	('V239L', 'SUBSTITUTION', 'None', (115, 120))	('S46', 'Var', (147, 150))	('TP53', 'Gene', '7157', (39, 43))	('S392', 'Var', (156, 160))	('V239L', 'Var', (115, 120))	('phosphorylation on S15', 'Var', (123, 145))	('oncogenic', 'CPA', (178, 187))
446244	32195170	This statement could be supported by previous studies showing that S15 phosphorylation of TP53 contributed mutant TP53 stability, thereby prolonging cell viability in ovarian cancer cells, and S392 phosphorylation in mutant TP53 could lead to tumor progression in esophageal squamous cell carcinoma.	('mutant', 'Var', (217, 223))	('carcinoma', 'Phenotype', 'HP:0030731', (289, 298))	('TP53', 'Gene', '7157', (90, 94))	('TP53', 'Gene', '7157', (114, 118))	('esophageal squamous cell carcinoma', 'Disease', (264, 298))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('tumor', 'Disease', (243, 248))	('ovarian cancer', 'Disease', 'MESH:D010051', (167, 181))	('S392 phosphorylation', 'Var', (193, 213))	('lead to', 'Reg', (235, 242))	('tumor', 'Disease', 'MESH:D009369', (243, 248))	('S15 phosphorylation', 'Var', (67, 86))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (275, 298))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (264, 298))	('TP53', 'Gene', (224, 228))	('prolonging', 'PosReg', (138, 148))	('ovarian cancer', 'Disease', (167, 181))	('cell viability', 'CPA', (149, 163))	('TP53', 'Gene', (90, 94))	('TP53', 'Gene', (114, 118))	('ovarian cancer', 'Phenotype', 'HP:0100615', (167, 181))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))	('stability', 'MPA', (119, 128))	('mutant', 'Var', (107, 113))	('TP53', 'Gene', '7157', (224, 228))
446245	32195170	While it was reported that T198 phosphorylation of cell cycle regulator p27 promotes cyclin D1-CDK4-p27 complex assembly, as well as increases p27-RhoA-mediated cell motility, HK2 silencing-mediated T198 p27 loss could be a potential underlying cue in controlling HNSCC cell growth and migration.	('p27', 'Gene', '3429', (143, 146))	('p27', 'Gene', (143, 146))	('p27', 'Gene', '3429', (72, 75))	('CDK4', 'Gene', '1019', (95, 99))	('T198', 'Var', (27, 31))	('p27', 'Gene', (72, 75))	('HK2', 'Gene', (176, 179))	('HNSCC', 'Phenotype', 'HP:0012288', (264, 269))	('silencing-mediated', 'Var', (180, 198))	('p27', 'Gene', '3429', (100, 103))	('p27', 'Gene', (100, 103))	('RhoA', 'Gene', (147, 151))	('promotes', 'PosReg', (76, 84))	('p27', 'Gene', '3429', (204, 207))	('p27', 'Gene', (204, 207))	('loss', 'NegReg', (208, 212))	('cyclin D1', 'Gene', (85, 94))	('increases', 'PosReg', (133, 142))	('RhoA', 'Gene', '387', (147, 151))	('T198', 'Var', (199, 203))	('CDK4', 'Gene', (95, 99))	('cyclin D1', 'Gene', '595', (85, 94))
446246	32195170	Further elucidation for roles of different TP53 phosphorylation sites in both wild-type and mutant HNSCC cells in regulating tumorigenicity is expected.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('HNSCC', 'Gene', (99, 104))	('tumor', 'Disease', (125, 130))	('mutant', 'Var', (92, 98))	('HNSCC', 'Phenotype', 'HP:0012288', (99, 104))	('TP53', 'Gene', '7157', (43, 47))	('TP53', 'Gene', (43, 47))
446248	32195170	Taking the most promising HK2-targeting drug, 3-bromopyruvate (3-BP), as an example, although single treatment of 3-BP, at the appropriate dose and formulation, could effectively destroy glycolytic tumors and seems to be non-toxic to all sorts of vertebrates, certain failure cases were still reported in clinical test.	('destroy', 'NegReg', (179, 186))	('3-bromopyruvate', 'Chemical', 'MESH:C017092', (46, 61))	('3-BP', 'Chemical', 'MESH:C017092', (63, 67))	('3-BP', 'Chemical', 'MESH:C017092', (114, 118))	('glycolytic tumors', 'Disease', 'MESH:D009369', (187, 204))	('glycolytic tumors', 'Disease', (187, 204))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('3-BP', 'Var', (114, 118))	('tumors', 'Phenotype', 'HP:0002664', (198, 204))
446302	29320468	Blockade of the interaction between programmed death receptor 1 and its ligand (PDL-1) disrupts the action of regulatory T and myeloid-derived suppressor cells, enabling cetuximab-induced immune cells to survive.	('Blockade', 'Var', (0, 8))	('survive', 'CPA', (204, 211))	('cetuximab', 'Chemical', 'MESH:D000068818', (170, 179))	('action', 'MPA', (100, 106))	('disrupts', 'NegReg', (87, 95))	('interaction', 'Interaction', (16, 27))	('PDL-1', 'Gene', '29126', (80, 85))	('PDL-1', 'Gene', (80, 85))	('enabling', 'PosReg', (161, 169))
446304	29320468	Disruption of the stimulatory pathway for PD-1 via the blockade of EGFR, in concert with direct antagonism of the PD-1 receptor, may inhibit the deactivation of cytotoxic T lymphocytes.	('PD-1', 'Gene', (42, 46))	('inhibit', 'NegReg', (133, 140))	('PD-1', 'Gene', '5133', (42, 46))	('deactivation', 'CPA', (145, 157))	('blockade', 'Var', (55, 63))	('EGFR', 'Gene', '1956', (67, 71))	('EGFR', 'Gene', (67, 71))	('PD-1', 'Gene', (114, 118))	('PD-1', 'Gene', '5133', (114, 118))
446311	29320468	One case also demonstrated near-complete regression without recurrence with REGN2810, a PD-1 inhibitor.	('REGN2810', 'Chemical', 'MESH:C000627974', (76, 84))	('PD-1', 'Gene', '5133', (88, 92))	('REGN2810', 'Var', (76, 84))	('PD-1', 'Gene', (88, 92))
446313	29320468	The selection of patients most likely to benefit from immunotherapy remains a pivotal concern, and the indications for immunotherapy, such as PDL-1 positivity or PD-1 expression, continue to evolve.	('PD-1', 'Gene', '5133', (162, 166))	('PDL-1', 'Gene', '29126', (142, 147))	('patients', 'Species', '9606', (17, 25))	('PD-1', 'Gene', (162, 166))	('positivity', 'Var', (148, 158))	('PDL-1', 'Gene', (142, 147))
446315	29320468	For certain sites such as head and neck, lung, and melanoma, PD-L1 positivity >1% has been reported to predict response, yet this has not been consistent.	('lung', 'Disease', (41, 45))	('response', 'Disease', (111, 119))	('PD-L1', 'Gene', (61, 66))	('PD-L1', 'Gene', '29126', (61, 66))	('positivity', 'Var', (67, 77))	('melanoma', 'Phenotype', 'HP:0002861', (51, 59))	('melanoma', 'Disease', (51, 59))	('melanoma', 'Disease', 'MESH:D008545', (51, 59))
446317	29320468	More recently, immunotherapy use has been approved for recurrent/metastatic solid tumors independent of site; required criteria include high microsatellite instability (MSI-high) or mismatch repair-deficiency (MMR-deficient).	('MSI', 'Gene', (169, 172))	('tumors', 'Disease', (82, 88))	('MSI', 'Gene', '5928', (169, 172))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('mismatch', 'Var', (182, 190))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('MMR-deficient', 'Disease', (210, 223))	('high microsatellite instability', 'MPA', (136, 167))	('MMR-deficient', 'Disease', 'MESH:C536143', (210, 223))
446341	27165743	For example, an elevated mutation rate of EGFR in female patients with non-small cell lung cancer may contribute to enhanced response rates among female patients; and H3K27me3 demethylase UTX has been identified as a sex-specific tumor suppressor in T-cell acute lymphoblastic leukemia.	('small cell lung cancer', 'Phenotype', 'HP:0030357', (75, 97))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (71, 97))	('leukemia', 'Phenotype', 'HP:0001909', (277, 285))	('mutation', 'Var', (25, 33))	('EGFR', 'Gene', (42, 46))	('tumor', 'Disease', (230, 235))	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (257, 285))	('non-small cell lung cancer', 'Disease', (71, 97))	('lung cancer', 'Phenotype', 'HP:0100526', (86, 97))	('T-cell acute lymphoblastic leukemia', 'Phenotype', 'HP:0006727', (250, 285))	('tumor', 'Disease', 'MESH:D009369', (230, 235))	('H3K27me3 demethylase', 'Var', (167, 187))	('enhanced', 'PosReg', (116, 124))	('EGFR', 'Gene', '1956', (42, 46))	('patients', 'Species', '9606', (153, 161))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (263, 285))	('patients', 'Species', '9606', (57, 65))	('T-cell acute lymphoblastic leukemia', 'Disease', 'MESH:D054218', (250, 285))	('T-cell acute lymphoblastic leukemia', 'Disease', (250, 285))	('response rates', 'CPA', (125, 139))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (71, 97))
446347	27165743	We focused on 13 major TCGA cancer types with sufficient sample sizes (>=30 for both male and female patients) for at least 5 out of 6 molecular data types (somatic mutations, somatic copy-number alternations [SCNAs], mRNA expression, DNA methylation, miRNA expression and protein expression, Table 1).	('patients', 'Species', '9606', (101, 109))	('miRNA expression', 'MPA', (252, 268))	('DNA methylation', 'MPA', (235, 250))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('copy-number alternations', 'Var', (184, 208))	('mRNA expression', 'MPA', (218, 233))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('protein expression', 'MPA', (273, 291))	('cancer', 'Disease', (28, 34))
446366	27165743	Clinically, inactivating mutations in this gene may predict sensitivity to mTOR inhibitors, SRC inhibitors and the metabolism drug phenformin in lung cancer.	('metabolism drug phenformin', 'MPA', (115, 141))	('predict', 'Reg', (52, 59))	('lung cancer', 'Disease', 'MESH:D008175', (145, 156))	('SRC', 'Gene', '6714', (92, 95))	('SRC', 'Gene', (92, 95))	('phenformin', 'Chemical', 'MESH:D010629', (131, 141))	('inactivating mutations', 'Var', (12, 34))	('lung cancer', 'Disease', (145, 156))	('lung cancer', 'Phenotype', 'HP:0100526', (145, 156))	('mTOR', 'Gene', (75, 79))	('mTOR', 'Gene', '2475', (75, 79))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
446368	27165743	The mutations in this gene were highly biased toward female patients (8.4% vs. 19.6%, p < 3.7x10-4, FDR = 0.029).	('mutations', 'Var', (4, 13))	('patients', 'Species', '9606', (60, 68))	('biased', 'Reg', (39, 45))
446369	27165743	EGFR, a major therapeutic target in LUAD, showed a higher mutation frequency in female patients but did not reach the FDR cutoff (9.8% vs 15.8%, p < 0.042, FDR = 0.28), which is consistent with previous reports.	('mutation', 'Var', (58, 66))	('patients', 'Species', '9606', (87, 95))	('EGFR', 'Gene', '1956', (0, 4))	('EGFR', 'Gene', (0, 4))
446372	27165743	Figure 3 provides an overview of the statistical significance of sex-biased focal amplifications and deletions in these three cancer types, showing a total of 21 significant peaks (FDR <= 0.1).	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('focal amplifications', 'Var', (76, 96))	('deletions', 'Var', (101, 110))
446374	27165743	In LUSC, a SCNA (17q11.2) harboring NF1 is more frequently deleted in females, and the inactivation of this gene has been associated with sensitivity to mTOR inhibitors and resistance to MEK inhibitors.	('associated', 'Reg', (122, 132))	('NF1', 'Gene', (36, 39))	('NF1', 'Gene', '4763', (36, 39))	('mTOR', 'Gene', (153, 157))	('mTOR', 'Gene', '2475', (153, 157))	('inactivation', 'Var', (87, 99))	('MEK', 'Gene', (187, 190))	('MEK', 'Gene', '5609', (187, 190))
446375	27165743	In KIRP, the 4q34.3 deletion containing FBXW7 occurs more frequently in females, and the deletion of this gene may affect the sensitivity to rapamycin treatment and antitubulin chemotherapeutics.	('sensitivity to rapamycin treatment', 'MPA', (126, 160))	('antitubulin chemotherapeutics', 'MPA', (165, 194))	('affect', 'Reg', (115, 121))	('FBXW7', 'Gene', (40, 45))	('men', 'Species', '9606', (156, 159))	('deletion', 'Var', (89, 97))	('rapamycin', 'Chemical', 'MESH:D020123', (141, 150))	('FBXW7', 'Gene', '55294', (40, 45))
446376	27165743	In KIRC, the amplicon 3q26 containing PI3KCA occurs more frequently in females, and PI3KCA activation has been reported to predict the sensitivity to PI3K/AKT/mTOR inhibitors; and the deletions of 1p36.23 (harboring MTOR) and 10q23.31 (harboring PTEN) are more prevalent in male patients.	('AKT', 'Gene', (155, 158))	('1p36.23', 'Gene', (197, 204))	('mTOR', 'Gene', (159, 163))	('mTOR', 'Gene', '2475', (159, 163))	('PTEN', 'Gene', (246, 250))	('10q23.31', 'Gene', (226, 234))	('PTEN', 'Gene', '5728', (246, 250))	('AKT', 'Gene', '207', (155, 158))	('patients', 'Species', '9606', (279, 287))	('MTOR', 'Gene', (216, 220))	('sensitivity', 'MPA', (135, 146))	('deletions', 'Var', (184, 193))	('PI3KCA', 'Var', (38, 44))	('MTOR', 'Gene', '2475', (216, 220))
446379	27165743	The deletion involving PDCD1 (PD-1) shows a similar bias; this gene represents an immune checkpoint and has been a major focus in the development of immunotherapy.	('PD-1', 'Disease', (30, 34))	('men', 'Species', '9606', (141, 144))	('PD-1', 'Disease', 'MESH:D010300', (30, 34))	('deletion', 'Var', (4, 12))	('PDCD1', 'Gene', '5133', (23, 28))	('PDCD1', 'Gene', (23, 28))
446383	27165743	One of the most commonly identified genes is XIST, a major effector of chromosome X inactivation; and its role in cancer has been extensively studied.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('genes', 'Var', (36, 41))	('XIST', 'Gene', '7503', (45, 49))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('XIST', 'Gene', (45, 49))	('cancer', 'Disease', (114, 120))
446384	27165743	We also identified sex-biased miRNA genes in 6 cancer types, 5 of which are in the strong sex-effect group.	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('miRNA', 'Var', (30, 35))	('cancer', 'Disease', (47, 53))	('cancer', 'Disease', 'MESH:D009369', (47, 53))
446396	27165743	Thus, targeted inhibition of SRC signaling has been suggested as an effective therapeutic strategy and has been under intensive clinical investigation in several cancers, including renal cell cancer.	('cancers', 'Disease', 'MESH:D009369', (162, 169))	('cancers', 'Disease', (162, 169))	('SRC', 'Gene', '6714', (29, 32))	('cancers', 'Phenotype', 'HP:0002664', (162, 169))	('SRC', 'Gene', (29, 32))	('targeted inhibition', 'Var', (6, 25))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('renal cell cancer', 'Phenotype', 'HP:0005584', (181, 198))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('renal cell cancer', 'Disease', (181, 198))	('renal cell cancer', 'Disease', 'MESH:C538614', (181, 198))
446451	32184217	We are developing CRISPR-directed gene editing for the treatment of non-small cell lung carcinoma (NSCLC) focusing on disabling Nuclear Factor Erythroid 2-Related Factor-Like (NRF2), a transcription factor that regulates chemoresistance and whose genetic disruption would enhance chemosensitivity.	('Nuclear Factor Erythroid 2-Related Factor-Like', 'Gene', '4780', (128, 174))	('Nuclear Factor Erythroid 2-Related Factor-Like', 'Gene', (128, 174))	('lung carcinoma', 'Disease', 'MESH:D008175', (83, 97))	('enhance', 'PosReg', (272, 279))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('NRF2', 'Gene', (176, 180))	('chemosensitivity', 'CPA', (280, 296))	('small cell lung carcinoma', 'Phenotype', 'HP:0030357', (72, 97))	('non-small cell lung carcinoma', 'Phenotype', 'HP:0030358', (68, 97))	('lung carcinoma', 'Disease', (83, 97))	('NSCLC', 'Disease', (99, 104))	('genetic disruption', 'Var', (247, 265))	('NSCLC', 'Disease', 'MESH:D002289', (99, 104))
446469	32184217	Previously, we discovered that successful functional knockout of the NRF2 gene in chemo-resistant lung cancer cells significantly increased the anticancer activity of cisplatin, carboplatin and vinorelbine in both cell culture and mouse models.	('cancer', 'Disease', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('cisplatin', 'Chemical', 'MESH:D002945', (167, 176))	('carboplatin', 'Chemical', 'MESH:D016190', (178, 189))	('lung cancer', 'Disease', (98, 109))	('NRF2', 'Gene', (69, 73))	('knockout', 'Var', (53, 61))	('lung cancer', 'Phenotype', 'HP:0100526', (98, 109))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('mouse', 'Species', '10090', (231, 236))	('vinorelbine', 'Chemical', 'MESH:D000077235', (194, 205))	('increased', 'PosReg', (130, 139))	('cancer', 'Disease', (103, 109))	('lung cancer', 'Disease', 'MESH:D008175', (98, 109))
446470	32184217	And, second, is there enough sequence divergence between normal and tumor cell genomes so that CRISPR complexes can selectively cleave and disrupt the NRF2 gene in the tumor cell?	('tumor', 'Disease', (68, 73))	('tumor', 'Disease', (168, 173))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('disrupt', 'NegReg', (139, 146))	('cleave', 'Var', (128, 134))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('NRF2', 'Gene', (151, 155))
446472	32184217	Our results indicate that the localization of the exogenously added CRISPR/Cas complex into the nucleus of the lung tumor cell is efficient and rapid; however, NRF2 gene disruption lags significantly, seen after about eight hours as the gene editing components are visualized exiting the nucleus.	('lung tumor', 'Disease', 'MESH:D008175', (111, 121))	('cat', 'Gene', (16, 19))	('Cas', 'Gene', (75, 78))	('lung tumor', 'Phenotype', 'HP:0100526', (111, 121))	('cat', 'Gene', '847', (16, 19))	('Cas', 'Gene', '9564', (75, 78))	('NRF2', 'Gene', (160, 164))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('lung tumor', 'Disease', (111, 121))	('gene disruption', 'Var', (165, 180))
446474	32184217	Regarding the second question, Kerins and Ooi catalogued somatic NRF2 mutations in various cancer cases reported in The Cancer Genome Atlas.	('mutations', 'Var', (70, 79))	('Cancer', 'Disease', (120, 126))	('NRF2', 'Gene', (65, 69))	('Kerins', 'Chemical', '-', (31, 37))	('cat', 'Gene', (46, 49))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('Cancer', 'Disease', 'MESH:D009369', (120, 126))	('Cancer', 'Phenotype', 'HP:0002664', (120, 126))	('cat', 'Gene', '847', (46, 49))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))
446475	32184217	They reported 214 cases of NRF2 mutations, predominately found within the Neh2 domain or known as the KEAP1 binding domain of the protein.	('NRF2', 'Gene', (27, 31))	('Neh2', 'Gene', '252969', (74, 78))	('KEAP1', 'Gene', (102, 107))	('mutations', 'Var', (32, 41))	('KEAP1', 'Gene', '9817', (102, 107))	('Neh2', 'Gene', (74, 78))
446476	32184217	These mutations disrupt KEAP1 binding and lead to constitutive expression of NRF2 in cancer cells.	('KEAP1', 'Gene', '9817', (24, 29))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('KEAP1', 'Gene', (24, 29))	('cancer', 'Disease', (85, 91))	('constitutive expression', 'MPA', (50, 73))	('disrupt', 'NegReg', (16, 23))	('lead to', 'Reg', (42, 49))	('binding', 'Interaction', (30, 37))	('NRF2', 'Gene', (77, 81))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('mutations', 'Var', (6, 15))
446477	32184217	The most common NRF2 mutation noted, R34G, is of special interest because this mutation creates a new protospacer adjacent motif (PAM) for Cas9 recognition.	('Cas', 'Gene', (139, 142))	('R34G', 'Var', (37, 41))	('Cas', 'Gene', '9564', (139, 142))	('R34G', 'Mutation', 'p.R34G', (37, 41))	('NRF2', 'Gene', (16, 20))
446478	32184217	After cleavage, Cas9 creates blunt-end, double-stranded breaks which are then repaired by one of two mechanisms: non-homologous end joining (NHEJ) or homology-directed repair (HDR).	('Cas', 'Gene', (16, 19))	('Cas', 'Gene', '9564', (16, 19))	('blunt-end', 'Var', (29, 38))
446490	32184217	The NRF2 gene-coding sequence was entered into Benchling (https://benchling.com) and the R34G mutation-specific gRNA 5'-GATATAGATCTTGGAGTAAG-3' and the nonspecific gRNA 5'-GTAACGGCAGACTTCTCCTC-3' (HBB RNP) were selected.	('R34G', 'Var', (89, 93))	('RNP', 'Gene', '55599', (201, 204))	('R34G', 'Mutation', 'p.R34G', (89, 93))	('RNP', 'Gene', (201, 204))
446492	32184217	Prior to mixing with cells, crRNA:tracrRNA duplex (100 muM or 250 muM) and spCas9 protein (100 muM or 50 muM) were mixed together and set to incubate at room temperature for 15 minutes.	('Cas', 'Gene', (77, 80))	('100 muM', 'Var', (91, 98))	('Cas', 'Gene', '9564', (77, 80))
446518	32184217	CDM was achieved using two Cas12a cleavage sites (crRNA: 5'-ATTGACATACTTTGGAGGCAA-3', 5'- GAGTTGTTCTTGTCTTTCCTT-3') and two oligonucleotides, containing the intended R34G mutation, (ssDNA: 5'-CAAGATATAGATCTTGGAGTAAGTGGAGAAGTATTTGAC TTCAGTCAGCGACGGAAAGAGTATGAGCTGGAAAAACAGAAAAAACTTG-3', 5'- CTTTTCAAGTTTTTTCTGTTTTTCCAGCTCATACTCTTTCCGTCGCTGACTGAAGTCAAATACTTCTCCACTTACTCCAAGATCTATA-3') were annealed to create the template.	('R34G', 'Var', (166, 170))	('Cas', 'Gene', '9564', (27, 30))	('R34G', 'Mutation', 'p.R34G', (166, 170))	('oligonucleotides', 'Chemical', 'MESH:D009841', (124, 140))	('Cas', 'Gene', (27, 30))
446529	32184217	Quadrant 1 (Q1) contains cells positive for only GFP (Cas9) while quadrant 2 (Q2) reflects cells containing both GFP and ATTO 550 (tracrRNA) fluorescence (outlined in green).	('GFP', 'Var', (113, 116))	('Cas', 'Gene', (54, 57))	('Cas', 'Gene', '9564', (54, 57))
446549	32184217	The R34G mutation was initially found because it inhibits KEAP1-mediated degradation of NRF2 which in turn, causes increased NRF2 stability and nuclear accumulation.	('R34G', 'Mutation', 'p.R34G', (4, 8))	('degradation', 'MPA', (73, 84))	('KEAP1', 'Gene', '9817', (58, 63))	('increased', 'PosReg', (115, 124))	('inhibits', 'NegReg', (49, 57))	('nuclear', 'CPA', (144, 151))	('KEAP1', 'Gene', (58, 63))	('NRF2', 'Protein', (125, 129))	('R34G', 'Var', (4, 8))	('stability', 'MPA', (130, 139))	('NRF2', 'Protein', (88, 92))
446551	32184217	As proof of concept, the following experiments were conducted to assess the level of discrimination and selectivity of the R34G mutation-specific CRISPR/Cas9 complex.	('R34G', 'Mutation', 'p.R34G', (123, 127))	('Cas', 'Gene', (153, 156))	('Cas', 'Gene', '9564', (153, 156))	('R34G', 'Var', (123, 127))
446554	32184217	For this experiment, wildtype and R34G-mutated NRF2 PCR products (901 bp) from an NRF2 expression plasmid (Figure 5B) were incubated with R34G-specific RNP (1 muM).	('R34G-mutated', 'Var', (34, 46))	('NRF2', 'Gene', (47, 51))	('R34G', 'Mutation', 'p.R34G', (34, 38))	('RNP', 'Gene', '55599', (152, 155))	('R34G', 'Mutation', 'p.R34G', (138, 142))	('RNP', 'Gene', (152, 155))	('R34G-specific', 'Var', (138, 151))
446556	32184217	In lane 6 (R34G NRF2 - R34G RNP), two new bands (222 & 679 bp) appear and are the result of tumor genome specific RNP cleavage; the R34G-targeting RNP only recognizes and cleaves the mutated DNA sequence.	('and', 'MPA', (167, 170))	('RNP', 'Gene', '55599', (114, 117))	('the', 'Var', (128, 131))	('R34G', 'Mutation', 'p.R34G', (23, 27))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('R34G', 'Mutation', 'p.R34G', (11, 15))	('R34G', 'Mutation', 'p.R34G', (132, 136))	('RNP', 'Gene', (147, 150))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('RNP', 'Gene', '55599', (147, 150))	('RNP', 'Gene', (114, 117))	('RNP', 'Gene', (28, 31))	('tumor', 'Disease', (92, 97))	('the', 'Var', (179, 182))	('RNP', 'Gene', '55599', (28, 31))
446557	32184217	To assess specificity and fidelity of the R34G-mutation specific RNP in lung tumor cells, we use the well-established non-small-cell lung adenocarcinoma cell line A549 because it is often used as a gold standard for the discovery of anti-cancer therapeutics.	('lung tumor', 'Disease', 'MESH:D008175', (72, 82))	('cancer', 'Disease', (238, 244))	('cancer', 'Disease', 'MESH:D009369', (238, 244))	('R34G', 'Mutation', 'p.R34G', (42, 46))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (133, 152))	('lung tumor', 'Phenotype', 'HP:0100526', (72, 82))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('RNP', 'Gene', (65, 68))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('lung adenocarcinoma', 'Disease', (133, 152))	('R34G-mutation', 'Var', (42, 55))	('A549', 'CellLine', 'CVCL:0023', (163, 167))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (133, 152))	('carcinoma', 'Phenotype', 'HP:0030731', (143, 152))	('lung tumor', 'Disease', (72, 82))	('RNP', 'Gene', '55599', (65, 68))
446558	32184217	We genetically engineered the A549 cell line to contain the R34G mutation in exon 2 of the NRF2 gene using previously established methods.	('R34G', 'Var', (60, 64))	('NRF2', 'Gene', (91, 95))	('A549', 'CellLine', 'CVCL:0023', (30, 34))	('R34G', 'Mutation', 'p.R34G', (60, 64))
446560	32184217	The parental A549 cell line, R34G-mutated A549 cell line (A549 R34G-6) and NCI-H1703 cell line were sequenced across exon 2 to verify the sequence of the Neh2 domain.	('R34G', 'Mutation', 'p.R34G', (63, 67))	('A549', 'CellLine', 'CVCL:0023', (58, 62))	('A549', 'CellLine', 'CVCL:0023', (42, 46))	('Neh2', 'Gene', '252969', (154, 158))	('R34G', 'Mutation', 'p.R34G', (29, 33))	('R34G-mutated', 'Var', (29, 41))	('NCI-H1703', 'CellLine', 'CVCL:1490', (75, 84))	('A549', 'CellLine', 'CVCL:0023', (13, 17))	('Neh2', 'Gene', (154, 158))
446561	32184217	Both A549 and NCI-H1703 parental cell lines contain no mutations within exon 2 of the NRF2 gene, whereas, the A549 R34G-6 cell line contains a heterozygous R34G mutation (Figure 6A).	('NCI-H1703', 'CellLine', 'CVCL:1490', (14, 23))	('R34G', 'Var', (156, 160))	('A549', 'CellLine', 'CVCL:0023', (110, 114))	('NRF2', 'Gene', (86, 90))	('R34G', 'Mutation', 'p.R34G', (156, 160))	('R34G', 'Mutation', 'p.R34G', (115, 119))	('A549', 'CellLine', 'CVCL:0023', (5, 9))
446562	32184217	The A549 cell line is known to be bi- and tri-allelic, therefore, the R34G mutation in the A549 R34G-6 clone is believed to be on two of three alleles as seen by the double peak of the 'G' nucleotide (black peak) as compared to the peak of the 'C' nucleotide (blue peak), indicated by the red arrow under 'A549 R34G-6' (Figure 6A).	('R34G', 'Mutation', 'p.R34G', (96, 100))	('A549', 'CellLine', 'CVCL:0023', (4, 8))	('cat', 'Gene', (276, 279))	('R34G', 'Mutation', 'p.R34G', (70, 74))	('A549', 'Gene', (91, 95))	('A549', 'CellLine', 'CVCL:0023', (306, 310))	('cat', 'Gene', '847', (276, 279))	('R34G', 'Mutation', 'p.R34G', (311, 315))	('A549', 'CellLine', 'CVCL:0023', (91, 95))	('R34G', 'Var', (70, 74))
446564	32184217	The R34G-targeting RNP was used at two concentrations (1 & 5 pmol) with each sample (lanes 2, 3, 5, 6, 8, 9).	('R34G', 'Mutation', 'p.R34G', (4, 8))	('RNP', 'Gene', (19, 22))	('R34G-targeting', 'Var', (4, 18))	('RNP', 'Gene', '55599', (19, 22))
446565	32184217	Minimal cleavage is seen with wildtype NRF2 sequence in the A549 and NCI-H1703 parental cell lines (lanes 3 & 6), whereas cleavage products (145 & 385 bp) are abundantly clear in the A549 R34G-6 cell line with the R34G-mutated NRF2 sequence (lanes 8 & 9).	('NCI-H1703', 'CellLine', 'CVCL:1490', (69, 78))	('A549', 'CellLine', 'CVCL:0023', (183, 187))	('with', 'Var', (205, 209))	('R34G', 'Mutation', 'p.R34G', (214, 218))	('the', 'Gene', (210, 213))	('R34G', 'Mutation', 'p.R34G', (188, 192))	('A549', 'CellLine', 'CVCL:0023', (60, 64))
446566	32184217	These data further confirm the specificity and efficacy of the R34G-targeting RNP, only recognizing the target DNA in the presence of the R34G mutation in exon 2 of NRF2.	('R34G', 'Mutation', 'p.R34G', (138, 142))	('R34G', 'Mutation', 'p.R34G', (63, 67))	('RNP', 'Gene', (78, 81))	('RNP', 'Gene', '55599', (78, 81))	('R34G', 'Var', (138, 142))	('NRF2', 'Gene', (165, 169))
446569	32184217	The range of concentrations do not result in cleavage of wildtype NRF2 sequence whereas with a R34G-mutated NRF2 sequence, cleavage products can be seen even with half of the standard concentration of the R34G-targeting RNP (Supplemental Figure 3).	('NRF2', 'Gene', (108, 112))	('R34G', 'Mutation', 'p.R34G', (205, 209))	('RNP', 'Gene', (220, 223))	('R34G-targeting', 'Var', (205, 219))	('R34G-mutated', 'Var', (95, 107))	('RNP', 'Gene', '55599', (220, 223))	('R34G', 'Mutation', 'p.R34G', (95, 99))
446571	32184217	Figure 7 depicts the genetic analysis of each cell line after transfection of the R34G-targeting RNP under three different conditions: 1) equimolar concentration of duplexed guide RNA to Cas9 (top panel); 2) five times the amount of duplexed guide RNA to Cas9 (middle panel); 3) five times the amount of single guide RNA to Cas9 (bottom panel).	('RNP', 'Gene', '55599', (97, 100))	('Cas', 'Gene', '9564', (255, 258))	('Cas', 'Gene', (187, 190))	('Cas', 'Gene', '9564', (324, 327))	('Cas', 'Gene', '9564', (187, 190))	('R34G', 'Mutation', 'p.R34G', (82, 86))	('R34G-targeting', 'Var', (82, 96))	('Cas', 'Gene', (255, 258))	('RNP', 'Gene', (97, 100))	('Cas', 'Gene', (324, 327))
446572	32184217	Wildtype or uncut sequences appear at the 0 tick mark as a pink bar and would indicate alleles unaffected by the cleavage activity of the R34G-specific RNP.	('RNP', 'Gene', '55599', (152, 155))	('R34G', 'Mutation', 'p.R34G', (138, 142))	('cat', 'Gene', (82, 85))	('RNP', 'Gene', (152, 155))	('R34G-specific', 'Var', (138, 151))	('cat', 'Gene', '847', (82, 85))
446573	32184217	Figure 7A depicts the genetic analysis after transfection of the R34G-targeting RNP in the A549 parental cells.	('RNP', 'Gene', (80, 83))	('R34G-targeting', 'Var', (65, 79))	('R34G', 'Mutation', 'p.R34G', (65, 69))	('RNP', 'Gene', '55599', (80, 83))	('A549', 'CellLine', 'CVCL:0023', (91, 95))
446574	32184217	The A549 parental cells contain a wildtype NRF2 gene therefore there is no native CRISPR/Cas9 recognition site for the R34G-targeting RNP.	('A549', 'CellLine', 'CVCL:0023', (4, 8))	('RNP', 'Gene', (134, 137))	('Cas', 'Gene', '9564', (89, 92))	('Cas', 'Gene', (89, 92))	('RNP', 'Gene', '55599', (134, 137))	('NRF2', 'Gene', (43, 47))	('R34G-targeting', 'Var', (119, 133))	('R34G', 'Mutation', 'p.R34G', (119, 123))
446575	32184217	Figure 7B depicts the genetic analysis after transfection of the R34G-targeting RNP in the A549 R34G-mutated clonal cell line (A549 R34G-6).	('R34G', 'Mutation', 'p.R34G', (96, 100))	('RNP', 'Gene', (80, 83))	('R34G-targeting', 'Var', (65, 79))	('RNP', 'Gene', '55599', (80, 83))	('R34G', 'Mutation', 'p.R34G', (65, 69))	('R34G', 'Mutation', 'p.R34G', (132, 136))	('A549', 'CellLine', 'CVCL:0023', (127, 131))	('A549', 'CellLine', 'CVCL:0023', (91, 95))
446576	32184217	The A549 R34G-6 cells contain a heterozygous R34G mutation in exon 2 of the NRF2 gene, creating a new CRISPR/Cas9 recognition site for the R34G-targeting RNP.	('A549', 'CellLine', 'CVCL:0023', (4, 8))	('RNP', 'Gene', (154, 157))	('NRF2', 'Gene', (76, 80))	('R34G-targeting', 'Var', (139, 153))	('RNP', 'Gene', '55599', (154, 157))	('Cas', 'Gene', (109, 112))	('R34G', 'Mutation', 'p.R34G', (9, 13))	('R34G mutation', 'Var', (45, 58))	('R34G', 'Mutation', 'p.R34G', (139, 143))	('Cas', 'Gene', '9564', (109, 112))	('R34G', 'Mutation', 'p.R34G', (45, 49))
446578	32184217	Figure 7C depicts the genetic analysis after transfection of the R34G-targeting RNP in the NCI-H1703 cell line, which contains a wildtype NRF2 gene and no native CRISPR recognition site.	('RNP', 'Gene', (80, 83))	('R34G-targeting', 'Var', (65, 79))	('RNP', 'Gene', '55599', (80, 83))	('NRF2', 'Gene', (138, 142))	('R34G', 'Mutation', 'p.R34G', (65, 69))	('NCI-H1703', 'CellLine', 'CVCL:1490', (91, 100))
446579	32184217	Taken together, these data confirm the highly specific activity of the R34G RNP in the presence of the R34G mutation.	('RNP', 'Gene', '55599', (76, 79))	('R34G', 'Mutation', 'p.R34G', (103, 107))	('R34G', 'Var', (71, 75))	('specific activity', 'MPA', (46, 63))	('R34G', 'Var', (103, 107))	('R34G', 'Mutation', 'p.R34G', (71, 75))	('RNP', 'Gene', (76, 79))
446580	32184217	We can infer that the R34G mutation does in fact create a new CRISPR/Cas9 recognition site that is actively cleaved when tested in vivo.	('R34G', 'Var', (22, 26))	('Cas', 'Gene', (69, 72))	('Cas', 'Gene', '9564', (69, 72))	('R34G', 'Mutation', 'p.R34G', (22, 26))
446581	32184217	The R34G-targeting RNP differentiates between the wildtype and R34G-mutated NRF2 alleles within the A549 R34G-6 clonal cell line.	('R34G', 'Mutation', 'p.R34G', (4, 8))	('RNP', 'Gene', (19, 22))	('R34G-mutated', 'Var', (63, 75))	('R34G-targeting', 'Var', (4, 18))	('A549', 'CellLine', 'CVCL:0023', (100, 104))	('R34G', 'Mutation', 'p.R34G', (63, 67))	('NRF2', 'Gene', (76, 80))	('RNP', 'Gene', '55599', (19, 22))	('R34G', 'Mutation', 'p.R34G', (105, 109))	('differentiates', 'Reg', (23, 37))
446590	32184217	The initialization of genetic disruption through gene editing begins with a CRISPR/Cas complex aligning in homologous register with a target gene, facilitating site-specific double-stranded DNA breakage.	('genetic', 'Var', (22, 29))	('Cas', 'Gene', (83, 86))	('Cas', 'Gene', '9564', (83, 86))
446593	32184217	Multiple pathways contribute to the repair of a Cas9 induced double-strand break and relative activity of each is dependent on the locus, the metabolic state of the cell, and the half-life of the bound CRISPR complex.	('activity', 'MPA', (94, 102))	('Cas', 'Gene', '9564', (48, 51))	('Cas', 'Gene', (48, 51))	('double-strand', 'Var', (61, 74))
446595	32184217	A NRF2 gene expression plasmid was used as a template to generate PCR products that we showed were specifically and uniquely cleaved by the R34G RNP, in the presence of the R34G mutation.	('R34G', 'Var', (173, 177))	('R34G', 'Var', (140, 144))	('RNP', 'Gene', (145, 148))	('R34G', 'Mutation', 'p.R34G', (173, 177))	('RNP', 'Gene', '55599', (145, 148))	('R34G', 'Mutation', 'p.R34G', (140, 144))
446596	32184217	We followed up with a series of experiments, that utilized a genetically modified cell line containing the R34G mutation as a new PAM site to create an in vivo PCR product that was subsequently cleaved again specifically by the R34G RNP.	('R34G', 'Var', (107, 111))	('R34G', 'Var', (228, 232))	('RNP', 'Gene', (233, 236))	('R34G', 'Mutation', 'p.R34G', (107, 111))	('RNP', 'Gene', '55599', (233, 236))	('R34G', 'Mutation', 'p.R34G', (228, 232))
446597	32184217	Finally, we targeted several cell lines directly using the R34G RNP and showed by TIDE analysis that efficient and highly specific indel formation is observed in a cell line that bears the R34G PAM site.	('R34G', 'Mutation', 'p.R34G', (189, 193))	('RNP', 'Gene', (64, 67))	('RNP', 'Gene', '55599', (64, 67))	('R34G', 'Var', (189, 193))	('R34G', 'Mutation', 'p.R34G', (59, 63))
446598	32184217	Thus, by multiple iterations of the same basic experiment, we conclude that the R34G RNP demonstrates a high level of specificity of NRF2 gene disruption in an efficacious and efficient fashion.	('R34G', 'Var', (80, 84))	('RNP', 'Gene', (85, 88))	('R34G', 'Mutation', 'p.R34G', (80, 84))	('RNP', 'Gene', '55599', (85, 88))	('NRF2', 'Gene', (133, 137))
446600	32184217	NRF2 mutations occur in about 15% of lung squamous cell carcinomas, among other common cancer types.	('cancer', 'Disease', (87, 93))	('NRF2', 'Gene', (0, 4))	('carcinomas', 'Phenotype', 'HP:0030731', (56, 66))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('mutations', 'Var', (5, 14))	('lung squamous cell carcinomas', 'Disease', (37, 66))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (42, 66))	('occur', 'Reg', (15, 20))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (37, 65))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (42, 65))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('lung squamous cell carcinomas', 'Disease', 'MESH:D002294', (37, 66))	('carcinoma', 'Phenotype', 'HP:0030731', (56, 65))
446601	32184217	Disrupted NRF2 protein accumulates in the cytoplasm and nucleus, causing these cells to become resistant to toxic insults such as platinum-based drugs or radiation.	('causing', 'Reg', (65, 72))	('NRF2', 'Gene', (10, 14))	('accumulates', 'PosReg', (23, 34))	('platinum', 'Chemical', 'MESH:D010984', (130, 138))	('protein', 'Protein', (15, 22))	('Disrupted', 'Var', (0, 9))
446602	32184217	Despite the prevalence of mutations and the dismal prognosis of patients with elevated NRF2 expression, there is no targeted therapy.	('NRF2', 'Gene', (87, 91))	('patients', 'Species', '9606', (64, 72))	('elevated', 'PosReg', (78, 86))	('mutations', 'Var', (26, 35))	('expression', 'MPA', (92, 102))
446603	32184217	Clinically, we envision a unique approach to target NRF2 mutations using the gene editing tool, CRISPR/Cas9.	('mutations', 'Var', (57, 66))	('Cas', 'Gene', (103, 106))	('Cas', 'Gene', '9564', (103, 106))	('NRF2', 'Gene', (52, 56))
446604	32184217	These mutations have been noted in other cancer types as well which makes this approach a platform therapy.	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('noted', 'Reg', (26, 31))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('mutations', 'Var', (6, 15))
446616	32184217	We see two phases: Phase I encompasses RNP delivery and nuclear uptake, along with the initial signals of CRISPR-directed DNA cleavage of a single target site; phase II reveals elevated levels of indel formation likely through resection and repair of the target site after cleavage, along with the exit of the two fluorescent CRISPR/Cas components from the cell.	('RNP', 'Gene', (39, 42))	('indel', 'Var', (196, 201))	('RNP', 'Gene', '55599', (39, 42))	('Cas', 'Gene', (333, 336))	('Cas', 'Gene', '9564', (333, 336))
446633	30633894	Most checkpoint inhibitors target the interactions of the lymphocytic cell surface receptor PD-1 (programmed cell death protein 1) and its 2 ligands, which are present on tumor cells and/or immune cells: PD-L1 (programmed cell death 1 ligand 1) and PD-L2 (programmed cell death 1 ligand 2).	('PD-1', 'Gene', (92, 96))	('PD-L2', 'Gene', (249, 254))	('PD-L1', 'Var', (204, 209))	('interactions', 'Interaction', (38, 50))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('programmed cell death protein 1', 'Gene', (98, 129))	('programmed cell death protein 1', 'Gene', '100533201', (98, 129))	('target', 'Reg', (27, 33))	('tumor', 'Disease', (171, 176))
446684	30633894	Looking at PD-L1 and PD-L2 expression by cell type, the tumor cells in all 18 cases (100%) expressed PD-L1 (Figure 2, Middle left), while the tumor cells in 9 cases (50%) expressed PD-L2 (Figure 2, Middle right).	('PD-L1', 'Var', (101, 106))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Disease', (142, 147))	('tumor', 'Disease', (56, 61))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
446687	30633894	PD-L1 stromal and endothelial expression was typically lower than expression in the tumor cells (mean 2.4 out of 5 for stroma, 0.7 out of 5 for endothelial cells, and 3.2 out of 5 for tumor cells).	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumor', 'Disease', (84, 89))	('PD-L1', 'Var', (0, 5))	('tumor', 'Disease', (184, 189))	('lower', 'NegReg', (55, 60))
446691	30633894	Control sections of uninflamed normal conjunctiva and conjunctiva with chronic conjunctivitis or primary lymphoid follicles also revealed scattered rare stromal and endothelial cell PD-L1 and PD-L2 positivity, with overall greater PD-L1 positivity than PD-L2 positivity (Supplemental Figure; Supplemental Material available at AJO.com).	('conjunctivitis', 'Phenotype', 'HP:0000509', (79, 93))	('PD-L1', 'Gene', (231, 236))	('conjunctivitis', 'Disease', (79, 93))	('greater', 'PosReg', (223, 230))	('conjunctivitis', 'Disease', 'MESH:D003231', (79, 93))	('PD-L2', 'Gene', (192, 197))	('positivity', 'Var', (198, 208))	('PD-L1', 'Gene', (182, 187))
446704	30633894	Third, the study reports that PD-L1 is expressed to a greater degree than PD-L2 in invasive conjunctival squamous cell carcinomas.	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (105, 129))	('invasive conjunctival squamous cell carcinomas', 'Disease', (83, 129))	('PD-L1', 'Var', (30, 35))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (105, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('carcinomas', 'Phenotype', 'HP:0030731', (119, 129))	('invasive conjunctival squamous cell carcinomas', 'Disease', 'MESH:D002294', (83, 129))
446718	30633894	Moreover, the proportion of positive tumor cells was much higher for PD-L1 than PD-L2.	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('higher', 'PosReg', (58, 64))	('PD-L1', 'Var', (69, 74))
446727	30633894	Although there are many interactions between CD8-positive T lymphocytes and PD-L1-expressing tumor cells, the presence of CD8-positive T lymphocytes has been found to be an independent prognostic factor in certain studies when analyzed with respect to PD-L1.	('presence', 'Var', (110, 118))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('positive T lymphocytes', 'Phenotype', 'HP:0100828', (126, 148))	('tumor', 'Disease', (93, 98))	('CD8', 'Gene', (122, 125))	('positive T lymphocytes', 'Phenotype', 'HP:0100828', (49, 71))	('CD8', 'Gene', (45, 48))	('CD8', 'Gene', '925', (122, 125))	('CD8', 'Gene', '925', (45, 48))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
446734	30633894	p16 positivity is often used as a marker of HPV infection.	('HPV infection', 'Disease', 'MESH:D030361', (44, 57))	('HPV infection', 'Disease', (44, 57))	('positivity', 'Var', (4, 14))	('p16', 'Protein', (0, 3))
446736	30633894	Comparable studies have revealed variable HPV positivity in ocular surface squamous neoplasia.	('HPV', 'Species', '10566', (42, 45))	('squamous neoplasia', 'Disease', (75, 93))	('HPV', 'Gene', (42, 45))	('neoplasia', 'Phenotype', 'HP:0002664', (84, 93))	('positivity', 'Var', (46, 56))	('squamous neoplasia', 'Disease', 'MESH:D002294', (75, 93))	('squamous neoplasia', 'Phenotype', 'HP:0002860', (75, 93))
446741	30633894	In these 2 patients, with either a tumor recurrence or a metastasis and concomitant PD-L1 and p16 positivity, an argument can be made for a role for a checkpoint inhibitor if conventional approaches are not sufficient.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('PD-L1', 'Gene', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumor', 'Disease', (35, 40))	('metastasis', 'CPA', (57, 67))	('p16', 'Gene', (94, 97))	('patients', 'Species', '9606', (11, 19))	('positivity', 'Var', (98, 108))
446788	32650779	Overexpression of HOTAIR has been associated with poor prognosis, invasiveness and aggressiveness of various cancer types.	('aggressiveness', 'Phenotype', 'HP:0000718', (83, 97))	('HOTAIR', 'Gene', (18, 24))	('invasiveness and aggressiveness of various cancer', 'Disease', 'MESH:D009362', (66, 115))	('HOTAIR', 'Gene', '100124700', (18, 24))	('Overexpression', 'Var', (0, 14))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))
446789	32650779	Complex secondary structure and ability to form independent structural domains ensure the multi-acting nature of HOTAIR and it has been defined to contribute to various cellular mechanisms via different molecular interactions such as scaffolding protein complexes, decoying microRNAs, epigenetically targeting genes and enabling RNA-protein/DNA-protein interactions.	('microRNAs', 'MPA', (274, 283))	('epigenetically targeting', 'Var', (285, 309))	('enabling', 'PosReg', (320, 328))	('HOTAIR', 'Gene', (113, 119))	('RNA-protein/DNA-protein interactions', 'Interaction', (329, 365))	('contribute', 'Reg', (147, 157))	('HOTAIR', 'Gene', '100124700', (113, 119))	('genes', 'Gene', (310, 315))	('decoying', 'NegReg', (265, 273))
446826	32650779	The cells were lysed using RIPA lysis buffer containing 1 mM Na3VO2, 1 mM NaF, and 1% protease inhibitor cocktail (Roche Diagnostics, Indianapolis, IN, USA), and the lysates were subjected to Western blot analysis as described previously.	('NaF', 'Gene', '3576', (74, 77))	('NaF', 'Gene', (74, 77))	('Na3VO2', 'Chemical', '-', (61, 67))	('RIPA lysis buffer', 'Chemical', '-', (27, 44))	('Na3VO2', 'Var', (61, 67))
446862	32650779	Analysis of three independent experiments showed that average of 45% knock-down of HOTAIR (Fig.	('knock-down', 'Var', (69, 79))	('HOTAIR', 'Gene', (83, 89))	('HOTAIR', 'Gene', '100124700', (83, 89))
446890	32650779	We further confirmed the rescue of HGF-suppressed HOTAIR expression after c-Met tyrosine kinase inhibition by SU11274 in HCC cell lines HuH-7, SNU-449, MAHLAVU and SK-HEP-1.	('HCC', 'Gene', '619501', (121, 124))	('HuH-7', 'Gene', '284424', (136, 141))	('SK-HEP-1', 'CellLine', 'CVCL:0525', (164, 172))	('HuH-7', 'Gene', (136, 141))	('HOTAIR', 'Gene', (50, 56))	('HGF', 'Gene', (35, 38))	('c-Met', 'Gene', (74, 79))	('SNU-449', 'CellLine', 'CVCL:0454', (143, 150))	('HCC', 'Gene', (121, 124))	('c-Met', 'Gene', '4233', (74, 79))	('HOTAIR', 'Gene', '100124700', (50, 56))	('SU11274', 'Var', (110, 117))	('SU11274', 'Chemical', 'MESH:C478479', (110, 117))	('HGF', 'Gene', '3082', (35, 38))	('inhibition', 'NegReg', (96, 106))
446891	32650779	c-Met tyrosine kinase inhibition rescued HGF-induced HOTAIR suppression in HCC cell lines (Fig.	('inhibition', 'Var', (22, 32))	('c-Met', 'Gene', '4233', (0, 5))	('HCC', 'Gene', '619501', (75, 78))	('HOTAIR', 'Gene', (53, 59))	('HGF', 'Gene', (41, 44))	('HOTAIR', 'Gene', '100124700', (53, 59))	('HGF', 'Gene', '3082', (41, 44))	('HCC', 'Gene', (75, 78))	('c-Met', 'Gene', (0, 5))
446921	32650779	Immunofluorescent analysis of cytoskeletal organization of F-actin and Vimentin in SNU-398 MET OE clones showed that ectopic MET expression and its suppressive effect on HOTAIR expression was also resulted in thickening of F-actin stress fibrils, and increase in Vimentin expression and polarity (Supplementary Fig.	('Vimentin', 'Gene', '7431', (71, 79))	('ectopic MET expression', 'Var', (117, 139))	('SNU-398', 'CellLine', 'CVCL:0077', (83, 90))	('expression', 'MPA', (272, 282))	('polarity', 'CPA', (287, 295))	('HOTAIR', 'Gene', (170, 176))	('Vimentin', 'Gene', (263, 271))	('HOTAIR', 'Gene', '100124700', (170, 176))	('Vimentin', 'Gene', (71, 79))	('F-actin stress', 'Protein', (223, 237))	('increase', 'PosReg', (251, 259))	('Vimentin', 'Gene', '7431', (263, 271))	('thickening', 'PosReg', (209, 219))
446943	32650779	It is very important to note that inhibition of expression with siRNAs is limited mostly with cytoplasmic HOTAIR mRNA targeting and further studies should be done to address the detailed mechanism of HOTAIR action in means of molecular interactions and/or epigenetic function in HCC cells.	('HOTAIR', 'Gene', (200, 206))	('HCC', 'Gene', '619501', (279, 282))	('HOTAIR', 'Gene', '100124700', (200, 206))	('HCC', 'Gene', (279, 282))	('epigenetic function', 'Var', (256, 275))	('HOTAIR', 'Gene', (106, 112))	('HOTAIR', 'Gene', '100124700', (106, 112))
446951	32650779	HOTAIR over-expression reduced Caveolin-1 expression and activation via suppressing activation of c-Met and its downstream effector Src kinase.	('HOTAIR', 'Gene', '100124700', (0, 6))	('Src', 'Gene', '6714', (132, 135))	('Caveolin-1', 'Gene', '857', (31, 41))	('expression', 'MPA', (42, 52))	('HOTAIR', 'Gene', (0, 6))	('Caveolin-1', 'Gene', (31, 41))	('c-Met', 'Gene', (98, 103))	('over-expression', 'Var', (7, 22))	('activation', 'MPA', (84, 94))	('suppressing', 'NegReg', (72, 83))	('Src', 'Gene', (132, 135))	('reduced', 'NegReg', (23, 30))	('c-Met', 'Gene', '4233', (98, 103))	('activation', 'MPA', (57, 67))
446953	32650779	defined function of HOTAIR in epigenetic regulation of its target genes and they reported Caveolin-1 as one of the most differentially expressed genes in response to HOTAIR knock-down in foreskin fibroblasts.	('epigenetic regulation', 'MPA', (30, 51))	('HOTAIR', 'Gene', (166, 172))	('Caveolin-1', 'Gene', '857', (90, 100))	('HOTAIR', 'Gene', '100124700', (166, 172))	('HOTAIR', 'Gene', (20, 26))	('Caveolin-1', 'Gene', (90, 100))	('knock-down', 'Var', (173, 183))	('HOTAIR', 'Gene', '100124700', (20, 26))
446954	32650779	In addition to the HOTAIR OE data, we showed that HOTAIR knock-down elevated CAV1 expression in HuH-7 cells (Supplementary Fig.	('CAV1', 'Gene', (77, 81))	('expression', 'MPA', (82, 92))	('HOTAIR', 'Gene', (19, 25))	('HOTAIR', 'Gene', (50, 56))	('elevated', 'PosReg', (68, 76))	('HuH-7', 'Gene', '284424', (96, 101))	('HOTAIR', 'Gene', '100124700', (19, 25))	('CAV1', 'Gene', '857', (77, 81))	('HuH-7', 'Gene', (96, 101))	('HOTAIR', 'Gene', '100124700', (50, 56))	('knock-down', 'Var', (57, 67))
446969	32650779	As expected, by attainment of those abilities, HOTAIR over-expression increased metastatic ability of SNU-449 cells which was defined to be highly metastatic in our previous studies in zebrafish xenograft model.	('zebrafish', 'Species', '7955', (185, 194))	('increased', 'PosReg', (70, 79))	('over-expression', 'Var', (54, 69))	('SNU-449', 'CellLine', 'CVCL:0454', (102, 109))	('HOTAIR', 'Gene', (47, 53))	('HOTAIR', 'Gene', '100124700', (47, 53))	('metastatic ability', 'CPA', (80, 98))
446977	32650779	Consistent with HOTAIR over-expression data in SNU-449 cells, c-Met overexpression in SNU-398 cells increased F-actin stress fibrils and Vimentin expression and, HOTAIR knock-down induced Vimentin expression in HuH-7 cells (Supplementary Fig.	('HuH-7', 'Gene', (211, 216))	('c-Met', 'Gene', (62, 67))	('SNU-449', 'CellLine', 'CVCL:0454', (47, 54))	('HOTAIR', 'Gene', '100124700', (162, 168))	('F-actin stress fibrils', 'MPA', (110, 132))	('expression', 'MPA', (146, 156))	('Vimentin', 'Gene', '7431', (188, 196))	('increased', 'PosReg', (100, 109))	('HOTAIR', 'Gene', (162, 168))	('HOTAIR', 'Gene', '100124700', (16, 22))	('Vimentin', 'Gene', (188, 196))	('HuH-7', 'Gene', '284424', (211, 216))	('SNU-398', 'CellLine', 'CVCL:0077', (86, 93))	('c-Met', 'Gene', '4233', (62, 67))	('HOTAIR', 'Gene', (16, 22))	('knock-down', 'Var', (169, 179))	('expression', 'MPA', (197, 207))	('Vimentin', 'Gene', '7431', (137, 145))	('induced', 'Reg', (180, 187))	('Vimentin', 'Gene', (137, 145))
446990	32650779	Analysis of available data generated by siRNA knock-down of HOTAIR in an HCC cell line HepG2, (Fig.	('HCC', 'Gene', '619501', (73, 76))	('HOTAIR', 'Gene', (60, 66))	('HCC', 'Gene', (73, 76))	('HOTAIR', 'Gene', '100124700', (60, 66))	('knock-down', 'Var', (46, 56))	('HepG2', 'CellLine', 'CVCL:0027', (87, 92))
446997	32650779	Considering the complex structure and multifunctional behavior, HOTAIR might be regulating c-Met signaling through physically interacting and epigenetic or transcriptional suppression of c-Met and/or its regulators.	('c-Met', 'Gene', (187, 192))	('HOTAIR', 'Gene', (64, 70))	('epigenetic or transcriptional', 'Var', (142, 171))	('c-Met', 'Gene', (91, 96))	('c-Met', 'Gene', '4233', (187, 192))	('c-Met', 'Gene', '4233', (91, 96))	('regulating', 'Reg', (80, 90))	('HOTAIR', 'Gene', '100124700', (64, 70))	('suppression', 'NegReg', (172, 183))
446999	32650779	In conclusion, HOTAIR over-expression suppresses c-Met expression, activation and also disrupts its organization on plasma membrane by modulating Caveolin-1 expression and activation.	('expression', 'MPA', (157, 167))	('c-Met', 'Gene', (49, 54))	('over-expression', 'Var', (22, 37))	('Caveolin-1', 'Gene', '857', (146, 156))	('activation', 'MPA', (172, 182))	('c-Met', 'Gene', '4233', (49, 54))	('HOTAIR', 'Gene', (15, 21))	('modulating', 'Reg', (135, 145))	('organization on plasma membrane', 'MPA', (100, 131))	('disrupts', 'NegReg', (87, 95))	('HOTAIR', 'Gene', '100124700', (15, 21))	('suppresses', 'NegReg', (38, 48))	('Caveolin-1', 'Gene', (146, 156))	('activation', 'MPA', (67, 77))
447008	32650779	https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE89377 Wu et al., 2018, performed an integrated proteomic and transcriptomic analysis to examine the overall transcriptomic changes in HepG2 cells after HOTAIR knockdown by RNA sequencing (data accessible at NCBI GEO database (Wu et al., 2018), accession GSE98091).	('HepG2', 'CellLine', 'CVCL:0027', (188, 193))	('knockdown', 'Var', (213, 222))	('HOTAIR', 'Gene', '100124700', (206, 212))	('HOTAIR', 'Gene', (206, 212))
447028	31497073	We first summarize the survey of TE expression variation found in the RNA-seq data from 697 samples of cancer-adjacent non-tumorous tissue.	('tumor', 'Disease', (123, 128))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('variation', 'Var', (47, 56))
447036	31497073	L2a_dup21781(chr2:113980079-113981081) is embedded in an intron of PAX8.	('L2a_dup21781', 'Var', (0, 12))	('chr2:113980079-113981081', 'STRUCTURAL_ABNORMALITY', 'None', (13, 37))	('PAX8', 'Gene', '7849', (67, 71))	('PAX8', 'Gene', (67, 71))
447080	31497073	We were more likely to see an enhancer-like mark (DNase + H3K27ac) for TE loci that are expressed compared to non-expressed TEs, and we were more likely to see a promoter-like mark (DNase + H3K4me3) for ZFP bound TE loci compared to TEs with no binding (Fig.	('DNase + H3K27ac', 'Var', (50, 65))	('DNase + H3K4me3', 'Var', (182, 197))	('enhancer-like', 'PosReg', (30, 43))	('ZFP', 'Gene', '55888', (203, 206))	('ZFP', 'Gene', (203, 206))
447090	31497073	8), and opposite of the pattern observed in several cancer studies, where DNA hypomethylation and expression of endogeneous retrovirus activates interferon signaling.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('interferon signaling', 'MPA', (145, 165))	('activates', 'PosReg', (135, 144))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('hypomethylation', 'Var', (78, 93))
447130	29073727	Mouse double minute 4 variants modify susceptibility to risk of recurrence in patients with squamous cell carcinoma of the oropharynx Given the crucial role of Mouse double minute 4 (MDM4) oncoprotein in p53 pathway, single nucleotide polymorphisms (SNPs) could serve as such biomarkers for prediction of SCCOP recurrence.	('patients', 'Species', '9606', (78, 86))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('Mouse', 'Species', '10090', (160, 165))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (92, 115))	('Mouse', 'Species', '10090', (0, 5))	('squamous cell carcinoma', 'Disease', (92, 115))	('modify', 'Reg', (31, 37))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (92, 115))	('variants', 'Var', (22, 30))
447131	29073727	Thus, we investigated associations between three tagging putatively functional variants of MDM4, two in the 3' untranslated region of 3' UTR [rs11801299 (NC_000001.10:g.204529084G>A) and rs10900598(NC_000001.10:g.204525568G>T)] and one in intron 1 [rs1380576(NC_000001.10:g.204488278G>C)], and recurrence risk of SCCOP in 1,008 incident patients.	('[rs1380576', 'Var', (248, 258))	('g.204529084G>A', 'Var', (167, 181))	('rs11801299', 'Mutation', 'rs11801299', (142, 152))	('rs1380576', 'Mutation', 'rs1380576', (249, 258))	('rs10900598', 'Var', (187, 197))	('NC_000001.10:g.204525568G>T', 'Mutation', 'rs10900598', (198, 225))	('investigated', 'Reg', (9, 21))	('NC_000001.10:g.204529084G>A', 'Mutation', 'rs11801299', (154, 181))	('NC_000001.10:g.204488278G>C', 'Mutation', 'rs1380576', (259, 286))	('rs10900598', 'Mutation', 'rs10900598', (187, 197))	('patients', 'Species', '9606', (337, 345))	('associations', 'Interaction', (22, 34))	('MDM4', 'Gene', (91, 95))
447132	29073727	Patients with MDM4-rs10900598 GT/TT had a worse disease-free survival (DFS) compared with corresponding GG genotype, while those with rs11801299 AG/AA genotypes had a lower recurrence risk than the cases with rs11801299 GG genotype (both log-rank, P<0.001).	('rs10900598', 'Mutation', 'rs10900598', (19, 29))	('rs11801299', 'Var', (134, 144))	('rs11801299', 'Mutation', 'rs11801299', (134, 144))	('rs11801299', 'Mutation', 'rs11801299', (209, 219))	('Patients', 'Species', '9606', (0, 8))	('disease-free survival', 'CPA', (48, 69))	('MDM4-rs10900598', 'Var', (14, 29))
447133	29073727	Multivariable analysis showed that significantly different recurrence risk were found among patients with MDM4-rs10900598 GT/TT and rs11801299 AG/AA variant genotypes (HR, 2.0, 95% CI, 1.4-2.9 and HR, 0.4, 95% CI, 0.3-0.6, respectively) compared with their corresponding common homozygous genotypes.	('rs11801299 AG/AA', 'Var', (132, 148))	('patients', 'Species', '9606', (92, 100))	('MDM4-rs10900598', 'Gene', (106, 121))	('rs10900598', 'Mutation', 'rs10900598', (111, 121))	('rs11801299', 'Mutation', 'rs11801299', (132, 142))
447136	29073727	Our findings suggest that the MDM4 polymorphisms may, individually or in combination, confer an independent risk of SCCOP recurrence, particularly in HPV-positive SCCOP patients.	('patients', 'Species', '9606', (169, 177))	('MDM4', 'Gene', (30, 34))	('polymorphisms', 'Var', (35, 48))	('HPV', 'Species', '10566', (150, 153))	('SCCOP recurrence', 'Disease', (116, 132))	('SCCOP', 'Disease', (163, 168))
447146	29073727	Many studies have revealed that single nucleotide polymorphisms (SNP), may modify genetic susceptibility to development or outcomes of SCCOP, and could serve as reliable and efficient prognostic biomarkers to allow accurately identify SCCOP patients with high-risk of recurrence.	('SCCOP', 'Disease', (235, 240))	('modify', 'Reg', (75, 81))	('SCCOP', 'Disease', (135, 140))	('single nucleotide polymorphisms', 'Var', (32, 63))	('patients', 'Species', '9606', (241, 249))
447147	29073727	p53, an important tumor suppressor protein, plays a critical role in genome integrity, acting as "the guardian of genome", is mutated in about half of all human cancers, especially in SCCHN.	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('tumor', 'Disease', (18, 23))	('human', 'Species', '9606', (155, 160))	('cancers', 'Disease', 'MESH:D009369', (161, 168))	('SCCHN', 'Disease', (184, 189))	('cancers', 'Phenotype', 'HP:0002664', (161, 168))	('cancers', 'Disease', (161, 168))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('mutated', 'Var', (126, 133))
447150	29073727	Amplification or overexpression of MDM4 gene may contribute to tumor development and prognosis, individually or synergistically with MDM2.	('tumor', 'Disease', (63, 68))	('Amplification', 'Var', (0, 13))	('prognosis', 'CPA', (85, 94))	('MDM4', 'Gene', (35, 39))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('overexpression', 'PosReg', (17, 31))	('contribute', 'Reg', (49, 59))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
447152	29073727	MDM4 polymorphisms have been reported to be associated with the risk of developing gastric cancer, prostate cancer, and SCCHN, as well as HPV16-related SCCOP.	('associated', 'Reg', (44, 54))	('SCCHN', 'Disease', (120, 125))	('gastric cancer', 'Phenotype', 'HP:0012126', (83, 97))	('MDM4', 'Gene', (0, 4))	('prostate cancer', 'Disease', (99, 114))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('HPV16', 'Species', '333760', (138, 143))	('HPV16-related', 'Gene', (138, 151))	('gastric cancer', 'Disease', (83, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('gastric cancer', 'Disease', 'MESH:D013274', (83, 97))	('prostate cancer', 'Disease', 'MESH:D011471', (99, 114))	('polymorphisms', 'Var', (5, 18))	('prostate cancer', 'Phenotype', 'HP:0012125', (99, 114))
447155	29073727	Additionally, polymorphisms in the 3'-UTR of MDM4 are useful predictors of the outcome in advanced lung cancer patients treated with chemotherapy.	('lung cancer', 'Disease', (99, 110))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('MDM4', 'Gene', (45, 49))	('lung cancer', 'Disease', 'MESH:D008175', (99, 110))	('polymorphisms', 'Var', (14, 27))	('lung cancer', 'Phenotype', 'HP:0100526', (99, 110))	('patients', 'Species', '9606', (111, 119))
447157	29073727	In the present study, we evaluated the associations of 3 MDM4 variants with the likelihood of recurrence among 1008 SCCOP patients.	('patients', 'Species', '9606', (122, 130))	('variants', 'Var', (62, 70))	('associations', 'Interaction', (39, 51))	('MDM4', 'Gene', (57, 61))
447172	29073727	Finally, we identified three tagging SNPs: rs11801299 (NC_000001.10:g.204529084G>A), rs10900598 (NC_000001.10:g.204525568G>T), and rs1380576 (NC_000001.10:g.204488278G>C).	('rs1380576', 'Mutation', 'rs1380576', (131, 140))	('rs10900598', 'Mutation', 'rs10900598', (85, 95))	('rs11801299', 'Var', (43, 53))	('NC_000001.10:g.204529084G>A', 'Mutation', 'rs11801299', (55, 82))	('g.204529084G>A', 'Var', (68, 82))	('rs11801299', 'Mutation', 'rs11801299', (43, 53))	('NC_000001.10:g.204525568G>T', 'Mutation', 'rs10900598', (97, 124))	('g.204525568G>T', 'Var', (110, 124))	('NC_000001.10:g.204488278G>C', 'Mutation', 'rs1380576', (142, 169))	('g.204488278G>C', 'Var', (155, 169))
447173	29073727	For these three identified SNPs, both rs11801299and rs10900598 are located in the 3' UTR of the MDM4 gene; and rs1380576 is located in intron 1 of the gene.	('rs11801299and', 'Var', (38, 51))	('MDM4', 'Gene', (96, 100))	('rs10900598', 'Mutation', 'rs10900598', (52, 62))	('rs11801299', 'Mutation', 'rs11801299', (38, 48))	('rs1380576', 'Var', (111, 120))	('rs10900598', 'Var', (52, 62))	('rs1380576', 'Mutation', 'rs1380576', (111, 120))
447175	29073727	To assess the combined effect of these three SNPs, we categorized all putative risk (aHRs > 1.0) genotypes of each polymorphism into a new variable according to the number of risk genotypes carried by an individual for each of the 3 polymorphisms (for the rs1380576 and rs11801299 genotypes, we reversed the reference group to reflect the protective effects of the variant genotypes of CG/GG for rs1380576 and AG/AA for rs11801299).	('rs1380576', 'Mutation', 'rs1380576', (396, 405))	('rs11801299', 'Mutation', 'rs11801299', (270, 280))	('rs1380576', 'Mutation', 'rs1380576', (256, 265))	('aHR', 'Gene', (85, 88))	('rs1380576', 'Var', (396, 405))	('aHR', 'Gene', '196', (85, 88))	('CG', 'Chemical', 'MESH:C028505', (386, 388))	('rs11801299', 'Mutation', 'rs11801299', (420, 430))	('rs11801299', 'Var', (420, 430))
447179	29073727	The MDM4 rs10900598 (both T and G alleles) and rs11801299 (both A and G alleles) allelic reporter constructs were generated by amplifying a 633-bp and 675 fragment of the MDM4 3'-UTR region from subjects homozygous for the rs10900598 TT or rs10900598 GG genotype as well as rs11801299AA or rs11801299GG genotype.	('rs11801299GG', 'Var', (290, 302))	('rs11801299', 'Mutation', 'rs11801299', (47, 57))	('rs11801299AA', 'Var', (274, 286))	('rs11801299', 'Mutation', 'rs11801299', (290, 300))	('rs10900598', 'Mutation', 'rs10900598', (223, 233))	('rs11801299', 'Mutation', 'rs11801299', (274, 284))	('rs10900598 GG', 'Var', (240, 253))	('rs10900598', 'Mutation', 'rs10900598', (240, 250))	('rs10900598', 'Mutation', 'rs10900598', (9, 19))	('rs10900598', 'Var', (223, 233))
447196	29073727	Patients with the MDM4-rs10900598 GT/TT, MDM4-rs11801299 GG genotypes had significantly worse DFS compared with their corresponding GG and AG/AA genotypes (log-rank, P = 0.0002 and P < 0.001, respectively) (Figure 1).	('rs11801299', 'Mutation', 'rs11801299', (46, 56))	('Patients', 'Species', '9606', (0, 8))	('MDM4-rs11801299', 'Var', (41, 56))	('worse', 'NegReg', (88, 93))	('DFS', 'MPA', (94, 97))	('MDM4-rs10900598', 'Var', (18, 33))	('rs10900598', 'Mutation', 'rs10900598', (23, 33))
447197	29073727	The similar findings were found among 324 patients with HPV16-positive SCCOP (log-rank, P = 0.051 for MDM4-rs10900598 and P = 0.029 for MDM4-rs11801299; Figure 1).	('MDM4-rs11801299', 'Var', (136, 151))	('MDM4-rs10900598', 'Var', (102, 117))	('rs10900598', 'Mutation', 'rs10900598', (107, 117))	('HPV16', 'Species', '333760', (56, 61))	('patients', 'Species', '9606', (42, 50))	('rs11801299', 'Mutation', 'rs11801299', (141, 151))
447198	29073727	In multivariable Cox proportional hazards regression analyses, the risk of disease recurrence differed significantly in patients carrying the MDM4-rs10900598 GT/TT and MDM4-rs11801299 GG genotypes compared with their corresponding GG and AG/AA genotypes (HR, 2.0, 95% CI, 1.4-2.9 and HR, 0.4, 95% CI, 0.3-0.6) after adjusted for some possible confounders (Table 2).	('MDM4-rs10900598 GT/TT', 'Var', (142, 163))	('rs10900598', 'Mutation', 'rs10900598', (147, 157))	('disease', 'Disease', (75, 82))	('patients', 'Species', '9606', (120, 128))	('MDM4-rs11801299 GG', 'Var', (168, 186))	('rs11801299', 'Mutation', 'rs11801299', (173, 183))
447199	29073727	Given the roles of both MDM4 and HPV involving in the p53 pathway, we further evaluated the associations between genotypes of the three MDM4 polymorphisms and recurrence risk among 324 HPV16-positive SCCOP cases.	('MDM4', 'Gene', (136, 140))	('HPV', 'Species', '10566', (185, 188))	('HPV16', 'Species', '333760', (185, 190))	('associations', 'Interaction', (92, 104))	('p53 pathway', 'Pathway', (54, 65))	('HPV', 'Species', '10566', (33, 36))	('polymorphisms', 'Var', (141, 154))	('SCCOP', 'Disease', (200, 205))
447200	29073727	Table 3 showed that patients with MDM4-rs10900598 GT/TT variant genotypes had a significantly higher recurrence risk than those with GG common homozygous genotype (aHR, 1.8; 95% CI, 1.0-3.9), while patients with MDM4-rs11801299 AG/AA had a significantly lower risk of recurrence than those carrying MDM4-rs11801299 GG common homozygous genotype (aHR, 0.4; 95% CI, 0.2-0.9).	('variant', 'Var', (56, 63))	('patients', 'Species', '9606', (198, 206))	('rs11801299', 'Mutation', 'rs11801299', (304, 314))	('rs11801299', 'Mutation', 'rs11801299', (217, 227))	('aHR', 'Gene', (164, 167))	('MDM4-rs10900598', 'Var', (34, 49))	('aHR', 'Gene', (346, 349))	('recurrence', 'MPA', (101, 111))	('patients', 'Species', '9606', (20, 28))	('rs10900598', 'Mutation', 'rs10900598', (39, 49))	('aHR', 'Gene', '196', (346, 349))	('aHR', 'Gene', '196', (164, 167))
447207	29073727	To further support the 3-UTR binding site SNP (MDM4-rs10900598 and MDM4-rs11801299) of MDM4 as a risk factor for SCCOP recurrence, we replaced the 3'-UTR of a luciferase reporter gene with the 633-bp or 675-bp MDM4 3'-UTR containing either rs10900598 T or rs10900598 G and rs11801299A or rs11801299G, respectively (Fig.	('rs11801299A', 'Var', (273, 284))	('rs11801299', 'Mutation', 'rs11801299', (288, 298))	('rs11801299G', 'Var', (288, 299))	('rs11801299', 'Mutation', 'rs11801299', (273, 283))	('rs10900598 T', 'Var', (240, 252))	('rs10900598', 'Mutation', 'rs10900598', (52, 62))	('rs10900598', 'Mutation', 'rs10900598', (240, 250))	('rs11801299', 'Mutation', 'rs11801299', (72, 82))	('rs10900598 G', 'Var', (256, 268))	('rs10900598', 'Mutation', 'rs10900598', (256, 266))
447208	29073727	3, significantly lower levels of luciferase expression were observed when UMSCC4 and UMSCC47 cells were cotransfected with MDM4 3'UTR luciferase reporter plasmids carrying the rs11801299A allele than with those plasmids carrying the G allele in both cell lines (P = 0.032 in UMSCC4 and P = 0.019 in UMSCC47 cells), While borderline significantly higher levels of luciferase expression were observed when UMSCC4 and UMSCC47 cells were cotransfected with MDM4 3'UTR luciferase reporter plasmids carrying the rs10900598 T allele than with those plasmids carrying the G allele in both cell lines (P = 0.058 in UMSCC4 and P = 0.053 in UMSCC47 cells).	('UMSCC47', 'CellLine', 'CVCL:7759', (85, 92))	('lower', 'NegReg', (17, 22))	('UMSCC47', 'CellLine', 'CVCL:7759', (415, 422))	('UMSCC47', 'CellLine', 'CVCL:7759', (299, 306))	('rs10900598 T', 'Var', (506, 518))	('rs11801299', 'Mutation', 'rs11801299', (176, 186))	('rs11801299A', 'Var', (176, 187))	('rs10900598', 'Mutation', 'rs10900598', (506, 516))	('UMSCC47', 'CellLine', 'CVCL:7759', (630, 637))
447210	29073727	MDM4-rs10900598 and MDM4-rs11801299 variants may individually, or more likely jointly, significantly modulate the risk of SCCOP recurrence after adjusting for other important confounders, particularly in HPV16-positive tumors of SCCOP.	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('modulate', 'Reg', (101, 109))	('rs10900598', 'Mutation', 'rs10900598', (5, 15))	('HPV16-positive tumors', 'Disease', 'MESH:D009369', (204, 225))	('tumors', 'Phenotype', 'HP:0002664', (219, 225))	('MDM4-rs11801299', 'Gene', (20, 35))	('HPV16-positive tumors', 'Disease', (204, 225))	('variants', 'Var', (36, 44))	('MDM4-rs10900598', 'Gene', (0, 15))	('rs11801299', 'Mutation', 'rs11801299', (25, 35))	('SCCOP recurrence', 'Disease', (122, 138))
447211	29073727	To our knowledge, this study is the first to investigate the associations between MDM4 polymorphisms and increased risk of recurrence in SCCOP patients.	('SCCOP', 'Disease', (137, 142))	('patients', 'Species', '9606', (143, 151))	('polymorphisms', 'Var', (87, 100))	('associations', 'Interaction', (61, 73))	('MDM4', 'Gene', (82, 86))
447212	29073727	Our previous study reported that combined effect of 3 MDM4 variants may be linked to the risk of SCCOP, particularly for HPV16-positive SCCOP.	('HPV16', 'Species', '333760', (121, 126))	('variants', 'Var', (59, 67))	('linked', 'Reg', (75, 81))	('SCCOP', 'Disease', (97, 102))	('MDM4', 'Gene', (54, 58))
447213	29073727	If our results are further validated, improved strategies based on these MDM4 genetic variants could be used to identify patients with higher recurrence risk.	('MDM4', 'Gene', (73, 77))	('patients', 'Species', '9606', (121, 129))	('variants', 'Var', (86, 94))
447216	29073727	Previous studies have shown that other genetic changes, such as amplification or overexpression, of MDM4 was associated with tumor progression and poor prognosis.	('associated', 'Reg', (109, 119))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('MDM4', 'Gene', (100, 104))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('amplification', 'Var', (64, 77))	('overexpression', 'PosReg', (81, 95))	('tumor', 'Disease', (125, 130))
447217	29073727	Therefore, it is our speculation that these three SNPs in MDM4 may affect expression of MDM4, result in different efficacy for binding to p53 or MDM2, and consequently attenuate the p53-mediated tumor-suppressing activities involving in regulation of several cellular activities, such as cell cycle control, DNA repair and apoptosis, eventually contributing to recurrence of SCCOP.	('SCCOP', 'Disease', (375, 380))	('expression', 'MPA', (74, 84))	('cell cycle control', 'CPA', (288, 306))	('tumor', 'Disease', (195, 200))	('SNPs', 'Var', (50, 54))	('binding', 'Interaction', (127, 134))	('DNA repair', 'CPA', (308, 318))	('attenuate', 'NegReg', (168, 177))	('affect', 'Reg', (67, 73))	('MDM4', 'Gene', (58, 62))	('contributing', 'Reg', (345, 357))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('apoptosis', 'CPA', (323, 332))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('MDM4', 'Gene', (88, 92))
447218	29073727	For example, in the luciferase reporter determination, the rs11801299 variant A allele was found to be associated with significantly lower luciferase activity compared with the G allele, indicating the A variant allele might be biologically functional to reduce expression of MDM4.	('luciferase', 'Enzyme', (139, 149))	('expression', 'MPA', (262, 272))	('reduce', 'NegReg', (255, 261))	('rs11801299', 'Var', (59, 69))	('rs11801299', 'Mutation', 'rs11801299', (59, 69))	('lower', 'NegReg', (133, 138))	('activity', 'MPA', (150, 158))
447221	29073727	In this study, we found that the association were statistically significant between MDM4 variants and risk of recurrence among HPV-positive SCCOP.	('variants', 'Var', (89, 97))	('MDM4', 'Gene', (84, 88))	('HPV', 'Species', '10566', (127, 130))	('significant', 'Reg', (64, 75))
447222	29073727	Thus, these MDM4 polymorphisms may modify the susceptibility to radiotherapy through interaction with HPV16 in p53 pathway, affect the risk of recurrence.	('HPV16', 'Species', '333760', (102, 107))	('susceptibility to radiotherapy', 'Phenotype', 'HP:0011133', (46, 76))	('affect', 'Reg', (124, 130))	('polymorphisms', 'Var', (17, 30))	('p53 pathway', 'Pathway', (111, 122))	('HPV16', 'Gene', (102, 107))	('recurrence', 'CPA', (143, 153))	('interaction', 'Interaction', (85, 96))	('susceptibility to', 'MPA', (46, 63))	('modify', 'Reg', (35, 41))	('MDM4', 'Gene', (12, 16))
447224	29073727	In addition, there was a significant combined effect of the 3 MDM4 variants on risk of recurrence among SCCOP patients in the present study.	('MDM4', 'Gene', (62, 66))	('patients', 'Species', '9606', (110, 118))	('variants', 'Var', (67, 75))	('combined', 'Interaction', (37, 45))
447227	29073727	Second, this is the first study to date to examine the effects of MDM4 polymorphisms on SCCOP recurrence risk based on HPV16 tumor status instead of serology.	('polymorphisms', 'Var', (71, 84))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('MDM4', 'Gene', (66, 70))	('HPV16', 'Species', '333760', (119, 124))	('tumor', 'Disease', (125, 130))	('SCCOP recurrence', 'Disease', (88, 104))
447233	29073727	In conclusion, our report provides the first evidence that the MDM4 genetic variants may individually, and more like jointly contribute to susceptibility to SCCOP recurrence risk, particularly in HPV16-positive tumors of SCCOP.	('HPV16-positive tumors', 'Disease', (196, 217))	('MDM4', 'Gene', (63, 67))	('SCCOP recurrence', 'Disease', (157, 173))	('variants', 'Var', (76, 84))	('HPV16-positive tumors', 'Disease', 'MESH:D009369', (196, 217))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('contribute', 'Reg', (125, 135))	('susceptibility', 'Reg', (139, 153))	('tumors', 'Phenotype', 'HP:0002664', (211, 217))	('SCCOP', 'Disease', (221, 226))
447234	29073727	MDM4            Mouse double minute 4 CI confidence interval HPV human papillomavirus HRs hazard ratios SCCOP squamous cell carcinoma of oropharynx SCCHN squamous cell carcinoma of head and neck SNP single nucleotide polymorphisms DFS disease-free survival	('carcinoma', 'Phenotype', 'HP:0030731', (168, 177))	('papillomavirus', 'Disease', (71, 85))	('human', 'Species', '9606', (65, 70))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (110, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('squamous cell carcinoma', 'Disease', (110, 133))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (110, 133))	('Mouse', 'Species', '10090', (16, 21))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (154, 177))	('carcinoma of head and neck', 'Phenotype', 'HP:0012288', (168, 194))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (154, 177))	('papillomavirus', 'Disease', 'MESH:D030361', (71, 85))	('squamous cell carcinoma', 'Disease', (154, 177))	('single nucleotide polymorphisms', 'Var', (199, 230))	('HPV', 'Species', '10566', (61, 64))
447273	26491674	Positive expression of OPN was independently associated with a high risk of cancer death (HR 2.206, p = 0.028) and recurrence of cancer (HR 2.509, p = 0.009) in our multivariate analysis.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('Positive expression', 'Var', (0, 19))	('cancer death', 'Disease', (76, 88))	('cancer death', 'Disease', 'MESH:D003643', (76, 88))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('associated', 'Reg', (45, 55))	('recurrence', 'CPA', (115, 125))	('OPN', 'Gene', (23, 26))
447276	26491674	OPN can interact with two types of receptors: integrin, including a4b1, a9b1, a9b4, av(b1, b3, b5), and CD44, which in turn can activate many different signal transduction pathways to regulate cell growth.	('a4b1', 'Var', (66, 70))	('interact', 'Interaction', (8, 16))	('a4b1', 'Species', '267016', (66, 70))	('cell growth', 'CPA', (193, 204))	('integrin', 'Protein', (46, 54))	('a9b1', 'Var', (72, 76))	('CD44', 'Var', (104, 108))	('activate', 'PosReg', (128, 136))	('signal transduction pathways', 'Pathway', (152, 180))	('a9b4', 'Var', (78, 82))
447288	24930674	Frequent amplification of ORAOV1 gene in esophageal squamous cell cancer promotes an aggressive phenotype via proline metabolism and ROS production Chromosomal band 11q13 seems to be one of the most frequently amplified lesions in human cancer, including esophageal squamous cell cancer (ESCC).	('ORAOV1', 'Gene', '220064', (26, 32))	('cancer', 'Disease', (280, 286))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('ORAOV1', 'Gene', (26, 32))	('human', 'Species', '9606', (231, 236))	('cancer', 'Phenotype', 'HP:0002664', (280, 286))	('esophageal squamous cell cancer', 'Disease', 'MESH:D002294', (255, 286))	('esophageal squamous cell cancer', 'Disease', 'MESH:D002294', (41, 72))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('cancer', 'Disease', (237, 243))	('ROS', 'Chemical', 'MESH:D017382', (133, 136))	('cancer', 'Disease', 'MESH:D009369', (280, 286))	('amplification', 'Var', (9, 22))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('aggressive phenotype', 'MPA', (85, 105))	('proline metabolism', 'MPA', (110, 128))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (266, 286))	('esophageal squamous cell cancer', 'Disease', (255, 286))	('esophageal squamous cell cancer', 'Disease', (41, 72))	('promotes', 'PosReg', (73, 81))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (52, 72))	('proline', 'Chemical', 'MESH:D011392', (110, 117))	('cancer', 'Disease', 'MESH:D009369', (237, 243))	('cancer', 'Disease', (66, 72))
447291	24930674	ORAOV1 amplification was significantly associated with a poorly differentiated histology and tumors located in the upper or middle esophagus.	('poorly differentiated histology', 'CPA', (57, 88))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumors', 'Disease', 'MESH:D009369', (93, 99))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('associated', 'Reg', (39, 49))	('ORAOV1', 'Gene', '220064', (0, 6))	('tumors', 'Disease', (93, 99))	('amplification', 'Var', (7, 20))	('ORAOV1', 'Gene', (0, 6))
447305	24930674	Chromosomal band 11q13 seems to be one of the most frequently amplified lesions in human cancer, including esophageal squamous cell cancer (ESCC), and can be associated with an advanced stage and poor prognosis.	('cancer', 'Disease', (132, 138))	('esophageal squamous cell cancer', 'Disease', 'MESH:D002294', (107, 138))	('associated', 'Reg', (158, 168))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (118, 138))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('human', 'Species', '9606', (83, 88))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('cancer', 'Disease', (89, 95))	('esophageal squamous cell cancer', 'Disease', (107, 138))	('Chromosomal band 11q13', 'Var', (0, 22))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
447317	24930674	To develop a high-throughput method for detecting ORAOV1 amplification in a clinical setting, we verified a real-time PCR-based detection method, the TaqMan Copy Number Assay.	('ORAOV1', 'Gene', (50, 56))	('ORAOV1', 'Gene', '220064', (50, 56))	('clinical', 'Species', '191496', (76, 84))	('amplification', 'Var', (57, 70))
447318	24930674	Using a cut off of 4 copies, the number was 0.98-3.3 copies in the non-amplified cell lines; however, the number in the ORAOV1-amplified cell lines was 4.2-14.4 copies (KYSE140, KYSE180, KYSE220, and T.T).	('T.T', 'Var', (200, 203))	('ORAOV1', 'Gene', '220064', (120, 126))	('ORAOV1', 'Gene', (120, 126))	('KYSE180', 'Var', (178, 185))	('KYSE220', 'Var', (187, 194))
447320	24930674	Next, ORAOV1 amplification was evaluated using Hs03772057_cn (intron 2) in 94 FFPE samples of stage III ESCC specimens.	('ORAOV1', 'Gene', '220064', (6, 12))	('ORAOV1', 'Gene', (6, 12))	('Hs03772057_cn', 'Var', (47, 60))
447324	24930674	Specifically, patients with ORAOV1 amplification tended to have poorly differentiated tumors in the upper or middle region of the esophagus.	('amplification', 'Var', (35, 48))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('tumors', 'Disease', (86, 92))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('ORAOV1', 'Gene', '220064', (28, 34))	('ORAOV1', 'Gene', (28, 34))	('patients', 'Species', '9606', (14, 22))
447326	24930674	Patients with ORAOV1 amplification tended to have a shorter disease-free survival (DFS) and overall survival (OS) after surgery, compared with patients without amplification, although the differences were not significant (median DFS, 11.6 vs. 12.6 months, P = 0.50, and median OS, 21.6 vs. 33.7 months, P = 0.16, respectively) (Figure 3A and B).	('disease-free survival', 'CPA', (60, 81))	('ORAOV1', 'Gene', (14, 20))	('shorter', 'NegReg', (52, 59))	('patients', 'Species', '9606', (143, 151))	('Patients', 'Species', '9606', (0, 8))	('overall survival', 'CPA', (92, 108))	('amplification', 'Var', (21, 34))	('ORAOV1', 'Gene', '220064', (14, 20))
447345	24930674	Chromosomal band 11q13 seems to be one of the most frequently amplified lesions in human cancer, including ESCC, and is associated with an advanced disease stage and a poor prognosis.	('associated with', 'Reg', (120, 135))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('human', 'Species', '9606', (83, 88))	('cancer', 'Disease', (89, 95))	('Chromosomal band 11q13', 'Var', (0, 22))	('ESCC', 'Disease', (107, 111))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
447358	24930674	Therefore, as was seen in our study, the ORAOV1 gene enhances tumorigenicity and tumor growth.	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('enhances', 'PosReg', (53, 61))	('gene', 'Var', (48, 52))	('tumor', 'Disease', (62, 67))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('ORAOV1', 'Gene', '220064', (41, 47))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('ORAOV1', 'Gene', (41, 47))	('tumor', 'Disease', (81, 86))
447359	24930674	In our cohort, the ORAOV1 gene was amplified in approximately half of the stage III ESCC, and patients with ORAOV1 amplification tended to have a shorter OS than patients without amplification, although the difference was not significant.	('ORAOV1', 'Gene', (108, 114))	('patients', 'Species', '9606', (162, 170))	('patients', 'Species', '9606', (94, 102))	('amplification', 'Var', (115, 128))	('ORAOV1', 'Gene', '220064', (19, 25))	('ORAOV1', 'Gene', (19, 25))	('stage III ESCC', 'Disease', (74, 88))	('ORAOV1', 'Gene', '220064', (108, 114))
447363	24930674	Therefore, patients with ORAOV1 amplification may exhibit the amplification of other cancer-related genes, which might also be related to a poor prognosis.	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('amplification', 'Var', (32, 45))	('related', 'Reg', (127, 134))	('amplification', 'MPA', (62, 75))	('cancer', 'Disease', (85, 91))	('exhibit', 'Reg', (50, 57))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('ORAOV1', 'Gene', '220064', (25, 31))	('patients', 'Species', '9606', (11, 19))	('ORAOV1', 'Gene', (25, 31))
447364	24930674	ORAOV1 amplification was significantly associated with a poorly differentiated histology and, in our xenograft study, ORAOV1-overexpressed cells produced poorly differentiated tumors.	('ORAOV1', 'Gene', '220064', (118, 124))	('poorly differentiated histology', 'CPA', (57, 88))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('ORAOV1', 'Gene', (118, 124))	('tumors', 'Disease', (176, 182))	('tumors', 'Disease', 'MESH:D009369', (176, 182))	('tumors', 'Phenotype', 'HP:0002664', (176, 182))	('associated', 'Reg', (39, 49))	('ORAOV1', 'Gene', '220064', (0, 6))	('amplification', 'Var', (7, 20))	('ORAOV1', 'Gene', (0, 6))
447383	24930674	The primer IDs used for the ORAOV1 gene were Hs03772057_cn (intron 2) and Hs03793932_cn (intron 3).	('ORAOV1', 'Gene', '220064', (28, 34))	('Hs03793932_cn', 'Var', (74, 87))	('Hs03772057_cn', 'Var', (45, 58))	('ORAOV1', 'Gene', (28, 34))
447457	28656243	Notably, high mRNA level of PTPRA was significantly correlated with poorer prognosis in 675 SCC patients from the Kaplan-Meier plotter database.	('PTPRA', 'Gene', (28, 33))	('PTPRA', 'Gene', '5786', (28, 33))	('SCC', 'Gene', '6317', (92, 95))	('mRNA level', 'MPA', (14, 24))	('SCC', 'Phenotype', 'HP:0030359', (92, 95))	('patients', 'Species', '9606', (96, 104))	('SCC', 'Gene', (92, 95))	('high', 'Var', (9, 13))
447459	28656243	The Kaplan-Meier plot suggested that high expression of PTPRA had poorer overall survival in SCC patients (P=0.009).	('high expression', 'Var', (37, 52))	('PTPRA', 'Gene', (56, 61))	('SCC', 'Gene', (93, 96))	('PTPRA', 'Gene', '5786', (56, 61))	('poorer', 'NegReg', (66, 72))	('SCC', 'Gene', '6317', (93, 96))	('SCC', 'Phenotype', 'HP:0030359', (93, 96))	('overall survival', 'MPA', (73, 89))	('patients', 'Species', '9606', (97, 105))
447506	28656243	Antibodies for Src, non-phosphate/Src (Tyr527), phosphate/Src (Tyr527) and phosphate/Src (Tyr419) were purchased from Cell Signaling Technology (USA).	('phosphate', 'Chemical', 'MESH:D010710', (48, 57))	('Src', 'Gene', (85, 88))	('Src', 'Gene', '6714', (85, 88))	('Tyr527', 'Var', (63, 69))	('Tyr527', 'Chemical', '-', (63, 69))	('Src', 'Gene', (58, 61))	('Src', 'Gene', '6714', (58, 61))	('Src', 'Gene', (34, 37))	('Src', 'Gene', '6714', (34, 37))	('Tyr419', 'Chemical', '-', (90, 96))	('phosphate', 'Chemical', 'MESH:D010710', (75, 84))	('Tyr527', 'Chemical', '-', (39, 45))	('phosphate', 'Chemical', 'MESH:D010710', (24, 33))	('Src', 'Gene', (15, 18))	('Src', 'Gene', '6714', (15, 18))
447521	28656243	As shown in Table I, high expression of PTPRA was significantly correlated with tumor size (P=0.002), lymph node metastasis (P=0.008), depth of tumor invasion (P<0.001) and clinical stage (P<0.001).	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor', 'Disease', (144, 149))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumor', 'Disease', (80, 85))	('lymph node metastasis', 'CPA', (102, 123))	('high expression', 'Var', (21, 36))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('correlated', 'Reg', (64, 74))	('PTPRA', 'Gene', (40, 45))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('PTPRA', 'Gene', '5786', (40, 45))
447533	28656243	5A, overexpression of PTPRA led to the dephosphorylation of c-Src at Tyr527 but increased phosphorylation of c-Src at Tyr419, and the results were consistent with previous reports performed in other cell lines.	('PTPRA', 'Gene', '5786', (22, 27))	('increased', 'PosReg', (80, 89))	('Tyr527', 'Chemical', '-', (69, 75))	('c-Src', 'Gene', (60, 65))	('c-Src', 'Gene', '6714', (60, 65))	('c-Src', 'Gene', (109, 114))	('phosphorylation', 'MPA', (90, 105))	('Tyr527', 'Var', (69, 75))	('c-Src', 'Gene', '6714', (109, 114))	('PTPRA', 'Gene', (22, 27))	('overexpression', 'PosReg', (4, 18))	('Tyr419', 'Chemical', '-', (118, 124))	('dephosphorylation', 'MPA', (39, 56))
447545	28656243	PTPRB was found to be downregulated in NSCLC, and knockdown of PTPRB increased Src phosphorylation and cell invasion.	('increased', 'PosReg', (69, 78))	('knockdown', 'Var', (50, 59))	('cell invasion', 'CPA', (103, 116))	('PTPRB', 'Gene', '5787', (0, 5))	('PTPRB', 'Gene', (0, 5))	('Src', 'Gene', (79, 82))	('Src', 'Gene', '6714', (79, 82))	('PTPRB', 'Gene', '5787', (63, 68))	('PTPRB', 'Gene', (63, 68))	('NSCLC', 'Disease', (39, 44))	('NSCLC', 'Disease', 'MESH:D002289', (39, 44))	('downregulated', 'NegReg', (22, 35))
447546	28656243	PTPN13 was found to be a tumor suppressor candidate gene and it was frequently inactivated in NSCLC tissues through the loss of mRNA or protein expression level or the somatic mutation of the gene.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('loss', 'NegReg', (120, 124))	('mRNA or protein expression level', 'MPA', (128, 160))	('inactivated', 'NegReg', (79, 90))	('tumor', 'Disease', (25, 30))	('PTPN13', 'Gene', '5783', (0, 6))	('NSCLC', 'Disease', (94, 99))	('PTPN13', 'Gene', (0, 6))	('NSCLC', 'Disease', 'MESH:D002289', (94, 99))	('mutation', 'Var', (176, 184))	('tumor', 'Disease', 'MESH:D009369', (25, 30))
447550	28656243	In the present study, we determined the relationship between PTPRA expression and activation state of c-Src in SCC samples and the cell line H520, which provided evidence that PTPRA expression has a potential to dephosphorylate the site of Tyr527 in PTK c-Src and activates the c-Src in SCC cells.	('dephosphorylate', 'MPA', (212, 227))	('PTPRA', 'Gene', (176, 181))	('SCC', 'Phenotype', 'HP:0030359', (287, 290))	('SCC', 'Phenotype', 'HP:0030359', (111, 114))	('Tyr527', 'Chemical', '-', (240, 246))	('c-Src', 'Gene', (254, 259))	('c-Src', 'Gene', (278, 283))	('PTPRA', 'Gene', '5786', (61, 66))	('SCC', 'Gene', '6317', (287, 290))	('c-Src', 'Gene', (102, 107))	('PTPRA', 'Gene', (61, 66))	('SCC', 'Gene', '6317', (111, 114))	('c-Src', 'Gene', '6714', (254, 259))	('SCC', 'Gene', (287, 290))	('activates', 'PosReg', (264, 273))	('c-Src', 'Gene', '6714', (278, 283))	('PTPRA', 'Gene', '5786', (176, 181))	('Tyr527', 'Var', (240, 246))	('SCC', 'Gene', (111, 114))	('c-Src', 'Gene', '6714', (102, 107))
447551	28656243	These results provide evidence that high expression of PTPRA may dephosphorylate and activate c-Src, and might exert an oncogenic effect in the development of SCC.	('high expression', 'Var', (36, 51))	('c-Src', 'Gene', (94, 99))	('c-Src', 'Gene', '6714', (94, 99))	('PTPRA', 'Gene', (55, 60))	('activate', 'PosReg', (85, 93))	('SCC', 'Gene', (159, 162))	('dephosphorylate', 'MPA', (65, 80))	('oncogenic effect', 'CPA', (120, 136))	('PTPRA', 'Gene', '5786', (55, 60))	('SCC', 'Gene', '6317', (159, 162))	('SCC', 'Phenotype', 'HP:0030359', (159, 162))
447568	28656243	The authors reconciled the apparent conflict between the Src-activation and reduced growth in experimental tumor cells, with the reasons that high PTPRA expression in a subset of tumors is a remnant of an earlier disease stage, where it may have contributed to initiation, or early progression, but is lost at later stages in favour of more aggressive progression events.	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('PTPRA', 'Gene', (147, 152))	('Src', 'Gene', (57, 60))	('PTPRA', 'Gene', '5786', (147, 152))	('tumor', 'Disease', (107, 112))	('Src', 'Gene', '6714', (57, 60))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumors', 'Disease', (179, 185))	('tumors', 'Phenotype', 'HP:0002664', (179, 185))	('contributed', 'Reg', (246, 257))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('tumors', 'Disease', 'MESH:D009369', (179, 185))	('high', 'Var', (142, 146))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('tumor', 'Disease', (179, 184))
447574	27831464	We found that the presence of heterochromatin in the tissue-of-origin contributes to the recurrence and length of CNAs in the respective cancer type.	('presence', 'Var', (18, 26))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('heterochromatin', 'Protein', (30, 45))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('CNAs', 'Disease', (114, 118))	('cancer', 'Disease', (137, 143))
447576	27831464	There are several different types of DNA alterations and one that is frequently seen in cancer cells is known as a "copy number alteration" (or CNA for short).	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('alterations', 'Var', (41, 52))
447580	27831464	Analysing datasets from almost 6000 patients with 20 different types of cancer showed that mutations in several genes are linked to a higher or lower number of CNAs in patients.	('patients', 'Species', '9606', (36, 44))	('lower', 'NegReg', (144, 149))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('mutations', 'Var', (91, 100))	('CNAs', 'Disease', (160, 164))	('patients', 'Species', '9606', (168, 176))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('cancer', 'Disease', (72, 78))
447588	27831464	It has also been observed that DNA contact points in genome-wide chromosome conformation capture (HiC) proximity maps are more likely to become CNA breakpoints.	('HiC', 'Gene', '29969', (98, 101))	('DNA contact points', 'Var', (31, 49))	('HiC', 'Gene', (98, 101))
447589	27831464	The observation that certain genes tend to be mutated in CNA-rich (TP53 and SPOP) or CNA-poor (CTCF and ARID1A) cancers implies that, besides epigenetic factors, the genetic background of the cell influences CNA variation.	('SPOP', 'Gene', '8405', (76, 80))	('CTCF', 'Gene', '10664', (95, 99))	('cancers', 'Phenotype', 'HP:0002664', (112, 119))	('mutated', 'Var', (46, 53))	('CNA-rich', 'Disease', (57, 65))	('cancers', 'Disease', 'MESH:D009369', (112, 119))	('SPOP', 'Gene', (76, 80))	('ARID1A', 'Gene', '8289', (104, 110))	('ARID1A', 'Gene', (104, 110))	('cancers', 'Disease', (112, 119))	('TP53', 'Gene', '7157', (67, 71))	('TP53', 'Gene', (67, 71))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('influences', 'Reg', (197, 207))	('CTCF', 'Gene', (95, 99))
447591	27831464	We identify mutations in genes that are statistically linked to the number of CNAs in cancer patients.	('mutations', 'Var', (12, 21))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('CNAs', 'Disease', (78, 82))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('linked', 'Reg', (54, 60))	('patients', 'Species', '9606', (93, 101))	('cancer', 'Disease', (86, 92))
447602	27831464	Mutations in 62 of these genes are associated with significantly fewer CNAs, whereas one gene (TP53) is associated with a significantly higher number of CNAs (see Supplementary file 1 for the full gene list and Figure 2A for two examples).	('CNAs', 'Disease', (71, 75))	('Mutations', 'Var', (0, 9))	('fewer', 'NegReg', (65, 70))	('TP53', 'Gene', '7157', (95, 99))	('TP53', 'Gene', (95, 99))
447605	27831464	We contemplated whether mutations in the remaining 48 genes contribute to the progression of the cancer or are just a by-product of the increased mutation rates found in cancer cells.	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('cancer', 'Disease', (97, 103))	('cancer', 'Disease', (170, 176))	('contribute', 'Reg', (60, 70))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('mutations', 'Var', (24, 33))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
447606	27831464	Accordingly, we used functional impact scores to estimate the pathogenicity of the mutations found in CONIM genes that had not been previously implicated in cancer progression.	('mutations', 'Var', (83, 92))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('CONIM genes', 'Gene', (102, 113))	('cancer', 'Disease', (157, 163))
447607	27831464	To estimate the temporal order of somatic events, we compared the variant allele fractions (VAFs) of mutations in non-cancer CONIM genes to the VAFs of mutations from equally often mutated genes.	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('non-cancer', 'Disease', (114, 124))	('mutations', 'Var', (101, 110))	('non-cancer', 'Disease', 'MESH:D009369', (114, 124))
447608	27831464	We found that in two out of five cancer types tested, mutations in CONIM genes were associated with a lower VAF (Figure 2:figure supplement 1).	('lower', 'NegReg', (102, 107))	('cancer', 'Disease', (33, 39))	('CONIM genes', 'Gene', (67, 78))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('mutations', 'Var', (54, 63))	('VAF', 'CPA', (108, 111))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))
447609	27831464	To investigate the potential mechanisms through which mutations in genes encoding CONIM proteins affect the amount of CNAs in a tumor, we explored the functions of the CONIM gene set.	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('affect', 'Reg', (97, 103))	('mutations', 'Var', (54, 63))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('CONIM', 'Gene', (82, 87))	('tumor', 'Disease', (128, 133))	('amount of CNAs in a', 'MPA', (108, 127))
447618	27831464	The overlap between the mutated genes found in samples with a differential CNA length and those found in samples with a differential CNA number was larger than expected by chance (p < e-16; chi-square test).	('e-16', 'Gene', (184, 188))	('e-16', 'Gene', '26766', (184, 188))	('differential', 'Var', (62, 74))
447620	27831464	Mutations in components of the SWI/SNF complex have been observed in different tumor types, but their contribution to carcinogenesis is only poorly understood.	('carcinogenesis', 'Disease', (118, 132))	('tumor', 'Disease', (79, 84))	('SWI/SNF', 'Gene', (31, 38))	('observed', 'Reg', (57, 65))	('Mutations', 'Var', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('carcinogenesis', 'Disease', 'MESH:D063646', (118, 132))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
447623	27831464	Instead, we explicitly tested whether epigenetic marks around breakpoints are enriched in those tissues where the breakpoint frequently occurs during cancer development versus those tissues where the breakpoint does not occur.	('tested', 'Reg', (23, 29))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('cancer', 'Disease', (150, 156))	('epigenetic marks', 'Var', (38, 54))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
447627	27831464	We found that non-silent mutations in these genes affect a greater proportion of samples in cancer types (luad, lusc, lihc and skcm) that show a strong H3K9me3 enrichment (> 2-fold change in 10 kb windows around breakpoints; p < 0.05; Mann-Whitney-Wilcoxon test) in their tissue-of-origin (p < e-6; chi-square test).	('mutations', 'Var', (25, 34))	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('affect', 'Reg', (50, 56))	('H3K9me3', 'Protein', (152, 159))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('non-silent mutations', 'Var', (14, 34))
447633	27831464	Mutations in NIPBL have been associated with chromatin decompaction and, indeed, mutations that are predicted to have a more severe effect on NIPBL exhibit a stronger effect on chromatin.	('NIPBL', 'Gene', '25836', (13, 18))	('NIPBL', 'Gene', (13, 18))	('NIPBL', 'Gene', '25836', (142, 147))	('stronger effect', 'PosReg', (158, 173))	('NIPBL', 'Gene', (142, 147))	('chromatin decompaction', 'MPA', (45, 67))	('Mutations', 'Var', (0, 9))	('mutations', 'Var', (81, 90))	('associated', 'Reg', (29, 39))	('chromatin', 'MPA', (177, 186))
447634	27831464	We therefore tested whether mutations in the HEAT domain, which is necessary to target NIPBL to sites of DNA damage, have a stronger effect on CNA number in cancers than do other missense mutations.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('CNA number', 'MPA', (143, 153))	('NIPBL', 'Gene', '25836', (87, 92))	('cancers', 'Disease', 'MESH:D009369', (157, 164))	('NIPBL', 'Gene', (87, 92))	('cancers', 'Phenotype', 'HP:0002664', (157, 164))	('cancers', 'Disease', (157, 164))	('effect', 'Reg', (133, 139))	('mutations', 'Var', (28, 37))
447635	27831464	We also checked whether cancers with truncating mutations in the N-terminus of NIPBL are associated with a significantly lower CNA number as compared to those with truncating mutations in the C-terminus (Figure 5B).	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('NIPBL', 'Gene', '25836', (79, 84))	('CNA number', 'CPA', (127, 137))	('NIPBL', 'Gene', (79, 84))	('lower', 'NegReg', (121, 126))	('cancers', 'Phenotype', 'HP:0002664', (24, 31))	('truncating mutations in', 'Var', (37, 60))	('cancers', 'Disease', 'MESH:D009369', (24, 31))	('cancers', 'Disease', (24, 31))
447636	27831464	In both cases, we observed a significant difference, with mutations that have an anticipated stronger functional or structural impact on NIPBL being associated with fewer CNAs.	('mutations', 'Var', (58, 67))	('CNAs', 'Disease', (171, 175))	('NIPBL', 'Gene', '25836', (137, 142))	('NIPBL', 'Gene', (137, 142))	('fewer', 'NegReg', (165, 170))
447646	27831464	One explanation for this observation could be that mutations in CONIM genes tend to occur late during cancer development.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('mutations', 'Var', (51, 60))	('CONIM genes', 'Gene', (64, 75))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))
447650	27831464	Inactivation of TP53 decreases sensitivity to apoptosis, and therefore more DNA damage (including CNAs) is tolerated.	('decreases', 'NegReg', (21, 30))	('sensitivity to apoptosis', 'MPA', (31, 55))	('TP53', 'Gene', '7157', (16, 20))	('TP53', 'Gene', (16, 20))	('Inactivation', 'Var', (0, 12))
447652	27831464	The CNA-rich group has been associated with recurrent mutations in TP53 and the mutation-rich (and CNA-depleted) group with mutations in ARID1A and CTCF.	('ARID1A', 'Gene', '8289', (137, 143))	('mutations', 'Var', (124, 133))	('ARID1A', 'Gene', (137, 143))	('associated', 'Reg', (28, 38))	('mutations', 'Var', (54, 63))	('CTCF', 'Gene', (148, 152))	('CTCF', 'Gene', '10664', (148, 152))	('TP53', 'Gene', '7157', (67, 71))	('TP53', 'Gene', (67, 71))
447659	27831464	ATM is required for the repair of DNA double-strand breaks in heterochromatic regions, a process which is characterised by slow repair kinetics.	('ATM', 'Gene', (0, 3))	('DNA double-strand breaks', 'Var', (34, 58))	('ATM', 'Gene', '472', (0, 3))
447660	27831464	ATM-mediated phosphorylation of KAP1 (KRAB-associated protein 1) triggers local decondensation of heterochromatin and thereby facilitates efficient repair.	('facilitates', 'PosReg', (126, 137))	('heterochromatin', 'Protein', (98, 113))	('KAP1', 'Gene', (32, 36))	('KRAB-associated protein 1', 'Gene', (38, 63))	('repair', 'MPA', (148, 154))	('local decondensation', 'MPA', (74, 94))	('KAP1', 'Gene', '10155', (32, 36))	('phosphorylation', 'Var', (13, 28))	('ATM', 'Gene', (0, 3))	('KRAB-associated protein 1', 'Gene', '10155', (38, 63))	('ATM', 'Gene', '472', (0, 3))
447663	27831464	These factors are governed by the properties of the tissue-of-origin (which contribute to the variability in the number, length and distribution of CNAs over cancer types) and could be influenced by abnormal activity of epigenetic modifiers through mutation or differential expression (contributing to the variation on the patient-level).	('mutation', 'Var', (249, 257))	('influenced by', 'Reg', (185, 198))	('differential expression', 'Var', (261, 284))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('cancer', 'Disease', (158, 164))	('patient', 'Species', '9606', (323, 330))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
447665	27831464	In accordance with previous studies, we show that TP53 deficiency is strongly associated with high CNA numbers.	('associated', 'Reg', (78, 88))	('TP53', 'Gene', '7157', (50, 54))	('high CNA numbers', 'CPA', (94, 110))	('deficiency', 'Var', (55, 65))	('TP53', 'Gene', (50, 54))
447666	27831464	In summary, our observations suggest that the epigenome impacts CNA occurrence in a tissue- and patient-specific manner.	('epigenome', 'Var', (46, 55))	('CNA', 'Disease', (64, 67))	('patient', 'Species', '9606', (96, 103))	('impacts', 'Reg', (56, 63))
447682	27831464	We computed VAFs as the read count supporting mutation divided by the total read count for each mutation in ucec, hnsc, luad, brca and skcm, as these cancer types had at least 100 mutations in non-cancer CONIM genes (considering genes with at least 15 non-silent mutations), read count information and cancer gene classification available.	('brca', 'Gene', '672', (126, 130))	('cancer', 'Disease', 'MESH:D009369', (197, 203))	('brca', 'Gene', (126, 130))	('mutations', 'Var', (180, 189))	('non-cancer', 'Disease', 'MESH:D009369', (193, 203))	('cancer', 'Phenotype', 'HP:0002664', (302, 308))	('cancer', 'Disease', (197, 203))	('non-cancer', 'Disease', (193, 203))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('cancer', 'Disease', (150, 156))	('cancer', 'Disease', 'MESH:D009369', (302, 308))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('cancer', 'Disease', (302, 308))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
447722	27831464	Since ovarian cancer has frequent TP53 mutations, the question was raised as to whether TP53-mutatant cancers exhibit the same relations between heterochromatin and CNA burden.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('TP53', 'Gene', (34, 38))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('ovarian cancer', 'Phenotype', 'HP:0100615', (6, 20))	('ovarian cancer', 'Disease', 'MESH:D010051', (6, 20))	('mutations', 'Var', (39, 48))	('cancers', 'Disease', 'MESH:D009369', (102, 109))	('TP53', 'Gene', '7157', (88, 92))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))	('cancers', 'Disease', (102, 109))	('TP53', 'Gene', (88, 92))	('ovarian cancer', 'Disease', (6, 20))	('TP53', 'Gene', '7157', (34, 38))
447725	27831464	"The manuscript is improved but the primary result-that 62 genes are associated with decreased CNA rates and only one (TP53) was associated with increased rates-raises the concern that a confounder continues to drive much of the association between mutation rates in specific genes and lack of CNAs.	('mutation', 'Var', (249, 257))	('CNA rates', 'CPA', (95, 104))	('decreased', 'NegReg', (85, 94))	('TP53', 'Gene', '7157', (119, 123))	('TP53', 'Gene', (119, 123))
447737	27831464	We see that in the previous version of the manuscript 1) the motivation was not very well explained, 2) presenting the two pipelines at different positions of the manuscript was confusing and 3) combining the single cancer p-values with the Fisher Method also suppresses cancer type-specific effects.	('cancer', 'Disease', 'MESH:D009369', (216, 222))	('cancer', 'Phenotype', 'HP:0002664', (271, 277))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('suppresses', 'NegReg', (260, 270))	('cancer', 'Disease', 'MESH:D009369', (271, 277))	('cancer', 'Disease', (216, 222))	('p-values', 'Var', (223, 231))	('cancer', 'Disease', (271, 277))
447747	27831464	We agree with the reviewers that ovarian cancer may not show the same behavior like other cancer types due to frequent TP53 mutations and we include a corresponding paragraph in the Discussion section.	('ovarian cancer', 'Disease', 'MESH:D010051', (33, 47))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('mutations', 'Var', (124, 133))	('ovarian cancer', 'Disease', (33, 47))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('ovarian cancer', 'Phenotype', 'HP:0100615', (33, 47))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('TP53', 'Gene', '7157', (119, 123))	('cancer', 'Disease', (90, 96))	('TP53', 'Gene', (119, 123))
447752	27831464	This suggests that even though we have a variation in dependence of the specific algorithmic details or the underlying data, we observe a robust functional enrichment towards epigenetic modifiers and a higher number of genes associated with lower CNA number (with exception of the cancer type-specific pipeline where the second effect is less pronounced).	('cancer', 'Disease', 'MESH:D009369', (281, 287))	('CNA', 'MPA', (247, 250))	('cancer', 'Disease', (281, 287))	('lower', 'NegReg', (241, 246))	('epigenetic', 'Var', (175, 185))	('cancer', 'Phenotype', 'HP:0002664', (281, 287))
447756	27831464	We again observed elevated mutation frequencies in cancer types that correspond to H3K9me3-enriched tissues.	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('mutation', 'Var', (27, 35))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('elevated', 'PosReg', (18, 26))
447757	27831464	Also, we do not filter genes that do not give a signal in single cancer types or those that are also associated with silent mutations.	('cancer', 'Disease', (65, 71))	('silent mutations', 'Var', (117, 133))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))
447761	31313072	WHIM syndrome is usually caused by autosomal dominant mutations in the G protein-coupled chemokine receptor CXCR4 that impair desensitization, resulting in enhanced and prolonged G protein- and beta-arrestin-dependent responses.	('caused', 'Reg', (25, 31))	('impair', 'NegReg', (119, 125))	('WHIM syndrome', 'Disease', 'MESH:C536697', (0, 13))	('chemokine receptor', 'Gene', '7852', (89, 107))	('mutations', 'Var', (54, 63))	('desensitization', 'MPA', (126, 141))	('chemokine receptor', 'Gene', (89, 107))	('enhanced', 'PosReg', (156, 164))	('WHIM syndrome', 'Disease', (0, 13))
447792	31313072	Two siblings from Slovenia who presented with myelokathexis and recurrent infections but not warts or hypogammaglobulinemia were found to have an autosomal recessive loss-of-function (ERK phosphorylation, chemotaxis) mutation in CXCR2, designated p.H323fs329X.	('myelokathexis', 'Disease', (46, 59))	('CXCR2', 'Gene', (229, 234))	('p.H323fs', 'FRAMESHIFT', 'None', (247, 255))	('recurrent infection', 'Phenotype', 'HP:0002719', (64, 83))	('autosomal recessive loss-of-function', 'Disease', 'MESH:D030342', (146, 182))	('ERK', 'Gene', '5594', (184, 187))	('p.H323fs', 'Var', (247, 255))	('hypogammaglobulinemia', 'Disease', 'MESH:D000361', (102, 123))	('infections', 'Disease', 'MESH:D007239', (74, 84))	('myelokathexis', 'Phenotype', 'HP:0031160', (46, 59))	('ERK', 'Gene', (184, 187))	('autosomal recessive loss-of-function', 'Disease', (146, 182))	('recurrent infections', 'Phenotype', 'HP:0002719', (64, 84))	('hypogammaglobulinemia', 'Phenotype', 'HP:0004313', (102, 123))	('infections', 'Disease', (74, 84))	('wart', 'Phenotype', 'HP:0200043', (93, 97))	('hypogammaglobulinemia', 'Disease', (102, 123))	('warts', 'Phenotype', 'HP:0200043', (93, 98))
447796	31313072	The only myelokathexis-associated missense mutation is CXCR4 p.E343K, which involves a single amino acid substitution and a charge change.	('myelokathexis', 'Phenotype', 'HP:0031160', (9, 22))	('p.E343K', 'Var', (61, 68))	('p.E343K', 'Mutation', 'p.E343K', (61, 68))	('myelokathexis-associated', 'Disease', (9, 33))
447799	31313072	Interestingly, acquired CXCR4 WHIM-like mutations, including R334X, also occur in ~28% of cases of Waldenstrom's macroglobulinemia, a plasma cell cancer, and are associated with poorer prognosis and worse treatment responses.	("Waldenstrom's macroglobulinemia", 'Disease', 'MESH:D008258', (99, 130))	("Waldenstrom's macroglobulinemia", 'Disease', (99, 130))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('cancer', 'Disease', (146, 152))	('R334X', 'Mutation', 'rs104893624', (61, 66))	('R334X', 'Var', (61, 66))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	("Waldenstrom's macroglobulinemia", 'Phenotype', 'HP:0005508', (99, 130))
447806	31313072	Where it has been looked for, myelokathexis has almost always been found in patients with germline gain-of-function CXCR4 mutations.	('patients', 'Species', '9606', (76, 84))	('gain-of-function', 'PosReg', (99, 115))	('myelokathexis', 'Disease', (30, 43))	('mutations', 'Var', (122, 131))	('CXCR4', 'Gene', (116, 121))	('myelokathexis', 'Phenotype', 'HP:0031160', (30, 43))
447833	31313072	Approximately 20% of ToF cases in the general population are syndromic, and ~75% of these have 22q11.2 deletion syndrome, caused by mutations in the T-box transcription factor TBX1.	('22q11.2 deletion syndrome', 'Disease', (95, 120))	('TBX1', 'Gene', '6899', (176, 180))	('TBX1', 'Gene', (176, 180))	('mutations', 'Var', (132, 141))	('caused by', 'Reg', (122, 131))	('ToF', 'Disease', (21, 24))
447835	31313072	Interestingly, Cxcl12, Cxcr4 and Ackr3 knockout mice also have cardiovascular defects, as mentioned previously, and Cxcl12 and Cxcr4 knockout mice commonly have ventricular septal defect, which has been reported as a stand-alone cardiovascular phenotype in WHIM patients but also occurs as one of multiple malformations that comprise ToF.	('cardiovascular defects', 'Disease', 'MESH:D002318', (63, 85))	('ventricular septal defect', 'Phenotype', 'HP:0001629', (161, 186))	('Cxcr4 knockout', 'Var', (127, 141))	('multiple malformations', 'Disease', (297, 319))	('Cxcl12', 'Var', (116, 122))	('Ackr3', 'Gene', (33, 38))	('mice', 'Species', '10090', (48, 52))	('Ackr3', 'Gene', '12778', (33, 38))	('septal defect', 'Phenotype', 'HP:0001671', (173, 186))	('mice', 'Species', '10090', (142, 146))	('multiple malformations', 'Disease', 'MESH:D000014', (297, 319))	('cardiovascular defects', 'Disease', (63, 85))	('cardiovascular defects', 'Phenotype', 'HP:0001626', (63, 85))	('ventricular septal defect', 'Disease', 'MESH:D018658', (161, 186))	('patients', 'Species', '9606', (262, 270))	('ventricular septal defect', 'Disease', (161, 186))
447855	31313072	Cohen Syndrome is caused by truncating autosomal recessive mutations in VPS13B (vacuolar protein sorting 13 homolog B) encoding a Golgi protein thought to be involved in intracellular protein glycosylation, sorting and trafficking.	('Cohen Syndrome', 'Disease', (0, 14))	('truncating autosomal', 'Var', (28, 48))	('vacuolar protein sorting 13 homolog B', 'Gene', '157680', (80, 117))	('Cohen Syndrome', 'Disease', 'MESH:C536438', (0, 14))	('VPS13B', 'Gene', (72, 78))	('caused by', 'Reg', (18, 27))	('vacuolar protein sorting 13 homolog B', 'Gene', (80, 117))
447856	31313072	Interestingly, features of myelokathexis and possibly other Cohen syndrome manifestations are phenocopied in border collies with the Trapped Neutrophil Syndrome, which is caused by mutations in the canine homologue of VPS13B.	('myelokathexis', 'Phenotype', 'HP:0031160', (27, 40))	('canine', 'Species', '9615', (198, 204))	('Cohen syndrome', 'Disease', 'MESH:C536438', (60, 74))	('caused by', 'Reg', (171, 180))	('mutations', 'Var', (181, 190))	('Trapped Neutrophil Syndrome', 'Disease', (133, 160))	('myelokathexis', 'Disease', (27, 40))	('VPS13B', 'Gene', (218, 224))	('Cohen syndrome', 'Disease', (60, 74))
447871	31313072	This has been observed for multiple WHIM receptor variants expressed in cell lines using multiple signaling assays, including calcium flux, chemotaxis, Akt/protein kinase B and ERK phosphorylation, and direct G protein activation.	('ERK', 'Gene', '5594', (177, 180))	('protein kinase B', 'Gene', (156, 172))	('calcium flux', 'MPA', (126, 138))	('ERK', 'Gene', (177, 180))	('Akt', 'Gene', (152, 155))	('activation', 'PosReg', (219, 229))	('G protein', 'Protein', (209, 218))	('protein kinase B', 'Gene', '2185', (156, 172))	('calcium', 'Chemical', 'MESH:D002118', (126, 133))	('variants', 'Var', (50, 58))	('Akt', 'Gene', '207', (152, 155))
447872	31313072	Probing this general model mechanistically using phosphosite-specific CXCR4 antibodies, Mueller et al uncovered a hierarchical organization of CXCR4 phosphorylation events which may explain in part how small structural changes from WHIM mutations are leveraged into large functional effects in CXCR4.	('WHIM', 'Gene', (232, 236))	('mutations', 'Var', (237, 246))	('phosphosite', 'Chemical', '-', (49, 60))
447873	31313072	In particular, CXCL12 was found to induce long-lasting GRK2/3-dependent phosphorylation of a serine 346/347 phosphosite which preceded less stable phosphorylation at serine 324/325 and serine 338/339 phosphosites.	('GRK2/3', 'Gene', '156;157', (55, 61))	('CXCL12', 'Var', (15, 21))	('phosphosite', 'Chemical', '-', (200, 211))	('serine 346/347 phosphosite', 'MPA', (93, 119))	('phosphorylation', 'MPA', (72, 87))	('serine', 'Chemical', 'MESH:D012694', (185, 191))	('GRK2/3', 'Gene', (55, 61))	('phosphosite', 'Chemical', '-', (108, 119))	('serine', 'Chemical', 'MESH:D012694', (93, 99))	('serine', 'Chemical', 'MESH:D012694', (166, 172))
447874	31313072	WHIM mutants lacking the serine 346/347 phosphosite as well as the E343K missense WHIM mutant all had impaired phosphorylation at the intact proximal serine 324/325 and serine 338/339 sites and impaired CXCL12-induced receptor internalization.	('E343K', 'Mutation', 'p.E343K', (67, 72))	('CXCL12-induced receptor internalization', 'MPA', (203, 242))	('E343K missense', 'Var', (67, 81))	('lacking', 'NegReg', (13, 20))	('impaired', 'NegReg', (194, 202))	('serine', 'Chemical', 'MESH:D012694', (25, 31))	('impaired', 'NegReg', (102, 110))	('serine 346/347 phosphosite', 'MPA', (25, 51))	('phosphosite', 'Chemical', '-', (40, 51))	('serine', 'Chemical', 'MESH:D012694', (169, 175))	('phosphorylation', 'MPA', (111, 126))	('serine', 'Chemical', 'MESH:D012694', (150, 156))
447875	31313072	Lagane et al have reported that, contrary to the classical model, the S338X WHIM mutation does not abrogate beta-arrestin-2 binding to CXCR4, but instead unexpectedly enhances and prolongs beta-arrestin-2-dependent signaling, which is important for the chemotactic response.	('S338X', 'Mutation', 'rs104893626', (70, 75))	('beta-arrestin-2', 'Gene', (189, 204))	('beta-arrestin-2', 'Gene', '409', (189, 204))	('beta-arrestin-2', 'Gene', (108, 123))	('beta-arrestin-2', 'Gene', '409', (108, 123))	('enhances', 'PosReg', (167, 175))	('S338X', 'Var', (70, 75))	('prolongs', 'NegReg', (180, 188))	('WHIM', 'Gene', (76, 80))
447876	31313072	The SHSK motif in intracellular loop 3 of this WHIM receptor was important for beta arrestin-2-dependent signaling, but not coupling to G proteins, and disrupting it normalized chemotactic signaling.	('disrupting', 'Var', (152, 162))	('beta arrestin-2', 'Gene', (79, 94))	('beta arrestin-2', 'Gene', '409', (79, 94))	('normalized chemotactic signaling', 'MPA', (166, 198))
447880	31313072	The two most common WHIM variants, R334X and S338X, have been tested and shown to have enhanced G protein activation when stimulated with CXCL12, but only in transfection systems.	('S338X', 'Mutation', 'rs104893626', (45, 50))	('R334X', 'Var', (35, 40))	('enhanced', 'PosReg', (87, 95))	('S338X', 'Var', (45, 50))	('G protein', 'Protein', (96, 105))	('activation', 'PosReg', (106, 116))	('R334X', 'Mutation', 'rs104893624', (35, 40))
447891	31313072	Regarding this last point, the mouse model is a knock-in of the second most common human WHIM mutation CXCR4 S338X into mouse Cxcr4 (Table 2).	('mutation CXCR4', 'Var', (94, 108))	('S338X', 'Var', (109, 114))	('mouse', 'Species', '10090', (31, 36))	('CXCR4', 'Var', (103, 108))	('human', 'Species', '9606', (83, 88))	('S338X', 'Mutation', 'rs104893626', (109, 114))	('WHIM', 'Gene', (89, 93))	('mouse', 'Species', '10090', (120, 125))
447893	31313072	The dysmorphic neutrophil features characteristic of myelokathexis have been described in detail in 3 patients with the S338X mutation but are not found in the S338X knock-in mice.	('mice', 'Species', '10090', (175, 179))	('S338X', 'Var', (120, 125))	('dysmorphic neutrophil', 'Disease', (4, 25))	('dysmorphic neutrophil', 'Disease', 'MESH:C564275', (4, 25))	('patients', 'Species', '9606', (102, 110))	('S338X', 'Mutation', 'rs104893626', (160, 165))	('S338X', 'Mutation', 'rs104893626', (120, 125))	('myelokathexis', 'Phenotype', 'HP:0031160', (53, 66))
447916	31313072	In addition, transducing the WHIM allele R334X into human CD34+ progenitor cells enhanced homing to mouse bone marrow from blood compared to cells transduced with wild-type CXCR4.	('R334X', 'Var', (41, 46))	('enhanced', 'PosReg', (81, 89))	('mouse', 'Species', '10090', (100, 105))	('human', 'Species', '9606', (52, 57))	('homing to mouse bone marrow from blood', 'CPA', (90, 128))	('CD34', 'Gene', '947', (58, 62))	('R334X', 'Mutation', 'rs104893624', (41, 46))	('CD34', 'Gene', (58, 62))
447918	31313072	This has been confirmed in wild-type mice, although the provenance of the cells is not settled, with indirect and direct mobilization studies suggesting bone marrow as the most important source and direct imaging studies indicating that plerixafor does not mobilize bone marrow neutrophils but rather increases the ANC by mobilizing neutrophils from the marginal pool of the lung and by inhibiting neutrophil return from blood to bone marrow.	('inhibiting', 'NegReg', (387, 397))	('ANC', 'MPA', (315, 318))	('plerixafor', 'Chemical', 'MESH:C088327', (237, 247))	('neutrophil return from blood to bone marrow', 'MPA', (398, 441))	('increases', 'PosReg', (301, 310))	('mice', 'Species', '10090', (37, 41))	('plerixafor', 'Var', (237, 247))	('mobilizing neutrophils', 'MPA', (322, 344))
447929	31313072	This model is consistent with the discovery of loss-of-function CXCR2 mutations and gain-of-function CXCR4 mutations in myelokathexis patients, as described in the Genetics Section.	('mutations', 'Var', (70, 79))	('mutations', 'Var', (107, 116))	('loss-of-function', 'NegReg', (47, 63))	('CXCR4', 'Gene', (101, 106))	('gain-of-function', 'PosReg', (84, 100))	('CXCR2', 'Gene', (64, 69))	('patients', 'Species', '9606', (134, 142))	('myelokathexis', 'Disease', (120, 133))	('myelokathexis', 'Phenotype', 'HP:0031160', (120, 133))
447945	31313072	Conversely, as suggested previously, this defect could conceivably protect against some non-infectious neutrophil-mediated acute and chronic inflammatory diseases such as chronic obstructive lung disease and may help WHIM patients who develop bronchiectasis from repeated infection, although this has not been studied.	('inflammatory diseases', 'Disease', (141, 162))	('died', 'Disease', (313, 317))	('chronic obstructive lung disease', 'Disease', (171, 203))	('bronchiectasis', 'Disease', (243, 257))	('infection', 'Disease', (272, 281))	('lung disease', 'Phenotype', 'HP:0002088', (191, 203))	('infection', 'Disease', 'MESH:D007239', (272, 281))	('patients', 'Species', '9606', (222, 230))	('obstructive lung disease', 'Phenotype', 'HP:0006536', (179, 203))	('chronic obstructive lung disease', 'Disease', 'MESH:D029424', (171, 203))	('inflammatory diseases', 'Disease', 'MESH:D007249', (141, 162))	('defect', 'Var', (42, 48))	('bronchiectasis', 'Phenotype', 'HP:0002110', (243, 257))	('died', 'Disease', 'MESH:D003643', (313, 317))
447948	31313072	NK cell development is not affected by WHIM mutations; however, circulating NK cell levels are reduced in a subset of WHIM patients.	('circulating NK cell levels', 'MPA', (64, 90))	('WHIM', 'Var', (118, 122))	('patients', 'Species', '9606', (123, 131))	('mutations', 'Var', (44, 53))	('reduced', 'NegReg', (95, 102))
447956	31313072	The circulating levels of T cells may also be reduced in WHIM patients but usually less severely and less consistently than B cells and neutrophils.	('patients', 'Species', '9606', (62, 70))	('reduced', 'NegReg', (46, 53))	('WHIM', 'Var', (57, 61))	('circulating levels', 'MPA', (4, 22))
447966	31313072	Splenectomized wild-type mice given plerixafor have much higher absolute lymphocyte counts in the blood after plerixafor administration than sham-operated mice, suggesting the spleen may be a storage site and not a source for plerixafor-mobilized cells, although there are other possible explanations.	('mice', 'Species', '10090', (25, 29))	('higher', 'PosReg', (57, 63))	('absolute lymphocyte counts in the', 'CPA', (64, 97))	('plerixafor', 'Chemical', 'MESH:C088327', (36, 46))	('plerixafor', 'Var', (36, 46))	('plerixafor', 'Chemical', 'MESH:C088327', (226, 236))	('mice', 'Species', '10090', (155, 159))	('plerixafor', 'Chemical', 'MESH:C088327', (110, 120))
447975	31313072	Consistent with B lymphopenia as a major effect of gain-of-function WHIM mutations, targeted deletion of Cxcr4 in B cells causes premature egress of B cell precursors from bone marrow.	('premature egress', 'MPA', (129, 145))	('Cxcr4', 'Gene', (105, 110))	('WHIM', 'Gene', (68, 72))	('B lymphopenia', 'Phenotype', 'HP:0010976', (16, 29))	('lymphopenia', 'Phenotype', 'HP:0001888', (18, 29))	('B cell precursors', 'CPA', (149, 166))	('B lymphopenia', 'Disease', (16, 29))	('B lymphopenia', 'Disease', 'MESH:D008231', (16, 29))	('deletion', 'Var', (93, 101))	('mutations', 'Var', (73, 82))
447993	31313072	Of note, low-dose, long-term twice daily plerixafor injections in five WHIM patients durably raised the circulating B cell levels in a biphasic manner and reduced infection frequency but had only modest if any effects on immunoglobulin levels.	('patients', 'Species', '9606', (76, 84))	('reduced', 'NegReg', (155, 162))	('raised', 'PosReg', (93, 99))	('circulating B cell levels', 'MPA', (104, 129))	('infection', 'Disease', (163, 172))	('injections', 'Var', (52, 62))	('plerixafor', 'Chemical', 'MESH:C088327', (41, 51))	('infection', 'Disease', 'MESH:D007239', (163, 172))
448012	31313072	In some patients, WHIM T cells appeared to proliferate normally and to produce cytokines in response to mitogenic stimulation or TCR cross-linking with anti-CD3 plus costimulation with anti-CD28.	('produce cytokines', 'MPA', (71, 88))	('CD28', 'Gene', '940', (190, 194))	('response', 'MPA', (92, 100))	('anti-CD3', 'Var', (152, 160))	('proliferate', 'CPA', (43, 54))	('CD28', 'Gene', (190, 194))	('patients', 'Species', '9606', (8, 16))
448023	31313072	CXCL12 signaling in immortalized keratinocytes expressing wild type CXCR4 induced cell motility and survival, whereas cells expressing the S338X WHIM CXCR4 variant became transformed.	('cell motility', 'CPA', (82, 95))	('CXCL12 signaling', 'MPA', (0, 16))	('S338X', 'Mutation', 'rs104893626', (139, 144))	('survival', 'CPA', (100, 108))	('S338X', 'Var', (139, 144))	('induced', 'PosReg', (74, 81))
448059	31313072	Long-term (6 months to ~5 years), open label low-dose twice daily plerixafor administration in 5 patients was associated with durable mobilization responses to blood for most leukocyte subsets tested, lower infection frequency and wart burdens, stabilization of HPV16+ head and neck squamous cell carcinoma in one patient, improved myelokathexis, and improved quality of life.	('myelokathexis', 'CPA', (332, 345))	('improved', 'PosReg', (351, 359))	('plerixafor', 'Chemical', 'MESH:C088327', (66, 76))	('patient', 'Species', '9606', (97, 104))	('quality of life', 'CPA', (360, 375))	('mobilization responses to blood for', 'MPA', (134, 169))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (283, 306))	('neck squamous cell carcinoma', 'Disease', (278, 306))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (278, 306))	('infection', 'Disease', (207, 216))	('infection', 'Disease', 'MESH:D007239', (207, 216))	('lower', 'NegReg', (201, 206))	('wart burdens', 'CPA', (231, 243))	('improved', 'PosReg', (323, 331))	('HPV16+', 'Var', (262, 268))	('HPV16', 'Species', '333760', (262, 267))	('myelokathexis', 'Phenotype', 'HP:0031160', (332, 345))	('patients', 'Species', '9606', (97, 105))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (269, 306))	('wart', 'Phenotype', 'HP:0200043', (231, 235))	('carcinoma', 'Phenotype', 'HP:0030731', (297, 306))	('patient', 'Species', '9606', (314, 321))
448068	31313072	In a phase 1 clinical trial consisting of eight WHIM patients , X4P-001 was well-tolerated and increased the ANC and ALC in a dose-dependent manner.	('ALC', 'Gene', (117, 120))	('ALC', 'Gene', '55821', (117, 120))	('patients', 'Species', '9606', (53, 61))	('ANC', 'MPA', (109, 112))	('X4P-001', 'Var', (64, 71))	('increased', 'PosReg', (95, 104))
448082	31313072	Two observations suggest WHIM allele inactivation may be superior to correction and that WHIM syndrome may be particularly amenable to cure by gene therapy: 1) patient WHIM-09 was cured by spontaneous chromothriptic deletion of the WHIM allele in HSCs (Figure 6), and 2) in an attempt to recapitulate WHIM-09's cure experimentally, Cxcr4+/o HSCs displayed a marked long-term advantage over Cxcr4+/+ and Cxcr4+/WHIM HSCs for supporting blood chimerism after transplantation in the context of both lethally irradiated and non-conditioned congenic recipients.	('supporting blood chimerism', 'CPA', (424, 450))	('WHIM-09', 'Chemical', '-', (168, 175))	('WHIM syndrome', 'Disease', 'MESH:C536697', (89, 102))	('WHIM-09', 'Chemical', '-', (301, 308))	('deletion', 'Var', (216, 224))	('patient', 'Species', '9606', (160, 167))	('advantage', 'PosReg', (375, 384))	('WHIM syndrome', 'Disease', (89, 102))
448097	30444046	Simultaneously, tumor suppressor genes (TSGs) can be inactivated by promoter hypermethylation (Llinas-Arias and Esteller, 2017).	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('promoter hypermethylation', 'Var', (68, 93))	('Llinas-Arias', 'Disease', (95, 107))	('tumor', 'Disease', (16, 21))	('inactivated', 'NegReg', (53, 64))	('Llinas-Arias', 'Disease', 'MESH:D005878', (95, 107))
448098	30444046	CpG island hypermethylation in cancer cells is associated with a decrease in histone active marks: histone H3 and H4 acetylation, H3K4 trimethylation, and gain of repressive marks: H3K9me3 and H3K27me3 (Llinas-Arias and Esteller, 2017).	('H3K27me3', 'Var', (193, 201))	('H3K4', 'Protein', (130, 134))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('hypermethylation', 'Var', (11, 27))	('H3K9me3', 'Protein', (181, 188))	('histone H3', 'Protein', (99, 109))	('Llinas-Arias', 'Disease', 'MESH:D005878', (203, 215))	('gain', 'PosReg', (155, 159))	('histone', 'MPA', (77, 84))	('decrease', 'NegReg', (65, 73))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('repressive', 'MPA', (163, 173))	('cancer', 'Disease', (31, 37))	('Llinas-Arias', 'Disease', (203, 215))
448113	30444046	This KRAB-ZNF is upregulated in bladder cancer, while its knockdown induces apoptosis and reduces the viability of cancer cells in in vitro and in vivo experiments (Kawahara et al., 2016).	('induces', 'Reg', (68, 75))	('cancer', 'Disease', (115, 121))	('bladder cancer', 'Phenotype', 'HP:0009725', (32, 46))	('bladder cancer', 'Disease', 'MESH:D001749', (32, 46))	('bladder cancer', 'Disease', (32, 46))	('upregulated', 'PosReg', (17, 28))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('reduces', 'NegReg', (90, 97))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('cancer', 'Disease', (40, 46))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('ZNF', 'Gene', (10, 13))	('apoptosis', 'CPA', (76, 85))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('knockdown', 'Var', (58, 67))	('ZNF', 'Gene', '284390', (10, 13))
448143	30444046	For breast cancer, we used nine different cell lines representing distinct molecular subtypes: luminal A (MCF7, T47D), luminal B (BT474), basal (BT20, BT549, HS578T, MDA-MB231, MDA-MB468), and HER2 positive (SKBR3).	('T47D', 'CellLine', 'CVCL:0553', (112, 116))	('HER2', 'Gene', (193, 197))	('MDA-MB231', 'CellLine', 'CVCL:0062', (166, 175))	('MDA-MB231', 'Var', (166, 175))	('BT549', 'CellLine', 'CVCL:1092', (151, 156))	('MDA-MB468', 'Var', (177, 186))	('HER2', 'Gene', '2064', (193, 197))	('breast cancer', 'Disease', 'MESH:D001943', (4, 17))	('HS578T', 'CellLine', 'CVCL:0332', (158, 164))	('MDA-MB468', 'CellLine', 'CVCL:0419', (177, 186))	('SKBR3', 'CellLine', 'CVCL:0033', (208, 213))	('breast cancer', 'Phenotype', 'HP:0003002', (4, 17))	('breast cancer', 'Disease', (4, 17))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('MCF7', 'CellLine', 'CVCL:0031', (106, 110))	('BT20', 'Var', (145, 149))	('HS578T', 'Var', (158, 164))
448165	30444046	Interestingly, the majority of the KRAB-ZNFs with an altered mRNA level exhibited reduced expression, while only a small but distinct cluster of 16 KRAB-ZNFs showed upregulation in multiple cancer types (Fig.	('ZNFs', 'Chemical', '-', (40, 44))	('altered', 'Var', (53, 60))	('expression', 'MPA', (90, 100))	('multiple cancer', 'Disease', (181, 196))	('ZNFs', 'Chemical', '-', (153, 157))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('reduced', 'NegReg', (82, 89))	('mRNA level', 'MPA', (61, 71))	('multiple cancer', 'Disease', 'MESH:D009369', (181, 196))	('upregulation', 'PosReg', (165, 177))
448199	30444046	As aberrant splicing is a frequent event in carcinogenesis, we wanted to explore the isoform signature for cancer-associated KRAB-ZNFs in TCGA datasets.	('carcinogenesis', 'Disease', 'MESH:D063646', (44, 58))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('carcinogenesis', 'Disease', (44, 58))	('aberrant splicing', 'Var', (3, 20))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('cancer', 'Disease', (107, 113))	('ZNFs', 'Chemical', '-', (130, 134))
448202	30444046	As expected, we found that a majority of splicing variants (84.5%) were overexpressed in cancer tissues compared to their normal counterparts (Fig.	('splicing variants', 'Var', (41, 58))	('overexpressed', 'PosReg', (72, 85))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('cancer', 'Disease', (89, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
448203	30444046	Out of 490 significant isoforms, 21 variants (4.3%) showed expression only in cancer tissues, 220 variants (44.9%) were strongly overexpressed in cancer compared to normal (>= 2-fold overexpression, with the highest level reaching 652-fold change), and 173 variants (35.3%) showed mild overexpression (FC < 2 and >= 1.2).	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('expression', 'MPA', (59, 69))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('variants', 'Var', (36, 44))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('overexpression', 'PosReg', (286, 300))	('overexpressed', 'PosReg', (129, 142))	('variants', 'Var', (98, 106))
448204	30444046	It is of note that 21 isoforms that fell below the detection threshold in normal samples included mainly truncated and nonsense variants of ZNF695.	('ZNF695', 'Gene', '57116', (140, 146))	('nonsense', 'Var', (119, 127))	('ZNF695', 'Gene', (140, 146))
448209	30444046	ZNF273, the isoform with a 5' partial deletion of the KRAB domain, was switched to three other isoforms, which could be translated to a full-length protein, a variant with a C-terminal partial deletion of the KRAB domain, and a protein devoid of the zinc finger domain.	('ZNF273', 'Gene', (0, 6))	('partial deletion', 'Var', (30, 46))	('ZNF273', 'Gene', '10793', (0, 6))
448214	30444046	Four out of five ZNF273 variants (Fig.	('ZNF273', 'Gene', '10793', (17, 23))	('ZNF273', 'Gene', (17, 23))	('variants', 'Var', (24, 32))
448272	30444046	Finally, our survival analysis indicated that the expression of KRAB-ZNFs may act as a risk factor.	('KRAB-ZNFs', 'Gene', (64, 73))	('ZNFs', 'Chemical', '-', (69, 73))	('expression', 'Var', (50, 60))
448273	30444046	Patients with high expression of five out of 10 analyzed KRAB-ZNFs presented significantly shorter overall survival than those with low expression (Fig.	('ZNFs', 'Chemical', '-', (62, 66))	('overall survival', 'MPA', (99, 115))	('Patients', 'Species', '9606', (0, 8))	('high expression', 'Var', (14, 29))	('KRAB-ZNFs', 'Gene', (57, 66))	('shorter', 'NegReg', (91, 98))
448275	30444046	In contrast, high expression was associated with better prognosis in the case of ZNF205 (P < 0.001, hazard ratio = 0.5), ZNF707 (P = 0.001, hazard ratio = 0.5), and ZNF789 (P = 0.017, hazard ratio = 0.5) (Fig.	('ZNF205', 'Gene', (81, 87))	('high', 'Var', (13, 17))	('ZNF707', 'Gene', '286075', (121, 127))	('ZNF789', 'Gene', (165, 171))	('ZNF789', 'Gene', '285989', (165, 171))	('better', 'PosReg', (49, 55))	('ZNF205', 'Gene', '7755', (81, 87))	('ZNF707', 'Gene', (121, 127))
448290	30444046	We observed that the majority of variants was detected both in normal and cancer tissues, but as expected, they had a higher level in tumors.	('tumors', 'Disease', (134, 140))	('tumors', 'Disease', 'MESH:D009369', (134, 140))	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('cancer', 'Disease', (74, 80))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('variants', 'Var', (33, 41))
448291	30444046	The differential expression of KRAB-ZNF splicing isoforms in cancer was reported only by Juarez-Mendez and colleagues (Juarez-Mendez et al., 2013), who demonstrated a specific increase of ZNF695 variants in ovarian cancer compared to normal cells.	('ZNF', 'Gene', (36, 39))	('variants', 'Var', (195, 203))	('increase', 'PosReg', (176, 184))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('cancer', 'Disease', (215, 221))	('cancer', 'Disease', 'MESH:D009369', (215, 221))	('ovarian cancer', 'Disease', (207, 221))	('cancer', 'Disease', (61, 67))	('ZNF', 'Gene', (188, 191))	('ZNF', 'Gene', '284390', (36, 39))	('ZNF695', 'Gene', '57116', (188, 194))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('ZNF', 'Gene', '284390', (188, 191))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('ovarian cancer', 'Disease', 'MESH:D010051', (207, 221))	('ovarian cancer', 'Phenotype', 'HP:0100615', (207, 221))	('ZNF695', 'Gene', (188, 194))
448302	30444046	Furthermore, we have previously shown that ZNF695 was upregulated in pluripotent stem cells compared to more specialized cell types, whereas its knockdown resulted in the loss of self-renewal properties and differentiation of pluripotent stem cells (Oleksiewicz et al., 2017).	('ZNF695', 'Gene', '57116', (43, 49))	('knockdown', 'Var', (145, 154))	('upregulated', 'PosReg', (54, 65))	('self-renewal properties', 'CPA', (179, 202))	('differentiation', 'CPA', (207, 222))	('ZNF695', 'Gene', (43, 49))	('loss', 'NegReg', (171, 175))
448325	29703234	In addition, OSCC patients with expression of TRAF6 showed a trend towards poorer cancer-specific survival when compared with patients without TRAF6 expression.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('TRAF6', 'Gene', (46, 51))	('expression', 'Var', (32, 42))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('OSCC', 'Disease', (13, 17))	('patients', 'Species', '9606', (126, 134))	('patients', 'Species', '9606', (18, 26))	('poorer', 'NegReg', (75, 81))
448334	29703234	In general, ubiquitins are conjugated via a lysine residue at position 48 to target proteins for degradation.	('lysine', 'Var', (44, 50))	('degradation', 'MPA', (97, 108))	('lysine', 'Chemical', 'MESH:D008239', (44, 50))	('proteins', 'Protein', (84, 92))	('ubiquitins', 'Protein', (12, 22))
448335	29703234	Whereas for proteins tagged with lysine 63 (K63)-linked polyubiquitin chains of ubiquitin, instead of being targeted for proteasomal degradation, they alter protein function or localization and thereby regulate signaling activation including receptor endocytosis, protein trafficking, kinase activity and DNA repair.	('kinase activity', 'MPA', (285, 300))	('signaling activation', 'MPA', (211, 231))	('DNA repair', 'MPA', (305, 315))	('protein function', 'MPA', (157, 173))	('protein trafficking', 'MPA', (264, 283))	('lysine', 'Chemical', 'MESH:D008239', (33, 39))	('regulate', 'Reg', (202, 210))	('alter', 'Reg', (151, 156))	('localization', 'MPA', (177, 189))	('lysine 63 (K63)-linked', 'Var', (33, 55))	('receptor endocytosis', 'MPA', (242, 262))
448337	29703234	This polyubiquitination promotes membrane recruitment of PKB/Akt and its phosphorylation and activation upon growth factor stimulation.	('membrane recruitment', 'MPA', (33, 53))	('PKB', 'Gene', (57, 60))	('PKB', 'Gene', '207;11651', (57, 60))	('Akt', 'Gene', '207', (61, 64))	('Akt', 'Gene', (61, 64))	('promotes', 'PosReg', (24, 32))	('activation', 'MPA', (93, 103))	('polyubiquitination', 'Var', (5, 23))	('phosphorylation', 'MPA', (73, 88))
448365	29703234	We used TransIT-X2 transfection reagent (Mirus Bio Corporation, Madison, WI) to transfect ATG5 shRNA into SAS cells.	('ATG5', 'Gene', (90, 94))	('ATG5', 'Gene', '9474', (90, 94))	('transfect', 'Var', (80, 89))
448420	29703234	As shown in Additional file 2: Figure S1d, Akt ubiquitination was significantly decreased by TRAF6 shRNA.	('Akt', 'Gene', (43, 46))	('Akt', 'Gene', '207', (43, 46))	('decreased', 'NegReg', (80, 89))	('TRAF6 shRNA', 'Var', (93, 104))
448431	29703234	Compared with control shRNA, SAS cells transfected with TRAF6 shRNAs had decreased Akt, mTOR and p65 phosphorylation levels compared to control shRNA.	('p65', 'Gene', '5970', (97, 100))	('TRAF6', 'Var', (56, 61))	('decreased', 'NegReg', (73, 82))	('Akt', 'Gene', (83, 86))	('mTOR', 'Gene', (88, 92))	('mTOR', 'Gene', '2475', (88, 92))	('Akt', 'Gene', '207', (83, 86))	('p65', 'Gene', (97, 100))
448432	29703234	We next evaluated the anti-tumor growth effect of TRAF6 shRNAs in vivo.	('tumor', 'Disease', (27, 32))	('TRAF6', 'Var', (50, 55))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))
448436	29703234	The tumor volume and tumor weight were reduced in the TRAF6 shRNA groups compared with the control groups (Fig.	('tumor', 'Disease', (4, 9))	('tumor', 'Disease', (21, 26))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('reduced', 'NegReg', (39, 46))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('TRAF6 shRNA', 'Var', (54, 65))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
448437	29703234	In tumor tissues, the expression levels of TRAF6, p-Akt, p-mTOR and p-p65 proteins were decreased in the TRAF6 shRNA groups compared with the control groups (Fig.	('tumor', 'Phenotype', 'HP:0002664', (3, 8))	('tumor', 'Disease', (3, 8))	('Akt', 'Gene', (52, 55))	('p65', 'Gene', '5970', (70, 73))	('Akt', 'Gene', '207', (52, 55))	('decreased', 'NegReg', (88, 97))	('expression levels', 'MPA', (22, 39))	('tumor', 'Disease', 'MESH:D009369', (3, 8))	('mTOR', 'Gene', '2475', (59, 63))	('TRAF6 shRNA', 'Var', (105, 116))	('p65', 'Gene', (70, 73))	('mTOR', 'Gene', (59, 63))
448439	29703234	The tumors in the TRAF6 shRNA groups were composed of cells with a lower nucleus to cytoplasm ratios than the controls.	('TRAF6', 'Var', (18, 23))	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('tumors', 'Disease', (4, 10))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('lower', 'NegReg', (67, 72))
448441	29703234	TRAF6 expression was decreased in tumors from mice from the TRAF6 shRNA groups compared with the control (Fig.	('tumors', 'Disease', (34, 40))	('tumors', 'Disease', 'MESH:D009369', (34, 40))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('decreased', 'NegReg', (21, 30))	('expression', 'MPA', (6, 16))	('mice', 'Species', '10090', (46, 50))	('TRAF6', 'Var', (60, 65))	('TRAF6', 'Gene', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
448457	29703234	In an analysis using both expression of TRAF6 and differentiation grade as predictor groups of CSS, patients with expression of TRAF6 and moderate/poor differentiation had the worst survival when compared with the other groups (p = 0.033, Fig.	('worst', 'NegReg', (176, 181))	('CSS', 'Disease', (95, 98))	('TRAF6', 'Var', (128, 133))	('CSS', 'Chemical', '-', (95, 98))	('patients', 'Species', '9606', (100, 108))
448469	29703234	As indicated in our previous study, TRAF6 could serve as a direct E3 ligase for K63-linked ubiquitination of oncogenic Akt, leading to its membrane recruitment and phosphorylation in cells treated with insulin-like growth factor-1 (IGF-1).	('insulin-like growth factor-1', 'Gene', (202, 230))	('K63-linked', 'Var', (80, 90))	('phosphorylation', 'MPA', (164, 179))	('Akt', 'Gene', '207', (119, 122))	('insulin-like growth factor-1', 'Gene', '3479', (202, 230))	('IGF-1', 'Gene', (232, 237))	('IGF-1', 'Gene', '3479', (232, 237))	('oncogenic', 'Gene', (109, 118))	('Akt', 'Gene', (119, 122))	('membrane recruitment', 'MPA', (139, 159))
448483	29703234	In the current study, transfection of TRAF6 shRNA resulted in decreased NF-kappaB/Akt activation, increased autophagy and reduced viability of SAS cells compared with control shRNA (Figs.	('viability', 'CPA', (130, 139))	('decreased', 'NegReg', (62, 71))	('Akt', 'Gene', '207', (82, 85))	('transfection', 'Var', (22, 34))	('autophagy', 'CPA', (108, 117))	('NF-kappaB', 'Gene', '4790', (72, 81))	('increased', 'PosReg', (98, 107))	('NF-kappaB', 'Gene', (72, 81))	('Akt', 'Gene', (82, 85))	('activation', 'PosReg', (86, 96))	('reduced', 'NegReg', (122, 129))	('TRAF6', 'Var', (38, 43))
448486	29703234	also found that high TRAF6 expression levels had significantly poorer survival when compared with those with low levels (P < 0.05) in 135 patients with colon cancer.	('TRAF6', 'Gene', (21, 26))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('survival', 'MPA', (70, 78))	('colon cancer', 'Disease', (152, 164))	('expression levels', 'MPA', (27, 44))	('high', 'Var', (16, 20))	('poorer', 'NegReg', (63, 69))	('colon cancer', 'Phenotype', 'HP:0003003', (152, 164))	('patients', 'Species', '9606', (138, 146))	('colon cancer', 'Disease', 'MESH:D015179', (152, 164))
448507	29057889	The numbers of tumor driver mutations are differentiated (p < 0.05) over the racial groups in five cancers, such as lung adenocarcinoma.	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (116, 135))	('cancers', 'Disease', 'MESH:D009369', (99, 106))	('cancers', 'Phenotype', 'HP:0002664', (99, 106))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('cancers', 'Disease', (99, 106))	('tumor', 'Disease', (15, 20))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('lung adenocarcinoma', 'Disease', (116, 135))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (116, 135))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('mutations', 'Var', (28, 37))
448508	29057889	By treating a specific cancer type and a racial group as an "experimental unit", driver mutation numbers demonstrate a significant (r = 0.46, p < 0.002) positive correlation with cancer incidence rates, especially when the five cancers with mutational disparities are exclusively focused (r = 0.88, p < 0.00002).	('cancers', 'Phenotype', 'HP:0002664', (228, 235))	('mutation', 'Var', (88, 96))	('cancer', 'Disease', (228, 234))	('cancers', 'Disease', (228, 235))	('cancers', 'Disease', 'MESH:D009369', (228, 235))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('cancer', 'Disease', (23, 29))	('cancer', 'Disease', 'MESH:D009369', (23, 29))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('cancer', 'Disease', (179, 185))	('cancer', 'Disease', 'MESH:D009369', (228, 234))
448516	29057889	reported that racial differences in TP53 mutation, PAM50 basal subtype and triple-negative tumor prevalence influence the magnitude and significance of racial disparity in tumor recurrence of breast cancer.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('breast cancer', 'Disease', 'MESH:D001943', (192, 205))	('tumor', 'Disease', (91, 96))	('tumor', 'Disease', (172, 177))	('breast cancer', 'Disease', (192, 205))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('TP53', 'Gene', '7157', (36, 40))	('breast cancer', 'Phenotype', 'HP:0003002', (192, 205))	('mutation', 'Var', (41, 49))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('TP53', 'Gene', (36, 40))	('influence', 'Reg', (108, 117))
448518	29057889	They further found that a novel deletion of the LSAMP locus, as a prevalent genomic alteration in AA CaP, was associated with rapid disease progression.	('associated with', 'Reg', (110, 125))	('deletion', 'Var', (32, 40))	('LSAMP', 'Gene', (48, 53))	('LSAMP', 'Gene', '4045', (48, 53))
448555	29057889	As shown in Table 2, racial disparities (p < 0.05) are observed in five cancer types regarding the mutations present in the pcDriver genes.	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('mutations', 'Var', (99, 108))	('pcDriver', 'Gene', (124, 132))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('cancer', 'Disease', (72, 78))
448558	29057889	On the other hand, white patients suffer more mutations than black patients for UCEC and KIRP.	('mutations', 'Var', (46, 55))	('patients', 'Species', '9606', (67, 75))	('UCEC', 'Disease', (80, 84))	('suffer', 'Reg', (34, 40))	('patients', 'Species', '9606', (25, 33))	('KIRP', 'Disease', (89, 93))
448564	29057889	The association between cancer incidence rate and the number of mutations in the pan-cancer driver (pcDriver) genes or the log2 transformed number of mutations in the HOGO genes is estimated by the Pearson correlation (r).	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('pcDriver', 'Gene', (100, 108))	('cancer', 'Disease', (85, 91))	('cancer', 'Disease', (24, 30))	('cancer', 'Disease', 'MESH:D009369', (24, 30))	('mutations', 'Var', (64, 73))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
448567	29057889	3) largely confirm the positive association between cancer incidence and mutation burden observed in AS-1.	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('mutation', 'Var', (73, 81))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('cancer', 'Disease', (52, 58))
448574	29057889	In this regard, the number of mutations in pcDriver genes in a tumor should be considered as an estimate (or a representative metric) of its driver mutation burden.	('tumor', 'Disease', (63, 68))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('mutations', 'Var', (30, 39))	('pcDriver genes', 'Gene', (43, 57))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
448575	29057889	Of the total 33400 non-synonymous pcDriver gene mutations in all 4839 tumor samples analyzed in this study, 29623 (amounting to 88.7%) are single nucleotide variations (SNVs).	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('pcDriver gene', 'Gene', (34, 47))	('tumor', 'Disease', (70, 75))	('29623', 'Var', (108, 113))	('single nucleotide variations', 'Var', (139, 167))	('mutations', 'Var', (48, 57))
448579	29057889	The mutations not occurring in cancer driver genes are typically known as passenger mutations.	('mutations', 'Var', (4, 13))	('cancer', 'Disease', (31, 37))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))
448588	29057889	In this study, we found that the numbers of tumor driver mutations are differentiated (p < 0.05) over the racial groups in five cancers.	('cancers', 'Disease', 'MESH:D009369', (128, 135))	('cancers', 'Phenotype', 'HP:0002664', (128, 135))	('cancers', 'Disease', (128, 135))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('mutations', 'Var', (57, 66))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumor', 'Disease', (44, 49))
448594	29057889	This association seems to deviate from the well-known perception that relates cancer incidence rate to the total number of (driver) mutations that can be accumulated in a tissue during the lifespan of a person.	('mutations', 'Var', (132, 141))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('person', 'Species', '9606', (203, 209))
448596	29057889	A potential explanation for the paradox is that: the requirement for driver mutations to develop cancer in a tissue with a large population of stem cells (and/or being readily subject to mutagens) could be relatively high but the precancerous cells meeting the threshold in such a tissue still outnumber the precancerous cells in a "smaller" (and/or "safe") tissue.	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('mutations', 'Var', (76, 85))	('cancer', 'Disease', (97, 103))	('cancer', 'Disease', (311, 317))	('cancer', 'Disease', 'MESH:D009369', (311, 317))	('cancer', 'Disease', (233, 239))	('cancer', 'Disease', 'MESH:D009369', (233, 239))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('cancer', 'Phenotype', 'HP:0002664', (311, 317))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
448621	27285985	The mechanism underlying radiation-induced cell death includes the induction of apoptosis, and recent studies have revealed that micro (mi)RNAs (miRs) may post-transcriptionally increase or decrease the expression of stress response genes that control cell survival and apoptosis.	('decrease', 'NegReg', (190, 198))	('stress', 'MPA', (217, 223))	('expression', 'MPA', (203, 213))	('miR', 'Gene', '220972', (145, 148))	('increase', 'PosReg', (178, 186))	('miR', 'Gene', (145, 148))	('micro (mi)RNAs', 'Var', (129, 143))
448637	27285985	Images of the apoptosis array (Figure 1) revealed that apoptosis-related proteins, namely p21, p53 (phosphorylated at S15, S46, or S392), TNF RI, FADD, cIAP-1, HIF-1alpha, and TRAIL R1, exhibited different expression levels in the irradiated OC3 cells pretreated with miR-17-5p AS ODN and the cells treated with control ODN (Figure 1B).	('TNF RI', 'Gene', '7132', (138, 144))	('TRAIL R1', 'Gene', (176, 184))	('FADD', 'Gene', '8772', (146, 150))	('S392', 'Var', (131, 135))	('p21', 'Gene', '1026', (90, 93))	('expression levels', 'MPA', (206, 223))	('S46', 'Var', (123, 126))	('p53', 'Gene', (95, 98))	('cIAP-1', 'Gene', (152, 158))	('HIF-1alpha', 'Gene', '3091', (160, 170))	('cIAP-1', 'Gene', '329', (152, 158))	('FADD', 'Gene', (146, 150))	('ODN', 'Chemical', '-', (320, 323))	('apoptosis-related', 'Gene', (55, 72))	('TRAIL R1', 'Gene', '8797', (176, 184))	('ODN', 'Chemical', '-', (281, 284))	('p21', 'Gene', (90, 93))	('miR-17-5p', 'Gene', '406952', (268, 277))	('miR-17-5p', 'Gene', (268, 277))	('TNF RI', 'Gene', (138, 144))	('HIF-1alpha', 'Gene', (160, 170))
448641	27285985	The ratios were 1.54 +- 0.12, 5.9 +- 0.21, and 3.04 +- 0.13 for p21, p-p53-S15, and p-p53-S46, respectively.	('p-p53-S46', 'Var', (84, 93))	('p21', 'Gene', '1026', (64, 67))	('p-p53-S15', 'Var', (69, 78))	('p21', 'Gene', (64, 67))
448642	27285985	Furthermore, for p-p53-S392, TNF RI, and FADD, the ratios were 7.37 +- 0.14, 1.5 +- 0.12, and 1.69 +- 0.13, respectively.	('p-p53-S392', 'Var', (17, 27))	('FADD', 'Gene', (41, 45))	('FADD', 'Gene', '8772', (41, 45))	('TNF RI', 'Gene', '7132', (29, 35))	('TNF RI', 'Gene', (29, 35))
448644	27285985	We further confirmed the expression of p21, p-p53 (phosphorylated at S15, S46, and S392), TNF RI, FADD, cIAP-1, HIF-1alpha, and TRAIL R1 in irradiated OC3 cells through Western blotting (Figure 3).	('p-p53', 'Var', (44, 49))	('FADD', 'Gene', (98, 102))	('HIF-1alpha', 'Gene', '3091', (112, 122))	('cIAP-1', 'Gene', '329', (104, 110))	('TNF RI', 'Gene', '7132', (90, 96))	('S46', 'Var', (74, 77))	('S392', 'Var', (83, 87))	('cIAP-1', 'Gene', (104, 110))	('TRAIL R1', 'Gene', (128, 136))	('HIF-1alpha', 'Gene', (112, 122))	('TNF RI', 'Gene', (90, 96))	('p21', 'Gene', '1026', (39, 42))	('p21', 'Gene', (39, 42))	('TRAIL R1', 'Gene', '8797', (128, 136))	('FADD', 'Gene', '8772', (98, 102))
448646	27285985	Because miR-17-5p downregulated p-p53 (phosphorylated at S15, S46, and S392) in the OC3 cells, we further determined the effect of p53 on irradiated OC3 cells.	('S392', 'Var', (71, 75))	('downregulated', 'NegReg', (18, 31))	('S46', 'Var', (62, 65))	('miR-17-5p', 'Gene', '406952', (8, 17))	('miR-17-5p', 'Gene', (8, 17))	('p-p53', 'Protein', (32, 37))
448648	27285985	While treated with mir-17-5p AS ODN to irradiated p53 expressing cells, the effect of p53 on cell cycle arrest was significantly enhanced (Figure 4).	('enhanced', 'PosReg', (129, 137))	('mir-17', 'Gene', '406952', (19, 25))	('cell cycle arrest', 'CPA', (93, 110))	('-17-5p', 'Chemical', '-', (22, 28))	('mir-17', 'Gene', (19, 25))	('p53', 'Var', (86, 89))	('ODN', 'Chemical', '-', (32, 35))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (93, 110))
448671	27285985	In the present work, miR-17-5p downregulated the expression of p21, p-p53 (phosphorylated at S15, S46, and S392), TNF RI, and FADD, which might play roles in the radiosensitivity of irradiated tumor cells.	('p-p53', 'Var', (68, 73))	('FADD', 'Gene', '8772', (126, 130))	('miR-17-5p', 'Gene', '406952', (21, 30))	('p21', 'Gene', (63, 66))	('FADD', 'Gene', (126, 130))	('TNF RI', 'Gene', '7132', (114, 120))	('miR-17-5p', 'Gene', (21, 30))	('expression', 'MPA', (49, 59))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('downregulated', 'NegReg', (31, 44))	('S392', 'Var', (107, 111))	('TNF RI', 'Gene', (114, 120))	('tumor', 'Disease', (193, 198))	('p21', 'Gene', '1026', (63, 66))
448672	27285985	reported that the phosphorylation of p53 could result in increased radiosensitivity and the inhibition of tumor reproduction.	('inhibition', 'NegReg', (92, 102))	('p53', 'Protein', (37, 40))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('radiosensitivity', 'CPA', (67, 83))	('increased radiosensitivity', 'Phenotype', 'HP:0010997', (57, 83))	('increased', 'PosReg', (57, 66))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('phosphorylation', 'Var', (18, 33))	('tumor', 'Disease', (106, 111))
448674	27285985	DNA damage induces phosphorylation of p53 at S15, S20 and S37, reducing its interaction with the oncoprotein MDM2.	('phosphorylation', 'MPA', (19, 34))	('oncoprotein MDM2', 'Gene', '4193', (97, 113))	('interaction', 'Interaction', (76, 87))	('reducing', 'NegReg', (63, 71))	('S37', 'Var', (58, 61))	('oncoprotein MDM2', 'Gene', (97, 113))	('S15', 'Var', (45, 48))	('S20', 'Var', (50, 53))	('p53', 'Protein', (38, 41))
448675	27285985	The phosphorylation by cdk-activating kinase at S392 is increased in human tumors and has been reported to influence the growth suppressor function, DNA binding and transcriptional activation of p53.	('p53', 'Gene', (195, 198))	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('growth suppressor function', 'CPA', (121, 147))	('increased', 'PosReg', (56, 65))	('phosphorylation', 'MPA', (4, 19))	('human', 'Species', '9606', (69, 74))	('DNA binding', 'Interaction', (149, 160))	('at S392', 'Var', (45, 52))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('influence', 'Reg', (107, 116))	('transcriptional activation', 'MPA', (165, 191))	('tumors', 'Disease', (75, 81))
448684	27285985	MR-17-5p upregulates the expression of cIAP1, HIF-1alpha, and TRAIL R1, which might play roles in the radioresistance of irradiated tumor cells.	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('upregulates', 'PosReg', (9, 20))	('MR-17-5p', 'Var', (0, 8))	('expression', 'MPA', (25, 35))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('TRAIL R1', 'Gene', (62, 70))	('-17-5p', 'Chemical', '-', (2, 8))	('HIF-1alpha', 'Gene', (46, 56))	('cIAP1', 'Gene', (39, 44))	('tumor', 'Disease', (132, 137))	('TRAIL R1', 'Gene', '8797', (62, 70))	('cIAP1', 'Gene', '329', (39, 44))	('HIF-1alpha', 'Gene', '3091', (46, 56))
448685	27285985	The overexpression of the antiapoptotic protein, cIAP1, caused by its genetic amplification was reported in certain cancers, such as hepatocellular carcinoma, esophageal squamous cell carcinoma, cervical cancer, and lung cancer, and this factor conferred resistance to chemotherapy and RT.	('carcinoma', 'Phenotype', 'HP:0030731', (184, 193))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (133, 157))	('lung cancer', 'Disease', 'MESH:D008175', (216, 227))	('genetic amplification', 'Var', (70, 91))	('cIAP1', 'Gene', (49, 54))	('lung cancer', 'Phenotype', 'HP:0100526', (216, 227))	('cancers', 'Disease', 'MESH:D009369', (116, 123))	('overexpression', 'PosReg', (4, 18))	('esophageal squamous cell carcinoma', 'Disease', (159, 193))	('hepatocellular carcinoma', 'Disease', (133, 157))	('carcinoma', 'Phenotype', 'HP:0030731', (148, 157))	('cIAP1', 'Gene', '329', (49, 54))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cervical cancer', 'Disease', (195, 210))	('cervical cancer', 'Disease', 'MESH:D002583', (195, 210))	('lung cancer', 'Disease', (216, 227))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (159, 193))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (170, 193))	('cancers', 'Phenotype', 'HP:0002664', (116, 123))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (133, 157))	('cancers', 'Disease', (116, 123))
448687	27285985	demonstrated that some cervical cancer cell lines showed amplification and a consistent overexpression of cIAP1 as well as significant resistance to radiation-induced cell death compared with the cell lines showing no cIAP1 amplification.	('cIAP1', 'Gene', (106, 111))	('cIAP1', 'Gene', '329', (106, 111))	('overexpression', 'PosReg', (88, 102))	('cervical cancer', 'Disease', 'MESH:D002583', (23, 38))	('cervical cancer', 'Disease', (23, 38))	('amplification', 'Var', (57, 70))	('resistance', 'CPA', (135, 145))	('cIAP1', 'Gene', (218, 223))	('cIAP1', 'Gene', '329', (218, 223))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))
448714	27285985	investigated the radiosensitization effect of MLN4924, an SKP1, Cullins, and F-box protein E3 ubiquitin ligase substrate inhibitor, which is known to stimulate growth arrest, apoptosis, and the DNA-damage response; they observed that MLN4924 is a potent radiosensitizing target of breast cancer in the SK-BR-3 breast cancer cell line.	('cancer', 'Phenotype', 'HP:0002664', (288, 294))	('MLN4924', 'Var', (234, 241))	('growth arrest', 'Disease', 'MESH:D006323', (160, 173))	('breast cancer', 'Disease', (281, 294))	('growth arrest', 'Disease', (160, 173))	('SKP1', 'Gene', (58, 62))	('breast cancer', 'Phenotype', 'HP:0003002', (281, 294))	('apoptosis', 'CPA', (175, 184))	('growth arrest', 'Phenotype', 'HP:0001510', (160, 173))	('MLN4924', 'Var', (46, 53))	('cancer', 'Phenotype', 'HP:0002664', (317, 323))	('breast cancer', 'Disease', 'MESH:D001943', (310, 323))	('SKP1', 'Gene', '6500', (58, 62))	('breast cancer', 'Disease', (310, 323))	('SK-BR-3', 'CellLine', 'CVCL:0033', (302, 309))	('breast cancer', 'Phenotype', 'HP:0003002', (310, 323))	('breast cancer', 'Disease', 'MESH:D001943', (281, 294))
448715	27285985	Moreover, in MCF7 cells, p21 was overexpressed in the MLN4924 treatment plus radiation group but not in the single-treatment group.	('p21', 'Gene', (25, 28))	('MLN4924 treatment', 'Var', (54, 71))	('overexpressed', 'PosReg', (33, 46))	('MCF7', 'CellLine', 'CVCL:0031', (13, 17))	('p21', 'Gene', '1026', (25, 28))
448716	27285985	also evaluated the role of p21 by using small interfering RNA, and their results revealed that p21 knockdown partially inhibited MLN4924-induced G2/M arrest and radiosensitization.	('M arrest', 'Disease', 'MESH:D006323', (148, 156))	('radiosensitization', 'CPA', (161, 179))	('p21', 'Gene', (27, 30))	('M arrest', 'Disease', (148, 156))	('p21', 'Gene', '1026', (27, 30))	('p21', 'Gene', '1026', (95, 98))	('inhibited', 'NegReg', (119, 128))	('MLN4924-induced', 'Var', (129, 144))	('p21', 'Gene', (95, 98))
448731	27285985	Our finding from animal study revealed that microRNA-17-5p AS ODN therapy enhanced the radiosensitivity of OC-3 tumor growth, suggesting that miR-17-5p AS ODN therapy may be a strategy for betel nut chewing-associated oral cancer.	('-17-5p', 'Chemical', '-', (52, 58))	('oral cancer', 'Disease', (218, 229))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('miR-17-5p', 'Gene', '406952', (142, 151))	('microRNA-17-5p', 'Var', (44, 58))	('-17-5p', 'Chemical', '-', (145, 151))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('ODN', 'Chemical', '-', (62, 65))	('nut', 'Gene', '256646', (195, 198))	('miR-17-5p', 'Gene', (142, 151))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('ODN', 'Chemical', '-', (155, 158))	('tumor', 'Disease', (112, 117))	('nut', 'Gene', (195, 198))	('enhanced', 'PosReg', (74, 82))	('oral cancer', 'Disease', 'MESH:D009062', (218, 229))
448746	27285985	Antibodies to p21, p-p53 (phosphorylated at S15, S46, and S392), tumor necrosis factor receptor I (TNF RI), Fas-associated death domain protein (FADD), cellular inhibitor of apoptosis protein 1 (cIAP-1), hypoxia-inducible factor (HIF)-1alpha, and TNF-related apoptosis-inducing ligand receptor 1 (TRAIL R1) were purchased from R&D Systems.	('p21', 'Gene', '1026', (14, 17))	('cellular inhibitor of apoptosis protein 1', 'Gene', (152, 193))	('Fas-associated death domain protein', 'Gene', '8772', (108, 143))	('p-p53', 'Var', (19, 24))	('tumor necrosis factor receptor I', 'Gene', (65, 97))	('cellular inhibitor of apoptosis protein 1', 'Gene', '329', (152, 193))	('S392', 'Var', (58, 62))	('FADD', 'Gene', '8772', (145, 149))	('TNF-related apoptosis-inducing ligand receptor 1', 'Gene', '8797', (247, 295))	('p21', 'Gene', (14, 17))	('TRAIL R1', 'Gene', '8797', (297, 305))	('hypoxia-inducible factor (HIF)-1alpha', 'Gene', '3091', (204, 241))	('Fas-associated death domain protein', 'Gene', (108, 143))	('tumor necrosis factor receptor I', 'Gene', '7132', (65, 97))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('TNF RI', 'Gene', (99, 105))	('cIAP-1', 'Gene', (195, 201))	('cIAP-1', 'Gene', '329', (195, 201))	('FADD', 'Gene', (145, 149))	('TNF-related apoptosis-inducing ligand receptor 1', 'Gene', (247, 295))	('TNF RI', 'Gene', '7132', (99, 105))	('TRAIL R1', 'Gene', (297, 305))
448767	33712556	Preclinical small molecule WEHI-7326 overcomes drug resistance and elicits response in patient-derived xenograft models of human treatment-refractory tumors Targeting cell division by chemotherapy is a highly effective strategy to treat a wide range of cancers.	('WEHI-7326', 'Var', (27, 36))	('overcomes', 'PosReg', (37, 46))	('tumors', 'Disease', (150, 156))	('tumors', 'Disease', 'MESH:D009369', (150, 156))	('tumors', 'Phenotype', 'HP:0002664', (150, 156))	('rat', 'Species', '10116', (221, 224))	('cancers', 'Phenotype', 'HP:0002664', (253, 260))	('drug resistance', 'Phenotype', 'HP:0020174', (47, 62))	('human', 'Species', '9606', (123, 128))	('cancers', 'Disease', (253, 260))	('cancers', 'Disease', 'MESH:D009369', (253, 260))	('drug resistance', 'MPA', (47, 62))	('patient', 'Species', '9606', (87, 94))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('WEHI-7326', 'Chemical', '-', (27, 36))	('cancer', 'Phenotype', 'HP:0002664', (253, 259))
448770	33712556	We describe results with a new anti-cancer small molecule, WEHI-7326, which causes cell cycle arrest in G2/M, cell death in vitro, and displays efficacious anti-tumor activity in vivo.	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('arrest', 'Disease', 'MESH:D006323', (94, 100))	('cancer', 'Disease', (36, 42))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('arrest', 'Disease', (94, 100))	('WEHI-7326', 'Chemical', '-', (59, 68))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('WEHI-7326', 'Var', (59, 68))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (83, 100))	('cell death', 'CPA', (110, 120))	('tumor', 'Disease', (161, 166))
448771	33712556	WEHI-7326 induces cell death in a broad range of cancer cell lines, including taxane-resistant cells, and inhibits growth of human colon, brain, lung, prostate and breast tumors in mice xenografts.	('mice', 'Species', '10090', (181, 185))	('lung', 'Disease', (145, 149))	('prostate', 'Disease', (151, 159))	('brain', 'CPA', (138, 143))	('growth', 'MPA', (115, 121))	('cancer', 'Disease', (49, 55))	('tumors', 'Phenotype', 'HP:0002664', (171, 177))	('human colon', 'Disease', 'MESH:D003110', (125, 136))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('cell death', 'CPA', (18, 28))	('taxane', 'Chemical', 'MESH:C080625', (78, 84))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('human colon', 'Disease', (125, 136))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('breast tumors', 'Disease', (164, 177))	('breast tumors', 'Disease', 'MESH:D001943', (164, 177))	('inhibits', 'NegReg', (106, 114))	('breast tumors', 'Phenotype', 'HP:0100013', (164, 177))	('WEHI-7326', 'Chemical', '-', (0, 9))	('WEHI-7326', 'Var', (0, 9))
448773	33712556	In combination with standard-of-care, WEHI-7326 induces a remarkable complete response in a mouse model of high-risk neuroblastoma.	('neuroblastoma', 'Phenotype', 'HP:0003006', (117, 130))	('WEHI-7326', 'Chemical', '-', (38, 47))	('neuroblastoma', 'Disease', 'MESH:D009447', (117, 130))	('mouse', 'Species', '10090', (92, 97))	('WEHI-7326', 'Var', (38, 47))	('neuroblastoma', 'Disease', (117, 130))
448774	33712556	WEHI-7326 is mechanistically distinct from known microtubule-targeting agents and blocks cells early in mitosis to inhibit cell division, ultimately leading to apoptotic cell death.	('apoptotic cell death', 'CPA', (160, 180))	('mitosis', 'Disease', 'None', (104, 111))	('inhibit', 'NegReg', (115, 122))	('WEHI-7326', 'Chemical', '-', (0, 9))	('WEHI-7326', 'Var', (0, 9))	('cell division', 'CPA', (123, 136))	('mitosis', 'Disease', (104, 111))	('leading to', 'Reg', (149, 159))
448777	33712556	WEHI-7326 has the potential to complement current frontline anti-cancer drugs and to overcome drug resistance in a wide range of cancers.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('cancers', 'Disease', 'MESH:D009369', (129, 136))	('cancers', 'Phenotype', 'HP:0002664', (129, 136))	('overcome', 'Reg', (85, 93))	('cancer', 'Disease', (129, 135))	('cancers', 'Disease', (129, 136))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('WEHI-7326', 'Chemical', '-', (0, 9))	('drug resistance', 'Phenotype', 'HP:0020174', (94, 109))	('WEHI-7326', 'Var', (0, 9))	('drug resistance', 'MPA', (94, 109))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))
448790	33712556	We have generated the anti-mitotic small molecule WEHI-7326, which shows broad in vivo efficacy in a range of tumor models.	('WEHI-7326', 'Chemical', '-', (50, 59))	('rat', 'Species', '10116', (12, 15))	('WEHI-7326', 'Var', (50, 59))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
448791	33712556	From a clinical perspective, WEHI-7326 is efficacious and well tolerated in vivo in patient-derived mouse xenograft (PDX) models of standard-of-care chemotherapy-resistant triple-negative breast cancer (TNBC), lung squamous cell carcinoma (LUSC), high-grade serous ovarian cancer (HGSOC), and high-risk neuroblastoma (HR-NB).	('breast cancer', 'Phenotype', 'HP:0003002', (188, 201))	('neuroblastoma', 'Phenotype', 'HP:0003006', (303, 316))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (215, 238))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (210, 238))	('lung squamous cell carcinoma', 'Disease', (210, 238))	('breast cancer', 'Disease', 'MESH:D001943', (188, 201))	('WEHI-7326', 'Var', (29, 38))	('neuroblastoma (HR-NB', 'Disease', 'MESH:D009447', (303, 323))	('serous ovarian cancer', 'Disease', 'MESH:D018284', (258, 279))	('breast cancer', 'Disease', (188, 201))	('WEHI-7326', 'Chemical', '-', (29, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (229, 238))	('rat', 'Species', '10116', (67, 70))	('mouse', 'Species', '10090', (100, 105))	('ovarian cancer', 'Phenotype', 'HP:0100615', (265, 279))	('patient', 'Species', '9606', (84, 91))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('serous ovarian cancer', 'Disease', (258, 279))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (210, 238))	('cancer', 'Phenotype', 'HP:0002664', (273, 279))	('LUSC', 'Phenotype', 'HP:0030359', (240, 244))
448793	33712556	Our data indicate that WEHI-7326 (1) is a promising agent suitable for clinical evaluation in cancer therapy.	('WEHI-7326', 'Var', (23, 32))	('WEHI-7326', 'Chemical', '-', (23, 32))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
448798	33712556	Our lead compound WEHI-7326 exceeded potency of myoseverin B (3) by almost ten-fold (Supplementary Fig.	('WEHI-7326', 'Chemical', '-', (18, 27))	('potency', 'MPA', (37, 44))	('myoseverin B (3', 'Chemical', '-', (48, 63))	('WEHI-7326', 'Var', (18, 27))
448802	33712556	Typically, WEHI-7326 caused accumulation of cells in G2/M with nanomolar EC50 values in cancer cell lines, as assessed via flow cytometry (Fig.	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('accumulation', 'PosReg', (28, 40))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('WEHI-7326', 'Var', (11, 20))	('WEHI-7326', 'Chemical', '-', (11, 20))
448804	33712556	Accordingly, WEHI-7326 inhibited cellular proliferation in the low nanomolar range on a broad range of tumor cell types (Table 1).	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('inhibited', 'NegReg', (23, 32))	('cellular proliferation', 'CPA', (33, 55))	('tumor', 'Disease', (103, 108))	('WEHI-7326', 'Chemical', '-', (13, 22))	('WEHI-7326', 'Var', (13, 22))	('rat', 'Species', '10116', (49, 52))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
448805	33712556	In a panel of cancer cell lines, WEHI-7326's anti-proliferative activity was comparable to nocodazole, over 10-fold higher than myoseverin B's, and not as high as paclitaxel's (Supplementary Fig.	('cancer', 'Disease', (14, 20))	('WEHI-7326', 'Var', (33, 42))	('anti-proliferative activity', 'MPA', (45, 72))	('nocodazole', 'Chemical', 'MESH:D015739', (91, 101))	('higher', 'PosReg', (116, 122))	('WEHI-7326', 'Chemical', '-', (33, 42))	('myoseverin B', 'Chemical', '-', (128, 140))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('paclitaxel', 'Chemical', 'MESH:D017239', (163, 173))	('rat', 'Species', '10116', (57, 60))	('cancer', 'Disease', 'MESH:D009369', (14, 20))
448806	33712556	When cells were treated with WEHI-7326, a rapid and strong mitotic arrest marked by phospho-Ser10 histone H3 (p-HH3) expression was observed (Fig.	('WEHI-7326', 'Var', (29, 38))	('WEHI-7326', 'Chemical', '-', (29, 38))	('HH3', 'Gene', '110258', (112, 115))	('mitotic arrest', 'Disease', (59, 73))	('mitotic arrest', 'Disease', 'MESH:D006323', (59, 73))	('phospho-Ser10 histone H3', 'Chemical', '-', (84, 108))	('HH3', 'Gene', (112, 115))
448809	33712556	Analysis via AnnexinV/PI flow cytometry and Western blotting for cleaved caspase-3 revealed a positive correlation between treatment with WEHI-7326 and induction of these apoptotic markers in cells (Supplementary Fig.	('Annexin', 'Gene', (13, 20))	('WEHI-7326', 'Var', (138, 147))	('Annexin', 'Gene', '105245705', (13, 20))	('caspase-3', 'Gene', '12367', (73, 82))	('WEHI-7326', 'Chemical', '-', (138, 147))	('caspase-3', 'Gene', (73, 82))
448810	33712556	Live-cell imaging of SW480 cells treated with WEHI-7326 revealed membrane blebbing and morphological features of apoptotic death (see Supplementary Videos S1 and S2).	('apoptotic death', 'CPA', (113, 128))	('WEHI-7326', 'Var', (46, 55))	('WEHI-7326', 'Chemical', '-', (46, 55))	('membrane blebbing', 'CPA', (65, 82))	('SW480', 'CellLine', 'CVCL:0546', (21, 26))
448812	33712556	S5), WEHI-7326 caused arrest in an earlier stage of prometaphase, characterized by dissolution of the nuclear envelope and condensed chromosome.	('arrest', 'Disease', 'MESH:D006323', (22, 28))	('arrest', 'Disease', (22, 28))	('WEHI-7326', 'Chemical', '-', (5, 14))	('WEHI-7326', 'Var', (5, 14))
448813	33712556	Similar to MTAs morphologically, WEHI-7326 treatment resulted in rounded cells.	('resulted in', 'Reg', (53, 64))	('WEHI-7326', 'Chemical', '-', (33, 42))	('rounded cells', 'CPA', (65, 78))	('WEHI-7326', 'Var', (33, 42))
448814	33712556	Unlike paclitaxel and other MTAs, polymerized tubulin structures or spindle formation were not observed with WEHI-7326 even at high concentration (1 muM, 10x EC50, as shown in Fig.	('paclitaxel', 'Chemical', 'MESH:D017239', (7, 17))	('spindle formation', 'CPA', (68, 85))	('rat', 'Species', '10116', (139, 142))	('WEHI-7326', 'Var', (109, 118))	('WEHI-7326', 'Chemical', '-', (109, 118))
448816	33712556	S5); however, chromosome bundling was observed with WEHI-7326 but not with nocodazole treatment.	('WEHI-7326', 'Var', (52, 61))	('chromosome bundling', 'CPA', (14, 33))	('nocodazole', 'Chemical', 'MESH:D015739', (75, 85))	('WEHI-7326', 'Chemical', '-', (52, 61))
448818	33712556	We observed no significant change in the ratio of polymerized to soluble tubulin after treatment with WEHI-7326 at 100 nM (IC50) compared with control cells (Fig.	('WEHI-7326', 'Chemical', '-', (102, 111))	('WEHI-7326', 'Var', (102, 111))	('rat', 'Species', '10116', (41, 44))	('polymerized to soluble', 'MPA', (50, 72))
448822	33712556	These results suggest that WEHI-7326 can affect microtubule dynamics.	('WEHI-7326', 'Var', (27, 36))	('WEHI-7326', 'Chemical', '-', (27, 36))	('affect', 'Reg', (41, 47))	('microtubule dynamics', 'MPA', (48, 68))
448824	33712556	When tested on epothilone-resistant leukemia cell lines CEM-dEpoB30 and dEpoB300 that are cross-resistant to paclitaxel, WEHI-7326 retained nanomolar potency (Table 1 and Supplementary Fig.	('WEHI-7326', 'Chemical', '-', (121, 130))	('epothilone', 'Chemical', 'MESH:D034261', (15, 25))	('nanomolar potency', 'MPA', (140, 157))	('leukemia', 'Phenotype', 'HP:0001909', (36, 44))	('paclitaxel', 'Chemical', 'MESH:D017239', (109, 119))	('leukemia', 'Disease', (36, 44))	('leukemia', 'Disease', 'MESH:D007938', (36, 44))	('WEHI-7326', 'Var', (121, 130))
448825	33712556	This suggests the mechanism-of-action driving WEHI-7326's anti-proliferative activity is distinct from that of paclitaxel and other MTAs, bearing great potential benefits to patients with taxane-refractory or MTA treatment-resistant tumors.	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('rat', 'Species', '10116', (70, 73))	('WEHI-7326', 'Var', (46, 55))	('tumors', 'Disease', (233, 239))	('tumors', 'Disease', 'MESH:D009369', (233, 239))	('tumors', 'Phenotype', 'HP:0002664', (233, 239))	('WEHI-7326', 'Chemical', '-', (46, 55))	('paclitaxel', 'Chemical', 'MESH:D017239', (111, 121))	('fits', 'Disease', 'MESH:D012640', (166, 170))	('anti-proliferative activity', 'MPA', (58, 85))	('patients', 'Species', '9606', (174, 182))	('taxane', 'Chemical', 'MESH:C080625', (188, 194))	('fits', 'Disease', (166, 170))
448832	33712556	WEHI-7326 was effective in reducing tumor growth in LIM2537, LoVo (colon carcinomas), U87MG-(Delta2-7) (recombinant glioblastoma) and H1437 (non-small cell lung carcinoma) tumors (Fig.	('colon carcinomas', 'Disease', 'MESH:D003110', (67, 83))	('tumor', 'Disease', (172, 177))	('glioblastoma', 'Disease', 'MESH:D005909', (116, 128))	('non-small cell lung carcinoma', 'Phenotype', 'HP:0030358', (141, 170))	('small cell lung carcinoma', 'Phenotype', 'HP:0030357', (145, 170))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('U87MG-', 'Var', (86, 92))	('tumor', 'Disease', (36, 41))	('LoVo', 'Chemical', '-', (61, 65))	('glioblastoma', 'Disease', (116, 128))	('tumors', 'Phenotype', 'HP:0002664', (172, 178))	('carcinomas', 'Phenotype', 'HP:0030731', (73, 83))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('glioblastoma', 'Phenotype', 'HP:0012174', (116, 128))	('LIM2537', 'Var', (52, 59))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('H1437 (non-small cell lung carcinoma) tumors', 'Disease', 'MESH:D002289', (134, 178))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('U87MG', 'CellLine', 'CVCL:0022', (86, 91))	('Delta2-7', 'Gene', (93, 101))	('reducing', 'NegReg', (27, 35))	('colon carcinomas', 'Disease', (67, 83))	('WEHI-7326', 'Chemical', '-', (0, 9))	('WEHI-7326', 'Var', (0, 9))	('carcinoma', 'Phenotype', 'HP:0030731', (161, 170))	('Delta2-7', 'Gene', '10683;54567', (93, 101))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
448833	33712556	Effectiveness in the xenograft studies correlated with the tumor growth rates: WEHI-7326 was more effective in the fast growing and more aggressive U87MG-(Delta2-7) and H1437 tumors than in the comparably slower growing LIM2537 and LoVo tumor xenografts.	('tumors', 'Disease', (175, 181))	('tumor', 'Disease', (59, 64))	('H1437', 'Var', (169, 174))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))	('tumors', 'Disease', 'MESH:D009369', (175, 181))	('rat', 'Species', '10116', (72, 75))	('Delta2-7', 'Gene', (155, 163))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('tumor', 'Disease', (175, 180))	('U87MG-', 'Var', (148, 154))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('U87MG', 'CellLine', 'CVCL:0022', (148, 153))	('LoVo', 'Chemical', '-', (232, 236))	('tumors', 'Phenotype', 'HP:0002664', (175, 181))	('tumor', 'Disease', (237, 242))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('tumor', 'Disease', 'MESH:D009369', (237, 242))	('Delta2-7', 'Gene', '10683;54567', (155, 163))	('WEHI-7326', 'Chemical', '-', (79, 88))	('WEHI-7326', 'Var', (79, 88))
448836	33712556	Preliminary toxicology of mice treated with WEHI-7326 for 36 days showed no gross alterations of the major organs, except for enlargement of the spleen (H1437, as shown in Supplementary Fig.	('enlargement', 'PosReg', (126, 137))	('WEHI-7326', 'Chemical', '-', (44, 53))	('WEHI-7326', 'Var', (44, 53))	('rat', 'Species', '10116', (86, 89))	('mice', 'Species', '10090', (26, 30))
448837	33712556	The efficacy results show a 60% tumor growth inhibition in the LoVo human colon carcinoma model following treatment with WEHI-7326 at 25 mg/kg (Fig.	('colon carcinoma', 'Disease', (74, 89))	('WEHI-7326', 'Chemical', '-', (121, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('human colon', 'Disease', (68, 79))	('human colon', 'Disease', 'MESH:D003110', (68, 79))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('LoVo', 'Chemical', '-', (63, 67))	('colon carcinoma', 'Disease', 'MESH:D003110', (74, 89))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumor', 'Disease', (32, 37))	('WEHI-7326', 'Var', (121, 130))
448840	33712556	The efficacy of WEHI-7326 vs standard-of-care chemotherapy docetaxel were compared in a PC3 xenograft model of human prostate cancer in male nude mice.	('nude mice', 'Species', '10090', (141, 150))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('prostate cancer', 'Disease', 'MESH:D011471', (117, 132))	('prostate cancer', 'Phenotype', 'HP:0012125', (117, 132))	('human', 'Species', '9606', (111, 116))	('WEHI-7326', 'Var', (16, 25))	('WEHI-7326', 'Chemical', '-', (16, 25))	('prostate cancer', 'Disease', (117, 132))	('docetaxel', 'Chemical', 'MESH:D000077143', (59, 68))
448841	33712556	The results showed a strong tumor growth inhibition following treatment with either docetaxel or WEHI-7326 (~75% TGI at day 17 for WEHI-7326) (Fig.	('WEHI-7326', 'Var', (97, 106))	('tumor', 'Disease', (28, 33))	('docetaxel', 'Chemical', 'MESH:D000077143', (84, 93))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('WEHI-7326', 'Chemical', '-', (97, 106))	('WEHI-7326', 'Chemical', '-', (131, 140))
448842	33712556	Importantly, WEHI-7326 was better tolerated than docetaxel which induced toxicity after only three doses in this model: mice had to be culled one week after dose three as they reached a pre-determined toxicity ethical endpoint (Supplementary Fig.	('mice', 'Species', '10090', (120, 124))	('docetaxel', 'Chemical', 'MESH:D000077143', (49, 58))	('toxicity', 'Disease', 'MESH:D064420', (201, 209))	('toxicity', 'Disease', 'MESH:D064420', (73, 81))	('toxicity', 'Disease', (201, 209))	('toxicity', 'Disease', (73, 81))	('WEHI-7326', 'Chemical', '-', (13, 22))	('WEHI-7326', 'Var', (13, 22))	('rat', 'Species', '10116', (38, 41))
448849	33712556	Notably, WEHI-7326 caused tumor regression.	('WEHI-7326', 'Chemical', '-', (9, 18))	('WEHI-7326', 'Var', (9, 18))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))
448857	33712556	However, both models responded well to single-agent therapy with WEHI-7326 without significant weight loss (Supplementary Fig.	('weight loss', 'Phenotype', 'HP:0001824', (95, 106))	('responded', 'Reg', (21, 30))	('weight loss', 'Disease', 'MESH:D015431', (95, 106))	('WEHI-7326', 'Chemical', '-', (65, 74))	('WEHI-7326', 'Var', (65, 74))	('weight loss', 'Disease', (95, 106))
448858	33712556	WEHI-7326 significantly inhibited tumor growth in both models and consequently increased survival times compared to docetaxel (11 days vs 45 days for 24 T and 7 days vs 18 days for 322 T), even after cessation of treatment at day 21.	('increased', 'PosReg', (79, 88))	('tumor', 'Disease', (34, 39))	('inhibited', 'NegReg', (24, 33))	('WEHI-7326', 'Chemical', '-', (0, 9))	('WEHI-7326', 'Var', (0, 9))	('docetaxel', 'Chemical', 'MESH:D000077143', (116, 125))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('survival times', 'CPA', (89, 103))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
448859	33712556	The effects of short-time treatment with WEHI-7326 on the 24 T tumor cells was further studied in vivo and compared to docetaxel (Supplementary Fig.	('WEHI-7326', 'Var', (41, 50))	('tumor', 'Disease', (63, 68))	('docetaxel', 'Chemical', 'MESH:D000077143', (119, 128))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('WEHI-7326', 'Chemical', '-', (41, 50))
448860	33712556	S11): at 16 h post single-dose treatment, a reduction in proliferation (Ki67 expression) and increased induction of apoptosis (cleaved/activated caspase-3) was found in both treatment groups but was significantly higher in the WEHI-7326 arm.	('caspase-3', 'Gene', (145, 154))	('apoptosis', 'CPA', (116, 125))	('higher', 'PosReg', (213, 219))	('rat', 'Species', '10116', (64, 67))	('Ki67', 'Gene', '17345', (72, 76))	('reduction', 'NegReg', (44, 53))	('proliferation', 'CPA', (57, 70))	('caspase-3', 'Gene', '12367', (145, 154))	('WEHI-7326', 'Chemical', '-', (227, 236))	('Ki67', 'Gene', (72, 76))	('WEHI-7326', 'Var', (227, 236))
448867	33712556	Both PDX models responded to WEHI-7326 with prolonged survival of animals compared to vehicle control or docetaxel for MH792 (Fig.	('WEHI-7326', 'Var', (29, 38))	('prolonged', 'PosReg', (44, 53))	('WEHI-7326', 'Chemical', '-', (29, 38))	('docetaxel', 'Chemical', 'MESH:D000077143', (105, 114))	('survival', 'CPA', (54, 62))
448868	33712556	The median survival of the mice with MH792 tumors treated with WEHI-7326 was 34 days compared to 19 days with vehicle alone or 22 days with docetaxel.	('mice', 'Species', '10090', (27, 31))	('docetaxel', 'Chemical', 'MESH:D000077143', (140, 149))	('MH792', 'Gene', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumors', 'Disease', (43, 49))	('WEHI-7326', 'Var', (63, 72))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('WEHI-7326', 'Chemical', '-', (63, 72))	('tumors', 'Disease', 'MESH:D009369', (43, 49))
448869	33712556	For the mice with AH406 tumors, treatment with WEHI-7326 showed a slight but significant (p = 0.05) improved survival over the docetaxel treatment group with a median survival of 29 days (WEHI-7326) versus 24 days (docetaxel).	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('docetaxel', 'Chemical', 'MESH:D000077143', (127, 136))	('improved', 'PosReg', (100, 108))	('tumors', 'Disease', (24, 30))	('tumors', 'Disease', 'MESH:D009369', (24, 30))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('WEHI-7326', 'Chemical', '-', (47, 56))	('WEHI-7326', 'Var', (47, 56))	('AH406', 'Var', (18, 23))	('docetaxel', 'Chemical', 'MESH:D000077143', (215, 224))	('WEHI-7326', 'Chemical', '-', (188, 197))	('WEHI-7326', 'Var', (188, 197))	('mice', 'Species', '10090', (8, 12))	('survival', 'CPA', (109, 117))
448870	33712556	WEHI-7326 was well tolerated with little toxicity reported during the course of treatment and no change in animal body weight.	('toxicity', 'Disease', 'MESH:D064420', (41, 49))	('toxicity', 'Disease', (41, 49))	('rat', 'Species', '10116', (23, 26))	('WEHI-7326', 'Chemical', '-', (0, 9))	('WEHI-7326', 'Var', (0, 9))
448871	33712556	The in vivo efficacy and tolerability of WEHI-7326 was evaluated in a larger cohort of well annotated PDX models of high grade serous ovarian cancer (HGSOC) with defined in vivo responses to a platinum-based chemotherapy, cisplatin.	('WEHI-7326', 'Var', (41, 50))	('ovarian cancer', 'Phenotype', 'HP:0100615', (134, 148))	('serous ovarian cancer', 'Disease', 'MESH:D018284', (127, 148))	('platinum', 'Chemical', 'MESH:D010984', (193, 201))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('cisplatin', 'Chemical', 'MESH:D002945', (222, 231))	('WEHI-7326', 'Chemical', '-', (41, 50))	('serous ovarian cancer', 'Disease', (127, 148))
448876	33712556	Within the group of chemo-naive PDX models - 134056 (gBRCA1 mutant), 134183 (RAD51C methylated), 134197 (C5 Tothill molecular subtype with HMGA2, MYCN and Lin28b expression) and 134036 (C5 Tothill molecular subtype) - 2 of 4 PDX showed statistically significant responses to WEHI-7326 (Fig.	('WEHI-7326', 'Chemical', '-', (275, 284))	('HMGA2', 'Gene', (139, 144))	('responses', 'MPA', (262, 271))	('MYCN', 'Gene', (146, 150))	('Lin28b', 'Gene', (155, 161))	('134036', 'Var', (178, 184))	('HMGA2', 'Gene', '15364', (139, 144))	('134183', 'Var', (69, 75))	('MYCN', 'Gene', '18109', (146, 150))	('RAD51C', 'Gene', (77, 83))	('Lin28b', 'Gene', '380669', (155, 161))	('BRCA1', 'Gene', '12189', (54, 59))	('RAD51C', 'Gene', '114714', (77, 83))	('134197', 'Var', (97, 103))	('BRCA1', 'Gene', (54, 59))
448881	33712556	Lastly, the 134036 C5 platinum refractory PDX was completely unresponsive to WEHI-7326.	('WEHI-7326', 'Chemical', '-', (77, 86))	('platinum refractory PDX', 'Disease', (22, 45))	('134036 C5', 'Var', (12, 21))	('platinum', 'Chemical', 'MESH:D010984', (22, 30))
448882	33712556	In all PDX models tested, WEHI-7326 was well tolerated over the 6 weeks treatment regimen and only minimal body weight losses were observed during this period (Supplementary Fig.	('weight loss', 'Disease', (112, 123))	('weight loss', 'Phenotype', 'HP:0001824', (112, 123))	('WEHI-7326', 'Chemical', '-', (26, 35))	('WEHI-7326', 'Var', (26, 35))	('weight losses', 'Phenotype', 'HP:0001824', (112, 125))	('rat', 'Species', '10116', (49, 52))	('weight loss', 'Disease', 'MESH:D015431', (112, 123))
448884	33712556	In the 134111 (CCNE1 58x amplification), there was a trend towards improved outcome with WEHI-7326 treatment, however, due to individual outliers in the treatment arm, this failed to reach statistical significance.	('CCNE1', 'Gene', '12447', (15, 20))	('CCNE1', 'Gene', (15, 20))	('outcome', 'MPA', (76, 83))	('134111', 'Var', (7, 13))	('WEHI-7326', 'Chemical', '-', (89, 98))	('WEHI-7326', 'Var', (89, 98))	('improved', 'PosReg', (67, 75))
448886	33712556	Interestingly, we observed very short-lived tumor regression in most tumors treated of the 34931 PDX model, leading to a small improvement in time to PD but no improvement in median TTH, as the tumor regression was not sustained.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('time', 'MPA', (142, 146))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('tumor', 'Disease', (69, 74))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('34931', 'Var', (91, 96))	('tumors', 'Disease', (69, 75))	('tumor', 'Disease', (194, 199))	('tumors', 'Disease', 'MESH:D009369', (69, 75))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('improvement', 'PosReg', (127, 138))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('tumor', 'Disease', (44, 49))
448890	33712556	Similarly, in COG-N-440x, a model established from a relapsed patient, WEHI-7326 extended median survival from 28 days to 39 days (Fig.	('COG-N-440x', 'Var', (14, 24))	('median', 'MPA', (90, 96))	('WEHI-7326', 'Var', (71, 80))	('patient', 'Species', '9606', (62, 69))	('WEHI-7326', 'Chemical', '-', (71, 80))	('COG-N-440x', 'Chemical', '-', (14, 24))	('extended', 'PosReg', (81, 89))
448898	33712556	This led to the discovery of WEHI-7326, a potent G2/M blocker causing mitotic arrest and leading to apoptotic cell death.	('WEHI-7326', 'Var', (29, 38))	('causing', 'Reg', (62, 69))	('WEHI-7326', 'Chemical', '-', (29, 38))	('mitotic arrest', 'Disease', 'MESH:D006323', (70, 84))	('mitotic arrest', 'Disease', (70, 84))	('apoptotic cell death', 'CPA', (100, 120))
448899	33712556	WEHI-7326 displays antiproliferative activity across a broad range of cancer cell lines comparable to clinically approved MTAs.	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('rat', 'Species', '10116', (30, 33))	('WEHI-7326', 'Chemical', '-', (0, 9))	('antiproliferative', 'CPA', (19, 36))	('WEHI-7326', 'Var', (0, 9))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))
448902	33712556	Resistance to MTAs can develop through beta-tubulin mutations or overexpression of betaIII-tubulin.	('mutations', 'Var', (52, 61))	('develop', 'Reg', (23, 30))	('betaIII-tubulin', 'Gene', '22152', (83, 98))	('beta-tubulin', 'Protein', (39, 51))	('overexpression', 'PosReg', (65, 79))	('betaIII-tubulin', 'Gene', (83, 98))
448903	33712556	Although WEHI-7326 affected tubulin polymerization in vitro at high concentrations, this effect was much less pronounced than that observed with known MTAs with similar (paclitaxel) or even lower (nocodazole, myoseverin B) cellular potency.	('nocodazole', 'Chemical', 'MESH:D015739', (197, 207))	('affected', 'Reg', (19, 27))	('WEHI-7326', 'Chemical', '-', (9, 18))	('rat', 'Species', '10116', (75, 78))	('tubulin polymerization', 'MPA', (28, 50))	('WEHI-7326', 'Var', (9, 18))	('paclitaxel', 'Chemical', 'MESH:D017239', (170, 180))	('lower', 'NegReg', (190, 195))	('myoseverin B', 'Chemical', '-', (209, 221))
448907	33712556	WEHI-7326 proved to be an effective in vivo single agent in reducing the growth of human breast, lung, prostate, brain and colon tumor xenografts in nude mice.	('colon tumor', 'Disease', 'MESH:D003110', (123, 134))	('nude mice', 'Species', '10090', (149, 158))	('human', 'Species', '9606', (83, 88))	('growth', 'CPA', (73, 79))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('WEHI-7326', 'Chemical', '-', (0, 9))	('colon tumor', 'Phenotype', 'HP:0100273', (123, 134))	('WEHI-7326', 'Var', (0, 9))	('brain and', 'CPA', (113, 122))	('prostate', 'CPA', (103, 111))	('lung', 'CPA', (97, 101))	('reducing', 'NegReg', (60, 68))	('colon tumor', 'Disease', (123, 134))
448909	33712556	Some evidence of toxicity was observed in the nude mice xenograft models at the higher doses of WEHI-7326, but overall WEHI-7326 was well tolerated especially in comparison with anti-cancer drugs such as docetaxel.	('toxicity', 'Disease', 'MESH:D064420', (17, 25))	('cancer', 'Disease', (183, 189))	('toxicity', 'Disease', (17, 25))	('nude mice', 'Species', '10090', (46, 55))	('docetaxel', 'Chemical', 'MESH:D000077143', (204, 213))	('cancer', 'Disease', 'MESH:D009369', (183, 189))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('WEHI-7326', 'Chemical', '-', (119, 128))	('WEHI-7326', 'Var', (119, 128))	('WEHI-7326', 'Chemical', '-', (96, 105))	('rat', 'Species', '10116', (142, 145))	('WEHI-7326', 'Var', (96, 105))
448910	33712556	MTAs can adversely interfere with non-cancerous cells and lead to toxicities in patients (e.g., neuropathies, bone marrow suppression), thus lowering their therapeutic index.	('toxicities', 'Disease', (66, 76))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('patients', 'Species', '9606', (80, 88))	('bone marrow suppression', 'Phenotype', 'HP:0005528', (110, 133))	('MTAs', 'Var', (0, 4))	('neuropathies', 'Phenotype', 'HP:0009830', (96, 108))	('bone marrow suppression', 'Disease', (110, 133))	('bone marrow suppression', 'Disease', 'MESH:D001855', (110, 133))	('lead to', 'Reg', (58, 65))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('toxicities', 'Disease', 'MESH:D064420', (66, 76))	('interfere', 'Reg', (19, 28))	('cancer', 'Disease', (38, 44))	('neuropathies', 'Disease', (96, 108))	('therapeutic index', 'MPA', (156, 173))	('neuropathies', 'Disease', 'MESH:D009422', (96, 108))	('lowering', 'NegReg', (141, 149))
448911	33712556	No evidence of bone marrow suppression was found in the toxicity studies with WEHI-7326.	('bone marrow suppression', 'Phenotype', 'HP:0005528', (15, 38))	('WEHI-7326', 'Chemical', '-', (78, 87))	('WEHI-7326', 'Var', (78, 87))	('toxicity', 'Disease', 'MESH:D064420', (56, 64))	('toxicity', 'Disease', (56, 64))	('bone marrow suppression', 'Disease', (15, 38))	('bone marrow suppression', 'Disease', 'MESH:D001855', (15, 38))
448916	33712556	The highly aggressive and docetaxel-resistant MDA-MB-231 LNA-DRE line xenograft regressed with WEHI-7326 treatment, while docetaxel treatment showed significant toxicity.	('toxicity', 'Disease', 'MESH:D064420', (161, 169))	('toxicity', 'Disease', (161, 169))	('WEHI-7326', 'Var', (95, 104))	('WEHI-7326', 'Chemical', '-', (95, 104))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (46, 56))	('docetaxel', 'Chemical', 'MESH:D000077143', (26, 35))	('docetaxel', 'Chemical', 'MESH:D000077143', (122, 131))
448918	33712556	This finding highlights the therapeutic potential of WEHI-7326 for treatment of TNBC and it is expected that combination with standard-of-care therapies would prove highly beneficial.	('TNBC', 'Disease', (80, 84))	('WEHI-7326', 'Chemical', '-', (53, 62))	('WEHI-7326', 'Var', (53, 62))
448919	33712556	Additional xenograft experiments are required to investigate the role of WEHI-7326 in combination in other breast cancer subtypes such as ER + (with tamoxifen/fulvestrant or aromatase inhibitors) and HER-2 amplified (with Herceptin), but also in BRCA1 mutant BC (with PARP-inhibitor).	('HER-2', 'Gene', (200, 205))	('amplified', 'PosReg', (206, 215))	('breast cancer', 'Disease', 'MESH:D001943', (107, 120))	('PARP', 'Gene', (268, 272))	('mutant', 'Var', (252, 258))	('BRCA1', 'Gene', '12189', (246, 251))	('breast cancer', 'Disease', (107, 120))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('breast cancer', 'Phenotype', 'HP:0003002', (107, 120))	('PARP', 'Gene', '11545', (268, 272))	('WEHI-7326', 'Chemical', '-', (73, 82))	('HER-2', 'Gene', '13866', (200, 205))	('Herceptin', 'Chemical', 'MESH:D000068878', (222, 231))	('WEHI-7326', 'Var', (73, 82))	('BRCA1', 'Gene', (246, 251))
448922	33712556	Treatment with WEHI-7326 reduced tumor growth in vivo in two PDX models of NSCLC resistant to platinum therapy.	('reduced', 'NegReg', (25, 32))	('WEHI-7326', 'Chemical', '-', (15, 24))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('platinum', 'Chemical', 'MESH:D010984', (94, 102))	('WEHI-7326', 'Var', (15, 24))	('NSCLC', 'Phenotype', 'HP:0030358', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('NSCLC', 'Disease', (75, 80))	('tumor', 'Disease', (33, 38))	('NSCLC', 'Disease', 'MESH:D002289', (75, 80))
448924	33712556	Given the limited toxicity of WEHI-7326, further combination studies with targeting or immunotherapy drugs would need to be explored.	('toxicity', 'Disease', 'MESH:D064420', (18, 26))	('WEHI-7326', 'Chemical', '-', (30, 39))	('WEHI-7326', 'Var', (30, 39))	('toxicity', 'Disease', (18, 26))
448927	33712556	However, they represent especially highly refractory HGSOC in the clinical setting: 134111 is resistant to chemotherapy except MTAs; 134169 is resistant to both platinum and PARPi; and 34931 is refractory to cisplatin.	('PARP', 'Gene', (174, 178))	('PARP', 'Gene', '11545', (174, 178))	('cisplatin', 'Chemical', 'MESH:D002945', (208, 217))	('platinum', 'Chemical', 'MESH:D010984', (161, 169))	('134169', 'Var', (133, 139))	('34931', 'Var', (185, 190))	('134111', 'Var', (84, 90))
448930	33712556	Interestingly, the best HGSOC responder is 134056 PDX, which carries a gBRCA1 mutation and bears most molecular resemblance to TNBC.	('BRCA1', 'Gene', '12189', (72, 77))	('mutation', 'Var', (78, 86))	('BRCA1', 'Gene', (72, 77))
448932	33712556	Olaparib has been shown to reduce the risk of ovarian cancer progression and death in carriers of gBRCA1/2 mutations by 70% and the addition of WEHI-7326 has the potential to improve outcomes for these women.	('BRCA1', 'Gene', '12189', (99, 104))	('ovarian cancer', 'Phenotype', 'HP:0100615', (46, 60))	('carriers', 'Reg', (86, 94))	('ovarian cancer', 'Disease', 'MESH:D010051', (46, 60))	('mutations', 'Var', (107, 116))	('BRCA1', 'Gene', (99, 104))	('ovarian cancer', 'Disease', (46, 60))	('Olaparib', 'Chemical', 'MESH:C531550', (0, 8))	('improve', 'PosReg', (175, 182))	('reduce', 'NegReg', (27, 33))	('WEHI-7326', 'Chemical', '-', (144, 153))	('women', 'Species', '9606', (202, 207))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
448933	33712556	WEHI-7326 was highly effective in a neuroblastoma transgenic mouse model when combined with two different standard-of-care regimens used to treat high-risk patients with relapsed or refractory disease.	('patients', 'Species', '9606', (156, 164))	('refractory disease', 'Disease', (182, 200))	('neuroblastoma', 'Disease', 'MESH:D009447', (36, 49))	('transgenic', 'Species', '10090', (50, 60))	('neuroblastoma', 'Disease', (36, 49))	('WEHI-7326', 'Chemical', '-', (0, 9))	('WEHI-7326', 'Var', (0, 9))	('mouse', 'Species', '10090', (61, 66))	('neuroblastoma', 'Phenotype', 'HP:0003006', (36, 49))	('refractory disease', 'Disease', 'MESH:D000069279', (182, 200))
448935	33712556	In conclusion, our pre-clinical data demonstrate that WEHI-7326 represents a new class of anti-cancer agents with good therapeutic window and developability.	('WEHI-7326', 'Var', (54, 63))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('WEHI-7326', 'Chemical', '-', (54, 63))	('cancer', 'Disease', (95, 101))	('rat', 'Species', '10116', (44, 47))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))
448936	33712556	WEHI-7326 is both tolerable and efficacious in vivo and, notably, offers potential as alternative therapy for cancers hard to treat with current standard-of-care chemotherapy.	('cancers', 'Disease', (110, 117))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('WEHI-7326', 'Chemical', '-', (0, 9))	('WEHI-7326', 'Var', (0, 9))	('cancers', 'Phenotype', 'HP:0002664', (110, 117))	('cancers', 'Disease', 'MESH:D009369', (110, 117))
448938	33712556	Anti-mitotic drugs and reagents were purchased from Sigma-Aldrich (St. Louis, MS, USA): epothilone B (98%, E2656), paclitaxel (97%, T7191), docetaxel (97%, 01885), myoseverin B (97%, M3316), nocodazole (99%, M1404), DAPI (D9542), propidium iodide (P4864), RNAse (R6148), bovine serum albumin (A2153), DPX mounting medium (06522).	('A2153', 'Var', (293, 298))	('nocodazole', 'Chemical', 'MESH:D015739', (191, 201))	('serum albumin', 'Gene', (278, 291))	('myoseverin B', 'Chemical', '-', (164, 176))	('paclitaxel', 'Chemical', 'MESH:D017239', (115, 125))	('E2656', 'CellLine', 'CVCL:Z894', (107, 112))	('DAPI', 'Chemical', 'MESH:C007293', (216, 220))	('epothilone', 'Chemical', 'MESH:D034261', (88, 98))	('P4864', 'Var', (248, 253))	('propidium iodide', 'Chemical', 'MESH:D011419', (230, 246))	('serum albumin', 'Gene', '11657', (278, 291))	('R6148', 'Var', (263, 268))	('docetaxel', 'Chemical', 'MESH:D000077143', (140, 149))
448939	33712556	Antibodies: Caspase-3/cleaved caspase-3 (CST9665, Cell Signaling Technology, MS, USA), phospho-Ser10 histone H3 (06-570, Merck Millipore, Darmstadt, Germany), anti-H2AX S139ph (CST9718, Cell Signaling Technology), beta-actin antibody conjugated to HRP (ab49900), beta-tubulin (ab6046), Alexa Fluor 488 (ab150077) from Abcam (Cambridge, UK), Alexa Fluor 647 (A28181, Invitrogen, Carslbad, CA, USA) and IRDye 800CW (926-32211) from Li-Cor (Lincoln, NB, US).	('Caspase-3', 'Gene', '12367', (12, 21))	('H2AX', 'Gene', '15270', (164, 168))	('caspase-3', 'Gene', '12367', (30, 39))	('phospho-Ser10 histone H3', 'Chemical', '-', (87, 111))	('926-32211', 'Var', (414, 423))	('Cor', 'Gene', (433, 436))	('ab49900', 'Var', (253, 260))	('Cor', 'Gene', '108031', (433, 436))	('Alexa Fluor 488', 'Chemical', '-', (286, 301))	('beta-tubulin', 'Protein', (263, 275))	('caspase-3', 'Gene', (30, 39))	('Caspase-3', 'Gene', (12, 21))	('H2AX', 'Gene', (164, 168))	('beta-actin antibody', 'Protein', (214, 233))
448965	33712556	anti-H3S10ph and anti-H2AX S139ph antibodies were diluted in 1X TBS with 1% BSA and subsequently incubated with the cells after the removal of the blocking buffer overnight at 4  C. Cells were then washed twice in 1X TBST for 10 mins each, followed by incubation using Alexa Fluor 488 or 647 conjugated secondary antibodies and Hoechst 33258 at 10 microM for 2 h at RT.	('Hoechst 33258', 'Chemical', 'MESH:D006690', (328, 341))	('Alexa Fluor 488', 'Chemical', '-', (269, 284))	('TBST', 'Chemical', '-', (217, 221))	('H2AX', 'Gene', (22, 26))	('H3S10ph', 'Chemical', '-', (5, 12))	('H2AX', 'Gene', '15270', (22, 26))	('anti-H3S10ph', 'Var', (0, 12))
449016	33712556	Sections were subjected to antigen retrieval and then incubated with antibodies against Ki-67 (BD Pharmingen) and cleaved caspase-3 (Cell Signaling) for 30 min at room temperature, followed by biotinylated anti-IgG secondary antibodies (Vector Labs).	('rat', 'Species', '10116', (173, 176))	('caspase-3', 'Gene', '12367', (122, 131))	('Ki-67', 'Gene', '17345', (88, 93))	('cleaved', 'Var', (114, 121))	('caspase-3', 'Gene', (122, 131))	('Ki-67', 'Gene', (88, 93))
449036	33712556	PDX models COG-N-440x and COG-N-496x were obtained from the Childhood Cancer Repository, Texas Tech University Health Sciences Center in Lubbock, TX, USA.	('COG-N-496x', 'Var', (26, 36))	('COG-N', 'Chemical', '-', (11, 16))	('COG-N-440x', 'Chemical', '-', (11, 21))	('Cancer', 'Phenotype', 'HP:0002664', (70, 76))	('Cancer', 'Disease', (70, 76))	('Cancer', 'Disease', 'MESH:D009369', (70, 76))	('COG-N-440x', 'Var', (11, 21))	('COG-N', 'Chemical', '-', (26, 31))
449052	33712556	in 5% glucose for 5 days), WEHI-7326 in combination with cyclophosphamide/topotecan, or WEHI-7326 in combination with irinotecan/temozolomide (schedules as above).	('WEHI-7326', 'Var', (27, 36))	('irinotecan', 'Chemical', 'MESH:D000077146', (118, 128))	('temozolomide', 'Chemical', 'MESH:D000077204', (129, 141))	('WEHI-7326', 'Chemical', '-', (88, 97))	('WEHI-7326', 'Var', (88, 97))	('cyclophosphamide', 'Chemical', 'MESH:D003520', (57, 73))	('topotecan', 'Chemical', 'MESH:D019772', (74, 83))	('WEHI-7326', 'Chemical', '-', (27, 36))	('glucose', 'Chemical', 'MESH:D005947', (6, 13))
449057	32475345	We herein report a recurrent case of ovarian squamous cell carcinoma with MET gene copy number variation.	('MET gene copy number variation', 'Var', (74, 104))	('ovarian squamous cell carcinoma', 'Disease', (37, 68))	('ovarian squamous cell carcinoma', 'Disease', 'MESH:D002294', (37, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (59, 68))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (45, 68))
449084	32475345	There were mutations in 7 known driver genes including TP53, CDKN2A, ATR, PTCH1, MCM-7, RAG-1 and SPTAN-1.	('mutations', 'Var', (11, 20))	('MCM-7', 'Gene', '4176', (81, 86))	('RAG-1', 'Gene', '5896', (88, 93))	('TP53', 'Gene', '7157', (55, 59))	('TP53', 'Gene', (55, 59))	('CDKN2A', 'Gene', (61, 67))	('RAG-1', 'Gene', (88, 93))	('PTCH1', 'Gene', '5727', (74, 79))	('CDKN2A', 'Gene', '1029', (61, 67))	('SPTAN-1', 'Gene', (98, 105))	('ATR', 'Gene', '545', (69, 72))	('ATR', 'Gene', (69, 72))	('MCM-7', 'Gene', (81, 86))	('PTCH1', 'Gene', (74, 79))	('SPTAN-1', 'Gene', '6709', (98, 105))
449085	32475345	Mutations in MET, MYC and JAK2 were all synonymous SNV.	('MET', 'Gene', (13, 16))	('JAK2', 'Gene', '3717', (26, 30))	('MYC', 'Gene', (18, 21))	('JAK2', 'Gene', (26, 30))	('Mutations', 'Var', (0, 9))	('MYC', 'Gene', '4609', (18, 21))
449088	32475345	Besides, MET gene copy number was elevated with copy number of six which indicated the patient may benefit from c-MET small molecule tyrosine kinase inhibitors such as crizotinib.	('MET', 'MPA', (9, 12))	('c-MET', 'Gene', (112, 117))	('crizotinib', 'Chemical', 'MESH:D000077547', (168, 178))	('patient', 'Species', '9606', (87, 94))	('elevated', 'PosReg', (34, 42))	('benefit', 'PosReg', (99, 106))	('copy number of six', 'Var', (48, 66))	('c-MET', 'Gene', '4233', (112, 117))
449095	32475345	Our patient is a postmenopausal woman with a 142*115 mm mass and mildly elevated the level of tumor markers.	('elevated', 'PosReg', (72, 80))	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('woman', 'Species', '9606', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('patient', 'Species', '9606', (4, 11))	('tumor', 'Disease', (94, 99))	('142*115 mm', 'Var', (45, 55))
449098	32475345	Minimization of tumor burden may improve the effect of adjuvant treatment.	('improve', 'PosReg', (33, 40))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('Minimization', 'Var', (0, 12))	('tumor', 'Disease', (16, 21))
449103	32475345	Several studies showed that malignant transformation of OMCTs may be associated with genetic mutations, high-risk human papillomavirus infection and metaplastic squamous epithelium.	('papillomavirus infection', 'Disease', 'MESH:D030361', (120, 144))	('malignant transformation', 'CPA', (28, 52))	('papillomavirus infection', 'Phenotype', 'HP:0012740', (120, 144))	('associated', 'Reg', (69, 79))	('papillomavirus infection', 'Disease', (120, 144))	('metaplastic squamous epithelium', 'Disease', (149, 180))	('genetic mutations', 'Var', (85, 102))	('human papillomavirus', 'Species', '10566', (114, 134))	('OMCTs', 'Disease', (56, 61))
449106	32475345	In the study done by Iwasa et al., overexpression of the p53 protein was observed in 67% SCC cases (14 in 21 cases), while four of them had point mutations in the p53.	('point mutations', 'Var', (140, 155))	('SCC', 'Gene', '6317', (89, 92))	('p53', 'Gene', (163, 166))	('p53', 'Gene', '7157', (163, 166))	('p53', 'Gene', (57, 60))	('overexpression', 'PosReg', (35, 49))	('protein', 'Protein', (61, 68))	('p53', 'Gene', '7157', (57, 60))	('SCC', 'Gene', (89, 92))
449108	32475345	Expression of p16 protein decreased in 86% patients (18 in 21 cases), and p16 hypermethylation and point mutation was noticed in 6 and 7 respectively.	('point mutation', 'Var', (99, 113))	('p16', 'Gene', (74, 77))	('p16', 'Gene', '1029', (14, 17))	('Expression', 'MPA', (0, 10))	('patients', 'Species', '9606', (43, 51))	('p16', 'Gene', '1029', (74, 77))	('p16', 'Gene', (14, 17))	('decreased', 'NegReg', (26, 35))
449126	32475345	Aberrant c-Met activation is associated with cancer progression such as more sites of metastasis and an adverse outcome in many malignant tumers.	('activation', 'PosReg', (15, 25))	('Aberrant', 'Var', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('c-Met', 'Gene', (9, 14))	('c-Met', 'Gene', '4233', (9, 14))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('associated', 'Reg', (29, 39))	('cancer', 'Disease', (45, 51))
449128	32475345	Patients with high c-Met levels had a shorter median survival compared with those with low c-Met expression (17 months versus 32 months, P = 0.001).	('shorter', 'NegReg', (38, 45))	('c-Met', 'Gene', (19, 24))	('high', 'Var', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('c-Met', 'Gene', '4233', (19, 24))	('c-Met', 'Gene', (91, 96))	('c-Met', 'Gene', '4233', (91, 96))
449131	32475345	CNV of MET was a common characteristic in malignant tumor.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('malignant tumor', 'Disease', 'MESH:D009369', (42, 57))	('malignant tumor', 'Disease', (42, 57))	('CNV', 'Var', (0, 3))
449132	32475345	The high polysomy CNV of the MET gene and was found in 18% (16/89) clear-cell adenocarcinomas and 1.88% (3/106) non-clear-cell type ovarian carcinomas.	('MET', 'Gene', (29, 32))	('adenocarcinomas', 'Disease', 'MESH:D000230', (78, 93))	('high polysomy CNV', 'Var', (4, 21))	('adenocarcinomas', 'Disease', (78, 93))	('type ovarian carcinomas', 'Disease', 'MESH:D010051', (127, 150))	('carcinomas', 'Phenotype', 'HP:0030731', (83, 93))	('type ovarian carcinomas', 'Disease', (127, 150))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))	('ovarian carcinomas', 'Phenotype', 'HP:0025318', (132, 150))	('carcinomas', 'Phenotype', 'HP:0030731', (140, 150))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))	('found', 'Reg', (46, 51))
449133	32475345	Another study indicated that high polysomy of chromosome 7 was found in 9.5% (10/105) ovarian cancers and most of them were high-grade serous carcinomas.	('high polysomy', 'Var', (29, 42))	('found', 'Reg', (63, 68))	('cancers', 'Phenotype', 'HP:0002664', (94, 101))	('carcinomas', 'Phenotype', 'HP:0030731', (142, 152))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('ovarian cancer', 'Phenotype', 'HP:0100615', (86, 100))	('ovarian cancers', 'Phenotype', 'HP:0100615', (86, 101))	('ovarian cancers', 'Disease', (86, 101))	('serous carcinomas', 'Disease', (135, 152))	('serous carcinomas', 'Disease', 'MESH:D018297', (135, 152))	('ovarian cancers', 'Disease', 'MESH:D010051', (86, 101))	('carcinoma', 'Phenotype', 'HP:0030731', (142, 151))
449134	32475345	In addition, MET amplification was found in several tumors associated with adverse prognostic factors in carcinoma origin from lung, stomach, gallbladder and ovary.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('ovary', 'Disease', (158, 163))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('MET amplification', 'Var', (13, 30))	('carcinoma', 'Disease', 'MESH:D009369', (105, 114))	('tumors', 'Disease', (52, 58))	('ovary', 'Disease', 'MESH:D010051', (158, 163))	('gallbladder', 'Disease', (142, 153))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('stomach', 'Disease', (133, 140))	('lung', 'Disease', (127, 131))	('carcinoma', 'Disease', (105, 114))	('found', 'Reg', (35, 40))
449154	29970482	We therefore hypothesized that EphB3 amplification plays a pro-tumorigenic role in HNSCC and that EphB3 and PIK3CA are co-operating oncogenes that contribute toward its pathogenesis.	('tumor', 'Disease', (63, 68))	('HNSCC', 'Disease', (83, 88))	('HNSCC', 'Phenotype', 'HP:0012288', (83, 88))	('EphB3', 'Gene', (31, 36))	('amplification', 'Var', (37, 50))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('PIK3CA', 'Gene', (108, 114))	('EphB3', 'Gene', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('PIK3CA', 'Gene', '5290', (108, 114))
449155	29970482	This hypothesis was not experimentally supported since EphB3 knockdown failed to alter HNSCC tumor cell growth in vitro or in vivo with an orthotopic model.	('HNSCC', 'Phenotype', 'HP:0012288', (87, 92))	('HNSCC tumor', 'Disease', (87, 98))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('EphB3', 'Gene', (55, 60))	('knockdown', 'Var', (61, 70))	('HNSCC tumor', 'Disease', 'MESH:D000077195', (87, 98))
449156	29970482	However, responsiveness of EphB3 knockdown tumors to the PI3K inhibitor, BKM120, was significantly decreased in terms of both tumor growth delay and survival.	('EphB3', 'Gene', (27, 32))	('decreased', 'NegReg', (99, 108))	('growth delay', 'Phenotype', 'HP:0001510', (132, 144))	('BKM120', 'Chemical', 'MESH:C571178', (73, 79))	('knockdown', 'Var', (33, 42))	('PI3', 'Gene', '5266', (57, 60))	('tumor growth delay', 'Disease', 'MESH:D006130', (126, 144))	('responsiveness', 'MPA', (9, 23))	('PI3', 'Gene', (57, 60))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor growth delay', 'Disease', (126, 144))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumors', 'Disease', (43, 49))	('survival', 'CPA', (149, 157))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('tumors', 'Disease', 'MESH:D009369', (43, 49))
449157	29970482	This is correlated with an increase in pro-survival proteins, S6 and BcL-XL in the EphB3 shRNA tumors treated with BKM120 compared to controls.	('BcL-XL', 'Gene', (69, 75))	('EphB3', 'Gene', (83, 88))	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('BKM120', 'Var', (115, 121))	('increase', 'PosReg', (27, 35))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('BKM120', 'Chemical', 'MESH:C571178', (115, 121))	('tumors', 'Disease', (95, 101))	('BcL-XL', 'Gene', '598', (69, 75))
449158	29970482	Forced EphB3 phosphorylation with an ephrin-B2-Fc fusion protein resulted in decreased HNSCC migration and cell growth and enhanced response to BKM120 in vitro.	('enhanced', 'PosReg', (123, 131))	('response to BKM120', 'MPA', (132, 150))	('EphB3', 'Gene', (7, 12))	('cell growth', 'CPA', (107, 118))	('HNSCC', 'Phenotype', 'HP:0012288', (87, 92))	('BKM120', 'Chemical', 'MESH:C571178', (144, 150))	('ephrin-B2', 'Gene', '1948', (37, 46))	('decreased', 'NegReg', (77, 86))	('phosphorylation', 'Var', (13, 28))	('HNSCC migration', 'CPA', (87, 102))	('ephrin-B2', 'Gene', (37, 46))
449161	29970482	Scientific developments over the past few years have enhanced our understanding of dysregulated cell signaling pathways potentiating cancer progression, and Eph receptors have emerged as attractive candidates for therapeutic intervention.	('Eph', 'Gene', (157, 160))	('dysregulated', 'Var', (83, 95))	('cell signaling pathways', 'Pathway', (96, 119))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('cancer', 'Disease', (133, 139))	('potentiating', 'Reg', (120, 132))	('Eph', 'Gene', '2041', (157, 160))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('enhanced', 'PosReg', (53, 61))
449162	29970482	The paradoxical nature of Eph activities in different cancer types, however, poses a significant challenge, and we are now beginning to understand the dichotomy of Eph receptors and how their dysregulated expression can promote or inhibit tumor progression.	('Eph', 'Gene', (164, 167))	('tumor', 'Disease', 'MESH:D009369', (239, 244))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('inhibit', 'NegReg', (231, 238))	('tumor', 'Phenotype', 'HP:0002664', (239, 244))	('cancer', 'Disease', (54, 60))	('promote', 'PosReg', (220, 227))	('Eph', 'Gene', '2041', (26, 29))	('tumor', 'Disease', (239, 244))	('Eph', 'Gene', '2041', (164, 167))	('dysregulated', 'Var', (192, 204))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('expression', 'MPA', (205, 215))	('Eph', 'Gene', (26, 29))
449167	29970482	Furthermore, knockdown of EphB3 resulted in decreased tumorigenesis and metastasis in vivo .	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('EphB3', 'Gene', (26, 31))	('tumor', 'Disease', (54, 59))	('knockdown', 'Var', (13, 22))	('decreased', 'NegReg', (44, 53))
449170	29970482	Interrogation of the TCGA database led us to identify EphB3 as a new gene target with high copy number amplification in head and neck squamous cell carcinoma (HNSCC).	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (129, 157))	('HNSCC', 'Phenotype', 'HP:0012288', (159, 164))	('high copy number amplification', 'Var', (86, 116))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (134, 157))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (120, 157))	('neck squamous cell carcinoma', 'Disease', (129, 157))	('EphB3', 'Gene', (54, 59))	('carcinoma', 'Phenotype', 'HP:0030731', (148, 157))
449172	29970482	We undertook a loss of function approach with shRNA knockdown to examine the effects on HNSCC growth, migration, and sensitivity to PI3K inhibitors.	('PI3', 'Gene', (132, 135))	('shRNA', 'Gene', (46, 51))	('HNSCC', 'Phenotype', 'HP:0012288', (88, 93))	('knockdown', 'Var', (52, 61))	('PI3', 'Gene', '5266', (132, 135))
449173	29970482	Our data surprisingly showed that EphB3 knockdown does not alter tumor growth, but promotes migration, upregulation of epithelial-to-mesenchymal transition (EMT) and decreases responsiveness to PI3K inhibitors.	('upregulation', 'PosReg', (103, 115))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('tumor', 'Disease', (65, 70))	('knockdown', 'Var', (40, 49))	('PI3', 'Gene', (194, 197))	('promotes', 'PosReg', (83, 91))	('decreases', 'NegReg', (166, 175))	('migration', 'CPA', (92, 101))	('epithelial-to-mesenchymal transition', 'CPA', (119, 155))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('responsiveness to', 'MPA', (176, 193))	('PI3', 'Gene', '5266', (194, 197))	('EphB3', 'Gene', (34, 39))
449174	29970482	Furthermore, forced phosphorylation of EphB3 with ephrin-B2-Fc fusion protein decreased HNSCC migration and cell growth, and enhanced responsiveness of these cells to PI3K inhibitor.	('PI3', 'Gene', '5266', (167, 170))	('cell growth', 'CPA', (108, 119))	('responsiveness', 'Interaction', (134, 148))	('HNSCC migration', 'CPA', (88, 103))	('EphB3', 'Gene', (39, 44))	('HNSCC', 'Phenotype', 'HP:0012288', (88, 93))	('ephrin-B2', 'Gene', (50, 59))	('PI3', 'Gene', (167, 170))	('enhanced', 'PosReg', (125, 133))	('decreased', 'NegReg', (78, 87))	('phosphorylation', 'Var', (20, 35))	('ephrin-B2', 'Gene', '1948', (50, 59))
449177	29970482	Cohorts containing significant amplification of EPHB3 including Head and Neck Provisional (n=530), Lung Squamous Cell Carcinoma Provisional (n=530), and Cervical Cancer Provisional (n=309) were re-queried for alterations in PIK3CA gene commonly found altered in head and neck cancers.	('Cervical Cancer', 'Disease', 'MESH:D002583', (153, 168))	('EPHB3', 'Gene', (48, 53))	('PIK3CA', 'Gene', '5290', (224, 230))	('head and neck cancer', 'Disease', 'MESH:D006258', (262, 282))	('Carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('Cancer', 'Phenotype', 'HP:0002664', (162, 168))	('Lung Squamous Cell Carcinoma', 'Disease', 'MESH:D002294', (99, 127))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (104, 127))	('head and neck cancers', 'Phenotype', 'HP:0012288', (262, 283))	('EPHB3', 'Gene', '2049', (48, 53))	('neck cancers', 'Disease', (271, 283))	('cancers', 'Phenotype', 'HP:0002664', (276, 283))	('neck cancers', 'Disease', 'MESH:D006258', (271, 283))	('PIK3CA', 'Gene', (224, 230))	('Cervical Cancer', 'Disease', (153, 168))	('cancer', 'Phenotype', 'HP:0002664', (276, 282))	('Lung Squamous Cell Carcinoma', 'Phenotype', 'HP:0030359', (99, 127))	('Lung Squamous Cell Carcinoma', 'Disease', (99, 127))	('head and neck cancer', 'Phenotype', 'HP:0012288', (262, 282))	('amplification', 'Var', (31, 44))
449220	29970482	All primary antibodies against p-AKT (S473), AKT, p-S6 (S235/S236), S6, Bcl-XL were obtained from Cell Signaling Technology (Danvers, MA, USA).	('Bcl-XL', 'Gene', (72, 78))	('p-S6', 'Gene', '338413', (50, 54))	('AKT', 'Gene', (45, 48))	('AKT', 'Gene', '207', (33, 36))	('p-S6', 'Gene', (50, 54))	('Bcl-XL', 'Gene', '598', (72, 78))	('AKT', 'Gene', (33, 36))	('AKT', 'Gene', '207', (45, 48))	('S473', 'Var', (38, 42))
449233	29970482	Alterations in EPHB3 across cancer types in the TCGA database were accessed via cBioportal and analyzed.	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('Alterations', 'Var', (0, 11))	('EPHB3', 'Gene', '2049', (15, 20))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('cancer', 'Disease', (28, 34))	('EPHB3', 'Gene', (15, 20))
449245	29970482	In Ly2 cells, cells were EphB3 was knocked down also showed a trend towards increased migration compared to the control counterpart (Supplementary figure 3B).	('EphB3', 'Gene', (25, 30))	('migration', 'CPA', (86, 95))	('increased', 'PosReg', (76, 85))	('knocked down', 'Var', (35, 47))	('Ly2', 'CellLine', 'CVCL:8799', (3, 6))
449248	29970482	It was noted that ~18-43% patients have co-amplification of EPHB3 and PIK3CA, a catalytic subunit of PI3K (Figure 3A, Table 1).	('co-amplification', 'Var', (40, 56))	('EPHB3', 'Gene', (60, 65))	('PIK3CA', 'Gene', '5290', (70, 76))	('PI3', 'Gene', (101, 104))	('patients', 'Species', '9606', (26, 34))	('PIK3CA', 'Gene', (70, 76))	('EPHB3', 'Gene', '2049', (60, 65))	('PI3', 'Gene', '5266', (101, 104))
449251	29970482	CAL27 cells were grown in the presence of increasing concentrations of BKM120, a pan-class I PI3K inhibitor, until they had acquired resistance to 2.5 muM BKM120.	('BKM120', 'Chemical', 'MESH:C571178', (71, 77))	('muM', 'Gene', '56925', (151, 154))	('PI3', 'Gene', (93, 96))	('muM', 'Gene', (151, 154))	('BKM120', 'Var', (71, 77))	('BKM120', 'Chemical', 'MESH:C571178', (155, 161))	('PI3', 'Gene', '5266', (93, 96))
449252	29970482	SRB proliferation assay demonstrates that CAL27-BKM120-resistant cells proliferate more slowly than parental CAL27 cells but are less sensitive to BKM120 treatment than parental cells which are acutely sensitive to BKM120 (Figure 3B).	('slowly', 'NegReg', (88, 94))	('SRB', 'Gene', (0, 3))	('SRB', 'Gene', '10575', (0, 3))	('CAL27-BKM120-resistant', 'Var', (42, 64))	('BKM120', 'Chemical', 'MESH:C571178', (147, 153))	('proliferate', 'CPA', (71, 82))	('BKM120', 'Chemical', 'MESH:C571178', (48, 54))	('BKM120', 'Chemical', 'MESH:C571178', (215, 221))
449256	29970482	Parental CAL27 cells treated with BKM120 had reduced levels of p-AKT and p-S6, downstream effectors of PI3K signaling pathway (Figure 3C).	('PI3', 'Gene', (103, 106))	('p-S6', 'Gene', (73, 77))	('reduced', 'NegReg', (45, 52))	('AKT', 'Gene', (65, 68))	('BKM120', 'Chemical', 'MESH:C571178', (34, 40))	('PI3', 'Gene', '5266', (103, 106))	('p-S6', 'Gene', '338413', (73, 77))	('AKT', 'Gene', '207', (65, 68))	('BKM120', 'Var', (34, 40))
449260	29970482	The data show a minor increase in the levels of p-AKT and p-S6 in the CAL27 EphB3 knockdown clones compared to the control shRNA cells in the absence of BKM120 inhibitor.	('p-S6', 'Gene', (58, 62))	('AKT', 'Gene', '207', (50, 53))	('EphB3', 'Gene', (76, 81))	('knockdown', 'Var', (82, 91))	('increase', 'PosReg', (22, 30))	('AKT', 'Gene', (50, 53))	('p-S6', 'Gene', '338413', (58, 62))	('CAL27 EphB3', 'Gene', (70, 81))	('BKM120', 'Chemical', 'MESH:C571178', (153, 159))
449261	29970482	The levels of p-S6 protein are slightly increased in the EphB3 knockdown cells compared to the control samples in the presence of high dose of BKM120 (Figure 3D).	('levels', 'MPA', (4, 10))	('BKM120', 'Chemical', 'MESH:C571178', (143, 149))	('EphB3', 'Gene', (57, 62))	('p-S6', 'Gene', '338413', (14, 18))	('increased', 'PosReg', (40, 49))	('knockdown', 'Var', (63, 72))	('p-S6', 'Gene', (14, 18))
449267	29970482	In our experimental model, we observed that knockdown of EphB3 did not significantly affect CAL27 tumor growth compared to the control group (Figure 4A).	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('EphB3', 'Gene', (57, 62))	('knockdown', 'Var', (44, 53))	('tumor', 'Disease', (98, 103))
449268	29970482	Due to the aggressive tumor growth pattern, most of the mice in the EphB3 knockdown and control group subjected to vehicle treatment were sacrificed after day 20 post-vehicle treatment.	('EphB3', 'Gene', (68, 73))	('knockdown', 'Var', (74, 83))	('aggressive tumor', 'Disease', 'MESH:D001523', (11, 27))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('mice', 'Species', '10090', (56, 60))	('aggressive tumor', 'Disease', (11, 27))
449269	29970482	We also interrogated whether EphB3 knockdown in head and neck cancer cells alters in vivo sensitivity towards PI3K inhibition.	('knockdown', 'Var', (35, 44))	('sensitivity towards', 'MPA', (90, 109))	('alters', 'Reg', (75, 81))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('head and neck cancer', 'Phenotype', 'HP:0012288', (48, 68))	('EphB3', 'Gene', (29, 34))	('PI3', 'Gene', '5266', (110, 113))	('head and neck cancer', 'Disease', 'MESH:D006258', (48, 68))	('PI3', 'Gene', (110, 113))
449270	29970482	We found that EphB3 knockdown in CAL27 tumors that were administered with BKM120 had significantly enhanced tumor growth by approximately1.5 fold compared to the control BKM120 treated xenografts at day 42 post-treatment with BKM120 (Figure 4B).	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('EphB3', 'Gene', (14, 19))	('BKM120', 'Chemical', 'MESH:C571178', (74, 80))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('enhanced', 'PosReg', (99, 107))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('BKM120', 'Chemical', 'MESH:C571178', (226, 232))	('CAL27 tumors', 'Disease', 'MESH:D009369', (33, 45))	('tumor', 'Disease', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('BKM120', 'Var', (74, 80))	('tumor', 'Disease', (39, 44))	('knockdown', 'Var', (20, 29))	('CAL27 tumors', 'Disease', (33, 45))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('BKM120', 'Chemical', 'MESH:C571178', (170, 176))
449271	29970482	In addition, we investigated whether EphB3 knockdown in CAL27 tumors had an effect on overall survival in vivo.	('CAL27 tumors', 'Disease', 'MESH:D009369', (56, 68))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('effect', 'Reg', (76, 82))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('knockdown', 'Var', (43, 52))	('CAL27 tumors', 'Disease', (56, 68))	('EphB3', 'Gene', (37, 42))
449273	29970482	Treatment of CAL27 control tumors with BKM120 also provided survival benefit compared to other groups with median survival of approximately 70 days (Figure 4C).	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('benefit', 'PosReg', (69, 76))	('tumors', 'Disease', (27, 33))	('tumors', 'Disease', 'MESH:D009369', (27, 33))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('BKM120', 'Var', (39, 45))	('survival', 'MPA', (60, 68))	('BKM120', 'Chemical', 'MESH:C571178', (39, 45))
449274	29970482	However, EphB3 knockdown tumors treated with BKM120 reduced the median survival to 50 days (Figure 4C).	('median', 'CPA', (64, 70))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('BKM120', 'Var', (45, 51))	('reduced', 'NegReg', (52, 59))	('tumors', 'Disease', (25, 31))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('EphB3', 'Gene', (9, 14))	('tumors', 'Disease', 'MESH:D009369', (25, 31))	('BKM120', 'Chemical', 'MESH:C571178', (45, 51))
449281	29970482	Given that our in vitro data showed an increase in HNSCC migration following EphB3 knockdown, we sought to determine the mechanisms underlying changes in tumor cell growth observed in vivo particularly following BKM120 inhibitor treatment.	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('HNSCC', 'Phenotype', 'HP:0012288', (51, 56))	('BKM120', 'Chemical', 'MESH:C571178', (212, 218))	('increase', 'PosReg', (39, 47))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('EphB3', 'Gene', (77, 82))	('HNSCC migration', 'CPA', (51, 66))	('knockdown', 'Var', (83, 92))	('tumor', 'Disease', (154, 159))
449282	29970482	Immunohistochemical analysis on tumor sections was performed on tumors derived from EphB3 knockdown and control tumors with vehicle or BKM120 treatment.	('tumors', 'Disease', 'MESH:D009369', (112, 118))	('tumors', 'Disease', (64, 70))	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('tumor', 'Disease', (64, 69))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('knockdown', 'Var', (90, 99))	('BKM120', 'Chemical', 'MESH:C571178', (135, 141))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('EphB3', 'Gene', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Disease', (112, 117))	('tumor', 'Disease', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('tumors', 'Disease', (112, 118))
449283	29970482	Our data show that knockdown of EphB3 did not affect tumor cell proliferation to a significant extent compared to the control vehicle as evident by PCNA staining (Figure 4F).	('knockdown', 'Var', (19, 28))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('EphB3', 'Gene', (32, 37))	('tumor', 'Disease', (53, 58))
449284	29970482	The CAL27 tumors treated with BKM120 showed reduced PCNA staining compared to the control vehicle treated group (Figure 4F).	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('BKM120', 'Chemical', 'MESH:C571178', (30, 36))	('CAL27 tumors', 'Disease', (4, 16))	('PCNA staining', 'MPA', (52, 65))	('tumors', 'Phenotype', 'HP:0002664', (10, 16))	('reduced', 'NegReg', (44, 51))	('BKM120', 'Var', (30, 36))	('CAL27 tumors', 'Disease', 'MESH:D009369', (4, 16))
449285	29970482	However, when tumors with EphB3 knockdown were treated with BKM120, a significant increase in the levels of PCNA was observed compared to control BKM120 and EphB3 KD vehicle (Figure 4F), suggesting that EphB3 knockdown decreases response to BKM120 inhibitor treatment and results in increased tumor cell proliferation.	('EphB3', 'Gene', (203, 208))	('tumor', 'Disease', 'MESH:D009369', (293, 298))	('increased', 'PosReg', (283, 292))	('BKM120', 'Var', (60, 66))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('decreases', 'NegReg', (219, 228))	('tumor', 'Phenotype', 'HP:0002664', (293, 298))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('knockdown', 'Var', (209, 218))	('EphB3', 'Gene', (26, 31))	('response', 'MPA', (229, 237))	('tumors', 'Disease', (14, 20))	('tumor', 'Disease', (14, 19))	('BKM120', 'Chemical', 'MESH:C571178', (60, 66))	('knockdown', 'Var', (32, 41))	('BKM120', 'Chemical', 'MESH:C571178', (241, 247))	('tumor', 'Disease', (293, 298))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('BKM120', 'Chemical', 'MESH:C571178', (146, 152))
449286	29970482	Since we observed an increase in migration of EphB3 knockdown cells in vitro, we also analyzed the levels of E-cadherin (an epithelial cell marker) and vimentin (a mesenchymal marker), proteins reported to play a role in tumor cell migration.	('vimentin', 'Gene', '7431', (152, 160))	('vimentin', 'Gene', (152, 160))	('migration', 'CPA', (33, 42))	('tumor', 'Disease', (221, 226))	('EphB3', 'Gene', (46, 51))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('E-cadherin', 'Gene', (109, 119))	('increase', 'PosReg', (21, 29))	('E-cadherin', 'Gene', '999', (109, 119))	('knockdown', 'Var', (52, 61))	('tumor', 'Disease', 'MESH:D009369', (221, 226))
449289	29970482	We observed significant upregulation of E-cadherin in control tumors treated with BKM120 compared to the non-treated counterparts (Figure 4G).	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('BKM120', 'Chemical', 'MESH:C571178', (82, 88))	('tumors', 'Disease', (62, 68))	('E-cadherin', 'Gene', (40, 50))	('E-cadherin', 'Gene', '999', (40, 50))	('tumors', 'Disease', 'MESH:D009369', (62, 68))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('BKM120', 'Var', (82, 88))	('upregulation', 'PosReg', (24, 36))
449298	29970482	Additionally, forced phosphorylation with ephrin-B2-Fc stimulation significantly decreased CAL27 HNSCC migration in a Boyden chamber assay (Figure 5C) and cell growth by MTT assay (Figure 5D) Furthermore, we observed a significant reduction in cell growth when ephrin-B2 stimulated CAL27 cells were treated with BKM120 compared to the Control-Fc treated group (Figure 5E).	('decreased', 'NegReg', (81, 90))	('MTT', 'Chemical', 'MESH:C070243', (170, 173))	('HNSCC', 'Phenotype', 'HP:0012288', (97, 102))	('reduction', 'NegReg', (231, 240))	('cell growth by MTT assay', 'CPA', (155, 179))	('CAL27', 'Protein', (91, 96))	('ephrin-B2', 'Gene', (42, 51))	('BKM120', 'Chemical', 'MESH:C571178', (312, 318))	('ephrin-B2', 'Gene', (261, 270))	('BKM120', 'Var', (312, 318))	('ephrin-B2', 'Gene', '1948', (42, 51))	('ephrin-B2', 'Gene', '1948', (261, 270))	('cell growth', 'CPA', (244, 255))
449302	29970482	Analysis of the phosphorylation status of EphB3 in CAL27 and Ly2 cells transfected with control shRNA and EphB3-specific shRNA by immunoprecipitation analysis shows reduced levels of p-EphB3 present in both CAL27 (Figure 5H) and Ly2 cells (Figure 5I) transfected with EphB3-specific shRNA as compared to the control shRNA clones.	('reduced', 'NegReg', (165, 172))	('Ly2', 'CellLine', 'CVCL:8799', (229, 232))	('Ly2', 'CellLine', 'CVCL:8799', (61, 64))	('p-EphB3', 'Var', (183, 190))
449305	29970482	Survival analysis revealed a trend that patients with high EphB3 expression have better overall survival (median overall survival ~ 49 months) compared to the patients with low EphB3 expression (median overall survival ~ 28 months) (Figure 6B).	('better', 'PosReg', (81, 87))	('high', 'Var', (54, 58))	('patients', 'Species', '9606', (40, 48))	('overall survival', 'MPA', (88, 104))	('patients', 'Species', '9606', (159, 167))	('EphB3', 'Gene', (59, 64))
449306	29970482	Patients with high EphB3 expression also showed significantly higher disease-free survival rates with median survival ~71 months as compared to the patients with low EphB3 expression with median survival ~28 months (Figure 6C).	('patients', 'Species', '9606', (148, 156))	('EphB3', 'Gene', (19, 24))	('high', 'Var', (14, 18))	('higher', 'PosReg', (62, 68))	('disease-free survival rates', 'CPA', (69, 96))	('Patients', 'Species', '9606', (0, 8))	('expression', 'Var', (25, 35))
449308	29970482	Dysregulated expression of both Eph receptors and their cognate ligands has been reported to contribute towards tumor progression, and metastasis.	('metastasis', 'CPA', (135, 145))	('contribute', 'Reg', (93, 103))	('expression', 'MPA', (13, 23))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('Eph', 'Gene', '2041', (32, 35))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('Dysregulated', 'Var', (0, 12))	('Eph', 'Gene', (32, 35))	('tumor', 'Disease', (112, 117))
449309	29970482	Aberrant expression of EphB3, a member of the Eph receptor gene family, has been reported in different cancers.	('cancers', 'Disease', 'MESH:D009369', (103, 110))	('Aberrant expression', 'Var', (0, 19))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('Eph', 'Gene', '2041', (46, 49))	('Eph', 'Gene', '2041', (23, 26))	('Eph', 'Gene', (46, 49))	('cancers', 'Phenotype', 'HP:0002664', (103, 110))	('Eph', 'Gene', (23, 26))	('reported', 'Reg', (81, 89))	('cancers', 'Disease', (103, 110))
449312	29970482	Yet, in a different manuscript done by the same group a year later, it was reported that inhibition of EphB3 promoted NSCLC migration and metastasis.	('EphB3', 'Gene', (103, 108))	('promoted', 'PosReg', (109, 117))	('NSCLC', 'Phenotype', 'HP:0030358', (118, 123))	('inhibition', 'Var', (89, 99))	('NSCLC', 'Disease', (118, 123))	('NSCLC', 'Disease', 'MESH:D002289', (118, 123))
449315	29970482	Given that the high levels of expression and the association between Eph receptor tumor promoting properties and the AKT pathway, we hypothesized that EphB3 amplification plays a pro-tumorigenic role in HNSCC and that EphB3 and PIK3CA are co-operating oncogenes that contribute toward its pathogenesis.	('Eph', 'Gene', '2041', (151, 154))	('HNSCC', 'Phenotype', 'HP:0012288', (203, 208))	('Eph', 'Gene', (69, 72))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('tumor', 'Disease', (82, 87))	('Eph', 'Gene', '2041', (69, 72))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('AKT', 'Gene', (117, 120))	('Eph', 'Gene', (218, 221))	('PIK3CA', 'Gene', '5290', (228, 234))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('Eph', 'Gene', '2041', (218, 221))	('tumor', 'Disease', (183, 188))	('HNSCC', 'Disease', (203, 208))	('AKT', 'Gene', '207', (117, 120))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('Eph', 'Gene', (151, 154))	('association', 'Interaction', (49, 60))	('amplification', 'Var', (157, 170))	('PIK3CA', 'Gene', (228, 234))
449319	29970482	Knockdown of EphB3 also reduced sensitivity to BKM120 via an increase in AKT and p-S6 proteins.	('BKM120', 'Chemical', 'MESH:C571178', (47, 53))	('sensitivity to BKM120', 'MPA', (32, 53))	('Knockdown', 'Var', (0, 9))	('reduced', 'NegReg', (24, 31))	('AKT', 'Gene', (73, 76))	('p-S6', 'Gene', '338413', (81, 85))	('p-S6', 'Gene', (81, 85))	('increase', 'PosReg', (61, 69))	('EphB3', 'Gene', (13, 18))	('AKT', 'Gene', '207', (73, 76))
449321	29970482	PI3K-AKT-mTOR pathway alterations are implicated in almost a third of HNSCC, with PIK3CA commonly mutated and multiple PI3K-AKT-mTOR pathway aberrations associated with disease progression.	('PIK3CA', 'Gene', '5290', (82, 88))	('mTOR', 'Gene', (128, 132))	('PI3', 'Gene', '5266', (119, 122))	('AKT', 'Gene', (124, 127))	('mTOR', 'Gene', (9, 13))	('PI3', 'Gene', '5266', (0, 3))	('AKT', 'Gene', (5, 8))	('PIK3CA', 'Gene', (82, 88))	('HNSCC', 'Disease', (70, 75))	('mTOR', 'Gene', '2475', (128, 132))	('mTOR', 'Gene', '2475', (9, 13))	('PI3', 'Gene', (119, 122))	('implicated', 'Reg', (38, 48))	('mutated', 'Var', (98, 105))	('PI3', 'Gene', (0, 3))	('AKT', 'Gene', '207', (124, 127))	('HNSCC', 'Phenotype', 'HP:0012288', (70, 75))	('AKT', 'Gene', '207', (5, 8))	('alterations', 'Var', (22, 33))	('associated', 'Reg', (153, 163))
449323	29970482	Our data suggests that EphB3 knockdown reduces sensitivity to PI3K inhibitors.	('knockdown', 'Var', (29, 38))	('PI3', 'Gene', '5266', (62, 65))	('EphB3', 'Gene', (23, 28))	('sensitivity to', 'MPA', (47, 61))	('PI3', 'Gene', (62, 65))	('reduces', 'NegReg', (39, 46))
449480	28322515	<=60 Gy vs. >60 Gy), there were proportionally more N2, stage IIIB, and tumor length >8 cm in the <=60 Gy group.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('more', 'PosReg', (47, 51))	('tumor', 'Disease', (72, 77))	('stage', 'Disease', (56, 61))	('<=60', 'Var', (98, 102))	('tumor', 'Disease', 'MESH:D009369', (72, 77))
449538	28322515	In the two patients who suffered from grade 4 respiratory failure, one received an RT dose of 64 Gy, lung V20 = 32%, lung V10 = 59%, and mean lung dose of 16 Gy, while the other received an RT dose of 60 Gy, lung V20 = 13%, lung V10 = 50%, and mean lung dose of 12 Gy.	('lung V20 = 13%', 'Var', (208, 222))	('respiratory failure', 'Disease', (46, 65))	('lung V10 =', 'Var', (117, 127))	('lung V10 =', 'Var', (224, 234))	('respiratory failure', 'Disease', 'MESH:D012131', (46, 65))	('lung V20 =', 'Var', (101, 111))	('patients', 'Species', '9606', (11, 19))	('respiratory failure', 'Phenotype', 'HP:0002878', (46, 65))
449554	33061453	Oncogene miR-324-5p was predicted to interact with GATA6-AS1.	('miR-324-5p', 'Var', (9, 19))	('GATA6-AS1', 'Gene', (51, 60))	('miR-324-5p', 'Chemical', '-', (9, 19))	('GATA6-AS1', 'Gene', '100128893;2627;5729', (51, 60))	('interact', 'Interaction', (37, 45))
449567	33061453	For example, miR-324-5p, which is a recently defined oncogenic miRNA in lung cancer, is frequently upregulated in lung cancer and facilitates lung cancer cell proliferation and invasion.	('miR-324-5p', 'Chemical', '-', (13, 23))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('lung cancer', 'Disease', 'MESH:D008175', (114, 125))	('upregulated', 'PosReg', (99, 110))	('invasion', 'CPA', (177, 185))	('lung cancer', 'Disease', 'MESH:D008175', (142, 153))	('lung cancer', 'Disease', (142, 153))	('lung cancer', 'Disease', (72, 83))	('lung cancer', 'Disease', (114, 125))	('lung cancer', 'Phenotype', 'HP:0100526', (142, 153))	('lung cancer', 'Phenotype', 'HP:0100526', (114, 125))	('lung cancer', 'Phenotype', 'HP:0100526', (72, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('miR-324-5p', 'Var', (13, 23))	('facilitates', 'PosReg', (130, 141))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('lung cancer', 'Disease', 'MESH:D008175', (72, 83))
449568	33061453	In addition, miR-324-5p also targets FBXO11, a regulator of epithelial-mesenchymal transition (EMT), to promote development of drug resistance for lung cancer, whereasthe mechanism underlying the aberrant expression of miR-324-5p in lung cancer remains elusive.	('FBXO11', 'Gene', (37, 43))	('miR-324-5p', 'Chemical', '-', (219, 229))	('miR-324-5p', 'Chemical', '-', (13, 23))	('drug resistance', 'Phenotype', 'HP:0020174', (127, 142))	('lung cancer', 'Phenotype', 'HP:0100526', (233, 244))	('lung cancer', 'Disease', (233, 244))	('lung cancer', 'Disease', (147, 158))	('lung cancer', 'Phenotype', 'HP:0100526', (147, 158))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('drug resistance', 'MPA', (127, 142))	('promote', 'PosReg', (104, 111))	('lung cancer', 'Disease', 'MESH:D008175', (233, 244))	('lung cancer', 'Disease', 'MESH:D008175', (147, 158))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('miR-324-5p', 'Var', (13, 23))	('development', 'MPA', (112, 123))	('FBXO11', 'Gene', '80204', (37, 43))
449571	33061453	GATA6-AS1 sponged oncogene miR-324-5p and inhibited cell proliferation and invasion in lung cancer cells.	('miR-324-5p', 'Var', (27, 37))	('miR-324-5p', 'Chemical', '-', (27, 37))	('GATA6-AS1', 'Gene', '100128893;2627;5729', (0, 9))	('lung cancer', 'Disease', 'MESH:D008175', (87, 98))	('inhibited', 'NegReg', (42, 51))	('lung cancer', 'Disease', (87, 98))	('GATA6-AS1', 'Gene', (0, 9))	('lung cancer', 'Phenotype', 'HP:0100526', (87, 98))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
449593	33061453	Site mutations were introduced into pmiRGLO-GATA6-AS1 and pmiRGLO-FBXO11 3'UTR with QuikChange Lightning Site-Directed Mutagenesis Kit (Agilent Technologies, Santa Clara, CA).	('GATA6-AS1', 'Gene', '100128893;2627;5729', (44, 53))	('mutations', 'Var', (5, 14))	('FBXO11', 'Gene', '80204', (66, 72))	('FBXO11', 'Gene', (66, 72))	('GATA6-AS1', 'Gene', (44, 53))
449603	33061453	Interestingly, high expression of GATA5-AS1 was associated with prolonged OS in patients with lung cancer (Figure 1D).	('GATA5', 'Gene', (34, 39))	('high expression', 'Var', (15, 30))	('lung cancer', 'Disease', 'MESH:D008175', (94, 105))	('patients', 'Species', '9606', (80, 88))	('GATA5', 'Gene', '140628', (34, 39))	('AS1', 'Gene', (40, 43))	('associated', 'Reg', (48, 58))	('AS1', 'Gene', '5729', (40, 43))	('lung cancer', 'Disease', (94, 105))	('lung cancer', 'Phenotype', 'HP:0100526', (94, 105))	('prolonged OS', 'Disease', (64, 76))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
449612	33061453	We used miRDB software to predict potential binding sites for miRNAs in GATA6-AS1 sequence.	('binding', 'Interaction', (44, 51))	('miRNAs', 'Var', (62, 68))	('GATA6-AS1', 'Gene', (72, 81))	('GATA6-AS1', 'Gene', '100128893;2627;5729', (72, 81))
449613	33061453	Among 41 binding sites, we noticed that there was a site for oncogene miR-324-5p in GATA6-AS1 (Figure 3A).	('GATA6-AS1', 'Gene', (84, 93))	('miR-324-5p', 'Chemical', '-', (70, 80))	('miR-324-5p', 'Var', (70, 80))	('GATA6-AS1', 'Gene', '100128893;2627;5729', (84, 93))
449615	33061453	Furthermore, transfection of miR-324-5p inhibitor decreased miR-324-5p expression in NCI-H1975 and A549 cells (Figure 3C), and the downregulation of miR-324-5p elevated GATA6-AS1 levels in these cells (Figure 3D).	('A549', 'CellLine', 'CVCL:0023', (99, 103))	('elevated', 'PosReg', (160, 168))	('miR-324-5p', 'Var', (149, 159))	('GATA6-AS1', 'Gene', '100128893;2627;5729', (169, 178))	('NCI-H1975', 'CellLine', 'CVCL:1511', (85, 94))	('miR-324-5p', 'Chemical', '-', (149, 159))	('GATA6-AS1', 'Gene', (169, 178))	('decreased', 'NegReg', (50, 59))	('miR-324-5p', 'Chemical', '-', (29, 39))	('downregulation', 'NegReg', (131, 145))	('miR-324-5p', 'Chemical', '-', (60, 70))	('miR-324-5p expression', 'MPA', (60, 81))
449616	33061453	We constructed luciferase vector containing GATA6-AS1-wild type or GATA6-AS1-Mutant (with point-mutation in the predicted binding site) (Figure 4A).	('GATA6-AS1', 'Gene', '100128893;2627;5729', (44, 53))	('GATA6-AS1', 'Gene', (67, 76))	('GATA6-AS1', 'Gene', (44, 53))	('point-mutation', 'Var', (90, 104))	('GATA6-AS1', 'Gene', '100128893;2627;5729', (67, 76))
449617	33061453	miR-324-5p was increased in NCI-H1975 and A549 cells upon transfection of miR-324-5p mimic (Figure 4B).	('miR-324-5p', 'Chemical', '-', (0, 10))	('miR-324-5p', 'Gene', (0, 10))	('A549', 'CellLine', 'CVCL:0023', (42, 46))	('miR-324-5p mimic', 'Var', (74, 90))	('increased', 'PosReg', (15, 24))	('NCI-H1975', 'CellLine', 'CVCL:1511', (28, 37))	('miR-324-5p', 'Chemical', '-', (74, 84))
449620	33061453	FBXO11, a key regulator of EMT, was a verified target of miR-324-5p in lung cancer cells.	('lung cancer', 'Disease', 'MESH:D008175', (71, 82))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('FBXO11', 'Gene', '80204', (0, 6))	('miR-324-5p', 'Chemical', '-', (57, 67))	('miR-324-5p', 'Var', (57, 67))	('FBXO11', 'Gene', (0, 6))	('lung cancer', 'Disease', (71, 82))	('lung cancer', 'Phenotype', 'HP:0100526', (71, 82))
449627	33061453	To examine whether miR-324-5p was involved in regulation of FBXO11, we co-transfected GATA6-AS1 and miR-324-5p mimic into lung cancer cells.	('miR-324-5p', 'Var', (100, 110))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('lung cancer', 'Disease', (122, 133))	('FBXO11', 'Gene', '80204', (60, 66))	('lung cancer', 'Phenotype', 'HP:0100526', (122, 133))	('miR-324-5p', 'Chemical', '-', (100, 110))	('GATA6-AS1', 'Gene', (86, 95))	('FBXO11', 'Gene', (60, 66))	('GATA6-AS1', 'Gene', '100128893;2627;5729', (86, 95))	('lung cancer', 'Disease', 'MESH:D008175', (122, 133))	('miR-324-5p', 'Chemical', '-', (19, 29))
449628	33061453	In NCI-H1975, the Western blotting showed that miR-324-5p mimic reversed upregulation of FBXO11 and downregulation of SNAIL protein levels which were induced by transfection of GATA6-AS1 (Figure 6A).	('SNAIL', 'Gene', '6615', (118, 123))	('SNAIL', 'Gene', (118, 123))	('FBXO11', 'Gene', '80204', (89, 95))	('FBXO11', 'Gene', (89, 95))	('miR-324-5p', 'Var', (47, 57))	('GATA6-AS1', 'Gene', (177, 186))	('NCI-H1975', 'CellLine', 'CVCL:1511', (3, 12))	('downregulation', 'NegReg', (100, 114))	('miR-324-5p', 'Chemical', '-', (47, 57))	('GATA6-AS1', 'Gene', '100128893;2627;5729', (177, 186))	('upregulation', 'PosReg', (73, 85))
449630	33061453	At the mRNA level, miR-324-5p mimic also attenuated the upregulation of FBXO11 in NCI-H1975 and A549 cells (Figure 6C).	('attenuated', 'NegReg', (41, 51))	('upregulation', 'PosReg', (56, 68))	('A549', 'CellLine', 'CVCL:0023', (96, 100))	('NCI-H1975', 'CellLine', 'CVCL:1511', (82, 91))	('miR-324-5p', 'Var', (19, 29))	('FBXO11', 'Gene', '80204', (72, 78))	('FBXO11', 'Gene', (72, 78))	('miR-324-5p', 'Chemical', '-', (19, 29))
449631	33061453	We constructed luciferase vector containing FBXO11 3'UTR-wild type or FBXO11 3'UTR -Mutant (with point-mutation in the binding site) (Figure 6D).	('point-mutation', 'Var', (97, 111))	('FBXO11', 'Gene', '80204', (44, 50))	('FBXO11', 'Gene', (44, 50))	('FBXO11', 'Gene', '80204', (70, 76))	('FBXO11', 'Gene', (70, 76))
449634	33061453	In addition, the CCK-8 assay showed that miR-324-5p mimic attenuated the effect of GATA6-AS1 overexpression on cell proliferation in NCI-H1975 and A549 cells (Figure 7BC).	('miR-324-5p', 'Var', (41, 51))	('GATA6-AS1', 'Gene', (83, 92))	('attenuated', 'NegReg', (58, 68))	('miR-324-5p', 'Chemical', '-', (41, 51))	('A549', 'CellLine', 'CVCL:0023', (147, 151))	('NCI-H1975', 'CellLine', 'CVCL:1511', (133, 142))	('GATA6-AS1', 'Gene', '100128893;2627;5729', (83, 92))	('cell proliferation', 'CPA', (111, 129))	('CCK-8', 'Chemical', 'MESH:D012844', (17, 22))	('overexpression', 'PosReg', (93, 107))
449648	33061453	miR-324-5p targeted TGFbeta2 and inhibited gallbladder carcinoma cell metastasis.	('TGFbeta2', 'Gene', (20, 28))	('miR-324-5p', 'Chemical', '-', (0, 10))	('carcinoma', 'Phenotype', 'HP:0030731', (55, 64))	('gallbladder carcinoma', 'Disease', (43, 64))	('TGFbeta2', 'Gene', '7042', (20, 28))	('miR-324-5p', 'Var', (0, 10))	('inhibited', 'NegReg', (33, 42))	('gallbladder carcinoma', 'Disease', 'MESH:D005706', (43, 64))
449649	33061453	miR-324-5p directly repressed ELAVL1 to inhibit cell proliferation and invasion of colorectal cancer.	('colorectal cancer', 'Disease', 'MESH:D015179', (83, 100))	('ELAVL1', 'Gene', '1994', (30, 36))	('miR-324-5p', 'Chemical', '-', (0, 10))	('inhibit', 'NegReg', (40, 47))	('colorectal cancer', 'Phenotype', 'HP:0003003', (83, 100))	('ELAVL1', 'Gene', (30, 36))	('invasion', 'CPA', (71, 79))	('cell proliferation', 'CPA', (48, 66))	('colorectal cancer', 'Disease', (83, 100))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('miR-324-5p', 'Var', (0, 10))
449650	33061453	On the contrary, in lung cancer, upregulation of miR-324-5p was observed in most patients.	('miR-324-5p', 'Var', (49, 59))	('lung cancer', 'Disease', 'MESH:D008175', (20, 31))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('miR-324-5p', 'Chemical', '-', (49, 59))	('patients', 'Species', '9606', (81, 89))	('lung cancer', 'Disease', (20, 31))	('upregulation', 'PosReg', (33, 45))	('lung cancer', 'Phenotype', 'HP:0100526', (20, 31))
449652	33061453	Via bioinformatic analysis, we found that there was a binding site for miR-324-5p in GATA6-AS1 sequence.	('GATA6-AS1', 'Gene', '100128893;2627;5729', (85, 94))	('miR-324-5p', 'Chemical', '-', (71, 81))	('miR-324-5p', 'Var', (71, 81))	('GATA6-AS1', 'Gene', (85, 94))	('binding', 'Interaction', (54, 61))
449653	33061453	We further confirmed that there was a mutual regulatory association between GATA6-AS1 and miR-324-5p.	('miR-324-5p', 'Chemical', '-', (90, 100))	('GATA6-AS1', 'Gene', '100128893;2627;5729', (76, 85))	('GATA6-AS1', 'Gene', (76, 85))	('miR-324-5p', 'Var', (90, 100))
449654	33061453	One recent study discovered that miR-324-5p directly suppressed FBXO11 expression in lung cancer cells.	('expression', 'MPA', (71, 81))	('lung cancer', 'Disease', (85, 96))	('lung cancer', 'Phenotype', 'HP:0100526', (85, 96))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('FBXO11', 'Gene', '80204', (64, 70))	('FBXO11', 'Gene', (64, 70))	('miR-324-5p', 'Var', (33, 43))	('lung cancer', 'Disease', 'MESH:D008175', (85, 96))	('miR-324-5p', 'Chemical', '-', (33, 43))	('suppressed', 'NegReg', (53, 63))
449657	33061453	Moreover, miR-324-5p mimic attenuated the effect of GATA6-AS1 on FBXO11 and SNAIL expression in lung cancer cells.	('SNAIL', 'Gene', (76, 81))	('attenuated', 'NegReg', (27, 37))	('GATA6-AS1', 'Gene', (52, 61))	('lung cancer', 'Disease', 'MESH:D008175', (96, 107))	('miR-324-5p', 'Var', (10, 20))	('SNAIL', 'Gene', '6615', (76, 81))	('miR-324-5p', 'Chemical', '-', (10, 20))	('GATA6-AS1', 'Gene', '100128893;2627;5729', (52, 61))	('lung cancer', 'Disease', (96, 107))	('lung cancer', 'Phenotype', 'HP:0100526', (96, 107))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('FBXO11', 'Gene', '80204', (65, 71))	('FBXO11', 'Gene', (65, 71))
449661	32231272	SNP rs17079281 decreases lung cancer risk through creating an YY1-binding site to suppress DCBLD1 expression Genome-wide association studies (GWAS) have identified numerous genetic variants that are associated with lung cancer risk, but the biological mechanisms underlying these associations remain largely unknown.	('lung cancer', 'Disease', (215, 226))	('associated', 'Reg', (199, 209))	('suppress', 'NegReg', (82, 90))	('rs17079281', 'Var', (4, 14))	('lung cancer', 'Disease', 'MESH:D008175', (25, 36))	('decreases lung cancer', 'Disease', (15, 36))	('YY1', 'Gene', '7528', (62, 65))	('DCBLD1', 'Gene', '285761', (91, 97))	('lung cancer', 'Disease', 'MESH:D008175', (215, 226))	('lung cancer', 'Phenotype', 'HP:0100526', (25, 36))	('YY1', 'Gene', (62, 65))	('DCBLD1', 'Gene', (91, 97))	('lung cancer', 'Phenotype', 'HP:0100526', (215, 226))	('decreases lung cancer', 'Disease', 'MESH:D008175', (15, 36))	('rs17079281', 'Mutation', 'rs17079281', (4, 14))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('SNP rs17079281', 'Var', (0, 14))	('expression', 'MPA', (98, 108))
449663	32231272	We performed linkage disequilibrium (LD) analysis and bioinformatic prediction to screen functional SNPs linked to a tagSNP in 6q22.2 loci, followed by two case-control studies and a meta-analysis with 4403 cases and 5336 controls to identify if these functional SNPs were associated with lung cancer risk.	('lung cancer', 'Disease', 'MESH:D008175', (289, 300))	('tagSNP', 'Var', (117, 123))	('lung cancer', 'Disease', (289, 300))	('lung cancer', 'Phenotype', 'HP:0100526', (289, 300))	('associated', 'Reg', (273, 283))	('cancer', 'Phenotype', 'HP:0002664', (294, 300))
449665	32231272	Compared with those with C allele, patients with T allele had lower risk of adenocarcinoma (adjusted OR = 0.86; 95% CI: 0.80-0.92), but not squamous cell carcinoma (adjusted OR = 0.99; 95% CI: 0.91-1.10), and patients with the C/T or T/T genotype had lower levels of DCBLD1 expression than those with C/C genotype in lung adenocarcinoma tissues.	('carcinoma', 'Phenotype', 'HP:0030731', (327, 336))	('lower', 'NegReg', (251, 256))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (317, 336))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (317, 336))	('adenocarcinoma', 'Disease', (322, 336))	('adenocarcinoma', 'Disease', (76, 90))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (140, 163))	('patients', 'Species', '9606', (35, 43))	('C/T', 'Var', (227, 230))	('adenocarcinoma', 'Disease', 'MESH:D000230', (322, 336))	('patients', 'Species', '9606', (209, 217))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (140, 163))	('levels', 'MPA', (257, 263))	('adenocarcinoma', 'Disease', 'MESH:D000230', (76, 90))	('DCBLD1 expression', 'MPA', (267, 284))	('lung adenocarcinoma', 'Disease', (317, 336))	('lower', 'NegReg', (62, 67))	('carcinoma', 'Phenotype', 'HP:0030731', (154, 163))	('squamous cell carcinoma', 'Disease', (140, 163))
449666	32231272	The results showed that the T allele of rs17079281 had higher binding affinity to transcription factor YY1 than the C allele, which suppressed DCBLD1 expression.	('DCBLD1', 'Gene', (143, 149))	('expression', 'MPA', (150, 160))	('rs17079281', 'Var', (40, 50))	('rs17079281', 'Mutation', 'rs17079281', (40, 50))	('transcription', 'Protein', (82, 95))	('YY1', 'Gene', '7528', (103, 106))	('YY1', 'Gene', (103, 106))	('higher', 'PosReg', (55, 61))	('binding affinity', 'Interaction', (62, 78))	('suppressed', 'NegReg', (132, 142))
449668	32231272	These findings suggest that the functional variant rs17079281C>T decreased lung adenocarcinoma risk by creating an YY1-binding site to suppress DCBLD1 expression, which may serve as a biomarker for assessing lung cancer susceptibility.	('lung cancer', 'Phenotype', 'HP:0100526', (208, 219))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (75, 94))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('YY1', 'Gene', (115, 118))	('decreased', 'NegReg', (65, 74))	('suppress', 'NegReg', (135, 143))	('rs17079281C>T', 'Var', (51, 64))	('rs17079281C>T', 'DBSNP_MENTION', 'None', (51, 64))	('expression', 'MPA', (151, 161))	('decreased lung', 'Phenotype', 'HP:0002089', (65, 79))	('lung adenocarcinoma', 'Disease', (75, 94))	('lung cancer', 'Disease', 'MESH:D008175', (208, 219))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (75, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('YY1', 'Gene', '7528', (115, 118))	('DCBLD1', 'Gene', (144, 150))	('lung cancer', 'Disease', (208, 219))
449674	32231272	Several GWAS reports have been published suggesting that a number of SNPs in chromosome 8q24, 3q28, 5q15.33, 3q12.12, 13q12.12, and 22q12.2 are associated with lung cancer risk in Han Chinese.	('associated with', 'Reg', (144, 159))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('lung cancer', 'Disease', 'MESH:D008175', (160, 171))	('SNPs', 'Var', (69, 73))	('lung cancer', 'Disease', (160, 171))	('lung cancer', 'Phenotype', 'HP:0100526', (160, 171))
449676	32231272	Thus, it is critical for us to identify the functional variants from those tag SNPs and characterize their biological functions related to tumorigenesis.	('variants', 'Var', (55, 63))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('tumor', 'Disease', (139, 144))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))
449678	32231272	In a previous GWAS, SNP rs9387478 in 6q22.2 was found to be associated with lung cancer risk in Asians, which has recently been reported for the same cancer in European populations.	('lung cancer', 'Disease', 'MESH:D008175', (76, 87))	('SNP rs9387478', 'Var', (20, 33))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('6q22.2', 'Gene', (37, 43))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('cancer', 'Disease', (81, 87))	('rs9387478', 'Mutation', 'rs9387478', (24, 33))	('lung cancer', 'Disease', (76, 87))	('lung cancer', 'Phenotype', 'HP:0100526', (76, 87))	('cancer', 'Disease', (150, 156))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('associated with', 'Reg', (60, 75))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
449683	32231272	In two case-control studies and a meta-analysis of 4403 cases and 5336 controls including additional three lung cancer GWASs data from our previous studies, we identified and confirmed that SNP rs17079281 was associated with lung cancer.	('associated', 'Reg', (209, 219))	('rs17079281', 'Mutation', 'rs17079281', (194, 204))	('lung cancer', 'Phenotype', 'HP:0100526', (225, 236))	('SNP rs17079281', 'Var', (190, 204))	('lung cancer', 'Disease', 'MESH:D008175', (107, 118))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('lung cancer', 'Disease', 'MESH:D008175', (225, 236))	('lung cancer', 'Disease', (107, 118))	('lung cancer', 'Phenotype', 'HP:0100526', (107, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('lung cancer', 'Disease', (225, 236))
449684	32231272	We further performed functional experiments to demonstrate the biological implication of rs17079281 in lung cancer.	('lung cancer', 'Disease', 'MESH:D008175', (103, 114))	('rs17079281', 'Var', (89, 99))	('rs17079281', 'Mutation', 'rs17079281', (89, 99))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('lung cancer', 'Disease', (103, 114))	('lung cancer', 'Phenotype', 'HP:0100526', (103, 114))
449691	32231272	Three SNPs (rs17079281, rs6911915, rs4946259) were in Hardy-Weinberg equilibrium (p > 0.01), and SNP rs9320604 was not.	('rs17079281', 'Var', (12, 22))	('rs17079281', 'Mutation', 'rs17079281', (12, 22))	('rs4946259', 'Mutation', 'rs4946259', (35, 44))	('rs4946259', 'Var', (35, 44))	('rs6911915', 'Var', (24, 33))	('rs9320604', 'Mutation', 'rs9320604', (101, 110))	('rs6911915', 'Mutation', 'rs6911915', (24, 33))
449694	32231272	No consistent associations with lung cancer were found for SNP rs4946259, rs9320604, and rs6911915.	('rs4946259', 'Mutation', 'rs4946259', (63, 72))	('rs6911915', 'Mutation', 'rs6911915', (89, 98))	('rs4946259', 'Var', (63, 72))	('rs6911915', 'Var', (89, 98))	('lung cancer', 'Disease', 'MESH:D008175', (32, 43))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('rs9320604', 'Var', (74, 83))	('rs9320604', 'Mutation', 'rs9320604', (74, 83))	('lung cancer', 'Disease', (32, 43))	('lung cancer', 'Phenotype', 'HP:0100526', (32, 43))
449696	32231272	Table S3 shows that patients with the C/T genotype had lower risk of lung cancer compared to those with the C/C genotype (adjusted OR = 0.73; 95% CI: 0.56-0.95).	('lung cancer', 'Disease', 'MESH:D008175', (69, 80))	('lung cancer', 'Disease', (69, 80))	('patients', 'Species', '9606', (20, 28))	('lower', 'NegReg', (55, 60))	('lung cancer', 'Phenotype', 'HP:0100526', (69, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('C/T', 'Var', (38, 41))
449699	32231272	In analysis of association by histology, the SNP rs17079281 was associated only with adenomacarcinoma (adjusted OR = 0.86; 95% CI: 0.80-0.92) (Fig.	('associated', 'Reg', (64, 74))	('adenomacarcinoma', 'Disease', (85, 101))	('adenomacarcinoma', 'Disease', 'None', (85, 101))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('rs17079281', 'Var', (49, 59))	('rs17079281', 'Mutation', 'rs17079281', (49, 59))
449701	32231272	SNP rs17079281 is located in the promoter of DCBLD1, which may affect the binding of transcription factors (Fig.	('affect', 'Reg', (63, 69))	('DCBLD1', 'Gene', (45, 51))	('transcription', 'Protein', (85, 98))	('rs17079281', 'Mutation', 'rs17079281', (4, 14))	('binding', 'Interaction', (74, 81))	('SNP', 'Var', (0, 3))
449703	32231272	We found that patients with homozygous T/T genotype or heterozygous C/T genotype had lower DCBLD1 expression than those with C/C genotype in lung adenocarcinoma (Fig.	('lung adenocarcinoma', 'Disease', (141, 160))	('lower', 'NegReg', (85, 90))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (141, 160))	('C/T', 'Var', (68, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (151, 160))	('DCBLD1', 'Gene', (91, 97))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (141, 160))	('patients', 'Species', '9606', (14, 22))	('T/T', 'Var', (39, 42))	('expression', 'MPA', (98, 108))
449705	32231272	We used TRANSFAC software to predict that C>T mutation may create a transcription factor YY1 binding site (Fig.	('YY1', 'Gene', (89, 92))	('YY1', 'Gene', '7528', (89, 92))	('C>T mutation', 'Var', (42, 54))	('binding', 'Interaction', (93, 100))
449706	32231272	To assess if YY1 binds to the SNP region and the binding is affected by the SNP genotype, we constructed two luciferase reporter plasmids, one with C and one with T alleles of rs17079281 (Fig.	('rs17079281', 'Mutation', 'rs17079281', (176, 186))	('YY1', 'Gene', (13, 16))	('YY1', 'Gene', '7528', (13, 16))	('rs17079281', 'Var', (176, 186))
449707	32231272	Luciferase reporter assays showed that, in comparison to the construct with the rs17079281[C] allele, the construct with the rs17079281[T] allele had significantly reduced luciferase activity in the in 293T cells and lung cancer cells A549 with YY1 overexpression (Fig.	('293T', 'CellLine', 'CVCL:0063', (202, 206))	('rs17079281', 'Mutation', 'rs17079281', (80, 90))	('lung cancer', 'Disease', (217, 228))	('YY1', 'Gene', (245, 248))	('lung cancer', 'Phenotype', 'HP:0100526', (217, 228))	('activity', 'MPA', (183, 191))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('rs17079281', 'Mutation', 'rs17079281', (125, 135))	('A549', 'CellLine', 'CVCL:0023', (235, 239))	('luciferase', 'Enzyme', (172, 182))	('lung cancer', 'Disease', 'MESH:D008175', (217, 228))	('YY1', 'Gene', '7528', (245, 248))	('reduced', 'NegReg', (164, 171))	('rs17079281[', 'Var', (125, 136))
449709	32231272	These results support our speculation that rs17079281 regulated DCBLD1 expression by modulating the binding of transcriptional suppressor YY1 to its promoter.	('expression', 'MPA', (71, 81))	('regulated', 'Reg', (54, 63))	('modulating', 'Reg', (85, 95))	('rs17079281', 'Var', (43, 53))	('rs17079281', 'Mutation', 'rs17079281', (43, 53))	('binding', 'Interaction', (100, 107))	('YY1', 'Gene', '7528', (138, 141))	('DCBLD1', 'Gene', (64, 70))	('YY1', 'Gene', (138, 141))
449710	32231272	To further demonstrate if rs17079281 C>T affects DCBLD1 expression, we used CRISPR/Cas9 to modify the genotype of rs17079281 in a normal lung cell line Beas2B (C/T at rs17079281).	('rs17079281', 'Mutation', 'rs17079281', (114, 124))	('DCBLD1', 'Gene', (49, 55))	('rs17079281', 'Mutation', 'rs17079281', (26, 36))	('rs17079281', 'Mutation', 'rs17079281', (167, 177))	('expression', 'MPA', (56, 66))	('affects', 'Reg', (41, 48))	('Beas2B', 'CellLine', 'CVCL:0168', (152, 158))	('rs17079281 C>T', 'Var', (26, 40))	('rs17079281', 'Var', (114, 124))
449712	32231272	To examine if the YY1 binding affinity to DCBLD1 differed between the C and T alleles of rs17079281, we performed CHIP-qPCR analysis on the wild-type Beas2B cells (C/T at rs17079281) and the modified cells with C/C knockin (Fig.	('rs17079281', 'Mutation', 'rs17079281', (171, 181))	('rs17079281', 'Var', (89, 99))	('rs17079281', 'Mutation', 'rs17079281', (89, 99))	('YY1', 'Gene', '7528', (18, 21))	('YY1', 'Gene', (18, 21))	('Beas2B', 'CellLine', 'CVCL:0168', (150, 156))
449713	32231272	The T allele of rs17079281 showed a higher binding affinity to YY1 than the C allele, supporting our speculation that the genetic polymorphism at rs17079281 confers an allele-specific binding ability to YY1.	('higher', 'PosReg', (36, 42))	('rs17079281', 'Mutation', 'rs17079281', (146, 156))	('rs17079281', 'Var', (16, 26))	('rs17079281', 'Mutation', 'rs17079281', (16, 26))	('YY1', 'Gene', '7528', (63, 66))	('YY1', 'Gene', '7528', (203, 206))	('binding affinity', 'Interaction', (43, 59))	('YY1', 'Gene', (203, 206))	('YY1', 'Gene', (63, 66))	('binding', 'Interaction', (184, 191))
449717	32231272	Colony formation of A549 and NCI-H1299 cells was suppressed by DCBLD1 knockdown and promoted by DCBLD1 overexpression (Fig.	('promoted', 'PosReg', (84, 92))	('knockdown', 'Var', (70, 79))	('NCI-H1299', 'CellLine', 'CVCL:0060', (29, 38))	('A549', 'CellLine', 'CVCL:0023', (20, 24))	('DCBLD1', 'Gene', (63, 69))	('suppressed', 'NegReg', (49, 59))	('Colony formation', 'CPA', (0, 16))
449718	32231272	To evaluate if DCBLD1 had similar effects in vivo, we developed a xenograft model by injecting A549 cells with stable knockdown of DCBLD1 into nude mice (Fig.	('nude mice', 'Species', '10090', (143, 152))	('DCBLD1', 'Gene', (131, 137))	('knockdown', 'Var', (118, 127))	('A549', 'CellLine', 'CVCL:0023', (95, 99))
449721	32231272	Flow cytometry analysis suggested that DCBLD1 knockdown resulted in significant accumulation of A549 and NCI-H1299 cells in G1 phase, accompanied by a substantial decrease in S and G2 phases (Fig.	('knockdown', 'Var', (46, 55))	('A549', 'CellLine', 'CVCL:0023', (96, 100))	('NCI-H1299', 'CellLine', 'CVCL:0060', (105, 114))	('DCBLD1', 'Gene', (39, 45))	('accumulation', 'PosReg', (80, 92))	('decrease', 'NegReg', (163, 171))
449722	32231272	We found that expression of cyclin D1 and cyclin E1 in A549 and NCI-H1299 cells were downregulated by DCBLD1 knockdown (Fig.	('cyclin E1', 'Gene', (42, 51))	('DCBLD1', 'Gene', (102, 108))	('downregulated', 'NegReg', (85, 98))	('A549', 'CellLine', 'CVCL:0023', (55, 59))	('cyclin E1', 'Gene', '898', (42, 51))	('expression', 'MPA', (14, 24))	('knockdown', 'Var', (109, 118))	('NCI-H1299', 'CellLine', 'CVCL:0060', (64, 73))	('cyclin D1', 'Gene', '595', (28, 37))	('cyclin D1', 'Gene', (28, 37))
449723	32231272	We performed LD analysis on SNP rs9387478 discovered by GWAS in search for functional variants, and found that SNP rs17079281, located in the DCBLD1 promoter, was associated with lung cancer.	('rs17079281', 'Mutation', 'rs17079281', (115, 125))	('rs9387478', 'Mutation', 'rs9387478', (32, 41))	('lung cancer', 'Disease', (179, 190))	('lung cancer', 'Phenotype', 'HP:0100526', (179, 190))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('associated with', 'Reg', (163, 178))	('lung cancer', 'Disease', 'MESH:D008175', (179, 190))	('rs17079281', 'Var', (115, 125))
449724	32231272	Intriguingly, we demonstrated that C>T transition at SNP rs17079281 created a YY1-binding site, resulting in decreased DCBLD1 expression.	('decreased', 'NegReg', (109, 118))	('YY1', 'Gene', '7528', (78, 81))	('rs17079281', 'Var', (57, 67))	('expression', 'MPA', (126, 136))	('rs17079281', 'Mutation', 'rs17079281', (57, 67))	('YY1', 'Gene', (78, 81))	('DCBLD1', 'Gene', (119, 125))
449726	32231272	These results indicated how a variant allele contributed to the susceptibility to lung cancer (Fig.	('lung cancer', 'Phenotype', 'HP:0100526', (82, 93))	('susceptibility', 'Reg', (64, 78))	('lung cancer', 'Disease', (82, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('variant', 'Var', (30, 37))	('lung cancer', 'Disease', 'MESH:D008175', (82, 93))
449727	32231272	Our genotype analysis showed that individuals with T allele at SNPrs17079281 had lower risk of lung cancer compared to those with the C allele.	('lung cancer', 'Disease', (95, 106))	('lower', 'NegReg', (81, 86))	('lung cancer', 'Phenotype', 'HP:0100526', (95, 106))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('lung cancer', 'Disease', 'MESH:D008175', (95, 106))	('rs17079281', 'Mutation', 'rs17079281', (66, 76))	('SNPrs17079281', 'Var', (63, 76))
449728	32231272	We further established that the SNP rs17079281 was distinctly associated with risk of Lung adenocarcinoma and not with the squamous cell carcinoma.	('Lung adenocarcinoma', 'Disease', (86, 105))	('squamous cell carcinoma', 'Disease', (123, 146))	('Lung adenocarcinoma', 'Disease', 'MESH:D000077192', (86, 105))	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('rs17079281', 'Var', (36, 46))	('associated', 'Reg', (62, 72))	('SNP', 'Var', (32, 35))	('rs17079281', 'Mutation', 'rs17079281', (36, 46))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (123, 146))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (123, 146))	('Lung adenocarcinoma', 'Phenotype', 'HP:0030078', (86, 105))
449730	32231272	To elucidate the effect of SNP rs17079281 on expression of gene DCBLD1, we analyzed the relationship between DCBLD1 genotype and phenotype in lung tumor samples, and found an expression quantitative trait loci between SNP rs17079281 and DCBLD1 mRNA levels in lung adenocarcinoma tissues, but not in lung squamous cell carcinoma.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('lung tumor', 'Disease', (142, 152))	('mRNA levels', 'MPA', (244, 255))	('DCBLD1', 'Gene', (237, 243))	('lung tumor', 'Disease', 'MESH:D008175', (142, 152))	('carcinoma', 'Phenotype', 'HP:0030731', (269, 278))	('rs17079281', 'Mutation', 'rs17079281', (222, 232))	('lung adenocarcinoma', 'Disease', (259, 278))	('carcinoma', 'Phenotype', 'HP:0030731', (318, 327))	('rs17079281', 'Mutation', 'rs17079281', (31, 41))	('SNP rs17079281', 'Var', (218, 232))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (259, 278))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (299, 327))	('lung tumor', 'Phenotype', 'HP:0100526', (142, 152))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (304, 327))	('lung squamous cell carcinoma', 'Disease', (299, 327))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (259, 278))	('DCBLD1', 'Gene', (64, 70))
449732	32231272	Bioinformatics analysis suggests that the C-to-T polymorphism is situated in a transcription factor YY1 binding site.	('YY1', 'Gene', '7528', (100, 103))	('YY1', 'Gene', (100, 103))	('C-to-T polymorphism', 'Var', (42, 61))	('polymorphism', 'Var', (49, 61))
449736	32231272	The luciferase assay showed that transcription factor YY1 could suppress DCBLD1 expression by interacting with the T alleles of rs17079281 more strongly than the C alleles in the DCBLD1 promoter.	('rs17079281', 'Mutation', 'rs17079281', (128, 138))	('rs17079281', 'Var', (128, 138))	('YY1', 'Gene', (54, 57))	('suppress', 'NegReg', (64, 72))	('DCBLD1', 'Gene', (73, 79))	('expression', 'MPA', (80, 90))	('interacting', 'Interaction', (94, 105))	('YY1', 'Gene', '7528', (54, 57))
449747	32231272	Our mechanistic findings were consistent with the epidemiology results which showed that SNP rs17079281 T allele was associated with reduced risk of lung cancer.	('lung cancer', 'Disease', 'MESH:D008175', (149, 160))	('rs17079281', 'Mutation', 'rs17079281', (93, 103))	('lung cancer', 'Phenotype', 'HP:0100526', (149, 160))	('lung cancer', 'Disease', (149, 160))	('SNP rs17079281 T', 'Var', (89, 105))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('reduced', 'NegReg', (133, 140))
449748	32231272	In summary, in search for functional SNPs in high LD with SNP rs9387478 identified by lung cancer GWAS, we found that SNP rs17079281, located in the promoter region of DCBLD1, was associated with lung cancer risk.	('DCBLD1', 'Gene', (168, 174))	('lung cancer', 'Disease', (196, 207))	('lung cancer', 'Phenotype', 'HP:0100526', (196, 207))	('lung cancer', 'Phenotype', 'HP:0100526', (86, 97))	('SNP', 'Var', (118, 121))	('rs17079281', 'Var', (122, 132))	('rs17079281', 'Mutation', 'rs17079281', (122, 132))	('rs9387478', 'Mutation', 'rs9387478', (62, 71))	('lung cancer', 'Disease', (86, 97))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('associated with', 'Reg', (180, 195))	('lung cancer', 'Disease', 'MESH:D008175', (196, 207))	('lung cancer', 'Disease', 'MESH:D008175', (86, 97))
449759	32231272	Our search for causal SNPs was centered on SNP rs9387478, a lung cancer-associated SNP discovered by GWAS.	('rs9387478', 'Mutation', 'rs9387478', (47, 56))	('lung cancer', 'Disease', (60, 71))	('lung cancer', 'Phenotype', 'HP:0100526', (60, 71))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('lung cancer', 'Disease', 'MESH:D008175', (60, 71))	('SNP', 'Var', (43, 46))
449760	32231272	We conducted a LD-based search of the HapMap and 1000Genomes database for SNPs that were located within 100 kb up and downstream of rs9387478 in Han Chinese using the Haploview softerware 4.2.	('rs9387478', 'Mutation', 'rs9387478', (132, 141))	('rs9387478', 'Var', (132, 141))	('SNPs', 'Gene', (74, 78))
449761	32231272	Relevant SNPs were selected on the basis of following criteria: (i) in high LD with rs9387478 (D' > 0.8); (ii) located in the coding or regulatory regions of the gene DCBLD1; (iii) were labeled as Category 1 by RegulomeDB (http://www.regulomedb.org/); and (iv) had MAF > 0.05.	('DCBLD1', 'Gene', (167, 173))	('rs9387478', 'Mutation', 'rs9387478', (84, 93))	('rs9387478', 'Var', (84, 93))
449762	32231272	Four SNPs in DCBLD1 met these selection criteria, including rs17079281 in the promoter region, and rs6911915, rs9320604 and rs4946259 in the first intron.	('DCBLD1', 'Gene', (13, 19))	('rs6911915', 'Var', (99, 108))	('rs17079281', 'Var', (60, 70))	('rs17079281', 'Mutation', 'rs17079281', (60, 70))	('rs4946259', 'Mutation', 'rs4946259', (124, 133))	('rs9320604', 'Var', (110, 119))	('rs6911915', 'Mutation', 'rs6911915', (99, 108))	('rs4946259', 'Var', (124, 133))	('rs9320604', 'Mutation', 'rs9320604', (110, 119))
449767	32231272	A 20-nt single-guide RNA (sgRNA) was designed based on the genomic sequences flanking rs17079281 and evaluated for potential off-target activity using the CRISPR Design tool at (http://crispr.mit.edu/).	('A 20', 'Gene', (0, 4))	('rs17079281', 'Var', (86, 96))	('rs17079281', 'Mutation', 'rs17079281', (86, 96))	('A 20', 'Gene', '7128', (0, 4))
449785	31311441	Peroxiredoxin 4, a typical endoplasmic reticulum-resident 2-Cys antioxidant of peroxiredoxins, can fine-tune hydrogen peroxide catabolism which affects cell survival by affecting redox balance, oxidative protein folding, and regulation of hydrogen peroxide signaling.	('hydrogen peroxide catabolism', 'MPA', (109, 137))	('regulation of hydrogen peroxide signaling', 'MPA', (225, 266))	('Peroxiredoxin 4', 'Gene', '10549', (0, 15))	('oxidative protein folding', 'MPA', (194, 219))	('redox balance', 'MPA', (179, 192))	('2-Cys', 'Chemical', '-', (58, 63))	('Peroxiredoxin 4', 'Gene', (0, 15))	('hydrogen peroxide', 'Chemical', 'MESH:D006861', (239, 256))	('affects', 'Reg', (144, 151))	('hydrogen peroxide', 'Chemical', 'MESH:D006861', (109, 126))	('fine-tune', 'Var', (99, 108))	('affecting', 'Reg', (169, 178))
449819	31311441	In addition, PRDX4 regulates signal transduction via fine-tune H2O2 concentration, which is critical in cell proliferation.	('regulates', 'Reg', (19, 28))	('signal transduction', 'MPA', (29, 48))	('H2O2 concentration', 'MPA', (63, 81))	('PRDX4', 'Gene', (13, 18))	('fine-tune', 'Var', (53, 62))	('H2O2', 'Chemical', 'MESH:D006861', (63, 67))
449821	31311441	At low to modest doses, ROS are considered crucial for regulation of normal physiological functions but excessive production of ROS induces oxidative-stress damage to proteins, lipids, nucleic acids, membranes, and even organelles, which sequentially lead to cell death processes such as apoptosis.	('production', 'Var', (114, 124))	('cell death processes', 'CPA', (259, 279))	('ROS', 'Chemical', 'MESH:D017382', (24, 27))	('oxidative-stress', 'Phenotype', 'HP:0025464', (140, 156))	('ROS', 'Chemical', 'MESH:D017382', (128, 131))	('apoptosis', 'CPA', (288, 297))	('oxidative-stress damage', 'MPA', (140, 163))	('lead to', 'Reg', (251, 258))	('lipids', 'Chemical', 'MESH:D008055', (177, 183))	('induces', 'Reg', (132, 139))	('ROS', 'Gene', (128, 131))	('proteins', 'Protein', (167, 175))
449822	31311441	Moreover, ROS are shown to be important promoting factors in carcinogenesis.	('carcinogenesis', 'CPA', (61, 75))	('ROS', 'Chemical', 'MESH:D017382', (10, 13))	('ROS', 'Var', (10, 13))
449827	31311441	Because of the unpaired electrons, H2O2 is in an extremely unstable state and reacts easily with other molecules, such as protein, lipids, DNA, and so on.	('H2O2', 'Var', (35, 39))	('H2O2', 'Chemical', 'MESH:D006861', (35, 39))	('lipids', 'Chemical', 'MESH:D008055', (131, 137))	('unpaired', 'Var', (15, 23))	('reacts', 'Interaction', (78, 84))
449842	31311441	Peroxiredoxin 4 that is oxidized by H2O2 receives electrons provided by reduced Trx.	('Peroxiredoxin 4', 'Gene', '10549', (0, 15))	('H2O2', 'Chemical', 'MESH:D006861', (36, 40))	('H2O2', 'Var', (36, 40))	('Trx', 'Gene', '7295', (80, 83))	('Peroxiredoxin 4', 'Gene', (0, 15))	('Trx', 'Gene', (80, 83))
449849	31311441	"Cytosolic H2O2 enhances protein tyrosine phosphorylation by inactivating protein tyrosine phosphatases while activating protein tyrosine kinases."	('H2O2', 'Chemical', 'MESH:D006861', (11, 15))	('H2O2', 'Var', (11, 15))	('protein tyrosine phosphorylation', 'MPA', (25, 57))	('protein tyrosine kinases', 'Enzyme', (121, 145))	('enhances', 'PosReg', (16, 24))	('inactivating', 'NegReg', (61, 73))	('tyrosine', 'Chemical', 'MESH:D014443', (33, 41))	('activating', 'PosReg', (110, 120))	('tyrosine', 'Chemical', 'MESH:D014443', (129, 137))	('tyrosine', 'Chemical', 'MESH:D014443', (82, 90))	('protein', 'Protein', (74, 81))
449851	31311441	H2O2 transiently oxidizes PTP to cysteine sulfenic acid form (-SOH) and the oxidized PTP could be irreversibly oxidized to sulfinic/sulfonic acid (-SO2/SO3H) by excess H2O2, causing inactivation of PTP (Figure 3).	('sulfonic acid', 'Chemical', 'MESH:D013451', (132, 145))	('PTP', 'Gene', (26, 29))	('sulfinic', 'Chemical', '-', (123, 131))	('(-SOH', 'Chemical', '-', (61, 66))	('cysteine sulfenic acid', 'Chemical', 'MESH:C100870', (33, 55))	('PTP', 'Gene', (198, 201))	('H2O2', 'Chemical', 'MESH:D006861', (168, 172))	('PTP', 'Gene', (85, 88))	('SO3H', 'Chemical', '-', (152, 156))	('-SO2', 'Chemical', 'MESH:D013458', (147, 151))	('PTP', 'Gene', '995', (26, 29))	('inactivation', 'MPA', (182, 194))	('H2O2', 'Chemical', 'MESH:D006861', (0, 4))	('H2O2', 'Var', (0, 4))	('PTP', 'Gene', '995', (85, 88))	('PTP', 'Gene', '995', (198, 201))
449865	31311441	Hansen proved that there are various somatic genomic alterations in breast cancer cell lines associated with the acquisition of docetaxel resistance and a lot of PRDX4 copy number losses on chromosome X, which could contribute to the development of docetaxel resistance.	('breast cancer', 'Disease', 'MESH:D001943', (68, 81))	('breast cancer', 'Phenotype', 'HP:0003002', (68, 81))	('breast cancer', 'Disease', (68, 81))	('associated', 'Reg', (93, 103))	('docetaxel', 'Chemical', 'MESH:D000077143', (128, 137))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('docetaxel', 'Chemical', 'MESH:D000077143', (249, 258))	('docetaxel resistance', 'MPA', (128, 148))	('contribute', 'Reg', (216, 226))	('copy number losses', 'Var', (168, 186))	('PRDX4', 'Gene', (162, 167))
449868	31311441	Overexpression of PRDX4 remarkably improves the growth rate of the prostate cancer cell lines while knockdown of PRDX4 differentially affects the proliferation depending on the cellular background.	('knockdown', 'Var', (100, 109))	('affects', 'Reg', (134, 141))	('prostate cancer', 'Disease', (67, 82))	('proliferation', 'CPA', (146, 159))	('PRDX4', 'Gene', (113, 118))	('growth rate', 'CPA', (48, 59))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('prostate cancer', 'Disease', 'MESH:D011471', (67, 82))	('PRDX4', 'Gene', (18, 23))	('prostate cancer', 'Phenotype', 'HP:0012125', (67, 82))	('improves', 'PosReg', (35, 43))
449875	31311441	Sulfiredoxin (Srx) is an antioxidant protein induced by H2O2.	('Sulfiredoxin', 'Gene', (0, 12))	('H2O2', 'Var', (56, 60))	('H2O2', 'Chemical', 'MESH:D006861', (56, 60))	('Sulfiredoxin', 'Gene', '140809', (0, 12))
449876	31311441	Sulfiredoxin serves as a catalyst in reducing the hyperoxidized PRDXs to restore their peroxidase activity.	('Sulfiredoxin', 'Gene', (0, 12))	('hyperoxidized', 'Var', (50, 63))	('restore', 'PosReg', (73, 80))	('peroxidase activity', 'MPA', (87, 106))	('Sulfiredoxin', 'Gene', '140809', (0, 12))
449881	31311441	Single-nucleotide polymorphisms in genes coding for PRDX4 were confirmed to be significantly associated with clearance of docetaxel in patients with locally advanced NSCLC.	('patients', 'Species', '9606', (135, 143))	('clearance of docetaxel', 'MPA', (109, 131))	('Single-nucleotide polymorphisms', 'Var', (0, 31))	('NSCLC', 'Disease', (166, 171))	('docetaxel', 'Chemical', 'MESH:D000077143', (122, 131))	('NSCLC', 'Disease', 'MESH:D002289', (166, 171))	('associated with', 'Reg', (93, 108))	('NSCLC', 'Phenotype', 'HP:0030358', (166, 171))	('PRDX4', 'Gene', (52, 57))
449895	31311441	And PRDX4 knockdown by shRNA in high-grade glioma (HGG) cells reduces tumor cell growth rate and accelerates apoptosis.	('accelerates', 'PosReg', (97, 108))	('glioma', 'Phenotype', 'HP:0009733', (43, 49))	('reduces', 'NegReg', (62, 69))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('glioma', 'Disease', (43, 49))	('tumor', 'Disease', (70, 75))	('apoptosis', 'CPA', (109, 118))	('PRDX4', 'Gene', (4, 9))	('knockdown', 'Var', (10, 19))	('glioma', 'Disease', 'MESH:D005910', (43, 49))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
449911	31311441	Furthermore, another fusion gene related to PRDX4 was observed resulted from a translocation (X;18)(p22;q23) in one patient with acute lymphocytic leukemia.	('p22', 'Gene', '11261', (100, 103))	('leukemia', 'Phenotype', 'HP:0001909', (147, 155))	('patient', 'Species', '9606', (116, 123))	('translocation (X', 'Var', (79, 95))	('acute lymphocytic leukemia', 'Disease', 'MESH:D054198', (129, 155))	('PRDX4', 'Gene', (44, 49))	('X;', 'Var', (94, 96))	('acute lymphocytic leukemia', 'Phenotype', 'HP:0006721', (129, 155))	('p22', 'Gene', (100, 103))	('resulted from', 'Reg', (63, 76))	('acute lymphocytic leukemia', 'Disease', (129, 155))
449933	30333042	Genetic alterations associated with each metabolic pathway differed between cancers, however, they were a part of cancer drivers in most cancer types.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('Genetic alterations', 'Var', (0, 19))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('cancers', 'Disease', 'MESH:D009369', (76, 83))	('cancers', 'Phenotype', 'HP:0002664', (76, 83))	('cancers', 'Disease', (76, 83))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('metabolic pathway', 'Pathway', (41, 58))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('cancer', 'Disease', (137, 143))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('cancer', 'Disease', (114, 120))
449943	30333042	We also show that genetic alterations associated with cancer metabolic heterogeneity were a part of cancer drivers in most cancer types.	('genetic alterations', 'Var', (18, 37))	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('cancer', 'Disease', (54, 60))	('cancer', 'Disease', (123, 129))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
449970	30333042	Accordingly, aggressive malignant phenotypes of cancer cells obtained by accumulated mutations change metabolic phenotypes to demand energy source represented by carbohydrate and elements for proliferation represented by nucleotide.	('change', 'Reg', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('metabolic phenotypes', 'MPA', (102, 122))	('carbohydrate', 'Chemical', 'MESH:D002241', (162, 174))	('mutations', 'Var', (85, 94))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))
449973	30333042	An example of carbohydrate metabolism-related genetic alterations of LGG is presented (Fig.	('carbohydrate', 'Chemical', 'MESH:D002241', (14, 26))	('LGG', 'Gene', (69, 72))	('genetic alterations', 'Var', (46, 65))
449974	30333042	The tumors with high carbohydrate metabolism showed significantly more mutations of EGFR and fewer mutations of FUBP1, CIC, and IDH1.	('FUBP1', 'Gene', (112, 117))	('fewer', 'NegReg', (93, 98))	('IDH1', 'Gene', '3417', (128, 132))	('CIC', 'Gene', '23152', (119, 122))	('tumors', 'Disease', (4, 10))	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('EGFR', 'Gene', '1956', (84, 88))	('mutations', 'Var', (71, 80))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('CIC', 'Gene', (119, 122))	('FUBP1', 'Gene', '8880', (112, 117))	('EGFR', 'Gene', (84, 88))	('IDH1', 'Gene', (128, 132))	('carbohydrate', 'Chemical', 'MESH:D002241', (21, 33))
449987	30333042	It corresponds to the Darwinian selection of cancer cells which carry driver mutations facilitate cellular survival and growth by changing a favorable metabolic landscape.	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('facilitate', 'PosReg', (87, 97))	('cellular survival', 'CPA', (98, 115))	('mutations', 'Var', (77, 86))	('changing', 'Reg', (130, 138))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('favorable metabolic landscape', 'MPA', (141, 170))	('cancer', 'Disease', (45, 51))	('growth', 'CPA', (120, 126))
449988	30333042	The results also suggest that the metabolic change as a hallmark of cancer may be one of the tumorigenesis processes caused by genetic alterations rather than an independent process.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('tumor', 'Disease', 'MESH:D009369', (93, 98))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('caused', 'Reg', (117, 123))	('tumor', 'Disease', (93, 98))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('cancer', 'Disease', (68, 74))	('genetic alterations', 'Var', (127, 146))	('metabolic', 'MPA', (34, 43))
449990	30333042	Genetic alterations closely associated with metabolic heterogeneity were a part of cancer drivers in most cancers rather than genes affiliated to metabolic pathways.	('Genetic alterations', 'Var', (0, 19))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('cancers', 'Phenotype', 'HP:0002664', (106, 113))	('cancer', 'Disease', (106, 112))	('cancers', 'Disease', (106, 113))	('cancers', 'Disease', 'MESH:D009369', (106, 113))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('cancer', 'Disease', (83, 89))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
450016	28808491	Prognosis of the disease is based on the TNM cancer staging system, where T1-T4 stands for primary tumor's spreading (increasing the tumor's size or invasive growth by direct penetration to the surrounding tissue), N0-N3 for dissemination to the regional lymph nodes, and an M0-M1 for absence or presence of distant metastases.	('primary tumor', 'Disease', 'MESH:D009369', (91, 104))	('tumor', 'Disease', (99, 104))	('increasing', 'PosReg', (118, 128))	('TNM cancer', 'Disease', (41, 51))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('metastases', 'Disease', 'MESH:D009362', (316, 326))	('TNM cancer', 'Disease', 'MESH:D009369', (41, 51))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('invasive growth', 'CPA', (149, 164))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Disease', (133, 138))	('T1-T4', 'Var', (74, 79))	('N0-N3', 'Var', (215, 220))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('primary tumor', 'Disease', (91, 104))	('metastases', 'Disease', (316, 326))
450130	26986233	However, we noted that abrogating miR-155 with the miR-155 antagomir suppressed CAL27 cell proliferation, migration and invasion, upregulated BCL6 and reduced cyclin D2 expression.	('upregulated', 'PosReg', (130, 141))	('miR-155', 'Gene', '406947', (34, 41))	('miR-155', 'Gene', '406947', (51, 58))	('CAL27', 'Protein', (80, 85))	('reduced', 'NegReg', (151, 158))	('cyclin D2', 'Gene', (159, 168))	('cyclin D2', 'Gene', '894', (159, 168))	('CAL27', 'CellLine', 'CVCL:1107', (80, 85))	('BCL6', 'Gene', (142, 146))	('miR-155', 'Gene', (34, 41))	('miR-155', 'Gene', (51, 58))	('invasion', 'CPA', (120, 128))	('suppressed', 'NegReg', (69, 79))	('expression', 'MPA', (169, 179))	('migration', 'CPA', (106, 115))	('BCL6', 'Gene', '604', (142, 146))	('abrogating', 'Var', (23, 33))
450136	26986233	Previous research has demonstrated that aberrant miRNA expression is related to the development of several types of human cancer.	('related to', 'Reg', (69, 79))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('miR', 'Gene', '220972', (49, 52))	('miR', 'Gene', (49, 52))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('aberrant', 'Var', (40, 48))	('human', 'Species', '9606', (116, 121))
450145	26986233	Cyclin D2 plays an important role in the cell cycle, and the ectopic expression of cyclin D2 is closely related to invasion in OSCC cells.	('invasion', 'Disease', (115, 123))	('Cyclin D2', 'Gene', (0, 9))	('ectopic', 'Var', (61, 68))	('OSCC', 'Disease', (127, 131))	('cyclin D2', 'Gene', '894', (83, 92))	('related', 'Reg', (104, 111))	('Cyclin D2', 'Gene', '894', (0, 9))	('cyclin D2', 'Gene', (83, 92))
450174	26986233	After blocking in 5% milk, the membranes were incubated with rabbit monoclonal anti-BCL6 antibody (D65C10, diluted 1:1,000), rabbit monoclonal anti-cyclin D2 antibody (D52F9, diluted 1:1,000) (both from Cell Signaling Technology, Boston, MA, USA), mouse monoclonal anti-GAPDH antibody (ab125247, diluted 1:2,000), and rabbit polyclonal anti-H2A.X antibody (ab10475, diluted 1:500) (both from Abcam, Cambridge, MA, USA) at 4 C overnight.	('cyclin D2', 'Gene', (148, 157))	('BCL6', 'Gene', '604', (84, 88))	('mouse', 'Species', '10090', (248, 253))	('rabbit', 'Species', '9986', (125, 131))	('rabbit', 'Species', '9986', (318, 324))	('BCL6', 'Gene', (84, 88))	('rabbit', 'Species', '9986', (61, 67))	('GAPDH', 'Gene', '2597', (270, 275))	('ab10475', 'Var', (357, 364))	('cyclin D2', 'Gene', '894', (148, 157))	('GAPDH', 'Gene', (270, 275))
450181	26986233	The growth rate of CAL27 cells transfected with 5 nM miR-155 mimic was significantly higher than that of cells transfected with mimic-NC (miR-155 mimic OD/mimic-NC OD) at 24 h (113.14+-2.75%, P<0.05), 48 h (125.39+-6.49%, P<0.01), and 72 h (120.6+-0.41%, P<0.01) (Fig.	('miR-155', 'Gene', (53, 60))	('miR-155', 'Gene', '406947', (138, 145))	('higher', 'PosReg', (85, 91))	('CAL27', 'CellLine', 'CVCL:1107', (19, 24))	('mimic', 'Var', (61, 66))	('growth rate', 'CPA', (4, 15))	('miR-155', 'Gene', '406947', (53, 60))	('miR-155', 'Gene', (138, 145))
450185	26986233	At 24 h after transfection, the number of migrated cells in the group transfected with 5 nM miR-155 mimic was significantly higher than in the group treated with mimic-NC (P<0.01) (Fig.	('higher', 'PosReg', (124, 130))	('miR-155', 'Gene', '406947', (92, 99))	('mimic', 'Var', (100, 105))	('miR-155', 'Gene', (92, 99))
450192	26986233	Therefore, in order to validate whether miR-155 regulates BCL6 and its downstream gene cyclin D2 in OSCC cells, we compared the alteration in BCL6 and cyclin D2 expression in CAL27 cells transfected with miR-155 mimic, mimic-NC, miR-155 antagomir or antagomir-NC.	('miR-155', 'Gene', (40, 47))	('mimic-NC', 'Var', (219, 227))	('BCL6', 'Gene', (142, 146))	('mimic', 'Var', (212, 217))	('miR-155', 'Gene', '406947', (40, 47))	('BCL6', 'Gene', '604', (58, 62))	('CAL27', 'CellLine', 'CVCL:1107', (175, 180))	('cyclin D2', 'Gene', '894', (87, 96))	('miR-155', 'Gene', (229, 236))	('miR-155', 'Gene', '406947', (229, 236))	('cyclin D2', 'Gene', '894', (151, 160))	('cyclin D2', 'Gene', (87, 96))	('BCL6', 'Gene', '604', (142, 146))	('miR-155', 'Gene', (204, 211))	('miR-155', 'Gene', '406947', (204, 211))	('antagomir', 'Var', (237, 246))	('cyclin D2', 'Gene', (151, 160))	('BCL6', 'Gene', (58, 62))	('antagomir-NC', 'Var', (250, 262))
450200	26986233	We found that miR-155 expression was higher in CAL27 cells than in NOK-SI cells.	('NOK', 'Gene', (67, 70))	('higher', 'PosReg', (37, 43))	('miR-155', 'Gene', '406947', (14, 21))	('CAL27', 'CellLine', 'CVCL:1107', (47, 52))	('CAL27', 'Var', (47, 52))	('miR-155', 'Gene', (14, 21))	('NOK', 'Gene', '55359', (67, 70))	('expression', 'MPA', (22, 32))
450206	26986233	Recently, Rather et al reported that antagomir-155 decreased the proliferation of the OSCC cell line KB through CDC73.	('antagomir-155', 'Var', (37, 50))	('decreased', 'NegReg', (51, 60))	('CDC73', 'Gene', (112, 117))	('CDC73', 'Gene', '79577', (112, 117))	('proliferation of the OSCC cell line KB', 'CPA', (65, 103))
450229	26986233	These data indicate that ectopic expression of miR-155 downregulates BCL6 expression and increases cyclin D2 expression, and subsequently facilitates cell proliferation, migration and invasion.	('expression', 'MPA', (74, 84))	('BCL6', 'Gene', (69, 73))	('invasion', 'CPA', (184, 192))	('expression', 'MPA', (109, 119))	('miR-155', 'Gene', (47, 54))	('migration', 'CPA', (170, 179))	('cell proliferation', 'CPA', (150, 168))	('miR-155', 'Gene', '406947', (47, 54))	('facilitates', 'PosReg', (138, 149))	('cyclin D2', 'Gene', '894', (99, 108))	('cyclin D2', 'Gene', (99, 108))	('BCL6', 'Gene', '604', (69, 73))	('downregulates', 'NegReg', (55, 68))	('ectopic expression', 'Var', (25, 43))	('increases', 'PosReg', (89, 98))
450237	25693567	Instead, different genomic regions vary by up to 5-fold in the local density of somatic mutations, posing a fundamental problem for statistical methods of cancer genomics.	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('mutations', 'Var', (88, 97))	('cancer', 'Disease', (155, 161))	('cancer', 'Disease', 'MESH:D009369', (155, 161))
450239	25693567	We investigated the distribution of mutations in multiple samples of diverse cancer types and compared them to cell-type-specific epigenomic features.	('cancer type', 'Disease', (77, 88))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('mutations', 'Var', (36, 45))	('cancer type', 'Disease', 'MESH:D009369', (77, 88))
450240	25693567	Here, we show that chromatin accessibility and modification, together with replication timing, explain up to 86% of the variance in mutation rates along cancer genomes.	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('cancer', 'Disease', (153, 159))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('mutation', 'Var', (132, 140))	('chromatin accessibility', 'MPA', (19, 42))	('modification', 'MPA', (47, 59))
450243	25693567	We show further that the cell type of origin of a cancer can be accurately determined based on the distribution of mutations along its genome.	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('mutations', 'Var', (115, 124))	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))
450252	25693567	We compared the genomic distribution of mutations in these cancer genomes to 424 epigenetic features that were measured by the Epigenome Roadmap consortium [EC00].	('mutations', 'Var', (40, 49))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))
450259	25693567	As another example, even though H3K4me1 marks in melanocytes and hepatocytes are highly correlated (r=0.8), the distribution of mutations in liver cancer followed the levels of H3K4me1 in hepatocytes, but not in melanocytes, while melanoma mutations correlated with the levels of H3K4me1 in melanocytes but not in hepatocytes (Figure 1c).	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('mutations', 'Var', (128, 137))	('melanoma', 'Disease', 'MESH:D008545', (231, 239))	('melanoma', 'Phenotype', 'HP:0002861', (231, 239))	('melanoma', 'Disease', (231, 239))	('liver cancer', 'Phenotype', 'HP:0002896', (141, 153))	('liver cancer', 'Disease', 'MESH:D006528', (141, 153))	('liver cancer', 'Disease', (141, 153))
450260	25693567	Remarkably epigenetic marks, together with replication timing measured in ENCODE cell lines , collectively explained 74-86% of the variance in mutation density in seven cancer types (Figure 2a).	('mutation', 'Var', (143, 151))	('cancer type', 'Disease', (169, 180))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('explained', 'Reg', (107, 116))	('cancer type', 'Disease', 'MESH:D009369', (169, 180))	('epigenetic marks', 'Var', (11, 27))
450262	25693567	This is substantially higher than in earlier studies and indicates that, at least for these cancer types, we have identified a set of epigenetic variables and cell types that almost fully predict the mutational variability along the genome.	('cancer type', 'Disease', 'MESH:D009369', (92, 103))	('mutational variability', 'Var', (200, 222))	('predict', 'Reg', (188, 195))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('cancer type', 'Disease', (92, 103))
450264	25693567	As a point of direct comparison with an earlier study that did not use cell type specific chromatin marks, our model explained 50% of the variance in mutation density in the melanoma cell line COLO829, for which the earlier study explained 29% of the variance.	('COLO829', 'CellLine', 'CVCL:1137', (193, 200))	('mutation', 'Var', (150, 158))	('melanoma', 'Disease', 'MESH:D008545', (174, 182))	('melanoma', 'Phenotype', 'HP:0002861', (174, 182))	('melanoma', 'Disease', (174, 182))
450268	25693567	There was a sweeping association between cancer mutations and chromatin marks measured in the cell type of origin of each cancer (Figures 3a).	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('mutations', 'Var', (48, 57))
450273	25693567	Lung adenocarcinoma and lung squamous cell carcinoma were the only exceptions in that the top predictors were scattered among different tissue groups; the lack of tissue specificity in these cases likely results from the absence of epigenetic marks from normal lung epithelial cells in our dataset.	('absence', 'NegReg', (221, 228))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (24, 52))	('adenocarcinoma and lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (5, 52))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (29, 52))	('epigenetic marks', 'Var', (232, 248))	('carcinoma', 'Phenotype', 'HP:0030731', (43, 52))	('Lung adenocarcinoma', 'Phenotype', 'HP:0030078', (0, 19))	('carcinoma', 'Phenotype', 'HP:0030731', (10, 19))
450274	25693567	The results of the Random Forest regression were confirmed using backward feature selection to identify the minimal set of epigenetic predictors of mutations in each cancer type (Methods).	('cancer type', 'Disease', 'MESH:D009369', (166, 177))	('mutations', 'Var', (148, 157))	('cancer type', 'Disease', (166, 177))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))
450276	25693567	The above results pose a key question on whether epigenomic features derived from the cell type of origin are the strongest determinants of cancer mutations, or whether they simply serve as the best available proxies to the chromatin organization of the corresponding malignant cells.	('mutations', 'Var', (147, 156))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))
450278	25693567	Surprisingly, in both cases, epigenomic features from the cell type of origin resulted in a higher prediction accuracy than those from the cancer cell lines.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('prediction', 'MPA', (99, 109))	('higher', 'PosReg', (92, 98))	('epigenomic features', 'Var', (29, 48))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('cancer', 'Disease', (139, 145))
450282	25693567	First, most of the mutations observed in cancers may arise prior to the epigenetic changes linked to neoplastic progression.	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('mutations', 'Var', (19, 28))	('cancers', 'Phenotype', 'HP:0002664', (41, 48))	('cancers', 'Disease', 'MESH:D009369', (41, 48))	('cancers', 'Disease', (41, 48))
450287	25693567	Thus, mutational patterns contain sufficient information for identifying the cell type of origin of a tumor.	('mutational', 'Var', (6, 16))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('tumor', 'Disease', 'MESH:D009369', (102, 107))
450303	25693567	We also determined the mutation densities for all possible types of mutations in each cancer types by counting different types of mutations in 1 Mb windows and normalizing for the sequence composition of each window.	('cancer type', 'Disease', (86, 97))	('mutations', 'Var', (130, 139))	('cancer type', 'Disease', 'MESH:D009369', (86, 97))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))
450328	32219034	The mRNA expression levels in the NFI family were significantly downregulated in most cancers compared with normal tissues and DNA hypermethylation might downregulate the NFI family expression.	('expression', 'MPA', (182, 192))	('NFI family', 'Gene', (34, 44))	('hypermethylation', 'Var', (131, 147))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('mRNA expression levels', 'MPA', (4, 26))	('downregulate', 'NegReg', (154, 166))	('cancers', 'Phenotype', 'HP:0002664', (86, 93))	('cancers', 'Disease', (86, 93))	('cancers', 'Disease', 'MESH:D009369', (86, 93))	('NFI', 'Protein', (171, 174))	('downregulated', 'NegReg', (64, 77))
450331	32219034	Further survival analyses based on the KM plotter and SurvExpress databases showed dysregulations of the NFI genes were significantly correlated with survival outcomes in breast, lung, and head and neck cancers.	('head and neck cancer', 'Phenotype', 'HP:0012288', (189, 209))	('head and neck cancers', 'Phenotype', 'HP:0012288', (189, 210))	('head and neck cancers', 'Disease', 'MESH:D006258', (189, 210))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('dysregulations', 'Var', (83, 97))	('breast', 'Disease', (171, 177))	('cancers', 'Phenotype', 'HP:0002664', (203, 210))	('lung', 'Disease', (179, 183))	('NFI genes', 'Gene', (105, 114))	('correlated with', 'Reg', (134, 149))
450379	32219034	Breast invasive carcinoma patients with a NFIX gene alteration showed significantly poor overall survival (OS) and disease-free survival (DFS) compared with breast invasive carcinoma patients without NFIX gene alteration.	('breast invasive carcinoma', 'Phenotype', 'HP:0003002', (157, 182))	('OS', 'Chemical', '-', (107, 109))	('poor', 'NegReg', (84, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (173, 182))	('carcinoma', 'Phenotype', 'HP:0030731', (16, 25))	('Breast invasive carcinoma', 'Disease', (0, 25))	('Breast invasive carcinoma', 'Phenotype', 'HP:0003002', (0, 25))	('alteration', 'Var', (52, 62))	('disease-free survival', 'CPA', (115, 136))	('NFIX', 'Gene', (42, 46))	('Breast invasive carcinoma', 'Disease', 'MESH:D018270', (0, 25))	('breast invasive carcinoma', 'Disease', 'MESH:D018270', (157, 182))	('overall survival', 'CPA', (89, 105))	('breast invasive carcinoma', 'Disease', (157, 182))
450384	32219034	Decreased NFIA expression showed better RFS, OS and DMFS in the HER2-enriched subtype.	('OS', 'Chemical', '-', (45, 47))	('NFIA', 'Protein', (10, 14))	('Decreased', 'NegReg', (0, 9))	('DMFS', 'Var', (52, 56))	('RFS', 'MPA', (40, 43))	('expression', 'MPA', (15, 25))	('better', 'PosReg', (33, 39))
450398	32219034	The NFI genes in lung cancer were analyzed and depicted as oncoprints representing mutation, amplification, deep deletion, mRNA high, mRNA low, and multiple alterations (Figs.	('amplification', 'Var', (93, 106))	('deep deletion', 'Var', (108, 121))	('lung cancer', 'Disease', (17, 28))	('lung cancer', 'Phenotype', 'HP:0100526', (17, 28))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('lung cancer', 'Disease', 'MESH:D008175', (17, 28))	('NFI', 'Gene', (4, 7))
450399	32219034	Lung adenocarcinoma patients with NFIB gene alteration showed better DFS compared with lung adenocarcinoma patients without NFIB gene alteration (Fig.	('Lung adenocarcinoma', 'Disease', 'MESH:D000077192', (0, 19))	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('lung adenocarcinoma', 'Disease', (87, 106))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (87, 106))	('better', 'PosReg', (62, 68))	('DFS', 'MPA', (69, 72))	('carcinoma', 'Phenotype', 'HP:0030731', (10, 19))	('Lung adenocarcinoma', 'Phenotype', 'HP:0030078', (0, 19))	('Lung adenocarcinoma', 'Disease', (0, 19))	('NFIB', 'Gene', (34, 38))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (87, 106))	('gene alteration', 'Var', (39, 54))
450400	32219034	Lung squamous cell carcinoma patients with NFIA gene alteration showed worse OS compared with lung squamous cell carcinoma patients without NFIA gene alterations (Fig.	('carcinoma', 'Phenotype', 'HP:0030731', (19, 28))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (94, 122))	('gene alteration', 'Var', (48, 63))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (99, 122))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (94, 122))	('lung squamous cell carcinoma', 'Disease', (94, 122))	('OS', 'Chemical', '-', (77, 79))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (5, 28))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('squamous cell carcinoma', 'Disease', (5, 28))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (99, 122))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (5, 28))
450417	32219034	Bladder urothelial carcinoma patients with NFIB gene alteration showed significantly better OS compared with bladder urothelial patients without NFIB gene alteration.	('better', 'PosReg', (85, 91))	('urothelial carcinoma', 'Disease', (8, 28))	('carcinoma', 'Phenotype', 'HP:0030731', (19, 28))	('gene alteration', 'Var', (48, 63))	('NFIB', 'Gene', (43, 47))	('urothelial carcinoma', 'Disease', 'MESH:D014526', (8, 28))	('OS', 'Chemical', '-', (92, 94))	('bladder urothelial', 'Disease', 'MESH:D001745', (109, 127))	('bladder urothelial', 'Disease', (109, 127))
450432	32219034	Head and neck cancer patients with NFIA gene alteration showed better OS compared with head and neck cancer patients without NFIA gene alteration.	('OS', 'Chemical', '-', (70, 72))	('neck cancer', 'Disease', 'MESH:D006258', (96, 107))	('NFIA', 'Gene', (35, 39))	('head and neck cancer', 'Phenotype', 'HP:0012288', (87, 107))	('neck cancer', 'Disease', 'MESH:D006258', (9, 20))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('neck cancer', 'Disease', (9, 20))	('Head and neck cancer', 'Phenotype', 'HP:0012288', (0, 20))	('better', 'PosReg', (63, 69))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('gene alteration', 'Var', (40, 55))	('neck cancer', 'Disease', (96, 107))
450461	32219034	The NFI genes in kidney cancer were analyzed and depicted as oncoprints representing mutation, amplification, deep deletion, mRNA high, mRNA low and multiple alterations (Figs.	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('kidney cancer', 'Phenotype', 'HP:0009726', (17, 30))	('kidney cancer', 'Disease', 'MESH:D007680', (17, 30))	('deep deletion', 'Var', (110, 123))	('kidney cancer', 'Disease', (17, 30))	('amplification', 'Var', (95, 108))	('NFI', 'Gene', (4, 7))
450463	32219034	Kidney renal papillary cell carcinoma patients with NFIX gene alteration showed worse OS compared with kidney renal papillary cell carcinoma patients without NFIX gene alteration (Fig.	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('kidney renal papillary cell carcinoma', 'Disease', (103, 140))	('OS', 'Chemical', '-', (86, 88))	('kidney renal papillary cell carcinoma', 'Disease', 'MESH:D007681', (103, 140))	('Kidney renal papillary cell carcinoma', 'Disease', (0, 37))	('gene alteration', 'Var', (57, 72))	('carcinoma', 'Phenotype', 'HP:0030731', (28, 37))	('Kidney renal papillary cell carcinoma', 'Disease', 'MESH:D007681', (0, 37))	('NFIX', 'Gene', (52, 56))
450500	32219034	In the KM plotter database, high NFIA and NFIX expression predicted better OS and disease-specific survival (DSS) in liver cancer patients.	('DSS', 'Chemical', '-', (109, 112))	('NFIX', 'Protein', (42, 46))	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('disease-specific survival', 'CPA', (82, 107))	('better', 'PosReg', (68, 74))	('liver cancer', 'Phenotype', 'HP:0002896', (117, 129))	('liver cancer', 'Disease', 'MESH:D006528', (117, 129))	('OS', 'Chemical', '-', (75, 77))	('liver cancer', 'Disease', (117, 129))	('NFIA', 'Protein', (33, 37))	('high', 'Var', (28, 32))
450518	32219034	Survival analysis indicated that almost none of the NFI genes with gene alterations were associated with OS or DFS.	('associated', 'Reg', (89, 99))	('gene alterations', 'Var', (67, 83))	('NFI genes', 'Gene', (52, 61))	('OS', 'Chemical', '-', (105, 107))	('DFS', 'Disease', (111, 114))
450519	32219034	These findings indicate that NFI gene alterations might not independently influence its transcription in various tumors.	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('tumors', 'Disease', (113, 119))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('alterations', 'Var', (38, 49))	('NFI gene', 'Gene', (29, 37))	('transcription', 'MPA', (88, 101))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
450523	32219034	Glioblastoma multiforme (GBM) patients with higher NFIB expression survived significantly longer than patients with lower NFIB expression.	('Glioblastoma multiforme', 'Disease', 'MESH:D005909', (0, 23))	('Glioblastoma multiforme', 'Disease', (0, 23))	('Glioblastoma', 'Phenotype', 'HP:0012174', (0, 12))	('expression', 'Var', (56, 66))	('NFIB', 'Gene', (51, 55))
450524	32219034	In another study, NFIX DNA hypermethylation was reportedly associated with significantly decreased NFIX expression and was related to shorter OS and RFS in patients with lung adenocarcinoma.	('hypermethylation', 'Var', (27, 43))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (170, 189))	('RFS', 'MPA', (149, 152))	('carcinoma', 'Phenotype', 'HP:0030731', (180, 189))	('OS', 'Chemical', '-', (142, 144))	('lung adenocarcinoma', 'Disease', (170, 189))	('shorter OS', 'Disease', (134, 144))	('expression', 'MPA', (104, 114))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (170, 189))	('NFIX', 'Protein', (99, 103))	('NFIX', 'Gene', (18, 22))	('decreased', 'NegReg', (89, 98))
450526	32219034	In a previous study, high NFIA expression was shown an independent predictor of poor prognosis in esophageal squamous carcinoma, and high NFIB expression was a negative prognostic value in esophagogastric junction adenocarcinoma.	('high', 'Var', (133, 137))	('esophagogastric junction adenocarcinoma', 'Phenotype', 'HP:0011459', (189, 228))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('high', 'Var', (21, 25))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (109, 127))	('esophagogastric junction adenocarcinoma', 'Disease', (189, 228))	('esophagogastric junction adenocarcinoma', 'Disease', 'MESH:C537006', (189, 228))	('esophageal squamous carcinoma', 'Disease', 'MESH:D000077277', (98, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (219, 228))	('esophageal squamous carcinoma', 'Phenotype', 'HP:0011459', (98, 127))	('esophageal squamous carcinoma', 'Disease', (98, 127))
450528	32219034	In the present study, high expression of NFIA, NFIB and NFIX was significantly associated with improved prognosis in breast cancer.	('high expression', 'Var', (22, 37))	('NFIX', 'Gene', (56, 60))	('breast cancer', 'Disease', 'MESH:D001943', (117, 130))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('breast cancer', 'Disease', (117, 130))	('NFIB', 'Gene', (47, 51))	('improved', 'PosReg', (95, 103))	('breast cancer', 'Phenotype', 'HP:0003002', (117, 130))	('NFIA', 'Gene', (41, 45))
450534	32219034	In gastric cancer, high NFIX expression was significantly correlated with better overall prognosis in gastric cancer and HER2+ gastric cancer, and marginally correlated with PPS in HER2-gastric cancer.	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('HER2-gastric cancer', 'Disease', 'MESH:D013274', (181, 200))	('gastric cancer', 'Disease', (102, 116))	('gastric cancer', 'Phenotype', 'HP:0012126', (186, 200))	('gastric cancer', 'Disease', (127, 141))	('NFIX', 'Protein', (24, 28))	('gastric cancer', 'Phenotype', 'HP:0012126', (3, 17))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('gastric cancer', 'Disease', 'MESH:D013274', (102, 116))	('gastric cancer', 'Disease', 'MESH:D013274', (127, 141))	('better', 'PosReg', (74, 80))	('HER2-gastric cancer', 'Disease', (181, 200))	('PPS', 'Chemical', '-', (174, 177))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('gastric cancer', 'Disease', (3, 17))	('expression', 'MPA', (29, 39))	('gastric cancer', 'Phenotype', 'HP:0012126', (102, 116))	('gastric cancer', 'Phenotype', 'HP:0012126', (127, 141))	('high', 'Var', (19, 23))	('gastric cancer', 'Disease', 'MESH:D013274', (186, 200))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('gastric cancer', 'Disease', 'MESH:D013274', (3, 17))
450540	32219034	The breast cancer cell line, MCF7, treated with NFIC siRNA, enhanced EMT, motility, migration and invasion.	('EMT', 'CPA', (69, 72))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('NFIC', 'Var', (48, 52))	('breast cancer', 'Disease', 'MESH:D001943', (4, 17))	('MCF7', 'CellLine', 'CVCL:0031;0.06756287128990074', (29, 33))	('invasion', 'CPA', (98, 106))	('breast cancer', 'Phenotype', 'HP:0003002', (4, 17))	('breast cancer', 'Disease', (4, 17))	('motility', 'CPA', (74, 82))	('enhanced', 'PosReg', (60, 68))
450543	32219034	Genomic analysis showed the alterations in each NFI family gene were less frequent in various tumors and had little influence on survival outcomes.	('NFI family gene', 'Gene', (48, 63))	('alterations', 'Var', (28, 39))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('tumors', 'Disease', (94, 100))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('less', 'NegReg', (69, 73))
450545	32219034	A certain negative correlation was observed, indicating that epigenetic alteration is an important mechanism of dysregulated NFI expression in human cancers.	('cancers', 'Disease', (149, 156))	('NFI', 'Gene', (125, 128))	('cancers', 'Disease', 'MESH:D009369', (149, 156))	('epigenetic alteration', 'Var', (61, 82))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('cancers', 'Phenotype', 'HP:0002664', (149, 156))
450609	28059068	CDK4/6 or MAPK blockade enhances efficacy of EGFR inhibition in oesophageal squamous cell carcinoma Oesophageal squamous cell carcinoma is a deadly disease where systemic therapy has relied upon empiric chemotherapy despite the presence of genomic alterations pointing to candidate therapeutic targets, including recurrent amplification of the gene encoding receptor tyrosine kinase epidermal growth factor receptor (EGFR).	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('as', 'Chemical', 'MESH:D001151', (180, 182))	('as', 'Chemical', 'MESH:D001151', (379, 381))	('CDK4/6', 'Gene', (0, 6))	('EGFR', 'Gene', '1956', (45, 49))	('EGFR', 'Gene', '1956', (417, 421))	('MAPK', 'Gene', (10, 14))	('Oesophageal squamous cell carcinoma', 'Disease', 'MESH:D002294', (100, 135))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('enhances', 'PosReg', (24, 32))	('oesophageal squamous cell carcinoma', 'Disease', (64, 99))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (76, 99))	('efficacy', 'MPA', (33, 41))	('oesophageal squamous cell carcinoma', 'Disease', 'MESH:D002294', (64, 99))	('deadly disease', 'Disease', 'MESH:D004194', (141, 155))	('CDK4/6', 'Gene', '1019;1021', (0, 6))	('deadly disease', 'Disease', (141, 155))	('squamous cell carcinoma Oesophageal squamous cell carcinoma', 'Phenotype', 'HP:0030359', (76, 135))	('epidermal growth factor receptor', 'Gene', (383, 415))	('epidermal growth factor receptor', 'Gene', '1956', (383, 415))	('EGFR', 'Gene', (45, 49))	('Oesophageal squamous cell carcinoma', 'Disease', (100, 135))	('inhibition', 'NegReg', (50, 60))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (112, 135))	('EGFR', 'Gene', (417, 421))	('as', 'Chemical', 'MESH:D001151', (152, 154))	('amplification', 'Var', (323, 336))
450612	28059068	We demonstrate that blockade of this rebound activation with MEK (mitogen-activated protein kinase kinase) inhibition enhances EGFR inhibitor-induced apoptosis and cell cycle arrest, and delays resistance to EGFR monotherapy.	('enhances', 'PosReg', (118, 126))	('MEK', 'Gene', (61, 64))	('cell cycle arrest', 'CPA', (164, 181))	('resistance', 'MPA', (194, 204))	('mitogen-activated protein kinase kinase', 'Gene', (66, 105))	('mitogen-activated protein kinase kinase', 'Gene', '5609', (66, 105))	('delays', 'NegReg', (187, 193))	('inhibition', 'Var', (107, 117))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (164, 181))	('EGFR', 'Gene', (127, 131))
450621	28059068	Genomic characterization in ESCC has demonstrated that 7-28% of tumours harbour amplifications of the gene encoding receptor tyrosine kinase epidermal growth factor receptor (EGFR).	('tumours', 'Phenotype', 'HP:0002664', (64, 71))	('EGFR', 'Gene', (175, 179))	('epidermal growth factor receptor', 'Gene', (141, 173))	('as', 'Chemical', 'MESH:D001151', (137, 139))	('as', 'Chemical', 'MESH:D001151', (34, 36))	('tumours', 'Disease', (64, 71))	('tumours', 'Disease', 'MESH:D009369', (64, 71))	('amplifications', 'Var', (80, 94))	('epidermal growth factor receptor', 'Gene', '1956', (141, 173))	('tumour', 'Phenotype', 'HP:0002664', (64, 70))
450625	28059068	The sole responder in a phase II trial was a patient with EGFR amplification, and patients with higher tumour EGFR expression showed significantly longer survival.	('as', 'Chemical', 'MESH:D001151', (40, 42))	('tumour', 'Disease', (103, 109))	('patient', 'Species', '9606', (82, 89))	('as', 'Chemical', 'MESH:D001151', (26, 28))	('patients', 'Species', '9606', (82, 90))	('tumour', 'Phenotype', 'HP:0002664', (103, 109))	('tumour', 'Disease', 'MESH:D009369', (103, 109))	('longer', 'PosReg', (147, 153))	('patient', 'Species', '9606', (45, 52))	('amplification', 'Var', (63, 76))	('survival', 'MPA', (154, 162))
450629	28059068	When such resistance is induced by a clear secondary mutation, such as a secondary EGFR T790M mutation in non-small-cell lung cancer, targeted use of an appropriate secondary inhibitor can be highly effective.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('lung cancer', 'Disease', 'MESH:D008175', (121, 132))	('T790M', 'Mutation', 'rs121434569', (88, 93))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (106, 132))	('as', 'Chemical', 'MESH:D001151', (68, 70))	('EGFR', 'Gene', (83, 87))	('T790M', 'Var', (88, 93))	('lung cancer', 'Disease', (121, 132))	('lung cancer', 'Phenotype', 'HP:0100526', (121, 132))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (110, 132))	('induced', 'Reg', (24, 31))	('resistance', 'MPA', (10, 20))
450635	28059068	These results identified several ESCC cell lines, TE8, OE21, KYSE30, KYSE140, KYSE180, KYSE450 and KYSE520, with EGFR gene amplification.	('KYSE180', 'Var', (78, 85))	('KYSE450', 'Chemical', '-', (87, 94))	('KYSE140', 'Chemical', '-', (69, 76))	('KYSE520', 'Var', (99, 106))
450636	28059068	Within these models, EGFR protein, EGFR phosphorylation and downstream effectors extracellular signal-regulated kinase (ERK) and AKT were variably present, but consistently higher than observed in two EGFR nonamplified ESCC lines, TE10 and KYSE70 (Fig.	('AKT', 'Gene', '207', (129, 132))	('ERK', 'Gene', '5594', (120, 123))	('TE10', 'CellLine', 'CVCL:1760', (231, 235))	('AKT', 'Gene', (129, 132))	('KYSE70', 'Var', (240, 246))	('EGFR phosphorylation', 'MPA', (35, 55))	('EGFR protein', 'Protein', (21, 33))	('extracellular signal-regulated kinase', 'Gene', '5594', (81, 118))	('ERK', 'Gene', (120, 123))	('extracellular signal-regulated kinase', 'Gene', (81, 118))	('higher', 'PosReg', (173, 179))
450638	28059068	Among these cell lines, OE21, KYSE140 and KYSE450 had greater in vitro sensitivity to EGFR inhibitors.	('KYSE140', 'Chemical', '-', (30, 37))	('KYSE140', 'Var', (30, 37))	('KYSE450', 'Chemical', '-', (42, 49))	('KYSE450', 'Var', (42, 49))
450642	28059068	In contrast, TE8 and KYSE520 showed de novo resistance to EGFR inhibition, without any apparent genomic alterations.	('EGFR', 'Protein', (58, 62))	('KYSE520', 'Var', (21, 28))	('resistance', 'MPA', (44, 54))	('inhibition', 'NegReg', (63, 73))	('as', 'Chemical', 'MESH:D001151', (8, 10))
450665	28059068	We also generated KYSE140-erlotinib and KYSE140-afatinib resistant lines that are able to proliferate in 3 muM erlotinib and 300 nM afatinib.	('proliferate', 'CPA', (90, 101))	('erlotinib', 'Chemical', 'MESH:D000069347', (111, 120))	('KYSE140', 'Chemical', '-', (40, 47))	('muM', 'Gene', '56925', (107, 110))	('afatinib', 'Chemical', 'MESH:D000077716', (48, 56))	('erlotinib', 'Chemical', 'MESH:D000069347', (26, 35))	('afatinib', 'Chemical', 'MESH:D000077716', (132, 140))	('muM', 'Gene', (107, 110))	('KYSE140-afatinib', 'Var', (40, 56))	('KYSE140', 'Chemical', '-', (18, 25))
450671	28059068	In addition, KYSE520 showed strong expression of N-cadherin, vimentin and AXL.	('KYSE520', 'Var', (13, 20))	('AXL', 'Gene', '558', (74, 77))	('expression', 'MPA', (35, 45))	('N-cadherin', 'Gene', (49, 59))	('AXL', 'Gene', (74, 77))	('vimentin', 'Gene', '7431', (61, 69))	('N-cadherin', 'Gene', '1000', (49, 59))	('vimentin', 'Gene', (61, 69))
450672	28059068	Both TE8 and KYSE520 also showed no expression of the squamous lineage marker SOX2 (Fig.	('SOX2', 'Gene', '6657', (78, 82))	('expression', 'MPA', (36, 46))	('KYSE520', 'Var', (13, 20))	('SOX2', 'Gene', (78, 82))
450676	28059068	In the OE21ER cells, we first evaluated R428, a pharmacological small-molecule ATP competitor of AXL in combination with EGFR inhibitors.	('AXL', 'Gene', (97, 100))	('ATP', 'Chemical', 'MESH:D000255', (79, 82))	('R428', 'Chemical', '-', (40, 44))	('R428', 'Var', (40, 44))	('AXL', 'Gene', '558', (97, 100))
450677	28059068	R428 enhanced the antiproliferative activity of EMT-associated intrinsic and acquired resistant cell lines other than one RAS mutant line (Supplementary Fig.	('R428', 'Chemical', '-', (0, 4))	('R428', 'Var', (0, 4))	('as', 'Chemical', 'MESH:D001151', (52, 54))	('enhanced', 'PosReg', (5, 13))	('antiproliferative activity', 'CPA', (18, 44))
450679	28059068	Moreover, genomically silencing AXL could not resensitize these resistance cells to EGFR inhibition or block downstream pathways (Supplementary Fig.	('downstream pathways', 'Pathway', (109, 128))	('block', 'NegReg', (103, 108))	('AXL', 'Gene', (32, 35))	('genomically silencing', 'Var', (10, 31))	('EGFR inhibition', 'MPA', (84, 99))	('AXL', 'Gene', '558', (32, 35))
450687	28059068	We observed that even with a dose of only 2 nM of trametinib, MEK blockade could inhibit rebound ERK1/2 phosphorylation (Fig.	('MEK', 'Gene', (62, 65))	('trametinib', 'Chemical', 'MESH:C560077', (50, 60))	('ERK1/2', 'Gene', (97, 103))	('inhibit', 'NegReg', (81, 88))	('ERK1/2', 'Gene', '5595;5594', (97, 103))	('blockade', 'Var', (66, 74))	('rebound', 'MPA', (89, 96))
450690	28059068	Further investigation showed that 48 h of treatment with erlotinib, afatinib, trametinib or the combinations thereof increased G0/G1 arrest in OE21 and KYSE140 with the magnitude of cell cycle arrest greater with combination treatment (Fig.	('cell cycle', 'CPA', (182, 192))	('KYSE140', 'Chemical', '-', (152, 159))	('as', 'Chemical', 'MESH:D001151', (122, 124))	('increased', 'PosReg', (117, 126))	('G0/G1 arrest', 'MPA', (127, 139))	('trametinib', 'Chemical', 'MESH:C560077', (78, 88))	('erlotinib', 'Chemical', 'MESH:D000069347', (57, 66))	('KYSE140', 'Var', (152, 159))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (182, 199))	('afatinib', 'Chemical', 'MESH:D000077716', (68, 76))
450691	28059068	Furthermore, combination therapy led to greater annexin V-positive cells with 72 h of treatment, suggesting that MEK inhibition augmented apoptosis induced by EGFR inhibitors (Fig.	('augmented', 'PosReg', (128, 137))	('EGFR', 'Gene', (159, 163))	('inhibitors', 'Var', (164, 174))	('apoptosis', 'CPA', (138, 147))	('inhibition', 'Var', (117, 127))	('V', 'Chemical', 'MESH:D014639', (56, 57))	('MEK', 'Gene', (113, 116))
450700	28059068	Trametinib was able to augment erlotinib/afatinib sensitivity and successfully block the persistent phosphorylation of ERK in the KYSE30 cells that harbour the combination of EGFR amplification and HRAS mutation (Supplementary Fig.	('amplification', 'Var', (180, 193))	('Trametinib', 'Chemical', 'MESH:C560077', (0, 10))	('as', 'Chemical', 'MESH:D001151', (12, 14))	('block', 'NegReg', (79, 84))	('persistent phosphorylation', 'MPA', (89, 115))	('EGFR', 'Gene', (175, 179))	('afatinib', 'Chemical', 'MESH:D000077716', (41, 49))	('erlotinib/afatinib', 'MPA', (31, 49))	('HRAS', 'Gene', '3265', (198, 202))	('ERK', 'Gene', (119, 122))	('mutation', 'Var', (203, 211))	('ERK', 'Gene', '5594', (119, 122))	('HRAS', 'Gene', (198, 202))	('sensitivity', 'MPA', (50, 61))	('augment', 'PosReg', (23, 30))	('erlotinib', 'Chemical', 'MESH:D000069347', (31, 40))
450703	28059068	Based upon genomic data from ESCC that have supported amplification of CCND1 as a prominent feature in these cancers, we evaluated the co-occurrence of alterations in this pathway in genomic data from TCGA.	('as', 'Chemical', 'MESH:D001151', (77, 79))	('amplification', 'Var', (54, 67))	('cancers', 'Disease', 'MESH:D009369', (109, 116))	('as', 'Chemical', 'MESH:D001151', (1, 3))	('CCND1', 'Gene', (71, 76))	('cancers', 'Phenotype', 'HP:0002664', (109, 116))	('cancers', 'Disease', (109, 116))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('CCND1', 'Gene', '595', (71, 76))
450705	28059068	Among these, the most notable secondary alteration was the focal amplification at chromosome 11q13, at the locus of CCND1, in 10 samples (66.7%).	('as', 'Chemical', 'MESH:D001151', (52, 54))	('CCND1', 'Gene', (116, 121))	('focal amplification', 'Var', (59, 78))	('CCND1', 'Gene', '595', (116, 121))
450706	28059068	We also observed deletion or truncating mutation of CDKN2A in 9 samples (60%), RB1 deletion in 1 sample (6.7%) and CDK6 amplification in 5 samples (33.3%).	('RB1', 'Gene', (79, 82))	('truncating', 'MPA', (29, 39))	('RB1', 'Gene', '5925', (79, 82))	('deletion', 'Var', (17, 25))	('CDKN2A', 'Gene', (52, 58))	('deletion', 'Var', (83, 91))	('CDK6', 'Gene', (115, 119))	('CDKN2A', 'Gene', '1029', (52, 58))	('CDK6', 'Gene', '1021', (115, 119))
450707	28059068	These data suggest joint EGFR amplification and cell cycle dysregulation are prominently co-occurring features in these tumours.	('tumour', 'Phenotype', 'HP:0002664', (120, 126))	('tumours', 'Phenotype', 'HP:0002664', (120, 127))	('amplification', 'Var', (30, 43))	('cell cycle dysregulation', 'CPA', (48, 72))	('tumours', 'Disease', 'MESH:D009369', (120, 127))	('tumours', 'Disease', (120, 127))	('cell cycle dysregulation', 'Phenotype', 'HP:0011018', (48, 72))	('EGFR', 'Protein', (25, 29))
450708	28059068	Re-review of our models showed that the OE21 cell line harbours co-occurring amplification of CCND1 and CDKN2A deletion, whereas the KYSE140 cell line harbours CDKN2A deletion in addition to EGFR amplification (Supplementary Table 2).	('CDKN2A', 'Gene', '1029', (104, 110))	('amplification', 'MPA', (77, 90))	('CCND1', 'Gene', (94, 99))	('CDKN2A', 'Gene', (160, 166))	('as', 'Chemical', 'MESH:D001151', (126, 128))	('CDKN2A', 'Gene', '1029', (160, 166))	('CCND1', 'Gene', '595', (94, 99))	('KYSE140', 'Chemical', '-', (133, 140))	('CDKN2A', 'Gene', (104, 110))	('deletion', 'Var', (111, 119))
450709	28059068	These data raised hypotheses regarding possible augmentation of EGFR blockade with cyclin-dependent kinase 4/6 (CDK4/6) inhibition, analogous to data in breast cancer where such agents act synergistically with PI3K blockade.	('breast cancer', 'Phenotype', 'HP:0003002', (153, 166))	('CDK4/6', 'Gene', (112, 118))	('breast cancer', 'Disease', 'MESH:D001943', (153, 166))	('augmentation', 'PosReg', (48, 60))	('inhibition', 'NegReg', (120, 130))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('blockade', 'Var', (69, 77))	('EGFR', 'Gene', (64, 68))	('cyclin-dependent kinase 4/6', 'Gene', (83, 110))	('cyclin-dependent kinase 4/6', 'Gene', '1019;1021', (83, 110))	('breast cancer', 'Disease', (153, 166))
450712	28059068	Similarly, combined EGFR and CDK4/6 inhibition did not alter the effects of phosphorylation of downstream signalling mediators AKT, nor did it block p-ERK rebound (Supplementary Fig.	('inhibition', 'Var', (36, 46))	('p-ERK', 'Gene', '9451', (149, 154))	('CDK4/6', 'Protein', (29, 35))	('p-ERK', 'Gene', (149, 154))	('AKT', 'Gene', '207', (127, 130))	('AKT', 'Gene', (127, 130))
450724	28059068	Beyond the better apparent response to the EGFR and CDK4/6 combination, we also observed less apparent toxicity with this combination compared with the MEK doublet.	('CDK4/6', 'Gene', (52, 58))	('combination', 'Var', (59, 70))	('toxicity', 'Disease', 'MESH:D064420', (103, 111))	('toxicity', 'Disease', (103, 111))
450736	28059068	Despite the presence of multiple FDA-approved inhibitors to EGFR and the documented presence of EGFR amplification as a common feature of ESCC, treatment of systemic disease remains reliant upon cytotoxic therapy.	('systemic disease', 'Disease', 'MESH:D034721', (157, 173))	('as', 'Chemical', 'MESH:D001151', (115, 117))	('amplification', 'Var', (101, 114))	('EGFR', 'Gene', (96, 100))	('systemic disease', 'Disease', (157, 173))	('ESCC', 'Disease', (138, 142))	('as', 'Chemical', 'MESH:D001151', (170, 172))
450738	28059068	Initial studies investigating this target suffered from both the failure to utilize biomarkers to select patients with somatic alterations of EGFR and from the reliance upon monotherapy against EGFR as a targeting strategy.	('EGFR', 'Gene', (142, 146))	('patients', 'Species', '9606', (105, 113))	('as', 'Chemical', 'MESH:D001151', (199, 201))	('alterations', 'Var', (127, 138))
450750	28059068	Indeed, among EGFR-mutant lung cancers with acquired resistance to their initial EGFR inhibitor, there is growing evidence that all resistant cells may not share the same, but exhibit different resistance mechanisms, likely reflecting both intratumoural and intertumoural heterogeneity, as well as dynamic changes in the relative populations of resistant clones over time.	('tumour', 'Disease', 'MESH:D009369', (245, 251))	('tumour', 'Disease', (263, 269))	('as', 'Chemical', 'MESH:D001151', (295, 297))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('tumour', 'Disease', (245, 251))	('lung cancer', 'Phenotype', 'HP:0100526', (26, 37))	('EGFR-mutant', 'Gene', (14, 25))	('lung cancers', 'Disease', 'MESH:D008175', (26, 38))	('lung cancers', 'Phenotype', 'HP:0100526', (26, 38))	('tumour', 'Phenotype', 'HP:0002664', (263, 269))	('tumour', 'Disease', 'MESH:D009369', (263, 269))	('cancers', 'Phenotype', 'HP:0002664', (31, 38))	('tumour', 'Phenotype', 'HP:0002664', (245, 251))	('EGFR-mutant', 'Var', (14, 25))	('lung cancers', 'Disease', (26, 38))	('as', 'Chemical', 'MESH:D001151', (287, 289))
450752	28059068	In colorectal cancer, acquired drug resistance to EGFR antibody cetuximab is also being observed to converge upon ERK reactivation that, in turn, could be rationally targeted by further lines of therapy.	('reactivation', 'Var', (118, 130))	('ERK', 'Gene', (114, 117))	('colorectal cancer', 'Phenotype', 'HP:0003003', (3, 20))	('cetuximab', 'Chemical', 'MESH:D000068818', (64, 73))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('drug resistance', 'Phenotype', 'HP:0020174', (31, 46))	('colorectal cancer', 'Disease', (3, 20))	('cetuximab', 'Gene', (64, 73))	('colorectal cancer', 'Disease', 'MESH:D015179', (3, 20))	('ERK', 'Gene', '5594', (114, 117))
450759	28059068	In a phase II clinical trial, combinations of targeted agents conferred advantages over sequential treatments in melanoma patients treated concomitantly with anti-BRAF and anti-MEK drugs.	('BRAF', 'Gene', (163, 167))	('BRAF', 'Gene', '673', (163, 167))	('combinations', 'Var', (30, 42))	('melanoma', 'Phenotype', 'HP:0002861', (113, 121))	('as', 'Chemical', 'MESH:D001151', (7, 9))	('melanoma', 'Disease', (113, 121))	('patients', 'Species', '9606', (122, 130))	('melanoma', 'Disease', 'MESH:D008545', (113, 121))	('advantages', 'PosReg', (72, 82))
450760	28059068	In addition, initial co-targeting of EGFR and MEK has been shown experimentally to impede the development of acquired resistance in EGFR-mutant lung cancer.	('impede', 'NegReg', (83, 89))	('lung cancer', 'Disease', (144, 155))	('lung cancer', 'Phenotype', 'HP:0100526', (144, 155))	('co-targeting', 'Var', (21, 33))	('EGFR-mutant', 'Gene', (132, 143))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('acquired resistance', 'MPA', (109, 128))	('as', 'Chemical', 'MESH:D001151', (51, 53))	('lung cancer', 'Disease', 'MESH:D008175', (144, 155))	('MEK', 'Gene', (46, 49))	('EGFR', 'Gene', (37, 41))
450763	28059068	Reactivation of MAPK signalling is thus likely independent of the mechanisms driving acquired resistance and thus likely enables cancer cells to survive and subsequently activate other bypass routes for survival and proliferation.	('MAPK', 'Gene', (16, 20))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('as', 'Chemical', 'MESH:D001151', (188, 190))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('Reactivation', 'Var', (0, 12))
450764	28059068	We showed that amplifications of cell cycle-related genes such as CCND1 and CDK4/6 and deletion of CDKN2A gene co-exist in considerable proportions of EGFR-amplified ESCC.	('CDKN2A', 'Gene', (99, 105))	('CCND1', 'Gene', '595', (66, 71))	('CDKN2A', 'Gene', '1029', (99, 105))	('as', 'Chemical', 'MESH:D001151', (63, 65))	('deletion', 'Var', (87, 95))	('ESCC', 'Disease', (166, 170))	('CCND1', 'Gene', (66, 71))
450767	28059068	Concomitant inhibition of CDK4/6 with PI3K inhibitors has been shown to enhance sensitivity in preclinical breast cancer models, suggesting that this capacity is not EGFR inhibitor specific.	('inhibitors', 'Var', (43, 53))	('inhibition', 'NegReg', (12, 22))	('enhance', 'PosReg', (72, 79))	('sensitivity', 'MPA', (80, 91))	('breast cancer', 'Disease', 'MESH:D001943', (107, 120))	('CDK4/6', 'Protein', (26, 32))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('PI3K', 'Gene', (38, 42))	('breast cancer', 'Disease', (107, 120))	('as', 'Chemical', 'MESH:D001151', (110, 112))	('as', 'Chemical', 'MESH:D001151', (55, 57))	('breast cancer', 'Phenotype', 'HP:0003002', (107, 120))
450769	28059068	In conclusion, genomic amplifications of the gene encoding EGFR in ESCC has a clear potential to serve as biomarker to guide the use of targeted inhibitors.	('genomic amplifications', 'Var', (15, 37))	('EGFR', 'Gene', (59, 63))	('ESCC', 'Gene', (67, 71))	('as', 'Chemical', 'MESH:D001151', (103, 105))	('as', 'Chemical', 'MESH:D001151', (73, 75))
450774	28059068	OE21, KYSE30, KYSE70, KYSE140, KYSE180, KYSE450 and KYSE520 were obtained from The Broad Institute.	('KYSE140', 'Chemical', '-', (22, 29))	('KYSE520', 'Var', (52, 59))	('KYSE30', 'Var', (6, 12))	('KYSE450', 'Chemical', '-', (40, 47))	('KYSE70', 'Var', (14, 20))	('KYSE140', 'Var', (22, 29))	('KYSE450', 'Var', (40, 47))	('KYSE180', 'Var', (31, 38))
450779	28059068	Small-molecule inhibitors such as erlotinib (S1023), afatinib (S1011), trametinib (S2673), palbociclib (S1116), GDC0941 (S1065) and R428 (S2841) were purchased from Selleck Chemicals (Houston, TX, USA).	('trametinib', 'Chemical', 'MESH:C560077', (71, 81))	('S1116', 'Var', (104, 109))	('S1023', 'Var', (45, 50))	('S1065', 'Var', (121, 126))	('R428', 'Chemical', '-', (132, 136))	('S1011', 'Var', (63, 68))	('as', 'Chemical', 'MESH:D001151', (31, 33))	('as', 'Chemical', 'MESH:D001151', (155, 157))	('palbociclib', 'Chemical', 'MESH:C500026', (91, 102))	('S2673', 'Var', (83, 88))	('erlotinib', 'Chemical', 'MESH:D000069347', (34, 43))	('afatinib', 'Chemical', 'MESH:D000077716', (53, 61))	('GDC0941', 'Chemical', 'MESH:C532162', (112, 119))
450793	28059068	The membranes were incubated with primary antibodies overnight at 4  C. The following antibodies were used for western blotting (all from Cell Signaling Technologies, Beverly, MA, USA, except where indicated): anti-phospho EGFR Tyr 1068 (3777, 1:2,000), anti-EGFR (4267, 1:6,000), anti-phospho AKT Ser-473 (4060, 1:500), total AKT (9272, 1:1,000), anti-phospho ERK1/2 Thr 202/204 (4370, 1:500), anti-ERK1/2 (4695, 1:1,000), anti-vimentin (5741, 1:1,000), anti-SOX2 (14962, 1:1,000), anti-AXL (8661, 1:1,000), anti-phospho S6RP Ser235/236 (2211, 1:1,000), anti-S6 (2217, 1:2,000), anti-phospho RB Ser807/811 (9308, 1:500) and anti-Rb (9309, 1:1,000).	('vimentin', 'Gene', (429, 437))	('ERK1/2', 'Gene', '5595;5594', (400, 406))	('AXL', 'Gene', (488, 491))	('AKT', 'Gene', '207', (327, 330))	('anti-phospho', 'Var', (509, 521))	('ERK1/2', 'Gene', (361, 367))	('AKT', 'Gene', '207', (294, 297))	('vimentin', 'Gene', '7431', (429, 437))	('ERK1/2', 'Gene', (400, 406))	('AKT', 'Gene', (327, 330))	('ERK1/2', 'Gene', '5595;5594', (361, 367))	('SOX2', 'Gene', (460, 464))	('AXL', 'Gene', '558', (488, 491))	('SOX2', 'Gene', '6657', (460, 464))	('AKT', 'Gene', (294, 297))
450794	28059068	Anti-N-cadherin (BDB610920, 1:1,000) and anti-E-cadherin (BD 610181, 1:1,000) were obtained from BD Biosciences.	('E-cadherin', 'Gene', (46, 56))	('N-cadherin', 'Gene', (5, 15))	('N-cadherin', 'Gene', '1000', (5, 15))	('E-cadherin', 'Gene', '999', (46, 56))	('BDB610920', 'Var', (17, 26))
450824	26528858	Mutually exclusive mutations in NOTCH1 and PIK3CA associated with clinical prognosis and chemotherapy responses of esophageal squamous cell carcinoma in China Recurrent genetic abnormalities that correlate with clinical features could be used to determine patients' prognosis, select treatments and predict responses to therapy.	('genetic abnormalities', 'Disease', (169, 190))	('PIK3CA', 'Gene', '5290', (43, 49))	('NOTCH1', 'Gene', '4851', (32, 38))	('NOTCH1', 'Gene', (32, 38))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (115, 149))	('patients', 'Species', '9606', (256, 264))	('mutations', 'Var', (19, 28))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))	('genetic abnormalities', 'Disease', 'MESH:D030342', (169, 190))	('esophageal squamous cell carcinoma', 'Disease', (115, 149))	('associated', 'Reg', (50, 60))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (126, 149))	('PIK3CA', 'Gene', (43, 49))
450826	26528858	Univariate and multivariate analyses with Cox proportional hazards model were used to examine the association between mutations and overall survival and response to chemotherapy.	('Cox', 'Gene', (42, 45))	('overall', 'CPA', (132, 139))	('mutations', 'Var', (118, 127))	('Cox', 'Gene', '1351', (42, 45))
450828	26528858	We identified statistically significant mutual exclusivity between mutations in NOTCH1 and PIK3CA in ESCC samples.	('PIK3CA', 'Gene', (91, 97))	('PIK3CA', 'Gene', '5290', (91, 97))	('mutations', 'Var', (67, 76))	('ESCC', 'Disease', (101, 105))	('NOTCH1', 'Gene', (80, 86))
450829	26528858	Mutations in NOTCH1 were associated with well-differentiated, early-stage malignancy and less metastasis to regional lymph nodes.	('malignancy', 'Disease', (74, 84))	('well-differentiated', 'CPA', (41, 60))	('associated', 'Reg', (25, 35))	('NOTCH1', 'Gene', (13, 19))	('less metastasis to regional lymph nodes', 'CPA', (89, 128))	('Mutations', 'Var', (0, 9))	('malignancy', 'Disease', 'MESH:D009369', (74, 84))
450830	26528858	Nonetheless, patients with NOTCH1 mutations had shorter survival times than patients without NOTCH1 mutations, and failed to respond to chemotherapy.	('patients', 'Species', '9606', (76, 84))	('survival times', 'CPA', (56, 70))	('patients', 'Species', '9606', (13, 21))	('shorter', 'NegReg', (48, 55))	('NOTCH1', 'Gene', (27, 33))	('mutations', 'Var', (34, 43))
450831	26528858	In contrast, patients with mutations in PIK3CA had better responses to chemotherapy and longer survival times than patients without PIK3CA mutations.	('mutations', 'Var', (27, 36))	('patients', 'Species', '9606', (115, 123))	('PIK3CA', 'Gene', (40, 46))	('PIK3CA', 'Gene', '5290', (40, 46))	('patients', 'Species', '9606', (13, 21))	('PIK3CA', 'Gene', '5290', (132, 138))	('responses to chemotherapy', 'MPA', (58, 83))	('better', 'PosReg', (51, 57))	('PIK3CA', 'Gene', (132, 138))	('longer', 'PosReg', (88, 94))	('survival times', 'CPA', (95, 109))
450832	26528858	In a genetic analysis of ESCCs from patients in China, we identified mutually exclusive mutations in NOTCH1 and PIK3CA.	('NOTCH1', 'Gene', (101, 107))	('patients', 'Species', '9606', (36, 44))	('PIK3CA', 'Gene', '5290', (112, 118))	('mutations', 'Var', (88, 97))	('PIK3CA', 'Gene', (112, 118))
450848	26528858	In this study, we describe the identification and validation of mutually exclusive mutational patterns of NOTCH1 and PIK3CA, two significantly mutated genes (SMGs) identified in ESCC via genomic analyses, and their associations with clinical variables.	('mutational', 'Var', (83, 93))	('PIK3CA', 'Gene', (117, 123))	('NOTCH1', 'Gene', (106, 112))	('PIK3CA', 'Gene', '5290', (117, 123))	('associations', 'Interaction', (215, 227))	('ESCC', 'Disease', (178, 182))
450850	26528858	Mutations of SMGs are likely to be 'drivers' in pathogenesis and these genes may affect the biology of a given tumor.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('SMGs', 'Gene', (13, 17))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumor', 'Disease', (111, 116))	('Mutations', 'Var', (0, 9))	('affect', 'Reg', (81, 87))
450853	26528858	Although one patient was found, and further validated via PCR-Sanger sequencing, with concomitant mutations of NOTCH1 and PIK3CA, the frequency of double mutations was 0.0096, which is not significantly different from 0.0 by chi-squared analysis.	('PIK3CA', 'Gene', (122, 128))	('patient', 'Species', '9606', (13, 20))	('PIK3CA', 'Gene', '5290', (122, 128))	('mutations', 'Var', (98, 107))	('NOTCH1', 'Gene', (111, 117))
450856	26528858	When the tumors from cohorts #1 and #2 (n=193), that recruited patients from Taihang Mountains and exhibited similar pattern of NOTCH1 and PIK3CA mutations, were combined, this mutually exclusive pattern between NOTCH1 and PIK3CA mutations was highly significant (Figure 1F).	('PIK3CA', 'Gene', '5290', (139, 145))	('mutations', 'Var', (146, 155))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('PIK3CA', 'Gene', (223, 229))	('NOTCH1', 'Gene', (212, 218))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('patients', 'Species', '9606', (63, 71))	('PIK3CA', 'Gene', '5290', (223, 229))	('PIK3CA', 'Gene', (139, 145))	('tumors', 'Disease', (9, 15))	('tumors', 'Disease', 'MESH:D009369', (9, 15))	('NOTCH1', 'Gene', (128, 134))
450857	26528858	Together, these data suggest that there is a strong inverse relationship between the NOTCH1 and PIK3CA mutations in ESCC that was previously undiscovered.	('mutations', 'Var', (103, 112))	('ESCC', 'Gene', (116, 120))	('NOTCH1', 'Gene', (85, 91))	('PIK3CA', 'Gene', (96, 102))	('PIK3CA', 'Gene', '5290', (96, 102))	('inverse', 'NegReg', (52, 59))
450858	26528858	The overall frequency of tumor samples with NOTCH1 or PIK3CA mutations in cohort #1 or #2 was statistically higher than that of cohort #3 or #4 (Supplementary Figure 1B).	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('PIK3CA', 'Gene', '5290', (54, 60))	('tumor', 'Disease', (25, 30))	('mutations', 'Var', (61, 70))	('NOTCH1', 'Gene', (44, 50))	('higher', 'PosReg', (108, 114))	('PIK3CA', 'Gene', (54, 60))
450859	26528858	Moreover, the frequencies of the most common tumor-associated PIK3CA mutations, involving either the helical domain (exon 9: c.1624G>A:p.Glu542Lys and c.1633G>A:p.Glu545Lys) or kinase domain (exon 20: c.3140A>G:p.His1047Arg), were significantly different among these cohorts, with 77.8% (14/18) in cohort #1, 85.7% (12/14) in cohort #2, 75% (3/4) in cohort #3, and 25% (2/8) in cohort #5 (Supplementary Figure 1C).	('p.His1047Arg', 'Mutation', 'rs121913279', (211, 223))	('p.His1047Arg', 'Var', (211, 223))	('c.1624G>A', 'Mutation', 'rs121913273', (125, 134))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('PIK3CA', 'Gene', (62, 68))	('c.3140A>G:p.His1047Arg', 'Var', (201, 223))	('tumor', 'Disease', (45, 50))	('c.1633G>A', 'Var', (151, 160))	('c.3140A>G', 'Mutation', 'rs121913279', (201, 210))	('p.Glu545Lys', 'Mutation', 'rs104886003', (161, 172))	('c.1633G>A', 'Mutation', 'rs104886003', (151, 160))	('PIK3CA', 'Gene', '5290', (62, 68))	('c.1624G>A', 'Var', (125, 134))	('p.Glu542Lys', 'Mutation', 'rs121913273', (135, 146))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
450866	26528858	In cohort #1, NOTCH1 mutations were significantly associated with well-differentiation (P = 0.001) and an absence of regional lymph node metastases (N0, P = 0.002), and were dramatically enriched in stage I tumors (P = 0.011, Table 1).	('metastases', 'Disease', 'MESH:D009362', (137, 147))	('absence', 'NegReg', (106, 113))	('tumors', 'Phenotype', 'HP:0002664', (207, 213))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('I tumors', 'Disease', (205, 213))	('metastases', 'Disease', (137, 147))	('well-differentiation', 'CPA', (66, 86))	('I tumors', 'Disease', 'MESH:D009369', (205, 213))	('NOTCH1', 'Gene', (14, 20))	('mutations', 'Var', (21, 30))
450867	26528858	The association of NOTCH1 mutations with tumor stage and lymph node metastasis also held true in this cohort (P < 0.0001, Supplementary Table 2).	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Disease', (41, 46))	('NOTCH1', 'Gene', (19, 25))	('lymph node metastasis', 'CPA', (57, 78))	('mutations', 'Var', (26, 35))	('tumor', 'Disease', 'MESH:D009369', (41, 46))
450868	26528858	Collectively, our results strongly suggest that the NOTCH1 mutations were associated with ESCC metastasis; ESCC patients who harbor NOTCH1 mutations show less risk of metastasis.	('NOTCH1', 'Gene', (132, 138))	('mutations', 'Var', (139, 148))	('patients', 'Species', '9606', (112, 120))	('NOTCH1', 'Gene', (52, 58))	('mutations', 'Var', (59, 68))	('ESCC', 'Disease', (90, 94))	('associated', 'Reg', (74, 84))
450869	26528858	However, PIK3CA mutations were not correlated with clinicopathological characteristics, including tumor differentiation, pathologic stage, and lymph node metastasis.	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('mutations', 'Var', (16, 25))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('PIK3CA', 'Gene', (9, 15))	('tumor', 'Disease', (98, 103))	('PIK3CA', 'Gene', '5290', (9, 15))
450870	26528858	Next, we used Kaplan-Meier analysis to assess the impact of NOTCH1 or PIK3CA mutations on OS in cohort #1 and validated it in cohort #2.	('PIK3CA', 'Gene', (70, 76))	('PIK3CA', 'Gene', '5290', (70, 76))	('mutations', 'Var', (77, 86))	('NOTCH1', 'Gene', (60, 66))
450871	26528858	The patients showed a median OS of 60 months and 80 months for the NOTCH1-mutated and NOTCH1-wild type (WT) groups, respectively, in cohort #1 (Table 1).	('NOTCH1-mutated', 'Var', (67, 81))	('NOTCH1-wild', 'Var', (86, 97))	('patients', 'Species', '9606', (4, 12))
450872	26528858	Surprisingly, although ESCC patients with NOTCH1 mutations showed less risk of metastasis, the association of NOTCH1 mutations with OS was not statistically significant (Log-rank (Mantel-Cox), P = 0.310, Figure 2A; Cox regression analysis, P = 0.318, Figure 2B).	('NOTCH1', 'Gene', (110, 116))	('mutations', 'Var', (117, 126))	('mutations', 'Var', (49, 58))	('Cox', 'Gene', '1351', (215, 218))	('Cox', 'Gene', (187, 190))	('NOTCH1', 'Gene', (42, 48))	('Cox', 'Gene', '1351', (187, 190))	('patients', 'Species', '9606', (28, 36))	('metastasis', 'CPA', (79, 89))	('Cox', 'Gene', (215, 218))
450874	26528858	We did, however, find a significant effect on OS for the PIK3CA mutations.	('PIK3CA', 'Gene', '5290', (57, 63))	('effect', 'Reg', (36, 42))	('mutations', 'Var', (64, 73))	('PIK3CA', 'Gene', (57, 63))
450875	26528858	The PIK3CA mutations showed a positive correlation with OS (log-rank P = 0.048) in cohort #1 (Figure 3A).	('mutations', 'Var', (11, 20))	('PIK3CA', 'Gene', (4, 10))	('PIK3CA', 'Gene', '5290', (4, 10))
450877	26528858	These data indicate that the PIK3CA mutation may be a marker of favorable prognosis for ESCC patients from the population in Taihang Mountains, Northern China.	('ESCC', 'Disease', (88, 92))	('patients', 'Species', '9606', (93, 101))	('PIK3CA', 'Gene', (29, 35))	('PIK3CA', 'Gene', '5290', (29, 35))	('mutation', 'Var', (36, 44))
450878	26528858	Based on the mutually exclusivity of NOTCH1 and PIK3CA, ESCC patients could be divided into three groups: patients with NOTCH1 mutations, patients with PIK3CA mutations, and patients without mutations of either gene (Supplementary Table 4).	('ESCC', 'Disease', (56, 60))	('PIK3CA', 'Gene', '5290', (152, 158))	('PIK3CA', 'Gene', (152, 158))	('mutations', 'Var', (159, 168))	('PIK3CA', 'Gene', (48, 54))	('NOTCH1', 'Gene', (120, 126))	('patients', 'Species', '9606', (61, 69))	('patients', 'Species', '9606', (174, 182))	('patients', 'Species', '9606', (106, 114))	('PIK3CA', 'Gene', '5290', (48, 54))	('mutations', 'Var', (127, 136))	('patients', 'Species', '9606', (138, 146))
450879	26528858	We extended our survival analysis in these groups and found that patients with PIK3CA mutations had a significantly longer OS (median OS of 80.9 months) than patients without mutations in either gene (median OS 40 months) (log-rank P = 0.026, Figure 4A; Cox regression analysis, P = 0.037, Figure 4B).	('mutations', 'Var', (86, 95))	('longer', 'PosReg', (116, 122))	('Cox', 'Gene', '1351', (254, 257))	('PIK3CA', 'Gene', (79, 85))	('Cox', 'Gene', (254, 257))	('patients', 'Species', '9606', (65, 73))	('patients', 'Species', '9606', (158, 166))	('PIK3CA', 'Gene', '5290', (79, 85))
450880	26528858	Notably, although NOTCH1 mutations were significantly associated with tumor well-differentiation, early pathologic stage, and low lymph node metastasis, patients with NOTCH1 mutations tended to have an even shorter OS than patients with PIK3CA mutations; the OS of patients with NOTCH1 mutations was not different from that of patients without mutations in these two genes (Cox regression analysis, P = 0.144, Figure 4B).	('NOTCH1', 'Gene', (18, 24))	('Cox', 'Gene', (374, 377))	('low lymph node metastasis', 'Disease', 'MESH:D009362', (126, 151))	('mutations', 'Var', (25, 34))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('patients', 'Species', '9606', (265, 273))	('PIK3CA', 'Gene', '5290', (237, 243))	('mutations', 'Var', (174, 183))	('low lymph node metastasis', 'Disease', (126, 151))	('low lymph node', 'Phenotype', 'HP:0002732', (126, 140))	('associated', 'Reg', (54, 64))	('patients', 'Species', '9606', (327, 335))	('patients', 'Species', '9606', (153, 161))	('NOTCH1', 'Gene', (167, 173))	('tumor', 'Disease', (70, 75))	('Cox', 'Gene', '1351', (374, 377))	('PIK3CA', 'Gene', (237, 243))	('patients', 'Species', '9606', (223, 231))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
450881	26528858	PIK3CA mutations correlate with OS (Cox regression analysis, P < 0.001, HR=0.002, 95% CI: 0.0-0.038, Figure 4D), whereas NOTCH1 mutations show no correlation with OS (Cox regression analysis, P = 0.561, Figure 4D).	('Cox', 'Gene', '1351', (167, 170))	('Cox', 'Gene', (167, 170))	('PIK3CA', 'Gene', (0, 6))	('PIK3CA', 'Gene', '5290', (0, 6))	('Cox', 'Gene', '1351', (36, 39))	('Cox', 'Gene', (36, 39))	('mutations', 'Var', (7, 16))
450884	26528858	In cohort #1, 70 patients received standard chemotherapy, including 16 patients with NOTCH1 mutations, 12 patients with PIK3CA mutations, 1 patient with both the NOTCH1 and PIK3CA mutations, and 41 patients with neither NOTCH1 nor PIK3CA mutations (Supplementary Table 5).	('PIK3CA', 'Gene', '5290', (173, 179))	('PIK3CA', 'Gene', (231, 237))	('PIK3CA', 'Gene', (120, 126))	('patient', 'Species', '9606', (198, 205))	('PIK3CA', 'Gene', '5290', (231, 237))	('patients', 'Species', '9606', (198, 206))	('patients', 'Species', '9606', (71, 79))	('patient', 'Species', '9606', (106, 113))	('patient', 'Species', '9606', (17, 24))	('patient', 'Species', '9606', (140, 147))	('NOTCH1', 'Gene', (85, 91))	('mutations', 'Var', (92, 101))	('PIK3CA', 'Gene', '5290', (120, 126))	('patients', 'Species', '9606', (106, 114))	('patients', 'Species', '9606', (17, 25))	('mutations', 'Var', (127, 136))	('patient', 'Species', '9606', (71, 78))	('PIK3CA', 'Gene', (173, 179))
450887	26528858	Patients with NOTCH1 mutations showed a median OS of 27.09 months, whereas those with PIK3CA mutations showed a median OS of 80 months.	('PIK3CA', 'Gene', (86, 92))	('Patients', 'Species', '9606', (0, 8))	('PIK3CA', 'Gene', '5290', (86, 92))	('NOTCH1', 'Gene', (14, 20))	('mutations', 'Var', (21, 30))
450889	26528858	Of 17 patients who had NOTCH1 mutations and received standard chemotherapy, 70.6% (12 out of 17) exhibited failure of chemotherapy.	('patients', 'Species', '9606', (6, 14))	('mutations', 'Var', (30, 39))	('NOTCH1', 'Gene', (23, 29))
450890	26528858	Surprisingly, we found no benefit of standard chemotherapy for patients with NOTCH1 mutations compared to those with mutations in neither gene (P = 0.389, Fisher's exact test).	('mutations', 'Var', (84, 93))	('NOTCH1', 'Gene', (77, 83))	('patients', 'Species', '9606', (63, 71))
450891	26528858	Conversely, having a PIK3CA mutation was associated with a better response than having mutations in neither gene (P = 0.026, Fisher's exact test).	('mutation', 'Var', (28, 36))	('PIK3CA', 'Gene', (21, 27))	('response', 'MPA', (66, 74))	('PIK3CA', 'Gene', '5290', (21, 27))
450892	26528858	Of 13 patients with PIK3CA mutations who received standard chemotherapy, only 23% (3 out of 13) showed failure of chemotherapy.	('mutations', 'Var', (27, 36))	('PIK3CA', 'Gene', (20, 26))	('patients', 'Species', '9606', (6, 14))	('PIK3CA', 'Gene', '5290', (20, 26))
450893	26528858	Moreover, patients with PIK3CA mutations showed significantly better responses than those with NOTCH1 mutations (P = 0.01, Fisher's exact test, Figure 5A, right panel).	('mutations', 'Var', (31, 40))	('PIK3CA', 'Gene', (24, 30))	('responses', 'MPA', (69, 78))	('better', 'PosReg', (62, 68))	('PIK3CA', 'Gene', '5290', (24, 30))	('patients', 'Species', '9606', (10, 18))
450894	26528858	This cohort included 18 patients with NOTCH1 mutations, 14 patients with PIK3CA mutations, and 57 patients mutations in neither gene.	('PIK3CA', 'Gene', (73, 79))	('mutations', 'Var', (45, 54))	('PIK3CA', 'Gene', '5290', (73, 79))	('patients', 'Species', '9606', (98, 106))	('patients', 'Species', '9606', (59, 67))	('NOTCH1', 'Gene', (38, 44))	('patients', 'Species', '9606', (24, 32))
450895	26528858	Patients in cohort #2 had a median OS of 44.6 months, with a median OS of 32.78 months for patients with NOTCH1 mutations and 60 months for those with PIK3CA mutations.	('patients', 'Species', '9606', (91, 99))	('NOTCH1', 'Gene', (105, 111))	('PIK3CA', 'Gene', (151, 157))	('mutations', 'Var', (112, 121))	('Patients', 'Species', '9606', (0, 8))	('PIK3CA', 'Gene', '5290', (151, 157))
450896	26528858	A total of 13 out of 18 patients with NOTCH1 mutations failed to respond to chemotherapy, whereas 12 out of 14 patients with PIK3CA mutations responded to chemotherapy (P = 0.001, Fisher's exact test, Supplementary Figure 4A and Supplementary Table 5), consistent with the trend seen in cohort #1.	('mutations', 'Var', (45, 54))	('responded', 'MPA', (142, 151))	('PIK3CA', 'Gene', (125, 131))	('NOTCH1', 'Gene', (38, 44))	('patients', 'Species', '9606', (24, 32))	('PIK3CA', 'Gene', '5290', (125, 131))	('patients', 'Species', '9606', (111, 119))
450897	26528858	Next, we examined the effects of NOTCH1 and PIK3CA mutations on the progression-free survival (PFS) of patients in cohorts #1 and #2 who received standard chemotherapy.	('PIK3CA', 'Gene', (44, 50))	('NOTCH1', 'Gene', (33, 39))	('mutations', 'Var', (51, 60))	('PIK3CA', 'Gene', '5290', (44, 50))	('patients', 'Species', '9606', (103, 111))
450898	26528858	As expected, patients in cohort #1 with PIK3CA mutations showed significantly longer PFS than those with NOTCH1 mutations by Log-rank (Mantel-Cox) (P = 0.018, Figure 5B) and univariate analyses (P = 0.03, HR = 4.124, 95% CI: 1.145-14.86, Figure 5C).	('PFS', 'MPA', (85, 88))	('longer', 'PosReg', (78, 84))	('PIK3CA', 'Gene', (40, 46))	('PIK3CA', 'Gene', '5290', (40, 46))	('patients', 'Species', '9606', (13, 21))	('mutations', 'Var', (47, 56))	('Cox', 'Gene', '1351', (142, 145))	('Cox', 'Gene', (142, 145))
450899	26528858	Our data suggest that patients with NOTCH1 mutations, who are likely to exhibit a better outcome without chemotherapy, might suffer unnecessarily from side effects of chemotherapy.	('NOTCH1', 'Gene', (36, 42))	('patients', 'Species', '9606', (22, 30))	('mutations', 'Var', (43, 52))
450900	26528858	However, patients with PIK3CA mutations could benefit from standard chemotherapy, and could thus survive longer.	('patients', 'Species', '9606', (9, 17))	('PIK3CA', 'Gene', (23, 29))	('PIK3CA', 'Gene', '5290', (23, 29))	('mutations', 'Var', (30, 39))	('benefit', 'PosReg', (46, 53))
450901	26528858	Therefore, PIK3CA mutational status may have a potential role as a biomarker for standard chemotherapy and prognosis in ESCC patients from Taihang Mountains, Northern China.	('mutational', 'Var', (18, 28))	('ESCC', 'Disease', (120, 124))	('PIK3CA', 'Gene', (11, 17))	('PIK3CA', 'Gene', '5290', (11, 17))	('patients', 'Species', '9606', (125, 133))
450903	26528858	However, in our study, we found frequent NOTCH1 mutations in early-stage malignancy and less metastasis to regional lymph nodes, but with poor prognosis in ESCC patients.	('less', 'NegReg', (88, 92))	('malignancy', 'Disease', 'MESH:D009369', (73, 83))	('malignancy', 'Disease', (73, 83))	('metastasis to regional lymph nodes', 'CPA', (93, 127))	('patients', 'Species', '9606', (161, 169))	('NOTCH1', 'Gene', (41, 47))	('mutations', 'Var', (48, 57))	('ESCC', 'Disease', (156, 160))
450905	26528858	Therefore, we had very rare relapsed tumors to analyze NOTCH1 mutation status.	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('mutation', 'Var', (62, 70))	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('NOTCH1', 'Gene', (55, 61))	('tumors', 'Disease', (37, 43))	('tumors', 'Disease', 'MESH:D009369', (37, 43))
450906	26528858	Alternatively, we performed mutation analysis of NOTCH1 in regional metastatic lymph nodes from 37 of stage III ESCC patients in cohort #1 and 19 of stage III ESCC patients in cohort #2.	('stage III ESCC', 'Disease', (102, 116))	('patients', 'Species', '9606', (164, 172))	('mutation analysis', 'Var', (28, 45))	('patients', 'Species', '9606', (117, 125))	('NOTCH1', 'Gene', (49, 55))
450911	26528858	However, we observed no correlation of NOTCH1 gene with cell migration and invasion as monitored by the iCELLigence RTCA DP system (Figure 6C-6D), indicating that NOTCH1 may involve cell proliferation but not migration and invasion in ESCC cells.	('NOTCH1', 'Var', (163, 169))	('cell proliferation', 'CPA', (182, 200))	('involve', 'Reg', (174, 181))	('DP', 'Chemical', '-', (121, 123))	('RTCA', 'Gene', (116, 120))	('RTCA', 'Gene', '8634', (116, 120))
450913	26528858	A striking finding of this study is the previously unreported, significant mutually exclusive mutational pattern between NOTCH1 and PIK3CA in ESCC.	('mutational', 'Var', (94, 104))	('ESCC', 'Disease', (142, 146))	('PIK3CA', 'Gene', (132, 138))	('NOTCH1', 'Gene', (121, 127))	('PIK3CA', 'Gene', '5290', (132, 138))
450914	26528858	Moreover, our results suggest that patients who harbor NOTCH1 mutations have a statistically significant association with well differentiation, an early stage of malignancy, and less regional lymph node metastasis; however, they exhibited a poor outcome and failure to respond to standard chemotherapy treatment.	('malignancy', 'Disease', 'MESH:D009369', (162, 172))	('malignancy', 'Disease', (162, 172))	('well differentiation', 'CPA', (122, 142))	('patients', 'Species', '9606', (35, 43))	('less', 'NegReg', (178, 182))	('NOTCH1', 'Gene', (55, 61))	('mutations', 'Var', (62, 71))
450915	26528858	In contrast, patients who harbor PIK3CA mutations showed a better response to standard chemotherapy and exhibited favorable survival.	('PIK3CA', 'Gene', '5290', (33, 39))	('patients', 'Species', '9606', (13, 21))	('mutations', 'Var', (40, 49))	('better', 'PosReg', (59, 65))	('PIK3CA', 'Gene', (33, 39))	('response', 'MPA', (66, 74))
450919	26528858	The frequencies of PIK3CA and NOTCH1 mutations in cohorts #1 and #2 (from Taihang Mountain, Northern China) were higher than those of cohorts #3 (from Chaoshan District, Southern China) and cohorts #4 and #5 (recruited from CICAMS, where patients came from all over the country and did not have a limited geographic distribution pattern).	('PIK3CA', 'Gene', (19, 25))	('PIK3CA', 'Gene', '5290', (19, 25))	('higher', 'PosReg', (113, 119))	('NOTCH1', 'Gene', (30, 36))	('mutations', 'Var', (37, 46))	('patients', 'Species', '9606', (238, 246))
450922	26528858	NOTCH1 was mutated in around 20% out of ESCC patients, and correlated with well differentiation, early TNM stage, and absence of regional lymph node metastases.	('ESCC', 'Disease', (40, 44))	('metastases', 'Disease', (149, 159))	('TNM', 'Gene', '10178', (103, 106))	('metastases', 'Disease', 'MESH:D009362', (149, 159))	('well differentiation', 'CPA', (75, 95))	('patients', 'Species', '9606', (45, 53))	('NOTCH1', 'Gene', (0, 6))	('TNM', 'Gene', (103, 106))	('mutated', 'Var', (11, 18))
450923	26528858	The close link between NOTCH1 mutation types and clinicopathological features leads us to speculate that ESCC patients with NOTCH1 mutations may have a better prognosis.	('NOTCH1', 'Gene', (124, 130))	('mutations', 'Var', (131, 140))	('ESCC', 'Disease', (105, 109))	('patients', 'Species', '9606', (110, 118))
450925	26528858	Meanwhile, a worse response to standard chemotherapy was observed on patients with NOTCH1 mutations compared to those with PIK3CA mutations.	('mutations', 'Var', (90, 99))	('PIK3CA', 'Gene', (123, 129))	('PIK3CA', 'Gene', '5290', (123, 129))	('patients', 'Species', '9606', (69, 77))	('NOTCH1', 'Gene', (83, 89))
450928	26528858	Considering that NOTCH1 mutations associated with early stage and non-lymph node metastasis that was supporting by both genetics alterations and functional study, however, no statistically significant differences in patient outcome and standard chemotherapy benefit were observed in patients contained NOTCH1 mutations, we speculate that there is a possibility that patients harbor NNOTCH1 mutations who should exhibit a better outcome may suffer side-effect of chemotherapy or receive extra treatment.	('patient', 'Species', '9606', (366, 373))	('NOTCH1', 'Gene', (302, 308))	('associated', 'Reg', (34, 44))	('mutations', 'Var', (390, 399))	('patients', 'Species', '9606', (283, 291))	('NNOTCH1', 'Gene', (382, 389))	('patient', 'Species', '9606', (216, 223))	('patients', 'Species', '9606', (366, 374))	('NOTCH1', 'Gene', (17, 23))	('mutations', 'Var', (24, 33))	('suffer', 'Reg', (440, 446))	('patient', 'Species', '9606', (283, 290))
450931	26528858	In our and others' cohorts of ESCC patients, many of the missense mutations in the NOTCH1 gene occurred at or near identified important domains, such as the ligand-binding domain (EGF repeats) and the majority of the mutations were predicted to alter the protein N-terminal to the transmembrane region.	('missense mutations', 'Var', (57, 75))	('alter', 'Reg', (245, 250))	('protein', 'Protein', (255, 262))	('patients', 'Species', '9606', (35, 43))	('mutations', 'Var', (217, 226))	('NOTCH1', 'Gene', (83, 89))
450932	26528858	c.2234G>A:p.Trp745*) observed in NOTCH1 gene generate a premature stop codon, which results in a truncated NOTCH1 protein that lacks the C-terminal domain, which contains a proline-glutamate-serine-threonine (PEST) sequence and is important for transcription activation.	('NOTCH1', 'Gene', (33, 39))	('results in', 'Reg', (84, 94))	('glutamate', 'Chemical', 'MESH:D018698', (181, 190))	('protein', 'Protein', (114, 121))	('threonine', 'Chemical', 'MESH:D013912', (198, 207))	('p.Trp745*', 'Mutation', 'p.W745*', (10, 19))	('proline', 'Chemical', 'MESH:D011392', (173, 180))	('truncated', 'MPA', (97, 106))	('serine', 'Chemical', 'MESH:D012694', (191, 197))	('c.2234G>A', 'Mutation', 'c.2234G>A', (0, 9))	('NOTCH1', 'Gene', (107, 113))	('c.2234G>A', 'Var', (0, 9))
450933	26528858	Thus, although the activating mutations in NOTCH1 were identified in T-cell acute lymphoblastic leukemia, chronic lymphoblastic leukemia, and breast cancer, the pattern of the mutations in genes that involve the NOTCH pathway suggests its potential tumor suppressing roles in ESCC, as has been reported for head and neck squamous cell carcinoma, chronic myelomonocytic leukemia, and lung squamous cell carcinoma.	('mutations', 'Var', (176, 185))	('activating', 'PosReg', (19, 29))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (307, 344))	('breast cancer', 'Disease', 'MESH:D001943', (142, 155))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (383, 411))	('breast cancer', 'Disease', (142, 155))	('carcinoma', 'Phenotype', 'HP:0030731', (335, 344))	('tumor', 'Disease', (249, 254))	('NOTCH', 'Gene', (212, 217))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (388, 411))	('chronic myelomonocytic leukemia', 'Phenotype', 'HP:0012325', (346, 377))	('lung squamous cell carcinoma', 'Disease', (383, 411))	('squamous cell carcinoma', 'Disease', (321, 344))	('tumor', 'Disease', 'MESH:D009369', (249, 254))	('lymphoblastic leukemia', 'Disease', 'MESH:D054198', (114, 136))	('chronic lymphoblastic leukemia', 'Disease', 'MESH:D015451', (106, 136))	('lymphoblastic leukemia', 'Disease', 'MESH:D054198', (82, 104))	('NOTCH', 'Gene', '4851;18128', (212, 217))	('chronic lymphoblastic leukemia', 'Phenotype', 'HP:0005550', (106, 136))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (388, 411))	('lymphoblastic leukemia', 'Disease', (82, 104))	('T-cell acute lymphoblastic leukemia', 'Phenotype', 'HP:0006727', (69, 104))	('chronic myelomonocytic leukemia', 'Disease', (346, 377))	('tumor', 'Phenotype', 'HP:0002664', (249, 254))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (321, 344))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('NOTCH', 'Gene', (43, 48))	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (76, 104))	('mutations', 'Var', (30, 39))	('chronic lymphoblastic leukemia', 'Disease', (106, 136))	('leukemia', 'Phenotype', 'HP:0001909', (369, 377))	('ESCC', 'Disease', (276, 280))	('carcinoma', 'Phenotype', 'HP:0030731', (402, 411))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (114, 136))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (383, 411))	('leukemia', 'Phenotype', 'HP:0001909', (96, 104))	('leukemia', 'Phenotype', 'HP:0001909', (128, 136))	('NOTCH', 'Gene', '4851;18128', (43, 48))	('chronic myelomonocytic leukemia', 'Disease', 'MESH:D015477', (346, 377))	('breast cancer', 'Phenotype', 'HP:0003002', (142, 155))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (82, 104))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (321, 344))
450934	26528858	This interpretation is consistent with the functional studies of the role of NOTCH1 in ESCC cells, as NOTCH1 depletion promotes tumor cell proliferation in tissue culture.	('promotes', 'PosReg', (119, 127))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('depletion', 'Var', (109, 118))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('NOTCH1', 'Gene', (102, 108))	('tumor', 'Disease', (128, 133))
450935	26528858	Inhibition of NOTCH1 pathway has been shown to sensitize cancer cells to chemotherapy in prostate cancer, ovarian cancer, colon cancer, and glioma.	('glioma', 'Disease', 'MESH:D005910', (140, 146))	('ovarian cancer', 'Disease', 'MESH:D010051', (106, 120))	('cancer', 'Disease', (57, 63))	('colon cancer', 'Phenotype', 'HP:0003003', (122, 134))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('cancer', 'Disease', (98, 104))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('prostate cancer', 'Disease', 'MESH:D011471', (89, 104))	('cancer', 'Disease', (128, 134))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('NOTCH1 pathway', 'Pathway', (14, 28))	('prostate cancer', 'Phenotype', 'HP:0012125', (89, 104))	('glioma', 'Phenotype', 'HP:0009733', (140, 146))	('prostate cancer', 'Disease', (89, 104))	('colon cancer', 'Disease', 'MESH:D015179', (122, 134))	('ovarian cancer', 'Disease', (106, 120))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('ovarian cancer', 'Phenotype', 'HP:0100615', (106, 120))	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('sensitize', 'Reg', (47, 56))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('Inhibition', 'Var', (0, 10))	('colon cancer', 'Disease', (122, 134))	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('glioma', 'Disease', (140, 146))	('cancer', 'Disease', (114, 120))
450936	26528858	Recent studies have aimed to develop antibodies against specific NOTCH receptors and ligands with the hope of limiting side effects while providing the same therapeutic benefit as gamma secretase inhibitors (drugs that inhibit NOTCH signaling); these studies were carried out in human cancers with commonly overactivated mutations in NOTCH1 that confer a survival advantage on the tumors, leading to poorer outcomes for the patients.	('NOTCH', 'Gene', (334, 339))	('tumors', 'Phenotype', 'HP:0002664', (381, 387))	('tumor', 'Phenotype', 'HP:0002664', (381, 386))	('NOTCH', 'Gene', '4851;18128', (334, 339))	('tumors', 'Disease', (381, 387))	('human', 'Species', '9606', (279, 284))	('survival', 'CPA', (355, 363))	('cancers', 'Phenotype', 'HP:0002664', (285, 292))	('NOTCH', 'Gene', (227, 232))	('cancers', 'Disease', (285, 292))	('patients', 'Species', '9606', (424, 432))	('tumors', 'Disease', 'MESH:D009369', (381, 387))	('advantage', 'PosReg', (364, 373))	('cancer', 'Phenotype', 'HP:0002664', (285, 291))	('NOTCH', 'Gene', (65, 70))	('NOTCH', 'Gene', '4851;18128', (227, 232))	('mutations', 'Var', (321, 330))	('overactivated', 'PosReg', (307, 320))	('NOTCH', 'Gene', '4851;18128', (65, 70))	('cancers', 'Disease', 'MESH:D009369', (285, 292))
450938	26528858	In accordance with the previous literature, the PIK3CA mutation could serve as a favorable predictive biomarker in ESCC patients from Taihang Mountains, Northern China.	('ESCC', 'Disease', (115, 119))	('PIK3CA', 'Gene', (48, 54))	('patients', 'Species', '9606', (120, 128))	('PIK3CA', 'Gene', '5290', (48, 54))	('mutation', 'Var', (55, 63))
450939	26528858	However, PIK3CA mutations were not associated with patient outcomes in ESCC patients from the Chaoshan population, Southern China (cohort #3) and from CICAMS, which does not have any geographic distribution limitations (cohort #5).	('patients', 'Species', '9606', (76, 84))	('ESCC', 'Disease', (71, 75))	('mutations', 'Var', (16, 25))	('patient', 'Species', '9606', (51, 58))	('PIK3CA', 'Gene', (9, 15))	('patient', 'Species', '9606', (76, 83))	('PIK3CA', 'Gene', '5290', (9, 15))
450941	26528858	In addition to the different mutation frequencies of PIK3CA among the cohorts, the most common tumor-associated PIK3CA mutations (those involving the helical domain (exon 9: c.1624G>A:p.Glu542Lys and c.1633G>A:p.Glu545Lys) or the kinase domain (exon 20: c.3140A>G:p.His1047Arg)) had significantly different frequencies among these cohorts.	('p.Glu545Lys', 'Mutation', 'rs104886003', (210, 221))	('PIK3CA', 'Gene', '5290', (53, 59))	('PIK3CA', 'Gene', '5290', (112, 118))	('p.Glu542Lys', 'Mutation', 'rs121913273', (184, 195))	('c.3140A>G', 'Mutation', 'rs121913279', (254, 263))	('c.1624G>A', 'Mutation', 'rs121913273', (174, 183))	('c.1624G>A', 'Var', (174, 183))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('p.His1047Arg', 'Mutation', 'rs121913279', (264, 276))	('p.His1047Arg', 'Var', (264, 276))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('c.1633G>A:p.Glu545Lys', 'Var', (200, 221))	('c.1633G>A', 'Mutation', 'rs104886003', (200, 209))	('PIK3CA', 'Gene', (53, 59))	('PIK3CA', 'Gene', (112, 118))	('tumor', 'Disease', (95, 100))
450942	26528858	In previous studies, the c.1633G>A:p.Glu545Lys and c.3140A>G:p.His1047Arg mutations have been implicated in favorable overall survival in the ESCC patients.	('p.Glu545Lys', 'Mutation', 'rs104886003', (35, 46))	('favorable', 'PosReg', (108, 117))	('c.3140A>G:p.His1047Arg', 'Var', (51, 73))	('p.His1047Arg', 'Mutation', 'rs121913279', (61, 73))	('p.His1047Arg', 'Var', (61, 73))	('c.1633G>A:p.Glu545Lys', 'Var', (25, 46))	('c.3140A>G', 'Mutation', 'rs121913279', (51, 60))	('patients', 'Species', '9606', (147, 155))	('c.1633G>A', 'Mutation', 'rs104886003', (25, 34))	('ESCC', 'Disease', (142, 146))	('p.Glu545Lys', 'Var', (35, 46))
450943	26528858	PIK3CA has been named as the key oncogenic effector and could be a potential driver mutation in tumorigenesis of ESCC and these mutants have previously shown oncogenic effects in vivo and may act as a p otential target site of treatment as in other cancer types.	('ESCC', 'Gene', (113, 117))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('mutants', 'Var', (128, 135))	('cancer', 'Disease', 'MESH:D009369', (249, 255))	('tumor', 'Disease', (96, 101))	('PIK3CA', 'Gene', (0, 6))	('cancer', 'Disease', (249, 255))	('PIK3CA', 'Gene', '5290', (0, 6))	('oncogenic effects', 'CPA', (158, 175))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('cancer', 'Phenotype', 'HP:0002664', (249, 255))
450944	26528858	We speculate that the lower frequency of mutations in PIK3CA hotspots in cohort #5 results in a negative association between PIK3CA mutations and survival.	('mutations', 'Var', (41, 50))	('PIK3CA', 'Gene', '5290', (54, 60))	('survival', 'MPA', (146, 154))	('mutations', 'Var', (132, 141))	('negative', 'NegReg', (96, 104))	('PIK3CA', 'Gene', (125, 131))	('PIK3CA', 'Gene', '5290', (125, 131))	('PIK3CA', 'Gene', (54, 60))
450945	26528858	Moreover, our previous mutational signature analysis showed that hotspot mutations (c.1624G>A:p.Glu542Lys, c.1633G>A:p.Glu545Lys) of PIK3CA were significantly enriched in ESCC tumors that had an apolipoprotein B mRNA-editing enzyme catalytic (APOBEC) signature in both cohort #1 and cohort #3, which implicates APOBEC activity as a common key driver of PIK3CA mutagenesis in ESCC patients from Northern or Southern populations in China.	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('PIK3CA', 'Gene', (353, 359))	('apolipoprotein B', 'Gene', (195, 211))	('ESCC tumors', 'Disease', (171, 182))	('PIK3CA', 'Gene', (133, 139))	('c.1633G>A', 'Var', (107, 116))	('c.1624G>A:', 'Var', (84, 94))	('PIK3CA', 'Gene', '5290', (133, 139))	('apolipoprotein B', 'Gene', '338', (195, 211))	('patients', 'Species', '9606', (380, 388))	('c.1624G>A', 'Mutation', 'rs121913273', (84, 93))	('PIK3CA', 'Gene', '5290', (353, 359))	('p.Glu542Lys', 'Mutation', 'rs121913273', (94, 105))	('ESCC tumors', 'Disease', 'MESH:D004938', (171, 182))	('tumors', 'Phenotype', 'HP:0002664', (176, 182))	('c.1633G>A', 'Mutation', 'rs104886003', (107, 116))	('p.Glu545Lys', 'Mutation', 'rs104886003', (117, 128))
450946	26528858	Therefore, the effect of PIK3CA mutations on survival prognosis might be observed when cohort #3 is extended to increase the sample size.	('mutations', 'Var', (32, 41))	('PIK3CA', 'Gene', '5290', (25, 31))	('effect', 'Reg', (15, 21))	('PIK3CA', 'Gene', (25, 31))
450947	26528858	Together with previously reported NGS data, our results document for the first time that NOTCH1 and PIK3CA mutations are mutually exclusive alterations in ESCC.	('mutations', 'Var', (107, 116))	('PIK3CA', 'Gene', (100, 106))	('NOTCH1', 'Gene', (89, 95))	('PIK3CA', 'Gene', '5290', (100, 106))	('ESCC', 'Disease', (155, 159))
450948	26528858	Although NOTCH1 mutations had a statistically significant association with well-differentiation, early stage of malignancy and less regional lymph node metastasis in ESCC, patients who harbor NOTCH1 mutations would not benefit from standard chemotherapy, and alternative therapeutic strategy must be developed for these patients.	('mutations', 'Var', (16, 25))	('less regional lymph node metastasis', 'CPA', (127, 162))	('NOTCH1', 'Gene', (192, 198))	('patients', 'Species', '9606', (320, 328))	('malignancy', 'Disease', 'MESH:D009369', (112, 122))	('patients', 'Species', '9606', (172, 180))	('mutations', 'Var', (199, 208))	('NOTCH1', 'Gene', (9, 15))	('ESCC', 'Disease', (166, 170))	('malignancy', 'Disease', (112, 122))	('well-differentiation', 'CPA', (75, 95))
450949	26528858	Conversely, patients who harbor PIK3CA mutations could benefit from standard chemotherapy, and thus PIK3CA mutational status may have a potential role as a biomarker for standard chemotherapy and prognosis.	('patients', 'Species', '9606', (12, 20))	('PIK3CA', 'Gene', '5290', (32, 38))	('benefit', 'PosReg', (55, 62))	('PIK3CA', 'Gene', (100, 106))	('mutations', 'Var', (39, 48))	('PIK3CA', 'Gene', '5290', (100, 106))	('PIK3CA', 'Gene', (32, 38))
450950	26528858	These results raise the possibility for the categorization of ESCC using the mutations of NOTCH1 and PIK3CA.	('PIK3CA', 'Gene', '5290', (101, 107))	('mutations', 'Var', (77, 86))	('NOTCH1', 'Gene', (90, 96))	('ESCC', 'Disease', (62, 66))	('PIK3CA', 'Gene', (101, 107))
450951	26528858	However, the NOTCH1 and PIK3CA mutated samples represented a small proportion of ESCC, and the majority of samples had wild-type NOTCH1 and PIK3CA.	('PIK3CA', 'Gene', (140, 146))	('PIK3CA', 'Gene', (24, 30))	('ESCC', 'Disease', (81, 85))	('NOTCH1', 'Gene', (13, 19))	('PIK3CA', 'Gene', '5290', (140, 146))	('PIK3CA', 'Gene', '5290', (24, 30))	('mutated', 'Var', (31, 38))
450958	26528858	Additionally, to provide high-confidence mutations, 96 pairs of tumors and matched normal tissue were selected for deep target capture-based validation (TCS, at least 365x).	('mutations', 'Var', (41, 50))	('tumors', 'Disease', (64, 70))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
450970	26528858	Briefly, n columns correspond to NOTCH1 and PIK3CA mutations and m rows correspond to patients whose tumor samples were collected (with m n).	('PIK3CA', 'Gene', (44, 50))	('NOTCH1', 'Gene', (33, 39))	('mutations', 'Var', (51, 60))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('PIK3CA', 'Gene', '5290', (44, 50))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('patients', 'Species', '9606', (86, 94))
450973	26528858	Fisher's exact test was used to analyze categorical features such as the association of NOTCH1 or PIK3CA mutations with clinical and pathological features, the distribution of gene mutations in different clusters or different cohorts, and the response rate to chemotherapy among the subgroups.	('NOTCH1', 'Gene', (88, 94))	('PIK3CA', 'Gene', (98, 104))	('association', 'Interaction', (73, 84))	('PIK3CA', 'Gene', '5290', (98, 104))	('mutations', 'Var', (105, 114))
450980	26528858	Univariate and multivariate analyses with the Cox proportional hazards model were used to examine the association between mutations and overall survival and response to chemotherapy.	('Cox', 'Gene', '1351', (46, 49))	('Cox', 'Gene', (46, 49))	('overall', 'MPA', (136, 143))	('mutations', 'Var', (122, 131))
450983	26528858	For overexpression experiments, NOTCH1 wild-type and NOTCH1-W745X mutant were cloned into pLV-EGFP(2A)-puro-GFP-vector and validated by sequencing.	('NOTCH1', 'Gene', (32, 38))	('W745X', 'Mutation', 'p.W745X', (60, 65))	('NOTCH1-W745X', 'Var', (53, 65))
451001	25850010	In the comparative study with 45 LM patients, the initial detection rate of the Thinprep method was significantly higher than that of the Cytospin method (73.3% vs. 57.8%, P<0.01).	('higher', 'PosReg', (114, 120))	('patients', 'Species', '9606', (36, 44))	('Thinprep', 'Var', (80, 88))
451173	33534860	In multivariate Poisson regression, under-reporting of HNSCC in cause-of-death records significantly increased in 2012 compared to 2010 (+7%) and was independently associated with a primary HNSCC site other than the larynx, a former primary or second synchronous cancer other than HNSCC, distant metastasis, palliative care, and death in hospitals other than comprehensive cancer care centers.	('HNSCC', 'Gene', (55, 60))	('under-reporting', 'Var', (36, 51))	('cancer', 'Disease', 'MESH:D009369', (263, 269))	('cancer', 'Phenotype', 'HP:0002664', (373, 379))	('associated with', 'Reg', (164, 179))	('palliative care', 'Disease', (308, 323))	('increased', 'PosReg', (101, 110))	('death', 'Disease', (329, 334))	('cancer', 'Disease', (263, 269))	('death', 'Disease', 'MESH:D003643', (73, 78))	('death', 'Disease', 'MESH:D003643', (329, 334))	('synchronous cancer', 'Disease', 'MESH:D009369', (251, 269))	('synchronous cancer', 'Disease', (251, 269))	('cancer', 'Disease', 'MESH:D009369', (373, 379))	('cancer', 'Phenotype', 'HP:0002664', (263, 269))	('cancer', 'Disease', (373, 379))	('distant metastasis', 'Disease', (288, 306))	('death', 'Disease', (73, 78))
451248	33534860	Under-reporting was significantly higher in 2012 compared to 2010 (+7%) and was independently associated with intermediate ages (45-74 years), a primary HNSCC site other than the larynx, a former primary or second synchronous cancer other than HNSCC, any record of distant metastasis after HNSCC diagnosis, HIV/AIDS, depression, palliative care, and death in hospitals other than a comprehensive cancer care center (Table 3).	('distant metastasis', 'CPA', (265, 283))	('cancer', 'Disease', 'MESH:D009369', (396, 402))	('death', 'Disease', (350, 355))	('AIDS', 'Disease', (311, 315))	('synchronous cancer', 'Disease', 'MESH:D009369', (214, 232))	('HIV', 'Disease', 'MESH:D015658', (307, 310))	('depression', 'Disease', 'MESH:D000275', (317, 327))	('associated', 'Reg', (94, 104))	('cancer', 'Disease', 'MESH:D009369', (226, 232))	('HIV', 'Disease', (307, 310))	('death', 'Disease', 'MESH:D003643', (350, 355))	('cancer', 'Disease', (396, 402))	('depression', 'Phenotype', 'HP:0000716', (317, 327))	('higher', 'PosReg', (34, 40))	('AIDS', 'Disease', 'MESH:D000163', (311, 315))	('cancer', 'Phenotype', 'HP:0002664', (396, 402))	('synchronous cancer', 'Disease', (214, 232))	('depression', 'Disease', (317, 327))	('cancer', 'Disease', (226, 232))	('Under-reporting', 'Var', (0, 15))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
451253	33534860	In addition, under-reporting was independently associated with dying at home, which, together with public local hospitals, was the place of death associated with the highest rate of under-reporting.	('death', 'Disease', 'MESH:D003643', (140, 145))	('death', 'Disease', (140, 145))	('dying at home', 'Disease', (63, 76))	('under-reporting', 'Var', (13, 28))
451360	33534860	One additional comment to consider is to add to the discussion that some of the head and neck SCC deaths may be hidden/included in the group of ICD 10 codes C76-C80 Malignant neoplasms of ill-defined, secondary and unspecified site.	('neck SCC deaths', 'Disease', 'MESH:D003643', (89, 104))	('C76-C80', 'Var', (157, 164))	('men', 'Species', '9606', (18, 21))	('neck SCC deaths', 'Disease', (89, 104))	('neoplasms', 'Phenotype', 'HP:0002664', (175, 184))	('Malignant neoplasms', 'Disease', 'MESH:D009369', (165, 184))	('Malignant neoplasms', 'Disease', (165, 184))	('unspecified', 'Species', '32644', (215, 226))
451380	33302540	In this study, we determined that DANCR knockdown (KD) impeded cell migration and reduced stem-like characteristics in two NSCLC cell lines, A549 and H1755.	('NSCLC', 'Disease', (123, 128))	('DANCR', 'Gene', '57291', (34, 39))	('NSCLC', 'Disease', 'MESH:D002289', (123, 128))	('knockdown', 'Var', (40, 49))	('cell migration', 'CPA', (63, 77))	('A549', 'CellLine', 'CVCL:0023', (141, 145))	('NSCLC', 'Phenotype', 'HP:0030358', (123, 128))	('impeded', 'NegReg', (55, 62))	('reduced', 'NegReg', (82, 89))	('stem-like characteristics', 'CPA', (90, 115))	('DANCR', 'Gene', (34, 39))
451393	33302540	In particular, miR-216a was described as an inhibitor of NSCLC cell growth, invasion, and metastasis.	('metastasis', 'CPA', (90, 100))	('NSCLC', 'Phenotype', 'HP:0030358', (57, 62))	('miR-216a', 'Var', (15, 23))	('NSCLC', 'Disease', (57, 62))	('invasion', 'CPA', (76, 84))	('NSCLC', 'Disease', 'MESH:D002289', (57, 62))
451399	33302540	Aberrations in Wnt signaling have been connected to unregulated proliferation, cancer development, stem cell maintenance, and metastasis in multiple cancer types.	('cancer', 'Disease', (149, 155))	('connected', 'Reg', (39, 48))	('stem cell maintenance', 'CPA', (99, 120))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('unregulated proliferation', 'CPA', (52, 77))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('Wnt', 'Pathway', (15, 18))	('metastasis', 'CPA', (126, 136))	('Aberrations', 'Var', (0, 11))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (149, 155))
451403	33302540	Given the important role of Wnt in lung homeostasis, it is not surprising that alterations in Wnt/beta-catenin signaling have also been shown to majorly impact NSCLC tumorigenesis and progression.	('impact', 'Reg', (153, 159))	('progression', 'CPA', (184, 195))	('alterations', 'Var', (79, 90))	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('NSCLC', 'Phenotype', 'HP:0030358', (160, 165))	('tumor', 'Disease', (166, 171))	('beta-catenin', 'Gene', (98, 110))	('NSCLC', 'Disease', (160, 165))	('beta-catenin', 'Gene', '1499', (98, 110))	('NSCLC', 'Disease', 'MESH:D002289', (160, 165))
451404	33302540	In this study, we report that DANCR knockdown (KD) reduces migration, cell viability, and stem-like characteristics.	('DANCR', 'Gene', '57291', (30, 35))	('reduces', 'NegReg', (51, 58))	('cell viability', 'CPA', (70, 84))	('knockdown', 'Var', (36, 45))	('migration', 'CPA', (59, 68))	('DANCR', 'Gene', (30, 35))	('stem-like characteristics', 'CPA', (90, 115))
451405	33302540	We also show that DANCR overexpression in NSCLC activates Wnt/beta-catenin signaling, which can be effectively blocked by miR-216a overexpression.	('DANCR', 'Gene', (18, 23))	('NSCLC', 'Disease', (42, 47))	('beta-catenin', 'Gene', (62, 74))	('DANCR', 'Gene', '57291', (18, 23))	('NSCLC', 'Disease', 'MESH:D002289', (42, 47))	('beta-catenin', 'Gene', '1499', (62, 74))	('overexpression', 'PosReg', (24, 38))	('NSCLC', 'Phenotype', 'HP:0030358', (42, 47))	('activates', 'PosReg', (48, 57))	('miR-216a', 'Var', (122, 130))
451412	33302540	H1975, H661, H1299, H358, and HBE2 were a generous gift from Dr. Feng Jiang, University of Maryland School of Medicine.	('HBE2', 'CellLine', 'CVCL:0287', (30, 34))	('H1299', 'Var', (13, 18))	('H358', 'CellLine', 'CVCL:1559', (20, 24))	('H661', 'CellLine', 'CVCL:1577', (7, 11))	('H358', 'Var', (20, 24))	('H1299', 'CellLine', 'CVCL:0060', (13, 18))	('H661', 'Var', (7, 11))	('H1975', 'Var', (0, 5))	('H1975', 'CellLine', 'CVCL:1511', (0, 5))
451431	33302540	The following antibodies were used from Santa Cruz Biotchnology, Inc. (Dallas, TX, USA): Sox2 (sc-365823), beta-catenin (sc-7963), GAPDH (sc-32233); Cell Signaling: c-Myc (CST-5605), Axin2 (CST-5863); and Sigma: beta-actin (A5441).	('Sox2', 'Gene', (89, 93))	('c-Myc', 'Gene', (165, 170))	('beta-catenin', 'Gene', (107, 119))	('Axin2', 'Gene', (183, 188))	('GAPDH', 'Gene', '2597', (131, 136))	('Axin2', 'Gene', '8313', (183, 188))	('beta-catenin', 'Gene', '1499', (107, 119))	('CST-5605', 'Var', (172, 180))	('GAPDH', 'Gene', (131, 136))	('c-Myc', 'Gene', '4609', (165, 170))	('Sox2', 'Gene', '6657', (89, 93))	('CST-5863', 'Var', (190, 198))	('sc-32233', 'Var', (138, 146))
451444	33302540	We further examined DANCR expression in NSCLC adenocarcinoma cell lines A549, H1975, H1755, H1944, H2087, and H358, and NSCLC large cell carcinoma cell lines H661 and H1299, and found that DANCR was significantly increased in 7 of the 8 NSCLC cell lines compared to human bronchial epithelial cell line HBE2 (Figure 1B).	('NSCLC', 'Disease', 'MESH:D002289', (237, 242))	('human', 'Species', '9606', (266, 271))	('H661', 'CellLine', 'CVCL:1577', (158, 162))	('NSCLC', 'Phenotype', 'HP:0030358', (120, 125))	('NSCLC', 'Disease', (40, 45))	('DANCR', 'Gene', (20, 25))	('H2087', 'Var', (99, 104))	('large cell carcinoma', 'Phenotype', 'HP:0030360', (126, 146))	('DANCR', 'Gene', '57291', (189, 194))	('NSCLC', 'Disease', (237, 242))	('NSCLC large cell carcinoma', 'Disease', 'MESH:D018287', (120, 146))	('NSCLC large cell carcinoma', 'Disease', (120, 146))	('NSCLC', 'Phenotype', 'HP:0030358', (40, 45))	('A549', 'CellLine', 'CVCL:0023', (72, 76))	('NSCLC', 'Phenotype', 'HP:0030358', (237, 242))	('H1944', 'Var', (92, 97))	('DANCR', 'Gene', '57291', (20, 25))	('H2087', 'CellLine', 'CVCL:1524', (99, 104))	('DANCR', 'Gene', (189, 194))	('NSCLC', 'Disease', 'MESH:D002289', (120, 125))	('NSCLC adenocarcinoma', 'Disease', 'MESH:D000230', (40, 60))	('H1944', 'CellLine', 'CVCL:1508', (92, 97))	('HBE2', 'CellLine', 'CVCL:0287', (303, 307))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('H358', 'CellLine', 'CVCL:1559', (110, 114))	('H1299', 'CellLine', 'CVCL:0060', (167, 172))	('H1975', 'CellLine', 'CVCL:1511', (78, 83))	('NSCLC adenocarcinoma', 'Disease', (40, 60))	('increased', 'PosReg', (213, 222))	('NSCLC', 'Disease', (120, 125))	('NSCLC', 'Disease', 'MESH:D002289', (40, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (51, 60))
451446	33302540	In order to investigate the functional role of DANCR in NSCLC, we employed transient methods to knockdown (KD) DANCR expression.	('knockdown', 'Var', (96, 105))	('DANCR', 'Gene', (111, 116))	('NSCLC', 'Disease', (56, 61))	('DANCR', 'Gene', '57291', (111, 116))	('NSCLC', 'Disease', 'MESH:D002289', (56, 61))	('DANCR', 'Gene', (47, 52))	('DANCR', 'Gene', '57291', (47, 52))	('NSCLC', 'Phenotype', 'HP:0030358', (56, 61))
451475	33302540	We further explored the expression of downstream Wnt target genes Axin2 and c-Myc, and found that both mRNA and protein expression were downregulated upon DANCR KD (Figure 4C,D).	('Axin2', 'Gene', (66, 71))	('DANCR KD', 'Chemical', '-', (155, 163))	('downregulated', 'NegReg', (136, 149))	('Axin2', 'Gene', '8313', (66, 71))	('c-Myc', 'Gene', '4609', (76, 81))	('c-Myc', 'Gene', (76, 81))	('DANCR KD', 'Var', (155, 163))
451477	33302540	Using in silico analysis, DANCR was predicted to contain an MRE site for miR-216a (Figure 5A).	('DANCR', 'Gene', (26, 31))	('miR-216a', 'Var', (73, 81))	('DANCR', 'Gene', '57291', (26, 31))
451478	33302540	Previous reports showed that miR-216a reduced migration and invasion in glioma, and colorectal and pancreatic cancer.	('glioma', 'Disease', (72, 78))	('reduced', 'NegReg', (38, 45))	('colorectal and pancreatic cancer', 'Disease', 'MESH:D015179', (84, 116))	('glioma', 'Phenotype', 'HP:0009733', (72, 78))	('miR-216a', 'Var', (29, 37))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (99, 116))	('glioma', 'Disease', 'MESH:D005910', (72, 78))
451482	33302540	These results demonstrated that miR-216a was pulled down almost fourfold more in MS2-DANCR cells than in MS2-Vector cells (Figure 5B).	('DANCR', 'Gene', '57291', (85, 90))	('MS2', 'Species', '2710868', (105, 108))	('miR-216a', 'Var', (32, 40))	('MS2', 'Species', '2710868', (81, 84))	('DANCR', 'Gene', (85, 90))
451486	33302540	As expected, miR-216a was downregulated in a number of different NSCLC cell lines, including H2087, H1755, H661, H1944, A549, H358, and H1975 compared to HBE2 cells (Figure 5D).	('H1944', 'Var', (113, 118))	('downregulated', 'NegReg', (26, 39))	('HBE2', 'CellLine', 'CVCL:0287', (154, 158))	('H2087', 'CellLine', 'CVCL:1524', (93, 98))	('H2087', 'Var', (93, 98))	('H661', 'CellLine', 'CVCL:1577', (107, 111))	('H1755', 'Var', (100, 105))	('NSCLC', 'Disease', 'MESH:D002289', (65, 70))	('H358', 'CellLine', 'CVCL:1559', (126, 130))	('H1944', 'CellLine', 'CVCL:1508', (113, 118))	('NSCLC', 'Phenotype', 'HP:0030358', (65, 70))	('miR-216a', 'Gene', (13, 21))	('H1975', 'Var', (136, 141))	('H1975', 'CellLine', 'CVCL:1511', (136, 141))	('H661', 'Var', (107, 111))	('NSCLC', 'Disease', (65, 70))	('A549', 'CellLine', 'CVCL:0023', (120, 124))
451490	33302540	An increase in DANCR expression was detected 48 h after transfection (Figure 6A), which increased beta-catenin protein expression compared to that in vector control cells (Figure 6B).	('beta-catenin', 'Gene', (98, 110))	('increased', 'PosReg', (88, 97))	('DANCR', 'Gene', (15, 20))	('transfection', 'Var', (56, 68))	('DANCR', 'Gene', '57291', (15, 20))	('beta-catenin', 'Gene', '1499', (98, 110))
451493	33302540	Western blot analysis revealed DANCR and vector-transfected cells increased beta-catenin protein expression compared to vector and vector control cells, and the combination of DANCR and miR-216a decreased beta-catenin expression.	('increased', 'PosReg', (66, 75))	('miR-216a', 'Var', (186, 194))	('DANCR', 'Gene', (176, 181))	('DANCR', 'Gene', (31, 36))	('beta-catenin', 'Gene', (205, 217))	('beta-catenin', 'Gene', (76, 88))	('DANCR', 'Gene', '57291', (176, 181))	('beta-catenin', 'Gene', '1499', (205, 217))	('DANCR', 'Gene', '57291', (31, 36))	('combination', 'Interaction', (161, 172))	('beta-catenin', 'Gene', '1499', (76, 88))	('decreased', 'NegReg', (195, 204))
451496	33302540	Aberrant Wnt signaling has been observed in many cancer types, including lung cancer, and the overexpression or activation of Wnt is associated with poor prognosis.	('overexpression', 'PosReg', (94, 108))	('lung cancer', 'Disease', 'MESH:D008175', (73, 84))	('observed', 'Reg', (32, 40))	('Aberrant', 'Var', (0, 8))	('activation', 'PosReg', (112, 122))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('lung cancer', 'Phenotype', 'HP:0100526', (73, 84))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('lung cancer', 'Disease', (73, 84))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('Wnt signaling', 'Pathway', (9, 22))	('cancer', 'Disease', (49, 55))
451502	33302540	The H1944 cell line could have developed and progressed from different mutations than those of the other lines, and DANCR overexpression was thereby unnecessary for its survival and growth.	('DANCR', 'Gene', '57291', (116, 121))	('mutations', 'Var', (71, 80))	('DANCR', 'Gene', (116, 121))	('H1944', 'CellLine', 'CVCL:1508', (4, 9))
451504	33302540	DANCR KD resulted in typical Wnt/beta-catenin-inactivation features, including impedance in cell migration, the inhibition of long-term clonogenic potential, and a reduction in stem-like characteristics (Figure 2).	('impedance', 'MPA', (79, 88))	('beta-catenin', 'Gene', '1499', (33, 45))	('stem-like characteristics', 'CPA', (177, 202))	('inhibition', 'NegReg', (112, 122))	('long-term clonogenic potential', 'CPA', (126, 156))	('beta-catenin', 'Gene', (33, 45))	('DANCR KD', 'Chemical', '-', (0, 8))	('DANCR KD', 'Var', (0, 8))	('reduction', 'NegReg', (164, 173))
451507	33302540	A more consistent reduction in proliferation was reported in A549 cells, with stable knockdown of DANCR via shRNA, which we also observed by Day 4 (Figure S1B).	('proliferation', 'CPA', (31, 44))	('DANCR', 'Gene', '57291', (98, 103))	('shRNA', 'Gene', (108, 113))	('knockdown', 'Var', (85, 94))	('DANCR', 'Gene', (98, 103))	('A549', 'CellLine', 'CVCL:0023', (61, 65))	('reduction', 'NegReg', (18, 27))
451510	33302540	Moreover, our experiments revealed a nearly twofold increase in DANCR expression in H1755 compared to that in A549 (Figure 1B).	('DANCR', 'Gene', '57291', (64, 69))	('A549', 'CellLine', 'CVCL:0023', (110, 114))	('increase', 'PosReg', (52, 60))	('H1755', 'Var', (84, 89))	('DANCR', 'Gene', (64, 69))
451514	33302540	We further showed that DANCR KD can inactivate beta-catenin activity and reduce beta-catenin protein expression (Figure 4).	('beta-catenin', 'Gene', '1499', (47, 59))	('inactivate', 'NegReg', (36, 46))	('DANCR KD', 'Chemical', '-', (23, 31))	('DANCR KD', 'Var', (23, 31))	('beta-catenin', 'Gene', (80, 92))	('beta-catenin', 'Gene', '1499', (80, 92))	('beta-catenin', 'Gene', (47, 59))	('reduce', 'NegReg', (73, 79))
451516	33302540	In addition, while DANCR and miR-216a interaction was previously reported in HEK293, breast, and hepatocellular carcinoma cells, we are the first to confirm this interaction in NSCLC (Figure 4B).	('HEK293', 'CellLine', 'CVCL:0045', (77, 83))	('NSCLC', 'Phenotype', 'HP:0030358', (177, 182))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (97, 121))	('miR-216a', 'Var', (29, 37))	('hepatocellular carcinoma', 'Disease', (97, 121))	('DANCR', 'Gene', (19, 24))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (97, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('NSCLC', 'Disease', (177, 182))	('DANCR', 'Gene', '57291', (19, 24))	('NSCLC', 'Disease', 'MESH:D002289', (177, 182))	('interaction', 'Interaction', (38, 49))
451517	33302540	Importantly, we observed that DANCR overexpression in A549 cells induced beta-catenin protein expression, which could subsequently be blocked with miR-216a overexpression (Figure 6).	('DANCR', 'Gene', '57291', (30, 35))	('beta-catenin', 'Gene', (73, 85))	('beta-catenin', 'Gene', '1499', (73, 85))	('A549', 'CellLine', 'CVCL:0023', (54, 58))	('DANCR', 'Gene', (30, 35))	('miR-216a', 'Var', (147, 155))
451528	33302540	The gene expression of SOX2 is highly expressed in NSCLC subtypes, and the inhibition of Sox2 downregulates Wnt1/2 and c-myc gene expression, induces cell apoptosis, and reduces metastatic potential in lung cancer.	('downregulates', 'NegReg', (94, 107))	('Sox2', 'Gene', (89, 93))	('inhibition', 'Var', (75, 85))	('lung cancer', 'Phenotype', 'HP:0100526', (202, 213))	('reduces', 'NegReg', (170, 177))	('metastatic potential', 'CPA', (178, 198))	('c-myc', 'Gene', (119, 124))	('Wnt1/2', 'Gene', (108, 114))	('induces', 'PosReg', (142, 149))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('Sox2', 'Gene', '6657', (89, 93))	('lung cancer', 'Disease', (202, 213))	('cell apoptosis', 'CPA', (150, 164))	('NSCLC', 'Disease', 'MESH:D002289', (51, 56))	('SOX2', 'Gene', (23, 27))	('SOX2', 'Gene', '6657', (23, 27))	('c-myc', 'Gene', '4609', (119, 124))	('NSCLC', 'Disease', (51, 56))	('Wnt1/2', 'Gene', '7480;7471;7472', (108, 114))	('lung cancer', 'Disease', 'MESH:D008175', (202, 213))	('NSCLC', 'Phenotype', 'HP:0030358', (51, 56))
451535	33302540	Thus, if miR-216a does target Sox2 in addition to Wnt signaling molecules, it could implicate the underlying role of miR-216a in CSC regulation.	('implicate', 'Reg', (84, 93))	('Sox2', 'Gene', (30, 34))	('miR-216a', 'Var', (117, 125))	('miR-216a', 'Gene', (9, 17))	('Sox2', 'Gene', '6657', (30, 34))	('CSC', 'Disease', (129, 132))
451543	33302540	Representative images of effect of DANCR KD on clonogenic growth in (top) A549 and (bottom) H1755 cells compared to scramble control.	('clonogenic growth', 'CPA', (47, 64))	('DANCR KD', 'Var', (35, 43))	('A549', 'CellLine', 'CVCL:0023', (74, 78))	('DANCR KD', 'Chemical', '-', (35, 43))
451614	31942111	The tumor cells induce epigenetic changes in normal fibroblasts and mutate them into CAF.	('tumor', 'Disease', (4, 9))	('epigenetic changes', 'MPA', (23, 41))	('CAF', 'Gene', (85, 88))	('mutate', 'Var', (68, 74))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('CAF', 'Gene', '8850', (85, 88))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))
451634	29221217	There is evidence that HPV infection, especially HPV 16 and HPV 18 infection, significantly increase the risk of lung cancer.	('HPV infection', 'Disease', (23, 36))	('HPV 16', 'Species', '333760', (49, 55))	('HPV 18 infection', 'Disease', (60, 76))	('lung cancer', 'Disease', (113, 124))	('lung cancer', 'Phenotype', 'HP:0100526', (113, 124))	('HPV', 'Var', (49, 52))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('lung cancer', 'Disease', 'MESH:D008175', (113, 124))	('HPV infection', 'Disease', 'MESH:D030361', (23, 36))	('HPV 18 infection', 'Disease', 'MESH:D030361', (60, 76))	('increase', 'Reg', (92, 100))
451661	29221217	Stratified by HPV detection method, significantly higher HPV infection rates were found in polymerase chain reaction (PCR), in situ hybridization (ISH), southern blot/dot blot (SB/DB), sequencing and bead-based multiplex serology method (BMSM), but not in multiplex liquid bead microarray antibody assay (LBMA).	('HPV infection', 'Disease', (57, 70))	('higher', 'PosReg', (50, 56))	('HPV', 'Species', '10566', (14, 17))	('polymerase', 'Var', (91, 101))	('HPV infection', 'Disease', 'MESH:D030361', (57, 70))	('HPV', 'Species', '10566', (57, 60))
451706	29221217	In this study, HPV 16, HPV 18 and HPV 11 infection significantly increase the risk of lung cancer, while HPV 6 and HPV 31 infection are not significantly associated with lung cancer.	('lung cancer', 'Disease', 'MESH:D008175', (170, 181))	('lung cancer', 'Disease', (86, 97))	('HPV 31 infection', 'Disease', (115, 131))	('HPV', 'Var', (15, 18))	('lung cancer', 'Phenotype', 'HP:0100526', (170, 181))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('HPV', 'Species', '10566', (115, 118))	('HPV', 'Species', '10566', (105, 108))	('HPV 18', 'Gene', (23, 29))	('lung cancer', 'Disease', 'MESH:D008175', (86, 97))	('HPV', 'Species', '10566', (34, 37))	('lung cancer', 'Phenotype', 'HP:0100526', (86, 97))	('infection', 'Var', (41, 50))	('lung cancer', 'Disease', (170, 181))	('increase', 'PosReg', (65, 73))	('HPV 16', 'Species', '333760', (15, 21))	('HPV 11', 'Gene', (34, 40))	('HPV 31 infection', 'Disease', 'MESH:D030361', (115, 131))	('HPV', 'Species', '10566', (15, 18))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('HPV 11', 'Species', '10580', (34, 40))	('HPV', 'Species', '10566', (23, 26))
451708	29221217	There is no significant difference of carcinogenic risk between HPV 16 and HPV 18 in lung cancer.	('HPV', 'Var', (64, 67))	('lung cancer', 'Disease', (85, 96))	('lung cancer', 'Phenotype', 'HP:0100526', (85, 96))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('carcinogenic', 'Disease', 'MESH:D063646', (38, 50))	('HPV 16', 'Species', '333760', (64, 70))	('carcinogenic', 'Disease', (38, 50))	('lung cancer', 'Disease', 'MESH:D008175', (85, 96))	('HPV', 'Species', '10566', (75, 78))	('HPV', 'Species', '10566', (64, 67))
451719	29221217	In summary, our meta-analysis indicates that HPV infection, especially HPV 16 and 18, increases lung cancer risk, particularly in squamous cell carcinoma and small cell carcinoma.	('small cell carcinoma', 'Disease', 'MESH:D018288', (158, 178))	('HPV 16', 'Species', '333760', (71, 77))	('increases lung cancer', 'Disease', 'MESH:D008175', (86, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (169, 178))	('HPV infection', 'Disease', 'MESH:D030361', (45, 58))	('small cell carcinoma', 'Phenotype', 'HP:0030357', (158, 178))	('HPV infection', 'Disease', (45, 58))	('lung cancer', 'Phenotype', 'HP:0100526', (96, 107))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (130, 153))	('small cell carcinoma', 'Disease', (158, 178))	('squamous cell carcinoma', 'Disease', (130, 153))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('HPV', 'Var', (71, 74))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (130, 153))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('increases lung cancer', 'Disease', (86, 107))
451745	27542262	Their aberrant expressions are correlated with tumor cell growth, invasion, metastasis and a poor prognosis.	('metastasis', 'CPA', (76, 86))	('aberrant', 'Var', (6, 14))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('invasion', 'CPA', (66, 74))	('tumor', 'Disease', (47, 52))	('correlated', 'Reg', (31, 41))
451751	27542262	Overexpression of EF2 is also correlated with cancer cell progression and early tumor recurrence.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('EF2', 'Gene', (18, 21))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('cancer', 'Disease', (46, 52))	('correlated', 'Reg', (30, 40))	('tumor', 'Disease', (80, 85))	('Overexpression', 'Var', (0, 14))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))
451783	27542262	Posttranslational modifications (PTMs) of proteins are involved in multiple biological processes, such as gene regulation, cellular function, tissue development, and metabolism, whose alterations trigger occurrence of cancers and other diseases.	('proteins', 'Protein', (42, 50))	('cancers', 'Disease', 'MESH:D009369', (218, 225))	('cancers', 'Phenotype', 'HP:0002664', (218, 225))	('alterations', 'Var', (184, 195))	('involved', 'Reg', (55, 63))	('Posttranslational modifications', 'Var', (0, 31))	('cancers', 'Disease', (218, 225))	('trigger', 'Reg', (196, 203))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))
451790	27542262	Akt pathway is vital to growth-factor stimulation of mammalian target of rapamycin (mTOR) signaling through inactivation of TSC2, an upstream regulator of mTOR, resulting in activation of EF2 through the inactivation of the EF2 kinase.	('EF2', 'Gene', (188, 191))	('mammalian target of rapamycin', 'Gene', (53, 82))	('mammalian target of rapamycin', 'Gene', '2475', (53, 82))	('EF2 kinase', 'Enzyme', (224, 234))	('mTOR', 'Gene', '2475', (155, 159))	('mTOR', 'Gene', (155, 159))	('TSC2', 'Gene', '7249', (124, 128))	('inactivation', 'Var', (108, 120))	('inactivation', 'MPA', (204, 216))	('TSC2', 'Gene', (124, 128))	('mTOR', 'Gene', '2475', (84, 88))	('Akt', 'Gene', '207', (0, 3))	('mTOR', 'Gene', (84, 88))	('activation', 'PosReg', (174, 184))	('Akt', 'Gene', (0, 3))
451794	27542262	Overexpression of EF2 in LSCC significantly promoted cell growth in vitro and in vivo through the acceleration of the G2/M progression in the cell cycle, through activation of Cdc2/Cylin B1.	('promoted', 'PosReg', (44, 52))	('Cdc2', 'Gene', '983', (176, 180))	('cell growth', 'CPA', (53, 64))	('EF2', 'Var', (18, 21))	('LSCC', 'Phenotype', 'HP:0030359', (25, 29))	('G2/M progression in the cell cycle', 'CPA', (118, 152))	('Cdc2', 'Gene', (176, 180))	('acceleration', 'PosReg', (98, 110))	('activation', 'PosReg', (162, 172))
451826	27542262	The expression vector for EF2 was constructed by inserting CDS sequence (2577bp, Nucleotide of EF2: BC126259) into the XhoI/ HindIII sites in pcDNA3.1/myc-His(-)B vector (Vigorous Biotechnology Beijing Co., Ltd.).	('CDS', 'Chemical', 'MESH:D002104', (59, 62))	('2577bp', 'Var', (73, 79))	('EF2', 'Gene', (95, 98))
451978	33653340	2, a high expression of TUBA1C was significantly associated with the following parameters: different disease states (Tumor or Normal) (P < 0.05), pathological stage (P = 1.82e-04), overall survival (P = 3.8e-05), and disease-free survival (P = 0.047).	('TUBA1C', 'Gene', '84790', (24, 30))	('high', 'Var', (5, 9))	('Tumor', 'Phenotype', 'HP:0002664', (117, 122))	('disease-free survival', 'CPA', (217, 238))	('associated', 'Reg', (49, 59))	('overall survival', 'CPA', (181, 197))	('TUBA1C', 'Gene', (24, 30))
451987	33653340	In particular, activated CD4 T cell, effector memory CD8 T cell, gamma-delta T cell, memory B cell, natural killer T cell, and regulatory T cell were present in higher proportions in the high expression group than in others.	('CD8', 'Gene', (53, 56))	('CD8', 'Gene', '925', (53, 56))	('gamma-delta T cell', 'CPA', (65, 83))	('CD4', 'Gene', '920', (25, 28))	('natural killer T cell', 'CPA', (100, 121))	('high expression', 'Var', (187, 202))	('CD4', 'Gene', (25, 28))
451988	33653340	Moreover, activated B cell, central memory CD4 T cell, eosinophils, immature B cell, mast cell, and type 2 T -helper cell were also present in higher proportion in the high expression group (Fig.	('high expression', 'Var', (168, 183))	('CD4', 'Gene', (43, 46))	('CD4', 'Gene', '920', (43, 46))
452031	33653340	These studies have reported that CD4 + Th1 cells and activated CD8 + T cells often elicited type I immune responses, which indicate a favorable prognosis of LUAD; however, Th2, Th17, and Foxp3 + regulatory T (Treg) cells were found to be associated with tumor progression and unfavorable prognosis.	('Th2', 'Var', (172, 175))	('LUAD', 'Phenotype', 'HP:0030078', (157, 161))	('tumor', 'Disease', (254, 259))	('elicited', 'Reg', (83, 91))	('tumor', 'Disease', 'MESH:D009369', (254, 259))	('Foxp3', 'Gene', '50943', (187, 192))	('Foxp3', 'Gene', (187, 192))	('CD8', 'Gene', (63, 66))	('Th17', 'CPA', (177, 181))	('type I immune responses', 'MPA', (92, 115))	('associated', 'Reg', (238, 248))	('CD4', 'Gene', (33, 36))	('CD8', 'Gene', '925', (63, 66))	('CD4', 'Gene', '920', (33, 36))	('tumor', 'Phenotype', 'HP:0002664', (254, 259))	('LUAD', 'Disease', (157, 161))
452099	33408743	Cyclin dependent kinase 1 (CDK1) is essential both for cell division in the embryo and inhibition of CDK1 induces cell death in human tumor cells (, 1).	('Cyclin dependent kinase 1', 'Gene', '983', (0, 25))	('induces', 'Reg', (106, 113))	('Cyclin dependent kinase 1', 'Gene', (0, 25))	('death', 'Disease', 'MESH:D003643', (119, 124))	('death', 'Disease', (119, 124))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('CDK1', 'Gene', '983', (27, 31))	('human', 'Species', '9606', (128, 133))	('CDK1', 'Gene', (27, 31))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('CDK1', 'Gene', '983', (101, 105))	('inhibition', 'Var', (87, 97))	('tumor', 'Disease', (134, 139))	('CDK1', 'Gene', (101, 105))
452113	32025015	Our analyses confirm previously reported drivers, raise doubts about others and identify novel candidates, including point mutations in the 5' region of TP53, in the 3' untranslated regions of NFKBIZ and TOB1, focal deletions in BRD4 and rearrangements in the loci of AKR1C genes.	('TOB1', 'Gene', (204, 208))	('BRD4', 'Gene', (229, 233))	('NFKBIZ', 'Gene', '64332', (193, 199))	('TOB1', 'Gene', '10140', (204, 208))	('AKR1C', 'Gene', (268, 273))	('TP53', 'Gene', '7157', (153, 157))	('point mutations', 'Var', (117, 132))	('BRD4', 'Gene', '23476', (229, 233))	('NFKBIZ', 'Gene', (193, 199))	('rearrangements', 'Var', (238, 252))	('TP53', 'Gene', (153, 157))
452114	32025015	We show that although point mutations and structural variants that drive cancer are less frequent in non-coding genes and regulatory sequences than in protein-coding genes, additional examples of these drivers will be found as more cancer genomes become available.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (232, 238))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('cancer', 'Disease', (232, 238))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('variants', 'Var', (53, 61))
452115	32025015	Analyses of 2,658 whole genomes across 38 types of cancer identify the contribution of non-coding point mutations and structural variants to driving cancer.	('cancer', 'Disease', (149, 155))	('structural variants', 'Var', (118, 137))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (149, 155))
452119	32025015	Finally, to assess the potential for future non-coding driver discoveries, we quantify our statistical power in the PCAWG dataset and estimate the overall excess of point mutations in non-coding regulatory regions around known cancer genes.	('point mutations', 'Var', (165, 180))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('cancer', 'Disease', (227, 233))	('cancer', 'Disease', 'MESH:D009369', (227, 233))
452135	32025015	1b), and these mutations were strongly associated with higher TERT expression, as has previously been reported (Extended Data Fig.	('associated with', 'Reg', (39, 54))	('TERT', 'Gene', (62, 66))	('mutations', 'Var', (15, 24))	('TERT', 'Gene', '7015', (62, 66))
452136	32025015	Mutations in the promoter and/or 5' UTR of MTG2 (which encodes a GTPase involved in the mitochondrial ribosome) were associated with an expression of MTG2 that was marginally significantly lower, in both the pan-cancer (P = 0.036, fold difference = 0.8) and carcinoma (P = 0.029, fold difference = 0.8) meta-cohorts (Extended Data Figs.	('expression', 'MPA', (136, 146))	('lower', 'NegReg', (189, 194))	('carcinoma', 'Disease', (258, 267))	('MTG2', 'Gene', '26164', (43, 47))	('carcinoma', 'Phenotype', 'HP:0030731', (258, 267))	('MTG2', 'Gene', '26164', (150, 154))	('MTG2', 'Gene', (43, 47))	('cancer', 'Disease', (212, 218))	('Mutations', 'Var', (0, 9))	('cancer', 'Disease', 'MESH:D009369', (212, 218))	('carcinoma', 'Disease', 'MESH:D002277', (258, 267))	('MTG2', 'Gene', (150, 154))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))
452137	32025015	Mutations in the 5' UTR have previously been shown to decrease MTG2 expression in vitro.	('MTG2', 'Gene', (63, 67))	('decrease', 'NegReg', (54, 62))	('expression', 'MPA', (68, 78))	('Mutations', 'Var', (0, 9))	('MTG2', 'Gene', '26164', (63, 67))
452141	32025015	Tumours with 3' UTR mutations in TOB1 showed a trend towards decreased expression (P = 0.053, fold difference = 0.7).	('expression', 'MPA', (71, 81))	('TOB1', 'Gene', (33, 37))	('TOB1', 'Gene', '10140', (33, 37))	('Tumour', 'Phenotype', 'HP:0002664', (0, 6))	('decreased', 'NegReg', (61, 70))	('Tumours', 'Phenotype', 'HP:0002664', (0, 7))	('mutations', 'Var', (20, 29))
452143	32025015	NFKBIZ is a transcription factor that is mutated in diffuse large B cell lymphoma and amplified in primary lymphomas.	('mutated', 'Var', (41, 48))	('NFKBIZ', 'Gene', (0, 6))	('lymphomas', 'Disease', (107, 116))	('lymphomas', 'Disease', 'MESH:D008223', (107, 116))	('large B cell', 'Phenotype', 'HP:0005404', (60, 72))	('B cell lymphoma', 'Disease', 'MESH:D016393', (66, 81))	('B cell lymphoma', 'Disease', (66, 81))	('lymphomas', 'Phenotype', 'HP:0002665', (107, 116))	('B cell lymphoma', 'Phenotype', 'HP:0012191', (66, 81))	('NFKBIZ', 'Gene', '64332', (0, 6))	('lymphoma', 'Phenotype', 'HP:0002665', (73, 81))	('lymphoma', 'Phenotype', 'HP:0002665', (107, 115))
452145	32025015	Previous functional experiments have associated these mutations with increased NFKBIZ expression, which we observed in our lymphoma cohort (P = 0.035, fold difference = 3.2; after correction for copy number, P = 0.03) (Extended Data Fig.	('lymphoma cohort', 'Disease', (123, 138))	('lymphoma cohort', 'Disease', 'MESH:D008223', (123, 138))	('increased', 'PosReg', (69, 78))	('NFKBIZ', 'Gene', (79, 85))	('mutations', 'Var', (54, 63))	('lymphoma', 'Phenotype', 'HP:0002665', (123, 131))	('expression', 'MPA', (86, 96))	('NFKBIZ', 'Gene', '64332', (79, 85))
452147	32025015	Germline RMRP mutations cause cartilage-hair hypoplasia, and previous in vitro studies have shown that some somatic promoter mutations are functional.	('RMRP', 'Gene', '6023', (9, 13))	('cause', 'Reg', (24, 29))	('hair hypoplasia', 'Phenotype', 'HP:0001006', (40, 55))	('cartilage-hair hypoplasia', 'Disease', (30, 55))	('cartilage-hair hypoplasia', 'Disease', 'MESH:C535916', (30, 55))	('mutations', 'Var', (14, 23))	('RMRP', 'Gene', (9, 13))
452150	32025015	The locus is a known AID off-target region in lymphoma, but 7 out of 8  mutations in the mature miRNA mir-142-p3--for which the largest functional effect is expected--were not assigned to AID, which suggests that these mutations are under selection.	('AID', 'Gene', '57379', (21, 24))	('mutations', 'Var', (72, 81))	('lymphoma', 'Phenotype', 'HP:0002665', (46, 54))	('mir', 'Gene', '220972', (102, 105))	('AID', 'Gene', (21, 24))	('mir', 'Gene', (102, 105))	('lymphoma', 'Disease', (46, 54))	('AID', 'Gene', '57379', (188, 191))	('AID', 'Gene', (188, 191))	('lymphoma', 'Disease', 'MESH:D008223', (46, 54))
452152	32025015	Finally, we performed restricted hypothesis testing to boost the statistical power to detect cis-regulatory driver mutations near cancer genes from the CGC (Supplementary Table 7).	('cancer', 'Disease', (130, 136))	('mutations', 'Var', (115, 124))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))
452153	32025015	Restricted hypothesis testing of cancer gene promoters revealed a significant recurrence of TP53 promoter mutations (11 patients in pan-cancer, Q = 0.044), mostly comprising SNVs and deletions that affect the transcription start site or donor splice site of the first non-coding exon.	('transcription', 'MPA', (209, 222))	('cancer', 'Disease', (33, 39))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('cancer', 'Disease', (136, 142))	('patients', 'Species', '9606', (120, 128))	('TP53', 'Gene', '7157', (92, 96))	('mutations', 'Var', (106, 115))	('TP53', 'Gene', (92, 96))	('deletions', 'Var', (183, 192))	('donor', 'Species', '9606', (237, 242))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
452155	32025015	To our knowledge, this is the first report of a relatively infrequent:but impactful:form of TP53 inactivation by non-coding mutations.	('TP53', 'Gene', (92, 96))	('non-coding mutations', 'Var', (113, 133))	('TP53', 'Gene', '7157', (92, 96))	('inactivation', 'NegReg', (97, 109))
452161	32025015	ALB, NEAT1 and MALAT1 mutations were not associated with changes in gene expression (Extended Data Fig.	('NEAT1', 'Gene', (5, 10))	('ALB', 'Gene', (0, 3))	('ALB', 'Gene', '213', (0, 3))	('MALAT1', 'Gene', '378938', (15, 21))	('mutations', 'Var', (22, 31))	('NEAT1', 'Gene', '283131', (5, 10))	('MALAT1', 'Gene', (15, 21))
452163	32025015	Likewise, indels in MIR122 were downstream of the mature miRNA, and were not associated with altered expression of the targets of this miRNA (Supplementary Note 5).	('MIR122', 'Gene', (20, 26))	('MIR122', 'Gene', '406906', (20, 26))	('indels', 'Var', (10, 16))
452164	32025015	Indeed, indels in NEAT1, MALAT1, MIR122 and ALB were strongly enriched in 2-5-bp-long events (Fisher's P < 6.8 x 10-5, for all) (Fig.	('NEAT1', 'Gene', '283131', (18, 23))	('MIR122', 'Gene', '406906', (33, 39))	('MALAT1', 'Gene', (25, 31))	('ALB', 'Gene', '213', (44, 47))	('NEAT1', 'Gene', (18, 23))	('ALB', 'Gene', (44, 47))	('enriched', 'Reg', (62, 70))	('MIR122', 'Gene', (33, 39))	('MALAT1', 'Gene', '378938', (25, 31))	('indels', 'Var', (8, 14))
452166	32025015	Overall, our findings suggest that the indels in MALAT1, NEAT1, ALB and MIR122 are not driver events and are the result of a transcription-associated mutational process.	('NEAT1', 'Gene', (57, 62))	('indels', 'Var', (39, 45))	('MALAT1', 'Gene', '378938', (49, 55))	('result', 'Reg', (113, 119))	('MALAT1', 'Gene', (49, 55))	('NEAT1', 'Gene', '283131', (57, 62))	('MIR122', 'Gene', (72, 78))	('ALB', 'Gene', '213', (64, 67))	('ALB', 'Gene', (64, 67))	('MIR122', 'Gene', '406906', (72, 78))
452167	32025015	The previously reported oncogenic effect of altered MALAT1 and NEAT1 expression may thus be unrelated to these mutations.	('MALAT1', 'Gene', '378938', (52, 58))	('MALAT1', 'Gene', (52, 58))	('NEAT1', 'Gene', '283131', (63, 68))	('NEAT1', 'Gene', (63, 68))	('altered', 'Var', (44, 51))
452168	32025015	Our findings also suggest that although FOXA1 protein-coding indels are drivers, 3' UTR indels might be passengers.	('FOXA1', 'Gene', '3169', (40, 45))	('protein-coding', 'Protein', (46, 60))	('indels', 'Var', (61, 67))	('FOXA1', 'Gene', (40, 45))
452169	32025015	Driver structural variants may act by disrupting one or both of their breakpoint loci (for example, deactivating a tumour suppressor), or by generating a novel juxtaposition between loci.	('juxtaposition', 'Interaction', (160, 173))	('generating', 'Reg', (141, 151))	('deactivating', 'NegReg', (100, 112))	('variants', 'Var', (18, 26))	('disrupting', 'NegReg', (38, 48))	('tumour', 'Phenotype', 'HP:0002664', (115, 121))	('tumour', 'Disease', 'MESH:D009369', (115, 121))	('tumour', 'Disease', (115, 121))
452178	32025015	Five of the eight deletion-associated SRBs were associated with biallelic inactivation of nearby known tumour suppressors, compared to none of the 12 fragile-like SRBs (P = 0.039) (Extended Data Fig.	('SRBs', 'Chemical', '-', (163, 167))	('tumour', 'Phenotype', 'HP:0002664', (103, 109))	('tumour', 'Disease', 'MESH:D009369', (103, 109))	('deletion-associated', 'Var', (18, 37))	('biallelic', 'Var', (64, 73))	('SRBs', 'Disease', (38, 42))	('tumour', 'Disease', (103, 109))	('SRBs', 'Chemical', '-', (38, 42))
452185	32025015	The first comprised structural variants at 10p15, which were associated with a greater than twofold upregulation of AKR1C1, AKR1C2 and AKR1C3 in seven cases of lung squamous cell carcinoma and two cases of liver hepatocellular carcinoma (Extended Data Fig.	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (212, 236))	('carcinoma', 'Phenotype', 'HP:0030731', (227, 236))	('variants', 'Var', (31, 39))	('AKR1C1', 'Gene', '83702', (116, 122))	('liver hepatocellular carcinoma', 'Disease', (206, 236))	('AKR1C3', 'Gene', (135, 141))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (160, 188))	('AKR1C3', 'Gene', '8644', (135, 141))	('liver hepatocellular carcinoma', 'Disease', 'MESH:D006528', (206, 236))	('AKR1C1', 'Gene', (116, 122))	('AKR1C2', 'Gene', (124, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (179, 188))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (165, 188))	('upregulation', 'PosReg', (100, 112))	('lung squamous cell carcinoma', 'Disease', (160, 188))
452187	32025015	Ectopic expression transforms cell lines, and germline mutations have previously been linked to an increased risk of developing lung cancer.	('linked to', 'Reg', (86, 95))	('lung cancer', 'Disease', 'MESH:D008175', (128, 139))	('germline mutations', 'Var', (46, 64))	('lung cancer', 'Disease', (128, 139))	('lung cancer', 'Phenotype', 'HP:0100526', (128, 139))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('Ectopic expression', 'MPA', (0, 18))
452188	32025015	The second SRB contains recurrent microdeletions (<50 kb) involving the 5' end of BRD4 in ovarian (eight cases, P < 10-7) and breast tumours (six cases, P < 0.04) (Fig.	('breast tumours', 'Disease', (126, 140))	('P < 10-7', 'Gene', (112, 120))	('tumour', 'Phenotype', 'HP:0002664', (133, 139))	('SRB', 'Gene', (11, 14))	('ovarian', 'Disease', 'MESH:D010049', (90, 97))	('ovarian', 'Disease', (90, 97))	('SRB', 'Gene', '10575', (11, 14))	('BRD4', 'Gene', (82, 86))	('tumours', 'Phenotype', 'HP:0002664', (133, 140))	('breast tumours', 'Disease', 'MESH:D001943', (126, 140))	('BRD4', 'Gene', '23476', (82, 86))	('P < 10-7', 'Gene', '5933', (112, 120))	('microdeletions', 'Var', (34, 48))
452189	32025015	These deletions were highly enriched in cancers that amplified a segment that includes BRD4 and NOTCH3 (P < 0.004) (Fig.	('cancers', 'Phenotype', 'HP:0002664', (40, 47))	('BRD4', 'Gene', '23476', (87, 91))	('cancers', 'Disease', 'MESH:D009369', (40, 47))	('deletions', 'Var', (6, 15))	('NOTCH3', 'Gene', (96, 102))	('cancers', 'Disease', (40, 47))	('BRD4', 'Gene', (87, 91))	('amplified', 'PosReg', (53, 62))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('NOTCH3', 'Gene', '4854', (96, 102))
452192	32025015	However, the microdeletions are associated with a lower expression of BRD4 in breast (P = 0.001) and ovarian tumours (P = 0.04), but not of the neighbouring gene NOTCH3 (Fig.	('microdeletions', 'Var', (13, 27))	('lower', 'NegReg', (50, 55))	('tumours', 'Phenotype', 'HP:0002664', (109, 116))	('tumour', 'Phenotype', 'HP:0002664', (109, 115))	('ovarian tumours', 'Disease', 'MESH:D010051', (101, 116))	('NOTCH3', 'Gene', (162, 168))	('BRD4', 'Gene', '23476', (70, 74))	('expression', 'MPA', (56, 66))	('ovarian tumours', 'Disease', (101, 116))	('BRD4', 'Gene', (70, 74))	('NOTCH3', 'Gene', '4854', (162, 168))
452193	32025015	The focal deletions in BRD4 overlap a prominent exon-1 H3K4me3 peak and intron-1 enhancer elements in HMEC (normal breast) and MCF-7 (breast tumour) cells (Extended Data Fig.	('breast tumour', 'Disease', 'MESH:D001943', (134, 147))	('tumour', 'Phenotype', 'HP:0002664', (141, 147))	('BRD4', 'Gene', (23, 27))	('MCF-7', 'CellLine', 'CVCL:0031', (127, 132))	('HMEC', 'CellLine', 'CVCL:0307', (102, 106))	('deletions', 'Var', (10, 19))	('BRD4', 'Gene', '23476', (23, 27))	('breast tumour', 'Disease', (134, 147))
452197	32025015	Most canonical driver rearrangements have previously been found in single tumour types, often associated with tissue-specific expression.	('tumour type', 'Disease', (74, 85))	('tumour type', 'Disease', 'MESH:D009369', (74, 85))	('associated', 'Reg', (94, 104))	('rearrangements', 'Var', (22, 36))	('tumour', 'Phenotype', 'HP:0002664', (74, 80))
452199	32025015	Such tissue specificity is not observed for cancer genes affected by SCNAs, for which the top 10 are altered in 11.9 cancer types (on average), or by point mutations (for which the top 10 are altered in 6.7 cancer types, on average) (Supplementary Table 16).	('SCNAs', 'Disease', (69, 74))	('point mutations', 'Var', (150, 165))	('cancer', 'Disease', 'MESH:D009369', (207, 213))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('cancer', 'Disease', (207, 213))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('altered', 'Reg', (101, 108))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('cancer', 'Disease', (117, 123))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
452200	32025015	The latter seems to be more likely because: (i) SRJs are associated with significant overexpression of only one of the rearrangement partners (the 'primary locus') relative to randomly selected rearrangements (primary locus, P < 10-4 (Fig.	('P < 10-4', 'Gene', (225, 233))	('overexpression', 'PosReg', (85, 99))	('SRJs', 'Var', (48, 52))	('P < 10-4', 'Gene', '4820', (225, 233))
452205	32025015	Among melanomas, these rearrangements are mutually exclusive with the C228T and C250T mutations of the TERT promoter (P < 10-3) (Fig.	('C228T', 'Mutation', 'c.228C>T', (70, 75))	('C228T', 'Var', (70, 75))	('melanoma', 'Phenotype', 'HP:0002861', (6, 14))	('melanomas', 'Disease', (6, 15))	('melanomas', 'Phenotype', 'HP:0002861', (6, 15))	('TERT', 'Gene', (103, 107))	('C250T', 'Mutation', 'c.250C>T', (80, 85))	('TERT', 'Gene', '7015', (103, 107))	('melanomas', 'Disease', 'MESH:D008545', (6, 15))	('C250T', 'Var', (80, 85))
452211	32025015	To measure this effect in the PCAWG data, we quantified our ability to detect mutations (detection sensitivity) in cancer gene promoters.	('cancer', 'Disease', (115, 121))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('mutations', 'Var', (78, 87))
452215	32025015	10c) and found that about 263 (95% confidence interval 232-295) TERT hotspot mutations were probably missed owing to a lack of detection sensitivity.	('TERT', 'Gene', (64, 68))	('TERT', 'Gene', '7015', (64, 68))	('10c', 'Gene', '64333', (0, 3))	('mutations', 'Var', (77, 86))	('10c', 'Gene', (0, 3))
452217	32025015	To determine whether the paucity of non-coding drivers discovered thus far could be due to the limited statistical power of current datasets, we estimated the overall excess of point mutations above background (that is, the expected number of driver events) in coding and cis-regulatory non-coding sequences in 603 cancer genes (Methods, Supplementary Table 7, Supplementary Note 11).	('cancer', 'Disease', 'MESH:D009369', (315, 321))	('excess', 'PosReg', (167, 173))	('cancer', 'Disease', (315, 321))	('cancer', 'Phenotype', 'HP:0002664', (315, 321))	('point mutations', 'Var', (177, 192))
452220	32025015	Overall, this approach predicted more than 1,475 driver mutations (95% confidence interval 1,410-1,687; 1,069 SNVs and 406 indels) in the protein-coding sequences of these cancer genes (Fig.	('cancer', 'Disease', (172, 178))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('mutations', 'Var', (56, 65))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))
452221	32025015	4d), compared to only 96 (95% confidence interval 30-190) estimated driver mutations in promoters (73 attributed to TERT), 22 (95% confidence interval 0-88) in 5'UTRs, and 68 (95% confidence interval 0-178) in 3' UTRs.	('TERT', 'Gene', '7015', (116, 120))	('mutations', 'Var', (75, 84))	('TERT', 'Gene', (116, 120))
452222	32025015	Non-coding mutations in cancer-gene promoters were also not generally associated with loss-of-heterozygosity or altered expression, as one would expect if they were enriched with drivers (Supplementary Note 12).	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('expression', 'MPA', (120, 130))	('loss-of-heterozygosity', 'NegReg', (86, 108))	('cancer', 'Disease', (24, 30))	('cancer', 'Disease', 'MESH:D009369', (24, 30))	('Non-coding mutations', 'Var', (0, 20))	('altered', 'Reg', (112, 119))
452223	32025015	These results collectively indicate that, independently of statistical power, non-coding cis-regulatory driver mutations in known cancer genes besides TERT are much less frequent than protein-coding drivers.	('mutations', 'Var', (111, 120))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('cancer', 'Disease', (130, 136))	('TERT', 'Gene', (151, 155))	('TERT', 'Gene', '7015', (151, 155))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))
452225	32025015	Our findings and the methods introduced here for the discovery of point-mutation and structural-variant drivers, method integration, vetting of candidates and identification of local hypermutation and fragile sites represent an important contribution to the collective effort towards charting all malignant changes that drive the cancer of each patient.	('cancer', 'Phenotype', 'HP:0002664', (330, 336))	('patient', 'Species', '9606', (345, 352))	('cancer', 'Disease', 'MESH:D009369', (330, 336))	('point-mutation', 'Var', (66, 80))	('cancer', 'Disease', (330, 336))	('malignant changes', 'Phenotype', 'HP:0002664', (297, 314))
452226	32025015	Among the most interesting candidate non-coding driver elements we uncovered are the 5'-end mutations in TP53; 3' UTR mutations in NFKBIZ and TOB1; and rearrangements involving AKR1C genes and BRD4.	('NFKBIZ', 'Gene', '64332', (131, 137))	('TOB1', 'Gene', '10140', (142, 146))	('NFKBIZ', 'Gene', (131, 137))	('mutations', 'Var', (118, 127))	('mutations', 'Var', (92, 101))	('BRD4', 'Gene', '23476', (193, 197))	('AKR1C genes', 'Gene', (177, 188))	('TP53', 'Gene', '7157', (105, 109))	('TP53', 'Gene', (105, 109))	('rearrangements', 'Var', (152, 166))	('TOB1', 'Gene', (142, 146))	('BRD4', 'Gene', (193, 197))
452231	32025015	The paucity of promoter driver mutations in well-established cancer genes suggests that point mutations markedly affect the function of non-coding regulatory elements only rarely.	('mutations', 'Var', (31, 40))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('cancer', 'Disease', (61, 67))	('function', 'MPA', (124, 132))	('affect', 'Reg', (113, 119))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))
452233	32025015	For other cancer genes, directly mutating protein-coding sequences or altering expression levels by copy-number change may provide larger phenotypic effects.	('expression levels', 'MPA', (79, 96))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('copy-number change', 'Var', (100, 118))	('protein-coding', 'Protein', (42, 56))	('mutating', 'Var', (33, 41))	('altering', 'Reg', (70, 78))	('cancer', 'Disease', 'MESH:D009369', (10, 16))	('cancer', 'Disease', (10, 16))
452236	32025015	We found that 110 additional myeloid-AML samples had robust structural variant calls despite SNV artefacts; we included these in structural variant analyses, for a total of 2,693 samples.	('AML', 'Disease', 'MESH:D015470', (37, 40))	('structural variant', 'Var', (60, 78))	('AML', 'Disease', (37, 40))
452244	32025015	We required at least three mutations to be present in candidate elements, in at least three patients of the tested cohort; more than 50% of mutations in mappable regions; less than 50% of mutations in palindromic DNA; and less than 50% of mutations attributed to APOBEC activity.	('mutations', 'Var', (188, 197))	('patients', 'Species', '9606', (92, 100))	('mutations', 'Var', (140, 149))
452245	32025015	For lymphoid tumours and skin melanoma, we required that <35% and <50% of mutations were attributed to the AID and UV-light mutational signatures, respectively.	('tumour', 'Phenotype', 'HP:0002664', (13, 19))	('skin melanoma', 'Disease', 'MESH:D008545', (25, 38))	('AID', 'Gene', (107, 110))	('AID', 'Gene', '57379', (107, 110))	('lymphoid tumours', 'Disease', 'MESH:D009369', (4, 20))	('tumours', 'Phenotype', 'HP:0002664', (13, 20))	('mutations', 'Var', (74, 83))	('skin melanoma', 'Disease', (25, 38))	('melanoma', 'Phenotype', 'HP:0002861', (30, 38))	('lymphoid tumours', 'Disease', (4, 20))
452255	32025015	In addition, to access somatic single-nucleotide variants derived from TCGA donors, researchers will also need to obtain dbGaP authorization.	('donor', 'Species', '9606', (76, 81))	('single-nucleotide variants', 'Var', (31, 57))	('TCGA', 'Gene', (71, 75))
452257	31897186	Monitoring methylation-driven genes as prognostic biomarkers in patients with lung squamous cell cancer Aberrant DNA methylations have been reported to be significantly associated with lung squamous cell cancer (LUSC).	('lung squamous cell cancer', 'Disease', (78, 103))	('LUSC', 'Disease', 'MESH:D018307', (212, 216))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (83, 103))	('patients', 'Species', '9606', (64, 72))	('lung squamous cell cancer', 'Phenotype', 'HP:0030359', (185, 210))	('lung squamous cell cancer', 'Disease', 'MESH:D018307', (185, 210))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('Aberrant', 'Var', (104, 112))	('lung squamous cell cancer', 'Disease', (185, 210))	('associated', 'Reg', (169, 179))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (190, 210))	('LUSC', 'Phenotype', 'HP:0030359', (212, 216))	('lung squamous cell cancer', 'Phenotype', 'HP:0030359', (78, 103))	('lung squamous cell cancer', 'Disease', 'MESH:D018307', (78, 103))	('LUSC', 'Disease', (212, 216))
452285	31897186	In a study of the integrative analysis of DNA methylation and mRNA expression, Shi et al revealed the function of epigenetic changes on LUSC.	('epigenetic changes', 'Var', (114, 132))	('LUSC', 'Disease', 'MESH:D018307', (136, 140))	('LUSC', 'Disease', (136, 140))	('LUSC', 'Phenotype', 'HP:0030359', (136, 140))
452286	31897186	However, the mechanism contributing to oncogenesis is unclear, and in view of this, Gevaert developed MethylMix, a new computational algorithm implemented in R software, to identify abnormal methylated genes and predict changes in transcription.	('transcription', 'MPA', (231, 244))	('men', 'Species', '9606', (148, 151))	('changes', 'Reg', (220, 227))	('MethylMix', 'Chemical', 'MESH:C057051', (102, 111))	('methylated', 'Var', (191, 201))
452294	31897186	The LIMMA 3.40.6 package  in R language was employed to identify aberrant methylated genes and differentially expressed genes between lung cancer and normal tissues.	('lung cancer', 'Disease', (134, 145))	('lung cancer', 'Phenotype', 'HP:0100526', (134, 145))	('aberrant methylated genes', 'Var', (65, 90))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('lung cancer', 'Disease', 'MESH:D008175', (134, 145))
452307	31897186	Methylation-driven genes were enriched in 'intracellular membrane-bounded organelle', 'Smc5-Smc6 complex', and 'SUMO ligase complex' (Fig.	('Methylation-driven', 'Var', (0, 18))	('Smc5', 'Gene', (87, 91))	('Smc5', 'Gene', '23137', (87, 91))	('Smc6', 'Gene', '79677', (92, 96))	('Smc6', 'Gene', (92, 96))
452315	31897186	Epigenetic changes are involved in important aspects of lung cancer development, and its regulatory mechanisms mainly involve DNA methylation, and non-coding RNA expression regulation and histone modification.	('lung cancer', 'Phenotype', 'HP:0100526', (56, 67))	('lung cancer', 'Disease', 'MESH:D008175', (56, 67))	('men', 'Species', '9606', (75, 78))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('histone', 'MPA', (188, 195))	('lung cancer', 'Disease', (56, 67))	('Epigenetic changes', 'Var', (0, 18))	('involved', 'Reg', (23, 31))
452317	31897186	DNA methylation is an epigenetic mechanism that leads to tumorigenesis, and has attracted a lot of attention from researchers.	('leads to', 'Reg', (48, 56))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('methylation', 'Var', (4, 15))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Disease', (57, 62))
452318	31897186	DNA methylation abnormalities have been found at the genome level in the majority of tumors, including lung cancer, and the frequency of CpG island hypermethylation in tumor cells is much higher compared with that of gene mutation.	('tumor', 'Disease', (85, 90))	('lung cancer', 'Disease', 'MESH:D008175', (103, 114))	('tumor', 'Disease', (168, 173))	('tumors', 'Disease', 'MESH:D009369', (85, 91))	('hypermethylation', 'Var', (148, 164))	('found', 'Reg', (40, 45))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('lung cancer', 'Disease', (103, 114))	('abnormalities', 'Var', (16, 29))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('lung cancer', 'Phenotype', 'HP:0100526', (103, 114))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('tumors', 'Disease', (85, 91))
452319	31897186	Abnormalities in DNA methylation often occur in the early stages of cancer, and persist throughout the development of the cancer.	('DNA', 'Gene', (17, 20))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('Abnormalities', 'Var', (0, 13))	('men', 'Species', '9606', (110, 113))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('methylation', 'Var', (21, 32))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('cancer', 'Disease', (68, 74))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('occur', 'Reg', (39, 44))
452320	31897186	Methylation or demethylation may lead to tumor gene activation or inactivation of cancer suppressor genes.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('lead to', 'Reg', (33, 40))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('tumor', 'Disease', (41, 46))	('Methylation', 'Var', (0, 11))	('inactivation', 'NegReg', (66, 78))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('demethylation', 'Var', (15, 28))	('activation', 'PosReg', (52, 62))
452321	31897186	DNA methylation is considered to be a vitally important mechanism that causes cells to change from a normal to malignant state, and is the possible cause of tumor treatment tolerance.	('tumor', 'Disease', (157, 162))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('methylation', 'Var', (4, 15))	('cause', 'Reg', (148, 153))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('men', 'Species', '9606', (168, 171))
452322	31897186	However, some studies have found that differentially methylated genes serve as potential cancer driver genes.	('differentially methylated genes', 'Var', (38, 69))	('cancer', 'Disease', (89, 95))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
452323	31897186	Previous research findings have verified that enhanced expression of genes caused by hypomethylation, and decreased expression caused by hypermethylation, serve an important role in the regulation and development of malignant carcinoma.	('decreased', 'NegReg', (106, 115))	('hypomethylation', 'Var', (85, 100))	('expression', 'MPA', (116, 126))	('expression', 'MPA', (55, 65))	('men', 'Species', '9606', (208, 211))	('malignant carcinoma', 'Disease', 'MESH:D002277', (216, 235))	('carcinoma', 'Phenotype', 'HP:0030731', (226, 235))	('enhanced', 'PosReg', (46, 54))	('malignant carcinoma', 'Disease', (216, 235))
452325	31897186	For example, Sugimoto et al found that patients benefit from aberrant methylation of GRWD1 (glutamate rich WD repeat containing 1) in tumor development, due to activity of the GRWD1 gene being inhibited by its own methylation in tumor cells, whereas expression of the GRWD1 gene can benefit tumor cell growth.	('patients', 'Species', '9606', (39, 47))	('glutamate rich WD repeat containing 1', 'Gene', (92, 129))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('tumor', 'Disease', 'MESH:D009369', (291, 296))	('activity', 'MPA', (160, 168))	('methylation', 'Var', (70, 81))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('GRWD1', 'Gene', (176, 181))	('GRWD1', 'Gene', '83743', (268, 273))	('glutamate rich WD repeat containing 1', 'Gene', '83743', (92, 129))	('GRWD1', 'Gene', '83743', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (291, 296))	('inhibited', 'NegReg', (193, 202))	('benefit', 'PosReg', (48, 55))	('tumor', 'Disease', (229, 234))	('GRWD1', 'Gene', (268, 273))	('GRWD1', 'Gene', '83743', (176, 181))	('tumor', 'Disease', (134, 139))	('tumor', 'Disease', 'MESH:D009369', (229, 234))	('aberrant methylation', 'Var', (61, 81))	('GRWD1', 'Gene', (85, 90))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('tumor', 'Disease', (291, 296))	('men', 'Species', '9606', (147, 150))
452326	31897186	In contrast, Chen et al found that hypermethylation of the AGTR1 promoter is more common in patients with LUSC.	('hypermethylation', 'Var', (35, 51))	('LUSC', 'Disease', 'MESH:D018307', (106, 110))	('AGTR1', 'Gene', (59, 64))	('AGTR1', 'Gene', '185', (59, 64))	('patients', 'Species', '9606', (92, 100))	('LUSC', 'Phenotype', 'HP:0030359', (106, 110))	('common', 'Reg', (82, 88))	('LUSC', 'Disease', (106, 110))
452328	31897186	A study by Guo et al found that the hypermethylated state of WIF-1 gene, commonly found in NSCLC, is not only more likely to occur in squamous cell carcinoma, but its expression was also correlated with poor clinical prognosis.	('NSCLC', 'Disease', 'MESH:D002289', (91, 96))	('WIF-1', 'Gene', '11197', (61, 66))	('NSCLC', 'Phenotype', 'HP:0030358', (91, 96))	('hypermethylated', 'Var', (36, 51))	('Guo', 'Chemical', 'MESH:C089471', (11, 14))	('occur', 'Reg', (125, 130))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (134, 157))	('SCLC', 'Phenotype', 'HP:0030357', (92, 96))	('squamous cell carcinoma', 'Disease', (134, 157))	('NSCLC', 'Disease', (91, 96))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (134, 157))	('expression', 'MPA', (167, 177))	('carcinoma', 'Phenotype', 'HP:0030731', (148, 157))	('WIF-1', 'Gene', (61, 66))
452329	31897186	In a study on tumor and corresponding non-malignant lung tissue specimens, Kim et al demonstrated that high methylation of the Wrap53alpha promoter predicts a worse prognosis in patients with borderline significance.	('men', 'Species', '9606', (69, 72))	('tumor', 'Disease', (14, 19))	('patients', 'Species', '9606', (178, 186))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('high methylation', 'Var', (103, 119))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('Wrap53alpha', 'Protein', (127, 138))
452330	31897186	Zhang et al reported that PAX6 gene hypermethylation is an independent prognostic indicator, and is significantly correlated with an overall low survival rate of NSCLC, which may therefore be a potentially attractive biomarker for prognostic assessment in NSCLC patients.	('NSCLC', 'Disease', 'MESH:D002289', (256, 261))	('correlated', 'Reg', (114, 124))	('SCLC', 'Phenotype', 'HP:0030357', (257, 261))	('PAX6', 'Gene', (26, 30))	('men', 'Species', '9606', (248, 251))	('survival', 'MPA', (145, 153))	('PAX6', 'Gene', '5080', (26, 30))	('NSCLC', 'Phenotype', 'HP:0030358', (256, 261))	('NSCLC', 'Disease', (162, 167))	('hypermethylation', 'Var', (36, 52))	('NSCLC', 'Disease', 'MESH:D002289', (162, 167))	('SCLC', 'Phenotype', 'HP:0030357', (163, 167))	('low', 'NegReg', (141, 144))	('patients', 'Species', '9606', (262, 270))	('NSCLC', 'Disease', (256, 261))	('NSCLC', 'Phenotype', 'HP:0030358', (162, 167))
452337	31897186	Survival analysis confirmed that methylation of the genes DXQ1, GPR75, STX12 and TRIM61 is closely related to prognosis.	('methylation', 'Var', (33, 44))	('STX12', 'Gene', '23673', (71, 76))	('TRIM61', 'Gene', (81, 87))	('related', 'Reg', (99, 106))	('STX12', 'Gene', (71, 76))	('TRIM61', 'Gene', '391712', (81, 87))	('GPR75', 'Gene', '10936', (64, 69))	('GPR75', 'Gene', (64, 69))	('DXQ1', 'Gene', (58, 62))
452350	31897186	The present study has revealed that the expression of STX12 is negatively correlated with methylation, and hypermethylation of STX12 is associated with favorable clinical results in LUSC.	('associated', 'Reg', (136, 146))	('expression', 'MPA', (40, 50))	('LUSC', 'Phenotype', 'HP:0030359', (182, 186))	('LUSC', 'Disease', (182, 186))	('negatively', 'NegReg', (63, 73))	('STX12', 'Gene', '23673', (54, 59))	('methylation', 'MPA', (90, 101))	('hypermethylation', 'Var', (107, 123))	('LUSC', 'Disease', 'MESH:D018307', (182, 186))	('STX12', 'Gene', (54, 59))	('STX12', 'Gene', '23673', (127, 132))	('STX12', 'Gene', (127, 132))
452353	31897186	Methylation-driven genes are expected to be identified as novel tumor markers for clinical application in the future.	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('Methylation-driven', 'Var', (0, 18))	('tumor', 'Disease', (64, 69))	('tumor', 'Disease', 'MESH:D009369', (64, 69))
452356	31354634	Originally identified as a B-cell chemoattractant, CXCL13 exerts important functions in lymphoid neogenesis, and has been widely implicated in the pathogenesis of a number of autoimmune diseases and inflammatory conditions, as well as in lymphoproliferative disorders.	('autoimmune diseases', 'Disease', 'MESH:D001327', (175, 194))	('lymphoid neogenesis', 'Phenotype', 'HP:0002665', (88, 107))	('B-cell chemoattractant', 'Gene', (27, 49))	('lymphoid neogenesis', 'Disease', (88, 107))	('B-cell chemoattractant', 'Gene', '10563', (27, 49))	('autoimmune diseases', 'Disease', (175, 194))	('implicated', 'Reg', (129, 139))	('lymphoproliferative disorders', 'Disease', (238, 267))	('autoimmune disease', 'Phenotype', 'HP:0002960', (175, 193))	('lymphoproliferative disorders', 'Disease', 'MESH:D008232', (238, 267))	('autoimmune diseases', 'Phenotype', 'HP:0002960', (175, 194))	('lymphoproliferative disorders', 'Phenotype', 'HP:0005523', (238, 267))	('CXCL13', 'Var', (51, 57))	('lymphoid neogenesis', 'Disease', 'MESH:D008223', (88, 107))
452360	31354634	Carcinogens have been found to induce CXCL13 production, and production of this chemokine within the tumor milieu has been shown to impact the proliferation, migration, and invasive properties of cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('CXCL13 production', 'MPA', (38, 55))	('production', 'Var', (61, 71))	('impact', 'Reg', (132, 138))	('cancer', 'Disease', 'MESH:D009369', (196, 202))	('cancer', 'Disease', (196, 202))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('proliferation', 'CPA', (143, 156))	('migration', 'CPA', (158, 167))
452364	31354634	Multiple diseases have been associated with aberrant production of chemokines and cytokines, including infectious diseases, chronic inflammation, and autoimmune disorders.	('autoimmune disorders', 'Disease', (150, 170))	('inflammation', 'Disease', 'MESH:D007249', (132, 144))	('autoimmune disorders', 'Disease', 'MESH:D001327', (150, 170))	('associated', 'Reg', (28, 38))	('Multiple diseases', 'Disease', 'MESH:D000015', (0, 17))	('inflammation', 'Disease', (132, 144))	('infectious diseases', 'Disease', 'MESH:D003141', (103, 122))	('aberrant', 'Var', (44, 52))	('Multiple diseases', 'Disease', (0, 17))	('autoimmune disorders', 'Phenotype', 'HP:0002960', (150, 170))	('infectious diseases', 'Disease', (103, 122))	('production', 'MPA', (53, 63))
452386	31354634	This phenotype was explained in experiments assessing the migration pattern of BLR1-deficient B-cells when transferred into wild-type mice, which showed that BLR1-/- B lymphocytes entered T-cell areas of lymphoid tissues but not areas that foster B-cell development that are normally populated by B-cells.	('men', 'Species', '9606', (38, 41))	('men', 'Species', '9606', (261, 264))	('BLR1-deficient', 'Disease', 'MESH:D007153', (79, 93))	('mice', 'Species', '10090', (134, 138))	('BLR1-/- B', 'Var', (158, 167))	('BLR1-deficient', 'Disease', (79, 93))
452394	31354634	Similar to CXCR1, CXCR5 activation was found to stimulate intracellular Ca2+ influx, ERK/MAPK signaling, and induce cellular chemotaxis, an effect that was mediated primarily by the second intracellular domain of CXCR5, called IC2.	('intracellular Ca2+ influx', 'MPA', (58, 83))	('CXCR1', 'Gene', (11, 16))	('MAPK', 'Gene', '5595;5594;26413;5595', (89, 93))	('MAPK', 'Gene', (89, 93))	('cellular chemotaxis', 'CPA', (116, 135))	('Ca2+', 'Chemical', 'MESH:D000069285', (72, 76))	('CXCR1', 'Gene', '3577', (11, 16))	('stimulate', 'PosReg', (48, 57))	('IC2', 'Gene', (227, 230))	('IC2', 'Gene', '1781', (227, 230))	('induce', 'Reg', (109, 115))	('CXCR5 activation', 'Var', (18, 34))
452398	31354634	After the studies outlined above identified the roles of CXCL13 and CXCR5 in the development of differentiated B-cells and their secondary lymphoid structures, it was natural to hypothesize that aberrant activation of this signaling axis contributes to autoimmune conditions.	('activation', 'PosReg', (204, 214))	('aberrant', 'Var', (195, 203))	('men', 'Species', '9606', (88, 91))	('contributes', 'Reg', (238, 249))	('autoimmune conditions', 'Disease', (253, 274))	('autoimmune conditions', 'Phenotype', 'HP:0002960', (253, 274))
452407	31354634	Dysregulation of this process in autoimmune disease was first described in SLE, wherein an aberrant overabundance of TFH cells can cause spontaneous germinal center formation and autoimmunity.	('autoimmune disease', 'Disease', (33, 51))	('autoimmunity', 'Disease', 'MESH:D001327', (179, 191))	('autoimmune disease', 'Disease', 'MESH:D001327', (33, 51))	('autoimmune disease', 'Phenotype', 'HP:0002960', (33, 51))	('overabundance', 'PosReg', (100, 113))	('autoimmunity', 'Phenotype', 'HP:0002960', (179, 191))	('spontaneous germinal center formation', 'CPA', (137, 174))	('SLE', 'Disease', (75, 78))	('SLE', 'Disease', 'MESH:D008180', (75, 78))	('autoimmunity', 'Disease', (179, 191))	('cause', 'Reg', (131, 136))	('SLE', 'Phenotype', 'HP:0002725', (75, 78))	('aberrant', 'Var', (91, 99))
452410	31354634	Overall, dysregulation of the CXCL13:CXCR5 axis affecting both B- and TFH cell function is major player in autoimmune disorders, and potentially serves as a biomarker for disease progression and therapeutic response.	('autoimmune disorders', 'Phenotype', 'HP:0002960', (107, 127))	('autoimmune disorders', 'Disease', 'MESH:D001327', (107, 127))	('dysregulation', 'Var', (9, 22))	('autoimmune disorders', 'Disease', (107, 127))
452427	31354634	Similar to neuroborreliosis, CXCL13 has been implicated in the pathogenesis of neurosyphilis, a serious complication of untreated syphilis.	('CXCL13', 'Var', (29, 35))	('neurosyphilis', 'Disease', (79, 92))	('neuroborreliosis', 'Disease', 'MESH:D008193', (11, 27))	('neuroborreliosis', 'Disease', (11, 27))	('implicated', 'Reg', (45, 55))
452433	31354634	Imbalances in the CXCL13:CXCR5 axis may contribute to pathologies involving B-cells and THF cells.	('THF', 'Chemical', '-', (88, 91))	('Imbalances', 'Phenotype', 'HP:0002172', (0, 10))	('contribute', 'Reg', (40, 50))	('CXCL13:CXCR5 axis', 'MPA', (18, 35))	('Imbalances', 'Var', (0, 10))
452460	31354634	CXCL13 was also identified as a predictive factor for risk of early stage lung adenocarcinoma.	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (74, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('CXCL13', 'Var', (0, 6))	('lung adenocarcinoma', 'Disease', (74, 93))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (74, 93))
452467	31354634	Secretion of CXCL13 by the tumor infiltrating lymphocytes expressing high PD-1 levels serves to attract other immune cell subsets to the tumor microenvironment, including TFH cells and B-cells, and, strikingly, it strongly predicts response to anti-PD-1 therapy that correlates with increased overall survival and durable responses.	('PD-1', 'Gene', '5133', (249, 253))	('PD-1', 'Gene', '5133', (74, 78))	('men', 'Species', '9606', (155, 158))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumor', 'Disease', (137, 142))	('tumor', 'Disease', (27, 32))	('attract', 'PosReg', (96, 103))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('increased', 'PosReg', (283, 292))	('high', 'Var', (69, 73))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('Secretion of CXCL13', 'MPA', (0, 19))	('predicts', 'Reg', (223, 231))	('PD-1', 'Gene', (249, 253))	('PD-1', 'Gene', (74, 78))
452478	31354634	The potential involvement of SPP1 was confirmed by silencing its expression, which led to impaired migration of lung cancer cells in co-culture models.	('silencing', 'Var', (51, 60))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('lung cancer', 'Phenotype', 'HP:0100526', (112, 123))	('expression', 'MPA', (65, 75))	('impaired migration of lung cancer', 'Disease', (90, 123))	('impaired migration of lung cancer', 'Disease', 'MESH:D008175', (90, 123))	('men', 'Species', '9606', (21, 24))	('SPP1', 'Gene', (29, 33))
452502	31354634	Likewise, the recent association between high CXCL13 and distant disease-free survival in early-stage breast cancer patients provided evidence that humoral immunity influences the survival outcomes in these patients, particularly those with TNBC.	('breast cancer', 'Disease', (102, 115))	('patients', 'Species', '9606', (207, 215))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('breast cancer', 'Phenotype', 'HP:0003002', (102, 115))	('patients', 'Species', '9606', (116, 124))	('influences', 'Reg', (165, 175))	('high', 'Var', (41, 45))	('distant disease-free survival', 'CPA', (57, 86))	('survival', 'CPA', (180, 188))	('breast cancer', 'Disease', 'MESH:D001943', (102, 115))
452504	31354634	In an early study using CXCR5-expressing breast cancer cells, CXCL13 induced changes in the expression of markers consistent with epithelial-to-mesenchymal transition (EMT).	('changes', 'Reg', (77, 84))	('breast cancer', 'Disease', 'MESH:D001943', (41, 54))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('breast cancer', 'Disease', (41, 54))	('breast cancer', 'Phenotype', 'HP:0003002', (41, 54))	('expression of markers', 'MPA', (92, 113))	('CXCL13', 'Var', (62, 68))	('epithelial-to-mesenchymal transition', 'CPA', (130, 166))
452505	31354634	Indeed, CXCL13 up-regulates mesenchymal markers vimentin, Snail, Slug, N-cadherin, MMP9 and RANKL while down-regulating E-cadherin expression.	('down-regulating', 'NegReg', (104, 119))	('vimentin', 'Protein', (48, 56))	('N-cadherin', 'Protein', (71, 81))	('MMP9', 'Gene', '4318', (83, 87))	('MMP9', 'Gene', (83, 87))	('RANKL', 'Gene', '8600', (92, 97))	('mesenchymal markers', 'CPA', (28, 47))	('RANKL', 'Gene', (92, 97))	('Snail', 'CPA', (58, 63))	('E-cadherin expression', 'MPA', (120, 141))	('up-regulates', 'PosReg', (15, 27))	('CXCL13', 'Var', (8, 14))
452508	31354634	Interestingly, a recent study showed that an anti-CXCL13 antibody reduces MDA-MB-231 breast cancer cell viability by promoting apoptosis.	('anti-CXCL13', 'Var', (45, 56))	('breast cancer', 'Disease', 'MESH:D001943', (85, 98))	('promoting', 'PosReg', (117, 126))	('reduces', 'NegReg', (66, 73))	('breast cancer', 'Disease', (85, 98))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (74, 84))	('breast cancer', 'Phenotype', 'HP:0003002', (85, 98))	('apoptosis', 'CPA', (127, 136))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('MDA-MB-231', 'Gene', (74, 84))
452513	31354634	Silencing of p53 in these cells not only up-regulates CXCR5, but also potentiates CXCL13-mediated chemotaxis.	('up-regulates', 'PosReg', (41, 53))	('CXCR5', 'MPA', (54, 59))	('p53', 'Gene', (13, 16))	('CXCL13-mediated chemotaxis', 'MPA', (82, 108))	('Silencing', 'Var', (0, 9))	('potentiates', 'PosReg', (70, 81))	('p53', 'Gene', '7157', (13, 16))
452520	31354634	Furthermore, patients with positive CXCR5 and CXCL13 expression have poor prognosis, both in terms of 5 year overall survival and 5 year relapse-free survival.	('CXCL13', 'MPA', (46, 52))	('patients', 'Species', '9606', (13, 21))	('relapse-free', 'CPA', (137, 149))	('CXCR5', 'Var', (36, 41))
452522	31354634	From a functional standpoint, CXCL13 induces proliferation and migration in CXCR5-expressing colon cancer cells.	('colon cancer', 'Disease', (93, 105))	('proliferation', 'CPA', (45, 58))	('CXCL13', 'Var', (30, 36))	('colon cancer', 'Disease', 'MESH:D015179', (93, 105))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('colon cancer', 'Phenotype', 'HP:0003003', (93, 105))	('induces', 'PosReg', (37, 44))	('migration', 'CPA', (63, 72))
452526	31354634	CXCL13 also promotes growth, migration, and invasion in human SW620 colon carcinoma cells.	('growth', 'CPA', (21, 27))	('colon carcinoma', 'Disease', 'MESH:D015179', (68, 83))	('colon carcinoma', 'Disease', (68, 83))	('invasion', 'CPA', (44, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('migration', 'CPA', (29, 38))	('human', 'Species', '9606', (56, 61))	('CXCL13', 'Var', (0, 6))	('SW620', 'CellLine', 'CVCL:0547', (62, 67))	('promotes', 'PosReg', (12, 20))
452530	31354634	In gastric cancer, CXCL13 expression is predictive of shorter overall survival.	('CXCL13 expression', 'Var', (19, 36))	('overall', 'MPA', (62, 69))	('gastric cancer', 'Phenotype', 'HP:0012126', (3, 17))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('gastric cancer', 'Disease', (3, 17))	('shorter', 'NegReg', (54, 61))	('gastric cancer', 'Disease', 'MESH:D013274', (3, 17))
452531	31354634	Within the T2-T4 stage patient group, low CXCL13 expression is associated with longer survival, particularly in patients who received adjuvant chemotherapy.	('patient', 'Species', '9606', (112, 119))	('patients', 'Species', '9606', (112, 120))	('longer', 'PosReg', (79, 85))	('CXCL13 expression', 'MPA', (42, 59))	('low', 'Var', (38, 41))	('patient', 'Species', '9606', (23, 30))
452545	31354634	Deletion of the Hif1a gene in mice surprisingly accelerates pancreatic carcinogenesis, which was accompanied by increased infiltration of B lymphocytes.	('mice', 'Species', '10090', (30, 34))	('pancreatic carcinogenesis', 'Disease', 'MESH:D063646', (60, 85))	('Hif1a', 'Gene', '15251', (16, 21))	('infiltration', 'CPA', (122, 134))	('increased', 'PosReg', (112, 121))	('accelerates', 'PosReg', (48, 59))	('Hif1a', 'Gene', (16, 21))	('pancreatic carcinogenesis', 'Disease', (60, 85))	('Deletion', 'Var', (0, 8))
452560	31354634	In normal tissue and benign prostate hyperplasia samples, CXCR5 displays a predominant membrane and/or cytoplasmic distribution while in advanced prostate cancers it shows high nuclear expression.	('benign prostate hyperplasia', 'Disease', (21, 48))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('benign prostate hyperplasia', 'Phenotype', 'HP:0008711', (21, 48))	('nuclear expression', 'MPA', (177, 195))	('prostate cancers', 'Disease', 'MESH:D011471', (146, 162))	('prostate cancer', 'Phenotype', 'HP:0012125', (146, 161))	('CXCR5', 'Var', (58, 63))	('benign prostate hyperplasia', 'Disease', 'MESH:D011470', (21, 48))	('cancers', 'Phenotype', 'HP:0002664', (155, 162))	('prostate cancers', 'Phenotype', 'HP:0012125', (146, 162))	('prostate cancers', 'Disease', (146, 162))
452563	31354634	Furthermore, CXCL13 produced by bone marrow endothelial cells in response to IL-6 was able to induce prostate cancer cell invasion in a CXCR5-dependent manner.	('prostate cancer', 'Disease', (101, 116))	('IL-6', 'Gene', (77, 81))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('CXCL13', 'Var', (13, 19))	('prostate cancer', 'Disease', 'MESH:D011471', (101, 116))	('IL-6', 'Gene', '3569', (77, 81))	('induce', 'PosReg', (94, 100))	('prostate cancer', 'Phenotype', 'HP:0012125', (101, 116))
452573	31354634	Indeed, silencing CXCR5 from prostate cancer cells reduces their proliferative, tumorigenic and motile capacities.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('prostate cancer', 'Disease', (29, 44))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('reduces', 'NegReg', (51, 58))	('silencing', 'Var', (8, 17))	('CXCR5', 'Gene', (18, 23))	('tumor', 'Disease', (80, 85))	('prostate cancer', 'Disease', 'MESH:D011471', (29, 44))	('prostate cancer', 'Phenotype', 'HP:0012125', (29, 44))	('proliferative', 'CPA', (65, 78))
452576	31354634	Furthermore, silencing IKKalpha and NIK, key elements in the non-canonical NF-kappaB pathway, down-regulates CXCL13 mRNA levels and CXCL13 gene transcriptional activity (Figure 5).	('NIK', 'Gene', (36, 39))	('CXCL13 mRNA levels', 'MPA', (109, 127))	('CXCL13 gene transcriptional activity', 'MPA', (132, 168))	('men', 'Species', '9606', (48, 51))	('IKKalpha', 'Gene', '1147', (23, 31))	('IKKalpha', 'Gene', (23, 31))	('down-regulates', 'NegReg', (94, 108))	('NIK', 'Gene', '9448', (36, 39))	('silencing', 'Var', (13, 22))
452593	31354634	One interesting study showed that specific chemokine signatures may contribute to overall survival in wild-type and mutant p53 ovarian cancers, and CXCL13 was specifically associated with better overall survival.	('ovarian cancer', 'Phenotype', 'HP:0100615', (127, 141))	('cancers', 'Phenotype', 'HP:0002664', (135, 142))	('ovarian cancers', 'Phenotype', 'HP:0100615', (127, 142))	('ovarian cancers', 'Disease', (127, 142))	('contribute', 'Reg', (68, 78))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('ovarian cancers', 'Disease', 'MESH:D010051', (127, 142))	('p53', 'Gene', (123, 126))	('mutant', 'Var', (116, 122))	('p53', 'Gene', '7157', (123, 126))
452649	30655849	Type II CK possesses a higher molecular weight and is located at chromosome 12q11-12, and CK1-CK9 belong to type II CK.	('CK1-CK9', 'Var', (90, 97))	('CK1', 'Species', '2498238', (90, 93))	('higher', 'PosReg', (23, 29))
452665	29304754	The cancer research community refers to 'cancer driver' genes as genes whose perturbation (in the expression levels or in the sequence) confers a selective advantage to tumour growth.	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('selective advantage', 'CPA', (146, 165))	("'cancer", 'Disease', (40, 47))	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('perturbation', 'Var', (77, 89))	('cancer', 'Disease', 'MESH:D009369', (4, 10))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('tumour growth', 'Disease', (169, 182))	("'cancer", 'Disease', 'MESH:D009369', (40, 47))	('tumour', 'Phenotype', 'HP:0002664', (169, 175))	('cancer', 'Disease', (4, 10))	('tumour growth', 'Disease', 'MESH:D006130', (169, 182))
452667	29304754	those genes whose mutation does not give any fitness advantage to the tumour.	('fitness advantage to the tumour', 'Disease', 'MESH:D012640', (45, 76))	('tumour', 'Phenotype', 'HP:0002664', (70, 76))	('mutation', 'Var', (18, 26))	('fitness advantage to the tumour', 'Disease', (45, 76))
452668	29304754	In cancer, driver genes are those that accumulate mutations, or those that are differentially expressed in tumours vs normal samples (differentially expressed genes).	('tumours', 'Disease', 'MESH:D009369', (107, 114))	('tumours', 'Disease', (107, 114))	('mutations', 'Var', (50, 59))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('tumour', 'Phenotype', 'HP:0002664', (107, 113))	('cancer', 'Disease', (3, 9))	('tumours', 'Phenotype', 'HP:0002664', (107, 114))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
452718	29304754	DNA2 nuclease has a role in the mechanism of double strand break repair and its mutation has been reported in gastric and colorectal carcinomas.	('carcinomas', 'Phenotype', 'HP:0030731', (133, 143))	('gastric', 'Disease', (110, 117))	('colorectal carcinomas', 'Disease', (122, 143))	('colorectal carcinomas', 'Disease', 'MESH:D015179', (122, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('double strand break repair', 'MPA', (45, 71))	('DNA2', 'Gene', (0, 4))	('DNA2', 'Gene', '1763', (0, 4))	('mutation', 'Var', (80, 88))	('reported', 'Reg', (98, 106))
452721	29304754	Since previous studies have shown that the absence of mutations in genes with a high degree centrality is vital for the organism survival, we found a list of 1322 network genes highly connected in at least two networks for each pathway, and we studied their behavior in 16 different types of cancer.	('cancer', 'Disease', (292, 298))	('cancer', 'Phenotype', 'HP:0002664', (292, 298))	('mutations', 'Var', (54, 63))	('cancer', 'Disease', 'MESH:D009369', (292, 298))	('connected', 'Reg', (184, 193))
452747	29304754	Polymorphisms in this gene are associated with different types of cancer (e.g.	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('Polymorphisms', 'Var', (0, 13))	('associated', 'Reg', (31, 41))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('cancer', 'Disease', (66, 72))
452757	29304754	With these tools cancer drivers were defined as 1) genes with unexpected mutation rates in phosphorylation-specific regions (ActiveDriver), 2) proteins with higher-than-expected mutation rates regardless of the protein regions (OncodriveCLUST), 3) proteins with somatic missense mutations in different protein functional regions, such as domains and intrinsically disordered regions (e-Driver), 4) genes analyzing the impact of mutations on the protein function (OncodriveFM and Simon).	('missense mutations', 'Var', (270, 288))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('cancer', 'Disease', (17, 23))	('disordered', 'Disease', 'MESH:D030342', (364, 374))	('mutation', 'Var', (73, 81))	('disordered', 'Disease', (364, 374))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
452758	29304754	The second group includes Dendrix and CoMDP, two software tools that use an alternative approach to identify cancer driver genes: they examine mutations in the context of functional pathways.	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('cancer', 'Disease', (109, 115))	('mutations', 'Var', (143, 152))	('cancer', 'Disease', 'MESH:D009369', (109, 115))
452791	28430665	Extensive studies have been conducted on P2XR and/or NLRP3 inflammasome in colon cancer, melanoma, prostate cancer, and lung cancer, but only a few studies has been done in the field of Head and Neck Squamous Cell Carcinoma (HNSCC).	('colon cancer', 'Phenotype', 'HP:0003003', (75, 87))	('Neck Squamous Cell Carcinoma', 'Disease', (195, 223))	('lung cancer', 'Disease', (120, 131))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (200, 223))	('HNSCC', 'Phenotype', 'HP:0012288', (225, 230))	('prostate cancer', 'Disease', (99, 114))	('melanoma', 'Phenotype', 'HP:0002861', (89, 97))	('melanoma', 'Disease', (89, 97))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('NLRP3', 'Gene', (53, 58))	('NLRP3', 'Gene', '114548', (53, 58))	('colon cancer', 'Disease', 'MESH:D015179', (75, 87))	('lung cancer', 'Disease', 'MESH:D008175', (120, 131))	('P2XR', 'Var', (41, 45))	('Neck Squamous Cell Carcinoma', 'Disease', 'MESH:D000077195', (195, 223))	('lung cancer', 'Phenotype', 'HP:0100526', (120, 131))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('colon cancer', 'Disease', (75, 87))	('melanoma', 'Disease', 'MESH:D008545', (89, 97))	('Head and Neck Squamous Cell Carcinoma', 'Phenotype', 'HP:0012288', (186, 223))	('SCC', 'Phenotype', 'HP:0002860', (227, 230))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('prostate cancer', 'Disease', 'MESH:D011471', (99, 114))	('Carcinoma', 'Phenotype', 'HP:0030731', (214, 223))	('prostate cancer', 'Phenotype', 'HP:0012125', (99, 114))
452840	28430665	MCC950 does not block AIM2, NLRC4, TLR pathways nor the K+ efflux, Ca2+ efflux, or NLRP3-ASC interaction, which makes it ideal to independently examine NLRP3 and P2X7 in LPS-primed cells.	('TLR pathways', 'Pathway', (35, 47))	('P2X7', 'Gene', (162, 166))	('Ca2+ efflux', 'MPA', (67, 78))	('Ca2+', 'Chemical', 'MESH:D000069285', (67, 71))	('P2X7', 'Gene', '5027', (162, 166))	('NLRC4', 'Gene', (28, 33))	('NLRP3', 'Gene', (83, 88))	('MCC950', 'Var', (0, 6))	('NLRP3', 'Gene', '114548', (83, 88))	('AIM2', 'Gene', '9447', (22, 26))	('NLRP3', 'Gene', (152, 157))	('LPS', 'Chemical', 'MESH:D008070', (170, 173))	('MCC950', 'Chemical', 'MESH:C000597426', (0, 6))	('NLRP3', 'Gene', '114548', (152, 157))	('ASC', 'Gene', '29108', (89, 92))	('NLRC4', 'Gene', '58484', (28, 33))	('K+ efflux', 'MPA', (56, 65))	('AIM2', 'Gene', (22, 26))	('ASC', 'Gene', (89, 92))
452842	28430665	CCK8 cell viability assay results showed significant decrease in cellular respiratory rate only when P2X7R and NLRP3 inflammasome were both inhibited by oATP and MCC950 in A253 cells (P = 0.0117, n = 6) (Figure 5A).	('P2X7R', 'Gene', (101, 106))	('MCC950', 'Var', (162, 168))	('decrease', 'NegReg', (53, 61))	('NLRP3', 'Gene', '114548', (111, 116))	('cellular respiratory rate', 'MPA', (65, 90))	('oATP', 'Chemical', 'MESH:C004282', (153, 157))	('MCC950', 'Chemical', 'MESH:C000597426', (162, 168))	('inhibited', 'NegReg', (140, 149))	('NLRP3', 'Gene', (111, 116))	('P2X7R', 'Gene', '5027', (101, 106))
452844	28430665	This decrease in the cell viability by MCC950+oATP treatment was not observed in normal cells including HSG and primary cultured human fibroblast cells from a section of biopsied sample histologically diagnosed as normal (Figure 5B).	('oATP', 'Chemical', 'MESH:C004282', (46, 50))	('cell viability', 'CPA', (21, 35))	('MCC950', 'Chemical', 'MESH:C000597426', (39, 45))	('MCC950+oATP treatment', 'Var', (39, 60))	('human', 'Species', '9606', (129, 134))	('decrease', 'NegReg', (5, 13))
452879	28430665	In addition the MCC950+oATP combination did not induce cell death in normal cells which neither overexpress P2X7R nor NLRP3 inflammasome components.	('NLRP3', 'Gene', (118, 123))	('P2X7R', 'Gene', (108, 113))	('NLRP3', 'Gene', '114548', (118, 123))	('MCC950+oATP', 'Var', (16, 27))	('MCC950', 'Chemical', 'MESH:C000597426', (16, 22))	('oATP', 'Chemical', 'MESH:C004282', (23, 27))	('P2X7R', 'Gene', '5027', (108, 113))
452925	28430665	Another plate was subjected to Synergy 2 microplate reader (Biotek) to measure fluorescence intensity of PI (Ex: 540/25 Em: 590/20) and Calcein AM (Ex: 485/20 Em:528/20).	('Ex: 540/25 Em:', 'Var', (109, 123))	('fluorescence intensity', 'MPA', (79, 101))	('Calcein AM', 'Chemical', 'MESH:C085925', (136, 146))
452938	27424798	We identify an additional four susceptibility loci: 11q23.3 CADM1, a metastasis suppressor gene involved in modifying tumour interaction with cell-mediated immunity; 2p22.3; 7p21.1 AHR, the dioxin receptor involved in anti-apoptotic pathways and melanoma progression; and 9q34.3 SEC16A, a putative oncogene with roles in secretion and cellular proliferation.	('CADM1', 'Gene', (60, 65))	('tumour', 'Disease', (118, 124))	('SEC16A', 'Gene', (279, 285))	('CADM1', 'Gene', '23705', (60, 65))	('7p21.1', 'Var', (174, 180))	('melanoma', 'Phenotype', 'HP:0002861', (246, 254))	('2p22.3; 7p21.1', 'Var', (166, 180))	('melanoma', 'Disease', (246, 254))	('melanoma', 'Disease', 'MESH:D008545', (246, 254))	('SEC16A', 'Gene', '9919', (279, 285))	('tumour', 'Phenotype', 'HP:0002664', (118, 124))	('tumour', 'Disease', 'MESH:D009369', (118, 124))	('AHR', 'Gene', '196', (181, 184))	('AHR', 'Gene', (181, 184))
452951	27424798	In stage 1, the most significant single-nucleotide polymorphism (SNP) at each locus associated with SCC (P<10-5) was identified, yielding a list of 14 index SNPs (Fig.	('SCC', 'Gene', (100, 103))	('P<10-5', 'Gene', '1012', (105, 111))	('P<10-5', 'Gene', (105, 111))	('SCC', 'Phenotype', 'HP:0002860', (100, 103))	('SCC', 'Gene', '6317', (100, 103))	('single-nucleotide polymorphism', 'Var', (33, 63))	('associated', 'Reg', (84, 94))
452954	27424798	Out of the 11 genome-wide significant SNPs, 9 were associated with an increased SCC risk relative to the minor allele, whereas 2 (SLC45A2 rs35407 and BNC2 rs10810657) were protective (Table 2).	('SCC', 'Gene', '6317', (80, 83))	('SCC', 'Phenotype', 'HP:0002860', (80, 83))	('SLC45A2', 'Gene', '51151', (130, 137))	('rs35407', 'Var', (138, 145))	('rs35407', 'Mutation', 'rs35407', (138, 145))	('BNC2', 'Gene', '54796', (150, 154))	('SLC45A2', 'Gene', (130, 137))	('BNC2', 'Gene', (150, 154))	('rs10810657', 'Mutation', 'rs10810657', (155, 165))	('rs10810657', 'Var', (155, 165))	('SCC', 'Gene', (80, 83))
452968	27424798	In our study, these SNPs include the following: rs1805007 (MC1R R151C), a red hair allele associated with photosensitivity and increased BCC risk; rs12203592, which lies within an enhancer of IRF4 transcription in melanocytes and is associated with increased risk of actinic keratoses (SCC precursors) independent of skin pigmentation; rs1126809 (TYR R402Q), associated with photosensitivity, tanning and increased risk of BCC and melanoma; rs6059655, intergenic near RALY-ASIP and associated with facial pigmented spots; and rs35407, in modest linkage disequilibrium with rs16891982 (SLC45A2 F374L, r2=0.33, D'=1), associated with human pigmentation and melanoma risk.	('R402Q', 'Mutation', 'rs1126809', (351, 356))	('rs35407', 'Mutation', 'rs35407', (526, 533))	('human pigmentation', 'Disease', (632, 650))	('ASIP', 'Gene', '434', (473, 477))	('photosensitivity', 'Phenotype', 'HP:0000992', (375, 391))	('rs6059655', 'Var', (441, 450))	('ASIP', 'Gene', (473, 477))	('rs16891982', 'Mutation', 'rs16891982', (573, 583))	('BCC', 'Phenotype', 'HP:0002671', (137, 140))	('F374L', 'Mutation', 'rs16891982', (593, 598))	('rs1805007', 'Var', (48, 57))	('BCC', 'Disease', (423, 426))	('IRF4', 'Gene', '3662', (192, 196))	('BCC', 'Phenotype', 'HP:0002671', (423, 426))	('melanoma', 'Disease', 'MESH:D008545', (655, 663))	('SLC45A2', 'Gene', '51151', (585, 592))	('RALY', 'Gene', (468, 472))	('RALY', 'Gene', '22913', (468, 472))	('rs1126809', 'Mutation', 'rs1126809', (336, 345))	('melanoma', 'Disease', 'MESH:D008545', (431, 439))	('men', 'Species', '9606', (325, 328))	('SCC', 'Phenotype', 'HP:0002860', (286, 289))	('rs6059655', 'Mutation', 'rs6059655', (441, 450))	('IRF4', 'Gene', (192, 196))	('associated', 'Reg', (482, 492))	('rs12203592', 'Mutation', 'rs12203592', (147, 157))	('TYR', 'Chemical', 'MESH:D014443', (347, 350))	('MC1R', 'Gene', '4157', (59, 63))	('actinic keratoses', 'Phenotype', 'HP:0025127', (267, 284))	('MC1R', 'Gene', (59, 63))	('rs35407', 'Var', (526, 533))	('men', 'Species', '9606', (508, 511))	('rs1805007', 'Mutation', 'rs1805007', (48, 57))	('skin pigmentation', 'Phenotype', 'HP:0000953', (317, 334))	('SLC45A2', 'Gene', (585, 592))	('skin pigmentation', 'Disease', (317, 334))	('rs12203592', 'Var', (147, 157))	('red hair', 'Phenotype', 'HP:0002297', (74, 82))	('men', 'Species', '9606', (641, 644))	('facial pigmented spots', 'Disease', (498, 520))	('SCC', 'Gene', '6317', (286, 289))	('melanoma', 'Disease', (655, 663))	('melanoma', 'Phenotype', 'HP:0002861', (655, 663))	('associated', 'Reg', (616, 626))	('R151C', 'Mutation', 'rs1805007', (64, 69))	('rs1126809', 'Var', (336, 345))	('human', 'Species', '9606', (632, 637))	('melanoma', 'Phenotype', 'HP:0002861', (431, 439))	('melanoma', 'Disease', (431, 439))	('SCC', 'Gene', (286, 289))	('skin pigmentation', 'Disease', 'MESH:D010859', (317, 334))	('photosensitivity', 'Phenotype', 'HP:0000992', (106, 122))
452970	27424798	We also performed sensitivity analysis on OCA2 rs1800407 and IRF4 rs12203592 using high imputation quality subsets and directly genotyped data sets (Supplementary Table 8).	('rs1800407', 'Mutation', 'rs1800407', (47, 56))	('men', 'Species', '9606', (155, 158))	('rs12203592', 'Mutation', 'rs12203592', (66, 76))	('OCA2', 'Gene', '4948', (42, 46))	('rs1800407', 'Var', (47, 56))	('IRF4', 'Gene', '3662', (61, 65))	('rs12203592', 'Var', (66, 76))	('OCA2', 'Gene', (42, 46))	('IRF4', 'Gene', (61, 65))
452972	27424798	rs10810657 lies ~13 kb upstream of the basonuclin 2 (BNC2) transcription start site in a potential enhancer in foreskin melanocytes and other cell types.	('BNC2', 'Gene', '54796', (53, 57))	('basonuclin 2', 'Gene', (39, 51))	('BNC2', 'Gene', (53, 57))	('rs10810657', 'Mutation', 'rs10810657', (0, 10))	('rs10810657', 'Var', (0, 10))	('basonuclin 2', 'Gene', '54796', (39, 51))	('enhancer', 'PosReg', (99, 107))
452973	27424798	This SNP is in linkage disequilibrium with rs12350739 (r2=0.90, D'=1.00), which resides in an enhancer element regulating BNC2 transcription in human melanocytes.	('human', 'Species', '9606', (144, 149))	('BNC2', 'Gene', '54796', (122, 126))	('rs12350739', 'Mutation', 'rs12350739', (43, 53))	('BNC2', 'Gene', (122, 126))	('rs12350739', 'Var', (43, 53))	('men', 'Species', '9606', (106, 109))
452976	27424798	Variants in the BNC2 locus have recently been associated with skin colour, freckling and age-related pigmentation spots in Europeans, in addition to SCC.	('Variants', 'Var', (0, 8))	('BNC2', 'Gene', '54796', (16, 20))	('SCC', 'Gene', (149, 152))	('men', 'Species', '9606', (104, 107))	('associated', 'Reg', (46, 56))	('freckling', 'Phenotype', 'HP:0001480', (75, 84))	('BNC2', 'Gene', (16, 20))	('SCC', 'Phenotype', 'HP:0002860', (149, 152))	('SCC', 'Gene', '6317', (149, 152))	('freckling', 'Disease', (75, 84))	('skin colour', 'Disease', (62, 73))	('age-related pigmentation spots', 'Disease', (89, 119))
452979	27424798	rs57994353 at 9q34.3 (P=7.5 x 10-9, OR=1.12, logistic regression) resides within an intron of SEC16A in tight linkage disequilibrium with rs3812594 SEC16A R1039C (r2=0.90, D'=1).	('rs3812594', 'Mutation', 'rs3812594', (138, 147))	('R1039C', 'Mutation', 'rs3812594', (155, 161))	('SEC16A', 'Gene', (94, 100))	('SEC16A', 'Gene', (148, 154))	('rs57994353', 'Mutation', 'rs57994353', (0, 10))	('R1039C', 'Var', (155, 161))	('SEC16A', 'Gene', '9919', (94, 100))	('rs57994353', 'Var', (0, 10))	('SEC16A', 'Gene', '9919', (148, 154))	('rs3812594', 'Var', (138, 147))
452983	27424798	Another novel SCC risk variant, rs74899442 at 11q23.3, reached genome-wide significance in the overall meta-analysis (P=8.7 x 10-9, OR=2.13, logistic regression).	('SCC', 'Gene', (14, 17))	('SCC', 'Phenotype', 'HP:0002860', (14, 17))	('rs74899442', 'Mutation', 'rs74899442', (32, 42))	('rs74899442', 'Var', (32, 42))	('SCC', 'Gene', '6317', (14, 17))
452985	27424798	CADM1 is also a putative tumour suppressor in many human carcinomas, including SCC, as it is frequently downregulated in these tissues via promoter methylation.	('CADM1', 'Gene', (0, 5))	('SCC', 'Gene', (79, 82))	('CADM1', 'Gene', '23705', (0, 5))	('promoter methylation', 'Var', (139, 159))	('tumour', 'Phenotype', 'HP:0002664', (25, 31))	('carcinoma', 'Phenotype', 'HP:0030731', (57, 66))	('SCC', 'Phenotype', 'HP:0002860', (79, 82))	('tumour', 'Disease', 'MESH:D009369', (25, 31))	('human', 'Species', '9606', (51, 56))	('SCC', 'Gene', '6317', (79, 82))	('downregulated', 'NegReg', (104, 117))	('carcinomas', 'Phenotype', 'HP:0030731', (57, 67))	('carcinomas', 'Disease', (57, 67))	('carcinomas', 'Disease', 'MESH:D002277', (57, 67))	('tumour', 'Disease', (25, 31))
452990	27424798	The third and fourth novel susceptibility variants rs192481803 and rs117132860 reached genome-wide significance in the overall meta-analysis.	('rs192481803', 'Var', (51, 62))	('rs117132860', 'Var', (67, 78))	('rs192481803', 'Mutation', 'rs192481803', (51, 62))	('rs117132860', 'Mutation', 'rs117132860', (67, 78))
452992	27424798	rs117132860 (P=3.6 x 10-8, OR=1.48, logistic regression), located at 7p21.1, is situated within a DNAse hypersensitivity site 203 kb upstream of AHR, the aryl hydrocarbon receptor, and has predicted enhancer activity in multiple tissues including keratinocytes.	('aryl hydrocarbon receptor', 'Gene', '196', (154, 179))	('enhancer', 'PosReg', (199, 207))	('aryl hydrocarbon receptor', 'Gene', (154, 179))	('hypersensitivity', 'Disease', (104, 120))	('hypersensitivity', 'Disease', 'MESH:D004342', (104, 120))	('activity', 'MPA', (208, 216))	('rs117132860', 'Var', (0, 11))	('rs117132860', 'Mutation', 'rs117132860', (0, 11))	('AHR', 'Gene', '196', (145, 148))	('AHR', 'Gene', (145, 148))
452997	27424798	Three loci, 6p21.32 (rs28993540), 3q28 (rs11715549) and 8q23.3 (rs199816436), with high imputation quality (R2>0.9) were associated with SCC risk in stage 1 (P<10-5) but did not reach P<0.05 in stage 2, or P<5 x 10-8 in the overall meta-analysis (Supplementary Table 11 and Supplementary Fig.	('SCC', 'Phenotype', 'HP:0002860', (137, 140))	('rs199816436', 'Var', (64, 75))	('rs11715549', 'Var', (40, 50))	('associated with', 'Reg', (121, 136))	('SCC', 'Gene', '6317', (137, 140))	('rs28993540', 'Mutation', 'rs28993540', (21, 31))	('P<10-5', 'Gene', '1012', (158, 164))	('rs11715549', 'Mutation', 'rs11715549', (40, 50))	('P<10-5', 'Gene', (158, 164))	('rs28993540', 'Var', (21, 31))	('men', 'Species', '9606', (280, 283))	('rs199816436', 'Mutation', 'rs199816436', (64, 75))	('men', 'Species', '9606', (253, 256))	('SCC', 'Gene', (137, 140))
452998	27424798	rs28993540 lies 35 kb upstream of HLA-DQB1.	('HLA-DQB1', 'Gene', (34, 42))	('rs28993540', 'Mutation', 'rs28993540', (0, 10))	('HLA-DQB1', 'Gene', '3119', (34, 42))	('rs28993540', 'Var', (0, 10))
453000	27424798	HLA-DQB1 alleles have been associated with risk of squamous cell cervical cancer and may function by altering the efficiency of the T-cell-mediated immune response to HPV antigens.	('associated', 'Reg', (27, 37))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('HLA-DQB1', 'Gene', '3119', (0, 8))	('altering', 'Reg', (101, 109))	('squamous cell cervical cancer', 'Disease', (51, 80))	('alleles', 'Var', (9, 16))	('squamous cell cervical cancer', 'Disease', 'MESH:D002294', (51, 80))	('function', 'Reg', (89, 97))	('HLA-DQB1', 'Gene', (0, 8))
453001	27424798	rs11715549 resides in a potential enhancer in keratinocytes within LPP, a gene involved in epithelial cell motility and cell-cell adhesion.	('enhancer', 'PosReg', (34, 42))	('LPP', 'Gene', (67, 70))	('rs11715549', 'Var', (0, 10))	('rs11715549', 'Mutation', 'rs11715549', (0, 10))	('LPP', 'Gene', '4026', (67, 70))
453002	27424798	rs11715549 is in tight linkage disequilibrium with SNPs associated with vitiligo (rs9851967, r2=0.93), celiac disease (rs1464510, r2=0.74) and allergy (rs9860547, r2=0.87).	('celiac disease', 'Disease', 'MESH:D002446', (103, 117))	('rs9860547', 'Mutation', 'rs9860547', (152, 161))	('rs9851967', 'Mutation', 'rs9851967', (82, 91))	('vitiligo', 'Phenotype', 'HP:0001045', (72, 80))	('celiac disease', 'Disease', (103, 117))	('allergy', 'Disease', (143, 150))	('celiac disease', 'Phenotype', 'HP:0002608', (103, 117))	('rs11715549', 'Var', (0, 10))	('rs1464510', 'Mutation', 'rs1464510', (119, 128))	('vitiligo', 'Disease', (72, 80))	('rs9851967', 'Var', (82, 91))	('allergy', 'Phenotype', 'HP:0012393', (143, 150))	('rs11715549', 'Mutation', 'rs11715549', (0, 10))	('rs1464510', 'Var', (119, 128))	('rs9860547', 'Var', (152, 161))	('allergy', 'Disease', 'MESH:D004342', (143, 150))	('SNPs', 'Disease', (51, 55))
453003	27424798	rs199816436 lies inside an intron in TRPS1, a transcription factor that represses GATA-regulated genes and binds to a dynein light chain protein.	('rs199816436', 'Mutation', 'rs199816436', (0, 11))	('binds', 'Interaction', (107, 112))	('dynein', 'Protein', (118, 124))	('represses', 'NegReg', (72, 81))	('rs199816436', 'Var', (0, 11))	('TRPS1', 'Gene', '7227', (37, 42))	('TRPS1', 'Gene', (37, 42))	('a dynein', 'Protein', (116, 124))
453004	27424798	rs199816436 is tightly correlated with rs10808475 (r2=0.85) and is a TRPS1 expression quantitative trait locus (eQTL) in liver.	('rs199816436', 'Mutation', 'rs199816436', (0, 11))	('rs10808475', 'Var', (39, 49))	('rs199816436', 'Var', (0, 11))	('rs10808475', 'Mutation', 'rs10808475', (39, 49))	('TRPS1', 'Gene', '7227', (69, 74))	('TRPS1', 'Gene', (69, 74))
453005	27424798	Defects in TRPS1 lead to trichorhinophalangeal syndrome, a genetic syndrome characterized by coarse facies, brittle hair and skeletal defects.	('genetic syndrome', 'Disease', 'MESH:D030342', (59, 75))	('trichorhinophalangeal syndrome', 'Disease', 'MESH:C536820', (25, 55))	('trichorhinophalangeal syndrome', 'Disease', (25, 55))	('coarse facies', 'Phenotype', 'HP:0000280', (93, 106))	('brittle hair and skeletal defects', 'Disease', 'MESH:C536320', (108, 141))	('lead to', 'Reg', (17, 24))	('skeletal defects', 'Phenotype', 'HP:0000924', (125, 141))	('Defects', 'Var', (0, 7))	('TRPS1', 'Gene', '7227', (11, 16))	('TRPS1', 'Gene', (11, 16))	('genetic syndrome', 'Disease', (59, 75))	('brittle hair', 'Phenotype', 'HP:0002299', (108, 120))
453049	27424798	The Illumia HumanHap data set comprises several platforms: Illumina 550 K (NHS-breast cancer, NHS-Pancreas cancer and HPFS-pancreas cancer), Illumina 610Q (NHS-kidney stone, HPFS-kidney stone and HPFS-prostate cancer) and Illumina 660 (NHS-glaucoma and HPFS-glaucoma).	('HPFS-pancreas cancer', 'Disease', (118, 138))	('NHS-breast cancer', 'Disease', 'MESH:C538336', (75, 92))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('HPFS-glaucoma', 'Disease', (253, 266))	('prostate cancer', 'Phenotype', 'HP:0012125', (201, 216))	('kidney stone', 'Phenotype', 'HP:0000787', (179, 191))	('HPFS-kidney stone', 'Disease', (174, 191))	('HPFS-kidney stone', 'Disease', 'MESH:D007669', (174, 191))	('Illumina', 'Var', (141, 149))	('glaucoma', 'Phenotype', 'HP:0000501', (258, 266))	('HPFS-pancreas cancer', 'Disease', 'MESH:D010190', (118, 138))	('pancreas cancer', 'Phenotype', 'HP:0002894', (123, 138))	('NHS-breast cancer', 'Disease', (75, 92))	('glaucoma', 'Phenotype', 'HP:0000501', (240, 248))	('NHS-glaucoma', 'Disease', (236, 248))	('HPFS-glaucoma', 'Disease', 'MESH:D005901', (253, 266))	('kidney stone', 'Phenotype', 'HP:0000787', (160, 172))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('NHS-glaucoma', 'Disease', 'MESH:D005901', (236, 248))	('NHS-Pancreas cancer', 'Disease', (94, 113))	('Human', 'Species', '9606', (12, 17))	('HPFS-prostate cancer', 'Disease', 'MESH:D011471', (196, 216))	('HPFS-prostate cancer', 'Disease', (196, 216))	('Pancreas cancer', 'Phenotype', 'HP:0002894', (98, 113))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('breast cancer', 'Phenotype', 'HP:0003002', (79, 92))	('NHS-Pancreas cancer', 'Disease', 'MESH:C538336', (94, 113))	('NHS-kidney stone', 'Disease', 'MESH:D007669', (156, 172))	('NHS-kidney stone', 'Disease', (156, 172))
453061	27424798	We used ProbABEL software to test the GWAS association between minor allele counts and SCC risk using imputed dosage data.	('minor allele counts', 'Var', (63, 82))	('SCC', 'Gene', (87, 90))	('SCC', 'Phenotype', 'HP:0002860', (87, 90))	('SCC', 'Gene', '6317', (87, 90))
453067	27424798	For each novel SCC susceptibility variant, we searched for evidence of regulatory function using HaploReg version 4 (refs) (http://www.broadinstitute.org/mammals/haploreg/haploreg.php).	('SCC', 'Phenotype', 'HP:0002860', (15, 18))	('SCC', 'Gene', (15, 18))	('SCC', 'Gene', '6317', (15, 18))	('variant', 'Var', (34, 41))
453069	27424798	Data were also extracted from Roadmap Epigenomics Consortium 2015 on enhancer and promoter chromatin segmentation states, specifically using the following states: 15-state HMM, 25-state HMM, H3K4me1, H3K4me3, H3K27ac and H3K9ac.	('H3K4me3', 'Var', (200, 207))	('men', 'Species', '9606', (104, 107))	('H3K9ac', 'Var', (221, 227))	('H3K4me1', 'Var', (191, 198))	('H3K27ac', 'Var', (209, 216))
453080	33579299	Furthermore, we illustrated that gene FCER1G stratified glioma cases into high and low FCER1G expression subgroups that demonstrated with distinct clinical outcomes and T cell activation.	('glioma', 'Disease', (56, 62))	('glioma', 'Disease', 'MESH:D005910', (56, 62))	('glioma', 'Phenotype', 'HP:0009733', (56, 62))	('FCER1G', 'Gene', (87, 93))	('FCER1G', 'Gene', (38, 44))	('gene', 'Var', (33, 37))	('expression', 'MPA', (94, 104))	('low', 'NegReg', (83, 86))
453081	33579299	At last, we demonstrated that high FCER1G levels presented great immunotherapeutic response in glioma patients.	('glioma', 'Phenotype', 'HP:0009733', (95, 101))	('immunotherapeutic response', 'CPA', (65, 91))	('patients', 'Species', '9606', (102, 110))	('glioma', 'Disease', (95, 101))	('high', 'Var', (30, 34))	('FCER1G', 'Gene', (35, 41))	('glioma', 'Disease', 'MESH:D005910', (95, 101))
453091	33579299	Currently, cancer immunotherapy based on immune checkpoint blockades (ICBs), notably anti-CTLA4 (cytotoxic T-lymphocyte associated protein 4), anti-PDCD1/PD-1 (programmed cell death 1), anti-CD274/PD-L1, has emerged as a revolutionary treatment for patients with advanced highly aggressive therapy-resistant tumors.	('programmed cell death 1', 'Gene', '100533201', (160, 183))	('anti-CD274/PD-L1', 'Var', (186, 202))	('tumors', 'Disease', 'MESH:D009369', (308, 314))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('cytotoxic T-lymphocyte associated protein 4', 'Gene', '397286', (97, 140))	('patients', 'Species', '9606', (249, 257))	('tumors', 'Phenotype', 'HP:0002664', (308, 314))	('anti-PDCD1/PD-1', 'Var', (143, 158))	('cancer', 'Disease', 'MESH:D009369', (11, 17))	('tumor', 'Phenotype', 'HP:0002664', (308, 313))	('cytotoxic T-lymphocyte associated protein 4', 'Gene', (97, 140))	('anti-CTLA4', 'Var', (85, 95))	('cancer', 'Disease', (11, 17))	('programmed cell death 1', 'Gene', (160, 183))	('tumors', 'Disease', (308, 314))
453126	33579299	Specifically speaking, patients with high expression level of FCER1G showed a shorter overall survival (OS), progression-free interval (PFI) and disease-specific survival (DSS) than low expression patients both in LGG and GBM cohort (Fig.	('GBM', 'Phenotype', 'HP:0012174', (222, 225))	('patients', 'Species', '9606', (197, 205))	('patients', 'Species', '9606', (23, 31))	('FCER1G', 'Gene', (62, 68))	('progression-free interval', 'CPA', (109, 134))	('disease-specific', 'MPA', (145, 161))	('high expression level', 'Var', (37, 58))	('shorter', 'NegReg', (78, 85))	('overall survival', 'MPA', (86, 102))
453143	33579299	To improve the stability of the results, a fixed effects model was employed to pool the HRs of the six cohorts, and the result also validated that patients with high level of FCER1G expression exerted shorter OS times than patients with low expression level (RR = 1.30, 95 % CI  1.24-1.38, Fig.	('FCER1G', 'Gene', (175, 181))	('patients', 'Species', '9606', (147, 155))	('shorter', 'NegReg', (201, 208))	('patients', 'Species', '9606', (223, 231))	('high level', 'Var', (161, 171))	('OS times', 'MPA', (209, 217))
453146	33579299	Through univariate analysis of clinical characteristics, we found that FCER1G was more likely to be associated with older age (P = 0.002), high malignancy (P < 0.001), GBM type (P < 0.001), post-operative relapse (P < 0.001), poorer survival (P < 0.001), IDH wild type (P < 0.001), and different therapeutic options (Radiotherapy, P = 0.047; chemotherapy, P = 0.009), however, there is no significant differences in gender (Table 1).	('IDH', 'Gene', (255, 258))	('IDH', 'Gene', '3417', (255, 258))	('GBM', 'Phenotype', 'HP:0012174', (168, 171))	('high malignancy', 'Disease', 'MESH:D009369', (139, 154))	('FCER1G', 'Var', (71, 77))	('poorer survival', 'CPA', (226, 241))	('high malignancy', 'Disease', (139, 154))
453157	33579299	The result showed that FCER1G had a closely interactions with FCGR3A, ITGB2, LYN, SYK, in which FCER1G acts as a core gene (Fig.	('FCGR3A', 'Gene', (62, 68))	('FCER1G', 'Var', (96, 102))	('SYK', 'Gene', (82, 85))	('ITGB2', 'Gene', (70, 75))	('FCGR3A', 'Gene', '2214', (62, 68))	('SYK', 'Gene', '6850', (82, 85))	('LYN', 'Gene', '4067', (77, 80))	('LYN', 'Gene', (77, 80))	('ITGB2', 'Gene', '3689', (70, 75))	('interactions', 'Interaction', (44, 56))
453171	33579299	Patients with high FCER1G expression showed high levels of the therapeutic targets PD1, PDL1 and CTLA4, which indicated a hypothetic treatment as immune checkpoint.	('high', 'Var', (14, 18))	('CTLA4', 'MPA', (97, 102))	('FCER1G', 'Gene', (19, 25))	('Patients', 'Species', '9606', (0, 8))
453172	33579299	Patients with high FCER1G expression get higher scores in the TIS signature (P < 0.001), reporting to be correlated with response to anti PDL1 checkpoint inhibitor pembrolizumab, which supporting the hypothesis (Fig.	('pembrolizumab', 'Chemical', 'MESH:C582435', (164, 177))	('FCER1G', 'Gene', (19, 25))	('TIS signature', 'MPA', (62, 75))	('high', 'Var', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('higher', 'PosReg', (41, 47))
453174	33579299	The ImmuCellAI predicted that patients with high FCER1G levels were more likely to respond to immunotherapy (81.6 %, 413/506, CGGA) than low FCER1G subgroup (52.5 %, 266/507, CGGA.	('FCER1G', 'Gene', (49, 55))	('patients', 'Species', '9606', (30, 38))	('high', 'Var', (44, 48))	('respond', 'CPA', (83, 90))
453189	33579299	Furthermore, we illustrated gene FCER1G as a novel diagnostic and therapeutic target for the first time, which stratified glioma cases into high and low FCER1G expression subgroups that demonstrated with distinct clinical outcomes.	('expression', 'MPA', (160, 170))	('FCER1G', 'Gene', (153, 159))	('high', 'Var', (140, 144))	('glioma', 'Disease', (122, 128))	('low', 'NegReg', (149, 152))	('glioma', 'Disease', 'MESH:D005910', (122, 128))	('glioma', 'Phenotype', 'HP:0009733', (122, 128))
453200	33579299	Notably, patients with high FCER1G expression showed high levels of the therapeutic targets PDL1 and CTLA4, which indicated a hypothetic treatment as immune checkpoint.	('high', 'Var', (23, 27))	('patients', 'Species', '9606', (9, 17))	('FCER1G', 'Gene', (28, 34))	('CTLA4', 'Gene', (101, 106))
453204	33579299	The possibility of immunotherapy response was predicted in patients with gliomas by ImmuCellAI, SubMap and TIDE algorithm, both of which suggested that high levels of FCER1G tended to more likely respond to immunotherapy.	('respond to immunotherapy', 'CPA', (196, 220))	('gliomas', 'Disease', 'MESH:D005910', (73, 80))	('gliomas', 'Phenotype', 'HP:0009733', (73, 80))	('FCER1G', 'Gene', (167, 173))	('more', 'PosReg', (184, 188))	('high levels', 'Var', (152, 163))	('patients', 'Species', '9606', (59, 67))	('glioma', 'Phenotype', 'HP:0009733', (73, 79))	('gliomas', 'Disease', (73, 80))
453212	31024613	NoMAS: A Computational Approach to Find Mutated Subnetworks Associated With Survival in Genome-Wide Cancer Studies Next-generation sequencing technologies allow to measure somatic mutations in a large number of patients from the same cancer type: one of the main goals in their analysis is the identification of mutations associated with clinical parameters.	('patients', 'Species', '9606', (211, 219))	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('cancer', 'Disease', 'MESH:D009369', (234, 240))	('Cancer', 'Disease', 'MESH:D009369', (100, 106))	('Cancer', 'Disease', (100, 106))	('mutations', 'Var', (312, 321))	('Cancer', 'Phenotype', 'HP:0002664', (100, 106))	('cancer', 'Disease', (234, 240))
453217	31024613	Recent advances in next-generation sequencing technologies have enabled the collection of sequence information from many genomes and exomes, with many large human and cancer genetic studies measuring mutations in all genes for a large number of patients of a specific disease (Cancer Genome Atlas Research Network,; Cancer Genome Atlas Network,; Cancer Genome Atlas Research Network et al.,; Raphael et al.,).	('Cancer Genome Atlas', 'Disease', (346, 365))	('Cancer', 'Phenotype', 'HP:0002664', (346, 352))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (346, 365))	('mutations', 'Var', (200, 209))	('patients', 'Species', '9606', (245, 253))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('Cancer Genome Atlas', 'Disease', (277, 296))	('Cancer', 'Phenotype', 'HP:0002664', (277, 283))	('cancer', 'Disease', (167, 173))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (277, 296))	('Cancer Genome Atlas', 'Disease', (316, 335))	('Cancer', 'Phenotype', 'HP:0002664', (316, 322))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (316, 335))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('human', 'Species', '9606', (157, 162))
453218	31024613	For example, in large cancer studies one is interested in finding somatic mutations that are associated with survival and that can be used for prognosis and therapeutic decisions.	('survival', 'Disease', (109, 117))	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('cancer', 'Disease', (22, 28))	('mutations', 'Var', (74, 83))	('associated', 'Reg', (93, 103))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))
453219	31024613	One of the main obstacles in finding mutations that are clinically relevant is the large number of mutations present in each cancer genome.	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('mutations', 'Var', (99, 108))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))
453221	31024613	In recent years, several computational and statistical methods have been designed to identify driver mutations and distinguish them from passenger mutations, exploiting data from large cancer studies (Raphael et al.,).	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('cancer', 'Disease', (185, 191))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('mutations', 'Var', (101, 110))
453230	31024613	For a given group of genes, one can assess the association of mutations in the genes of the group with survival by comparing the survival of the patients having a mutation in at least one of the genes with the survival of the patients with no mutation in the genes.	('patients', 'Species', '9606', (145, 153))	('patients', 'Species', '9606', (226, 234))	('mutation', 'Var', (163, 171))	('mutations', 'Var', (62, 71))	('association', 'Interaction', (47, 58))
453232	31024613	In this paper we study the problem of finding sets of interacting genes with mutations associated to survival using data from large cancer sequencing studies and interaction information from a genome-scale interaction network.	('cancer', 'Disease', (132, 138))	('mutations', 'Var', (77, 86))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))
453253	31024613	Therefore O(ln(1/delta)ek) iterations would be enough to ensure that the probability of OPT not being discovered is <= delta, resulting in an overall time complexity of O(mln(1/delta) E (4e)k).	('OPT', 'Gene', '26254', (88, 91))	('OPT', 'Gene', (88, 91))	('O(mln(1/delta) E (4e)k', 'Var', (169, 191))
453257	31024613	For any optimal colorful connected subnetwork  of size k >= 3 and any color-coding algorithm  which obtains subnetworks with colorsets of cardinality i by combining 2 subnetworks with colorsets of cardinality < i, by adding 3 neighbors to  we have that  may not discover S. Intuitively, Proposition 1 and Theorem 3 show that if mutations are placed adversarially (and the optimal solution OPT has many neighbors), our algorithm may not identify OPT.	('OPT', 'Gene', '26254', (389, 392))	('mutations', 'Var', (328, 337))	('OPT', 'Gene', '26254', (445, 448))	('OPT', 'Gene', (389, 392))	('OPT', 'Gene', (445, 448))
453259	31024613	Intuitively: (3.1) above states that the subnetwork  has mutations associated with survival; (3.1) states that each gene  contributes to the association of mutations in  to survival; (3.1) states that each gene  should have the same association to survival (increased or decreased) as ; and (3.1) states that all mutations outside  are independent of all other events (including survival time and censoring of patients).	('patients', 'Species', '9606', (410, 418))	('mutations', 'Var', (156, 165))	('mutations', 'Var', (57, 66))	('associated', 'Reg', (67, 77))
453263	31024613	In particular, we consider somatic mutations (single nucleotide variants and small indels) for 268 samples of glioblastoma multiforme (GBM), 315 samples of ovarian adenocarcinoma (OV) and 174 samples of lung squamous cell carcinoma (LUSC) for which survival data is available.	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (110, 133))	('ovarian adenocarcinoma', 'Disease', 'MESH:D010051', (156, 178))	('carcinoma', 'Phenotype', 'HP:0030731', (169, 178))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (203, 231))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (208, 231))	('carcinoma', 'Phenotype', 'HP:0030731', (222, 231))	('single nucleotide variants', 'Var', (46, 72))	('ovarian adenocarcinoma', 'Phenotype', 'HP:0025318', (156, 178))	('glioblastoma multiforme', 'Disease', (110, 133))	('lung squamous cell carcinoma', 'Disease', (203, 231))	('ovarian adenocarcinoma', 'Disease', (156, 178))	('glioblastoma', 'Phenotype', 'HP:0012174', (110, 122))
453278	31024613	It only focuses on phosphorylation-associated mutations, and the approach is based on a local search algorithm that builds a subnetwork by starting from one seed vertex and then greedily adding neighbors (at distance at most 2) from the seed, extending the approach used in different types of network analyses (Chuang et al.,).	('most 2', 'Gene', '57000', (220, 226))	('most 2', 'Gene', (220, 226))	('mutations', 'Var', (46, 55))
453302	29788963	The pure small cell carcinoma of uterine cervix had similar mutation or wild type pattern for TP53 compared with composite tumor (P = 0.224).	('small cell carcinoma', 'Phenotype', 'HP:0030357', (9, 29))	('mutation', 'Var', (60, 68))	('uterine cervix', 'Phenotype', 'HP:0030160', (33, 47))	('tumor', 'Disease', (123, 128))	('carcinoma of uterine', 'Phenotype', 'HP:0010784', (20, 40))	('small cell carcinoma', 'Disease', (9, 29))	('TP53', 'Gene', '7157', (94, 98))	('TP53', 'Gene', (94, 98))	('small cell carcinoma', 'Disease', 'MESH:D018288', (9, 29))	('small cell carcinoma of uterine cervix', 'Phenotype', 'HP:0031522', (9, 47))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (20, 29))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
453408	29788963	5c) and in one case of squamous cell carcinoma in situ, which revealed TP53 missense mutation.	('carcinoma', 'Phenotype', 'HP:0030731', (37, 46))	('missense mutation', 'Var', (76, 93))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (37, 54))	('squamous cell carcinoma', 'Disease', (23, 46))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (23, 46))	('TP53', 'Gene', '7157', (71, 75))	('TP53', 'Gene', (71, 75))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (23, 46))
453411	29788963	Three cases of composite tumors showed negative staining both in small cell carcinoma and in adenocarcinoma or squamous cell carcinoma in situ, which suggested TP53 nonsense mutation.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('small cell carcinoma', 'Disease', 'MESH:D018288', (65, 85))	('adenocarcinoma or squamous cell carcinoma', 'Disease', 'MESH:D002294', (93, 134))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (111, 134))	('tumors', 'Disease', (25, 31))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (125, 142))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('TP53', 'Gene', '7157', (160, 164))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('tumors', 'Disease', 'MESH:D009369', (25, 31))	('nonsense mutation', 'Var', (165, 182))	('adenocarcinoma or squamous cell carcinoma', 'Disease', (93, 134))	('TP53', 'Gene', (160, 164))	('small cell carcinoma', 'Phenotype', 'HP:0030357', (65, 85))	('small cell carcinoma', 'Disease', (65, 85))
453446	29788963	These findings are in line with the notion that HPV 18 infection is involved in the development of cervical small cell carcinoma and HPV 16 infection promotes the occurrence of cervical squamous cell carcinoma and adenocarcinoma.	('cervical small cell carcinoma', 'Disease', 'MESH:D018288', (99, 128))	('cervical small cell carcinoma', 'Phenotype', 'HP:0031522', (99, 128))	('HPV 16', 'Gene', (133, 139))	('cervical squamous cell carcinoma and adenocarcinoma', 'Disease', 'MESH:D002294', (177, 228))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (186, 209))	('promotes', 'PosReg', (150, 158))	('carcinoma', 'Phenotype', 'HP:0030731', (200, 209))	('HPV 18 infection', 'Disease', 'MESH:D030361', (48, 64))	('infection', 'Var', (140, 149))	('HPV 16', 'Species', '333760', (133, 139))	('HPV 18 infection', 'Disease', (48, 64))	('cervical small cell carcinoma', 'Disease', (99, 128))	('small cell carcinoma', 'Phenotype', 'HP:0030357', (108, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (219, 228))
453466	29788963	These observations indicated TP53 mutation might involved in the occurrence of small cell carcinoma as in squamous cell carcinoma and adenocarcinoma of uterine cervix, but the pathogenesis of small cell carcinoma was not completely same to those of squamous cell carcinoma or adenocarcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (263, 272))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('uterine cervix', 'Phenotype', 'HP:0030160', (152, 166))	('involved', 'Reg', (49, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('TP53', 'Gene', (29, 33))	('squamous cell carcinoma or adenocarcinoma', 'Disease', 'MESH:D002294', (249, 290))	('small cell carcinoma', 'Phenotype', 'HP:0030357', (79, 99))	('small cell carcinoma', 'Disease', (192, 212))	('small cell carcinoma', 'Disease', 'MESH:D018288', (192, 212))	('carcinoma of uterine', 'Phenotype', 'HP:0010784', (139, 159))	('mutation', 'Var', (34, 42))	('small cell carcinoma', 'Disease', (79, 99))	('small cell carcinoma', 'Disease', 'MESH:D018288', (79, 99))	('squamous cell carcinoma or adenocarcinoma', 'Disease', (249, 290))	('adenocarcinoma of uterine', 'Phenotype', 'HP:0010784', (134, 159))	('TP53', 'Gene', '7157', (29, 33))	('carcinoma', 'Phenotype', 'HP:0030731', (203, 212))	('squamous cell carcinoma and adenocarcinoma', 'Disease', 'MESH:D002294', (106, 148))	('carcinoma', 'Phenotype', 'HP:0030731', (139, 148))	('small cell carcinoma', 'Phenotype', 'HP:0030357', (192, 212))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (249, 272))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (106, 129))
453485	29351293	In this population, the proportion of patient samples with an FGFR1 amplification was three times higher than in reported for SCCA of the head and neck.	('patient', 'Species', '9606', (38, 45))	('higher', 'PosReg', (98, 104))	('FGFR1', 'Gene', (62, 67))	('amplification', 'Var', (68, 81))	('FGFR1', 'Gene', '2260', (62, 67))
453487	29351293	However, FGFR1 amplification is not prognostic in laryngeal squamous cell carcinomas.	('FGFR1', 'Gene', '2260', (9, 14))	('amplification', 'Var', (15, 28))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (60, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (60, 83))	('carcinomas', 'Phenotype', 'HP:0030731', (74, 84))	('laryngeal squamous cell carcinomas', 'Disease', (50, 84))	('laryngeal squamous cell carcinomas', 'Disease', 'MESH:D002294', (50, 84))	('FGFR1', 'Gene', (9, 14))	('laryngeal squamous cell carcinomas', 'Phenotype', 'HP:0012118', (50, 84))
453492	29351293	Fibroblast growth factor receptor 1 (FGFR1) amplification is one of the most common genetic alterations in human cancers.	('FGFR1', 'Gene', (37, 42))	('FGFR1', 'Gene', '2260', (37, 42))	('Fibroblast growth factor receptor 1', 'Gene', (0, 35))	('human', 'Species', '9606', (107, 112))	('cancers', 'Disease', 'MESH:D009369', (113, 120))	('cancers', 'Phenotype', 'HP:0002664', (113, 120))	('amplification', 'Var', (44, 57))	('cancers', 'Disease', (113, 120))	('Fibroblast growth factor receptor 1', 'Gene', '2260', (0, 35))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
453496	29351293	FGFR1 amplification has been reported in breast adenocarcinomas and described as the first actionable target in lung squamous cell carcinoma (SCCa).	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (112, 140))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (117, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('breast adenocarcinomas', 'Disease', (41, 63))	('lung squamous cell carcinoma', 'Disease', (112, 140))	('SCCa', 'Phenotype', 'HP:0002860', (142, 146))	('FGFR1', 'Gene', (0, 5))	('FGFR1', 'Gene', '2260', (0, 5))	('carcinoma', 'Phenotype', 'HP:0030731', (53, 62))	('reported', 'Reg', (29, 37))	('carcinomas', 'Phenotype', 'HP:0030731', (53, 63))	('amplification', 'Var', (6, 19))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (112, 140))	('breast adenocarcinomas', 'Disease', 'MESH:D000230', (41, 63))
453498	29351293	The discovery of FGFR1 amplification resulted in the immediate initiation of a phase I clinical trial of small-molecule FGFR inhibition therapy for patients with stage IV SCC disease (NCT01004224).	('patients', 'Species', '9606', (148, 156))	('IV SCC disease', 'Disease', (168, 182))	('amplification', 'Var', (23, 36))	('FGFR1', 'Gene', (17, 22))	('FGFR1', 'Gene', '2260', (17, 22))	('IV SCC disease', 'Disease', 'MESH:D020432', (168, 182))
453499	29351293	FGFR1 amplification has also been found in local and distant metastases suggesting a clonal event in tumor progression, therefore also suggesting that FGFR1 amplification occurs early in tumorigenesis and in turn, provides promise for treating patients with advanced disease.	('advanced disease', 'Disease', 'MESH:D020178', (258, 274))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('FGFR1', 'Gene', (0, 5))	('advanced disease', 'Disease', (258, 274))	('metastases', 'Disease', (61, 71))	('FGFR1', 'Gene', '2260', (0, 5))	('tumor', 'Disease', (187, 192))	('amplification', 'Var', (157, 170))	('FGFR1', 'Gene', (151, 156))	('patients', 'Species', '9606', (244, 252))	('metastases', 'Disease', 'MESH:D009362', (61, 71))	('FGFR1', 'Gene', '2260', (151, 156))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
453501	29351293	FGFR1 amplification has also been identified in SCCa of the head and neck.	('amplification', 'Var', (6, 19))	('FGFR1', 'Gene', (0, 5))	('FGFR1', 'Gene', '2260', (0, 5))	('SCCa', 'Phenotype', 'HP:0002860', (48, 52))
453502	29351293	FGFR1 amplification in head and neck SCCa is only found in HPV-negative tumors, suggesting a separate pathway of tumor progression.	('tumor', 'Disease', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Disease', (72, 77))	('FGFR1', 'Gene', (0, 5))	('tumors', 'Disease', (72, 78))	('FGFR1', 'Gene', '2260', (0, 5))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('amplification', 'Var', (6, 19))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('SCCa', 'Phenotype', 'HP:0002860', (37, 41))	('tumor', 'Disease', 'MESH:D009369', (72, 77))
453503	29351293	Similar to FGFR1 amplified lung cancer, it has also been associated with worse outcomes and strong association with tobacco and alcohol use.	('tobacco', 'Species', '4097', (116, 123))	('lung cancer', 'Disease', 'MESH:D008175', (27, 38))	('lung cancer', 'Disease', (27, 38))	('alcohol use', 'Phenotype', 'HP:0030955', (128, 139))	('lung cancer', 'Phenotype', 'HP:0100526', (27, 38))	('alcohol', 'Chemical', 'MESH:D000438', (128, 135))	('FGFR1', 'Gene', (11, 16))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('tobacco', 'Disease', (116, 123))	('FGFR1', 'Gene', '2260', (11, 16))	('association', 'Interaction', (99, 110))	('amplified', 'Var', (17, 26))	('associated', 'Reg', (57, 67))
453504	29351293	Goke et al found FGFR1 amplification in 15% of primary SCCA of the head and neck.	('FGFR1', 'Gene', '2260', (17, 22))	('amplification', 'Var', (23, 36))	('FGFR1', 'Gene', (17, 22))
453529	29351293	The commercial assay employed in this study has been shown to have an assay specificity of > 95% and yield copy number calls within 10% of expected (Bio-Rad Bulletin 6444).	('copy number calls', 'Var', (107, 124))	('Rad', 'Gene', (153, 156))	('Rad', 'Gene', '6236', (153, 156))
453532	29351293	Four distinct droplet populations were observed, corresponding to absence of signal (-/-), the presence of FGFR1/absence of RPPO30 (+/-), the presence of both signals (+/+), and the absence of FGFR1/presence of RPPO30 (-/+).	('RPPO30', 'Gene', (124, 130))	('FGFR1', 'Gene', (193, 198))	('signal', 'MPA', (77, 83))	('FGFR1', 'Gene', '2260', (193, 198))	('absence', 'NegReg', (66, 73))	('presence', 'Var', (95, 103))	('FGFR1', 'Gene', (107, 112))	('FGFR1', 'Gene', '2260', (107, 112))
453540	29351293	In order to determine whether copy number correlated with tumor stage, tumor stages 1-2 and 3-4 were grouped and compared to FGFR1 CN (Table 1).	('FGFR1', 'Gene', '2260', (125, 130))	('tumor', 'Disease', (58, 63))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('copy number', 'Var', (30, 41))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('correlated', 'Reg', (42, 52))	('FGFR1', 'Gene', (125, 130))	('tumor', 'Disease', (71, 76))
453543	29351293	The factors of gender, race, FGFR1 copy number, tumor stage (T = 1,2), and lymph node stage were evaluated for 70 subjects (n = 26 dead, 44 = alive) and the results are shown in Table 2.	('FGFR1', 'Gene', '2260', (29, 34))	('tumor', 'Disease', (48, 53))	('copy number', 'Var', (35, 46))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('FGFR1', 'Gene', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
453544	29351293	The hazard ratios for gender, race, and FGFR1 amplification were potentially clinically important individually, but not when placed in a multivariate model.	('FGFR1', 'Gene', (40, 45))	('FGFR1', 'Gene', '2260', (40, 45))	('amplification', 'Var', (46, 59))
453545	29351293	FGFR1 amplification in head and neck squamous cell carcinoma has recently been reported to be most common in the larynx.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (37, 60))	('FGFR1', 'Gene', (0, 5))	('FGFR1', 'Gene', '2260', (0, 5))	('amplification', 'Var', (6, 19))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (23, 60))	('neck squamous cell carcinoma', 'Disease', (32, 60))	('common', 'Reg', (99, 105))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (32, 60))	('carcinoma', 'Phenotype', 'HP:0030731', (51, 60))
453554	29351293	Using the more sensitive ddPCR assay, the percentage of FGFR1 CN variants increased to 54%, incorporating values between 2.2-3 CN.	('variants', 'Var', (65, 73))	('FGFR1', 'Gene', '2260', (56, 61))	('FGFR1', 'Gene', (56, 61))
453556	29351293	This study documented the first cases of FGFR1 amplification in African American and Native American patients.	('amplification', 'Var', (47, 60))	('FGFR1', 'Gene', (41, 46))	('patients', 'Species', '9606', (101, 109))	('FGFR1', 'Gene', '2260', (41, 46))
453558	29351293	Identification of 3 samples with apparent deletions of FGFR1 was also observed.	('FGFR1', 'Gene', (55, 60))	('FGFR1', 'Gene', '2260', (55, 60))	('deletions', 'Var', (42, 51))
453563	29351293	Young and colleagues (2013) found FGFR1 amplification in 10% of cases with oral tongue squamous cell carcinoma but no correlation to survival.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (87, 110))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('oral tongue squamous cell carcinoma', 'Disease', (75, 110))	('FGFR1', 'Gene', (34, 39))	('amplification', 'Var', (40, 53))	('FGFR1', 'Gene', '2260', (34, 39))	('oral tongue squamous cell carcinoma', 'Disease', 'MESH:D002294', (75, 110))	('tongue squamous cell carcinoma', 'Phenotype', 'HP:0030413', (80, 110))
453564	29351293	An extensive study of FGFR1 amplification in lung cancer also failed to detect a relationship between copy number and patient outcome.	('lung cancer', 'Disease', 'MESH:D008175', (45, 56))	('FGFR1', 'Gene', '2260', (22, 27))	('lung cancer', 'Disease', (45, 56))	('lung cancer', 'Phenotype', 'HP:0100526', (45, 56))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('patient', 'Species', '9606', (118, 125))	('amplification', 'Var', (28, 41))	('FGFR1', 'Gene', (22, 27))
453565	29351293	In studies of non-small cell lung cancer, FGFR1 amplification has been significantly associated with shorter overall survival and shorter disease-free survival on univariate analysis but was not statistically significant on multivariate analysis.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (18, 40))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (14, 40))	('FGFR1', 'Gene', (42, 47))	('shorter', 'NegReg', (101, 108))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (14, 40))	('overall', 'MPA', (109, 116))	('FGFR1', 'Gene', '2260', (42, 47))	('disease-free', 'MPA', (138, 150))	('shorter', 'NegReg', (130, 137))	('non-small cell lung cancer', 'Disease', (14, 40))	('lung cancer', 'Phenotype', 'HP:0100526', (29, 40))	('amplification', 'Var', (48, 61))
453566	29351293	In contrast, FGFR1 amplification has been associated with parameters for worse outcomes, specifically smoking and alcohol consumption.	('smoking', 'Disease', (102, 109))	('amplification', 'Var', (19, 32))	('FGFR1', 'Gene', (13, 18))	('associated', 'Reg', (42, 52))	('alcohol consumption', 'Disease', (114, 133))	('FGFR1', 'Gene', '2260', (13, 18))	('alcohol', 'Chemical', 'MESH:D000438', (114, 121))
453572	29351293	After more data is gathered, FGFR1 amplification may be used as a marker for aggressive disease.	('amplification', 'Var', (35, 48))	('FGFR1', 'Gene', '2260', (29, 34))	('aggressive disease', 'Disease', 'MESH:D001523', (77, 95))	('aggressive disease', 'Disease', (77, 95))	('FGFR1', 'Gene', (29, 34))
453578	29351293	This study documents FGFR1 amplification in African Americans and Native Americans as well as Caucasian populations.	('FGFR1', 'Gene', (21, 26))	('FGFR1', 'Gene', '2260', (21, 26))	('amplification', 'Var', (27, 40))
453603	27193097	DLT was defined as any of the following adverse events occurring within 28 days after completion of the protocol treatment: (1) febrile neutropenia lasting >4 days; (2) grade 4 thrombocytopenia (<0.25 x 109/l); (3) grade 3 or 4 non-hematologic toxic effects, except grade 3 alopecia, anorexia, nausea, vomiting, constipation, stomatitis, esophagitis or infection due to stomatitis; (4) discontinuation of treatment due to an adverse event; or (5) treatment-related death.	('stomatitis', 'Phenotype', 'HP:0010280', (326, 336))	('thrombocytopenia', 'Disease', (177, 193))	('febrile neutropenia', 'Disease', 'MESH:D009503', (128, 147))	('esophagitis or infection', 'Disease', 'MESH:D004941', (338, 362))	('anorexia', 'Disease', (284, 292))	('vomiting', 'Phenotype', 'HP:0002013', (302, 310))	('esophagitis or infection', 'Disease', (338, 362))	('stomatitis', 'Disease', 'MESH:D013280', (370, 380))	('vomiting', 'Disease', (302, 310))	('stomatitis', 'Disease', (370, 380))	('nausea', 'Phenotype', 'HP:0002018', (294, 300))	('<0.25 x 109/l', 'Var', (195, 208))	('constipation', 'Phenotype', 'HP:0002019', (312, 324))	('thrombocytopenia', 'Disease', 'MESH:D013921', (177, 193))	('thrombocytopenia', 'Phenotype', 'HP:0001873', (177, 193))	('alopecia', 'Phenotype', 'HP:0001596', (274, 282))	('nausea', 'Disease', (294, 300))	('stomatitis', 'Phenotype', 'HP:0010280', (370, 380))	('constipation', 'Disease', 'MESH:D003248', (312, 324))	('febrile neutropenia', 'Disease', (128, 147))	('stomatitis', 'Disease', 'MESH:D013280', (326, 336))	('stomatitis', 'Disease', (326, 336))	('neutropenia', 'Phenotype', 'HP:0001875', (136, 147))	('nausea', 'Disease', 'MESH:D009325', (294, 300))	('constipation', 'Disease', (312, 324))	('esophagitis', 'Phenotype', 'HP:0100633', (338, 349))	('anorexia', 'Phenotype', 'HP:0002039', (284, 292))	('vomiting', 'Disease', 'MESH:D014839', (302, 310))
453604	27193097	Adjacent organs were considered to be involved if the tumor extended into the lumen or caused a deformity of the airway in the trachea or tracheobronchial tree, and if the tumor was attached to the organ at a contact angle >=90  in the thoracic aorta as observed on the CT scan.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('deformity of the airway', 'Phenotype', 'HP:0002086', (96, 119))	('deformity', 'Disease', (96, 105))	('thoracic aorta', 'Phenotype', 'HP:0012727', (236, 250))	('caused', 'Reg', (87, 93))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('deformity of the airway in the trachea', 'Phenotype', 'HP:0002778', (96, 134))	('tumor', 'Var', (54, 59))	('deformity', 'Disease', 'MESH:D009140', (96, 105))
453618	27193097	Although these survival data were equivalent to those of our present study, DCF-R was associated with a relatively high incidence of FN (grade 3 or more, 38.1 %) and late toxic effects, namely grade 3 or more pericardial effusion (2.6 %), esophagus-related toxicities (7.7 %) and cardiovascular toxicities (2.6 %).	('cardiovascular toxicities', 'Disease', (280, 305))	('pericardial effusion', 'Disease', 'MESH:D010490', (209, 229))	('cardiovascular toxicities', 'Disease', 'MESH:D002318', (280, 305))	('pericardial effusion', 'Phenotype', 'HP:0001698', (209, 229))	('esophagus-related toxicities', 'Disease', (239, 267))	('pericardial effusion', 'Disease', (209, 229))	('DCF-R', 'Var', (76, 81))
453699	33184998	Immune checkpoint blockade therapy through modulation of the PD-L1 or PD-1 axis has been shown to yield satisfactory patient outcome.	('modulation', 'Var', (43, 53))	('PD-1 axis', 'Gene', (70, 79))	('patient', 'Species', '9606', (117, 124))
453701	33184998	The enrichment results showed the primary involvement of DEGs in cell adhesion molecules, HIF-1 signalling pathway, as well as antigen processing and presentation.	('involvement', 'Reg', (42, 53))	('cell adhesion', 'Protein', (65, 78))	('antigen processing', 'MPA', (127, 145))	('DEGs', 'Var', (57, 61))	('HIF-1', 'Gene', (90, 95))	('HIF-1', 'Gene', '3091', (90, 95))
453703	33184998	To validate the prognostic importance of the two aforementioned gene, additional NSCLC data sets (accession numbers GSE11969, GSE13213, GSE30219, GSE41271 and GSE42127) were explored.	('GSE41271', 'Var', (146, 154))	('NSCLC', 'Phenotype', 'HP:0030358', (81, 86))	('GSE30219', 'Var', (136, 144))	('NSCLC', 'Disease', (81, 86))	('NSCLC', 'Disease', 'MESH:D002289', (81, 86))
453705	33184998	Unlike the high-risk community, patients in the low-risk group had significantly longer OS (GES11969: Log-rank P = .0058; GSE13213: Log-rank P = .022; GSE30219: Log-rank P = .0001; GSE41271: Log-rank P = .005; GSE42127: Log-rank P = .011), indicating that ENO1 and SLC34A2 may be important in validation sets.	('GSE41271', 'Var', (181, 189))	('patients', 'Species', '9606', (32, 40))	('longer', 'PosReg', (81, 87))	('SLC34A2', 'Gene', (265, 272))	('GSE30219', 'Var', (151, 159))	('ENO1', 'Gene', '2023', (256, 260))	('ENO1', 'Gene', (256, 260))	('GSE42127', 'Var', (210, 218))	('SLC34A2', 'Gene', '10568', (265, 272))	('GSE13213', 'Var', (122, 130))
453741	31638335	In addition, metastasis-associated Src tyrosine kinase signalling, cell migration and epithelial-to-mesenchymal transition (EMT) were all inhibited by thiostrepton.	('metastasis-associated', 'CPA', (13, 34))	('epithelial-to-mesenchymal transition', 'CPA', (86, 122))	('tyrosine', 'Chemical', 'None', (39, 47))	('Src', 'Gene', (35, 38))	('Src', 'Gene', '6714', (35, 38))	('thiostrepton', 'Chemical', 'MESH:D013883', (151, 163))	('inhibited', 'NegReg', (138, 147))	('cell migration', 'CPA', (67, 81))	('thiostrepton', 'Var', (151, 163))
453754	31638335	We also provided evidence that thiostrepton can suppress cancer cell proliferation, migration and CSC-like properties in vitro, as well as inhibit tumorigenesis in vivo.	('suppress', 'NegReg', (48, 56))	('thiostrepton', 'Var', (31, 43))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('cancer', 'Disease', (57, 63))	('inhibit', 'NegReg', (139, 146))	('tumorigenesis', 'CPA', (147, 160))	('CSC-like properties', 'CPA', (98, 117))	('migration', 'CPA', (84, 93))	('thiostrepton', 'Chemical', 'MESH:D013883', (31, 43))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))
453796	31638335	The anti-CSC gene signature from GSE18150 and cancer cells treated with thiostrepton had a strong enrichment score in our 11 641 L1000 assays (normalized enrichment score = 1.914, P-value <.0001, Figure 1B).	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('cancer', 'Disease', (46, 52))	('anti-CSC gene', 'Gene', (4, 17))	('GSE18150', 'Var', (33, 41))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('thiostrepton', 'Chemical', 'MESH:D013883', (72, 84))
453816	31638335	By using an Aldefluor assay, we found CL141 tumour spheres were enriched with ALDH1+ cells (S: 1.2%) compared with their parental counterparts (P: 0.5%, Figure 3A), and the relative ALDH activity was significantly increased (Figure 3B).	('ALDH', 'CPA', (182, 186))	('tumour', 'Disease', 'MESH:D009369', (44, 50))	('activity', 'MPA', (187, 195))	('tumour', 'Disease', (44, 50))	('ALDH1', 'Gene', (78, 83))	('increased', 'PosReg', (214, 223))	('ALDH1', 'Gene', '216', (78, 83))	('Aldefluor', 'Chemical', 'None', (12, 21))	('CL141', 'Var', (38, 43))	('tumour', 'Phenotype', 'HP:0002664', (44, 50))
453827	31638335	CD133 and Oct-4A, the CSC markers, have been suggested as protectors for cancer cells from apoptosis induced by chemotherapeutic agents.25, 26, 36 Significantly increased apoptosis-related proteins:cleaved caspase-3 and cleaved PARP:were observed in cells treated with gemcitabine plus thiostrepton (Figure 4C).	('cancer', 'Disease', (73, 79))	('PARP', 'Gene', (228, 232))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('gemcitabine', 'Chemical', 'MESH:C056507', (269, 280))	('caspase-3', 'Gene', '836', (206, 215))	('PARP', 'Gene', '1302', (228, 232))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('increased', 'PosReg', (161, 170))	('agents.25', 'Var', (129, 138))	('CD133', 'Gene', (0, 5))	('CD133', 'Gene', '8842', (0, 5))	('thiostrepton', 'Chemical', 'MESH:D013883', (286, 298))	('caspase-3', 'Gene', (206, 215))
453834	31638335	In the presence of thiostrepton, CL141 spheres also responded to gemcitabine at a lower concentration and underwent apoptotic cell death as reflected by the elevated level of cleavage of PARP.	('thiostrepton', 'Chemical', 'MESH:D013883', (19, 31))	('responded to gemcitabine at', 'MPA', (52, 79))	('cleavage', 'MPA', (175, 183))	('gemcitabine', 'Chemical', 'MESH:C056507', (65, 76))	('PARP', 'Gene', '1302', (187, 191))	('elevated', 'PosReg', (157, 165))	('CL141', 'Var', (33, 38))	('PARP', 'Gene', (187, 191))
453853	31638335	Ectopic expression of Oct4 and Nanog in lung cancer cells was associated with a significant increase in the percentage of CD133+ cell and mesenchymal cell populations, the ability to form tumour spheres and enhanced drug resistance.25 To provide further support the contention that thiostrepton is a potential anti-CSC agent, we utilized a cell model that A549 cells with overexpression of Oct-4A/Nanog exhibits enhanced CSC characteristics and EMT potential.	('tumour', 'Phenotype', 'HP:0002664', (188, 194))	('Nanog', 'Gene', '79923', (397, 402))	('Nanog', 'Gene', (397, 402))	('tumour', 'Disease', 'MESH:D009369', (188, 194))	('tumour', 'Disease', (188, 194))	('EMT potential', 'CPA', (445, 458))	('Nanog', 'Gene', '79923', (31, 36))	('Nanog', 'Gene', (31, 36))	('lung cancer', 'Disease', 'MESH:D008175', (40, 51))	('thiostrepton', 'Chemical', 'MESH:D013883', (282, 294))	('lung cancer', 'Phenotype', 'HP:0100526', (40, 51))	('CSC characteristics', 'CPA', (421, 440))	('A549', 'CellLine', 'CVCL:0023', (356, 360))	('drug resistance', 'Phenotype', 'HP:0020174', (216, 231))	('Oct4', 'Gene', '5460', (22, 26))	('enhanced', 'PosReg', (412, 420))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('overexpression', 'Var', (372, 386))	('CD133', 'Gene', (122, 127))	('CD133', 'Gene', '8842', (122, 127))	('lung cancer', 'Disease', (40, 51))	('Oct4', 'Gene', (22, 26))
453876	30971301	One hundred ninety-six patients with T1bN + M0 or T2-4aN0-2 M0 oesophageal squamous cell cancer will be randomised to the DCRT group or the surgery group.	('M0 oesophageal squamous cell cancer', 'Disease', 'MESH:D002294', (60, 95))	('M0 oesophageal squamous cell cancer', 'Disease', (60, 95))	('patients', 'Species', '9606', (23, 31))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (75, 95))	('DCRT', 'Chemical', '-', (122, 126))	('T1bN + M0', 'Var', (37, 46))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
453910	30971301	A total of 196 ESCC patients with T1bN + M0 or T2-4aN0-2 M0 will be randomised to the CRT group or the surgery group.	('ESCC', 'Disease', (15, 19))	('patients', 'Species', '9606', (20, 28))	('T1bN + M0', 'Var', (34, 43))	('T2-4aN0-2 M0', 'Var', (47, 59))
453911	30971301	Age 18-75 years Mainland Chinese Oesophageal squamous cell cancer confirmed by histology Tumour is resectable Clinical stage cT1bN + M0 or cT2-4aN0-2 M0 Performance status score 0-2.	('Oesophageal squamous cell cancer', 'Disease', 'MESH:D002294', (33, 65))	('Oesophageal squamous cell cancer', 'Disease', (33, 65))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (45, 65))	('Tumour', 'Phenotype', 'HP:0002664', (89, 95))	('cT1bN + M0', 'Var', (125, 135))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('cT2-4aN0-2 M0', 'Var', (139, 152))
453929	30971301	Xelox: oxaliplatin 65 mg/m2, d1, 8, 22, 29, plus capecitabine, 625 mg/m2, bid, d1-5; 6 weeks in total Single capecitabine: capecitabine, 625 mg/m2, bid, d1-5; q1w, 6 weeks in total PF: cisplatin, 75 mg/m2, d1, 29, 5-FU, 750 mg/m2, CIV 24 h, d1-4, d29-32.	('oxaliplatin', 'Chemical', 'MESH:D000077150', (7, 18))	('capecitabine', 'Chemical', 'MESH:D000069287', (49, 61))	('bid', 'Gene', (148, 151))	('bid', 'Gene', '637', (148, 151))	('d1-4', 'Gene', (241, 245))	('capecitabine', 'Chemical', 'MESH:D000069287', (109, 121))	('Xelox', 'Chemical', 'MESH:C519688', (0, 5))	('d1-4', 'Gene', '25802;1734;1735;397', (241, 245))	('d1-5', 'Gene', '25802;1734;1735;397', (153, 157))	('d1-5', 'Gene', '25802;1734;1735;397', (79, 83))	('bid', 'Gene', (74, 77))	('d29-32', 'Var', (247, 253))	('5-FU', 'Chemical', 'MESH:D005472', (214, 218))	('capecitabine', 'Chemical', 'MESH:D000069287', (123, 135))	('bid', 'Gene', '637', (74, 77))	('PF', 'Chemical', 'MESH:C002997', (181, 183))	('d1-5', 'Gene', (153, 157))	('cisplatin', 'Chemical', 'MESH:D002945', (185, 194))	('d1-5', 'Gene', (79, 83))
454033	30335795	The 2-year actuarial LRC rate of N1/N2a, N2b/N2c, and N3 patients was 84.6%, 68.3%, and 30.0%, respectively (p <0.01) "Fig 1A".	('patients', 'Species', '9606', (57, 65))	('N1/N2a', 'Var', (33, 39))	('N2b/N2c', 'Var', (41, 48))
454036	30335795	The 5-year cumulative DSS rates of N1/N2a, N2b/N2c, and N3 patients were 83.9%, 64.3%, and 36.7%, respectively(p = 0.013) "Fig 2A".	('DSS', 'Chemical', '-', (22, 25))	('N1/N2a', 'Var', (35, 41))	('patients', 'Species', '9606', (59, 67))	('N2b/N2c', 'Var', (43, 50))
454106	29190918	Additionally, deregulated lipid metabolism can alter membrane composition and permeability, which might cause the development and progression of many diseases, especially malignant carcinoma.	('membrane composition', 'MPA', (53, 73))	('permeability', 'MPA', (78, 90))	('lipid metabolism', 'MPA', (26, 42))	('lipid', 'Chemical', 'MESH:D008055', (26, 31))	('malignant carcinoma', 'Disease', 'MESH:D009369', (171, 190))	('carcinoma', 'Phenotype', 'HP:0030731', (181, 190))	('alter', 'Reg', (47, 52))	('deregulated', 'Var', (14, 25))	('cause', 'Reg', (104, 109))	('malignant carcinoma', 'Disease', (171, 190))
454148	29190918	In present study, nine polyunsaturated PCs were differentially expressed between OSCC patients and controls and four of them had a step-wise decrease with the development and progression of OSCC, namely PC(32:2), PC(34:4), PC(36:7) and PC(36:6).	('PC', 'Chemical', '-', (203, 205))	('PC(34:4', 'Var', (213, 220))	('PC', 'Chemical', '-', (39, 41))	('OSCC', 'Disease', (190, 194))	('PC', 'Chemical', '-', (236, 238))	('OSCC', 'Disease', (81, 85))	('PC(36:7', 'Var', (223, 230))	('PC', 'Chemical', '-', (213, 215))	('polyunsaturated PCs', 'Chemical', '-', (23, 42))	('PC(36:6', 'Var', (236, 243))	('PC', 'Chemical', '-', (223, 225))	('PC(32:2', 'Var', (203, 210))	('decrease', 'NegReg', (141, 149))	('patients', 'Species', '9606', (86, 94))
454197	27852700	We find that both primary and recurrent ASCC tumors harbor mutations in genes such as PIK3CA and FBXW7 that are also mutated in other HPV-associated cancers.	('cancers', 'Disease', (149, 156))	('cancers', 'Phenotype', 'HP:0002664', (149, 156))	('ASCC tumors', 'Disease', (40, 51))	('HPV', 'Species', '10566', (134, 137))	('ASCC tumors', 'Disease', 'MESH:D009369', (40, 51))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('PIK3CA', 'Gene', (86, 92))	('FBXW7', 'Gene', '55294', (97, 102))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('mutations', 'Var', (59, 68))	('PIK3CA', 'Gene', '5290', (86, 92))	('FBXW7', 'Gene', (97, 102))	('cancers', 'Disease', 'MESH:D009369', (149, 156))
454199	27852700	In two cases, clonally related pre- and post-CRT tumors harbored distinct oncogenic driver mutations in the same cancer gene (KRAS or FBXW7).	('KRAS', 'Gene', '3845', (126, 130))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('FBXW7', 'Gene', (134, 139))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('cancer', 'Disease', (113, 119))	('tumors', 'Disease', (49, 55))	('mutations', 'Var', (91, 100))	('tumors', 'Disease', 'MESH:D009369', (49, 55))	('pre-', 'Disease', (31, 35))	('FBXW7', 'Gene', '55294', (134, 139))	('KRAS', 'Gene', (126, 130))
454200	27852700	A patient with recurrent disease achieved an exceptional response to anti-Programmed Death (PD-1) therapy, and genomic dissection revealed high mutational burden and predicted neoantigen load.	('mutational', 'Var', (144, 154))	('patient', 'Species', '9606', (2, 9))	('neoantigen load', 'MPA', (176, 191))
454208	27852700	Targeted sequencing of known cancer genes has revealed mutations in EGFR, KRAS, and PIK3CA, and a recent study using a combination of targeted sequencing and immunohistochemistry (IHC) revealed high levels of EGFR expression and frequent mutations in the PIK3CA/AKT pathway.	('PIK3CA', 'Gene', '5290', (84, 90))	('cancer', 'Disease', (29, 35))	('EGFR', 'Gene', (209, 213))	('mutations', 'Var', (55, 64))	('AKT', 'Gene', (262, 265))	('AKT', 'Gene', '207', (262, 265))	('EGFR', 'Gene', '1956', (209, 213))	('PIK3CA', 'Gene', (255, 261))	('mutations', 'Reg', (238, 247))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('KRAS', 'Gene', (74, 78))	('EGFR', 'Gene', '1956', (68, 72))	('PIK3CA', 'Gene', '5290', (255, 261))	('PIK3CA', 'Gene', (84, 90))	('KRAS', 'Gene', '3845', (74, 78))	('EGFR', 'Gene', (68, 72))	('cancer', 'Disease', 'MESH:D009369', (29, 35))	('expression', 'MPA', (214, 224))
454214	27852700	An additional novel filtering technique utilizing the COSMIC (version 75) database of somatic mutations in cancer and the ExAC database of 60,000 germline samples was applied to the extension cohort in an attempt to remove additional germline events (Supplementary Methods).	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('cancer', 'Disease', (107, 113))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('mutations', 'Var', (94, 103))
454215	27852700	Probability distributions of possible cancer cell fractions (CCFs) of point mutations were calculated based on local copy-number and the estimated sample purity.	('point mutations', 'Var', (70, 85))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('cancer', 'Disease', (38, 44))
454235	27852700	Among the thirteen primary tumors in the pilot cohort, four (31%) had a missense mutation in FBXW7, an E3 ubiquitin ligase that targets known oncoproteins such as c-Myc and cyclin E and is significantly mutated in multiple tumor types.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('Myc', 'Gene', '4609', (165, 168))	('multiple tumor', 'Disease', (214, 228))	('Myc', 'Gene', (165, 168))	('missense mutation', 'Var', (72, 89))	('multiple tumor', 'Disease', 'MESH:D009369', (214, 228))	('FBXW7', 'Gene', '55294', (93, 98))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('primary tumors', 'Disease', (19, 33))	('FBXW7', 'Gene', (93, 98))	('cyclin E', 'Protein', (173, 181))	('primary tumors', 'Disease', 'MESH:D009369', (19, 33))
454236	27852700	All four FBXW7 missense mutations occurred at conserved arginines that play a role in substrate binding and are known mutational hotspots.	('binding', 'Interaction', (96, 103))	('FBXW7', 'Gene', '55294', (9, 14))	('role', 'Reg', (78, 82))	('arginines', 'Chemical', 'MESH:D001120', (56, 65))	('missense mutations', 'Var', (15, 33))	('occurred', 'Reg', (34, 42))	('FBXW7', 'Gene', (9, 14))
454237	27852700	We also noted multiple events in other squamous cell carcinoma genes, including known activating mutations in PIK3CA, alterations in the KEAP-1 binding domain of NFE2L2, and mutations in TP63 and EP300, genes involved in squamous cell differentiation (Fig.	('mutations', 'Var', (97, 106))	('TP63', 'Gene', (187, 191))	('TP63', 'Gene', '8626', (187, 191))	('NFE2L2', 'Gene', (162, 168))	('alterations', 'Var', (118, 129))	('EP300', 'Gene', '2033', (196, 201))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (39, 62))	('activating', 'PosReg', (86, 96))	('EP300', 'Gene', (196, 201))	('squamous cell carcinoma', 'Disease', (39, 62))	('carcinoma', 'Phenotype', 'HP:0030731', (53, 62))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (39, 62))	('mutations', 'Var', (174, 183))	('PIK3CA', 'Gene', (110, 116))	('NFE2L2', 'Gene', '4780', (162, 168))	('PIK3CA', 'Gene', '5290', (110, 116))
454238	27852700	In addition, activating MAPK1 and inactivating PTEN mutations were noted in individual cases.	('mutations', 'Var', (52, 61))	('activating', 'PosReg', (13, 23))	('MAPK1', 'Gene', (24, 29))	('PTEN', 'Gene', (47, 51))	('PTEN', 'Gene', '5728', (47, 51))	('inactivating', 'NegReg', (34, 46))	('MAPK1', 'Gene', '5594', (24, 29))
454239	27852700	Interestingly, the single HPV negative case did not have a TP53 mutation, whereas two of the 11 HPV positive cases harbored TP53 mutations.	('HPV', 'Species', '10566', (96, 99))	('TP53', 'Gene', '7157', (124, 128))	('mutation', 'Var', (64, 72))	('TP53', 'Gene', (59, 63))	('TP53', 'Gene', (124, 128))	('HPV', 'Species', '10566', (26, 29))	('TP53', 'Gene', '7157', (59, 63))
454242	27852700	In the combined (pilot plus extension) cohort, 10 of 31 tumors (32%) harbored a PIK3CA mutation, similar to the rate reported in recent targeted sequencing studies.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumors', 'Disease', (56, 62))	('harbored', 'Reg', (69, 77))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('PIK3CA', 'Gene', (80, 86))	('PIK3CA', 'Gene', '5290', (80, 86))	('mutation', 'Var', (87, 95))
454246	27852700	There was a trend towards increased frequency of EP300 mutations in tumors that did not recur during follow-up (3/14 vs 0/17, p=0.08) and increased frequency of FBXW7 mutations in tumors that did recur (5/17 vs 1/14, p=0.18).	('FBXW7', 'Gene', '55294', (161, 166))	('tumors', 'Disease', (68, 74))	('FBXW7', 'Gene', (161, 166))	('tumors', 'Disease', 'MESH:D009369', (68, 74))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('tumors', 'Phenotype', 'HP:0002664', (180, 186))	('mutations', 'Var', (167, 176))	('EP300', 'Gene', (49, 54))	('EP300', 'Gene', '2033', (49, 54))	('tumors', 'Disease', (180, 186))	('tumors', 'Disease', 'MESH:D009369', (180, 186))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))
454247	27852700	Analysis of both pilot and extension cohorts revealed frequent chromosome 3q amplification, an event that has previously been reported in HPV-associated malignancies and is associated with progression from dysplasia to invasive disease in both anal and cervical squamous cell carcinomas (Supplementary Fig.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (262, 285))	('carcinoma', 'Phenotype', 'HP:0030731', (276, 285))	('dysplasia to invasive disease', 'Disease', 'MESH:D009362', (206, 235))	('malignancies', 'Disease', (153, 165))	('HPV', 'Species', '10566', (138, 141))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (262, 286))	('dysplasia to invasive disease', 'Disease', (206, 235))	('carcinomas', 'Phenotype', 'HP:0030731', (276, 286))	('associated with', 'Reg', (173, 188))	('squamous cell carcinomas', 'Disease', (262, 286))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (262, 286))	('malignancies', 'Disease', 'MESH:D009369', (153, 165))	('chromosome 3q amplification', 'Var', (63, 90))	('anal', 'Disease', (244, 248))
454256	27852700	Four of the six recurrent HPV negative tumors harbored a TP53 mutation, whereas only one of the 22 HPV positive recurrent tumors had a TP53 mutation (p=0.003, Fisher's exact test).	('tumors', 'Phenotype', 'HP:0002664', (122, 128))	('tumors', 'Disease', (122, 128))	('tumors', 'Disease', 'MESH:D009369', (122, 128))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('negative', 'NegReg', (30, 38))	('TP53', 'Gene', '7157', (135, 139))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('mutation', 'Var', (62, 70))	('TP53', 'Gene', (135, 139))	('HPV', 'Species', '10566', (26, 29))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('TP53', 'Gene', '7157', (57, 61))	('TP53', 'Gene', (57, 61))	('HPV', 'Species', '10566', (99, 102))	('tumors', 'Disease', (39, 45))
454257	27852700	One TP53-mutated tumor had a nonsense mutation in CDKN2A, an event frequently observed in TP53-mutated, HPV-negative head and neck SCC.	('CDKN2A', 'Gene', (50, 56))	('nonsense mutation', 'Var', (29, 46))	('tumor', 'Disease', (17, 22))	('HPV', 'Species', '10566', (104, 107))	('TP53', 'Gene', (4, 8))	('TP53', 'Gene', '7157', (90, 94))	('TP53', 'Gene', (90, 94))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('TP53', 'Gene', '7157', (4, 8))
454259	27852700	In most cases, primary-recurrent pairs had mutations and copy number alterations that were shared as well as events that were unique to either the primary or recurrent tumor (Supplementary Fig.	('tumor', 'Disease', (168, 173))	('mutations', 'Var', (43, 52))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('copy number alterations', 'Var', (57, 80))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
454260	27852700	However, in order to further characterize genomic evolution in the context of CRT, we used sample purity and local copy-number data from ABSOLUTE to calculate the cancer cell fraction (CCF) of point mutations and generate sibling models for patient-matched pre- and post-CRT tumors from the pilot cohort (n = 5; Methods).	('tumor', 'Phenotype', 'HP:0002664', (275, 280))	('tumors', 'Disease', (275, 281))	('patient', 'Species', '9606', (241, 248))	('tumors', 'Phenotype', 'HP:0002664', (275, 281))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('tumors', 'Disease', 'MESH:D009369', (275, 281))	('cancer', 'Disease', (163, 169))	('cancer', 'Disease', 'MESH:D009369', (163, 169))	('point mutations', 'Var', (193, 208))
454268	27852700	In two of the primary-recurrent pairs, we observed distinct mutations in a single cancer gene in phylogenetically-related primary and recurrent tumors.	('tumors', 'Disease', (144, 150))	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('tumors', 'Disease', 'MESH:D009369', (144, 150))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('mutations', 'Var', (60, 69))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))
454272	27852700	Similarly, in another primary-recurrent tumor pair (AC-P12), one FBXW7 hotspot mutation (R465C) in the primary tumor was replaced by a different FBXW7 hotspot mutation (R505G) in the recurrent tumor (Fig.	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('R465C', 'Mutation', 'rs867384286', (89, 94))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('FBXW7', 'Gene', '55294', (65, 70))	('FBXW7', 'Gene', '55294', (145, 150))	('primary tumor', 'Disease', 'MESH:D009369', (103, 116))	('tumor', 'Disease', (193, 198))	('P12', 'Gene', '56655', (55, 58))	('primary tumor', 'Disease', (103, 116))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('tumor', 'Disease', (111, 116))	('P12', 'Gene', (55, 58))	('tumor', 'Disease', (40, 45))	('R465C', 'Var', (89, 94))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('R505G', 'Mutation', 'rs149680468', (169, 174))	('FBXW7', 'Gene', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('R505G', 'Var', (169, 174))	('FBXW7', 'Gene', (145, 150))
454274	27852700	In addition, there were examples in which a recurrent tumor harbored a putative driver mutation in a gene that was not mutated in the primary tumor.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('primary tumor', 'Disease', 'MESH:D009369', (134, 147))	('tumor', 'Disease', (142, 147))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('gene', 'Gene', (101, 105))	('tumor', 'Disease', (54, 59))	('mutation', 'Var', (87, 95))	('primary tumor', 'Disease', (134, 147))
454275	27852700	For example, a novel KEAP1 mutation was observed in a recurrent KRAS mutated tumor (Fig.	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('KRAS', 'Gene', (64, 68))	('mutation', 'Var', (27, 35))	('KEAP1', 'Gene', (21, 26))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('KRAS', 'Gene', '3845', (64, 68))	('tumor', 'Disease', (77, 82))	('KEAP1', 'Gene', '9817', (21, 26))
454276	27852700	Activation of the NRF2 pathway by mutation of NFE2L2 or KEAP1 suppresses reactive oxygen species (ROS)-mediated cellular damage, particularly in KRAS-mutated tumors, and is associated with poor response to chemotherapy in lung squamous cell cancer.	('tumors', 'Phenotype', 'HP:0002664', (158, 164))	('ROS', 'Chemical', 'MESH:D017382', (98, 101))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('tumors', 'Disease', (158, 164))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (73, 96))	('NRF2', 'Gene', '4780', (18, 22))	('NFE2L2', 'Gene', (46, 52))	('KEAP1', 'Gene', '9817', (56, 61))	('mutation', 'Var', (34, 42))	('KRAS', 'Gene', '3845', (145, 149))	('KEAP1', 'Gene', (56, 61))	('NRF2', 'Gene', (18, 22))	('tumors', 'Disease', 'MESH:D009369', (158, 164))	('KRAS', 'Gene', (145, 149))	('Activation', 'PosReg', (0, 10))	('suppresses', 'NegReg', (62, 72))	('lung squamous cell cancer', 'Disease', 'MESH:D002294', (222, 247))	('lung squamous cell cancer', 'Disease', (222, 247))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (227, 247))	('NFE2L2', 'Gene', '4780', (46, 52))
454282	27852700	Given that DNA damage-induced somatic mutations can result in novel cancer-specific neoantigens, we used patient-specific non-synonymous mutations and HLA types to predict putative immunogenic neoantigens for matched primary and recurrent tumors from the pilot cohort (Methods, Supplementary Information).	('tumors', 'Disease', (239, 245))	('patient', 'Species', '9606', (105, 112))	('tumors', 'Disease', 'MESH:D009369', (239, 245))	('tumors', 'Phenotype', 'HP:0002664', (239, 245))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('neoantigens', 'MPA', (84, 95))	('tumor', 'Phenotype', 'HP:0002664', (239, 244))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('cancer', 'Disease', (68, 74))	('mutations', 'Var', (38, 47))	('result in', 'Reg', (52, 61))
454285	27852700	However, in one case (AC-P-04), the recurrent tumor harbored significantly more mutations and neoantigens than the primary tumor, and this difference was contributed almost entirely by mutations attributed to the unique mutational signature (Supplementary Fig.	('primary tumor', 'Disease', 'MESH:D009369', (115, 128))	('tumor', 'Disease', (123, 128))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Disease', (46, 51))	('AC-P-04', 'Chemical', '-', (22, 29))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('primary tumor', 'Disease', (115, 128))	('mutations', 'MPA', (80, 89))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('mutations', 'Var', (185, 194))	('neoantigens', 'MPA', (94, 105))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
454291	27852700	Analysis of the primary tumor from the patient revealed missense mutations in PIK3CA, PIK3CB, and ERBB2 (Fig.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('primary tumor', 'Disease', 'MESH:D009369', (16, 29))	('PIK3CA', 'Gene', (78, 84))	('ERBB2', 'Gene', '2064', (98, 103))	('patient', 'Species', '9606', (39, 46))	('ERBB2', 'Gene', (98, 103))	('PIK3CB', 'Gene', (86, 92))	('PIK3CA', 'Gene', '5290', (78, 84))	('missense mutations', 'Var', (56, 74))	('PIK3CB', 'Gene', '5291', (86, 92))	('primary tumor', 'Disease', (16, 29))
454292	27852700	The overall mutational burden and predicted neoantigens were higher than all but one other tumor in the pilot cohort, but this difference was not statistically significant (Fig.	('higher', 'PosReg', (61, 67))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('mutational', 'Var', (12, 22))	('neoantigens', 'MPA', (44, 55))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor', 'Disease', (91, 96))
454297	27852700	TP53 mutations were significantly more common in HPV negative tumors, and HPV negative tumors were enriched among recurrent cases.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('HPV', 'Species', '10566', (49, 52))	('tumors', 'Disease', (62, 68))	('tumors', 'Disease', 'MESH:D009369', (62, 68))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('mutations', 'Var', (5, 14))	('common', 'Reg', (39, 45))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('HPV', 'Species', '10566', (74, 77))	('tumors', 'Disease', (87, 93))	('HPV', 'Disease', (49, 52))	('negative', 'NegReg', (53, 61))	('tumors', 'Disease', 'MESH:D009369', (87, 93))
454303	27852700	One notable exception was AC-P04, a case in which the recurrent tumor had significantly higher mutational burden than the primary tumor and emergence of a novel mutational signature characterized by C>A transversions.	('higher', 'PosReg', (88, 94))	('primary tumor', 'Disease', 'MESH:D009369', (122, 135))	('tumor', 'Disease', (64, 69))	('mutational burden', 'MPA', (95, 112))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('C>A transversions', 'Var', (199, 216))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('AC-P04', 'Chemical', '-', (26, 32))	('primary tumor', 'Disease', (122, 135))	('tumor', 'Disease', (130, 135))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
454307	27852700	In several cases, we observed interesting patterns of evolution among driver mutations in pre- and post-CRT tumors.	('pre-', 'Disease', (90, 94))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('mutations', 'Var', (77, 86))	('tumors', 'Disease', 'MESH:D009369', (108, 114))	('tumors', 'Disease', (108, 114))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))
454324	32635458	High glycolysis tumors exhibited specific driver genes altered by copy number aberrations (CNAs) in most cancer types.	('High glycolysis tumors', 'Disease', (0, 22))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('altered', 'Reg', (55, 62))	('High glycolysis tumors', 'Disease', 'MESH:C564972', (0, 22))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('copy number aberrations', 'Var', (66, 89))
454328	32635458	Our study provides a comprehensive molecular-level understanding of glycolysis with a large sample data and demonstrates the hypoxia pressure, growth signals, oncogene mutation and other potential signals could activate glycolysis, thereby to regulate cell cycle, energy material synthesis, cell proliferation and cancer progression.	('oncogene', 'Gene', (159, 167))	('cell proliferation', 'CPA', (291, 309))	('regulate', 'Reg', (243, 251))	('cancer', 'Disease', (314, 320))	('energy material synthesis', 'MPA', (264, 289))	('cancer', 'Phenotype', 'HP:0002664', (314, 320))	('hypoxia pressure', 'Disease', 'MESH:D006973', (125, 141))	('mutation', 'Var', (168, 176))	('cell cycle', 'CPA', (252, 262))	('hypoxia pressure', 'Disease', (125, 141))	('activate', 'PosReg', (211, 219))	('glycolysis', 'MPA', (220, 230))	('cancer', 'Disease', 'MESH:D009369', (314, 320))
454336	32635458	A crucial results underlying such condition in a highly hypoxia tumor microenvironment (TME) is metabolic reprogramming of tumor cells, such as, glycolysis is an adaptation to this low oxygen pressure microenvironment for activation by hypoxia-inducible factor 1 subunit alpha (HIF1A) which can stimulate glycolytic by transactivation genes involved in SLC2A1 and ALDOA.	('stimulate', 'PosReg', (295, 304))	('HIF1A', 'Gene', (278, 283))	('glycolytic', 'MPA', (305, 315))	('low oxygen pressure', 'Phenotype', 'HP:0012418', (181, 200))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('transactivation', 'Var', (319, 334))	('tumor', 'Disease', (123, 128))	('hypoxia tumor', 'Disease', (56, 69))	('SLC2A1', 'Gene', '6513', (353, 359))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('hypoxia', 'Disease', (56, 63))	('hypoxia', 'Disease', (236, 243))	('HIF1A', 'Gene', '3091', (278, 283))	('hypoxia tumor', 'Disease', 'MESH:D000860', (56, 69))	('ALDOA', 'Gene', (364, 369))	('hypoxia', 'Disease', 'MESH:D000860', (56, 63))	('SLC2A1', 'Gene', (353, 359))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('hypoxia', 'Disease', 'MESH:D000860', (236, 243))	('ALDOA', 'Gene', '226', (364, 369))	('tumor', 'Disease', (64, 69))	('oxygen', 'Chemical', 'MESH:D010100', (185, 191))	('tumor', 'Disease', 'MESH:D009369', (64, 69))
454349	32635458	Furthermore, it provides the theoretical basis for understanding critical roles of metabolic alteration, which is the evolutionary choice to resist the pressure from the external environment and cancer cell proliferation in cancer progression and suggests a framework to guide therapeutic optimization to block the glycolysis and control tumor progression.	('metabolic', 'MPA', (83, 92))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('tumor', 'Phenotype', 'HP:0002664', (338, 343))	('cancer', 'Disease', (195, 201))	('tumor', 'Disease', (338, 343))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('glycolysis', 'MPA', (315, 325))	('cancer', 'Disease', 'MESH:D009369', (224, 230))	('block', 'NegReg', (305, 310))	('cancer', 'Disease', (224, 230))	('alteration', 'Var', (93, 103))	('tumor', 'Disease', 'MESH:D009369', (338, 343))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
454370	32635458	p < 10-10) and reduced CDH1 mutations (adj.	('reduced', 'NegReg', (15, 22))	('CDH1', 'Gene', (23, 27))	('mutations', 'Var', (28, 37))	('CDH1', 'Gene', '999', (23, 27))
454372	32635458	High glycolysis tumors in UCEC were associated with MUC16, PTEN and TTN mutations (adj.	('TTN', 'Gene', (68, 71))	('mutations', 'Var', (72, 81))	('MUC16', 'Gene', (52, 57))	('High glycolysis tumors', 'Disease', (0, 22))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('High glycolysis tumors', 'Disease', 'MESH:C564972', (0, 22))	('TTN', 'Gene', '7273', (68, 71))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('MUC16', 'Gene', '94025', (52, 57))	('associated', 'Reg', (36, 46))	('PTEN', 'Gene', (59, 63))	('PTEN', 'Gene', '5728', (59, 63))
454373	32635458	Besides, alterations in other gene mutations were also associated with glycolysis in other cancer types, for example, higher PIK3CA mutation event was found in glycolysis-high group of COAD (adj.	('higher', 'PosReg', (118, 124))	('COAD', 'Disease', (185, 189))	('glycolysis-high group', 'Disease', (160, 181))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('associated', 'Reg', (55, 65))	('PIK3CA', 'Gene', (125, 131))	('alterations', 'Var', (9, 20))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('COAD', 'Disease', 'MESH:D029424', (185, 189))	('PIK3CA', 'Gene', '5290', (125, 131))	('mutation', 'Var', (132, 140))
454375	32635458	p = 10-2, respectively); TTN mutation was found in high glycolysis group of STAD (adj.	('mutation', 'Var', (29, 37))	('TTN', 'Gene', (25, 28))	('TTN', 'Gene', '7273', (25, 28))	('high glycolysis', 'MPA', (51, 66))
454376	32635458	High glycolysis tumors were more likely to harbor loss of RBL1 in COAD (adj.	('High glycolysis tumors', 'Disease', (0, 22))	('RBL1', 'Gene', (58, 62))	('High glycolysis tumors', 'Disease', 'MESH:C564972', (0, 22))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('COAD', 'Disease', (66, 70))	('loss', 'Var', (50, 54))	('RBL1', 'Gene', '5933', (58, 62))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('COAD', 'Disease', 'MESH:D029424', (66, 70))
454378	32635458	p < 10-2), loss of AOX1 in HNSC, loss of ERBB4 in LUSC (adj.	('AOX1', 'Gene', '316', (19, 23))	('loss', 'Var', (11, 15))	('loss', 'NegReg', (33, 37))	('LUSC', 'Phenotype', 'HP:0030359', (50, 54))	('ERBB4', 'Gene', '2066', (41, 46))	('AOX1', 'Gene', (19, 23))	('HNSC', 'Phenotype', 'HP:0012288', (27, 31))	('ERBB4', 'Gene', (41, 46))
454388	32635458	High glycolysis samples had significantly increased TMB in 11 cancer types, such as BRCA, STAD and UCEC (Figure S2c).	('increased', 'PosReg', (42, 51))	('TMB', 'MPA', (52, 55))	('High', 'Var', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('STAD', 'Disease', (90, 94))	('UCEC', 'Disease', (99, 103))	('BRCA', 'Phenotype', 'HP:0003002', (84, 88))	('TMB', 'Chemical', '-', (52, 55))	('cancer', 'Disease', (62, 68))	('BRCA', 'Gene', '672', (84, 88))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('BRCA', 'Gene', (84, 88))
454393	32635458	As expected, tumor cell proliferation signature score was positively correlated with glycolysis score in 23 cancer types (r = 0.11~0.67) (Figure 3b, Table S6), implying that the high glycolysis tumor is characterized by a high proliferation rate.	('tumor', 'Disease', (13, 18))	('glycolysis score', 'MPA', (85, 101))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('glycolysis tumor', 'Disease', (183, 199))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('cancer', 'Disease', 'MESH:D009369', (108, 114))	('tumor', 'Disease', (194, 199))	('high', 'Var', (178, 182))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('cancer', 'Disease', (108, 114))	('glycolysis tumor', 'Disease', 'MESH:C564972', (183, 199))
454410	32635458	Here, we also found the positive correlation between single HIF1A expression and glycolysis score in 18 cancer types (r = 0.17 ~ 0.52, p < 0.05), such as r = 0.45 in LUAD (Figure 4d, Figure S5c).	('HIF1A', 'Gene', (60, 65))	('HIF1A', 'Gene', '3091', (60, 65))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('glycolysis score', 'MPA', (81, 97))	('LUAD', 'Disease', (166, 170))	('expression', 'MPA', (66, 76))	('LUAD', 'Phenotype', 'HP:0030078', (166, 170))	('single', 'Var', (53, 59))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))
454426	32635458	The highest glycolysis score, LDHA and PGK1 mRNA abundance were observed under high hypoxia and high P4HA1 expression in some cancer types (Figure 6c, Figure S7c, Table S10).	('hypoxia', 'Disease', (84, 91))	('LDHA', 'Gene', (30, 34))	('hypoxia', 'Disease', 'MESH:D000860', (84, 91))	('LDHA', 'Gene', '3939', (30, 34))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('P4HA1', 'Gene', '5033', (101, 106))	('mRNA abundance', 'MPA', (44, 58))	('expression', 'MPA', (107, 117))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('PGK1', 'Gene', '5230', (39, 43))	('PGK1', 'Gene', (39, 43))	('highest', 'PosReg', (4, 11))	('high', 'Var', (96, 100))	('glycolysis score', 'MPA', (12, 28))	('S7', 'Gene', '6264', (158, 160))	('P4HA1', 'Gene', (101, 106))
454428	32635458	The highest glycolysis score, PGK1 and PGAM1 mRNA abundance were observed under high hypoxia and high HSPA8 expression across cancer types (Figure 6d, Figure S7d, Table S10).	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('HSPA8', 'Gene', (102, 107))	('hypoxia', 'Disease', 'MESH:D000860', (85, 92))	('hypoxia', 'Disease', (85, 92))	('HSPA8', 'Gene', '3312', (102, 107))	('PGAM1', 'Gene', (39, 44))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('highest', 'PosReg', (4, 11))	('PGAM1', 'Gene', '5223', (39, 44))	('expression', 'MPA', (108, 118))	('PGK1', 'Gene', '5230', (30, 34))	('PGK1', 'Gene', (30, 34))	('mRNA abundance', 'MPA', (45, 59))	('S7', 'Gene', '6264', (158, 160))	('high', 'Var', (97, 101))	('glycolysis score', 'MPA', (12, 28))
454442	32635458	This identified P4HA1 and HSPA8 as candidate factors underlying gene expression differences in glycolysis-high and -low tumor cells and in other TME stromal cells, respectively, seemed responsible for tumor-specific cell glycolysis phenotypes in hypoxia microenvironment.	('hypoxia', 'Disease', (246, 253))	('hypoxia', 'Disease', 'MESH:D000860', (246, 253))	('HSPA8', 'Gene', (26, 31))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('HSPA8', 'Gene', '3312', (26, 31))	('differences', 'Var', (80, 91))	('low tumor', 'Disease', 'MESH:D009800', (116, 125))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('P4HA1', 'Gene', '5033', (16, 21))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('low tumor', 'Disease', (116, 125))	('tumor', 'Disease', (201, 206))	('glycolysis-high', 'MPA', (95, 110))	('tumor', 'Disease', (120, 125))	('P4HA1', 'Gene', (16, 21))
454443	32635458	For this, our findings support the model that cancer cells favor glycolysis under hypoxia pressure, growth signals, as well as oncogene mutation, which is an important biological process that active cell cycle and promote cancer cell proliferation.	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('promote', 'PosReg', (214, 221))	('cancer', 'Disease', 'MESH:D009369', (222, 228))	('cancer', 'Disease', (46, 52))	('mutation', 'Var', (136, 144))	('cancer', 'Disease', (222, 228))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('hypoxia pressure', 'Disease', 'MESH:D006973', (82, 98))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('oncogene', 'Gene', (127, 135))	('favor', 'PosReg', (59, 64))	('glycolysis', 'MPA', (65, 75))	('hypoxia pressure', 'Disease', (82, 98))
454466	32635458	In the present study, amplification in MYC and AKT1 show a strong consistency with transcript levels and glycolysis-high tumors harbor increased MYC and AKT1 expression, suggesting that AKT1 and MYC activation contribute the glycolytic activation in some cancer type.	('MYC', 'Gene', (195, 198))	('MYC', 'Gene', (145, 148))	('MYC', 'Gene', '4609', (39, 42))	('amplification', 'Var', (22, 35))	('glycolysis-high tumors', 'Disease', 'MESH:C564972', (105, 127))	('cancer', 'Disease', (255, 261))	('glycolytic activation', 'MPA', (225, 246))	('AKT1', 'Gene', (47, 51))	('cancer', 'Phenotype', 'HP:0002664', (255, 261))	('AKT1', 'Gene', '207', (186, 190))	('MYC', 'Gene', '4609', (195, 198))	('MYC', 'Gene', '4609', (145, 148))	('glycolysis-high tumors', 'Disease', (105, 127))	('expression', 'MPA', (158, 168))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('AKT1', 'Gene', '207', (153, 157))	('cancer', 'Disease', 'MESH:D009369', (255, 261))	('AKT1', 'Gene', (186, 190))	('MYC', 'Gene', (39, 42))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('increased', 'PosReg', (135, 144))	('AKT1', 'Gene', (153, 157))	('AKT1', 'Gene', '207', (47, 51))
454467	32635458	Oncogenes including KRAS, TP53, PIK3CA, TTN, CDH1 and MUC16 may be considered glycolysis-associated utations, as they mutated in glycolysis-high tumors.	('TP53', 'Gene', (26, 30))	('glycolysis-high tumors', 'Disease', (129, 151))	('TTN', 'Gene', (40, 43))	('PIK3CA', 'Gene', '5290', (32, 38))	('KRAS', 'Gene', '3845', (20, 24))	('TTN', 'Gene', '7273', (40, 43))	('MUC16', 'Gene', '94025', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('CDH1', 'Gene', '999', (45, 49))	('mutated', 'Var', (118, 125))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('CDH1', 'Gene', (45, 49))	('MUC16', 'Gene', (54, 59))	('glycolysis-high tumors', 'Disease', 'MESH:C564972', (129, 151))	('TP53', 'Gene', '7157', (26, 30))	('KRAS', 'Gene', (20, 24))	('PIK3CA', 'Gene', (32, 38))
454468	32635458	Previous research has confirmed that KRAS, TP53, PIK3CA and CDH1 mutations participate in regulation of glycolysis to affect cancer development.	('regulation', 'MPA', (90, 100))	('CDH1', 'Gene', '999', (60, 64))	('affect', 'Reg', (118, 124))	('TP53', 'Gene', '7157', (43, 47))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('participate', 'Reg', (75, 86))	('KRAS', 'Gene', (37, 41))	('PIK3CA', 'Gene', (49, 55))	('CDH1', 'Gene', (60, 64))	('PIK3CA', 'Gene', '5290', (49, 55))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('TP53', 'Gene', (43, 47))	('KRAS', 'Gene', '3845', (37, 41))	('glycolysis', 'MPA', (104, 114))	('mutations', 'Var', (65, 74))
454475	32635458	The previous authoritative study on hypoxia shows that TP53, TTN and CDH1 mutations as well as MYC amplification and PTEN deletion are associated with hypoxia, which is also observed in this study (Figure 2) and these molecular features may be the regulators to glycolysis and they may serve as an intermediate bridge linking hypoxia and upstream of glycolysis.	('hypoxia', 'Disease', 'MESH:D000860', (36, 43))	('PTEN', 'Gene', (117, 121))	('CDH1', 'Gene', '999', (69, 73))	('associated', 'Reg', (135, 145))	('CDH1', 'Gene', (69, 73))	('TP53', 'Gene', '7157', (55, 59))	('PTEN', 'Gene', '5728', (117, 121))	('hypoxia', 'Disease', (326, 333))	('MYC', 'Gene', (95, 98))	('hypoxia', 'Disease', (151, 158))	('hypoxia', 'Disease', 'MESH:D000860', (326, 333))	('TTN', 'Gene', '7273', (61, 64))	('hypoxia', 'Disease', 'MESH:D000860', (151, 158))	('TTN', 'Gene', (61, 64))	('MYC', 'Gene', '4609', (95, 98))	('hypoxia', 'Disease', (36, 43))	('TP53', 'Gene', (55, 59))	('mutations', 'Var', (74, 83))	('deletion', 'Var', (122, 130))
454483	32635458	ROS-mediated direct oxidation of Cys (358) on PKM2 could decrease its activity and divert glucose flux into the pentose phosphate pathway and thereby allow cancer cells to withstand oxidative stress and support cell survival.	('Cys (358', 'Var', (33, 41))	('decrease', 'NegReg', (57, 65))	('glucose', 'Chemical', 'MESH:D005947', (90, 97))	('stress', 'Disease', (192, 198))	('allow', 'Reg', (150, 155))	('cancer', 'Disease', (156, 162))	('activity', 'MPA', (70, 78))	('ROS', 'Chemical', 'MESH:D017382', (0, 3))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('oxidative stress', 'Phenotype', 'HP:0025464', (182, 198))	('divert', 'Reg', (83, 89))	('Cys', 'Chemical', 'MESH:D003545', (33, 36))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('glucose flux', 'MPA', (90, 102))	('PKM2', 'Gene', (46, 50))	('pentose phosphate', 'Chemical', 'MESH:D010428', (112, 129))	('PKM2', 'Gene', '5315', (46, 50))	('stress', 'Disease', 'MESH:D000079225', (192, 198))
454497	32635458	The Gene Expression Omnibus (GEO) data was downloaded from NCBI GEO dataset including GSE21217, GSE101644, GSE3188, GSE30979, GSE36562, GSE55935, GSE77307 and GSE75034 as validation data set.	('GSE77307', 'Var', (146, 154))	('GSE36562', 'Var', (126, 134))	('GSE3188', 'Chemical', '-', (107, 114))	('GSE3188', 'Var', (107, 114))	('GSE21217', 'Var', (86, 94))	('GSE55935', 'Var', (136, 144))	('GSE30979', 'Var', (116, 124))	('GSE101644', 'Var', (96, 105))
454510	32635458	Copy-number changes were associated with glycolysis activity by a comparison of glycolysis scores between tumors that were copy-number neutral to those with a copy-number gain (or to those with a loss; T test).	('gain', 'PosReg', (171, 175))	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('glycolysis scores', 'MPA', (80, 97))	('associated', 'Reg', (25, 35))	('copy-number neutral', 'Var', (123, 142))	('tumors', 'Disease', (106, 112))	('Copy-number changes', 'Var', (0, 19))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('copy-number', 'Var', (159, 170))	('glycolysis activity', 'MPA', (41, 60))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))
454511	32635458	For each gene with SNV data, glycolysis scores were compared between tumors with a nonsynonymous mutation or without (T test).	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('glycolysis scores', 'MPA', (29, 46))	('compared', 'Reg', (52, 60))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('tumors', 'Disease', 'MESH:D009369', (69, 75))	('tumors', 'Disease', (69, 75))	('nonsynonymous mutation', 'Var', (83, 105))
454515	32635458	For each oncogene, differences in glycolysis scores were compared between tumors that were copy-number neutral and those with a copy-number gain.	('copy-number gain', 'Var', (128, 144))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('glycolysis scores', 'MPA', (34, 51))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('tumors', 'Disease', 'MESH:D009369', (74, 80))	('copy-number neutral', 'Var', (91, 110))	('tumors', 'Disease', (74, 80))
454516	32635458	For each tumor-suppressor gene, differences in glycolysis scores were compared between tumors that were copy-number neutral and those with a copy-number loss (T test).	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('glycolysis scores', 'MPA', (47, 64))	('copy-number loss', 'Var', (141, 157))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumor-suppressor', 'Gene', (9, 25))	('copy-number neutral', 'Var', (104, 123))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('tumors', 'Disease', (87, 93))	('tumor-suppressor', 'Gene', '7248', (9, 25))	('tumors', 'Disease', 'MESH:D009369', (87, 93))
454533	32635458	This work shows that the hypoxia pressure, growth signals, oncogene mutation and other potential signals could activate glycolysis, thereby to regulate cell cycle, energy material synthesis, cell proliferation and cancer progression.	('cancer', 'Disease', (214, 220))	('hypoxia pressure', 'Disease', 'MESH:D006973', (25, 41))	('mutation', 'Var', (68, 76))	('hypoxia pressure', 'Disease', (25, 41))	('energy material synthesis', 'MPA', (164, 189))	('regulate', 'Reg', (143, 151))	('glycolysis', 'MPA', (120, 130))	('activate', 'PosReg', (111, 119))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('cell proliferation', 'CPA', (191, 209))	('cell cycle', 'CPA', (152, 162))	('oncogene', 'Gene', (59, 67))	('cancer', 'Disease', 'MESH:D009369', (214, 220))
454573	31971663	The expression of HPV E6 and E7 oncoproteins and the inactivation of tumor suppressor genes can accelerate tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('HPV', 'Species', '10566', (18, 21))	('tumor', 'Disease', (69, 74))	('HPV', 'Gene', (18, 21))	('accelerate', 'PosReg', (96, 106))	('oncoproteins', 'Protein', (32, 44))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('inactivation', 'Var', (53, 65))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('E7 oncoproteins', 'Protein', (29, 44))
454575	31971663	Some scholars believe that high-risk HPV infection is also closely related to the occurrence of lung cancer due to the high affinity for HPV on squamous epithelium and major tissue types of bronchi and lung epithelium.3 HPV is the second most common cause of lung cancer after cigarette smoking9 and has been proven to be involved in human bronchioloalveolar carcinoma.	('lung cancer', 'Disease', (259, 270))	('lung cancer', 'Disease', 'MESH:D008175', (96, 107))	('lung cancer', 'Phenotype', 'HP:0100526', (259, 270))	('HPV', 'Species', '10566', (220, 223))	('epithelium.3 HPV', 'Var', (207, 223))	('cause', 'Reg', (250, 255))	('carcinoma', 'Phenotype', 'HP:0030731', (359, 368))	('bronchioloalveolar carcinoma', 'Disease', 'MESH:D002282', (340, 368))	('cancer', 'Phenotype', 'HP:0002664', (264, 270))	('lung cancer', 'Disease', 'MESH:D008175', (259, 270))	('human', 'Species', '9606', (334, 339))	('lung cancer', 'Disease', (96, 107))	('lung cancer', 'Phenotype', 'HP:0100526', (96, 107))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('HPV', 'Species', '10566', (37, 40))	('bronchioloalveolar carcinoma', 'Disease', (340, 368))	('HPV', 'Species', '10566', (137, 140))
454605	31971663	The specific types of HPV infection in the 13 positive cases were: four HPV16, three HPV42, two HPV18, two HPV51, one HPV44, and one multiple infection (HPV35, 42, 44).	('HPV', 'Species', '10566', (96, 99))	('multiple infection', 'Disease', 'MESH:D007239', (133, 151))	('HPV', 'Species', '10566', (153, 156))	('HPV42', 'Species', '10590', (85, 90))	('HPV', 'Species', '10566', (107, 110))	('HPV', 'Species', '10566', (118, 121))	('multiple infection', 'Disease', (133, 151))	('HPV16', 'Disease', (72, 77))	('HPV', 'Species', '10566', (22, 25))	('HPV', 'Species', '10566', (72, 75))	('HPV18', 'Var', (96, 101))	('HPV16', 'Species', '333760', (72, 77))	('HPV35', 'Species', '10587', (153, 158))	('HPV', 'Species', '10566', (85, 88))	('multiple infection', 'Phenotype', 'HP:0002719', (133, 151))	('HPV51', 'Var', (107, 112))
454607	31971663	The specific types of HPV infection in the 16 positive cases were: seven HPV16, four HPV18, three HPV42, one HPV6, and one multiple infection (HPV18, 33).	('HPV', 'Species', '10566', (143, 146))	('multiple infection', 'Disease', (123, 141))	('HPV', 'Species', '10566', (73, 76))	('HPV', 'Species', '10566', (98, 101))	('multiple infection', 'Disease', 'MESH:D007239', (123, 141))	('HPV', 'Species', '10566', (22, 25))	('multiple infection', 'Phenotype', 'HP:0002719', (123, 141))	('HPV18', 'Disease', (85, 90))	('HPV42', 'Species', '10590', (98, 103))	('HPV', 'Species', '10566', (109, 112))	('HPV16', 'Disease', (73, 78))	('HPV42', 'Var', (98, 103))	('HPV', 'Species', '10566', (85, 88))	('HPV16', 'Species', '333760', (73, 78))
454611	31971663	The chi2 test or Fisher's exact test showed no significant difference in the positive detection rates of HPV infection between the normal blood index and abnormal blood index groups.	('HPV', 'Gene', (105, 108))	('HPV', 'Species', '10566', (105, 108))	('abnormal', 'Var', (154, 162))
454621	31971663	Finally, the positive detection rate of HPV infection was higher in the low FRC and RV/TLC groups than in the high FRC and RV/TLC groups, respectively.	('low FRC', 'Var', (72, 79))	('RV/TLC', 'Disease', (84, 90))	('HPV', 'Species', '10566', (40, 43))	('higher', 'PosReg', (58, 64))	('HPV', 'Gene', (40, 43))
454624	31971663	Notably, HPV has a high degree of affinity to the squamous epithelial mucosa and can cause abnormal proliferation of the host mucosa.16 Therefore, HPV infection is likely to be closely related to the occurrence and development of primary lung cancer.	('cancer', 'Phenotype', 'HP:0002664', (243, 249))	('HPV', 'Gene', (147, 150))	('primary lung cancer', 'Disease', (230, 249))	('HPV', 'Species', '10566', (9, 12))	('primary lung cancer', 'Disease', 'MESH:D008175', (230, 249))	('lung cancer', 'Phenotype', 'HP:0100526', (238, 249))	('infection', 'Var', (151, 160))	('related to', 'Reg', (185, 195))	('HPV', 'Species', '10566', (147, 150))
454629	31971663	It has been reported that HPV infection is closely related to lung squamous cell carcinoma,25 and studies have also found that HPV-positive lung cancers were all lung adenocarcinoma.26 However, a meta-analysis27 showed that high-risk HPV infection was significantly associated with the risk of lung squamous cell cancer, but not with lung adenocarcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (344, 353))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('cancer', 'Phenotype', 'HP:0002664', (313, 319))	('lung cancers', 'Phenotype', 'HP:0100526', (140, 152))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('lung squamous cell cancer', 'Disease', 'MESH:D018307', (294, 319))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (162, 181))	('HPV', 'Species', '10566', (234, 237))	('lung adenocarcinoma', 'Disease', (162, 181))	('HPV', 'Species', '10566', (26, 29))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (334, 353))	('high-risk', 'Var', (224, 233))	('lung adenocarcinoma', 'Disease', (334, 353))	('lung squamous cell cancer', 'Disease', (294, 319))	('HPV', 'Gene', (234, 237))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (62, 90))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (299, 319))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (67, 90))	('lung squamous cell carcinoma', 'Disease', (62, 90))	('HPV', 'Species', '10566', (127, 130))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (162, 181))	('carcinoma', 'Phenotype', 'HP:0030731', (172, 181))	('associated', 'Reg', (266, 276))	('infection', 'Var', (238, 247))	('lung cancer', 'Phenotype', 'HP:0100526', (140, 151))	('lung cancers', 'Disease', 'MESH:D008175', (140, 152))	('lung squamous cell cancer', 'Phenotype', 'HP:0030359', (294, 319))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (334, 353))	('cancers', 'Phenotype', 'HP:0002664', (145, 152))	('lung cancers', 'Disease', (140, 152))
454631	31971663	The platelet count is usually elevated in patients with lung cancer and significantly higher than that in patients with benign lung disease.28 Our current study indicated that HPV infection increased the platelet count and platelet pressure in lung cancer patients.	('platelet pressure', 'MPA', (223, 240))	('benign lung disease', 'Disease', (120, 139))	('lung cancer', 'Disease', (56, 67))	('cancer', 'Phenotype', 'HP:0002664', (249, 255))	('lung cancer', 'Disease', (244, 255))	('pressure in lung', 'Phenotype', 'HP:0100598', (232, 248))	('platelet count', 'MPA', (204, 218))	('lung cancer', 'Disease', 'MESH:D008175', (56, 67))	('HPV', 'Species', '10566', (176, 179))	('increased the platelet count', 'Phenotype', 'HP:0001894', (190, 218))	('patients', 'Species', '9606', (106, 114))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('patients', 'Species', '9606', (42, 50))	('lung cancer', 'Phenotype', 'HP:0100526', (56, 67))	('benign lung disease', 'Disease', 'MESH:D008171', (120, 139))	('lung cancer', 'Disease', 'MESH:D008175', (244, 255))	('patients', 'Species', '9606', (256, 264))	('increased', 'PosReg', (190, 199))	('lung cancer', 'Phenotype', 'HP:0100526', (244, 255))	('HPV', 'Gene', (176, 179))	('infection', 'Var', (180, 189))
454634	31971663	The results of our current study suggest that HPV infection may affect lung function, resulting in relatively lower RV, FRC and RV/TLC values.	('affect lung function', 'Phenotype', 'HP:0005952', (64, 84))	('HPV', 'Species', '10566', (46, 49))	('lower', 'NegReg', (110, 115))	('lung function', 'MPA', (71, 84))	('HPV', 'Gene', (46, 49))	('affect', 'Reg', (64, 70))	('RV/TLC values', 'MPA', (128, 141))	('infection', 'Var', (50, 59))
454642	31971663	However, even if the number of HPV positive patients is low, there may be a tendency for HPV infection to affect platelet and residual lung function in primary lung cancer patients.	('HPV', 'Gene', (89, 92))	('primary lung cancer', 'Disease', 'MESH:D008175', (152, 171))	('HPV', 'Species', '10566', (31, 34))	('patients', 'Species', '9606', (44, 52))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('platelet', 'MPA', (113, 121))	('HPV', 'Species', '10566', (89, 92))	('lung cancer', 'Phenotype', 'HP:0100526', (160, 171))	('residual lung function', 'MPA', (126, 148))	('patients', 'Species', '9606', (172, 180))	('affect', 'Reg', (106, 112))	('infection', 'Var', (93, 102))	('primary lung cancer', 'Disease', (152, 171))
454799	28735527	In this group, all individuals had tumors diagnosed as pT2 or pT3, N0-N2 and M0 according to the TNM classification, and the second group had tumors diagnosed as pT2 or pT3, N0-N3 and M0 according to the pTNM classification (applied according to the guidelines from the American Joint Committee on Cancer staging manual) and received neoadjuvant chemoradiotherapy before surgery.	('TNM', 'Gene', (205, 208))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('pT3', 'Gene', '7694', (62, 65))	('Cancer', 'Phenotype', 'HP:0002664', (298, 304))	('tumors', 'Disease', 'MESH:D009369', (35, 41))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))	('pT3', 'Gene', (169, 172))	('tumors', 'Disease', (142, 148))	('N0-N2', 'Var', (67, 72))	('pT3', 'Gene', (62, 65))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('TNM', 'Gene', '10178', (97, 100))	('pT3', 'Gene', '7694', (169, 172))	('pT2', 'Var', (55, 58))	('tumors', 'Disease', 'MESH:D009369', (142, 148))	('TNM', 'Gene', (97, 100))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumors', 'Disease', (35, 41))	('TNM', 'Gene', '10178', (205, 208))
454905	27390594	Sections were incubated at 4 C for 24 h with primary antibodies including polyclonal antibody against anti-CPA4 (Sigma-Aldrich), anti-Survivin and anti-VEGF (Santa Cruz Inc., USA).	('CPA4', 'Gene', '51200', (107, 111))	('VEGF', 'Gene', (152, 156))	('CPA4', 'Gene', (107, 111))	('VEGF', 'Gene', '7422', (152, 156))	('anti-Survivin', 'Var', (129, 142))
454935	27390594	When classified according to histologic type of lung cancer, the serum levels of CPA4 were 2961+-814 pg/mL in lung squamous cell carcinoma (LSCC, n=52), and 2.866+-0.672 in lung Adenocarcinoma (AD, n=48), which were also higher than normal ones (Figure 4B).	('AD', 'Disease', 'MESH:D000544', (194, 196))	('lung Adenocarcinoma', 'Disease', 'MESH:D000077192', (173, 192))	('type of lung cancer', 'Disease', 'MESH:D008175', (40, 59))	('higher', 'PosReg', (221, 227))	('carcinoma', 'Phenotype', 'HP:0030731', (183, 192))	('CPA4', 'Gene', '51200', (81, 85))	('lung Adenocarcinoma', 'Phenotype', 'HP:0030078', (173, 192))	('2961+-814 pg/mL', 'Var', (91, 106))	('type of lung cancer', 'Disease', (40, 59))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (110, 138))	('lung squamous cell carcinoma', 'Disease', (110, 138))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('CPA4', 'Gene', (81, 85))	('lung cancer', 'Phenotype', 'HP:0100526', (48, 59))	('serum levels', 'MPA', (65, 77))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('AD', 'Disease', (194, 196))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (115, 138))	('lung Adenocarcinoma', 'Disease', (173, 192))
454942	27390594	As shown in Figure 4D, the AUCs of VEGF, Survivin, NSE, CYFRA21-1 and SCCA were 0.531 (95% CI: 0.445-0.618), 0.368 (95% CI: 0.287-0.450), 0.288 (95% CI: 0.214-0.362), 0.607 (95% CI: 0.522-0.692) and 0.493 (95% CI: 0.408-0.578), respectively.	('0.288', 'Var', (138, 143))	('VEGF', 'Gene', (35, 39))	('NSE', 'Gene', '2026', (51, 54))	('0.368', 'Var', (109, 114))	('VEGF', 'Gene', '7422', (35, 39))	('NSE', 'Gene', (51, 54))	('0.531', 'Var', (80, 85))
454963	27390594	Moreover, high CPA4 expression was significantly associated with for NSCLC patients, as an independent prognostic factor.	('expression', 'MPA', (20, 30))	('CPA4', 'Gene', '51200', (15, 19))	('NSCLC', 'Disease', (69, 74))	('associated', 'Reg', (49, 59))	('CPA4', 'Gene', (15, 19))	('patients', 'Species', '9606', (75, 83))	('NSCLC', 'Disease', 'MESH:D002289', (69, 74))	('high', 'Var', (10, 14))	('NSCLC', 'Phenotype', 'HP:0030358', (69, 74))
454970	27390594	We also found that combinations of CPA4 and CYFRA21-1 can improve diagnostic efficacy compared with a single marker, and area under the ROC curve (AUC) was increased to 0.830.	('CPA4', 'Gene', '51200', (35, 39))	('improve', 'PosReg', (58, 65))	('CPA4', 'Gene', (35, 39))	('combinations', 'Interaction', (19, 31))	('CYFRA21-1', 'Var', (44, 53))	('diagnostic efficacy', 'CPA', (66, 85))
455007	33936201	Also, we limited our analysis to stage IB-IIA patients and patients with stage IA2 were excluded for the prevalence of positive nodes, or pelvic wall recurrence is much lower in patients with stage IA2 cervical cancer than in patients with stage IB-IIA cervical cancer.	('IB-IIA cervical cancer', 'Disease', (246, 268))	('stage IA2', 'Var', (192, 201))	('cancer', 'Phenotype', 'HP:0002664', (262, 268))	('cervical cancer', 'Disease', (202, 217))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('IB-IIA cervical cancer', 'Disease', 'MESH:D002583', (246, 268))	('lower', 'NegReg', (169, 174))
455014	32493454	The low expression of miR-550a-3-5p correlated with higher tumor size and nodal metastasis of HPV-positive OSCC patients.	('tumor', 'Disease', (59, 64))	('miR-550a-3-5p', 'Chemical', '-', (22, 35))	('HPV', 'Species', '10566', (94, 97))	('patients', 'Species', '9606', (112, 120))	('low', 'NegReg', (4, 7))	('nodal metastasis', 'CPA', (74, 90))	('higher', 'PosReg', (52, 58))	('expression', 'MPA', (8, 18))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('miR-550a-3-5p', 'Var', (22, 35))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
455015	32493454	Then, we found that miR-550a-3-5p suppressed the migration, invasion and EMT of HPV-positive OSCC cells dependent on decreasing M2 macrophages polarization.	('miR-550a-3-5p', 'Var', (20, 33))	('invasion', 'CPA', (60, 68))	('suppressed', 'NegReg', (34, 44))	('migration', 'CPA', (49, 58))	('miR-550a-3-5p', 'Chemical', '-', (20, 33))	('M2 macrophages polarization', 'CPA', (128, 155))	('HPV', 'Species', '10566', (80, 83))	('decreasing', 'NegReg', (117, 127))	('EMT of HPV-positive OSCC cells', 'CPA', (73, 103))
455016	32493454	Moreover, miR-550a-3-5p, down-regulated by E6 oncoprotein, inhibited M2 macrophages polarization by YAP/CCL2 signaling, which in turn abrogating EMT program in HPV-positive OSCC cells.	('E6', 'Chemical', '-', (43, 45))	('miR-550a-3-5p', 'Var', (10, 23))	('abrogating', 'NegReg', (134, 144))	('inhibited', 'NegReg', (59, 68))	('miR-550a-3-5p', 'Chemical', '-', (10, 23))	('EMT program in HPV-positive OSCC cells', 'CPA', (145, 183))	('HPV', 'Species', '10566', (160, 163))
455017	32493454	In addition, in both xenografts and clinical HPV-positive OSCC samples, miR-550a-3-5p levels were inversely associated with YAP, CCL2 expressions and the number of M2 macrophages.	('inversely', 'NegReg', (98, 107))	('HPV', 'Species', '10566', (45, 48))	('miR-550a-3-5p', 'Var', (72, 85))	('YAP', 'Disease', (124, 127))	('associated', 'Interaction', (108, 118))	('CCL2', 'Gene', (129, 133))	('miR-550a-3-5p', 'Chemical', '-', (72, 85))
455018	32493454	E6/miR-550a-3-5p/YAP/CCL2 signaling induces M2 macrophages polarization to enhance EMT and progression, revealing a novel crosstalk between cancer cells and immune cells in HPV-positive OSCC microenvironment.	('M2 macrophages', 'MPA', (44, 58))	('induces', 'Reg', (36, 43))	('HPV', 'Species', '10566', (173, 176))	('miR-550a-3-5p', 'Chemical', '-', (3, 16))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('E6', 'Chemical', '-', (0, 2))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('enhance', 'PosReg', (75, 82))	('E6/miR-550a-3-5p/YAP/CCL2', 'Var', (0, 25))
455021	32493454	HPV-positive OSCC defines a novel and independent entity with distinct genetic nature and clinicopathological features when compared to HPV-negative OSCC, while treatment approaches towards them are essentially the same which depend on the site and stage of the tumor.	('tumor', 'Phenotype', 'HP:0002664', (262, 267))	('HPV', 'Species', '10566', (0, 3))	('tumor', 'Disease', (262, 267))	('HPV', 'Species', '10566', (136, 139))	('tumor', 'Disease', 'MESH:D009369', (262, 267))	('HPV-positive', 'Var', (0, 12))
455033	32493454	Multiple studies have uncovered that miRNAs have crucial roles in the development and progression of human cancers, exerting their effects by affecting the intrinsic mechanisms, or communicating with extrinsic properties.	('cancers', 'Disease', (107, 114))	('cancers', 'Disease', 'MESH:D009369', (107, 114))	('miRNAs', 'Var', (37, 43))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('human', 'Species', '9606', (101, 106))	('intrinsic mechanisms', 'MPA', (156, 176))	('communicating', 'Reg', (181, 194))	('affecting', 'Reg', (142, 151))	('cancers', 'Phenotype', 'HP:0002664', (107, 114))
455036	32493454	In the present study, we clarified that decreased miR-550a-3-5p expression was correlated with HPV-positive OSCC metastasis.	('HPV', 'Species', '10566', (95, 98))	('miR-550a-3-5p', 'Chemical', '-', (50, 63))	('decreased', 'NegReg', (40, 49))	('miR-550a-3-5p', 'Var', (50, 63))
455037	32493454	Functional experiments identified that miR-550a-3-5p inhibited M2 macrophages polarization, which in turn suppressed migration, invasion and EMT of HPV-positive OSCC cells.	('miR-550a-3-5p', 'Chemical', '-', (39, 52))	('EMT', 'CPA', (141, 144))	('inhibited', 'NegReg', (53, 62))	('migration', 'CPA', (117, 126))	('HPV', 'Species', '10566', (148, 151))	('M2 macrophages polarization', 'CPA', (63, 90))	('suppressed', 'NegReg', (106, 116))	('miR-550a-3-5p', 'Var', (39, 52))	('invasion', 'CPA', (128, 136))
455038	32493454	Furthermore, mechanistic studies revealed that miR-550a-3-5p, reduced by E6 oncoprotein, inhibited M2 macrophages polarization by regulating YAP/CCL2 axis, the correlation of which was confirmed in both xenografts of nude mice and clinical specimens.	('M2 macrophages polarization', 'CPA', (99, 126))	('miR-550a-3-5p', 'Var', (47, 60))	('regulating', 'Reg', (130, 140))	('miR-550a-3-5p', 'Chemical', '-', (47, 60))	('inhibited', 'NegReg', (89, 98))	('nude mice', 'Species', '10090', (217, 226))	('YAP/CCL2 axis', 'MPA', (141, 154))	('E6', 'Chemical', '-', (73, 75))
455039	32493454	These findings improved our knowledge of the molecular mechanisms by which miRNA regulated HPV-positive OSCC progression, and provided possible therapeutic target for HPV-positive OSCC.	('progression', 'CPA', (109, 120))	('HPV-positive OSCC', 'Disease', (91, 108))	('regulated', 'Reg', (81, 90))	('miRNA', 'Var', (75, 80))	('HPV', 'Species', '10566', (91, 94))	('HPV', 'Species', '10566', (167, 170))
455051	32493454	Primary antibodies were listed as follows: anti-E-cadherin (1:5000, mouse anti-human, Cell Signaling Technology Inc.), anti-Vimentin (1:2000, mouse anti-human, Abcam), anti-HPV16 E6 + HPV18 E6 (1:1000, mouse anti-human papillomavirus, Abcam), anti-HPV16 E7 (1:1000, mouse anti-human papillomavirus, Abcam), anti-YAP (1:2000, mouse anti-human, Proteintech), anti-TAZ (1:2000, mouse anti-human, Proteintech), anti-CCL2 (1:2000, mouse anti-human, Proteintech), anti-flag-YAP (1:1000, mouse, Abbkine), anti-GAPDH (1:2000, rabbit anti-human, Sigma-Aldrich).	('papillomavirus', 'Disease', 'MESH:D030361', (219, 233))	('mouse', 'Species', '10090', (142, 147))	('human', 'Species', '9606', (153, 158))	('TAZ', 'Gene', '6901', (362, 365))	('E6', 'Chemical', '-', (179, 181))	('papillomavirus', 'Disease', (283, 297))	('TAZ', 'Gene', (362, 365))	('mouse', 'Species', '10090', (325, 330))	('human', 'Species', '9606', (79, 84))	('papillomavirus', 'Disease', (219, 233))	('Vimentin', 'Gene', '7431', (124, 132))	('HPV16', 'Species', '333760', (248, 253))	('anti-flag-YAP', 'Var', (458, 471))	('human', 'Species', '9606', (437, 442))	('E6', 'Chemical', '-', (190, 192))	('human', 'Species', '9606', (277, 282))	('human', 'Species', '9606', (386, 391))	('Vimentin', 'Gene', (124, 132))	('human', 'Species', '9606', (213, 218))	('mouse', 'Species', '10090', (426, 431))	('human', 'Species', '9606', (530, 535))	('mouse', 'Species', '10090', (481, 486))	('HPV', 'Species', '10566', (248, 251))	('HPV', 'Species', '10566', (184, 187))	('mouse', 'Species', '10090', (266, 271))	('mouse', 'Species', '10090', (68, 73))	('mouse', 'Species', '10090', (202, 207))	('HPV', 'Species', '10566', (173, 176))	('mouse', 'Species', '10090', (375, 380))	('papillomavirus', 'Disease', 'MESH:D030361', (283, 297))	('HPV16', 'Species', '333760', (173, 178))	('human', 'Species', '9606', (336, 341))
455060	32493454	And the following primary antibodies were listed: anti-p16 for detecting p16, a surrogate biomarker of HPV E7 oncoprotein function (1:500, rabbit anti-human, Bioss), anti-Ki-67 (1:200, rabbit anti-human, HUABIO), anti-E-cadherin (1:500, mouse anti-human, Cell Signaling Technology Inc.), anti-Vimentin (1:200, mouse anti-human, Abcam), anti-CD31 (1:300, rabbit anti-human, Biorbyt), anti-CD34 (1:300, mouse anti-human, HUABIO), anti-YAP (1:600, mouse anti-human, Proteintech), anti-CCL2 (1:200, mouse anti-human, Proteintech), anti-CD163 (1:500, rabbit anti-human, Biorbyt).	('CD31', 'Gene', '5175', (341, 345))	('human', 'Species', '9606', (248, 253))	('human', 'Species', '9606', (456, 461))	('mouse', 'Species', '10090', (310, 315))	('CD34', 'Gene', '947', (388, 392))	('Vimentin', 'Gene', '7431', (293, 301))	('anti-CD163', 'Var', (527, 537))	('human', 'Species', '9606', (558, 563))	('human', 'Species', '9606', (366, 371))	('mouse', 'Species', '10090', (445, 450))	('mouse', 'Species', '10090', (237, 242))	('Vimentin', 'Gene', (293, 301))	('Ki-67', 'Gene', '17345', (171, 176))	('p16', 'Gene', (73, 76))	('mouse', 'Species', '10090', (401, 406))	('CD31', 'Gene', (341, 345))	('human', 'Species', '9606', (412, 417))	('p16', 'Gene', '1029', (73, 76))	('human', 'Species', '9606', (151, 156))	('p16', 'Gene', (55, 58))	('CD34', 'Gene', (388, 392))	('human', 'Species', '9606', (506, 511))	('human', 'Species', '9606', (197, 202))	('anti-CCL2', 'Var', (477, 486))	('Ki-67', 'Gene', (171, 176))	('p16', 'Gene', '1029', (55, 58))	('mouse', 'Species', '10090', (495, 500))	('HPV', 'Species', '10566', (103, 106))	('human', 'Species', '9606', (321, 326))
455075	32493454	Stably-transfected OSCC cells with miR-550a-3-5p overexpression were derived from the parental cells by a fluorescence microscope (Olympus BX51) detection and puromycin (Sigma-Aldrich) selection.	('overexpression', 'PosReg', (49, 63))	('puromycin', 'Chemical', 'MESH:D011691', (159, 168))	('miR-550a-3-5p', 'Var', (35, 48))	('miR-550a-3-5p', 'Chemical', '-', (35, 48))
455095	32493454	The associations between miR-550a-3-5p and YAP, YAP and CCL2, and CCL2 and CD163 expressions in HPV-positive OSCC specimens were assessed using 2-tailed Pearson's statistics.	('HPV', 'Species', '10566', (96, 99))	('CD163', 'Gene', (75, 80))	('miR-550a-3-5p', 'Var', (25, 38))	('miR-550a-3-5p', 'Chemical', '-', (25, 38))	('associations', 'Interaction', (4, 16))
455101	32493454	By in silico and literature analysis, we selected miR-550a-3-5p, miR-451a, and miR-210-3p to validate their expression differences.	('miR-451a', 'Gene', '574411', (65, 73))	('miR-451a', 'Gene', (65, 73))	('miR-550a-3-5p', 'Var', (50, 63))	('miR-550a-3-5p', 'Chemical', '-', (50, 63))	('miR-210-3p', 'Var', (79, 89))
455106	32493454	The red fluorescent distribution indicated that miR-550a-3-5p was mainly localized in the cytoplasm of both OSCC and normal cells, and had a highest expression in normal mucosa while lowest expression in HPV-positive OSCC specimens (Fig.	('miR-550a-3-5p', 'Var', (48, 61))	('HPV', 'Species', '10566', (204, 207))	('expression', 'MPA', (149, 159))	('miR-550a-3-5p', 'Chemical', '-', (48, 61))	('expression', 'MPA', (190, 200))	('lowest', 'NegReg', (183, 189))
455108	32493454	Then, the qRT-PCR results of miR-550a-3-5p and their associations with corresponding clinicopathological features in HPV-positive and HPV-negtive OSCC patients were summarized.	('HPV', 'Species', '10566', (117, 120))	('patients', 'Species', '9606', (151, 159))	('miR-550a-3-5p', 'Var', (29, 42))	('associations', 'Interaction', (53, 65))	('miR-550a-3-5p', 'Chemical', '-', (29, 42))	('HPV', 'Species', '10566', (134, 137))
455109	32493454	After differentiating miR-550a-3-5p expressions into lower and higher part according to the cut-off point of their median, we found that in HPV-positive OSCC patients, lower miR-550a-3-5p expression was associated with higher tumor size (P = 0.025) and the presence of nodal metastasis (P = 0.009), but had no correlations with age, gender, drink, smoke, differentiation, clinical stage and recurrence (Table 1).	('OSCC', 'Disease', (153, 157))	('miR-550a-3-5p', 'Chemical', '-', (22, 35))	('nodal metastasis', 'CPA', (269, 285))	('miR-550a-3-5p', 'Chemical', '-', (174, 187))	('lower', 'NegReg', (168, 173))	('higher', 'PosReg', (219, 225))	('tumor', 'Disease', 'MESH:D009369', (226, 231))	('miR-550a-3-5p expression', 'Var', (174, 198))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('patients', 'Species', '9606', (158, 166))	('HPV-positive', 'Gene', (140, 152))	('tumor', 'Disease', (226, 231))	('HPV', 'Species', '10566', (140, 143))
455110	32493454	However, miR-550a-3-5p expression was associated with none of these features in HPV-negative OSCC patients.	('OSCC', 'Disease', (93, 97))	('patients', 'Species', '9606', (98, 106))	('miR-550a-3-5p expression', 'Var', (9, 33))	('HPV', 'Species', '10566', (80, 83))	('miR-550a-3-5p', 'Chemical', '-', (9, 22))
455112	32493454	Patients with higher miR-550a-3-5p expression, no matter in HPV-positive OSCC (HR 0.48; P>0.05) or HPV-negative OSCC (HR 0.46; P>0.05), exhibited better survival than those having lower miR-550a-3-5p expression (Fig.	('miR-550a-3-5p', 'Chemical', '-', (21, 34))	('Patients', 'Species', '9606', (0, 8))	('HPV', 'Species', '10566', (60, 63))	('miR-550a-3-5p', 'Chemical', '-', (186, 199))	('better', 'PosReg', (146, 152))	('HPV', 'Species', '10566', (99, 102))	('survival', 'CPA', (153, 161))	('miR-550a-3-5p expression', 'Var', (21, 45))
455113	32493454	Thus, miR-550a-3-5p levels were frequently down-regulated in HPV-positive OSCC, particularly in patients with higher tumor size, nodal metastasis, which indicated a potential role for miR-550a-3-5p in targeting HPV-positive OSCC progression.	('down-regulated', 'NegReg', (43, 57))	('miR-550a-3-5p levels', 'MPA', (6, 26))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('HPV-positive OSCC', 'Disease', (61, 78))	('tumor', 'Disease', (117, 122))	('miR-550a-3-5p', 'Chemical', '-', (6, 19))	('miR-550a-3-5p', 'Var', (184, 197))	('HPV', 'Species', '10566', (211, 214))	('patients', 'Species', '9606', (96, 104))	('miR-550a-3-5p', 'Chemical', '-', (184, 197))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('HPV', 'Species', '10566', (61, 64))
455115	32493454	The same as expressional differences in tissue specimens, miR-550a-3-5p levels were highest in normal oral keratinocytes (NOK), then dysplasia oral keratinocytes (DOK), HPV-negative OSCC cell lines, and lowest in HPV-positive OSCC cell lines (Supplementary Fig.	('highest', 'Reg', (84, 91))	('miR-550a-3-5p', 'Var', (58, 71))	('dysplasia', 'Disease', 'MESH:C536170', (133, 142))	('dysplasia', 'Disease', (133, 142))	('HPV', 'Species', '10566', (169, 172))	('miR-550a-3-5p', 'Chemical', '-', (58, 71))	('HPV', 'Species', '10566', (213, 216))
455117	32493454	miR-550a-3-5p overexpression decreased cell proliferation rate in HPV-positive (- 25.01%, UPCI:SCC090; - 40.08%, UM-SCC-47) and HPV-negative cells (- 36.69%, Cal-27; - 13.13%, SCC25), while its inhibition increased cell proliferation rate in HPV-positive (15.56%, UPCI:SCC090; 54.49%, UM-SCC-47) and HPV-negative cells (36.03%, Cal-27; 31.97%, SCC25) (Fig.	('UM-SCC-47', 'CellLine', 'CVCL:7759', (113, 122))	('miR-550a-3-5p', 'Var', (0, 13))	('inhibition', 'NegReg', (194, 204))	('HPV', 'Species', '10566', (66, 69))	('HPV', 'Species', '10566', (128, 131))	('miR-550a-3-5p', 'Chemical', '-', (0, 13))	('HPV', 'Species', '10566', (300, 303))	('increased', 'PosReg', (205, 214))	('HPV', 'Species', '10566', (242, 245))	('UM-SCC-47', 'CellLine', 'CVCL:7759', (285, 294))	('decreased', 'NegReg', (29, 38))	('cell proliferation rate', 'CPA', (39, 62))	('cell proliferation rate', 'CPA', (215, 238))
455118	32493454	Using Flow cytometry assay, miR-550a-3-5p overexpression led to significantly increased apoptosis in HPV-positive (62.39%, UPCI:SCC090; 81.82%, UM-SCC-47) and HPV-negative cells (95.21%, Cal-27; 76.27%, SCC25), and its inhibition decreased cell apoptosis (- 45.55%, UPCI:SCC090; - 62.63%, UM-SCC-47; - 55.43%, Cal-27; - 45.9%, SCC25) (Fig.	('apoptosis', 'CPA', (88, 97))	('UM-SCC-47', 'CellLine', 'CVCL:7759', (144, 153))	('HPV', 'Species', '10566', (159, 162))	('miR-550a-3-5p', 'Var', (28, 41))	('UM-SCC-47', 'CellLine', 'CVCL:7759', (289, 298))	('increased', 'PosReg', (78, 87))	('miR-550a-3-5p', 'Chemical', '-', (28, 41))	('HPV', 'Species', '10566', (101, 104))	('cell apoptosis', 'CPA', (240, 254))
455120	32493454	The results showed that miR-550a-3-5p overexpression decreased the migrated area (14.64%, Cal-27; 11.04%, SCC25) and invasive ability (68.29%, Cal-27; 58.88%, SCC25) in HPV-negative cells, while had no evident impacts on HPV-positive cells.	('invasive ability', 'CPA', (117, 133))	('miR-550a-3-5p', 'Var', (24, 37))	('migrated area', 'CPA', (67, 80))	('HPV', 'Species', '10566', (169, 172))	('miR-550a-3-5p', 'Chemical', '-', (24, 37))	('HPV', 'Species', '10566', (221, 224))	('decreased', 'NegReg', (53, 62))	('SCC25', 'CPA', (106, 111))
455122	32493454	As EMT leads a crucial role in the process of epithelial cancer progression, we examined both the epithelial and mesenchymal markers in miR-550a-3-5p-overexpressed HPV-positive and negative OSCC cells by qRT-PCR.	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('cancer', 'Disease', (57, 63))	('miR-550a-3-5p', 'Chemical', '-', (136, 149))	('miR-550a-3-5p-overexpressed', 'Var', (136, 163))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('miR-550a-3-5p-overexpressed', 'PosReg', (136, 163))	('HPV', 'Species', '10566', (164, 167))	('epithelial cancer', 'Phenotype', 'HP:0031492', (46, 63))
455123	32493454	2e, miR-550a-3-5p overexpression resulted in a significant increase in E-cadherin and decrease in Vimentin in HPV-negative cells, while had no effects on EMT of HPV-positive cells.	('miR-550a-3-5p', 'Var', (4, 17))	('HPV', 'Species', '10566', (110, 113))	('E-cadherin', 'Protein', (71, 81))	('miR-550a-3-5p', 'Chemical', '-', (4, 17))	('Vimentin', 'Gene', (98, 106))	('decrease', 'NegReg', (86, 94))	('HPV', 'Species', '10566', (161, 164))	('Vimentin', 'Gene', '7431', (98, 106))	('overexpression', 'PosReg', (18, 32))	('increase', 'PosReg', (59, 67))
455126	32493454	miR-550a-3-5p overexpression, both in HPV-positive and HPV-negative OSCC cells, led to a decrease in tumor volume and tumor weight with respect to the vector control group (Fig.	('miR-550a-3-5p', 'Var', (0, 13))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('HPV', 'Species', '10566', (38, 41))	('HPV', 'Species', '10566', (55, 58))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumor', 'Disease', (101, 106))	('decrease', 'NegReg', (89, 97))	('miR-550a-3-5p', 'Chemical', '-', (0, 13))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (118, 123))	('overexpression', 'PosReg', (14, 28))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
455129	32493454	Interestingly, Ki-67 and Vimentin were reduced but E-cadherin was increased, along with inhibited angiogenesis (CD31 and CD34) in both miR-550a-3-5p-overexpressed HPV-positive and HPV-negative OSCC cells-derived xenografts (Fig.	('inhibited', 'NegReg', (88, 97))	('miR-550a-3-5p-overexpressed', 'Var', (135, 162))	('increased', 'PosReg', (66, 75))	('Vimentin', 'Gene', '7431', (25, 33))	('E-cadherin', 'Protein', (51, 61))	('Ki-67', 'Gene', '17345', (15, 20))	('Vimentin', 'Gene', (25, 33))	('CD31', 'Gene', (112, 116))	('HPV', 'Species', '10566', (180, 183))	('HPV', 'Species', '10566', (163, 166))	('CD34', 'Gene', '947', (121, 125))	('reduced', 'NegReg', (39, 46))	('Ki-67', 'Gene', (15, 20))	('CD31', 'Gene', '5175', (112, 116))	('miR-550a-3-5p', 'Chemical', '-', (135, 148))	('CD34', 'Gene', (121, 125))
455130	32493454	The above contradiction of in vitro and in vivo results in HPV-positive OSCC suggested that miR-550a-3-5p might participate in a cell nonautonomous mechanism to exert its tumor-suppressive effects.	('HPV', 'Species', '10566', (59, 62))	('miR-550a-3-5p', 'Chemical', '-', (92, 105))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('participate', 'Reg', (112, 123))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', (171, 176))	('miR-550a-3-5p', 'Var', (92, 105))
455136	32493454	However, macrophages treated with CM from miR-550a-3-5p mimic-transfected HPV-positive cells exhibited lower levels of M2 macrophage markers including CD163, IL-10 and Arginase-1 when compared with those treated with CM from mimic NC-transfected HPV-positive cells, while M1 macrophage markers such as CD80, IL-12p40 and TNF-alpha showed no evident differences (Fig.	('M2 macrophage markers', 'MPA', (119, 140))	('IL-10', 'Gene', '3586', (158, 163))	('miR-550a-3-5p', 'Var', (42, 55))	('HPV', 'Species', '10566', (246, 249))	('CD163', 'MPA', (151, 156))	('lower', 'NegReg', (103, 108))	('IL-10', 'Gene', (158, 163))	('CD80', 'Gene', (302, 306))	('levels', 'MPA', (109, 115))	('HPV-positive', 'Gene', (74, 86))	('Arginase-1', 'Gene', (168, 178))	('Arginase-1', 'Gene', '383', (168, 178))	('TNF-alpha', 'Gene', '7124', (321, 330))	('miR-550a-3-5p', 'Chemical', '-', (42, 55))	('HPV', 'Species', '10566', (74, 77))	('CD80', 'Gene', '941', (302, 306))	('TNF-alpha', 'Gene', (321, 330))
455137	32493454	These indicated that TAMs of a mixed M1/M2 phenotype were induced by HPV-positive OSCC cells, while miR-550a-3-5p overexpression down-regulated the polarization of M2 macrophages.	('down-regulated', 'NegReg', (129, 143))	('TAMs', 'Chemical', '-', (21, 25))	('HPV', 'Species', '10566', (69, 72))	('miR-550a-3-5p', 'Var', (100, 113))	('miR-550a-3-5p', 'Chemical', '-', (100, 113))	('polarization of M2 macrophages', 'CPA', (148, 178))
455139	32493454	4d, miR-550a-3-5p overexpression decreased the migrated area (14.10%, UPCI:SCC090; 23.12%, UM-SCC-47) and invasive ability (68.74%, UPCI:SCC090; 62.39%, UM-SCC-47) in HPV-positive cells.	('miR-550a-3-5p', 'Var', (4, 17))	('UM-SCC-47', 'CellLine', 'CVCL:7759', (153, 162))	('miR-550a-3-5p', 'Chemical', '-', (4, 17))	('invasive ability', 'CPA', (106, 122))	('migrated area', 'CPA', (47, 60))	('decreased', 'NegReg', (33, 42))	('UM-SCC-47', 'CellLine', 'CVCL:7759', (91, 100))	('HPV', 'Species', '10566', (167, 170))
455140	32493454	Meanwhile, we verified whether TAMs could suppress the EMT of miR-550a-3-5p-overexpressed HPV-positive cells.	('suppress', 'NegReg', (42, 50))	('EMT', 'CPA', (55, 58))	('HPV', 'Species', '10566', (90, 93))	('TAMs', 'Chemical', '-', (31, 35))	('miR-550a-3-5p', 'Chemical', '-', (62, 75))	('miR-550a-3-5p-overexpressed', 'Var', (62, 89))
455141	32493454	qRT-PCR showed that TAMs co-culture significantly increased the epithelial markers such as E-cadherin and beta-catenin, and decreased the mesenchymal markers such as N-cadherin and Vimentin in miR-550a-3-5p-overexpressed HPV-positive cells.	('miR-550a-3-5p', 'Chemical', '-', (193, 206))	('N-cadherin', 'Gene', '1000', (166, 176))	('TAMs', 'Chemical', '-', (20, 24))	('beta-catenin', 'Gene', '1499', (106, 118))	('miR-550a-3-5p-overexpressed', 'Var', (193, 220))	('Vimentin', 'Gene', '7431', (181, 189))	('mesenchymal markers', 'CPA', (138, 157))	('increased', 'PosReg', (50, 59))	('E-cadherin', 'Protein', (91, 101))	('decreased', 'NegReg', (124, 133))	('epithelial markers', 'CPA', (64, 82))	('HPV', 'Species', '10566', (221, 224))	('N-cadherin', 'Gene', (166, 176))	('beta-catenin', 'Gene', (106, 118))	('Vimentin', 'Gene', (181, 189))
455143	32493454	Taken together, our findings revealed that miR-550a-3-5p suppressed migration, invasion and EMT of HPV-positive OSCC cells by inhibiting M2 polarization.	('miR-550a-3-5p', 'Chemical', '-', (43, 56))	('inhibiting', 'NegReg', (126, 136))	('EMT of HPV-positive OSCC cells', 'CPA', (92, 122))	('suppressed', 'NegReg', (57, 67))	('invasion', 'CPA', (79, 87))	('miR-550a-3-5p', 'Var', (43, 56))	('HPV', 'Species', '10566', (99, 102))	('migration', 'CPA', (68, 77))	('M2 polarization', 'CPA', (137, 152))
455144	32493454	We hypothesized that a mechanism between HPV-positive OSCC cells and TAMs exists that explains at least partly the previously depicted tumor-suppressive behaviors of miR-550a-3-5p.	('HPV', 'Species', '10566', (41, 44))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('TAMs', 'Chemical', '-', (69, 73))	('tumor', 'Disease', (135, 140))	('miR-550a-3-5p', 'Var', (166, 179))	('miR-550a-3-5p', 'Chemical', '-', (166, 179))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
455146	32493454	We found that miR-550a-3-5p expression was induced after E6 knockdown, while not influenced after E7 inhibiting in HPV-positive cells (Fig.	('E6', 'Chemical', '-', (57, 59))	('HPV', 'Species', '10566', (115, 118))	('miR-550a-3-5p', 'Chemical', '-', (14, 27))	('knockdown', 'Var', (60, 69))	('miR-550a-3-5p', 'Gene', (14, 27))	('induced', 'PosReg', (43, 50))
455148	32493454	Results showed that miR-550a-3-5p expression was significantly decreased after E6 overexpressing (Fig.	('miR-550a-3-5p', 'Var', (20, 33))	('decreased', 'NegReg', (63, 72))	('miR-550a-3-5p', 'Chemical', '-', (20, 33))	('overexpressing', 'PosReg', (82, 96))	('E6', 'Chemical', '-', (79, 81))
455149	32493454	Moreover, TAMs which were treated with CM from E6-silencing HPV-positive cells, exhibited lower levels of CD163, while this effect was mostly abrogated when treated with CM from miR-550a-3-5p inhibitor and E6 siRNA-cotransfected HPV-positive cells (Fig.	('CD163', 'MPA', (106, 111))	('levels', 'MPA', (96, 102))	('TAMs', 'Chemical', '-', (10, 14))	('E6-silencing', 'Var', (47, 59))	('HPV-positive', 'Gene', (60, 72))	('E6', 'Chemical', '-', (47, 49))	('lower', 'NegReg', (90, 95))	('HPV', 'Species', '10566', (229, 232))	('miR-550a-3-5p', 'Chemical', '-', (178, 191))	('HPV', 'Species', '10566', (60, 63))	('E6', 'Chemical', '-', (206, 208))
455150	32493454	These suggested that miR-550a-3-5p was negatively regulated by E6 oncoprotein in HPV-positive OSCC cells.	('miR-550a-3-5p', 'Var', (21, 34))	('miR-550a-3-5p', 'Chemical', '-', (21, 34))	('negatively', 'NegReg', (39, 49))	('HPV', 'Species', '10566', (81, 84))	('E6', 'Chemical', '-', (63, 65))	('E6 oncoprotein', 'Protein', (63, 77))
455151	32493454	To determine what downstream signals of miR-550a-3-5p contributed to inhibition of M2 macrophages polarization, we looked at the GO (molecular function) and KEGG (signaling pathway) analysis of miR-550a-3-5p.	('miR-550a-3-5p', 'Chemical', '-', (40, 53))	('M2 macrophages polarization', 'CPA', (83, 110))	('miR-550a-3-5p', 'Var', (40, 53))	('miR-550a-3-5p', 'Var', (194, 207))	('miR-550a-3-5p', 'Chemical', '-', (194, 207))
455152	32493454	Results found that miR-550a-3-5p was related to the cytokine, chemokine activity, and Hippo signaling pathway (Supplementary Fig.	('related', 'Reg', (37, 44))	('chemokine activity', 'MPA', (62, 80))	('cytokine', 'MPA', (52, 60))	('Hippo signaling pathway', 'Pathway', (86, 109))	('miR-550a-3-5p', 'Var', (19, 32))	('miR-550a-3-5p', 'Chemical', '-', (19, 32))
455154	32493454	Overexpression of miR-550a-3-5p significantly inhibited YAP mRNA and protein levels in HPV-positive cells, but had no effects on TAZ expression (Fig.	('TAZ', 'Gene', '6901', (129, 132))	('TAZ', 'Gene', (129, 132))	('miR-550a-3-5p', 'Var', (18, 31))	('HPV', 'Species', '10566', (87, 90))	('miR-550a-3-5p', 'Chemical', '-', (18, 31))	('inhibited', 'NegReg', (46, 55))
455155	32493454	Then in silico analysis revealed that miR-550a-3-5p had three putative targets in 3'UTR of YAP mRNA, which were further validated by Dual luciferase reporter gene assays.	('miR-550a-3-5p', 'Chemical', '-', (38, 51))	("3'UTR of", 'MPA', (82, 90))	('miR-550a-3-5p', 'Var', (38, 51))
455157	32493454	Our results revealed that YAP was directly regulated by miR-550a-3-5p.	('regulated', 'Reg', (43, 52))	('YAP', 'MPA', (26, 29))	('miR-550a-3-5p', 'Chemical', '-', (56, 69))	('miR-550a-3-5p', 'Var', (56, 69))
455159	32493454	Results found that CCL2 and CXCL5 were significantly inhibited after YAP knockdown in both UPCI:SCC090 and UM-SCC-47 cells, while TLR9 and CSF1 were not changed evidently in both of them.	('CSF1', 'Gene', (139, 143))	('CSF1', 'Gene', '1435', (139, 143))	('inhibited', 'NegReg', (53, 62))	('YAP', 'Gene', (69, 72))	('TLR9', 'Gene', (130, 134))	('UM-SCC-47', 'CellLine', 'CVCL:7759', (107, 116))	('CXCL5', 'Gene', (28, 33))	('CXCL5', 'Gene', '6374', (28, 33))	('TLR9', 'Gene', '54106', (130, 134))	('knockdown', 'Var', (73, 82))
455160	32493454	Moreover, only CCL2 expression showed an obvious decrease in miR-550a-3-5p-overexpressed UPCI:SCC090 and UM-SCC-47 cells, which led us to speculate that CCL2 may serve as a downstream factor of miR-550a-3-5p/YAP in HPV-positive OSCC (Fig.	('miR-550a-3-5p', 'Chemical', '-', (61, 74))	('miR-550a-3-5p-overexpressed', 'Var', (61, 88))	('decrease', 'NegReg', (49, 57))	('HPV', 'Species', '10566', (215, 218))	('CCL2', 'Gene', (15, 19))	('UM-SCC-47', 'CellLine', 'CVCL:7759', (105, 114))	('miR-550a-3-5p', 'Chemical', '-', (194, 207))
455163	32493454	To further analyze whether CCL2 was regulated by miR-550a-3-5p/YAP signaling, the YAP-5SA active mutant (serine-to-alanine mutation at all putative LATS kinase phosphorylation sites on YAP including S61A, S109A, S127/128A, S131A, S163/164A, and S381A, thus leading to constitutive YAP activation) was used in the miR-550a-3-5p-overexpressed HPV-positive cells.	('S381A', 'Var', (245, 250))	('S109A', 'Mutation', 'p.S109A', (205, 210))	('S131A', 'Mutation', 'p.S131A', (223, 228))	('S131A', 'Var', (223, 228))	('S61A', 'Mutation', 'p.S61A', (199, 203))	('S163/164A', 'Var', (230, 239))	('HPV', 'Species', '10566', (341, 344))	('S381A', 'Mutation', 'p.S381A', (245, 250))	('miR-550a-3-5p', 'Chemical', '-', (313, 326))	('S127/128A', 'Var', (212, 221))	('miR-550a-3-5p', 'Chemical', '-', (49, 62))	('S109A', 'Var', (205, 210))	('S61A', 'Var', (199, 203))	('serine', 'Chemical', 'MESH:D012694', (105, 111))
455164	32493454	YAP-5SA transfection obviously rescued miR-550a-3-5p-induced repression of CCL2, which identified the role of miR-550a-3-5p/YAP in regulating CCL2 expression (Fig.	('miR-550a-3-5p', 'Chemical', '-', (39, 52))	('CCL2', 'Gene', (75, 79))	('expression', 'MPA', (147, 157))	('repression', 'MPA', (61, 71))	('miR-550a-3-5p-induced', 'Var', (39, 60))	('miR-550a-3-5p', 'Chemical', '-', (110, 123))
455165	32493454	Furthermore, classical target genes of YAP were also detected, and the ability of YAP-5SA rescuing miR-550a-3-5p-induced repression of CCNE2 and CDC6 might indicate the reason why miR-550a-3-5p affected proliferation and apoptosis in OSCC cells (Supplementary Fig.	('CDC6', 'Gene', '990', (145, 149))	('affected', 'Reg', (194, 202))	('proliferation', 'CPA', (203, 216))	('CDC6', 'Gene', (145, 149))	('CCNE2', 'Gene', '9134', (135, 140))	('miR-550a-3-5p', 'Chemical', '-', (99, 112))	('miR-550a-3-5p', 'Var', (180, 193))	('miR-550a-3-5p', 'Chemical', '-', (180, 193))	('repression', 'NegReg', (121, 131))	('apoptosis', 'CPA', (221, 230))	('CCNE2', 'Gene', (135, 140))
455166	32493454	Accordingly, we examined whether the role of miR-550a-3-5p in inhibiting migration, invasion and EMT of HPV-positive OSCC cells was dependent on YAP/CCL2-induced M2 macrophages infiltration.	('migration', 'CPA', (73, 82))	('invasion', 'CPA', (84, 92))	('HPV', 'Species', '10566', (104, 107))	('miR-550a-3-5p', 'Var', (45, 58))	('EMT', 'CPA', (97, 100))	('inhibiting', 'NegReg', (62, 72))	('miR-550a-3-5p', 'Chemical', '-', (45, 58))
455168	32493454	Then, after co-culturing with these CM-induced TMAs for 48 h, we found that increased mRNA expressions of E-cadherin in both UPCI:SCC090 and UM-SCC-47 cells by miR-550a-3-5p overexpression or YAP knockdown were mostly abolished when co-transfected with YAP-5SA or added CCL2.	('mRNA expressions', 'MPA', (86, 102))	('knockdown', 'Var', (196, 205))	('increased', 'PosReg', (76, 85))	('UM-SCC-47', 'CellLine', 'CVCL:7759', (141, 150))	('overexpression', 'PosReg', (174, 188))	('miR-550a-3-5p', 'Var', (160, 173))	('miR-550a-3-5p', 'Chemical', '-', (160, 173))	('E-cadherin', 'Protein', (106, 116))
455169	32493454	Completely opposite results were observed in Vimentin expressions, and protein levels of E-cadherin and Vimentin were confirmed by Western blot, suggesting that the effects of miR-550a-3-5p on inhibiting EMT of HPV-positive OSCC cells were dependent on suppression of YAP/CCL2-mediated M2 macrophages polarization (Fig.	('Vimentin', 'Gene', (45, 53))	('Vimentin', 'Gene', (104, 112))	('EMT of HPV-positive OSCC cells', 'CPA', (204, 234))	('Vimentin', 'Gene', '7431', (45, 53))	('Vimentin', 'Gene', '7431', (104, 112))	('HPV', 'Species', '10566', (211, 214))	('miR-550a-3-5p', 'Var', (176, 189))	('miR-550a-3-5p', 'Chemical', '-', (176, 189))	('inhibiting', 'NegReg', (193, 203))
455172	32493454	Results showed that tongue lesions caused by 4NQO treatment were more obvious in vehicle-treated mice than VP-treated mice.	('4NQO treatment', 'Var', (45, 59))	('4NQO', 'Chemical', 'MESH:D015112', (45, 49))	('mice', 'Species', '10090', (97, 101))	('tongue lesions', 'CPA', (20, 34))	('mice', 'Species', '10090', (118, 122))	('VP', 'Chemical', 'MESH:D000077362', (107, 109))
455174	32493454	These revealed that VP weakened the formation of tongue lesions induced by 4NQO.	('weakened', 'NegReg', (23, 31))	('4NQO', 'Chemical', 'MESH:D015112', (75, 79))	('formation of tongue lesions', 'CPA', (36, 63))	('VP', 'Chemical', 'MESH:D000077362', (20, 22))	('4NQO', 'Var', (75, 79))
455175	32493454	Then, HE staining demonstrated that the tumors present in the VP-treated mice were minimally dysplastic as compared to the more advanced in Vehicle-treated mice (Fig.	('HE', 'Chemical', 'MESH:D006371', (6, 8))	('VP-treated', 'Var', (62, 72))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('tumors', 'Disease', 'MESH:D009369', (40, 46))	('mice', 'Species', '10090', (73, 77))	('VP', 'Chemical', 'MESH:D000077362', (62, 64))	('mice', 'Species', '10090', (156, 160))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumors', 'Disease', (40, 46))
455180	32493454	Results of immunohistochemistry staining showed that miR-550a-3-5p overexpression was significantly correlated with decreased nuclear-stained of active YAP, cytoplasmic-stained of CCL2 and CD163.	('miR-550a-3-5p', 'Chemical', '-', (53, 66))	('active YAP', 'CPA', (145, 155))	('nuclear-stained', 'MPA', (126, 141))	('overexpression', 'PosReg', (67, 81))	('miR-550a-3-5p', 'Var', (53, 66))	('decreased', 'NegReg', (116, 125))
455181	32493454	Consistently, miR-550a-3-5p overexpression was associated with decreased mRNA levels of YAP, CCL2 and CD163 (Fig.	('miR-550a-3-5p', 'Var', (14, 27))	('decreased', 'NegReg', (63, 72))	('mRNA levels of YAP', 'MPA', (73, 91))	('miR-550a-3-5p', 'Chemical', '-', (14, 27))	('overexpression', 'PosReg', (28, 42))	('CCL2', 'MPA', (93, 97))	('CD163', 'MPA', (102, 107))
455184	32493454	Similarly, low miR-550a-3-5p expressions tended to be associated with high levels of YAP and CCL2, and more M2 macrophages infiltration in HPV-positive OSCC patients (Fig.	('OSCC', 'Disease', (152, 156))	('high levels', 'MPA', (70, 81))	('patients', 'Species', '9606', (157, 165))	('low', 'NegReg', (11, 14))	('more', 'PosReg', (103, 107))	('miR-550a-3-5p expressions', 'Var', (15, 40))	('M2 macrophages infiltration', 'CPA', (108, 135))	('HPV', 'Species', '10566', (139, 142))	('miR-550a-3-5p', 'Chemical', '-', (15, 28))	('CCL2', 'MPA', (93, 97))
455187	32493454	Mechanistically, a study has revealed that HPV 16 E7 oncoprotein expression in keratinocytes could epigenetically repress the E-cadherin expression by augmenting cellular DNA methyltransferase I activity.	('epigenetically', 'Var', (99, 113))	('augmenting', 'NegReg', (151, 161))	('HPV 16', 'Species', '333760', (43, 49))	('repress', 'NegReg', (114, 121))	('cellular', 'MPA', (162, 170))	('E-cadherin', 'Protein', (126, 136))	('HPV 16', 'Gene', (43, 49))	('activity', 'MPA', (195, 203))
455190	32493454	Consistently, our study found that in HPV-positive OSCC cells, the effects of miR-550a-3-5p on suppressing M2 macrophages polarization, and thus migration, invasion and EMT phenotype relied on the regulation of its upstream factor E6 oncoprotein.	('miR-550a-3-5p', 'Chemical', '-', (78, 91))	('suppressing', 'NegReg', (95, 106))	('HPV', 'Species', '10566', (38, 41))	('E6', 'Chemical', '-', (231, 233))	('M2 macrophages polarization', 'CPA', (107, 134))	('migration', 'CPA', (145, 154))	('EMT phenotype', 'CPA', (169, 182))	('miR-550a-3-5p', 'Var', (78, 91))	('invasion', 'CPA', (156, 164))
455194	32493454	A previous study has reported that E6/7-dependent maintenance of the malignant phenotype of HPV-positive cancer cells is linked to specific changes of intracellular miRNA pool.	('intracellular miRNA pool', 'MPA', (151, 175))	('HPV-positive cancer', 'Disease', (92, 111))	('E6/7-dependent', 'Var', (35, 49))	('changes', 'Reg', (140, 147))	('malignant phenotype', 'CPA', (69, 88))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('E6', 'Chemical', '-', (35, 37))	('HPV-positive cancer', 'Disease', 'MESH:D030361', (92, 111))
455195	32493454	For example, Peta and colleagues found that HPV16 E6 and E7 could repress miR-146a-5p expression at the promoter level through elevating transcription factor c-MYC.	('repress', 'NegReg', (66, 73))	('HPV16', 'Species', '333760', (44, 49))	('E6', 'Chemical', '-', (50, 52))	('c-MYC', 'Gene', '4609', (158, 163))	('HPV16 E6', 'Var', (44, 52))	('miR-146a', 'Gene', '406938', (74, 82))	('elevating', 'PosReg', (127, 136))	('c-MYC', 'Gene', (158, 163))	('miR-146a', 'Gene', (74, 82))
455196	32493454	In addition, HPV16 E6 could inhibit miR-22 expression, and thus suppress proliferation, migration and induce apoptosis of cervical cancer cells by down-regulating p53, a direct transcriptional regulator of miR-22.	('HPV16', 'Species', '333760', (13, 18))	('miR-22', 'Gene', (36, 42))	('down-regulating', 'NegReg', (147, 162))	('miR-22', 'Gene', '407004', (36, 42))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('E6', 'Chemical', '-', (19, 21))	('apoptosis', 'CPA', (109, 118))	('suppress', 'NegReg', (64, 72))	('p53', 'Gene', '7157', (163, 166))	('inhibit', 'NegReg', (28, 35))	('cancer', 'Disease', (131, 137))	('miR-22', 'Gene', '407004', (206, 212))	('induce', 'PosReg', (102, 108))	('proliferation', 'CPA', (73, 86))	('miR-22', 'Gene', (206, 212))	('p53', 'Gene', (163, 166))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('migration', 'CPA', (88, 97))	('HPV16 E6', 'Var', (13, 21))	('expression', 'MPA', (43, 53))
455198	32493454	In our study, miR-550a-3-5p expression and its subsequent inhibitory effects on M2 macrophages polarization were negatively regulated by E6 oncoprotein, while the specific mechanisms remain unknown and need further investigation.	('miR-550a-3-5p', 'Var', (14, 27))	('expression', 'MPA', (28, 38))	('M2 macrophages polarization', 'CPA', (80, 107))	('E6', 'Chemical', '-', (137, 139))	('E6 oncoprotein', 'Protein', (137, 151))	('miR-550a-3-5p', 'Chemical', '-', (14, 27))	('negatively', 'NegReg', (113, 123))
455200	32493454	For example, miR-141-3p was able to inhibit normal fibroblasts' transition to cancer-associated fibroblasts via STAT4/wnt/beta-catenin pathway, thus leading to suppressed migration and invasion in gastric cancer cells.	('miR-141-3p', 'Chemical', '-', (13, 23))	('transition', 'CPA', (64, 74))	('cancer', 'Disease', 'MESH:D009369', (205, 211))	('STAT4', 'Gene', '6775', (112, 117))	('beta-catenin', 'Gene', '1499', (122, 134))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('suppressed', 'NegReg', (160, 170))	('gastric cancer', 'Disease', (197, 211))	('STAT4', 'Gene', (112, 117))	('invasion', 'CPA', (185, 193))	('migration', 'CPA', (171, 180))	('cancer', 'Disease', (205, 211))	('inhibit', 'NegReg', (36, 43))	('cancer', 'Disease', (78, 84))	('gastric cancer', 'Disease', 'MESH:D013274', (197, 211))	('miR-141-3p', 'Var', (13, 23))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('gastric cancer', 'Phenotype', 'HP:0012126', (197, 211))	('beta-catenin', 'Gene', (122, 134))
455202	32493454	Also in this study, we found a signaling pathway that influenced tumor microenvironment and was mediated by miR-550a-3-5p, which modulated TAMs polarization and in turn affected migration, invasion, and EMT of HPV-positive OSCC cells.	('TAMs polarization', 'CPA', (139, 156))	('HPV', 'Species', '10566', (210, 213))	('affected', 'Reg', (169, 177))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('tumor', 'Disease', (65, 70))	('modulated', 'Reg', (129, 138))	('influenced', 'Reg', (54, 64))	('miR-550a-3-5p', 'Chemical', '-', (108, 121))	('miR-550a-3-5p', 'Var', (108, 121))	('invasion', 'CPA', (189, 197))	('TAMs', 'Chemical', '-', (139, 143))	('migration', 'CPA', (178, 187))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('EMT', 'CPA', (203, 206))
455205	32493454	In colorectal cancer cells, miR-550a-5p was inversely regulated by tumor suppressor Brg-1, and promoted migration and invasion via RNF43/Wnt/beta-catenin pathway.	('RNF43', 'Gene', (131, 136))	('promoted', 'PosReg', (95, 103))	('migration', 'CPA', (104, 113))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('colorectal cancer', 'Phenotype', 'HP:0003003', (3, 20))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('beta-catenin', 'Gene', (141, 153))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('beta-catenin', 'Gene', '1499', (141, 153))	('colorectal cancer', 'Disease', (3, 20))	('Brg-1', 'Gene', (84, 89))	('miR-550a-5p', 'Var', (28, 39))	('tumor', 'Disease', (67, 72))	('invasion', 'CPA', (118, 126))	('miR-550', 'Chemical', '-', (28, 35))	('Brg-1', 'Gene', '6597', (84, 89))	('colorectal cancer', 'Disease', 'MESH:D015179', (3, 20))	('RNF43', 'Gene', '54894', (131, 136))
455206	32493454	However, due to the tissue specificity, miR-550 also exerts tumor-suppressor roles.	('miR-550', 'Chemical', '-', (40, 47))	('miR-550', 'Var', (40, 47))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Disease', (60, 65))
455208	32493454	The same as above, miR-550a-3-5p was negatively associated with the growth and metastatic potential of both HPV-positive and negative OSCC cells in our study.	('metastatic potential', 'CPA', (79, 99))	('associated', 'Reg', (48, 58))	('HPV', 'Species', '10566', (108, 111))	('negatively', 'NegReg', (37, 47))	('miR-550a-3-5p', 'Var', (19, 32))	('growth', 'CPA', (68, 74))	('miR-550a-3-5p', 'Chemical', '-', (19, 32))
455210	32493454	Furthermore, unlike in other types of cancer, though its inhibitory roles in HPV-negative OSCC and in growth of HPV-positive OSCC might derive from direct mechanisms which need further investigation, miR-550a-3-5p affected migration and invasion of HPV-positive OSCC cells indirectly as the discrepancy between in vivo and in vitro studies.	('migration', 'CPA', (223, 232))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('affected', 'Reg', (214, 222))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('miR-550a-3-5p', 'Var', (200, 213))	('HPV', 'Species', '10566', (77, 80))	('invasion', 'CPA', (237, 245))	('cancer', 'Disease', (38, 44))	('miR-550a-3-5p', 'Chemical', '-', (200, 213))	('HPV', 'Species', '10566', (249, 252))	('HPV', 'Species', '10566', (112, 115))
455211	32493454	Thus, here we aimed to search for the downstream pathways of miR-550a-3-5p and verify whether these molecules resulted in the indirect tumor-suppressive influences of miR-550a-3-5p.	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('miR-550a-3-5p', 'Chemical', '-', (61, 74))	('miR-550a-3-5p', 'Chemical', '-', (167, 180))	('miR-550a-3-5p', 'Gene', (61, 74))	('tumor', 'Disease', (135, 140))	('miR-550a-3-5p', 'Var', (167, 180))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
455212	32493454	Through bioinformatics analysis, gene expression patterns and dual luciferase reporter gene assays, we found that miR-550a-3-5p directly targeted YAP which emerged to exhibit great roles in cancer immunity, and further regulated M2 macrophages polarization and migration, invasion and EMT of HPV-positive OSCC cells via YAP/CCL2 signaling.	('miR-550a-3-5p', 'Chemical', '-', (114, 127))	('cancer', 'Disease', (190, 196))	('EMT', 'CPA', (285, 288))	('HPV', 'Species', '10566', (292, 295))	('migration', 'CPA', (261, 270))	('cancer', 'Disease', 'MESH:D009369', (190, 196))	('YAP', 'Gene', (146, 149))	('invasion', 'CPA', (272, 280))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('miR-550a-3-5p', 'Var', (114, 127))	('regulated', 'Reg', (219, 228))	('M2 macrophages polarization', 'CPA', (229, 256))
455213	32493454	Similarly, a recent study also reported that miR-550a-3-5p could directly target YAP to exert tumor-suppressor roles in various cancers containing colon cancer, breast cancer, lung cancer, and head and neck cancer.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('colon cancer', 'Disease', 'MESH:D015179', (147, 159))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('YAP', 'Protein', (81, 84))	('cancers', 'Phenotype', 'HP:0002664', (128, 135))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('cancers', 'Disease', (128, 135))	('lung cancer', 'Disease', 'MESH:D008175', (176, 187))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('head and neck cancer', 'Phenotype', 'HP:0012288', (193, 213))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('colon cancer', 'Disease', (147, 159))	('lung cancer', 'Phenotype', 'HP:0100526', (176, 187))	('breast cancer', 'Phenotype', 'HP:0003002', (161, 174))	('miR-550a-3-5p', 'Chemical', '-', (45, 58))	('head and neck cancer', 'Disease', 'MESH:D006258', (193, 213))	('cancers', 'Disease', 'MESH:D009369', (128, 135))	('breast cancer', 'Disease', 'MESH:D001943', (161, 174))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('miR-550a-3-5p', 'Var', (45, 58))	('breast cancer', 'Disease', (161, 174))	('target', 'Reg', (74, 80))	('colon cancer', 'Phenotype', 'HP:0003003', (147, 159))	('tumor', 'Disease', (94, 99))	('lung cancer', 'Disease', (176, 187))
455220	32493454	In our study, we put forward a pathway in which miR-550a-3-5p, down-regulated by E6 oncoprotein, inhibited YAP but not TAZ in HPV-positive OSCC.	('TAZ', 'Gene', '6901', (119, 122))	('TAZ', 'Gene', (119, 122))	('E6', 'Chemical', '-', (81, 83))	('miR-550a-3-5p', 'Var', (48, 61))	('YAP', 'CPA', (107, 110))	('miR-550a-3-5p', 'Chemical', '-', (48, 61))	('inhibited', 'NegReg', (97, 106))	('HPV', 'Species', '10566', (126, 129))
455224	32493454	We have detected its classical target genes including CTGF, CYR61, CCNE2, CDC6 and CDK2 in our study, and only CCNE2 and CDC6 were up-regulated in YAP-activated HPV-positive OSCC cells, while miR-550a-3-5p overexpression could weaken these effects.	('CCNE2', 'Gene', (111, 116))	('CDC6', 'Gene', (121, 125))	('CDK2', 'Gene', (83, 87))	('miR-550a-3-5p', 'Var', (192, 205))	('CCNE2', 'Gene', (67, 72))	('CCNE2', 'Gene', '9134', (111, 116))	('CDC6', 'Gene', '990', (74, 78))	('up-regulated', 'PosReg', (131, 143))	('CCNE2', 'Gene', '9134', (67, 72))	('CDC6', 'Gene', (74, 78))	('CYR61', 'Gene', (60, 65))	('CTGF', 'Gene', (54, 58))	('miR-550a-3-5p', 'Chemical', '-', (192, 205))	('CTGF', 'Gene', '1490', (54, 58))	('CDK2', 'Gene', '1017', (83, 87))	('CYR61', 'Gene', '3491', (60, 65))	('HPV', 'Species', '10566', (161, 164))	('CDC6', 'Gene', '990', (121, 125))
455225	32493454	These may partly explain the mechanism by which miR-550a-3-5p regulated proliferation and apoptosis of cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('miR-550a-3-5p', 'Var', (48, 61))	('cancer', 'Disease', (103, 109))	('proliferation', 'CPA', (72, 85))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('miR-550a-3-5p', 'Chemical', '-', (48, 61))	('apoptosis', 'CPA', (90, 99))	('regulated', 'Reg', (62, 71))
455229	32493454	In line with this, we found that YAP, down-regulated by miR-550a-3-5p, could promote CCL2 expression transcriptionally by interaction with TEAD family, thus contributing to M2 macrophages polarization.	('interaction', 'Interaction', (122, 133))	('CCL2', 'Gene', (85, 89))	('promote', 'PosReg', (77, 84))	('down-regulated', 'NegReg', (38, 52))	('expression transcriptionally', 'MPA', (90, 118))	('miR-550a-3-5p', 'Var', (56, 69))	('M2 macrophages polarization', 'CPA', (173, 200))	('miR-550a-3-5p', 'Chemical', '-', (56, 69))	('contributing', 'Reg', (157, 169))
455231	32493454	In addition, CCL2 also enhances TAMs infiltration and exerts tumor-promoting effects indirectly.	('CCL2', 'Var', (13, 17))	('TAMs infiltration', 'Disease', (32, 49))	('TAMs infiltration', 'Disease', 'MESH:D017254', (32, 49))	('enhances', 'PosReg', (23, 31))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Disease', (61, 66))
455234	32493454	Our results revealed that E6/miR-550a-3-5p/YAP could promote M2 macrophages polarization through increasing CCL2, thus leading to the enhanced EMT in HPV-positive OSCC cells.	('E6/miR-550a-3-5p/YAP', 'Var', (26, 46))	('enhanced', 'PosReg', (134, 142))	('E6', 'Chemical', '-', (26, 28))	('miR-550a-3-5p', 'Chemical', '-', (29, 42))	('M2 macrophages polarization', 'CPA', (61, 88))	('HPV', 'Species', '10566', (150, 153))	('CCL2', 'MPA', (108, 112))	('EMT', 'CPA', (143, 146))	('increasing', 'PosReg', (97, 107))	('promote', 'PosReg', (53, 60))
455235	32493454	Taken together, E6/miR-550a-3-5p/YAP/CCL2 is a novel signaling axis identified in HPV-positive OSCC and involved in mediation of crosstalk between cancer cells and macrophages.	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('E6', 'Chemical', '-', (16, 18))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('OSCC', 'Disease', (95, 99))	('E6/miR-550a-3-5p/YAP/CCL2', 'Var', (16, 41))	('cancer', 'Disease', (147, 153))	('HPV', 'Species', '10566', (82, 85))	('miR-550a-3-5p', 'Chemical', '-', (19, 32))
455236	32493454	Although this signaling pathway concerns complicated immune networks that need to be studied further in detail, miR-550a-3-5p overexpression combined with YAP inhibition or immunotherapy might be a new strategy for advanced HPV-positive OSCC.	('HPV-positive OSCC', 'Disease', (224, 241))	('miR-550a-3-5p', 'Chemical', '-', (112, 125))	('miR-550a-3-5p', 'Var', (112, 125))	('HPV', 'Species', '10566', (224, 227))
455237	32493454	CM Conditioned media CSCC Cervical squamous cell carcinoma; DOK Dysplasia human oral keratinocytes EMT Epithelial-mesenchymal transition FISH Fluorescence in situ hybridization HPV Human papillomavirus IHC Immunohistochemistry miRNA microRNA MUT Mutant NC Negative control NOK Normal human oral keratinocytes OE Overexpression OSCC Oral squamous cell carcinoma siRNA small-interfering RNA TAM Tumor-associated macrophage VP Verteporfin WT Wild type Supplementary information accompanies this paper at 10.1186/s13046-020-01602-1.	('carcinoma', 'Phenotype', 'HP:0030731', (351, 360))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (35, 58))	('Oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (332, 360))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (337, 360))	('Verteporfin', 'Chemical', 'MESH:D000077362', (424, 435))	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('squamous cell carcinoma', 'Disease', (35, 58))	('HPV', 'Species', '10566', (177, 180))	('Oral squamous cell carcinoma', 'Disease', (332, 360))	('Dysplasia', 'Disease', (64, 73))	('Mutant', 'Var', (246, 252))	('VP', 'Chemical', 'MESH:D000077362', (421, 423))	('Tumor', 'Phenotype', 'HP:0002664', (393, 398))	('Dysplasia', 'Disease', 'MESH:C536170', (64, 73))	('TAM', 'Chemical', '-', (389, 392))	('human', 'Species', '9606', (284, 289))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (35, 58))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (337, 360))	('human', 'Species', '9606', (74, 79))	('Human papillomavirus', 'Species', '10566', (181, 201))
455242	26689913	We find that the frequency of rare germline truncations in 114 cancer-susceptibility-associated genes varies widely, from 4% (acute myeloid leukaemia (AML)) to 19% (ovarian cancer), with a notably high frequency of 11% in stomach cancer.	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('cancer', 'Disease', 'MESH:D009369', (230, 236))	('acute myeloid leukaemia', 'Disease', (126, 149))	('stomach cancer', 'Disease', 'MESH:D013274', (222, 236))	('stomach cancer', 'Phenotype', 'HP:0012126', (222, 236))	('ovarian cancer', 'Disease', (165, 179))	('myeloid leukaemia', 'Phenotype', 'HP:0012324', (132, 149))	('ovarian cancer', 'Phenotype', 'HP:0100615', (165, 179))	('AML', 'Disease', 'MESH:D015470', (151, 154))	('cancer', 'Disease', (230, 236))	('AML', 'Disease', (151, 154))	('cancer', 'Disease', (63, 69))	('cancer', 'Disease', (173, 179))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('acute myeloid leukaemia', 'Disease', 'MESH:D007938', (126, 149))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('stomach cancer', 'Disease', (222, 236))	('germline truncations', 'Var', (35, 55))	('acute myeloid leukaemia', 'Phenotype', 'HP:0004808', (126, 149))	('ovarian cancer', 'Disease', 'MESH:D010051', (165, 179))	('cancer', 'Disease', 'MESH:D009369', (63, 69))
455245	26689913	Moreover, our homology-directed repair assay of 68 BRCA1 rare missense variants supports the utility of allelic enrichment analysis for characterizing variants of unknown significance.	('missense variants', 'Var', (62, 79))	('BRCA1', 'Gene', '672', (51, 56))	('BRCA1', 'Gene', (51, 56))
455246	26689913	The scale of this analysis and the somatic-germline integration enable the detection of rare variants that may affect individual susceptibility to tumour development, a critical step toward precision medicine.	('affect', 'Reg', (111, 117))	('tumour', 'Phenotype', 'HP:0002664', (147, 153))	('variants', 'Var', (93, 101))	('tumour', 'Disease', 'MESH:D009369', (147, 153))	('tumour', 'Disease', (147, 153))
455247	26689913	Published sequencing data sets of cancer samples could be used to identify genetic variants associated with the risk of developing cancer.	('cancer', 'Disease', (131, 137))	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('variants', 'Var', (83, 91))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('cancer', 'Disease', (34, 40))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('associated', 'Reg', (92, 102))
455248	26689913	analyse over 4,000 tumour-normal pairs to reveal variable frequencies of inherited susceptibilities across 12 cancer types and find enrichment of functionally validated missense variants of unknown significance.	('tumour', 'Disease', 'MESH:D009369', (19, 25))	('missense variants', 'Var', (169, 186))	('cancer', 'Disease', (110, 116))	('tumour', 'Disease', (19, 25))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('tumour', 'Phenotype', 'HP:0002664', (19, 25))	('cancer', 'Disease', 'MESH:D009369', (110, 116))
455250	26689913	For example, it was recently estimated that up to 20-25% of ovarian cancers are due to a germline loss-of-function variant in one of several genes that confer moderate-to-high risk, while other cancer types (for example, lung) have strong environmental components with little evidence of genetic predisposition.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('ovarian cancer', 'Phenotype', 'HP:0100615', (60, 74))	('cancer', 'Disease', (194, 200))	('variant', 'Var', (115, 122))	('ovarian cancers', 'Disease', (60, 75))	('loss-of-function', 'NegReg', (98, 114))	('ovarian cancers', 'Phenotype', 'HP:0100615', (60, 75))	('cancers', 'Phenotype', 'HP:0002664', (68, 75))	('ovarian cancers', 'Disease', 'MESH:D010051', (60, 75))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('cancer', 'Disease', (68, 74))	('cancer', 'Disease', 'MESH:D009369', (194, 200))
455253	26689913	The availability of large-scale normal and tumour-sequencing data from cancer cases now allows for discovery of rare variants influencing cancer susceptibility through analysis of both germline and somatic sequencing data.	('cancer', 'Disease', (138, 144))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('cancer', 'Disease', (71, 77))	('tumour', 'Disease', (43, 49))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('variants', 'Var', (117, 125))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('tumour', 'Phenotype', 'HP:0002664', (43, 49))	('cancer', 'Disease', 'MESH:D009369', (138, 144))	('tumour', 'Disease', 'MESH:D009369', (43, 49))
455254	26689913	Their cooperation is best exemplified by the 'two-hit hypothesis', in which a tumour suppressor gene is inactivated by the combination of an initial germline mutation of one allele, followed by the somatic inactivation of the other.	('germline mutation', 'Var', (149, 166))	('tumour', 'Disease', 'MESH:D009369', (78, 84))	('inactivated', 'NegReg', (104, 115))	('tumour', 'Disease', (78, 84))	('tumour', 'Phenotype', 'HP:0002664', (78, 84))
455255	26689913	Loss of heterozygosity (LOH), whereby the wild-type (WT) allele for a two-hit tumour suppressor is eliminated, has been implicated in many cancers.	('Loss of heterozygosity', 'Var', (0, 22))	('cancers', 'Disease', 'MESH:D009369', (139, 146))	('cancers', 'Phenotype', 'HP:0002664', (139, 146))	('tumour', 'Disease', 'MESH:D009369', (78, 84))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('cancers', 'Disease', (139, 146))	('implicated', 'Reg', (120, 130))	('tumour', 'Disease', (78, 84))	('tumour', 'Phenotype', 'HP:0002664', (78, 84))
455258	26689913	Stomach cancer has a relatively high rate of rare germline truncations, in large part due to frequent PALB2 and ATM mutations.	('Stomach cancer', 'Phenotype', 'HP:0012126', (0, 14))	('Stomach cancer', 'Disease', (0, 14))	('germline truncations', 'Var', (50, 70))	('PALB2', 'Gene', '79728', (102, 107))	('Stomach cancer', 'Disease', 'MESH:D013274', (0, 14))	('ATM', 'Gene', (112, 115))	('PALB2', 'Gene', (102, 107))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('mutations', 'Var', (116, 125))	('ATM', 'Gene', '472', (112, 115))
455260	26689913	Experimental validation of 68 BRCA1 variants, with 62 having previously unknown functional significance or not reported by the NHGRI Breast Cancer Information Core (BIC) database, identified 9 with complete or partial loss of homology-directed repair (HDR) function, further supporting LOH analysis results.	('BRCA1', 'Gene', (30, 35))	('Breast Cancer', 'Disease', (133, 146))	('function', 'MPA', (257, 265))	('Breast Cancer', 'Disease', 'MESH:D001943', (133, 146))	('Cancer', 'Phenotype', 'HP:0002664', (140, 146))	('loss', 'NegReg', (218, 222))	('variants', 'Var', (36, 44))	('Breast Cancer', 'Phenotype', 'HP:0003002', (133, 146))	('BRCA1', 'Gene', '672', (30, 35))	('homology-directed repair', 'MPA', (226, 250))
455262	26689913	We searched for candidate germline cancer predisposition variants in the exome sequence data from 4,034 cancer patients across 12 diverse cancer types: breast adenocarcinoma (BRCA), glioblastoma multiforme (GBM), head and neck squamous cell carcinoma (HNSC), kidney renal clear cell carcinoma (KIRC), acute myeloid leukaemia (AML), low grade glioma (LGG), lung adenocarcinoma (LUAD), lung squamous cell carcinoma (LUSC), ovarian carcinoma (OV), prostate adenocarcinoma (PRAD), stomach adenocarcinoma (STAD) and uterine corpus endometrial carcinoma (UCEC).	('stomach adenocarcinoma', 'Disease', (477, 499))	('carcinoma', 'Phenotype', 'HP:0030731', (241, 250))	('cancer', 'Disease', (138, 144))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (389, 412))	('lung squamous cell carcinoma', 'Disease', (384, 412))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('carcinoma', 'Phenotype', 'HP:0030731', (366, 375))	('breast adenocarcinoma (BRCA), glioblastoma multiforme', 'Disease', 'MESH:D005909', (152, 205))	('cancer', 'Disease', (104, 110))	('LUAD', 'Disease', 'None', (377, 381))	('myeloid leukaemia', 'Phenotype', 'HP:0012324', (307, 324))	('acute myeloid leukaemia', 'Disease', 'MESH:D007938', (301, 324))	('AML', 'Disease', 'MESH:D015470', (326, 329))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('glioma', 'Disease', (342, 348))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (356, 375))	('prostate adenocarcinoma', 'Disease', (445, 468))	('acute myeloid leukaemia', 'Phenotype', 'HP:0004808', (301, 324))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('AML', 'Disease', (326, 329))	('variants', 'Var', (57, 65))	('stomach adenocarcinoma', 'Disease', 'MESH:D013274', (477, 499))	('glioma', 'Disease', 'MESH:D005910', (342, 348))	('cancer', 'Disease', 'MESH:D009369', (138, 144))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (227, 250))	('carcinoma', 'Phenotype', 'HP:0030731', (283, 292))	('carcinoma', 'Phenotype', 'HP:0030731', (403, 412))	('ovarian carcinoma', 'Disease', (421, 438))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (526, 547))	('carcinoma', 'Phenotype', 'HP:0030731', (164, 173))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (384, 412))	('acute myeloid leukaemia', 'Disease', (301, 324))	('LUAD', 'Disease', (377, 381))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('breast adenocarcinoma', 'Phenotype', 'HP:0003002', (152, 173))	('neck squamous cell carcinoma (HNSC), kidney renal clear cell carcinoma', 'Disease', 'MESH:C538614', (222, 292))	('glioma', 'Phenotype', 'HP:0009733', (342, 348))	('corpus endometrial carcinoma', 'Disease', (519, 547))	('corpus endometrial carcinoma', 'Disease', 'MESH:D016889', (519, 547))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (421, 438))	('glioblastoma', 'Phenotype', 'HP:0012174', (182, 194))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (213, 250))	('lung adenocarcinoma', 'Disease', (356, 375))	('cancer', 'Disease', (35, 41))	('patients', 'Species', '9606', (111, 119))
455271	26689913	Sequencing data for samples from the National Heart Lung and Blood Institute (NHBLI) Women's Health Initiative Exome Sequencing Project (WHISP) were downloaded, processed and used for comparison of genetic variants to TCGA cancer cases.	('Women', 'Species', '9606', (85, 90))	('Nat', 'Gene', (37, 40))	('variants', 'Var', (206, 214))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('cancer', 'Disease', 'MESH:D009369', (223, 229))	('Nat', 'Gene', '6046', (37, 40))	('cancer', 'Disease', (223, 229))
455275	26689913	We identified 2,089 truncation variants (splice site, frameshift indels, nonstop and nonsense) in the TCGA discovery cohort in 624 cancer-associated genes (see Methods and Supplementary Data 2,3,4).	('frameshift indels', 'Var', (54, 71))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('cancer', 'Disease', (131, 137))
455277	26689913	After manual curation, we retained 838 truncation variants in 249 genes previously implicated in cancer (Supplementary Data 2); 69 of them with whole genome sequencing coverage have all been confirmed (Supplementary Data 4).	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('truncation variants', 'Var', (39, 58))	('cancer', 'Disease', (97, 103))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
455286	26689913	As expected, most variants were detected in ovarian and breast cancer cases.	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('variants', 'Var', (18, 26))	('detected', 'Reg', (32, 40))	('breast cancer', 'Phenotype', 'HP:0003002', (56, 69))	('ovarian and breast cancer', 'Disease', 'MESH:D010051', (44, 69))
455288	26689913	The average age at diagnosis of BRCA1 and BRCA2 germline truncation carriers versus non-carriers was non-significantly younger for endometrial (52.7 versus 63.1), stomach (59.7 versus 66.1) and lung (63.0 versus 66.1) cancers, providing support that these variants may contribute to younger onsets of these cancer types, though additional data is required for confirmation and to reach statistical significance.	('BRCA1', 'Gene', (32, 37))	('cancer', 'Disease', (307, 313))	('cancer', 'Disease', 'MESH:D009369', (218, 224))	('variants', 'Var', (256, 264))	('cancer', 'Disease', 'MESH:D009369', (307, 313))	('BRCA2', 'Gene', '675', (42, 47))	('cancer', 'Disease', (218, 224))	('stomach', 'Disease', (163, 170))	('cancers', 'Disease', 'MESH:D009369', (218, 225))	('endometrial', 'Disease', (131, 142))	('cancers', 'Phenotype', 'HP:0002664', (218, 225))	('cancer', 'Phenotype', 'HP:0002664', (307, 313))	('cancers', 'Disease', (218, 225))	('lung', 'Disease', (194, 198))	('germline', 'Var', (48, 56))	('BRCA1', 'Gene', '672', (32, 37))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('BRCA2', 'Gene', (42, 47))
455289	26689913	We also observed 32 truncations in BRCA1 and BRCA2 interacting proteins: PALB2 (n=12, 4 in stomach, 3 in ovarian, 2 in head and neck and each in breast, lung and prostate cancers), BRIP1 (n=16, 3 each in breast, ovarian and lung, 2 in stomach, 1 each in GBM, HNSC, KIRC, LGG and UCEC), and BAP1 (n=2, in kidney) and BARD1 (n=2, 1 each in PRAD and BRCA).	('BRCA', 'Gene', '672', (45, 49))	('BRCA2', 'Gene', '675', (45, 50))	('BRCA', 'Gene', '672', (347, 351))	('prostate cancer', 'Phenotype', 'HP:0012125', (162, 177))	('prostate cancers', 'Phenotype', 'HP:0012125', (162, 178))	('truncations', 'Var', (20, 31))	('BRIP1', 'Gene', '83990', (181, 186))	('PALB2', 'Gene', '79728', (73, 78))	('BRCA', 'Gene', (45, 49))	('BRCA1', 'Gene', '672', (35, 40))	('BAP1', 'Gene', '8314', (290, 294))	('BRCA', 'Gene', (347, 351))	('BRCA1', 'Gene', (35, 40))	('BARD1', 'Gene', '580', (316, 321))	('lung and prostate cancers', 'Disease', 'MESH:D011471', (153, 178))	('BARD1', 'Gene', (316, 321))	('BRCA', 'Gene', '672', (35, 39))	('BRIP1', 'Gene', (181, 186))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('BAP1', 'Gene', (290, 294))	('BRCA2', 'Gene', (45, 50))	('BRCA', 'Gene', (35, 39))	('cancers', 'Phenotype', 'HP:0002664', (171, 178))	('PALB2', 'Gene', (73, 78))
455298	26689913	We also sought to identify genes enriched for truncations that were significantly associated with single or a subset of cancer types.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('associated', 'Reg', (82, 92))	('truncations', 'Var', (46, 57))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('single', 'Disease', (98, 104))
455299	26689913	RAD51C was found to be significant in OV and significant and top ranked in AML, while PALB2 truncations were associated with STAD and OV (Fig.	('associated', 'Reg', (109, 119))	('RAD51C', 'Gene', (0, 6))	('AML', 'Disease', 'MESH:D015470', (75, 78))	('STAD', 'Disease', (125, 129))	('truncations', 'Var', (92, 103))	('AML', 'Disease', (75, 78))	('PALB2', 'Gene', '79728', (86, 91))	('PALB2', 'Gene', (86, 91))	('RAD51C', 'Gene', '5889', (0, 6))
455301	26689913	Significant enrichment of MSH6 (6 were close to the C terminus of the protein) and MRE11A truncations were found in UCEC.	('MSH6', 'Gene', '2956', (26, 30))	('MRE11A', 'Gene', (83, 89))	('MRE11A', 'Gene', '4361', (83, 89))	('MSH6', 'Gene', (26, 30))	('truncations', 'Var', (90, 101))
455306	26689913	Notably, 10 rare PMS2 truncations were found in the validation set, with 4 from UCEC, 2 each from LUAD and LUSC and 1 each from BRCA and PRAD; these observations confirm the significance of PMS2 in susceptibility and broaden its role in cancer types not previously implicated.	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('PMS2', 'Gene', (17, 21))	('PMS2', 'Gene', '5395', (17, 21))	('BRCA', 'Gene', (128, 132))	('truncations', 'Var', (22, 33))	('BRCA', 'Gene', '672', (128, 132))	('PMS2', 'Gene', (190, 194))	('PMS2', 'Gene', '5395', (190, 194))	('cancer', 'Disease', 'MESH:D009369', (237, 243))	('cancer', 'Disease', (237, 243))	('LUAD', 'Disease', 'None', (98, 102))	('significance', 'Reg', (174, 186))	('LUAD', 'Disease', (98, 102))
455307	26689913	Another example is XPA detected as significant using the discovery cohort and confirmed by the identification of two additional rare truncations (E111* and V244fs) in prostate cancer using the validation cohort.	('prostate cancer', 'Phenotype', 'HP:0012125', (167, 182))	('V244fs', 'Mutation', 'p.V244fsX', (156, 162))	('V244fs', 'Var', (156, 162))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('prostate cancer', 'Disease', (167, 182))	('E111*', 'SUBSTITUTION', 'None', (146, 151))	('E111*', 'Var', (146, 151))	('prostate cancer', 'Disease', 'MESH:D011471', (167, 182))
455309	26689913	Overall, our results from the validation cohort strengthen provisional conclusions derived in the discovery phase, but also indicate that larger cohorts are required for accurately assessing frequencies of germline mutations, as well as detecting low frequency events in individual cancer types.	('cancer', 'Disease', (282, 288))	('germline', 'Var', (206, 214))	('cancer', 'Disease', 'MESH:D009369', (282, 288))	('cancer', 'Phenotype', 'HP:0002664', (282, 288))
455315	26689913	Consistent with expectations, BRCA1 and BRCA2 had the highest percentage of significant variants demonstrating LOH (44 of 48 (92%) and 21 of 30 (70%), respectively).	('BRCA1', 'Gene', (30, 35))	('BRCA2', 'Gene', (40, 45))	('BRCA1', 'Gene', '672', (30, 35))	('variants', 'Var', (88, 96))	('BRCA2', 'Gene', '675', (40, 45))	('LOH', 'Disease', (111, 114))
455316	26689913	Other genes demonstrating variants with LOH include: PALB2, which functions in maintenance and repair and cooperates with BRCA2 (ref.)	('PALB2', 'Gene', (53, 58))	('PALB2', 'Gene', '79728', (53, 58))	('variants', 'Var', (26, 34))	('BRCA2', 'Gene', (122, 127))	('BRCA2', 'Gene', '675', (122, 127))
455317	26689913	(5 significant truncation mutations of 11, 45%); ATM, which is activated by double-strand breaks (8 of 17 significant, 47%); BAP1, a transcriptional repressor involved in BRCA1-mediated cell growth suppression (2 of 2, 100%); and FANCM, which plays a role in DNA repair (3 of 9, 33%).	('FANCM', 'Gene', (230, 235))	('ATM', 'Gene', '472', (49, 52))	('BRCA1', 'Gene', (171, 176))	('BAP1', 'Gene', '8314', (125, 129))	('truncation mutations', 'Var', (15, 35))	('BAP1', 'Gene', (125, 129))	('ATM', 'Gene', (49, 52))	('FANCM', 'Gene', '57697', (230, 235))	('BRCA1', 'Gene', '672', (171, 176))
455318	26689913	It is worth noting that although LOH in cases with BRCA1 and BRCA2 truncations mutations were largely restricted to OV and BRCA, the majority of LOH truncations in other genes (for example, ATM, PALB2, BAP1, FANCM) were found across cancer types (Fig.	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('ATM', 'Gene', '472', (190, 193))	('BRCA', 'Gene', '672', (61, 65))	('BRCA', 'Gene', '672', (123, 127))	('mutations', 'Var', (79, 88))	('BRCA', 'Gene', '672', (51, 55))	('BRCA1', 'Gene', '672', (51, 56))	('PALB2', 'Gene', (195, 200))	('BRCA1', 'Gene', (51, 56))	('cancer', 'Disease', 'MESH:D009369', (233, 239))	('BAP1', 'Gene', '8314', (202, 206))	('BRCA', 'Gene', (61, 65))	('truncations mutations', 'Var', (67, 88))	('BRCA', 'Gene', (123, 127))	('ATM', 'Gene', (190, 193))	('BRCA', 'Gene', (51, 55))	('BRCA2', 'Gene', (61, 66))	('PALB2', 'Gene', '79728', (195, 200))	('BAP1', 'Gene', (202, 206))	('truncations', 'Var', (149, 160))	('FANCM', 'Gene', '57697', (208, 213))	('cancer', 'Disease', (233, 239))	('FANCM', 'Gene', (208, 213))	('BRCA2', 'Gene', '675', (61, 66))
455319	26689913	We further compared VAFs of missense variants in the seven significant LOH genes above, finding that four in BRCA1, ATM, BRCA2 and RAD51C are significant.	('BRCA1', 'Gene', (109, 114))	('RAD51C', 'Gene', '5889', (131, 137))	('BRCA2', 'Gene', '675', (121, 126))	('RAD51C', 'Gene', (131, 137))	('ATM', 'Gene', (116, 119))	('missense variants', 'Var', (28, 45))	('BRCA1', 'Gene', '672', (109, 114))	('ATM', 'Gene', '472', (116, 119))	('BRCA2', 'Gene', (121, 126))
455320	26689913	3b) and the potential importance of missense events in cancer.	('missense events', 'Var', (36, 51))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('cancer', 'Disease', (55, 61))
455322	26689913	Of note, our LOH analysis identified G245V in TP53 as highly significant (FDR=1.18e-07) although no rare TP53 truncations were found.	('G245V', 'Mutation', 'rs121912656', (37, 42))	('TP53', 'Gene', '7157', (46, 50))	('TP53', 'Gene', '7157', (105, 109))	('TP53', 'Gene', (46, 50))	('TP53', 'Gene', (105, 109))	('G245V', 'Var', (37, 42))
455323	26689913	To further investigate the effect of missense events on cancer susceptibility, we sought to determine whether there are any larger informative patterns associated with their LOH, specifically whether the significant instances of LOH spatially cluster in or near specific protein regions/domains.	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('missense', 'Var', (37, 45))
455324	26689913	Indeed, analysis shows statistically significant difference in spatial clustering, further supporting the mechanistic roles of these variants in cancer (Fig.	('cancer', 'Disease', (145, 151))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('variants', 'Var', (133, 141))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))
455325	26689913	For example, there is a strong grouping of variants (FDR=0.34%) that overlaps both a kinase-like and a PIK kinase domain near the end of ATM, which participate in chromosome maintenance and repair.	('variants', 'Var', (43, 51))	('ATM', 'Gene', (137, 140))	('ATM', 'Gene', '472', (137, 140))
455330	26689913	Notably, ATM germline truncations were found to be mutually exclusive of TP53 somatic mutations in LUAD (permutation test, P=0.041), consistent with the paradigm that ATM activates TP53 to trigger apoptosis and the need to disrupt only one gene to confer an anti-apoptotic effect.	('LUAD', 'Disease', (99, 103))	('mutations', 'Var', (86, 95))	('apoptosis', 'CPA', (197, 206))	('TP53', 'Gene', '7157', (73, 77))	('TP53', 'Gene', (181, 185))	('ATM', 'Gene', (9, 12))	('trigger', 'PosReg', (189, 196))	('TP53', 'Gene', (73, 77))	('ATM', 'Gene', '472', (9, 12))	('ATM', 'Gene', (167, 170))	('LUAD', 'Disease', 'None', (99, 103))	('TP53', 'Gene', '7157', (181, 185))	('ATM', 'Gene', '472', (167, 170))
455332	26689913	BRCA1 germline truncations have previously been reported to be associated with the basal subtype breast cancer, which tends to exhibit a molecular profile similar to ovarian cancer.	('BRCA1', 'Gene', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('associated', 'Reg', (63, 73))	('basal subtype breast cancer', 'Disease', (83, 110))	('ovarian cancer', 'Phenotype', 'HP:0100615', (166, 180))	('breast cancer', 'Phenotype', 'HP:0003002', (97, 110))	('basal subtype breast cancer', 'Disease', 'MESH:D001943', (83, 110))	('ovarian cancer', 'Disease', 'MESH:D010051', (166, 180))	('BRCA1', 'Gene', '672', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('germline truncations', 'Var', (6, 26))	('ovarian cancer', 'Disease', (166, 180))
455334	26689913	In addition, we also observed a co-occurrence of BRCA2 germline truncations and TP53 somatic mutations in ovarian cancer, as expected.	('ovarian cancer', 'Disease', 'MESH:D010051', (106, 120))	('ovarian cancer', 'Phenotype', 'HP:0100615', (106, 120))	('BRCA2', 'Gene', '675', (49, 54))	('TP53', 'Gene', '7157', (80, 84))	('TP53', 'Gene', (80, 84))	('ovarian cancer', 'Disease', (106, 120))	('germline', 'Var', (55, 63))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('BRCA2', 'Gene', (49, 54))
455335	26689913	Our data suggest that the combinational effects of BRCA1/BRCA2 germline mutations, along with the high frequency of LOH events and somatic TP53 mutations result in aggressive basal subtype breast cancer and ovarian cancer.	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('aggressive basal subtype breast cancer', 'Disease', (164, 202))	('BRCA1', 'Gene', '672', (51, 56))	('ovarian cancer', 'Disease', (207, 221))	('BRCA2', 'Gene', (57, 62))	('breast cancer', 'Phenotype', 'HP:0003002', (189, 202))	('TP53', 'Gene', '7157', (139, 143))	('result in', 'Reg', (154, 163))	('BRCA1', 'Gene', (51, 56))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('BRCA2', 'Gene', '675', (57, 62))	('TP53', 'Gene', (139, 143))	('aggressive basal subtype breast cancer', 'Disease', 'MESH:D001943', (164, 202))	('mutations', 'Var', (144, 153))	('ovarian cancer', 'Disease', 'MESH:D010051', (207, 221))	('ovarian cancer', 'Phenotype', 'HP:0100615', (207, 221))
455338	26689913	Analysis of the expanded 34 burden test genes revealed that patients with germline BRCA1 and BRCA2 truncations had significantly higher somatic mutation frequencies than cases without such changes in both breast and ovarian cancers (Fig.	('BRCA1', 'Gene', '672', (83, 88))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('BRCA2', 'Gene', '675', (93, 98))	('truncations', 'Var', (99, 110))	('patients', 'Species', '9606', (60, 68))	('higher', 'PosReg', (129, 135))	('ovarian cancer', 'Phenotype', 'HP:0100615', (216, 230))	('breast and ovarian cancers', 'Disease', 'MESH:D010051', (205, 231))	('BRCA1', 'Gene', (83, 88))	('ovarian cancers', 'Phenotype', 'HP:0100615', (216, 231))	('cancers', 'Phenotype', 'HP:0002664', (224, 231))	('somatic mutation frequencies', 'MPA', (136, 164))	('germline', 'Var', (74, 82))	('BRCA2', 'Gene', (93, 98))
455342	26689913	In UCEC, MSH6 germline truncations are found to be significantly associated with higher mutation frequencies, as expected (Wilcoxon rank-sum test, P=0.014) (Fig.	('germline truncations', 'Var', (14, 34))	('MSH6', 'Gene', (9, 13))	('higher', 'PosReg', (81, 87))	('mutation frequencies', 'MPA', (88, 108))	('MSH6', 'Gene', '2956', (9, 13))
455346	26689913	Not surprisingly, we found that germline truncation variants in 47 Fanconi Anaemia genes and 114 cancer susceptibility reported in Rahman et al.	('Fanconi Anaemia', 'Disease', (67, 82))	('cancer', 'Disease', (97, 103))	('Anaemia', 'Phenotype', 'HP:0001903', (75, 82))	('Fanconi Anaemia', 'Phenotype', 'HP:0001994', (67, 82))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('germline truncation variants', 'Var', (32, 60))	('Fanconi Anaemia', 'Disease', 'MESH:D005199', (67, 82))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
455348	26689913	To investigate the effect of missense variants on BRCA1 function and evaluate LOH analysis for missense variants, 68 variants were selected based on MAF and protein domains for functional validation using the HDR assay (see Methods and Supplementary Data 21); 47 of them had previously been assigned as variants of unknown clinical importance in the NHGRI BIC database and 15 variants were not reported at all in BIC.	('BRCA1', 'Gene', (50, 55))	('variants', 'Var', (104, 112))	('MAF', 'Gene', '4094', (149, 152))	('MAF', 'Gene', (149, 152))	('BRCA1', 'Gene', '672', (50, 55))
455349	26689913	One known deleterious truncation mutation in the carboxyl terminus of the BRCA1 protein Q1779fs and three other truncations:E1250*, E1415fs and E23fs:discovered in UCEC were also included in the experiment.	('Q1779fs', 'Var', (88, 95))	('E1415fs', 'Var', (132, 139))	('Q1779fs', 'Mutation', 'rs80357590', (88, 95))	('E23fs', 'Var', (144, 149))	('E1250*', 'Var', (124, 130))	('BRCA1', 'Gene', '672', (74, 79))	('E1415fs', 'Mutation', 'rs80357981', (132, 139))	('BRCA1', 'Gene', (74, 79))	('E23fs', 'Mutation', 'rs80357914', (144, 149))
455350	26689913	We successfully introduced 68 missense variants and 4 truncation variants into full-length BRCA1 expression plasmid pcDNA-5'HA-BRCA1 for the in vitro HDR assay as previously described (Supplementary Data 21).	('BRCA1', 'Gene', (91, 96))	('BRCA1', 'Gene', '672', (127, 132))	('BRCA1', 'Gene', (127, 132))	('missense variants', 'Var', (30, 47))	('BRCA1', 'Gene', '672', (91, 96))
455352	26689913	Among all tested variants, all four truncations (three from UCEC) and six missense variants retained less than 30% of homologous recombination activities relative to WT BRCA1, and are therefore considered HDR-defective (Supplementary Data 22).	('less', 'NegReg', (101, 105))	('homologous recombination activities', 'MPA', (118, 153))	('variants', 'Var', (17, 25))	('BRCA1', 'Gene', '672', (169, 174))	('BRCA1', 'Gene', (169, 174))
455353	26689913	These missense variants included C61G (observed in four cases), C64G (two cases), T1685I (one case), R1699W (two cases), L1786P (one case) and G1788V (one case); all of them showed significant enrichments in the tumour samples based on LOH analysis (Fig.	('L1786P', 'Var', (121, 127))	('G1788V', 'Mutation', 'rs80357069', (143, 149))	('R1699W', 'Mutation', 'rs55770810', (101, 107))	('tumour', 'Phenotype', 'HP:0002664', (212, 218))	('L1786P', 'Mutation', 'rs398122697', (121, 127))	('T1685I', 'Mutation', 'rs80357043', (82, 88))	('T1685I', 'Var', (82, 88))	('G1788V', 'Var', (143, 149))	('R1699W', 'Var', (101, 107))	('tumour', 'Disease', 'MESH:D009369', (212, 218))	('tumour', 'Disease', (212, 218))	('C61G', 'Var', (33, 37))	('C64G', 'Mutation', 'rs80357064', (64, 68))	('C61G', 'Mutation', 'rs28897672', (33, 37))	('C64G', 'Var', (64, 68))
455354	26689913	Comparative analysis of RNA-seq data from two carriers and four non-carriers suggests C64G is in fact a variant affecting splicing (Supplementary Fig.	('affecting', 'Reg', (112, 121))	('C64G', 'Mutation', 'rs80357064', (86, 90))	('splicing', 'MPA', (122, 130))	('C64G', 'Var', (86, 90))
455357	26689913	Our analysis of the crystal structure of the BRCT domain showed that the substitution of leucine with proline in L1786P will likely result in the termination of the alpha helix structure, which may cause the loss of BRCA1 HDR function.	('alpha helix structure', 'MPA', (165, 186))	('proline', 'Chemical', 'MESH:D011392', (102, 109))	('function', 'MPA', (226, 234))	('BRCA1', 'Gene', (216, 221))	('leucine', 'Var', (89, 96))	('loss', 'NegReg', (208, 212))	('termination', 'NegReg', (146, 157))	('L1786P', 'Var', (113, 119))	('leucine', 'Chemical', 'MESH:D007930', (89, 96))	('L1786P', 'Mutation', 'rs398122697', (113, 119))	('BRCA1', 'Gene', '672', (216, 221))
455358	26689913	Interestingly, additional three variants, A1708V, M1783T and R1835Q (from one patient each) consistently displayed less than 70% HDR function in comparison to WT BRCA1 (partial HDR-defective, Fig.	('less', 'NegReg', (115, 119))	('HDR function', 'MPA', (129, 141))	('patient', 'Species', '9606', (78, 85))	('BRCA1', 'Gene', '672', (162, 167))	('BRCA1', 'Gene', (162, 167))	('M1783T', 'Var', (50, 56))	('R1835Q', 'Mutation', 'rs273902776', (61, 67))	('M1783T', 'Mutation', 'rs55808233', (50, 56))	('A1708V', 'Mutation', 'rs28897696', (42, 48))	('A1708V', 'Var', (42, 48))	('R1835Q', 'Var', (61, 67))
455359	26689913	It is worth noting that A1708V and R1835Q were found in male patients with kidney and stomach cancers, respectively; both developed cancers at age of 48.	('cancers', 'Disease', 'MESH:D009369', (94, 101))	('cancers', 'Disease', (132, 139))	('stomach cancers', 'Phenotype', 'HP:0012126', (86, 101))	('cancers', 'Disease', 'MESH:D009369', (132, 139))	('R1835Q', 'Mutation', 'rs273902776', (35, 41))	('stomach cancer', 'Phenotype', 'HP:0012126', (86, 100))	('patients', 'Species', '9606', (61, 69))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('A1708V', 'Var', (24, 30))	('R1835Q', 'Var', (35, 41))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('A1708V', 'Mutation', 'rs28897696', (24, 30))	('kidney and stomach cancers', 'Disease', 'MESH:D013274', (75, 101))	('cancers', 'Phenotype', 'HP:0002664', (94, 101))	('cancers', 'Phenotype', 'HP:0002664', (132, 139))	('cancers', 'Disease', (94, 101))
455360	26689913	A1708V has previously been characterized as a low-to-moderate risk variant and R1835Q has been identified in a Malay population of early-onset breast cancer patients with a personal or family breast cancer history.	('breast cancer', 'Disease', 'MESH:D001943', (143, 156))	('R1835Q', 'Mutation', 'rs273902776', (79, 85))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('breast cancer', 'Disease', 'MESH:D001943', (192, 205))	('breast cancer', 'Disease', (143, 156))	('breast cancer', 'Disease', (192, 205))	('breast cancer', 'Phenotype', 'HP:0003002', (143, 156))	('breast cancer', 'Phenotype', 'HP:0003002', (192, 205))	('R1835Q', 'Var', (79, 85))	('patients', 'Species', '9606', (157, 165))	('A1708V', 'Mutation', 'rs28897696', (0, 6))	('A1708V', 'Var', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
455361	26689913	One endometrial cancer patient harbouring M1783T was diagnosed at age of 65.	('M1783T', 'Var', (42, 48))	('endometrial cancer', 'Phenotype', 'HP:0012114', (4, 22))	('M1783T', 'Mutation', 'rs55808233', (42, 48))	('endometrial cancer', 'Disease', 'MESH:D016889', (4, 22))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('endometrial cancer', 'Disease', (4, 22))	('patient', 'Species', '9606', (23, 30))
455362	26689913	The BRCA1 protein harbouring this variant was previously shown to possess enhanced protease sensitivity.	('protein', 'Protein', (10, 17))	('BRCA1', 'Gene', (4, 9))	('protease sensitivity', 'MPA', (83, 103))	('BRCA1', 'Gene', '672', (4, 9))	('variant', 'Var', (34, 41))	('enhanced', 'PosReg', (74, 82))
455363	26689913	In addition, these nine HDR-defective (or partial HDR defective) missense variants are mutually exclusive to BRCA1 somatic mutations and germline truncation variants (Supplementary Data 2 and 14).	('HDR-defective', 'Disease', (24, 37))	('missense variants', 'Var', (65, 82))	('BRCA1', 'Gene', (109, 114))	('BRCA1', 'Gene', '672', (109, 114))
455364	26689913	Using the systematic BRCA1 missense variant validation data, we evaluated the prediction power of LOH analysis for identifying candidate variants of functional relevance.	('BRCA1', 'Gene', '672', (21, 26))	('BRCA1', 'Gene', (21, 26))	('variants', 'Var', (137, 145))
455367	26689913	Our systematic analysis indicated that an estimated 18% of cancer cases from the TCGA cohort had >=1 rare truncations in 624 genes associated with cancer.	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('624', 'Gene', (121, 124))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('truncations', 'Var', (106, 117))	('cancer', 'Disease', (147, 153))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))
455368	26689913	Further, there was significant enrichment of rare truncation variants in 13 genes and suggestive evidence of increases in 21 more, comprising 8.3% (333 out of 4,034) of TCGA cancer cases.	('cancer', 'Disease', (174, 180))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('truncation variants', 'Var', (50, 69))	('increases', 'PosReg', (109, 118))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))
455370	26689913	Across cancer types, a higher percentage of breast and ovarian cancer cases were identified as having rare truncation variants in cancer genes versus other cancer types, due predominantly to high frequencies in BRCA1/2.	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('cancer', 'Disease', 'MESH:D009369', (7, 13))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('cancer', 'Disease', (156, 162))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('cancer', 'Disease', (130, 136))	('truncation variants', 'Var', (107, 126))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('BRCA1/2', 'Gene', (211, 218))	('breast and ovarian cancer', 'Disease', 'MESH:D010051', (44, 69))	('ovarian cancer', 'Phenotype', 'HP:0100615', (55, 69))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('cancer', 'Disease', (7, 13))	('BRCA1/2', 'Gene', '672;675', (211, 218))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('cancer', 'Disease', (63, 69))
455371	26689913	The percentage of breast and ovarian cancer cases carrying BRCA1/2 germline truncation variants in the TCGA cohort was 4.4% and 11.6%, respectively, consistent with previous reports.	('breast and ovarian cancer', 'Disease', 'MESH:D010051', (18, 43))	('BRCA1/2', 'Gene', '672;675', (59, 66))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('ovarian cancer', 'Phenotype', 'HP:0100615', (29, 43))	('BRCA1/2', 'Gene', (59, 66))	('germline', 'Var', (67, 75))
455372	26689913	Interestingly, stomach cancer has the second highest percentage of rare truncations in 114 genes previously reported, largely due to the contributions from ATM, BRIP1, PALB2, XRCC2 and others.	('stomach cancer', 'Disease', 'MESH:D013274', (15, 29))	('rare truncations', 'Var', (67, 83))	('XRCC2', 'Gene', '7516', (175, 180))	('ATM', 'Gene', '472', (156, 159))	('XRCC2', 'Gene', (175, 180))	('stomach cancer', 'Phenotype', 'HP:0012126', (15, 29))	('stomach cancer', 'Disease', (15, 29))	('BRIP1', 'Gene', (161, 166))	('PALB2', 'Gene', (168, 173))	('PALB2', 'Gene', '79728', (168, 173))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('BRIP1', 'Gene', '83990', (161, 166))	('ATM', 'Gene', (156, 159))
455374	26689913	Our results indicated that germline truncation and missense variants in several genes were under selection in the tumour, with ATM, BRCA1, BRCA2 and RAD51C determined as significant from both truncation and missense analyses and BAP1, BRIP1, FANCM, PALB2 and RAD51D from truncation analysis alone.	('BRCA1', 'Gene', '672', (132, 137))	('BAP1', 'Gene', '8314', (229, 233))	('BRCA2', 'Gene', '675', (139, 144))	('RAD51D', 'Gene', (259, 265))	('BRCA1', 'Gene', (132, 137))	('RAD51C', 'Gene', '5889', (149, 155))	('ATM', 'Gene', (127, 130))	('missense', 'Var', (207, 215))	('tumour', 'Phenotype', 'HP:0002664', (114, 120))	('BRIP1', 'Gene', '83990', (235, 240))	('BAP1', 'Gene', (229, 233))	('tumour', 'Disease', 'MESH:D009369', (114, 120))	('tumour', 'Disease', (114, 120))	('RAD51C', 'Gene', (149, 155))	('PALB2', 'Gene', (249, 254))	('FANCM', 'Gene', '57697', (242, 247))	('RAD51D', 'Gene', '5892', (259, 265))	('FANCM', 'Gene', (242, 247))	('missense variants', 'Var', (51, 68))	('PALB2', 'Gene', '79728', (249, 254))	('BRCA2', 'Gene', (139, 144))	('BRIP1', 'Gene', (235, 240))	('ATM', 'Gene', '472', (127, 130))
455376	26689913	More importantly, our integrated germline and somatic study identified BRCA1, BRCA2, RAD51C, RAD51D, FANCM, EME1 and MSH6 germline truncations significantly associated with increased somatic mutation frequencies in specific cancer types, suggesting that germline defects in DNA repair expand to the somatic level.	('germline', 'Var', (122, 130))	('increased', 'PosReg', (173, 182))	('cancer', 'Disease', (224, 230))	('somatic mutation frequencies', 'CPA', (183, 211))	('FANCM', 'Gene', '57697', (101, 106))	('truncations', 'Var', (131, 142))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('MSH6', 'Gene', (117, 121))	('BRCA2', 'Gene', (78, 83))	('FANCM', 'Gene', (101, 106))	('MSH6', 'Gene', '2956', (117, 121))	('RAD51C', 'Gene', '5889', (85, 91))	('RAD51D', 'Gene', (93, 99))	('associated', 'Reg', (157, 167))	('RAD51C', 'Gene', (85, 91))	('EME1', 'Gene', '146956', (108, 112))	('BRCA1', 'Gene', '672', (71, 76))	('cancer', 'Disease', 'MESH:D009369', (224, 230))	('BRCA2', 'Gene', '675', (78, 83))	('BRCA1', 'Gene', (71, 76))	('EME1', 'Gene', (108, 112))	('RAD51D', 'Gene', '5892', (93, 99))
455377	26689913	Further, our search for co-occurring or mutually exclusive germline truncation/somatic mutations across 12 cancer types revealed a number of important insights in terms of genes and pathways involved including: (1) the association between germline BRCA1/2 germline truncations and frequent TP53 and infrequent PIK3CA somatic mutations confirm breast cancer clinical subtype classification; and (2) ATM as a bona fide (third frequently truncated) susceptibility gene demonstrated by both burden and LOH analyses is the only common gene highly mutated at both germline and somatic levels.	('PIK3CA', 'Gene', '5290', (310, 316))	('BRCA1/2', 'Gene', (248, 255))	('breast cancer', 'Disease', 'MESH:D001943', (343, 356))	('breast cancer', 'Phenotype', 'HP:0003002', (343, 356))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('cancer', 'Disease', 'MESH:D009369', (350, 356))	('breast cancer', 'Disease', (343, 356))	('ATM', 'Gene', (398, 401))	('cancer', 'Disease', (350, 356))	('mutations', 'Var', (325, 334))	('BRCA1/2', 'Gene', '672;675', (248, 255))	('TP53', 'Gene', '7157', (290, 294))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('PIK3CA', 'Gene', (310, 316))	('cancer', 'Phenotype', 'HP:0002664', (350, 356))	('cancer', 'Disease', (107, 113))	('TP53', 'Gene', (290, 294))	('ATM', 'Gene', '472', (398, 401))
455379	26689913	In addition, the vast majority of TCGA cases in our sample set were of European background, emphasizing the need for the development of a reference source of genomic data on germline cancer predisposition variants from ancestrally diverse population groups.	('cancer', 'Disease', (183, 189))	('TCGA', 'Disease', (34, 38))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('variants', 'Var', (205, 213))	('cancer', 'Disease', 'MESH:D009369', (183, 189))
455381	26689913	The combination of high throughput discovery and experimental validation should identify the most functionally and clinically relevant variants for cancer risk assessment.	('cancer', 'Disease', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('variants', 'Var', (135, 143))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))
455382	26689913	Approval for access to TCGA case sequence and clinical data was obtained from the database of Genotypes and Phenotypes (dbGaP) (document #3281 Discover germline cancer predisposition variants).	('cancer', 'Disease', (161, 167))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('variants', 'Var', (183, 191))
455385	26689913	For comparative analysis, all ESP variants were filtered for <0.1% total MAF to minimize false-positives.	('MAF', 'Gene', (73, 76))	('variants', 'Var', (34, 42))	('MAF', 'Gene', '4094', (73, 76))
455387	26689913	Germline SNPs were identified using Varscan (version 2.2.6 with default parameters except -min-var-freq 0.10--P value 0.1--min-coverage 8-map-quality 10) and GATK (revision5336) in single-sample mode for normal and tumour BAMs.	('tumour', 'Disease', (215, 221))	('tumour', 'Phenotype', 'HP:0002664', (215, 221))	('tumour', 'Disease', 'MESH:D009369', (215, 221))	('revision5336', 'Var', (164, 176))
455389	26689913	Germline indels were identified using Varscan 2.2.9 (with default parameters except --min-coverage 3-min-var-freq 0.2-P-value 0.10-strand-filter 1-map-quality 10) and GATK (revision5336, only for AML, BRCA, OV and UCEC) in a single-sample mode.	('revision5336', 'Var', (173, 185))	('BRCA', 'Gene', '672', (201, 205))	('AML', 'Disease', 'MESH:D015470', (196, 199))	('BRCA', 'Gene', (201, 205))	('AML', 'Disease', (196, 199))
455391	26689913	For each cancer type, all variants were limited to coding regions of full length transcripts obtained from Ensembl release 70.	('cancer', 'Disease', (9, 15))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('variants', 'Var', (26, 34))
455394	26689913	Thirty-nine additional genes were included based on the analysis of driver mutations in publicly available TCGA data, the published guidelines for return of results of the American College of Genetics and Genomics and 18 novel cancer driver genes identified in recently published large-scale studies.	('TCGA', 'Gene', (107, 111))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('mutations', 'Var', (75, 84))	('cancer', 'Disease', (227, 233))	('cancer', 'Disease', 'MESH:D009369', (227, 233))
455395	26689913	Recurrent somatic mutations were extracted from the high confidence filtered set of somatic mutations and germline variants overlapping them were further filtered to remove those having a reported global MAF>0.5% in the NHLBI Exomes (ESP6500SI-V2).	('MAF', 'Gene', (204, 207))	('ESP6500SI-V2', 'Var', (234, 246))	('MAF', 'Gene', '4094', (204, 207))
455396	26689913	Remaining variants were filtered to remove artifacts due to ambiguous alignments, simple repeats, reference sequence errors, putative somatic mutations in adjacent normal tissue, somatic mutations associated with clonal expansion in blood and variants with a VAF<10% in tumour or normal.	('tumour', 'Disease', 'MESH:D009369', (270, 276))	('tumour', 'Phenotype', 'HP:0002664', (270, 276))	('tumour', 'Disease', (270, 276))	('variants', 'Var', (243, 251))
455397	26689913	This included three cases carrying CYP2D6 (H352R), as well as one carrier of ABCC2 (E943K; rs3740065).	('ABCC2', 'Gene', (77, 82))	('H352R', 'Mutation', 'rs61736517', (43, 48))	('ABCC2', 'Gene', '1244', (77, 82))	('E943K', 'Mutation', 'rs3740065', (84, 89))	('CYP2D6', 'Gene', '1565', (35, 41))	('E943K; rs3740065', 'Var', (84, 100))	('rs3740065', 'Mutation', 'rs3740065', (91, 100))	('CYP2D6', 'Gene', (35, 41))
455398	26689913	Variants in both genes have been reported to be associated with poor outcome in post-menopausal women treated with tamoxifen but their association with cancer predisposition remains undetermined.	('Variants', 'Var', (0, 8))	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('associated', 'Reg', (48, 58))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('women', 'Species', '9606', (96, 101))	('tamoxifen', 'Chemical', 'MESH:D013629', (115, 124))
455399	26689913	In addition, a germline variant at somatic R423Q site was found in the CARD11 oncogene and another germline variant S650L in PDGFRB was identified.	('PDGFRB', 'Gene', '5159', (125, 131))	('CARD11', 'Gene', (71, 77))	('CARD11', 'Gene', '84433', (71, 77))	('R423Q', 'Mutation', 'rs577877958', (43, 48))	('PDGFRB', 'Gene', (125, 131))	('S650L', 'Var', (116, 121))	('S650L', 'Mutation', 'rs758280032', (116, 121))
455400	26689913	Interestingly, a FLT3 germline variant (R387Q) was identified to have an overlapping somatic mutation in endometrial cancer.	('endometrial cancer', 'Disease', 'MESH:D016889', (105, 123))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('endometrial cancer', 'Phenotype', 'HP:0012114', (105, 123))	('R387Q', 'Var', (40, 45))	('FLT3', 'Gene', '2322', (17, 21))	('endometrial cancer', 'Disease', (105, 123))	('R387Q', 'Mutation', 'rs751562024', (40, 45))	('FLT3', 'Gene', (17, 21))
455405	26689913	Burden test analysis was performed by comparing the frequency of rare germline truncation mutations in cancer-associated genes from the Pan-Cancer 12 germline data set (from 12 cancer types; cohort size=4,034) with WHI 1,039 control samples and those downloaded from the NHLBI ESP (6,503 including 2,203 African-Americans and 4,300 European-Americans unrelated individuals).	('cancer', 'Disease', (177, 183))	('cancer', 'Disease', 'MESH:D009369', (177, 183))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('Cancer', 'Phenotype', 'HP:0002664', (140, 146))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('germline truncation mutations', 'Var', (70, 99))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))
455406	26689913	The truncation variants (nonsense, splice_site, and frameshift indels) from both groups were limited to a list of genes previously associated with cancer (see cancer-associated genes section).	('cancer', 'Disease', (159, 165))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('frameshift indels', 'Var', (52, 69))	('associated', 'Reg', (131, 141))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('cancer', 'Disease', (147, 153))	('cancer', 'Disease', 'MESH:D009369', (159, 165))
455410	26689913	The evaluation at each tumour variant site (truncation or missense) is based on two complementary aspects related to its VAF: (1) whether it is significantly higher than the VAF at its corresponding site in the matched normal sample and (2) whether it is significantly higher than the characteristic VAF in the general population of genes having somatic mutations.	('tumour', 'Phenotype', 'HP:0002664', (23, 29))	('tumour', 'Disease', 'MESH:D009369', (23, 29))	('variant', 'Var', (30, 37))	('higher', 'PosReg', (158, 164))	('tumour', 'Disease', (23, 29))	('higher', 'PosReg', (269, 275))
455411	26689913	The first aspect was implemented using Fisher's exact test on a 2 x 2 table of allele type (reference and variant) versus sample type (tumour and normal).	('tumour', 'Disease', 'MESH:D009369', (135, 141))	('tumour', 'Phenotype', 'HP:0002664', (135, 141))	('tumour', 'Disease', (135, 141))	('variant', 'Var', (106, 113))
455417	26689913	Variants were incorporated into a full-length BRCA1 expression plasmid, pcDNA-5'HA-BRCA1, using Q5 site-directed mutagenesis kit (New England BioLabs).	('Variants', 'Var', (0, 8))	('BRCA1', 'Gene', '672', (83, 88))	('BRCA1', 'Gene', '672', (46, 51))	('BRCA1', 'Gene', (83, 88))	('BRCA1', 'Gene', (46, 51))
455419	26689913	Co-transfection of HeLa-DR cells with the BRCA1 expression plasmid containing the test variant and siRNA targeting the 3'-untranslated region of the BRCA1 gene to deplete endogenous BRCA1 expression was performed.	('BRCA1', 'Gene', '672', (42, 47))	('BRCA1', 'Gene', '672', (182, 187))	('HeLa-DR', 'CellLine', 'CVCL:0030', (19, 26))	('expression', 'MPA', (188, 198))	('BRCA1', 'Gene', (42, 47))	('BRCA1', 'Gene', (182, 187))	('BRCA1', 'Gene', '672', (149, 154))	('BRCA1', 'Gene', (149, 154))	('variant', 'Var', (87, 94))
455421	26689913	All BRCA1 variants were tested in triplicate and the percentage of cells with GFP expression was normalized to the rescue by wild-type BRCA1 expression plasmid.	('BRCA1', 'Gene', (4, 9))	('variants', 'Var', (10, 18))	('BRCA1', 'Gene', '672', (135, 140))	('BRCA1', 'Gene', (135, 140))	('BRCA1', 'Gene', '672', (4, 9))
455422	24947164	Nicotine and oxidative stress induced exomic variations are concordant and overrepresented in cancer-associated genes Although the connection between cancer and cigarette smoke is well established, nicotine is not characterized as a carcinogen.	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('oxidative stress', 'Phenotype', 'HP:0025464', (13, 29))	('nicotine', 'Chemical', 'MESH:D009538', (198, 206))	('Nicotine', 'Chemical', 'MESH:D009538', (0, 8))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('variations', 'Var', (45, 55))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('cancer', 'Disease', (150, 156))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
455423	24947164	Here, we used exome sequencing to identify nicotine and oxidative stress-induced somatic mutations in normal human epithelial cells and its correlation with cancer.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('human', 'Species', '9606', (109, 114))	('nicotine', 'Chemical', 'MESH:D009538', (43, 51))	('nicotine', 'MPA', (43, 51))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('cancer', 'Disease', (157, 163))	('mutations', 'Var', (89, 98))	('oxidative stress', 'Phenotype', 'HP:0025464', (56, 72))
455424	24947164	We identified over 6,400 SNVs, indels and microsatellites in each of the stress exposed cells relative to the control, of which, 2,159 were consistently observed at all nicotine doses.	('microsatellites', 'Var', (42, 57))	('observed', 'Reg', (153, 161))	('indels', 'Var', (31, 37))	('nicotine', 'Chemical', 'MESH:D009538', (169, 177))
455427	24947164	Nicotine induced mutations were distributed across 1,585 genes, of which 49% were associated with cancer.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('associated', 'Reg', (82, 92))	('Nicotine', 'Chemical', 'MESH:D009538', (0, 8))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('cancer', 'Disease', (98, 104))	('mutations', 'Var', (17, 26))
455429	24947164	Analysis of 591 lung carcinoma tumor exomes from The Cancer Genome Atlas (TCGA) revealed that 20% of non-small-cell lung cancer tumors in smokers have mutations in at least one of the MUC4, MUC6 or MUC12 genes in contrast to only 6% in non-smokers.	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (105, 127))	('lung cancer', 'Phenotype', 'HP:0100526', (116, 127))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (101, 127))	('lung cancer tumors', 'Disease', 'MESH:D008175', (116, 134))	('MUC12', 'Gene', (198, 203))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (53, 72))	('MUC6', 'Gene', (190, 194))	('mutations', 'Var', (151, 160))	('MUC6', 'Gene', '4588', (190, 194))	('Cancer Genome Atlas', 'Disease', (53, 72))	('MUC4', 'Gene', '4585', (184, 188))	('MUC12', 'Gene', '10071', (198, 203))	('MUC4', 'Gene', (184, 188))	('carcinoma', 'Phenotype', 'HP:0030731', (21, 30))	('lung carcinoma tumor', 'Disease', 'MESH:D009369', (16, 36))	('Cancer', 'Phenotype', 'HP:0002664', (53, 59))	('lung cancer tumors', 'Disease', (116, 134))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('lung carcinoma tumor', 'Disease', (16, 36))
455441	24947164	Aberrant activation of NF-kB through oncogenic mutations in regulatory genes is associated with cancer.	('activation', 'PosReg', (9, 19))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('NF-kB', 'Protein', (23, 28))	('mutations', 'Var', (47, 56))	('associated', 'Reg', (80, 90))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Disease', (96, 102))
455447	24947164	This study suggests that nicotine exposure can adversely affect the human genome by inducing somatic mutations and over the period of significant exposure, may contribute to increased cancer incidence, characterizing nicotine as a carcinogen or mutagen.	('cancer', 'Disease', (184, 190))	('nicotine', 'Var', (25, 33))	('human', 'Species', '9606', (68, 73))	('contribute', 'Reg', (160, 170))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('nicotine', 'Chemical', 'MESH:D009538', (217, 225))	('nicotine', 'Chemical', 'MESH:D009538', (25, 33))	('inducing', 'Reg', (84, 92))	('somatic mutations', 'CPA', (93, 110))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('increased', 'PosReg', (174, 183))
455448	24947164	We further identified specific mutation targets that could be used for lung cancer diagnosis, prognosis and as an indicator for those exposed to nicotine.	('nicotine', 'Chemical', 'MESH:D009538', (145, 153))	('lung cancer', 'Disease', 'MESH:D008175', (71, 82))	('mutation', 'Var', (31, 39))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('lung cancer', 'Disease', (71, 82))	('lung cancer', 'Phenotype', 'HP:0100526', (71, 82))
455454	24947164	Compared to the unexposed control, we identified a total of 6,506, 6,610, and 7,138 single nucleotide (SNVs), indel and microsatellite variations in 0.5, 3 and 5mM nicotine stressed cells, respectively.	('indel', 'Var', (110, 115))	('microsatellite variations', 'Var', (120, 145))	('nicotine', 'Chemical', 'MESH:D009538', (164, 172))	('single nucleotide', 'Var', (84, 101))
455455	24947164	In comparison, we identified 6,804 total variations in hydrogen peroxide (oxidative stress) stressed cells, which included 1,251 nsSNVs, of which 211 were cancer associated and 191 were predicted as functionally damaging by Polyphen (Table 1).	('Polyphen', 'Chemical', '-', (224, 232))	('hydrogen peroxide', 'Chemical', 'MESH:D006861', (55, 72))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('variations', 'Var', (41, 51))	('cancer', 'Disease', (155, 161))	('cancer', 'Disease', 'MESH:D009369', (155, 161))	('oxidative stress', 'Phenotype', 'HP:0025464', (74, 90))
455457	24947164	The COSMIC (Catalogue of Somatic Mutations in Cancer) database indicated 79 of the 2,159 mutations had an association with cancer.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('association', 'Interaction', (106, 117))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('cancer', 'Disease', (123, 129))	('mutations', 'Var', (89, 98))	('Cancer', 'Phenotype', 'HP:0002664', (46, 52))
455485	24947164	However, of the consistently induced variants at all nicotine doses, 81% of the SNVs and indels and 100% of the microsatellite variations were concordant with those observed in the oxidative stress induced samples (Table 2).	('variants', 'Var', (37, 45))	('induced', 'Reg', (29, 36))	('nicotine', 'Chemical', 'MESH:D009538', (53, 61))	('oxidative stress', 'Phenotype', 'HP:0025464', (181, 197))
455489	24947164	We found that 18% (66 of 360) lung adenocarcinoma tumor samples in smokers had mutations in at least one of these three MUC genes (p-value <=0.03), in contrast to just 7% (4 of 58) from non-smokers.	('lung adenocarcinoma tumor', 'Disease', (30, 55))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (30, 49))	('MUC', 'Gene', '100508689', (120, 123))	('MUC', 'Gene', (120, 123))	('lung adenocarcinoma tumor', 'Disease', 'MESH:D000077192', (30, 55))	('carcinoma', 'Phenotype', 'HP:0030731', (40, 49))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('mutations', 'Var', (79, 88))
455490	24947164	Similarly, 23% (38 of 167) squamous cell carcinoma tumor samples from smokers had mutations in at least one of these three MUC genes, whereas no mutations (0 of 6) were detected in any of three MUC genes in non-smokers (p-value <=0.3).	('MUC', 'Gene', '100508689', (194, 197))	('carcinoma', 'Phenotype', 'HP:0030731', (41, 50))	('squamous cell carcinoma tumor', 'Disease', (27, 56))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('MUC', 'Gene', (123, 126))	('squamous cell carcinoma tumor', 'Disease', 'MESH:D002294', (27, 56))	('MUC', 'Gene', '100508689', (123, 126))	('mutations', 'Var', (82, 91))	('MUC', 'Gene', (194, 197))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (27, 50))
455491	24947164	Overall, 20% of all non-small-cell lung carcinoma (NSCLC) tumors in smokers had mutations in at least one of three MUC genes in contrast to only 6% in non-smokers (p-value <=0.006) (Supplementary Table S3).	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('mutations', 'Var', (80, 89))	('carcinoma', 'Phenotype', 'HP:0030731', (40, 49))	('lung carcinoma (NSCLC) tumors', 'Disease', 'MESH:D009369', (35, 64))	('MUC', 'Gene', (115, 118))	('MUC', 'Gene', '100508689', (115, 118))
455498	24947164	Both studies identify statistically significant cancer-associated genes differentially expressed and/or mutated upon nicotine exposure.	('nicotine', 'Chemical', 'MESH:D009538', (117, 125))	('mutated', 'Var', (104, 111))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('differentially', 'Reg', (72, 86))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))
455499	24947164	However, none of the mutated MUC genes were reported as differentially expressed in transcriptome study indicating that expression level changes of the altered MUC transcripts (and presumably proteins) may not be associated with nicotine or oxidative stress.	('MUC', 'Gene', '100508689', (160, 163))	('MUC', 'Gene', (29, 32))	('MUC', 'Gene', (160, 163))	('MUC', 'Gene', '100508689', (29, 32))	('nicotine', 'Chemical', 'MESH:D009538', (229, 237))	('altered', 'Var', (152, 159))	('oxidative stress', 'Phenotype', 'HP:0025464', (241, 257))
455503	24947164	Nicotine has been previously reported to induce oxidative stress in cultured cells.	('oxidative stress', 'MPA', (48, 64))	('induce', 'Reg', (41, 47))	('Nicotine', 'Var', (0, 8))	('Nicotine', 'Chemical', 'MESH:D009538', (0, 8))	('oxidative stress', 'Phenotype', 'HP:0025464', (48, 64))
455509	24947164	It has been suggested that nicotine could cause cell proliferation through Ras-Raf-MEK-ERK signaling pathway.	('nicotine', 'Var', (27, 35))	('Raf', 'Gene', '22882', (79, 82))	('MEK', 'Gene', (83, 86))	('cell proliferation', 'CPA', (48, 66))	('MEK', 'Gene', '5609', (83, 86))	('cause', 'PosReg', (42, 47))	('Raf', 'Gene', (79, 82))	('nicotine', 'Chemical', 'MESH:D009538', (27, 35))
455512	24947164	In our study, 5% of the variations measured were transversions (104 out of 2,158 mutations), which suggests this possible carcinogenic characteristic of nicotine.	('variations', 'Var', (24, 34))	('nicotine', 'Chemical', 'MESH:D009538', (153, 161))	('carcinogenic', 'Disease', 'MESH:D063646', (122, 134))	('carcinogenic', 'Disease', (122, 134))	('transversions', 'Var', (49, 62))	('mutations', 'Var', (81, 90))
455518	24947164	A key area of cancer research is to identify and investigate genetic and epigenetic alterations occurring during cancer development that may serve as clinical tools for disease diagnosis and prognosis.	('cancer', 'Disease', (14, 20))	('epigenetic', 'Var', (73, 83))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('cancer', 'Disease', (113, 119))	('cancer', 'Disease', 'MESH:D009369', (14, 20))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
455519	24947164	We identified 79 consistently occurring mutations that are cancer associated per the COSMIC database.	('mutations', 'Var', (40, 49))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))
455520	24947164	Together, these suggest that nicotine exposure results in many reproducible genetic variations that drive cells towards the cancer state.	('nicotine', 'Chemical', 'MESH:D009538', (29, 37))	('cancer', 'Disease', (124, 130))	('drive', 'Reg', (100, 105))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('variations', 'Var', (84, 94))	('cancer', 'Disease', 'MESH:D009369', (124, 130))	('genetic variations', 'Var', (76, 94))
455521	24947164	Of particular note, we observed frequent mutations in a number of MUC family genes, in particular MUC4.	('mutations', 'Var', (41, 50))	('MUC4', 'Gene', (98, 102))	('MUC', 'Gene', (98, 101))	('MUC', 'Gene', '100508689', (98, 101))	('MUC', 'Gene', (66, 69))	('MUC4', 'Gene', '4585', (98, 102))	('MUC', 'Gene', '100508689', (66, 69))
455523	24947164	For example, in one breast cancer study, silencing MUC4 led to reduced expression of HER2, although the molecular mechanism of this interaction is unknown.	('expression', 'MPA', (71, 81))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('silencing', 'Var', (41, 50))	('breast cancer', 'Disease', 'MESH:D001943', (20, 33))	('reduced', 'NegReg', (63, 70))	('MUC4', 'Gene', (51, 55))	('breast cancer', 'Disease', (20, 33))	('breast cancer', 'Phenotype', 'HP:0003002', (20, 33))	('HER2', 'Gene', (85, 89))	('one breast', 'Phenotype', 'HP:0012813', (16, 26))	('HER2', 'Gene', '2064', (85, 89))	('MUC4', 'Gene', '4585', (51, 55))
455528	24947164	We correlated the mutation frequency of MUC4, MUC6, and MUC12 with the non-small-cell lung carcinoma, and identified a distinct mutation frequency in tumor samples from smokers (20%) and non-smokers (6%), which cumulatively designates these MUC genes as diagnostic and prognostic markers in smokers.	('MUC', 'Gene', '100508689', (46, 49))	('MUC', 'Gene', (40, 43))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('MUC', 'Gene', (56, 59))	('MUC', 'Gene', (46, 49))	('MUC12', 'Gene', (56, 61))	('MUC6', 'Gene', (46, 50))	('MUC', 'Gene', '100508689', (241, 244))	('mutation', 'Var', (18, 26))	('MUC6', 'Gene', '4588', (46, 50))	('lung carcinoma', 'Disease', 'MESH:D008175', (86, 100))	('MUC12', 'Gene', '10071', (56, 61))	('MUC4', 'Gene', '4585', (40, 44))	('MUC', 'Gene', (241, 244))	('MUC4', 'Gene', (40, 44))	('tumor', 'Disease', (150, 155))	('MUC', 'Gene', '100508689', (40, 43))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('MUC', 'Gene', '100508689', (56, 59))	('lung carcinoma', 'Disease', (86, 100))
455533	24947164	It reveals that nicotine exposure causes somatic mutations, which are substantially concordant with those induced from oxidative stress and implicates nicotine in carcinogenesis/mutagenesis.	('carcinogenesis', 'Disease', (163, 177))	('oxidative stress', 'Phenotype', 'HP:0025464', (119, 135))	('nicotine', 'Chemical', 'MESH:D009538', (16, 24))	('somatic mutations', 'CPA', (41, 58))	('carcinogenesis', 'Disease', 'MESH:D063646', (163, 177))	('nicotine', 'Chemical', 'MESH:D009538', (151, 159))	('nicotine', 'Var', (16, 24))
455535	24947164	We discovered that 14% of the non-small-cell lung cancer tumors in smokers have mutations in at least one of three MUC genes establishing MUC family genes as strong genetic marker for nicotine stress in smokers and for diagnosis and prognosis in the lung cancer.	('lung cancer tumors', 'Disease', (45, 63))	('lung cancer', 'Phenotype', 'HP:0100526', (250, 261))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('cancer', 'Phenotype', 'HP:0002664', (255, 261))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (30, 56))	('mutations', 'Var', (80, 89))	('lung cancer tumors', 'Disease', 'MESH:D008175', (45, 63))	('MUC', 'Gene', '100508689', (138, 141))	('MUC', 'Gene', '100508689', (115, 118))	('lung cancer', 'Disease', (250, 261))	('nicotine', 'Chemical', 'MESH:D009538', (184, 192))	('MUC', 'Gene', (138, 141))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('MUC', 'Gene', (115, 118))	('lung cancer', 'Disease', 'MESH:D008175', (45, 56))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (34, 56))	('lung cancer', 'Disease', 'MESH:D008175', (250, 261))	('lung cancer', 'Phenotype', 'HP:0100526', (45, 56))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))
455545	24947164	Additionally, we have previously demonstrated array specificity and sensitivity by demonstrating the ability of the array to detect Epstein-Barr virus (EBV) transformation within cell line samples by detecting EBV's singular and specific microsatellite motif/locus GAGCAG.	('Epstein-Barr virus', 'Disease', (132, 150))	('EBV', 'Species', '10376', (152, 155))	('microsatellite motif/locus', 'Var', (238, 264))	('EBV', 'Gene', (210, 213))	('EBV', 'Species', '10376', (210, 213))	('detecting', 'Reg', (200, 209))
455563	33931649	Among these abnormalities, cancer-specific DNA hypermethylation at CpG-Island (CGI) promoters is perhaps the most well-established epigenetic deregulation.	('cancer', 'Disease', 'MESH:D009369', (27, 33))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('DNA hypermethylation', 'Var', (43, 63))	('cancer', 'Disease', (27, 33))
455564	33931649	DNA hypermethylation results in transcriptional repression of a large number of genes in cancer.	('transcriptional repression', 'MPA', (32, 58))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('cancer', 'Disease', (89, 95))	('hypermethylation', 'Var', (4, 20))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
455565	33931649	While some are known tumor suppressors, such as BRCA1, MLH1, and VHL, the majority of such hypermethylated genes are "passengers" (little or no functional contribution to cancer biology).	('VHL', 'Gene', '7428', (65, 68))	('BRCA1', 'Gene', '672', (48, 53))	('hypermethylated', 'Var', (91, 106))	('tumor', 'Disease', (21, 26))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('BRCA1', 'Gene', (48, 53))	('cancer', 'Disease', (171, 177))	('MLH1', 'Gene', '4292', (55, 59))	('MLH1', 'Gene', (55, 59))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('VHL', 'Gene', (65, 68))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
455566	33931649	In virtually every cancer type, hundreds of CGI promoters are DNA hypermethylated.	('cancer', 'Disease', (19, 25))	('DNA', 'Var', (62, 65))	('cancer', 'Disease', 'MESH:D009369', (19, 25))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))
455577	33931649	Among them, H3K27me3 is considered as a hallmark of PcG-dependent transcriptional repression.	('PcG', 'Gene', '40358', (52, 55))	('H3K27me3', 'Var', (12, 20))	('PcG', 'Gene', (52, 55))
455580	33931649	While numerous studies have focused on the hypermethylation and epigenetic silencing of PRC2-associated genes, very few have looked systematically at how the entire class of PRC2-occupied CGI promoters are dysregulated in cancer.	('cancer', 'Disease', 'MESH:D009369', (222, 228))	('cancer', 'Disease', (222, 228))	('dysregulated', 'Reg', (206, 218))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('epigenetic', 'Var', (64, 74))	('PRC2-associated genes', 'Gene', (88, 109))
455592	33931649	Using ESC chromatin marks to define PRC2+ and PRC2- gene classes has been a common practice in the definition of CpG Island Methylator Phenotype (CIMP) and other cancer methylation signatures, due to the more diffuse distribution of H3K27me3 ChIP-Seq in differentiated cell types and the fact that PRC2 ChIP-Seq has been attempted in very few differentiated cell types.	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('PRC2+', 'Chemical', '-', (36, 41))	('cancer', 'Disease', (162, 168))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('H3K27me3', 'Var', (233, 241))
455596	33931649	PRC2+-CGI genes with an FPKM greater than 4 showed a marked increase in H3K27ac in most cell types (Supplementary Fig.	('PRC2+', 'Chemical', '-', (0, 5))	('H3K27ac', 'Protein', (72, 79))	('increase', 'PosReg', (60, 68))	('PRC2+-CGI genes', 'Var', (0, 15))
455597	33931649	2a), and the H3K27me3 mark, a hallmark of PRC2-occupancy, was only positive in PRC2+-CGI genes with FPKM < 4 (Supplementary Fig.	('PRC2+-CGI', 'Gene', (79, 88))	('H3K27me3', 'Var', (13, 21))	('PRC2+', 'Chemical', '-', (79, 84))
455601	33931649	As described below, we independently analyzed each of these 16 TCGA cancer types, using transcriptome and DNA methylation profiles to define three distinct gene groups: hypermethylated PRC2+-CGI, upregulated PRC2+-CGI, and upregulated PRC2--CGI (Fig.	('hypermethylated', 'Var', (169, 184))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('PRC2+', 'Chemical', '-', (185, 190))	('upregulated', 'PosReg', (223, 234))	('upregulated', 'PosReg', (196, 207))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('PRC2+-CGI', 'CPA', (208, 217))	('PRC2', 'Gene', (235, 239))	('cancer', 'Disease', (68, 74))	('PRC2+', 'Chemical', '-', (208, 213))	('PRC2+-CGI', 'Gene', (185, 194))
455603	33931649	Consistent with well-established findings, almost 52% of PRC2+-CGI genes (2,274 of 4,378) became hypermethylated in at least one cancer type, corresponding to 4,260 promoters (56% of all PRC2+-CGI promoters).	('hypermethylated', 'Var', (97, 112))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('PRC2+-CGI genes', 'Gene', (57, 72))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('PRC2+', 'Chemical', '-', (187, 192))	('PRC2+', 'Chemical', '-', (57, 62))
455604	33931649	Most cancer types (12/16) had > 400 hypermethylated PRC2+-CGI genes (Fig.	('cancer', 'Disease', 'MESH:D009369', (5, 11))	('PRC2+-CGI genes', 'Gene', (52, 67))	('hypermethylated', 'Var', (36, 51))	('cancer', 'Disease', (5, 11))	('PRC2+', 'Chemical', '-', (52, 57))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))
455605	33931649	1b), confirming the pervasiveness of this type of epigenetic silencing across human cancers.	('cancers', 'Phenotype', 'HP:0002664', (84, 91))	('cancers', 'Disease', 'MESH:D009369', (84, 91))	('cancers', 'Disease', (84, 91))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('epigenetic silencing', 'Var', (50, 70))	('human', 'Species', '9606', (78, 83))
455611	33931649	Shown as an example, the LEF1 gene is marked with both H3K27me3 and H3K4me3 and devoid of H3K27ac in normal colon tissue.	('H3K27me3', 'Var', (55, 63))	('H3K4me3', 'Var', (68, 75))	('LEF1', 'Gene', '51176', (25, 29))	('LEF1', 'Gene', (25, 29))
455615	33931649	For example, CEP72, the gene encoding a centrosomal protein associated with regulation of cell cycle, harbors an active promoter marked with H3K27ac and ATAC-Seq chromatin accessibility in normal colon tissue, and becomes transcriptionally upregulated in colon cancer with an increase in both H3K27ac and ATAC-Seq accessibility (Fig.	('CEP72', 'Gene', '55722', (13, 18))	('CEP72', 'Gene', (13, 18))	('increase', 'PosReg', (276, 284))	('H3K27ac', 'Var', (141, 148))	('cancer', 'Phenotype', 'HP:0002664', (261, 267))	('H3K27ac', 'Var', (293, 300))	('upregulated', 'PosReg', (240, 251))	('ATAC-Seq accessibility', 'MPA', (305, 327))	('colon cancer', 'Disease', 'MESH:D015179', (255, 267))	('colon cancer', 'Phenotype', 'HP:0003003', (255, 267))	('colon cancer', 'Disease', (255, 267))
455616	33931649	As anticipated, H3K27me3 levels were similarly high in both PRC2+-CGI hypermethylated and PRC2+-CGI upregulated promoters, but undetectable in PRC2--CGI promoters.	('H3K27me3', 'Protein', (16, 24))	('high', 'PosReg', (47, 51))	('PRC2+-CGI', 'Var', (60, 69))	('PRC2+', 'Chemical', '-', (90, 95))	('upregulated', 'PosReg', (100, 111))	('PRC2+-CGI', 'Var', (90, 99))	('PRC2+', 'Chemical', '-', (60, 65))
455620	33931649	Interestingly, despite high H3K27me3 signal in both PRC2+-CGI classes, hypermethylated PRC2+ promoters showed much stronger enrichment in LADs than upregulated PRC2+ promoters (Fig.	('hypermethylated', 'Var', (71, 86))	('LADs', 'Disease', 'None', (138, 142))	('LADs', 'Disease', (138, 142))	('PRC2+', 'Chemical', '-', (52, 57))	('PRC2+', 'Chemical', '-', (87, 92))	('H3K27me3', 'Protein', (28, 36))	('PRC2+', 'Chemical', '-', (160, 165))
455622	33931649	Extending the LAD analysis to pan-cancer samples, we found that the hypermethylated PRC2+-CGI class had an average of 2.4X more genes (37.8% vs 15.7%) within LADs than the upregulated PRC2+-CGI class.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('LADs', 'Disease', (158, 162))	('more', 'PosReg', (123, 127))	('LAD', 'Disease', (14, 17))	('LAD', 'Disease', 'MESH:C535887', (158, 161))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('hypermethylated', 'Var', (68, 83))	('cancer', 'Disease', (34, 40))	('LAD', 'Disease', 'MESH:C535887', (14, 17))	('PRC2+', 'Chemical', '-', (84, 89))	('genes', 'MPA', (128, 133))	('LAD', 'Disease', (158, 161))	('PRC2+', 'Chemical', '-', (184, 189))	('LADs', 'Disease', 'None', (158, 162))
455625	33931649	Similarly, expression in normal tissue was (negatively) correlated with hypermethylated PRC2+-CGI promoters but not upregulated PRC2+-CGI promoters.	('PRC2+', 'Chemical', '-', (88, 93))	('expression', 'MPA', (11, 21))	('PRC2+-CGI', 'Gene', (88, 97))	('hypermethylated', 'Var', (72, 87))	('PRC2+', 'Chemical', '-', (128, 133))
455628	33931649	Looking specifically at DMVs, we found that they were associated both with hypermethylation and upregulation of PRC2+-CGI genes in similar ratios (Supplementary Fig.	('hypermethylation', 'MPA', (75, 91))	('PRC2+-CGI genes', 'Gene', (112, 127))	('upregulation', 'PosReg', (96, 108))	('PRC2+', 'Chemical', '-', (112, 117))	('DMVs', 'Var', (24, 28))
455642	33931649	Consistent with earlier reports, hypermethylated PRC2+-CGI genes were slightly downregulated in TCGA tumors relative to adjacent nonmalignant tissues (Fig.	('tumors', 'Disease', 'MESH:D009369', (101, 107))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('hypermethylated', 'Var', (33, 48))	('downregulated', 'NegReg', (79, 92))	('PRC2+', 'Chemical', '-', (49, 54))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('tumors', 'Disease', (101, 107))	('PRC2+-CGI genes', 'Gene', (49, 64))
455649	33931649	While hypermethylated genes are known to have some cancer-type specificity, this class had the lowest percentage of cancer-type-restricted genes in all but 2 cancer types (Fig.	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('cancer', 'Disease', (158, 164))	('hypermethylated', 'Var', (6, 21))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
455652	33931649	Indeed, in every cancer type, the fraction of these "plastic genes" was much higher in PRC2+- than PRC2--CGI class (Fig.	('higher', 'PosReg', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('PRC2+', 'Chemical', '-', (87, 92))	('cancer', 'Disease', (17, 23))	('fraction', 'MPA', (34, 42))	('PRC2+-', 'Var', (87, 93))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
455697	33931649	Interestingly, the TFBSs of PRC2--CGI promoters had higher CpG densities than the TFBSs of PRC2+-CGI promoters (Supplementary Fig.	('PRC2+', 'Chemical', '-', (91, 96))	('PRC2--CGI promoters', 'Var', (28, 47))	('TF', 'Gene', '2152', (19, 21))	('CpG densities', 'CPA', (59, 72))	('TF', 'Gene', '2152', (82, 84))	('higher', 'PosReg', (52, 58))
455698	33931649	Enhancer regions showed the opposite pattern of promoter regions, with the PRC2+-CGI class being more enriched for enhancer motifs than the PRC2--CGI class in almost all cancer types (an average of 11 motifs for PRC2+-CGI vs. 4 motifs for PRC2--CGI, Fig.	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('PRC2+', 'Chemical', '-', (75, 80))	('PRC2+', 'Chemical', '-', (212, 217))	('cancer', 'Disease', (170, 176))	('PRC2+-CGI', 'Var', (212, 221))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))
455705	33931649	As predicted, in both HCT116 (COAD) and A549 (LUAD) cells, SP1-binding events were considerably more enriched in PRC2-- (53.2%-76.1%) than PRC2+-CGI promoters (15.8%-28.4%, Fig.	('PRC2--', 'Var', (113, 119))	('COAD', 'Disease', (30, 34))	('HCT116', 'CellLine', 'CVCL:0291', (22, 28))	('SP1-binding', 'Protein', (59, 70))	('COAD', 'Disease', 'MESH:D029424', (30, 34))	('A549', 'CellLine', 'CVCL:0023', (40, 44))	('PRC2+', 'Chemical', '-', (139, 144))
455734	33931649	Additionally, this regulation appeared to be PRC2+-CGI-specific:only 1 out of 17 PRC2--CGI genes (5.9%) overlapping with HNF4A ChIP-Seq was downregulated in the knockdown (Fig.	('HNF4A', 'Gene', '3172', (121, 126))	('downregulated', 'NegReg', (140, 153))	('HNF4A', 'Gene', (121, 126))	('PRC2+', 'Chemical', '-', (45, 50))	('knockdown', 'Var', (161, 170))	('PRC2--CGI', 'Gene', (81, 90))
455735	33931649	As H3K27me3 data was unavailable for any of these cell types other than normal esophagus, we performed promoter H3K27me3 ChIP-qPCR in OE19 HNF4A-wildtype and HNF4A-knockdown cells.	('HNF4A', 'Gene', (158, 163))	('HNF4A', 'Gene', '3172', (139, 144))	('H3K27me3', 'Var', (112, 120))	('HNF4A', 'Gene', (139, 144))	('HNF4A', 'Gene', '3172', (158, 163))
455737	33931649	All gene promoters showed gain of H3K27me3 signal in the knockdown of HNF4A (Fig.	('HNF4A', 'Gene', '3172', (70, 75))	('HNF4A', 'Gene', (70, 75))	('knockdown', 'Var', (57, 66))	('H3K27me3', 'Protein', (34, 42))	('gain', 'PosReg', (26, 30))
455741	33931649	Consistent with prior findings, we showed that many PRC2+-CGI genes were commonly hypermethylated and downregulated in most cancers, affecting 2,274 of 4,378 genes across in one or more of 16 cancer types.	('affecting', 'Reg', (133, 142))	('cancer', 'Disease', (124, 130))	('downregulated', 'NegReg', (102, 115))	('PRC2+-CGI genes', 'Gene', (52, 67))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('PRC2+', 'Chemical', '-', (52, 57))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('cancer', 'Disease', (192, 198))	('hypermethylated', 'Var', (82, 97))	('cancer', 'Disease', 'MESH:D009369', (192, 198))	('cancers', 'Phenotype', 'HP:0002664', (124, 131))	('cancers', 'Disease', (124, 131))	('cancer', 'Disease', 'MESH:D009369', (124, 130))	('cancers', 'Disease', 'MESH:D009369', (124, 131))
455745	33931649	In tumors, our analysis showed that unlike hypermethylated PRC2+-CGI promoters, upregulated PRC2+-CGI promoters gain accessibility and the H3K27ac mark (illustrated in Fig.	('tumors', 'Phenotype', 'HP:0002664', (3, 9))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))	('H3K27ac mark', 'Var', (139, 151))	('PRC2+-CGI', 'Var', (92, 101))	('tumors', 'Disease', (3, 9))	('tumors', 'Disease', 'MESH:D009369', (3, 9))	('PRC2+', 'Chemical', '-', (59, 64))	('upregulated', 'PosReg', (80, 91))	('accessibility', 'MPA', (117, 130))	('gain', 'PosReg', (112, 116))	('PRC2+', 'Chemical', '-', (92, 97))
455748	33931649	This property allowed for better clustering of cancer types and subtypes using the upregulated PRC2+-CGI class than either of the other two classes, although hypermethylated PRC2+-CGI also showed good clustering.	('PRC2+', 'Chemical', '-', (95, 100))	('PRC2+', 'Chemical', '-', (174, 179))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('PRC2+-CGI', 'Var', (95, 104))	('cancer', 'Disease', (47, 53))	('upregulated', 'PosReg', (83, 94))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))
455749	33931649	Interestingly, nearly half (762/1,543) of upregulated PRC2+-CGI genes were also hypermethylated in other cancer types, including some known tumor suppressors, such as DKK1, NFGR, PRICKLE1.	('hypermethylated', 'Var', (80, 95))	('DKK1', 'Gene', '22943', (167, 171))	('DKK1', 'Gene', (167, 171))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('cancer', 'Disease', (105, 111))	('PRICKLE1', 'Gene', (179, 187))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('PRC2+-CGI genes', 'Gene', (54, 69))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('upregulated', 'PosReg', (42, 53))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('PRICKLE1', 'Gene', '144165', (179, 187))	('PRC2+', 'Chemical', '-', (54, 59))	('tumor', 'Disease', (140, 145))
455756	33931649	Functionally, upregulated PRC2+- and PRC2--CGI genes controlled distinct sets of pathways in cancer.	('PRC2+-', 'Gene', (26, 32))	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('PRC2+', 'Chemical', '-', (26, 31))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('upregulated', 'PosReg', (14, 25))	('PRC2--', 'Var', (37, 43))
455762	33931649	Indeed, consistent with this notion, recent studies have shown that EZH2 inhibition leads to heightened anti-cancer immunity and synergizes with immune-checkpoint blockade therapy in different cancer types.	('EZH2', 'Gene', (68, 72))	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('cancer', 'Disease', (193, 199))	('cancer', 'Disease', (109, 115))	('heightened', 'PosReg', (93, 103))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('EZH2', 'Gene', '2146', (68, 72))	('inhibition', 'Var', (73, 83))
455770	33931649	While this mode of activation appears to be prevalent in cancer based on our analysis, additional layers of deregulation of these genes may be caused by genetic disruption of PRC2 proteins themselves, given the discovery of both loss-of-function and gain-of-function mutations of PRC2 complex (particularly EZH2) in cancer.	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('PRC2 complex', 'Gene', (280, 292))	('cancer', 'Phenotype', 'HP:0002664', (316, 322))	('cancer', 'Disease', (57, 63))	('activation', 'PosReg', (19, 29))	('mutations', 'Var', (267, 276))	('EZH2', 'Gene', (307, 311))	('EZH2', 'Gene', '2146', (307, 311))	('genetic', 'Var', (153, 160))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('cancer', 'Disease', 'MESH:D009369', (316, 322))	('disruption', 'NegReg', (161, 171))	('loss-of-function', 'NegReg', (229, 245))	('cancer', 'Disease', (316, 322))	('PRC2', 'Gene', (175, 179))	('gain-of-function', 'PosReg', (250, 266))
455781	33931649	The following additional datasets were collected: H3K27ac ChIP-Seq in nonmalignant colonic crypts and primary colon cancer cells (GSE77737), H3K27ac ChIP-Seq in nonmalignant and tumor samples of kidney renal clear cell carcinoma (KIRC) from GSE86095, HNF4A ChIP-Seq in OE19 (E-MTAB-6858) and Caco-2 (GSE23436) cell lines, TP63 ChIP-Seq in HCC95 cell line (GSE46837), SP1 and JUND ChIP-Seq in HCT116 and A549 cell lines (ENCODE), H3K27ac ChIP-Seq in OE19 (GSE132686), HCC95 (GSE66992), HCT116 (ENCODE), Caco-2 (GSE96069) and A549 (ENCODE) cell lines.	('kidney renal clear cell carcinoma', 'Disease', (195, 228))	('nonmalignant colonic crypts and primary colon cancer', 'Disease', 'MESH:D015179', (70, 122))	('JUND', 'Gene', (375, 379))	('A549', 'CellLine', 'CVCL:0023', (524, 528))	('HCT116', 'CellLine', 'CVCL:0291', (392, 398))	('tumor', 'Disease', (178, 183))	('JUND', 'Gene', '3727', (375, 379))	('Caco-2', 'CellLine', 'CVCL:0025', (502, 508))	('HCT116', 'CellLine', 'CVCL:0291', (485, 491))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('colon cancer', 'Phenotype', 'HP:0003003', (110, 122))	('HCC95', 'CellLine', 'CVCL:5137', (467, 472))	('Caco-2', 'CellLine', 'CVCL:0025', (292, 298))	('HNF4A', 'Gene', '3172', (251, 256))	('HNF4A', 'Gene', (251, 256))	('TP63', 'Gene', (322, 326))	('HCC95', 'CellLine', 'CVCL:5137', (339, 344))	('A549', 'CellLine', 'CVCL:0023', (403, 407))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (219, 228))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('kidney renal clear cell carcinoma', 'Disease', 'MESH:C538614', (195, 228))	('TP63', 'Gene', '8626', (322, 326))	('H3K27ac ChIP-Seq', 'Var', (429, 445))
455783	33931649	RNA-Seq of HNF4A knockdown, ATAC-Seq of nonmalignant esophageal epithelium, EAC tissues, normal esophageal cells (HET1A) and OE19 tumor cells were downloaded from E-MTAB-6756, E-MTAB-5169 and E-MTAB-6931.	('HNF4A', 'Gene', (11, 16))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('knockdown', 'Var', (17, 26))	('tumor', 'Disease', (130, 135))	('HNF4A', 'Gene', '3172', (11, 16))
455788	33931649	H3K27me3 and H3K27ac ChIP-Seq profiles in both ESCs (H1) and normal tissues (colonic mucosa, lung, breast epithelium, rectum, esophagus, uterus and liver) were obtained from the combined NIH RoadMap/ENCODE data repository.	('colonic mucosa', 'Disease', 'MESH:D003110', (77, 91))	('H1', 'CellLine', 'CVCL:Z499', (53, 55))	('H3K27me3', 'Var', (0, 8))	('colonic mucosa', 'Disease', (77, 91))	('ESCs', 'Disease', (47, 51))	('H3K27ac', 'Var', (13, 20))
455791	33931649	An FPKM value of 4 in TCGA normal tissues readily separated PRC2+-CGI genes with divergent H3K27ac levels: PRC2+-CGI genes with FPKM < 4 had considerably lower H3K27ac signals than those with FPKM >= 4 (Supplementary Fig.	('lower', 'NegReg', (154, 159))	('H3K27ac signals', 'MPA', (160, 175))	('FPKM < 4', 'Var', (128, 136))	('PRC2+', 'Chemical', '-', (107, 112))	('PRC2+', 'Chemical', '-', (60, 65))
455792	33931649	Furthermore, we confirmed that PRC2+-CGI genes with FPKM < 4 had much higher H3K27me3 levels than those with FPKM >= 4 (Supplementary Fig.	('PRC2+-CGI genes', 'Gene', (31, 46))	('FPKM < 4', 'Var', (52, 60))	('H3K27me3 levels', 'MPA', (77, 92))	('PRC2+', 'Chemical', '-', (31, 36))	('higher', 'PosReg', (70, 76))
455805	33931649	Considering that TFs from the same TF family can recognize identical binding sequences (such as GATA and SOX families), we retained only those  motifs corresponding to TFs with FPKM > 10 and p-value < 0.01 in the corresponding cancer types.	('FPKM > 10', 'Var', (177, 186))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('cancer', 'Disease', 'MESH:D009369', (227, 233))	('TF', 'Gene', '2152', (17, 19))	('TF', 'Gene', '2152', (168, 170))	('TF', 'Gene', '2152', (35, 37))	('cancer', 'Disease', (227, 233))	('GATA', 'Gene', (96, 100))	('GATA', 'Gene', '55278', (96, 100))
455806	33931649	Breast cancer cell lines HS578T (#HTB-126) and MDAMB436 (#HTB-130) were obtained from ATCC, and EAC cells OE19 were obtained from Sigma-Aldrich, and were authenticated by the STR-PCR analysis.	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('Breast cancer', 'Phenotype', 'HP:0003002', (0, 13))	('Breast cancer', 'Disease', 'MESH:D001943', (0, 13))	('HS578T', 'CellLine', 'CVCL:0332', (25, 31))	('#HTB-130', 'Var', (57, 65))	('Breast cancer', 'Disease', (0, 13))
455816	33931649	The ATAC-Seq data used in this study are available in ArrayExpress database under accession code E-MTAB-5169 and E-MTAB-6931; ENCODE project [https://www.encodeproject.org/] and NSCLC ATAC Project [https://pms.cd120.com/index.html].	('NSCLC', 'Disease', 'MESH:D002289', (178, 183))	('NSCLC', 'Disease', (178, 183))	('E-MTAB-6931', 'Var', (113, 124))
455824	33324676	Based on Kaplan-Meier plotter and the PrognoScan database, we found high SPP1 expression was significantly correlated with poor survival in various cancers.	('cancers', 'Disease', 'MESH:D009369', (148, 155))	('cancers', 'Phenotype', 'HP:0002664', (148, 155))	('expression', 'MPA', (78, 88))	('high', 'Var', (68, 72))	('cancers', 'Disease', (148, 155))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('poor survival', 'CPA', (123, 136))	('SPP1', 'Gene', (73, 77))
455854	33324676	For data validation, the gene expression profiles of 139 COAD samples from GSE21510 and GSE110224, 1098 LUAD samples from GSE30219, GSE31210, GES3141, GSE37745, GSE50081, and GSE68465, 211 LUSC samples from GSE43580, GSE73403, and GSE67061 and 80 HNSC samples from GSE6631 and GSE13601 were obtained from the GEO data portal8 and analyzed using R language.	('COAD', 'Disease', (57, 61))	('LUAD', 'Phenotype', 'HP:0030078', (104, 108))	('COAD', 'Disease', 'MESH:D029424', (57, 61))	('GSE50081', 'Var', (161, 169))	('GSE30219', 'Var', (122, 130))	('GSE110224', 'Var', (88, 97))	('GSE37745', 'Var', (151, 159))	('LUSC', 'Phenotype', 'HP:0030359', (189, 193))	('GSE21510', 'Var', (75, 83))	('GSE31210', 'Var', (132, 140))	('GES3141', 'Var', (142, 149))
455867	33324676	Contrastingly, high SPP1 expression showed better prognosis in READ (OS HR = 0.39, 95% CI = 0.18-0.85, Cox P = 0.015), LIHC (OS HR = 0.63, 95% CI = 0.43-0.91, Cox P = 0.013), and pancreatic ductal adenocarcinoma (PAAD) (OS HR = 0.57, 95% CI = 0.38-0.88, Cox P = 0.011; RFS HR = 0.38, 95% CI = 0.13-1, Cox P = 0.043) (Figures 2C,F,I,J).	('high', 'Var', (15, 19))	('LIHC', 'Disease', (119, 123))	('PAAD', 'Phenotype', 'HP:0006725', (213, 217))	('SPP1', 'Gene', (20, 24))	('carcinoma', 'Phenotype', 'HP:0030731', (202, 211))	('LIHC', 'Disease', 'None', (119, 123))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (179, 211))	('READ', 'Disease', (63, 67))	('pancreatic ductal adenocarcinoma', 'Disease', (179, 211))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (179, 211))
455871	33324676	We also found patients with high SPP1 expression has a poor RFS in LUAD (RFS HR = 2.18, 95% CI = 1.57-3.02, Cox P = 3e-06) rather than in LUSC (RFS HR = 0.97, 95% CI = 0.82-1.14, Cox P = 0.721), this phenomenon was possibly resulted from the few LUSC patients.	('LUSC', 'Phenotype', 'HP:0030359', (138, 142))	('SPP1', 'Gene', (33, 37))	('poor', 'NegReg', (55, 59))	('expression', 'MPA', (38, 48))	('RFS', 'MPA', (60, 63))	('LUSC', 'Phenotype', 'HP:0030359', (246, 250))	('patients', 'Species', '9606', (251, 259))	('LUAD', 'Disease', (67, 71))	('high', 'Var', (28, 32))	('LUAD', 'Phenotype', 'HP:0030078', (67, 71))	('patients', 'Species', '9606', (14, 22))
455887	33324676	Consequently, most of 22 genes were more highly expressed in SPP1 high group than in SPP1 low group and 17 genes expressed in COAD, 12 in HNSC, 19 in LUAD, and 15 in LUSC, respectively (Figure 5A).	('COAD', 'Disease', (126, 130))	('highly expressed', 'PosReg', (41, 57))	('SPP1 high', 'Var', (61, 70))	('LUSC', 'Phenotype', 'HP:0030359', (166, 170))	('high', 'Var', (66, 70))	('COAD', 'Disease', 'MESH:D029424', (126, 130))	('LUAD', 'Phenotype', 'HP:0030078', (150, 154))
455896	33324676	As shown in Figure 7A, in COAD, HNSC, and LUAD, compared with low SPP1 expression group, the mRNAsi in high SPP1 group increased.	('high SPP1', 'Var', (103, 112))	('LUAD', 'Phenotype', 'HP:0030078', (42, 46))	('mRNAsi', 'Disease', (93, 99))	('COAD', 'Disease', 'MESH:D029424', (26, 30))	('mRNAsi', 'Disease', 'None', (93, 99))	('increased', 'PosReg', (119, 128))	('COAD', 'Disease', (26, 30))
455919	33324676	The high SPP1 expression facilitated the infiltration level of immune cells and their markers, further confirming the interactions between SPP1 and common genes and miRNA in cancers.	('infiltration level of immune cells', 'MPA', (41, 75))	('cancers', 'Phenotype', 'HP:0002664', (174, 181))	('cancers', 'Disease', (174, 181))	('expression', 'MPA', (14, 24))	('cancers', 'Disease', 'MESH:D009369', (174, 181))	('facilitated', 'PosReg', (25, 36))	('high', 'Var', (4, 8))	('interactions', 'Interaction', (118, 130))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('SPP1', 'Gene', (9, 13))
455929	33324676	For better exploring the SPP1 mechanism in promoting tumor progression and poor prognosis, we investigated and identified somatic mutations and CNV in COAD, HNSC, LUAD, and LUSC.	('COAD', 'Disease', (151, 155))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('LUAD', 'Phenotype', 'HP:0030078', (163, 167))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('LUSC', 'Phenotype', 'HP:0030359', (173, 177))	('mutations', 'Var', (130, 139))	('COAD', 'Disease', 'MESH:D029424', (151, 155))	('tumor', 'Disease', (53, 58))	('CNV', 'Gene', (144, 147))
455930	33324676	Some important gene mutations such as TTN mutation in COAD and LUAD, LRP1B mutation in HNSC, TP53 mutation in LUAD were found (Supplementary Figure S1).	('LRP1B', 'Gene', '53353', (69, 74))	('LUAD', 'Phenotype', 'HP:0030078', (63, 67))	('mutation', 'Var', (98, 106))	('LUAD', 'Phenotype', 'HP:0030078', (110, 114))	('COAD', 'Disease', 'MESH:D029424', (54, 58))	('mutation', 'Var', (75, 83))	('TP53', 'Gene', '7157', (93, 97))	('TP53', 'Gene', (93, 97))	('TTN', 'Gene', (38, 41))	('mutation', 'Var', (42, 50))	('LRP1B', 'Gene', (69, 74))	('TTN', 'Gene', '7273', (38, 41))	('COAD', 'Disease', (54, 58))
455937	33324676	It is reasonable to believe that the effects of SPP1 on these common genes promote immune infiltration and cancer progression.	('promote', 'PosReg', (75, 82))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('effects', 'Var', (37, 44))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('SPP1', 'Gene', (48, 52))	('cancer', 'Disease', (107, 113))	('immune infiltration', 'CPA', (83, 102))
455939	33324676	Moreover, the miRNA-gene regulation network revealed that CTSB was the target gene of hsa-miR-30c-5p, and MSR1 was the target gene of hsa-miR-152-3p.	('hsa-miR-30c-5p', 'Var', (86, 100))	('CTSB', 'Gene', (58, 62))	('MSR1', 'Gene', '4481', (106, 110))	('CTSB', 'Gene', '1508', (58, 62))	('MSR1', 'Gene', (106, 110))
455962	33324676	have reported that SPP1 interacts with ITGB1 increase mesenchymal stem cells (MSCs) motility resulting in the enhanced metastasis and migration of cancer cells.	('ITGB1 increase', 'Phenotype', 'HP:0030269', (39, 53))	('SPP1', 'Gene', (19, 23))	('ITGB1', 'Gene', '3688', (39, 44))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('interacts', 'Var', (24, 33))	('enhanced', 'PosReg', (110, 118))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('metastasis', 'CPA', (119, 129))	('cancer', 'Disease', (147, 153))	('ITGB1', 'Gene', (39, 44))	('increase', 'PosReg', (45, 53))
455981	31827393	In addition, we found that miR-135-5p directly targeted DANCR, which was negatively correlated with DANCR on TSCC progression.	('DANCR', 'Protein', (56, 61))	('TSCC', 'Phenotype', 'HP:0030413', (109, 113))	('miR-135-5p', 'Chemical', '-', (27, 37))	('miR-135-5p', 'Var', (27, 37))	('targeted', 'Reg', (47, 55))
455983	31827393	Furthermore, the expression of KLF8 evidently altered by both DANCR and miR-135a-5p.	('KLF8', 'Gene', '11279', (31, 35))	('expression', 'MPA', (17, 27))	('miR-135a-5p', 'Var', (72, 83))	('altered', 'Reg', (46, 53))	('KLF8', 'Gene', (31, 35))	('miR-135a-5p', 'Chemical', '-', (72, 83))
455990	31827393	For example, high-expression of lncRNA AFAP1-AS1 in TSCC tumor tissues enhances tumor progression via the activation of Wnt/beta-catenin signaling pathway.	('AFAP1', 'Gene', (39, 44))	('AS1', 'Gene', '5729', (45, 48))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('AFAP1', 'Gene', '60312', (39, 44))	('TSCC', 'Phenotype', 'HP:0030413', (52, 56))	('beta-catenin', 'Gene', (124, 136))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('AS1', 'Gene', (45, 48))	('beta-catenin', 'Gene', '1499', (124, 136))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('enhances', 'PosReg', (71, 79))	('high-expression', 'Var', (13, 28))	('tumor', 'Disease', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Disease', (57, 62))	('activation', 'PosReg', (106, 116))
455994	31827393	In non-small cell lung cancer (NSCLC), miR-135a-5p is demonstrated to inhibit cell migration and invasion through targeting Kruppel-like Factor 8 (KLF8).	('NSCLC', 'Disease', 'MESH:D002289', (31, 36))	('inhibit', 'NegReg', (70, 77))	('KLF8', 'Gene', '11279', (147, 151))	('lung cancer', 'Disease', 'MESH:D008175', (18, 29))	('NSCLC', 'Disease', (31, 36))	('lung cancer', 'Phenotype', 'HP:0100526', (18, 29))	('invasion', 'CPA', (97, 105))	('NSCLC', 'Phenotype', 'HP:0030358', (31, 36))	('targeting', 'Reg', (114, 123))	('KLF8', 'Gene', (147, 151))	('miR-135a-5p', 'Chemical', '-', (39, 50))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (3, 29))	('Kruppel-like Factor 8', 'Gene', '11279', (124, 145))	('Kruppel-like Factor 8', 'Gene', (124, 145))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (7, 29))	('miR-135a-5p', 'Var', (39, 50))	('lung cancer', 'Disease', (18, 29))	('cell migration', 'CPA', (78, 92))
456003	31827393	The sequences of siRNAs (5'-3') targeting human DANCR were designed as follows: si-DANCR-1 sense GUUGACAACUACAGGCACATT and antisense UGUGCCUGUAGUUGUCAACTT; si-DANCR-2 sense CUAGAGCAGUGACAAUGCUTT and antisense AGCAUUGUCACUGCUCUAGTT.	('human', 'Species', '9606', (42, 47))	('antisense', 'Var', (199, 208))	('si-DANCR-2', 'Var', (156, 166))
456004	31827393	Furthermore, we also designed the interfering sequences (5'-3') for human KLF8 as follows: si-KLF8 sense CGAUAUGGAUAAACUCAUATT and antisense UAUGAGUUUAUCCAUAUCGAC.	('antisense', 'Var', (131, 140))	('human', 'Species', '9606', (68, 73))	('KLF8', 'Gene', '11279', (94, 98))	('KLF8', 'Gene', '11279', (74, 78))	('KLF8', 'Gene', (94, 98))	('KLF8', 'Gene', (74, 78))
456008	31827393	Furthermore, the co-transfection of miR-135a-5p inhibitor and si-DANCR or si-KLF8 was also mediated by Lipofectamine 2000.	('KLF8', 'Gene', (77, 81))	('mediated', 'Reg', (91, 99))	('co-transfection', 'Interaction', (17, 32))	('KLF8', 'Gene', '11279', (77, 81))	('Lipofectamine 2000', 'Chemical', 'MESH:C086724', (103, 121))	('miR-135a-5p', 'Var', (36, 47))	('miR-135a-5p', 'Chemical', '-', (36, 47))
456037	31827393	MTT assay was considered to indicate cell proliferation, and the results showed that DANCR knockdown reduced the viable number of CAL-27 and TCa-8113 cells (Fig.	('viable number of CAL-27', 'CPA', (113, 136))	('CAL', 'Chemical', '-', (130, 133))	('TCa-8113', 'CellLine', 'CVCL:6851', (141, 149))	('MTT', 'Chemical', 'MESH:C070243', (0, 3))	('knockdown', 'Var', (91, 100))	('reduced', 'NegReg', (101, 108))	('DANCR', 'Gene', (85, 90))
456038	31827393	These results indicate that DANCR knockdown may attenuate TSCC malignancies in vitro.	('DANCR', 'Protein', (28, 33))	('TSCC', 'Disease', (58, 62))	('TSCC', 'Phenotype', 'HP:0030413', (58, 62))	('attenuate', 'NegReg', (48, 57))	('malignancies', 'Disease', 'MESH:D009369', (63, 75))	('malignancies', 'Disease', (63, 75))	('knockdown', 'Var', (34, 43))
456041	31827393	Functional analysis from SCC9 and TSCCA cells indicated that the ectopic expression of DANCR induced increments of cell viability, migratory distance and invasive cell number (Fig.	('TSCC', 'Phenotype', 'HP:0030413', (34, 38))	('DANCR', 'Gene', (87, 92))	('migratory distance', 'CPA', (131, 149))	('cell viability', 'CPA', (115, 129))	('invasive cell number', 'CPA', (154, 174))	('SCC9', 'CellLine', 'CVCL:1685', (25, 29))	('increments', 'PosReg', (101, 111))	('ectopic expression', 'Var', (65, 83))
456044	31827393	Then we observed a marked increase of miR-135a-5p level in CAL-27 and TCa-8113 cells transfected with si-DANCR (Fig.	('miR-135a-5p level', 'MPA', (38, 55))	('TCa-8113', 'CellLine', 'CVCL:6851', (70, 78))	('miR-135a-5p', 'Chemical', '-', (38, 49))	('si-DANCR', 'Var', (102, 110))	('increase', 'PosReg', (26, 34))	('CAL', 'Chemical', '-', (59, 62))
456045	31827393	3c, d), but a significant reduction of miR-135a-5p in SCC9 and TSCCA cells transfected with pcDNA3.1-DANCR (Fig.	('pcDNA3.1-DANCR', 'Var', (92, 106))	('TSCC', 'Phenotype', 'HP:0030413', (63, 67))	('miR-135a-5p', 'Chemical', '-', (39, 50))	('SCC9', 'CellLine', 'CVCL:1685', (54, 58))	('reduction', 'NegReg', (26, 35))	('miR-135a-5p', 'MPA', (39, 50))
456046	31827393	In addition, KLF8 mRNA was down-expressed by knockdown of DANCR in CAL-27 (Fig.	('KLF8', 'Gene', (13, 17))	('DANCR', 'Gene', (58, 63))	('CAL', 'Chemical', '-', (67, 70))	('down-expressed', 'NegReg', (27, 41))	('KLF8', 'Gene', '11279', (13, 17))	('knockdown', 'Var', (45, 54))
456053	31827393	4c-e showed that overexpression of miR-135a-5p reduced viable cells, shortened migratory distance and decreased invasive cells in CAL-27 cells and TCa-8113 cells.	('invasive cells', 'CPA', (112, 126))	('viable cells', 'CPA', (55, 67))	('migratory distance', 'CPA', (79, 97))	('shortened', 'NegReg', (69, 78))	('TCa-8113', 'CellLine', 'CVCL:6851', (147, 155))	('miR-135a-5p', 'Var', (35, 46))	('miR-135a-5p', 'Chemical', '-', (35, 46))	('CAL', 'Chemical', '-', (130, 133))	('reduced', 'NegReg', (47, 54))	('decreased', 'NegReg', (102, 111))
456054	31827393	In addition, KLF8 mRNA and protein expression were also suppressed by miR-135a-5p (Fig.	('KLF8', 'Gene', (13, 17))	('miR-135a-5p', 'Var', (70, 81))	('suppressed', 'NegReg', (56, 66))	('KLF8', 'Gene', '11279', (13, 17))	('miR-135a-5p', 'Chemical', '-', (70, 81))
456055	31827393	All results indicate that miR-135a-5p may protect against TSCC malignant phenotypes with the involvement of KLF8 suppression.	('KLF8', 'Gene', '11279', (108, 112))	('miR-135a-5p', 'Chemical', '-', (26, 37))	('TSCC', 'Phenotype', 'HP:0030413', (58, 62))	('TSCC', 'Disease', (58, 62))	('KLF8', 'Gene', (108, 112))	('protect', 'NegReg', (42, 49))	('miR-135a-5p', 'Var', (26, 37))
456056	31827393	Although miR-135a-5p had been identified to target DANCR and be beneficial for TSCC progress, whether miR-135a-5p was responsible for the effects of DANCR on tumor malignancies was unclear.	('miR-135a-5p', 'Chemical', '-', (9, 20))	('TSCC', 'Phenotype', 'HP:0030413', (79, 83))	('TSCC', 'Disease', (79, 83))	('miR-135a-5p', 'Chemical', '-', (102, 113))	('tumor malignancies', 'Disease', 'MESH:D009369', (158, 176))	('DANCR', 'Protein', (51, 56))	('tumor malignancies', 'Disease', (158, 176))	('beneficial', 'PosReg', (64, 74))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('miR-135a-5p', 'Var', (9, 20))
456057	31827393	5a, the reduction of viable cells by DANCR knockdown was enhanced by miR-135a-5p inhibitor.	('miR-135a-5p', 'Chemical', '-', (69, 80))	('DANCR', 'Protein', (37, 42))	('knockdown', 'Var', (43, 52))	('reduction', 'NegReg', (8, 17))
456060	31827393	5d showed that the decrease of MMP-2 and MMP-9 protein levels induced by DANCR silence was partially increased by miR-135a-5p inhibitor.	('MMP-9', 'Gene', '4318', (41, 46))	('decrease', 'NegReg', (19, 27))	('MMP-9', 'Gene', (41, 46))	('MMP-2', 'Gene', (31, 36))	('miR-135a-5p', 'Var', (114, 125))	('miR-135a-5p', 'Chemical', '-', (114, 125))	('MMP-2', 'Gene', '4313', (31, 36))	('DANCR silence', 'Gene', (73, 86))
456062	31827393	Together the results further suggest that DANCR/miR-135a-5p may modulate TSCC progression by the regulation of KLF8.	('TSCC', 'Phenotype', 'HP:0030413', (73, 77))	('KLF8', 'Gene', '11279', (111, 115))	('TSCC', 'Disease', (73, 77))	('modulate', 'Reg', (64, 72))	('KLF8', 'Gene', (111, 115))	('miR-135a-5p', 'Chemical', '-', (48, 59))	('DANCR/miR-135a-5p', 'Var', (42, 59))
456070	31827393	7a, b, it showed that the tumor size and weight could be suppressed by knockdown of DANCR.	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('knockdown', 'Var', (71, 80))	('DANCR', 'Gene', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('suppressed', 'NegReg', (57, 67))
456075	31827393	Furthermore, miR-135a-5p was demonstrated to be complementary with DANCR and negatively regulated by DANCR.	('miR-135a-5p', 'Chemical', '-', (13, 24))	('miR-135a-5p', 'Var', (13, 24))	('negatively', 'NegReg', (77, 87))
456076	31827393	Overexpression of miR-135a-5p prevented the malignant phenotypes of TSCC cells and reduced the expression of KLF8.	('prevented', 'NegReg', (30, 39))	('reduced', 'NegReg', (83, 90))	('KLF8', 'Gene', '11279', (109, 113))	('TSCC', 'Phenotype', 'HP:0030413', (68, 72))	('miR-135a-5p', 'Var', (18, 29))	('malignant phenotypes of', 'CPA', (44, 67))	('miR-135a-5p', 'Chemical', '-', (18, 29))	('KLF8', 'Gene', (109, 113))	('expression', 'MPA', (95, 105))
456078	31827393	KLF8 was responsible for the regulatory role of miR-135a-5p through modulating MMP-2/9 expression.	('modulating', 'Reg', (68, 78))	('MMP-2/9', 'Gene', '4313;4318', (79, 86))	('MMP-2/9', 'Gene', (79, 86))	('KLF8', 'Gene', (0, 4))	('miR-135a-5p', 'Var', (48, 59))	('expression', 'MPA', (87, 97))	('miR-135a-5p', 'Chemical', '-', (48, 59))	('KLF8', 'Gene', '11279', (0, 4))
456083	31827393	The in vivo results further demonstrated that inhibition of DANCR prevented the tumor growth, which indicates the oncogenic role of DANCR in TSCC tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('DANCR', 'Protein', (60, 65))	('inhibition', 'Var', (46, 56))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('TSCC', 'Phenotype', 'HP:0030413', (141, 145))	('tumor', 'Disease', (146, 151))	('tumor', 'Disease', (80, 85))	('prevented', 'NegReg', (66, 75))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
456086	31827393	In this current study, functional experiments indicated that miR-135a-5p overexpression protected against the proliferation, migration and invasion of TSCC cells in vitro, which was showed to directly target DANCR.	('miR-135a-5p', 'Var', (61, 72))	('invasion', 'CPA', (139, 147))	('migration', 'CPA', (125, 134))	('miR-135a-5p', 'Chemical', '-', (61, 72))	('proliferation', 'CPA', (110, 123))	('TSCC', 'Phenotype', 'HP:0030413', (151, 155))
456087	31827393	The inhibitory effects of DANCR silence on TSCC progress could be rescued by silencing miR-135a-5p.	('silencing', 'Var', (77, 86))	('miR-135a-5p', 'Chemical', '-', (87, 98))	('miR-135a-5p', 'Gene', (87, 98))	('TSCC', 'Phenotype', 'HP:0030413', (43, 47))
456088	31827393	Altogether, this study shows that miR-135a-5p serves as a "sponge" miRNA of DANCR to prevent the progression of TSCC.	('miR-135a-5p', 'Var', (34, 45))	('TSCC', 'Phenotype', 'HP:0030413', (112, 116))	('TSCC', 'Disease', (112, 116))	('miR-135a-5p', 'Chemical', '-', (34, 45))
456091	31827393	Although KLF8 expression was altered by DANCR and miR-135a-5p, whether KLF8 was the downstream effector of DANCR/miR-135a-5p to mediate the regulation of TSCC progression was not well understood.	('KLF8', 'Gene', (71, 75))	('KLF8', 'Gene', '11279', (9, 13))	('miR-135a-5p', 'Chemical', '-', (113, 124))	('DANCR', 'Var', (40, 45))	('expression', 'MPA', (14, 24))	('KLF8', 'Gene', '11279', (71, 75))	('altered', 'Reg', (29, 36))	('KLF8', 'Gene', (9, 13))	('miR-135a-5p', 'Var', (50, 61))	('TSCC', 'Phenotype', 'HP:0030413', (154, 158))	('miR-135a-5p', 'Chemical', '-', (50, 61))
456093	31827393	More importantly, KLF8 was reported to be a direct target of miR-135a-5p to inhibit NSCLC cell migration, invasion and EMT process by Shi et al..	('miR-135a-5p', 'Var', (61, 72))	('NSCLC', 'Phenotype', 'HP:0030358', (84, 89))	('EMT process', 'CPA', (119, 130))	('inhibit', 'NegReg', (76, 83))	('miR-135a-5p', 'Chemical', '-', (61, 72))	('KLF8', 'Gene', (18, 22))	('NSCLC', 'Disease', (84, 89))	('invasion', 'CPA', (106, 114))	('NSCLC', 'Disease', 'MESH:D002289', (84, 89))	('KLF8', 'Gene', '11279', (18, 22))
456099	31827393	Therefore, we conclude that DANCR serves as a "sponge" of miR-135a-5p to activate KLF8/MMP-2/9 signaling pathway, thus stimulating the development and progression of TSCC.	('development', 'CPA', (135, 146))	('KLF8', 'Gene', (82, 86))	('miR-135a-5p', 'Var', (58, 69))	('MMP-2/9', 'Gene', '4313;4318', (87, 94))	('stimulating', 'PosReg', (119, 130))	('TSCC', 'Disease', (166, 170))	('miR-135a-5p', 'Chemical', '-', (58, 69))	('MMP-2/9', 'Gene', (87, 94))	('progression', 'CPA', (151, 162))	('TSCC', 'Phenotype', 'HP:0030413', (166, 170))	('KLF8', 'Gene', '11279', (82, 86))	('activate', 'PosReg', (73, 81))
456107	31555381	High expression of RBAK was associated with poor disease-free survival of patients with NSCLC by analyzing TCGA dataset.	('High', 'Var', (0, 4))	('NSCLC', 'Phenotype', 'HP:0030358', (88, 93))	('patients', 'Species', '9606', (74, 82))	('poor', 'NegReg', (44, 48))	('RBAK', 'Gene', (19, 23))	('NSCLC', 'Disease', (88, 93))	('NSCLC', 'Disease', 'MESH:D002289', (88, 93))	('RBAK', 'Gene', '57786', (19, 23))
456111	31555381	Transwell and wound healing assays demonstrated that knockdown of RBAK suppressed NSCLC cell migration and invasion.	('RBAK', 'Gene', (66, 70))	('NSCLC', 'Phenotype', 'HP:0030358', (82, 87))	('NSCLC', 'Disease', 'MESH:D002289', (82, 87))	('knockdown', 'Var', (53, 62))	('RBAK', 'Gene', '57786', (66, 70))	('invasion', 'CPA', (107, 115))	('NSCLC', 'Disease', (82, 87))	('suppressed', 'NegReg', (71, 81))
456122	31555381	Wan et al revealed that knockdown of RBAK inhibits PCa growth by inducing cell apoptosis.	('inhibits', 'NegReg', (42, 50))	('inducing', 'Reg', (65, 73))	('PCa', 'Disease', (51, 54))	('PCa', 'Disease', 'MESH:D011471', (51, 54))	('cell apoptosis', 'CPA', (74, 88))	('RBAK', 'Gene', (37, 41))	('PCa', 'Phenotype', 'HP:0012125', (51, 54))	('knockdown', 'Var', (24, 33))	('RBAK', 'Gene', '57786', (37, 41))
456123	31555381	A high expression level of RBAK has been associated with a shorter survival time for patients with PCa following radical prostatectomy.	('survival time', 'CPA', (67, 80))	('PCa', 'Disease', (99, 102))	('PCa', 'Disease', 'MESH:D011471', (99, 102))	('RBAK', 'Gene', '57786', (27, 31))	('PCa', 'Phenotype', 'HP:0012125', (99, 102))	('high', 'Var', (2, 6))	('shorter', 'NegReg', (59, 66))	('patients', 'Species', '9606', (85, 93))	('RBAK', 'Gene', (27, 31))
456130	31555381	Furthermore, GSE19804 contains 60 paired NSCLC and normal samples, and GSE18842 includes 46 NSCLC samples and 45 control samples.	('NSCLC', 'Disease', (41, 46))	('NSCLC', 'Phenotype', 'HP:0030358', (92, 97))	('NSCLC', 'Disease', 'MESH:D002289', (41, 46))	('NSCLC', 'Disease', (92, 97))	('NSCLC', 'Phenotype', 'HP:0030358', (41, 46))	('GSE19804', 'Var', (13, 21))	('NSCLC', 'Disease', 'MESH:D002289', (92, 97))
456143	31555381	The present study first analyzed RBAK expression in NSCLC using three GEO datasets, namely GSE19188, GSE19804 and GSE18842.	('NSCLC', 'Disease', (52, 57))	('NSCLC', 'Disease', 'MESH:D002289', (52, 57))	('RBAK', 'Gene', (33, 37))	('GSE19804', 'Var', (101, 109))	('RBAK', 'Gene', '57786', (33, 37))	('NSCLC', 'Phenotype', 'HP:0030358', (52, 57))
456167	31555381	6, it was revealed that RBAK knockdown significantly decreased the number of migrating A549 cells compared with that in the negative control group (Fig.	('RBAK', 'Gene', (24, 28))	('RBAK', 'Gene', '57786', (24, 28))	('knockdown', 'Var', (29, 38))	('number of migrating A549 cells', 'CPA', (67, 97))	('decreased', 'NegReg', (53, 62))
456169	31555381	It was identified that knockdown of RBAK significantly inhibited A549 cell invasion.	('RBAK', 'Gene', (36, 40))	('RBAK', 'Gene', '57786', (36, 40))	('knockdown', 'Var', (23, 32))	('inhibited', 'NegReg', (55, 64))
456170	31555381	RBAK knockdown decreased the number of invading A549 cells by 88% compared with that in the negative control group (Fig.	('RBAK', 'Gene', '57786', (0, 4))	('knockdown', 'Var', (5, 14))	('decreased', 'NegReg', (15, 24))	('RBAK', 'Gene', (0, 4))
456174	31555381	RBAK was observed to be overexpressed in NSCLC and high expression was associated with shorter DFS times in patients with NSCLC.	('NSCLC', 'Disease', 'MESH:D002289', (122, 127))	('NSCLC', 'Disease', (41, 46))	('RBAK', 'Gene', '57786', (0, 4))	('NSCLC', 'Disease', 'MESH:D002289', (41, 46))	('NSCLC', 'Phenotype', 'HP:0030358', (122, 127))	('shorter', 'NegReg', (87, 94))	('high expression', 'Var', (51, 66))	('patients', 'Species', '9606', (108, 116))	('NSCLC', 'Phenotype', 'HP:0030358', (41, 46))	('NSCLC', 'Disease', (122, 127))	('RBAK', 'Gene', (0, 4))	('DFS times', 'MPA', (95, 104))
456176	31555381	These roles were experimentally validated, and in vitro assays confirmed that knockdown of RBAK suppressed NSCLC cell migration and invasion.	('NSCLC', 'Disease', (107, 112))	('knockdown', 'Var', (78, 87))	('NSCLC', 'Disease', 'MESH:D002289', (107, 112))	('suppressed', 'NegReg', (96, 106))	('RBAK', 'Gene', (91, 95))	('NSCLC', 'Phenotype', 'HP:0030358', (107, 112))	('RBAK', 'Gene', '57786', (91, 95))	('invasion', 'CPA', (132, 140))
456181	31555381	Furthermore, a high RBAK expression level was associated with poorer DFS of NSCLC patients.	('high', 'Var', (15, 19))	('RBAK', 'Gene', '57786', (20, 24))	('patients', 'Species', '9606', (82, 90))	('NSCLC', 'Disease', (76, 81))	('poorer', 'NegReg', (62, 68))	('NSCLC', 'Phenotype', 'HP:0030358', (76, 81))	('DFS', 'MPA', (69, 72))	('NSCLC', 'Disease', 'MESH:D002289', (76, 81))	('expression level', 'MPA', (25, 41))	('RBAK', 'Gene', (20, 24))
456190	31555381	Ras association domain-containing protein 1 suppresses the invasion of NSCLC by inhibiting Yes-associated protein 1. miR-483-5p promotes LUAD metastasis by targeting Rho GDP dissociation inhibitor 1 and activated leukocyte cell adhesion molecule.	('LUAD', 'Disease', 'MESH:C538231', (137, 141))	('LUAD', 'Disease', (137, 141))	('NSCLC', 'Phenotype', 'HP:0030358', (71, 76))	('Yes-associated protein 1', 'Gene', (91, 115))	('activated', 'Protein', (203, 212))	('miR-483-5p', 'Var', (117, 127))	('Rho GDP dissociation inhibitor 1', 'Gene', (166, 198))	('Yes-associated protein 1', 'Gene', '10413', (91, 115))	('Ras association domain-containing protein 1', 'Gene', (0, 43))	('promotes', 'PosReg', (128, 136))	('NSCLC', 'Disease', (71, 76))	('LUAD', 'Phenotype', 'HP:0030078', (137, 141))	('Ras association domain-containing protein 1', 'Gene', '11186', (0, 43))	('Rho GDP dissociation inhibitor 1', 'Gene', '396', (166, 198))	('targeting', 'Reg', (156, 165))	('NSCLC', 'Disease', 'MESH:D002289', (71, 76))
456191	31555381	The present study reported that silencing of RBAK suppresses NSCLC migration and invasion, suggesting that RBAK promotes metastasis-associated processes in NSCLC.	('promotes', 'PosReg', (112, 120))	('RBAK', 'Gene', (107, 111))	('RBAK', 'Gene', '57786', (45, 49))	('invasion', 'CPA', (81, 89))	('suppresses', 'NegReg', (50, 60))	('NSCLC', 'Phenotype', 'HP:0030358', (61, 66))	('NSCLC', 'Phenotype', 'HP:0030358', (156, 161))	('silencing', 'Var', (32, 41))	('RBAK', 'Gene', '57786', (107, 111))	('NSCLC', 'Disease', (61, 66))	('NSCLC', 'Disease', (156, 161))	('NSCLC', 'Disease', 'MESH:D002289', (61, 66))	('metastasis-associated processes', 'CPA', (121, 152))	('NSCLC', 'Disease', 'MESH:D002289', (156, 161))	('RBAK', 'Gene', (45, 49))
456210	29384959	We analyzed 22 R/M HNSCC patients who received pembrolizumab, a monoclonal antibody against PD-1, as salvage therapy.	('PD-1', 'Gene', (92, 96))	('SCC', 'Gene', (21, 24))	('PD-1', 'Gene', '5133', (92, 96))	('SCC', 'Gene', '6317', (21, 24))	('22 R/M', 'Var', (12, 18))	('patients', 'Species', '9606', (25, 33))	('pembrolizumab', 'Chemical', 'MESH:C582435', (47, 60))	('HNSCC', 'Phenotype', 'HP:0012288', (19, 24))	('22 R/M', 'SUBSTITUTION', 'None', (12, 18))
456284	29384959	The patient started radiation therapy to treat the sternum mass (4500 cGy in 15 fractions) in May 2016.	('sternum', 'Disease', (51, 58))	('4500 cGy', 'Var', (65, 73))	('patient', 'Species', '9606', (4, 11))
456304	29384959	The overall response rate was 18%, and the percentage of patients with positive responses was greater among those who were HPV positive (n = 5, 25%) than HPV negative (n = 7, 19%).	('HPV', 'Gene', (123, 126))	('patients', 'Species', '9606', (57, 65))	('positive', 'Var', (127, 135))	('HPV', 'Species', '10566', (123, 126))	('HPV', 'Species', '10566', (154, 157))
456306	29384959	Among these previously treated patients, those given nivolumab had improved OS relative to those given single-agent chemotherapy (methotrexate, docetaxel, or cetuximab).	('nivolumab', 'Chemical', 'MESH:D000077594', (53, 62))	('cetuximab', 'Chemical', 'MESH:D000068818', (158, 167))	('nivolumab', 'Var', (53, 62))	('patients', 'Species', '9606', (31, 39))	('improved', 'PosReg', (67, 75))	('docetaxel', 'Chemical', 'MESH:D000077143', (144, 153))	('methotrexate', 'Chemical', 'MESH:D008727', (130, 142))
456354	29384959	The KEYNOTE-012 trial showed discordance between PDL-1 and PDL-2 expression in a subpopulation of patients, and the researchers suggested that PDL-2 expression is associated with a higher overall response rate after adjusting for PDL-1 expression.	('PDL-2', 'Gene', (59, 64))	('PDL-2', 'Gene', (143, 148))	('PDL-1', 'Gene', '29126', (230, 235))	('PDL-2', 'Gene', '80380', (143, 148))	('patients', 'Species', '9606', (98, 106))	('PDL-1', 'Gene', (230, 235))	('higher', 'PosReg', (181, 187))	('response', 'MPA', (196, 204))	('PDL-1', 'Gene', '29126', (49, 54))	('PDL-2', 'Gene', '80380', (59, 64))	('PDL-1', 'Gene', (49, 54))	('expression', 'Var', (149, 159))
456404	29642934	In many cancers, APOBEC3B increases the mutation load, generating clusters of closely spaced, single-strand-specific DNA substitutions with a characteristic hypermutation signature.	('cancers', 'Disease', 'MESH:D009369', (8, 15))	('cancers', 'Phenotype', 'HP:0002664', (8, 15))	('cancers', 'Disease', (8, 15))	('substitutions', 'Var', (121, 134))	('generating', 'Reg', (55, 65))	('APOBEC3B', 'Gene', (17, 25))	('mutation load', 'MPA', (40, 53))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('increases', 'PosReg', (26, 35))
456407	29642934	We used information from the Cancer Cell Line Encyclopedia and the Genomics of Drug Sensitivity in Cancer resources to examine associations of the prevalence of APOBEC-like motifs and mutational loads with expression of APOBEC3A, APOBEC3B, REV1, UNG, and FHIT and with cell line chemosensitivity to 255 antitumor drugs.	('Cancer Cell Line Encyclopedia', 'Disease', (29, 58))	('Cancer', 'Phenotype', 'HP:0002664', (99, 105))	('Drug Sensitivity', 'Phenotype', 'HP:0020174', (79, 95))	('APOBEC3A', 'Gene', '200315', (220, 228))	('tumor', 'Disease', (307, 312))	('REV1', 'Gene', (240, 244))	('Cancer', 'Disease', 'MESH:D009369', (29, 35))	('tumor', 'Disease', 'MESH:D009369', (307, 312))	('Cancer', 'Disease', (99, 105))	('APOBEC3B', 'Gene', (230, 238))	('associations', 'Interaction', (127, 139))	('UNG', 'Gene', (246, 249))	('mutational loads', 'Var', (184, 200))	('Cancer', 'Disease', 'MESH:D009369', (99, 105))	('tumor', 'Phenotype', 'HP:0002664', (307, 312))	('FHIT', 'Gene', (255, 259))	('Cancer Cell Line Encyclopedia', 'Disease', 'MESH:C538614', (29, 58))	('Cancer', 'Phenotype', 'HP:0002664', (29, 35))	('APOBEC-like motifs', 'Gene', (161, 179))	('FHIT', 'Gene', '2272', (255, 259))	('UNG', 'Gene', '7374', (246, 249))	('APOBEC3A', 'Gene', (220, 228))	('Cancer', 'Disease', (29, 35))	('REV1', 'Gene', '51455', (240, 244))
456410	29642934	The strongest correlations of gene expression levels with mutational loads or with measures of prevalence of APOBEC-like motif counts and kataegis clusters were observed for REV1, UNG, and APOBEC3A.	('APOBEC3A', 'Gene', '200315', (189, 197))	('UNG', 'Gene', '7374', (180, 183))	('REV1', 'Gene', '51455', (174, 178))	('UNG', 'Gene', (180, 183))	('REV1', 'Gene', (174, 178))	('correlations', 'Interaction', (14, 26))	('APOBEC3A', 'Gene', (189, 197))	('mutational', 'Var', (58, 68))
456411	29642934	Sensitivity or resistance of cell lines to JQ1, palbociclib, bicalutamide, 17-AAG, TAE684, MEK inhibitors refametinib, PD-0325901, and trametinib and a number of other agents was correlated with candidate gene expression levels or with abundance of APOBEC-like motif clusters in specific cancers or across cancer types.	('cancers', 'Phenotype', 'HP:0002664', (288, 295))	('AAG', 'Gene', '4350', (78, 81))	('cancer', 'Disease', (288, 294))	('cancers', 'Disease', (288, 295))	('bicalutamide', 'Chemical', 'MESH:C053541', (61, 73))	('cancer', 'Disease', 'MESH:D009369', (306, 312))	('cancer', 'Phenotype', 'HP:0002664', (288, 294))	('MEK', 'Gene', '5609', (91, 94))	('refametinib', 'Chemical', 'MESH:C544830', (106, 117))	('PD-0325901', 'Var', (119, 129))	('MEK', 'Gene', (91, 94))	('AAG', 'Gene', (78, 81))	('cancer', 'Disease', 'MESH:D009369', (288, 294))	('cancers', 'Disease', 'MESH:D009369', (288, 295))	('TAE684', 'Chemical', 'MESH:C516714', (83, 89))	('cancer', 'Disease', (306, 312))	('cancer', 'Phenotype', 'HP:0002664', (306, 312))	('palbociclib', 'Chemical', 'MESH:C500026', (48, 59))	('PD-0325901', 'Chemical', 'MESH:C506614', (119, 129))	('trametinib', 'Chemical', 'MESH:C560077', (135, 145))
456417	29642934	APOBEC3B is an endogenous mutagen which generates DNA substitutions, most frequently C to T, via a process that involves cytosine to uracil deamination of single-stranded DNA, most commonly in the 5'-TCW-3' (where W is either A or T) sequence context.	('cytosine to uracil', 'MPA', (121, 139))	('APOBEC3B', 'Gene', (0, 8))	('substitutions', 'Var', (54, 67))	('cytosine', 'Chemical', 'MESH:D003596', (121, 129))	('uracil', 'Chemical', 'MESH:D014498', (133, 139))
456418	29642934	In multiple human cancer categories, increased APOBEC3B gene expression has been associated with genome-wide hypermutation and with kataegis, a mutagenic process that generates clusters of closely spaced, single-strand-specific DNA substitutions, which are predominantly C to T. Clusters of APOBEC3B mutations are often localized at breakpoints of chromosomal rearrangements.	('cancer', 'Disease', 'MESH:D009369', (18, 24))	('APOBEC3B', 'Gene', (47, 55))	('mutations', 'Var', (300, 309))	('APOBEC3B', 'Gene', (291, 299))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('increased', 'PosReg', (37, 46))	('human', 'Species', '9606', (12, 17))	('cancer', 'Disease', (18, 24))	('expression', 'MPA', (61, 71))
456419	29642934	Increased APOBEC3B gene expression, germline polymorphisms in the APOBEC3 genome region, and higher degree of abundance of APOBEC3B mutational signatures have been associated with increased cancer risk and patient survival.	('cancer', 'Disease', (190, 196))	('cancer', 'Disease', 'MESH:D009369', (190, 196))	('germline polymorphisms', 'Var', (36, 58))	('associated', 'Reg', (164, 174))	('APOBEC3B', 'Gene', (123, 131))	('expression', 'MPA', (24, 34))	('patient', 'Species', '9606', (206, 213))	('APOBEC3B', 'Gene', (10, 18))	('Increased', 'PosReg', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('APOBEC3', 'Gene', (66, 73))
456421	29642934	According to various reports, in addition to the C>T transitions, these patterns may include possible C>G and, in some specific cancer types such as ovarian carcinomas, C>A transversions, as well as a possible 5'-TC(A or G)-3' sequence context, so that possible mutational motifs could be represented as 5'-T(C>K)W-3', 5'-T(C>D)R-3', or 5'-T(C>D)D-3', where K is [G or T], W is [A or T], R is [A or G], and D is [A or G or T] according to the IUB-IUPAC ambiguity codes.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('ovarian carcinomas', 'Disease', 'MESH:D010051', (149, 167))	('carcinomas', 'Phenotype', 'HP:0030731', (157, 167))	('D is [A', 'Var', (407, 414))	('ovarian carcinomas', 'Disease', (149, 167))	('carcinoma', 'Phenotype', 'HP:0030731', (157, 166))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('ovarian carcinomas', 'Phenotype', 'HP:0025318', (149, 167))	('R is [A', 'Var', (388, 395))	('W is [A', 'Var', (373, 380))	('cancer', 'Disease', (128, 134))
456422	29642934	Below, we present these sequence motifs in the 5' to 3' direction as T(C>K)W, T(C>D)R, and T(C>D)D. While APOBEC3B plays a prominent role in cancer mutagenesis, several other AID/APOBEC family members also have mutagenic roles and affect DNA integrity.	('T(C>D)R', 'Var', (78, 85))	('DNA integrity', 'CPA', (238, 251))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('mutagenic', 'CPA', (211, 220))	('APOBEC3B', 'Gene', (106, 114))	('affect', 'Reg', (231, 237))	('T(C>D)D.', 'Var', (91, 99))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('AID', 'Gene', '57379', (175, 178))	('AID', 'Gene', (175, 178))	('cancer', 'Disease', (141, 147))
456425	29642934	An APOBEC3A-APOBEC3B fusion transcript may be produced due to a germline deletion polymorphism, which results in the complete loss of the coding part of the APOBEC3B gene and abolishes APOBEC3B gene expression; this deletion polymorphism produces a fusion product of the APOBEC3A gene with the 3'-UTR of APOBEC3B gene, and it has been associated with an increased risk of several types of cancer.	('APOBEC3B', 'Gene', (304, 312))	('associated with', 'Reg', (335, 350))	('APOBEC3A', 'Gene', '200315', (271, 279))	('expression', 'MPA', (199, 209))	('APOBEC3A', 'Gene', '200315', (3, 11))	('APOBEC3B', 'Gene', (157, 165))	('cancer', 'Disease', 'MESH:D009369', (389, 395))	('cancer', 'Phenotype', 'HP:0002664', (389, 395))	('deletion polymorphism', 'Var', (216, 237))	('abolishes', 'NegReg', (175, 184))	('produces', 'Reg', (238, 246))	('APOBEC3B gene', 'Gene', (185, 198))	('APOBEC3A', 'Gene', (271, 279))	('loss', 'NegReg', (126, 130))	('cancer', 'Disease', (389, 395))	('APOBEC3A', 'Gene', (3, 11))
456429	29642934	Based on the strong evidence for APOBEC-associated mutagenesis in a variety of cancer types, it is important to learn whether such mutagenic processes may affect cancer response to therapy, in order to exploit potential pathways involved in sensitivity and to avoid potential mechanisms of resistance.	('APOBEC-associated', 'Gene', (33, 50))	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('affect', 'Reg', (155, 161))	('cancer', 'Disease', (162, 168))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('mutagenesis', 'Var', (51, 62))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))
456430	29642934	Some studies suggested a potential role of APOBEC mutagenesis in tumor resistance to therapy, with a possible resistance mechanism explained by increased tumor heterogeneity when APOBEC3B activity is elevated.	('tumor', 'Disease', (65, 70))	('APOBEC3B', 'Gene', (179, 187))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('mutagenesis', 'Var', (50, 61))	('activity', 'MPA', (188, 196))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('tumor', 'Disease', (154, 159))
456434	29642934	Experimental in vitro overexpression of APOBEC3B in the 293-A3B and 293-GFP cell lines with inactivated p53 resulted in an increase in APOBEC mutagenesis and kataegic events, which were accompanied by cell hypersensitivity to small-molecule DNA damage response inhibitors including ATR (VX-970 and AZD673), CHEK1 (SAR020106), CHEK2 (CCT241553), PARP (olaparib and BMN-673), and WEE1 (AZD1775) inhibitors, as well as by sensitivity to combinations of cisplatin/ATR inhibitor, ATR/PARP inhibitor, and PARP/WEE1 inhibitor.	('PARP', 'Gene', '142', (499, 503))	('p53', 'Gene', '7157', (104, 107))	('WEE1', 'Gene', (504, 508))	('ATR', 'Gene', (460, 463))	('SAR', 'Gene', (314, 317))	('ATR', 'Gene', (475, 478))	('PARP', 'Gene', (499, 503))	('WEE1', 'Gene', (378, 382))	('ATR', 'Gene', '545', (282, 285))	('inhibitors', 'MPA', (393, 403))	('p53', 'Gene', (104, 107))	('APOBEC3B', 'Gene', (40, 48))	('hypersensitivity', 'Disease', (206, 222))	('293-GFP', 'CellLine', 'CVCL:0045', (68, 75))	('PARP', 'Gene', '142', (345, 349))	('PARP', 'Gene', '142', (479, 483))	('increase', 'PosReg', (123, 131))	('SAR', 'Gene', '1757', (314, 317))	('APOBEC', 'Gene', (135, 141))	('CHEK2', 'Gene', (326, 331))	('PARP', 'Gene', (479, 483))	('PARP', 'Gene', (345, 349))	('hypersensitivity', 'Disease', 'MESH:D004342', (206, 222))	('inactivated', 'Var', (92, 103))	('WEE1', 'Gene', '7465', (504, 508))	('ATR', 'Gene', '545', (460, 463))	('kataegic events', 'CPA', (158, 173))	('CHEK1', 'Gene', '1111', (307, 312))	('CHEK2', 'Gene', '11200', (326, 331))	('ATR', 'Gene', '545', (475, 478))	('WEE1', 'Gene', '7465', (378, 382))	('293-A3B', 'CellLine', 'CVCL:6910', (56, 63))	('ATR', 'Gene', (282, 285))	('CHEK1', 'Gene', (307, 312))
456453	29642934	To examine possible associations of expression levels of APOBEC3A and APOBEC3B with the germline APOBEC3B gene deletion, we downloaded the copy number status of the APOBEC3B gene from the CCLE web resource of the Broad Institute.	('APOBEC3A', 'Gene', (57, 65))	('APOBEC3B', 'Gene', (165, 173))	('CCLE', 'Chemical', '-', (188, 192))	('APOBEC3B', 'Gene', (97, 105))	('deletion', 'Var', (111, 119))	('APOBEC3A', 'Gene', '200315', (57, 65))
456481	29642934	APOBEC-derived mutagenesis is considered to be the predominant mutation source in 65% of invasive bladder cancers in the TCGA dataset.	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('invasive bladder', 'Phenotype', 'HP:0100645', (89, 105))	('invasive bladder cancers', 'Disease', 'MESH:D001749', (89, 113))	('cancers', 'Phenotype', 'HP:0002664', (106, 113))	('mutagenesis', 'Var', (15, 26))	('invasive bladder cancers', 'Disease', (89, 113))	('bladder cancer', 'Phenotype', 'HP:0009725', (98, 112))	('bladder cancers', 'Phenotype', 'HP:0009725', (98, 113))
456482	29642934	Similarly, a genomic signature attributed to APOBEC3 activity was reported in a subset of patients with all melanoma subtypes, although C>T transitions attributed to APOBEC activity could be confounded with UV-induced substitutions in many melanoma cells.	('C>T', 'Var', (136, 139))	('melanoma', 'Disease', 'MESH:D008545', (108, 116))	('melanoma', 'Disease', 'MESH:D008545', (240, 248))	('melanoma subtypes', 'Disease', (108, 125))	('melanoma', 'Phenotype', 'HP:0002861', (240, 248))	('melanoma subtypes', 'Disease', 'MESH:D008545', (108, 125))	('melanoma', 'Disease', (240, 248))	('patients', 'Species', '9606', (90, 98))	('melanoma', 'Phenotype', 'HP:0002861', (108, 116))	('melanoma', 'Disease', (108, 116))	('APOBEC3', 'Gene', (45, 52))
456483	29642934	Increased expression and activity of both APOBEC3A and APOBEC3B were also reported in multiple myeloma patients, most commonly in those with the t(14:16) translocation, which was associated with poor survival.	('multiple myeloma', 'Phenotype', 'HP:0006775', (86, 102))	('multiple myeloma', 'Disease', 'MESH:D009101', (86, 102))	('multiple myeloma', 'Disease', (86, 102))	('expression', 'MPA', (10, 20))	('APOBEC3A', 'Gene', '200315', (42, 50))	('APOBEC3B', 'Gene', (55, 63))	('Increased', 'PosReg', (0, 9))	('activity', 'MPA', (25, 33))	('patients', 'Species', '9606', (103, 111))	('APOBEC3A', 'Gene', (42, 50))	('t(14:16) translocation', 'Var', (145, 167))
456486	29642934	Because abrogated FHIT activity may increase the levels of mutagenesis both as a standalone mechanism and synergistically with APOBEC3B, we note that cell lines from several cancer types including head and neck (4.85) and sarcoma (4.87) had a considerably lower mean FHIT expression than the pan-cancer average (5.74).	('cancer', 'Phenotype', 'HP:0002664', (296, 302))	('expression', 'MPA', (272, 282))	('sarcoma', 'Disease', 'MESH:D012509', (222, 229))	('levels of mutagenesis', 'MPA', (49, 70))	('sarcoma', 'Disease', (222, 229))	('FHIT', 'Gene', (267, 271))	('increase', 'PosReg', (36, 44))	('cancer', 'Disease', (174, 180))	('activity', 'MPA', (23, 31))	('cancer', 'Disease', 'MESH:D009369', (296, 302))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('sarcoma', 'Phenotype', 'HP:0100242', (222, 229))	('lower', 'NegReg', (256, 261))	('abrogated', 'Var', (8, 17))	('FHIT', 'Gene', '2272', (267, 271))	('FHIT', 'Gene', (18, 22))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('cancer', 'Disease', (296, 302))	('FHIT', 'Gene', '2272', (18, 22))
456501	29642934	Prevalence of mutation counts and single nucleotide positions in the combined analysis of all cancer categories and within individual cancer types in the 325 cell lines with available WES data is provided in Table 3.	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('single nucleotide positions', 'Var', (34, 61))	('mutation', 'Var', (14, 22))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
456504	29642934	However, clusters of mutations in genome regions have been reported to provide a more robust representation of mutational processes in tumor genomes that do average mutation rates at single positions.	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('tumor', 'Disease', (135, 140))	('tumor', 'Disease', 'MESH:D009369', (135, 140))	('mutations', 'Var', (21, 30))
456509	29642934	For the most specific APOBEC motif, T(C>K)W, the highest mean number of motifs per cell line was observed in cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC; mean = 736 motifs per cell line), followed by bladder cancer (mean = 716 motifs), and melanoma (mean = 642 motifs; Fig.	('T(C>K)W', 'Var', (36, 43))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('melanoma', 'Phenotype', 'HP:0002861', (267, 275))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (118, 141))	('melanoma', 'Disease', (267, 275))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))	('squamous cell carcinoma and endocervical adenocarcinoma', 'Disease', 'MESH:D002294', (118, 173))	('melanoma', 'Disease', 'MESH:D008545', (267, 275))	('bladder cancer', 'Phenotype', 'HP:0009725', (227, 241))	('carcinoma', 'Phenotype', 'HP:0030731', (164, 173))	('bladder cancer', 'Disease', 'MESH:D001749', (227, 241))	('bladder cancer', 'Disease', (227, 241))
456511	29642934	The highest mean number of the 5/1000 kataegis clusters with the T(C>K)W motif was observed in bladder cancer (mean = 0.33 clusters per cell line), followed by mature B cell lymphoma (MATBCL; mean = 0.28 clusters), and NSCLC (mean = 0.19 clusters; Fig.	('NSCLC', 'Disease', (219, 224))	('SCLC', 'Phenotype', 'HP:0030357', (220, 224))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('B cell lymphoma', 'Disease', 'MESH:D016393', (167, 182))	('NSCLC', 'Disease', 'MESH:D002289', (219, 224))	('B cell lymphoma', 'Disease', (167, 182))	('B cell lymphoma', 'Phenotype', 'HP:0012191', (167, 182))	('lymphoma', 'Phenotype', 'HP:0002665', (174, 182))	('bladder cancer', 'Disease', 'MESH:D001749', (95, 109))	('bladder cancer', 'Disease', (95, 109))	('T(C>K)W', 'Var', (65, 72))	('bladder cancer', 'Phenotype', 'HP:0009725', (95, 109))
456514	29642934	The highest mean number of the 5/1000 kataegis clusters with the T(C>D)R motif was observed for THCA (mean = 1.00 cluster), followed by MATBCL (mean = 0.83 clusters) and the liver hepatocellular carcinoma (LIHC; mean = 0.76; Fig.	('liver hepatocellular carcinoma', 'Disease', (174, 204))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (180, 204))	('liver hepatocellular carcinoma', 'Disease', 'MESH:D006528', (174, 204))	('T(C>D)R motif', 'Var', (65, 78))	('carcinoma', 'Phenotype', 'HP:0030731', (195, 204))	('THCA', 'Chemical', '-', (96, 100))
456517	29642934	The highest numbers of 5/1000 kataegis clusters with the T(C>D)D motif were observed in LIHC (mean = 2.65 clusters), renal cell carcinoma (RCC; mean = 2.50 clusters), and UCEC (mean = 2.50 clusters; Fig.	('renal cell carcinoma', 'Disease', (117, 137))	('T(C>D)D', 'Var', (57, 64))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (117, 137))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (117, 137))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('RCC', 'Phenotype', 'HP:0005584', (139, 142))	('LIHC', 'Disease', (88, 92))	('RCC', 'Disease', 'MESH:C538614', (139, 142))	('UCEC', 'Disease', (171, 175))	('RCC', 'Disease', (139, 142))
456518	29642934	When 6/10000 kataegis clusters (data not shown), the two cancer types with the highest mean numbers of kataegis clusters were LIHC (mean = 0.76 clusters for T(C>K)W, 1.24 clusters for T(C>D)R, and 3.24 clusters for the T(C>D)D motif) and RCC (mean = 0.38, 0.88, and 2.13 clusters, respectively).	('T(C>D)R', 'Var', (184, 191))	('RCC', 'Phenotype', 'HP:0005584', (238, 241))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('RCC', 'Disease', 'MESH:C538614', (238, 241))	('RCC', 'Disease', (238, 241))	('cancer', 'Disease', (57, 63))	('T(C>K)W', 'Var', (157, 164))	('T(C>D)D motif', 'Var', (219, 232))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))
456519	29642934	Our findings for bladder cancer, melanoma, non-small cell lung cancer, uterine corpus endometrial carcinoma, and prostate adenocarcinoma were consistent with previous reports which suggested the roles for APOBEC3 mutagenesis in those cancer types.	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('APOBEC3', 'Gene', (205, 212))	('melanoma', 'Phenotype', 'HP:0002861', (33, 41))	('melanoma', 'Disease', (33, 41))	('lung cancer', 'Phenotype', 'HP:0100526', (58, 69))	('non-small cell lung cancer', 'Disease', (43, 69))	('bladder cancer', 'Disease', 'MESH:D001749', (17, 31))	('bladder cancer', 'Disease', (17, 31))	('cancer', 'Disease', (25, 31))	('prostate adenocarcinoma', 'Disease', (113, 136))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (86, 107))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('bladder cancer', 'Phenotype', 'HP:0009725', (17, 31))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (86, 107))	('cancer', 'Disease', 'MESH:D009369', (234, 240))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (43, 69))	('cancer', 'Disease', (63, 69))	('prostate adenocarcinoma', 'Disease', 'MESH:D011471', (113, 136))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (47, 69))	('melanoma', 'Disease', 'MESH:D008545', (33, 41))	('cancer', 'Disease', 'MESH:D009369', (25, 31))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (43, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('endometrial carcinoma', 'Disease', (86, 107))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('cancer', 'Disease', (234, 240))	('mutagenesis', 'Var', (213, 224))
456520	29642934	In contrast, APOBEC3B was reported to be less likely to play a role in mutagenesis of renal cell carcinoma cell lines, suggesting that high prevalence of mutation clusters in the RCC cell lines observed in our study could be generated by molecular factors other than APOBEC3B.	('RCC', 'Phenotype', 'HP:0005584', (179, 182))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (86, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('mutation', 'Var', (154, 162))	('renal cell carcinoma', 'Disease', (86, 106))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (86, 106))	('RCC', 'Disease', 'MESH:C538614', (179, 182))	('RCC', 'Disease', (179, 182))
456521	29642934	The increased prevalence of mutagenic clusters in mature B cell lymphoma cell lines may be explained by the effects of translesion synthesis DNA polymerase eta.	('lymphoma', 'Phenotype', 'HP:0002665', (64, 72))	('mutagenic', 'Var', (28, 37))	('DNA polymerase eta', 'Gene', '5429', (141, 159))	('B cell lymphoma', 'Phenotype', 'HP:0012191', (57, 72))	('DNA polymerase eta', 'Gene', (141, 159))	('B cell lymphoma', 'Disease', 'MESH:D016393', (57, 72))	('B cell lymphoma', 'Disease', (57, 72))
456522	29642934	It is also possible that some of the mutations in MATBCL could be explained by a partial overlap of the motifs examined in our study with a characteristic signature for another member of the APOBEC family, the activation-induced cytidine deaminase (AID), which has been linked to mutagenesis in MATBCL.	('MATBCL', 'Gene', (50, 56))	('activation-induced cytidine deaminase', 'Gene', (210, 247))	('mutations', 'Var', (37, 46))	('AID', 'Gene', '57379', (249, 252))	('AID', 'Gene', (249, 252))	('activation-induced cytidine deaminase', 'Gene', '57379', (210, 247))
456530	29642934	Among individual cancer types, we observed a strong (rho between - 0.738 and - 0.902) and statistically significant (padj < 0.05) negative correlation of the frequencies of C>T, C>G, and C>K substitutions and overall nucleotide substitution counts with REV1 expression in sarcoma and UNG expression in melanoma (Table 5).	('melanoma', 'Phenotype', 'HP:0002861', (302, 310))	('melanoma', 'Disease', (302, 310))	('sarcoma', 'Disease', (272, 279))	('negative', 'NegReg', (130, 138))	('expression', 'MPA', (258, 268))	('melanoma', 'Disease', 'MESH:D008545', (302, 310))	('sarcoma', 'Phenotype', 'HP:0100242', (272, 279))	('REV1', 'Gene', '51455', (253, 257))	('C>G', 'Var', (178, 181))	('C>K', 'Var', (187, 190))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('REV1', 'Gene', (253, 257))	('C>T', 'Var', (173, 176))	('cancer', 'Disease', (17, 23))	('UNG', 'Gene', '7374', (284, 287))	('sarcoma', 'Disease', 'MESH:D012509', (272, 279))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))	('UNG', 'Gene', (284, 287))
456533	29642934	APOBEC3B expression also had the strongest correlation with mutation counts in RCC as opposed to other cancer categories; however, such correlations for APOBEC3B were somewhat weaker and less significant (rho <= 0.86, padj >= 0.16) than those for APOBEC3A (data not shown).	('RCC', 'Phenotype', 'HP:0005584', (79, 82))	('APOBEC3B', 'Var', (153, 161))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('APOBEC3A', 'Gene', '200315', (247, 255))	('APOBEC3B', 'Gene', (0, 8))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('APOBEC3A', 'Gene', (247, 255))	('cancer', 'Disease', (103, 109))	('weaker', 'NegReg', (176, 182))	('RCC', 'Disease', 'MESH:C538614', (79, 82))	('RCC', 'Disease', (79, 82))
456535	29642934	A large proportion of C>T and C>G substitutions in melanoma cell lines were likely generated via mutagenic processes related to UV radiation exposure.	('C>G substitutions', 'Var', (30, 47))	('C>T', 'Var', (22, 25))	('melanoma', 'Phenotype', 'HP:0002861', (51, 59))	('melanoma', 'Disease', (51, 59))	('melanoma', 'Disease', 'MESH:D008545', (51, 59))
456536	29642934	However, the role for APOBEC3 in melanoma mutagenesis has also been established in a subset of melanomas, and experimental evidence has suggested an important role of APOBEC3A generating mutations specific to skin lesions.	('APOBEC3A', 'Gene', '200315', (167, 175))	('melanomas', 'Disease', (95, 104))	('melanoma', 'Phenotype', 'HP:0002861', (33, 41))	('APOBEC3', 'Gene', (22, 29))	('melanoma', 'Disease', (33, 41))	('melanoma', 'Disease', 'MESH:D008545', (95, 103))	('melanoma', 'Disease', (95, 103))	('melanoma', 'Phenotype', 'HP:0002861', (95, 103))	('melanoma', 'Disease', 'MESH:D008545', (33, 41))	('mutations', 'Var', (187, 196))	('melanomas', 'Phenotype', 'HP:0002861', (95, 104))	('skin lesions', 'Disease', (209, 221))	('APOBEC3A', 'Gene', (167, 175))	('melanomas', 'Disease', 'MESH:D008545', (95, 104))	('skin lesions', 'Disease', 'MESH:D012871', (209, 221))
456537	29642934	Among the correlations of gene expression levels with APOBEC-like motif counts and measures of kataegis, significant or nearly significant correlations were observed for UNG expression with kataegis measures (rho between - 0.81 and - 0.80, 0.039 <= padj <= 0.063, n = 17, Ntests = 475) of the T(C>D)D motif in melanoma, and for APOBEC3A expression with motif counts and kataegis measures in renal cell carcinoma (rho between 0.93 and 0.98, 0.008 <= padj <= 0.087 with n = 8 and Ntests = 510 for the T(C>D)R and T(C>D)D motifs; data not shown).	('renal cell carcinoma', 'Disease', 'MESH:C538614', (391, 411))	('APOBEC3A', 'Gene', '200315', (328, 336))	('carcinoma', 'Phenotype', 'HP:0030731', (402, 411))	('melanoma', 'Phenotype', 'HP:0002861', (310, 318))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (391, 411))	('melanoma', 'Disease', (310, 318))	('melanoma', 'Disease', 'MESH:D008545', (310, 318))	('APOBEC3A', 'Gene', (328, 336))	('T(C>D)R', 'Var', (499, 506))	('renal cell carcinoma', 'Disease', (391, 411))	('UNG', 'Gene', '7374', (170, 173))	('UNG', 'Gene', (170, 173))
456542	29642934	Expression of REV1 in the non-small cell lung cancer cell lines was significantly positively correlated with log(IC50) of MEK (mitogen-activated protein kinase) inhibitors PD-0325901, RDEA119, and trametinib, as well as AKT inhibitor VIII, XIAP inhibitor embelin, PI3Kbeta inhibitor AZD6482, and a cyclin-dependent kinase (CDK) 4/6 inhibitor PD-0332991, or palbociclib (Table 6; 0.348 <= rho <= 0.405, padj <= 0.0436, n >= 100, Ntests = 26,610).	('XIAP', 'Gene', '331', (240, 244))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (26, 52))	('AKT', 'Gene', (220, 223))	('PD-0325901', 'Chemical', 'MESH:C506614', (172, 182))	('trametinib', 'Chemical', 'MESH:C560077', (197, 207))	('lung cancer', 'Phenotype', 'HP:0100526', (41, 52))	('VIII', 'Gene', (234, 238))	('non-small cell lung cancer', 'Disease', (26, 52))	('REV1', 'Gene', '51455', (14, 18))	('PI3Kbeta', 'Gene', (264, 272))	('mitogen-activated protein kinase', 'Gene', '5609', (127, 159))	('XIAP', 'Gene', (240, 244))	('MEK', 'Gene', '5609', (122, 125))	('PD-0325901', 'Var', (172, 182))	('AKT', 'Gene', '207', (220, 223))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('REV1', 'Gene', (14, 18))	('cyclin-dependent kinase (CDK) 4/6', 'Gene', '1019;1021', (298, 331))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (26, 52))	('palbociclib', 'Chemical', 'MESH:C500026', (357, 368))	('PI3Kbeta', 'Gene', '5291', (264, 272))	('MEK', 'Gene', (122, 125))	('VIII', 'Gene', '1351', (234, 238))	('mitogen-activated protein kinase', 'Gene', (127, 159))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (30, 52))
456544	29642934	PD-0325901 has an in vitro inhibiting effect in NSCLC; however, a phase II clinical trial of that antitumor agent in NSCLC patients did not meet the primary efficacy end point.	('NSCLC', 'Disease', (117, 122))	('NSCLC', 'Disease', (48, 53))	('SCLC', 'Phenotype', 'HP:0030357', (49, 53))	('NSCLC', 'Disease', 'MESH:D002289', (48, 53))	('PD-0325901', 'Var', (0, 10))	('inhibiting', 'NegReg', (27, 37))	('patients', 'Species', '9606', (123, 131))	('NSCLC', 'Disease', 'MESH:D002289', (117, 122))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('SCLC', 'Phenotype', 'HP:0030357', (118, 122))	('PD-0325901', 'Chemical', 'MESH:C506614', (0, 10))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))
456546	29642934	In melanoma cell lines, FHIT expression was associated with chemoresistance to the ALK inhibitor TAE684 (Table 6; rho = 0.621, padj = 0.0326, n = 38, Ntests = 26,610).	('expression', 'Var', (29, 39))	('ALK', 'Gene', '238', (83, 86))	('melanoma', 'Phenotype', 'HP:0002861', (3, 11))	('chemoresistance', 'CPA', (60, 75))	('FHIT', 'Gene', (24, 28))	('TAE684', 'Chemical', 'MESH:C516714', (97, 103))	('ALK', 'Gene', (83, 86))	('FHIT', 'Gene', '2272', (24, 28))	('melanoma', 'Disease', (3, 11))	('melanoma', 'Disease', 'MESH:D008545', (3, 11))	('associated with', 'Reg', (44, 59))
456559	29642934	Among notable correlations, the combined length of clusters with the T(C>D)D motif had a strong correlation (5 <= n <= 7, Ntests = 1834) with chemoresistance to bicalutamide, a nonsteroidal antiandrogen drug, in the pancreatic adenocarcinoma and breast cancer cell lines (Table 7; Fig.	('breast cancer', 'Disease', (246, 259))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D010190', (216, 241))	('chemoresistance', 'CPA', (142, 157))	('breast cancer', 'Phenotype', 'HP:0003002', (246, 259))	('pancreatic adenocarcinoma', 'Disease', (216, 241))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (216, 241))	('T(C>D)D', 'Var', (69, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (232, 241))	('bicalutamide', 'Chemical', 'MESH:C053541', (161, 173))	('breast cancer', 'Disease', 'MESH:D001943', (246, 259))	('correlation', 'Reg', (96, 107))	('cancer', 'Phenotype', 'HP:0002664', (253, 259))
456560	29642934	As discussed above, we did not observe a statistically significant correlation between expression of any candidate gene and the prevalence of T(C>D)D or any other motif in breast cancer cell lines.	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('breast cancer', 'Disease', 'MESH:D001943', (172, 185))	('breast cancer', 'Disease', (172, 185))	('T(C>D)D', 'Var', (142, 149))	('breast cancer', 'Phenotype', 'HP:0003002', (172, 185))
456561	29642934	Sequence variation of breast cancer genomes is shaped by a diversity of mutational processes, and further investigation is needed to establish whether the T(C>D)D motif in the breast cancer cell lines is predominantly generated by APOBEC3B and APOBEC3A and/or requires an additional role or REV1, UNG, and FHIT, or whether it involves other molecular mechanisms.	('APOBEC3B', 'Gene', (231, 239))	('FHIT', 'Gene', '2272', (306, 310))	('APOBEC3A', 'Gene', (244, 252))	('breast cancer', 'Disease', (22, 35))	('breast cancer', 'Phenotype', 'HP:0003002', (22, 35))	('APOBEC3A', 'Gene', '200315', (244, 252))	('UNG', 'Gene', '7374', (297, 300))	('T(C>D)D', 'Var', (155, 162))	('REV1', 'Gene', '51455', (291, 295))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('REV1', 'Gene', (291, 295))	('breast cancer', 'Disease', 'MESH:D001943', (176, 189))	('breast cancer', 'Phenotype', 'HP:0003002', (176, 189))	('UNG', 'Gene', (297, 300))	('breast cancer', 'Disease', (176, 189))	('breast cancer', 'Disease', 'MESH:D001943', (22, 35))	('FHIT', 'Gene', (306, 310))
456564	29642934	To our knowledge, no relationship between the abundance of APOBEC-like signatures and sensitivity to this agent has been reported, although HER2-enriched cell lines have been reported to have high levels of APOBEC mutagenesis and to be among the breast cancer categories that are likely to be sensitive to bicalutamide.	('breast cancer', 'Disease', (246, 259))	('APOBEC', 'Protein', (207, 213))	('breast cancer', 'Phenotype', 'HP:0003002', (246, 259))	('bicalutamide', 'Chemical', 'MESH:C053541', (306, 318))	('mutagenesis', 'Var', (214, 225))	('HER2', 'Gene', (140, 144))	('breast cancer', 'Disease', 'MESH:D001943', (246, 259))	('HER2', 'Gene', '2064', (140, 144))	('cancer', 'Phenotype', 'HP:0002664', (253, 259))
456571	29642934	Similarly, log(IC50) of the hedgehog signaling pathway inhibitor vismodegib and of the PPARgamma/PPARdelta inhibitor FH535 were associated with the overall counts of the T(C>D)R motif.	('PPARgamma', 'Gene', '5468', (87, 96))	('hedgehog signaling pathway', 'Pathway', (28, 54))	('PPARdelta', 'Gene', (97, 106))	('associated', 'Reg', (128, 138))	('FH535', 'Chemical', 'MESH:C575430', (117, 122))	('PPARdelta', 'Gene', '5467', (97, 106))	('PPARgamma', 'Gene', (87, 96))	('T(C>D)R motif', 'Var', (170, 183))
456572	29642934	The overall counts of the T(C>D)D motif were associated with log(IC50) of the PKCB inhibitor LY317615, whereas the length of its predicted kataegis regions was associated with log(IC50) of the Aurora kinase A/B inhibitor Genentech Cpd10, a DNA-damaging agent gemcitabine, and, as discussed above, with a nonsteroidal antiandrogen agent bicalutamide (Table 7).	('LY317615', 'Var', (93, 101))	('PKCB', 'Gene', (78, 82))	('Aurora kinase A/B', 'Gene', '6790;9212', (193, 210))	('LY317615', 'Chemical', 'MESH:C504878', (93, 101))	('Aurora kinase A/B', 'Gene', (193, 210))	('bicalutamide', 'Chemical', 'MESH:C053541', (336, 348))	('inhibitor LY317615', 'Var', (83, 101))	('PKCB', 'Gene', '5579', (78, 82))	('gemcitabine', 'Chemical', 'MESH:C056507', (259, 270))
456576	29642934	The bimodal distribution of APOBEC3B is likely due to several reasons which include previously reported differences in expression levels of this gene among specific cancer types and individual cell lines within specific cancer categories, along with the germline deletion polymorphism that results in the loss the APOBEC3B gene in a subset of the samples.	('expression levels', 'MPA', (119, 136))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('cancer', 'Disease', 'MESH:D009369', (220, 226))	('cancer', 'Disease', (165, 171))	('loss', 'NegReg', (305, 309))	('APOBEC3B', 'Gene', (28, 36))	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('germline deletion polymorphism', 'Var', (254, 284))	('cancer', 'Disease', (220, 226))	('APOBEC3B', 'Gene', (314, 322))
456581	29642934	2f, a strong correlation between APOBEC3A and APOBEC3B expression levels (Table 2) appeared to be independent from the APOBEC3B deletion polymorphism which removes the coding area of the APOBEC3B gene and creates a fusion transcript of APOBEC3A with the 3'-UTR of the APOBEC3 gene, although earlier reports suggest that this transcript increases APOBEC3A levels due to the increase in stability of the fusion transcript.	('APOBEC3A', 'Gene', '200315', (236, 244))	('APOBEC3A', 'Gene', '200315', (346, 354))	('creates', 'Reg', (205, 212))	('coding', 'MPA', (168, 174))	('stability', 'MPA', (385, 394))	('APOBEC3A', 'Gene', (236, 244))	('APOBEC3A', 'Gene', (33, 41))	('APOBEC3A', 'Gene', (346, 354))	('increase', 'PosReg', (373, 381))	('APOBEC3A', 'Gene', '200315', (33, 41))	('APOBEC3B', 'Gene', (187, 195))	('increases', 'PosReg', (336, 345))	('polymorphism', 'Var', (137, 149))	('removes', 'NegReg', (156, 163))	('deletion', 'Var', (128, 136))
456583	29642934	Mutagenesis in cancer cells generated due to the activity of APOBEC family members, and in particular of APOBEC3B, has been a subject of many recent studies.	('activity', 'MPA', (49, 57))	('cancer', 'Disease', (15, 21))	('Mutagenesis', 'Var', (0, 11))	('cancer', 'Disease', 'MESH:D009369', (15, 21))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('APOBEC3B', 'Gene', (105, 113))	('APOBEC family', 'Gene', (61, 74))
456588	29642934	While we found an increased number of APOBEC-like motifs in mature B cell lymphoma, we did not include the AID gene expression in our analysis because both the mutational sequence specificity of AID and the biological context in which AID mutations occur are different from those of APOBEC3B and APOBEC3A.	('AID', 'Gene', '57379', (107, 110))	('AID', 'Gene', (107, 110))	('APOBEC3A', 'Gene', (296, 304))	('lymphoma', 'Phenotype', 'HP:0002665', (74, 82))	('mutations', 'Var', (239, 248))	('APOBEC3A', 'Gene', '200315', (296, 304))	('AID', 'Gene', '57379', (235, 238))	('AID', 'Gene', (235, 238))	('B cell lymphoma', 'Phenotype', 'HP:0012191', (67, 82))	('B cell lymphoma', 'Disease', 'MESH:D016393', (67, 82))	('B cell lymphoma', 'Disease', (67, 82))	('AID', 'Gene', '57379', (195, 198))	('AID', 'Gene', (195, 198))
456591	29642934	AID deaminates cytosines within the characteristic WRC motif, or more broadly the WRCY/RGYW motif, with several other AID motif variants having been reported.	('deaminates', 'Var', (4, 14))	('cytosines', 'MPA', (15, 24))	('cytosine', 'Chemical', 'MESH:D003596', (15, 23))	('AID', 'Gene', '57379', (118, 121))	('AID', 'Gene', (118, 121))	('variants', 'Var', (128, 136))	('AID', 'Gene', '57379', (0, 3))	('AID', 'Gene', (0, 3))
456596	29642934	Expression levels of APOBEC3A, APOBEC3B, APOBEC3D, APOBEC3G, and APOBEC3H in tumor specimens from cancer patients were associated with varying clinical responses to chemotherapy and with overall patient survival, and possible suggested mechanisms of such associations, which may also involve other APOBEC genes, include immune targeting of increased mutation diversity due to higher levels of APOBEC mutagenesis, associated inflammation, PD-L1 expression on tumor-infiltrating mononuclear cells, and the degree of T lymphocyte infiltration.	('patient', 'Species', '9606', (105, 112))	('PD-L1', 'Gene', (438, 443))	('APOBEC3A', 'Gene', '200315', (21, 29))	('tumor', 'Disease', 'MESH:D009369', (458, 463))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('PD-L1', 'Gene', '29126', (438, 443))	('cancer', 'Disease', (98, 104))	('APOBEC3D', 'Gene', (41, 49))	('associated', 'Reg', (119, 129))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('APOBEC3G', 'Gene', (51, 59))	('inflammation', 'Disease', 'MESH:D007249', (424, 436))	('tumor', 'Phenotype', 'HP:0002664', (458, 463))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('APOBEC3H', 'Gene', '164668', (65, 73))	('APOBEC3H', 'Gene', (65, 73))	('patients', 'Species', '9606', (105, 113))	('mutation', 'Var', (350, 358))	('APOBEC3A', 'Gene', (21, 29))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('inflammation', 'Disease', (424, 436))	('higher', 'PosReg', (376, 382))	('APOBEC3G', 'Gene', '60489', (51, 59))	('APOBEC3D', 'Gene', '140564', (41, 49))	('patient', 'Species', '9606', (195, 202))	('tumor', 'Disease', (458, 463))	('APOBEC', 'Gene', (393, 399))	('tumor', 'Disease', (77, 82))
456613	29642934	When using measures of kataegis clusters, we observed correlations of the combined length of kataegis clusters of the least specific T(C>D)D motif with sensitivity to various agents in breast, pancreatic adenocarcinoma, and colon adenocarcinoma and rectum adenocarcinoma cancer cell lines.	('T(C>D)D motif', 'Var', (133, 146))	('carcinoma', 'Phenotype', 'HP:0030731', (261, 270))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (193, 218))	('cancer', 'Phenotype', 'HP:0002664', (271, 277))	('carcinoma', 'Phenotype', 'HP:0030731', (235, 244))	('correlations', 'Reg', (54, 66))	('least', 'NegReg', (118, 123))	('colon adenocarcinoma and rectum adenocarcinoma cancer', 'Disease', 'MESH:D012004', (224, 277))	('carcinoma', 'Phenotype', 'HP:0030731', (209, 218))	('sensitivity', 'MPA', (152, 163))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D010190', (193, 218))	('pancreatic adenocarcinoma', 'Disease', (193, 218))
456642	29107016	Cloning the TCR sequence in viral vectors and transducing T lymphocytes isolated from peripheral blood can generate large numbers of tumor-specific T cells without the cumbersome process of isolation and expansion of TILs.	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('TCR', 'Gene', (12, 15))	('Cloning', 'Var', (0, 7))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumor', 'Disease', (133, 138))	('TCR', 'Gene', '6962', (12, 15))
456644	29107016	High-throughput analysis of TILs, in combination with deep sequencing of the autologous tumor, has led to T-cell therapy that targets tumor neoantigens arising from mutations.	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('led to', 'Reg', (99, 105))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('mutations', 'Var', (165, 174))	('tumor', 'Disease', (88, 93))	('tumor', 'Disease', (134, 139))
456673	29107016	A subsequent dose-escalation Phase I/II study established feasibility and safety of administering HER2-targeted CAR T cells (104/m2-108/m2) to patients with recurrent or refractory HER2-positive tumors; however, the clinical benefit was limited as only 4 of 17 evaluable patients had stable disease.	('tumors', 'Disease', (195, 201))	('tumors', 'Disease', 'MESH:D009369', (195, 201))	('tumors', 'Phenotype', 'HP:0002664', (195, 201))	('stable disease', 'Disease', (284, 298))	('104/m2-108/m2', 'Var', (125, 138))	('stable disease', 'Disease', 'MESH:D060050', (284, 298))	('HER2', 'Gene', (98, 102))	('patients', 'Species', '9606', (143, 151))	('HER2', 'Gene', (181, 185))	('patients', 'Species', '9606', (271, 279))	('HER2', 'Gene', '2064', (98, 102))	('HER2', 'Gene', '2064', (181, 185))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))
456681	29107016	Overexpression of MSLN is correlated with tumor aggressiveness, KRAS mutation positivity, and decreased survival in lung ADC.	('positivity', 'Var', (78, 88))	('mutation', 'Reg', (69, 77))	('lung ADC', 'Disease', (116, 124))	('expression', 'Species', '29278', (4, 14))	('aggressiveness', 'Phenotype', 'HP:0000718', (48, 62))	('tumor aggressiveness', 'Disease', (42, 62))	('KRAS', 'Gene', (64, 68))	('decreased', 'NegReg', (94, 103))	('survival', 'CPA', (104, 112))	('MSLN', 'Var', (18, 22))	('KRAS', 'Gene', '3845', (64, 68))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (42, 62))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
456684	29107016	A case from a clinical trial (NCT01355965) conducted by the University of Pennsylvania that tested the safety and feasibility of repetitive intravenous or intratumoral administration of mRNA engineered T cells that transiently expressed an anti-MSLN CAR did not reveal evidence of off-tumor toxicities; however, epitope spreading was observed as a result of the antitumor efficacy.	('tumor', 'Disease', (366, 371))	('CAR', 'Gene', (250, 253))	('tumor toxicities', 'Disease', (285, 301))	('anti-MSLN', 'Var', (240, 249))	('CAR', 'Gene', '9970', (250, 253))	('tumor toxicities', 'Disease', 'MESH:D009369', (285, 301))	('tumor', 'Phenotype', 'HP:0002664', (285, 290))	('tumor', 'Disease', (285, 290))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('tumor', 'Disease', 'MESH:D009369', (366, 371))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('tumor', 'Phenotype', 'HP:0002664', (366, 371))	('tumor', 'Disease', (160, 165))	('tumor', 'Disease', 'MESH:D009369', (285, 290))
456685	29107016	An anaphylactic event caused by immunogenicity against the scFv of murine origin occurred after repeated infusions.	('scFv', 'Gene', '652070', (59, 63))	('murine', 'Species', '10090', (67, 73))	('scFv', 'Gene', (59, 63))	('immunogenicity', 'Var', (32, 46))	('anaphylactic event', 'Phenotype', 'HP:0100845', (3, 21))	('anaphylactic', 'Disease', (3, 15))
456687	29107016	Based on our preclinical data of enhanced antitumor efficacy following regional, rather than systemic, administration of CAR T cells, we are conducting a Phase I clinical trial to evaluate the safety of regionally administered MSLN-targeted CAR T cells in patients with primary or secondary pleural malignancies (NCT02414269).	('enhanced', 'PosReg', (33, 41))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('pleural malignancies', 'Disease', (291, 311))	('patients', 'Species', '9606', (256, 264))	('tumor', 'Disease', (46, 51))	('MSLN-targeted', 'Var', (227, 240))	('pleural malignancies', 'Disease', 'MESH:D016066', (291, 311))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
456704	29107016	Recent research has shown that FAP-targeting CAR T cells disrupt stromagenesis, diminish tumor angiogenesis, and may increase immune cell infiltration in highly desmoplastic tumors.	('tumor', 'Disease', (174, 179))	('stromagenesis', 'CPA', (65, 78))	('increase', 'PosReg', (117, 125))	('FAP-targeting', 'Var', (31, 44))	('diminish', 'NegReg', (80, 88))	('tumor', 'Disease', (89, 94))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('desmoplastic tumors', 'Disease', 'MESH:D058405', (161, 180))	('desmoplastic tumors', 'Disease', (161, 180))	('immune cell infiltration', 'CPA', (126, 150))	('desmoplastic tumors', 'Phenotype', 'HP:0100245', (161, 180))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('disrupt', 'NegReg', (57, 64))	('tumors', 'Phenotype', 'HP:0002664', (174, 180))
456720	29107016	Our published observations that intrapleural administration of anti-MSLN CAR T cells yields long-term antitumor activity, even at a 30-fold lower doses to achieve complete response in a preclinical model, provides a clinically significant opportunity to treat pleural malignancies; the current annual incidence in the U.S. alone is 150 000 patients.	('pleural', 'Disease', (260, 267))	('pleural malignancies', 'Disease', (260, 280))	('anti-MSLN', 'Var', (63, 72))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('patients', 'Species', '9606', (340, 348))	('pleural', 'Disease', 'MESH:D010995', (260, 267))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('pleural', 'Disease', 'MESH:D010995', (37, 44))	('pleural malignancies', 'Disease', 'MESH:D016066', (260, 280))	('tumor', 'Disease', (106, 111))	('pleural', 'Disease', (37, 44))
456826	25045670	Long Non-Coding RNA Deregulation in Tongue Squamous Cell Carcinoma Background.	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (43, 66))	('Carcinoma', 'Phenotype', 'HP:0030731', (57, 66))	('Tongue Squamous Cell Carcinoma', 'Disease', (36, 66))	('Deregulation', 'Var', (20, 32))	('Tongue Squamous Cell Carcinoma', 'Phenotype', 'HP:0030413', (36, 66))	('Tongue Squamous Cell Carcinoma', 'Disease', 'MESH:D002294', (36, 66))
456865	25045670	For example, in non-small cell lung cancer, it has been reported that cancer cells with high lncRNA AK126698 expression are associated with the cisplatin resistant phenotype.	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (16, 42))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (16, 42))	('non-small cell lung cancer', 'Disease', (16, 42))	('lung cancer', 'Phenotype', 'HP:0100526', (31, 42))	('associated', 'Reg', (124, 134))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (20, 42))	('cisplatin resistant', 'MPA', (144, 163))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('high lncRNA AK126698', 'Var', (88, 108))
456871	33500650	Gene Set Enrichment Analysis (GSEA) was performed to investigate the potential molecular mechanisms during LARGE1 alteration in NSCLC.	('LARGE1', 'Gene', '9215', (107, 113))	('NSCLC', 'Disease', (128, 133))	('LARGE1', 'Gene', (107, 113))	('NSCLC', 'Disease', 'MESH:D002289', (128, 133))	('alteration', 'Var', (114, 124))	('GSEA', 'Chemical', '-', (30, 34))
456897	33500650	We used the tool to initially analyze the association of LARGE1 expression with OS in lung cancer with Auto select best cutoff value and the JetSet best probe set (215543_s_at) for LARGE1.	('LARGE1', 'Gene', (57, 63))	('LARGE1', 'Gene', '9215', (181, 187))	('association', 'Interaction', (42, 53))	('lung cancer', 'Phenotype', 'HP:0100526', (86, 97))	('LARGE1', 'Gene', (181, 187))	('LARGE1', 'Gene', '9215', (57, 63))	('lung cancer', 'Disease', (86, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('lung cancer', 'Disease', 'MESH:D008175', (86, 97))	('215543_s_at', 'Var', (164, 175))
456908	33500650	For the cell cycle pathway, its score is the sum of the relative protein levels of CDK1, CYCLINB1, CYCLIND1, CYCLINDE1, CYCLINE2, P27PT157, P27PT198, and PCNA.	('CYCLINB1', 'Gene', '891', (89, 97))	('P27PT198', 'Var', (140, 148))	('CYCLIND1', 'Gene', (99, 107))	('PCNA', 'Gene', (154, 158))	('CYCLIND1', 'Gene', '595', (99, 107))	('CYCLINE2', 'Gene', '9134', (120, 128))	('CDK1', 'Gene', (83, 87))	('CYCLINE2', 'Gene', (120, 128))	('PCNA', 'Gene', '5111', (154, 158))	('CDK1', 'Gene', '983', (83, 87))	('P27PT157', 'Var', (130, 138))	('cell cycle pathway', 'Pathway', (8, 26))	('CYCLINB1', 'Gene', (89, 97))
456919	33500650	Effects of LARGE1 expression levels on OS in NSCLC was first examined using Kaplan-Meier plotter (KM plotter) and high LARGE1 expression was found to be associated with favorable OS in 1,925 NSCLC patients (Figure 2A).	('LARGE1', 'Gene', '9215', (11, 17))	('high', 'Var', (114, 118))	('patients', 'Species', '9606', (197, 205))	('NSCLC', 'Disease', (45, 50))	('LARGE1', 'Gene', (119, 125))	('NSCLC', 'Disease', 'MESH:D002289', (45, 50))	('NSCLC', 'Disease', (191, 196))	('LARGE1', 'Gene', (11, 17))	('NSCLC', 'Disease', 'MESH:D002289', (191, 196))	('LARGE1', 'Gene', '9215', (119, 125))
456930	33500650	Datasets GSE42127, GSE14814, GSE29013, and GSE68465 contained resected NSCLC cases treated with ACT or not and provided OS information (Table S1).	('GSE42127', 'Var', (9, 17))	('NSCLC', 'Disease', (71, 76))	('GSE14814', 'Var', (19, 27))	('GSE29013', 'Var', (29, 37))	('GSE68465', 'Var', (43, 51))	('NSCLC', 'Disease', 'MESH:D002289', (71, 76))
456931	33500650	Similar to the results from the TCGA cohort, in both GSE42127 and GSE14814 cohorts, LARGE1 expression was associated with OS in patients with ACT while not in patients without ACT, and ACT was associated with OS in patients with high LARGE1 expression while not in patients with low LARGE1 expression (Figures S1 and S2; Table 2).	('patients', 'Species', '9606', (215, 223))	('LARGE1', 'Gene', (283, 289))	('LARGE1', 'Gene', '9215', (234, 240))	('associated', 'Reg', (106, 116))	('ACT', 'Disease', (142, 145))	('LARGE1', 'Gene', '9215', (84, 90))	('LARGE1', 'Gene', '9215', (283, 289))	('patients', 'Species', '9606', (265, 273))	('GSE14814', 'Var', (66, 74))	('LARGE1', 'Gene', (234, 240))	('patients', 'Species', '9606', (128, 136))	('patients', 'Species', '9606', (159, 167))	('LARGE1', 'Gene', (84, 90))
456952	33500650	In our study, we performed GSEA and found cell cycle regulation during LARGE1 alteration might be involved in carcinogenesis of lung adenocarcinoma, which might also be associated with ACT sensitivity.	('LARGE1', 'Gene', (71, 77))	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('involved', 'Reg', (98, 106))	('carcinogenesis of lung adenocarcinoma', 'Disease', 'MESH:D063646', (110, 147))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (128, 147))	('alteration', 'Var', (78, 88))	('LARGE1', 'Gene', '9215', (71, 77))	('associated', 'Reg', (169, 179))	('cell', 'MPA', (42, 46))	('carcinogenesis of lung adenocarcinoma', 'Disease', (110, 147))	('GSEA', 'Chemical', '-', (27, 31))
456958	33500650	External cohorts confirmed these results, indicating that high LARGE expression could be used to identify the NSCLC patients who benefited from adjuvant chemotherapy.	('NSCLC', 'Disease', 'MESH:D002289', (110, 115))	('NSCLC', 'Disease', (110, 115))	('patients', 'Species', '9606', (116, 124))	('high', 'Var', (58, 62))
456985	31247015	The frequency of clinicopathological characteristics at diagnosis, including calendar period, level of education, age, ECOG performance status, smoking history, Elixhauser comorbidities, TNM stage, and EGFR mutation status (advanced stage adenocarcinoma, years 2010-2016) were calculated for men and women.	('EGFR', 'Gene', (202, 206))	('men', 'Species', '9606', (292, 295))	('adenocarcinoma', 'Disease', (239, 253))	('men', 'Species', '9606', (302, 305))	('adenocarcinoma', 'Disease', 'MESH:D000230', (239, 253))	('mutation', 'Var', (207, 215))	('EGFR', 'Gene', '1956', (202, 206))	('women', 'Species', '9606', (300, 305))	('carcinoma', 'Phenotype', 'HP:0030731', (244, 253))
457023	31247015	Despite the inclusion of a wide range of relevant covariates, we did not have access to individual-level data on every established prognostic factor, and data on EGFR and ALK mutations was limited to year 2010-2016 and 2016, respectively.	('EGFR', 'Gene', '1956', (162, 166))	('EGFR', 'Gene', (162, 166))	('ALK', 'Gene', (171, 174))	('mutations', 'Var', (175, 184))	('ALK', 'Gene', '238', (171, 174))
457024	31247015	All register-based studies may suffer from misclassification, under-reporting and under-diagnosis, it is however unlikely that these biases would differ substantially between men and women.	('men', 'Species', '9606', (185, 188))	('women', 'Species', '9606', (183, 188))	('under-diagnosis', 'Var', (82, 97))	('misclassification', 'MPA', (43, 60))	('men', 'Species', '9606', (175, 178))
457096	31002369	Notably, the patients with EAC who expressed a high level of these cell cycle-associated genes exhibited poorer prognosis with regard to disease/progression-free survival compared with patients without altered expression of these genes (median months disease-free: 15.67 vs. 24.06; Fig.	('high', 'Var', (47, 51))	('patients', 'Species', '9606', (13, 21))	('EAC', 'Phenotype', 'HP:0011459', (27, 30))	('patients', 'Species', '9606', (185, 193))	('EAC', 'Disease', (27, 30))
457106	31002369	Immunohistochemical scoring for the cancer tissues from these patients indicated that high PARP4 expression was associated with poorer survival (Fig.	('expression', 'MPA', (97, 107))	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('survival', 'MPA', (135, 143))	('PARP4', 'Gene', (91, 96))	('cancer', 'Disease', (36, 42))	('poorer', 'NegReg', (128, 134))	('PARP4', 'Gene', '143', (91, 96))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('patients', 'Species', '9606', (62, 70))	('high', 'Var', (86, 90))
457120	31002369	This finding holds considerable promise, as in the clinic numerous compounds are already utilized that can target components of cell cycle signaling, including cyclin-dependent kinase (CDK)4/CDK6 (palbociclib, ribociclib and abemaciclib), aurora kinases (AT9283 and MLN8237), Wee1 kinase (MK-1775), KSP (ispinesib) and tubulin (taxanes and vinca alkaloids).	('vinca alkaloids', 'Chemical', 'MESH:D014748', (340, 355))	('MLN8237', 'Var', (266, 273))	('AT9283', 'Var', (255, 261))	('tubulin', 'Protein', (319, 326))	('CDK)4', 'Gene', '1019', (185, 190))	('Wee1', 'Gene', (276, 280))	('Wee1', 'Gene', '7465', (276, 280))	('KSP', 'Protein', (299, 302))	('taxanes', 'Chemical', 'MESH:D043823', (328, 335))	('CDK6', 'Gene', '1021', (191, 195))	('CDK6', 'Gene', (191, 195))
457205	29856819	ICG has been studied as an activatable fluorescent dye and it has been shown that quenched ICG regains fluorescence ability after binding to target antigens, internalization of target cells and then metabolization in lysosomes.	('internalization', 'MPA', (158, 173))	('ICG', 'Chemical', 'MESH:D007208', (0, 3))	('fluorescence ability', 'MPA', (103, 123))	('ICG', 'Chemical', 'MESH:D007208', (91, 94))	('regains', 'PosReg', (95, 102))	('quenched', 'Var', (82, 90))	('binding', 'Interaction', (130, 137))	('ICG', 'Gene', (91, 94))
457211	29856819	As mentioned in a previous murine study, activatable J591-ICG was shown to be a promising molecular imaging probe for detecting both primary and metastatic prostate cancer if positive for the prostate-specific membrane antigen.	('prostate-specific membrane antigen', 'Gene', '2346', (192, 226))	('prostate cancer', 'Disease', (156, 171))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('primary', 'Disease', (133, 140))	('prostate-specific membrane antigen', 'Gene', (192, 226))	('prostate cancer', 'Disease', 'MESH:D011471', (156, 171))	('J591-ICG', 'Var', (53, 61))	('prostate cancer', 'Phenotype', 'HP:0012125', (156, 171))	('murine', 'Species', '10090', (27, 33))	('ICG', 'Chemical', 'MESH:D007208', (58, 61))
457215	29856819	Although the safety of Pan has been demonstrated in non-small cell lung cancer, the optimal dose still requires clarification because research has shown that conjugating ICG to Pan increased toxicity without a discernible impact on efficacy.	('small cell lung cancer', 'Phenotype', 'HP:0030357', (56, 78))	('increased', 'PosReg', (181, 190))	('lung cancer', 'Phenotype', 'HP:0100526', (67, 78))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (52, 78))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('ICG', 'Chemical', 'MESH:D007208', (170, 173))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (52, 78))	('conjugating', 'Var', (158, 169))	('toxicity', 'Disease', 'MESH:D064420', (191, 199))	('toxicity', 'Disease', (191, 199))	('non-small cell lung cancer', 'Disease', (52, 78))
457258	27775076	As described in Supplementary Methods, NSCLC cases were subtyped according to each of the individual data platforms for DNA methylation, DNA copy alteration, mRNA expression, miRNA expression, and protein expression.	('mRNA expression', 'MPA', (158, 173))	('copy alteration', 'Var', (141, 156))	('miRNA expression', 'MPA', (175, 191))	('NSCLC', 'Disease', (39, 44))	('protein expression', 'MPA', (197, 215))	('NSCLC', 'Disease', 'MESH:D002289', (39, 44))
457268	27775076	In this present study, the 1023 TCGA NSCLC cases were subtyped according to each of the data platforms for DNA methylation, DNA copy alteration, mRNA expression, miRNA expression, and protein expression, with the various subtype calls for each sample then being consolidated to define multiplatform-based molecular subtypes.	('mRNA expression', 'MPA', (145, 160))	('NSCLC', 'Disease', (37, 42))	('copy alteration', 'Var', (128, 143))	('NSCLC', 'Disease', 'MESH:D002289', (37, 42))	('miRNA expression', 'MPA', (162, 178))
457273	27775076	The nine genomic subtypes of TCGA lung cancers included: three different subtypes of predominantly lung SQCC cases:designated here as "SQ.1" (n=259), "SQ.2a" (n=257), and "SQ.2b" (n=123):and six different subtypes of predominantly lung AD cases:"AD.1" (n=128), "AD.2" (n=128), "AD.3" (n=106), "AD.4" (n=121), "AD.5a" (n=43) and "AD.5b" (n=74).	('lung cancers', 'Disease', (34, 46))	('cancers', 'Phenotype', 'HP:0002664', (39, 46))	('lung AD', 'Disease', (231, 238))	('lung cancer', 'Phenotype', 'HP:0100526', (34, 45))	('AD.5b', 'Var', (329, 334))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('lung cancers', 'Disease', 'MESH:D008175', (34, 46))	('lung cancers', 'Phenotype', 'HP:0100526', (34, 46))	('AD.5a', 'Var', (310, 315))	('AD.2" (n=128), "AD.3" (n=106', 'Var', (262, 290))
457277	27775076	Copy gain of SOX2 associated with lung SQCC-associated subtypes, but events were more frequent in SQ.2a/SQ.2b tumors compared to SQ.1 tumors, with SOX2 expression also higher in SQ.2a/SQ.2b.	('tumors', 'Disease', (134, 140))	('tumors', 'Disease', 'MESH:D009369', (134, 140))	('gain', 'Disease', (5, 9))	('SOX2', 'Gene', (13, 17))	('gain', 'Disease', 'MESH:D015430', (5, 9))	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('lung SQCC-associated', 'Disease', (34, 54))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumors', 'Disease', (110, 116))	('SQ.2a/SQ.2b', 'Var', (98, 109))	('tumors', 'Disease', 'MESH:D009369', (110, 116))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('SOX2', 'Gene', '6657', (13, 17))	('SOX2', 'Gene', '6657', (147, 151))	('expression', 'MPA', (152, 162))	('SOX2', 'Gene', (147, 151))
457278	27775076	Within AD-associated subtypes, KRAS mutations were most frequent in AD.2 and AD.5b, and STK11 mutations were most frequent in AD.1 and AD.5b (Figures 1d and S2a).	('AD.2', 'Var', (68, 72))	('KRAS', 'Gene', (31, 35))	('AD.5b', 'Var', (135, 140))	('mutations', 'Var', (94, 103))	('STK11', 'Gene', '6794', (88, 93))	('AD.5b', 'Var', (77, 82))	('mutations', 'Var', (36, 45))	('KRAS', 'Gene', '3845', (31, 35))	('STK11', 'Gene', (88, 93))	('frequent', 'Reg', (114, 122))	('frequent', 'Reg', (56, 64))
457279	27775076	TP53 mutations coupled with lower expression of associated targets were most frequently observed in SQ.2a, SQ.2b, AD.1, AD.2, and AD.3 subtypes (Figures 1d, S2a, and S2b).	('SQ.2a', 'Disease', (100, 105))	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('expression', 'MPA', (34, 44))	('observed', 'Reg', (88, 96))	('mutations', 'Var', (5, 14))
457280	27775076	Compared to other lung AD subtypes, AD.5a and AD.5b had the highest proportion of patients who were never-smokers or long-term non-smokers (Figures 1d and S2c), as well as the highest proportion of patients with low manifestation of a mutation signature of C>A transversions related to smoking (Figure S2c).	('lung AD subtype', 'Disease', 'MESH:D000544', (18, 33))	('AD.5b', 'Var', (46, 51))	('patients', 'Species', '9606', (198, 206))	('patients', 'Species', '9606', (82, 90))	('lung AD subtype', 'Disease', (18, 33))	('AD.5a', 'Var', (36, 41))
457297	27775076	The SQCC-associated subtypes had more PTEN gene copy loss and decreased protein levels, while the AD-associated subtypes tended to have more STK11 somatic mutation events, copy loss, and decreased STK11/LKB1 protein levels.	('PTEN', 'Gene', '5728', (38, 42))	('copy loss', 'Var', (172, 181))	('LKB1', 'Gene', (203, 207))	('decreased', 'NegReg', (62, 71))	('STK11', 'Gene', '6794', (197, 202))	('SQCC-associated', 'Disease', (4, 19))	('LKB1', 'Gene', '6794', (203, 207))	('STK11', 'Gene', '6794', (141, 146))	('STK11', 'Gene', (141, 146))	('decreased', 'NegReg', (187, 196))	('STK11', 'Gene', (197, 202))	('PTEN', 'Gene', (38, 42))	('protein levels', 'MPA', (72, 86))
457298	27775076	Both phospholevels of mTOR and a phosphoprotein signature of the MAP kinase pathway were highest in the AD.4 and AD.5a/AD.5b subtypes, as compared to all other subtypes (Figure 3a).	('highest', 'Reg', (89, 96))	('phospholevels', 'MPA', (5, 18))	('AD.5a/AD.5b', 'Var', (113, 124))	('AD.4', 'Var', (104, 108))	('MAP kinase pathway', 'Pathway', (65, 83))	('mTOR', 'Gene', '2475', (22, 26))	('mTOR', 'Gene', (22, 26))	('phosphoprotein signature', 'MPA', (33, 57))
457299	27775076	Differences between AD.4/AD.5a/AD.5b subtypes versus AD.1/AD.2 subtypes were also apparent when examining individual key proteins in the context of PI3K/AKT, mTOR, and MAP kinase pathways (Figure 3b).	('AKT', 'Gene', '207', (153, 156))	('MAP kinase pathways', 'Pathway', (168, 187))	('AD.4/AD.5a/AD.5b', 'Var', (20, 36))	('AKT', 'Gene', (153, 156))	('mTOR', 'Gene', (158, 162))	('mTOR', 'Gene', '2475', (158, 162))
457300	27775076	While AD.4/AD.5a/AD.5b cases had relatively higher PTEN levels corresponding with low phospho-AKT, low STK11/LKB1 could presumably account for the higher levels of phospho-mTOR, phospho-S6K, and phospho-S6 observed in AD.4/AD.5a/AD.5b versus SQCC.	('AKT', 'Gene', '207', (94, 97))	('mTOR', 'Gene', (172, 176))	('low', 'NegReg', (99, 102))	('higher', 'PosReg', (44, 50))	('AD.4/AD.5a/AD.5b', 'Var', (6, 22))	('AKT', 'Gene', (94, 97))	('low', 'NegReg', (82, 85))	('STK11', 'Gene', (103, 108))	('LKB1', 'Gene', (109, 113))	('LKB1', 'Gene', '6794', (109, 113))	('STK11', 'Gene', '6794', (103, 108))	('PTEN', 'Gene', (51, 55))	('AD.4/AD.5a/AD.5b', 'Var', (218, 234))	('mTOR', 'Gene', '2475', (172, 176))	('PTEN', 'Gene', '5728', (51, 55))
457304	27775076	AD.2, AD.3, and AD.4 NSCLC subtypes all had relatively higher expression of several genes representing potential targets for immunotherapy (Figures 4a, 4b, and 4c), including PDCD1 (PD1), CD247 (CD3), CD274 (PDL1), PDCD1LG2 (PDL2), CTLA4 (CD152), TNFRSF9 (CD137), TNFRSF4 (CD134), and TLR9.	('TNFRSF4', 'Gene', '7293', (264, 271))	('PDCD1', 'Gene', (215, 220))	('CD152', 'Gene', (239, 244))	('CD3', 'Gene', (195, 198))	('AD.3', 'Var', (6, 10))	('CD152', 'Gene', '1493', (239, 244))	('PDL2', 'Gene', '80380', (225, 229))	('higher', 'PosReg', (55, 61))	('NSCLC', 'Disease', 'MESH:D002289', (21, 26))	('TNFRSF4', 'Gene', (264, 271))	('PDCD1LG2', 'Gene', '80380', (215, 223))	('TLR9', 'Gene', (285, 289))	('PD1', 'Gene', '5133', (182, 185))	('TNFRSF9', 'Gene', (247, 254))	('CD274', 'Gene', '29126', (201, 206))	('AD.4', 'Var', (16, 20))	('PDL2', 'Gene', (225, 229))	('TNFRSF9', 'Gene', '3604', (247, 254))	('NSCLC', 'Disease', (21, 26))	('TLR9', 'Gene', '54106', (285, 289))	('expression', 'MPA', (62, 72))	('CD137', 'Gene', (256, 261))	('CD137', 'Gene', '3604', (256, 261))	('CTLA4', 'Gene', '1493', (232, 237))	('PDCD1LG2', 'Gene', (215, 223))	('CD3', 'Gene', '397455', (195, 198))	('PDCD1', 'Gene', (175, 180))	('CD274', 'Gene', (201, 206))	('CD134', 'Gene', '7293', (273, 278))	('PDCD1', 'Gene', '5133', (175, 180))	('CD247', 'Gene', '919', (188, 193))	('CD247', 'Gene', (188, 193))	('PD1', 'Gene', (182, 185))	('CTLA4', 'Gene', (232, 237))	('PDCD1', 'Gene', '5133', (215, 220))	('CD134', 'Gene', (273, 278))
457310	27775076	In a compendium of expression datasets representing 1403 lung AD cases, profiles were also classified according to TCGA-based lung AD subtype (Figure S7) with significant differences in patient survival being observed (Figure 5c, p<1E-10); in particular, lung AD subtypes associated with poorer AD differentiation by gene signature (AD.1/AD.2/AD.3, Figure 1d) all showed worse prognosis.	('poorer', 'NegReg', (288, 294))	('lung AD subtype', 'Disease', (255, 270))	('lung AD subtype', 'Disease', (126, 141))	('AD differentiation', 'CPA', (295, 313))	('patient', 'Species', '9606', (186, 193))	('AD.1/AD.2/AD.3', 'Var', (333, 347))	('lung AD subtype', 'Disease', 'MESH:D000544', (126, 141))	('lung AD subtype', 'Disease', 'MESH:D000544', (255, 270))
457312	27775076	Cancer-derived PDL1, lymphocyte-derived PD1, and markers of T cells including CD3 and CD8 were all elevated in the AD.2/AD.3/AD.4 subtypes relative to the AD.1/AD.5a/AD.5b subtypes (Figure 5d and Figure S8 and Figure S9), consistent with observations in TCGA cohort (Figure 4a).	('CD8', 'Gene', (86, 89))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('PD1', 'Gene', '5133', (40, 43))	('elevated', 'PosReg', (99, 107))	('CD3', 'Gene', '397455', (78, 81))	('CD8', 'Gene', '925', (86, 89))	('PD1', 'Gene', (40, 43))	('AD.2/AD.3/AD.4', 'Var', (115, 129))	('CD3', 'Gene', (78, 81))
457314	27775076	Three of the six AD-associated subtypes (AD.4, AD.5a, AD.5b) were further characterized by patterns of higher differentiation, better patient survival, and increased p38 and mTOR signaling.	('patient survival', 'CPA', (134, 150))	('patient', 'Species', '9606', (134, 141))	('AD-associated', 'Disease', (17, 30))	('better', 'PosReg', (127, 133))	('p38', 'Gene', (166, 169))	('increased', 'PosReg', (156, 165))	('AD.5b', 'Var', (54, 59))	('higher', 'PosReg', (103, 109))	('mTOR', 'Gene', (174, 178))	('mTOR', 'Gene', '2475', (174, 178))	('p38', 'Gene', '1432', (166, 169))	('AD.5a', 'Var', (47, 52))
457316	27775076	Expression of numerous cancer-testis antigen genes, also relevant to immune response pathway, was observed in five of the nine subtypes (SQ.1, SQ.2a, SQ.2b, AD.1, AD.3).	('numerous cancer-testis', 'Disease', 'MESH:D013736', (14, 36))	('numerous cancer-testis', 'Disease', (14, 36))	('Expression', 'MPA', (0, 10))	('SQ.1', 'Var', (137, 141))	('SQ.2b', 'Var', (150, 155))	('observed', 'Reg', (98, 106))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('AD.1', 'Var', (157, 161))
457411	27524911	Li et al reported that the 1-year and 3-year OS rates were 81% and 36.5%, respectively, for nonsurgical ESCC patients treated with chemoradiation therapy, including docetaxel and cisplatin, and a radiation dose of 60-64 Gy, whereas the 1-year and 3-year OS rates were 84.4% and 45.6%, respectively, for advanced esophageal cancer treated with 5-FU, cisplatin, and a radiation dose of 60 Gy.	('nonsurgical', 'Disease', (92, 103))	('patients', 'Species', '9606', (109, 117))	('cisplatin', 'Chemical', 'MESH:D002945', (179, 188))	('cisplatin', 'Var', (349, 358))	('esophageal cancer', 'Disease', (312, 329))	('cancer', 'Phenotype', 'HP:0002664', (323, 329))	('docetaxel', 'Chemical', 'MESH:D000077143', (165, 174))	('cisplatin', 'Chemical', 'MESH:D002945', (349, 358))	('esophageal cancer', 'Disease', 'MESH:D004938', (312, 329))	('5-FU', 'Chemical', 'MESH:D005472', (343, 347))
457420	27524911	Patients with a high ERCC1 expression had a poor prognosis than those with low expression.	('ERCC1', 'Gene', (21, 26))	('high', 'Var', (16, 20))	('ERCC1', 'Gene', '2067', (21, 26))	('expression', 'MPA', (27, 37))	('Patients', 'Species', '9606', (0, 8))
457424	27524911	In another study including 175 cases of esophageal carcinoma, ERCC1-negative patients benefited from cisplatin before surgery, but high ERCC1 expression was correlated with better long-term prognosis.	('ERCC1', 'Gene', (136, 141))	('cisplatin', 'MPA', (101, 110))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (40, 60))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (40, 60))	('cisplatin', 'Chemical', 'MESH:D002945', (101, 110))	('ERCC1', 'Gene', (62, 67))	('ERCC1', 'Gene', '2067', (62, 67))	('patients', 'Species', '9606', (77, 85))	('esophageal carcinoma', 'Disease', (40, 60))	('expression', 'MPA', (142, 152))	('carcinoma', 'Phenotype', 'HP:0030731', (51, 60))	('high', 'Var', (131, 135))	('ERCC1', 'Gene', '2067', (136, 141))
457425	27524911	This study showed a poor prognosis in high ERCC1 expression patients, two cases out of the three patients were cT4N1M0 IIIc stage, and another one case was cT3N1M0 IIIa stage.	('patients', 'Species', '9606', (60, 68))	('high', 'Var', (38, 42))	('ERCC1', 'Gene', '2067', (43, 48))	('ERCC1', 'Gene', (43, 48))	('patients', 'Species', '9606', (97, 105))
457430	27524911	First, the genome and tumor heterogeneity will affect an individual's response to drugs.	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('heterogeneity', 'Var', (28, 41))	('affect', 'Reg', (47, 53))	('tumor', 'Disease', (22, 27))	('response to drugs', 'MPA', (70, 87))
457506	24636231	The most significant associations were found with the mass-based concentrations of PM2.5 and PM10.	('PM2.5', 'Var', (83, 88))	('PM2', 'Chemical', '-', (83, 86))	('PM10', 'Var', (93, 97))
457509	24636231	The concentrations of PM2.5 and PM10 were affected by a wider range of sources, including motorized traffic.	('affected', 'Reg', (42, 50))	('PM10', 'Var', (32, 36))	('PM2', 'Chemical', '-', (22, 25))	('PM2.5', 'Var', (22, 27))
457513	24636231	However, we did study the independent effects of fine (PM2.5) and coarse (PM10 - PM2.5) particles.	('PM2.5', 'Var', (55, 60))	('PM2', 'Chemical', '-', (81, 84))	('PM2', 'Chemical', '-', (55, 58))	('PM10 - PM2.5', 'Var', (74, 86))
457514	24636231	In single-pollutant models, the RR for PM2.5 was higher than that for coarse particles (1.18 vs. 1.09 per 5 microg/m3).	('PM2.5', 'Var', (39, 44))	('PM2', 'Chemical', '-', (39, 42))	('higher', 'PosReg', (49, 55))
457517	24636231	In the ACS study, lung cancer was associated with PM2.5, but not with coarse particles.	('PM2', 'Chemical', '-', (50, 53))	('lung cancer', 'Disease', 'MESH:D008175', (18, 29))	('associated', 'Interaction', (34, 44))	('lung cancer', 'Phenotype', 'HP:0100526', (18, 29))	('lung cancer', 'Disease', (18, 29))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('PM2.5', 'Var', (50, 55))
457518	24636231	Although the number of studies that evaluated the effects of long-term exposure to coarse particles on lung cancer is still limited, and we should not draw strong conclusions, the lack of clear associations between coarse particles and lung cancer is consistent with the lack of an association with natural cause and cardiovascular mortality.	('lung cancer', 'Phenotype', 'HP:0100526', (236, 247))	('lung cancer', 'Disease', 'MESH:D008175', (103, 114))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('lung cancer', 'Disease', 'MESH:D008175', (236, 247))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('lung cancer', 'Disease', (103, 114))	('associations', 'Interaction', (194, 206))	('lung cancer', 'Phenotype', 'HP:0100526', (103, 114))	('coarse', 'Var', (215, 221))	('lung cancer', 'Disease', (236, 247))
457553	32158692	As early as 1954, squamous cell carcinoma (SCC) of the cheek was induced in hamsters by 9,10-dimethyl-1,2-benzanthracene (DMBA), and hamster SCC exhibits many similarities to human OSCC, including the morphology, histology, infiltration and metastasis, expression of biomarkers, and genetic and epigenetic alterations.	('OSCC', 'Disease', 'MESH:D002294', (181, 185))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (18, 41))	('DMBA', 'Chemical', 'MESH:D015127', (122, 126))	('SCC', 'Disease', 'MESH:D002294', (43, 46))	('hamster', 'Species', '10034', (133, 140))	('9,10-dimethyl-1,2-benzanthracene', 'Chemical', 'MESH:D015127', (88, 120))	('induced', 'Reg', (65, 72))	('human', 'Species', '9606', (175, 180))	('SCC', 'Phenotype', 'HP:0002860', (182, 185))	('SCC', 'Disease', (43, 46))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (18, 41))	('carcinoma', 'Phenotype', 'HP:0030731', (32, 41))	('SCC', 'Phenotype', 'HP:0002860', (141, 144))	('OSCC', 'Disease', (181, 185))	('SCC', 'Disease', 'MESH:D002294', (182, 185))	('SCC', 'Disease', 'MESH:D002294', (141, 144))	('SCC', 'Disease', (182, 185))	('hamster', 'Species', '10034', (76, 83))	('epigenetic alterations', 'Var', (295, 317))	('squamous cell carcinoma', 'Disease', (18, 41))	('SCC', 'Disease', (141, 144))	('SCC', 'Phenotype', 'HP:0002860', (43, 46))
457574	32158692	Researches have proved that 4NQO mimics tobacco and plays a carcinogenic role by causing intracellular oxidative stress, DNA adduction, mutagenesis, and tumor induction (Figure 2).	('tobacco', 'Species', '4097', (40, 47))	('carcinogenic', 'Disease', (60, 72))	('intracellular oxidative stress', 'MPA', (89, 119))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('4NQO', 'Var', (28, 32))	('DNA adduction', 'MPA', (121, 134))	('4NQO', 'Chemical', 'MESH:D015112', (28, 32))	('tumor', 'Disease', (153, 158))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('causing', 'PosReg', (81, 88))	('oxidative stress', 'Phenotype', 'HP:0025464', (103, 119))	('mutagenesis', 'CPA', (136, 147))	('carcinogenic', 'Disease', 'MESH:D063646', (60, 72))
457576	32158692	Although 4NQO is not a direct carcinogen, it is an electrophilic species produced by metabolism in the body and undergoes an irreversible reaction with the nucleophilic part of DNA, which ultimately introduce mutations.	('introduce', 'Reg', (199, 208))	('4NQO', 'Chemical', 'MESH:D015112', (9, 13))	('mutations', 'Var', (209, 218))
457581	32158692	The imbalance between the two pathways is the leading cause of tumor induction by 4NQO.	('tumor', 'Disease', (63, 68))	('cause', 'Reg', (54, 59))	('4NQO', 'Chemical', 'MESH:D015112', (82, 86))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('imbalance', 'Reg', (4, 13))	('4NQO', 'Var', (82, 86))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('imbalance', 'Phenotype', 'HP:0002172', (4, 13))
457584	32158692	Mutations caused by these DNA adducts result in guanine to pyrimidine substitution.	('guanine to pyrimidine substitution', 'MPA', (48, 82))	('guanine', 'Chemical', 'MESH:D006147', (48, 55))	('pyrimidine', 'Chemical', 'MESH:C030986', (59, 69))	('Mutations', 'Var', (0, 9))	('result in', 'Reg', (38, 47))
457601	32158692	4NQO can induce carcinogenesis in many parts of the oral cavity, such as the dorsal tongue, ventral tongue, and palate.	('carcinogenesis', 'Disease', (16, 30))	('palate', 'Disease', (112, 118))	('induce', 'Reg', (9, 15))	('4NQO', 'Chemical', 'MESH:D015112', (0, 4))	('palate', 'Disease', 'MESH:D002972', (112, 118))	('carcinogenesis', 'Disease', 'MESH:D063646', (16, 30))	('4NQO', 'Var', (0, 4))
457609	32158692	After 16 weeks of treatment with 100 mug/mL 4NQO, tongue lesions were observed in 100% of C57BL/6 mice, but visible gross lesions were not seen until the following 4-12 weeks.	('4NQO', 'Chemical', 'MESH:D015112', (44, 48))	('tongue lesions', 'Disease', 'MESH:D014060', (50, 64))	('tongue lesions', 'Disease', (50, 64))	('4NQO', 'Var', (44, 48))	('men', 'Species', '9606', (23, 26))	('mice', 'Species', '10090', (98, 102))
457624	32158692	Because 4NQO simulates tobacco-related gene mutation and can induce primary OSCC, this model has been used to explore the pathogenesis of OSCC.	('4NQO', 'Chemical', 'MESH:D015112', (8, 12))	('OSCC', 'Disease', (76, 80))	('tobacco', 'Species', '4097', (23, 30))	('OSCC', 'Disease', 'MESH:D002294', (138, 142))	('SCC', 'Phenotype', 'HP:0002860', (77, 80))	('4NQO', 'Var', (8, 12))	('OSCC', 'Disease', 'MESH:D002294', (76, 80))	('SCC', 'Phenotype', 'HP:0002860', (139, 142))	('induce', 'Reg', (61, 67))	('OSCC', 'Disease', (138, 142))
457626	32158692	The murine lesions induced by 4NQO constitute a dynamic and continuous process and can be used to study the early detection and prevention of precancerous OSCC lesions.	('cancer', 'Disease', (145, 151))	('OSCC', 'Disease', (155, 159))	('4NQO', 'Chemical', 'MESH:D015112', (30, 34))	('OSCC', 'Disease', 'MESH:D002294', (155, 159))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('SCC', 'Phenotype', 'HP:0002860', (156, 159))	('murine', 'Species', '10090', (4, 10))	('4NQO', 'Var', (30, 34))	('cancer', 'Disease', 'MESH:D009369', (145, 151))
457632	32158692	compared the effect of coal tar and B[a]P on tumor induction and discovered that the mice fed with 100 ppm B[a]P developed tongue lesions (papillomas and carcinomas) with an incidence of 23/48.	('mice', 'Species', '10090', (85, 89))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('B[a]P', 'Var', (107, 112))	('tumor', 'Disease', (45, 50))	('tongue lesions', 'Disease', 'MESH:D014060', (123, 137))	('tongue lesions', 'Disease', (123, 137))	('papillomas and carcinomas', 'Disease', 'MESH:D010212', (139, 164))	('papillomas', 'Phenotype', 'HP:0012740', (139, 149))	('carcinoma', 'Phenotype', 'HP:0030731', (154, 163))	('carcinomas', 'Phenotype', 'HP:0030731', (154, 164))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
457634	32158692	DB[a,l]P is a potent carcinogen produced in cigarette smoke and has been used to induce carcinogenesis of the lung, skin, mammary gland, and oral cavity in mice and rats.	('induce', 'PosReg', (81, 87))	('rats', 'Species', '10116', (165, 169))	('carcinogenesis of the lung', 'Disease', (88, 114))	('DB[a', 'Var', (0, 4))	('DB[a,l]P', 'Chemical', '-', (0, 8))	('mice', 'Species', '10090', (156, 160))	('carcinogenesis of the lung', 'Disease', 'MESH:D063646', (88, 114))
457637	32158692	compared the carcinogenesis and mutations resulting from the administration of DB[a,l]P, NNN, and both NNN and DB[a,l]P. DB[a,l]P (0.16 mumol) was topically applied on the tongue of lacI mice three times per week, while NNN (8.46 mumol) was applied two times per week.	('DB[a,l]P', 'Chemical', '-', (111, 119))	('DB[a,l]P', 'Chemical', '-', (121, 129))	('NNN', 'Chemical', 'MESH:C008655', (220, 223))	('NNN', 'Chemical', 'MESH:C008655', (103, 106))	('carcinogenesis', 'Disease', 'MESH:D063646', (13, 27))	('lacI', 'Gene', '21788', (182, 186))	('carcinogenesis', 'Disease', (13, 27))	('mutations', 'Var', (32, 41))	('mice', 'Species', '10090', (187, 191))	('lacI', 'Gene', (182, 186))	('NNN', 'Chemical', 'MESH:C008655', (89, 92))	('DB[a,l]P', 'Chemical', '-', (79, 87))	('DB[a', 'Var', (79, 83))	('DB[a', 'Var', (111, 115))
457642	32158692	They found that 100% of the mice induced by both 4NQO (200 mug/mL) and arecoline (500 mug/mL) developed tongue tumors, while 57 and 0% of the mice exposed to only 4NQO or arecoline developed tongue tumors, respectively.	('arecoline', 'Chemical', 'MESH:D001115', (71, 80))	('tongue tumors', 'Disease', (191, 204))	('tongue tumors', 'Phenotype', 'HP:0100648', (191, 204))	('arecoline', 'Chemical', 'MESH:D001115', (171, 180))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('mice', 'Species', '10090', (28, 32))	('tongue tumors', 'Disease', 'MESH:D014062', (104, 117))	('500 mug/mL', 'Var', (82, 92))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('mice', 'Species', '10090', (142, 146))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('4NQO', 'Chemical', 'MESH:D015112', (49, 53))	('tongue tumors', 'Disease', 'MESH:D014062', (191, 204))	('tongue tumors', 'Disease', (104, 117))	('tumors', 'Phenotype', 'HP:0002664', (198, 204))	('4NQO', 'Chemical', 'MESH:D015112', (163, 167))	('tongue tumors', 'Phenotype', 'HP:0100648', (104, 117))
457680	32158692	Different gene mutations cause varying degrees of immunodeficiency in the four kinds of mice.	('immunodeficiency', 'Phenotype', 'HP:0002721', (50, 66))	('mutations', 'Var', (15, 24))	('immunodeficiency', 'Disease', 'MESH:D007153', (50, 66))	('immunodeficiency', 'Disease', (50, 66))	('mice', 'Species', '10090', (88, 92))
457708	32158692	To evaluate the antineoplastic effect of near-infrared photoimmunotherapy (NIR-PIT) produced by conjugating IR700DX (a photo-absorber) with anti-CD44 monoclonal antibodies, Nagaya et al.	('IR700DX', 'Var', (108, 115))	('antineoplastic', 'MPA', (16, 30))	('CD44', 'Gene', (145, 149))	('CD44', 'Gene', '12505', (145, 149))
457710	32158692	The authors ultimately demonstrated that NIR-PIT could significantly inhibit tumor growth in the three models.	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('NIR-PIT', 'Var', (41, 48))	('tumor', 'Disease', (77, 82))	('inhibit', 'NegReg', (69, 76))
457743	32158692	The high-risk subtypes of HPV are mainly HPV16 and HPV18, while the former is considered to be associated with 90% of HPV-related cancers.	('HPV', 'Disease', (26, 29))	('HPV', 'Species', '10566', (41, 44))	('cancers', 'Phenotype', 'HP:0002664', (130, 137))	('HPV', 'Species', '10566', (51, 54))	('cancers', 'Disease', (130, 137))	('cancers', 'Disease', 'MESH:D009369', (130, 137))	('HPV', 'Species', '10566', (118, 121))	('HPV16', 'Disease', (41, 46))	('HPV', 'Species', '10566', (26, 29))	('HPV18', 'Var', (51, 56))	('HPV16', 'Species', '333760', (41, 46))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('associated', 'Reg', (95, 105))
457745	32158692	Thus, the current mouse models of HPV-related oral cancer mainly focus on the construction of cell lines or mouse strains expressing HPV16 E6/E7.	('oral cancer', 'Disease', (46, 57))	('HPV16', 'Species', '333760', (133, 138))	('HPV16', 'Gene', (133, 138))	('mouse', 'Species', '10090', (18, 23))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('mouse', 'Species', '10090', (108, 113))	('E6/E7', 'Var', (139, 144))	('oral cancer', 'Disease', 'MESH:D009062', (46, 57))	('HPV', 'Species', '10566', (133, 136))	('HPV', 'Species', '10566', (34, 37))
457763	32158692	developed a novel HPV-positive HNSCC mouse model in which 1 x 105 HPV16 E6/E7-expressing MTECs were transplanted into the submental region of the FOM.	('HNSCC', 'Disease', 'MESH:C535575', (31, 36))	('HPV', 'Species', '10566', (66, 69))	('HNSCC', 'Disease', (31, 36))	('HPV', 'Species', '10566', (18, 21))	('HNSCC', 'Phenotype', 'HP:0012288', (31, 36))	('men', 'Species', '9606', (125, 128))	('E6/E7-expressing', 'Var', (72, 88))	('mouse', 'Species', '10090', (37, 42))	('HPV16', 'Species', '333760', (66, 71))	('HPV16', 'Gene', (66, 71))	('SCC', 'Phenotype', 'HP:0002860', (33, 36))
457772	32158692	Conventional GEMMs alter the gene of interest in every cell in the body, which is inconsistent with the reality where multiple mutational gene sites in a single cell suppress cell apoptosis and promote proliferation, resulting in tumorigenesis.	('tumor', 'Disease', (230, 235))	('promote', 'PosReg', (194, 201))	('proliferation', 'CPA', (202, 215))	('suppress', 'NegReg', (166, 174))	('cell apoptosis', 'CPA', (175, 189))	('tumor', 'Disease', 'MESH:D009369', (230, 235))	('sites', 'Var', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))
457773	32158692	GEMMs enable the editing of specific genes through the activation or overexpression of oncogenes and the inactivation or silencing of tumor-suppressor genes.	('overexpression', 'PosReg', (69, 83))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('editing', 'Var', (17, 24))	('silencing', 'NegReg', (121, 130))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('inactivation', 'Var', (105, 117))	('oncogenes', 'Gene', (87, 96))	('tumor', 'Disease', (134, 139))	('activation', 'PosReg', (55, 65))
457775	32158692	By the age of 5-6 months, histologic examination of L2D1+/p53+/- and L2D1+/p53-/- mice revealed hyperkeratosis, hyperplasia, severe epithelial dysplasia, and even cancer.	('mice', 'Species', '10090', (82, 86))	('L2D1+/p53+/-', 'Var', (52, 64))	('hyperplasia', 'Disease', 'MESH:D006965', (112, 123))	('epithelial dysplasia', 'Disease', (132, 152))	('hyperkeratosis', 'Disease', 'MESH:D017488', (96, 110))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('epithelial dysplasia', 'Disease', 'MESH:C567703', (132, 152))	('hyperkeratosis', 'Phenotype', 'HP:0000962', (96, 110))	('hyperplasia', 'Disease', (112, 123))	('L2D1+/p53-/-', 'Var', (69, 81))	('hyperkeratosis', 'Disease', (96, 110))	('cancer', 'Disease', (163, 169))	('cancer', 'Disease', 'MESH:D009369', (163, 169))
457778	32158692	Secondly, because of the full range of genetic changes caused by gene editing, GEMMs have a short lifespan and a high mortality rate, and highly malignant OSCC may not develop.	('SCC', 'Phenotype', 'HP:0002860', (156, 159))	('gene editing', 'Var', (65, 77))	('OSCC', 'Disease', (155, 159))	('OSCC', 'Disease', 'MESH:D002294', (155, 159))
457779	32158692	For example, at 5 months, p53-/- and L2D1+/p53-/- mice had to be euthanized as a result of the morbidity caused by systemic lymphomas or sarcomas.	('sarcomas', 'Disease', (137, 145))	('systemic lymphomas', 'Disease', (115, 133))	('systemic lymphomas', 'Disease', 'MESH:D008223', (115, 133))	('lymphomas', 'Phenotype', 'HP:0002665', (124, 133))	('sarcomas', 'Disease', 'MESH:D012509', (137, 145))	('mice', 'Species', '10090', (50, 54))	('sarcomas', 'Phenotype', 'HP:0100242', (137, 145))	('L2D1+/p53-/-', 'Var', (37, 49))	('p53-/-', 'Var', (26, 32))
457780	32158692	Thirdly, the development of the human tumor is caused by mutations in a small number of cells surrounded by normal cells, while the introduction of exogenous genes or the knockout of endogenous genes in GEMMs will occur in all (conventional GEMMs) or most (conditional GEMMs) of the cells.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('development', 'CPA', (13, 24))	('caused by', 'Reg', (47, 56))	('mutations', 'Var', (57, 66))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('human', 'Species', '9606', (32, 37))	('men', 'Species', '9606', (20, 23))
457781	32158692	Human tumors are usually accompanied by multiple mutations and metastases, which is not the case with GEMMs.	('Human', 'Species', '9606', (0, 5))	('mutations', 'Var', (49, 58))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('metastases', 'Disease', 'MESH:D009362', (63, 73))	('tumors', 'Disease', (6, 12))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('metastases', 'Disease', (63, 73))
457784	32158692	Almost all HPV-positive oral cancer patients are p53 wild type, which indicates that GEMMs of OSCC generated by p53 gene mutation are not representative of HPV-positive oral cancer.	('HPV', 'Species', '10566', (11, 14))	('OSCC', 'Disease', (94, 98))	('patients', 'Species', '9606', (36, 44))	('oral cancer', 'Disease', 'MESH:D009062', (24, 35))	('oral cancer', 'Disease', 'MESH:D009062', (169, 180))	('oral cancer', 'Disease', (24, 35))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('HPV', 'Species', '10566', (156, 159))	('mutation', 'Var', (121, 129))	('p53', 'Gene', (112, 115))	('oral cancer', 'Disease', (169, 180))	('OSCC', 'Disease', 'MESH:D002294', (94, 98))	('SCC', 'Phenotype', 'HP:0002860', (95, 98))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))
457806	32158692	Tamoxifen treatment in this model generated the development of oral tumors that detected the expression of HPV biomarkers p16 and MCM7, PIK3CA, and PTEN mutations following HNSCC sequencing data and an active mTOR-PI3K pathway.	('PTEN', 'Gene', (148, 152))	('oral tumors', 'Disease', (63, 74))	('HNSCC', 'Disease', 'MESH:C535575', (173, 178))	('mutations', 'Var', (153, 162))	('Tamoxifen', 'Chemical', 'MESH:D013629', (0, 9))	('mTOR-PI3K pathway', 'Pathway', (209, 226))	('SCC', 'Phenotype', 'HP:0002860', (175, 178))	('p16', 'Gene', (122, 125))	('HPV', 'Species', '10566', (107, 110))	('oral tumor', 'Phenotype', 'HP:0100649', (63, 73))	('PTEN', 'Gene', '19211', (148, 152))	('PIK3CA', 'Gene', (136, 142))	('men', 'Species', '9606', (55, 58))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('oral tumors', 'Disease', 'MESH:D009062', (63, 74))	('HNSCC', 'Disease', (173, 178))	('men', 'Species', '9606', (15, 18))	('oral tumors', 'Phenotype', 'HP:0100649', (63, 74))	('HPV', 'Gene', (107, 110))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('MCM7', 'Gene', (130, 134))	('HNSCC', 'Phenotype', 'HP:0012288', (173, 178))	('PIK3CA', 'Gene', '18706', (136, 142))
457808	32158692	First, Mutant Kras was required for the development of HPV-positive tumors, while the ras family mutations account for only about 5% of HNSCC cases.	('tumors', 'Disease', (68, 74))	('tumors', 'Disease', 'MESH:D009369', (68, 74))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('HPV', 'Species', '10566', (55, 58))	('SCC', 'Phenotype', 'HP:0002860', (138, 141))	('HNSCC', 'Disease', 'MESH:C535575', (136, 141))	('HNSCC', 'Disease', (136, 141))	('men', 'Species', '9606', (47, 50))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('HNSCC', 'Phenotype', 'HP:0012288', (136, 141))	('Mutant', 'Var', (7, 13))
457813	32158692	The expression of HPV16 E6/E7 and the tissue-specific expression of mutant PIK3CAE545K were induced by intra-lingual tamoxifen delivery, which replicated the histological and molecular characteristics of human HPV-positive OPSCC, including robust immune cell infiltration.	('HPV', 'Species', '10566', (210, 213))	('PIK3CA', 'Gene', (75, 81))	('OPSCC', 'Phenotype', 'HP:0012182', (223, 228))	('E6/E7', 'Var', (24, 29))	('HPV', 'Species', '10566', (18, 21))	('SCC', 'Phenotype', 'HP:0002860', (225, 228))	('SCC', 'Disease', 'MESH:D002294', (225, 228))	('HPV16', 'Gene', (18, 23))	('HPV16', 'Species', '333760', (18, 23))	('human', 'Species', '9606', (204, 209))	('PIK3CA', 'Gene', '18706', (75, 81))	('tamoxifen', 'Chemical', 'MESH:D013629', (117, 126))	('SCC', 'Disease', (225, 228))	('mutant', 'Var', (68, 74))
457814	32158692	Meanwhile, oropharyngeal lesions were accompanied by robust S6 phosphorylation at Ser235/236 in oropharyngeal tumors and low-level ERK1/2 activation (Thr202/Tyr204 phosphorylation).	('oropharyngeal lesions', 'Phenotype', 'HP:0100638', (11, 32))	('Ser235/236', 'Var', (82, 92))	('S6 phosphorylation', 'MPA', (60, 78))	('Tyr204', 'Chemical', '-', (157, 163))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('ERK1/2', 'Gene', (131, 137))	('Ser235', 'Chemical', '-', (82, 88))	('oropharyngeal tumors', 'Phenotype', 'HP:0100638', (96, 116))	('oropharyngeal lesions', 'Disease', (11, 32))	('tumors', 'Disease', (110, 116))	('tumors', 'Disease', 'MESH:D009369', (110, 116))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('Thr202/Tyr204', 'Var', (150, 163))	('activation', 'PosReg', (138, 148))	('Thr202', 'Chemical', '-', (150, 156))	('ERK1/2', 'Gene', '26417;26413', (131, 137))
457825	30871030	Despite the development of targeted therapies that inhibit oncogenic mutations of lung cancer cases, continued research into new therapeutic approaches is required for untreatable lung cancer patients, and the development of therapeutic modalities has proven elusive.	('mutations', 'Var', (69, 78))	('lung cancer', 'Phenotype', 'HP:0100526', (82, 93))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('lung cancer', 'Disease', 'MESH:D008175', (180, 191))	('lung cancer', 'Disease', (82, 93))	('patients', 'Species', '9606', (192, 200))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('lung cancer', 'Phenotype', 'HP:0100526', (180, 191))	('lung cancer', 'Disease', 'MESH:D008175', (82, 93))	('lung cancer', 'Disease', (180, 191))	('inhibit', 'NegReg', (51, 58))
457831	30871030	Mutations in cancer genes may be classified into loss-of-function or gain-of-function defects; synthetic lethality interactions are more commonly associated with loss-of-function alleles but can also apply to gain-of-function alleles.	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('cancer', 'Disease', (13, 19))	('cancer', 'Disease', 'MESH:D009369', (13, 19))	('Mutations', 'Var', (0, 9))	('loss-of-function', 'NegReg', (162, 178))	('synthetic lethality', 'CPA', (95, 114))
457834	30871030	Nonetheless, it remains unclear to what extent synthetic lethal interactions proved in experiments can be applied to clinical settings because multiple factors, such as epigenetic and tumor micro-environmental factors, have been postulated to cause effects.	('tumor', 'Disease', (184, 189))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('epigenetic', 'Var', (169, 179))
457842	30871030	A single cancer cell normally has mutations in multiple genes, DNA rearrangements, and gross chromosomal abnormalities, leading to widespread alterations in its gene expression profile.	('cancer', 'Disease', (9, 15))	('gene expression profile', 'MPA', (161, 184))	('alterations', 'Reg', (142, 153))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('chromosomal abnormalities', 'Disease', (93, 118))	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (93, 118))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('mutations', 'Var', (34, 43))
457843	30871030	When a gene has some defect, such as missing or overactivation, the change in the DNA sequence of the genome can occur and leads to cancer.	('missing', 'Var', (37, 44))	('DNA sequence of', 'MPA', (82, 97))	('cancer', 'Disease', (132, 138))	('overactivation', 'Var', (48, 62))	('change', 'Reg', (68, 74))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('leads to', 'Reg', (123, 131))
457844	30871030	Early insights into the central role of the genome in cancer development were observed in the late 19th and early 20th centuries, and the discovery of DNA and the determination of its structure led to the concept that DNA damage and generations of mutations can cause cancer.	('cancer', 'Disease', (268, 274))	('mutations', 'Var', (248, 257))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('cancer', 'Phenotype', 'HP:0002664', (268, 274))	('cancer', 'Disease', (54, 60))	('cause', 'Reg', (262, 267))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('cancer', 'Disease', 'MESH:D009369', (268, 274))
457845	30871030	Researchers have established that the multistage process of tumor formation is driven by activating mutations in dominant growth-enhancing genes (oncogenes) and inactivating mutations in recessive growth-inhibitory genes (tumor suppressor genes).	('driven', 'Reg', (79, 85))	('tumor', 'Disease', 'MESH:D009369', (222, 227))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('tumor', 'Disease', (222, 227))	('activating mutations', 'Var', (89, 109))	('tumor', 'Disease', (60, 65))	('inactivating mutations', 'Var', (161, 183))
457852	30871030	There is a general consensus for cancer genes; mutations in more than 1% of genes contribute to human cancer.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('cancer', 'Disease', (33, 39))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('human', 'Species', '9606', (96, 101))	('mutations', 'Var', (47, 56))	('contribute', 'Reg', (82, 92))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))
457858	30871030	Large-scale genetic interactions can contribute to the identification of a synthetic lethal therapeutic approach, which is of particular interest for harnessing new cancer treatment targets.	('interactions', 'Interaction', (20, 32))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('cancer', 'Disease', (165, 171))	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('genetic', 'Var', (12, 19))
457873	30871030	In lung cancer, there is the rapid development of targeted therapies with newer and more potent generations of drugs; cancer cells have acquired mechanisms of resistance, particularly in patients with EGFR mutations, in which the most common resistant cause, the T790M mutation, has been successfully treated with osimertinib.	('patients', 'Species', '9606', (187, 195))	('cancer', 'Disease', (118, 124))	('mutations', 'Var', (206, 215))	('T790M', 'Mutation', 'rs121434569', (263, 268))	('cancer', 'Disease', (8, 14))	('lung cancer', 'Disease', (3, 14))	('T790M', 'Var', (263, 268))	('EGFR', 'Gene', '1956', (201, 205))	('lung cancer', 'Phenotype', 'HP:0100526', (3, 14))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('EGFR', 'Gene', (201, 205))	('osimertinib', 'Chemical', 'MESH:C000603933', (314, 325))	('lung cancer', 'Disease', 'MESH:D008175', (3, 14))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('cancer', 'Disease', 'MESH:D009369', (8, 14))
457884	30871030	In SCLC, targeted therapy is not well established, and almost all cases are linked to inactivating TP53 and RB1 mutations.	('inactivating', 'Var', (86, 98))	('TP53', 'Gene', (99, 103))	('SCLC', 'Gene', '7864', (3, 7))	('SCLC', 'Gene', (3, 7))	('SCLC', 'Phenotype', 'HP:0030357', (3, 7))	('RB1', 'Gene', (108, 111))	('linked', 'Reg', (76, 82))	('mutations', 'Var', (112, 121))	('RB1', 'Gene', '5925', (108, 111))	('TP53', 'Gene', '7157', (99, 103))
457885	30871030	The identification of targetable gene alterations has transformed the management of lung cancer; however, some intracellular oncogene products have proven difficult to target.	('lung cancer', 'Disease', (84, 95))	('lung cancer', 'Phenotype', 'HP:0100526', (84, 95))	('lung cancer', 'Disease', 'MESH:D008175', (84, 95))	('alterations', 'Var', (38, 49))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
457887	30871030	Major subtypes of NSCLC are associated with smoking; the identification of driver gene alterations has allowed targeted therapies.	('NSCLC', 'Disease', (18, 23))	('associated', 'Reg', (28, 38))	('alterations', 'Var', (87, 98))	('NSCLC', 'Disease', 'MESH:D002289', (18, 23))	('NSCLC', 'Phenotype', 'HP:0030358', (18, 23))	('SCLC', 'Phenotype', 'HP:0030357', (19, 23))
457891	30871030	Through a chemical library screen, oncrasin-1 (oncogenic Ras tumor-inhibiting compound 1) showed synthetic lethality for KRAS and protein kinase C iota (PKCi), and phenformin, a mitochondrial inhibitor and analog of the diabetes therapeutic metformin, induced apoptosis in LKB1-deficient NSCLC cells.	('diabetes', 'Disease', 'MESH:D003920', (220, 228))	('oncogenic Ras tumor', 'Disease', 'MESH:D000074723', (47, 66))	('phenformin', 'Chemical', 'MESH:D010629', (164, 174))	('NSCLC', 'Phenotype', 'HP:0030358', (288, 293))	('protein kinase C iota', 'Gene', (130, 151))	('oncogenic Ras tumor', 'Disease', (47, 66))	('phenformin', 'Var', (164, 174))	('SCLC', 'Phenotype', 'HP:0030357', (289, 293))	('KRAS', 'Gene', '3845', (121, 125))	('apoptosis', 'CPA', (260, 269))	('LKB1-deficient NSCLC', 'Disease', (273, 293))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('induced', 'PosReg', (252, 259))	('metformin', 'Chemical', 'MESH:D008687', (241, 250))	('protein kinase C iota', 'Gene', '5584', (130, 151))	('diabetes', 'Disease', (220, 228))	('KRAS', 'Gene', (121, 125))	('LKB1-deficient NSCLC', 'Disease', 'MESH:D002289', (273, 293))	('PKCi', 'Gene', (153, 157))	('PKCi', 'Gene', '5584', (153, 157))
457896	30871030	The main targeted genes in activated mutant RAS are STK33, TBK1, PLK1, WT1, CDK4 and GATA2 as synthetic lethal targets.	('PLK1', 'Gene', (65, 69))	('WT1', 'Gene', (71, 74))	('PLK1', 'Gene', '5347', (65, 69))	('STK33', 'Gene', (52, 57))	('CDK4', 'Gene', (76, 80))	('CDK4', 'Gene', '1019', (76, 80))	('TBK1', 'Gene', '29110', (59, 63))	('TBK1', 'Gene', (59, 63))	('GATA2', 'Gene', '2624', (85, 90))	('mutant', 'Var', (37, 43))	('WT1', 'Gene', '7490', (71, 74))	('RAS', 'Gene', (44, 47))	('STK33', 'Gene', '65975', (52, 57))	('activated', 'PosReg', (27, 36))	('GATA2', 'Gene', (85, 90))
457907	30871030	Determining complex genomic alterations and rearrangements in SCLC, which are undetectable by the existing gene analysis technologies, might further contribute to understanding of SCLC occurrence; therefore, performing whole-genome sequencing is necessary; one of the hallmarks of SCLC is the high frequency of mutations in TP53 and RB1.	('SCLC', 'Gene', (62, 66))	('SCLC', 'Gene', '7864', (62, 66))	('SCLC', 'Phenotype', 'HP:0030357', (62, 66))	('SCLC', 'Gene', '7864', (180, 184))	('SCLC', 'Phenotype', 'HP:0030357', (180, 184))	('SCLC', 'Gene', (180, 184))	('TP53', 'Gene', '7157', (324, 328))	('TP53', 'Gene', (324, 328))	('mutations', 'Var', (311, 320))	('RB1', 'Gene', (333, 336))	('SCLC', 'Gene', '7864', (281, 285))	('SCLC', 'Phenotype', 'HP:0030357', (281, 285))	('SCLC', 'Gene', (281, 285))	('RB1', 'Gene', '5925', (333, 336))
457908	30871030	Most of the discovered mutations observed in SCLC are passengers that do not essentially contribute to cancer cell growth, invasion or progression to metastatic lesions, and the most common mutations, that is, those in TP53 and RB1, are rarely targeted directly.	('SCLC', 'Gene', '7864', (45, 49))	('SCLC', 'Phenotype', 'HP:0030357', (45, 49))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('TP53', 'Gene', (219, 223))	('RB1', 'Gene', (228, 231))	('mutations', 'Var', (23, 32))	('RB1', 'Gene', '5925', (228, 231))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('SCLC', 'Gene', (45, 49))	('TP53', 'Gene', '7157', (219, 223))
457910	30871030	The comprehensive analysis of somatic alterations in SCLC provides proof for universal bi-allelic inactivation of TP53 and RB1.	('RB1', 'Gene', '5925', (123, 126))	('bi-allelic inactivation', 'Var', (87, 110))	('TP53', 'Gene', '7157', (114, 118))	('SCLC', 'Gene', '7864', (53, 57))	('RB1', 'Gene', (123, 126))	('SCLC', 'Gene', (53, 57))	('TP53', 'Gene', (114, 118))	('SCLC', 'Phenotype', 'HP:0030357', (53, 57))
457915	30871030	The potential benefits of gene-targeted therapy have been studied for SCLC, and recent work showing the frequent occurrence of genomic TP73 alterations in SCLC indicates that there are potentially promising targets in SCLC tumors.	('SCLC tumors', 'Disease', (218, 229))	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('SCLC', 'Gene', (155, 159))	('SCLC', 'Gene', '7864', (70, 74))	('SCLC', 'Phenotype', 'HP:0030357', (70, 74))	('SCLC', 'Gene', (70, 74))	('SCLC', 'Gene', '7864', (155, 159))	('SCLC', 'Phenotype', 'HP:0030357', (155, 159))	('tumors', 'Phenotype', 'HP:0002664', (223, 229))	('TP73', 'Gene', '7161', (135, 139))	('SCLC', 'Gene', (218, 222))	('TP73', 'Gene', (135, 139))	('alterations', 'Var', (140, 151))	('SCLC', 'Gene', '7864', (218, 222))	('SCLC', 'Phenotype', 'HP:0030357', (218, 222))	('SCLC tumors', 'Disease', 'MESH:D018288', (218, 229))
457919	30871030	Tumor-specific inactivation of the MYC-associated factor X gene (MAX) with alterations of BRG1 revealed synthetic lethality related to an aberrant SWI/SNF-MYC network in SCLC.	('BRG1', 'Gene', (90, 94))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('MYC', 'Gene', (155, 158))	('MYC', 'Gene', (35, 38))	('BRG1', 'Gene', '6597', (90, 94))	('MYC-associated factor X', 'Gene', '4149', (35, 58))	('aberrant', 'Var', (138, 146))	('MYC', 'Gene', '4609', (155, 158))	('MYC-associated factor X', 'Gene', (35, 58))	('SCLC', 'Gene', '7864', (170, 174))	('SCLC', 'Phenotype', 'HP:0030357', (170, 174))	('SCLC', 'Gene', (170, 174))	('alterations', 'Var', (75, 86))	('MYC', 'Gene', '4609', (35, 38))	('inactivation', 'Var', (15, 27))
457924	30871030	In the process of cancer progression, loss-of-function mutations are common events, and targeting these mutations via synthetic lethal interactions will lead to an expansion of therapeutic approaches toward tumors without dominant oncogenes, such as SCLC.	('mutations', 'Var', (104, 113))	('mutations', 'Var', (55, 64))	('loss-of-function', 'NegReg', (38, 54))	('tumors', 'Phenotype', 'HP:0002664', (207, 213))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('SCLC', 'Gene', (250, 254))	('tumors', 'Disease', 'MESH:D009369', (207, 213))	('tumors', 'Disease', (207, 213))	('SCLC', 'Gene', '7864', (250, 254))	('SCLC', 'Phenotype', 'HP:0030357', (250, 254))	('cancer', 'Disease', (18, 24))	('cancer', 'Disease', 'MESH:D009369', (18, 24))
457933	30871030	From the viewpoint of tumor heterogeneity, artificial situations such as clear knockdown or upregulation of single or specific genes do not necessarily maintain the tumor characteristics seen in clinical settings.	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('upregulation', 'PosReg', (92, 104))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('tumor', 'Disease', (22, 27))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('knockdown', 'Var', (79, 88))	('tumor', 'Disease', (165, 170))
457935	29950003	Driver gene mutations based clustering of tumors: methods and applications Somatic mutations in proto-oncogenes and tumor suppressor genes constitute a major category of causal genetic abnormalities in tumor cells.	('mutations', 'Var', (83, 92))	('tumor', 'Disease', (42, 47))	('genetic abnormalities', 'Disease', (177, 198))	('tumor', 'Disease', (202, 207))	('tumors', 'Disease', (42, 48))	('tumors', 'Disease', 'MESH:D009369', (42, 48))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('genetic abnormalities', 'Disease', 'MESH:D030342', (177, 198))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('tumor', 'Disease', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))
457951	29950003	Third, the relevance of a non-synonymous mutation to the formation and progression of tumors intuitively depends on the confidence in its host gene as a true cancer gene.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('tumors', 'Disease', (86, 92))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('cancer', 'Disease', (158, 164))	('non-synonymous', 'Var', (26, 40))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
457977	29950003	wild and mutant) of the two most frequently mutated cancer driver genes for the specific cancer type.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('mutant', 'Var', (9, 15))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('cancer', 'Disease', (89, 95))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
457985	29950003	M3 is a zero-one filled matrix, indicating the mutation status of the driver genes in the tumor samples of a cancer patient cohort.	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('patient', 'Species', '9606', (116, 123))	('mutation', 'Var', (47, 55))	('tumor', 'Disease', (90, 95))	('cancer', 'Disease', (109, 115))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
457988	29950003	Step-2M4 is adjusted to obtain a weighted between-gene similarity matrix (M5) by the Equation M5 The ith row jth column element of M5, represents the 'strength' of the genes gi and gj for connecting two tumor samples that have a mutation on either of them, respectively.	('mutation', 'Var', (229, 237))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('tumor', 'Disease', (203, 208))	('tumor', 'Disease', 'MESH:D009369', (203, 208))
458002	29950003	While some tumors in the TCGA data have over 10 mutations in the putative cancer genes, a recent study showed that most cancer types only require 3 driver mutations.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('tumors', 'Phenotype', 'HP:0002664', (11, 17))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('tumors', 'Disease', 'MESH:D009369', (11, 17))	('cancer', 'Disease', (74, 80))	('tumors', 'Disease', (11, 17))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('mutations', 'Var', (48, 57))
458014	29950003	For example, the survival stratification of the partition obtained by ccpwModel in LIHC is much clearer than that from nbsModel.	('ccpwModel', 'Var', (70, 79))	('nbs', 'Gene', (119, 122))	('nbs', 'Gene', '4830', (119, 122))
458016	29950003	It clearly shows that the UCEC patients with tumors in which both PTEN and PICK3A genes are mutated demonstrate a desired survival curve, a highly useful signature for predicting the prognosis of UCEC patients (Page-15 of Supplementary Material).	('patients', 'Species', '9606', (201, 209))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('PTEN', 'Gene', (66, 70))	('PTEN', 'Gene', '5728', (66, 70))	('tumors', 'Disease', (45, 51))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('tumors', 'Disease', 'MESH:D009369', (45, 51))	('patients', 'Species', '9606', (31, 39))	('mutated', 'Var', (92, 99))	('PICK3A genes', 'Gene', (75, 87))
458024	29950003	Among them, Cluster-3 is of our special interest because ~95% of patients in this group have mutated TP53 gene and its survival profile is poorer than that of the other clusters with a modest significance (P = 0.07, logRank test).	('survival profile', 'CPA', (119, 135))	('mutated', 'Var', (93, 100))	('TP53', 'Gene', '7157', (101, 105))	('poorer', 'NegReg', (139, 145))	('TP53', 'Gene', (101, 105))	('patients', 'Species', '9606', (65, 73))
458032	29950003	Using ccpwModel, we identify a lethal LIHC sub-type (Cluster 4), in which tumor cells are characterized by the mutation-disturbed RAS/PI3K pathways (Fig.	('RAS/PI3K pathways', 'Pathway', (130, 147))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor', 'Disease', (74, 79))	('mutation-disturbed', 'Var', (111, 129))
458033	29950003	Another sub-type (Cluster-3), in which tumor cells are characterized by the mutation-disturbed DNA damage control and cell cycle/apoptosis mechanisms, has a relatively low short-term (within 20 months) survival rate.	('mutation-disturbed', 'Var', (76, 94))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('DNA damage control', 'MPA', (95, 113))	('low', 'NegReg', (168, 171))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumor', 'Disease', (39, 44))	('cell cycle/apoptosis', 'CPA', (118, 138))
458045	29950003	In this study, we find statistically significant associations between the mutation-based tumor clusters and the racial groups of patients in six cancer types.	('cancer', 'Disease', (145, 151))	('mutation-based', 'Var', (74, 88))	('significant associations', 'Reg', (37, 61))	('patients', 'Species', '9606', (129, 137))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
458053	29950003	Another unique aspect of this study is that it demonstrates a way to integrate the results of mutations based tumor clustering with the widely available gene expression data for prognostic signature identification.	('tumor', 'Disease', 'MESH:D009369', (110, 115))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('mutations', 'Var', (94, 103))
458055	29950003	For example, the signature in LIHC is selected based on the lethal outcome of patients whose tumors are characterized by mutation-disturbed DNA damage control or RAS/PI3K pathways.	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumors', 'Disease', 'MESH:D009369', (93, 99))	('DNA damage control', 'MPA', (140, 158))	('patients', 'Species', '9606', (78, 86))	('RAS/PI3K pathways', 'Pathway', (162, 179))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('tumors', 'Disease', (93, 99))	('mutation-disturbed', 'Var', (121, 139))
458056	29950003	have showed that RAS mutation predicts early lung recurrence and worse survival after curative resection of colorectal liver metastases.	('RAS', 'Gene', (17, 20))	('mutation', 'Var', (21, 29))	('colorectal liver metastases', 'Disease', 'MESH:D009362', (108, 135))	('colorectal liver metastases', 'Disease', (108, 135))	('lung recurrence', 'Disease', (45, 60))
458060	28626254	Additionally, patients with a DeltaSUVmax >=0.9 had significantly worse survival outcomes (28.9% vs 92.6%; p < 0.01).	('DeltaSUVmax', 'Var', (30, 41))	('worse', 'NegReg', (66, 71))	('survival', 'MPA', (72, 80))	('patients', 'Species', '9606', (14, 22))
458092	28626254	Patients with a low SUV early (< 5.7) and low SUV delayed (< 6.5) had significantly better OS rates than those with a high SUV early (>= 5.7) and a high SUV delayed (>= 6.5), with the OS rates being 92.0% and 39.1% respectively (p < 0.01; Fig.	('Patients', 'Species', '9606', (0, 8))	('< 6.5', 'Var', (59, 64))	('OS rates', 'CPA', (91, 99))	('< 5.7', 'Var', (31, 36))	('better', 'PosReg', (84, 90))
458106	28626254	reported that in 31 maxillary sinus cancer patients, SUVmax values for the primary tumor of >= 16 and >= 17 were predictors of progression-free survival (PFS) and OS respectively.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('progression-free survival', 'CPA', (127, 152))	('tumor', 'Disease', (83, 88))	('patients', 'Species', '9606', (43, 51))	('maxillary sinus cancer', 'Disease', (20, 42))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('>= 17', 'Var', (102, 107))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('maxillary sinus cancer', 'Disease', 'MESH:D008444', (20, 42))
458113	28626254	Additionally, the RI calculated using DTP 18F-FDG PET has been reported to reflect the expression of hexokinase, and may be an index of the phosphorylation rate.)	('DTP 18F-FDG', 'Var', (38, 49))	('DTP', 'Chemical', '-', (38, 41))	('expression', 'MPA', (87, 97))	('hexokinase', 'Gene', (101, 111))	('18F-FDG', 'Chemical', 'MESH:D019788', (42, 49))	('hexokinase', 'Gene', '3098', (101, 111))
458118	28626254	also found that a DeltaSUVmax > 1 for the primary tumor was significantly associated with PFS in 117 NSCLC patients.	('PFS', 'Disease', (90, 93))	('NSCLC', 'Disease', (101, 106))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('NSCLC', 'Disease', 'MESH:D002289', (101, 106))	('DeltaSUVmax', 'Var', (18, 29))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('patients', 'Species', '9606', (107, 115))	('tumor', 'Disease', (50, 55))	('associated', 'Reg', (74, 84))
458126	28626254	Our indications are that high 18F-FDG uptake is associated with poor outcome, and these patients may need to receive an aggressive medical treatment.	('high', 'Var', (25, 29))	('patients', 'Species', '9606', (88, 96))	('18F-FDG', 'Protein', (30, 37))	('18F-FDG', 'Chemical', 'MESH:D019788', (30, 37))
458135	27585651	Investigating cellular network heterogeneity and modularity in cancer: a network entropy and unbalanced motif approach Cancer is increasingly recognized as a cellular system phenomenon that is attributed to the accumulation of genetic or epigenetic alterations leading to the perturbation of the molecular network architecture.	('epigenetic alterations', 'Var', (238, 260))	('Cancer', 'Disease', (119, 125))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('Cancer', 'Disease', 'MESH:D009369', (119, 125))	('Cancer', 'Phenotype', 'HP:0002664', (119, 125))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('cancer', 'Disease', (63, 69))
458147	27585651	Analyses of massive amounts of cancer genomics data generated from The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC) has suggested that cancer is a systems-level, network phenomenon attributed to the accumulation of genetic or epigenetic alterations under molecular network architecture.	('Cancer', 'Disease', (71, 77))	('Cancer Genome Atlas', 'Disease', (71, 90))	('Cancer', 'Disease', (120, 126))	('Cancer', 'Disease', 'MESH:D009369', (71, 77))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (71, 90))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('Cancer', 'Disease', 'MESH:D009369', (120, 126))	('Cancer', 'Phenotype', 'HP:0002664', (120, 126))	('cancer', 'Disease', (171, 177))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('cancer', 'Disease', (31, 37))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('epigenetic alterations', 'Var', (262, 284))	('Cancer', 'Phenotype', 'HP:0002664', (71, 77))
458181	27585651	Among the 8 cancer types, four: LUSC (0.9957 +- 0.0001), LUAD (0.9950 +- 0.0001), BRCA (0.9947 +- 0.0001), and HNSC (0.9945 +- 0.0001), showed the highest average local network entropy distribution.	('local network entropy', 'MPA', (163, 184))	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('BRCA', 'Gene', (82, 86))	('cancer', 'Disease', (12, 18))	('0.9950 +- 0.0001', 'Var', (63, 79))	('0.9945 +- 0.0001', 'Var', (117, 133))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('LUAD', 'Phenotype', 'HP:0030078', (57, 61))	('0.9947 +- 0.0001', 'Var', (88, 104))	('BRCA', 'Gene', '672', (82, 86))
458184	27585651	A previous study revealed that an average somatic mutation frequency in smokers was more than 10-fold higher in never-smokers in non-small cell lung cancer.	('cell lung cancer', 'Disease', 'MESH:D008175', (139, 155))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (129, 155))	('lung cancer', 'Phenotype', 'HP:0100526', (144, 155))	('somatic mutation', 'Var', (42, 58))	('higher', 'PosReg', (102, 108))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (133, 155))	('cell lung cancer', 'Disease', (139, 155))
458198	27585651	Similar to the genome-wide network entropy analysis, BRCA and LUAD indicated the lowest network entropy for SMGs in stage IV (p < 0.01) compared to that in stages I-III (Additional file 1: Figure S1).	('BRCA', 'Gene', '672', (53, 57))	('SMGs', 'Var', (108, 112))	('lowest', 'NegReg', (81, 87))	('LUAD', 'Phenotype', 'HP:0030078', (62, 66))	('BRCA', 'Gene', (53, 57))	('network entropy', 'MPA', (88, 103))
458216	27585651	5 showed that Gefitinib resistant lung cancer cell lines were often characterized by elevated network entropy.	('lung cancer', 'Disease', (34, 45))	('lung cancer', 'Phenotype', 'HP:0100526', (34, 45))	('network entropy', 'MPA', (94, 109))	('elevated', 'PosReg', (85, 93))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('lung cancer', 'Disease', 'MESH:D008175', (34, 45))	('Gefitinib', 'Chemical', 'MESH:D000077156', (14, 23))	('Gefitinib', 'Var', (14, 23))
458262	27585651	CePIN Co-expressed Protein Interaction Network ICGC International Cancer Genome Consortium OG Oncogene PCC Pearson Correlation Coefficient PIN Protein Interaction Network PPI Protein-Protein Interaction TCGA The Cancer Genome Atlas TSG Tumor Suppressor Gene	('PIN', 'Gene', (2, 5))	('Cancer', 'Disease', (212, 218))	('PIN', 'Gene', (139, 142))	('PIN', 'Gene', '8655', (2, 5))	('Cancer Genome Atlas', 'Disease', (212, 231))	('PIN', 'Gene', '8655', (139, 142))	('PPI', 'Var', (171, 174))	('Cancer', 'Disease', 'MESH:D009369', (212, 218))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (212, 231))	('Tumor Suppressor', 'Gene', '7248', (236, 252))	('CePIN', 'Chemical', '-', (0, 5))	('Cancer', 'Disease', (66, 72))	('Cancer', 'Phenotype', 'HP:0002664', (212, 218))	('Tumor Suppressor', 'Gene', (236, 252))	('Cancer', 'Phenotype', 'HP:0002664', (66, 72))	('Tumor', 'Phenotype', 'HP:0002664', (236, 241))	('Cancer', 'Disease', 'MESH:D009369', (66, 72))
458327	27356955	Similarly, Koneri et al reported that knockdown of Beclin-1 in a colon cancer cell line resulted in growth inhibition.	('colon cancer', 'Disease', (65, 77))	('colon cancer', 'Phenotype', 'HP:0003003', (65, 77))	('Beclin-1', 'Gene', (51, 59))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('colon cancer', 'Disease', 'MESH:D015179', (65, 77))	('growth', 'MPA', (100, 106))	('knockdown', 'Var', (38, 47))
458328	27356955	In addition, Liang et al also reported that Beclin-1 expression in the MCF-7 human breast carcinoma cell line significantly inhibited clonogenicity in vitro and tumourigenesis in nude mice.	('clonogenicity', 'CPA', (134, 147))	('Beclin-1', 'Gene', (44, 52))	('breast carcinoma', 'Phenotype', 'HP:0003002', (83, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('expression', 'Var', (53, 63))	('tumour', 'Phenotype', 'HP:0002664', (161, 167))	('breast carcinoma', 'Disease', (83, 99))	('tumour', 'Disease', 'MESH:D009369', (161, 167))	('nude mice', 'Species', '10090', (179, 188))	('tumour', 'Disease', (161, 167))	('breast carcinoma', 'Disease', 'MESH:D001943', (83, 99))	('inhibited', 'NegReg', (124, 133))	('MCF-7', 'CellLine', 'CVCL:0031', (71, 76))	('human', 'Species', '9606', (77, 82))
458379	26817708	We can therefore set the representative of x, say y, as follows, using the same notation as our previous equation:   where N(x) is the neighborhood of x, yk+1 is the (k+1)st candidate for medoid, yk is the kth medoid candidate, phi=-Phi', and other variables are defined as above.	('phi', 'Gene', '2821', (228, 231))	('Phi', 'Gene', '2821', (233, 236))	('Phi', 'Gene', (233, 236))	('yk+1', 'Var', (154, 158))	('phi', 'Gene', (228, 231))
458424	25646180	Aberrant activation of Hh signaling is implicated in multiple aspects of transformation including the maintenance of the cancer stem cell (CSC) phenotype.	('activation', 'PosReg', (9, 19))	('Aberrant', 'Var', (0, 8))	('implicated', 'Reg', (39, 49))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('cancer', 'Disease', (121, 127))
458426	25646180	However, to date, Hh inhibitors, specifically those targeting Smoothened (such as Vismodegib, BMS-833923, Saridegib (IPI-926), Sonidegib/Erismodegib (LDE225), PF-04449913, LY2940680, LEQ 506 and TAK-441) have demonstrated good efficacy as monotherapy in patients with basal cell carcinoma and medulloblastoma, but have shown limited activity in other tumor types.	('basal cell carcinoma', 'Disease', 'MESH:D002280', (268, 288))	('medulloblastoma', 'Disease', 'MESH:D008527', (293, 308))	('medulloblastoma', 'Phenotype', 'HP:0002885', (293, 308))	('BMS-833923', 'Var', (94, 104))	('carcinoma', 'Phenotype', 'HP:0030731', (279, 288))	('medulloblastoma', 'Disease', (293, 308))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (268, 288))	('IPI-926', 'Chemical', 'MESH:C541444', (117, 124))	('tumor', 'Disease', (351, 356))	('LEQ 506', 'Var', (183, 190))	('Smoothened', 'Gene', (62, 72))	('tumor', 'Disease', 'MESH:D009369', (351, 356))	('LY2940680', 'Var', (172, 181))	('LDE225', 'Chemical', 'MESH:C561435', (150, 156))	('basal cell carcinoma', 'Disease', (268, 288))	('LEQ', 'Chemical', '-', (183, 186))	('Smoothened', 'Gene', '6608', (62, 72))	('tumor', 'Phenotype', 'HP:0002664', (351, 356))	('PF-04449913', 'Var', (159, 170))	('patients', 'Species', '9606', (254, 262))	('LY2940680', 'Chemical', 'MESH:C581399', (172, 181))
458429	25646180	Aberrant Hh pathway activation controls multiple aspects of tumorigenesis including initiation, progression and relapse, at least in part, by driving a cancer stem cell (CSC) phenotype.	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('Aberrant', 'Var', (0, 8))	('tumor', 'Disease', (60, 65))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('activation', 'PosReg', (20, 30))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('driving', 'PosReg', (142, 149))
458430	25646180	Mutational Hh pathway activation drives tumor formation in several tumor types, and many other tumors exhibit epigenetic Hh pathway activation.	('epigenetic', 'Var', (110, 120))	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('Mutational', 'Var', (0, 10))	('Hh pathway', 'Pathway', (11, 21))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('activation', 'PosReg', (22, 32))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Disease', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('tumors', 'Disease', (95, 101))	('tumor', 'Disease', (95, 100))
458441	25646180	Alterations in one or more of these modulatory mechanisms can lead to pathway deregulation and cancer.	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('Alterations', 'Var', (0, 11))	('cancer', 'Disease', (95, 101))	('pathway deregulation', 'MPA', (70, 90))	('lead to', 'Reg', (62, 69))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))
458443	25646180	Germline or somatic loss-of-function PTCH or SUFU, and gain-of-function SMO, mutations constitutively activate ligand-independent Hh signaling and drive basal cell carcinoma (BCC), medulloblastoma (MB), rhabdomyosarcoma and meningioma tumor development.	('activate', 'PosReg', (102, 110))	('SUFU', 'Gene', (45, 49))	('SMO', 'Gene', (72, 75))	('loss-of-function', 'NegReg', (20, 36))	('drive', 'PosReg', (147, 152))	('basal cell carcinoma', 'Disease', (153, 173))	('meningioma tumor', 'Disease', (224, 240))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (203, 219))	('PTCH', 'Gene', '5727', (37, 41))	('meningioma tumor', 'Disease', 'MESH:D008577', (224, 240))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (203, 219))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('medulloblastoma', 'Disease', 'MESH:D008527', (181, 196))	('medulloblastoma', 'Phenotype', 'HP:0002885', (181, 196))	('meningioma', 'Phenotype', 'HP:0002858', (224, 234))	('medulloblastoma', 'Disease', (181, 196))	('ligand-independent Hh signaling', 'MPA', (111, 142))	('SUFU', 'Gene', '51684', (45, 49))	('mutations', 'Var', (77, 86))	('basal cell carcinoma', 'Disease', 'MESH:D002280', (153, 173))	('carcinoma', 'Phenotype', 'HP:0030731', (164, 173))	('PTCH', 'Gene', (37, 41))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (153, 173))	('rhabdomyosarcoma', 'Disease', (203, 219))	('gain-of-function', 'PosReg', (55, 71))
458444	25646180	GLI1 amplification occurs in glioblastoma and rhabdomyosarcoma, and activating mutations in GLI1 and GLI3 are evident in pancreatic adenocarcinomas, although the function of these mutations is not fully explored.	('GLI1', 'Gene', (0, 4))	('GLI3', 'Gene', '2737', (101, 105))	('pancreatic adenocarcinomas', 'Disease', 'MESH:D010190', (121, 147))	('activating', 'PosReg', (68, 78))	('glioblastoma', 'Phenotype', 'HP:0012174', (29, 41))	('GLI3', 'Gene', (101, 105))	('pancreatic adenocarcinomas', 'Disease', (121, 147))	('GLI1', 'Gene', '2735', (92, 96))	('pancreatic adenocarcinomas', 'Phenotype', 'HP:0006725', (121, 147))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (46, 62))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('amplification', 'PosReg', (5, 18))	('GLI1', 'Gene', (92, 96))	('GLI1', 'Gene', '2735', (0, 4))	('glioblastoma and rhabdomyosarcoma', 'Disease', 'MESH:D005909', (29, 62))	('mutations', 'Var', (79, 88))
458445	25646180	Pallister-Hall syndrome, characterized by formation of benign hypothalamic hamartomas, is caused by a frameshift GLI3 mutation that generates a C-terminal truncated protein resembling physiologically-generated GLI3 repressor.	('GLI3', 'Gene', '2737', (210, 214))	('benign hypothalamic hamartomas', 'Disease', 'MESH:C537158', (55, 85))	('Pallister-Hall syndrome', 'Disease', 'MESH:D054975', (0, 23))	('GLI3', 'Gene', (210, 214))	('GLI3', 'Gene', '2737', (113, 117))	('hypothalamic hamartomas', 'Phenotype', 'HP:0002444', (62, 85))	('mutation', 'Var', (118, 126))	('benign hypothalamic hamartomas', 'Disease', (55, 85))	('GLI3', 'Gene', (113, 117))	('hamartomas', 'Phenotype', 'HP:0010566', (75, 85))	('Pallister-Hall syndrome', 'Disease', (0, 23))	('frameshift', 'Var', (102, 112))	('caused by', 'Reg', (90, 99))
458462	25646180	Though cyclopamine is not clinically useful due to its low potency and bioavailability, more potent and specific SMO inhibitors Vismodegib, BMS-833923, Saridegib (IPI-926), Sonidegib/Erismodegib (LDE225), PF-04449913, LY2940680, LEQ 506 and TAK-441 (Fig.	('BMS-833923', 'Var', (140, 150))	('IPI-926', 'Chemical', 'MESH:C541444', (163, 170))	('LY2940680', 'Chemical', 'MESH:C581399', (218, 227))	('LEQ', 'Chemical', '-', (229, 232))	('LY2940680', 'Var', (218, 227))	('LDE225', 'Chemical', 'MESH:C561435', (196, 202))	('cyclopamine', 'Chemical', 'MESH:C000541', (7, 18))	('PF-04449913', 'Var', (205, 216))	('LEQ 506', 'Var', (229, 236))
458463	25646180	SMO inhibitors are particularly effective against MBs and BCCs harboring SMO or PTCH mutations, and FDA approval of Vismodegib for advanced BCC solidified Hh as a bona fide therapeutic target.	('PTCH', 'Gene', (80, 84))	('mutations', 'Var', (85, 94))	('PTCH', 'Gene', '5727', (80, 84))	('SMO', 'Gene', (73, 76))
458472	25646180	Cyclopamine preferentially inhibits pancreatic CSCs but not bulk tumor cells, and GLI or SMO gene-silencing, or cyclopamine, decreases glioblastoma CSC proliferation, survival and self-renewal.	('decreases glioblastoma', 'Disease', (125, 147))	('pancreatic CSCs', 'Disease', (36, 51))	('inhibits', 'NegReg', (27, 35))	('Cyclopamine', 'Chemical', 'MESH:C000541', (0, 11))	('tumor', 'Disease', (65, 70))	('glioblastoma', 'Phenotype', 'HP:0012174', (135, 147))	('survival', 'CPA', (167, 175))	('cyclopamine', 'Chemical', 'MESH:C000541', (112, 123))	('SMO', 'Gene', (89, 92))	('GLI', 'Gene', (82, 85))	('decreases glioblastoma', 'Disease', 'MESH:D005909', (125, 147))	('gene-silencing', 'Var', (93, 107))	('pancreatic CSCs', 'Disease', 'MESH:D010195', (36, 51))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('self-renewal', 'CPA', (180, 192))	('GLI', 'Gene', '2735', (82, 85))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
458473	25646180	shRNA-mediated knockdown of HHAT or GLI1, or treatment with SMO inhibitor LDE225, blocks growth of lung squamous cell carcinoma (LSCC) CSCs in vitro and tumor formation in vivo.	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (104, 127))	('lung squamous cell carcinoma', 'Disease', (99, 127))	('knockdown', 'Var', (15, 24))	('blocks', 'NegReg', (82, 88))	('GLI1', 'Gene', '2735', (36, 40))	('growth', 'MPA', (89, 95))	('HHAT', 'Gene', '55733', (28, 32))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('GLI1', 'Gene', (36, 40))	('LDE225', 'Chemical', 'MESH:C561435', (74, 80))	('tumor', 'Disease', (153, 158))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('HHAT', 'Gene', (28, 32))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (99, 127))
458477	25646180	SMO inhibitors are extremely effective against BCC and MB tumors that harbor driver Hh pathway mutations (Table 1).	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('MB tumors', 'Disease', 'OMIM:613675', (55, 64))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('BCC', 'Disease', (47, 50))	('mutations', 'Var', (95, 104))	('MB tumors', 'Disease', (55, 64))
458478	25646180	However, despite promising preclinical results, SMO inhibitors have yielded little or no clinical benefit in tumors not harboring pathway mutations (Table 1).	('tumors', 'Disease', 'MESH:D009369', (109, 115))	('tumors', 'Disease', (109, 115))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('mutations', 'Var', (138, 147))
458493	25646180	Amplification of chromosome 3q26, which occurs in ~70% of LSCCs, results in the co-amplification and co-overexpression of PKCiota and SOX2 which cooperate to drive cell-autonomous Hh signaling in LSCC CSCs (Fig.	('co-overexpression', 'PosReg', (101, 118))	('Amplification', 'Var', (0, 13))	('co-amplification', 'MPA', (80, 96))	('LSCC CSCs', 'Disease', (196, 205))	('drive', 'PosReg', (158, 163))	('LSCCs', 'Disease', (58, 63))	('PKCiota', 'Gene', '5584', (122, 129))	('SOX2', 'Gene', '6657', (134, 138))	('PKCiota', 'Gene', (122, 129))	('SOX2', 'Gene', (134, 138))
458499	25646180	ANF inhibits expression of PKCiota-dependent transcriptional targets HHAT, GLI1 and MMP10, whereas LDE225 causes decreased GLI1, consistent with on-target effects of these agents.	('MMP10', 'Gene', '4319', (84, 89))	('PKCiota', 'Gene', (27, 34))	('inhibits', 'NegReg', (4, 12))	('LDE225', 'Var', (99, 105))	('expression', 'MPA', (13, 23))	('LDE225', 'Chemical', 'MESH:C561435', (99, 105))	('MMP10', 'Gene', (84, 89))	('HHAT', 'Gene', '55733', (69, 73))	('GLI1', 'Gene', '2735', (123, 127))	('HHAT', 'Gene', (69, 73))	('GLI1', 'Gene', '2735', (75, 79))	('PKCiota', 'Gene', '5584', (27, 34))	('GLI1', 'Gene', (75, 79))	('decreased', 'NegReg', (113, 122))	('GLI1', 'Gene', (123, 127))
458500	25646180	Combined ANF and LDE225 caused a more pronounced inhibition of downstream effectors when compared to either agent alone (Fig.	('ANF', 'Var', (9, 12))	('LDE225', 'Gene', (17, 23))	('LDE225', 'Chemical', 'MESH:C561435', (17, 23))	('inhibition', 'NegReg', (49, 59))	('downstream effectors', 'MPA', (63, 83))
458501	25646180	Since the PKCiota-SOX2-Hh signaling axis is driven by chromosome 3q26 amplification, combined PKCiota and SMO inhibitor may represent a particularly effective treatment strategy for LSCCs harboring chromosome 3q26 amplification.	('PKCiota', 'Gene', (10, 17))	('PKCiota', 'Gene', (94, 101))	('SOX2', 'Gene', '6657', (18, 22))	('SOX2', 'Gene', (18, 22))	('LSCCs', 'Disease', (182, 187))	('PKCiota', 'Gene', '5584', (10, 17))	('PKCiota', 'Gene', '5584', (94, 101))	('amplification', 'Var', (70, 83))
458503	25646180	Indeed, chromosome 3q26 amplification is the most prevalent genetic copy number gain alteration in human cancers, occurring in approximately 15% of human tumors.	('tumors', 'Disease', (154, 160))	('tumors', 'Disease', 'MESH:D009369', (154, 160))	('cancers', 'Phenotype', 'HP:0002664', (105, 112))	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('human', 'Species', '9606', (148, 153))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('chromosome 3q26 amplification', 'Var', (8, 37))	('human', 'Species', '9606', (99, 104))
458506	25646180	Hh inhibitors have been successfully employed as monotherapy for BCC and MB tumors harboring Hh pathway mutations.	('mutations', 'Var', (104, 113))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('MB tumors', 'Disease', (73, 82))	('BCC', 'Disease', (65, 68))	('MB tumors', 'Disease', 'OMIM:613675', (73, 82))	('Hh pathway', 'Gene', (93, 103))
458509	25646180	Tumors not harboring Hh pathway mutations are unlikely to respond to Hh inhibitors alone.	('Tumors', 'Disease', (0, 6))	('mutations', 'Var', (32, 41))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))
458513	25646180	The high prevalence of chromosome 3q26 copy number gains, and the resulting co-amplification of PKCiota and SOX2, in many tumor types (~15% of human tumors) raises the exciting possibility that combined Hh and PKCiota inhibitor therapy will prove effective in the large target patient population whose tumors harbor chromosome 3q26 copy number gains and a CSC phenotype driven by PKCXiota-SOX2-Hh pathway activation.	('tumor', 'Phenotype', 'HP:0002664', (302, 307))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('chromosome', 'Gene', (23, 33))	('tumors', 'Disease', (302, 308))	('tumors', 'Phenotype', 'HP:0002664', (149, 155))	('PKCiota', 'Gene', '5584', (210, 217))	('tumor', 'Disease', (122, 127))	('PKCiota', 'Gene', (210, 217))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('tumors', 'Disease', (149, 155))	('tumors', 'Disease', 'MESH:D009369', (302, 308))	('PKCiota', 'Gene', '5584', (96, 103))	('PKCiota', 'Gene', (96, 103))	('human', 'Species', '9606', (143, 148))	('patient', 'Species', '9606', (277, 284))	('SOX2', 'Gene', '6657', (389, 393))	('tumor', 'Disease', (302, 307))	('SOX2', 'Gene', (389, 393))	('tumors', 'Disease', 'MESH:D009369', (149, 155))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('copy number gains', 'Var', (39, 56))	('copy number gains', 'Var', (332, 349))	('tumor', 'Disease', 'MESH:D009369', (302, 307))	('SOX2', 'Gene', '6657', (108, 112))	('SOX2', 'Gene', (108, 112))	('tumors', 'Phenotype', 'HP:0002664', (302, 308))	('tumor', 'Disease', (149, 154))	('chromosome', 'Gene', (316, 326))
458514	32303268	The prevalent modifications on mRNA include N6-methyladenosine (m6A), N1-methyladenosine (m1A), 5-methylcytosine (m5C), 5-hydroxymethylcytosine (hm5C), pseudouridine (Psi), inosine (I), uridine (U) and ribosemethylation (2'-O-Me).	('m5C', 'Chemical', '-', (114, 117))	('m5C', 'Chemical', '-', (146, 149))	('m1A', 'Chemical', '-', (90, 93))	('m6A', 'Gene', (64, 67))	('5-methylcytosine', 'Chemical', 'MESH:D044503', (96, 112))	('pseudouridine', 'Chemical', 'MESH:D011560', (152, 165))	('uridine', 'Chemical', 'MESH:D014529', (186, 193))	('hm5C', 'Chemical', '-', (145, 149))	('N6-methyladenosine', 'Chemical', 'MESH:C010223', (44, 62))	('inosine', 'Chemical', 'MESH:D007288', (173, 180))	('N6-methyladenosine', 'Var', (44, 62))	('uridine', 'Chemical', 'MESH:D014529', (158, 165))	('ribosemethylation', 'Chemical', '-', (202, 219))	("2'-O-Me", 'Chemical', '-', (221, 228))	('ribosemethylation', 'MPA', (202, 219))	('N1-methyladenosine', 'Var', (70, 88))	('uridine', 'MPA', (186, 193))	('5-hydroxymethylcytosine', 'Chemical', 'MESH:C011865', (120, 143))	('U', 'Chemical', 'MESH:D014529', (195, 196))	('N1-methyladenosine', 'Chemical', 'MESH:C002230', (70, 88))	('m6A', 'Gene', '56339', (64, 67))
458516	32303268	Functioning as the bridge between transcription and translation, RNA modifications are vital for the progression of numerous diseases and can even regulate the fate of cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('regulate', 'Reg', (147, 155))	('cancer', 'Disease', (168, 174))	('modifications', 'Var', (69, 82))
458518	32303268	The revealed mRNA modifications included but were not limited to N6-methyladenosine (m6A), N1-methyladenosine (m1A), 5-methylcytosine (m5C), 5-hydroxymethylcytosine (hm5C), pseudouridine (Psi), inosine (I), uridine (U) and ribose-methylation (2'-O-Me) (Figs.	("2'-O-Me", 'Chemical', '-', (243, 250))	('inosine', 'Chemical', 'MESH:D007288', (194, 201))	('mRNA modifications', 'MPA', (13, 31))	('m6A', 'Gene', '56339', (85, 88))	('uridine', 'Chemical', 'MESH:D014529', (179, 186))	('5-hydroxymethylcytosine', 'Chemical', 'MESH:C011865', (141, 164))	('N1-methyladenosine', 'Chemical', 'MESH:C002230', (91, 109))	('ribose', 'Chemical', 'MESH:D012266', (223, 229))	('m6A', 'Gene', (85, 88))	('m5C', 'Chemical', '-', (167, 170))	('U', 'Chemical', 'MESH:D014529', (216, 217))	('pseudouridine', 'Chemical', 'MESH:D011560', (173, 186))	('m5C', 'Chemical', '-', (135, 138))	('uridine', 'Chemical', 'MESH:D014529', (207, 214))	('m1A', 'Chemical', '-', (111, 114))	('hm5C', 'Chemical', '-', (166, 170))	('5-methylcytosine', 'Chemical', 'MESH:D044503', (117, 133))	('N6-methyladenosine', 'Chemical', 'MESH:C010223', (65, 83))	('N6-methyladenosine', 'Var', (65, 83))
458524	32303268	General m6A modifications occur in mammals, plants, bacteria and even other types of eukaryotic RNA.	('m6A', 'Gene', '56339', (8, 11))	('m6A', 'Gene', (8, 11))	('modifications', 'Var', (12, 25))
458528	32303268	It has been reported that methylated adenosine in the 5'UTR of mRNA can support cap-independent translation commencement and can increase translation.	('methylated', 'Var', (26, 36))	('adenosine', 'Chemical', 'MESH:D000241', (37, 46))	('increase', 'PosReg', (129, 137))	('cap-independent translation commencement', 'MPA', (80, 120))	('support', 'PosReg', (72, 79))	('translation', 'MPA', (138, 149))	('U', 'Chemical', 'MESH:D014529', (56, 57))
458536	32303268	Both cyclo-leucine and NPC are inhibitors of methylation that can be used to investigate m6A.	('methylation', 'MPA', (45, 56))	('leucine', 'Chemical', 'MESH:D007930', (11, 18))	('NPC', 'Gene', (23, 26))	('m6A', 'Gene', (89, 92))	('NPC', 'Gene', '4864', (23, 26))	('cyclo-leucine', 'Var', (5, 18))	('m6A', 'Gene', '56339', (89, 92))
458544	32303268	Subsequently, knockdown of ALKBH5 leads to acceleration of mRNA export, suggesting that m6A is essential to regulating mRNA export.	('mRNA export', 'MPA', (59, 70))	('m6A', 'Gene', (88, 91))	('m6A', 'Gene', '56339', (88, 91))	('knockdown', 'Var', (14, 23))	('ALKBH5', 'Gene', '54890', (27, 33))	('acceleration', 'PosReg', (43, 55))	('ALKBH5', 'Gene', (27, 33))
458552	32303268	Under heat shock conditions, dysfunction of FTO in 5'UTRs, which is regulated by YTHDF2, contributes to the promotion of cap-independent translation.	('YTHDF2', 'Gene', '51441', (81, 87))	('FTO', 'Gene', (44, 47))	('promotion', 'PosReg', (108, 117))	('U', 'Chemical', 'MESH:D014529', (53, 54))	('YTHDF2', 'Gene', (81, 87))	('U', 'Chemical', 'MESH:D014529', (0, 1))	('dysfunction', 'Var', (29, 40))	('FTO', 'Gene', '79068', (44, 47))	('cap-independent translation', 'MPA', (121, 148))	('shock', 'Phenotype', 'HP:0031273', (11, 16))
458556	32303268	The translation efficiency is increased when METTL3 is knocked out in mouse embryonic stem cells (mESCs) and embryoid bodies (EBs) (Fig.	('EB', 'Chemical', '-', (126, 128))	('knocked out', 'Var', (55, 66))	('METTL3', 'Gene', (45, 51))	('mouse', 'Species', '10090', (70, 75))	('translation efficiency', 'MPA', (4, 26))	('increased', 'PosReg', (30, 39))
458559	32303268	However, m1A-containing mRNA is 10 times less common than m6A-containing mRNA.	('m1A-containing', 'Var', (9, 23))	('m6A', 'Gene', (58, 61))	('m6A', 'Gene', '56339', (58, 61))	('m1A', 'Chemical', '-', (9, 12))
458563	32303268	Because the distribution of m1A is imbalanced, the large number of m1A modifications on tRNA results in more tRNA m1A MTases than writers on mRNA.	('modifications', 'Var', (71, 84))	('m1A', 'Chemical', '-', (114, 117))	('m1A', 'Chemical', '-', (28, 31))	('more', 'PosReg', (104, 108))	('m1A', 'Gene', (67, 70))	('m1A', 'Chemical', '-', (67, 70))	('tRNA', 'MPA', (109, 113))
458568	32303268	It has been reported that m1A methylation occurs in highly structured or GC-rich regions of 5'UTRs (which is also the most frequent location) and may modify the predicted secondary structure, which hints at the potential of m1A to alter mRNA structural stability.Moreover, m1A methylation can not only increase translation by decreasing the binding of the releasing factor but also prevent effective translation of m1A-containing CDS in mt-mRNA.	('m1A', 'Chemical', '-', (26, 29))	('U', 'Chemical', 'MESH:D014529', (94, 95))	('translation', 'MPA', (400, 411))	('releasing', 'Protein', (356, 365))	('m1A', 'Chemical', '-', (273, 276))	('increase', 'PosReg', (302, 310))	('decreasing', 'NegReg', (326, 336))	('methylation', 'Var', (277, 288))	('translation', 'MPA', (311, 322))	('m1A', 'Chemical', '-', (415, 418))	('m1A', 'Chemical', '-', (224, 227))	('GC', 'Phenotype', 'HP:0012126', (73, 75))	('binding', 'Interaction', (341, 348))	('prevent', 'NegReg', (382, 389))	('m1A', 'Gene', (273, 276))
458569	32303268	Ultimately, it has been reported that the protein level is higher when a transcript carries the m1A modification around the initiation codon.	('m1A modification', 'Var', (96, 112))	('protein level', 'MPA', (42, 55))	('modification', 'Var', (100, 112))	('m1A', 'Chemical', '-', (96, 99))	('U', 'Chemical', 'MESH:D014529', (0, 1))	('higher', 'PosReg', (59, 65))
458572	32303268	Since a number of studies have investigated the function of m5C in specific mRNAs, we concluded that m5C modifications in different locations (5'UTRs, 3'UTRs, coding regions) exert different transcriptional regulation activities.	('U', 'Chemical', 'MESH:D014529', (153, 154))	('U', 'Chemical', 'MESH:D014529', (145, 146))	('m5C', 'Chemical', '-', (101, 104))	('modifications', 'Var', (105, 118))	('m5C', 'Chemical', '-', (60, 63))	('m5C', 'Gene', (101, 104))	('transcriptional regulation activities', 'MPA', (191, 228))
458579	32303268	Deleting NSUN2 in human diploid fibroblasts (HDFs) can induce the elevation of p27, and overexpressing NSUN2 results in contrasting outcomes.	('NSUN2', 'Gene', (103, 108))	('p27', 'Gene', '3429', (79, 82))	('human', 'Species', '9606', (18, 23))	('HDFs', 'Disease', 'None', (45, 49))	('NSUN2', 'Gene', (9, 14))	('NSUN2', 'Gene', '54888', (103, 108))	('p27', 'Gene', (79, 82))	('HDFs', 'Disease', (45, 49))	('Deleting', 'Var', (0, 8))	('elevation', 'PosReg', (66, 75))	('NSUN2', 'Gene', '54888', (9, 14))
458581	32303268	However, the m5C modifications added by NSUN2 to the 3'UTRs of p21 mRNA coordinate with the m6A modifications added by METTL3/METTL14 together to enhance the expression of p21.	('modifications', 'Var', (17, 30))	('U', 'Chemical', 'MESH:D014529', (55, 56))	('p21', 'Gene', (172, 175))	('NSUN2', 'Gene', '54888', (40, 45))	('METTL14', 'Gene', '57721', (126, 133))	('p21', 'Gene', '644914', (172, 175))	('p21', 'Gene', (63, 66))	('expression', 'MPA', (158, 168))	('METTL14', 'Gene', (126, 133))	('p21', 'Gene', '644914', (63, 66))	('m6A', 'Gene', (92, 95))	('enhance', 'PosReg', (146, 153))	('m5C', 'Chemical', '-', (13, 16))	('NSUN2', 'Gene', (40, 45))	('U', 'Chemical', 'MESH:D014529', (42, 43))	('m6A', 'Gene', '56339', (92, 95))
458582	32303268	With regard to m5C modification in mRNA coding regions, it was revealed that in both bacterial whole-cell extracts and HeLa cell extracts, m5C could diminish translation significantly.	('diminish', 'NegReg', (149, 157))	('m5C', 'Chemical', '-', (15, 18))	('m5C', 'Chemical', '-', (139, 142))	('m5C', 'Var', (139, 142))	('translation', 'MPA', (158, 169))	('HeLa', 'CellLine', 'CVCL:0030', (119, 123))
458583	32303268	Moreover, we demonstrated that when the m5C modification was present on interleukin-17A (IL-17A) mRNA, this modification could promote the translation of IL-17A.	('translation', 'MPA', (139, 150))	('interleukin-17A', 'Gene', '3605', (72, 87))	('IL-17A', 'Gene', '3605', (154, 160))	('promote', 'PosReg', (127, 134))	('IL-17A', 'Gene', '3605', (89, 95))	('interleukin-17A', 'Gene', (72, 87))	('m5C', 'Chemical', '-', (40, 43))	('IL-17A', 'Gene', (154, 160))	('m5C', 'Var', (40, 43))	('modification', 'Var', (108, 120))	('IL-17A', 'Gene', (89, 95))
458584	32303268	The results of the above investigations revealed that the m5C RNA modification affects the expression of proteins by regulating both translation efficiency and transcript export (Table 2).	('m5C', 'Chemical', '-', (58, 61))	('transcript export', 'MPA', (160, 177))	('m5C RNA modification', 'Var', (58, 78))	('translation efficiency', 'MPA', (133, 155))	('regulating', 'Reg', (117, 127))	('expression of proteins', 'MPA', (91, 113))	('affects', 'Reg', (79, 86))
458587	32303268	However, in contrast to m5C methylation in the coding regions of mRNA, which plays a negative role in translation, hm5C tends to associate with translation activation in Drosophila.	('hm5C', 'Chemical', '-', (115, 119))	('Drosophila', 'Species', '7227', (170, 180))	('activation', 'PosReg', (156, 166))	('hm5C', 'Var', (115, 119))	('translation', 'MPA', (144, 155))	('m5C', 'Chemical', '-', (116, 119))	('m5C', 'Chemical', '-', (24, 27))
458599	32303268	Subsequently, after exploring several intestinal mRNAs, it was revealed that the protein level is altered by C-to-U editing of RNA.	('U', 'Chemical', 'MESH:D014529', (114, 115))	('RNA', 'Gene', (127, 130))	('protein level', 'MPA', (81, 94))	('C-to-U editing', 'Var', (109, 123))	('altered', 'Reg', (98, 105))
458603	32303268	It was revealed that by escaping the suppression mediated by IFN-induced proteins with tetratricopeptide repeats (IFIT), 2'-O-Me-modifiedviral RNA disrupts native host antiviral responses.	("2'-O-Me", 'Chemical', '-', (121, 128))	('IFIT', 'Chemical', '-', (114, 118))	("2'-O-Me-modifiedviral", 'Var', (121, 142))	('disrupts', 'NegReg', (147, 155))
458605	32303268	This phenomenon hints at the hypothesis that 2'-O-Me has the potential to affect translation efficiency, which has previously been demonstrated in bacterial mRNA.	('translation efficiency', 'MPA', (81, 103))	("2'-O-Me", 'Var', (45, 52))	("2'-O-Me", 'Chemical', '-', (45, 52))	('affect', 'Reg', (74, 80))
458606	32303268	In acute myeloid leukaemia (AML), FTO decreases m6A abundance on ASB2 and RARA mRNA in several certain subtypes of AML, including t(11q23)/MLL rearrangements, t(15;17)/PML-RARA, FLT3-ITD, and/or NPM1 mutations.	('decreases', 'NegReg', (38, 47))	('MLL', 'Gene', (139, 142))	('AML', 'Disease', 'MESH:D015470', (115, 118))	('AML', 'Phenotype', 'HP:0004808', (28, 31))	('AML', 'Disease', (28, 31))	('acute myeloid leukaemia', 'Phenotype', 'HP:0004808', (3, 26))	('mutations', 'Var', (200, 209))	('RARA', 'Gene', (172, 176))	('AML', 'Phenotype', 'HP:0004808', (115, 118))	('m6A', 'Gene', '56339', (48, 51))	('AML', 'Disease', (115, 118))	('PML', 'Gene', (168, 171))	('NPM1', 'Gene', '4869', (195, 199))	('RARA', 'Gene', (74, 78))	('m6A', 'Gene', (48, 51))	('rearrangements', 'Var', (143, 157))	('FTO', 'Gene', '79068', (34, 37))	('abundance', 'MPA', (52, 61))	('acute myeloid leukaemia', 'Disease', (3, 26))	('FTO', 'Gene', (34, 37))	('ASB2', 'Gene', (65, 69))	('FLT3', 'Gene', (178, 182))	('PML', 'Gene', '5371', (168, 171))	('NPM1', 'Gene', (195, 199))	('ASB2', 'Gene', '51676', (65, 69))	('FLT3', 'Gene', '2322', (178, 182))	('RARA', 'Gene', '5914', (172, 176))	('myeloid leukaemia', 'Phenotype', 'HP:0012324', (9, 26))	('RARA', 'Gene', '5914', (74, 78))	('AML', 'Disease', 'MESH:D015470', (28, 31))	('acute myeloid leukaemia', 'Disease', 'MESH:D015470', (3, 26))	('MLL', 'Gene', '4297', (139, 142))
458609	32303268	According to the datasets from The Cancer Genome Atlas, nearly 10.5% of AML patients carry copy number variations (CNVs) of ALKBH5, which predicts poor prognosis and p53 mutations.	('AML', 'Disease', 'MESH:D015470', (72, 75))	('patients', 'Species', '9606', (76, 84))	('ALKBH5', 'Gene', (124, 130))	('AML', 'Phenotype', 'HP:0004808', (72, 75))	('AML', 'Disease', (72, 75))	('p53', 'Gene', (166, 169))	('copy number variations', 'Var', (91, 113))	('p53', 'Gene', '7157', (166, 169))	('Cancer', 'Phenotype', 'HP:0002664', (35, 41))	('Cancer', 'Disease', (35, 41))	('Cancer', 'Disease', 'MESH:D009369', (35, 41))	('ALKBH5', 'Gene', '54890', (124, 130))
458610	32303268	In gastric cancer (GC), METTL3 can cause m6A to accumulate on HDGF mRNA, which indicates proliferation and poor prognosis and enhances the stability of zinc finger MYM-type containing 1 (ZMYM1) mRNA so that it accelerates epithelial-mesenchymal transition (EMT) and metastasis.	('zinc finger MYM-type containing 1', 'Gene', '79830', (152, 185))	('m6A', 'Gene', '56339', (41, 44))	('gastric cancer', 'Phenotype', 'HP:0012126', (3, 17))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('METTL3', 'Var', (24, 30))	('ZMYM1', 'Gene', (187, 192))	('HDGF', 'Gene', '3068', (62, 66))	('gastric cancer', 'Disease', (3, 17))	('stability', 'MPA', (139, 148))	('zinc finger MYM-type containing 1', 'Gene', (152, 185))	('enhances', 'PosReg', (126, 134))	('ZMYM1', 'Gene', '79830', (187, 192))	('accelerates', 'PosReg', (210, 221))	('GC', 'Phenotype', 'HP:0012126', (19, 21))	('m6A', 'Gene', (41, 44))	('gastric cancer', 'Disease', 'MESH:D013274', (3, 17))	('HDGF', 'Gene', (62, 66))	('epithelial-mesenchymal', 'CPA', (222, 244))
458618	32303268	Furthermore, SUMOylated METTL3 promotes non-small-cell lung cancer (NSCLC) by diminishing the amount of m6A.	('lung cancer', 'Disease', 'MESH:D008175', (55, 66))	('NSCLC', 'Disease', 'MESH:D002289', (68, 73))	('m6A', 'Gene', '56339', (104, 107))	('METTL3', 'Gene', (24, 30))	('promotes', 'PosReg', (31, 39))	('SUMOylated', 'Var', (13, 23))	('lung cancer', 'Disease', (55, 66))	('lung cancer', 'Phenotype', 'HP:0100526', (55, 66))	('diminishing', 'NegReg', (78, 89))	('U', 'Chemical', 'MESH:D014529', (14, 15))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('m6A', 'Gene', (104, 107))	('NSCLC', 'Disease', (68, 73))
458624	32303268	Consequently, a high level of ALKBH5 predicts poor prognosis.	('high', 'Var', (16, 20))	('ALKBH5', 'Gene', (30, 36))	('ALKBH5', 'Gene', '54890', (30, 36))
458628	32303268	In prostate cancer, reduced YTHDF2 elevates m6A contents dramatically, which suppresses proliferation and migration.	('prostate cancer', 'Phenotype', 'HP:0012125', (3, 18))	('YTHDF2', 'Gene', '51441', (28, 34))	('reduced', 'Var', (20, 27))	('suppresses', 'NegReg', (77, 87))	('elevates', 'PosReg', (35, 43))	('m6A', 'Gene', (44, 47))	('YTHDF2', 'Gene', (28, 34))	('prostate cancer', 'Disease', (3, 18))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('m6A', 'Gene', '56339', (44, 47))	('prostate cancer', 'Disease', 'MESH:D011471', (3, 18))
458630	32303268	Aberrant m6A modification can also lead to carcinomas in the reproductive system.	('Aberrant', 'Var', (0, 8))	('m6A', 'Gene', (9, 12))	('modification', 'Var', (13, 25))	('carcinoma', 'Phenotype', 'HP:0030731', (43, 52))	('carcinomas', 'Disease', 'MESH:D009369', (43, 53))	('carcinomas', 'Phenotype', 'HP:0030731', (43, 53))	('m6A', 'Gene', '56339', (9, 12))	('lead to', 'Reg', (35, 42))	('carcinomas', 'Disease', (43, 53))
458635	32303268	In endometrial cancer, either mutated METTL14 or reduced METTL3 limits the expression of m6A.	('endometrial cancer', 'Phenotype', 'HP:0012114', (3, 21))	('reduced', 'NegReg', (49, 56))	('METTL14', 'Gene', (38, 45))	('endometrial cancer', 'Disease', 'MESH:D016889', (3, 21))	('endometrial cancer', 'Disease', (3, 21))	('mutated', 'Var', (30, 37))	('METTL14', 'Gene', '57721', (38, 45))	('limits', 'NegReg', (64, 70))	('m6A', 'Gene', (89, 92))	('METTL3', 'Gene', (57, 63))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('expression', 'MPA', (75, 85))	('m6A', 'Gene', '56339', (89, 92))
458637	32303268	Besides the regular cancers with high incidence referenced above, aberrant m6A modifications also play roles in sensory organs.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('sensory organs', 'Disease', (112, 126))	('play roles', 'Reg', (98, 108))	('m6A', 'Gene', (75, 78))	('aberrant', 'Var', (66, 74))	('cancers', 'Phenotype', 'HP:0002664', (20, 27))	('m6A', 'Gene', '56339', (75, 78))	('cancers', 'Disease', (20, 27))	('cancers', 'Disease', 'MESH:D009369', (20, 27))
458638	32303268	The fate of ocular melanoma can be modulated by m6A modifications.	('modifications', 'Var', (52, 65))	('melanoma', 'Phenotype', 'HP:0002861', (19, 27))	('m6A', 'Gene', '56339', (48, 51))	('ocular melanoma', 'Disease', 'MESH:D008545', (12, 27))	('ocular melanoma', 'Disease', (12, 27))	('ocular melanoma', 'Phenotype', 'HP:0007716', (12, 27))	('m6A', 'Gene', (48, 51))	('modulated', 'Reg', (35, 44))
458639	32303268	With the help of YTHDF1, the translation of methylated HINT2 mRNA, a tumour suppressor of ocular melanoma, was significantly accelerated, meaning m6A modification obviously inhibits the progression of ocular melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (97, 105))	('ocular melanoma', 'Disease', (90, 105))	('translation', 'MPA', (29, 40))	('melanoma', 'Phenotype', 'HP:0002861', (208, 216))	('tumour', 'Phenotype', 'HP:0002664', (69, 75))	('ocular melanoma', 'Disease', (201, 216))	('tumour', 'Disease', 'MESH:D009369', (69, 75))	('HINT2', 'Gene', (55, 60))	('tumour', 'Disease', (69, 75))	('ocular melanoma', 'Phenotype', 'HP:0007716', (90, 105))	('YTHDF1', 'Gene', (17, 23))	('ocular melanoma', 'Phenotype', 'HP:0007716', (201, 216))	('inhibits', 'NegReg', (173, 181))	('accelerated', 'PosReg', (125, 136))	('HINT2', 'Gene', '84681', (55, 60))	('ocular melanoma', 'Disease', 'MESH:D008545', (90, 105))	('m6A', 'Gene', '56339', (146, 149))	('ocular melanoma', 'Disease', 'MESH:D008545', (201, 216))	('YTHDF1', 'Gene', '54915', (17, 23))	('methylated', 'Var', (44, 54))	('m6A', 'Gene', (146, 149))	('modification', 'Var', (150, 162))	('progression', 'CPA', (186, 197))
458641	32303268	In ovarian and breast cancers, demethylation of m1A by ALKBH3 induces increased modified CSF-1 mRNA, which contains m1A in the 5'UTR near the translation initiation site.	('modified', 'MPA', (80, 88))	('increased', 'PosReg', (70, 79))	('CSF-1', 'Gene', '1435', (89, 94))	('m1A', 'Chemical', '-', (116, 119))	('cancers', 'Phenotype', 'HP:0002664', (22, 29))	('ovarian and breast cancers', 'Disease', 'MESH:D001943', (3, 29))	('ALKBH3', 'Gene', (55, 61))	('breast cancers', 'Phenotype', 'HP:0003002', (15, 29))	('CSF-1', 'Gene', (89, 94))	('ALKBH3', 'Gene', '221120', (55, 61))	('m1A', 'Chemical', '-', (48, 51))	('U', 'Chemical', 'MESH:D014529', (129, 130))	('demethylation', 'Var', (31, 44))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('breast cancer', 'Phenotype', 'HP:0003002', (15, 28))
458644	32303268	Additionally, silencing of ALKBH3 arrests the cell cycle at the G1 phase and contributes to the progression, angiogenesis and invasion of urothelial carcinomas by modulating NADPH oxidase-2-reactive oxygen species (NOX-2-ROX) and TNF-like weak inducer of apoptosis (TWEAK)/Fibroblast growth factor-inducible 14 (Fn14)-VEGF signals.	('progression', 'CPA', (96, 107))	('NOX-2', 'Gene', '1536', (215, 220))	('silencing', 'Var', (14, 23))	('cell cycle at the G1 phase', 'CPA', (46, 72))	('ROX', 'Gene', '84864', (221, 224))	('NOX-2', 'Gene', (215, 220))	('Fn14', 'Gene', (312, 316))	('VEGF', 'Gene', '7422', (318, 322))	('NADPH oxidase-2', 'Gene', '1536', (174, 189))	('ROX', 'Gene', (221, 224))	('urothelial carcinomas', 'Disease', 'MESH:D014523', (138, 159))	('carcinoma', 'Phenotype', 'HP:0030731', (149, 158))	('carcinomas', 'Phenotype', 'HP:0030731', (149, 159))	('angiogenesis', 'CPA', (109, 121))	('ALKBH3', 'Gene', '221120', (27, 33))	('VEGF', 'Gene', (318, 322))	('TNF-like weak inducer of apoptosis (TWEAK)', 'Gene', '8742', (230, 272))	('arrests', 'NegReg', (34, 41))	('contributes', 'Reg', (77, 88))	('ALKBH3', 'Gene', (27, 33))	('oxygen', 'Chemical', 'MESH:D010100', (199, 205))	('invasion', 'CPA', (126, 134))	('urothelial carcinomas', 'Disease', (138, 159))	('Fn14', 'Gene', '51330', (312, 316))	('modulating', 'Reg', (163, 173))	('TNF-like weak inducer of apoptosis (TWEAK', 'Gene', (230, 271))	('NADPH oxidase-2', 'Gene', (174, 189))
458647	32303268	For instance, diminishing NSUN2 leads to decreased levels of translation and an increased tumour initiating population in skin cancer.	('levels of translation', 'MPA', (51, 72))	('NSUN2', 'Gene', '54888', (26, 31))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('skin cancer', 'Phenotype', 'HP:0008069', (122, 133))	('decreased', 'NegReg', (41, 50))	('skin cancer', 'Disease', (122, 133))	('increased', 'PosReg', (80, 89))	('tumour', 'Phenotype', 'HP:0002664', (90, 96))	('skin cancer', 'Disease', 'MESH:D012878', (122, 133))	('tumour', 'Disease', 'MESH:D009369', (90, 96))	('NSUN2', 'Gene', (26, 31))	('tumour', 'Disease', (90, 96))	('diminishing', 'Var', (14, 25))
458649	32303268	For patients with urothelial carcinoma of the bladder (UCB), m5C-modified 3'UTR in HDGF mRNA can be recognized by YBX1 and activate the oncogene of UCB.	('U', 'Chemical', 'MESH:D014529', (55, 56))	('U', 'Chemical', 'MESH:D014529', (148, 149))	('carcinoma', 'Phenotype', 'HP:0030731', (29, 38))	('HDGF', 'Gene', '3068', (83, 87))	('UCB', 'Gene', (148, 151))	('YBX1', 'Gene', (114, 118))	('urothelial carcinoma of the bladder', 'Disease', 'MESH:D001749', (18, 53))	('urothelial carcinoma of the bladder', 'Disease', (18, 53))	('m5C', 'Chemical', '-', (61, 64))	('patients', 'Species', '9606', (4, 12))	('U', 'Chemical', 'MESH:D014529', (76, 77))	('m5C-modified', 'Var', (61, 73))	('YBX1', 'Gene', '4904', (114, 118))	('HDGF', 'Gene', (83, 87))	('oncogene', 'Pathway', (136, 144))	('activate', 'PosReg', (123, 131))
458650	32303268	m5C can also be regarded as a cancer biomarker because the amount of m5C RNA modification is increased in circulating tumour cells from patients with lung cancer.	('m5C', 'Var', (69, 72))	('lung cancer', 'Phenotype', 'HP:0100526', (150, 161))	('tumour', 'Disease', (118, 124))	('amount', 'MPA', (59, 65))	('lung cancer', 'Disease', (150, 161))	('increased', 'PosReg', (93, 102))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('cancer', 'Disease', (30, 36))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('lung cancer', 'Disease', 'MESH:D008175', (150, 161))	('patients', 'Species', '9606', (136, 144))	('tumour', 'Phenotype', 'HP:0002664', (118, 124))	('tumour', 'Disease', 'MESH:D009369', (118, 124))	('m5C', 'Chemical', '-', (0, 3))	('cancer', 'Disease', (155, 161))	('cancer', 'Disease', 'MESH:D009369', (155, 161))	('m5C', 'Chemical', '-', (69, 72))
458653	32303268	Regarded as the gene encoding the Psi synthase, the mutation of DKC1 causes downregulated Psi and X-linked dyskeratosis congenita (X-DC).	('Psi and X-linked dyskeratosis congenita', 'Disease', 'MESH:D019871', (90, 129))	('DKC1', 'Gene', (64, 68))	('downregulated', 'NegReg', (76, 89))	('DKC1', 'Gene', '1736', (64, 68))	('mutation', 'Var', (52, 60))
458654	32303268	The risk for cancer development is higher in patients with X-DC than those without gene mutation.	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('X-DC', 'Var', (59, 63))	('cancer', 'Disease', (13, 19))	('cancer', 'Disease', 'MESH:D009369', (13, 19))	('patients', 'Species', '9606', (45, 53))
458656	32303268	Subsequently, edited AZIN1 stimulates a serine to glycine (S/G) conversion in HCC and leads to proliferation and poor prognosis.	('AZIN1', 'Gene', (21, 26))	('HCC', 'Gene', (78, 81))	('serine', 'Chemical', 'MESH:D012694', (40, 46))	('HCC', 'Gene', '619501', (78, 81))	('edited', 'Var', (14, 20))	('stimulates', 'PosReg', (27, 37))	('leads to', 'Reg', (86, 94))	('HCC', 'Phenotype', 'HP:0001402', (78, 81))	('glycine', 'Chemical', 'MESH:D005998', (50, 57))	('proliferation', 'CPA', (95, 108))	('AZIN1', 'Gene', '51582', (21, 26))
458657	32303268	In HCC and in cervical cancer, increased editing of BLCAP activates the AKT/mTOR signalling pathway or STAT3, which can increase cell proliferation and limit apoptosis.	('BLCAP', 'Gene', '10904', (52, 57))	('mTOR', 'Gene', (76, 80))	('STAT3', 'Gene', (103, 108))	('AKT', 'Gene', (72, 75))	('apoptosis', 'CPA', (158, 167))	('cancer', 'Disease', 'MESH:D009369', (23, 29))	('STAT3', 'Gene', '6774', (103, 108))	('cell proliferation', 'CPA', (129, 147))	('mTOR', 'Gene', '2475', (76, 80))	('BLCAP', 'Gene', (52, 57))	('limit', 'NegReg', (152, 157))	('AKT', 'Gene', '207', (72, 75))	('cancer', 'Disease', (23, 29))	('HCC', 'Gene', '619501', (3, 6))	('HCC', 'Phenotype', 'HP:0001402', (3, 6))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('activates', 'PosReg', (58, 67))	('HCC', 'Gene', (3, 6))	('editing', 'Var', (41, 48))	('increase', 'PosReg', (120, 128))
458658	32303268	In breast cancer, editing of DHFR transcripts at the 3'UTR by ADAR1 stabilizes the mRNA and enhances cell growth.	('U', 'Chemical', 'MESH:D014529', (55, 56))	('stabilizes', 'MPA', (68, 78))	('DHFR', 'Gene', (29, 33))	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('DHFR', 'Gene', '1719', (29, 33))	('cell growth', 'CPA', (101, 112))	('enhances', 'PosReg', (92, 100))	('breast cancer', 'Disease', (3, 16))	('ADAR1', 'Gene', (62, 67))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('ADAR1', 'Gene', '103', (62, 67))	('editing', 'Var', (18, 25))	('mRNA', 'MPA', (83, 87))
458660	32303268	It is suggests that downregulated ADAR1 can contribute to methotrexate treatment.	('ADAR1', 'Gene', (34, 39))	('methotrexate', 'Chemical', 'MESH:D008727', (58, 70))	('ADAR1', 'Gene', '103', (34, 39))	('contribute', 'Reg', (44, 54))	('downregulated', 'Var', (20, 33))	('methotrexate', 'Disease', (58, 70))
458661	32303268	In gastric cancer, ADAR2 edits the CDS of PODXL, which induces a histidine to arginine conversion.	('arginine', 'Chemical', 'MESH:D001120', (78, 86))	('PODXL', 'Gene', '5420', (42, 47))	('gastric cancer', 'Phenotype', 'HP:0012126', (3, 17))	('ADAR2', 'Gene', '104', (19, 24))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('PODXL', 'Gene', (42, 47))	('gastric cancer', 'Disease', 'MESH:D013274', (3, 17))	('induces', 'Reg', (55, 62))	('edits', 'Var', (25, 30))	('histidine', 'Chemical', 'MESH:D006639', (65, 74))	('gastric cancer', 'Disease', (3, 17))	('histidine to arginine conversion', 'MPA', (65, 97))	('ADAR2', 'Gene', (19, 24))
458737	29984070	performed NGS of 6 gastroenteropancreatic MiNEN tumors and found common driver mutations in each of the 2 tumor components.	('tumor', 'Disease', (48, 53))	('gastroenteropancreatic MiNEN tumors', 'Disease', (19, 54))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('mutations', 'Var', (79, 88))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('gastroenteropancreatic MiNEN tumors', 'Disease', 'MESH:C535650', (19, 54))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('tumor', 'Disease', (106, 111))
458738	29984070	Well-recognized mutations, such as mutations in p53 and KRAS, were present in both the neuroendocrine and adenocarcinoma components.	('p53', 'Gene', (48, 51))	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('p53', 'Gene', '7157', (48, 51))	('KRAS', 'Gene', (56, 60))	('KRAS', 'Gene', '3845', (56, 60))	('adenocarcinoma component', 'Disease', (106, 130))	('present', 'Reg', (67, 74))	('adenocarcinoma component', 'Disease', 'MESH:D000230', (106, 130))	('neuroendocrine and adenocarcinoma', 'Disease', 'MESH:D018358', (87, 120))	('mutations', 'Var', (35, 44))
458739	29984070	We present a pathway for tumor differentiation based on the mutations discovered in our case (Fig.	('mutations', 'Var', (60, 69))	('tumor', 'Disease', (25, 30))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))
458740	29984070	The neuroendocrine component contained both CDK6 and TOP2A amplification, which are commonly detected in carcinomas of neuroendocrine origin from various organ types, while the squamous component contained an amplification in TERC, which is a common finding in squamous cell carcinoma with different tissues of origin.	('carcinoma', 'Phenotype', 'HP:0030731', (275, 284))	('squamous cell carcinoma', 'Disease', (261, 284))	('CDK6', 'Gene', (44, 48))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (261, 284))	('carcinomas of neuroendocrine', 'Disease', 'MESH:D018278', (105, 133))	('CDK6', 'Gene', '1021', (44, 48))	('neuroendocrine component', 'Disease', 'MESH:D018358', (4, 28))	('TERC', 'Gene', (226, 230))	('TOP2A', 'Gene', '7153', (53, 58))	('TERC', 'Gene', '7012', (226, 230))	('TOP2A', 'Gene', (53, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('amplification', 'Var', (59, 72))	('carcinomas of neuroendocrine', 'Disease', (105, 133))	('carcinomas', 'Phenotype', 'HP:0030731', (105, 115))	('neuroendocrine component', 'Disease', (4, 28))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (261, 284))
458744	29984070	In addition, mutations in either NF1 or PTEN have FDA-approved therapies in other tumor types.	('NF1', 'Gene', (33, 36))	('PTEN', 'Gene', (40, 44))	('PTEN', 'Gene', '5728', (40, 44))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('NF1', 'Gene', '4763', (33, 36))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('mutations', 'Var', (13, 22))	('tumor', 'Disease', (82, 87))
458746	29984070	Everolimus is an mTOR inhibitor that is FDA approved for neuroendocrine tumors, and either inactivating mutations in PTEN or NF1 have predicted response to mTOR inhibitors in various tumor models.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('PTEN', 'Gene', (117, 121))	('neuroendocrine tumors', 'Disease', (57, 78))	('mTOR', 'Gene', '2475', (156, 160))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('inactivating mutations', 'Var', (91, 113))	('mTOR', 'Gene', (17, 21))	('NF1', 'Gene', '4763', (125, 128))	('PTEN', 'Gene', '5728', (117, 121))	('response', 'MPA', (144, 152))	('mTOR', 'Gene', '2475', (17, 21))	('neuroendocrine tumors', 'Disease', 'MESH:D018358', (57, 78))	('NF1', 'Gene', (125, 128))	('tumor', 'Disease', (72, 77))	('tumor', 'Disease', (183, 188))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('predicted', 'Reg', (134, 143))	('neuroendocrine tumor', 'Phenotype', 'HP:0100634', (57, 77))	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (57, 78))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('mTOR', 'Gene', (156, 160))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('Everolimus', 'Chemical', 'MESH:D000068338', (0, 10))
458747	29984070	Further development of the database of mutations in such tumors will provide potential targets for future treatments.	('mutations', 'Var', (39, 48))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('tumors', 'Disease', (57, 63))	('tumors', 'Disease', 'MESH:D009369', (57, 63))
458758	26156831	Survival duration of esophageal adenocarcinoma did not significantly differ between patients with high CA9 expression and those with low expression.	('patients', 'Species', '9606', (84, 92))	('high', 'Var', (98, 102))	('carcinoma', 'Phenotype', 'HP:0030731', (37, 46))	('esophageal adenocarcinoma', 'Disease', (21, 46))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (21, 46))	('CA9', 'Protein', (103, 106))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (21, 46))
458759	26156831	High CA9 expression is significantly associated with BMI1, cyclin E, Ki67, MCM4 and MCM7 expression.	('High', 'Var', (0, 4))	('BMI1', 'Gene', (53, 57))	('MCM4', 'Gene', '4173', (75, 79))	('BMI1', 'Gene', '648', (53, 57))	('expression', 'MPA', (9, 19))	('cyclin', 'MPA', (59, 65))	('MCM7', 'Gene', '4176', (84, 88))	('associated', 'Reg', (37, 47))	('MCM4', 'Gene', (75, 79))	('MCM7', 'Gene', (84, 88))
458769	26156831	Inhibition of CA9 has been shown to slow tumor growth, inhibit metastasis, and decrease tumor stem cells in mice.	('slow', 'NegReg', (36, 40))	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('metastasis', 'CPA', (63, 73))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('tumor', 'Disease', (41, 46))	('CA9', 'Gene', (14, 17))	('decrease', 'NegReg', (79, 87))	('mice', 'Species', '10090', (108, 112))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('Inhibition', 'Var', (0, 10))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('tumor', 'Disease', (88, 93))	('inhibit', 'NegReg', (55, 62))
458773	26156831	Mutations of the common prolyl hydroxylation and pVHL binding domain lead to the loss of CA9 mRNA, and protein.	('VHL', 'Gene', (50, 53))	('VHL', 'Gene', '7428', (50, 53))	('protein', 'Protein', (103, 110))	('Mutations', 'Var', (0, 9))	('loss', 'NegReg', (81, 85))	('CA9 mRNA', 'MPA', (89, 97))
458777	26156831	Amplification and overexpression of cyclin E have been reported in various cancers.	('Amplification', 'Var', (0, 13))	('cancers', 'Disease', 'MESH:D009369', (75, 82))	('cancers', 'Phenotype', 'HP:0002664', (75, 82))	('reported', 'Reg', (55, 63))	('cancers', 'Disease', (75, 82))	('cyclin E', 'Protein', (36, 44))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('overexpression', 'PosReg', (18, 32))
458783	26156831	In current study, we first explored the relationship of CA9 high expression with gastroesophageal reflux disease including columnar cell metaplasia, Barrett's esophagus, low-and high-grade dysplasia.	("Barrett's esophagus", 'Disease', (149, 168))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (149, 168))	('dysplasia', 'Disease', 'MESH:D004476', (189, 198))	('high expression', 'Var', (60, 75))	('gastroesophageal reflux disease', 'Disease', (81, 112))	('columnar cell metaplasia', 'Disease', (123, 147))	('gastroesophageal reflux', 'Phenotype', 'HP:0002020', (81, 104))	('gastroesophageal reflux disease', 'Disease', 'MESH:D005764', (81, 112))	('CA9', 'Gene', (56, 59))	('columnar cell metaplasia', 'Disease', 'MESH:D008679', (123, 147))	('dysplasia', 'Disease', (189, 198))
458798	26156831	After endogenous peroxidase activity was quenched and nonspecific binding was blocked, the sections were incubated with mouse monoclonal anti-CA9 (1:200; Thermo Fisher Scientific Pierce, Rockford, IL), anti-BMI1 (1:100; EMD Millipore, Billerica, MA), anti-cyclin E (1:100; Santa Cruz Biotechnology, Santa Cruz, CA), anti-MCM4 (1:50; Santa Cruz, CA), anti-MCM7 (1:50; Santa Cruz, CA) at 4  C overnight, and anti-Ki67 (1:100; Santa Cruz, CA) at room temperature for 20 min.	('MCM7', 'Gene', '4176', (355, 359))	('MCM4', 'Gene', '4173', (321, 325))	('1:50;', 'Var', (327, 332))	('1:50;', 'Var', (361, 366))	('MCM7', 'Gene', (355, 359))	('BMI1', 'Gene', '648', (207, 211))	('MCM4', 'Gene', (321, 325))	('BMI1', 'Gene', (207, 211))	('mouse', 'Species', '10090', (120, 125))
458805	26156831	Kaplan-Meier survival analysis and the log-rank test were used to analyze overall survival between the high CA9 expression group and the low CA9 expression group in esophageal adenocarcinoma.	('esophageal adenocarcinoma', 'Disease', (165, 190))	('high CA9', 'Var', (103, 111))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (165, 190))	('carcinoma', 'Phenotype', 'HP:0030731', (181, 190))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (165, 190))
458808	26156831	High CA9 expression occurred predominantly in columnar cell lesions but was rare or absent in squamous cell carcinoma and squamous epithelium (Fig.	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('High', 'Var', (0, 4))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (94, 117))	('squamous cell carcinoma', 'Disease', (94, 117))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (94, 117))	('columnar cell lesions', 'Disease', (46, 67))	('expression', 'MPA', (9, 19))	('occurred', 'Reg', (20, 28))
458809	26156831	We intended to analyze the association of high CA9 expression with clinicopathologic features in the esophageal adenocarcinoma and squamous cell carcinoma groups.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (131, 154))	('esophageal adenocarcinoma', 'Disease', (101, 126))	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('carcinoma', 'Phenotype', 'HP:0030731', (145, 154))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (101, 126))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (131, 154))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (101, 126))	('squamous cell carcinoma', 'Disease', (131, 154))	('expression', 'MPA', (51, 61))	('high', 'Var', (42, 46))
458813	26156831	The odds of high CA9 expression were 2.8 times higher in men than in women.	('high', 'Var', (12, 16))	('CA9', 'Protein', (17, 20))	('men', 'Species', '9606', (71, 74))	('expression', 'MPA', (21, 31))	('men', 'Species', '9606', (57, 60))	('women', 'Species', '9606', (69, 74))
458817	26156831	The median survival duration for patients with esophageal adenocarcinoma in the high CA9 expression group was 20 months, with a mean survival of 40 months.	('patients', 'Species', '9606', (33, 41))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (47, 72))	('esophageal adenocarcinoma', 'Disease', (47, 72))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (47, 72))	('high CA9 expression', 'Var', (80, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))
458819	26156831	The survival duration did not significantly differ between patients with high CA9 expression and low CA9 expression (P = .8488).	('CA9', 'Protein', (78, 81))	('CA9', 'Protein', (101, 104))	('patients', 'Species', '9606', (59, 67))	('high', 'Var', (73, 77))	('expression', 'MPA', (105, 115))	('low', 'NegReg', (97, 100))
458820	26156831	The rate of high CA9 expression was statistically associated with BMI1, cyclin E high expression and MCM4, MCM7 and Ki67 expression (P < .001) with Pearson correlation method.	('CA9', 'Gene', (17, 20))	('high', 'Var', (12, 16))	('MCM7', 'Gene', '4176', (107, 111))	('cyclin', 'Protein', (72, 78))	('BMI1', 'Gene', '648', (66, 70))	('MCM4', 'Gene', (101, 105))	('expression', 'MPA', (21, 31))	('high', 'PosReg', (81, 85))	('MCM7', 'Gene', (107, 111))	('BMI1', 'Gene', (66, 70))	('MCM4', 'Gene', '4173', (101, 105))
458824	26156831	However, high CA9 expression was significantly more frequent in glandular lesions than in squamous epithelium (0 %) and squamous cell carcinoma (9 %).	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (120, 143))	('high', 'Var', (9, 13))	('CA9', 'Protein', (14, 17))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('expression', 'MPA', (18, 28))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (120, 143))	('squamous cell carcinoma', 'Disease', (120, 143))	('glandular lesions', 'Disease', (64, 81))
458829	26156831	CA9 is a well-known hypoxic indicator and plays an important role in maintaining the intracellular pH despite increased extracellular acidosis, thereby promoting cancer cell survival and growth in hypoxic-acidic environments.	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('men', 'Species', '9606', (219, 222))	('cancer', 'Disease', (162, 168))	('acidosis', 'Disease', 'MESH:D000138', (134, 142))	('promoting', 'PosReg', (152, 161))	('CA9', 'Var', (0, 3))	('increased', 'PosReg', (110, 119))	('intracellular pH', 'MPA', (85, 101))	('growth', 'CPA', (187, 193))	('acidosis', 'Phenotype', 'HP:0001941', (134, 142))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('hypoxic-acidic', 'Disease', (197, 211))	('hypoxic-acidic', 'Disease', 'MESH:D000326', (197, 211))	('acidosis', 'Disease', (134, 142))
458834	26156831	In our study, the rate of high CA9 expression was very high in esophageal adenocarcinoma (90 %) and precancerous lesions (74 %-94 %) but was very low in esophageal squamous cell carcinoma (9 %).	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (63, 88))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('high', 'Var', (26, 30))	('expression', 'MPA', (35, 45))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (153, 187))	('CA9', 'Protein', (31, 34))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (63, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (178, 187))	('precancerous lesions', 'Disease', 'MESH:D011230', (100, 120))	('esophageal adenocarcinoma', 'Disease', (63, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (164, 187))	('precancerous lesions', 'Disease', (100, 120))	('esophageal squamous cell carcinoma', 'Disease', (153, 187))
458843	26156831	Many studies have shown that CA9 high expression is associated with worse prognosis in solid tumors than lower or no CA9 expression in them.	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('high expression', 'Var', (33, 48))	('solid tumors', 'Disease', (87, 99))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('CA9', 'Gene', (29, 32))	('solid tumors', 'Disease', 'MESH:D009369', (87, 99))
458845	26156831	Additionally, the high CA9 expression was not associated with clinicopathologic features such as age, lymph node metastasis, tumor stage, and prognosis but was significantly associated with male sex (P = .0011).	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('associated', 'Reg', (174, 184))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('expression', 'MPA', (27, 37))	('tumor', 'Disease', (125, 130))	('male sex', 'Disease', (190, 198))	('high', 'Var', (18, 22))	('CA9', 'Protein', (23, 26))
458848	26156831	Inhibition of CA9 with sulfonamide and/or coumarin inhibitors was recently shown to lead to a potent retardation for the growth of both primary tumors and metastases.	('tumors', 'Disease', (144, 150))	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('growth', 'CPA', (121, 127))	('retardation', 'Disease', (101, 112))	('coumarin', 'Chemical', 'MESH:C030123', (42, 50))	('tumors', 'Disease', 'MESH:D009369', (144, 150))	('metastases', 'Disease', 'MESH:D009362', (155, 165))	('retardation', 'Disease', 'MESH:D008607', (101, 112))	('sulfonamide', 'Chemical', 'MESH:D013449', (23, 34))	('Inhibition', 'Var', (0, 10))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('metastases', 'Disease', (155, 165))
458858	26156831	Our findings of the significant association of high CA9 expression with BMI1 imply that CA9 may be involved in esophageal tumorigenesis through esophageal stem cells.	('BMI1', 'Gene', (72, 76))	('high', 'Var', (47, 51))	('involved', 'Reg', (99, 107))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('BMI1', 'Gene', '648', (72, 76))	('expression', 'MPA', (56, 66))	('CA9', 'Gene', (52, 55))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumor', 'Disease', (122, 127))
458859	26156831	High CA9 expression was significantly associated with cyclin E expression in esophageal adenocarcinoma and precancerous lesions.	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('associated', 'Reg', (38, 48))	('High', 'Var', (0, 4))	('precancerous lesions', 'Disease', (107, 127))	('cyclin E expression', 'MPA', (54, 73))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (77, 102))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('esophageal adenocarcinoma', 'Disease', (77, 102))	('expression', 'MPA', (9, 19))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (77, 102))	('precancerous lesions', 'Disease', 'MESH:D011230', (107, 127))
458861	26156831	High CA9 expression was significantly associated with MCM4, MCM7 and Ki67 expression in esophageal adenocarcinoma and precancerous lesions.	('associated', 'Reg', (38, 48))	('precancerous lesions', 'Disease', (118, 138))	('High', 'Var', (0, 4))	('MCM4', 'Gene', '4173', (54, 58))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (88, 113))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('esophageal adenocarcinoma', 'Disease', (88, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('MCM7', 'Gene', '4176', (60, 64))	('precancerous lesions', 'Disease', 'MESH:D011230', (118, 138))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (88, 113))	('expression', 'MPA', (9, 19))	('MCM4', 'Gene', (54, 58))	('Ki67', 'Gene', (69, 73))	('CA9', 'Gene', (5, 8))	('MCM7', 'Gene', (60, 64))
458862	26156831	However, the correlation was low (r = .1388) with Ki67 and relative higher (r = .2946; r = .3106) with MCM4 and MCM7.	('MCM7', 'Gene', (112, 116))	('MCM4', 'Gene', (103, 107))	('correlation', 'Interaction', (13, 24))	('low', 'NegReg', (29, 32))	('higher', 'PosReg', (68, 74))	('MCM7', 'Gene', '4176', (112, 116))	('MCM4', 'Gene', '4173', (103, 107))	('Ki67', 'Var', (50, 54))
458881	24995504	In the canonical pathway, ligation of cytokines to their respective cell-surface receptors induces dimerization and auto-phosphorylation of various tyrosine residues of Janus kinases (JAKs), which then serve as the docking sites for the inactive, monomeric STAT3 molecules.	('JAKs', 'Gene', '16451;3717;16452', (184, 188))	('tyrosine', 'Chemical', 'MESH:D014443', (148, 156))	('dimerization', 'MPA', (99, 111))	('auto-phosphorylation', 'MPA', (116, 136))	('ligation', 'Var', (26, 34))	('JAKs', 'Gene', (184, 188))	('induces', 'Reg', (91, 98))
458888	24995504	STAT3C contains two cysteine substitutions at the residues A661 and N663, leading to the formation of disulfide bridges between two STAT3 molecules and mimicking STAT3 homodimerization that occurs in the normal activation process.	('STAT3 homodimerization', 'MPA', (162, 184))	('A661', 'Var', (59, 63))	('formation of disulfide bridges', 'MPA', (89, 119))	('disulfide', 'Chemical', 'MESH:D004220', (102, 111))	('N663', 'Var', (68, 72))	('cysteine', 'Chemical', 'MESH:D003545', (20, 28))
458889	24995504	It has been demonstrated that STAT3C can effectively induce malignant transformation, and that STATC can transcriptionally increase the expression of many genes that are important in promoting cellular proliferation, resistance to apoptosis, angiogenesis, immune evasion, invasion and metastasis, all of which are hallmarks of cancer.	('metastasis', 'CPA', (285, 295))	('angiogenesis', 'CPA', (242, 254))	('expression', 'MPA', (136, 146))	('STATC', 'Var', (95, 100))	('cancer', 'Disease', (327, 333))	('cancer', 'Disease', 'MESH:D009369', (327, 333))	('STAT3C', 'Var', (30, 36))	('cellular proliferation', 'CPA', (193, 215))	('cancer', 'Phenotype', 'HP:0002664', (327, 333))	('promoting', 'PosReg', (183, 192))	('malignant transformation', 'CPA', (60, 84))	('increase', 'PosReg', (123, 131))	('induce', 'Reg', (53, 59))	('invasion', 'CPA', (272, 280))	('resistance to apoptosis', 'CPA', (217, 240))	('immune evasion', 'MPA', (256, 270))
458893	24995504	To reinforce the concept that STAT3 is oncogenic when it is inappropriately or constitutively activated, many laboratories have shown that the dominant negative STAT3 mutant construct, often labeled STAT3-DN in the literature, can effectively mediate cell cycle arrest and/or induce apoptosis in cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (296, 302))	('mediate', 'Reg', (243, 250))	('apoptosis', 'CPA', (283, 292))	('cell cycle arrest', 'CPA', (251, 268))	('negative', 'NegReg', (152, 160))	('mutant', 'Var', (167, 173))	('cancer', 'Disease', 'MESH:D009369', (296, 302))	('STAT3', 'Gene', (161, 166))	('min', 'Gene', (145, 148))	('cancer', 'Disease', (296, 302))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (251, 268))	('induce', 'PosReg', (276, 282))	('min', 'Gene', '11789', (145, 148))
458908	24995504	In this regard, epigenetic silencing of SOCS3 has been found in various types of cancer, including lung cancer, head and neck squamous cell carcinoma, hepatocellular carcinoma and Barrett-associated esophageal adenocarcinoma.	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (151, 175))	('cancer', 'Disease', (81, 87))	('neck squamous cell carcinoma', 'Disease', (121, 149))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (121, 149))	('esophageal adenocarcinoma', 'Disease', (199, 224))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('cancer', 'Disease', (104, 110))	('hepatocellular carcinoma', 'Disease', (151, 175))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('carcinoma', 'Phenotype', 'HP:0030731', (166, 175))	('SOCS3', 'Gene', (40, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (215, 224))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (126, 149))	('lung cancer', 'Disease', (99, 110))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('SOCS3', 'Gene', '12702', (40, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (151, 175))	('found', 'Reg', (55, 60))	('lung cancer', 'Disease', 'MESH:D008175', (99, 110))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (199, 224))	('epigenetic silencing', 'Var', (16, 36))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (199, 224))	('lung cancer', 'Phenotype', 'HP:0100526', (99, 110))
458909	24995504	Experimental results have revealed that loss of SOCS3 indeed contributes to the activation of STAT3 in cancer cells, thereby promoting their proliferation, survival and motility.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('promoting', 'PosReg', (125, 134))	('STAT3', 'Gene', (94, 99))	('motility', 'CPA', (169, 177))	('loss', 'Var', (40, 44))	('proliferation', 'CPA', (141, 154))	('SOCS3', 'Gene', '12702', (48, 53))	('survival', 'CPA', (156, 164))	('SOCS3', 'Gene', (48, 53))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('activation', 'PosReg', (80, 90))
458910	24995504	SOCS1, another member of the SOCS family, is also frequently silenced by gene methylation, and this biochemical aberrancy has been shown to contribute to constitutive STAT3 activation in a wide range of cancer types.	('methylation', 'Var', (78, 89))	('activation', 'PosReg', (173, 183))	('cancer', 'Disease', (203, 209))	('cancer', 'Disease', 'MESH:D009369', (203, 209))	('constitutive STAT3', 'MPA', (154, 172))	('silenced', 'NegReg', (61, 69))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('SOCS1', 'Gene', (0, 5))
458914	24995504	For example, SHP-1, a member of the tyrosine phosphatases highly expressed in normal lymphoid cells, is lost in many types of hematologic malignancies due to epigenetic silencing.	('epigenetic silencing', 'Var', (158, 178))	('lost', 'NegReg', (104, 108))	('tyrosine', 'Chemical', 'MESH:D014443', (36, 44))	('SHP-1', 'Gene', (13, 18))	('hematologic malignancies', 'Disease', 'MESH:D019337', (126, 150))	('SHP-1', 'Gene', '15170', (13, 18))	('hematologic malignancies', 'Disease', (126, 150))
458915	24995504	Loss of SHP-1 has been shown to directly contribute to the constitutive activation of STAT3 in these cancer types, including ALK-positive anaplastic large cell lymphoma, chronic myeloid leukemia and multiple myeloma, since gene transfection of SHP1 in these cells can substantially decrease the level of STAT3 activation.	('multiple myeloma', 'Disease', 'MESH:D009101', (199, 215))	('anaplastic large cell lymphoma', 'Phenotype', 'HP:0012193', (138, 168))	('SHP1', 'Gene', '15170', (244, 248))	('ALK', 'Gene', (125, 128))	('chronic myeloid leukemia', 'Disease', (170, 194))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('lymphoma', 'Phenotype', 'HP:0002665', (160, 168))	('multiple myeloma', 'Disease', (199, 215))	('ALK', 'Gene', '11682', (125, 128))	('cell lymphoma', 'Phenotype', 'HP:0012191', (155, 168))	('SHP-1', 'Gene', '15170', (8, 13))	('decrease', 'NegReg', (282, 290))	('activation', 'PosReg', (72, 82))	('level', 'MPA', (295, 300))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (178, 194))	('leukemia', 'Phenotype', 'HP:0001909', (186, 194))	('Loss', 'Var', (0, 4))	('chronic myeloid leukemia', 'Phenotype', 'HP:0005506', (170, 194))	('chronic myeloid leukemia', 'Disease', 'MESH:D015464', (170, 194))	('SHP-1', 'Gene', (8, 13))	('multiple myeloma', 'Phenotype', 'HP:0006775', (199, 215))	('SHP1', 'Gene', (244, 248))	('cancer', 'Disease', (101, 107))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))
458917	24995504	Thus, loss of SHP-1 and the constitutive activation of STAT3 form a vicious cycle in these lymphoma cells.	('lymphoma', 'Phenotype', 'HP:0002665', (91, 99))	('loss', 'Var', (6, 10))	('STAT3', 'Gene', (55, 60))	('SHP-1', 'Gene', '15170', (14, 19))	('SHP-1', 'Gene', (14, 19))	('activation', 'PosReg', (41, 51))
458920	24995504	Transfection of PIAS3 into lung cancer cell lines can suppress cell proliferation and enhance the sensitivity of cells to chemotherapeutic drugs.	('PIAS3', 'Gene', '229615', (16, 21))	('enhance', 'PosReg', (86, 93))	('sensitivity of cells', 'CPA', (98, 118))	('lung cancer', 'Disease', (27, 38))	('lung cancer', 'Phenotype', 'HP:0100526', (27, 38))	('suppress', 'NegReg', (54, 62))	('cell proliferation', 'CPA', (63, 81))	('Transfection', 'Var', (0, 12))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('lung cancer', 'Disease', 'MESH:D008175', (27, 38))	('PIAS3', 'Gene', (16, 21))
458930	24995504	Normally, the activation status of Src is increased by de-phosphorylation of Y527 and phosphorylation of Y416.	('increased', 'PosReg', (42, 51))	('de-phosphorylation', 'MPA', (55, 73))	('Y527', 'Var', (77, 81))	('activation status', 'MPA', (14, 31))	('Y416', 'Chemical', '-', (105, 109))	('Src', 'Gene', '20779', (35, 38))	('phosphorylation', 'MPA', (86, 101))	('Src', 'Gene', (35, 38))	('Y416', 'Var', (105, 109))
458931	24995504	In cancer cells, de-phosphorylation of Y527 can be due to the activity of tyrosine phosphatases (such as PTP1B), Y527F mutation or deletion of Y527.	('Y527', 'Var', (39, 43))	('Y527', 'Gene', (143, 147))	('PTP1B', 'Gene', (105, 110))	('activity', 'MPA', (62, 70))	('tyrosine phosphatases', 'Enzyme', (74, 95))	('Y527F mutation', 'Var', (113, 127))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('tyrosine', 'Chemical', 'MESH:D014443', (74, 82))	('Y527F', 'Mutation', 'p.Y527F', (113, 118))	('cancer', 'Disease', (3, 9))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))	('de-phosphorylation', 'MPA', (17, 35))	('PTP1B', 'Gene', '19246', (105, 110))	('deletion', 'Var', (131, 139))
458932	24995504	Phosphorylation of Y416, which correlates with Src activation and its malignant transforming ability, can be found in cancer cells.	('cancer', 'Disease', (118, 124))	('Src', 'Gene', '20779', (47, 50))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('Src', 'Gene', (47, 50))	('min', 'Gene', (88, 91))	('Y416', 'Chemical', '-', (19, 23))	('min', 'Gene', '11789', (88, 91))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('Y416', 'Var', (19, 23))	('activation', 'PosReg', (51, 61))
458936	24995504	In one study, immortalized mouse embryonic fibroblasts with intact STAT3 expression were transformed by NPM-ALK, whereas STAT3 gene knockout dramatically decreased the malignant transformation by NPM-ALK.	('decreased', 'NegReg', (154, 163))	('malignant transformation', 'CPA', (168, 192))	('mouse', 'Species', '10090', (27, 32))	('NPM', 'Gene', '18148', (196, 199))	('NPM', 'Gene', (196, 199))	('ALK', 'Gene', '11682', (108, 111))	('NPM', 'Gene', '18148', (104, 107))	('STAT3', 'Gene', (67, 72))	('NPM', 'Gene', (104, 107))	('ALK', 'Gene', '11682', (200, 203))	('ALK', 'Gene', (108, 111))	('ALK', 'Gene', (200, 203))	('knockout', 'Var', (132, 140))
458937	24995504	Gain-of-function mutations involving JAKs have been implicated in activating STAT3 in specific types of cancer.	('JAKs', 'Gene', (37, 41))	('JAKs', 'Gene', '16451;3717;16452', (37, 41))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('activating', 'MPA', (66, 76))	('Gain-of-function', 'PosReg', (0, 16))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('STAT3', 'Gene', (77, 82))	('cancer', 'Disease', (104, 110))	('mutations', 'Var', (17, 26))
458938	24995504	JAK2-V617F and other JAK mutants are known to activate STAT3 and contribute to the pathogenesis of chronic myeloproliferative neoplasms and leukemias.	('chronic myeloproliferative neoplasms', 'Disease', (99, 135))	('leukemias', 'Disease', 'MESH:D007938', (140, 149))	('STAT3', 'Gene', (55, 60))	('chronic myeloproliferative neoplasms', 'Disease', 'MESH:D009196', (99, 135))	('leukemia', 'Phenotype', 'HP:0001909', (140, 148))	('myeloproliferative neoplasms', 'Phenotype', 'HP:0005547', (107, 135))	('V617F', 'SUBSTITUTION', 'None', (5, 10))	('JAK2', 'Gene', (0, 4))	('activate', 'PosReg', (46, 54))	('neoplasms', 'Phenotype', 'HP:0002664', (126, 135))	('leukemias', 'Disease', (140, 149))	('V617F', 'Var', (5, 10))	('leukemias', 'Phenotype', 'HP:0001909', (140, 149))	('contribute', 'Reg', (65, 75))	('JAK2', 'Gene', '16452', (0, 4))
458939	24995504	Mutations in the kinase domain of the epidermal growth factor receptor also have been reported to sustain STAT3 activation by promoting IL-6 production in lung cancer cells.	('promoting', 'PosReg', (126, 135))	('epidermal growth factor receptor', 'Gene', (38, 70))	('epidermal growth factor receptor', 'Gene', '13649', (38, 70))	('lung cancer', 'Disease', (155, 166))	('IL-6', 'Gene', (136, 140))	('IL-6', 'Gene', '16193', (136, 140))	('lung cancer', 'Phenotype', 'HP:0100526', (155, 166))	('Mutations in', 'Var', (0, 12))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('STAT3 activation', 'MPA', (106, 122))	('lung cancer', 'Disease', 'MESH:D008175', (155, 166))
458940	24995504	In glioblastoma, a constitutively active mutant of epidermal growth factor receptor was found, and this mutant contributes to and sustains STAT3 activation by inducing a cytokine circuit involving IL-6 and leukemia inhibitory factor, which in turn activates gp130 in the neighboring cells that harbor wild-type epidermal growth factor receptor, leading to an enhanced growth of the entire tumor.	('leukemia', 'Phenotype', 'HP:0001909', (206, 214))	('tumor', 'Phenotype', 'HP:0002664', (389, 394))	('leukemia inhibitory factor', 'Gene', (206, 232))	('inducing', 'Reg', (159, 167))	('epidermal growth factor receptor', 'Gene', '13649', (51, 83))	('gp130', 'Gene', '16195', (258, 263))	('enhanced', 'PosReg', (359, 367))	('epidermal growth factor receptor', 'Gene', '13649', (311, 343))	('IL-6', 'Gene', (197, 201))	('mutant', 'Var', (104, 110))	('STAT3 activation', 'MPA', (139, 155))	('glioblastoma', 'Disease', 'MESH:D005909', (3, 15))	('IL-6', 'Gene', '16193', (197, 201))	('tumor', 'Disease', (389, 394))	('epidermal growth factor receptor', 'Gene', (51, 83))	('glioblastoma', 'Disease', (3, 15))	('leukemia inhibitory factor', 'Gene', '16878', (206, 232))	('glioblastoma', 'Phenotype', 'HP:0012174', (3, 15))	('gp130', 'Gene', (258, 263))	('epidermal growth factor receptor', 'Gene', (311, 343))	('tumor', 'Disease', 'MESH:D009369', (389, 394))	('growth of the', 'CPA', (368, 381))	('cytokine circuit', 'MPA', (170, 186))
458949	24995504	Blocking this positive feedback loop in either cell types was shown to decrease tumor growth and metastasis.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('Blocking', 'Var', (0, 8))	('decrease', 'NegReg', (71, 79))	('tumor', 'Disease', (80, 85))
458951	24995504	In one study, pyruvate kinase M2 (PKM2), a protein that is known to be essential for the Warburg effect and proliferation of cancer cells, was found to activate STAT3 via catalyzing its phosphorylation at Y705.	('STAT3', 'MPA', (161, 166))	('Y705', 'Var', (205, 209))	('catalyzing', 'MPA', (171, 181))	('PKM2', 'Gene', (34, 38))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('pyruvate kinase M2', 'Gene', '18746', (14, 32))	('activate', 'PosReg', (152, 160))	('cancer', 'Disease', (125, 131))	('PKM2', 'Gene', '18746', (34, 38))	('phosphorylation', 'MPA', (186, 201))	('pyruvate kinase M2', 'Gene', (14, 32))
458956	24995504	Recently, somatic mutations in STAT3 were discovered in hepatocellular adenomas and many types of hematopoietic malignancies, such as T-cell large granular lymphocytic leukemia (T-cell LGL), chronic lymphoproliferative disorders of natural killer cells (CLPD-NKs), diffuse large B-cell lymphoma, and CD30+ T-cell lymphomas.	('granular lymphocytic leukemia', 'Disease', 'MESH:D054066', (147, 176))	('leukemia', 'Phenotype', 'HP:0001909', (168, 176))	('LGL', 'Gene', (185, 188))	('diffuse large B-cell lymphoma', 'Disease', (265, 294))	('lymphoproliferative disorders', 'Disease', (199, 228))	('hematopoietic malignancies', 'Disease', 'MESH:D019337', (98, 124))	('lymphomas', 'Disease', 'MESH:D008223', (313, 322))	('lymphoproliferative disorders', 'Disease', 'MESH:D008232', (199, 228))	('STAT3', 'Gene', (31, 36))	('hepatocellular adenomas', 'Disease', (56, 79))	('lymphomas', 'Phenotype', 'HP:0002665', (313, 322))	('lymphoma', 'Phenotype', 'HP:0002665', (286, 294))	('cell lymphoma', 'Phenotype', 'HP:0012191', (281, 294))	('CLPD-NKs', 'Disease', (254, 262))	('hepatocellular adenomas', 'Phenotype', 'HP:0012028', (56, 79))	('lymphomas', 'Disease', (313, 322))	('CD30', 'Gene', (300, 304))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (279, 294))	('granular lymphocytic leukemia', 'Disease', (147, 176))	('lymphoproliferative disorders', 'Phenotype', 'HP:0005523', (199, 228))	('hepatocellular adenomas', 'Disease', 'MESH:D018248', (56, 79))	('T-cell lymphomas', 'Phenotype', 'HP:0012190', (306, 322))	('CLPD-NKs', 'Disease', 'MESH:C531816', (254, 262))	('hematopoietic malignancies', 'Disease', (98, 124))	('CD30', 'Gene', '21941', (300, 304))	('cell lymphoma', 'Phenotype', 'HP:0012191', (308, 321))	('LGL', 'Gene', '16862', (185, 188))	('lymphoma', 'Phenotype', 'HP:0002665', (313, 321))	('mutations', 'Var', (18, 27))
458957	24995504	identified seven STAT3 mutations in 6/114 hepatocellular adenomas examined.	('STAT3', 'Gene', (17, 22))	('hepatocellular adenomas', 'Disease', 'MESH:D018248', (42, 65))	('hepatocellular adenomas', 'Disease', (42, 65))	('mutations', 'Var', (23, 32))	('hepatocellular adenomas', 'Phenotype', 'HP:0012028', (42, 65))	('min', 'Gene', (69, 72))	('min', 'Gene', '11789', (69, 72))
458958	24995504	Notably, all six of these tumors were inflammatory hepatocellular adenomas, suggesting the specificity of somatic STAT3 mutations for this type of hepatocellular tumor.	('hepatocellular tumor', 'Disease', (147, 167))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('hepatocellular adenomas', 'Disease', (51, 74))	('hepatocellular adenomas', 'Disease', 'MESH:D018248', (51, 74))	('STAT3', 'Gene', (114, 119))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('mutations', 'Var', (120, 129))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('hepatocellular tumor', 'Disease', 'MESH:D006528', (147, 167))	('hepatocellular adenomas', 'Phenotype', 'HP:0012028', (51, 74))	('hepatocellular tumor', 'Phenotype', 'HP:0001402', (147, 167))	('tumors', 'Disease', (26, 32))
458959	24995504	Somatic STAT3 mutations have also been shown to be frequent in T-cell LGL and CLPD-NKs.	('LGL', 'Gene', (70, 73))	('CLPD-NKs', 'Disease', (78, 86))	('CLPD-NKs', 'Disease', 'MESH:C531816', (78, 86))	('LGL', 'Gene', '16862', (70, 73))	('STAT3', 'Gene', (8, 13))	('frequent', 'Reg', (51, 59))	('mutations', 'Var', (14, 23))
458960	24995504	Four independent studies have revealed somatic STAT3 mutations in T-cell LGL, and the reported percentages of cases carrying STAT3 mutations were 4/36 (11%), 33/120 (28%), 31/77 (40%) and 40/55 (73%), respectively.	('LGL', 'Gene', (73, 76))	('STAT3', 'Gene', (47, 52))	('LGL', 'Gene', '16862', (73, 76))	('mutations', 'Var', (53, 62))
458961	24995504	Two independent studies in CLPD-NKs have described the finding of somatic STAT3 mutations occurring in 3/7 (43%) and 15/50 (30%) of the cases, respectively.	('STAT3', 'Gene', (74, 79))	('CLPD-NKs', 'Disease', 'MESH:C531816', (27, 35))	('CLPD-NKs', 'Disease', (27, 35))	('mutations', 'Var', (80, 89))
458962	24995504	It is notable that mutations in Y640 and D661 were shown to account for the vast majority of somatic mutations in the STAT3 gene in both T-cell LGL and CLPD-NKs, representing about 80% of all mutations detected.	('D661', 'Var', (41, 45))	('Y640', 'Var', (32, 36))	('mutations', 'Var', (19, 28))	('STAT3', 'Gene', (118, 123))	('CLPD-NKs', 'Disease', (152, 160))	('CLPD-NKs', 'Disease', 'MESH:C531816', (152, 160))	('LGL', 'Gene', '16862', (144, 147))	('LGL', 'Gene', (144, 147))
458963	24995504	Intriguingly, most of the STAT3 mutations discovered (e.g., Y640F, D661H, D661V, D661Y, and N647I) reside in the SH2 domain that normally directs STAT3 dimerization, and many of these mutations were suggested to induce amino acid changes that confer higher hydrophobicity to the STAT3 SH2 dimerization surface, potentially facilitating phosphorylation of STAT3Y705 and thus the activation of STAT3.	('facilitating', 'PosReg', (323, 335))	('N647I', 'Var', (92, 97))	('phosphorylation', 'MPA', (336, 351))	('D661H', 'Var', (67, 72))	('D661V', 'Mutation', 'p.D661V', (74, 79))	('mutations', 'Var', (32, 41))	('STAT3', 'MPA', (146, 151))	('D661H', 'Mutation', 'p.D661H', (67, 72))	('hydrophobicity', 'MPA', (257, 271))	('higher', 'PosReg', (250, 256))	('Y640F', 'Var', (60, 65))	('Y640F', 'Mutation', 'rs769031989', (60, 65))	('D661V', 'Var', (74, 79))	('D661Y', 'Mutation', 'rs747639500', (81, 86))	('activation', 'PosReg', (378, 388))	('min', 'Gene', (220, 223))	('STAT3', 'Gene', (26, 31))	('D661Y', 'Var', (81, 86))	('min', 'Gene', '11789', (220, 223))	('N647I', 'Mutation', 'rs770986654', (92, 97))
458964	24995504	Correlating with this concept, both the STAT3-Y640F and STAT3-D661V mutants were shown to increase the transcriptional activity of STAT3 in T-cell LGL, leading to the up-regulation of the downstream target genes of the STAT3 pathway including IFNGR2, BCL2L1 and JAK2.	('IFNGR2', 'Gene', '15980', (243, 249))	('increase', 'PosReg', (90, 98))	('STAT3', 'Gene', (131, 136))	('STAT3-D661V', 'Var', (56, 67))	('IFNGR2', 'Gene', (243, 249))	('transcriptional activity', 'MPA', (103, 127))	('Y640F', 'Mutation', 'rs769031989', (46, 51))	('BCL2L1', 'Gene', (251, 257))	('BCL2L1', 'Gene', '12048', (251, 257))	('STAT3-Y640F', 'Var', (40, 51))	('up-regulation', 'PosReg', (167, 180))	('LGL', 'Gene', (147, 150))	('STAT3 pathway', 'Pathway', (219, 232))	('JAK2', 'Gene', (262, 266))	('LGL', 'Gene', '16862', (147, 150))	('D661V', 'Mutation', 'p.D661V', (62, 67))	('JAK2', 'Gene', '16452', (262, 266))
458965	24995504	Moreover, Y640F, one of the most common STAT3 mutations, was shown to allow homodimerization of STAT3 independent of IL-6 or enhance the STAT3 homodimerization in response to IL-6.	('IL-6', 'Gene', '16193', (117, 121))	('allow', 'PosReg', (70, 75))	('Y640F', 'Mutation', 'rs769031989', (10, 15))	('IL-6', 'Gene', (117, 121))	('IL-6', 'Gene', (175, 179))	('Y640F', 'Var', (10, 15))	('IL-6', 'Gene', '16193', (175, 179))	('enhance', 'PosReg', (125, 132))	('STAT3', 'Gene', (40, 45))	('homodimerization', 'MPA', (76, 92))	('STAT3', 'Protein', (96, 101))	('STAT3 homodimerization', 'MPA', (137, 159))
458966	24995504	Recently, a M206K mutation that localizes in the coiled-coil domain of STAT3 was discovered in diffuse large B cell lymphoma, and this mutation was demonstrated to enhance both the STAT3Y705 phosphorylation and its transcriptional activity.	('enhance', 'PosReg', (164, 171))	('B cell lymphoma', 'Phenotype', 'HP:0012191', (109, 124))	('lymphoma', 'Phenotype', 'HP:0002665', (116, 124))	('cell lymphoma', 'Phenotype', 'HP:0012191', (111, 124))	('diffuse', 'Disease', (95, 102))	('M206K', 'Mutation', 'p.M206K', (12, 17))	('large B cell', 'Phenotype', 'HP:0005404', (103, 115))	('transcriptional', 'MPA', (215, 230))	('STAT3', 'Gene', (71, 76))	('STAT3Y705 phosphorylation', 'MPA', (181, 206))	('M206K', 'Var', (12, 17))
458967	24995504	Compared with cells harboring wild-type STAT3, STAT3-M206K mutant cells were resistant to the JAK2 inhibitor TG101348, suggesting that this STAT3 mutant possesses constitutive activity.	('JAK2', 'Gene', '16452', (94, 98))	('STAT3-M206K', 'Var', (47, 58))	('TG101348', 'Chemical', 'MESH:C528327', (109, 117))	('M206K', 'Mutation', 'p.M206K', (53, 58))	('JAK2', 'Gene', (94, 98))
458970	24995504	A specific example is the observation that enforced expression of the STAT3-DN construct suppressed the proliferation of head and neck squamous cell carcinoma cells by lowering the expression of Cyclin D1.	('STAT3-DN', 'Var', (70, 78))	('expression', 'MPA', (181, 191))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (135, 158))	('Cyclin D1', 'Gene', '12443', (195, 204))	('carcinoma', 'Phenotype', 'HP:0030731', (149, 158))	('proliferation', 'CPA', (104, 117))	('suppressed', 'NegReg', (89, 99))	('lowering', 'NegReg', (168, 176))	('Cyclin D1', 'Gene', (195, 204))	('neck squamous cell carcinoma', 'Disease', (130, 158))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (130, 158))
458972	24995504	Resistance to apoptosis: STAT3C has been shown to promote the survival of tumors cells in various models.	('promote', 'PosReg', (50, 57))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumors', 'Disease', (74, 80))	('STAT3C', 'Var', (25, 31))	('tumors', 'Disease', 'MESH:D009369', (74, 80))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))
458973	24995504	In many cancer cell types, STAT3 can transcriptionally increase the expression of various anti-apoptotic proteins involved in the intrinsic apoptotic pathway, such as survivin and the Bcl-2 family members (e.g., Bcl-xL, Bcl-2 and Mcl-1).	('Mcl-1', 'Gene', '17210', (230, 235))	('increase', 'PosReg', (55, 63))	('Bcl-2', 'Gene', '12043', (220, 225))	('cancer', 'Disease', (8, 14))	('expression', 'MPA', (68, 78))	('cancer', 'Disease', 'MESH:D009369', (8, 14))	('Bcl-2', 'Gene', '12043', (184, 189))	('Mcl-1', 'Gene', (230, 235))	('Bcl-2', 'Gene', (184, 189))	('Bcl-xL', 'Gene', (212, 218))	('Bcl-xL', 'Gene', '12048', (212, 218))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('survivin', 'Gene', '11799', (167, 175))	('STAT3', 'Var', (27, 32))	('survivin', 'Gene', (167, 175))	('Bcl-2', 'Gene', (220, 225))
458975	24995504	Induction of angiogenesis: STAT3 has been shown to augment tumor angiogenesis in multiple cancer types, such as melanoma, pancreatic cancer, cervical cancer and renal carcinoma.	('tumor', 'Disease', (59, 64))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (167, 176))	('melanoma', 'Phenotype', 'HP:0002861', (112, 120))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (122, 139))	('melanoma', 'Disease', (112, 120))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('cervical cancer', 'Disease', (141, 156))	('cervical cancer', 'Disease', 'MESH:D002583', (141, 156))	('cancer', 'Disease', (150, 156))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('pancreatic cancer', 'Disease', 'MESH:D010190', (122, 139))	('renal carcinoma', 'Disease', 'MESH:C538614', (161, 176))	('renal carcinoma', 'Disease', (161, 176))	('cancer', 'Disease', (133, 139))	('melanoma', 'Disease', 'MESH:D008545', (112, 120))	('renal carcinoma', 'Phenotype', 'HP:0005584', (161, 176))	('pancreatic cancer', 'Disease', (122, 139))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('augment', 'PosReg', (51, 58))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('STAT3', 'Var', (27, 32))	('cancer', 'Disease', (90, 96))
458978	24995504	Furthermore, ectopic expression of STAT3C in B16 melanoma cells was found to promote the formation of capillaries in the xenografts established in nude mice.	('B16', 'CellLine', 'CVCL:N540', (45, 48))	('melanoma', 'Disease', 'MESH:D008545', (49, 57))	('promote', 'PosReg', (77, 84))	('STAT3C', 'Gene', (35, 41))	('melanoma', 'Phenotype', 'HP:0002861', (49, 57))	('formation of capillaries', 'CPA', (89, 113))	('ectopic expression', 'Var', (13, 31))	('nude mice', 'Species', '10090', (147, 156))	('melanoma', 'Disease', (49, 57))
458981	24995504	found that VEGF stimulates STAT3 phosphorylation and nuclear translocation in human dermal microvascular endothelial cells, and inhibition of STAT3 using a dominant negative construct significantly impaired VEGF-induced migration and tube formation of these cells.	('stimulates', 'PosReg', (16, 26))	('min', 'Gene', (158, 161))	('impaired', 'NegReg', (198, 206))	('min', 'Gene', '11789', (158, 161))	('STAT3 phosphorylation', 'MPA', (27, 48))	('nuclear translocation', 'MPA', (53, 74))	('inhibition', 'Var', (128, 138))	('human', 'Species', '9606', (78, 83))	('tube formation of', 'CPA', (234, 251))
458984	24995504	First, STAT3 can trigger epithelial to mesenchymal transition (EMT) by upregulating several key EMT regulators such as Twist-1, Snail and ZEB-1.	('upregulating', 'PosReg', (71, 83))	('trigger', 'PosReg', (17, 24))	('ZEB-1', 'Gene', '21417', (138, 143))	('Twist-1', 'Gene', (119, 126))	('ZEB-1', 'Gene', (138, 143))	('epithelial to mesenchymal transition', 'CPA', (25, 61))	('STAT3', 'Var', (7, 12))	('Twist-1', 'Gene', '22160', (119, 126))	('Snail', 'Gene', (128, 133))	('Snail', 'Gene', '20613', (128, 133))
458986	24995504	Third, STAT3 can directly enhance the expression of focal adhesion molecules, such as integrin alpha6 and CTEN (C-terminal tensin-like).	('integrin alpha6', 'Gene', '16403', (86, 101))	('C-terminal tensin-like', 'Gene', (112, 134))	('expression', 'MPA', (38, 48))	('focal adhesion molecules', 'Protein', (52, 76))	('integrin alpha6', 'Gene', (86, 101))	('CTEN', 'Gene', '217169', (106, 110))	('C-terminal tensin-like', 'Gene', '217169', (112, 134))	('STAT3', 'Var', (7, 12))	('CTEN', 'Gene', (106, 110))	('enhance', 'PosReg', (26, 33))
458991	24995504	For example, blocking STAT3 in macrophages has been shown to activate anti-tumor immune responses in a murine model of breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('blocking', 'Var', (13, 21))	('activate', 'PosReg', (61, 69))	('breast cancer', 'Disease', 'MESH:D001943', (119, 132))	('breast cancer', 'Disease', (119, 132))	('breast cancer', 'Phenotype', 'HP:0003002', (119, 132))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('STAT3', 'Gene', (22, 27))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('murine', 'Species', '10090', (103, 109))	('tumor', 'Disease', (75, 80))
458996	24995504	In one study, transfection of STAT3C in glioblastoma cells was found to increase the expression of several stem cell factors, such as Sox2, Oct4 and Nanog.	('expression', 'MPA', (85, 95))	('Sox2', 'Gene', (134, 138))	('increase', 'PosReg', (72, 80))	('glioblastoma', 'Disease', 'MESH:D005909', (40, 52))	('Oct4', 'Gene', (140, 144))	('glioblastoma', 'Phenotype', 'HP:0012174', (40, 52))	('Nanog', 'Gene', '71950', (149, 154))	('Sox2', 'Gene', '20674', (134, 138))	('Nanog', 'Gene', (149, 154))	('transfection', 'Var', (14, 26))	('Oct4', 'Gene', '18999', (140, 144))	('STAT3C', 'Gene', (30, 36))	('glioblastoma', 'Disease', (40, 52))
458998	24995504	Further investigation indicated that the IL-6/JAK2/STAT3 pathway was preferentially active in CD44+CD24- breast cancer stem cells, and inhibition of JAK2 decreased the number of cancer stem cell number and blocked the growth of xenografts in mice.	('decreased', 'NegReg', (154, 163))	('CD44', 'Gene', '12505', (94, 98))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('cancer', 'Disease', (112, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('inhibition', 'Var', (135, 145))	('mice', 'Species', '10090', (242, 246))	('breast cancer', 'Phenotype', 'HP:0003002', (105, 118))	('JAK2', 'Gene', (46, 50))	('JAK2', 'Gene', '16452', (46, 50))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('active', 'PosReg', (84, 90))	('CD24', 'Gene', (99, 103))	('breast cancer', 'Disease', 'MESH:D001943', (105, 118))	('IL-6', 'Gene', (41, 45))	('growth of xenografts in mice', 'CPA', (218, 246))	('breast cancer', 'Disease', (105, 118))	('CD44', 'Gene', (94, 98))	('JAK2', 'Gene', (149, 153))	('JAK2', 'Gene', '16452', (149, 153))	('cancer', 'Disease', (178, 184))	('CD24', 'Gene', '12484', (99, 103))	('blocked', 'NegReg', (206, 213))	('IL-6', 'Gene', '16193', (41, 45))
458999	24995504	In glioblastoma, it has been shown that the stem cell factor EZH2 interacts with STAT3 and tri-methylates its K180 residue, thereby activates STAT3 and promotes tumorigenesis.	('EZH2', 'Gene', '14056', (61, 65))	('EZH2', 'Gene', (61, 65))	('K180', 'Var', (110, 114))	('activates', 'PosReg', (132, 141))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('STAT3', 'MPA', (142, 147))	('glioblastoma', 'Disease', (3, 15))	('glioblastoma', 'Disease', 'MESH:D005909', (3, 15))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('glioblastoma', 'Phenotype', 'HP:0012174', (3, 15))	('promotes', 'PosReg', (152, 160))	('tumor', 'Disease', (161, 166))	('interacts', 'Interaction', (66, 75))	('tri-methylates', 'Var', (91, 105))
459002	24995504	discovered that STAT3 interacts with DNA methyltransferase 1 (DNMT1) and histone deacetylase 1 (HDAC1), by which STAT3 facilitates gene methylation and silencing of SHP-1 in malignant T lymphocytes; furthermore, blocking the expression of either DNMT1 or STAT3 using siRNA was found to induce DNA demethylation and re-expression of SHP-1 in these cells.	('DNA demethylation', 'MPA', (293, 310))	('DNMT1', 'Gene', (246, 251))	('HDAC1', 'Gene', '433759', (96, 101))	('DNMT1', 'Gene', (62, 67))	('histone deacetylase 1', 'Gene', '433759', (73, 94))	('blocking', 'Var', (212, 220))	('induce', 'Reg', (286, 292))	('DNA methyltransferase 1', 'Gene', (37, 60))	('DNA methyltransferase 1', 'Gene', '13433', (37, 60))	('SHP-1', 'Gene', '15170', (332, 337))	('DNMT1', 'Gene', '13433', (246, 251))	('silencing', 'NegReg', (152, 161))	('SHP-1', 'Gene', '15170', (165, 170))	('re-expression', 'MPA', (315, 328))	('DNMT1', 'Gene', '13433', (62, 67))	('gene methylation', 'MPA', (131, 147))	('facilitates', 'PosReg', (119, 130))	('SHP-1', 'Gene', (332, 337))	('SHP-1', 'Gene', (165, 170))	('HDAC1', 'Gene', (96, 101))	('histone deacetylase 1', 'Gene', (73, 94))
459003	24995504	In another study, it was revealed that K685-acetylated STAT3 cooperates with DNMT1 to silence several tumor suppressor genes, including TP53, SHP-1, SOCS3 and CDKN2A, in melanomas; mutation of STAT3K685 or treatment with resveratrol (a histone deacetylase activator) was found to diminish the tumor-promoting function of STAT3 in melanoma.	('melanomas', 'Disease', 'MESH:D008545', (170, 179))	('tumor', 'Disease', 'MESH:D009369', (293, 298))	('min', 'Gene', (282, 285))	('melanomas', 'Disease', (170, 179))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('min', 'Gene', '11789', (282, 285))	('SHP-1', 'Gene', '15170', (142, 147))	('melanoma', 'Disease', 'MESH:D008545', (170, 178))	('tumor', 'Phenotype', 'HP:0002664', (293, 298))	('DNMT1', 'Gene', (77, 82))	('CDKN2A', 'Gene', '12578', (159, 165))	('melanoma', 'Phenotype', 'HP:0002861', (330, 338))	('melanoma', 'Disease', (330, 338))	('SOCS3', 'Gene', (149, 154))	('CDKN2A', 'Gene', (159, 165))	('melanomas', 'Phenotype', 'HP:0002861', (170, 179))	('resveratrol', 'Chemical', 'MESH:D000077185', (221, 232))	('SHP-1', 'Gene', (142, 147))	('tumor', 'Disease', (102, 107))	('TP53', 'Gene', (136, 140))	('DNMT1', 'Gene', '13433', (77, 82))	('SOCS3', 'Gene', '12702', (149, 154))	('melanoma', 'Phenotype', 'HP:0002861', (170, 178))	('melanoma', 'Disease', (170, 178))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('tumor', 'Disease', (293, 298))	('mutation', 'Var', (181, 189))	('melanoma', 'Disease', 'MESH:D008545', (330, 338))	('TP53', 'Gene', '22059', (136, 140))
459004	24995504	demonstrated that histone acetyltransferase p300 is responsible for STAT3 acetylation at K685, and this process can be reversed by histone deacetylase 1.	('histone deacetylase 1', 'Gene', '433759', (131, 152))	('histone acetyltransferase p300', 'Gene', '328572', (18, 48))	('STAT3 acetylation', 'MPA', (68, 85))	('K685', 'Var', (89, 93))	('histone deacetylase 1', 'Gene', (131, 152))	('responsible', 'Reg', (52, 63))	('histone acetyltransferase p300', 'Gene', (18, 48))
459005	24995504	Recently, it also was shown that nuclear localized CD44 facilitates STAT3 acetylation on K685 residue.	('STAT3 acetylation on', 'MPA', (68, 88))	('facilitates', 'PosReg', (56, 67))	('K685', 'Var', (89, 93))	('CD44', 'Gene', '12505', (51, 55))	('CD44', 'Gene', (51, 55))
459008	24995504	Third, in prostate cancer and chronic lymphocytic leukemia, phosphorylation of STAT3Ser727 rather than STAT3Y705 was found to be crucial for the nuclear translocation, DNA binding and the tumor-promoting function of STAT3.	('phosphorylation', 'MPA', (60, 75))	('DNA binding', 'Interaction', (168, 179))	('tumor', 'Disease', (188, 193))	('prostate cancer', 'Disease', 'MESH:D011471', (10, 25))	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (30, 58))	('chronic lymphocytic leukemia', 'Disease', (30, 58))	('nuclear translocation', 'MPA', (145, 166))	('prostate cancer', 'Phenotype', 'HP:0012125', (10, 25))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('prostate cancer', 'Disease', (10, 25))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('leukemia', 'Phenotype', 'HP:0001909', (50, 58))	('chronic lymphocytic leukemia', 'Disease', 'MESH:D015451', (30, 58))	('STAT3Ser727', 'Var', (79, 90))
459010	24995504	Correlating with this concept, the authors were able to show that the observed oncogenic effect of STAT3 was independent of its phosphorylation at Y705, whereas the N-terminal domain of STAT3 is indispensable, because the N-terminal domain was shown to be required for the dimerization of un-phosphorylated STAT3.	('min', 'Gene', '11789', (227, 230))	('min', 'Gene', (170, 173))	('min', 'Gene', '11789', (170, 173))	('STAT3', 'Gene', (99, 104))	('Y705', 'Var', (147, 151))	('min', 'Gene', (227, 230))	('oncogenic effect', 'CPA', (79, 95))
459012	24995504	More recently, the significance of mitochondrial STAT3 also has been documented in breast cancer, in which it promotes tumor growth and metastasis by suppressing the generation of reactive oxygen species; again, this biological effect is dependent on phosphorylation of STAT3S727 but not that of STAT3Y705.	('tumor', 'Disease', (119, 124))	('STAT3S727', 'Var', (270, 279))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('suppressing', 'NegReg', (150, 161))	('breast cancer', 'Disease', 'MESH:D001943', (83, 96))	('generation of reactive oxygen species', 'MPA', (166, 203))	('breast cancer', 'Disease', (83, 96))	('metastasis', 'CPA', (136, 146))	('promotes', 'PosReg', (110, 118))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('breast cancer', 'Phenotype', 'HP:0003002', (83, 96))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (180, 203))
459018	24995504	While the oncogenic effects of STAT3 have been well recognized, a relatively small number of studies published previously have shown that STAT3 carries tumor suppressor functions, a seemingly paradoxical notion.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('tumor', 'Disease', (152, 157))	('min', 'Gene', (185, 188))	('STAT3', 'Var', (138, 143))	('min', 'Gene', '11789', (185, 188))
459021	24995504	Using astrocytes derived from conditional STAT3 knockout mice, the authors found that the simultaneous deletion of STAT3 and shRNA knockdown of PTEN resulted in a dramatic increase in cell proliferation in vitro and tumor formation in SCID mice, whereas siRNA knockdown of PTEN alone (i.e., in the presence of normal STAT3 expression) resulted in significantly less tumorigenic effects in these cells.	('tumor', 'Disease', (366, 371))	('tumor', 'Disease', (216, 221))	('SCID', 'Disease', (235, 239))	('increase', 'PosReg', (172, 180))	('mice', 'Species', '10090', (57, 61))	('SCID', 'Disease', 'MESH:D053632', (235, 239))	('STAT3', 'Gene', (115, 120))	('shRNA', 'Gene', (125, 130))	('mice', 'Species', '10090', (240, 244))	('tumor', 'Phenotype', 'HP:0002664', (366, 371))	('tumor', 'Disease', 'MESH:D009369', (366, 371))	('cell proliferation', 'CPA', (184, 202))	('tumor', 'Disease', 'MESH:D009369', (216, 221))	('PTEN', 'Gene', (144, 148))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('deletion', 'Var', (103, 111))
459024	24995504	Interestingly, in the same study using astrocytes harvested from the same conditional STAT3 knockout mice, the authors also found that transfection of EGFRvIII (epidermal growth factor receptor type III variant) in STAT3+/+ astrocytes resulted in tumor formation in SCID mice, whereas the same treatment did not result in any tumor formation in STAT3-/- astrocytes.	('tumor', 'Phenotype', 'HP:0002664', (247, 252))	('SCID', 'Disease', (266, 270))	('epidermal growth factor receptor', 'Gene', (161, 193))	('epidermal growth factor receptor', 'Gene', '13649', (161, 193))	('mice', 'Species', '10090', (271, 275))	('tumor', 'Disease', (247, 252))	('resulted in', 'Reg', (235, 246))	('tumor', 'Disease', 'MESH:D009369', (326, 331))	('tumor', 'Phenotype', 'HP:0002664', (326, 331))	('mice', 'Species', '10090', (101, 105))	('EGFRvIII', 'Gene', (151, 159))	('tumor', 'Disease', (326, 331))	('transfection', 'Var', (135, 147))	('tumor', 'Disease', 'MESH:D009369', (247, 252))	('SCID', 'Disease', 'MESH:D053632', (266, 270))
459027	24995504	Using ras-transformed mouse hepatocytes harvested from homozygous p19ARF knockout mice, the authors found that transfection of STAT3 or STAT3C significantly suppressed tumorigenecity in a SCID mouse xenograft model.	('mice', 'Species', '10090', (82, 86))	('SCID', 'Disease', 'MESH:D053632', (188, 192))	('p19ARF', 'Gene', (66, 72))	('tumor', 'Disease', (168, 173))	('SCID', 'Disease', (188, 192))	('STAT3C', 'Var', (136, 142))	('suppressed', 'NegReg', (157, 167))	('p19ARF', 'Gene', '12578', (66, 72))	('STAT3', 'Var', (127, 132))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('mouse', 'Species', '10090', (22, 27))	('mouse', 'Species', '10090', (193, 198))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
459028	24995504	In comparison, transfection of a double STAT3 mutant in which both Y705 and S727 cannot be phosphorylated led to significant tumor growth in SCID mice.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('Y705', 'Var', (67, 71))	('S727', 'Var', (76, 80))	('tumor', 'Disease', (125, 130))	('mice', 'Species', '10090', (146, 150))	('SCID', 'Disease', 'MESH:D053632', (141, 145))	('SCID', 'Disease', (141, 145))
459029	24995504	In the same paper, the authors also found that cells transfected with the double STAT3 mutant resulted in liver and lung metastasis after intravenous injection of the cells, while transfection with STAT3 or STAT3C significantly decreased the metastatic potential of these hepatocytes.	('decreased', 'NegReg', (228, 237))	('metastatic potential of', 'CPA', (242, 265))	('mutant', 'Var', (87, 93))	('STAT3', 'Gene', (81, 86))	('liver and lung metastasis', 'Disease', 'MESH:D009362', (106, 131))	('double', 'Var', (74, 80))	('resulted in', 'Reg', (94, 105))
459033	24995504	By crossing these animals with conditional STAT3 knockout mice, the authors were able to generate mice with which they assessed the impact of STAT3 knockout in the Apc(Min/+)-carrying intestinal epithelial cells.	('knockout', 'Var', (148, 156))	('Min', 'Gene', '11789', (168, 171))	('STAT3', 'Gene', (142, 147))	('Min', 'Phenotype', 'HP:0200008', (168, 171))	('Min', 'Gene', (168, 171))	('mice', 'Species', '10090', (58, 62))	('Apc', 'Gene', (164, 167))	('Apc', 'Gene', '11789', (164, 167))	('mice', 'Species', '10090', (98, 102))
459034	24995504	While deletion of STAT3 in the intestinal epithelial cells reduced the multiplicity of early adenoma formation (i.e., oncogenic role), ablation of STAT3 in the later stage of tumor progression significantly increased the invasiveness of the tumors and decreased the survival of the animals (i.e., tumor suppressor role).	('reduced', 'NegReg', (59, 66))	('tumors', 'Disease', 'MESH:D009369', (241, 247))	('tumor', 'Disease', (297, 302))	('tumor', 'Disease', (241, 246))	('tumor', 'Disease', 'MESH:D009369', (297, 302))	('deletion', 'Var', (6, 14))	('tumor', 'Disease', 'MESH:D009369', (241, 246))	('survival', 'CPA', (266, 274))	('tumor', 'Disease', (175, 180))	('tumors', 'Phenotype', 'HP:0002664', (241, 247))	('tumor', 'Phenotype', 'HP:0002664', (297, 302))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('adenoma', 'Disease', (93, 100))	('decreased', 'NegReg', (252, 261))	('STAT3', 'Gene', (147, 152))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))	('STAT3', 'Gene', (18, 23))	('ablation', 'Var', (135, 143))	('tumors', 'Disease', (241, 247))	('increased', 'PosReg', (207, 216))	('adenoma', 'Disease', 'MESH:D000236', (93, 100))	('multiplicity', 'CPA', (71, 83))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))
459036	24995504	It was found that the hepatocytes with STAT3 expression had a significantly less tumor formation induced by chronic carbon tetrachloride, as compared to hepatocytes with STAT3 knockout.	('less', 'NegReg', (76, 80))	('carbon tetrachloride', 'Chemical', 'MESH:D002251', (116, 136))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('STAT3 expression', 'Var', (39, 55))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Disease', (81, 86))
459037	24995504	In contrast, hepatocytes with STAT3 expression were found to have a significantly higher tumor formation induced by diethylnitrosamine, as compared to hepatocytes with no STAT3 expression.	('diethylnitrosamine', 'Chemical', 'MESH:D004052', (116, 134))	('higher', 'PosReg', (82, 88))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('diethylnitrosamine', 'MPA', (116, 134))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))	('STAT3 expression', 'Var', (30, 46))
459038	24995504	In other words, STAT3 can be either oncogenic or tumor suppressive, depending on the use of different carcinogens.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('STAT3', 'Var', (16, 21))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor', 'Disease', (49, 54))	('oncogenic', 'CPA', (36, 45))
459042	24995504	In contrast, in the diethylnitrosamine model, the authors believed that the oncogenic effects of STAT3 are due to the fact that STAT3 can increase the expression of cyclin D1 and suppress the expression of p21.	('increase', 'PosReg', (138, 146))	('p21', 'Gene', (206, 209))	('diethylnitrosamine', 'Chemical', 'MESH:D004052', (20, 38))	('STAT3', 'Var', (128, 133))	('cyclin D1', 'Gene', '12443', (165, 174))	('expression', 'MPA', (192, 202))	('expression', 'MPA', (151, 161))	('p21', 'Gene', '12575', (206, 209))	('cyclin D1', 'Gene', (165, 174))	('suppress', 'NegReg', (179, 187))
459046	24995504	found that siRNA knockdown of STAT3 resulted in significantly increased tumor growth, and this observation correlated with increased glucose consumption, lactate production, and expression of HIF-1alpha target genes in the tumor cells.	('glucose consumption', 'MPA', (133, 152))	('increased', 'PosReg', (62, 71))	('increased', 'PosReg', (123, 132))	('tumor', 'Disease', (223, 228))	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Disease', (72, 77))	('expression', 'MPA', (178, 188))	('lactate', 'Chemical', 'MESH:D019344', (154, 161))	('lactate production', 'MPA', (154, 172))	('tumor', 'Disease', 'MESH:D009369', (223, 228))	('knockdown', 'Var', (17, 26))	('STAT3', 'Gene', (30, 35))	('glucose', 'Chemical', 'MESH:D005947', (133, 140))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('increased glucose', 'Phenotype', 'HP:0003074', (123, 140))	('HIF-1alpha', 'Gene', '15251', (192, 202))	('HIF-1alpha', 'Gene', (192, 202))
459047	24995504	These findings suggest that one of the mechanisms by which STAT3 inhibits tumorigenesis is mediated by inhibiting aerobic glycolysis in the tumor cells.	('aerobic glycolysis', 'MPA', (114, 132))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('inhibits', 'NegReg', (65, 73))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('inhibiting', 'NegReg', (103, 113))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('tumor', 'Disease', (74, 79))	('STAT3', 'Var', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('tumor', 'Disease', (140, 145))
459050	24995504	In another study, c-Myc was shown to function as a molecular switch to alter the function of oncostatin M-activated STAT3 in human mammary epithelial cells deficient in both p53 and p16.	('p16', 'Var', (182, 185))	('function', 'MPA', (81, 89))	('alter', 'Reg', (71, 76))	('c-Myc', 'Gene', (18, 23))	('human', 'Species', '9606', (125, 130))	('p53', 'Var', (174, 177))	('c-Myc', 'Gene', '4609', (18, 23))	('oncostatin M-activated STAT3', 'MPA', (93, 121))
459055	24995504	found that that ablation of STAT3 significantly increase the invasiveness of colorectal cancer, a finding that is in parallel to that reported by Musteanu.	('STAT3', 'Gene', (28, 33))	('ablation', 'Var', (16, 24))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('invasiveness of colorectal cancer', 'Disease', 'MESH:D015179', (61, 94))	('colorectal cancer', 'Phenotype', 'HP:0003003', (77, 94))	('invasiveness of colorectal cancer', 'Disease', (61, 94))	('increase', 'PosReg', (48, 56))
459057	24995504	While the majority of studies evaluating the prognostic value of STAT3 and/or pSTAT3 have pointed to its oncogenic effects, a few studies have reported contradictory observations, with the expression of STAT3/pSTAT3 found to be "paradoxically" associated with a better prognosis in various types of cancer, including those of the head and neck, salivary gland, breast, nasopharynx and rectum.	('STAT3/pSTAT3', 'Var', (203, 215))	('salivary gland', 'Disease', (345, 359))	('breast', 'Disease', (361, 367))	('cancer', 'Phenotype', 'HP:0002664', (299, 305))	('better', 'PosReg', (262, 268))	('associated', 'Reg', (244, 254))	('nasopharynx', 'Disease', (369, 380))	('rectum', 'Disease', (385, 391))	('cancer', 'Disease', (299, 305))	('cancer', 'Disease', 'MESH:D009369', (299, 305))
459058	24995504	For instance, high expression of pSTAT3 or nuclear STAT3 in head and neck cancer was found to be associated with a favorable clinical outcome; the progression free survival for patients carrying tumors with high expression of nuclear STAT3 was significantly longer than that of patients carrying tumors with relatively low STAT3 expression.	('tumors', 'Disease', (195, 201))	('tumors', 'Disease', 'MESH:D009369', (195, 201))	('tumors', 'Phenotype', 'HP:0002664', (195, 201))	('progression free survival', 'CPA', (147, 172))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('head and neck cancer', 'Disease', 'MESH:D006258', (60, 80))	('tumor', 'Phenotype', 'HP:0002664', (296, 301))	('patients', 'Species', '9606', (177, 185))	('tumors', 'Phenotype', 'HP:0002664', (296, 302))	('longer', 'PosReg', (258, 264))	('tumors', 'Disease', (296, 302))	('tumors', 'Disease', 'MESH:D009369', (296, 302))	('patients', 'Species', '9606', (278, 286))	('head and neck cancer', 'Phenotype', 'HP:0012288', (60, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('nuclear STAT3', 'Var', (226, 239))
459059	24995504	In another study including a large cohort of patients with salivary gland tumors, patients carrying tumors with strong nuclear pSTAT3 immunostaining were found to have a better clinical outcome compared with those carrying tumors with moderate or weak nuclear pSTAT3 staining; moreover, strong nuclear pSTAT3 also significantly correlated with a low histologic grade, as well as the absence of lymph node and distant metastases.	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('metastases', 'Disease', (417, 427))	('strong nuclear pSTAT3', 'Var', (287, 308))	('tumors', 'Disease', (223, 229))	('correlated', 'Reg', (328, 338))	('patients', 'Species', '9606', (45, 53))	('tumors', 'Disease', 'MESH:D009369', (74, 80))	('salivary gland tumors', 'Disease', (59, 80))	('tumors', 'Disease', 'MESH:D009369', (223, 229))	('salivary gland tumors', 'Disease', 'MESH:D012468', (59, 80))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('patients', 'Species', '9606', (82, 90))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumors', 'Disease', (100, 106))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('tumors', 'Phenotype', 'HP:0002664', (223, 229))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('metastases', 'Disease', 'MESH:D009362', (417, 427))	('salivary gland tumors', 'Phenotype', 'HP:0100684', (59, 80))	('tumors', 'Disease', (74, 80))
459060	24995504	In breast cancer, two studies have documented that nuclear pSTAT3 expression significantly correlated with a favorable clinical outcome, although this correlation was restricted to patients with low-grade tumors or node-negative tumors.	('tumors', 'Disease', 'MESH:D009369', (205, 211))	('tumors', 'Disease', 'MESH:D009369', (229, 235))	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('breast cancer', 'Disease', (3, 16))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('tumors', 'Disease', (205, 211))	('tumors', 'Phenotype', 'HP:0002664', (205, 211))	('patients', 'Species', '9606', (181, 189))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumors', 'Phenotype', 'HP:0002664', (229, 235))	('nuclear', 'Var', (51, 58))	('correlated with', 'Reg', (91, 106))	('tumors', 'Disease', (229, 235))	('pSTAT3', 'Gene', (59, 65))
459061	24995504	To illustrate this point, STAT3 was reported to be a marker of worse clinical outcome in head and neck cancer as well as breast cancer, the same types of cancer in which STAT3 was found to be associated with a better clinical outcome in other studies.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('head and neck cancer', 'Phenotype', 'HP:0012288', (89, 109))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('cancer', 'Disease', (154, 160))	('STAT3', 'Var', (26, 31))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('breast cancer', 'Disease', 'MESH:D001943', (121, 134))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('breast cancer', 'Disease', (121, 134))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('head and neck cancer', 'Disease', 'MESH:D006258', (89, 109))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('breast cancer', 'Phenotype', 'HP:0003002', (121, 134))	('cancer', 'Disease', (128, 134))
459065	24995504	Briefly, STAT3beta is a result of the deletion of the first 50 nucleotides of exon 23, leading to a frame shift that introduces 7 amino acid residues followed by a stop codon.	('min', 'Gene', '11789', (131, 134))	('STAT3beta', 'Disease', (9, 18))	('deletion', 'Var', (38, 46))	('min', 'Gene', (131, 134))
459068	24995504	The difference in their biological behaviors was also highlighted in a study, in which STAT3beta was found to have a higher DNA binding ability than STAT3alpha in COS-7 cells that had been serum starved.	('COS-7', 'CellLine', 'CVCL:0224', (163, 168))	('STAT3beta', 'Var', (87, 96))	('DNA binding', 'Interaction', (124, 135))	('higher', 'PosReg', (117, 123))
459069	24995504	Correlating with these observations, a subsequent study revealed that the negatively charged 55 amino acids present in the C-terminus of STAT3alpha confer a decreased stability of the STAT3alpha dimers, and this difference in the dimer stability between STAT3alpha and STAT3beta is believed to be responsible for the longer half-life and nuclear retention of pSTAT3beta.	('min', 'Gene', '11789', (97, 100))	('STAT3alpha', 'Protein', (184, 194))	('min', 'Gene', (97, 100))	('dimer stability', 'MPA', (230, 245))	('STAT3alpha', 'Gene', (137, 147))	('negatively', 'Var', (74, 84))	('min', 'Gene', (128, 131))	('decreased', 'NegReg', (157, 166))	('min', 'Gene', '11789', (128, 131))	('stability', 'MPA', (167, 176))
459070	24995504	Another study showed that the unique C-terminal 7-amino acid domain of STAT3beta also contributes to the increased nuclear retention of STAT3beta, since with the deletion of this domain was shown to decrease the nuclear retention time of STAT3beta.	('deletion', 'Var', (162, 170))	('nuclear retention time', 'MPA', (212, 234))	('nuclear retention', 'MPA', (115, 132))	('min', 'Gene', '11789', (51, 54))	('decrease', 'NegReg', (199, 207))	('min', 'Gene', (51, 54))	('increased', 'PosReg', (105, 114))	('min', 'Gene', (42, 45))	('min', 'Gene', '11789', (42, 45))
459072	24995504	Without the STAT3 transactivation domain, STAT3beta is expected to be unable to activate promoters carrying the interferon/IL-6:responsive element.	('STAT3beta', 'Var', (42, 51))	('IL-6', 'Gene', (123, 127))	('IL-6', 'Gene', '16193', (123, 127))
459074	24995504	In other studies, it has been demonstrated that STAT3beta can abolish the transcriptional activation of several STAT3 downstream targets including Cyclin D1, Bcl-xL and Mcl-1, leading to inhibition of tumor growth and promotion of apoptosis.	('apoptosis', 'CPA', (231, 240))	('abolish', 'NegReg', (62, 69))	('inhibition', 'NegReg', (187, 197))	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('Cyclin D1', 'Gene', '12443', (147, 156))	('Bcl-xL', 'Gene', (158, 164))	('Bcl-xL', 'Gene', '12048', (158, 164))	('transcriptional activation', 'MPA', (74, 100))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('promotion', 'PosReg', (218, 227))	('STAT3beta', 'Var', (48, 57))	('Mcl-1', 'Gene', '17210', (169, 174))	('tumor', 'Disease', (201, 206))	('Cyclin D1', 'Gene', (147, 156))	('Mcl-1', 'Gene', (169, 174))
459076	24995504	In addition to its dominant negative role, STAT3beta is believed to carry other functions, considering the fact that it possesses most of the important STAT3 functional domains including the activation domain (i.e., which carries the tyrosine 705 residue), the Src homology2 (SH2) domain that is responsible for STAT3 dimerization and its binding to the receptor complex (e.g., JAKs), the coiled-coil domain that allows STAT3 to interact with other proteins, and the DNA binding domain.	('interact', 'Interaction', (429, 437))	('binding', 'Interaction', (339, 346))	('min', 'Gene', (21, 24))	('Src', 'Gene', '20779', (261, 264))	('JAKs', 'Gene', (378, 382))	('Src', 'Gene', (261, 264))	('min', 'Gene', '11789', (21, 24))	('JAKs', 'Gene', '16451;3717;16452', (378, 382))	('tyrosine 705', 'Var', (234, 246))	('tyrosine', 'Chemical', 'MESH:D014443', (234, 242))
459078	24995504	In another study, STAT3beta was found to compensate the function of STAT3; specifically, transfection of STAT3beta effectively induced the expression of acute phase genes in STAT3-null hepatocytes challenged with lipopolysaccharide.	('transfection', 'Var', (89, 101))	('STAT3beta', 'Var', (105, 114))	('lipopolysaccharide', 'Chemical', 'MESH:D008070', (213, 231))	('acute phase genes', 'Gene', (153, 170))	('expression', 'MPA', (139, 149))	('induced', 'PosReg', (127, 134))
459080	24995504	Another study showed that, compared with the wild-type mice, mice with specific STAT3beta ablation were hypersensitive to lipopolysaccharide-induced inflammation, and these findings correlated with the dramatic alterations of the expression of lipopolysaccharide-responsive genes in the hepatocytes.	('mice', 'Species', '10090', (61, 65))	('STAT3beta', 'Gene', (80, 89))	('hypersensitive', 'Disease', 'MESH:D004342', (104, 118))	('hypersensitive to lipopolysaccharide', 'Phenotype', 'HP:0002848', (104, 140))	('inflammation', 'Disease', 'MESH:D007249', (149, 161))	('hypersensitive', 'Disease', (104, 118))	('alterations', 'Reg', (211, 222))	('lipopolysaccharide', 'Chemical', 'MESH:D008070', (122, 140))	('expression', 'MPA', (230, 240))	('mice', 'Species', '10090', (55, 59))	('inflammation', 'Disease', (149, 161))	('lipopolysaccharide', 'Chemical', 'MESH:D008070', (244, 262))	('ablation', 'Var', (90, 98))
459082	24995504	The shift from STAT3alpha to STAT3beta was found to dramatically decreased tumor growth, which was shown to be mediated by STAT3beta-specific downstream targets.	('decreased', 'NegReg', (65, 74))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('shift', 'Var', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', (75, 80))
459085	24995504	In one study, STAT3beta was found to upregulate and prolong the phosphorylation of STAT3alphaY705 upon stimulation with oncostatin M in murine embryonic fibroblasts.	('phosphorylation', 'MPA', (64, 79))	('upregulate', 'PosReg', (37, 47))	('prolong', 'PosReg', (52, 59))	('murine', 'Species', '10090', (136, 142))	('STAT3alphaY705', 'Var', (83, 97))
459087	24995504	In contrast, in the presence of STAT3beta, phosphorylation of STAT3alphaY705 was sustained at a high level for 120 min.	('min', 'Gene', (115, 118))	('min', 'Gene', '11789', (115, 118))	('STAT3alphaY705', 'Var', (62, 76))	('phosphorylation', 'MPA', (43, 58))
459091	24995504	For instance, transient STAT3beta transfection in murine B16 melanoma cells induced cell cycle arrest as well as apoptosis.	('murine', 'Species', '10090', (50, 56))	('apoptosis', 'CPA', (113, 122))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (84, 101))	('melanoma', 'Phenotype', 'HP:0002861', (61, 69))	('transfection', 'Var', (34, 46))	('melanoma', 'Disease', (61, 69))	('B16', 'CellLine', 'CVCL:N540', (57, 60))	('melanoma', 'Disease', 'MESH:D008545', (61, 69))	('cell cycle arrest', 'CPA', (84, 101))	('STAT3beta', 'Gene', (24, 33))
459092	24995504	Furthermore, electro-injection of STAT3beta cDNA into established B16 melanoma xenografts in SCID mice induced apoptosis and suppressed tumor growth.	('melanoma', 'Disease', (70, 78))	('melanoma', 'Phenotype', 'HP:0002861', (70, 78))	('melanoma', 'Disease', 'MESH:D008545', (70, 78))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('B16', 'CellLine', 'CVCL:N540', (66, 69))	('suppressed', 'NegReg', (125, 135))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('SCID', 'Disease', 'MESH:D053632', (93, 97))	('tumor', 'Disease', (136, 141))	('SCID', 'Disease', (93, 97))	('STAT3beta cDNA', 'Var', (34, 48))	('apoptosis', 'CPA', (111, 120))	('mice', 'Species', '10090', (98, 102))
459093	24995504	In another study, gene transfer of STAT3beta was found to result in marked shrinkage of xenografts in SCID mice, whereas siRNA knockdown of STAT3 resulted no significant effect on breast tumor growth.	('shrinkage', 'NegReg', (75, 84))	('STAT3beta', 'Gene', (35, 44))	('breast tumor', 'Disease', 'MESH:D001943', (180, 192))	('SCID', 'Disease', (102, 106))	('gene transfer', 'Var', (18, 31))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('SCID', 'Disease', 'MESH:D053632', (102, 106))	('breast tumor', 'Disease', (180, 192))	('mice', 'Species', '10090', (107, 111))	('breast tumor', 'Phenotype', 'HP:0100013', (180, 192))
459094	24995504	Interestingly, in one study, apoptosis induced by STAT3beta was found in STAT3beta-transfected cells as well as the bystander non-transfected cells in the same tissue culture, due to the production of TRAIL (TNF-related apoptosis inducing ligand) induced by STAT3beta transfection.	('TNF-related apoptosis inducing ligand', 'Gene', (208, 245))	('TNF-related apoptosis inducing ligand', 'Gene', '22035', (208, 245))	('transfection', 'Var', (268, 280))
459095	24995504	Moreover, it has been shown that transfection of STAT3beta cDNA in a human melanoma cell line increases FAS expression and enhances apoptosis induced by FAS-ligand and UV irradiation.	('apoptosis', 'CPA', (132, 141))	('enhances', 'PosReg', (123, 131))	('FAS', 'Protein', (104, 107))	('human', 'Species', '9606', (69, 74))	('increases', 'PosReg', (94, 103))	('melanoma', 'Phenotype', 'HP:0002861', (75, 83))	('melanoma', 'Disease', (75, 83))	('expression', 'MPA', (108, 118))	('melanoma', 'Disease', 'MESH:D008545', (75, 83))	('FAS-ligand', 'Protein', (153, 163))	('STAT3beta', 'Var', (49, 58))
459096	24995504	A few years later, the same research team reported that STAT3beta can effectively suppress the growth of human melanomas xenografted in nude mice by increasing the expression of TRAIL receptor 2, a pro-apoptotic factor expressed on the cell surface of the tumor cells.	('melanomas', 'Disease', 'MESH:D008545', (111, 120))	('melanoma', 'Phenotype', 'HP:0002861', (111, 119))	('TRAIL', 'Protein', (178, 183))	('expression', 'MPA', (164, 174))	('nude mice', 'Species', '10090', (136, 145))	('tumor', 'Disease', 'MESH:D009369', (256, 261))	('melanomas', 'Disease', (111, 120))	('STAT3beta', 'Var', (56, 65))	('tumor', 'Phenotype', 'HP:0002664', (256, 261))	('suppress', 'NegReg', (82, 90))	('human', 'Species', '9606', (105, 110))	('melanomas', 'Phenotype', 'HP:0002861', (111, 120))	('growth', 'CPA', (95, 101))	('increasing', 'PosReg', (149, 159))	('tumor', 'Disease', (256, 261))
459101	24995504	In other words, accurate evaluation of the biological and clinical significance of STAT3 in human tumor samples will require some understanding of the relevant coexisting biochemical defects (e.g., c-myc, PTEN and p14ARF) as well as the simultaneous evaluation of STAT3alpha and STAT3beta.	('tumor', 'Disease', (98, 103))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('PTEN', 'Var', (205, 209))	('p14ARF', 'Gene', '1029', (214, 220))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('c-myc', 'Gene', '4609', (198, 203))	('c-myc', 'Gene', (198, 203))	('human', 'Species', '9606', (92, 97))	('p14ARF', 'Gene', (214, 220))
459124	33392181	A clinical trial study of patients with advanced ESCC found that pembrolizumab (also known as "Keytruda"), acting as a second-line therapy, could remarkably improve OS compared to chemotherapy.	('pembrolizumab', 'Var', (65, 78))	('improve', 'PosReg', (157, 164))	('pembrolizumab', 'Chemical', 'MESH:C582435', (65, 78))	('patients', 'Species', '9606', (26, 34))
459125	33392181	In 2019, the U.S. Food and Drug Administration approved the use of pembrolizumab for patients with advanced ESCC and high PD-L1 expression.	('high', 'Var', (117, 121))	('pembrolizumab', 'Chemical', 'MESH:C582435', (67, 80))	('PD-L1', 'Gene', (122, 127))	('patients', 'Species', '9606', (85, 93))	('ESCC', 'Disease', (108, 112))	('PD-L1', 'Gene', '29126', (122, 127))
459162	33392181	We established a risk score model based on the expressions of these six genes and corresponding coefficients for patients with ESCC: risk score = (0.1272 x TSPAN2 expression) + (0.2423 x AMBP expression) + (0.2201 x C6 expression) + (0.1651 x PRLR expression) - (0.2720 x ITLN1 expression) - (0.2724 x MADCAM1 expression).	('0.1272', 'Var', (147, 153))	('PRLR', 'Gene', (243, 247))	('MADCAM1', 'Gene', '8174', (302, 309))	('PRLR', 'Gene', '5618', (243, 247))	('ESCC', 'Disease', (127, 131))	('TSPAN2', 'Gene', '10100', (156, 162))	('patients', 'Species', '9606', (113, 121))	('AMBP', 'Gene', (187, 191))	('MADCAM1', 'Gene', (302, 309))	('ITLN1', 'Gene', (272, 277))	('ITLN1', 'Gene', '55600', (272, 277))	('AMBP', 'Gene', '259', (187, 191))	('TSPAN2', 'Gene', (156, 162))
459232	33392181	Meanwhile, one of the risky genes - TSPAN2 - inhibited macrophage secretion of lipopolysaccharide-induced tumor necrosis factor alpha (TNF-alpha) and interleukin 6 (IL-6).	('genes -', 'Var', (28, 35))	('interleukin 6', 'Gene', (150, 163))	('TNF-alpha', 'Gene', '7124', (135, 144))	('IL-6', 'Gene', '3569', (165, 169))	('TSPAN2', 'Gene', '10100', (36, 42))	('TNF-alpha', 'Gene', (135, 144))	('IL-6', 'Gene', (165, 169))	('interleukin 6', 'Gene', '3569', (150, 163))	('lipopolysaccharide', 'Chemical', 'MESH:D008070', (79, 97))	('tumor necrosis factor alpha', 'Gene', '7124', (106, 133))	('tumor necrosis factor alpha', 'Gene', (106, 133))	('inhibited', 'NegReg', (45, 54))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('TSPAN2', 'Gene', (36, 42))
459236	33392181	For example, TNFSF4 - also known as OX40L - is a ligand of OX40, and its combination with OX40 regulates T-cell proliferation, activation, and survival and even has an effect on cytokine release from T cells.	('has', 'Reg', (161, 164))	('OX40', 'Gene', '7293', (59, 63))	('survival', 'CPA', (143, 151))	('OX40', 'Gene', (59, 63))	('OX40L', 'Gene', '7292', (36, 41))	('regulates', 'Reg', (95, 104))	('TNFSF4', 'Gene', '7292', (13, 19))	('OX40L', 'Gene', (36, 41))	('combination', 'Var', (73, 84))	('OX40', 'Gene', '7293', (90, 94))	('OX40', 'Gene', (90, 94))	('OX40', 'Gene', '7293', (36, 40))	('cytokine release from T cells', 'MPA', (178, 207))	('T-cell proliferation', 'CPA', (105, 125))	('OX40', 'Gene', (36, 40))	('activation', 'CPA', (127, 137))	('effect', 'Reg', (168, 174))	('TNFSF4', 'Gene', (13, 19))
459255	28969100	Overexpression of lncRNA UCA1 correlates with resistance to chemotherapeutics such as cisplatin, gemcitabine, 5-FU, tamoxifen, imatinib and EGFR-TKIs, whereas lncRNA UCA1 knockdown restores drug sensitivity.	('UCA1', 'Gene', '652995', (166, 170))	('EGFR', 'Gene', (140, 144))	('UCA1', 'Gene', (166, 170))	('knockdown', 'Var', (171, 180))	('drug sensitivity', 'Phenotype', 'HP:0020174', (190, 206))	('drug sensitivity', 'MPA', (190, 206))	('resistance to chemotherapeutics', 'MPA', (46, 77))	('lncRNA', 'Gene', (18, 24))	('gemcitabine', 'Chemical', 'MESH:C056507', (97, 108))	('EGFR', 'Gene', '1956', (140, 144))	('tamoxifen', 'Chemical', 'MESH:D013629', (116, 125))	('cisplatin', 'Chemical', 'MESH:D002945', (86, 95))	('5-FU', 'Chemical', 'MESH:D005472', (110, 114))	('UCA1', 'Gene', '652995', (25, 29))	('UCA1', 'Gene', (25, 29))	('gemcitabine', 'MPA', (97, 108))	('restores', 'PosReg', (181, 189))	('tamoxifen', 'MPA', (116, 125))	('imatinib', 'Chemical', 'MESH:D000068877', (127, 135))
459271	28969100	Ectopic expression of lncRNA UCA1 in bladder cancer cell line BLS-211 promoted cancer progression demonstrating that lncRNA UCA1 was oncogenic.	('UCA1', 'Gene', (124, 128))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('bladder cancer', 'Phenotype', 'HP:0009725', (37, 51))	('UCA1', 'Gene', '652995', (29, 33))	('bladder cancer', 'Disease', 'MESH:D001749', (37, 51))	('bladder cancer', 'Disease', (37, 51))	('UCA1', 'Gene', (29, 33))	('Ectopic expression', 'Var', (0, 18))	('BLS-211', 'CellLine', 'CVCL:9W20', (62, 69))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('promoted', 'PosReg', (70, 78))	('cancer', 'Disease', (45, 51))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('UCA1', 'Gene', '652995', (124, 128))
459290	28969100	A recent study reported that knockdown of miR-1 resulted in Ago2-slicer-dependent lncRNA UCA1 overexpression, whereas miR-1 overexpression decreased UCA1 levels in bladder cancer cells.	('overexpression', 'PosReg', (94, 108))	('miR-1', 'Gene', '79187', (118, 123))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('UCA1', 'Gene', '652995', (149, 153))	('knockdown', 'Var', (29, 38))	('bladder cancer', 'Phenotype', 'HP:0009725', (164, 178))	('UCA1', 'Gene', (149, 153))	('miR-1', 'Gene', (118, 123))	('Ago2', 'Gene', '27161', (60, 64))	('miR-1', 'Gene', '79187', (42, 47))	('UCA1', 'Gene', '652995', (89, 93))	('bladder cancer', 'Disease', 'MESH:D001749', (164, 178))	('bladder cancer', 'Disease', (164, 178))	('UCA1', 'Gene', (89, 93))	('miR-1', 'Gene', (42, 47))	('Ago2', 'Gene', (60, 64))
459291	28969100	postulated that miR-1 targets and cleaves lncRNA UCA1 in an Ago2-dependent manner similar to degradation of protein-coding mRNAs by miRNAs.	('miR-1', 'Gene', '79187', (16, 21))	('cleaves', 'Var', (34, 41))	('Ago2', 'Gene', '27161', (60, 64))	('miR-1', 'Gene', (16, 21))	('UCA1', 'Gene', '652995', (49, 53))	('UCA1', 'Gene', (49, 53))	('Ago2', 'Gene', (60, 64))
459307	28969100	These include aberrant expression of glutathione transferase and topoisomerase II, reduced uptake of water-soluble drugs, enhanced DNA damage repair, enhanced drug metabolism, decreased apoptosis, and increased energy-dependent efflux of chemotherapeutic drugs, all of which reduce the effects of the cancer therapeutics.	('glutathione', 'Protein', (37, 48))	('enhanced', 'PosReg', (122, 130))	('enhanced', 'PosReg', (150, 158))	('drug metabolism', 'MPA', (159, 174))	('increased', 'PosReg', (201, 210))	('reduced', 'NegReg', (83, 90))	('cancer', 'Disease', 'MESH:D009369', (301, 307))	('water', 'Chemical', 'MESH:D014867', (101, 106))	('uptake of water-soluble drugs', 'MPA', (91, 120))	('cancer', 'Disease', (301, 307))	('decreased', 'NegReg', (176, 185))	('aberrant', 'Var', (14, 22))	('energy-dependent efflux of', 'MPA', (211, 237))	('topoisomerase II', 'Enzyme', (65, 81))	('cancer', 'Phenotype', 'HP:0002664', (301, 307))	('DNA damage repair', 'MPA', (131, 148))	('apoptosis', 'CPA', (186, 195))	('expression', 'MPA', (23, 33))
459316	28969100	The expression of lncRNA UCA1 was higher in the T24-cisplatin resistant cells than T24 cells.	('cisplatin', 'Chemical', 'MESH:D002945', (52, 61))	('T24-cisplatin resistant', 'Var', (48, 71))	('higher', 'PosReg', (34, 40))	('expression', 'MPA', (4, 14))	('UCA1', 'Gene', '652995', (25, 29))	('UCA1', 'Gene', (25, 29))
459320	28969100	demonstrated that forced expression of lncRNA UCA1 in the bladder cancer cell line UMUC-2 reduced apoptosis upon cisplatin/gemcitabine treatment, whereas silencing of lncRNA UCA1 in the bladder cancer cell line 5637 increased cellular apoptosis.	('gemcitabine', 'Chemical', 'MESH:C056507', (123, 134))	('reduced', 'NegReg', (90, 97))	('UCA1', 'Gene', '652995', (46, 50))	('apoptosis', 'MPA', (98, 107))	('UCA1', 'Gene', (46, 50))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('bladder cancer', 'Phenotype', 'HP:0009725', (58, 72))	('cisplatin', 'Chemical', 'MESH:D002945', (113, 122))	('UCA1', 'Gene', '652995', (174, 178))	('UCA1', 'Gene', (174, 178))	('increased', 'PosReg', (216, 225))	('UMUC-2', 'CellLine', 'CVCL:8155', (83, 89))	('silencing', 'Var', (154, 163))	('bladder cancer', 'Disease', 'MESH:D001749', (186, 200))	('cellular apoptosis', 'CPA', (226, 244))	('bladder cancer', 'Disease', (186, 200))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('bladder cancer', 'Disease', 'MESH:D001749', (58, 72))	('bladder cancer', 'Disease', (58, 72))	('bladder cancer', 'Phenotype', 'HP:0009725', (186, 200))
459321	28969100	Both in vitro and in vivo experiments confirmed that lncRNA UCA1 induced cisplatin/gemcitabine resistance through activation of CREB by p-AKT and subsequent upregulation of miR-196a-5p.	('activation', 'PosReg', (114, 124))	('miR-1', 'Gene', '79187', (173, 178))	('cisplatin', 'Chemical', 'MESH:D002945', (73, 82))	('AKT', 'Gene', (138, 141))	('lncRNA', 'Var', (53, 59))	('UCA1', 'Gene', '652995', (60, 64))	('gemcitabine', 'Chemical', 'MESH:C056507', (83, 94))	('CREB', 'Gene', (128, 132))	('miR-1', 'Gene', (173, 178))	('UCA1', 'Gene', (60, 64))	('CREB', 'Gene', '1385', (128, 132))	('upregulation', 'PosReg', (157, 169))	('induced', 'Reg', (65, 72))	('cisplatin/gemcitabine resistance', 'MPA', (73, 105))	('AKT', 'Gene', '207', (138, 141))
459329	28969100	However, knockdown of SRPK1 overcomes cisplatin resistance in SKOV3-pcDNA-UCA1 cells and increased Bcl-2 and decreased Bax, Caspase-3 and Caspase-9 expression is observed.	('SRPK1', 'Gene', (22, 27))	('Bax', 'Gene', (119, 122))	('Caspase-3', 'Gene', '836', (124, 133))	('Bcl-2', 'Gene', (99, 104))	('cisplatin', 'Chemical', 'MESH:D002945', (38, 47))	('Bax', 'Gene', '581', (119, 122))	('knockdown', 'Var', (9, 18))	('Caspase-9', 'Gene', '842', (138, 147))	('cisplatin resistance', 'MPA', (38, 58))	('UCA1', 'Gene', '652995', (74, 78))	('UCA1', 'Gene', (74, 78))	('Caspase-9', 'Gene', (138, 147))	('Bcl-2', 'Gene', '596', (99, 104))	('increased', 'PosReg', (89, 98))	('SKOV3', 'CellLine', 'CVCL:0532', (62, 67))	('decreased', 'NegReg', (109, 118))	('SRPK1', 'Gene', '6732', (22, 27))	('Caspase-3', 'Gene', (124, 133))	('overcomes', 'NegReg', (28, 37))	('expression', 'MPA', (148, 158))
459331	28969100	observed that lncRNA UCA1 levels were significantly higher in ovarian cancer tissues compared to normal ovarian tissues, and high UCA1 expression was associated with more lymph node metastasis, advanced FIGO stage, and bad response to platinum-based chemotherapy.	('associated', 'Reg', (150, 160))	('more', 'PosReg', (166, 170))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('ovarian cancer', 'Phenotype', 'HP:0100615', (62, 76))	('platinum', 'Chemical', 'MESH:D010984', (235, 243))	('lymph node metastasis', 'CPA', (171, 192))	('ovarian cancer', 'Disease', 'MESH:D010051', (62, 76))	('UCA1', 'Gene', '652995', (130, 134))	('expression', 'MPA', (135, 145))	('ovarian cancer', 'Disease', (62, 76))	('UCA1', 'Gene', (130, 134))	('higher', 'PosReg', (52, 58))	('UCA1', 'Gene', '652995', (21, 25))	('UCA1', 'Gene', (21, 25))	('high', 'Var', (125, 129))	('advanced FIGO stage', 'CPA', (194, 213))
459336	28969100	showed that knockdown of lncRNA UCA1 in tamoxifen resistant LCC2 and LCC9 cells increased apoptosis upon tamoxifen treatment accompanied by significant reduction in p-AKT and p-mTOR.	('AKT', 'Gene', (167, 170))	('UCA1', 'Gene', '652995', (32, 36))	('UCA1', 'Gene', (32, 36))	('tamoxifen', 'Chemical', 'MESH:D013629', (40, 49))	('tamoxifen', 'Chemical', 'MESH:D013629', (105, 114))	('increased', 'PosReg', (80, 89))	('knockdown', 'Var', (12, 21))	('mTOR', 'Gene', (177, 181))	('LCC9', 'CellLine', 'CVCL:W648', (69, 73))	('mTOR', 'Gene', '2475', (177, 181))	('AKT', 'Gene', '207', (167, 170))	('apoptosis', 'CPA', (90, 99))	('reduction', 'NegReg', (152, 161))
459344	28969100	Also, knockdown of lncRNA UCA1 prevented the nuclear translocation of beta-catenin, thereby inhibiting the Wnt signaling pathway.	('beta-catenin', 'Gene', (70, 82))	('prevented', 'NegReg', (31, 40))	('beta-catenin', 'Gene', '1499', (70, 82))	('nuclear translocation of', 'MPA', (45, 69))	('UCA1', 'Gene', '652995', (26, 30))	('UCA1', 'Gene', (26, 30))	('Wnt signaling pathway', 'Pathway', (107, 128))	('knockdown', 'Var', (6, 15))	('inhibiting', 'NegReg', (92, 102))
459347	28969100	Further, LCC2 exosomes with impaired UCA1 could not induce tamoxifen resistance in MCF-7 cells.	('induce', 'Reg', (52, 58))	('not', 'NegReg', (48, 51))	('MCF-7', 'CellLine', 'CVCL:0031', (83, 88))	('UCA1', 'Gene', '652995', (37, 41))	('UCA1', 'Gene', (37, 41))	('tamoxifen', 'Chemical', 'MESH:D013629', (59, 68))	('impaired', 'Var', (28, 36))
459351	28969100	Functional analysis indicated that a secondary T790M mutation is the major cause of acquired resistance ; c-MET amplification, PIK3CA mutations (~5%), BRAF mutations and small-cell lung cancer transformation were also associated with acquired resistance.	('cause', 'Reg', (75, 80))	('c-MET', 'Gene', '4233', (106, 111))	('T790M', 'Mutation', 'rs121434569', (47, 52))	('mutations', 'Var', (156, 165))	('acquired resistance', 'MPA', (84, 103))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('T790M', 'Var', (47, 52))	('PIK3CA', 'Gene', (127, 133))	('BRAF', 'Gene', '673', (151, 155))	('small-cell lung cancer', 'Disease', 'MESH:D055752', (170, 192))	('lung cancer', 'Phenotype', 'HP:0100526', (181, 192))	('PIK3CA', 'Gene', '5290', (127, 133))	('BRAF', 'Gene', (151, 155))	('c-MET', 'Gene', (106, 111))	('mutations', 'Var', (134, 143))	('associated', 'Reg', (218, 228))	('acquired', 'MPA', (234, 242))	('small-cell lung cancer', 'Disease', (170, 192))
459355	28969100	Functional analysis showed that knockdown of UCA1 in PC9/R cells without T790M mutation partly restored gefitinib sensitivity with increased expression of caspase 3 and caspase 8, whereas H1975 cells with T790M mutation remained gefitinib resistant.	('gefitinib sensitivity', 'MPA', (104, 125))	('T790M', 'Mutation', 'rs121434569', (205, 210))	('UCA1', 'Gene', (45, 49))	('increased', 'PosReg', (131, 140))	('caspase 3', 'Gene', (155, 164))	('T790M', 'Var', (73, 78))	('gefitinib', 'Chemical', 'MESH:D000077156', (104, 113))	('caspase 8', 'Gene', '841', (169, 178))	('caspase 3', 'Gene', '836', (155, 164))	('gefitinib', 'Chemical', 'MESH:D000077156', (229, 238))	('caspase 8', 'Gene', (169, 178))	('expression', 'MPA', (141, 151))	('UCA1', 'Gene', '652995', (45, 49))	('PC9', 'Gene', (53, 56))	('PC9', 'Gene', '255738', (53, 56))	('T790M', 'Mutation', 'rs121434569', (73, 78))	('restored', 'PosReg', (95, 103))	('H1975', 'CellLine', 'CVCL:1511', (188, 193))
459356	28969100	Moreover, both in vitro and in vivo analysis confirmed that lncRNA UCA1 contributed to non-T790M acquired resistance to EGFR-TKIs by activating the AKT/mTOR pathway and EMT.	('activating', 'PosReg', (133, 143))	('AKT', 'Gene', '207', (148, 151))	('T790M', 'Mutation', 'rs121434569', (91, 96))	('mTOR', 'Gene', (152, 156))	('mTOR', 'Gene', '2475', (152, 156))	('AKT', 'Gene', (148, 151))	('UCA1', 'Gene', '652995', (67, 71))	('EMT', 'Gene', (169, 172))	('UCA1', 'Gene', (67, 71))	('EMT', 'Gene', '3702', (169, 172))	('resistance', 'MPA', (106, 116))	('EGFR', 'Gene', '1956', (120, 124))	('non-T790M', 'Var', (87, 96))	('EGFR', 'Gene', (120, 124))
459362	28969100	showed that lncRNA UCA1 levels were higher in SGC7901/ADR cells compared to the parental SGC7901 cells and this resulted in a 4.3 fold increase in IC50 after adriamycin treatment.	('SGC7901/ADR', 'Var', (46, 57))	('higher', 'PosReg', (36, 42))	('increase', 'PosReg', (135, 143))	('UCA1', 'Gene', '652995', (19, 23))	('UCA1', 'Gene', (19, 23))	('adriamycin', 'Chemical', 'MESH:D004317', (158, 168))	('IC50', 'MPA', (147, 151))
459375	28969100	In addition, lncRNA UCA1 overexpression increased Sirt1 expression in PNT2 cells, while silencing of endogenous lncRNA UCA1 decreased Sirt1 expression in LNCaP and 22RV1 cells.	('22RV1', 'CellLine', 'CVCL:1045', (164, 169))	('Sirt1', 'Gene', '23411', (50, 55))	('expression', 'MPA', (140, 150))	('LNCaP', 'CellLine', 'CVCL:0395', (154, 159))	('UCA1', 'Gene', '652995', (119, 123))	('decreased', 'NegReg', (124, 133))	('UCA1', 'Gene', (119, 123))	('silencing', 'Var', (88, 97))	('expression', 'MPA', (56, 66))	('Sirt1', 'Gene', (50, 55))	('Sirt1', 'Gene', (134, 139))	('increased', 'PosReg', (40, 49))	('UCA1', 'Gene', '652995', (20, 24))	('UCA1', 'Gene', (20, 24))	('Sirt1', 'Gene', '23411', (134, 139))
459377	28969100	Interestingly, lncRNA UCA1 and Sirt1 levels were significantly upregulated in 22RV1/DR cells compared to the parental 22RV1 cells and miR-204 was downregulated.	('Sirt1', 'Gene', (31, 36))	('miR-204', 'Gene', (134, 141))	('Sirt1', 'Gene', '23411', (31, 36))	('UCA1', 'Gene', '652995', (22, 26))	('UCA1', 'Gene', (22, 26))	('upregulated', 'PosReg', (63, 74))	('22RV1', 'CellLine', 'CVCL:1045', (118, 123))	('miR-204', 'Gene', '406987', (134, 141))	('22RV1/DR', 'Var', (78, 86))	('22RV1', 'CellLine', 'CVCL:1045', (78, 83))
459383	28969100	The underlying mechanisms of imatinib resistance could be a result of point mutations in the breakpoint cluster region-Abelson murine leukemia (BCR-ABL) kinase domain, amplification of the BCR-ABL gene, and overexpression of the multidrug resistance protein 1 (MRP1) gene in tumor cells.	('tumor', 'Disease', (275, 280))	('murine', 'Species', '10090', (127, 133))	('tumor', 'Disease', 'MESH:D009369', (275, 280))	('MRP1', 'Gene', '18669', (261, 265))	('BCR', 'Gene', '613', (144, 147))	('drug resistance', 'Phenotype', 'HP:0020174', (234, 249))	('leukemia', 'Phenotype', 'HP:0001909', (134, 142))	('imatinib', 'Chemical', 'MESH:D000068877', (29, 37))	('multidrug resistance protein 1', 'Gene', (229, 259))	('MRP1', 'Gene', (261, 265))	('multidrug resistance protein 1', 'Gene', '18669', (229, 259))	('BCR', 'Gene', (144, 147))	('leukemia', 'Disease', 'MESH:D007938', (134, 142))	('BCR', 'Gene', '613', (189, 192))	('leukemia', 'Disease', (134, 142))	('tumor', 'Phenotype', 'HP:0002664', (275, 280))	('overexpression', 'PosReg', (207, 221))	('BCR', 'Gene', (189, 192))	('amplification', 'PosReg', (168, 181))	('point mutations', 'Var', (70, 85))
459385	28969100	Further, MDR1 protein expression was higher in K562/IM-R and lower in K562/IM cells compared to K562 cells.	('K562/IM', 'Var', (70, 77))	('lower', 'NegReg', (61, 66))	('higher', 'PosReg', (37, 43))	('protein', 'Protein', (14, 21))	('MDR1', 'Gene', '5243', (9, 13))	('K562/IM-R', 'Var', (47, 56))	('K562', 'CellLine', 'CVCL:0004', (96, 100))	('K562', 'CellLine', 'CVCL:0004', (70, 74))	('MDR1', 'Gene', (9, 13))	('K562', 'CellLine', 'CVCL:0004', (47, 51))
459386	28969100	Also, lncRNA UCA1 expression was higher in K562/IM-R and lower in K562/IM cells than in K562 cells, which indicated the role of lncRNA UCA1 in IM resistance of CML cells.	('K562', 'CellLine', 'CVCL:0004', (43, 47))	('higher', 'PosReg', (33, 39))	('CML', 'Disease', (160, 163))	('UCA1', 'Gene', '652995', (135, 139))	('UCA1', 'Gene', (135, 139))	('K562/IM-R', 'Var', (43, 52))	('K562', 'CellLine', 'CVCL:0004', (66, 70))	('UCA1', 'Gene', '652995', (13, 17))	('expression', 'MPA', (18, 28))	('UCA1', 'Gene', (13, 17))	('CML', 'Disease', 'MESH:D015464', (160, 163))	('CML', 'Phenotype', 'HP:0005506', (160, 163))	('K562', 'CellLine', 'CVCL:0004', (88, 92))	('K562/IM', 'Var', (66, 73))	('lower', 'NegReg', (57, 62))
459387	28969100	Stable transfection of lncRNA UCA1 in K562 cells markedly upregulated MDR1 mRNA and protein levels and resulted in IM resistance, whereas silencing of UCA1 in K562/IM cells significantly inhibited MDR1 expression.	('resulted in', 'Reg', (103, 114))	('MDR1', 'Gene', (197, 201))	('UCA1', 'Gene', '652995', (151, 155))	('MDR1', 'Gene', '5243', (70, 74))	('silencing', 'Var', (138, 147))	('K562', 'CellLine', 'CVCL:0004', (38, 42))	('MDR1', 'Gene', '5243', (197, 201))	('expression', 'MPA', (202, 212))	('upregulated', 'PosReg', (58, 69))	('IM resistance', 'MPA', (115, 128))	('UCA1', 'Gene', '652995', (30, 34))	('MDR1', 'Gene', (70, 74))	('UCA1', 'Gene', (30, 34))	('K562', 'CellLine', 'CVCL:0004', (159, 163))	('UCA1', 'Gene', (151, 155))	('inhibited', 'NegReg', (187, 196))
459404	28969100	The positive correlation between lncRNA UCA1 expression and poor prognosis in a great number of cancer types as mentioned in the above meta-analysis suggests that lncRNA UCA1 could act as an independent prognostic factor for cancer patients.	('lncRNA', 'Var', (163, 169))	('UCA1', 'Gene', '652995', (170, 174))	('UCA1', 'Gene', '652995', (40, 44))	('UCA1', 'Gene', (170, 174))	('cancer', 'Disease', 'MESH:D009369', (225, 231))	('patients', 'Species', '9606', (232, 240))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('cancer', 'Disease', (225, 231))	('UCA1', 'Gene', (40, 44))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('cancer', 'Disease', (96, 102))
459407	28969100	The majority of these results of drug resistance were from in vitro studies, whereas clinical data was available only in ovarian cancers where high lncRNA UCA1 expression was associated with the response to platinum-based chemotherapy.	('expression', 'MPA', (160, 170))	('UCA1', 'Gene', (155, 159))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('associated with', 'Reg', (175, 190))	('platinum', 'Chemical', 'MESH:D010984', (207, 215))	('cancers', 'Phenotype', 'HP:0002664', (129, 136))	('ovarian cancer', 'Phenotype', 'HP:0100615', (121, 135))	('ovarian cancers', 'Phenotype', 'HP:0100615', (121, 136))	('ovarian cancers', 'Disease', (121, 136))	('high lncRNA', 'Var', (143, 154))	('ovarian cancers', 'Disease', 'MESH:D010051', (121, 136))	('drug resistance', 'Phenotype', 'HP:0020174', (33, 48))	('UCA1', 'Gene', '652995', (155, 159))
459414	28969100	The two main approaches in RNA targeted therapeutics include double stranded RNA-mediated interference (RNAi) and antisense oligonucleotides (ASO).	('double', 'Var', (61, 67))	('antisense oligonucleotides', 'Var', (114, 140))	('oligonucleotides', 'Chemical', 'MESH:D009841', (124, 140))
459418	28969100	In fact, knockdown of lncRNA UCA1 by short interfering RNAs (siRNA) or short hairpin RNA (shRNA) has been shown to reverse drug resistance in various cancer cells such as bladder cancer, breast cancer, lung cancer, gastric cancer, colorectal cancer, prostate cancer, CML, ovarian cancer.	('cancer', 'Disease', 'MESH:D009369', (259, 265))	('colorectal cancer', 'Disease', 'MESH:D015179', (231, 248))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('cancer', 'Disease', (280, 286))	('prostate cancer', 'Disease', (250, 265))	('gastric cancer', 'Disease', (215, 229))	('lung cancer', 'Phenotype', 'HP:0100526', (202, 213))	('drug resistance', 'MPA', (123, 138))	('ovarian cancer', 'Disease', 'MESH:D010051', (272, 286))	('colorectal cancer', 'Disease', (231, 248))	('cancer', 'Disease', (223, 229))	('cancer', 'Disease', 'MESH:D009369', (194, 200))	('drug resistance', 'Phenotype', 'HP:0020174', (123, 138))	('CML', 'Phenotype', 'HP:0005506', (267, 270))	('cancer', 'Disease', 'MESH:D009369', (242, 248))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('cancer', 'Disease', (207, 213))	('UCA1', 'Gene', '652995', (29, 33))	('short', 'MPA', (71, 76))	('UCA1', 'Gene', (29, 33))	('gastric cancer', 'Disease', 'MESH:D013274', (215, 229))	('cancer', 'Disease', (150, 156))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('ovarian cancer', 'Disease', (272, 286))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('cancer', 'Disease', (259, 265))	('breast cancer', 'Phenotype', 'HP:0003002', (187, 200))	('cancer', 'Disease', 'MESH:D009369', (280, 286))	('short', 'MPA', (37, 42))	('knockdown', 'Var', (9, 18))	('ovarian cancer', 'Phenotype', 'HP:0100615', (272, 286))	('lung cancer', 'Disease', (202, 213))	('bladder cancer', 'Disease', 'MESH:D001749', (171, 185))	('bladder cancer', 'Disease', (171, 185))	('colorectal cancer', 'Phenotype', 'HP:0003003', (231, 248))	('cancer', 'Disease', 'MESH:D009369', (223, 229))	('breast cancer', 'Disease', 'MESH:D001943', (187, 200))	('gastric cancer', 'Phenotype', 'HP:0012126', (215, 229))	('CML', 'Disease', 'MESH:D015464', (267, 270))	('breast cancer', 'Disease', (187, 200))	('bladder cancer', 'Phenotype', 'HP:0009725', (171, 185))	('cancer', 'Disease', 'MESH:D009369', (207, 213))	('cancer', 'Disease', (194, 200))	('cancer', 'Disease', (242, 248))	('CML', 'Disease', (267, 270))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('reverse', 'NegReg', (115, 122))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('prostate cancer', 'Disease', 'MESH:D011471', (250, 265))	('prostate cancer', 'Phenotype', 'HP:0012125', (250, 265))	('cancer', 'Disease', (179, 185))	('lung cancer', 'Disease', 'MESH:D008175', (202, 213))
459423	28969100	Thus, Ets-2, C/EBPalpha, HIF-1alpha, and transcriptional complexes (TAZ/YAP/TEAD/SMAD2/3) are potential targets to knockdown the expression of lncRNA UCA1.	('YAP', 'Gene', '10413', (72, 75))	('TAZ', 'Gene', '6901', (68, 71))	('Ets-2', 'Gene', '2114', (6, 11))	('HIF-1alpha', 'Gene', (25, 35))	('TAZ', 'Gene', (68, 71))	('C/EBPalpha', 'Gene', (13, 23))	('YAP', 'Gene', (72, 75))	('HIF-1alpha', 'Gene', '3091', (25, 35))	('C/EBPalpha', 'Gene', '1050', (13, 23))	('UCA1', 'Gene', '652995', (150, 154))	('UCA1', 'Gene', (150, 154))	('Ets-2', 'Gene', (6, 11))	('knockdown', 'Var', (115, 124))
459428	28969100	Direct targeting of the UCA1 genomic locus is another method to knockdown UCA1 expression in malignant tumors.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('malignant tumors', 'Disease', 'MESH:D018198', (93, 109))	('expression', 'MPA', (79, 89))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('UCA1', 'Gene', '652995', (74, 78))	('UCA1', 'Gene', (74, 78))	('knockdown', 'Var', (64, 73))	('malignant tumors', 'Disease', (93, 109))	('UCA1', 'Gene', '652995', (24, 28))	('UCA1', 'Gene', (24, 28))
459512	33072070	Clinical Implications of Aberrant PD-1 and CTLA4 Expression for Cancer Immunity and Prognosis: A Pan-Cancer Study Combination therapy with inhibitors of cytotoxic T lymphocyte-associated protein (CTLA)4 and programmed death (PD)-1 has demonstrated efficacy in cancer patients.	('death', 'Disease', 'MESH:D003643', (218, 223))	('Cancer', 'Disease', (64, 70))	('death', 'Disease', (218, 223))	('CTLA4', 'Gene', (43, 48))	('Aberrant', 'Var', (25, 33))	('Cancer', 'Disease', 'MESH:D009369', (101, 107))	('PD-1', 'Gene', (34, 38))	('Combination', 'Interaction', (114, 125))	('Cancer', 'Disease', 'MESH:D009369', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (260, 266))	('patients', 'Species', '9606', (267, 275))	('cytotoxic T lymphocyte-associated protein (CTLA)4', 'Gene', '1493', (153, 202))	('Cancer', 'Phenotype', 'HP:0002664', (64, 70))	('cancer', 'Disease', (260, 266))	('CTLA4', 'Gene', '1493', (43, 48))	('cancer', 'Phenotype', 'HP:0002664', (260, 266))	('Cancer', 'Phenotype', 'HP:0002664', (101, 107))	('Cancer', 'Disease', (101, 107))
459526	33072070	For example, tumor hypoxia-associated multi-omic investigations have shown that some molecular variants are correlated with antitumor drug sensitivity or resistance, which has important implications for cancer treatment.	('tumor', 'Disease', (13, 18))	('correlated', 'Reg', (108, 118))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('variants', 'Var', (95, 103))	('tumor hypoxia', 'Disease', 'MESH:D000860', (13, 26))	('tumor hypoxia', 'Disease', (13, 26))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('resistance', 'MPA', (154, 164))	('cancer', 'Disease', (203, 209))	('cancer', 'Disease', 'MESH:D009369', (203, 209))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('tumor', 'Disease', (128, 133))	('drug sensitivity', 'Phenotype', 'HP:0020174', (134, 150))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))
459533	33072070	PD-1 is a transmembrane protein that is expressed by immunocytes; blocking PD-1 signaling enhances the anticancer effect of T cells, thereby promoting cancer cell killing.	('PD-1', 'Gene', (75, 79))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('promoting', 'PosReg', (141, 150))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('cancer', 'Disease', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('blocking', 'Var', (66, 74))	('cancer', 'Disease', (107, 113))	('enhances', 'PosReg', (90, 98))
459535	33072070	Although PD-1 and CTLA4 overexpression, mutations, and gene amplification have been reported in certain cancers, the studies had small sample sizes and used different experimental approaches, making it difficult to compare the findings.	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('CTLA4', 'Gene', (18, 23))	('gene amplification', 'Var', (55, 73))	('mutations', 'Var', (40, 49))	('overexpression', 'PosReg', (24, 38))	('cancers', 'Phenotype', 'HP:0002664', (104, 111))	('cancers', 'Disease', (104, 111))	('PD-1', 'Gene', (9, 13))	('cancers', 'Disease', 'MESH:D009369', (104, 111))
459563	33072070	Patients with high MSI (MSI-H) cancers benefit from immunotherapy, and MSI is an index used for cancer detection.	('MSI-H', 'Gene', (24, 29))	('MSI', 'Gene', '5928', (71, 74))	('MSI', 'Gene', (71, 74))	('MSI', 'Gene', (24, 27))	('cancer', 'Disease', (96, 102))	('MSI', 'Gene', '5928', (24, 27))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('high', 'Var', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('MSI-H', 'Gene', '5928', (24, 29))	('cancers', 'Phenotype', 'HP:0002664', (31, 38))	('cancers', 'Disease', (31, 38))	('cancer', 'Disease', (31, 37))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('benefit', 'PosReg', (39, 46))	('MSI', 'Gene', (19, 22))	('immunotherapy', 'CPA', (52, 65))	('MSI', 'Gene', '5928', (19, 22))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('cancers', 'Disease', 'MESH:D009369', (31, 38))
459565	33072070	Gene mutation frequency may be increased in cancer cells as a result of downregulation of MMR genes or defective MMR.	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('Gene mutation', 'Var', (0, 13))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('MMR', 'Gene', (113, 116))	('downregulation', 'NegReg', (72, 86))	('defective', 'NegReg', (103, 112))	('MMR genes', 'Gene', (90, 99))
459581	33072070	The Kaplan-Meier survival analysis showed that subjects with higher PD-1 levels had shorter OS than those with lower levels in GBM (P = 0.037), KIRP (P = 0.040), LAML (P = 0.002), low-grade glioma (LGG) (P < 0.001), and UVM (P < 0.001).	('glioma', 'Disease', (190, 196))	('glioma', 'Disease', 'MESH:D005910', (190, 196))	('glioma', 'Phenotype', 'HP:0009733', (190, 196))	('shorter', 'NegReg', (84, 91))	('levels', 'Var', (73, 79))	('UVM', 'Phenotype', 'HP:0007716', (220, 223))	('PD-1', 'Gene', (68, 72))
459584	33072070	The Kaplan-Meier survival analysis showed that patients with higher CTLA4 expression had shorter OS than those with lower CTLA4 expression in KIRC (P = 0.008), LGG (P < 0.001), and THYM (P = 0.040).	('THYM', 'Phenotype', 'HP:0100522', (181, 185))	('higher', 'PosReg', (61, 67))	('CTLA4', 'Gene', (68, 73))	('patients', 'Species', '9606', (47, 55))	('expression', 'Var', (74, 84))	('shorter', 'NegReg', (89, 96))
459606	33072070	Our results showed that PD-1 and CTLA4 expression varies across cancer types and that most cancers are characterized by PD-1 and CTLA4 mutations that lead to their abnormal expression, which can serve as a prognostic biomarker.	('PD-1', 'Gene', (120, 124))	('cancers', 'Disease', 'MESH:D009369', (91, 98))	('cancers', 'Phenotype', 'HP:0002664', (91, 98))	('cancer', 'Disease', (91, 97))	('cancers', 'Disease', (91, 98))	('cancer', 'Disease', (64, 70))	('mutations', 'Var', (135, 144))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('expression', 'MPA', (173, 183))	('CTLA4', 'Gene', (129, 134))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
459609	33072070	Identifying aberrantly expressed genes in tumors is important for the development of individualized treatments, which can improve therapeutic outcomes.	('aberrantly expressed', 'Var', (12, 32))	('tumors', 'Disease', (42, 48))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('tumors', 'Disease', 'MESH:D009369', (42, 48))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
459615	33072070	Gene mutations are the major cause of cancer development, and specific mutations predict treatment response and prognosis.	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('mutations', 'Var', (71, 80))	('predict', 'Reg', (81, 88))	('cancer', 'Disease', (38, 44))	('cause', 'Reg', (29, 34))
459616	33072070	TMB affects the generation of immunogenic peptides, thereby affecting patients' response to immune checkpoint inhibitor treatment.	('patients', 'Species', '9606', (70, 78))	('affecting', 'Reg', (60, 69))	('TMB', 'Chemical', '-', (0, 3))	('affects', 'Reg', (4, 11))	('TMB', 'Var', (0, 3))	('generation of immunogenic peptides', 'MPA', (16, 50))	('response to immune checkpoint inhibitor treatment', 'MPA', (80, 129))
459625	33072070	However, it remains to be determined whether the combination of PD-1 and CTLA4 inhibitors has greater efficacy than monotherapy in these cancers.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('PD-1', 'Gene', (64, 68))	('cancers', 'Disease', 'MESH:D009369', (137, 144))	('inhibitors', 'Var', (79, 89))	('cancers', 'Phenotype', 'HP:0002664', (137, 144))	('cancers', 'Disease', (137, 144))	('CTLA4', 'Gene', (73, 78))
459626	33072070	Epigenetic modifications modulate gene expression and can be exploited by tumor cells to evade immune surveillance.	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('gene expression', 'MPA', (34, 49))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor', 'Disease', (74, 79))	('modulate', 'Reg', (25, 33))	('Epigenetic modifications', 'Var', (0, 24))
459633	32194639	Dysregulation of RNA binding proteins (RBPs) has been found in a variety of cancers and is related to oncogenesis and progression.	('cancers', 'Disease', 'MESH:D009369', (76, 83))	('cancers', 'Phenotype', 'HP:0002664', (76, 83))	('related', 'Reg', (91, 98))	('cancers', 'Disease', (76, 83))	('Dysregulation', 'Var', (0, 13))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('found', 'Reg', (54, 59))	('RBP', 'Gene', '5950', (39, 42))	('RBP', 'Gene', (39, 42))
459646	32194639	Owing to differences in genetic and epigenetic changes among different subtypes of lung cancer, effective treatment targets of adenocarcinoma may not be suitable for LUSC.	('lung cancer', 'Disease', 'MESH:D008175', (83, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('LUSC', 'Phenotype', 'HP:0030359', (166, 170))	('adenocarcinoma', 'Disease', (127, 141))	('LUSC', 'Disease', 'MESH:D002294', (166, 170))	('LUSC', 'Disease', (166, 170))	('lung cancer', 'Disease', (83, 94))	('lung cancer', 'Phenotype', 'HP:0100526', (83, 94))	('adenocarcinoma', 'Disease', 'MESH:D000230', (127, 141))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('epigenetic changes', 'Var', (36, 54))
459651	32194639	Given that RPBs perform various critical functions in post-transcriptional events, it is unsurprising that alterations in RBPs are closely related to the initiation and progression of many human diseases.	('related', 'Reg', (139, 146))	('RBP', 'Gene', (122, 125))	('human', 'Species', '9606', (189, 194))	('alterations', 'Var', (107, 118))	('RBP', 'Gene', '5950', (122, 125))
459654	32194639	It is well-known that the dysregulation of RBPs in cancer cells is mainly caused by genomic alterations, microRNA-mediated regulation, epigenetic mechanisms, and post-translational modifications.	('post-translational modifications', 'Var', (162, 194))	('epigenetic', 'Var', (135, 145))	('RBP', 'Gene', (43, 46))	('genomic', 'Var', (84, 91))	('caused by', 'Reg', (74, 83))	('microRNA-mediated regulation', 'MPA', (105, 133))	('dysregulation', 'MPA', (26, 39))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('RBP', 'Gene', '5950', (43, 46))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))
459699	32194639	The amplification of MRPL47 was the most frequent copy-number alteration among these 10 hub genes.	('MRPL47', 'Gene', (21, 27))	('amplification', 'Var', (4, 17))	('MRPL47', 'Gene', '57129', (21, 27))
459700	32194639	We also found that mitochondrial translation-related genes, including GFM1, MTIF2, MTRF1, MRPS10, MRPS11, MRPL1, MRPL9, and PTCD3, were closely associated with alterations of the 10 hub genes.	('associated', 'Reg', (144, 154))	('MTIF2', 'Gene', '4528', (76, 81))	('mitochondrial translation-related genes', 'Gene', (19, 58))	('MRPS10', 'Gene', '55173', (90, 96))	('MTRF1', 'Gene', '9617', (83, 88))	('MRPS10', 'Gene', (90, 96))	('PTCD3', 'Gene', '55037', (124, 129))	('MRPL9', 'Gene', (113, 118))	('MRPL1', 'Gene', (106, 111))	('PTCD3', 'Gene', (124, 129))	('alterations', 'Var', (160, 171))	('MRPL1', 'Gene', '65008', (106, 111))	('MRPS11', 'Gene', '64963', (98, 104))	('GFM1', 'Gene', '85476', (70, 74))	('MTIF2', 'Gene', (76, 81))	('GFM1', 'Gene', (70, 74))	('MTRF1', 'Gene', (83, 88))	('MRPL9', 'Gene', '65005', (113, 118))	('MRPS11', 'Gene', (98, 104))
459707	32194639	Then we performed a time-dependent ROC analysis to further evaluate the prognostic performance of the nine-RBP gene signature; the AUC of the ROC curve for OS was 0.712 at 3 years and 0.696 at 5 years (Figure 7B).	('OS', 'Chemical', '-', (156, 158))	('0.696', 'Var', (184, 189))	('RBP', 'Gene', (107, 110))	('RBP', 'Gene', '5950', (107, 110))
459710	32194639	The results indicated that patients with high-risk score had poorer OS than those with low-risk score in the GSE73403 cohorts (Figures 8A-C).	('OS', 'Chemical', '-', (68, 70))	('patients', 'Species', '9606', (27, 35))	('high-risk score', 'Var', (41, 56))	('poorer', 'NegReg', (61, 67))
459718	32194639	This includes gain of function mutations of oncogenes and functional deletion alterations of tumor-suppressor genes, or disabling of genome maintenance genes.	('mutations', 'Var', (31, 40))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('deletion alterations', 'Var', (69, 89))	('tumor', 'Disease', (93, 98))	('oncogenes', 'Gene', (44, 53))	('gain of function', 'PosReg', (14, 30))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
459751	32194639	We investigated the expression, potential functions, and prognostic values of aberrantly expressed RBPs via a series of bioinformatics analysis in LUSC.	('RBP', 'Gene', (99, 102))	('aberrantly expressed', 'Var', (78, 98))	('investigated', 'Reg', (3, 15))	('LUSC', 'Phenotype', 'HP:0030359', (147, 151))	('RBP', 'Gene', '5950', (99, 102))	('LUSC', 'Disease', 'MESH:D002294', (147, 151))	('LUSC', 'Disease', (147, 151))
459773	30837581	In fact, among the most common driver oncogene mutations in PSC there are those ones involving KRAS (30-40% of patients) and MET genes (13-20%).	('KRAS', 'Gene', '3845', (95, 99))	('PSC', 'Disease', (60, 63))	('mutations', 'Var', (47, 56))	('KRAS', 'Gene', (95, 99))	('MET genes', 'Gene', (125, 134))	('patients', 'Species', '9606', (111, 119))
459817	30837581	Moreover, it was demonstrated that depletion of SLMAP results in the constitutive activation of the Hippo Pathway, whose disruption was associated with tumorigenesis, cancer progression and tumor immunogenicity.	('associated', 'Reg', (136, 146))	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('SLMAP', 'Gene', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('cancer', 'Disease', (167, 173))	('tumor', 'Disease', (152, 157))	('activation', 'PosReg', (82, 92))	('tumor', 'Disease', (190, 195))	('Hippo Pathway', 'Pathway', (100, 113))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('depletion', 'Var', (35, 44))	('SLMAP', 'Gene', '7871', (48, 53))
459824	30837581	Considering that this pathway is essential for the response to DNA damage, its enrichment in PSC might then explain why these tumors are less susceptible to DNA cross-link based chemotherapy and may suggest new therapeutic strategies based on the inhibition or downregulation of FA, which was already demonstrated to be able to reverse acquired resistance to cisplatin in NSCLC cell lines.	('PSC', 'Disease', (93, 96))	('tumors', 'Disease', (126, 132))	('tumors', 'Disease', 'MESH:D009369', (126, 132))	('NSCLC', 'Disease', (372, 377))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('cisplatin', 'Chemical', 'MESH:D002945', (359, 368))	('NSCLC', 'Disease', 'MESH:D002289', (372, 377))	('FA', 'Phenotype', 'HP:0001994', (279, 281))	('inhibition', 'Var', (247, 257))	('downregulation', 'NegReg', (261, 275))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('NSCLC', 'Phenotype', 'HP:0030358', (372, 377))
459831	30837581	In fact, activating mutations in PIK3CA result in increased AKT activity and the consequent phosphorylation of FOXO proteins.	('FOXO proteins', 'Protein', (111, 124))	('phosphorylation', 'MPA', (92, 107))	('PIK3CA', 'Gene', '5290', (33, 39))	('AKT', 'Gene', '207', (60, 63))	('increased', 'PosReg', (50, 59))	('activating', 'PosReg', (9, 19))	('AKT', 'Gene', (60, 63))	('PIK3CA', 'Gene', (33, 39))	('mutations', 'Var', (20, 29))
459844	30837581	The limit of detection of this assay ranges from 2.5% to 5% for the most frequent mutation hotspots in NSCLC.	('mutation', 'Var', (82, 90))	('NSCLC', 'Disease', (103, 108))	('NSCLC', 'Phenotype', 'HP:0030358', (103, 108))	('NSCLC', 'Disease', 'MESH:D002289', (103, 108))
459874	33391473	Results: The results showed that patients with high RS showed substantially higher objective response rate than those with low RS in training set (P < 0.001), validation set (P < 0.001) and real-world cohort (P = 0.019).	('high RS', 'Var', (47, 54))	('higher', 'PosReg', (76, 82))	('objective response rate', 'CPA', (83, 106))	('patients', 'Species', '9606', (33, 41))
459875	33391473	Notably, variant allele frequency (VAF) calculated from an ultra-deep sequencing platform significantly reduced in patients experienced a complete or partial response after 2 cycles of chemotherapy (P < 0.001), while it significantly increased in these of non-responder (P < 0.001).	('patients', 'Species', '9606', (115, 123))	('variant', 'Var', (9, 16))	('reduced', 'NegReg', (104, 111))	('partial', 'NegReg', (150, 157))
459889	33391473	Our results showed that patients with high RS showed significantly superior objective response rate (ORR), progression-free survival (PFS) and overall survival (OS) than those with low RS in training, validation set and an external real-world cohort.	('superior', 'PosReg', (67, 75))	('high RS', 'Var', (38, 45))	('progression-free survival', 'CPA', (107, 132))	('objective response rate', 'CPA', (76, 99))	('patients', 'Species', '9606', (24, 32))	('overall survival', 'CPA', (143, 159))
459896	33391473	in previous studies; (iv) genes potentially correlated with the transport, metabolism and resistance of chemotherapeutic agents in previous publications; (v) genes involved in several biological processes associated with cancer cell survival, growth and apoptosis such as DNA replication, transcription and damage repair, cell cycle, immune response pathways and so on.	('cancer', 'Disease', 'MESH:D009369', (221, 227))	('cancer', 'Disease', (221, 227))	('involved', 'Reg', (164, 172))	('genes', 'Var', (158, 163))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('DNA', 'Disease', (272, 275))
459925	33391473	42 patients with advanced NSCLC received docetaxel plus cisplatin/carboplatin as first-line treatment (Figure S13A).	('cisplatin', 'Chemical', 'MESH:D002945', (56, 65))	('NSCLC', 'Disease', (26, 31))	('S13A', 'SUBSTITUTION', 'None', (110, 114))	('docetaxel', 'Chemical', 'MESH:D000077143', (41, 50))	('NSCLC', 'Phenotype', 'HP:0030358', (26, 31))	('carboplatin', 'Chemical', 'MESH:D016190', (66, 77))	('patients', 'Species', '9606', (3, 11))	('S13A', 'Var', (110, 114))	('NSCLC', 'Disease', 'MESH:D002289', (26, 31))
459926	33391473	The results showed that high RS was also correlated with significantly better ORR (54.5% vs. 15.0%, P = 0.019; Figure S13B) and PFS (HR = 0.42, P = 0.0023; Figure S13C) than those with low RS.	('high RS', 'Var', (24, 31))	('S13C', 'Mutation', 'p.S13C', (163, 167))	('PFS', 'MPA', (128, 131))	('S13B', 'Var', (118, 122))	('S13B', 'SUBSTITUTION', 'None', (118, 122))	('ORR', 'MPA', (78, 81))
459928	33391473	Here, we designed the Panel 2 covering 29 prevalent tumor related driver genes (Table S3) to explore whether changes of VAF in cfDNA could monitor chemotherapy response (Figure 1B).	('tumor', 'Disease', (52, 57))	('changes', 'Var', (109, 116))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))
459930	33391473	Moreover, patients of VAF undetectable at cycle 2 had significantly higher ORR (78.7% vs. 31.3%, P < 0.001; Figure 6B) and longer PFS (HR = 0.41, P < 0.0001; Figure 6C) than those of VAF detectable.	('undetectable', 'Var', (26, 38))	('PFS', 'MPA', (130, 133))	('higher', 'PosReg', (68, 74))	('patients', 'Species', '9606', (10, 18))	('VAF', 'Gene', (22, 25))	('ORR', 'MPA', (75, 78))
459932	33391473	VAF undetectable at cycle 2 was correlated with substantially better ORR and PFS in both LP (ORR: 87.0% vs. 31.3%, P < 0.001, Figure S14B; PFS: HR = 0.36, P < 0.0001, Figure S14C) and GP group (ORR: 70.8% vs. 31.3%, P = 0.014, Figure S13E; PFS: HR = 0.46, P = 0.0089, Figure S14F) than those with detectable VAF.	('S14B', 'Var', (133, 137))	('S14C', 'Mutation', 'rs746010901', (174, 178))	('S14F', 'Mutation', 'rs746010901', (275, 279))	('ORR', 'MPA', (69, 72))	('S13E', 'Mutation', 'p.S13E', (234, 238))	('GP', 'Gene', '55819', (184, 186))	('LP', 'Chemical', 'MESH:D008070', (89, 91))	('S14B', 'SUBSTITUTION', 'None', (133, 137))
459933	33391473	These findings suggested that changes of VAF in cfDNA could monitor the response to first-line chemotherapy in patients with advanced LUSC.	('changes', 'Var', (30, 37))	('VAF', 'Gene', (41, 44))	('LUSC', 'Phenotype', 'HP:0030359', (134, 138))	('patients', 'Species', '9606', (111, 119))
459937	33391473	We found that patients with high RS showed significantly superior ORR, PFS and OS than those with low RS in both training and validation set.	('PFS', 'CPA', (71, 74))	('high RS', 'Var', (28, 35))	('ORR', 'MPA', (66, 69))	('superior', 'PosReg', (57, 65))	('patients', 'Species', '9606', (14, 22))
459942	33391473	Single gene alterations as predictor for first-line chemotherapy in NSCLC went through a tortuous course and most of them finally failed.	('NSCLC', 'Phenotype', 'HP:0030358', (68, 73))	('Single gene alterations', 'Var', (0, 23))	('NSCLC', 'Disease', 'MESH:D002289', (68, 73))	('NSCLC', 'Disease', (68, 73))
459958	33391473	found that patients with circulating EGFR mutation clearance at cycle 3 had longer PFS and OS, suggesting that dynamic change of blood-based EGFR status could be a useful predictive marker.	('EGFR', 'Gene', '1956', (141, 145))	('EGFR', 'Gene', (141, 145))	('EGFR', 'Gene', '1956', (37, 41))	('mutation', 'Var', (42, 50))	('longer', 'PosReg', (76, 82))	('PFS', 'CPA', (83, 86))	('patients', 'Species', '9606', (11, 19))	('EGFR', 'Gene', (37, 41))
459971	33391473	cfDNA cell-free DNA CI confidence interval CNV copy number variations CR complete response DCR disease control rate ECOG PS Eastern Cooperative Oncology Group performance status HR hazard ratios ICP individually customized panel LUSC lung squamous cell carcinoma NGS next generation sequencing NSCLC non-small-cell lung cancer ORR objective response rate OS overall survival ROC Receiver operator characteristic RS RESPONSE SCORE PD progressive disease PD-1 programmed cell death 1 PD-L1 programmed cell death ligand 1 PR partial response SD stable disease TMB tumor mutation burden VAF variant allele frequency	('progressive disease', 'Disease', 'MESH:D018450', (433, 452))	('NSCLC', 'Disease', 'MESH:D002289', (294, 299))	('VAF', 'Gene', (583, 586))	('progressive disease', 'Disease', (433, 452))	('PD', 'Disease', 'MESH:D010300', (453, 455))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (234, 262))	('lung squamous cell carcinoma', 'Disease', (234, 262))	('cancer', 'Phenotype', 'HP:0002664', (320, 326))	('PD', 'Disease', 'MESH:D010300', (430, 432))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (300, 326))	('Oncology', 'Phenotype', 'HP:0002664', (144, 152))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (239, 262))	('NSCLC', 'Disease', (294, 299))	('lung cancer', 'Disease', (315, 326))	('tumor', 'Phenotype', 'HP:0002664', (561, 566))	('LUSC', 'Phenotype', 'HP:0030359', (229, 233))	('carcinoma', 'Phenotype', 'HP:0030731', (253, 262))	('NSCLC', 'Phenotype', 'HP:0030358', (294, 299))	('variant', 'Var', (587, 594))	('PD', 'Disease', 'MESH:D010300', (482, 484))	('CR', 'Chemical', '-', (70, 72))	('PR', 'Gene', '140738', (519, 521))	('PD-L1', 'Gene', (482, 487))	('lung cancer', 'Disease', 'MESH:D008175', (315, 326))	('programmed cell death 1', 'Gene', (458, 481))	('TMB', 'Chemical', '-', (557, 560))	('PD-L1', 'Gene', '29126', (482, 487))	('programmed cell death 1', 'Gene', '5133', (458, 481))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (304, 326))	('lung cancer', 'Phenotype', 'HP:0100526', (315, 326))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (234, 262))	('ROC', 'Chemical', '-', (375, 378))	('tumor', 'Disease', (561, 566))	('CR', 'Chemical', '-', (92, 94))	('SD', 'Disease', 'MESH:D029461', (539, 541))	('tumor', 'Disease', 'MESH:D009369', (561, 566))
459973	31968252	Chromosome 3q26 copy number gain (CNG) is a genetic hallmark of LSCC present in >90% of tumors.	('LSCC', 'Disease', (64, 68))	('copy number', 'Var', (16, 27))	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumors', 'Disease', (88, 94))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))
459974	31968252	We report that 3q26 CNGs occur early in LSCC tumorigenesis, persist during tumor progression, and drive coordinate overexpression of PRKCI, SOX2, and ECT2.	('PRKCI', 'Protein', (133, 138))	('overexpression', 'PosReg', (115, 129))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('3q26 CNGs', 'Var', (15, 24))	('tumor', 'Disease', (45, 50))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', (75, 80))	('LSCC', 'Disease', (40, 44))
459978	31968252	report that three oncogenes, PRKCI, SOX2, and ECT2, which are coordinately amplified and overexpressed in lung squamous cell carcinoma (LSCC), can transform Trp53-/- mouse lung basal stem cells into tumors with histological and genomic features of LSCC and drive oncogenic signaling necessary to maintain a LSCC phenotype.	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('tumors', 'Disease', (199, 205))	('tumors', 'Disease', 'MESH:D009369', (199, 205))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (106, 134))	('lung squamous cell carcinoma', 'Disease', (106, 134))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (111, 134))	('tumors', 'Phenotype', 'HP:0002664', (199, 205))	('LSCC', 'Disease', (248, 252))	('mouse', 'Species', '10090', (166, 171))	('oncogenic signaling', 'MPA', (263, 282))	('transform', 'Reg', (147, 156))	('drive', 'PosReg', (257, 262))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('Trp53-/-', 'Var', (157, 165))	('ECT2', 'Gene', (46, 50))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (106, 134))
459980	31968252	Copy number gains (CNGs) at chromosome 3q26 and mutation of the tumor sup- pressor gene TP53 are the most prevalent genetic alterations in LSCC, occurring concomitantly in >90% of LSCC cases.	('LSCC', 'Disease', (139, 143))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('tumor', 'Disease', (64, 69))	('Copy number gains', 'Var', (0, 17))	('TP53', 'Gene', '7157', (88, 92))	('mutation', 'Var', (48, 56))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('LSCC', 'Disease', (180, 184))	('TP53', 'Gene', (88, 92))	('rat', 'Species', '10116', (128, 131))
459988	31968252	Low CNG (genomic identification of significant targets in cancer [GISTIC] score of +1) and high CNG/gene amplification (GISTIC score of +2) lead to a stepwise increase in PRKCI, SOX2, and ECT2 expression when compared to tumors without CNG (GISTIC scores 0 or -1) (Figures 1B-1D).	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('PRKCI', 'Protein', (171, 176))	('tumors', 'Phenotype', 'HP:0002664', (221, 227))	('TIC', 'Phenotype', 'HP:0100033', (244, 247))	('TIC', 'Phenotype', 'HP:0100033', (69, 72))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('tumors', 'Disease', 'MESH:D009369', (221, 227))	('tumors', 'Disease', (221, 227))	('cancer', 'Disease', (58, 64))	('expression', 'MPA', (193, 203))	('ECT2', 'Protein', (188, 192))	('TIC', 'Phenotype', 'HP:0100033', (123, 126))	('SOX2', 'Protein', (178, 182))	('increase', 'PosReg', (159, 167))	('high CNG/gene amplification', 'Var', (91, 118))
459993	31968252	qPCR confirmed efficient knockdown (KD) of PKCi and SOX2 in PRKCI and SOX2 KD cells, respectively, and decreased expression of the PKCi-dependent SOX2 transcriptional target HHAT (; Figure S1A).	('HHAT', 'Gene', '55733', (174, 178))	('expression', 'MPA', (113, 123))	('SOX2', 'Gene', (52, 56))	('HHAT', 'Gene', (174, 178))	('decreased', 'NegReg', (103, 112))	('PKCi', 'Enzyme', (43, 47))	('knockdown', 'Var', (25, 34))
459996	31968252	To identify pathways, and associated genes, that correlate with PRKCI and SOX2 expression in LSCC cells and primary LSCC tumors, we first identified genes differentially expressed in LSCC tumors expressing high PRKCI and SOX2 versus low PRKCI and SOX2 (top versus bottom 20%; n = 44/group) within the TCGA LSCC dataset.	('tumors', 'Phenotype', 'HP:0002664', (188, 194))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('LSCC tumors', 'Disease', (183, 194))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('LSCC tumors', 'Disease', 'MESH:D009369', (116, 127))	('LSCC tumors', 'Disease', (116, 127))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('LSCC tumors', 'Disease', 'MESH:D009369', (183, 194))	('high PRKCI', 'Var', (206, 216))
460001	31968252	Expression of PKCi-SOX2 target genes was not inhibited by ECT2 KD in H1299 cells, or H520 LSCC cells harboring 3q26 CNG, demonstrating that the PKCi-ECT2 signaling axis is not involved in their regulation (Figures S1C and S1D).	('Expression', 'MPA', (0, 10))	('3q26 CNG', 'Var', (111, 119))	('H520 LSCC', 'CellLine', 'CVCL:1566', (85, 94))	('ECT2 KD', 'Var', (58, 65))	('rat', 'Species', '10116', (128, 131))	('H1299', 'CellLine', 'CVCL:0060', (69, 74))
460004	31968252	PKCi-dependent SOX2 promoter occupancy was also observed in H520 LSCC cells harboring PRKCI and SOX2 CNG (Figure 2G) but not in H2170 LSSC cells without PRKCI and SOX2 CNG (Figure 2H), or in A549 LADC cells (Figure 2I).	('H2170 LSSC', 'CellLine', 'CVCL:1535', (128, 138))	('CNG', 'Var', (101, 104))	('A549 LADC', 'CellLine', 'CVCL:0023', (191, 200))	('H520 LSCC', 'CellLine', 'CVCL:1566', (60, 69))	('SOX2', 'Gene', (15, 19))
460007	31968252	In each case, shRNA-mediated KD significantly inhibited transformed growth of H1299, H520, and H2170 cells, but had little or no effect on A549 LADC cells.	('transformed growth', 'CPA', (56, 74))	('A549 LADC', 'CellLine', 'CVCL:0023', (139, 148))	('H1299', 'CellLine', 'CVCL:0060', (78, 83))	('H2170', 'Var', (95, 100))	('H2170', 'CellLine', 'CVCL:1535', (95, 100))	('inhibited', 'NegReg', (46, 55))
460012	31968252	Analysis of an independent LSCC gene expression dataset revealed a similar enrichment of PKCi-SOX2 and PKCi-ECT2 Eigengene scores in Classical and Primitive LSCC subtype tumors, respectively, providing independent validation (Figures S3D and S3E).	('PKCi-ECT2', 'Gene', (103, 112))	('Classical', 'Disease', (133, 142))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('PKCi-SOX2', 'Gene', (89, 98))	('Primitive LSCC', 'Disease', (147, 161))	('tumors', 'Disease', 'MESH:D009369', (170, 176))	('tumors', 'Phenotype', 'HP:0002664', (170, 176))	('Eigengene scores', 'Var', (113, 129))	('tumors', 'Disease', (170, 176))
460017	31968252	Interrogation of these data revealed that 3q26 CNG (Figure 5A), and elevated expression of PRKCI, SOX2, and ECT2 (Figures 5B-5D), are significantly associated with progressive CIS lesions.	('expression', 'MPA', (77, 87))	('3q26 CNG', 'Var', (42, 50))	('PRKCI', 'Protein', (91, 96))	('ECT2', 'Gene', (108, 112))	('CIS lesions', 'Disease', 'MESH:D001768', (176, 187))	('elevated', 'PosReg', (68, 76))	('CIS lesions', 'Disease', (176, 187))	('associated with', 'Reg', (148, 163))	('SOX2', 'Gene', (98, 102))
460018	31968252	Interestingly, progressive CIS lesions also exhibited a significantly higher incidence of TP53 mutations (28/29) than regressive lesions (5/10), whereas mutations in other tumor suppressors were detected with much lower prevalence and did not significantly associate with progressive versus regressive lesions (Figure 5A).	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('progressive versus regressive lesions', 'Disease', 'MESH:C537770', (272, 309))	('CIS lesions', 'Disease', 'MESH:D001768', (27, 38))	('tumor', 'Disease', (172, 177))	('CIS lesions', 'Disease', (27, 38))	('TP53', 'Gene', '7157', (90, 94))	('progressive versus regressive lesions', 'Disease', (272, 309))	('TP53', 'Gene', (90, 94))	('mutations', 'Var', (95, 104))	('higher', 'PosReg', (70, 76))	('tumor', 'Disease', 'MESH:D009369', (172, 177))
460019	31968252	Interestingly, three of the regressive CIS lesions harboring a TP53 mutation and 3q26 CNG ultimately progressed to LSCC after the preset clinical endpoint, making the correlation between these genetic alterations and oncogenic progression even stronger.	('3q26 CNG', 'Var', (81, 89))	('TP53', 'Gene', '7157', (63, 67))	('rat', 'Species', '10116', (205, 208))	('TP53', 'Gene', (63, 67))	('mutation', 'Var', (68, 76))	('progressed', 'Reg', (101, 111))	('LSCC', 'Disease', (115, 119))	('CIS lesions', 'Disease', 'MESH:D001768', (39, 50))	('CIS lesions', 'Disease', (39, 50))
460020	31968252	Analysis of the TCGA LSCC dataset revealed that TP53 mutation is by far the most frequently mutated tumor suppressor gene in LSCC (~86% of tumors), rivaling in frequency, and occurring concomitantly with, PRKCI, SOX2, and ECT2 CNGs (Figure S4A).	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('TP53', 'Gene', '7157', (48, 52))	('mutation', 'Var', (53, 61))	('tumor', 'Disease', (100, 105))	('TP53', 'Gene', (48, 52))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('LSCC', 'Disease', (125, 129))	('tumors', 'Disease', (139, 145))	('tumors', 'Disease', 'MESH:D009369', (139, 145))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('tumor', 'Disease', 'MESH:D009369', (100, 105))
460021	31968252	Like 3q26 CNG (Figure 1E), TP53 mutations are detected at equally high frequency in early- and late-stage LSCC tumors (Figure S4B), consistent with the early acquisition of TP53 mutation in progressive premalignant CIS lesions (Figure 5A).	('TP53', 'Gene', '7157', (27, 31))	('TP53', 'Gene', (27, 31))	('premalignant CIS lesions', 'Disease', 'MESH:D001768', (202, 226))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('LSCC tumors', 'Disease', 'MESH:D009369', (106, 117))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('premalignant CIS lesions', 'Disease', (202, 226))	('mutations', 'Var', (32, 41))	('LSCC tumors', 'Disease', (106, 117))	('TP53', 'Gene', '7157', (173, 177))	('TP53', 'Gene', (173, 177))
460026	31968252	However, Trp53-/- LBSCs cultures exhibit an increase in sphere number and size compared to Ad Null-treated Trp53fl/fl LBSC cultures (Figures 5I and 5J), consistent with the established role of Trp53 loss in LBSC proliferation ex vivo.	('sphere number', 'CPA', (56, 69))	('Trp53-/-', 'Var', (9, 17))	('increase', 'PosReg', (44, 52))	('rat', 'Species', '10116', (219, 222))	('loss', 'NegReg', (199, 203))
460027	31968252	S/P/Trp53-/- LBSCs express elevated phospho-Thr118-SOX2 (Figure 5K) and increased expression of the 9 validated direct PKCi-SOX2 transcriptional targets (Figure 5L).	('Thr118', 'Chemical', '-', (44, 50))	('increased', 'PosReg', (72, 81))	('expression', 'MPA', (82, 92))	('S/P/Trp53-/- LBSCs', 'Var', (0, 18))	('elevated', 'PosReg', (27, 35))	('phospho-Thr118-SOX2', 'MPA', (36, 55))
460028	31968252	Thus, S/P/Trp53-/- LBSCs exhibit enhanced proliferation, morphological transformation, and activated PKCi-SOX2 signaling consistent with that observed in human Proliferative PMLs, progressive CIS lesions, and Classical LSCC tumors.	('CIS lesions', 'Disease', 'MESH:D001768', (192, 203))	('human', 'Species', '9606', (154, 159))	('CIS lesions', 'Disease', (192, 203))	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('proliferation', 'CPA', (42, 55))	('morphological transformation', 'CPA', (57, 85))	('tumors', 'Phenotype', 'HP:0002664', (224, 230))	('Classical LSCC tumors', 'Disease', 'MESH:D020240', (209, 230))	('PKCi-SOX2 signaling', 'MPA', (101, 120))	('S/P/Trp53-/- LBSCs', 'Var', (6, 24))	('activated', 'PosReg', (91, 100))	('rat', 'Species', '10116', (167, 170))	('Classical LSCC tumors', 'Disease', (209, 230))	('rat', 'Species', '10116', (49, 52))	('enhanced', 'PosReg', (33, 41))
460029	31968252	S/P/E/Trp53-/- LBSCs exhibit increased abundance of Mmp10 and 45S ribosomal RNA (Figure 6E) and elevated levels of PKCi-induced phospho-Thr328-ECT2 (Figure 6F), biochemical changes consistent with activation of oncogenic PKCi-ECT2 signaling.	('S/P/E/Trp53-/- LBSCs', 'Var', (0, 20))	('Thr328', 'Chemical', '-', (136, 142))	('PKCi-induced phospho-Thr328-ECT2', 'MPA', (115, 147))	('increased', 'PosReg', (29, 38))	('levels', 'MPA', (105, 111))	('Mmp10', 'Gene', '4319', (52, 57))	('45S ribosomal RNA', 'MPA', (62, 79))	('elevated', 'PosReg', (96, 104))	('Mmp10', 'Gene', (52, 57))
460030	31968252	Interestingly, overexpression of ECT2 in S/Trp53-/- LBSCs (Figure S5A) led to a small but significant increase in sphere size, but no change in sphere number or morphology (Figures S5B-S5D), indicating that full morphological transformation and enhanced transformed growth of LBSCs occurs only when all three cooperating 3q26 oncogenes are coordinately overexpressed.	('S/Trp53-/- LBSCs', 'Var', (41, 57))	('overexpression', 'PosReg', (15, 29))	('rat', 'Species', '10116', (314, 317))	('increase', 'PosReg', (102, 110))	('sphere size', 'CPA', (114, 125))	('enhanced', 'PosReg', (245, 253))	('transformed growth', 'CPA', (254, 272))	('ECT2', 'Gene', (33, 37))
460031	31968252	To assess the role of PKCi-mediated SOX2 and ECT2 phosphorylation in LBSC transformation, we utilized lentiviruses expressing previously characterized SOX2 and ECT2 mutants, SOX2T118A (ST118A) and ECT2T328A (ET328A), that cannot be phosphorylated by PKCi (; Figure 6G).	('ECT2T328A', 'Var', (197, 206))	('ET328A', 'Chemical', '-', (208, 214))	('SOX2T118A', 'Var', (174, 183))	('ECT2', 'Gene', (160, 164))	('SOX2', 'Gene', (151, 155))
460032	31968252	As expected, S/P/E/Trp53-/- LBSCs produced large, proliferative cell masses exhibiting loss of cell polarity, whereas ST118A/P/E/Trp53-/- LBSCs produce polarized cysts resembling S/Trp53-/- LBSCs, but of increased size comparable to S/P/E/Trp53-/- LBSCs (Figures 6G-6I).	('rat', 'Species', '10116', (57, 60))	('polarized cysts', 'CPA', (152, 167))	('ST118A/P/E/Trp53-/- LBSCs', 'Var', (118, 143))
460034	31968252	In each case, target gene knockdown induced a significant decrease in the number of S/P/E/Trp53-/- LBSC spheres, indicating that each of these PKCi-SOX2 target genes contributes to mouse LBSC transformation.	('decrease', 'NegReg', (58, 66))	('knockdown', 'Var', (26, 35))	('S/P/E/Trp53-/- LBSC', 'Var', (84, 103))	('mouse', 'Species', '10090', (181, 186))
460036	31968252	Furthermore, treatment of S/P/E/Trp53-/- LBSCs with GANT61, LDE225, and LDN- 193189 at concentrations that inhibited transformed growth of LSCC cells exhibiting 3q26 CNG (Figures 3J-3L), significantly inhibited sphere growth (Figure 6L).	('rat', 'Species', '10116', (94, 97))	('sphere growth', 'CPA', (211, 224))	('GANT61', 'Chemical', 'MESH:C551027', (52, 58))	('LDE225', 'Chemical', 'MESH:C561435', (60, 66))	('3q26 CNG', 'Var', (161, 169))	('inhibited', 'NegReg', (201, 210))	('inhibited', 'NegReg', (107, 116))	('S/P/E/Trp53-/-', 'Var', (26, 40))	('transformed growth', 'CPA', (117, 135))
460039	31968252	In contrast, S/P/E/Trp53-/- LBSCs generate larger, exponentially growing tumors (Figure 7A) that are clearly detectable by both IVIS and micro-computed tomography (mCT) as distinct intrapulmonary masses (Figure 7B).	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('tumors', 'Disease', (73, 79))	('tumors', 'Disease', 'MESH:D009369', (73, 79))	('S/P/E/Trp53-/- LBSCs', 'Var', (13, 33))	('rat', 'Species', '10116', (38, 41))
460042	31968252	S/Trp53-/- and S/P/E/Trp53-/- lesions retain expression of SOX2, and the basal cell markers TP63 and KRT5, confirming their squamous nature (Figure 7C, upper and middle panels).	('KRT5', 'Gene', '3852', (101, 105))	('TP63', 'Gene', '8626', (92, 96))	('TP63', 'Gene', (92, 96))	('expression', 'MPA', (45, 55))	('S/Trp53-/-', 'Var', (0, 10))	('S/P/E/Trp53-/-', 'Var', (15, 29))	('SOX2', 'Protein', (59, 63))	('KRT5', 'Gene', (101, 105))
460043	31968252	Interestingly, S/Trp53-/- lesions exhibit low KI67 staining consistent with limited proliferative potential, whereas S/P/E/ Trp53-/- tumors show elevated KI67 staining indicative of aggressive growth (Figure 7C, upper and middle panels, right).	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('elevated', 'PosReg', (145, 153))	('aggressive growth', 'CPA', (182, 199))	('KI67 staining', 'MPA', (46, 59))	('tumors', 'Disease', (133, 139))	('tumors', 'Disease', 'MESH:D009369', (133, 139))	('rat', 'Species', '10116', (91, 94))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('KI67 staining', 'MPA', (154, 167))	('low', 'NegReg', (42, 45))	('S/P/E/ Trp53-/-', 'Var', (117, 132))
460045	31968252	Immunohistochemistry (IHC) revealed that S/Trp53-/- lesions express low but detectable levels of WNT11, GLI2, and LEF1, and moderate levels of PKCi (Figure 7D, upper panels).	('LEF1', 'Gene', '51176', (114, 118))	('WNT11', 'Gene', '7481', (97, 102))	('LEF1', 'Gene', (114, 118))	('PKCi', 'MPA', (143, 147))	('S/Trp53-/-', 'Var', (41, 51))	('WNT11', 'Gene', (97, 102))	('rat', 'Species', '10116', (128, 131))	('GLI2', 'Gene', (104, 108))	('GLI2', 'Gene', '2736', (104, 108))
460059	31968252	The proportion of early human squamous lesions with PTEN and CDKN2A/B alterations is relatively small, and their loss is not significantly associated with progressive versus regressive squamous CIS lesions.	('alterations', 'Var', (70, 81))	('PTEN', 'Gene', (52, 56))	('human', 'Species', '9606', (24, 29))	('PTEN', 'Gene', '5728', (52, 56))	('rat', 'Species', '10116', (74, 77))	('squamous lesions', 'Disease', 'MESH:D000081483', (30, 46))	('CDKN2A/B', 'Gene', '1029;1030', (61, 69))	('squamous lesions', 'Disease', (30, 46))	('progressive versus regressive squamous CIS lesions', 'Disease', 'MESH:D000081483', (155, 205))	('CDKN2A/B', 'Gene', (61, 69))	('progressive versus regressive squamous CIS lesions', 'Disease', (155, 205))
460060	31968252	Thus, mutation of these tumor suppressors, while clearly relevant to LSCC, may contribute preferentially to LSCC progression rather than initiation.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('rat', 'Species', '10116', (125, 128))	('tumor', 'Disease', (24, 29))	('preferentially', 'PosReg', (90, 104))	('mutation', 'Var', (6, 14))	('contribute', 'Reg', (79, 89))	('LSCC', 'Disease', (108, 112))	('tumor', 'Disease', 'MESH:D009369', (24, 29))
460062	31968252	Interestingly, Trp53 has been shown to control proliferation and differentiation of progenitor cells including regional airway stem cells and inactivation of Trp53 promotes LBSC self-renewal in vivo.	('LBSC self-renewal', 'CPA', (173, 190))	('Trp53', 'Gene', (158, 163))	('rat', 'Species', '10116', (54, 57))	('promotes', 'PosReg', (164, 172))	('inactivation', 'Var', (142, 154))
460063	31968252	Our newly described model of LSCC tumor initiation, driven solely by collaboration of three key 3q26 oncogenes and loss of Trp53, provides a valuable complement to previously described LSCC models, and represents a genetically tractable model of the Classical subtype of LSCC, the most prevalent LSCC molecular subtype.	('rat', 'Species', '10116', (76, 79))	('LSCC', 'Disease', (271, 275))	('LSCC tumor initiation', 'Disease', (29, 50))	('LSCC tumor initiation', 'Disease', 'MESH:D009369', (29, 50))	('loss', 'Var', (115, 119))	('Trp53', 'Protein', (123, 128))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
460067	31968252	Our model also facilitates biochemical and genetic dissection of the roles of specific genetic alterations, and their associated signaling pathways, in LSCC initiation and progression ex vivo, and in tumor initiation and maintenance in syngeneic mice in vivo.	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('tumor initiation', 'Disease', 'MESH:D009369', (200, 216))	('rat', 'Species', '10116', (99, 102))	('alterations', 'Var', (95, 106))	('tumor initiation', 'Disease', (200, 216))	('LSCC', 'Disease', (152, 156))	('mice', 'Species', '10090', (246, 250))
460124	31968252	For drug studies on S/P/E/Trp53-/- LBSCs, inhibitors were added to both layers of growth factor reduced Matrigel at the concentrations indicated in the figure legend.	('S/P/E/Trp53-/-', 'Var', (20, 34))	('rat', 'Species', '10116', (127, 130))	('Matrigel', 'CPA', (104, 112))	('reduced', 'NegReg', (96, 103))
460134	31968252	GSE108124 was downloaded to analyze TP53 mutation, 3q26 CN and PKCi, SOX2, and ECT2 expression in regressive and progressive LSCC CIS lesions.	('LSCC CIS lesions', 'Disease', 'MESH:D001768', (125, 141))	('TP53', 'Gene', '7157', (36, 40))	('mutation', 'Var', (41, 49))	('TP53', 'Gene', (36, 40))	('LSCC CIS lesions', 'Disease', (125, 141))
460140	31968252	Genes that were up (or down) regulated in PKCiH.SOX2H group and that responded to PKCiL.SOX2L group with significance (p < 0.05) and folder change (F > 1.5) were considered to be differential expressed genes (DEGs) in TCGA LSCC primary tumors.	('TCGA LSCC', 'Disease', (218, 227))	('tumors', 'Phenotype', 'HP:0002664', (236, 242))	('tumor', 'Phenotype', 'HP:0002664', (236, 241))	('PKCiL.SOX2L', 'Var', (82, 93))	('tumors', 'Disease', (236, 242))	('tumors', 'Disease', 'MESH:D009369', (236, 242))
460146	31968252	3q26 CNG and TP53 mutation associate with progression of carcinoma in situ to LSCC PRKCI, SOX2, and ECT2 overexpression transforms Trp53-/- mouse lung basal stem cells Active PKCi-SOX2 and PKCi-ECT2 signaling is required for LBSC transformation A PKCi-SOX2 molecular signature suggests unique therapeutic vulnerabilities in LSCC	('mouse', 'Species', '10090', (140, 145))	('TP53', 'Gene', (13, 17))	('carcinoma', 'Disease', 'MESH:D009369', (57, 66))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (57, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (57, 66))	('mutation', 'Var', (18, 26))	('TP53', 'Gene', '7157', (13, 17))	('carcinoma', 'Disease', (57, 66))
460202	32024523	While the first two studies explored the association between CDKN2B-AS1 and esophageal cancer by way of genetic mutations, the third did so from the prospective of expression level.	('CDKN2B-AS1', 'Gene', '100048912', (61, 71))	('esophageal cancer', 'Disease', (76, 93))	('association', 'Interaction', (41, 52))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('explored', 'Reg', (28, 36))	('mutations', 'Var', (112, 121))	('esophageal cancer', 'Disease', 'MESH:D004938', (76, 93))	('CDKN2B-AS1', 'Gene', (61, 71))
460229	32024523	showed that inhibition of MALAT1 can prevent OSCC proliferation whereas its overexpression can promote OSCC.	('OSCC', 'Disease', (103, 107))	('inhibition', 'Var', (12, 22))	('OSCC', 'Disease', 'MESH:D002294', (45, 49))	('prevent', 'NegReg', (37, 44))	('promote', 'PosReg', (95, 102))	('OSCC', 'Disease', 'MESH:D002294', (103, 107))	('MALAT1', 'Gene', '378938', (26, 32))	('OSCC', 'Disease', (45, 49))	('MALAT1', 'Gene', (26, 32))	('overexpression', 'PosReg', (76, 90))
460288	29866045	We further described the landscape of TF deregulation in these three major lung cancer subtypes.	('lung cancer', 'Disease', (75, 86))	('lung cancer', 'Phenotype', 'HP:0100526', (75, 86))	('deregulation', 'Var', (41, 53))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('lung cancer', 'Disease', 'MESH:D008175', (75, 86))
460295	29866045	Then, for each TF, we counted the number of its target genes that were up- and down-regulated in cancers ('n_up' and 'n_down', respectively), and classified the TF-targets group as 'up' if the TF was overexpressed and n_up/n_down>=10 (vice versa).	('cancers', 'Disease', 'MESH:D009369', (97, 104))	('cancers', 'Phenotype', 'HP:0002664', (97, 104))	('cancers', 'Disease', (97, 104))	('down-regulated', 'NegReg', (79, 93))	('overexpressed', 'PosReg', (200, 213))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('up-', 'PosReg', (71, 74))	('n_up/n_down>=10', 'Var', (218, 233))
460305	29866045	The functional implication of DMRT3 in LUSC was not well known, though two earlier studies found that DMRT3 could be lost through copy number alteration mechanisms in LUSC.	('DMRT3', 'Gene', (102, 107))	('DMRT3', 'Gene', (30, 35))	('DMRT3', 'Gene', '58524', (30, 35))	('lost', 'NegReg', (117, 121))	('LUSC', 'Disease', (167, 171))	('DMRT3', 'Gene', '58524', (102, 107))	('copy number alteration', 'Var', (130, 152))
460307	29866045	We found that the copy number status of DMRT3 was heterogeneous in LUSC, with tumors not bearing DMRT3 deletions having significantly higher DMRT3 expression, as well as significantly increased TP63/SOX2 expression (Additional file 3: Figure S2C-E).	('DMRT3', 'Gene', '58524', (97, 102))	('TP63', 'Gene', '8626', (194, 198))	('expression', 'MPA', (147, 157))	('higher', 'PosReg', (134, 140))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('DMRT3', 'Gene', (40, 45))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('DMRT3', 'Gene', (141, 146))	('DMRT3', 'Gene', '58524', (40, 45))	('SOX2', 'Gene', '6657', (199, 203))	('SOX2', 'Gene', (199, 203))	('tumors', 'Disease', (78, 84))	('DMRT3', 'Gene', '58524', (141, 146))	('increased', 'PosReg', (184, 193))	('deletions', 'Var', (103, 112))	('expression', 'MPA', (204, 214))	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('TP63', 'Gene', (194, 198))	('DMRT3', 'Gene', (97, 102))
460398	28218910	Heterotypic adhesion between both cell types mediates not only force transmission and mechanotransduction but also CAF polarization.	('mediates', 'Reg', (45, 53))	('CAF', 'Gene', '8850', (115, 118))	('Heterotypic', 'Var', (0, 11))	('mechanotransduction', 'CPA', (86, 105))	('CAF', 'Gene', (115, 118))	('force transmission', 'CPA', (63, 81))
460453	28218910	E-cadherin knockout did not lead to compensatory expression of N-cadherin, although P-cadherin levels increased modestly (Supplementary Figure 4a).	('P-cadherin levels', 'MPA', (84, 101))	('expression', 'Species', '29278', (49, 59))	('N-cadherin', 'Gene', (63, 73))	('E-cadherin', 'Gene', (0, 10))	('N-cadherin', 'Gene', '1000', (63, 73))	('knockout', 'Var', (11, 19))	('E-cadherin', 'Gene', '999', (0, 10))
460455	28218910	Importantly, knocking out E-cadherin resulted in a large drop in N-cadherin bead binding, which supports the existence of a heterophilic adhesion between N-cadherin and E-cadherin (Fig.	('N-cadherin', 'Gene', (154, 164))	('E-cadherin', 'Gene', (169, 179))	('N-cadherin', 'Gene', '1000', (154, 164))	('E-cadherin', 'Gene', '999', (169, 179))	('E-cadherin', 'Gene', (26, 36))	('N-cadherin', 'Gene', (65, 75))	('E-cadherin', 'Gene', '999', (26, 36))	('knocking out', 'Var', (13, 25))	('N-cadherin', 'Gene', '1000', (65, 75))	('binding', 'Interaction', (81, 88))	('drop', 'NegReg', (57, 61))
460461	28218910	To further investigate this interaction in CAFs, we used siRNA to knockdown N-cadherin (CAFs-siNcad, see Supplementary Figure 4f,h-k, n, q) and repeated the pulse application.	('CAF', 'Gene', (88, 91))	('CAF', 'Gene', (43, 46))	('N-cadherin', 'Gene', (76, 86))	('CAF', 'Gene', '8850', (88, 91))	('CAF', 'Gene', '8850', (43, 46))	('knockdown', 'Var', (66, 75))	('N-cadherin', 'Gene', '1000', (76, 86))
460467	28218910	These results establish that a heterophilic E-cadherin/N-cadherin junction triggers a specific mechanotransduction response.	('mechanotransduction response', 'MPA', (95, 123))	('heterophilic', 'Var', (31, 43))	('triggers', 'Reg', (75, 83))	('E-cadherin', 'Gene', (44, 54))	('E-cadherin', 'Gene', '999', (44, 54))	('N-cadherin', 'Gene', (55, 65))	('N-cadherin', 'Gene', '1000', (55, 65))
460476	28218910	To study whether this mechanism explains mechanotransduction of the E-cadherin/N-cadherin junction we used CRISPR/Cas9 to knock out alpha-catenin in A431 cells (A431-alphacatKO) and expressed alpha-catenin lacking the vinculin binding site (A431-alphacatDeltaVBS) or wild type alpha-catenin (A431-alphacatWT, rescue control).	('alpha-catenin', 'Protein', (132, 145))	('vinculin', 'Gene', (218, 226))	('N-cadherin', 'Gene', (79, 89))	('knock out', 'Var', (122, 131))	('lacking', 'NegReg', (206, 213))	('N-cadherin', 'Gene', '1000', (79, 89))	('E-cadherin', 'Gene', (68, 78))	('E-cadherin', 'Gene', '999', (68, 78))	('vinculin', 'Gene', '7414', (218, 226))
460486	28218910	When E-cadherin was knocked out in A431 cells, force transmission levels fell dramatically compared to the control case (Fig.	('force transmission levels', 'MPA', (47, 72))	('E-cadherin', 'Gene', (5, 15))	('E-cadherin', 'Gene', '999', (5, 15))	('fell', 'NegReg', (73, 77))	('knocked out', 'Var', (20, 31))
460514	28218910	Depletion of afadin in CAFs led to a >2-fold decrease the fraction of leaders and perturbed CAF repolarization following contact with cancer cells (Fig.	('repolarization', 'MPA', (96, 110))	('CAF', 'Gene', (92, 95))	('perturbed', 'Reg', (82, 91))	('CAF', 'Gene', (23, 26))	('afadin', 'Gene', (13, 19))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('Depletion', 'Var', (0, 9))	('CAF', 'Gene', '8850', (92, 95))	('CAF', 'Gene', '8850', (23, 26))	('decrease', 'NegReg', (45, 53))	('afadin', 'Gene', '4301', (13, 19))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('leaders', 'MPA', (70, 77))
460517	28218910	Strikingly, E-cadherin knockout in A431 cells greatly reduced cancer cell invasion; CAFs invaded the ECM but A431 cells were unable to follow them and remained cohesive in the spheroid (Figs 8b and 8f).	('CAF', 'Gene', (84, 87))	('E-cadherin', 'Gene', (12, 22))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('knockout', 'Var', (23, 31))	('CAF', 'Gene', '8850', (84, 87))	('E-cadherin', 'Gene', '999', (12, 22))	('reduced', 'NegReg', (54, 61))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))
460554	28218910	We also observed nectins and afadin at heterotypic contact sites and afadin depletion prevented CAF re-polarization.	('afadin', 'Gene', '4301', (69, 75))	('afadin', 'Gene', '4301', (29, 35))	('CAF', 'Gene', (96, 99))	('prevented', 'NegReg', (86, 95))	('afadin', 'Gene', (69, 75))	('depletion', 'Var', (76, 85))	('afadin', 'Gene', (29, 35))	('CAF', 'Gene', '8850', (96, 99))
460583	28218910	siRNA was purchased from Life Technologies and sequences are listed below: N-cadherin, Gene: CDH2, siRNA: #s2771, #s2772, #s2773, sequence 5'-3': GUGCAACAGUAUACGUUAAtt,GGGUAAUCCUCCCAAAUCAtt,GAACAUAUGUGAUGACCGUtt, siRNA CT Negative control siRNA, #4390843, Afadin, Gene: MTTL4, siRNA: #144142, # 144143, #144144, sequence 5'-3': CCUGAUAUGCGAAUGGCUGUtt, GGUGGUUAUGAAACGACGGtt, CCUCUAGUUGUACAACUGAtt, Cadherin 11, Gene: CDH11 siRNA: #s2798, #s2799, #s2800, sequence 5'-3': CGACAGAUUUUUCACUAUUtt, CCACCAAAGUUUCCGCAGAtt, GAAUCCUGAUGGUAUCAAUtt.	('#s2799', 'Var', (438, 444))	('Afadin', 'Gene', '4301', (256, 262))	('Afadin', 'Gene', (256, 262))	('CDH2', 'Gene', '1000', (93, 97))	('Cadherin 11', 'Gene', '1009', (398, 409))	('N-cadherin', 'Gene', '1000', (75, 85))	('Cadherin 11', 'Gene', (398, 409))	('CDH11', 'Gene', '1009', (417, 422))	('CDH11', 'Gene', (417, 422))	('#s2800', 'Var', (446, 452))	('CDH2', 'Gene', (93, 97))	('N-cadherin', 'Gene', (75, 85))
460601	28218910	Briefly, fresh frozen sections were fixed in 4% paraformaldehyde, permeablised in 0.2% TX100, and stained with the following antibodies: anti-E-cadherin monoclonal antibody (HECD-1 Crick Institute hybridoma cell services), anti-beta-catenin (Santa Cruz #sc7963), anti-p120catenin (BD Biosciences #610133), anti-Afadin (Atlas Ab # HPA030212, anti-alphaSMA (Sigma #A2547), anti-active integrin beta1 (9EG7 BD Pharmingen #556048), and anti-fibronectin (Sigma #F3648).	('Afadin', 'Gene', (311, 317))	('E-cadherin', 'Gene', (142, 152))	('integrin beta1', 'Gene', (383, 397))	('E-cadherin', 'Gene', '999', (142, 152))	('Sigma #F3648', 'Var', (450, 462))	('integrin beta1', 'Gene', '3688', (383, 397))	('p120catenin', 'Gene', (268, 279))	('Afadin', 'Gene', '4301', (311, 317))	('fibronectin', 'Gene', (437, 448))	('beta-catenin', 'Gene', (228, 240))	('p120catenin', 'Gene', '1500', (268, 279))	('beta-catenin', 'Gene', '1499', (228, 240))	('paraformaldehyde', 'Chemical', 'MESH:C003043', (48, 64))	('fibronectin', 'Gene', '2335', (437, 448))
460669	32965722	4  Several studies have reported that aberrant expression of miRNAs in multiple tumor types, and miRNAs target more than 60% of all protein-coding genes.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('miRNAs', 'Gene', (61, 67))	('aberrant', 'Var', (38, 46))	('tumor', 'Disease', (80, 85))	('expression', 'MPA', (47, 57))
460692	32965722	A KRT5 3'-UTR mutant was constructed by mutagenesis of the let-7a-5p binding site from GAGGUAG to CUCCAUC, whereas an NKX2-1 3'-UTR mutant was generated by mutagenesis of the miR-338 binding site from CCAGCA to GGUCGU.	('KRT5', 'Gene', (2, 6))	('let-7a-5p', 'Gene', (59, 68))	('mutagenesis', 'Var', (156, 167))	('NKX2-1', 'Gene', (118, 124))	('mutagenesis', 'Var', (40, 51))	('KRT5', 'Gene', '3852', (2, 6))	('miR-338', 'Gene', (175, 182))	('NKX2-1', 'Gene', '7080', (118, 124))	('miR-338', 'Gene', '442906', (175, 182))
460704	32965722	Thereafter, the reporter plasmid containing the KRT5 3'-UTR were used to transfect human embryonic kidney 293 T (HEK293T) cells, which showed significantly decreased luciferase activity in the presence of ectopic let-7a-5p.	('luciferase', 'Enzyme', (166, 176))	('embryonic kidney 293 T', 'Disease', (89, 111))	('ectopic let-7a-5p', 'Var', (205, 222))	('embryonic kidney 293 T', 'Disease', 'MESH:D007674', (89, 111))	('HEK293T', 'CellLine', 'CVCL:0063', (113, 120))	('human', 'Species', '9606', (83, 88))	('activity', 'MPA', (177, 185))	('let-7a-5p', 'Var', (213, 222))	('KRT5', 'Gene', (48, 52))	('decreased', 'NegReg', (156, 165))	('KRT5', 'Gene', '3852', (48, 52))
460705	32965722	When the conserved seed sequence was mutated, the miRNA-induced repression of the KRT5 3'-UTR was abrogated (Figure 3F).	('KRT5', 'Gene', (82, 86))	('abrogated', 'NegReg', (98, 107))	('KRT5', 'Gene', '3852', (82, 86))	('mutated', 'Var', (37, 44))	('repression', 'MPA', (64, 74))
460717	32965722	When the conserved seed sequence was mutated, the miRNA-induced repression of the NKX2-1 3'-UTR was abrogated (Figure 4F).	('NKX2-1', 'Gene', (82, 88))	('abrogated', 'NegReg', (100, 109))	('NKX2-1', 'Gene', '7080', (82, 88))	('mutated', 'Var', (37, 44))	('repression', 'MPA', (64, 74))
460719	32965722	Conversely, inhibition of miR-338 using an antisense oligonucleotide increased the NKX2-1 protein level (Figure 4I).	('NKX2-1', 'Gene', (83, 89))	('increased', 'PosReg', (69, 78))	('inhibition', 'NegReg', (12, 22))	('miR-338', 'Gene', '442906', (26, 33))	('miR-338', 'Gene', (26, 33))	('antisense oligonucleotide', 'Var', (43, 68))	('oligonucleotide', 'Chemical', 'MESH:D009841', (53, 68))	('NKX2-1', 'Gene', '7080', (83, 89))
460732	32965722	20 ,  21 ,  22 ,  23   A considerable number of miRNAs have been reported to associate with NSCLC; these include miR-206, 24  miR-335-5p, 25  miR-30a-5p, 26  miR-205, 27  miR-29b, 28  miR-847, 29  miR-449c, 30  miR-138, 31  miR-100, 32  and miR-155.	('NSCLC', 'Disease', 'MESH:D002289', (92, 97))	('miR-30a-5p', 'Var', (142, 152))	('miR-100', 'Gene', (224, 231))	('associate', 'Reg', (77, 86))	('NSCLC', 'Disease', (92, 97))	('miR-29b', 'Gene', '407024', (171, 178))	('miR-138', 'Var', (211, 218))	('miR-205', 'Var', (158, 165))	('miR-335', 'Gene', '442904', (126, 133))	('NSCLC', 'Phenotype', 'HP:0030358', (92, 97))	('miR-155', 'Gene', (241, 248))	('miR-100', 'Gene', '406892', (224, 231))	('miR-206', 'Gene', (113, 120))	('miR-847', 'Var', (184, 191))	('miR-155', 'Gene', '406947', (241, 248))	('miR-206', 'Gene', '406989', (113, 120))	('miR-29b', 'Gene', (171, 178))	('miR-449c', 'Var', (197, 205))	('miR-335', 'Gene', (126, 133))
460733	32965722	Some of the miRNAs have already been shown to strongly correlate with lung cancer.	('lung cancer', 'Disease', 'MESH:D008175', (70, 81))	('miRNAs', 'Var', (12, 18))	('lung cancer', 'Disease', (70, 81))	('lung cancer', 'Phenotype', 'HP:0100526', (70, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('correlate', 'Reg', (55, 64))
460742	32965722	In this study, we found that let-7a-5p may prevent LUAD by inhibiting KRT5 expression, which was previously found to be up-regulated in LUAD.	('LUAD', 'Phenotype', 'HP:0030078', (51, 55))	('let-7a-5p', 'Var', (29, 38))	('LUAD', 'Disease', (51, 55))	('prevent', 'NegReg', (43, 50))	('KRT5', 'Gene', '3852', (70, 74))	('inhibiting', 'NegReg', (59, 69))	('KRT5', 'Gene', (70, 74))	('expression', 'MPA', (75, 85))	('LUAD', 'Phenotype', 'HP:0030078', (136, 140))
460765	26590333	Though the presence of HPV DNA has been noted in oral and OP mucosal tumors since the 1980s and cervical cancer research has found HPV 16 and 18 to be tumorigenic, causation with OPSCC was not clearly identified until 2000.	('HPV 16', 'Species', '333760', (131, 137))	('SCC', 'Gene', (181, 184))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('HPV', 'Species', '10566', (131, 134))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('mucosal tumors', 'Disease', 'MESH:D052016', (61, 75))	('SCC', 'Phenotype', 'HP:0002860', (181, 184))	('mucosal tumors', 'Disease', (61, 75))	('tumor', 'Disease', (69, 74))	('tumor', 'Disease', (151, 156))	('SCC', 'Gene', '6317', (181, 184))	('cervical cancer', 'Disease', 'MESH:D002583', (96, 111))	('HPV', 'Species', '10566', (23, 26))	('cervical cancer', 'Disease', (96, 111))	('HPV 16', 'Var', (131, 137))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
460769	26590333	Molecular and pathologic analysis of these HPV positive tumors demonstrated decreased risk of p53 mutation, a non-keratizining/basaloid morphology and southern blot evidence of viral DNA integration.	('HPV positive tumors', 'Disease', 'MESH:D030361', (43, 62))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('p53', 'Gene', (94, 97))	('mutation', 'Var', (98, 106))	('HPV positive tumors', 'Disease', (43, 62))	('decreased', 'NegReg', (76, 85))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))
460832	26590333	found nine of 78 non-smoking oral tongue cancers were positive for p16 on IHC, but HPV E6/E7 mRNA transcripts were detected in only one.	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('oral tongue cancers', 'Disease', (29, 48))	('HPV', 'Species', '10566', (83, 86))	('oral tongue cancers', 'Disease', 'MESH:D014062', (29, 48))	('p16', 'Var', (67, 70))	('cancers', 'Phenotype', 'HP:0002664', (41, 48))	('positive', 'Reg', (54, 62))
460847	30424545	miRNA Mediated Noise Making of 3'UTR Mutations in Cancer Somatic mutations in 3'-untranslated regions (3'UTR) do not alter amino acids and are considered to be silent in cancers.	('cancers', 'Phenotype', 'HP:0002664', (170, 177))	('Cancer', 'Phenotype', 'HP:0002664', (50, 56))	('cancers', 'Disease', (170, 177))	('Mutations', 'Var', (37, 46))	('cancers', 'Disease', 'MESH:D009369', (170, 177))	('amino', 'MPA', (123, 128))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))
460848	30424545	We found that such mutations can promote tumor progression by altering microRNA (miRNA) targeting efficiency and consequently affecting miRNA-mRNA interactions.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('promote', 'PosReg', (33, 40))	('tumor', 'Disease', (41, 46))	('altering', 'Reg', (62, 70))	('affecting', 'Reg', (126, 135))	('mutations', 'Var', (19, 28))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('miRNA-mRNA interactions', 'MPA', (136, 159))
460850	30424545	Our findings elucidate a complex relationship between miRNA, mRNA, and mutations, and suggest that 3'UTR mutations may play an important role in tumor development.	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('play', 'Reg', (119, 123))	('tumor', 'Disease', (145, 150))	('mutations', 'Var', (105, 114))	("3'UTR", 'Gene', (99, 104))
460853	30424545	A small number of mutations are identified to be "driver mutations" that yield a selective clonal growth advantage to cancer cells.	('cancer', 'Disease', (118, 124))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('mutations', 'Var', (18, 27))
460854	30424545	Meanwhile, the large majority of mutations are "passenger mutations" which do not explicitly yield a growth advantage but may nonetheless provide useful information about the evolutionary forces within the cancer genome.	('cancer', 'Disease', (206, 212))	('cancer', 'Disease', 'MESH:D009369', (206, 212))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('mutations', 'Var', (33, 42))
460856	30424545	For instance, the UV-induced mutation was strongly associated with C>T and CC>TT alterations, and it was recently suggested that temozolomide (TMZ) treatment may also increase the C>T alterations in glioblastoma multiforme (GBM) patients.	('mutation', 'Var', (29, 37))	('patients', 'Species', '9606', (229, 237))	('temozolomide', 'Chemical', 'MESH:D000077204', (129, 141))	('CC>TT', 'Gene', (75, 80))	('glioblastoma multiforme', 'Disease', (199, 222))	('associated', 'Reg', (51, 61))	('glioblastoma', 'Phenotype', 'HP:0012174', (199, 211))	('TMZ', 'Chemical', 'MESH:D000077204', (143, 146))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (199, 222))
460857	30424545	Non-synonymous gene mutations which alter the amino acids of protein products may result in significant functional changes and accelerate the progression of tumors.	('Non-synonymous gene mutations', 'Var', (0, 29))	('tumors', 'Phenotype', 'HP:0002664', (157, 163))	('result', 'Reg', (82, 88))	('tumors', 'Disease', (157, 163))	('accelerate', 'PosReg', (127, 137))	('tumors', 'Disease', 'MESH:D009369', (157, 163))	('functional', 'MPA', (104, 114))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))
460859	30424545	By changing the function of the enzyme to produce 2-hydroxyglutarate, the IDH1 mutation remodeled the environment to fuel tumor cell development.	('IDH1', 'Gene', (74, 78))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('2-hydroxyglutarate', 'Chemical', 'MESH:C019417', (50, 68))	('mutation', 'Var', (79, 87))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('changing', 'Reg', (3, 11))	('IDH1', 'Gene', '3417', (74, 78))	('remodeled', 'Reg', (88, 97))	('function', 'MPA', (16, 24))	('tumor', 'Disease', (122, 127))
460860	30424545	present a compelling analysis that suggests synonymous mutations in cancer can be oncogenic by altering transcript splicing and thereby affecting protein function.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('affecting', 'Reg', (136, 145))	('transcript splicing', 'MPA', (104, 123))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('protein function', 'MPA', (146, 162))	('cancer', 'Disease', (68, 74))	('altering', 'Reg', (95, 103))	('synonymous mutations', 'Var', (44, 64))
460861	30424545	Others have also implicated mutations in cancer.	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('implicated', 'Reg', (17, 27))	('mutations', 'Var', (28, 37))
460862	30424545	found a 3'UTR polymorphism that can influence PLK1 mRNA stability and may be a factor for response to PLK1 inhibitors, suggesting that the mutations residing in the 3'UTR may alter miRNA binding efficiency and consequently trigger loss/gain of gene function.	('miRNA', 'MPA', (181, 186))	('loss/gain', 'PosReg', (231, 240))	('PLK1', 'Gene', (46, 50))	('mutations', 'Var', (139, 148))	('influence', 'Reg', (36, 45))	('gene function', 'MPA', (244, 257))	('mRNA stability', 'MPA', (51, 65))	('alter', 'Reg', (175, 180))	('PLK1', 'Gene', '5347', (46, 50))	('PLK1', 'Gene', (102, 106))	('loss/gain', 'NegReg', (231, 240))	('PLK1', 'Gene', '5347', (102, 106))
460863	30424545	found 11 mutations in 3'UTR that alter miRNA target sites in cancer-related genes.	('alter', 'Reg', (33, 38))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('mutations', 'Var', (9, 18))	("3'UTR", 'Gene', (22, 27))	('cancer', 'Disease', (61, 67))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('miRNA target sites', 'MPA', (39, 57))
460864	30424545	Systematic characterization of the functional implications of mutations in cancers remains to be done.	('cancers', 'Phenotype', 'HP:0002664', (75, 82))	('cancers', 'Disease', 'MESH:D009369', (75, 82))	('cancers', 'Disease', (75, 82))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('mutations', 'Var', (62, 71))
460866	30424545	Functional enrichment analysis revealed that the funcMutations may regulate gene expression and affect cancer-related signaling pathways (e.g., WNT signaling pathway).	('affect', 'Reg', (96, 102))	('regulate', 'Reg', (67, 75))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('gene expression', 'MPA', (76, 91))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('funcMutations', 'Var', (49, 62))
460867	30424545	Our findings suggest that 3'UTR mutations may perturb miRNA-mRNA interactions and consequently have important implications for tumor development.	('miRNA-mRNA interactions', 'MPA', (54, 77))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('implications', 'Reg', (110, 122))	('tumor', 'Disease', (127, 132))	('mutations', 'Var', (32, 41))	("3'UTR", 'Gene', (26, 31))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('perturb', 'NegReg', (46, 53))
460869	30424545	Variants calling results (VCF files) of whole-exome target sequencing (WES) datasets of 10,429 tumors for 33 cancer types were obtained from TCGA which detected 1,648,474 potential single nucleotide variants in 3'UTRs.	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('tumors', 'Disease', (95, 101))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('cancer', 'Disease', (109, 115))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('single nucleotide variants', 'Var', (181, 207))
460877	30424545	For each somatic mutation in human mRNA 3'UTR regions, we assessed whether its two alleles would cause different miRNA-mRNA target binding.	('mutation', 'Var', (17, 25))	('binding', 'Interaction', (131, 138))	('human', 'Species', '9606', (29, 34))	('cause', 'Reg', (97, 102))	('miRNA-mRNA target', 'MPA', (113, 130))
460878	30424545	Mutect2 will provide at least 80% power to detect mutations with an allelic fraction of 0.3 if the coverage of depth is more than 14-fold in tumors and 8-fold in normal samples.	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('mutations', 'Var', (50, 59))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('tumors', 'Disease', 'MESH:D009369', (141, 147))	('tumors', 'Disease', (141, 147))
460879	30424545	In order to confirm whether the capture kit for WES can provide efficient power to detect mutations in 3'UTR, we analyzed the coverage of depth of 3'UTR in both tumor and normal samples.	('mutations', 'Var', (90, 99))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('tumor', 'Disease', (161, 166))	("3'UTR", 'Gene', (103, 108))
460882	30424545	Patient histories have revealed an association between treatment with the alkylating agent TMZ and Signature 11 mutations.	('mutations', 'Var', (112, 121))	('Signature 11', 'Gene', (99, 111))	('Patient', 'Species', '9606', (0, 7))	('TMZ', 'Chemical', 'MESH:D000077204', (91, 94))
460883	30424545	Accordingly, we speculate that some mutations can impact cancer development by altering miRNA targeting efficiency and thereby affecting miRNA-mRNA binding status.	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('impact', 'Reg', (50, 56))	('miRNA targeting efficiency', 'MPA', (88, 114))	('cancer', 'Disease', (57, 63))	('altering', 'Reg', (79, 87))	('affecting', 'Reg', (127, 136))	('mutations', 'Var', (36, 45))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('miRNA-mRNA binding status', 'MPA', (137, 162))
460889	30424545	By leveraging permutation analysis, we selected some of the tarGenes which exhibited large numbers of mutations relative to genes involved in an equal number of hallmarks, as shown in Supplement Table S3, as we speculated they may be important for tumor progression.	('mutations', 'Var', (102, 111))	('tumor', 'Disease', (248, 253))	('tumor', 'Disease', 'MESH:D009369', (248, 253))	('tumor', 'Phenotype', 'HP:0002664', (248, 253))
460893	30424545	The 3'UTR mutations in HIPK2 generally resulted in a gain of binding affinity to miRNAs, as shown in Figure 4C.	('miRNAs', 'Protein', (81, 87))	('HIPK2', 'Gene', (23, 28))	('gain', 'PosReg', (53, 57))	('mutations', 'Var', (10, 19))	('HIPK2', 'Gene', '28996', (23, 28))	('binding', 'Interaction', (61, 68))
460894	30424545	The miRNAs may down-regulate the expression of HIPK2 and thereby promote tumor progression.	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('HIPK2', 'Gene', (47, 52))	('tumor', 'Disease', (73, 78))	('promote', 'PosReg', (65, 72))	('expression', 'MPA', (33, 43))	('miRNAs', 'Var', (4, 10))	('down-regulate', 'NegReg', (15, 28))	('HIPK2', 'Gene', '28996', (47, 52))
460895	30424545	The 3'UTR mutations in PPARD (permutation p-value = 0.001, mutations = 10) were associated with loss of miRNA binding, as shown in Figure 4D.	('PPARD', 'Gene', '5467', (23, 28))	('miRNA', 'MPA', (104, 109))	('mutations', 'Var', (10, 19))	('loss', 'NegReg', (96, 100))	('PPARD', 'Gene', (23, 28))
460897	30424545	These findings together indicate that mutations in the 3'UTR of tarGenes may have a complex impact on tumor progression by changing binding affinity of a spectrum of miRNAs.	('impact', 'Reg', (92, 98))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('changing', 'Reg', (123, 131))	('binding', 'Interaction', (132, 139))	('tarGenes', 'Gene', (64, 72))	('mutations', 'Var', (38, 47))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))
460899	30424545	In general, the 3'UTR mutations in cancers contributed to a loss of binding affinity (69.3% of the funcMutations were identified triggering the loss of miRNA-mRNA binding), as shown in Figure 5A.	('binding', 'Interaction', (68, 75))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('loss', 'NegReg', (60, 64))	('mutations', 'Var', (22, 31))	('cancers', 'Phenotype', 'HP:0002664', (35, 42))	('cancers', 'Disease', 'MESH:D009369', (35, 42))	('loss', 'NegReg', (144, 148))	('cancers', 'Disease', (35, 42))
460900	30424545	To explore the function of changes in binding ability (designated as a loss and gain status), we applied the tumor hallmark enrichment analysis of the corresponding tarGenes to each of the miRNAs.	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('changes', 'Var', (27, 34))	('tumor', 'Disease', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))
460904	30424545	that re-gained the tarGene binding site may inhibit pathways otherwise involved in tumor suppression (e.g., the P53 pathway) or activate pathways involved with oncogenesis (e.g., the IL6/JAK/STAT3 pathway), as shown in Figure 5C.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('pathways', 'Pathway', (137, 145))	('P53', 'Gene', (112, 115))	('STAT3', 'Gene', '6774', (191, 196))	('tumor', 'Disease', (83, 88))	('inhibit', 'NegReg', (44, 51))	('binding', 'Interaction', (27, 34))	('re-gained', 'Var', (5, 14))	('IL6', 'Gene', '3569', (183, 186))	('STAT3', 'Gene', (191, 196))	('activate', 'PosReg', (128, 136))	('P53', 'Gene', '7157', (112, 115))	('pathways', 'Pathway', (52, 60))	('IL6', 'Gene', (183, 186))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
460907	30424545	Mutations of 3'UTR may affect tumor progression.	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('Mutations', 'Var', (0, 9))	('affect', 'Reg', (23, 29))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	("3'UTR", 'Gene', (13, 18))	('tumor', 'Disease', (30, 35))
460909	30424545	To explore how mutations may affect tumor progression, we assessed the position feature and base substitution characteristics of 3'UTR mutations.	('affect', 'Reg', (29, 35))	('mutations', 'Var', (15, 24))	('mutations', 'Var', (135, 144))	("3'UTR", 'Gene', (129, 134))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumor', 'Disease', (36, 41))
460910	30424545	We found that some 3'UTR mutations alter miRNA targeting efficiency and thereby can impact tumor development.	('impact', 'Reg', (84, 90))	('mutations', 'Var', (25, 34))	('alter', 'Reg', (35, 40))	("3'UTR", 'Gene', (19, 24))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('miRNA targeting efficiency', 'MPA', (41, 67))	('tumor', 'Disease', (91, 96))
460914	30424545	Overall, the differential analysis demonstrated that the 3'UTR mutations in cancers generally caused an increasing loss of miRNA binding ability.	('mutations', 'Var', (63, 72))	('cancers', 'Disease', 'MESH:D009369', (76, 83))	('cancers', 'Phenotype', 'HP:0002664', (76, 83))	('loss', 'NegReg', (115, 119))	('cancers', 'Disease', (76, 83))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('miRNA', 'Protein', (123, 128))
460917	30424545	Our findings together demonstrate that 3'UTR mutations may play an important role in tumor development and the phenomenon should be further investigated.	('tumor', 'Disease', (85, 90))	('mutations', 'Var', (45, 54))	("3'UTR", 'Protein', (39, 44))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('play', 'Reg', (59, 63))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))
460946	25091190	We recently described a ratiometric version of ACPPs (RACPPs) that employs Cy5 as a far-red fluorescent resonance energy transfer (FRET) donor and Cy7 as near-infrared FRET acceptor.	('Cy5', 'Var', (75, 78))	('ACPP', 'Gene', (55, 59))	('ACPP', 'Gene', '55', (47, 51))	('RACPP', 'Chemical', '-', (54, 59))	('Cy5', 'Chemical', 'MESH:C085321', (75, 78))	('Cy7', 'Var', (147, 150))	('ACPP', 'Gene', (47, 51))	('ACPP', 'Gene', '55', (55, 59))	('donor', 'Species', '9606', (137, 142))	('Cy7', 'Chemical', '-', (147, 150))
460966	25091190	Following cleavage by MMPs, the polycationic portion conjugated to Cy5 is dequenched and becomes trapped within nearby tissue.	('Cy5', 'Chemical', 'MESH:C085321', (67, 70))	('Cy5', 'Gene', (67, 70))	('MMPs', 'Gene', (22, 26))	('dequenched', 'MPA', (74, 84))	('MMPs', 'Gene', '4313;17390;4318;17395;4323', (22, 26))	('polycationic', 'Var', (32, 44))
460969	25091190	Nu/nu mice (age, 3-6 months) were injected with cultured HNSCC cells (~106 for CAL-27, ~5 x 106 for SCC-4, SCC-9, SCC-15, SCC-25) into the tip of the tongue.	('HNSCC', 'Phenotype', 'HP:0012288', (57, 62))	('mice', 'Species', '10090', (6, 10))	('SCC-15', 'Gene', (114, 120))	('~106', 'Var', (70, 74))	('SCC-15', 'Gene', '100034867', (114, 120))	('SCC-9', 'Gene', (107, 112))	('SCC-9', 'Gene', '112207', (107, 112))
460975	25091190	For ratio imaging, numerator (Cy5) and denominator (Cy7) images were generated by integrating spectral images over a defined range at 10 nm intervals (660-720 nm for Cy5 and 760-830 nm for Cy7).	('Cy5', 'Chemical', 'MESH:C085321', (166, 169))	('760-830 nm', 'Var', (174, 184))	('Cy7', 'Chemical', '-', (52, 55))	('Cy5', 'Chemical', 'MESH:C085321', (30, 33))	('660-720 nm', 'Var', (151, 161))	('Cy5', 'Var', (166, 169))	('Cy7', 'Chemical', '-', (189, 192))
460995	25091190	The second highest expressing MMP in tumor tissue was MMP2.	('MMP2', 'Var', (54, 58))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('tumor', 'Disease', 'MESH:D009369', (37, 42))
460996	25091190	We found that both MMP2 (P < 10-10) and MMP9 (P < 10-6) have significantly greater RNA expression in HNSCC tumors compared to paired-control tissue (n = 37; 34 HPV- and 3 HPV+, Wilcoxon signed-rank test).	('HPV', 'Species', '10566', (171, 174))	('MMP9', 'Gene', '17395', (40, 44))	('MMP2', 'Var', (19, 23))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('HNSCC tumors', 'Disease', 'MESH:D000077195', (101, 113))	('HNSCC', 'Phenotype', 'HP:0012288', (101, 106))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('MMP9', 'Gene', (40, 44))	('HPV', 'Species', '10566', (160, 163))	('RNA expression', 'MPA', (83, 97))	('greater', 'PosReg', (75, 82))	('HNSCC tumors', 'Disease', (101, 113))
461000	25091190	Interestingly, we found that in patients with HPV+ HNSCC, increased expression levels of MMP2 and MMP14 correlated with worse survival (Figures 1C, 1D, P < .01).	('patients', 'Species', '9606', (32, 40))	('MMP14', 'Gene', '4323', (98, 103))	('increased', 'PosReg', (58, 67))	('MMP14', 'Gene', (98, 103))	('HNSCC', 'Phenotype', 'HP:0012288', (51, 56))	('MMP2', 'Protein', (89, 93))	('HPV', 'Species', '10566', (46, 49))	('HPV+ HNSCC', 'Var', (46, 56))	('expression levels', 'MPA', (68, 85))	('worse', 'NegReg', (120, 125))
461001	25091190	Patients with HPV+ tumors who have the highest MMP2 and MMP14 expression (Figures 1C, 1D red lines) had significantly worse 5-year survival compared to patients with the lowest expression levels of these proteases (Figures 1C, 1D blue lines).	('MMP2', 'Var', (47, 51))	('HPV+ tumors', 'Disease', 'MESH:D030361', (14, 25))	('HPV+ tumors', 'Disease', (14, 25))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('Patients', 'Species', '9606', (0, 8))	('MMP14', 'Gene', '4323', (56, 61))	('worse', 'NegReg', (118, 123))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('MMP14', 'Gene', (56, 61))	('patients', 'Species', '9606', (152, 160))
461005	25091190	The cause of this is multifactorial and likely related to the observation that HPV- tumors have more genetic mutations compared HPV+ tumors.	('genetic mutations', 'Var', (101, 118))	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('HPV- tumors', 'Disease', (79, 90))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('HPV+ tumors', 'Disease', 'MESH:D030361', (128, 139))	('HPV+ tumors', 'Disease', (128, 139))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('HPV- tumors', 'Disease', 'MESH:D030361', (79, 90))
461017	25091190	Following intravenous administration of MMP2/9-cleavable RACPP, mice showed greater normalized Cy5/Cy7 ratio in tumor (1.61 +- 0.05, n = 22) compared to normal tongue (1.11 +- 0.03, n = 20, P < 10-8).	('normalized Cy5/Cy7 ratio', 'MPA', (84, 108))	('RACPP', 'Chemical', '-', (57, 62))	('Cy5', 'Chemical', 'MESH:C085321', (95, 98))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('Cy7', 'Chemical', '-', (99, 102))	('tumor', 'Disease', (112, 117))	('MMP2/9-cleavable', 'Var', (40, 56))	('mice', 'Species', '10090', (64, 68))
461060	32854705	Many targeted therapies are effective only for patients with specific genetic alterations (known as driver mutations) that help cancer cells form and grow.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('patients', 'Species', '9606', (47, 55))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('genetic alterations', 'Var', (70, 89))	('cancer', 'Disease', (128, 134))
461131	32854705	also showed that the epigenetic silencing of SLC39A8 expression by DNA methylation is involved in the acquisition of resistance against cadmium in lung cells and the relation between cadmium and lung cancer has received much attention.	('resistance against cadmium', 'MPA', (117, 143))	('SLC39A8', 'Gene', '64116', (45, 52))	('epigenetic silencing', 'Var', (21, 41))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('lung cancer', 'Disease', (195, 206))	('acquisition', 'PosReg', (102, 113))	('SLC39A8', 'Gene', (45, 52))	('cadmium', 'Chemical', 'MESH:D002104', (183, 190))	('lung cancer', 'Phenotype', 'HP:0100526', (195, 206))	('involved', 'Reg', (86, 94))	('cadmium', 'Chemical', 'MESH:D002104', (136, 143))	('lung cancer', 'Disease', 'MESH:D008175', (195, 206))
461141	32854705	MAMDC2 is known as a target of miR-196a in head and neck squamous cell carcinoma.	('MAMDC2', 'Gene', '256691', (0, 6))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (57, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('neck squamous cell carcinoma', 'Disease', (52, 80))	('miR-196a', 'Var', (31, 39))	('MAMDC2', 'Gene', (0, 6))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (52, 80))
461161	31776338	Our studies indicate that tumor progression relies on precise T3 availability, suggesting that pharmacological inactivation of D2 and TH signaling may suppress the metastatic proclivity of SCC.	('metastatic proclivity of', 'CPA', (164, 188))	('SCC', 'Gene', (189, 192))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('SCC', 'Phenotype', 'HP:0002860', (189, 192))	('SCC', 'Gene', '6317', (189, 192))	('inactivation', 'Var', (111, 123))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('suppress', 'NegReg', (151, 159))	('TH signaling', 'MPA', (134, 146))
461172	31776338	Attenuation of TH by D3 in BCC cells is sufficient to enhance susceptibility to cancer formation.	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('Attenuation', 'Var', (0, 11))	('enhance', 'PosReg', (54, 61))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('cancer', 'Disease', (80, 86))
461195	31776338	In detail, D2 expression was associated with reduced E-cadherin and enhanced vimentin expression, which is a sign of the EMT typical of advanced SCCs (Fig.	('D2 expression', 'Var', (11, 24))	('enhanced', 'PosReg', (68, 76))	('expression', 'Var', (14, 24))	('reduced', 'NegReg', (45, 52))	('E-cadherin', 'Protein', (53, 63))	('SCC', 'Gene', (145, 148))	('SCC', 'Phenotype', 'HP:0002860', (145, 148))	('expression', 'MPA', (86, 96))	('vimentin', 'Gene', '22352', (77, 85))	('SCC', 'Gene', '6317', (145, 148))	('SCCs', 'Phenotype', 'HP:0002860', (145, 149))	('vimentin', 'Gene', (77, 85))
461200	31776338	To this end, we crossed D3fl/fl or D2fl/fl mice with K14CreERT mice.	('mice', 'Species', '10090', (43, 47))	('K14', 'Gene', '16664', (53, 56))	('mice', 'Species', '10090', (63, 67))	('D2fl/fl', 'Var', (35, 42))	('K14', 'Gene', (53, 56))	('D3fl/fl', 'Var', (24, 31))
461201	31776338	First, we depleted D3 by treating K14CreERT+/-, D3fl/fl (skin D3KO, sD3KO) and K14CreERT-/-, D3fl/fl (CTR) mice with tamoxifen, and applied DMBA/TPA to their dorsal skin one week later (Fig.	('K14', 'Gene', '16664', (79, 82))	('K14', 'Gene', (79, 82))	('CTR', 'Gene', '12311', (102, 105))	('DMBA', 'Chemical', 'MESH:D015127', (140, 144))	('mice', 'Species', '10090', (107, 111))	('TPA', 'Chemical', 'MESH:C052698', (145, 148))	('tamoxifen', 'Chemical', 'MESH:D013629', (117, 126))	('K14', 'Gene', '16664', (34, 37))	('K14', 'Gene', (34, 37))	('CTR', 'Gene', (102, 105))	('D3fl/fl', 'Var', (93, 100))
461202	31776338	Eight weeks after DMBA treatment, the analysis of skin morphology and of the markers of epidermal hyperplasia, i.e., K14 and K6, showed that tumor formation was much lower in sD3KO mice than in controls (Fig.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('epidermal hyperplasia', 'Disease', (88, 109))	('mice', 'Species', '10090', (181, 185))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('K14', 'Gene', (117, 120))	('tumor', 'Disease', (141, 146))	('epidermal hyperplasia', 'Disease', 'MESH:D006965', (88, 109))	('lower', 'NegReg', (166, 171))	('DMBA', 'Chemical', 'MESH:D015127', (18, 22))	('sD3KO', 'Var', (175, 180))	('K14', 'Gene', '16664', (117, 120))
461204	31776338	D3-depletion reduced the frequency (number of tumors at each time point) and the incidence (time of lesion appearance) of cancers (Fig.	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('cancers', 'Disease', 'MESH:D009369', (122, 129))	('cancers', 'Phenotype', 'HP:0002664', (122, 129))	('cancers', 'Disease', (122, 129))	('D3-depletion', 'Var', (0, 12))	('tumors', 'Disease', (46, 52))	('reduced', 'NegReg', (13, 20))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('tumors', 'Disease', 'MESH:D009369', (46, 52))
461206	31776338	Accordingly, K8 expression was higher in D3KO mice than in control mice, which suggests that D3-depletion accelerates SCC formation (Fig.	('SCC', 'Gene', (118, 121))	('accelerates', 'PosReg', (106, 117))	('rat', 'Species', '10116', (112, 115))	('mice', 'Species', '10090', (46, 50))	('SCC', 'Phenotype', 'HP:0002860', (118, 121))	('SCC', 'Gene', '6317', (118, 121))	('higher', 'PosReg', (31, 37))	('expression', 'MPA', (16, 26))	('mice', 'Species', '10090', (67, 71))	('D3KO', 'Var', (41, 45))
461207	31776338	The E-cadherin/N-cadherin ratio was lower in D3KO lesions than in control lesions, which confirms the more advanced stage of these lesions in D3KO mice (Fig.	('mice', 'Species', '10090', (147, 151))	('lower', 'NegReg', (36, 41))	('rat', 'Species', '10116', (26, 29))	('N-cadherin', 'Gene', (15, 25))	('N-cadherin', 'Gene', '12558', (15, 25))	('D3KO lesions', 'Var', (45, 57))
461210	31776338	3b, c, D2-depletion increased the frequency of hyperplastic lesions and papillomas.	('increased', 'PosReg', (20, 29))	('D2-depletion', 'Var', (7, 19))	('papillomas', 'Phenotype', 'HP:0012740', (72, 82))	('hyperplastic lesions and papillomas', 'Disease', 'MESH:D010212', (47, 82))	('papilloma', 'Phenotype', 'HP:0012740', (72, 81))
461211	31776338	sD2KO mice developed skin papillomas at an average of 10 weeks after the first application of DMBA, compared with 14 weeks in control mice (Fig.	('papillomas', 'Phenotype', 'HP:0012740', (26, 36))	('mice', 'Species', '10090', (134, 138))	('sD2KO', 'Var', (0, 5))	('mice', 'Species', '10090', (6, 10))	('DMBA', 'Chemical', 'MESH:D015127', (94, 98))	('papilloma', 'Phenotype', 'HP:0012740', (26, 35))	('developed', 'Reg', (11, 20))	('skin papillomas', 'Disease', 'MESH:D010212', (21, 36))	('skin papillomas', 'Disease', (21, 36))
461212	31776338	By week 20, 100% of sD2KO mice and only 70% of control mice developed tumors.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('sD2KO', 'Var', (20, 25))	('mice', 'Species', '10090', (55, 59))	('tumors', 'Disease', 'MESH:D009369', (70, 76))	('tumors', 'Disease', (70, 76))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('mice', 'Species', '10090', (26, 30))
461214	31776338	Notably, the greater tumor growth in D2KO mice was not associated with greater tumor progression and invasive conversion.	('D2KO', 'Var', (37, 41))	('tumor', 'Disease', (79, 84))	('tumor', 'Disease', (21, 26))	('mice', 'Species', '10090', (42, 46))	('invasive conversion', 'CPA', (101, 120))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
461215	31776338	3d, e, K8 expression was lower in sD2KO mice than in control mice, which indicates that D2KO papillomas resist progression to SCC.	('D2KO', 'Var', (88, 92))	('mice', 'Species', '10090', (61, 65))	('SCC', 'Phenotype', 'HP:0002860', (126, 129))	('SCC', 'Gene', '6317', (126, 129))	('papillomas', 'Disease', (93, 103))	('papillomas', 'Disease', 'MESH:D010212', (93, 103))	('expression', 'MPA', (10, 20))	('lower', 'NegReg', (25, 30))	('papillomas', 'Phenotype', 'HP:0012740', (93, 103))	('papilloma', 'Phenotype', 'HP:0012740', (93, 102))	('mice', 'Species', '10090', (40, 44))	('SCC', 'Gene', (126, 129))
461217	31776338	This finding demonstrates that TH attenuation via D2-depletion reduces the EMT, and that, while increasing tumor formation, it slows tumor progression.	('slows', 'NegReg', (127, 132))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('reduces', 'NegReg', (63, 70))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('D2-depletion', 'Var', (50, 62))	('EMT', 'CPA', (75, 78))	('increasing', 'PosReg', (96, 106))	('tumor', 'Disease', (133, 138))	('rat', 'Species', '10116', (20, 23))	('tumor', 'Disease', 'MESH:D009369', (107, 112))
461219	31776338	In this case, the total number of tumors was similar in the sD2KO and control mice.	('tumors', 'Disease', 'MESH:D009369', (34, 40))	('tumors', 'Disease', (34, 40))	('sD2KO', 'Var', (60, 65))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('mice', 'Species', '10090', (78, 82))
461221	31776338	3f), tumor progression was delayed in the sD2KO mice.	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('mice', 'Species', '10090', (48, 52))	('delayed', 'NegReg', (27, 34))	('sD2KO', 'Var', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('tumor', 'Disease', (5, 10))
461222	31776338	Indeed, by week 25, sD2KO mice developed an average of 1.1 carcinoma-like, large tumors (>3 mm) per mouse compared with 4.4 large tumors per mouse in their control littermates (P < 0.01; Fig.	('carcinoma', 'Disease', (59, 68))	('tumors', 'Disease', (130, 136))	('tumors', 'Disease', 'MESH:D009369', (130, 136))	('tumors', 'Disease', (81, 87))	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('sD2KO', 'Var', (20, 25))	('mouse', 'Species', '10090', (100, 105))	('mouse', 'Species', '10090', (141, 146))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('carcinoma', 'Disease', 'MESH:D002277', (59, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (59, 68))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('mice', 'Species', '10090', (26, 30))
461223	31776338	Moreover, K8 levels were lower in sD2KO mice than in control mice (Fig.	('mice', 'Species', '10090', (61, 65))	('sD2KO', 'Var', (34, 39))	('lower', 'NegReg', (25, 30))	('mice', 'Species', '10090', (40, 44))	('K8 levels', 'MPA', (10, 19))
461233	31776338	Given the effects of D2-depletion and D3-depletion in SCC progression and invasiveness, we investigated whether the TH signal is a positive regulator of the invasive conversion of cancer cells.	('cancer', 'Disease', (180, 186))	('SCC', 'Gene', '6317', (54, 57))	('effects', 'Reg', (10, 17))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('SCC', 'Phenotype', 'HP:0002860', (54, 57))	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('SCC', 'Gene', (54, 57))	('D3-depletion', 'Var', (38, 50))	('D2-depletion', 'Var', (21, 33))
461240	31776338	Indeed, the E-cadherin/N-cadherin ratio at mRNA and protein level was reduced in D3KO cells and in T3-treated cells (Fig.	('N-cadherin', 'Gene', (23, 33))	('N-cadherin', 'Gene', '12558', (23, 33))	('reduced', 'NegReg', (70, 77))	('rat', 'Species', '10116', (34, 37))	('D3KO', 'Var', (81, 85))
461241	31776338	Accordingly, the E-cadherin/N-cadherin ratio was elevated in D2KO cells versus control cells (Fig.	('D2KO', 'Var', (61, 65))	('N-cadherin', 'Gene', '12558', (28, 38))	('N-cadherin', 'Gene', (28, 38))	('rat', 'Species', '10116', (39, 42))	('elevated', 'PosReg', (49, 57))
461242	31776338	The expression of the EMT markers vimentin and Twist was also inversely regulated in D2KO cells versus D3KO cells (Supplementary Fig.	('vimentin', 'Gene', (34, 42))	('Twist', 'Gene', (47, 52))	('D2KO', 'Var', (85, 89))	('expression', 'MPA', (4, 14))	('vimentin', 'Gene', '22352', (34, 42))
461247	31776338	Accordingly, D3-depletion in D3KO cells caused growth attenuation, but enhanced migration (Supplementary Fig.	('enhanced', 'PosReg', (71, 79))	('rat', 'Species', '10116', (83, 86))	('attenuation', 'NegReg', (54, 65))	('migration', 'CPA', (80, 89))	('D3-depletion', 'Var', (13, 25))	('growth', 'CPA', (47, 53))
461252	31776338	Real-time PCR analysis revealed that the expression of MMP 2, 3, 7, and 13 was higher in D3KO cells, and lower in D2KO cells than in controls (Supplementary Fig.	('D3KO', 'Var', (89, 93))	('lower', 'NegReg', (105, 110))	('expression', 'MPA', (41, 51))	('MMP 2', 'Gene', '17390', (55, 60))	('MMP 2', 'Gene', (55, 60))	('higher', 'PosReg', (79, 85))
461255	31776338	In particular, 22 EMT-positive regulators, among which vimentin, N-cadherin, ZEB-1, and Col1a2, were up-regulated in D3KO cells, while 13 genes were down-regulated, among which, the epidermal markers keratin 14 and E-cadherin, which indicates massive induction of the EMT-mediating cascade (Fig.	('rat', 'Species', '10116', (202, 205))	('ZEB-1', 'Gene', (77, 82))	('vimentin', 'Gene', (55, 63))	('D3KO', 'Var', (117, 121))	('up-regulated', 'PosReg', (101, 113))	('N-cadherin', 'Gene', (65, 75))	('Col1a2', 'Gene', (88, 94))	('N-cadherin', 'Gene', '12558', (65, 75))	('E-cadherin', 'Protein', (215, 225))	('down-regulated', 'NegReg', (149, 163))	('Col1a2', 'Gene', '12843', (88, 94))	('EMT-positive', 'Gene', (18, 30))	('vimentin', 'Gene', '22352', (55, 63))
461260	31776338	6h, i) and in in vivo tumors from DMBA/TPA-treated D2KO and D3KO mice.	('tumors', 'Phenotype', 'HP:0002664', (22, 28))	('TPA', 'Chemical', 'MESH:C052698', (39, 42))	('tumors', 'Disease', 'MESH:D009369', (22, 28))	('DMBA', 'Chemical', 'MESH:D015127', (34, 38))	('mice', 'Species', '10090', (65, 69))	('D2KO', 'Var', (51, 55))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('D3KO', 'Var', (60, 64))	('tumors', 'Disease', (22, 28))
461264	31776338	Moreover, the number of metastatic lesions in liver, lung, and lymph nodes in D2KO, D3KO, and control mice treated with DMBA/TPA for 20 and 30 weeks was higher in D3KO mice and lower in D2KO mice versus control mice (Fig.	('lower', 'NegReg', (177, 182))	('mice', 'Species', '10090', (102, 106))	('higher', 'PosReg', (153, 159))	('metastatic lesions', 'CPA', (24, 42))	('DMBA', 'Chemical', 'MESH:D015127', (120, 124))	('mice', 'Species', '10090', (168, 172))	('D3KO', 'Var', (163, 167))	('mice', 'Species', '10090', (191, 195))	('mice', 'Species', '10090', (211, 215))	('TPA', 'Chemical', 'MESH:C052698', (125, 128))
461272	31776338	Kaplan-Meier plots from both data sets showed a striking significant correlation between high D2 levels and risk of relapse, and an inverse correlation with the percent survival of patients (Fig.	('high', 'Var', (89, 93))	('D2 levels', 'MPA', (94, 103))	('patients', 'Species', '9606', (181, 189))	('inverse', 'NegReg', (132, 139))
461276	31776338	In this study, we demonstrate that TH activation enhances the invasiveness and metastatic propensity of SCC cells in an in vivo model of chemical cancerogenesis.	('TH activation', 'Var', (35, 48))	('invasiveness', 'CPA', (62, 74))	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('SCC', 'Gene', (104, 107))	('SCC', 'Phenotype', 'HP:0002860', (104, 107))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('rat', 'Species', '10116', (25, 28))	('SCC', 'Gene', '6317', (104, 107))	('enhances', 'PosReg', (49, 57))	('metastatic propensity', 'CPA', (79, 100))
461279	31776338	These conclusions are based on the following results: (1) TH treatment of SCC cells reduced cell proliferation whereas it increased cell migration and invasive capability; (2) TH treatment of SCC cells also attenuated tumor formation, but accelerated the metastatic conversion of SCC; and lastly, (3) TH-attenuation in vivo accelerated tumor formation and reduced invasiveness and the development of metastatic tumors compared with wild-type littermates.	('SCC', 'Phenotype', 'HP:0002860', (192, 195))	('SCC', 'Phenotype', 'HP:0002860', (74, 77))	('accelerated', 'PosReg', (239, 250))	('cell migration', 'CPA', (132, 146))	('tumor', 'Disease', (218, 223))	('tumor', 'Phenotype', 'HP:0002664', (411, 416))	('tumor', 'Disease', (336, 341))	('SCC', 'Gene', '6317', (74, 77))	('SCC', 'Gene', '6317', (280, 283))	('accelerated', 'PosReg', (324, 335))	('tumors', 'Phenotype', 'HP:0002664', (411, 417))	('SCC', 'Gene', '6317', (192, 195))	('rat', 'Species', '10116', (245, 248))	('tumor', 'Disease', 'MESH:D009369', (218, 223))	('tumor', 'Disease', 'MESH:D009369', (336, 341))	('attenuated', 'NegReg', (207, 217))	('SCC', 'Gene', (74, 77))	('SCC', 'Gene', (280, 283))	('increased', 'PosReg', (122, 131))	('rat', 'Species', '10116', (330, 333))	('invasive capability', 'CPA', (151, 170))	('SCC', 'Gene', (192, 195))	('tumors', 'Disease', (411, 417))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('TH-attenuation', 'Var', (301, 315))	('cell proliferation', 'CPA', (92, 110))	('rat', 'Species', '10116', (140, 143))	('reduced', 'NegReg', (356, 363))	('metastatic conversion', 'CPA', (255, 276))	('tumor', 'Phenotype', 'HP:0002664', (336, 341))	('invasiveness', 'CPA', (364, 376))	('tumor', 'Disease', (411, 416))	('tumors', 'Disease', 'MESH:D009369', (411, 417))	('reduced', 'NegReg', (84, 91))	('tumor', 'Disease', 'MESH:D009369', (411, 416))	('SCC', 'Phenotype', 'HP:0002860', (280, 283))	('rat', 'Species', '10116', (104, 107))
461284	31776338	On the contrary, cell migration and invasion were reduced in D2KO mice.	('invasion', 'CPA', (36, 44))	('cell migration', 'CPA', (17, 31))	('D2KO', 'Var', (61, 65))	('mice', 'Species', '10090', (66, 70))	('rat', 'Species', '10116', (25, 28))	('reduced', 'NegReg', (50, 57))
461287	31776338	Although D3 is not a canonical oncogene per se and D3 overexpression is not sufficient for tumor initiation (unpublished data), D3-depletion drastically attenuates the growth of a variety of tumors.	('tumors', 'Phenotype', 'HP:0002664', (191, 197))	('growth', 'CPA', (168, 174))	('D3-depletion', 'Var', (128, 140))	('tumors', 'Disease', 'MESH:D009369', (191, 197))	('tumor initiation', 'Disease', 'MESH:D009369', (91, 107))	('attenuates', 'NegReg', (153, 163))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumors', 'Disease', (191, 197))	('tumor initiation', 'Disease', (91, 107))
461293	31776338	A search in public databases showed that D2 expression correlates with advanced tumor grading, postsurgical relapse, and a shorter disease-free survival (Fig.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('shorter', 'NegReg', (123, 130))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('expression', 'Var', (44, 54))	('tumor', 'Disease', (80, 85))	('postsurgical relapse', 'CPA', (95, 115))	('disease-free survival', 'CPA', (131, 152))
461295	31776338	Indeed, they suggest that D2 expression correlates with such features of malignant tumors as short overall survival, poor prognosis, and dismal outcome.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('expression', 'Var', (29, 39))	('short', 'NegReg', (93, 98))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('malignant tumors', 'Disease', (73, 89))	('malignant tumors', 'Disease', 'MESH:D009369', (73, 89))
461302	31776338	Chromatin immunoprecipitation assays revealed that among various EMT-related genes, ZEB-1 is physically bound by T3 in SCC cells and that inhibition of ZEB-1 drastically reduced the TH-dependent EMT (Fig.	('SCC', 'Gene', '6317', (119, 122))	('bound', 'Interaction', (104, 109))	('reduced', 'NegReg', (170, 177))	('ZEB-1', 'Gene', (152, 157))	('inhibition', 'Var', (138, 148))	('ZEB-1', 'Gene', (84, 89))	('SCC', 'Gene', (119, 122))	('SCC', 'Phenotype', 'HP:0002860', (119, 122))
461308	31776338	On the contrary, D3KO tumors have a high ZEB-1/E-cadherin ratio and are highly invasive (Fig.	('tumors', 'Phenotype', 'HP:0002664', (22, 28))	('ZEB-1/E-cadherin', 'Protein', (41, 57))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('rat', 'Species', '10116', (58, 61))	('D3KO', 'Var', (17, 21))	('tumors', 'Disease', 'MESH:D009369', (22, 28))	('tumors', 'Disease', (22, 28))
461311	31776338	By altering the TH signal via cell-specific deiodinase knock-down, we demonstrate that modulation of TH concentration can delay tumor cell growth and invasion depending on tumor stage, and can affect the malignant epithelial tumor phenotype.	('tumor', 'Disease', 'MESH:D009369', (225, 230))	('rat', 'Species', '10116', (111, 114))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('epithelial tumor', 'Phenotype', 'HP:0031492', (214, 230))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('delay', 'NegReg', (122, 127))	('rat', 'Species', '10116', (77, 80))	('tumor', 'Disease', (172, 177))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('modulation', 'Var', (87, 97))	('affect', 'Reg', (193, 199))	('tumor', 'Disease', (225, 230))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('TH concentration', 'MPA', (101, 117))	('tumor', 'Disease', (128, 133))	('tumor', 'Disease', 'MESH:D009369', (172, 177))
461312	31776338	Therefore, we conclude that D2 is an endogenous "metastasis promoter" and that D2 inhibition can help to reduce human cancer metastasis.	('cancer', 'Disease', (118, 124))	('reduce', 'NegReg', (105, 111))	('inhibition', 'Var', (82, 92))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('human', 'Species', '9606', (112, 117))	('cancer', 'Disease', 'MESH:D009369', (118, 124))
461319	31776338	Targeted mutagenesis of Dio3 and Dio2 in SCC was achieved by using the CRISPR/Cas9 system from Santa Cruz Biotechnology.	('Dio3', 'Gene', '107585', (24, 28))	('SCC', 'Gene', (41, 44))	('SCC', 'Phenotype', 'HP:0002860', (41, 44))	('SCC', 'Gene', '6317', (41, 44))	('Dio2', 'Gene', '13371', (33, 37))	('Dio2', 'Gene', (33, 37))	('Dio3', 'Gene', (24, 28))	('mutagenesis', 'Var', (9, 20))
461354	31776338	For immunofluorescence and histology, dorsal skin from sD2KO, sD3KO, D2-3xFlag, and control mice was embedded in paraffin, cut into 7-mum sections, and H&E-stained.	('sD3KO', 'Var', (62, 67))	('sD2KO', 'Var', (55, 60))	('D2-3xFlag', 'Var', (69, 78))	('mice', 'Species', '10090', (92, 96))
461368	31776338	Endogenous alkaline phosphatase activity was quenched by adding levamisole to buffer AP (substrate buffer); the slides were rinsed with TRIS + Tween20 pH 7.4 buffer, and incubated in a humidified chamber with primary antibodies anti-E-cadherin (mouse monoclonal antibody, diluted 1:300 1 h at room temperature, BD Biosciences), anti-ZEB-1 (rabbit polyclonal antibody, diluted 1:200 1 h at room temperature, NBP1-05987 Novus Biologicals, UK) and anti-D3.	('rat', 'Species', '10116', (94, 97))	('rat', 'Species', '10116', (303, 306))	('rat', 'Species', '10116', (399, 402))	('anti-E-cadherin', 'Var', (228, 243))	('levamisole', 'Chemical', 'MESH:D007978', (64, 74))	('anti-ZEB-1', 'Var', (328, 338))	('mouse', 'Species', '10090', (245, 250))	('quenched', 'NegReg', (45, 53))	('NBP1', 'Gene', (407, 411))	('Tween20', 'Chemical', 'MESH:D011136', (143, 150))	('rabbit', 'Species', '9986', (340, 346))	('NBP1', 'Gene', '109019', (407, 411))
461387	31776338	performed the intra-tumoral TH measurements; A.B., S. Staibano, C.B., C. Missero, and D.S.	('intra-tumoral', 'Disease', (14, 27))	('C. Missero', 'Var', (70, 80))	('C.B.', 'Var', (64, 68))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('intra-tumoral', 'Disease', 'MESH:D009369', (14, 27))
461388	29204322	Diagnosis value of aberrantly expressed microRNA profiles in lung squamous cell carcinoma: a study based on the Cancer Genome Atlas Lung cancer is considered as one of the most frequent and deadly cancers with high mortality all around the world.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('Cancer Genome Atlas', 'Disease', (112, 131))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('Lung cancer', 'Disease', 'MESH:D008175', (132, 143))	('Cancer', 'Phenotype', 'HP:0002664', (112, 118))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (112, 131))	('lung squamous cell carcinoma', 'Disease', (61, 89))	('cancers', 'Phenotype', 'HP:0002664', (197, 204))	('aberrantly', 'Var', (19, 29))	('Lung cancer', 'Phenotype', 'HP:0100526', (132, 143))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (61, 89))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('deadly cancers', 'Disease', 'MESH:D009369', (190, 204))	('deadly cancers', 'Disease', (190, 204))	('Lung cancer', 'Disease', (132, 143))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (66, 89))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (61, 89))
461404	29204322	However, most early studies identified lung cancer-related miRNAs from small sample sizes or only one or few key miRNAs, such as analyzed 129 LUSC samples in The Cancer Genome Atlas (TCGA) and built the whole genome integrative network by the Bayesian method to find novel candidate key, such as the methylation of ARHGDIB and HOXD3, microRNA let-7a and miR-31, and the CNV of AGAP2.	('lung cancer', 'Phenotype', 'HP:0100526', (39, 50))	('LUSC', 'Phenotype', 'HP:0030359', (142, 146))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('lung cancer', 'Disease', (39, 50))	('HOXD3', 'Gene', '3232', (327, 332))	('ARHGDIB', 'Gene', '397', (315, 322))	('miR-31', 'Gene', (354, 360))	('AGAP2', 'Gene', '116986', (377, 382))	('lung cancer', 'Disease', 'MESH:D008175', (39, 50))	('HOXD3', 'Gene', (327, 332))	('methylation', 'Var', (300, 311))	('ARHGDIB', 'Gene', (315, 322))	('miR-31', 'Gene', '407035', (354, 360))	('Cancer Genome Atlas', 'Disease', (162, 181))	('let-7a', 'Gene', (343, 349))	('Cancer', 'Phenotype', 'HP:0002664', (162, 168))	('AGAP2', 'Gene', (377, 382))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (162, 181))
461423	29204322	Each sample expression was calculated by the 2-DeltaDeltaCt method (DeltaCt = CtmiRNAs - CtU6 and DeltaDeltaCt = DeltaCttumor tissues - DeltaCtadjacent non-tumor tissues).	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('DeltaDeltaCt', 'Var', (98, 110))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('tumor', 'Disease', (156, 161))	('tumor', 'Disease', (120, 125))
461433	29204322	Five of these miRNAs were significantly associated with the overall survival status of 332 LUSC patients (log-rank p < 0.05): three (miR-139-5p, miR-139-3p and miR-326) negatively (p < 0.05) and two (miR-30d-3p and miR-486-5p) positively (p < 0.05) (Fig.	('miR-139-5p', 'Var', (133, 143))	('miR-486', 'Gene', (215, 222))	('miR-139-3p', 'Gene', (145, 155))	('miR-326', 'Gene', (160, 167))	('miR-30d', 'Gene', (200, 207))	('negatively', 'NegReg', (169, 179))	('miR-139-3p', 'Gene', '406931', (145, 155))	('miR-486', 'Gene', '619554', (215, 222))	('miR-30d', 'Gene', '407033', (200, 207))	('LUSC', 'Phenotype', 'HP:0030359', (91, 95))	('miR-326', 'Gene', '442900', (160, 167))	('patients', 'Species', '9606', (96, 104))	('5p', 'Chemical', '-', (223, 225))	('5p', 'Chemical', '-', (141, 143))	('associated', 'Reg', (40, 50))
461436	29204322	The area under ROC curve (AUC) = 0.930, 0.950, 0.961, 0.919 and 0.952 for miR-30d-3p, miR-139-5p, miR-139-3p, miR-326 and miR-486-5p (p < 0.01, Fig.	('miR-326', 'Gene', (110, 117))	('miR-139-3p', 'Gene', '406931', (98, 108))	('miR-326', 'Gene', '442900', (110, 117))	('miR-486', 'Gene', (122, 129))	('miR-139-3p', 'Gene', (98, 108))	('5p', 'Chemical', '-', (130, 132))	('miR-30d', 'Gene', (74, 81))	('miR-139-5p', 'Var', (86, 96))	('miR-486', 'Gene', '619554', (122, 129))	('5p', 'Chemical', '-', (94, 96))	('miR-30d', 'Gene', '407033', (74, 81))
461459	29204322	Some related reports has reported that miR-139-5p, miR-139-3p, miR-326, miR-486-5p were related to overall survival in some cancers, but there is no study about miR-30d-3p.	('miR-326', 'Gene', (63, 70))	('miR-139-5p', 'Var', (39, 49))	('5p', 'Chemical', '-', (80, 82))	('miR-139-3p', 'Gene', (51, 61))	('miR-30d', 'Gene', '407033', (161, 168))	('related', 'Reg', (88, 95))	('miR-326', 'Gene', '442900', (63, 70))	('miR-139-3p', 'Gene', '406931', (51, 61))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('miR-486', 'Gene', (72, 79))	('5p', 'Chemical', '-', (47, 49))	('cancers', 'Disease', (124, 131))	('cancers', 'Phenotype', 'HP:0002664', (124, 131))	('overall', 'MPA', (99, 106))	('miR-486', 'Gene', '619554', (72, 79))	('miR-30d', 'Gene', (161, 168))	('cancers', 'Disease', 'MESH:D009369', (124, 131))
461482	28614291	Currently, cisplatin is a major drug used in chemotherapy of NSCLC, and it facilitates cross-linking between heavy metal ions and cell DNA chain through the connection with nuclear protein, ultimately damaging DNA.	('cisplatin', 'Chemical', 'MESH:D002945', (11, 20))	('NSCLC', 'Phenotype', 'HP:0030358', (61, 66))	('cross-linking', 'MPA', (87, 100))	('metal', 'Chemical', 'MESH:D008670', (115, 120))	('connection', 'Interaction', (157, 167))	('DNA', 'MPA', (210, 213))	('NSCLC', 'Disease', (61, 66))	('nuclear protein', 'Protein', (173, 188))	('cisplatin', 'Var', (11, 20))	('facilitates', 'PosReg', (75, 86))	('NSCLC', 'Disease', 'MESH:D002289', (61, 66))	('damaging', 'Reg', (201, 209))
461494	28614291	A total of 55 patients with NSCLC admitted to our hospital between October 2013 and October 2015 were included in the present study.	('NSCLC', 'Disease', (28, 33))	('NSCLC', 'Disease', 'MESH:D002289', (28, 33))	('NSCLC', 'Phenotype', 'HP:0030358', (28, 33))	('patients', 'Species', '9606', (14, 22))	('October', 'Var', (84, 91))
461538	28614291	The data showed that IC50 of A549/CDDP cells was significantly higher than that of A549 cells (P<0.05) (Table 1).	('CDDP', 'Chemical', 'MESH:D002945', (34, 38))	('A549', 'CellLine', 'CVCL:0023', (83, 87))	('A549/CDDP', 'Var', (29, 38))	('A549', 'CellLine', 'CVCL:0023', (29, 33))	('higher', 'PosReg', (63, 69))	('IC50', 'MPA', (21, 25))
461541	28614291	qRT-PCR showed that CLDN1 mRNA levels in A549/CDDP cells were significantly higher than that in A549 cells (P<0.05) (Figure 2A), and Western blotting showed that CLDN1 protein expression in A549/CDDP cells was significantly increased compared with that in A549 cells (P<0.05) (Figure 2B).	('CLDN1', 'Gene', '9076', (20, 25))	('CDDP', 'Chemical', 'MESH:D002945', (195, 199))	('A549', 'CellLine', 'CVCL:0023', (41, 45))	('protein', 'Protein', (168, 175))	('A549', 'CellLine', 'CVCL:0023', (96, 100))	('CLDN1', 'Gene', (20, 25))	('CLDN1', 'Gene', '9076', (162, 167))	('mRNA levels', 'MPA', (26, 37))	('A549/CDDP', 'Var', (41, 50))	('CDDP', 'Chemical', 'MESH:D002945', (46, 50))	('expression', 'MPA', (176, 186))	('A549', 'CellLine', 'CVCL:0023', (190, 194))	('CLDN1', 'Gene', (162, 167))	('higher', 'PosReg', (76, 82))	('increased', 'PosReg', (224, 233))	('A549', 'CellLine', 'CVCL:0023', (256, 260))
461546	28614291	CCK-8 assay showed that the absorbance of A549/CDDP cells with silenced CLDN1 expression was significantly lower than that of A549/CDDP cells transfected with siR-NC (P<0.05) (Figure 4).	('A549', 'CellLine', 'CVCL:0023', (126, 130))	('absorbance', 'MPA', (28, 38))	('lower', 'NegReg', (107, 112))	('A549', 'CellLine', 'CVCL:0023', (42, 46))	('expression', 'Var', (78, 88))	('CDDP', 'Chemical', 'MESH:D002945', (131, 135))	('CLDN1', 'Gene', '9076', (72, 77))	('CLDN1', 'Gene', (72, 77))	('CDDP', 'Chemical', 'MESH:D002945', (47, 51))
461550	28614291	The data showed that the apoptotic rate of A549/CDDP cells with silenced CLDN1 expression was higher than that of A549/CDDP cells treated with siR-NC (P<0.05) (Figure 6).	('apoptotic rate', 'CPA', (25, 39))	('CDDP', 'Chemical', 'MESH:D002945', (48, 52))	('CLDN1', 'Gene', '9076', (73, 78))	('A549', 'CellLine', 'CVCL:0023', (114, 118))	('expression', 'Var', (79, 89))	('CLDN1', 'Gene', (73, 78))	('silenced', 'Var', (64, 72))	('CDDP', 'Chemical', 'MESH:D002945', (119, 123))	('A549', 'CellLine', 'CVCL:0023', (43, 47))	('higher', 'PosReg', (94, 100))
461553	28614291	Western blotting showed that the ratio of LC3B II/I in A549/CDDP cells was significantly higher than that in A549 cells (P<0.05).	('A549', 'CellLine', 'CVCL:0023', (55, 59))	('LC3B', 'Gene', (42, 46))	('higher', 'PosReg', (89, 95))	('A549/CDDP', 'Var', (55, 64))	('CDDP', 'Chemical', 'MESH:D002945', (60, 64))	('A549', 'CellLine', 'CVCL:0023', (109, 113))	('LC3B', 'Gene', '81631', (42, 46))
461574	28614291	showed that deletion of Keratin 8 and 18 genes induces the up-regulation of CLDN1, and promotes the proliferation, migration, and invasion of HepG2 tumor cells.	('deletion', 'Var', (12, 20))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('migration', 'CPA', (115, 124))	('tumor', 'Disease', (148, 153))	('proliferation', 'CPA', (100, 113))	('invasion', 'CPA', (130, 138))	('CLDN1', 'Gene', '9076', (76, 81))	('Keratin 8', 'Gene', (24, 33))	('promotes', 'PosReg', (87, 95))	('Keratin 8', 'Gene', '3856', (24, 33))	('CLDN1', 'Gene', (76, 81))	('HepG2', 'CellLine', 'CVCL:0027', (142, 147))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('up-regulation', 'PosReg', (59, 72))
461576	28614291	reported that silencing CLDN1 expression inhibits distant migration of breast cancer cells.	('silencing', 'Var', (14, 23))	('breast cancer', 'Disease', (71, 84))	('CLDN1', 'Gene', '9076', (24, 29))	('inhibits', 'NegReg', (41, 49))	('breast cancer', 'Phenotype', 'HP:0003002', (71, 84))	('CLDN1', 'Gene', (24, 29))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('breast cancer', 'Disease', 'MESH:D001943', (71, 84))
461584	28614291	Inhibition of autophagy enhances the killing effect of CDDP on tumor cells, and it is of great value to determine the mechanism of autophagy for the clinical treatment of cancers.	('autophagy', 'CPA', (14, 23))	('tumor', 'Disease', (63, 68))	('CDDP', 'Chemical', 'MESH:D002945', (55, 59))	('killing effect', 'CPA', (37, 51))	('cancers', 'Disease', 'MESH:D009369', (171, 178))	('cancers', 'Phenotype', 'HP:0002664', (171, 178))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('Inhibition', 'Var', (0, 10))	('cancers', 'Disease', (171, 178))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('enhances', 'PosReg', (24, 32))
461586	28614291	showed that miR-199a-5p enhances the sensitivity of osteosarcoma cells to cisplatin by inhibiting autophagy.	('osteosarcoma', 'Disease', (52, 64))	('cisplatin', 'Chemical', 'MESH:D002945', (74, 83))	('osteosarcoma', 'Phenotype', 'HP:0002669', (52, 64))	('miR-199a-5p', 'Var', (12, 23))	('autophagy', 'CPA', (98, 107))	('osteosarcoma', 'Disease', 'MESH:D012516', (52, 64))	('inhibiting', 'NegReg', (87, 97))	('enhances', 'PosReg', (24, 32))	('sensitivity', 'MPA', (37, 48))
461587	28614291	Our study shows that LC3B II/I ratio of A549/CDDP cells is significantly higher than that of A549 cells, and interference of CLDN1 expression decreases LC3B II/I ratio of A549/CDDP cells.	('A549/CDDP', 'Var', (40, 49))	('A549', 'CellLine', 'CVCL:0023', (171, 175))	('CDDP', 'Chemical', 'MESH:D002945', (45, 49))	('LC3B', 'Gene', (21, 25))	('LC3B', 'Gene', '81631', (152, 156))	('interference', 'Var', (109, 121))	('decreases', 'NegReg', (142, 151))	('CLDN1', 'Gene', '9076', (125, 130))	('A549', 'CellLine', 'CVCL:0023', (93, 97))	('CDDP', 'Chemical', 'MESH:D002945', (176, 180))	('LC3B', 'Gene', (152, 156))	('A549', 'CellLine', 'CVCL:0023', (40, 44))	('CLDN1', 'Gene', (125, 130))	('LC3B', 'Gene', '81631', (21, 25))	('higher', 'PosReg', (73, 79))
461588	28614291	Confocal microscopy shows that the number of autophagosomes in A549/CDDP cells is significantly higher than that in A549 cells, but in the siR-CLDN1 group it is significantly lower than in the siR-NC group.	('CLDN1', 'Gene', '9076', (143, 148))	('A549/CDDP', 'Var', (63, 72))	('A549', 'CellLine', 'CVCL:0023', (63, 67))	('CLDN1', 'Gene', (143, 148))	('autophagosomes', 'CPA', (45, 59))	('CDDP', 'Chemical', 'MESH:D002945', (68, 72))	('higher', 'PosReg', (96, 102))	('A549', 'CellLine', 'CVCL:0023', (116, 120))
461589	28614291	Inhibition of A549/CDDP cell autophagy by addition of 3-MA significantly decreases the fold change of drug resistance of the cells, but after the promotion of autophagy of A549/CDDP cells in the siR-CLDN1 group by addition of Rapamycin, the fold change of drug resistance is enhanced.	('fold change', 'MPA', (241, 252))	('CLDN1', 'Gene', '9076', (199, 204))	('drug resistance', 'Phenotype', 'HP:0020174', (102, 117))	('A549', 'CellLine', 'CVCL:0023', (14, 18))	('Rapamycin', 'Chemical', 'MESH:D020123', (226, 235))	('drug resistance', 'MPA', (256, 271))	('A549/CDDP', 'Var', (172, 181))	('enhanced', 'PosReg', (275, 283))	('CLDN1', 'Gene', (199, 204))	('autophagy', 'CPA', (159, 168))	('fold change', 'MPA', (87, 98))	('A549', 'CellLine', 'CVCL:0023', (172, 176))	('drug resistance', 'Phenotype', 'HP:0020174', (256, 271))	('CDDP', 'Chemical', 'MESH:D002945', (19, 23))	('CDDP', 'Chemical', 'MESH:D002945', (177, 181))
461596	26267899	Loss-of-Function PTPRD Mutations Lead to Increased STAT3 Activation and Sensitivity to STAT3 Inhibition in Head and Neck Cancer Protein tyrosine phosphatase receptor type D (PTPRD) is a putative tumor suppressor in several cancers including head and neck squamous cell carcinoma (HNSCC).	('STAT3', 'Gene', '6774', (51, 56))	('STAT3', 'Gene', (87, 92))	('tumor', 'Disease', (195, 200))	('PTPRD', 'Gene', (17, 22))	('Cancer', 'Phenotype', 'HP:0002664', (121, 127))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('STAT3', 'Gene', '6774', (87, 92))	('Loss-of-Function', 'NegReg', (0, 16))	('Protein tyrosine phosphatase receptor type D', 'Gene', (128, 172))	('Head and Neck Cancer', 'Phenotype', 'HP:0012288', (107, 127))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('Protein tyrosine phosphatase receptor type D', 'Gene', '5789', (128, 172))	('Activation', 'PosReg', (57, 67))	('PTPRD', 'Gene', (174, 179))	('PTPRD', 'Gene', '5789', (17, 22))	('Sensitivity', 'MPA', (72, 83))	('HNSCC', 'Phenotype', 'HP:0012288', (280, 285))	('cancers', 'Phenotype', 'HP:0002664', (223, 230))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (241, 278))	('cancers', 'Disease', (223, 230))	('Mutations', 'Var', (23, 32))	('carcinoma', 'Phenotype', 'HP:0030731', (269, 278))	('PTPRD', 'Gene', '5789', (174, 179))	('neck squamous cell carcinoma', 'Disease', (250, 278))	('Neck Cancer', 'Disease', (116, 127))	('Increased', 'PosReg', (41, 50))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (250, 278))	('Neck Cancer', 'Disease', 'MESH:D006258', (116, 127))	('STAT3', 'Gene', (51, 56))	('cancers', 'Disease', 'MESH:D009369', (223, 230))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (255, 278))
461598	26267899	As STAT3 is a direct substrate of PTPRD, we sought to determine the genetic or epigenetic alterations of PTPRD that contribute to overactive STAT3 in HNSCC.	('STAT3', 'Gene', (3, 8))	('epigenetic alterations', 'Var', (79, 101))	('STAT3', 'Gene', '6774', (141, 146))	('PTPRD', 'Gene', '5789', (34, 39))	('PTPRD', 'Gene', (34, 39))	('STAT3', 'Gene', (141, 146))	('HNSCC', 'Disease', (150, 155))	('overactive', 'PosReg', (130, 140))	('STAT3', 'Gene', '6774', (3, 8))	('HNSCC', 'Phenotype', 'HP:0012288', (150, 155))	('PTPRD', 'Gene', '5789', (105, 110))	('PTPRD', 'Gene', (105, 110))
461601	26267899	Our findings indicate that PTPRD mutation, rather than methylation or copy number alteration, is the primary mechanism by which PTPRD function is lost in HNSCC.	('PTPRD', 'Gene', '5789', (128, 133))	('mutation', 'Var', (33, 41))	('function', 'MPA', (134, 142))	('PTPRD', 'Gene', '5789', (27, 32))	('PTPRD', 'Gene', (27, 32))	('lost', 'NegReg', (146, 150))	('HNSCC', 'Disease', (154, 159))	('PTPRD', 'Gene', (128, 133))	('HNSCC', 'Phenotype', 'HP:0012288', (154, 159))
461602	26267899	We demonstrate that overexpression of wild-type PTPRD in HNSCC cells significantly inhibits growth and STAT3 activation while PTPRD mutants do not, suggesting that mutation may lead to loss of function and subsequent hyper-phosphorylation of PTPRD substrates, especially STAT3.	('STAT3', 'Gene', (271, 276))	('PTPRD', 'Gene', '5789', (126, 131))	('PTPRD', 'Gene', (126, 131))	('HNSCC', 'Phenotype', 'HP:0012288', (57, 62))	('STAT3', 'Gene', (103, 108))	('PTPRD', 'Gene', '5789', (48, 53))	('loss of function', 'NegReg', (185, 201))	('inhibits', 'NegReg', (83, 91))	('hyper-phosphorylation', 'MPA', (217, 238))	('PTPRD', 'Gene', (48, 53))	('mutation', 'Var', (164, 172))	('STAT3', 'Gene', '6774', (103, 108))	('PTPRD', 'Gene', '5789', (242, 247))	('STAT3', 'Gene', '6774', (271, 276))	('PTPRD', 'Gene', (242, 247))
461603	26267899	Importantly, we determined that HNSCC cells harboring an endogenous PTPRD mutation are more sensitive to STAT3 blockade than PTPRD wild-type cells.	('mutation', 'Var', (74, 82))	('STAT3', 'Gene', '6774', (105, 110))	('PTPRD', 'Gene', '5789', (68, 73))	('PTPRD', 'Gene', (68, 73))	('HNSCC', 'Phenotype', 'HP:0012288', (32, 37))	('PTPRD', 'Gene', '5789', (125, 130))	('PTPRD', 'Gene', (125, 130))	('STAT3', 'Gene', (105, 110))
461604	26267899	We additionally found that PTPRD mRNA expression does not correlate with pSTAT3 expression, suggesting that alterations that manifest through altered mRNA expression, including hypermethylation and gene copy number alterations, do not significantly contribute to STAT3 overactivation in HNSCC.	('STAT3', 'Gene', '6774', (263, 268))	('STAT3', 'Gene', '6774', (74, 79))	('mRNA expression', 'MPA', (150, 165))	('PTPRD', 'Gene', '5789', (27, 32))	('PTPRD', 'Gene', (27, 32))	('altered', 'Reg', (142, 149))	('STAT3', 'Gene', (263, 268))	('STAT3', 'Gene', (74, 79))	('HNSCC', 'Disease', (287, 292))	('hypermethylation', 'Var', (177, 193))	('HNSCC', 'Phenotype', 'HP:0012288', (287, 292))	('overactivation', 'PosReg', (269, 283))
461605	26267899	PTPRD mutation, but not methylation or copy number loss, may serve as a predictive biomarker of sensitivity to STAT3 inhibitors in HNSCC.	('STAT3', 'Gene', (111, 116))	('PTPRD', 'Gene', '5789', (0, 5))	('HNSCC', 'Phenotype', 'HP:0012288', (131, 136))	('PTPRD', 'Gene', (0, 5))	('HNSCC', 'Disease', (131, 136))	('mutation', 'Var', (6, 14))	('STAT3', 'Gene', '6774', (111, 116))
461608	26267899	Dysregulation of PTPR signaling by genetic and/or epigenetic mechanisms may therefore ultimately lead to cancerous phenotypes.	('cancerous', 'Disease', 'MESH:D009369', (105, 114))	('Dysregulation', 'Var', (0, 13))	('epigenetic', 'Var', (50, 60))	('cancerous', 'Disease', (105, 114))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('lead to', 'Reg', (97, 104))
461609	26267899	Several PTPR family members, including PTPRD, have been reported to function as tumor suppressors where loss of function alterations may drive tumor growth.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('alterations', 'Var', (121, 132))	('tumor', 'Disease', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('drive', 'PosReg', (137, 142))	('tumor', 'Disease', (80, 85))	('PTPR', 'Gene', (8, 12))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('PTPRD', 'Gene', '5789', (39, 44))	('PTPRD', 'Gene', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
461610	26267899	Genetic events including mutation, gene deletion, or epigenetic silencing may lead to decreased phosphatase activity of PTPRs and enhanced oncogenic signaling.	('enhanced', 'PosReg', (130, 138))	('phosphatase activity', 'MPA', (96, 116))	('oncogenic signaling', 'CPA', (139, 158))	('PTPRs', 'Gene', (120, 125))	('decreased phosphatase', 'Phenotype', 'HP:0003282', (86, 107))	('mutation', 'Var', (25, 33))	('gene deletion', 'Var', (35, 48))	('decreased', 'NegReg', (86, 95))	('PTPRs', 'Gene', '5802', (120, 125))	('epigenetic silencing', 'Var', (53, 73))
461611	26267899	We recently reported the cumulative mutation profile of the PTPR gene family in cancer with a focus on PTPRT mutation leading to STAT3 activation in head and neck squamous cell carcinoma (HNSCC).	('activation', 'PosReg', (135, 145))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (163, 186))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (158, 186))	('STAT3', 'Gene', '6774', (129, 134))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (149, 186))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('STAT3', 'Gene', (129, 134))	('carcinoma', 'Phenotype', 'HP:0030731', (177, 186))	('PTPRT', 'Gene', '11122', (103, 108))	('PTPRT', 'Gene', (103, 108))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('neck squamous cell carcinoma', 'Disease', (158, 186))	('HNSCC', 'Phenotype', 'HP:0012288', (188, 193))	('cancer', 'Disease', (80, 86))	('mutation', 'Var', (109, 117))
461612	26267899	Our analysis revealed that 15 solid tumor types harbored mutations of at least one PTPR gene.	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('mutations', 'Var', (57, 66))	('harbored', 'Reg', (48, 56))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumor', 'Disease', (36, 41))	('PTPR', 'Gene', (83, 87))
461614	26267899	PTPRD is also mutated, deleted, or hyper-methylated in glioblastoma (GBM), while the gene is unmethylated and expressed in normal brain tissue.	('PTPRD', 'Gene', '5789', (0, 5))	('PTPRD', 'Gene', (0, 5))	('glioblastoma', 'Disease', (55, 67))	('GBM', 'Phenotype', 'HP:0012174', (69, 72))	('hyper-methylated', 'Var', (35, 51))	('glioblastoma', 'Disease', 'MESH:D005909', (55, 67))	('deleted', 'Var', (23, 30))	('glioblastoma', 'Phenotype', 'HP:0012174', (55, 67))
461615	26267899	Furthermore, PTPRD mutations were found to be associated with increased expression of phosphorylated STAT3, a direct PTPRD substrate, in GBM.	('STAT3', 'Gene', '6774', (101, 106))	('increased', 'PosReg', (62, 71))	('PTPRD', 'Gene', '5789', (13, 18))	('PTPRD', 'Gene', (13, 18))	('GBM', 'Phenotype', 'HP:0012174', (137, 140))	('STAT3', 'Gene', (101, 106))	('PTPRD', 'Gene', '5789', (117, 122))	('mutations', 'Var', (19, 28))	('PTPRD', 'Gene', (117, 122))	('expression', 'MPA', (72, 82))
461616	26267899	In addition to GBM, 13% and 25% of HNSCC tumors analyzed in the above study harbored PTPRD mutation or promoter methylation, respectively.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('GBM', 'Phenotype', 'HP:0012174', (15, 18))	('mutation', 'Var', (91, 99))	('PTPRD', 'Gene', '5789', (85, 90))	('PTPRD', 'Gene', (85, 90))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('HNSCC', 'Phenotype', 'HP:0012288', (35, 40))	('promoter', 'MPA', (103, 111))	('HNSCC tumors', 'Disease', (35, 47))	('harbored', 'Reg', (76, 84))	('HNSCC tumors', 'Disease', 'MESH:D000077195', (35, 47))
461617	26267899	Homozygous deletion of PTPRD has additionally been reported in laryngeal cancer, suggesting that genetic aberrations affecting PTPRD function may be a common event across many cancers.	('cancers', 'Disease', (176, 183))	('cancers', 'Disease', 'MESH:D009369', (176, 183))	('cancers', 'Phenotype', 'HP:0002664', (176, 183))	('reported', 'Reg', (51, 59))	('laryngeal cancer', 'Disease', (63, 79))	('laryngeal cancer', 'Phenotype', 'HP:0012118', (63, 79))	('PTPRD', 'Gene', '5789', (127, 132))	('PTPRD', 'Gene', (127, 132))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('Homozygous deletion', 'Var', (0, 19))	('laryngeal cancer', 'Disease', 'MESH:D007822', (63, 79))	('PTPRD', 'Gene', '5789', (23, 28))	('PTPRD', 'Gene', (23, 28))
461618	26267899	These cumulative findings led us to hypothesize that genetic and/or epigenetic alteration of PTPRD may contribute to enhanced signaling and growth in HNSCC where key components of the pathway may serve as plausible therapeutic targets.	('HNSCC', 'Phenotype', 'HP:0012288', (150, 155))	('epigenetic alteration', 'Var', (68, 89))	('signaling', 'MPA', (126, 135))	('PTPRD', 'Gene', '5789', (93, 98))	('PTPRD', 'Gene', (93, 98))	('enhanced', 'PosReg', (117, 125))	('HNSCC', 'Disease', (150, 155))	('contribute', 'Reg', (103, 113))	('genetic', 'Var', (53, 60))	('growth', 'CPA', (140, 146))
461620	26267899	We then tested the consequences of PTPRD alterations found in human HNSCC tumors in relevant preclinical models to assess STAT3 activity and sensitivity to STAT3 inhibition.	('tested', 'Reg', (8, 14))	('human', 'Species', '9606', (62, 67))	('HNSCC tumors', 'Disease', (68, 80))	('STAT3', 'Gene', '6774', (156, 161))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('HNSCC tumors', 'Disease', 'MESH:D000077195', (68, 80))	('PTPRD', 'Gene', '5789', (35, 40))	('STAT3', 'Gene', '6774', (122, 127))	('PTPRD', 'Gene', (35, 40))	('STAT3', 'Gene', (156, 161))	('STAT3', 'Gene', (122, 127))	('HNSCC', 'Phenotype', 'HP:0012288', (68, 73))	('alterations', 'Var', (41, 52))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))
461629	26267899	PTPRD mutations (K1502M, S384R, T1100M and L1147F) were generated from the wild-type plasmid using the Phusion site-directed mutagenesis kit (Thermo Fisher Scientific, Waltham, MA) following the manufacturer's protocol and confirmed by Sanger sequencing.	('L1147F', 'Var', (43, 49))	('S384R', 'Var', (25, 30))	('PTPRD', 'Gene', '5789', (0, 5))	('PTPRD', 'Gene', (0, 5))	('S384R', 'Mutation', 'p.S384R', (25, 30))	('L1147F', 'Mutation', 'p.L1147F', (43, 49))	('T1100M', 'Mutation', 'rs200684369', (32, 38))	('K1502M', 'Mutation', 'p.K1502M', (17, 23))	('T1100M', 'Var', (32, 38))	('K1502M', 'Var', (17, 23))
461630	26267899	Primary antibodies for pSTAT3 (Y705) and STAT3 were obtained from Cell Signaling Technology (Danvers, MA).	('Y705', 'Var', (31, 35))	('STAT3', 'Gene', (41, 46))	('STAT3', 'Gene', '6774', (24, 29))	('STAT3', 'Gene', '6774', (41, 46))	('STAT3', 'Gene', (24, 29))
461636	26267899	After 24 hours, cells were transfected with vector control, wild-type PTPRD, or PTPRD mutants in triplicate using 4 mug of plasmid DNA, 12 muL FuGENE HD (Promega Corporation, Madison, WI), and 200 muL Opti-MEM (Life Technologies, Grand Island, NY) per well added directly to wells containing 3 mL complete medium.	('mutants', 'Var', (86, 93))	('HD', 'Disease', 'MESH:D006816', (150, 152))	('PTPRD', 'Gene', '5789', (70, 75))	('PTPRD', 'Gene', (70, 75))	('PTPRD', 'Gene', '5789', (80, 85))	('Opti-MEM', 'Chemical', '-', (201, 209))	('PTPRD', 'Gene', (80, 85))
461639	26267899	Eighteen non-synonymous PTPRD mutations have been identified to date in HNSCC tumors.	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('HNSCC tumors', 'Disease', 'MESH:D000077195', (72, 84))	('HNSCC', 'Phenotype', 'HP:0012288', (72, 77))	('PTPRD', 'Gene', '5789', (24, 29))	('PTPRD', 'Gene', (24, 29))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('mutations', 'Var', (30, 39))	('HNSCC tumors', 'Disease', (72, 84))
461641	26267899	In addition to HNSCC, PTPRD mutations are also widely observed in other cancer types.	('PTPRD', 'Gene', (22, 27))	('PTPRD', 'Gene', '5789', (22, 27))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('observed', 'Reg', (54, 62))	('HNSCC', 'Disease', (15, 20))	('HNSCC', 'Phenotype', 'HP:0012288', (15, 20))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('mutations', 'Var', (28, 37))	('cancer', 'Disease', (72, 78))
461642	26267899	(Fig 1B) In The Cancer Genome Atlas (TCGA) collection, PTPRD is most frequently mutated in cutaneous melanoma (59/344 cases, 17.2%), followed by lung adenocarcinoma (33/230 cases, 14.3%), and stomach adenocarcinoma (30/289 cases, 10.4%).	('carcinoma', 'Phenotype', 'HP:0030731', (155, 164))	('Cancer', 'Phenotype', 'HP:0002664', (16, 22))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (16, 35))	('lung adenocarcinoma', 'Disease', (145, 164))	('melanoma', 'Phenotype', 'HP:0002861', (101, 109))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (145, 164))	('carcinoma', 'Phenotype', 'HP:0030731', (205, 214))	('mutated', 'Var', (80, 87))	('stomach adenocarcinoma', 'Disease', 'MESH:D013274', (192, 214))	('PTPRD', 'Gene', '5789', (55, 60))	('PTPRD', 'Gene', (55, 60))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (145, 164))	('cutaneous melanoma', 'Disease', (91, 109))	('stomach adenocarcinoma', 'Disease', (192, 214))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (91, 109))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (91, 109))	('Cancer Genome Atlas', 'Disease', (16, 35))
461644	26267899	The only mutation detected in HNSCC that has been previously identified in another cancer is T1100M, which was reported in chronic lymphocytic leukemia.	('leukemia', 'Phenotype', 'HP:0001909', (143, 151))	('HNSCC', 'Gene', (30, 35))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('lymphocytic leukemia', 'Disease', 'MESH:D007945', (131, 151))	('lymphocytic leukemia', 'Disease', (131, 151))	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (123, 151))	('T1100M', 'Mutation', 'rs200684369', (93, 99))	('T1100M', 'Var', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('HNSCC', 'Phenotype', 'HP:0012288', (30, 35))	('cancer', 'Disease', (83, 89))
461646	26267899	For example, while K204E is observed in HNSCC, K204Q has been reported in esophageal cancer.	('K204Q', 'Chemical', '-', (47, 52))	('K204Q', 'Var', (47, 52))	('K204E', 'Var', (19, 24))	('reported', 'Reg', (62, 70))	('K204E', 'Mutation', 'rs767829342', (19, 24))	('esophageal cancer', 'Disease', (74, 91))	('HNSCC', 'Phenotype', 'HP:0012288', (40, 45))	('esophageal cancer', 'Disease', 'MESH:D004938', (74, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
461647	26267899	In addition, a review of the COSMIC database (http://cancer.sanger.ac.uk/cancergenome/projects/cosmic/) demonstrates detection of L503V in liver cancer (compared to L503I in HNSCC) and L1036M in colon adenocarcinoma (compared to L1036P in HNSCC).	('cancer', 'Disease', (145, 151))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('liver cancer', 'Disease', 'MESH:D006528', (139, 151))	('L503V', 'Mutation', 'p.L503V', (130, 135))	('cancer', 'Disease', (73, 79))	('colon adenocarcinoma', 'Disease', 'MESH:D003110', (195, 215))	('L1036M', 'Mutation', 'rs372802313', (185, 191))	('L503V', 'Var', (130, 135))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('L1036M', 'Var', (185, 191))	('HNSCC', 'Phenotype', 'HP:0012288', (239, 244))	('liver cancer', 'Phenotype', 'HP:0002896', (139, 151))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('liver cancer', 'Disease', (139, 151))	('carcinoma', 'Phenotype', 'HP:0030731', (206, 215))	('cancer', 'Disease', (53, 59))	('L503I', 'Mutation', 'p.L503I', (165, 170))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('colon adenocarcinoma', 'Disease', (195, 215))	('HNSCC', 'Phenotype', 'HP:0012288', (174, 179))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('L1036P', 'Mutation', 'p.L1036P', (229, 235))
461648	26267899	Ding et al additionally reported a mutation at this site (L1036Q) in lung adenocarcinoma.	('lung adenocarcinoma', 'Disease', (69, 88))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (69, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('L1036Q', 'Var', (58, 64))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (69, 88))	('L1036Q', 'Mutation', 'p.L1036Q', (58, 64))
461649	26267899	Interestingly, while K1502M is the only catalytic domain mutation identified to date in HNSCC, TCGA has identified a K1502* nonsense mutation in lung adenocarcinoma.	('K1502M', 'Var', (21, 27))	('carcinoma', 'Phenotype', 'HP:0030731', (155, 164))	('lung adenocarcinoma', 'Disease', (145, 164))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (145, 164))	('K1502*', 'Var', (117, 123))	('HNSCC', 'Phenotype', 'HP:0012288', (88, 93))	('K1502*', 'SUBSTITUTION', 'None', (117, 123))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (145, 164))	('K1502M', 'Mutation', 'p.K1502M', (21, 27))
461650	26267899	Together, these findings suggest that while the specific PTPRD mutations found to date in HNSCC are unique, the amino acid sites at which they occur may represent important residues that are susceptible to genetic alterations.	('mutations', 'Var', (63, 72))	('HNSCC', 'Disease', (90, 95))	('HNSCC', 'Phenotype', 'HP:0012288', (90, 95))	('PTPRD', 'Gene', '5789', (57, 62))	('PTPRD', 'Gene', (57, 62))
461653	26267899	To determine the functional consequences of PTPRD mutation in HNSCC, we generated several representative HNSCC-derived PTPRD mutants by site-directed mutagenesis, including one mutation in the extracellular domain (S384R), one in the catalytic domain (K1502M), and two in the transmembrane region (T1100M and L1147F).	('PTPRD', 'Gene', (44, 49))	('HNSCC', 'Phenotype', 'HP:0012288', (62, 67))	('L1147F', 'Mutation', 'p.L1147F', (309, 315))	('T1100M', 'Mutation', 'rs200684369', (298, 304))	('PTPRD', 'Gene', (119, 124))	('T1100M', 'Var', (298, 304))	('PTPRD', 'Gene', '5789', (119, 124))	('K1502M', 'Mutation', 'p.K1502M', (252, 258))	('HNSCC', 'Phenotype', 'HP:0012288', (105, 110))	('S384R', 'Var', (215, 220))	('K1502M', 'Var', (252, 258))	('S384R', 'Mutation', 'p.S384R', (215, 220))	('L1147F', 'Var', (309, 315))	('PTPRD', 'Gene', '5789', (44, 49))
461654	26267899	Transient overexpression of these constructs in a HNSCC cell line with no endogenous PTPR family mutations (PE/CA-PJ34clone12) revealed that all of the PTPRD mutants tested led to increased growth as determined by MTT assay relative to PTPRD wild-type-transfected cells.	('growth', 'MPA', (190, 196))	('PTPRD', 'Gene', (236, 241))	('a HNSCC', 'CellLine', 'CVCL:5985', (48, 55))	('MTT', 'Chemical', 'MESH:C070243', (214, 217))	('increased', 'PosReg', (180, 189))	('PTPRD', 'Gene', '5789', (152, 157))	('PTPRD', 'Gene', (152, 157))	('HNSCC', 'Phenotype', 'HP:0012288', (50, 55))	('mutants', 'Var', (158, 165))	('PTPRD', 'Gene', '5789', (236, 241))
461656	26267899	Collectively, these results suggest that PTPRD mutations inactivate the tumor suppressive function of PTPRD irrespective of their localization throughout the gene, leading to increased growth/proliferation in HNSCC cells.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('PTPRD', 'Gene', '5789', (102, 107))	('PTPRD', 'Gene', (102, 107))	('tumor', 'Disease', (72, 77))	('inactivate', 'NegReg', (57, 67))	('mutations', 'Var', (47, 56))	('PTPRD', 'Gene', '5789', (41, 46))	('PTPRD', 'Gene', (41, 46))	('increased', 'PosReg', (175, 184))	('growth/proliferation', 'CPA', (185, 205))	('HNSCC', 'Phenotype', 'HP:0012288', (209, 214))	('tumor', 'Disease', 'MESH:D009369', (72, 77))
461657	26267899	STAT3 is hyper-activated by constitutive phosphorylation of tyrosine 705 (Y705) in many cancer types, including HNSCC.	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('hyper-activated', 'PosReg', (9, 24))	('tyrosine', 'Chemical', 'MESH:D014443', (60, 68))	('STAT3', 'Gene', '6774', (0, 5))	('Y705', 'Var', (74, 78))	('HNSCC', 'Disease', (112, 117))	('HNSCC', 'Phenotype', 'HP:0012288', (112, 117))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('STAT3', 'Gene', (0, 5))
461658	26267899	Importantly, pSTAT3 (Y705) is a known direct substrate of PTPRD.	('STAT3', 'Gene', (14, 19))	('Y705', 'Var', (21, 25))	('PTPRD', 'Gene', '5789', (58, 63))	('PTPRD', 'Gene', (58, 63))	('STAT3', 'Gene', '6774', (14, 19))
461659	26267899	To determine the effect of PTPRD mutation on STAT3 phosphorylation in HNSCC, we first examined 200 HNSCC tumors with both whole exome sequencing and RPPA analyses performed by TCGA and The Cancer Proteome Atlas (TCPA).	('Cancer Proteome Atlas', 'Disease', 'MESH:D009369', (189, 210))	('mutation', 'Var', (33, 41))	('HNSCC tumors', 'Disease', (99, 111))	('STAT3', 'Gene', (45, 50))	('HNSCC', 'Phenotype', 'HP:0012288', (70, 75))	('PTPRD', 'Gene', '5789', (27, 32))	('PTPRD', 'Gene', (27, 32))	('HNSCC', 'Phenotype', 'HP:0012288', (99, 104))	('HNSCC tumors', 'Disease', 'MESH:D000077195', (99, 111))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('TCPA', 'Chemical', '-', (212, 216))	('Cancer', 'Phenotype', 'HP:0002664', (189, 195))	('Cancer Proteome Atlas', 'Disease', (189, 210))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('STAT3', 'Gene', '6774', (45, 50))
461660	26267899	HNSCC tumors with non-synonymous PTPRD mutations express significantly higher levels of pSTAT3 (Y705) relative to tumors with wild-type PTPRD (Fig 3A).	('higher', 'PosReg', (71, 77))	('PTPRD', 'Gene', (136, 141))	('STAT3', 'Gene', '6774', (89, 94))	('tumors', 'Disease', 'MESH:D009369', (114, 120))	('PTPRD', 'Gene', '5789', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('PTPRD', 'Gene', '5789', (136, 141))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('mutations', 'Var', (39, 48))	('levels', 'MPA', (78, 84))	('HNSCC tumors', 'Disease', 'MESH:D000077195', (0, 12))	('HNSCC', 'Phenotype', 'HP:0012288', (0, 5))	('HNSCC tumors', 'Disease', (0, 12))	('tumors', 'Disease', (6, 12))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('tumors', 'Disease', (114, 120))	('STAT3', 'Gene', (89, 94))	('PTPRD', 'Gene', (33, 38))
461662	26267899	To test the association between PTPRD mutation and pSTAT3 expression directly, we transfected an HNSCC cell line with known endogenous PTPRD mutation (Cal27 harboring mutation S387L) with wild-type PTPRD or vector control and found that overexpression of wild-type PTPRD leads to significantly decreased pSTAT3 expression (P <= 0.05).	('S387L', 'Var', (176, 181))	('PTPRD', 'Gene', '5789', (265, 270))	('PTPRD', 'Gene', (135, 140))	('PTPRD', 'Gene', (198, 203))	('Cal27', 'CellLine', 'CVCL:1107', (151, 156))	('PTPRD', 'Gene', (32, 37))	('HNSCC', 'Phenotype', 'HP:0012288', (97, 102))	('PTPRD', 'Gene', '5789', (135, 140))	('PTPRD', 'Gene', '5789', (198, 203))	('PTPRD', 'Gene', '5789', (32, 37))	('decreased', 'NegReg', (294, 303))	('STAT3', 'Gene', (52, 57))	('mutation S387L', 'Var', (167, 181))	('STAT3', 'Gene', (305, 310))	('STAT3', 'Gene', '6774', (52, 57))	('STAT3', 'Gene', '6774', (305, 310))	('overexpression', 'PosReg', (237, 251))	('PTPRD', 'Gene', (265, 270))	('S387L', 'Mutation', 'rs750058892', (176, 181))
461663	26267899	(Fig 3B and 3C) Furthermore, overexpression of mutant PTPRD in HNSCC cells without endogenous PTPR family mutations (PE/CA-PJ34clone12) leads to increased pSTAT3 (Y705) expression relative to PTPRD wild-type-overexpressing cells for nearly all mutations tested.	('PTPRD', 'Gene', '5789', (54, 59))	('overexpression', 'PosReg', (29, 43))	('PTPRD', 'Gene', (54, 59))	('PTPRD', 'Gene', '5789', (192, 197))	('PTPRD', 'Gene', (192, 197))	('STAT3', 'Gene', '6774', (156, 161))	('increased', 'PosReg', (145, 154))	('STAT3', 'Gene', (156, 161))	('expression', 'MPA', (169, 179))	('mutant', 'Var', (47, 53))	('HNSCC', 'Phenotype', 'HP:0012288', (63, 68))
461664	26267899	(Fig 3D and 3E) Together, these results demonstrate that PTPRD mutation leads to increased STAT3 signaling in HNSCC cells and tumors.	('tumors', 'Disease', (126, 132))	('tumors', 'Disease', 'MESH:D009369', (126, 132))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('HNSCC', 'Phenotype', 'HP:0012288', (110, 115))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('mutation', 'Var', (63, 71))	('STAT3', 'Gene', '6774', (91, 96))	('STAT3', 'Gene', (91, 96))	('increased', 'PosReg', (81, 90))	('PTPRD', 'Gene', '5789', (57, 62))	('PTPRD', 'Gene', (57, 62))
461665	26267899	Since PTPRD mutations increase STAT3 activation in HNSCC, we next sought to determine if PTPRD mutation leads to increased sensitivity to STAT3 pathway inhibition.	('STAT3', 'Gene', (138, 143))	('PTPRD', 'Gene', '5789', (89, 94))	('STAT3', 'Gene', (31, 36))	('PTPRD', 'Gene', (89, 94))	('PTPRD', 'Gene', (6, 11))	('mutations', 'Var', (12, 21))	('PTPRD', 'Gene', '5789', (6, 11))	('HNSCC', 'Phenotype', 'HP:0012288', (51, 56))	('increase', 'PosReg', (22, 30))	('STAT3', 'Gene', '6774', (138, 143))	('STAT3', 'Gene', '6774', (31, 36))
461666	26267899	To test our hypothesis, we employed HNSCC cells that harbor an endogenous PTPRD mutation (PE/CA-PJ49).	('PTPRD', 'Gene', (74, 79))	('HNSCC', 'Phenotype', 'HP:0012288', (36, 41))	('mutation', 'Var', (80, 88))	('PTPRD', 'Gene', '5789', (74, 79))
461667	26267899	Treatment with the JAK/STAT inhibitor JSI-124 revels that these PTPRD mutant cells exhibit enhanced sensitivity relative to PTPR family wild-type cells (PE/CA-PJ34clone12), suggesting that PTPRD mutation may serve as a predictive biomarker for response to STAT3 pathway inhibitors (Fig 4).	('PTPRD', 'Gene', '5789', (189, 194))	('PTPRD', 'Gene', '5789', (64, 69))	('PTPRD', 'Gene', (189, 194))	('PTPRD', 'Gene', (64, 69))	('mutant', 'Var', (70, 76))	('STAT3', 'Gene', '6774', (256, 261))	('sensitivity', 'MPA', (100, 111))	('JSI-124', 'Chemical', 'MESH:C038106', (38, 45))	('STAT3', 'Gene', (256, 261))	('enhanced', 'PosReg', (91, 99))
461668	26267899	Promoter hypermethylation and gene copy number loss represent two additional mechanisms that may lead to loss of function of PTPRD via downregulation of mRNA expression.	('gene copy number loss', 'Var', (30, 51))	('mRNA expression', 'MPA', (153, 168))	('PTPRD', 'Gene', '5789', (125, 130))	('PTPRD', 'Gene', (125, 130))	('downregulation', 'NegReg', (135, 149))	('loss of function', 'NegReg', (105, 121))	('Promoter hypermethylation', 'Var', (0, 25))
461671	26267899	In order to validate these findings, we performed methylation-specific PCR on an independent cohort of HNSCC tumors and found evidence of PTPRD promoter methylation in 75% of tumors analyzed (30/40) (representative analysis in S2 Fig).	('HNSCC', 'Phenotype', 'HP:0012288', (103, 108))	('tumors', 'Disease', (175, 181))	('tumors', 'Disease', 'MESH:D009369', (175, 181))	('tumors', 'Disease', 'MESH:D009369', (109, 115))	('tumors', 'Phenotype', 'HP:0002664', (175, 181))	('PTPRD', 'Gene', '5789', (138, 143))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('PTPRD', 'Gene', (138, 143))	('HNSCC tumors', 'Disease', (103, 115))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('methylation', 'Var', (153, 164))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('tumors', 'Disease', (109, 115))	('HNSCC tumors', 'Disease', 'MESH:D000077195', (103, 115))
461673	26267899	PTPRD copy number alterations occur to a substantial degree in HNSCC and other cancers (Fig 5A), where gene copy loss, particularly heterozygous loss, occurs more frequently than gain in HNSCC and all cancers analyzed with the exception of colorectal and cervical cancers.	('cancers', 'Phenotype', 'HP:0002664', (201, 208))	('cancers', 'Disease', (201, 208))	('PTPRD', 'Gene', (0, 5))	('HNSCC', 'Phenotype', 'HP:0012288', (187, 192))	('colorectal and cervical cancers', 'Disease', 'MESH:D015179', (240, 271))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('cancers', 'Phenotype', 'HP:0002664', (264, 271))	('HNSCC', 'Disease', (63, 68))	('cancers', 'Disease', (264, 271))	('PTPRD', 'Gene', '5789', (0, 5))	('gene copy', 'Var', (103, 112))	('cancer', 'Phenotype', 'HP:0002664', (264, 270))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('HNSCC', 'Phenotype', 'HP:0012288', (63, 68))	('cancers', 'Disease', (79, 86))	('alterations', 'Var', (18, 29))	('cancers', 'Disease', 'MESH:D009369', (201, 208))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('cancers', 'Disease', 'MESH:D009369', (264, 271))	('copy number alterations', 'Var', (6, 29))	('cancers', 'Disease', 'MESH:D009369', (79, 86))
461674	26267899	Together, these findings suggest that promoter hypermethylation and gene copy number loss do not significantly contribute to STAT3 overactivation in HNSCC.	('gene copy number loss', 'Var', (68, 89))	('STAT3', 'Gene', (125, 130))	('HNSCC', 'Phenotype', 'HP:0012288', (149, 154))	('HNSCC', 'Disease', (149, 154))	('STAT3', 'Gene', '6774', (125, 130))
461676	26267899	Potential mechanisms that may result in increased STAT3 activation in cancer include increased signaling through upstream receptor or non-receptor tyrosine kinases such as EGFR and JAK, and/or inactivation of negative regulators of STAT3, including protein tyrosine phosphatases.	('EGFR', 'Gene', '1956', (172, 176))	('tyrosine', 'Chemical', 'MESH:D014443', (147, 155))	('signaling', 'MPA', (95, 104))	('STAT3', 'Gene', '6774', (232, 237))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('tyrosine', 'Chemical', 'MESH:D014443', (257, 265))	('EGFR', 'Gene', (172, 176))	('STAT3', 'Gene', '6774', (50, 55))	('STAT3', 'Gene', (232, 237))	('STAT3', 'Gene', (50, 55))	('increased', 'PosReg', (40, 49))	('increased', 'PosReg', (85, 94))	('inactivation', 'Var', (193, 205))	('cancer', 'Disease', (70, 76))	('activation', 'PosReg', (56, 66))	('cancer', 'Disease', 'MESH:D009369', (70, 76))
461677	26267899	We recently reported that the receptor-type protein tyrosine phosphatase (PTPR) family is frequently mutated in HNSCC and other cancers and demonstrated that HNSCC-derived mutations of PTPRT induce STAT3 phosphorylation and drive HNSCC cell survival.	('mutations', 'Var', (172, 181))	('cancers', 'Disease', 'MESH:D009369', (128, 135))	('cancers', 'Phenotype', 'HP:0002664', (128, 135))	('STAT3', 'Gene', '6774', (198, 203))	('cancers', 'Disease', (128, 135))	('tyrosine', 'Chemical', 'MESH:D014443', (52, 60))	('PTPRT', 'Gene', '11122', (185, 190))	('PTPRT', 'Gene', (185, 190))	('HNSCC', 'Disease', (112, 117))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('STAT3', 'Gene', (198, 203))	('drive', 'PosReg', (224, 229))	('HNSCC', 'Phenotype', 'HP:0012288', (112, 117))	('HNSCC', 'Phenotype', 'HP:0012288', (230, 235))	('induce', 'PosReg', (191, 197))	('HNSCC', 'Disease', (230, 235))	('HNSCC', 'Phenotype', 'HP:0012288', (158, 163))
461678	26267899	As PTPRD represents an additional receptor-like phosphatase that directly targets STAT3, we sought to determine if genetic or epigenetic loss of PTPRD function may contribute to STAT3 overactivation in HNSCC.	('HNSCC', 'Disease', (202, 207))	('STAT3', 'Gene', '6774', (178, 183))	('HNSCC', 'Phenotype', 'HP:0012288', (202, 207))	('PTPRD', 'Gene', '5789', (3, 8))	('STAT3', 'Gene', '6774', (82, 87))	('PTPRD', 'Gene', (3, 8))	('contribute', 'Reg', (164, 174))	('loss', 'NegReg', (137, 141))	('epigenetic', 'Var', (126, 136))	('PTPRD', 'Gene', (145, 150))	('STAT3', 'Gene', (82, 87))	('PTPRD', 'Gene', '5789', (145, 150))	('overactivation', 'PosReg', (184, 198))	('STAT3', 'Gene', (178, 183))
461679	26267899	In the present study, we first identified 18 previously uncharacterized PTPRD mutations in HNSCC tumors.	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('HNSCC tumors', 'Disease', 'MESH:D000077195', (91, 103))	('mutations', 'Var', (78, 87))	('PTPRD', 'Gene', '5789', (72, 77))	('PTPRD', 'Gene', (72, 77))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('HNSCC', 'Phenotype', 'HP:0012288', (91, 96))	('HNSCC tumors', 'Disease', (91, 103))
461681	26267899	We have shown that overexpression of wild-type PTPRD leads to growth suppression in HNSCC cells, while overexpression of representative mutants does not, thus establishing a functional consequence of PTPRD mutation in HNSCC models.	('PTPRD', 'Gene', (47, 52))	('growth suppression', 'CPA', (62, 80))	('HNSCC', 'Phenotype', 'HP:0012288', (84, 89))	('HNSCC', 'Phenotype', 'HP:0012288', (218, 223))	('mutation', 'Var', (206, 214))	('PTPRD', 'Gene', '5789', (200, 205))	('PTPRD', 'Gene', (200, 205))	('PTPRD', 'Gene', '5789', (47, 52))
461683	26267899	These cumulative findings suggest that PTPRD mutations in cancer lead to loss of its tumor suppressive function.	('loss', 'NegReg', (73, 77))	('tumor', 'Disease', (85, 90))	('mutations', 'Var', (45, 54))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('cancer', 'Disease', (58, 64))	('PTPRD', 'Gene', '5789', (39, 44))	('PTPRD', 'Gene', (39, 44))
461684	26267899	In order to determine if PTPRD mutation affects the activity of STAT3, a PTPRD substrate, we analyzed TCGA and TCPA data and found that HNSCC tumors with PTPRD mutations express significantly elevated pSTAT3 (Y705) relative to PTPRD-wild-type tumors.	('PTPRD', 'Gene', '5789', (154, 159))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('tumors', 'Disease', 'MESH:D009369', (243, 249))	('mutations', 'Var', (160, 169))	('PTPRD', 'Gene', (25, 30))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))	('PTPRD', 'Gene', (73, 78))	('STAT3', 'Gene', (64, 69))	('PTPRD', 'Gene', '5789', (25, 30))	('elevated', 'PosReg', (192, 200))	('STAT3', 'Gene', '6774', (64, 69))	('PTPRD', 'Gene', '5789', (73, 78))	('tumors', 'Disease', (142, 148))	('HNSCC tumors', 'Disease', 'MESH:D000077195', (136, 148))	('HNSCC', 'Phenotype', 'HP:0012288', (136, 141))	('tumors', 'Phenotype', 'HP:0002664', (243, 249))	('TCPA', 'Chemical', '-', (111, 115))	('PTPRD', 'Gene', (227, 232))	('HNSCC tumors', 'Disease', (136, 148))	('tumors', 'Disease', 'MESH:D009369', (142, 148))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))	('STAT3', 'Gene', (202, 207))	('PTPRD', 'Gene', (154, 159))	('tumors', 'Disease', (243, 249))	('PTPRD', 'Gene', '5789', (227, 232))	('activity', 'MPA', (52, 60))	('STAT3', 'Gene', '6774', (202, 207))
461685	26267899	We previously reported a similar association between pSTAT3 (Y705) expression and mutation of a group of putative PTPR tumor suppressor genes, including PTPRD.	('tumor', 'Disease', (119, 124))	('mutation', 'Var', (82, 90))	('STAT3', 'Gene', '6774', (54, 59))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('STAT3', 'Gene', (54, 59))	('PTPRD', 'Gene', '5789', (153, 158))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('PTPRD', 'Gene', (153, 158))
461686	26267899	When each gene is considered individually rather than as a group, PTPRD is the only PTPR family member for which mutation is significantly associated with pSTAT3 (Y705) expression (S4 Fig).	('mutation', 'Var', (113, 121))	('STAT3', 'Gene', '6774', (156, 161))	('PTPRD', 'Gene', '5789', (66, 71))	('STAT3', 'Gene', (156, 161))	('PTPRD', 'Gene', (66, 71))	('associated', 'Reg', (139, 149))	('expression', 'MPA', (169, 179))
461687	26267899	This result suggests that while the number of tumors harboring a mutation in any single PTPR family member may be insufficient to detect a significant difference in pSTAT3 (Y705) expression, PTPRD mutation in particular is uniquely associated with an increase in pSTAT3 (Y705) expression that is sufficiently large to detect statistical significance.	('expression', 'MPA', (277, 287))	('PTPRD', 'Gene', '5789', (191, 196))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumors', 'Disease', (46, 52))	('STAT3', 'Gene', (166, 171))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('tumors', 'Disease', 'MESH:D009369', (46, 52))	('insufficient', 'Disease', (114, 126))	('insufficient', 'Disease', 'MESH:D000309', (114, 126))	('STAT3', 'Gene', '6774', (264, 269))	('increase', 'PosReg', (251, 259))	('STAT3', 'Gene', '6774', (166, 171))	('mutation', 'Var', (197, 205))	('STAT3', 'Gene', (264, 269))	('PTPRD', 'Gene', (191, 196))
461688	26267899	Futhermore, overexpression of wild-type PTPRD in HNSCC cell lines harboring endogenous PTPRD mutations leads to downregulation of pSTAT3 (Y705), thus confirming that PTPRD regulates STAT3 activation in HNSCC models.	('STAT3', 'Gene', (182, 187))	('PTPRD', 'Gene', '5789', (40, 45))	('PTPRD', 'Gene', (40, 45))	('mutations', 'Var', (93, 102))	('STAT3', 'Gene', (131, 136))	('downregulation', 'NegReg', (112, 126))	('HNSCC', 'Phenotype', 'HP:0012288', (49, 54))	('HNSCC', 'Phenotype', 'HP:0012288', (202, 207))	('PTPRD', 'Gene', '5789', (87, 92))	('PTPRD', 'Gene', (87, 92))	('PTPRD', 'Gene', '5789', (166, 171))	('PTPRD', 'Gene', (166, 171))	('STAT3', 'Gene', '6774', (182, 187))	('STAT3', 'Gene', '6774', (131, 136))
461689	26267899	While wild-type PTPRD leads to downregulation of pSTAT3 (Y705) in HNSCC cells, overexpression of most HNSCC-derived mutants does not alter pSTAT3 (Y705) expression relative to vector control, suggesting that these mutations lead to loss of function, but not in a dominant negative manner.	('PTPRD', 'Gene', (16, 21))	('HNSCC', 'Phenotype', 'HP:0012288', (66, 71))	('STAT3', 'Gene', '6774', (50, 55))	('STAT3', 'Gene', (50, 55))	('STAT3', 'Gene', '6774', (140, 145))	('loss', 'NegReg', (232, 236))	('HNSCC', 'Phenotype', 'HP:0012288', (102, 107))	('downregulation', 'NegReg', (31, 45))	('mutants', 'Var', (116, 123))	('STAT3', 'Gene', (140, 145))	('PTPRD', 'Gene', '5789', (16, 21))
461690	26267899	In the case of the L1147F mutation tested herein, overexpression in HNSCC cells leads to increased growth, but not increased pSTAT3 (Y705) expression (see Figs 2A and 3D), indicating that certain mutations may lead to cancerous phenotypes in a STAT3-independent manner.	('HNSCC', 'Phenotype', 'HP:0012288', (68, 73))	('L1147F', 'Var', (19, 25))	('growth', 'MPA', (99, 105))	('cancerous', 'Disease', (218, 227))	('L1147F', 'Mutation', 'p.L1147F', (19, 25))	('lead to', 'Reg', (210, 217))	('STAT3', 'Gene', '6774', (126, 131))	('STAT3', 'Gene', '6774', (244, 249))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('cancerous', 'Disease', 'MESH:D009369', (218, 227))	('increased', 'PosReg', (89, 98))	('STAT3', 'Gene', (126, 131))	('STAT3', 'Gene', (244, 249))
461691	26267899	As PTPRD mutation leads to increased STAT3 activation in HNSCC, we next tested whether cells harboring a PTPRD mutation may be more sensitive to STAT3 pathway inhibition.	('mutation', 'Var', (9, 17))	('increased', 'PosReg', (27, 36))	('STAT3', 'Gene', (145, 150))	('STAT3', 'Gene', '6774', (37, 42))	('PTPRD', 'Gene', '5789', (3, 8))	('STAT3', 'Gene', (37, 42))	('PTPRD', 'Gene', (3, 8))	('HNSCC', 'Phenotype', 'HP:0012288', (57, 62))	('PTPRD', 'Gene', '5789', (105, 110))	('STAT3', 'Gene', '6774', (145, 150))	('PTPRD', 'Gene', (105, 110))
461692	26267899	Here we demonstrate that HNSCC cells with an endogenous PTPRD mutation are more sensitive to the JAK/STAT inhibitor JSI-124 than HNSCC cells harboring no PTPR family mutations, suggesting that HNSCC tumors with PTPRD mutations may be exquisitely sensitive to STAT3 inhibitors that are currently in preclinical and clinical development.	('PTPRD', 'Gene', (211, 216))	('STAT3', 'Gene', '6774', (259, 264))	('tumors', 'Phenotype', 'HP:0002664', (199, 205))	('HNSCC tumors', 'Disease', 'MESH:D000077195', (193, 205))	('HNSCC', 'Phenotype', 'HP:0012288', (25, 30))	('STAT3', 'Gene', (259, 264))	('PTPRD', 'Gene', '5789', (56, 61))	('JSI-124', 'Chemical', 'MESH:C038106', (116, 123))	('PTPRD', 'Gene', (56, 61))	('HNSCC', 'Phenotype', 'HP:0012288', (129, 134))	('mutation', 'Var', (62, 70))	('HNSCC', 'Phenotype', 'HP:0012288', (193, 198))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('mutations', 'Var', (217, 226))	('HNSCC tumors', 'Disease', (193, 205))	('PTPRD', 'Gene', '5789', (211, 216))
461693	26267899	In order to devise an optimal treatment strategy for HNSCC patients with PTPRD mutations, further study of additional PTPRD-interacting proteins that may serve as therapeutic targets may be warranted.	('mutations', 'Var', (79, 88))	('HNSCC', 'Phenotype', 'HP:0012288', (53, 58))	('patients', 'Species', '9606', (59, 67))	('PTPRD', 'Gene', '5789', (73, 78))	('PTPRD', 'Gene', (73, 78))	('PTPRD', 'Gene', '5789', (118, 123))	('PTPRD', 'Gene', (118, 123))
461694	26267899	In particular, PTPRD mutation may additionally confer sensitivity to aurora kinase A inhibitors currently in clinical development, where aurora kinase A phosphorylation and stability are normally regulated by PTPRD.	('PTPRD', 'Gene', '5789', (209, 214))	('aurora kinase A', 'Gene', '6790', (137, 152))	('PTPRD', 'Gene', (209, 214))	('aurora kinase A', 'Gene', (137, 152))	('mutation', 'Var', (21, 29))	('aurora kinase A', 'Gene', '6790', (69, 84))	('aurora kinase A', 'Gene', (69, 84))	('stability', 'MPA', (173, 182))	('PTPRD', 'Gene', '5789', (15, 20))	('sensitivity', 'MPA', (54, 65))	('PTPRD', 'Gene', (15, 20))
461695	26267899	An additional mechanism by which PTPRD function may be lost is through mRNA downregulation, including by promoter hypermethylation or gene copy number loss.	('PTPRD', 'Gene', (33, 38))	('promoter hypermethylation', 'Var', (105, 130))	('mRNA', 'MPA', (71, 75))	('PTPRD', 'Gene', '5789', (33, 38))	('downregulation', 'NegReg', (76, 90))	('gene copy number loss', 'Var', (134, 155))
461698	26267899	Indeed, our overexpression studies in HNSCC cells suggest that expression of PTPRD would be expected to impact pSTAT3 (Y705) expression.	('HNSCC', 'Phenotype', 'HP:0012288', (38, 43))	('STAT3', 'Gene', '6774', (112, 117))	('STAT3', 'Gene', (112, 117))	('impact', 'Reg', (104, 110))	('PTPRD', 'Gene', '5789', (77, 82))	('expression', 'Var', (63, 73))	('PTPRD', 'Gene', (77, 82))
461703	26267899	A similar lack of aberrant PTPRD promoter hypermethylation has also been reported in cutaneous squamous cell carcinoma, suggesting this may be an uncommon event in multiple epithelial malignancies.	('malignancies', 'Disease', (184, 196))	('cutaneous squamous cell carcinoma', 'Disease', 'MESH:D002294', (85, 118))	('cutaneous squamous cell carcinoma', 'Phenotype', 'HP:0006739', (85, 118))	('PTPRD', 'Gene', '5789', (27, 32))	('aberrant', 'Var', (18, 26))	('PTPRD', 'Gene', (27, 32))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (95, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('malignancies', 'Disease', 'MESH:D009369', (184, 196))	('cutaneous squamous cell carcinoma', 'Disease', (85, 118))	('epithelial malignancies', 'Phenotype', 'HP:0031492', (173, 196))
461704	26267899	Our analysis of TCGA data indicates that nearly half of HNSCC tumors harbor a copy number alteration of PTPRD and that copy number loss is more frequent than copy number gain in HNSCC and across nearly all cancers analyzed.	('HNSCC', 'Phenotype', 'HP:0012288', (178, 183))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('HNSCC', 'Phenotype', 'HP:0012288', (56, 61))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('copy number loss', 'Var', (119, 135))	('cancers', 'Disease', 'MESH:D009369', (206, 213))	('PTPRD', 'Gene', '5789', (104, 109))	('copy number alteration', 'Var', (78, 100))	('PTPRD', 'Gene', (104, 109))	('cancers', 'Phenotype', 'HP:0002664', (206, 213))	('cancers', 'Disease', (206, 213))	('HNSCC tumors', 'Disease', (56, 68))	('HNSCC tumors', 'Disease', 'MESH:D000077195', (56, 68))
461705	26267899	PTPRD homozygous or heterozygous deletion has also been reported in cutaneous squamous cell carcinoma, GBM, lung cancer, neuroblastoma, metastatic melanoma, squamous cell carcinoma of the vulva, hepatocellular carcinoma, and laryngeal squamous cell carcinoma.	('neuroblastoma', 'Disease', (121, 134))	('carcinoma', 'Phenotype', 'HP:0030731', (210, 219))	('cutaneous squamous cell carcinoma', 'Disease', 'MESH:D002294', (68, 101))	('PTPRD', 'Gene', (0, 5))	('laryngeal squamous cell carcinoma', 'Disease', 'MESH:D002294', (225, 258))	('neuroblastoma', 'Phenotype', 'HP:0003006', (121, 134))	('melanoma', 'Disease', 'MESH:D008545', (147, 155))	('neuroblastoma', 'Disease', 'MESH:D009447', (121, 134))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (195, 219))	('PTPRD', 'Gene', '5789', (0, 5))	('lung cancer', 'Disease', (108, 119))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (78, 101))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (157, 180))	('squamous cell carcinoma of the vulva', 'Disease', 'MESH:D002294', (157, 193))	('cutaneous squamous cell carcinoma', 'Phenotype', 'HP:0006739', (68, 101))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (195, 219))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('reported', 'Reg', (56, 64))	('GBM', 'Disease', (103, 106))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (235, 258))	('laryngeal squamous cell carcinoma', 'Disease', (225, 258))	('carcinoma', 'Phenotype', 'HP:0030731', (171, 180))	('melanoma', 'Phenotype', 'HP:0002861', (147, 155))	('melanoma', 'Disease', (147, 155))	('squamous cell carcinoma of the vulva', 'Phenotype', 'HP:0030417', (157, 193))	('hepatocellular carcinoma', 'Disease', (195, 219))	('lung cancer', 'Disease', 'MESH:D008175', (108, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (249, 258))	('cutaneous squamous cell carcinoma', 'Disease', (68, 101))	('squamous cell carcinoma of the vulva', 'Disease', (157, 193))	('lung cancer', 'Phenotype', 'HP:0100526', (108, 119))	('heterozygous deletion', 'Var', (20, 41))	('GBM', 'Phenotype', 'HP:0012174', (103, 106))
461709	26267899	While promoter methylation and copy number loss are detectable at the PTPRD locus, these events are not associated with upregulation of pSTAT3 (Y705) expression.	('STAT3', 'Gene', (137, 142))	('promoter', 'MPA', (6, 14))	('PTPRD', 'Gene', '5789', (70, 75))	('PTPRD', 'Gene', (70, 75))	('STAT3', 'Gene', '6774', (137, 142))	('copy number loss', 'Var', (31, 47))
461711	26267899	These findings suggest that PTPRD mutation may represent a predictive biomarker for exquisite response to STAT3 targeted therapy in HNSCC.	('mutation', 'Var', (34, 42))	('PTPRD', 'Gene', '5789', (28, 33))	('HNSCC', 'Disease', (132, 137))	('PTPRD', 'Gene', (28, 33))	('HNSCC', 'Phenotype', 'HP:0012288', (132, 137))	('STAT3', 'Gene', '6774', (106, 111))	('STAT3', 'Gene', (106, 111))
461733	33477935	It has a crucial role in miRNA function related to mRNA degradation in the case of perfect complementarity, or inhibition of translation in the case of non-complementarity of thereof.	('mRNA degradation', 'MPA', (51, 67))	('inhibition', 'MPA', (111, 121))	('perfect complementarity', 'Var', (83, 106))	('men', 'Species', '9606', (97, 100))	('miR', 'Gene', '220972', (25, 28))	('men', 'Species', '9606', (162, 165))	('miR', 'Gene', (25, 28))	('translation', 'MPA', (125, 136))
461757	33477935	These facts along with new methodology development, resulted in investigation of the epigenetic markers, including DNA methylation, miRNA expression or histone modification.	('DNA methylation', 'Var', (115, 130))	('men', 'Species', '9606', (46, 49))	('histone modification', 'MPA', (152, 172))	('miR', 'Gene', '220972', (132, 135))	('miR', 'Gene', (132, 135))
461766	33477935	There are also other processes, which could influence miRNA expression, such as dysregulation of key transcription factors, epigenetic modulation, or mutation or aberrant expression of any component of the miRNA biogenesis pathway (reviewed by).	('expression', 'MPA', (171, 181))	('epigenetic', 'MPA', (124, 134))	('miR', 'Gene', '220972', (54, 57))	('miR', 'Gene', (54, 57))	('mutation', 'Var', (150, 158))	('miR', 'Gene', '220972', (206, 209))	('influence', 'Reg', (44, 53))	('miR', 'Gene', (206, 209))	('aberrant', 'Var', (162, 170))	('dysregulation', 'Var', (80, 93))
461821	33477935	A total of 18 reports focused on the investigation of the effects of particulate matter (PM) of various aerodynamic diameter (PM10, PM2.5, ultrafine particles (UFP)), often along with other traffic- or combustion-related pollutants (NOx, CO, CO2, black carbon (BC)).	('carbon', 'Chemical', 'MESH:D002244', (253, 259))	('PM10', 'Var', (126, 130))	('PM10', 'Chemical', '-', (126, 130))	('PM2.5', 'Var', (132, 137))	('CO', 'Chemical', 'MESH:D002248', (238, 240))	('CO2', 'Chemical', 'MESH:D002245', (242, 245))	('CO', 'Chemical', 'MESH:D002248', (242, 244))	('PM2', 'Chemical', '-', (132, 135))
461828	33477935	Another study that involved 24 healthy subjects exposed to air pollutants during physical activity and the resting phase used NGS technology to correlate miRNA present in blood plasma with exposure to PM10, PM2.5, NO, NO2, CO, CO2, BC and UFP.	('miR', 'Gene', '220972', (154, 157))	('miR', 'Gene', (154, 157))	('NO2', 'Var', (218, 221))	('CO', 'Chemical', 'MESH:D002248', (223, 225))	('CO', 'Chemical', 'MESH:D002248', (227, 229))	('PM2.5', 'Var', (207, 212))	('NO2', 'Chemical', '-', (218, 221))	('CO2', 'Chemical', 'MESH:D002245', (227, 230))	('PM10', 'Var', (201, 205))	('PM10', 'Chemical', '-', (201, 205))	('PM2', 'Chemical', '-', (207, 210))
461832	33477935	The authors identified 54 circulating miRNAs associated with exposure to PM10, PM2.5, black carbon, UFP and NO2 following only 2h exposure to air pollution.	('PM2.5', 'Var', (79, 84))	('NO2', 'Chemical', '-', (108, 111))	('associated', 'Reg', (45, 55))	('PM2', 'Chemical', '-', (79, 82))	('miR', 'Gene', '220972', (38, 41))	('miR', 'Gene', (38, 41))	('PM10', 'Var', (73, 77))	('PM10', 'Chemical', '-', (73, 77))	('2h', 'Chemical', 'MESH:D003903', (127, 129))	('carbon', 'Chemical', 'MESH:D002244', (92, 98))
461833	33477935	The effect of short (2h) PM10, PM2.5, NO, NO2, CO, CO2, BC and UFP exposure on miRNA expression in whole blood was further investigated using microarray technology among a total of 89 volunteers, including healthy subjects and those with COPD and IHD.	('COPD', 'Disease', (238, 242))	('NO2', 'Chemical', '-', (42, 45))	('CO', 'Chemical', 'MESH:D002248', (47, 49))	('PM2', 'Chemical', '-', (31, 34))	('PM2.5', 'Var', (31, 36))	('CO2', 'Chemical', 'MESH:D002245', (51, 54))	('CO', 'Chemical', 'MESH:D002248', (51, 53))	('miR', 'Gene', '220972', (79, 82))	('miR', 'Gene', (79, 82))	('PM10', 'Var', (25, 29))	('IHD', 'Disease', 'None', (247, 250))	('PM10', 'Chemical', '-', (25, 29))	('CO', 'Chemical', 'MESH:D002248', (238, 240))	('2h', 'Chemical', 'MESH:D003903', (21, 23))	('COPD', 'Phenotype', 'HP:0006510', (238, 242))	('COPD', 'Disease', 'MESH:D029424', (238, 242))	('IHD', 'Disease', (247, 250))
461847	33477935	PM10 affected the expression of 12 miRNAs in office workers only, while short-term EC exposure had significant impacts on 28 miRNAs in office workers and 29 miRNAs in truck drivers, although only 5 miRNAs were common in both groups (miR-125a-5p, miR-1274a, miR-600, miR-1283, miR-10a).	('miR', 'Gene', (198, 201))	('miR-1', 'Gene', (276, 281))	('miR-1', 'Gene', '79187', (266, 271))	('miR', 'Gene', (157, 160))	('miR', 'Gene', '220972', (233, 236))	('miR', 'Gene', '220972', (257, 260))	('miR-1', 'Gene', (246, 251))	('miR', 'Gene', '220972', (35, 38))	('PM10', 'Var', (0, 4))	('miR-1', 'Gene', '79187', (233, 238))	('miR-600', 'Gene', '693185', (257, 264))	('miR-600', 'Gene', (257, 264))	('miR', 'Gene', (125, 128))	('miR-128', 'Chemical', '-', (266, 273))	('EC', 'Chemical', 'MESH:D002244', (83, 85))	('miR', 'Gene', (266, 269))	('miR-10a', 'Gene', (276, 283))	('miR', 'Gene', (257, 260))	('miR', 'Gene', (233, 236))	('miR', 'Gene', (35, 38))	('expression', 'MPA', (18, 28))	('miR-1', 'Gene', '79187', (276, 281))	('affected', 'Reg', (5, 13))	('miR', 'Gene', '220972', (246, 249))	('miR-1', 'Gene', '79187', (246, 251))	('miR-1', 'Gene', (266, 271))	('miR', 'Gene', '220972', (276, 279))	('miR', 'Gene', (246, 249))	('miR-1', 'Gene', (233, 238))	('miR', 'Gene', '220972', (198, 201))	('impacts', 'Reg', (111, 118))	('miR', 'Gene', '220972', (157, 160))	('miR-10a', 'Gene', '406902', (276, 283))	('PM10', 'Chemical', '-', (0, 4))	('miR', 'Gene', '220972', (125, 128))	('miR', 'Gene', (276, 279))	('miR', 'Gene', '220972', (266, 269))
461848	33477935	The deregulated miRNAs seem to play a role in the immune response.	('immune response', 'CPA', (50, 65))	('play', 'Reg', (31, 35))	('deregulated', 'Var', (4, 15))	('miR', 'Gene', '220972', (16, 19))	('miR', 'Gene', (16, 19))
461861	33477935	In a small group of 22 subjects, exposure to PM2.5 was linked with increased blood pressure and positively associated with miR-199a/b and miR-223-3p expression in extracellular vesicles.	('miR-223-3p expression', 'MPA', (138, 159))	('exposure', 'Var', (33, 41))	('blood pressure', 'MPA', (77, 91))	('increased blood pressure', 'Phenotype', 'HP:0032263', (67, 91))	('PM2.5', 'Var', (45, 50))	('miR-1', 'Gene', '79187', (123, 128))	('miR-223-3p', 'Chemical', '-', (138, 148))	('increased', 'PosReg', (67, 76))	('associated', 'Interaction', (107, 117))	('PM2', 'Chemical', '-', (45, 48))	('miR-1', 'Gene', (123, 128))
461862	33477935	The expression of miR-199a/b was further affected by DNA methylation near the enhancer region of the gene encoding this molecule.	('expression', 'MPA', (4, 14))	('DNA methylation', 'Var', (53, 68))	('affected', 'Reg', (41, 49))	('miR-1', 'Gene', '79187', (18, 23))	('miR-1', 'Gene', (18, 23))
461867	33477935	The deregulated miRNAs most likely participate in HMGB1/RAGE signaling pathway that is associated with the enhanced expression of proinflammatory cytokines.	('HMGB1', 'Gene', (50, 55))	('expression', 'MPA', (116, 126))	('HMGB1', 'Gene', '3146', (50, 55))	('RAGE', 'Gene', '177', (56, 60))	('enhanced', 'PosReg', (107, 115))	('deregulated', 'Var', (4, 15))	('miR', 'Gene', '220972', (16, 19))	('miR', 'Gene', (16, 19))	('RAGE', 'Gene', (56, 60))	('participate', 'Reg', (35, 46))
461869	33477935	A larger investigation of 1630 subjects showed downregulation of let-7c-5p, miR-106a-5p, miR-143-3p, miR-185-5p, miR-218-5p, miR-331-3p, miR-642-5p, miR-652-3p and miR-99b-5p expression in extracellular vesicles after short-term exposure to PM10.	('downregulation', 'NegReg', (47, 61))	('let-7c', 'Gene', '406885', (65, 71))	('miR', 'Gene', (164, 167))	('miR-642', 'Gene', '693227', (137, 144))	('miR-185', 'Gene', (101, 108))	('miR', 'Gene', '220972', (76, 79))	('miR-642', 'Gene', (137, 144))	('miR', 'Gene', (125, 128))	('miR', 'Gene', (101, 104))	('miR-106a', 'Gene', (76, 84))	('expression', 'MPA', (175, 185))	('miR', 'Gene', '220972', (113, 116))	('miR', 'Gene', '220972', (89, 92))	('miR', 'Gene', '220972', (137, 140))	('miR-143', 'Gene', '406935', (89, 96))	('miR-143', 'Gene', (89, 96))	('miR-331', 'Gene', (125, 132))	('miR-21', 'Gene', '406991', (113, 119))	('miR', 'Gene', (76, 79))	('miR-331', 'Gene', '442903', (125, 132))	('miR', 'Gene', (113, 116))	('miR', 'Gene', (89, 92))	('miR', 'Gene', (137, 140))	('miR', 'Gene', '220972', (149, 152))	('miR-185', 'Gene', '406961', (101, 108))	('PM10', 'Chemical', '-', (241, 245))	('miR-106a', 'Gene', '406899', (76, 84))	('miR-21', 'Gene', (113, 119))	('let-7c', 'Gene', (65, 71))	('miR', 'Gene', '220972', (164, 167))	('miR', 'Gene', (149, 152))	('PM10', 'Var', (241, 245))	('miR', 'Gene', '220972', (125, 128))	('miR', 'Gene', '220972', (101, 104))
461870	33477935	These miRNAs exhibit a putative role in cardiovascular disease and mediate changes of fibrinogen levels associated with PM10 exposure suggesting a role of PM in increased coagulation.	('fibrinogen', 'Gene', '2244', (86, 96))	('fibrinogen', 'Gene', (86, 96))	('changes', 'Reg', (75, 82))	('cardiovascular disease', 'Phenotype', 'HP:0001626', (40, 62))	('increased coagulation', 'Phenotype', 'HP:0001928', (161, 182))	('cardiovascular disease', 'Disease', 'MESH:D002318', (40, 62))	('PM10', 'Var', (120, 124))	('PM10', 'Chemical', '-', (120, 124))	('miR', 'Gene', '220972', (6, 9))	('miR', 'Gene', (6, 9))	('cardiovascular disease', 'Disease', (40, 62))	('increased', 'PosReg', (161, 170))
461871	33477935	In another study, decreased miRNA expression in the peripheral blood of 90 obese subjects was found after exposure to PM10 48 h before sample collection.	('PM10', 'Var', (118, 122))	('obese', 'Disease', 'MESH:D009765', (75, 80))	('PM10', 'Chemical', '-', (118, 122))	('decreased', 'NegReg', (18, 27))	('obese', 'Disease', (75, 80))	('miR', 'Gene', '220972', (28, 31))	('miR', 'Gene', (28, 31))
461873	33477935	PM10 exposure was associated with a blood pressure increase further modulated by miRNA-101 expression.	('increase', 'PosReg', (51, 59))	('miR', 'Gene', '220972', (81, 84))	('miR', 'Gene', (81, 84))	('blood pressure', 'MPA', (36, 50))	('PM10', 'Var', (0, 4))	('blood pressure increase', 'Phenotype', 'HP:0032263', (36, 59))	('PM10', 'Chemical', '-', (0, 4))
461879	33477935	In a study of 63 workers, increased expression of miR-128 and miR-302c after 3 days exposure to PM was detected.	('miR-128', 'Var', (50, 57))	('increased', 'PosReg', (26, 35))	('miR-302c', 'Gene', (62, 70))	('miR-302c', 'Gene', '442895', (62, 70))	('expression', 'MPA', (36, 46))	('miR-128', 'Chemical', '-', (50, 57))
461882	33477935	While COPD is a pulmonary disease linked with genetic and environmental factors, dysregulation of miRNAs has also been shown to play a role.	('pulmonary disease', 'Disease', 'MESH:D008171', (16, 33))	('COPD', 'Phenotype', 'HP:0006510', (6, 10))	('men', 'Species', '9606', (65, 68))	('dysregulation', 'Var', (81, 94))	('miR', 'Gene', '220972', (98, 101))	('miR', 'Gene', (98, 101))	('COPD', 'Disease', 'MESH:D029424', (6, 10))	('COPD', 'Disease', (6, 10))	('pulmonary disease', 'Disease', (16, 33))
461896	33477935	As the analyzed miRNAs are important modulators involved in vascular dysfunction and atherosclerosis, the results indicate a greater health risk associated with burning wood than using LPG.	('atherosclerosis', 'Phenotype', 'HP:0002621', (85, 100))	('vascular dysfunction', 'Disease', (60, 80))	('LPG', 'Chemical', '-', (185, 188))	('atherosclerosis', 'Disease', 'MESH:D050197', (85, 100))	('burning wood', 'Var', (161, 173))	('vascular dysfunction', 'Disease', 'MESH:D002561', (60, 80))	('atherosclerosis', 'Disease', (85, 100))	('miR', 'Gene', '220972', (16, 19))	('miR', 'Gene', (16, 19))
461915	33477935	Our literature review indicates that its expression was also associated with exposure to mixtures of air pollutants, specifically to PM10, PM2.5, UFP, black carbon, organic carbon, sulphates, and ozone.	('PM2', 'Chemical', '-', (139, 142))	('carbon', 'Chemical', 'MESH:D002244', (157, 163))	('expression', 'MPA', (41, 51))	('PM10', 'Chemical', '-', (133, 137))	('ozone', 'Chemical', 'MESH:D010126', (196, 201))	('organic', 'MPA', (165, 172))	('carbon', 'Chemical', 'MESH:D002244', (173, 179))	('sulphates', 'Chemical', 'MESH:D013431', (181, 190))	('PM2.5', 'Var', (139, 144))	('associated', 'Reg', (61, 71))	('organic carbon', 'Chemical', '-', (165, 179))
461921	33477935	In addition, its expression is affected by exposure to air pollutants (PM2.5 and PM10, black carbon, organic carbon, and sulphates) as reported in four studies.	('organic carbon', 'Chemical', '-', (101, 115))	('expression', 'MPA', (17, 27))	('affected', 'Reg', (31, 39))	('PM10', 'Var', (81, 85))	('sulphates', 'Chemical', 'MESH:D013431', (121, 130))	('PM10', 'Chemical', '-', (81, 85))	('carbon', 'Chemical', 'MESH:D002244', (93, 99))	('carbon', 'Chemical', 'MESH:D002244', (109, 115))	('PM2.5', 'Var', (71, 76))	('PM2', 'Chemical', '-', (71, 74))
461936	33477935	Similar to miR-126-3p, its expression was modified by PM2.5, black and organic carbon, as well as wood smoke exposure.	('modified', 'Reg', (42, 50))	('PM2', 'Chemical', '-', (54, 57))	('organic carbon', 'Chemical', '-', (71, 85))	('miR-126-3p', 'Gene', '100302148', (11, 21))	('miR-126-3p', 'Gene', (11, 21))	('expression', 'MPA', (27, 37))	('PM2.5', 'Var', (54, 59))
461941	33477935	miR223-3p was further detected to be overexpressed in neutrophils of patients with asthma.	('miR223-3p', 'Var', (0, 9))	('asthma', 'Disease', 'MESH:D001249', (83, 89))	('asthma', 'Disease', (83, 89))	('miR223-3p', 'Chemical', '-', (0, 9))	('asthma', 'Phenotype', 'HP:0002099', (83, 89))	('patients', 'Species', '9606', (69, 77))	('overexpressed', 'PosReg', (37, 50))
461952	33477935	Additionally, the effect of various confounders, including e.g., age of human subjects, lenght of exposure, genetic variability associated single nucleotide polymorphisms (SNPs) in genes encoding miRNAs, or the role of epigenetic adaptation should be considered.	('miR', 'Gene', '220972', (196, 199))	('single nucleotide polymorphisms', 'Var', (139, 170))	('miR', 'Gene', (196, 199))	('human', 'Species', '9606', (72, 77))
461953	33477935	In particular, the process of epigenetic adaptation, previously reported by us and other authors (reviewed e.g., in), significantly modifies the environment-organism interactions potentially resulting in a reduction of negative impacts of pollutants on the organism.	('reduction', 'NegReg', (206, 215))	('modifies', 'Reg', (132, 140))	('epigenetic adaptation', 'Var', (30, 51))	('men', 'Species', '9606', (152, 155))	('interactions', 'Interaction', (166, 178))	('negative impacts of pollutants', 'MPA', (219, 249))
461955	33477935	The study was further supported by the Ministry of Education, Youth and Sports of the Czech Republic (Research Infrastructures NanoEnviCZ, LM2018124; EATRIS-CZ, LM2018133), by the EU and the Ministry of Education, Youth and Sports of the Czech Republic as a JPND 2020 project ADAIR (8F20008) and by the Czech Science Foundation (18-02079S).	('LM2018133', 'CellLine', 'CVCL:5998', (161, 170))	('LM2018133', 'Var', (161, 170))	('LM2018124', 'Var', (139, 148))
461959	32793482	Next, we found that the immune cell infiltration levels were associated with the ACK1 gene copy numbers in lung cancer.	('immune cell infiltration levels', 'MPA', (24, 55))	('copy numbers', 'Var', (91, 103))	('ACK1', 'Gene', '10188', (81, 85))	('lung cancer', 'Disease', 'MESH:D008175', (107, 118))	('ACK1', 'Gene', (81, 85))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('lung cancer', 'Disease', (107, 118))	('lung cancer', 'Phenotype', 'HP:0100526', (107, 118))	('associated', 'Reg', (61, 71))
461960	32793482	Consistently, our RNA-seq data unveiled that the silencing of ACK1 upregulated several immune pathways in lung cancer cells, including the T cell receptor signaling pathway.	('silencing', 'Var', (49, 58))	('lung cancer', 'Disease', (106, 117))	('immune pathways', 'Pathway', (87, 102))	('lung cancer', 'Phenotype', 'HP:0100526', (106, 117))	('T cell receptor signaling pathway', 'Pathway', (139, 172))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('ACK1', 'Gene', '10188', (62, 66))	('ACK1', 'Gene', (62, 66))	('lung cancer', 'Disease', 'MESH:D008175', (106, 117))	('upregulated', 'PosReg', (67, 78))
461972	32793482	In several clinical trials, a fraction of patients achieved a partial response after receiving immune checkpoint inhibitors that enhance the cytotoxic activity of immune effector cells by neutralizing cytotoxic T-lymphocyte antigen-4 (CTLA4), programmed cell death protein 1 (PD-1), or PD-1 ligand (PD-L1).	('programmed cell death protein 1', 'Gene', '5133', (243, 274))	('PD-L1', 'Gene', '29126', (299, 304))	('cytotoxic T-lymphocyte antigen-4', 'Gene', '1493', (201, 233))	('cytotoxic T-lymphocyte antigen-4', 'Gene', (201, 233))	('PD-1', 'Gene', '5133', (276, 280))	('neutralizing', 'Var', (188, 200))	('programmed cell death protein 1', 'Gene', (243, 274))	('PD-1', 'Gene', (286, 290))	('patients', 'Species', '9606', (42, 50))	('PD-1', 'Gene', '5133', (286, 290))	('CTLA4', 'Gene', '1493', (235, 240))	('PD-L1', 'Gene', (299, 304))	('cytotoxic activity', 'CPA', (141, 159))	('PD-1', 'Gene', (276, 280))	('enhance', 'PosReg', (129, 136))	('CTLA4', 'Gene', (235, 240))
461979	32793482	The ACK1 gene located on chromosome 3q29 is frequently amplified or mutated in several types of cancers, which generally leads to an abnormal activity of the ACK1 signaling cascades.	('cancers', 'Phenotype', 'HP:0002664', (96, 103))	('activity', 'MPA', (142, 150))	('ACK1', 'Gene', '10188', (4, 8))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('ACK1', 'Gene', '10188', (158, 162))	('ACK1', 'Gene', (4, 8))	('ACK1', 'Gene', (158, 162))	('leads to', 'Reg', (121, 129))	('cancers', 'Disease', 'MESH:D009369', (96, 103))	('mutated', 'Var', (68, 75))	('cancers', 'Disease', (96, 103))
461994	32793482	We knocked down the ACK1 gene by infecting A549 cells with lentiviral vectors encoding shRNA against ACK1 (tgCTTCCTCTTCCACCCAATT) or shRNA control vectors purchased from the GeneChem (Shanghai, China).	('ACK1', 'Gene', '10188', (20, 24))	('knocked', 'Var', (3, 10))	('ACK1', 'Gene', (20, 24))	('ACK1', 'Gene', '10188', (101, 105))	('ACK1', 'Gene', (101, 105))	('A549', 'CellLine', 'CVCL:0023', (43, 47))
462025	32793482	Our RNA-seq results revealed that the silencing of the ACK1 gene in A549 cells activated several immune-related signaling pathways, including the T cell receptor, chemokine, JAK-STAT, and Toll-like receptor signaling pathway (Figures 4A-D).	('immune-related signaling pathways', 'Pathway', (97, 130))	('chemokine', 'Pathway', (163, 172))	('JAK-STAT', 'MPA', (174, 182))	('ACK1', 'Gene', '10188', (55, 59))	('ACK1', 'Gene', (55, 59))	('Toll-like receptor signaling pathway', 'Pathway', (188, 224))	('activated', 'PosReg', (79, 88))	('T cell receptor', 'Pathway', (146, 161))	('A549', 'CellLine', 'CVCL:0023', (68, 72))	('silencing', 'Var', (38, 47))
462035	32793482	The Kaplan-Meier survival curve elucidated that patients with low-risk scores had significantly longer survival than those with high risk (log-rank test, P < 0.001) (Figure 6C).	('survival', 'MPA', (103, 111))	('scores', 'Var', (71, 77))	('longer', 'PosReg', (96, 102))	('patients', 'Species', '9606', (48, 56))
462054	32793482	We found that ACK1 gene copy numbers were inversely associated with the infiltration levels of B cell, CD8+ T cell, CD4+ T cell, macrophage, neutrophil, and dendritic cells in lung cancer.	('inversely', 'NegReg', (42, 51))	('lung cancer', 'Phenotype', 'HP:0100526', (176, 187))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('CD4', 'Gene', '920', (116, 119))	('lung cancer', 'Disease', 'MESH:D008175', (176, 187))	('CD8', 'Gene', '925', (103, 106))	('associated', 'Reg', (52, 62))	('ACK1', 'Gene', '10188', (14, 18))	('ACK1', 'Gene', (14, 18))	('CD8', 'Gene', (103, 106))	('copy numbers', 'Var', (24, 36))	('infiltration levels of B cell', 'MPA', (72, 101))	('lung cancer', 'Disease', (176, 187))	('CD4', 'Gene', (116, 119))
462059	32793482	The ACK1 blockade was found to suppress the MAPK signaling pathway previously.	('ACK1', 'Gene', '10188', (4, 8))	('ACK1', 'Gene', (4, 8))	('suppress', 'NegReg', (31, 39))	('MAPK signaling pathway', 'Pathway', (44, 66))	('blockade', 'Var', (9, 17))
462063	32793482	Taken together, it is biologically plausible to speculate that the ACK1 inhibitors may also be able to boost tumor immunity, thereby favoring the antitumor efficacy of immune checkpoint blockers.	('boost', 'PosReg', (103, 108))	('ACK1', 'Gene', (67, 71))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('favoring', 'PosReg', (133, 141))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('inhibitors', 'Var', (72, 82))	('tumor', 'Disease', (150, 155))	('tumor', 'Disease', (109, 114))	('ACK1', 'Gene', '10188', (67, 71))
462082	29740957	 EGFR exon 20 insertion mutation in advanced thymic squamous cell carcinoma: Response to apatinib and clinical outcomes Thymic carcinoma (TC) is a rare malignant tumor of the mediastinum with occult onset, rapid development, and poor prognosis.	('men', 'Species', '9606', (219, 222))	('squamous cell carcinoma', 'Disease', (52, 75))	('carcinoma', 'Disease', (127, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (66, 75))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (52, 75))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('carcinoma', 'Disease', (66, 75))	('malignant tumor', 'Disease', (152, 167))	('insertion mutation', 'Var', (14, 32))	('EGFR', 'Gene', '1956', (1, 5))	('carcinoma', 'Disease', 'MESH:D002277', (127, 136))	('EGFR', 'Gene', (1, 5))	('malignant tumor', 'Disease', 'MESH:D018198', (152, 167))	('apatinib', 'Chemical', 'MESH:C553458', (89, 97))	('carcinoma', 'Disease', 'MESH:D002277', (66, 75))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (52, 75))
462086	29740957	Herein we report a case of advanced thymic squamous cell carcinoma harboring EGFR exon 20 insertion in which apatinib was administered after multi-line chemotherapy and radiotherapy and a partial response was achieved after five months of treatment.	('men', 'Species', '9606', (244, 247))	('apatinib', 'Chemical', 'MESH:C553458', (109, 117))	('carcinoma', 'Phenotype', 'HP:0030731', (57, 66))	('EGFR', 'Gene', '1956', (77, 81))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (43, 66))	('insertion', 'Var', (90, 99))	('squamous cell carcinoma', 'Disease', (43, 66))	('EGFR', 'Gene', (77, 81))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (43, 66))
462115	29740957	Histopathology combined with immunohistochemistry results (CD5-, CD117+, TTF-1-, P63+, P40+, CK5/6+, CK7+, CK8/18+, Ki-67+) showed non-keratinizing squamous cell carcinoma (Fig 2a,c-h).	('CK7', 'Gene', (101, 104))	('carcinoma', 'Phenotype', 'HP:0030731', (162, 171))	('CK5', 'Gene', '3852', (93, 96))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (148, 171))	('CK7', 'Gene', '3855', (101, 104))	('squamous cell carcinoma', 'Disease', (148, 171))	('CD5-', 'Var', (59, 63))	('TTF-1', 'Gene', (73, 78))	('CD117+', 'Var', (65, 71))	('P40+', 'Var', (87, 91))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (148, 171))	('TTF-1', 'Gene', '7270', (73, 78))	('CK8', 'Gene', '3856', (107, 110))	('CK8', 'Gene', (107, 110))	('CK5', 'Gene', (93, 96))	('Ki-67+', 'Var', (116, 122))	('P63+', 'Var', (81, 85))
462116	29740957	We performed next generation sequencing and examined PD-L1 expression using the same biopsy tissue sample, which showed EGFR exon 20 insertion (770-771insGly) and JAK2 exon 17 missense (Lys752Thr) mutations, but PD-L1 expression was negative (Table 1, Figs 2b, 3).	('PD-L1', 'Gene', (53, 58))	('JAK2', 'Gene', (163, 167))	('Lys752Thr', 'Mutation', 'p.K752T', (186, 195))	('PD-L1', 'Gene', '29126', (53, 58))	('PD-L1', 'Gene', (212, 217))	('EGFR', 'Gene', '1956', (120, 124))	('JAK2', 'Gene', '3717', (163, 167))	('missense (Lys752Thr', 'Var', (176, 195))	('PD-L1', 'Gene', '29126', (212, 217))	('EGFR', 'Gene', (120, 124))
462130	29740957	We tested gene mutation and PD-L1 expression in this patient, which showed EGFR exon 20 insertion (770-771insGly) and JAK2 exon 17 missense (Lys752Thr) mutations, but negative PD-L1 expression.	('Lys752Thr', 'Mutation', 'p.K752T', (141, 150))	('negative', 'NegReg', (167, 175))	('PD-L1', 'Gene', '29126', (28, 33))	('expression', 'MPA', (182, 192))	('Lys752Thr', 'Var', (141, 150))	('patient', 'Species', '9606', (53, 60))	('JAK2', 'Gene', (118, 122))	('PD-L1', 'Gene', '29126', (176, 181))	('PD-L1', 'Gene', (176, 181))	('EGFR', 'Gene', '1956', (75, 79))	('PD-L1', 'Gene', (28, 33))	('JAK2', 'Gene', '3717', (118, 122))	('EGFR', 'Gene', (75, 79))
462132	29740957	Only three in a study of 158 patients had EGFR mutations, including two cases of L858R mutation and one case of G863D mutation in exon 21.15 Mutations in these two loci have been reported in cases of non-small cell lung cancer (NSCLC) and TKI treatment has been effective.16 EGFR 20 exon insertion mutations can be divided into two subtypes: Ala767 to Cys775, and Glu761 to Met766 mutations.	('Ala767', 'Var', (342, 348))	('NSCLC', 'Disease', 'MESH:D002289', (228, 233))	('EGFR', 'Gene', '1956', (275, 279))	('patients', 'Species', '9606', (29, 37))	('men', 'Species', '9606', (248, 251))	('non-small cell lung cancer', 'Disease', (200, 226))	('Cys775', 'Chemical', '-', (352, 358))	('EGFR', 'Gene', (42, 46))	('NSCLC', 'Disease', (228, 233))	('lung cancer', 'Phenotype', 'HP:0100526', (215, 226))	('L858R', 'Mutation', 'rs121434568', (81, 86))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (200, 226))	('Ala767', 'Chemical', '-', (342, 348))	('EGFR', 'Gene', (275, 279))	('EGFR', 'Gene', '1956', (42, 46))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (204, 226))	('Cys775', 'Var', (352, 358))	('Glu761', 'Var', (364, 370))	('G863D', 'Mutation', 'rs909797662', (112, 117))	('Glu761', 'Chemical', '-', (364, 370))	('Met766 mutations', 'Var', (374, 390))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (200, 226))
462175	25197285	Abnormalities of calcium homeostasis are an uncommon complication of Marjolin's ulcer.	('Abnormalities', 'Var', (0, 13))	('Abnormalities of calcium homeostasis', 'Phenotype', 'HP:0004363', (0, 36))	('ulcer', 'Disease', 'MESH:D014456', (80, 85))	('ulcer', 'Disease', (80, 85))	('calcium', 'Chemical', 'MESH:D002118', (17, 24))
462193	32649944	Whole exome sequencing (WES) identified UV-signature mutations in multiple genes including Notch 1-3 in the epidermis and SCCIS and oncogenic TP53 mutations in SCCIS.	('mutations', 'Var', (147, 156))	('Notch 1-3', 'Gene', '4851;4853;4854', (91, 100))	('TP53', 'Gene', '7157', (142, 146))	('TP53', 'Gene', (142, 146))	('mutations', 'Var', (53, 62))	('Notch 1-3', 'Gene', (91, 100))
462194	32649944	The frequency and distribution of NOTCH and TP53 mutations indicate that NOTCH mutations may precede TP53 mutations.	('NOTCH mutations', 'Var', (73, 88))	('mutations', 'Var', (49, 58))	('TP53', 'Gene', '7157', (101, 105))	('TP53', 'Gene', (101, 105))	('TP53', 'Gene', '7157', (44, 48))	('TP53', 'Gene', (44, 48))
462200	32649944	Targeted deep sequencing of 74 genes from blepharoplasty samples revealed multiple, potentially oncogenic, UV-signature mutations in NOTCH 1 and 2, TP53, FGFR3 and FAT1 in clinically unremarkable skin.	('FGFR3', 'Gene', (154, 159))	('TP53', 'Gene', '7157', (148, 152))	('TP53', 'Gene', (148, 152))	('NOTCH 1 and 2', 'Gene', '4851;4853', (133, 146))	('clinically unremarkable skin', 'Phenotype', 'HP:0000973', (172, 200))	('mutations', 'Var', (120, 129))	('FAT1', 'Gene', '2195', (164, 168))	('FGFR3', 'Gene', '2261', (154, 159))	('FAT1', 'Gene', (164, 168))	('oncogenic', 'Reg', (96, 105))
462201	32649944	This study correlates with data from earlier studies that showed UV-signature mutations in TP53 and NOTCH 1 and 2 genes in AKs and cSCC.	('TP53', 'Gene', (91, 95))	('NOTCH 1 and 2', 'Gene', '4851;4853', (100, 113))	('cSCC', 'Disease', (131, 135))	('mutations', 'Var', (78, 87))	('AKs', 'Disease', (123, 126))	('TP53', 'Gene', '7157', (91, 95))
462202	32649944	Subsequent studies with exomic sequencing of UV-exposed skin, AKs and cSCCs showed mutations in TP53, NOTCH 1-2, FAT1 and MLL2 but not FGFR3 as likely drivers of cSCC formation.	('mutations', 'Var', (83, 92))	('cSCC', 'Disease', (162, 166))	('TP53', 'Gene', (96, 100))	('FAT1', 'Gene', '2195', (113, 117))	('NOTCH 1-2', 'Gene', '4851;4853', (102, 111))	('MLL2', 'Gene', '9757', (122, 126))	('FAT1', 'Gene', (113, 117))	('FGFR3', 'Gene', '2261', (135, 140))	('MLL2', 'Gene', (122, 126))	('FGFR3', 'Gene', (135, 140))	('NOTCH 1-2', 'Gene', (102, 111))	('TP53', 'Gene', '7157', (96, 100))
462203	32649944	Our whole exome sequencing (WES) data show a high frequency of UV-signature mutations in NOTCH 1-3 in both the epidermal and SCCIS samples with more mutations present in the former.	('NOTCH 1-3', 'Gene', (89, 98))	('NOTCH 1-3', 'Gene', '4851;4853;4854', (89, 98))	('mutations', 'Var', (76, 85))	('UV-signature', 'Gene', (63, 75))
462204	32649944	The data show prevalent UV-signature mutations in TP53 in SCCIS (6/10 samples) and none in the epidermis.	('mutations', 'Var', (37, 46))	('TP53', 'Gene', '7157', (50, 54))	('TP53', 'Gene', (50, 54))
462205	32649944	This suggests acquisition of oncogenic TP53 mutation(s) may follow NOTCH 1-3 LOF mutation in promoting SCCIS.	('mutation', 'Var', (44, 52))	('NOTCH 1-3', 'Gene', '4851;4853;4854', (67, 76))	('LOF', 'NegReg', (77, 80))	('mutation', 'Var', (81, 89))	('promoting SCCIS', 'Disease', (93, 108))	('TP53', 'Gene', '7157', (39, 43))	('NOTCH 1-3', 'Gene', (67, 76))	('TP53', 'Gene', (39, 43))
462212	32649944	For the joint variants, protein-coding variants are enriched in SCCIS compared to epidermis in almost all patients (Figure 2a), suggesting these mutations are not negatively selected against in SCCIS.	('SCCIS', 'Disease', (64, 69))	('variants', 'Var', (14, 22))	('patients', 'Species', '9606', (106, 114))	('variants', 'Var', (39, 47))
462214	32649944	With these subclonal variants, we estimated a lesion mutation burden (LMB) similar to the tumor mutation burden (TMB) found in comparable studies (Chalmers et al., 2017; Chan et al., 2019; Zehir et al., 2017).	('variants', 'Var', (21, 29))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('lesion mutation burden', 'MPA', (46, 68))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('TMB', 'Chemical', '-', (113, 116))
462218	32649944	Instead, non-UV induced, non-disruptive variants appeared more frequently in multiple patients, suggesting they are likely germline variants or population polymorphisms.	('non-disruptive', 'NegReg', (25, 39))	('variants', 'Var', (40, 48))	('patients', 'Species', '9606', (86, 94))
462222	32649944	Interestingly, the estimated dN/dS ratios were lower in the paired SCCIS samples except for one patient, suggesting the positive effect of these variants were less profound once SCCIS formed (Supplementary Table S7).	('lower', 'NegReg', (47, 52))	('estimated dN/dS ratios', 'MPA', (19, 41))	('dS', 'Chemical', 'MESH:D003903', (32, 34))	('dN', 'Chemical', 'MESH:C022306', (29, 31))	('patient', 'Species', '9606', (96, 103))	('variants', 'Var', (145, 153))
462224	32649944	The top targets, usually with multiple variants in different family members, include NOTCH1-3, Axonemal dyneins (DNAH1/2/7/12/14), SLFN5/13/14, Ryanodine receptors (RYR1/2/3) and Laminins (LAMC1/2/3) (Figure 3d).	('RYR1/2/3', 'Gene', (165, 173))	('NOTCH1-3', 'Gene', '4851;4853;4854', (85, 93))	('RYR1/2/3', 'Gene', '6261;6262;6263', (165, 173))	('DNAH1/2/7/12/14', 'Gene', (113, 128))	('DNAH1/2/7/12/14', 'Gene', '201625;25981;146754', (113, 128))	('variants', 'Var', (39, 47))	('Axonemal dyneins', 'Protein', (95, 111))	('LAMC1/2/3', 'Gene', '3915;3918;10319', (189, 198))	('Ryanodine receptors', 'Protein', (144, 163))	('SLFN5/13/14', 'Gene', '162394;146857;342618', (131, 142))	('NOTCH1-3', 'Gene', (85, 93))	('LAMC1/2/3', 'Gene', (189, 198))	('SLFN5/13/14', 'Gene', (131, 142))
462225	32649944	Almost all (19/20) NOTCH1-3 mutations were located in the extracellular or transmembrane domains, consistent with a LOF mutation (Supplementary Figure S2).	('NOTCH1-3', 'Gene', '4851;4853;4854', (19, 27))	('mutations', 'Var', (28, 37))	('NOTCH1-3', 'Gene', (19, 27))
462227	32649944	The bias for SCCIS TP53 mutations suggests this mutation may be key for lesion development.	('mutations', 'Var', (24, 33))	('TP53', 'Gene', '7157', (19, 23))	('TP53', 'Gene', (19, 23))
462230	32649944	Additionally, only 4.3%, 32%, 44% and 29% of those subclonal variants have decreased MAF for the Dyneins, Schlafen, Laminin and NUP gene families/super-families, respectively.	('Laminin', 'Protein', (116, 123))	('NUP', 'Gene', '729857', (128, 131))	('NUP', 'Gene', (128, 131))	('Dyneins', 'Protein', (97, 104))	('MAF', 'MPA', (85, 88))	('Schlafen', 'Gene', (106, 114))	('variants', 'Var', (61, 69))	('decreased', 'NegReg', (75, 84))
462231	32649944	These results suggest that human SCCIS development selects keratinocytes harboring UVD mutations impacting gene families that regulate cancer development.	('cancer', 'Disease', (135, 141))	('gene', 'Protein', (107, 111))	('cancer', 'Disease', 'MESH:D009369', (135, 141))	('UVD', 'Gene', (83, 86))	('human', 'Species', '9606', (27, 32))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('impacting', 'Reg', (97, 106))	('mutations', 'Var', (87, 96))
462233	32649944	We speculate this is because short-term transcriptomic changes caused by prior genomic mutations may have been compensated for by cumulative cellular events that occurred in the years between the genomic mutations and the procurement of the patient samples for RNA-seq experiments.	('mutations', 'Var', (204, 213))	('mutations', 'Var', (87, 96))	('patient', 'Species', '9606', (241, 248))
462236	32649944	Transcription factors containing subclonal UVD variants are predicted to regulate more gene targets (6.34 targets) than the average of 3.53 targets for human transcription factors.	('human', 'Species', '9606', (152, 157))	('gene targets', 'MPA', (87, 99))	('variants', 'Var', (47, 55))
462237	32649944	Genes with subclonal UVD variants included proto-oncogenes and DNA damage repair genes, such as FLI1, MYC, ERCC2 and GLI1, which have significant numbers of known transcriptional targets (Figure 4d).	('variants', 'Var', (25, 33))	('FLI1', 'Gene', (96, 100))	('GLI1', 'Gene', '2735', (117, 121))	('FLI1', 'Gene', '2313', (96, 100))	('GLI1', 'Gene', (117, 121))	('ERCC2', 'Gene', (107, 112))	('MYC', 'Gene', '4609', (102, 105))	('ERCC2', 'Gene', '2068', (107, 112))	('MYC', 'Gene', (102, 105))
462245	32649944	Gene families with low frequency UV-signature mutations in the epidermis and positive selection of analogous mutations in SCCIS included NOTCH, Dyneins, SLFN (Schlafen genes), Laminins and NUP (Figure 3d).	('SCCIS', 'Gene', (122, 127))	('SLFN', 'Gene', (153, 157))	('mutations', 'Var', (46, 55))	('NUP', 'Gene', (189, 192))	('NUP', 'Gene', '729857', (189, 192))	('Dyneins', 'Protein', (144, 151))	('mutations', 'Var', (109, 118))	('NOTCH', 'Protein', (137, 142))
462246	32649944	The WES data indicate that acquisition of an oncogenic TP53 mutation promotes SCCIS formation as these mutations were present in 60% of SCCIS (Supplementary Tables S1 and 2).	('mutation', 'Var', (60, 68))	('TP53', 'Gene', '7157', (55, 59))	('TP53', 'Gene', (55, 59))	('SCCIS', 'Disease', (78, 83))	('promotes', 'PosReg', (69, 77))	('S1 and 2', 'Gene', '5707;6187', (164, 172))
462247	32649944	All TP53 mutations found in SCCIS have been identified in other tumors including esophageal SCCs (Cosmic database v89).	('tumors', 'Disease', (64, 70))	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('TP53', 'Gene', (4, 8))	('mutations', 'Var', (9, 18))	('esophageal SCCs', 'Disease', (81, 96))	('identified', 'Reg', (44, 54))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('TP53', 'Gene', '7157', (4, 8))
462249	32649944	Nevertheless, our data suggest such mutations are rare in epidermis verified to have no dysplasia.	('dysplasia', 'Disease', (88, 97))	('mutations', 'Var', (36, 45))	('dysplasia', 'Disease', 'MESH:C536170', (88, 97))
462250	32649944	The distribution of NOTCH and TP53 mutations in our epidermal and SCCIS libraries indicates the transition from an epidermal Notch-deficient keratinocyte clone to SCCIS may be driven by a TP53 mutation (Figures 5d and e).	('TP53', 'Gene', (30, 34))	('TP53', 'Gene', '7157', (30, 34))	('mutation', 'Var', (193, 201))	('TP53', 'Gene', '7157', (188, 192))	('TP53', 'Gene', (188, 192))	('mutations', 'Var', (35, 44))
462251	32649944	This suggests that activating RAS mutations are rare-to-absent in the early stages of human UV-induced skin cancer.	('skin cancer', 'Disease', 'MESH:D012878', (103, 114))	('activating', 'PosReg', (19, 29))	('human', 'Species', '9606', (86, 91))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('skin cancer', 'Phenotype', 'HP:0008069', (103, 114))	('RAS', 'Gene', (30, 33))	('skin cancer', 'Disease', (103, 114))	('mutations', 'Var', (34, 43))
462252	32649944	This differs from the murine DMBA/TPA model of skin cancer where precancerous papillomas harbor activating HRAS mutations.	('precancerous papillomas', 'Phenotype', 'HP:0031287', (65, 88))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('papillomas', 'Phenotype', 'HP:0012740', (78, 88))	('skin cancer', 'Disease', (47, 58))	('HRAS', 'Gene', '15461', (107, 111))	('murine', 'Species', '10090', (22, 28))	('precancerous papillomas', 'Disease', (65, 88))	('TPA', 'Chemical', '-', (34, 37))	('activating', 'PosReg', (96, 106))	('skin cancer', 'Disease', 'MESH:D012878', (47, 58))	('mutations', 'Var', (112, 121))	('HRAS', 'Gene', (107, 111))	('precancerous papillomas', 'Disease', 'MESH:D010212', (65, 88))	('DMBA', 'Chemical', 'MESH:C082386', (29, 33))	('skin cancer', 'Phenotype', 'HP:0008069', (47, 58))
462254	32649944	This is of interest as Schlafen 5 knockdown activates Akt and B-catenin signaling; pathways known to be activated in human SCCIS.	('Akt', 'Gene', '207', (54, 57))	('human', 'Species', '9606', (117, 122))	('Akt', 'Gene', (54, 57))	('Schlafen 5', 'Gene', (23, 33))	('activates', 'PosReg', (44, 53))	('B-catenin', 'Gene', (62, 71))	('B-catenin', 'Gene', '1499', (62, 71))	('knockdown', 'Var', (34, 43))
462268	32649944	These studies showed a high prevalence of UV-signature mutations in NOTCH 1-2, TP53, FAT1 and MLL2 in cSCC.	('NOTCH 1-2', 'Gene', (68, 77))	('NOTCH 1-2', 'Gene', '4851;4853', (68, 77))	('MLL2', 'Gene', (94, 98))	('TP53', 'Gene', '7157', (79, 83))	('TP53', 'Gene', (79, 83))	('mutations', 'Var', (55, 64))	('FAT1', 'Gene', (85, 89))	('FAT1', 'Gene', '2195', (85, 89))	('cSCC', 'Disease', (102, 106))	('MLL2', 'Gene', '9757', (94, 98))
462269	32649944	However, our data show a strong prevalence for oncogenic TP53 mutations in the SCCIS compared to adjacent UV-exposed epidermis, perhaps due to the precision of LCM.	('TP53', 'Gene', '7157', (57, 61))	('TP53', 'Gene', (57, 61))	('oncogenic', 'Reg', (47, 56))	('mutations', 'Var', (62, 71))
462270	32649944	The data support a model where clinically unremarkable Notch-deficient clones acquire oncogenic p53 mutations and/or upregulate NEURL1 to form SCCIS (Figures 5d and e).	('mutations', 'Var', (100, 109))	('NEURL1', 'Gene', '9148', (128, 134))	('p53', 'Gene', (96, 99))	('p53', 'Gene', '7157', (96, 99))	('upregulate', 'PosReg', (117, 127))	('NEURL1', 'Gene', (128, 134))
462271	32649944	Thus, dysregulation of the p53/Notch1,2,3/p21 pathway at multiple levels may be favorable for SCCIS formation.	('p53', 'Gene', '7157', (27, 30))	('Notch1', 'Gene', (31, 37))	('SCCIS formation', 'Disease', (94, 109))	('p21', 'Gene', (42, 45))	('Notch1', 'Gene', '4851', (31, 37))	('dysregulation', 'Var', (6, 19))	('p21', 'Gene', '644914', (42, 45))	('p53', 'Gene', (27, 30))
462375	32323844	In the present study, polyploid CTCs were associated with distant metastases, indicating that highly proliferating tumor cells may be more likely to metastasize.	('metastases', 'Disease', (66, 76))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('metastases', 'Disease', 'MESH:D009362', (66, 76))	('associated', 'Reg', (42, 52))	('CTCs', 'Gene', (32, 36))	('tumor', 'Disease', (115, 120))	('polyploid', 'Var', (22, 31))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
462377	32323844	The 3-year PFS of patients with positive CTCs post-treatment was significantly lower than that of patients with negative CTCs post-treatment.	('positive CTCs', 'Var', (32, 45))	('lower', 'NegReg', (79, 84))	('patients', 'Species', '9606', (98, 106))	('PFS', 'CPA', (11, 14))	('patients', 'Species', '9606', (18, 26))
462382	32323844	For patients with hypopharyngeal carcinoma, CTC counts >=3/3.2 ml before and after treatment were associated with a significantly reduced PFS and OS compared with patients with CTC counts <3/3.2 ml (P<0.05).	('>=3/3.2', 'Var', (55, 62))	('patients', 'Species', '9606', (163, 171))	('PFS', 'Disease', (138, 141))	('CTC counts', 'MPA', (44, 54))	('hypopharyngeal carcinoma', 'Disease', 'MESH:D007012', (18, 42))	('carcinoma', 'Phenotype', 'HP:0030731', (33, 42))	('hypopharyngeal carcinoma', 'Phenotype', 'HP:0012182', (18, 42))	('reduced', 'NegReg', (130, 137))	('hypopharyngeal carcinoma', 'Disease', (18, 42))	('patients', 'Species', '9606', (4, 12))
462390	32323844	vi) Polyploid CTCs were revealed to be associated with distant metastases, indicating that highly proliferating tumor cells are more likely to metastasize.	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('metastases', 'Disease', 'MESH:D009362', (63, 73))	('Polyploid', 'Var', (4, 13))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('associated', 'Reg', (39, 49))	('metastasize', 'CPA', (143, 154))	('tumor', 'Disease', (112, 117))	('metastases', 'Disease', (63, 73))
462447	28355175	The YD-38 cells were treated with 20, 40, 60, 80, and 100 mug/ml beta-elemene for 48 h. The results showed that beta-elemene inhibited the viability of YD-38 cells in a dose-dependent manner (Figure 1).	('beta-elemene', 'Var', (112, 124))	('viability', 'CPA', (139, 148))	('beta-elemene', 'Chemical', 'MESH:C445979', (112, 124))	('YD-38', 'Chemical', '-', (4, 9))	('inhibited', 'NegReg', (125, 134))	('beta-elemene', 'Chemical', 'MESH:C445979', (65, 77))	('YD-38', 'Chemical', '-', (152, 157))
462454	28355175	YD-38 cells were treated with cisplatin (1 to 64 muM) and beta-elemene (40 mug/ml) for 48 h. The results showed that cisplatin induced a significant apoptosis compared to the control group, and a significant increasing apoptosis rate induced by cisplatin was observed when combined with beta-elemene (Figure 4).	('muM', 'Gene', '56925', (49, 52))	('cisplatin', 'Chemical', 'MESH:D002945', (117, 126))	('beta-elemene', 'Chemical', 'MESH:C445979', (287, 299))	('cisplatin', 'Chemical', 'MESH:D002945', (245, 254))	('muM', 'Gene', (49, 52))	('beta-elemene', 'Chemical', 'MESH:C445979', (58, 70))	('YD-38', 'Chemical', '-', (0, 5))	('cisplatin', 'Chemical', 'MESH:D002945', (30, 39))	('cisplatin', 'Var', (117, 126))
462480	28355175	The apoptosis pathway can be triggered through the cleavage of caspase-3.	('apoptosis pathway', 'Pathway', (4, 21))	('caspase-3', 'Gene', (63, 72))	('caspase-3', 'Gene', '836', (63, 72))	('cleavage', 'Var', (51, 59))
462483	28355175	Therefore, inhibition of STAT3 activation has potential in cancer treatment.	('STAT3', 'Gene', (25, 30))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('inhibition', 'Var', (11, 21))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('STAT3', 'Gene', '6774', (25, 30))
462489	28355175	These results suggest that inactivation of STAT3 might be a critical mechanism by which beta-elemene suppresses cell proliferation and induces apoptosis in GSCC.	('cell proliferation', 'CPA', (112, 130))	('inactivation', 'Var', (27, 39))	('suppresses', 'NegReg', (101, 111))	('beta-elemene', 'Chemical', 'MESH:C445979', (88, 100))	('GSCC', 'Chemical', '-', (156, 160))	('STAT3', 'Gene', '6774', (43, 48))	('apoptosis', 'CPA', (143, 152))	('STAT3', 'Gene', (43, 48))	('induces', 'Reg', (135, 142))
462496	30834050	We retrospectively collected 175 wild-type EGFR adenocarcinomas, 131 NSCLCs harboring mutant EGFR and 110 squamous cell carcinomas.	('EGFR', 'Gene', '1956', (93, 97))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (106, 130))	('mutant', 'Var', (86, 92))	('squamous cell carcinomas', 'Disease', (106, 130))	('NSCLC', 'Disease', (69, 74))	('adenocarcinomas', 'Disease', 'MESH:D000230', (48, 63))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (106, 129))	('EGFR', 'Gene', (93, 97))	('NSCLC', 'Disease', 'MESH:D002289', (69, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('EGFR', 'Gene', '1956', (43, 47))	('carcinomas', 'Phenotype', 'HP:0030731', (53, 63))	('adenocarcinomas', 'Disease', (48, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (53, 62))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (106, 130))	('carcinomas', 'Phenotype', 'HP:0030731', (120, 130))	('EGFR', 'Gene', (43, 47))
462501	30834050	The good LIPI group survived longer than the intermediate and poor LIPI groups in wild-type EGFR adenocarcinoma (good, intermediate and poor LIPI groups: median 19.6, 11.5 and 3.3 months, P < 0.01, respectively) and mutant EGFR NSCLC (45.4, 25.6 and 15.7 months, P < 0.01).	('LIPI', 'Chemical', '-', (9, 13))	('adenocarcinoma', 'Disease', 'MESH:D000230', (97, 111))	('EGFR', 'Gene', '1956', (223, 227))	('mutant', 'Var', (216, 222))	('LIPI', 'Chemical', '-', (67, 71))	('EGFR', 'Gene', (223, 227))	('EGFR', 'Gene', (92, 96))	('NSCLC', 'Disease', (228, 233))	('EGFR', 'Gene', '1956', (92, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('adenocarcinoma', 'Disease', (97, 111))	('NSCLC', 'Disease', 'MESH:D002289', (228, 233))	('LIPI', 'Chemical', '-', (141, 145))
462502	30834050	The PFS of good LIPI group was significantly longer that those of the other two groups in mutant EGFR NSCLC (16.6, 12.6 and 8.3 months, P < 0.01).	('NSCLC', 'Disease', 'MESH:D002289', (102, 107))	('EGFR', 'Gene', '1956', (97, 101))	('mutant', 'Var', (90, 96))	('LIPI', 'Chemical', '-', (16, 20))	('EGFR', 'Gene', (97, 101))	('NSCLC', 'Disease', (102, 107))
462503	30834050	The intermediate group (hazard ratio (HR) 1.49, 95% confidential interval (CI) 1.03 - 2.15, P = 0.04) of wild-type EGFR adenocarcinoma, intermediate (HR 2.30, 95% CI 1.33 - 3.99, P < 0.01) and poor (HR 2.76, 95% CI 1.03 - 7.42, P = 0.04) groups of mutant EGFR NSCLC were independent prognostic factors of poor OS.	('adenocarcinoma', 'Disease', (120, 134))	('EGFR', 'Gene', '1956', (255, 259))	('EGFR', 'Gene', (255, 259))	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('OS', 'Chemical', '-', (310, 312))	('mutant', 'Var', (248, 254))	('EGFR', 'Gene', '1956', (115, 119))	('adenocarcinoma', 'Disease', 'MESH:D000230', (120, 134))	('poor OS', 'Disease', (305, 312))	('EGFR', 'Gene', (115, 119))	('NSCLC', 'Disease', (260, 265))	('NSCLC', 'Disease', 'MESH:D002289', (260, 265))
462504	30834050	The intermediate (HR 1.57, 95% CI 1.01 - 2.44, P = 0.04) and poor (HR 2.63, 95% CI 1.14 - 6.07, P = 0.02) groups were significant prognostic factors of PFS of mutant EGFR NSCLC.	('mutant', 'Var', (159, 165))	('EGFR', 'Gene', '1956', (166, 170))	('EGFR', 'Gene', (166, 170))	('NSCLC', 'Disease', (171, 176))	('NSCLC', 'Disease', 'MESH:D002289', (171, 176))
462505	30834050	LIPI was an independent prognostic factor of chemotherapy for adenocarcinoma with wild-type EGFR and of EGFR-TKI for NSCLC harboring mutant EGFR.	('NSCLC', 'Disease', (117, 122))	('EGFR', 'Gene', '1956', (104, 108))	('EGFR', 'Gene', (104, 108))	('EGFR', 'Gene', (140, 144))	('adenocarcinoma', 'Disease', 'MESH:D000230', (62, 76))	('adenocarcinoma', 'Disease', (62, 76))	('NSCLC', 'Disease', 'MESH:D002289', (117, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('LIPI', 'Chemical', '-', (0, 4))	('EGFR', 'Gene', '1956', (92, 96))	('EGFR', 'Gene', (92, 96))	('mutant', 'Var', (133, 139))	('EGFR', 'Gene', '1956', (140, 144))
462507	30834050	Non-small cell lung cancer (NSCLC) has been classified into several subsets according to histological and genetic characteristics in the past decade: squamous cell carcinoma and non-squamous NSCLC with or without driver mutations such as epidermal growth factor receptor (EGFR) mutation and anaplastic lymphoma kinase (ALK) rearrangement.	('anaplastic lymphoma kinase', 'Gene', (291, 317))	('Non-small cell lung cancer', 'Disease', 'MESH:D002289', (0, 26))	('NSCLC', 'Disease', (191, 196))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (150, 173))	('non-squamous NSCLC', 'Disease', 'MESH:D002294', (178, 196))	('EGFR', 'Gene', (272, 276))	('NSCLC', 'Disease', 'MESH:D002289', (28, 33))	('Non-small cell lung cancer', 'Disease', (0, 26))	('ALK', 'Gene', '238', (319, 322))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (150, 173))	('lymphoma', 'Phenotype', 'HP:0002665', (302, 310))	('NSCLC', 'Disease', (28, 33))	('ALK', 'Gene', (319, 322))	('Non-small cell lung cancer', 'Phenotype', 'HP:0030358', (0, 26))	('carcinoma', 'Phenotype', 'HP:0030731', (164, 173))	('mutation', 'Var', (278, 286))	('squamous cell carcinoma', 'Disease', (150, 173))	('lung cancer', 'Phenotype', 'HP:0100526', (15, 26))	('EGFR', 'Gene', '1956', (272, 276))	('non-squamous NSCLC', 'Disease', (178, 196))	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (291, 310))	('epidermal growth factor receptor', 'Gene', (238, 270))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (4, 26))	('NSCLC', 'Disease', 'MESH:D002289', (191, 196))	('epidermal growth factor receptor', 'Gene', '1956', (238, 270))	('anaplastic lymphoma kinase', 'Gene', '238', (291, 317))
462509	30834050	For patients with NSCLC harboring a driver mutation, a specific tyrosine kinase inhibitor (TKI) is recommended as the first-line regimen.	('mutation', 'Var', (43, 51))	('patients', 'Species', '9606', (4, 12))	('NSCLC', 'Disease', (18, 23))	('NSCLC', 'Disease', 'MESH:D002289', (18, 23))
462514	30834050	For patients with advanced NSCLC, poor baseline LIPI was correlated with poor outcomes of overall survival (OS), progression-free survival (PFS) and disease control rate (DCR) for ICIs therapy of PD-1/PD-L1 inhibitors, but not for chemotherapy.	('PD-L1', 'Gene', (201, 206))	('NSCLC', 'Disease', (27, 32))	('disease', 'Disease', (149, 156))	('OS', 'Chemical', '-', (108, 110))	('NSCLC', 'Disease', 'MESH:D002289', (27, 32))	('ICI', 'Chemical', '-', (180, 183))	('poor', 'Var', (34, 38))	('PD-L1', 'Gene', '29126', (201, 206))	('patients', 'Species', '9606', (4, 12))	('LIPI', 'Chemical', '-', (48, 52))
462521	30834050	We retrospectively collected three cohorts according to histological and genetic backgrounds: 1) Adenocarcinoma without active EGFR mutations; 2) NSCLC harboring active EGFR mutation, and 3) Squamous cell carcinoma.	('Squamous cell carcinoma', 'Disease', (191, 214))	('mutation', 'Var', (174, 182))	('NSCLC', 'Disease', (146, 151))	('EGFR', 'Gene', '1956', (169, 173))	('carcinoma', 'Phenotype', 'HP:0030731', (205, 214))	('Squamous cell carcinoma', 'Disease', 'MESH:D002294', (191, 214))	('NSCLC', 'Disease', 'MESH:D002289', (146, 151))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('EGFR', 'Gene', (169, 173))	('Adenocarcinoma', 'Disease', 'MESH:D000230', (97, 111))	('Adenocarcinoma', 'Disease', (97, 111))	('EGFR', 'Gene', '1956', (127, 131))	('EGFR', 'Gene', (127, 131))	('Squamous cell carcinoma', 'Phenotype', 'HP:0002860', (191, 214))
462522	30834050	The patients met all the following criteria: 1) Between July 2007 and August 2017 at our hospital, first-line cytotoxic chemotherapy or EGFR-TKI monotherapy, irrespective of chemotherapeutic lines, being initiated for patients with wild-type EGFR adenocarcinoma and squamous cell carcinoma or for patients with mutant EGFR NSCLC, respectively; 2) Histologically or cytologically diagnosed with NSCLC; 3) For non-squamous NSCLC, the peptide nucleic acid-locked nucleic acid PCR clamp method or EGFR gene mutation analysis COBAS version 2 by LSI Medience Cooperation (Tokyo, Japan) confirmed wild-type or positive EGFR mutation status; 4) For adenocarcinoma with wild-type EGFR status, immunohistochemically negative or unknown anaplastic lymphoma kinase (ALK) rearrangement; 5) c-stage IIIB or IV based on the seventh tumor, node, metastasis (TNM) classification of lung cancer by the Union for International Cancer Control (UICC), or recurrence after curative-intent thoracic surgery or radiotherapy without adjuvant chemotherapy, and only for NSCLC with active EGFR mutation, c-stage IIIA was included when neither curative operation nor radiotherapy was intended; and 6) Available blood sample within 2 weeks prior to the first day of the first-line cytotoxic chemotherapy or EGFR-TKI monotherapy.	('EGFR', 'Gene', '1956', (1278, 1282))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (726, 745))	('tumor', 'Disease', 'MESH:D009369', (817, 822))	('Cancer', 'Phenotype', 'HP:0002664', (908, 914))	('lung cancer', 'Disease', (865, 876))	('EGFR', 'Gene', '1956', (1062, 1066))	('mutation', 'Var', (1067, 1075))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (266, 289))	('cancer', 'Phenotype', 'HP:0002664', (870, 876))	('NSCLC', 'Disease', 'MESH:D002289', (323, 328))	('squamous cell carcinoma', 'Disease', (266, 289))	('adenocarcinoma', 'Disease', 'MESH:D000230', (247, 261))	('EGFR', 'Gene', (242, 246))	('NSCLC', 'Disease', (421, 426))	('non-squamous NSCLC', 'Disease', 'MESH:D002294', (408, 426))	('anaplastic lymphoma kinase', 'Gene', '238', (726, 752))	('tumor', 'Phenotype', 'HP:0002664', (817, 822))	('adenocarcinoma', 'Disease', (641, 655))	('NSCLC', 'Disease', 'MESH:D002289', (1044, 1049))	('NSCLC', 'Disease', 'MESH:D002289', (394, 399))	('anaplastic lymphoma kinase', 'Gene', (726, 752))	('NSCLC', 'Disease', (323, 328))	('EGFR', 'Gene', '1956', (671, 675))	('EGFR', 'Gene', (612, 616))	('patients', 'Species', '9606', (4, 12))	('EGFR', 'Gene', (493, 497))	('EGFR', 'Gene', (318, 322))	('NSCLC', 'Disease', (1044, 1049))	('lung cancer', 'Disease', 'MESH:D008175', (865, 876))	('EGFR', 'Gene', (136, 140))	('NSCLC', 'Disease', (394, 399))	('EGFR', 'Gene', (1278, 1282))	('adenocarcinoma', 'Disease', 'MESH:D000230', (641, 655))	('patients', 'Species', '9606', (218, 226))	('patients', 'Species', '9606', (297, 305))	('lung cancer', 'Phenotype', 'HP:0100526', (865, 876))	('carcinoma', 'Phenotype', 'HP:0030731', (252, 261))	('EGFR', 'Gene', '1956', (242, 246))	('lymphoma', 'Phenotype', 'HP:0002665', (737, 745))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (266, 289))	('EGFR', 'Gene', (1062, 1066))	('ALK', 'Gene', '238', (754, 757))	('carcinoma', 'Phenotype', 'HP:0030731', (646, 655))	('non-squamous NSCLC', 'Disease', (408, 426))	('tumor', 'Disease', (817, 822))	('carcinoma', 'Phenotype', 'HP:0030731', (280, 289))	('ALK', 'Gene', (754, 757))	('adenocarcinoma', 'Disease', (247, 261))	('EGFR', 'Gene', '1956', (612, 616))	('EGFR', 'Gene', '1956', (318, 322))	('EGFR', 'Gene', '1956', (493, 497))	('EGFR', 'Gene', (671, 675))	('EGFR', 'Gene', '1956', (136, 140))	('NSCLC', 'Disease', 'MESH:D002289', (421, 426))
462524	30834050	We collected clinical data from the electrical medical records, including age, sex, histology, EGFR mutation status, ALK rearrangement status, PD-L1 tumor proportion score, pretreatment laboratory data, chemotherapeutic regimens, its efficacy and survival.	('ALK', 'Gene', '238', (117, 120))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('mutation', 'Var', (100, 108))	('EGFR', 'Gene', '1956', (95, 99))	('ALK', 'Gene', (117, 120))	('PD-L1 tumor', 'Disease', (143, 154))	('PD-L1 tumor', 'Disease', 'MESH:D010300', (143, 154))	('EGFR', 'Gene', (95, 99))
462529	30834050	We collected 175 patients with wild-type EGFR adenocarcinoma, 131 patients with NSCLC harboring active EGFR mutation and 110 patients with squamous cell carcinoma.	('EGFR', 'Gene', '1956', (103, 107))	('EGFR', 'Gene', (41, 45))	('adenocarcinoma', 'Disease', (46, 60))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (139, 162))	('adenocarcinoma', 'Disease', 'MESH:D000230', (46, 60))	('carcinoma', 'Phenotype', 'HP:0030731', (153, 162))	('squamous cell carcinoma', 'Disease', (139, 162))	('EGFR', 'Gene', (103, 107))	('NSCLC', 'Disease', (80, 85))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (139, 162))	('NSCLC', 'Disease', 'MESH:D002289', (80, 85))	('patients', 'Species', '9606', (17, 25))	('mutation', 'Var', (108, 116))	('EGFR', 'Gene', '1956', (41, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (51, 60))	('patients', 'Species', '9606', (66, 74))	('patients', 'Species', '9606', (125, 133))
462532	30834050	In wild-type EGFR adenocarcinoma (good, intermediate and poor LIPI groups: median 19.6, 11.5 and 3.3 months, P < 0.01, respectively) and EGFR mutant NSCLC (45.4, 25.6 and 15.7 months, P < 0.01), the good LIPI group survived longer than the intermediate and poor LIPI groups (Fig.	('EGFR', 'Gene', (137, 141))	('adenocarcinoma', 'Disease', 'MESH:D000230', (18, 32))	('LIPI', 'Chemical', '-', (204, 208))	('LIPI', 'Chemical', '-', (262, 266))	('survived', 'CPA', (215, 223))	('NSCLC', 'Disease', (149, 154))	('carcinoma', 'Phenotype', 'HP:0030731', (23, 32))	('mutant', 'Var', (142, 148))	('adenocarcinoma', 'Disease', (18, 32))	('EGFR', 'Gene', '1956', (137, 141))	('LIPI', 'Chemical', '-', (62, 66))	('NSCLC', 'Disease', 'MESH:D002289', (149, 154))	('EGFR', 'Gene', '1956', (13, 17))	('EGFR', 'Gene', (13, 17))
462534	30834050	In EGFR mutant NSCLC, the PFS of good LIPI group was significantly longer than those of the other two groups (16.6, 12.6 and 8.3 months, P < 0.01) (Fig.	('EGFR', 'Gene', '1956', (3, 7))	('EGFR', 'Gene', (3, 7))	('mutant', 'Var', (8, 14))	('NSCLC', 'Disease', (15, 20))	('LIPI', 'Chemical', '-', (38, 42))	('NSCLC', 'Disease', 'MESH:D002289', (15, 20))	('longer', 'PosReg', (67, 73))
462536	30834050	As poorer prognostic factors of OS, multivariate Cox proportional hazard analyses found intermediate group (HR 1.49, 95% CI 1.03 - 2.15, P = 0.04) of wild-type EGFR adenocarcinoma, and intermediate (HR 2.30, 95% CI 1.33 - 3.99, P < 0.01) and poor (HR 2.76, 95% CI 1.03 - 7.42, P = 0.04) LIPI groups of EGFR mutant NSCLC (Table 5).	('carcinoma', 'Phenotype', 'HP:0030731', (170, 179))	('LIPI', 'Chemical', '-', (287, 291))	('EGFR', 'Gene', '1956', (302, 306))	('EGFR', 'Gene', '1956', (160, 164))	('adenocarcinoma', 'Disease', (165, 179))	('NSCLC', 'Disease', (314, 319))	('EGFR', 'Gene', (302, 306))	('mutant', 'Var', (307, 313))	('HR 1.49', 'Disease', 'OMIM:617237', (108, 115))	('OS', 'Chemical', '-', (32, 34))	('NSCLC', 'Disease', 'MESH:D002289', (314, 319))	('HR 1.49', 'Disease', (108, 115))	('EGFR', 'Gene', (160, 164))	('adenocarcinoma', 'Disease', 'MESH:D000230', (165, 179))
462537	30834050	Multivariate analyses detected intermediate (HR 1.57, 95% CI 1.01 - 2.44, P = 0.04) and poor (HR 2.63, 95% CI 1.14 - 6.07, P = 0.02) LIPI groups as poor prognostic factors of PFS of EGFR mutant NSCLC (Table 6).	('EGFR', 'Gene', '1956', (182, 186))	('EGFR', 'Gene', (182, 186))	('LIPI', 'Chemical', '-', (133, 137))	('NSCLC', 'Disease', (194, 199))	('mutant', 'Var', (187, 193))	('NSCLC', 'Disease', 'MESH:D002289', (194, 199))
462538	30834050	This study demonstrated that pretreatment LIPI is a prognostic marker for adenocarcinoma with wild-type EGFR and for NSCLC with active EGFR mutation, but not for squamous cell carcinoma.	('NSCLC', 'Disease', (117, 122))	('adenocarcinoma', 'Disease', (74, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (176, 185))	('EGFR', 'Gene', (104, 108))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (162, 185))	('squamous cell carcinoma', 'Disease', (162, 185))	('mutation', 'Var', (140, 148))	('EGFR', 'Gene', '1956', (135, 139))	('adenocarcinoma', 'Disease', 'MESH:D000230', (74, 88))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (162, 185))	('NSCLC', 'Disease', 'MESH:D002289', (117, 122))	('EGFR', 'Gene', (135, 139))	('LIPI', 'Chemical', '-', (42, 46))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('EGFR', 'Gene', '1956', (104, 108))
462540	30834050	Our multivariate analyses and comparisons of OS and PFS showed this marker as independent prognostic factors of OS of first-line cytotoxic chemotherapy for adenocarcinoma with wild-type EGFR, and of OS and PFS of EGFR-TKI therapy for NSCLC with active EGFR mutation.	('adenocarcinoma', 'Disease', (156, 170))	('OS', 'Chemical', '-', (199, 201))	('NSCLC', 'Disease', (234, 239))	('OS', 'Chemical', '-', (45, 47))	('adenocarcinoma', 'Disease', 'MESH:D000230', (156, 170))	('EGFR', 'Gene', (213, 217))	('NSCLC', 'Disease', 'MESH:D002289', (234, 239))	('mutation', 'Var', (257, 265))	('EGFR', 'Gene', '1956', (186, 190))	('EGFR', 'Gene', (186, 190))	('carcinoma', 'Phenotype', 'HP:0030731', (161, 170))	('OS', 'Chemical', '-', (112, 114))	('EGFR', 'Gene', '1956', (252, 256))	('EGFR', 'Gene', (252, 256))	('EGFR', 'Gene', '1956', (213, 217))
462542	30834050	In the study by Mezquita, chemotherapy cohort (N = 162) was composed only of patients who had received second or later chemotherapy, and included various subsets of NSCLC: 72% of adenocarcinoma, 14% of squamous cell carcinoma, 23% of positive EGFR mutation or ALK rearrangement.	('ALK', 'Gene', (260, 263))	('squamous cell carcinoma', 'Disease', (202, 225))	('NSCLC', 'Disease', 'MESH:D002289', (165, 170))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (202, 225))	('carcinoma', 'Phenotype', 'HP:0030731', (184, 193))	('adenocarcinoma', 'Disease', (179, 193))	('adenocarcinoma', 'Disease', 'MESH:D000230', (179, 193))	('patients', 'Species', '9606', (77, 85))	('mutation', 'Var', (248, 256))	('carcinoma', 'Phenotype', 'HP:0030731', (216, 225))	('ALK', 'Gene', '238', (260, 263))	('Mezquita', 'Chemical', '-', (16, 24))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (202, 225))	('EGFR', 'Gene', '1956', (243, 247))	('EGFR', 'Gene', (243, 247))	('NSCLC', 'Disease', (165, 170))
462548	30834050	On the other hand, NLR was significantly useful for NSCLC harboring mutant EGFR, though mGPS was not investigated in our previous study.	('NSCLC', 'Disease', (52, 57))	('NSCLC', 'Disease', 'MESH:D002289', (52, 57))	('EGFR', 'Gene', '1956', (75, 79))	('EGFR', 'Gene', (75, 79))	('mutant', 'Var', (68, 74))
462566	26302210	Recent studies suggested that PTS inhibits tumor progression by induction of tumor necrosis.	('PTS', 'Var', (30, 33))	('tumor necrosis', 'Disease', (77, 91))	('inhibits', 'NegReg', (34, 42))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumor necrosis', 'Disease', 'MESH:D009336', (77, 91))	('PTS', 'Chemical', 'MESH:C025417', (30, 33))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Disease', (43, 48))	('tumor', 'Disease', (77, 82))
462569	26302210	Disturbance of lysosomal stability induces cancer cell death.	('cancer cell death', 'Disease', 'MESH:D003643', (43, 60))	('lysosomal stability', 'CPA', (15, 34))	('induces', 'Reg', (35, 42))	('Disturbance', 'Var', (0, 11))	('cancer cell death', 'Disease', (43, 60))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))
462642	26302210	Using the UMBG assay for beta-galactosidase activity, PTS was shown to significantly increase free enzyme activity in a dose-dependent manner, which suggests that PTS induces lysosomal membrane permeabilization (LMP) and lysosomal damage (Fig.	('PTS', 'Chemical', 'MESH:C025417', (163, 166))	('lysosomal damage', 'Disease', (221, 237))	('lysosomal membrane permeabilization', 'CPA', (175, 210))	('LMP', 'Chemical', '-', (212, 215))	('free', 'MPA', (94, 98))	('PTS', 'Chemical', 'MESH:C025417', (54, 57))	('lysosomal damage', 'Disease', 'MESH:D020140', (221, 237))	('PTS', 'Var', (163, 166))	('increase', 'PosReg', (85, 93))
462651	26302210	These results suggest that PTS induces mitochondrial damage and exerts a metabolic arrest effect on cancer cells.	('arrest', 'Disease', 'MESH:D006323', (83, 89))	('arrest', 'Disease', (83, 89))	('induces', 'Reg', (31, 38))	('mitochondrial damage', 'CPA', (39, 59))	('PTS', 'Var', (27, 30))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('PTS', 'Chemical', 'MESH:C025417', (27, 30))
462654	26302210	PTS inhibits tumor progression by simultaneously inducing apoptosis, and necrosis and suppressing invasive ability in Tca-8113 cells.	('tumor', 'Disease', (13, 18))	('inhibits', 'NegReg', (4, 12))	('inducing', 'NegReg', (49, 57))	('Tca-8113', 'Chemical', '-', (118, 126))	('necrosis', 'Disease', (73, 81))	('PTS', 'Chemical', 'MESH:C025417', (0, 3))	('PTS', 'Var', (0, 3))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('suppressing', 'NegReg', (86, 97))	('apoptosis', 'CPA', (58, 67))	('invasive ability', 'CPA', (98, 114))	('necrosis', 'Disease', 'MESH:D009336', (73, 81))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
462655	26302210	Moreover, our results suggest that PTS triggers cell death through disturbing lysosomal stability and inducing mitochondrial dysfunction.	('inducing', 'Reg', (102, 110))	('lysosomal', 'MPA', (78, 87))	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (111, 136))	('mitochondrial dysfunction', 'Disease', 'MESH:D028361', (111, 136))	('disturbing', 'NegReg', (67, 77))	('PTS', 'Var', (35, 38))	('mitochondrial dysfunction', 'Disease', (111, 136))	('PTS', 'Chemical', 'MESH:C025417', (35, 38))
462662	26302210	In addition, PTS is reported to exert a selective killing effect on lung cancer cells compared with normal bronchial epithelium cells, or result in a smaller injury area to normal tissue than does ethanol in a xenograft mouse model.	('lung cancer', 'Disease', (68, 79))	('PTS', 'Var', (13, 16))	('lung cancer', 'Phenotype', 'HP:0100526', (68, 79))	('injury', 'MPA', (158, 164))	('mouse', 'Species', '10090', (220, 225))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('ethanol', 'Chemical', 'MESH:D000431', (197, 204))	('PTS', 'Chemical', 'MESH:C025417', (13, 16))	('lung cancer', 'Disease', 'MESH:D008175', (68, 79))	('smaller', 'NegReg', (150, 157))
462666	26302210	However, disturbed lysosomal stability and increased LMP sensitize cells to the lysosome-mediated cell death pathway.	('disturbed', 'Var', (9, 18))	('lysosomal stability', 'CPA', (19, 38))	('LMP', 'MPA', (53, 56))	('sensitize', 'Reg', (57, 66))	('increased', 'PosReg', (43, 52))	('lysosome-mediated cell death pathway', 'Pathway', (80, 116))	('LMP', 'Chemical', '-', (53, 56))
462673	26302210	A growing number of studies suggest that LMP could induce mitochondrial dysfunction, associated with the release of apoptogenic factors, such as cytochrome c, from the mitochondria, followed by caspase activation.	('mitochondrial dysfunction', 'Disease', 'MESH:D028361', (58, 83))	('mitochondrial dysfunction', 'Phenotype', 'HP:0003287', (58, 83))	('cytochrome c', 'Gene', (145, 157))	('release', 'MPA', (105, 112))	('LMP', 'Chemical', '-', (41, 44))	('mitochondrial dysfunction', 'Disease', (58, 83))	('induce', 'Reg', (51, 57))	('cytochrome c', 'Gene', '54205', (145, 157))	('apoptogenic factors', 'MPA', (116, 135))	('LMP', 'Var', (41, 44))
462674	26302210	Reactive oxygen species generated after mitochondrial damage feeds back to the lysosomes, leading to further lysosomal breakdown and exacerbation of apoptosis.	('apoptosis', 'CPA', (149, 158))	('exacerbation', 'PosReg', (133, 145))	('lysosomal breakdown', 'CPA', (109, 128))	('damage', 'Var', (54, 60))	('Reactive oxygen species', 'Chemical', 'MESH:D017382', (0, 23))
462678	26302210	These findings suggest that PTS might induce mitochondrial damage and cell death by disturbing lysosomal stability and activating LMP.	('induce', 'Reg', (38, 44))	('lysosomal', 'MPA', (95, 104))	('LMP', 'Chemical', '-', (130, 133))	('LMP', 'MPA', (130, 133))	('disturbing', 'NegReg', (84, 94))	('PTS', 'Chemical', 'MESH:C025417', (28, 31))	('cell death', 'CPA', (70, 80))	('PTS', 'Var', (28, 31))	('mitochondrial damage', 'CPA', (45, 65))	('activating', 'Reg', (119, 129))
462700	26538881	This concept was further explored with respect to reactive oxygen and nitrogen species generated by inflammatory cells, which were suspected to play a pivotal role in causing mutation and leading to cancer formation.	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('mutation', 'Var', (175, 183))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('reactive oxygen and nitrogen species', 'Chemical', '-', (50, 86))	('cancer', 'Disease', (199, 205))	('causing', 'Reg', (167, 174))
462717	31789398	Lentiviruses carrying short hairpin (sh) RNA targeting ITGA7 were used to knockdown its expression in CAL-27 and HSC-4 cells, and then proliferation, apoptosis and stemness were measured.	('ITGA7', 'Gene', '3679', (55, 60))	('apoptosis', 'CPA', (150, 159))	('HSC-4', 'CellLine', 'CVCL:1289', (113, 118))	('knockdown', 'Var', (74, 83))	('stemness', 'CPA', (164, 172))	('measured', 'Reg', (178, 186))	('expression', 'MPA', (88, 98))	('ITGA7', 'Gene', (55, 60))
462721	31789398	In CAL-27 and HSC-4 cells, ITGA7 knockdown inhibited cell proliferation, promoted apoptosis, increased CD24 expression, decreased CD44 and CD133 expression, reduced drug resistance to cisplatin and attenuated sphere formation efficiency.	('drug resistance', 'Phenotype', 'HP:0020174', (165, 180))	('increased', 'PosReg', (93, 102))	('CD44', 'Gene', '960', (130, 134))	('CD44', 'Gene', (130, 134))	('cisplatin', 'Chemical', 'MESH:D002945', (184, 193))	('expression', 'MPA', (145, 155))	('ITGA7', 'Gene', (27, 32))	('decreased', 'NegReg', (120, 129))	('ITGA7', 'Gene', '3679', (27, 32))	('inhibited', 'NegReg', (43, 52))	('drug resistance to cisplatin', 'MPA', (165, 193))	('attenuated', 'NegReg', (198, 208))	('HSC-4', 'CellLine', 'CVCL:1289', (14, 19))	('CD24', 'Gene', '100133941', (103, 107))	('CD24', 'Gene', (103, 107))	('sphere formation efficiency', 'CPA', (209, 236))	('apoptosis', 'CPA', (82, 91))	('knockdown', 'Var', (33, 42))	('cell proliferation', 'CPA', (53, 71))	('reduced', 'NegReg', (157, 164))	('CD133', 'Gene', (139, 144))	('CD133', 'Gene', '8842', (139, 144))	('expression', 'MPA', (108, 118))	('promoted', 'PosReg', (73, 81))
462723	31789398	In conclusion, ITGA7 knockdown inhibited tumor cell proliferation and stemness in TSCC cells.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('ITGA7', 'Gene', (15, 20))	('tumor', 'Disease', (41, 46))	('ITGA7', 'Gene', '3679', (15, 20))	('knockdown', 'Var', (21, 30))	('inhibited', 'NegReg', (31, 40))	('tumor', 'Disease', 'MESH:D009369', (41, 46))
462796	31789398	Differences between the OS of patients with low and high ITGA7 expression were determined via Kaplan-Meier analysis, followed a log-rank test.	('ITGA7', 'Gene', (57, 62))	('patients', 'Species', '9606', (30, 38))	('high', 'Var', (52, 56))	('ITGA7', 'Gene', '3679', (57, 62))
462808	31789398	In addition, high ITGA7 mRNA expression was associated with advanced pathological grade (P=0.003), increased T stage (P=0.002) and higher TNM stage (P=0.010) in patients with TSCC (Table IV).	('ITGA7', 'Gene', '3679', (18, 23))	('T stage', 'CPA', (109, 116))	('high', 'Var', (13, 17))	('advanced', 'PosReg', (60, 68))	('patients', 'Species', '9606', (161, 169))	('ITGA7', 'Gene', (18, 23))	('increased', 'PosReg', (99, 108))	('pathological grade', 'CPA', (69, 87))	('higher', 'PosReg', (131, 137))	('TNM stage', 'CPA', (138, 147))
462809	31789398	Kaplan-Meier analysis revealed that the OS was shorter in patients with high ITGA7 protein expression levels [mean OS: 36.2 months, 95% confidence interval (CI): 31.24-41.1 months] compared with those possessing low ITGA7 protein expression (mean OS: 48.1 months, 95% CI: 44.9-51.3 months; P=0.013; Fig.	('shorter', 'NegReg', (47, 54))	('ITGA7', 'Gene', (77, 82))	('protein', 'Protein', (83, 90))	('ITGA7', 'Gene', (216, 221))	('ITGA7', 'Gene', '3679', (216, 221))	('patients', 'Species', '9606', (58, 66))	('ITGA7', 'Gene', '3679', (77, 82))	('high', 'Var', (72, 76))
462832	31789398	These findings indicated that ITGA7 knockdown inhibited cell proliferation, but promoted apoptosis in CAL-27 and HSC-4 cells.	('promoted', 'PosReg', (80, 88))	('apoptosis', 'CPA', (89, 98))	('ITGA7', 'Gene', (30, 35))	('HSC-4', 'CellLine', 'CVCL:1289', (113, 118))	('knockdown', 'Var', (36, 45))	('cell proliferation', 'CPA', (56, 74))	('ITGA7', 'Gene', '3679', (30, 35))	('inhibited', 'NegReg', (46, 55))
462842	31789398	These results suggested that ITGA7 knockdown regulated the expression of common CSC markers in CAL-27 and HSC-4 cells.	('knockdown', 'Var', (35, 44))	('ITGA7', 'Gene', (29, 34))	('HSC-4', 'CellLine', 'CVCL:1289', (106, 111))	('ITGA7', 'Gene', '3679', (29, 34))	('expression', 'MPA', (59, 69))	('regulated', 'Reg', (45, 54))
462848	31789398	A CCK-8 assay revealed that the relative cell viability decreased in the cisplatin + ITGA7(-) group compared with the cisplatin + NC group for CAL-27 cells (P<0.01; Fig.	('cisplatin', 'Chemical', 'MESH:D002945', (73, 82))	('decreased', 'NegReg', (56, 65))	('cisplatin', 'Chemical', 'MESH:D002945', (118, 127))	('ITGA7', 'Gene', (85, 90))	('CCK-8', 'Chemical', '-', (2, 7))	('cisplatin', 'Var', (73, 82))	('ITGA7', 'Gene', '3679', (85, 90))
462850	31789398	In addition, the rate of apoptosis increased in the cisplatin + ITGA7(-) group compared with the cisplatin + NC group of CAL-27 cells (P<0.01; Fig.	('cisplatin', 'Chemical', 'MESH:D002945', (52, 61))	('cisplatin', 'Var', (52, 61))	('cisplatin', 'Chemical', 'MESH:D002945', (97, 106))	('ITGA7', 'Gene', (64, 69))	('apoptosis', 'CPA', (25, 34))	('ITGA7', 'Gene', '3679', (64, 69))
462852	31789398	These results suggested that ITGA7 knockdown decreased drug resistance to cisplatin in these cell lines.	('knockdown', 'Var', (35, 44))	('ITGA7', 'Gene', (29, 34))	('drug resistance', 'Phenotype', 'HP:0020174', (55, 70))	('decreased', 'NegReg', (45, 54))	('cisplatin', 'Chemical', 'MESH:D002945', (74, 83))	('ITGA7', 'Gene', '3679', (29, 34))	('drug resistance to cisplatin', 'MPA', (55, 83))
462853	31789398	To further validate the effects of ITGA7 knockdown on the sternness of TSCC cells, sphere formation assays were performed in CAL-27 and HSC-4 cells.	('knockdown', 'Var', (41, 50))	('ITGA7', 'Gene', '3679', (35, 40))	('ITGA7', 'Gene', (35, 40))	('HSC-4', 'CellLine', 'CVCL:1289', (136, 141))
462857	31789398	These data indicated that ITGA7 knockdown decreased the sphere formation ability of CAL-27 and HSC-4 cells.	('decreased', 'NegReg', (42, 51))	('sphere formation ability of CAL-27', 'CPA', (56, 90))	('ITGA7', 'Gene', (26, 31))	('knockdown', 'Var', (32, 41))	('HSC-4', 'CellLine', 'CVCL:1289', (95, 100))	('ITGA7', 'Gene', '3679', (26, 31))
462863	31789398	The number of spheres/1,000 cells was increased in the R-CAL-27 (P<0.01; Fig.	('R-CAL-27', 'Var', (55, 63))	('R-CAL', 'Chemical', '-', (55, 60))	('increased', 'PosReg', (38, 47))
462892	31789398	The results revealed that ITGA7 knockdown suppressed proliferation, but promoted apoptosis in CAL-27 and HSC-4 cells.	('ITGA7', 'Gene', (26, 31))	('apoptosis', 'CPA', (81, 90))	('knockdown', 'Var', (32, 41))	('HSC-4', 'CellLine', 'CVCL:1289', (105, 110))	('suppressed', 'NegReg', (42, 52))	('proliferation', 'CPA', (53, 66))	('ITGA7', 'Gene', '3679', (26, 31))	('promoted', 'PosReg', (72, 80))
462898	31789398	The findings indicated that ITGA7 knockdown promoted the expression of CD24, while it downregulated that of CD44 and CD133, compared with the NC group of CAL-27 and HSC-4 cells.	('expression', 'MPA', (57, 67))	('CD44', 'Gene', (108, 112))	('promoted', 'PosReg', (44, 52))	('ITGA7', 'Gene', '3679', (28, 33))	('CD44', 'Gene', '960', (108, 112))	('CD133', 'Gene', '8842', (117, 122))	('CD24', 'Gene', '100133941', (71, 75))	('CD24', 'Gene', (71, 75))	('downregulated', 'NegReg', (86, 99))	('HSC-4', 'CellLine', 'CVCL:1289', (165, 170))	('ITGA7', 'Gene', (28, 33))	('knockdown', 'Var', (34, 43))	('CD133', 'Gene', (117, 122))
462899	31789398	This suggested that ITGA7 knockdown regulated the expression of common CSC markers in TSCC cells.	('regulated', 'Reg', (36, 45))	('ITGA7', 'Gene', (20, 25))	('knockdown', 'Var', (26, 35))	('ITGA7', 'Gene', '3679', (20, 25))	('expression', 'MPA', (50, 60))
462900	31789398	In addition, ITGA7 knockdown reduced drug resistance to cisplatin and decreased the sphere formation ability of CAL-27 and HSC-4 cells.	('drug resistance to cisplatin', 'MPA', (37, 65))	('cisplatin', 'Chemical', 'MESH:D002945', (56, 65))	('knockdown', 'Var', (19, 28))	('decreased', 'NegReg', (70, 79))	('ITGA7', 'Gene', (13, 18))	('reduced', 'NegReg', (29, 36))	('HSC-4', 'CellLine', 'CVCL:1289', (123, 128))	('drug resistance', 'Phenotype', 'HP:0020174', (37, 52))	('ITGA7', 'Gene', '3679', (13, 18))
462902	31789398	Furthermore, ITGA7-silenced KYSE180 and KYSE520 cells formed smaller and fewer spheroids compared with control cells.	('spheroids', 'CPA', (79, 88))	('fewer', 'NegReg', (73, 78))	('ITGA7', 'Gene', '3679', (13, 18))	('ITGA7', 'Gene', (13, 18))	('KYSE520', 'Var', (40, 47))	('KYSE180', 'Var', (28, 35))
462903	31789398	Therefore, the present results indicated that ITGA7 knockdown decreased TSCC cell stemness.	('decreased', 'NegReg', (62, 71))	('ITGA7', 'Gene', '3679', (46, 51))	('TSCC cell stemness', 'CPA', (72, 90))	('knockdown', 'Var', (52, 61))	('ITGA7', 'Gene', (46, 51))
462910	31789398	In addition, ITGA7 knockdown suppressed proliferation and stemness, but promoted apoptosis, in TSCC cells in vitro.	('knockdown', 'Var', (19, 28))	('apoptosis', 'CPA', (81, 90))	('stemness', 'CPA', (58, 66))	('ITGA7', 'Gene', (13, 18))	('proliferation', 'CPA', (40, 53))	('promoted', 'PosReg', (72, 80))	('ITGA7', 'Gene', '3679', (13, 18))	('suppressed', 'NegReg', (29, 39))
462922	31495050	Two out of three studies suggested that a high number of D2-40+ vessels predicated low overall survival (OS); the third study reported that the ratio of D2-40+ over factor VIII + vessels is associated with low OS.	('overall', 'MPA', (87, 94))	('D2-40+', 'Var', (153, 159))	('factor VIII', 'Gene', (165, 176))	('factor VIII', 'Gene', '2157', (165, 176))	('low', 'NegReg', (83, 86))
462943	31495050	In contrast, Sasahira et al21 revealed that high CD34 expression was associated with poor prognosis and reduced DFS when they analyzed 101 TSCC patients (P = .0249).	('expression', 'MPA', (54, 64))	('high', 'Var', (44, 48))	('reduced', 'NegReg', (104, 111))	('DFS', 'MPA', (112, 115))	('CD34', 'Gene', '947', (49, 53))	('TSCC', 'Phenotype', 'HP:0030413', (139, 143))	('TSCC', 'Disease', 'MESH:D002294', (139, 143))	('patients', 'Species', '9606', (144, 152))	('TSCC', 'Disease', (139, 143))	('CD34', 'Gene', (49, 53))
462944	31495050	Similarly, Shao et al22 reported a significantly reduced OS in TSCC patients (n = 59) with high CD34 expression compared with those with low or moderate expression.	('TSCC', 'Disease', 'MESH:D002294', (63, 67))	('TSCC', 'Phenotype', 'HP:0030413', (63, 67))	('TSCC', 'Disease', (63, 67))	('reduced', 'NegReg', (49, 56))	('high', 'Var', (91, 95))	('expression', 'Var', (101, 111))	('patients', 'Species', '9606', (68, 76))	('CD34', 'Gene', '947', (96, 100))	('CD34', 'Gene', (96, 100))
462954	31495050	Al-Shareef et al28 revealed a strong correlation between D2-40 and LN metastasis in 80 TSCC patients.	('correlation', 'Interaction', (37, 48))	('TSCC', 'Phenotype', 'HP:0030413', (87, 91))	('TSCC', 'Disease', 'MESH:D002294', (87, 91))	('Al', 'Chemical', 'MESH:D000535', (0, 2))	('TSCC', 'Disease', (87, 91))	('patients', 'Species', '9606', (92, 100))	('N', 'Chemical', 'MESH:D009584', (68, 69))	('D2-40', 'Var', (57, 62))	('LN metastasis', 'CPA', (67, 80))
462956	31495050	A significant reduction in OS was observed by Yan et al29 in 80 TSCC cases associated with high D2-40, which also indicated higher nodal metastasis.	('D2-40', 'Var', (96, 101))	('TSCC', 'Disease', 'MESH:D002294', (64, 68))	('TSCC', 'Phenotype', 'HP:0030413', (64, 68))	('high D2-40', 'Var', (91, 101))	('TSCC', 'Disease', (64, 68))	('reduction', 'NegReg', (14, 23))
463002	29184782	With the development of new strategies including novel targeted therapy and immunotherapy, current treatment paradigms may shift to emphasize the implementation of epidermal growth receptor (EGFR) inhibitors and program death receptor 1 (PD-1) inhibitors in the treatment of advanced or metastatic penile SCC.	('PD-1', 'Gene', '5133', (238, 242))	('men', 'Species', '9606', (151, 154))	('inhibitors', 'Var', (197, 207))	('men', 'Species', '9606', (104, 107))	('men', 'Species', '9606', (267, 270))	('EGFR', 'Gene', '1956', (191, 195))	('EGFR', 'Gene', (191, 195))	('men', 'Species', '9606', (16, 19))	('SCC', 'Gene', (305, 308))	('program death receptor 1', 'Gene', (212, 236))	('SCC', 'Gene', '6317', (305, 308))	('program death receptor 1', 'Gene', '5133', (212, 236))	('SCC', 'Phenotype', 'HP:0002860', (305, 308))	('PD-1', 'Gene', (238, 242))	('advanced', 'Disease', (275, 283))
463008	29184782	Differently from EGFR, they found the expression of phosphate-EGFR (p-EGFR) was present in only 25% of penile SCC, and the p-EGFR in tumor with HPV-negative significantly more expressed than HPV-positive cancers.	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('EGFR', 'Gene', (17, 21))	('HPV-negative', 'Var', (144, 156))	('EGFR', 'Gene', '1956', (62, 66))	('HPV-positive cancers', 'Disease', (191, 211))	('EGFR', 'Gene', '1956', (125, 129))	('EGFR', 'Gene', '1956', (70, 74))	('SCC', 'Phenotype', 'HP:0002860', (110, 113))	('expressed', 'MPA', (176, 185))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('tumor', 'Disease', (133, 138))	('EGFR', 'Gene', '1956', (17, 21))	('SCC', 'Gene', '6317', (110, 113))	('cancers', 'Phenotype', 'HP:0002664', (204, 211))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('EGFR', 'Gene', (62, 66))	('more', 'PosReg', (171, 175))	('SCC', 'Gene', (110, 113))	('EGFR', 'Gene', (125, 129))	('HPV-positive cancers', 'Disease', 'MESH:D030361', (191, 211))	('EGFR', 'Gene', (70, 74))
463009	29184782	The expression of EGFR appeared to be predictive of poor prognosis in a number of malignancies, including non-small-cell lung cancer, oropharyngeal cancer as well as penile cancer.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('lung cancer', 'Disease', 'MESH:D008175', (121, 132))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (106, 132))	('EGFR', 'Gene', '1956', (18, 22))	('malignancies', 'Disease', (82, 94))	('oropharyngeal cancer', 'Disease', (134, 154))	('penile cancer', 'Disease', (166, 179))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('EGFR', 'Gene', (18, 22))	('lung cancer', 'Disease', (121, 132))	('lung cancer', 'Phenotype', 'HP:0100526', (121, 132))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (110, 132))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('expression', 'Var', (4, 14))	('penile cancer', 'Disease', 'MESH:D004414', (166, 179))	('oropharyngeal cancer', 'Disease', 'MESH:D009959', (134, 154))	('malignancies', 'Disease', 'MESH:D009369', (82, 94))
463010	29184782	In a study of 30 cases with penile SCC, EGFR expressed was noted in all patients, and positivity for cytosolic p-EGFR were predictive for recurrence and poor survival.	('SCC', 'Gene', (35, 38))	('SCC', 'Phenotype', 'HP:0002860', (35, 38))	('positivity', 'Var', (86, 96))	('EGFR', 'Gene', '1956', (40, 44))	('EGFR', 'Gene', '1956', (113, 117))	('EGFR', 'Gene', (40, 44))	('EGFR', 'Gene', (113, 117))	('SCC', 'Gene', '6317', (35, 38))	('recurrence', 'CPA', (138, 148))	('patients', 'Species', '9606', (72, 80))
463012	29184782	FISH analysis, as determined by signals of the EGFR gene and chromosome 7, revealed the alteration (polysomy and amplification) as an independent risk factor for poor survival.	('amplification', 'Var', (113, 126))	('EGFR', 'Gene', '1956', (47, 51))	('EGFR', 'Gene', (47, 51))
463014	29184782	EGFR mutation is known as an actionable driver mutations in patients with NSCLC, and sensitizing the EGFR mutations play an important role, because of the high prevalence of approximately 10% in Caucasian patients and up to 50% in Asian patients.	('patients', 'Species', '9606', (205, 213))	('EGFR', 'Gene', (0, 4))	('NSCLC', 'Phenotype', 'HP:0030358', (74, 79))	('patients', 'Species', '9606', (60, 68))	('EGFR', 'Gene', '1956', (101, 105))	('EGFR', 'Gene', (101, 105))	('mutations', 'Var', (47, 56))	('NSCLC', 'Disease', (74, 79))	('mutations', 'Var', (106, 115))	('NSCLC', 'Disease', 'MESH:D002289', (74, 79))	('patients', 'Species', '9606', (237, 245))	('EGFR', 'Gene', '1956', (0, 4))	('mutation', 'Var', (5, 13))
463016	29184782	It is reported that up of 80% to 90% of patients with EGFR-mutated NSCLC will have either an exon 19 deletion or an L858R point mutation in exon 21.	('L858R', 'Mutation', 'rs121434568', (116, 121))	('patients', 'Species', '9606', (40, 48))	('NSCLC', 'Phenotype', 'HP:0030358', (67, 72))	('L858R point', 'Var', (116, 127))	('EGFR', 'Gene', '1956', (54, 58))	('NSCLC', 'Disease', (67, 72))	('exon 19 deletion', 'Var', (93, 109))	('EGFR', 'Gene', (54, 58))	('NSCLC', 'Disease', 'MESH:D002289', (67, 72))
463017	29184782	It is noted that most mutations involving exons 18, 19, and 21 are considered predictive of sensitivity to EGFR tyrosine kinase inhibitors (TKIs), whereas mutations in exon 20 are typically resistant to these agents.	('EGFR', 'Gene', '1956', (107, 111))	('sensitivity', 'Reg', (92, 103))	('mutations', 'Var', (22, 31))	('EGFR', 'Gene', (107, 111))
463018	29184782	In penile carcinoma, multiple studies have identified that overexpression of EGFR is not associated with gene amplification, or gene copy number gain.	('gene copy number', 'Var', (128, 144))	('EGFR', 'Gene', '1956', (77, 81))	('penile carcinoma', 'Disease', 'MESH:D004414', (3, 19))	('carcinoma', 'Phenotype', 'HP:0030731', (10, 19))	('EGFR', 'Gene', (77, 81))	('penile carcinoma', 'Disease', (3, 19))
463019	29184782	In a study of a series of 20 cases with penile SCC, targeted next-generation sequencing showed EGFR amplification was seen in about 4/20 (20%) patients.	('amplification', 'Var', (100, 113))	('SCC', 'Phenotype', 'HP:0002860', (47, 50))	('SCC', 'Gene', '6317', (47, 50))	('patients', 'Species', '9606', (143, 151))	('EGFR', 'Gene', '1956', (95, 99))	('SCC', 'Gene', (47, 50))	('EGFR', 'Gene', (95, 99))
463020	29184782	A recent study performed targeted next-generation sequencing to identify somatic genomic alterations in a cohort of 60 samples from 43 patients and the results showed EGFR expression by IHC does not appear to be correlated with EGFR copy number.	('patients', 'Species', '9606', (135, 143))	('EGFR', 'Gene', '1956', (228, 232))	('copy number', 'Var', (233, 244))	('expression', 'MPA', (172, 182))	('EGFR', 'Gene', '1956', (167, 171))	('EGFR', 'Gene', (228, 232))	('EGFR', 'Gene', (167, 171))
463021	29184782	The EGFR gains/amplifications accounts for approximately 10% of penile SCC cases, with significant heterogeneity between paired primary tumors and lymph node metastases.	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('EGFR', 'Gene', '1956', (4, 8))	('EGFR', 'Gene', (4, 8))	('gains/amplifications', 'Var', (9, 29))	('primary tumors', 'Disease', (128, 142))	('metastases', 'Disease', (158, 168))	('SCC', 'Gene', (71, 74))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('primary tumors', 'Disease', 'MESH:D009369', (128, 142))	('SCC', 'Phenotype', 'HP:0002860', (71, 74))	('SCC', 'Gene', '6317', (71, 74))	('metastases', 'Disease', 'MESH:D009362', (158, 168))
463025	29184782	KRAS mutations are mostly found in codons 12 and 13, which harbor in exon2.	('KRAS', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))	('KRAS', 'Gene', '3845', (0, 4))
463026	29184782	KRAS gene mutation has been recognized as a negative predictor for responsiveness of CRC to cetuximab.	('mutation', 'Var', (10, 18))	('cetuximab', 'Chemical', 'MESH:D000068818', (92, 101))	('CRC', 'Phenotype', 'HP:0003003', (85, 88))	('KRAS', 'Gene', (0, 4))	('KRAS', 'Gene', '3845', (0, 4))
463027	29184782	However, KRAS mutation has no effect on the overall survival of patients with CRC.	('patients', 'Species', '9606', (64, 72))	('KRAS', 'Gene', (9, 13))	('CRC', 'Disease', (78, 81))	('mutation', 'Var', (14, 22))	('KRAS', 'Gene', '3845', (9, 13))	('CRC', 'Phenotype', 'HP:0003003', (78, 81))
463028	29184782	KRAS mutations were reported to be rare in penile SCC.	('SCC', 'Gene', '6317', (50, 53))	('mutations', 'Var', (5, 14))	('SCC', 'Gene', (50, 53))	('SCC', 'Phenotype', 'HP:0002860', (50, 53))	('KRAS', 'Gene', (0, 4))	('KRAS', 'Gene', '3845', (0, 4))
463029	29184782	In a small sample size of 28 cases, Andersson and colleges found 1 mutations in KRAS gene.	('KRAS', 'Gene', '3845', (80, 84))	('KRAS', 'Gene', (80, 84))	('mutations', 'Var', (67, 76))
463030	29184782	In an analysis of 107 samples from Brazil, only 1 sample presented a mutation in exon 12/13 of KRAS.	('KRAS', 'Gene', '3845', (95, 99))	('mutation in exon', 'Var', (69, 85))	('KRAS', 'Gene', (95, 99))
463033	29184782	Similarly, KRAS gene mutation was also rare in HNSCCs and was estimated to occur in <3%.	('KRAS', 'Gene', (11, 15))	('HNSCCs', 'Disease', 'MESH:D000077195', (47, 53))	('SCC', 'Phenotype', 'HP:0002860', (49, 52))	('KRAS', 'Gene', '3845', (11, 15))	('mutation', 'Var', (21, 29))	('HNSCC', 'Phenotype', 'HP:0012288', (47, 52))	('HNSCCs', 'Disease', (47, 53))
463035	29184782	Mutations of BRAF were found in several tumors, such as pilocytic astrocytoma, melanoma, colorectal, thyroid and ovarian cancers.	('pilocytic astrocytoma', 'Disease', 'MESH:D001254', (56, 77))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('BRAF', 'Gene', '673', (13, 17))	('tumors', 'Disease', 'MESH:D009369', (40, 46))	('found', 'Reg', (23, 28))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('astrocytoma', 'Phenotype', 'HP:0009592', (66, 77))	('ovarian cancers', 'Phenotype', 'HP:0100615', (113, 128))	('BRAF', 'Gene', (13, 17))	('colorectal, thyroid and ovarian cancers', 'Disease', 'MESH:D015179', (89, 128))	('Mutations', 'Var', (0, 9))	('pilocytic astrocytoma', 'Disease', (56, 77))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('melanoma', 'Phenotype', 'HP:0002861', (79, 87))	('melanoma', 'Disease', (79, 87))	('cancers', 'Phenotype', 'HP:0002664', (121, 128))	('tumors', 'Disease', (40, 46))	('melanoma', 'Disease', 'MESH:D008545', (79, 87))
463036	29184782	The presence of BRAF mutations also very rare in penile SCC.	('BRAF', 'Gene', '673', (16, 20))	('BRAF', 'Gene', (16, 20))	('SCC', 'Gene', (56, 59))	('SCC', 'Phenotype', 'HP:0002860', (56, 59))	('SCC', 'Gene', '6317', (56, 59))	('mutations', 'Var', (21, 30))
463055	29184782	In the patients who received EGFR-targeted inhibitors plus chemotherapy, over a half of them showed a response to treatment, with a median TTP of 3.2 months.	('inhibitors', 'Var', (43, 53))	('EGFR', 'Gene', '1956', (29, 33))	('EGFR', 'Gene', (29, 33))	('men', 'Species', '9606', (119, 122))	('patients', 'Species', '9606', (7, 15))
463080	29184782	The other two are going to open for recruiting patients, which are phase 2 trial for investigating the efficacy and safety of Nivolumab (NCT03012581) and phase 2 trials of evaluating efficacy of Ipilimuab and Nivolumab for selected rare cancer types (NCT02834013).	('Ipilimuab', 'Chemical', '-', (195, 204))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('Nivolumab', 'Chemical', 'MESH:D000077594', (209, 218))	('Nivolumab', 'Chemical', 'MESH:D000077594', (126, 135))	('patients', 'Species', '9606', (47, 55))	('NCT02834013', 'Var', (251, 262))	('cancer', 'Disease', 'MESH:D009369', (237, 243))	('cancer', 'Disease', (237, 243))
463082	29184782	High expression of EGFR and the rarity of KRAS mutation make the rational in the use of anti-EGFR inhibitors in advanced penile SCC promising.	('KRAS', 'Gene', (42, 46))	('EGFR', 'Gene', '1956', (93, 97))	('KRAS', 'Gene', '3845', (42, 46))	('SCC', 'Gene', (128, 131))	('mutation', 'Var', (47, 55))	('EGFR', 'Gene', (93, 97))	('EGFR', 'Gene', '1956', (19, 23))	('SCC', 'Phenotype', 'HP:0002860', (128, 131))	('SCC', 'Gene', '6317', (128, 131))	('EGFR', 'Gene', (19, 23))
463095	33202816	Her2 and c-Met were associated with high tobacco consumption (p = 0.016; p = 0.04).	('associated', 'Reg', (20, 30))	('high tobacco consumption', 'MPA', (36, 60))	('tobacco', 'Species', '4097', (41, 48))	('Her2', 'Gene', (0, 4))	('Her2', 'Gene', '2064', (0, 4))	('c-Met', 'Var', (9, 14))
463096	33202816	High EGFR, Her3, Her4 and c-Met expression were associated with worse overall and disease-free survival (p <= 0.05).	('disease-free survival', 'CPA', (82, 103))	('worse', 'NegReg', (64, 69))	('Her3', 'Gene', '2065', (11, 15))	('High', 'Var', (0, 4))	('Her4', 'Gene', '2066', (17, 21))	('EGFR', 'Gene', '1956', (5, 9))	('overall', 'CPA', (70, 77))	('Her4', 'Gene', (17, 21))	('EGFR', 'Gene', (5, 9))	('Her3', 'Gene', (11, 15))	('expression', 'MPA', (32, 42))	('c-Met', 'Protein', (26, 31))
463125	33202816	Combined targeted treatment against GFR is, therefore, possibly able to function as an alternative in de-escalation strategies for HPV-positive OPSCC.	('rat', 'Species', '10116', (118, 121))	('targeted treatment', 'Var', (9, 27))	('GFR', 'Gene', (36, 39))	('OPSCC', 'Disease', (144, 149))	('GFR', 'Gene', '9771', (36, 39))	('HPV', 'Species', '10566', (131, 134))
463150	33202816	High c-Met expression was correlated with several unfavorable clinical factors, such as tobacco consumption over 20 pack-years (p < 0.01), higher T category (p = 0.02), p16 negativity (p = 0.02) and positive distant metastasis (p = 0.04).	('p16', 'Gene', '1029', (169, 172))	('High', 'Var', (0, 4))	('tobacco', 'Species', '4097', (88, 95))	('expression', 'MPA', (11, 21))	('p16', 'Gene', (169, 172))	('T category', 'CPA', (146, 156))	('c-Met', 'Protein', (5, 10))	('higher', 'PosReg', (139, 145))
463159	33202816	Furthermore, high EGFR-(hazard ratio (HR) = 2.53, p = 0.01, 95% CI = 1.24-5.18) and c-Met expression (HR = 2.45, p = 0.02, 95% CI = 1.13-5.35) were associated with poor overall survival.	('EGFR', 'Gene', '1956', (18, 22))	('high', 'Var', (13, 17))	('overall', 'MPA', (169, 176))	('EGFR', 'Gene', (18, 22))	('poor', 'NegReg', (164, 168))	('c-Met expression', 'MPA', (84, 100))	('rat', 'Species', '10116', (31, 34))
463178	33202816	Furthermore, our results show a relevant negative influence of high EGFR expression on overall and disease-free survival.	('negative', 'NegReg', (41, 49))	('disease-free survival', 'CPA', (99, 120))	('EGFR', 'Gene', '1956', (68, 72))	('high', 'Var', (63, 67))	('overall', 'CPA', (87, 94))	('EGFR', 'Gene', (68, 72))
463206	33202816	This fact could be understood as a compensatory mechanism to tumor-promoting influences of EGFR, Her2, Her3 and c-Met.	('Her3', 'Gene', '2065', (103, 107))	('EGFR', 'Gene', (91, 95))	('Her2', 'Gene', '2064', (97, 101))	('c-Met', 'Var', (112, 117))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('Her3', 'Gene', (103, 107))	('EGFR', 'Gene', '1956', (91, 95))	('Her2', 'Gene', (97, 101))	('tumor', 'Disease', (61, 66))
463207	33202816	Coexpression between EGFR and nuclear Her4 suggested a negative influence on overall and disease-free survival.	('EGFR', 'Gene', '1956', (21, 25))	('EGFR', 'Gene', (21, 25))	('disease-free survival', 'CPA', (89, 110))	('negative', 'NegReg', (55, 63))	('Her4', 'Gene', '2066', (38, 42))	('Her4', 'Gene', (38, 42))	('Coexpression', 'Var', (0, 12))
463219	33202816	High positive c-Met and p16 negative tumors are notably associated with poor prognosis.	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('p16', 'Gene', '1029', (24, 27))	('c-Met', 'Protein', (14, 19))	('p16', 'Gene', (24, 27))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('High positive', 'Var', (0, 13))	('tumors', 'Disease', (37, 43))	('tumors', 'Disease', 'MESH:D009369', (37, 43))
463223	33202816	Be-sides c-Met expression, it is possible to prevent Her2 and Her3 upregulation in HNSCC, which could explain the lower expression of Her2 and Her3 in this study.	('c-Met expression', 'Var', (9, 25))	('expression', 'Var', (15, 25))	('Her3', 'Gene', '2065', (62, 66))	('Her3', 'Gene', (143, 147))	('Her2', 'Gene', (53, 57))	('Her2', 'Gene', (134, 138))	('prevent', 'NegReg', (45, 52))	('Her3', 'Gene', (62, 66))	('upregulation', 'PosReg', (67, 79))	('Her2', 'Gene', '2064', (53, 57))	('Her3', 'Gene', '2065', (143, 147))	('Her2', 'Gene', '2064', (134, 138))
463224	33202816	Phase 2 trial of humanized monoclonal anti c-Met antibody ficlatuzumab with or without cetuximab in cetuximab resistant recurrent or metastatic HNSCC may be able to show possible effects NCT03422536).	('cetuximab', 'Chemical', 'MESH:D000068818', (87, 96))	('recurrent', 'Disease', (120, 129))	('human', 'Species', '9606', (17, 22))	('cetuximab', 'Chemical', 'MESH:D000068818', (100, 109))	('NCT03422536', 'Var', (187, 198))	('ficlatuzumab', 'Chemical', 'MESH:C583360', (58, 70))
463254	33202816	Staining of c-Met was performed with anti-Met antibodies (SP44 790-4430; rabbit monoclonal; F. Hoffmann-La Roche, Basel, Switzerland) and with the standard procedure of the Ventana BenchMark Ultra system.	('Met', 'Gene', '79811', (14, 17))	('Met', 'Gene', '79811', (42, 45))	('Met', 'Gene', (42, 45))	('Met', 'Gene', (14, 17))	('SP44 790-4430;', 'Var', (58, 72))
463277	33176745	However, correlations between BRF2 alterations and clinical outcomes in breast cancer are limited.	('alterations', 'Var', (35, 46))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('BRF2', 'Gene', (30, 34))	('breast cancer', 'Disease', 'MESH:D001943', (72, 85))	('breast cancer', 'Disease', (72, 85))	('breast cancer', 'Phenotype', 'HP:0003002', (72, 85))
463278	33176745	We conducted this review to analyze BRF2 alterations in genomic data sets housed in Oncomine and cBioPortal to identify potential correlations between BRF2 alterations and clinical outcomes.	('Oncomine', 'Chemical', '-', (84, 92))	('BRF2', 'Gene', (36, 40))	('alterations', 'Var', (41, 52))
463279	33176745	The authors queried both Oncomine and cBioPortal for alterations in BRF2 in human cancers and performed meta-analyses identifying significant correlations between BRF2 and clinical outcomes in invasive breast cancer (IBC).	('BRF2', 'Gene', (163, 167))	('correlations', 'Interaction', (142, 154))	('invasive breast cancer', 'Disease', 'MESH:D001943', (193, 215))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('cancers', 'Phenotype', 'HP:0002664', (82, 89))	('alterations', 'Var', (53, 64))	('BRF2', 'Gene', (68, 72))	('cancers', 'Disease', (82, 89))	('human', 'Species', '9606', (76, 81))	('IBC', 'Chemical', '-', (217, 220))	('cancers', 'Disease', 'MESH:D009369', (82, 89))	('invasive breast cancer', 'Disease', (193, 215))	('breast cancer', 'Phenotype', 'HP:0003002', (202, 215))	('Oncomine', 'Chemical', '-', (25, 33))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
463282	33176745	Overall survival in IBC patients with BRF2 alterations (21%) is significantly decreased (p = 9.332e-3).	('IBC', 'Chemical', '-', (20, 23))	('IBC', 'Disease', (20, 23))	('patients', 'Species', '9606', (24, 32))	('BRF2', 'Gene', (38, 42))	('alterations', 'Var', (43, 54))	('Overall', 'MPA', (0, 7))	('decreased', 'NegReg', (78, 87))
463283	33176745	IBC patients with BRF2 alterations aged 46 to 50 have a significantly poor survival outcome (p = 7.093e-3).	('poor', 'NegReg', (70, 74))	('IBC', 'Chemical', '-', (0, 3))	('survival', 'MPA', (75, 83))	('alterations', 'Var', (23, 34))	('patients', 'Species', '9606', (4, 12))	('BRF2', 'Gene', (18, 22))
463296	33176745	Atypical RNA pol III transcription is a common feature of many cancer types.	('Atypical', 'Var', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('RNA pol III transcription', 'Gene', (9, 34))	('cancer', 'Disease', (63, 69))
463302	33176745	Amplification of BRF2, 8p11.23, and chromosome 8 frequently occurs in somatic breast cancer.	('breast cancer', 'Phenotype', 'HP:0003002', (78, 91))	('Amplification', 'Var', (0, 13))	('occurs', 'Reg', (60, 66))	('BRF2', 'Gene', (17, 21))	('breast cancer', 'Disease', 'MESH:D001943', (78, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('breast cancer', 'Disease', (78, 91))
463309	33176745	In this study, we performed a meta-analysis of patient data from both Oncomine and cBioPortal databases to analyze BRF2 alterations in human cancers, with a focus on breast cancer.	('BRF2', 'Gene', (115, 119))	('patient', 'Species', '9606', (47, 54))	('Oncomine', 'Chemical', '-', (70, 78))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('breast cancer', 'Phenotype', 'HP:0003002', (166, 179))	('breast cancer', 'Disease', 'MESH:D001943', (166, 179))	('human', 'Species', '9606', (135, 140))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('breast cancer', 'Disease', (166, 179))	('cancers', 'Phenotype', 'HP:0002664', (141, 148))	('cancers', 'Disease', 'MESH:D009369', (141, 148))	('alterations', 'Var', (120, 131))	('cancers', 'Disease', (141, 148))
463313	33176745	We performed a comprehensive query of the Oncomine Research Edition, a cancer microarray database and web-based data-mining platform containing 715 data sets (86, 733 samples), to determine the frequency of BRF2 mutations, alterations in BRF2 DNA copy number, and BRF2 gene expression in human cancers.	('BRF2', 'Gene', (207, 211))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('human', 'Species', '9606', (288, 293))	('BRF2', 'Gene', (238, 242))	('cancer', 'Disease', (71, 77))	('cancer', 'Disease', 'MESH:D009369', (294, 300))	('cancers', 'Disease', 'MESH:D009369', (294, 301))	('cancers', 'Phenotype', 'HP:0002664', (294, 301))	('cancer', 'Disease', (294, 300))	('cancers', 'Disease', (294, 301))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('mutations', 'Var', (212, 221))	('Oncomine', 'Chemical', '-', (42, 50))	('cancer', 'Phenotype', 'HP:0002664', (294, 300))	('BRF2', 'Gene', (264, 268))
463320	33176745	In our current analysis of BRF2 alterations in IBC, we included the data available in cBioPortal's TCGA, Firehose Legacy data set for analysis consisting of 960 patients with available mutation, CNA, and mRNA microarray expression (z-score threshold + 2.0).	('IBC', 'Chemical', '-', (47, 50))	('mRNA', 'MPA', (204, 208))	('alterations', 'Var', (32, 43))	('patients', 'Species', '9606', (161, 169))	('BRF2', 'Gene', (27, 31))
463321	33176745	BRF2 alterations in the Breast Cancer METABRIC (Nature 2012 & Nature 2016) data set analyzed included patients with mutation, CNA, and mRNA microarray expression (z-score threshold + 2.0).	('Breast Cancer', 'Phenotype', 'HP:0003002', (24, 37))	('Breast Cancer', 'Disease', (24, 37))	('patients', 'Species', '9606', (102, 110))	('Cancer', 'Phenotype', 'HP:0002664', (31, 37))	('alterations', 'Var', (5, 16))	('with', 'Var', (111, 115))	('Breast Cancer', 'Disease', 'MESH:D001943', (24, 37))	('BRF2', 'Gene', (0, 4))
463322	33176745	We queried Oncomine, containing 715 data sets (86,733 samples), to determine the frequency of BRF2 alterations in human cancers.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('BRF2', 'Gene', (94, 98))	('Oncomine', 'Chemical', '-', (11, 19))	('cancers', 'Phenotype', 'HP:0002664', (120, 127))	('alterations', 'Var', (99, 110))	('cancers', 'Disease', (120, 127))	('human', 'Species', '9606', (114, 119))	('cancers', 'Disease', 'MESH:D009369', (120, 127))
463349	33176745	1d), prompted a more detailed look at BRF2 alterations in subtypes of breast cancer (Fig.	('breast cancer', 'Disease', 'MESH:D001943', (70, 83))	('breast cancer', 'Disease', (70, 83))	('BRF2', 'Gene', (38, 42))	('alterations', 'Var', (43, 54))	('breast cancer', 'Phenotype', 'HP:0003002', (70, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))
463360	33176745	BRF2 copy number events occur most frequently in breast cancer, 5.9%, as compared to other human cancers analyzed (Fig.	('cancers', 'Disease', 'MESH:D009369', (97, 104))	('cancers', 'Phenotype', 'HP:0002664', (97, 104))	('cancers', 'Disease', (97, 104))	('breast cancer', 'Phenotype', 'HP:0003002', (49, 62))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('breast cancer', 'Disease', 'MESH:D001943', (49, 62))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('copy number events', 'Var', (5, 23))	('breast cancer', 'Disease', (49, 62))	('BRF2', 'Gene', (0, 4))	('human', 'Species', '9606', (91, 96))
463366	33176745	The estimated BRF2 copy numbers ranged from 0.8 to 9.2 in 2389 patients diagnosed with IDC.	('BRF2', 'Gene', (14, 18))	('IDC', 'Disease', (87, 90))	('copy numbers', 'Var', (19, 31))	('patients', 'Species', '9606', (63, 71))
463388	33176745	In our current analysis of BRF2 in IBC, we included the 960 patients with mutation, CNA, and mRNA microarray expression (z-score threshold + 2.0) data available in cBioPortal's TCGA, Firehose Legacy data set to identify if BRF2 alterations correlate with overall patient survival potentially.	('patient', 'Species', '9606', (263, 270))	('patient', 'Species', '9606', (60, 67))	('patients', 'Species', '9606', (60, 68))	('alterations', 'Var', (228, 239))	('correlate with', 'Reg', (240, 254))	('IBC', 'Chemical', '-', (35, 38))	('BRF2', 'Gene', (223, 227))
463390	33176745	The majority of the BRF2 alterations are amplifications of copy number (7.7%) and an increase in BRF2 mRNA expression (3.85%), but multiple BRF2 alterations (5.31%) co-occur in IBC (data not shown).	('alterations', 'Var', (25, 36))	('mRNA expression', 'MPA', (102, 117))	('copy number', 'MPA', (59, 70))	('BRF2', 'Gene', (20, 24))	('increase', 'PosReg', (85, 93))	('IBC', 'Chemical', '-', (177, 180))	('BRF2', 'Gene', (97, 101))	('IBC', 'Disease', (177, 180))
463391	33176745	The Kaplan-Meier estimate of overall survival was determined by comparing overall patient survival status, by month, in IBC patients with BRF2 alterations (red line) to those without alterations in BRF2 (blue line) (Fig.	('patient', 'Species', '9606', (82, 89))	('IBC', 'Chemical', '-', (120, 123))	('IBC', 'Disease', (120, 123))	('patient', 'Species', '9606', (124, 131))	('BRF2', 'Gene', (138, 142))	('alterations', 'Var', (143, 154))	('patients', 'Species', '9606', (124, 132))
463399	33176745	Figure 5 suggests BRF2 alterations specifically and significantly correlate with overall patient survival in patients with IBC.	('patient', 'Species', '9606', (89, 96))	('patient', 'Species', '9606', (109, 116))	('IBC', 'Chemical', '-', (123, 126))	('patients', 'Species', '9606', (109, 117))	('IBC', 'Disease', (123, 126))	('correlate with', 'Reg', (66, 80))	('alterations', 'Var', (23, 34))	('BRF2', 'Gene', (18, 22))
463400	33176745	No significant decrease in overall survival for patients with alterations in ERBB2 (HER2) (Fig.	('decrease', 'NegReg', (15, 23))	('ERBB2', 'Gene', '2064', (77, 82))	('overall', 'MPA', (27, 34))	('HER2', 'Gene', (84, 88))	('ERBB2', 'Gene', (77, 82))	('HER2', 'Gene', '2064', (84, 88))	('patients', 'Species', '9606', (48, 56))	('alterations', 'Var', (62, 73))
463403	33176745	Patients with BRF2 alterations had a median survival of 111.99 months (p = 9.332e-3) as compared to a median survival of 212.09 months in patients without BRF2 alterations (Fig.	('BRF2', 'Gene', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('alterations', 'Var', (19, 30))	('patients', 'Species', '9606', (138, 146))
463404	33176745	In queries of the IBC (TCGA, Firehose Legacy) data set in the cBioPortal, the Disease/Progression-free Kaplan median months disease-free were not available for patients with BRF2 alterations.	('patients', 'Species', '9606', (160, 168))	('alterations', 'Var', (179, 190))	('BRF2', 'Gene', (174, 178))	('IBC', 'Chemical', '-', (18, 21))
463405	33176745	To elucidate if BRF2 alterations co-occur with alterations in known oncogenes and biomarkers in IBC we analyzed copy-number alteration frequency in breast cancer patients with BRF2 alterations (Fig.	('alterations', 'Var', (181, 192))	('patients', 'Species', '9606', (162, 170))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('breast cancer', 'Disease', 'MESH:D001943', (148, 161))	('IBC', 'Chemical', '-', (96, 99))	('breast cancer', 'Disease', (148, 161))	('breast cancer', 'Phenotype', 'HP:0003002', (148, 161))	('BRF2', 'Gene', (176, 180))
463408	33176745	MYC is frequently amplified in breast cancer and amplification is associated with poor prognosis.	('MYC', 'Gene', (0, 3))	('amplification', 'Var', (49, 62))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('breast cancer', 'Disease', 'MESH:D001943', (31, 44))	('breast cancer', 'Disease', (31, 44))	('breast cancer', 'Phenotype', 'HP:0003002', (31, 44))	('MYC', 'Gene', '4609', (0, 3))
463409	33176745	MYC is amplified in 35.5% of patients with BRF2 alterations, p = 6.638e-6 (Fig.	('MYC', 'Gene', (0, 3))	('patients', 'Species', '9606', (29, 37))	('alterations', 'Var', (48, 59))	('BRF2', 'Gene', (43, 47))	('MYC', 'Gene', '4609', (0, 3))
463410	33176745	The breast cancer biomarkers ERBB2 (HER2), ESR1(ER), PIK3CA are not significantly altered in patients with BRF2 alterations (Fig.	('ESR1', 'Gene', (43, 47))	('BRF2', 'Gene', (107, 111))	('ERBB2', 'Gene', (29, 34))	('ER', 'Gene', '2099', (48, 50))	('patients', 'Species', '9606', (93, 101))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('HER2', 'Gene', (36, 40))	('PIK3CA', 'Gene', '5290', (53, 59))	('breast cancer', 'Disease', 'MESH:D001943', (4, 17))	('breast cancer', 'Phenotype', 'HP:0003002', (4, 17))	('ESR1', 'Gene', '2099', (43, 47))	('HER2', 'Gene', '2064', (36, 40))	('breast cancer', 'Disease', (4, 17))	('ER', 'Gene', '2099', (29, 31))	('ER', 'Gene', '2099', (37, 39))	('alterations', 'Var', (112, 123))	('PIK3CA', 'Gene', (53, 59))	('ERBB2', 'Gene', '2064', (29, 34))
463415	33176745	BRF2 alterations tend to co-occur with MYC alterations (p = 0.008), Fig.	('MYC', 'Gene', '4609', (39, 42))	('co-occur', 'Reg', (25, 33))	('alterations', 'Var', (5, 16))	('BRF2', 'Gene', (0, 4))	('MYC', 'Gene', (39, 42))
463416	33176745	6c, we determined if BRF2 alterations also co-occurred or are mutually exclusive with well-established breast cancer biomarkers.	('breast cancer', 'Disease', 'MESH:D001943', (103, 116))	('alterations', 'Var', (26, 37))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('breast cancer', 'Disease', (103, 116))	('breast cancer', 'Phenotype', 'HP:0003002', (103, 116))	('BRF2', 'Gene', (21, 25))
463417	33176745	BRF2 alterations tend to be mutually exclusive from PIK3CA alterations (p = 0.002), Fig.	('BRF2', 'Gene', (0, 4))	('alterations', 'Var', (5, 16))	('PIK3CA', 'Gene', '5290', (52, 58))	('PIK3CA', 'Gene', (52, 58))
463418	33176745	6a-c, prompted an examination of overall survival for patients with breast invasive carcinoma with concurrent alterations in BRF2 and breast cancer biomarkers which were determined to be either co-occurring or mutually exclusive and statistically significant, Fig.	('breast invasive carcinoma', 'Disease', (68, 93))	('alterations', 'Var', (110, 121))	('breast cancer', 'Disease', (134, 147))	('breast cancer', 'Phenotype', 'HP:0003002', (134, 147))	('patients', 'Species', '9606', (54, 62))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('breast invasive carcinoma', 'Disease', 'MESH:D001943', (68, 93))	('BRF2', 'Gene', (125, 129))	('breast cancer', 'Disease', 'MESH:D001943', (134, 147))
463419	33176745	Kaplan-Meier estimate was determined comparing overall patient survival status, by month, in patients with alterations (red line) to those without alterations (blue line) in PIK3CA (Fig.	('PIK3CA', 'Gene', (174, 180))	('alterations', 'Var', (107, 118))	('PIK3CA', 'Gene', '5290', (174, 180))	('patient', 'Species', '9606', (93, 100))	('patient', 'Species', '9606', (55, 62))	('patients', 'Species', '9606', (93, 101))
463425	33176745	These data suggest co-occurring alterations in BRF2 and MYC significantly decrease overall survival in patients with breast invasive carcinoma.	('breast invasive carcinoma', 'Disease', 'MESH:D001943', (117, 142))	('overall survival', 'MPA', (83, 99))	('decrease', 'NegReg', (74, 82))	('BRF2', 'Gene', (47, 51))	('MYC', 'Gene', (56, 59))	('breast invasive carcinoma', 'Disease', (117, 142))	('alterations', 'Var', (32, 43))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('patients', 'Species', '9606', (103, 111))	('MYC', 'Gene', '4609', (56, 59))
463426	33176745	MYC and ESR1(ER) alterations tend to co-occur in breast invasive carcinoma (p < 0.001), Fig.	('co-occur', 'Reg', (37, 45))	('MYC', 'Gene', (0, 3))	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('breast invasive carcinoma', 'Disease', (49, 74))	('breast invasive carcinoma', 'Disease', 'MESH:D001943', (49, 74))	('ESR1', 'Gene', '2099', (8, 12))	('ESR1', 'Gene', (8, 12))	('MYC', 'Gene', '4609', (0, 3))	('alterations', 'Var', (17, 28))	('ER', 'Gene', '2099', (13, 15))
463427	33176745	The overall survival for alterations in MYC alone were significant as previously reported (Fig.	('alterations', 'Var', (25, 36))	('MYC', 'Gene', '4609', (40, 43))	('MYC', 'Gene', (40, 43))
463429	33176745	Next, we investigated if age of first IBC diagnosis correlated with BRF2 alterations and overall survival outcome as BRF2 alterations significantly correlated with poor survival (p = 9.332e-3), Fig.	('alterations', 'Var', (122, 133))	('poor survival', 'MPA', (164, 177))	('BRF2', 'Gene', (117, 121))	('IBC', 'Chemical', '-', (38, 41))
463431	33176745	The overall Kaplan-Meier estimate was determined by comparing overall patient survival status, by month, in patients with BRF2 alterations (red line) to those without BRF2 alterations (blue line) by selected age ranges.	('patient', 'Species', '9606', (70, 77))	('BRF2', 'Gene', (122, 126))	('patient', 'Species', '9606', (108, 115))	('alterations', 'Var', (127, 138))	('patients', 'Species', '9606', (108, 116))
463432	33176745	12% of women aged 35 < X < 40 (n = 59), had alterations in BRF2, classified as amplification in IBC, and have an overall decrease in patient survival (p = 0.032), Fig.	('patient survival', 'CPA', (133, 149))	('patient', 'Species', '9606', (133, 140))	('IBC', 'Chemical', '-', (96, 99))	('BRF2', 'Gene', (59, 63))	('alterations', 'Var', (44, 55))	('decrease', 'NegReg', (121, 129))	('women', 'Species', '9606', (7, 12))
463433	33176745	In patients aged 40 < X < 45 (n = 81), BRF2 is altered (17%) and these alterations are overwhelmingly amplifications in IBC and correlated with overall patient survival (p = 0.0123), Fig.	('BRF2', 'Gene', (39, 43))	('IBC', 'Chemical', '-', (120, 123))	('patient', 'Species', '9606', (3, 10))	('IBC', 'Disease', (120, 123))	('alterations', 'Var', (71, 82))	('patients', 'Species', '9606', (3, 11))	('correlated with', 'Reg', (128, 143))	('altered', 'Reg', (47, 54))	('patient', 'Species', '9606', (152, 159))
463434	33176745	13% of patients aged 45 < X < 50 (n = 121) have amplifications in BRF2 in both IBC and invasive lobular carcinoma (ILC), Fig.	('invasive lobular carcinoma', 'Disease', 'MESH:D018275', (87, 113))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (96, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('amplifications', 'Var', (48, 62))	('IBC', 'Chemical', '-', (79, 82))	('IBC', 'Disease', (79, 82))	('BRF2', 'Gene', (66, 70))	('patients', 'Species', '9606', (7, 15))	('invasive lobular carcinoma', 'Disease', (87, 113))
463437	33176745	However, in our analysis of women with BRF2 alterations (13%) aged 50 < X < 55 (n = 119) showed no significant decrease in overall survival, Fig.	('BRF2', 'Gene', (39, 43))	('overall survival', 'MPA', (123, 139))	('alterations', 'Var', (44, 55))	('women', 'Species', '9606', (28, 33))	('decrease', 'NegReg', (111, 119))
463438	33176745	Survival in women with BRF2 alterations (17%) aged 55 < X < 60 (n = 118) were unaffected (p = 0.305), data not shown.	('women', 'Species', '9606', (12, 17))	('BRF2', 'Gene', (23, 27))	('alterations', 'Var', (28, 39))
463440	33176745	Further, BRF2 alterations may be useful as an age-related prognostic marker for women, aged 35 < X < 50, with a first-time diagnosis of IBC or ILC.	('alterations', 'Var', (14, 25))	('women', 'Species', '9606', (80, 85))	('BRF2', 'Gene', (9, 13))	('IBC', 'Chemical', '-', (136, 139))	('IBC', 'Disease', (136, 139))	('ILC', 'Disease', (143, 146))
463443	33176745	Using the cBioPortal we queried for BRF2 alteration in the two available metastatic breast cancer data sets: Metastatic Breast Cancer (INSERM, PLoS Med 2016) and the Metastatic Breast Cancer Project (Provisional, October 2018).	('Breast Cancer', 'Phenotype', 'HP:0003002', (120, 133))	('breast cancer', 'Phenotype', 'HP:0003002', (84, 97))	('BRF2', 'Gene', (36, 40))	('Breast Cancer', 'Disease', (120, 133))	('Breast Cancer', 'Disease', 'MESH:D001943', (177, 190))	('ER', 'Gene', '2099', (138, 140))	('Cancer', 'Phenotype', 'HP:0002664', (127, 133))	('alteration', 'Var', (41, 51))	('Breast Cancer', 'Disease', 'MESH:D001943', (120, 133))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('Breast Cancer', 'Phenotype', 'HP:0003002', (177, 190))	('Cancer', 'Phenotype', 'HP:0002664', (184, 190))	('breast cancer', 'Disease', 'MESH:D001943', (84, 97))	('Breast Cancer', 'Disease', (177, 190))	('breast cancer', 'Disease', (84, 97))
463445	33176745	In these metastatic breast cancer data sets, BRF2 alterations are predominately amplifications, 14.57%.	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('breast cancer', 'Disease', 'MESH:D001943', (20, 33))	('breast cancer', 'Disease', (20, 33))	('alterations', 'Var', (50, 61))	('breast cancer', 'Phenotype', 'HP:0003002', (20, 33))	('BRF2', 'Gene', (45, 49))
463446	33176745	BRF2 alterations were identified in subtypes of metastatic breast invasive carcinoma, including IDL, IBC, breast mixed ductal and lobular carcinoma, and IBC NOS, Fig.	('IBC', 'Disease', (153, 156))	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('lobular carcinoma', 'Disease', (130, 147))	('breast invasive carcinoma', 'Disease', (59, 84))	('lobular carcinoma', 'Phenotype', 'HP:0030076', (130, 147))	('breast mixed ductal', 'Disease', (106, 125))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('IDL', 'Disease', (96, 99))	('alterations', 'Var', (5, 16))	('BRF2', 'Gene', (0, 4))	('IBC', 'Chemical', '-', (101, 104))	('lobular carcinoma', 'Disease', 'MESH:D018275', (130, 147))	('breast invasive carcinoma', 'Disease', 'MESH:D001943', (59, 84))	('IBC', 'Disease', (101, 104))	('IBC', 'Chemical', '-', (153, 156))
463449	33176745	The highest frequency of BRF2 alterations, 33%, occur in women with metastatic breast cancer aged 45 < x < 50, Fig.	('breast cancer', 'Disease', 'MESH:D001943', (79, 92))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('women', 'Species', '9606', (57, 62))	('breast cancer', 'Disease', (79, 92))	('breast cancer', 'Phenotype', 'HP:0003002', (79, 92))	('BRF2', 'Gene', (25, 29))	('alterations', 'Var', (30, 41))
463452	33176745	MYC and BRF2 alterations specifically co-occur in women aged 45 < x < 50 (p = 0.053) with metastatic breast cancer, Fig.	('MYC', 'Gene', (0, 3))	('BRF2', 'Gene', (8, 12))	('co-occur', 'Reg', (38, 46))	('women', 'Species', '9606', (50, 55))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('breast cancer', 'Disease', 'MESH:D001943', (101, 114))	('MYC', 'Gene', '4609', (0, 3))	('alterations', 'Var', (13, 24))	('breast cancer', 'Disease', (101, 114))	('breast cancer', 'Phenotype', 'HP:0003002', (101, 114))
463454	33176745	Interestingly, deletions in BRF2 have been identified in the 33% of women aged 45 < x < 50, Fig.	('BRF2', 'Gene', (28, 32))	('women', 'Species', '9606', (68, 73))	('deletions', 'Var', (15, 24))	('identified', 'Reg', (43, 53))
463456	33176745	The data presented in this study agree with previous data demonstrating that 8p deletions have been linked to advanced tumor stage, MYC amplification, inversely associated with ER receptor expression, and shortened overall survival.	('tumor', 'Disease', (119, 124))	('associated', 'Reg', (161, 171))	('8p deletions', 'Var', (77, 89))	('expression', 'MPA', (189, 199))	('MYC', 'Gene', (132, 135))	('ER', 'Gene', '2099', (177, 179))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('amplification', 'Var', (136, 149))	('overall', 'MPA', (215, 222))	('inversely', 'NegReg', (151, 160))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('shortened', 'NegReg', (205, 214))	('MYC', 'Gene', '4609', (132, 135))
463457	33176745	Further analysis of the patients with BRF2 deletions had clinical data available, which is correlative.	('deletions', 'Var', (43, 52))	('BRF2', 'Gene', (38, 42))	('patients', 'Species', '9606', (24, 32))
463458	33176745	For example, all these patients with BRF2 deletions are ages 45 < x < 50, self-reported race as white, were diagnosed as III high grade (poorly differentiated) and had negative ER and PR status per the medical record (MedR) diagnostic.	('patients', 'Species', '9606', (23, 31))	('PR', 'Gene', '5241', (184, 186))	('BRF2', 'Gene', (37, 41))	('deletions', 'Var', (42, 51))	('ER', 'Gene', '2099', (177, 179))
463463	33176745	Together, these data suggest additional studies are warranted to determine if tamoxifen treatment would be beneficial in patients with IBC and BRF2 alterations.	('tamoxifen', 'Chemical', 'MESH:D013629', (78, 87))	('alterations', 'Var', (148, 159))	('BRF2', 'Gene', (143, 147))	('IBC', 'Chemical', '-', (135, 138))	('patients', 'Species', '9606', (121, 129))	('IBC', 'Disease', (135, 138))
463469	33176745	Together, these data prompted a more detailed analysis of BRF2 alterations in IBC.	('IBC', 'Disease', (78, 81))	('alterations', 'Var', (63, 74))	('BRF2', 'Gene', (58, 62))	('IBC', 'Chemical', '-', (78, 81))
463476	33176745	The cytogenetic location of BRF2 is 8p11.23 and amplification of the short arm of chromosome 8 is a frequent feature of breast cancer cell lines and tumors.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('breast cancer', 'Disease', (120, 133))	('breast cancer', 'Disease', 'MESH:D001943', (120, 133))	('breast cancer', 'Phenotype', 'HP:0003002', (120, 133))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('tumors', 'Disease', (149, 155))	('tumors', 'Disease', 'MESH:D009369', (149, 155))	('short arm', 'Phenotype', 'HP:0009824', (69, 78))	('tumors', 'Phenotype', 'HP:0002664', (149, 155))	('BRF2', 'Gene', (28, 32))	('amplification', 'Var', (48, 61))
463477	33176745	In this study, we demonstrate that BRF2 is amplified in 5.9% of all breast cancers and 6.9% of all ductal breast carcinomas queried (Fig.	('BRF2', 'Gene', (35, 39))	('breast carcinomas', 'Disease', 'MESH:D001943', (106, 123))	('breast carcinomas', 'Disease', (106, 123))	('breast cancers', 'Disease', 'MESH:D001943', (68, 82))	('cancers', 'Phenotype', 'HP:0002664', (75, 82))	('breast cancers', 'Disease', (68, 82))	('breast cancer', 'Phenotype', 'HP:0003002', (68, 81))	('breast carcinomas', 'Phenotype', 'HP:0003002', (106, 123))	('amplified', 'Var', (43, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('breast carcinoma', 'Phenotype', 'HP:0003002', (106, 122))	('carcinomas', 'Phenotype', 'HP:0030731', (113, 123))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('breast cancers', 'Phenotype', 'HP:0003002', (68, 82))
463480	33176745	In this analysis, the estimated BRF2 copy numbers ranged from 0.8 to 9.2 in 2389 patients diagnosed with IDC, Fig.	('BRF2', 'Gene', (32, 36))	('patients', 'Species', '9606', (81, 89))	('IDC', 'Disease', (105, 108))	('copy numbers', 'Var', (37, 49))
463484	33176745	As such, we then queried for BRF2 alterations and clinical outcomes, specifically overall patient survival.	('patient', 'Species', '9606', (90, 97))	('alterations', 'Var', (34, 45))	('BRF2', 'Gene', (29, 33))
463485	33176745	A query of the TCGA Firehose Legacy data set in the cBioPortal for BRF2 alterations and patient overall survival status demonstrated a statistically significant correlation, Fig.	('patient', 'Species', '9606', (88, 95))	('BRF2', 'Gene', (67, 71))	('alterations', 'Var', (72, 83))
463486	33176745	Notably, in patients with BRF2 alterations, 21%, overall survival was drastically decreased, p = 9.332e-3, Fig.	('alterations', 'Var', (31, 42))	('patients', 'Species', '9606', (12, 20))	('BRF2', 'Gene', (26, 30))	('overall', 'CPA', (49, 56))	('decreased', 'NegReg', (82, 91))
463490	33176745	5d) showed no correlation with overall survival in the same invasive breast cancer data set we examined for BRF2 alterations.	('invasive breast cancer', 'Disease', 'MESH:D001943', (60, 82))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('breast cancer', 'Phenotype', 'HP:0003002', (69, 82))	('alterations', 'Var', (113, 124))	('invasive breast cancer', 'Disease', (60, 82))	('BRF2', 'Gene', (108, 112))
463491	33176745	Overall survival was dramatically decreased in breast cancer patients with co-occurring alterations in BRF2 and MYC, p = 5.299e-3, Fig.	('breast cancer', 'Disease', (47, 60))	('decreased', 'NegReg', (34, 43))	('breast cancer', 'Phenotype', 'HP:0003002', (47, 60))	('MYC', 'Gene', '4609', (112, 115))	('patients', 'Species', '9606', (61, 69))	('alterations', 'Var', (88, 99))	('Overall survival', 'CPA', (0, 16))	('BRF2', 'Gene', (103, 107))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('MYC', 'Gene', (112, 115))	('breast cancer', 'Disease', 'MESH:D001943', (47, 60))
463496	33176745	However, a separate query of the Breast Cancer METABRIC data set in the cBioPortal for BRF2 alterations and overall survival was correlative.	('Cancer', 'Phenotype', 'HP:0002664', (40, 46))	('Breast Cancer', 'Disease', 'MESH:D001943', (33, 46))	('alterations', 'Var', (92, 103))	('Breast Cancer', 'Phenotype', 'HP:0003002', (33, 46))	('BRF2', 'Gene', (87, 91))	('Breast Cancer', 'Disease', (33, 46))
463497	33176745	In patients aged 55-60, BRF2 was altered in 16% (36 of 229 patients) and median months survival in patients with alterations in BRF2 was 143.13 and 213.20, in patients with no alterations, p = 6.47e-3 (Supplemental Table 1).	('patients', 'Species', '9606', (99, 107))	('altered', 'Reg', (33, 40))	('patients', 'Species', '9606', (3, 11))	('patients', 'Species', '9606', (59, 67))	('alterations', 'Var', (113, 124))	('patients', 'Species', '9606', (159, 167))	('BRF2', 'Gene', (128, 132))
463499	33176745	Further query of the Breast Cancer METABRIC, for patients aged 55-60 with BRF2 alterations, ER positive status (n = 170) correlated with a decrease in overall survival, p = 7.87e-3, whereas ER negative status (n = 59) did not, p = 0.516 (Supplemental Table 1).	('alterations', 'Var', (79, 90))	('BRF2', 'Gene', (74, 78))	('ER', 'Gene', '2099', (190, 192))	('Breast Cancer', 'Phenotype', 'HP:0003002', (21, 34))	('Breast Cancer', 'Disease', (21, 34))	('Cancer', 'Phenotype', 'HP:0002664', (28, 34))	('patients', 'Species', '9606', (49, 57))	('overall survival', 'MPA', (151, 167))	('ER', 'Gene', '2099', (92, 94))	('Breast Cancer', 'Disease', 'MESH:D001943', (21, 34))	('decrease', 'NegReg', (139, 147))
463501	33176745	All patients with BRF2 alterations were coded as postmenopausal in the METABRIC) data set which differed from patients with BRF2 alterations in the TCGA, Firehose Legacy data set.	('patients', 'Species', '9606', (110, 118))	('BRF2', 'Gene', (18, 22))	('alterations', 'Var', (23, 34))	('patients', 'Species', '9606', (4, 12))
463502	33176745	Our study presents data suggesting BRF2 alterations in patients aged 35 to 50 correlates with overall survival (Fig.	('BRF2', 'Gene', (35, 39))	('overall survival', 'MPA', (94, 110))	('correlates with', 'Reg', (78, 93))	('alterations', 'Var', (40, 51))	('patients', 'Species', '9606', (55, 63))
463504	33176745	The decrease in overall survival in patients, 46-50, classified as ER- and with BRF2 alterations, correlated with postmenopausal status, p = 1.377e-4 (data not shown).	('BRF2', 'Gene', (80, 84))	('patients', 'Species', '9606', (36, 44))	('overall survival', 'MPA', (16, 32))	('decrease', 'NegReg', (4, 12))	('postmenopausal status', 'Phenotype', 'HP:0008209', (114, 135))	('ER', 'Gene', '2099', (67, 69))	('alterations', 'Var', (85, 96))
463507	33176745	A larger study of BRF2 alterations and ER status in breast cancer is needed to determine correlative value.	('breast cancer', 'Disease', 'MESH:D001943', (52, 65))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('ER', 'Gene', '2099', (39, 41))	('breast cancer', 'Disease', (52, 65))	('breast cancer', 'Phenotype', 'HP:0003002', (52, 65))	('alterations', 'Var', (23, 34))	('BRF2', 'Gene', (18, 22))
463515	33176745	Recently, it has been hypothesized that an oncogenic event, such as the mutation of c-MYC, is required to facilitate an aberrant increase in RNA pol III activity for the initiation and progression in a model of breast cancer.	('c-MYC', 'Gene', '4609', (84, 89))	('c-MYC', 'Gene', (84, 89))	('RNA pol III', 'Enzyme', (141, 152))	('breast cancer', 'Disease', 'MESH:D001943', (211, 224))	('activity', 'MPA', (153, 161))	('increase', 'PosReg', (129, 137))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('mutation', 'Var', (72, 80))	('breast cancer', 'Phenotype', 'HP:0003002', (211, 224))	('breast cancer', 'Disease', (211, 224))
463516	33176745	There is evidence that MYC amplifies transcription of RNA pol III genes when RNA pol III genes are hypomethylated in breast cancer, specifically the nc886 gene, a short noncoding RNA, which has been shown to be occupied by BRF1 and deregulated in cancer.	('cancer', 'Disease', (124, 130))	('nc886', 'Gene', '100126299', (149, 154))	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('MYC', 'Gene', '4609', (23, 26))	('breast cancer', 'Disease', 'MESH:D001943', (117, 130))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('cancer', 'Disease', (247, 253))	('hypomethylated', 'Var', (99, 113))	('breast cancer', 'Disease', (117, 130))	('cancer', 'Disease', 'MESH:D009369', (247, 253))	('breast cancer', 'Phenotype', 'HP:0003002', (117, 130))	('BRF1', 'Gene', (223, 227))	('MYC', 'Gene', (23, 26))	('BRF1', 'Gene', '2972', (223, 227))	('nc886', 'Gene', (149, 154))	('cancer', 'Disease', 'MESH:D009369', (124, 130))
463519	33176745	In this study, we demonstrate MYC and BRF2 alterations co-occur in breast invasive carcinoma, p = 0.008 (Fig.	('MYC', 'Gene', '4609', (30, 33))	('breast invasive carcinoma', 'Disease', 'MESH:D001943', (67, 92))	('co-occur', 'Reg', (55, 63))	('BRF2', 'Gene', (38, 42))	('alterations', 'Var', (43, 54))	('MYC', 'Gene', (30, 33))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))	('breast invasive carcinoma', 'Disease', (67, 92))
463522	33176745	8f) and co-occurring MYC and BRF2 alterations significantly decreased overall survival, p = 5.299e-3 (Fig.	('decreased', 'NegReg', (60, 69))	('overall survival', 'MPA', (70, 86))	('BRF2', 'Gene', (29, 33))	('MYC', 'Gene', '4609', (21, 24))	('alterations', 'Var', (34, 45))	('MYC', 'Gene', (21, 24))
463621	30171413	reported a significantly lower incidence of stenosis in 29 patients with esophageal cancer who underwent endoscopic resection lesions involving > 3/4th of the esophageal circumference and received prophylactic balloon dilatation begun within 1 week after the operation, as compared to a group that did not receive prophylactic balloon dilatation.	('dilatation', 'Phenotype', 'HP:0002617', (335, 345))	('stenosis', 'MPA', (44, 52))	('esophageal cancer', 'Disease', (73, 90))	('lesions', 'Var', (126, 133))	('lower', 'NegReg', (25, 30))	('esophageal cancer', 'Disease', 'MESH:D004938', (73, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('patients', 'Species', '9606', (59, 67))	('dilatation', 'Phenotype', 'HP:0002617', (218, 228))
463636	30171413	conducted a randomized comparative study of radiotherapy and chemoradiotherapy in patients with T1-3 N0-1 M0 esophageal cancer.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('M0 esophageal cancer', 'Disease', (106, 126))	('M0 esophageal cancer', 'Disease', 'MESH:D004938', (106, 126))	('patients', 'Species', '9606', (82, 90))	('T1-3 N0-1', 'Var', (96, 105))	('M0 esophageal cancer', 'Phenotype', 'HP:0011459', (106, 126))
463640	30171413	A prospective phase II clinical study (the JCOG9708 Study) conducted in Japan revealed promising results of chemoradiotherapy (60 Gy, cisplatin + 5-fluorouracil [5-FU]) in cStage I cases, with a complete response rate of 87.5%, 4-year survival rate of 80.5%, and 4-year recurrence-free survival rate of 68.1%, with no occurrences of any Grade >= 4 adverse events.	('5-fluorouracil', 'Chemical', 'MESH:D005472', (146, 160))	('JCOG9708', 'CellLine', 'None', (43, 51))	('cisplatin', 'Var', (134, 143))	('5-FU', 'Chemical', 'MESH:D005472', (162, 166))	('cisplatin', 'Chemical', 'MESH:D002945', (134, 143))	('cStage', 'Disease', (172, 178))
463815	26057471	By implementing a triple-filtering approach we identified a subset of highly biologically relevant miRNA-mRNA interactions and we demonstrated that the same genes/pathways affected by somatic mutations in cancer are affected by changes in the abundance of miRNAs.	('miR', 'Gene', '220972', (256, 259))	('miR', 'Gene', (256, 259))	('cancer', 'Disease', 'MESH:D009369', (205, 211))	('miR', 'Gene', '220972', (99, 102))	('miR', 'Gene', (99, 102))	('cancer', 'Disease', (205, 211))	('affected', 'Reg', (216, 224))	('abundance', 'MPA', (243, 252))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('mutations', 'Var', (192, 201))	('changes', 'Reg', (228, 235))
463824	26057471	Head and neck carcinogenesis is a multistep process driven by an accumulation of several genetic and epigenetic alterations in oncogenes and tumor suppressor genes leading to the progression of a normal cell to a cancer cell.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('epigenetic alterations', 'Var', (101, 123))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumor', 'Disease', (141, 146))	('cancer', 'Disease', 'MESH:D009369', (213, 219))	('neck carcinogenesis', 'Disease', (9, 28))	('cancer', 'Disease', (213, 219))	('oncogenes', 'Gene', (127, 136))	('neck carcinogenesis', 'Disease', 'MESH:D063646', (9, 28))
463825	26057471	Recently, next-generation sequencing (NGS) studies have revealed that the genetic alterations in HNSCC are mainly in a group of molecular pathways and/or biological processes including p53 pathways (TP53), mitogenic pathways (RAS/PI3K/mTOR pathway, PIK3CA, HRAS), cell cycle (CDKN2A), Notch pathways (NOTCH1, NOTCH2, NOTCH3), and cell communication and death (FAT1, CASP8) (Reviewed in).	('CASP8', 'Gene', '841', (366, 371))	('p53', 'Gene', '7157', (185, 188))	('cell cycle', 'CPA', (264, 274))	('PIK3CA', 'Gene', '5290', (249, 255))	('NOTCH2', 'Gene', (309, 315))	('NOTCH1', 'Gene', (301, 307))	('CDKN2A', 'Gene', '1029', (276, 282))	('mTOR', 'Gene', '2475', (235, 239))	('NOTCH3', 'Gene', (317, 323))	('HRAS', 'Gene', '3265', (257, 261))	('TP53', 'Gene', '7157', (199, 203))	('p53', 'Gene', (185, 188))	('NOTCH1', 'Gene', '4851', (301, 307))	('HRAS', 'Gene', (257, 261))	('CASP8', 'Gene', (366, 371))	('alterations', 'Var', (82, 93))	('FAT1', 'Gene', (360, 364))	('Notch pathways', 'Pathway', (285, 299))	('PIK3CA', 'Gene', (249, 255))	('mitogenic', 'CPA', (206, 215))	('NOTCH2', 'Gene', '4853', (309, 315))	('CDKN2A', 'Gene', (276, 282))	('cell communication', 'CPA', (330, 348))	('TP53', 'Gene', (199, 203))	('mTOR', 'Gene', (235, 239))	('FAT1', 'Gene', '2195', (360, 364))	('NOTCH3', 'Gene', '4854', (317, 323))
463828	26057471	Recent evidence has shown that miRNA mutations or mis-expression correlate with various human cancers and indicates that miRNAs can function as tumor suppressors and/or oncogenes (Reviewed in).	('cancers', 'Disease', 'MESH:D009369', (94, 101))	('tumor', 'Disease', (144, 149))	('cancers', 'Phenotype', 'HP:0002664', (94, 101))	('mis', 'Gene', '268', (50, 53))	('miR', 'Gene', '220972', (31, 34))	('miR', 'Gene', (31, 34))	('mutations', 'Var', (37, 46))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('miR', 'Gene', '220972', (121, 124))	('mis', 'Gene', (50, 53))	('human', 'Species', '9606', (88, 93))	('miR', 'Gene', (121, 124))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('cancers', 'Disease', (94, 101))
463884	26057471	Importantly, according to published data, the DAPK gene is one of the more often methylated in laryngeal squamous cell carcinoma and ablation of Klf4 in mice results in more severe dysplastic lesions in oral mucosa and higher incidence of squamous cell carcinoma.	('Klf4', 'Gene', (145, 149))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (239, 262))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (105, 128))	('more', 'PosReg', (169, 173))	('dysplastic lesions in oral', 'Phenotype', 'HP:0100649', (181, 207))	('carcinoma', 'Phenotype', 'HP:0030731', (253, 262))	('laryngeal squamous cell carcinoma', 'Disease', 'MESH:D002294', (95, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (239, 262))	('dysplastic lesions', 'Disease', 'MESH:D021782', (181, 199))	('dysplastic lesions', 'Disease', (181, 199))	('mice', 'Species', '10090', (153, 157))	('DAPK', 'Gene', (46, 50))	('squamous cell carcinoma', 'Disease', (239, 262))	('Klf4', 'Gene', '16600', (145, 149))	('ablation', 'Var', (133, 141))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (105, 128))	('DAPK', 'Gene', '1612', (46, 50))	('laryngeal squamous cell carcinoma', 'Disease', (95, 128))
463898	26057471	Mutations in the CDKN2A gene are found in approximately 25% of head and neck squamous cell carcinomas (HNSCC).	('head and neck squamous cell carcinomas', 'Phenotype', 'HP:0012288', (63, 101))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (77, 101))	('found', 'Reg', (33, 38))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (77, 100))	('neck squamous cell carcinomas', 'Disease', (72, 101))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (63, 100))	('CDKN2A', 'Gene', (17, 23))	('Mutations', 'Var', (0, 9))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('carcinomas', 'Phenotype', 'HP:0030731', (91, 101))	('CDKN2A', 'Gene', '1029', (17, 23))	('neck squamous cell carcinomas', 'Disease', 'MESH:D000077195', (72, 101))
463899	26057471	Most of these mutations lead to production of little or no functional p16(INK4a), a protein that regulate cell growth and division (reviewed in).	('p16', 'Gene', '1029', (70, 73))	('INK4a', 'Gene', '1029', (74, 79))	('p16', 'Gene', (70, 73))	('INK4a', 'Gene', (74, 79))	('mutations', 'Var', (14, 23))
463908	26057471	Regarding to miRNAs with reduced levels in the circulation of the HNSCC patients, our interaction network analysis underscores the key role of let-7a/f and miR-26a/b, among others.	('miR', 'Gene', '220972', (13, 16))	('miR', 'Gene', (13, 16))	('miR', 'Gene', '220972', (156, 159))	('miR', 'Gene', (156, 159))	('let-7a/f', 'Var', (143, 151))	('patients', 'Species', '9606', (72, 80))
463913	26057471	Yang and colleagues demonstrated that a polymorphism in the let-7 binding site in the 3'-UTR of the KRAS gene was associated with increased oncogenic KRAS expression in an in vitro model.	('KRAS', 'Gene', (100, 104))	('KRAS', 'Gene', '3845', (100, 104))	('binding', 'Interaction', (66, 73))	('let-7', 'Gene', (60, 65))	('polymorphism', 'Var', (40, 52))	('increased', 'PosReg', (130, 139))	('KRAS', 'Gene', (150, 154))	('KRAS', 'Gene', '3845', (150, 154))
463924	26057471	Remarkably, Kota and colleagues found that systemic administration of miR-26a in a mouse model of hepatocellular carcinoma resulted in inhibition of cancer cell proliferation, induction of tumor-specific apoptosis, and dramatic protection from disease progression.	('inhibition', 'NegReg', (135, 145))	('disease progression', 'CPA', (244, 263))	('tumor', 'Disease', (189, 194))	('cancer', 'Disease', (149, 155))	('miR-26a', 'Var', (70, 77))	('cancer', 'Disease', 'MESH:D009369', (149, 155))	('mouse', 'Species', '10090', (83, 88))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (98, 122))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('hepatocellular carcinoma', 'Disease', (98, 122))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (98, 122))	('protection', 'NegReg', (228, 238))
463936	26057471	In addition, a full exome and transcriptome sequencing of a large set of HNSCC-derived cells revealed that most HNSCC cells harbor multiple mutations and copy number variations in the 3'-UTR of EP300 that encompases the miR-150 binding site may contribute to HNSCC initiation and progression.	('HNSCC', 'Gene', (112, 117))	('HNSCC initiation', 'Disease', (259, 275))	('EP300', 'Gene', '2033', (194, 199))	('HNSCC initiation', 'Disease', 'MESH:D000077195', (259, 275))	('miR-150', 'Gene', (220, 227))	('mutations', 'Var', (140, 149))	('EP300', 'Gene', (194, 199))	('variations', 'Var', (166, 176))	('miR-150', 'Gene', '406942', (220, 227))	('contribute', 'Reg', (245, 255))
463941	26057471	By conducting miRNA-mRNA interaction network analysis of overtargeted COSMIC genes (triple-filtering strategy described in Material and Methods), we demonstrated that the same genes/pathways affected by somatic mutations in cancer are affected by changes in the abundance of miRNAs that target the respective relevant genes.	('affected', 'Reg', (235, 243))	('abundance', 'MPA', (262, 271))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('mutations', 'Var', (211, 220))	('changes', 'Reg', (247, 254))	('miR', 'Gene', '220972', (275, 278))	('miR', 'Gene', (275, 278))	('cancer', 'Disease', 'MESH:D009369', (224, 230))	('miR', 'Gene', (14, 17))	('miR', 'Gene', '220972', (14, 17))	('cancer', 'Disease', (224, 230))
463951	26057471	The association between cancer and changes in these novel circulating RNA species raises the possibility of a causal connection between carcinogenesis and the tRNA- and YRNA-derived small RNAs.	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('carcinogenesis', 'Disease', 'MESH:D063646', (136, 150))	('association', 'Interaction', (4, 15))	('tRNA-', 'Gene', (159, 164))	('carcinogenesis', 'Disease', (136, 150))	('cancer', 'Disease', (24, 30))	('cancer', 'Disease', 'MESH:D009369', (24, 30))	('tRNA-', 'Gene', '4563', (159, 164))	('changes', 'Var', (35, 42))
463973	26057471	Expression values of miRNAs and tRNA- and YRNA-derived small RNAs obtained as described above were analyzed with the Bioconductor package edgeR to detect statistical differences in the levels of circulating small RNAs between HNSCC and control groups.	('HNSCC', 'Var', (226, 231))	('miR', 'Gene', '220972', (21, 24))	('miR', 'Gene', (21, 24))	('tRNA-', 'Gene', (32, 37))	('tRNA-', 'Gene', '4563', (32, 37))
463987	24550697	The majority of these novel techniques in cancer diagnostic are based on detection of mutations on the DNA level or aberrant gene expression, relying on quantification of mRNA transcripts.	('mutations', 'Var', (86, 95))	('N', 'Chemical', 'MESH:D009584', (173, 174))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('N', 'Chemical', 'MESH:D009584', (104, 105))	('aberrant gene expression', 'Var', (116, 140))
463991	24550697	Typical molecular biomarkers currently used in clinical setting are proteins, specific variations in the DNA sequence (germline or somatic), abnormal methylation patterns, aberrant transcripts, miRNAs, or other biological molecules, such as lipids and metabolic products.	('miRNAs', 'Var', (194, 200))	('lipids', 'Chemical', 'MESH:D008055', (241, 247))	('N', 'Chemical', 'MESH:D009584', (197, 198))	('abnormal', 'Var', (141, 149))	('N', 'Chemical', 'MESH:D009584', (106, 107))	('variations', 'Var', (87, 97))	('proteins', 'Protein', (68, 76))	('clinical', 'Species', '191496', (47, 55))	('methylation', 'MPA', (150, 161))	('DNA sequence', 'Gene', (105, 117))	('aberrant transcripts', 'Var', (172, 192))
464000	24550697	The interrogation of data on aberrant posttranslational modifications of proteins could reveal proteins, whose genetic information is intact, but pathogenic alterations render these proteins either nonfunctional, more stable, or more prone to degradation, or they could even obtain the ability to form new interactions with other cellular molecules such as proteins, nucleic acids, lipids, and cofactors, which are not their normal binding partners.	('nonfunctional', 'MPA', (198, 211))	('more', 'PosReg', (213, 217))	('obtain', 'Reg', (275, 281))	('lipids', 'Chemical', 'MESH:D008055', (382, 388))	('degradation', 'MPA', (243, 254))	('interactions', 'Interaction', (306, 318))	('form', 'Reg', (297, 301))	('alterations', 'Var', (157, 168))
464004	24550697	Deciphering the clinical relevance of candidate proteins or protein profiles and introduction of new protein biomarkers into clinical setting is further complicated by the vast dynamic range of proteins and their normal isoforms, new isoforms associated with the particular type of cancer, aberrant processing into mature forms, anomalous chemical modifications of proteins, formation of immunocomplexes or complexes with other molecules, and heterogeneity of the disease.	('formation', 'Reg', (375, 384))	('associated', 'Reg', (243, 253))	('cancer', 'Phenotype', 'HP:0002664', (282, 288))	('clinical', 'Species', '191496', (125, 133))	('anomalous', 'Var', (329, 338))	('immunocomplexes', 'Interaction', (388, 403))	('clinical', 'Species', '191496', (16, 24))	('cancer', 'Disease', 'MESH:D009369', (282, 288))	('cancer', 'Disease', (282, 288))	('aberrant', 'Var', (290, 298))	('complexes', 'Interaction', (407, 416))
464008	24550697	Cancer molecular heterogeneity can be observed on several levels: (1) genetic heterogeneity:copy number variations, point mutations, and different levels of gene expression; (2) heterogeneity in the germline background, which promotes generation of different aberrations in tumour cells and surrounding tumour stroma in individual patients; (3) epigenetic heterogeneity; and (4) phenotypic heterogeneity.	('tumour', 'Disease', (303, 309))	('tumour', 'Phenotype', 'HP:0002664', (274, 280))	('epigenetic heterogeneity', 'Var', (345, 369))	('copy', 'Var', (92, 96))	('tumour', 'Disease', 'MESH:D009369', (274, 280))	('tumour', 'Disease', (274, 280))	('tumour stroma', 'Disease', (303, 316))	('heterogeneity', 'Var', (178, 191))	('Cancer', 'Disease', (0, 6))	('variations', 'Var', (104, 114))	('tumour stroma', 'Disease', 'MESH:D009369', (303, 316))	('tumour', 'Phenotype', 'HP:0002664', (303, 309))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('tumour', 'Disease', 'MESH:D009369', (303, 309))	('patients', 'Species', '9606', (331, 339))
464042	24550697	Mutated TP53 and RB1 are also associated with a higher risk, and other candidate genes include cholinergic receptor nicotinic alpha 3 (CHRNA3), cholinergic receptor nicotinic beta 4 (CHRNB4), and CHRNA5 , as well as EGFR.	('EGFR', 'Gene', (216, 220))	('EGFR', 'Gene', '1956', (216, 220))	('CHRNA5', 'Gene', '1138', (196, 202))	('Mutated', 'Var', (0, 7))	('CHRNA3', 'Gene', (135, 141))	('RB1', 'Gene', '5925', (17, 20))	('cholinergic receptor nicotinic alpha 3', 'Gene', '1136', (95, 133))	('CHRNA3', 'Gene', '1136', (135, 141))	('cholinergic receptor nicotinic alpha 3', 'Gene', (95, 133))	('TP53', 'Gene', '7157', (8, 12))	('TP53', 'Gene', (8, 12))	('cholinergic receptor nicotinic beta 4', 'Gene', '1143', (144, 181))	('CHRNB4', 'Gene', '1143', (183, 189))	('CHRNB4', 'Gene', (183, 189))	('RB1', 'Gene', (17, 20))	('CHRNA5', 'Gene', (196, 202))	('cholinergic receptor nicotinic beta 4', 'Gene', (144, 181))
464072	24550697	Another candidate for a cancer specific single marker capable of identifying early-stage lung cancer within at-risk groups without resort to invasive procedures is a variant form of the nuclear matrix-associated DNA replication factor Ciz1.	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('lung cancer', 'Disease', (89, 100))	('lung cancer', 'Phenotype', 'HP:0100526', (89, 100))	('Ciz1', 'Gene', (235, 239))	('cancer', 'Disease', (24, 30))	('cancer', 'Disease', 'MESH:D009369', (24, 30))	('N', 'Chemical', 'MESH:D009584', (213, 214))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('Ciz1', 'Gene', '25792', (235, 239))	('cancer', 'Disease', 'MESH:D009369', (94, 100))	('lung cancer', 'Disease', 'MESH:D008175', (89, 100))	('cancer', 'Disease', (94, 100))	('variant', 'Var', (166, 173))
464116	24550697	A familial history of prostate cancer, increasing age, ethnicity, low testosterone levels, diet rich in fats, and BRCA1/2 mutations can contribute to the development of this neoplasm.	('neoplasm', 'Phenotype', 'HP:0002664', (174, 182))	('prostate cancer', 'Disease', (22, 37))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('BRCA1/2', 'Gene', (114, 121))	('contribute', 'Reg', (136, 146))	('prostate cancer', 'Disease', 'MESH:D011471', (22, 37))	('BRCA1/2', 'Gene', '672;675', (114, 121))	('fats', 'Chemical', 'MESH:D005223', (104, 108))	('mutations', 'Var', (122, 131))	('low', 'NegReg', (66, 69))	('testosterone', 'Chemical', 'MESH:D013739', (70, 82))	('prostate cancer', 'Phenotype', 'HP:0012125', (22, 37))	('low testosterone', 'Phenotype', 'HP:0040171', (66, 82))	('testosterone levels', 'MPA', (70, 89))	('men', 'Species', '9606', (161, 164))
464149	24550697	The major disease pathways include the aneuploidy or chromosomal instability pathway involving mutations in APC, DCC, TP53, KRAS, SMAD2, and SMAD4 and the CpG island methylator phenotype (CIMP) pathway, which is the second major pathway leading to the development of sporadic colorectal cancers and includes sporadic microsatellite instability (MSI) high cancers.	('KRAS', 'Gene', (124, 128))	('sporadic microsatellite instability (MSI) high cancers', 'Disease', 'MESH:D053842', (308, 362))	('CIMP', 'Chemical', '-', (188, 192))	('cancer', 'Phenotype', 'HP:0002664', (287, 293))	('TP53', 'Gene', (118, 122))	('APC', 'Gene', '324', (108, 111))	('aneuploidy', 'Disease', 'MESH:D000782', (39, 49))	('SMAD4', 'Gene', (141, 146))	('SMAD2', 'Gene', (130, 135))	('cancers', 'Phenotype', 'HP:0002664', (287, 294))	('DCC', 'Gene', '1630', (113, 116))	('mutations', 'Var', (95, 104))	('leading to', 'Reg', (237, 247))	('chromosomal instability', 'Phenotype', 'HP:0040012', (53, 76))	('DCC', 'Gene', (113, 116))	('aneuploidy', 'Disease', (39, 49))	('SMAD4', 'Gene', '4089', (141, 146))	('cancer', 'Phenotype', 'HP:0002664', (355, 361))	('TP53', 'Gene', '7157', (118, 122))	('APC', 'Gene', (108, 111))	('sporadic colorectal cancers', 'Disease', 'MESH:D015179', (267, 294))	('cancers', 'Phenotype', 'HP:0002664', (355, 362))	('sporadic colorectal cancers', 'Disease', (267, 294))	('KRAS', 'Gene', '3845', (124, 128))	('colorectal cancer', 'Phenotype', 'HP:0003003', (276, 293))	('men', 'Species', '9606', (259, 262))	('SMAD2', 'Gene', '4087', (130, 135))
464150	24550697	The third pathway, the MSI pathway, is the consequence of germline mutation in a DNA mismatch repair (MMR) genes (i.e., MLH1, MSH2, MSH6, and PMS2).	('MSH6', 'Gene', (132, 136))	('MLH1', 'Gene', '4292', (120, 124))	('PMS2', 'Gene', (142, 146))	('MSI pathway', 'Pathway', (23, 34))	('MLH1', 'Gene', (120, 124))	('MSH2', 'Gene', (126, 130))	('N', 'Chemical', 'MESH:D009584', (82, 83))	('MSH2', 'Gene', '4436', (126, 130))	('MSH6', 'Gene', '2956', (132, 136))	('germline mutation', 'Var', (58, 75))	('MMR) genes', 'Gene', (102, 112))	('PMS2', 'Gene', '5395', (142, 146))
464153	24550697	It is caused by biallelic germline mutations in the Mut Y human homologue (MUTYH) gene, encoding A/G specific adenine DNA glycosylase excision repair protein.	('MUTYH', 'Gene', (75, 80))	('MUTYH', 'Gene', '4595', (75, 80))	('human', 'Species', '9606', (58, 63))	('N', 'Chemical', 'MESH:D009584', (119, 120))	('biallelic', 'Var', (16, 25))	('caused by', 'Reg', (6, 15))
464155	24550697	With regard to risk stratification, the most robust identification strategy to date is detecting germline mutations in genes that cause these and other hereditary colon cancer syndromes (e.g., APC mutations in FAP and MSI and mutations in MMR genes in Lynch syndrome, MUTYH biallelic mutations in MAP, and BMPR1A in juvenile polyposis, etc.).	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('Lynch syndrome', 'Disease', (252, 266))	('BMPR1A', 'Gene', '657', (306, 312))	('juvenile polyposis', 'Disease', (316, 334))	('juvenile polyposis', 'Phenotype', 'HP:0004784', (316, 334))	('MUTYH', 'Gene', (268, 273))	('Lynch syndrome', 'Disease', 'MESH:D003123', (252, 266))	('APC', 'Gene', '324', (193, 196))	('BMPR1A', 'Gene', (306, 312))	('mutations', 'Var', (197, 206))	('MUTYH', 'Gene', '4595', (268, 273))	('hereditary colon cancer syndromes', 'Disease', (152, 185))	('mutations', 'Var', (226, 235))	('colon cancer', 'Phenotype', 'HP:0003003', (163, 175))	('MAP', 'Gene', (297, 300))	('hereditary colon cancer syndromes', 'Disease', 'MESH:D015179', (152, 185))	('cause', 'Reg', (130, 135))	('MSI', 'Gene', (218, 221))	('MMR', 'Gene', (239, 242))	('APC', 'Gene', (193, 196))	('mutations', 'Var', (106, 115))	('FAP', 'Gene', (210, 213))	('juvenile polyposis', 'Disease', 'MESH:C537702', (316, 334))
464158	24550697	In some cases, there is no known family history of the inherited syndrome; diagnosis is then based on certain histopathological characteristics of polyps and/or tumours, followed by confirmation of inherited genetic factors using genetic testing for mutations in MMR genes, MUTYH, and APC.	('MMR genes', 'Gene', (263, 272))	('MUTYH', 'Gene', (274, 279))	('MUTYH', 'Gene', '4595', (274, 279))	('polyps and/or tumours', 'Disease', 'MESH:D011127', (147, 168))	('tumour', 'Phenotype', 'HP:0002664', (161, 167))	('tumours', 'Phenotype', 'HP:0002664', (161, 168))	('APC', 'Gene', (285, 288))	('inherited syndrome', 'Disease', (55, 73))	('mutations', 'Var', (250, 259))	('APC', 'Gene', '324', (285, 288))	('inherited syndrome', 'Disease', 'None', (55, 73))	('polyps and/or tumours', 'Disease', (147, 168))
464163	24550697	It is well established that early screening for polyps in family members of patients with characterized mutations in MMR (Lynch syndrome), APC (FAP), or MUTYH (MAP) genes is beneficial in improving detection of malignant changes and reduces mortality.	('reduces', 'NegReg', (233, 240))	('patients', 'Species', '9606', (76, 84))	('mutations', 'Var', (104, 113))	('APC', 'Gene', '324', (139, 142))	('MMR', 'Gene', (117, 120))	('polyps', 'Disease', (48, 54))	('malignant changes', 'Phenotype', 'HP:0002664', (211, 228))	('Lynch syndrome', 'Disease', (122, 136))	('improving', 'PosReg', (188, 197))	('MUTYH', 'Gene', '4595', (153, 158))	('polyps', 'Disease', 'MESH:D011127', (48, 54))	('Lynch syndrome', 'Disease', 'MESH:D003123', (122, 136))	('APC', 'Gene', (139, 142))	('MUTYH', 'Gene', (153, 158))	('detection', 'MPA', (198, 207))	('mortality', 'CPA', (241, 250))
464181	24550697	Another interesting approach involves detecting mutant tumour proteins in the serum or tissues of colorectal cancer patients using immunoprecipitation or gel-based methods for enrichment of tumour specific biomarkers, followed by LC-MS/MS and targeted mass spectrometry approach, such as selected reaction monitoring (SRM) MS or multiple reaction monitoring (MRM) MS. Ruppen-Canas et al.	('colorectal cancer', 'Disease', (98, 115))	('tumour', 'Disease', (55, 61))	('tumour', 'Disease', (190, 196))	('mutant', 'Var', (48, 54))	('patients', 'Species', '9606', (116, 124))	('colorectal cancer', 'Disease', 'MESH:D015179', (98, 115))	('tumour', 'Phenotype', 'HP:0002664', (55, 61))	('tumour', 'Phenotype', 'HP:0002664', (190, 196))	('tumour', 'Disease', 'MESH:D009369', (55, 61))	('colorectal cancer', 'Phenotype', 'HP:0003003', (98, 115))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('men', 'Species', '9606', (182, 185))	('tumour', 'Disease', 'MESH:D009369', (190, 196))
464182	24550697	used immuno-LC-MS-SRM approach to detect wild-type and mutant RAS proteins in colorectal and pancreatic cancer tissues, benign skin tumours, and pancreatic cyst fluid.	('benign skin tumours', 'Disease', 'MESH:D012878', (120, 139))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('proteins', 'Protein', (66, 74))	('pancreatic cyst', 'Disease', (145, 160))	('mutant', 'Var', (55, 61))	('pancreatic cyst', 'Disease', 'MESH:D010181', (145, 160))	('pancreatic cyst', 'Phenotype', 'HP:0001737', (145, 160))	('tumour', 'Phenotype', 'HP:0002664', (132, 138))	('tumours', 'Phenotype', 'HP:0002664', (132, 139))	('benign skin tumours', 'Disease', (120, 139))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (93, 110))	('colorectal and pancreatic cancer', 'Disease', 'MESH:D010190', (78, 110))	('RAS', 'Gene', (62, 65))
464184	24550697	Identification of mutant proteins in clinical samples could potentially serve as drug-related biomarkers and aid in selection of appropriate chemotherapy strategies.	('aid', 'Gene', (109, 112))	('mutant', 'Var', (18, 24))	('aid', 'Gene', '57379', (109, 112))	('clinical samples', 'Species', '191496', (37, 53))	('proteins', 'Protein', (25, 33))
464195	24550697	In another small-scale screening Ang and colleagues identified nine proteins, a-1-antityrpsin, a-1-acid glycoprotein, complement C3, fibrinogen, haptoglobin, hemoglobin alpha, hemoglobin beta, myeloblastin, and transferrin, which were detected only in the samples from patients with colorectal cancer.	('Ang', 'Gene', (33, 36))	('myeloblastin', 'Gene', (193, 205))	('colorectal cancer', 'Phenotype', 'HP:0003003', (283, 300))	('haptoglobin', 'Gene', (145, 156))	('patients', 'Species', '9606', (269, 277))	('hemoglobin beta', 'Gene', '3043', (176, 191))	('complement C3', 'Gene', '718', (118, 131))	('a-1-antityrpsin', 'Var', (78, 93))	('fibrinogen', 'Gene', '2244', (133, 143))	('cancer', 'Phenotype', 'HP:0002664', (294, 300))	('complement C3', 'Gene', (118, 131))	('colorectal cancer', 'Disease', 'MESH:D015179', (283, 300))	('Ang', 'Gene', '283', (33, 36))	('transferrin', 'Gene', (211, 222))	('colorectal cancer', 'Disease', (283, 300))	('hemoglobin beta', 'Gene', (176, 191))	('myeloblastin', 'Gene', '5657', (193, 205))	('fibrinogen', 'Gene', (133, 143))	('transferrin', 'Gene', '7018', (211, 222))	('haptoglobin', 'Gene', '3240', (145, 156))
464205	24550697	It is caused by a germline mutation in CDH1, a gene coding for E-cadherin, a calcium dependent cell dependent cell adhesion protein responsible for cell-cell interaction and cell polarity.	('E-cadherin', 'Gene', '999', (63, 73))	('E-cadherin', 'Gene', (63, 73))	('CDH1', 'Gene', (39, 43))	('calcium', 'Chemical', 'MESH:D002118', (77, 84))	('caused by', 'Reg', (6, 15))	('germline mutation', 'Var', (18, 35))	('CDH1', 'Gene', '999', (39, 43))
464237	24550697	Proteomic approaches based on ELISA identified potential saliva biomarkers in patients with oral cancer, such as underrepresentation of secretory immunoglobulin A, 8-oxoguanine DNA glycosylase, phosphorylated-Src, and mammary serine protease inhibitor (Maspin) and overrepresentation of insulin growth factor I, metalloproteinases MMP-9, MMP-2, CD44, cytokeratin 19 fragment, tissue polypeptide antigen, CA125, and Cyclin D1.	('CD44', 'Gene', (345, 349))	('MMP-9', 'Gene', '4318', (331, 336))	('patients', 'Species', '9606', (78, 86))	('MMP-9', 'Gene', (331, 336))	('CA125', 'Gene', '94025', (404, 409))	('oral cancer', 'Disease', 'MESH:D009062', (92, 103))	('underrepresentation', 'Var', (113, 132))	('oral cancer', 'Disease', (92, 103))	('MMP-2', 'Gene', '4313', (338, 343))	('8-oxoguanine DNA glycosylase', 'Gene', (164, 192))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('8-oxoguanine DNA glycosylase', 'Gene', '4968', (164, 192))	('overrepresentation', 'PosReg', (265, 283))	('Src', 'Gene', (209, 212))	('Maspin', 'Gene', '5268', (253, 259))	('MMP-2', 'Gene', (338, 343))	('insulin growth', 'Protein', (287, 301))	('cytokeratin 19', 'Gene', (351, 365))	('CA125', 'Gene', (404, 409))	('Src', 'Gene', '6714', (209, 212))	('Cyclin D1', 'Gene', '595', (415, 424))	('cytokeratin 19', 'Gene', '3880', (351, 365))	('Cyclin D1', 'Gene', (415, 424))	('tissue', 'Protein', (376, 382))	('men', 'Species', '9606', (370, 373))	('Maspin', 'Gene', (253, 259))	('CD44', 'Gene', '960', (345, 349))
464266	33173410	Genes encoding HNF1B transcription factors are prone to various types of mutations, causing the occurrence and progression of various diseases, including diabetes, renal insufficiency, and various malignant tumors.	('diabetes', 'Disease', (154, 162))	('malignant tumors', 'Disease', 'MESH:D009369', (197, 213))	('diabetes', 'Disease', 'MESH:D003920', (154, 162))	('renal insufficiency', 'Disease', (164, 183))	('HNF1B', 'Gene', '6928', (15, 20))	('tumors', 'Phenotype', 'HP:0002664', (207, 213))	('HNF1B', 'Gene', (15, 20))	('renal insufficiency', 'Disease', 'MESH:D051437', (164, 183))	('renal insufficiency', 'Phenotype', 'HP:0000083', (164, 183))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('causing', 'Reg', (84, 91))	('malignant tumors', 'Disease', (197, 213))	('mutations', 'Var', (73, 82))
464267	33173410	In the present study, we evaluated expression and mutations of HNF1B in different types of cancer from The Cancer Genome Atlas (TCGA) database.	('mutations', 'Var', (50, 59))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('Cancer', 'Phenotype', 'HP:0002664', (107, 113))	('Cancer', 'Disease', (107, 113))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('HNF1B', 'Gene', '6928', (63, 68))	('Cancer', 'Disease', 'MESH:D009369', (107, 113))	('HNF1B', 'Gene', (63, 68))
464273	33173410	The cBio cancer genomics portal was used to explore mutations and copy-number alterations of HNF1B in the TCGA pan-cancer studies.	('mutations', 'Var', (52, 61))	('HNF1B', 'Gene', (93, 98))	('cancer', 'Disease', (115, 121))	('cancer', 'Disease', (9, 15))	('copy-number alterations', 'Var', (66, 89))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('HNF1B', 'Gene', '6928', (93, 98))
464287	33173410	As shown in Figure 2A, the mutation types of HNF1B included missense mutations, truncating mutations, in-frame mutations and other mutations.	('truncating', 'MPA', (80, 90))	('HNF1B', 'Gene', (45, 50))	('missense mutations', 'Var', (60, 78))	('in-frame mutations', 'Var', (102, 120))	('HNF1B', 'Gene', '6928', (45, 50))
464289	33173410	Additionally, cancer patients with HNF1B mutations are more susceptible to many other gene mutations, including TP53, TTN, MUC16, CSMD3, SYNE1, ZFHX4, LRP1B, XIRP2, PCLO, FLG, FAT4, DNAH5, HYDIN, PIK3CA, USH2A, HMCN1, RYR2, CSMD1, FAT3 and KMT2D (Figure 2C).	('ZFHX4', 'Gene', (144, 149))	('SYNE1', 'Gene', (137, 142))	('MUC16', 'Gene', '94025', (123, 128))	('HNF1B', 'Gene', (35, 40))	('DNAH5', 'Gene', '1767', (182, 187))	('PIK3CA', 'Gene', (196, 202))	('LRP1B', 'Gene', (151, 156))	('XIRP2', 'Gene', (158, 163))	('patients', 'Species', '9606', (21, 29))	('TP53', 'Gene', '7157', (112, 116))	('PCLO', 'Gene', (165, 169))	('HYDIN', 'Gene', (189, 194))	('cancer', 'Disease', 'MESH:D009369', (14, 20))	('FAT3', 'Gene', (231, 235))	('SYNE1', 'Gene', '23345', (137, 142))	('TTN', 'Gene', '7273', (118, 121))	('HMCN1', 'Gene', (211, 216))	('mutations', 'Var', (41, 50))	('FLG', 'Gene', (171, 174))	('ZFHX4', 'Gene', '79776', (144, 149))	('FAT4', 'Gene', '79633', (176, 180))	('TTN', 'Gene', (118, 121))	('CSMD3', 'Gene', '114788', (130, 135))	('KMT2D', 'Gene', '8085', (240, 245))	('MUC16', 'Gene', (123, 128))	('CSMD1', 'Gene', '64478', (224, 229))	('DNAH5', 'Gene', (182, 187))	('CSMD1', 'Gene', (224, 229))	('FAT3', 'Gene', '120114', (231, 235))	('LRP1B', 'Gene', '53353', (151, 156))	('FLG', 'Gene', '2312', (171, 174))	('USH2A', 'Gene', (204, 209))	('PIK3CA', 'Gene', '5290', (196, 202))	('HMCN1', 'Gene', '83872', (211, 216))	('CSMD3', 'Gene', (130, 135))	('PCLO', 'Gene', '27445', (165, 169))	('TP53', 'Gene', (112, 116))	('cancer', 'Disease', (14, 20))	('XIRP2', 'Gene', '129446', (158, 163))	('FAT4', 'Gene', (176, 180))	('RYR2', 'Gene', (218, 222))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('HYDIN', 'Gene', '54768', (189, 194))	('KMT2D', 'Gene', (240, 245))	('RYR2', 'Gene', '6262', (218, 222))	('USH2A', 'Gene', '7399', (204, 209))	('HNF1B', 'Gene', '6928', (35, 40))
464307	33173410	As shown in Figure 6A, CD8+ T cell levels were negatively associated with overall survival in the low HNF1B expression group of kidney renal papillary cell carcinoma (KIRP, HR=3.76, P=0.00305) and uveal melanoma (UVM, HR=2.99, P=0.0479).	('CD8', 'Gene', (23, 26))	('kidney renal papillary cell carcinoma', 'Disease', (128, 165))	('renal papillary cell carcinoma', 'Phenotype', 'HP:0006766', (135, 165))	('CD8', 'Gene', '925', (23, 26))	('carcinoma', 'Phenotype', 'HP:0030731', (156, 165))	('kidney renal papillary cell carcinoma', 'Disease', 'MESH:C538614', (128, 165))	('uveal melanoma', 'Phenotype', 'HP:0007716', (197, 211))	('uveal melanoma', 'Disease', 'MESH:C536494', (197, 211))	('low', 'Var', (98, 101))	('HNF1B', 'Gene', '6928', (102, 107))	('uveal melanoma', 'Disease', (197, 211))	('HNF1B', 'Gene', (102, 107))	('melanoma', 'Phenotype', 'HP:0002861', (203, 211))	('negatively', 'NegReg', (47, 57))	('overall', 'MPA', (74, 81))
464309	33173410	In the low HNF1B expression group of liver hepatocellular carcinoma (LIHC), CD8+ T cells were revealed to be positively associated with overall survival.	('associated', 'Reg', (120, 130))	('HNF1B', 'Gene', '6928', (11, 16))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (43, 67))	('HNF1B', 'Gene', (11, 16))	('low', 'Var', (7, 10))	('CD8', 'Gene', '925', (76, 79))	('CD8', 'Gene', (76, 79))	('liver hepatocellular carcinoma', 'Disease', 'MESH:D006528', (37, 67))	('overall', 'MPA', (136, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))	('liver hepatocellular carcinoma', 'Disease', (37, 67))
464321	33173410	Moreover, it has been reported that the single nucleotide polymorphism (SNP) of HNF1B can affect the susceptibility of endometrial tumors.	('affect', 'Reg', (90, 96))	('endometrial tumors', 'Disease', 'MESH:D016889', (119, 137))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('HNF1B', 'Gene', (80, 85))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('endometrial tumors', 'Disease', (119, 137))	('single nucleotide polymorphism', 'Var', (40, 70))	('HNF1B', 'Gene', '6928', (80, 85))
464322	33173410	conducted gene sequencing studies on endometrial cancer patients and control groups and found that HNF1B gene SNP (rs4430796, G A) can reduce the incidence of endometrial cancer.	('rs4430796', 'Var', (115, 124))	('patients', 'Species', '9606', (56, 64))	('rs4430796', 'Mutation', 'rs4430796', (115, 124))	('endometrial cancer', 'Disease', (159, 177))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('endometrial cancer', 'Disease', (37, 55))	('endometrial cancer', 'Phenotype', 'HP:0012114', (37, 55))	('HNF1B', 'Gene', '6928', (99, 104))	('endometrial cancer', 'Disease', 'MESH:D016889', (159, 177))	('endometrial cancer', 'Phenotype', 'HP:0012114', (159, 177))	('endometrial cancer', 'Disease', 'MESH:D016889', (37, 55))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('HNF1B', 'Gene', (99, 104))	('reduce', 'NegReg', (135, 141))
464325	33173410	Most HNF1B mutations are clustered in the first 4 exons of the gene.	('HNF1B', 'Gene', (5, 10))	('mutations', 'Var', (11, 20))	('HNF1B', 'Gene', '6928', (5, 10))
464327	33173410	A total of 106 HNF1B gene mutations, including gene deletion (34%), missense mutation (31%), frameshift deletion or insertion mutation (15%), nonsense mutation (11%) and splicing point mutation (8%) have been reported.	('frameshift deletion', 'Var', (93, 112))	('HNF1B', 'Gene', '6928', (15, 20))	('HNF1B', 'Gene', (15, 20))	('missense mutation', 'Var', (68, 85))	('insertion mutation', 'Var', (116, 134))	('splicing', 'MPA', (170, 178))	('nonsense mutation', 'Var', (142, 159))	('gene deletion', 'Var', (47, 60))
464328	33173410	According to these results, our study found that HNF1B mutations occurred widely in human cancers and that the most common type is missense mutations.	('cancers', 'Disease', (90, 97))	('mutations', 'Var', (55, 64))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('HNF1B', 'Gene', (49, 54))	('human', 'Species', '9606', (84, 89))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('missense mutations', 'Var', (131, 149))	('cancers', 'Disease', 'MESH:D009369', (90, 97))	('HNF1B', 'Gene', '6928', (49, 54))
464329	33173410	Additionally, patients with HNF1B mutations are more prone to mutations in other genes, such as TP53, TTN and MUC16.	('TTN', 'Gene', (102, 105))	('TP53', 'Gene', (96, 100))	('MUC16', 'Gene', (110, 115))	('TTN', 'Gene', '7273', (102, 105))	('prone', 'Reg', (53, 58))	('MUC16', 'Gene', '94025', (110, 115))	('mutations', 'Var', (34, 43))	('patients', 'Species', '9606', (14, 22))	('HNF1B', 'Gene', '6928', (28, 33))	('mutations', 'Var', (62, 71))	('TP53', 'Gene', '7157', (96, 100))	('HNF1B', 'Gene', (28, 33))
464341	33173410	HNF1B mutations are widely observed in tumors and interact with different genes in different cancer types, which may be the cause of the distinct prognostic values in cancers.	('interact', 'Reg', (50, 58))	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('cancer', 'Disease', (167, 173))	('cancers', 'Phenotype', 'HP:0002664', (167, 174))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('cancers', 'Disease', (167, 174))	('HNF1B', 'Gene', '6928', (0, 5))	('cancers', 'Disease', 'MESH:D009369', (167, 174))	('HNF1B', 'Gene', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('tumors', 'Disease', (39, 45))	('mutations', 'Var', (6, 15))
464346	33020242	Other mechanisms for promoting antitumor T-cell function are the targeting of costimulatory molecules expressed on the surface of T cells, such as 4-1BB, OX40, inducible T-cell costimulator and glucocorticoid-induced tumor necrosis factor receptor.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('promoting', 'PosReg', (21, 30))	('tumor', 'Disease', (217, 222))	('4-1BB', 'Var', (147, 152))	('inducible T-cell costimulator', 'Gene', '54167', (160, 189))	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('OX40', 'Var', (154, 158))	('tumor necrosis', 'Disease', (217, 231))	('tumor', 'Disease', (35, 40))	('inducible T-cell costimulator', 'Gene', (160, 189))	('tumor', 'Disease', 'MESH:D009369', (217, 222))	('tumor necrosis', 'Disease', 'MESH:D009336', (217, 231))
464361	33020242	4-1BB, OX40, glucocorticoid-induced tumor necrosis factor (TNF) receptor (GITR) and other receptors in the TNF superfamily can synergize with TCR signaling to enhance T-cell responses and survival.	('TCR', 'Gene', (142, 145))	('tumor necrosis', 'Disease', (36, 50))	('TNF', 'Gene', (59, 62))	('survival', 'CPA', (188, 196))	('TNF', 'Gene', (107, 110))	('TNF', 'Gene', '7124', (59, 62))	('enhance T-cell responses', 'Phenotype', 'HP:0005419', (159, 183))	('enhance', 'PosReg', (159, 166))	('OX40', 'Var', (7, 11))	('tumor necrosis', 'Disease', 'MESH:D009336', (36, 50))	('TNF', 'Gene', '7124', (107, 110))	('TCR', 'Gene', '6962', (142, 145))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('T-cell responses', 'CPA', (167, 183))
464369	33020242	OX40 is expressed frequently in breast cancer, melanoma, head and neck cancer, colon cancer, and B cell lymphoma cells.	('colon cancer', 'Disease', (79, 91))	('breast cancer', 'Phenotype', 'HP:0003002', (32, 45))	('B cell lymphoma', 'Disease', 'MESH:D016393', (97, 112))	('breast cancer', 'Disease', 'MESH:D001943', (32, 45))	('lymphoma', 'Phenotype', 'HP:0002665', (104, 112))	('breast cancer', 'Disease', (32, 45))	('colon cancer', 'Phenotype', 'HP:0003003', (79, 91))	('melanoma', 'Phenotype', 'HP:0002861', (47, 55))	('melanoma', 'Disease', (47, 55))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('neck cancer', 'Disease', 'MESH:D006258', (66, 77))	('B cell lymphoma', 'Phenotype', 'HP:0012191', (97, 112))	('neck cancer', 'Disease', (66, 77))	('colon cancer', 'Disease', 'MESH:D015179', (79, 91))	('head and neck cancer', 'Phenotype', 'HP:0012288', (57, 77))	('B cell lymphoma', 'Disease', (97, 112))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('OX40', 'Var', (0, 4))	('melanoma', 'Disease', 'MESH:D008545', (47, 55))
464370	33020242	The signals from the binding of OX40 and its ligand promote effector T-cell expansion and survival by enhancing the expression of cyclin A, cyclin-dependent kinases, Bcl-2 antiapoptotic molecules, multiple cytokines and related receptors like interleukin (IL)-2.	('cyclin-dependent', 'Protein', (140, 156))	('expression', 'MPA', (116, 126))	('Bcl-2', 'Gene', (166, 171))	('enhancing', 'PosReg', (102, 111))	('cyclin A', 'Gene', (130, 138))	('Bcl-2', 'Gene', '596', (166, 171))	('cyclin A', 'Gene', '890', (130, 138))	('binding', 'Var', (21, 28))	('effector T-cell expansion', 'CPA', (60, 85))	('interleukin (IL)-2', 'Gene', '3558', (243, 261))	('survival', 'CPA', (90, 98))	('interleukin (IL)-2', 'Gene', (243, 261))	('OX40', 'Gene', (32, 36))	('promote', 'PosReg', (52, 59))
464371	33020242	In addition, OX40 signaling promotes the generation of memory T cells and inhibits the function of Tregs.	('OX40 signaling', 'Var', (13, 27))	('Tregs', 'Chemical', '-', (99, 104))	('memory T', 'Disease', 'MESH:D008569', (55, 63))	('promotes', 'PosReg', (28, 36))	('memory T', 'Disease', (55, 63))	('inhibits', 'NegReg', (74, 82))	('function of Tregs', 'CPA', (87, 104))
464372	33020242	Several in vivo studies have demonstrated that OX40 antagonizes Foxp3+ induction in naive CD4 T cells and inhibits IL-10 expression in inducible Tregs.	('inhibits', 'NegReg', (106, 114))	('Foxp3', 'Gene', (64, 69))	('OX40', 'Var', (47, 51))	('induction', 'MPA', (71, 80))	('antagonizes', 'NegReg', (52, 63))	('expression', 'MPA', (121, 131))	('IL-10', 'Gene', '3586', (115, 120))	('Foxp3', 'Gene', '50943', (64, 69))	('IL-10', 'Gene', (115, 120))	('Tregs', 'Chemical', '-', (145, 150))
464373	33020242	Moreover, agonistic OX40 antibodies help deplete tumor-infiltrating Tregs that express OX40 via the antibody-dependent cell cytotoxicity that myeloid and natural killer cells induce after interacting with Tregs.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('Tregs', 'Chemical', '-', (205, 210))	('interacting', 'Interaction', (188, 199))	('OX40', 'Var', (87, 91))	('tumor', 'Disease', (49, 54))	('toxicity', 'Disease', 'MESH:D064420', (128, 136))	('toxicity', 'Disease', (128, 136))	('Tregs', 'Chemical', '-', (68, 73))
464376	33020242	Thus, OX40 affects the ability of Tregs to suppress immune reactions in both positive and negative directions and on the basis of the cytokine milieu.	('OX40', 'Var', (6, 10))	('suppress', 'NegReg', (43, 51))	('Tregs', 'Chemical', '-', (34, 39))	('suppress immune reactions', 'Phenotype', 'HP:0002721', (43, 68))	('immune reactions', 'CPA', (52, 68))
464381	33020242	The proliferation rate for both CD4+ and CD8+ T cells increased substantially in a dose-dependent manner, as determined by flow cytometric analysis.	('CD8', 'Gene', (41, 44))	('increased', 'PosReg', (54, 63))	('CD8', 'Gene', '925', (41, 44))	('T cells increased', 'Phenotype', 'HP:0100828', (46, 63))	('CD4+', 'Var', (32, 36))	('proliferation rate', 'CPA', (4, 22))
464390	33020242	In an orthotopically transplanted murine mammary tumor virus polyoma middle T murine model of mammary cancer refractory to PD-1 blockade, OX40 stimulation delayed tumor growth.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('delayed', 'NegReg', (155, 162))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('murine', 'Species', '10090', (78, 84))	('tumor', 'Disease', (49, 54))	('tumor virus polyoma middle T', 'Disease', 'None', (49, 77))	('OX40', 'Var', (138, 142))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('murine', 'Species', '10090', (34, 40))	('tumor', 'Disease', (163, 168))	('tumor virus polyoma middle T', 'Disease', (49, 77))	('PD-1 blockade', 'Disease', (123, 136))	('PD-1 blockade', 'Disease', 'MESH:D010300', (123, 136))
464397	33020242	Thirty-three (63%) of these patients had no cancer progression after treatment with PF-04518600.	('PF-04518600', 'Chemical', '-', (84, 95))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('PF-04518600', 'Var', (84, 95))	('patients', 'Species', '9606', (28, 36))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
464404	33020242	On conjunction with its ligand CD137L, 4-1BB forms a heterotrimer with the TNF-associated factors TRAF1 and TRAF2, resulting in downstream activation of the nuclear factor kappa-light-chain-enhancer of activated B cells, extracellular signal-regulated kinase, c-Jun N-terminal kinase and mitogen-activated protein kinase signaling pathways.	('TRAF2', 'Gene', (108, 113))	('CD137L', 'Gene', (31, 37))	('activation', 'PosReg', (139, 149))	('nuclear factor kappa-light-chain-enhancer', 'Pathway', (157, 198))	('TRAF1', 'Gene', (98, 103))	('TNF', 'Gene', (75, 78))	('extracellular signal-regulated kinase', 'Pathway', (221, 258))	('4-1BB', 'Var', (39, 44))	('TRAF2', 'Gene', '7186', (108, 113))	('TNF', 'Gene', '7124', (75, 78))	('CD137L', 'Gene', '8744', (31, 37))	('TRAF1', 'Gene', '7185', (98, 103))
464410	33020242	4-1BB is a candidate costimulatory domain, and CD19 chimeric antigen receptor T-cell therapy with 4-1BB has shown promising results in the treatment of hematological malignancies.	('CD19', 'Gene', (47, 51))	('hematological malignancies', 'Phenotype', 'HP:0004377', (152, 178))	('CD19', 'Gene', '930', (47, 51))	('malignancies', 'Disease', 'MESH:D009369', (166, 178))	('4-1BB', 'Var', (98, 103))	('malignancies', 'Disease', (166, 178))
464471	33020242	An active study of the anti-GITR agonist BMS-986156 and nivolumab suggested that the incidence rate for grade 1 TRAEs was 70% in patients receiving combination therapy compared with 59% in those receiving monotherapy; no patients in either group experienced DLT (table 1).	('patients', 'Species', '9606', (221, 229))	('patients', 'Species', '9606', (129, 137))	('combination', 'Var', (148, 159))	('nivolumab', 'Chemical', 'MESH:D000077594', (56, 65))	('grade', 'Disease', (104, 109))
464475	33020242	A phase 1 study of MK4166 (NCT02132754) with and without pembrolizumab demonstrated a similar safety profile but higher response rates in immune checkpoint inhibitor-naive melanoma patients.	('melanoma', 'Disease', 'MESH:D008545', (172, 180))	('MK4166', 'Chemical', '-', (19, 25))	('higher', 'PosReg', (113, 119))	('pembrolizumab', 'Chemical', 'MESH:C582435', (57, 70))	('patients', 'Species', '9606', (181, 189))	('response', 'MPA', (120, 128))	('MK4166', 'Var', (19, 25))	('melanoma', 'Phenotype', 'HP:0002861', (172, 180))	('melanoma', 'Disease', (172, 180))
464479	33020242	CD40 ligation of B cells also increases B cells' antigen-presentation capacity and promotes immunoglobulin class switching.	('CD40', 'Gene', (0, 4))	('ligation', 'Var', (5, 13))	('promotes', 'PosReg', (83, 91))	('immunoglobulin class switching', 'MPA', (92, 122))	('B cells', 'MPA', (40, 47))	('antigen-presentation capacity', 'MPA', (49, 78))	('increases B cells', 'Phenotype', 'HP:0005404', (30, 47))	('CD40', 'Gene', '958', (0, 4))	('increases', 'PosReg', (30, 39))
464489	33020242	CDX-1140, APX005M and SEA-CD40 are other candidate agonistic CD40 monoclonal antibodies for cancer immunotherapy, but they resulted in minor antitumor responses in early-phase studies (table 1).	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('cancer', 'Disease', (92, 98))	('APX005M', 'Var', (10, 17))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('CDX', 'Chemical', '-', (0, 3))	('CD40', 'Gene', '958', (26, 30))	('tumor', 'Disease', (145, 150))	('CD40', 'Gene', '958', (61, 65))	('CD40', 'Gene', (26, 30))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('CD40', 'Gene', (61, 65))
464496	33020242	CP-870, 893 has also shown good results when combined with paclitaxel/cisplatin and administered to cohorts of mostly melanoma patients.	('melanoma', 'Phenotype', 'HP:0002861', (118, 126))	('melanoma', 'Disease', (118, 126))	('paclitaxel', 'Chemical', 'MESH:D017239', (59, 69))	('melanoma', 'Disease', 'MESH:D008545', (118, 126))	('cisplatin', 'Chemical', 'MESH:D002945', (70, 79))	('patients', 'Species', '9606', (127, 135))	('CP-870', 'Var', (0, 6))	('CP-870', 'Chemical', '-', (0, 6))
464497	33020242	In other studies, CP-870, 893 combined with cisplatin and pemetrexed in patients with malignant pleural mesothelioma had tolerable toxicity profiles and tumor control effects (overall response rate, 40%, respectively) (table 1).	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('CP-870', 'Chemical', '-', (18, 24))	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (86, 116))	('tumor', 'Disease', (153, 158))	('pemetrexed', 'Chemical', 'MESH:D000068437', (58, 68))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (96, 116))	('CP-870', 'Var', (18, 24))	('malignant pleural mesothelioma', 'Disease', (86, 116))	('toxicity', 'Disease', 'MESH:D064420', (131, 139))	('toxicity', 'Disease', (131, 139))	('cisplatin', 'Chemical', 'MESH:D002945', (44, 53))	('patients', 'Species', '9606', (72, 80))
464512	33020242	Of the 106 patients who received JTX2011 in combination with nivolumab, 8 (7.5%) had PRs (table 2).	('patients', 'Species', '9606', (11, 19))	('JTX2011', 'Var', (33, 40))	('nivolumab', 'Chemical', 'MESH:D000077594', (61, 70))	('PRs', 'Disease', (85, 88))
464513	33020242	The anti-ICOS monoclonal antibody KY1044 targets depletion of intratumoral Tregs and stimulation of T effectors.	('stimulation', 'PosReg', (85, 96))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('Tregs', 'Chemical', '-', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('T effectors', 'CPA', (100, 111))	('KY1044', 'Var', (34, 40))	('tumor', 'Disease', (67, 72))	('KY1044', 'Chemical', '-', (34, 40))
464522	33020242	Various factors contribute to resistance to checkpoint blockade immunotherapy, such as changes in tumor mutations, T-cell infiltration, suppressive tumor microenvironments, antigen presentation deficiencies and other non-specific issues.	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('tumor', 'Disease', (98, 103))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Disease', (148, 153))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('deficiencies', 'Var', (194, 206))	('changes', 'Reg', (87, 94))	('tumor', 'Disease', 'MESH:D009369', (148, 153))
464524	33020242	Overall, a deeper understanding of the impact of these agents in vivo is needed to help identify logical combination approaches that can be tested in the clinic Regarding subtypes of cancers, patients treated with urelumab with nivolumab and MK-4166 with pembrolizumab in melanoma patients have had overall response rates of more than 50%.	('urelumab', 'Chemical', 'MESH:C000620833', (214, 222))	('melanoma', 'Disease', 'MESH:D008545', (272, 280))	('cancers', 'Disease', (183, 190))	('pembrolizumab', 'Chemical', 'MESH:C582435', (255, 268))	('patients', 'Species', '9606', (192, 200))	('MK-4166', 'Var', (242, 249))	('patients', 'Species', '9606', (281, 289))	('MK-4166', 'Chemical', '-', (242, 249))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('cancers', 'Phenotype', 'HP:0002664', (183, 190))	('melanoma', 'Phenotype', 'HP:0002861', (272, 280))	('melanoma', 'Disease', (272, 280))	('nivolumab', 'Chemical', 'MESH:D000077594', (228, 237))	('cancers', 'Disease', 'MESH:D009369', (183, 190))
464532	33020242	In the orthotopically transplanted murine mammary tumor virus polyoma middle T murine model of mammary cancer refractory to PD-1 blockade, OX40 stimulation followed by PD-1 blockage delayed tumor growth and increased the durable responses of CD4+ and CD8+ T cells to tumors.	('durable responses', 'CPA', (221, 238))	('PD-1 blockade', 'Disease', 'MESH:D010300', (124, 137))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('cancer', 'Disease', (103, 109))	('tumors', 'Phenotype', 'HP:0002664', (267, 273))	('murine', 'Species', '10090', (79, 85))	('PD-1 blockage delayed tumor', 'Disease', 'MESH:D010300', (168, 195))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('tumor virus polyoma middle T', 'Disease', (50, 78))	('CD8', 'Gene', '925', (251, 254))	('tumor', 'Phenotype', 'HP:0002664', (267, 272))	('tumor virus polyoma middle T', 'Disease', 'None', (50, 78))	('OX40', 'Var', (139, 143))	('tumors', 'Disease', (267, 273))	('PD-1 blockage delayed tumor', 'Disease', (168, 195))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('tumors', 'Disease', 'MESH:D009369', (267, 273))	('murine', 'Species', '10090', (35, 41))	('CD8', 'Gene', (251, 254))	('increased', 'PosReg', (207, 216))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('PD-1 blockade', 'Disease', (124, 137))
464536	33020242	It has also been shown that 4-1BB administered with radiation therapy enhances antitumor activity.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('4-1BB', 'Var', (28, 33))	('tumor', 'Disease', (83, 88))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('enhances', 'PosReg', (70, 78))
464543	33020242	Agonists of T cells can boost the original immune effects of cancer, have unexpected off-target effects, or aggravate pre-existing autoimmune disease.	('autoimmune disease', 'Disease', 'MESH:D001327', (131, 149))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('autoimmune disease', 'Phenotype', 'HP:0002960', (131, 149))	('aggravate', 'PosReg', (108, 117))	('cancer', 'Disease', (61, 67))	('Agonists', 'Var', (0, 8))	('autoimmune disease', 'Disease', (131, 149))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('boost', 'PosReg', (24, 29))
464552	33020242	Agonists of costimulatory molecules may lead to improved T-cell activation and tumor control.	('tumor', 'Disease', (79, 84))	('improved', 'PosReg', (48, 56))	('Agonists', 'Var', (0, 8))	('T-cell activation', 'CPA', (57, 74))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
464571	31092229	Administration of STAT3 inhibitor WP1066 could prevent MVP knockdown induced tumorigenesis.	('rat', 'Species', '10116', (8, 11))	('prevent', 'NegReg', (47, 54))	('MVP', 'Var', (55, 58))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Disease', (77, 82))
464583	31092229	Yet, MVP also promotes survival and migration of glioblastoma, and suppresses apoptosis of human senescent diploid fibroblasts and human colon cancer cells.	('MVP', 'Var', (5, 8))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('suppresses', 'NegReg', (67, 77))	('apoptosis', 'CPA', (78, 87))	('colon cancer', 'Phenotype', 'HP:0003003', (137, 149))	('glioblastoma', 'Disease', (49, 61))	('human', 'Species', '9606', (131, 136))	('colon cancer', 'Disease', 'MESH:D015179', (137, 149))	('promotes', 'PosReg', (14, 22))	('rat', 'Species', '10116', (39, 42))	('migration', 'CPA', (36, 45))	('colon cancer', 'Disease', (137, 149))	('glioblastoma', 'Disease', 'MESH:D005909', (49, 61))	('glioblastoma', 'Phenotype', 'HP:0012174', (49, 61))	('survival', 'CPA', (23, 31))	('human', 'Species', '9606', (91, 96))
464587	31092229	When MVP was knocked down in Lewis lung carcinoma (LLC) cells and the MVP suppressed LLC cells were injected subcutaneously into mice, it promoted lung cancer growth and the tumor cell apoptosis was inhibited.	('tumor', 'Disease', (174, 179))	('Lewis lung carcinoma', 'Disease', 'MESH:D018827', (29, 49))	('knocked down', 'Var', (13, 25))	('lung cancer', 'Disease', (147, 158))	('mice', 'Species', '10090', (129, 133))	('lung cancer', 'Phenotype', 'HP:0100526', (147, 158))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('carcinoma', 'Phenotype', 'HP:0030731', (40, 49))	('promoted', 'PosReg', (138, 146))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('Lewis lung carcinoma', 'Disease', (29, 49))	('MVP', 'Gene', (5, 8))	('lung cancer', 'Disease', 'MESH:D008175', (147, 158))
464615	31092229	Primary antibodies against Cyclin-D, p-Rb, Rb, Capase 3, p-STAT3, STAT3, LMNB1, p-JAK, JAK, p-Raf, Raf, p-MEK, MEK, p-ERK, ERK, p-AKT, and AKT were purchased from Cell Signaling Technology.	('Raf', 'Gene', '387609', (99, 102))	('p-Rb', 'Gene', '19645', (37, 41))	('AKT', 'Gene', '11651', (139, 142))	('ERK', 'Gene', '26413', (118, 121))	('ERK', 'Gene', (123, 126))	('MEK', 'Gene', (111, 114))	('AKT', 'Gene', '11651', (130, 133))	('p-ERK', 'Gene', '13666', (116, 121))	('LMNB1', 'Gene', (73, 78))	('LMNB1', 'Gene', '16906', (73, 78))	('Rb', 'Gene', '19645', (43, 45))	('Cyclin', 'Gene', '18538', (27, 33))	('p-Rb', 'Gene', (37, 41))	('MEK', 'Gene', '17242', (106, 109))	('ERK', 'Gene', '26413', (123, 126))	('Raf', 'Gene', (94, 97))	('p-JAK', 'Var', (80, 85))	('AKT', 'Gene', (139, 142))	('Cyclin', 'Gene', (27, 33))	('Raf', 'Gene', '387609', (94, 97))	('AKT', 'Gene', (130, 133))	('p-ERK', 'Gene', (116, 121))	('Raf', 'Gene', (99, 102))	('MEK', 'Gene', (106, 109))	('ERK', 'Gene', (118, 121))	('MEK', 'Gene', '17242', (111, 114))	('Rb', 'Gene', '19645', (39, 41))
464630	31092229	As shown in Additional file 1: Figure S1A and B, MVP significantly increased the overall survival time of patients with adenocarcinoma but which was not detected in patients with squamous cell carcinoma.	('adenocarcinoma', 'Disease', (120, 134))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (179, 202))	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('squamous cell carcinoma', 'Disease', (179, 202))	('MVP', 'Var', (49, 52))	('adenocarcinoma', 'Disease', 'MESH:D000230', (120, 134))	('carcinoma', 'Phenotype', 'HP:0030731', (193, 202))	('increased', 'PosReg', (67, 76))	('patients', 'Species', '9606', (106, 114))	('patients', 'Species', '9606', (165, 173))	('overall survival', 'CPA', (81, 97))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (179, 202))
464633	31092229	Consistently, adenocarcinoma patients with higher MVP expression had better prognosis and less lymph node metastasis (Additional file 1: Figure S1F, Table 1).	('less', 'NegReg', (90, 94))	('patients', 'Species', '9606', (29, 37))	('carcinoma', 'Phenotype', 'HP:0030731', (19, 28))	('adenocarcinoma', 'Disease', (14, 28))	('lymph node metastasis', 'CPA', (95, 116))	('better', 'PosReg', (69, 75))	('MVP expression', 'Var', (50, 64))	('adenocarcinoma', 'Disease', 'MESH:D000230', (14, 28))
464634	31092229	Taken together, these results suggest that MVP be associated with the pathogenesis of lung cancer, especially with adenocarcinoma.	('adenocarcinoma', 'Disease', 'MESH:D000230', (115, 129))	('MVP', 'Var', (43, 46))	('lung cancer', 'Phenotype', 'HP:0100526', (86, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('lung cancer', 'Disease', (86, 97))	('adenocarcinoma', 'Disease', (115, 129))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('associated', 'Reg', (50, 60))	('lung cancer', 'Disease', 'MESH:D008175', (86, 97))
464638	31092229	We found that tumors carrying MVP hairpins were significantly larger and heavier than the tumors carrying control hairpin (Fig.	('MVP hairpins', 'Var', (30, 42))	('heavier', 'PosReg', (73, 80))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumors', 'Disease', (14, 20))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('tumors', 'Disease', (90, 96))	('tumors', 'Disease', 'MESH:D009369', (90, 96))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
464639	31092229	Consistently, IHC analysis indicated that Ki67 and CD31, a cell division marker and an angiogenesis marker respectively, were enhanced in both MVP knockdown groups (Fig.	('Ki67', 'Gene', '17345', (42, 46))	('enhanced', 'PosReg', (126, 134))	('CD31', 'Gene', '18613', (51, 55))	('CD31', 'Gene', (51, 55))	('cell division', 'CPA', (59, 72))	('Ki67', 'Gene', (42, 46))	('knockdown', 'Var', (147, 156))
464641	31092229	These data reveal that knockdown of MVP in tumor cells may promote lung cancer growth in mice.	('mice', 'Species', '10090', (89, 93))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('knockdown', 'Var', (23, 32))	('lung cancer', 'Disease', 'MESH:D008175', (67, 78))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('MVP', 'Gene', (36, 39))	('promote', 'PosReg', (59, 66))	('tumor', 'Disease', (43, 48))	('lung cancer', 'Disease', (67, 78))	('lung cancer', 'Phenotype', 'HP:0100526', (67, 78))
464646	31092229	MVP knockdown also promoted the proliferation of SPC-A1 cells and inhibited the apoptosis (Additional file 3: Figure S3C and D).	('promoted', 'PosReg', (19, 27))	('MVP', 'Gene', (0, 3))	('SPC-A1', 'CellLine', 'CVCL:6955', (49, 55))	('rat', 'Species', '10116', (39, 42))	('proliferation', 'CPA', (32, 45))	('inhibited', 'NegReg', (66, 75))	('knockdown', 'Var', (4, 13))	('apoptosis', 'CPA', (80, 89))
464652	31092229	We measured Caspase-3 cleavage in LLC cells and found that cleaved Caspase-3 was dramatically decreased in MVP suppressed cells (Fig.	('Caspase-3', 'Gene', '12367', (12, 21))	('decreased', 'NegReg', (94, 103))	('Caspase-3', 'Gene', (12, 21))	('cleaved', 'MPA', (59, 66))	('Caspase-3', 'Gene', (67, 76))	('MVP suppressed', 'Var', (107, 121))	('Caspase-3', 'Gene', '12367', (67, 76))
464653	31092229	As such, MVP may inhibit apoptosis of lung cancer cells.	('apoptosis', 'CPA', (25, 34))	('lung cancer', 'Disease', (38, 49))	('lung cancer', 'Phenotype', 'HP:0100526', (38, 49))	('inhibit', 'NegReg', (17, 24))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('lung cancer', 'Disease', 'MESH:D008175', (38, 49))	('MVP', 'Var', (9, 12))
464656	31092229	When FBS was used for the activation of starved tumor cells, we found that STAT3 phosphorylation was enhanced in the MVP knockdown LLC cells in both basal level group and FBS stimulated group (Fig.	('knockdown', 'Var', (121, 130))	('tumor', 'Disease', (48, 53))	('MVP', 'Gene', (117, 120))	('enhanced', 'PosReg', (101, 109))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('STAT3 phosphorylation', 'MPA', (75, 96))
464659	31092229	We found that knockdown of MVP enhanced phosphorylation of JAK2 and ERK at both basal level and after serum addition (Fig.	('MVP', 'Gene', (27, 30))	('enhanced', 'PosReg', (31, 39))	('JAK2', 'Gene', (59, 63))	('ERK', 'Gene', (68, 71))	('knockdown', 'Var', (14, 23))	('JAK2', 'Gene', '16452', (59, 63))	('ERK', 'Gene', '26413', (68, 71))	('phosphorylation', 'MPA', (40, 55))
464664	31092229	We found that MVP knockdown induced acceleration in LLC cell proliferation was obviously dampened by treatment with WP1066.	('knockdown', 'Var', (18, 27))	('LLC cell proliferation', 'CPA', (52, 74))	('MVP', 'Gene', (14, 17))	('acceleration', 'PosReg', (36, 48))	('rat', 'Species', '10116', (68, 71))	('rat', 'Species', '10116', (42, 45))
464665	31092229	Therefore, these results suggested that STAT3 activity be requisite for the tumorigenesis caused by MVP knockdown.	('MVP', 'Gene', (100, 103))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('knockdown', 'Var', (104, 113))
464668	31092229	For example, Gefitinib and other EGFR tyrosine kinase inhibitors (TKIs) have been developed to treat patients with EGFR mutations which may be the most successful targeted therapy.	('Gefitinib', 'Chemical', 'MESH:D000077156', (13, 22))	('patients', 'Species', '9606', (101, 109))	('EGFR', 'Gene', (115, 119))	('mutations', 'Var', (120, 129))
464669	31092229	ALK inhibitor Crizotinib has been approved for treatment of patients carrying EML4-ALK fusion mutation.	('ALK', 'Gene', '238', (83, 86))	('fusion mutation', 'Var', (87, 102))	('EML4', 'Gene', '27436', (78, 82))	('patients', 'Species', '9606', (60, 68))	('Crizotinib', 'Chemical', 'MESH:D000077547', (14, 24))	('ALK', 'Gene', (0, 3))	('ALK', 'Gene', (83, 86))	('EML4', 'Gene', (78, 82))	('ALK', 'Gene', '238', (0, 3))
464670	31092229	Therapies targeting K-RAS mutation, MET amplification, ROS1 rearrangements, and other oncogenic drivers are under clinical trials.	('rearrangements', 'Var', (60, 74))	('K-RAS', 'Gene', '16653', (20, 25))	('K-RAS', 'Gene', (20, 25))	('mutation', 'Var', (26, 34))	('ROS1', 'Gene', (55, 59))	('ROS1', 'Gene', '19886', (55, 59))	('MET amplification', 'Var', (36, 53))
464671	31092229	However, only 10 to 25% NSCLC patients carry EGFR mutations.	('NSCLC', 'Disease', (24, 29))	('EGFR', 'Gene', (45, 49))	('NSCLC', 'Disease', 'MESH:D002289', (24, 29))	('mutations', 'Var', (50, 59))	('patients', 'Species', '9606', (30, 38))	('NSCLC', 'Phenotype', 'HP:0030358', (24, 29))
464686	31092229	Following the identification of KRAS and BRAF mutations, epidermal growth factor receptor (EGFR) mutations were discovered in patients with lung adenocarcinoma and were associated with response to EGFR inhibitors.	('mutations', 'Var', (97, 106))	('EGFR', 'Gene', (91, 95))	('mutations', 'Var', (46, 55))	('epidermal growth factor receptor', 'Gene', '1956', (57, 89))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (140, 159))	('KRAS', 'Gene', (32, 36))	('BRAF', 'Gene', '673', (41, 45))	('KRAS', 'Gene', '3845', (32, 36))	('carcinoma', 'Phenotype', 'HP:0030731', (150, 159))	('associated', 'Reg', (169, 179))	('lung adenocarcinoma', 'Disease', (140, 159))	('patients', 'Species', '9606', (126, 134))	('BRAF', 'Gene', (41, 45))	('epidermal growth factor receptor', 'Gene', (57, 89))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (140, 159))
464687	31092229	Instead, for lung squamous cell carcinoma, genes such as DDR2, FGFR and genes in the PI3K pathway seem to be more commonly mutated.	('PI3', 'Gene', '20702', (85, 88))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (13, 41))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (18, 41))	('lung squamous cell carcinoma', 'Disease', (13, 41))	('FGFR', 'Gene', (63, 67))	('DDR2', 'Gene', '18214', (57, 61))	('carcinoma', 'Phenotype', 'HP:0030731', (32, 41))	('DDR2', 'Gene', (57, 61))	('PI3', 'Gene', (85, 88))	('mutated', 'Var', (123, 130))
464689	31092229	For example, STAT3 mediates the oncogenic effects of EGFR kinase domain mutations in human lung adenocarcinoma.	('domain mutations', 'Var', (65, 81))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (91, 110))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (91, 110))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('lung adenocarcinoma', 'Disease', (91, 110))	('EGFR', 'Gene', (53, 57))	('human', 'Species', '9606', (85, 90))
464690	31092229	The efficacy of EGFR tyrosine kinase inhibitors (TKIs) in EGFR-mutant NSCLC is limited by adaptive activation of STAT3.	('EGFR-mutant', 'Gene', (58, 69))	('NSCLC', 'Disease', (70, 75))	('NSCLC', 'Disease', 'MESH:D002289', (70, 75))	('EGFR-mutant', 'Var', (58, 69))	('NSCLC', 'Phenotype', 'HP:0030358', (70, 75))
464691	31092229	The association of high expression of MVP with better clinical outcome in adenocarcinoma may be attributed partly to the suppressive effect of MVP on STAT3 signaling pathway.	('adenocarcinoma', 'Disease', (74, 88))	('high', 'Var', (19, 23))	('expression', 'MPA', (24, 34))	('MVP', 'Gene', (38, 41))	('adenocarcinoma', 'Disease', 'MESH:D000230', (74, 88))	('STAT3 signaling pathway', 'Pathway', (150, 173))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('suppressive', 'NegReg', (121, 132))
464692	31092229	However, the anti-tumorigenesis effect of MVP has been challenged in glioblastoma and colon cancer cells, in which MVP promotes tumor cell survival and clonogenicity and inhibits cell apoptosis.	('promotes', 'PosReg', (119, 127))	('tumor', 'Disease', (128, 133))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('colon cancer', 'Disease', (86, 98))	('tumor', 'Disease', (18, 23))	('glioblastoma', 'Disease', 'MESH:D005909', (69, 81))	('cell apoptosis', 'CPA', (179, 193))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('clonogenicity', 'CPA', (152, 165))	('inhibits', 'NegReg', (170, 178))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('glioblastoma', 'Disease', (69, 81))	('MVP', 'Var', (115, 118))	('colon cancer', 'Phenotype', 'HP:0003003', (86, 98))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('colon cancer', 'Disease', 'MESH:D015179', (86, 98))	('glioblastoma', 'Phenotype', 'HP:0012174', (69, 81))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
464698	31092229	MVP can also promote the degradation of HIF1alpha, a known tumor promoting factor, and function as a tumor suppressor in renal adenocarcinoma cells.	('degradation', 'MPA', (25, 36))	('HIF1alpha', 'Gene', (40, 49))	('tumor', 'Disease', (59, 64))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('MVP', 'Var', (0, 3))	('renal adenocarcinoma', 'Phenotype', 'HP:0005584', (121, 141))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('renal adenocarcinoma', 'Disease', (121, 141))	('promote', 'PosReg', (13, 20))	('renal adenocarcinoma', 'Disease', 'MESH:C538614', (121, 141))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('HIF1alpha', 'Gene', '15251', (40, 49))
464699	31092229	We demonstrate that MVP may directly inhibit lung cell proliferation and stimulate cell apoptosis.	('MVP', 'Var', (20, 23))	('inhibit', 'NegReg', (37, 44))	('stimulate', 'PosReg', (73, 82))	('cell apoptosis', 'CPA', (83, 97))	('rat', 'Species', '10116', (62, 65))	('lung cell proliferation', 'CPA', (45, 68))	('rat', 'Species', '10116', (10, 13))
464704	31092229	Our results reveal that MVP inhibited lung cancer growth by suppression of STAT3 signal pathway, which is regulated by JAK2 and RAF-MEK-ERK pathways.	('ERK', 'Gene', '26413', (136, 139))	('lung cancer', 'Disease', (38, 49))	('MEK', 'Gene', '17242', (132, 135))	('lung cancer', 'Phenotype', 'HP:0100526', (38, 49))	('JAK2', 'Gene', (119, 123))	('RAF', 'Gene', (128, 131))	('MVP', 'Var', (24, 27))	('RAF', 'Gene', '387609', (128, 131))	('MEK', 'Gene', (132, 135))	('inhibited', 'NegReg', (28, 37))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('lung cancer', 'Disease', 'MESH:D008175', (38, 49))	('suppression', 'NegReg', (60, 71))	('ERK', 'Gene', (136, 139))	('JAK2', 'Gene', '16452', (119, 123))	('STAT3 signal pathway', 'Pathway', (75, 95))
464710	31092229	We report here that MVP is associated with a better prognosis of lung adenocarcinoma.	('MVP', 'Var', (20, 23))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (65, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (65, 84))	('lung adenocarcinoma', 'Disease', (65, 84))
464718	30429154	In this study, we show that knockdown of PICSAR in cSCC cells upregulates expression of alpha2, alpha5 and beta1 integrins, resulting in increased cell adhesion and decreased cell migration on collagen I and fibronectin.	('expression', 'MPA', (74, 84))	('cell adhesion', 'CPA', (147, 160))	('decreased', 'NegReg', (165, 174))	('PICSAR', 'Gene', (41, 47))	('beta1 integrin', 'Gene', '3688', (107, 121))	('beta1 integrin', 'Gene', (107, 121))	('cSCC', 'Phenotype', 'HP:0006739', (51, 55))	('collagen I and fibronectin', 'Gene', '2335', (193, 219))	('increased', 'PosReg', (137, 146))	('PICSAR', 'Gene', '378825', (41, 47))	('alpha2, alpha5 and beta1', 'Gene', '10678', (88, 112))	('knockdown', 'Var', (28, 37))	('upregulates', 'PosReg', (62, 73))
464727	30429154	We showed that knockdown of PICSAR inhibits cSCC cell proliferation and migration on an uncoated surface and suppresses growth of human cSCC xenografts in vivo, providing evidence for its tumorigenic function.	('tumor', 'Disease', (188, 193))	('cSCC cell proliferation', 'CPA', (44, 67))	('knockdown', 'Var', (15, 24))	('cSCC', 'Phenotype', 'HP:0006739', (44, 48))	('inhibits', 'NegReg', (35, 43))	('suppresses', 'NegReg', (109, 119))	('cSCC', 'Phenotype', 'HP:0006739', (136, 140))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('PICSAR', 'Gene', (28, 34))	('PICSAR', 'Gene', '378825', (28, 34))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('growth', 'CPA', (120, 126))	('migration on an uncoated surface', 'CPA', (72, 104))	('human', 'Species', '9606', (130, 135))
464732	30429154	The cell tracking assay showed that silencing of PICSAR decreased migration of cSCC cells on collagen I and fibronectin compared to control siRNA transfected cells (Fig.	('PICSAR', 'Gene', (49, 55))	('migration', 'CPA', (66, 75))	('collagen I and fibronectin', 'Gene', '2335', (93, 119))	('decreased', 'NegReg', (56, 65))	('silencing', 'Var', (36, 45))	('cSCC', 'Phenotype', 'HP:0006739', (79, 83))	('PICSAR', 'Gene', '378825', (49, 55))
464734	30429154	The results showed that PICSAR knockdown significantly increased adhesion of cSCC cells to collagen I and fibronectin compared to control siRNA transfected cells (Fig.	('adhesion', 'MPA', (65, 73))	('increased', 'PosReg', (55, 64))	('cSCC', 'Phenotype', 'HP:0006739', (77, 81))	('PICSAR', 'Gene', '378825', (24, 30))	('collagen I and fibronectin', 'Gene', '2335', (91, 117))	('PICSAR', 'Gene', (24, 30))	('knockdown', 'Var', (31, 40))
464735	30429154	After PICSAR knockdown the morphology of cSCC cells was less spherical than in the control siRNA transfected cultures and cells extended multiple lamellipodia around them (Fig.	('less', 'NegReg', (56, 60))	('cSCC', 'Phenotype', 'HP:0006739', (41, 45))	('PICSAR', 'Gene', '378825', (6, 12))	('knockdown', 'Var', (13, 22))	('PICSAR', 'Gene', (6, 12))
464736	30429154	The relative number of cSCC cells with lamellipodia on collagen I and fibronectin was higher in cultures after PICSAR knockdown, as compared to control siRNA transfected cultures (Fig.	('PICSAR', 'Gene', (111, 117))	('knockdown', 'Var', (118, 127))	('collagen I and fibronectin', 'Gene', '2335', (55, 81))	('cSCC', 'Phenotype', 'HP:0006739', (23, 27))	('PICSAR', 'Gene', '378825', (111, 117))	('higher', 'PosReg', (86, 92))
464742	30429154	For instance, alpha2beta1 integrin has been shown to exert a tumor suppressive function in breast and prostate cancer, whereas loss of alpha2beta1 integrin correlates with metastasis in cancer patients and promotes tumor cell intravasation in vivo and in vitro, indicating that loss of integrin-mediated cell adhesion is an important event in invasion and metastasis of cancer cells.	('metastasis', 'Disease', (172, 182))	('loss', 'Var', (127, 131))	('cancer', 'Disease', 'MESH:D009369', (370, 376))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('cancer', 'Disease', (111, 117))	('metastasis of cancer', 'Disease', (356, 376))	('breast and prostate cancer', 'Disease', 'MESH:D011471', (91, 117))	('cancer', 'Disease', 'MESH:D009369', (186, 192))	('metastasis', 'Disease', 'MESH:D009362', (172, 182))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('metastasis of cancer', 'Disease', 'MESH:D009362', (356, 376))	('patients', 'Species', '9606', (193, 201))	('beta1 integrin', 'Gene', (141, 155))	('cancer', 'Disease', (370, 376))	('metastasis', 'Disease', (356, 366))	('tumor', 'Disease', (215, 220))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('cancer', 'Disease', (186, 192))	('cancer', 'Phenotype', 'HP:0002664', (370, 376))	('prostate cancer', 'Phenotype', 'HP:0012125', (102, 117))	('beta1 integrin', 'Gene', (20, 34))	('beta1 integrin', 'Gene', '3688', (141, 155))	('tumor', 'Disease', 'MESH:D009369', (215, 220))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('promotes', 'PosReg', (206, 214))	('metastasis', 'Disease', 'MESH:D009362', (356, 366))	('beta1 integrin', 'Gene', '3688', (20, 34))	('tumor', 'Disease', (61, 66))
464743	30429154	Quantitation of integrin mRNA levels in cSCC cells after PICSAR knockdown with qPCR showed elevated expression of alpha2, alpha5 and beta1 integrins in cSCC cells after PICSAR knockdown (Fig.	('PICSAR', 'Gene', '378825', (169, 175))	('cSCC', 'Phenotype', 'HP:0006739', (40, 44))	('alpha2, alpha5 and beta1', 'Gene', '10678', (114, 138))	('elevated', 'PosReg', (91, 99))	('PICSAR', 'Gene', '378825', (57, 63))	('cSCC', 'Phenotype', 'HP:0006739', (152, 156))	('PICSAR', 'Gene', (169, 175))	('PICSAR', 'Gene', (57, 63))	('expression', 'MPA', (100, 110))	('beta1 integrin', 'Gene', '3688', (133, 147))	('knockdown', 'Var', (176, 185))	('beta1 integrin', 'Gene', (133, 147))
464744	30429154	Furthermore, flow cytometry analysis showed increased expression of alpha2 and alpha5 integrins on the surface of cSCC cells after PICSAR knockdown, compared to the control siRNA transfected cells (Fig.	('expression', 'MPA', (54, 64))	('knockdown', 'Var', (138, 147))	('alpha5 integrins', 'Protein', (79, 95))	('cSCC', 'Phenotype', 'HP:0006739', (114, 118))	('PICSAR', 'Gene', (131, 137))	('alpha2', 'Protein', (68, 74))	('increased', 'PosReg', (44, 53))	('PICSAR', 'Gene', '378825', (131, 137))
464746	30429154	2C; ), whereas in UT-SCC12A cells the effect was less potent after PICSAR knockdown (Fig.	('PICSAR', 'Gene', (67, 73))	('PICSAR', 'Gene', '378825', (67, 73))	('knockdown', 'Var', (74, 83))	('UT-SCC12A', 'CellLine', 'CVCL:7807', (18, 27))
464768	30429154	Here, decreased expression of Src in cSCC cells was noted after PICSAR knockdown (Fig.	('Src', 'Gene', (30, 33))	('Src', 'Gene', '6714', (30, 33))	('decreased', 'NegReg', (6, 15))	('PICSAR', 'Gene', '378825', (64, 70))	('cSCC', 'Phenotype', 'HP:0006739', (37, 41))	('knockdown', 'Var', (71, 80))	('PICSAR', 'Gene', (64, 70))	('expression', 'MPA', (16, 26))
464776	30429154	The results of the present study show that PICSAR knockdown results in increased expression of alpha2beta1 and alpha5beta1 integrins on the cell surface, which explains the decreased migration of cSCC cells after PICSAR knockdown when cells adhere more efficiently on a collagen I and fibronectin coated surface.	('beta1', 'Gene', '10678', (117, 122))	('PICSAR', 'Gene', (213, 219))	('expression', 'MPA', (81, 91))	('PICSAR', 'Gene', '378825', (43, 49))	('beta1 integrin', 'Gene', (117, 131))	('knockdown', 'Var', (50, 59))	('migration', 'CPA', (183, 192))	('beta1', 'Gene', '10678', (101, 106))	('PICSAR', 'Gene', (43, 49))	('cSCC', 'Phenotype', 'HP:0006739', (196, 200))	('PICSAR', 'Gene', '378825', (213, 219))	('collagen I and fibronectin', 'Gene', '2335', (270, 296))	('increased', 'PosReg', (71, 80))	('knockdown', 'Var', (220, 229))	('beta1 integrin', 'Gene', '3688', (117, 131))	('decreased', 'NegReg', (173, 182))	('beta1', 'Gene', (117, 122))	('beta1', 'Gene', (101, 106))
464782	30429154	cSCC cells were cultured to 50% confluence and transfected with negative control siRNA (AllStars Negative Control siRNA, Qiagen) and following commercially available siRNAs (75 nM, Qiagen) targeting two distinct areas in PICSAR 3' end, as previously described: Hs_C21orf113_1, 5'-CACGGCCAACGTGGAGCTCTA-3' (siRNA1); Hs_C21orf113_3, 5'-CTGCAGTCACTTCACAGTGAA-3' (siRNA2).	('Hs_C21orf113_3', 'Var', (315, 329))	('PICSAR', 'Gene', (221, 227))	('PICSAR', 'Gene', '378825', (221, 227))	('cSCC', 'Phenotype', 'HP:0006739', (0, 4))
464789	30429154	PICSAR siRNA and control siRNA treated cSCC cells were plated 72 h after siRNA transfection and cells were imaged using the IncuCyte ZOOM  real-time cell imaging system (Essen BioScience).	('transfection', 'Var', (79, 91))	('PICSAR', 'Gene', (0, 6))	('PICSAR', 'Gene', '378825', (0, 6))	('cSCC', 'Phenotype', 'HP:0006739', (39, 43))
464801	30429154	After blocking, cells were stained with monoclonal antibodies (all in 1:100 dilution) specific for integrin alpha2 (555668), integrin alpha5 (555615) and integrin beta1 (553715) (all from BD Biosciences) in 1% FCS-PBS for 1 h in +4 C. Cells were washed with PBS and highly precross-absorbed Alexa Fluor  488 conjugated goat anti-mouse antibody (Invitrogen) was used as secondary antibody in 1:200 dilution and cells were analyzed using FACSCalibur flow cytometer (BD Biosciences).	('555668', 'Var', (116, 122))	('FCS-PBS', 'Disease', 'MESH:D011535', (210, 217))	('integrin alpha5', 'Gene', '3678', (125, 140))	('integrin beta1', 'Gene', (154, 168))	('553715', 'Var', (170, 176))	('FCS-PBS', 'Disease', (210, 217))	('integrin alpha2', 'Gene', (99, 114))	('goat', 'Species', '9925', (319, 323))	('PBS', 'Chemical', '-', (214, 217))	('integrin beta1', 'Gene', '3688', (154, 168))	('integrin alpha2', 'Gene', '3673', (99, 114))	('Alexa Fluor  488', 'Chemical', '-', (291, 307))	('PBS', 'Chemical', '-', (258, 261))	('integrin alpha5', 'Gene', (125, 140))	('555615', 'Var', (142, 148))	('mouse', 'Species', '10090', (329, 334))
464804	30429154	Cells were labeled with primary antibodies against integrin alpha2 (MCA2025, Serotec, Raleigh, USA) or integrin alpha5 (AB1949, Merck Millipore) in 1:100 dilution in blocking solution.	('integrin alpha2', 'Gene', '3673', (51, 66))	('integrin alpha2', 'Gene', (51, 66))	('integrin alpha5', 'Gene', '3678', (103, 118))	('integrin alpha5', 'Gene', (103, 118))	('MCA2025', 'Var', (68, 75))
464810	30429154	To analyze potential miRNA target sites in PICSAR, following computational programs with different algorithms for miRNA-binding prediction were used; miRWalk , TargetScan  and DIANA-lncBase v2 .	('PICSAR', 'Gene', (43, 49))	('PICSAR', 'Gene', '378825', (43, 49))	('miRWalk', 'Var', (150, 157))
464893	27642589	miRNAs regulate a variety of essential biological functions such as cellular differentiation, apoptosis, and proliferation and thus play critical role in cancer progression.	('role', 'Reg', (146, 150))	('cancer', 'Disease', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('regulate', 'Reg', (7, 15))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('miRNAs', 'Var', (0, 6))	('proliferation', 'CPA', (109, 122))	('apoptosis', 'CPA', (94, 103))	('cellular differentiation', 'CPA', (68, 92))
464896	27642589	Aberrant activation of the Wnt/beta-catenin pathway plays a critical role in tumor initiation, progression, and metastasis of lung cancer.	('activation', 'PosReg', (9, 19))	('tumor initiation', 'Disease', (77, 93))	('beta-catenin', 'Gene', (31, 43))	('Aberrant', 'Var', (0, 8))	('beta-catenin', 'Gene', '1499', (31, 43))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('metastasis of lung cancer', 'Disease', 'MESH:D009362', (112, 137))	('lung cancer', 'Phenotype', 'HP:0100526', (126, 137))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor initiation', 'Disease', 'MESH:D009369', (77, 93))	('metastasis of lung cancer', 'Disease', (112, 137))
464898	27642589	Circular RNA-ITCH (cir-ITCH) shared some miRNAs binding sites with the 3'-untranslated region (UTR) of ITCH, including those for miR-7, miR-17, miR-214, miR-128, and miR-216b.	('miR-128', 'Var', (153, 160))	('miR-17', 'Gene', '406952', (136, 142))	('cir', 'Gene', (19, 22))	('ITCH', 'Gene', (103, 107))	('-ITCH', 'Phenotype', 'HP:0000989', (12, 17))	('miR-216b', 'Gene', (166, 174))	('miRNAs', 'MPA', (41, 47))	('ITCH', 'Gene', (23, 27))	('ITCH', 'Gene', (13, 17))	('miR-17', 'Gene', (136, 142))	('ITCH', 'Gene', '83737', (103, 107))	('miR-214', 'Gene', '406996', (144, 151))	('miR-216b', 'Gene', '100126319', (166, 174))	('miR-7', 'Gene', (129, 134))	('ITCH', 'Gene', '83737', (23, 27))	('ITCH', 'Gene', '83737', (13, 17))	('ITCH', 'Phenotype', 'HP:0000989', (103, 107))	('cir', 'Gene', '9541', (19, 22))	('ITCH', 'Phenotype', 'HP:0000989', (23, 27))	('miR-214', 'Gene', (144, 151))	('-ITCH', 'Phenotype', 'HP:0000989', (22, 27))	('miR-7', 'Gene', '10859', (129, 134))	('ITCH', 'Phenotype', 'HP:0000989', (13, 17))
464980	27642589	These results were not fully consistent with study in cell lines of esophageal squamous cell carcinoma, in which cir-ITCH acts as a sponge for five miRNAs: miR-216b, miR-17, miR-214, miR-7, and miR-128.	('cir', 'Gene', (113, 116))	('ITCH', 'Phenotype', 'HP:0000989', (117, 121))	('miR-128', 'Var', (194, 201))	('miR-7', 'Gene', (183, 188))	('esophageal squamous cell carcinoma', 'Disease', (68, 102))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (79, 102))	('miR-216b', 'Gene', (156, 164))	('ITCH', 'Gene', (117, 121))	('miR-17', 'Gene', '406952', (166, 172))	('miR-7', 'Gene', '10859', (183, 188))	('miR-214', 'Gene', '406996', (174, 181))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (68, 102))	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('ITCH', 'Gene', '83737', (117, 121))	('cir', 'Gene', '9541', (113, 116))	('miR-214', 'Gene', (174, 181))	('miR-17', 'Gene', (166, 172))	('miR-216b', 'Gene', '100126319', (156, 164))	('-ITCH', 'Phenotype', 'HP:0000989', (116, 121))
464988	27642589	Deregulated Wnt/beta-catenin signaling with cancers has been well documented in tumor initiation, progression, and metastasis, including lung cancer.	('Deregulated', 'Var', (0, 11))	('cancers', 'Phenotype', 'HP:0002664', (44, 51))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('lung cancer', 'Disease', (137, 148))	('lung cancer', 'Phenotype', 'HP:0100526', (137, 148))	('cancers', 'Disease', (44, 51))	('tumor initiation', 'Disease', 'MESH:D009369', (80, 96))	('cancers', 'Disease', 'MESH:D009369', (44, 51))	('beta-catenin', 'Gene', (16, 28))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('lung cancer', 'Disease', 'MESH:D008175', (137, 148))	('beta-catenin', 'Gene', '1499', (16, 28))	('tumor initiation', 'Disease', (80, 96))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
465016	27495079	Taking into account the bleeding of the aortic arch pseudoaneurysm, the endovascular stent graft (31 mm x 150 mm, W.L.	('bleeding of the aortic arch pseudoaneurysm', 'Disease', (24, 66))	('pseudoaneurysm', 'Phenotype', 'HP:0031625', (52, 66))	('31', 'Var', (98, 100))	('bleeding of the aortic arch pseudoaneurysm', 'Disease', 'MESH:D017541', (24, 66))
465068	24886289	Amplification is one of the activating mechanisms of proto-oncogenes during carcinogenesis.	('Amplification', 'Var', (0, 13))	('carcinogenesis', 'Disease', (76, 90))	('carcinogenesis', 'Disease', 'MESH:D063646', (76, 90))
465069	24886289	Among the frequently amplified regions in human malignancies, amplifications of 11q13 were found in breast cancers, esophageal squamous cell carcinoma, and head and neck cancers.	('cancers', 'Phenotype', 'HP:0002664', (170, 177))	('human', 'Species', '9606', (42, 47))	('found', 'Reg', (91, 96))	('breast cancers', 'Disease', 'MESH:D001943', (100, 114))	('head and neck cancer', 'Phenotype', 'HP:0012288', (156, 176))	('breast cancers', 'Disease', (100, 114))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (116, 150))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (127, 150))	('amplifications', 'Var', (62, 76))	('breast cancers', 'Phenotype', 'HP:0003002', (100, 114))	('malignancies', 'Disease', 'MESH:D009369', (48, 60))	('breast cancer', 'Phenotype', 'HP:0003002', (100, 113))	('malignancies', 'Disease', (48, 60))	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('11q13', 'Gene', (80, 85))	('head and neck cancers', 'Phenotype', 'HP:0012288', (156, 177))	('esophageal squamous cell carcinoma', 'Disease', (116, 150))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('head and neck cancers', 'Disease', 'MESH:D006258', (156, 177))	('cancers', 'Phenotype', 'HP:0002664', (107, 114))
465099	24886289	Cases showing light brown color in more than 5% and dark brown color in less than 50% of tumor cells were counted as a weakly positive group.	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('dark brown color', 'Var', (52, 68))	('tumor', 'Disease', (89, 94))	('tumor', 'Disease', 'MESH:D009369', (89, 94))
465114	24886289	According to the previous reports, high expression of FADD was associated with factors indicating poor prognosis in squamous cell carcinoma of the head and neck and oral squamous cell carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (184, 193))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (165, 193))	('carcinoma of the head and neck', 'Phenotype', 'HP:0012288', (130, 160))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (170, 193))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (116, 139))	('oral squamous cell carcinoma', 'Disease', (165, 193))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (170, 193))	('squamous cell carcinoma', 'Disease', (116, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (116, 139))	('FADD', 'Gene', '8772', (54, 58))	('high', 'Var', (35, 39))	('FADD', 'Gene', (54, 58))
465116	24886289	Colorectal cancer cell growth was inhibited by FADD expression and high FADD expression after neoadjuvant breast cancer treatment was associated with a good prognosis group in breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('FADD', 'Gene', (72, 76))	('Colorectal cancer', 'Disease', 'MESH:D015179', (0, 17))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('FADD', 'Gene', (47, 51))	('associated', 'Reg', (134, 144))	('inhibited', 'NegReg', (34, 43))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('Colorectal cancer', 'Disease', (0, 17))	('breast cancer', 'Phenotype', 'HP:0003002', (106, 119))	('breast cancer', 'Phenotype', 'HP:0003002', (176, 189))	('FADD', 'Gene', '8772', (72, 76))	('FADD', 'Gene', '8772', (47, 51))	('breast cancer', 'Disease', 'MESH:D001943', (106, 119))	('expression', 'MPA', (77, 87))	('high', 'Var', (67, 71))	('breast cancer', 'Disease', (106, 119))	('breast cancer', 'Disease', 'MESH:D001943', (176, 189))	('Colorectal cancer', 'Phenotype', 'HP:0003003', (0, 17))	('breast cancer', 'Disease', (176, 189))
465120	24886289	Because the hazard score was associated with perineural invasion status of invasive ductal cancer of the breast, we may speculate that combination of TMEM16A, FADD and PPFIA1 expressions influence the invasiveness of the tumor cells and affect the ultimate prognosis of these cases.	('affect', 'Reg', (237, 243))	('influence', 'Reg', (187, 196))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('tumor', 'Disease', (221, 226))	('PPFIA1', 'Gene', '8500', (168, 174))	('cancer of the breast', 'Phenotype', 'HP:0100013', (91, 111))	('TMEM16A', 'Gene', (150, 157))	('invasive ductal cancer', 'Disease', 'MESH:D018270', (75, 97))	('FADD', 'Gene', '8772', (159, 163))	('invasive ductal cancer', 'Disease', (75, 97))	('FADD', 'Gene', (159, 163))	('combination', 'Var', (135, 146))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('TMEM16A', 'Gene', '55107', (150, 157))	('tumor', 'Disease', 'MESH:D009369', (221, 226))	('PPFIA1', 'Gene', (168, 174))
465123	24886289	PPFIA1 amplification was only reported to have significant association with poor prognosis in ER-positive cancer and PPFIA1 expression in terms of prognosis was not studied.	('PPFIA1', 'Gene', (0, 6))	('PPFIA1', 'Gene', (117, 123))	('ER', 'Gene', '2099', (94, 96))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('PPFIA1', 'Gene', '8500', (0, 6))	('PPFIA1', 'Gene', '8500', (117, 123))	('cancer', 'Disease', (106, 112))	('amplification', 'Var', (7, 20))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
465134	24886289	In summary, we screened TMEM16A, FADD, and PPFIA1 expression in breast cancer and found that combination of the three gene expressions was associated with disease-free survival in invasive ductal carcinoma of the breast.	('associated with', 'Reg', (139, 154))	('PPFIA1', 'Gene', '8500', (43, 49))	('breast cancer', 'Phenotype', 'HP:0003002', (64, 77))	('FADD', 'Gene', '8772', (33, 37))	('TMEM16A', 'Gene', '55107', (24, 31))	('invasive ductal carcinoma of the breast', 'Disease', (180, 219))	('invasive ductal carcinoma of the breast', 'Disease', 'MESH:D018270', (180, 219))	('combination', 'Var', (93, 104))	('PPFIA1', 'Gene', (43, 49))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (189, 205))	('carcinoma of the breast', 'Phenotype', 'HP:0100013', (196, 219))	('breast cancer', 'Disease', 'MESH:D001943', (64, 77))	('carcinoma', 'Phenotype', 'HP:0030731', (196, 205))	('FADD', 'Gene', (33, 37))	('TMEM16A', 'Gene', (24, 31))	('breast cancer', 'Disease', (64, 77))
465145	32823874	Not surprisingly, defects in microtubule assembly or properties can lead to severe diseases, including cancer.	('defects', 'Var', (18, 25))	('lead to', 'Reg', (68, 75))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('properties', 'MPA', (53, 63))	('microtubule', 'Protein', (29, 40))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))
465158	32823874	Additionally, six small helices (H1', H2', H2", H3', H9', and H11') are located on loops near the larger structures.	("H2'", 'Var', (38, 41))	("H1'", 'Var', (33, 36))	('H11', 'Gene', '3024', (62, 65))	('H11', 'Gene', (62, 65))	('H3', 'Chemical', 'MESH:C012616', (48, 50))	('small helices', 'Phenotype', 'HP:0008589', (18, 31))	("H9'", 'Var', (53, 56))
465163	32823874	The minus end surface includes the amino acids of helix H10 and loops H3-S4, T7, and H10-S9 (Figure 1).	('helix', 'Protein', (50, 55))	('H10', 'Gene', '3005', (85, 88))	('H10', 'Gene', (56, 59))	('H10', 'Gene', '3005', (56, 59))	('H3-S4', 'Var', (70, 75))	('H10', 'Gene', (85, 88))	('H3', 'Chemical', 'MESH:C012616', (70, 72))
465164	32823874	The plus end is composed of residues from helices H1, H6, and H11; strand S3; and loops T3, T5, H6-H7, and H11-H12 (Figure 1).	('H6-H7', 'Var', (96, 101))	('H11', 'Gene', (107, 110))	('H6-H7', 'CellLine', 'CVCL:J418', (96, 101))	('H12', 'Gene', (111, 114))	('H11', 'Gene', '3024', (62, 65))	('H12', 'Gene', '3006', (111, 114))	('H11', 'Gene', (62, 65))	('H11', 'Gene', '3024', (107, 110))
465171	32823874	The hydrolysis of alpha-tubulin-GTP causes compaction of the heterodimer and sub-nanometer shortening of the protofilament, changing longitudinal but not lateral forces within the microtubule.	('changing', 'Reg', (124, 132))	('longitudinal but', 'MPA', (133, 149))	('alpha-tubulin', 'Gene', (18, 31))	('heterodimer', 'Protein', (61, 72))	('compaction', 'MPA', (43, 53))	('alpha-tubulin', 'Gene', '10376', (18, 31))	('hydrolysis', 'Var', (4, 14))	('GTP', 'Chemical', 'MESH:D006160', (32, 35))	('causes', 'Reg', (36, 42))
465174	32823874	The H3 surface consist of helix H3 and strand S3 as well as loops H1-B1, H2-B2, and H4-S4, while the ML surface contains helices H6, H9, and H10 and loops H6-H7, S7-H9 (M-loop), and H9-S8 (Figure 1).	('H6-H7', 'Var', (155, 160))	('S7-H9', 'Var', (162, 167))	('H10', 'Gene', (141, 144))	('H2-B2', 'Gene', (73, 78))	('S7-H9', 'CellLine', 'CVCL:1240', (162, 167))	('H2-B2', 'Gene', '8348', (73, 78))	('H3', 'Chemical', 'MESH:C012616', (32, 34))	('H4-S4', 'Var', (84, 89))	('H10', 'Gene', '3005', (141, 144))	('H6-H7', 'CellLine', 'CVCL:J418', (155, 160))	('H9-S8', 'Var', (182, 187))	('H3', 'Chemical', 'MESH:C012616', (4, 6))
465184	32823874	The silencing of betaI expression in differentiating human neuroblastoma cells was lethal, while depletion of betaI in undifferentiated cells had no apparent effect on cell survival.	('neuroblastoma', 'Phenotype', 'HP:0003006', (59, 72))	('neuroblastoma', 'Disease', 'MESH:D009447', (59, 72))	('betaI', 'Gene', (17, 22))	('human', 'Species', '9606', (53, 58))	('neuroblastoma', 'Disease', (59, 72))	('silencing', 'Var', (4, 13))
465187	32823874	The silencing of betaII inhibits neurite outgrowth in differentiating neuroblastoma cells, while betaIII was suggested to protect cells against oxidative stress.	('neuroblastoma', 'Disease', (70, 83))	('neuroblastoma', 'Phenotype', 'HP:0003006', (70, 83))	('inhibits', 'NegReg', (24, 32))	('betaII', 'Gene', '114548', (97, 103))	('oxidative stress', 'Phenotype', 'HP:0025464', (144, 160))	('neurite outgrowth in differentiating', 'CPA', (33, 69))	('betaII', 'Gene', (97, 103))	('betaII', 'Gene', '114548', (17, 23))	('silencing', 'Var', (4, 13))	('neuroblastoma', 'Disease', 'MESH:D009447', (70, 83))	('betaII', 'Gene', (17, 23))
465192	32823874	Among the investigated beta-tubulin isotypes (betaII, betaIII, and betaIV), betaIII is the most divergent, with substitutions in globular protein body including: (i) helix H3 (serine in positions 124 and 126 is substituted by cysteine and asparagine, respectively), (ii) loops H1-S2 and H2-S3 (structures involved in the formation of H3 surface), (iii) structures located proximal to the ML surface (H6-H7 loop threonine 217 and S7-H9 loop serine 275 substituted to alanine), and (iv) T7 loop (minus end surface) near colchicine-binding site (cysteine 239 substituted by serine).	('betaII', 'Gene', '114548', (76, 82))	('asparagine', 'Chemical', 'MESH:D001216', (239, 249))	('betaII', 'Gene', (46, 52))	('H6-H7', 'CellLine', 'CVCL:J418', (400, 405))	('threonine', 'Chemical', 'MESH:D013912', (411, 420))	('betaII', 'Gene', (54, 60))	('betaII', 'Gene', (76, 82))	('serine', 'Chemical', 'MESH:D012694', (440, 446))	('serine', 'Chemical', 'MESH:D012694', (176, 182))	('H3', 'Chemical', 'MESH:C012616', (334, 336))	('serine', 'Chemical', 'MESH:D012694', (571, 577))	('cysteine 239 substituted by serine', 'Mutation', 'p.C239S', (543, 577))	('betaII', 'Gene', '114548', (54, 60))	('betaII', 'Gene', '114548', (46, 52))	('serine 275 substituted to alanine', 'Mutation', 'p.S275A', (440, 473))	('substitutions', 'Var', (112, 125))	('colchicine', 'Chemical', 'MESH:D003078', (518, 528))	('S7-H9', 'CellLine', 'CVCL:1240', (429, 434))	('H3', 'Chemical', 'MESH:C012616', (172, 174))
465196	32823874	However, how betaIII substitution relates to its specific properties is mainly unknown.	('betaII', 'Gene', '114548', (13, 19))	('betaII', 'Gene', (13, 19))	('substitution', 'Var', (21, 33))
465204	32823874	For instance, acetylation of lysine 252 of beta-tubulin by San acetyltransferase slows down the rate of tubulin incorporation into the microtubule and consequently reduces the rate of MT assembly.	('tubulin incorporation into the microtubule', 'MPA', (104, 146))	('reduces', 'NegReg', (164, 171))	('acetylation', 'Var', (14, 25))	('rat', 'Species', '10116', (176, 179))	('lysine', 'Chemical', 'MESH:D008239', (29, 35))	('lysine 252', 'Var', (29, 39))	('MT assembly', 'MPA', (184, 195))	('rate', 'MPA', (96, 100))	('rat', 'Species', '10116', (119, 122))	('slows down', 'NegReg', (81, 91))	('beta-tubulin', 'Protein', (43, 55))	('rate', 'MPA', (176, 180))	('rat', 'Species', '10116', (96, 99))
465205	32823874	Phosphorylation of serine 172 of beta-tubulin by minikinase/DYRK1a (neurons) or cyclin-dependent kinase Cdk1 (mammalian mitotic cells) inhibits the incorporation of tubulin heterodimers, while heterodimers containing alphaIc-tubulin phosphorylated at serine 165 assemble more effectively than unmodified ones.	('rat', 'Species', '10116', (155, 158))	('DYRK1a', 'Gene', (60, 66))	('serine', 'Chemical', 'MESH:D012694', (251, 257))	('mammalian', 'Species', '9606', (110, 119))	('DYRK1a', 'Gene', '1859', (60, 66))	('Phosphorylation', 'Var', (0, 15))	('incorporation', 'MPA', (148, 161))	('tubulin', 'Protein', (165, 172))	('Cdk1', 'Gene', '983', (104, 108))	('inhibits', 'NegReg', (135, 143))	('serine', 'Var', (19, 25))	('Cdk1', 'Gene', (104, 108))	('serine', 'Chemical', 'MESH:D012694', (19, 25))
465216	32823874	The positions of the main polyamination sites near the GTP pocket (glutamine 15 in beta-tubulin) and alpha-tubulin minus end suggest that tubulin polyamination could affect GTP binding or hydrolysis and microtubule lattice stabilization.	('polyamination', 'Var', (146, 159))	('hydrolysis', 'MPA', (188, 198))	('GTP', 'MPA', (173, 176))	('glutamine', 'Chemical', 'MESH:D005973', (67, 76))	('alpha-tubulin', 'Gene', (101, 114))	('affect', 'Reg', (166, 172))	('microtubule', 'MPA', (203, 214))	('GTP', 'Chemical', 'MESH:D006160', (173, 176))	('GTP', 'Chemical', 'MESH:D006160', (55, 58))	('alpha-tubulin', 'Gene', '10376', (101, 114))
465220	32823874	For example, XMAP215 can be classified as both an MT nucleator and a plus end-binding protein while kinesin-13 family proteins are motor proteins that bind to microtubule plus ends and have MT-depolymerizing properties.	('XMAP215', 'Var', (13, 20))	('polymer', 'Chemical', 'MESH:D011108', (195, 202))	('microtubule plus ends', 'MPA', (159, 180))	('bind', 'Interaction', (151, 155))
465235	32823874	For example, tyrosination increases the affinity of MT to the stabilizing protein, CLIP-170/CLIP-1 but, also to depolymerizing proteins from the kinesin-13 family.	('affinity', 'MPA', (40, 48))	('CLIP-1', 'Gene', (92, 98))	('tyrosination', 'Var', (13, 25))	('depolymerizing proteins', 'MPA', (112, 135))	('CLIP-1', 'Gene', '6249', (83, 89))	('CLIP-170', 'Gene', (83, 91))	('CLIP-1', 'Gene', '6249', (92, 98))	('polymer', 'Chemical', 'MESH:D011108', (114, 121))	('CLIP-1', 'Gene', (83, 89))	('increases', 'PosReg', (26, 35))	('CLIP-170', 'Gene', '6249', (83, 91))
465238	32823874	This feature of MTAs is used in cancer therapy, as it was shown that treatment of cancer cells with MTAs led to the mitotic arrest and consequent cell death.	('mitotic arrest', 'Disease', 'MESH:D006323', (116, 130))	('MTA', 'Chemical', '-', (100, 103))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('MTAs', 'Var', (100, 104))	('cancer', 'Disease', (32, 38))	('MTA', 'Chemical', '-', (16, 19))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('cell death', 'CPA', (146, 156))	('mitotic arrest', 'Disease', (116, 130))
465252	32823874	They both have the unique ability to bind covalently to taxane-site residues asparagine 228/histidine 229 and aspartic acid 226.	('taxane', 'Chemical', 'MESH:C080625', (56, 62))	('histidine', 'Chemical', 'MESH:D006639', (92, 101))	('asparagine', 'Chemical', 'MESH:D001216', (77, 87))	('aspartic', 'Var', (110, 118))	('bind', 'Interaction', (37, 41))	('aspartic acid', 'Chemical', 'MESH:D001224', (110, 123))	('asparagine', 'Var', (77, 87))
465254	32823874	The taxane (Figure 2) site is located near the ML surface, on the "inside" side of the tubulin (which in MT, faces the lumen), and is formed by hydrophobic residues of H7, S7, and loops H6-H7, S7-H9 (M loop), and S9-S10 (Figure 2).	('H6-H7', 'Var', (186, 191))	('S9-S10', 'Var', (213, 219))	('H6-H7', 'CellLine', 'CVCL:J418', (186, 191))	('S7-H9', 'CellLine', 'CVCL:1240', (193, 198))	('taxane', 'Chemical', 'MESH:C080625', (4, 10))
465273	32823874	The vinca site is located at the plus end surface of beta-tubulin and is formed by residues of H6 and loops T5 and H6-H7; however, several agents also bind to H7 and beta-tubulin-bound nucleotide sites.	('H6-H7', 'Var', (115, 120))	('H6-H7', 'CellLine', 'CVCL:J418', (115, 120))	('bind', 'Interaction', (151, 155))
465280	32823874	It is worth noting that PM060184 is currently under clinical evaluation, while ado-trastuzumab emtansine was recently approved for adjuvant treatment of patients with HER2-positive early breast cancer and was shown to prolong patient survival with a manageable safety profile.	('patient survival', 'CPA', (226, 242))	('breast cancer', 'Phenotype', 'HP:0003002', (187, 200))	('patients', 'Species', '9606', (153, 161))	('PM060184', 'Var', (24, 32))	('patient', 'Species', '9606', (226, 233))	('HER2', 'Gene', (167, 171))	('ado-trastuzumab', 'Chemical', 'MESH:C550911', (79, 94))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('HER2', 'Gene', '2064', (167, 171))	('prolong', 'PosReg', (218, 225))	('patient', 'Species', '9606', (153, 160))	('emtansine', 'Chemical', 'MESH:D008453', (95, 104))	('breast cancer', 'Disease', 'MESH:D001943', (187, 200))	('breast cancer', 'Disease', (187, 200))
465281	32823874	The maytansine site is located in close vicinity to NBP and the vinca site, but is formed by other structures, including H3', H11, H11', and loops H11-H11', T3, and T5 (Figure 2).	('H11', 'Gene', '3024', (151, 154))	("H3'", 'Var', (121, 124))	('H11', 'Gene', '3024', (131, 134))	('maytansine', 'Chemical', 'MESH:D008453', (4, 14))	('H11', 'Gene', (131, 134))	('H11', 'Gene', '3024', (147, 150))	('H11', 'Gene', (151, 154))	('H11', 'Gene', (126, 129))	('H3', 'Chemical', 'MESH:C012616', (121, 123))	('H11', 'Gene', (147, 150))	('H11', 'Gene', '3024', (126, 129))
465295	32823874	It is a big pocket formed by the hydrophobic and polar residues of H7, H8, S7, S8, and loop H7-H8 (T7 loop) that can be divided into three zones: central zone 2 and two accessory zones, zone 1 facing alpha-tubulin and zone 3 buried deeper within the beta-tubulin pocket.	('loop H7-H8', 'Var', (87, 97))	('alpha-tubulin', 'Gene', '10376', (200, 213))	('alpha-tubulin', 'Gene', (200, 213))
465301	32823874	It is worth noting that pironetin is, to date, the only known compound that exclusively targets the alpha-tubulin subunit and covalently binds to Cys316 of alpha-tubulin.	('binds', 'Interaction', (137, 142))	('alpha-tubulin', 'Gene', (100, 113))	('Cys316', 'Var', (146, 152))	('alpha-tubulin', 'Gene', (156, 169))	('Cys316', 'Chemical', '-', (146, 152))	('pironetin', 'Chemical', 'MESH:C088446', (24, 33))	('alpha-tubulin', 'Gene', '10376', (100, 113))	('alpha-tubulin', 'Gene', '10376', (156, 169))
465307	32823874	Thus, it is not surprising that numerous alterations in tubulins, including mutations and variations in isotype expression level, post-translational modifications, and MAP composition, were identified in cancer cells.	('cancer', 'Disease', (204, 210))	('isotype expression level', 'MPA', (104, 128))	('cancer', 'Disease', 'MESH:D009369', (204, 210))	('mutations', 'Var', (76, 85))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('rat', 'Species', '10116', (45, 48))	('post-translational modifications', 'MPA', (130, 162))	('tubulins', 'Protein', (56, 64))	('variations', 'Reg', (90, 100))	('MAP composition', 'MPA', (168, 183))	('alterations', 'Reg', (41, 52))
465314	32823874	High betaI expression is associated with the acquisition of chemoresistance to MTAs and poor prognosis in ovarian serous carcinoma and lung adenocarcinoma, but not in lung squamous cell carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (135, 154))	('MTA', 'Chemical', '-', (79, 82))	('ovarian serous carcinoma', 'Disease', 'MESH:D010051', (106, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (145, 154))	('High', 'Var', (0, 4))	('lung adenocarcinoma', 'Disease', (135, 154))	('lung squamous cell carcinoma', 'Disease', (167, 195))	('associated', 'Reg', (25, 35))	('expression', 'MPA', (11, 21))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (167, 195))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (135, 154))	('carcinoma', 'Phenotype', 'HP:0030731', (186, 195))	('betaI', 'Protein', (5, 10))	('ovarian serous carcinoma', 'Disease', (106, 130))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (172, 195))	('chemoresistance', 'MPA', (60, 75))
465324	32823874	Nuclear localization of betaII was recently associated with poor outcomes in colorectal cancer patients.	('associated', 'Reg', (44, 54))	('betaII', 'Gene', (24, 30))	('colorectal cancer', 'Disease', (77, 94))	('patients', 'Species', '9606', (95, 103))	('colorectal cancer', 'Disease', 'MESH:D015179', (77, 94))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('betaII', 'Gene', '114548', (24, 30))	('colorectal cancer', 'Phenotype', 'HP:0003003', (77, 94))	('Nuclear localization', 'Var', (0, 20))
465341	32823874	In fact, siRNA knockdown of IVb beta-tubulin expression in NSCLC and pancreatic ductal carcinoma cell lines increases the response to vinca alkaloids.	('response to vinca alkaloids', 'MPA', (122, 149))	('NSCLC', 'Disease', 'MESH:D002289', (59, 64))	('ductal carcinoma', 'Phenotype', 'HP:0030075', (80, 96))	('knockdown', 'Var', (15, 24))	('IVb', 'Gene', (28, 31))	('increases', 'PosReg', (108, 117))	('pancreatic ductal carcinoma', 'Disease', 'MESH:D021441', (69, 96))	('pancreatic ductal carcinoma', 'Disease', (69, 96))	('vinca alkaloids', 'Chemical', 'MESH:D014748', (134, 149))	('NSCLC', 'Disease', (59, 64))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))
465347	32823874	Similar, in NSCLC patients with a low level of betaV and high level of betaIII expression, the outcome was much worse than in patients with high betaV and low betaIII, while patients with either a high or low level of both isotypes had an intermediate outcome.	('betaII', 'Gene', '114548', (159, 165))	('betaII', 'Gene', (159, 165))	('patients', 'Species', '9606', (174, 182))	('NSCLC', 'Disease', (12, 17))	('betaII', 'Gene', '114548', (71, 77))	('low', 'Var', (34, 37))	('betaII', 'Gene', (71, 77))	('patients', 'Species', '9606', (126, 134))	('patients', 'Species', '9606', (18, 26))	('NSCLC', 'Disease', 'MESH:D002289', (12, 17))	('worse', 'NegReg', (112, 117))
465349	32823874	MTA resistance in cancer could also be related to mutations of beta-tubulin.	('MTA', 'Chemical', '-', (0, 3))	('mutations', 'Var', (50, 59))	('related', 'Reg', (39, 46))	('beta-tubulin', 'Protein', (63, 75))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('MTA', 'MPA', (0, 3))	('cancer', 'Disease', (18, 24))	('cancer', 'Disease', 'MESH:D009369', (18, 24))
465350	32823874	Studies conducted on cell lines showed that mutations of predominating beta-tubulin isotypes within the taxane-, colchicine-, and vinca-binding sites can be associated with altered MT dynamics and/or resistance to MTA (reviewed in).	('associated', 'Reg', (157, 167))	('taxane', 'Chemical', 'MESH:C080625', (104, 110))	('altered', 'Reg', (173, 180))	('MTA', 'Chemical', '-', (214, 217))	('mutations', 'Var', (44, 53))	('beta-tubulin', 'Protein', (71, 83))	('resistance', 'CPA', (200, 210))	('colchicine', 'Chemical', 'MESH:D003078', (113, 123))
465351	32823874	Most beta-tubulin mutations located within close proximity to the taxane-binding site did not change the affinity of tubulin to taxanes or epothilones, but probably destabilized MTs in the absence of any drugs.	('taxane', 'Chemical', 'MESH:C080625', (66, 72))	('MTs', 'CPA', (178, 181))	('epothilones', 'Chemical', 'MESH:D034261', (139, 150))	('taxanes', 'Chemical', 'MESH:D043823', (128, 135))	('taxane', 'Chemical', 'MESH:C080625', (128, 134))	('beta-tubulin', 'Protein', (5, 17))	('destabilized', 'NegReg', (165, 177))	('mutations', 'Var', (18, 27))
465352	32823874	Only mutation at F270V, T274I, and R282N residues were reported to have a direct effect on drug-binding affinity.	('T274I', 'Var', (24, 29))	('T274I', 'Mutation', 'p.T274I', (24, 29))	('R282N residues', 'Var', (35, 49))	('F270V', 'Mutation', 'p.F270V', (17, 22))	('R282N', 'Mutation', 'p.R282N', (35, 40))	('effect', 'Reg', (81, 87))	('drug-binding affinity', 'MPA', (91, 112))
465353	32823874	A similar effect was observed when point mutations were located in the M-loop (T274I, R282Q) or in helix H9, which is essential for interdimer interactions (Q292E).	('Q292E', 'Mutation', 'p.Q292E', (157, 162))	('T274I', 'Var', (79, 84))	('R282Q', 'Mutation', 'p.R282Q', (86, 91))	('T274I', 'Mutation', 'p.T274I', (79, 84))	('R282Q', 'Var', (86, 91))
465354	32823874	A recent study on a large number of samples of breast cancer tumors identified several mutations in betaI, betaIIa, and betaIVb tubulins in which a gene-encoded residue was replaced by the amino acid present in the corresponding position in betaIII.	('betaIVb', 'Gene', (120, 127))	('betaII', 'Gene', '114548', (107, 113))	('breast cancer tumors', 'Disease', 'MESH:D001943', (47, 67))	('breast cancer', 'Phenotype', 'HP:0003002', (47, 60))	('betaII', 'Gene', (107, 113))	('betaII', 'Gene', (241, 247))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('betaI', 'Gene', (100, 105))	('breast cancer tumors', 'Disease', (47, 67))	('mutations', 'Var', (87, 96))	('betaII', 'Gene', '114548', (241, 247))
465355	32823874	It was proposed that such mutations could influence the clinical outcome in a similar manner as overexpression of betaIII-tubulin.	('mutations', 'Var', (26, 35))	('betaII', 'Gene', (114, 120))	('betaII', 'Gene', '114548', (114, 120))	('influence', 'Reg', (42, 51))
465366	32823874	Recent studies provide evidence that phosphorylation of serine 21 of HDAC6 by G protein-coupled receptor kinase 5 (GRK5) promotes deacetylase activity in ovarian (HeLa) and breast (MDA MB 231) cancer cell lines.	('serine 21', 'Var', (56, 65))	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('GRK5', 'Gene', (115, 119))	('HeLa', 'CellLine', 'CVCL:0030', (163, 167))	('cancer', 'Disease', (193, 199))	('G protein-coupled receptor kinase 5', 'Gene', (78, 113))	('phosphorylation', 'Var', (37, 52))	('MDA MB 231', 'CellLine', 'CVCL:0062', (181, 191))	('serine', 'Chemical', 'MESH:D012694', (56, 62))	('HDAC6', 'Gene', (69, 74))	('promotes', 'PosReg', (121, 129))	('deacetylase activity', 'MPA', (130, 150))	('GRK5', 'Gene', '2869', (115, 119))	('HDAC6', 'Gene', '10013', (69, 74))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('ovarian', 'Disease', 'MESH:D010049', (154, 161))	('ovarian', 'Disease', (154, 161))	('G protein-coupled receptor kinase 5', 'Gene', '2869', (78, 113))
465368	32823874	The high expression of HDAC6 was also linked to poor prognosis of oral squamous cell carcinoma (OSCC), oncogenic transformation, and EMT.	('linked', 'Reg', (38, 44))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (66, 94))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (71, 94))	('oral squamous cell carcinoma', 'Disease', (66, 94))	('expression', 'MPA', (9, 19))	('oncogenic transformation', 'CPA', (103, 127))	('high', 'Var', (4, 8))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('HDAC6', 'Gene', '10013', (23, 28))	('EMT', 'CPA', (133, 136))	('HDAC6', 'Gene', (23, 28))
465378	32823874	Some studies suggested that the silencing of the Stathmin-1-encoding gene can inhibit cancer cell migration and metastatic potential.	('Stathmin-1', 'Gene', '3925', (49, 59))	('Stathmin-1', 'Gene', (49, 59))	('rat', 'Species', '10116', (101, 104))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('silencing', 'Var', (32, 41))	('inhibit', 'NegReg', (78, 85))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('cancer', 'Disease', (86, 92))
465391	32823874	Overexpression of MAP2 in melanoma cell lines leads to microtubule stabilization, associated with G2-M phase cell cycle arrest, growth inhibition, and cancer cell apoptosis, both in vitro and in a nude mouse model.	('arrest', 'Disease', (120, 126))	('MAP2', 'Gene', (18, 22))	('microtubule stabilization', 'MPA', (55, 80))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('mouse', 'Species', '10090', (202, 207))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (109, 126))	('arrest', 'Disease', 'MESH:D006323', (120, 126))	('melanoma', 'Phenotype', 'HP:0002861', (26, 34))	('cancer', 'Disease', (151, 157))	('melanoma', 'Disease', (26, 34))	('Overexpression', 'Var', (0, 14))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('growth inhibition', 'CPA', (128, 145))	('melanoma', 'Disease', 'MESH:D008545', (26, 34))
465394	32823874	Silencing of MAP1B in urothelial cancer cell lines decreased the cell migration and invasiveness.	('urothelial cancer', 'Disease', (22, 39))	('urothelial cancer', 'Disease', 'MESH:D014523', (22, 39))	('cell migration', 'CPA', (65, 79))	('decreased', 'NegReg', (51, 60))	('invasiveness', 'CPA', (84, 96))	('MAP1B', 'Gene', (13, 18))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('Silencing', 'Var', (0, 9))	('rat', 'Species', '10116', (73, 76))	('MAP1B', 'Gene', '4131', (13, 18))
465411	32429941	cancer-related differentially expressed genes or structural variations, as well as predicting the clinical outcomes, such as the risk stratification for the patients in cancers.	('cancer', 'Disease', (169, 175))	('cancers', 'Disease', (169, 176))	('differentially expressed genes', 'Gene', (15, 45))	('structural variations', 'Var', (49, 70))	('cancer', 'Phenotype', 'HP:0002664', (0, 6))	('patients', 'Species', '9606', (157, 165))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('cancer', 'Disease', 'MESH:D009369', (0, 6))	('cancer', 'Disease', (0, 6))	('cancers', 'Phenotype', 'HP:0002664', (169, 176))	('cancer', 'Disease', 'MESH:D009369', (169, 175))	('cancers', 'Disease', 'MESH:D009369', (169, 176))
465440	32429941	In terms of details, for the easily predicted cancer types, the performance of SWT-CNN was better than that of SVM.	('better', 'PosReg', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('cancer', 'Disease', (46, 52))	('SWT-CNN', 'Var', (79, 86))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))
465443	32429941	When predicting the tumor stages of KIRC, the mean AUC achieved by SWT-CNN (mean AUC = 0.74) was 0.19 higher than that achieved by SVM (mean AUC = 0.55).	('higher', 'PosReg', (102, 108))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('AUC', 'MPA', (51, 54))	('SWT-CNN', 'Var', (67, 74))	('tumor', 'Disease', (20, 25))
465502	32429941	The gene fusion of SLC34A2 and ROS1 played an important role in the progression of non-small cell lung cancer.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('lung cancer', 'Phenotype', 'HP:0100526', (98, 109))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (83, 109))	('gene fusion', 'Var', (4, 15))	('SLC34A2', 'Gene', '10568', (19, 26))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (83, 109))	('ROS1', 'Gene', (31, 35))	('non-small cell lung cancer', 'Disease', (83, 109))	('ROS1', 'Gene', '6098', (31, 35))	('SLC34A2', 'Gene', (19, 26))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (87, 109))
465568	31789390	Gene Set Enrichment Analysis showed that the expression level of IGSF10 was significantly associated with the activation of the integrin-beta1/focal adhesion kinase (FAK) pathway.	('FAK', 'Gene', (166, 169))	('activation', 'PosReg', (110, 120))	('expression level', 'Var', (45, 61))	('IGSF10', 'Gene', '285313', (65, 71))	('integrin-beta1', 'Gene', '3688', (128, 142))	('IGSF10', 'Gene', (65, 71))	('FAK', 'Gene', '5747', (166, 169))	('integrin-beta1', 'Gene', (128, 142))
465569	31789390	Western blotting revealed that knockout of IGSF10 resulted in the activation of the integrin-beta1/FAK pathway, as the protein expression levels of integrin-beta1, phosphorylated (p)-FAK and p-AKT were significantly upregulated.	('integrin-beta1', 'Gene', (148, 162))	('integrin-beta1', 'Gene', (84, 98))	('AKT', 'Gene', '207', (193, 196))	('IGSF10', 'Gene', (43, 49))	('FAK', 'Gene', (99, 102))	('FAK', 'Gene', '5747', (99, 102))	('upregulated', 'PosReg', (216, 227))	('integrin-beta1', 'Gene', '3688', (148, 162))	('protein expression levels', 'MPA', (119, 144))	('AKT', 'Gene', (193, 196))	('integrin-beta1', 'Gene', '3688', (84, 98))	('IGSF10', 'Gene', '285313', (43, 49))	('knockout', 'Var', (31, 39))	('FAK', 'Gene', (183, 186))	('FAK', 'Gene', '5747', (183, 186))	('activation', 'PosReg', (66, 76))
465570	31789390	Activation of the integrin-beta1/FAK pathway, following knockout of IGSF10, affected the proliferation and adhesion of lung cancer cells.	('proliferation', 'CPA', (89, 102))	('knockout', 'Var', (56, 64))	('FAK', 'Gene', '5747', (33, 36))	('lung cancer', 'Disease', (119, 130))	('lung cancer', 'Phenotype', 'HP:0100526', (119, 130))	('FAK', 'Gene', (33, 36))	('adhesion', 'CPA', (107, 115))	('IGSF10', 'Gene', (68, 74))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('integrin-beta1', 'Gene', '3688', (18, 32))	('Activation', 'PosReg', (0, 10))	('lung cancer', 'Disease', 'MESH:D008175', (119, 130))	('affected', 'Reg', (76, 84))	('IGSF10', 'Gene', '285313', (68, 74))	('integrin-beta1', 'Gene', (18, 32))
465664	31789390	The reduction efficiency was evaluated by siRNA knockdown of IGSF10, followed by RT-qPCR and western blotting (Fig.	('IGSF10', 'Gene', '285313', (61, 67))	('IGSF10', 'Gene', (61, 67))	('knockdown', 'Var', (48, 57))
465669	31789390	These results suggest that knockdown of IGSF10 significantly promoted the proliferation of lung cancer cells.	('lung cancer', 'Phenotype', 'HP:0100526', (91, 102))	('knockdown', 'Var', (27, 36))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('promoted', 'PosReg', (61, 69))	('IGSF10', 'Gene', (40, 46))	('lung cancer', 'Disease', 'MESH:D008175', (91, 102))	('IGSF10', 'Gene', '285313', (40, 46))	('proliferation', 'CPA', (74, 87))	('lung cancer', 'Disease', (91, 102))
465671	31789390	Wound healing experiments revealed that the knockdown of IGSF10 significantly increased the migration ability of A549 and PC9 cells (Fig.	('migration ability', 'CPA', (92, 109))	('PC9', 'Gene', (122, 125))	('IGSF10', 'Gene', (57, 63))	('IGSF10', 'Gene', '285313', (57, 63))	('increased', 'PosReg', (78, 87))	('A549', 'CellLine', 'CVCL:0023', (113, 117))	('knockdown', 'Var', (44, 53))	('PC9', 'Gene', '255738', (122, 125))
465676	31789390	12, the protein expression levels of integrin-beta1, p-FAK and p-AKT were significantly upregulated following the knockout of IGSF10 in A549 and PC9 cells.	('upregulated', 'PosReg', (88, 99))	('PC9', 'Gene', '255738', (145, 148))	('integrin-beta1', 'Gene', (37, 51))	('AKT', 'Gene', (65, 68))	('protein expression levels', 'MPA', (8, 33))	('IGSF10', 'Gene', (126, 132))	('PC9', 'Gene', (145, 148))	('integrin-beta1', 'Gene', '3688', (37, 51))	('FAK', 'Gene', (55, 58))	('FAK', 'Gene', '5747', (55, 58))	('AKT', 'Gene', '207', (65, 68))	('IGSF10', 'Gene', '285313', (126, 132))	('knockout', 'Var', (114, 122))	('A549', 'CellLine', 'CVCL:0023', (136, 140))
465678	31789390	These results showed that after knocking out IGSF10, the activation of the integrin-beta1/FAK pathway in NSCLC cells may promote the malignant phenotype of tumour cells (Fig.	('NSCLC', 'Disease', 'MESH:D002289', (105, 110))	('tumour', 'Disease', 'MESH:D009369', (156, 162))	('integrin-beta1', 'Gene', (75, 89))	('tumour', 'Disease', (156, 162))	('activation', 'PosReg', (57, 67))	('NSCLC', 'Disease', (105, 110))	('knocking', 'Var', (32, 40))	('integrin-beta1', 'Gene', '3688', (75, 89))	('tumour', 'Phenotype', 'HP:0002664', (156, 162))	('IGSF10', 'Gene', (45, 51))	('FAK', 'Gene', (90, 93))	('promote', 'PosReg', (121, 128))	('FAK', 'Gene', '5747', (90, 93))	('IGSF10', 'Gene', '285313', (45, 51))
465690	31789390	Chen et al found that the high expression of PRC1 can promote the proliferation and metastasis of hepatocellular carcinoma (HCC) cells through a mutual regulation of the Wnt/beta-catenin signalling pathway, thus promoting the early recurrence and poor prognosis of HCC.	('promote', 'PosReg', (54, 61))	('high expression', 'Var', (26, 41))	('PRC1', 'Gene', (45, 49))	('PRC1', 'Gene', '9055', (45, 49))	('early recurrence', 'CPA', (226, 242))	('metastasis of hepatocellular carcinoma', 'Disease', (84, 122))	('proliferation', 'CPA', (66, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('HCC', 'Disease', (265, 268))	('metastasis of hepatocellular carcinoma', 'Disease', 'MESH:D009362', (84, 122))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (98, 122))	('promoting', 'PosReg', (212, 221))	('beta-catenin', 'Gene', (174, 186))	('beta-catenin', 'Gene', '1499', (174, 186))
465698	31789390	The overall survival rate of patients with lung adenocarcinoma with a high expression of KIF2C was significantly decreased.	('patients', 'Species', '9606', (29, 37))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (43, 62))	('KIF2C', 'Gene', '11004', (89, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (53, 62))	('high expression', 'Var', (70, 85))	('lung adenocarcinoma', 'Disease', (43, 62))	('decreased', 'NegReg', (113, 122))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (43, 62))	('KIF2C', 'Gene', (89, 94))
465703	31789390	The experimental results showed that knockout of IGSF10 significantly promoted the proliferation of lung cancer cells, enhanced the adhesion between cells and the matrix, and activated the integrin-beta1/FAK pathway, as demonstrated by an increase in the protein expression of integrin-beta1, p-FAK and p-AKT.	('FAK', 'Gene', (204, 207))	('knockout', 'Var', (37, 45))	('integrin-beta1', 'Gene', '3688', (277, 291))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('IGSF10', 'Gene', (49, 55))	('enhanced', 'PosReg', (119, 127))	('FAK', 'Gene', '5747', (204, 207))	('IGSF10', 'Gene', '285313', (49, 55))	('integrin-beta1', 'Gene', '3688', (189, 203))	('integrin-beta1', 'Gene', (277, 291))	('integrin-beta1', 'Gene', (189, 203))	('lung cancer', 'Disease', (100, 111))	('AKT', 'Gene', (305, 308))	('promoted', 'PosReg', (70, 78))	('proliferation', 'CPA', (83, 96))	('protein expression', 'MPA', (255, 273))	('FAK', 'Gene', (295, 298))	('activated', 'PosReg', (175, 184))	('lung cancer', 'Disease', 'MESH:D008175', (100, 111))	('AKT', 'Gene', '207', (305, 308))	('FAK', 'Gene', '5747', (295, 298))	('lung cancer', 'Phenotype', 'HP:0100526', (100, 111))	('increase', 'PosReg', (239, 247))
465779	33023466	In addition, circ-0000495 has been shown to sponge miR-488-3p expression and epigenetically silence TROP2 expression, resulting in the weakening of the proliferative capacity of HNSCC.	('HNSCC', 'Phenotype', 'HP:0012288', (178, 183))	('TROP2', 'Gene', (100, 105))	('proliferative capacity', 'CPA', (152, 174))	('epigenetically', 'Var', (77, 91))	('weakening', 'NegReg', (135, 144))	('TROP2', 'Gene', '4070', (100, 105))	('expression', 'MPA', (106, 116))	('miR', 'Gene', '220972', (51, 54))	('miR', 'Gene', (51, 54))
465790	33023466	The 11 DEMs verified from the LASSO regression analysis were used to generate a risk signature as per the following formula: Risk score = (0.236 x expression miR-204-5p) + (0.059 x expression miR-499a-5p) + (0.212 x expression miR-498-5p) - (0.062 x expression miR-155-3p) + (0.434 x expression miR-4714-3p) - (0.141 x expression miR-365a-5p) + (0.321 x expression miR-30a-5p) + (0.123 x expression miR-1-5p) + (0.240 x expression miR-548f-3p) + (0.196 x expression miR-518a-3p) - (0.140 x expression miR-196b-5p).	('miR-204', 'Gene', (158, 165))	('miR', 'Gene', (330, 333))	('miR', 'Gene', '220972', (399, 402))	('miR', 'Gene', '220972', (227, 230))	('miR-499a', 'Gene', (192, 200))	('miR-548f-3p', 'Gene', '100302159', (431, 442))	('miR', 'Gene', '220972', (431, 434))	('miR-548f-3p', 'Gene', (431, 442))	('miR', 'Gene', '220972', (192, 195))	('miR', 'Gene', '220972', (501, 504))	('miR', 'Gene', (399, 402))	('miR', 'Gene', (227, 230))	('miR-204', 'Gene', '406987', (158, 165))	('miR-498', 'Gene', '574460', (227, 234))	('miR', 'Gene', (431, 434))	('miR', 'Gene', '220972', (158, 161))	('miR', 'Gene', '220972', (295, 298))	('miR', 'Gene', (192, 195))	('miR', 'Gene', (501, 504))	('miR-499a', 'Gene', '574501', (192, 200))	('miR-30a', 'Gene', '407029', (365, 372))	('miR', 'Gene', '220972', (261, 264))	('miR', 'Gene', '220972', (365, 368))	('miR', 'Gene', '220972', (466, 469))	('miR', 'Gene', (158, 161))	('miR', 'Gene', (295, 298))	('miR-498', 'Gene', (227, 234))	('0.240 x', 'Var', (412, 419))	('miR-155-3p', 'Chemical', '-', (261, 271))	('miR', 'Gene', '220972', (330, 333))	('miR', 'Gene', (261, 264))	('miR-365a-5p', 'Chemical', '-', (330, 341))	('miR-30a', 'Gene', (365, 372))	('miR', 'Gene', (365, 368))	('miR', 'Gene', (466, 469))
465811	33023466	In addition, miR-518a-3p has been shown to promote the proliferation, migration, and invasion of choriocarcinoma cells; knockdown of miR-518a-3p expression has been found to induce S phase arrest in choriocarcinoma cells.	('induce', 'Reg', (174, 180))	('choriocarcinoma', 'Disease', 'MESH:D002822', (97, 112))	('arrest', 'Disease', 'MESH:D006323', (189, 195))	('miR', 'Gene', '220972', (13, 16))	('miR', 'Gene', (13, 16))	('choriocarcinoma', 'Disease', (199, 214))	('miR', 'Gene', (133, 136))	('miR', 'Gene', '220972', (133, 136))	('choriocarcinoma', 'Phenotype', 'HP:0100768', (199, 214))	('arrest', 'Disease', (189, 195))	('carcinoma', 'Phenotype', 'HP:0030731', (205, 214))	('choriocarcinoma', 'Disease', (97, 112))	('knockdown', 'Var', (120, 129))	('choriocarcinoma', 'Phenotype', 'HP:0100768', (97, 112))	('choriocarcinoma', 'Disease', 'MESH:D002822', (199, 214))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))
465813	33023466	miR-365a-5p inhibits the viability, colony formation, migration, and invasion of non-small cell lung cancer cells by negatively regulating Pellino E3 ubiquitin protein ligase family member 3 (PELI3), and PELI3 silencing promotes the miR-365a-5p-mediated suppression of pro-tumoral effects.	('promotes', 'PosReg', (220, 228))	('viability', 'CPA', (25, 34))	('miR-365a-5p', 'Chemical', '-', (233, 244))	('PELI3', 'Gene', '246330', (192, 197))	('migration', 'CPA', (54, 63))	('negatively regulating', 'NegReg', (117, 138))	('tumor', 'Disease', (273, 278))	('PELI3', 'Gene', (192, 197))	('suppression', 'NegReg', (254, 265))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('miR-365a-5p-mediated', 'Var', (233, 253))	('tumor', 'Disease', 'MESH:D009369', (273, 278))	('colony formation', 'CPA', (36, 52))	('lung cancer', 'Phenotype', 'HP:0100526', (96, 107))	('inhibits', 'NegReg', (12, 20))	('PELI3', 'Gene', '246330', (204, 209))	('silencing', 'NegReg', (210, 219))	('PELI3', 'Gene', (204, 209))	('miR-365a-5p', 'Var', (0, 11))	('Pellino E3 ubiquitin protein ligase family member 3', 'Gene', '246330', (139, 190))	('miR-365a-5p', 'Chemical', '-', (0, 11))	('tumor', 'Phenotype', 'HP:0002664', (273, 278))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (81, 107))	('cancer', 'Disease', (101, 107))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (85, 107))	('invasion', 'CPA', (69, 77))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))
465908	31073279	Mice deficient in ANGPT2 have abnormalities in the blood and lymphatic vasculatures, and also show deficits in rapid leukocyte recruitment to sites of inflammation.	('rapid leukocyte recruitment to', 'CPA', (111, 141))	('ANGPT2', 'Gene', (18, 24))	('abnormalities', 'Reg', (30, 43))	('inflammation', 'Disease', 'MESH:D007249', (151, 163))	('Mice', 'Species', '10090', (0, 4))	('deficits', 'NegReg', (99, 107))	('inflammation', 'Disease', (151, 163))	('deficient', 'Var', (5, 14))
465910	31073279	ESM1 endothelial cell specific molecule-1 HNSCC head and neck squamous cell carcinoma TCGA The Cancer Genome Atlas ANGPT2 angiopoietin-2 ENCODE Encyclopedia of DNA Elements HPV human papilloma virus TUBB3 betaIII-tubulin HOX homeobox gene family MMPs metalloproteinases TNF-alpha tumor necrosis factor-alpha IL interleukin VEGF vascular endothelial growth factor UCSC University of California, Santa Cruz HRP horseradish peroxidase DAB diaminobenzidine HOMER Hypergeometric Optimization of Motif EnRichment TSS transcription start site CNV copy number variation TFBSs TF binding sites NGFR nerve growth factor receptor STAT3 signal transducer and activator of transcription 3 TBP TATA-box binding protein GATA2 GATA binding protein 2	('TUBB3', 'Gene', '10381', (199, 204))	('angiopoietin-2', 'Gene', '285', (122, 136))	('VEGF', 'Gene', (323, 327))	('papilloma', 'Phenotype', 'HP:0012740', (183, 192))	('TBP', 'Gene', '6908', (676, 679))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (95, 114))	('GATA binding protein 2', 'Gene', '2624', (711, 733))	('STAT3', 'Gene', (619, 624))	('NGFR', 'Gene', (585, 589))	('GATA2', 'Gene', '2624', (705, 710))	('horseradish', 'Species', '3704', (409, 420))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (62, 85))	('TATA-box binding protein', 'Gene', '6908', (680, 704))	('neck squamous cell carcinoma', 'Disease', (57, 85))	('HNSCC', 'Phenotype', 'HP:0012288', (42, 47))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (57, 85))	('variation', 'Var', (552, 561))	('STAT3', 'Gene', '6774', (619, 624))	('Cancer Genome Atlas', 'Disease', (95, 114))	('GATA2', 'Gene', (705, 710))	('nerve growth factor receptor', 'Gene', (590, 618))	('human papilloma virus', 'Species', '10566', (177, 198))	('GATA binding protein 2', 'Gene', (711, 733))	('HOX', 'Chemical', '-', (221, 224))	('signal transducer and activator of transcription 3', 'Gene', '6774', (625, 675))	('tumor necrosis factor-alpha', 'Gene', (280, 307))	('angiopoietin-2', 'Gene', (122, 136))	('vascular endothelial growth factor', 'Gene', '7422', (328, 362))	('Cancer', 'Phenotype', 'HP:0002664', (95, 101))	('NGFR', 'Gene', '18053', (585, 589))	('DAB', 'Chemical', 'MESH:D015100', (432, 435))	('endothelial cell specific molecule-1', 'Gene', (5, 41))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (48, 85))	('TUBB3', 'Gene', (199, 204))	('vascular endothelial growth factor', 'Gene', (328, 362))	('endothelial cell specific molecule-1', 'Gene', '11082', (5, 41))	('TBP', 'Gene', (676, 679))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('HPV', 'Species', '10566', (173, 176))	('VEGF', 'Gene', '7422', (323, 327))	('tumor', 'Phenotype', 'HP:0002664', (280, 285))	('TATA-box binding protein', 'Gene', (680, 704))	('TNF-alpha', 'Gene', '7124', (270, 279))	('diaminobenzidine', 'Chemical', '-', (436, 452))	('TNF-alpha', 'Gene', (270, 279))	('tumor necrosis factor-alpha', 'Gene', '7124', (280, 307))	('nerve growth factor receptor', 'Gene', '18053', (590, 618))
466028	29958123	All patients received the full panel of tumor marker test including CEA, CA125, CYFRA21-1, SCC and NSE before the commencement of therapy.	('CA125', 'Gene', (73, 78))	('NSE', 'Gene', (99, 102))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('CYFRA21-1', 'Var', (80, 89))	('CEA', 'Gene', (68, 71))	('CEA', 'Gene', '1048', (68, 71))	('SCC', 'Gene', (91, 94))	('patients', 'Species', '9606', (4, 12))	('CA125', 'Gene', '94025', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('NSE', 'Gene', '2026', (99, 102))	('SCC', 'Phenotype', 'HP:0002860', (91, 94))	('SCC', 'Gene', '6317', (91, 94))
466047	29958123	As shown in Table 2, patients with CYFRA 21-1 <= 5.2 ng/ml had significantly better OS (median: 27.1 vs. 20.6 months, P = .033), LRPFS (median: 30.8 vs. 16.4 months, P = .040) and PFS (median: 20.4 vs. 10.9 months, P = .015), as well as a DMFS benefit with a trend approaching significance (median: not reached vs. 44.2, P = .082).	('better', 'PosReg', (77, 83))	('LRPFS', 'MPA', (129, 134))	('patients', 'Species', '9606', (21, 29))	('DMFS', 'MPA', (239, 243))	('PFS', 'MPA', (180, 183))	('CYFRA 21-1 <= 5.2 ng/ml', 'Var', (35, 58))	('DMFS', 'Chemical', '-', (239, 243))
466049	29958123	Univariate analysis also identified significant superior OS in the subgroup of patients with CEA <= 5.3 ng/ml or SCC <= 2.5 ng/ml.	('superior', 'PosReg', (48, 56))	('<= 5.3 ng/ml', 'Var', (97, 109))	('SCC', 'Gene', '6317', (113, 116))	('CEA', 'Gene', (93, 96))	('patients', 'Species', '9606', (79, 87))	('SCC', 'Gene', (113, 116))	('SCC', 'Phenotype', 'HP:0002860', (113, 116))	('CEA', 'Gene', '1048', (93, 96))
466059	29958123	Node 1 included patients with stage IIIA disease; node 2 patients had stage IIIB disease, with KPS >= 80, baseline CEA <= 5.3 ng/ml and CYFRA 21-1 <= 5.2 ng/ml; node 3 patients carried stage IIIB disease, with KPS >= 80, baseline CEA <= 5.3 ng/ml but CYFRA 21-1 > 5.2 ng/ml; patients at node 4 had stage IIIB disease, KPS >= 80 and baseline CEA> 5.3 ng/ml; and patients at node 5 had IIIB disease and KPS< 80.	('patients', 'Species', '9606', (361, 369))	('CEA', 'Gene', (341, 344))	('CEA', 'Gene', '1048', (115, 118))	('CEA', 'Gene', '1048', (341, 344))	('patients', 'Species', '9606', (57, 65))	('CEA', 'Gene', (115, 118))	('stage IIIB disease', 'Disease', (298, 316))	('patients', 'Species', '9606', (16, 24))	('KPS >= 80', 'Var', (318, 327))	('patients', 'Species', '9606', (168, 176))	('CEA', 'Gene', '1048', (230, 233))	('patients', 'Species', '9606', (275, 283))	('CEA', 'Gene', (230, 233))
466065	29958123	In terms of inoperable locally-advanced NSCLC, though diverse results were reported with respect to the prognostic value of multiple serum tumor markers, CYFRAL 21-1 appeared to be most frequently reported as a prognostic determinant.	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('NSCLC', 'Phenotype', 'HP:0030358', (40, 45))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('NSCLC', 'Disease', (40, 45))	('CYFRAL 21-1', 'Var', (154, 165))	('NSCLC', 'Disease', 'MESH:D002289', (40, 45))
466096	28148898	Then, some functional SNPs in hub genes that may affect gene expression have been annotated.	('affect', 'Reg', (49, 55))	('SNPs', 'Var', (22, 26))	('hub', 'Gene', (30, 33))	('hub', 'Gene', '1993', (30, 33))	('gene expression', 'MPA', (56, 71))
466099	28148898	By using database annotation, we got 8 candidate functional SNPs that may affect the expression level of hub proteins.	('SNPs', 'Var', (60, 64))	('hub', 'Gene', (105, 108))	('affect', 'Reg', (74, 80))	('expression level', 'MPA', (85, 101))	('hub', 'Gene', '1993', (105, 108))
466100	28148898	In the case-control study, we found that rs4754-T allele, rs959173-C allele and rs2239144-G allele were the protective allele of NSCLC risk.	('NSCLC', 'Phenotype', 'HP:0030358', (129, 134))	('NSCLC', 'Disease', 'MESH:D002289', (129, 134))	('rs2239144-G', 'Var', (80, 91))	('rs2239144', 'Mutation', 'rs2239144', (80, 89))	('rs4754-T', 'Var', (41, 49))	('NSCLC', 'Disease', (129, 134))	('rs959173', 'Mutation', 'rs959173', (58, 66))	('rs4754', 'Mutation', 'rs4754', (41, 47))	('SCLC', 'Phenotype', 'HP:0030357', (130, 134))	('rs959173-C', 'Var', (58, 68))
466101	28148898	In dominant model, rs4754-CT+TT genotype were associated with a shorter survival time.	('survival time', 'CPA', (72, 85))	('rs4754-CT+TT', 'Var', (19, 31))	('shorter', 'NegReg', (64, 71))	('rs4754', 'Mutation', 'rs4754', (19, 25))
466106	28148898	A growing number of studies have indicated that genetic aberrations may be important in the genesis and development of human cancer.	('genetic aberrations', 'Var', (48, 67))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('important', 'Reg', (75, 84))	('human', 'Species', '9606', (119, 124))
466111	28148898	Thereafter, we scanned those SNPs in the significant nodes (hub proteins) in PPI network, and found those functional SNPs may affect hub proteins level.	('hub', 'Gene', '1993', (60, 63))	('hub', 'Gene', '1993', (133, 136))	('hub', 'Gene', (60, 63))	('hub', 'Gene', (133, 136))	('affect', 'Reg', (126, 132))	('SNPs', 'Var', (117, 121))
466120	28148898	After database annotation, we selected 8 SNPs in hub genes which may be related to gene expression.	('hub', 'Gene', '1993', (49, 52))	('SNPs', 'Var', (41, 45))	('hub', 'Gene', (49, 52))
466121	28148898	For rs4754, the A allele is a protective allele for NSCLC risk (adjusted OR = 0.762, 95% CI = 0.614-0.946, p = 0.014).	('rs4754', 'Var', (4, 10))	('NSCLC', 'Disease', (52, 57))	('NSCLC', 'Disease', 'MESH:D002289', (52, 57))	('SCLC', 'Phenotype', 'HP:0030357', (53, 57))	('rs4754', 'Mutation', 'rs4754', (4, 10))	('NSCLC', 'Phenotype', 'HP:0030358', (52, 57))
466122	28148898	Take rs4754-CC genotype as reference, TT genotype showed a relatively low risk of NSCLC (adjusted OR = 0.530, 95% CI = 0.317-0.884, p = 0.015).	('NSCLC', 'Phenotype', 'HP:0030358', (82, 87))	('SCLC', 'Phenotype', 'HP:0030357', (83, 87))	('rs4754', 'Mutation', 'rs4754', (5, 11))	('NSCLC', 'Disease', (82, 87))	('rs4754-CC', 'Var', (5, 14))	('NSCLC', 'Disease', 'MESH:D002289', (82, 87))
466123	28148898	Compared with homozygous carriers of rs959173-TT genotype, TC genotype and TC + CC dominant model showed a lower risk of NSCLC (adjusted OR = 0.567, 95% CI = 0.347-0.928, p = 0.024; adjusted OR = 0.576, 95% CI = 0.354-0.936, p = 0.026, respectively).	('rs959173', 'Mutation', 'rs959173', (37, 45))	('rs959173-TT', 'Var', (37, 48))	('lower', 'NegReg', (107, 112))	('NSCLC', 'Disease', (121, 126))	('NSCLC', 'Disease', 'MESH:D002289', (121, 126))	('TC', 'Chemical', 'MESH:D013667', (59, 61))	('SCLC', 'Phenotype', 'HP:0030357', (122, 126))	('NSCLC', 'Phenotype', 'HP:0030358', (121, 126))	('TC', 'Chemical', 'MESH:D013667', (75, 77))
466124	28148898	For rs2239144 we observed significant differences, the GT and TT genotypes were associated with a 1.508-fold (95%CI=1.105-2.058, p = 0.010) and 2.183-fold (95% CI = 1.450-3.287, p < 0.001) increased risk of NSCLC compared with GG genotype, T allele is a risk allele for NSCLC (adjusted OR = 1.513, 95% CI = 1.237-1.850, p < 0.001).	('rs2239144', 'Var', (4, 13))	('NSCLC', 'Disease', 'MESH:D002289', (270, 275))	('NSCLC', 'Phenotype', 'HP:0030358', (207, 212))	('NSCLC', 'Phenotype', 'HP:0030358', (270, 275))	('SCLC', 'Phenotype', 'HP:0030357', (208, 212))	('NSCLC', 'Disease', (207, 212))	('SCLC', 'Phenotype', 'HP:0030357', (271, 275))	('NSCLC', 'Disease', (270, 275))	('rs2239144', 'Mutation', 'rs2239144', (4, 13))	('NSCLC', 'Disease', 'MESH:D002289', (207, 212))
466125	28148898	As shown in Supplementary Table 1, there were statistical differences between rs2239144, rs3181385, rs4754 and risk of lung adenocarcinoma.	('rs4754', 'Var', (100, 106))	('rs3181385', 'Var', (89, 98))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (119, 138))	('rs3181385', 'Mutation', 'rs3181385', (89, 98))	('rs2239144', 'Mutation', 'rs2239144', (78, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('differences', 'Reg', (58, 69))	('lung adenocarcinoma', 'Disease', (119, 138))	('rs4754', 'Mutation', 'rs4754', (100, 106))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (119, 138))	('rs2239144', 'Var', (78, 87))
466128	28148898	Patients with rs4754-CC genotype showed a significantly longer survival time compared with those with CT or TT genotypes (25.124 months vs. 21.181 months), as shown in Figure 4.	('rs4754-CC', 'Var', (14, 23))	('survival time', 'CPA', (63, 76))	('Patients', 'Species', '9606', (0, 8))	('longer', 'PosReg', (56, 62))	('rs4754', 'Mutation', 'rs4754', (14, 20))
466144	28148898	In lung carcinoma cell line, inactivation of MMP9 can inhibit tumor invasion.	('MMP9', 'Gene', '4318', (45, 49))	('MMP9', 'Gene', (45, 49))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('inhibit', 'NegReg', (54, 61))	('carcinoma', 'Phenotype', 'HP:0030731', (8, 17))	('tumor', 'Disease', (62, 67))	('lung carcinoma', 'Disease', 'MESH:D008175', (3, 17))	('lung carcinoma', 'Disease', (3, 17))	('inactivation', 'Var', (29, 41))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
466147	28148898	Some SNPs in exonic splice enhancer (ESE) or exonic splice silencer (ESS) have been confirmed to be likely to affect the risk of disease by causing aberrant splicing.	('SNPs', 'Var', (5, 9))	('affect', 'Reg', (110, 116))	('ESS', 'Chemical', '-', (69, 72))	('disease', 'Disease', (129, 136))	('causing', 'Reg', (140, 147))	('aberrant splicing', 'MPA', (148, 165))
466149	28148898	Rs4754 located at the fifth exon of SPP1 gene, and it was predicted located at ESE or ESS binding sites.	('Rs4754', 'Var', (0, 6))	('SPP1', 'Gene', '6696', (36, 40))	('SPP1', 'Gene', (36, 40))	('ESS', 'Chemical', '-', (86, 89))
466150	28148898	Our study found that rs4754 could change the risk and survival of NSCLC.	('change', 'Reg', (34, 40))	('NSCLC', 'Phenotype', 'HP:0030358', (66, 71))	('NSCLC', 'Disease', (66, 71))	('NSCLC', 'Disease', 'MESH:D002289', (66, 71))	('SCLC', 'Phenotype', 'HP:0030357', (67, 71))	('rs4754', 'Mutation', 'rs4754', (21, 27))	('rs4754', 'Var', (21, 27))	('survival', 'CPA', (54, 62))
466151	28148898	Previously, there were three studies on the relationship between rs4754 and cancer risk.	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('rs4754', 'Var', (65, 71))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('rs4754', 'Mutation', 'rs4754', (65, 71))
466152	28148898	The results of one study on gastric cancer are consistent with our findings that rs4754-C allele is a risk allele for cancer risk.	('cancer', 'Disease', (118, 124))	('gastric cancer', 'Phenotype', 'HP:0012126', (28, 42))	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('cancer', 'Disease', (36, 42))	('rs4754', 'Mutation', 'rs4754', (81, 87))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('gastric cancer', 'Disease', (28, 42))	('rs4754-C', 'Var', (81, 89))	('gastric cancer', 'Disease', 'MESH:D013274', (28, 42))	('cancer', 'Disease', 'MESH:D009369', (118, 124))
466154	28148898	IL-6 was initially thought to play a major role in immune and inflammatory responses, however IL6 abnormalities were found in many types of cancer, and some evidence showed that in cancer IL6 may play its downstream effects through JAK/STAT pathway.	('IL6', 'Gene', '3569', (188, 191))	('IL6', 'Gene', (188, 191))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('cancer', 'Disease', (140, 146))	('JAK/STAT pathway', 'Pathway', (232, 248))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('IL6', 'Gene', '3569', (94, 97))	('IL-6', 'Gene', (0, 4))	('IL6', 'Gene', (94, 97))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('abnormalities', 'Var', (98, 111))	('cancer', 'Disease', (181, 187))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('IL-6', 'Gene', '3569', (0, 4))
466155	28148898	Rs2069837 were predicted located at TFBS of IL6 gene.	('IL6', 'Gene', (44, 47))	('Rs2069837', 'Var', (0, 9))	('IL6', 'Gene', '3569', (44, 47))	('Rs2069837', 'Mutation', 'Rs2069837', (0, 9))
466156	28148898	There are three articles about the association between rs2069837 and cancer risk, and their results consistently showed that the rs2069837-AA genotype was a protective factor for cervical cancer and hepatocellular carcinoma, one study found that rs2069837 were related to the IL6 expression level in cervical tissues..	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('hepatocellular carcinoma', 'Disease', (199, 223))	('rs2069837', 'Var', (55, 64))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (199, 223))	('rs2069837', 'Mutation', 'rs2069837', (55, 64))	('rs2069837', 'Mutation', 'rs2069837', (129, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (214, 223))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('rs2069837', 'Mutation', 'rs2069837', (246, 255))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('IL6', 'Gene', '3569', (276, 279))	('cancer', 'Disease', (188, 194))	('rs2069837-AA', 'Var', (129, 141))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('IL6', 'Gene', (276, 279))	('cancer', 'Disease', (69, 75))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (199, 223))
466157	28148898	Rs3181385 is a SNP located at miRNA binding site of ADCY4 gene, in the present study there is a bordering significant association with the risk of NSCLC.	('NSCLC', 'Disease', (147, 152))	('ADCY4', 'Gene', (52, 57))	('NSCLC', 'Disease', 'MESH:D002289', (147, 152))	('SCLC', 'Phenotype', 'HP:0030357', (148, 152))	('Rs3181385', 'Mutation', 'Rs3181385', (0, 9))	('NSCLC', 'Phenotype', 'HP:0030358', (147, 152))	('Rs3181385', 'Var', (0, 9))	('ADCY4', 'Gene', '196883', (52, 57))
466159	28148898	In our study, CAV1 rs959173 was annotated as eQTL.	('CAV1', 'Gene', '857', (14, 18))	('rs959173', 'Mutation', 'rs959173', (19, 27))	('rs959173', 'Var', (19, 27))	('eQTL', 'Disease', (45, 49))	('CAV1', 'Gene', (14, 18))
466160	28148898	One previously study found that rs959173-C allele was a protective allele and with a higher CAV1 protein level in systemic sclerosis patients.	('rs959173', 'Mutation', 'rs959173', (32, 40))	('systemic sclerosis', 'Disease', (114, 132))	('CAV1', 'Gene', (92, 96))	('higher', 'PosReg', (85, 91))	('patients', 'Species', '9606', (133, 141))	('rs959173-C', 'Var', (32, 42))	('systemic sclerosis', 'Disease', 'MESH:D012595', (114, 132))	('CAV1', 'Gene', '857', (92, 96))
466161	28148898	In our study, rs959173-C allele was a protective allele for NSCLC risk and the expression of CAV1 was down regulated in lung cancer tissue, which suggested us that rs959173 is likely to participate in the onset and development of NSCLC by affecting the expression of CAV1.	('participate', 'Reg', (186, 197))	('lung cancer', 'Disease', (120, 131))	('CAV1', 'Gene', '857', (93, 97))	('NSCLC', 'Phenotype', 'HP:0030358', (230, 235))	('CAV1', 'Gene', '857', (267, 271))	('SCLC', 'Phenotype', 'HP:0030357', (61, 65))	('rs959173-C', 'Var', (14, 24))	('expression', 'MPA', (79, 89))	('lung cancer', 'Disease', 'MESH:D008175', (120, 131))	('CAV1', 'Gene', (93, 97))	('rs959173', 'Var', (164, 172))	('NSCLC', 'Disease', 'MESH:D002289', (60, 65))	('CAV1', 'Gene', (267, 271))	('lung cancer', 'Phenotype', 'HP:0100526', (120, 131))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('SCLC', 'Phenotype', 'HP:0030357', (231, 235))	('rs959173', 'Mutation', 'rs959173', (14, 22))	('NSCLC', 'Disease', (60, 65))	('affecting', 'Reg', (239, 248))	('expression', 'MPA', (253, 263))	('NSCLC', 'Disease', 'MESH:D002289', (230, 235))	('NSCLC', 'Phenotype', 'HP:0030358', (60, 65))	('rs959173', 'Mutation', 'rs959173', (164, 172))	('NSCLC', 'Disease', (230, 235))	('down regulated', 'NegReg', (102, 116))
466197	27399176	In addition to single-nucleotide variants, copy-number alterations, and alterations of multiple signaling pathways in human ESCC, these studies further demonstrated (1) genomic alterations in a precancerous lesion, atypical hyperplasia; (2) mutual exclusivity of NOTCH1 and PIK3CA mutations; (3) structural variations, including deletions and translocations through non-homologous end joining or alternative end-joining mechanisms and local chromosomal misarrangements through the mechanisms of chromothripsis, kataegis, and breakage-fusion bridge.	('deletions', 'Var', (329, 338))	('PIK3CA', 'Gene', (274, 280))	('NOTCH1', 'Gene', (263, 269))	('chromothripsis', 'Disease', (495, 509))	('PIK3CA', 'Gene', '5290', (274, 280))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('hyperplasia', 'Disease', 'MESH:D006965', (224, 235))	('precancerous lesion', 'Disease', (194, 213))	('translocations', 'Var', (343, 357))	('precancerous lesion', 'Disease', 'MESH:D011230', (194, 213))	('mutations', 'Var', (281, 290))	('human', 'Species', '9606', (118, 123))	('hyperplasia', 'Disease', (224, 235))	('alternative end-joining', 'CPA', (396, 419))	('NOTCH1', 'Gene', '4851', (263, 269))
466203	27399176	Among the single-nucleotide variants, copy-number alterations, and alterations of multiple signaling pathways, SOX2 amplification is clearly a cancer driver leading to ESCC.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('SOX2', 'Gene', (111, 115))	('amplification', 'Var', (116, 129))	('alterations', 'Reg', (67, 78))	('single-nucleotide variants', 'Var', (10, 36))	('cancer', 'Disease', (143, 149))	('leading to', 'Reg', (157, 167))	('cancer', 'Disease', 'MESH:D009369', (143, 149))
466220	27399176	Silencing of DeltaNp63alpha in ESCC cells inhibited cell proliferation and colony formation via downregulation of Akt signaling.	('Akt', 'Gene', (114, 117))	('p63', 'Gene', '8626', (19, 22))	('cell proliferation', 'CPA', (52, 70))	('colony formation', 'CPA', (75, 91))	('inhibited', 'NegReg', (42, 51))	('downregulation', 'NegReg', (96, 110))	('Akt', 'Gene', '207', (114, 117))	('p63', 'Gene', (19, 22))	('Silencing', 'Var', (0, 9))
466225	27399176	CBX3 regulates RNA processing genome-wide, and loss of CBX3 leads to dramatic accumulation of unspliced nascent transcripts and alterations in target gene expression.	('CBX3', 'Gene', (55, 59))	('unspliced nascent transcripts', 'MPA', (94, 123))	('alterations', 'Reg', (128, 139))	('CBX3', 'Gene', '11335', (0, 4))	('CBX3', 'Gene', '11335', (55, 59))	('expression', 'MPA', (155, 165))	('loss', 'Var', (47, 51))	('RNA processing', 'MPA', (15, 29))	('CBX3', 'Gene', (0, 4))	('accumulation', 'PosReg', (78, 90))
466228	27399176	Loss of KLF5 in the context of TP53 deletion drives invasive progression of ESCC, and restoration of KLF5 leads to apoptosis and suppresses cell survival.	('restoration', 'Var', (86, 97))	('cell survival', 'CPA', (140, 153))	('deletion', 'Var', (36, 44))	('TP53', 'Gene', '7157', (31, 35))	('invasive progression', 'CPA', (52, 72))	('KLF5', 'Gene', (101, 105))	('suppresses', 'NegReg', (129, 139))	('TP53', 'Gene', (31, 35))	('Loss', 'NegReg', (0, 4))	('KLF5', 'Gene', '688', (101, 105))	('KLF5', 'Gene', (8, 12))	('KLF5', 'Gene', '688', (8, 12))	('apoptosis', 'CPA', (115, 124))	('ESCC', 'Disease', (76, 80))
466229	27399176	PARP1 interacts with and poly(ADP-ribosyl)ates SOX2 directly for degradation of SOX2 protein.	('poly(ADP-ribosyl)ates', 'Chemical', '-', (25, 46))	('degradation of SOX2 protein', 'MPA', (65, 92))	('interacts', 'Interaction', (6, 15))	('poly(ADP-ribosyl', 'Var', (25, 41))	('PARP1', 'Gene', (0, 5))	('PARP1', 'Gene', '142', (0, 5))
466230	27399176	As a result, PARP1 knockout enhances SOX2 expression and modifies cell differentiation.	('PARP1', 'Gene', (13, 18))	('knockout', 'Var', (19, 27))	('modifies', 'Reg', (57, 65))	('expression', 'MPA', (42, 52))	('SOX2', 'Protein', (37, 41))	('cell differentiation', 'CPA', (66, 86))	('enhances', 'PosReg', (28, 36))	('PARP1', 'Gene', '142', (13, 18))
466237	27399176	Four approaches are potentially applicable for ESCC: (1) using small interfering RNA (siRNA) to target SOX2 and/or DeltaNp63alpha, although this approach is not feasible at this time; (2) enhancing the immune reaction against cancer cells with overexpressed SOX2 and DeltaNp63alpha participate; and (4) targeting epigenetic modifications in which SOX2 and DeltaNp63alpha are involved.	('enhancing', 'PosReg', (188, 197))	('p63', 'Gene', '8626', (273, 276))	('p63', 'Gene', (121, 124))	('immune', 'MPA', (202, 208))	('epigenetic modifications', 'Var', (313, 337))	('cancer', 'Disease', (226, 232))	('p63', 'Gene', (362, 365))	('cancer', 'Disease', 'MESH:D009369', (226, 232))	('p63', 'Gene', '8626', (121, 124))	('p63', 'Gene', (273, 276))	('p63', 'Gene', '8626', (362, 365))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
466238	27399176	For example, specific inhibitors of KDM1A/LSD1, a SOX2-associated protein, selectively impair the growth of SOX2+ lung squamous cell carcinoma, but not that of SOX2- cells.	('LSD1', 'Gene', (42, 46))	('inhibitors', 'Var', (22, 32))	('KDM1A', 'Gene', '23028', (36, 41))	('LSD1', 'Gene', '23028', (42, 46))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (114, 142))	('growth', 'MPA', (98, 104))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('KDM1A', 'Gene', (36, 41))	('impair', 'NegReg', (87, 93))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (114, 142))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (119, 142))	('lung squamous cell carcinoma', 'Disease', (114, 142))
466239	27399176	Inactivation of KDM1A reduces SOX2 expression, promotes G1 cell cycle arrest, and induces genes for differentiation by selectively modulating the methylation states of H3K4 and H3K9.	('induces', 'Reg', (82, 89))	('H3K9', 'Protein', (177, 181))	('KDM1A', 'Gene', '23028', (16, 21))	('promotes', 'PosReg', (47, 55))	('expression', 'MPA', (35, 45))	('KDM1A', 'Gene', (16, 21))	('genes for differentiation', 'MPA', (90, 115))	('modulating', 'Reg', (131, 141))	('G1 cell cycle arrest', 'CPA', (56, 76))	('reduces', 'NegReg', (22, 29))	('SOX2', 'Protein', (30, 34))	('H3K4', 'Protein', (168, 172))	('methylation states', 'MPA', (146, 164))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (59, 76))	('Inactivation', 'Var', (0, 12))
466241	27399176	Second, there is a possibility of inducing phenotype switching of cancer cells (i.e., transdifferentiation of ESCC cells into adenosquamous cells or even adenocarcinoma cells), as loss of SOX2 and p63 is an early event in intestinal metaplasia of the esophageal squamous epithelium.	('p63', 'Gene', '8626', (197, 200))	('inducing', 'Reg', (34, 42))	('intestinal metaplasia of the esophageal squamous', 'Disease', 'MESH:D000077277', (222, 270))	('carcinoma', 'Phenotype', 'HP:0030731', (159, 168))	('adenocarcinoma', 'Disease', (154, 168))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('loss', 'Var', (180, 184))	('adenocarcinoma', 'Disease', 'MESH:D000230', (154, 168))	('SOX2', 'Gene', (188, 192))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('p63', 'Gene', (197, 200))	('cancer', 'Disease', (66, 72))	('intestinal metaplasia of the esophageal squamous', 'Disease', (222, 270))
466257	26918517	T-5224 significantly inhibited the invasion, migration, and MMP activity of HNSCC cells in a dose-dependent manner; there was no significant influence on cell proliferation.	('migration', 'CPA', (45, 54))	('HNSCC', 'Phenotype', 'HP:0012288', (76, 81))	('T-5224', 'Var', (0, 6))	('invasion', 'CPA', (35, 43))	('MMP activity of HNSCC cells', 'CPA', (60, 87))	('inhibited', 'NegReg', (21, 30))	('T-5224', 'Chemical', 'MESH:C568912', (0, 6))
466258	26918517	The antimetastatic effect of T-5224 was also confirmed in our animal study.	('T-5224', 'Chemical', 'MESH:C568912', (29, 35))	('T-5224', 'Var', (29, 35))	('antimetastatic effect', 'CPA', (4, 25))
466259	26918517	The rate of cervical lymph node metastasis in the model was 40.0% in the T-5224-treated group (n = 30) versus 74.1% in the vehicle-treated group (n = 27; P < 0.05).	('T-5224', 'Chemical', 'MESH:C568912', (73, 79))	('cervical lymph node metastasis', 'CPA', (12, 42))	('T-5224-treated', 'Var', (73, 87))	('cervical lymph node metastasis', 'Phenotype', 'HP:0025289', (12, 42))
466260	26918517	In conclusion, T-5224 inhibited the invasion and migration of HNSCC cells in vitro, and prevented lymph node metastasis in head and neck cancer in an animal model.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('neck cancer', 'Disease', 'MESH:D006258', (132, 143))	('HNSCC', 'Phenotype', 'HP:0012288', (62, 67))	('inhibited', 'NegReg', (22, 31))	('T-5224', 'Chemical', 'MESH:C568912', (15, 21))	('neck cancer', 'Disease', (132, 143))	('lymph node metastasis', 'CPA', (98, 119))	('T-5224', 'Var', (15, 21))	('prevented', 'NegReg', (88, 97))	('head and neck cancer', 'Phenotype', 'HP:0012288', (123, 143))
466262	26918517	In this study, we hypothesized that the selective activator protein-1 (AP-1) inhibitor T-5224 might exert an antimetastatic effect on HNSCC by inhibiting the multigenic programs associated with metastasis.	('T-5224', 'Chemical', 'MESH:C568912', (87, 93))	('activator protein-1', 'Gene', (50, 69))	('inhibiting', 'NegReg', (143, 153))	('activator protein-1', 'Gene', '2353', (50, 69))	('T-5224', 'Var', (87, 93))	('antimetastatic effect', 'CPA', (109, 130))	('HNSCC', 'Disease', (134, 139))	('HNSCC', 'Phenotype', 'HP:0012288', (134, 139))	('multigenic programs', 'CPA', (158, 177))
466310	26918517	To investigate whether treatment with T-5224 inhibits the invasion activity of highly metastatic tumor cell line HSC-3-M3, we used an invasion assay system.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('inhibits', 'NegReg', (45, 53))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('T-5224', 'Var', (38, 44))	('HSC-3', 'Gene', (113, 118))	('tumor', 'Disease', (97, 102))	('invasion activity', 'CPA', (58, 75))	('T-5224', 'Chemical', 'MESH:C568912', (38, 44))	('HSC-3', 'Gene', '150353', (113, 118))
466312	26918517	T-5224 significantly inhibited the invasion activity of HSC-3-M3 cells in a dose-dependent manner (Fig.	('HSC-3', 'Gene', '150353', (56, 61))	('T-5224', 'Var', (0, 6))	('inhibited', 'NegReg', (21, 30))	('HSC-3', 'Gene', (56, 61))	('T-5224', 'Chemical', 'MESH:C568912', (0, 6))
466319	26918517	Cell migration was potently inhibited by T-5224 in both cell lines in a dose-dependent manner.	('T-5224', 'Var', (41, 47))	('inhibited', 'NegReg', (28, 37))	('T-5224', 'Chemical', 'MESH:C568912', (41, 47))	('Cell migration', 'CPA', (0, 14))
466324	26918517	Fluorescence microscopic images of HSC-3-M3 and OSC-19 cells incubated with T-5224 maintained epithelial-like morphology and showed inhibited lamellipodia formation (Fig.	('inhibited', 'NegReg', (132, 141))	('epithelial-like morphology', 'CPA', (94, 120))	('lamellipodia formation', 'CPA', (142, 164))	('HSC-3', 'Gene', '150353', (35, 40))	('T-5224', 'Var', (76, 82))	('OSC-19', 'CellLine', 'CVCL:3086', (48, 54))	('T-5224', 'Chemical', 'MESH:C568912', (76, 82))	('HSC-3', 'Gene', (35, 40))
466328	26918517	However, the rate of positive metastasis was significantly lower in the T-5224-treated group than in the control group (74.1% in control group versus 40% in treatment group (P < 0.05); Fig.	('positive metastasis', 'CPA', (21, 40))	('T-5224-treated', 'Var', (72, 86))	('T-5224', 'Chemical', 'MESH:C568912', (72, 78))	('lower', 'NegReg', (59, 64))
466329	26918517	T-5224 showed significant inhibitory effects against lymph node metastasis in the animal model of HNSCC.	('T-5224', 'Var', (0, 6))	('lymph node metastasis', 'CPA', (53, 74))	('HNSCC', 'Disease', (98, 103))	('HNSCC', 'Phenotype', 'HP:0012288', (98, 103))	('T-5224', 'Chemical', 'MESH:C568912', (0, 6))	('inhibitory', 'NegReg', (26, 36))
466330	26918517	We investigated whether the expression of MMP mRNA was inhibited by T-5224 in vitro.	('T-5224', 'Var', (68, 74))	('expression', 'MPA', (28, 38))	('MMP', 'Gene', (42, 45))	('T-5224', 'Chemical', 'MESH:C568912', (68, 74))	('inhibited', 'NegReg', (55, 64))
466332	26918517	The relative expression levels of MMP-2 and -9 mRNA were significantly reduced by incubation with 0-80 muM T-5224 in comparison with the control (Fig.	('expression levels', 'MPA', (13, 30))	('MMP-2 and -9', 'Gene', '4313;4318', (34, 46))	('muM', 'Gene', '56925', (103, 106))	('T-5224', 'Var', (107, 113))	('reduced', 'NegReg', (71, 78))	('muM', 'Gene', (103, 106))	('T-5224', 'Chemical', 'MESH:C568912', (107, 113))
466335	26918517	To access the mechanism by which T-5224 inhibits invasion activity, we carried out in vitro gelatin zymography to assess the activities of MMP-2 and -9.	('T-5224', 'Chemical', 'MESH:C568912', (33, 39))	('T-5224', 'Var', (33, 39))	('invasion activity', 'CPA', (49, 66))	('inhibits', 'NegReg', (40, 48))	('MMP-2 and -9', 'Gene', '4313;4318', (139, 151))
466336	26918517	HSC-3-M3 cells were incubated in medium containing T-5224, and the supernatant of each dish was collected and electrophoresed.	('HSC-3', 'Gene', (0, 5))	('T-5224', 'Chemical', 'MESH:C568912', (51, 57))	('HSC-3', 'Gene', '150353', (0, 5))	('T-5224', 'Var', (51, 57))
466338	26918517	The activities of both MMPs were attenuated by T-5224 in a concentration-dependent manner (Fig.	('activities', 'MPA', (4, 14))	('MMPs', 'Gene', '4313;4318', (23, 27))	('MMPs', 'Gene', (23, 27))	('T-5224', 'Chemical', 'MESH:C568912', (47, 53))	('attenuated', 'NegReg', (33, 43))	('T-5224', 'Var', (47, 53))
466344	26918517	These findings indicate that T-5224 inhibited the gelatinolytic activity of MMP-2 and -9 in the stromal tissue at the invasive front of tumor cells, which is critical for the initiation of tumor invasion and metastasis.	('T-5224', 'Chemical', 'MESH:C568912', (29, 35))	('tumor', 'Disease', (189, 194))	('inhibited', 'NegReg', (36, 45))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('gelatinolytic activity', 'MPA', (50, 72))	('MMP-2 and -9', 'Gene', '4313;4318', (76, 88))	('T-5224', 'Var', (29, 35))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('tumor', 'Disease', (136, 141))
466345	26918517	In this study, we demonstrated that T-5224, a selective AP-1 inhibitor, inhibited tumor cell migration and invasion in a dose-dependent manner, and that oral administration of T-5224 resulted in successful prevention of cervical lymph node metastasis in an orthotropic tumor implantation animal model.	('tumor', 'Disease', 'MESH:D009369', (269, 274))	('T-5224', 'Chemical', 'MESH:C568912', (36, 42))	('tumor', 'Phenotype', 'HP:0002664', (269, 274))	('inhibited', 'NegReg', (72, 81))	('T-5224', 'Var', (176, 182))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Disease', (269, 274))	('cervical lymph node metastasis', 'Phenotype', 'HP:0025289', (220, 250))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('T-5224', 'Var', (36, 42))	('T-5224', 'Chemical', 'MESH:C568912', (176, 182))	('tumor', 'Disease', (82, 87))	('cervical lymph node metastasis', 'CPA', (220, 250))	('prevention', 'NegReg', (206, 216))
466346	26918517	Our results suggest that inhibition of the expression of MMP-2 and MMP-9, and decreased cell motility may be one of the mechanisms by which T-5224 prevents tumor metastasis.	('T-5224', 'Var', (140, 146))	('MMP-2', 'Gene', (57, 62))	('MMP-9', 'Gene', (67, 72))	('tumor metastasis', 'Disease', 'MESH:D009362', (156, 172))	('MMP-2', 'Gene', '4313', (57, 62))	('T-5224', 'Chemical', 'MESH:C568912', (140, 146))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('prevents', 'NegReg', (147, 155))	('MMP-9', 'Gene', '4318', (67, 72))	('decreased', 'NegReg', (78, 87))	('expression', 'MPA', (43, 53))	('tumor metastasis', 'Disease', (156, 172))	('cell motility', 'CPA', (88, 101))
466352	26918517	Both MMP-2 and -9 play important roles in the initiation of tumor invasion and migration by degrading type IV collagen.15, 16 This is important in the context of metastasis and the prognosis of HNSCC patients.17, 18, 19 The MMP genes have an AP-1 binding sequence in their promoter regions and are transcriptionally regulated by AP-1.20 In this study, T-5224 successfully inhibited the invasion and gelatinolytic activities of MMPs in a dose-dependent manner (Figs 1 and 6).	('patients', 'Species', '9606', (200, 208))	('MMPs', 'Gene', (427, 431))	('MMPs', 'Gene', '4313;4318', (427, 431))	('T-5224', 'Chemical', 'MESH:C568912', (352, 358))	('HNSCC', 'Phenotype', 'HP:0012288', (194, 199))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('MMP', 'Gene', (224, 227))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('T-5224', 'Var', (352, 358))	('inhibited', 'NegReg', (372, 381))	('tumor', 'Disease', (60, 65))	('MMP-2 and -9', 'Gene', '4313;4318', (5, 17))
466353	26918517	Moreover, T-5224 strongly inhibited invasion activity even at low concentrations in the invasion assay.	('T-5224', 'Var', (10, 16))	('T-5224', 'Chemical', 'MESH:C568912', (10, 16))	('inhibited', 'NegReg', (26, 35))	('invasion activity', 'CPA', (36, 53))
466354	26918517	These results indicate that T-5224 potently inhibits the essential steps of metastasis, infiltration through the basement membrane barrier and migration into the ECM, by transcriptionally suppressing the expression of MMP-2 and -9.	('MMP-2 and -9', 'Gene', '4313;4318', (218, 230))	('T-5224', 'Var', (28, 34))	('suppressing', 'NegReg', (188, 199))	('migration into the ECM', 'CPA', (143, 165))	('T-5224', 'Chemical', 'MESH:C568912', (28, 34))	('infiltration through the basement membrane barrier', 'CPA', (88, 138))	('inhibits', 'NegReg', (44, 52))	('expression', 'MPA', (204, 214))
466357	26918517	Our results showed that these activities were also significantly inhibited by T-5224.	('activities', 'MPA', (30, 40))	('T-5224', 'Chemical', 'MESH:C568912', (78, 84))	('inhibited', 'NegReg', (65, 74))	('T-5224', 'Var', (78, 84))
466358	26918517	Together with the results of the real-time semiquantitative PCR, these findings suggest that transcriptional inhibition of the expression of MMPs by T-5224 is not limited to tumor cells only; it also occurs in the ECM of the surrounding tissue, and consequently, inhibits tumor cells from infiltrating the surrounding tissue.	('tumor', 'Disease', (174, 179))	('MMPs', 'Gene', '4313;4318', (141, 145))	('tumor', 'Phenotype', 'HP:0002664', (272, 277))	('T-5224', 'Chemical', 'MESH:C568912', (149, 155))	('transcriptional', 'MPA', (93, 108))	('tumor', 'Disease', (272, 277))	('T-5224', 'Var', (149, 155))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('inhibition', 'NegReg', (109, 119))	('tumor', 'Disease', 'MESH:D009369', (272, 277))	('inhibits', 'NegReg', (263, 271))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('MMPs', 'Gene', (141, 145))
466359	26918517	T-5224 also significantly inhibited cell motility.	('T-5224', 'Chemical', 'MESH:C568912', (0, 6))	('T-5224', 'Var', (0, 6))	('cell motility', 'CPA', (36, 49))	('inhibited', 'NegReg', (26, 35))
466360	26918517	Close observation of migrating tumor cells revealed that T-5224 inhibited lamellipodia formation and ruffling.	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('T-5224', 'Chemical', 'MESH:C568912', (57, 63))	('inhibited', 'NegReg', (64, 73))	('tumor', 'Disease', (31, 36))	('lamellipodia formation', 'CPA', (74, 96))	('ruffling', 'CPA', (101, 109))	('T-5224', 'Var', (57, 63))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
466361	26918517	Other studies have indicated that AP-1 is important for cell motility and that it is a key factor in cytoskeletal rearrangement, which is necessary for lamellipodia formation and cell motility.14, 21, 22, 23 Malliri et al.14 reported that EGF-induced cell motility and lamellipodia formation were inhibited by the induction of dominant negative c-Jun in squamous cell carcinoma cells.	('dominant negative', 'Var', (327, 344))	('inhibited', 'NegReg', (297, 306))	('c-Jun', 'Gene', (345, 350))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (354, 377))	('squamous cell carcinoma', 'Disease', (354, 377))	('lamellipodia formation', 'CPA', (269, 291))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (354, 377))	('c-Jun', 'Gene', '3725', (345, 350))	('EGF-induced cell motility', 'CPA', (239, 264))	('carcinoma', 'Phenotype', 'HP:0030731', (368, 377))
466362	26918517	Our study showed a similar effect against cell motility, caused by the administration of T-5224.	('T-5224', 'Chemical', 'MESH:C568912', (89, 95))	('cell motility', 'CPA', (42, 55))	('T-5224', 'Var', (89, 95))
466369	26918517	Although T-5224 exerted its antimetastatic effect by inhibiting migration and invasion of tumor cells, by itself, it was not cytotoxic.	('T-5224', 'Chemical', 'MESH:C568912', (9, 15))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('antimetastatic effect', 'MPA', (28, 49))	('tumor', 'Disease', (90, 95))	('T-5224', 'Var', (9, 15))	('inhibiting', 'NegReg', (53, 63))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
466371	26918517	However, application of T-5224 to HNSCC cells had no or limited effect on tumor growth in vitro or in vivo in our study.	('T-5224', 'Var', (24, 30))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('T-5224', 'Chemical', 'MESH:C568912', (24, 30))	('tumor', 'Disease', (74, 79))	('HNSCC', 'Phenotype', 'HP:0012288', (34, 39))
466373	26918517	However, p53 mutation is most commonly found in malignant tumors, including HNSCC,35 and certain forms of mutant p53 protein are resistant to p53-mediated growth inhibition.	('p53', 'Gene', (113, 116))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('mutant', 'Var', (106, 112))	('p53', 'Gene', (142, 145))	('p53', 'Gene', '7157', (142, 145))	('found', 'Reg', (39, 44))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('HNSCC', 'Phenotype', 'HP:0012288', (76, 81))	('protein', 'Protein', (117, 124))	('p53', 'Gene', (9, 12))	('p53', 'Gene', '7157', (9, 12))	('p53', 'Gene', '7157', (113, 116))	('malignant tumors', 'Disease', (48, 64))	('malignant tumors', 'Disease', 'MESH:D018198', (48, 64))
466374	26918517	As for cell lines used in this study, HSC-3, a parental cell line of HSC-3-M3, has a p53 mutation lacking the ability to phosphorylate Ser46 of p53,36 resulting in resistance to p53-mediated growth inhibition, and OSC-19 has a disruptive mutation that leads to loss of p53 expression.37 This might explain the lack of tumor growth inhibition in the HNSCC cell lines by T-5224.	('HSC-3', 'Gene', '150353', (38, 43))	('T-5224', 'Chemical', 'MESH:C568912', (369, 375))	('p53', 'Gene', '7157', (269, 272))	('p53', 'Gene', '7157', (144, 147))	('HSC-3', 'Gene', '150353', (69, 74))	('p53', 'Gene', '7157', (85, 88))	('tumor', 'Disease', (318, 323))	('Ser46', 'Chemical', '-', (135, 140))	('p53', 'Gene', (144, 147))	('p53', 'Gene', (269, 272))	('lacking', 'NegReg', (98, 105))	('tumor', 'Disease', 'MESH:D009369', (318, 323))	('mutation', 'Var', (89, 97))	('HSC-3', 'Gene', (38, 43))	('HSC-3', 'Gene', (69, 74))	('p53', 'Gene', (85, 88))	('OSC-19', 'CellLine', 'CVCL:3086', (214, 220))	('p53', 'Gene', '7157', (178, 181))	('HNSCC', 'Phenotype', 'HP:0012288', (349, 354))	('tumor', 'Phenotype', 'HP:0002664', (318, 323))	('p53', 'Gene', (178, 181))
466376	26918517	We consider that the effective dose in vivo depends on the nature of the disease, and it is possible that higher doses might be required for cells in which activity of AP-1 is intensively and constitutively activated by genetic mutations or substantial inflammation.	('inflammation', 'Disease', 'MESH:D007249', (253, 265))	('activity', 'MPA', (156, 164))	('AP-1', 'Gene', (168, 172))	('genetic mutations', 'Var', (220, 237))	('inflammation', 'Disease', (253, 265))
466394	30643431	Bleomycin results in pulmonary damage, anthracyclines cause cardiotoxicity, and platinum-based agents cause nephrotoxic lesions, vomiting, and diarrhea.	('cardiotoxicity', 'Disease', 'MESH:D066126', (60, 74))	('anthracyclines', 'Chemical', 'MESH:D018943', (39, 53))	('diarrhea', 'Disease', 'MESH:D003967', (143, 151))	('nephrotoxic lesions', 'Disease', (108, 127))	('cause', 'Reg', (102, 107))	('pulmonary damage', 'Disease', 'MESH:D008171', (21, 37))	('results in', 'Reg', (10, 20))	('pulmonary damage', 'Disease', (21, 37))	('Bleomycin', 'Chemical', 'MESH:D001761', (0, 9))	('nephrotoxic lesions', 'Disease', 'MESH:D007674', (108, 127))	('diarrhea', 'Phenotype', 'HP:0002014', (143, 151))	('vomiting', 'Disease', 'MESH:D014839', (129, 137))	('platinum', 'Chemical', 'MESH:D010984', (80, 88))	('vomiting', 'Phenotype', 'HP:0002013', (129, 137))	('cardiotoxicity', 'Disease', (60, 74))	('vomiting', 'Disease', (129, 137))	('Bleomycin', 'Var', (0, 9))	('diarrhea', 'Disease', (143, 151))	('anthracyclines', 'Var', (39, 53))
466402	30643431	In addition, cinobufotalin exerts local analgesic effect by activating the POMC/beta-END/mu-OR pathway in cancer tissues.	('cinobufotalin', 'Var', (13, 26))	('local analgesic effect', 'MPA', (34, 56))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('POMC', 'Gene', (75, 79))	('cancer', 'Disease', (106, 112))	('cinobufotalin', 'Chemical', 'MESH:C063451', (13, 26))	('POMC', 'Gene', '5443', (75, 79))	('activating', 'Reg', (60, 70))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
466441	30643431	We observed that cell growth was drastically inhibited when treated with cinobufotalin or TPF, compared to that of the control.	('cinobufotalin', 'Chemical', 'MESH:C063451', (73, 86))	('TPF', 'Gene', (90, 93))	('cinobufotalin', 'Var', (73, 86))	('cell growth', 'CPA', (17, 28))	('TPF', 'Chemical', '-', (90, 93))	('inhibited', 'NegReg', (45, 54))
466442	30643431	The maximum cell growth inhibition was observed when treated with the combination of cinobufotalin and TPF, with only a small number of monoclonal cell clusters remaining (Figure 3).	('cinobufotalin', 'Var', (85, 98))	('TPF', 'Gene', (103, 106))	('cell growth', 'CPA', (12, 23))	('TPF', 'Chemical', '-', (103, 106))	('cinobufotalin', 'Chemical', 'MESH:C063451', (85, 98))	('combination', 'Interaction', (70, 81))
466456	30643431	Marcuello showed that single-nucleotide polymorphism in the 5' tandem repeat sequences of thymidylate synthase gene results in different responses to fluorouracil-based chemotherapy in advanced colorectal cancer.	('responses to fluorouracil-based chemotherapy', 'MPA', (137, 181))	('thymidylate synthase', 'Gene', '7298', (90, 110))	('single-nucleotide polymorphism in', 'Var', (22, 55))	('colorectal cancer', 'Disease', 'MESH:D015179', (194, 211))	('fluorouracil', 'Chemical', 'MESH:D005472', (150, 162))	('colorectal cancer', 'Phenotype', 'HP:0003003', (194, 211))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('thymidylate synthase', 'Gene', (90, 110))	('colorectal cancer', 'Disease', (194, 211))
466461	30643431	In addition, the emergence of drug resistance reduces the efficacy of chemotherapy and a significant number of patients are forced to discontinue treatment.	('drug resistance', 'Var', (30, 45))	('efficacy of chemotherapy', 'CPA', (58, 82))	('reduces', 'NegReg', (46, 53))	('drug resistance', 'Phenotype', 'HP:0020174', (30, 45))	('patients', 'Species', '9606', (111, 119))
466462	30643431	For example, drug resistance leads to high recurrence and poor five-year survival rate in patients with ovarian cancer.	('drug resistance', 'Phenotype', 'HP:0020174', (13, 28))	('ovarian cancer', 'Disease', (104, 118))	('drug resistance', 'Var', (13, 28))	('ovarian cancer', 'Phenotype', 'HP:0100615', (104, 118))	('ovarian cancer', 'Disease', 'MESH:D010051', (104, 118))	('poor', 'NegReg', (58, 62))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('patients', 'Species', '9606', (90, 98))
466466	30643431	Cinobufotalin has been reported to inhibit proliferation and induce apoptosis in U2OS cells via the ROS/JNK/p38 signaling pathway.	('Cinobufotalin', 'Var', (0, 13))	('induce', 'PosReg', (61, 67))	('U2OS', 'CellLine', 'CVCL:0042', (81, 85))	('ROS', 'Chemical', '-', (100, 103))	('p38', 'Gene', (108, 111))	('Cinobufotalin', 'Chemical', 'MESH:C063451', (0, 13))	('apoptosis', 'CPA', (68, 77))	('proliferation', 'CPA', (43, 56))	('p38', 'Gene', '1432', (108, 111))	('inhibit', 'NegReg', (35, 42))
466469	30643431	In addition, cinobufotalin increased the apoptotic effects of chemotherapy agents, as well as the intracellular accumulation of DOX and Rho123 in MDR cells.	('increased', 'PosReg', (27, 36))	('apoptotic effects', 'CPA', (41, 58))	('cinobufotalin', 'Var', (13, 26))	('DOX', 'Chemical', 'MESH:D004317', (128, 131))	('intracellular accumulation of DOX', 'MPA', (98, 131))	('cinobufotalin', 'Chemical', 'MESH:C063451', (13, 26))
466480	30643431	In addition, to the best of our knowledge, we report for the first time that cinobufotalin suppressed proliferation and promoted apoptosis of UMSCC5 and FADU cells.	('suppressed', 'NegReg', (91, 101))	('cinobufotalin', 'Var', (77, 90))	('cinobufotalin', 'Chemical', 'MESH:C063451', (77, 90))	('apoptosis', 'CPA', (129, 138))	('promoted', 'PosReg', (120, 128))	('proliferation', 'CPA', (102, 115))
466481	30643431	Subsequent experiments indicated that cinobufotalin can increase TPF regimen-induced inhibition of proliferation as well as promotion of apoptosis of both UMSCC5 and FADU cells, thereby providing novel insights into effective therapy for HSCC and LSCC.	('HSCC', 'Disease', (238, 242))	('apoptosis', 'CPA', (137, 146))	('promotion', 'PosReg', (124, 133))	('LSCC', 'Disease', (247, 251))	('cinobufotalin', 'Var', (38, 51))	('inhibition', 'NegReg', (85, 95))	('TPF', 'Chemical', '-', (65, 68))	('cinobufotalin', 'Chemical', 'MESH:C063451', (38, 51))	('HSCC', 'Phenotype', 'HP:0012182', (238, 242))	('HSCC', 'Chemical', '-', (238, 242))	('proliferation', 'CPA', (99, 112))
466511	30323196	Dysfunction of lncRNAs is clearly associated with the development and progression of a wide range of cancers, such as leukaemia, breast cancer, lung cancer, prostate cancer, and ovarian cancer.	('ovarian cancer', 'Disease', 'MESH:D010051', (178, 192))	('lung cancer', 'Disease', 'MESH:D008175', (144, 155))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('cancers', 'Disease', 'MESH:D009369', (101, 108))	('leukaemia', 'Disease', 'MESH:D007938', (118, 127))	('lung cancer', 'Phenotype', 'HP:0100526', (144, 155))	('ovarian cancer', 'Disease', (178, 192))	('breast cancer', 'Phenotype', 'HP:0003002', (129, 142))	('ovarian cancer', 'Phenotype', 'HP:0100615', (178, 192))	('Dysfunction', 'Var', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('breast cancer', 'Disease', 'MESH:D001943', (129, 142))	('breast cancer', 'Disease', (129, 142))	('prostate cancer', 'Disease', 'MESH:D011471', (157, 172))	('associated', 'Reg', (34, 44))	('cancers', 'Phenotype', 'HP:0002664', (101, 108))	('prostate cancer', 'Phenotype', 'HP:0012125', (157, 172))	('lung cancer', 'Disease', (144, 155))	('lncRNAs', 'Protein', (15, 22))	('cancers', 'Disease', (101, 108))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('leukaemia', 'Disease', (118, 127))	('prostate cancer', 'Disease', (157, 172))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))
466512	30323196	Many reports have already shown that dysregulation of lncRNAs can also affect the regulation of the eukaryotic genome, resulting in cancer progression and uncontrolled growth.	('cancer', 'Disease', (132, 138))	('dysregulation', 'Var', (37, 50))	('uncontrolled growth', 'CPA', (155, 174))	('lncRNAs', 'Protein', (54, 61))	('regulation of the eukaryotic genome', 'MPA', (82, 117))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('affect', 'Reg', (71, 77))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('resulting in', 'Reg', (119, 131))
466518	30323196	This study screened and analysed for lncRNAs that affect the prognosis of HNSCC using a bioinformatic method, and 5 lncRNAs, namely, RP11-180M15.7, RP11-197N18.2, AC021188.4, RP11-474D1.3, and RP11-347C18.5, were identified.	('RP11', 'Gene', '26121', (175, 179))	('RP11', 'Gene', (148, 152))	('AC021188.4', 'Var', (163, 173))	('RP11', 'Gene', (193, 197))	('HNSCC', 'Disease', (74, 79))	('RP11', 'Gene', '26121', (148, 152))	('RP11', 'Gene', '26121', (193, 197))	('affect', 'Reg', (50, 56))	('RP11', 'Gene', (133, 137))	('RP11', 'Gene', '26121', (133, 137))	('RP11', 'Gene', (175, 179))
466521	30323196	There have been very few studies on RP11-180M15.7, RP11-197N18.2, AC021188.4, RP11-474D1.3, and RP11-347C18.5.	('RP11', 'Gene', '26121', (51, 55))	('RP11', 'Gene', '26121', (96, 100))	('RP11', 'Gene', (36, 40))	('RP11', 'Gene', (78, 82))	('RP11', 'Gene', '26121', (36, 40))	('RP11', 'Gene', '26121', (78, 82))	('AC021188.4', 'Var', (66, 76))	('RP11', 'Gene', (51, 55))	('RP11', 'Gene', (96, 100))
466543	30323196	Four head and neck cancer cell lines (6-10B, 5-8F, Tu-686 and Fadu) and one human immortalized normal cell line (DOK) were used in this study, all of which were cultured in complete medium (RPMI-1640) supplemented with 10% foetal bovine serum (Gibco; Thermo Fisher Scientific, Inc., Waltham, MA, USA), streptomycin (100 mg/ml), penicillin (100 U/ml), 25 mM 4-(2-hydroxyethyl)-1-piperazineethanesulphonic acid (HEPES) and 2 mM glutamine.	('head and neck cancer', 'Disease', 'MESH:D006258', (5, 25))	('bovine', 'Species', '9913', (230, 236))	('100 U/ml', 'Var', (340, 348))	('human', 'Species', '9606', (76, 81))	('head and neck cancer', 'Phenotype', 'HP:0012288', (5, 25))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('100', 'Var', (316, 319))
466577	30064463	Patients with high circ-CER expression have significantly worse overall survival (OS) than those with low circ-CER expression.	('worse', 'NegReg', (58, 63))	('high circ-CER expression', 'Var', (14, 38))	('overall survival', 'MPA', (64, 80))	('Patients', 'Species', '9606', (0, 8))	('OS', 'Chemical', '-', (82, 84))
466585	30064463	In addition, the overexpression of hsa_circ_0000064 in lung cancer is positively correlated with T and N stage.	('lung cancer', 'Disease', 'MESH:D008175', (55, 66))	('lung cancer', 'Disease', (55, 66))	('hsa_circ_0000064', 'Var', (35, 51))	('lung cancer', 'Phenotype', 'HP:0100526', (55, 66))	('overexpression', 'PosReg', (17, 31))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('T and', 'Disease', (97, 102))
466589	30064463	A recent study has identified two circRNAs (hsa_circ_0122662 and hsa_circ_0001358) in five patients with DCIS/IDC and the MCF-7 invasive breast cancer cell line.	('breast cancer', 'Phenotype', 'HP:0003002', (137, 150))	('patients', 'Species', '9606', (91, 99))	('MCF-7 invasive breast cancer', 'Disease', 'MESH:D001943', (122, 150))	('hsa_circ_0122662', 'Var', (44, 60))	('MCF-7 invasive breast cancer', 'Disease', (122, 150))	('hsa_circ_0001358', 'Var', (65, 81))	('IDC', 'Gene', '4000', (110, 113))	('IDC', 'Gene', (110, 113))	('DCIS', 'Phenotype', 'HP:0030075', (105, 109))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
466595	30064463	The combination of hsa_circ_006054, hsa_circ_100219, and hsa_circ_406697 provides valuable insights into the diagnosis of breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('breast cancer', 'Disease', (122, 135))	('breast cancer', 'Phenotype', 'HP:0003002', (122, 135))	('hsa_circ_406697', 'Var', (57, 72))	('breast cancer', 'Disease', 'MESH:D001943', (122, 135))	('hsa_circ_006054', 'Var', (19, 34))
466600	30064463	A total of 25 binding sites of circ-Foxo3 for eight miRNAs (miR-22, miR-136, miR-138, miR-149, miR-433, miR-762, miR-3614-5p, and miR-3622b-5p) are detected, and transfection of these miRNAs into MDA-MB-231 cells can reduce apoptosis.	('miR-762', 'Gene', '100313837', (104, 111))	('miR', 'Gene', (77, 80))	('miR', 'Gene', '220972', (68, 71))	('miR', 'Gene', '220972', (60, 63))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (196, 206))	('binding', 'Interaction', (14, 21))	('miR', 'Gene', '220972', (52, 55))	('miR-22', 'Gene', '407004', (60, 66))	('miR-22', 'Gene', (60, 66))	('miR-762', 'Gene', (104, 111))	('miR', 'Gene', '220972', (113, 116))	('miR', 'Gene', (68, 71))	('miR', 'Gene', (60, 63))	('miR-149', 'Gene', (86, 93))	('miR', 'Gene', '220972', (130, 133))	('Foxo3', 'Gene', (36, 41))	('miR', 'Gene', '220972', (104, 107))	('miR-433', 'Gene', (95, 102))	('miR', 'Gene', (52, 55))	('miR', 'Gene', '220972', (184, 187))	('miR', 'Gene', '220972', (95, 98))	('miR', 'Gene', (113, 116))	('reduce', 'NegReg', (217, 223))	('miR', 'Gene', '220972', (86, 89))	('miR', 'Gene', (130, 133))	('apoptosis', 'CPA', (224, 233))	('miR-149', 'Gene', '406941', (86, 93))	('transfection', 'Var', (162, 174))	('miR', 'Gene', (104, 107))	('miR-136', 'Gene', (68, 75))	('Foxo3', 'Gene', '2309', (36, 41))	('miR', 'Gene', (184, 187))	('miR-136', 'Gene', '406927', (68, 75))	('miR', 'Gene', '220972', (77, 80))	('miR', 'Gene', (95, 98))	('miR', 'Gene', (86, 89))	('miR-433', 'Gene', '574034', (95, 102))
466603	30064463	In addition, circ_000911 is poorly expressed in breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('breast cancer', 'Disease', 'MESH:D001943', (48, 61))	('breast cancer', 'Phenotype', 'HP:0003002', (48, 61))	('breast cancer', 'Disease', (48, 61))	('circ_000911', 'Var', (13, 24))
466604	30064463	In vitro experiments have confirmed that upregulation of circ_000911 increases Notch1 expression via binding to miR-449a, thereby suppressing the proliferation, invasion, and metastasis of breast cancer cells.	('suppressing', 'NegReg', (130, 141))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('increases', 'PosReg', (69, 78))	('proliferation', 'CPA', (146, 159))	('Notch1', 'Gene', (79, 85))	('miR-449a', 'Gene', '554213', (112, 120))	('circ_000911', 'Var', (57, 68))	('invasion', 'CPA', (161, 169))	('metastasis of breast cancer', 'Disease', 'MESH:D009362', (175, 202))	('expression', 'MPA', (86, 96))	('breast cancer', 'Phenotype', 'HP:0003002', (189, 202))	('Notch1', 'Gene', '4851', (79, 85))	('binding', 'Interaction', (101, 108))	('metastasis of breast cancer', 'Disease', (175, 202))	('upregulation', 'PosReg', (41, 53))	('miR-449a', 'Gene', (112, 120))
466605	30064463	In contrast, hsa_circ_0001982, hsa_circ_0005239, and hsa_circ_0008717 are upregulated in breast cancer, and knockdown of their expressions inhibits cell proliferation and promotes apoptosis.	('knockdown', 'Var', (108, 117))	('hsa_circ_0008717', 'Var', (53, 69))	('promotes', 'PosReg', (171, 179))	('upregulated', 'PosReg', (74, 85))	('breast cancer', 'Disease', 'MESH:D001943', (89, 102))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('breast cancer', 'Disease', (89, 102))	('breast cancer', 'Phenotype', 'HP:0003002', (89, 102))	('cell proliferation', 'CPA', (148, 166))	('inhibits', 'NegReg', (139, 147))	('apoptosis', 'CPA', (180, 189))
466606	30064463	circ_0006528 is highly expressed in chemotherapy-resistant breast cancer cell lines, and the sensitivity of these cells to chemotherapy is significantly increased after knocking down circ_0006528.	('breast cancer', 'Disease', 'MESH:D001943', (59, 72))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('breast cancer', 'Disease', (59, 72))	('increased', 'PosReg', (153, 162))	('breast cancer', 'Phenotype', 'HP:0003002', (59, 72))	('sensitivity', 'MPA', (93, 104))	('knocking down circ_0006528', 'Var', (169, 195))	('circ_0006528', 'Var', (183, 195))
466609	30064463	Several dysregulated circRNAs are found in ESCC, including hsa_circ_000167, hsa_circ_001059, hsa_circ_0067934, and circ-ITCH.	('-ITCH', 'Phenotype', 'HP:0000989', (119, 124))	('ESCC', 'Disease', (43, 47))	('ITCH', 'Gene', (120, 124))	('hsa_circ_000167', 'Var', (59, 74))	('hsa_circ_001059', 'Var', (76, 91))	('ITCH', 'Gene', '83737', (120, 124))	('hsa_circ_0067934', 'Var', (93, 109))
466612	30064463	identified more than 3700 human circRNAs, among which hsa_circ_000167 and hsa_circ_001059 in the KYSE-150R human radiation-resistant esophageal cancer cell line are significantly different from the KYSE-150 parental cell line.	('hsa_circ_001059', 'Var', (74, 89))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('human', 'Species', '9606', (107, 112))	('esophageal cancer', 'Disease', (133, 150))	('esophageal cancer', 'Disease', 'MESH:D004938', (133, 150))	('human', 'Species', '9606', (26, 31))
466614	30064463	found that hsa_circ_0067934 encoded by PRKCI is upregulated in 51 cases of ESCC tissues compared to adjacent noncancerous tissues, and they reported that hsa_circ_0067934 is associated with poor tumor differentiation and advanced TNM stage.	('TNM', 'Gene', '10178', (230, 233))	('tumor', 'Disease', (195, 200))	('associated', 'Reg', (174, 184))	('PRKCI', 'Gene', '5584', (39, 44))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('PRKCI', 'Gene', (39, 44))	('ESCC', 'Disease', (75, 79))	('hsa_circ_0067934', 'Var', (154, 170))	('TNM', 'Gene', (230, 233))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('upregulated', 'PosReg', (48, 59))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))
466615	30064463	Silencing hsa_circ_0067934 by siRNA induces cell cycle arrest and inhibits proliferation and migration of ESCC cells.	('arrest', 'Disease', 'MESH:D006323', (55, 61))	('inhibits', 'NegReg', (66, 74))	('arrest', 'Disease', (55, 61))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (44, 61))	('Silencing', 'Var', (0, 9))	('hsa_circ_0067934', 'Gene', (10, 26))	('induces', 'Reg', (36, 43))
466616	30064463	Given that TNM staging is applied to predict patient outcomes, hsa_circ_0067934 may serve as a potential prognostic marker for ESCC.	('TNM', 'Gene', '10178', (11, 14))	('ESCC', 'Disease', (127, 131))	('TNM', 'Gene', (11, 14))	('patient', 'Species', '9606', (45, 52))	('hsa_circ_0067934', 'Var', (63, 79))
466621	30064463	Hsa_circ_0047905, hsa_circ_0087198, and hsa_circ_0138960 are also highly expressed in gastric cancer tissues.	('gastric cancer', 'Disease', 'MESH:D013274', (86, 100))	('gastric cancer', 'Phenotype', 'HP:0012126', (86, 100))	('Hsa_circ_0047905', 'Var', (0, 16))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('gastric cancer', 'Disease', (86, 100))	('hsa_circ_0138960', 'Var', (40, 56))
466625	30064463	Knockdown of hsa_circ_0000096 reduces the expression of cyclin D1, CDK6, matrix metalloproteinase (MPP)-2, and MMP-9, and it significantly inhibits cell proliferation and migration and blocks cell cycle (preventing gastric cancer cells from leaving G0/G1 phase to enter S phase), as well as inhibits tumor growth in a xenograft nude mouse model.	('matrix metalloproteinase (MPP)-2', 'Gene', '50997', (73, 105))	('CDK6', 'Gene', (67, 71))	('expression', 'MPA', (42, 52))	('gastric cancer', 'Disease', (215, 229))	('cyclin D1', 'Gene', '12443', (56, 65))	('cyclin D1', 'Gene', (56, 65))	('tumor', 'Phenotype', 'HP:0002664', (300, 305))	('mouse', 'Species', '10090', (333, 338))	('cell cycle', 'CPA', (192, 202))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('gastric cancer', 'Disease', 'MESH:D013274', (215, 229))	('inhibits', 'NegReg', (291, 299))	('blocks', 'NegReg', (185, 191))	('inhibits', 'NegReg', (139, 147))	('gastric cancer', 'Phenotype', 'HP:0012126', (215, 229))	('reduces', 'NegReg', (30, 37))	('hsa_circ_0000096', 'Var', (13, 29))	('tumor', 'Disease', (300, 305))	('MMP-9', 'Gene', '17395', (111, 116))	('MMP-9', 'Gene', (111, 116))	('cell proliferation', 'CPA', (148, 166))	('tumor', 'Disease', 'MESH:D009369', (300, 305))
466626	30064463	The circRNA database shows that hsa_circ_0000096 can interact with 17 different types of miRNAs.	('miR', 'Gene', '220972', (89, 92))	('hsa_circ_0000096', 'Var', (32, 48))	('interact', 'Interaction', (53, 61))	('miR', 'Gene', (89, 92))
466627	30064463	Downregulation of hsa_circ_0000096 results in a decrease in miR-224 (a modulator of CD40) and an increase in miR-200a (targeting E-cadherin).	('increase', 'PosReg', (97, 105))	('Downregulation', 'NegReg', (0, 14))	('miR-224', 'Gene', (60, 67))	('miR-224', 'Gene', '407009', (60, 67))	('E-cadherin', 'Gene', (129, 139))	('E-cadherin', 'Gene', '999', (129, 139))	('CD40', 'Gene', '958', (84, 88))	('decrease', 'NegReg', (48, 56))	('hsa_circ_0000096', 'Var', (18, 34))	('CD40', 'Gene', (84, 88))	('miR-200a', 'Gene', (109, 117))	('miR-200a', 'Gene', '406983', (109, 117))
466635	30064463	Hsa_circ_0000190 is considered to have better sensitivity and specificity compared to CEA and CA19-9.	('Hsa_circ_0000190', 'Var', (0, 16))	('CEA', 'Gene', (86, 89))	('CEA', 'Gene', '5670', (86, 89))
466637	30064463	Hsa_circ_0014717 is also lowly expressed in gastric cancer, and such downregulation is associated with distant metastasis and clinical staging.	('gastric cancer', 'Phenotype', 'HP:0012126', (44, 58))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('lowly', 'NegReg', (25, 30))	('gastric cancer', 'Disease', (44, 58))	('gastric cancer', 'Disease', 'MESH:D013274', (44, 58))	('distant metastasis', 'CPA', (103, 121))	('Hsa_circ_0014717', 'Var', (0, 16))	('downregulation', 'NegReg', (69, 83))
466638	30064463	Hsa_circ_0000181, hsa_circ_0001649, hsa_circ_0000520, hsa_circ_0003159, and hsa_circ_0074362 are also lowly expressed in tissues or plasma of gastric cancer patients, and their expression is negatively correlated with distant metastasis and TNM staging.	('Hsa_circ_0000181', 'Var', (0, 16))	('TNM', 'Gene', '10178', (241, 244))	('gastric cancer', 'Disease', (142, 156))	('gastric cancer', 'Disease', 'MESH:D013274', (142, 156))	('distant metastasis', 'CPA', (218, 236))	('hsa_circ_0003159', 'Var', (54, 70))	('patients', 'Species', '9606', (157, 165))	('gastric cancer', 'Phenotype', 'HP:0012126', (142, 156))	('TNM', 'Gene', (241, 244))	('negatively', 'NegReg', (191, 201))	('lowly', 'NegReg', (102, 107))	('hsa_circ_0000520', 'Var', (36, 52))	('correlated', 'Reg', (202, 212))	('expression', 'MPA', (177, 187))	('hsa_circ_0074362', 'Var', (76, 92))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('hsa_circ_0001649', 'Var', (18, 34))
466639	30064463	The plasma levels of hsa_circ_0001017 and hsa_circ_0061276 are also downregulated, making them suitable for the diagnosis and prognosis of gastric cancer.	('gastric cancer', 'Disease', (139, 153))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('gastric cancer', 'Disease', 'MESH:D013274', (139, 153))	('downregulated', 'NegReg', (68, 81))	('hsa_circ_0001017', 'Var', (21, 37))	('gastric cancer', 'Phenotype', 'HP:0012126', (139, 153))	('hsa_circ_0061276', 'Var', (42, 58))	('plasma levels', 'MPA', (4, 17))
466640	30064463	Moreover, hsa_circ_0000745 is expressed at a higher level in gastric cancer tissues than normal tissues, and its expression in plasma of gastric cancer patients is also higher than that of healthy controls.	('expression', 'MPA', (113, 123))	('higher', 'PosReg', (169, 175))	('gastric cancer', 'Disease', (61, 75))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('gastric cancer', 'Disease', 'MESH:D013274', (61, 75))	('gastric cancer', 'Disease', (137, 151))	('gastric cancer', 'Disease', 'MESH:D013274', (137, 151))	('gastric cancer', 'Phenotype', 'HP:0012126', (61, 75))	('higher', 'PosReg', (45, 51))	('hsa_circ_0000745', 'Var', (10, 26))	('patients', 'Species', '9606', (152, 160))	('gastric cancer', 'Phenotype', 'HP:0012126', (137, 151))
466641	30064463	Hsa_circ_0000745 expression in gastric cancer tissues and plasma is associated with tumor differentiation and lymph node metastasis, respectively, and plasma hsa_circ_0000745 combined with CEA has a greater diagnostic value for gastric cancer.	('CEA', 'Gene', '5670', (189, 192))	('lymph node metastasis', 'CPA', (110, 131))	('associated', 'Reg', (68, 78))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('gastric cancer', 'Disease', 'MESH:D013274', (228, 242))	('gastric cancer', 'Disease', (228, 242))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('gastric cancer', 'Phenotype', 'HP:0012126', (31, 45))	('Hsa_circ_0000745', 'Gene', (0, 16))	('gastric cancer', 'Phenotype', 'HP:0012126', (228, 242))	('tumor', 'Disease', (84, 89))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('hsa_circ_0000745', 'Var', (158, 174))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('CEA', 'Gene', (189, 192))	('gastric cancer', 'Disease', 'MESH:D013274', (31, 45))	('gastric cancer', 'Disease', (31, 45))
466653	30064463	In addition, hsa_circ_0001649, hsa_circ_0003906, and circRNA derived from ITCH78 are also downregulated in CRC, and the first two circRNAs are related to the pathological differentiation of CRC and may be used as diagnostic indicators of CRC.	('CRC', 'Disease', (107, 110))	('CRC', 'Disease', (238, 241))	('CRC', 'Phenotype', 'HP:0030731', (238, 241))	('ITCH', 'Gene', (74, 78))	('CRC', 'Phenotype', 'HP:0030731', (107, 110))	('CRC', 'Disease', (190, 193))	('CRC', 'Phenotype', 'HP:0030731', (190, 193))	('hsa_circ_0001649', 'Var', (13, 29))	('downregulated', 'NegReg', (90, 103))	('ITCH', 'Gene', '83737', (74, 78))
466658	30064463	As a positive regulator of CRC cell proliferation and invasion, hsa_circ_001569 exhibits higher expression in CRC tissues than noncancerous tissues.	('hsa_circ_001569', 'Var', (64, 79))	('CRC', 'Disease', (110, 113))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('CRC', 'Phenotype', 'HP:0030731', (110, 113))	('cancer', 'Disease', (130, 136))	('expression', 'MPA', (96, 106))	('higher', 'PosReg', (89, 95))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('CRC', 'Phenotype', 'HP:0030731', (27, 30))
466674	30064463	Comparison of three syngeneic CRC cell lines with different KRAS mutation status, including DLD-1, DKO-1, and DKs-8, has shown that extracellular circRNAs are more abundant than intracellular circRNAs, and most circRNAs are downregulated in the KRAS-mutated CRC cell lines.	('downregulated', 'NegReg', (224, 237))	('KRAS', 'Gene', (245, 249))	('KRAS', 'Gene', (60, 64))	('KRAS', 'Gene', '3845', (245, 249))	('mutation', 'Var', (65, 73))	('CRC', 'Phenotype', 'HP:0030731', (30, 33))	('KRAS', 'Gene', '3845', (60, 64))	('extracellular circRNAs', 'MPA', (132, 154))	('CRC', 'Phenotype', 'HP:0030731', (258, 261))
466675	30064463	circRNA is associated with KRAS mutations, and it is a promising biomarker of CRC, especially for KRAS-mutated CRC.	('KRAS', 'Gene', '3845', (27, 31))	('associated', 'Reg', (11, 21))	('CRC', 'Phenotype', 'HP:0030731', (111, 114))	('CRC', 'Disease', (78, 81))	('mutations', 'Var', (32, 41))	('CRC', 'Phenotype', 'HP:0030731', (78, 81))	('KRAS', 'Gene', (98, 102))	('KRAS', 'Gene', (27, 31))	('KRAS', 'Gene', '3845', (98, 102))
466687	30064463	Hsa_circ_0001649 was also lowly expressed in HCC tissues compared to normal tissues, and the expression level of hsa_circ_0001649 is related to tumor size and tumor thrombus.	('HCC', 'Phenotype', 'HP:0001402', (45, 48))	('tumor', 'Disease', (144, 149))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('hsa_circ_0001649', 'Var', (113, 129))	('related', 'Reg', (133, 140))	('HCC', 'Gene', (45, 48))	('tumor', 'Disease', (159, 164))	('tumor thrombus', 'Disease', (159, 173))	('expression', 'MPA', (93, 103))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('tumor thrombus', 'Disease', 'MESH:D013927', (159, 173))	('HCC', 'Gene', '619501', (45, 48))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('tumor', 'Disease', 'MESH:D009369', (159, 164))
466692	30064463	The expression level of hsa_circ_0005986 in HCC cell lines, including HepG2, Huh7, SMMC7721, HCCLM3, MHCC97H, and MHCC97L, is significantly lower than that in the L02 normal liver cell line.	('lower', 'NegReg', (140, 145))	('SMMC7721', 'CellLine', 'CVCL:0534', (83, 91))	('hsa_circ_0005986', 'Var', (24, 40))	('Huh7', 'Gene', (77, 81))	('Huh7', 'Gene', '284424', (77, 81))	('HCC', 'Gene', '619501', (102, 105))	('HCC', 'Phenotype', 'HP:0001402', (102, 105))	('HepG2', 'CellLine', 'CVCL:0027', (70, 75))	('HCC', 'Gene', '619501', (93, 96))	('HCC', 'Phenotype', 'HP:0001402', (93, 96))	('HCC', 'Gene', (102, 105))	('HCC', 'Gene', '619501', (44, 47))	('HCC', 'Gene', (93, 96))	('HCC', 'Phenotype', 'HP:0001402', (44, 47))	('expression level', 'MPA', (4, 20))	('HCC', 'Gene', (44, 47))	('HCC', 'Gene', '619501', (115, 118))	('HCC', 'Phenotype', 'HP:0001402', (115, 118))	('HCC', 'Gene', (115, 118))
466693	30064463	Both hsa_circ_0005986 and Notch1 mRNA can bind to miR-129-5p, and downregulation of hsa_circ_0005986 releases miR-129-5p to decrease the level of Notch1 mRNA, accelerating the cell proliferation by promoting G0/G1 to S phase transition.	('miR-129-5p', 'Gene', '100302178', (110, 120))	('level', 'MPA', (137, 142))	('miR-129-5p', 'Gene', (110, 120))	('downregulation', 'Var', (66, 80))	('miR-129-5p', 'Gene', '100302178', (50, 60))	('G0/G1 to S phase transition', 'CPA', (208, 235))	('accelerating', 'PosReg', (159, 171))	('Notch1', 'Gene', (146, 152))	('miR-129-5p', 'Gene', (50, 60))	('promoting', 'PosReg', (198, 207))	('cell proliferation', 'CPA', (176, 194))	('hsa_circ_0005986', 'Gene', (84, 100))	('Notch1', 'Gene', (26, 32))	('decrease', 'NegReg', (124, 132))	('Notch1', 'Gene', '4851', (146, 152))	('Notch1', 'Gene', '4851', (26, 32))
466698	30064463	When ciRS-7 is knocked down, miR-7 is released and proliferation and invasion of HCC cells are also significantly inhibited.	('knocked down', 'Var', (15, 27))	('ciRS-7', 'Gene', (5, 11))	('HCC', 'Gene', '619501', (81, 84))	('miR-7', 'Gene', (29, 34))	('HCC', 'Phenotype', 'HP:0001402', (81, 84))	('released', 'PosReg', (38, 46))	('ciRS-7', 'Gene', '103611090', (5, 11))	('miR-7', 'Gene', '10859', (29, 34))	('HCC', 'Gene', (81, 84))	('inhibited', 'NegReg', (114, 123))
466704	30064463	Knockdown of has_circ_0067934 significantly inhibits the proliferation, invasion, and metastasis of Hep3B and HuH7 cells and induces apoptosis.	('HuH7', 'Gene', (110, 114))	('apoptosis', 'CPA', (133, 142))	('Hep3B', 'CellLine', 'CVCL:0326', (100, 105))	('has_circ_0067934', 'Var', (13, 29))	('HuH7', 'Gene', '284424', (110, 114))	('induces', 'Reg', (125, 132))	('inhibits', 'NegReg', (44, 52))	('invasion', 'CPA', (72, 80))	('metastasis', 'CPA', (86, 96))
466705	30064463	Hsa_circ_0005075 is considered to be closely related to cell adhesion, which is an important part of tumor cell proliferation and metastasis.	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('Hsa_circ_0005075', 'Var', (0, 16))	('cell', 'CPA', (56, 60))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
466706	30064463	A recent study showed that the expression level of hsa_circ_0005075 is significantly different between HCC and normal liver tissues and is related to HCC tumor size.	('HCC', 'Gene', (150, 153))	('different', 'Reg', (85, 94))	('related', 'Reg', (139, 146))	('HCC', 'Phenotype', 'HP:0001402', (103, 106))	('HCC tumor', 'Disease', 'MESH:D006528', (150, 159))	('HCC', 'Gene', '619501', (103, 106))	('HCC', 'Gene', '619501', (150, 153))	('hsa_circ_0005075', 'Var', (51, 67))	('HCC', 'Phenotype', 'HP:0001402', (150, 153))	('HCC', 'Gene', (103, 106))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('expression level', 'MPA', (31, 47))	('HCC tumor', 'Disease', (150, 159))
466707	30064463	Larger tumor sizes correlated with higher expression of hsa_circ_0005075.	('tumor', 'Disease', (7, 12))	('expression', 'MPA', (42, 52))	('hsa_circ_0005075', 'Var', (56, 72))	('tumor', 'Disease', 'MESH:D009369', (7, 12))	('higher', 'PosReg', (35, 41))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
466708	30064463	Thus, hsa_circ_0005075 has the potential to become an ideal biomarker for HCC.	('HCC', 'Gene', '619501', (74, 77))	('hsa_circ_0005075', 'Var', (6, 22))	('HCC', 'Gene', (74, 77))	('HCC', 'Phenotype', 'HP:0001402', (74, 77))
466718	30064463	Hsa_circ_0046701 is highly expressed in glioma tissues.	('glioma', 'Phenotype', 'HP:0009733', (40, 46))	('glioma', 'Disease', (40, 46))	('Hsa_circ_0046701', 'Var', (0, 16))	('glioma', 'Disease', 'MESH:D005910', (40, 46))
466719	30064463	Silencing hsa_circ_0046701 upregulates miR-142, resulting in a decrease of ITGB8 and inhibition of cell proliferation and invasion.	('ITGB8', 'Gene', '3696', (75, 80))	('inhibition', 'NegReg', (85, 95))	('decrease', 'NegReg', (63, 71))	('miR-142', 'Gene', '406934', (39, 46))	('hsa_circ_0046701', 'Gene', (10, 26))	('miR-142', 'Gene', (39, 46))	('ITGB8', 'Gene', (75, 80))	('upregulates', 'PosReg', (27, 38))	('Silencing', 'Var', (0, 9))
466721	30064463	circ-SHKBP1 is highly expressed in high-grade gliomas, and knockdown of circ-SHKBP1 significantly inhibits cell proliferation and metastasis.	('SHKBP1', 'Gene', (5, 11))	('SHKBP1', 'Gene', '92799', (77, 83))	('SHKBP1', 'Gene', '92799', (5, 11))	('SHKBP1', 'Gene', (77, 83))	('gliomas', 'Disease', (46, 53))	('gliomas', 'Disease', 'MESH:D005910', (46, 53))	('gliomas', 'Phenotype', 'HP:0009733', (46, 53))	('knockdown', 'Var', (59, 68))	('inhibits', 'NegReg', (98, 106))	('glioma', 'Phenotype', 'HP:0009733', (46, 52))
466725	30064463	Silencing cZNF292 inactivates the Wnt/beta-catenin signaling pathway in U87MG and U251 cells, thereby arresting cell cycle and inhibiting cell proliferation.	('beta-catenin', 'Gene', (38, 50))	('cZNF292', 'Gene', (10, 17))	('arrest', 'Disease', (102, 108))	('inactivates', 'NegReg', (18, 29))	('Silencing', 'Var', (0, 9))	('beta-catenin', 'Gene', '1499', (38, 50))	('inhibiting', 'NegReg', (127, 137))	('U87MG', 'CellLine', 'CVCL:0022', (72, 77))	('cell proliferation', 'CPA', (138, 156))	('cell cycle', 'CPA', (112, 122))	('U251', 'CellLine', 'CVCL:0021', (82, 86))	('arrest', 'Disease', 'MESH:D006323', (102, 108))
466726	30064463	Hsa_circ_022705 (circ-FBXW7) is lowly expressed in glioma tissues and cells, and it is positively correlated with the prognosis of patients with glioma.	('patients', 'Species', '9606', (131, 139))	('glioma', 'Disease', (145, 151))	('glioma', 'Disease', (51, 57))	('correlated with', 'Reg', (98, 113))	('FBXW7', 'Gene', (22, 27))	('glioma', 'Disease', 'MESH:D005910', (51, 57))	('glioma', 'Phenotype', 'HP:0009733', (51, 57))	('glioma', 'Disease', 'MESH:D005910', (145, 151))	('glioma', 'Phenotype', 'HP:0009733', (145, 151))	('FBXW7', 'Gene', '55294', (22, 27))	('Hsa_circ_022705', 'Var', (0, 15))
466728	30064463	Upregulation of FBXW7-185aa significantly inhibits the proliferation of tumor cells, while silencing this protein promotes the malignant phenotype.	('Upregulation', 'PosReg', (0, 12))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('inhibits', 'NegReg', (42, 50))	('FBXW7', 'Gene', (16, 21))	('tumor', 'Disease', (72, 77))	('malignant phenotype', 'CPA', (127, 146))	('promotes', 'PosReg', (114, 122))	('silencing', 'Var', (91, 100))	('FBXW7', 'Gene', '55294', (16, 21))	('tumor', 'Disease', 'MESH:D009369', (72, 77))
466741	30064463	High-throughput microarray analysis has been used to identify six circRNAs that are differentially expressed in bladder cancer and normal tissues as follows: circPTK2 (hsa_circ_0005273), circTCF25 (hsa_circ_0041103), circBC048201 (hsa_circ_0061265), and circZFR (hsa_circ_0072088) are significantly upregulated and circTRIM24 (hsa_circ_0082582) and circFAM169A (hsa_circ_0007158) are downregulated.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('bladder cancer', 'Disease', 'MESH:D001749', (112, 126))	('bladder cancer', 'Disease', (112, 126))	('PTK2', 'Gene', '5747', (162, 166))	('hsa_circ_0061265', 'Var', (231, 247))	('upregulated', 'PosReg', (299, 310))	('bladder cancer', 'Phenotype', 'HP:0009725', (112, 126))	('PTK2', 'Gene', (162, 166))
466756	30064463	Hsa_circ_0000977 is abnormally upregulated in pancreatic cancer tissues, and silencing hsa_circ_0000977 inhibits cell proliferation and induces cell cycle arrest.	('arrest', 'Disease', 'MESH:D006323', (155, 161))	('cell proliferation', 'CPA', (113, 131))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (46, 63))	('inhibits', 'NegReg', (104, 112))	('pancreatic cancer', 'Disease', (46, 63))	('silencing', 'Var', (77, 86))	('arrest', 'Disease', (155, 161))	('pancreatic cancer', 'Disease', 'MESH:D010190', (46, 63))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('hsa_circ_0000977', 'Gene', (87, 103))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (144, 161))	('induces', 'Reg', (136, 143))
466757	30064463	The interaction of hsa_circ_0000977, hsa-miR-874-3p, and PLK1A has been verified by dual luciferase reporter assay and fluorescence in situ hybridization (FISH) assay, and inhibition of hsa_circ_0000977 can reduce the expression of PLK1.	('reduce', 'NegReg', (207, 213))	('miR', 'Gene', '220972', (41, 44))	('PLK1', 'Gene', (57, 61))	('miR', 'Gene', (41, 44))	('inhibition', 'Var', (172, 182))	('PLK1', 'Gene', (232, 236))	('PLK1', 'Gene', '5347', (232, 236))	('PLK1', 'Gene', '5347', (57, 61))	('expression', 'MPA', (218, 228))
466758	30064463	In animal experiments, silencing hsa_circ_0000977 inhibits tumor growth.	('hsa_circ_0000977', 'Gene', (33, 49))	('tumor', 'Disease', (59, 64))	('silencing', 'Var', (23, 32))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('inhibits', 'NegReg', (50, 58))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
466769	30064463	Hsa_circ_0001564 is significantly overexpressed in osteosarcoma tissues and cells.	('osteosarcoma', 'Phenotype', 'HP:0002669', (51, 63))	('osteosarcoma tissues', 'Disease', 'MESH:D012516', (51, 71))	('Hsa_circ_0001564', 'Var', (0, 16))	('osteosarcoma tissues', 'Disease', (51, 71))	('overexpressed', 'PosReg', (34, 47))
466772	30064463	Hsa_circ_0009910 is also overexpressed in osteosarcoma cells.	('osteosarcoma', 'Disease', (42, 54))	('overexpressed', 'PosReg', (25, 38))	('osteosarcoma', 'Phenotype', 'HP:0002669', (42, 54))	('Hsa_circ_0009910', 'Var', (0, 16))	('osteosarcoma', 'Disease', 'MESH:D012516', (42, 54))
466773	30064463	Knockdown of circ_0009910 inhibits the proliferation of osteosarcoma cells, leading to cell cycle arrest and apoptosis.	('arrest', 'Disease', (98, 104))	('inhibits', 'NegReg', (26, 34))	('apoptosis', 'CPA', (109, 118))	('osteosarcoma', 'Phenotype', 'HP:0002669', (56, 68))	('osteosarcoma', 'Disease', (56, 68))	('proliferation', 'CPA', (39, 52))	('osteosarcoma', 'Disease', 'MESH:D012516', (56, 68))	('circ_0009910', 'Var', (13, 25))	('arrest', 'Disease', 'MESH:D006323', (98, 104))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (87, 104))
466774	30064463	However, inhibition of miR-449a eliminates this effect.	('inhibition', 'Var', (9, 19))	('miR-449a', 'Gene', '554213', (23, 31))	('miR-449a', 'Gene', (23, 31))
466775	30064463	As the sponge of miR-449a, circ_0009910 upregulates the functional target gene IL6R and promotes the development of osteosarcoma.	('promotes', 'PosReg', (88, 96))	('IL6R', 'Gene', '3570', (79, 83))	('miR-449a', 'Gene', (17, 25))	('osteosarcoma', 'Phenotype', 'HP:0002669', (116, 128))	('upregulates', 'PosReg', (40, 51))	('osteosarcoma', 'Disease', 'MESH:D012516', (116, 128))	('miR-449a', 'Gene', '554213', (17, 25))	('IL6R', 'Gene', (79, 83))	('circ_0009910', 'Var', (27, 39))	('osteosarcoma', 'Disease', (116, 128))
466776	30064463	In osteosarcoma cells and tissues, hsa_circRNA_103801 is upregulated, while hsa_circRNA_104980 is downregulated.	('osteosarcoma', 'Disease', (3, 15))	('osteosarcoma', 'Phenotype', 'HP:0002669', (3, 15))	('osteosarcoma', 'Disease', 'MESH:D012516', (3, 15))	('hsa_circRNA_103801', 'Var', (35, 53))	('upregulated', 'PosReg', (57, 68))
466777	30064463	The potential target miRNAs for hsa_circRNA_103801 include hsa-miR-338-3p, hsa-miR-370-3p, and hsa-miR-877-3p, which are involved in the HIF-1, Rap1, PI3K-Akt, VEGF, and angiogenesis pathways.	('HIF-1', 'Gene', (137, 142))	('miR', 'Gene', '220972', (99, 102))	('miR', 'Gene', (99, 102))	('miR', 'Gene', '220972', (21, 24))	('VEGF', 'Gene', (160, 164))	('miR', 'Gene', (21, 24))	('Rap1', 'Gene', '5906', (144, 148))	('Rap1', 'Gene', (144, 148))	('miR', 'Gene', '220972', (79, 82))	('miR', 'Gene', (79, 82))	('miR', 'Gene', '220972', (63, 66))	('miR', 'Gene', (63, 66))	('Akt', 'Gene', '207', (155, 158))	('HIF-1', 'Gene', '3091', (137, 142))	('VEGF', 'Gene', '7422', (160, 164))	('hsa_circRNA_103801', 'Var', (32, 50))	('Akt', 'Gene', (155, 158))
466778	30064463	The potential target miRNAs for hsa_circRNA_104980 are hsa-miR-660-3p and hsa-miR-1298-3p, which participate in the tight junction pathway.	('miR', 'Gene', '220972', (78, 81))	('miR', 'Gene', (78, 81))	('miR', 'Gene', '220972', (21, 24))	('miR', 'Gene', (21, 24))	('hsa_circRNA_104980', 'Var', (32, 50))	('miR', 'Gene', '220972', (59, 62))	('miR', 'Gene', (59, 62))
466786	30064463	In addition, the OS rate of ccRCC patients with high expression of circ-RIAT1 is superior to that of patients with low circ-RIAT1.	('patients', 'Species', '9606', (101, 109))	('circ-RIAT1', 'Disease', 'None', (67, 77))	('circ-RIAT1', 'Disease', (119, 129))	('ccRCC', 'Phenotype', 'HP:0006770', (28, 33))	('circ-RIAT1', 'Disease', 'None', (119, 129))	('patients', 'Species', '9606', (34, 42))	('ccRCC', 'Disease', (28, 33))	('high expression', 'Var', (48, 63))	('circ-RIAT1', 'Disease', (67, 77))	('OS', 'Chemical', '-', (17, 19))
466794	30064463	Hsa_circ_0022383 and hsa_circ_0022392 are the most significantly downregulated circRNAs and derived from FADS2 gene.	('FADS2', 'Gene', '9415', (105, 110))	('FADS2', 'Gene', (105, 110))	('circRNAs', 'MPA', (79, 87))	('downregulated', 'NegReg', (65, 78))	('Hsa_circ_0022383', 'Var', (0, 16))
466801	30064463	Functional analysis has revealed that knockdown of circRNA_100290 reduces CDK6 expression, induces G1/S arrest, and significantly inhibits the proliferation of SCC9 cell lines.	('circRNA_100290', 'Var', (51, 65))	('S arrest', 'Disease', (102, 110))	('SCC9', 'CellLine', 'CVCL:1685', (160, 164))	('CDK6', 'Gene', (74, 78))	('expression', 'MPA', (79, 89))	('reduces', 'NegReg', (66, 73))	('S arrest', 'Disease', 'MESH:D006323', (102, 110))	('proliferation of SCC9 cell lines', 'CPA', (143, 175))	('induces', 'Reg', (91, 98))	('inhibits', 'NegReg', (130, 138))
466802	30064463	In a nude mouse model, interference with circRNA_100290 also reduces tumor growth.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('mouse', 'Species', '10090', (10, 15))	('tumor', 'Disease', (69, 74))	('reduces', 'NegReg', (61, 68))	('circRNA_100290', 'Var', (41, 55))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
466807	30064463	Overexpression of ciRS-7 is closely related to later TNM staging, lymph node infiltration, and postoperative recurrence.	('lymph node infiltration', 'CPA', (66, 89))	('related', 'Reg', (36, 43))	('TNM', 'Gene', (53, 56))	('ciRS-7', 'Gene', '103611090', (18, 24))	('ciRS-7', 'Gene', (18, 24))	('Overexpression', 'Var', (0, 14))	('TNM', 'Gene', '10178', (53, 56))
466808	30064463	The OS of cholangiocarcinoma patients with high ciRS-7 expression is inferior to that of patients with low ciRS-7 expression.	('cholangiocarcinoma', 'Disease', (10, 28))	('patients', 'Species', '9606', (29, 37))	('ciRS-7', 'Gene', '103611090', (48, 54))	('ciRS-7', 'Gene', '103611090', (107, 113))	('OS', 'Chemical', '-', (4, 6))	('high', 'Var', (43, 47))	('carcinoma', 'Phenotype', 'HP:0030731', (19, 28))	('ciRS-7', 'Gene', (48, 54))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (10, 28))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (10, 28))	('patients', 'Species', '9606', (89, 97))	('ciRS-7', 'Gene', (107, 113))	('expression', 'Var', (55, 65))
466811	30064463	Overexpression of hsa_circ_0001649 inhibits cell proliferation, migration, and invasion but induces apoptosis of KMBC and Huh-28 cells.	('Huh-28', 'CellLine', 'CVCL:0336', (122, 128))	('cell proliferation', 'CPA', (44, 62))	('induces', 'Reg', (92, 99))	('inhibits', 'NegReg', (35, 43))	('invasion', 'CPA', (79, 87))	('migration', 'CPA', (64, 73))	('apoptosis', 'CPA', (100, 109))	('hsa_circ_0001649', 'Var', (18, 34))
466813	30064463	circRNA-000284 is significantly upregulated in cervical cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('cervical cancer', 'Disease', (47, 62))	('cervical cancer', 'Disease', 'MESH:D002583', (47, 62))	('circRNA-000284', 'Var', (0, 14))	('upregulated', 'PosReg', (32, 43))
466814	30064463	It promotes the proliferation and invasion of cervical cancer cells and that knockdown of circRNA-000284 causes G0/G1 cell cycle arrest, resulting in inhibition of cell proliferation and invasion.	('cervical cancer', 'Disease', 'MESH:D002583', (46, 61))	('arrest', 'Disease', (129, 135))	('cervical cancer', 'Disease', (46, 61))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (118, 135))	('cell proliferation', 'CPA', (164, 182))	('knockdown', 'Var', (77, 86))	('invasion', 'CPA', (34, 42))	('promotes', 'PosReg', (3, 11))	('inhibition', 'NegReg', (150, 160))	('arrest', 'Disease', 'MESH:D006323', (129, 135))	('circRNA-000284', 'Gene', (90, 104))	('proliferation', 'CPA', (16, 29))	('invasion', 'CPA', (187, 195))
466815	30064463	miR-506 is a miRNA related to circRNA-000284, and circRNA-000284 positively regulates the expression of Snail-2 which is a target gene of miR-506.	('Snail-2', 'Gene', '6591', (104, 111))	('miR', 'Gene', '220972', (13, 16))	('miR', 'Gene', (13, 16))	('Snail-2', 'Gene', (104, 111))	('miR', 'Gene', '220972', (0, 3))	('miR', 'Gene', (0, 3))	('miR', 'Gene', '220972', (138, 141))	('circRNA-000284', 'Var', (50, 64))	('expression', 'MPA', (90, 100))	('miR', 'Gene', (138, 141))	('regulates', 'Reg', (76, 85))	('miR-506', 'Gene', '574511', (0, 7))	('miR-506', 'Gene', (0, 7))	('miR-506', 'Gene', '574511', (138, 145))	('miR-506', 'Gene', (138, 145))
466817	30064463	Thus, circRNA-000284 is expected to be a new therapeutic target for cervical cancer.	('circRNA-000284', 'Var', (6, 20))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('cervical cancer', 'Disease', (68, 83))	('cervical cancer', 'Disease', 'MESH:D002583', (68, 83))
466823	30064463	The combination of hsa_circ_006054, hsa_circ_100219, and hsa_circ_406697 is helpful for the diagnosis of breast cancer.	('hsa_circ_406697', 'Var', (57, 72))	('breast cancer', 'Disease', 'MESH:D001943', (105, 118))	('hsa_circ_006054', 'Var', (19, 34))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('breast cancer', 'Disease', (105, 118))	('breast cancer', 'Phenotype', 'HP:0003002', (105, 118))
466824	30064463	Hsa_circ_0067934, a potential prognostic marker for ESCC, is overexpressed in ESCC tissues and correlates with poor differentiation and more advanced TNM staging.	('poor', 'NegReg', (111, 115))	('TNM', 'Gene', (150, 153))	('Hsa_circ_0067934', 'Var', (0, 16))	('ESCC', 'Disease', (52, 56))	('TNM', 'Gene', '10178', (150, 153))	('overexpressed', 'PosReg', (61, 74))	('differentiation', 'CPA', (116, 131))
466826	30064463	The downregulation of circMTO1, circ-ITCH, and cSMARCA5 or upregulation of circRNA_100338 in HCC is associated with poor prognosis.	('HCC', 'Gene', '619501', (93, 96))	('-ITCH', 'Phenotype', 'HP:0000989', (36, 41))	('ITCH', 'Gene', (37, 41))	('HCC', 'Phenotype', 'HP:0001402', (93, 96))	('SMARCA5', 'Gene', '8467', (48, 55))	('HCC', 'Gene', (93, 96))	('MTO1', 'Gene', '25821', (26, 30))	('downregulation', 'NegReg', (4, 18))	('ITCH', 'Gene', '83737', (37, 41))	('MTO1', 'Gene', (26, 30))	('upregulation', 'PosReg', (59, 71))	('SMARCA5', 'Gene', (48, 55))	('circRNA_100338', 'Var', (75, 89))
466828	30064463	Overexpression of ciRS-7 in cholangiocarcinoma is significantly correlated with later TNM staging, lymph node infiltration, and postoperative recurrence, and it may be an independent negative prognostic biomarker with good sensitivity and specificity.	('cholangiocarcinoma', 'Disease', (28, 46))	('lymph', 'Disease', (99, 104))	('TNM', 'Gene', '10178', (86, 89))	('ciRS-7', 'Gene', '103611090', (18, 24))	('carcinoma', 'Phenotype', 'HP:0030731', (37, 46))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (28, 46))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (28, 46))	('Overexpression', 'Var', (0, 14))	('TNM', 'Gene', (86, 89))	('correlated', 'Reg', (64, 74))	('ciRS-7', 'Gene', (18, 24))
466829	30064463	Hsa_circ_0001649 has been reported to have potential diagnostic and prognostic value in gastric cancer, CRC, HCC, and cholangiocarcinoma, and it may be a sensitive indicator for distant metastasis in gastric cancer and HCC.	('gastric cancer', 'Disease', 'MESH:D013274', (200, 214))	('gastric cancer', 'Disease', 'MESH:D013274', (88, 102))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('HCC', 'Gene', '619501', (109, 112))	('gastric cancer', 'Phenotype', 'HP:0012126', (200, 214))	('HCC', 'Phenotype', 'HP:0001402', (109, 112))	('Hsa_circ_0001649', 'Var', (0, 16))	('gastric cancer', 'Phenotype', 'HP:0012126', (88, 102))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('CRC', 'Disease', (104, 107))	('HCC', 'Gene', (109, 112))	('HCC', 'Gene', '619501', (219, 222))	('HCC', 'Phenotype', 'HP:0001402', (219, 222))	('gastric cancer', 'Disease', (200, 214))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (118, 136))	('CRC', 'Phenotype', 'HP:0030731', (104, 107))	('gastric cancer', 'Disease', (88, 102))	('HCC', 'Gene', (219, 222))	('cholangiocarcinoma', 'Disease', (118, 136))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (118, 136))
466831	30064463	Overexpression of circ-LDLRAD3 in pancreatic cancer is significantly correlated with venous and lymphatic infiltration as well as distant metastasis, and it is also a potential diagnostic marker for pancreatic cancer.	('pancreatic cancer', 'Disease', (199, 216))	('correlated', 'Reg', (69, 79))	('pancreatic cancer', 'Disease', 'MESH:D010190', (34, 51))	('pancreatic cancer', 'Disease', 'MESH:D010190', (199, 216))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('LDLRAD3', 'Gene', (23, 30))	('distant metastasis', 'CPA', (130, 148))	('LDLRAD3', 'Gene', '143458', (23, 30))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (34, 51))	('Overexpression', 'Var', (0, 14))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (199, 216))	('pancreatic cancer', 'Disease', (34, 51))
466833	30064463	For example, hsa_circ_002059, hsa_circ_0001017, and hsa_circ_0061276 can be stably detected in the plasma of gastric cancer patients.	('gastric cancer', 'Phenotype', 'HP:0012126', (109, 123))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('gastric cancer', 'Disease', (109, 123))	('gastric cancer', 'Disease', 'MESH:D013274', (109, 123))	('hsa_circ_0001017', 'Var', (30, 46))	('hsa_circ_0061276', 'Var', (52, 68))	('patients', 'Species', '9606', (124, 132))	('hsa_circ_002059', 'Var', (13, 28))
466836	30064463	The sensitivity and specificity of hsa_circ_0000190 as a diagnostic marker for gastric cancer are even better than that of CEA and CA19-9.	('gastric cancer', 'Phenotype', 'HP:0012126', (79, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('hsa_circ_0000190', 'Var', (35, 51))	('CEA', 'Gene', (123, 126))	('CEA', 'Gene', '5670', (123, 126))	('gastric cancer', 'Disease', (79, 93))	('gastric cancer', 'Disease', 'MESH:D013274', (79, 93))
466837	30064463	The plasma level of hsa_circ_0000745 in gastric cancer patients is related to lymph node metastasis, and it has a good diagnostic value in combination with CEA.	('related', 'Reg', (67, 74))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('CEA', 'Gene', (156, 159))	('gastric cancer', 'Disease', (40, 54))	('lymph node metastasis', 'CPA', (78, 99))	('plasma level', 'MPA', (4, 16))	('gastric cancer', 'Disease', 'MESH:D013274', (40, 54))	('CEA', 'Gene', '5670', (156, 159))	('hsa_circ_0000745', 'Var', (20, 36))	('patients', 'Species', '9606', (55, 63))	('gastric cancer', 'Phenotype', 'HP:0012126', (40, 54))
466840	30064463	Alternatively, it is possible to interfere with back-splicing by antisense oligonucleotides that are complementary to the back-splice signals in the precursor mRNA.	('antisense oligonucleotides', 'Var', (65, 91))	('oligonucleotides', 'Chemical', 'MESH:D009841', (75, 91))	('interfere', 'Reg', (33, 42))	('back-splicing', 'MPA', (48, 61))
466846	30064463	Because some circRNAs serve as a template for protein expression, cassettes containing tumor suppressor proteins can convert circRNAs into an effective treatment method for tumors.	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Disease', (87, 92))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumor', 'Disease', (173, 178))	('tumors', 'Disease', (173, 179))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('tumors', 'Disease', 'MESH:D009369', (173, 179))	('tumors', 'Phenotype', 'HP:0002664', (173, 179))	('cassettes', 'Var', (66, 75))
466864	28784613	Despite a low mutation burden, mutations in PIK3CA, MLL2, and MLL3 were among the most commonly mutated genes.	('PIK3CA', 'Gene', (44, 50))	('mutations', 'Var', (31, 40))	('MLL3', 'Gene', '58508', (62, 66))	('PIK3CA', 'Gene', '5290', (44, 50))	('MLL2', 'Gene', '9757', (52, 56))	('MLL3', 'Gene', (62, 66))	('MLL2', 'Gene', (52, 56))
466865	28784613	An association between TP53 mutations and HPV-negative SCCA tumors was observed.	('HPV', 'Species', '10566', (42, 45))	('association', 'Interaction', (3, 14))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('SCCA tumors', 'Disease', (55, 66))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('TP53', 'Gene', '7157', (23, 27))	('TP53', 'Gene', (23, 27))	('mutations', 'Var', (28, 37))	('SCCA tumors', 'Disease', 'MESH:D009369', (55, 66))
466866	28784613	Gene expression analysis suggested distinct tumor subpopulations harboring PIK3CA mutations and for which HPV had integrated into the host genome.	('PIK3CA', 'Gene', (75, 81))	('PIK3CA', 'Gene', '5290', (75, 81))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('mutations', 'Var', (82, 91))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumor', 'Disease', (44, 49))	('HPV', 'Species', '10566', (106, 109))
466899	28784613	All of the mutations were located in the exon 2 and 4 hotspots (Figure 2A) known to generate oncogenic activity of PIK3CA/mTOR signaling.	('mutations', 'Var', (11, 20))	('mTOR', 'Gene', '2475', (122, 126))	('mTOR', 'Gene', (122, 126))	('PIK3CA', 'Gene', (115, 121))	('PIK3CA', 'Gene', '5290', (115, 121))
466900	28784613	Missense mutations of RRBP1 were likewise present in 7 patients with metastatic anal cancer.	('RRBP1', 'Gene', (22, 27))	('anal cancer', 'Phenotype', 'HP:0032186', (80, 91))	('RRBP1', 'Gene', '6238', (22, 27))	('present', 'Reg', (42, 49))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('cancer', 'Disease', (85, 91))	('patients', 'Species', '9606', (55, 63))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('Missense mutations', 'Var', (0, 18))
466902	28784613	Other genes mutated in 2 or greater of the 24 sequenced tumors are listed in Figure 1.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('mutated', 'Var', (12, 19))	('tumors', 'Disease', (56, 62))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('tumors', 'Disease', 'MESH:D009369', (56, 62))
466903	28784613	MLL3 and MLL2 were mutated in 25% and 21% of tumors, respectively.	('MLL2', 'Gene', '9757', (9, 13))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('MLL2', 'Gene', (9, 13))	('tumors', 'Disease', (45, 51))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('MLL3', 'Gene', (0, 4))	('tumors', 'Disease', 'MESH:D009369', (45, 51))	('mutated', 'Var', (19, 26))	('MLL3', 'Gene', '58508', (0, 4))
466909	28784613	The median number of mutations/Mb is similar to what has been seen from publicly available data for cervical cancer and HPV-positive head/neck cancer, and lower than squamous cell cancer of the lung (P<.001).	('cervical cancer', 'Disease', 'MESH:D002583', (100, 115))	('squamous cell cancer of the lung', 'Disease', 'MESH:D002294', (166, 198))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('squamous cell cancer of the lung', 'Phenotype', 'HP:0030359', (166, 198))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('cancer of the lung', 'Phenotype', 'HP:0100526', (180, 198))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (166, 186))	('head/neck cancer', 'Phenotype', 'HP:0012288', (133, 149))	('mutations/Mb', 'Var', (21, 33))	('lower', 'NegReg', (155, 160))	('cervical cancer', 'Disease', (100, 115))	('HPV-positive head/neck cancer', 'Disease', (120, 149))	('HPV-positive head/neck cancer', 'Disease', 'MESH:D006258', (120, 149))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('squamous cell cancer of the lung', 'Disease', (166, 198))
466911	28784613	TP53 mutations were present in both of the HPV-negative tumors and were more likely to be associated with the absence of HPV relative to HPV-positive tumors (odds ratio [OR] 52, P = .03).	('tumors', 'Disease', (150, 156))	('tumors', 'Disease', 'MESH:D009369', (150, 156))	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('tumors', 'Phenotype', 'HP:0002664', (150, 156))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('HPV-positive tumors', 'Disease', 'MESH:D030361', (137, 156))	('HPV', 'Species', '10566', (121, 124))	('mutations', 'Var', (5, 14))	('tumors', 'Disease', (56, 62))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('HPV-positive tumors', 'Disease', (137, 156))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('HPV', 'Species', '10566', (43, 46))	('HPV', 'Species', '10566', (137, 140))
466917	28784613	Similarly, a trend towards a mutation in PIK3CA (OR 25, P=.07) and subgroup 3 was also observed.	('mutation', 'Var', (29, 37))	('OR 25', 'Gene', '390756', (49, 54))	('OR 25', 'Gene', (49, 54))	('PIK3CA', 'Gene', (41, 47))	('PIK3CA', 'Gene', '5290', (41, 47))
466923	28784613	The E545K substitution was the most commonly detected mutation of PIK3CA.	('PIK3CA', 'Gene', '5290', (66, 72))	('E545K', 'Var', (4, 9))	('PIK3CA', 'Gene', (66, 72))	('E545K', 'Mutation', 'rs104886003', (4, 9))
466924	28784613	In previous studies of patients with anal cancer sequenced with more limited gene panels, PIK3CA was mutated in approximately one-third of all cases, consistent with our findings here.	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('patients', 'Species', '9606', (23, 31))	('mutated', 'Var', (101, 108))	('PIK3CA', 'Gene', (90, 96))	('anal cancer', 'Phenotype', 'HP:0032186', (37, 48))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('PIK3CA', 'Gene', '5290', (90, 96))
466925	28784613	Similarly, for squamous cell carcinomas of the head/neck, PIK3CA is more frequently mutated in HPV-positive tumors relative to the HPV-negative counterparts and at similar prevalence to our observations here for anal cancer, a disease in which the majority of tumors are HPV-positive.	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (15, 39))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (15, 39))	('tumors', 'Phenotype', 'HP:0002664', (260, 266))	('squamous cell carcinomas of the head/neck', 'Phenotype', 'HP:0012288', (15, 56))	('PIK3CA', 'Gene', (58, 64))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (15, 38))	('mutated', 'Var', (84, 91))	('HPV', 'Species', '10566', (131, 134))	('cancer', 'Disease', 'MESH:D009369', (217, 223))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('anal cancer', 'Phenotype', 'HP:0032186', (212, 223))	('tumor', 'Phenotype', 'HP:0002664', (260, 265))	('squamous cell carcinomas', 'Disease', (15, 39))	('tumors', 'Disease', (260, 266))	('HPV', 'Species', '10566', (271, 274))	('carcinoma', 'Phenotype', 'HP:0030731', (29, 38))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('HPV-positive tumors', 'Disease', (95, 114))	('carcinomas', 'Phenotype', 'HP:0030731', (29, 39))	('tumors', 'Disease', (108, 114))	('HPV', 'Species', '10566', (95, 98))	('tumors', 'Disease', 'MESH:D009369', (260, 266))	('HPV-positive tumors', 'Disease', 'MESH:D030361', (95, 114))	('cancer', 'Disease', (217, 223))	('PIK3CA', 'Gene', '5290', (58, 64))	('tumors', 'Disease', 'MESH:D009369', (108, 114))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))
466927	28784613	Based on the relatively high prevalence of PIK3CA mutations in this disease, further analysis of PI3K inhibitors in PIK3CA mutant models, once available, are warranted to assess the potential application of these agents.	('PIK3CA', 'Gene', (116, 122))	('PIK3CA', 'Gene', '5290', (43, 49))	('mutations', 'Var', (50, 59))	('PIK3CA', 'Gene', '5290', (116, 122))	('mutant', 'Var', (123, 129))	('PIK3CA', 'Gene', (43, 49))
466928	28784613	Nonetheless, these findings lend further support to the notion that aberrant PIK3CA activity is present across the spectrum of HPV-associated malignancies.	('PIK3CA', 'Gene', (77, 83))	('PIK3CA', 'Gene', '5290', (77, 83))	('malignancies', 'Disease', 'MESH:D009369', (142, 154))	('activity', 'MPA', (84, 92))	('malignancies', 'Disease', (142, 154))	('HPV', 'Species', '10566', (127, 130))	('aberrant', 'Var', (68, 76))	('HPV-associated', 'Disease', (127, 141))
466929	28784613	For examples, mutations in MLL2 and MLL3 were present in 21% and 31% of cases, with the latter being the most commonly mutated gene among all that were assessed across the entire 41 patient cohort.	('MLL3', 'Gene', (36, 40))	('patient', 'Species', '9606', (182, 189))	('MLL2', 'Gene', '9757', (27, 31))	('MLL3', 'Gene', '58508', (36, 40))	('MLL2', 'Gene', (27, 31))	('mutations', 'Var', (14, 23))
466930	28784613	EP300, a histone acetyltransferase that modulates transcription of genes critical to physiologic cell proliferation and differentiation including TP53, was mutated in 17% of anal cancers.	('modulates', 'Reg', (40, 49))	('TP53', 'Gene', '7157', (146, 150))	('EP300', 'Gene', (0, 5))	('EP300', 'Gene', '2033', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('TP53', 'Gene', (146, 150))	('mutated', 'Var', (156, 163))	('anal cancer', 'Phenotype', 'HP:0032186', (174, 185))	('cancers', 'Disease', 'MESH:D009369', (179, 186))	('transcription', 'MPA', (50, 63))	('cancers', 'Phenotype', 'HP:0002664', (179, 186))	('cancers', 'Disease', (179, 186))
466931	28784613	MLL2 and MLL3 belong to the family of histone H3-lysine-4 (H3K4) methyltransferases, and trimethylation of H3K4 promotes physiologic gene expression.	('promotes', 'PosReg', (112, 120))	('MLL2', 'Gene', '9757', (0, 4))	('physiologic gene expression', 'MPA', (121, 148))	('MLL3', 'Gene', '58508', (9, 13))	('H3K4', 'Protein', (107, 111))	('trimethylation', 'Var', (89, 103))	('MLL2', 'Gene', (0, 4))	('MLL3', 'Gene', (9, 13))
466932	28784613	Mutations in MLL2 and MLL3 generate aberrant methylation of H3K4 and have been associated with oncogenic transformation in preclinical models.	('oncogenic transformation', 'CPA', (95, 119))	('methylation', 'MPA', (45, 56))	('H3K4', 'Protein', (60, 64))	('MLL3', 'Gene', (22, 26))	('MLL2', 'Gene', '9757', (13, 17))	('associated with', 'Reg', (79, 94))	('MLL2', 'Gene', (13, 17))	('Mutations', 'Var', (0, 9))	('MLL3', 'Gene', '58508', (22, 26))
466934	28784613	Similarly, high frequencies of double-stranded DNA breaks have been identified in tumor cells with MLL2 mutations, and are attributed to decreased expression of the RNAPOLII gene encoding for the DNA-proofreading RNA polymerase II.	('double-stranded DNA breaks', 'MPA', (31, 57))	('RNAPOLII', 'Gene', (165, 173))	('mutations', 'Var', (104, 113))	('MLL2', 'Gene', '9757', (99, 103))	('expression', 'MPA', (147, 157))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('MLL2', 'Gene', (99, 103))	('decreased', 'NegReg', (137, 146))	('tumor', 'Disease', (82, 87))
466936	28784613	This notion may be critical for all anal squamous cancers regardless of HPV status, as HPV-negative tumors were also associated in our study with TP53 mutations, consistent with prior genomic characterizations of other HPV-associated squamous cancers.	('cancers', 'Phenotype', 'HP:0002664', (50, 57))	('squamous cancers', 'Disease', 'MESH:D002294', (234, 250))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('HPV', 'Species', '10566', (219, 222))	('associated', 'Reg', (117, 127))	('TP53', 'Gene', (146, 150))	('squamous cancers', 'Disease', 'MESH:D002294', (41, 57))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('mutations', 'Var', (151, 160))	('squamous cancers regardless of HPV status', 'Disease', (41, 82))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumors', 'Disease', (100, 106))	('TP53', 'Gene', '7157', (146, 150))	('squamous cancers', 'Disease', (234, 250))	('cancers', 'Phenotype', 'HP:0002664', (243, 250))	('HPV', 'Species', '10566', (87, 90))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('HPV', 'Species', '10566', (72, 75))	('squamous cancers regardless of HPV status', 'Disease', 'MESH:D030361', (41, 82))	('cancer', 'Phenotype', 'HP:0002664', (243, 249))
466937	28784613	Mutated RRBP1 was a novel finding present in 29% of anal cancers analyzed across the entire exome, and all mutations localized to the same hotspot.	('RRBP1', 'Gene', (8, 13))	('RRBP1', 'Gene', '6238', (8, 13))	('anal cancer', 'Phenotype', 'HP:0032186', (52, 63))	('cancers', 'Phenotype', 'HP:0002664', (57, 64))	('cancers', 'Disease', (57, 64))	('cancers', 'Disease', 'MESH:D009369', (57, 64))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('Mutated', 'Var', (0, 7))
466938	28784613	While these mutations have not been previously described for RRBP1, overexpression of this gene has been reported in other solid tumors, including breast and colorectal adenocarcinomas.	('breast', 'Disease', (147, 153))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('carcinoma', 'Phenotype', 'HP:0030731', (174, 183))	('RRBP1', 'Gene', (61, 66))	('solid tumors', 'Disease', (123, 135))	('mutations', 'Var', (12, 21))	('colorectal adenocarcinomas', 'Disease', 'MESH:D015179', (158, 184))	('RRBP1', 'Gene', '6238', (61, 66))	('overexpression', 'PosReg', (68, 82))	('solid tumors', 'Disease', 'MESH:D009369', (123, 135))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('reported', 'Reg', (105, 113))	('colorectal adenocarcinomas', 'Disease', (158, 184))	('carcinomas', 'Phenotype', 'HP:0030731', (174, 184))
466939	28784613	In non-metastatic colorectal cancer, high expression of RRBP1 has been described as a poor prognostic biomarker.	('high expression', 'Var', (37, 52))	('colorectal cancer', 'Phenotype', 'HP:0003003', (18, 35))	('non-metastatic colorectal cancer', 'Phenotype', 'HP:0030358', (3, 35))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('colorectal cancer', 'Disease', (18, 35))	('RRBP1', 'Gene', (56, 61))	('RRBP1', 'Gene', '6238', (56, 61))	('colorectal cancer', 'Disease', 'MESH:D015179', (18, 35))
466940	28784613	While no effect on metastatic survival was noted in this population of patients with metastatic SCCA based on RRBP1 mutation status, our findings of this gene warrants further evaluation in future studies for anal cancer.	('cancer', 'Disease', (214, 220))	('mutation', 'Var', (116, 124))	('patients', 'Species', '9606', (71, 79))	('cancer', 'Disease', 'MESH:D009369', (214, 220))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('anal cancer', 'Phenotype', 'HP:0032186', (209, 220))	('RRBP1', 'Gene', '6238', (110, 115))	('RRBP1', 'Gene', (110, 115))
466942	28784613	Lack of such mutations has been previously described in anal cancer and is also consistent with other HPV-positive squamous tumors.	('HPV-positive squamous tumors', 'Disease', (102, 130))	('HPV-positive squamous tumors', 'Disease', 'MESH:D030361', (102, 130))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('anal cancer', 'Phenotype', 'HP:0032186', (56, 67))	('cancer', 'Disease', (61, 67))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('mutations', 'Var', (13, 22))
466943	28784613	Based on our findings, we do not believe routine testing for mutations in KRAS, NRAS, or BRAF is required, as the results are unlikely to influence clinical decision making in the management of metastatic anal cancer.	('NRAS', 'Gene', (80, 84))	('anal cancer', 'Phenotype', 'HP:0032186', (205, 216))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('mutations', 'Var', (61, 70))	('NRAS', 'Gene', '4893', (80, 84))	('BRAF', 'Gene', '673', (89, 93))	('KRAS', 'Gene', (74, 78))	('KRAS', 'Gene', '3845', (74, 78))	('cancer', 'Disease', 'MESH:D009369', (210, 216))	('BRAF', 'Gene', (89, 93))	('influence', 'Reg', (138, 147))	('cancer', 'Disease', (210, 216))
466961	28784613	In addition, mutation profiles for our series are consistent with prior data for other HPV-positive malignancies and provide further rationale for the study of these solid tumors not only by disease site but also by the responsible underlying biological drivers.	('solid tumors', 'Disease', 'MESH:D009369', (166, 178))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('malignancies', 'Disease', 'MESH:D009369', (100, 112))	('tumors', 'Phenotype', 'HP:0002664', (172, 178))	('mutation', 'Var', (13, 21))	('HPV', 'Species', '10566', (87, 90))	('malignancies', 'Disease', (100, 112))	('solid tumors', 'Disease', (166, 178))
466963	29851970	Methylation of L1RE1, RARB, and RASSF1 function as possible biomarkers for the differential diagnosis of lung cancer Lung cancer is the major cause of cancer-related deaths worldwide.	('RASSF1', 'Gene', (32, 38))	('lung cancer', 'Disease', 'MESH:D008175', (105, 116))	('RARB', 'Gene', (22, 26))	('Lung cancer', 'Disease', 'MESH:D008175', (117, 128))	('RARB', 'Gene', '5915', (22, 26))	('lung cancer', 'Phenotype', 'HP:0100526', (105, 116))	('Methylation', 'Var', (0, 11))	('Lung cancer', 'Phenotype', 'HP:0100526', (117, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('RASSF1', 'Gene', '11186', (32, 38))	('Lung cancer', 'Disease', (117, 128))	('cancer', 'Disease', (151, 157))	('cancer', 'Disease', (110, 116))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('L1RE1', 'Gene', (15, 20))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('lung cancer', 'Disease', (105, 116))	('cancer', 'Disease', (122, 128))	('L1RE1', 'Gene', '4029', (15, 20))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (110, 116))
466964	29851970	Epigenetic changes are frequently tissue-specific events in carcinogenesis and hence may serve as diagnostic biomarkers.	('carcinogenesis', 'Disease', (60, 74))	('carcinogenesis', 'Disease', 'MESH:D063646', (60, 74))	('Epigenetic changes', 'Var', (0, 18))
466970	29851970	L1RE1 methylation associated significantly with tumor type and grade (p<0.001) with highest methylation in the control group.	('tumor', 'Disease', (48, 53))	('associated', 'Reg', (18, 28))	('methylation', 'Var', (6, 17))	('L1RE1', 'Gene', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('L1RE1', 'Gene', '4029', (0, 5))
466973	29851970	Hypomethylation of L1RE1 is frequent in tumors compared to benign controls and associates with higher grade, whereas increasing methylation of RARB is an independent marker for tumors and higher grade.	('tumors', 'Phenotype', 'HP:0002664', (177, 183))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('tumors', 'Disease', 'MESH:D009369', (40, 46))	('Hypomethylation', 'Var', (0, 15))	('L1RE1', 'Gene', (19, 24))	('tumors', 'Disease', 'MESH:D009369', (177, 183))	('methylation', 'MPA', (128, 139))	('L1RE1', 'Gene', '4029', (19, 24))	('RARB', 'Gene', (143, 147))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumors', 'Disease', (177, 183))	('RARB', 'Gene', '5915', (143, 147))	('associates', 'Reg', (79, 89))	('tumors', 'Disease', (40, 46))	('higher', 'Disease', (95, 101))
466974	29851970	RASSF1 hypermethylation was frequent in tumors and most prominent in NET making it an auxiliary marker for separation of NSCLC and NET.	('hypermethylation', 'Var', (7, 23))	('NET', 'Phenotype', 'HP:0100634', (131, 134))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('tumors', 'Disease', 'MESH:D009369', (40, 46))	('NSCLC', 'Disease', (121, 126))	('RASSF1', 'Gene', '11186', (0, 6))	('NSCLC', 'Disease', 'MESH:D002289', (121, 126))	('frequent', 'Reg', (28, 36))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('NET', 'Phenotype', 'HP:0100634', (69, 72))	('SCLC', 'Phenotype', 'HP:0030357', (122, 126))	('RASSF1', 'Gene', (0, 6))	('tumors', 'Disease', (40, 46))	('NSCLC', 'Phenotype', 'HP:0030358', (121, 126))
466978	29851970	In cancer, a global hypomethylation of the cancer cell genome is prominent, but certain genes, particularly tumor suppressor genes, present with de novo methylation leading to transcriptional inactivation.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('genes', 'Gene', (88, 93))	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('cancer', 'Disease', (43, 49))	('transcriptional', 'MPA', (176, 191))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('tumor', 'Disease', (108, 113))	('cancer', 'Disease', (3, 9))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('methylation', 'Var', (153, 164))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
466979	29851970	Furthermore, aberrant methylation is an early event in carcinogenesis and considered as one of the possible alterations that underlie the hallmarks of cancer.	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('cancer', 'Disease', (151, 157))	('methylation', 'MPA', (22, 33))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('carcinogenesis', 'Disease', 'MESH:D063646', (55, 69))	('aberrant', 'Var', (13, 21))	('carcinogenesis', 'Disease', (55, 69))
466980	29851970	Therefore, gene-specific methylation changes and their assessment were considered as molecular markers for risk stratification, tumor detection, and as therapy targets.	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('methylation changes', 'Var', (25, 44))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumor', 'Disease', (128, 133))
466982	29851970	Hypermethylation of tumor suppressor genes such as CDKN2A, FHIT, and RARB were reported to correlate with prognosis in adenocarcinomas.	('CDKN2A', 'Gene', '1029', (51, 57))	('adenocarcinomas', 'Disease', 'MESH:D000230', (119, 134))	('RARB', 'Gene', (69, 73))	('adenocarcinomas', 'Disease', (119, 134))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('carcinomas', 'Phenotype', 'HP:0030731', (124, 134))	('Hypermethylation', 'Var', (0, 16))	('RARB', 'Gene', '5915', (69, 73))	('FHIT', 'Gene', (59, 63))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('FHIT', 'Gene', '2272', (59, 63))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('CDKN2A', 'Gene', (51, 57))	('correlate with', 'Reg', (91, 105))	('tumor', 'Disease', (20, 25))
466983	29851970	RASSF1 hypermethylation is another frequent event in lung cancer affecting approximately 60% of adenocarcinomas (ADC) and up to 100% of small cell lung carcinomas (SCLC).	('carcinoma', 'Phenotype', 'HP:0030731', (152, 161))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('RASSF1', 'Gene', '11186', (0, 6))	('small cell lung carcinomas', 'Phenotype', 'HP:0030357', (136, 162))	('lung cancer', 'Disease', (53, 64))	('RASSF1', 'Gene', (0, 6))	('hypermethylation', 'Var', (7, 23))	('SCLC', 'Phenotype', 'HP:0030357', (164, 168))	('small cell lung carcinomas', 'Disease', (136, 162))	('small cell lung carcinoma', 'Phenotype', 'HP:0030357', (136, 161))	('carcinomas', 'Phenotype', 'HP:0030731', (152, 162))	('SCLC', 'Gene', '7864', (164, 168))	('SCLC', 'Gene', (164, 168))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('lung cancer', 'Disease', 'MESH:D008175', (53, 64))	('adenocarcinomas', 'Disease', 'MESH:D000230', (96, 111))	('adenocarcinomas', 'Disease', (96, 111))	('small cell lung carcinomas', 'Disease', 'MESH:D055752', (136, 162))	('lung cancer', 'Phenotype', 'HP:0100526', (53, 64))	('carcinomas', 'Phenotype', 'HP:0030731', (101, 111))
466984	29851970	In contrast, hypomethylation of EFEMP1 was identified as independent prognostic marker of non-small cell lung carcinoma (NSCLC).	('hypomethylation', 'Var', (13, 28))	('EFEMP1', 'Gene', (32, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('non-small cell lung carcinoma', 'Disease', 'MESH:D002289', (90, 119))	('non-small cell lung carcinoma', 'Phenotype', 'HP:0030358', (90, 119))	('NSCLC', 'Disease', (121, 126))	('NSCLC', 'Disease', 'MESH:D002289', (121, 126))	('EFEMP1', 'Gene', '2202', (32, 38))	('non-small cell lung carcinoma', 'Disease', (90, 119))	('SCLC', 'Phenotype', 'HP:0030357', (122, 126))	('small cell lung carcinoma', 'Phenotype', 'HP:0030357', (94, 119))	('NSCLC', 'Phenotype', 'HP:0030358', (121, 126))
466985	29851970	Another potential methylation biomarker is L1RE1 (also known as LINE1), which is an autonomous transposable element in mammals and presents with hypomethylation in several cancers.	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('L1RE1', 'Gene', (43, 48))	('hypomethylation', 'Var', (145, 160))	('cancers', 'Disease', 'MESH:D009369', (172, 179))	('cancers', 'Phenotype', 'HP:0002664', (172, 179))	('L1RE1', 'Gene', '4029', (43, 48))	('cancers', 'Disease', (172, 179))
466987	29851970	Hypomethylation of L1RE1 associates with stronger transcriptional activity, higher retrotransposition and hence genetic instability.	('retrotransposition', 'CPA', (83, 101))	('Hypomethylation', 'Var', (0, 15))	('L1RE1', 'Gene', (19, 24))	('stronger', 'PosReg', (41, 49))	('genetic instability', 'CPA', (112, 131))	('L1RE1', 'Gene', '4029', (19, 24))	('transcriptional activity', 'MPA', (50, 74))	('higher', 'PosReg', (76, 82))
467023	29851970	L1RE1 was able to discriminate tumor samples and controls (p<0.001, Table 4) with a sensitivity of 88.8% and a specificity of 95%, when using a threshold of <78.5% methylation, as determined by ROC analysis.	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('methylation', 'Var', (164, 175))	('tumor', 'Disease', (31, 36))	('L1RE1', 'Gene', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('L1RE1', 'Gene', '4029', (0, 5))
467026	29851970	High-grade NET (LCNEC and SCLC) could be separated from ADC as well as SQCC with a sensitivity of 72.5% and a specificity of 89.5% at a threshold of >14.25% methylation.	('methylation', 'Var', (157, 168))	('ADC', 'Disease', (56, 59))	('NET', 'Phenotype', 'HP:0100634', (11, 14))	('SCLC', 'Gene', '7864', (26, 30))	('SCLC', 'Phenotype', 'HP:0030357', (26, 30))	('SCLC', 'Gene', (26, 30))
467031	29851970	Furthermore, according to the CART results the combination of L1RE1 and RARB was able to separate tumor and benign tissue with a failure rate of 1.4% (91% specificity and 100% sensitivity).	('combination', 'Var', (47, 58))	('L1RE1', 'Gene', (62, 67))	('L1RE1', 'Gene', '4029', (62, 67))	('RARB', 'Gene', (72, 76))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('CART', 'Gene', '9607', (30, 34))	('RARB', 'Gene', '5915', (72, 76))	('tumor', 'Disease', (98, 103))	('CART', 'Gene', (30, 34))
467048	29851970	L1RE1 hypermethylation was more prominent in benign compared to lung cancer samples.	('lung cancer', 'Disease', (64, 75))	('benign', 'Disease', (45, 51))	('lung cancer', 'Phenotype', 'HP:0100526', (64, 75))	('hypermethylation', 'Var', (6, 22))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('lung cancer', 'Disease', 'MESH:D008175', (64, 75))	('L1RE1', 'Gene', (0, 5))	('prominent', 'Reg', (32, 41))	('L1RE1', 'Gene', '4029', (0, 5))
467061	29851970	Hypomethylation of L1RE1 (also known as LINE1) was identified as a marker for aggressiveness in several cancers, which is confirmed by our data.	('aggressiveness', 'Disease', 'MESH:D001523', (78, 92))	('aggressiveness', 'Disease', (78, 92))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('Hypomethylation', 'Var', (0, 15))	('L1RE1', 'Gene', (19, 24))	('aggressiveness', 'Phenotype', 'HP:0000718', (78, 92))	('L1RE1', 'Gene', '4029', (19, 24))	('cancers', 'Phenotype', 'HP:0002664', (104, 111))	('cancers', 'Disease', (104, 111))	('cancers', 'Disease', 'MESH:D009369', (104, 111))
467063	29851970	L1RE1 is one of the most common transposons in mammals and has a major impact on gene organization and gene expression depending on its methylation status, and aberrant methylation is associated with higher genetic instability and more aggressive behavior of the respective tumor.	('impact', 'Reg', (71, 77))	('aggressive behavior', 'CPA', (236, 255))	('higher genetic instability', 'MPA', (200, 226))	('aberrant methylation', 'Var', (160, 180))	('tumor', 'Disease', 'MESH:D009369', (274, 279))	('aggressive behavior', 'Phenotype', 'HP:0000718', (236, 255))	('L1RE1', 'Gene', (0, 5))	('associated', 'Reg', (184, 194))	('tumor', 'Phenotype', 'HP:0002664', (274, 279))	('tumor', 'Disease', (274, 279))	('more', 'PosReg', (231, 235))	('L1RE1', 'Gene', '4029', (0, 5))
467065	29851970	With respect to our results, hypomethylation (<=78.5% methylation) of L1RE1 is frequent in lung cancer and can separate tumor from benign tissue with high specificity (95.5%) and sensitivity (88.8%), using CART.	('separate', 'Reg', (111, 119))	('lung cancer', 'Phenotype', 'HP:0100526', (91, 102))	('L1RE1', 'Gene', (70, 75))	('L1RE1', 'Gene', '4029', (70, 75))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('tumor', 'Disease', (120, 125))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('CART', 'Gene', '9607', (206, 210))	('lung cancer', 'Disease', 'MESH:D008175', (91, 102))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('frequent', 'Reg', (79, 87))	('hypomethylation', 'Var', (29, 44))	('CART', 'Gene', (206, 210))	('lung cancer', 'Disease', (91, 102))
467067	29851970	In our study, RASSF1 hypermethylation was mainly observed in NET of the lung and increased from low-grade TC to high-grade SCLC.	('hypermethylation', 'Var', (21, 37))	('RASSF1', 'Gene', (14, 20))	('TC', 'Chemical', '-', (106, 108))	('NET', 'Phenotype', 'HP:0100634', (61, 64))	('observed', 'Reg', (49, 57))	('RASSF1', 'Gene', '11186', (14, 20))	('SCLC', 'Gene', (123, 127))	('increased', 'PosReg', (81, 90))	('SCLC', 'Gene', '7864', (123, 127))	('SCLC', 'Phenotype', 'HP:0030357', (123, 127))
467068	29851970	Interestingly, in the thyroid, another endocrine organ, RASSF1 promoter methylation was observed as an early event in follicular thyroid hyperplasia and it was suggested that it paves the way for thyroid tumorigenesis indicating a mechanism that might be specific for (neuro-)endocrine tumors.	('follicular thyroid hyperplasia', 'Disease', (118, 148))	('thyroid', 'Disease', (196, 203))	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('endocrine tumors', 'Disease', 'MESH:D004701', (276, 292))	('tumor', 'Disease', (286, 291))	('tumor', 'Phenotype', 'HP:0002664', (286, 291))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('tumors', 'Phenotype', 'HP:0002664', (286, 292))	('endocrine tumors', 'Disease', (276, 292))	('methylation', 'Var', (72, 83))	('tumor', 'Disease', (204, 209))	('RASSF1', 'Gene', '11186', (56, 62))	('tumor', 'Disease', 'MESH:D009369', (286, 291))	('thyroid hyperplasia', 'Phenotype', 'HP:0008249', (129, 148))	('RASSF1', 'Gene', (56, 62))	('follicular thyroid hyperplasia', 'Disease', 'MESH:C572845', (118, 148))
467070	29851970	Besides, their results and ours indicate RASSF1 hypermethylation to be specific for NET of the lung.	('NET', 'Phenotype', 'HP:0100634', (84, 87))	('hypermethylation', 'Var', (48, 64))	('RASSF1', 'Gene', (41, 47))	('RASSF1', 'Gene', '11186', (41, 47))	('NET of the lung', 'Disease', (84, 99))
467071	29851970	RARB is an important tumor suppressor and loss of expression is associated with uncontrolled tumor growth and evasion of apoptosis in several tissues.	('associated', 'Reg', (64, 74))	('RARB', 'Gene', '5915', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Disease', (21, 26))	('RARB', 'Gene', (0, 4))	('tumor', 'Disease', (93, 98))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))	('evasion', 'CPA', (110, 117))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('loss of', 'Var', (42, 49))	('expression', 'MPA', (50, 60))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
467072	29851970	Furthermore, hypermethylation of RARB is linked to chemoresistance, therefore a clinical trial tested isotretinoin (13-cis-retinoic acid) as a therapeutic drug.	('linked', 'Reg', (41, 47))	('isotretinoin', 'Chemical', 'MESH:D015474', (102, 114))	('RARB', 'Gene', (33, 37))	('RARB', 'Gene', '5915', (33, 37))	('hypermethylation', 'Var', (13, 29))	('13-cis-retinoic acid', 'Chemical', 'MESH:D015474', (116, 136))	('chemoresistance', 'CPA', (51, 66))
467073	29851970	High RARB methylation may lead to lowered RARB expression sensitizing tumors for therapy with isotretinoin.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('RARB', 'Gene', '5915', (42, 46))	('lowered', 'NegReg', (34, 41))	('expression', 'MPA', (47, 57))	('RARB', 'Gene', (5, 9))	('tumors', 'Disease', (70, 76))	('tumors', 'Disease', 'MESH:D009369', (70, 76))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('methylation', 'Var', (10, 21))	('RARB', 'Gene', '5915', (5, 9))	('isotretinoin', 'Chemical', 'MESH:D015474', (94, 106))	('RARB', 'Gene', (42, 46))
467074	29851970	Isotretinoin was tested in comparison to a placebo and it was found that risk for second primary cancers was reduced significantly after 32 months of follow-up in the isotretinoin-arm as compared to placebo, indicating that isotretinoin could be a potent drug in these tumors.	('cancers', 'Phenotype', 'HP:0002664', (97, 104))	('primary cancers', 'Disease', 'MESH:D009369', (89, 104))	('tumor', 'Phenotype', 'HP:0002664', (269, 274))	('isotretinoin', 'Chemical', 'MESH:D015474', (167, 179))	('tumors', 'Phenotype', 'HP:0002664', (269, 275))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('tumors', 'Disease', (269, 275))	('isotretinoin', 'Chemical', 'MESH:D015474', (224, 236))	('tumors', 'Disease', 'MESH:D009369', (269, 275))	('reduced', 'NegReg', (109, 116))	('Isotretinoin', 'Chemical', 'MESH:D015474', (0, 12))	('isotretinoin-arm', 'Var', (167, 183))	('primary cancers', 'Disease', (89, 104))
467075	29851970	In our study, increasing RARB methylation was associated with more aggressive subtypes of lung cancer and also increased with tumor grade (both p<0.001).	('lung cancer', 'Disease', 'MESH:D008175', (90, 101))	('methylation', 'Var', (30, 41))	('increased', 'PosReg', (111, 120))	('RARB', 'Gene', '5915', (25, 29))	('lung cancer', 'Disease', (90, 101))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('lung cancer', 'Phenotype', 'HP:0100526', (90, 101))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('RARB', 'Gene', (25, 29))	('tumor', 'Disease', (126, 131))
467076	29851970	Inactivation of the tumor suppressors RARB and CDKN2A was identified as crucial hallmark of tumor development and maintenance in distinct tumor types and loss of CDKN2A is expected to have a similar effect as loss of TP53 correlating with more aggressive tumors.	('aggressive tumors', 'Disease', (244, 261))	('RARB', 'Gene', '5915', (38, 42))	('TP53', 'Gene', '7157', (217, 221))	('tumor', 'Phenotype', 'HP:0002664', (255, 260))	('tumor', 'Disease', (138, 143))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('aggressive tumors', 'Disease', 'MESH:D001523', (244, 261))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('CDKN2A', 'Gene', (162, 168))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('crucial hallmark of tumor', 'Disease', (72, 97))	('Inactivation', 'Var', (0, 12))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('tumor', 'Disease', (255, 260))	('TP53', 'Gene', (217, 221))	('CDKN2A', 'Gene', (47, 53))	('CDKN2A', 'Gene', '1029', (162, 168))	('tumor', 'Disease', 'MESH:D009369', (255, 260))	('crucial hallmark of tumor', 'Disease', 'MESH:D009369', (72, 97))	('loss', 'Var', (154, 158))	('tumors', 'Phenotype', 'HP:0002664', (255, 261))	('CDKN2A', 'Gene', '1029', (47, 53))	('tumor', 'Disease', (92, 97))	('RARB', 'Gene', (38, 42))	('tumor', 'Disease', (20, 25))
467077	29851970	In the present study, CDKN2A methylation correlated with lymph node invasion, but overall methylation of CDKN2A was only minimal.	('methylation', 'Var', (29, 40))	('lymph node invasion', 'CPA', (57, 76))	('CDKN2A', 'Gene', (105, 111))	('CDKN2A', 'Gene', (22, 28))	('CDKN2A', 'Gene', '1029', (22, 28))	('CDKN2A', 'Gene', '1029', (105, 111))	('correlated', 'Reg', (41, 51))
467090	29851970	In conclusion, we have confirmed that aberrant promoter methylations of RASSF1, L1RE1, and RARB have the potential to separate lung tumors from benign tissue but are limited in their ability to diagnose specific subtypes.	('lung tumors', 'Disease', 'MESH:D008175', (127, 138))	('RASSF1', 'Gene', (72, 78))	('lung tumor', 'Phenotype', 'HP:0100526', (127, 137))	('L1RE1', 'Gene', (80, 85))	('L1RE1', 'Gene', '4029', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('lung tumors', 'Disease', (127, 138))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('lung tumors', 'Phenotype', 'HP:0100526', (127, 138))	('RASSF1', 'Gene', '11186', (72, 78))	('aberrant promoter methylations', 'Var', (38, 68))	('RARB', 'Gene', (91, 95))	('RARB', 'Gene', '5915', (91, 95))
467094	29285222	The overall 5-yr survival rate is approximately 50% when surgery, radiation, or both are employed as treatment options, but lymph node involvement greatly influences this estimate, by decreasing the survival rate by about 50%.	('men', 'Species', '9606', (142, 145))	('influences', 'Reg', (155, 165))	('lymph', 'Var', (124, 129))	('decreasing', 'NegReg', (184, 194))	('survival', 'MPA', (199, 207))	('men', 'Species', '9606', (106, 109))
467119	29285222	Muscle contraction (GO:0006936, enrichment ratio = 12.62, adjusted p-value = 1.94e-05) resulted to be the most significant Biological Process, according to WebGestalt analysis.	('men', 'Species', '9606', (38, 41))	('Muscle contraction', 'CPA', (0, 18))	('GO:0006936', 'Var', (20, 30))
467134	29285222	We noticed that two relevant genes: DSC2 (encoding desmocollin 2, involved in cell adhesion, GO:0007155), and KRT17 (encoding keratin 17, involved in morphogenesis of an epithelium, GO:0002009; signal transduction GO:0007165; epidermis development, GO:0008544; positive regulation of cell growth, GO:0030307) are highly expressed in oral squamous cell carcinoma cell line, while they are down regulated in specimens from patients with lymph node involvement.	('keratin 17', 'Gene', '3872', (126, 136))	('men', 'Species', '9606', (411, 414))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (333, 361))	('patients', 'Species', '9606', (421, 429))	('desmocollin 2', 'Gene', '1824', (51, 64))	('down regulated', 'NegReg', (388, 402))	('KRT17', 'Gene', '3872', (110, 115))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (338, 361))	('keratin 17', 'Gene', (126, 136))	('DSC2', 'Gene', (36, 40))	('men', 'Species', '9606', (453, 456))	('carcinoma', 'Phenotype', 'HP:0030731', (352, 361))	('GO:0030307', 'Var', (297, 307))	('KRT17', 'Gene', (110, 115))	('desmocollin 2', 'Gene', (51, 64))	('oral squamous cell carcinoma', 'Disease', (333, 361))	('men', 'Species', '9606', (243, 246))	('DSC2', 'Gene', '1824', (36, 40))
467138	29285222	Among the other, down-regulated genes in samples obtained from lymph node positive patients, we found that IGFBP2 (encoding insulin-like growth factor binding protein 2 and involved in regulation of cell growth, GO:0001558; regulation of insulin-like growth factor receptor signaling pathway, GO:0043567) and PTHLH (encoding parathyroid hormone-like hormone and involved in cell-cell signaling, GO:0007267; endoderm development, GO:0007492; positive regulation of cell proliferation, GO:0008284; negative regulation of cell proliferation, GO:0008285; epithelial cell differentiation, GO:0030855) are generally down-regulated also in OSCC cell line and in OSCC metastasis.	('insulin-like growth factor binding protein 2', 'Gene', (124, 168))	('insulin-like growth factor binding protein 2', 'Gene', '3485', (124, 168))	('insulin', 'Gene', (124, 131))	('insulin', 'Gene', '3630', (238, 245))	('men', 'Species', '9606', (423, 426))	('PTHLH', 'Gene', (309, 314))	('patients', 'Species', '9606', (83, 91))	('IGFBP2', 'Gene', '3485', (107, 113))	('down-regulated', 'NegReg', (610, 624))	('OSCC', 'Disease', (633, 637))	('GO:0008284', 'Var', (484, 494))	('OSCC', 'Disease', (655, 659))	('insulin', 'Gene', '3630', (124, 131))	('insulin', 'Gene', (238, 245))	('endoderm development', 'CPA', (407, 427))	('IGFBP2', 'Gene', (107, 113))	('parathyroid hormone-like hormone', 'Gene', '5744', (325, 357))	('PTHLH', 'Gene', '5744', (309, 314))	('parathyroid hormone-like hormone', 'Gene', (325, 357))
467161	29285222	Among the genes found down-regulated in the specimens obtained from lymph node positive patients, the NQO1 gene encodes the phase II drug-metabolizing enzyme NAD(P)H:quinine oxidoreductase 1 (NQO1) and is considered significant for susceptibility to general carcinogenesis, and the genomic mutation in NQO1 is frequently found in cancer of colon, bladder, lung and pediatric leukemia.	('found', 'Reg', (321, 326))	('NQO1', 'Gene', (102, 106))	('carcinogenesis', 'Disease', (258, 272))	('cancer of colon', 'Disease', (330, 345))	('bladder', 'Disease', (347, 354))	('men', 'Species', '9606', (49, 52))	('pediatric leukemia', 'Disease', 'MESH:D063766', (365, 383))	('pediatric leukemia', 'Disease', (365, 383))	('carcinogenesis', 'Disease', 'MESH:D063646', (258, 272))	('NQO1', 'Gene', '1728', (192, 196))	('NAD(P)H:quinine oxidoreductase 1', 'Gene', '1728', (158, 190))	('lung', 'Disease', (356, 360))	('down-regulated', 'NegReg', (22, 36))	('NQO1', 'Gene', (192, 196))	('NQO1', 'Gene', '1728', (302, 306))	('cancer of colon', 'Disease', 'MESH:D015179', (330, 345))	('cancer', 'Phenotype', 'HP:0002664', (330, 336))	('patients', 'Species', '9606', (88, 96))	('genomic mutation', 'Var', (282, 298))	('NQO1', 'Gene', '1728', (102, 106))	('leukemia', 'Phenotype', 'HP:0001909', (375, 383))	('NQO1', 'Gene', (302, 306))	('cancer of colon', 'Phenotype', 'HP:0100273', (330, 345))
467162	29285222	In addition, the genomic polymorphism in NQO1 is related to OSCC susceptibility, representing a genetic risk factor for OSCC carcinogenesis.	('OSCC carcinogenesis', 'Disease', 'MESH:D063646', (120, 139))	('OSCC susceptibility', 'Disease', (60, 79))	('genomic polymorphism', 'Var', (17, 37))	('OSCC carcinogenesis', 'Disease', (120, 139))	('NQO1', 'Gene', (41, 45))	('related', 'Reg', (49, 56))	('NQO1', 'Gene', '1728', (41, 45))
467186	29285222	Comparison with public resources was carried out by using GENEVESTIGATOR 4.0 and retrieving recalibrated expression data for published "oral mucosa" and "oral squamous cell carcinoma line" experiments (GEO accession numbers: GSE3526, GSE7307, GSE17913, GSE15101, GSE7307, GSE14905, GSE8056, GSE30999, GSE13355, GSE27280, GSE46239, GSE41664, GSE15101, GSE32924, GSE32473, GSE17539, GSE28914, GSE33169; GSE36133 for OSCC cell line SCC-4, SCC-9, SCC-15, SCC-25, BHY, BICR1 and HN).	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (154, 182))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (159, 182))	('SCC-15', 'CellLine', 'CVCL:1681', (443, 449))	('GSE41664', 'Var', (331, 339))	('GSE36133', 'Var', (401, 409))	('GSE8056', 'Var', (282, 289))	('carcinoma', 'Phenotype', 'HP:0030731', (173, 182))	('oral squamous cell carcinoma', 'Disease', (154, 182))	('GSE17539', 'Var', (371, 379))	('SCC-4', 'Gene', '23383', (429, 434))	('GSE32924', 'Var', (351, 359))	('GSE28914', 'Var', (381, 389))	('GSE27280', 'Var', (311, 319))	('SCC-4', 'Gene', (429, 434))	('SCC-9', 'CellLine', 'CVCL:1685', (436, 441))	('GSE33169; GSE36133', 'Var', (391, 409))	('men', 'Species', '9606', (195, 198))	('GSE32473', 'Var', (361, 369))
467194	34012728	Further analysis showed that four (cg07589773, cg10474350, cg13011388 and cg15208375 mapped to gene IKZF1, HOXA7, EFS and TSHZ3, respectively) of these 841 DMPs could form and establish a diagnostic model after stratified them with the corresponding normal blood samples and other common human cancers.	('cg07589773', 'Chemical', '-', (35, 45))	('cg15208375', 'Var', (74, 84))	('TSHZ3', 'Gene', (122, 127))	('IKZF1', 'Gene', (100, 105))	('cg15208375', 'Chemical', '-', (74, 84))	('EFS', 'Gene', '10278', (114, 117))	('TSHZ3', 'Gene', '57616', (122, 127))	('HOXA7', 'Gene', '3204', (107, 112))	('human', 'Species', '9606', (288, 293))	('EFS', 'Gene', (114, 117))	('cancers', 'Phenotype', 'HP:0002664', (294, 301))	('cancers', 'Disease', (294, 301))	('cg10474350', 'Chemical', '-', (47, 57))	('cg07589773', 'Var', (35, 45))	('cancer', 'Phenotype', 'HP:0002664', (294, 300))	('cg10474350', 'Var', (47, 57))	('IKZF1', 'Gene', '10320', (100, 105))	('cg13011388', 'Chemical', '-', (59, 69))	('cg13011388', 'Var', (59, 69))	('HOXA7', 'Gene', (107, 112))	('cancers', 'Disease', 'MESH:D009369', (294, 301))	('DMPs', 'Chemical', '-', (156, 160))
467200	34012728	Towards this end, assessment of epigenetic alterations in various human cancers showed a great potential as biomarkers in cancer early diagnosis; for example, detection of aberrant DNA methylation, one of the major forms in epigenetic alterations, had also been observed to associate with development of numerous human diseases, including cancer.	('human', 'Species', '9606', (313, 318))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('human', 'Species', '9606', (66, 71))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('aberrant DNA methylation', 'Var', (172, 196))	('cancer', 'Disease', (339, 345))	('cancer', 'Disease', 'MESH:D009369', (339, 345))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('associate', 'Reg', (274, 283))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('cancers', 'Disease', (72, 79))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('cancers', 'Disease', 'MESH:D009369', (72, 79))	('cancer', 'Phenotype', 'HP:0002664', (339, 345))	('cancer', 'Disease', (72, 78))
467201	34012728	Altered DNA methylation showed as an early step in transformation of metaplasia to dysplasia and neoplasia.	('neoplasia', 'Phenotype', 'HP:0002664', (97, 106))	('Altered', 'Var', (0, 7))	('neoplasia', 'Disease', 'MESH:D009369', (97, 106))	('metaplasia to dysplasia', 'Disease', (69, 92))	('metaplasia to dysplasia', 'Disease', 'MESH:D008679', (69, 92))	('methylation', 'Var', (12, 23))	('neoplasia', 'Disease', (97, 106))
467205	34012728	In ESCC, aberrantly methylated genes were significantly enriched in IL-10 anti-inflammatory signaling and cell communication pathway.	('IL-10', 'Gene', '3586', (68, 73))	('aberrantly methylated genes', 'Var', (9, 36))	('IL-10', 'Gene', (68, 73))	('ESCC', 'Disease', (3, 7))	('cell communication pathway', 'Pathway', (106, 132))
467206	34012728	Different from ESCC, several cancer-associated pathway genes were aberrantly methylated in EAC, including genes in the epithelial-mesenchymal transition (EMT), cell adhesion, Wingless and Int-1 (WNT), and Transforming growth factor (TGF) pathways.	('cancer', 'Disease', (29, 35))	('WNT', 'Gene', (195, 198))	('WNT', 'Gene', '7471', (195, 198))	('Int-1', 'Gene', (188, 193))	('Int-1', 'Gene', '7471', (188, 193))	('EAC', 'Disease', (91, 94))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('cell adhesion', 'CPA', (160, 173))	('EAC', 'Phenotype', 'HP:0011459', (91, 94))	('epithelial-mesenchymal transition', 'CPA', (119, 152))	('cancer', 'Disease', 'MESH:D009369', (29, 35))	('aberrantly methylated', 'Var', (66, 87))
467229	34012728	The majority of these DMPs were hypermethylated (90%), although their distribution had no distinct difference in TSS200 or TSS1500 (Fig.	('TSS1500', 'Var', (123, 130))	('hypermethylated', 'Var', (32, 47))	('DMPs', 'Chemical', '-', (22, 26))
467230	34012728	The number of the hypermethylated DMPs was reduced dramatically in "opensea", "shelves" and "shores" regions (Fig.	('DMPs', 'Chemical', '-', (34, 38))	('reduced', 'NegReg', (43, 50))	('DMPs', 'Protein', (34, 38))	('hypermethylated', 'Var', (18, 33))
467232	34012728	Moreover, 841 hypermethylated DMPs was reversely associated expression of 320 genes and 57 hypomethylated DMPs were negatively associated with expression of 43 genes based on Spearman correlation analysis of methylome and transcriptome data.	('expression', 'MPA', (60, 70))	('expression', 'MPA', (143, 153))	('DMPs', 'Chemical', '-', (106, 110))	('associated', 'Reg', (49, 59))	('DMPs', 'Chemical', '-', (30, 34))	('negatively', 'NegReg', (116, 126))	('hypermethylated', 'Var', (14, 29))
467234	34012728	After that, we screened hypermethylated DMPs between EAC and normal samples and excluded those with higher methylation levels in normal blood samples than in EAC tissues.	('EAC', 'Phenotype', 'HP:0011459', (53, 56))	('EAC', 'Phenotype', 'HP:0011459', (158, 161))	('hypermethylated', 'Var', (24, 39))	('DMPs', 'Protein', (40, 44))	('DMPs', 'Chemical', '-', (40, 44))
467235	34012728	We found a total of 834 hypermethylated DMPs, among which 649 CpGs also occurred in all six datasets, and heatmap of these 649 CpGs is shown in Fig.	('hypermethylated', 'Var', (24, 39))	('DMPs', 'Gene', (40, 44))	('DMPs', 'Chemical', '-', (40, 44))
467238	34012728	We then performed the binary logistic regression and LASSO methods and identified four CpGs to construct the risk score model (Table 1), in which we utilized the formula: The risk score = 2.186 x beta value of cg07589773 + 0.504 x beta value of cg10474350 + 1.550 x beta value of cg13011388 + 2.371 x beta value of cg15208375.	('cg07589773 + 0.504', 'Var', (210, 228))	('cg10474350', 'Chemical', '-', (245, 255))	('cg10474350 +', 'Var', (245, 257))	('cg15208375', 'Chemical', '-', (315, 325))	('cg15208375', 'Var', (315, 325))	('cg13011388 +', 'Var', (280, 292))	('cg07589773', 'Chemical', '-', (210, 220))	('cg13011388', 'Chemical', '-', (280, 290))
467245	34012728	We identified differential methylated CpGs and stratified by their gene expression and found a total of 841 hypermethylated DMPs with downregulated genes.	('DMPs', 'Chemical', '-', (124, 128))	('hypermethylated', 'Var', (108, 123))	('downregulated', 'NegReg', (134, 147))
467249	34012728	DNA methylation epigenetically modifies gene expression; thus, aberrant gene promoter methylation was associated with cancer development and progression.	('cancer', 'Disease', (118, 124))	('associated', 'Reg', (102, 112))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('progression', 'CPA', (141, 152))	('aberrant gene', 'Var', (63, 76))	('cancer', 'Disease', 'MESH:D009369', (118, 124))
467250	34012728	For example, the E3 ubiquitin-protein ligase CHFR showed to be required in maintenance of the antephase checkpoint that regulates cell cycle and was hypermethylated in EAC.	('E3 ubiquitin-protein ligase CHFR', 'Gene', '55743', (17, 49))	('regulates', 'Reg', (120, 129))	('EAC', 'Phenotype', 'HP:0011459', (168, 171))	('E3 ubiquitin-protein ligase CHFR', 'Gene', (17, 49))	('cell cycle', 'CPA', (130, 140))	('hypermethylated', 'Var', (149, 164))
467251	34012728	The promoters of glutathione peroxidase 7 (GPX7) and glutathione S-transferase Mu 2 (GSTM2) were reported to be frequently hypermethylated in 67% and 69% of EAC, respectively, expression of which was also reduced respectively.	('glutathione peroxidase 7', 'Gene', (17, 41))	('GSTM2', 'Gene', (85, 90))	('GPX7', 'Gene', (43, 47))	('glutathione S-transferase Mu 2', 'Gene', '2946', (53, 83))	('glutathione S-transferase Mu 2', 'Gene', (53, 83))	('EAC', 'Phenotype', 'HP:0011459', (157, 160))	('glutathione peroxidase 7', 'Gene', '2882', (17, 41))	('reduced', 'NegReg', (205, 212))	('hypermethylated', 'Var', (123, 138))	('GSTM2', 'Gene', '2946', (85, 90))	('expression', 'MPA', (176, 186))	('EAC', 'Disease', (157, 160))	('GPX7', 'Gene', '2882', (43, 47))
467252	34012728	Moreover, aberrant hypermethylation of the secreted frizzled-related protein 1 (SFRP1) promoter regions associated with reduced SFRP1 expression, which occurred in early EAC, while altered methylation in Eyes absent homolog 4 (EYA4) promoter occurred in esophageal mucosa metaplasia and Barrett's esophagus progression to EAC and hypermethylation of Runt-related transcription factor 3 (RUNX3) promoter was reported as an independent risk factor associated with Barrett's esophagus-related EAC development.	('Eyes absent homolog 4', 'Gene', (204, 225))	('SFRP1', 'Gene', (80, 85))	('Eyes absent', 'Phenotype', 'HP:0000528', (204, 215))	('SFRP1', 'Gene', (128, 133))	('RUNX3', 'Gene', (387, 392))	('EAC', 'Phenotype', 'HP:0011459', (490, 493))	('EYA4', 'Gene', (227, 231))	('EYA4', 'Gene', '2070', (227, 231))	('Runt-related transcription factor 3', 'Gene', '864', (350, 385))	('Runt-related transcription factor 3', 'Gene', (350, 385))	('secreted frizzled-related protein 1', 'Gene', (43, 78))	('reduced', 'NegReg', (120, 127))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (462, 481))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (287, 306))	('expression', 'MPA', (134, 144))	('hypermethylation', 'Var', (330, 346))	('EAC', 'Phenotype', 'HP:0011459', (322, 325))	('secreted frizzled-related protein 1', 'Gene', '6422', (43, 78))	('SFRP1', 'Gene', '6422', (80, 85))	('SFRP1', 'Gene', '6422', (128, 133))	('Eyes absent homolog 4', 'Gene', '2070', (204, 225))	('RUNX3', 'Gene', '864', (387, 392))	('EAC', 'Phenotype', 'HP:0011459', (170, 173))	('EAC development', 'Disease', (490, 505))
467255	34012728	Moreover, EFS protein acts as a scaffolding protein for cell signaling in the immune system and altered EFS expression was associated with cancer development.	('EFS', 'Gene', (10, 13))	('altered', 'Var', (96, 103))	('associated with', 'Reg', (123, 138))	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('EFS', 'Gene', (104, 107))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('EFS', 'Gene', '10278', (10, 13))	('expression', 'MPA', (108, 118))	('EFS', 'Gene', '10278', (104, 107))	('cancer', 'Disease', (139, 145))
467256	34012728	In addition, TSHZ3 controls breathing and has been identified as a critical region of the heterozygous deletions at 19q12-q13.11, in development of autism spectrum disorder symptoms.	('TSHZ3', 'Gene', '57616', (13, 18))	('autism spectrum disorder', 'Phenotype', 'HP:0000729', (148, 172))	('controls', 'Reg', (19, 27))	('autism', 'Phenotype', 'HP:0000717', (148, 154))	('autism spectrum disorder symptoms', 'Disease', (148, 181))	('deletions', 'Var', (103, 112))	('autism spectrum disorder symptoms', 'Disease', 'MESH:D051271', (148, 181))	('breathing', 'MPA', (28, 37))	('TSHZ3', 'Gene', (13, 18))
467261	34012728	Further study will validate and investigate the mechanisms underlying aberrant methylation in EAC tumorigenesis.	('aberrant methylation', 'Var', (70, 90))	('EAC', 'Disease', (94, 97))	('EAC', 'Phenotype', 'HP:0011459', (94, 97))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('methylation', 'Var', (79, 90))	('tumor', 'Disease', (98, 103))
467275	31797633	These datasets have a rich catalogue of molecular alterations that provide an opportunity to quantify and assess drug responses in patients within and across tumor types.	('patients', 'Species', '9606', (131, 139))	('tumor', 'Disease', (158, 163))	('alterations', 'Var', (50, 61))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))
467317	31797633	First, while our method of matching patient tumors with cell lines can be applied on any types of omics profiles, here we used Reverse Phase Protein Array (RPPA)-based functional proteomics data for two primary reasons: 1) this type of data can adequately capture downstream aberrations of proteins missed by (upstream) genomics and transcriptomics data; 2) aberrations in proteomic markers are more closely related to eventual clinical phenotypes or outcomes.	('tumors', 'Disease', (44, 50))	('tumors', 'Disease', 'MESH:D009369', (44, 50))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('aberrations', 'Var', (358, 369))	('related', 'Reg', (408, 415))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('patient', 'Species', '9606', (36, 43))
467332	31797633	H1623, the top matching cell line for LUSC patients, was derived from a metastatic NSCLC patient, and H1650 (ranked #2) has often been used to test the efficacy of gefitinib in inhibiting EGFR pathway.	('gefitinib', 'Chemical', 'MESH:D000077156', (164, 173))	('H1650', 'Var', (102, 107))	('inhibiting', 'NegReg', (177, 187))	('patient', 'Species', '9606', (89, 96))	('patient', 'Species', '9606', (43, 50))	('NSCLC', 'Disease', (83, 88))	('patients', 'Species', '9606', (43, 51))	('NSCLC', 'Disease', 'MESH:D002289', (83, 88))	('EGFR', 'Gene', '1956', (188, 192))	('EGFR', 'Gene', (188, 192))
467348	31797633	We found that the PIDS-Scores of LUSC patients to alectinib (beta = -1.50, adjusted P-value < 0.001) and CX-5461 (beta = -0.63, adjusted P-value = 0.007) are significantly associated with their survival data using a false discovery rate adjustment.	('CX-5461', 'Var', (105, 112))	('associated', 'Reg', (172, 182))	('alectinib', 'Chemical', 'MESH:C582670', (50, 59))	('patients', 'Species', '9606', (38, 46))
467365	32189968	Moreover, HIPK3 was significantly promoted cell proliferation and migration of ESCC cells.	('migration', 'CPA', (66, 75))	('ESCC', 'Disease', 'MESH:C562729', (79, 83))	('HIPK3', 'Var', (10, 15))	('promoted', 'PosReg', (34, 42))	('ESCC', 'Disease', (79, 83))	('cell proliferation', 'CPA', (43, 61))
467390	32189968	Many studies have shown that miRNA aberrant expression is closely related to the occurrence, development and prognosis of malignant tumors by regulating the expression of tumor suppressor genes and oncogenes.	('men', 'Species', '9606', (100, 103))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('expression', 'MPA', (157, 167))	('miR', 'Gene', (29, 32))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('malignant tumors', 'Disease', (122, 138))	('malignant tumors', 'Disease', 'MESH:D009369', (122, 138))	('miR', 'Gene', '751557', (29, 32))	('aberrant expression', 'Var', (35, 54))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('tumor', 'Disease', (132, 137))	('related', 'Reg', (66, 73))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', (171, 176))	('regulating', 'Reg', (142, 152))
467399	32189968	ESCC cell line (kyse-150, kyse-410, KYSE-510, ECA-109, EC-18 and TE-13) and normal immortalized cell line (NE1) were purchased from the Chinese Academy of Sciences Cell Bank (Shanghai, China).	('TE-13', 'CellLine', 'CVCL:4463', (65, 70))	('ESCC', 'Disease', 'MESH:C562729', (0, 4))	('KYSE-510', 'Var', (36, 44))	('kyse-410', 'Var', (26, 34))	('EC', 'Disease', 'MESH:D004938', (55, 57))	('NE1', 'CellLine', 'CVCL:E306', (107, 110))	('EC', 'Disease', 'MESH:D004938', (46, 48))	('ESCC', 'Disease', (0, 4))
467423	32189968	The overexpression of HIPK3 was positively correlated with late TNM stage, lymph node metastasis and tumor size, but not with other parameters such as age, gender, alcohol As shown in Figure 2A and B, HIPK3 expression was significantly changed after siRNA or LV-HIPK3 transfection, indicating a successful transfection.	('HIPK3', 'Gene', (22, 27))	('HIPK3', 'Gene', (201, 206))	('TNM', 'Gene', (64, 67))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('lymph node metastasis', 'CPA', (75, 96))	('alcohol', 'Chemical', 'MESH:D000438', (164, 171))	('changed', 'Reg', (236, 243))	('overexpression', 'PosReg', (4, 18))	('expression', 'MPA', (207, 217))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('TNM', 'Gene', '10178', (64, 67))	('LV-HIPK3 transfection', 'Var', (259, 280))
467433	32189968	In addition, as shown in Figure 3E, HIPK3 knockdown can significantly increase the expression level of miR-599 in TE-13 cells.	('expression level', 'MPA', (83, 99))	('increase', 'PosReg', (70, 78))	('HIPK3', 'Gene', (36, 41))	('TE-13', 'CellLine', 'CVCL:4463', (114, 119))	('miR-599', 'Var', (103, 110))	('knockdown', 'Var', (42, 51))
467434	32189968	HIPK3 knockdown can significantly up-regulate the expression level of miR-599 in TE-13 cells, while HIPK3 overexpression can significantly down-regulate the expression level of miR-599 in TE-13 cells.	('up-regulate', 'PosReg', (34, 45))	('TE-13', 'CellLine', 'CVCL:4463', (188, 193))	('HIPK3', 'Gene', (0, 5))	('expression level', 'MPA', (50, 66))	('miR-599', 'Gene', (70, 77))	('TE-13', 'CellLine', 'CVCL:4463', (81, 86))	('HIPK3', 'Gene', (100, 105))	('knockdown', 'Var', (6, 15))	('expression level', 'MPA', (157, 173))	('down-regulate', 'NegReg', (139, 152))
467435	32189968	Next the expression pattern of miR-599 in ESCC was analyzed.	('miR-599', 'Var', (31, 38))	('ESCC', 'Disease', (42, 46))	('ESCC', 'Disease', 'MESH:C562729', (42, 46))
467438	32189968	In summary, these results indicated that circHIPK3 may exert its biological function through miR-599.	('miR-599', 'Var', (93, 100))	('cir', 'Gene', (41, 44))	('cir', 'Gene', '9541', (41, 44))
467449	32189968	As shown in Figure 5E and F, HIPK3 knockdown inhibited c-MYC expression levels, while miR-559 mimics further increased c-MYC expression levels.	('knockdown', 'Var', (35, 44))	('HIPK3', 'Gene', (29, 34))	('miR-559', 'Gene', (86, 93))	('miR-559', 'Gene', '693144', (86, 93))	('c-MYC', 'Gene', (55, 60))	('c-MYC', 'Gene', '4609', (119, 124))	('c-MYC', 'Gene', '4609', (55, 60))	('inhibited', 'NegReg', (45, 54))	('increased', 'PosReg', (109, 118))	('c-MYC', 'Gene', (119, 124))
467453	32189968	In order to further determine the effect of HIPK3 on ESCC progression in vivo, ESCC cells transfected with si-HIPK3 or si-HIPK3/miR-599 agomir were injected subcutaneously into nude mice.	('si-HIPK3', 'Var', (107, 115))	('ESCC', 'Disease', (53, 57))	('ESCC', 'Disease', 'MESH:C562729', (79, 83))	('nude mice', 'Species', '10090', (177, 186))	('ESCC', 'Disease', (79, 83))	('si-HIPK3/miR-599', 'Var', (119, 135))	('ESCC', 'Disease', 'MESH:C562729', (53, 57))
467454	32189968	As shown in Figue 6A-C, the tumor size and tumor weight of the si-HIPK3 group were significantly lower compared with that in the control group.	('tumor', 'Disease', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('lower', 'NegReg', (97, 102))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('tumor', 'Disease', (43, 48))	('si-HIPK3', 'Var', (63, 71))
467455	32189968	In the miR-599 agomir treatment group, the tumor growth of si-HIPK3 transfected cells was further inhibited.	('inhibited', 'NegReg', (98, 107))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('miR-599', 'Gene', (7, 14))	('si-HIPK3', 'Var', (59, 67))	('tumor', 'Disease', (43, 48))	('men', 'Species', '9606', (27, 30))
467456	32189968	Furthermore, as shown in Figure 6D, HIPK3 silencing significantly inhibited c-MYC expression, while miR-599 agomir treatment further reduced c-MYC expression levels in tumors.	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('c-MYC', 'Gene', (76, 81))	('c-MYC', 'Gene', (141, 146))	('HIPK3', 'Gene', (36, 41))	('tumors', 'Disease', (168, 174))	('tumors', 'Disease', 'MESH:D009369', (168, 174))	('silencing', 'NegReg', (42, 51))	('c-MYC', 'Gene', '4609', (76, 81))	('inhibited', 'NegReg', (66, 75))	('c-MYC', 'Gene', '4609', (141, 146))	('reduced', 'NegReg', (133, 140))	('miR-599', 'Var', (100, 107))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('men', 'Species', '9606', (120, 123))
467470	32189968	The results of this study showed that the expression of HIPK3 in cancer tissues and cells was significantly lower than that in normal adjacent normal tissues and normal cells (P<0.05).Moreover, overexpression of HIPK3 was positively correlated with advanced TNM stage and tumor size, but not with other parameters such as age, gender, alcohol consumption, smoking history or differentiation status.HIPK3 silencing inhibited cell viability, promoted apoptosis and reduced cell migration and invasiveness, while HIPK3 overexpression can increase cell viability, inhibit cell apoptosis and increase cell migration and invasion.	('HIPK3', 'Gene', (510, 515))	('silencing', 'Var', (404, 413))	('invasion', 'CPA', (615, 623))	('cancer', 'Disease', (65, 71))	('invasiveness', 'Disease', (490, 502))	('tumor', 'Disease', (272, 277))	('TNM', 'Gene', '10178', (258, 261))	('cell migration', 'CPA', (471, 485))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('reduced', 'NegReg', (463, 470))	('tumor', 'Disease', 'MESH:D009369', (272, 277))	('TNM', 'Gene', (258, 261))	('invasiveness', 'Disease', 'MESH:D009361', (490, 502))	('status.HIPK3', 'Gene', (391, 403))	('inhibited', 'NegReg', (414, 423))	('inhibit', 'NegReg', (560, 567))	('apoptosis', 'CPA', (449, 458))	('promoted', 'PosReg', (440, 448))	('cell migration', 'CPA', (596, 610))	('increase', 'PosReg', (535, 543))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('tumor', 'Phenotype', 'HP:0002664', (272, 277))	('alcohol', 'Chemical', 'MESH:D000438', (335, 342))	('cell viability', 'CPA', (424, 438))	('cell viability', 'CPA', (544, 558))	('increase', 'PosReg', (587, 595))	('cell apoptosis', 'CPA', (568, 582))
467482	32189968	Here, for the first time, we identified MYC as a target of miR-599 and showed that the miR-599-MYC axis regulates cell proliferation and migration in ESCC.	('MYC', 'Gene', '4609', (95, 98))	('MYC', 'Gene', '4609', (40, 43))	('ESCC', 'Disease', (150, 154))	('migration', 'CPA', (137, 146))	('MYC', 'Gene', (95, 98))	('regulates', 'Reg', (104, 113))	('MYC', 'Gene', (40, 43))	('miR-599', 'Var', (59, 66))	('cell proliferation', 'CPA', (114, 132))	('ESCC', 'Disease', 'MESH:C562729', (150, 154))
467491	31349879	A statistical directly association between differential methylation probes (DMPs) and TMB level was observed in our cohort (r = 0.63, P value =0.0003) and this was confirmed by using TCGA NSCLC dataset (r = 0.43, P value =0.006).	('TMB level', 'MPA', (86, 95))	('differential', 'Var', (43, 55))	('NSCLC', 'Disease', 'MESH:D002289', (188, 193))	('TMB', 'Chemical', '-', (86, 89))	('NSCLC', 'Phenotype', 'HP:0030358', (188, 193))	('DMPs', 'Chemical', '-', (76, 80))	('NSCLC', 'Disease', (188, 193))
467492	31349879	Relatively high TMB group (n = 16, 7.5-13.9 mutations/Mb) harbors more differential DMPs while less in relatively low TMB group (n = 13, 1.1-2.4 mutations/Mb).	('DMPs', 'Chemical', '-', (84, 88))	('mutations/Mb', 'Var', (44, 56))	('TMB', 'Chemical', '-', (118, 121))	('TMB', 'Chemical', '-', (16, 19))	('differential DMPs', 'MPA', (71, 88))
467494	31349879	In addition, 437 genes show DNAm aberrance status in high TMB patient group and 99 have been reported as its association with lung cancer.	('TMB', 'Chemical', '-', (58, 61))	('patient', 'Species', '9606', (62, 69))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('lung cancer', 'Disease', (126, 137))	('lung cancer', 'Phenotype', 'HP:0100526', (126, 137))	('association', 'Interaction', (109, 120))	('lung cancer', 'Disease', 'MESH:D008175', (126, 137))	('DNAm aberrance status', 'Var', (28, 49))
467500	31349879	Traditional target therapies have been effective against target population but they often suffer rapid relapse, such as target therapies against EGFR mutations, EMLA4-ALK fusion, and ROS-1 rearrangement positive.	('EGFR', 'Gene', '1956', (145, 149))	('ROS-1', 'Gene', (183, 188))	('ALK', 'Gene', (167, 170))	('ROS-1', 'Gene', '6098', (183, 188))	('EGFR', 'Gene', (145, 149))	('mutations', 'Var', (150, 159))	('ALK', 'Gene', '238', (167, 170))
467505	31349879	In addition, PD-L1 expression, microsatellite instability and deficient mutation mismatch repair have been used as companion diagnostic biomarkers for ICI therapy.	('mutation', 'MPA', (72, 80))	('microsatellite instability', 'Var', (31, 57))	('expression', 'MPA', (19, 29))	('ICI', 'Disease', (151, 154))	('PD-L1', 'Gene', (13, 18))	('deficient', 'Var', (62, 71))	('PD-L1', 'Gene', '29126', (13, 18))
467508	31349879	Epigenetic modification, particularly DNA methylation (DNAm) has been linked to genomic instability, such as mutations in a DNA methyltransferase gene may cause chromosome instability in human and mouse, and the LINE-1 hypomethylation has been found to associate with global loss of imprinting, which induce chromosomal instability in colorectal cancer and head and neck squamous cell carcinoma.	('colorectal cancer', 'Disease', 'MESH:D015179', (335, 352))	('chromosome instability', 'MPA', (161, 183))	('neck squamous cell carcinoma', 'Disease', (366, 394))	('colorectal cancer', 'Disease', (335, 352))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (366, 394))	('chromosome instability', 'Phenotype', 'HP:0040012', (161, 183))	('mouse', 'Species', '10090', (197, 202))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (371, 394))	('chromosomal instability', 'Phenotype', 'HP:0040012', (308, 331))	('linked', 'Reg', (70, 76))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (357, 394))	('mutations', 'Var', (109, 118))	('cause', 'Reg', (155, 160))	('cancer', 'Phenotype', 'HP:0002664', (346, 352))	('colorectal cancer', 'Phenotype', 'HP:0003003', (335, 352))	('DNA', 'Gene', (124, 127))	('human', 'Species', '9606', (187, 192))	('loss', 'NegReg', (275, 279))	('carcinoma', 'Phenotype', 'HP:0030731', (385, 394))
467519	31349879	Briefly, variants in the tumor sample were initially and used as query in the control sample.	('variants', 'Var', (9, 17))	('tumor', 'Disease', (25, 30))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))
467522	31349879	TMB level is defined by two ways: one is as number of nonsynonymous coding somatic mutations (NOMs) per tumor, including single nucleotide variation (SNVs) and short insertion/deletion polymorphism (INDELs); the other is the number of mutations is proportion to the size of UCSC Refseq annotations (33.4 Mb).	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('single nucleotide variation', 'Var', (121, 148))	('TMB', 'Chemical', '-', (0, 3))	('short insertion/deletion polymorphism', 'Var', (160, 197))	('tumor', 'Disease', (104, 109))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
467536	31349879	GISTIC is a tool that identifies genes targeted by somatic copy-number alterations (SCNAs) that trigger cancer growth.	('trigger', 'PosReg', (96, 103))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('copy-number alterations', 'Var', (59, 82))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))
467543	31349879	The mean coverage is achieved at 167x, 161x in tumor samples and normal samples, respectively.	('tumor', 'Disease', (47, 52))	('161x', 'Var', (39, 43))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor', 'Disease', 'MESH:D009369', (47, 52))
467546	31349879	In order to further explore the relationship between DNAm and TMB, 13 relatively low (37-79 mutations or 1.1-2.4 mutations/Mb) and 16 relatively high (252-465 mutations or 7.5-13.9 mutations/Mb) TMB samples were selected for subsequent methylation level detection.	('TMB', 'Chemical', '-', (195, 198))	('TMB', 'Chemical', '-', (62, 65))	('252-465 mutations', 'Var', (151, 168))	('mutations', 'Var', (92, 101))
467550	31349879	Based on the methylation level of 865,918 sites, differential global methylation status (unpaired t test, P value < 0.001) was seen between high TMB group (median beta-value of 0.643) and its matched controls (median beta-value of 0.629), while 0.631 and 0.629 in low TMB group (Fig.	('TMB', 'Chemical', '-', (268, 271))	('high TMB', 'Var', (140, 148))	('methylation status', 'MPA', (69, 87))	('TMB', 'Chemical', '-', (145, 148))
467555	31349879	292121 significant DMPs with a BH-adjusted P-value below 0.05 were found while none in low TMB group.	('DMPs', 'Chemical', '-', (19, 23))	('DMPs', 'MPA', (19, 23))	('292121', 'Var', (0, 6))	('TMB', 'Chemical', '-', (91, 94))	('BH', 'Chemical', '-', (31, 33))
467556	31349879	Box plot analysis further shows that high TMB group (median TMB =343) harbors significantly more differential methylation locis (31,279~391,387, with median of 188,637) with  delta beta  > 0.2 than low TMB group (median TMB =62; 10,479~92,932, with median of 43,340) in Fig.	('TMB', 'Chemical', '-', (202, 205))	('TMB', 'Chemical', '-', (42, 45))	('TMB', 'Chemical', '-', (220, 223))	('methylation', 'MPA', (110, 121))	('delta beta  > 0.2', 'Var', (175, 192))	('TMB', 'Chemical', '-', (60, 63))
467571	31349879	CpG hypomethylation status has been reported to be related to genetic instabilities, and global hypomethylation in tumor indicates more genomic instabilities.	('global hypomethylation', 'Var', (89, 111))	('genetic instabilities', 'Disease', 'MESH:D030342', (62, 83))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumor', 'Disease', (115, 120))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('related', 'Reg', (51, 58))	('genetic instabilities', 'Disease', (62, 83))
467576	31349879	3a shows the top 6 DMPs (cg16732616/DMRTA2, cg26521404/HOXA9, cg20326647/intergenic region, cg02443967/TLL2, cg09792881/DMRTA2 and cg16928066/EMX1) as representives.	('DMPs', 'Chemical', '-', (19, 23))	('TLL2', 'Gene', (103, 107))	('EMX1', 'Gene', '2016', (142, 146))	('HOXA9', 'Gene', '3205', (55, 60))	('DMRTA2', 'Gene', '63950', (36, 42))	('DMRTA2', 'Gene', '63950', (120, 126))	('TLL2', 'Gene', '7093', (103, 107))	('cg20326647/intergenic', 'Var', (62, 83))	('DMRTA2', 'Gene', (36, 42))	('DMRTA2', 'Gene', (120, 126))	('EMX1', 'Gene', (142, 146))	('HOXA9', 'Gene', (55, 60))
467584	31349879	Recent studies had demonstrated that loss of TP53 function increased genomic instability.	('TP53', 'Gene', (45, 49))	('genomic instability', 'CPA', (69, 88))	('loss', 'Var', (37, 41))	('increased', 'PosReg', (59, 68))	('TP53', 'Gene', '7157', (45, 49))
467585	31349879	An important driver gene of Chinese NSCLCs, EGFR mutations, which are closely related to the efficacy of molecularly targeted therapy (EGFR TKIs), have been reported to negatively correlate with TMB value.	('mutations', 'Var', (49, 58))	('TMB', 'Chemical', '-', (195, 198))	('NSCLC', 'Phenotype', 'HP:0030358', (36, 41))	('EGFR', 'Gene', '1956', (135, 139))	('negatively', 'NegReg', (169, 179))	('NSCLC', 'Disease', (36, 41))	('EGFR', 'Gene', (135, 139))	('EGFR', 'Gene', (44, 48))	('TMB value', 'MPA', (195, 204))	('EGFR', 'Gene', '1956', (44, 48))	('NSCLC', 'Disease', 'MESH:D002289', (36, 41))
467586	31349879	Heatmap plot shows that frequently mutated genes such as TP53 gene, which tends to been enriched in high TMB group (top 30 samples, range: 139-465 NOMs) in lung cancer; EGFR mutants in low TMB (bottom 30 samples, range: 37-82 NOMs), and patients with co-existence of TP53 and EGFR mutations in the intermediate TMB level (median 29 samples, range: 83-136 NOMs) (Fig.	('mutants', 'Var', (174, 181))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('TMB', 'Chemical', '-', (105, 108))	('TMB', 'Chemical', '-', (189, 192))	('lung cancer', 'Disease', 'MESH:D008175', (156, 167))	('EGFR', 'Gene', '1956', (169, 173))	('EGFR', 'Gene', '1956', (276, 280))	('EGFR', 'Gene', (276, 280))	('TP53', 'Gene', '7157', (267, 271))	('mutations', 'Var', (281, 290))	('EGFR', 'Gene', (169, 173))	('TMB', 'Chemical', '-', (311, 314))	('TP53', 'Gene', '7157', (57, 61))	('TP53', 'Gene', (57, 61))	('lung cancer', 'Disease', (156, 167))	('lung cancer', 'Phenotype', 'HP:0100526', (156, 167))	('TP53', 'Gene', (267, 271))	('patients', 'Species', '9606', (237, 245))
467595	31349879	Since signature 4 is a well-known tobacco-related signature characterized by transcriptional strand bias in C > A mutations, it matches the phenotype of smoking-history among high TMB patients.	('patients', 'Species', '9606', (184, 192))	('mutations', 'Var', (114, 123))	('C > A', 'Gene', (108, 113))	('TMB', 'Chemical', '-', (180, 183))	('tobacco', 'Species', '4097', (34, 41))
467598	31349879	Interestingly, the frequency of TP53 and EGFR mutations between our cohort and TCGA cohort was different (TP53: Chinese 46%, TCGA 70%, EGFR; Chinese 39%, TCGA 17%) (Fig.	('EGFR', 'Gene', (41, 45))	('mutations', 'Var', (46, 55))	('TP53', 'Gene', '7157', (32, 36))	('EGFR', 'Gene', '1956', (135, 139))	('TP53', 'Gene', (32, 36))	('EGFR', 'Gene', (135, 139))	('EGFR', 'Gene', '1956', (41, 45))	('TP53', 'Gene', '7157', (106, 110))	('TP53', 'Gene', (106, 110))
467602	31349879	After further analysis, it indicates that TP53 mutations significantly affect TMB level in both Chinese NSCLCs between TP53+ and TP53- mutation group (unpaired t test, P value < 0.001) and TCGA LUAD/LUSC (unpaired t test, P value < 0.001) (Fig.	('LUSC', 'Phenotype', 'HP:0030359', (199, 203))	('TP53', 'Gene', '7157', (42, 46))	('NSCLC', 'Disease', (104, 109))	('TP53', 'Gene', (42, 46))	('mutations', 'Var', (47, 56))	('affect', 'Reg', (71, 77))	('TP53', 'Gene', '7157', (129, 133))	('TMB level', 'MPA', (78, 87))	('NSCLC', 'Disease', 'MESH:D002289', (104, 109))	('LUAD', 'Phenotype', 'HP:0030078', (194, 198))	('TP53', 'Gene', (129, 133))	('TP53', 'Gene', '7157', (119, 123))	('TMB', 'Chemical', '-', (78, 81))	('TP53', 'Gene', (119, 123))	('NSCLC', 'Phenotype', 'HP:0030358', (104, 109))
467611	31349879	To our knowledge, this is the first NSCLC cohort study to directly link the methylome alteration to TMB.	('TMB', 'Disease', (100, 103))	('TMB', 'Chemical', '-', (100, 103))	('NSCLC', 'Phenotype', 'HP:0030358', (36, 41))	('NSCLC', 'Disease', (36, 41))	('methylome', 'Var', (76, 85))	('NSCLC', 'Disease', 'MESH:D002289', (36, 41))
467617	31349879	Among these genes, an important cluster of genes with hypermethylated CpGs is HOX gene family and its hypermethylation status has been reported to be associated with the low expression of HOX in lung cancer.	('expression', 'MPA', (174, 184))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('lung cancer', 'Disease', (195, 206))	('hypermethylation status', 'Var', (102, 125))	('lung cancer', 'Phenotype', 'HP:0100526', (195, 206))	('HOX', 'Chemical', '-', (78, 81))	('HOX', 'Gene', (78, 81))	('lung cancer', 'Disease', 'MESH:D008175', (195, 206))	('HOX', 'Chemical', '-', (188, 191))
467629	31349879	For example, Chinese lung cancer patients tends to harbor a much higher frequency of EGFR mutations.	('EGFR', 'Gene', (85, 89))	('mutations', 'Var', (90, 99))	('patients', 'Species', '9606', (33, 41))	('lung cancer', 'Disease', (21, 32))	('lung cancer', 'Phenotype', 'HP:0100526', (21, 32))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('EGFR', 'Gene', '1956', (85, 89))	('lung cancer', 'Disease', 'MESH:D008175', (21, 32))
467630	31349879	It has also been observed that TMB is much lower in EGFR mutated patients both in our cohort and TCGA dataset and the presence of driver alterations may provide clinically useful predictors of response to anti-PD-1/anti-PD-L1 therapies.	('TMB', 'MPA', (31, 34))	('PD-L1', 'Gene', '29126', (220, 225))	('EGFR', 'Gene', '1956', (52, 56))	('EGFR', 'Gene', (52, 56))	('PD-1', 'Gene', (210, 214))	('TMB', 'Chemical', '-', (31, 34))	('PD-1', 'Gene', '5133', (210, 214))	('patients', 'Species', '9606', (65, 73))	('PD-L1', 'Gene', (220, 225))	('mutated', 'Var', (57, 64))	('clinical', 'Species', '191496', (161, 169))	('lower', 'NegReg', (43, 48))
467634	31349879	Our data also confirmed the association between TP53 mutations and high TMB levels in the Chinese and TCGA LUAD/LUSC, and the association between cigarette smoking and high TMB levels.	('TP53', 'Gene', '7157', (48, 52))	('LUAD', 'Phenotype', 'HP:0030078', (107, 111))	('TP53', 'Gene', (48, 52))	('mutations', 'Var', (53, 62))	('TMB', 'Chemical', '-', (173, 176))	('TMB', 'Chemical', '-', (72, 75))	('LUSC', 'Phenotype', 'HP:0030359', (112, 116))	('high TMB levels', 'MPA', (67, 82))
467693	31223315	The combination of mutational and protoplast fusion techniques is effective in increasing the amount of paclitaxel produced by endophytic fungi.	('mutational', 'Var', (19, 29))	('amount of paclitaxel produced', 'MPA', (94, 123))	('paclitaxel', 'Chemical', 'MESH:D017239', (104, 114))	('increasing', 'PosReg', (79, 89))
467705	31223315	The highest recorded concentration of paclitaxel extracted from E. coli was 570 mg/l, and this was achieved by optimizing the P450 expression of taxanes, combining different cross-reductases, and modifying the N-termini of different enzymes.	('cross-reductases', 'Disease', 'MESH:C537866', (174, 190))	('modifying', 'Var', (196, 205))	('cross-reductases', 'Disease', (174, 190))	('E. coli', 'Species', '562', (64, 71))	('P450', 'Enzyme', (126, 130))	('paclitaxel', 'Chemical', 'MESH:D017239', (38, 48))	('taxanes', 'Chemical', 'MESH:D043823', (145, 152))
467718	31223315	The apoptosis-inducing receptor CD95 (APO-1/Fas) plays a key role in apoptosis and is up-regulated with increasing RT25.	('APO-1', 'Gene', '355', (38, 43))	('CD95', 'Gene', (32, 36))	('up-regulated', 'PosReg', (86, 98))	('CD95', 'Gene', '355', (32, 36))	('RT25', 'Var', (115, 119))	('APO-1', 'Gene', (38, 43))
467734	31223315	In human cancers, tyrosine kinases of the epidermal growth factor receptor (EGFR) family are frequently mutated.	('cancers', 'Disease', 'MESH:D009369', (9, 16))	('cancers', 'Phenotype', 'HP:0002664', (9, 16))	('mutated', 'Var', (104, 111))	('cancers', 'Disease', (9, 16))	('human', 'Species', '9606', (3, 8))	('EGFR', 'Gene', '1956', (76, 80))	('epidermal growth factor receptor', 'Gene', (42, 74))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('EGFR', 'Gene', (76, 80))	('epidermal growth factor receptor', 'Gene', '1956', (42, 74))	('tyrosine kinases', 'Enzyme', (18, 34))
467777	27907906	Silencing Chemerin in senescent fibroblasts or the CCRL2 and GPR1 receptors in the SCL-1 cSCC cell line abrogates the Chemerin-mediated chemotaxis.	('GPR1', 'Gene', (61, 65))	('abrogates', 'NegReg', (104, 113))	('Chemerin', 'Gene', '5919', (118, 126))	('Chemerin', 'Gene', '5919', (10, 18))	('CCRL2', 'Gene', (51, 56))	('Chemerin-', 'Gene', (118, 127))	('Chemerin', 'Gene', (10, 18))	('cSCC', 'Phenotype', 'HP:0006739', (89, 93))	('Chemerin-', 'Gene', '5919', (118, 127))	('GPR1', 'Gene', '2825', (61, 65))	('Chemerin', 'Gene', (118, 126))	('Silencing', 'Var', (0, 9))	('CCRL2', 'Gene', '9034', (51, 56))	('SCL-1', 'CellLine', 'CVCL:A789', (83, 88))
467782	27907906	Mutations in the epidermal stem/progenitor cells affecting oncogenes like Ras or tumor suppressor genes such as p53 are frequently causal for cSCC initiation.	('cSCC', 'Disease', (142, 146))	('causal', 'Reg', (131, 137))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('Mutations', 'Var', (0, 9))	('p53', 'Gene', (112, 115))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('cSCC', 'Phenotype', 'HP:0006739', (142, 146))	('p53', 'Gene', '7157', (112, 115))	('tumor', 'Disease', (81, 86))
467796	27907906	Overexpression of Chemerin was linked to enhanced tumor angiogenesis and poor clinical outcome in oral squamous cell carcinoma (OSCC), and progression of esophageal squamous cell carcinoma (ESCC).	('Chemerin', 'Gene', '5919', (18, 26))	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('esophageal squamous cell carcinoma', 'Disease', (154, 188))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (103, 126))	('enhanced', 'PosReg', (41, 49))	('oral squamous cell carcinoma', 'Disease', (98, 126))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('Overexpression', 'Var', (0, 14))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (154, 188))	('carcinoma', 'Phenotype', 'HP:0030731', (179, 188))	('Chemerin', 'Gene', (18, 26))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (165, 188))	('tumor', 'Disease', (50, 55))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (98, 126))
467826	27907906	Two days after transfection, RARRES2 transcripts and Chemerin secretion dramatically decreased to less than 5% of the mock-treated fibroblasts as shown with qRT-PCR and ELISA (Figure 3E and 3F), respectively.	('RARRES2', 'Gene', (29, 36))	('Chemerin', 'Gene', (53, 61))	('decreased', 'NegReg', (85, 94))	('RARRES2', 'Gene', '5919', (29, 36))	('Chemerin', 'Gene', '5919', (53, 61))	('transcripts', 'MPA', (37, 48))	('transfection', 'Var', (15, 27))
467858	27907906	Next we addressed the question whether the inhibition of the MAPK pathway can suppress Chemerin- or SASP-mediated migration of cSCC tumor cells.	('inhibition', 'Var', (43, 53))	('SASP', 'Gene', (100, 104))	('SASP', 'Gene', '7295', (100, 104))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('Chemerin-', 'Gene', '5919', (87, 96))	('cSCC', 'Phenotype', 'HP:0006739', (127, 131))	('Chemerin-', 'Gene', (87, 96))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumor', 'Disease', (132, 137))	('cSCC', 'Disease', (127, 131))	('suppress', 'NegReg', (78, 86))
467859	27907906	Notably, the ERK1/2 inhibitor FR180204, and the JNK inhibitor SP600125, in a concentration-dependent manner, mitigated the ability of senescent CM to induce SCL-1 cell migration.	('FR180204', 'Chemical', 'MESH:C505241', (30, 38))	('JNK', 'Gene', (48, 51))	('induce', 'PosReg', (150, 156))	('ERK1/2', 'Gene', '5595;5594', (13, 19))	('JNK', 'Gene', '5599', (48, 51))	('SCL-1', 'CellLine', 'CVCL:A789', (157, 162))	('SCL-1 cell migration', 'CPA', (157, 177))	('SP600125', 'Chemical', 'MESH:C432165', (62, 70))	('mitigated', 'NegReg', (109, 118))	('FR180204', 'Var', (30, 38))	('ERK1/2', 'Gene', (13, 19))	('SP600125', 'Var', (62, 70))
467860	27907906	The SASP-mediated SCL-1 cell migration was almost completely abolished following treatment with 30 muM FR180204 and to a lesser extent with SP600125 (Figure 6C).	('FR180204', 'Var', (103, 111))	('SASP', 'Gene', (4, 8))	('muM', 'Gene', (99, 102))	('SASP', 'Gene', '7295', (4, 8))	('FR180204', 'Chemical', 'MESH:C505241', (103, 111))	('SP600125', 'Chemical', 'MESH:C432165', (140, 148))	('muM', 'Gene', '56925', (99, 102))	('abolished', 'NegReg', (61, 70))	('SP600125', 'Var', (140, 148))	('SCL-1', 'CellLine', 'CVCL:A789', (18, 23))
467862	27907906	A concentration of 10 muM FR180204 or SP600125 but not BIRB796 blocked the rh Chemerin-induced SCL-1 cell migration (> 70%) in comparison to control (Figure 6D), suggesting that Chemerin regulates the cSCC cell migration through ERK1/2 and JNK- but independently of the p38 MAPK pathway.	('SP600125', 'Var', (38, 46))	('p38', 'Gene', '5594', (270, 273))	('JNK', 'Gene', '5599', (240, 243))	('cSCC cell migration', 'CPA', (201, 220))	('SCL-1', 'CellLine', 'CVCL:A789', (95, 100))	('Chemerin-', 'Gene', '5919', (78, 87))	('regulates', 'Reg', (187, 196))	('FR180204', 'Chemical', 'MESH:C505241', (26, 34))	('SP600125', 'Chemical', 'MESH:C432165', (38, 46))	('BIRB796', 'Chemical', 'MESH:C452139', (55, 62))	('Chemerin', 'Gene', (78, 86))	('Chemerin', 'Gene', '5919', (78, 86))	('muM', 'Gene', '56925', (22, 25))	('p38', 'Gene', (270, 273))	('ERK1/2', 'Gene', (229, 235))	('FR180204', 'Var', (26, 34))	('ERK1/2', 'Gene', '5595;5594', (229, 235))	('muM', 'Gene', (22, 25))	('Chemerin', 'Gene', (178, 186))	('Chemerin-', 'Gene', (78, 87))	('Chemerin', 'Gene', '5919', (178, 186))	('JNK', 'Gene', (240, 243))	('cSCC', 'Phenotype', 'HP:0006739', (201, 205))
467870	27907906	Dysregulated expression of Chemerin has been correlated with tumor progression in glioma, squamous cell carcinoma of oral tongue, esophageal cancer and with tumor suppression in melanoma.	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('melanoma', 'Disease', 'MESH:D008545', (178, 186))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('esophageal cancer', 'Disease', 'MESH:D004938', (130, 147))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('squamous cell carcinoma of oral tongue', 'Phenotype', 'HP:0030413', (90, 128))	('Dysregulated', 'Var', (0, 12))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('glioma', 'Disease', (82, 88))	('squamous cell carcinoma of oral tongue', 'Disease', (90, 128))	('esophageal cancer', 'Disease', (130, 147))	('glioma', 'Disease', 'MESH:D005910', (82, 88))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('melanoma', 'Phenotype', 'HP:0002861', (178, 186))	('melanoma', 'Disease', (178, 186))	('squamous cell carcinoma of oral tongue', 'Disease', 'MESH:D002294', (90, 128))	('tumor', 'Disease', (157, 162))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (90, 113))	('glioma', 'Phenotype', 'HP:0009733', (82, 88))	('expression', 'MPA', (13, 23))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('Chemerin', 'Gene', (27, 35))	('Chemerin', 'Gene', '5919', (27, 35))	('tumor', 'Disease', (61, 66))	('correlated', 'Reg', (45, 55))
467879	27907906	Second, as to the functional consequences of senescence-associated Chemerin upregulation in old skin, we showed that rh Chemerin increased the directed cSCC cell migration; and silencing of Chemerin in senescent fibroblasts significantly reduced their potential to induce cSCC cell migration.	('Chemerin', 'Gene', (67, 75))	('Chemerin', 'Gene', (190, 198))	('cSCC', 'Phenotype', 'HP:0006739', (272, 276))	('induce cSCC cell migration', 'CPA', (265, 291))	('reduced', 'NegReg', (238, 245))	('Chemerin', 'Gene', '5919', (190, 198))	('increased', 'PosReg', (129, 138))	('Chemerin', 'Gene', (120, 128))	('silencing', 'Var', (177, 186))	('Chemerin', 'Gene', '5919', (67, 75))	('Chemerin', 'Gene', '5919', (120, 128))	('directed cSCC cell migration', 'CPA', (143, 171))	('cSCC', 'Phenotype', 'HP:0006739', (152, 156))
467881	27907906	Third, we showed that, in the absence of CMKLR1, both the CCRL2 and GPR1 receptors are required for Chemerin-mediated cSCC cell migration, as silencing of either receptors suppressed the migratory response of cSCC cells to a Chemerin gradient.	('silencing', 'Var', (142, 151))	('Chemerin', 'Gene', (225, 233))	('CCRL2', 'Gene', (58, 63))	('cSCC', 'Phenotype', 'HP:0006739', (118, 122))	('migratory response of cSCC cells', 'CPA', (187, 219))	('Chemerin', 'Gene', '5919', (225, 233))	('Chemerin-', 'Gene', '5919', (100, 109))	('cSCC', 'Phenotype', 'HP:0006739', (209, 213))	('suppressed', 'NegReg', (172, 182))	('Chemerin-', 'Gene', (100, 109))	('CCRL2', 'Gene', '9034', (58, 63))	('GPR1', 'Gene', '2825', (68, 72))	('Chemerin', 'Gene', (100, 108))	('CMKLR1', 'Gene', '1240', (41, 47))	('Chemerin', 'Gene', '5919', (100, 108))	('GPR1', 'Gene', (68, 72))	('CMKLR1', 'Gene', (41, 47))
467885	27907906	This notion is based on the finding that CCRL2 possesses an altered amino acid sequence (QRYLVFL in huCCRL2 and QRYRVSF in mCCRL2 instead of the conserved DRYLAIV motif) in the second intracellular loop which is essential for signal transduction.	('QRYLVFL', 'Var', (89, 96))	('CCRL2', 'Gene', (41, 46))	('CCRL2', 'Gene', '9034', (102, 107))	('CCRL2', 'Gene', '9034', (124, 129))	('CCRL2', 'Gene', (124, 129))	('altered', 'Reg', (60, 67))	('CCRL2', 'Gene', '9034', (41, 46))	('QRYRVSF', 'Var', (112, 119))	('CCRL2', 'Gene', (102, 107))
467892	27907906	Previously, Chemerin was shown to activate the p38 and ERK1/2 MAPK pathways in gastric cancer cells, and PI3K, Akt, and p38 in CMKLR1-expressing macrophages.	('gastric cancer', 'Disease', 'MESH:D013274', (79, 93))	('activate', 'PosReg', (34, 42))	('Akt', 'Gene', (111, 114))	('p38', 'Gene', '5594', (47, 50))	('CMKLR1', 'Gene', (127, 133))	('gastric cancer', 'Phenotype', 'HP:0012126', (79, 93))	('ERK1/2', 'Gene', (55, 61))	('ERK1/2', 'Gene', '5595;5594', (55, 61))	('Chemerin', 'Gene', '5919', (12, 20))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('p38', 'Gene', '5594', (120, 123))	('PI3K', 'Var', (105, 109))	('CMKLR1', 'Gene', '1240', (127, 133))	('gastric cancer', 'Disease', (79, 93))	('p38', 'Gene', (47, 50))	('p38', 'Gene', (120, 123))	('Akt', 'Gene', '207', (111, 114))	('Chemerin', 'Gene', (12, 20))
467918	27907906	Recombinant human (rh) Chemerin (#2324-CM/CF) and rh RANTES/CCL5 (#278-RN/CF) were purchased from R&D Systems (Minneapolis, MN, USA).	('RANTES', 'Gene', '6352', (53, 59))	('CCL5', 'Gene', '6352', (60, 64))	('Chemerin', 'Gene', (23, 31))	('MN', 'CellLine', 'CVCL:U508', (124, 126))	('#2324-CM/CF', 'Var', (33, 44))	('#278-RN/CF', 'Var', (66, 76))	('Chemerin', 'Gene', '5919', (23, 31))	('human', 'Species', '9606', (12, 17))	('CCL5', 'Gene', (60, 64))	('RANTES', 'Gene', (53, 59))
467926	27907906	Primary antibodies targeting the following proteins were used at indicated concentrations: Chemerin (#ab72965, 1:50, Abcam, Cambridge, UK), FSP-1 (#GTX62977, 1:200; GenetTex, Irvine, CA, USA), Cytokeratin (#M3515, 1:100, Dako, Bollschweil, Germany), CCRL2 (#ab136057, 1:100, Abcam).	('Chemerin', 'Gene', (91, 99))	('#ab72965', 'Var', (101, 109))	('#ab136057', 'Var', (257, 266))	('CCRL2', 'Gene', '9034', (250, 255))	('FSP-1', 'Gene', '51062', (140, 145))	('#M3515', 'Var', (206, 212))	('Chemerin', 'Gene', '5919', (91, 99))	('FSP-1', 'Gene', (140, 145))	('#GTX62977', 'Var', (147, 156))	('CCRL2', 'Gene', (250, 255))
467928	27907906	CCRL2, GPR1 and CMKLR1 cell surface expression was measured using APC-conjugated anti-CCRL2 (#FAB23501A, 1:100, R&D Systems), Alexa488-conjugated anti-GPR1 mAb (#bs-13509R-A488, 1:100, Bioss, Woburn, MA, USA) and PE-conjugated CMKLR1 (#FAB362P, 1:100, R&D systems) according to the manufacturer's recommendations.	('CCRL2', 'Gene', (0, 5))	('#FAB23501A', 'Var', (93, 103))	('GPR1', 'Gene', '2825', (7, 11))	('GPR1', 'Gene', (151, 155))	('GPR1', 'Gene', (7, 11))	('CCRL2', 'Gene', (86, 91))	('CMKLR1', 'Gene', (16, 22))	('CCRL2', 'Gene', '9034', (0, 5))	('CMKLR1', 'Gene', '1240', (16, 22))	('CCRL2', 'Gene', '9034', (86, 91))	('Alexa488', 'Chemical', '-', (126, 134))	('GPR1', 'Gene', '2825', (151, 155))	('CMKLR1', 'Gene', '1240', (227, 233))	('CMKLR1', 'Gene', (227, 233))
467933	27907906	Fibroblasts (1 x 105 cells/well) were transfected with four different silencing RNAs (siRNAs; 30 nM) against Chemerin (# GS5919, Qiagen, Supplementary Table S3) or scrambled control (#1027280, Qiagen) using Lipofectamine RNAi Max Transfection Reagent (#13778, Thermo Fisher Scientific, USA).	('Lipofectamine', 'Chemical', 'MESH:C086724', (207, 220))	('Chemerin', 'Gene', '5919', (109, 117))	('# GS5919', 'Var', (119, 127))	('Chemerin', 'Gene', (109, 117))
467947	27366943	Nonetheless, the extension and relevance of the MYC-PVT1 deregulation in tumorigenesis has not yet been systematically addressed.	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('MYC-PVT1', 'Gene', (48, 56))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Disease', (73, 78))	('MYC-PVT1', 'Gene', '4609;5820', (48, 56))	('deregulation', 'Var', (57, 69))
467950	27366943	PVT1 misregulation in KIRC is mostly associated to promoter hypomethylation rather than locus amplification.	('promoter hypomethylation', 'Var', (51, 75))	('PVT1', 'Gene', (0, 4))	('misregulation', 'Var', (5, 18))	('associated', 'Reg', (37, 47))	('PVT1', 'Gene', '5820', (0, 4))
467961	27366943	However, the extension and relevance of MYC and PVT1 alterations in tumorigenesis has not yet been thoroughly addressed.	('tumor', 'Disease', (68, 73))	('alterations', 'Var', (53, 64))	('PVT1', 'Gene', (48, 52))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('MYC', 'Gene', (40, 43))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('PVT1', 'Gene', '5820', (48, 52))
467965	27366943	Moreover, we found that PVT1 up-regulation in KIRC is the result of promoter hypomethylation rather than copy number amplification.	('PVT1', 'Gene', (24, 28))	('promoter hypomethylation', 'Var', (68, 92))	('PVT1', 'Gene', '5820', (24, 28))	('up-regulation', 'PosReg', (29, 42))
467967	27366943	We set out to investigate the impact of MYC-PVT1 deregulation in several cancers using multi-omics data for approximately 7000 patients from the TCGA (Table S1).	('cancers', 'Disease', (73, 80))	('MYC-PVT1', 'Gene', '4609;5820', (40, 48))	('deregulation', 'Var', (49, 61))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('patients', 'Species', '9606', (127, 135))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('MYC-PVT1', 'Gene', (40, 48))	('cancers', 'Disease', 'MESH:D009369', (73, 80))
467969	27366943	MYC-PVT1 locus amplification was widespread and present in over half of the patients for most tumor types (Figure S1A).	('MYC-PVT1', 'Gene', (0, 8))	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('patients', 'Species', '9606', (76, 84))	('amplification', 'Var', (15, 28))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Disease', (94, 99))	('MYC-PVT1', 'Gene', '4609;5820', (0, 8))
467980	27366943	Furthermore, supporting the impact of PVT1 in the clinical outcome of KIRC patients, we observed that high expression levels were significantly associated with neoplasm status after surgery and advanced clinical stage or metastasis (Fisher's Exact -test p-value < 0.05) (Figure 2D).	('associated with', 'Reg', (144, 159))	('high', 'Var', (102, 106))	('PVT1', 'Gene', (38, 42))	('patients', 'Species', '9606', (75, 83))	('metastasis', 'CPA', (221, 231))	('neoplasm', 'Disease', (160, 168))	('neoplasm', 'Phenotype', 'HP:0002664', (160, 168))	('PVT1', 'Gene', '5820', (38, 42))	('neoplasm', 'Disease', 'MESH:D009369', (160, 168))
467989	27366943	Further analysis revealed that most KIRC patients with PVT1 up-regulation also presented PVT1 promoter hypomethylation (Fisher's Exact -test p-value < 0.005, Figure 3C).	('up-regulation', 'PosReg', (60, 73))	('promoter', 'MPA', (94, 102))	('PVT1', 'Gene', (89, 93))	('hypomethylation', 'Var', (103, 118))	('patients', 'Species', '9606', (41, 49))	('PVT1', 'Gene', (55, 59))	('PVT1', 'Gene', '5820', (89, 93))	('PVT1', 'Gene', '5820', (55, 59))
467993	27366943	In general, PVT1 locus amplification contributed significantly for PVT1 misregulation in most cancer types (Figure 3F and S3E).	('PVT1', 'Gene', (67, 71))	('PVT1', 'Gene', '5820', (12, 16))	('PVT1', 'Gene', '5820', (67, 71))	('misregulation', 'Var', (72, 85))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('contributed', 'Reg', (37, 48))	('PVT1', 'Gene', (12, 16))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
467995	27366943	Overall, our results suggest that PVT1 misregulation in KIRC is the result of promoter hypomethylation.	('PVT1', 'Gene', (34, 38))	('PVT1', 'Gene', '5820', (34, 38))	('misregulation', 'Var', (39, 52))
467997	27366943	We found that patients with high PVT1 expression levels also showed a significant increase of MYC protein concentration for five cancers, including KIRC (Figure 4A).	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('cancers', 'Disease', 'MESH:D009369', (129, 136))	('cancers', 'Phenotype', 'HP:0002664', (129, 136))	('PVT1', 'Gene', '5820', (33, 37))	('cancers', 'Disease', (129, 136))	('expression levels', 'Var', (38, 55))	('increase', 'PosReg', (82, 90))	('high', 'Var', (28, 32))	('MYC protein concentration', 'MPA', (94, 119))	('PVT1', 'Gene', (33, 37))	('KIRC', 'Disease', (148, 152))	('patients', 'Species', '9606', (14, 22))
467998	27366943	Because MYC is an oncogenic transcription-factor we then explored whether MYC-PVT1 deregulation would impact genes responsive to MYC.	('MYC-PVT1', 'Gene', '4609;5820', (74, 82))	('deregulation', 'Var', (83, 95))	('genes responsive', 'MPA', (109, 125))	('impact', 'Reg', (102, 108))	('MYC-PVT1', 'Gene', (74, 82))
468001	27366943	Collectively, our results show that MYC-PVT1 misregulation appears to be an important predictor of poor prognosis in renal carcinoma.	('MYC-PVT1', 'Gene', '4609;5820', (36, 44))	('misregulation', 'Var', (45, 58))	('renal carcinoma', 'Disease', 'MESH:C538614', (117, 132))	('MYC-PVT1', 'Gene', (36, 44))	('renal carcinoma', 'Disease', (117, 132))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('renal carcinoma', 'Phenotype', 'HP:0005584', (117, 132))
468003	27366943	Our pan-cancer analysis using diverse multi-omics data revealed that KIRC is the malignancy for which MYC-PVT1 misregulation is most strongly associated with a poor overall survival.	('poor', 'NegReg', (160, 164))	('cancer', 'Disease', (8, 14))	('misregulation', 'Var', (111, 124))	('MYC-PVT1', 'Gene', '4609;5820', (102, 110))	('malignancy', 'Disease', 'MESH:D009369', (81, 91))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('KIRC', 'Disease', (69, 73))	('associated', 'Reg', (142, 152))	('overall survival', 'MPA', (165, 181))	('malignancy', 'Disease', (81, 91))	('MYC-PVT1', 'Gene', (102, 110))	('cancer', 'Disease', 'MESH:D009369', (8, 14))
468006	27366943	Hence, our results suggest that promoter hypomethylation is an important cause of PVT1 up-regulation in tumor patients lacking 8q24 locus amplification.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('up-regulation', 'PosReg', (87, 100))	('PVT1', 'Gene', (82, 86))	('tumor', 'Disease', (104, 109))	('PVT1', 'Gene', '5820', (82, 86))	('promoter hypomethylation', 'Var', (32, 56))	('patients', 'Species', '9606', (110, 118))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
468015	27366943	Inhibition of MYC is an attractive pharmacological approach for cancer treatment.	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('MYC', 'Protein', (14, 17))	('Inhibition', 'Var', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
468018	27366943	Since loss of PVT1 RNA in colon cancer cell line reduces MYC protein to more normal levels, inhibiting PVT1 could be a more accessible and feasible therapeutic strategy for renal cancer.	('MYC protein', 'Protein', (57, 68))	('renal cancer', 'Disease', 'MESH:D007680', (173, 185))	('loss', 'Var', (6, 10))	('reduces', 'NegReg', (49, 56))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('colon cancer', 'Phenotype', 'HP:0003003', (26, 38))	('PVT1', 'Gene', (103, 107))	('PVT1', 'Gene', (14, 18))	('colon cancer', 'Disease', 'MESH:D015179', (26, 38))	('colon cancer', 'Disease', (26, 38))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('renal cancer', 'Disease', (173, 185))	('PVT1', 'Gene', '5820', (14, 18))	('renal cancer', 'Phenotype', 'HP:0009726', (173, 185))	('PVT1', 'Gene', '5820', (103, 107))
468019	27366943	Modulation of lncRNAs functions have showed promising anticancer effects and expanded the development of lncRNA-based cancer therapies involving small interfering RNAs, antisense oligonucleotides, ribozymes and aptamers.	('Modulation', 'Var', (0, 10))	('cancer', 'Disease', (118, 124))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('oligonucleotides', 'Chemical', 'MESH:D009841', (179, 195))	('antisense oligonucleotides', 'Var', (169, 195))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('RNAs', 'Protein', (163, 167))	('small interfering', 'Var', (145, 162))	('cancer', 'Disease', (58, 64))	('cancer', 'Disease', 'MESH:D009369', (118, 124))
468025	27366943	RNA-seq and BS-seq data for HEK293 and KIRC cell lines were obtained from the GEO (http://www.ncbi.nlm.nih.gov/geo/, GSE68938, GSE51867, GSE64451, GSE44866).	('HEK293', 'CellLine', 'CVCL:0045', (28, 34))	('GSE64451', 'Var', (137, 145))	('GSE44866', 'Var', (147, 155))	('GSE51867', 'Var', (127, 135))	('GSE68938', 'Var', (117, 125))
468026	27366943	Putative magnitudes of variations were considered for linear models analysis, whereas to determine patients with locus gain or deletion values were resumed to -1 (loss) or 1 (gain).	('deletion', 'Var', (127, 135))	('patients', 'Species', '9606', (99, 107))	('gain', 'PosReg', (119, 123))
468043	27366943	The statistical significance of differences in MYC protein levels between patients with low and high PVT1 expression was assessed using Student's T-test.	('PVT1', 'Gene', '5820', (101, 105))	('low', 'NegReg', (88, 91))	('patients', 'Species', '9606', (74, 82))	('expression', 'MPA', (106, 116))	('high', 'Var', (96, 100))	('PVT1', 'Gene', (101, 105))	('MYC protein levels', 'MPA', (47, 65))
468051	24400102	Alterations in DNA methylation (DNAm) levels are among the earliest changes in human carcinogenesis, and hence offer novel strategies to identify individuals who might be at risk of developing such illnesses or individuals with early stage cancers.	('carcinogenesis', 'Disease', 'MESH:D063646', (85, 99))	('human', 'Species', '9606', (79, 84))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('Alterations', 'Var', (0, 11))	('carcinogenesis', 'Disease', (85, 99))	('cancers', 'Phenotype', 'HP:0002664', (240, 247))	('cancers', 'Disease', (240, 247))	('cancers', 'Disease', 'MESH:D009369', (240, 247))	('DNA methylation', 'MPA', (15, 30))
468056	24400102	We show that this measure associates significantly with overall survival outcome independent of known prognostic markers in several data sets and cancer types, and that groups of these significant gene-gene network interactions identify subnetwork modules, with a well-controlled false discovery rate.	('cancer', 'Disease', (146, 152))	('interactions', 'Var', (215, 227))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('overall', 'MPA', (56, 63))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))
468088	24400102	F5 is factor five, a protein of the coagulation system; its deficiency leads to predisposition for haemorrhage.	('haemorrhage', 'Disease', (99, 110))	('deficiency', 'Var', (60, 70))	('haemorrhage', 'Disease', 'MESH:D006470', (99, 110))
468116	24400102	The key point in this metazoan model is that, whereas the conventional model of tumourigenesis holds that proliferative characteristics acquired by cancers occur as a result of random genetic and epigenetic mutation, these archaic metazoan characteristics are present in humans all along, but lie dormant until they are released in cancer.	('tumour', 'Disease', (80, 86))	('cancer', 'Disease', (148, 154))	('cancers', 'Disease', 'MESH:D009369', (148, 155))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('cancer', 'Phenotype', 'HP:0002664', (332, 338))	('cancers', 'Phenotype', 'HP:0002664', (148, 155))	('cancers', 'Disease', (148, 155))	('epigenetic mutation', 'Var', (196, 215))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (332, 338))	('tumour', 'Phenotype', 'HP:0002664', (80, 86))	('cancer', 'Disease', (332, 338))	('tumour', 'Disease', 'MESH:D009369', (80, 86))	('humans', 'Species', '9606', (271, 277))
468153	24209638	Genetic changes that bring about HNSCC are usually a consequence of continued exposure to carcinogens associated with tobacco.	('HNSCC', 'Disease', (33, 38))	('Genetic changes', 'Var', (0, 15))	('tobacco', 'Species', '4097', (118, 125))
468228	24209638	Similar to other types of cancer, inactivation of p53 is an extremely common event in head and neck cancers, with mutant p53 status found in nearly 50% of the cases and commonly associated with poor prognosis.	('found', 'Reg', (132, 137))	('cancer', 'Disease', (26, 32))	('p53', 'Gene', '7157', (121, 124))	('mutant', 'Var', (114, 120))	('p53', 'Gene', (50, 53))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('p53', 'Gene', (121, 124))	('inactivation', 'Var', (34, 46))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('cancer', 'Disease', (100, 106))	('cancers', 'Phenotype', 'HP:0002664', (100, 107))	('neck cancers', 'Disease', (95, 107))	('head and neck cancers', 'Phenotype', 'HP:0012288', (86, 107))	('neck cancers', 'Disease', 'MESH:D006258', (95, 107))	('associated', 'Reg', (178, 188))	('head and neck cancer', 'Phenotype', 'HP:0012288', (86, 106))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('p53', 'Gene', '7157', (50, 53))
468288	32443727	Among six high-affinity IGFBPs, which are IGFBP-1 through 6, IGFBP-3 is the most extensively investigated IGFBP species with respect to its IGF/IGF-I receptor (IGF-IR)-independent biological actions beyond its endocrine/paracrine/autocrine role in modulating IGF action in cancer.	('IGF-IR', 'Gene', '3480', (160, 166))	('IGFBPs', 'Gene', (24, 30))	('cancer', 'Disease', (273, 279))	('cancer', 'Disease', 'MESH:D009369', (273, 279))	('IGFBPs', 'Gene', '3485;3486;16009;24484', (24, 30))	('IGF-I receptor', 'Gene', '3480', (144, 158))	('cancer', 'Phenotype', 'HP:0002664', (273, 279))	('IGF-I receptor', 'Gene', (144, 158))	('IGFBP-3', 'Var', (61, 68))	('IGF-IR', 'Gene', (160, 166))
468289	32443727	Disruption of IGFBP-3 at transcriptional and post-translational levels has been implicated in the pathophysiology of many different types of cancer including breast, prostate, and lung cancer.	('prostate', 'Disease', (166, 174))	('implicated', 'Reg', (80, 90))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('IGFBP-3', 'Gene', (14, 21))	('lung cancer', 'Disease', 'MESH:D008175', (180, 191))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('lung cancer', 'Disease', (180, 191))	('lung cancer', 'Phenotype', 'HP:0100526', (180, 191))	('breast', 'Disease', (158, 164))	('cancer', 'Disease', (185, 191))	('cancer', 'Disease', (141, 147))	('Disruption', 'Var', (0, 10))
468295	32443727	Dysregulation of the IGF system attributes to pathophysiology of a variety of human diseases such as cancer, diabetes, chronic inflammatory disease, and malnutrition.	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('malnutrition', 'Phenotype', 'HP:0004395', (153, 165))	('cancer', 'Disease', (101, 107))	('Dysregulation', 'Var', (0, 13))	('inflammatory disease', 'Disease', (127, 147))	('inflammatory disease', 'Disease', 'MESH:D007249', (127, 147))	('diabetes', 'Disease', (109, 117))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('diabetes', 'Disease', 'MESH:D003920', (109, 117))	('human', 'Species', '9606', (78, 83))	('malnutrition', 'Disease', (153, 165))
468324	32443727	Further studies using p53 mutants have revealed a link between p53's activation of IGFBP-3 transcription and its induction of apoptosis by showing that the mutants that lost the ability to activate IGFBP-3 could not induce apoptosis.	('transcription', 'MPA', (91, 104))	('p53', 'Gene', (63, 66))	('p53', 'Gene', '7157', (63, 66))	('IGFBP-3', 'Gene', (83, 90))	('p53', 'Gene', (22, 25))	('mutants', 'Var', (156, 163))	('apoptosis', 'CPA', (223, 232))	('mutants', 'Var', (26, 33))	('p53', 'Gene', '7157', (22, 25))	('activation', 'PosReg', (69, 79))
468325	32443727	Further research also demonstrated that the transfection of doxycycline-inducible p53 plasmids resulted in increased expression of p53 and IGFBP-3 and, subsequently, induced apoptosis in p53-negative PC-3 prostate cancer cells.	('induced', 'Reg', (166, 173))	('prostate cancer', 'Disease', (205, 220))	('transfection', 'Var', (44, 56))	('PC-3', 'CellLine', 'CVCL:0035', (200, 204))	('p53', 'Gene', (187, 190))	('increased', 'PosReg', (107, 116))	('expression', 'MPA', (117, 127))	('apoptosis', 'CPA', (174, 183))	('p53', 'Gene', (131, 134))	('p53', 'Gene', '7157', (187, 190))	('doxycycline', 'Chemical', 'MESH:D004318', (60, 71))	('prostate cancer', 'Disease', 'MESH:D011471', (205, 220))	('p53', 'Gene', '7157', (131, 134))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('IGFBP-3', 'Gene', (139, 146))	('p53', 'Gene', (82, 85))	('p53', 'Gene', '7157', (82, 85))	('prostate cancer', 'Phenotype', 'HP:0012125', (205, 220))
468326	32443727	This p53-depedent induction of apoptosis was inhibited by treating with IGF-I, IGFBP-3 blocking antibodies, and IGFBP-3 antisense oligonucleotides, which demonstrated p53-dependent IGFBP-3's proapoptotic function.	('inhibited', 'NegReg', (45, 54))	('IGFBP-3', 'Gene', (79, 86))	('oligonucleotides', 'Chemical', 'MESH:D009841', (130, 146))	('IGF-I', 'Gene', '3479', (72, 77))	('p53', 'Gene', (5, 8))	('p53', 'Gene', '7157', (167, 170))	('p53', 'Gene', '7157', (5, 8))	('antisense oligonucleotides', 'Var', (120, 146))	('p53', 'Gene', (167, 170))	('IGF-I', 'Gene', (72, 77))	('IGFBP-3', 'Gene', (112, 119))	('apoptosis', 'CPA', (31, 40))
468328	32443727	It appears that DeltaNp63alpha binds the p53 binding sites, Box A and Box B, in the IGFBP-3 gene, and, thereby, inhibits p53-dependent IGFBP-3 expression and presumably suppresses IGFBP-3-induced apoptosis.	('suppresses', 'NegReg', (169, 179))	('p53', 'Gene', '7157', (41, 44))	('DeltaNp63alpha', 'Var', (16, 30))	('expression', 'MPA', (143, 153))	('p53', 'Gene', (121, 124))	('p53', 'Gene', '7157', (121, 124))	('IGFBP-3', 'Gene', (135, 142))	('IGFBP-3', 'Gene', (84, 91))	('inhibits', 'NegReg', (112, 120))	('p53', 'Gene', (41, 44))
468357	32443727	Humanin is a mitochondrial-derived peptide that inhibits neuronal cell death induced by mutant genes in Alzheimer's disease.	('Human', 'Species', '9606', (0, 5))	('death', 'Disease', 'MESH:D003643', (71, 76))	('death', 'Disease', (71, 76))	('mutant genes', 'Var', (88, 100))	('inhibits', 'NegReg', (48, 56))	("Alzheimer's disease", 'Disease', 'MESH:D000544', (104, 123))	("Alzheimer's disease", 'Phenotype', 'HP:0002511', (104, 123))	("Alzheimer's disease", 'Disease', (104, 123))
468379	32443727	However, recent studies also showed that IGFBP-3 mutants that failed to translocate to the nucleus and lost binding ability to RXR-alpha, still induced apoptosis in breast cancer cells.	('breast cancer', 'Disease', 'MESH:D001943', (165, 178))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('breast cancer', 'Disease', (165, 178))	('IGFBP-3', 'Gene', (41, 48))	('mutants', 'Var', (49, 56))	('breast cancer', 'Phenotype', 'HP:0003002', (165, 178))	('binding', 'Interaction', (108, 115))	('RXR-alpha', 'Gene', '6256', (127, 136))	('induced', 'Reg', (144, 151))	('apoptosis', 'CPA', (152, 161))	('RXR-alpha', 'Gene', (127, 136))
468393	32443727	Additionally, IGFBP-3R activates caspase-8-induced apoptosis in unconventional ways: (1) IGFBP-3R and inactive procaspase-8 is pre-complexed at the resting stage, and IGFBP-3 binding to IGFBP-3R releases procaspase-8, and, thereby, activates caspase-8-dependent apoptosis, and (2) IGFBP-3R complexes with procasepase-8 without involvement of a typical death domain (DD) sequence.	('binding', 'Interaction', (175, 182))	('releases', 'PosReg', (195, 203))	('caspase-8', 'Gene', (33, 42))	('caspase-8', 'Gene', (114, 123))	('activates', 'PosReg', (232, 241))	('caspase-8', 'Gene', (207, 216))	('caspase-8', 'Gene', '841', (242, 251))	('IGFBP-3', 'Var', (167, 174))	('caspase-8', 'Gene', '841', (207, 216))	('caspase-8', 'Gene', (242, 251))	('caspase-8', 'Gene', '841', (114, 123))	('caspase-8', 'Gene', '841', (33, 42))	('death', 'Disease', 'MESH:D003643', (352, 357))	('death', 'Disease', (352, 357))
468404	32443727	This inhibitory action of IGFBP-3 was IGF/IGF-IR-independent since the IGFBP-3 mutant devoid of IGF binding affinity had a similar inhibitory effect.	('IGF-IR', 'Gene', (42, 48))	('IGFBP-3', 'Gene', (71, 78))	('mutant', 'Var', (79, 85))	('IGF-IR', 'Gene', '3480', (42, 48))
468435	32443727	Survival in pan-kidney cohort (KICH+KIRC+KIRP), lower grade glioma, mesothelioma, colorectal adenocarcinoma was similarly affected by IGFBP-3 to a lesser extent (FDR = 1.74 10-6 (HR = 2.73), 1.25 10-5 (HR = 2.36), 1.22 10-3 (HR = 2.98), 3.87 10-3 (HR = 2.20), respectively) (Figure 6B,C).	('mesothelioma', 'Disease', (68, 80))	('colorectal adenocarcinoma', 'Disease', (82, 107))	('glioma', 'Disease', 'MESH:D005910', (60, 66))	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (82, 107))	('KICH+KIRC+KIRP', 'Disease', 'None', (31, 45))	('glioma', 'Phenotype', 'HP:0009733', (60, 66))	('affected', 'Reg', (122, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('mesothelioma', 'Disease', 'MESH:D008654', (68, 80))	('IGFBP-3', 'Var', (134, 141))	('glioma', 'Disease', (60, 66))	('KICH+KIRC+KIRP', 'Disease', (31, 45))
468438	32443727	Of note, the observed dichotomy of IGFBP-3 expression and patients' survival in various cancers may be attributed to other factors such as IGF-1/IGF-2 expression, IGFBP-3 polymorphism status, tumor suppressor p53 family status, tumor metabolic characteristics, and others.	('IGFBP-3', 'Gene', (35, 42))	('tumor', 'Disease', 'MESH:D009369', (228, 233))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('polymorphism', 'Var', (171, 183))	('IGF-1', 'Gene', (139, 144))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('cancers', 'Disease', (88, 95))	('IGF-1', 'Gene', '3479', (139, 144))	('tumor', 'Disease', (192, 197))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('patients', 'Species', '9606', (58, 66))	('p53', 'Gene', '7157', (209, 212))	('IGF-2', 'Gene', (145, 150))	('IGFBP-3', 'Gene', (163, 170))	('cancers', 'Disease', 'MESH:D009369', (88, 95))	('IGF-2', 'Gene', '3481', (145, 150))	('tumor', 'Disease', (228, 233))	('p53', 'Gene', (209, 212))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))
468453	32443727	Similar results were observed for clinical subgroups in mesothelioma, the pan-kidney cohort, rectum adenocarcinoma, colorectal adenocarcinoma, and colon adenocarcinoma cancers, where low expression of IGFBP-3 was similarly associated with better survival outcome.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('colon adenocarcinoma cancers', 'Disease', 'MESH:D015179', (147, 175))	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (116, 141))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('rectum adenocarcinoma', 'Disease', (93, 114))	('associated', 'Reg', (223, 233))	('colon adenocarcinoma cancers', 'Disease', (147, 175))	('IGFBP-3', 'Gene', (201, 208))	('cancers', 'Phenotype', 'HP:0002664', (168, 175))	('rectum adenocarcinoma', 'Disease', 'MESH:D012004', (93, 114))	('mesothelioma', 'Disease', (56, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (158, 167))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('low expression', 'Var', (183, 197))	('colorectal adenocarcinoma', 'Disease', (116, 141))	('mesothelioma', 'Disease', 'MESH:D008654', (56, 68))
468454	32443727	These results confirm previous observations that the expression of IGFBP-3 may affect survival in glioma, mesothelioma, kidney, and colorectal cancers.	('affect', 'Reg', (79, 85))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('mesothelioma', 'Disease', (106, 118))	('glioma', 'Disease', 'MESH:D005910', (98, 104))	('expression', 'Var', (53, 63))	('kidney', 'Disease', (120, 126))	('glioma', 'Phenotype', 'HP:0009733', (98, 104))	('cancers', 'Phenotype', 'HP:0002664', (143, 150))	('mesothelioma', 'Disease', 'MESH:D008654', (106, 118))	('colorectal cancers', 'Disease', 'MESH:D015179', (132, 150))	('survival', 'CPA', (86, 94))	('IGFBP-3', 'Gene', (67, 74))	('glioma', 'Disease', (98, 104))	('colorectal cancers', 'Disease', (132, 150))
468455	32443727	Further analyses of the effect of IGFBP-3 and TMEM219 expression in specific clinical subgroups revealed that kidney renal papillary cell carcinoma is the only cancer where the expression of both IGFBP-3 and TMEM219 is marginally associated with survival in "race-black or the African-American" subgroup.	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('kidney renal papillary cell carcinoma', 'Disease', 'MESH:C538614', (110, 147))	('cancer', 'Disease', (160, 166))	('associated', 'Reg', (230, 240))	('expression', 'Var', (177, 187))	('renal papillary cell carcinoma', 'Phenotype', 'HP:0006766', (117, 147))	('TMEM219', 'Gene', '124446', (46, 53))	('TMEM219', 'Gene', '124446', (208, 215))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('kidney renal papillary cell carcinoma', 'Disease', (110, 147))	('IGFBP-3', 'Gene', (196, 203))	('TMEM219', 'Gene', (46, 53))	('TMEM219', 'Gene', (208, 215))
468462	32443727	Of note were race-specific survival effects with high expression of IGFBP-3 being beneficial in the "race-black or African-American" subgroup (FDR = 2.01 10-1 (HR = 0.42), Figure 10E) and TMEM219 high expression being beneficial in the "race-Asian" subgroup (FDR = 1.16 10-1 (HR = 0.00), Figure 10D).	('TMEM219', 'Gene', (188, 195))	('high expression', 'Var', (49, 64))	('TMEM219', 'Gene', '124446', (188, 195))	('beneficial', 'PosReg', (82, 92))	('IGFBP-3', 'Gene', (68, 75))
468463	32443727	Confirming our previous observations, the survival benefits of IGFBP-3 expression in breast cancer were consistently associated with high IGFBP-3 expression, while the effect of TMEM219 was more diverse and subgroup-specific.	('breast cancer', 'Disease', 'MESH:D001943', (85, 98))	('IGFBP-3', 'Gene', (63, 70))	('TMEM219', 'Gene', (178, 185))	('breast cancer', 'Disease', (85, 98))	('high', 'Var', (133, 137))	('IGFBP-3', 'Gene', (138, 145))	('breast cancer', 'Phenotype', 'HP:0003002', (85, 98))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('TMEM219', 'Gene', '124446', (178, 185))	('expression', 'MPA', (146, 156))	('benefits', 'PosReg', (51, 59))	('high IGFBP', 'Phenotype', 'HP:0030269', (133, 143))
468469	32443727	Given the fact that IGFBP-3/IGFBP-3R (TMEM219) axis is impaired and shown to have great impact on the survival outcome in specific cancers, IGFBP-3 and TMEM219 may serve as new diagnostic and prognostic biomarkers in specific cancers.	('cancers', 'Disease', 'MESH:D009369', (131, 138))	('cancers', 'Phenotype', 'HP:0002664', (131, 138))	('impact', 'Reg', (88, 94))	('TMEM219', 'Gene', '124446', (38, 45))	('cancers', 'Disease', (131, 138))	('TMEM219', 'Gene', '124446', (152, 159))	('TMEM219', 'Gene', (38, 45))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('cancers', 'Phenotype', 'HP:0002664', (226, 233))	('cancers', 'Disease', (226, 233))	('cancers', 'Disease', 'MESH:D009369', (226, 233))	('IGFBP-3/IGFBP-3R', 'Gene', (20, 36))	('IGFBP-3', 'Var', (140, 147))	('TMEM219', 'Gene', (152, 159))	('impaired', 'NegReg', (55, 63))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
468483	32148378	The 10-year overall survival (OS), progression-free survival (PFS) and relapse-free survival (RFS) rates between high and low ORM expression groups in liver cancer patients were determined using the Kaplan-Meier plotter tool.	('high', 'Var', (113, 117))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('liver cancer', 'Phenotype', 'HP:0002896', (151, 163))	('liver cancer', 'Disease', 'MESH:D006528', (151, 163))	('ORM', 'Gene', (126, 129))	('low', 'NegReg', (122, 125))	('liver cancer', 'Disease', (151, 163))	('patients', 'Species', '9606', (164, 172))	('ORM', 'Gene', '5004', (126, 129))
468491	32148378	Moreover, apoptosis, IFN-alpha responses, IFN-gamma responses and humoral immune responses were upregulated in the ORM2 high group.	('IFN-gamma', 'Gene', '3458', (42, 51))	('IFN-gamma', 'Gene', (42, 51))	('high', 'Var', (120, 124))	('humoral immune responses', 'CPA', (66, 90))	('apoptosis', 'CPA', (10, 19))	('upregulated', 'PosReg', (96, 107))	('IFN-alpha', 'Gene', '3439', (21, 30))	('IFN-alpha', 'Gene', (21, 30))	('ORM2', 'Gene', (115, 119))
468527	32148378	GSE36376 contained 193 cases of non-tumor liver and 240 cases of liver tumor tissues, and GSE14520 contained 220 cases of non-tumor liver and 225 cases of liver tumor tissues.	('liver tumor', 'Disease', (65, 76))	('liver tumor', 'Phenotype', 'HP:0002896', (155, 166))	('tumor liver', 'Phenotype', 'HP:0002896', (36, 47))	('non-tumor liver', 'Disease', (32, 47))	('non-tumor liver', 'Disease', 'MESH:D008113', (122, 137))	('tumor liver', 'Phenotype', 'HP:0002896', (126, 137))	('GSE36376', 'Var', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('non-tumor liver', 'Disease', (122, 137))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('liver tumor', 'Disease', 'MESH:D008113', (155, 166))	('non-tumor liver', 'Disease', 'MESH:D008113', (32, 47))	('GSE14520', 'Var', (90, 98))	('liver tumor', 'Disease', (155, 166))	('liver tumor', 'Disease', 'MESH:D008113', (65, 76))	('liver tumor', 'Phenotype', 'HP:0002896', (65, 76))
468615	32148378	Furthermore, drug resistance could shorten the survival time of liver cancer patients.	('liver cancer', 'Disease', (64, 76))	('survival time', 'CPA', (47, 60))	('drug resistance', 'Phenotype', 'HP:0020174', (13, 28))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('drug resistance', 'Var', (13, 28))	('shorten', 'NegReg', (35, 42))	('patients', 'Species', '9606', (77, 85))	('liver cancer', 'Phenotype', 'HP:0002896', (64, 76))	('liver cancer', 'Disease', 'MESH:D006528', (64, 76))
468627	32148378	The high ORM2 expression group showed better survival rates in liver cancer patients upon OS, PFS and RFS analysis.	('patients', 'Species', '9606', (76, 84))	('liver cancer', 'Phenotype', 'HP:0002896', (63, 75))	('liver cancer', 'Disease', 'MESH:D006528', (63, 75))	('better', 'PosReg', (38, 44))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('liver cancer', 'Disease', (63, 75))	('high', 'Var', (4, 8))	('ORM2', 'Gene', (9, 13))	('survival rates', 'CPA', (45, 59))
468641	31061821	For example, anti-apoptotic BCL2 in chronic lymphocytic leukemia (CLL) and other cancers and BMI1 in gastric cancer as well as pancreatic cancer act as a stem cell marker and promoter of migration and invasion.	('pancreatic cancer', 'Disease', 'MESH:D010190', (127, 144))	('BCL2', 'Gene', '596', (28, 32))	('cancers', 'Phenotype', 'HP:0002664', (81, 88))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('gastric cancer', 'Phenotype', 'HP:0012126', (101, 115))	('leukemia', 'Phenotype', 'HP:0001909', (56, 64))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('invasion', 'CPA', (201, 209))	('pancreatic cancer', 'Disease', (127, 144))	('BCL2', 'Gene', (28, 32))	('BMI1', 'Gene', (93, 97))	('gastric cancer', 'Disease', (101, 115))	('anti-apoptotic', 'Var', (13, 27))	('migration', 'CPA', (187, 196))	('chronic lymphocytic leukemia', 'Disease', 'MESH:D015451', (36, 64))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (127, 144))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('chronic lymphocytic leukemia', 'Disease', (36, 64))	('gastric cancer', 'Disease', 'MESH:D013274', (101, 115))	('BMI1', 'Gene', '648', (93, 97))	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (36, 64))
468651	31061821	The results showed that although the probability of death in the low-expression group was 1.165 times higher than that in the high-expression group, there was no statistical difference (HR=1.165, 95%CI 0.95-1.44; P=0.150).	('low-expression', 'Var', (65, 79))	('death', 'Disease', 'MESH:D003643', (52, 57))	('death', 'Disease', (52, 57))
468652	31061821	However, in the survival analysis of a single cancer types, we found that low-expression miRNA-15a was significantly associated with worse OS in bladder Carcinoma (HR=1.49, 95%CI 1.11-2.00; P=0.0081), head-neck squamous cell carcinoma (HR=1.43, 95%CI 1.04-1.96; P=0.027), liver hepatocellular carcinoma (HR=1.54, 95%CI 1.08-2.22; P=0.017), lung squamous cell carcinoma (HR=1.69, 95%CI 1.22-2.38; P=0.0014), pancreatic ductal adenocarcinoma (HR=2.22, 95%CI 1.43-3.45; P=0.0002), rectum adenocarcinoma (HR=2.63, 95%CI 1.19-5.88; P=0.013), stomach adenocarcinoma (HR=1.52, 95%CI 1.10-2.08; P=0.011), and uterine corpus endometrial carcinoma (HR=1.69, 95%CI 1.10-2.63; P=0.015), whereas the results were opposite in cervical squamous cell carcinoma (HR=0.55, 95%CI 0.32-0.93; P=0.026) and esophageal carcinoma (HR=0.53, 95%CI 0.34-0.85; P=0.0072) (Figure 3).	('carcinoma', 'Phenotype', 'HP:0030731', (359, 368))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (407, 439))	('head-neck squamous cell carcinoma', 'Disease', (201, 234))	('bladder Carcinoma', 'Phenotype', 'HP:0002862', (145, 162))	('bladder Carcinoma (HR=1.49', 'Disease', 'MESH:D001749', (145, 171))	('carcinoma', 'Phenotype', 'HP:0030731', (430, 439))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (616, 637))	('miRNA-15a', 'Gene', (89, 98))	('pancreatic ductal adenocarcinoma', 'Disease', (407, 439))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (721, 744))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (785, 805))	('head-neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (201, 234))	('liver hepatocellular carcinoma', 'Disease', (272, 302))	('rectum adenocarcinoma', 'Disease', (478, 499))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (340, 368))	('stomach adenocarcinoma', 'Disease', (537, 559))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (211, 234))	('carcinoma', 'Phenotype', 'HP:0030731', (293, 302))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('uterine corpus endometrial carcinoma', 'Disease', (601, 637))	('Carcinoma', 'Phenotype', 'HP:0030731', (153, 162))	('carcinoma', 'Phenotype', 'HP:0030731', (490, 499))	('low-expression', 'Var', (74, 88))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (278, 302))	('carcinoma', 'Phenotype', 'HP:0030731', (225, 234))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (345, 368))	('lung squamous cell carcinoma', 'Disease', (340, 368))	('cervical squamous cell carcinoma', 'Disease', (712, 744))	('esophageal carcinoma', 'Disease', (785, 805))
468656	31061821	MiRNA-15a belongs to the miRNA-15 family, which is located on chromosome 13 (13q14) and consists of miRNA-15a/b, miRNA-16-1, miRNA-16-2, miRNA-497, and miRNA-195.	('miRNA-16-1', 'Gene', '406950', (113, 123))	('miRNA-15a/b', 'Var', (100, 111))	('miRNA-195', 'Gene', (152, 161))	('miRNA-195', 'Gene', '406971', (152, 161))	('miRNA-16-1', 'Gene', (113, 123))
468672	26937903	The presence of a positive UDT-Seq panel (n = 77) significantly improved risk stratification for all the survival endpoints as compared with traditional AJCC staging (P < 0.0001).	('risk stratification', 'MPA', (73, 92))	('UDT-Seq panel', 'Gene', (27, 40))	('UDT-Seq', 'Chemical', '-', (27, 34))	('presence', 'Var', (4, 12))	('improved', 'PosReg', (64, 72))
468727	26937903	The results demonstrated that the presence of a positive UDT-Seq panel (n = 77) significantly improved risk stratification with wider ranges of 4 subgroups in curves for 5-year distant metastases and survival rates seen with the use of the prognostic scoring system compared with the traditional AJCC staging (P < 0.0001).	('UDT-Seq', 'Chemical', '-', (57, 64))	('risk stratification', 'MPA', (103, 122))	('improved', 'PosReg', (94, 102))	('UDT-Seq panel', 'Gene', (57, 70))	('metastases', 'Disease', (185, 195))	('survival', 'CPA', (200, 208))	('metastases', 'Disease', 'MESH:D009362', (185, 195))	('presence', 'Var', (34, 42))
468728	26937903	The P values for the -2log likelihood tests (multivariate Cox regression models for predicting DFS) were 6.4 x 10-5, 1.1273 x 10-7, and 9.5195 x 10-11 for AJCC staging, pT3-4/ECS, and UDT-Seq/pT3-4/ECS, respectively.	('pT3', 'Gene', (169, 172))	('pT3', 'Gene', '7694', (192, 195))	('Cox', 'Gene', '1351', (58, 61))	('Cox', 'Gene', (58, 61))	('pT3', 'Gene', (192, 195))	('UDT-Seq', 'Chemical', '-', (184, 191))	('pT3', 'Gene', '7694', (169, 172))	('AJCC staging', 'Disease', (155, 167))	('1.1273', 'Var', (117, 123))
468734	26937903	Among pN+ patients who presented with p-Stage IV disease (n = 260), the presence of a positive UDT-Seq panel (n = 62) also significantly improved risk stratification for DFS and DSS as compared with traditional AJCC staging (P < 0.0001, Figure 4E and F).	('DFS', 'Disease', (170, 173))	('UDT-Seq', 'Chemical', '-', (95, 102))	('DSS', 'Chemical', '-', (178, 181))	('DSS', 'Disease', (178, 181))	('presence', 'Var', (72, 80))	('UDT-Seq panel', 'Gene', (95, 108))	('patients', 'Species', '9606', (10, 18))	('improved', 'PosReg', (137, 145))	('p-Stage', 'Disease', (38, 45))
468742	26937903	We also aimed at investigating whether UDT-Seq-identified genetic mutations might improve risk stratification beyond traditional clinicopathological RFs.	('risk stratification', 'MPA', (90, 109))	('UDT-Seq', 'Chemical', '-', (39, 46))	('improve', 'PosReg', (82, 89))	('genetic mutations', 'Var', (58, 75))
468743	26937903	Among the 45 genes submitted to UDT-Seq, we identified mutations in 10 genes as significantly associated with 5-year DFS.	('UDT-Seq', 'Chemical', '-', (32, 39))	('associated with', 'Reg', (94, 109))	('5-year DFS', 'Disease', (110, 120))	('mutations', 'Var', (55, 64))
468753	26937903	KIT mutations have been frequently reported in patients with primary adenoid cystic carcinoma of the salivary glands, but rarely in oral cavity cancer.	('carcinoma of the salivary glands', 'Phenotype', 'HP:0100684', (84, 116))	('primary adenoid cystic carcinoma of the salivary glands', 'Disease', 'MESH:D003528', (61, 116))	('reported', 'Reg', (35, 43))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('patients', 'Species', '9606', (47, 55))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('rarely in oral cavity cancer', 'Phenotype', 'HP:0100649', (122, 150))	('cancer', 'Disease', (144, 150))	('mutations', 'Var', (4, 13))	('KIT', 'Gene', (0, 3))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
468756	26937903	Although HRAS mutations are common in OSCC, BRAF gene mutations are generally found in approximately 3% of such tumors.	('tumors', 'Disease', 'MESH:D009369', (112, 118))	('BRAF', 'Gene', '673', (44, 48))	('found', 'Reg', (78, 83))	('HRAS', 'Gene', '3265', (9, 13))	('BRAF', 'Gene', (44, 48))	('mutations', 'Var', (54, 63))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('OSCC', 'Disease', (38, 42))	('HRAS', 'Gene', (9, 13))	('OS', 'Chemical', '-', (38, 40))	('mutations', 'Var', (14, 23))	('tumors', 'Disease', (112, 118))
468761	26937903	Moreover, PTEN genetic mutations have been shown to predict prognosis in patients with head-and-neck squamous cell carcinoma undergoing postoperative RT.	('genetic mutations', 'Var', (15, 32))	('PTEN', 'Gene', '5728', (10, 14))	('predict', 'Reg', (52, 59))	('neck squamous cell carcinoma', 'Disease', (96, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (101, 124))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (96, 124))	('head-and-neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (87, 124))	('patients', 'Species', '9606', (73, 81))	('PTEN', 'Gene', (10, 14))
468773	26937903	Importantly, the UDT-Seq-identified molecular mutations improved the prognostic stratification beyond that provided by traditional AJCC staging.	('mutations', 'Var', (46, 55))	('UDT-Seq-identified', 'Gene', (17, 35))	('UDT-Seq', 'Chemical', '-', (17, 24))	('improved', 'PosReg', (56, 64))	('prognostic stratification', 'MPA', (69, 94))
468779	25653693	The patient received adjuvant chemotherapy for a diagnosis of T0N1M0 lung cancer.	('lung cancer', 'Disease', 'MESH:D008175', (69, 80))	('patient', 'Species', '9606', (4, 11))	('T0N1M0', 'Var', (62, 68))	('lung cancer', 'Disease', (69, 80))	('lung cancer', 'Phenotype', 'HP:0100526', (69, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
468813	25653693	Because of the above reasons, intrathoracic lymph node with metastasis form a CUP are diagnosed and treated as T0N1M0 or T0N2M0 lung cancer.	('lung cancer', 'Disease', 'MESH:D008175', (128, 139))	('T0N1M0', 'Var', (111, 117))	('lung cancer', 'Disease', (128, 139))	('lung cancer', 'Phenotype', 'HP:0100526', (128, 139))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('T0N2M0', 'Var', (121, 127))
468823	24138928	Low age-acceleration of cancer tissue is associated with a high number of somatic mutations and TP53 mutations, while mutations in steroid receptors greatly accelerate DNA methylation age in breast cancer.	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('mutations', 'Var', (101, 110))	('TP53', 'Gene', (96, 100))	('cancer', 'Disease', (198, 204))	('accelerate', 'PosReg', (157, 167))	('breast cancer', 'Phenotype', 'HP:0003002', (191, 204))	('DNA methylation age', 'MPA', (168, 187))	('mutations', 'Var', (118, 127))	('cancer', 'Disease', (24, 30))	('cancer', 'Disease', 'MESH:D009369', (24, 30))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('breast cancer', 'Disease', (191, 204))	('breast cancer', 'Disease', 'MESH:D001943', (191, 204))	('TP53', 'Gene', '7157', (96, 100))
468863	24138928	Fourth, mutations in TP53 should be associated with a lower age acceleration of cancer tissue if one further assumes that p53 signaling helps trigger the EMS.	('TP53', 'Gene', (21, 25))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('mutations', 'Var', (8, 17))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('p53', 'Gene', (122, 125))	('TP53', 'Gene', '7157', (21, 25))	('cancer', 'Disease', (80, 86))	('p53', 'Gene', '7157', (122, 125))
468872	24138928	Specifically, a significant negative relationship between age acceleration and the number of somatic mutations can be observed in the following seven affected tissues/cancers: bone marrow (AML data from TCGA), breast carcinoma (BRCA data), kidney renal cell carcinoma (KIRC), kidney renal papillary cell carcinoma (KIRP), ovarian cancer (OVAR), prostate (PRAD), and thyroid (THCA).	('ovarian cancer', 'Disease', (322, 336))	('kidney renal papillary cell carcinoma', 'Disease', 'MESH:D007681', (276, 313))	('ovarian cancer', 'Phenotype', 'HP:0100615', (322, 336))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('breast carcinoma', 'Phenotype', 'HP:0003002', (210, 226))	('PR', 'Gene', '5241', (355, 357))	('BRCA', 'Disease', (228, 232))	('kidney renal cell carcinoma', 'Disease', 'MESH:D007674', (240, 267))	('breast carcinoma', 'Disease', (210, 226))	('cancers', 'Phenotype', 'HP:0002664', (167, 174))	('cancers', 'Disease', (167, 174))	('renal papillary cell carcinoma', 'Phenotype', 'HP:0006766', (283, 313))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (247, 267))	('bone marrow', 'Disease', (176, 187))	('BRCA', 'Disease', 'MESH:C537443', (228, 232))	('mutations', 'Var', (101, 110))	('AML', 'Disease', 'MESH:D015470', (189, 192))	('carcinoma', 'Phenotype', 'HP:0030731', (258, 267))	('AML', 'Disease', (189, 192))	('ovarian cancer', 'Disease', 'MESH:D010051', (322, 336))	('prostate', 'Disease', (345, 353))	('kidney renal papillary cell carcinoma', 'Disease', (276, 313))	('cancer', 'Phenotype', 'HP:0002664', (330, 336))	('carcinoma', 'Phenotype', 'HP:0030731', (304, 313))	('kidney renal cell carcinoma', 'Disease', (240, 267))	('breast carcinoma', 'Disease', 'MESH:D001943', (210, 226))	('cancers', 'Disease', 'MESH:D009369', (167, 174))	('thyroid', 'Disease', (366, 373))	('carcinoma', 'Phenotype', 'HP:0030731', (217, 226))
468875	24138928	Further, TP53 mutation is associated with significantly lower age acceleration in five different cancer types (Additional file 17), including AML (P = 0.0023), breast cancer (P = 1.4E-5 and P = 3.7E-8), ovarian cancer (P = 0.03), and uterine corpus endometrioid (P = 0.00093).	('cancer', 'Disease', (167, 173))	('TP53', 'Gene', '7157', (9, 13))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('ovarian cancer', 'Disease', (203, 217))	('ovarian cancer', 'Phenotype', 'HP:0100615', (203, 217))	('cancer', 'Disease', (97, 103))	('cancer', 'Disease', 'MESH:D009369', (211, 217))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('AML', 'Disease', 'MESH:D015470', (142, 145))	('uterine corpus endometrioid', 'Disease', (234, 261))	('AML', 'Disease', (142, 145))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('lower', 'NegReg', (56, 61))	('TP53', 'Gene', (9, 13))	('age', 'MPA', (62, 65))	('breast cancer', 'Phenotype', 'HP:0003002', (160, 173))	('cancer', 'Disease', 'MESH:D009369', (97, 103))	('cancer', 'Disease', (211, 217))	('ovarian cancer', 'Disease', 'MESH:D010051', (203, 217))	('mutation', 'Var', (14, 22))	('breast cancer', 'Disease', 'MESH:D001943', (160, 173))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('breast cancer', 'Disease', (160, 173))
468877	24138928	I could only find one cancer type (glioblastoma multiforme (GBM)) where mutations in TP53 are associated with a nominally significant increased age acceleration (P = 0.02; Figure 5H).	('TP53', 'Gene', (85, 89))	('mutations', 'Var', (72, 81))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (35, 58))	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('age', 'Disease', (144, 147))	('cancer', 'Disease', (22, 28))	('acceleration', 'PosReg', (148, 160))	('increased age acceleration', 'Phenotype', 'HP:0007495', (134, 160))	('glioblastoma multiforme', 'Disease', (35, 58))	('glioblastoma', 'Phenotype', 'HP:0012174', (35, 47))	('TP53', 'Gene', '7157', (85, 89))	('increased', 'PosReg', (134, 143))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))
468880	24138928	Somatic mutations in steroid receptors have a pronounced effect on DNAm age in breast cancer samples: samples with a mutated estrogen receptor (ER) or mutated progesterone receptor (PR) exhibit a much higher age acceleration than ER- or PR- samples in four independent data sets (Figure 8).	('ER', 'Gene', '2099', (144, 146))	('mutated', 'Var', (117, 124))	('mutated', 'Var', (151, 158))	('ER', 'Gene', '2099', (230, 232))	('breast cancer', 'Disease', 'MESH:D001943', (79, 92))	('age', 'MPA', (208, 211))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('progesterone receptor', 'Gene', (159, 180))	('breast cancer', 'Disease', (79, 92))	('progesterone receptor', 'Gene', '5241', (159, 180))	('estrogen receptor', 'Gene', '2099', (125, 142))	('breast cancer', 'Phenotype', 'HP:0003002', (79, 92))	('estrogen receptor', 'Gene', (125, 142))	('PR', 'Gene', '5241', (237, 239))	('PR', 'Gene', '5241', (182, 184))	('higher', 'PosReg', (201, 207))	('acceleration', 'PosReg', (212, 224))
468884	24138928	The lowest age acceleration can be observed for basal-like tumors (often triple negative ER-, PR-, HER2-) and HER2 type tumors (typically HER2+, ER-, PR-).	('tumors', 'Disease', (120, 126))	('tumors', 'Disease', 'MESH:D009369', (59, 65))	('PR', 'Gene', '5241', (150, 152))	('HER2', 'Gene', '2064', (110, 114))	('HER2', 'Gene', (138, 142))	('tumors', 'Disease', 'MESH:D009369', (120, 126))	('PR', 'Gene', '5241', (94, 96))	('ER', 'Gene', '2099', (111, 113))	('HER2', 'Gene', (99, 103))	('HER2 type tumors', 'Disease', (110, 126))	('ER', 'Gene', '2099', (100, 102))	('ER', 'Gene', '2099', (139, 141))	('basal-like tumors', 'Phenotype', 'HP:0002671', (48, 65))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('HER2', 'Gene', (110, 114))	('HER2 type tumors', 'Disease', 'MESH:D009369', (110, 126))	('HER2', 'Gene', '2064', (138, 142))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('ER', 'Gene', '2099', (145, 147))	('tumors', 'Disease', (59, 65))	('HER2', 'Gene', '2064', (99, 103))	('triple negative', 'Var', (73, 88))	('ER', 'Gene', '2099', (89, 91))
468886	24138928	Echoing previous results, TP53 mutations appear to be associated with decreased age acceleration (marginally significant P = 0.073; Figure 9B).	('TP53', 'Gene', (26, 30))	('mutations', 'Var', (31, 40))	('decreased', 'NegReg', (70, 79))	('TP53', 'Gene', '7157', (26, 30))	('age acceleration', 'CPA', (80, 96))
468887	24138928	Promoter hypermethylation of the mismatch repair gene MLH1 leads to the most significant increase in age acceleration (P = 5.7E-5; Figure 9D), which supports the EMS model of DNAm age.	('age acceleration', 'CPA', (101, 117))	('MLH1', 'Gene', '4292', (54, 58))	('MLH1', 'Gene', (54, 58))	('increase', 'PosReg', (89, 97))	('Promoter hypermethylation', 'Var', (0, 25))
468889	24138928	Interestingly, age acceleration in GBM samples is highly significantly (P = 3.3E-7; Figure 9J) associated with certain mutations in H3F3A, which encodes the replication-independent histone variant H3.3.	('H3F3A', 'Gene', '3020', (132, 137))	('acceleration', 'PosReg', (19, 31))	('mutations', 'Var', (119, 128))	('associated', 'Reg', (95, 105))	('H3F3A', 'Gene', (132, 137))
468890	24138928	These mutations are single-nucleotide variants changing lysine 27 to methionine (K27M) or changing glycine 34 to arginine (G34R).	('lysine 27', 'MPA', (56, 65))	('K27M', 'Mutation', 'p.K27M', (81, 85))	('changing', 'Reg', (47, 55))	('glycine 34 to arginine', 'MPA', (99, 121))	('glycine 34 to arginine', 'Mutation', 'rs1057519902', (99, 121))	('G34R', 'SUBSTITUTION', 'None', (123, 127))	('lysine 27 to methionine', 'Mutation', 'p.K27M', (56, 79))	('G34R', 'Var', (123, 127))
468891	24138928	The fact that GBMs with a G34R mutation in H3F3A have a much higher age acceleration than those with a K27M mutation (Figure 9J,L) makes sense since each H3F3A mutation defines an epigenetic subgroup of GBM with a distinct global methylation pattern and acts through a different set of genes.	('H3F3A', 'Gene', '3020', (154, 159))	('H3F3A', 'Gene', (43, 48))	('age acceleration', 'CPA', (68, 84))	('higher', 'PosReg', (61, 67))	('H3F3A', 'Gene', (154, 159))	('K27M', 'Mutation', 'p.K27M', (103, 107))	('G34R', 'SUBSTITUTION', 'None', (26, 30))	('H3F3A', 'Gene', '3020', (43, 48))	('G34R', 'Var', (26, 30))
468892	24138928	Lysine 27 is a critical residue of histone 3 variants, and methylation at this position (H3K27me), which may be mimicked by the terminal CH3 of methionine substituted at this residue, is commonly associated with transcriptional repression while H3K36 methylation or acetylation typically promotes gene transcription.	('H3K36', 'Protein', (245, 250))	('associated', 'Reg', (196, 206))	('variants', 'Var', (45, 53))	('transcriptional repression', 'MPA', (212, 238))	('methionine', 'Chemical', 'MESH:D008715', (144, 154))	('methylation', 'Var', (59, 70))	('acetylation', 'Var', (266, 277))	('Lysine', 'Chemical', 'MESH:D008239', (0, 6))	('gene transcription', 'MPA', (297, 315))	('promotes', 'PosReg', (288, 296))
468893	24138928	G34-mutant cells exhibit increased RNA polymerase II binding, and increased gene expression, most notably that of the oncogene MYCN.	('MYCN', 'Gene', '4613', (127, 131))	('increased', 'PosReg', (66, 75))	('increased', 'PosReg', (25, 34))	('RNA polymerase', 'Protein', (35, 49))	('G34-mutant', 'Var', (0, 10))	('gene expression', 'MPA', (76, 91))	('binding', 'Interaction', (53, 60))	('MYCN', 'Gene', (127, 131))
468894	24138928	Both H3F3A mutations are mutually exclusive with IDH1 mutations, which characterize a third mutation-defined subgroup.	('mutations', 'Var', (11, 20))	('IDH1', 'Gene', '3417', (49, 53))	('H3F3A', 'Gene', (5, 10))	('H3F3A', 'Gene', '3020', (5, 10))	('IDH1', 'Gene', (49, 53))
468895	24138928	Age acceleration in GBM samples is also associated with the following genomic aberrations: TP53 mutation, ATRX mutation, chromosome 7 gain, chromosome 10 loss, CDKN2A deletion, and EGFR amplification (Figure 9G-I).	('acceleration', 'PosReg', (4, 16))	('TP53', 'Gene', (91, 95))	('ATRX', 'Gene', (106, 110))	('mutation', 'Var', (111, 119))	('EGFR', 'Gene', (181, 185))	('CDKN2A', 'Gene', (160, 166))	('chromosome 10', 'Gene', (140, 153))	('mutation', 'Var', (96, 104))	('CDKN2A', 'Gene', '1029', (160, 166))	('ATRX', 'Gene', '546', (106, 110))	('deletion', 'Var', (167, 175))	('chromosome 7', 'Gene', (121, 133))	('TP53', 'Gene', '7157', (91, 95))	('loss', 'NegReg', (154, 158))	('EGFR', 'Gene', '1956', (181, 185))	('gain', 'PosReg', (134, 138))
468896	24138928	Mutations in IDH1 (similar to the case of GBM), FLT, RAS, NPMc, and various well characterized translocations do not seem to relate to age acceleration in AML samples (Figure 9S-W).	('AML', 'Disease', (155, 158))	('FLT', 'Gene', '2321', (48, 51))	('FLT', 'Gene', (48, 51))	('IDH1', 'Gene', (13, 17))	('Mutations', 'Var', (0, 9))	('IDH1', 'Gene', '3417', (13, 17))	('AML', 'Disease', 'MESH:D015470', (155, 158))
468909	24138928	Mutations in TP53 are associated with lower DNAm age.	('TP53', 'Gene', (13, 17))	('lower', 'NegReg', (38, 43))	('Mutations', 'Var', (0, 9))	('DNAm age', 'MPA', (44, 52))	('TP53', 'Gene', '7157', (13, 17))
468942	24138928	Toward this end, I used the occupancy counts of Suz12, Eed, and H3K27me3 published in.	('Eed', 'Gene', '8726', (55, 58))	('H3K27me3', 'Var', (64, 72))	('Eed', 'Gene', (55, 58))	('Suz12', 'Gene', (48, 53))	('Suz12', 'Gene', '23512', (48, 53))
468950	33299862	EZH2 was also highly expressed in lung cancers with positive KRAS expression, and the correlation was positive in lung adenocarcinoma (r = 0.3129 and p < 0.001).	('lung cancers', 'Disease', (34, 46))	('lung adenocarcinoma', 'Disease', (114, 133))	('cancers', 'Phenotype', 'HP:0002664', (39, 46))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('EZH2', 'Gene', (0, 4))	('lung cancer', 'Phenotype', 'HP:0100526', (34, 45))	('cancers', 'Disease', (39, 46))	('KRAS', 'Protein', (61, 65))	('cancers', 'Disease', 'MESH:D009369', (39, 46))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('lung cancers', 'Disease', 'MESH:D008175', (34, 46))	('lung cancers', 'Phenotype', 'HP:0100526', (34, 46))	('positive', 'Var', (52, 60))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (114, 133))
468957	33299862	We extracted from TCGA database from lung adenocarcinoma patients (among which 165 were nonsmokers and 361 were smokers) and lung squamous carcinoma patients (among which 86 were nonsmokers and 464 were smokers), 526 lung adenocarcinoma patients and 550 lung squamous carcinoma patients with EGFR expression, 585 lung adenocarcinoma patients and 550 lung squamous carcinoma patients with KRAS expression, and 527 lung adenocarcinoma patients and 502 lung squamous carcinoma patients with BRAF expression.	('lung squamous carcinoma', 'Phenotype', 'HP:0030359', (254, 277))	('lung squamous carcinoma', 'Disease', (350, 373))	('lung squamous carcinoma', 'Phenotype', 'HP:0030359', (125, 148))	('expression', 'Var', (297, 307))	('lung squamous carcinoma', 'Disease', 'MESH:D002294', (350, 373))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (130, 148))	('carcinoma', 'Phenotype', 'HP:0030731', (47, 56))	('lung squamous carcinoma', 'Phenotype', 'HP:0030359', (450, 473))	('carcinoma', 'Phenotype', 'HP:0030731', (268, 277))	('lung squamous carcinoma', 'Disease', (254, 277))	('lung squamous carcinoma', 'Disease', (125, 148))	('carcinoma', 'Phenotype', 'HP:0030731', (323, 332))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (455, 473))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (37, 56))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (217, 236))	('lung squamous carcinoma', 'Disease', 'MESH:D002294', (254, 277))	('lung squamous carcinoma', 'Disease', 'MESH:D002294', (125, 148))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (313, 332))	('carcinoma', 'Phenotype', 'HP:0030731', (227, 236))	('lung squamous carcinoma', 'Disease', (450, 473))	('lung squamous carcinoma', 'Phenotype', 'HP:0030359', (350, 373))	('carcinoma', 'Phenotype', 'HP:0030731', (139, 148))	('lung squamous carcinoma', 'Disease', 'MESH:D002294', (450, 473))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (355, 373))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (413, 432))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (259, 277))
468965	33299862	In an experiment, it was found that a lentivirus expressing shRNA mediated EZH2 gene knockdown, inhibiting the mRNA and protein expression levels of PD-L1, thereby delaying the progression of lung cancer in vivo by enhancing the antitumor immune response.	('PD-L1', 'Gene', (149, 154))	('enhancing', 'PosReg', (215, 224))	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('EZH2', 'Gene', (75, 79))	('lung cancer', 'Disease', (192, 203))	('lung cancer', 'Phenotype', 'HP:0100526', (192, 203))	('delaying', 'NegReg', (164, 172))	('PD-L1', 'Gene', '29126', (149, 154))	('inhibiting', 'NegReg', (96, 106))	('knockdown', 'Var', (85, 94))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('antitumor immune response', 'CPA', (229, 254))
468969	33299862	Studies have shown that exposure to tobacco smoke condensate induces increased the expression of EZH2 in cultured lung cancer cell lines, and DNA hypermethylation is a common risk factor for smoking behavior in NSCLC patients.	('tobacco', 'Species', '4097', (36, 43))	('increased', 'PosReg', (69, 78))	('NSCLC', 'Phenotype', 'HP:0030358', (211, 216))	('hypermethylation', 'Var', (146, 162))	('lung cancer', 'Phenotype', 'HP:0100526', (114, 125))	('expression', 'MPA', (83, 93))	('EZH2', 'Gene', (97, 101))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
468970	33299862	Previous research results indicate that RAS is a key downstream effector of epidermal growth factor receptor (EGFR), which is activated by mutation and/or overexpression in a variety of human cancers.	('mutation', 'Var', (139, 147))	('EGFR', 'Gene', (110, 114))	('cancers', 'Phenotype', 'HP:0002664', (192, 199))	('epidermal growth factor receptor', 'Gene', (76, 108))	('activated', 'PosReg', (126, 135))	('epidermal growth factor receptor', 'Gene', '1956', (76, 108))	('overexpression', 'PosReg', (155, 169))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))
468976	33299862	pointed out that EZH2 is the target of various types of deletions and mutations in bone marrow dysplasia (MDS), and EZH2 may play the role of an oncogene.	('mutations', 'Var', (70, 79))	('EZH2', 'Gene', (17, 21))	('bone marrow dysplasia', 'Disease', 'MESH:D001855', (83, 104))	('deletions', 'Var', (56, 65))	('bone marrow dysplasia', 'Disease', (83, 104))
468978	33299862	found that diffuse large B cell lymphomas based on EZH2 mutations and BCL2 translocation genetic subtypes have higher survival rates than other subtypes.	('lymphomas', 'Phenotype', 'HP:0002665', (32, 41))	('lymphoma', 'Phenotype', 'HP:0002665', (32, 40))	('mutations', 'Var', (56, 65))	('BCL2', 'Gene', '596', (70, 74))	('large B cell', 'Phenotype', 'HP:0005404', (19, 31))	('cell lymphoma', 'Phenotype', 'HP:0012191', (27, 40))	('EZH2', 'Gene', (51, 55))	('survival rates', 'CPA', (118, 132))	('B cell lymphoma', 'Phenotype', 'HP:0012191', (25, 40))	('lymphomas', 'Disease', (32, 41))	('BCL2', 'Gene', (70, 74))	('lymphomas', 'Disease', 'MESH:D008223', (32, 41))	('higher', 'PosReg', (111, 117))	('B cell lymphomas', 'Phenotype', 'HP:0012191', (25, 41))
469000	32777812	The study design was: 1) participants: patients with cervical cancer; 2)intervention: TV-CDFI detection and Adler grading; 3)comparison: no applicable; 4)outcomes: Adler secores and antigens CA125 and CA199.	('cervical cancer', 'Disease', (53, 68))	('CA199', 'Var', (201, 206))	('patients', 'Species', '9606', (39, 47))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('CA199', 'Chemical', '-', (201, 206))	('participants', 'Species', '9606', (25, 37))	('CA125', 'Gene', (191, 196))	('TV-CDFI', 'Chemical', '-', (86, 93))	('cervical cancer', 'Disease', 'MESH:D002583', (53, 68))	('CA125', 'Gene', '94025', (191, 196))
469018	32777812	As Table 2 showed, the cancer size differed significantly among the different Adler grades (p = 0.004), but there were no significantly differences in the level of CA125, CA199 among the different Adler grades (all p>0.05).	('CA125', 'Gene', '94025', (164, 169))	('CA199', 'Var', (171, 176))	('cancer', 'Disease', (23, 29))	('cancer', 'Disease', 'MESH:D009369', (23, 29))	('CA199', 'Chemical', '-', (171, 176))	('CA125', 'Gene', (164, 169))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))
469019	32777812	There were significant differences in the level of CA125, CA199 between the squamous cell carcinoma and adenocarcinoma (all p<0.05), no significant difference was found in the cancer size between the squamous cell carcinoma and adenocarcinoma (p = 0.143).	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('squamous cell carcinoma', 'Disease', (76, 99))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (200, 223))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('CA199', 'Chemical', '-', (58, 63))	('adenocarcinoma', 'Disease', 'MESH:D000230', (104, 118))	('adenocarcinoma', 'Disease', (228, 242))	('carcinoma', 'Phenotype', 'HP:0030731', (214, 223))	('squamous cell carcinoma', 'Disease', (200, 223))	('CA199', 'Var', (58, 63))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('CA125', 'Gene', (51, 56))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (76, 99))	('adenocarcinoma', 'Disease', 'MESH:D000230', (228, 242))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (200, 223))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (76, 99))	('CA125', 'Gene', '94025', (51, 56))	('adenocarcinoma', 'Disease', (104, 118))	('cancer', 'Disease', (176, 182))	('carcinoma', 'Phenotype', 'HP:0030731', (233, 242))
469020	32777812	No significant differences were found in the cancer size, CA125 and CA199 between the keratinized and no-keratinized squamous cell carcinoma (all p>0.05).	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (117, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('squamous cell carcinoma', 'Disease', (117, 140))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (117, 140))	('CA125', 'Gene', '94025', (58, 63))	('CA199', 'Var', (68, 73))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('CA199', 'Chemical', '-', (68, 73))	('cancer', 'Disease', (45, 51))	('CA125', 'Gene', (58, 63))
469040	32777812	Several studies have shown that cervical cancer is also closely related to the marker CA125 and CA199.	('cervical cancer', 'Disease', 'MESH:D002583', (32, 47))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('cervical cancer', 'Disease', (32, 47))	('CA199', 'Chemical', '-', (96, 101))	('CA125', 'Gene', '94025', (86, 91))	('CA199', 'Var', (96, 101))	('CA125', 'Gene', (86, 91))
469041	32777812	It has been reported that the carbohydrate antigens CA125 and CA199 are expressed at high levels in a variety of malignancies.	('carbohydrate', 'Chemical', 'MESH:D002241', (30, 42))	('malignancies', 'Disease', (113, 125))	('CA125', 'Gene', '94025', (52, 57))	('CA199', 'Var', (62, 67))	('CA199', 'Chemical', '-', (62, 67))	('CA125', 'Gene', (52, 57))	('malignancies', 'Disease', 'MESH:D009369', (113, 125))
469042	32777812	In this study, the levels of CA125 and CA199 in patients with adenocarcinoma were significantly higher than those in patients with squamous cell carcinoma.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (131, 154))	('CA199', 'Var', (39, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (145, 154))	('CA125', 'Gene', (29, 34))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (131, 154))	('CA199', 'Chemical', '-', (39, 44))	('squamous cell carcinoma', 'Disease', (131, 154))	('adenocarcinoma', 'Disease', 'MESH:D000230', (62, 76))	('adenocarcinoma', 'Disease', (62, 76))	('levels', 'MPA', (19, 25))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('CA125', 'Gene', '94025', (29, 34))	('patients', 'Species', '9606', (117, 125))	('higher', 'PosReg', (96, 102))	('patients', 'Species', '9606', (48, 56))
469043	32777812	Even through the Spearman correlation analysis shows that there is no correlation between Adler grade and CA125 and CA199, it may be explained that the samples in this present study is not large enough to powerfully detect the difference, future studies with larger population samples are warranted to identify the role of CA125 and CA199 in cervical cancer.	('CA125', 'Gene', '94025', (106, 111))	('cancer', 'Phenotype', 'HP:0002664', (351, 357))	('cervical cancer', 'Disease', 'MESH:D002583', (342, 357))	('CA199', 'Var', (333, 338))	('CA125', 'Gene', '94025', (323, 328))	('cervical cancer', 'Disease', (342, 357))	('CA199', 'Chemical', '-', (333, 338))	('CA125', 'Gene', (106, 111))	('CA199', 'Chemical', '-', (116, 121))	('CA125', 'Gene', (323, 328))
469061	30886526	Reactivation of p53 tumour suppressor protein through HPV E6 inactivation results in the restoration of molecular mechanisms that are meant to maintain normal homeostasis.	('inactivation', 'Var', (61, 73))	('molecular mechanisms', 'MPA', (104, 124))	('tumour', 'Disease', 'MESH:D009369', (20, 26))	('HPV E6', 'Gene', (54, 60))	('tumour', 'Disease', (20, 26))	('Reactivation', 'MPA', (0, 12))	('HPV', 'Species', '10566', (54, 57))	('restoration', 'PosReg', (89, 100))	('tumour', 'Phenotype', 'HP:0002664', (20, 26))
469062	30886526	Tumour suppressor protein, p53, has also been documented to be negatively regulated by retinoblastoma-binding protein 6 (RBBP6) and increased RBBP6 expression consequently results in tumourigenesis, whereas its knockdown results in cell growth arrest and apoptosis.	('growth arrest', 'Phenotype', 'HP:0001510', (237, 250))	('arrest', 'Disease', 'MESH:D006323', (244, 250))	('tumour', 'Disease', (183, 189))	('negatively', 'NegReg', (63, 73))	('retinoblastoma-binding protein 6', 'Gene', (87, 119))	('retinoblastoma', 'Phenotype', 'HP:0009919', (87, 101))	('increased', 'PosReg', (132, 141))	('RBBP6', 'Gene', (142, 147))	('arrest', 'Disease', (244, 250))	('knockdown', 'Var', (211, 220))	('apoptosis', 'CPA', (255, 264))	('retinoblastoma-binding protein 6', 'Gene', '5930', (87, 119))	('Tumour', 'Phenotype', 'HP:0002664', (0, 6))	('expression', 'MPA', (148, 158))	('tumour', 'Phenotype', 'HP:0002664', (183, 189))	('tumour', 'Disease', 'MESH:D009369', (183, 189))	('results in', 'Reg', (172, 182))	('p53', 'Gene', (27, 30))
469115	30886526	Using fluorescent in situ hybridization (FISH), RBBP6 variants were found to be abundantly transcribed in cervical cancer cases.	('RBBP6', 'Gene', (48, 53))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('cervical cancer', 'Disease', (106, 121))	('cervical cancer', 'Disease', 'MESH:D002583', (106, 121))	('variants', 'Var', (54, 62))
469118	30886526	The FISH results showed a progressive decrease in the transcription of the RBBP6 mRNAs, as indicated in our previous work; RBBP6 variant 3-mRNA transcription was lost in tumours (Figure 2C).	('tumours', 'Disease', 'MESH:D009369', (170, 177))	('tumours', 'Disease', (170, 177))	('variant', 'Var', (129, 136))	('RBBP6', 'Gene', (123, 128))	('decrease', 'NegReg', (38, 46))	('lost', 'NegReg', (162, 166))	('tumour', 'Phenotype', 'HP:0002664', (170, 176))	('transcription', 'MPA', (54, 67))	('tumours', 'Phenotype', 'HP:0002664', (170, 177))
469121	30886526	In an attempt to differentiate between the two bigger transcripts, an exon 16 probe was used and there was high stromal expression of RBBP6 variant 1 (Figure 4C) compared with well-differentiated carcinoma (Figure 2D).	('RBBP6', 'Gene', (134, 139))	('carcinoma', 'Disease', (196, 205))	('variant 1', 'Var', (140, 149))	('carcinoma', 'Disease', 'MESH:D002277', (196, 205))	('carcinoma', 'Phenotype', 'HP:0030731', (196, 205))
469144	30886526	In the invasive squamous cell carcinoma, almost all cells of the surface epithelium and tumour islands in the underlying stroma were Ki67 positive (Figure 2K).	('tumour', 'Disease', 'MESH:D009369', (88, 94))	('invasive squamous cell carcinoma', 'Disease', 'MESH:D002294', (7, 39))	('Ki67', 'Var', (133, 137))	('tumour', 'Disease', (88, 94))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (16, 39))	('tumour', 'Phenotype', 'HP:0002664', (88, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (30, 39))	('invasive squamous cell carcinoma', 'Disease', (7, 39))	('Ki67', 'Chemical', '-', (133, 137))
469146	30886526	There were increased levels of RBBP6 in cervical cancers in contrast to normal tissues suggesting that RBBP6 is involved in cervical cancer pathogenesis.	('cervical cancers', 'Disease', (40, 56))	('RBBP6', 'Var', (103, 108))	('involved', 'Reg', (112, 120))	('cervical cancers', 'Disease', 'MESH:D002583', (40, 56))	('increased', 'PosReg', (11, 20))	('cervical cancer', 'Disease', 'MESH:D002583', (40, 55))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('cancers', 'Phenotype', 'HP:0002664', (49, 56))	('cervical cancer', 'Disease', (124, 139))	('cervical cancer', 'Disease', 'MESH:D002583', (124, 139))	('levels', 'MPA', (21, 27))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
469151	30886526	Silencing of RBBP6 in mouse models resulted in a reduction in p53 polyubiquitination, which caused apoptosis and cell growth hindrance due to p53 buildup.	('reduction', 'NegReg', (49, 58))	('RBBP6', 'Gene', (13, 18))	('apoptosis', 'CPA', (99, 108))	('growth hindrance', 'Phenotype', 'HP:0001510', (118, 134))	('cell growth hindrance', 'CPA', (113, 134))	('p53', 'Protein', (62, 65))	('caused', 'Reg', (92, 98))	('mouse', 'Species', '10090', (22, 27))	('polyubiquitination', 'MPA', (66, 84))	('Silencing', 'Var', (0, 9))
469191	30886526	A previous study indicated a significant correlation between the presence of HPV E6 protein and Bcl-2.	('Bcl-2', 'Gene', (96, 101))	('Bcl-2', 'Gene', '596', (96, 101))	('correlation', 'Interaction', (41, 52))	('HPV', 'Species', '10566', (77, 80))	('HPV', 'Gene', (77, 80))	('presence', 'Var', (65, 73))
469194	30886526	Bcl-2 protein was downregulated at the sites where RBBP6 was highly expressed, further supporting the notion that RBBP6 is involved in the regulation of apoptosis.	('involved', 'Reg', (123, 131))	('RBBP6', 'Var', (114, 119))	('downregulated', 'NegReg', (18, 31))	('RBBP6', 'Gene', (51, 56))	('Bcl-2', 'Gene', (0, 5))	('Bcl-2', 'Gene', '596', (0, 5))
469254	26980915	When we compared our spindle cell cohort to our comparison group of oral cavity patients, there was a statistically significant difference in age, with the spindle cell variant affecting older patients (68.8 years versus 54.2 years; p<0.001).	('variant', 'Var', (169, 176))	('affecting', 'Reg', (177, 186))	('patients', 'Species', '9606', (193, 201))	('patients', 'Species', '9606', (80, 88))	('spindle cell', 'Gene', (156, 168))
469257	26980915	As with the spindle cell variant, cMet positivity was predictive of overall survival (0.0% versus 51.5%, p = 0.009), disease specific survival (0.0% versus 66.9%, p < 0.001) and recurrence free survival (0.0% versus 59.4%, p = 0.006), although the proportion of patients staining for cMet was significantly lower with only 2 tumors positive for cMet in this group.	('tumors', 'Disease', (325, 331))	('disease specific survival', 'CPA', (117, 142))	('tumors', 'Disease', 'MESH:D009369', (325, 331))	('tumors', 'Phenotype', 'HP:0002664', (325, 331))	('cMet', 'Gene', (345, 349))	('cMet', 'Gene', '4233', (34, 38))	('cMet', 'Gene', (284, 288))	('positivity', 'Var', (39, 49))	('recurrence free survival', 'CPA', (178, 202))	('cMet', 'Gene', '4233', (284, 288))	('patients', 'Species', '9606', (262, 270))	('cMet', 'Gene', (34, 38))	('cMet', 'Gene', '4233', (345, 349))	('tumor', 'Phenotype', 'HP:0002664', (325, 330))
469258	26980915	In contrast, neither cyclin D1, p16 nor EGFR positivity were predictive of overall survival (p = 0.70, p = 0.79, and p = 0.15 respectively), disease specific survival (p = 0.52, p = 0.60, and p 0.60 respectively), or recurrence free survival (p = 0.17, p = 0.52, and p = 0.92 respectively) (Table 2).	('disease specific survival', 'CPA', (141, 166))	('p16', 'Gene', '1029', (32, 35))	('positivity', 'Var', (45, 55))	('EGFR', 'Gene', '1956', (40, 44))	('EGFR', 'Gene', (40, 44))	('cyclin D1', 'Gene', '595', (21, 30))	('p16', 'Gene', (32, 35))	('cyclin D1', 'Gene', (21, 30))
469267	26980915	Amplification and mutations of cMET occur in several malignancies, including cancers of the lung and kidney in addition to head and neck SCC.	('SCC', 'Phenotype', 'HP:0002860', (137, 140))	('mutations', 'Var', (18, 27))	('cancers of the lung', 'Disease', 'MESH:D008175', (77, 96))	('cancers', 'Phenotype', 'HP:0002664', (77, 84))	('malignancies', 'Disease', (53, 65))	('cMET', 'Gene', '4233', (31, 35))	('SCC', 'Gene', '6317', (137, 140))	('cMET', 'Gene', (31, 35))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('cancers of the lung', 'Disease', (77, 96))	('malignancies', 'Disease', 'MESH:D009369', (53, 65))	('occur', 'Reg', (36, 41))	('SCC', 'Gene', (137, 140))
469268	26980915	In the head and neck, cMet mutations occur in up to 25% of cancers.	('mutations', 'Var', (27, 36))	('cMet', 'Gene', '4233', (22, 26))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('cMet', 'Gene', (22, 26))	('cancers', 'Disease', 'MESH:D009369', (59, 66))	('cancers', 'Phenotype', 'HP:0002664', (59, 66))	('occur', 'Reg', (37, 42))	('cancers', 'Disease', (59, 66))
469269	26980915	In lung cancer, cMet mutations are present in up to 20% of patients with resistance to EGFR inhibitors, such as cetuximab, as these mutations lead to activation of pathways that induce resistance to EGFR inhibitors.	('cMet', 'Gene', '4233', (16, 20))	('EGFR', 'Gene', '1956', (87, 91))	('lung cancer', 'Disease', (3, 14))	('EGFR', 'Gene', (199, 203))	('lung cancer', 'Phenotype', 'HP:0100526', (3, 14))	('mutations', 'Var', (132, 141))	('activation', 'PosReg', (150, 160))	('EGFR', 'Gene', (87, 91))	('pathways', 'Pathway', (164, 172))	('resistance', 'MPA', (185, 195))	('cMet', 'Gene', (16, 20))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('patients', 'Species', '9606', (59, 67))	('cetuximab', 'Chemical', 'MESH:D000068818', (112, 121))	('lung cancer', 'Disease', 'MESH:D008175', (3, 14))	('EGFR', 'Gene', '1956', (199, 203))
469273	26980915	While cMet was also predictive in the control group of oral cavity tumors in a univariate analysis, it is interesting that cMet positivity was significantly more prevalent in spindle cell variant tumors.	('prevalent', 'Reg', (162, 171))	('tumors', 'Phenotype', 'HP:0002664', (196, 202))	('cMet', 'Gene', '4233', (123, 127))	('oral cavity tumors', 'Phenotype', 'HP:0100649', (55, 73))	('tumors', 'Disease', 'MESH:D009369', (67, 73))	('tumors', 'Disease', (196, 202))	('tumors', 'Disease', 'MESH:D009369', (196, 202))	('cMet', 'Gene', '4233', (6, 10))	('positivity', 'Var', (128, 138))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('cMet', 'Gene', (123, 127))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('cMet', 'Gene', (6, 10))	('tumors', 'Disease', (67, 73))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))
469277	26980915	Cyclin D1 positivity was also shown to be predictive of recurrence and worse disease specific survival in SpSCC.	('SCC', 'Gene', (108, 111))	('Cyclin D1', 'Gene', '595', (0, 9))	('positivity', 'Var', (10, 20))	('SCC', 'Phenotype', 'HP:0002860', (108, 111))	('SCC', 'Gene', '6317', (108, 111))	('Cyclin D1', 'Gene', (0, 9))
469304	25918252	The EGFR inhibitors also significantly reduced tube formation of endothelial cells.	('EGFR', 'Gene', (4, 8))	('tube formation of endothelial cells', 'CPA', (47, 82))	('reduced', 'NegReg', (39, 46))	('inhibitors', 'Var', (9, 19))	('EGFR', 'Gene', '1956', (4, 8))
469314	25918252	Overexpression of EGFR is associated with aggressive behaviour including increased proliferation, metastasis, and therapeutic resistance in squamous cell carcinoma (SCC) of the oral cavity and oropharynx.	('increased', 'PosReg', (73, 82))	('proliferation', 'CPA', (83, 96))	('SCC', 'Gene', (165, 168))	('EGFR', 'Gene', '1956', (18, 22))	('SCC', 'Phenotype', 'HP:0002860', (165, 168))	('therapeutic resistance', 'CPA', (114, 136))	('metastasis', 'CPA', (98, 108))	('EGFR', 'Gene', (18, 22))	('SCC', 'Gene', '6317', (165, 168))	('Overexpression', 'Var', (0, 14))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (140, 163))	('aggressive behaviour', 'Phenotype', 'HP:0000718', (42, 62))	('carcinoma', 'Phenotype', 'HP:0030731', (154, 163))	('squamous cell carcinoma', 'Disease', (140, 163))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (140, 163))
469329	25918252	A recent study reported that BPD-mediated PDT initiates nuclear signaling of EGFR and STAT3 which results in decreased cancer cell cytotoxicity following PDT.	('decreased', 'NegReg', (109, 118))	('nuclear signaling', 'MPA', (56, 73))	('STAT3', 'Gene', (86, 91))	('cytotoxicity', 'Disease', 'MESH:D064420', (131, 143))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('cancer', 'Disease', (119, 125))	('BPD', 'Chemical', '-', (29, 32))	('EGFR', 'Gene', '1956', (77, 81))	('cytotoxicity', 'Disease', (131, 143))	('STAT3', 'Gene', '6774', (86, 91))	('EGFR', 'Gene', (77, 81))	('PDT', 'Var', (154, 157))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
469330	25918252	This suggests that EGFR inhibitors can have potential synergistic effect when administered with PDT, and this could be highly relevant for clinical use.	('inhibitors', 'Var', (24, 34))	('synergistic effect', 'MPA', (54, 72))	('EGFR', 'Gene', '1956', (19, 23))	('EGFR', 'Gene', (19, 23))
469359	25918252	Invasion of cells was significantly lower for all the inhibitor groups compared to control in all the cell lines except OSCC.	('lower', 'NegReg', (36, 41))	('inhibitor', 'Var', (54, 63))	('Invasion of cells', 'CPA', (0, 17))	('SCC', 'Gene', (121, 124))	('SCC', 'Phenotype', 'HP:0002860', (121, 124))	('SCC', 'Gene', '6317', (121, 124))
469366	25918252	Treatment response in OSCC (Figure 5A) and SCC (Figure 5C) cells was comparable with 22 to 27% (p < 0.001) cell survival post PDT and significantly lower cell viability of 2-14% (p < 0.001) in the combination therapy groups of PDT + nimotuzumab and PDT + cetuximab compared to control.	('cell viability', 'CPA', (154, 168))	('cetuximab', 'Chemical', 'MESH:D000068818', (255, 264))	('SCC', 'Gene', '6317', (23, 26))	('SCC', 'Gene', '6317', (43, 46))	('PDT', 'Var', (126, 129))	('lower', 'NegReg', (148, 153))	('nimotuzumab', 'Chemical', 'MESH:C501466', (233, 244))	('SCC', 'Phenotype', 'HP:0002860', (23, 26))	('SCC', 'Gene', (23, 26))	('SCC', 'Gene', (43, 46))	('SCC', 'Phenotype', 'HP:0002860', (43, 46))
469368	25918252	40-56% cell survival was observed post PDT and variable range of 4.8 to 32% cell viability was observed in the combination therapy groups of PDT + EGFR inhibitors compared to control.	('combination', 'Interaction', (111, 122))	('EGFR', 'Gene', (147, 151))	('inhibitors', 'Var', (152, 162))	('cell survival', 'CPA', (7, 20))	('cell viability', 'CPA', (76, 90))	('EGFR', 'Gene', '1956', (147, 151))
469369	25918252	We also observed that in HSC-3 cells the higher dose of PDT (100 muM) + EGFR inhibitor (100 mug/ml) induced significantly greater cell death compared to lower dose of PDT (50 muM) + EGFR inhibitor (50 mug/ml).	('cell death', 'CPA', (130, 140))	('EGFR', 'Gene', '1956', (182, 186))	('PDT', 'Gene', (56, 59))	('EGFR', 'Gene', (182, 186))	('EGFR', 'Gene', '1956', (72, 76))	('muM', 'Gene', (175, 178))	('muM', 'Gene', '56925', (65, 68))	('HSC-3', 'Gene', '150353', (25, 30))	('EGFR', 'Gene', (72, 76))	('muM', 'Gene', (65, 68))	('HSC-3', 'Gene', (25, 30))	('100 mug/ml', 'Var', (88, 98))	('muM', 'Gene', '56925', (175, 178))
469371	25918252	Around 13 to 19% (p < 0.001) cell survival was observed post PDT and significantly lower cell viability of 4 to 7.5% (p < 0.001) was observed in the combination therapy groups compared to control.	('PDT', 'Var', (61, 64))	('lower', 'NegReg', (83, 88))	('cell survival', 'CPA', (29, 42))	('to 7', 'Species', '1214577', (109, 113))	('cell viability', 'CPA', (89, 103))
469374	25918252	Based on the difference in logarithms (DL) and p values, it was determined that PDT + nimotuzumab and PDT + cetuximab synergistically induced cell death in all the cell lines (Table 1).	('PDT', 'Var', (102, 105))	('cetuximab', 'Chemical', 'MESH:D000068818', (108, 117))	('nimotuzumab', 'Chemical', 'MESH:C501466', (86, 97))	('PDT', 'Var', (80, 83))	('cell death', 'CPA', (142, 152))
469378	25918252	Tumors treated with the combination therapy of PDT + Nimotuzumab exhibited significantly greater treatment response compared to control, nimotuzumab and PDT treated groups (p < 0.05).	('treatment response', 'CPA', (97, 115))	('PDT', 'Var', (47, 50))	('nimotuzumab', 'Chemical', 'MESH:C501466', (137, 148))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('greater', 'PosReg', (89, 96))	('Nimotuzumab', 'Chemical', 'MESH:C501466', (53, 64))
469380	25918252	The percentage survival of 88% was observed in animals treated with PDT + nimotuzumab which was significantly greater compared to control (36%), PDT alone (45%) and nimotuzumab alone (55%) treated animals.	('nimotuzumab', 'Chemical', 'MESH:C501466', (165, 176))	('nimotuzumab', 'Chemical', 'MESH:C501466', (74, 85))	('greater', 'PosReg', (110, 117))	('PDT', 'Var', (68, 71))
469386	25918252	Increased EGFR expression was observed in the tumors treated with PDT (22.6%) when compared to control (17.8%) and nimotuzumab treated tumors (15.3%).	('EGFR', 'Gene', '1956', (10, 14))	('nimotuzumab', 'Chemical', 'MESH:C501466', (115, 126))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('EGFR', 'Gene', (10, 14))	('PDT', 'Var', (66, 69))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('tumors', 'Disease', (135, 141))	('expression', 'MPA', (15, 25))	('Increased', 'PosReg', (0, 9))	('tumors', 'Disease', 'MESH:D009369', (135, 141))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))	('tumors', 'Disease', (46, 52))	('tumors', 'Disease', 'MESH:D009369', (46, 52))
469392	25918252	Significantly lower (p < 0.001) and more scattered microvessel staining (CD31) was observed in the PDT + nimotuzumab (Microvessel density (MVD) 45.4/mm2) tumors compared to control (MVD 67.4/mm2), PDT (MVD 77.8/mm2) and nimotuzumab treated tumors (MVD 57/mm2).	('nimotuzumab', 'Chemical', 'MESH:C501466', (220, 231))	('tumors', 'Disease', (154, 160))	('tumors', 'Disease', 'MESH:D009369', (154, 160))	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('lower', 'NegReg', (14, 19))	('nimotuzumab', 'Chemical', 'MESH:C501466', (105, 116))	('tumors', 'Phenotype', 'HP:0002664', (240, 246))	('tumors', 'Disease', (240, 246))	('tumors', 'Disease', 'MESH:D009369', (240, 246))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('PDT + nimotuzumab', 'Var', (99, 116))	('CD31', 'Gene', (73, 77))	('tumor', 'Phenotype', 'HP:0002664', (240, 245))	('CD31', 'Gene', '5175', (73, 77))
469397	25918252	The urea nitrogen mildly increased in the PDT + nimotuzumab (13.5 mg/dL) group compared to control (12.4 mg/dL), PDT (12.8 mg/dL) and nimotuzumab (13 mg/dL) treated animals.	('nitrogen', 'Chemical', 'MESH:D009584', (9, 17))	('increased', 'PosReg', (25, 34))	('urea nitrogen', 'MPA', (4, 17))	('nimotuzumab', 'Chemical', 'MESH:C501466', (134, 145))	('urea nitrogen mildly increased', 'Phenotype', 'HP:0008180', (4, 34))	('urea', 'Chemical', 'MESH:D014508', (4, 8))	('nimotuzumab', 'Chemical', 'MESH:C501466', (48, 59))	('PDT +', 'Var', (42, 47))
469415	25918252	Therefore inhibition of EGFR and its downstream signalling pathways presents a promising strategy to prevent tumor progression.	('EGFR', 'Gene', '1956', (24, 28))	('EGFR', 'Gene', (24, 28))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('inhibition', 'Var', (10, 20))	('tumor', 'Disease', (109, 114))
469421	25918252	Based on our results, nimotuzumab could successfully prevent endothelial cell migration, invasion and endothelial cell tube formation and moreover its effects were comparable to cetuximab, and bevacizumab which is a well-known anti-angiogenic agent.	('nimotuzumab', 'Chemical', 'MESH:C501466', (22, 33))	('bevacizumab', 'Chemical', 'MESH:D000068258', (193, 204))	('endothelial cell tube formation', 'CPA', (102, 133))	('nimotuzumab', 'Var', (22, 33))	('cetuximab', 'Chemical', 'MESH:D000068818', (178, 187))	('endothelial cell migration', 'CPA', (61, 87))	('prevent', 'NegReg', (53, 60))
469435	25918252	Based on statistical calculations, it was noted that different dosages of both PDT + nimotuzumab and PDT + cetuximab synergistically induced cell death in all the cell lines.	('cetuximab', 'Chemical', 'MESH:D000068818', (107, 116))	('nimotuzumab', 'Chemical', 'MESH:C501466', (85, 96))	('induced', 'Reg', (133, 140))	('cell death', 'CPA', (141, 151))	('PDT', 'Var', (101, 104))
469437	25918252	Ce6-PDT significantly increased cell death in oral cancer cells and nimotuzumab and cetuximab significantly enhanced the anti-tumor effect of PDT.	('oral cancer', 'Disease', (46, 57))	('tumor', 'Disease', (126, 131))	('Ce6-PDT', 'Var', (0, 7))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('nimotuzumab', 'Chemical', 'MESH:C501466', (68, 79))	('enhanced', 'PosReg', (108, 116))	('increased', 'PosReg', (22, 31))	('cetuximab', 'Chemical', 'MESH:D000068818', (84, 93))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('oral cancer', 'Disease', 'MESH:D009062', (46, 57))	('Ce6', 'Chemical', 'MESH:C062985', (0, 3))	('cell death in', 'CPA', (32, 45))
469438	25918252	Similar to our results, pheophorbide-a (Pa)-PDT in an oral cancer cell line reduced cell viability by 50% and produced reactive oxygen species (ROS).	('oral cancer', 'Disease', (54, 65))	('reactive oxygen species', 'MPA', (119, 142))	('produced', 'Reg', (110, 118))	('ROS', 'Chemical', 'MESH:D017382', (144, 147))	('oral cancer', 'Disease', 'MESH:D009062', (54, 65))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (119, 142))	('reduced', 'NegReg', (76, 83))	('cell viability', 'CPA', (84, 98))	('pheophorbide-a', 'Chemical', 'MESH:C032623', (24, 38))	('Pa', 'Chemical', 'MESH:C032623', (40, 42))	('pheophorbide-a', 'Var', (24, 38))
469439	25918252	Compared to this, Ce6-PDT reduced cell viability by around 70%.	('reduced', 'NegReg', (26, 33))	('cell viability', 'CPA', (34, 48))	('Ce6', 'Chemical', 'MESH:C062985', (18, 21))	('Ce6-PDT', 'Var', (18, 25))
469440	25918252	Ce6-PDT predominantly causes apoptosis of tumor cells and about 80% apoptosis was observed in colon carcinoma CT-26 when treated with a light dose of 1 J/cm2.	('apoptosis', 'CPA', (29, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('tumor', 'Disease', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('Ce6-PDT', 'Var', (0, 7))	('colon carcinoma', 'Disease', 'MESH:D015179', (94, 109))	('colon carcinoma', 'Disease', (94, 109))	('CT-26', 'CellLine', 'CVCL:7254', (110, 115))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('Ce6', 'Chemical', 'MESH:C062985', (0, 3))
469443	25918252	Photosensitization of human vascular smooth muscle cells with Ce6 has also shown to result in the generation of ROS, a decrease in cell membrane polarization, caspase-3 activation, as well as DNA-fragmentation.	('ROS', 'Chemical', 'MESH:D017382', (112, 115))	('decrease', 'NegReg', (119, 127))	('ROS', 'Protein', (112, 115))	('activation', 'PosReg', (169, 179))	('caspase-3', 'Gene', (159, 168))	('caspase-3', 'Gene', '836', (159, 168))	('DNA-fragmentation', 'CPA', (192, 209))	('cell', 'CPA', (131, 135))	('human', 'Species', '9606', (22, 27))	('Ce6', 'Var', (62, 65))	('Ce6', 'Chemical', 'MESH:C062985', (62, 65))
469444	25918252	Similar to our results, the efficacy of Zn-BC-AM-PDT was increased in nasopharyngeal carcinoma cells (NPC) through the inhibition of EGFR/PI3K/Akt and EGFR/MEK/ERK signaling pathways using an EGFR inhibitor AG1478.	('Akt', 'Gene', '207', (143, 146))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (70, 94))	('inhibition', 'NegReg', (119, 129))	('EGFR', 'Gene', '1956', (133, 137))	('MEK', 'Gene', '5609', (156, 159))	('efficacy', 'MPA', (28, 36))	('EGFR', 'Gene', (192, 196))	('ERK', 'Gene', '5594', (160, 163))	('MEK', 'Gene', (156, 159))	('Zn-BC-AM-PDT', 'Var', (40, 52))	('Zn-BC-AM', 'Chemical', 'MESH:C497948', (40, 48))	('EGFR', 'Gene', (151, 155))	('ERK', 'Gene', (160, 163))	('nasopharyngeal carcinoma', 'Disease', (70, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('increased', 'PosReg', (57, 66))	('EGFR', 'Gene', '1956', (192, 196))	('EGFR', 'Gene', (133, 137))	('nasopharyngeal carcinoma', 'Disease', 'MESH:D000077274', (70, 94))	('Akt', 'Gene', (143, 146))	('AG1478', 'Chemical', 'MESH:C101044', (207, 213))	('EGFR', 'Gene', '1956', (151, 155))
469455	25918252	It has been widely reported that vascular-targeting PDT can induce alterations in the tumor vasculature leading to vasoconstriction, microvascular shutdown and blood flow stasis.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Disease', (86, 91))	('blood flow stasis', 'CPA', (160, 177))	('microvascular', 'MPA', (133, 146))	('alterations', 'Reg', (67, 78))	('vascular-targeting PDT', 'Var', (33, 55))	('PDT', 'Var', (52, 55))	('vasoconstriction', 'MPA', (115, 131))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
469457	25918252	Thus, modifying the PDT protocol to target both the vasculature and cellular components in the tumor microenvironment can substantially improve treatment outcome.	('improve', 'PosReg', (136, 143))	('modifying', 'Var', (6, 15))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Disease', (95, 100))
469467	25918252	Inhibition of EGFR signalling can lead to increased PDT cytotoxicity through a mechanism that involves increased apoptotic cell death.	('increased', 'PosReg', (42, 51))	('EGFR', 'Gene', '1956', (14, 18))	('EGFR', 'Gene', (14, 18))	('increased', 'PosReg', (103, 112))	('cytotoxicity', 'Disease', 'MESH:D064420', (56, 68))	('apoptotic cell death', 'CPA', (113, 133))	('Inhibition', 'Var', (0, 10))	('cytotoxicity', 'Disease', (56, 68))
469468	25918252	Similarly, PDT + C225, an EGFR inhibitor, produced synergistic reductions in mean tumor burden when compared with PDT only or C225.	('EGFR', 'Gene', (26, 30))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('EGFR', 'Gene', '1956', (26, 30))	('tumor', 'Disease', (82, 87))	('reductions', 'NegReg', (63, 73))	('PDT + C225', 'Var', (11, 21))
469469	25918252	Median survival was approximately threefold greater for mice in the PDT + C225 group than for mice in the no-treatment control group.	('Median survival', 'CPA', (0, 15))	('mice', 'Species', '10090', (56, 60))	('mice', 'Species', '10090', (94, 98))	('PDT + C225', 'Var', (68, 78))	('greater', 'PosReg', (44, 51))
469470	25918252	Inhibition of EGFR has been shown to increase the antitumor activity of radiotherapy and chemotherapy in preclinical and clinical studies.	('EGFR', 'Gene', '1956', (14, 18))	('EGFR', 'Gene', (14, 18))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('increase', 'PosReg', (37, 45))	('Inhibition', 'Var', (0, 10))	('tumor', 'Disease', (54, 59))
469474	25918252	Similarly, del Carmen and colleagues also presented evidence that intraperitoneal administration of C225 (cetuximab) and benzoporphyrin derivative monoacid-A (BPD)-PDT act synergistically to prevent or inhibit tumor cell growth and extend survival in a murine model of ovarian cancer peritoneal metastasis.	('benzoporphyrin', 'Chemical', '-', (121, 135))	('survival', 'CPA', (239, 247))	('BPD', 'Chemical', '-', (159, 162))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('C225', 'Var', (100, 104))	('murine', 'Species', '10090', (253, 259))	('tumor', 'Disease', (210, 215))	('monoacid-A', 'Chemical', '-', (147, 157))	('ovarian cancer', 'Phenotype', 'HP:0100615', (269, 283))	('inhibit', 'NegReg', (202, 209))	('cetuximab', 'Chemical', 'MESH:D000068818', (106, 115))	('ovarian cancer', 'Disease', 'MESH:D010051', (269, 283))	('extend', 'PosReg', (232, 238))	('cancer', 'Phenotype', 'HP:0002664', (277, 283))	('tumor', 'Disease', 'MESH:D009369', (210, 215))	('ovarian cancer', 'Disease', (269, 283))
469475	25918252	Another study reported that ERK1/2 and EGFR-PI3K-Akt pathways seem to be involved in cellular survival after PDT and EGFR inhibitors and PDT act synergistically to reduce malignant tumors effectively.	('ERK1/2', 'Gene', (28, 34))	('ERK1/2', 'Gene', '5595;5594', (28, 34))	('tumors', 'Phenotype', 'HP:0002664', (181, 187))	('EGFR', 'Gene', '1956', (117, 121))	('EGFR', 'Gene', (117, 121))	('malignant tumors', 'Disease', (171, 187))	('inhibitors', 'Var', (122, 132))	('reduce', 'NegReg', (164, 170))	('malignant tumors', 'Disease', 'MESH:D018198', (171, 187))	('PDT', 'Gene', (109, 112))	('Akt', 'Gene', '207', (49, 52))	('EGFR', 'Gene', '1956', (39, 43))	('involved', 'Reg', (73, 81))	('EGFR', 'Gene', (39, 43))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('Akt', 'Gene', (49, 52))
469476	25918252	Treatment of U87MG brain tumours with nimotuzumab and radiation has also shown enhanced inhibition of EGFR-signalling activation.	('inhibition', 'NegReg', (88, 98))	('tumour', 'Phenotype', 'HP:0002664', (25, 31))	('enhanced', 'PosReg', (79, 87))	('brain tumours', 'Disease', 'MESH:D001932', (19, 32))	('nimotuzumab', 'Chemical', 'MESH:C501466', (38, 49))	('brain tumours', 'Phenotype', 'HP:0030692', (19, 32))	('brain tumours', 'Disease', (19, 32))	('U87MG', 'CellLine', 'CVCL:0022', (13, 18))	('tumours', 'Phenotype', 'HP:0002664', (25, 32))	('U87MG', 'Var', (13, 18))	('EGFR', 'Gene', '1956', (102, 106))	('EGFR', 'Gene', (102, 106))
469483	25918252	Though, PDT treated tumors expressed greater EGFR levels, the increase in tumor size was not as significant as the control tumors.	('tumors', 'Disease', 'MESH:D009369', (123, 129))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('tumor', 'Disease', (74, 79))	('EGFR', 'Gene', '1956', (45, 49))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('tumor', 'Disease', (123, 128))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('greater', 'PosReg', (37, 44))	('tumors', 'Disease', (20, 26))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('tumors', 'Disease', (123, 129))	('tumors', 'Disease', 'MESH:D009369', (20, 26))	('EGFR', 'Gene', (45, 49))	('PDT treated', 'Var', (8, 19))	('tumor', 'Disease', (20, 25))
469603	33649808	Aged MTSS1 KO mice have also been found to have an increased tendency to develop B cell malignancies, in which aberrant CXCR4 internalization has been suggested to play a role.	('MTSS1 KO', 'Var', (5, 13))	('malignancies', 'Disease', (88, 100))	('develop', 'PosReg', (73, 80))	('mice', 'Species', '10090', (14, 18))	('CXCR4 internalization', 'MPA', (120, 141))	('malignancies', 'Disease', 'MESH:D009369', (88, 100))
469650	33649808	After confirming the presence of individual colonies expressing bright GFP fluorescence under an inverted fluorescence microscope at x200 magnification (EFD-3, Nikon Corporation), the individual colonies were digested in 0.25% trypsin and transferred into culture plates for further culture in the presence of selective medium containing 200 microg/ml G418.	('G418', 'Var', (352, 356))	('G418', 'Chemical', 'MESH:C010680', (352, 356))	('GFP fluorescence', 'MPA', (71, 87))
469667	33649808	SW480 and SW620 are 2 lines from the same colon cancer patient.	('SW480', 'CellLine', 'CVCL:0546', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('SW620', 'Var', (10, 15))	('SW620', 'CellLine', 'CVCL:0547', (10, 15))	('colon cancer', 'Phenotype', 'HP:0003003', (42, 54))	('colon cancer', 'Disease', 'MESH:D015179', (42, 54))	('patient', 'Species', '9606', (55, 62))	('colon cancer', 'Disease', (42, 54))
469675	33649808	The results revealed that the expression levels of Rac and CDC42 in the MTSS1+ cells were downregulated compared with the NC group, and upregulated in the MTSS1- group compared with the NC group in both cell lines.	('upregulated', 'PosReg', (136, 147))	('CDC42', 'Gene', '998', (59, 64))	('Rac', 'Gene', (51, 54))	('CDC42', 'Gene', (59, 64))	('MTSS1-', 'Var', (155, 161))	('downregulated', 'NegReg', (90, 103))	('Rac', 'Gene', '207', (51, 54))	('expression levels', 'MPA', (30, 47))
469676	33649808	Following the treatment of the cells with CXCL12 for 30 min, the intracellular expression levels of Rac and CDC42 were upregulated in all groups; however, the expression levels in the MTSS1+ group remained lower compared with those in the NC group, while they were higher in the MTSS1-group compared with the NC group (Fig.	('Rac', 'Gene', (100, 103))	('upregulated', 'PosReg', (119, 130))	('intracellular expression levels', 'MPA', (65, 96))	('expression levels', 'MPA', (159, 176))	('lower', 'NegReg', (206, 211))	('CDC42', 'Gene', '998', (108, 113))	('Rac', 'Gene', '207', (100, 103))	('CDC42', 'Gene', (108, 113))	('MTSS1+', 'Var', (184, 190))
469682	33649808	Agarwal et al identified MTSS1 as a novel AKT2-regulated gene and showed that the knockdown of MTSS1 was a key step in the metastasis-promoting effects of AKT2 in CRC cells.	('AKT2', 'Gene', (42, 46))	('AKT2', 'Gene', '208', (42, 46))	('AKT2', 'Gene', (155, 159))	('AKT2', 'Gene', '208', (155, 159))	('MTSS1', 'Gene', (95, 100))	('knockdown', 'Var', (82, 91))	('metastasis-promoting effects', 'CPA', (123, 151))	('MTSS1', 'Gene', (25, 30))
469689	33649808	The CXCR4/CXCL12 signaling axis has also been reported to play an important role in the liver metastasis of CRC and the inhibition of CXCR4 reduced the contribution of tumor and stromal cells to metastatic growth in the liver.	('tumor', 'Disease', (168, 173))	('inhibition', 'Var', (120, 130))	('liver metastasis', 'CPA', (88, 104))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('metastatic growth', 'CPA', (195, 212))	('reduced', 'NegReg', (140, 147))
469698	28481876	Forced expression of MCM8 in RWPE1 cells, the immortalized but non-transformed prostate epithelial cell line, exhibited fast cell growth and transformation, while knocked down of MCM8 in PC3, DU145 and LNCaP cells induced cell growth arrest, and decreased tumor volumes and mortality of severe combined immunodeficiency mice xenografted with PC3 and DU145 cells.	('MCM8', 'Gene', (179, 183))	('growth arrest', 'Disease', (227, 240))	('transformation', 'CPA', (141, 155))	('immunodeficiency', 'Disease', (303, 319))	('severe combined immunodeficiency', 'Phenotype', 'HP:0004430', (287, 319))	('combined immunodeficiency', 'Phenotype', 'HP:0005387', (294, 319))	('immunodeficiency', 'Disease', 'MESH:D007153', (303, 319))	('decreased tumor', 'Disease', 'MESH:D009369', (246, 261))	('DU145', 'CellLine', 'CVCL:0105', (350, 355))	('mice', 'Species', '10090', (320, 324))	('DU145', 'CellLine', 'CVCL:0105', (192, 197))	('LNCaP', 'CellLine', 'CVCL:0395', (202, 207))	('immunodeficiency', 'Phenotype', 'HP:0002721', (303, 319))	('growth arrest', 'Phenotype', 'HP:0001510', (227, 240))	('cell growth', 'CPA', (125, 136))	('RWPE1', 'CellLine', 'CVCL:3791', (29, 34))	('decreased tumor', 'Disease', (246, 261))	('mortality', 'CPA', (274, 283))	('MCM8', 'Gene', (21, 25))	('knocked down', 'Var', (163, 175))	('growth arrest', 'Disease', 'MESH:D006323', (227, 240))	('tumor', 'Phenotype', 'HP:0002664', (256, 261))
469701	28481876	As a result, our study showed that copy number increase and overexpression of MCM8 may play critical roles in human cancer development.	('MCM8', 'Gene', (78, 82))	('cancer', 'Disease', (116, 122))	('overexpression', 'PosReg', (60, 74))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('human', 'Species', '9606', (110, 115))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('copy number increase', 'Var', (35, 55))	('men', 'Species', '9606', (130, 133))
469710	28481876	Comprehensive genomic and transcriptomic analyses of human cancers had revealed numerous numerical or mutational, or epigenomic changes in the cancer genome that may drive gene expression alterations in cancers.	('epigenomic changes', 'Var', (117, 135))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (203, 209))	('alterations', 'Reg', (188, 199))	('cancers', 'Phenotype', 'HP:0002664', (203, 210))	('gene expression', 'MPA', (172, 187))	('drive', 'Reg', (166, 171))	('cancer', 'Disease', (143, 149))	('cancers', 'Disease', 'MESH:D009369', (59, 66))	('cancers', 'Disease', 'MESH:D009369', (203, 210))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('cancer', 'Disease', (203, 209))	('cancer', 'Disease', (59, 65))	('human', 'Species', '9606', (53, 58))	('changes', 'Var', (128, 135))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('cancers', 'Phenotype', 'HP:0002664', (59, 66))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('mutational', 'Var', (102, 112))	('cancers', 'Disease', (59, 66))	('cancers', 'Disease', (203, 210))
469717	28481876	Forced expression in immortalized prostate epithelial cell lines RWPE1 induced transformation, while knocked down of MCM8 induced growth arrest of PC3, DU145, and LNCaP cells.	('LNCaP', 'CellLine', 'CVCL:0395', (163, 168))	('transformation', 'CPA', (79, 93))	('induced', 'Reg', (71, 78))	('growth arrest', 'Disease', 'MESH:D006323', (130, 143))	('growth arrest', 'Disease', (130, 143))	('RWPE1', 'Gene', (65, 70))	('RWPE1', 'CellLine', 'CVCL:3791', (65, 70))	('growth arrest', 'Phenotype', 'HP:0001510', (130, 143))	('knocked down', 'Var', (101, 113))	('MCM8', 'Gene', (117, 121))	('DU145', 'CellLine', 'CVCL:0105', (152, 157))
469719	28481876	Significant evidence suggests that amplification and overexpression of DNA replication licensing factor have been associated with aggressive human malignancies.	('amplification', 'Var', (35, 48))	('overexpression', 'PosReg', (53, 67))	('malignancies', 'Disease', (147, 159))	('human', 'Species', '9606', (141, 146))	('associated', 'Reg', (114, 124))	('DNA', 'Gene', (71, 74))	('malignancies', 'Disease', 'MESH:D009369', (147, 159))
469730	28481876	In some breast and colon cancer samples, up to 16 copies of MCM8 were found in the genomes of cancer cells, suggesting that the gain of MCM8 was the result of amplification of the genome sequence encoding MCM8 in some of these cancers.	('amplification', 'Var', (159, 172))	('breast and colon cancer', 'Disease', 'MESH:D001943', (8, 31))	('colon cancer', 'Phenotype', 'HP:0003003', (19, 31))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('gain', 'PosReg', (128, 132))	('MCM8', 'Gene', (136, 140))	('cancer', 'Disease', 'MESH:D009369', (94, 100))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (25, 31))	('cancer', 'Disease', (227, 233))	('cancer', 'Disease', 'MESH:D009369', (227, 233))	('cancers', 'Disease', 'MESH:D009369', (227, 234))	('cancer', 'Disease', (25, 31))	('cancers', 'Phenotype', 'HP:0002664', (227, 234))	('cancers', 'Disease', (227, 234))	('cancer', 'Disease', (94, 100))	('MCM8', 'Gene', (205, 209))
469731	28481876	These analyses suggest that the copy number gain of MCM8 is probably the underlying mechanism of MCM8 overexpression in human malignancies.	('MCM8', 'Gene', (97, 101))	('human', 'Species', '9606', (120, 125))	('malignancies', 'Disease', 'MESH:D009369', (126, 138))	('copy number gain', 'Var', (32, 48))	('overexpression', 'PosReg', (102, 116))	('malignancies', 'Disease', (126, 138))	('MCM8', 'Gene', (52, 56))
469738	28481876	As shown in figure 1A, the gain of MCM8 was not detected in any of the organ donor prostates and benign prostate tissues adjacent to cancer, while 52% (52/93) of the prostate cancer samples were detected with a gain of MCM8.	('prostate cancer', 'Disease', (166, 181))	('cancer', 'Disease', (175, 181))	('MCM8', 'Var', (219, 223))	('donor', 'Species', '9606', (77, 82))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('prostate cancer', 'Disease', 'MESH:D011471', (166, 181))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('cancer', 'Disease', (133, 139))	('prostate cancer', 'Phenotype', 'HP:0012125', (166, 181))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
469744	28481876	Kaplan-Meir analysis based on the status of MCM8 gain showed that patients with MCM8 gain in their cancer genome had PSA-free survival rate of 33.3%, while patients with no MCM8 gain had the 5-year PSA-free survival rate of 74.5% (figure 1D), suggesting that the gain of MCM8 signals a significantly poorer clinical outcomes (p=7.8 x 10-5) for prostate cancer.	('patients', 'Species', '9606', (156, 164))	('gain', 'PosReg', (85, 89))	('prostate cancer', 'Disease', 'MESH:D011471', (344, 359))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('cancer', 'Disease', 'MESH:D009369', (353, 359))	('poorer', 'NegReg', (300, 306))	('cancer', 'Disease', (99, 105))	('cancer', 'Disease', (353, 359))	('prostate cancer', 'Phenotype', 'HP:0012125', (344, 359))	('MCM8', 'Var', (80, 84))	('prostate cancer', 'Disease', (344, 359))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('cancer', 'Phenotype', 'HP:0002664', (353, 359))	('patients', 'Species', '9606', (66, 74))
469754	28481876	To investigate the biological role of MCM8 over-expression in prostate epithelial cells, RWPE1, the immortalized but non-transformed prostate epithelial cells, were transfected with pCDNA4-MCM8-FLAG.	('MCM8', 'Gene', (38, 42))	('RWPE1', 'CellLine', 'CVCL:3791', (89, 94))	('pCDNA4-MCM8-FLAG', 'Var', (182, 198))
469755	28481876	As shown in figure 3A and B, induced expression of MCM8 in RWPE1 cells resulted in an average of 2.5 fold (p<0.01) increase of S-phase and concomitant 32.6% (p<0.01) decrease of G0/G1 phase cells.	('expression', 'Var', (37, 47))	('increase', 'PosReg', (115, 123))	('MCM8', 'Gene', (51, 55))	('RWPE1', 'CellLine', 'CVCL:3791', (59, 64))	('S-phase', 'CPA', (127, 134))	('G0/G1 phase cells', 'CPA', (178, 195))	('decrease', 'NegReg', (166, 174))
469756	28481876	MCM8 expression increased colony formation by 2.8 fold (p<0.01) and anchorage independent growth by 12.7 fold (p<0.01) of RWPE1 cells (figure 3C and D).	('anchorage independent growth', 'CPA', (68, 96))	('colony formation', 'CPA', (26, 42))	('expression', 'Var', (5, 15))	('increased', 'PosReg', (16, 25))	('RWPE1', 'CellLine', 'CVCL:3791', (122, 127))	('MCM8', 'Gene', (0, 4))
469760	28481876	These biological changes were accompanied by drops of DNA replication licensing of Cdt1 (average 66.7% for M8P#5 and M8P#7), MCM6 (average 59.2%) and MCM7 (average 78.7%), suggesting that down-regulation of MCM8 have significant negative impact on DNA replication licensing.	('MCM7', 'Gene', (150, 154))	('Cdt1', 'Gene', '81620', (83, 87))	('MCM6', 'Gene', '4175', (125, 129))	('M8P#7', 'Var', (117, 122))	('Cdt1', 'Gene', (83, 87))	('DNA replication licensing', 'MPA', (54, 79))	('M8P#5', 'Var', (107, 112))	('drops', 'NegReg', (45, 50))	('down-regulation', 'NegReg', (188, 203))	('MCM7', 'Gene', '4176', (150, 154))	('MCM6', 'Gene', (125, 129))
469761	28481876	Similar results were also found when DU145 (51% knocked-down for M8D#1 and 75% for M8D#4) and LNCaP (65% for M8L#3 and 63% M8L#5) cells were knocked down with shRNA specific for MCM8: 65% drop (p<0.01) in S-phase cells and 94% drop (p<0.01) in colony formation for DU145, and 44% drop (p<0.01) in S-phase cells and 91% drop (p<0.01) in colony formation for LNCaP cells.	('drop', 'NegReg', (319, 323))	('S-phase cells', 'CPA', (205, 218))	('DU145', 'CellLine', 'CVCL:0105', (37, 42))	('LNCaP', 'CellLine', 'CVCL:0395', (94, 99))	('drop', 'NegReg', (227, 231))	('colony formation', 'CPA', (336, 352))	('LNCaP', 'CellLine', 'CVCL:0395', (357, 362))	('drop', 'NegReg', (280, 284))	('DU145', 'CellLine', 'CVCL:0105', (265, 270))	('knocked', 'Var', (141, 148))	('drop', 'NegReg', (188, 192))	('colony formation', 'CPA', (244, 260))
469762	28481876	Over-expression of MCM8 in non-transforming prostate epithelial cells RWPE1 (RM8#2 and RM8#9, average 2.3 fold) resulted in 2.5 fold increase of S-phase entry in average (figure 3A and B).	('RWPE1', 'CellLine', 'CVCL:3791', (70, 75))	('RM8', 'Var', (87, 90))	('MCM8', 'Gene', (19, 23))	('S-phase entry', 'MPA', (145, 158))	('increase', 'PosReg', (133, 141))
469767	28481876	As shown in figure 3E-F, mice treated with doxycycline water (5mug/ml) had 74.3% (p<0.01) decrease in tumor volume for M8P#5 cells and 65% (p<0.01) decrease for M8D#1 cells, in comparison with the untreated controls.	('mice', 'Species', '10090', (25, 29))	('doxycycline water', 'Chemical', '-', (43, 60))	('decrease', 'NegReg', (90, 98))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('M8P#', 'Var', (119, 123))	('decrease', 'NegReg', (148, 156))	('tumor', 'Disease', (102, 107))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))
469780	28481876	To validate the interaction between MCM8 and cyclin D1 in vitro, MCM8 coding region was segmented into 4 regions: MCM8N (aa2-204), MCM8M1 (aa205-409), MCM8M2 (aa409-618), MCM8C (aa615-880).	('men', 'Species', '9606', (91, 94))	('aa409-618', 'Var', (159, 168))	('cyclin D1', 'Gene', '595', (45, 54))	('aa205-409', 'Var', (139, 148))	('cyclin D1', 'Gene', (45, 54))
469784	28481876	The results of the binding assays indicate that GST-MCM8M1 (aa408-618) bound with cyclin D1 in the cell-free system (figure 4D and E), while GST-MCM8N, GST-MCM8M2, and GST-MCM8C were negative in the binding assays.	('cyclin D1', 'Gene', '595', (82, 91))	('GST-MCM8M1', 'Var', (48, 58))	('bound', 'Interaction', (71, 76))	('cyclin D1', 'Gene', (82, 91))
469787	28481876	A series of deletion mutants of GST-MCM8M1 were assayed to identify the motif that is required for interaction with cyclin D1.	('cyclin D1', 'Gene', '595', (116, 125))	('deletion', 'Var', (12, 20))	('cyclin D1', 'Gene', (116, 125))	('GST-MCM8M1', 'Gene', (32, 42))
469788	28481876	A stretch of 30 amino acid sequence located in 261-290 of MCM8 was found crucial for MCM8 binding with cyclin D1 because the fusion proteins with deletion of this sequence did not bind with cyclin D1, while all proteins containing this sequence bound with cyclin D1 (figure 4D and E).	('cyclin D1', 'Gene', '595', (190, 199))	('deletion', 'Var', (146, 154))	('bind', 'Interaction', (180, 184))	('cyclin D1', 'Gene', (190, 199))	('cyclin D1', 'Gene', '595', (256, 265))	('cyclin D1', 'Gene', (256, 265))	('MCM8', 'Gene', (85, 89))	('cyclin D1', 'Gene', '595', (103, 112))	('bound', 'Interaction', (245, 250))	('cyclin D1', 'Gene', (103, 112))
469790	28481876	Interestingly, in vitro binding assays indicate that the presence of MCM8 produced a multi-protein complex that includes CDK4, cyclin D1and MCM8 (figure 5A).	('CDK4', 'Gene', '1019', (121, 125))	('presence', 'Var', (57, 65))	('cyclin D1', 'Gene', '595', (127, 136))	('MCM8', 'Gene', (69, 73))	('cyclin D1', 'Gene', (127, 136))	('CDK4', 'Gene', (121, 125))
469792	28481876	As shown in figure 5, the presence of recombinant GST-MCM8 enhanced kinase activity of CDK4 and reduced the Km value by 6.8 fold (455 muM vs. 3100 muM) in comparison with cyclin D1/CDK4 alone.	('muM', 'Gene', '56925', (134, 137))	('GST-MCM8', 'Gene', (50, 58))	('muM', 'Gene', (147, 150))	('muM', 'Gene', (134, 137))	('enhanced', 'PosReg', (59, 67))	('cyclin D1', 'Gene', '595', (171, 180))	('cyclin D1', 'Gene', (171, 180))	('kinase activity', 'MPA', (68, 83))	('CDK4', 'Gene', (181, 185))	('Km value', 'MPA', (108, 116))	('presence', 'Var', (26, 34))	('CDK4', 'Gene', '1019', (181, 185))	('CDK4', 'Gene', '1019', (87, 91))	('CDK4', 'Gene', (87, 91))	('muM', 'Gene', '56925', (147, 150))	('reduced', 'NegReg', (96, 103))
469795	28481876	The peptide corresponding to aa261-290 of MCM8 blocked the kinase enhancement effect of MCM8 on CDK4/cyclin D1 complex (figure 5B).	('cyclin D1', 'Gene', '595', (101, 110))	('men', 'Species', '9606', (73, 76))	('cyclin D1', 'Gene', (101, 110))	('kinase enhancement', 'MPA', (59, 77))	('MCM8', 'Gene', (88, 92))	('blocked', 'NegReg', (47, 54))	('aa261-290', 'Var', (29, 38))	('CDK4', 'Gene', (96, 100))	('MCM8', 'Gene', (42, 46))	('CDK4', 'Gene', '1019', (96, 100))
469799	28481876	The in vitro CDK4 kinase activity also showed similar decreases when MCM8 was knocked down in these cell lines (figure 6B).	('knocked down', 'Var', (78, 90))	('CDK4', 'Gene', '1019', (13, 17))	('CDK4', 'Gene', (13, 17))	('decreases', 'NegReg', (54, 63))	('MCM8', 'Gene', (69, 73))
469801	28481876	To examine whether binding of MCM8 with cyclin D1 is required for CDK4 kinase activation, a mutant MCM8 that contains only 31 amino acids from MCM8 (aa1,261-290) and FLAG-TAG sequence was ligated into pCDNA4 to create pCDNA4-CBM-FLAG (cyclin D1 binding motif-FLAG) to interfere the binding between MCM8 and cyclin D1.	('cyclin D1', 'Gene', '595', (307, 316))	('cyclin D1', 'Gene', (307, 316))	('cyclin D1', 'Gene', '595', (235, 244))	('binding', 'Interaction', (282, 289))	('cyclin D1', 'Gene', (235, 244))	('cyclin D1', 'Gene', '595', (40, 49))	('MCM8', 'Gene', (99, 103))	('cyclin D1', 'Gene', (40, 49))	('mutant', 'Var', (92, 98))	('CDK4', 'Gene', (66, 70))	('CDK4', 'Gene', '1019', (66, 70))
469802	28481876	As shown in figure 6A, induction of mutant MCM8 effectively decreased the phosphorylation level of Rb, in comparison with uninduced controls.	('phosphorylation level', 'MPA', (74, 95))	('decreased', 'NegReg', (60, 69))	('Rb', 'Phenotype', 'HP:0009919', (99, 101))	('Rb', 'Gene', '5925', (99, 101))	('MCM8', 'Gene', (43, 47))	('mutant', 'Var', (36, 42))
469803	28481876	Similar decreases were also identified in the in vitro kinase assays (figure 6B), while MCM8 mutant that contains no cyclin D1 binding motif had no impact on Rb phosphorylation (figure 6A-B), DNA replication licensing and cell cycle S-phase entry (figure 3B).	('cyclin D1', 'Gene', (117, 126))	('phosphorylation', 'MPA', (161, 176))	('DNA replication licensing', 'CPA', (192, 217))	('Rb', 'Phenotype', 'HP:0009919', (158, 160))	('MCM8', 'Gene', (88, 92))	('mutant', 'Var', (93, 99))	('Rb', 'Gene', '5925', (158, 160))	('cell cycle S-phase entry', 'CPA', (222, 246))	('cyclin D1', 'Gene', '595', (117, 126))
469806	28481876	Interestingly, over-expression of cyclin D1 partially reversed the inhibitory effect induced by MCM8 knockdown (58-65% for M8P#5 and 41-67% for M8D#1) in cell cycle analysis (figure 6C and D), probably due to forcing more CDK4/cyclin D1 complex formation due to a larger quantity of cyclin D1.	('cell cycle analysis', 'CPA', (154, 173))	('cyclin D1', 'Gene', (227, 236))	('cyclin D1', 'Gene', '595', (283, 292))	('CDK4', 'Gene', (222, 226))	('inhibitory effect', 'MPA', (67, 84))	('cyclin D1', 'Gene', (283, 292))	('complex', 'Interaction', (237, 244))	('more', 'PosReg', (217, 221))	('cyclin D1', 'Gene', '595', (34, 43))	('CDK4', 'Gene', '1019', (222, 226))	('over-expression', 'PosReg', (15, 30))	('MCM8', 'Gene', (96, 100))	('cyclin D1', 'Gene', (34, 43))	('cyclin D1', 'Gene', '595', (227, 236))	('knockdown', 'Var', (101, 110))
469809	28481876	Mutations of MCM8 resulted in human gonadal failure.	('human', 'Species', '9606', (30, 35))	('gonadal failure', 'Disease', 'MESH:D006058', (36, 51))	('MCM8', 'Gene', (13, 17))	('gonadal failure', 'Disease', (36, 51))	('Mutations', 'Var', (0, 9))	('resulted in', 'Reg', (18, 29))
469812	28481876	Most aggressive cancer genomes demonstrate extensive chromosome rearrangement, deletion, and amplification of genes critical to cell survival, growth and migration.	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('men', 'Species', '9606', (73, 76))	('aggressive cancer', 'Disease', 'MESH:D009369', (5, 22))	('aggressive cancer', 'Disease', (5, 22))	('amplification', 'MPA', (93, 106))	('chromosome rearrangement', 'CPA', (53, 77))	('deletion', 'Var', (79, 87))
469815	28481876	It is possible that MCM8 serves as one of the assembly factors in building CDK4/cyclin D1 complex since the presence of MCM8 enhanced the recruitment of CDK4/cyclin D1 complex.	('presence', 'Var', (108, 116))	('recruitment', 'MPA', (138, 149))	('men', 'Species', '9606', (145, 148))	('CDK4', 'Gene', '1019', (153, 157))	('CDK4', 'Gene', (153, 157))	('cyclin D1', 'Gene', (80, 89))	('CDK4', 'Gene', (75, 79))	('MCM8', 'Gene', (120, 124))	('cyclin D1', 'Gene', '595', (158, 167))	('CDK4', 'Gene', '1019', (75, 79))	('cyclin D1', 'Gene', (158, 167))	('enhanced', 'PosReg', (125, 133))	('cyclin D1', 'Gene', '595', (80, 89))
469816	28481876	In addition, our analysis showed that MCM8 is crucial in CDK4 activation by significantly lowering the substrate threshold required for CDK4 kinase activation.	('substrate threshold required', 'MPA', (103, 131))	('CDK4', 'Gene', (57, 61))	('MCM8', 'Var', (38, 42))	('CDK4', 'Gene', (136, 140))	('CDK4', 'Gene', '1019', (57, 61))	('CDK4', 'Gene', '1019', (136, 140))	('lowering', 'NegReg', (90, 98))
469818	28481876	Indeed, forced expression of MCM8 in cancer cell lines resulted in dramatic increase of cell entry into S phase in non-transformed cells, while knocked down of MCM8 generates growth arrest of cancer cells.	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('MCM8', 'Gene', (29, 33))	('MCM8', 'Gene', (160, 164))	('increase', 'PosReg', (76, 84))	('growth arrest of cancer', 'Disease', (175, 198))	('cancer', 'Disease', (37, 43))	('knocked down', 'Var', (144, 156))	('cell entry into S phase', 'CPA', (88, 111))	('cancer', 'Disease', (192, 198))	('cancer', 'Disease', 'MESH:D009369', (192, 198))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('growth arrest', 'Phenotype', 'HP:0001510', (175, 188))	('growth arrest of cancer', 'Disease', 'MESH:D006323', (175, 198))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))
469819	28481876	Over-expression of MCM8 may produce two consequences: Promoting cell growth through increasing phosphorylation and inactivation of Rb molecule and promoting DNA recombination that produces abnormal chromosome rearrangements and mutations.	('increasing', 'PosReg', (84, 94))	('promoting', 'PosReg', (147, 156))	('DNA recombination', 'CPA', (157, 174))	('inactivation', 'MPA', (115, 127))	('Promoting', 'PosReg', (54, 63))	('MCM8', 'Gene', (19, 23))	('chromosome rearrangements', 'CPA', (198, 223))	('men', 'Species', '9606', (218, 221))	('cell growth', 'CPA', (64, 75))	('abnormal chromosome', 'Phenotype', 'HP:0031411', (189, 208))	('Over-expression', 'Var', (0, 15))	('Rb', 'Gene', '5925', (131, 133))	('Rb', 'Phenotype', 'HP:0009919', (131, 133))	('phosphorylation', 'MPA', (95, 110))	('mutations', 'MPA', (228, 237))
469820	28481876	As a result, abnormal expression of MCM8 could be one of the fundamental causes that initiate the carcinogenic process.	('carcinogenic process', 'Disease', (98, 118))	('men', 'Species', '9606', (66, 69))	('MCM8', 'Gene', (36, 40))	('abnormal', 'Var', (13, 21))	('expression', 'MPA', (22, 32))	('carcinogenic process', 'Disease', 'MESH:D009385', (98, 118))
469824	28481876	The continuing presence of MCM8 throughout the cell cycle may induce improper DNA synthesis that leads to genome instability of cancer cells, in addition to increased recruitment of larger proportion of cell population into the proliferation cycle.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('induce', 'Reg', (62, 68))	('MCM8', 'Var', (27, 31))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('recruitment', 'MPA', (167, 178))	('leads to', 'Reg', (97, 105))	('increased', 'PosReg', (157, 166))	('genome instability', 'MPA', (106, 124))	('improper DNA synthesis', 'MPA', (69, 91))	('men', 'Species', '9606', (174, 177))	('cancer', 'Disease', (128, 134))
469826	28481876	Overexpression of MCM8 gene in prostate immortalized epithelial cells inducing marked transformation underlies the important role of this gene in cancer development.	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('inducing', 'Reg', (70, 78))	('Overexpression', 'Var', (0, 14))	('men', 'Species', '9606', (160, 163))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('marked transformation', 'CPA', (79, 100))	('MCM8', 'Gene', (18, 22))
469833	28481876	The genomes of these cell lines were tested for a short tandem repeat (STR) DNA profile on eight different loci (CSF1PO, D13S317, D16S539, D5S818, D7S820, THO1, TPOX, and vWA) of the genomes by PCR using the primer sets for CSF1PO, D13S317, D16S539, D5S818, D7S820, TH01, TPOX, vWA recommended by ATCC on April 22, 2016 (latest).	('THO1', 'Gene', (155, 159))	('THO1', 'Gene', '9984', (155, 159))	('D5S818', 'Var', (250, 256))	('D7S820', 'Var', (258, 264))	('D16S539', 'Var', (241, 248))	('men', 'Species', '9606', (287, 290))	('D13S317', 'Var', (232, 239))
469834	28481876	All antibodies were purchased from Santa Cruz Biotechnology, Inc. (Santa Cruz, CA), including: Antibodies for MCM6 (sc-55577), MCM7 (sc-9966), MCM8 (sc-47117), Cdt1 (sc-28262), CCND1 (sc-20044), p27 (sc-1641), p21 (sc-6246), CDK4 (sc-136241), Rb (sc-102), pRb (sc-271930) and beta-actin (sc-47778).	('MCM7', 'Gene', (127, 131))	('beta-actin', 'Gene', (276, 286))	('Rb', 'Gene', '5925', (243, 245))	('Cdt1', 'Gene', '81620', (160, 164))	('Cdt1', 'Gene', (160, 164))	('MCM7', 'Gene', '4176', (127, 131))	('CCND1', 'Gene', '595', (177, 182))	('Rb', 'Gene', '5925', (257, 259))	('sc-136241', 'Var', (231, 240))	('CDK4', 'Gene', (225, 229))	('CCND1', 'Gene', (177, 182))	('Rb', 'Phenotype', 'HP:0009919', (243, 245))	('pRb', 'Gene', (256, 259))	('Rb', 'Phenotype', 'HP:0009919', (257, 259))	('p27', 'Gene', '3429', (195, 198))	('beta-actin', 'Gene', '728378', (276, 286))	('CDK4', 'Gene', '1019', (225, 229))	('p27', 'Gene', (195, 198))	('pRb', 'Gene', '5925', (256, 259))	('MCM6', 'Gene', '4175', (110, 114))	('p21', 'Gene', (210, 213))	('p21', 'Gene', '644914', (210, 213))	('MCM6', 'Gene', (110, 114))
469855	28481876	Power analysis were performed based on the assumption that 75% mice xenografted with M8P#5 and M8D#1 without doxycycline treatment may die in 6 weeks, while mice treated with doxycycline may have a mortality of 27% in the same period.	('men', 'Species', '9606', (126, 129))	('mice', 'Species', '10090', (157, 161))	('M8D#1', 'Var', (95, 100))	('doxycycline', 'Chemical', 'MESH:D004318', (109, 120))	('mice', 'Species', '10090', (63, 67))	('M8P#5', 'Var', (85, 90))	('doxycycline', 'Chemical', 'MESH:D004318', (175, 186))
469866	28481876	Groups were segregated based on MCM8 gain or non-gain status (figure 1) or MCM8 expression score>=2 or <2 status (figure 2) or treated with or without doxycycline (figure 3).	('MCM8', 'Gene', (32, 36))	('>=2', 'Var', (96, 99))	('MCM8', 'Gene', (75, 79))	('non-gain', 'NegReg', (45, 53))	('gain', 'PosReg', (37, 41))	('doxycycline', 'Chemical', 'MESH:D004318', (151, 162))
469889	28725753	Additionally, ECM rigidity, cell tension, and changes in cell geometry activate a YAP-dependent mechanoresponse independent of Hippo signaling.	('activate', 'PosReg', (71, 79))	('ECM rigidity', 'Disease', 'MESH:D009127', (14, 26))	('changes', 'Var', (46, 53))	('YAP-dependent mechanoresponse', 'MPA', (82, 111))	('rigidity', 'Phenotype', 'HP:0002063', (18, 26))	('ECM rigidity', 'Disease', (14, 26))
469911	28725753	Overall, the median fibroblast count with nYAP expression was 35.4 cells/HPF in the tumoral stroma, which was nearly 10 times higher than that found in the benign stroma (3.9 cells/HPF; Table 1).	('tumoral stroma', 'Disease', (84, 98))	('tumoral stroma', 'Disease', 'MESH:D009369', (84, 98))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('nYAP', 'Chemical', '-', (42, 46))	('nYAP expression', 'Var', (42, 57))
469926	28725753	In our study, we found that high level of nYAP in CAFs is associated with perineural invasion, with fibroblasts that have a low level of cpYAP expression indicating a more aggressive pattern of invasion.	('perineural', 'Disease', (74, 84))	('associated', 'Reg', (58, 68))	('CAF', 'Gene', (50, 53))	('CAF', 'Gene', '8850', (50, 53))	('nYAP', 'Chemical', '-', (42, 46))	('nYAP', 'Var', (42, 46))	('aggressive pattern', 'Phenotype', 'HP:0000718', (172, 190))
469930	28725753	In conclusion, strong nYAP staining in perineural invasion associated with stromal fibroblasts in head and neck squamous cell carcinoma suggests that YAP-mediated transcription programs may contribute to perineural invasion.	('contribute', 'Reg', (190, 200))	('nYAP', 'Chemical', '-', (22, 26))	('perineural invasion', 'CPA', (204, 223))	('nYAP staining', 'Var', (22, 35))	('perineural invasion', 'CPA', (39, 58))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (112, 135))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (98, 135))	('neck squamous cell carcinoma', 'Disease', (107, 135))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (107, 135))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))
469931	27759562	TP53 exon-6 truncating mutations produce separation of function isoforms with pro-tumorigenic functions TP53 truncating mutations are common in human tumors and are thought to give rise to p53-null alleles.	('tumors', 'Disease', (150, 156))	('TP53', 'Gene', '7157', (0, 4))	('truncating mutations', 'Var', (109, 129))	('TP53', 'Gene', (0, 4))	('TP53', 'Gene', '7157', (104, 108))	('TP53', 'Gene', (104, 108))	('tumors', 'Disease', 'MESH:D009369', (150, 156))	('human', 'Species', '9606', (144, 149))	('tumors', 'Phenotype', 'HP:0002664', (150, 156))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))
469932	27759562	Here, we show that TP53 exon-6 truncating mutations occur at higher than expected frequencies and produce proteins that lack canonical p53 tumor suppressor activities but promote cancer cell proliferation, survival, and metastasis.	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('survival', 'CPA', (206, 214))	('truncating mutations', 'Var', (31, 51))	('promote', 'PosReg', (171, 178))	('tumor', 'Disease', (139, 144))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('cancer', 'Disease', (179, 185))	('TP53 exon-6', 'Gene', (19, 30))	('metastasis', 'CPA', (220, 230))
469933	27759562	Accordingly, these mutants can localize to the mitochondria where they promote tumor phenotypes by binding and activating the mitochondria inner pore permeability regulator, Cyclophilin D (CypD).	('promote', 'PosReg', (71, 78))	('tumor', 'Disease', (79, 84))	('Cyclophilin D', 'Gene', (174, 187))	('activating', 'PosReg', (111, 121))	('mutants', 'Var', (19, 26))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('binding', 'Interaction', (99, 106))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('Cyclophilin D', 'Gene', '10105', (174, 187))
469934	27759562	Together, our studies reveal that TP53 exon-6 truncating mutations, contrary to current beliefs, act beyond p53 loss to promote tumorigenesis, and could inform the development of strategies to target cancers driven by these prevalent mutations.	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('TP53', 'Gene', (34, 38))	('cancers', 'Disease', 'MESH:D009369', (200, 207))	('cancers', 'Phenotype', 'HP:0002664', (200, 207))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('cancers', 'Disease', (200, 207))	('promote', 'PosReg', (120, 127))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumor', 'Disease', (128, 133))	('truncating mutations', 'Var', (46, 66))
469936	27759562	Genetic studies show that, in most tumors, TP53 point mutations co-occur with the loss of one copy of the TP53 gene (LOH) due to deletions in chromosome 17 where the TP53 locus is located.	('deletions', 'Var', (129, 138))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('TP53 gene', 'Gene', (106, 115))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('tumors', 'Disease', (35, 41))	('tumors', 'Disease', 'MESH:D009369', (35, 41))	('loss', 'NegReg', (82, 86))	('point mutations', 'Var', (48, 63))	('TP53', 'Gene', (43, 47))
469938	27759562	The high frequency of these mutations led to the hypothesis that these hotspot mutations could not only result in loss of function activities, but also could confer an advantage of growth to cancer cells.	('growth', 'CPA', (181, 187))	('cancer', 'Disease', (191, 197))	('cancer', 'Disease', 'MESH:D009369', (191, 197))	('loss', 'NegReg', (114, 118))	('function activities', 'MPA', (122, 141))	('advantage', 'PosReg', (168, 177))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('mutations', 'Var', (79, 88))
469939	27759562	Indeed, many lines of evidence have now demonstrated that certain p53 missense mutants could exhibit a gain of function activities during tumorigenesis.	('missense mutants', 'Var', (70, 86))	('tumor', 'Disease', (138, 143))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('gain of function', 'PosReg', (103, 119))	('p53', 'Gene', (66, 69))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
469940	27759562	For instance, some of the gain of function mutations, including R175H, R248Q, R273H, resulted in an increase in cell invasion, cell migration, cell proliferation and anti-apoptosis in different in-vitro models.	('cell invasion', 'CPA', (112, 125))	('cell migration', 'CPA', (127, 141))	('gain of function', 'PosReg', (26, 42))	('R248Q', 'Mutation', 'rs11540652', (71, 76))	('cell proliferation', 'CPA', (143, 161))	('anti-apoptosis', 'CPA', (166, 180))	('R273H', 'Var', (78, 83))	('R273H', 'Mutation', 'rs28934576', (78, 83))	('R175H', 'Mutation', 'rs28934578', (64, 69))	('R248Q', 'Var', (71, 76))	('R175H', 'Var', (64, 69))	('increase', 'PosReg', (100, 108))
469941	27759562	Additionally, mice expressing TP53 R172H (human R175H) and R270H (human R273H) mutations manifest a broad spectrum of aggressive tumors that are more metastatic in nature when compared to p53-null mice.	('R172H', 'Mutation', 'p.R172H', (35, 40))	('TP53 R172H', 'Var', (30, 40))	('R273H', 'Mutation', 'rs28934576', (72, 77))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('human', 'Species', '9606', (42, 47))	('aggressive tumors', 'Disease', 'MESH:D001523', (118, 135))	('mice', 'Species', '10090', (14, 18))	('R270H', 'Var', (59, 64))	('human', 'Species', '9606', (66, 71))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('aggressive tumors', 'Disease', (118, 135))	('R270H', 'Mutation', 'rs55819519', (59, 64))	('mice', 'Species', '10090', (197, 201))	('R175H', 'Mutation', 'rs28934578', (48, 53))
469942	27759562	Though different gain of function mutants exhibit various pro-tumorigenic phenotypes, their mechanism of function mostly relies on alterations to the p53 transcription program.	('mutants', 'Var', (34, 41))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', (62, 67))	('gain of function', 'PosReg', (17, 33))	('p53', 'Gene', (150, 153))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
469943	27759562	In this study, we similarly report that certain TP53 truncating mutations promote tumorigenesis rather than halt it.	('truncating mutations', 'Var', (53, 73))	('promote', 'PosReg', (74, 81))	('TP53', 'Gene', (48, 52))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumor', 'Disease', (82, 87))
469944	27759562	As we have shown in this study, these p53 mutants lack transcriptional activity and, instead, have phenotypes that depend on their molecular and functional interactions with Cyclophilin D in the mitochondria.	('mutants', 'Var', (42, 49))	('p53', 'Gene', (38, 41))	('Cyclophilin D', 'Gene', (174, 187))	('transcriptional activity', 'MPA', (55, 79))	('lack', 'NegReg', (50, 54))	('interactions', 'Interaction', (156, 168))	('Cyclophilin D', 'Gene', '10105', (174, 187))
469945	27759562	Much like EGFR, ROS and ALK mutations have been candidates for precision medicine, the relatively frequent distribution of exon-6 TP53 truncating mutations in certain tumors, combined with the availability of CypD inhibitors, implies that these mutations may similarly be successfully targeted with precision medicine.	('EGFR', 'Gene', '1956', (10, 14))	('ALK', 'Gene', '238', (24, 27))	('tumors', 'Disease', 'MESH:D009369', (167, 173))	('EGFR', 'Gene', (10, 14))	('ROS', 'Chemical', '-', (16, 19))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('ALK', 'Gene', (24, 27))	('TP53', 'Gene', (130, 134))	('tumors', 'Disease', (167, 173))	('truncating mutations', 'Var', (135, 155))	('tumors', 'Phenotype', 'HP:0002664', (167, 173))
469947	27759562	Studies were selected for inclusion on the basis of having more than 100 samples per tumor type and at least 10 tumors with TP53 mutations (Supplementary file 1).	('tumor', 'Disease', (85, 90))	('mutations', 'Var', (129, 138))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('TP53', 'Gene', (124, 128))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('tumor', 'Disease', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumors', 'Disease', 'MESH:D009369', (112, 118))	('tumors', 'Disease', (112, 118))
469949	27759562	We also observed that the distribution of TP53 mutations differs in various tumor types, ranging from 7.3 to 94.9% in the case of multiple myeloma (MM) and ovarian serous cystadenocarcinoma (OVCA) respectively (Supplementary file 1).	('ovarian serous cystadenocarcinoma', 'Phenotype', 'HP:0012887', (156, 189))	('carcinoma', 'Phenotype', 'HP:0030731', (180, 189))	('TP53', 'Gene', (42, 46))	('tumor', 'Disease', (76, 81))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('mutations', 'Var', (47, 56))	('multiple myeloma (MM) and ovarian serous cystadenocarcinoma', 'Disease', 'MESH:D018284', (130, 189))	('multiple myeloma', 'Phenotype', 'HP:0006775', (130, 146))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
469953	27759562	This phenomenon is best exemplified by our observations of lung small cell carcinoma (LUSCC) wherein, despite the nearly ubiquitous presence of TP53 alterations, we found no exon-6 truncations (Figure 1F and Figure 1:figure supplement 3).	('TP53', 'Gene', (144, 148))	('alterations', 'Var', (149, 160))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('lung small cell carcinoma', 'Disease', 'MESH:D055752', (59, 84))	('lung small cell carcinoma', 'Phenotype', 'HP:0030357', (59, 84))	('lung small cell carcinoma', 'Disease', (59, 84))	('lung small', 'Phenotype', 'HP:0002089', (59, 69))
469954	27759562	Strikingly, in the MSKCC cohort, we found a statistically significant increase in the frequency of TP53 exon-6 truncating mutations in colorectal cancer (CRC) metastatic site tumors with respect to primary tumors (Figure 1G and Supplementary file 3).	('tumors', 'Disease', (175, 181))	('tumors', 'Disease', 'MESH:D009369', (175, 181))	('tumors', 'Phenotype', 'HP:0002664', (175, 181))	('colorectal cancer', 'Disease', 'MESH:D015179', (135, 152))	('increase', 'PosReg', (70, 78))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('tumors', 'Phenotype', 'HP:0002664', (206, 212))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('colorectal cancer', 'Disease', (135, 152))	('tumors', 'Disease', (206, 212))	('tumors', 'Disease', 'MESH:D009369', (206, 212))	('colorectal cancer', 'Phenotype', 'HP:0003003', (135, 152))	('primary tumors', 'Disease', (198, 212))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('truncating mutations', 'Var', (111, 131))	('primary tumors', 'Disease', 'MESH:D009369', (198, 212))	('TP53 exon-6', 'Gene', (99, 110))
469955	27759562	This is reminiscent of a previous study in which an analysis of colorectal cancers revealed an increased representation of TP53 exon-6 mutations in liver metastases.	('colorectal cancers', 'Disease', 'MESH:D015179', (64, 82))	('cancers', 'Phenotype', 'HP:0002664', (75, 82))	('colorectal cancers', 'Disease', (64, 82))	('mutations', 'Var', (135, 144))	('liver metastases', 'Disease', (148, 164))	('liver metastases', 'Disease', 'MESH:D009362', (148, 164))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('colorectal cancer', 'Phenotype', 'HP:0003003', (64, 81))	('TP53', 'Gene', (123, 127))
469956	27759562	Although we found an increase in In-Frame indel mutations in metastatic tumors compared to primary tumors, this increase was not deemed statistically significant as the number of primary tumors identified with mutations was very low (n = 3 for primary and n = 10 for metastasis).	('primary tumors', 'Disease', (179, 193))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumors', 'Disease', 'MESH:D009369', (99, 105))	('In-Frame indel mutations', 'Var', (33, 57))	('primary tumors', 'Disease', 'MESH:D009369', (179, 193))	('metastatic', 'Disease', (61, 71))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('tumors', 'Disease', (72, 78))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumors', 'Disease', (187, 193))	('primary tumors', 'Disease', (91, 105))	('tumors', 'Disease', 'MESH:D009369', (187, 193))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))	('tumors', 'Phenotype', 'HP:0002664', (187, 193))	('primary tumors', 'Disease', 'MESH:D009369', (91, 105))	('tumors', 'Disease', (99, 105))
469957	27759562	On the other hand, and as has been demonstrated for a gain of function TP53 mutations, higher than expected frequency of TP53 exon-6 truncating mutations could instead underlie a selective advantage during tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('mutations', 'Var', (76, 85))	('tumor', 'Disease', (206, 211))	('TP53', 'Gene', (121, 125))	('TP53', 'Gene', (71, 75))	('tumor', 'Disease', 'MESH:D009369', (206, 211))
469958	27759562	To test this hypothesis, we generated cell lines ectopically expressing multiple p53 C-terminal truncated proteins mirroring the R213* and R196* exon-6 p53 truncating mutants, and compared their activities to p53 full length (i.e., p53-WT), a longer p53 truncating mutant (G325*) and a shorter p53 truncating mutant (W146*) (Figure 2A and B and Figure 2:figure supplement 2).	('activities', 'MPA', (195, 205))	('R213*', 'SUBSTITUTION', 'None', (129, 134))	('G325*', 'Var', (273, 278))	('G325*', 'SUBSTITUTION', 'None', (273, 278))	('R196*', 'SUBSTITUTION', 'None', (139, 144))	('W146*', 'Var', (317, 322))	('W146*', 'SUBSTITUTION', 'None', (317, 322))	('R196*', 'Var', (139, 144))	('R213*', 'Var', (129, 134))
469959	27759562	As it is consistent with their lack of tumor suppressor activities, different p53 C-terminal truncating proteins ectopically expressed in a p53 homozygous deletion cell line (H1299) failed to decrease cell viability (Figure 2C).	('decrease', 'NegReg', (192, 200))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('cell viability', 'CPA', (201, 215))	('deletion', 'Var', (155, 163))	('tumor', 'Disease', (39, 44))	('H1299', 'CellLine', 'CVCL:0060', (175, 180))	('p53', 'Gene', (140, 143))
469960	27759562	Yet, as shown in Figure 2, ectopic expression of TP53 exon-6 truncations in A549 cell line (lung cancer-derived epithelial line) induced changes in the morphological appearances of cells (Figure 2D) and the acquisition of mesenchymal-like features such as (i) the transition of filamentous actin from a cortical distribution to stress fibers formation (Figure 2D), (ii) decreased expression and localization of E-cadherin (Figure 2D and E), (iii) increased expression of vimentin, and (iv) increased expression of the master regulators of epithelial to mesenchymal transition (EMT): Slug, Snail and Zeb1 (Figure 2E).	('TP53 exon-6 truncations', 'Var', (49, 72))	('lung cancer', 'Phenotype', 'HP:0100526', (92, 103))	('increased', 'PosReg', (490, 499))	('localization', 'MPA', (395, 407))	('vimentin', 'Gene', '7431', (471, 479))	('vimentin', 'Gene', (471, 479))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('Zeb1', 'Gene', '6935', (599, 603))	('Snail', 'Gene', (589, 594))	('increased', 'PosReg', (447, 456))	('expression', 'MPA', (380, 390))	('expression', 'MPA', (500, 510))	('Slug', 'Gene', (583, 587))	('lung cancer', 'Disease', (92, 103))	('Zeb1', 'Gene', (599, 603))	('stress fibers formation', 'CPA', (328, 351))	('decreased', 'NegReg', (370, 379))	('changes', 'Reg', (137, 144))	('expression', 'MPA', (457, 467))	('truncations', 'Var', (61, 72))	('A549', 'CellLine', 'CVCL:0023', (76, 80))	('E-cadherin', 'Gene', (411, 421))	('lung cancer', 'Disease', 'MESH:D008175', (92, 103))	('cortical distribution', 'CPA', (303, 324))	('E-cadherin', 'Gene', '999', (411, 421))	('Snail', 'Gene', '6615', (589, 594))	('Slug', 'Gene', '6591', (583, 587))
469961	27759562	As these features are typically associated with metastatic spread, we next employed a melanoma model to compare the lung colonization potential of diverse p53 truncating mutants.	('melanoma', 'Disease', 'MESH:D008545', (86, 94))	('melanoma', 'Phenotype', 'HP:0002861', (86, 94))	('p53', 'Gene', (155, 158))	('melanoma', 'Disease', (86, 94))	('lung colonization potential', 'CPA', (116, 143))	('truncating mutants', 'Var', (159, 177))
469962	27759562	Specifically, we injected B16-F1 melanoma murine cells ectopically expressing the p53 W146*, R213*, G325* mutants, as well as the vector control Td-Tomato (Figure 2:figure supplement 2), into C57BL/6J mice via tail vein as previously described.	('Tomato', 'Species', '4081', (148, 154))	('melanoma', 'Phenotype', 'HP:0002861', (33, 41))	('G325*', 'SUBSTITUTION', 'None', (100, 105))	('melanoma', 'Disease', (33, 41))	('melanoma', 'Disease', 'MESH:D008545', (33, 41))	('mice', 'Species', '10090', (201, 205))	('W146*', 'Var', (86, 91))	('R213*', 'Var', (93, 98))	('murine', 'Species', '10090', (42, 48))	('G325*', 'Var', (100, 105))	('R213*', 'SUBSTITUTION', 'None', (93, 98))	('W146*', 'SUBSTITUTION', 'None', (86, 91))	('B16-F1', 'CellLine', 'CVCL:0158', (26, 32))
469963	27759562	As shown in Figure 2H and I and Figure 2:figure supplement 4, at day 14 post-injection, we observed a dramatic increase in the number of melanoma colonies in lung in the case of cells expressing the p53 R213* mutant.	('melanoma colonies', 'Disease', 'MESH:D008545', (137, 154))	('increase', 'PosReg', (111, 119))	('R213*', 'Var', (203, 208))	('melanoma colonies', 'Disease', (137, 154))	('R213*', 'SUBSTITUTION', 'None', (203, 208))	('melanoma', 'Phenotype', 'HP:0002861', (137, 145))
469964	27759562	Yet, it has been shown that not all premature truncating transcripts undergo NMD, and that variation in NMD efficiency among different tissues, cell types and even individuals could lead to the expression of variable amounts of truncated proteins that could impact the clinical presentation and outcome of diseases.	('variation', 'Var', (91, 100))	('NMD efficiency', 'Disease', 'MESH:C536214', (104, 118))	('proteins', 'Protein', (238, 246))	('NMD efficiency', 'Disease', (104, 118))	('lead to', 'Reg', (182, 189))	('impact', 'Reg', (258, 264))	('clinical presentation', 'CPA', (269, 290))	('expression', 'MPA', (194, 204))	('truncated', 'MPA', (228, 237))
469965	27759562	For example, no NMD-mediated mRNA diminution was observed in the lymphoblasts and bone cells of patients carrying premature termination codons in the collagen X gene.	('collagen X', 'Gene', (150, 160))	('premature termination codons', 'Var', (114, 142))	('patients', 'Species', '9606', (96, 104))
469967	27759562	We confirmed that TP53 exon-6 truncating mutations partially escape NMD by western blot analysis of protein extracts from multiple tumor-derived cell lines harboring different TP53 mutations (Figure 3B).	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('TP53', 'Gene', (18, 22))	('escape', 'NegReg', (61, 67))	('NMD', 'MPA', (68, 71))	('tumor', 'Disease', (131, 136))	('TP53', 'Gene', (176, 180))	('mutations', 'Var', (181, 190))
469968	27759562	As shown in Figure 3C and in Figure 3:figure supplement 3, we observed that p53 exon-6 truncating mutants were indeed expressed in the SW684, Calu-6 and DMS114 cell extracts.	('SW684', 'CellLine', 'CVCL:1726', (135, 140))	('truncating mutants', 'Var', (87, 105))	('DMS114', 'Chemical', '-', (153, 159))	('exon-6', 'Gene', (80, 86))	('p53 exon-6', 'Gene', (76, 86))
469969	27759562	Having previously shown that these mutants are expressed in cancer cells, we next extended our functional studies to include cancer cell lines harboring TP53 exon-6 truncating mutations.	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('truncating mutations', 'Var', (165, 185))	('cancer', 'Disease', (60, 66))	('TP53', 'Gene', (153, 157))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('exon-6', 'Var', (158, 164))
469970	27759562	Acute inactivation of p53 (i.e., 2-4 days) with two independent p53 shRNAs in cells that exclusively expressed the p53 R213* and R196* mutants resulted in a down-regulation of EMT markers and up-regulation of E-cadherin (Figure 3D, and Figure 3:figure supplement 4A).	('R196*', 'Var', (129, 134))	('inactivation', 'NegReg', (6, 18))	('R213*', 'Var', (119, 124))	('E-cadherin', 'Gene', (209, 219))	('p53', 'Gene', (115, 118))	('R213*', 'SUBSTITUTION', 'None', (119, 124))	('R196*', 'SUBSTITUTION', 'None', (129, 134))	('down-regulation', 'NegReg', (157, 172))	('E-cadherin', 'Gene', '999', (209, 219))	('EMT markers', 'CPA', (176, 187))	('up-regulation', 'PosReg', (192, 205))
469971	27759562	This was consistent with the pro-metastatic activities we observed in cells ectopically expressing TP53 exon-6 truncating mutations and with the genetic data summarized in Figure 1 and Figure 2 Yet, prolonged inactivation (i.e., more than 6 days) of p53 in tumor-derived cell lines harboring TP53 exon-6 truncating mutations resulted in a dramatic decrease in the viability of the cells over time (Figure 3E and F).	('inactivation', 'NegReg', (209, 221))	('tumor', 'Disease', (257, 262))	('truncating mutations', 'Var', (304, 324))	('TP53', 'Gene', (292, 296))	('p53', 'Gene', (250, 253))	('tumor', 'Disease', 'MESH:D009369', (257, 262))	('decrease', 'NegReg', (348, 356))	('tumor', 'Phenotype', 'HP:0002664', (257, 262))	('viability of the cells over time', 'CPA', (364, 396))
469972	27759562	This appeared to be unique to cells expressing the R213* and R196* exon-6 truncating mutations (SW684, DMS114 and Calu-6) as silencing p53 in cell lines harboring (i) a wild type p53 allele (A549 and MCF7 cells), (ii) a 'hotspot' missense p53 mutant (AU565), (iii) a longer truncation (HCC1937), (iv) a shorter truncation (H2126), or (v) a p53 homozygous deletion (H1299) did not affect the number of viable cells (Figure 3F and G).	('silencing', 'NegReg', (125, 134))	('R196*', 'Var', (61, 66))	('SW684', 'CellLine', 'CVCL:1726', (96, 101))	('H1299', 'CellLine', 'CVCL:0060', (365, 370))	('DMS114', 'Chemical', '-', (103, 109))	('HCC1937', 'Var', (286, 293))	('MCF7', 'CellLine', 'CVCL:0031', (200, 204))	('H2126', 'Var', (323, 328))	('A549', 'CellLine', 'CVCL:0023', (191, 195))	('mutations', 'Var', (85, 94))	('p53', 'Gene', (239, 242))	('R196*', 'SUBSTITUTION', 'None', (61, 66))	('R213*', 'Var', (51, 56))	('R213*', 'SUBSTITUTION', 'None', (51, 56))	('HCC1937', 'CellLine', 'CVCL:0290', (286, 293))	('H2126', 'CellLine', 'CVCL:1532', (323, 328))	("'hotspot'", 'PosReg', (220, 229))	('H1299', 'Var', (365, 370))
469973	27759562	To eliminate the possibility that these differences were due to the efficiency of p53 inactivation or variance in the cells' sturdiness, we next measured p53 knockdown efficiency as well as the effect of inactivation of the essential gene RPA3 on cell viability across all the cell lines (Figure 3F and G and Figure 3:figure supplement 5).	('p53', 'Gene', (154, 157))	('RPA3', 'Gene', '6119', (239, 243))	('RPA3', 'Gene', (239, 243))	('inactivation', 'Var', (204, 216))
469974	27759562	In all cases we found similar efficiency of knockdown and comparable decrease in the viability of cells upon RPA3 silencing.	('RPA3', 'Gene', '6119', (109, 113))	('decrease', 'NegReg', (69, 77))	('silencing', 'Var', (114, 123))	('RPA3', 'Gene', (109, 113))
469975	27759562	As demonstrated in Senturk et al., a p53-psi like protein can also be generated by mutations occurring at the splice acceptor site in exon-7 (Hop62, c.673-2A>G TP53 mutation).	('c.673-2A>G', 'Mutation', 'c.673-2A>G', (149, 159))	('c.673-2A>G', 'Var', (149, 159))	('TP53', 'Gene', (160, 164))
469976	27759562	Like p53-psi, these p53 mutants lack most of the domains required for p53 canonical tumor suppressor activities (i.e., nuclear localization, oligomerization domains, and the alpha helix required for p53-DNA binding) and are capable of reprogramming the cells towards the acquisition of pro-metastatic features.	('p53', 'Gene', (20, 23))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('mutants', 'Var', (24, 31))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('domains', 'MPA', (49, 56))	('reprogramming', 'Reg', (235, 248))	('tumor', 'Disease', (84, 89))	('lack', 'NegReg', (32, 36))	('nuclear localization', 'MPA', (119, 139))	('binding', 'Interaction', (207, 214))
469978	27759562	Specifically, they were able to demonstrate that the tumor promoting activities of p53-psi requires its molecular and functional interaction with CypD (Figure 4A).	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('p53-psi', 'Var', (83, 90))	('tumor', 'Disease', (53, 58))	('interaction', 'Interaction', (129, 140))
469982	27759562	To test the functional role of a CypD/p53 exon-6 truncations interactions, we analyzed changes in the permeability of the MPTP by using a calcein fluorescence assay in cells ectopically expressing W146*, R196*, R213*, p53-psi and G325*.	('R213*', 'Var', (211, 216))	('G325*', 'SUBSTITUTION', 'None', (230, 235))	('R213*', 'SUBSTITUTION', 'None', (211, 216))	('p53-psi', 'Var', (218, 225))	('R196*', 'SUBSTITUTION', 'None', (204, 209))	('G325*', 'Var', (230, 235))	('W146*', 'SUBSTITUTION', 'None', (197, 202))	('R196*', 'Var', (204, 209))	('W146*', 'Var', (197, 202))
469983	27759562	We found an increased permeability of the MPTP only in the case of p53-psi and the R196* and R213* mutants.	('R196*', 'SUBSTITUTION', 'None', (83, 88))	('permeability of the MPTP', 'MPA', (22, 46))	('increased', 'PosReg', (12, 21))	('R196*', 'Var', (83, 88))	('R213*', 'Var', (93, 98))	('R213*', 'SUBSTITUTION', 'None', (93, 98))	('p53-psi', 'Var', (67, 74))
469984	27759562	Interestingly, in the cells expressing the W146* p53 mutants we instead observed a decrease of MPTP permeability (Figure 4F).	('decrease', 'NegReg', (83, 91))	('W146*', 'Var', (43, 48))	('MPTP permeability', 'MPA', (95, 112))	('W146*', 'SUBSTITUTION', 'None', (43, 48))
469986	27759562	We found that in the presence of CsA, the increase in the pore permeability that we observed in cells expressing R196*, R213* p53 exon-6 mutants and p53-psi was completely ablated (Figure 4F).	('CsA', 'Chemical', 'MESH:D016572', (33, 36))	('R196*', 'Var', (113, 118))	('R213*', 'Var', (120, 125))	('R213*', 'SUBSTITUTION', 'None', (120, 125))	('R196*', 'SUBSTITUTION', 'None', (113, 118))	('pore permeability', 'MPA', (58, 75))	('p53', 'Gene', (126, 129))	('increase', 'PosReg', (42, 50))
469987	27759562	To further validate the possible function of p53 exon-6 truncations and p53-psi in regulating the MPTP function, we performed similar experiments in tumor-derived cell lines with p53-psi splicing mutation (Hop62), exon-6 truncating mutation (SW684, DMS114 and Calu-6), p53-WT (A549, MCF7), a shorter truncation (H2126) and a p53 homozygous deletion (H1299) upon knock down of p53.	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('shorter', 'NegReg', (292, 299))	('H1299', 'Var', (350, 355))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('p53', 'Gene', (376, 379))	('SW684', 'CellLine', 'CVCL:1726', (242, 247))	('H2126', 'CellLine', 'CVCL:1532', (312, 317))	('p53', 'Gene', (325, 328))	('MCF7', 'CellLine', 'CVCL:0031', (283, 287))	('tumor', 'Disease', (149, 154))	('truncation', 'MPA', (300, 310))	('H1299', 'CellLine', 'CVCL:0060', (350, 355))	('A549', 'CellLine', 'CVCL:0023', (277, 281))	('H2126', 'Var', (312, 317))	('DMS114', 'Chemical', '-', (249, 255))
469989	27759562	Figure 5A demonstrates that short-term inactivation of CypD led to a decrease in mesenchymal markers in cells specifically expressing p53-psi or exon-6 truncating mutants (Hop62, DMS114 and Calu-6).	('CypD', 'Var', (55, 59))	('Hop62', 'Var', (172, 177))	('DMS114', 'Chemical', '-', (179, 185))	('decrease', 'NegReg', (69, 77))	('mesenchymal markers', 'CPA', (81, 100))	('inactivation', 'Var', (39, 51))	('DMS114', 'Var', (179, 185))	('p53-psi', 'Var', (134, 141))
469992	27759562	Figure 5E and F show that the inactivation of CypD expression in xenograft models using an inducible CRISPR-Cas9 gene editing system decreased the tumor volume of p53 exon-6 truncating mutant-expressing cells (Calu6), but not the tumor volume of p53-WT expressing cells (A549) (Figure 5:figure supplement 2).	('A549', 'CellLine', 'CVCL:0023', (271, 275))	('tumor', 'Disease', (230, 235))	('tumor', 'Disease', (147, 152))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('inactivation', 'Var', (30, 42))	('p53', 'Gene', (163, 166))	('CypD', 'Gene', (46, 50))	('tumor', 'Disease', 'MESH:D009369', (230, 235))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))	('decreased', 'NegReg', (133, 142))
469993	27759562	In summary, our analysis of human tumors, combined with the detailed molecular characterization of TP53 exon-6 truncating mutations, offers strong support for the idea that chromosome 17p deletions and, particularly, TP53 mutations produce a multiplicity of alleles with diverse activities that contribute differently to tumorigenesis by providing distinct, selective advantages.	('tumors', 'Disease', (34, 40))	('tumors', 'Disease', 'MESH:D009369', (34, 40))	('tumor', 'Disease', (34, 39))	('produce', 'Reg', (232, 239))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('activities', 'MPA', (279, 289))	('human', 'Species', '9606', (28, 33))	('TP53', 'Gene', (217, 221))	('tumor', 'Disease', 'MESH:D009369', (321, 326))	('deletions', 'Var', (188, 197))	('tumor', 'Phenotype', 'HP:0002664', (321, 326))	('mutations', 'Var', (222, 231))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('tumor', 'Disease', (321, 326))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('advantages', 'PosReg', (368, 378))
469995	27759562	Consistent with the capabilities of these p53 mutants to promote rather than halt tumorigenesis, TP53 exon-6 truncating mutations are highly abundant and are enriched in certain tumors (Figure 1).	('tumor', 'Disease', (178, 183))	('tumors', 'Disease', (178, 184))	('promote', 'PosReg', (57, 64))	('tumors', 'Disease', 'MESH:D009369', (178, 184))	('tumors', 'Phenotype', 'HP:0002664', (178, 184))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('TP53', 'Gene', (97, 101))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('mutants', 'Var', (46, 53))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('tumor', 'Disease', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))
469996	27759562	Although, in principle this implies that these specific mutants could increase the fitness of tumors, we cannot exclude the possibility that the higher than expected frequency we observed in tumors could alternatively be explained by a specific etiology and/or a particular mutagenic modality.	('tumors', 'Phenotype', 'HP:0002664', (191, 197))	('increase', 'PosReg', (70, 78))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('fitness of tumors', 'Disease', 'MESH:D012640', (83, 100))	('mutants', 'Var', (56, 63))	('tumors', 'Disease', 'MESH:D009369', (191, 197))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('tumors', 'Disease', (94, 100))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('fitness of tumors', 'Disease', (83, 100))	('tumors', 'Disease', (191, 197))
469999	27759562	The requirement of mitochondria localization, interaction with CypD and the lack of transcriptional activities distinguish TP53 exon-6 truncating mutations from other p53 gain of function mutants with pro-tumorigenic functions (e.g.	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('gain of function', 'PosReg', (171, 187))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumor', 'Disease', (205, 210))	('p53', 'Gene', (167, 170))	('truncating mutations', 'Var', (135, 155))	('TP53', 'Gene', (123, 127))
470000	27759562	In our study, structure-function analysis has also shown that the p53 W146* mutant is unable to interact with CypD despite its ability to localize to the mitochondria.	('W146*', 'SUBSTITUTION', 'None', (70, 75))	('W146*', 'Var', (70, 75))	('localize', 'MPA', (138, 146))
470001	27759562	Interestingly and contrary to p53-psi and p53 exon-6 truncating mutants, the expression of the p53 W146* mutant increased the expression of E-cadherin instead of reducing it (Figure 2D and E), and decreased the permeability of the MPTP in a calcein assay (Figure 4F).	('expression', 'MPA', (126, 136))	('W146*', 'Var', (99, 104))	('E-cadherin', 'Gene', (140, 150))	('E-cadherin', 'Gene', '999', (140, 150))	('p53', 'Gene', (95, 98))	('reducing', 'NegReg', (162, 170))	('increased', 'PosReg', (112, 121))	('decreased', 'NegReg', (197, 206))	('W146*', 'SUBSTITUTION', 'None', (99, 104))	('permeability of the MPTP in a calcein assay', 'MPA', (211, 254))
470002	27759562	To explain this observation, it is tempting to speculate that the p53 W146* mutant may interact with other components of the MPTP and antagonize the function of CypD.	('W146*', 'SUBSTITUTION', 'None', (70, 75))	('interact', 'Interaction', (87, 95))	('antagonize', 'NegReg', (134, 144))	('W146*', 'Var', (70, 75))	('function', 'MPA', (149, 157))
470003	27759562	The selective dependencies of cancer cells harboring exon-6 TP53 truncating mutations to CypD activity (Figure 5B-F) is particularly exciting, as it begs the design of novel targeted therapeutics.	('cancer', 'Disease', (30, 36))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('truncating mutations', 'Var', (65, 85))	('exon-6', 'Var', (53, 59))	('TP53', 'Gene', (60, 64))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
470004	27759562	Notably, the high prevalence of p53-psi or TP53 exon-6 truncating mutations in certain tumors also suggests that this class of TP53 mutations represents a strong precision medicine candidate target comparable to the well-documented EGFR, ROS and ALK mutations in NSCLC.	('ALK', 'Gene', (246, 249))	('EGFR', 'Gene', '1956', (232, 236))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('p53-psi', 'Gene', (32, 39))	('mutations', 'Var', (132, 141))	('EGFR', 'Gene', (232, 236))	('ROS', 'Chemical', '-', (238, 241))	('ALK', 'Gene', '238', (246, 249))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('NSCLC', 'Disease', (263, 268))	('tumors', 'Disease', (87, 93))	('NSCLC', 'Disease', 'MESH:D002289', (263, 268))	('TP53', 'Gene', (43, 47))	('TP53', 'Gene', (127, 131))	('tumors', 'Disease', 'MESH:D009369', (87, 93))
470006	27759562	As these mutations structurally and functionally mimic the naturally occurring p53-psi isoform, we propose that TP53 exon-6 mutations are best described as 'separation of function' rather than simply 'gain of function' or 'loss of function' Interestingly, approximately one-third of all human genetic disorders are caused by mutations that generate premature stop codons.	('mutations', 'Var', (124, 133))	('TP53 exon-6', 'Gene', (112, 123))	('genetic disorders', 'Disease', (293, 310))	('caused by', 'Reg', (315, 324))	('genetic disorders', 'Disease', 'MESH:D030342', (293, 310))	('human', 'Species', '9606', (287, 292))
470008	27759562	A549 and Calu-6 lung cancer cells were plated and infected in-vitro with lentiviruses carrying Renila and p53 sgRNAs at a multiplicity of infection (MOI) of 1.	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('A549', 'CellLine', 'CVCL:0023', (0, 4))	('Calu-6 lung cancer', 'Disease', (9, 27))	('Calu-6 lung cancer', 'Disease', 'MESH:D008175', (9, 27))	('p53', 'Var', (106, 109))	('Ren', 'Gene', (95, 98))	('lung cancer', 'Phenotype', 'HP:0100526', (16, 27))	('Ren', 'Gene', '5972', (95, 98))
470013	27759562	Tail vein assay for B16-F1 cells with p53 truncations was conducted as previously described.	('B16-F1', 'CellLine', 'CVCL:0158', (20, 26))	('truncations', 'Var', (42, 53))	('p53', 'Gene', (38, 41))
470062	27759562	To measure MPTP opening, ectopically expressing p53 truncations cells were grown in 2% FBS for 36 hr and were treated with vehicle or 2 muM of CsA for 2 hr before collecting for analysis.	('p53', 'Gene', (48, 51))	('FBS', 'Disease', (87, 90))	('CsA', 'Chemical', 'MESH:D016572', (143, 146))	('FBS', 'Disease', 'MESH:D005198', (87, 90))	('truncations', 'Var', (52, 63))
470069	27759562	Summary: In this manuscript, Sordella and colleagues report the characterization of p53 exon 6 truncation mutants in human cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('human', 'Species', '9606', (117, 122))	('truncation mutants', 'Var', (95, 113))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('p53', 'Gene', (84, 87))	('cancer', 'Disease', (123, 129))
470070	27759562	The manuscript contains a number of interesting observations, that could be summarized as follows: 1) Exon 6 nonsense (truncation) p53 mutants occur at a higher frequency relative to missense mutations, are stably expressed in many tumor cell lines (effectively bypassing nonsense-mediated decay) and, in the case of colorectal tumors, are more common in metastases than primary tumors.	('tumors', 'Phenotype', 'HP:0002664', (328, 334))	('colorectal tumors', 'Disease', 'MESH:D015179', (317, 334))	('tumor', 'Disease', 'MESH:D009369', (379, 384))	('common', 'Reg', (345, 351))	('colorectal tumors', 'Disease', (317, 334))	('tumor', 'Phenotype', 'HP:0002664', (379, 384))	('tumor', 'Disease', 'MESH:D009369', (232, 237))	('p53', 'Gene', (131, 134))	('metastases than primary tumors', 'Disease', 'MESH:D009362', (355, 385))	('tumor', 'Disease', 'MESH:D009369', (328, 333))	('tumors', 'Phenotype', 'HP:0002664', (379, 385))	('tumor', 'Disease', (379, 384))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('mutants', 'Var', (135, 142))	('metastases than primary tumors', 'Disease', (355, 385))	('tumor', 'Phenotype', 'HP:0002664', (328, 333))	('tumor', 'Disease', (232, 237))	('tumor', 'Disease', (328, 333))
470071	27759562	2) Exon 6 nonsense p53 mutants harbor gain-of-function (GOF) activity, promoting cell viability, EMT-like properties in vitro and metastasis in a mouse model.	('mouse', 'Species', '10090', (146, 151))	('metastasis', 'CPA', (130, 140))	('gain-of-function', 'PosReg', (38, 54))	('p53', 'Gene', (19, 22))	('promoting', 'PosReg', (71, 80))	('EMT-like properties', 'CPA', (97, 116))	('mutants', 'Var', (23, 30))	('cell viability', 'CPA', (81, 95))
470072	27759562	3) Exon 6 nonsense p53 mutants are mostly excluded from the nucleus, localizing instead to cytoplasm and mitochondria, where they bind to cyclophilin D (CypD) and promote mitochondrial membrane permeability.	('cyclophilin D', 'Gene', '10105', (138, 151))	('mitochondrial membrane permeability', 'MPA', (171, 206))	('p53', 'Gene', (19, 22))	('bind', 'Interaction', (130, 134))	('mutants', 'Var', (23, 30))	('promote', 'PosReg', (163, 170))	('cyclophilin D', 'Gene', (138, 151))
470073	27759562	4) Cancer cell lines expressing exon 6 nonsense mutants display dependency on both mutant p53 and CypD, suggesting an epistatic relationship between these proteins in promoting cell survival and EMT features.	('p53', 'Gene', (90, 93))	('mutant', 'Var', (83, 89))	('Cancer', 'Disease', (3, 9))	('promoting', 'PosReg', (167, 176))	('Cancer', 'Disease', 'MESH:D009369', (3, 9))	('Cancer', 'Phenotype', 'HP:0002664', (3, 9))	('EMT features', 'CPA', (195, 207))	('cell survival', 'CPA', (177, 190))	('exon', 'Gene', (32, 36))
470074	27759562	The data show that mutant p53 R213* binds to CypD but it is unclear whether this interaction occurs in the mitochondria or in the cytoplasm (if in the cytoplasm, it would imply that mutant p53 inhibits localization of CypD to the mitochondria which would explain its reduced mitochondrial localization in H1299 cells overexpressing R213* or R196*).	('R213*', 'Var', (332, 337))	('R196*', 'SUBSTITUTION', 'None', (341, 346))	('R213*', 'Var', (30, 35))	('p53', 'Gene', (189, 192))	('R213*', 'SUBSTITUTION', 'None', (30, 35))	('R213*', 'SUBSTITUTION', 'None', (332, 337))	('inhibits', 'NegReg', (193, 201))	('p53', 'Gene', (26, 29))	('mitochondrial localization', 'MPA', (275, 301))	('H1299', 'CellLine', 'CVCL:0060', (305, 310))	('mutant', 'Var', (19, 25))	('R196*', 'Var', (341, 346))	('reduced', 'NegReg', (267, 274))	('mutant', 'Var', (182, 188))	('localization', 'MPA', (202, 214))
470075	27759562	Furthermore, it is unclear whether overexpression of CypD abolishes MPTP closure promoted by depletion of mutant p53 R213*.	('depletion', 'MPA', (93, 102))	('MPTP closure', 'CPA', (68, 80))	('R213*', 'Var', (117, 122))	('R213*', 'SUBSTITUTION', 'None', (117, 122))	('abolishes', 'NegReg', (58, 67))
470076	27759562	Specific questions that must be answered experimentally are: 1.1) Is casein fluorescence (which indicates MPTP closure) dependent on CypD in the cell lines with truncated p53 (HoP62, DMS114, Calu-6 and SW684)?	('DMS114', 'Var', (183, 189))	('dependent', 'Reg', (120, 129))	('SW684', 'CellLine', 'CVCL:1726', (202, 207))	('HoP62', 'Var', (176, 181))	('DMS114', 'Chemical', '-', (183, 189))	('casein fluorescence', 'MPA', (69, 88))	('SW684', 'Var', (202, 207))	('p53', 'Gene', (171, 174))
470077	27759562	1.2) Does knock-down of endogenous mutant p53 in cell lines expressing R213* or R196* change mitochondrial localization of CypD (HoP62, DMS114, Calu-6 and SW684 cell lines)?	('p53', 'Gene', (42, 45))	('R213*', 'Var', (71, 76))	('SW684', 'CellLine', 'CVCL:1726', (155, 160))	('mitochondrial localization of CypD', 'MPA', (93, 127))	('R213*', 'SUBSTITUTION', 'None', (71, 76))	('R196*', 'SUBSTITUTION', 'None', (80, 85))	('change', 'Reg', (86, 92))	('R196*', 'Var', (80, 85))	('DMS114', 'Chemical', '-', (136, 142))
470078	27759562	1.3) Does knock-down of CypD change mitochondrial localization of endogenous mutant p53 in HoP62, DMS114, Calu-6 and SW684?	('SW684', 'CellLine', 'CVCL:1726', (117, 122))	('DMS114', 'Chemical', '-', (98, 104))	('p53', 'Gene', (84, 87))	('mutant', 'Var', (77, 83))	('mitochondrial localization', 'MPA', (36, 62))
470079	27759562	1.4) Does depletion of endogenous mutant p53 R213* or R196* in HoP62, DMS114, Calu-6 and SW684 change mitochondrial polarization and thus ATP production (this could be done by measuring fluorescence of JC-1 marker or rhodamine marker)?	('R196*', 'Var', (54, 59))	('change', 'Reg', (95, 101))	('R196*', 'SUBSTITUTION', 'None', (54, 59))	('ATP production', 'MPA', (138, 152))	('HoP62', 'Gene', (63, 68))	('DMS114', 'Var', (70, 76))	('DMS114', 'Chemical', '-', (70, 76))	('ATP', 'Chemical', 'MESH:D000255', (138, 141))	('rhodamine', 'Chemical', 'MESH:D012235', (217, 226))	('R213*', 'Var', (45, 50))	('R213*', 'SUBSTITUTION', 'None', (45, 50))	('mitochondrial polarization', 'MPA', (102, 128))	('SW684', 'CellLine', 'CVCL:1726', (89, 94))
470081	27759562	Panel B - there are no size markers on the western blots; there are multiple protein species in cells transfected with mutants R306* and G325*.	('R306*', 'SUBSTITUTION', 'None', (127, 132))	('R306*', 'Var', (127, 132))	('G325*', 'Var', (137, 142))	('G325*', 'SUBSTITUTION', 'None', (137, 142))
470083	27759562	Also, the DAPI stain cannot be seen properly in the R196*and R213* merges.	('R196*', 'Var', (52, 57))	('R213*', 'Var', (61, 66))	('R213*', 'SUBSTITUTION', 'None', (61, 66))	('DAPI', 'Chemical', 'MESH:C007293', (10, 14))
470089	27759562	Panel I - please define what Ren g 208 and p53g.140 is in the legend.	('Ren', 'Gene', (29, 32))	('Ren', 'Gene', '5972', (29, 32))	('p53g.140', 'Var', (43, 51))
470091	27759562	Paragraph 4 in subsection 'p53 exon-6 mutations partially localize to the mitochondria where by interacting with Cyclophilin D control the mitochondria inner-pore permeability' about the W146* mutant is for the discussion, not the results, and it is poorly written.	('Cyclophilin D', 'Gene', '10105', (113, 126))	("mitochondria inner-pore permeability'", 'MPA', (139, 176))	('W146*', 'SUBSTITUTION', 'None', (187, 192))	('Cyclophilin D', 'Gene', (113, 126))	('W146*', 'Var', (187, 192))
470092	27759562	The right hand panel shows that KD of p53 increases tumor growth - this seems to be the opposite of what is stated in the text (subsection 'Cyclophilin D activity is required for phenotypes associated with p53 exon-6 truncating mutations', although the result is to be expected).	('p53', 'Gene', (206, 209))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('Cyclophilin D', 'Gene', (140, 153))	('increases tumor', 'Disease', (42, 57))	('increases tumor', 'Disease', 'MESH:D009369', (42, 57))	('p53', 'Var', (38, 41))	('Cyclophilin D', 'Gene', '10105', (140, 153))
470094	27759562	Specific questions that must be answered experimentally are:  1.1) Is casein fluorescence (which indicates MPTP closure) dependent on CypD in the cell lines with truncated p53 (HoP62, DMS114, Calu-6 and SW684)?	('DMS114', 'Var', (184, 190))	('HoP62', 'Var', (177, 182))	('SW684', 'CellLine', 'CVCL:1726', (203, 208))	('DMS114', 'Chemical', '-', (184, 190))	('casein fluorescence', 'MPA', (70, 89))	('dependent', 'Reg', (121, 130))	('SW684', 'Var', (203, 208))	('p53', 'Gene', (172, 175))
470095	27759562	As shown in Figure 4:figure supplement 4A, knockdown of CypD by shRNA in Hop62, SW684, DMS114 and Calu-6 results in an increase in the percentage of calcein positive cells which, in turn, suggests the closure of the MPTP upon decreased expression of CypD.	('DMS114', 'Var', (87, 93))	('SW684', 'Var', (80, 85))	('CypD', 'Gene', (56, 60))	('knockdown', 'Var', (43, 52))	('SW684', 'CellLine', 'CVCL:1726', (80, 85))	('Hop62', 'Var', (73, 78))	('calcein positive', 'MPA', (149, 165))	('DMS114', 'Chemical', '-', (87, 93))	('increase', 'PosReg', (119, 127))
470097	27759562	Western blot analysis of total and mitochondria cell extracts indicated that knockdown of endogenous p53 in Hop62, DMS114, SW684 and Calu-6 cell lines did not affect the overall levels of CypD nor its mitochondrial localization.	('knockdown', 'Var', (77, 86))	('p53', 'Gene', (101, 104))	('DMS114', 'Chemical', '-', (115, 121))	('levels', 'MPA', (178, 184))	('mitochondrial localization', 'MPA', (201, 227))	('SW684', 'CellLine', 'CVCL:1726', (123, 128))
470098	27759562	As suggested by the reviewers, we utilized the JC-1 assay to evaluate changes in mitochondrial polarization upon p53 and CypD knockdown in A549, Hop62, DMS114, Calu-6 and SW684 cells.	('CypD knockdown', 'Var', (121, 135))	('p53', 'Var', (113, 116))	('changes', 'Reg', (70, 77))	('A549', 'CellLine', 'CVCL:0023', (139, 143))	('DMS114', 'Chemical', '-', (152, 158))	('SW684', 'CellLine', 'CVCL:1726', (171, 176))	('knockdown', 'Var', (126, 135))	('mitochondrial polarization', 'MPA', (81, 107))
470101	27759562	Therefore, we calculated the frequency of missense mutations observed in tumors was 1.5 and 1.9 fold higher than the expected frequencies in the TCGA and in the MSKCC datasets respectively.	('higher', 'PosReg', (101, 107))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('missense mutations', 'Var', (42, 60))	('tumors', 'Disease', (73, 79))	('tumors', 'Disease', 'MESH:D009369', (73, 79))
470106	27759562	- Panel G. While the ratio between IF-indel is higher in the metastatic group, the low number of samples with primary tumors (n= 3 primary and n= 10 metastatic tumor site) rendered this finding statistically insignificant, as indicated.	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('higher', 'PosReg', (47, 53))	('IF-indel', 'Var', (35, 43))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('primary tumors', 'Disease', (110, 124))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('tumor', 'Disease', (118, 123))	('primary tumors', 'Disease', 'MESH:D009369', (110, 124))	('tumor', 'Disease', (160, 165))
470110	27759562	The reason why we used A549 cells to illustrate differences in the morphology of cells upon ectopic expression of p53 mutants was mainly based on the fact that A549 cells form a nice columnar epithelial monolayer when they reach confluence.	('A549', 'CellLine', 'CVCL:0023', (23, 27))	('mutants', 'Var', (118, 125))	('A549', 'CellLine', 'CVCL:0023', (160, 164))	('p53', 'Gene', (114, 117))
470112	27759562	Nevertheless, as shown in in Figure 2:figure supplement 3, also in the H1299 cells we observed that ectopic expression of R196* and R213* induced an increase in the expression of mesenchymal markers (p-value *<0.05, unpaired t-test).	('R213*', 'SUBSTITUTION', 'None', (132, 137))	('mesenchymal markers', 'CPA', (179, 198))	('R196*', 'Var', (122, 127))	('increase', 'PosReg', (149, 157))	('expression', 'MPA', (165, 175))	('H1299', 'CellLine', 'CVCL:0060', (71, 76))	('R196*', 'SUBSTITUTION', 'None', (122, 127))	('R213*', 'Var', (132, 137))
470114	27759562	We have added additional information describing Ren g.208 and p53 g.140 in the figure legend, and we have provided the sequence of the guide RNAs used in this study in Supplementary file 5.	('Ren', 'Gene', (48, 51))	('p53 g.140', 'Var', (62, 71))	('Ren', 'Gene', '5972', (48, 51))
470115	27759562	We have substantially amended this section, adding the p53 status of Hop62 cells, results for R196* and information regarding CsA.	('R196*', 'SUBSTITUTION', 'None', (94, 99))	('CsA', 'Disease', (126, 129))	('CsA', 'Chemical', 'MESH:D016572', (126, 129))	('R196*', 'Var', (94, 99))
470117	27759562	As shown in the chart in Figure 5F, CypD knockdown in Calu-6 (R196*) reduced tumor volume as expected.	('R196*', 'SUBSTITUTION', 'None', (62, 67))	('reduced', 'NegReg', (69, 76))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('R196*', 'Var', (62, 67))	('tumor', 'Disease', (77, 82))	('Calu-6', 'Gene', (54, 60))
470120	27759562	The latter does not modify the conclusion of our study indicating that cells harboring p53 exon-6 truncation are 'addicted' to CypD, but could have clinical/therapeutic implications as it argues the need of stratifying patients for p53 mutations when considering treatments based on CypD inhibition.	('p53', 'Gene', (87, 90))	('patients', 'Species', '9606', (219, 227))	('mutations', 'Var', (236, 245))	('p53', 'Gene', (232, 235))
470144	27209351	The autoimmune response is elicited by the ectopic expression of neural antigens in neoplastic tissues, which eventually attack the nervous system of PNS patients.	('autoimmune response', 'Phenotype', 'HP:0002960', (4, 23))	('ectopic expression', 'Var', (43, 61))	('attack', 'Reg', (121, 127))	('patients', 'Species', '9606', (154, 162))
470203	27209351	Matsumoto L. reported that CIS of the testis triggered severe hypokinesis as a paraneoplastic manifestation and detection of anti-Ma2 antibodies.	('hypokinesis', 'Disease', 'MESH:D018754', (62, 73))	('Ma2', 'Gene', (130, 133))	('CIS', 'Phenotype', 'HP:0030075', (27, 30))	('CIS', 'Var', (27, 30))	('Ma2', 'Gene', '10687', (130, 133))	('hypokinesis', 'Disease', (62, 73))
470210	27209351	Table 3 shows that the bladder cancer antibodies inducing PNS are anti-Ri, anti-Hu, anti-Yo and anti-VGKC.	('bladder cancer', 'Disease', 'MESH:D001749', (23, 37))	('bladder cancer', 'Disease', (23, 37))	('anti-Yo', 'Var', (84, 91))	('Yo', 'Chemical', '-', (89, 91))	('anti-VGKC', 'Var', (96, 105))	('anti-Ri', 'Var', (66, 73))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('bladder cancer', 'Phenotype', 'HP:0009725', (23, 37))	('anti-Hu', 'Var', (75, 82))
470211	27209351	SCC and CYFRA21-1 are squamous cell carcinoma markers and not paraneoplastic antibodies.	('SCC', 'Disease', (0, 3))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (22, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (36, 45))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (22, 45))	('CYFRA21-1', 'Var', (8, 17))	('squamous cell carcinoma', 'Disease', (22, 45))
470294	31554354	Many types of malignancy are caused by errant metastatic cells from nearby organs (lung, liver, stomach, or ovary) occupying serous cavities.	('malignancy', 'Disease', (14, 24))	('errant', 'Var', (39, 45))	('malignancy', 'Disease', 'MESH:D009369', (14, 24))	('caused by', 'Reg', (29, 38))
470332	31554354	Ber-EP4 is an adenocarcinoma marker for which the respective expression of Ber-EP4 was no staining, +- < 10%, 1+ and 2+ in 3/60 (5.0%), 2/60 (3.3%), 17/60 (28.3%) and 38/60 (63.3%) cases of adenocarcinoma.	('adenocarcinoma', 'Disease', 'MESH:D000230', (190, 204))	('carcinoma', 'Phenotype', 'HP:0030731', (19, 28))	('EP4', 'Gene', '5734', (79, 82))	('adenocarcinoma', 'Disease', (14, 28))	('adenocarcinoma', 'Disease', (190, 204))	('EP4', 'Gene', (4, 7))	('EP4', 'Gene', '5734', (4, 7))	('carcinoma', 'Phenotype', 'HP:0030731', (195, 204))	('EP4', 'Gene', (79, 82))	('+- < 10%', 'Var', (100, 108))	('adenocarcinoma', 'Disease', 'MESH:D000230', (14, 28))
470483	34001250	We propose that molecular changes in the expression of plakins leads to the transition of benign ovarian tumours to carcinomas, as well as floating cellular aggregates (commonly known as spheroids) in the ascites microenvironment, which may contribute to the sustenance and progression of the disease.	('tumours', 'Phenotype', 'HP:0002664', (105, 112))	('changes', 'Var', (26, 33))	('spheroids', 'Chemical', '-', (187, 196))	('leads to', 'Reg', (63, 71))	('ovarian tumour', 'Phenotype', 'HP:0100615', (97, 111))	('benign ovarian tumours to carcinomas', 'Disease', (90, 126))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('carcinomas', 'Phenotype', 'HP:0030731', (116, 126))	('tumour', 'Phenotype', 'HP:0002664', (105, 111))	('ascites', 'Phenotype', 'HP:0001541', (205, 212))	('benign ovarian tumours to carcinomas', 'Disease', 'MESH:D010051', (90, 126))	('ascites', 'Disease', 'MESH:D001201', (205, 212))	('ascites', 'Disease', (205, 212))
470497	34001250	In the case of EVPL, PPL and DSP the head domain also consists of a number of spectrin repeats and a Src homology 3 domain (SH3).	('spectrin repeats', 'Protein', (78, 94))	('consists', 'Reg', (54, 62))	('PPL', 'Var', (21, 24))	('Src', 'Gene', '6714', (101, 104))	('Src', 'Gene', (101, 104))	('DSP', 'Var', (29, 32))
470510	34001250	In the same study it was shown that deletion of PPL gene in mice improved survival from bleomycin-induced lung injury due to enhanced expression of anti-inflammatory cytokines, reduced expression of pro-fibrotic mediators and diminished response to TGFbeta signalling, suggesting that the expression of PPL may have a role in initiating a anti-inflammatory response in lungs.	('survival', 'CPA', (74, 82))	('deletion', 'Var', (36, 44))	('lung injury', 'Disease', 'MESH:D055370', (106, 117))	('PPL', 'Gene', (48, 51))	('improved', 'PosReg', (65, 73))	('reduced', 'NegReg', (177, 184))	('expression of pro-fibrotic mediators', 'MPA', (185, 221))	('diminished', 'NegReg', (226, 236))	('response to TGFbeta signalling', 'MPA', (237, 267))	('bleomycin', 'Chemical', 'MESH:D001761', (88, 97))	('lung injury', 'Disease', (106, 117))	('enhanced', 'PosReg', (125, 133))	('mice', 'Species', '10090', (60, 64))	('expression of anti-inflammatory cytokines', 'MPA', (134, 175))
470525	34001250	Deletion of PLEC enables its disassociation with integrin alpha6beta4, which trigger Erk activation with a resultant migratory behaviour.	('disassociation', 'MPA', (29, 43))	('alpha6', 'Gene', '28873', (58, 64))	('Erk', 'Gene', (85, 88))	('PLEC', 'Gene', (12, 16))	('activation', 'PosReg', (89, 99))	('alpha6', 'Gene', (58, 64))	('migratory behaviour', 'CPA', (117, 136))	('Erk', 'Gene', '5594', (85, 88))	('Deletion', 'Var', (0, 8))
470540	34001250	Changes in protein expression or function through genetic changes often leads to the skin condition epidermolysis bullosa simplex (EBS), a skin blistering condition with hyperkeratosis of hands and feet.	('hyperkeratosis', 'Disease', (170, 184))	('protein', 'Protein', (11, 18))	('skin condition epidermolysis bullosa simplex', 'Disease', (85, 129))	('leads to', 'Reg', (72, 80))	('Changes', 'Reg', (0, 7))	('hyperkeratosis', 'Disease', 'MESH:D017488', (170, 184))	('blistering', 'Phenotype', 'HP:0008066;HP:0200037', (144, 154))	('hyperkeratosis', 'Phenotype', 'HP:0000962', (170, 184))	('skin condition', 'Phenotype', 'HP:0000951', (85, 99))	('skin blistering', 'Phenotype', 'HP:0008066', (139, 154))	('genetic changes', 'Var', (50, 65))	('function', 'MPA', (33, 41))	('skin condition epidermolysis bullosa simplex', 'Disease', 'MESH:D016110', (85, 129))
470554	34001250	Using genetically modified mice in pancreatic neuroendocrine tumours changes in DSP and other desmosomal protein expression is an early event in the tumourigenic process and preludes changes in the expression of adheren junction proteins and tumour cell invasion.	('expression', 'MPA', (113, 123))	('tumour', 'Disease', 'MESH:D009369', (61, 67))	('tumour', 'Disease', 'MESH:D009369', (242, 248))	('tumour', 'Disease', (242, 248))	('mice', 'Species', '10090', (27, 31))	('tumours', 'Phenotype', 'HP:0002664', (61, 68))	('tumour', 'Disease', (61, 67))	('tumour', 'Phenotype', 'HP:0002664', (149, 155))	('tumour', 'Phenotype', 'HP:0002664', (61, 67))	('DSP', 'Protein', (80, 83))	('neuroendocrine tumour', 'Phenotype', 'HP:0100634', (46, 67))	('tumour', 'Phenotype', 'HP:0002664', (242, 248))	('pancreatic neuroendocrine tumours', 'Disease', (35, 68))	('tumour', 'Disease', 'MESH:D009369', (149, 155))	('changes', 'Var', (69, 76))	('pancreatic neuroendocrine tumours', 'Disease', 'MESH:D010190', (35, 68))	('tumour', 'Disease', (149, 155))
470558	34001250	In that context, epigenetic silencing of DSP was observed in primary lung tumours and cell lines.	('DSP', 'Protein', (41, 44))	('lung tumours', 'Disease', 'MESH:D008175', (69, 81))	('tumours', 'Phenotype', 'HP:0002664', (74, 81))	('lung tumours', 'Disease', (69, 81))	('tumour', 'Phenotype', 'HP:0002664', (74, 80))	('epigenetic silencing', 'Var', (17, 37))
470563	34001250	Silencing of DSP expression by siRNA resulted in the prevention of E2-dependent cell adhesion, indicating there is a functional relationship between estrogen receptors, DSP and desmosome formation and thus cell adhesion.	('E2', 'Chemical', 'MESH:D004958', (67, 69))	('E2-dependent cell adhesion', 'CPA', (67, 93))	('prevention', 'NegReg', (53, 63))	('Silencing', 'Var', (0, 9))	('desmosome formation', 'CPA', (177, 196))	('DSP expression', 'Gene', (13, 27))
470564	34001250	The modulation of desmosomes by estrogen and its receptor could help maintain epithelial tissue integrity and explain the lower invasiveness seen in ERalpha positive breast tumours.	('breast tumours', 'Disease', 'MESH:D001943', (166, 180))	('epithelial tissue integrity', 'CPA', (78, 105))	('modulation', 'Var', (4, 14))	('invasiveness', 'CPA', (128, 140))	('ERalpha', 'Gene', (149, 156))	('tumour', 'Phenotype', 'HP:0002664', (173, 179))	('ERalpha', 'Gene', '2099', (149, 156))	('tumours', 'Phenotype', 'HP:0002664', (173, 180))	('breast tumours', 'Disease', (166, 180))
470571	34001250	Using immunohistochemistry, PPL expression was observed at cell-cell boundaries of normal oesophageal epithelium and dysplastic lesions, whereas it relocated to the cytoplasm in early cancers and was scarcely expressed in advanced tumours.	('PPL', 'Var', (28, 31))	('tumours', 'Phenotype', 'HP:0002664', (231, 238))	('cancers', 'Phenotype', 'HP:0002664', (184, 191))	('cancers', 'Disease', (184, 191))	('tumours', 'Disease', 'MESH:D009369', (231, 238))	('cancers', 'Disease', 'MESH:D009369', (184, 191))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('tumours', 'Disease', (231, 238))	('dysplastic lesions', 'Disease', 'MESH:D004416', (117, 135))	('dysplastic lesions', 'Disease', (117, 135))	('tumour', 'Phenotype', 'HP:0002664', (231, 237))
470572	34001250	In patients with a history of smoking and who present with hyper-methylation of oesophageal mucosa, DNA methylation of PPL promoter sequences leads to reduced expression of PPL and have been linked to the development of oesophageal squamous cell carcinoma, suggesting that loss of PPL may be one of the early events in the progression of oesophageal cancer.	('DNA', 'Var', (100, 103))	('oesophageal squamous cell carcinoma', 'Disease', (220, 255))	('reduced', 'NegReg', (151, 158))	('cancer', 'Disease', 'MESH:D009369', (350, 356))	('carcinoma', 'Phenotype', 'HP:0030731', (246, 255))	('linked to', 'Reg', (191, 200))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (232, 255))	('cancer', 'Disease', (350, 356))	('expression', 'MPA', (159, 169))	('patients', 'Species', '9606', (3, 11))	('oesophageal squamous cell carcinoma', 'Disease', 'MESH:D002294', (220, 255))	('loss', 'Var', (273, 277))	('PPL', 'Protein', (173, 176))	('cancer', 'Phenotype', 'HP:0002664', (350, 356))	('PPL', 'Gene', (119, 122))
470581	34001250	The absence of PPL expression hinders collective migration and wound closures in epithelial cancer cells grown as monolayers as PPL facilitates the reorganization of keratin filaments at the edge of wounds.	('PPL', 'Var', (128, 131))	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('hinders', 'NegReg', (30, 37))	('keratin filaments', 'Protein', (166, 183))	('epithelial cancer', 'Phenotype', 'HP:0031492', (81, 98))	('facilitates', 'PosReg', (132, 143))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('PPL', 'Gene', (15, 18))	('absence', 'Var', (4, 11))	('reorganization', 'MPA', (148, 162))
470583	34001250	On the contrary, in a colon cancer cell line model (HT29), increased proliferation, migration, invasion and EMT initiating ability was noted in response to PPL knockdown.	('EMT initiating ability', 'CPA', (108, 130))	('invasion', 'CPA', (95, 103))	('HT29', 'CellLine', 'CVCL:0320', (52, 56))	('proliferation', 'CPA', (69, 82))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('knockdown', 'Var', (160, 169))	('colon cancer', 'Phenotype', 'HP:0003003', (22, 34))	('migration', 'CPA', (84, 93))	('colon cancer', 'Disease', 'MESH:D015179', (22, 34))	('PPL', 'Gene', (156, 159))	('colon cancer', 'Disease', (22, 34))	('increased', 'PosReg', (59, 68))
470585	34001250	Decreased proliferation in response to PPL overexpression was due to higher rate of G1/G0 cell cycle arrest resulting from increased expression of CDK inhibitors p21, p27kip and p-Rb.	('p-Rb', 'Var', (178, 182))	('increased', 'PosReg', (123, 132))	('expression', 'MPA', (133, 143))	('p27kip', 'Var', (167, 173))	('proliferation', 'CPA', (10, 23))	('CDK', 'Gene', '983', (147, 150))	('Decreased', 'NegReg', (0, 9))	('arrest', 'Disease', 'MESH:D006323', (101, 107))	('p21', 'Gene', (162, 165))	('CDK', 'Gene', (147, 150))	('higher', 'PosReg', (69, 75))	('p21', 'Gene', '644914', (162, 165))	('arrest', 'Disease', (101, 107))
470593	34001250	In HeLa cells increased migration was observed when EPPK1 expression was suppressed by knockdown while decreased migration was noted in EPPK1 overexpressed cells.	('increased', 'PosReg', (14, 23))	('expression', 'MPA', (58, 68))	('suppressed', 'NegReg', (73, 83))	('HeLa', 'CellLine', 'CVCL:0030', (3, 7))	('EPPK1', 'Gene', (52, 57))	('migration', 'CPA', (24, 33))	('knockdown', 'Var', (87, 96))
470595	34001250	However, in 2D cultures EPPK1 stabilised the keratin networks via colocalization with zonula occludens-1 (ZO-1), a marker of tight junctions, and inhibited the motility of cells by reorganizing the actin filaments.	('EPPK1', 'Var', (24, 29))	('ZO-1', 'Gene', (106, 110))	('keratin networks', 'Protein', (45, 61))	('actin filaments', 'CPA', (198, 213))	('inhibited', 'NegReg', (146, 155))	('motility of cells', 'CPA', (160, 177))	('zonula occludens-1', 'Gene', (86, 104))	('ZO-1', 'Gene', '7082', (106, 110))	('stabilised', 'PosReg', (30, 40))	('zonula occludens-1', 'Gene', '7082', (86, 104))	('colocalization', 'Interaction', (66, 80))
470596	34001250	Plectin expression was significantly higher in the SW480 colon cancer cell line than the lower grade HT29 colon cancer cell line.	('Plectin', 'Gene', (0, 7))	('higher', 'PosReg', (37, 43))	('HT29', 'CellLine', 'CVCL:0320', (101, 105))	('SW480', 'Var', (51, 56))	('colon cancer', 'Phenotype', 'HP:0003003', (57, 69))	('colon cancer', 'Disease', 'MESH:D015179', (57, 69))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('colon cancer', 'Phenotype', 'HP:0003003', (106, 118))	('colon cancer', 'Disease', 'MESH:D015179', (106, 118))	('Plectin', 'Gene', '5339', (0, 7))	('SW480', 'CellLine', 'CVCL:0546', (51, 56))	('colon cancer', 'Disease', (57, 69))	('expression', 'MPA', (8, 18))	('colon cancer', 'Disease', (106, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))
470600	34001250	High PLEC expression has been noted in head and neck squamous cell carcinomas (HNSCC) and has been associated with increased recurrence and decreased survival rates in patients.	('decreased', 'NegReg', (140, 149))	('neck squamous cell carcinomas', 'Disease', (48, 77))	('SCC', 'Gene', '6317', (81, 84))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (53, 77))	('High PLEC expression', 'Var', (0, 20))	('increased', 'PosReg', (115, 124))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (53, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('carcinomas', 'Phenotype', 'HP:0030731', (67, 77))	('patients', 'Species', '9606', (168, 176))	('survival rates', 'CPA', (150, 164))	('neck squamous cell carcinomas', 'Disease', 'MESH:D000077195', (48, 77))	('SCC', 'Gene', (81, 84))	('SCC', 'Phenotype', 'HP:0002860', (81, 84))
470609	34001250	Normal keratinocytes, even though expressing PLEC1a, 1f and integrin beta4, do not produce exosomes.	('integrin beta4', 'Gene', '3691', (60, 74))	('PLEC1a', 'Var', (45, 51))	('integrin beta4', 'Gene', (60, 74))
470632	34001250	In the last fifteen years, extensive immunohistochemical analysis of the Fallopian tubes obtained during salpingo-oophorectomy from women with inherited mutation in germline breast cancer susceptibility proteins type 1,2 (BRCA 1,2) have shown that the fimbriae end of the Fallopian tube that expresses serous tubal intraepithelial carcinoma (STIC) lesions, to be a potential source of high-grade serous ovarian tumours.	('breast cancer', 'Disease', 'MESH:D001943', (174, 187))	('BRCA 1,2', 'Gene', (222, 230))	('carcinoma', 'Phenotype', 'HP:0030731', (331, 340))	('women', 'Species', '9606', (132, 137))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('breast cancer', 'Disease', (174, 187))	('tumour', 'Phenotype', 'HP:0002664', (411, 417))	('serous ovarian tumours', 'Disease', 'MESH:D010051', (396, 418))	('breast cancer', 'Phenotype', 'HP:0003002', (174, 187))	('tumours', 'Phenotype', 'HP:0002664', (411, 418))	('BRCA 1,2)', 'Gene', '672;675', (222, 231))	('serous tubal intraepithelial carcinoma (STIC) lesions', 'Disease', 'MESH:D002278', (302, 355))	('ovarian tumour', 'Phenotype', 'HP:0100615', (403, 417))	('serous ovarian tumours', 'Disease', (396, 418))	('mutation', 'Var', (153, 161))
470633	34001250	Women with BRCA1,2 mutations are predisposed to breast/ovarian cancer syndrome and carry a lifetime risk of 60-80% for breast cancer and 40-50% ovarian cancer respectively.	('breast/ovarian cancer syndrome', 'Disease', (48, 78))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('breast cancer', 'Disease', 'MESH:D001943', (119, 132))	('breast/ovarian cancer syndrome', 'Disease', 'MESH:D061325', (48, 78))	('Women', 'Species', '9606', (0, 5))	('BRCA1', 'Gene', '672', (11, 16))	('ovarian cancer', 'Phenotype', 'HP:0100615', (144, 158))	('breast cancer', 'Disease', (119, 132))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('ovarian cancer', 'Disease', 'MESH:D010051', (144, 158))	('breast cancer', 'Phenotype', 'HP:0003002', (119, 132))	('mutations', 'Var', (19, 28))	('BRCA1', 'Gene', (11, 16))	('ovarian cancer', 'Phenotype', 'HP:0100615', (55, 69))	('predisposed', 'Reg', (33, 44))	('ovarian cancer', 'Disease', (144, 158))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('ovarian cancer', 'Disease', 'MESH:D010051', (55, 69))
470635	34001250	The cells within STICs have a high proliferative index (indicated by high Ki67 expression) and a 'p53 signature' (mutated, non-functional p53) and exhibit the DNA damage marker gamma-H2AX indicating damaged DNA double strand breaks.	('p53', 'Gene', (138, 141))	('proliferative index', 'CPA', (35, 54))	('mutated', 'Var', (114, 121))	('p53', 'Gene', '7157', (138, 141))	('p53', 'Gene', (98, 101))	('p53', 'Gene', '7157', (98, 101))
470636	34001250	Later clinical studies have shown that 38% of this signature persists in women with BRCA1,2 mutations and 80% of that occurs in STICs located at the fimbriae end of the Fallopian tube, potentially identifying the Fallopian tube as the origin of high-grade serous ovarian cancers.	('serous ovarian cancers', 'Disease', (256, 278))	('ovarian cancers', 'Phenotype', 'HP:0100615', (263, 278))	('women', 'Species', '9606', (73, 78))	('cancer', 'Phenotype', 'HP:0002664', (271, 277))	('serous ovarian cancers', 'Disease', 'MESH:D018284', (256, 278))	('BRCA1', 'Gene', '672', (84, 89))	('mutations', 'Var', (92, 101))	('ovarian cancer', 'Phenotype', 'HP:0100615', (263, 277))	('cancers', 'Phenotype', 'HP:0002664', (271, 278))	('BRCA1', 'Gene', (84, 89))
470648	34001250	In addition, TNT-induced transfer of mitochondria from bone-marrow stromal cells to myeloid leukemic cells or endothelial cells to cancer cells during chemotherapy treatment has been shown to promote survival of resistant cancer cells.	('cancer', 'Disease', (131, 137))	('TNT', 'Chemical', '-', (13, 16))	('cancer', 'Disease', 'MESH:D009369', (222, 228))	('leukemic', 'Disease', (92, 100))	('cancer', 'Disease', (222, 228))	('promote', 'PosReg', (192, 199))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('transfer', 'Var', (25, 33))	('leukemic', 'Disease', 'MESH:D007938', (92, 100))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('survival', 'CPA', (200, 208))
470654	34001250	A recent study of 174 primary ovarian and 34 metastatic tumours suggested EMT was a poor prognostic indicator for ovarian cancer by associating low E-cadherin and high Snail expression with high peritoneal dissemination, low overall and progression-free survival in patients.	('high', 'Var', (163, 167))	('tumours', 'Disease', 'MESH:D009369', (56, 63))	('tumours', 'Disease', (56, 63))	('patients', 'Species', '9606', (266, 274))	('expression', 'MPA', (174, 184))	('ovarian cancer', 'Disease', (114, 128))	('E-cadherin', 'Protein', (148, 158))	('tumour', 'Phenotype', 'HP:0002664', (56, 62))	('Snail', 'Gene', '6615', (168, 173))	('Snail', 'Gene', (168, 173))	('high peritoneal dissemination', 'CPA', (190, 219))	('ovarian cancer', 'Phenotype', 'HP:0100615', (114, 128))	('low', 'NegReg', (144, 147))	('tumours', 'Phenotype', 'HP:0002664', (56, 63))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('ovarian cancer', 'Disease', 'MESH:D010051', (114, 128))	('low', 'NegReg', (221, 224))
470665	34001250	It is postulated that the alterations in E/M or EMT/MET phenomenon in intraperitoneal ovarian tumour cells is not due to any genetic mutation but is likely due to the origin of ovarian cancer itself which arises either from ovarian surface epithelium or differentiated columnar epithelial cells both of which contain epithelial and mesenchymal traits.	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('E/M', 'Gene', '3702', (41, 44))	('ovarian cancer', 'Disease', (177, 191))	('MET', 'Gene', '79811', (52, 55))	('ovarian tumour', 'Disease', 'MESH:D010051', (86, 100))	('alterations', 'Var', (26, 37))	('ovarian tumour', 'Phenotype', 'HP:0100615', (86, 100))	('tumour', 'Phenotype', 'HP:0002664', (94, 100))	('E/M', 'Gene', (41, 44))	('ovarian cancer', 'Phenotype', 'HP:0100615', (177, 191))	('MET', 'Gene', (52, 55))	('ovarian tumour', 'Disease', (86, 100))	('ovarian cancer', 'Disease', 'MESH:D010051', (177, 191))
470671	34001250	Loss of KRT14+ cells diminished the invasive capacity of ovarian cancer spheroids, suggesting a potential role of E/M KRT14 + cells in peritoneal invasion.	('KRT14', 'Gene', '3861', (8, 13))	('ovarian cancer', 'Phenotype', 'HP:0100615', (57, 71))	('KRT14', 'Gene', (118, 123))	('ovarian cancer spheroids', 'Disease', 'MESH:C000598645', (57, 81))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('E/M', 'Gene', (114, 117))	('KRT14', 'Gene', (8, 13))	('diminished', 'NegReg', (21, 31))	('E/M', 'Gene', '3702', (114, 117))	('ovarian cancer spheroids', 'Disease', (57, 81))	('Loss', 'Var', (0, 4))	('KRT14', 'Gene', '3861', (118, 123))
470687	34001250	Among these PI3 kinase/Akt/PTEN, Jak2/Stat3, NFkappaB, Wnt, Notch and Hedgehog have been shown to facilitate tumour progression and chemotherapy resistance in ovarian cancer.	('tumour', 'Disease', 'MESH:D009369', (109, 115))	('PI3', 'Var', (12, 15))	('tumour', 'Disease', (109, 115))	('Akt', 'Gene', (23, 26))	('chemotherapy resistance', 'CPA', (132, 155))	('NFkappaB', 'Gene', (45, 53))	('facilitate', 'PosReg', (98, 108))	('PTEN', 'Gene', (27, 31))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('Notch', 'Gene', (60, 65))	('Akt', 'Gene', '207', (23, 26))	('Hedgehog', 'Gene', (70, 78))	('Stat3', 'Gene', (38, 43))	('PTEN', 'Gene', '5728', (27, 31))	('ovarian cancer', 'Disease', 'MESH:D010051', (159, 173))	('Stat3', 'Gene', '6774', (38, 43))	('ovarian cancer', 'Disease', (159, 173))	('Jak2', 'Gene', (33, 37))	('Jak2', 'Gene', '3717', (33, 37))	('NFkappaB', 'Gene', '4790', (45, 53))	('ovarian cancer', 'Phenotype', 'HP:0100615', (159, 173))	('Wnt', 'Gene', (55, 58))	('tumour', 'Phenotype', 'HP:0002664', (109, 115))
470688	34001250	Inhibiting these pathways in in vitro cultures has shown suppression of tumourigenesis and chemosensitivity in cell line and animal models.	('Inhibiting', 'Var', (0, 10))	('tumour', 'Phenotype', 'HP:0002664', (72, 78))	('suppression', 'NegReg', (57, 68))	('chemosensitivity', 'CPA', (91, 107))	('tumour', 'Disease', 'MESH:D009369', (72, 78))	('tumour', 'Disease', (72, 78))
470689	34001250	The BRCA1, 2 genes are involved in DSB repair, with inherited mutations in these genes causing specific defects in the DNA repair capacity of the cell.	('defects', 'NegReg', (104, 111))	('BRCA1', 'Gene', (4, 9))	('causing', 'Reg', (87, 94))	('DNA repair capacity of the', 'MPA', (119, 145))	('BRCA1', 'Gene', '672', (4, 9))	('mutations', 'Var', (62, 71))
470691	34001250	Inhibition of PARP1 can trigger 'synthetic lethality' in cells with BRCA1/2 mutations (and other faulty DSB repair mechanisms).	('BRCA1/2', 'Gene', '672;675', (68, 75))	('PARP1', 'Gene', (14, 19))	('mutations', 'Var', (76, 85))	("'synthetic lethality'", 'CPA', (32, 53))	('BRCA1/2', 'Gene', (68, 75))	('Inhibition', 'Var', (0, 10))	('PARP1', 'Gene', '142', (14, 19))
470692	34001250	The use of PARP inhibitors has been successful in ovarian cancers in both BRCA1/2 mutated and non-mutated patients.	('PARP', 'Gene', '142', (11, 15))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('ovarian cancers', 'Phenotype', 'HP:0100615', (50, 65))	('ovarian cancers', 'Disease', (50, 65))	('ovarian cancers', 'Disease', 'MESH:D010051', (50, 65))	('cancers', 'Phenotype', 'HP:0002664', (58, 65))	('BRCA1/2', 'Gene', (74, 81))	('mutated', 'Var', (82, 89))	('patients', 'Species', '9606', (106, 114))	('PARP', 'Gene', (11, 15))	('BRCA1/2', 'Gene', '672;675', (74, 81))	('ovarian cancer', 'Phenotype', 'HP:0100615', (50, 64))
470727	34001250	Our previous studies have also shown a sustained loss of PLEC and vimentin in an OCT4A knockdown HEY ovarian cancer cell line.	('loss', 'NegReg', (49, 53))	('OCT4A', 'Gene', (81, 86))	('vimentin', 'Gene', '7431', (66, 74))	('vimentin', 'Gene', (66, 74))	('HEY ovarian cancer', 'Disease', (97, 115))	('HEY ovarian cancer', 'Disease', 'MESH:D010051', (97, 115))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('ovarian cancer', 'Phenotype', 'HP:0100615', (101, 115))	('PLEC', 'Protein', (57, 61))	('OCT4A', 'Chemical', '-', (81, 86))	('knockdown', 'Var', (87, 96))
470728	34001250	OCT4 is a transcription factor, with the OCT4A variant being required to maintain the self-renewal properties of stem cells and is a nuclear marker of embryonic and CSCs.	('variant', 'Var', (47, 54))	('OCT4A', 'Chemical', '-', (41, 46))	('OCT4', 'Gene', '5460', (41, 45))	('self-renewal properties of stem cells', 'CPA', (86, 123))	('OCT4', 'Gene', '5460', (0, 4))	('OCT4', 'Gene', (41, 45))	('OCT4', 'Gene', (0, 4))
470732	34001250	In a later proteomics study, we identified and validated that stable knockdown of OCT4A in HEY ovarian cancer cell line and the associated xenografts showed a loss of PLEC and vimentin expression.	('OCT4A', 'Chemical', '-', (82, 87))	('vimentin', 'Gene', '7431', (176, 184))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('OCT4A', 'Gene', (82, 87))	('loss', 'NegReg', (159, 163))	('vimentin', 'Gene', (176, 184))	('PLEC', 'Protein', (167, 171))	('knockdown', 'Var', (69, 78))	('HEY ovarian cancer', 'Disease', 'MESH:D010051', (91, 109))	('HEY ovarian cancer', 'Disease', (91, 109))	('ovarian cancer', 'Phenotype', 'HP:0100615', (95, 109))
470756	32969465	High TTK expression associated with a higher histological stage, advanced TNM stage, high frequency of positive lymph nodes, and worse 5-year overall survival.	('TTK', 'Gene', '7272', (5, 8))	('High', 'Var', (0, 4))	('TNM', 'Gene', (74, 77))	('high frequency of positive lymph nodes', 'Phenotype', 'HP:0032536', (85, 123))	('higher', 'PosReg', (38, 44))	('TTK', 'Gene', (5, 8))	('histological stage', 'CPA', (45, 63))	('TNM', 'Gene', '10178', (74, 77))
470774	32969465	In the present study, three original gene expression profile datasets (GSE31552, GSE43458, and GSE44077) were obtained from the Gene Expression Omnibus to identify the NSCLC-associated DEGs in the tumor tissue versus non-tumor lung samples.	('DEGs', 'Chemical', '-', (185, 189))	('NSCLC', 'Disease', 'MESH:D002289', (168, 173))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('tumor tissue versus non-tumor', 'Disease', (197, 226))	('GSE44077', 'Var', (95, 103))	('NSCLC', 'Phenotype', 'HP:0030358', (168, 173))	('GSE31552', 'Var', (71, 79))	('tumor lung', 'Phenotype', 'HP:0100526', (221, 231))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('tumor tissue versus non-tumor', 'Disease', 'MESH:D009369', (197, 226))	('DEGs', 'Var', (185, 189))	('NSCLC', 'Disease', (168, 173))
470783	32969465	The DEGs with log FC<0 were supposed as down-regulated genes, while the DEGs with log FC>0 were regarded as up-regulated genes.	('DEGs', 'Chemical', '-', (72, 76))	('log FC', 'Var', (82, 88))	('log FC<0', 'Var', (14, 22))	('DEGs', 'Chemical', '-', (4, 8))	('down-regulated', 'NegReg', (40, 54))
470812	32969465	In GSE31552, 57 adenocarcinomas/squamous cell carcinoma and 57 corresponding non-tumor tissues were included.	('adenocarcinomas/squamous cell carcinoma', 'Disease', (16, 55))	('carcinoma', 'Phenotype', 'HP:0030731', (46, 55))	('GSE31552', 'Var', (3, 11))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (32, 55))	('adenocarcinomas/squamous cell carcinoma', 'Disease', 'MESH:D002294', (16, 55))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('carcinoma', 'Phenotype', 'HP:0030731', (21, 30))	('tumor', 'Disease', (81, 86))
470814	32969465	In GSE44077, 18 adenocarcinomas/squamous cell carcinoma and 18 corresponding non-tumor tissues were included.	('adenocarcinomas/squamous cell carcinoma', 'Disease', (16, 55))	('carcinoma', 'Phenotype', 'HP:0030731', (46, 55))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (32, 55))	('adenocarcinomas/squamous cell carcinoma', 'Disease', 'MESH:D002294', (16, 55))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('carcinoma', 'Phenotype', 'HP:0030731', (21, 30))	('GSE44077', 'Var', (3, 11))	('tumor', 'Disease', (81, 86))
470815	32969465	By using Venn online software, 378, 888, and 1133 DEGs were extracted from GSE31552, GSE43458, and GSE44077 datasets, respectively.	('GSE44077', 'Var', (99, 107))	('GSE31552', 'Var', (75, 83))	('DEGs', 'Chemical', '-', (50, 54))	('GSE43458', 'Var', (85, 93))
470824	32969465	For up-regulated DEGs, the cell cycle signaling pathway was enriched by KEGG analysis (FDR = 1.70E-5, P=3.30E-07, Supplementary Table S5).	('DEGs', 'Chemical', '-', (17, 21))	('DEGs', 'Var', (17, 21))	('cell cycle signaling pathway', 'Pathway', (27, 55))	('up-regulated', 'PosReg', (4, 16))
470868	32969465	There is no significant difference in age, gender, location, and distant metastasis between the low TTK group and the high TTK group (Table 1, P>0.05).	('distant metastasis', 'CPA', (65, 83))	('TTK', 'Gene', (100, 103))	('TTK', 'Gene', '7272', (100, 103))	('low', 'Var', (96, 99))	('TTK', 'Gene', (123, 126))	('TTK', 'Gene', '7272', (123, 126))
470872	32969465	Whereas, in the high TTK group, 15(53.6%) were in TNM stages I-II, and 13 (46.4%) were in TNM stages III-IV, indicating that high TTK expression is significantly associated with advanced TNM stage in NSCLC (P=0.015, Table 1).	('NSCLC', 'Phenotype', 'HP:0030358', (200, 205))	('TNM', 'Gene', (50, 53))	('TTK', 'Gene', '7272', (21, 24))	('TTK', 'Gene', '7272', (130, 133))	('TNM', 'Gene', '10178', (90, 93))	('NSCLC', 'Disease', (200, 205))	('TNM', 'Gene', '10178', (187, 190))	('associated with', 'Reg', (162, 177))	('NSCLC', 'Disease', 'MESH:D002289', (200, 205))	('TNM', 'Gene', '10178', (50, 53))	('TNM', 'Gene', (90, 93))	('TTK', 'Gene', (21, 24))	('TTK', 'Gene', (130, 133))	('high', 'Var', (125, 129))	('TNM', 'Gene', (187, 190))
470877	32969465	Patients with high TTK expression achieved better overall 5-year survival compared with patients with low TTK expression (P<0.0001, Figure 8A).	('TTK', 'Gene', '7272', (106, 109))	('patients', 'Species', '9606', (88, 96))	('high', 'Var', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('TTK', 'Gene', (19, 22))	('better', 'PosReg', (43, 49))	('TTK', 'Gene', '7272', (19, 22))	('TTK', 'Gene', (106, 109))
470885	32969465	We achieved the following new findings: (1) We identified 284 DEGs may play an important role in the development of NSCLC, with 75 up-regulated DEGs and 209 down-regulated DEGs, these identified DEGs were important for multiple cell processes and cell singling pathways, such as mitotic cell division, angiogenesis, and cell cycle.	('NSCLC', 'Disease', 'MESH:D002289', (116, 121))	('DEGs', 'Chemical', '-', (62, 66))	('DEGs', 'Chemical', '-', (172, 176))	('down-regulated', 'NegReg', (157, 171))	('NSCLC', 'Phenotype', 'HP:0030358', (116, 121))	('up-regulated', 'PosReg', (131, 143))	('DEGs', 'Var', (144, 148))	('DEGs', 'Chemical', '-', (195, 199))	('NSCLC', 'Disease', (116, 121))	('DEGs', 'Chemical', '-', (144, 148))
470898	32969465	In cancers, defects in cell cycle and checkpoint attribute gene mutations, chromosome damages which can eventually contribute to altered cell proliferation and tumorigenesis.	('cell cycle', 'CPA', (23, 33))	('cell proliferation', 'CPA', (137, 155))	('chromosome damages', 'CPA', (75, 93))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('cancers', 'Phenotype', 'HP:0002664', (3, 10))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('cancers', 'Disease', (3, 10))	('altered', 'Reg', (129, 136))	('mutations', 'Var', (64, 73))	('cancers', 'Disease', 'MESH:D009369', (3, 10))	('tumor', 'Disease', (160, 165))	('contribute', 'Reg', (115, 125))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
470915	32969465	The protein expression levels of TTK were increased in NSCLC tumor tissues and inhibition of TTK reduces A549 cell proliferation, migration and tumorigenesis.	('NSCLC tumor', 'Disease', 'MESH:D009369', (55, 66))	('TTK', 'Gene', (93, 96))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('TTK', 'Gene', '7272', (33, 36))	('inhibition', 'Var', (79, 89))	('reduces', 'NegReg', (97, 104))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('NSCLC', 'Phenotype', 'HP:0030358', (55, 60))	('increased', 'PosReg', (42, 51))	('tumor', 'Disease', (144, 149))	('TTK', 'Gene', '7272', (93, 96))	('protein expression levels', 'MPA', (4, 29))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('TTK', 'Gene', (33, 36))	('migration', 'CPA', (130, 139))	('NSCLC tumor', 'Disease', (55, 66))	('A549', 'CellLine', 'CVCL:0023', (105, 109))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('tumor', 'Disease', (61, 66))
470917	32969465	As expected, high TTK expression associated with higher histological stage, advanced TNM stage, high frequency of positive lymph nodes and worse 5-year overall survival.	('TTK', 'Gene', (18, 21))	('high', 'Var', (13, 17))	('TNM', 'Gene', (85, 88))	('TTK', 'Gene', '7272', (18, 21))	('TNM', 'Gene', '10178', (85, 88))	('higher', 'PosReg', (49, 55))	('high frequency of positive lymph nodes', 'Phenotype', 'HP:0032536', (96, 134))	('histological stage', 'CPA', (56, 74))
470995	29533533	They expressed CD29, CD73, CD90, CD105, CD49d, CD44, CD54, human leukocyte antigen (HLA) class I, PD-L1, and PD-L2.	('CD90', 'Gene', (27, 31))	('CD73', 'Gene', '4907', (21, 25))	('human', 'Species', '9606', (59, 64))	('CD54', 'Gene', (53, 57))	('CD44', 'Gene', '960', (47, 51))	('CD29', 'Gene', (15, 19))	('CD49d', 'Gene', (40, 45))	('PD-L1', 'Gene', (98, 103))	('CD73', 'Gene', (21, 25))	('CD44', 'Gene', (47, 51))	('CD105', 'Var', (33, 38))	('PD-L2', 'Gene', (109, 114))	('PD-L2', 'Gene', '80380', (109, 114))	('PD-L1', 'Gene', '29126', (98, 103))	('CD49d', 'Gene', '3676', (40, 45))	('CD29', 'Gene', '3688', (15, 19))	('CD90', 'Gene', '7070', (27, 31))	('CD54', 'Gene', '3383', (53, 57))
471121	27321817	As it is known that aberrations cause (in)activation of specific pathways in cancer, we analyzed aberrations across pathways, which shows a birds-eye view of the aberration landscape and facilitates the identification of functional themes in each cancer type.	('aberrations', 'Var', (20, 31))	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('cancer', 'Disease', (247, 253))	('cancer', 'Disease', 'MESH:D009369', (247, 253))	('activation', 'PosReg', (42, 52))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))
471135	27321817	Across cancer types, the number of affected genes was similar for activating (oncogene-like) and inactivating (tumor suppressor-like) aberrations but highly dependent on the data type.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('activating', 'Var', (66, 76))	('tumor', 'Disease', (111, 116))	('aberrations', 'Var', (134, 145))	('cancer', 'Disease', (7, 13))	('cancer', 'Disease', 'MESH:D009369', (7, 13))
471148	27321817	First, we analyzed the prioritization scores of cancer gene candidates frequently mutated in breast or colon cancer, across twelve or twenty one different cancer types.	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('cancer', 'Disease', (109, 115))	('breast or colon cancer', 'Disease', 'MESH:D001943', (93, 115))	('mutated', 'Var', (82, 89))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('breast or colon cancer', 'Disease', (93, 115))	('colon cancer', 'Phenotype', 'HP:0003003', (103, 115))	('cancer', 'Disease', (155, 161))	('cancer', 'Disease', 'MESH:D009369', (155, 161))
471166	27321817	It was mentioned in only five cancer-related publications implicating it as frequently mutated in melanoma and as potential drug target for colorectal cancer.	('mutated', 'Var', (87, 94))	('colorectal cancer', 'Disease', (140, 157))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('cancer', 'Disease', (30, 36))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('rectal cancer', 'Phenotype', 'HP:0100743', (144, 157))	('melanoma', 'Disease', 'MESH:D008545', (98, 106))	('melanoma', 'Phenotype', 'HP:0002861', (98, 106))	('cancer', 'Disease', (151, 157))	('melanoma', 'Disease', (98, 106))	('colorectal cancer', 'Disease', 'MESH:D015179', (140, 157))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('colorectal cancer', 'Phenotype', 'HP:0003003', (140, 157))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
471171	27321817	However, we identified potentially activating aberrations for several known tumor suppressor genes.	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('activating', 'PosReg', (35, 45))	('aberrations', 'Var', (46, 57))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
471181	27321817	PTK2B was ranked among the ten genes with highest tumor suppressor score (sum of TS scores = 20, sum of OG scores = 9), mostly because of DNA copy number and methylation changes (Fig.	('methylation changes', 'Var', (158, 177))	('PTK2B', 'Gene', (0, 5))	('DNA copy number', 'Var', (138, 153))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('PTK2B', 'Gene', '2185', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Disease', (50, 55))
471187	27321817	Cancer is a disease of pathways, which can be affected by aberrations in different genes, for example mutations in BRAF and KRAS leading to activation of the MAP kinase pathway.	('BRAF', 'Gene', '673', (115, 119))	('MAP kinase pathway', 'Pathway', (158, 176))	('KRAS', 'Gene', (124, 128))	('BRAF', 'Gene', (115, 119))	('KRAS', 'Gene', '3845', (124, 128))	('activation', 'PosReg', (140, 150))	('Cancer', 'Disease', (0, 6))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('mutations', 'Var', (102, 111))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('affected', 'Reg', (46, 54))
471189	27321817	Calcium signaling, recognized for its importance in cancer, was targeted by inactivating aberrations in most genes with the exception of growth factor receptors and PLC-beta isozymes (Figs 4 and S8).	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('Calcium signaling', 'MPA', (0, 17))	('Calcium', 'Chemical', 'MESH:D002118', (0, 7))	('inactivating aberrations', 'Var', (76, 100))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))
471194	27321817	We also identified the mutations in BRAF as being specific for CMS1.	('mutations', 'Var', (23, 32))	('BRAF', 'Gene', (36, 40))	('BRAF', 'Gene', '673', (36, 40))	('CMS1', 'Disease', (63, 67))
471207	27321817	Few genes were found frequently mutated in the cell lines and a substantially higher number of genes were affected by DNA copy number alterations and gene expression changes, similar to the observations in tumors.	('changes', 'Var', (166, 173))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('tumors', 'Phenotype', 'HP:0002664', (206, 212))	('gene expression', 'MPA', (150, 165))	('affected', 'Reg', (106, 114))	('tumors', 'Disease', (206, 212))	('DNA', 'Gene', (118, 121))	('tumors', 'Disease', 'MESH:D009369', (206, 212))	('copy number alterations', 'Var', (122, 145))
471227	27321817	Aberrations found in the panel of colon cancer cell lines closely resembled colon tumors, which is in line with previous results.	('colon cancer', 'Disease', (34, 46))	('colon tumors', 'Phenotype', 'HP:0100273', (76, 88))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('colon tumors', 'Disease', 'MESH:D015179', (76, 88))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('colon cancer', 'Phenotype', 'HP:0003003', (34, 46))	('colon cancer', 'Disease', 'MESH:D015179', (34, 46))	('colon tumors', 'Disease', (76, 88))	('Aberrations', 'Var', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))
471230	27321817	They identified significant differences in the mutation rates of important oncogenes and tumor suppressor genes between tumors and cell lines.	('tumors', 'Disease', (120, 126))	('tumors', 'Disease', 'MESH:D009369', (120, 126))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('mutation', 'Var', (47, 55))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('oncogenes', 'Gene', (75, 84))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))	('tumor', 'Disease', (120, 125))
471260	27321817	A gene was scored as potential tumor suppressor or oncogene if 1) its copy-number value in tumor samples was significantly lower or higher than in normal samples and 2) the copy-number was significantly (FDR < 0.05) positively correlated with gene expression across the tumor samples.	('higher', 'PosReg', (132, 138))	('copy-number value', 'MPA', (70, 87))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumor', 'Disease', (270, 275))	('correlated', 'Interaction', (227, 237))	('gene expression', 'MPA', (243, 258))	('lower', 'NegReg', (123, 128))	('tumor', 'Disease', (31, 36))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('copy-number', 'Var', (173, 184))	('tumor', 'Disease', 'MESH:D009369', (270, 275))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (270, 275))	('tumor', 'Disease', (91, 96))	('positively', 'PosReg', (216, 226))
471266	27321817	We divided mutations according to their classification into oncogene mutations (missense mutations and in frame deletion/insertions) and tumor suppressor mutations (frame-shift deletions/insertions, nonsense mutations and splice site mutations).	('tumor', 'Disease', (137, 142))	('oncogene', 'Gene', (60, 68))	('missense mutations', 'Var', (80, 98))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('frame-shift deletions/insertions', 'Var', (165, 197))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
471273	27321817	In order to estimate which samples were affected by alterations in gene expression, DNA copy number or methylation of a specific gene, we first obtained the distribution of differences between tumor and normal samples.	('tumor', 'Disease', (193, 198))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('alterations', 'Var', (52, 63))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))
471365	33396696	RPSA gene expression was decreased by 62% after RPSA siRNA transfection compared to control (Figure 3A).	('RPSA', 'Gene', (0, 4))	('decreased', 'NegReg', (25, 34))	('RPSA', 'Gene', '3921', (0, 4))	('expression', 'MPA', (10, 20))	('RPSA', 'Gene', '3921', (48, 52))	('transfection', 'Var', (59, 71))	('RPSA', 'Gene', (48, 52))
471368	33396696	Even partial RPSA invalidation abolished the AG-9-induced effects on MMP-2 secretion (Figure 3C) and MT1-MMP expression (Figure 3D).	('RPSA', 'Gene', (13, 17))	('RPSA', 'Gene', '3921', (13, 17))	('AG-9', 'Chemical', 'MESH:C060641', (45, 49))	('abolished', 'NegReg', (31, 40))	('MMP-2', 'Gene', (69, 74))	('AG-9-induced', 'Gene', (45, 57))	('MT1-MMP', 'Gene', '4323', (101, 108))	('invalidation', 'Var', (18, 30))	('MMP-2', 'Gene', '4313', (69, 74))	('MT1-MMP', 'Gene', (101, 108))
471375	33396696	Finally, the analysis of the RPSA residues making contact with the ligands evidenced common interactions with R117, 120RL121, and the region 140VNLP143 (Figure 3G).	('RPSA', 'Gene', (29, 33))	('R117', 'Var', (110, 114))	('120RL121', 'Var', (116, 124))	('RPSA', 'Gene', '3921', (29, 33))	('interactions', 'Interaction', (92, 104))
471388	33396696	Its cleavage by elastase-proteinases such as metalloproteinases or leucocyte elastase is known to unmask cryptic sites within the macromolecule and to release matrikines, called elastin derived peptides (EDPs) or elastokines.	('elastin', 'Gene', '2006', (178, 185))	('cleavage', 'Var', (4, 12))	('proteinase', 'Gene', '100862683', (52, 62))	('EDP', 'Chemical', '-', (204, 207))	('elastin', 'Gene', (178, 185))	('release matrikines', 'MPA', (151, 169))	('proteinase', 'Gene', (25, 35))	('proteinase', 'Gene', '100862683', (25, 35))	('proteinase', 'Gene', (52, 62))
471392	33396696	In vivo study showed that AG-9 peptide promotes melanoma progression even more than the well described VG-6 peptide.	('melanoma', 'Disease', (48, 56))	('promotes', 'PosReg', (39, 47))	('AG-9 peptide', 'Chemical', '-', (26, 38))	('AG-9 peptide', 'Var', (26, 38))	('melanoma', 'Disease', 'MESH:D008545', (48, 56))	('melanoma', 'Phenotype', 'HP:0002861', (48, 56))
471398	33396696	EDP were previously reported to increase MMP secretion, especially MMP-2.	('increase', 'PosReg', (32, 40))	('MMP', 'Gene', '4313;4322;4323', (67, 70))	('MMP', 'Gene', (41, 44))	('MMP-2', 'Gene', '4313', (67, 72))	('EDP', 'Var', (0, 3))	('MMP', 'Gene', (67, 70))	('EDP', 'Chemical', '-', (0, 3))	('MMP', 'Gene', '4313;4322;4323', (41, 44))	('MMP-2', 'Gene', (67, 72))
471399	33396696	AG-9 increased MMP-2 secretion, as reported for MIA PaCa-2 cells; this effect was biphasic, with an optimal effect obtained for 1.10-7 M AG-9.	('AG-9', 'Chemical', 'MESH:C060641', (137, 141))	('AG-9', 'Chemical', 'MESH:C060641', (0, 4))	('MMP-2', 'Gene', '4313', (15, 20))	('MIA PaCa-2', 'CellLine', 'CVCL:0428', (48, 58))	('AG-9', 'Var', (0, 4))	('increased', 'PosReg', (5, 14))	('MMP-2', 'Gene', (15, 20))
471400	33396696	Moreover, AG-9 increases MT1-MMP expression.	('MT1-MMP', 'Gene', '4323', (25, 32))	('AG-9', 'Chemical', 'MESH:C060641', (10, 14))	('MT1-MMP', 'Gene', (25, 32))	('increases', 'PosReg', (15, 24))	('AG-9', 'Var', (10, 14))
471413	33396696	EGCG was also able to inhibit SCC-4, SCC-9, and SCC-15 cell.	('SCC-15', 'CellLine', 'CVCL:1681', (48, 54))	('SCC-9', 'CPA', (37, 42))	('SCC-15 cell', 'CPA', (48, 59))	('inhibit', 'NegReg', (22, 29))	('SCC-9', 'CellLine', 'CVCL:1685', (37, 42))	('EGCG', 'Chemical', 'MESH:C045651', (0, 4))	('EGCG', 'Var', (0, 4))	('SCC-4', 'CPA', (30, 35))
471415	33396696	In addition, 10 microM EGCG also inhibits MMP-2 secretion as previously described for CAL 27 cells, nasopharyngeal carcinoma, and buccal mucosa cancer cells.	('buccal mucosa cancer', 'Disease', 'MESH:D009369', (130, 150))	('nasopharyngeal', 'Disease', (100, 114))	('EGCG', 'Chemical', 'MESH:C045651', (23, 27))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (100, 124))	('MMP-2', 'Gene', (42, 47))	('EGCG', 'Var', (23, 27))	('carcinoma', 'Disease', (115, 124))	('MMP-2', 'Gene', '4313', (42, 47))	('buccal mucosa cancer', 'Disease', (130, 150))	('inhibits', 'NegReg', (33, 41))	('carcinoma', 'Disease', 'MESH:D009369', (115, 124))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
471420	33422052	LncRNA LINC00240 suppresses invasion and migration in non-small cell lung cancer by sponging miR-7-5p lncRNAs have important roles in regulating cancer biology.	('cancer', 'Disease', (145, 151))	('lung cancer', 'Disease', 'MESH:D008175', (69, 80))	('LINC00240', 'Gene', (7, 16))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('LINC00240', 'Gene', '100133205', (7, 16))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('cancer', 'Disease', (74, 80))	('suppresses', 'NegReg', (17, 27))	('lung cancer', 'Disease', (69, 80))	('lung cancer', 'Phenotype', 'HP:0100526', (69, 80))	('miR-7-5p', 'Var', (93, 101))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (58, 80))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (54, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
471421	33422052	Accumulating evidence has established a link between the dysregulation of lncRNAs and microRNA in cancer progression.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('dysregulation', 'Var', (57, 70))	('lncRNAs', 'Protein', (74, 81))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('microRNA', 'CPA', (86, 94))	('cancer', 'Disease', (98, 104))
471430	33422052	Further investigations revealed that the knockdown of LINC00240 induced the overexpression of miR-7-5p.	('overexpression', 'MPA', (76, 90))	('miR-7-5p', 'Gene', (94, 102))	('miR-7-5p', 'Gene', '407045', (94, 102))	('LINC00240', 'Gene', (54, 63))	('LINC00240', 'Gene', '100133205', (54, 63))	('knockdown', 'Var', (41, 50))
471433	33422052	Silencing LINC00240 suppressed the invasion and migration of lung cancer cells, whereas LINC00240 overexpression exerted the opposite effect.	('lung cancer', 'Disease', (61, 72))	('lung cancer', 'Phenotype', 'HP:0100526', (61, 72))	('LINC00240', 'Gene', (10, 19))	('suppressed', 'NegReg', (20, 30))	('LINC00240', 'Gene', '100133205', (10, 19))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('LINC00240', 'Gene', (88, 97))	('lung cancer', 'Disease', 'MESH:D008175', (61, 72))	('Silencing', 'Var', (0, 9))	('LINC00240', 'Gene', '100133205', (88, 97))
471443	33422052	Mature miRNAs regulate their target genes through partial sequence complementarity to the 3' untranslated region (UTR) of the target genes, thereby resulting in mRNA degradation or/and translational repression.	('mRNA degradation', 'MPA', (161, 177))	('UTR', 'Gene', '2837', (114, 117))	('resulting in', 'Reg', (148, 160))	('partial sequence complementarity', 'Var', (50, 82))	('translational repression', 'MPA', (185, 209))	('UTR', 'Gene', (114, 117))
471472	33422052	To luciferase assay, Hcc1438 cells were transfected with psiCHECK-2 plasmid containing position s 174-179 of the LINC00240 with or without mutations of binding site and with miR-7-5p mimic or negative control.	('LINC00240', 'Gene', (113, 122))	('psiCHECK', 'Disease', (57, 65))	('LINC00240', 'Gene', '100133205', (113, 122))	('mutations', 'Var', (139, 148))	('binding', 'Interaction', (152, 159))	('miR-7-5p', 'Gene', (174, 182))	('miR-7-5p', 'Gene', '407045', (174, 182))	('psiCHECK', 'Disease', 'None', (57, 65))
471504	33422052	In the cell motility assay, LINC00240 knock-down led to repressed cell invasion and migration in the H1299 cells (Fig.	('H1299', 'CellLine', 'CVCL:0060', (101, 106))	('LINC00240', 'Gene', (28, 37))	('knock-down', 'Var', (38, 48))	('migration', 'CPA', (84, 93))	('LINC00240', 'Gene', '100133205', (28, 37))	('cell invasion', 'CPA', (66, 79))
471520	33422052	We showed that LINC00240 was downregulated in a lung cancer cell line after miR-7-5p mimic transfection.	('transfection', 'Var', (91, 103))	('miR-7-5p', 'Gene', (76, 84))	('lung cancer', 'Disease', 'MESH:D008175', (48, 59))	('miR-7-5p', 'Gene', '407045', (76, 84))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('lung cancer', 'Disease', (48, 59))	('lung cancer', 'Phenotype', 'HP:0100526', (48, 59))	('LINC00240', 'Gene', (15, 24))	('downregulated', 'NegReg', (29, 42))	('LINC00240', 'Gene', '100133205', (15, 24))
471521	33422052	Further investigations revealed that the knockdown of LINC00240 induced the upregulation of miR-7-5p.	('upregulation', 'PosReg', (76, 88))	('miR-7-5p', 'Gene', (92, 100))	('LINC00240', 'Gene', (54, 63))	('miR-7-5p', 'Gene', '407045', (92, 100))	('LINC00240', 'Gene', '100133205', (54, 63))	('knockdown', 'Var', (41, 50))
471523	33422052	Silencing LINC00240 suppressed the invasion and migration of the lung cancer cells, whereas LINC00240 overexpression exerted an opposite effect.	('LINC00240', 'Gene', '100133205', (92, 101))	('lung cancer', 'Disease', 'MESH:D008175', (65, 76))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('LINC00240', 'Gene', (10, 19))	('suppressed', 'NegReg', (20, 30))	('LINC00240', 'Gene', '100133205', (10, 19))	('lung cancer', 'Disease', (65, 76))	('lung cancer', 'Phenotype', 'HP:0100526', (65, 76))	('LINC00240', 'Gene', (92, 101))	('Silencing', 'Var', (0, 9))
471528	33422052	Subsequent studies elucidated the correlation between HOTAIR deregulation and cancer progression in 26 human tumor types.	('human', 'Species', '9606', (103, 108))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('HOTAIR', 'Gene', (54, 60))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('deregulation', 'Var', (61, 73))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('HOTAIR', 'Gene', '100124700', (54, 60))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('tumor', 'Disease', (109, 114))
471534	33422052	Regarding lung cancer, the up regulation of a potent oncogene, ERBB4, generated by UCA1 was achieved by binding miR-193-3p.	('up regulation', 'PosReg', (27, 40))	('ERBB4', 'Gene', '2066', (63, 68))	('miR-193-3p', 'Chemical', '-', (112, 122))	('binding', 'Interaction', (104, 111))	('miR-193-3p', 'Var', (112, 122))	('lung cancer', 'Disease', (10, 21))	('ERBB4', 'Gene', (63, 68))	('lung cancer', 'Phenotype', 'HP:0100526', (10, 21))	('UCA1', 'Gene', '652995', (83, 87))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('lung cancer', 'Disease', 'MESH:D008175', (10, 21))	('UCA1', 'Gene', (83, 87))
471535	33422052	In contrast, the sequestration of miR-181-a enabled MEG3 to up-regulate Bcl-2 in the case of gastric cancer.	('gastric cancer', 'Disease', 'MESH:D013274', (93, 107))	('Bcl-2', 'Gene', (72, 77))	('MEG3', 'Gene', '55384', (52, 56))	('sequestration', 'MPA', (17, 30))	('Bcl-2', 'Gene', '596', (72, 77))	('gastric cancer', 'Phenotype', 'HP:0012126', (93, 107))	('MEG3', 'Gene', (52, 56))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('miR-181-a', 'Var', (34, 43))	('up-regulate', 'PosReg', (60, 71))	('gastric cancer', 'Disease', (93, 107))
471544	33422052	The loss of LINC00240 suppressed cervical cancer development through the sponging of miR-124-3p and the overexpression of LINC00240 induced cervical cancer development.	('LINC00240', 'Gene', (122, 131))	('suppressed', 'NegReg', (22, 32))	('LINC00240', 'Gene', '100133205', (122, 131))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('cervical cancer', 'Disease', (33, 48))	('cervical cancer', 'Disease', 'MESH:D002583', (33, 48))	('cervical cancer', 'Disease', (140, 155))	('cervical cancer', 'Disease', 'MESH:D002583', (140, 155))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('induced', 'PosReg', (132, 139))	('miR-124-3p', 'Gene', '406909', (85, 95))	('LINC00240', 'Gene', (12, 21))	('miR-124-3p', 'Gene', (85, 95))	('LINC00240', 'Gene', '100133205', (12, 21))	('overexpression', 'PosReg', (104, 118))	('loss', 'Var', (4, 8))
471548	33422052	The establishment, growth and upkeep of epithelial tissues are primarily attributed to the EGFR signaling network, alterations in which may trigger malignant transformation.	('EGFR', 'Gene', (91, 95))	('malignant transformation', 'CPA', (148, 172))	('alterations', 'Var', (115, 126))	('trigger', 'Reg', (140, 147))	('growth', 'CPA', (19, 25))	('EGFR', 'Gene', '1956', (91, 95))	('upkeep', 'PosReg', (30, 36))
471555	33422052	These data suggest that replacement of miR-7-5p in specific human cancers could represent a new treatment approach.	('replacement', 'Var', (24, 35))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('miR-7-5p', 'Gene', (39, 47))	('cancers', 'Phenotype', 'HP:0002664', (66, 73))	('miR-7-5p', 'Gene', '407045', (39, 47))	('cancers', 'Disease', (66, 73))	('cancers', 'Disease', 'MESH:D009369', (66, 73))	('human', 'Species', '9606', (60, 65))
471557	33422052	In the case of adenocarcinoma, in particular, driver mutations and the corresponding drugs already exists and thus, it reacts well to targeted therapy, which includes, but is not limited to EGFR, ALK, and ROS1, resulting in good outcomes.	('adenocarcinoma', 'Disease', 'MESH:D000230', (15, 29))	('carcinoma', 'Phenotype', 'HP:0030731', (20, 29))	('EGFR', 'Gene', '1956', (190, 194))	('ALK', 'Gene', (196, 199))	('mutations', 'Var', (53, 62))	('EGFR', 'Gene', (190, 194))	('ROS1', 'Gene', (205, 209))	('ALK', 'Gene', '238', (196, 199))	('adenocarcinoma', 'Disease', (15, 29))	('ROS1', 'Gene', '6098', (205, 209))
471559	33422052	EGFR overexpression or amplification occurs more frequently in squamous cell carcinoma than in adenocarcinoma, but EGFR mutations occurs mostly in adenocarcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (152, 161))	('amplification', 'MPA', (23, 36))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('EGFR', 'Gene', (0, 4))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (63, 86))	('adenocarcinoma', 'Disease', (95, 109))	('squamous cell carcinoma', 'Disease', (63, 86))	('adenocarcinoma', 'Disease', (147, 161))	('adenocarcinoma', 'Disease', 'MESH:D000230', (95, 109))	('overexpression', 'PosReg', (5, 19))	('EGFR', 'Gene', '1956', (115, 119))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (63, 86))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('EGFR', 'Gene', (115, 119))	('mutations', 'Var', (120, 129))	('adenocarcinoma', 'Disease', 'MESH:D000230', (147, 161))	('EGFR', 'Gene', '1956', (0, 4))
471560	33422052	The significantly different expression of LINC00240 only in squamous cell cancer provides clues to explaining the augmented EGFR expression, drawing on the findings of high expression of EGFR and marginal EGFR mutations in squamous cell cancer.	('mutations', 'Var', (210, 219))	('LINC00240', 'Gene', (42, 51))	('EGFR', 'Gene', '1956', (205, 209))	('augmented', 'PosReg', (114, 123))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('squamous cell cancer', 'Disease', (223, 243))	('expression', 'MPA', (129, 139))	('EGFR', 'Gene', '1956', (124, 128))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (223, 243))	('EGFR', 'Gene', '1956', (187, 191))	('squamous cell cancer', 'Disease', 'MESH:D002294', (223, 243))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('squamous cell cancer', 'Disease', (60, 80))	('EGFR', 'Gene', (205, 209))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (60, 80))	('squamous cell cancer', 'Disease', 'MESH:D002294', (60, 80))	('LINC00240', 'Gene', '100133205', (42, 51))	('EGFR', 'Gene', (124, 128))	('EGFR', 'Gene', (187, 191))
471662	29141854	Mutations in TP53 tumor suppressor gene have been found in approximately 50% of lung adenocarcinoma cases, but the presence of a TP53 mutation does not always associate with increased mortality.	('TP53', 'Gene', (13, 17))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (80, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('tumor', 'Disease', (18, 23))	('lung adenocarcinoma', 'Disease', (80, 99))	('TP53', 'Gene', '7157', (13, 17))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (80, 99))	('found', 'Reg', (50, 55))	('TP53', 'Gene', '7157', (129, 133))	('Mutations', 'Var', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('TP53', 'Gene', (129, 133))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
471663	29141854	The Cancer Genome Atlas (TCGA) RNA-seq data of lung adenocarcinoma were used to define a novel gene signature for P53 deficiency.	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (47, 66))	('P53', 'Gene', '7157', (114, 117))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (47, 66))	('carcinoma', 'Phenotype', 'HP:0030731', (57, 66))	('Cancer', 'Phenotype', 'HP:0002664', (4, 10))	('lung adenocarcinoma', 'Disease', (47, 66))	('Cancer Genome Atlas', 'Disease', (4, 23))	('P53', 'Gene', (114, 117))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (4, 23))	('deficiency', 'Var', (118, 128))
471668	29141854	The P53 deficiency score was a better predictor of recurrence-free survival compared to P53 mutation status and provided additional prognostic values to established clinical factors.	('P53', 'Gene', (88, 91))	('P53', 'Gene', '7157', (88, 91))	('P53', 'Gene', (4, 7))	('recurrence-free survival', 'CPA', (51, 75))	('deficiency', 'Var', (8, 18))	('P53', 'Gene', '7157', (4, 7))
471678	29141854	For example, approximately 30%-60% of lung adenocarcinoma cases are associated with mutations in EGFR, KRAS or ALK genes.	('KRAS', 'Gene', (103, 107))	('associated', 'Reg', (68, 78))	('KRAS', 'Gene', '3845', (103, 107))	('EGFR', 'Gene', '1956', (97, 101))	('ALK', 'Gene', '238', (111, 114))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (38, 57))	('mutations', 'Var', (84, 93))	('EGFR', 'Gene', (97, 101))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (38, 57))	('lung adenocarcinoma', 'Disease', (38, 57))	('ALK', 'Gene', (111, 114))	('carcinoma', 'Phenotype', 'HP:0030731', (48, 57))
471691	29141854	The highest rates of TP53 mutation have been observed in small cell lung cancer (>90%) and squamous cell carcinomas (81%), which are the subtypes that are most consistently associated with long-term smoking.	('TP53', 'Gene', (21, 25))	('small cell lung cancer', 'Disease', (57, 79))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (91, 115))	('lung cancer', 'Phenotype', 'HP:0100526', (68, 79))	('mutation', 'Var', (26, 34))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('small cell lung cancer', 'Disease', 'MESH:D055752', (57, 79))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (91, 114))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (57, 79))	('associated', 'Reg', (173, 183))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (91, 115))	('TP53', 'Gene', '7157', (21, 25))	('carcinomas', 'Phenotype', 'HP:0030731', (105, 115))	('squamous cell carcinomas', 'Disease', (91, 115))
471699	29141854	While most non-synonymous mutations of TP53 result in aberrant P53 activity in a dominant manner, the effects of different mutations vary significantly.	('P53', 'Gene', (40, 43))	('non-synonymous mutations', 'Var', (11, 35))	('result', 'Reg', (44, 50))	('P53', 'Gene', '7157', (40, 43))	('activity', 'MPA', (67, 75))	('TP53', 'Gene', '7157', (39, 43))	('P53', 'Gene', (63, 66))	('P53', 'Gene', '7157', (63, 66))	('TP53', 'Gene', (39, 43))
471701	29141854	In addition, loss of P53 activity can be caused by other mechanisms, including DNA hypermethylation in the promoter of TP53, deletion of TP53, or indirectly, by the dysregulation of P53 regulators.	('P53', 'Gene', '7157', (138, 141))	('dysregulation', 'Reg', (165, 178))	('P53', 'Gene', (120, 123))	('P53', 'Gene', (182, 185))	('P53', 'Gene', (21, 24))	('P53', 'Gene', '7157', (120, 123))	('P53', 'Gene', '7157', (182, 185))	('P53', 'Gene', '7157', (21, 24))	('P53', 'Gene', (138, 141))	('loss', 'NegReg', (13, 17))	('TP53', 'Gene', '7157', (137, 141))	('TP53', 'Gene', (137, 141))	('TP53', 'Gene', '7157', (119, 123))	('TP53', 'Gene', (119, 123))	('deletion', 'Var', (125, 133))	('activity', 'MPA', (25, 33))
471707	29141854	All these datasets are available from the public GEO (Gene Expression Omnibus) database with the following accession IDs: GSE31210, GSE8894, GSE68465, GSE13213, GSE3141, GSE42127.	('GSE42127', 'Var', (170, 178))	('accession IDs', 'Disease', (107, 120))	('GSE31210', 'Var', (122, 130))	('GSE8894', 'Var', (132, 139))	('GSE68465', 'Var', (141, 149))	('GSE3141', 'Chemical', '-', (161, 168))	('accession IDs', 'Disease', 'MESH:C535742', (107, 120))	('GSE3141', 'Var', (161, 168))	('GSE13213', 'Var', (151, 159))	('GSE8894', 'Chemical', '-', (132, 139))
471713	29141854	Samples containing synonymous TP53 mutations were assigned to the wild-type group.	('TP53', 'Gene', '7157', (30, 34))	('TP53', 'Gene', (30, 34))	('mutations', 'Var', (35, 44))
471723	29141854	Patients with high PDSs are more likely to have P53 mutation while patients with low PDSs are likely to have wild-type P53.	('patients', 'Species', '9606', (67, 75))	('PDS', 'Chemical', '-', (19, 22))	('P53', 'Gene', (119, 122))	('PDS', 'Chemical', '-', (85, 88))	('P53', 'Gene', '7157', (119, 122))	('Patients', 'Species', '9606', (0, 8))	('P53', 'Gene', (48, 51))	('mutation', 'Var', (52, 60))	('P53', 'Gene', '7157', (48, 51))
471733	29141854	The P53 gain of function group was determined by containing R248Q, R27H or R175H mutation in protein sequence.	('P53', 'Gene', '7157', (4, 7))	('R27H', 'Mutation', 'p.R27H', (67, 71))	('R248Q', 'Mutation', 'rs11540652', (60, 65))	('P53', 'Gene', (4, 7))	('R175H', 'Mutation', 'rs28934578', (75, 80))	('R175H', 'Var', (75, 80))	('R27H', 'Var', (67, 71))	('gain of function', 'PosReg', (8, 24))	('R248Q', 'Var', (60, 65))
471734	29141854	The P53 loss of function group was determined by having P53 nonsense mutations or frame shift mutations in the transcript sequence.	('nonsense mutations', 'Var', (60, 78))	('P53', 'Gene', '7157', (56, 59))	('P53', 'Gene', '7157', (4, 7))	('P53', 'Gene', (4, 7))	('loss of function', 'NegReg', (8, 24))	('frame shift mutations', 'Var', (82, 103))	('P53', 'Gene', (56, 59))
471736	29141854	None of those four cell lines has P53 mutation.	('P53', 'Gene', (34, 37))	('mutation', 'Var', (38, 46))	('P53', 'Gene', '7157', (34, 37))
471745	29141854	We demonstrated that PDS is prognostic even after adjusting clinical variables including age, stage, P53 mutation status, and smoking status.	('PDS', 'Disease', (21, 24))	('P53', 'Gene', (101, 104))	('P53', 'Gene', '7157', (101, 104))	('mutation status', 'Var', (105, 120))	('PDS', 'Chemical', '-', (21, 24))
471754	29141854	Figure S1, patients with P53 loss of function mutation showed the significantly higher PDSs comparing to the patients with wild-type P53 (p=2e-7).	('loss of function', 'NegReg', (29, 45))	('patients', 'Species', '9606', (109, 117))	('P53', 'Gene', (133, 136))	('P53', 'Gene', (25, 28))	('P53', 'Gene', '7157', (133, 136))	('P53', 'Gene', '7157', (25, 28))	('patients', 'Species', '9606', (11, 19))	('mutation', 'Var', (46, 54))	('higher', 'PosReg', (80, 86))	('PDSs', 'MPA', (87, 91))	('PDS', 'Chemical', '-', (87, 90))
471760	29141854	The mutation status of P53 was not predictive of patient overall survival (OS) as shown in Figure 2C.	('patient', 'Species', '9606', (49, 56))	('P53', 'Gene', '7157', (23, 26))	('mutation', 'Var', (4, 12))	('P53', 'Gene', (23, 26))
471761	29141854	However, when patients were dichotomized into two groups with either high or low PDS, we observed significantly shorter OS of the high-PDS (PDS-Hi) group compared to the low-PDS (PDS-Lo) group (Figure 2D).	('PDS', 'Chemical', '-', (135, 138))	('high-PDS', 'Var', (130, 138))	('PDS-Hi', 'Chemical', '-', (140, 146))	('PDS', 'Chemical', '-', (81, 84))	('PDS', 'Chemical', '-', (174, 177))	('PDS', 'Chemical', '-', (140, 143))	('PDS', 'Chemical', '-', (179, 182))	('patients', 'Species', '9606', (14, 22))	('shorter', 'NegReg', (112, 119))
471762	29141854	This suggested that P53 deficiency was associated with poor prognosis.	('deficiency', 'Var', (24, 34))	('P53', 'Gene', (20, 23))	('P53', 'Gene', '7157', (20, 23))
471763	29141854	We next separated patients into two subsets based on their P53 mutation status and examined the predictive power of PDS in each subset (Figure 2E).	('mutation', 'Var', (63, 71))	('P53', 'Gene', (59, 62))	('PDS', 'Chemical', '-', (116, 119))	('patients', 'Species', '9606', (18, 26))	('P53', 'Gene', '7157', (59, 62))
471765	29141854	For wild-type patients, the PDS-Hi group had overall mortality rates 2.67-fold higher than the PDS-Lo group.	('PDS', 'Chemical', '-', (95, 98))	('PDS-Hi', 'Chemical', '-', (28, 34))	('PDS-Hi', 'Var', (28, 34))	('higher', 'PosReg', (79, 85))	('patients', 'Species', '9606', (14, 22))	('PDS', 'Chemical', '-', (28, 31))
471770	29141854	As shown in Figure 3, results in the four datasets consistently showed that high-PDS is associated with significantly shorter RFS in lung adenocarcinoma.	('PDS', 'Chemical', '-', (81, 84))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (133, 152))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (133, 152))	('shorter', 'NegReg', (118, 125))	('lung adenocarcinoma', 'Disease', (133, 152))	('high-PDS', 'Var', (76, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (143, 152))	('RFS', 'MPA', (126, 129))
471771	29141854	Although we showed that there was an association between PDS and P53 mutation status in the TCGA LUAD data, the underlying P53-deficiency gene signature was defined based on LUAD data and the prognostic analysis was based on OS instead of RFS.	('mutation status', 'Var', (69, 84))	('LUAD', 'Phenotype', 'HP:0030078', (174, 178))	('P53-deficiency', 'Disease', (123, 137))	('P53', 'Gene', (123, 126))	('LUAD', 'Phenotype', 'HP:0030078', (97, 101))	('PDS', 'Chemical', '-', (57, 60))	('P53', 'Gene', '7157', (123, 126))	('P53', 'Gene', (65, 68))	('P53-deficiency', 'Disease', 'MESH:D007153', (123, 137))	('P53', 'Gene', '7157', (65, 68))	('PDS', 'Disease', (57, 60))
471772	29141854	Thus, we further validated the association between PDS and P53 mutation status in the GSE13213 dataset.	('mutation status', 'Var', (63, 78))	('PDS', 'Disease', (51, 54))	('P53', 'Gene', (59, 62))	('P53', 'Gene', '7157', (59, 62))	('PDS', 'Chemical', '-', (51, 54))
471775	29141854	Neither TP53 expression level (Figure 4C) or P53 mutation status (Figure 4D) was predictive of RFS in this dataset, however, consistent with Figure 2E, PDS was significantly associated with RFS in P53 wild-type but not in P53-mutant patients (Figure 4E).	('P53', 'Gene', (9, 12))	('PDS', 'Chemical', '-', (152, 155))	('associated', 'Reg', (174, 184))	('P53', 'Gene', '7157', (9, 12))	('RFS', 'Var', (190, 193))	('P53', 'Gene', '7157', (197, 200))	('P53', 'Gene', (222, 225))	('P53', 'Gene', '7157', (45, 48))	('PDS', 'Disease', (152, 155))	('P53', 'Gene', '7157', (222, 225))	('P53', 'Gene', (45, 48))	('TP53', 'Gene', '7157', (8, 12))	('TP53', 'Gene', (8, 12))	('patients', 'Species', '9606', (233, 241))	('P53', 'Gene', (197, 200))
471800	29141854	Moreover, TP53 mutations, the most common mutations in human cancers, have been researched as a predictive biomarker for prognosis in lung cancer patients in recent years.	('lung cancer', 'Disease', (134, 145))	('lung cancer', 'Phenotype', 'HP:0100526', (134, 145))	('TP53', 'Gene', (10, 14))	('mutations', 'Var', (15, 24))	('human', 'Species', '9606', (55, 60))	('cancers', 'Disease', 'MESH:D009369', (61, 68))	('cancers', 'Phenotype', 'HP:0002664', (61, 68))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('cancers', 'Disease', (61, 68))	('lung cancer', 'Disease', 'MESH:D008175', (134, 145))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('patients', 'Species', '9606', (146, 154))	('TP53', 'Gene', '7157', (10, 14))
471804	29141854	Our results indicated that PDS was associated with P53 mutation status and smoking status, and was predictive of patient RFS with high consistency in multiple lung adenocarcinoma datasets.	('patient', 'Species', '9606', (113, 120))	('mutation status', 'Var', (55, 70))	('PDS', 'Disease', (27, 30))	('carcinoma', 'Phenotype', 'HP:0030731', (169, 178))	('associated', 'Reg', (35, 45))	('P53', 'Gene', (51, 54))	('PDS', 'Chemical', '-', (27, 30))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (159, 178))	('P53', 'Gene', '7157', (51, 54))	('multiple lung adenocarcinoma', 'Disease', 'MESH:D000077192', (150, 178))	('multiple lung adenocarcinoma', 'Disease', (150, 178))
471809	29141854	More than 75% of TP53 mutations result in an abnormal P53 protein that deactivates the P53 pathway via a dominant-negative regulation of wild-type P53; however, the severity of distinct P53 mutations varies substantially.	('P53', 'Gene', (54, 57))	('result', 'Reg', (32, 38))	('P53', 'Gene', '7157', (186, 189))	('P53', 'Gene', (147, 150))	('P53', 'Gene', '7157', (54, 57))	('P53', 'Gene', '7157', (87, 90))	('P53', 'Gene', (18, 21))	('mutations', 'Var', (22, 31))	('P53', 'Gene', '7157', (147, 150))	('P53', 'Gene', '7157', (18, 21))	('P53', 'Gene', (87, 90))	('TP53', 'Gene', '7157', (17, 21))	('P53', 'Gene', (186, 189))	('TP53', 'Gene', (17, 21))	('deactivates', 'NegReg', (71, 82))
471810	29141854	Moreover, the P53 pathway can also be deactivated by other biological mechanisms, including epigenetic regulation and deletion of TP53 genes, or through alterations of other genes in this pathway.	('P53', 'Gene', '7157', (14, 17))	('P53', 'Gene', '7157', (131, 134))	('alterations', 'Reg', (153, 164))	('epigenetic regulation', 'Var', (92, 113))	('P53', 'Gene', (14, 17))	('deletion', 'Var', (118, 126))	('TP53', 'Gene', '7157', (130, 134))	('TP53', 'Gene', (130, 134))	('deactivated', 'NegReg', (38, 49))	('P53', 'Gene', (131, 134))
471818	29141854	In breast cancer, a 32-gene signature has been proposed by Miller et al to predict P53 mutation status and patient prognosis.	('mutation status', 'Var', (87, 102))	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('breast cancer', 'Disease', (3, 16))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('P53', 'Gene', (83, 86))	('patient', 'Species', '9606', (107, 114))	('P53', 'Gene', '7157', (83, 86))
471829	27737879	Cxcl5 expression was associated with mutant Kras expression and regulated by NF-kappaB activation.	('mutant', 'Var', (37, 43))	('Kras', 'Gene', (44, 48))	('Kras', 'Gene', '16653', (44, 48))	('Cxcl5 expression', 'MPA', (0, 16))
471830	27737879	Host CXCR2 inhibition by genetic ablation prevented neutrophil accumulation in pancreatic tumors and led to a T cell-dependent suppression of tumor growth.	('pancreatic tumors', 'Disease', 'MESH:D010190', (79, 96))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('pancreatic tumors', 'Disease', (79, 96))	('neutrophil accumulation', 'MPA', (52, 75))	('tumor', 'Disease', (142, 147))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('prevented', 'NegReg', (42, 51))	('pancreatic tumors', 'Phenotype', 'HP:0002894', (79, 96))	('genetic ablation', 'Var', (25, 41))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('Host CXCR2 inhibition', 'MPA', (0, 21))	('pancreatic tumor', 'Phenotype', 'HP:0002894', (79, 95))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('suppression', 'NegReg', (127, 138))
471842	27737879	Although immune checkpoint blockade with anti-PD-1/PD-L1 or anti-CTLA-4 is ineffective in stimulating antitumor immunity, depleting or "re-educating" immunosuppressive myeloid populations has proven to be more effective at eliciting antitumor T-cell responses in models of PDA.	('depleting', 'Var', (122, 131))	('tumor', 'Disease', (237, 242))	('eliciting', 'Reg', (223, 232))	('CTLA-4', 'Gene', (65, 71))	('PDA', 'Disease', (273, 276))	('CTLA-4', 'Gene', '12477', (65, 71))	('PD-L1', 'Gene', '60533', (51, 56))	('PDA', 'Chemical', '-', (273, 276))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('PD-1', 'Gene', '18566', (46, 50))	('tumor', 'Disease', 'MESH:D009369', (237, 242))	('PD-1', 'Gene', (46, 50))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('PDA', 'Phenotype', 'HP:0006725', (273, 276))	('tumor', 'Disease', (106, 111))	('PD-L1', 'Gene', (51, 56))
471849	27737879	High intratumoral CXCL5, a chemokine for neutrophils, have also been associated with poorer overall survival.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('poorer', 'NegReg', (85, 91))	('rat', 'Species', '10116', (8, 11))	('High', 'Var', (0, 4))	('tumor', 'Disease', (10, 15))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('overall', 'MPA', (92, 99))
471894	27737879	For T-cell depletion studies, 200 microg of anti-CD4 (BioXCell, GK1.5l) and 200 microg of anti-CD8 (BioXCell, YTS 169.4), or 400 microg of isotype control (BioXCell, LTF-2) were administered intraperitoneally every 3 days for the duration of the study, starting 4 days prior to tumor implantation, an approach validated as previously published.	('tumor', 'Phenotype', 'HP:0002664', (278, 283))	('GK1', 'Gene', '16623', (64, 67))	('CD4', 'Gene', (49, 52))	('rat', 'Species', '10116', (232, 235))	('tumor', 'Disease', (278, 283))	('CD4', 'Gene', '12504', (49, 52))	('anti-CD8', 'Var', (90, 98))	('GK1', 'Gene', (64, 67))	('tumor', 'Disease', 'MESH:D009369', (278, 283))
471927	27737879	Of the 16 other immune populations tested, the macrophage and gammadelta T-cell gene sets were also significantly enriched in TAN-high compared to TAN-medium and TAN-low tumors (Fig.	('gammadelta T-cell gene sets', 'Gene', (62, 89))	('TAN-low tumors', 'Disease', (162, 176))	('TAN-high', 'Var', (126, 134))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('TAN-low tumors', 'Disease', 'MESH:D009800', (162, 176))	('tumors', 'Phenotype', 'HP:0002664', (170, 176))	('macrophage', 'Gene', (47, 57))
471978	27737879	To explore the effects of mutant Kras and mutant Trp53 in regulating CXCR2 ligand expression, we compared the expression of all CXCR2 ligands in YFP+ pancreatic-lineage or YFP- stromal cells in 4-6 months old CY, PCY, and KCY mice (Fig.	('mutant', 'Var', (42, 48))	('Kras', 'Gene', (33, 37))	('Kras', 'Gene', '16653', (33, 37))	('mice', 'Species', '10090', (226, 230))	('Trp53', 'Gene', '22059', (49, 54))	('Trp53', 'Gene', (49, 54))	('pancreatic', 'Disease', 'MESH:D010195', (150, 160))	('pancreatic', 'Disease', (150, 160))	('mutant', 'Var', (26, 32))
471979	27737879	Increased expression of Cxcl5 in YFP+ tumor cells and Cxcl2 in YFP- stromal cells were associated with mutant Kras and not mutant Trp53 expression.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('Trp53', 'Gene', '22059', (130, 135))	('mutant', 'Var', (103, 109))	('expression', 'MPA', (10, 20))	('Cxcl2', 'Gene', '20310', (54, 59))	('Cxcl2', 'Gene', (54, 59))	('Increased', 'PosReg', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('Kras', 'Gene', (110, 114))	('Kras', 'Gene', '16653', (110, 114))	('Trp53', 'Gene', (130, 135))
471983	27737879	Inhibition of MEK resulted in a significant increase in Cxcl5 expression compared to control (Fig.	('MEK', 'Gene', '17242', (14, 17))	('MEK', 'Gene', (14, 17))	('increase', 'PosReg', (44, 52))	('Cxcl5 expression', 'MPA', (56, 72))	('Inhibition', 'Var', (0, 10))
471990	27737879	Unlike the observations in prostate cancer, knock down of Yap1 did not significantly alter Cxcl5 expression in PDA cells in our model.	('prostate cancer', 'Disease', 'MESH:D011471', (27, 42))	('Yap1', 'Gene', '22601', (58, 62))	('PDA', 'Chemical', '-', (111, 114))	('prostate cancer', 'Phenotype', 'HP:0012125', (27, 42))	('alter', 'Reg', (85, 90))	('knock down', 'Var', (44, 54))	('PDA', 'Phenotype', 'HP:0006725', (111, 114))	('Yap1', 'Gene', (58, 62))	('prostate cancer', 'Disease', (27, 42))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('Cxcl5 expression', 'MPA', (91, 107))
471996	27737879	These results showed that NF-kappaB activity can potently induce CXCL5 secretion in PDA cells, but does not seem to affect baseline levels.	('CXCL5 secretion', 'MPA', (65, 80))	('induce', 'Reg', (58, 64))	('PDA', 'Chemical', '-', (84, 87))	('NF-kappaB', 'Protein', (26, 35))	('activity', 'Var', (36, 44))	('PDA', 'Phenotype', 'HP:0006725', (84, 87))
471997	27737879	We then tested the hypothesis that NF-kappaB signaling in the setting of KRAS/MEK inhibition is responsible for the increased CXCL5 level.	('CXCL5 level', 'MPA', (126, 137))	('tested', 'Reg', (8, 14))	('MEK', 'Gene', (78, 81))	('KRAS', 'Gene', (73, 77))	('inhibition', 'Var', (82, 92))	('MEK', 'Gene', '17242', (78, 81))	('increased', 'PosReg', (116, 125))	('NF-kappaB signaling', 'MPA', (35, 54))	('KRAS', 'Gene', '16653', (73, 77))
471998	27737879	Indeed, NF-kappaB inhibition completely abrogated the increase in CXCL5 in the presence of MEK inhibition (Fig.	('CXCL5', 'MPA', (66, 71))	('increase', 'PosReg', (54, 62))	('NF-kappaB', 'Protein', (8, 17))	('MEK', 'Gene', '17242', (91, 94))	('abrogated', 'NegReg', (40, 49))	('inhibition', 'Var', (18, 28))	('MEK', 'Gene', (91, 94))
472008	27737879	Using flow cytometry to compare tumor-infiltrating immune populations on days 10, 14, and 21 after implantation, we noted a striking reduction in the density of tumor-infiltrating CD11b+Ly6G+ neutrophils in Cxcr2-/- compared to Cxcr2+/+ hosts, with no difference in the density of F4/80+ macrophages and CD11b+Ly6C+ monocytes (Figs.	('Ly6G', 'Gene', (186, 190))	('rat', 'Species', '10116', (173, 176))	('Ly6C', 'Gene', (310, 314))	('reduction', 'NegReg', (133, 142))	('Ly6C', 'Gene', '17067', (310, 314))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('rat', 'Species', '10116', (44, 47))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('Ly6G', 'Gene', '546644', (186, 190))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('F4/80', 'Gene', (281, 286))	('tumor', 'Disease', (32, 37))	('Cxcr2-/-', 'Var', (207, 215))	('tumor', 'Disease', (161, 166))	('F4/80', 'Gene', '13733', (281, 286))
472011	27737879	5F) Importantly, the density of tumor infiltrating CD3+ T cells was significantly elevated in Cxcr2-/- compared to Cxcr2+/+ hosts 21 days post-implantation.	('CD3', 'Gene', (51, 54))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('rat', 'Species', '10116', (44, 47))	('elevated', 'PosReg', (82, 90))	('density', 'CPA', (21, 28))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('CD3', 'Gene', '12501', (51, 54))	('tumor', 'Disease', (32, 37))	('Cxcr2-/-', 'Var', (94, 102))
472016	27737879	In contrast, we found a significant increase in the infiltration of CD3+ T cells in Cxcr2-/- compared to Cxcr2+/+ hosts (Fig.	('Cxcr2-/-', 'Var', (84, 92))	('CD3', 'Gene', (68, 71))	('increase', 'PosReg', (36, 44))	('CD3', 'Gene', '12501', (68, 71))	('rat', 'Species', '10116', (58, 61))	('infiltration', 'CPA', (52, 64))
472017	27737879	Correspondingly, there was also a significant increase in the density of tumor-infiltrating CD4+ T cells in Cxcr2-/- compared to Cxcr2+/+ hosts (Fig.	('CD4', 'Gene', '12504', (92, 95))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('increase', 'PosReg', (46, 54))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('rat', 'Species', '10116', (85, 88))	('density', 'CPA', (62, 69))	('Cxcr2-/-', 'Var', (108, 116))	('tumor', 'Disease', (73, 78))	('CD4', 'Gene', (92, 95))
472025	27737879	We further hypothesized that tumor-infiltrating effector T cells are more functional in Cxcr2-/- than in Cxcr2+/+ hosts.	('Cxcr2-/-', 'Var', (88, 96))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumor', 'Disease', (29, 34))	('rat', 'Species', '10116', (41, 44))	('more', 'PosReg', (69, 73))
472026	27737879	Indeed, ex vivo PMA/ionomycin stimulation induced higher proportions of IFNgamma-expressing cells in both CD4+ and CD8+ T-cell populations in Cxcr2-/- compared to Cxcr2+/+ hosts (Fig.	('CD4', 'Gene', (106, 109))	('higher', 'PosReg', (50, 56))	('CD4', 'Gene', '12504', (106, 109))	('Cxcr2-/-', 'Var', (142, 150))	('ionomycin', 'Chemical', 'MESH:D015759', (20, 29))	('IFNgamma', 'Gene', (72, 80))	('IFNgamma', 'Gene', '15978', (72, 80))
472038	27737879	We report: (1) neutrophils are an important aspect of the human PDA TME particularly in the squamous subtype; (2) human PDA has particularly high CXCL5 expression and other CXCR2 ligands compared to other cancer types, as confirmed in our murine model; (3) CXCL5 expression is correlated to NF-kB signaling pathways in human PDA and, in our mouse model, CXCL5 is strongly induced by NF-kB activation; (4) abrogation of CXCR2 signaling slows tumor growth in mice and triggers an influx of activated and functional CD4+ T cells into the TME; and (5) depletion of T cells completely reverses the antitumor effects of CXCR2 inhibition.	('PDA', 'Phenotype', 'HP:0006725', (64, 67))	('cancer', 'Disease', 'MESH:D009369', (205, 211))	('PDA', 'Phenotype', 'HP:0006725', (120, 123))	('human', 'Species', '9606', (58, 63))	('triggers', 'Reg', (466, 474))	('murine', 'Species', '10090', (239, 245))	('mouse', 'Species', '10090', (341, 346))	('human', 'Species', '9606', (114, 119))	('tumor', 'Disease', (441, 446))	('human', 'Species', '9606', (319, 324))	('CD4', 'Gene', (513, 516))	('tumor', 'Disease', 'MESH:D009369', (441, 446))	('mice', 'Species', '10090', (457, 461))	('TME', 'Gene', '110080', (535, 538))	('TME', 'Gene', (535, 538))	('tumor', 'Disease', (597, 602))	('depletion', 'Var', (548, 557))	('cancer', 'Disease', (205, 211))	('TME', 'Gene', '110080', (68, 71))	('TME', 'Gene', (68, 71))	('CD4', 'Gene', '12504', (513, 516))	('tumor', 'Phenotype', 'HP:0002664', (441, 446))	('abrogation', 'Var', (405, 415))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('tumor', 'Disease', 'MESH:D009369', (597, 602))	('slows', 'NegReg', (435, 440))	('PDA', 'Chemical', '-', (325, 328))	('influx', 'MPA', (478, 484))	('PDA', 'Chemical', '-', (120, 123))	('PDA', 'Chemical', '-', (64, 67))	('PDA', 'Phenotype', 'HP:0006725', (325, 328))	('tumor', 'Phenotype', 'HP:0002664', (597, 602))
472050	27737879	showed that CXCL1 is elevated in a RIP1/3-dependent manner and that anti-CXCL1 treatment reduces the infiltration of GR1+CD11b+ cells, which consist of a heterogeneous population including TANs and monocytes.	('infiltration', 'CPA', (101, 113))	('RIP1', 'Gene', (35, 39))	('RIP1', 'Gene', '8737', (35, 39))	('TANs', 'Chemical', '-', (189, 193))	('anti-CXCL1', 'Var', (68, 78))	('CXCL1', 'MPA', (12, 17))	('reduces', 'NegReg', (89, 96))	('rat', 'Species', '10116', (107, 110))
472052	27737879	In addition, our data revealed that CXCR2 ablation specifically inhibited the accumulation of neutrophils, without affecting infiltration of other myeloid populations.	('rat', 'Species', '10116', (131, 134))	('CXCR2 ablation', 'Var', (36, 50))	('inhibited', 'NegReg', (64, 73))	('accumulation of neutrophils', 'MPA', (78, 105))
472076	27737879	using pancreas-targeted knockout of IKKbeta in Pdx1-Cre;LSL-KrasG12D;Ink4a/ArfF/F mice showed that inactivation of NF-kappaB signaling completely inhibited PDA development.	('mice', 'Species', '10090', (82, 86))	('PDA', 'Chemical', '-', (156, 159))	('PDA development', 'CPA', (156, 171))	('inhibited', 'NegReg', (146, 155))	('Pdx1-Cre', 'Gene', '18609', (47, 55))	('PDA', 'Phenotype', 'HP:0006725', (156, 159))	('IKKbeta', 'Gene', (36, 43))	('inactivation', 'Var', (99, 111))	('Pdx1-Cre', 'Gene', (47, 55))
472079	27737879	Although the mechanism of this increased activity remains to be determined, we speculate that it may have resulted from enhanced PI3K/AKT signaling, which is upstream of NF-kappaB activation, upon MEK inhibition.	('AKT', 'Gene', (134, 137))	('enhanced', 'PosReg', (120, 128))	('MEK', 'Gene', '17242', (197, 200))	('AKT', 'Gene', '11651', (134, 137))	('MEK', 'Gene', (197, 200))	('inhibition', 'Var', (201, 211))	('activity', 'MPA', (41, 49))
472098	27737879	However, in our model with syngeneic immunocompetent mice, depletion of CD4+ and CD8+ T cells was sufficient to rescue tumor growth in Cxcr2-/- hosts.	('tumor', 'Disease', (119, 124))	('CD4', 'Gene', (72, 75))	('depletion', 'Var', (59, 68))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('CD4', 'Gene', '12504', (72, 75))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('mice', 'Species', '10090', (53, 57))
472118	27457382	The presence of Foxp3 expression in cancer cells has been proved to be associated with tumor biological behaviors regulation.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('cancer', 'Disease', (36, 42))	('tumor', 'Disease', (87, 92))	('Foxp3', 'Gene', '50943', (16, 21))	('Foxp3', 'Gene', (16, 21))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('presence', 'Var', (4, 12))	('associated', 'Reg', (71, 81))
472119	27457382	A series of studies have illustrated that the mutation or loss of Foxp3 might lead to a high rate of tumor formation, such as developing in mammary or prostatic epithelial tissues, which indicated Foxp3 as an oncosuppressive factor.	('loss', 'NegReg', (58, 62))	('Foxp3', 'Gene', '50943', (66, 71))	('Foxp3', 'Gene', (66, 71))	('lead to', 'Reg', (78, 85))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('Foxp3', 'Gene', '50943', (197, 202))	('mutation', 'Var', (46, 54))	('Foxp3', 'Gene', (197, 202))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
472121	27457382	In contrast, only two retrospective studies in patients with tongue squamous cell carcinoma (TSCC) and orohypopharynx squamous cell carcinoma (OHSCC) have demonstrated accordant results that high Foxp3 expression was associated with poor overall survival.	('orohypopharynx squamous cell carcinoma', 'Disease', (103, 141))	('Foxp3', 'Gene', '50943', (196, 201))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('Foxp3', 'Gene', (196, 201))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (118, 141))	('TSCC', 'Phenotype', 'HP:0030413', (93, 97))	('patients', 'Species', '9606', (47, 55))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('tongue squamous cell carcinoma', 'Phenotype', 'HP:0030413', (61, 91))	('orohypopharynx squamous cell carcinoma', 'Phenotype', 'HP:0012182', (103, 141))	('overall', 'MPA', (238, 245))	('OHSCC', 'Phenotype', 'HP:0012182', (143, 148))	('tongue squamous cell carcinoma', 'Disease', 'MESH:D002294', (61, 91))	('tongue squamous cell carcinoma', 'Disease', (61, 91))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (68, 91))	('high', 'Var', (191, 195))	('orohypopharynx squamous cell carcinoma', 'Disease', 'MESH:D002294', (103, 141))
472153	27457382	Multivariate analyses were used to reveal that T stage, N stage, Clinical stage and Foxp3 expression were the independent risk factors for OS, and Foxp3 expression were the most important risk factor for relapse (Tables 2 and 3; Fig.	('Foxp3', 'Gene', '50943', (147, 152))	('Foxp3', 'Gene', (147, 152))	('Foxp3', 'Gene', '50943', (84, 89))	('Foxp3', 'Gene', (84, 89))	('expression', 'Var', (90, 100))
472154	27457382	The results showed that the median overall survival time in patients with high levels of Foxp3 expression (stain value = 3) (14, 2-56 months, n = 68) was significantly shorter than that in patients with a low level of Foxp3 expression (stain value = 1) (43, 4-93 months, n = 99) (P = 0.000) and medium level of Foxp3 expression (stain value = 2) (38, 2-81 months, n = 106) (P = 0.000).	('Foxp3', 'Gene', '50943', (311, 316))	('overall survival time', 'CPA', (35, 56))	('shorter', 'NegReg', (168, 175))	('high levels', 'Var', (74, 85))	('patients', 'Species', '9606', (60, 68))	('Foxp3', 'Gene', '50943', (218, 223))	('patients', 'Species', '9606', (189, 197))	('Foxp3', 'Gene', (218, 223))	('Foxp3', 'Gene', '50943', (89, 94))	('Foxp3', 'Gene', (311, 316))	('Foxp3', 'Gene', (89, 94))
472157	27457382	The hazard ratio of 5 years OS for low and medium Foxp3 expression group are 0.197 (P = 0.000) and 0.271 (P = 0.000), respectively, while that of relapse-free survival (RFS) for low and medium Foxp3 expression group are 0.451 (P = 0.014) and 0.371 (P = 0.003) taking high Foxp3 expression group as reference (Table 3).	('Foxp3', 'Gene', (272, 277))	('Foxp3', 'Gene', '50943', (193, 198))	('Foxp3', 'Gene', '50943', (50, 55))	('low', 'Var', (35, 38))	('Foxp3', 'Gene', (193, 198))	('medium', 'Var', (43, 49))	('Foxp3', 'Gene', (50, 55))	('Foxp3', 'Gene', '50943', (272, 277))
472161	27457382	While the potential role of tumor Foxp3 as prognostic biomarker of overall survival has been previously investigated, only two studies addressed this issue and draw accordant conclusion that high Foxp3 expression was associated with poor overall survival in patients with TSCC and OHSCC respectively.	('tumor', 'Disease', (28, 33))	('Foxp3', 'Gene', '50943', (196, 201))	('overall survival', 'MPA', (238, 254))	('Foxp3', 'Gene', (34, 39))	('Foxp3', 'Gene', (196, 201))	('TSCC', 'Disease', (272, 276))	('TSCC', 'Phenotype', 'HP:0030413', (272, 276))	('OHSCC', 'Phenotype', 'HP:0012182', (281, 286))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('expression', 'MPA', (202, 212))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('poor', 'NegReg', (233, 237))	('patients', 'Species', '9606', (258, 266))	('high', 'Var', (191, 195))	('Foxp3', 'Gene', '50943', (34, 39))	('OHSCC', 'Disease', (281, 286))
472196	24669077	Somatic mutations within the tyrosine kinase catalytic domain of EGFR lead to conformational changes that promote permanent active status and are found in approximately 20% of lung adenocarcinomas.	('lung adenocarcinomas', 'Disease', (176, 196))	('EGFR', 'Gene', '1956', (65, 69))	('EGFR', 'Gene', (65, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (186, 195))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (176, 196))	('carcinomas', 'Phenotype', 'HP:0030731', (186, 196))	('promote', 'PosReg', (106, 113))	('mutations', 'Var', (8, 17))	('found', 'Reg', (146, 151))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (176, 196))	('permanent active status', 'MPA', (114, 137))	('lead to', 'Reg', (70, 77))	('conformational changes', 'MPA', (78, 100))
472229	24669077	Presence of EGFR mutations in adenocarcinoma is a predictor of responsiveness to EGFR tyrosine kinase inhibitors.	('carcinoma', 'Phenotype', 'HP:0030731', (35, 44))	('adenocarcinoma', 'Disease', (30, 44))	('adenocarcinoma', 'Disease', 'MESH:D000230', (30, 44))	('EGFR', 'Gene', '1956', (12, 16))	('EGFR', 'Gene', (12, 16))	('mutations', 'Var', (17, 26))	('EGFR', 'Gene', '1956', (81, 85))	('EGFR', 'Gene', (81, 85))
472257	24669077	evaluated the EGFR mutations in 350 cases of 2105 patients (16.6%).	('patients', 'Species', '9606', (50, 58))	('EGFR', 'Gene', '1956', (14, 18))	('EGFR', 'Gene', (14, 18))	('mutations', 'Var', (19, 28))
472258	24669077	Mutations were frequently found in women (69.7%), in those who never smoked (66.6%) and in those with adenocarcinomas (80.9%).	('women', 'Species', '9606', (35, 40))	('adenocarcinomas', 'Disease', 'MESH:D000230', (102, 117))	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('carcinomas', 'Phenotype', 'HP:0030731', (107, 117))	('adenocarcinomas', 'Disease', (102, 117))	('found', 'Reg', (26, 31))	('Mutations', 'Var', (0, 9))
472259	24669077	The presence of KRAS, HER2, BRAF, PI3K, LKB1 and SHP2 mutations is associated with a lack of response to EGFR-TKIs in the treatment of lung cancer.	('lack', 'NegReg', (85, 89))	('SHP2', 'Gene', '5781', (49, 53))	('HER2', 'Gene', (22, 26))	('EGFR', 'Gene', (105, 109))	('lung cancer', 'Disease', (135, 146))	('LKB1', 'Gene', '6794', (40, 44))	('PI3K', 'Var', (34, 38))	('SHP2', 'Gene', (49, 53))	('mutations', 'Var', (54, 63))	('men', 'Species', '9606', (127, 130))	('EGFR', 'Gene', '1956', (105, 109))	('lung cancer', 'Disease', 'MESH:D008175', (135, 146))	('HER2', 'Gene', '2064', (22, 26))	('KRAS', 'Gene', '3845', (16, 20))	('BRAF', 'Gene', (28, 32))	('BRAF', 'Gene', '673', (28, 32))	('LKB1', 'Gene', (40, 44))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('lung cancer', 'Phenotype', 'HP:0100526', (135, 146))	('KRAS', 'Gene', (16, 20))
472260	24669077	Therefore, additional mutational analysis of genes other than EGFR may be necessary to improve patient selection for EGFR-targeted therapies, and EGFR amplification and/or overexpression are also predictors of response to TKI treatment.	('EGFR', 'Gene', '1956', (62, 66))	('EGFR', 'Gene', '1956', (146, 150))	('patient', 'Species', '9606', (95, 102))	('EGFR', 'Gene', '1956', (117, 121))	('EGFR', 'Gene', (117, 121))	('EGFR', 'Gene', (62, 66))	('EGFR', 'Gene', (146, 150))	('men', 'Species', '9606', (231, 234))	('overexpression', 'PosReg', (172, 186))	('amplification', 'Var', (151, 164))
472262	24669077	The EGFR mutation status is best determined by fluorescence in situ hybridization (FISH) or chromogenic in situ hybridization (CISH) and protein expression determined by IHC with mutation-specific antibodies.	('EGFR', 'Gene', (4, 8))	('mutation', 'Var', (9, 17))	('EGFR', 'Gene', '1956', (4, 8))
472271	24669077	EGFR mutation is a predictive biomarker for EGFR-TKI therapy.	('EGFR', 'Gene', (0, 4))	('EGFR', 'Gene', '1956', (44, 48))	('EGFR', 'Gene', (44, 48))	('EGFR', 'Gene', '1956', (0, 4))	('mutation', 'Var', (5, 13))
472272	24669077	In our study, 89% of the adenocarcinomas showed EGFR positivity and 11% were EGFR negative.	('EGFR', 'Gene', '1956', (48, 52))	('adenocarcinomas', 'Disease', 'MESH:D000230', (25, 40))	('adenocarcinomas', 'Disease', (25, 40))	('EGFR', 'Gene', (48, 52))	('EGFR', 'Gene', '1956', (77, 81))	('positivity', 'Var', (53, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (30, 39))	('carcinomas', 'Phenotype', 'HP:0030731', (30, 40))	('EGFR', 'Gene', (77, 81))
472273	24669077	Although the status of EGFR has been assessed by IHC, CISH and FISH, mutational analysis has been shown to be the best predictor of tumor response to EGFR-TKI, which will be assessed in future studies.	('EGFR', 'Gene', (150, 154))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('EGFR', 'Gene', '1956', (23, 27))	('tumor', 'Disease', (132, 137))	('mutational analysis', 'Var', (69, 88))	('EGFR', 'Gene', (23, 27))	('EGFR', 'Gene', '1956', (150, 154))
472275	32007910	The NQO1 bioactivatable agent beta-lapachone can target cells with high NQO1 expression but relies in the generation of reactive oxygen species (ROS), which are actively scavenged in cells with NRF2/KEAP1 mutations.	('expression', 'MPA', (77, 87))	('oxygen', 'Chemical', 'MESH:D010100', (129, 135))	('mutations', 'Var', (205, 214))	('beta-lapachone', 'Chemical', 'MESH:C014638', (30, 44))	('NRF2/KEAP1', 'Gene', (194, 204))	('NQO1', 'Gene', (72, 76))
472276	32007910	However, whether NRF2/KEAP1 mutations influence the response to beta-lapachone treatment remains unknown.	('influence', 'Reg', (38, 47))	('NRF2/KEAP1', 'Gene', (17, 27))	('beta-lapachone', 'Chemical', 'MESH:C014638', (64, 78))	('response to beta-lapachone treatment', 'MPA', (52, 88))	('mutations', 'Var', (28, 37))
472277	32007910	To address this question, we assessed the cytotoxicity of beta-lapachone in a panel of NSCLC cell lines bearing either wild-type or mutant KEAP1.	('cytotoxicity', 'Disease', 'MESH:D064420', (42, 54))	('NSCLC', 'Disease', (87, 92))	('NSCLC', 'Disease', 'MESH:D002289', (87, 92))	('mutant', 'Var', (132, 138))	('cytotoxicity', 'Disease', (42, 54))	('beta-lapachone', 'Chemical', 'MESH:C014638', (58, 72))	('NSCLC', 'Phenotype', 'HP:0030358', (87, 92))
472278	32007910	We found that, despite overexpression of NQO1, KEAP1 mutant cells were resistant to beta-lapachone due to enhanced detoxification of ROS, which prevented DNA damage and cell death.	('KEAP1', 'Gene', (47, 52))	('detoxification of ROS', 'MPA', (115, 136))	('beta-lapachone', 'Chemical', 'MESH:C014638', (84, 98))	('enhanced', 'PosReg', (106, 114))	('DNA damage', 'MPA', (154, 164))	('mutant', 'Var', (53, 59))	('resistant', 'MPA', (71, 80))
472281	32007910	Interestingly, inhibition of SOD1 selectively sensitized KEAP1 mutant cells to beta-lapachone exposure.	('KEAP1', 'Gene', (57, 62))	('mutant', 'Var', (63, 69))	('SOD1', 'Gene', (29, 33))	('beta-lapachone', 'Chemical', 'MESH:C014638', (79, 93))	('sensitized', 'Reg', (46, 56))	('inhibition', 'Var', (15, 25))
472282	32007910	Our results suggest that NRF2/KEAP1 mutational status might serve as a predictive biomarker for response to NQO1-bioactivatable quinones in patients.	('quinones', 'Chemical', 'MESH:D011809', (128, 136))	('mutational', 'Var', (36, 46))	('NRF2/KEAP1', 'Gene', (25, 35))
472283	32007910	Aberrant activation of NRF2 in non-small cell lung cancer promotes resistance to beta-lapachone via the antioxidant defense.	('non-small cell lung cancer', 'Disease', (31, 57))	('activation', 'PosReg', (9, 19))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (35, 57))	('Aberrant', 'Var', (0, 8))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (31, 57))	('promotes', 'PosReg', (58, 66))	('beta-lapachone', 'Chemical', 'MESH:C014638', (81, 95))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('resistance to beta-lapachone', 'MPA', (67, 95))	('antioxidant defense', 'MPA', (104, 123))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (31, 57))	('NRF2', 'Gene', (23, 27))	('lung cancer', 'Phenotype', 'HP:0100526', (46, 57))
472285	32007910	Mutations in the NRF2/KEAP1 pathway might serve as predictive biomarker for response to beta-lapachone in patients.	('Mutations', 'Var', (0, 9))	('beta-lapachone', 'Chemical', 'MESH:C014638', (88, 102))	('NRF2/KEAP1', 'Gene', (17, 27))
472286	32007910	It is estimated that 38% of lung squamous cell carcinomas (LuSC) and 18% of lung adenocarcinomas (LuAD) harbor mutations in Nuclear factor erythroid 2-related factor 2 (NRF2), or its negative regulator Kelch-like ECH-associated protein 1 (KEAP1), making this pathway one of the most commonly mutated in non-small cell lung cancer (NSCLC).	('lung adenocarcinomas', 'Disease', (76, 96))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (307, 329))	('NSCLC', 'Disease', 'MESH:D002289', (331, 336))	('lung adenocarcinomas', 'Disease', 'MESH:C538231', (76, 96))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (303, 329))	('mutations', 'Var', (111, 120))	('NSCLC', 'Disease', (331, 336))	('lung squamous cell carcinomas', 'Disease', 'MESH:D002294', (28, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (47, 56))	('carcinomas', 'Phenotype', 'HP:0030731', (47, 57))	('NSCLC', 'Phenotype', 'HP:0030358', (331, 336))	('lung cancer', 'Phenotype', 'HP:0100526', (318, 329))	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('carcinomas', 'Phenotype', 'HP:0030731', (86, 96))	('non-small cell lung cancer', 'Disease', (303, 329))	('NRF2', 'Gene', (169, 173))	('lung squamous cell carcinomas', 'Disease', (28, 57))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (33, 56))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (33, 57))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (76, 96))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (303, 329))	('cancer', 'Phenotype', 'HP:0002664', (323, 329))	('LuAD', 'Phenotype', 'HP:0030078', (98, 102))
472287	32007910	Loss-of-function mutations in KEAP1 and gain-of-function mutations in NRF2 found in NSCLC abolish this control and lead to constitutive NRF2 activity.	('constitutive', 'MPA', (123, 135))	('Loss-of-function', 'NegReg', (0, 16))	('gain-of-function', 'PosReg', (40, 56))	('NSCLC', 'Phenotype', 'HP:0030358', (84, 89))	('abolish', 'NegReg', (90, 97))	('activity', 'MPA', (141, 149))	('NRF2', 'Gene', (70, 74))	('NSCLC', 'Disease', (84, 89))	('mutations', 'Var', (57, 66))	('control', 'MPA', (103, 110))	('NSCLC', 'Disease', 'MESH:D002289', (84, 89))	('mutations', 'Var', (17, 26))
472288	32007910	High expression of the detoxification enzyme and bona fide NRF2 target gene NAD(P)H:quinone oxidoreductase 1 (NQO1) is a distinct biomarker of NRF2/KEAP1 mutant NSCLC tumors.	('expression', 'MPA', (5, 15))	('NRF2/KEAP1', 'Gene', (143, 153))	('NSCLC', 'Phenotype', 'HP:0030358', (161, 166))	('NSCLC tumors', 'Disease', 'MESH:D009369', (161, 173))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('NSCLC tumors', 'Disease', (161, 173))	('NQO1', 'Gene', (110, 114))	('tumors', 'Phenotype', 'HP:0002664', (167, 173))	('NAD(P)H:quinone oxidoreductase', 'Disease', 'MESH:D016111', (76, 106))	('mutant', 'Var', (154, 160))
472298	32007910	Although beta-lapachone has been tested in phase 1 and 2 clinical trials for advanced solid tumors as the analogs ARQ 501 and ARQ 761, none of the clinical trials designed to date have been focused on lung cancer patients.	('solid tumors', 'Disease', 'MESH:D009369', (86, 98))	('beta-lapachone', 'Chemical', 'MESH:C014638', (9, 23))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('lung cancer', 'Disease', 'MESH:D008175', (201, 212))	('ARQ', 'Var', (126, 129))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('solid tumors', 'Disease', (86, 98))	('lung cancer', 'Phenotype', 'HP:0100526', (201, 212))	('lung cancer', 'Disease', (201, 212))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))
472299	32007910	Remarkably, a large fraction of NSCLC with high NQO1 also harbor sustained NRF2 activation, which in turn could hinder the cytotoxic effects of beta-lapachone through the active scavenging of ROS.	('cytotoxic', 'CPA', (123, 132))	('NSCLC', 'Phenotype', 'HP:0030358', (32, 37))	('NQO1', 'Var', (48, 52))	('NSCLC', 'Disease', (32, 37))	('ROS', 'MPA', (192, 195))	('beta-lapachone', 'Chemical', 'MESH:C014638', (144, 158))	('high NQO1', 'Var', (43, 52))	('NSCLC', 'Disease', 'MESH:D002289', (32, 37))	('NRF2', 'Gene', (75, 79))	('hinder', 'NegReg', (112, 118))	('activation', 'PosReg', (80, 90))
472300	32007910	Therefore, although high levels of NQO1 could be exploited with a therapeutic intent in NRF2/KEAP1 mutant cancer cells, it is unclear whether actions of NRF2 could limit beta-lapachone efficacy.	('beta-lapachone', 'Chemical', 'MESH:C014638', (170, 184))	('limit', 'NegReg', (164, 169))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('beta-lapachone efficacy', 'MPA', (170, 193))	('cancer', 'Disease', (106, 112))	('mutant', 'Var', (99, 105))	('NRF2/KEAP1', 'Gene', (88, 98))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
472301	32007910	In this study, we aim to clarify whether NQO1 represents a druggable strategy for NRF2/KEAP1 mutant NSCLC or, conversely, these alterations promote resistance to beta-lapachone.	('NSCLC', 'Disease', (100, 105))	('NRF2/KEAP1', 'Gene', (82, 92))	('resistance to beta-lapachone', 'MPA', (148, 176))	('promote', 'PosReg', (140, 147))	('NSCLC', 'Disease', 'MESH:D002289', (100, 105))	('mutant', 'Var', (93, 99))	('NSCLC', 'Phenotype', 'HP:0030358', (100, 105))	('beta-lapachone', 'Chemical', 'MESH:C014638', (162, 176))
472305	32007910	Further, tumors harboring NRF2/KEAP1 mutations displayed significantly higher expression of NQO1 than those lacking mutations in this pathway, consistent with the direct transcriptional regulation of NQO1 by NRF2.	('higher', 'PosReg', (71, 77))	('NRF2/KEAP1', 'Gene', (26, 36))	('expression', 'MPA', (78, 88))	('NQO1', 'Gene', (92, 96))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('mutations', 'Var', (37, 46))	('tumors', 'Disease', (9, 15))	('tumors', 'Disease', 'MESH:D009369', (9, 15))
472307	32007910	To examine the influence of KEAP1/NRF2 mutations on NSCLC response to beta-lapachone treatment, we assessed the cytotoxic efficacy of beta-lapachone in a panel of sixteen NSCLC cell lines, seven of which harbor characterized inactivating mutations of KEAP1 (Fig.	('NSCLC', 'Disease', (52, 57))	('NSCLC', 'Phenotype', 'HP:0030358', (171, 176))	('NSCLC', 'Disease', 'MESH:D002289', (52, 57))	('KEAP1', 'Gene', (251, 256))	('inactivating mutations', 'Var', (225, 247))	('mutations', 'Var', (39, 48))	('beta-lapachone', 'Chemical', 'MESH:C014638', (134, 148))	('NSCLC', 'Disease', (171, 176))	('NSCLC', 'Phenotype', 'HP:0030358', (52, 57))	('beta-lapachone', 'Chemical', 'MESH:C014638', (70, 84))	('NSCLC', 'Disease', 'MESH:D002289', (171, 176))
472310	32007910	Remarkably, KEAP1 mutation conferred resistance to beta-lapachone treatment (Fig.	('resistance to beta-lapachone treatment', 'MPA', (37, 75))	('beta-lapachone', 'Chemical', 'MESH:C014638', (51, 65))	('KEAP1', 'Gene', (12, 17))	('mutation', 'Var', (18, 26))
472317	32007910	To determine whether beta-lapachone resistance was NRF2-dependent, H1299 cells (KEAP1WT) were infected with virus encoding for an inactivating mutation of KEAP1 (C273S) or a gain-of function NRF2 mutation (T80K), to promote the aberrant activation of NRF2.	('beta-lapachone', 'Chemical', 'MESH:C014638', (21, 35))	('C273S', 'Mutation', 'p.C273S', (162, 167))	('C273S', 'Var', (162, 167))	('NRF2', 'Gene', (251, 255))	('T80K', 'Mutation', 'p.T80K', (206, 210))	('NRF2', 'Gene', (191, 195))	('H1299', 'CellLine', 'CVCL:0060', (67, 72))	('promote', 'PosReg', (216, 223))	('T80K', 'Var', (206, 210))	('gain-of function', 'PosReg', (174, 190))	('activation', 'PosReg', (237, 247))
472318	32007910	In agreement with our previous findings, overexpression of KEAP1C273S and NRF2T80K but not KEAP1WT led to the accumulation of NRF2, which promoted resistance to beta-lapachone exposure (Fig.	('resistance to beta-lapachone exposure', 'MPA', (147, 184))	('NRF2T80K', 'Gene', (74, 82))	('accumulation', 'PosReg', (110, 122))	('KEAP1C273S', 'Var', (59, 69))	('C273S', 'Mutation', 'p.C273S', (64, 69))	('promoted', 'PosReg', (138, 146))	('T80K', 'Mutation', 'p.T80K', (78, 82))	('overexpression', 'PosReg', (41, 55))	('beta-lapachone', 'Chemical', 'MESH:C014638', (161, 175))	('NRF2', 'Gene', (126, 130))
472321	32007910	In agreement with our previous data, NRF2-knockout cells exhibited increased sensitivity to beta-lapachone compared to cells reconstituted for NRF2 expression.	('NRF2-knockout', 'Gene', (37, 50))	('beta-lapachone', 'Chemical', 'MESH:C014638', (92, 106))	('increased', 'PosReg', (67, 76))	('NRF2-knockout', 'Var', (37, 50))	('sensitivity to beta-lapachone', 'MPA', (77, 106))
472322	32007910	Collectively, these results indicate that aberrant activation of NRF2 in KEAP1 mutant lung cancer cells confers resistance to beta-lapachone exposure.	('NRF2', 'Gene', (65, 69))	('resistance', 'MPA', (112, 122))	('mutant', 'Var', (79, 85))	('lung cancer', 'Phenotype', 'HP:0100526', (86, 97))	('beta-lapachone', 'Chemical', 'MESH:C014638', (126, 140))	('lung cancer', 'Disease', (86, 97))	('KEAP1', 'Gene', (73, 78))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('activation', 'PosReg', (51, 61))	('lung cancer', 'Disease', 'MESH:D008175', (86, 97))
472329	32007910	We observed a time-dependent accumulation of DNA damage in H1299 cells (KEAP1WT), while A549 cells (KEAP1MUT) did not exhibit increased gamma-H2AX following 2-h treatment with 3 muM beta-lapachone (Fig.	('H1299', 'Var', (59, 64))	('A549', 'CellLine', 'CVCL:0023', (88, 92))	('beta-lapachone', 'Chemical', 'MESH:C014638', (182, 196))	('H1299', 'CellLine', 'CVCL:0060', (59, 64))	('DNA damage', 'MPA', (45, 55))
472331	32007910	Accordingly, ectopic expression of KEAP1C273S or NRF2T80K in H1299 cells also promoted resistance to beta-lapachone-induced DNA damage and decreased accumulation of ROS (Fig.	('accumulation', 'MPA', (149, 161))	('beta-lapachone', 'Chemical', 'MESH:C014638', (101, 115))	('promoted', 'PosReg', (78, 86))	('C273S', 'Mutation', 'p.C273S', (40, 45))	('decreased', 'NegReg', (139, 148))	('H1299', 'CellLine', 'CVCL:0060', (61, 66))	('KEAP1C273S', 'Var', (35, 45))	('T80K', 'Mutation', 'p.T80K', (53, 57))	('resistance to beta-lapachone-induced DNA damage', 'MPA', (87, 134))	('ROS', 'MPA', (165, 168))	('NRF2T80K', 'Gene', (49, 57))
472332	32007910	We next assessed whether depletion of NRF2 could exacerbate beta-lapachone-induced DNA damage in KEAP1MUT cells (Fig.	('NRF2', 'Gene', (38, 42))	('beta-lapachone', 'Chemical', 'MESH:C014638', (60, 74))	('exacerbate', 'PosReg', (49, 59))	('depletion', 'Var', (25, 34))
472333	32007910	Indeed, shRNA-mediated silencing of NRF2 in H460 and HCC15 cells increased gamma-H2AX levels following beta-lapachone exposure.	('gamma-H2AX levels', 'MPA', (75, 92))	('increased', 'PosReg', (65, 74))	('NRF2', 'Gene', (36, 40))	('silencing', 'Var', (23, 32))	('HCC15', 'CellLine', 'CVCL:2057', (53, 58))	('beta-lapachone', 'Chemical', 'MESH:C014638', (103, 117))
472336	32007910	Consistently, A549 NRF2-knockout cells exhibited greater production of ROS and accumulation of DNA damage markers compared to cells expressing NRF2.	('production', 'MPA', (57, 67))	('A549', 'CellLine', 'CVCL:0023', (14, 18))	('greater', 'PosReg', (49, 56))	('ROS', 'MPA', (71, 74))	('A549', 'Var', (14, 18))	('accumulation of DNA damage markers', 'MPA', (79, 113))	('NRF2-knockout', 'Gene', (19, 32))
472341	32007910	We observed that depletion of catalase did not affect the beta-lapachone sensitivity of NSCLC cells, regardless of KEAP1 mutational status.	('mutational', 'Var', (121, 131))	('NSCLC', 'Phenotype', 'HP:0030358', (88, 93))	('NSCLC', 'Disease', (88, 93))	('beta-lapachone', 'Chemical', 'MESH:C014638', (58, 72))	('depletion of catalase', 'Phenotype', 'HP:0012517', (17, 38))	('NSCLC', 'Disease', 'MESH:D002289', (88, 93))	('depletion', 'MPA', (17, 26))	('beta-lapachone sensitivity', 'MPA', (58, 84))
472350	32007910	Depletion of glutathione did not increase the sensitivity to beta-lapachone treatment, while auranofin significantly increased beta-lapachone-induced cell death and DNA damage in KEAP1MUTcells (Fig.	('glutathione', 'Chemical', 'MESH:D005978', (13, 24))	('cell', 'CPA', (150, 154))	('beta-lapachone', 'Chemical', 'MESH:C014638', (61, 75))	('DNA damage', 'CPA', (165, 175))	('auranofin', 'Chemical', 'MESH:D001310', (93, 102))	('beta-lapachone-induced', 'Var', (127, 149))	('beta-lapachone', 'Chemical', 'MESH:C014638', (127, 141))
472352	32007910	These data suggest that although inhibition of the TXN-dependent system increases sensitivity of KEAP1MUT cells to beta-lapachone, the inherent reinforcement of this antioxidant pathway in KEAP1MUT cells might represent a challenge in vivo.	('inhibition', 'Var', (33, 43))	('sensitivity', 'MPA', (82, 93))	('increases', 'PosReg', (72, 81))	('beta-lapachone', 'Chemical', 'MESH:C014638', (115, 129))	('reinforcement', 'PosReg', (144, 157))
472357	32007910	Depletion of SOD1 markedly increased beta-lapachone-mediated cell death in KEAP1MUT cell lines and increased DNA damage (Fig.	('increased', 'PosReg', (27, 36))	('beta-lapachone', 'Chemical', 'MESH:C014638', (37, 51))	('Depletion', 'Var', (0, 9))	('DNA damage', 'MPA', (109, 119))	('increased', 'PosReg', (99, 108))	('SOD1', 'Gene', (13, 17))	('beta-lapachone-mediated', 'MPA', (37, 60))
472362	32007910	Thus, indirect inhibition of SOD1 can be achieved through copper chelation, while the mitochondrial SOD activity should remain intact.	('SOD1', 'Gene', (29, 33))	('inhibition', 'NegReg', (15, 25))	('copper chelation', 'Var', (58, 74))	('copper', 'Chemical', 'MESH:D003300', (58, 64))
472365	32007910	Inhibition of SOD1 resulted in increased sensitivity of KEAP1MUT cells to beta-lapachone-mediated cell death and DNA damage (Fig.	('SOD1', 'Gene', (14, 18))	('increased', 'PosReg', (31, 40))	('sensitivity', 'MPA', (41, 52))	('beta-lapachone', 'Chemical', 'MESH:C014638', (74, 88))	('Inhibition', 'Var', (0, 10))	('DNA damage', 'MPA', (113, 123))
472367	32007910	KEAP1 mutant cells did not exhibit significantly higher levels of SOD1, suggesting that inactivation of KEAP1 does not confer a reinforced capacity to detoxify cytosolic superoxide radicals through SOD1 upregulation.	('detoxify cytosolic superoxide radicals', 'MPA', (151, 189))	('SOD1', 'Gene', (198, 202))	('superoxide', 'Chemical', 'MESH:D013481', (170, 180))	('KEAP1', 'Gene', (104, 109))	('upregulation', 'PosReg', (203, 215))	('inactivation', 'Var', (88, 100))
472373	32007910	Altogether, these data demonstrate that inhibition of SOD1 selectively increases beta-lapachone efficacy in KEAP1MUT NSCLC cells.	('NSCLC', 'Disease', (117, 122))	('inhibition', 'Var', (40, 50))	('NSCLC', 'Disease', 'MESH:D002289', (117, 122))	('SOD1', 'Gene', (54, 58))	('beta-lapachone', 'Chemical', 'MESH:C014638', (81, 95))	('increases', 'PosReg', (71, 80))	('beta-lapachone efficacy', 'MPA', (81, 104))	('NSCLC', 'Phenotype', 'HP:0030358', (117, 122))
472376	32007910	We find that inhibitors of the TXN-dependent peroxide detoxification system and SOD1, but not glutathione or catalase depletion, can reverse the resistance of KEAP1MUT cells to beta-lapachone.	('resistance', 'MPA', (145, 155))	('inhibitors', 'Var', (13, 23))	('glutathione', 'Chemical', 'MESH:D005978', (94, 105))	('SOD1', 'Gene', (80, 84))	('beta-lapachone', 'Chemical', 'MESH:C014638', (177, 191))	('reverse', 'Reg', (133, 140))	('peroxide', 'Chemical', 'MESH:D010545', (45, 53))	('catalase depletion', 'Phenotype', 'HP:0012517', (109, 127))
472385	32007910	In agreement with our findings, a recent study found that SOD1 deletion or modulation of copper availability sensitized Jurkat cells to the superoxide generating compound paraquat.	('SOD1', 'Gene', (58, 62))	('paraquat', 'Chemical', 'MESH:D010269', (171, 179))	('superoxide', 'Chemical', 'MESH:D013481', (140, 150))	('modulation', 'Var', (75, 85))	('deletion', 'Var', (63, 71))	('Jurkat', 'CellLine', 'CVCL:0065', (120, 126))	('sensitized', 'Reg', (109, 119))	('copper', 'Chemical', 'MESH:D003300', (89, 95))
472387	32007910	Authors also found that SOD1 inhibition was synergistic with glutathione depletion, suggesting that alternative combinations to inhibit the antioxidant capacity of KEAP1 mutant cells may be possible.	('glutathione', 'Chemical', 'MESH:D005978', (61, 72))	('inhibit', 'NegReg', (128, 135))	('glutathione', 'MPA', (61, 72))	('antioxidant capacity', 'MPA', (140, 160))	('mutant', 'Var', (170, 176))
472390	32007910	However, cautions should be taken when considering combination of beta-lapachone and inhibition of antioxidant systems for in vivo studies, as it might increase toxicity.	('increase', 'PosReg', (152, 160))	('toxicity', 'Disease', 'MESH:D064420', (161, 169))	('toxicity', 'Disease', (161, 169))	('beta-lapachone', 'Var', (66, 80))	('beta-lapachone', 'Chemical', 'MESH:C014638', (66, 80))
472395	32007910	In agreement with our data, authors also observed that depletion of TXNRD1 also conferred sensitivity to Napabucasin in pancreatic cancer cells.	('pancreatic cancer', 'Disease', 'MESH:D010190', (120, 137))	('TXNRD1', 'Gene', (68, 74))	('conferred', 'Reg', (80, 89))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (120, 137))	('sensitivity to Napabucasin', 'MPA', (90, 116))	('depletion', 'Var', (55, 64))	('pancreatic cancer', 'Disease', (120, 137))
472397	32007910	Nitrotetrazolium Blue chloride powder (N6639), riboflavin (R7649), Auranofin (A6733-10MG) and Catalase from bovine liver (C1345) were all obtained from Sigma Aldrich.	('N6639', 'Var', (39, 44))	('R7649', 'Var', (59, 64))	('N6639', 'Chemical', 'MESH:D009584', (39, 44))	('Nitrotetrazolium Blue chloride', 'Chemical', 'MESH:D009580', (0, 30))	('A6733-10MG', 'Var', (78, 88))	('riboflavin', 'Chemical', 'MESH:D012256', (47, 57))	('Auranofin', 'Chemical', 'MESH:D001310', (67, 76))
472462	32007910	Alterations in the NRF2/KEAP1 pathway confer resistance to beta-lapachone exposure.	('Alterations', 'Var', (0, 11))	('resistance', 'MPA', (45, 55))	('NRF2/KEAP1 pathway', 'Pathway', (19, 37))	('beta-lapachone', 'Chemical', 'MESH:C014638', (59, 73))
472468	32007910	Activation of NRF2 renders NSCLC cells resistant to beta-lapachone-induced DNA damage and promotes ROS scavenging (A) H1299 cells (KEAP1 WT) were infected with virus coding for NRF2-T80K, KEAP1 C273S or an empty control as vehicle.	('NRF2', 'Gene', (14, 18))	('ROS scavenging', 'MPA', (99, 113))	('T80K', 'Mutation', 'p.T80K', (182, 186))	('C273S', 'Mutation', 'p.C273S', (194, 199))	('NSCLC', 'Disease', (27, 32))	('NRF2-T80K', 'Var', (177, 186))	('H1299', 'CellLine', 'CVCL:0060', (118, 123))	('NSCLC', 'Disease', 'MESH:D002289', (27, 32))	('NSCLC', 'Phenotype', 'HP:0030358', (27, 32))	('beta-lapachone', 'Chemical', 'MESH:C014638', (52, 66))	('KEAP1', 'Var', (188, 193))
472477	32007910	1C, S3B and S4B are a reprobing of the same blot and share the loading control (tubulin).	('S3B', 'Chemical', 'MESH:D013455', (4, 7))	('S4B', 'Chemical', 'MESH:D013455', (12, 15))	('S4B', 'Var', (12, 15))	('S3B', 'Var', (4, 7))
472486	31908484	Mutation of the NOTCH1 gene is common in head and neck cancer.	('NOTCH1', 'Gene', '4851', (16, 22))	('common', 'Reg', (31, 37))	('head and neck cancer', 'Phenotype', 'HP:0012288', (41, 61))	('NOTCH1', 'Gene', (16, 22))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('Mutation', 'Var', (0, 8))	('head and neck cancer', 'Disease', 'MESH:D006258', (41, 61))
472544	31908484	In addition, via intercellular signaling, the aberrant "microenvironment" selectively promotes the mutant lineages that lead to tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('lead to', 'Reg', (120, 127))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('promotes', 'PosReg', (86, 94))	('tumor', 'Disease', (128, 133))	('mutant', 'Var', (99, 105))
472550	31908484	HNSCC develops via a prolonged multistage process that involves an accumulation of genetic and epigenetic alterations.	('HNSCC', 'Phenotype', 'HP:0012288', (0, 5))	('epigenetic', 'Var', (95, 105))	('HNSCC', 'Disease', 'MESH:C535575', (0, 5))	('HNSCC', 'Disease', (0, 5))
472553	31908484	Agrawal et al and Stransky et al confirmed the genes previously reported to play a role in HNSCC, and they also reported novel mutations in NOTCH1.	('NOTCH1', 'Gene', '4851', (140, 146))	('NOTCH1', 'Gene', (140, 146))	('HNSCC', 'Disease', 'MESH:C535575', (91, 96))	('HNSCC', 'Disease', (91, 96))	('HNSCC', 'Phenotype', 'HP:0012288', (91, 96))	('mutations', 'Var', (127, 136))
472554	31908484	The inactivating mutations of NOTCH1 were found in 10-15% of HNSCC tumors in both of those studies, which suggests NOTCH1 as the second most frequently mutated gene after TP53.	('TP53', 'Gene', (171, 175))	('inactivating mutations', 'Var', (4, 26))	('NOTCH1', 'Gene', (115, 121))	('tumors', 'Disease', 'MESH:D009369', (67, 73))	('NOTCH1', 'Gene', '4851', (30, 36))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('NOTCH1', 'Gene', (30, 36))	('HNSCC', 'Disease', 'MESH:C535575', (61, 66))	('HNSCC', 'Phenotype', 'HP:0012288', (61, 66))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('HNSCC', 'Disease', (61, 66))	('NOTCH1', 'Gene', '4851', (115, 121))	('tumors', 'Disease', (67, 73))	('TP53', 'Gene', '7157', (171, 175))
472557	31908484	Several studies suggested that NOTCH1 mutation can have pleiotropic effects.	('NOTCH1', 'Gene', (31, 37))	('mutation', 'Var', (38, 46))	('NOTCH1', 'Gene', '4851', (31, 37))
472558	31908484	It was reported that gain-of-function NOTCH1 mutations are observed in leukemia's cluster of the negative regulatory region and the C-terminal PEST domain.	('mutations', 'Var', (45, 54))	('leukemia', 'Disease', (71, 79))	('leukemia', 'Phenotype', 'HP:0001909', (71, 79))	('gain-of-function', 'PosReg', (21, 37))	('NOTCH1', 'Gene', '4851', (38, 44))	('NOTCH1', 'Gene', (38, 44))	('leukemia', 'Disease', 'MESH:D007938', (71, 79))
472559	31908484	In contrast, loss-of-function NOTCH1 mutations were observed in cutaneous and lung squamous cell carcinoma.	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (78, 106))	('loss-of-function', 'NegReg', (13, 29))	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (83, 106))	('lung squamous cell carcinoma', 'Disease', (78, 106))	('NOTCH1', 'Gene', '4851', (30, 36))	('NOTCH1', 'Gene', (30, 36))	('mutations', 'Var', (37, 46))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (78, 106))
472560	31908484	The cancer genome atlas of HNSCC reveals loss-of-function mutations of NOTCH1, and concludes that NOTCH1 acts as a tumor suppressor.	('mutations', 'Var', (58, 67))	('HNSCC', 'Disease', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('HNSCC', 'Phenotype', 'HP:0012288', (27, 32))	('NOTCH1', 'Gene', (71, 77))	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('loss-of-function', 'NegReg', (41, 57))	('tumor', 'Disease', (115, 120))	('NOTCH1', 'Gene', '4851', (98, 104))	('NOTCH1', 'Gene', (98, 104))	('cancer', 'Disease', 'MESH:D009369', (4, 10))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('cancer', 'Disease', (4, 10))	('HNSCC', 'Disease', 'MESH:C535575', (27, 32))	('NOTCH1', 'Gene', '4851', (71, 77))
472563	31908484	Despite the fact that no statistically significant difference was observed between groups, the high rate of NICD inactivation in this study supports its role as a tumor suppressor gene.	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('tumor', 'Disease', (163, 168))	('NICD', 'Gene', (108, 112))	('inactivation', 'Var', (113, 125))
472564	31908484	Since the NOTCH gene would be unlikely to present in a significant proportion of normal cells, negative IHC staining may not be solely caused by loss of function due to mutation of NOTCH1.	('mutation', 'Var', (169, 177))	('NOTCH1', 'Gene', '4851', (181, 187))	('NOTCH1', 'Gene', (181, 187))
472565	31908484	In hematologic malignancy, the perturbation of Notch signaling is mediated by aberration of Notch transcriptional coactivators.	('aberration', 'Var', (78, 88))	('hematologic malignancy', 'Disease', (3, 25))	('hematologic malignancy', 'Disease', 'MESH:D019337', (3, 25))	('Notch signaling', 'MPA', (47, 62))	('hematologic malignancy', 'Phenotype', 'HP:0004377', (3, 25))
472568	31908484	Moreover, the expression of Notch1 might be used as an independent prognostic indicator of oral cancer.	('expression', 'Var', (14, 24))	('oral cancer', 'Disease', (91, 102))	('Notch1', 'Gene', (28, 34))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('Notch1', 'Gene', '4851', (28, 34))	('oral cancer', 'Disease', 'MESH:D009062', (91, 102))
472572	31908484	Further study of other regulators, such as ligand binders and downstream activators, might provide more information about NOTCH1 mutation in HNSCC.	('HNSCC', 'Disease', 'MESH:C535575', (141, 146))	('mutation', 'Var', (129, 137))	('HNSCC', 'Disease', (141, 146))	('NOTCH1', 'Gene', (122, 128))	('NOTCH1', 'Gene', '4851', (122, 128))	('HNSCC', 'Phenotype', 'HP:0012288', (141, 146))
472573	31908484	In order to conclude the absence of protein expression caused by the NOTCH1 mutation, whole exome sequencing (WES) would be necessary.	('absence', 'NegReg', (25, 32))	('protein expression', 'MPA', (36, 54))	('mutation', 'Var', (76, 84))	('NOTCH1', 'Gene', '4851', (69, 75))	('NOTCH1', 'Gene', (69, 75))
472583	27452673	The occurrence of mutations in these binding sites provides new opportunities to develop small-molecule probes to explore their function in cancer.	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('cancer', 'Disease', (140, 146))	('mutations', 'Var', (18, 27))
472587	27452673	Analysis of this genomic data has revealed that the complex phenotypes that define cancer are driven by tens of somatic mutations that occur on proteins across the cellular network.	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('driven by', 'Reg', (94, 103))	('mutations', 'Var', (120, 129))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('cancer', 'Disease', (83, 89))
472589	27452673	Tumors were found to harbor tens of mutations.	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('mutations', 'Var', (36, 45))
472630	27452673	As expected, there were significantly fewer binding sites that occurred at PPI interfaces than any of the other classes of binding sites.	('PPI', 'Var', (75, 78))	('binding', 'Interaction', (44, 51))	('fewer', 'NegReg', (38, 43))	('PPI', 'Chemical', '-', (75, 78))
472640	27452673	However, the overexpression of protease inhibitors such as TIMPs and serpins suggest that inhibition of proteases may oppose growth and metastasis of a tumor.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('oppose', 'NegReg', (118, 124))	('tumor', 'Disease', (152, 157))	('overexpression', 'PosReg', (13, 27))	('inhibition', 'Var', (90, 100))
472674	27452673	Alteration of individual genes within these signaling pathways lead to cancer related processes such as cell growth and adhesion.	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('Alteration', 'Var', (0, 10))	('cancer', 'Disease', (71, 77))	('lead to', 'Reg', (63, 70))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('adhesion', 'CPA', (120, 128))	('cell growth', 'CPA', (104, 115))
472712	27452673	On the most commonly mutated target, PIK3CA, mutation rates are approximately five-fold less at the binding site than the entire protein.	('less', 'NegReg', (88, 92))	('PIK3CA', 'Gene', '5290', (37, 43))	('mutation', 'Var', (45, 53))	('PIK3CA', 'Gene', (37, 43))
472713	27452673	Also, among the top targets is BRAF, which features the common V600E mutation, which has been used for the rational design of small-molecule inhibitors of the mutant protein.	('BRAF', 'Gene', '673', (31, 35))	('V600E', 'Var', (63, 68))	('V600E', 'Mutation', 'rs113488022', (63, 68))	('BRAF', 'Gene', (31, 35))
472714	27452673	We matched these proteins with missense mutations with their gene expression levels and correlation with patient outcome.	('gene expression levels', 'MPA', (61, 83))	('missense mutations', 'Var', (31, 49))	('patient', 'Species', '9606', (105, 112))
472715	27452673	We find 29 binding sites on 26 proteins that are i) overexpressed (log2 fold change >= 2); (ii) correlate with patient outcome (hazard ratio > 1); and (iii) have a missense mutation adjacent to a binding site in a given disease (Table 8).	('missense mutation', 'Var', (164, 181))	('binding', 'Interaction', (11, 18))	('overexpressed', 'PosReg', (52, 65))	('patient', 'Species', '9606', (111, 118))	('proteins', 'Protein', (31, 39))
472717	27452673	Among these mutations adjacent to binding sites is the W167L mutation on the PPI interface between MAD2L1 and MAD1L1 in LUAD (Figure 5C).	('MAD1L1', 'Gene', '8379', (110, 116))	('MAD2L1', 'Gene', (99, 105))	('MAD1L1', 'Gene', (110, 116))	('W167L', 'Mutation', 'p.W167L', (55, 60))	('MAD2L1', 'Gene', '4085', (99, 105))	('W167L', 'Var', (55, 60))	('PPI', 'Chemical', '-', (77, 80))
472718	27452673	Considering the significant reduction in contact area upon replacing tryptophan with leucine, and the fact that tryptophan residues tend to often occur at protein-protein interaction interfaces, we expect that this mutation may impair the protein-protein interaction.	('contact area', 'MPA', (41, 53))	('mutation', 'Var', (215, 223))	('leucine', 'Chemical', 'MESH:D007930', (85, 92))	('tryptophan', 'Chemical', 'MESH:D014364', (69, 79))	('tryptophan', 'Chemical', 'MESH:D014364', (112, 122))	('impair', 'NegReg', (228, 234))	('reduction', 'NegReg', (28, 37))	('protein-protein', 'Protein', (239, 254))
472719	27452673	Another mutation is the R121P mutation adjacent to the DNA-binding OTH binding site on EXO1 in LUAD (Figure 5D).	('R121P', 'Mutation', 'p.R121P', (24, 29))	('R121P', 'Var', (24, 29))	('EXO1', 'Gene', (87, 91))	('EXO1', 'Gene', '9156', (87, 91))
472720	27452673	Unlike the previous mutation, arginine contains a positively charged group while proline is a neutral non-polar amino acid.	('arginine', 'Chemical', 'MESH:D001120', (30, 38))	('positively charged group', 'MPA', (50, 74))	('proline', 'Chemical', 'MESH:D011392', (81, 88))	('arginine', 'Var', (30, 38))
472721	27452673	For example, mutations to alanine is less favored in the pocket or on the surface of the protein than it is in the interior, especially at charged or polar groups.	('mutations', 'Var', (13, 22))	('alanine', 'Chemical', 'MESH:D000409', (26, 33))	('alanine', 'Var', (26, 33))
472724	27452673	The lack of such cavities is partly responsible for the difficulty in developing small-molecule therapeutic agents that bind directly to highly promising cancer targets such as mutated RAS GTPase or transcription factors such as c-MYC.	('MYC', 'Gene', '4609', (231, 234))	('cancer', 'Disease', (154, 160))	('mutated', 'Var', (177, 184))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('MYC', 'Gene', (231, 234))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('RAS GTPase', 'Gene', (185, 195))
472752	27452673	Finally, we mapped mutations that were previously identified at TCGA onto the three-dimensional structure of proteins that are encoded by overexpressed genes that correlate with patient outcome.	('TCGA', 'Gene', (64, 68))	('patient', 'Species', '9606', (178, 185))	('mutations', 'Var', (19, 28))
472753	27452673	A recent study explored the role of mutations on tumorigenesis and more recently using a structural genomics based approach.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Disease', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('mutations', 'Var', (36, 45))
472754	27452673	Most of the enzyme mutations appear to involve dramatic changes in physico-chemical properties such as H113Q, G568W, R140L, M80R for CA6, KIFC1, NEK2, and SULT4A1.	('G568W', 'Mutation', 'rs931581234', (110, 115))	('M80R', 'Mutation', 'p.M80R', (124, 128))	('M80R', 'Var', (124, 128))	('H113Q', 'SUBSTITUTION', 'None', (103, 108))	('CA6', 'Gene', '765', (133, 136))	('CA6', 'Gene', (133, 136))	('NEK2', 'Gene', '4751', (145, 149))	('R140L', 'Var', (117, 122))	('R140L', 'Mutation', 'p.R140L', (117, 122))	('G568W', 'Var', (110, 115))	('SULT4A1', 'Gene', '25830', (155, 162))	('KIFC1', 'Gene', (138, 143))	('NEK2', 'Gene', (145, 149))	('physico-chemical', 'MPA', (67, 83))	('SULT4A1', 'Gene', (155, 162))	('H113Q', 'Var', (103, 108))	('KIFC1', 'Gene', '3833', (138, 143))	('changes', 'Reg', (56, 63))
472755	27452673	Others involved subtler mutations such as V46A, A287S, and M52T for CHEK1, PCK1, and PSPH, respectively.	('CHEK1', 'Gene', '1111', (68, 73))	('PSPH', 'Gene', (85, 89))	('M52T', 'Var', (59, 63))	('CHEK1', 'Gene', (68, 73))	('A287S', 'Var', (48, 53))	('A287S', 'Mutation', 'rs747837917', (48, 53))	('PSPH', 'Gene', '5723', (85, 89))	('PCK1', 'Gene', (75, 79))	('M52T', 'Mutation', 'rs104894036', (59, 63))	('PCK1', 'Gene', '5105', (75, 79))	('V46A', 'Var', (42, 46))	('V46A', 'Mutation', 'p.V46A', (42, 46))
472756	27452673	Three mutations were identified to occur at protein-protein interfaces, R293P, W167L, and Q107H, which correspond to ADORA2A, MAD2L1, and RHCG, respectively.	('Q107H', 'Mutation', 'p.Q107H', (90, 95))	('W167L', 'Mutation', 'p.W167L', (79, 84))	('R293P', 'Mutation', 'p.R293P', (72, 77))	('Q107H', 'Var', (90, 95))	('R293P', 'Var', (72, 77))	('ADORA2A', 'Gene', '135', (117, 124))	('MAD2L1', 'Gene', (126, 132))	('ADORA2A', 'Gene', (117, 124))	('RHCG', 'Gene', '51458', (138, 142))	('W167L', 'Var', (79, 84))	('MAD2L1', 'Gene', '4085', (126, 132))	('RHCG', 'Gene', (138, 142))
472757	27452673	The first two may have disruptive effects considering that proline residues tend to disrupt secondary structures and tryptophan residues are generally believed to tighten protein-protein interactions.	('protein-protein', 'Protein', (171, 186))	('tryptophan', 'Chemical', 'MESH:D014364', (117, 127))	('proline', 'Chemical', 'MESH:D011392', (59, 66))	('tighten', 'PosReg', (163, 170))	('secondary structures', 'MPA', (92, 112))	('disrupt', 'NegReg', (84, 91))	('proline residues', 'Var', (59, 75))
472783	24887090	The aim of the present study was to investigate whether selective Cox-2 inhibitors restore the expression of E-cadherin in head and neck squamous cell carcinoma (HNSCC) cells, and to examine the possible correlations of the expression levels of EMT-related molecules with clinicopathological factors in HNSCC.	('Cox-2', 'Gene', '5743', (66, 71))	('Cox-2', 'Gene', (66, 71))	('HNSCC', 'Phenotype', 'HP:0012288', (162, 167))	('HNSCC', 'Disease', (303, 308))	('HNSCC', 'Phenotype', 'HP:0012288', (303, 308))	('E-cadherin', 'Gene', (109, 119))	('E-cadherin', 'Gene', '999', (109, 119))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (123, 160))	('restore', 'PosReg', (83, 90))	('neck squamous cell carcinoma', 'Disease', (132, 160))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (137, 160))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (132, 160))	('inhibitors', 'Var', (72, 82))	('expression', 'MPA', (95, 105))	('carcinoma', 'Phenotype', 'HP:0030731', (151, 160))
472787	24887090	The selective Cox-2 inhibitors upregulated the E-cadherin expression on the cell surface of the HNSCC cells through the downregulation of its transcriptional repressors.	('Cox-2', 'Gene', (14, 19))	('HNSCC', 'Phenotype', 'HP:0012288', (96, 101))	('downregulation', 'NegReg', (120, 134))	('E-cadherin', 'Gene', (47, 57))	('expression', 'MPA', (58, 68))	('inhibitors', 'Var', (20, 30))	('E-cadherin', 'Gene', '999', (47, 57))	('upregulated', 'PosReg', (31, 42))	('transcriptional repressors', 'MPA', (142, 168))	('Cox-2', 'Gene', '5743', (14, 19))
472809	24887090	We conducted the present study to determine whether selective Cox-2 inhibitors restore the expression of E-cadherin through the downregulation of its transcriptional repressors to suppress the EMT in HNSCC cells, and to determine whether the gene expression levels of the molecules that are implicated in the EMT are correlated with clinicopathological parameters in HNSCC.	('Cox-2', 'Gene', '5743', (62, 67))	('expression', 'MPA', (91, 101))	('suppress', 'NegReg', (180, 188))	('Cox-2', 'Gene', (62, 67))	('transcriptional repressors', 'MPA', (150, 176))	('E-cadherin', 'Gene', (105, 115))	('E-cadherin', 'Gene', '999', (105, 115))	('HNSCC', 'Phenotype', 'HP:0012288', (200, 205))	('EMT', 'CPA', (193, 196))	('inhibitors', 'Var', (68, 78))	('restore', 'PosReg', (79, 86))	('HNSCC', 'Disease', (367, 372))	('downregulation', 'NegReg', (128, 142))	('HNSCC', 'Phenotype', 'HP:0012288', (367, 372))
472819	24887090	Specific primers and probes were obtained from Applied Biosystems as TaqMan  Gene Expression Assays, with the following IDs: human E-cadherin/CDH-1, Hs00170423_m1; Snail/SNAI1, Hs00195591_m1; SIP1/ZFHX1B, Hs00207691_m1; twist/TWIST1, Hs00361186_m1; Cox-2/PTGS2, Hs01573471_m1; and GAPDH (glyceraldehyde-3-phosphate dehydrogenase)/GAPDH, Hs99999905_m1.	('SNAI1', 'Gene', (170, 175))	('TWIST1', 'Gene', '7291', (226, 232))	('Snail', 'Gene', (164, 169))	('SIP1', 'Gene', '9839', (192, 196))	('GAPDH', 'Gene', (330, 335))	('E-cadherin', 'Gene', (131, 141))	('GAPDH', 'Gene', (281, 286))	('E-cadherin', 'Gene', '999', (131, 141))	('PTGS2', 'Gene', (255, 260))	('Cox-2', 'Gene', '5743', (249, 254))	('Hs99999905_m1', 'Var', (337, 350))	('ZFHX1B', 'Gene', (197, 203))	('Snail', 'Gene', '6615', (164, 169))	('human', 'Species', '9606', (125, 130))	('SIP1', 'Gene', (192, 196))	('glyceraldehyde-3-phosphate dehydrogenase', 'Gene', (288, 328))	('CDH-1', 'Gene', '999', (142, 147))	('TWIST1', 'Gene', (226, 232))	('ZFHX1B', 'Gene', '9839', (197, 203))	('GAPDH', 'Gene', '2597', (330, 335))	('PTGS2', 'Gene', '5743', (255, 260))	('CDH-1', 'Gene', (142, 147))	('glyceraldehyde-3-phosphate dehydrogenase', 'Gene', '2597', (288, 328))	('Cox-2', 'Gene', (249, 254))	('GAPDH', 'Gene', '2597', (281, 286))	('SNAI1', 'Gene', '6615', (170, 175))
472821	24887090	For the quantitative analysis of E-cadherin expression at protein level, we harvested cells that had been treated with each of the selective Cox-2 inhibitors for 24 h, using a cell dissociation solution (C 5914, Sigma-Aldrich, St. Louis, MO).	('Cox-2', 'Gene', (141, 146))	('E-cadherin', 'Gene', (33, 43))	('E-cadherin', 'Gene', '999', (33, 43))	('Cox-2', 'Gene', '5743', (141, 146))	('C 5914', 'Var', (204, 210))
472852	24887090	In line with these results, all three transcriptional repressors of E-cadherin were clearly downregulated in the HSC-2 cells by each of the Cox-2 inhibitors, with decreasing by 0.18-0.34-, 0.15-0.32-, and 0.35-0.47-fold in SIP1, Snail, and Twist, respectively (Figure 2C), whereas the Cox-2 inhibition in the HSC-4 cells led to relatively less downregulation of these transcriptional repressors (Figure 2D).	('Snail', 'Gene', '6615', (229, 234))	('inhibitors', 'Var', (146, 156))	('Cox-2', 'Gene', (285, 290))	('HSC-2', 'CellLine', 'CVCL:1287', (113, 118))	('Snail', 'Gene', (229, 234))	('Cox-2', 'Gene', '5743', (285, 290))	('E-cadherin', 'Gene', (68, 78))	('E-cadherin', 'Gene', '999', (68, 78))	('SIP1', 'Gene', '9839', (223, 227))	('transcriptional', 'MPA', (38, 53))	('HSC-4', 'CellLine', 'CVCL:1289', (309, 314))	('Cox-2', 'Gene', (140, 145))	('Cox-2', 'Gene', '5743', (140, 145))	('SIP1', 'Gene', (223, 227))	('decreasing', 'NegReg', (163, 173))	('downregulated', 'NegReg', (92, 105))
472856	24887090	In line with aforementioned results, Cox-2 inhibition elevated the cell surface expression of E-cadherin compared to DMSO treatment in the HSC-2 cells, increasing by more than 1.76-, 1.47-, and 1.21-fold with celecoxib, NS-398, and SC-791, respectively (Figure 3B and D), whereas Cox-2 inhibition in the HSC-4 cells resulted in a slight increase of E-cadherin expression by less than 1.10-fold with any of the inhibitors (Figure 3C).	('E-cadherin', 'Gene', (94, 104))	('E-cadherin', 'Gene', '999', (94, 104))	('increasing', 'PosReg', (152, 162))	('inhibition', 'Var', (43, 53))	('cell surface expression', 'MPA', (67, 90))	('NS-398', 'Chemical', 'MESH:C080955', (220, 226))	('celecoxib', 'Chemical', 'MESH:D000068579', (209, 218))	('elevated', 'PosReg', (54, 62))	('HSC-4', 'CellLine', 'CVCL:1289', (304, 309))	('Cox-2', 'Gene', '5743', (37, 42))	('E-cadherin', 'Gene', (349, 359))	('Cox-2', 'Gene', (37, 42))	('Cox-2', 'Gene', (280, 285))	('E-cadherin', 'Gene', '999', (349, 359))	('SC-791', 'Chemical', 'MESH:C553330', (232, 238))	('Cox-2', 'Gene', '5743', (280, 285))	('HSC-2', 'CellLine', 'CVCL:1287', (139, 144))	('DMSO', 'Chemical', 'MESH:D004121', (117, 121))
472868	24887090	Our in vitro results revealed that, in HNSCC cells, the selective Cox-2 inhibitors led to the suppression of the EMT by restoring the expression of E-cadherin through the downregulation of its transcriptional repressors.	('E-cadherin', 'Gene', (148, 158))	('Cox-2', 'Gene', '5743', (66, 71))	('expression', 'MPA', (134, 144))	('Cox-2', 'Gene', (66, 71))	('downregulation', 'NegReg', (171, 185))	('transcriptional repressors', 'MPA', (193, 219))	('E-cadherin', 'Gene', '999', (148, 158))	('HNSCC', 'Phenotype', 'HP:0012288', (39, 44))	('restoring', 'PosReg', (120, 129))	('EMT', 'CPA', (113, 116))	('inhibitors', 'Var', (72, 82))
472875	24887090	Aside from the use of Cox-2 inhibitors, the Cox-2-dependent regulation of E-cadherin expression in HNSCC cells was demonstrated in a study using KB cells transfected with Cox-2 cDNA and gene silencing with Cox-2 siRNA, although the specific signaling pathway between Cox-2 and E-cadherin was not referred to.	('Cox-2', 'Gene', (206, 211))	('Cox-2', 'Gene', '5743', (206, 211))	('E-cadherin', 'Gene', (277, 287))	('E-cadherin', 'Gene', (74, 84))	('E-cadherin', 'Gene', '999', (277, 287))	('Cox-2', 'Gene', (267, 272))	('E-cadherin', 'Gene', '999', (74, 84))	('HNSCC', 'Phenotype', 'HP:0012288', (99, 104))	('Cox-2', 'Gene', '5743', (267, 272))	('Cox-2', 'Gene', '5743', (22, 27))	('Cox-2', 'Gene', (44, 49))	('Cox-2', 'Gene', (22, 27))	('Cox-2', 'Gene', '5743', (171, 176))	('Cox-2', 'Gene', '5743', (44, 49))	('Cox-2', 'Gene', (171, 176))	('gene silencing', 'Var', (186, 200))
472878	24887090	Regarding the direct mechanisms underlying the downregulation of E-cadherin, it has been suggested that transcriptional repression and promoter hypermethylation are primarily responsible in sporadic carcinoma, whereas other mechanisms such as genomic deletion and loss of heterozygosity associated with germline mutation are observed in hereditary carcinoma.	('hereditary carcinoma', 'Disease', (337, 357))	('sporadic carcinoma', 'Disease', (190, 208))	('sporadic carcinoma', 'Disease', 'MESH:C538614', (190, 208))	('genomic deletion', 'Var', (243, 259))	('carcinoma', 'Phenotype', 'HP:0030731', (348, 357))	('loss of heterozygosity', 'Var', (264, 286))	('promoter', 'MPA', (135, 143))	('hereditary carcinoma', 'Disease', 'MESH:C565972', (337, 357))	('responsible', 'Reg', (175, 186))	('transcriptional repression', 'MPA', (104, 130))	('E-cadherin', 'Gene', (65, 75))	('E-cadherin', 'Gene', '999', (65, 75))	('carcinoma', 'Phenotype', 'HP:0030731', (199, 208))
472879	24887090	According to the study that examined CpG island methylation around the promoter region of CDH-1 in HNSCC cell lines by methylation-specific PCR, the methylation was partially found in the HSC-2 cells, but not in the HSC-4 cells, which may also accounts for the low base-line expression of E-cadherin in the HSC-2 cells.	('E-cadherin', 'Gene', (289, 299))	('E-cadherin', 'Gene', '999', (289, 299))	('HSC-2', 'CellLine', 'CVCL:1287', (188, 193))	('CDH-1', 'Gene', '999', (90, 95))	('CDH-1', 'Gene', (90, 95))	('HSC-2', 'CellLine', 'CVCL:1287', (307, 312))	('HSC-4', 'CellLine', 'CVCL:1289', (216, 221))	('HNSCC', 'Phenotype', 'HP:0012288', (99, 104))	('methylation', 'Var', (48, 59))
472885	24887090	In HNSCC cells, inhibition of Akt activity was shown to decrease NF-kappaB signaling, thereby downregulate the expression of Snail and Twist, but not SIP-1, to induce the mesenchymal-to-epithelial reverting transition.	('HNSCC', 'Phenotype', 'HP:0012288', (3, 8))	('downregulate', 'NegReg', (94, 106))	('mesenchymal-to-epithelial reverting transition', 'CPA', (171, 217))	('Akt', 'Gene', '207', (30, 33))	('Twist', 'Gene', (135, 140))	('SIP-1', 'Gene', '9839', (150, 155))	('expression', 'MPA', (111, 121))	('Akt', 'Gene', (30, 33))	('SIP-1', 'Gene', (150, 155))	('Snail', 'Gene', '6615', (125, 130))	('Snail', 'Gene', (125, 130))	('decrease', 'NegReg', (56, 64))	('induce', 'PosReg', (160, 166))	('NF-kappaB signaling', 'MPA', (65, 84))	('inhibition', 'Var', (16, 26))
472887	24887090	In addition to the suppression of the EMT, some other anti-cancer effects of Cox-2 inhibitors in HNSCC have been reported, which include the inhibition of VEGF-A expression by celecoxib, the suppression of invasiveness by NS-398 and celecoxib, the inhibition of proliferation by celecoxib, NS-398, nimesulide, and meloxicam, and the induction of apoptosis by celecoxib.	('meloxicam', 'Chemical', 'MESH:D000077239', (314, 323))	('proliferation', 'CPA', (262, 275))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('suppression', 'NegReg', (191, 202))	('Cox-2', 'Gene', '5743', (77, 82))	('inhibition', 'NegReg', (141, 151))	('HNSCC', 'Phenotype', 'HP:0012288', (97, 102))	('apoptosis', 'CPA', (346, 355))	('celecoxib', 'Chemical', 'MESH:D000068579', (233, 242))	('VEGF-A', 'Gene', '7422', (155, 161))	('celecoxib', 'Chemical', 'MESH:D000068579', (176, 185))	('celecoxib', 'Chemical', 'MESH:D000068579', (359, 368))	('NS-398', 'Chemical', 'MESH:C080955', (290, 296))	('invasiveness', 'CPA', (206, 218))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('nimesulide', 'Chemical', 'MESH:C012655', (298, 308))	('celecoxib', 'Chemical', 'MESH:D000068579', (279, 288))	('Cox-2', 'Gene', (77, 82))	('inhibition', 'NegReg', (248, 258))	('NS-398', 'Chemical', 'MESH:C080955', (222, 228))	('expression', 'MPA', (162, 172))	('VEGF-A', 'Gene', (155, 161))	('cancer', 'Disease', (59, 65))	('inhibitors', 'Var', (83, 93))
472889	24887090	Considering the multifaceted function of Cox-2 itself, a variety of mechanisms are thought to be involved in the anti-cancer effects of selective Cox-2 inhibitors, and these mechanisms are presumed to exert their effects cooperatively.	('cancer', 'Disease', (118, 124))	('Cox-2', 'Gene', '5743', (41, 46))	('inhibitors', 'Var', (152, 162))	('Cox-2', 'Gene', (146, 151))	('Cox-2', 'Gene', (41, 46))	('Cox-2', 'Gene', '5743', (146, 151))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('cancer', 'Disease', 'MESH:D009369', (118, 124))
472912	24887090	In addition, the appropriately selective administration of selective Cox-2 inhibitors may lead to an anti-metastatic effect as suppression of the EMT by restoring E-cadherin expression through the downregulation of its transcriptional repressors, cooperatively with various other mechanisms.	('Cox-2', 'Gene', (69, 74))	('downregulation', 'NegReg', (197, 211))	('Cox-2', 'Gene', '5743', (69, 74))	('inhibitors', 'Var', (75, 85))	('expression', 'MPA', (174, 184))	('anti-metastatic effect', 'CPA', (101, 123))	('EMT', 'CPA', (146, 149))	('E-cadherin', 'Gene', '999', (163, 173))	('restoring', 'PosReg', (153, 162))	('E-cadherin', 'Gene', (163, 173))	('suppression', 'NegReg', (127, 138))
472925	32597160	The abnormal expression of specific miRNAs can lead to cancer progression (Momen-Heravi and Bala, 2018).	('abnormal', 'Var', (4, 12))	('expression', 'MPA', (13, 23))	('lead to', 'Reg', (47, 54))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('cancer', 'Disease', (55, 61))
472950	32597160	Recent studies have found evidences of strong correlation between increased levels of HIF-1 and tumor metastasis, angiogenesis, and tumor resistance therapy (Masoud and Li, 2015).	('HIF-1', 'Gene', '3091', (86, 91))	('increased', 'PosReg', (66, 75))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('HIF-1', 'Gene', (86, 91))	('tumor metastasis', 'Disease', 'MESH:D009362', (96, 112))	('tumor metastasis', 'Disease', (96, 112))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumor', 'Disease', (96, 101))	('levels', 'Var', (76, 82))	('tumor', 'Disease', (132, 137))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('angiogenesis', 'CPA', (114, 126))
472972	32597160	Increasing evidence has indicated that the dysregulation of miRNAs play a significant role in the pathogenesis of variety of cancer types, including OSCC.	('OSCC', 'Disease', (149, 153))	('dysregulation', 'Var', (43, 56))	('miRNAs', 'Protein', (60, 66))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))
473040	32382338	The results of the present study were also consistent with a previous study on oral squamous cell carcinoma demonstrating that high ID-1 expression levels were associated with poor prognosis.	('high', 'Var', (127, 131))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (79, 107))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (84, 107))	('ID-1', 'Gene', (132, 136))	('oral squamous cell carcinoma', 'Disease', (79, 107))	('associated', 'Reg', (160, 170))	('expression levels', 'MPA', (137, 154))
473051	32382338	Univariate survival analysis indicated that the median DSS times of patients in the low ID-1 expression level group were significantly longer compared with those with high ID-1 expression levels.	('DSS times', 'MPA', (55, 64))	('low', 'Var', (84, 87))	('DSS', 'Chemical', '-', (55, 58))	('patients', 'Species', '9606', (68, 76))	('expression', 'MPA', (93, 103))	('longer', 'PosReg', (135, 141))
473053	32382338	In non-small cell lung cancer, high ID-1 expression levels were associated with a shorter survival time, and genetic knockdown of ID-1 led to a significant increase in survival time in a nude mice with glioblastoma.	('ID-1', 'Gene', (130, 134))	('glioblastoma', 'Disease', 'MESH:D005909', (202, 214))	('non-small cell lung cancer', 'Disease', (3, 29))	('increase', 'PosReg', (156, 164))	('glioblastoma', 'Disease', (202, 214))	('lung cancer', 'Phenotype', 'HP:0100526', (18, 29))	('glioblastoma', 'Phenotype', 'HP:0012174', (202, 214))	('high', 'Var', (31, 35))	('shorter', 'NegReg', (82, 89))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (3, 29))	('survival time', 'CPA', (90, 103))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('ID-1', 'Gene', (36, 40))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (7, 29))	('expression levels', 'MPA', (41, 58))	('nude mice', 'Species', '10090', (187, 196))	('survival time', 'CPA', (168, 181))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (3, 29))	('knockdown', 'Var', (117, 126))
473059	32382338	Through targeting bone morphogenetic protein receptor type 1A and blocking BMP/Smad/ID-1 signaling, miRNA-885-3p was demonstrated to inhibit growth of HT-29 colon cancer cell xenografts in nude mice via angiogenetic disruption.	('growth', 'CPA', (141, 147))	('colon cancer', 'Phenotype', 'HP:0003003', (157, 169))	('HT-29 colon cancer', 'Disease', (151, 169))	('bone morphogenetic protein receptor type 1A and blocking BMP', 'Gene', '657', (18, 78))	('inhibit', 'NegReg', (133, 140))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('nude mice', 'Species', '10090', (189, 198))	('miRNA-885-3p', 'Var', (100, 112))	('HT-29 colon cancer', 'Disease', 'MESH:D015179', (151, 169))
473108	32094374	When the association of the expression levels of DIP-centered modules (i.e., DIPs and their interacting partners) with prognostic outcome was investigated through survival analyses, we observed that a total of 90 DIP-centered modules showed high impact on overall patient survival (p < 0.05 and HR > 1.3) in several tumors (Supplementary Table S4) as exemplified in Fig.	('impact', 'Reg', (246, 252))	('DIPs', 'Chemical', '-', (77, 81))	('tumor', 'Phenotype', 'HP:0002664', (316, 321))	('DIP', 'Chemical', '-', (77, 80))	('tumors', 'Phenotype', 'HP:0002664', (316, 322))	('DIP', 'Chemical', '-', (213, 216))	('tumors', 'Disease', (316, 322))	('tumors', 'Disease', 'MESH:D009369', (316, 322))	('DIP-centered', 'Var', (213, 225))	('patient', 'Species', '9606', (264, 271))	('DIP', 'Chemical', '-', (49, 52))
473116	32094374	Furthermore, a large number of dPPIs highlighted pathways and processes that enable the acquisition of or maintain hallmarks of cancer including sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, activating invasion and metastasis, deregulating cellular energetics, avoiding immune destruction, genome instability and mutation (Supplementary Fig.	('mutation', 'Var', (410, 418))	('activating', 'PosReg', (288, 298))	('sustaining proliferative signaling', 'MPA', (145, 179))	('hallmarks of cancer', 'Disease', (115, 134))	('cellular energetics', 'CPA', (337, 356))	('angiogenesis', 'CPA', (274, 286))	('inducing', 'PosReg', (265, 273))	('cell death', 'CPA', (219, 229))	('dPPIs', 'Chemical', '-', (31, 36))	('genome instability', 'CPA', (387, 405))	('enabling', 'PosReg', (231, 239))	('immune destruction', 'CPA', (367, 385))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('invasion', 'CPA', (299, 307))	('metastasis', 'CPA', (312, 322))	('hallmarks of cancer', 'Disease', 'MESH:D009369', (115, 134))	('replicative immortality', 'CPA', (240, 263))	('deregulating', 'PosReg', (324, 336))
473117	32094374	By using the published driver gene information, we investigated whether DIPs had the feature of driver genes and found that 13 DIPs were among 43 cancer predisposition genes, 6 DIPs were among 13 driver genes affected by amplification or homozygous deletion, and 70 DIPs were among 125 driver genes affected by subtle mutations (Supplementary Table S5).	('cancer', 'Disease', (146, 152))	('DIPs', 'Chemical', '-', (127, 131))	('DIPs', 'Chemical', '-', (177, 181))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('amplification', 'Var', (221, 234))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('DIPs', 'Chemical', '-', (72, 76))	('DIPs', 'Chemical', '-', (266, 270))
473138	32094374	These observations paved the way for the hypothesis that DIPs transmit pathophysiological cues along molecular networks to promote tumorigenesis, tumor progression, invasion, and/or metastasis.	('DIPs', 'Chemical', '-', (57, 61))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('DIPs', 'Var', (57, 61))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('promote', 'PosReg', (123, 130))	('tumor', 'Disease', (146, 151))	('invasion', 'CPA', (165, 173))	('tumor', 'Disease', (131, 136))	('metastasis', 'CPA', (182, 192))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
473154	32094374	The estimation of the probability that any state is encountered in tumor condition was represented by q value as follows: In the current formulation, the PPIs ensuring the following criteria were considered in further analyses; (1) having q-value lower than 0.10 (significantly repressed in tumor phenotype) or higher than 0.90 (significantly activated in tumor phenotype), (2) having a normalized observation frequency either in normal or tumor phenotype higher than 20%.	('q-value', 'Var', (239, 246))	('tumor', 'Disease', 'MESH:D009369', (440, 445))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Disease', (440, 445))	('tumor', 'Phenotype', 'HP:0002664', (440, 445))	('tumor', 'Disease', 'MESH:D009369', (291, 296))	('activated', 'PosReg', (343, 352))	('lower', 'NegReg', (247, 252))	('tumor', 'Disease', 'MESH:D009369', (356, 361))	('higher than 0.90', 'Var', (311, 327))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (291, 296))	('tumor', 'Disease', (67, 72))	('tumor', 'Disease', (291, 296))	('tumor', 'Phenotype', 'HP:0002664', (356, 361))	('tumor', 'Disease', (356, 361))
473166	27476776	MCM4 and MCM7 may serve as more sensitive proliferative markers for the evaluation of esophageal lesions.	('esophageal lesions', 'Disease', (86, 104))	('MCM7', 'Gene', (9, 13))	('MCM4', 'Var', (0, 4))	('esophageal lesions', 'Disease', 'MESH:D004935', (86, 104))
473168	27476776	Aberrant expressions of MCM proteins have been reported to be promising prognostic markers in a number of malignancies.	('malignancies', 'Disease', 'MESH:D009369', (106, 118))	('Aberrant', 'Var', (0, 8))	('malignancies', 'Disease', (106, 118))	('MCM proteins', 'Protein', (24, 36))	('expressions', 'MPA', (9, 20))
473173	27476776	In addition, we previously found aberrant expression and amplification of cyclin E significantly increased in dysplastic esophageal lesions.	('dysplastic esophageal lesions', 'Disease', (110, 139))	('increased', 'PosReg', (97, 106))	('expression', 'MPA', (42, 52))	('dysplastic esophageal lesions', 'Disease', 'MESH:D004935', (110, 139))	('cyclin', 'Protein', (74, 80))	('aberrant', 'Var', (33, 41))	('amplification', 'MPA', (57, 70))
473186	27476776	In breast cancer, high level of MCM4 expression was associated with disease progression, ER-negative or high-grade breast tumors, and shorter survival.	('ER-negative', 'Disease', (89, 100))	('breast tumors', 'Disease', 'MESH:D001943', (115, 128))	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('breast tumors', 'Disease', (115, 128))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('breast cancer', 'Disease', (3, 16))	('associated', 'Reg', (52, 62))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('disease progression', 'CPA', (68, 87))	('MCM4 expression', 'Var', (32, 47))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('breast tumors', 'Phenotype', 'HP:0100013', (115, 128))	('tumors', 'Phenotype', 'HP:0002664', (122, 128))	('shorter', 'NegReg', (134, 141))
473187	27476776	In the gastrointestinal tract, MCM7 expression was found to be a poor prognostic factor for gastric and colorectal cancer.	('colorectal cancer', 'Disease', 'MESH:D015179', (104, 121))	('colorectal cancer', 'Disease', (104, 121))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('MCM7 expression', 'Var', (31, 46))	('colorectal cancer', 'Phenotype', 'HP:0003003', (104, 121))	('gastric', 'Disease', (92, 99))
473188	27476776	Studies also showed MCM7 expression had poorer prognosis in lung adenocarcinoma.	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (60, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('MCM7 expression', 'Var', (20, 35))	('lung adenocarcinoma', 'Disease', (60, 79))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (60, 79))
473193	25264519	Performance of standard procedures in detection of EGFR mutations in daily practice in advanced NSCLC patients selected according to the ESMO guideline: a large Caucasian cohort study ESMO consensus recommends EGFR mutation testing in never/former light smokers (<15 pack-years) or patients with non-squamous NSCLC.	('mutation', 'Var', (215, 223))	('NSCLC', 'Disease', (309, 314))	('mutations', 'Var', (56, 65))	('NSCLC', 'Disease', (96, 101))	('EGFR', 'Gene', (51, 55))	('EGFR', 'Gene', (210, 214))	('NSCLC', 'Disease', 'MESH:D002289', (309, 314))	('patients', 'Species', '9606', (102, 110))	('NSCLC', 'Disease', 'MESH:D002289', (96, 101))	('patients', 'Species', '9606', (282, 290))	('EGFR', 'Gene', '1956', (51, 55))	('EGFR', 'Gene', '1956', (210, 214))
473194	25264519	The aim of this work was to determine the frequency and clinical predictors of EGFR mutations, and the role of specimen sampling tests, in Caucasian standard practice setting.	('mutations', 'Var', (84, 93))	('EGFR', 'Gene', '1956', (79, 83))	('EGFR', 'Gene', (79, 83))
473197	25264519	An EGFR activating mutation was found in 32 patients (11%), twelve exon 19 deletions, two exon 18 and eighteen exon 21 point mutations.	('EGFR', 'Gene', '1956', (3, 7))	('deletions', 'Var', (75, 84))	('mutation', 'Var', (19, 27))	('EGFR', 'Gene', (3, 7))	('patients', 'Species', '9606', (44, 52))	('activating', 'PosReg', (8, 18))
473199	25264519	The Therascreen acted as a sensitive test in all types of samples: 7 activating mutations were found in samples rated to have <5% of tumour cells, and there were only 4 test failures in the whole series.	('tumour', 'Phenotype', 'HP:0002664', (133, 139))	('mutations', 'Var', (80, 89))	('tumour cells', 'Disease', (133, 145))	('activating', 'PosReg', (69, 79))	('tumour cells', 'Disease', 'MESH:C538614', (133, 145))
473200	25264519	In this Caucasian standard practice NSCLC cohort, tested according to the ESMO consensus, activating EGFR mutation occurred in 11% of the patients.	('EGFR', 'Gene', '1956', (101, 105))	('mutation', 'Var', (106, 114))	('EGFR', 'Gene', (101, 105))	('activating', 'PosReg', (90, 100))	('NSCLC', 'Disease', (36, 41))	('NSCLC', 'Disease', 'MESH:D002289', (36, 41))	('patients', 'Species', '9606', (138, 146))
473206	25264519	A few years later, somatic mutations in the EGFR gene were discovered in these highly responsive tumours.	('mutations', 'Var', (27, 36))	('tumours', 'Disease', (97, 104))	('EGFR', 'Gene', '1956', (44, 48))	('EGFR', 'Gene', (44, 48))	('tumours', 'Phenotype', 'HP:0002664', (97, 104))	('tumour', 'Phenotype', 'HP:0002664', (97, 103))	('tumours', 'Disease', 'MESH:D009369', (97, 104))
473209	25264519	Recent randomised trials demonstrated that the presence of an EGFR activating mutation was the best predictive factor for response and progression-free survival (PFS) to EGFR TKIs when compared to platinum doublet chemotherapy in the first-line therapy of advanced NSCLC,.	('EGFR', 'Gene', '1956', (62, 66))	('mutation', 'Var', (78, 86))	('EGFR', 'Gene', '1956', (170, 174))	('NSCLC', 'Disease', (265, 270))	('platinum', 'Chemical', 'MESH:D010984', (197, 205))	('EGFR', 'Gene', (62, 66))	('NSCLC', 'Disease', 'MESH:D002289', (265, 270))	('EGFR', 'Gene', (170, 174))	('activating', 'PosReg', (67, 77))
473210	25264519	Given this strong benefit of EGFR-TKIs in patients with a tumour with an EGFR activating mutation (EGFR mut + tumour), molecular profiling became necessary in the assessment of stage IV NSCLC.	('EGFR', 'Gene', (99, 103))	('EGFR', 'Gene', '1956', (73, 77))	('tumour', 'Disease', 'MESH:D009369', (110, 116))	('tumour', 'Phenotype', 'HP:0002664', (58, 64))	('mutation', 'Var', (89, 97))	('EGFR', 'Gene', (73, 77))	('NSCLC', 'Disease', (186, 191))	('tumour', 'Disease', 'MESH:D009369', (58, 64))	('tumour', 'Phenotype', 'HP:0002664', (110, 116))	('EGFR', 'Gene', '1956', (29, 33))	('tumour', 'Disease', (58, 64))	('EGFR', 'Gene', (29, 33))	('NSCLC', 'Disease', 'MESH:D002289', (186, 191))	('EGFR', 'Gene', '1956', (99, 103))	('patients', 'Species', '9606', (42, 50))	('tumour', 'Disease', (110, 116))
473211	25264519	EGFR mutations are known to be associated with clinical characteristics such as never-smoking status, female gender, adenocarcinoma histology and South-East Asian ethnicity.	('EGFR', 'Gene', (0, 4))	('adenocarcinoma', 'Disease', (117, 131))	('mutations', 'Var', (5, 14))	('associated', 'Reg', (31, 41))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('adenocarcinoma', 'Disease', 'MESH:D000230', (117, 131))	('EGFR', 'Gene', '1956', (0, 4))
473213	25264519	The EGFR mutation occurrence is much lower in Caucasian populations.	('EGFR', 'Gene', (4, 8))	('mutation', 'Var', (9, 17))	('EGFR', 'Gene', '1956', (4, 8))
473215	25264519	Based on the South-Asian experience and the occurrence of the different NSCLC histologies in Europe, a European guideline (ESMO consensus) recommends EGFR mutation testing in never-/former light (<15 pack-years) smokers or patients with non-squamous NSCLC.	('NSCLC', 'Disease', 'MESH:D002289', (250, 255))	('EGFR', 'Gene', (150, 154))	('NSCLC', 'Disease', (72, 77))	('EGFR', 'Gene', '1956', (150, 154))	('NSCLC', 'Disease', 'MESH:D002289', (72, 77))	('mutation', 'Var', (155, 163))	('patients', 'Species', '9606', (223, 231))	('NSCLC', 'Disease', (250, 255))
473220	25264519	Study aims were (1) the frequency of EGFR mutations (exon 18-21) in a large Caucasian cohort; (2) clinical and pathological predictors; (3) the sensitivity of the Therascreen kit; and (4) the performance of cytology versus biopsy samples for mutation analyses.	('EGFR', 'Gene', '1956', (37, 41))	('EGFR', 'Gene', (37, 41))	('mutations', 'Var', (42, 51))
473221	25264519	All consecutive EGFR mutation analysis reports in the period from September 2010 until December 2011 included were retrieved from the molecular genetics database.	('EGFR', 'Gene', '1956', (16, 20))	('EGFR', 'Gene', (16, 20))	('mutation', 'Var', (21, 29))
473222	25264519	During this period, our local policy was to order EGFR mutation testing in all patients diagnosed with advanced NSCLC, either of adenocarcinomas or not-otherwise specified (NOS) histology, irrespective of smoking history, or in those rare patients with squamous cell carcinoma with a negative or light (<15 pack years) smoking history.	('adenocarcinomas', 'Disease', (129, 144))	('carcinomas', 'Phenotype', 'HP:0030731', (134, 144))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (253, 276))	('patients', 'Species', '9606', (239, 247))	('EGFR', 'Gene', '1956', (50, 54))	('carcinoma', 'Phenotype', 'HP:0030731', (267, 276))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('testing', 'Reg', (64, 71))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (253, 276))	('patients', 'Species', '9606', (79, 87))	('adenocarcinomas', 'Disease', 'MESH:D000230', (129, 144))	('NSCLC', 'Disease', (112, 117))	('EGFR', 'Gene', (50, 54))	('mutation', 'Var', (55, 63))	('NSCLC', 'Disease', 'MESH:D002289', (112, 117))	('squamous cell carcinoma', 'Disease', (253, 276))
473234	25264519	For EGFR mutation analysis, one H&E slide followed by 10 serial unstained sections (4-muM thick) and a final H&E were prepared from the paraffin block and both H&E sections were evaluated for the presence and amount of tumour cells by an experienced pathologist.	('mutation', 'Var', (9, 17))	('paraffin', 'Chemical', 'MESH:D010232', (136, 144))	('tumour', 'Phenotype', 'HP:0002664', (219, 225))	('EGFR', 'Gene', '1956', (4, 8))	('EGFR', 'Gene', (4, 8))	('tumour cells', 'Disease', (219, 231))	('tumour cells', 'Disease', 'MESH:C538614', (219, 231))
473237	25264519	The Therascreen assay is a sequence of two techniques, ARMS and Scorpion, to detect mutations in real-time PCRs with a reported detection limit of 1% mutant alleles in DNA from tumour tissue.	('tumour', 'Disease', 'MESH:D009369', (177, 183))	('tumour', 'Disease', (177, 183))	('mutations', 'Var', (84, 93))	('tumour', 'Phenotype', 'HP:0002664', (177, 183))	('mutant', 'Var', (150, 156))
473238	25264519	This kit allows the detection of the nineteen deletions between 2235 and 2258 in exon 19, three insertions in exon 20 and the point mutations G719A/S/C (exon 18), S768I (exon 20), T790M (exon 20), L858R (exon 21) and L861Q (exon 21).	('L858R', 'Mutation', 'rs121434568', (197, 202))	('L861Q', 'Var', (217, 222))	('S768I', 'Mutation', 'rs121913465', (163, 168))	('G719A/S/C', 'Mutation', 'rs121913428', (142, 151))	('T790M', 'Var', (180, 185))	('L861Q', 'Mutation', 'rs121913444', (217, 222))	('T790M', 'Mutation', 'rs121434569', (180, 185))	('G719A/S/C', 'Var', (142, 151))	('S768I', 'Var', (163, 168))	('L858R', 'Var', (197, 202))
473255	25264519	Activating EGFR mutations (EGFR mut+) were found in 32 patients (11%, Table 1): twelve patients had exon 19 deletions (38%), two patients had G719A/S/C point mutations in exon 18 (6%) and eighteen patients had exon 21 point mutations (56%), of which fifteen L858R mutations and three L861Q mutations.	('EGFR', 'Gene', '1956', (27, 31))	('Activating', 'PosReg', (0, 10))	('EGFR', 'Gene', (27, 31))	('L858R mutations', 'Var', (258, 273))	('patients', 'Species', '9606', (197, 205))	('L861Q mutations', 'Var', (284, 299))	('EGFR', 'Gene', '1956', (11, 15))	('L861Q', 'Mutation', 'rs121913444', (284, 289))	('EGFR', 'Gene', (11, 15))	('patients', 'Species', '9606', (129, 137))	('mutations', 'Var', (16, 25))	('G719A/S/C', 'Mutation', 'rs121913428', (142, 151))	('L858R', 'Mutation', 'rs121434568', (258, 263))	('deletions', 'Var', (108, 117))	('patients', 'Species', '9606', (55, 63))	('exon 19 deletions', 'Var', (100, 117))	('G719A/S/C', 'Var', (142, 151))	('patients', 'Species', '9606', (87, 95))
473269	25264519	In the time interval September 2010 - December 2011, we selected advanced NSCLC patients for EGFR mutation screening in exon 18-21 by a PCR based test according to the ESMO criteria.	('EGFR', 'Gene', '1956', (93, 97))	('mutation', 'Var', (98, 106))	('patients', 'Species', '9606', (80, 88))	('EGFR', 'Gene', (93, 97))	('NSCLC', 'Disease', (74, 79))	('NSCLC', 'Disease', 'MESH:D002289', (74, 79))
473271	25264519	Not surprisingly, activating mutations were more frequently reported in women, never smokers, and pure adenocarcinoma.	('activating mutations', 'Var', (18, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('adenocarcinoma', 'Disease', (103, 117))	('adenocarcinoma', 'Disease', 'MESH:D000230', (103, 117))	('women', 'Species', '9606', (72, 77))
473272	25264519	Based on this series and review of other European findings, we believe that 9 to 12% may well be the real frequency of activating EGFR mutations in advanced NSCLC in Europe (Tables 2 and 3).	('activating', 'PosReg', (119, 129))	('mutations', 'Var', (135, 144))	('NSCLC', 'Disease', (157, 162))	('EGFR', 'Gene', '1956', (130, 134))	('EGFR', 'Gene', (130, 134))	('NSCLC', 'Disease', 'MESH:D002289', (157, 162))
473273	25264519	It has been postulated that mutations in the tyrosine kinase domain of EGFR are early events in lung carcinogenesis, already present in 50% of precancerous conditions such as atypical adenomatous hyperplasia, as well as in normal lung tissue surrounding a tumour.	('tumour', 'Disease', 'MESH:D009369', (256, 262))	('lung carcinogenesis', 'Disease', (96, 115))	('tumour', 'Disease', (256, 262))	('atypical adenomatous hyperplasia', 'Disease', (175, 207))	('lung carcinogenesis', 'Disease', 'MESH:D063646', (96, 115))	('atypical adenomatous hyperplasia', 'Disease', 'MESH:D011125', (175, 207))	('mutations in', 'Var', (28, 40))	('EGFR', 'Gene', '1956', (71, 75))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('tumour', 'Phenotype', 'HP:0002664', (256, 262))	('EGFR', 'Gene', (71, 75))
473280	25264519	In this group consisting of 86% never- or former smokers, the EGFR mutation rate was 14%.	('EGFR', 'Gene', '1956', (62, 66))	('EGFR', 'Gene', (62, 66))	('mutation', 'Var', (67, 75))
473281	25264519	We found no EGFR mutations in our never- or light-smokers with squamous cell carcinoma.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (63, 86))	('squamous cell carcinoma', 'Disease', (63, 86))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (63, 86))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('EGFR', 'Gene', '1956', (12, 16))	('EGFR', 'Gene', (12, 16))	('mutations', 'Var', (17, 26))
473282	25264519	All European series found no mutations in squamous cell carcinoma, except for the Norwegian study, where two activating mutations were reported in surgical resection specimens.	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (42, 65))	('squamous cell carcinoma', 'Disease', (42, 65))	('mutations', 'Var', (29, 38))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (42, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (56, 65))
473286	25264519	We investigated the tumour cell percentage on cytology and biopsy samples, and its effect on PCR-based detection of EGFR mutations.	('mutations', 'Var', (121, 130))	('tumour', 'Disease', 'MESH:D009369', (20, 26))	('tumour', 'Disease', (20, 26))	('EGFR', 'Gene', '1956', (116, 120))	('EGFR', 'Gene', (116, 120))	('tumour', 'Phenotype', 'HP:0002664', (20, 26))
473288	25264519	A brief report from the Netherlands in 2010 suggested that specimens from FNA of the left adrenal gland were suitable for EGFR mutation analysis in 77% of the cases.	('mutation', 'Var', (127, 135))	('EGFR', 'Gene', '1956', (122, 126))	('EGFR', 'Gene', (122, 126))
473289	25264519	In a comparative study of biopsy and fine needle aspiration samples, the latter yielded lower DNA amounts but a comparable success rate in EGFR mutation analysis.	('EGFR', 'Gene', '1956', (139, 143))	('mutation analysis', 'Var', (144, 161))	('EGFR', 'Gene', (139, 143))	('lower', 'NegReg', (88, 93))	('DNA amounts', 'MPA', (94, 105))	('aspiration', 'Phenotype', 'HP:0002835', (49, 59))
473290	25264519	In a recent large series, EGFR mutation analysis was possible on cell block samples of 107/119 (90%) patients in whom it was requested.	('EGFR', 'Gene', '1956', (26, 30))	('EGFR', 'Gene', (26, 30))	('patients', 'Species', '9606', (101, 109))	('mutation', 'Var', (31, 39))
473291	25264519	ESMO guidelines advocate an EGFR TKI as the preferred first-line treatment in NSCLC patients whose tumour harbours an activating EGFR mutation.	('EGFR', 'Gene', '1956', (28, 32))	('tumour', 'Disease', 'MESH:D009369', (99, 105))	('patients', 'Species', '9606', (84, 92))	('tumour', 'Disease', (99, 105))	('mutation', 'Var', (134, 142))	('EGFR', 'Gene', (28, 32))	('EGFR', 'Gene', (129, 133))	('EGFR', 'Gene', '1956', (129, 133))	('NSCLC', 'Disease', (78, 83))	('activating', 'PosReg', (118, 128))	('tumour', 'Phenotype', 'HP:0002664', (99, 105))	('NSCLC', 'Disease', 'MESH:D002289', (78, 83))
473292	25264519	A remaining practical controversy is how waiting time for EGFR mutation analysis should be balanced with delay of start of treatment with platinum doublet chemotherapy, especially as the overall survival with both strategies has hitherto not been shown to be significantly different.	('EGFR', 'Gene', '1956', (58, 62))	('platinum', 'Chemical', 'MESH:D010984', (138, 146))	('EGFR', 'Gene', (58, 62))	('mutation analysis', 'Var', (63, 80))	('analysis', 'Var', (72, 80))
473293	25264519	Clinical features are related to but not sufficiently reliable to estimate the presence of EGFR mutations.	('EGFR', 'Gene', '1956', (91, 95))	('EGFR', 'Gene', (91, 95))	('mutations', 'Var', (96, 105))
473294	25264519	Consequently, a rapid test with high negative predictive value (NPV) for EGFR mutations is welcome.	('EGFR', 'Gene', '1956', (73, 77))	('EGFR', 'Gene', (73, 77))	('mutations', 'Var', (78, 87))
473296	25264519	Indeed, in series where this relationship is reported (Table 4), the NPV varies between 96 and 100%, although the NPV may be overestimated, as all series have a rather low prevalence of EGFR mutation.	('EGFR', 'Gene', (186, 190))	('mutation', 'Var', (191, 199))	('EGFR', 'Gene', '1956', (186, 190))
473298	25264519	If an EGFR mutation is eventually detected, the EGFR-TKI can be given thereafter.	('EGFR', 'Gene', '1956', (48, 52))	('EGFR', 'Gene', (6, 10))	('EGFR', 'Gene', (48, 52))	('mutation', 'Var', (11, 19))	('EGFR', 'Gene', '1956', (6, 10))
473300	25264519	Both types are known to harbour more frequently activating EGFR mutations.	('EGFR', 'Gene', '1956', (59, 63))	('activating', 'PosReg', (48, 58))	('mutations', 'Var', (64, 73))	('EGFR', 'Gene', (59, 63))
473301	25264519	Both biopsies and cell blocks of EBUS-TBNA are suitable samples for EGFR mutation analysis when a sensitive method such as the Therascreen EGFR RGQ PCR mutation kit is used.	('EGFR', 'Gene', '1956', (139, 143))	('EGFR', 'Gene', '1956', (68, 72))	('EGFR', 'Gene', (139, 143))	('mutation', 'Var', (73, 81))	('EGFR', 'Gene', (68, 72))
473303	31791231	A probabilistic method for leveraging functional annotations to enhance estimation of the temporal order of pathway mutations during carcinogenesis Cancer arises through accumulation of somatically acquired genetic mutations.	('Cancer', 'Phenotype', 'HP:0002664', (148, 154))	('mutations', 'Var', (116, 125))	('Cancer', 'Disease', 'MESH:D009369', (148, 154))	('Cancer', 'Disease', (148, 154))
473307	31791231	Simulation studies and analysis of whole exome sequencing data from The Cancer Genome Atlas (TCGA) demonstrate that PATOPA is able to accurately estimate the temporal order of pathway mutations and provides new biological insights on carcinogenesis of colorectal and lung cancers.	('lung cancer', 'Phenotype', 'HP:0100526', (267, 278))	('cancer', 'Phenotype', 'HP:0002664', (272, 278))	('mutations', 'Var', (184, 193))	('colorectal and lung cancers', 'Disease', 'MESH:D015179', (252, 279))	('lung cancers', 'Phenotype', 'HP:0100526', (267, 279))	('Cancer', 'Phenotype', 'HP:0002664', (72, 78))	('Cancer', 'Disease', (72, 78))	('cancers', 'Phenotype', 'HP:0002664', (272, 279))	('Cancer', 'Disease', 'MESH:D009369', (72, 78))
473310	31791231	For example, colorectal cancer is frequently initiated by mutations that affect the Wnt signaling pathway, and then progress upon subsequent mutations in genes involved in MAPK, PI3K, TGF-beta, and p53 signaling pathways.	('mutations', 'Var', (58, 67))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('mutations', 'Var', (141, 150))	('affect', 'Reg', (73, 79))	('colorectal cancer', 'Disease', (13, 30))	('initiated', 'Reg', (45, 54))	('rectal cancer', 'Phenotype', 'HP:0100743', (17, 30))	('TGF-beta', 'Gene', (184, 192))	('p53', 'Gene', (198, 201))	('p53', 'Gene', '7157', (198, 201))	('colorectal cancer', 'Disease', 'MESH:D015179', (13, 30))	('Wnt signaling pathway', 'Pathway', (84, 105))	('TGF-beta', 'Gene', '7039', (184, 192))	('colorectal cancer', 'Phenotype', 'HP:0003003', (13, 30))
473314	31791231	Different patients may have different driver mutations from the same pathway with a converged phenotype of perturbing the pathway.	('perturbing', 'Reg', (107, 117))	('mutations', 'Var', (45, 54))	('patients', 'Species', '9606', (10, 18))
473316	31791231	However, many non-synonymous mutations are passenger mutations that do not contribute to cancer progression.	('non-synonymous mutations', 'Var', (14, 38))	('cancer', 'Disease', (89, 95))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
473317	31791231	Several bioinformatics tools, such as SIFT, PolyPhen-2, Mutation Assessor, and PROVBEAN, have been developed to predict the potential effect of a mutation on the stability and function of human proteins.	('human', 'Species', '9606', (188, 193))	('stability', 'MPA', (162, 171))	('function', 'MPA', (176, 184))	('effect', 'Reg', (134, 140))	('mutation', 'Var', (146, 154))
473319	31791231	We start from profiles of non-silent somatic mutations along with their associated pathway and functional annotation information for a cohort of patients at various stages of a certain type of cancer.	('patients', 'Species', '9606', (145, 153))	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('cancer', 'Disease', (193, 199))	('non-silent', 'Var', (26, 36))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))
473320	31791231	Notice that all patients who have mutations in pathway B (patients 2, 3 and 5) also have mutations in pathway A.	('pathway A', 'Pathway', (102, 111))	('patients', 'Species', '9606', (16, 24))	('pathway', 'Pathway', (47, 54))	('mutations', 'Var', (89, 98))	('patients', 'Species', '9606', (58, 66))	('mutations', 'Var', (34, 43))
473323	31791231	1, patient 5 has mutations in both pathways A and B.	('patient', 'Species', '9606', (3, 10))	('mutations', 'Var', (17, 26))	('pathways A', 'Pathway', (35, 45))
473328	31791231	To mimic real world situation, we set the true pathway order probabilities based on TCGA rectal cancer mutation data from the p53 signaling (our pathway A, 8 genes) and cell cycle (our pathway B, 89 genes) pathways.	('p53', 'Gene', '7157', (126, 129))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('TCGA', 'Gene', (84, 88))	('rectal cancer', 'Phenotype', 'HP:0100743', (89, 102))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('mutation', 'Var', (103, 111))	('p53', 'Gene', (126, 129))	('cancer', 'Disease', (96, 102))
473329	31791231	Specifically, we applied PATOPA to TCGA rectal cancer data to estimate pk,A and pk,B, the probability that the kth functional mutation was from pathways A and B, respectively.	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('cancer', 'Disease', (47, 53))	('mutation', 'Var', (126, 134))	('rectal cancer', 'Phenotype', 'HP:0100743', (40, 53))	('pk,B', 'Gene', '207', (80, 84))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))
473332	31791231	Under the same simulation setting described in the previous subsection, we increased or decreased the PolyPhen-2 scores of all mutations in the p53 signaling pathway (pathway A).	('PolyPhen-2 scores', 'MPA', (102, 119))	('p53', 'Gene', '7157', (144, 147))	('increased', 'PosReg', (75, 84))	('decreased', 'NegReg', (88, 97))	('mutations', 'Var', (127, 136))	('p53', 'Gene', (144, 147))
473340	31791231	The comparison between the orders PATOPA found from seperate analysis of rectal cancer and colon cancer mutation data and those reported in the literature for colorectal combined tumor is presented in Figure S11 in Additional file 1.	('cancer', 'Disease', (97, 103))	('colon cancer', 'Disease', 'MESH:D015179', (91, 103))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('colon cancer', 'Disease', (91, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('mutation', 'Var', (104, 112))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('colorectal combined tumor', 'Disease', (159, 184))	('rectal cancer', 'Phenotype', 'HP:0100743', (73, 86))	('colorectal combined tumor', 'Disease', 'MESH:D015179', (159, 184))	('colon cancer', 'Phenotype', 'HP:0003003', (91, 103))	('cancer', 'Disease', (80, 86))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
473341	31791231	Most of the inferred temporal orders of pathway mutations were consistent with cancer research literature.	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('mutations', 'Var', (48, 57))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))
473348	31791231	The Wnt signaling pathway had more mutations with high PolyPhen-2 scores than the MAPK and p53 signaling pathways, which supports our model inference that the Wnt signaling pathway was altered prior to the MAPK and p53 signaling pathways.	('altered', 'Reg', (185, 192))	('Wnt signaling pathway', 'Pathway', (4, 25))	('p53', 'Gene', (215, 218))	('p53', 'Gene', '7157', (215, 218))	('p53', 'Gene', (91, 94))	('p53', 'Gene', '7157', (91, 94))	('Wnt signaling pathway', 'Pathway', (159, 180))	('mutations', 'Var', (35, 44))
473352	31791231	The mutations in the MAPK signaling pathway ranked on the top of lung adenocarcinoma.	('MAPK signaling pathway', 'Pathway', (21, 43))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (65, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (65, 84))	('mutations', 'Var', (4, 13))	('lung adenocarcinoma', 'Disease', (65, 84))
473354	31791231	In both lung adenocarcinoma and squamous cell carcinoma, the mutations of the Wnt signaling ranked just below the MAPK signaling.	('Wnt signaling', 'Gene', (78, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (18, 27))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (8, 27))	('carcinoma', 'Phenotype', 'HP:0030731', (46, 55))	('lung adenocarcinoma', 'Disease', (8, 27))	('mutations', 'Var', (61, 70))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (32, 55))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (8, 27))	('squamous cell carcinoma', 'Disease', (32, 55))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (32, 55))
473356	31791231	However, from biological evidences, the most prevalent mutations found in lung cancer are those of p53 signaling pathway.	('prevalent', 'Reg', (45, 54))	('p53', 'Gene', (99, 102))	('lung cancer', 'Disease', (74, 85))	('lung cancer', 'Phenotype', 'HP:0100526', (74, 85))	('mutations', 'Var', (55, 64))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('lung cancer', 'Disease', 'MESH:D008175', (74, 85))	('p53', 'Gene', '7157', (99, 102))
473357	31791231	Interestingly, we notice that mutation of the p53 pathway appeared to be in distinct positions of orders in lung adenocarcinoma and squamous cell carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('lung adenocarcinoma', 'Disease', (108, 127))	('p53', 'Gene', (46, 49))	('mutation', 'Var', (30, 38))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (132, 155))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (108, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('squamous cell carcinoma', 'Disease', (132, 155))	('p53', 'Gene', '7157', (46, 49))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (132, 155))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (108, 127))
473358	31791231	While p53 pathway mutation was downstream of most of the other pathway mutations in lung adenocarcinoma, it was at the upstream of all signaling pathway mutations in lung squamous cell carcinoma (Fig.	('p53', 'Gene', (6, 9))	('p53', 'Gene', '7157', (6, 9))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (84, 103))	('mutations', 'Var', (153, 162))	('lung adenocarcinoma', 'Disease', (84, 103))	('mutations', 'Var', (71, 80))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (84, 103))	('mutation', 'Var', (18, 26))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (166, 194))	('carcinoma', 'Phenotype', 'HP:0030731', (185, 194))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (171, 194))	('lung squamous cell carcinoma', 'Disease', (166, 194))
473359	31791231	Previous findings suggest that p53 pathway mutations are involved in 80% of lung squamous cell carcinoma, while the mutations are involved in 50% of lung adenocarcinoma.	('p53', 'Gene', (31, 34))	('p53', 'Gene', '7157', (31, 34))	('carcinoma', 'Phenotype', 'HP:0030731', (159, 168))	('lung adenocarcinoma', 'Disease', (149, 168))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (149, 168))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('mutations', 'Var', (43, 52))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (76, 104))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (81, 104))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (149, 168))	('lung squamous cell carcinoma', 'Disease', (76, 104))	('involved', 'Reg', (57, 65))
473365	31791231	Therefore, temporal orders inferred by PATOPA were closer to the cancer research literature than those inferred by H-CBN.	('PATOPA', 'Var', (39, 45))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))
473376	31791231	Incorporating intra-tumor heterogeneity and tumor evolution information may substantially improve the estimation of pathway mutation orders, which is an important direction of future research.	('intra-tumor', 'Disease', (14, 25))	('pathway', 'Pathway', (116, 123))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('improve', 'PosReg', (90, 97))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('mutation', 'Var', (124, 132))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('intra-tumor', 'Disease', 'MESH:D009369', (14, 25))	('tumor', 'Disease', (44, 49))	('tumor', 'Disease', (20, 25))
473380	31791231	Let  indicate whether the kth mutation is functional (=1) or not (=0) for k=1,...,mj, and  be the total number of functional mutations in patient j.	('k=1', 'Gene', '3848', (74, 77))	('mutations', 'Var', (125, 134))	('k=1', 'Gene', (74, 77))	('patient', 'Species', '9606', (138, 145))
473392	31791231	This work was supported by National Institutes of Health (NIH) [R21CA205778, UL1TR001998, P20GM103436-15 and the Cloud Credits Model Pilot, a component of the NIH Big Data to Knowledge (BD2K) program], the Kentucky Lung Cancer Research Program [PO2 415 1400004000, PO2 415 1600001032], and the Biostatistics and Bioinformatics Shared Resource Facility of the University of Kentucky Markey Cancer Center [P30 CA177558].	('PO2 415 1600001032]', 'Var', (265, 284))	('Kentucky Lung Cancer', 'Disease', 'MESH:D008175', (206, 226))	('P30', 'Gene', '201161', (404, 407))	('Lung Cancer', 'Phenotype', 'HP:0100526', (215, 226))	('P30', 'Gene', (404, 407))	('Kentucky Lung Cancer', 'Disease', (206, 226))	('Cancer', 'Disease', (220, 226))	('Cancer', 'Disease', (389, 395))	('Cancer', 'Phenotype', 'HP:0002664', (389, 395))	('Cancer', 'Disease', 'MESH:D009369', (220, 226))	('Cancer', 'Phenotype', 'HP:0002664', (220, 226))	('Cancer', 'Disease', 'MESH:D009369', (389, 395))
473394	30647803	TM levels (CEA, CA125, CA15-3, CA19-9, CA72-4, CYFRA21-1, and SCC-Ag) in 424 cases of lung adenocarcinoma (LAC), 166 cases of lung squamous cell carcinoma (LSCC), and 103 cases of benign chest disease (BCD) were analyzed before treatment.	('SCC', 'Gene', (157, 160))	('carcinoma', 'Phenotype', 'HP:0030731', (145, 154))	('LAC', 'Phenotype', 'HP:0030078', (107, 110))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (86, 105))	('CA15-3', 'Gene', (23, 29))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (86, 105))	('benign chest disease', 'Disease', (180, 200))	('benign chest disease', 'Disease', 'MESH:D002637', (180, 200))	('CA72-4', 'Chemical', '-', (39, 45))	('CEA', 'Gene', (11, 14))	('CYFRA21-1', 'Var', (47, 56))	('CA125', 'Gene', '94025', (16, 21))	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('adenocarcinoma', 'Disease', (91, 105))	('LSCC', 'Phenotype', 'HP:0030359', (156, 160))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (126, 154))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (131, 154))	('SCC', 'Gene', '6317', (62, 65))	('CEA', 'Gene', '1048', (11, 14))	('SCC', 'Gene', (62, 65))	('lung adenocarcinoma', 'Disease', (86, 105))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (126, 154))	('lung squamous cell carcinoma', 'Disease', (126, 154))	('CA125', 'Gene', (16, 21))	('CA15-3', 'Gene', '4582', (23, 29))	('SCC', 'Gene', '6317', (157, 160))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (131, 154))	('adenocarcinoma', 'Disease', 'MESH:D000230', (91, 105))
473398	30647803	Other common TM also increased in NSCLC, including carbohydrate antigen 125 (CA125), CA15-3, CA19-9, and CA72-4.	('CA72-4', 'Var', (105, 111))	('CA19-9', 'Var', (93, 99))	('CA125', 'Var', (77, 82))	('NSCLC', 'Disease', (34, 39))	('carbohydrate antigen', 'Chemical', '-', (51, 71))	('NSCLC', 'Phenotype', 'HP:0030358', (34, 39))	('CA15-3', 'Var', (85, 91))
473406	30647803	The AUC of CEA, CA12-5, CA15-3, CA72-4, and CYFRA21-1 was statistically significant in LAC (all p < 0.05).	('LAC', 'Phenotype', 'HP:0030078', (87, 90))	('CA12-5', 'Gene', '94025', (16, 22))	('CA12-5', 'Gene', (16, 22))	('LAC', 'Disease', (87, 90))	('CA72-4', 'Var', (32, 38))	('CYFRA21-1', 'Var', (44, 53))	('CA15-3', 'Var', (24, 30))
473411	30647803	CYFRA21-1 was an independent predictor of NSCLC metastasis.	('NSCLC metastasis', 'Disease', (42, 58))	('NSCLC metastasis', 'Disease', 'MESH:D009362', (42, 58))	('CYFRA21-1', 'Var', (0, 9))	('NSCLC', 'Phenotype', 'HP:0030358', (42, 47))
473412	30647803	The expression of CA125 was not related to the degree of malignancy but related to the degree of tissue differentiation.	('malignancy', 'Disease', (57, 67))	('CA125', 'Var', (18, 23))	('malignancy', 'Disease', 'MESH:D009369', (57, 67))	('related', 'Reg', (72, 79))	('tissue differentiation', 'CPA', (97, 119))
473486	29394219	Despite the poor prognosis of metaplastic breast carcinoma, reduced axillary node metastasis is observed due to its hematogenous over lymphatic spread.	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('breast carcinoma', 'Phenotype', 'HP:0003002', (42, 58))	('breast carcinoma', 'Disease', (42, 58))	('reduced axillary', 'Phenotype', 'HP:0000327', (60, 76))	('reduced', 'NegReg', (60, 67))	('breast carcinoma', 'Disease', 'MESH:D001943', (42, 58))	('axillary node metastasis', 'CPA', (68, 92))	('metaplastic', 'Var', (30, 41))
473499	29394219	It is characterized by a larger size at presentation, lower rates of axillary nodal involvement, higher rates of both local and distant recurrence, and higher rates of ER, PR, and Her2 negativity.	('PR', 'Gene', '5241', (172, 174))	('higher', 'PosReg', (152, 158))	('axillary nodal involvement', 'CPA', (69, 95))	('Her2', 'Gene', (180, 184))	('ER', 'Gene', '2099', (168, 170))	('Her2', 'Gene', '2064', (180, 184))	('negativity', 'Var', (185, 195))	('lower', 'NegReg', (54, 59))
473566	28145643	Analysis of Fifty Hotspot Mutations of Lung Squamous Cell Carcinoma in Never-smokers Smoking is the major risk factor for lung squamous cell carcinoma (SCC), although a small number of lung SCCs occurs in never-smokers.	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (122, 150))	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (122, 150))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (127, 150))	('Squamous Cell Carcinoma', 'Disease', 'MESH:D002294', (44, 67))	('lung squamous cell carcinoma', 'Disease', (122, 150))	('Mutations', 'Var', (26, 35))	('SCC', 'Gene', (152, 155))	('Carcinoma', 'Phenotype', 'HP:0030731', (58, 67))	('SCC', 'Gene', (190, 193))	('Lung Squamous Cell Carcinoma', 'Phenotype', 'HP:0030359', (39, 67))	('Squamous Cell Carcinoma', 'Disease', (44, 67))	('SCC', 'Phenotype', 'HP:0002860', (152, 155))	('SCC', 'Gene', '6317', (152, 155))	('SCC', 'Phenotype', 'HP:0002860', (190, 193))	('SCC', 'Gene', '6317', (190, 193))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (44, 67))
473567	28145643	The purpose of this study was to compare 50 hotspot mutations of lung SCCs between never-smokers and smokers.	('mutations', 'Var', (52, 61))	('SCC', 'Gene', (70, 73))	('SCC', 'Gene', '6317', (70, 73))	('SCC', 'Phenotype', 'HP:0002860', (70, 73))
473569	28145643	Formalin-fixed, paraffin-embedded tumor samples were used for analysis of hotspot mutations.	('Formalin', 'Chemical', 'MESH:D005557', (0, 8))	('tumor', 'Disease', (34, 39))	('mutations', 'Var', (82, 91))	('paraffin', 'Chemical', 'MESH:D010232', (16, 24))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
473574	28145643	In the 26 lung SCC tumor samples (12 from never-smokers and 14 from ever-smokers) sequenced using personal genome machine, the most common mutations were in TP53 (75.0%), RAS (66.7%), and STK11 (33.3%), but mutations were also found in EGFR, KIT, and PTEN.	('TP53', 'Gene', (157, 161))	('RAS', 'Gene', (171, 174))	('STK11', 'Gene', (188, 193))	('mutations', 'Var', (139, 148))	('SCC tumor', 'Disease', 'MESH:D009369', (15, 24))	('KIT', 'Gene', (242, 245))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('TP53', 'Gene', '7157', (157, 161))	('STK11', 'Gene', '6794', (188, 193))	('EGFR', 'Gene', '1956', (236, 240))	('PTEN', 'Gene', '5728', (251, 255))	('SCC', 'Phenotype', 'HP:0002860', (15, 18))	('PTEN', 'Gene', (251, 255))	('EGFR', 'Gene', (236, 240))	('SCC tumor', 'Disease', (15, 24))
473575	28145643	The 50 hotspot mutations of lung SCC in never-smokers were similar to those of ever-smokers.	('SCC', 'Gene', '6317', (33, 36))	('mutations', 'Var', (15, 24))	('SCC', 'Gene', (33, 36))	('SCC', 'Phenotype', 'HP:0002860', (33, 36))
473583	28145643	Therefore, we compared 50 hotspot mutations of lung SCCs between never-smokers and smokers.	('SCC', 'Phenotype', 'HP:0002860', (52, 55))	('SCC', 'Gene', '6317', (52, 55))	('mutations', 'Var', (34, 43))	('SCC', 'Gene', (52, 55))
473593	28145643	Purified genomic DNA was used for library construction with the Ion AmpliSeq  Cancer hotspot panel v2 (Life Technologies) that targets mutations in the following 50 genes: ABL1, AKT1, ALK, ATM, APC, BRAF, CDH1, CDKN2A, CSF1R, CTNNB1, EGFR, ERBB2, ERBB4, EZH2, FBXW7, FGFR1, FGFR2, FGFR3, FLT3, GNAQ, GNAS, GNA11, HNF1A, HRAS, IDH1, IDH2, JAK2, JAK3, KDR, KIT, KRAS, MET, MLH1, MPL, NOTCH1, NPM1 NRAS, PDGFRA, PIK3CA, PTEN, PTPN11, RB1, SMAD4, SMARCB1, SMO, SRC, STK11,TP53, RET, and VHL.	('NOTCH1', 'Gene', (382, 388))	('PTEN', 'Gene', (417, 421))	('FGFR1', 'Gene', '2260', (267, 272))	('CSF1R', 'Gene', '1436', (219, 224))	('JAK3', 'Gene', (344, 348))	('PTPN11', 'Gene', '5781', (423, 429))	('IDH2', 'Gene', (332, 336))	('IDH2', 'Gene', '3418', (332, 336))	('VHL', 'Disease', 'MESH:D006623', (483, 486))	('ATM', 'Gene', '472', (189, 192))	('EZH2', 'Gene', (254, 258))	('JAK2', 'Gene', '3717', (338, 342))	('GNA11', 'Gene', (306, 311))	('GNAS', 'Gene', '2778', (300, 304))	('RB1', 'Gene', (431, 434))	('SMARCB1', 'Gene', (443, 450))	('ATM', 'Gene', (189, 192))	('FGFR3', 'Gene', '2261', (281, 286))	('VHL', 'Disease', (483, 486))	('TP53', 'Gene', (468, 472))	('APC', 'Disease', (194, 197))	('ABL1', 'Gene', (172, 176))	('Cancer', 'Phenotype', 'HP:0002664', (78, 84))	('RB1', 'Gene', '5925', (431, 434))	('FBXW7', 'Gene', '55294', (260, 265))	('ABL1', 'Gene', '25', (172, 176))	('NPM1', 'Gene', (390, 394))	('GNA11', 'Gene', '2767', (306, 311))	('CDKN2A', 'Gene', (211, 217))	('MPL', 'Gene', (377, 380))	('IDH1', 'Gene', (326, 330))	('FGFR2', 'Gene', (274, 279))	('CSF1R', 'Gene', (219, 224))	('CDKN2A', 'Gene', '1029', (211, 217))	('GNAS', 'Gene', (300, 304))	('EGFR', 'Gene', '1956', (234, 238))	('STK11', 'Gene', (462, 467))	('FGFR1', 'Gene', (267, 272))	('RET', 'Gene', '5979', (474, 477))	('FGFR3', 'Gene', (281, 286))	('SMAD4', 'Gene', '4089', (436, 441))	('NPM1', 'Gene', '4869', (390, 394))	('AKT1', 'Gene', '207', (178, 182))	('ALK', 'Gene', '238', (184, 187))	('SMARCB1', 'Gene', '6598', (443, 450))	('GNAQ', 'Gene', '2776', (294, 298))	('APC', 'Disease', 'MESH:D011125', (194, 197))	('JAK2', 'Gene', (338, 342))	('AKT1', 'Gene', (178, 182))	('ERBB2', 'Gene', (240, 245))	('SMO', 'Gene', '6608', (452, 455))	('PTPN11', 'Gene', (423, 429))	('SRC', 'Gene', (457, 460))	('EGFR', 'Gene', (234, 238))	('ERBB4', 'Gene', '2066', (247, 252))	('HNF1A', 'Gene', '6927', (313, 318))	('PDGFRA', 'Gene', (401, 407))	('SMAD4', 'Gene', (436, 441))	('SMO', 'Gene', (452, 455))	('NRAS', 'Gene', '4893', (395, 399))	('HNF1A', 'Gene', (313, 318))	('TP53', 'Gene', '7157', (468, 472))	('CTNNB1', 'Gene', (226, 232))	('mutations', 'Var', (135, 144))	('FGFR2', 'Gene', '2263', (274, 279))	('IDH1', 'Gene', '3417', (326, 330))	('KRAS', 'Gene', (360, 364))	('FBXW7', 'Gene', (260, 265))	('HRAS', 'Gene', (320, 324))	('ALK', 'Gene', (184, 187))	('MPL', 'Gene', '4352', (377, 380))	('GNAQ', 'Gene', (294, 298))	('RET', 'Gene', (474, 477))	('PIK3CA', 'Gene', '5290', (409, 415))	('CDH1', 'Gene', (205, 209))	('MLH1', 'Gene', (371, 375))	('ERBB2', 'Gene', '2064', (240, 245))	('ERBB4', 'Gene', (247, 252))	('KDR', 'Gene', '3791', (350, 353))	('BRAF', 'Gene', (199, 203))	('BRAF', 'Gene', '673', (199, 203))	('PDGFRA', 'Gene', '5156', (401, 407))	('KRAS', 'Gene', '3845', (360, 364))	('NOTCH1', 'Gene', '4851', (382, 388))	('EZH2', 'Gene', '2146', (254, 258))	('PTEN', 'Gene', '5728', (417, 421))	('MLH1', 'Gene', '4292', (371, 375))	('PIK3CA', 'Gene', (409, 415))	('JAK3', 'Gene', '3718', (344, 348))	('FLT3', 'Gene', (288, 292))	('FLT3', 'Gene', '2322', (288, 292))	('HRAS', 'Gene', '3265', (320, 324))	('NRAS', 'Gene', (395, 399))	('SRC', 'Gene', '6714', (457, 460))	('KDR', 'Gene', (350, 353))	('STK11', 'Gene', '6794', (462, 467))	('CDH1', 'Gene', '999', (205, 209))	('CTNNB1', 'Gene', '1499', (226, 232))
473607	28145643	The most common mutations were in the TP53 (84.6%), RAS (69.2%), and KIT (34.5%) genes (Fig.	('KIT', 'Gene', (69, 72))	('TP53', 'Gene', (38, 42))	('mutations', 'Var', (16, 25))	('RAS', 'Gene', (52, 55))	('TP53', 'Gene', '7157', (38, 42))
473608	28145643	As no comparison had previously been reported for lung SCC according to smoking history, we compared the hotspot mutations of never-smokers with those of ever-smokers, and found no significant differences in their distributions (Table 2).	('SCC', 'Phenotype', 'HP:0002860', (55, 58))	('SCC', 'Gene', (55, 58))	('mutations', 'Var', (113, 122))	('SCC', 'Gene', '6317', (55, 58))
473609	28145643	Both groups displayed a similarly high rate of mutations in TP53 (75.0% in never-smokers and 92.9% in ever-smokers; Fisher's exact P = 0.306) and RAS (66.7% in never-smokers and 71.4% in ever-smokers; Fisher's exact P > 0.99), and mutations in HRAS, NRAS, KRAS, EGFR, KIT, and PTEN were also observed at comparable frequencies.	('EGFR', 'Gene', '1956', (262, 266))	('HRAS', 'Gene', (244, 248))	('KIT', 'Gene', (268, 271))	('EGFR', 'Gene', (262, 266))	('RAS', 'Gene', (146, 149))	('mutations', 'Var', (47, 56))	('NRAS', 'Gene', (250, 254))	('PTEN', 'Gene', (277, 281))	('TP53', 'Gene', '7157', (60, 64))	('PTEN', 'Gene', '5728', (277, 281))	('KRAS', 'Gene', (256, 260))	('NRAS', 'Gene', '4893', (250, 254))	('KRAS', 'Gene', '3845', (256, 260))	('TP53', 'Gene', (60, 64))	('HRAS', 'Gene', '3265', (244, 248))
473610	28145643	EGFR mutations were present in 14.3% and 25.0% of tumors from ever-smokers and never-smokers, respectively, and this difference was also not statistically significant (P = 0.637).	('EGFR', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumors', 'Disease', (50, 56))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('tumors', 'Disease', 'MESH:D009369', (50, 56))	('EGFR', 'Gene', '1956', (0, 4))
473611	28145643	In an analysis of 50 hotspot mutations in lung SCC of never-smokers and ever-smokers, we found that there was a similar mutational profile in tumors regardless of smoking history.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('SCC', 'Phenotype', 'HP:0002860', (47, 50))	('SCC', 'Gene', '6317', (47, 50))	('mutations', 'Var', (29, 38))	('tumors', 'Disease', 'MESH:D009369', (142, 148))	('tumors', 'Disease', (142, 148))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))	('SCC', 'Gene', (47, 50))
473612	28145643	The analyzed mutations included those in the TP53 and RAS genes, which have been found to occur more frequently in lung carcinomas from smokers compared to never-smokers.	('RAS genes', 'Gene', (54, 63))	('TP53', 'Gene', (45, 49))	('lung carcinomas', 'Disease', (115, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('mutations', 'Var', (13, 22))	('carcinomas', 'Phenotype', 'HP:0030731', (120, 130))	('TP53', 'Gene', '7157', (45, 49))	('lung carcinomas', 'Disease', 'MESH:D008175', (115, 130))
473617	28145643	Numerous studies have found that genomic alterations in lung SCC, particularly mutations in TP53, PIK3CA, PTEN, and FGFR1 amplification are common in SCC but not in adenocarcinoma.	('SCC', 'Gene', '6317', (61, 64))	('FGFR1', 'Gene', '2260', (116, 121))	('PIK3CA', 'Gene', '5290', (98, 104))	('common', 'Reg', (140, 146))	('TP53', 'Gene', (92, 96))	('SCC', 'Gene', (61, 64))	('SCC', 'Phenotype', 'HP:0002860', (150, 153))	('mutations', 'Var', (79, 88))	('adenocarcinoma', 'Disease', (165, 179))	('PTEN', 'Gene', (106, 110))	('SCC', 'Gene', '6317', (150, 153))	('PIK3CA', 'Gene', (98, 104))	('FGFR1', 'Gene', (116, 121))	('TP53', 'Gene', '7157', (92, 96))	('SCC', 'Gene', (150, 153))	('PTEN', 'Gene', '5728', (106, 110))	('adenocarcinoma', 'Disease', 'MESH:D000230', (165, 179))	('carcinoma', 'Phenotype', 'HP:0030731', (170, 179))	('SCC', 'Phenotype', 'HP:0002860', (61, 64))
473619	28145643	A whole genome sequencing study by TCGA reported recurrent mutations in 18 genes, including TP53 and genes in the CDKN2A/RB1, NFE2L2/KEAP1/CUL3, PI3K/AKT, and SOX2/TP63/NOTCH1 pathways.	('NOTCH1', 'Gene', '4851', (169, 175))	('NFE2L2', 'Gene', (126, 132))	('RB1', 'Gene', '5925', (121, 124))	('TP53', 'Gene', (92, 96))	('CDKN2A', 'Gene', (114, 120))	('CUL3', 'Gene', (139, 143))	('AKT', 'Gene', '207', (150, 153))	('KEAP1', 'Gene', '9817', (133, 138))	('KEAP1', 'Gene', (133, 138))	('CDKN2A', 'Gene', '1029', (114, 120))	('SOX2', 'Gene', (159, 163))	('SOX2', 'Gene', '6657', (159, 163))	('TP53', 'Gene', '7157', (92, 96))	('mutations', 'Var', (59, 68))	('TP63', 'Gene', (164, 168))	('CUL3', 'Gene', '8452', (139, 143))	('NFE2L2', 'Gene', '4780', (126, 132))	('NOTCH1', 'Gene', (169, 175))	('RB1', 'Gene', (121, 124))	('TP63', 'Gene', '8626', (164, 168))	('AKT', 'Gene', (150, 153))
473620	28145643	A comparative mutational analysis of lung SCC patients in East Asia also demonstrated a high rate of mutations in TP53, RB1, PTEN, NFE2L2, KEAP1, MLL2, and PIK3CA.	('patients', 'Species', '9606', (46, 54))	('PTEN', 'Gene', (125, 129))	('SCC', 'Phenotype', 'HP:0002860', (42, 45))	('TP53', 'Gene', '7157', (114, 118))	('NFE2L2', 'Gene', '4780', (131, 137))	('PIK3CA', 'Gene', (156, 162))	('RB1', 'Gene', '5925', (120, 123))	('PTEN', 'Gene', '5728', (125, 129))	('SCC', 'Gene', '6317', (42, 45))	('NFE2L2', 'Gene', (131, 137))	('mutations', 'Var', (101, 110))	('SCC', 'Gene', (42, 45))	('MLL2', 'Gene', '8085', (146, 150))	('TP53', 'Gene', (114, 118))	('MLL2', 'Gene', (146, 150))	('PIK3CA', 'Gene', '5290', (156, 162))	('KEAP1', 'Gene', '9817', (139, 144))	('KEAP1', 'Gene', (139, 144))	('RB1', 'Gene', (120, 123))
473621	28145643	We found a similar rate of mutations in genes, including TP53, PTEN, and FGFR.	('mutations', 'Var', (27, 36))	('PTEN', 'Gene', '5728', (63, 67))	('FGFR', 'Gene', (73, 77))	('TP53', 'Gene', '7157', (57, 61))	('TP53', 'Gene', (57, 61))	('PTEN', 'Gene', (63, 67))
473622	28145643	With respect to smoking status, a 10-fold higher mutation rate has been reported in smokers compared to never-smokers, and Ras association domain family 1A (RASSF1A) methylation and FGFR1 amplification occur more frequently in ever-smokers than in never-smokers.	('amplification', 'MPA', (188, 201))	('RASSF1A', 'Gene', (157, 164))	('Ras association domain family 1A', 'Gene', (123, 155))	('RASSF1A', 'Gene', '11186', (157, 164))	('Ras association domain family 1A', 'Gene', '11186', (123, 155))	('FGFR1', 'Gene', (182, 187))	('mutation', 'Var', (49, 57))	('FGFR1', 'Gene', '2260', (182, 187))	('methylation', 'Var', (166, 177))
473633	28145643	In conclusion, we found no significant differences in 50 hotspot mutations in lung SCCs between never-smokers and ever-smokers.	('SCC', 'Gene', (83, 86))	('SCC', 'Gene', '6317', (83, 86))	('SCC', 'Phenotype', 'HP:0002860', (83, 86))	('mutations', 'Var', (65, 74))
473672	31561451	The fluorescence of AF555-EGFR-Ab was divided by the FITC fluorescence of the NPs to determine the coupling efficiency.	('AF555-EGFR-Ab', 'Var', (20, 33))	('coupling', 'MPA', (99, 107))	('FITC', 'Chemical', 'MESH:D016650', (53, 57))
473687	31561451	Confocal laser scanning microscopy of in vitro staining with AF555-EGFR-FITC-SiO2-NPs and FITC-SiO2-NPs: To show the binding of the AF555-EGFR-FITC-SiO2-NPs to the surface of EGF receptor expressing tumor cells, HNSCCUM-02T cells were seeded onto mu-slides 8-well ibidiTreat (ibidi GmbH, Munich, Germany) at 5000 cells per well.	('tumor', 'Disease', (199, 204))	('HNSCCUM-02T', 'CellLine', 'CVCL:W875', (212, 223))	('FITC-SiO2', 'Chemical', 'MESH:D012825', (143, 152))	('binding', 'Interaction', (117, 124))	('FITC-SiO2', 'Chemical', 'MESH:D012825', (72, 81))	('EGF receptor', 'Gene', '1956', (175, 187))	('FITC-SiO2', 'Chemical', 'MESH:D012825', (90, 99))	('EGF receptor', 'Gene', (175, 187))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('AF555-EGFR-FITC-SiO2-NPs', 'Var', (132, 156))
473693	31561451	Confocal laser scanning microscopy of in vitro staining with AF555-EGFR-FITC-SiO2-NPs and AF555-EGFR-Ab: The contrast enhancement capabilities of AF555-EGFR-FITC-SiO2-NPs were compared to AF555-EGFR-Ab in HNSCCUM-02T cells and primary human fibroblasts.	('enhancement', 'PosReg', (118, 129))	('FITC-SiO2', 'Chemical', 'MESH:D012825', (72, 81))	('contrast', 'MPA', (109, 117))	('HNSCCUM-02T', 'CellLine', 'CVCL:W875', (205, 216))	('human', 'Species', '9606', (235, 240))	('AF555-EGFR-FITC-SiO2-NPs', 'Var', (146, 170))	('FITC-SiO2', 'Chemical', 'MESH:D012825', (157, 166))
473734	31561451	The quotient of the fluorescence of AF555 and FITC was significantly greater (2.9-fold) for AF555-EGFR-FITC-SiO2-NPs than for FITC-SiO2-NPs, indicating a successful antibody conjugation, as shown in Figure 5.	('quotient', 'MPA', (4, 12))	('AF555-EGFR-FITC-SiO2-NPs', 'Var', (92, 116))	('fluorescence', 'MPA', (20, 32))	('FITC-SiO2', 'Chemical', 'MESH:D012825', (126, 135))	('FITC', 'Chemical', 'MESH:D016650', (46, 50))	('FITC-SiO2', 'Chemical', 'MESH:D012825', (103, 112))	('greater', 'PosReg', (69, 76))	('FITC', 'Chemical', 'MESH:D016650', (126, 130))	('FITC', 'Chemical', 'MESH:D016650', (103, 107))
473739	31561451	The cell line HNSCCUM-02T was incubated with AF555-EGFR-FITC-SiO2-NPs and FITC-SiO2-NPs for 30 min to evaluate nanoparticle binding in vitro.	('HNSCCUM-02T', 'CellLine', 'CVCL:W875', (14, 25))	('FITC-SiO2', 'Chemical', 'MESH:D012825', (56, 65))	('binding', 'Interaction', (124, 131))	('AF555-EGFR-FITC-SiO2-NPs', 'Var', (45, 69))	('FITC-SiO2', 'Chemical', 'MESH:D012825', (74, 83))
473740	31561451	AF555-EGFR-Ab signal and FITC signal were observed with confocal laser scanning microscopy and binding of nanoparticles to the cellular membranes was noted.	('AF555-EGFR-Ab', 'Var', (0, 13))	('binding', 'Interaction', (95, 102))	('FITC', 'Chemical', 'MESH:D016650', (25, 29))
473746	31561451	More AF555-EGFR-FITC-SiO2-NPs bound to HNSCCUM-02T cells than primary human fibroblasts.	('AF555-EGFR-FITC-SiO2-NPs', 'Var', (5, 29))	('human', 'Species', '9606', (70, 75))	('FITC-SiO2', 'Chemical', 'MESH:D012825', (16, 25))	('HNSCCUM-02T', 'CellLine', 'CVCL:W875', (39, 50))	('bound', 'Interaction', (30, 35))
473755	31561451	However, EGFR-FITC-SiO2-NPs frequently occurred in the liver, the organ with the highest blood circulation.	('EGFR-FITC-SiO2-NPs', 'Var', (9, 27))	('FITC-SiO2', 'Chemical', 'MESH:D012825', (14, 23))	('occurred', 'Reg', (39, 47))
473761	31561451	Only the tumor sample showed a signal of EGFR-FITC-SiO2-NPs while the FITC-SiO2-NPs (controls) exhibited no signal.	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('FITC-SiO2', 'Chemical', 'MESH:D012825', (70, 79))	('FITC-SiO2', 'Chemical', 'MESH:D012825', (46, 55))	('tumor', 'Disease', (9, 14))	('EGFR-FITC-SiO2-NPs', 'Var', (41, 59))
473762	31561451	Therefore, EGFR-FITC-SiO2-NPs preferably bind to tumor tissue, and the malignant area can be visualized by confocal laser endomicroscopy.	('EGFR-FITC-SiO2-NPs', 'Var', (11, 29))	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('preferably', 'PosReg', (30, 40))	('tumor', 'Disease', (49, 54))	('FITC-SiO2', 'Chemical', 'MESH:D012825', (16, 25))	('bind', 'Interaction', (41, 45))
473776	31561451	However, more AF555-EGFR-FITC-SiO2-NPs than FITC-SiO2-NPs seemed to bind to the cells after 30 min of incubation and AF555 signal overlap with FITC indicated successful conjugation of the AF555-EGFR-Ab to the FITC-SiO2-NPs.	('FITC-SiO2', 'Chemical', 'MESH:D012825', (44, 53))	('FITC-SiO2', 'Chemical', 'MESH:D012825', (209, 218))	('FITC-SiO2', 'Chemical', 'MESH:D012825', (25, 34))	('AF555 signal', 'Var', (117, 129))	('FITC', 'Chemical', 'MESH:D016650', (44, 48))	('conjugation', 'Interaction', (169, 180))	('FITC', 'Chemical', 'MESH:D016650', (143, 147))	('bind', 'Interaction', (68, 72))	('FITC', 'Chemical', 'MESH:D016650', (209, 213))	('FITC', 'Chemical', 'MESH:D016650', (25, 29))
473777	31561451	Additionally, more AF555-EGFR-FITC-SiO2-NPs were associated with HNSCCUM-02T cells than primary human fibroblasts and the AF555-EGFR-Ab alone did not stain the cells.	('FITC-SiO2', 'Chemical', 'MESH:D012825', (30, 39))	('AF555-EGFR-FITC-SiO2-NPs', 'Var', (19, 43))	('HNSCCUM-02T', 'CellLine', 'CVCL:W875', (65, 76))	('human', 'Species', '9606', (96, 101))	('HNSCCUM-02T', 'Disease', (65, 76))
473778	31561451	Moreover, EGFR-FITC-SiO2-NPs were detected in the tumor and the liver in the CAM assay while FITC-SiO2-NPs were only rarely detected in the liver.	('FITC-SiO2', 'Chemical', 'MESH:D012825', (93, 102))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('FITC-SiO2', 'Chemical', 'MESH:D012825', (15, 24))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Disease', (50, 55))	('EGFR-FITC-SiO2-NPs', 'Var', (10, 28))
473785	31561451	In vivo tumor imaging in mice indicated an increase in methylene blue signal over time and a higher intensity for EGFR-targeted nanoparticles compared to untargeted nanoparticles.	('higher', 'PosReg', (93, 99))	('mice', 'Species', '10090', (25, 29))	('nanoparticles', 'Var', (128, 141))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('intensity', 'MPA', (100, 109))	('increase', 'PosReg', (43, 51))	('tumor', 'Disease', (8, 13))	('EGFR-targeted', 'Gene', (114, 127))	('methylene blue signal', 'MPA', (55, 76))	('methylene blue', 'Chemical', 'MESH:D008751', (55, 69))
473786	31561451	Yet, methylene blue is a monoamine oxidase inhibitor and can cause serotonin syndrome when applied together with serotonergic drugs.	('cause', 'Reg', (61, 66))	('methylene blue', 'Chemical', 'MESH:D008751', (5, 19))	('serotonin syndrome', 'Disease', 'MESH:D020230', (67, 85))	('serotonin syndrome', 'Disease', (67, 85))	('methylene blue', 'Var', (5, 19))
473791	31561451	We here used the CAM assay to analyze in vivo distribution of the nanoparticles and could identify EGFR-FITC-SiO2-NPs in the tumor and in the liver.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumor', 'Disease', (125, 130))	('FITC-SiO2', 'Chemical', 'MESH:D012825', (104, 113))	('EGFR-FITC-SiO2-NPs', 'Var', (99, 117))
473796	24322982	Cancer-derived mutations in KEAP1 impair NRF2 degradation but not ubiquitination NRF2 is a transcription factor that mediates stress responses.	('NRF2', 'Gene', (41, 45))	('KEAP1', 'Gene', '9817', (28, 33))	('impair', 'NegReg', (34, 40))	('mutations', 'Var', (15, 24))	('KEAP1', 'Gene', (28, 33))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('degradation', 'MPA', (46, 57))	('NRF2', 'Gene', '4780', (81, 85))	('NRF2', 'Gene', '4780', (41, 45))	('NRF2', 'Gene', (81, 85))
473797	24322982	Oncogenic mutations in NRF2 localize to one of its two binding interfaces with KEAP1, an E3 ubiquitin ligase that promotes proteasome-dependent degradation of NRF2.	('proteasome-dependent degradation', 'MPA', (123, 155))	('NRF2', 'Gene', '4780', (159, 163))	('E3 ubiquitin ligase', 'Gene', '79594', (89, 108))	('KEAP1', 'Gene', (79, 84))	('NRF2', 'Gene', '4780', (23, 27))	('E3 ubiquitin ligase', 'Gene', (89, 108))	('NRF2', 'Gene', (159, 163))	('promotes', 'PosReg', (114, 122))	('NRF2', 'Gene', (23, 27))	('mutations', 'Var', (10, 19))	('KEAP1', 'Gene', '9817', (79, 84))
473799	24322982	These mutations distribute throughout the KEAP1 protein but little is known about their functional impact.	('KEAP1', 'Gene', '9817', (42, 47))	('mutations', 'Var', (6, 15))	('KEAP1', 'Gene', (42, 47))
473800	24322982	In this study, we characterized 18 KEAP1 mutations defined in a lung squamous cell carcinoma tumor set.	('mutations', 'Var', (41, 50))	('lung squamous cell carcinoma tumor', 'Disease', (64, 98))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('KEAP1', 'Gene', '9817', (35, 40))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (69, 92))	('KEAP1', 'Gene', (35, 40))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (64, 92))	('lung squamous cell carcinoma tumor', 'Disease', 'MESH:D002294', (64, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))
473802	24322982	R554Q, W544C, N469fs, P318fs, and G333C mutations attenuated binding and suppression of NRF2 activity.	('G333C', 'Mutation', 'rs1218502799', (34, 39))	('P318fs', 'Mutation', 'p.P318fsX', (22, 28))	('N469fs', 'Var', (14, 20))	('N469fs', 'Mutation', 'p.N469fsX', (14, 20))	('W544C', 'Var', (7, 12))	('P318fs', 'Var', (22, 28))	('R554Q', 'Var', (0, 5))	('activity', 'MPA', (93, 101))	('suppression', 'NegReg', (73, 84))	('R554Q', 'Mutation', 'rs751295594', (0, 5))	('NRF2', 'Gene', '4780', (88, 92))	('W544C', 'SUBSTITUTION', 'None', (7, 12))	('NRF2', 'Gene', (88, 92))	('attenuated', 'NegReg', (50, 60))	('G333C', 'Var', (34, 39))	('binding', 'Interaction', (61, 68))
473803	24322982	The remaining mutations exhibited hypomorphic suppression of NRF2, binding both NRF2 and CUL3.	('NRF2', 'Gene', '4780', (80, 84))	('CUL3', 'Gene', '8452', (89, 93))	('NRF2', 'Gene', (61, 65))	('NRF2', 'Gene', (80, 84))	('CUL3', 'Gene', (89, 93))	('suppression', 'NegReg', (46, 57))	('NRF2', 'Gene', '4780', (61, 65))	('binding', 'Interaction', (67, 74))	('mutations', 'Var', (14, 23))
473804	24322982	Proteomic analysis revealed that the R320Q, R470C, G423V, D422N, G186R, S243C, and V155F mutations augmented the binding of KEAP1 and NRF2.	('augmented', 'PosReg', (99, 108))	('G186R', 'Var', (65, 70))	('R470C', 'Mutation', 'p.R470C', (44, 49))	('R320Q', 'Var', (37, 42))	('G186R', 'Mutation', 'rs750271277', (65, 70))	('R320Q', 'Mutation', 'p.R320Q', (37, 42))	('S243C', 'Mutation', 'p.S243C', (72, 77))	('D422N', 'Mutation', 'p.D422N', (58, 63))	('V155F', 'Var', (83, 88))	('D422N', 'Var', (58, 63))	('G423V', 'Var', (51, 56))	('V155F', 'Mutation', 'p.V155F', (83, 88))	('binding', 'Interaction', (113, 120))	('G423V', 'Mutation', 'p.G423V', (51, 56))	('NRF2', 'Gene', '4780', (134, 138))	('R470C', 'Var', (44, 49))	('S243C', 'Var', (72, 77))	('KEAP1', 'Gene', '9817', (124, 129))	('KEAP1', 'Gene', (124, 129))	('NRF2', 'Gene', (134, 138))
473805	24322982	Intriguingly, these 'super-binder' mutants exhibited reduced degradation of NRF2.	("'super-binder", 'PosReg', (20, 33))	('mutants', 'Var', (35, 42))	('NRF2', 'Gene', '4780', (76, 80))	('NRF2', 'Gene', (76, 80))	('reduced', 'NegReg', (53, 60))	('degradation', 'MPA', (61, 72))
473806	24322982	Cell-based and in vitro biochemical analyses demonstrated that despite its inability to suppress NRF2 activity, the R320Q 'superbinder' mutant maintained the ability to ubiquitinate NRF2.	('R320Q', 'Mutation', 'p.R320Q', (116, 121))	('NRF2', 'Gene', '4780', (97, 101))	('NRF2', 'Gene', (182, 186))	('ability', 'MPA', (158, 165))	('NRF2', 'Gene', (97, 101))	('activity', 'MPA', (102, 110))	('ubiquitinate', 'MPA', (169, 181))	('R320Q', 'Var', (116, 121))	('NRF2', 'Gene', '4780', (182, 186))
473807	24322982	These data strengthen the genetic interactions between KEAP1 and NRF2 in cancer and provide new insight into KEAP1 mechanics.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('NRF2', 'Gene', (65, 69))	('KEAP1', 'Gene', '9817', (55, 60))	('KEAP1', 'Gene', (109, 114))	('interactions', 'Interaction', (34, 46))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('KEAP1', 'Gene', (55, 60))	('NRF2', 'Gene', '4780', (65, 69))	('KEAP1', 'Gene', '9817', (109, 114))	('genetic', 'Var', (26, 33))
473808	24322982	In contrast to the mutational clustering seen in oncogenes, where a few residues are frequently affected, mutations in tumor suppressor proteins typically lack focal enrichment.	('tumor', 'Disease', (119, 124))	('lack', 'NegReg', (155, 159))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('mutations', 'Var', (106, 115))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))
473811	24322982	Among these were activating mutations in the NFE2L2 (NRF2) oncogene and presumed loss-of-function mutations within the KEAP1 tumor suppressor gene, at 15% and 12% of tumors, respectively.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('activating', 'PosReg', (17, 27))	('NFE2L2', 'Gene', '4780', (45, 51))	('NRF2', 'Gene', (53, 57))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('NFE2L2', 'Gene', (45, 51))	('tumors', 'Disease', (166, 172))	('KEAP1', 'Gene', '9817', (119, 124))	('KEAP1', 'Gene', (119, 124))	('loss-of-function', 'NegReg', (81, 97))	('tumor', 'Disease', (166, 171))	('tumors', 'Disease', 'MESH:D009369', (166, 172))	('mutations', 'Var', (28, 37))	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('NRF2', 'Gene', '4780', (53, 57))	('tumor', 'Disease', (125, 130))	('mutations', 'Var', (98, 107))
473813	24322982	Regardless of tissue origin, nearly all somatic mutations within NRF2 fall to either the ETGE or the DLG motif, two regulatory short amino acid sequences within NRF2 that contact KEAP1.	('NRF2', 'Gene', (161, 165))	('NRF2', 'Gene', (65, 69))	('KEAP1', 'Gene', (179, 184))	('ETGE', 'Chemical', '-', (89, 93))	('NRF2', 'Gene', '4780', (161, 165))	('fall', 'Phenotype', 'HP:0002527', (70, 74))	('NRF2', 'Gene', '4780', (65, 69))	('mutations', 'Var', (48, 57))	('KEAP1', 'Gene', '9817', (179, 184))
473814	24322982	As such, these mutations liberate NRF2 from KEAP1-mediated ubiquitination.	('NRF2', 'Gene', (34, 38))	('KEAP1', 'Gene', (44, 49))	('mutations', 'Var', (15, 24))	('KEAP1', 'Gene', '9817', (44, 49))	('NRF2', 'Gene', '4780', (34, 38))	('liberate', 'Reg', (25, 33))
473816	24322982	Like many discoveries from genomic sequencing efforts, the functional consequences of these KEAP1 mutations are largely not known.	('mutations', 'Var', (98, 107))	('KEAP1', 'Gene', (92, 97))	('KEAP1', 'Gene', '9817', (92, 97))
473817	24322982	The lung SQCC analysis revealed that as expected, KEAP1 mutations and NRF2 mutations do not co-occur in the same tumor, and that tumors with KEAP1 or NRF2 mutations express relatively high levels of NRF2-target mRNAs.	('NRF2', 'Gene', (150, 154))	('tumors', 'Disease', (129, 135))	('NRF2', 'Gene', (70, 74))	('KEAP1', 'Gene', '9817', (50, 55))	('tumor', 'Disease', (129, 134))	('KEAP1', 'Gene', (50, 55))	('tumors', 'Disease', 'MESH:D009369', (129, 135))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('NRF2', 'Gene', '4780', (199, 203))	('tumor', 'Disease', (113, 118))	('KEAP1', 'Gene', '9817', (141, 146))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('NRF2', 'Gene', '4780', (150, 154))	('KEAP1', 'Gene', (141, 146))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('mutations', 'Var', (155, 164))	('NRF2', 'Gene', (199, 203))	('NRF2', 'Gene', '4780', (70, 74))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))
473819	24322982	The expression of these genes strengthens the cellular defense system to neutralize reactive oxygen species (ROS), clear xenobiotic agents, and reprogram protein degradation machinery to restore homeostasis.	('expression', 'Species', '29278', (4, 14))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (84, 107))	('strengthens', 'PosReg', (30, 41))	('cellular defense system', 'MPA', (46, 69))	('homeostasis', 'MPA', (195, 206))	('neutralize reactive oxygen species', 'MPA', (73, 107))	('restore', 'PosReg', (187, 194))	('expression', 'Var', (4, 14))	('ROS', 'Chemical', 'MESH:D017382', (109, 112))
473823	24322982	Several mechanisms are easily recognized from cancer genomic studies: activating mutations in NRF2 free it from KEAP1 association, copy number amplifications of the NRF2 genomic locus increase protein expression, and KEAP1 promoter hypermethylation decreases its mRNA and protein expression.	('KEAP1', 'Gene', '9817', (217, 222))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('KEAP1', 'Gene', (217, 222))	('NRF2', 'Gene', (94, 98))	('mutations', 'Var', (81, 90))	('KEAP1', 'Gene', '9817', (112, 117))	('KEAP1', 'Gene', (112, 117))	('activating', 'PosReg', (70, 80))	('decreases', 'NegReg', (249, 258))	('protein expression', 'MPA', (193, 211))	('copy number amplifications', 'Var', (131, 157))	('cancer', 'Disease', (46, 52))	('expression', 'Species', '29278', (201, 211))	('NRF2', 'Gene', '4780', (165, 169))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('expression', 'Species', '29278', (280, 290))	('NRF2', 'Gene', '4780', (94, 98))	('increase', 'PosReg', (184, 192))	('NRF2', 'Gene', (165, 169))
473824	24322982	What remains uncertain is which somatic mutations within KEAP1 affect its function, to what degree do they impact function, and mechanistically how its function is compromised.	('affect', 'Reg', (63, 69))	('KEAP1', 'Gene', (57, 62))	('mutations', 'Var', (40, 49))	('function', 'MPA', (114, 122))	('impact', 'Reg', (107, 113))	('KEAP1', 'Gene', '9817', (57, 62))	('function', 'MPA', (74, 82))
473826	24322982	With these concepts in mind, we functionally tested and biochemically characterized KEAP1 mutations found within lung SQCC.	('KEAP1', 'Gene', '9817', (84, 89))	('KEAP1', 'Gene', (84, 89))	('mutations', 'Var', (90, 99))	('lung SQCC', 'Disease', (113, 122))
473828	24322982	Unexpectedly, we found that many KEAP1 mutant proteins bind and ubiquitinate NRF2, but do not promote its proteosomal degradation or suppress its transcriptional activity.	('bind', 'Interaction', (55, 59))	('proteins', 'Protein', (46, 54))	('NRF2', 'Gene', '4780', (77, 81))	('proteosomal degradation', 'MPA', (106, 129))	('suppress', 'NegReg', (133, 141))	('transcriptional activity', 'MPA', (146, 170))	('KEAP1', 'Gene', '9817', (33, 38))	('mutant', 'Var', (39, 45))	('promote', 'PosReg', (94, 101))	('KEAP1', 'Gene', (33, 38))	('NRF2', 'Gene', (77, 81))	('ubiquitinate', 'MPA', (64, 76))
473849	24322982	Ubiquitination of NRF2 under denaturing conditions was performed in HEK293T cells stably expressing FLAG-KEAP1 wild-type or R320Q, VSV-UB1, FLAG-NRF2, and Venus-NPM1.	('NRF2', 'Gene', '4780', (18, 22))	('NRF2', 'Gene', '4780', (145, 149))	('NRF2', 'Gene', (18, 22))	('R320Q', 'Var', (124, 129))	('HEK293T', 'CellLine', 'CVCL:0063', (68, 75))	('NPM1', 'Gene', (161, 165))	('NRF2', 'Gene', (145, 149))	('R320Q', 'Mutation', 'p.R320Q', (124, 129))	('KEAP1', 'Gene', '9817', (105, 110))	('NPM1', 'Gene', '4869', (161, 165))	('Ubiquitination', 'MPA', (0, 14))	('KEAP1', 'Gene', (105, 110))
473852	24322982	For the in vitro ubiquitination assay, wild-type KEAP1 or the R320Q mutant was mixed with recombinant human E1, UbcH5, CUL3-RBX1, ubiquitin and GST-tagged NRF2 NEH2 domain (GST-NRF2-Neh2) in buffer containing 40 mM Tris-HCl pH 8.0, 5 mM MgCl2, 2 mM DTT and 4 mM ATP.	('NRF2', 'Gene', '4780', (155, 159))	('CUL3', 'Gene', '8452', (119, 123))	('NEH2', 'Gene', (160, 164))	('R320Q', 'Var', (62, 67))	('UbcH5', 'Gene', (112, 117))	('NEH2', 'Gene', '252969', (160, 164))	('DTT', 'Chemical', 'MESH:D004229', (249, 252))	('R320Q', 'Mutation', 'p.R320Q', (62, 67))	('RBX1', 'Gene', (124, 128))	('KEAP1', 'Gene', '9817', (49, 54))	('NRF2', 'Gene', (155, 159))	('NRF2', 'Gene', '4780', (177, 181))	('KEAP1', 'Gene', (49, 54))	('human', 'Species', '9606', (102, 107))	('MgCl2', 'Chemical', 'MESH:D015636', (237, 242))	('Neh2', 'Gene', (182, 186))	('CUL3', 'Gene', (119, 123))	('Tris-HCl', 'Chemical', '-', (215, 223))	('Neh2', 'Gene', '252969', (182, 186))	('NRF2', 'Gene', (177, 181))	('UbcH5', 'Gene', '7321', (112, 117))	('RBX1', 'Gene', '9978', (124, 128))	('ATP', 'Chemical', 'MESH:D000255', (262, 265))
473863	24322982	Mapping these mutations onto the KEAP1 primary amino acid sequence revealed a mostly uniform distribution of affected residues (Fig.	('KEAP1', 'Gene', (33, 38))	('mutations', 'Var', (14, 23))	('KEAP1', 'Gene', '9817', (33, 38))
473864	24322982	The distribution of mutations specifically found in squamous cell lung carcinoma further reiterated the lack of a 'mutation cluster region' (Fig.	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('squamous cell lung carcinoma', 'Disease', 'MESH:D002294', (52, 80))	('squamous cell lung carcinoma', 'Phenotype', 'HP:0030359', (52, 80))	('squamous cell lung carcinoma', 'Disease', (52, 80))	('mutations', 'Var', (20, 29))
473865	24322982	Of the 18 mutations found in lung SQCC, only two mutations resulted in a truncated protein product (N469fs and P318fs).	('N469fs', 'Var', (100, 106))	('P318fs', 'Mutation', 'p.P318fsX', (111, 117))	('lung SQCC', 'Gene', (29, 38))	('resulted in', 'Reg', (59, 70))	('P318fs', 'Var', (111, 117))	('N469fs', 'Mutation', 'p.N469fsX', (100, 106))
473866	24322982	The remaining 16 missense mutations included the addition of three new cysteine residues (G333C, W544C, and S243C), which might alter KEAP1 reactivity to electrophilic agents.	('alter', 'Reg', (128, 133))	('G333C', 'Mutation', 'rs1218502799', (90, 95))	('KEAP1', 'Gene', (134, 139))	('S243C', 'Mutation', 'p.S243C', (108, 113))	('S243C', 'Var', (108, 113))	('G333C', 'Var', (90, 95))	('W544C', 'Var', (97, 102))	('cysteine', 'Chemical', 'MESH:D003545', (71, 79))	('KEAP1', 'Gene', '9817', (134, 139))	('W544C', 'SUBSTITUTION', 'None', (97, 102))
473867	24322982	One mutation, V155F occurred in two separate tumors, and interestingly, none of the mutations in KEAP1 were in residues that directly interface with NRF2.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('KEAP1', 'Gene', '9817', (97, 102))	('tumors', 'Disease', (45, 51))	('NRF2', 'Gene', '4780', (149, 153))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('V155F', 'Var', (14, 19))	('mutations', 'Var', (84, 93))	('tumors', 'Disease', 'MESH:D009369', (45, 51))	('KEAP1', 'Gene', (97, 102))	('NRF2', 'Gene', (149, 153))	('V155F', 'Mutation', 'p.V155F', (14, 19))
473868	24322982	Given the importance of KEAP1-NRF2 signaling in cancer and our inability to predict the functional consequences of KEAP1 mutation, we cloned and comparatively evaluated each of the 18 lung SQCC mutations.	('KEAP1', 'Gene', '9817', (24, 29))	('NRF2', 'Gene', (30, 34))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('KEAP1', 'Gene', (24, 29))	('KEAP1', 'Gene', '9817', (115, 120))	('mutations', 'Var', (194, 203))	('lung', 'Disease', (184, 188))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('KEAP1', 'Gene', (115, 120))	('NRF2', 'Gene', '4780', (30, 34))
473869	24322982	To test whether cancer-derived mutations in KEAP1 affect NRF2-driven transcription, we used an engineered reporter system, wherein the luciferase gene is expressed in a NRF2-dependent manner.	('mutations', 'Var', (31, 40))	('cancer', 'Disease', 'MESH:D009369', (16, 22))	('KEAP1', 'Gene', (44, 49))	('NRF2', 'Gene', '4780', (169, 173))	('cancer', 'Disease', (16, 22))	('NRF2', 'Gene', '4780', (57, 61))	('affect', 'Reg', (50, 56))	('NRF2', 'Gene', (169, 173))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('NRF2', 'Gene', (57, 61))	('KEAP1', 'Gene', '9817', (44, 49))
473871	24322982	By comparison, the KEAP1 mutants displayed variable suppression of NRF2-driven transcription.	('KEAP1', 'Gene', (19, 24))	('mutants', 'Var', (25, 32))	('NRF2', 'Gene', '4780', (67, 71))	('suppression', 'NegReg', (52, 63))	('KEAP1', 'Gene', '9817', (19, 24))	('NRF2', 'Gene', (67, 71))
473872	24322982	Specifically, L231V, S224Y, P318L and R71L suppressed NRF2 as well as wild-type KEAP1; these genotypes represent possible passenger mutations within KEAP1.	('L231V', 'Mutation', 'p.L231V', (14, 19))	('S224Y', 'Var', (21, 26))	('NRF2', 'Gene', (54, 58))	('P318L', 'Var', (28, 33))	('P318L', 'Mutation', 'p.P318L', (28, 33))	('R71L', 'Var', (38, 42))	('KEAP1', 'Gene', '9817', (149, 154))	('KEAP1', 'Gene', '9817', (80, 85))	('NRF2', 'Gene', '4780', (54, 58))	('R71L', 'Mutation', 'p.R71L', (38, 42))	('L231V', 'Var', (14, 19))	('S224Y', 'Mutation', 'p.S224Y', (21, 26))	('KEAP1', 'Gene', (149, 154))	('KEAP1', 'Gene', (80, 85))	('suppressed', 'NegReg', (43, 53))
473873	24322982	By contrast, N469fs, P318fs, and G333C exhibited a near-null phenotype.	('P318fs', 'Mutation', 'p.P318fsX', (21, 27))	('G333C', 'Mutation', 'rs1218502799', (33, 38))	('P318fs', 'Var', (21, 27))	('G333C', 'Var', (33, 38))	('N469fs', 'Var', (13, 19))	('N469fs', 'Mutation', 'p.N469fsX', (13, 19))
473874	24322982	Most surprisingly, of the 18 mutants examined, 11 retained partial ability to suppress NRF2-driven transcription.	('NRF2', 'Gene', '4780', (87, 91))	('mutants', 'Var', (29, 36))	('suppress', 'NegReg', (78, 86))	('NRF2', 'Gene', (87, 91))
473875	24322982	To further validate these data, we tested the panel in the lung adenocarcinoma cell line A549, which express mutant and inactive KEAP1G333C, and in Keap1 knockout mouse embryo fibroblasts (MEFs).	('A549', 'CellLine', 'CVCL:0023', (89, 93))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (59, 78))	('KEAP1G333C', 'Var', (129, 139))	('MEFs', 'CellLine', 'CVCL:9115', (189, 193))	('mouse', 'Species', '10090', (163, 168))	('mutant', 'Var', (109, 115))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (59, 78))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))	('lung adenocarcinoma', 'Disease', (59, 78))
473878	24322982	As such, we tested whether the relative activities of each KEAP1 mutant correlated with the expression of 15 NRF2 target genes within the lung SQCC TCGA cohort.	('correlated', 'Reg', (72, 82))	('tested', 'Reg', (12, 18))	('KEAP1', 'Gene', (59, 64))	('mutant', 'Var', (65, 71))	('NRF2', 'Gene', '4780', (109, 113))	('activities', 'MPA', (40, 50))	('NRF2', 'Gene', (109, 113))	('expression', 'Species', '29278', (92, 102))	('KEAP1', 'Gene', '9817', (59, 64))	('expression', 'MPA', (92, 102))
473879	24322982	1B-D) to the NRF2 transcriptional gene signature, we found that mutants that suppress like wild-type KEAP1 associate with decreased NRF2 activity, whereas mutants unable to completely suppress NRF2 correlate with increased NRF2 target gene expression (p=0.049; two-sided Wilcoxon Rank Sum Test) (Fig.	('NRF2', 'Gene', '4780', (132, 136))	('NRF2', 'Gene', (223, 227))	('NRF2', 'Gene', '4780', (193, 197))	('KEAP1', 'Gene', '9817', (101, 106))	('NRF2', 'Gene', (132, 136))	('expression', 'Species', '29278', (240, 250))	('NRF2', 'Gene', '4780', (13, 17))	('expression', 'MPA', (240, 250))	('activity', 'MPA', (137, 145))	('NRF2', 'Gene', (193, 197))	('mutants', 'Var', (64, 71))	('KEAP1', 'Gene', (101, 106))	('NRF2', 'Gene', '4780', (223, 227))	('NRF2', 'Gene', (13, 17))	('increased', 'PosReg', (213, 222))	('decreased', 'NegReg', (122, 131))
473881	24322982	Next, we sought molecular insight into how specific mutations differentially impacted KEAP1 function.	('mutations', 'Var', (52, 61))	('impacted', 'Reg', (77, 85))	('KEAP1', 'Gene', '9817', (86, 91))	('KEAP1', 'Gene', (86, 91))
473882	24322982	First, we determined whether the mutants expressed at levels similar to wild-type KEAP1, as non-synonymous mutations often impair protein folding to decrease protein stability.	('protein folding', 'MPA', (130, 145))	('protein stability', 'MPA', (158, 175))	('mutations', 'Var', (107, 116))	('impair', 'NegReg', (123, 129))	('KEAP1', 'Gene', (82, 87))	('KEAP1', 'Gene', '9817', (82, 87))	('decrease', 'NegReg', (149, 157))
473883	24322982	Transient expression from plasmid DNA indicates that the majority of KEAP1 mutants expressed at levels similar to wild-type protein (Fig.	('KEAP1', 'Gene', '9817', (69, 74))	('KEAP1', 'Gene', (69, 74))	('expression', 'Species', '29278', (10, 20))	('mutants', 'Var', (75, 82))
473884	24322982	Further study is required to determine if the reduced expression of mutants R554Q, W544C, N469fs, P318fs, G480W, and G333C is due to altered protein or mRNA stability.	('expression', 'MPA', (54, 64))	('G333C', 'Var', (117, 122))	('G333C', 'Mutation', 'rs1218502799', (117, 122))	('G480W', 'Mutation', 'p.G480W', (106, 111))	('W544C', 'Var', (83, 88))	('P318fs', 'Mutation', 'p.P318fsX', (98, 104))	('P318fs', 'Var', (98, 104))	('reduced', 'NegReg', (46, 53))	('W544C', 'SUBSTITUTION', 'None', (83, 88))	('protein', 'MPA', (141, 148))	('N469fs', 'Mutation', 'p.N469fsX', (90, 96))	('mRNA stability', 'MPA', (152, 166))	('expression', 'Species', '29278', (54, 64))	('R554Q', 'Mutation', 'rs751295594', (76, 81))	('G480W', 'Var', (106, 111))	('N469fs', 'Var', (90, 96))	('altered', 'Reg', (133, 140))
473885	24322982	To extend these data, the subcellular localization of KEAP1 and each KEAP1 mutant was evaluated in HEK293T cells; all mutants exhibited a localization pattern indistinguishable from wild-type KEAP1 (Fig.	('KEAP1', 'Gene', '9817', (192, 197))	('KEAP1', 'Gene', (54, 59))	('KEAP1', 'Gene', '9817', (69, 74))	('HEK293T', 'CellLine', 'CVCL:0063', (99, 106))	('mutants', 'Var', (118, 125))	('localization', 'MPA', (138, 150))	('KEAP1', 'Gene', (192, 197))	('KEAP1', 'Gene', (69, 74))	('KEAP1', 'Gene', '9817', (54, 59))	('exhibited', 'Reg', (126, 135))
473888	24322982	Following cysteine modification, either by reactive oxygen species or electrophilic agents like tert-butylhydroquinone (tBHQ), a conformational change within the KEAP1 homodimer creates an SDS-resistant form which is readily visualized under denaturing electrophoresis.	('cysteine', 'Chemical', 'MESH:D003545', (10, 18))	('KEAP1', 'Gene', '9817', (162, 167))	('conformational', 'Var', (129, 143))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (43, 66))	('SDS', 'Chemical', 'MESH:D012967', (189, 192))	('KEAP1', 'Gene', (162, 167))	('tert-butylhydroquinone', 'Chemical', 'MESH:C018855', (96, 118))	('SDS-resistant', 'MPA', (189, 202))	('tBHQ', 'Chemical', 'MESH:C018855', (120, 124))
473889	24322982	When treated with the pathway agonist, all 18 mutants formed an SDS-resistant dimer, suggesting that the mutations do not impair dimerization (Fig.	('dimerization', 'MPA', (129, 141))	('SDS-resistant', 'MPA', (64, 77))	('formed', 'Reg', (54, 60))	('SDS', 'Chemical', 'MESH:D012967', (64, 67))	('mutations', 'Var', (105, 114))	('mutants', 'Var', (46, 53))	('impair', 'NegReg', (122, 128))
473890	24322982	To more rigorously test this, FLAG-tagged KEAP1 mutants were transfected into HEK293T cells stably expressing wild-type hemagglutinin epitope (HA) tagged KEAP1.	('KEAP1', 'Gene', '9817', (42, 47))	('KEAP1', 'Gene', (154, 159))	('mutants', 'Var', (48, 55))	('HEK293T', 'CellLine', 'CVCL:0063', (78, 85))	('KEAP1', 'Gene', (42, 47))	('KEAP1', 'Gene', '9817', (154, 159))
473891	24322982	FLAG immunopurification of the mutant protein, followed by Western blot for the HA-tagged wild-type protein was performed to evaluate KEAP1 dimerization (Fig.	('KEAP1', 'Gene', (134, 139))	('mutant', 'Var', (31, 37))	('KEAP1', 'Gene', '9817', (134, 139))
473892	24322982	Each KEAP1 mutant protein retained the ability to dimerize with wild-type KEAP1.	('KEAP1', 'Gene', (5, 10))	('mutant', 'Var', (11, 17))	('dimerize', 'MPA', (50, 58))	('ability', 'MPA', (39, 46))	('protein', 'Protein', (18, 25))	('KEAP1', 'Gene', '9817', (74, 79))	('KEAP1', 'Gene', '9817', (5, 10))	('KEAP1', 'Gene', (74, 79))
473893	24322982	The most likely molecular explanation for how KEAP1 mutations compromise its ability to suppress NRF2 is that the mutations impact either the KEAP1-NRF2 association or the KEAP1-CUL3 association.	('mutations', 'Var', (114, 123))	('NRF2', 'Gene', (148, 152))	('NRF2', 'Gene', '4780', (97, 101))	('KEAP1', 'Gene', '9817', (142, 147))	('KEAP1', 'Gene', '9817', (46, 51))	('suppress', 'NegReg', (88, 96))	('KEAP1', 'Gene', (142, 147))	('compromise', 'NegReg', (62, 72))	('CUL3', 'Gene', (178, 182))	('KEAP1', 'Gene', (46, 51))	('NRF2', 'Gene', (97, 101))	('association', 'Interaction', (153, 164))	('NRF2', 'Gene', '4780', (148, 152))	('mutations', 'Var', (52, 61))	('ability', 'MPA', (77, 84))	('KEAP1', 'Gene', '9817', (172, 177))	('CUL3', 'Gene', '8452', (178, 182))	('KEAP1', 'Gene', (172, 177))	('impact', 'Reg', (124, 130))
473894	24322982	We evaluated whether the KEAP1 mutants maintain their ability to interact with endogenous CUL3 (Fig.	('ability', 'MPA', (54, 61))	('interact', 'Interaction', (65, 73))	('mutants', 'Var', (31, 38))	('KEAP1', 'Gene', '9817', (25, 30))	('KEAP1', 'Gene', (25, 30))	('CUL3', 'Gene', '8452', (90, 94))	('CUL3', 'Gene', (90, 94))
473895	24322982	Immunoprecipitation and Western blot analysis revealed that all of the KEAP1 mutants interact with CUL3 (Fig.	('KEAP1', 'Gene', (71, 76))	('CUL3', 'Gene', '8452', (99, 103))	('CUL3', 'Gene', (99, 103))	('KEAP1', 'Gene', '9817', (71, 76))	('mutants', 'Var', (77, 84))	('interact', 'Interaction', (85, 93))
473897	24322982	Next we determined if the KEAP1-NRF2 association was maintained among the mutants.	('KEAP1', 'Gene', (26, 31))	('NRF2', 'Gene', '4780', (32, 36))	('NRF2', 'Gene', (32, 36))	('KEAP1', 'Gene', '9817', (26, 31))	('mutants', 'Var', (74, 81))
473898	24322982	Western blot analysis of immunopurified KEAP1 and mutant KEAP1 protein complexes showed that the R554Q, W544C, N469fs, P318fs, and G333C mutants failed to bind NRF2 (Fig.	('N469fs', 'Var', (111, 117))	('KEAP1', 'Gene', (40, 45))	('KEAP1', 'Gene', (57, 62))	('bind', 'Interaction', (155, 159))	('P318fs', 'Mutation', 'p.P318fsX', (119, 125))	('NRF2', 'Gene', '4780', (160, 164))	('W544C', 'Var', (104, 109))	('G333C', 'Var', (131, 136))	('P318fs', 'Var', (119, 125))	('G333C', 'Mutation', 'rs1218502799', (131, 136))	('R554Q', 'Var', (97, 102))	('NRF2', 'Gene', (160, 164))	('W544C', 'SUBSTITUTION', 'None', (104, 109))	('KEAP1', 'Gene', '9817', (40, 45))	('KEAP1', 'Gene', '9817', (57, 62))	('R554Q', 'Mutation', 'rs751295594', (97, 102))	('N469fs', 'Mutation', 'p.N469fsX', (111, 117))	('failed', 'NegReg', (145, 151))
473899	24322982	Surprisingly, however, the remaining 13 KEAP1 mutants retained NRF2 binding.	('binding', 'Interaction', (68, 75))	('KEAP1', 'Gene', (40, 45))	('NRF2', 'Gene', (63, 67))	('mutants', 'Var', (46, 53))	('KEAP1', 'Gene', '9817', (40, 45))	('NRF2', 'Gene', '4780', (63, 67))
473900	24322982	Together, these data suggest that with the exception of R554Q, W544C, N469fs, P318fs, and G333C, SQCC-derived KEAP1 mutants maintain their ability to bind both NRF2 and CUL3.	('ability', 'MPA', (139, 146))	('P318fs', 'Mutation', 'p.P318fsX', (78, 84))	('G333C', 'Mutation', 'rs1218502799', (90, 95))	('P318fs', 'Var', (78, 84))	('NRF2', 'Gene', '4780', (160, 164))	('G333C', 'Var', (90, 95))	('R554Q', 'Var', (56, 61))	('W544C', 'SUBSTITUTION', 'None', (63, 68))	('KEAP1', 'Gene', '9817', (110, 115))	('NRF2', 'Gene', (160, 164))	('KEAP1', 'Gene', (110, 115))	('W544C', 'Var', (63, 68))	('R554Q', 'Mutation', 'rs751295594', (56, 61))	('bind', 'Interaction', (150, 154))	('CUL3', 'Gene', '8452', (169, 173))	('N469fs', 'Var', (70, 76))	('N469fs', 'Mutation', 'p.N469fsX', (70, 76))	('CUL3', 'Gene', (169, 173))
473902	24322982	To gather a global perspective of how the mutations affect KEAP1 protein interactions, we performed two experiments.	('KEAP1', 'Gene', (59, 64))	('mutations', 'Var', (42, 51))	('affect', 'Reg', (52, 58))	('KEAP1', 'Gene', '9817', (59, 64))
473903	24322982	The data show a distinct pattern among the KEAP1 mutants; those that do not bind NRF2 fail to bind several of the known interactors, including SLK, AMER1 (WTX), MCM3, DPP3, and IKBKB (IKKbeta) (Fig.	('DPP3', 'Gene', (167, 171))	('KEAP1', 'Gene', (43, 48))	('MCM3', 'Gene', '4172', (161, 165))	('AMER1', 'Gene', (148, 153))	('WTX', 'Gene', (155, 158))	('NRF2', 'Gene', '4780', (81, 85))	('IKKbeta', 'Gene', '3551', (184, 191))	('MCM3', 'Gene', (161, 165))	('mutants', 'Var', (49, 56))	('AMER1', 'Gene', '139285', (148, 153))	('SLK', 'Gene', (143, 146))	('DPP3', 'Gene', '10072', (167, 171))	('WTX', 'Gene', '139285', (155, 158))	('NRF2', 'Gene', (81, 85))	('IKBKB', 'Gene', (177, 182))	('IKBKB', 'Gene', '3551', (177, 182))	('bind', 'Interaction', (94, 98))	('SLK', 'Gene', '9748', (143, 146))	('IKKbeta', 'Gene', (184, 191))	('KEAP1', 'Gene', '9817', (43, 48))
473905	24322982	Two mutations, G480W and S224Y, show decreased binding to SLK, MCM3, and DPP3 as compared to NRF2 (Fig.	('NRF2', 'Gene', '4780', (93, 97))	('MCM3', 'Gene', '4172', (63, 67))	('S224Y', 'Var', (25, 30))	('DPP3', 'Gene', (73, 77))	('NRF2', 'Gene', (93, 97))	('G480W', 'Mutation', 'p.G480W', (15, 20))	('DPP3', 'Gene', '10072', (73, 77))	('G480W', 'Var', (15, 20))	('SLK', 'Gene', '9748', (58, 61))	('SLK', 'Gene', (58, 61))	('S224Y', 'Mutation', 'p.S224Y', (25, 30))	('decreased', 'NegReg', (37, 46))	('MCM3', 'Gene', (63, 67))	('binding', 'Interaction', (47, 54))
473906	24322982	Second, we employed affinity purification and shotgun mass spectrometry to define and compare the protein interaction network for wild-type KEAP1 and the following mutants: R554Q, R320Q, R470C, G480W, G423V, D422N, G186R, S243C, and V155F (Fig.	('R554Q', 'Mutation', 'rs751295594', (173, 178))	('R470C', 'Mutation', 'p.R470C', (187, 192))	('R320Q', 'Var', (180, 185))	('G480W', 'Var', (194, 199))	('R320Q', 'Mutation', 'p.R320Q', (180, 185))	('S243C', 'Mutation', 'p.S243C', (222, 227))	('G186R', 'Var', (215, 220))	('D422N', 'Mutation', 'p.D422N', (208, 213))	('D422N', 'Var', (208, 213))	('G423V', 'Var', (201, 206))	('G480W', 'Mutation', 'p.G480W', (194, 199))	('V155F', 'Var', (233, 238))	('G186R', 'Mutation', 'rs750271277', (215, 220))	('R470C', 'Var', (187, 192))	('V155F', 'Mutation', 'p.V155F', (233, 238))	('KEAP1', 'Gene', '9817', (140, 145))	('G423V', 'Mutation', 'p.G423V', (201, 206))	('KEAP1', 'Gene', (140, 145))	('S243C', 'Var', (222, 227))	('R554Q', 'Var', (173, 178))
473908	24322982	The superbinder mutants include R320Q, R470C, G423V, D422N, G186R, S243C and V155F.	('R320Q', 'Mutation', 'p.R320Q', (32, 37))	('G186R', 'Var', (60, 65))	('D422N', 'Var', (53, 58))	('V155F', 'Var', (77, 82))	('R470C', 'Mutation', 'p.R470C', (39, 44))	('S243C', 'Mutation', 'p.S243C', (67, 72))	('S243C', 'Var', (67, 72))	('G423V', 'Mutation', 'p.G423V', (46, 51))	('V155F', 'Mutation', 'p.V155F', (77, 82))	('R320Q', 'Var', (32, 37))	('G186R', 'Mutation', 'rs750271277', (60, 65))	('D422N', 'Mutation', 'p.D422N', (53, 58))	('R470C', 'Var', (39, 44))	('G423V', 'Var', (46, 51))
473910	24322982	Additionally, label-free mass spectrometry comparing wild-type KEAP1 and two superbinder mutants (R320Q and R470C) showed an increased abundance of NRF2 as compared to wild-type KEAP1; based on spectral counts, R320Q and R470C bound 3.3 and 3.2 fold more NRF2 than wild-type KEAP1, respectively (Fig.	('KEAP1', 'Gene', '9817', (178, 183))	('more', 'PosReg', (250, 254))	('NRF2', 'Gene', (148, 152))	('KEAP1', 'Gene', (178, 183))	('R470C', 'Var', (221, 226))	('NRF2', 'Gene', '4780', (255, 259))	('KEAP1', 'Gene', '9817', (63, 68))	('KEAP1', 'Gene', (63, 68))	('R320Q', 'Var', (211, 216))	('R320Q', 'Var', (98, 103))	('R470C', 'Mutation', 'p.R470C', (221, 226))	('R320Q', 'Mutation', 'p.R320Q', (98, 103))	('NRF2', 'Gene', (255, 259))	('R320Q', 'Mutation', 'p.R320Q', (211, 216))	('bound', 'Interaction', (227, 232))	('R470C', 'Var', (108, 113))	('NRF2', 'Gene', '4780', (148, 152))	('KEAP1', 'Gene', '9817', (275, 280))	('KEAP1', 'Gene', (275, 280))	('R470C', 'Mutation', 'p.R470C', (108, 113))
473911	24322982	For comparative purposes, we performed quantitative proteomic analysis on two non-superbinder mutant proteins: R554Q, which cannot bind NRF2 and G480W, which binds NRF2 similarly to wild-type (Fig.	('NRF2', 'Gene', (164, 168))	('G480W', 'Mutation', 'p.G480W', (145, 150))	('bind', 'Interaction', (131, 135))	('G480W', 'Var', (145, 150))	('NRF2', 'Gene', '4780', (136, 140))	('R554Q', 'Var', (111, 116))	('NRF2', 'Gene', '4780', (164, 168))	('R554Q', 'Mutation', 'rs751295594', (111, 116))	('NRF2', 'Gene', (136, 140))
473912	24322982	Despite an increased level of associated NRF2, the superbinder mutants were unable to suppress NRF2-mediated transcription of an artificial reporter gene (Fig.	('NRF2', 'Gene', (41, 45))	('suppress', 'NegReg', (86, 94))	('increased', 'PosReg', (11, 20))	('mutants', 'Var', (63, 70))	('NRF2', 'Gene', '4780', (95, 99))	('NRF2', 'Gene', '4780', (41, 45))	('NRF2', 'Gene', (95, 99))
473913	24322982	To confirm this using endogenous metrics of NRF2 activity, HEK293T cells, H2228 cells or A549 cells were transiently transfected with wild-type KEAP1 or the superbinder mutants before Western blot analysis of NRF2 and the NRF2 target gene HMOX1.	('KEAP1', 'Gene', '9817', (144, 149))	('H2228', 'CellLine', 'CVCL:1543', (74, 79))	('A549', 'CellLine', 'CVCL:0023', (89, 93))	('HMOX1', 'Gene', (239, 244))	('NRF2', 'Gene', '4780', (44, 48))	('KEAP1', 'Gene', (144, 149))	('mutants', 'Var', (169, 176))	('HMOX1', 'Gene', '3162', (239, 244))	('NRF2', 'Gene', '4780', (222, 226))	('NRF2', 'Gene', (44, 48))	('HEK293T', 'CellLine', 'CVCL:0063', (59, 66))	('NRF2', 'Gene', '4780', (209, 213))	('NRF2', 'Gene', (222, 226))	('NRF2', 'Gene', (209, 213))
473916	24322982	Our functional and biochemical examination revealed 7 KEAP1 mutations that show significantly impaired ability to suppress NRF2, but yet unexpectedly bind more NRF2 than wild-type KEAP1.	('KEAP1', 'Gene', (54, 59))	('suppress', 'NegReg', (114, 122))	('KEAP1', 'Gene', '9817', (180, 185))	('NRF2', 'Gene', '4780', (160, 164))	('KEAP1', 'Gene', (180, 185))	('NRF2', 'Gene', (160, 164))	('NRF2', 'Gene', '4780', (123, 127))	('KEAP1', 'Gene', '9817', (54, 59))	('mutations', 'Var', (60, 69))	('bind', 'Interaction', (150, 154))	('NRF2', 'Gene', (123, 127))
473918	24322982	Using a cycloheximide pulse-chase approach, NRF2 protein half-life was evaluated in HEK293T cells stably expressing: 1) wild-type KEAP1, 2) the R320Q superbinder, 3) R470C superbinder, 3) R554Q which does not bind NRF2, or 5) G480W which behaves like wild-type.	('R554Q', 'Var', (188, 193))	('KEAP1', 'Gene', (130, 135))	('HEK293T', 'CellLine', 'CVCL:0063', (84, 91))	('R320Q', 'Mutation', 'p.R320Q', (144, 149))	('NRF2', 'Gene', '4780', (44, 48))	('NRF2', 'Gene', '4780', (214, 218))	('cycloheximide', 'Chemical', 'MESH:D003513', (8, 21))	('R320Q', 'Var', (144, 149))	('R554Q', 'Mutation', 'rs751295594', (188, 193))	('NRF2', 'Gene', (44, 48))	('NRF2', 'Gene', (214, 218))	('R470C', 'Var', (166, 171))	('G480W', 'Mutation', 'p.G480W', (226, 231))	('KEAP1', 'Gene', '9817', (130, 135))	('R470C', 'Mutation', 'p.R470C', (166, 171))	('G480W', 'Var', (226, 231))
473919	24322982	The expression of R320Q or R470C dramatically stabilized the NRF2 protein as compared to no exogenous KEAP1, wild-type KEAP1 or G480W (Fig.	('R320Q', 'Var', (18, 23))	('KEAP1', 'Gene', (119, 124))	('protein', 'Protein', (66, 73))	('KEAP1', 'Gene', (102, 107))	('expression', 'Species', '29278', (4, 14))	('G480W', 'Mutation', 'p.G480W', (128, 133))	('KEAP1', 'Gene', '9817', (119, 124))	('R320Q', 'Mutation', 'p.R320Q', (18, 23))	('R470C', 'Var', (27, 32))	('NRF2', 'Gene', '4780', (61, 65))	('R470C', 'Mutation', 'p.R470C', (27, 32))	('stabilized', 'PosReg', (46, 56))	('KEAP1', 'Gene', '9817', (102, 107))	('NRF2', 'Gene', (61, 65))
473920	24322982	The increased NRF2 stability occurred as a result of binding R320Q or R470C, as unbound NRF2 in the flow-through eluate showed elevated levels but dynamic turnover (Fig.	('NRF2', 'Gene', (14, 18))	('R320Q', 'Mutation', 'p.R320Q', (61, 66))	('dynamic turnover', 'MPA', (147, 163))	('NRF2', 'Gene', '4780', (88, 92))	('NRF2', 'Gene', '4780', (14, 18))	('R470C', 'Var', (70, 75))	('NRF2', 'Gene', (88, 92))	('elevated', 'PosReg', (127, 135))	('stability', 'MPA', (19, 28))	('levels', 'MPA', (136, 142))	('R320Q', 'Var', (61, 66))	('R470C', 'Mutation', 'p.R470C', (70, 75))	('increased', 'PosReg', (4, 13))
473922	24322982	Together, these data suggest that the superbinder mutations within KEAP1 result in the stabilization of KEAP1-associated NRF2 and elevated levels of free NRF2, although the free NRF2 is still subject to dynamic turnover.	('KEAP1', 'Gene', (67, 72))	('NRF2', 'Gene', '4780', (121, 125))	('mutations', 'Var', (50, 59))	('NRF2', 'Gene', (178, 182))	('NRF2', 'Gene', '4780', (178, 182))	('NRF2', 'Gene', (121, 125))	('KEAP1', 'Gene', '9817', (104, 109))	('elevated', 'PosReg', (130, 138))	('NRF2', 'Gene', '4780', (154, 158))	('KEAP1', 'Gene', (104, 109))	('KEAP1', 'Gene', '9817', (67, 72))	('stabilization', 'MPA', (87, 100))	('NRF2', 'Gene', (154, 158))
473923	24322982	Given the increased NRF2 association and protein stability, we hypothesized that R320Q and other superbinder mutants impair NRF2 ubiquitination.	('ubiquitination', 'MPA', (129, 143))	('NRF2', 'Gene', '4780', (124, 128))	('NRF2', 'Gene', (20, 24))	('R320Q', 'Mutation', 'p.R320Q', (81, 86))	('impair', 'NegReg', (117, 123))	('association', 'Interaction', (25, 36))	('NRF2', 'Gene', (124, 128))	('NRF2', 'Gene', '4780', (20, 24))	('R320Q', 'Var', (81, 86))	('increased', 'PosReg', (10, 19))
473924	24322982	To test this, we performed two complementary experiments to evaluate NRF2 ubiquitination by wild-type KEAP1 or the R320Q superbinder.	('ubiquitination', 'MPA', (74, 88))	('KEAP1', 'Gene', (102, 107))	('NRF2', 'Gene', (69, 73))	('R320Q', 'Var', (115, 120))	('R320Q', 'Mutation', 'p.R320Q', (115, 120))	('KEAP1', 'Gene', '9817', (102, 107))	('NRF2', 'Gene', '4780', (69, 73))
473925	24322982	First, Western blot analysis of immunoprecipitated NRF2, after denaturation, showed robust ubiquitination by both wild-type KEAP1 and R320Q (Fig.	('R320Q', 'Mutation', 'p.R320Q', (134, 139))	('NRF2', 'Gene', (51, 55))	('KEAP1', 'Gene', '9817', (124, 129))	('KEAP1', 'Gene', (124, 129))	('NRF2', 'Gene', '4780', (51, 55))	('R320Q', 'Var', (134, 139))	('ubiquitination', 'MPA', (91, 105))
473926	24322982	Remarkably, both experimental approaches demonstrate that wild-type KEAP1 and R320Q ubiquitinate NRF2.	('NRF2', 'Gene', '4780', (97, 101))	('KEAP1', 'Gene', (68, 73))	('NRF2', 'Gene', (97, 101))	('R320Q', 'Var', (78, 83))	('ubiquitinate', 'MPA', (84, 96))	('R320Q', 'Mutation', 'p.R320Q', (78, 83))	('KEAP1', 'Gene', '9817', (68, 73))
473927	24322982	With some latitude, we can classify the 18 KEAP1 mutations into three classes.	('KEAP1', 'Gene', '9817', (43, 48))	('KEAP1', 'Gene', (43, 48))	('mutations', 'Var', (49, 58))
473928	24322982	First, the L231V, S224Y, P318L and R71L mutations did not impact the KEAP1-NRF2 association or the suppression of NRF2 activity.	('S224Y', 'Var', (18, 23))	('R71L', 'Mutation', 'p.R71L', (35, 39))	('L231V', 'Mutation', 'p.L231V', (11, 16))	('P318L', 'Mutation', 'p.P318L', (25, 30))	('KEAP1', 'Gene', '9817', (69, 74))	('P318L', 'Var', (25, 30))	('NRF2', 'Gene', '4780', (114, 118))	('association', 'Interaction', (80, 91))	('NRF2', 'Gene', '4780', (75, 79))	('KEAP1', 'Gene', (69, 74))	('activity', 'MPA', (119, 127))	('R71L', 'Var', (35, 39))	('suppression', 'NegReg', (99, 110))	('NRF2', 'Gene', (114, 118))	('S224Y', 'Mutation', 'p.S224Y', (18, 23))	('L231V', 'Var', (11, 16))	('NRF2', 'Gene', (75, 79))
473929	24322982	These mutations likely represent passenger events within KEAP1, at least with respect to NRF2.	('NRF2', 'Gene', (89, 93))	('KEAP1', 'Gene', (57, 62))	('NRF2', 'Gene', '4780', (89, 93))	('KEAP1', 'Gene', '9817', (57, 62))	('mutations', 'Var', (6, 15))
473930	24322982	Second, and not surprisingly, the frame shift mutations N469fs and P318fs, as well as G333C, R554Q and W544C did not bind NRF2 and did not or weakly suppressed NRF2-mediated transcription.	('P318fs', 'Var', (67, 73))	('bind', 'Interaction', (117, 121))	('G333C', 'Mutation', 'rs1218502799', (86, 91))	('W544C', 'Var', (103, 108))	('G333C', 'Var', (86, 91))	('not', 'NegReg', (113, 116))	('NRF2', 'Gene', '4780', (160, 164))	('R554Q', 'Var', (93, 98))	('NRF2', 'Gene', '4780', (122, 126))	('NRF2', 'Gene', (160, 164))	('W544C', 'SUBSTITUTION', 'None', (103, 108))	('R554Q', 'Mutation', 'rs751295594', (93, 98))	('suppressed', 'NegReg', (149, 159))	('NRF2', 'Gene', (122, 126))	('P318fs', 'Mutation', 'p.P318fsX', (67, 73))	('N469fs', 'Var', (56, 62))	('N469fs', 'Mutation', 'p.N469fsX', (56, 62))
473931	24322982	Third, the remaining nine mutations fell within a hypomorphic phenotypic range, with suppression occurring between 30-60% of the wild-type KEAP1.	('mutations', 'Var', (26, 35))	('KEAP1', 'Gene', (139, 144))	('KEAP1', 'Gene', '9817', (139, 144))
473932	24322982	Biochemically, the hypomorphic mutants displayed either reduced NRF2 binding or surprisingly, increased binding (the superbinders).	('mutants', 'Var', (31, 38))	('reduced', 'NegReg', (56, 63))	('increased', 'PosReg', (94, 103))	('NRF2', 'Gene', '4780', (64, 68))	('binding', 'Interaction', (104, 111))	('binding', 'Interaction', (69, 76))	('NRF2', 'Gene', (64, 68))
473933	24322982	Mutations in tumor suppressor genes often results in complete loss of protein expression or the expression of a truncated protein product.	('loss', 'NegReg', (62, 66))	('tumor', 'Disease', (13, 18))	('expression', 'Species', '29278', (96, 106))	('protein expression', 'MPA', (70, 88))	('expression of a truncated protein product', 'MPA', (96, 137))	('Mutations', 'Var', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('expression', 'Species', '29278', (78, 88))
473936	24322982	First, we found that many KEAP1 mutations result in a hypomorphic phenotype, rather than a genetic null.	('KEAP1', 'Gene', (26, 31))	('mutations', 'Var', (32, 41))	('hypomorphic phenotype', 'MPA', (54, 75))	('KEAP1', 'Gene', '9817', (26, 31))	('result in', 'Reg', (42, 51))
473937	24322982	Second, in general, these hypomorphic mutations do not affect the global KEAP1 protein interaction network, suggesting that some KEAP1 protein interactions are retained in the absence of NRF2 suppression (Fig.	('NRF2', 'Gene', '4780', (187, 191))	('KEAP1', 'Gene', '9817', (73, 78))	('NRF2', 'Gene', (187, 191))	('KEAP1', 'Gene', '9817', (129, 134))	('KEAP1', 'Gene', (73, 78))	('mutations', 'Var', (38, 47))	('KEAP1', 'Gene', (129, 134))
473940	24322982	Previously, we found that hypomorphic KEAP1 mutants can be further inactivated by the ETGE-containing competitive binding protein, DPP3.	('KEAP1', 'Gene', '9817', (38, 43))	('KEAP1', 'Gene', (38, 43))	('DPP3', 'Gene', '10072', (131, 135))	('mutants', 'Var', (44, 51))	('DPP3', 'Gene', (131, 135))	('ETGE', 'Chemical', '-', (86, 90))
473941	24322982	Coupled with the observed over-expression of DPP3 in lung squamous cell carcinoma, these observations suggest that from the perspective of cancer cell fitness, the presence of a hypomorphic KEAP1 mutation may be more valuable than a null mutant.	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (53, 81))	('cancer cell fitness', 'Disease', 'MESH:C538614', (139, 158))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (58, 81))	('DPP3', 'Gene', '10072', (45, 49))	('mutation', 'Var', (196, 204))	('lung squamous cell carcinoma', 'Disease', (53, 81))	('DPP3', 'Gene', (45, 49))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('expression', 'Species', '29278', (31, 41))	('KEAP1', 'Gene', '9817', (190, 195))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (53, 81))	('cancer cell fitness', 'Disease', (139, 158))	('KEAP1', 'Gene', (190, 195))
473943	24322982	First, by what mechanism could the 'superbinder' mutations affect NRF2 stability?	('affect', 'Reg', (59, 65))	('mutations', 'Var', (49, 58))	('NRF2', 'Gene', (66, 70))	('stability', 'MPA', (71, 80))	('NRF2', 'Gene', '4780', (66, 70))
473945	24322982	Analogously, the expression of a superbinder variant SH2 domain antagonizes epidermal growth factor signaling via competitive inhibition.	('expression', 'Species', '29278', (17, 27))	('epidermal', 'MPA', (76, 85))	('variant', 'Var', (45, 52))	('SH2 domain', 'Gene', (53, 63))	('antagonizes', 'NegReg', (64, 75))	('competitive', 'MPA', (114, 125))
473947	24322982	A second possibility is that the superbinder mutations simply slow the rate of CUL3 neddylation.	('mutations', 'Var', (45, 54))	('superbinder', 'Gene', (33, 44))	('CUL3', 'Gene', '8452', (79, 83))	('slow', 'NegReg', (62, 66))	('CUL3', 'Gene', (79, 83))	('rate', 'MPA', (71, 75))
473948	24322982	The striking observation that the enhanced NRF2 binding class of KEAP1 mutants ubiquitinates NRF2 suggests that the mutations functionally hinder one of the steps prior to proteolysis, but after ubiquitination.	('NRF2', 'Gene', '4780', (93, 97))	('enhanced', 'PosReg', (34, 42))	('KEAP1', 'Gene', (65, 70))	('steps prior to proteolysis', 'MPA', (157, 183))	('NRF2', 'Gene', (93, 97))	('NRF2', 'Gene', '4780', (43, 47))	('mutants', 'Var', (71, 78))	('mutations', 'Var', (116, 125))	('hinder', 'NegReg', (139, 145))	('NRF2', 'Gene', (43, 47))	('KEAP1', 'Gene', '9817', (65, 70))
473949	24322982	Here, immediate questions include whether the superbinder mutations affect the ubiquitin chain linkage on NRF2 or whether they perturb the interaction of KEAP1 with the proteasome.	('mutations', 'Var', (58, 67))	('perturb', 'NegReg', (127, 134))	('superbinder', 'Gene', (46, 57))	('KEAP1', 'Gene', (154, 159))	('proteasome', 'Protein', (169, 179))	('ubiquitin chain linkage', 'MPA', (79, 102))	('NRF2', 'Gene', '4780', (106, 110))	('interaction', 'Interaction', (139, 150))	('KEAP1', 'Gene', '9817', (154, 159))	('affect', 'Reg', (68, 74))	('NRF2', 'Gene', (106, 110))
473951	24322982	Importantly, as the KEAP1 mutants described in this study exhibit hypomorphic phenotypes, the superbinders could represent a novel mechanism cancer cells employ to enhance cellular fitness without compromising all cellular functions of multifunctional proteins.	('enhance', 'PosReg', (164, 171))	('KEAP1', 'Gene', (20, 25))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('KEAP1', 'Gene', '9817', (20, 25))	('cellular fitness', 'CPA', (172, 188))	('mutants', 'Var', (26, 33))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('cancer', 'Disease', (141, 147))
473952	24322982	Second, it is now widely accepted that elevated levels of NRF2 are associated with enhanced cell viability in several tumor types.	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('NRF2', 'Gene', (58, 62))	('levels', 'Var', (48, 54))	('enhanced', 'PosReg', (83, 91))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumor', 'Disease', (118, 123))	('NRF2', 'Gene', '4780', (58, 62))
473953	24322982	Although we show that 'superbinder' mutations result in NRF2 transcriptional activation, further studies are required to determine whether this KEAP1 mutant class is capable of enhancing cancer cell fitness in vivo, and whether that depends upon prolonged activation of NRF2.	('KEAP1', 'Gene', '9817', (144, 149))	('cancer cell fitness', 'Disease', 'MESH:C538614', (187, 206))	('NRF2', 'Gene', '4780', (56, 60))	('NRF2', 'Gene', (56, 60))	('activation', 'PosReg', (77, 87))	('KEAP1', 'Gene', (144, 149))	('NRF2', 'Gene', '4780', (270, 274))	('mutations', 'Var', (36, 45))	('transcriptional', 'MPA', (61, 76))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('NRF2', 'Gene', (270, 274))	('cancer cell fitness', 'Disease', (187, 206))	('enhancing', 'PosReg', (177, 186))
473954	24322982	Additionally, given emerging evidence identifying other putative KEAP1 substrates in cancer-relevant pathways, such as IKKbeta within NF-kappaB signaling, investigating how:if at all:superbinder mutations impact these proteins could also have clinical significance.	('impact', 'Reg', (205, 211))	('IKKbeta', 'Gene', '3551', (119, 126))	('KEAP1', 'Gene', (65, 70))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('cancer', 'Disease', (85, 91))	('mutations', 'Var', (195, 204))	('proteins', 'Protein', (218, 226))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('IKKbeta', 'Gene', (119, 126))	('KEAP1', 'Gene', '9817', (65, 70))
473955	24322982	Looking at the full set of KEAP1 mutant tumors and the expression of 15 NRF2 target genes, a marginal but statistically significant difference was observed between phenotypically 'silent' KEAP1 mutations and mutations which suppress KEAP1-driven NRF2 degradation (Fig.	('KEAP1', 'Gene', '9817', (27, 32))	('KEAP1', 'Gene', '9817', (233, 238))	('expression', 'Species', '29278', (55, 65))	('KEAP1', 'Gene', (233, 238))	('mutations', 'Var', (208, 217))	('KEAP1', 'Gene', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('degradation', 'MPA', (251, 262))	('suppress', 'NegReg', (224, 232))	('tumors', 'Disease', (40, 46))	('tumors', 'Disease', 'MESH:D009369', (40, 46))	('NRF2', 'Gene', '4780', (72, 76))	('NRF2', 'Gene', '4780', (246, 250))	('KEAP1', 'Gene', '9817', (188, 193))	('KEAP1', 'Gene', (188, 193))	('mutations', 'Var', (194, 203))	('NRF2', 'Gene', (72, 76))	('NRF2', 'Gene', (246, 250))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))
473958	24322982	Third, from a structural perspective, we noted weak correlation between the tertiary position of a mutation and whether the mutation produced a KEAP1 superbinder (Fig.	('KEAP1', 'Gene', '9817', (144, 149))	('KEAP1', 'Gene', (144, 149))	('mutation', 'Var', (124, 132))	('mutation', 'Var', (99, 107))
473959	24322982	Intriguingly, of the 181 missense mutations reported in KEAP1, 6 directly target the R320 superbinder residue, making it the most commonly affected amino acid in KEAP1 (Fig.	('target', 'Reg', (74, 80))	('KEAP1', 'Gene', '9817', (56, 61))	('KEAP1', 'Gene', '9817', (162, 167))	('missense mutations', 'Var', (25, 43))	('KEAP1', 'Gene', (56, 61))	('KEAP1', 'Gene', (162, 167))	('affected', 'Reg', (139, 147))
473960	24322982	Beyond the superbinder mutations, mapping all SQCC 19 mutations onto the KEAP1 structure failed to reveal a discernible pattern.	('KEAP1', 'Gene', '9817', (73, 78))	('mutations', 'Var', (54, 63))	('KEAP1', 'Gene', (73, 78))	('SQCC 19', 'Gene', (46, 53))
473962	24322982	Hence, for a cysteine-dependent biosensor like KEAP1, oncogenesis may partially suppress KEAP1 activity by selecting for mutations which add cysteines (S243C, G333C, R470C) or which reduce the relative pKa of existing cysteines, making them more sensitive to electrophilic attack.	('S243C', 'Mutation', 'p.S243C', (152, 157))	('G333C', 'Mutation', 'rs1218502799', (159, 164))	('reduce', 'NegReg', (182, 188))	('pKa', 'MPA', (202, 205))	('activity', 'MPA', (95, 103))	('R470C', 'Var', (166, 171))	('KEAP1', 'Gene', '9817', (89, 94))	('KEAP1', 'Gene', (89, 94))	('sensitive', 'MPA', (246, 255))	('cysteine', 'Chemical', 'MESH:D003545', (13, 21))	('KEAP1', 'Gene', '9817', (47, 52))	('cysteines', 'Chemical', 'MESH:D003545', (141, 150))	('R470C', 'Mutation', 'p.R470C', (166, 171))	('KEAP1', 'Gene', (47, 52))	('S243C', 'Var', (152, 157))	('cysteine', 'Chemical', 'MESH:D003545', (141, 149))	('G333C', 'Var', (159, 164))	('cysteines', 'MPA', (141, 150))	('cysteines', 'Chemical', 'MESH:D003545', (218, 227))	('cysteine', 'Chemical', 'MESH:D003545', (218, 226))
473965	24322982	By extension of this idea, cancer-derived mutations that create 'hyperactive' cysteines within KEAP1 would be expected to produce a hypomorphic phenotype, as we have observed.	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('KEAP1', 'Gene', (95, 100))	('hypomorphic phenotype', 'MPA', (132, 153))	("'hyperactive' cysteines", 'Disease', (64, 87))	("'hyperactive' cysteines", 'Disease', 'MESH:C565659', (64, 87))	('produce', 'Reg', (122, 129))	('cancer', 'Disease', (27, 33))	('cancer', 'Disease', 'MESH:D009369', (27, 33))	('mutations', 'Var', (42, 51))	('KEAP1', 'Gene', '9817', (95, 100))
473966	24322982	Further study is needed to support these ideas, perhaps through the functional and biochemical characterization of the other 213 cancer-derived mutations in KEAP1.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('KEAP1', 'Gene', (157, 162))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('KEAP1', 'Gene', '9817', (157, 162))	('mutations', 'Var', (144, 153))
473968	24322982	In summary, we describe the functional and biochemical characteristics of 18 mutations in the E3 ligase adaptor protein KEAP1, which were found in patient-derived lung cancers.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('lung cancers', 'Phenotype', 'HP:0100526', (163, 175))	('KEAP1', 'Gene', (120, 125))	('patient', 'Species', '9606', (147, 154))	('lung cancers', 'Disease', (163, 175))	('cancers', 'Phenotype', 'HP:0002664', (168, 175))	('mutations', 'Var', (77, 86))	('found', 'Reg', (138, 143))	('lung cancers', 'Disease', 'MESH:D008175', (163, 175))	('KEAP1', 'Gene', '9817', (120, 125))
473969	24322982	We show that while most of these mutations maintain similar protein interactions to wild-type KEAP1, all but four exhibit hypomorphic or null activity with respect to suppression of NRF2-mediated transcription.	('NRF2', 'Gene', (182, 186))	('suppression', 'NegReg', (167, 178))	('mutations', 'Var', (33, 42))	('KEAP1', 'Gene', '9817', (94, 99))	('hypomorphic', 'MPA', (122, 133))	('protein', 'Protein', (60, 67))	('KEAP1', 'Gene', (94, 99))	('NRF2', 'Gene', '4780', (182, 186))
473970	24322982	Intriguingly, a subset of these mutations exhibit enhanced binding to NRF2 despite an inability to suppress NRF2 activity.	('NRF2', 'Gene', '4780', (70, 74))	('binding', 'Interaction', (59, 66))	('NRF2', 'Gene', (108, 112))	('NRF2', 'Gene', (70, 74))	('mutations', 'Var', (32, 41))	('activity', 'MPA', (113, 121))	('enhanced', 'PosReg', (50, 58))	('NRF2', 'Gene', '4780', (108, 112))
473971	24322982	Functional analysis of one of these mutants, R320Q, revealed that these mutants are still able to ubiquitinate NRF2, but appear to be unable to facilitate its degradation.	('ubiquitinate', 'MPA', (98, 110))	('facilitate', 'PosReg', (144, 154))	('NRF2', 'Gene', '4780', (111, 115))	('degradation', 'MPA', (159, 170))	('R320Q', 'Var', (45, 50))	('NRF2', 'Gene', (111, 115))	('R320Q', 'Mutation', 'p.R320Q', (45, 50))	('unable', 'NegReg', (134, 140))
473972	24322982	Further studies are required to elucidate the mechanism of this class of KEAP1 mutations, including how they interact with the proteasome, as well as whether these mutants enhance viability of cancer cells via prolonged activation of NRF2.	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('NRF2', 'Gene', (234, 238))	('enhance', 'PosReg', (172, 179))	('cancer', 'Disease', (193, 199))	('KEAP1', 'Gene', '9817', (73, 78))	('interact', 'Interaction', (109, 117))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('KEAP1', 'Gene', (73, 78))	('viability', 'CPA', (180, 189))	('NRF2', 'Gene', '4780', (234, 238))	('activation', 'PosReg', (220, 230))	('mutants', 'Var', (164, 171))	('mutations', 'Var', (79, 88))
474018	33906487	The most significant downregulated term was regulation of cell activation, and the GO code was 0050865, corresponding to the LIM domain only 4 (LMO4) gene.	('LIM domain only 4', 'Gene', '8543', (125, 142))	('LIM domain only 4', 'Gene', (125, 142))	('downregulated', 'NegReg', (21, 34))	('0050865', 'Var', (95, 102))	('cell activation', 'CPA', (58, 73))
474024	33906487	These data suggest that the presence of genes associated with these pathways may be associated with HIV-infected cells.	('HIV-infected', 'Disease', 'MESH:D015658', (100, 112))	('HIV-infected', 'Disease', (100, 112))	('presence', 'Var', (28, 36))	('associated', 'Reg', (84, 94))
474037	33906487	Deletion of LMO4 impairs Ldb1 and SLK recruitment in migratory cells.	('Ldb1', 'Gene', (25, 29))	('men', 'Species', '9606', (45, 48))	('impairs', 'NegReg', (17, 24))	('SLK', 'Gene', '9748', (34, 37))	('SLK', 'Gene', (34, 37))	('Ldb1', 'Gene', '8861', (25, 29))	('LMO4', 'Gene', (12, 16))	('Deletion', 'Var', (0, 8))
474038	33906487	LMO4 is closely related to the occurrence of many malignant tumors, such as pancreatic cancer, non-small cell lung cancer, and head and neck cancer, and can affect the differentiation of T cells, leading to acute leukemia.	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (95, 121))	('LMO4', 'Var', (0, 4))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (99, 121))	('head and neck cancer', 'Disease', 'MESH:D006258', (127, 147))	('affect', 'Reg', (157, 163))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (95, 121))	('leukemia', 'Phenotype', 'HP:0001909', (213, 221))	('acute leukemia', 'Disease', (207, 221))	('pancreatic cancer', 'Disease', 'MESH:D010190', (76, 93))	('differentiation', 'CPA', (168, 183))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('malignant tumors', 'Disease', (50, 66))	('malignant tumors', 'Disease', 'MESH:D009369', (50, 66))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('pancreatic cancer', 'Disease', (76, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('lung cancer', 'Phenotype', 'HP:0100526', (110, 121))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('non-small cell lung cancer', 'Disease', (95, 121))	('leading to', 'Reg', (196, 206))	('acute leukemia', 'Disease', 'MESH:D015470', (207, 221))	('head and neck cancer', 'Phenotype', 'HP:0012288', (127, 147))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('acute leukemia', 'Phenotype', 'HP:0002488', (207, 221))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (76, 93))
474047	33906487	HIV can persist and permanently insert itself into selected chromosomal locations within infected cells; it can also reverse transcribe its genome, like all retroviruses.	('infected', 'Disease', 'MESH:D007239', (89, 97))	('infected', 'Disease', (89, 97))	('reverse transcribe', 'Var', (117, 135))
474059	33906487	A variety of approaches such as antiretroviral therapy, latency-reversing agents, structured treatment interruptions, therapeutic vaccines, chimeric antigen receptor, broadly neutralizing antibodies and immune checkpoint blockers are being tested to cure HIV, and the effectiveness of gene therapy is supported by most data.	('chimeric', 'Var', (140, 148))	('men', 'Species', '9606', (98, 101))	('HIV', 'Disease', (255, 258))
474060	33906487	Gene therapy has the advantages of specificity and persistence and has the potential to protect patients from subsequent infections.	('infections', 'Disease', (121, 131))	('Gene', 'Var', (0, 4))	('infections', 'Disease', 'MESH:D007239', (121, 131))	('patients', 'Species', '9606', (96, 104))
474065	33906487	As the principle suggests, gene therapy can cure HIV, and the improvement of current methods may lead to the optimization of transduction efficiency and persistence in vivo.	('gene', 'Var', (27, 31))	('men', 'Species', '9606', (69, 72))	('HIV', 'Disease', (49, 52))
474068	33906487	Our small sample size made it difficult to compare the genomic locations of TP63 and LMO4 mutations, and whether these differences in presentation and prognosis are related to the systemic effects of HIV-mediated immunosuppression or to specific biological characteristics of the primary tumor is still unclear.	('tumor', 'Disease', (288, 293))	('TP63', 'Gene', (76, 80))	('TP63', 'Gene', '8626', (76, 80))	('mutations', 'Var', (90, 99))	('LMO4', 'Gene', (85, 89))	('tumor', 'Disease', 'MESH:D009369', (288, 293))	('tumor', 'Phenotype', 'HP:0002664', (288, 293))
474080	33936227	We found only significant difference in survival rate between the patients with negative and positive CLCA2 expression (P=0.038 and P=0.019, respectively).	('CLCA2', 'Gene', '9635', (102, 107))	('positive', 'Var', (93, 101))	('CLCA2', 'Gene', (102, 107))	('negative', 'NegReg', (80, 88))	('patients', 'Species', '9606', (66, 74))
474099	33936227	Immunohistochemistry (IHC)  Immunohistochemistry was performed by using a panel of Rabbit Polyclonal antibodies against CLCA2 (LS-C664626) (LifeSpan BioSciences), SPATS2 (ab122495) (Abcam), ST6GALNAC1 (MBS7053229) (MyBioSource's Products) and Adipophilin (393A-1) (Sigma-Aldrich).	('MBS7053229', 'Var', (202, 212))	('CLCA2', 'Gene', '9635', (120, 125))	('SPATS2', 'Gene', (163, 169))	('Adipophilin', 'Gene', '123', (243, 254))	('Adipophilin', 'Gene', (243, 254))	('ST6GALNAC1', 'Gene', (190, 200))	('SPATS2', 'Gene', '65244', (163, 169))	('CLCA2', 'Gene', (120, 125))	('ST6GALNAC1', 'Gene', '55808', (190, 200))
474112	33936227	Associations Between CLCA2, SPATS2, ST6GALNAC1, and Adipophilin Expression and Survival of Included NSCLC Patients   Significant differences were found in the PFS and OS rates between patients with negative and positive CLCA2 expression (P=0.038 and P=0.019, respectively).	('Adipophilin', 'Gene', (52, 63))	('Associations', 'Interaction', (0, 12))	('differences', 'Reg', (129, 140))	('CLCA2', 'Gene', '9635', (220, 225))	('CLCA2', 'Gene', '9635', (21, 26))	('Patients', 'Species', '9606', (106, 114))	('Adipophilin', 'Gene', '123', (52, 63))	('ST6GALNAC1', 'Gene', (36, 46))	('SPATS2', 'Gene', (28, 34))	('SPATS2', 'Gene', '65244', (28, 34))	('NSCLC', 'Disease', 'MESH:D002289', (100, 105))	('PFS', 'CPA', (159, 162))	('negative', 'Var', (198, 206))	('NSCLC', 'Disease', (100, 105))	('ST6GALNAC1', 'Gene', '55808', (36, 46))	('positive', 'Var', (211, 219))	('CLCA2', 'Gene', (21, 26))	('CLCA2', 'Gene', (220, 225))	('patients', 'Species', '9606', (184, 192))
474141	33936227	Metabolic changes, as well as mutations, are defining characteristics in cancer biology.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('mutations', 'Var', (30, 39))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))
474157	32708015	In mammalian cells, the addition of m5C to RNA cytosines is carried out by enzymes of the NOL1/NOP2/SUN domain (NSUN) family as well as the DNA methyltransferase homologue DNMT2.	('mammalian', 'Species', '9606', (3, 12))	('NOP2', 'Gene', (95, 99))	('DNMT2', 'Gene', '1787', (172, 177))	('NOL1', 'Gene', '4839', (90, 94))	('m5C', 'Chemical', '-', (36, 39))	('NOP2', 'Gene', '4839', (95, 99))	('m5C', 'Var', (36, 39))	('DNMT2', 'Gene', (172, 177))	('cytosines', 'Chemical', 'MESH:D003596', (47, 56))	('NOL1', 'Gene', (90, 94))
474161	32708015	The most commonly found RNA modification in mRNA is called N6-methyladenosine (m6A) and was first described in 1974 by Desrosiers et al..	('N6-methyladenosine', 'Chemical', 'MESH:C010223', (59, 77))	('N6-methyladenosine', 'Var', (59, 77))	('m6A', 'Gene', (79, 82))	('m6A', 'Gene', '56339', (79, 82))
474191	32708015	Loss of NSUN2 in Drosophila was associated with severe short-term memory deficits, while deletion of NSUN2 in mice led to impaired neural development with inhibition of neural cell migration and impaired differentiation of neuronal stem cells, resulting in an accumulation of intermediate progenitors within the developing cerebral cortex and a loss of upper layer neurons.	('accumulation', 'PosReg', (260, 272))	('neural development', 'CPA', (131, 149))	('rat', 'Species', '10116', (184, 187))	('intermediate progenitors', 'CPA', (276, 300))	('NSUN2', 'Gene', (8, 13))	('deletion', 'Var', (89, 97))	('impaired', 'NegReg', (195, 203))	('memory deficits', 'Phenotype', 'HP:0002354', (66, 81))	('memory deficits', 'Disease', (66, 81))	('NSUN2', 'Gene', (101, 106))	('loss', 'NegReg', (345, 349))	('neural cell migration', 'CPA', (169, 190))	('impaired', 'NegReg', (122, 130))	('inhibition', 'NegReg', (155, 165))	('upper layer neurons', 'CPA', (353, 372))	('Drosophila', 'Species', '7227', (17, 27))	('Loss', 'Var', (0, 4))	('differentiation', 'CPA', (204, 219))	('mice', 'Species', '10090', (110, 114))	('memory deficits', 'Disease', 'MESH:D008569', (66, 81))
474192	32708015	Moreover, if DNMT2 and SUN2 are simultaneously deleted, they demonstrate a synthetic lethal interaction, which included a reduced thickness and organization of the cerebral cortex.	('thickness', 'CPA', (130, 139))	('SUN2', 'Gene', (23, 27))	('SUN2', 'Gene', '25777', (23, 27))	('DNMT2', 'Gene', (13, 18))	('rat', 'Species', '10116', (68, 71))	('organization of the cerebral cortex', 'CPA', (144, 179))	('reduced', 'NegReg', (122, 129))	('deleted', 'Var', (47, 54))	('DNMT2', 'Gene', '1787', (13, 18))
474193	32708015	One of the features of loss of m5C RNMTs is elevated tRNA degradation, leading to an accumulation of 5' tRNA-derived small RNA fragments.	('RNMT', 'Gene', (35, 39))	('m5C', 'Chemical', '-', (31, 34))	('tRNA degradation', 'MPA', (53, 69))	('m5C', 'Var', (31, 34))	('RNMT', 'Gene', '8731', (35, 39))	('elevated', 'PosReg', (44, 52))	('accumulation', 'PosReg', (85, 97))	("5' tRNA-derived small RNA fragments", 'MPA', (101, 136))
474195	32708015	Recently, NSUN2 has been shown to methylate mitochondrial tRNAs, and given the major role of mitochondria in neurological disorders involving neurodegeneration, it is perhaps conceivable that m5C RNA methylation deficiencies in both the nuclear and mitochondrial settings may play roles in neural disease.	('NSUN2', 'Gene', (10, 15))	('deficiencies', 'Var', (212, 224))	('neurodegeneration', 'Disease', (142, 159))	('neural disease', 'Disease', (290, 304))	('play roles', 'Reg', (276, 286))	('neurological disorders', 'Disease', 'MESH:D009422', (109, 131))	('neurodegeneration', 'Disease', 'MESH:D019636', (142, 159))	('m5C', 'Chemical', '-', (192, 195))	('neurological disorders', 'Disease', (109, 131))	('neurodegeneration', 'Phenotype', 'HP:0002180', (142, 159))
474196	32708015	In this regard, mutations of NSUN2 have been associated with autosomal recessive disorders associated with intellectual disability including Dubowitz syndrome (DS) and autism spectrum disorders (ASD).	('intellectual disability', 'Disease', (107, 130))	('autosomal recessive disorders', 'Disease', 'MESH:D030342', (61, 90))	('Dubowitz syndrome', 'Disease', 'MESH:C535718', (141, 158))	('autism spectrum disorders', 'Disease', (168, 193))	('mutations', 'Var', (16, 25))	('NSUN2', 'Gene', (29, 34))	('associated', 'Reg', (45, 55))	('intellectual disability', 'Phenotype', 'HP:0001249', (107, 130))	('autism spectrum disorders', 'Disease', 'MESH:D000067877', (168, 193))	('autism spectrum disorders', 'Phenotype', 'HP:0000729', (168, 193))	('Dubowitz syndrome', 'Disease', (141, 158))	('autosomal recessive disorders', 'Disease', (61, 90))	('autism', 'Phenotype', 'HP:0000717', (168, 174))	('ASD', 'Phenotype', 'HP:0000729', (195, 198))
474202	32708015	NSUN2 has been shown to methylate SHC Transforming Protein (SHC) mRNA, resulting in the enhanced translation of SHC isoforms under conditions of stress (oxidative or high glucose) and causing an accelerated senescence of human vascular endothelial cells (HUVECs).	('SHC', 'Gene', '6464', (60, 63))	('SHC', 'Gene', (34, 37))	('rat', 'Species', '10116', (201, 204))	('SHC', 'Gene', '6464', (112, 115))	('senescence', 'CPA', (207, 217))	('NSUN2', 'Var', (0, 5))	('high glucose', 'Phenotype', 'HP:0003074', (166, 178))	('causing', 'Reg', (184, 191))	('accelerated', 'PosReg', (195, 206))	('human', 'Species', '9606', (221, 226))	('SHC', 'Gene', '6464', (34, 37))	('SHC', 'Gene', (112, 115))	('glucose', 'Chemical', 'MESH:D005947', (171, 178))	('SHC', 'Gene', (60, 63))	('enhanced', 'PosReg', (88, 96))	('translation', 'MPA', (97, 108))
474203	32708015	Moreover, methylation of Intercellular Adhesion Molecule 1 (ICAM-1) mRNA by NSUN2 promotes enhanced translation of this adhesion molecule and results in increased adhesion of leukocytes to endothelial cells.	('ICAM-1', 'Gene', (60, 66))	('increased', 'PosReg', (153, 162))	('adhesion', 'MPA', (163, 171))	('NSUN2', 'Gene', (76, 81))	('Intercellular Adhesion Molecule 1', 'Gene', '3383', (25, 58))	('ICAM-1', 'Gene', '3383', (60, 66))	('methylation', 'Var', (10, 21))	('translation', 'MPA', (100, 111))	('Intercellular Adhesion Molecule 1', 'Gene', (25, 58))	('enhanced', 'PosReg', (91, 99))
474211	32708015	Using array-comparative genomic hybridization (a-CGH), Frye and colleagues subsequently demonstrated that, in a panel of breast cancer cell lines, 18 out of 50 cell lines analyzed had a copy number gain of the genomic region containing NSUN2 (5p15.31-33), and of these, 16 (16/18) were found to have significantly increased expression of NSUN2.	('copy number', 'Var', (186, 197))	('NSUN2', 'Gene', (338, 343))	('pan', 'Gene', (112, 115))	('rat', 'Species', '10116', (95, 98))	('increased', 'PosReg', (314, 323))	('rat', 'Species', '10116', (17, 20))	('breast cancer', 'Disease', 'MESH:D001943', (121, 134))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('expression', 'MPA', (324, 334))	('breast cancer', 'Disease', (121, 134))	('NSUN2', 'Gene', (236, 241))	('gain', 'PosReg', (198, 202))	('breast cancer', 'Phenotype', 'HP:0003002', (121, 134))	('pan', 'Gene', '51816', (112, 115))
474216	32708015	DNA hypomethylation has also been found to be associated with increased NSUN2 expression in breast cancer, and NSUN2 overexpression promoted cell proliferation, migration, and invasion while NSUN2 knockdown inhibited these processes in vitro and in vivo.	('increased', 'PosReg', (62, 71))	('breast cancer', 'Phenotype', 'HP:0003002', (92, 105))	('expression', 'MPA', (78, 88))	('breast cancer', 'Disease', (92, 105))	('hypomethylation', 'Var', (4, 19))	('NSUN2', 'Gene', (72, 77))	('overexpression', 'Var', (117, 131))	('rat', 'Species', '10116', (153, 156))	('NSUN2', 'Gene', (111, 116))	('cell proliferation', 'CPA', (141, 159))	('rat', 'Species', '10116', (164, 167))	('migration', 'CPA', (161, 170))	('promoted', 'PosReg', (132, 140))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('invasion', 'CPA', (176, 184))	('breast cancer', 'Disease', 'MESH:D001943', (92, 105))
474218	32708015	While the initial studies of NSUN2 in breast cancer found no association with ER status or Ki67, in contrast, the study by Yi et al.	('Ki67', 'Var', (91, 95))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('breast cancer', 'Disease', 'MESH:D001943', (38, 51))	('breast cancer', 'Disease', (38, 51))	('breast cancer', 'Phenotype', 'HP:0003002', (38, 51))
474225	32708015	This methylation inhibits the processing of pri-miR-125b2 into pre-miR-125b2, decreases the cleavage of pre-miR-125b2 into miR-125, and attenuates the recruitment of RISC by miR-125, thereby repressing the function of miR-125b in silencing gene expression.	('inhibits', 'NegReg', (17, 25))	('cleavage', 'MPA', (92, 100))	('recruitment', 'MPA', (151, 162))	('miR-125b2', 'Gene', (108, 117))	('methylation', 'Var', (5, 16))	('miR-125b2', 'Gene', '406912', (48, 57))	('processing', 'MPA', (30, 40))	('repressing', 'NegReg', (191, 201))	('RISC', 'Gene', (166, 170))	('miR-125', 'MPA', (123, 130))	('silencing gene expression', 'MPA', (230, 255))	('miR-125b2', 'Gene', (67, 76))	('miR-125b2', 'Gene', '406912', (108, 117))	('RISC', 'Gene', '59342', (166, 170))	('decreases', 'NegReg', (78, 87))	('miR-125b2', 'Gene', '406912', (67, 76))	('miR-125b2', 'Gene', (48, 57))	('attenuates', 'NegReg', (136, 146))
474235	32708015	Due to its original identification as a marker of proliferation, high expression of NSUN1 (NOP2/p120) has been identified as a prognostic biomarker in non-small cell lung cancer (NSCLC).	('NOP2', 'Gene', (91, 95))	('NSCLC', 'Disease', 'MESH:D002289', (179, 184))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (151, 177))	('NSUN1', 'Gene', (84, 89))	('NOP2', 'Gene', '4839', (91, 95))	('SCLC', 'Phenotype', 'HP:0030357', (180, 184))	('NSUN1', 'Gene', '4839', (84, 89))	('p120', 'Gene', '4839', (96, 100))	('NSCLC', 'Phenotype', 'HP:0030358', (179, 184))	('rat', 'Species', '10116', (57, 60))	('p120', 'Gene', (96, 100))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (151, 177))	('high expression', 'Var', (65, 80))	('lung cancer', 'Phenotype', 'HP:0100526', (166, 177))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('non-small cell lung cancer', 'Disease', (151, 177))	('NSCLC', 'Disease', (179, 184))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (155, 177))
474238	32708015	Mutation of NSUN3 has been shown to result in reduced mitochondrial protein translation and respiration, while some evidence has shown a role for NSUN3 in nuclear transcriptional regulation in leukemic cells.	('NSUN3', 'Gene', '63899', (12, 17))	('rat', 'Species', '10116', (97, 100))	('Mutation', 'Var', (0, 8))	('NSUN3', 'Gene', (146, 151))	('reduced', 'NegReg', (46, 53))	('respiration', 'MPA', (92, 103))	('NSUN3', 'Gene', '63899', (146, 151))	('mitochondrial protein translation', 'MPA', (54, 87))	('NSUN3', 'Gene', (12, 17))
474240	32708015	Most recently, a pan-cancer analysis of RNMTs has shown that alterations to NSUN2 are common in lung cancer, although this was not followed up in more detail.	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('lung cancer', 'Disease', 'MESH:D008175', (96, 107))	('pan', 'Gene', '51816', (17, 20))	('RNMT', 'Gene', (40, 44))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('common', 'Reg', (86, 92))	('cancer', 'Disease', (101, 107))	('RNMT', 'Gene', '8731', (40, 44))	('NSUN2', 'Gene', (76, 81))	('lung cancer', 'Disease', (96, 107))	('lung cancer', 'Phenotype', 'HP:0100526', (96, 107))	('alterations', 'Var', (61, 72))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('cancer', 'Disease', (21, 27))	('cancer', 'Disease', 'MESH:D009369', (21, 27))	('pan', 'Gene', (17, 20))	('rat', 'Species', '10116', (65, 68))
474241	32708015	In this regard, cBioPortal analysis of the TCGA lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) datasets indicates that alterations to NSUN2 were found in 37% and 44% of samples, respectively (Figure 3).	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (48, 67))	('AD', 'Disease', 'MESH:D000544', (71, 73))	('LUAD', 'Phenotype', 'HP:0030078', (69, 73))	('AD', 'Disease', (71, 73))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (79, 107))	('AD', 'Phenotype', 'HP:0002511', (71, 73))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('alterations', 'Var', (139, 150))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (79, 107))	('rat', 'Species', '10116', (143, 146))	('LUSC', 'Phenotype', 'HP:0030359', (109, 113))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (84, 107))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (48, 67))	('found', 'Reg', (165, 170))	('lung squamous cell carcinoma', 'Disease', (79, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))	('NSUN2', 'Gene', (154, 159))	('lung adenocarcinoma', 'Disease', (48, 67))
474244	32708015	The results are presented as OncoPrints, a compact means of visualizing distinct genomic alterations, including somatic mutations, copy number alterations, and mRNA expression changes across a set of cases.	('mRNA expression', 'MPA', (160, 175))	('copy number alterations', 'Var', (131, 154))	('rat', 'Species', '10116', (147, 150))	('changes', 'Reg', (176, 183))	('rat', 'Species', '10116', (93, 96))
474252	32708015	In agreement with the previous analyses, significant alterations were observed in both datasets for normal vs. tumor and when stratified by tumor stage, race, gender, age, smoking habit, nodal metastasis, and p53 mutation status, and the results are presented in Supplementary Figure S2.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('mutation', 'Var', (213, 221))	('alterations', 'Reg', (53, 64))	('tumor', 'Disease', (111, 116))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('rat', 'Species', '10116', (57, 60))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('p53', 'Gene', (209, 212))	('rat', 'Species', '10116', (128, 131))	('p53', 'Gene', '7157', (209, 212))	('tumor', 'Disease', (140, 145))
474255	32708015	When patients were stratified based on histology, it was shown that a high expression of NSUN was associated with significantly better OS in just the adenocarcinoma subtype (Figure 6B) and not in the squamous cell carcinoma subtype (Figure 6C), in agreement with the lung cancer explorer meta-analysis (Table 2).	('lung cancer', 'Phenotype', 'HP:0100526', (267, 278))	('carcinoma', 'Phenotype', 'HP:0030731', (155, 164))	('cancer', 'Phenotype', 'HP:0002664', (272, 278))	('adenocarcinoma', 'Disease', (150, 164))	('lung cancer', 'Disease', (267, 278))	('patients', 'Species', '9606', (5, 13))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (200, 223))	('carcinoma', 'Phenotype', 'HP:0030731', (214, 223))	('squamous cell carcinoma', 'Disease', (200, 223))	('adenocarcinoma', 'Disease', 'MESH:D000230', (150, 164))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (200, 223))	('NSUN', 'Gene', (89, 93))	('lung cancer', 'Disease', 'MESH:D008175', (267, 278))	('rat', 'Species', '10116', (21, 24))	('high expression', 'Var', (70, 85))	('better', 'PosReg', (128, 134))
474260	32708015	In ovarian cancer, an NSUN2/IGF2 signature has been identified, which has prognostic survival value, as patients with high NSUN2 expression and low IGF-II expression had significantly superior overall and disease progression-free survival.	('NSUN2', 'Gene', (123, 128))	('high', 'Var', (118, 122))	('IGF2', 'Gene', (28, 32))	('superior', 'PosReg', (184, 192))	('expression', 'MPA', (129, 139))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('ovarian cancer', 'Phenotype', 'HP:0100615', (3, 17))	('expression', 'MPA', (155, 165))	('IGF-II', 'Gene', (148, 154))	('ovarian cancer', 'Disease', 'MESH:D010051', (3, 17))	('IGF-II', 'Gene', '3481', (148, 154))	('disease progression-free survival', 'CPA', (205, 238))	('low', 'NegReg', (144, 147))	('ovarian cancer', 'Disease', (3, 17))	('low IGF', 'Phenotype', 'HP:0002850', (144, 151))	('IGF2', 'Gene', '3481', (28, 32))	('patients', 'Species', '9606', (104, 112))
474262	32708015	Moreover, high NSUN2 expression has been associated with T-cell activation in HNSCC, and there was a positive association between T-cell activation score and mortality in patients with low NSUN2 expression, which suggests that NSUN2 expression in HNSCC could be used as a marker to stratify patients for immune-checkpoint blockade.	('T-cell', 'CPA', (57, 63))	('expression', 'MPA', (195, 205))	('low', 'Var', (185, 188))	('HNSCC', 'Phenotype', 'HP:0012288', (247, 252))	('mortality', 'Disease', 'MESH:D003643', (158, 167))	('rat', 'Species', '10116', (284, 287))	('expression', 'MPA', (21, 31))	('NSUN2', 'Gene', (15, 20))	('patients', 'Species', '9606', (171, 179))	('patients', 'Species', '9606', (291, 299))	('HNSCC', 'Phenotype', 'HP:0012288', (78, 83))	('high', 'Var', (10, 14))	('mortality', 'Disease', (158, 167))	('NSUN2', 'Gene', (189, 194))
474264	32708015	Importantly, high co-expression of NUSN2, YBX1, and HDGF was found to predict the poorest survival in urothelial carcinoma of the bladder (UCB).	('YBX1', 'Gene', (42, 46))	('urothelial carcinoma of the bladder', 'Disease', (102, 137))	('urothelial carcinoma of the bladder', 'Phenotype', 'HP:0006740', (102, 137))	('UCB', 'Phenotype', 'HP:0006740', (139, 142))	('high', 'Var', (13, 17))	('YBX1', 'Gene', '4904', (42, 46))	('HDGF', 'Gene', '3068', (52, 56))	('NUSN2', 'Gene', (35, 40))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('HDGF', 'Gene', (52, 56))	('poorest', 'NegReg', (82, 89))	('urothelial carcinoma of the bladder', 'Disease', 'MESH:D001749', (102, 137))
474265	32708015	High expression of NSUN2 was found to occur in gallbladder carcinoma (GBC), and silencing of NSUN2 repressed GBC cell proliferation and tumorigenesis both in vitro and in vivo via an interaction with Ribosomal Protein L6 (RPL6).	('rat', 'Species', '10116', (125, 128))	('RPL6', 'Gene', '6128', (222, 226))	('silencing', 'Var', (80, 89))	('gallbladder carcinoma', 'Disease', (47, 68))	('NSUN2', 'Gene', (93, 98))	('Ribosomal Protein L6', 'Gene', '6128', (200, 220))	('gallbladder carcinoma', 'Disease', 'MESH:D005706', (47, 68))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('repressed', 'NegReg', (99, 108))	('interaction', 'Interaction', (183, 194))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('carcinoma', 'Phenotype', 'HP:0030731', (59, 68))	('RPL6', 'Gene', (222, 226))	('tumor', 'Disease', (136, 141))	('Ribosomal Protein L6', 'Gene', (200, 220))
474268	32708015	In this regard, knockdown of Sphingosine kinase 1 (SK1) was associated with downregulation of NSUN2 in breast and prostate cancer cells, suggesting that pharmacological inhibitors of SK1 could potentially benefit cancers with overexpressed NSUN2.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('NSUN2', 'Gene', (94, 99))	('prostate cancer', 'Phenotype', 'HP:0012125', (114, 129))	('knockdown', 'Var', (16, 25))	('overexpressed', 'PosReg', (226, 239))	('benefit', 'PosReg', (205, 212))	('cancers', 'Disease', 'MESH:D009369', (213, 220))	('cancers', 'Phenotype', 'HP:0002664', (213, 220))	('breast and prostate cancer', 'Disease', 'MESH:D001943', (103, 129))	('cancers', 'Disease', (213, 220))	('Sphingosine kinase 1', 'Gene', '8877', (29, 49))	('Sphingosine kinase 1', 'Gene', (29, 49))	('SK1', 'Gene', '8877', (51, 54))	('downregulation', 'NegReg', (76, 90))	('SK1', 'Gene', (51, 54))	('SK1', 'Gene', '8877', (183, 186))	('SK1', 'Gene', (183, 186))
474269	32708015	At the same time, directly knocking down NSUN2 in HeLa cells has been shown to potentiate the sensitivity of the cells to 5-fluorouracil (5-FU) but not that of cisplatin or paclitaxel.	('NSUN2', 'Gene', (41, 46))	('HeLa', 'CellLine', 'CVCL:0030', (50, 54))	('potentiate', 'PosReg', (79, 89))	('knocking down', 'Var', (27, 40))	('paclitaxel', 'Chemical', 'MESH:D017239', (173, 183))	('sensitivity', 'MPA', (94, 105))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (122, 136))	('5-FU', 'Chemical', 'MESH:D005472', (138, 142))	('cisplatin', 'Chemical', 'MESH:D002945', (160, 169))
474270	32708015	In esophageal cancer cells, NSUN2 was found to associate with and methylate an lncRNA, NMR (also known as LINC01672 or lnc-CAMTA1-1:2/CAMTA1-IT1), for which expression is associated with resistance to cisplatin or paclitaxel.	('cancer', 'Disease', (14, 20))	('associate', 'Interaction', (47, 56))	('IT1', 'Gene', (141, 144))	('CAMTA1', 'Gene', '23261', (134, 140))	('cisplatin', 'Chemical', 'MESH:D002945', (201, 210))	('CAMTA1', 'Gene', (134, 140))	('associated with', 'Reg', (171, 186))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('CAMTA1', 'Gene', (123, 129))	('paclitaxel', 'Chemical', 'MESH:D017239', (214, 224))	('methylate', 'Var', (66, 75))	('cancer', 'Disease', 'MESH:D009369', (14, 20))	('CAMTA1', 'Gene', '23261', (123, 129))	('IT1', 'Gene', '79441', (141, 144))	('NSUN2', 'Gene', (28, 33))
474273	32708015	Given that NSUN2 has been shown to exclusively methylate vtRNAs (and in particular vtRNA1.1) and that loss of m5C in vault RNAs causes aberrant processing of vtRNAs, targeting NSUN2 may represent a potentially new way to overcome resistance.	('vtRNA1.1', 'Gene', '56664', (83, 91))	('vtRNAs', 'MPA', (158, 164))	('m5C', 'Chemical', '-', (110, 113))	('vtRNA1.1', 'Gene', (83, 91))	('vtRNAs', 'Protein', (57, 63))	('processing', 'MPA', (144, 154))	('loss', 'Var', (102, 106))
474275	32708015	Alternatively, it may be possible to target NSUN2-mediated events such as that shown for the lncRNA NMR in esophageal cancer, whereby NSUN2-methylated NMR interacts with the chromatin remodeling factor Bromodomain PHD Finger Transcription Factor (BPTF) to regulate resistance to cisplatin.	('cancer', 'Disease', (118, 124))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('resistance to cisplatin', 'MPA', (265, 288))	('cisplatin', 'Chemical', 'MESH:D002945', (279, 288))	('regulate', 'Reg', (256, 264))	('BPTF', 'Gene', (247, 251))	('BPTF', 'Gene', '2186', (247, 251))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('Bromodomain PHD Finger Transcription Factor', 'Gene', (202, 245))	('interacts', 'Interaction', (155, 164))	('NSUN2-methylated', 'Var', (134, 150))	('Bromodomain PHD Finger Transcription Factor', 'Gene', '2186', (202, 245))
474278	32708015	Furthermore, additional studies will be required to assess if C620-0696 could sensitize patients to cisplatin therapy.	('patients', 'Species', '9606', (88, 96))	('C620-0696', 'Var', (62, 71))	('cisplatin', 'Chemical', 'MESH:D002945', (100, 109))	('sensitize', 'Reg', (78, 87))
474289	32708015	Targeting the proteins that add m5C modifications to DNA (particularly DNA methyltransferases) has been an area of active research in cancer.	('m5C', 'Chemical', '-', (32, 35))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('m5C modifications', 'Var', (32, 49))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
474294	32708015	Given that alterations involving increased expression of NSUN2 are common in breast cancer, colon cancer, and lung cancer as suggested in the suggestions above, molecularly targeting this RNMT would appear to an attractive approach moving forward.	('colon cancer', 'Disease', 'MESH:D015179', (92, 104))	('lung cancer', 'Disease', (110, 121))	('alterations', 'Var', (11, 22))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('rat', 'Species', '10116', (15, 18))	('breast cancer', 'Phenotype', 'HP:0003002', (77, 90))	('RNMT', 'Gene', (188, 192))	('common', 'Reg', (67, 73))	('colon cancer', 'Disease', (92, 104))	('breast cancer', 'Disease', 'MESH:D001943', (77, 90))	('breast cancer', 'Disease', (77, 90))	('lung cancer', 'Disease', 'MESH:D008175', (110, 121))	('increased', 'PosReg', (33, 42))	('lung cancer', 'Phenotype', 'HP:0100526', (110, 121))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('colon cancer', 'Phenotype', 'HP:0003003', (92, 104))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('RNMT', 'Gene', '8731', (188, 192))	('NSUN2', 'Gene', (57, 62))	('expression', 'MPA', (43, 53))
474304	32488496	Prostaglandin E2 receptor 3 (EP3) signaling promotes migration of cervical cancer via urokinase-type plasminogen activator receptor (uPAR) Cervical cancer metastasis results in poor prognosis and increased mortality, which is not separated from inflammatory reactions accumulated by prostaglandin E2 (PGE2).	('poor prognosis', 'CPA', (177, 191))	('urokinase-type plasminogen activator receptor', 'Gene', '5329', (86, 131))	('prostaglandin E2', 'Chemical', 'MESH:D015232', (283, 299))	('Cervical', 'Var', (139, 147))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('increased', 'PosReg', (196, 205))	('rat', 'Species', '10116', (56, 59))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('uPAR', 'Gene', (133, 137))	('mortality', 'Disease', 'MESH:D003643', (206, 215))	('Prostaglandin E2', 'Chemical', 'MESH:D015232', (0, 16))	('uPAR', 'Gene', '5329', (133, 137))	('rat', 'Species', '10116', (234, 237))	('PGE2', 'Chemical', 'MESH:D015232', (301, 305))	('cancer', 'Disease', (148, 154))	('urokinase-type plasminogen activator receptor', 'Gene', (86, 131))	('EP3', 'Gene', '5733', (29, 32))	('cancer', 'Disease', (75, 81))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('EP3', 'Gene', (29, 32))	('mortality', 'Disease', (206, 215))
474305	32488496	As a specific G-protein coupled PGE2 receptor, EP3 is demonstrated as a negative prognosticator of cervical malignancy.	('cervical malignancy', 'Disease', (99, 118))	('rat', 'Species', '10116', (61, 64))	('EP3', 'Var', (47, 50))	('cervical malignancy', 'Disease', 'MESH:D002583', (99, 118))	('PGE2', 'Chemical', 'MESH:D015232', (32, 36))
474309	32488496	In vitro studies showed that sulprostone (an EP3 agonist) enhanced the proliferation and migration of cervical cancer cells, whereas silencing of EP3 inhibited their proliferation and migration.	('rat', 'Species', '10116', (173, 176))	('rat', 'Species', '10116', (187, 190))	('inhibited', 'NegReg', (150, 159))	('enhanced', 'PosReg', (58, 66))	('proliferation', 'CPA', (166, 179))	('EP3', 'Gene', (146, 149))	('cervical cancer', 'Disease', (102, 117))	('cervical cancer', 'Disease', 'MESH:D002583', (102, 117))	('rat', 'Species', '10116', (92, 95))	('rat', 'Species', '10116', (78, 81))	('silencing', 'Var', (133, 142))	('sulprostone', 'Chemical', 'MESH:C016767', (29, 40))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('proliferation', 'CPA', (71, 84))	('migration', 'CPA', (89, 98))
474310	32488496	Furthermore, EP3 knockdown increased the expression of plasminogen activator inhibitor type 1 (PAI-1), urokinase-type plasminogen activator receptor (uPAR), and phosphorylated extracellular signal-regulated kinases 1/2 (p-ERK1/2), but decreased p53 expression.	('expression', 'MPA', (249, 259))	('extracellular signal-regulated kinases 1/2', 'Gene', '5595', (176, 218))	('increased', 'PosReg', (27, 36))	('PAI-1', 'Gene', (95, 100))	('expression', 'MPA', (41, 51))	('p53', 'Gene', (245, 248))	('urokinase-type plasminogen activator receptor', 'Gene', (103, 148))	('urokinase-type plasminogen activator receptor', 'Gene', '5329', (103, 148))	('decreased', 'NegReg', (235, 244))	('increased the expression of plasminogen', 'Phenotype', 'HP:0040228', (27, 66))	('knockdown', 'Var', (17, 26))	('extracellular signal-regulated kinases 1/2', 'Gene', (176, 218))	('EP3', 'Gene', (13, 16))
474325	32488496	GW627368X (a highly selective EP4 antagonist) inhibits the proliferation and angiogenesis of cervical carcinoma by blocking EP4/epidermal growth factor receptor (EGFR) signaling pathway in cervical cancer cell lines (HeLa, SiHa and ME180) and suppresses the tumor size in xenograft mice model (Parida et al.).	('tumor', 'Disease', (258, 263))	('EGFR', 'Gene', (162, 166))	('blocking', 'NegReg', (115, 123))	('suppresses', 'NegReg', (243, 253))	('inhibits', 'NegReg', (46, 54))	('EGFR', 'Gene', '13649', (162, 166))	('HeLa', 'CellLine', 'CVCL:0030', (217, 221))	('tumor', 'Disease', 'MESH:D009369', (258, 263))	('GW627368X', 'Chemical', 'MESH:C515270', (0, 9))	('mice', 'Species', '10090', (282, 286))	('EP4/epidermal growth factor receptor', 'Gene', (124, 160))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('cervical cancer', 'Disease', (189, 204))	('cervical cancer', 'Disease', 'MESH:D002583', (189, 204))	('tumor', 'Phenotype', 'HP:0002664', (258, 263))	('proliferation', 'CPA', (59, 72))	('rat', 'Species', '10116', (66, 69))	('GW627368X', 'Var', (0, 9))	('cervical carcinoma', 'Disease', 'MESH:D002583', (93, 111))	('angiogenesis', 'CPA', (77, 89))	('EP4/epidermal growth factor receptor', 'Gene', '13649;19219', (124, 160))	('cervical carcinoma', 'Disease', (93, 111))
474326	32488496	Our latest publication demonstrated that high expression of EP3 is associated with poor prognosis in overall survival rates of cervical cancer patients in both squamous cell carcinoma and adenocarcinoma (Heidegger et al.).	('rat', 'Species', '10116', (118, 121))	('adenocarcinoma', 'Disease', (188, 202))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (160, 183))	('high expression', 'Var', (41, 56))	('carcinoma', 'Phenotype', 'HP:0030731', (193, 202))	('adenocarcinoma', 'Disease', 'MESH:D000230', (188, 202))	('patients', 'Species', '9606', (143, 151))	('cervical cancer', 'Disease', 'MESH:D002583', (127, 142))	('rat', 'Species', '10116', (30, 33))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (160, 183))	('EP3', 'Gene', (60, 63))	('cervical cancer', 'Disease', (127, 142))	('squamous cell carcinoma', 'Disease', (160, 183))	('carcinoma', 'Phenotype', 'HP:0030731', (174, 183))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
474342	32488496	uPAR can be cleaved into soluble uPAR, both full-length and cleaved uPAR are involved in cell signaling, proliferation, migration and invasion of tumor cells (Magnussen et al.).	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('involved', 'Reg', (77, 85))	('uPAR', 'Gene', (68, 72))	('tumor', 'Disease', (146, 151))	('invasion', 'CPA', (134, 142))	('rat', 'Species', '10116', (112, 115))	('rat', 'Species', '10116', (123, 126))	('cleaved', 'Var', (60, 67))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
474345	32488496	In in vitro studies, we observed that EP3 silencing attenuated the proliferation and migration of cervical cancer cells and upregulated the expression of PAI-1 and uPAR.	('silencing', 'Var', (42, 51))	('EP3', 'Protein', (38, 41))	('expression', 'MPA', (140, 150))	('PAI-1', 'Gene', (154, 159))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('attenuated', 'NegReg', (52, 62))	('cervical cancer', 'Disease', 'MESH:D002583', (98, 113))	('rat', 'Species', '10116', (74, 77))	('rat', 'Species', '10116', (88, 91))	('cervical cancer', 'Disease', (98, 113))	('proliferation', 'CPA', (67, 80))	('uPAR', 'PosReg', (164, 168))	('upregulated', 'PosReg', (124, 135))
474346	32488496	By immunohistochemistry, we demonstrated that high uPAR expression was associated with the poor prognosis of cervical cancer patients with advanced stages (FIGO III-IV).	('cervical cancer', 'Disease', 'MESH:D002583', (109, 124))	('cervical cancer', 'Disease', (109, 124))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('rat', 'Species', '10116', (35, 38))	('high uPAR', 'Var', (46, 55))	('patients', 'Species', '9606', (125, 133))
474403	32488496	EP3 knockdown decreased the proliferation rate by 20.3% in HeLa cells (P = 0.028, Fig.	('proliferation rate', 'CPA', (28, 46))	('EP3', 'Gene', (0, 3))	('decreased', 'NegReg', (14, 23))	('knockdown', 'Var', (4, 13))	('HeLa', 'CellLine', 'CVCL:0030', (59, 63))	('rat', 'Species', '10116', (35, 38))	('rat', 'Species', '10116', (42, 45))
474415	32488496	In comparison, EP3 knockdown inhibited the migration rate by 20.0% in HeLa cells (P = 0.016, Fig.	('HeLa', 'CellLine', 'CVCL:0030', (70, 74))	('inhibited', 'NegReg', (29, 38))	('rat', 'Species', '10116', (46, 49))	('knockdown', 'Var', (19, 28))	('migration rate', 'CPA', (43, 57))	('rat', 'Species', '10116', (53, 56))
474422	32488496	Downregulation of EP3 enhanced the production of PAI-1 by 38.7% in the supernatants of HeLa cells compared to the negative control (0.55 +- 0.09 vs 0.40 +- 0.12 ng/ml, P = 0.003, Fig.	('EP3', 'Gene', (18, 21))	('Downregulation', 'Var', (0, 14))	('PAI-1', 'Gene', (49, 54))	('HeLa', 'CellLine', 'CVCL:0030', (87, 91))	('enhanced', 'PosReg', (22, 30))
474434	32488496	However, when patients had been stratified according to FIGO stage, the high expression of uPAR was correlated with poor prognosis in OS of cervical cancer patients with FIGO stages III/IV as shown in the Kaplan-Meier curve (P = 0.047, Fig.	('patients', 'Species', '9606', (156, 164))	('expression', 'MPA', (77, 87))	('OS of cervical cancer', 'Disease', 'MESH:D002583', (134, 155))	('uPAR', 'Gene', (91, 95))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('rat', 'Species', '10116', (34, 37))	('patients', 'Species', '9606', (14, 22))	('OS of cervical cancer', 'Disease', (134, 155))	('high', 'Var', (72, 76))
474443	32488496	Our latest study demonstrated that high expression of EP3 (IRS >= 2) is associated with poor prognosis in the OS rate of 250 cervical cancer patients in both squamous cell carcinoma and adenocarcinoma (Heidegger et al.).	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (158, 181))	('adenocarcinoma', 'Disease', 'MESH:D000230', (186, 200))	('patients', 'Species', '9606', (141, 149))	('EP3', 'Protein', (54, 57))	('rat', 'Species', '10116', (113, 116))	('carcinoma', 'Phenotype', 'HP:0030731', (191, 200))	('high expression', 'Var', (35, 50))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (158, 181))	('cervical cancer', 'Disease', 'MESH:D002583', (125, 140))	('adenocarcinoma', 'Disease', (186, 200))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('cervical cancer', 'Disease', (125, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (172, 181))	('squamous cell carcinoma', 'Disease', (158, 181))	('rat', 'Species', '10116', (24, 27))
474444	32488496	EP3 can increase the migration of HCA-7 human colon cancer cells through the activation of phosphatidylinositol 3-kinase (PI3K) and the phosphorylation of ERK1/2 signaling pathway (Fujino et al.).	('phosphorylation', 'MPA', (136, 151))	('increase', 'PosReg', (8, 16))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('phosphatidylinositol 3-kinase', 'Gene', (91, 120))	('colon cancer', 'Disease', (46, 58))	('activation', 'PosReg', (77, 87))	('phosphatidylinositol 3-kinase', 'Gene', '5294', (91, 120))	('colon cancer', 'Disease', 'MESH:D015179', (46, 58))	('ERK1/2 signaling pathway', 'Pathway', (155, 179))	('EP3', 'Var', (0, 3))	('rat', 'Species', '10116', (24, 27))	('migration', 'CPA', (21, 30))	('human', 'Species', '9606', (40, 45))	('colon cancer', 'Phenotype', 'HP:0003003', (46, 58))
474445	32488496	In accordance to those findings, we found that sulprostone (an EP1/EP3 agonist) induced the proliferation and migration of HeLa cells, while silencing EP3 reduced the proliferation and migration of HeLa and SiHa cells.	('EP1', 'Gene', '5731', (63, 66))	('silencing', 'Var', (141, 150))	('reduced', 'NegReg', (155, 162))	('migration', 'CPA', (110, 119))	('HeLa', 'CellLine', 'CVCL:0030', (123, 127))	('rat', 'Species', '10116', (99, 102))	('rat', 'Species', '10116', (113, 116))	('EP1', 'Gene', (63, 66))	('HeLa', 'CellLine', 'CVCL:0030', (198, 202))	('induced', 'PosReg', (80, 87))	('rat', 'Species', '10116', (174, 177))	('rat', 'Species', '10116', (188, 191))	('sulprostone', 'Chemical', 'MESH:C016767', (47, 58))	('proliferation', 'CPA', (167, 180))	('proliferation', 'CPA', (92, 105))	('migration', 'CPA', (185, 194))	('EP3', 'Gene', (151, 154))
474449	32488496	Additionally, we observed that EP3 was positively associated with PAI-1 in cervical malignancy, and PAI-1 was correlated with the OS of cervical cancer patients in both UALCAN and GEPIA databases.	('cervical malignancy', 'Disease', (75, 94))	('associated', 'Interaction', (50, 60))	('correlated', 'Reg', (110, 120))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('OS of cervical cancer', 'Disease', 'MESH:D002583', (130, 151))	('PAI-1', 'Gene', (66, 71))	('cervical malignancy', 'Disease', 'MESH:D002583', (75, 94))	('OS of cervical cancer', 'Disease', (130, 151))	('patients', 'Species', '9606', (152, 160))	('EP3', 'Var', (31, 34))
474452	32488496	PGE2 can increase mRNA and protein levels of PAI-1 by binding with EP1/EP3 receptor in rat ventricular fibroblasts, contributing to elevated fibrin deposition in aortic stenosis (Kassem et al.).	('elevated', 'PosReg', (132, 140))	('PGE2', 'Chemical', 'MESH:D015232', (0, 4))	('fibrin deposition', 'MPA', (141, 158))	('increase', 'PosReg', (9, 17))	('aortic stenosis', 'Phenotype', 'HP:0001650', (162, 177))	('PGE2', 'Var', (0, 4))	('PAI-1', 'Gene', (45, 50))	('elevated fibrin deposition', 'Phenotype', 'HP:0011899', (132, 158))	('aortic stenosis', 'Disease', 'MESH:D001024', (162, 177))	('aortic stenosis', 'Disease', (162, 177))	('binding', 'Interaction', (54, 61))	('rat', 'Species', '10116', (87, 90))
474453	32488496	suggested that TM5275 (a small molecular inhibitor of PAI-1) can increase the collagenase activity of SiHa and CaSki cells (Sato et al.	('increase', 'PosReg', (65, 73))	('collagenase activity', 'MPA', (78, 98))	('CaSki', 'CellLine', 'CVCL:1100', (111, 116))	('TM5275', 'Var', (15, 21))	('TM5275', 'Chemical', 'MESH:C549556', (15, 21))
474455	32488496	The latter study was in accordance with our study that silencing EP3 increased the production of PAI-1 and decreased the migration in HeLa and SiHa cells.	('rat', 'Species', '10116', (124, 127))	('increased', 'PosReg', (69, 78))	('EP3', 'Gene', (65, 68))	('silencing', 'Var', (55, 64))	('decreased', 'NegReg', (107, 116))	('HeLa', 'CellLine', 'CVCL:0030', (134, 138))	('production', 'MPA', (83, 93))	('PAI-1', 'Gene', (97, 102))
474464	32488496	Therefore, we deduced that the upregulated secretion of PAI-1 decreased uPAR cleavage in EP3 knockdown SiHa cells causing less soluble uPAR in the ECM and leaving more uPAR on the membrane, and these might contribute to decreased migration of SiHa cells (Fig.	('knockdown', 'Var', (93, 102))	('uPAR cleavage', 'MPA', (72, 85))	('secretion', 'MPA', (43, 52))	('decreased', 'NegReg', (220, 229))	('decreased', 'NegReg', (62, 71))	('upregulated', 'PosReg', (31, 42))	('less', 'NegReg', (122, 126))	('PAI-1', 'Gene', (56, 61))	('rat', 'Species', '10116', (233, 236))	('migration', 'CPA', (230, 239))	('EP3', 'Gene', (89, 92))
474477	32488496	In hepatocellular carcinoma cells, galectin-3 silencing attenuated uPAR expression and inhibited the proliferation, migration and invasion (Zheng et al.).	('carcinoma', 'Phenotype', 'HP:0030731', (18, 27))	('hepatocellular carcinoma', 'Disease', (3, 27))	('rat', 'Species', '10116', (108, 111))	('galectin-3', 'Gene', '3958', (35, 45))	('silencing', 'Var', (46, 55))	('attenuated', 'NegReg', (56, 66))	('uPAR', 'Protein', (67, 71))	('rat', 'Species', '10116', (119, 122))	('proliferation', 'CPA', (101, 114))	('inhibited', 'NegReg', (87, 96))	('galectin-3', 'Gene', (35, 45))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (3, 27))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (3, 27))
474479	32488496	Additionally, the positive correlation of H3K4me3 and uPAR expression in our study was in accordance with the finding that H3K4me3 is related to poor prognosis in cervical cancer patients and is an independent marker of relapse-free survival (Beyer et al.).	('cervical cancer', 'Disease', (163, 178))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('H3K4me3', 'Var', (123, 130))	('H3K4me3', 'Var', (42, 49))	('patients', 'Species', '9606', (179, 187))	('cervical cancer', 'Disease', 'MESH:D002583', (163, 178))
474483	32488496	The upregulated expression of p-ERK1/2 was observed in SiHa cells while the expression of ERK1/2 was too low to draw any conclusion in HeLa cells.	('HeLa', 'CellLine', 'CVCL:0030', (135, 139))	('upregulated', 'PosReg', (4, 15))	('expression', 'MPA', (16, 26))	('p-ERK1/2', 'Var', (30, 38))
474488	32488496	Taken all results together, EP3 might facilitate the migration of cervical cancer cells through modulating the production of PAI-1 and uPAR in advantaged stages of cervical malignancy.	('facilitate', 'PosReg', (38, 48))	('rat', 'Species', '10116', (56, 59))	('modulating', 'Reg', (96, 106))	('cervical malignancy', 'Disease', (164, 183))	('uPAR in', 'PosReg', (135, 142))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('migration', 'CPA', (53, 62))	('cervical cancer', 'Disease', (66, 81))	('cervical malignancy', 'Disease', 'MESH:D002583', (164, 183))	('cervical cancer', 'Disease', 'MESH:D002583', (66, 81))	('production', 'MPA', (111, 121))	('PAI-1', 'Protein', (125, 130))	('EP3', 'Var', (28, 31))
474490	32488496	EP3 and uPAR might represent novel therapeutic targets for cervical cancer and specific antagonists or inhibitors of EP3 and uPAR could be promising therapeutic treatments for cervical cancer.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('EP3', 'Gene', (117, 120))	('inhibitors', 'Var', (103, 113))	('cervical cancer', 'Disease', (59, 74))	('cervical cancer', 'Disease', 'MESH:D002583', (59, 74))	('cervical cancer', 'Disease', (176, 191))	('cervical cancer', 'Disease', 'MESH:D002583', (176, 191))
474497	32106831	Overall survival (OS) of the patients treated with surgery following NAC was significantly shorter in the group with high GR than that with low GR status (P = 0.0473).	('patients', 'Species', '9606', (29, 37))	('NAC', 'Chemical', '-', (69, 72))	('OS', 'Chemical', '-', (18, 20))	('Overall survival', 'MPA', (0, 16))	('high GR', 'Var', (117, 124))	('shorter', 'NegReg', (91, 98))
474499	32106831	Biopsy specimens before NAC showed significantly shorter DFS in the high Sgk1 group (P = 0.0095), while both OS and DFS were shorter in the high NDRG1 group (OS, P = 0.0233; DFS, P = 0.0006) than in the respective low groups.	('high', 'Var', (68, 72))	('DFS', 'MPA', (57, 60))	('NAC', 'Chemical', '-', (24, 27))	('Sgk1', 'Gene', (73, 77))	('shorter', 'NegReg', (49, 56))	('shorter', 'NegReg', (125, 132))	('OS', 'Chemical', '-', (109, 111))	('OS', 'Chemical', '-', (158, 160))
474500	32106831	In the high NDRG1 group of biopsy specimens before NAC, the tumor reduction rate by NAC was significantly attenuated (P = 0.021).	('attenuated', 'NegReg', (106, 116))	('NAC', 'Chemical', '-', (51, 54))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('NDRG1', 'Gene', (12, 17))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('high', 'Var', (7, 11))	('NAC', 'Chemical', '-', (84, 87))	('tumor', 'Disease', (60, 65))
474501	32106831	High GR, Sgk1, and NDRG1 statuses in ESCC after NAC was significantly associated with an overall worse prognosis, with no significant changes in their expression levels before and after NAC.	('High GR', 'Var', (0, 7))	('ESCC', 'Disease', (37, 41))	('NDRG1', 'Gene', (19, 24))	('NAC', 'Chemical', '-', (48, 51))	('associated', 'Reg', (70, 80))	('statuses', 'Var', (25, 33))	('NAC', 'Chemical', '-', (186, 189))	('Sgk1', 'Gene', (9, 13))	('ESCC', 'Disease', 'MESH:C562729', (37, 41))
474539	32106831	After washing three times for 5 min each in phosphate-buffered saline (PBS), the reacted slides were incubated in 1% normal goat serum for 30 min at room temperature to reduce nonspecific antibody binding and then incubated at 4  C overnight with rabbit monoclonal antibody against GR (D6H2L, Cell Signaling Technology, Danvers, MA, USA, diluted 1/400), Sgk1 (Y238, Abcam, Cambridge, UK, diluted 1/200), or NDRG1 (EPR5593, Abcam, diluted 1/400).	('Y238', 'Var', (360, 364))	('PBS', 'Chemical', '-', (71, 74))	('nonspecific antibody', 'MPA', (176, 196))	('binding', 'Interaction', (197, 204))	('reduce', 'NegReg', (169, 175))
474551	32106831	Five-year OS rate of the patients harboring high GR status was significantly shorter than those harboring low GR group (P = 0.0473) (Fig.	('OS', 'Chemical', '-', (10, 12))	('high GR status', 'Var', (44, 58))	('OS rate', 'MPA', (10, 17))	('patients', 'Species', '9606', (25, 33))	('shorter', 'NegReg', (77, 84))
474552	32106831	In addition, significantly shorter 5-year OS and DFS were detected in the patients with high Sgk1 than in those with low Sgk1 (OS: P = 0.0055, DFS: P = 0.0240) (Fig.	('high', 'Var', (88, 92))	('OS', 'Chemical', '-', (42, 44))	('shorter', 'NegReg', (27, 34))	('patients', 'Species', '9606', (74, 82))	('Sgk1', 'Gene', (93, 97))	('OS', 'Chemical', '-', (127, 129))
474553	32106831	The 5-year OS and DFS were both significantly shorter in those with high NDRG1 than in those with low NDRG1 (OS: P = 0.0021, DFS: P = 0.0086) (Fig.	('OS', 'Chemical', '-', (11, 13))	('DFS', 'CPA', (18, 21))	('high', 'Var', (68, 72))	('NDRG1', 'Gene', (73, 78))	('OS', 'Chemical', '-', (109, 111))	('shorter', 'NegReg', (46, 53))
474554	32106831	Univariate analysis revealed that patient survival was significantly associated with pT (P = 0.0011) and pN (P = 0.0002), pStage (P = 0.0001), lymphatic invasion (P = 0.0260), vascular invasion (P = 0.0178), RECIST grade (P = 0.0015), histopathological tumor regression grade (P = 0.0432), high GR (P = 0.0479), high Sgk1 (P = 0.0054), and high NDRG1 (P = 0.0033) (Table 2).	('vascular invasion', 'CPA', (176, 193))	('high GR', 'Var', (290, 297))	('patient survival', 'CPA', (34, 50))	('tumor', 'Disease', 'MESH:D009369', (253, 258))	('high', 'Var', (312, 316))	('associated', 'Reg', (69, 79))	('tumor', 'Phenotype', 'HP:0002664', (253, 258))	('high', 'Var', (340, 344))	('patient', 'Species', '9606', (34, 41))	('tumor', 'Disease', (253, 258))	('pStage', 'CPA', (122, 128))	('lymphatic invasion', 'CPA', (143, 161))
474557	32106831	In the biopsy specimens of ESCC patients prior to NAC, high GR, Sgk1, and NDRG1 were detected in 54.7% (23/42), 45.2% (19/42), and 42.9% (18/42) of the patients examined, respectively (Table 5).	('patients', 'Species', '9606', (32, 40))	('ESCC', 'Disease', 'MESH:C562729', (27, 31))	('NDRG1', 'Gene', (74, 79))	('ESCC', 'Disease', (27, 31))	('NAC', 'Chemical', '-', (50, 53))	('high GR', 'Var', (55, 62))	('detected', 'Reg', (85, 93))	('patients', 'Species', '9606', (152, 160))	('Sgk1', 'Gene', (64, 68))
474560	32106831	However, a significantly shorter DFS was detected in those with high pre-NAC Sgk1 status compared to those with low status (P = 0.0095) (Fig.	('DFS', 'MPA', (33, 36))	('shorter', 'NegReg', (25, 32))	('NAC', 'Chemical', '-', (73, 76))	('status', 'Var', (82, 88))	('Sgk1', 'Gene', (77, 81))	('high pre-NAC', 'Var', (64, 76))
474561	32106831	Significantly shorter OS and DFS were also detected in those with high pre-NAC NDRG1 status compared to those with low status (OS: P = 0.0233, DFS: P = 0.0006) (Fig.	('shorter', 'NegReg', (14, 21))	('status', 'Var', (85, 91))	('high pre-NAC', 'Var', (66, 78))	('OS', 'Chemical', '-', (22, 24))	('NAC', 'Chemical', '-', (75, 78))	('OS', 'Chemical', '-', (127, 129))	('NDRG1', 'Gene', (79, 84))
474572	32106831	Notably, the high GR, Sgk1, and NDRG1 status in resected specimens were significantly associated with shorter OS in those undergoing NAC.	('OS', 'Chemical', '-', (110, 112))	('high', 'Var', (13, 17))	('Sgk1', 'Gene', (22, 26))	('NDRG1', 'Gene', (32, 37))	('shorter OS', 'Disease', (102, 112))	('NAC', 'Chemical', '-', (133, 136))
474576	32106831	We found that the Sgk1 status in carcinoma cells was not only significantly associated with shorter OS and DFS but also with more advanced pT, pN, and lymphatic vessel invasion in ESCC patients.	('carcinoma cells', 'Disease', 'MESH:D002292', (33, 48))	('OS', 'Chemical', '-', (100, 102))	('carcinoma', 'Phenotype', 'HP:0030731', (33, 42))	('DFS', 'CPA', (107, 110))	('lymphatic vessel invasion', 'CPA', (151, 176))	('Sgk1', 'Gene', (18, 22))	('status', 'Var', (23, 29))	('associated', 'Reg', (76, 86))	('ESCC', 'Disease', 'MESH:C562729', (180, 184))	('patients', 'Species', '9606', (185, 193))	('ESCC', 'Disease', (180, 184))	('carcinoma cells', 'Disease', (33, 48))
474580	32106831	In our present study, a high NDRG1 status was significantly associated with shorter OS and DFS, higher pT, and local progression factors such as venous invasion in the patients, which is consistent with the results of previously reported studies.	('NDRG1', 'Gene', (29, 34))	('OS', 'Chemical', '-', (84, 86))	('DFS', 'CPA', (91, 94))	('venous invasion', 'Disease', (145, 160))	('high', 'Var', (24, 28))	('patients', 'Species', '9606', (168, 176))	('shorter', 'NegReg', (76, 83))	('higher', 'PosReg', (96, 102))	('status', 'Var', (35, 41))
474593	32106831	A high NDRG1 status in carcinoma cells in pre-NAC biopsy specimens was significantly associated with lower NAC effects, and a high GR and Sgk1 status in carcinoma cells tended to be associated with lower NAC effect.	('carcinoma cells', 'Disease', (23, 38))	('high', 'Var', (2, 6))	('carcinoma', 'Phenotype', 'HP:0030731', (153, 162))	('carcinoma', 'Phenotype', 'HP:0030731', (23, 32))	('Sgk1', 'Gene', (138, 142))	('NAC', 'Chemical', '-', (107, 110))	('lower', 'NegReg', (101, 106))	('status', 'Var', (13, 19))	('NAC effects', 'MPA', (107, 118))	('NAC', 'Chemical', '-', (204, 207))	('NAC', 'Chemical', '-', (46, 49))	('carcinoma cells', 'Disease', 'MESH:D002292', (153, 168))	('carcinoma cells', 'Disease', (153, 168))	('NDRG1', 'Gene', (7, 12))	('carcinoma cells', 'Disease', 'MESH:D002292', (23, 38))
474595	32106831	Therefore, these results suggest that NAC sensitivity was decreased in tumors with high expression of GR, Sgk1, and NDRG1, resulting in higher residual tumor cells and subsequent adverse clinical outcomes of patients.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('patients', 'Species', '9606', (208, 216))	('Sgk1', 'Gene', (106, 110))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('higher', 'PosReg', (136, 142))	('NAC', 'Chemical', '-', (38, 41))	('decreased', 'NegReg', (58, 67))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('NAC sensitivity', 'MPA', (38, 53))	('tumor', 'Disease', (152, 157))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('high expression', 'Var', (83, 98))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('tumors', 'Disease', (71, 77))	('NDRG1', 'Gene', (116, 121))	('tumor', 'Disease', (71, 76))	('tumors', 'Disease', 'MESH:D009369', (71, 77))
474597	32106831	We also examined whether a high NDRG1 status in biopsy specimens was significantly associated with decreased therapeutic effects of NAC in patients and observed no significant association.	('decreased', 'NegReg', (99, 108))	('patients', 'Species', '9606', (139, 147))	('high', 'Var', (27, 31))	('NDRG1', 'Gene', (32, 37))	('status', 'Var', (38, 44))	('NAC', 'Chemical', '-', (132, 135))	('therapeutic effects', 'CPA', (109, 128))
474611	32106831	Our results suggest that the status of GR, Sgk1, and NDRG1 in ESCC patients undergoing NAC was significantly related to the treatment outcomes and that the GR-Sgk1-NDRG1 pathway in carcinoma cells of ESCC might be involved in the clinical effects of chemotherapy in these patients.	('Sgk1', 'Gene', (43, 47))	('carcinoma', 'Phenotype', 'HP:0030731', (181, 190))	('status', 'Var', (29, 35))	('patients', 'Species', '9606', (67, 75))	('ESCC', 'Disease', 'MESH:C562729', (62, 66))	('carcinoma cells', 'Disease', 'MESH:D002292', (181, 196))	('related', 'Reg', (109, 116))	('carcinoma cells', 'Disease', (181, 196))	('NAC', 'Chemical', '-', (87, 90))	('NDRG1', 'Gene', (53, 58))	('ESCC', 'Disease', 'MESH:C562729', (200, 204))	('patients', 'Species', '9606', (272, 280))	('ESCC', 'Disease', (62, 66))	('ESCC', 'Disease', (200, 204))
474647	31293623	Second, SCIA has higher sensitivity and minimum FDR compared to two competitive methods (GSEA, CAMERA) under a high proportion of DEGs in background genes, which are conditions that make most self-contained methods invalid.	('sensitivity', 'MPA', (24, 35))	('DEGs', 'Var', (130, 134))	('higher', 'PosReg', (17, 23))	('FDR', 'MPA', (48, 51))	('GSEA', 'Chemical', '-', (89, 93))
474652	30279964	Intratumor heterogeneity of HMCN1 mutant alleles associated with poor prognosis in patients with breast cancer Human breast cancers comprise a complex and highly heterogeneous population of tumor cells.	('breast cancers', 'Phenotype', 'HP:0003002', (117, 131))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('associated', 'Reg', (49, 59))	('HMCN1', 'Gene', (28, 33))	('Human', 'Species', '9606', (111, 116))	('breast cancer', 'Phenotype', 'HP:0003002', (117, 130))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('breast cancer', 'Disease', 'MESH:D001943', (117, 130))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('patients', 'Species', '9606', (83, 91))	('HMCN1', 'Gene', '83872', (28, 33))	('tumor', 'Disease', (190, 195))	('breast cancer', 'Phenotype', 'HP:0003002', (97, 110))	('cancers', 'Phenotype', 'HP:0002664', (124, 131))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('breast cancers', 'Disease', 'MESH:D001943', (117, 131))	('breast cancers', 'Disease', (117, 131))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('breast cancer', 'Disease', 'MESH:D001943', (97, 110))	('tumor', 'Disease', (5, 10))	('breast cancer', 'Disease', (97, 110))	('mutant', 'Var', (34, 40))
474657	30279964	Although the detailed function of HMCN1 remains unknown, it is located in extracellular matrix and the mutation in the gene might be associated with cancer cell invasion and metastasis.	('cancer', 'Disease', (149, 155))	('HMCN1', 'Gene', '83872', (34, 39))	('HMCN1', 'Gene', (34, 39))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('mutation', 'Var', (103, 111))	('cancer', 'Disease', 'MESH:D009369', (149, 155))	('associated', 'Reg', (133, 143))
474677	30279964	Although mutations in breast cancer driver genes such as TP53, PIK3CA, and GATA3 have been extensively investigated, somatic alterations in other genes are also believed to be associated with breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('breast cancer', 'Disease', (22, 35))	('breast cancer', 'Disease', 'MESH:D001943', (192, 205))	('breast cancer', 'Phenotype', 'HP:0003002', (22, 35))	('breast cancer', 'Disease', (192, 205))	('mutations', 'Var', (9, 18))	('alterations', 'Var', (125, 136))	('breast cancer', 'Phenotype', 'HP:0003002', (192, 205))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('associated', 'Reg', (176, 186))	('GATA3', 'Gene', (75, 80))	('PIK3CA', 'Gene', (63, 69))	('PIK3CA', 'Gene', '5290', (63, 69))	('TP53', 'Gene', '7157', (57, 61))	('GATA3', 'Gene', '2625', (75, 80))	('TP53', 'Gene', (57, 61))	('breast cancer', 'Disease', 'MESH:D001943', (22, 35))
474680	30279964	We sought genes with one of four types of mutation (missense mutations, nonsense mutations, frameshift insertions, and frameshift deletions) in >= 50 samples derived from the 1,044 breast cancer datasets in TCGA.	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('breast cancer', 'Disease', 'MESH:D001943', (181, 194))	('breast cancer', 'Phenotype', 'HP:0003002', (181, 194))	('nonsense mutations', 'Var', (72, 90))	('breast cancer', 'Disease', (181, 194))	('missense mutations', 'Var', (52, 70))	('frameshift insertions', 'Var', (92, 113))	('frameshift deletions', 'Var', (119, 139))
474688	30279964	VAFs of HMCN1 was found to be possibly associated with breast cancer prognosis (FDR < 0.1) (Table 1), and we focused on HMCN1, for which no association with breast cancer has previously been reported.	('HMCN1', 'Gene', '83872', (120, 125))	('breast cancer', 'Disease', 'MESH:D001943', (157, 170))	('HMCN1', 'Gene', (120, 125))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('breast cancer', 'Disease', (157, 170))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('breast cancer', 'Phenotype', 'HP:0003002', (157, 170))	('breast cancer', 'Disease', 'MESH:D001943', (55, 68))	('VAFs', 'Var', (0, 4))	('VAF', 'Chemical', '-', (0, 3))	('associated', 'Reg', (39, 49))	('breast cancer', 'Disease', (55, 68))	('HMCN1', 'Gene', '83872', (8, 13))	('breast cancer', 'Phenotype', 'HP:0003002', (55, 68))	('HMCN1', 'Gene', (8, 13))
474690	30279964	Among samples with detectable HMCN1 mutations, 9.4% (6/64) contained two distinct mutations and 3.1% (2/64) contained more than two mutations.	('HMCN1', 'Gene', (30, 35))	('contained', 'Reg', (59, 68))	('mutations', 'Var', (36, 45))	('contained', 'Reg', (108, 117))	('HMCN1', 'Gene', '83872', (30, 35))
474691	30279964	Of the 78 HMCN1 mutations, 82.1% (64/78) were missense, whereas 10.3% (8/78) were nonsense and 7.7% (6/78) were indels.	('HMCN1', 'Gene', '83872', (10, 15))	('HMCN1', 'Gene', (10, 15))	('mutations', 'Var', (16, 25))	('nonsense', 'Var', (82, 90))	('missense', 'Var', (46, 54))
474692	30279964	Furthermore, 69.2% (54/78) of the mutations were clustered in the Ig-like C2-type domains of HMCN1.	('HMCN1', 'Gene', '83872', (93, 98))	('HMCN1', 'Gene', (93, 98))	('mutations', 'Var', (34, 43))
474699	30279964	We also found no significant differences in the relative HMCN1 mRNA expression levels between HMCN1 mutant and wild-type samples (P = 0.984) (Supplementary Figure 3D).	('mutant', 'Var', (100, 106))	('HMCN1', 'Gene', '83872', (94, 99))	('HMCN1', 'Gene', (94, 99))	('HMCN1', 'Gene', '83872', (57, 62))	('HMCN1', 'Gene', (57, 62))
474706	30279964	To investigate intratumor heterogeneity in individuals with HMCN1 mutations, we measured the number of subclones across each sample.	('mutations', 'Var', (66, 75))	('HMCN1', 'Gene', (60, 65))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('HMCN1', 'Gene', '83872', (60, 65))	('tumor', 'Disease', (20, 25))
474709	30279964	There is another index for intratumor heterogeneity, mutant-allele tumor heterogeneity (MATH), which can be calculated from VAF distribution in a sample.	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('mutant-allele', 'Var', (53, 66))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('VAF', 'Chemical', '-', (124, 127))	('tumor', 'Disease', (67, 72))	('tumor', 'Disease', (32, 37))
474714	30279964	These findings indicate that the prevalence of the mutations in HMCN1 might not be involved in the status of intratumor heterogeneity.	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('mutations', 'Var', (51, 60))	('HMCN1', 'Gene', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumor', 'Disease', (114, 119))	('HMCN1', 'Gene', '83872', (64, 69))
474716	30279964	Among the 64 samples harboring mutations in HMCN1, 22 and 23 also harbored mutations in TP53 and PIK3CA, respectively, and five harbored mutations in both genes.	('mutations', 'Var', (31, 40))	('PIK3CA', 'Gene', (97, 103))	('HMCN1', 'Gene', (44, 49))	('TP53', 'Gene', '7157', (88, 92))	('mutations', 'Var', (75, 84))	('harbored', 'Reg', (66, 74))	('TP53', 'Gene', (88, 92))	('HMCN1', 'Gene', '83872', (44, 49))	('PIK3CA', 'Gene', '5290', (97, 103))
474717	30279964	In the 22 samples with both TP53 and HMCN1 mutations, the mean TP53 VAF was 0.697 (SD = 0.249) and the mean HMCN1 VAF was 0.288 (SD = 0.201).	('TP53', 'Gene', '7157', (28, 32))	('TP53', 'Gene', '7157', (63, 67))	('TP53', 'Gene', (63, 67))	('VAF', 'Chemical', '-', (68, 71))	('TP53', 'Gene', (28, 32))	('HMCN1', 'Gene', '83872', (108, 113))	('mutations', 'Var', (43, 52))	('HMCN1', 'Gene', '83872', (37, 42))	('VAF', 'Chemical', '-', (114, 117))	('HMCN1', 'Gene', (108, 113))	('HMCN1', 'Gene', (37, 42))
474718	30279964	Meanwhile, in the 23 samples with both PIK3CA and HMCN1 mutations, the mean PIK3CA VAF was 0.442 (SD = 0.269) and the mean HMCN1 VAF was 0.230 (SD = 0.148).	('HMCN1', 'Gene', (50, 55))	('mutations', 'Var', (56, 65))	('PIK3CA', 'Gene', '5290', (76, 82))	('PIK3CA', 'Gene', '5290', (39, 45))	('VAF', 'Chemical', '-', (129, 132))	('HMCN1', 'Gene', (123, 128))	('HMCN1', 'Gene', '83872', (123, 128))	('PIK3CA', 'Gene', (76, 82))	('VAF', 'Chemical', '-', (83, 86))	('PIK3CA', 'Gene', (39, 45))	('HMCN1', 'Gene', '83872', (50, 55))
474719	30279964	A paired t-test showed that VAFs of the two driver genes were significantly higher than that of HMCN1 (TP53; P < 0.01, PIK3CA; P < 0.01) (Supplementary Figure 5), indicating that mutations in HMCN1 occurred later in the tumor evolutionary process than the mutations in TP53 and PIK3CA.	('TP53', 'Gene', '7157', (103, 107))	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('HMCN1', 'Gene', '83872', (192, 197))	('HMCN1', 'Gene', (192, 197))	('PIK3CA', 'Gene', (119, 125))	('HMCN1', 'Gene', '83872', (96, 101))	('TP53', 'Gene', (103, 107))	('tumor', 'Disease', (220, 225))	('PIK3CA', 'Gene', '5290', (119, 125))	('TP53', 'Gene', '7157', (269, 273))	('PIK3CA', 'Gene', (278, 284))	('HMCN1', 'Gene', (96, 101))	('PIK3CA', 'Gene', '5290', (278, 284))	('VAF', 'Chemical', '-', (28, 31))	('TP53', 'Gene', (269, 273))	('mutations', 'Var', (179, 188))	('tumor', 'Disease', 'MESH:D009369', (220, 225))
474720	30279964	This finding suggests that the mutations in HMCN1 might be involved in breast cancer progression.	('breast cancer', 'Disease', (71, 84))	('mutations', 'Var', (31, 40))	('breast cancer', 'Phenotype', 'HP:0003002', (71, 84))	('HMCN1', 'Gene', (44, 49))	('involved', 'Reg', (59, 67))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('breast cancer', 'Disease', 'MESH:D001943', (71, 84))	('HMCN1', 'Gene', '83872', (44, 49))
474721	30279964	Next, we evaluated the association between HMCN1 mutation status and clinical variables by chi2 test or Fisher's exact test.	('evaluated', 'Reg', (9, 18))	('HMCN1', 'Gene', '83872', (43, 48))	('HMCN1', 'Gene', (43, 48))	('mutation', 'Var', (49, 57))
474722	30279964	We found tumor size (P = 0.028) and molecular subtype (P = 0.021) were related with the HMCN1 mutation (Table 3).	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('related', 'Reg', (71, 78))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumor', 'Disease', (9, 14))	('HMCN1', 'Gene', '83872', (88, 93))	('mutation', 'Var', (94, 102))	('HMCN1', 'Gene', (88, 93))
474723	30279964	To assess the relationship of the HMCN1 VAF with prognosis, the 64 samples harboring HMCN1 mutations were divided into two groups according to VAFs and subjected to an OS analysis.	('VAF', 'Chemical', '-', (40, 43))	('HMCN1', 'Gene', '83872', (85, 90))	('HMCN1', 'Gene', (85, 90))	('HMCN1', 'Gene', '83872', (34, 39))	('HMCN1', 'Gene', (34, 39))	('VAF', 'Chemical', '-', (143, 146))	('mutations', 'Var', (91, 100))
474724	30279964	These groups were also compared with individuals without HMCN1 mutations (wild-type; WT).	('mutations', 'Var', (63, 72))	('HMCN1', 'Gene', '83872', (57, 62))	('HMCN1', 'Gene', (57, 62))
474727	30279964	To exclude the possibility that this significant association is not attributable to bias in the impact of mutations in the two groups, we evaluated the impact of single nucleotide variants in HMCN1 on protein structure and function using PolyPhen-2 scores.	('function', 'MPA', (223, 231))	('single nucleotide variants', 'Var', (162, 188))	('HMCN1', 'Gene', '83872', (192, 197))	('HMCN1', 'Gene', (192, 197))
474729	30279964	We found that the Polyphen-2 score of nonsynonymous HMCN1 mutations did not significantly associate with breast cancer prognosis (PolyPhen-2 scores of < 0.85 vs. WT; P = 0.801 and PolyPhen-2 scores of >= 0.85 vs WT; P = 0.671) (Supplementary Figure 6).	('mutations', 'Var', (58, 67))	('HMCN1', 'Gene', '83872', (52, 57))	('HMCN1', 'Gene', (52, 57))	('breast cancer', 'Disease', 'MESH:D001943', (105, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('breast cancer', 'Disease', (105, 118))	('breast cancer', 'Phenotype', 'HP:0003002', (105, 118))
474742	30279964	Through a VAF-based analysis of mutations, we showed that VAFs of HMCN1 was possibly associated with breast cancer prognosis.	('HMCN1', 'Gene', '83872', (66, 71))	('VAF', 'Chemical', '-', (58, 61))	('VAF', 'Chemical', '-', (10, 13))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('HMCN1', 'Gene', (66, 71))	('breast cancer', 'Disease', 'MESH:D001943', (101, 114))	('VAFs', 'Var', (58, 62))	('breast cancer', 'Disease', (101, 114))	('breast cancer', 'Phenotype', 'HP:0003002', (101, 114))	('associated', 'Reg', (85, 95))
474743	30279964	Although the detailed function of HMCN1 in humans remains unknown, mutations in HMCN1 might be associated with cancer cell invasion and metastasis.	('HMCN1', 'Gene', '83872', (34, 39))	('HMCN1', 'Gene', (34, 39))	('humans', 'Species', '9606', (43, 49))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('mutations', 'Var', (67, 76))	('metastasis', 'CPA', (136, 146))	('HMCN1', 'Gene', '83872', (80, 85))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('HMCN1', 'Gene', (80, 85))	('associated', 'Reg', (95, 105))
474749	30279964	HMCN1 mutations are believed to correlate with age-related macular degeneration.	('correlate', 'Reg', (32, 41))	('HMCN1', 'Gene', (0, 5))	('macular degeneration', 'Phenotype', 'HP:0000608', (59, 79))	('age-related macular degeneration', 'Disease', (47, 79))	('mutations', 'Var', (6, 15))	('HMCN1', 'Gene', '83872', (0, 5))
474750	30279964	According to another recent report, HMCN1 acts as a suppressor of gallbladder cancer metastasis and is commonly mutated in certain samples of head and neck squamous cell carcinoma.	('HMCN1', 'Gene', (36, 41))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (142, 179))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (170, 179))	('neck squamous cell carcinoma', 'Disease', (151, 179))	('gallbladder cancer metastasis', 'Disease', 'MESH:D009362', (66, 95))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (156, 179))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (151, 179))	('mutated', 'Var', (112, 119))	('HMCN1', 'Gene', '83872', (36, 41))	('gallbladder cancer metastasis', 'Disease', (66, 95))
474751	30279964	There are at least three possible functional implications of the mutations in HMCN1 in breast cancer metastasis.	('HMCN1', 'Gene', (78, 83))	('breast cancer metastasis', 'Disease', 'MESH:D009362', (87, 111))	('breast cancer metastasis', 'Disease', (87, 111))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('breast cancer', 'Phenotype', 'HP:0003002', (87, 100))	('HMCN1', 'Gene', '83872', (78, 83))	('mutations', 'Var', (65, 74))
474753	30279964	When HMCN1 does not function properly in cancer cell, sufficient cell adhesion might be inhibited and as a result of promoting cancer invasion due to instability of HMCN1 caused by the variants in the gene.	('HMCN1', 'Gene', '83872', (165, 170))	('inhibited', 'NegReg', (88, 97))	('HMCN1', 'Gene', '83872', (5, 10))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('promoting', 'PosReg', (117, 126))	('variants', 'Var', (185, 193))	('cell adhesion', 'CPA', (65, 78))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('HMCN1', 'Gene', (165, 170))	('cancer', 'Disease', (127, 133))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('HMCN1', 'Gene', (5, 10))
474754	30279964	For example, previous study reported that epigenetically silenced fibulin 5 promotes invasion and metastasis in lung cancer.	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('lung cancer', 'Phenotype', 'HP:0100526', (112, 123))	('fibulin 5', 'Gene', (66, 75))	('epigenetically silenced', 'Var', (42, 65))	('metastasis in lung cancer', 'Disease', (98, 123))	('fibulin 5', 'Gene', '10516', (66, 75))	('metastasis in lung cancer', 'Disease', 'MESH:D009362', (98, 123))	('promotes', 'PosReg', (76, 84))
474756	30279964	Therefore, HMCN1 mutations may be associated to cancer proliferation and metastasis because of the disruption of these functions.	('associated', 'Reg', (34, 44))	('metastasis', 'CPA', (73, 83))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('HMCN1', 'Gene', '83872', (11, 16))	('HMCN1', 'Gene', (11, 16))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('mutations', 'Var', (17, 26))
474766	30279964	However, intratumor heterogeneity may also be caused by copy number variants or mutations in noncoding regions, such as those in cis-regulatory elements and splice sites.	('tumor', 'Disease', (14, 19))	('mutations', 'Var', (80, 89))	('caused by', 'Reg', (46, 55))	('copy number variants', 'Var', (56, 76))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
474767	30279964	Moreover, epigenetic alterations can also promote cancer progression.	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('promote', 'PosReg', (42, 49))	('epigenetic alterations', 'Var', (10, 32))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))
474831	28122353	In this study, we found that the 3-year and 5-year OS, DSS, and DFS rates in the poorly differentiated group were significantly lower than those in the well-differentiated group.	('OS', 'Chemical', '-', (51, 53))	('lower', 'NegReg', (128, 133))	('DFS rates', 'CPA', (64, 73))	('DSS', 'Gene', (55, 58))	('DSS', 'Gene', '5376', (55, 58))	('poorly', 'Var', (81, 87))
474838	28122353	The death, disease recurrence, and metastasis rates of patients with poorly differentiated GSCC were significantly higher than those of patients with well-differentiated GSCC.	('death', 'Disease', 'MESH:D003643', (4, 9))	('disease recurrence', 'CPA', (11, 29))	('death', 'Disease', (4, 9))	('GSCC', 'Chemical', '-', (91, 95))	('metastasis rates', 'CPA', (35, 51))	('patients', 'Species', '9606', (55, 63))	('patients', 'Species', '9606', (136, 144))	('poorly differentiated', 'Var', (69, 90))	('higher', 'PosReg', (115, 121))	('GSCC', 'Chemical', '-', (170, 174))
474843	28122353	It is therefore biologically reasonable to find differences in their clinical behavior, as molecular changes may result in more aggressive disease in poorly differentiated GSCC and lead to a worse prognosis.	('aggressive disease', 'Disease', (128, 146))	('more', 'PosReg', (123, 127))	('molecular changes', 'Var', (91, 108))	('result in', 'Reg', (113, 122))	('GSCC', 'Chemical', '-', (172, 176))	('poorly differentiated GSCC', 'Disease', (150, 176))	('aggressive disease', 'Disease', 'MESH:D001523', (128, 146))
474912	33634138	Moreover, extensive N6-methyladenosine modification can drive the cap-independent translation of circRNAs together with m6A reader YTHDF3 and translation initiation factors eIF3A and eIF4G2.	('eIF3A', 'Gene', (173, 178))	('eIF4G2', 'Gene', (183, 189))	('N6-methyladenosine', 'Chemical', 'MESH:C010223', (20, 38))	('drive', 'PosReg', (56, 61))	('YTHDF3', 'Gene', (131, 137))	('eIF4G2', 'Gene', '1982', (183, 189))	('eIF3A', 'Gene', '8661', (173, 178))	('N6-methyladenosine modification', 'Var', (20, 51))	('YTHDF3', 'Gene', '253943', (131, 137))	('cap-independent translation', 'MPA', (66, 93))
474916	33634138	For instance, EcircRNAs generated from Formin (Fmn) and Duchenne muscular dystrophies traps (DMD) genes are able to cause inactivation of RNA transcripts with certain deletion mutations, thereby diminishing the expression levels of the corresponding functional proteins.	('diminishing', 'NegReg', (195, 206))	('inactivation', 'NegReg', (122, 134))	('Fmn', 'Gene', '342184', (47, 50))	('expression levels of the', 'MPA', (211, 235))	('Formin', 'Gene', '14260', (39, 45))	('functional proteins', 'MPA', (250, 269))	('deletion mutations', 'Var', (167, 185))	('Fmn', 'Gene', (47, 50))	('Formin', 'Gene', (39, 45))	('DMD', 'Disease', 'MESH:D020388', (93, 96))	('DMD', 'Disease', (93, 96))	('muscular dystrophies', 'Phenotype', 'HP:0003560', (65, 85))	('RNA', 'Gene', (138, 141))	('Duchenne muscular dystrophies', 'Disease', (56, 85))	('Duchenne muscular dystrophies', 'Disease', 'MESH:D020388', (56, 85))
474922	33634138	For example, hsa_circ_0013958 is indicated to be used as a potential biomarker for screening and early detecting lung adenocarcinoma.	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (113, 132))	('lung adenocarcinoma', 'Disease', (113, 132))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (113, 132))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('hsa_circ_0013958', 'Var', (13, 29))
474933	33634138	It is described above that circ-STXBP5L participates in the carcinogenesis of SCLC as an onco-circRNA by sponging miR-224-3p and miR-512-3p and regulating a subset of target genes, including Akts, NFkappaB and Pik3ca.	('carcinogenesis', 'Disease', 'MESH:D063646', (60, 74))	('NFkappaB', 'Gene', '4790', (197, 205))	('miR-224-3p', 'MPA', (114, 124))	('STXBP5L', 'Gene', '9515', (32, 39))	('regulating', 'Reg', (144, 154))	('miR-512-3p', 'MPA', (129, 139))	('STXBP5L', 'Gene', (32, 39))	('sponging', 'Var', (105, 113))	('carcinogenesis', 'Disease', (60, 74))	('Akts', 'Gene', (191, 195))	('SCLC', 'Gene', '7864', (78, 82))	('SCLC', 'Gene', (78, 82))	('SCLC', 'Phenotype', 'HP:0030357', (78, 82))	('Pik3ca', 'Gene', (210, 216))	('Pik3ca', 'Gene', '5290', (210, 216))	('NFkappaB', 'Gene', (197, 205))
474937	33634138	circRNA_102231 promotes cellular proliferation, invasion, and migration in lung cancer.	('lung cancer', 'Disease', (75, 86))	('migration', 'CPA', (62, 71))	('lung cancer', 'Phenotype', 'HP:0100526', (75, 86))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('circRNA_102231', 'Var', (0, 14))	('lung cancer', 'Disease', 'MESH:D008175', (75, 86))	('invasion', 'CPA', (48, 56))	('cellular proliferation', 'CPA', (24, 46))	('promotes', 'PosReg', (15, 23))
474938	33634138	Highly expressed circRNA_102231 may serve as a biomarker for both diagnosis and prognosis for lung cancer patients.	('lung cancer', 'Disease', 'MESH:D008175', (94, 105))	('lung cancer', 'Disease', (94, 105))	('lung cancer', 'Phenotype', 'HP:0100526', (94, 105))	('circRNA_102231', 'Var', (17, 31))	('patients', 'Species', '9606', (106, 114))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
474940	33634138	Particularly, circHIPK3 also functions as a negative autophagy regulator in lung cancer through the miR124-3p-STAT3-PRKAA pathway which is dependent on STK11 status.	('STAT3', 'Gene', '6774', (110, 115))	('lung cancer', 'Disease', 'MESH:D008175', (76, 87))	('STAT3', 'Gene', (110, 115))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('lung cancer', 'Disease', (76, 87))	('lung cancer', 'Phenotype', 'HP:0100526', (76, 87))	('miR124-3p', 'Gene', (100, 109))	('circHIPK3', 'Var', (14, 23))	('STK11', 'Gene', (152, 157))	('PRKAA', 'Gene', (116, 121))	('PRKAA', 'Gene', '5563', (116, 121))	('STK11', 'Gene', '6794', (152, 157))	('miR124-3p', 'Gene', '406909', (100, 109))
474945	33634138	It is reported that circ_0000376 can promote NSCLC progression by regulating the miR-1182/NOVA2 axis and is relative to the poor overall survival of NSCLC patients.	('circ_0000376', 'Var', (20, 32))	('SCLC', 'Phenotype', 'HP:0030357', (150, 154))	('promote', 'PosReg', (37, 44))	('miR-1182', 'Gene', '100302132', (81, 89))	('NSCLC', 'Disease', (45, 50))	('NSCLC', 'Disease', (149, 154))	('NOVA2', 'Gene', (90, 95))	('NOVA2', 'Gene', '4858', (90, 95))	('NSCLC', 'Disease', 'MESH:D002289', (45, 50))	('regulating', 'Reg', (66, 76))	('SCLC', 'Phenotype', 'HP:0030357', (46, 50))	('patients', 'Species', '9606', (155, 163))	('NSCLC', 'Disease', 'MESH:D002289', (149, 154))	('miR-1182', 'Gene', (81, 89))	('NSCLC', 'Phenotype', 'HP:0030358', (45, 50))	('NSCLC', 'Phenotype', 'HP:0030358', (149, 154))
474947	33634138	Manipulated inhibition of circ_0000376 suppresses the progressive activities of hypoxia-induced NSCLC cells both in vitro and in vivo.	('circ_0000376', 'Gene', (26, 38))	('inhibition', 'Var', (12, 22))	('suppresses', 'NegReg', (39, 49))	('NSCLC', 'Disease', (96, 101))	('hypoxia', 'Disease', 'MESH:D000860', (80, 87))	('NSCLC', 'Disease', 'MESH:D002289', (96, 101))	('SCLC', 'Phenotype', 'HP:0030357', (97, 101))	('progressive', 'CPA', (54, 65))	('NSCLC', 'Phenotype', 'HP:0030358', (96, 101))	('hypoxia', 'Disease', (80, 87))
474950	33634138	Serving as a sponge for miR-503, circ-BANP promotes proliferation, invasion, and migration while attenuates apoptosis of lung cancer cells through promotion of LARP1 expression.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('promotion', 'PosReg', (147, 156))	('lung cancer', 'Disease', 'MESH:D008175', (121, 132))	('proliferation', 'CPA', (52, 65))	('promotes', 'PosReg', (43, 51))	('miR-503', 'Gene', '574506', (24, 31))	('invasion', 'CPA', (67, 75))	('lung cancer', 'Disease', (121, 132))	('lung cancer', 'Phenotype', 'HP:0100526', (121, 132))	('miR-503', 'Gene', (24, 31))	('LARP1', 'Gene', '23367', (160, 165))	('attenuates', 'NegReg', (97, 107))	('circ-BANP', 'Var', (33, 42))	('migration', 'CPA', (81, 90))	('expression', 'MPA', (166, 176))	('apoptosis', 'CPA', (108, 117))	('LARP1', 'Gene', (160, 165))
474961	33634138	Silencing of circ-ENO1 inhibits glycolysis, cell proliferation, migration and EMT of lung adenocarcinoma.	('ENO1', 'Gene', (18, 22))	('inhibits', 'NegReg', (23, 31))	('ENO1', 'Gene', '2023', (18, 22))	('cell proliferation', 'CPA', (44, 62))	('glycolysis', 'MPA', (32, 42))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (85, 104))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('lung adenocarcinoma', 'Disease', (85, 104))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (85, 104))	('migration', 'CPA', (64, 73))	('Silencing', 'Var', (0, 9))	('EMT', 'CPA', (78, 81))
474965	33634138	Inhibition of circ-CPA4 suppresses NSCLC cell growth, mobility and EMT, while enhances cell death via downregulation of let-7/PD-L1 axis.	('CPA4', 'Gene', '51200', (19, 23))	('NSCLC', 'Disease', (35, 40))	('downregulation', 'NegReg', (102, 116))	('enhances', 'PosReg', (78, 86))	('EMT', 'CPA', (67, 70))	('SCLC', 'Phenotype', 'HP:0030357', (36, 40))	('CPA4', 'Gene', (19, 23))	('NSCLC', 'Disease', 'MESH:D002289', (35, 40))	('suppresses', 'NegReg', (24, 34))	('Inhibition', 'Var', (0, 10))	('NSCLC', 'Phenotype', 'HP:0030358', (35, 40))	('cell death', 'CPA', (87, 97))	('mobility', 'CPA', (54, 62))
474971	33634138	circ_0001649 is demonstrated to have a decreased expression in NSCLC tissues and cell lines with suppressive functions on cell growth and metastasis both in vitro and in vivo partially by sponging out miR-331-3p and miR-338-5p.	('NSCLC', 'Disease', (63, 68))	('miR-338-5p', 'Var', (216, 226))	('NSCLC', 'Disease', 'MESH:D002289', (63, 68))	('expression', 'MPA', (49, 59))	('NSCLC', 'Phenotype', 'HP:0030358', (63, 68))	('circ_0001649', 'Var', (0, 12))	('SCLC', 'Phenotype', 'HP:0030357', (64, 68))	('miR-331-3p', 'Var', (201, 211))	('decreased', 'NegReg', (39, 48))
474977	33634138	For example, acting as an endogenous sponge for miR-1252, has_circ_0043256 can upregulate the expression of ITCH and finally inhibit Wnt/beta-catenin pathway, leading to suppression of cell proliferation and enhancement of apoptosis in NSCLC.	('beta-catenin', 'Gene', '1499', (137, 149))	('cell proliferation', 'CPA', (185, 203))	('SCLC', 'Phenotype', 'HP:0030357', (237, 241))	('ITCH', 'Phenotype', 'HP:0000989', (108, 112))	('enhancement', 'PosReg', (208, 219))	('has_circ_0043256', 'Var', (58, 74))	('miR-1252', 'Gene', '100302136', (48, 56))	('NSCLC', 'Disease', 'MESH:D002289', (236, 241))	('ITCH', 'Gene', (108, 112))	('NSCLC', 'Disease', (236, 241))	('inhibit', 'NegReg', (125, 132))	('NSCLC', 'Phenotype', 'HP:0030358', (236, 241))	('expression', 'MPA', (94, 104))	('ITCH', 'Gene', '83737', (108, 112))	('suppression', 'NegReg', (170, 181))	('upregulate', 'PosReg', (79, 89))	('apoptosis', 'CPA', (223, 232))	('beta-catenin', 'Gene', (137, 149))	('miR-1252', 'Gene', (48, 56))
474979	33634138	Furthermore, circNOL10 inhibits lung cancer by enhancing transcriptional regulation of the HN polypeptide family, which exerts pivotal functions on biological processes such as proliferation, apoptosis, and cell cycle progression.	('lung cancer', 'Phenotype', 'HP:0100526', (32, 43))	('transcriptional regulation', 'MPA', (57, 83))	('circNOL10', 'Var', (13, 22))	('circNOL10', 'Chemical', '-', (13, 22))	('lung cancer', 'Disease', 'MESH:D008175', (32, 43))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('inhibits', 'NegReg', (23, 31))	('lung cancer', 'Disease', (32, 43))	('enhancing', 'PosReg', (47, 56))
474984	33634138	The most pronouncedly enriched pathways for aberrant circRNA-related host genes include VEGFR, EGFR, integrin, and rho GTPase signaling, which are all involved in the progression of chemo-resistance.	('VEGFR', 'Gene', (88, 93))	('VEGFR', 'Gene', '3791', (88, 93))	('aberrant', 'Var', (44, 52))	('EGFR', 'Gene', (95, 99))
474987	33634138	Recently, it is found that the expression of hsa_circ_0004350 and hsa_circ_0092857, both derived from EIF3a, varies prominently in cisplatin-resistant lung cancer cell line and the parental cell line.	('cisplatin', 'Chemical', 'MESH:D002945', (131, 140))	('hsa_circ_0004350', 'Var', (45, 61))	('lung cancer', 'Phenotype', 'HP:0100526', (151, 162))	('lung cancer', 'Disease', (151, 162))	('hsa_circ_0092857', 'Var', (66, 82))	('expression', 'MPA', (31, 41))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('EIF3a', 'Gene', (102, 107))	('EIF3a', 'Gene', '8669', (102, 107))	('varies', 'Reg', (109, 115))	('lung cancer', 'Disease', 'MESH:D008175', (151, 162))
474992	33634138	Furthermore, detection for EGFR driver mutation is hindered by problems such as cancer heterogeneity and lack of cancer tissues.	('EGFR', 'Gene', (27, 31))	('mutation', 'Var', (39, 47))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancer', 'Disease', (113, 119))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('cancer', 'Disease', (80, 86))
474993	33634138	By screening circRNAs expression profile via circRNA microarray, it is found that hsa_circ_0109320 and hsa_circ_0134501 are upregulated in gefitinib-effective NSCLC patients.	('hsa_circ_0109320', 'Var', (82, 98))	('NSCLC', 'Disease', (159, 164))	('hsa_circ_0134501', 'Var', (103, 119))	('NSCLC', 'Disease', 'MESH:D002289', (159, 164))	('SCLC', 'Phenotype', 'HP:0030357', (160, 164))	('patients', 'Species', '9606', (165, 173))	('upregulated', 'PosReg', (124, 135))	('NSCLC', 'Phenotype', 'HP:0030358', (159, 164))
474994	33634138	Moreover, hsa_circ_0109320 expression is associated with better progression-free survival (PFS), indicating its potential role as a prognostic biomarker for gefitinib-treated NSCLC patients.	('NSCLC', 'Disease', 'MESH:D002289', (175, 180))	('better', 'PosReg', (57, 63))	('NSCLC', 'Phenotype', 'HP:0030358', (175, 180))	('SCLC', 'Phenotype', 'HP:0030357', (176, 180))	('patients', 'Species', '9606', (181, 189))	('progression-free survival', 'CPA', (64, 89))	('hsa_circ_0109320 expression', 'Var', (10, 37))	('NSCLC', 'Disease', (175, 180))
474997	33634138	Further study indicates that hsa_circ_0004015 promotes NSCLC progression and gefitinib resistance through sponge for miR-1183 and induction of 3-phosphoinositide-dependent protein kinase 1 (PDPK) as well as the downstream AKT pathway.	('gefitinib resistance', 'MPA', (77, 97))	('3-phosphoinositide-dependent protein kinase 1', 'Gene', (143, 188))	('PDPK', 'Gene', (190, 194))	('NSCLC', 'Disease', (55, 60))	('PDPK', 'Gene', '5170', (190, 194))	('AKT', 'Gene', '207', (222, 225))	('NSCLC', 'Disease', 'MESH:D002289', (55, 60))	('miR-1183', 'Gene', '100302122', (117, 125))	('SCLC', 'Phenotype', 'HP:0030357', (56, 60))	('3-phosphoinositide-dependent protein kinase 1', 'Gene', '5170', (143, 188))	('miR-1183', 'Gene', (117, 125))	('hsa_circ_0004015', 'Var', (29, 45))	('AKT', 'Gene', (222, 225))	('promotes', 'PosReg', (46, 54))	('NSCLC', 'Phenotype', 'HP:0030358', (55, 60))
475004	33634138	Emerging evidence show that dysregulated chemokine receptor expression is one of the critical intrinsic reasons for tumor-promotion and immune system evasion.	('expression', 'MPA', (60, 70))	('dysregulated', 'Var', (28, 40))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('chemokine', 'Protein', (41, 50))	('tumor', 'Disease', (116, 121))
475007	33634138	Manipulated upregulation of circFGFR1 promotes the proliferation, invasion, migration, and immune evasion of NSCLC cells, while knockdown of CXCR4 resensitizes NSCLC cells to anti-PD-1 immunotherapy.	('promotes', 'PosReg', (38, 46))	('CXCR4', 'Gene', '7852', (141, 146))	('NSCLC', 'Disease', (160, 165))	('CXCR4', 'Gene', (141, 146))	('NSCLC', 'Disease', 'MESH:D002289', (109, 114))	('NSCLC', 'Phenotype', 'HP:0030358', (160, 165))	('invasion', 'CPA', (66, 74))	('NSCLC', 'Disease', (109, 114))	('SCLC', 'Phenotype', 'HP:0030357', (161, 165))	('upregulation', 'PosReg', (12, 24))	('migration', 'CPA', (76, 85))	('NSCLC', 'Phenotype', 'HP:0030358', (109, 114))	('immune evasion', 'CPA', (91, 105))	('circFGFR1', 'Gene', '2260', (28, 37))	('SCLC', 'Phenotype', 'HP:0030357', (110, 114))	('knockdown', 'Var', (128, 137))	('proliferation', 'CPA', (51, 64))	('circFGFR1', 'Gene', (28, 37))	('NSCLC', 'Disease', 'MESH:D002289', (160, 165))
475024	31510782	A circular RNA derived from MMP9 facilitates oral squamous cell carcinoma metastasis through regulation of MMP9 mRNA stability Emerging evidence demonstrates that dysregulation of circular RNA is linked to tumorigenesis and aggressive progression.	('linked', 'Reg', (196, 202))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('circular', 'Protein', (180, 188))	('MMP9', 'Gene', '4318', (28, 32))	('MMP9', 'Gene', (28, 32))	('tumor', 'Disease', (206, 211))	('aggressive progression', 'CPA', (224, 246))	('MMP9', 'Gene', (107, 111))	('tumor', 'Disease', 'MESH:D009369', (206, 211))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (50, 73))	('squamous cell carcinoma metastasis', 'Disease', 'MESH:D002294', (50, 84))	('squamous cell carcinoma metastasis', 'Disease', (50, 84))	('MMP9', 'Gene', '4318', (107, 111))	('dysregulation', 'Var', (163, 176))	('facilitates', 'PosReg', (33, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))
475027	31510782	Patients with high circular matrix metalloproteinase 9 expression were prone to lymph node metastasis and an advanced TNM stage.	('high circular', 'Var', (14, 27))	('matrix metalloproteinase 9', 'Gene', '4318', (28, 54))	('lymph node metastasis', 'CPA', (80, 101))	('Patients', 'Species', '9606', (0, 8))	('prone', 'Reg', (71, 76))	('matrix metalloproteinase 9', 'Gene', (28, 54))
475040	31510782	OSCC patients with high MMP9 expression are closely associated with metastatic clinical features and worse prognosis.	('metastatic clinical', 'CPA', (68, 87))	('high', 'Var', (19, 23))	('OSCC', 'Disease', 'MESH:D002294', (0, 4))	('patients', 'Species', '9606', (5, 13))	('associated', 'Reg', (52, 62))	('OSCC', 'Disease', (0, 4))	('MMP9', 'Gene', (24, 28))
475043	31510782	Circ-FLI1 located in the nucleus promoted breast cancer metastasis by epigenetic upregulation of FLI1 via coordinately regulating TET1 and DNMT1.	('TET1', 'Gene', '80312', (130, 134))	('promoted', 'PosReg', (33, 41))	('DNMT1', 'Gene', (139, 144))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('regulating', 'Reg', (119, 129))	('FLI1', 'Gene', (97, 101))	('breast cancer', 'Disease', 'MESH:D001943', (42, 55))	('breast cancer', 'Phenotype', 'HP:0003002', (42, 55))	('DNMT1', 'Gene', '1786', (139, 144))	('upregulation', 'PosReg', (81, 93))	('FLI1', 'Gene', (5, 9))	('breast cancer', 'Disease', (42, 55))	('FLI1', 'Gene', '2313', (97, 101))	('TET1', 'Gene', (130, 134))	('FLI1', 'Gene', '2313', (5, 9))	('epigenetic', 'Var', (70, 80))
475058	31510782	The primary antibodies used were: anti-MMP9 (1:1000 dilution, #13667, CST, Danvers, MA, USA); anti-AUF1 (1:5000 dilution, #12382, CST, Danvers, MA, USA); and anti-GAPDH (1:10000 dilution, #HRP-60004, Proteintech, Rosemont, IL, USA).	('GAPDH', 'Gene', '2597', (163, 168))	('AUF1', 'Gene', (99, 103))	('GAPDH', 'Gene', (163, 168))	('AUF1', 'Gene', '3184', (99, 103))	('#12382', 'Var', (122, 128))
475065	31510782	To evaluate the relationship between miR-149 and circ-MMP9/MMP9, the full-length sequences of circ-MMP9 and MMP9 3'-untranslated region (UTR) containing the wild-type or mutant miR-149 binding site were inserted into pmirGLO vector (Promega, Madison, WI, USA).	('miR-149', 'Gene', '406941', (177, 184))	('miR-149', 'Gene', (37, 44))	('miR-149', 'Gene', '406941', (37, 44))	('mutant', 'Var', (170, 176))	('miR-149', 'Gene', (177, 184))
475071	31510782	Further, we found that circ-MMP9 expression was closely related to lymph node metastasis (p=0.002) and clinical TNM stage (p=0.005), but not to age, gender, tumor size, or site (Table 1).	('tumor', 'Disease', (157, 162))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('lymph node metastasis', 'CPA', (67, 88))	('circ-MMP9', 'Var', (23, 32))	('expression', 'MPA', (33, 43))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('related', 'Reg', (56, 63))
475072	31510782	OSCC patients with high circ-MMP9 had a shorter overall survival time than those with low circ-MMP9 (Figure 1(c)).	('high circ-MMP9', 'Var', (19, 33))	('OSCC', 'Disease', 'MESH:D002294', (0, 4))	('overall survival', 'MPA', (48, 64))	('patients', 'Species', '9606', (5, 13))	('shorter', 'NegReg', (40, 47))	('OSCC', 'Disease', (0, 4))
475080	31510782	The wound healing assay showed the migration distance of UM1 and HSC-3 cells was significantly shortened after knockdown of circ-MMP9 (Figure 2(a)).	('circ-MMP9', 'Gene', (124, 133))	('knockdown', 'Var', (111, 120))	('HSC-3', 'Gene', '150353', (65, 70))	('shortened', 'NegReg', (95, 104))	('HSC-3', 'Gene', (65, 70))	('wound healing assay', 'CPA', (4, 23))
475083	31510782	Overall, these in vitro and in vivo results suggest that circ-MMP9 is a pro-metastasis circRNA in OSCC.	('circ-MMP9', 'Var', (57, 66))	('OSCC', 'Disease', 'MESH:D002294', (98, 102))	('OSCC', 'Disease', (98, 102))
475086	31510782	As expected, silencing AUF1 could significantly rescue the decreased MMP9 mRNA expression caused by circ-MMP9 depletion (Figure 3(d)).	('decreased', 'NegReg', (59, 68))	('AUF1', 'Gene', (23, 27))	('MMP9 mRNA expression', 'MPA', (69, 89))	('AUF1', 'Gene', '3184', (23, 27))	('silencing', 'Var', (13, 22))
475087	31510782	Through analyzing the RPISeq online tool, we found that circ-MMP9 probably interacted with AUF1 (RF classifier=0.88, SVM classifier=0.91) (Figure 3(e)).	('interacted', 'Reg', (75, 85))	('circ-MMP9', 'Var', (56, 65))	('AUF1', 'Gene', '3184', (91, 95))	('AUF1', 'Gene', (91, 95))
475092	31510782	Taken together, these findings demonstrate that circ-MMP9 enhances MMP9 mRNA stability via antagonizing AUF1-induced MMP9 mRNA decay in OSCC.	('OSCC', 'Disease', 'MESH:D002294', (136, 140))	('circ-MMP9', 'Var', (48, 57))	('MMP9 mRNA decay', 'MPA', (117, 132))	('AUF1', 'Gene', '3184', (104, 108))	('MMP9 mRNA stability', 'MPA', (67, 86))	('OSCC', 'Disease', (136, 140))	('AUF1', 'Gene', (104, 108))	('antagonizing', 'NegReg', (91, 103))	('enhances', 'PosReg', (58, 66))
475093	31510782	As mentioned above, AUF1 silencing could only partially rescue the reduced MMP9 mRNA caused by circ-MMP9 knockdown (Figure 3(d)), suggesting there are other factors mediating the regulation of circ-MMP9 on MMP9.	('silencing', 'Var', (25, 34))	('AUF1', 'Gene', '3184', (20, 24))	('MMP9 mRNA', 'MPA', (75, 84))	('knockdown', 'Var', (105, 114))	('reduced', 'NegReg', (67, 74))	('circ-MMP9', 'Gene', (95, 104))	('AUF1', 'Gene', (20, 24))
475098	31510782	These results indicate that circ-MMP9 can sponge miR-149 in OSCC cells.	('OSCC', 'Disease', (60, 64))	('sponge', 'Var', (42, 48))	('miR-149', 'Gene', (49, 56))	('miR-149', 'Gene', '406941', (49, 56))	('OSCC', 'Disease', 'MESH:D002294', (60, 64))
475103	31510782	Importantly, the decreased MMP9 mRNA and the attenuated migratory and invasive abilities caused by circ-MMP9 depletion were partly blocked by miR-149 silencing, and were totally abolished by MMP9 overexpression or miR-149 silencing combined with AUF1 knockdown (Figure 4(j) and (k)).	('invasive abilities', 'Disease', (70, 88))	('blocked', 'NegReg', (131, 138))	('miR-149', 'Gene', (214, 221))	('decreased', 'NegReg', (17, 26))	('miR-149', 'Gene', '406941', (214, 221))	('MMP9', 'Protein', (27, 31))	('AUF1', 'Gene', (246, 250))	('attenuated', 'NegReg', (45, 55))	('silencing', 'Var', (150, 159))	('AUF1', 'Gene', '3184', (246, 250))	('miR-149', 'Gene', (142, 149))	('miR-149', 'Gene', '406941', (142, 149))	('invasive abilities', 'Disease', 'MESH:D009361', (70, 88))	('knockdown', 'Var', (251, 260))
475104	31510782	Collectively, these data suggest circ-MMP9 promotes OSCC metastasis through regulating its parental gene stability via miR-149 and AUF1 (Figure 5).	('AUF1', 'Gene', (131, 135))	('miR-149', 'Gene', (119, 126))	('promotes', 'PosReg', (43, 51))	('miR-149', 'Gene', '406941', (119, 126))	('circ-MMP9', 'Var', (33, 42))	('OSCC', 'Disease', 'MESH:D002294', (52, 56))	('AUF1', 'Gene', '3184', (131, 135))	('stability', 'MPA', (105, 114))	('OSCC', 'Disease', (52, 56))
475108	31510782	More importantly, knockdown of circ-MMP9 significantly suppressed the metastatic capability of OSCC cells in animal models, implying that therapeutic targeting of circ-MMP9 may be a promising treatment intervention for patients with metastatic OSCC.	('knockdown', 'Var', (18, 27))	('circ-MMP9', 'Gene', (31, 40))	('patients', 'Species', '9606', (219, 227))	('OSCC', 'Disease', 'MESH:D002294', (95, 99))	('OSCC', 'Disease', 'MESH:D002294', (244, 248))	('OSCC', 'Disease', (95, 99))	('suppressed', 'NegReg', (55, 65))	('OSCC', 'Disease', (244, 248))
475110	31510782	For example, circ-HIPK3, circ-ZEB1.33, circ-100146, and circ-ANKS1B could effectively sponge miR-7, miR-200a-3p, miR-615-5p, miR-148/152, and miR-646 in colorectal cancer, hepatocellular carcinoma, non-small cell lung carcinoma, and breast cancer, respectively.	('colorectal cancer', 'Disease', 'MESH:D015179', (153, 170))	('miR-646', 'Gene', (142, 149))	('miR-646', 'Gene', '693231', (142, 149))	('colorectal cancer', 'Disease', (153, 170))	('miR-148/152', 'Var', (125, 136))	('miR-7', 'Gene', (93, 98))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (172, 196))	('miR-615-5p', 'Var', (113, 123))	('non-small cell lung carcinoma', 'Disease', 'MESH:D002289', (198, 227))	('miR-200a-3p', 'Var', (100, 111))	('ANKS1B', 'Gene', '56899', (61, 67))	('ZEB1', 'Gene', (30, 34))	('ANKS1B', 'Gene', (61, 67))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (172, 196))	('miR-7', 'Gene', '10859', (93, 98))	('breast cancer', 'Phenotype', 'HP:0003002', (233, 246))	('HIPK3', 'Gene', '10114', (18, 23))	('colorectal cancer', 'Phenotype', 'HP:0003003', (153, 170))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('small cell lung carcinoma', 'Phenotype', 'HP:0030357', (202, 227))	('breast cancer', 'Disease', 'MESH:D001943', (233, 246))	('carcinoma', 'Phenotype', 'HP:0030731', (187, 196))	('carcinoma', 'Phenotype', 'HP:0030731', (218, 227))	('hepatocellular carcinoma', 'Disease', (172, 196))	('breast cancer', 'Disease', (233, 246))	('HIPK3', 'Gene', (18, 23))	('non-small cell lung carcinoma', 'Phenotype', 'HP:0030358', (198, 227))	('ZEB1', 'Gene', '6935', (30, 34))	('non-small cell lung carcinoma', 'Disease', (198, 227))
475112	31510782	Intriguingly, a recent study also identified circ-MMP9 as an oncogene that contributed to glioblastoma multiforme cell tumorigenesis via sponging miR-124.	('circ-MMP9', 'Gene', (45, 54))	('tumor', 'Disease', (119, 124))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (90, 113))	('glioblastoma', 'Phenotype', 'HP:0012174', (90, 102))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('contributed', 'Reg', (75, 86))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('glioblastoma multiforme', 'Disease', (90, 113))	('sponging', 'Var', (137, 145))
475117	31510782	In the present study, we found that circ-MMP9 could physically bind to AUF1 to increase MMP9 mRNA stability.	('bind', 'Interaction', (63, 67))	('increase', 'PosReg', (79, 87))	('AUF1', 'Gene', '3184', (71, 75))	('AUF1', 'Gene', (71, 75))	('MMP9', 'Var', (88, 92))
475123	31828039	Despite genomic efforts to identify driver mutations and changes in protein-coding gene expression, developing effective diagnostic and prognostic biomarkers remains a priority to guide disease management and improve patient outcome.	('mutations', 'Var', (43, 52))	('changes', 'Reg', (57, 64))	('patient', 'Species', '9606', (217, 224))
475289	31652801	In fact, mutations, translocations, and deletions occurring within some subunits of SWI/SNF complex were found in ~20% of human tumors, making the complex one of the most commonly affected hallmarks in cancer.	('human', 'Species', '9606', (122, 127))	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('hallmarks in cancer', 'Disease', 'MESH:D009369', (189, 208))	('deletions', 'Var', (40, 49))	('mutations', 'Var', (9, 18))	('found', 'Reg', (105, 110))	('N', 'Chemical', 'MESH:D009584', (89, 90))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumors', 'Disease', (128, 134))	('SWI/SNF', 'Gene', (84, 91))	('tumors', 'Disease', 'MESH:D009369', (128, 134))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('translocations', 'Var', (20, 34))	('hallmarks in cancer', 'Disease', (189, 208))
475291	31652801	Mutations in the SWI/SNF complex are usually associated with loss of protein function, with SMARCB1/BAF47, SMARCA4/BRG1, and ARID1A/BAF250A subunits of the complex being characterized by very high mutation frequencies and a strong relation to disease development.	('men', 'Species', '9606', (258, 261))	('SWI/SNF', 'Gene', (17, 24))	('N', 'Chemical', 'MESH:D009584', (22, 23))	('BRG1', 'Gene', (115, 119))	('BAF47', 'Gene', '6598', (100, 105))	('BAF250A', 'Gene', '8289', (132, 139))	('protein', 'Protein', (69, 76))	('BAF47', 'Gene', (100, 105))	('SMARCB1', 'Gene', '6598', (92, 99))	('BRG1', 'Gene', '6597', (115, 119))	('SMARCA4', 'Gene', (107, 114))	('Mutations', 'Var', (0, 9))	('SMARCA4', 'Gene', '6597', (107, 114))	('SMARCB1', 'Gene', (92, 99))	('loss', 'NegReg', (61, 65))	('BAF250A', 'Gene', (132, 139))
475292	31652801	The roles of mutations in the individual BAF-complex subunits in the development of various human diseases will be discussed later.	('BAF', 'Gene', (41, 44))	('men', 'Species', '9606', (76, 79))	('mutations', 'Var', (13, 22))	('BAF', 'Gene', '8815', (41, 44))	('human', 'Species', '9606', (92, 97))
475296	31652801	The most frequent gene translocation associated with ESFT is t(11;22) (q24;q12) translocation, where fusion of EWS gene on 22q12 with FLI1 gene on 11q24 will produce EWS-FLI1 hybrid protein, and this fusion transcript will lead to increased transcription capacity compared with FLI1 alone.	('fusion', 'Var', (101, 107))	('transcription capacity', 'MPA', (241, 263))	('FLI1', 'Gene', (134, 138))	('FLI1', 'Gene', (278, 282))	('EWS', 'Gene', '2130', (166, 169))	('EWS', 'Gene', (166, 169))	('EWS', 'Gene', '2130', (111, 114))	('EWS', 'Gene', (111, 114))	('increased', 'PosReg', (231, 240))	('FLI1', 'Gene', (170, 174))	('FLI1', 'Gene', '2313', (278, 282))	('FLI1', 'Gene', '2313', (170, 174))	('produce', 'Reg', (158, 165))	('FLI1', 'Gene', '2313', (134, 138))
475298	31652801	Mutations within these pathways lead to tumor progression and unstable EWS-FLI1 expression.	('lead to', 'Reg', (32, 39))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('EWS', 'Gene', '2130', (71, 74))	('EWS', 'Gene', (71, 74))	('tumor', 'Disease', (40, 45))	('Mutations', 'Var', (0, 9))	('expression', 'MPA', (80, 90))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('FLI1', 'Gene', (75, 79))	('FLI1', 'Gene', '2313', (75, 79))
475305	31652801	In addition, the prion domain of EWSR1 at the N-terminus provides the BAF complex with a gain of function that is recruited to GGAA repeats microsatellites, and when this occurs, the closed chromatin is remodeled for activation of enhancer and oncogenic transcription.	('N', 'Chemical', 'MESH:D009584', (46, 47))	('oncogenic transcription', 'CPA', (244, 267))	('recruited', 'PosReg', (114, 123))	('BAF', 'Gene', '8815', (70, 73))	('gain of function', 'PosReg', (89, 105))	('BAF', 'Gene', (70, 73))	('EWS', 'Gene', '2130', (33, 36))	('EWS', 'Gene', (33, 36))	('prion', 'Species', '36469', (17, 22))	('microsatellites', 'Var', (140, 155))	('enhancer', 'CPA', (231, 239))
475310	31652801	Furthermore, the mRNA regions affected by alternative splicing predominantly encodes IDPRs.	('alternative splicing', 'Var', (42, 62))	('IDPRs', 'Disease', (85, 90))	('N', 'Chemical', 'MESH:D009584', (19, 20))	('encodes', 'Reg', (77, 84))
475340	31652801	The sections below briefly describe mutations in, and deregulations of, SMARCA4/BRG1 associated with the development of human diseases.	('human', 'Species', '9606', (120, 125))	('BRG1', 'Gene', (80, 84))	('SMARCA4', 'Gene', (72, 79))	('BRG1', 'Gene', '6597', (80, 84))	('mutations', 'Var', (36, 45))	('SMARCA4', 'Gene', '6597', (72, 79))	('deregulations', 'Var', (54, 67))	('men', 'Species', '9606', (112, 115))	('associated', 'Reg', (85, 95))
475342	31652801	Furthermore, mutations in BRG1 were found in 5-10% of cases of lung cancer.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('lung cancer', 'Disease', 'MESH:D008175', (63, 74))	('BRG1', 'Gene', (26, 30))	('found', 'Reg', (36, 41))	('lung cancer', 'Disease', (63, 74))	('lung cancer', 'Phenotype', 'HP:0100526', (63, 74))	('BRG1', 'Gene', '6597', (26, 30))	('mutations', 'Var', (13, 22))
475346	31652801	In almost all SCCOHT tumors, inactivating mutations leading to loss of BRG1/SMARCA4 expression have been exclusively found, and mutations of this protein were observed in 91% of cases.	('mutations', 'Var', (128, 137))	('tumors', 'Disease', (21, 27))	('tumors', 'Disease', 'MESH:D009369', (21, 27))	('BRG1', 'Gene', (71, 75))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))	('BRG1', 'Gene', '6597', (71, 75))	('SMARCA4', 'Gene', (76, 83))	('SMARCA4', 'Gene', '6597', (76, 83))	('loss', 'NegReg', (63, 67))	('expression', 'MPA', (84, 94))
475347	31652801	Blood neoplasm (Burkitt lymphoma) is linked to mutations in the BRG1/SMARCA4 and BAF250A/ARID1A tumor suppressor genes, with the nonsense and frame-shift mutations leading to loss of function constituting almost 30% of the genetic events occurring with BAF250A/ARID1A.	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('neoplasm', 'Phenotype', 'HP:0002664', (6, 14))	('Burkitt lymphoma', 'Disease', 'MESH:D002051', (16, 32))	('SMARCA4', 'Gene', '6597', (69, 76))	('BAF250A', 'Gene', '8289', (81, 88))	('BAF250A', 'Gene', (81, 88))	('mutations', 'Var', (47, 56))	('nonsense', 'Var', (129, 137))	('BRG1', 'Gene', '6597', (64, 68))	('lymphoma', 'Phenotype', 'HP:0002665', (24, 32))	('Blood neoplasm', 'Phenotype', 'HP:0004377', (0, 14))	('Burkitt lymphoma', 'Phenotype', 'HP:0030080', (16, 32))	('neoplasm', 'Disease', 'MESH:D009369', (6, 14))	('frame-shift mutations', 'Var', (142, 163))	('BRG1', 'Gene', (64, 68))	('loss of function', 'NegReg', (175, 191))	('tumor', 'Disease', (96, 101))	('SMARCA4', 'Gene', (69, 76))	('BAF250A', 'Gene', '8289', (253, 260))	('linked', 'Reg', (37, 43))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('neoplasm', 'Disease', (6, 14))	('BAF250A', 'Gene', (253, 260))	('Burkitt lymphoma', 'Disease', (16, 32))
475348	31652801	Group 3 and 4 pediatric medulloblastomas also linked to mutation in the BRG1/SMARCA4 gene represent a significant clinical challenge due to poor prognosis and lack of targeted therapy.	('pediatric medulloblastomas', 'Disease', (14, 40))	('pediatric medulloblastomas', 'Disease', 'MESH:D008527', (14, 40))	('BRG1', 'Gene', (72, 76))	('BRG1', 'Gene', '6597', (72, 76))	('linked', 'Reg', (46, 52))	('mutation', 'Var', (56, 64))	('SMARCA4', 'Gene', (77, 84))	('SMARCA4', 'Gene', '6597', (77, 84))
475356	31652801	Although mutated BRCA1 exposes individuals to the risk of breast cancer, it was also shown that BRCA1 could interact with the BRG1 subunit of a SWI/SNF complex.	('BRCA1', 'Gene', '672', (17, 22))	('interact', 'Interaction', (108, 116))	('BRCA1', 'Gene', '672', (96, 101))	('BRCA1', 'Gene', (17, 22))	('mutated', 'Var', (9, 16))	('breast cancer', 'Disease', 'MESH:D001943', (58, 71))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('breast cancer', 'Disease', (58, 71))	('BRCA1', 'Gene', (96, 101))	('BRG1', 'Gene', (126, 130))	('breast cancer', 'Phenotype', 'HP:0003002', (58, 71))	('BRG1', 'Gene', '6597', (126, 130))	('N', 'Chemical', 'MESH:D009584', (149, 150))
475357	31652801	Furthermore, a mutant form of BRG1 interfered with the transcriptional control mediated by BRCA1.	('BRCA1', 'Gene', (91, 96))	('transcriptional control', 'MPA', (55, 78))	('interfered', 'NegReg', (35, 45))	('BRG1', 'Gene', (30, 34))	('BRCA1', 'Gene', '672', (91, 96))	('mutant', 'Var', (15, 21))	('BRG1', 'Gene', '6597', (30, 34))
475358	31652801	Other tumors associated with BRG1 mutations are melanomas, colorectal cancer, oral cancer, and hepatocellular carcinoma, with BRG1 mutations being present in 5-10% of cases in melanoma and colorectal cancer, and increased expression of BRG1 mRNA identified in both oral cancer and hepatocellular carcinoma.	('colorectal cancer', 'Phenotype', 'HP:0003003', (189, 206))	('oral cancer', 'Disease', (78, 89))	('melanoma', 'Phenotype', 'HP:0002861', (176, 184))	('melanoma', 'Disease', (176, 184))	('BRG1', 'Gene', (29, 33))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('BRG1', 'Gene', (236, 240))	('hepatocellular carcinoma', 'Disease', (95, 119))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('melanoma', 'Phenotype', 'HP:0002861', (48, 56))	('melanoma', 'Disease', (48, 56))	('colorectal cancer', 'Phenotype', 'HP:0003003', (59, 76))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('oral cancer', 'Disease', 'MESH:D009062', (265, 276))	('hepatocellular carcinoma', 'Disease', (281, 305))	('N', 'Chemical', 'MESH:D009584', (243, 244))	('oral cancer', 'Disease', (265, 276))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (281, 305))	('cancer', 'Phenotype', 'HP:0002664', (270, 276))	('colorectal cancer', 'Disease', 'MESH:D015179', (189, 206))	('melanomas', 'Disease', 'MESH:D008545', (48, 57))	('melanoma', 'Disease', 'MESH:D008545', (176, 184))	('associated', 'Reg', (13, 23))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('colorectal cancer', 'Disease', (189, 206))	('melanomas', 'Disease', (48, 57))	('tumors', 'Disease', (6, 12))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (95, 119))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (281, 305))	('colorectal cancer', 'Disease', 'MESH:D015179', (59, 76))	('BRG1', 'Gene', '6597', (126, 130))	('melanoma', 'Disease', 'MESH:D008545', (48, 56))	('mutations', 'Var', (131, 140))	('colorectal cancer', 'Disease', (59, 76))	('BRG1', 'Gene', '6597', (29, 33))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('BRG1', 'Gene', (126, 130))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (95, 119))	('BRG1', 'Gene', '6597', (236, 240))	('increased', 'PosReg', (212, 221))	('oral cancer', 'Disease', 'MESH:D009062', (78, 89))	('mutations', 'Var', (34, 43))	('carcinoma', 'Phenotype', 'HP:0030731', (296, 305))
475359	31652801	Another malady linked to the mutated BRG1 is Coffin-Siris syndrome (CSS), a disease characterized by growth and developmental abnormalities as well as craniofacial features, such as sparse scalp hair, bushy eye brows, wide and prominent mouth, body hirsutism, absent or hypoplastic nails of fifth fingers, or toes with absent hypoplastic phalanges.	('hypoplastic nails of fifth fingers', 'Disease', 'MESH:C565090', (270, 304))	('developmental abnormalities', 'Disease', (112, 139))	('wide and prominent mouth', 'Phenotype', 'HP:0000154', (218, 242))	('BRG1', 'Gene', (37, 41))	('bushy eye brows', 'Disease', 'MESH:D000853', (201, 216))	('developmental abnormalities', 'Disease', 'MESH:D006130', (112, 139))	('absent', 'NegReg', (260, 266))	('absent hypoplastic phalanges', 'Disease', 'MESH:C536903', (319, 347))	('mutated', 'Var', (29, 36))	('hypoplastic nails', 'Phenotype', 'HP:0001792', (270, 287))	('body hirsutism', 'Disease', (244, 258))	('absent or hypoplastic nails', 'Phenotype', 'HP:0008386', (260, 287))	('hirsutism', 'Phenotype', 'HP:0001007', (249, 258))	('toes with absent', 'Phenotype', 'HP:0010760', (309, 325))	('Coffin-Siris syndrome', 'Disease', (45, 66))	('absent hypoplastic phalanges', 'Disease', (319, 347))	('Coffin-Siris syndrome', 'Disease', 'MESH:C536436', (45, 66))	('sparse scalp hair', 'Phenotype', 'HP:0002209', (182, 199))	('wide', 'Disease', (218, 222))	('hypoplastic phalanges', 'Phenotype', 'HP:0009803', (326, 347))	('developmental abnormalities', 'Phenotype', 'HP:0001263', (112, 139))	('prominent mouth', 'Disease', (227, 242))	('hypoplastic nails of fifth fingers', 'Disease', (270, 304))	('bushy eye brows', 'Disease', (201, 216))	('body hirsutism', 'Disease', 'MESH:D006628', (244, 258))	('fifth fingers', 'Phenotype', 'HP:0009237', (291, 304))	('prominent mouth', 'Disease', 'MESH:C538270', (227, 242))	('BRG1', 'Gene', '6597', (37, 41))
475361	31652801	Chromatin remodeling subunit SMARCA4/BRG1 has been found to be mutated in 11% of CSS patients, containing missense mutations with gain-of-function or dominant-negative effects.	('SMARCA4', 'Gene', '6597', (29, 36))	('missense mutations', 'Var', (106, 124))	('CSS', 'Disease', (81, 84))	('gain-of-function', 'PosReg', (130, 146))	('BRG1', 'Gene', (37, 41))	('patients', 'Species', '9606', (85, 93))	('BRG1', 'Gene', '6597', (37, 41))	('SMARCA4', 'Gene', (29, 36))
475362	31652801	Besides CSS, other neurodevelopmental disorders, such as Hirschsprung disease, autism spectrum disorder, and schizophrenia, have been associated with mutations in BRG1/BRM subunit of the BAF chromatin remodeling complex like.	('neurodevelopmental disorders', 'Disease', (19, 47))	('autism spectrum disorder', 'Disease', 'MESH:D002659', (79, 103))	('schizophrenia', 'Disease', (109, 122))	('BRG1', 'Gene', '6597', (163, 167))	('BRG1', 'Gene', (163, 167))	('associated', 'Reg', (134, 144))	('autism', 'Phenotype', 'HP:0000717', (79, 85))	('BRM', 'Gene', (168, 171))	('schizophrenia', 'Disease', 'MESH:D012559', (109, 122))	('mutations', 'Var', (150, 159))	('BAF', 'Gene', (187, 190))	('schizophrenia', 'Phenotype', 'HP:0100753', (109, 122))	('neurodevelopmental disorders', 'Disease', 'MESH:D002658', (19, 47))	('CSS', 'Disease', (8, 11))	('Hirschsprung disease', 'Phenotype', 'HP:0002251', (57, 77))	('autism spectrum disorder', 'Disease', (79, 103))	('BRM', 'Gene', '6595', (168, 171))	('neurodevelopmental disorders', 'Phenotype', 'HP:0012759', (19, 47))	('autism spectrum disorder', 'Phenotype', 'HP:0000729', (79, 103))	('BAF', 'Gene', '8815', (187, 190))	('Hirschsprung disease', 'Disease', (57, 77))	('Hirschsprung disease', 'Disease', 'MESH:D006627', (57, 77))	('developmental disorder', 'Phenotype', 'HP:0001263', (24, 46))
475363	31652801	Furthermore, SMARCA4/BRG1 mutations have been also linked to microphthalmia, a developmental disorder in which one or both eyes are abnormally small and have anatomic malformations.	('SMARCA4', 'Gene', (13, 20))	('linked', 'Reg', (51, 57))	('SMARCA4', 'Gene', '6597', (13, 20))	('anatomic malformations', 'Disease', (158, 180))	('developmental disorder', 'Disease', (79, 101))	('microphthalmia', 'Phenotype', 'HP:0000568', (61, 75))	('mutations', 'Var', (26, 35))	('developmental disorder', 'Phenotype', 'HP:0001263', (79, 101))	('anatomic malformations', 'Disease', 'MESH:D020763', (158, 180))	('BRG1', 'Gene', (21, 25))	('microphthalmia', 'Disease', 'MESH:D008850', (61, 75))	('developmental disorder', 'Disease', 'MESH:D002658', (79, 101))	('microphthalmia', 'Disease', (61, 75))	('BRG1', 'Gene', '6597', (21, 25))
475366	31652801	Among these functional domains and motifs are QLQ domain (residues 171-206) involved in protein-protein interactions, DNA-binding HSA domain (residues 460-532), BRK domain (residues 611-656), helicase (residues 766-1246) containing DEXHc ATP binding domain (residues 766-931) and helicase C-terminal domain HELICc (residues 1081-1246), and bromodomain (residues 1455-1566) interacting with acetylated lysines (Figure 5A).	('residues', 'Var', (258, 266))	('residues', 'Var', (142, 150))	('helicase', 'Gene', '164045', (280, 288))	('acetylated lysines', 'Chemical', 'MESH:C083300', (390, 408))	('helicase', 'Gene', '164045', (192, 200))	('N', 'Chemical', 'MESH:D009584', (119, 120))	('residues 611-656', 'Var', (173, 189))	('interacting', 'Interaction', (373, 384))	('residues 171-206', 'Var', (58, 74))	('helicase', 'Gene', (280, 288))	('residues 1081-1246', 'Var', (315, 333))	('residues 1455-1566', 'Var', (353, 371))	('acetylated lysines', 'MPA', (390, 408))	('residues 766-1246', 'Var', (202, 219))	('involved', 'Reg', (76, 84))	('ATP', 'Chemical', 'MESH:D000255', (238, 241))	('helicase', 'Gene', (192, 200))
475367	31652801	BRG1 also contains the Snf2 ATP coupling domain (residues 1321-1389), and several established functional regions, such as residues 1-282, necessary for interaction with SS18L1/CREST, RNA binding region interacting with lncRNA Evf2 (residues 462-748), and two regions sufficient for interaction with DLX1 (residues 837-916, and 1247-1446).	('Evf2', 'Gene', '285987', (226, 230))	('CREST', 'Gene', (176, 181))	('SS18L1', 'Gene', '26039', (169, 175))	('Snf2', 'Gene', (23, 27))	('residues 1321-1389', 'Var', (49, 67))	('Evf2', 'Gene', (226, 230))	('ATP', 'Chemical', 'MESH:D000255', (28, 31))	('Snf2', 'Gene', '6595', (23, 27))	('N', 'Chemical', 'MESH:D009584', (184, 185))	('BRG1', 'Gene', '6597', (0, 4))	('interaction', 'Interaction', (282, 293))	('N', 'Chemical', 'MESH:D009584', (223, 224))	('SS18L1', 'Gene', (169, 175))	('BRG1', 'Gene', (0, 4))	('DLX1', 'Gene', (299, 303))	('residues 837-916', 'Var', (305, 321))	('interaction', 'Interaction', (152, 163))	('residues 462-748', 'Var', (232, 248))	('CREST', 'Gene', '26039', (176, 181))	('DLX1', 'Gene', '1745', (299, 303))
475368	31652801	There are also several regions with compositional biases, such as the poly-Lys region (residues 578-588) and three poly-Glu regions (residues 663-672, 1360-1364, and 1571-1584).	('residues 578-588', 'Var', (87, 103))	('1360-1364', 'Var', (151, 160))	('poly-Lys', 'Chemical', 'MESH:C026591', (70, 78))	('poly-Glu', 'Chemical', 'MESH:C023843', (115, 123))	('residues 663-672', 'Var', (133, 149))
475369	31652801	Structural information is currently available for bromodomain by itself (see Figure 5B) and for a fragment of C-tail (residues 1591-1602) complexed with the Brd3 ET domain (see Figure 5C).	('Brd3', 'Gene', (157, 161))	('Brd3', 'Gene', '8019', (157, 161))	('men', 'Species', '9606', (102, 105))	('residues 1591-1602', 'Var', (118, 136))
475373	31652801	Similarly, the protein interacting QLQ domain (residues 171-206) is a part of a long N-terminal MoRF (residues 21-231).	('MoRF', 'Gene', '23522', (96, 100))	('residues 21-231', 'Var', (102, 117))	('N', 'Chemical', 'MESH:D009584', (85, 86))	('MoRF', 'Gene', (96, 100))	('residues 171-206', 'Var', (47, 63))
475374	31652801	Similarly, the 34-residue-long MoRF (residues 475-508) represents a large portion of the HSA domain spanning residues 460-532.	('MoRF', 'Gene', (31, 35))	('MoRF', 'Gene', '23522', (31, 35))	('residues 475-508', 'Var', (37, 53))
475376	31652801	Finally, BRG1 might exist in five experimentally validated isoforms generated by alternative splicing (AS), and there are 29 computationally mapped potential isoforms.	('men', 'Species', '9606', (40, 43))	('alternative splicing', 'Var', (81, 101))	('BRG1', 'Gene', (9, 13))	('BRG1', 'Gene', '6597', (9, 13))
475379	31652801	Note that all AS-induced sequence changes are concentrated within the intrinsically disordered C-terminal region of BRG1.	('BRG1', 'Gene', (116, 120))	('N', 'Chemical', 'MESH:D009584', (0, 1))	('BRG1', 'Gene', '6597', (116, 120))	('changes', 'Var', (34, 41))
475380	31652801	In fact, the missing 1259-1291 region includes one of the MoRFs (residues 1263-1282), changes at W1,388 affect another MoRF (residues 1381-1398), and elimination of S1,475 might affect yet another MoRF (residues 1458-1474).	('affect', 'Reg', (104, 110))	('MoRF', 'Gene', (119, 123))	('MoRFs', 'Chemical', 'MESH:C055328', (58, 63))	('MoRF', 'Gene', '23522', (58, 62))	('MoRF', 'Gene', (58, 62))	('MoRF', 'Gene', '23522', (197, 201))	('MoRF', 'Gene', (197, 201))	('MoRF', 'Gene', '23522', (119, 123))	('elimination', 'Var', (150, 161))	('affect', 'Reg', (178, 184))
475384	31652801	Human protein brahma homolog (BRM, also known as BAF190B, SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A member 2 (ATP-dependent helicase SMARCA2), or probable global transcription activator SNF2L2, UniProt ID: P51531) is a 1590 residue-long catalytic subunit of the multiprotein chromatin-remodeling SWI/SNF complexes.	('BRM', 'Gene', (30, 33))	('Human', 'Species', '9606', (0, 5))	('P51531', 'Chemical', 'MESH:D010695', (249, 255))	('N', 'Chemical', 'MESH:D009584', (230, 231))	('SNF2L2', 'Gene', '6595', (229, 235))	('P51531', 'Var', (249, 255))	('SMARCA2', 'Gene', (176, 183))	('helicase', 'Gene', '164045', (167, 175))	('N', 'Chemical', 'MESH:D009584', (63, 64))	('BRM', 'Gene', '6595', (30, 33))	('SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A member 2', 'Gene', '6595', (58, 151))	('BAF190B', 'Gene', '6595', (49, 56))	('BAF190B', 'Gene', (49, 56))	('SNF2L2', 'Gene', (229, 235))	('SMARCA2', 'Gene', '6595', (176, 183))	('helicase', 'Gene', (167, 175))	('N', 'Chemical', 'MESH:D009584', (344, 345))	('ATP', 'Chemical', 'MESH:D000255', (153, 156))
475385	31652801	BRM is encoded by the SMARCA2 gene, and has domain organization similar to that of BRG1, containing a QLQ domain (residues 173-208), an HSA domain (residues 436-508), a helicase ATP-binding domain (residues 736-901), a helicase C-terminal domain (residues 1054-1216), and a bromodomain (residues 1419-1489).	('residues 1054-1216', 'Var', (247, 265))	('SMARCA2', 'Gene', (22, 29))	('SMARCA2', 'Gene', '6595', (22, 29))	('BRG1', 'Gene', '6597', (83, 87))	('BRM', 'Gene', (0, 3))	('helicase', 'Gene', '164045', (169, 177))	('ATP', 'Chemical', 'MESH:D000255', (178, 181))	('residues 173-208', 'Var', (114, 130))	('residues 436-508', 'Var', (148, 164))	('helicase', 'Gene', (169, 177))	('helicase', 'Gene', '164045', (219, 227))	('residues 736-901', 'Var', (198, 214))	('BRM', 'Gene', '6595', (0, 3))	('BRG1', 'Gene', (83, 87))	('helicase', 'Gene', (219, 227))
475387	31652801	These include two poly-Gln regions (residues 216-238 and 245-253), a poly-Arg region (residues 559-562), and three poly-Glu regions (residues 643-650, 1291-1301, and 1518-1529).	('1291-1301', 'Var', (151, 160))	('residues 559-562', 'Var', (86, 102))	('residues 216-238', 'Var', (36, 52))	('poly-Gln', 'Chemical', 'MESH:C544323', (18, 26))	('1518-1529', 'Var', (166, 175))	('residues 643-650', 'Var', (133, 149))	('poly-Arg', 'Chemical', 'MESH:C056211', (69, 77))	('poly-Glu', 'Chemical', 'MESH:C023843', (115, 123))
475389	31652801	Multiple mutations in the SMARCA2 gene were identified in Nicolaides-Baraitser syndrome (NCBRS), which is a rare disease characterized by severe mental retardation with absent or limited speech, seizures, short stature, sparse hair, typical facial characteristics, brachydactyly, prominent finger joints, and broad distal phalanges.	('seizures', 'Disease', 'MESH:D012640', (195, 203))	('mutations', 'Var', (9, 18))	('seizures', 'Phenotype', 'HP:0001250', (195, 203))	('sparse hair', 'Disease', (220, 231))	('brachydactyly', 'Phenotype', 'HP:0001156', (265, 278))	('brachydactyly', 'Disease', 'MESH:D059327', (265, 278))	('short stature', 'Disease', 'MESH:D006130', (205, 218))	('Nicolaides-Baraitser syndrome', 'Disease', 'MESH:C536116', (58, 87))	('short stature', 'Disease', (205, 218))	('N', 'Chemical', 'MESH:D009584', (58, 59))	('broad distal phalanges', 'Phenotype', 'HP:0009836', (309, 331))	('SMARCA2', 'Gene', (26, 33))	('SMARCA2', 'Gene', '6595', (26, 33))	('mental retardation', 'Phenotype', 'HP:0001249', (145, 163))	('mental retardation', 'Disease', 'MESH:D008607', (145, 163))	('N', 'Chemical', 'MESH:D009584', (89, 90))	('Nicolaides-Baraitser syndrome', 'Disease', (58, 87))	('retardation with absent or limited speech', 'Phenotype', 'HP:0001344', (152, 193))	('brachydactyly', 'Disease', (265, 278))	('severe mental retardation', 'Phenotype', 'HP:0010864', (138, 163))	('mental retardation', 'Disease', (145, 163))	('short stature', 'Phenotype', 'HP:0004322', (205, 218))	('sparse hair', 'Phenotype', 'HP:0008070', (220, 231))	('seizures', 'Disease', (195, 203))	('identified', 'Reg', (44, 54))
475390	31652801	These SMARCA2 gene mutations cause BRM substitutions at Ala752, Arg755, Ile756, His851, Asp852, Lys852, Arg854, Asn854, Gly855, Arg881, Val881, Leu883, Tyr939, Ser946, Phe946, Cys1105, Pro1105, Pro1135, Arg1146, Val1158, Gly1159, Leu1159, Gln1159, His1162, Pro1188, Val1201, Cys1202, Gly1205, and Trp1213.	('Asn854', 'Chemical', 'MESH:C073821', (112, 118))	('Cys1202', 'Chemical', 'MESH:C577765', (275, 282))	('Ser946', 'Var', (160, 166))	('Arg1146', 'Chemical', 'MESH:C050547', (203, 210))	('SMARCA2', 'Gene', (6, 13))	('Arg854', 'Var', (104, 110))	('Pro1105', 'Gene', '56063', (185, 192))	('Gly1205', 'Var', (284, 291))	('His1162', 'Var', (248, 255))	('Val1158', 'Var', (212, 219))	('Gly1159', 'Var', (221, 228))	('BRM', 'Gene', (35, 38))	('Gly855', 'Var', (120, 126))	('SMARCA2', 'Gene', '6595', (6, 13))	('Leu883', 'Chemical', 'MESH:C054472', (144, 150))	('Ser', 'Chemical', 'MESH:C530429', (160, 163))	('Val1158', 'Chemical', 'MESH:C515245', (212, 219))	('Lys852', 'Var', (96, 102))	('Asp852', 'Var', (88, 94))	('Lys', 'Chemical', 'MESH:C026591', (96, 99))	('Phe946', 'Chemical', 'MESH:C086976', (168, 174))	('Cys1202', 'Var', (275, 282))	('Trp1213', 'Chemical', 'MESH:C113730', (297, 304))	('Ile756', 'Var', (72, 78))	('Arg881', 'Chemical', 'MESH:C035755', (128, 134))	('Val881', 'Var', (136, 142))	('Arg854', 'Chemical', 'MESH:C073821', (104, 110))	('Leu1159', 'Chemical', 'MESH:C006272', (230, 237))	('Asn854', 'Var', (112, 118))	('His851', 'Var', (80, 86))	('Gln1159', 'Var', (239, 246))	('Pro1135', 'Var', (194, 201))	('Arg755', 'Var', (64, 70))	('BRM', 'Gene', '6595', (35, 38))	('Ala752', 'Var', (56, 62))	('Leu1159', 'Var', (230, 237))	('Leu883', 'Var', (144, 150))	('Arg755', 'Chemical', 'MESH:C439606', (64, 70))	('Val1201', 'Var', (266, 273))	('Ala', 'Chemical', 'MESH:C026593', (56, 59))	('Val881', 'Chemical', 'MESH:C035755', (136, 142))	('Pro1188', 'Chemical', 'MESH:C073897', (257, 264))	('Tyr939', 'Chemical', 'MESH:C066169', (152, 158))	('Cys1105', 'Var', (176, 183))	('Cys1105', 'Chemical', 'MESH:C541937', (176, 183))	('Gln1159', 'Chemical', 'MESH:C006272', (239, 246))	('Pro1105', 'Gene', (185, 192))	('Tyr939', 'Var', (152, 158))	('Pro1188', 'Var', (257, 264))	('Asp852', 'Chemical', 'MESH:D005907', (88, 94))	('Gly1159', 'Chemical', 'MESH:C006272', (221, 228))	('Phe946', 'Var', (168, 174))	('Arg1146', 'Var', (203, 210))	('Trp1213', 'Var', (297, 304))	('Arg881', 'Var', (128, 134))
475391	31652801	Single nucleotide polymorphisms (SNPs) in this gene are also associated with schizophrenia.	('Single nucleotide polymorphisms', 'Var', (0, 31))	('schizophrenia', 'Disease', 'MESH:D012559', (77, 90))	('N', 'Chemical', 'MESH:D009584', (34, 35))	('schizophrenia', 'Disease', (77, 90))	('associated', 'Reg', (61, 71))	('schizophrenia', 'Phenotype', 'HP:0100753', (77, 90))
475392	31652801	According to the BioMuta database of single-nucleotide variations (SNVs) in cancer , mutations in the SMARCA2 gene are linked to melanoma, malignant glioma, thyroid carcinoma, and blastoma, as well as to uterine, urinary bladder, stomach, colorectal, kidney, ovarian, breast, liver, cervical, and lung cancer.	('SMARCA2', 'Gene', (102, 109))	('blastoma', 'Disease', (180, 188))	('SMARCA2', 'Gene', '6595', (102, 109))	('glioma', 'Phenotype', 'HP:0009733', (149, 155))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (157, 174))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('cancer', 'Disease', (302, 308))	('uterine', 'Disease', (204, 211))	('cancer', 'Phenotype', 'HP:0002664', (302, 308))	('N', 'Chemical', 'MESH:D009584', (68, 69))	('melanoma', 'Disease', 'MESH:D008545', (129, 137))	('colorectal, kidney, ovarian, breast, liver', 'Disease', 'MESH:D010051', (239, 281))	('carcinoma', 'Phenotype', 'HP:0030731', (165, 174))	('linked', 'Reg', (119, 125))	('lung cancer', 'Disease', (297, 308))	('mutations', 'Var', (85, 94))	('blastoma', 'Disease', 'MESH:D018202', (180, 188))	('cancer', 'Disease', 'MESH:D009369', (302, 308))	('urinary bladder', 'Disease', (213, 228))	('cancer', 'Disease', (76, 82))	('stomach', 'Disease', (230, 237))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (157, 174))	('malignant glioma', 'Disease', 'MESH:D005910', (139, 155))	('lung cancer', 'Disease', 'MESH:D008175', (297, 308))	('melanoma', 'Phenotype', 'HP:0002861', (129, 137))	('malignant glioma', 'Disease', (139, 155))	('melanoma', 'Disease', (129, 137))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('thyroid carcinoma', 'Disease', (157, 174))	('lung cancer', 'Phenotype', 'HP:0100526', (297, 308))	('cervical', 'Disease', (283, 291))
475393	31652801	X-ray crystal structure was solved for a construct containing helicase ATP-binding domain (residues 705-955) with N-terminally attached maltose binding protein (MBP) tag (PDB ID: 6EG3).	('N', 'Chemical', 'MESH:D009584', (114, 115))	('MBP', 'Gene', '4155', (161, 164))	('maltose binding protein', 'Gene', '4155', (136, 159))	('helicase', 'Gene', (62, 70))	('maltose binding protein', 'Gene', (136, 159))	('MBP', 'Gene', (161, 164))	('residues', 'Var', (91, 99))	('helicase', 'Gene', '164045', (62, 70))	('ATP', 'Chemical', 'MESH:D000255', (71, 74))
475408	31652801	Furthermore, BAF155 has a tumor suppressor activity in some tumors, such as colorectal cancer and ovarian carcinoma, as mutations of SMARCC1/BAF155 were also linked to the development of these tumors.	('men', 'Species', '9606', (179, 182))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (98, 115))	('ovarian carcinoma', 'Disease', (98, 115))	('SMARCC1', 'Gene', '6599', (133, 140))	('mutations', 'Var', (120, 129))	('BAF155', 'Gene', (141, 147))	('tumors', 'Disease', 'MESH:D009369', (193, 199))	('tumor', 'Disease', (60, 65))	('BAF155', 'Gene', '6599', (141, 147))	('colorectal cancer', 'Phenotype', 'HP:0003003', (76, 93))	('SMARCC1', 'Gene', (133, 140))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (98, 115))	('BAF155', 'Gene', (13, 19))	('tumor', 'Disease', (193, 198))	('tumor', 'Disease', (26, 31))	('BAF155', 'Gene', '6599', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumors', 'Phenotype', 'HP:0002664', (193, 199))	('tumors', 'Disease', (60, 66))	('colorectal cancer', 'Disease', 'MESH:D015179', (76, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('colorectal cancer', 'Disease', (76, 93))	('tumors', 'Disease', (193, 199))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('linked to', 'Reg', (158, 167))	('tumors', 'Disease', 'MESH:D009369', (60, 66))
475412	31652801	Human BAF155 (UniProt ID: Q92922) contains two functional domains, SWIRM (residues 449-546) that mediates specific PPIs required for the assembly of chromatin-protein complexes, and SANT (residues 618-669), which is another PPI module that can bind to tails of histone proteins.	('Human', 'Species', '9606', (0, 5))	('BAF155', 'Gene', '6599', (6, 12))	('N', 'Chemical', 'MESH:D009584', (184, 185))	('residues 449-546', 'Var', (74, 90))	('residues', 'Var', (188, 196))	('Q92922', 'Chemical', 'MESH:C000295', (26, 32))	('BAF155', 'Gene', (6, 12))
475413	31652801	Furthermore, there are several regions with amino acid composition biases in this protein, such as poly-Pro (residues 329-336), Glu-rich (residues 769-863), poly-Ala (residues 867-878), and Pro-rich regions (residues 977-1105).	('poly-Ala', 'Chemical', 'MESH:C022266', (157, 165))	('residues 329-336', 'Var', (109, 125))	('poly-Pro', 'Chemical', 'MESH:C008982', (99, 107))	('residues 867-878', 'Var', (167, 183))	('residues 769-863', 'Var', (138, 154))	('residues 977-1105', 'Var', (208, 225))	('Glu', 'Chemical', 'MESH:C094686', (128, 131))
475414	31652801	Structure is currently known for the SWIRM domain complexed with the with the repeat 1 (RPT1) domain of BAF47 (residues 183-289; PDB ID: 5GJK) and for the SANT domain (residues 610-675; PDB ID: 1RYU) (see Figure 7A,B).	('N', 'Chemical', 'MESH:D009584', (157, 158))	('residues 610-675;', 'Var', (168, 185))	('BAF47', 'Gene', '6598', (104, 109))	('BAF47', 'Gene', (104, 109))	('residues 183-289', 'Var', (111, 127))
475421	31652801	It has a domain organization similar to that of BAF155, containing SWIRM and SANT domains (residues 424-521 and 596-647, respectively), as well as a coiled-coil domain (residues 907-934).	('residues 424-521', 'Var', (91, 107))	('BAF155', 'Gene', '6599', (48, 54))	('596-647', 'Var', (112, 119))	('coiled-coil', 'MPA', (149, 160))	('N', 'Chemical', 'MESH:D009584', (79, 80))	('SWIRM', 'MPA', (67, 72))	('BAF155', 'Gene', (48, 54))	('residues 907-934', 'Var', (169, 185))
475422	31652801	It also has regions with amino acid composition biases, such as poly-Glu (residues 186-189), Glu-rich (residues 747-855), poly-Ala (residues 861-870), poly-Gln (residues 956-960), and Pro-rich regions (residues 961-1213).	('poly-Gln', 'Chemical', 'MESH:C544323', (151, 159))	('poly-Glu', 'Chemical', 'MESH:C023843', (64, 72))	('poly-Ala', 'Chemical', 'MESH:C022266', (122, 130))	('residues 747-855', 'Var', (103, 119))	('residues 861-870', 'Var', (132, 148))	('Glu', 'Chemical', 'MESH:C094686', (69, 72))	('residues 956-960', 'Var', (161, 177))	('residues 186-189', 'Var', (74, 90))	('residues 961-1213', 'Var', (202, 219))	('Glu', 'Chemical', 'MESH:C094686', (93, 96))
475423	31652801	SMARCC2 is one of the genes mutations that are associated with a rare and clinically and genetically heterogeneous disorder, Coffin-Siris syndrome.	('SMARCC2', 'Gene', (0, 7))	('SMARCC2', 'Gene', '6601', (0, 7))	('Coffin-Siris syndrome', 'Disease', (125, 146))	('Coffin-Siris syndrome', 'Disease', 'MESH:C536436', (125, 146))	('associated', 'Reg', (47, 57))	('mutations', 'Var', (28, 37))
475424	31652801	Furthermore, according to the BioMuta database of single-nucleotide variations (SNVs) in cancer, mutations in this gene are associated with liver, cancer, colorectal, stomach, lung, breast, and uterine cancers, as well as with melanoma and multiple other tumors.	('mutations', 'Var', (97, 106))	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('breast', 'Disease', (182, 188))	('tumor', 'Phenotype', 'HP:0002664', (255, 260))	('tumors', 'Disease', (255, 261))	('lung', 'Disease', (176, 180))	('cancer', 'Disease', (89, 95))	('colorectal', 'Disease', 'MESH:D015179', (155, 165))	('uterine cancers', 'Phenotype', 'HP:0010784', (194, 209))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('melanoma', 'Disease', 'MESH:D008545', (227, 235))	('liver', 'Disease', (140, 145))	('tumors', 'Disease', 'MESH:D009369', (255, 261))	('cancer', 'Disease', 'MESH:D009369', (202, 208))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('cancers', 'Disease', 'MESH:D009369', (202, 209))	('N', 'Chemical', 'MESH:D009584', (81, 82))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('associated', 'Reg', (124, 134))	('stomach', 'Disease', (167, 174))	('colorectal', 'Disease', (155, 165))	('melanoma', 'Phenotype', 'HP:0002861', (227, 235))	('melanoma', 'Disease', (227, 235))	('tumors', 'Phenotype', 'HP:0002664', (255, 261))	('uterine cancer', 'Phenotype', 'HP:0010784', (194, 208))	('cancers', 'Phenotype', 'HP:0002664', (202, 209))	('cancer', 'Disease', (202, 208))	('cancers', 'Disease', (202, 209))	('cancer', 'Disease', (147, 153))
475435	31652801	Mutations in the SMARCB1 gene are associated with Coffin-Siris syndrome 3 (CSS3), Schwannomatosis 1 (SWNTS1), rhabdoid tumor predisposition syndrome 1 (RTPS1), as well as familial multiple meningioma, familial rhabdoid tumor, and neurofibromatosis type 3.	('rhabdoid tumor', 'Disease', 'MESH:D018335', (110, 124))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('RTPS1', 'Gene', '6598', (152, 157))	('neurofibromatosis', 'Disease', (230, 247))	('Mutations', 'Var', (0, 9))	('SMARCB1', 'Gene', (17, 24))	('SMARCB1', 'Gene', '6598', (17, 24))	('RTPS1', 'Gene', (152, 157))	('neurofibromatosis', 'Disease', 'MESH:D017253', (230, 247))	('Schwannomatosis', 'Disease', 'MESH:C536641', (82, 97))	('rhabdoid tumor', 'Disease', (110, 124))	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('rhabdoid tumor', 'Disease', 'MESH:D018335', (210, 224))	('N', 'Chemical', 'MESH:D009584', (103, 104))	('associated', 'Reg', (34, 44))	('familial multiple meningioma', 'Disease', (171, 199))	('familial rhabdoid tumor', 'Disease', 'MESH:D018335', (201, 224))	('familial multiple meningioma', 'Disease', 'MESH:D008579', (171, 199))	('Coffin-Siris syndrome', 'Disease', (50, 71))	('Schwannomatosis', 'Disease', (82, 97))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (230, 247))	('familial rhabdoid tumor', 'Disease', (201, 224))	('meningioma', 'Phenotype', 'HP:0002858', (189, 199))	('Coffin-Siris syndrome', 'Disease', 'MESH:C536436', (50, 71))
475436	31652801	Furthermore, according to BioMuta , SNV mutations in SMARCB1 are found in various cancers, including uterine, lung, kidney, and stomach cancers.	('N', 'Chemical', 'MESH:D009584', (37, 38))	('cancers', 'Phenotype', 'HP:0002664', (136, 143))	('cancers', 'Phenotype', 'HP:0002664', (82, 89))	('cancers', 'Disease', (136, 143))	('cancers', 'Disease', (82, 89))	('found', 'Reg', (65, 70))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('stomach cancers', 'Disease', 'MESH:D013274', (128, 143))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('uterine', 'Disease', (101, 108))	('lung', 'Disease', (110, 114))	('mutations', 'Var', (40, 49))	('kidney', 'Disease', (116, 122))	('stomach cancers', 'Disease', (128, 143))	('stomach cancers', 'Phenotype', 'HP:0012126', (128, 143))	('cancers', 'Disease', 'MESH:D009369', (136, 143))	('cancers', 'Disease', 'MESH:D009369', (82, 89))	('SMARCB1', 'Gene', '6598', (53, 60))	('SMARCB1', 'Gene', (53, 60))
475437	31652801	Human BAF47 can be divided into several functional regions with specific activities, such as DNA-binding region (residues 1-113), HIV-1 integrase binding region (residues 183-243) that overlaps with MYC-binding region (residues 186-245), and PPP1R15A-interacting region (residues 304-318).	('Human', 'Species', '9606', (0, 5))	('BAF47', 'Gene', '6598', (6, 11))	('MYC', 'Gene', (199, 202))	('BAF47', 'Gene', (6, 11))	('residues 183-243', 'Var', (162, 178))	('PPP1R15A', 'Gene', '23645', (242, 250))	('MYC', 'Gene', '4609', (199, 202))	('PPP1R15A', 'Gene', (242, 250))	('HIV-1', 'Species', '11676', (130, 135))	('N', 'Chemical', 'MESH:D009584', (94, 95))
475449	31652801	Similar to BRG1, mutations and deregulation of BAF250A is associated with cancer pathogenesis.	('deregulation', 'Var', (31, 43))	('associated', 'Reg', (58, 68))	('BRG1', 'Gene', '6597', (11, 15))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('BAF250A', 'Gene', (47, 54))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('cancer', 'Disease', (74, 80))	('BAF250A', 'Gene', '8289', (47, 54))	('mutations', 'Var', (17, 26))	('BRG1', 'Gene', (11, 15))
475450	31652801	For example, Burkitt lymphoma has been linked to mutations in the genes coding for both BRG1 and BAF250A, with nonsense and frame-shift mutations in BAF250A that lead to loss of function constituting almost 30% of genetic events associated with this blood neoplasm.	('BAF250A', 'Gene', (97, 104))	('blood neoplasm', 'Phenotype', 'HP:0004377', (250, 264))	('neoplasm', 'Disease', 'MESH:D009369', (256, 264))	('mutations', 'Var', (49, 58))	('BRG1', 'Gene', (88, 92))	('Burkitt lymphoma', 'Disease', (13, 29))	('BAF250A', 'Gene', '8289', (149, 156))	('BAF250A', 'Gene', '8289', (97, 104))	('Burkitt lymphoma', 'Phenotype', 'HP:0030080', (13, 29))	('lymphoma', 'Phenotype', 'HP:0002665', (21, 29))	('linked', 'Reg', (39, 45))	('BRG1', 'Gene', '6597', (88, 92))	('Burkitt lymphoma', 'Disease', 'MESH:D002051', (13, 29))	('frame-shift mutations', 'Var', (124, 145))	('loss of function', 'NegReg', (170, 186))	('neoplasm', 'Disease', (256, 264))	('neoplasm', 'Phenotype', 'HP:0002664', (256, 264))	('BAF250A', 'Gene', (149, 156))
475451	31652801	Mutations in ARID1A encoding BAF250A associated with the loss of BAF250 function have been linked to ovarian clear cell carcinoma (OCCC), which is a rare form of cancer, accounting for approximately 5-10% of all ovarian carcinomas in North America, with a higher percentage in East Asia.	('ovarian carcinomas', 'Disease', (212, 230))	('BAF250A', 'Gene', (29, 36))	('cancer', 'Disease', (162, 168))	('ovarian carcinomas', 'Phenotype', 'HP:0025318', (212, 230))	('ovarian clear cell carcinoma', 'Disease', 'MESH:D010051', (101, 129))	('N', 'Chemical', 'MESH:D009584', (234, 235))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('BAF250', 'Gene', '8289', (65, 71))	('BAF250', 'Gene', (65, 71))	('Mutations', 'Var', (0, 9))	('associated', 'Reg', (37, 47))	('carcinoma', 'Phenotype', 'HP:0030731', (220, 229))	('BAF250', 'Gene', '8289', (29, 35))	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('BAF250', 'Gene', (29, 35))	('loss', 'NegReg', (57, 61))	('ovarian clear cell carcinoma', 'Disease', (101, 129))	('carcinomas', 'Phenotype', 'HP:0030731', (220, 230))	('ARID1A', 'Gene', (13, 19))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (212, 229))	('linked', 'Reg', (91, 97))	('BAF250A', 'Gene', '8289', (29, 36))	('ovarian carcinomas', 'Disease', 'MESH:D010051', (212, 230))
475453	31652801	Mutations in ARID1A with loss of BAF250 function have been also linked to the development of the subtypes of endometrioid carcinoma.	('BAF250', 'Gene', '8289', (33, 39))	('endometrioid carcinoma', 'Disease', (109, 131))	('ARID1A', 'Gene', (13, 19))	('BAF250', 'Gene', (33, 39))	('Mutations', 'Var', (0, 9))	('men', 'Species', '9606', (85, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('linked', 'Reg', (64, 70))	('loss', 'NegReg', (25, 29))	('function', 'MPA', (40, 48))	('endometrioid carcinoma', 'Disease', 'MESH:D018269', (109, 131))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (109, 131))
475454	31652801	In OCCC and endometrioid ovarian cancer, ARID1A mutations may be heterozygous or biallelic, with biallelic mutations being associated with BAF250A loss of function or loss of protein expression.	('BAF250A', 'Gene', (139, 146))	('OCCC and endometrioid ovarian cancer', 'Disease', 'MESH:D010051', (3, 39))	('loss of function', 'NegReg', (147, 163))	('ovarian cancer', 'Phenotype', 'HP:0100615', (25, 39))	('ARID1A', 'Gene', (41, 47))	('loss', 'NegReg', (167, 171))	('BAF250A', 'Gene', '8289', (139, 146))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('mutations', 'Var', (48, 57))	('protein expression', 'MPA', (175, 193))
475455	31652801	ARID1A mutations are also present in more than 10% of liver cancer cases.	('liver cancer', 'Phenotype', 'HP:0002896', (54, 66))	('ARID1A', 'Gene', (0, 6))	('present', 'Reg', (26, 33))	('liver cancer', 'Disease', 'MESH:D006528', (54, 66))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('liver cancer', 'Disease', (54, 66))	('mutations', 'Var', (7, 16))
475456	31652801	During initiation of the tumors, deletion of ARID1A was protective, causing a delay in the onset of hepatocellular carcinoma in mice, while it was also noticed that loss of ARID1A led to acceleration of colorectal cancer in mice.	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (100, 124))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('initiation of the tumors', 'Disease', (7, 31))	('deletion', 'Var', (33, 41))	('loss', 'Var', (165, 169))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (100, 124))	('colorectal cancer', 'Phenotype', 'HP:0003003', (203, 220))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('mice', 'Species', '10090', (224, 228))	('hepatocellular carcinoma', 'Disease', (100, 124))	('acceleration', 'PosReg', (187, 199))	('mice', 'Species', '10090', (128, 132))	('initiation of the tumors', 'Disease', 'MESH:D009369', (7, 31))	('ARID1A', 'Gene', (173, 179))	('colorectal cancer', 'Disease', 'MESH:D015179', (203, 220))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('ARID1A', 'Gene', (45, 51))	('colorectal cancer', 'Disease', (203, 220))
475458	31652801	In addition to the aforementioned pathologies, genome sequencing and comparative genomic hybridization (CGH) studies have detected ARID1A mutations or deletions in a share of additional cancer subtypes, such as gastric cancer (29%), breast cancer (4-13%), pancreatic cancer (33-45%), transitional cell carcinoma of the bladder (13%), Waldenstrom's macroglobulinemia (17%), and uterine cancer.	('cancer', 'Disease', 'MESH:D009369', (267, 273))	('cancer', 'Phenotype', 'HP:0002664', (385, 391))	("Waldenstrom's macroglobulinemia", 'Disease', 'MESH:D008258', (334, 365))	("Waldenstrom's macroglobulinemia", 'Disease', (334, 365))	('cancer', 'Disease', 'MESH:D009369', (219, 225))	('gastric cancer', 'Phenotype', 'HP:0012126', (211, 225))	('cancer', 'Disease', (240, 246))	('cancer', 'Disease', 'MESH:D009369', (186, 192))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('carcinoma', 'Phenotype', 'HP:0030731', (302, 311))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (256, 273))	('transitional cell carcinoma of the bladder', 'Phenotype', 'HP:0006740', (284, 326))	('cancer', 'Disease', 'MESH:D009369', (385, 391))	('men', 'Species', '9606', (24, 27))	('cancer', 'Disease', (267, 273))	('gastric cancer', 'Disease', (211, 225))	("Waldenstrom's macroglobulinemia", 'Phenotype', 'HP:0005508', (334, 365))	('breast cancer', 'Phenotype', 'HP:0003002', (233, 246))	('carcinoma of the bladder', 'Disease', 'MESH:D001749', (302, 326))	('cancer', 'Phenotype', 'HP:0002664', (267, 273))	('cancer', 'Disease', 'MESH:D009369', (240, 246))	('cancer', 'Disease', (219, 225))	('cancer', 'Disease', (186, 192))	('mutations', 'Var', (138, 147))	('pancreatic cancer', 'Disease', 'MESH:D010190', (256, 273))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('breast cancer', 'Disease', 'MESH:D001943', (233, 246))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('gastric cancer', 'Disease', 'MESH:D013274', (211, 225))	('carcinoma of the bladder', 'Disease', (302, 326))	('breast cancer', 'Disease', (233, 246))	('deletions', 'Var', (151, 160))	('ARID1A', 'Gene', (131, 137))	('cancer', 'Disease', (385, 391))	('pancreatic cancer', 'Disease', (256, 273))	('uterine cancer', 'Phenotype', 'HP:0010784', (377, 391))
475461	31652801	There are also four LXXL motifs (residues 295-299, 1709-1713, 1967-1971, and 2085-2089) and four regions of amino acid composition biases, including two poly-Glu regions (residues 479-482 and 561-567), a poly-Ser region (residues 998-1001), and a Glu-rich region (residues 1317-1404).	('poly-Glu', 'Chemical', 'MESH:C023843', (153, 161))	('poly-Ser', 'Chemical', 'MESH:C530429', (204, 212))	('residues 479-482', 'Var', (171, 187))	('residues 295-299', 'Var', (33, 49))	('Glu', 'Chemical', 'MESH:C094686', (158, 161))	('2085-2089', 'Var', (77, 86))	('1709-1713', 'Var', (51, 60))	('Glu', 'Chemical', 'MESH:C094686', (247, 250))	('residues 998-1001', 'Var', (221, 238))
475462	31652801	In addition to the canonical form, BAF250 may exist in two AS-generated isoforms, with missing residues 1367-1583 (isoform-1) or 1-383 (isoform-2).	('BAF250', 'Gene', '8289', (35, 41))	('BAF250', 'Gene', (35, 41))	('1-383', 'Var', (129, 134))	('missing residues 1367-1583', 'Var', (87, 113))
475471	31652801	In line with this conclusion, ARID1B was found to be mutated in more than 10% of patients with OCCC.	('ARID1B', 'Gene', '57492', (30, 36))	('patients', 'Species', '9606', (81, 89))	('mutated', 'Var', (53, 60))	('ARID1B', 'Gene', (30, 36))	('OCCC', 'Disease', (95, 99))
475472	31652801	ARID1B mutations were found in 5-10% of cases of colorectal cancer, which is the chief cause of morbidity and mortality all over the world, accounting for over 9% of all cancer incidence, and being the third most common cancer worldwide and the fourth most common cause of death.	('death', 'Disease', 'MESH:D003643', (273, 278))	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('ARID1B', 'Gene', (0, 6))	('cancer', 'Disease', (170, 176))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('colorectal cancer', 'Phenotype', 'HP:0003003', (49, 66))	('death', 'Disease', (273, 278))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('cancer', 'Disease', (60, 66))	('colorectal cancer', 'Disease', (49, 66))	('ARID1B', 'Gene', '57492', (0, 6))	('cancer', 'Disease', 'MESH:D009369', (220, 226))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('colorectal cancer', 'Disease', 'MESH:D015179', (49, 66))	('cancer', 'Disease', (220, 226))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('mutations', 'Var', (7, 16))
475474	31652801	ARID1B mutations are also found in 5-10% of cases of gastric cancer, which is one of the most common cancers and the second most common cause of cancer deaths worldwide.	('cancers', 'Disease', 'MESH:D009369', (101, 108))	('cancers', 'Phenotype', 'HP:0002664', (101, 108))	('ARID1B', 'Gene', (0, 6))	('cancers', 'Disease', (101, 108))	('cancer deaths', 'Disease', 'MESH:D003643', (145, 158))	('gastric cancer', 'Disease', (53, 67))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('gastric cancer', 'Disease', 'MESH:D013274', (53, 67))	('ARID1B', 'Gene', '57492', (0, 6))	('found', 'Reg', (26, 31))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('gastric cancer', 'Phenotype', 'HP:0012126', (53, 67))	('cancer deaths', 'Disease', (145, 158))	('mutations', 'Var', (7, 16))
475476	31652801	Finally, ARID1B can be mutated in hepatocellular carcinoma (HCC), which is a complex disease and a main cause of death in high endemic areas of hepatitis B virus (HBV) or hepatitis C virus (HCV) infection.	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (34, 58))	('HCC', 'Gene', '619501', (60, 63))	('hepatocellular carcinoma', 'Disease', (34, 58))	('death', 'Disease', 'MESH:D003643', (113, 118))	('death', 'Disease', (113, 118))	('ARID1B', 'Gene', (9, 15))	('hepatitis B virus (HBV) or hepatitis C virus (HCV) infection', 'Disease', 'MESH:D006526', (144, 204))	('mutated', 'Var', (23, 30))	('complex disease', 'Disease', (77, 92))	('complex disease', 'Disease', 'MESH:D007105', (77, 92))	('ARID1B', 'Gene', '57492', (9, 15))	('hepatitis', 'Phenotype', 'HP:0012115', (171, 180))	('hepatitis', 'Phenotype', 'HP:0012115', (144, 153))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (34, 58))	('HCC', 'Gene', (60, 63))
475479	31652801	In addition to ARID domain (residues 1041-1159) human BAF250B contains two LXXL motifs (residues 419-423 and 2036-2040), a nuclear localization signal (residues 1358-1,77), and 14 regions with amino acid composition biases, such as two Ala-rich segments (residues 2-47 and 329-493), two Ser-rich fragments (residues 35-57 and 684-771), two Gln-rich regions (residues 107-131 and 574-633), two poly-Ser segments (residues 1034-1037 and 1441-1444), a His-rich (residues 81-114), a poly-Gln (residues 114-131), a poly-Ala (residues 932-935), and a poly-Pro region (residues 1833-1836), as well as 261- and 139-residue-long Gly-rich and Pro-rich regions (residues 141-401 and 1459-1597, respectively).	('Ser', 'Chemical', 'MESH:C530429', (398, 401))	('residues', 'Var', (459, 467))	('BAF250B', 'Gene', (54, 61))	('residues', 'Var', (562, 570))	('poly-Gln', 'Chemical', 'MESH:C544323', (479, 487))	('Ser', 'Chemical', 'MESH:C530429', (287, 290))	('men', 'Species', '9606', (248, 251))	('human', 'Species', '9606', (48, 53))	('residues 114-131', 'Var', (489, 505))	('poly-Pro', 'Chemical', 'MESH:C008982', (545, 553))	('Gln', 'Chemical', 'MESH:C544323', (484, 487))	('Ala', 'Chemical', 'MESH:C026593', (515, 518))	('men', 'Species', '9606', (405, 408))	('Ala', 'Chemical', 'MESH:C026593', (236, 239))	('Gln', 'Chemical', 'MESH:C544323', (340, 343))	('BAF250B', 'Gene', '57492', (54, 61))	('poly-Ser', 'Chemical', 'MESH:C530429', (393, 401))	('men', 'Species', '9606', (300, 303))	('poly-Ala', 'Chemical', 'MESH:C022266', (510, 518))
475481	31652801	Similar to BAF250A, ARID domain (residues 1041-1159) of BAF250B was the only protein region with a known structure (see Figure 11A).	('residues 1041-1159', 'Var', (33, 51))	('BAF250B', 'Gene', (56, 63))	('BAF250B', 'Gene', '57492', (56, 63))	('BAF250A', 'Gene', (11, 18))	('BAF250A', 'Gene', '8289', (11, 18))
475486	31652801	A comparison of the data summarized in Figure 11 with the description of alternative splicing-generated alterations in the BAF250B amino acid sequence indicates that AS might affect the potential disorder-based functionality of this protein.	('BAF250B', 'Gene', '57492', (123, 130))	('alterations', 'Var', (104, 115))	('alternative splicing-generated', 'Var', (73, 103))	('disorder-based functionality', 'MPA', (196, 224))	('affect', 'Reg', (175, 181))	('BAF250B', 'Gene', (123, 130))
475487	31652801	For example, isoform-4 was missing 11 MoRFs and multiple phosphorylation and ubiquitination sites, whereas sequence changes in isoform-2 might affect two MoRFs (residues 543-578 and 583-604), and isoform-3 might change the local phosphorylation predisposition of this protein and introduce a new MoRF.	('MoRFs', 'Chemical', 'MESH:C055328', (154, 159))	('MoRFs', 'Chemical', 'MESH:C055328', (38, 43))	('MoRF', 'Gene', (154, 158))	('MoRF', 'Gene', '23522', (154, 158))	('MoRF', 'Gene', (38, 42))	('MoRF', 'Gene', '23522', (38, 42))	('local phosphorylation predisposition', 'MPA', (223, 259))	('change', 'Reg', (212, 218))	('MoRF', 'Gene', (296, 300))	('MoRF', 'Gene', '23522', (296, 300))	('583-604', 'Var', (182, 189))	('changes', 'Var', (116, 123))	('residues 543-578', 'Var', (161, 177))	('affect', 'Reg', (143, 149))
475493	31652801	SMARCE1 mutations have been found in the germline of families with a history of meningiomas and sporadic tumors.	('meningiomas', 'Disease', (80, 91))	('meningioma', 'Phenotype', 'HP:0002858', (80, 90))	('SMARCE1', 'Gene', (0, 7))	('mutations', 'Var', (8, 17))	('sporadic tumors', 'Disease', 'MESH:D020821', (96, 111))	('SMARCE1', 'Gene', '6605', (0, 7))	('meningiomas', 'Disease', 'MESH:D008579', (80, 91))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('meningiomas', 'Phenotype', 'HP:0002858', (80, 91))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('sporadic tumors', 'Disease', (96, 111))
475495	31652801	Germline SMARCE1 mutations were identified in 14% (9/63) of the solitary meningioma patients younger than 25 years, with all the affected individuals suffering from meningiomas of the clear cell type.	('SMARCE1', 'Gene', (9, 16))	('meningioma', 'Disease', 'MESH:D008579', (165, 175))	('SMARCE1', 'Gene', '6605', (9, 16))	('meningioma', 'Phenotype', 'HP:0002858', (73, 83))	('meningioma', 'Disease', 'MESH:D008579', (73, 83))	('patients', 'Species', '9606', (84, 92))	('meningiomas', 'Disease', 'MESH:D008579', (165, 176))	('meningiomas', 'Phenotype', 'HP:0002858', (165, 176))	('meningioma', 'Disease', (165, 175))	('meningioma', 'Phenotype', 'HP:0002858', (165, 175))	('mutations', 'Var', (17, 26))	('meningiomas', 'Disease', (165, 176))	('meningioma', 'Disease', (73, 83))
475496	31652801	Heterozygous loss of function mutations was also found in 4/9 individuals and loss of protein was found in all tumors.	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('tumors', 'Disease', (111, 117))	('tumors', 'Disease', 'MESH:D009369', (111, 117))	('loss', 'NegReg', (78, 82))	('mutations', 'Var', (30, 39))
475497	31652801	SMARCE1 mutations are thought to be involved other types of cancer, including breast, ovarian, and prostate.	('ovarian', 'Disease', (86, 93))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('SMARCE1', 'Gene', (0, 7))	('mutations', 'Var', (8, 17))	('cancer', 'Disease', (60, 66))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('SMARCE1', 'Gene', '6605', (0, 7))	('prostate', 'Disease', (99, 107))	('involved', 'Reg', (36, 44))	('breast', 'Disease', (78, 84))
475501	31652801	No structural information is available for this protein, which contains a long coiled-coil region (residues 220-319), as well as Pro-rich and Glu-rich regions (residues 5-65 and 320-411, respectively).	('coiled-coil', 'MPA', (79, 90))	('N', 'Chemical', 'MESH:D009584', (0, 1))	('residues 5-65', 'Var', (160, 173))	('residues 220-319', 'Var', (99, 115))	('Glu', 'Chemical', 'MESH:C094686', (142, 145))
475507	31652801	BAF180 acts as a tumor suppressor by functioning within the tumor suppressor pathways causing genetic inactivation in tumors, and also plays a role in tissue maintenance.	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('tumor', 'Disease', (17, 22))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('genetic inactivation', 'Var', (94, 114))	('BAF180', 'Gene', (0, 6))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('tumor', 'Disease', (118, 123))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('tumors', 'Disease', (118, 124))	('tumor', 'Disease', (60, 65))	('BAF180', 'Gene', '55193', (0, 6))	('tumors', 'Disease', 'MESH:D009369', (118, 124))
475508	31652801	Mutations in the PBRM1 gene are related to renal carcinoma.	('related', 'Reg', (32, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('PBRM1', 'Gene', (17, 22))	('renal carcinoma', 'Disease', (43, 58))	('renal carcinoma', 'Disease', 'MESH:D002292', (43, 58))	('renal carcinoma', 'Phenotype', 'HP:0005584', (43, 58))	('Mutations', 'Var', (0, 9))	('PBRM1', 'Gene', '55193', (17, 22))
475512	31652801	Heterozygous or biallelic inactivating mutations were found in 41% of clear cell tumor cases and mutations were found in more than 10% of renal cell carcinoma cases.	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (138, 158))	('renal cell carcinoma', 'Disease', 'MESH:D002292', (138, 158))	('carcinoma', 'Phenotype', 'HP:0030731', (149, 158))	('Heterozygous', 'Var', (0, 12))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('found', 'Reg', (54, 59))	('biallelic inactivating mutations', 'Var', (16, 48))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('renal cell carcinoma', 'Disease', (138, 158))	('tumor', 'Disease', (81, 86))
475519	31652801	Mutations in PBRM1 lead to loss of protein expression in 32% of cases of intrahepatic cholangiocarcinoma (n = 108).	('PBRM1', 'Gene', (13, 18))	('protein expression', 'MPA', (35, 53))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:C535533', (73, 104))	('Mutations', 'Var', (0, 9))	('PBRM1', 'Gene', '55193', (13, 18))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('intrahepatic cholangiocarcinoma', 'Disease', (73, 104))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (86, 104))	('loss', 'NegReg', (27, 31))
475520	31652801	Human BAF180 includes eight functional domains, such as bromodomains 1 through to 6 (residues 64-134, 200-270, 400-470, 538-608, 676-746, and 792-862), as well as domains BAH1 and BAH2 (residues 956-1074 and 1156-1272).	('Human', 'Species', '9606', (0, 5))	('400-470', 'Var', (111, 118))	('residues 956-1074', 'Var', (186, 203))	('538-608', 'Var', (120, 127))	('residues 64-134', 'Var', (85, 100))	('792-862', 'Var', (142, 149))	('BAF180', 'Gene', (6, 12))	('BAF180', 'Gene', '55193', (6, 12))
475526	31652801	B-cell CLL/lymphoma 7 protein family members A, B, and C (BCL7A, BCL7B, and BCL7C, UniProt IDs: Q4VC05, Q9BQE9, and Q8WUZ0, respectively) are relatively short proteins (of 210, 202, and 217 residues, respectively) encoded correspondingly by genes BCL7A, BCL7B, and BCL7C.	('BCL7A', 'Gene', (247, 252))	('B-cell CLL/lymphoma', 'Phenotype', 'HP:0012191', (0, 19))	('BCL7B', 'Gene', '9275', (254, 259))	('lymphoma', 'Phenotype', 'HP:0002665', (11, 19))	('BCL7A', 'Gene', '605', (58, 63))	('Q8WUZ0', 'Var', (116, 122))	('BCL7C', 'Gene', (76, 81))	('BCL7C', 'Gene', '9274', (76, 81))	('Q9BQE9', 'Var', (104, 110))	('BCL7B', 'Gene', (65, 70))	('BCL7A', 'Gene', '605', (247, 252))	('lymphoma', 'Disease', (11, 19))	('BCL7C', 'Gene', '9274', (265, 270))	('lymphoma', 'Disease', 'MESH:D008223', (11, 19))	('Q4VC05', 'Var', (96, 102))	('BCL7C', 'Gene', (265, 270))	('BCL7B', 'Gene', (254, 259))	('BCL7A', 'Gene', (58, 63))	('BCL7B', 'Gene', '9275', (65, 70))
475531	31652801	As per BioMuta annotations, among several tumors associated with non-synonymous SNVs in the BCL7A gene, the most abundant are uterine, hematologic, liver, and colorectal cancers.	('colorectal cancers', 'Disease', (159, 177))	('non-synonymous SNVs', 'Var', (65, 84))	('cancers', 'Phenotype', 'HP:0002664', (170, 177))	('SNVs', 'Var', (80, 84))	('N', 'Chemical', 'MESH:D009584', (81, 82))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('tumors', 'Disease', (42, 48))	('tumors', 'Disease', 'MESH:D009369', (42, 48))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('colorectal cancer', 'Phenotype', 'HP:0003003', (159, 176))	('colorectal cancers', 'Disease', 'MESH:D015179', (159, 177))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('hematologic', 'Disease', (135, 146))	('uterine', 'Disease', (126, 133))	('abundant', 'Reg', (113, 121))	('BCL7A', 'Gene', (92, 97))	('liver', 'Disease', (148, 153))	('BCL7A', 'Gene', '605', (92, 97))
475532	31652801	Mutations in the BCL7B gene can be related to lung tumor development or progression.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('lung tumor', 'Disease', (46, 56))	('BCL7B', 'Gene', (17, 22))	('BCL7B', 'Gene', '9275', (17, 22))	('lung tumor', 'Disease', 'MESH:D008175', (46, 56))	('Mutations', 'Var', (0, 9))	('progression', 'CPA', (72, 83))	('related', 'Reg', (35, 42))	('lung tumor', 'Phenotype', 'HP:0100526', (46, 56))	('men', 'Species', '9606', (64, 67))
475533	31652801	Aberrations of this gene are also linked to the Williams-Beuren syndrome (WBS) and, according to BioMuta, to liver and uterine cancers.	('Williams-Beuren syndrome', 'Disease', (48, 72))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('WBS', 'Disease', 'MESH:D018980', (74, 77))	('liver', 'Disease', (109, 114))	('cancers', 'Disease', 'MESH:D009369', (127, 134))	('cancers', 'Phenotype', 'HP:0002664', (127, 134))	('uterine cancer', 'Phenotype', 'HP:0010784', (119, 133))	('WBS', 'Disease', (74, 77))	('cancers', 'Disease', (127, 134))	('Williams-Beuren syndrome', 'Disease', 'MESH:D018980', (48, 72))	('Aberrations', 'Var', (0, 11))	('uterine cancers', 'Phenotype', 'HP:0010784', (119, 134))	('linked', 'Reg', (34, 40))
475535	31652801	Alterations in the human BCL7C gene are associated with the Sezary syndrome, which is a leukemic form of cutaneous T-cell lymphoma.	('leukemic', 'Disease', (88, 96))	('T-cell lymphoma', 'Phenotype', 'HP:0012190', (115, 130))	('Alterations', 'Var', (0, 11))	('cutaneous T-cell lymphoma', 'Phenotype', 'HP:0012192', (105, 130))	('cell lymphoma', 'Phenotype', 'HP:0012191', (117, 130))	('lymphoma', 'Phenotype', 'HP:0002665', (122, 130))	('leukemic', 'Disease', 'MESH:D007938', (88, 96))	('BCL7C', 'Gene', '9274', (25, 30))	('Sezary syndrome', 'Disease', (60, 75))	('BCL7C', 'Gene', (25, 30))	('cutaneous T-cell lymphoma', 'Disease', (105, 130))	('Sezary syndrome', 'Disease', 'MESH:D012751', (60, 75))	('human', 'Species', '9606', (19, 24))	('associated', 'Reg', (40, 50))	('cutaneous T-cell lymphoma', 'Disease', 'MESH:D016410', (105, 130))
475537	31652801	Human BCL7C contains a Pro-rich region (residues 108-217), whereas there are no segments with the compositional biases in BCL7A and BCL7B proteins.	('Human', 'Species', '9606', (0, 5))	('BCL7C', 'Gene', '9274', (6, 11))	('BCL7C', 'Gene', (6, 11))	('men', 'Species', '9606', (83, 86))	('residues 108-217', 'Var', (40, 56))	('BCL7B', 'Gene', (132, 137))	('BCL7B', 'Gene', '9275', (132, 137))	('BCL7A', 'Gene', '605', (122, 127))	('BCL7A', 'Gene', (122, 127))
475538	31652801	All three BCL7 family members contain several isoforms generated by alternative splicing.	('alternative splicing', 'Var', (68, 88))	('BCL7', 'Gene', '605', (10, 14))	('BCL7', 'Gene', (10, 14))
475540	31652801	Human BCL7B has four isoforms, where isoform 2 is missing residues 1-60 and has changed N-terminal region (residues 61-88), KSNSSAAREPNGFPSDASANSSLLLEFQ   MPGPWLCPEFLLRKMTTLSCCLCSVWFS, isoform 3 contains K   F substitution at position 163 and is missing residues 164-202, whereas residues 89-145 are missing in isoform 4.	('BCL7B', 'Gene', (6, 11))	('Human', 'Species', '9606', (0, 5))	('BCL7B', 'Gene', '9275', (6, 11))	('N', 'Chemical', 'MESH:D009584', (88, 89))	('residues', 'MPA', (254, 262))	('N', 'Chemical', 'MESH:D009584', (134, 135))	('changed', 'Reg', (80, 87))	('N', 'Chemical', 'MESH:D009584', (126, 127))	('missing', 'NegReg', (246, 253))	('N', 'Chemical', 'MESH:D009584', (143, 144))	('substitution', 'Var', (210, 222))
475541	31652801	In BCL7C, isoform 2 is different from the canonical form by changed residues 177-217 (DSGVRMTRRALHEKGLKTEPLRRLLPRRGLRTNVRPSSMAVPDTRAPGGGS KAPRAPRTI PQGKGR).	('changed', 'Var', (60, 67))	('N', 'Chemical', 'MESH:D009584', (118, 119))	('BCL7C', 'Gene', '9274', (3, 8))	('BCL7C', 'Gene', (3, 8))
475560	31652801	Due to the involvement of BCL11A in regulation of HbF, mutations in the human BCL11A gene can be associated with the pathogenesis of intellectual developmental disorder with persistence of fetal hemoglobin (IDPFH).	('BCL11A', 'Gene', '53335', (78, 84))	('IDPFH', 'Chemical', 'None', (207, 212))	('intellectual developmental disorder', 'Disease', 'MESH:D001037', (133, 168))	('mutations', 'Var', (55, 64))	('men', 'Species', '9606', (18, 21))	('fetal hemoglobin', 'Disease', (189, 205))	('developmental disorder', 'Phenotype', 'HP:0001263', (146, 168))	('human', 'Species', '9606', (72, 77))	('men', 'Species', '9606', (153, 156))	('intellectual developmental disorder', 'Disease', (133, 168))	('BCL11A', 'Gene', '53335', (26, 32))	('BCL11A', 'Gene', (26, 32))	('associated', 'Reg', (97, 107))	('BCL11A', 'Gene', (78, 84))
475561	31652801	Furthermore, according to the BioMuta database, mutations in this gene are related to a wide spectrum of tumors, such as uterine, lung, esophageal, stomach, hematologic, pancreatic, breast, colorectal, and liver cancers, as well as malignant glioma, blastoma, and melanoma.	('tumors', 'Disease', (105, 111))	('blastoma', 'Disease', 'MESH:D018202', (250, 258))	('breast', 'Disease', (182, 188))	('stomach', 'Disease', (148, 155))	('malignant glioma', 'Disease', (232, 248))	('malignant glioma', 'Disease', 'MESH:D005910', (232, 248))	('liver cancers', 'Disease', (206, 219))	('mutations', 'Var', (48, 57))	('tumors', 'Disease', 'MESH:D009369', (105, 111))	('related', 'Reg', (75, 82))	('colorectal', 'Disease', (190, 200))	('pancreatic', 'Disease', 'MESH:D010195', (170, 180))	('blastoma', 'Disease', (250, 258))	('glioma', 'Phenotype', 'HP:0009733', (242, 248))	('melanoma', 'Disease', 'MESH:D008545', (264, 272))	('hematologic', 'Disease', (157, 168))	('cancers', 'Phenotype', 'HP:0002664', (212, 219))	('pancreatic', 'Disease', (170, 180))	('liver cancers', 'Disease', 'MESH:D006528', (206, 219))	('colorectal', 'Disease', 'MESH:D015179', (190, 200))	('tumors', 'Phenotype', 'HP:0002664', (105, 111))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))	('esophageal', 'Disease', (136, 146))	('liver cancer', 'Phenotype', 'HP:0002896', (206, 218))	('uterine', 'Disease', (121, 128))	('liver cancers', 'Phenotype', 'HP:0002896', (206, 219))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('lung', 'Disease', (130, 134))	('melanoma', 'Phenotype', 'HP:0002861', (264, 272))	('melanoma', 'Disease', (264, 272))
475562	31652801	Mutations of BCL11B were found in 5.7-12.7% of cases of T-cell acute lymphoblastic leukemia (TALL), which is responsible for almost 15% and 25% of acute lymphoblastic leukemia in pediatrics and adult cohorts, correspondingly.	('T-cell acute lymphoblastic leukemia', 'Disease', 'MESH:D054218', (56, 91))	('BCL11B', 'Gene', (13, 19))	('T-cell acute lymphoblastic leukemia', 'Disease', (56, 91))	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (147, 175))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (153, 175))	('T-cell acute lymphoblastic leukemia', 'Phenotype', 'HP:0006727', (56, 91))	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (63, 91))	('acute lymphoblastic leukemia', 'Disease', (147, 175))	('leukemia', 'Phenotype', 'HP:0001909', (83, 91))	('Mutations', 'Var', (0, 9))	('acute lymphoblastic leukemia', 'Disease', 'MESH:D054198', (147, 175))	('acute lymphoblastic leukemia', 'Disease', 'MESH:D054198', (63, 91))	('found', 'Reg', (25, 30))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (69, 91))	('leukemia', 'Phenotype', 'HP:0001909', (167, 175))
475566	31652801	Human BCL11A protein contains a region required for nuclear body formation and recruitment of SUMO1 (residues 1-210), as well as Pro-rich and Glu-rich regions (residues 260-373 and 481-509, respectively).	('Human', 'Species', '9606', (0, 5))	('BCL11A', 'Gene', '53335', (6, 12))	('Glu', 'Chemical', 'MESH:C094686', (142, 145))	('men', 'Species', '9606', (86, 89))	('residues 260-373', 'Var', (160, 176))	('BCL11A', 'Gene', (6, 12))	('SUMO1', 'Gene', '7341', (94, 99))	('SUMO1', 'Gene', (94, 99))
475567	31652801	In human BCL11B, there are Glu- and Gly-rich regions (residues 529-553 and 569-661, respectively) and six zinc finger motifs of C2H2-type (residues 221-251, 427-454, 455-482, 796-823, 824-853, and 854-884).	('human', 'Species', '9606', (3, 8))	('residues 221-251', 'Var', (139, 155))	('427-454', 'Var', (157, 164))	('BCL11B', 'Gene', (9, 15))	('Glu', 'Chemical', 'MESH:C094686', (27, 30))	('455-482', 'Var', (166, 173))
475579	31652801	Aberrations in the SS18 gene are linked to synovial sarcoma, which is an aggressive subtype of soft tissue sarcomas, and although it is named "synovial", it arises from the mesenchyme.	('sarcomas', 'Disease', 'MESH:D012509', (107, 115))	('sarcomas', 'Phenotype', 'HP:0100242', (107, 115))	('synovial sarcoma', 'Disease', (43, 59))	('SS18', 'Gene', (19, 23))	('sarcoma', 'Phenotype', 'HP:0100242', (52, 59))	('sarcoma', 'Phenotype', 'HP:0100242', (107, 114))	('linked', 'Reg', (33, 39))	('sarcomas', 'Disease', (107, 115))	('synovial sarcoma', 'Phenotype', 'HP:0012570', (43, 59))	('soft tissue sarcomas', 'Phenotype', 'HP:0030448', (95, 115))	('Aberrations', 'Var', (0, 11))	('synovial sarcoma', 'Disease', 'MESH:D013584', (43, 59))	('SS18', 'Gene', '6760', (19, 23))
475581	31652801	Synovial sarcoma is a gene fusion-driven cancer, in which the underlying event is the chromosomal translocation t(X,18; p11, q11) that creates fusion of SS18 to SSX1 and SSX2.	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('SS18', 'Gene', (153, 157))	('SSX2', 'Gene', (170, 174))	('p11', 'Gene', (120, 123))	('SSX1', 'Gene', '6756', (161, 165))	('fusion', 'Var', (143, 149))	('Synovial sarcoma', 'Phenotype', 'HP:0012570', (0, 16))	('Synovial sarcoma', 'Disease', (0, 16))	('SSX1', 'Gene', (161, 165))	('Synovial sarcoma', 'Disease', 'MESH:D013584', (0, 16))	('p11', 'Gene', '6281', (120, 123))	('sarcoma', 'Phenotype', 'HP:0100242', (9, 16))	('SS18', 'Gene', '6760', (153, 157))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('SSX2', 'Gene', '6757', (170, 174))
475584	31652801	Translocations of the SS18 gene with SSX1 or SSX2 were found in 90% of the tumors (total n = 32).	('found', 'Reg', (55, 60))	('SSX1', 'Gene', '6756', (37, 41))	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('Translocations', 'Var', (0, 14))	('SSX1', 'Gene', (37, 41))	('SSX2', 'Gene', '6757', (45, 49))	('SS18', 'Gene', (22, 26))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('SSX2', 'Gene', (45, 49))	('tumors', 'Disease', (75, 81))	('SS18', 'Gene', '6760', (22, 26))
475585	31652801	Human SSXT protein contain two imperfect tandem repeats of 13 amino acids (residues 344-369) in addition to a poly-Pro region (residues 95-99), and four SH2 binding motifs (residues 50-53, 374-377, 392-401, and 412-416).	('Human', 'Species', '9606', (0, 5))	('residues 50-53', 'Var', (173, 187))	('binding', 'Interaction', (157, 164))	('SSXT', 'Gene', '6760', (6, 10))	('poly-Pro', 'Chemical', 'MESH:C008982', (110, 118))	('SSXT', 'Gene', (6, 10))
475593	31652801	Similar to ARID1A and ARID1B, mutations in the ARID2 gene are linked to hepatocellular carcinoma.	('ARID1B', 'Gene', '57492', (22, 28))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (72, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))	('hepatocellular carcinoma', 'Disease', (72, 96))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (72, 96))	('ARID2', 'Gene', '196528', (47, 52))	('ARID1B', 'Gene', (22, 28))	('ARID2', 'Gene', (47, 52))	('mutations', 'Var', (30, 39))	('linked', 'Reg', (62, 68))
475594	31652801	Heterozygous inactivating mutations in the ARID2 gene are found in 14% (total n = 43) of the HCV-associated tumors and mutations were found in 5-10% of cases.	('Heterozygous inactivating mutations', 'Var', (0, 35))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('HCV', 'Species', '11103', (93, 96))	('ARID2', 'Gene', '196528', (43, 48))	('tumors', 'Disease', (108, 114))	('tumors', 'Disease', 'MESH:D009369', (108, 114))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('ARID2', 'Gene', (43, 48))	('found', 'Reg', (58, 63))
475595	31652801	Aberrations in ARID were also observed in melanoma, which is a malignant tumor that affects the skin, particularly melanocytes.	('melanoma', 'Disease', (42, 50))	('tumor that affects the skin', 'Phenotype', 'HP:0008069', (73, 100))	('malignant tumor', 'Disease', (63, 78))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('malignant tumor', 'Disease', 'MESH:D009369', (63, 78))	('observed', 'Reg', (30, 38))	('Aberrations', 'Var', (0, 11))	('melanoma', 'Disease', 'MESH:D008545', (42, 50))	('melanoma', 'Phenotype', 'HP:0002861', (42, 50))
475603	31652801	Heterozygous loss of function mutations in the ARID2 gene is present in 7% of tumors (total n = 121), and mutations were found in 5-10% of cases.	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('tumors', 'Disease', (78, 84))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('ARID2', 'Gene', '196528', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('ARID2', 'Gene', (47, 52))	('mutations', 'Var', (30, 39))
475604	31652801	Another tumor commonly associated with the mutations in ARID2 is lung cancer, which is the most diagnosed cancer and the chief cause of death in men from cancer, while for women it is the fourth most common cancer to be diagnosed and the second cause of death from cancer.	('men', 'Species', '9606', (145, 148))	('death', 'Disease', (136, 141))	('cancer', 'Phenotype', 'HP:0002664', (265, 271))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('death', 'Disease', (254, 259))	('cancer', 'Disease', (106, 112))	('ARID2', 'Gene', '196528', (56, 61))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('lung cancer', 'Disease', 'MESH:D008175', (65, 76))	('cancer', 'Disease', (207, 213))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('lung cancer', 'Phenotype', 'HP:0100526', (65, 76))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (265, 271))	('associated', 'Reg', (23, 33))	('men', 'Species', '9606', (174, 177))	('death', 'Disease', 'MESH:D003643', (136, 141))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('ARID2', 'Gene', (56, 61))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('death', 'Disease', 'MESH:D003643', (254, 259))	('tumor', 'Disease', (8, 13))	('women', 'Species', '9606', (172, 177))	('cancer', 'Disease', 'MESH:D009369', (207, 213))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('cancer', 'Disease', (154, 160))	('lung cancer', 'Disease', (65, 76))	('mutations', 'Var', (43, 52))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('cancer', 'Disease', (265, 271))	('cancer', 'Disease', 'MESH:D009369', (70, 76))
475607	31652801	In lung cancer, biallelic inactivating mutations in the ARID2 gene were found in 5% in cases of non-small cell lung carcinoma (n = 82).	('found', 'Reg', (72, 77))	('lung cancer', 'Disease', (3, 14))	('ARID2', 'Gene', (56, 61))	('lung cancer', 'Phenotype', 'HP:0100526', (3, 14))	('non-small cell lung carcinoma', 'Disease', (96, 125))	('small cell lung carcinoma', 'Phenotype', 'HP:0030357', (100, 125))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('biallelic inactivating mutations', 'Var', (16, 48))	('ARID2', 'Gene', '196528', (56, 61))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('lung cancer', 'Disease', 'MESH:D008175', (3, 14))	('non-small cell lung carcinoma', 'Disease', 'MESH:D002289', (96, 125))	('non-small cell lung carcinoma', 'Phenotype', 'HP:0030358', (96, 125))
475608	31652801	Finally, ARID2 mutations were found in 5-10% of the colorectal cancer cases.	('ARID2', 'Gene', '196528', (9, 14))	('ARID2', 'Gene', (9, 14))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('mutations', 'Var', (15, 24))	('found', 'Reg', (30, 35))	('colorectal cancer', 'Phenotype', 'HP:0003003', (52, 69))	('colorectal cancer', 'Disease', (52, 69))	('colorectal cancer', 'Disease', 'MESH:D015179', (52, 69))
475609	31652801	Human BAF200 includes the ARID domain (residues 13-105), LXXLL motif (residues 313-317), two ARM repeats (residues 163-207 and 263-454), Gln-rich region (residues 793-1128), and zinc-finger motif of C2H2 type (residues 1632-1657).	('Human', 'Species', '9606', (0, 5))	('residues 313-317', 'Var', (70, 86))	('residues 1632-1657', 'Var', (210, 228))	('residues 793-1128', 'Var', (154, 171))	('BAF200', 'Gene', '196528', (6, 12))	('residues', 'Var', (39, 47))	('residues 163-207', 'Var', (106, 122))	('Gln', 'Chemical', 'MESH:C544323', (137, 140))	('BAF200', 'Gene', (6, 12))
475612	31652801	Note that region 1784-1835 that includes one MoRF (residues 1812-1818) was missing in isoform 2.	('N', 'Chemical', 'MESH:D009584', (0, 1))	('MoRF', 'Gene', (45, 49))	('MoRF', 'Gene', '23522', (45, 49))	('residues 1812-1818', 'Var', (51, 69))
475617	31652801	Although they are characterized by 37.1% sequence identity (53.0% sequence similarity), and although they both contain bromodomains (residues 148-218 and 153-223 in BRD7 and BRD9, respectively) with very similar structural organizations, these two proteins have rather different functions.	('BRD9', 'Gene', '65980', (174, 178))	('BRD7', 'Gene', '29117', (165, 169))	('BRD7', 'Gene', (165, 169))	('residues 148-218', 'Var', (133, 149))	('BRD9', 'Gene', (174, 178))
475623	31652801	According to BioMuta, non-synonymous single-nucleotide variations (nsSNVs) in the BRD7 gene are linked to bladder, breast, colorectal, liver, lung, urinary, and uterine cancers, as well as melanoma.	('cancers', 'Disease', (169, 176))	('BRD7', 'Gene', (82, 86))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('uterine cancer', 'Phenotype', 'HP:0010784', (161, 175))	('urinary', 'Disease', (148, 155))	('uterine cancers', 'Phenotype', 'HP:0010784', (161, 176))	('linked', 'Reg', (96, 102))	('lung', 'Disease', (142, 146))	('colorectal', 'Disease', 'MESH:D015179', (123, 133))	('breast', 'Disease', (115, 121))	('melanoma', 'Phenotype', 'HP:0002861', (189, 197))	('melanoma', 'Disease', (189, 197))	('cancers', 'Disease', 'MESH:D009369', (169, 176))	('bladder', 'Disease', (106, 113))	('non-synonymous single-nucleotide variations', 'Var', (22, 65))	('BRD7', 'Gene', '29117', (82, 86))	('colorectal', 'Disease', (123, 133))	('N', 'Chemical', 'MESH:D009584', (70, 71))	('melanoma', 'Disease', 'MESH:D008545', (189, 197))	('liver', 'Disease', (135, 140))	('cancers', 'Phenotype', 'HP:0002664', (169, 176))
475627	31652801	BRD9 also possesses a Lys-rich region (residues 64-95) and bromodomain (residues 153-223).	('Lys-rich region', 'MPA', (22, 37))	('residues 64-95', 'Var', (39, 53))	('Lys', 'Chemical', 'MESH:C026591', (22, 25))	('BRD9', 'Gene', '65980', (0, 4))	('BRD9', 'Gene', (0, 4))	('residues 153-223', 'Var', (72, 88))
475640	31652801	As per BioMuta, non-synonymous single-nucleotide variations (nsSNVs) in the SMARCD1 gene are linked to colorectal, liver, and uterine cancer.	('SMARCD1', 'Gene', (76, 83))	('SMARCD1', 'Gene', '6602', (76, 83))	('linked', 'Reg', (93, 99))	('cancer', 'Disease', (134, 140))	('colorectal', 'Disease', 'MESH:D015179', (103, 113))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('N', 'Chemical', 'MESH:D009584', (64, 65))	('non-synonymous single-nucleotide variations', 'Var', (16, 59))	('uterine cancer', 'Phenotype', 'HP:0010784', (126, 140))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('liver', 'Disease', (115, 120))	('colorectal', 'Disease', (103, 113))
475641	31652801	nsSNVs in SMARCD2 can be associated with melanoma and liver, colorectal, stomach, and uterine cancers, whereas mutations in SMARCD3 can cause liver, uterine and colorectal cancer, or melanoma.	('cancers', 'Disease', 'MESH:D009369', (94, 101))	('colorectal', 'Disease', 'MESH:D015179', (61, 71))	('melanoma', 'Phenotype', 'HP:0002861', (183, 191))	('melanoma', 'Disease', (183, 191))	('colorectal cancer', 'Disease', (161, 178))	('cause', 'Reg', (136, 141))	('associated', 'Reg', (25, 35))	('SMARCD3', 'Gene', (124, 131))	('colorectal', 'Disease', (161, 171))	('SMARCD2', 'Gene', '6603', (10, 17))	('mutations', 'Var', (111, 120))	('liver', 'Disease', (54, 59))	('N', 'Chemical', 'MESH:D009584', (3, 4))	('cancers', 'Phenotype', 'HP:0002664', (94, 101))	('SMARCD3', 'Gene', '6604', (124, 131))	('melanoma', 'Disease', 'MESH:D008545', (41, 49))	('colorectal cancer', 'Phenotype', 'HP:0003003', (161, 178))	('cancers', 'Disease', (94, 101))	('uterine cancer', 'Phenotype', 'HP:0010784', (86, 100))	('stomach', 'Disease', (73, 80))	('melanoma', 'Disease', 'MESH:D008545', (183, 191))	('uterine cancers', 'Phenotype', 'HP:0010784', (86, 101))	('colorectal', 'Disease', 'MESH:D015179', (161, 171))	('colorectal', 'Disease', (61, 71))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('SMARCD2', 'Gene', (10, 17))	('colorectal cancer', 'Disease', 'MESH:D015179', (161, 178))	('melanoma', 'Phenotype', 'HP:0002861', (41, 49))	('melanoma', 'Disease', (41, 49))	('liver', 'Disease', (142, 147))	('nsSNVs', 'Var', (0, 6))	('uterine', 'Disease', (149, 156))
475642	31652801	The common structural feature of these three proteins is the presence of the SWIB domain (residues 291-390, 307-382, and 259-334 in BAF60A, BAF60B, and BAF60C, respectively).	('BAF60C', 'Gene', (152, 158))	('BAF60A', 'Gene', (132, 138))	('BAF60A', 'Gene', '6602', (132, 138))	('BAF60C', 'Gene', '6604', (152, 158))	('BAF60B', 'Gene', '6603', (140, 146))	('259-334', 'Var', (121, 128))	('307-382', 'Var', (108, 115))	('residues 291-390', 'Var', (90, 106))	('BAF60B', 'Gene', (140, 146))
475644	31652801	Although human BAF60A contains a poly-Lys region (residues 124-127), and although there is a long Pro-rich segment (residues 10-129) in BAF60B, human BAF60C includes no regions with amino acid composition bias.	('human', 'Species', '9606', (144, 149))	('BAF60B', 'Gene', '6603', (136, 142))	('BAF60C', 'Gene', (150, 156))	('men', 'Species', '9606', (110, 113))	('human', 'Species', '9606', (9, 14))	('BAF60A', 'Gene', (15, 21))	('BAF60A', 'Gene', '6602', (15, 21))	('BAF60C', 'Gene', '6604', (150, 156))	('residues 124-127', 'Var', (50, 66))	('residues', 'Var', (116, 124))	('BAF60B', 'Gene', (136, 142))	('poly-Lys', 'Chemical', 'MESH:C026591', (33, 41))
475658	31652801	Mutations in the PHF10 gene are associated with uterine cancer and melanoma.	('PHF10', 'Gene', '55274', (17, 22))	('melanoma', 'Phenotype', 'HP:0002861', (67, 75))	('melanoma', 'Disease', (67, 75))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('melanoma', 'Disease', 'MESH:D008545', (67, 75))	('PHF10', 'Gene', (17, 22))	('Mutations', 'Var', (0, 9))	('associated', 'Reg', (32, 42))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('uterine cancer', 'Phenotype', 'HP:0010784', (48, 62))
475661	31652801	In AS-produced isoforms 2 and 3, residues 321-330 are missing and residue K226 is changed to ICGKRYK NRPGLSYHYTHTHLAEEEGEENAERHALPFHRKNNHKQ, and in addition, isoform 3 is missing residues 1-82.	('residues 321-330', 'Var', (33, 49))	('N', 'Chemical', 'MESH:D009584', (122, 123))	('N', 'Chemical', 'MESH:D009584', (134, 135))	('missing', 'NegReg', (54, 61))	('N', 'Chemical', 'MESH:D009584', (101, 102))	('N', 'Chemical', 'MESH:D009584', (135, 136))	('K226', 'Var', (74, 78))
475662	31652801	Similar to PHF10/BAF45A, DPF1/BAF45B contains two zinc-finger motifs of the PHD type (residues 254-311 and 308-368).	('BAF45A', 'Gene', '55274', (17, 23))	('DPF1', 'Gene', (25, 29))	('BAF45B', 'Gene', '8193', (30, 36))	('PHF10', 'Gene', '55274', (11, 16))	('BAF45A', 'Gene', (17, 23))	('DPF1', 'Gene', '8193', (25, 29))	('308-368', 'Var', (107, 114))	('PHF10', 'Gene', (11, 16))	('residues 254-311', 'Var', (86, 102))	('BAF45B', 'Gene', (30, 36))
475663	31652801	Mutations in the DPF1 gene are linked to the pathogenesis of uterine, liver, and lung cancers.	('lung cancer', 'Phenotype', 'HP:0100526', (81, 92))	('linked', 'Reg', (31, 37))	('DPF1', 'Gene', '8193', (17, 21))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('lung cancers', 'Disease', 'MESH:D008175', (81, 93))	('lung cancers', 'Phenotype', 'HP:0100526', (81, 93))	('uterine', 'Disease', (61, 68))	('Mutations', 'Var', (0, 9))	('cancers', 'Phenotype', 'HP:0002664', (86, 93))	('liver', 'Disease', (70, 75))	('lung cancers', 'Disease', (81, 93))	('DPF1', 'Gene', (17, 21))
475666	31652801	nsSNVs in the DPF2 gene are linked to Coffin-Siris syndrome 7 (CSS7), melanoma, blastoma, and liver, lung, and uterine cancers.	('melanoma', 'Disease', 'MESH:D008545', (70, 78))	('liver', 'Disease', (94, 99))	('uterine cancer', 'Phenotype', 'HP:0010784', (111, 125))	('cancers', 'Phenotype', 'HP:0002664', (119, 126))	('DPF2', 'Gene', (14, 18))	('N', 'Chemical', 'MESH:D009584', (3, 4))	('cancers', 'Disease', (119, 126))	('DPF2', 'Gene', '5977', (14, 18))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('melanoma', 'Phenotype', 'HP:0002861', (70, 78))	('blastoma', 'Disease', 'MESH:D018202', (80, 88))	('melanoma', 'Disease', (70, 78))	('Coffin-Siris syndrome', 'Disease', (38, 59))	('Coffin-Siris syndrome', 'Disease', 'MESH:C536436', (38, 59))	('lung', 'Disease', (101, 105))	('uterine cancers', 'Phenotype', 'HP:0010784', (111, 126))	('linked', 'Reg', (28, 34))	('blastoma', 'Disease', (80, 88))	('cancers', 'Disease', 'MESH:D009369', (119, 126))	('nsSNVs', 'Var', (0, 6))
475671	31652801	nsSNVs in the DPF3 gene are associated with blastoma, melanoma, stomach, liver, lung, and uterine cancer.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('uterine cancer', 'Phenotype', 'HP:0010784', (90, 104))	('nsSNVs', 'Var', (0, 6))	('associated', 'Reg', (28, 38))	('melanoma', 'Disease', 'MESH:D008545', (54, 62))	('N', 'Chemical', 'MESH:D009584', (3, 4))	('lung', 'Disease', (80, 84))	('DPF3', 'Gene', (14, 18))	('blastoma', 'Disease', (44, 52))	('melanoma', 'Disease', (54, 62))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('melanoma', 'Phenotype', 'HP:0002861', (54, 62))	('cancer', 'Disease', (98, 104))	('DPF3', 'Gene', '8110', (14, 18))	('stomach', 'Disease', (64, 71))	('liver', 'Disease', (73, 78))	('blastoma', 'Disease', 'MESH:D018202', (44, 52))
475672	31652801	Similar to DPF2/BAF45D, this protein contains a zinc-finger domain of C2H2 type (residues 198-221) and two zinc-finger motifs of the PHD type (residues 259-319 and 316-366).	('residues 198-221', 'Var', (81, 97))	('BAF45D', 'Gene', (16, 22))	('DPF2', 'Gene', (11, 15))	('DPF2', 'Gene', '5977', (11, 15))	('BAF45D', 'Gene', '5977', (16, 22))
475691	31652801	ACTL6A mutations have been found in patients with intellectual disability of variable severity, developmental delay, dysmorphic features, and digit abnormalities.	('intellectual disability', 'Disease', (50, 73))	('patients', 'Species', '9606', (36, 44))	('ACTL6A', 'Gene', (0, 6))	('ACTL6A', 'Gene', '86', (0, 6))	('digit abnormalities', 'Disease', (142, 161))	('men', 'Species', '9606', (103, 106))	('digit abnormalities', 'Phenotype', 'HP:0011297', (142, 161))	('intellectual disability', 'Phenotype', 'HP:0001249', (50, 73))	('developmental delay', 'Phenotype', 'HP:0001263', (96, 115))	('dysmorphic features', 'Disease', (117, 136))	('found', 'Reg', (27, 32))	('developmental delay', 'Disease', (96, 115))	('mutations', 'Var', (7, 16))
475696	31652801	According to the BioMuta database, non-synonymous single-nucleotide variations (nsSNVs) in the ACTL6B gene were found in liver, lung, and uterine cancers, and this gene was significantly down-regulated in esophageal cancer.	('cancers', 'Disease', (146, 153))	('cancers', 'Disease', 'MESH:D009369', (146, 153))	('ACTL6B', 'Gene', (95, 101))	('uterine cancer', 'Phenotype', 'HP:0010784', (138, 152))	('found', 'Reg', (112, 117))	('lung', 'Disease', (128, 132))	('esophageal cancer', 'Disease', (205, 222))	('ACTL6B', 'Gene', '51412', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('uterine cancers', 'Phenotype', 'HP:0010784', (138, 153))	('non-synonymous single-nucleotide variations', 'Var', (35, 78))	('N', 'Chemical', 'MESH:D009584', (83, 84))	('esophageal cancer', 'Disease', 'MESH:D004938', (205, 222))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('liver', 'Disease', (121, 126))	('cancers', 'Phenotype', 'HP:0002664', (146, 153))	('down-regulated', 'NegReg', (187, 201))
475704	31652801	Since actin is one of the most abundant, if not the most abundant eukaryotic protein, it is not surprising that mutations in ACTB genes are linked to numerous diseases, such as dystonia, juvenile-onset (DJO), Baraitser-Winter syndrome 1 (BRWS1), inherited myopathy, combined and complex dystonia, developmental malformations-deafness-dystonia syndrome, as well as multiple tumors, such as melanoma, blastoma, and hematologic, lung, urinary, uterine, bladder, kidney, and colorectal cancers.	('dystonia', 'Disease', 'MESH:D004421', (287, 295))	('myopathy', 'Disease', (256, 264))	('myopathy', 'Phenotype', 'HP:0003198', (256, 264))	('tumors', 'Phenotype', 'HP:0002664', (373, 379))	('colorectal cancers', 'Disease', 'MESH:D015179', (471, 489))	('mutations', 'Var', (112, 121))	('Baraitser-Winter syndrome', 'Disease', 'MESH:C536208', (209, 234))	('hematologic', 'Disease', (413, 424))	('bladder', 'Disease', (450, 457))	('tumor', 'Phenotype', 'HP:0002664', (373, 378))	('combined', 'Disease', (266, 274))	('blastoma', 'Disease', 'MESH:D018202', (399, 407))	('uterine', 'Disease', (441, 448))	('tumors', 'Disease', (373, 379))	('Baraitser-Winter syndrome', 'Disease', (209, 234))	('deafness', 'Phenotype', 'HP:0000365', (325, 333))	('urinary', 'Disease', (432, 439))	('dystonia', 'Disease', (334, 342))	('lung', 'Disease', (426, 430))	('kidney', 'Disease', (459, 465))	('melanoma', 'Disease', 'MESH:D008545', (389, 397))	('dystonia', 'Disease', (177, 185))	('tumors', 'Disease', 'MESH:D009369', (373, 379))	('cancers', 'Phenotype', 'HP:0002664', (482, 489))	('colorectal cancer', 'Phenotype', 'HP:0003003', (471, 488))	('dystonia', 'Disease', (287, 295))	('blastoma', 'Disease', (399, 407))	('colorectal cancers', 'Disease', (471, 489))	('myopathy', 'Disease', 'MESH:D009135', (256, 264))	('dystonia', 'Phenotype', 'HP:0001332', (334, 342))	('linked', 'Reg', (140, 146))	('cancer', 'Phenotype', 'HP:0002664', (482, 488))	('developmental malformations-deafness-dystonia syndrome', 'Disease', 'MESH:C535808', (297, 351))	('ACTB', 'Gene', '60', (125, 129))	('ACTB', 'Gene', (125, 129))	('dystonia', 'Phenotype', 'HP:0001332', (177, 185))	('dystonia', 'Phenotype', 'HP:0001332', (287, 295))	('dystonia', 'Disease', 'MESH:D004421', (334, 342))	('dystonia', 'Disease', 'MESH:D004421', (177, 185))	('melanoma', 'Phenotype', 'HP:0002861', (389, 397))	('melanoma', 'Disease', (389, 397))
475706	31652801	Aberrations in F-actin polymerization were also linked to intellectual and developmental disabilities (IDD) and autism spectrum disorders (ASD).	('linked', 'Reg', (48, 54))	('developmental disabilities', 'Disease', 'MESH:D002658', (75, 101))	('intellectual and developmental disabilities', 'Phenotype', 'HP:0001263', (58, 101))	('ASD', 'Disease', 'MESH:D001321', (139, 142))	('IDD', 'Disease', (103, 106))	('IDD', 'Disease', 'MESH:C535531', (103, 106))	('ASD', 'Disease', (139, 142))	('autism spectrum disorders', 'Phenotype', 'HP:0000729', (112, 137))	('autism', 'Phenotype', 'HP:0000717', (112, 118))	('autism spectrum disorder', 'Phenotype', 'HP:0000729', (112, 136))	('autism spectrum disorders', 'Disease', 'MESH:D002659', (112, 137))	('Aberrations', 'Var', (0, 11))	('autism spectrum disorders', 'Disease', (112, 137))	('developmental disabilities', 'Disease', (75, 101))	('F-actin', 'Protein', (15, 22))
475720	31652801	Alterations (nsSNVs) in the BICRA gene are associated with various tumors, such as melanoma, blastoma, and thyroid carcinoma, as well as stomach, breast, liver, lung, colorectal, and uterine cancers.	('lung', 'Disease', (161, 165))	('blastoma', 'Disease', (93, 101))	('Alterations', 'Var', (0, 11))	('colorectal', 'Disease', (167, 177))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (107, 124))	('melanoma', 'Disease', 'MESH:D008545', (83, 91))	('thyroid carcinoma', 'Disease', (107, 124))	('cancers', 'Phenotype', 'HP:0002664', (191, 198))	('uterine cancer', 'Phenotype', 'HP:0010784', (183, 197))	('cancers', 'Disease', (191, 198))	('uterine cancers', 'Phenotype', 'HP:0010784', (183, 198))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('stomach', 'Disease', (137, 144))	('colorectal', 'Disease', 'MESH:D015179', (167, 177))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (107, 124))	('liver', 'Disease', (154, 159))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('breast', 'Disease', (146, 152))	('blastoma', 'Disease', 'MESH:D018202', (93, 101))	('associated', 'Reg', (43, 53))	('tumors', 'Disease', (67, 73))	('melanoma', 'Phenotype', 'HP:0002861', (83, 91))	('melanoma', 'Disease', (83, 91))	('cancers', 'Disease', 'MESH:D009369', (191, 198))	('N', 'Chemical', 'MESH:D009584', (16, 17))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('BICRA', 'Gene', (28, 33))	('tumors', 'Disease', 'MESH:D009369', (67, 73))
475726	31652801	These include three poly-Pro segments (residues 935-940, 1333-1337, and 1345-1355), a poly-Gly region (residues 88-96), and a poly-Ser region (residues 1265-1276).	('residues 935-940', 'Var', (39, 55))	('poly-Gly', 'Chemical', 'MESH:C409505', (86, 94))	('men', 'Species', '9606', (32, 35))	('poly-Pro', 'Chemical', 'MESH:C008982', (20, 28))	('1345-1355', 'Var', (72, 81))	('1333-1337', 'Var', (57, 66))	('poly-Ser', 'Chemical', 'MESH:C530429', (126, 134))
475731	31652801	It was also shown that GLTSCR1 or GLTSCR1L knockouts in the metastatic prostate cancer cell line PC3 led to the loss of proliferation and colony-forming abilities.	('proliferation', 'CPA', (120, 133))	('colony-forming abilities', 'CPA', (138, 162))	('GLTSCR1L', 'Gene', '23506', (34, 42))	('prostate cancer', 'Disease', (71, 86))	('PC3', 'Gene', '3853', (97, 100))	('GLTSCR1', 'Gene', '29998', (34, 41))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('GLTSCR1', 'Gene', (23, 30))	('knockouts', 'Var', (43, 52))	('loss', 'NegReg', (112, 116))	('prostate cancer', 'Disease', 'MESH:D011471', (71, 86))	('GLTSCR1', 'Gene', '29998', (23, 30))	('prostate cancer', 'Phenotype', 'HP:0012125', (71, 86))	('GLTSCR1', 'Gene', (34, 41))	('PC3', 'Gene', (97, 100))	('GLTSCR1L', 'Gene', (34, 42))
475735	31652801	Non-synonymous single-nucleotide variations (nsSNVs) in the BICRAL gene are linked to blastoma, malignant glioma, and melanoma, as well as to stomach, uterine, pancreatic, colorectal, liver, and lung cancers, whereas significant down-regulation of the BICRAL gene was observed in urinary bladder cancer, head and neck cancer, lung squamous cell carcinoma, breast cancer, thyroid cancer, and esophageal cancer.	('lung cancers', 'Disease', (195, 207))	('blastoma', 'Disease', (86, 94))	('cancer', 'Phenotype', 'HP:0002664', (296, 302))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('breast cancer', 'Phenotype', 'HP:0003002', (356, 369))	('colorectal', 'Disease', 'MESH:D015179', (172, 182))	('lung cancer', 'Phenotype', 'HP:0100526', (195, 206))	('cancer', 'Phenotype', 'HP:0002664', (318, 324))	('lung cancers', 'Phenotype', 'HP:0100526', (195, 207))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (326, 354))	('melanoma', 'Phenotype', 'HP:0002861', (118, 126))	('bladder cancer', 'Phenotype', 'HP:0009725', (288, 302))	('melanoma', 'Disease', (118, 126))	('thyroid cancer', 'Disease', 'MESH:D013964', (371, 385))	('breast cancer', 'Disease', 'MESH:D001943', (356, 369))	('esophageal cancer', 'Disease', 'MESH:D004938', (391, 408))	('down-regulation', 'NegReg', (229, 244))	('Non-synonymous', 'Var', (0, 14))	('cancers', 'Phenotype', 'HP:0002664', (200, 207))	('breast cancer', 'Disease', (356, 369))	('urinary bladder cancer', 'Disease', (280, 302))	('head and neck cancer', 'Phenotype', 'HP:0012288', (304, 324))	('thyroid cancer', 'Phenotype', 'HP:0002890', (371, 385))	('single-nucleotide variations', 'Var', (15, 43))	('esophageal cancer', 'Disease', (391, 408))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (331, 354))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (326, 354))	('lung squamous cell carcinoma', 'Disease', (326, 354))	('pancreatic', 'Disease', 'MESH:D010195', (160, 170))	('cancer', 'Phenotype', 'HP:0002664', (379, 385))	('N', 'Chemical', 'MESH:D009584', (0, 1))	('N', 'Chemical', 'MESH:D009584', (48, 49))	('urinary bladder cancer', 'Disease', 'MESH:D001749', (280, 302))	('blastoma', 'Disease', 'MESH:D018202', (86, 94))	('BICRAL', 'Gene', (60, 66))	('liver', 'Disease', (184, 189))	('colorectal', 'Disease', (172, 182))	('cancer', 'Phenotype', 'HP:0002664', (363, 369))	('linked', 'Reg', (76, 82))	('melanoma', 'Disease', 'MESH:D008545', (118, 126))	('glioma', 'Phenotype', 'HP:0009733', (106, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (345, 354))	('head and neck cancer', 'Disease', 'MESH:D006258', (304, 324))	('stomach', 'Disease', (142, 149))	('lung cancers', 'Disease', 'MESH:D008175', (195, 207))	('pancreatic', 'Disease', (160, 170))	('malignant glioma', 'Disease', (96, 112))	('uterine', 'Disease', (151, 158))	('thyroid cancer', 'Disease', (371, 385))	('malignant glioma', 'Disease', 'MESH:D005910', (96, 112))
475765	30142876	We found that vismodegib decreases expression of the Hedgehog target genes glioma-associated oncogene homologue (GLI1) and the inhibitor of apoptosis protein (IAP) Survivin in a cell line- and irradiation-dependent manner, most pronounced in squamous cell carcinoma (SCC) cells.	('SCC', 'Gene', '6317', (267, 270))	('inhibitor of apoptosis protein', 'Gene', '84061', (127, 157))	('expression', 'MPA', (35, 45))	('glioma', 'Disease', (75, 81))	('carcinoma', 'Phenotype', 'HP:0030731', (256, 265))	('squamous cell carcinoma', 'Disease', (242, 265))	('SCC', 'Gene', (267, 270))	('glioma', 'Disease', 'MESH:D005910', (75, 81))	('IAP', 'Gene', (159, 162))	('GLI1', 'Gene', '2735', (113, 117))	('inhibitor of apoptosis protein', 'Gene', (127, 157))	('glioma', 'Phenotype', 'HP:0009733', (75, 81))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (242, 265))	('Survivin', 'Gene', (164, 172))	('Survivin', 'Gene', '11799', (164, 172))	('IAP', 'Gene', '84061', (159, 162))	('vismodegib', 'Var', (14, 24))	('decreases', 'NegReg', (25, 34))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (242, 265))	('GLI1', 'Gene', (113, 117))
475768	30142876	In summary, these findings indicate that inhibition of the Hedgehog signaling pathway may increase cellular radiation response in BCC and HNSCC cells.	('increase', 'PosReg', (90, 98))	('SCC', 'Gene', '6317', (140, 143))	('cellular radiation response', 'CPA', (99, 126))	('Hedgehog signaling pathway', 'Pathway', (59, 85))	('inhibition', 'Var', (41, 51))	('increase cellular radiation response', 'Phenotype', 'HP:0010997', (90, 126))	('SCC', 'Gene', (140, 143))
475772	30142876	Briefly, a reactivation of the hedgehog (Hh) signaling pathway has been involved in tumorigenesis in human BCC.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('human', 'Species', '9606', (101, 106))	('tumor', 'Disease', (84, 89))	('involved', 'Reg', (72, 80))	('reactivation', 'Var', (11, 23))
475775	30142876	An estimated 80-90% of sporadic BCC tumors have PTCH1 mutations, whereas 10% harbor SMO mutations.	('BCC tumors', 'Disease', (32, 42))	('mutations', 'Var', (54, 63))	('PTCH1', 'Gene', (48, 53))	('BCC tumors', 'Disease', 'MESH:D009369', (32, 42))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))	('PTCH1', 'Gene', '5727', (48, 53))
475782	30142876	Moreover, preclinical and clinical data indicate that an aberrant Hh signaling, mutations in PTCH1 and SMO and overexpression of components of the Hh pathway all correlate with poor clinical outcome in gastric, esophageal cancer and in head and neck SCC (HNSCC).	('SCC', 'Gene', '6317', (250, 253))	('Hh signaling', 'MPA', (66, 78))	('gastric', 'Disease', 'MESH:D013274', (202, 209))	('gastric', 'Disease', (202, 209))	('mutations', 'Var', (80, 89))	('PTCH1', 'Gene', '5727', (93, 98))	('SCC', 'Gene', '6317', (257, 260))	('SMO', 'Gene', (103, 106))	('PTCH1', 'Gene', (93, 98))	('esophageal cancer', 'Disease', (211, 228))	('esophageal cancer', 'Disease', 'MESH:D004938', (211, 228))	('SCC', 'Gene', (250, 253))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('overexpression', 'PosReg', (111, 125))	('aberrant', 'Var', (57, 65))	('SCC', 'Gene', (257, 260))
475783	30142876	In line with that, inhibition of Hh pathway if combined with radiation or radiochemotherapy (RCT), has been shown to result in improved therapeutic responses and survival, without increased unexpected side effects in a variety of preclinical models and clinical reports including non-small cell lung cancer, esophageal cancer, and HNSCC.	('esophageal cancer', 'Disease', 'MESH:D004938', (308, 325))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (280, 306))	('SCC', 'Gene', '6317', (333, 336))	('inhibition', 'Var', (19, 29))	('lung cancer', 'Phenotype', 'HP:0100526', (295, 306))	('therapeutic responses', 'CPA', (136, 157))	('cancer', 'Phenotype', 'HP:0002664', (300, 306))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (284, 306))	('non-small cell lung cancer', 'Disease', (280, 306))	('cancer', 'Phenotype', 'HP:0002664', (319, 325))	('Hh pathway', 'Pathway', (33, 43))	('survival', 'CPA', (162, 170))	('esophageal cancer', 'Disease', (308, 325))	('SCC', 'Gene', (333, 336))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (280, 306))	('improved', 'PosReg', (127, 135))
475804	30142876	While vismodegib monotherapy does not increase gammaH2AX/53BP1 nuclear foci in non-irradiated BCC-1 or SCC-25 cells, a combination of vismodegib and 4 Gy-irradiation significantly enhanced the number of persisting (24 h) foci in a concentration-dependent manner (Figure 4).	('P', 'Chemical', 'MESH:D010758', (60, 61))	('SCC-25', 'CellLine', 'CVCL:1682', (103, 109))	('BCC-1', 'Gene', '100307118', (94, 99))	('gammaH2AX', 'Chemical', '-', (47, 56))	('gammaH2AX/53BP1', 'Var', (47, 62))	('BCC-1', 'Gene', (94, 99))	('enhanced', 'PosReg', (180, 188))
475810	30142876	BCC and HNSCC tumorigenesis have been shown to be associated with an aberrant canonical Hh/GLI signaling pathway, mostly due to loss-of-function mutations in PTCH1, or gain-of-function mutations in SMO.	('tumor', 'Disease', (14, 19))	('SCC', 'Gene', (10, 13))	('GLI', 'Gene', (91, 94))	('mutations', 'Var', (145, 154))	('PTCH1', 'Gene', (158, 163))	('loss-of-function', 'NegReg', (128, 144))	('BCC', 'Disease', (0, 3))	('SCC', 'Gene', '6317', (10, 13))	('gain-of-function', 'PosReg', (168, 184))	('GLI', 'Gene', '2735', (91, 94))	('mutations', 'Var', (185, 194))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('SMO', 'Gene', (198, 201))	('PTCH1', 'Gene', '5727', (158, 163))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
475814	30142876	Our findings indicate that BCC-1 cells and SCC-25 cells treated with vismodegib are less resistant to irradiation and less viable when compared to untreated controls concomitant with a slight GLI1 and Survivin downregulation, cell cycle modulation and perturbed DNA repair.	('BCC-1', 'Gene', '100307118', (27, 32))	('less', 'NegReg', (118, 122))	('DNA repair', 'CPA', (262, 272))	('BCC-1', 'Gene', (27, 32))	('cell cycle modulation', 'CPA', (226, 247))	('GLI1', 'Gene', '2735', (192, 196))	('downregulation', 'NegReg', (210, 224))	('vismodegib', 'Var', (69, 79))	('Survivin', 'Gene', (201, 209))	('perturbed', 'NegReg', (252, 261))	('Survivin', 'Gene', '11799', (201, 209))	('SCC-25', 'CellLine', 'CVCL:1682', (43, 49))	('GLI1', 'Gene', (192, 196))
475819	30142876	Putative underlying mechanisms include morphological changes, altered cell-cell and cell-extracellular matrix contacts, activating cell adhesion molecules and different intracellular signaling pathways, differential gene expression or epigenetic changes.	('altered', 'Reg', (62, 69))	('epigenetic changes', 'Var', (235, 253))	('P', 'Chemical', 'MESH:D010758', (0, 1))	('intracellular signaling pathways', 'Pathway', (169, 201))	('cell', 'Protein', (131, 135))	('different', 'Reg', (159, 168))	('differential gene expression', 'Var', (203, 231))	('activating', 'PosReg', (120, 130))
475826	30142876	GLI translocation to the nucleus has been reported to promote cell cycle progression, and inhibition of GLI by GANT61 was shown to induce a G1 arrest in 22Rv1:but not in PC3 and DU145 pancreatic cancer cells, concomitant with radiosensitization only in p53 wildtype 22Rv1 cells.	('cell cycle progression', 'CPA', (62, 84))	('inhibition', 'Var', (90, 100))	('GLI', 'Gene', (104, 107))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (184, 201))	('GLI', 'Gene', (0, 3))	('p53', 'Gene', '7157', (253, 256))	('DU145', 'CellLine', 'CVCL:0105', (178, 183))	('22Rv1', 'CellLine', 'CVCL:1045', (266, 271))	('promote', 'PosReg', (54, 61))	('GLI', 'Gene', '2735', (104, 107))	('22Rv1', 'CellLine', 'CVCL:1045', (153, 158))	('G1 arrest', 'CPA', (140, 149))	('p53', 'Gene', (253, 256))	('GANT61', 'Gene', (111, 117))	('pancreatic cancer', 'Disease', 'MESH:D010190', (184, 201))	('GLI', 'Gene', '2735', (0, 3))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('PC3', 'CellLine', 'CVCL:0035', (170, 173))	('induce', 'Reg', (131, 137))	('pancreatic cancer', 'Disease', (184, 201))
475827	30142876	SCC-25 cells used in our experiments are heterozygous for a p53 mutation, while the p53 status of BCC-1 is not known at present.	('mutation', 'Var', (64, 72))	('SCC-25', 'CellLine', 'CVCL:1682', (0, 6))	('p53', 'Gene', (60, 63))	('p53', 'Gene', (84, 87))	('BCC-1', 'Gene', '100307118', (98, 103))	('p53', 'Gene', '7157', (84, 87))	('p53', 'Gene', '7157', (60, 63))	('BCC-1', 'Gene', (98, 103))
475858	30142876	PCR assays were performed in triplicate according to the manufacturer's instruction with the following PCR conditions/thermo-profile: 2 min at 94  C, followed by 40 cycles of 15 s at 94  C and 1 min at 54  C (ribosomal protein L37A (RPL37A) and BIRC5) or 60  C (GLI1).	('BIRC5', 'Gene', '332', (245, 250))	('P', 'Chemical', 'MESH:D010758', (234, 235))	('BIRC5', 'Gene', (245, 250))	('L37A', 'Var', (227, 231))	('GLI1', 'Gene', (262, 266))	('P', 'Chemical', 'MESH:D010758', (0, 1))	('P', 'Chemical', 'MESH:D010758', (103, 104))	('L37A', 'SUBSTITUTION', 'None', (227, 231))	('RPL37A', 'Gene', (233, 239))	('L37A', 'SUBSTITUTION', 'None', (235, 239))	('L37A', 'Var', (235, 239))	('RPL37A', 'Gene', '6168', (233, 239))	('GLI1', 'Gene', '2735', (262, 266))
475867	30142876	Blocking was performed in 5% bovine serum albumin (AppliChem) for 1 h and gammaH2AX/53BP1-positive foci were visualized with anti-gammaH2AX (clone JBW301, 05-636, Merck), anti-53BP1 (100-304, Novus Biologicals, Wiesbaden Nordenstadt, Germany) primary and fluorescent-dye conjugated secondary antibodies (Alexa Fluor 594 goat anti-mouse, Alexa Fluor 488 goat anti-rabbit, Thermo Fisher Scientific).	('gammaH2AX', 'Chemical', '-', (74, 83))	('S', 'Chemical', 'MESH:D013455', (385, 386))	('P', 'Chemical', 'MESH:D010758', (179, 180))	('goat', 'Species', '9925', (353, 357))	('gammaH2AX', 'Chemical', '-', (130, 139))	('mouse', 'Species', '10090', (330, 335))	('P', 'Chemical', 'MESH:D010758', (87, 88))	('anti-gammaH2AX', 'Var', (125, 139))	('bovine', 'Species', '9913', (29, 35))	('serum albumin (AppliChem) for 1 h', 'Gene', '213', (36, 69))	('anti-53BP1', 'Var', (171, 181))	('rabbit', 'Species', '9986', (363, 369))	('goat', 'Species', '9925', (320, 324))
475902	30069008	Among those, we found that knocking down DLEU1 (deleted in lymphocytic leukemia 1) strongly suppressed OSCC cell proliferation.	('OSCC cell proliferation', 'CPA', (103, 126))	('suppressed', 'NegReg', (92, 102))	('deleted in lymphocytic leukemia 1', 'Gene', '10301', (48, 81))	('leukemia', 'Phenotype', 'HP:0001909', (71, 79))	('knocking down', 'Var', (27, 40))	('deleted in lymphocytic leukemia 1', 'Gene', (48, 81))	('DLEU1', 'Gene', '10301', (41, 46))	('DLEU1', 'Gene', (41, 46))
475903	30069008	DLEU1 knockdown also suppressed migration, invasion, and xenograft formation by OSCC cells, which is suggestive of its oncogenic functionality.	('invasion', 'CPA', (43, 51))	('suppressed', 'NegReg', (21, 31))	('xenograft formation', 'CPA', (57, 76))	('DLEU1', 'Gene', '10301', (0, 5))	('DLEU1', 'Gene', (0, 5))	('migration', 'CPA', (32, 41))	('knockdown', 'Var', (6, 15))
475904	30069008	Microarray analysis revealed that DLEU1 knockdown significantly affects expression of a number of cancer-related genes in OSCC cells, including HAS3, CD44, and TP63, suggesting that DLEU1 regulates HA-CD44 signaling.	('CD44', 'Gene', (201, 205))	('TP63', 'Gene', (160, 164))	('DLEU1', 'Gene', (34, 39))	('cancer', 'Disease', (98, 104))	('HA', 'Chemical', 'MESH:D006820', (198, 200))	('HAS3', 'Gene', '3038', (144, 148))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('TP63', 'Gene', '8626', (160, 164))	('expression', 'MPA', (72, 82))	('DLEU1', 'Gene', '10301', (182, 187))	('CD44', 'Gene', '960', (150, 154))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('HAS3', 'Gene', (144, 148))	('CD44', 'Gene', (150, 154))	('DLEU1', 'Gene', (182, 187))	('HA', 'Chemical', 'MESH:D006820', (144, 146))	('affects', 'Reg', (64, 71))	('knockdown', 'Var', (40, 49))	('DLEU1', 'Gene', '10301', (34, 39))	('CD44', 'Gene', '960', (201, 205))
475905	30069008	Expression of DLEU1 was elevated in 71% of primary OSCC tissues, and high DLEU1 expression was associated with shorter overall survival of HNSCC patients.	('patients', 'Species', '9606', (145, 153))	('Expression', 'MPA', (0, 10))	('DLEU1', 'Gene', (74, 79))	('HNSCC', 'Phenotype', 'HP:0012288', (139, 144))	('shorter', 'NegReg', (111, 118))	('high', 'Var', (69, 73))	('expression', 'MPA', (80, 90))	('elevated', 'PosReg', (24, 32))	('DLEU1', 'Gene', (14, 19))	('overall survival', 'MPA', (119, 135))	('DLEU1', 'Gene', '10301', (14, 19))	('DLEU1', 'Gene', '10301', (74, 79))
475913	30069008	However, it is also well documented that cetuximab is less effective in cancers with KRAS mutations, and discovery of new therapeutic targets in oral cancer is needed.	('cancers', 'Disease', (72, 79))	('cancers', 'Disease', 'MESH:D009369', (72, 79))	('cetuximab', 'Chemical', 'MESH:D000068818', (41, 50))	('mutations', 'Var', (90, 99))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('oral cancer', 'Disease', 'MESH:D009062', (145, 156))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('KRAS', 'Gene', (85, 89))	('oral cancer', 'Disease', (145, 156))	('KRAS', 'Gene', '3845', (85, 89))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
475919	30069008	Dysregulation of lncRNAs has also been implicated in oral tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('implicated', 'Reg', (39, 49))	('Dysregulation', 'Var', (0, 13))	('lncRNAs', 'Protein', (17, 24))	('tumor', 'Disease', 'MESH:D009369', (58, 63))
475930	30069008	Expression of 6 lncRNAs (DLEU1, LINC00941, LINC00460, TCONS_00015845, TCONS_00025137, and TCONS_00005474) was significantly elevated in a majority of the OSCC cell lines, and we selected these lncRNAs for further analysis (Fig.	('LINC00941', 'Gene', (32, 41))	('LINC00460', 'Gene', (43, 52))	('LINC00941', 'Gene', '100287314', (32, 41))	('Expression', 'MPA', (0, 10))	('TCONS_00025137', 'Gene', (70, 84))	('DLEU1', 'Gene', '10301', (25, 30))	('TCONS_00015845', 'Var', (54, 68))	('TCONS_00005474', 'Var', (90, 104))	('LINC00460', 'Gene', '728192', (43, 52))	('elevated', 'PosReg', (124, 132))	('DLEU1', 'Gene', (25, 30))
475931	30069008	We found that siRNAs targeting DLEU1, LINC00941, TCONS_00015845, and TCONS_00025137 all significantly suppressed proliferation of Ca9-22 and MOT cells.	('DLEU1', 'Gene', (31, 36))	('Ca9-22', 'CellLine', 'CVCL:1102', (130, 136))	('LINC00941', 'Gene', '100287314', (38, 47))	('suppressed', 'NegReg', (102, 112))	('TCONS_00015845', 'Var', (49, 63))	('LINC00941', 'Gene', (38, 47))	('TCONS_00025137', 'Var', (69, 83))	('DLEU1', 'Gene', '10301', (31, 36))
475932	30069008	DLEU1 knockdown had the strongest suppressive effect on growth in all cell lines tested.	('growth', 'CPA', (56, 62))	('DLEU1', 'Gene', '10301', (0, 5))	('DLEU1', 'Gene', (0, 5))	('suppressive', 'NegReg', (34, 45))	('knockdown', 'Var', (6, 15))
475934	30069008	Cell viability assays showed that knocking down DLEU1 expression with either of the two siRNAs significantly suppressed proliferation of HSC-3, KON, Ca9-22, and MOT cells (Fig.	('knocking', 'Var', (34, 42))	('proliferation', 'CPA', (120, 133))	('Ca9-22', 'CellLine', 'CVCL:1102', (149, 155))	('suppressed', 'NegReg', (109, 119))	('HSC-3', 'Gene', '150353', (137, 142))	('MOT cells', 'CPA', (161, 170))	('DLEU1', 'Gene', '10301', (48, 53))	('HSC-3', 'Gene', (137, 142))	('DLEU1', 'Gene', (48, 53))
475935	30069008	Notably, DLEU1 knockdown not only suppressed KON cell proliferation, it also significantly decreased cell viability 96 h after transfection.	('DLEU1', 'Gene', (9, 14))	('knockdown', 'Var', (15, 24))	('suppressed', 'NegReg', (34, 44))	('cell viability 96 h', 'CPA', (101, 120))	('DLEU1', 'Gene', '10301', (9, 14))	('decreased', 'NegReg', (91, 100))	('KON cell proliferation', 'CPA', (45, 67))
475936	30069008	This suggests DLEU1 knockdown induced KON cell death (Fig.	('KON cell death', 'Disease', 'MESH:D003643', (38, 52))	('induced', 'Reg', (30, 37))	('DLEU1', 'Gene', '10301', (14, 19))	('KON cell death', 'Disease', (38, 52))	('knockdown', 'Var', (20, 29))	('DLEU1', 'Gene', (14, 19))
475938	30069008	Transwell chamber assays revealed that DLEU1 knockdown suppresses migration of HSC-3, KON, and Ca9-22 cells (Fig.	('DLEU1', 'Gene', '10301', (39, 44))	('migration', 'CPA', (66, 75))	('DLEU1', 'Gene', (39, 44))	('HSC-3', 'Gene', '150353', (79, 84))	('Ca9-22', 'CellLine', 'CVCL:1102', (95, 101))	('HSC-3', 'Gene', (79, 84))	('suppresses', 'NegReg', (55, 65))	('knockdown', 'Var', (45, 54))
475939	30069008	Matrigel invasion assays showed that DLEU1 knockdown suppresses invasion by OSCC cells (Fig.	('DLEU1', 'Gene', '10301', (37, 42))	('suppresses', 'NegReg', (53, 63))	('DLEU1', 'Gene', (37, 42))	('knockdown', 'Var', (43, 52))	('invasion by OSCC cells', 'CPA', (64, 86))
475940	30069008	The inhibitory effect of DLEU1 knockdown on cell migration was confirmed in wound healing assays (Fig.	('cell migration', 'CPA', (44, 58))	('DLEU1', 'Gene', '10301', (25, 30))	('knockdown', 'Var', (31, 40))	('DLEU1', 'Gene', (25, 30))
475941	30069008	When we then assessed the involvement of DLEU1 in cell cycle and apoptosis, we found that DLEU1 knockdown induces G2/M arrest in OSCC cells (Fig.	('knockdown', 'Var', (96, 105))	('DLEU1', 'Gene', (90, 95))	('induces', 'Reg', (106, 113))	('arrest', 'Disease', (119, 125))	('DLEU1', 'Gene', '10301', (90, 95))	('arrest', 'Disease', 'MESH:D006323', (119, 125))	('DLEU1', 'Gene', '10301', (41, 46))	('DLEU1', 'Gene', (41, 46))
475942	30069008	DLEU1 knockdown also upregulated expression of a G2 checkpoint kinase, WEE1, in OSCC cells, which is consistent with the cell cycle assay results (Supplementary Fig.	('upregulated', 'PosReg', (21, 32))	('WEE1', 'Gene', '7465', (71, 75))	('DLEU1', 'Gene', '10301', (0, 5))	('DLEU1', 'Gene', (0, 5))	('WEE1', 'Gene', (71, 75))	('expression', 'MPA', (33, 43))	('knockdown', 'Var', (6, 15))
475943	30069008	In addition, there was a mild increase in the G1 phase population and reduction in the S phase population of KON and Ca9-22 cells, which suggests DLEU1 depletion induces G1/S arrest (Supplementary Figs.	('depletion', 'Var', (152, 161))	('reduction', 'NegReg', (70, 79))	('S arrest', 'Disease', 'MESH:D006323', (173, 181))	('Ca9-22', 'CellLine', 'CVCL:1102', (117, 123))	('G1 phase population', 'CPA', (46, 65))	('increase', 'PosReg', (30, 38))	('DLEU1', 'Gene', '10301', (146, 151))	('S phase population', 'CPA', (87, 105))	('induces', 'Reg', (162, 169))	('DLEU1', 'Gene', (146, 151))	('S arrest', 'Disease', (173, 181))
475944	30069008	DLEU1 knockdown also induced apoptosis in OSCC cells (Fig.	('knockdown', 'Var', (6, 15))	('DLEU1', 'Gene', (0, 5))	('induced', 'Reg', (21, 28))	('DLEU1', 'Gene', '10301', (0, 5))
475948	30069008	Immunohistochemical analysis revealed that Ki-67 expression was decreased in tumors treated with the DLEU1 siRNA, which indicates DLEU1 knockdown suppresses tumor cell proliferation (Fig.	('suppresses', 'NegReg', (146, 156))	('tumors', 'Disease', (77, 83))	('tumor', 'Disease', (157, 162))	('DLEU1', 'Gene', (101, 106))	('tumors', 'Disease', 'MESH:D009369', (77, 83))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('DLEU1', 'Gene', '10301', (130, 135))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('expression', 'MPA', (49, 59))	('knockdown', 'Var', (136, 145))	('DLEU1', 'Gene', (130, 135))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('Ki-67', 'Gene', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('tumor', 'Disease', (77, 82))	('DLEU1', 'Gene', '10301', (101, 106))	('decreased', 'NegReg', (64, 73))
475950	30069008	We found that expression of 963 probe sets (814 unique genes) were altered (>2-fold) by DLEU1 knockdown in all three cell lines tested (Fig.	('knockdown', 'Var', (94, 103))	('DLEU1', 'Gene', '10301', (88, 93))	('DLEU1', 'Gene', (88, 93))	('expression', 'MPA', (14, 24))	('altered', 'Reg', (67, 74))
475962	30069008	Another study reported that elevated expression of LINC00460 is associated with advanced clinical stages, lymph node metastasis, and a poor prognosis in esophageal squamous cell carcinoma (ESCC), and that LINC00460 knockdown induces cell cycle arrest and apoptosis in ESCC cells.	('arrest', 'Disease', 'MESH:D006323', (244, 250))	('LINC00460', 'Gene', '728192', (51, 60))	('LINC00460', 'Gene', (51, 60))	('arrest', 'Disease', (244, 250))	('knockdown', 'Var', (215, 224))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (153, 187))	('apoptosis', 'CPA', (255, 264))	('lymph node metastasis', 'CPA', (106, 127))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (233, 250))	('carcinoma', 'Phenotype', 'HP:0030731', (178, 187))	('LINC00460', 'Gene', (205, 214))	('expression', 'MPA', (37, 47))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (164, 187))	('elevated', 'PosReg', (28, 36))	('esophageal squamous cell carcinoma', 'Disease', (153, 187))	('LINC00460', 'Gene', '728192', (205, 214))
475964	30069008	Among the candidate lncRNAs examined, we found that knocking down DLEU1 had the strongest anti-proliferative effects in multiple OSCC cell lines.	('knocking down', 'Var', (52, 65))	('anti-proliferative effects', 'CPA', (90, 116))	('DLEU1', 'Gene', '10301', (66, 71))	('DLEU1', 'Gene', (66, 71))
475968	30069008	Sequencing analysis of RNA variants suggests DLEU1 encodes a noncoding RNA, but the tumor suppressive function of DLEU1 is not fully understood.	('DLEU1', 'Gene', (45, 50))	('variants', 'Var', (27, 35))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('DLEU1', 'Gene', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumor', 'Disease', (84, 89))	('DLEU1', 'Gene', '10301', (45, 50))	('DLEU1', 'Gene', '10301', (114, 119))
475969	30069008	A recent study showed that expression of DLEU1 is upregulated via DNA demethylation in CLL, and that epigenetic aberration is associated with downregulation of neighboring tumor suppressor genes that regulate NF-kappaB signaling.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('upregulated', 'PosReg', (50, 61))	('DNA demethylation', 'Var', (66, 83))	('tumor', 'Disease', (172, 177))	('expression', 'MPA', (27, 37))	('epigenetic aberration', 'Var', (101, 122))	('DLEU1', 'Gene', '10301', (41, 46))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('DLEU1', 'Gene', (41, 46))	('downregulation', 'NegReg', (142, 156))
475971	30069008	In Burkitt lymphoma cells, DLEU1 knockdown significantly inhibits apoptosis and promotes cell proliferation, suggesting it acts as a tumor suppressor.	('cell proliferation', 'CPA', (89, 107))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('knockdown', 'Var', (33, 42))	('Burkitt lymphoma', 'Phenotype', 'HP:0030080', (3, 19))	('Burkitt lymphoma', 'Disease', (3, 19))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('lymphoma', 'Phenotype', 'HP:0002665', (11, 19))	('DLEU1', 'Gene', '10301', (27, 32))	('apoptosis', 'CPA', (66, 75))	('DLEU1', 'Gene', (27, 32))	('tumor', 'Disease', (133, 138))	('Burkitt lymphoma', 'Disease', 'MESH:D002051', (3, 19))	('promotes', 'PosReg', (80, 88))	('inhibits', 'NegReg', (57, 65))
475974	30069008	Because multiple variants are transcribed from the DLEU1 gene, we used siRNAs that targeted all three variants annotated in the RefSeq database (NR_109973, NR_002605, and NR_109974).	('DLEU1', 'Gene', (51, 56))	('NR_002605', 'Var', (156, 165))	('NR_109974', 'Var', (171, 180))	('NR_109973', 'Var', (145, 154))	('DLEU1', 'Gene', '10301', (51, 56))
475975	30069008	We found that DLEU1 knockdown inhibited proliferation, migration, and invasion by OSCC cells.	('inhibited', 'NegReg', (30, 39))	('migration', 'CPA', (55, 64))	('invasion by OSCC cells', 'CPA', (70, 92))	('DLEU1', 'Gene', '10301', (14, 19))	('knockdown', 'Var', (20, 29))	('DLEU1', 'Gene', (14, 19))	('proliferation', 'CPA', (40, 53))
475976	30069008	Depletion of DLEU1 induced cell cycle arrest and apoptosis in OSCC cells, which could have an anti-proliferative effect.	('cell cycle arrest', 'Phenotype', 'HP:0011018', (27, 44))	('arrest', 'Disease', (38, 44))	('DLEU1', 'Gene', '10301', (13, 18))	('Depletion', 'Var', (0, 9))	('DLEU1', 'Gene', (13, 18))	('apoptosis', 'CPA', (49, 58))	('arrest', 'Disease', 'MESH:D006323', (38, 44))
475978	30069008	Elevated expression of DLEU1 was frequently observed in clinical OSCC tumors, and high DLEU1 expression was associated with poorer survival among HNSCC patients.	('DLEU1', 'Gene', '10301', (23, 28))	('HNSCC', 'Phenotype', 'HP:0012288', (146, 151))	('OSCC tumors', 'Disease', (65, 76))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('DLEU1', 'Gene', (23, 28))	('high', 'Var', (82, 86))	('Elevated', 'PosReg', (0, 8))	('OSCC tumors', 'Disease', 'MESH:D009369', (65, 76))	('expression', 'MPA', (9, 19))	('expression', 'MPA', (93, 103))	('poorer', 'NegReg', (124, 130))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('DLEU1', 'Gene', '10301', (87, 92))	('DLEU1', 'Gene', (87, 92))	('patients', 'Species', '9606', (152, 160))
475982	30069008	For instance, DLEU1 knockdown led to decreased expression of HAS3 and CD44.	('HAS3', 'Gene', '3038', (61, 65))	('CD44', 'Gene', (70, 74))	('HAS3', 'Gene', (61, 65))	('DLEU1', 'Gene', '10301', (14, 19))	('knockdown', 'Var', (20, 29))	('DLEU1', 'Gene', (14, 19))	('CD44', 'Gene', '960', (70, 74))	('decreased', 'NegReg', (37, 46))	('expression', 'MPA', (47, 57))
475987	30069008	CD44 is a major HA receptor, and interaction between HA and CD44 promotes HNSCC progression and chemoresistance through activation of EGFR signaling.	('chemoresistance', 'CPA', (96, 111))	('CD44', 'Gene', '960', (60, 64))	('EGFR', 'Gene', (134, 138))	('CD44', 'Gene', (60, 64))	('CD44', 'Gene', '960', (0, 4))	('HNSCC', 'Disease', (74, 79))	('interaction', 'Var', (33, 44))	('activation', 'PosReg', (120, 130))	('HNSCC', 'Phenotype', 'HP:0012288', (74, 79))	('promotes', 'PosReg', (65, 73))	('CD44', 'Gene', (0, 4))	('HA', 'Chemical', 'MESH:D006820', (16, 18))	('HA', 'Chemical', 'MESH:D006820', (53, 55))	('EGFR', 'Gene', '1956', (134, 138))
475990	30069008	We also noted that DLEU1 knockdown suppressed expression of genes encoding the histone methylation modifiers SMYD2, SETD6, and KDM1B.	('SMYD2', 'Gene', '56950', (109, 114))	('DLEU1', 'Gene', '10301', (19, 24))	('DLEU1', 'Gene', (19, 24))	('SETD6', 'Gene', (116, 121))	('SMYD2', 'Gene', (109, 114))	('KDM1B', 'Gene', (127, 132))	('SETD6', 'Gene', '79918', (116, 121))	('KDM1B', 'Gene', '221656', (127, 132))	('suppressed', 'NegReg', (35, 45))	('expression', 'MPA', (46, 56))	('knockdown', 'Var', (25, 34))
475991	30069008	SMYD2 was identified as a lysine methyltransferase (KMT) for histone H3K36 and K370 of p53, and it is reportedly overexpressed in various tumors, including HNSCC.	('overexpressed', 'PosReg', (113, 126))	('p53', 'Gene', (87, 90))	('p53', 'Gene', '7157', (87, 90))	('SMYD2', 'Gene', (0, 5))	('HNSCC', 'Disease', (156, 161))	('histone H3K36', 'Protein', (61, 74))	('tumors', 'Disease', (138, 144))	('tumors', 'Disease', 'MESH:D009369', (138, 144))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('K370', 'Var', (79, 83))	('HNSCC', 'Phenotype', 'HP:0012288', (156, 161))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('SMYD2', 'Gene', '56950', (0, 5))
475996	30069008	In contrast to genes described above, we found that DLEU1 knockdown induces the expression of CDH1 in OSCC cells.	('CDH1', 'Gene', (94, 98))	('CDH1', 'Gene', '999', (94, 98))	('expression', 'MPA', (80, 90))	('DLEU1', 'Gene', '10301', (52, 57))	('DLEU1', 'Gene', (52, 57))	('knockdown', 'Var', (58, 67))	('induces', 'PosReg', (68, 75))
475998	30069008	CDH1 is frequently silenced in OSCC cells by CpG island hypermethylation, and CDH1 methylation and reduced E-cadherin expression are associated with invasion and metastasis in OSCC.	('E-cadherin', 'Gene', '999', (107, 117))	('OSCC', 'Disease', (176, 180))	('methylation', 'Var', (83, 94))	('CDH1', 'Gene', '999', (0, 4))	('E-cadherin', 'Gene', (107, 117))	('CDH1', 'Gene', (78, 82))	('reduced', 'NegReg', (99, 106))	('CDH1', 'Gene', '999', (78, 82))	('expression', 'MPA', (118, 128))	('CDH1', 'Gene', (0, 4))	('associated', 'Reg', (133, 143))
475999	30069008	These results suggest that altered expression of multiple cancer-related genes by DLEU1 knockdown contributes to the antitumor effects seen in OSCC cells.	('DLEU1', 'Gene', '10301', (82, 87))	('altered', 'Reg', (27, 34))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('DLEU1', 'Gene', (82, 87))	('tumor', 'Disease', (121, 126))	('expression', 'MPA', (35, 45))	('OSCC', 'Disease', (143, 147))	('knockdown', 'Var', (88, 97))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('cancer', 'Disease', (58, 64))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
476031	26013764	Based largely on differences in biogenesis and structure, small RNAs can be broadly divided into three groups: small interfering RNAs (siRNAs), microRNAs (miRNAs) and PIWI-interacting RNA (piRNAs).	('PIWI', 'Gene', '34521', (167, 171))	('PIWI', 'Gene', (167, 171))	('small interfering', 'Var', (111, 128))
476058	26013764	While expression of some mt-piRNAs such as FR015567 were highly variable across tumour-types, with particularly low expression levels in COAD, THCA and UCEC, other mt-piRNAs such as FR043670, were highly expressed across almost all tumour types (Fig.	('tumour', 'Disease', (80, 86))	('tumour-type', 'Disease', (80, 91))	('tumour', 'Disease', (232, 238))	('tumour-type', 'Disease', 'MESH:D009369', (80, 91))	('COAD', 'Disease', 'MESH:D029424', (137, 141))	('tumour', 'Phenotype', 'HP:0002664', (80, 86))	('tumour', 'Disease', 'MESH:D009369', (80, 86))	('tumour', 'Disease', 'MESH:D009369', (232, 238))	('FR015567', 'Var', (43, 51))	('tumour', 'Phenotype', 'HP:0002664', (232, 238))	('expression levels', 'MPA', (116, 133))	('COAD', 'Disease', (137, 141))
476060	26013764	Additionally, we assessed tumour piRNA expression data derived from independent cancer cohorts, including bladder (GSE31616, n = 10), breast (GSE29173 and GSE28884, n = 167), colon (GSE63119, n = 50), lung (GEO Accession numbers pending; adenocarcinoma subtype, n = 30, squamous cell carcinoma subtype, n = 30) and stomach (GSE36968, n = 25) tumours.	('adenocarcinoma subtype', 'Disease', (238, 260))	('GSE28884', 'Var', (155, 163))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (270, 293))	('GSE63119', 'Var', (182, 190))	('cancer', 'Disease', (80, 86))	('GSE36968', 'Var', (324, 332))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('GSE29173', 'Var', (142, 150))	('carcinoma', 'Phenotype', 'HP:0030731', (284, 293))	('squamous cell carcinoma subtype', 'Disease', 'MESH:D002294', (270, 301))	('tumours', 'Disease', (342, 349))	('tumour', 'Phenotype', 'HP:0002664', (26, 32))	('tumour', 'Phenotype', 'HP:0002664', (342, 348))	('tumour', 'Disease', 'MESH:D009369', (342, 348))	('squamous cell carcinoma subtype', 'Disease', (270, 301))	('tumour', 'Disease', 'MESH:D009369', (26, 32))	('tumours', 'Phenotype', 'HP:0002664', (342, 349))	('colon', 'Disease', (175, 180))	('tumour', 'Disease', (26, 32))	('carcinoma', 'Phenotype', 'HP:0030731', (243, 252))	('tumour', 'Disease', (342, 348))	('tumours', 'Disease', 'MESH:D009369', (342, 349))	('bladder', 'Disease', (106, 113))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('adenocarcinoma subtype', 'Disease', 'MESH:D000230', (238, 260))	('GSE31616', 'Var', (115, 123))	('lung', 'Disease', (201, 205))	('breast', 'Disease', (134, 140))
476073	26013764	For KIRC, we assessed whether metastasis, nodal status, stage and presence of Von Hippel-Lindau (VHL) mutation :a common mutation in kidney cancer: were significantly different across the three distinct tumour clusters (Fig.	('kidney cancer', 'Disease', (133, 146))	('Von Hippel-Lindau', 'Gene', '7428', (78, 95))	('VHL', 'Gene', '7428', (97, 100))	('tumour', 'Phenotype', 'HP:0002664', (203, 209))	('mutation', 'Var', (102, 110))	('Von Hippel-Lindau', 'Gene', (78, 95))	('tumour clusters', 'Disease', 'MESH:D003027', (203, 218))	('kidney cancer', 'Disease', 'MESH:D007680', (133, 146))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('kidney cancer', 'Phenotype', 'HP:0009726', (133, 146))	('VHL', 'Gene', (97, 100))	('tumour clusters', 'Disease', (203, 218))
476087	26013764	high levels of FR004819 associated with poorer patient survival in STAD, BLCA, THCA), or had opposite associations in different tumour types.	('poorer', 'NegReg', (40, 46))	('tumour', 'Disease', (128, 134))	('patient', 'Species', '9606', (47, 54))	('STAD', 'Disease', (67, 71))	('tumour', 'Phenotype', 'HP:0002664', (128, 134))	('FR004819', 'Var', (15, 23))	('BLCA', 'Disease', (73, 77))	('patient survival', 'CPA', (47, 63))	('tumour', 'Disease', 'MESH:D009369', (128, 134))
476088	26013764	For example, high expression of FR090905 is associated with poor patient survival in KIRC, and improved survival in UCEC.	('survival', 'MPA', (104, 112))	('poor', 'NegReg', (60, 64))	('patient', 'Species', '9606', (65, 72))	('improved', 'PosReg', (95, 103))	('FR090905', 'Var', (32, 40))
476089	26013764	Notably, FR090905 was significantly associated with survival in three different tumour types (KIRC, HNSC, and UCEC), and was nearly significant in LUSC (p value = 0.065, after false discovery rate correction for multiple testing), highlighting the potential importance of this piRNA in multiple tumour types.	('tumour', 'Disease', (80, 86))	('HNSC', 'Disease', (100, 104))	('tumour', 'Disease', 'MESH:D009369', (295, 301))	('tumour', 'Disease', (295, 301))	('tumour', 'Phenotype', 'HP:0002664', (80, 86))	('tumour', 'Disease', 'MESH:D009369', (80, 86))	('associated with', 'Reg', (36, 51))	('FR090905', 'Var', (9, 17))	('tumour', 'Phenotype', 'HP:0002664', (295, 301))
476091	26013764	Indeed, two piRNAs associated with survival in the TCGA breast cancer cohort (FR378984 and FR025321) validated in this external cohort (Supplementary Table 5).	('FR378984', 'Var', (78, 86))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('FR025321', 'Var', (91, 99))	('breast cancer', 'Disease', 'MESH:D001943', (56, 69))	('breast cancer', 'Phenotype', 'HP:0003002', (56, 69))	('breast cancer', 'Disease', (56, 69))	('associated with', 'Reg', (19, 34))
476100	26013764	This is expected, since piRNAs and PIWI proteins play critical roles in germline development and gametogenesis, including germline determination, stem cell maintenance, meiosis, spermatogenesis, and transposon silencing.	('transposon silencing', 'Var', (199, 219))	('meiosis', 'CPA', (169, 176))	('PIWI', 'Gene', (35, 39))	('stem cell maintenance', 'CPA', (146, 167))	('PIWI', 'Gene', '34521', (35, 39))	('spermatogenesis', 'CPA', (178, 193))
476129	26013764	A full description of a per-tissue processing can be found in the Synapse archive (www.synapse.org) within the following accessions: syn1461149 (BLCA), syn1461151 (BRCA), syn1461155 (COAD), syn1461156 (HNSC), syn1461159 (KIRC), syn1461166 (LUAD), syn1461168 (LUSC), syn1461171 (OV), syn1461173 (PRAD), syn1461177 (STAD), syn1461178 (THCA), syn1461180 (UCEC).	('syn1461159', 'Var', (209, 219))	('syn1461173', 'Var', (283, 293))	('BRCA', 'Gene', (164, 168))	('syn1461168', 'Var', (247, 257))	('syn1461151', 'Var', (152, 162))	('syn1461180', 'Var', (340, 350))	('syn1461166', 'Var', (228, 238))	('syn1461156', 'Var', (190, 200))	('COAD', 'Disease', (183, 187))	('syn1461171', 'Var', (266, 276))	('COAD', 'Disease', 'MESH:D029424', (183, 187))	('syn1461177', 'Var', (302, 312))	('syn1461178', 'Var', (321, 331))	('syn1461155', 'Var', (171, 181))	('BRCA', 'Gene', '672', (164, 168))	('syn1461149', 'Var', (133, 143))
476176	33003438	In addition, P. aeruginosa could injure epithelial cells by triggering DNA strand breaks.	('triggering', 'Reg', (60, 70))	('P. aeruginosa', 'Var', (13, 26))	('injure', 'NegReg', (33, 39))	('DNA strand breaks', 'MPA', (71, 88))	('P. aeruginosa', 'Species', '287', (13, 26))
476186	33003438	M. micronuciformis seemed to be the best candidate for a specific biomarker as it was detected only in the pre-cancer group.	('M. micronuciformis', 'Species', '187326', (0, 18))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('M. micronuciformis', 'Var', (0, 18))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))
476214	33003438	In vitro, oral bacteria such as P. gingivalis can lead to secondary impacts on the proliferation rate by modifying the expression levels of oncogenic-relevant alpha-defensin genes.	('expression levels', 'MPA', (119, 136))	('impacts', 'Reg', (68, 75))	('alpha-defensin', 'Protein', (159, 173))	('modifying', 'Reg', (105, 114))	('proliferation rate', 'CPA', (83, 101))	('P. gingivalis', 'Species', '837', (32, 45))	('P. gingivalis', 'Var', (32, 45))
476221	33003438	In addition, a study our team participated in found that when human oral keratinocyte cells were infected with inactivated Staphylococcus aureus in high-glucose Dulbecco's modified Eagle's medium, certain S. aureus genes upregulated COX-2 transcription, increased PGE2 production, and then induced higher expression of oral cancer-associated genes cyclin D1, which is associated with cell proliferation and growth regulation.	('expression', 'MPA', (305, 315))	('high-glucose', 'Phenotype', 'HP:0003074', (148, 160))	('S. aureus', 'Species', '1280', (205, 214))	('oral cancer', 'Disease', 'MESH:D009369', (319, 330))	('Staphylococcus aureus', 'Species', '1280', (123, 144))	('PGE2', 'Chemical', 'MESH:D015232', (264, 268))	('S. aureus', 'Gene', (205, 214))	('PGE2 production', 'MPA', (264, 279))	('glucose', 'Chemical', 'MESH:D005947', (153, 160))	('oral cancer', 'Disease', (319, 330))	('human', 'Species', '9606', (62, 67))	('cyclin D1', 'Gene', (348, 357))	('cancer', 'Phenotype', 'HP:0002664', (324, 330))	('infected', 'Disease', 'MESH:D007239', (97, 105))	('higher', 'PosReg', (298, 304))	('infected', 'Disease', (97, 105))	('COX-2', 'Gene', (233, 238))	('increased', 'PosReg', (254, 263))	('genes', 'Var', (215, 220))	('COX-2', 'Gene', '4513', (233, 238))	('transcription', 'MPA', (239, 252))	('upregulated', 'PosReg', (221, 232))
476259	33003438	infected OSCC cells with P. gingivalis twice a week for five weeks and found that P. gingivalis could stimulate MMP-1 and MMP-10 by releasing IL-8 and gingipain and increased the invasiveness of cancer cells.	('infected', 'Disease', 'MESH:D007239', (0, 8))	('MMP-1', 'Gene', (112, 117))	('P. gingivalis', 'Species', '837', (82, 95))	('MMP-10', 'Gene', (122, 128))	('gingipain', 'Protein', (151, 160))	('cancer', 'Disease', (195, 201))	('stimulate', 'PosReg', (102, 111))	('infected', 'Disease', (0, 8))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('P. gingivalis', 'Species', '837', (25, 38))	('releasing', 'PosReg', (132, 141))	('IL-8', 'Gene', '3576', (142, 146))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('IL-8', 'Gene', (142, 146))	('P. gingivalis', 'Var', (82, 95))	('increased', 'PosReg', (165, 174))
476286	33003438	P. gingivalis was able to inhibit the phagocytosis of oral cancer cells by macrophages, and membrane-component molecules of P. gingivalis such as proteins were speculated to be the effector components.	('oral cancer', 'Disease', (54, 65))	('P. gingivalis', 'Species', '837', (0, 13))	('P. gingivalis', 'Var', (0, 13))	('inhibit', 'NegReg', (26, 33))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('oral cancer', 'Disease', 'MESH:D009369', (54, 65))	('P. gingivalis', 'Species', '837', (124, 137))
476288	33003438	These results all indicated that P. gingivalis could promote the immuno-evasion of oral cancer by protecting cancer cells from macrophage attack.	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('oral cancer', 'Disease', 'MESH:D009369', (83, 94))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('cancer', 'Disease', (109, 115))	('promote', 'PosReg', (53, 60))	('oral cancer', 'Disease', (83, 94))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('P. gingivalis', 'Species', '837', (33, 46))	('P. gingivalis', 'Var', (33, 46))	('immuno-evasion', 'MPA', (65, 79))
476293	33003438	Alcohol dehydrogenase 2 (ALDH2) is the most effective enzyme in the detoxification of the alcohol metabolite acetaldehyde, and ALDH2 polymorphism may modify the association between alcohol use and periodontal pathogenic bacteria, and thus, affect the percentage of this kind of bacteria, while tobacco altered the composition of oral bacteria by causing shifts in functional pathways such as carbohydrate, energy and xenobiotic metabolism.	('acetaldehyde', 'Chemical', 'MESH:D000079', (109, 121))	('ALDH2', 'Gene', '217', (127, 132))	('modify', 'Reg', (150, 156))	('polymorphism', 'Var', (133, 145))	('alcohol use', 'MPA', (181, 192))	('functional pathways', 'MPA', (364, 383))	('alcohol', 'Chemical', 'MESH:D000438', (181, 188))	('ALDH2', 'Gene', (25, 30))	('alcohol use', 'Phenotype', 'HP:0030955', (181, 192))	('Alcohol', 'Chemical', 'MESH:D000438', (0, 7))	('shifts', 'Reg', (354, 360))	('ALDH2', 'Gene', (127, 132))	('alcohol', 'Chemical', 'MESH:D000438', (90, 97))	('percentage', 'MPA', (251, 261))	('affect', 'Reg', (240, 246))	('association', 'Interaction', (161, 172))	('tobacco', 'Species', '4097', (294, 301))	('ALDH2', 'Gene', '217', (25, 30))	('carbohydrate', 'Chemical', 'MESH:D002241', (392, 404))	('carbohydrate', 'MPA', (392, 404))
476297	33003438	Alcohol could produce more acetaldehyde, a mutagenic and carcinogenic substance that could interfere with the synthesis and repair of DNA, produce genetic mutations, cause genotoxicity, and bind cellular proteins and DNA, finally resulting in morphological and cellular injury.	('resulting in', 'Reg', (230, 242))	('carcinogenic', 'Disease', 'MESH:D063646', (57, 69))	('mutations', 'Var', (155, 164))	('carcinogenic', 'Disease', (57, 69))	('produce', 'Reg', (139, 146))	('interfere', 'NegReg', (91, 100))	('bind', 'Interaction', (190, 194))	('cause', 'Reg', (166, 171))	('synthesis', 'MPA', (110, 119))	('Alcohol', 'Chemical', 'MESH:D000438', (0, 7))	('genetic mutations', 'Var', (147, 164))	('cellular proteins', 'Protein', (195, 212))	('acetaldehyde', 'Chemical', 'MESH:D000079', (27, 39))	('genotoxicity', 'Disease', (172, 184))	('genotoxicity', 'Disease', 'None', (172, 184))
476298	33003438	Moreover, alcohol could also reduce salivary flow, increasing the risk of cancer development.	('reduce salivary flow', 'Phenotype', 'HP:0000217', (29, 49))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('alcohol', 'Var', (10, 17))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('salivary flow', 'MPA', (36, 49))	('cancer', 'Disease', (74, 80))	('alcohol', 'Chemical', 'MESH:D000438', (10, 17))	('reduce', 'NegReg', (29, 35))
476327	31105886	Many studies have shown that inhibition of GLUT-1 and HK-II expression aberrations can improve the treatment efficacy of malignant tumors.	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('HK-II', 'Gene', (54, 59))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('aberrations', 'Var', (71, 82))	('improve', 'PosReg', (87, 94))	('malignant tumors', 'Disease', (121, 137))	('GLUT-1', 'Protein', (43, 49))	('inhibition', 'Var', (29, 39))	('malignant tumors', 'Disease', 'MESH:D018198', (121, 137))
476343	31105886	They reported that inhibition of GLUT-1 expression can reduce the growth, apoptosis, and migration of malignant melanoma.	('apoptosis', 'CPA', (74, 83))	('malignant melanoma', 'Disease', 'MESH:D008545', (102, 120))	('growth', 'CPA', (66, 72))	('inhibition', 'Var', (19, 29))	('malignant melanoma', 'Disease', (102, 120))	('melanoma', 'Phenotype', 'HP:0002861', (112, 120))	('GLUT-1', 'Protein', (33, 39))	('reduce', 'NegReg', (55, 61))	('malignant melanoma', 'Phenotype', 'HP:0002861', (102, 120))
476348	31105886	found that high expression of GLUT-1 was associated with the clinical stage of pancreatic cancer and with the standard uptake value (SUV) and Ki67 expression.	('pancreatic cancer', 'Disease', 'MESH:D010190', (79, 96))	('associated', 'Reg', (41, 51))	('pancreatic cancer', 'Disease', (79, 96))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('standard uptake value', 'MPA', (110, 131))	('GLUT-1', 'Gene', (30, 36))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (79, 96))	('high', 'Var', (11, 15))	('expression', 'MPA', (16, 26))
476361	31105886	In pancreatic cancer, the expression of GLUT-1 was associated with not only tumor size, stage, and lymph node involvement but also tumor proliferation and a worse prognosis.	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('pancreatic cancer', 'Disease', (3, 20))	('pancreatic cancer', 'Disease', 'MESH:D010190', (3, 20))	('expression', 'Var', (26, 36))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('associated', 'Reg', (51, 61))	('tumor', 'Disease', (131, 136))	('lymph node involvement', 'Disease', 'MESH:D000072717', (99, 121))	('lymph node involvement', 'Disease', (99, 121))	('GLUT-1', 'Gene', (40, 46))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (3, 20))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
476362	31105886	Univariate analysis showed that the survival of patients with high GLUT-1 expression was 12.3 months, which was significantly shorter than that of those with low expression (22.2 months), suggesting that high GLUT-1 expression in pancreatic cancer predicts poor prognosis.	('pancreatic cancer', 'Disease', (230, 247))	('pancreatic cancer', 'Disease', 'MESH:D010190', (230, 247))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (230, 247))	('patients', 'Species', '9606', (48, 56))	('high', 'Var', (62, 66))	('GLUT-1', 'Gene', (209, 215))	('high', 'Var', (204, 208))
476373	31105886	The underlying mechanism of GLUT-1 expression, which induces chemo-radioresistance in cancer cells, remains unclear.	('GLUT-1', 'Gene', (28, 34))	('chemo-radioresistance', 'CPA', (61, 82))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('induces', 'PosReg', (53, 60))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('expression', 'Var', (35, 45))	('cancer', 'Disease', (86, 92))
476403	31105886	They also found that some clinicopathological parameters, including age (P=0.003), tumor size (P=0.002), and distant metastasis (P=0.007), were significantly correlated with high GLUT-1 expression.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumor', 'Disease', (83, 88))	('GLUT-1', 'Protein', (179, 185))	('distant metastasis', 'CPA', (109, 127))	('high', 'Var', (174, 178))	('correlated', 'Reg', (158, 168))	('expression', 'MPA', (186, 196))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
476412	31105886	In their study, a worse overall survival rate was found in cases with high GLUT-1 and GLUT-3 expression, but this was only a trend.	('expression', 'MPA', (93, 103))	('high', 'Var', (70, 74))	('GLUT-3', 'Gene', '6515', (86, 92))	('GLUT-3', 'Gene', (86, 92))	('GLUT-1', 'Protein', (75, 81))
476420	31105886	However, we found that the maximum SUV (SUVmax) (P=0.043) and PI3K (P=0.012) were significantly poor prognostic factors, and that GLUT-1, HIF-1alpha, and p-Akt were not correlated with prognosis, recurrence, or metastasis.	('Akt', 'Gene', (156, 159))	('HIF-1alpha', 'Gene', (138, 148))	('PI3K', 'Var', (62, 66))	('HIF-1alpha', 'Gene', '3091', (138, 148))	('Akt', 'Gene', '207', (156, 159))
476426	31105886	In vitro, we found that antisense oligodeoxynucleotides (AS-ODNs) against GLUT-1 decreased glucose uptake and proliferation of Hep-2 laryngeal carcinoma cells by reducing GLUT-1 mRNA and protein expression.	('GLUT-1', 'Protein', (171, 177))	('laryngeal carcinoma', 'Disease', (133, 152))	('decreased glucose uptake', 'Disease', (81, 105))	('Hep-2', 'CellLine', 'CVCL:1906', (127, 132))	('AS-ODNs', 'Chemical', '-', (57, 64))	('laryngeal carcinoma', 'Phenotype', 'HP:0012118', (133, 152))	('proliferation', 'CPA', (110, 123))	('laryngeal carcinoma', 'Disease', 'MESH:D007827', (133, 152))	('reducing', 'NegReg', (162, 170))	('decreased glucose uptake', 'Disease', 'MESH:C536778', (81, 105))	('GLUT-1', 'Gene', (74, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (143, 152))	('antisense oligodeoxynucleotides', 'Var', (24, 55))	('oligodeoxynucleotides', 'Chemical', 'MESH:D009838', (34, 55))
476430	31105886	Our subsequent studies demonstrated that inhibition of GLUT-1 expression in laryngeal carcinoma cells may enhance the chemo-radiosensitivity of laryngeal carcinoma.	('enhance', 'PosReg', (106, 113))	('laryngeal carcinoma', 'Disease', 'MESH:D007827', (76, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('GLUT-1', 'Gene', (55, 61))	('laryngeal carcinoma', 'Disease', (144, 163))	('expression', 'MPA', (62, 72))	('laryngeal carcinoma', 'Disease', 'MESH:D007827', (144, 163))	('inhibition', 'Var', (41, 51))	('laryngeal carcinoma', 'Phenotype', 'HP:0012118', (144, 163))	('chemo-radiosensitivity', 'CPA', (118, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (154, 163))	('laryngeal carcinoma', 'Disease', (76, 95))	('laryngeal carcinoma', 'Phenotype', 'HP:0012118', (76, 95))
476435	31105886	Inhibition of GLUT-1 expression in Hep-2 cells via AS-ODNs may gradually decrease survival rate and increase the apoptotic rate with prolonged culture time and increased radiation in vitro.	('GLUT-1', 'Gene', (14, 20))	('Hep-2', 'CellLine', 'CVCL:1906', (35, 40))	('decrease', 'NegReg', (73, 81))	('Inhibition', 'Var', (0, 10))	('AS-ODNs', 'Chemical', '-', (51, 58))	('apoptotic rate', 'CPA', (113, 127))	('increase', 'PosReg', (100, 108))	('survival rate', 'CPA', (82, 95))
476439	31105886	We first demonstrated co-inhibition of GLUT-1 expression via AS-ODNs and the PI3K/Akt pathway via specific inhibitors including Ly294002 and wortmannin.	('Ly294002', 'Chemical', 'MESH:C085911', (128, 136))	('Akt', 'Gene', '207', (82, 85))	('GLUT-1', 'Gene', (39, 45))	('Ly294002', 'Var', (128, 136))	('AS-ODNs', 'Chemical', '-', (61, 68))	('Akt', 'Gene', (82, 85))	('wortmannin', 'Chemical', 'MESH:D000077191', (141, 151))	('expression', 'MPA', (46, 56))
476440	31105886	After 10 Gy X-ray radiation, Ly294002, wortmannin, Ly294002 plus GLUT-1 AS-ODNs, and wortmannin plus GLUT-1 AS-ODNs reduced the tumor size significantly compared with tumors treated with 10 Gy X-ray radiation only (P<0.05).	('Ly294002', 'Chemical', 'MESH:C085911', (51, 59))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('Ly294002', 'Var', (29, 37))	('tumors', 'Disease', 'MESH:D009369', (167, 173))	('AS-ODNs', 'Chemical', '-', (72, 79))	('wortmannin', 'Chemical', 'MESH:D000077191', (39, 49))	('tumor', 'Disease', (167, 172))	('wortmannin', 'Chemical', 'MESH:D000077191', (85, 95))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('tumor', 'Disease', (128, 133))	('AS-ODNs', 'Chemical', '-', (108, 115))	('Ly294002 plus GLUT-1 AS-ODNs', 'Disease', (51, 79))	('tumors', 'Phenotype', 'HP:0002664', (167, 173))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('Ly294002 plus GLUT-1 AS-ODNs', 'Disease', 'MESH:C536830', (51, 79))	('Ly294002', 'Chemical', 'MESH:C085911', (29, 37))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('reduced', 'NegReg', (116, 123))	('tumors', 'Disease', (167, 173))
476443	31105886	In our recent study using Hep-2 and Tu212 laryngeal carcinoma cells, 10 Gy X-ray radiation decreased the weight of Hep-2 and Tu212 xenografts, while GLUT-1 AS-ODNs decreased the weight of Tu212 xenografts only.	('carcinoma', 'Phenotype', 'HP:0030731', (52, 61))	('Tu212', 'CellLine', 'CVCL:4915', (188, 193))	('Hep-2', 'CellLine', 'CVCL:1906', (26, 31))	('Tu212', 'Var', (125, 130))	('AS-ODNs', 'Chemical', '-', (156, 163))	('weight', 'MPA', (105, 111))	('laryngeal carcinoma', 'Disease', (42, 61))	('Tu212', 'CellLine', 'CVCL:4915', (125, 130))	('laryngeal carcinoma', 'Disease', 'MESH:D007827', (42, 61))	('laryngeal carcinoma', 'Phenotype', 'HP:0012118', (42, 61))	('Hep-2', 'CellLine', 'CVCL:1906', (115, 120))	('Tu212', 'CellLine', 'CVCL:4915', (36, 41))	('decreased', 'NegReg', (91, 100))
476464	31105886	found that GLUT-1 was highly expressed in 142 patients with oral squamous cell carcinoma, while GLUT-3 was highly expressed in 21.1% of these patients, and high protein expression of GLUT-1 and GLUT-3 was associated with poor prognosis.	('GLUT-1', 'Gene', (11, 17))	('patients', 'Species', '9606', (46, 54))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (65, 88))	('GLUT-3', 'Gene', '6515', (194, 200))	('GLUT-3', 'Gene', (194, 200))	('oral squamous cell carcinoma', 'Disease', (60, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('patients', 'Species', '9606', (142, 150))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (60, 88))	('GLUT-3', 'Gene', '6515', (96, 102))	('high', 'Var', (156, 160))	('GLUT-3', 'Gene', (96, 102))
476476	31105886	(2013) detected a rate of GLUT-1 positivity of 66.7% in 188 patients with PTC who underwent 18F-FDG-PET/CT examination.	('patients', 'Species', '9606', (60, 68))	('PET', 'Gene', '22095', (100, 103))	('18F-FDG', 'Chemical', '-', (92, 99))	('GLUT-1', 'Gene', (26, 32))	('positivity', 'Var', (33, 43))	('PET', 'Gene', (100, 103))
476498	31105886	Studies have shown that the disruption of HK-VDAC can lead to apoptosis via the PI3K/Akt signaling pathway.	('lead to', 'Reg', (54, 61))	('HK', 'Gene', '3098', (42, 44))	('Akt', 'Gene', '207', (85, 88))	('disruption', 'Var', (28, 38))	('apoptosis', 'CPA', (62, 71))	('Akt', 'Gene', (85, 88))
476524	31105886	They found that the median survival of 21 patients with high HK-II expression was 62.29 months, and that of 20 patients with low HK-II expression was 93.60 months.	('patients', 'Species', '9606', (42, 50))	('patients', 'Species', '9606', (111, 119))	('high HK-II expression', 'Var', (56, 77))	('expression', 'Var', (67, 77))
476525	31105886	It was also found that inhibition of HK-II expression enhanced the radiosensitivity of nasopharyngeal carcinoma.	('nasopharyngeal carcinoma', 'Disease', 'MESH:D000077274', (87, 111))	('inhibition', 'Var', (23, 33))	('nasopharyngeal carcinoma', 'Disease', (87, 111))	('HK-II expression', 'Protein', (37, 53))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (87, 111))	('radiosensitivity', 'CPA', (67, 83))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('enhanced', 'PosReg', (54, 62))
476558	31105886	In vitro, they found that knockdown of LDHA can reduce FDG uptake, GLUT-1 expression, and cell proliferation.	('expression', 'MPA', (74, 84))	('FDG uptake', 'CPA', (55, 65))	('FDG', 'Chemical', 'MESH:D019788', (55, 58))	('cell proliferation', 'CPA', (90, 108))	('knockdown', 'Var', (26, 35))	('reduce', 'NegReg', (48, 54))	('LDHA', 'Gene', (39, 43))	('GLUT-1', 'Protein', (67, 73))	('LDHA', 'Gene', '3939', (39, 43))
476582	31105886	As mentioned above, the development, metastasis, and poor prognosis of some malignant tumors were correlated with abnormal expression of GLUT-1 and HK-II.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('malignant tumors', 'Disease', 'MESH:D018198', (76, 92))	('expression', 'MPA', (123, 133))	('abnormal', 'Var', (114, 122))	('metastasis', 'CPA', (37, 47))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('correlated', 'Reg', (98, 108))	('poor prognosis', 'CPA', (53, 67))	('development', 'CPA', (24, 35))	('HK-II', 'Gene', (148, 153))	('GLUT-1', 'Gene', (137, 143))	('malignant tumors', 'Disease', (76, 92))
476584	31105886	Our previous studies found that high expression of GLUT-1 was associated with radioresistance in laryngeal carcinoma, and that inhibition of GLUT-1 expression by antisense oligodeoxynucleotides (AS-ODNs) may improve the radiosensitivity of laryngeal carcinoma, in vitro and in vivo.	('improve', 'PosReg', (208, 215))	('high', 'Var', (32, 36))	('oligodeoxynucleotides', 'Chemical', 'MESH:D009838', (172, 193))	('GLUT-1', 'Gene', (51, 57))	('laryngeal carcinoma', 'Phenotype', 'HP:0012118', (240, 259))	('laryngeal carcinoma', 'Phenotype', 'HP:0012118', (97, 116))	('associated', 'Reg', (62, 72))	('laryngeal carcinoma', 'Disease', 'MESH:D007827', (240, 259))	('radiosensitivity', 'CPA', (220, 236))	('GLUT-1', 'Gene', (141, 147))	('laryngeal carcinoma', 'Disease', 'MESH:D007827', (97, 116))	('radioresistance', 'CPA', (78, 93))	('inhibition', 'Var', (127, 137))	('expression', 'MPA', (37, 47))	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('carcinoma', 'Phenotype', 'HP:0030731', (250, 259))	('laryngeal carcinoma', 'Disease', (240, 259))	('AS-ODNs', 'Chemical', '-', (195, 202))	('laryngeal carcinoma', 'Disease', (97, 116))
476594	31105886	Inhibition of HK-II expression alone did not improve the sensitivity to radiotherapy and chemotherapy in laryngeal carcinoma cells, while co-inhibition of INPP4B and HK-II did.	('laryngeal carcinoma', 'Disease', (105, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('laryngeal carcinoma', 'Disease', 'MESH:D007827', (105, 124))	('laryngeal carcinoma', 'Phenotype', 'HP:0012118', (105, 124))	('INPP4B', 'Gene', '8821', (155, 161))	('HK-II', 'Protein', (14, 19))	('Inhibition', 'Var', (0, 10))	('INPP4B', 'Gene', (155, 161))	('sensitivity', 'MPA', (57, 68))
476598	31105886	GLUT-1 Glucose transporter 1 HK-II hexokinase-II HIF-1alpha hypoxia inducible factor-1alpha CA-IX carbonic anhydrase-IX VDAC voltage dependent anion channel PET protein, positron emission computed tomography LDHA lactate dehydrogenase AS-ODN antisense oligodeoxynucleotides 3-BrPA 3-bromo pyruvate INPP4B Inositol polyphosphate 4-phosphatase)	('lactate dehydrogenase', 'Gene', (213, 234))	('LDHA', 'Gene', (208, 212))	('INPP4B', 'Gene', (298, 304))	('CA-IX', 'Gene', (92, 97))	('hexokinase', 'Gene', (35, 45))	('antisense', 'Var', (242, 251))	('Glucose', 'Chemical', 'MESH:D005947', (7, 14))	('HIF-1alpha', 'Gene', '3091', (49, 59))	('hypoxia inducible factor-1alpha', 'Gene', '3091', (60, 91))	('hypoxia inducible factor-1alpha', 'Gene', (60, 91))	('3-BrPA', 'Chemical', '-', (274, 280))	('carbonic anhydrase-IX', 'Gene', '768', (98, 119))	('PET', 'Gene', '22095', (157, 160))	('hexokinase', 'Gene', '3098', (35, 45))	('CA-IX', 'Gene', '768', (92, 97))	('LDHA', 'Gene', '3939', (208, 212))	('HIF-1alpha', 'Gene', (49, 59))	('lactate dehydrogenase', 'Gene', '3939', (213, 234))	('PET', 'Gene', (157, 160))	('3-bromo pyruvate', 'Chemical', 'MESH:C017092', (281, 297))	('oligodeoxynucleotides', 'Chemical', 'MESH:D009838', (252, 273))	('carbonic anhydrase-IX', 'Gene', (98, 119))	('INPP4B', 'Gene', '8821', (298, 304))
476729	30262507	Therefore, we chose to test the MAGE-A in a similar autochthonous tumor model in which Braf V600E expression and PTEN loss are driven by Cre activation in melanocytes of the skin by tamoxifen induction (Tyr::CreER; BrafCA/+;Ptenlox/lox mice).	('lox', 'Gene', '16948', (228, 231))	('Braf', 'Gene', (215, 219))	('loss', 'NegReg', (118, 122))	('melanocytes of the skin', 'Phenotype', 'HP:0002861', (155, 178))	('lox', 'Gene', (228, 231))	('Braf', 'Gene', (87, 91))	('mice', 'Species', '10090', (236, 240))	('tumor', 'Disease', (66, 71))	('PTEN', 'Gene', (113, 117))	('tamoxifen', 'Chemical', 'MESH:D013629', (182, 191))	('V600E', 'Var', (92, 97))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('Cre', 'CPA', (137, 140))	('lox', 'Gene', '16948', (232, 235))	('Braf', 'Gene', '109880', (215, 219))	('Braf', 'Gene', '109880', (87, 91))	('V600E', 'SUBSTITUTION', 'None', (92, 97))	('lox', 'Gene', (232, 235))	('activation', 'PosReg', (141, 151))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('PTEN', 'Gene', '19211', (113, 117))	('Tyr', 'Chemical', 'MESH:C042696', (203, 206))
476748	30262507	The MAGE-A Consensus #1 vaccine generates cross-reactive immune responses against MAGE-A2, MAGE-A3, MAGE-A6 and MAGE-A12.	('A12', 'Gene', '28887', (117, 120))	('rat', 'Species', '10116', (36, 39))	('MAGE-A2', 'Gene', (82, 89))	('A12', 'Gene', (117, 120))	('MAGE-A6', 'Var', (100, 107))
476754	30262507	The reason for this independent regulation is not clear, nor is our understanding of the individual regulation; however, this family of antigens is thought to be silenced by promoter methylation in normal human tissues.	('human', 'Species', '9606', (205, 210))	('promoter methylation', 'Var', (174, 194))	('silenced', 'NegReg', (162, 170))
476755	30262507	This methylation is removed in tumor cells due to epigenetic re-programming.	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumor', 'Disease', (31, 36))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('epigenetic re-programming', 'Var', (50, 75))
476793	29769535	To explore the correlation between allele frequency of somatic variants and total gene expression of their harboring gene, we used the unique data set of matched tumor and normal RNA and DNA sequencing data of 5523 distinct single nucleotide variants in 381 individuals across 10 cancer types obtained from The Cancer Genome Atlas (TCGA).	('cancer', 'Disease', 'MESH:D009369', (280, 286))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('Cancer Genome Atlas', 'Disease', (311, 330))	('single nucleotide variants', 'Var', (224, 250))	('variants', 'Var', (63, 71))	('Cancer', 'Phenotype', 'HP:0002664', (311, 317))	('cancer', 'Disease', (280, 286))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (311, 330))	('tumor', 'Disease', (162, 167))	('cancer', 'Phenotype', 'HP:0002664', (280, 286))	('tumor', 'Disease', 'MESH:D009369', (162, 167))
476794	29769535	We documented higher allele frequency of somatic variants in cancer-implicated genes (Cancer Gene Census, CGC).	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('variants', 'Var', (49, 57))	('cancer', 'Disease', (61, 67))	('Cancer', 'Phenotype', 'HP:0002664', (86, 92))	('Cancer', 'Disease', (86, 92))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('Cancer', 'Disease', 'MESH:D009369', (86, 92))	('higher', 'PosReg', (14, 20))
476797	29769535	All together, our analyses suggest that high allele frequency of tumor somatic variants can indicate driving functionality and can serve to identify potential cancer-implicated genes.	('driving', 'MPA', (101, 108))	('cancer', 'Disease', (159, 165))	('tumor', 'Disease', (65, 70))	('variants', 'Var', (79, 87))	('indicate', 'Reg', (92, 100))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
476798	29769535	Both types of effects are likely to impact the abundance of the variant-bearing allele in the tumor transcriptome.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('impact', 'Reg', (36, 42))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Disease', (94, 99))	('abundance', 'MPA', (47, 56))	('effects', 'Var', (14, 21))
476800	29769535	Single nucleotide variations (SNVs) comprise a major fraction of the somatic alterations in the tumor genome and are a significant contributor to the tumor cell phenotype and functionality.	('Single nucleotide variations', 'Var', (0, 28))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumor', 'Disease', (96, 101))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('tumor', 'Disease', (150, 155))
476801	29769535	Imbalanced somatic allele prevalence can both cause and result from altered cellular functioning and can thereby play a substantial role in cancer initiation and progression.	('Imbalanced', 'Var', (0, 10))	('role', 'Reg', (132, 136))	('cellular functioning', 'CPA', (76, 96))	('play', 'Reg', (113, 117))	('cancer initiation', 'Disease', 'MESH:D009369', (140, 157))	('result', 'Reg', (56, 62))	('cause', 'Reg', (46, 51))	('cancer initiation', 'Disease', (140, 157))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('altered', 'Reg', (68, 75))
476802	29769535	Indeed, asymmetrically expressed alleles are reported to play a role in variety of cancer types, including blood, breast, ovarian, and lung cancer.	('play', 'Reg', (57, 61))	('lung cancer', 'Phenotype', 'HP:0100526', (135, 146))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('blood', 'Disease', (107, 112))	('cancer', 'Disease', (140, 146))	('breast', 'Disease', (114, 120))	('ovarian', 'Disease', (122, 129))	('role', 'Reg', (64, 68))	('lung cancer', 'Disease', 'MESH:D008175', (135, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('lung cancer', 'Disease', (135, 146))	('cancer', 'Disease', (83, 89))	('asymmetrically expressed alleles', 'Var', (8, 40))
476805	29769535	Among them, of ultimate importance is the corresponding DNA's allele content, which reflects both copy number alterations (CNAs) and admixture with non-tumor genomes.	('non-tumor', 'Disease', (148, 157))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('non-tumor', 'Disease', 'MESH:D009369', (148, 157))	('copy number alterations', 'Var', (98, 121))
476808	29769535	Herein, we report the results from the analysis on the allele-specific and total gene expression of somatic variants across 10 cancer types obtained through The Cancer Genome Atlas (TCGA): Urothelial Bladder Carcinoma (BLCA), Breast Invasive Carcinoma (BRCA), Head and Neck Squamous Cell Carcinoma (HNSC), Kidney Renal Clear Cell Carcinoma (KIRC), Liver Hepatocellular Carcinoma (LIHC), Lung Adenocarcinoma (LUAD), Lung Squamous Cell Carcinoma (LUSC), Prostate Adenocarcinoma (PRAD), Thyroid Carcinoma (THCA), and Uterine Corpus Endometrial Carcinoma (UCEC).	('Hepatocellular Carcinoma', 'Phenotype', 'HP:0001402', (354, 378))	('Lung Squamous Cell Carcinoma', 'Phenotype', 'HP:0030359', (415, 443))	('Cancer Genome Atlas', 'Disease', (161, 180))	('Neck Squamous Cell Carcinoma (HNSC), Kidney Renal Clear Cell Carcinoma', 'Disease', 'MESH:C538614', (269, 339))	('Urothelial Bladder Carcinoma', 'Disease', (189, 217))	('Cancer', 'Phenotype', 'HP:0002664', (161, 167))	('Liver Hepatocellular Carcinoma (LIHC), Lung Adenocarcinoma (LUAD), Lung Squamous Cell Carcinoma', 'Disease', 'MESH:D000077192', (348, 443))	('Carcinoma', 'Phenotype', 'HP:0030731', (330, 339))	('cancer', 'Disease', (127, 133))	('Carcinoma', 'Phenotype', 'HP:0030731', (369, 378))	('Carcinoma', 'Phenotype', 'HP:0030731', (242, 251))	('Corpus Endometrial Carcinoma', 'Disease', 'MESH:D016889', (522, 550))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('Prostate Adenocarcinoma (PRAD), Thyroid Carcinoma', 'Disease', 'MESH:D000230', (452, 501))	('Endometrial Carcinoma', 'Phenotype', 'HP:0012114', (529, 550))	('Breast Invasive Carcinoma', 'Phenotype', 'HP:0003002', (226, 251))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (420, 443))	('Thyroid Carcinoma', 'Phenotype', 'HP:0002890', (484, 501))	('Head and Neck Squamous Cell Carcinoma', 'Phenotype', 'HP:0012288', (260, 297))	('Breast Invasive Carcinoma', 'Disease', 'MESH:D018270', (226, 251))	('Carcinoma', 'Phenotype', 'HP:0030731', (208, 217))	('Bladder Carcinoma', 'Phenotype', 'HP:0002862', (200, 217))	('Urothelial Bladder Carcinoma', 'Disease', 'MESH:D001749', (189, 217))	('Carcinoma', 'Phenotype', 'HP:0030731', (288, 297))	('variants', 'Var', (108, 116))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('Corpus Endometrial Carcinoma', 'Disease', (522, 550))	('Lung Adenocarcinoma', 'Phenotype', 'HP:0030078', (387, 406))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (161, 180))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (274, 297))	('Breast Invasive Carcinoma', 'Disease', (226, 251))
476815	29769535	Across the ten cancer types, we called 350 SOM-E variants (6.3% of all variants) and 1044 (18.9%) as SOM-L (Fig.	('variants', 'Var', (71, 79))	('SOM', 'Gene', '57822', (43, 46))	('variants', 'Var', (49, 57))	('cancer', 'Disease', (15, 21))	('cancer', 'Disease', 'MESH:D009369', (15, 21))	('SOM', 'Gene', (101, 104))	('SOM', 'Gene', (43, 46))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('SOM', 'Gene', '57822', (101, 104))
476817	29769535	The highest proportion of SOM-E variants was observed in HNSC (consistent with another study exploring HNSC samples from TCGA), LUSC, and BLCA.	('HNSC', 'Disease', (57, 61))	('variants', 'Var', (32, 40))	('SOM', 'Gene', '57822', (26, 29))	('SOM', 'Gene', (26, 29))
476822	29769535	In the presented below results, we used VR:D to correlate with: (1) functional features of the mutation, including predicted effects on the protein, (2) position in genes that have been causally implicated in cancer, as defined by the CGC, (3) total gene expression, and, (4) location in transcription factor binding sites (TFBS).	('protein', 'Protein', (140, 147))	('TFBS', 'Chemical', '-', (324, 328))	('effects', 'Reg', (125, 132))	('cancer', 'Disease', 'MESH:D009369', (209, 215))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))	('cancer', 'Disease', (209, 215))	('mutation', 'Var', (95, 103))
476823	29769535	We next assessed the distribution of the tumor VR:D across the different categories of somatic mutations with regards to their predicted effect on the protein: stop-codon generating (premature terminating variants, PTV), missense, and silent.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Disease', (41, 46))	('silent', 'Var', (235, 241))	('missense', 'Var', (221, 229))	('tumor', 'Disease', 'MESH:D009369', (41, 46))
476824	29769535	The difference presented both as lower average VR:D, and higher proportion of mutations that are not expressed at all (SOM-L).	('SOM', 'Gene', '57822', (119, 122))	('VR:D', 'MPA', (47, 51))	('mutations', 'Var', (78, 87))	('SOM', 'Gene', (119, 122))	('lower', 'NegReg', (33, 38))
476825	29769535	2c), with higher average allele frequency, and a lower proportion of SOM-L variants (See Fig.	('SOM', 'Gene', '57822', (69, 72))	('lower', 'NegReg', (49, 54))	('variants', 'Var', (75, 83))	('SOM', 'Gene', (69, 72))
476828	29769535	1a), where PTVs showed higher VR:D and lower proportion of SOM-L variants in the CGC genes.	('SOM', 'Gene', (59, 62))	('variants', 'Var', (65, 73))	('CGC', 'Gene', (81, 84))	('higher', 'PosReg', (23, 29))	('SOM', 'Gene', '57822', (59, 62))	('lower', 'NegReg', (39, 44))
476836	29769535	To do that, we selected variants with VR:D > 2, (indicating at least 2-fold higher expressed allele frequency (VAFtRNA), as compared to the DNA allele frequency (VAFtDNA)), and at least a two-fold increase or decrease in the total gene expression in the tumor as compared to the normal tissue.	('expressed allele frequency', 'MPA', (83, 109))	('tumor', 'Disease', (254, 259))	('variants', 'Var', (24, 32))	('increase', 'PosReg', (197, 205))	('decrease', 'NegReg', (209, 217))	('total gene expression', 'MPA', (225, 246))	('VR:D > 2', 'Var', (38, 46))	('tumor', 'Disease', 'MESH:D009369', (254, 259))	('higher', 'PosReg', (76, 82))	('tumor', 'Phenotype', 'HP:0002664', (254, 259))
476838	29769535	To accomplish this, we assessed the variant and the reference motifs for TFBS using TRANSFAC, and then categorized the variants in the following three groups: generating a new TFBS (TFBS-gain, 2736 variants), destroying an existing TFBS (TFBS-loss, 1980 variants), and not changing a known motif (Supplementary Table 7).	('TFBS-loss', 'Disease', 'MESH:D015431', (238, 247))	('TFBS', 'Chemical', '-', (73, 77))	('TFBS', 'Chemical', '-', (176, 180))	('TFBS', 'Chemical', '-', (238, 242))	('TFBS-loss', 'Disease', (238, 247))	('TFBS', 'Chemical', '-', (232, 236))	('TFBS', 'Chemical', '-', (182, 186))	('destroying', 'NegReg', (209, 219))	('TFBS-gain', 'Disease', 'MESH:D015430', (182, 191))	('variants', 'Var', (119, 127))	('TFBS-gain', 'Disease', (182, 191))
476840	29769535	6a), however, in the TFBS-loss variants we detected a positive correlation with the gene expression levels (rs = 0.31, p = 0.03).	('TFBS-loss', 'Disease', 'MESH:D015431', (21, 30))	('TFBS-loss', 'Disease', (21, 30))	('gene expression levels', 'MPA', (84, 106))	('variants', 'Var', (31, 39))
476850	29769535	From this gene-set, three NMD-sensitive genes had multiple NMD-elicit PTVs with VR:D values similar or higher to the VR:D values of missense and silent mutations in the same gene: ARID1, TP53, and NSD1 (all of them CGC genes).	('TP53', 'Gene', '7157', (187, 191))	('NSD1', 'Gene', '64324', (197, 201))	('missense', 'Var', (132, 140))	('TP53', 'Gene', (187, 191))	('higher', 'PosReg', (103, 109))	('ARID1', 'Gene', (180, 185))	('NSD1', 'Gene', (197, 201))
476851	29769535	The CGC genes with lowest mean VR:D based on 3 and more mutations were the protein tyrosine phosphatases PTPRB and PTPRC, and FGFR1.	('mutations', 'Var', (56, 65))	('PTPRB', 'Gene', '5787', (105, 110))	('FGFR1', 'Gene', (126, 131))	('PTPRC', 'Gene', (115, 120))	('PTPRB', 'Gene', (105, 110))	('FGFR1', 'Gene', '2260', (126, 131))	('CGC', 'Gene', (4, 7))
476859	29769535	Alternatively, the mutant transcripts could be favored by the tumor cell due to a growth or a survival advantage provided by the mutation.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('mutation', 'Var', (129, 137))	('tumor', 'Disease', (62, 67))	('survival advantage', 'CPA', (94, 112))	('mutant', 'Var', (19, 25))	('favored', 'PosReg', (47, 54))	('growth', 'CPA', (82, 88))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
476860	29769535	Both scenarios infer functionality and/or tumorigenic potential, which are frequent features of mutations in tumor suppressors and oncogenes, and hence concur with the observed allele behavior in the CGC subset.	('tumor', 'Disease', (42, 47))	('infer', 'Reg', (15, 20))	('functionality', 'CPA', (21, 34))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('mutations', 'Var', (96, 105))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('tumor', 'Disease', (109, 114))
476863	29769535	All these studies illustrate the general tendency of the cancer transcriptome to favor advantage supplying variants, which are ultimately those with higher functionality and pathogenic potential.	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('cancer', 'Disease', (57, 63))	('variants', 'Var', (107, 115))	('advantage supplying', 'PosReg', (87, 106))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))
476873	29769535	While hg38 arguably supplies higher annotation accuracy, it is still in the process of assimilation into the genome-studying research community, and most of the major NMD studies so far have used hg19, which can partially account for the differences between these studies and our own.	('hg19', 'Var', (196, 200))	('hg38', 'Gene', (6, 10))	('hg38', 'Gene', '8549', (6, 10))	('annotation', 'MPA', (36, 46))
476875	29769535	Importantly, ranking of genes based on somatic allele frequency scores key cancer genes at top positions, and thus suggests that high somatic allele frequency can be used to indicate potential carcinogenic variants, and possibly, to identify cancer-driving genes.	('carcinogenic', 'Disease', (193, 205))	('variants', 'Var', (206, 214))	('cancer', 'Disease', (242, 248))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('cancer', 'Disease', 'MESH:D009369', (242, 248))	('cancer', 'Disease', (75, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('cancer', 'Phenotype', 'HP:0002664', (242, 248))	('carcinogenic', 'Disease', 'MESH:D063646', (193, 205))
476876	29769535	To systematically quantify somatic allele prevalence, we compiled data on single nucleotide somatic variants from The Cancer Genome Atlas (TCGA) for patients for whom the following sequencing datasets were available: normal exome (Nex), normal transcriptome (Ntr), tumor exome (Tex), and tumor transcriptome (Ttr).	('tumor', 'Disease', (288, 293))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (118, 137))	('patients', 'Species', '9606', (149, 157))	('tumor', 'Phenotype', 'HP:0002664', (265, 270))	('variants', 'Var', (100, 108))	('tumor', 'Disease', (265, 270))	('tumor', 'Disease', 'MESH:D009369', (265, 270))	('normal exome', 'MPA', (217, 229))	('tumor', 'Disease', 'MESH:D009369', (288, 293))	('tumor', 'Phenotype', 'HP:0002664', (288, 293))	('normal transcriptome', 'MPA', (237, 257))	('Cancer Genome Atlas', 'Disease', (118, 137))	('Cancer', 'Phenotype', 'HP:0002664', (118, 124))
476884	29769535	Over-expression of somatic mutations (SOM-E status) was defined as prevalence of variant sequencing reads in the transcriptome (VAFtRNA ~ 1), while SOM-L was defined by complete loss of the mutant allele in the transcriptome (VAFtRNA ~ 0).	('SOM', 'Gene', (38, 41))	('SOM', 'Gene', (148, 151))	('SOM', 'Gene', '57822', (38, 41))	('SOM', 'Gene', '57822', (148, 151))	('variant sequencing reads', 'Var', (81, 105))
477197	31228215	Several fluorescein-labeled protein bands were observed in CHL1 transfectant HEK293 cells but not in mock cells (Figure 3F, middle panel).	('fluorescein-labeled protein', 'MPA', (8, 35))	('HEK293', 'CellLine', 'CVCL:0045', (77, 83))	('transfectant', 'Var', (64, 76))	('observed', 'Reg', (47, 55))	('fluorescein', 'Chemical', 'MESH:D019793', (8, 19))	('CHL1', 'Gene', (59, 63))
477211	31228215	As shown in Figure S5A, double administration (CHL1 + PD173074, CHL1 + BTT3033 or PD173074 + BTT3033) was moderately effective (approximately 30% average inhibition), in contrast to single administration (approximately 10% average inhibition) for LK2 cells at Day 2.	('rat', 'Species', '10116', (110, 113))	('PD173074', 'Chemical', 'MESH:C115711', (54, 62))	('PD173074 + BTT3033', 'Var', (82, 100))	('rat', 'Species', '10116', (197, 200))	('PD173074', 'Chemical', 'MESH:C115711', (82, 90))	('BTT3033', 'Chemical', '-', (93, 100))	('LK2', 'CellLine', 'CVCL:1377', (247, 250))	('CHL1', 'Var', (47, 51))	('CHL1 + BTT3033', 'Var', (64, 78))	('rat', 'Species', '10116', (39, 42))	('BTT3033', 'Chemical', '-', (71, 78))
477228	31228215	In contrast, the upper bands were clearly reduced in only double administration samples (CHL1 + PD173074, CHL1 + BTT3033 or PD173074 + BTT3033) compared with the control and other single administration samples, despite equal amounts of loaded samples.	('reduced', 'NegReg', (42, 49))	('CHL1 + PD173074', 'Var', (89, 104))	('CHL1 + BTT3033', 'Var', (106, 120))	('PD173074', 'Chemical', 'MESH:C115711', (96, 104))	('BTT3033', 'Chemical', '-', (113, 120))	('PD173074 + BTT3033', 'Var', (124, 142))	('BTT3033', 'Chemical', '-', (135, 142))	('upper bands', 'MPA', (17, 28))	('rat', 'Species', '10116', (195, 198))	('PD173074', 'Chemical', 'MESH:C115711', (124, 132))	('rat', 'Species', '10116', (73, 76))
477229	31228215	As with CHL1, FGFR3 was detected as 2 bands and was reduced in both CHL1 + BTT3033 and PD173074 + BTT3033 double administration samples (Figure 6C "FGFR3").	('reduced', 'NegReg', (52, 59))	('CHL1 + BTT3033', 'Var', (68, 82))	('PD173074 + BTT3033 double', 'Var', (87, 112))	('BTT3033', 'Chemical', '-', (75, 82))	('FGFR3', 'Gene', (14, 19))	('PD173074', 'Chemical', 'MESH:C115711', (87, 95))	('BTT3033', 'Chemical', '-', (98, 105))	('rat', 'Species', '10116', (121, 124))
477231	31228215	The slight alterations of phosphorylation in FGFR3 were observed in double administration samples (CHL 1 + PD 173074, CHL 1 + BTT 3033 or PD 173074 + BTT 3033) (Figure 6D).	('PD 173074 + BTT 3033', 'Var', (138, 158))	('rat', 'Species', '10116', (83, 86))	('rat', 'Species', '10116', (15, 18))	('CHL 1', 'Gene', (118, 123))	('BTT', 'Chemical', '-', (150, 153))	('CHL 1', 'Gene', (99, 104))	('BTT', 'Chemical', '-', (126, 129))	('CHL 1', 'Gene', '10752', (118, 123))	('FGFR3', 'Gene', (45, 50))	('alterations', 'Reg', (11, 22))	('CHL 1', 'Gene', '10752', (99, 104))	('phosphorylation', 'MPA', (26, 41))
477279	29916534	The downregulation of miR-140-5p has also been shown to be associated with tumor stage and lymph node metastasis, and the restoration of miR-140-5p inhibits cell migration and invasion in HPSCC by targeting ADAM metallopeptidase (ADAM10), which is involved in the Notch1 signaling pathway.	('targeting', 'Reg', (197, 206))	('cell migration', 'CPA', (157, 171))	('HPSCC', 'Phenotype', 'HP:0012182', (188, 193))	('tumor', 'Disease', (75, 80))	('miR-140', 'Gene', (137, 144))	('Notch1', 'Gene', (264, 270))	('inhibits', 'NegReg', (148, 156))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('miR-140', 'Gene', '406932', (137, 144))	('HPSCC', 'Disease', (188, 193))	('ADAM10', 'Gene', (230, 236))	('Notch1', 'Gene', '4851', (264, 270))	('restoration', 'Var', (122, 133))	('ADAM10', 'Gene', '102', (230, 236))	('downregulation', 'NegReg', (4, 18))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('miR-140', 'Gene', (22, 29))	('miR-140', 'Gene', '406932', (22, 29))	('lymph node metastasis', 'CPA', (91, 112))
477280	29916534	The expression of AB209630, a long non-coding RNA, has been shown to be markedly lower in HPSCC cell lines and tumor tissues compared with the normal cells and tissues, and functions as a tumor suppressor in HPSCC.	('tumor', 'Disease', (188, 193))	('HPSCC', 'Phenotype', 'HP:0012182', (90, 95))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('lower', 'NegReg', (81, 86))	('HPSCC', 'Disease', (90, 95))	('HPSCC', 'Disease', (208, 213))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('HPSCC', 'Phenotype', 'HP:0012182', (208, 213))	('expression', 'MPA', (4, 14))	('tumor', 'Disease', (111, 116))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('AB209630', 'Var', (18, 26))
477281	29916534	In addition, abnormal methylation is associated with tumorigenesis in HSPCC.	('associated with', 'Reg', (37, 52))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('methylation', 'MPA', (22, 33))	('HSPCC', 'Disease', (70, 75))	('tumor', 'Disease', (53, 58))	('abnormal', 'Var', (13, 21))
477307	29916534	The most enriched 'molecular functions' of the DEGs were carbon-sulfur lyase activity (GO, 0016846), phosphotransferase activity, for other substituted phosphate groups (GO, 0016780) and CDP-alcohol phosphatidyltransferase activity (GO, 0017169).	('carbon-sulfur lyase', 'Enzyme', (57, 76))	('GO', 'Var', (170, 172))	('CDP-alcohol phosphatidyltransferase', 'Enzyme', (187, 222))	('phosphotransferase', 'Enzyme', (101, 119))	('activity', 'MPA', (223, 231))	('phosphate', 'Chemical', 'MESH:D010710', (152, 161))	('mole', 'Phenotype', 'HP:0003764', (19, 23))	('activity', 'MPA', (77, 85))	('activity', 'MPA', (120, 128))	('alcohol', 'Chemical', 'MESH:D000438', (191, 198))	('GO', 'Var', (87, 89))
477353	29916534	Additionally, this study demonstrated that CSDE1 is under the regulation of hsa-miR-497-5p and hsa-miR-125b-5p (Table VI).	('CSDE1', 'Gene', '7812', (43, 48))	('hsa-miR-125b-5p', 'Var', (95, 110))	('CSDE1', 'Gene', (43, 48))
477354	29916534	The expression of hsa-miR-497-5p has been reported to be significantly decreased in triple-negative breast cancer and to be negatively associated with survival in oropharyngeal squamous cell carcinoma.	('negatively', 'NegReg', (124, 134))	('hsa-miR-497-5p', 'Var', (18, 32))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (177, 200))	('expression', 'MPA', (4, 14))	('carcinoma', 'Phenotype', 'HP:0030731', (191, 200))	('associated', 'Reg', (135, 145))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (177, 200))	('breast cancer', 'Disease', 'MESH:D001943', (100, 113))	('breast cancer', 'Phenotype', 'HP:0003002', (100, 113))	('oropharyngeal squamous cell carcinoma', 'Phenotype', 'HP:0012182', (163, 200))	('squamous cell carcinoma', 'Disease', (177, 200))	('breast cancer', 'Disease', (100, 113))	('decreased', 'NegReg', (71, 80))
477356	29916534	The overexpression of hsa-miR-125b-5p has been shown to inhibit cell proliferation, migration and invasion in esophageal squamous cell carcinoma.	('cell proliferation', 'CPA', (64, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('invasion', 'CPA', (98, 106))	('migration', 'CPA', (84, 93))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (110, 144))	('hsa-miR-125b-5p', 'Var', (22, 37))	('overexpression', 'PosReg', (4, 18))	('esophageal squamous cell carcinoma', 'Disease', (110, 144))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (121, 144))	('inhibit', 'NegReg', (56, 63))
477357	29916534	The underlying molecular mechanism of CSDE1 under the regulation of hsa-miR-497-5p and hsa-miR-125b-5p in HPSCC need to be elaborated in future studies.	('CSDE1', 'Gene', (38, 43))	('CSDE1', 'Gene', '7812', (38, 43))	('mole', 'Phenotype', 'HP:0003764', (15, 19))	('hsa-miR-125b-5p', 'Var', (87, 102))	('HPSCC', 'Phenotype', 'HP:0012182', (106, 111))
477358	29916534	hsa-miR-15a-5p, hsa-miR-2278 and hsa-miR-125a-5p were the top 3 downregulated miRNAs in HPSCC.	('miR-15a', 'Gene', (4, 11))	('HPSCC', 'Phenotype', 'HP:0012182', (88, 93))	('HPSCC', 'Disease', (88, 93))	('hsa-miR-125a-5p', 'Var', (33, 48))	('miR-15a', 'Gene', '406948', (4, 11))	('downregulated', 'NegReg', (64, 77))
477361	29916534	hsa-miR-136-5p has been shown to be significantly upregulated in osteosarcoma and colorectal adenocarcinoma.	('upregulated', 'PosReg', (50, 61))	('colorectal adenocarcinoma', 'Disease', (82, 107))	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (82, 107))	('osteosarcoma', 'Phenotype', 'HP:0002669', (65, 77))	('osteosarcoma', 'Disease', (65, 77))	('osteosarcoma', 'Disease', 'MESH:D012516', (65, 77))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('hsa-miR-136-5p', 'Var', (0, 14))
477363	29916534	It has been confirmed that hsa-miR-143-5p inhibits the proliferation, invasion and migration of cervical cancer cells.	('inhibits', 'NegReg', (42, 50))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('hsa-miR-143-5p', 'Var', (27, 41))	('migration of cervical cancer', 'Disease', (83, 111))	('migration of cervical cancer', 'Disease', 'MESH:D002583', (83, 111))	('invasion', 'CPA', (70, 78))
477368	29916534	hsa-miR-125a-5p is known to act as a tumor suppressor and is downregulated in various malignant tumors, such as laryngeal carcinoma and verrucous carcinoma of the head and neck.	('hsa-miR-125a-5p', 'Var', (0, 15))	('laryngeal carcinoma', 'Disease', (112, 131))	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('downregulated', 'NegReg', (61, 74))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('laryngeal carcinoma', 'Disease', 'MESH:D007827', (112, 131))	('laryngeal carcinoma', 'Phenotype', 'HP:0012118', (112, 131))	('verrucous carcinoma', 'Disease', (136, 155))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('tumor', 'Disease', (96, 101))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('malignant tumors', 'Disease', (86, 102))	('verrucous carcinoma', 'Disease', 'MESH:D018289', (136, 155))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('malignant tumors', 'Disease', 'MESH:D018198', (86, 102))
477378	29620244	EGFR mutations subset in Chinese lung squamous cell carcinoma patients Research has identified that epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) possess large benefits for adenocarcinoma (ADC), although little benefit for squamous cell carcinoma (SCC).	('squamous cell carcinoma', 'Disease', (251, 274))	('adenocarcinoma', 'Disease', 'MESH:D000230', (201, 215))	('benefits', 'PosReg', (188, 196))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (33, 61))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (38, 61))	('EGFR', 'Gene', '1956', (134, 138))	('epidermal growth factor receptor', 'Gene', (100, 132))	('epidermal growth factor receptor', 'Gene', '1956', (100, 132))	('SCC', 'Phenotype', 'HP:0002860', (276, 279))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (251, 274))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (38, 61))	('lung squamous cell carcinoma', 'Disease', (33, 61))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (33, 61))	('carcinoma', 'Phenotype', 'HP:0030731', (206, 215))	('EGFR', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))	('adenocarcinoma', 'Disease', (201, 215))	('SCC', 'Gene', '6317', (276, 279))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (251, 274))	('carcinoma', 'Phenotype', 'HP:0030731', (52, 61))	('EGFR', 'Gene', (134, 138))	('SCC', 'Gene', (276, 279))	('EGFR', 'Gene', '1956', (0, 4))	('carcinoma', 'Phenotype', 'HP:0030731', (265, 274))
477379	29620244	The aim of the present study was to investigate the percentage of patients with SCC with the EGFR mutations subset and the benefits of EGFR TKIs in SCC.	('SCC', 'Gene', '6317', (80, 83))	('EGFR', 'Gene', '1956', (93, 97))	('EGFR', 'Gene', '1956', (135, 139))	('EGFR', 'Gene', (93, 97))	('mutations', 'Var', (98, 107))	('SCC', 'Gene', (148, 151))	('SCC', 'Phenotype', 'HP:0002860', (148, 151))	('EGFR', 'Gene', (135, 139))	('SCC', 'Gene', (80, 83))	('SCC', 'Phenotype', 'HP:0002860', (80, 83))	('SCC', 'Gene', '6317', (148, 151))	('patients', 'Species', '9606', (66, 74))
477382	29620244	A total of 94 out of 1,359 SCC patients were identified as having EGFR mutations, an EGFR mutation rate of 6.92%.	('SCC', 'Gene', (27, 30))	('EGFR', 'Gene', (85, 89))	('EGFR', 'Gene', '1956', (66, 70))	('EGFR', 'Gene', (66, 70))	('SCC', 'Phenotype', 'HP:0002860', (27, 30))	('SCC', 'Gene', '6317', (27, 30))	('mutations', 'Var', (71, 80))	('patients', 'Species', '9606', (31, 39))	('EGFR', 'Gene', '1956', (85, 89))
477383	29620244	The EGFR mutations subset in the 94 cases was identified as follows: 37.2% (35/94) in exon 19; 39.4% (37/94) in L858R; 5.3% (5/94) in T790M; 4.3% (4/94) in G719X; 2.1% (2/94) in L861Q; and 11.7% (11/94) in other mutations.	('L861Q', 'Var', (178, 183))	('L858R', 'Mutation', 'rs121434568', (112, 117))	('EGFR', 'Gene', (4, 8))	('T790M', 'Mutation', 'rs121434569', (134, 139))	('G719X', 'Var', (156, 161))	('L861Q', 'Mutation', 'rs121913444', (178, 183))	('T790M', 'Var', (134, 139))	('exon 19', 'Var', (86, 93))	('L858R', 'Var', (112, 117))	('G719X', 'Mutation', 'p.G719X', (156, 161))	('EGFR', 'Gene', '1956', (4, 8))
477385	29620244	In addition, the overall discordant rate of the EGFR mutations subset in SCC patients was relatively low.	('EGFR', 'Gene', '1956', (48, 52))	('SCC', 'Gene', (73, 76))	('EGFR', 'Gene', (48, 52))	('SCC', 'Phenotype', 'HP:0002860', (73, 76))	('mutations', 'Var', (53, 62))	('patients', 'Species', '9606', (77, 85))	('SCC', 'Gene', '6317', (73, 76))
477386	29620244	Due to the non-significant difference between TKI therapy and chemotherapy in terms of patient survival and the lower discordance rate of the EGFR mutations subset in SCC patients, EGFR TKIs could be a recommended treatment for SCC.	('mutations', 'Var', (147, 156))	('EGFR', 'Gene', (181, 185))	('patient', 'Species', '9606', (171, 178))	('SCC', 'Gene', '6317', (167, 170))	('SCC', 'Phenotype', 'HP:0002860', (167, 170))	('EGFR', 'Gene', '1956', (142, 146))	('EGFR', 'Gene', (142, 146))	('patients', 'Species', '9606', (171, 179))	('SCC', 'Gene', (228, 231))	('patient', 'Species', '9606', (87, 94))	('SCC', 'Phenotype', 'HP:0002860', (228, 231))	('SCC', 'Gene', '6317', (228, 231))	('EGFR', 'Gene', '1956', (181, 185))	('SCC', 'Gene', (167, 170))
477388	29620244	Particular mutations of EGFR, for example EGFR exon 19 deletion and exon 21 point mutation, serve a key role in the development of non-small cell lung cancer (NSCLC), such as promoting cancer cell proliferation, differentiation, revascularization and metastasis.	('EGFR', 'Gene', '1956', (24, 28))	('non-small cell lung cancer', 'Disease', (131, 157))	('mutations', 'Var', (11, 20))	('NSCLC', 'Disease', (159, 164))	('revascularization', 'CPA', (229, 246))	('deletion', 'Var', (55, 63))	('lung cancer', 'Phenotype', 'HP:0100526', (146, 157))	('exon', 'Var', (47, 51))	('cancer', 'Disease', (185, 191))	('NSCLC', 'Phenotype', 'HP:0030358', (159, 164))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('EGFR', 'Gene', (42, 46))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (131, 157))	('cancer', 'Disease', (151, 157))	('metastasis', 'CPA', (251, 261))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (135, 157))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('EGFR', 'Gene', (24, 28))	('point mutation', 'Var', (76, 90))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (131, 157))	('promoting', 'PosReg', (175, 184))	('EGFR', 'Gene', '1956', (42, 46))	('NSCLC', 'Disease', 'MESH:D002289', (159, 164))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('differentiation', 'CPA', (212, 227))
477391	29620244	The response rate of EGFR mutation activation to EGFR TKI treatment reaches 70%; TKI treatment may additionally prolong the NSCLC patients' progression free survival (PFS).	('EGFR', 'Gene', '1956', (21, 25))	('EGFR', 'Gene', '1956', (49, 53))	('EGFR', 'Gene', (21, 25))	('mutation', 'Var', (26, 34))	('progression free survival', 'CPA', (140, 165))	('EGFR', 'Gene', (49, 53))	('NSCLC', 'Disease', (124, 129))	('patients', 'Species', '9606', (130, 138))	('NSCLC', 'Disease', 'MESH:D002289', (124, 129))	('prolong', 'PosReg', (112, 119))	('activation', 'PosReg', (35, 45))	('NSCLC', 'Phenotype', 'HP:0030358', (124, 129))
477392	29620244	EGFR exon 19 deletion (Del 19) and exon 21 point mutation (L858R), the main EGFR mutation activation, primarily exist in females, never-smokers, East Asians (~50%) and patients with lung adenocarcinoma (ADC, ~30%).	('lung adenocarcinoma', 'Disease', (182, 201))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (182, 201))	('EGFR', 'Gene', (0, 4))	('EGFR', 'Gene', '1956', (76, 80))	('mutation', 'Var', (81, 89))	('deletion', 'Var', (13, 21))	('L858R', 'Mutation', 'rs121434568', (59, 64))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (182, 201))	('EGFR', 'Gene', (76, 80))	('patients', 'Species', '9606', (168, 176))	('EGFR', 'Gene', '1956', (0, 4))	('carcinoma', 'Phenotype', 'HP:0030731', (192, 201))
477395	29620244	In the present study, the mutation rate of SCC in all EGFR mutations was analyzed in our laboratory and the correlation of EGFR-mutations associated with SCC under clinicopathological parameters was conducted.	('EGFR', 'Gene', (123, 127))	('SCC', 'Gene', '6317', (154, 157))	('SCC', 'Gene', '6317', (43, 46))	('SCC', 'Phenotype', 'HP:0002860', (43, 46))	('SCC', 'Phenotype', 'HP:0002860', (154, 157))	('EGFR', 'Gene', '1956', (54, 58))	('mutations', 'Var', (59, 68))	('EGFR', 'Gene', '1956', (123, 127))	('SCC', 'Gene', (154, 157))	('SCC', 'Gene', (43, 46))	('EGFR', 'Gene', (54, 58))
477396	29620244	A Kaplan-Meier survival analysis performed to estimate the effect of the EGFR mutations in the survival rates of patient with SCC.	('patient', 'Species', '9606', (113, 120))	('EGFR', 'Gene', '1956', (73, 77))	('SCC', 'Phenotype', 'HP:0002860', (126, 129))	('SCC', 'Gene', '6317', (126, 129))	('EGFR', 'Gene', (73, 77))	('mutations', 'Var', (78, 87))	('SCC', 'Gene', (126, 129))
477397	29620244	Additionally, the potential implications of EGFR TKI treatment and the tumor biology of EGFR mutations in patients with SCC was investigated.	('mutations', 'Var', (93, 102))	('SCC', 'Phenotype', 'HP:0002860', (120, 123))	('SCC', 'Gene', '6317', (120, 123))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('EGFR', 'Gene', '1956', (88, 92))	('patients', 'Species', '9606', (106, 114))	('EGFR', 'Gene', '1956', (44, 48))	('EGFR', 'Gene', (44, 48))	('tumor', 'Disease', (71, 76))	('EGFR', 'Gene', (88, 92))	('SCC', 'Gene', (120, 123))
477406	29620244	EGFR mutation analysis of DNA was performed using ADx-ARMS  technology, a technology based on amplified refractory mutation system (ARMS).	('mutation', 'Var', (5, 13))	('EGFR', 'Gene', '1956', (0, 4))	('EGFR', 'Gene', (0, 4))
477408	29620244	A total of 26 mutations in exon 18 (G719A, G719S, G719C), exon 20 (T790M, S768I), and exon 21 (L858R, L861Q), and exon 19 (deletions, n=19) were detected.	('S768I', 'Var', (74, 79))	('G719S', 'Var', (43, 48))	('T790M', 'Mutation', 'rs121434569', (67, 72))	('L858R', 'Mutation', 'rs121434568', (95, 100))	('S768I', 'Mutation', 'rs121913465', (74, 79))	('T790M', 'Var', (67, 72))	('G719C', 'Mutation', 'rs28929495', (50, 55))	('L861Q', 'Mutation', 'rs121913444', (102, 107))	('G719S', 'Mutation', 'rs28929495', (43, 48))	('G719C', 'Var', (50, 55))	('G719A', 'Var', (36, 41))	('G719A', 'Mutation', 'rs121913428', (36, 41))	('L861Q', 'Var', (102, 107))	('L858R', 'Var', (95, 100))
477410	29620244	The qPCR amplification program was performed as follows: Initial denaturation at 95 C for 5 min, 15 cycles of amplification (at 95 C for 25 sec, 64 C for 20 sec, and 72 C for 20 sec) and a final denaturation followed by 31 cycles of amplification (at 93 C for 25 sec, 60 C for 35 sec, and 72 C for 20 sec), and the FAM and HEX signals were collected at 60 C. According to the manufacturer's protocols of the AmoyDx human EGFR Gene Mutation Detection kit described that samples were defined as EGFR mutation-negative when the Cq value>=34; when the sample mutation Cq value<31, the samples were defined as EGFR mutation-positive.	('human', 'Species', '9606', (415, 420))	('EGFR', 'Gene', '1956', (421, 425))	('EGFR', 'Gene', '1956', (605, 609))	('HEX', 'Gene', (323, 326))	('Cq value>=34', 'Var', (525, 537))	('EGFR', 'Gene', (605, 609))	('EGFR', 'Gene', (421, 425))	('EGFR', 'Gene', '1956', (493, 497))	('HEX', 'Gene', '3087', (323, 326))	('EGFR', 'Gene', (493, 497))
477412	29620244	Patients with lung SCC (n=14) with EGFR activating mutations were used for discordance rate of EGFR mutations analysis.	('SCC', 'Gene', '6317', (19, 22))	('mutations', 'Var', (51, 60))	('EGFR', 'Gene', '1956', (35, 39))	('EGFR', 'Gene', (35, 39))	('Patients', 'Species', '9606', (0, 8))	('SCC', 'Gene', (19, 22))	('EGFR', 'Gene', '1956', (95, 99))	('SCC', 'Phenotype', 'HP:0002860', (19, 22))	('EGFR', 'Gene', (95, 99))
477422	29620244	The EGFR mutations of each piece were detected independently.	('EGFR', 'Gene', (4, 8))	('mutations', 'Var', (9, 18))	('EGFR', 'Gene', '1956', (4, 8))
477423	29620244	The correlations of EGFR mutations with clinicopathological parameters were statistically analyzed using the Mann-Whitney U test, and Kruskal-Wallis H (mainly used to detect pathological differentiation).	('mutations', 'Var', (25, 34))	('EGFR', 'Gene', '1956', (20, 24))	('EGFR', 'Gene', (20, 24))
477424	29620244	Kaplan-Meier survival analysis was used to estimate the effect of the type of EGFR mutation on the survival of patients with SCC.	('SCC', 'Gene', (125, 128))	('mutation', 'Var', (83, 91))	('SCC', 'Phenotype', 'HP:0002860', (125, 128))	('EGFR', 'Gene', '1956', (78, 82))	('EGFR', 'Gene', (78, 82))	('SCC', 'Gene', '6317', (125, 128))	('patients', 'Species', '9606', (111, 119))
477425	29620244	A total of 94 out of 1,359 patients with lung SCC had EGFR mutations (6.92%), and 1,265 patients did not.	('patients', 'Species', '9606', (88, 96))	('patients', 'Species', '9606', (27, 35))	('EGFR', 'Gene', '1956', (54, 58))	('SCC', 'Gene', (46, 49))	('SCC', 'Phenotype', 'HP:0002860', (46, 49))	('mutations', 'Var', (59, 68))	('EGFR', 'Gene', (54, 58))	('SCC', 'Gene', '6317', (46, 49))
477426	29620244	All EGFR mutations identified are present in Table II: Exon 19 (n=35, 37.2%); L858R (n=37, 39.4%); T790M (n=5, 5.3%); G719X (n=4, 4.3%); L861Q (n=2, 2.1%); and other mutations (n=11, 11.7%).	('L858R', 'Mutation', 'rs121434568', (78, 83))	('L861Q', 'Var', (137, 142))	('G719X', 'Var', (118, 123))	('EGFR', 'Gene', (4, 8))	('T790M', 'Mutation', 'rs121434569', (99, 104))	('T790M', 'Var', (99, 104))	('L861Q', 'Mutation', 'rs121913444', (137, 142))	('L858R', 'Var', (78, 83))	('G719X', 'Mutation', 'p.G719X', (118, 123))	('EGFR', 'Gene', '1956', (4, 8))
477428	29620244	In 94 SCCs with EGFR mutations, there were 18 female and 76 male patients, with a median age of 59 years (range, 36-84 years).	('SCC', 'Gene', (6, 9))	('SCC', 'Phenotype', 'HP:0002860', (6, 9))	('SCC', 'Gene', '6317', (6, 9))	('EGFR', 'Gene', '1956', (16, 20))	('patients', 'Species', '9606', (65, 73))	('EGFR', 'Gene', (16, 20))	('mutations', 'Var', (21, 30))
477434	29620244	To determine the overall discordance rate of EGFR mutations, EGFR mutations in 14 SCCs were detected and analyzed.	('SCC', 'Phenotype', 'HP:0002860', (82, 85))	('SCC', 'Gene', '6317', (82, 85))	('EGFR', 'Gene', (45, 49))	('mutations', 'Var', (50, 59))	('SCC', 'Gene', (82, 85))	('EGFR', 'Gene', '1956', (61, 65))	('EGFR', 'Gene', '1956', (45, 49))	('EGFR', 'Gene', (61, 65))
477435	29620244	Three parts of each individual tumor were selected and examined for the EGFR mutations subset, and identical mutations were demonstrated in the three morphologically different tumor areas (Table VII).	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('EGFR', 'Gene', '1956', (72, 76))	('tumor', 'Disease', (176, 181))	('tumor', 'Disease', (31, 36))	('EGFR', 'Gene', (72, 76))	('mutations', 'Var', (77, 86))	('tumor', 'Disease', 'MESH:D009369', (176, 181))
477436	29620244	As three parts may be insufficient to detect the discordance rate of the EGFR mutations, five tumors were dissected into >100 pieces, and each piece was examined for EGFR mutations (Fig.	('EGFR', 'Gene', '1956', (73, 77))	('insufficient', 'Disease', (22, 34))	('insufficient', 'Disease', 'MESH:D000309', (22, 34))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('EGFR', 'Gene', (73, 77))	('EGFR', 'Gene', '1956', (166, 170))	('EGFR', 'Gene', (166, 170))	('mutations', 'Var', (78, 87))	('tumors', 'Disease', (94, 100))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))
477442	29620244	The prognosis of patients with lung SCC with EGFR mutations associated with distant metastases, EGFR mutations, and postoperative treatment (chemotherapy and EGFR TKI) were subsequently investigated.	('EGFR', 'Gene', (158, 162))	('EGFR', 'Gene', (45, 49))	('mutations', 'Var', (50, 59))	('metastases', 'Disease', (84, 94))	('EGFR', 'Gene', (96, 100))	('metastases', 'Disease', 'MESH:D009362', (84, 94))	('SCC', 'Gene', '6317', (36, 39))	('SCC', 'Gene', (36, 39))	('patients', 'Species', '9606', (17, 25))	('SCC', 'Phenotype', 'HP:0002860', (36, 39))	('EGFR', 'Gene', '1956', (158, 162))	('EGFR', 'Gene', '1956', (45, 49))	('associated', 'Reg', (60, 70))	('EGFR', 'Gene', '1956', (96, 100))
477449	29620244	It is only in recent years that driver oncogenes, including EGFR-activating mutations, and subsequent corresponding therapies have been identified.	('EGFR', 'Gene', (60, 64))	('EGFR', 'Gene', '1956', (60, 64))	('mutations', 'Var', (76, 85))
477450	29620244	The majority of patients with NSCLC with EGFR mutations respond well to EGFR TKIs (including gefitinib and erlotinib).	('NSCLC', 'Disease', 'MESH:D002289', (30, 35))	('erlotinib', 'Chemical', 'MESH:D000069347', (107, 116))	('EGFR', 'Gene', (41, 45))	('mutations', 'Var', (46, 55))	('EGFR', 'Gene', '1956', (72, 76))	('gefitinib', 'Chemical', 'MESH:D000077156', (93, 102))	('patients', 'Species', '9606', (16, 24))	('NSCLC', 'Phenotype', 'HP:0030358', (30, 35))	('EGFR', 'Gene', (72, 76))	('EGFR', 'Gene', '1956', (41, 45))	('NSCLC', 'Disease', (30, 35))
477451	29620244	EGFR mutations are frequently observed in female, non-smoking, ADC and Asian patients, but rare in SCC.	('SCC', 'Phenotype', 'HP:0002860', (99, 102))	('EGFR', 'Gene', (0, 4))	('SCC', 'Gene', '6317', (99, 102))	('ADC', 'Disease', (63, 66))	('mutations', 'Var', (5, 14))	('patients', 'Species', '9606', (77, 85))	('observed', 'Reg', (30, 38))	('SCC', 'Gene', (99, 102))	('EGFR', 'Gene', '1956', (0, 4))
477452	29620244	Research has identified that in pure SCC, there is the presence of fibroblast growth factor receptor 1, phosphatase and tensin homolog and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit a/AKT serine/threonine kinase 1 mutations, and an absence of EGFR and KRAS proto-oncogene GTPase mutations.	('AKT serine/threonine kinase 1', 'Gene', '207', (206, 235))	('SCC', 'Gene', '6317', (37, 40))	('fibroblast growth factor receptor 1', 'Gene', (67, 102))	('EGFR', 'Gene', '1956', (265, 269))	('GTPase', 'Gene', (294, 300))	('KRAS', 'Gene', (274, 278))	('absence', 'NegReg', (254, 261))	('EGFR', 'Gene', (265, 269))	('mutations', 'Var', (236, 245))	('KRAS', 'Gene', '3845', (274, 278))	('fibroblast growth factor receptor 1', 'Gene', '2260', (67, 102))	('SCC', 'Gene', (37, 40))	('SCC', 'Phenotype', 'HP:0002860', (37, 40))	('AKT serine/threonine kinase 1', 'Gene', (206, 235))
477455	29620244	Statistical analysis revealed that 6.9% (94/1,359) of the tumor samples were EGFR-activating mutations.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('mutations', 'Var', (93, 102))	('EGFR', 'Gene', '1956', (77, 81))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('EGFR', 'Gene', (77, 81))
477456	29620244	The EGFR mutated SCC samples were identified as follows: 37.2% (35/94) in exon 19; 39.4% (37/94) in L858R; 5.3% (5/94) in T790M; 4.3% (4/94) in G719X; 2.1% (2/94) in L861Q; and 11.7% (11/94) in other mutations (Table II).	('SCC', 'Phenotype', 'HP:0002860', (17, 20))	('exon 19', 'Var', (74, 81))	('EGFR', 'Gene', (4, 8))	('L858R', 'Var', (100, 105))	('SCC', 'Gene', '6317', (17, 20))	('G719X', 'Mutation', 'p.G719X', (144, 149))	('T790M', 'Mutation', 'rs121434569', (122, 127))	('L861Q', 'Var', (166, 171))	('T790M', 'Var', (122, 127))	('L858R', 'Mutation', 'rs121434568', (100, 105))	('G719X', 'Var', (144, 149))	('L861Q', 'Mutation', 'rs121913444', (166, 171))	('SCC', 'Gene', (17, 20))	('EGFR', 'Gene', '1956', (4, 8))
477457	29620244	Due to the limited number in the EGFR mutations subset, only the proportions of EGFR mutations in exon 19 (Del 19) and exon 21 (L858R) were larger (~76.6% of the total), although no significant difference in prognosis was observed between the EGFR Del 19 and L858R groups in SCC.	('SCC', 'Gene', (275, 278))	('SCC', 'Phenotype', 'HP:0002860', (275, 278))	('EGFR', 'Gene', '1956', (80, 84))	('EGFR', 'Gene', '1956', (33, 37))	('EGFR', 'Gene', (80, 84))	('mutations', 'Var', (85, 94))	('SCC', 'Gene', '6317', (275, 278))	('EGFR', 'Gene', (33, 37))	('EGFR', 'Gene', '1956', (243, 247))	('EGFR', 'Gene', (243, 247))	('L858R', 'Mutation', 'rs121434568', (259, 264))	('L858R', 'Mutation', 'rs121434568', (128, 133))
477462	29620244	The SCC patients identified as having EGFR activating mutations following surgery were treated as follows: 70.2% (66/94) with chemotherapy; 25.5% (24/94) with EGFR TKIs; 3.2% (3/94) with radiotherapy; and 1.1% (1/94) with chemotherapy and EGFR TKIs.	('SCC', 'Gene', (4, 7))	('EGFR', 'Gene', '1956', (38, 42))	('SCC', 'Phenotype', 'HP:0002860', (4, 7))	('EGFR', 'Gene', (38, 42))	('EGFR', 'Gene', '1956', (159, 163))	('mutations', 'Var', (54, 63))	('SCC', 'Gene', '6317', (4, 7))	('EGFR', 'Gene', (159, 163))	('EGFR', 'Gene', '1956', (239, 243))	('activating', 'PosReg', (43, 53))	('EGFR', 'Gene', (239, 243))	('patients', 'Species', '9606', (8, 16))
477464	29620244	In addition, EGFR TKIs are used for patients with EGFR mutation.	('patients', 'Species', '9606', (36, 44))	('EGFR', 'Gene', '1956', (50, 54))	('mutation', 'Var', (55, 63))	('EGFR', 'Gene', (50, 54))	('EGFR', 'Gene', '1956', (13, 17))	('EGFR', 'Gene', (13, 17))
477466	29620244	In the present study, the prognostic difference was not marked between the chemotherapy and the TKIs therapy groups, which indicated that EGFR TKIs were able to prolong patient survival in way comparable to the function of chemotherapy; therefore, it was hypothesized that EGFR TKIs may be an option for the treatment of SCC with EGFR mutations.	('EGFR', 'Gene', '1956', (138, 142))	('EGFR', 'Gene', (330, 334))	('EGFR', 'Gene', '1956', (330, 334))	('EGFR', 'Gene', (138, 142))	('SCC', 'Gene', (321, 324))	('patient', 'Species', '9606', (169, 176))	('EGFR', 'Gene', '1956', (273, 277))	('mutations', 'Var', (335, 344))	('SCC', 'Phenotype', 'HP:0002860', (321, 324))	('SCC', 'Gene', '6317', (321, 324))	('EGFR', 'Gene', (273, 277))
477467	29620244	In certain individual tumors, EGFR mutations were not evenly distributed, and this may be one of the causes of drug-resistance to EGFR TKIs.	('tumors', 'Phenotype', 'HP:0002664', (22, 28))	('causes', 'Reg', (101, 107))	('EGFR', 'Gene', (30, 34))	('tumors', 'Disease', 'MESH:D009369', (22, 28))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('drug-resistance', 'Phenotype', 'HP:0020174', (111, 126))	('EGFR', 'Gene', '1956', (30, 34))	('EGFR', 'Gene', '1956', (130, 134))	('tumors', 'Disease', (22, 28))	('EGFR', 'Gene', (130, 134))	('mutations', 'Var', (35, 44))
477468	29620244	In the present study, identical EGFR mutations were identified throughout individual tumors by examining 14 tumors divided into three parts and five tumors divided into 100 parts.	('tumors', 'Disease', 'MESH:D009369', (85, 91))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('EGFR', 'Gene', '1956', (32, 36))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('mutations', 'Var', (37, 46))	('tumors', 'Disease', (149, 155))	('tumors', 'Disease', 'MESH:D009369', (149, 155))	('tumors', 'Disease', (108, 114))	('EGFR', 'Gene', (32, 36))	('tumors', 'Disease', 'MESH:D009369', (108, 114))	('tumors', 'Phenotype', 'HP:0002664', (149, 155))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('tumors', 'Disease', (85, 91))
477471	29620244	In addition, the heterogeneous distribution of EGFR mutations in SCC is extremely rare.	('mutations', 'Var', (52, 61))	('SCC', 'Gene', (65, 68))	('SCC', 'Phenotype', 'HP:0002860', (65, 68))	('SCC', 'Gene', '6317', (65, 68))	('EGFR', 'Gene', '1956', (47, 51))	('EGFR', 'Gene', (47, 51))
477472	29620244	YS, XY and MW conducted the EGFR mutation test; JZ contributed to the follow-up; XW and JX interpreted the clinicopathological information statistics; YZ conducted the discordance rate of EGFR mutations analysis; and ZZ and XL performed statistical analysis.	('EGFR', 'Gene', '1956', (28, 32))	('mutation', 'Var', (33, 41))	('EGFR', 'Gene', (28, 32))	('mutations', 'Var', (193, 202))	('EGFR', 'Gene', '1956', (188, 192))	('EGFR', 'Gene', (188, 192))
477474	28076325	Identification of long noncoding RNAs for the detection of early stage lung squamous cell carcinoma by microarray analysis The aberrant expressions of long noncoding RNAs have been reported in numerous cancers, which have facilitated the cancer diagnosis.	('numerous cancers', 'Disease', 'MESH:D009369', (193, 209))	('cancer', 'Disease', (238, 244))	('cancer', 'Disease', 'MESH:D009369', (238, 244))	('reported', 'Reg', (181, 189))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (76, 99))	('aberrant', 'Var', (127, 135))	('numerous cancers', 'Disease', (193, 209))	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('long', 'Gene', (151, 155))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('cancer', 'Disease', 'MESH:D009369', (202, 208))	('cancers', 'Phenotype', 'HP:0002664', (202, 209))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (71, 99))	('cancer', 'Disease', (202, 208))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (71, 99))	('lung squamous cell carcinoma', 'Disease', (71, 99))
477477	28076325	Through high-throughput lncRNA microarray, we screened thousands of aberrantly expressed lncRNAs and mRNAs in early stage lung squamous cell carcinoma tissues compared to their corresponding adjacent nontumorous tissues.	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('tumor', 'Disease', (203, 208))	('mRNAs', 'Gene', (101, 106))	('stage lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (116, 150))	('stage lung squamous cell carcinoma', 'Disease', (116, 150))	('lncRNAs', 'Gene', (89, 96))	('aberrantly expressed', 'Var', (68, 88))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (127, 150))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (122, 150))
477485	28076325	Dysregulation of lncRNAs is associated with a number of cancer-related processes, including epigenetic regulation, microRNA silencing, DNA damage and cell cycle control.	('DNA damage', 'MPA', (135, 145))	('microRNA', 'MPA', (115, 123))	('associated', 'Reg', (28, 38))	('Dysregulation', 'Var', (0, 13))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('lncRNAs', 'Protein', (17, 24))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('cell cycle', 'CPA', (150, 160))	('epigenetic regulation', 'MPA', (92, 113))
477502	28076325	For example, intron sense overlapping lncRNA ENST00000453324, also named as LINC000969, is located on the sense strand of chromosome 3 and is transcribed from the intron area of gene mucin 20 (MUC20).	('MUC20', 'Gene', (193, 198))	('mucin 20', 'Gene', '200958', (183, 191))	('ENST00000453324', 'Var', (45, 60))	('MUC20', 'Gene', '200958', (193, 198))	('mucin 20', 'Gene', (183, 191))
477505	28076325	NR_028500 is located on the sense strand of chromosome 11 and is a transcript variant of gene lactate dehydrogenase A (LDHA).	('LDHA', 'Gene', '3939', (119, 123))	('lactate dehydrogenase A', 'Gene', (94, 117))	('lactate dehydrogenase A', 'Gene', '3939', (94, 117))	('LDHA', 'Gene', (119, 123))	('NR_028500', 'Var', (0, 9))
477509	28076325	The co-expression of NR_028500 and LDHA implies that NR_028500 may be involved in the anaerobic glycolysis of tumor cells.	('NR_028500', 'Var', (21, 30))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('LDHA', 'Gene', (35, 39))	('LDHA', 'Gene', '3939', (35, 39))	('NR_028500', 'Var', (53, 62))	('involved', 'Reg', (70, 78))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
477510	28076325	NR_046326, also named as PCAT6 (prostate cancer associated transcript 6), is located on the sense strand of chromosome 1, and is first reported highly expressed in prostate cancer.	('prostate cancer', 'Phenotype', 'HP:0012125', (164, 179))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('PCAT6', 'Gene', (25, 30))	('prostate cancer associated transcript 6', 'Gene', '100506696', (32, 71))	('NR_046326', 'Var', (0, 9))	('prostate cancer', 'Disease', (164, 179))	('PCAT6', 'Gene', '100506696', (25, 30))	('prostate cancer', 'Disease', 'MESH:D011471', (32, 47))	('prostate cancer associated transcript 6', 'Gene', (32, 71))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('prostate cancer', 'Phenotype', 'HP:0012125', (32, 47))	('prostate cancer', 'Disease', 'MESH:D011471', (164, 179))
477518	28076325	These findings above suggest that ENST00000441841 may be involved in the activation of onco-placental gene PLAC1.	('ENST00000441841', 'Var', (34, 49))	('PLAC1', 'Gene', (107, 112))	('PLAC1', 'Gene', '10761', (107, 112))
477558	25767605	The expression level of HAX-1 was defined as follows: "-" (negative, score of 0), "+" (weakly positive, score of 1-4), "++" (positive, score of 5-8), "+++" (strongly positive, score of 9-12).	('HAX-1', 'Gene', '10456', (24, 29))	('++" (positive, score of 5-8', 'Var', (120, 147))	('HAX-1', 'Gene', (24, 29))
477570	25767605	A431 cells were plated and transfected with siRNAs as described above in a 12-well plate at the density of 3x105cells per well.	('transfected', 'Var', (27, 38))	('siRNAs', 'Gene', (44, 50))	('A431', 'CellLine', 'CVCL:0037', (0, 4))
477597	25767605	Cell Counting Kit 8 (CCK-8) assay was used to examine the role of HAX-1 on proliferation of A431 cells with the transfection of siRNAs.	('HAX-1', 'Gene', '10456', (66, 71))	('A431', 'CellLine', 'CVCL:0037', (92, 96))	('HAX-1', 'Gene', (66, 71))	('transfection', 'Var', (112, 124))
477615	25767605	In ESCC, high expression of HAX-1 was associated with lymph node metastasis and survival in the patients with ESCC.	('ESCC', 'Phenotype', 'HP:0011459', (110, 114))	('HAX-1', 'Gene', '10456', (28, 33))	('associated', 'Reg', (38, 48))	('lymph node metastasis', 'CPA', (54, 75))	('HAX-1', 'Gene', (28, 33))	('ESCC', 'Phenotype', 'HP:0011459', (3, 7))	('ESCC', 'Disease', (3, 7))	('patients', 'Species', '9606', (96, 104))	('survival', 'CPA', (80, 88))	('high', 'Var', (9, 13))
477621	25767605	Besides that, we also found that there were significant differences in thickness, differentiation and TNM stages between high HAX-1 expression group and low HAX-1 expression group.	('HAX-1', 'Gene', '10456', (157, 162))	('HAX-1', 'Gene', (157, 162))	('thickness', 'CPA', (71, 80))	('HAX-1', 'Gene', (126, 131))	('TNM stages', 'CPA', (102, 112))	('differences', 'Reg', (56, 67))	('high', 'Var', (121, 125))	('differentiation', 'CPA', (82, 97))	('HAX-1', 'Gene', '10456', (126, 131))
477741	31850075	Thousands of mutations are detected for a cancer with the advances of DNA sequencing technologies.	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('mutations', 'Var', (13, 22))	('detected', 'Reg', (27, 35))
477743	31850075	Therefore, many algorithms have been developed to identify a panel of genes or pathways that mutate in a significantly high fraction of patients in a particular type of cancer.	('cancer', 'Disease', (169, 175))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('patients', 'Species', '9606', (136, 144))	('mutate', 'Var', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (169, 175))
477744	31850075	These identified mutation genes or pathways might be drivers contributing to cancer or potential diagnosis biomarkers for a cancer.	('cancer', 'Disease', (124, 130))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('mutation', 'Var', (17, 25))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (124, 130))
477745	31850075	identified a panel of 400 mutations covering more than 80% of the lung adenocarcinoma (LUAD) patients from The Cancer Genome Atlas (TCGA) database.	('lung adenocarcinoma', 'Disease', (66, 85))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (66, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('LUAD', 'Phenotype', 'HP:0030078', (87, 91))	('mutations', 'Var', (26, 35))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (66, 85))	('Cancer', 'Disease', 'MESH:D009369', (111, 117))	('Cancer', 'Disease', (111, 117))	('Cancer', 'Phenotype', 'HP:0002664', (111, 117))	('patients', 'Species', '9606', (93, 101))
477747	31850075	It has been reported that certain pathways are frequently altered across patients of a cancer by mutations in different genes of the pathways.	('cancer', 'Disease', (87, 93))	('mutations', 'Var', (97, 106))	('pathways', 'Pathway', (34, 42))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('patients', 'Species', '9606', (73, 81))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('altered', 'Reg', (58, 65))
477749	31850075	Panels of mutation genes have been reported to be a promising way to diagnose a specific cancer.	('mutation genes', 'Var', (10, 24))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('Panels', 'Var', (0, 6))	('cancer', 'Disease', (89, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
477750	31850075	It would be of great significance if we could find sub-pathways mutated in almost all patients of a cancer.	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('mutated', 'Var', (64, 71))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('patients', 'Species', '9606', (86, 94))
477751	31850075	Here, we think that the panel of mutation genes within a common sub-pathway will be a reliable diagnostic marker for a cancer when the common mutated sub-pathway is reproducible in different independent datasets of this cancer.	('mutation', 'Var', (33, 41))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('cancer', 'Disease', (119, 125))	('cancer', 'Disease', 'MESH:D009369', (220, 226))	('cancer', 'Disease', (220, 226))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
477776	31850075	According to the v value, the genes with v>0 are defined as subtype A specific genes (denoted as set Ga) and the genes with v>0 are defined as subtype A specific genes (denoted as set Ga) and the genes with v<0 are defined as subtype B specific genes (denoted as set Gb).	('v>0', 'Var', (41, 44))	('Ga', 'Chemical', 'MESH:D005708', (101, 103))	('Ga', 'Chemical', 'MESH:D005708', (184, 186))	('v>0', 'Var', (124, 127))
477788	31850075	The result indicated that the common mutated sub-pathways were highly reproducible in different sets of lung cancer samples, which suggests that the mutation genes within the common sub-pathways could be candidate panels of mutation genes for lung cancer diagnosis.	('lung cancer', 'Disease', 'MESH:D008175', (104, 115))	('lung cancer', 'Disease', (243, 254))	('lung cancer', 'Phenotype', 'HP:0100526', (243, 254))	('cancer', 'Phenotype', 'HP:0002664', (248, 254))	('lung cancer', 'Disease', (104, 115))	('lung cancer', 'Phenotype', 'HP:0100526', (104, 115))	('lung cancer', 'Disease', 'MESH:D008175', (243, 254))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('mutation', 'Var', (149, 157))
477800	31850075	For example, a LSCC-specific sub-pathway of cell cycle, including seven genes, was mutated in 102 of 166 patients, which had significantly poorer overall survival than the other 64 patients without the mutation of this sub-pathway (log-rank p = 0.02, Figure 4).	('mutated', 'Var', (83, 90))	('patients', 'Species', '9606', (105, 113))	('overall survival', 'MPA', (146, 162))	('LSCC', 'Phenotype', 'HP:0030359', (15, 19))	('LSCC-specific', 'Disease', (15, 28))	('poorer', 'NegReg', (139, 145))	('patients', 'Species', '9606', (181, 189))
477825	28174608	Distinct epigenetic drifts for hypo- and hypermethylation across CpG islands suggested independent mechanisms of hypo- and hypermethylation in OSCC development.	('hypo-', 'Var', (31, 36))	('hypermethylation', 'Var', (41, 57))	('men', 'Species', '9606', (155, 158))	('OSCC', 'Disease', (143, 147))
477826	28174608	Hypomethylation of immune genes reflect the lymphocyte infiltration into the tumor microenvironment.	('Hypomethylation', 'Var', (0, 15))	('immune genes', 'Gene', (19, 31))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('men', 'Species', '9606', (95, 98))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('reflect', 'Reg', (32, 39))	('tumor', 'Disease', (77, 82))
477830	28174608	These methylation changes may serve as potential molecular markers to define risk and to monitor the prognosis of OSCC patients in India.	('patients', 'Species', '9606', (119, 127))	('methylation changes', 'Var', (6, 25))	('OSCC', 'Disease', (114, 118))
477840	28174608	Oral cancer is a multifactorial disease involving genetic and epigenetic abnormalities.	('Oral cancer', 'Disease', 'MESH:D009062', (0, 11))	('Oral cancer', 'Disease', (0, 11))	('epigenetic abnormalities', 'Var', (62, 86))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))
477841	28174608	The addition of a methyl group at the cytosine residue of CpG dinucleotide have a profound effect on initiation and progression of cancer.	('cancer', 'Disease', (131, 137))	('addition', 'Var', (4, 12))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('effect', 'Reg', (91, 97))	('cytosine', 'Chemical', 'MESH:D003596', (38, 46))	('CpG', 'Gene', (58, 61))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('CpG dinucleotide', 'Chemical', 'MESH:C015772', (58, 74))
477842	28174608	Hypermethylation of CpG islands (CGIs) in the promoter region results in transcriptional silencing of tumor suppressor genes, whereas hypomethylation leads to oncogene activation in many cancers.	('cancers', 'Disease', 'MESH:D009369', (187, 194))	('cancers', 'Phenotype', 'HP:0002664', (187, 194))	('transcriptional', 'MPA', (73, 88))	('cancers', 'Disease', (187, 194))	('Hypermethylation', 'Var', (0, 16))	('oncogene', 'MPA', (159, 167))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('activation', 'PosReg', (168, 178))	('silencing', 'NegReg', (89, 98))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('hypomethylation', 'Var', (134, 149))
477843	28174608	As DNA methylation alteration often occurs early in cancer development, candidate methylation markers may be valuable for early and specific cancer detection.	('men', 'Species', '9606', (66, 69))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('alteration', 'Var', (19, 29))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('cancer', 'Disease', (141, 147))
477844	28174608	Studies have indicated involvement of genetic, epigenetic, and oral habits in the development of oral cancer.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('involvement', 'Reg', (23, 34))	('epigenetic', 'Var', (47, 57))	('oral cancer', 'Disease', 'MESH:D009062', (97, 108))	('men', 'Species', '9606', (30, 33))	('men', 'Species', '9606', (89, 92))	('oral cancer', 'Disease', (97, 108))
477845	28174608	Recently, candidate gene-specific studies identified epigenetic modifications in the promoter regions of OSCC patients in India.	('patients', 'Species', '9606', (110, 118))	('OSCC', 'Disease', (105, 109))	('epigenetic modifications', 'Var', (53, 77))
477849	28174608	However, most of these studies focused on cancer-associated hypermethylation at specific genes.	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('hypermethylation', 'Var', (60, 76))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))
477858	28174608	Probes showing  Deltabeta  >=0.20 between the cancer and adjacent normal tissues with adjusted P value <=0.05 were defined as differentially methylated probes (DMPs).	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('cancer', 'Disease', (46, 52))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('Deltabeta', 'Var', (16, 25))	('DMPs', 'Chemical', '-', (160, 164))
477869	28174608	On the contrary, significant hypomethylation (P value <=0.05) was observed across CGIs, shores, and shelves between tumors and adjacent normal tissues, suggesting different mechanisms of hypo- and hypermethylation in OSCC development (Fig.	('tumors', 'Disease', (116, 122))	('tumors', 'Disease', 'MESH:D009369', (116, 122))	('hypermethylation', 'Var', (197, 213))	('men', 'Species', '9606', (229, 232))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('hypo-', 'Var', (187, 192))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))	('OSCC development', 'Disease', (217, 233))
477871	28174608	Clonal validation showed hypermethylation for the HLA-DPB1 (12 to 81%), LDLRAD4 (0 to 38%), LHX1 (34 to 98%), and LXN (2 to 29%) promoters and hypomethylation for PTPN22 (86 to 30%) in tumors compared to adjacent normal tissues.	('HLA-DPB1', 'Gene', (50, 58))	('LDLRAD4', 'Gene', (72, 79))	('hypomethylation', 'Var', (143, 158))	('LDLRAD4', 'Gene', '753', (72, 79))	('LXN', 'Gene', (114, 117))	('LHX1', 'Gene', (92, 96))	('tumors', 'Disease', (185, 191))	('LHX1', 'Gene', '3975', (92, 96))	('tumors', 'Phenotype', 'HP:0002664', (185, 191))	('PTPN22', 'Gene', (163, 169))	('tumors', 'Disease', 'MESH:D009369', (185, 191))	('hypermethylation', 'MPA', (25, 41))	('PTPN22', 'Gene', '26191', (163, 169))	('HLA-DPB1', 'Gene', '3115', (50, 58))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('LXN', 'Gene', '56925', (114, 117))
477878	28174608	A closer look into the methylation data showed hypomethylation at the promoter region of another isoform of the HLA-DPB1 gene, which may be the reason for this discordant expression profile.	('HLA-DPB1', 'Gene', (112, 120))	('hypomethylation', 'Var', (47, 62))	('HLA-DPB1', 'Gene', '3115', (112, 120))
477884	28174608	Interestingly, a subset of differentially methylated probes (1165) were uniquely hypomethylated in tumor tissues of OSCC patients in India.	('tumor', 'Disease', (99, 104))	('OSCC', 'Disease', (116, 120))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('hypomethylated', 'Var', (81, 95))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('patients', 'Species', '9606', (121, 129))
477893	28174608	CTLA4 activation upon promoter hypomethylation indicates the negative regulation of effector T cell activation.	('CTLA4', 'Gene', (0, 5))	('CTLA4', 'Gene', '1493', (0, 5))	('promoter hypomethylation', 'Var', (22, 46))	('activation', 'PosReg', (6, 16))
477897	28174608	Both CD86 (P value = 6.10 x 10-3) and CTLA4 (P value = 1.30 x 10-3) showed significant overexpression in the OSCC tissues compared in the adjacent normal tissues, which further validated the epigenetic regulation of CD86 and CTLA4, specifically among the OSCC patients in India.	('CD86', 'Gene', '942', (216, 220))	('CTLA4', 'Gene', '1493', (38, 43))	('OSCC', 'Disease', (109, 113))	('CD86', 'Gene', (216, 220))	('epigenetic regulation', 'Var', (191, 212))	('CTLA4', 'Gene', (38, 43))	('patients', 'Species', '9606', (260, 268))	('CTLA4', 'Gene', '1493', (225, 230))	('CD86', 'Gene', '942', (5, 9))	('overexpression', 'PosReg', (87, 101))	('CTLA4', 'Gene', (225, 230))	('CD86', 'Gene', (5, 9))
477911	28174608	As observed in several cancers, we also found preferential enrichment of hypermethylated probes in the CpG-rich regions, while hypomethylated probes were primarily enriched at the open sea.	('men', 'Species', '9606', (65, 68))	('cancers', 'Disease', 'MESH:D009369', (23, 30))	('cancers', 'Phenotype', 'HP:0002664', (23, 30))	('cancers', 'Disease', (23, 30))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('hypermethylated', 'Var', (73, 88))
477913	28174608	This data suggests that two independent mechanisms of hypo- and hypermethylation are acting in OSCC development.	('hypo-', 'Var', (54, 59))	('OSCC', 'Disease', (95, 99))	('hypermethylation', 'Var', (64, 80))	('men', 'Species', '9606', (107, 110))
477914	28174608	Aberrant promoter methylation leading to transcriptional deregulation of a gene are often found in cancers.	('transcriptional deregulation', 'MPA', (41, 69))	('Aberrant', 'Var', (0, 8))	('cancers', 'Disease', 'MESH:D009369', (99, 106))	('cancers', 'Phenotype', 'HP:0002664', (99, 106))	('cancers', 'Disease', (99, 106))	('promoter', 'MPA', (9, 17))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
477918	28174608	It has previously been shown to be inhibited by promoter hypermethylation in malignant melanoma, gastric cancer, and prostate cancer.	('promoter hypermethylation', 'Var', (48, 73))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('gastric cancer', 'Disease', (97, 111))	('malignant melanoma', 'Disease', 'MESH:D008545', (77, 95))	('prostate cancer', 'Disease', 'MESH:D011471', (117, 132))	('gastric cancer', 'Disease', 'MESH:D013274', (97, 111))	('malignant melanoma', 'Disease', (77, 95))	('prostate cancer', 'Phenotype', 'HP:0012125', (117, 132))	('gastric cancer', 'Phenotype', 'HP:0012126', (97, 111))	('inhibited', 'NegReg', (35, 44))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('prostate cancer', 'Disease', (117, 132))	('malignant melanoma', 'Phenotype', 'HP:0002861', (77, 95))	('melanoma', 'Phenotype', 'HP:0002861', (87, 95))
477920	28174608	Inhibition of CTDSP family members promotes the G1/S-phase transition and have been found to be downregulated in hepatocellular carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('promotes', 'PosReg', (35, 43))	('CTDSP family', 'Gene', (14, 26))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (113, 137))	('downregulated', 'NegReg', (96, 109))	('Inhibition', 'Var', (0, 10))	('G1/S-phase transition', 'CPA', (48, 69))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (113, 137))	('hepatocellular carcinoma', 'Disease', (113, 137))
477921	28174608	Recently, epigenetic regulation of PTPN22 in the esophegal squamous cell carcinoma has been reported.We observed distinct hypomethylation of the PTPN22 promoter in OSCC, which also had inverse correlation with expression pattern of the gene.	('esophegal squamous cell carcinoma', 'Disease', 'MESH:D002294', (49, 82))	('PTPN22', 'Gene', (35, 41))	('hypomethylation', 'Var', (122, 137))	('PTPN22', 'Gene', (145, 151))	('PTPN22', 'Gene', '26191', (145, 151))	('PTPN22', 'Gene', '26191', (35, 41))	('OSCC', 'Disease', (164, 168))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (59, 82))	('esophegal squamous cell carcinoma', 'Disease', (49, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
477938	28174608	Hypomethylation of immune genes in unique and common clusters are clear indication of infiltration of immune cells into tumors.	('tumors', 'Disease', 'MESH:D009369', (120, 126))	('tumors', 'Disease', (120, 126))	('tumors', 'Phenotype', 'HP:0002664', (120, 126))	('Hypomethylation', 'Var', (0, 15))	('immune genes', 'Gene', (19, 31))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))
477947	28174608	Tumor necrosis factor receptor superfamily, member 4 (TNFRSF4) is a co-stimulatory molecule, and agonists of this molecule have been described to increase anti-tumor immunity through enhancing T cell response and suppressing T reg cells.	('agonists', 'Var', (97, 105))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('increase', 'PosReg', (146, 154))	('T cell response', 'CPA', (193, 208))	('TNFRSF4', 'Gene', '7293', (54, 61))	('suppressing', 'NegReg', (213, 224))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('T reg cells', 'CPA', (225, 236))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('Tumor necrosis factor receptor superfamily, member 4', 'Gene', '7293', (0, 52))	('enhancing', 'PosReg', (183, 192))	('tumor', 'Disease', (160, 165))	('TNFRSF4', 'Gene', (54, 61))
477951	28174608	Most importantly, we have observed all these genes to be regulated by hypomethylated regions in promoter that are unique among OSCC patients in India.	('regulated', 'Reg', (57, 66))	('OSCC', 'Disease', (127, 131))	('patients', 'Species', '9606', (132, 140))	('hypomethylated regions', 'Var', (70, 92))
477965	28174608	Gene ontology and IPA showed enrichment of differentially methylated promoters in immune regulation pathways including those mediated by CTLA4 and IL9 signaling.	('CTLA4', 'Gene', '1493', (137, 142))	('men', 'Species', '9606', (35, 38))	('CTLA4', 'Gene', (137, 142))	('IL9', 'Gene', (147, 150))	('differentially methylated', 'Var', (43, 68))	('IL9', 'Gene', '3578', (147, 150))	('immune regulation pathways', 'Pathway', (82, 108))
478010	33029143	A high expression of STC2 was associated with larger tumors (Figure 3(b)) and the presence of lymph node metastases (Figure 3(c)).	('larger tumors', 'CPA', (46, 59))	('associated', 'Reg', (30, 40))	('STC2', 'Gene', (21, 25))	('high', 'Var', (2, 6))	('metastases', 'Disease', (105, 115))	('expression', 'MPA', (7, 17))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('metastases', 'Disease', 'MESH:D009362', (105, 115))
478017	33029143	reported that the overexpression of GPR87 in non-small cell lung carcinoma is significantly correlated with poor patient survival.	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('non-small cell lung carcinoma', 'Phenotype', 'HP:0030358', (45, 74))	('small cell lung carcinoma', 'Phenotype', 'HP:0030357', (49, 74))	('lung carcinoma', 'Disease', 'MESH:D008175', (60, 74))	('lung carcinoma', 'Disease', (60, 74))	('GPR87', 'Var', (36, 41))	('overexpression', 'PosReg', (18, 32))
478018	33029143	Hyaluronan-mediated motility receptor (HMMR) is a regulator of homeostasis, mitosis, and meiosis, and its dysfunction may promote tumorigenesis and cancer progression.	('Hyaluronan-mediated motility receptor', 'Gene', '3161', (0, 37))	('dysfunction', 'Var', (106, 117))	('HMMR', 'Gene', (39, 43))	('tumorigenesis', 'CPA', (130, 143))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('promote', 'PosReg', (122, 129))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('cancer progression', 'CPA', (148, 166))	('Hyaluronan-mediated motility receptor', 'Gene', (0, 37))
478021	33029143	Although most studies focused on HK2, some studies found that the expression of HK1 is connected with disease progression, invasion, and poor survival in patients with esophageal squamous cell carcinoma.	('HK1', 'Gene', (80, 83))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (168, 202))	('HK2', 'Gene', (33, 36))	('HK2', 'Gene', '3099', (33, 36))	('esophageal squamous cell carcinoma', 'Disease', (168, 202))	('carcinoma', 'Phenotype', 'HP:0030731', (193, 202))	('expression', 'Var', (66, 76))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (179, 202))	('connected with', 'Reg', (87, 101))
478024	33029143	Mutations in exostosin-2 (EXT2) often cause multiple osteochondromas.	('osteochondromas', 'Phenotype', 'HP:0030431', (53, 68))	('EXT2', 'Gene', (26, 30))	('cause', 'Reg', (38, 43))	('osteochondromas', 'Disease', (53, 68))	('Mutations', 'Var', (0, 9))	('osteochondromas', 'Disease', 'MESH:D015831', (53, 68))	('exostosin-2', 'Gene', (13, 24))	('exostosin-2', 'Gene', '2132', (13, 24))
478025	33029143	showed that EXT2 is an independent prognostic factor for hepatocellular carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('EXT2', 'Var', (12, 16))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (57, 81))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (57, 81))	('hepatocellular carcinoma', 'Disease', (57, 81))
478029	29434705	Identification of a progression-associated long non-coding RNA signature for predicting the prognosis of lung squamous cell carcinoma Long non-coding RNAs (lncRNAs) have been indicated to have prognostic roles in various cancer types.	('cancer', 'Disease', 'MESH:D009369', (221, 227))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (110, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('cancer', 'Disease', (221, 227))	('R', 'Gene', '10327', (150, 151))	('R', 'Gene', '10327', (59, 60))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (105, 133))	('R', 'Gene', '10327', (159, 160))	('Long non-coding', 'Var', (134, 149))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (105, 133))	('lung squamous cell carcinoma', 'Disease', (105, 133))
478051	29434705	Dysregulated lncRNA expression has been implicated in various human cancers.	('R', 'Gene', '10327', (16, 17))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('human', 'Species', '9606', (62, 67))	('cancers', 'Phenotype', 'HP:0002664', (68, 75))	('cancers', 'Disease', (68, 75))	('implicated', 'Reg', (40, 50))	('cancers', 'Disease', 'MESH:D009369', (68, 75))	('Dysregulated', 'Var', (0, 12))
478136	24490161	Studies have revealed that miRNAs deregulation correlates and is involved with the initiation and progression of human tumors.	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('deregulation', 'Var', (34, 46))	('tumors', 'Disease', 'MESH:D009369', (119, 125))	('tumors', 'Disease', (119, 125))	('miR', 'Gene', '220972', (27, 30))	('miR', 'Gene', (27, 30))	('involved', 'Reg', (65, 73))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('human', 'Species', '9606', (113, 118))
478144	24490161	Many miRNAs are tissue- or differentiation-specific, and their temporal or short-lived expression modulates gene expression at the posttranscriptional level by base-pairing with complementary nucleotide sequences of target mRNAs.	('miR', 'Gene', '220972', (5, 8))	('miR', 'Gene', (5, 8))	('base-pairing', 'Var', (160, 172))	('gene expression', 'MPA', (108, 123))	('modulates', 'Reg', (98, 107))
478148	24490161	The first report documenting abnormalities in miRNA expression in tumor samples was on B-cell chronic lymphocytic leukemia (B-CLL), where miR-15 and miR-16 are frequently deleted and downregulated in B-CLL patients.	('deleted', 'Var', (171, 178))	('miR', 'Gene', (46, 49))	('miR-16', 'Gene', (149, 155))	('miR', 'Gene', '220972', (138, 141))	('lymphocytic leukemia', 'Disease', (102, 122))	('tumor', 'Disease', (66, 71))	('-cell chronic lymphocytic leukemia', 'Phenotype', 'HP:0005539', (88, 122))	('miR-1', 'Gene', (149, 154))	('miR', 'Gene', (138, 141))	('miR-16', 'Gene', '51573', (149, 155))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('downregulated', 'NegReg', (183, 196))	('miR-1', 'Gene', (138, 143))	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (94, 122))	('leukemia', 'Phenotype', 'HP:0001909', (114, 122))	('miR', 'Gene', '220972', (149, 152))	('miR-1', 'Gene', '79187', (149, 154))	('miR', 'Gene', '220972', (46, 49))	('lymphocytic leukemia', 'Disease', 'MESH:D007945', (102, 122))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('miR', 'Gene', (149, 152))	('patients', 'Species', '9606', (206, 214))	('miR-1', 'Gene', '79187', (138, 143))
478151	24490161	Studies have identified chromosomal alterations, gene expression changes, and aberrant promoter methylation associated with cervical cancer (CC), but little is known about the specific role of miRNAs.	('aberrant', 'Var', (78, 86))	('promoter', 'MPA', (87, 95))	('CC', 'Phenotype', 'HP:0002664', (141, 143))	('associated', 'Reg', (108, 118))	('cervical cancer', 'Disease', (124, 139))	('cervical cancer', 'Disease', 'MESH:D002583', (124, 139))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('miR', 'Gene', '220972', (193, 196))	('miR', 'Gene', (193, 196))
478157	24490161	These observations suggest that many aberrantly expressed miRNAs in CC could serve as diagnostic and prognostic biomarkers.	('aberrantly expressed', 'Var', (37, 57))	('CC', 'Phenotype', 'HP:0002664', (68, 70))	('miR', 'Gene', '220972', (58, 61))	('miR', 'Gene', (58, 61))
478161	24490161	Upregulation of miRNAs in human cancers can result from amplification, deregulation of a transcription factor, or demethylation of CpG islands in the promoter regions of the corresponding genes.	('Upregulation', 'PosReg', (0, 12))	('demethylation', 'Var', (114, 127))	('cancers', 'Disease', 'MESH:D009369', (32, 39))	('cancers', 'Phenotype', 'HP:0002664', (32, 39))	('cancers', 'Disease', (32, 39))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('miR', 'Gene', (16, 19))	('miR', 'Gene', '220972', (16, 19))	('deregulation', 'Var', (71, 83))	('human', 'Species', '9606', (26, 31))	('amplification', 'Var', (56, 69))
478162	24490161	MiRNAs acting as tumor suppressors can be downregulated in cancer by deletions, epigenetic silencing, or loss of transcription factor expression.	('transcription', 'MPA', (113, 126))	('tumor', 'Disease', (17, 22))	('MiRNAs', 'Protein', (0, 6))	('downregulated', 'NegReg', (42, 55))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('deletions', 'Var', (69, 78))	('loss', 'NegReg', (105, 109))	('epigenetic silencing', 'Var', (80, 100))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
478213	24490161	MCM7, a target of the E2F1 transcription factor, is a marker for CC and may be induced by both HPV16 E6 and E7.	('MCM7', 'Gene', (0, 4))	('HPV16 E6', 'Var', (95, 103))	('HPV16', 'Species', '333760', (95, 100))	('E2F1', 'Gene', '1869', (22, 26))	('CC', 'Phenotype', 'HP:0002664', (65, 67))	('E2F1', 'Gene', (22, 26))	('induced', 'Reg', (79, 86))	('MCM7', 'Gene', '4176', (0, 4))
478218	24490161	SPINK5 deficiency causes unregulated epidermal protease activity and degradation of desmoglein 1, which leads to inefficient stratum corneum adhesion and a resultant loss of skin barrier function.	('degradation', 'MPA', (69, 80))	('activity', 'MPA', (56, 64))	('SPINK5', 'Gene', '11005', (0, 6))	('loss', 'NegReg', (166, 170))	('epidermal protease', 'Enzyme', (37, 55))	('deficiency', 'Var', (7, 17))	('desmoglein 1', 'Gene', '1828', (84, 96))	('skin barrier function', 'CPA', (174, 195))	('desmoglein 1', 'Gene', (84, 96))	('stratum corneum adhesion', 'CPA', (125, 149))	('SPINK5', 'Gene', (0, 6))	('inefficient', 'NegReg', (113, 124))
478233	24490161	Inhibition of MNT expression promotes c-MYC activity and cell cycle progression in transformed cells such as colon cancer cells and CC cells (Figure 1).	('colon cancer', 'Phenotype', 'HP:0003003', (109, 121))	('colon cancer', 'Disease', 'MESH:D015179', (109, 121))	('MNT', 'Gene', (14, 17))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('c-MYC', 'Gene', '4609', (38, 43))	('colon cancer', 'Disease', (109, 121))	('cell cycle progression', 'CPA', (57, 79))	('Inhibition', 'Var', (0, 10))	('CC', 'Phenotype', 'HP:0002664', (132, 134))	('c-MYC', 'Gene', (38, 43))	('promotes', 'PosReg', (29, 37))
478249	24490161	Human papillomaviruses are a group of small DNA viruses that contain a small, double-stranded circular genome of ~8 kb and encode six viral early proteins (E6, E7, E1, E2, E4, and E5).	('Human', 'Disease', (0, 5))	('E5', 'Var', (180, 182))	('Human', 'Species', '9606', (0, 5))	('E6', 'Var', (156, 158))
478254	24490161	It is well know that a significant number of miRNAs are located in FRAs and that such sites are preferential targets for HPV16 integrations, sister chromatid exchange, translocation, deletion, and amplification in cervical tumors.	('HPV16', 'Species', '333760', (121, 126))	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('cervical tumors', 'Phenotype', 'HP:0030159', (214, 229))	('translocation', 'Var', (168, 181))	('tumors', 'Phenotype', 'HP:0002664', (223, 229))	('integrations', 'Var', (127, 139))	('amplification', 'Var', (197, 210))	('miR', 'Gene', (45, 48))	('sister chromatid exchange', 'Var', (141, 166))	('miR', 'Gene', '220972', (45, 48))	('HPV16', 'Gene', (121, 126))	('cervical tumors', 'Disease', 'MESH:D002583', (214, 229))	('deletion', 'Var', (183, 191))	('cervical tumors', 'Disease', (214, 229))
478261	24490161	miRNAs expression profiles by microarray analysis have shown that the miRNAs most highly expressed in normal cervix were miR-145, miR-26a, miR-99a, let-7a, miR-143, let-7b, let-7c, miR-125b, miR-126, and miR-195, in that order.	('miR-145', 'Gene', (121, 128))	('miR-143', 'Gene', '406935', (156, 163))	('miR-143', 'Gene', (156, 163))	('miR-1', 'Gene', '79187', (156, 161))	('let-7c', 'Gene', (173, 179))	('miR', 'Gene', (181, 184))	('let-7b', 'Gene', (165, 171))	('miR-1', 'Gene', (191, 196))	('miR-195', 'Gene', (204, 211))	('miR', 'Gene', (70, 73))	('miR-1', 'Gene', (181, 186))	('miR', 'Gene', (156, 159))	('miR', 'Gene', (204, 207))	('miR-1', 'Gene', '79187', (121, 126))	('miR', 'Gene', '220972', (139, 142))	('let-7a', 'Var', (148, 154))	('miR-1', 'Gene', (204, 209))	('miR', 'Gene', '220972', (130, 133))	('let-7c', 'Gene', '406885', (173, 179))	('let-7', 'Chemical', '-', (165, 170))	('miR', 'Gene', '220972', (121, 124))	('miR-26a', 'Gene', (130, 137))	('miR', 'Gene', '220972', (204, 207))	('miR', 'Gene', '220972', (191, 194))	('miR-126', 'Gene', (191, 198))	('let-7', 'Chemical', '-', (148, 153))	('miR', 'Gene', (139, 142))	('miR-1', 'Gene', '79187', (191, 196))	('miR-99a', 'Gene', (139, 146))	('let-7', 'Chemical', '-', (173, 178))	('miR-1', 'Gene', '79187', (181, 186))	('miR', 'Gene', (130, 133))	('miR', 'Gene', '220972', (0, 3))	('miR-26a', 'Gene', '407015', (130, 137))	('miR-1', 'Gene', (156, 161))	('miR', 'Gene', (121, 124))	('miR', 'Gene', (191, 194))	('miR-1', 'Gene', '79187', (204, 209))	('miR-1', 'Gene', (121, 126))	('miR-145', 'Gene', '406937', (121, 128))	('miR', 'Gene', '220972', (181, 184))	('let-7b', 'Gene', '406884', (165, 171))	('miR', 'Gene', (0, 3))	('miR', 'Gene', '220972', (70, 73))	('miR-126', 'Gene', '406913', (191, 198))	('highly', 'PosReg', (82, 88))	('miR-195', 'Gene', '406971', (204, 211))	('miR', 'Gene', '220972', (156, 159))	('miR-99a', 'Gene', '407055', (139, 146))
478264	24490161	Interestingly, it has been shown that also miR-218 is underexpressed in the cell lines containing integrated HPV16 DNA as compared to both the normal cervix and HPV-negative C-33A cell line.	('C-33A', 'Mutation', 'c.-33C>A', (174, 179))	('miR-21', 'Gene', '406991', (43, 49))	('HPV16', 'Species', '333760', (109, 114))	('underexpressed', 'NegReg', (54, 68))	('miR-21', 'Gene', (43, 49))	('HPV', 'Species', '10566', (109, 112))	('HPV', 'Species', '10566', (161, 164))	('HPV16 DNA', 'Var', (109, 118))
478265	24490161	So, this could suggest that miR-218 may be specifically affected by the presence of HPV16.	('HPV16', 'Gene', (84, 89))	('miR-21', 'Gene', (28, 34))	('presence', 'Var', (72, 80))	('affected', 'Reg', (56, 64))	('miR-21', 'Gene', '406991', (28, 34))	('HPV16', 'Species', '333760', (84, 89))
478277	24490161	It has been documented that transfection of miR-34a induces cell cycle arrest in immortalized mouse cells and in human tumor cell lines and sensitizes to apoptosis in response to genotoxic stress, which is consistent with the observed ability of miR-34a to downregulate genes promoting cell cycle including Cyclin E2, Cyclin D1, CDK4, CDK6, E2F1, E2F3, E2F5, and SIRT1.	('E2F5', 'Gene', (353, 357))	('Cyclin D1', 'Gene', '595', (318, 327))	('Cyclin E2', 'Gene', '9134', (307, 316))	('E2F3', 'Gene', '1871', (347, 351))	('Cyclin D1', 'Gene', (318, 327))	('CDK6', 'Gene', '1021', (335, 339))	('miR-34a', 'Var', (44, 51))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('human', 'Species', '9606', (113, 118))	('E2F1', 'Gene', (341, 345))	('cell cycle', 'CPA', (286, 296))	('downregulate', 'NegReg', (257, 269))	('CDK4', 'Gene', (329, 333))	('CDK6', 'Gene', (335, 339))	('mouse', 'Species', '10090', (94, 99))	('cell cycle arrest', 'CPA', (60, 77))	('E2F5', 'Gene', '1875', (353, 357))	('SIRT1', 'Gene', '23411', (363, 368))	('Cyclin E2', 'Gene', (307, 316))	('E2F1', 'Gene', '1869', (341, 345))	('transfection', 'Var', (28, 40))	('CDK4', 'Gene', '1019', (329, 333))	('tumor', 'Disease', (119, 124))	('E2F3', 'Gene', (347, 351))	('SIRT1', 'Gene', (363, 368))	('promoting', 'PosReg', (276, 285))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (60, 77))	('tumor', 'Disease', 'MESH:D009369', (119, 124))
478281	24490161	miR-218 is specifically underexpressed in cervical cell lines, cervical lesions, and cancer tissues containing integrated HPV16 DNA compared to the normal cervix.	('integrated', 'Var', (111, 121))	('HPV16', 'Species', '333760', (122, 127))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('miR-21', 'Gene', (0, 6))	('HPV16', 'Gene', (122, 127))	('cancer', 'Disease', (85, 91))	('underexpressed', 'NegReg', (24, 38))	('miR-21', 'Gene', '406991', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
478287	24490161	It is known that E7-mediated degradation of pRB releases E2F from the pRB-E2F complex to act as transcriptional factor.	('pRB', 'Gene', '5925', (70, 73))	('pRB', 'Gene', '5925', (44, 47))	('degradation', 'Var', (29, 40))	('pRB', 'Gene', (70, 73))	('pRB', 'Gene', (44, 47))	('E7-mediated', 'Var', (17, 28))
478299	24490161	Otherwise, several downstream targets of p63 were increased in E7-expressing cells, and their levels were inversely correlated with amounts of miR-203.	('p63', 'Gene', (41, 44))	('levels', 'MPA', (94, 100))	('increased', 'PosReg', (50, 59))	('p63', 'Gene', '8626', (41, 44))	('miR-203', 'Gene', '406986', (143, 150))	('miR-203', 'Gene', (143, 150))	('E7-expressing', 'Var', (63, 76))
478304	24490161	found that CDK6 was positively correlated with E6/E7 mRNA expression.	('correlated', 'Interaction', (31, 41))	('E6/E7', 'Var', (47, 52))	('CDK6', 'Gene', (11, 15))	('CDK6', 'Gene', '1021', (11, 15))
478306	24490161	This action requires cyclin D1 binding to CDK4 and CDK6, which phosphorylate and inactivate RB1, leading to the release of E2F transcription factors and the subsequent progression of the cell into the S phase.	('E2F', 'Protein', (123, 126))	('RB1', 'Gene', '5925', (92, 95))	('CDK4', 'Gene', '1019', (42, 46))	('inactivate', 'Var', (81, 91))	('binding', 'Interaction', (31, 38))	('release', 'MPA', (112, 119))	('CDK6', 'Gene', (51, 55))	('progression', 'CPA', (168, 179))	('CDK6', 'Gene', '1021', (51, 55))	('RB1', 'Gene', (92, 95))	('cyclin D1', 'Gene', '595', (21, 30))	('cyclin D1', 'Gene', (21, 30))	('CDK4', 'Gene', (42, 46))
478319	24490161	It has been observed that genes implicated in cell motility and cell adhesion are affected by E5 expression, which suggests that E5 is highly implicated in the carcinogenic process.	('implicated', 'Reg', (142, 152))	('expression', 'Var', (97, 107))	('affected', 'Reg', (82, 90))	('carcinogenic process', 'Disease', (160, 180))	('carcinogenic process', 'Disease', 'MESH:D009385', (160, 180))
478328	24490161	Additionally to the posttranscriptional negative regulation of PDZD2 by miR-146a, HR-HPVE6 may potentially interact with this PDZ domain containing protein and, after E6AP ubiquitin ligase recruitment, induce its degradation.	('induce', 'Reg', (202, 208))	('E6AP', 'Var', (167, 171))	('miR-146a', 'Gene', '406938', (72, 80))	('interact', 'Interaction', (107, 115))	('PDZD2', 'Gene', (63, 68))	('HR-HPV', 'Disease', 'MESH:D030361', (82, 88))	('miR-146a', 'Gene', (72, 80))	('degradation', 'MPA', (213, 224))	('HR-HPV', 'Disease', (82, 88))	('PDZD2', 'Gene', '23037', (63, 68))	('negative regulation', 'NegReg', (40, 59))
478346	24490161	This shows that many aberrantly expressed miRNAs in CC could serve as prognostic biomarkers (Table 1).	('aberrantly expressed', 'Var', (21, 41))	('CC', 'Phenotype', 'HP:0002664', (52, 54))	('miR', 'Gene', '220972', (42, 45))	('miR', 'Gene', (42, 45))
478364	33671768	Genotoxicity or epigenetic modifications by inflammatory cells resulted in gene mutations or altered gene expression, respectively.	('toxicity', 'Disease', 'MESH:D064420', (4, 12))	('altered', 'Reg', (93, 100))	('toxicity', 'Disease', (4, 12))	('gene', 'MPA', (75, 79))	('resulted in', 'Reg', (63, 74))	('epigenetic modifications', 'Var', (16, 40))	('gene expression', 'MPA', (101, 116))
478373	33671768	Inflammation is thus the most effective intrinsic factor required to repeatedly maintain the states of "tissue damage", "genetic instability", and "growth stimulation".	('Inflammation', 'Disease', 'MESH:D007249', (0, 12))	('genetic instability', 'Var', (121, 140))	('Inflammation', 'Disease', (0, 12))
478374	33671768	Moreover, epigenetic alterations such as aberrant DNA hypermethylation are involved in the inflammation-related cancers.	('involved', 'Reg', (75, 83))	('inflammation-related cancers', 'Disease', 'MESH:D009369', (91, 119))	('cancers', 'Phenotype', 'HP:0002664', (112, 119))	('aberrant DNA hypermethylation', 'Var', (41, 70))	('rat', 'Species', '10116', (25, 28))	('inflammation-related cancers', 'Disease', (91, 119))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))
478396	33671768	When mice were treated with 4-NQO and with ethanol in drinking water, they developed mast cell infiltration and had increased expressions of the inflammatory mediators, 5-lipoxygenase and cyclooxygenase-2 (COX-2), and, thereafter, developed oral dysplasia and squamous cell carcinoma.	('5-lipoxygenase', 'Gene', (169, 183))	('increased', 'PosReg', (116, 125))	('mice', 'Species', '10090', (5, 9))	('COX-2', 'Gene', (206, 211))	('4-NQO', 'Chemical', 'MESH:D015112', (28, 33))	('expressions', 'MPA', (126, 137))	('cyclooxygenase-2', 'Gene', '19225', (188, 204))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (260, 283))	('water', 'Chemical', 'MESH:D014867', (63, 68))	('cyclooxygenase-2', 'Gene', (188, 204))	('rat', 'Species', '10116', (101, 104))	('5-lipoxygenase', 'Gene', '11689', (169, 183))	('mast cell infiltration', 'CPA', (85, 107))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (260, 283))	('4-NQO', 'Var', (28, 33))	('COX-2', 'Gene', '19225', (206, 211))	('oral dysplasia', 'Disease', (241, 255))	('developed', 'PosReg', (231, 240))	('ethanol', 'Chemical', 'MESH:D000431', (43, 50))	('oral dysplasia', 'Disease', 'MESH:D020820', (241, 255))	('carcinoma', 'Phenotype', 'HP:0030731', (274, 283))	('squamous cell carcinoma', 'Disease', (260, 283))
478397	33671768	Overactivation of the inhibitor of nuclear factor kappa-B kinase (IKK) complex caused the activation of nuclear factor kappa-B (NF-kB), leading to severe inflammation.	('NF-kB', 'Gene', '81736', (128, 133))	('activation', 'PosReg', (90, 100))	('nuclear factor', 'Protein', (104, 118))	('leading to', 'Reg', (136, 146))	('IKK', 'Gene', (66, 69))	('NF-kB', 'Gene', (128, 133))	('IKK', 'Gene', '12675;16150', (66, 69))	('inflammation', 'Disease', 'MESH:D007249', (154, 166))	('inflammation', 'Disease', (154, 166))	('Overactivation', 'Var', (0, 14))
478398	33671768	In the oral epithelia of IKK subunit beta (IKKbeta) transgenic mice, produced in persistent lichenoid inflammation due to neutrophil, macrophage, and B cell infiltration, spontaneous oral squamous cell carcinomas were formed.	('carcinomas', 'Phenotype', 'HP:0030731', (202, 212))	('IKKbeta', 'Gene', '12675', (43, 50))	('IKK', 'Gene', '12675;16150', (43, 46))	('IKK', 'Gene', '12675;16150', (25, 28))	('lichenoid inflammation', 'Disease', 'MESH:D007249', (92, 114))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (188, 212))	('neu', 'Gene', '13866', (122, 125))	('lichenoid inflammation', 'Disease', (92, 114))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (188, 211))	('oral squamous cell carcinomas', 'Disease', 'MESH:D002294', (183, 212))	('rat', 'Species', '10116', (163, 166))	('lichenoid inflammation', 'Phenotype', 'HP:0031452', (92, 114))	('neu', 'Gene', (122, 125))	('IKKbeta', 'Gene', (43, 50))	('IKK', 'Gene', (43, 46))	('oral squamous cell carcinomas', 'Disease', (183, 212))	('transgenic', 'Var', (52, 62))	('transgenic mice', 'Species', '10090', (52, 67))	('IKK', 'Gene', (25, 28))	('carcinoma', 'Phenotype', 'HP:0030731', (202, 211))
478401	33671768	Homozygous deletion of Toll-like receptor 2 (TLR2-/-) using 4-NQO in mice increased the number of tongue-infiltrating M2 macrophages and resulted in the development of tongue cancer.	('rat', 'Species', '10116', (111, 114))	('Toll-like receptor 2', 'Gene', '24088', (23, 43))	('resulted in', 'Reg', (137, 148))	('tongue cancer', 'Disease', (168, 181))	('increased', 'PosReg', (74, 83))	('TLR2-/-', 'Gene', (45, 52))	('Toll-like receptor 2', 'Gene', (23, 43))	('mice', 'Species', '10090', (69, 73))	('tongue cancer', 'Disease', 'MESH:D014062', (168, 181))	('men', 'Species', '9606', (160, 163))	('development of tongue', 'Phenotype', 'HP:0012730', (153, 174))	('deletion', 'Var', (11, 19))	('4-NQO', 'Chemical', 'MESH:D015112', (60, 65))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
478404	33671768	The link between inflammation and esophageal cancer is well-established; in particular, interleukin (IL)-1beta is overexpressed in Barrett's esophagus, and polymorphisms in the IL-1beta gene are associated with Barrett's esophagus.	("Barrett's esophagus", 'Disease', (211, 230))	('esophageal cancer', 'Disease', (34, 51))	('IL-1beta', 'Gene', (177, 185))	('associated', 'Reg', (195, 205))	('esophageal cancer', 'Disease', 'MESH:D004938', (34, 51))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (211, 230))	('interleukin (IL)-1beta', 'Gene', (88, 110))	('interleukin (IL)-1beta', 'Gene', '16175', (88, 110))	('overexpressed', 'PosReg', (114, 127))	('inflammation', 'Disease', 'MESH:D007249', (17, 29))	("Barrett's esophagus", 'Disease', (131, 150))	("Barrett's esophagus", 'Phenotype', 'HP:0100580', (131, 150))	('polymorphisms', 'Var', (156, 169))	('inflammation', 'Disease', (17, 29))
478412	33671768	The C57BL/6 strain is considered to be carcinogenic-tolerant, while the BALB/c strain is moderately sensitive.	('carcinogenic-tolerant', 'Disease', 'MESH:D018149', (39, 60))	('carcinogenic-tolerant', 'Disease', (39, 60))	('C57BL/6', 'Var', (4, 11))	('rat', 'Species', '10116', (93, 96))
478414	33671768	The reason for the highest sensitivity of A/J mice to the development of lung tumors is that they have the K-ras intron 2 polymorphism and, thus, undergo activation of the K-ras oncogene.	('polymorphism', 'Var', (122, 134))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('men', 'Species', '9606', (65, 68))	('lung tumors', 'Disease', 'MESH:D008175', (73, 84))	('activation', 'PosReg', (154, 164))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('mice', 'Species', '10090', (46, 50))	('lung tumors', 'Phenotype', 'HP:0100526', (73, 84))	('lung tumors', 'Disease', (73, 84))
478431	33671768	Most of the experimental adenocarcinomas exhibited mutations in K-ras, either in codon 12 or in codon 61.	('K-ras', 'Protein', (64, 69))	('mutations', 'Var', (51, 60))	('exhibited', 'Reg', (41, 50))	('men', 'Species', '9606', (18, 21))	('adenocarcinomas', 'Disease', 'MESH:D000230', (25, 40))	('adenocarcinomas', 'Disease', (25, 40))	('carcinoma', 'Phenotype', 'HP:0030731', (30, 39))	('carcinomas', 'Phenotype', 'HP:0030731', (30, 40))
478432	33671768	Lung adenocarcinoma developed in mice treated with N-nitrosodimethylamine (NDMA) alone showed A-to-G transition (Q61R) at K-ras codon 61, whereas mice treated with NDMA and oropharyngeal administration of silica showed G-to-A transition (G12D) in codon 12.	('Q61R', 'Var', (113, 117))	('Q61R', 'Mutation', 'rs121913240', (113, 117))	('NDMA', 'Chemical', 'MESH:D004128', (75, 79))	('Lung adenocarcinoma', 'Phenotype', 'HP:0030078', (0, 19))	('G12D', 'Mutation', 'rs121913529', (238, 242))	('carcinoma', 'Phenotype', 'HP:0030731', (10, 19))	('mice', 'Species', '10090', (146, 150))	('NDMA', 'Chemical', 'MESH:D004128', (164, 168))	('mice', 'Species', '10090', (33, 37))	('rat', 'Species', '10116', (195, 198))	('min', 'Gene', (69, 72))	('min', 'Gene', (189, 192))	('silica', 'Chemical', 'MESH:D012822', (205, 211))	('Lung adenocarcinoma', 'Disease', (0, 19))	('Lung adenocarcinoma', 'Disease', 'MESH:D000077192', (0, 19))	('N-nitrosodimethylamine', 'Chemical', 'MESH:D004128', (51, 73))	('min', 'Gene', '11789', (189, 192))	('min', 'Gene', '11789', (69, 72))
478433	33671768	Therefore, among the K-ras mutation profiles of lung cancer, the Q61R to G12D mutations can occur in an inflammatory environment.	('G12D', 'Mutation', 'rs121913529', (73, 77))	('lung cancer', 'Disease', 'MESH:D008175', (48, 59))	('Q61R to G12D', 'Var', (65, 77))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('lung cancer', 'Disease', (48, 59))	('lung cancer', 'Phenotype', 'HP:0100526', (48, 59))	('Q61R', 'Mutation', 'rs121913240', (65, 69))
478434	33671768	Benzo[a]pyrene (B[a]P) is present in tobacco metabolites and is metabolized into epoxide, which induces DNA adducts and causes mutations due to ROS generation, which can together accelerate the process of lung tumorigenesis.	('Benzo[a]pyrene', 'Chemical', 'MESH:D001564', (0, 14))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('tobacco', 'Species', '4097', (37, 44))	('rat', 'Species', '10116', (152, 155))	('accelerate', 'PosReg', (179, 189))	('epoxide', 'Chemical', 'MESH:D004852', (81, 88))	('ROS', 'Chemical', 'MESH:D017382', (144, 147))	('tumor', 'Disease', (210, 215))	('ROS generation', 'MPA', (144, 158))	('induces', 'Reg', (96, 103))	('lung', 'Disease', (205, 209))	('B[a]P', 'Chemical', 'MESH:D001564', (16, 21))	('mutations', 'Var', (127, 136))	('DNA adducts', 'MPA', (104, 115))	('rat', 'Species', '10116', (185, 188))	('tumor', 'Disease', 'MESH:D009369', (210, 215))
478435	33671768	C57BL/6 mice exposed to B[a]p with intratracheal LPS administration formed more lung tumors than mice exposed to B[a]p alone.	('lung tumors', 'Phenotype', 'HP:0100526', (80, 91))	('B[a]p', 'Var', (24, 29))	('lung tumors', 'Disease', 'MESH:D008175', (80, 91))	('rat', 'Species', '10116', (61, 64))	('mice', 'Species', '10090', (97, 101))	('rat', 'Species', '10116', (38, 41))	('min', 'Gene', (55, 58))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('lung tumors', 'Disease', (80, 91))	('min', 'Gene', '11789', (55, 58))	('mice', 'Species', '10090', (8, 12))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))
478439	33671768	The homozygous conditional deletion of mitogen-induced gene 6 (Mig-6d/d) and mutated K-ras (K-RasG12D) occurs in transgenic mouse (Mig-6d/dK-RasG12D) in which a signaling molecule, Mig-6, is deleted and K-ras (G12D) is activated in lung Clara cells.	('Mig-6', 'Gene', '74155', (181, 186))	('Mig-6', 'Gene', (181, 186))	('G12D', 'Mutation', 'rs121913529', (97, 101))	('Mig-6', 'Gene', '74155', (63, 68))	('K-RasG12D', 'Gene', '16653', (92, 101))	('Mig-6', 'Gene', (63, 68))	('mouse', 'Species', '10090', (124, 129))	('Mig-6', 'Gene', '74155', (131, 136))	('deletion', 'Var', (27, 35))	('Mig-6', 'Gene', (131, 136))	('transgenic', 'Species', '10090', (113, 123))	('K-RasG12D', 'Gene', '16653', (139, 148))	('K-RasG12D', 'Gene', (92, 101))	('K-RasG12D', 'Gene', (139, 148))	('G12D', 'Mutation', 'rs121913529', (144, 148))	('G12D', 'Mutation', 'rs121913529', (210, 214))
478454	33671768	The histological types of gastric cancer developed by H. pylori and MNU caused poorly differentiated, signet-ring cells and well-differentiated adenocarcinoma.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('H. pylori', 'Var', (54, 63))	('caused', 'Reg', (72, 78))	('carcinoma', 'Phenotype', 'HP:0030731', (149, 158))	('MNU', 'Gene', (68, 71))	('adenocarcinoma', 'Disease', (144, 158))	('gastric cancer', 'Disease', (26, 40))	('gastric cancer', 'Disease', 'MESH:D013274', (26, 40))	('adenocarcinoma', 'Disease', 'MESH:D000230', (144, 158))	('MNU', 'Chemical', 'MESH:D008770', (68, 71))	('gastric cancer', 'Phenotype', 'HP:0012126', (26, 40))	('signet-ring cells', 'Disease', (102, 119))	('poorly differentiated', 'CPA', (79, 100))	('H. pylori', 'Species', '210', (54, 63))
478474	33671768	The homozygous knock-in substitution of a glycoprotein 130 (gp130Y757F/Y757F) mouse carries a mutated gp130 cytokine receptor signaling subunit that cannot bind the negative regulator of cytokine signaling SOCS3 and hyperactivates STAT1 and STAT3 signaling.	('Y757F', 'Mutation', 'p.Y757F', (71, 76))	('STAT3', 'Gene', (241, 246))	('STAT1', 'Gene', '20846', (231, 236))	('Y757F', 'Mutation', 'p.Y757F', (65, 70))	('hyperactivates', 'PosReg', (216, 230))	('STAT1', 'Gene', (231, 236))	('SOCS3', 'Gene', (206, 211))	('mouse', 'Species', '10090', (78, 83))	('SOCS3', 'Gene', '12702', (206, 211))	('gp130Y757F/Y757F', 'Var', (60, 76))	('STAT3', 'Gene', '20848', (241, 246))
478476	33671768	gp130Y757F/Y757F causes the development of those gastric cancer-accompanying hyperplasia, with histological features reminiscent of those intestinal-type and metaplastic gastric tumors in humans.	('men', 'Species', '9606', (35, 38))	('causes', 'Reg', (17, 23))	('gastric tumors', 'Disease', (170, 184))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('gastric cancer', 'Disease', 'MESH:D013274', (49, 63))	('hyperplasia', 'Disease', (77, 88))	('humans', 'Species', '9606', (188, 194))	('hyperplasia', 'Disease', 'MESH:D006965', (77, 88))	('Y757F', 'Mutation', 'p.Y757F', (5, 10))	('gp130Y757F/Y757F', 'Var', (0, 16))	('tumors', 'Phenotype', 'HP:0002664', (178, 184))	('gastric cancer', 'Phenotype', 'HP:0012126', (49, 63))	('min', 'Gene', (119, 122))	('min', 'Gene', '11789', (119, 122))	('gastric tumors', 'Disease', 'MESH:D013274', (170, 184))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('gastric tumors', 'Phenotype', 'HP:0006753', (170, 184))	('Y757F', 'Mutation', 'p.Y757F', (11, 16))	('gastric cancer', 'Disease', (49, 63))
478477	33671768	The stomach-specific expression of human IL-1beta in transgenic mice leads to gastric inflammation and cancer by the early recruitment of myeloid-derived suppressor cells, while T and B cells are not needed for this phenomenon.	('gastric inflammation', 'Disease', 'MESH:D013272', (78, 98))	('gastric inflammation', 'Disease', (78, 98))	('gastric inflammation', 'Phenotype', 'HP:0005263', (78, 98))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('transgenic mice', 'Species', '10090', (53, 68))	('human', 'Species', '9606', (35, 40))	('leads to', 'Reg', (69, 77))	('men', 'Species', '9606', (221, 224))	('IL-1beta', 'Gene', (41, 49))	('expression', 'Var', (21, 31))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('men', 'Species', '9606', (130, 133))
478480	33671768	Carriers of IL-1beta polymorphisms are at risk for human gastric cancer.	('IL-1beta', 'Gene', (12, 20))	('gastric cancer', 'Disease', (57, 71))	('gastric cancer', 'Disease', 'MESH:D013274', (57, 71))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('human', 'Species', '9606', (51, 56))	('risk', 'Reg', (42, 46))	('gastric cancer', 'Phenotype', 'HP:0012126', (57, 71))	('polymorphisms', 'Var', (21, 34))
478491	33671768	HBsAg in hepatocytes induces liver regeneration due to induction of inflammation and the associated ROS, which impairs their ability to replicate and allows the activation of hepatic stem cells.	('induces', 'PosReg', (21, 28))	('ROS', 'Chemical', 'MESH:D017382', (100, 103))	('inflammation', 'Disease', 'MESH:D007249', (68, 80))	('HBsAg', 'Var', (0, 5))	('rat', 'Species', '10116', (41, 44))	('ROS', 'Gene', (100, 103))	('inflammation', 'Disease', (68, 80))	('ability', 'MPA', (125, 132))	('liver', 'Disease', (29, 34))	('impairs', 'NegReg', (111, 118))
478516	33671768	Deletion of the ATP7B gene, which is homologous to the Wilson's disease gene, has been identified in LEC rats.	("Wilson's disease", 'Disease', (55, 71))	('ATP7B', 'Gene', '24218', (16, 21))	('ATP7B', 'Gene', (16, 21))	('LEC', 'Gene', (101, 104))	('LEC', 'Gene', '6360', (101, 104))	("Wilson's disease", 'Disease', 'MESH:D006527', (55, 71))	('rats', 'Species', '10116', (105, 109))	('Deletion', 'Var', (0, 8))
478542	33671768	Aberrant lipogenesis in the liver, which is closely linked to obesity and metabolic syndrome, causes nonalcoholic fatty liver disease (NAFLD), which is observed in 75-100% of overweight and obese adults and children.	('overweight', 'Phenotype', 'HP:0025502', (175, 185))	('fatty liver', 'Phenotype', 'HP:0001397', (114, 125))	('lipogenesis', 'MPA', (9, 20))	('nonalcoholic fatty liver disease', 'Disease', (101, 133))	('metabolic syndrome', 'Disease', 'MESH:D024821', (74, 92))	('obese', 'Disease', (190, 195))	('Aberrant', 'Var', (0, 8))	('obesity', 'Phenotype', 'HP:0001513', (62, 69))	('children', 'Species', '9606', (207, 215))	('causes', 'Reg', (94, 100))	('obese', 'Disease', 'MESH:D009765', (190, 195))	('nonalcoholic fatty liver disease', 'Disease', 'MESH:D065626', (101, 133))	('Aberrant lipogenesis', 'Phenotype', 'HP:0009125', (0, 20))	('liver disease', 'Phenotype', 'HP:0001392', (120, 133))	('obesity', 'Disease', (62, 69))	('NAFLD', 'Gene', (135, 140))	('NAFLD', 'Gene', '22084', (135, 140))	('obesity', 'Disease', 'MESH:D009765', (62, 69))	('metabolic syndrome', 'Disease', (74, 92))
478546	33671768	MSG induced beta cell proliferation and caused islet hypertrophy, leading to the development of obesity and steatosis with the infiltration of neutrophils and the onset of diabetes mellitus.	('obesity', 'Phenotype', 'HP:0001513', (96, 103))	('diabetes mellitus', 'Disease', 'MESH:D003920', (172, 189))	('MSG', 'Var', (0, 3))	('hypertrophy', 'Disease', 'MESH:D006984', (53, 64))	('diabetes mellitus', 'Phenotype', 'HP:0000819', (172, 189))	('rat', 'Species', '10116', (133, 136))	('neu', 'Gene', '13866', (143, 146))	('hypertrophy', 'Disease', (53, 64))	('men', 'Species', '9606', (88, 91))	('MSG', 'Chemical', 'MESH:D012970', (0, 3))	('islet', 'Disease', (47, 52))	('rat', 'Species', '10116', (29, 32))	('beta cell proliferation', 'CPA', (12, 35))	('obesity and steatosis', 'Disease', 'MESH:D009765', (96, 117))	('islet hypertrophy', 'Phenotype', 'HP:0004510', (47, 64))	('diabetes mellitus', 'Disease', (172, 189))	('steatosis', 'Phenotype', 'HP:0001397', (108, 117))	('neu', 'Gene', (143, 146))	('leading to', 'Reg', (66, 76))
478559	33671768	It is known that approximately half of human liver tumors have G-T (Q61K) mutations at codon 61 of the H-ras oncogene.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('liver tumors', 'Disease', 'MESH:D008113', (45, 57))	('G-T (Q61K', 'Var', (63, 72))	('H-ras', 'Gene', '3265', (103, 108))	('liver tumors', 'Disease', (45, 57))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('Q61K', 'Mutation', 'rs28933406', (68, 72))	('liver tumors', 'Phenotype', 'HP:0002896', (45, 57))	('H-ras', 'Gene', (103, 108))	('human', 'Species', '9606', (39, 44))
478560	33671768	Whole-exome sequencing of liver tumors formed in HFD mice showed that similar G-T point mutations occurred predominantly.	('liver tumors', 'Disease', 'MESH:D008113', (26, 38))	('point mutations', 'Var', (82, 97))	('liver tumors', 'Disease', (26, 38))	('liver tumors', 'Phenotype', 'HP:0002896', (26, 38))	('min', 'Gene', (112, 115))	('min', 'Gene', '11789', (112, 115))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('mice', 'Species', '10090', (53, 57))
478571	33671768	TAA stimulates the infiltration of inflammatory cells, hepatic macrophages, and CD3+ T cells.	('infiltration', 'CPA', (19, 31))	('TAA', 'Var', (0, 3))	('CD3', 'Gene', (80, 83))	('rat', 'Species', '10116', (25, 28))	('TAA', 'Chemical', 'MESH:D013853', (0, 3))	('CD3', 'Gene', '12501', (80, 83))
478575	33671768	CCl4 induced chronic hepatotoxicity, such as fatty change, fibrosis, and cirrhosis, and led to the development of hepatocellular adenomas and HCC.	('hepatocellular adenomas', 'Phenotype', 'HP:0012028', (114, 137))	('cirrhosis', 'Disease', (73, 82))	('chronic hepatotoxicity', 'Disease', 'MESH:D056487', (13, 35))	('chronic hepatotoxicity', 'Disease', (13, 35))	('fibrosis', 'Disease', (59, 67))	('led to', 'Reg', (88, 94))	('hepatocellular adenomas', 'Disease', 'MESH:D018248', (114, 137))	('cirrhosis', 'Phenotype', 'HP:0001394', (73, 82))	('fatty', 'Disease', (45, 50))	('hepatocellular adenomas', 'Disease', (114, 137))	('fibrosis', 'Disease', 'MESH:D005355', (59, 67))	('CCl4', 'Var', (0, 4))	('cirrhosis', 'Disease', 'MESH:D005355', (73, 82))	('HCC', 'Disease', (142, 145))	('HCC', 'Phenotype', 'HP:0001402', (142, 145))	('men', 'Species', '9606', (106, 109))
478578	33671768	The hepatocyte-specific homozygous deletion of Atg5 (Atg5-/-) mice resulted in increased inflammation and fibrosis and led to the formation of hepatocellular adenomas in the liver that was infiltrated with neutrophils and macrophages.	('hepatocellular adenomas', 'Disease', (143, 166))	('increased', 'PosReg', (79, 88))	('Atg5', 'Gene', '11793', (47, 51))	('fibrosis', 'Disease', (106, 114))	('mice', 'Species', '10090', (62, 66))	('fibrosis', 'Disease', 'MESH:D005355', (106, 114))	('Atg5', 'Gene', '11793', (53, 57))	('neu', 'Gene', (206, 209))	('hepatocellular adenomas', 'Phenotype', 'HP:0012028', (143, 166))	('inflammation', 'Disease', 'MESH:D007249', (89, 101))	('deletion', 'Var', (35, 43))	('rat', 'Species', '10116', (195, 198))	('neu', 'Gene', '13866', (206, 209))	('inflammation', 'Disease', (89, 101))	('led to', 'Reg', (119, 125))	('hepatocellular adenomas', 'Disease', 'MESH:D018248', (143, 166))	('Atg5', 'Gene', (47, 51))	('Atg5', 'Gene', (53, 57))
478582	33671768	The homozygous deletion of the farnesoid X receptor (Fxr-/-) in mice results in the accumulation of high levels of bile acids, which provokes inflammation-induced hepatocarcinogenesis with fibrosis and hepatosteatosis.	('provokes', 'Reg', (133, 141))	('high levels of bile acids', 'MPA', (100, 125))	('deletion', 'Var', (15, 23))	('inflammation-induced hepatocarcinogenesis', 'Disease', 'MESH:D007249', (142, 183))	('Fxr', 'Gene', (53, 56))	('high levels of bile acids', 'Phenotype', 'HP:0012202', (100, 125))	('bile acids', 'Chemical', 'MESH:D001647', (115, 125))	('inflammation-induced hepatocarcinogenesis', 'Disease', (142, 183))	('mice', 'Species', '10090', (64, 68))	('steatosis', 'Phenotype', 'HP:0001397', (208, 217))	('accumulation', 'PosReg', (84, 96))	('Fxr', 'Gene', '20186', (53, 56))	('fibrosis and hepatosteatosis', 'Disease', 'MESH:D005355', (189, 217))
478590	33671768	Due to the insufficient secretion of phospholipids into the bile, mice with a homozygous deletion of the Mdr2 P-glycoprotein (Mdr2-/-) gene develop nonsuppurative inflammatory cholangitis, which mainly contributes to B cells and stimulates tube proliferation, and most mice develop HCC.	('rat', 'Species', '10116', (156, 159))	('develop', 'PosReg', (140, 147))	('tube proliferation', 'CPA', (240, 258))	('rat', 'Species', '10116', (252, 255))	('HCC', 'Phenotype', 'HP:0001402', (282, 285))	('cholangitis', 'Disease', 'MESH:D002761', (176, 187))	('nonsuppurative inflammatory cholangitis', 'Phenotype', 'HP:0030987', (148, 187))	('Mdr2', 'Gene', (126, 130))	('mice', 'Species', '10090', (66, 70))	('phospholipids', 'Chemical', 'MESH:D010743', (37, 50))	('Mdr2', 'Gene', '18670', (105, 109))	('deletion', 'Var', (89, 97))	('cholangitis', 'Disease', (176, 187))	('mice', 'Species', '10090', (269, 273))	('cholangitis', 'Phenotype', 'HP:0030151', (176, 187))	('Mdr2', 'Gene', '18670', (126, 130))	('Mdr2', 'Gene', (105, 109))	('HCC', 'Disease', (282, 285))
478596	33671768	Oncogenic K-ras mutation represents the most frequent and earliest genetic alteration in PDAC patients, which highlights its role as a driver of PDAC.	('mutation', 'Var', (16, 24))	('PDAC', 'Chemical', '-', (89, 93))	('K-ras', 'Protein', (10, 15))	('patients', 'Species', '9606', (94, 102))	('PDAC', 'Chemical', '-', (145, 149))	('PDAC', 'Disease', (89, 93))	('PDAC', 'Phenotype', 'HP:0006725', (89, 93))	('rat', 'Species', '10116', (79, 82))	('Oncogenic', 'Var', (0, 9))	('PDAC', 'Phenotype', 'HP:0006725', (145, 149))
478611	33671768	DSS induces colonic inflammation and its associated dysplasia and carcinomas in guinea pigs, rabbits, hamsters, and mice with clinical and histopathological similarity to human ulcerative colitis (UC).	('dysplasia', 'Disease', (52, 61))	('carcinoma', 'Phenotype', 'HP:0030731', (66, 75))	('carcinomas', 'Phenotype', 'HP:0030731', (66, 76))	('ulcerative colitis', 'Phenotype', 'HP:0100279', (177, 195))	('colonic inflammation', 'Disease', (12, 32))	('DSS', 'Chemical', 'MESH:D016264', (0, 3))	('colitis', 'Phenotype', 'HP:0002583', (188, 195))	('hamster', 'Species', '10034', (102, 109))	('UC', 'Phenotype', 'HP:0100279', (197, 199))	('mice', 'Species', '10090', (116, 120))	('ulcerative colitis', 'Disease', (177, 195))	('dysplasia', 'Disease', 'MESH:C536170', (52, 61))	('carcinomas', 'Disease', (66, 76))	('colonic inflammation', 'Disease', 'MESH:D007249', (12, 32))	('induces', 'Reg', (4, 11))	('DSS', 'Var', (0, 3))	('ulcerative colitis', 'Disease', 'MESH:D003093', (177, 195))	('rabbits', 'Species', '9986', (93, 100))	('human', 'Species', '9606', (171, 176))	('guinea pigs', 'Species', '10141', (80, 91))	('carcinomas', 'Disease', 'MESH:D009369', (66, 76))
478652	33671768	The Min/Min homozygous mutation of the adenomatous polyposis coli gene in mice is lethal, and mice with a heterozygous mutation (ApcMin/+) survive but develop adenomas throughout the small intestine and only rarely in the colon; however, in humans with hereditary familial adenomatous polyposis, adenomas occur in the colon, duodenum, and rectum.	('Min', 'Gene', '11789', (4, 7))	('familial adenomatous polyposis', 'Disease', (264, 294))	('adenomatous polyposis coli', 'Phenotype', 'HP:0005227', (39, 65))	('adenomatous polyposis coli', 'Disease', 'MESH:D011125', (39, 65))	('familial adenomatous polyposis', 'Disease', 'MESH:D011125', (264, 294))	('mice', 'Species', '10090', (94, 98))	('adenomatous polyposis', 'Phenotype', 'HP:0005227', (273, 294))	('adenomatous polyposis coli', 'Disease', (39, 65))	('Min', 'Gene', (8, 11))	('Min', 'Gene', '11789', (8, 11))	('mice', 'Species', '10090', (74, 78))	('Min', 'Phenotype', 'HP:0200008', (132, 135))	('adenomatous polyposis', 'Phenotype', 'HP:0005227', (39, 60))	('Min', 'Phenotype', 'HP:0200008', (4, 7))	('humans', 'Species', '9606', (241, 247))	('adenomas', 'Disease', 'MESH:D000236', (159, 167))	('adenomas', 'Disease', 'MESH:D000236', (296, 304))	('adenomas', 'Disease', (159, 167))	('adenomas', 'Disease', (296, 304))	('Min', 'Gene', (132, 135))	('mutation', 'Var', (23, 31))	('Min', 'Gene', '11789', (132, 135))	('Min', 'Gene', (4, 7))	('Min', 'Phenotype', 'HP:0200008', (8, 11))
478655	33671768	There are three mouse strains with different codon sites for APC mutations, and the difference in mutation is represented by the difference in tumorigenesis site and number.	('APC', 'Disease', 'MESH:D011125', (61, 64))	('tumor', 'Disease', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('APC', 'Disease', (61, 64))	('mouse', 'Species', '10090', (16, 21))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('mutations', 'Var', (65, 74))
478667	33671768	The homozygous deletion of interleukin-10 (IL-10-/-) mice leads to enterocolitis, which is similar to human IBD.	('IL-10', 'Gene', '16153', (43, 48))	('mice', 'Species', '10090', (53, 57))	('deletion', 'Var', (15, 23))	('enterocolitis', 'Disease', (67, 80))	('IL-10', 'Gene', (43, 48))	('IBD', 'Disease', (108, 111))	('leads to', 'Reg', (58, 66))	('interleukin-10', 'Gene', '16153', (27, 41))	('IBD', 'Disease', 'MESH:D015212', (108, 111))	('colitis', 'Phenotype', 'HP:0002583', (73, 80))	('IBD', 'Phenotype', 'HP:0002037', (108, 111))	('enterocolitis', 'Phenotype', 'HP:0004387', (67, 80))	('interleukin-10', 'Gene', (27, 41))	('enterocolitis', 'Disease', 'MESH:D004760', (67, 80))	('human', 'Species', '9606', (102, 107))
478669	33671768	The treatment of IL-10-/- mice with AOM/DSS caused colitis and tumors as a result of microbial activation, but tumor development was suppressed under germ-free conditions.	('colitis', 'Disease', 'MESH:D003092', (51, 58))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('IL-10', 'Gene', (17, 22))	('AOM/DSS', 'Var', (36, 43))	('men', 'Species', '9606', (9, 12))	('tumors', 'Disease', (63, 69))	('colitis', 'Phenotype', 'HP:0002583', (51, 58))	('tumor', 'Disease', (63, 68))	('IL-10', 'Gene', '16153', (17, 22))	('activation', 'PosReg', (95, 105))	('tumor', 'Disease', (111, 116))	('AOM', 'Chemical', 'MESH:D001397', (36, 39))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('microbial', 'CPA', (85, 94))	('mice', 'Species', '10090', (26, 30))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('colitis', 'Disease', (51, 58))	('men', 'Species', '9606', (124, 127))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('caused', 'Reg', (44, 50))	('DSS', 'Chemical', 'MESH:D016264', (40, 43))
478673	33671768	C57BL/6-Ay mice show severe hyperphagia, polydipsia, impaired glucose tolerance, hyperinsulinemia, and hyperlipidemia.	('hyperlipidemia', 'Disease', 'MESH:D006949', (103, 117))	('hyperinsulinemia', 'Disease', 'MESH:D006946', (81, 97))	('hyperlipidemia', 'Phenotype', 'HP:0003077', (103, 117))	('polydipsia', 'Phenotype', 'HP:0001959', (41, 51))	('impaired glucose tolerance', 'Disease', 'MESH:D018149', (53, 79))	('polydipsia', 'Disease', (41, 51))	('hyperphagia', 'Disease', (28, 39))	('C57BL/6-Ay', 'Var', (0, 10))	('impaired glucose tolerance', 'Disease', (53, 79))	('hyperphagia', 'Phenotype', 'HP:0002591', (28, 39))	('hyperinsulinemia', 'Disease', (81, 97))	('hyperphagia', 'Disease', 'MESH:D006963', (28, 39))	('mice', 'Species', '10090', (11, 15))	('hyperlipidemia', 'Disease', (103, 117))	('impaired glucose tolerance', 'Phenotype', 'HP:0040270', (53, 79))	('hyperinsulinemia', 'Phenotype', 'HP:0000842', (81, 97))	('polydipsia', 'Disease', 'MESH:D059606', (41, 51))
478675	33671768	Since the diabetes (db) gene encodes the receptor for the obese (ob) gene product, leptin, mutations in the mouse db gene, cause leptin dysfunction, resulting in obesity and diabetes in a syndrome similar to that of human obesity.	('diabetes', 'Disease', (10, 18))	('human', 'Species', '9606', (216, 221))	('leptin dysfunction', 'Disease', (129, 147))	('obesity', 'Disease', 'MESH:D009765', (222, 229))	('leptin dysfunction', 'Disease', 'OMIM:614962', (129, 147))	('diabetes', 'Disease', (174, 182))	('obesity', 'Disease', (162, 169))	('leptin', 'Gene', (83, 89))	('obese (ob', 'Gene', (58, 67))	('obesity', 'Disease', 'MESH:D009765', (162, 169))	('leptin', 'Gene', '16846', (83, 89))	('obesity', 'Phenotype', 'HP:0001513', (222, 229))	('diabetes', 'Disease', 'MESH:D003920', (10, 18))	('leptin', 'Gene', '16846', (129, 135))	('leptin', 'Gene', (129, 135))	('mouse', 'Species', '10090', (108, 113))	('resulting in', 'Reg', (149, 161))	('diabetes', 'Disease', 'MESH:D003920', (174, 182))	('cause', 'Reg', (123, 128))	('obese (ob)', 'Gene', '16846', (58, 68))	('obesity', 'Disease', (222, 229))	('obesity', 'Phenotype', 'HP:0001513', (162, 169))	('mutations', 'Var', (91, 100))
478679	33671768	The homozygous deletion of lactoferrin (Lf-/-) mice showed higher susceptibility to AOM/DSS-induced colitis and developed dysplasia.	('DSS', 'Chemical', 'MESH:D016264', (88, 91))	('lactoferrin', 'Gene', '17002', (27, 38))	('colitis', 'Disease', 'MESH:D003092', (100, 107))	('deletion', 'Var', (15, 23))	('colitis', 'Disease', (100, 107))	('dysplasia', 'Disease', 'MESH:C536170', (122, 131))	('susceptibility', 'Reg', (66, 80))	('AOM', 'Chemical', 'MESH:D001397', (84, 87))	('colitis', 'Phenotype', 'HP:0002583', (100, 107))	('lactoferrin', 'Gene', (27, 38))	('dysplasia', 'Disease', (122, 131))	('higher', 'PosReg', (59, 65))	('mice', 'Species', '10090', (47, 51))	('developed', 'Reg', (112, 121))
478681	33671768	The homozygous deletion of Nrf2 (Nrf2-/-) mice treated with AOM/DSS demonstrates increased colitis and adenocarcinomas.	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('Nrf2', 'Gene', (33, 37))	('DSS', 'Chemical', 'MESH:D016264', (64, 67))	('Nrf2', 'Gene', '18024', (27, 31))	('deletion', 'Var', (15, 23))	('rat', 'Species', '10116', (75, 78))	('mice', 'Species', '10090', (42, 46))	('carcinomas', 'Phenotype', 'HP:0030731', (108, 118))	('colitis', 'Disease', 'MESH:D003092', (91, 98))	('Nrf2', 'Gene', (27, 31))	('adenocarcinomas', 'Disease', 'MESH:D000230', (103, 118))	('adenocarcinomas', 'Disease', (103, 118))	('colitis', 'Disease', (91, 98))	('AOM', 'Chemical', 'MESH:D001397', (60, 63))	('Nrf2', 'Gene', '18024', (33, 37))	('increased', 'PosReg', (81, 90))	('colitis', 'Phenotype', 'HP:0002583', (91, 98))
478684	33671768	The homozygous deletion of syndecan-1 (Sdc1-/-) mice results in an increased susceptibility to colitis-associated cancer induced by AOM/DSS through IL-6 and STAT3 signaling.	('Sdc1', 'Gene', '20969', (39, 43))	('deletion', 'Var', (15, 23))	('DSS', 'Chemical', 'MESH:D016264', (136, 139))	('colitis', 'Phenotype', 'HP:0002583', (95, 102))	('mice', 'Species', '10090', (48, 52))	('syndecan-1', 'Gene', (27, 37))	('AOM', 'Chemical', 'MESH:D001397', (132, 135))	('STAT3', 'Gene', '20848', (157, 162))	('colitis-associated cancer', 'Disease', (95, 120))	('Sdc1', 'Gene', (39, 43))	('colitis-associated cancer', 'Disease', 'MESH:D009369', (95, 120))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('STAT3', 'Gene', (157, 162))	('syndecan-1', 'Gene', '20969', (27, 37))	('susceptibility', 'Reg', (77, 91))
478685	33671768	Salmonella, a Gram-negative bacterium, causes gastroenteritis and sepsis, as well as intestinal injury in both humans and animals.	('causes', 'Reg', (39, 45))	('gastroenteritis and sepsis', 'Disease', 'MESH:D018805', (46, 72))	('Salmonella', 'Species', '90371', (0, 10))	('Salmonella', 'Var', (0, 10))	('intestinal injury', 'Disease', (85, 102))	('sepsis', 'Phenotype', 'HP:0100806', (66, 72))	('intestinal injury', 'Disease', 'MESH:D007410', (85, 102))	('humans', 'Species', '9606', (111, 117))
478741	33671768	Fe-NTA induced severe acute nephrotoxicity and the infiltration of leukocytes into the proximal tubular epithelium, as well as the resulting oxidative stress and hyperproliferative response.	('oxidative stress', 'MPA', (141, 157))	('hyperproliferative response', 'CPA', (162, 189))	('Fe-NTA', 'Var', (0, 6))	('rat', 'Species', '10116', (57, 60))	('rat', 'Species', '10116', (174, 177))	('Fe-NTA', 'Chemical', 'MESH:C020326', (0, 6))	('oxidative stress', 'Phenotype', 'HP:0025464', (141, 157))	('nephrotoxicity', 'Disease', (28, 42))	('infiltration', 'CPA', (51, 63))	('nephrotoxicity', 'Disease', 'MESH:D007674', (28, 42))
478755	33671768	In response to the DMBA-initiated and TPA-promoted skin carcinogenesis protocols, benign papillomas occur much faster in heterozygous p53 gene deletion (p53+/-) mice compared to wild-type mice.	('mice', 'Species', '10090', (188, 192))	('mice', 'Species', '10090', (161, 165))	('skin carcinogenesis', 'Disease', 'MESH:D063646', (51, 70))	('benign papillomas', 'Disease', 'MESH:D010212', (82, 99))	('papillomas', 'Phenotype', 'HP:0012740', (89, 99))	('faster', 'PosReg', (111, 117))	('TPA', 'Chemical', 'MESH:D013755', (38, 41))	('gene deletion', 'Var', (138, 151))	('papilloma', 'Phenotype', 'HP:0012740', (89, 98))	('skin carcinogenesis', 'Disease', (51, 70))	('p53', 'Gene', (153, 156))	('p53', 'Gene', '22059', (153, 156))	('benign papillomas', 'Disease', (82, 99))	('p53', 'Gene', (134, 137))	('p53', 'Gene', '22059', (134, 137))	('DMBA', 'Chemical', 'MESH:D015127', (19, 23))
478757	33671768	UVB induces signature mutations characterized by C-T or CC-TT mutations at pyrimidine-pyrimidine sequences.	('pyrimidine', 'Chemical', 'MESH:C030986', (75, 85))	('C-T', 'Disease', 'MESH:C537418', (57, 60))	('mutations', 'Var', (62, 71))	('C-T', 'Disease', (49, 52))	('C-T', 'Disease', 'MESH:C537418', (49, 52))	('pyrimidine', 'Chemical', 'MESH:C030986', (86, 96))	('C-T', 'Disease', (57, 60))
478758	33671768	These mutations are detectable in several tumor-suppressor genes, particularly Patched 1 (Ptch1) and p53 in UVB-exposed skin sites.	('Ptch1', 'Gene', (90, 95))	('Ptch1', 'Gene', '19206', (90, 95))	('p53', 'Gene', (101, 104))	('p53', 'Gene', '22059', (101, 104))	('mutations', 'Var', (6, 15))	('tumor-suppressor', 'Gene', '7248', (42, 58))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('Patched 1', 'Gene', (79, 88))	('Patched 1', 'Gene', '19206', (79, 88))	('tumor-suppressor', 'Gene', (42, 58))
478759	33671768	Since the homozygous deletion of Ptch1 is embryonic, Ptch1+/- mice were used for mating with SKH-1 hairless mice.	('Ptch1', 'Gene', '19206', (33, 38))	('Ptch1', 'Gene', (33, 38))	('Ptch1', 'Gene', (53, 58))	('Ptch1', 'Gene', '19206', (53, 58))	('mice', 'Species', '10090', (62, 66))	('deletion', 'Var', (21, 29))	('mice', 'Species', '10090', (108, 112))
478765	33671768	Homozygous deletions in XP group A (XPA-/-) mice are sensitive to UVB and induced a severe inflammatory response.	('sensitive to UVB', 'MPA', (53, 69))	('XP group A', 'Gene', (24, 34))	('induced', 'Reg', (74, 81))	('deletions', 'Var', (11, 20))	('XPA', 'Gene', (36, 39))	('inflammatory response', 'CPA', (91, 112))	('XPA', 'Gene', '22590', (36, 39))	('mice', 'Species', '10090', (44, 48))
478790	33671768	Spontaneous sarcoma development by inflammation induced by foreign body implantation in mice with heterozygous deletion of p53 (p53+/-) is associated with a higher rate of incidence and shorter tumor latency than those in wild-type mice.	('sarcoma', 'Disease', 'MESH:D012509', (12, 19))	('p53', 'Gene', (128, 131))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('p53', 'Gene', '22059', (128, 131))	('sarcoma', 'Disease', (12, 19))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('sarcoma', 'Phenotype', 'HP:0100242', (12, 19))	('p53', 'Gene', '22059', (123, 126))	('p53', 'Gene', (123, 126))	('tumor', 'Disease', (194, 199))	('inflammation', 'Disease', 'MESH:D007249', (35, 47))	('rat', 'Species', '10116', (164, 167))	('mice', 'Species', '10090', (88, 92))	('deletion', 'Var', (111, 119))	('men', 'Species', '9606', (27, 30))	('inflammation', 'Disease', (35, 47))	('mice', 'Species', '10090', (232, 236))
478794	33671768	Inflammation-related carcinogenesis models of each organ using laboratory animals were organized by the cause of inflammation:that is, chemical or irritant-induced inflammation (Table 1), surgery, hormone or diet-induced inflammation (Table 2), genetically modified host-induced inflammation (Table 3), infection-induced inflammation (Table 4), and foreign body-induced inflammation (Table 5).	('inflammation', 'Disease', 'MESH:D007249', (321, 333))	('inflammation', 'Disease', (221, 233))	('infection', 'Disease', (303, 312))	('infection', 'Disease', 'MESH:D007239', (303, 312))	('inflammation', 'Disease', 'MESH:D007249', (370, 382))	('inflammation', 'Disease', 'MESH:D007249', (164, 176))	('inflammation', 'Disease', 'MESH:D007249', (113, 125))	('foreign', 'Disease', (349, 356))	('inflammation', 'Disease', (321, 333))	('inflammation', 'Disease', (370, 382))	('inflammation', 'Disease', 'MESH:D007249', (279, 291))	('genetically', 'Var', (245, 256))	('inflammation', 'Disease', (164, 176))	('rat', 'Species', '10116', (67, 70))	('Inflammation', 'Disease', (0, 12))	('inflammation', 'Disease', (113, 125))	('Inflammation', 'Disease', 'MESH:D007249', (0, 12))	('irritant-', 'Phenotype', 'HP:0000737', (147, 156))	('inflammation', 'Disease', 'MESH:D007249', (221, 233))	('inflammation', 'Disease', (279, 291))
478804	33671768	The overall estimates have shown a 11% increase in the risk of all cancers for increased natural logarithm levels of CRP.	('cancers', 'Phenotype', 'HP:0002664', (67, 74))	('cancers', 'Disease', (67, 74))	('cancers', 'Disease', 'MESH:D009369', (67, 74))	('natural logarithm levels', 'Var', (89, 113))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('CRP', 'Gene', (117, 120))
478816	33671768	For instance, rheumatoid arthritis is not linked to cancer risk, even though the inflammatory regions in patients with rheumatoid arthritis show mutations in tumor-suppressor genes at similar frequencies to those of genes in the digestive tract tumors arising from chronic inflammatory reactions.	('rheumatoid arthritis', 'Disease', (14, 34))	('mutations', 'Var', (145, 154))	('digestive tract tumors', 'Phenotype', 'HP:0007378', (229, 251))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('tumors', 'Phenotype', 'HP:0002664', (245, 251))	('rheumatoid arthritis', 'Disease', 'MESH:D001172', (14, 34))	('rheumatoid arthritis', 'Phenotype', 'HP:0001370', (119, 139))	('tumor-suppressor', 'Gene', '7248', (158, 174))	('tumors', 'Disease', (245, 251))	('arthritis', 'Phenotype', 'HP:0001369', (130, 139))	('patients', 'Species', '9606', (105, 113))	('cancer', 'Disease', (52, 58))	('tumors', 'Disease', 'MESH:D009369', (245, 251))	('rheumatoid arthritis', 'Phenotype', 'HP:0001370', (14, 34))	('rheumatoid arthritis', 'Disease', (119, 139))	('tumor-suppressor', 'Gene', (158, 174))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('arthritis', 'Phenotype', 'HP:0001369', (25, 34))	('rheumatoid arthritis', 'Disease', 'MESH:D001172', (119, 139))
478847	30745810	Recently, Li et al found that hsa_circ_002059 was markedly down-regulated in gastric cancer tissues and plasma, in a study of 101 gastric cancer tissues with paired adjacent nontumorous tissues and 36 paired plasma samples from preoperative and postoperative patients.	('patients', 'Species', '9606', (259, 267))	('gastric cancer', 'Disease', (77, 91))	('gastric cancer', 'Disease', 'MESH:D013274', (77, 91))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('gastric cancer', 'Disease', (130, 144))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('down-regulated', 'NegReg', (59, 73))	('gastric cancer', 'Disease', 'MESH:D013274', (130, 144))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('gastric cancer', 'Phenotype', 'HP:0012126', (77, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('hsa_circ_002059', 'Var', (30, 45))	('tumor', 'Disease', (177, 182))	('gastric cancer', 'Phenotype', 'HP:0012126', (130, 144))
478853	30745810	In addition, hsa_circ_0014717 was also detected in human body fluid, suggesting its potential for development as a convenient biomarker for gastric cancer screening (Table 1).	('gastric cancer', 'Phenotype', 'HP:0012126', (140, 154))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('human', 'Species', '9606', (51, 56))	('gastric cancer', 'Disease', (140, 154))	('gastric cancer', 'Disease', 'MESH:D013274', (140, 154))	('hsa_circ_0014717', 'Var', (13, 29))
478861	30745810	The underlying mechanisms identified include hsa_circ_104916-mediated up-regulation of an epithelial molecule (E-cadherin) and down-regulation of mesenchymal molecules (N-cadherin and vimentin) and a zinc-finger transcriptional repressor (SLUG) that is active in pre-migratory neural crest cells during the epithelial to mesenchymal transition (EMT) of gastrulation.	('epithelial to mesenchymal transition', 'CPA', (307, 343))	('mesenchymal', 'CPA', (146, 157))	('E-cadherin', 'Gene', '999', (111, 121))	('up-regulation', 'PosReg', (70, 83))	('vimentin', 'Gene', '7431', (184, 192))	('SLUG', 'Gene', (239, 243))	('vimentin', 'Gene', (184, 192))	('hsa_circ_104916-mediated', 'Var', (45, 69))	('N-cadherin', 'Gene', (169, 179))	('down-regulation', 'NegReg', (127, 142))	('E-cadherin', 'Gene', (111, 121))	('N-cadherin', 'Gene', '1000', (169, 179))	('SLUG', 'Gene', '6591', (239, 243))
478862	30745810	Thus, hsa_circ_104916 may inhibit the migration and invasion of gastric cancer cells by inhibiting the EMT process (Figure 2), a pivotal cellular process in cancer metastasis.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('cancer metastasis', 'Disease', 'MESH:D009362', (157, 174))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('hsa_circ_104916', 'Var', (6, 21))	('EMT process', 'CPA', (103, 114))	('inhibit', 'NegReg', (26, 33))	('gastric cancer', 'Disease', (64, 78))	('gastric cancer', 'Disease', 'MESH:D013274', (64, 78))	('inhibiting', 'NegReg', (88, 98))	('cancer metastasis', 'Disease', (157, 174))	('gastric cancer', 'Phenotype', 'HP:0012126', (64, 78))
478863	30745810	Nevertheless, current studies indicate that circRNAs, including hsa_circ_100269 and hsa_circ_104916, are involved in the molecular pathogenic pathway of gastric cancers.	('hsa_circ_104916', 'Var', (84, 99))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('hsa_circ_100269', 'Var', (64, 79))	('gastric cancers', 'Phenotype', 'HP:0012126', (153, 168))	('gastric cancer', 'Phenotype', 'HP:0012126', (153, 167))	('cancers', 'Phenotype', 'HP:0002664', (161, 168))	('involved', 'Reg', (105, 113))	('gastric cancers', 'Disease', (153, 168))	('gastric cancers', 'Disease', 'MESH:D013274', (153, 168))
478864	30745810	As both hsa_circ_100269 and hsa_circ_104916 are down-regulated in gastric cancer and consequently promote its pathogenesis, the over-expression of both circRNAs would have therapeutic potential for gastric cancer.	('hsa_circ_100269', 'Var', (8, 23))	('gastric cancer', 'Disease', (198, 212))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('promote', 'PosReg', (98, 105))	('gastric cancer', 'Disease', 'MESH:D013274', (198, 212))	('gastric cancer', 'Phenotype', 'HP:0012126', (66, 80))	('down-regulated', 'NegReg', (48, 62))	('gastric cancer', 'Phenotype', 'HP:0012126', (198, 212))	('hsa_circ_104916', 'Var', (28, 43))	('gastric cancer', 'Disease', (66, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('pathogenesis', 'MPA', (110, 122))	('gastric cancer', 'Disease', 'MESH:D013274', (66, 80))
478870	30745810	However, the instances of HCC tissue samples having high ciRS-7 expression coincided with significantly higher levels of hepatic microvascular invasion and alpha-fetoprotein, as well as younger age at diagnosis, compared with the HCC tissue samples expressing low ciRS-7.	('ciRS-7', 'Gene', (57, 63))	('HCC', 'Gene', '619501', (26, 29))	('ciRS-7', 'Gene', '103611090', (264, 270))	('hepatic microvascular invasion', 'MPA', (121, 151))	('HCC', 'Gene', (230, 233))	('alpha-fetoprotein', 'Gene', '174', (156, 173))	('ciRS-7', 'Gene', '103611090', (57, 63))	('high', 'Var', (52, 56))	('alpha-fetoprotein', 'Gene', (156, 173))	('ciRS-7', 'Gene', (264, 270))	('HCC', 'Gene', '619501', (230, 233))	('higher', 'PosReg', (104, 110))	('HCC', 'Gene', (26, 29))
478872	30745810	In another study, Shang et al found that hsa_circ_0005075 was up-regulated in HCC tissues and that this differential expression was positively related to size of the HCC.	('HCC', 'Gene', (78, 81))	('HCC', 'Gene', '619501', (166, 169))	('hsa_circ_0005075', 'Var', (41, 57))	('up-regulated', 'PosReg', (62, 74))	('HCC', 'Gene', '619501', (78, 81))	('related', 'Reg', (143, 150))	('HCC', 'Gene', (166, 169))
478874	30745810	For instance, an analysis of 89 paired samples of HCC and adjacent liver tissues showed that circRNA hsa_circ_0001649 was significantly down-regulated in HCC and positively related to tumor size; receiver operating characteristic curve analysis provided further support for the potential diagnostic value of circ_0001649 for HCC (Table 1).	('down-regulated', 'NegReg', (136, 150))	('HCC', 'Gene', (154, 157))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('HCC', 'Gene', '619501', (325, 328))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('circ_0001649', 'Var', (308, 320))	('HCC', 'Gene', '619501', (50, 53))	('HCC', 'Gene', '619501', (154, 157))	('tumor', 'Disease', (184, 189))	('HCC', 'Gene', (50, 53))	('related', 'Reg', (173, 180))	('HCC', 'Gene', (325, 328))
478877	30745810	Importantly, hsa_circ_0004018 expression demonstrated a HCC stage-specific feature among diverse chronic liver diseases, highlighting its potential sensitivity and specificity for the diagnosis of HCC (Table 1).	('liver diseases', 'Phenotype', 'HP:0001392', (105, 119))	('HCC', 'Gene', '619501', (197, 200))	('liver diseases', 'Disease', (105, 119))	('hsa_circ_0004018 expression', 'Var', (13, 40))	('HCC', 'Gene', (56, 59))	('HCC', 'Gene', (197, 200))	('liver diseases', 'Disease', 'MESH:D008107', (105, 119))	('HCC', 'Gene', '619501', (56, 59))
478883	30745810	Moreover, knock-down of ciRS-7 was found to inhibit the proliferation and invasion of liver cancer cells through targeting of miR-7, resulting in increased expression of its target genes, namely CCNE1 and pik3cd .	('pik3cd', 'Gene', (205, 211))	('liver cancer', 'Phenotype', 'HP:0002896', (86, 98))	('proliferation', 'CPA', (56, 69))	('liver cancer', 'Disease', (86, 98))	('miR-7', 'Gene', (126, 131))	('invasion', 'CPA', (74, 82))	('increased', 'PosReg', (146, 155))	('targeting', 'Var', (113, 122))	('CCNE1', 'Gene', (195, 200))	('ciRS-7', 'Gene', '103611090', (24, 30))	('miR-7', 'Gene', '10859', (126, 131))	('pik3cd', 'Gene', '5293', (205, 211))	('ciRS-7', 'Gene', (24, 30))	('inhibit', 'NegReg', (44, 51))	('CCNE1', 'Gene', '898', (195, 200))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('liver cancer', 'Disease', 'MESH:D006528', (86, 98))	('knock-down', 'Var', (10, 20))	('expression', 'MPA', (156, 166))
478891	30745810	For the 101 total lung cancer patients (representing 51 diagnosed with squamous cell carcinomas and 50 diagnosed with adenocarcinoma) assessed, the overall survival time was significantly shorter for those who showed high expression of hsa_circ-100876 than for those with low hsa_circ_100876 expression.	('adenocarcinoma', 'Disease', 'MESH:D000230', (118, 132))	('lung cancer', 'Disease', 'MESH:D008175', (18, 29))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (71, 95))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (71, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('patients', 'Species', '9606', (30, 38))	('lung cancer', 'Phenotype', 'HP:0100526', (18, 29))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('survival time', 'CPA', (156, 169))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (71, 95))	('lung cancer', 'Disease', (18, 29))	('hsa_circ-100876', 'Var', (236, 251))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('adenocarcinoma', 'Disease', (118, 132))	('carcinomas', 'Phenotype', 'HP:0030731', (85, 95))	('squamous cell carcinomas', 'Disease', (71, 95))	('shorter', 'NegReg', (188, 195))
478895	30745810	Among these candidates, hsa_circ_0013958 was further confirmed to be highly expressed in all lung adenocarcinoma tissues as well as in plasma of these patients.	('hsa_circ_0013958', 'Var', (24, 40))	('lung adenocarcinoma', 'Disease', (93, 112))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (93, 112))	('patients', 'Species', '9606', (151, 159))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (93, 112))
478906	30745810	It is reported that hsa_circ_BANP and hsa_circ_0000069 were significantly over-expressed in CRC tissues, being positively correlated with patients' TNM stage.	('over-expressed', 'PosReg', (74, 88))	('BANP', 'Gene', '54971', (29, 33))	('BANP', 'Gene', (29, 33))	('hsa_circ_0000069', 'Var', (38, 54))	('correlated', 'Reg', (122, 132))	('patients', 'Species', '9606', (138, 146))
478907	30745810	The dysregulated CRC-related circRNAs promote tumor progression and/or metastasis by serving as sponges for miRNAs.	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Disease', (46, 51))	('metastasis', 'CPA', (71, 81))	('miR', 'Gene', '220972', (108, 111))	('CRC-related', 'Gene', (17, 28))	('promote', 'PosReg', (38, 45))	('miR', 'Gene', (108, 111))	('dysregulated', 'Var', (4, 16))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
478910	30745810	More recently, Xie et al determined that hsa_circ_001569 was markedly up-regulated in CRC tissues and promoted the proliferation and invasiveness of CRC cells by targeting miR-145.	('promoted', 'PosReg', (102, 110))	('up-regulated', 'PosReg', (70, 82))	('hsa_circ_001569', 'Var', (41, 56))	('proliferation', 'CPA', (115, 128))	('invasiveness', 'CPA', (133, 145))	('miR-145', 'Gene', (172, 179))	('targeting', 'Reg', (162, 171))	('miR-145', 'Gene', '406937', (172, 179))
478935	30745810	Up-regulation of hsa_circ_0067934 was positively related to poor differentiation, I-II T stage and I-II TNM stage, while silencing of hsa_circ_0067934 by siRNA in vitro inhibited the proliferation and migration of esophageal squamous cell carcinoma cells and blocked cell cycle progression, suggesting that hsa_circ_0067934 promotes the proliferation of esophageal squamous cell carcinoma cells by regulating the cell cycle.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (365, 388))	('carcinoma', 'Phenotype', 'HP:0030731', (239, 248))	('proliferation', 'CPA', (183, 196))	('cell cycle progression', 'CPA', (267, 289))	('promotes', 'PosReg', (324, 332))	('blocked', 'NegReg', (259, 266))	('I-II T', 'Disease', (99, 105))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (354, 388))	('cell cycle', 'CPA', (413, 423))	('esophageal squamous cell carcinoma', 'Disease', (214, 248))	('inhibited', 'NegReg', (169, 178))	('carcinoma', 'Phenotype', 'HP:0030731', (379, 388))	('proliferation', 'CPA', (337, 350))	('migration', 'CPA', (201, 210))	('I-II T', 'Disease', 'MESH:D056829', (99, 105))	('I-II T', 'Disease', (82, 88))	('hsa_circ_0067934', 'Gene', (134, 150))	('silencing', 'Var', (121, 130))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (225, 248))	('regulating', 'Reg', (398, 408))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (214, 248))	('I-II T', 'Disease', 'MESH:D056829', (82, 88))	('esophageal squamous cell carcinoma', 'Disease', (354, 388))
479053	30179157	The ROIs were 'tumor core' (TU_CORE), 'inner invasive margin' (MARG_500_IN) and 'outer invasive margin' (MARG_500_OUT).	('MARG_500_IN', 'Var', (63, 74))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('MARG_500_OUT', 'Var', (105, 117))	("'tumor", 'Disease', 'MESH:D009369', (14, 20))	("'tumor", 'Disease', (14, 20))
479152	29029488	Differential expression of lncRNAs has rapidly emerged in various studies of tumorigenesis and cancer progression, and the dysregulated lncRNAs play key roles in cancer prognosis.	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('cancer', 'Disease', (162, 168))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('cancer', 'Disease', (95, 101))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('dysregulated', 'Var', (123, 135))	('tumor', 'Disease', (77, 82))
479185	29029488	The prognostic risk score for predicting OS was calculated as previously reported: Risk score=explncRNA1 *betalncRNA1+explncRNA2*betalncRNA2+...explncRNA*betalncRNAn (exp: expression level, beta: the regression coefficient derived from the multivariate Cox regression model).	('explncRNA*', 'Var', (144, 154))	('Cox', 'Gene', (253, 256))	('OS', 'Chemical', '-', (41, 43))	('Cox', 'Gene', '1351', (253, 256))
479196	26899170	deconstructSigs confers the ability to define mutational processes driven by environmental exposures, DNA repair abnormalities, and mutagenic processes in individual tumors with implications for precision cancer medicine.	('cancer', 'Disease', 'MESH:D009369', (205, 211))	('tumors', 'Disease', 'MESH:D009369', (166, 172))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('cancer', 'Disease', (205, 211))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('abnormalities', 'Var', (113, 126))	('tumors', 'Disease', (166, 172))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))
479197	26899170	The set of somatic mutations observed in a tumor reflects the varied mutational processes that have been active during its life history, providing insights into the routes taken to carcinogenesis.	('carcinogenesis', 'Disease', 'MESH:D063646', (181, 195))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('mutations', 'Var', (19, 28))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('carcinogenesis', 'Disease', (181, 195))	('tumor', 'Disease', (43, 48))
479198	26899170	Exogenous mutagens, such as tobacco smoke and ultraviolet light, and endogenous processes, such as APOBEC enzymatic family functional activity or DNA mismatch repair deficiency, result in characteristic patterns of mutation.	('mutation', 'Var', (215, 223))	('result', 'Reg', (178, 184))	('deficiency', 'Disease', (166, 176))	('tobacco', 'Species', '4097', (28, 35))	('deficiency', 'Disease', 'MESH:D007153', (166, 176))
479206	26899170	analyzed approximately five million mutations from over 7000 cancer genomes and exomes to identify a set of 21 signatures found to be present across 30 tumor types.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('cancer', 'Disease', (61, 67))	('tumor', 'Disease', (152, 157))	('mutations', 'Var', (36, 45))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))
479207	26899170	About half of these signatures could be attributed to known mutational processes, such as tobacco smoke, exposure to ultraviolet light, activity of the APOBEC family of cytidine deaminases, DNA mismatch repair deficiency, or mutations in POLE.	('deficiency', 'Disease', (210, 220))	('mutations', 'Var', (225, 234))	('attributed', 'Reg', (40, 50))	('POLE', 'Gene', (238, 242))	('deficiency', 'Disease', 'MESH:D007153', (210, 220))	('tobacco', 'Species', '4097', (90, 97))	('APOBEC', 'Gene', (152, 158))
479214	26899170	sigs.input < - mut.to.sigs.input(mut.ref = sample.mut.ref, sample.id = "Sample", chr = "chr", pos = "pos", ref = "ref", alt = "alt") The input data frame T is generated by calculating the fraction of mutations found in each of the possible 96 trinucleotide contexts for each tumor sample.	('tumor', 'Phenotype', 'HP:0002664', (275, 280))	('tumor', 'Disease', (275, 280))	('mutations', 'Var', (200, 209))	('tumor', 'Disease', 'MESH:D009369', (275, 280))	('trinucleotide', 'Chemical', '-', (243, 256))
479220	26899170	First, we exclude any signatures containing a single trinucleotide context making up more than 20 % of the signature definition which is not present in T. This is done to account for the fact that some signatures are almost entirely characterized by mutations in specific trinucleotide contexts, and thus, without mutations found in those contexts, it is unlikely that that signature is active.	('trinucleotide', 'Chemical', '-', (272, 285))	('trinucleotide', 'Chemical', '-', (53, 66))	('mutations', 'Var', (250, 259))	('characterized by', 'Reg', (233, 249))
479236	26899170	This is of particular importance when the profile of the mutational signature is flat or without a strong peak at any of the trinucleotide contexts, as in these instances the mutational process could affect a greater number of trinucleotide contexts and a full profile would only be observed with sufficient mutations.	('affect', 'Reg', (200, 206))	('trinucleotide contexts', 'MPA', (227, 249))	('trinucleotide', 'Chemical', '-', (227, 240))	('mutational', 'Var', (175, 185))	('trinucleotide', 'Chemical', '-', (125, 138))
479237	26899170	For instance, in a colorectal carcinoma (TCGA-D5-6931) the WTSI Mutational Signature Framework determined 20.4 % of the mutational signature present was associated with a POLE hyper-mutator phenotype.	('POLE hyper-mutator', 'MPA', (171, 189))	('colorectal carcinoma', 'Disease', (19, 39))	('associated', 'Reg', (153, 163))	('mutational', 'Var', (120, 130))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (19, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (30, 39))
479238	26899170	Nevertheless, visual inspection of the mutational profile of this tumor did not reveal the presence of a POLE-associated signature and no evidence existed for the somatic exonuclease domain mutations in POLE that produce this specific pattern of predominantly C > A mutations in a TpCpT context and C > T mutations in a TpCpG context (Fig.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('C > T mutations', 'Var', (299, 314))	('tumor', 'Disease', (66, 71))	('C > A mutations', 'Var', (260, 275))	('tumor', 'Disease', 'MESH:D009369', (66, 71))
479242	26899170	Expanding the set of signatures also allowed us to identify outlier samples that appear to harbor a different set of mutational signatures compared with the rest of the cancer type or sample set they were analyzed with.	('mutational', 'Var', (117, 127))	('cancer', 'Disease', (169, 175))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('cancer', 'Disease', 'MESH:D009369', (169, 175))
479245	26899170	In two of these tumors, TCGA-A8-A09Z and TCGA-AN-A0AK, mutations in mismatch repair genes were evident (https://tcga-data.nci.nih.gov/tcga/).	('tumors', 'Disease', (16, 22))	('mismatch repair genes', 'Gene', (68, 89))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('mutations', 'Var', (55, 64))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('tumors', 'Disease', 'MESH:D009369', (16, 22))
479246	26899170	There was an MLH1 nonstop mutation in TCGA-A8-A09Z and separate MLH1 missense and splice site mutations, as well as an MSH6 frameshift mutation in TCGA-AN-A0AK.	('MLH1', 'Gene', (64, 68))	('MSH6', 'Gene', '2956', (119, 123))	('MLH1', 'Gene', '4292', (64, 68))	('mutation', 'Var', (26, 34))	('MLH1', 'Gene', (13, 17))	('MLH1', 'Gene', '4292', (13, 17))	('MSH6', 'Gene', (119, 123))
479247	26899170	Additionally, TCGA-A8-A09Z had a total of 1438 mutations with 253 small insertions or deletions and TCGA-AN-A0AK had a total of 1317 mutations with 352 small insertions or deletions, both indicative of a microsatellite instability high (MSIH) phenotype.	('MSIH', 'Disease', 'None', (237, 241))	('microsatellite instability high', 'MPA', (204, 235))	('MSIH', 'Disease', (237, 241))	('mutations', 'Var', (47, 56))
479248	26899170	The median number of mutations from the BRCA TCGA cohort is 38 and median number of insertions or deletions is 4.	('BRCA', 'Gene', (40, 44))	('BRCA', 'Gene', '672', (40, 44))	('mutations', 'Var', (21, 30))
479255	26899170	Indeed, in three of the five patients analyzed (L001, L004, and L008), the smoking signature was not assigned at all in the branches.	('patients', 'Species', '9606', (29, 37))	('L004', 'Var', (54, 58))	('L008', 'Var', (64, 68))	('L001', 'Var', (48, 52))
479261	26899170	In addition, in order to shed light on both the prevalence of mutational processes and their dynamics during tumor evolution, we also applied the deconstructSigs package to temporally dissected mutations (Additional file 7), according to published methods.	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('mutations', 'Var', (194, 203))	('tumor', 'Disease', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))
479264	26899170	Interestingly, this signature was found to contribute significantly more to early mutations compared with late mutations in esophageal squamous cell carcinoma but not in esophageal adenocarcinoma (ESCA squamous, p value = 0.006; ESCA adeno, p value = 0.716; Fig.	('esophageal adenocarcinoma', 'Disease', (170, 195))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (170, 195))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (135, 158))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (170, 195))	('carcinoma', 'Phenotype', 'HP:0030731', (149, 158))	('carcinoma', 'Phenotype', 'HP:0030731', (186, 195))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (124, 158))	('mutations', 'Var', (82, 91))	('esophageal squamous cell carcinoma', 'Disease', (124, 158))
479266	26899170	Further, in squamous cell tumors, APOBEC-mediated mutagenesis was found frequently to be a late event, reflecting similar findings in lung adenocarcinomas, head-and-neck tumors, and estrogen receptor-negative breast cancers (p value = 0.03; Fig.	('estrogen receptor', 'Gene', (182, 199))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (134, 153))	('cancers', 'Phenotype', 'HP:0002664', (216, 223))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('tumors', 'Disease', 'MESH:D009369', (170, 176))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (134, 154))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('carcinomas', 'Phenotype', 'HP:0030731', (144, 154))	('breast cancers', 'Disease', 'MESH:D001943', (209, 223))	('breast cancers', 'Disease', (209, 223))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('squamous cell tumors', 'Disease', (12, 32))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (134, 154))	('breast cancers', 'Phenotype', 'HP:0003002', (209, 223))	('squamous cell tumors', 'Disease', 'MESH:D002294', (12, 32))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('estrogen receptor', 'Gene', '2099', (182, 199))	('breast cancer', 'Phenotype', 'HP:0003002', (209, 222))	('mutagenesis', 'Var', (50, 61))	('lung adenocarcinomas', 'Disease', (134, 154))	('tumors', 'Phenotype', 'HP:0002664', (170, 176))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumors', 'Disease', (170, 176))	('tumors', 'Disease', (26, 32))
479269	26899170	Indeed, over 50 % of esophageal adenocarcinomas were found to exhibit an enrichment for T > G and T > C mutations at CpTpT sites.	('T > G', 'Var', (88, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (37, 46))	('carcinomas', 'Phenotype', 'HP:0030731', (37, 47))	('esophageal adenocarcinomas', 'Disease', 'MESH:D004938', (21, 47))	('T > C mutations', 'Var', (98, 113))	('esophageal adenocarcinomas', 'Disease', (21, 47))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (21, 46))
479270	26899170	The majority of these tumors (65 %) showed a tendency for signature 17 to be an early event, often being replaced by signature 1A.	('tumors', 'Disease', 'MESH:D009369', (22, 28))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('signature 17', 'Var', (58, 70))	('tumors', 'Phenotype', 'HP:0002664', (22, 28))	('tumors', 'Disease', (22, 28))
479271	26899170	For example, in one such tumor (TCGA-2H-A9GR), early mutations were almost exclusively characterized as signature 17 (90.4 %), while later arising mutations were characterized by an increase in signature 1A at the expense of signature 17.	('increase', 'PosReg', (182, 190))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('signature 1A', 'MPA', (194, 206))	('tumor', 'Disease', (25, 30))	('mutations', 'Var', (53, 62))	('tumor', 'Disease', 'MESH:D009369', (25, 30))
479292	31159203	Analyses of cellular gene expression and stained tissue sections indicated an increased immune cell infiltration in the sample expressing high levels of EBV transcripts compared to samples expressing low EBV transcripts.	('EBV', 'Gene', (153, 156))	('immune cell infiltration', 'CPA', (88, 112))	('EBV', 'Species', '10376', (204, 207))	('high levels', 'Var', (138, 149))	('EBV', 'Species', '10376', (153, 156))	('increased', 'PosReg', (78, 87))
479294	31159203	Lastly, inhibition of immune pathways and activation of oncogenic pathways were detected in the sample with high EBV transcripts compared to the EBV-low LC indicating the direct regulation of cancer pathways by EBV.	('EBV', 'Species', '10376', (145, 148))	('inhibition', 'NegReg', (8, 18))	('EBV', 'Gene', (113, 116))	('EBV', 'Species', '10376', (211, 214))	('LC', 'Phenotype', 'HP:0100526', (153, 155))	('transcripts', 'Var', (117, 128))	('cancer', 'Disease', (192, 198))	('immune pathways', 'Pathway', (22, 37))	('activation', 'PosReg', (42, 52))	('oncogenic pathways', 'Pathway', (56, 74))	('high', 'Var', (108, 112))	('cancer', 'Disease', 'MESH:D009369', (192, 198))	('EBV', 'Species', '10376', (113, 116))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))
479300	31159203	The first EBV-positive LC case was reported by Begin and colleagues in 1987 and histologically it seems that the EBV-positive LCs are more likely to be the primary pulmonary lymphoepithelioma-like carcinoma, a relatively rare form of non-small cell lung cancer (NSCLC) preferentially occurring in Asian patients.	('NSCLC', 'Disease', (262, 267))	('NSCLC', 'Phenotype', 'HP:0030358', (262, 267))	('LC', 'Phenotype', 'HP:0100526', (23, 25))	('lung cancer', 'Phenotype', 'HP:0100526', (249, 260))	('cancer', 'Phenotype', 'HP:0002664', (254, 260))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (234, 260))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (238, 260))	('EBV-positive', 'Var', (113, 125))	('LC', 'Phenotype', 'HP:0100526', (265, 267))	('pulmonary lymphoepithelioma-like carcinoma', 'Disease', 'MESH:D008175', (164, 206))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (234, 260))	('carcinoma', 'Phenotype', 'HP:0030731', (197, 206))	('EBV', 'Species', '10376', (113, 116))	('pulmonary lymphoepithelioma-like carcinoma', 'Disease', (164, 206))	('patients', 'Species', '9606', (303, 311))	('EBV', 'Species', '10376', (10, 13))	('NSCLC', 'Disease', 'MESH:D002289', (262, 267))	('non-small cell lung cancer', 'Disease', (234, 260))	('LC', 'Phenotype', 'HP:0100526', (126, 128))
479319	31159203	Interestingly, in the context of lung cancers, an increased immune cell infiltration was observed in the sample expressing high levels of EBV transcripts relative to samples expressing low EBV transcripts.	('lung cancer', 'Phenotype', 'HP:0100526', (33, 44))	('EBV', 'Species', '10376', (189, 192))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('lung cancers', 'Disease', 'MESH:D008175', (33, 45))	('lung cancers', 'Phenotype', 'HP:0100526', (33, 45))	('EBV', 'Species', '10376', (138, 141))	('immune cell infiltration', 'CPA', (60, 84))	('increased', 'PosReg', (50, 59))	('EBV', 'Gene', (138, 141))	('lung cancers', 'Disease', (33, 45))	('cancers', 'Phenotype', 'HP:0002664', (38, 45))	('high levels', 'Var', (123, 134))
479321	31159203	Lastly, our pathway analysis shows inhibition of immune pathways and activation of oncogenic pathways in the sample with high EBV transcripts, suggesting the direct regulation of tumor pathways by EBV.	('transcripts', 'Var', (130, 141))	('immune pathways', 'Pathway', (49, 64))	('regulation', 'Reg', (165, 175))	('EBV', 'Gene', (126, 129))	('EBV', 'Species', '10376', (197, 200))	('tumor', 'Disease', (179, 184))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('oncogenic pathways', 'Pathway', (83, 101))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('high', 'Var', (121, 125))	('EBV', 'Species', '10376', (126, 129))	('activation', 'PosReg', (69, 79))
479322	31159203	Overall, our current study strongly indicates that EBV is not a major carcinogen for LC in general, but EBV may play a critical role to promote the development of a subset of lung squamous cell carcinoma and lung adenocarcinoma cases.	('promote', 'PosReg', (136, 143))	('EBV', 'Species', '10376', (104, 107))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (180, 203))	('carcinoma', 'Phenotype', 'HP:0030731', (194, 203))	('EBV', 'Var', (104, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (218, 227))	('LC', 'Phenotype', 'HP:0100526', (85, 87))	('lung squamous cell carcinoma and lung adenocarcinoma', 'Disease', 'MESH:D000077192', (175, 227))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (175, 203))	('EBV', 'Species', '10376', (51, 54))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (208, 227))
479336	31159203	Hereafter, we classified the sample TCGA-96-A4JG as EBV-high, and the other three EBV(+) NSCLC as EBV-low.	('TCGA-96-A4JG', 'Var', (36, 48))	('NSCLC', 'Disease', 'MESH:D002289', (89, 94))	('EBV', 'Species', '10376', (52, 55))	('NSCLC', 'Phenotype', 'HP:0030358', (89, 94))	('EBV', 'Species', '10376', (82, 85))	('EBV', 'Species', '10376', (98, 101))	('LC', 'Phenotype', 'HP:0100526', (92, 94))	('NSCLC', 'Disease', (89, 94))
479417	31159203	H&E-stained tissue sections (Figure 8B and see Figure S4 in the supplementary material for a high-resolution image) revealed that the EBV-high LUSC had a higher level of infiltrating immune cells compared to the EBV-low LUSCs.	('of infiltrating immune', 'MPA', (167, 189))	('H&E', 'Chemical', '-', (0, 3))	('LUSC', 'Phenotype', 'HP:0030359', (143, 147))	('the', 'Var', (130, 133))	('EBV', 'Species', '10376', (134, 137))	('EBV', 'Species', '10376', (212, 215))	('LUSC', 'Phenotype', 'HP:0030359', (220, 224))
479431	31159203	A lung squamous cell carcinoma cell line, NCI-H1703 was then transfected with plasmids carrying either recombinant EBV M81 strain (rM81) or B95.8 strain (rB95.8), respectively.	('A lung squamous cell carcinoma', 'Disease', (0, 30))	('NCI-H1703', 'CellLine', 'CVCL:1490', (42, 51))	('A lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (0, 30))	('EBV', 'Species', '10376', (115, 118))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (2, 30))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (7, 30))	('B95.8 strain', 'Var', (140, 152))	('carcinoma', 'Phenotype', 'HP:0030731', (21, 30))
479436	31159203	Compared to the EBV negative NCI-H1703 control cells, cellular checkpoint molecules such as IDO, PD-1, CTLA-4, and VISTA were strongly induced in rB95.8 EBV(+) lung cancer cells (Supplementary Figure S5B).	('IDO', 'Gene', '3620', (92, 95))	('CTLA-4', 'Gene', (103, 109))	('VISTA', 'Gene', '64115', (115, 120))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('IDO', 'Gene', (92, 95))	('EBV', 'Species', '10376', (16, 19))	('EBV', 'Species', '10376', (153, 156))	('NCI-H1703', 'CellLine', 'CVCL:1490', (29, 38))	('lung cancer', 'Disease', 'MESH:D008175', (160, 171))	('PD-1', 'Gene', (97, 101))	('lung cancer', 'Disease', (160, 171))	('rB95.8', 'Var', (146, 152))	('PD-1', 'Gene', '5133', (97, 101))	('induced', 'PosReg', (135, 142))	('VISTA', 'Gene', (115, 120))	('CTLA-4', 'Gene', '1493', (103, 109))	('cellular', 'MPA', (54, 62))	('lung cancer', 'Phenotype', 'HP:0100526', (160, 171))
479438	31159203	The lower induction of cellular checkpoint molecules by rM81 EBV may be due to virus' high lytic activity, as evidenced by the high levels of lytic inducer BZLF1 in rM81 EBV(+) cells (Supplementary Figure S5C).	('rM81', 'Var', (56, 60))	('lower', 'NegReg', (4, 9))	('lytic activity', 'MPA', (91, 105))	('induction', 'MPA', (10, 19))	('EBV', 'Species', '10376', (170, 173))	('cellular checkpoint molecules', 'MPA', (23, 52))	('EBV', 'Species', '10376', (61, 64))	('BZLF1', 'Gene', (156, 161))	('BZLF1', 'Gene', '3783744', (156, 161))
479462	31159203	Moreover, the EBV-high sample was collected from a never-smoking patient, indicating that EBV may promote lung carcinogenesis in a smoking independent manner.	('lung carcinogenesis', 'Disease', (106, 125))	('EBV', 'Species', '10376', (14, 17))	('EBV', 'Species', '10376', (90, 93))	('promote', 'PosReg', (98, 105))	('lung carcinogenesis', 'Disease', 'MESH:D063646', (106, 125))	('EBV', 'Var', (90, 93))	('patient', 'Species', '9606', (65, 72))
479473	31159203	Previously, we and others have identified novel alternative splicing events of LMP2A in EBV associated cancers.	('cancers', 'Disease', 'MESH:D009369', (103, 110))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('EBV', 'Species', '10376', (88, 91))	('LMP2A', 'Gene', '17494231', (79, 84))	('alternative splicing events', 'Var', (48, 75))	('LMP2A', 'Gene', (79, 84))	('cancers', 'Phenotype', 'HP:0002664', (103, 110))	('cancers', 'Disease', (103, 110))
479478	31159203	Thus, together with previous findings, our data indicate that the alternative splicing of LMP2A may be more common than we previously expected and it may play important regulatory and functional roles in EBV's life cycle and pathogenesis.	('alternative splicing', 'Var', (66, 86))	('EBV', 'Species', '10376', (204, 207))	('roles', 'Reg', (195, 200))	('play', 'Reg', (154, 158))	('LMP2A', 'Gene', '17494231', (90, 95))	('LMP2A', 'Gene', (90, 95))
479484	31159203	We reported previously that gastric carcinomas with high levels of EBV reads exhibit activation of distinctive pathways, compared to samples with low/no EBV reads.	('distinctive pathways', 'Pathway', (99, 119))	('EBV reads', 'Var', (67, 76))	('EBV', 'Species', '10376', (67, 70))	('EBV', 'Species', '10376', (153, 156))	('carcinoma', 'Phenotype', 'HP:0030731', (36, 45))	('activation', 'PosReg', (85, 95))	('carcinomas', 'Phenotype', 'HP:0030731', (36, 46))	('gastric carcinomas', 'Disease', 'MESH:D013274', (28, 46))	('gastric carcinomas', 'Disease', (28, 46))
479535	31159203	Blue features represent lytic genes, red features represent latent genes, green features represent potential noncoding genes, aquamarine features represent microRNAs, and black features represent non-gene features (e.g., repeat regions), Figure S3: Alternative splicing in the EBV LMP2A in EBV-high NSCLC.	('LC', 'Phenotype', 'HP:0100526', (302, 304))	('NSCLC', 'Disease', (299, 304))	('LMP2A', 'Gene', '17494231', (281, 286))	('Alternative splicing', 'Var', (249, 269))	('LMP2A', 'Gene', (281, 286))	('NSCLC', 'Disease', 'MESH:D002289', (299, 304))	('EBV', 'Species', '10376', (290, 293))	('NSCLC', 'Phenotype', 'HP:0030358', (299, 304))	('EBV', 'Species', '10376', (277, 280))
479634	27519173	ISOexpresso: a web-based platform for isoform-level expression analysis in human cancer Alternative splicing events that result in the production of multiple gene isoforms reveals important molecular mechanisms.	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('Alternative splicing', 'Var', (88, 108))	('cancer', 'Disease', (81, 87))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('human', 'Species', '9606', (75, 80))	('result in', 'Reg', (121, 130))
479635	27519173	Specifically, recent studies show that aberrant regulation of alternative splicing frequently occurs in cancer to affect tumor cell transformation and growth.	('growth', 'CPA', (151, 157))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('alternative splicing', 'Var', (62, 82))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('affect', 'Reg', (114, 120))	('tumor', 'Disease', (121, 126))	('aberrant regulation', 'Var', (39, 58))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
479645	27519173	Aberrant splicing patterns that are commonly observed in human cancers have been associated with splicing regulators.	('Aberrant splicing patterns', 'Var', (0, 26))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('cancers', 'Phenotype', 'HP:0002664', (63, 70))	('associated', 'Reg', (81, 91))	('cancers', 'Disease', (63, 70))	('human', 'Species', '9606', (57, 62))	('cancers', 'Disease', 'MESH:D009369', (63, 70))
479646	27519173	For instance, dysregulated expression of splicing regulators (e.g., RBFOX2, PTB/PTBP1, and SRSF1 genes) has been reported to cause splicing pattern changes in genes.	('dysregulated', 'Var', (14, 26))	('PTB', 'Gene', '5725', (76, 79))	('PTB', 'Gene', (76, 79))	('RBFOX2', 'Gene', '23543', (68, 74))	('PTB', 'Gene', '5725', (80, 83))	('PTB', 'Gene', (80, 83))	('PTBP1', 'Gene', (80, 85))	('PTBP1', 'Gene', '5725', (80, 85))	('RBFOX2', 'Gene', (68, 74))	('SRSF1', 'Gene', (91, 96))	('cause', 'Reg', (125, 130))	('splicing pattern changes', 'MPA', (131, 155))	('SRSF1', 'Gene', '6426', (91, 96))
479671	27519173	Using the downloaded VCF file, we first identified the genes at the chromosomal positions with sequence variations, and then determined the major isoform for each gene.	('VCF', 'Gene', (21, 24))	('variations', 'Var', (104, 114))	('VCF', 'Gene', '1714', (21, 24))
479672	27519173	Second, ISOexpresso automatically annotates a given mutation list (VCF) with matching isoform expression data to help users select a specific transcript for predicting the functional effects of the mutations (User Data Annotation function).	('VCF', 'Gene', (67, 70))	('mutations', 'Var', (198, 207))	('VCF', 'Gene', '1714', (67, 70))
479675	27519173	Gene information may be provided in one of the following formats: gene symbol (e.g., FOXM1), gene name (e.g., Forkhead box M1), chromosomal location (e.g., chr12:2966847-2986206), RefSeq ID (e.g., NM_202002), UniProt ID (e.g., Q08050), or Ensembl gene ID (e.g., ENSG00000111206).	('Forkhead box M1', 'Gene', (110, 125))	('chr12:2966847-2986206', 'STRUCTURAL_ABNORMALITY', 'None', (156, 177))	('Q08050', 'Var', (227, 233))	('FOXM1', 'Gene', (85, 90))	('FOXM1', 'Gene', '2305', (85, 90))	('Forkhead box M1', 'Gene', '2305', (110, 125))
479680	27519173	2b-8, five known isoforms of the FOXM1 gene (uc001qle.3, uc001qlf.3, uc009zea.3, uc009zeb.3, and uc001qlg.3) are expressed in three cancer types (BRCA, LUAD, and PRAD).	('cancer', 'Disease', (132, 138))	('BRCA', 'Gene', '672', (146, 150))	('FOXM1', 'Gene', (33, 38))	('FOXM1', 'Gene', '2305', (33, 38))	('LUAD', 'Disease', (152, 156))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('BRCA', 'Gene', (146, 150))	('uc001qlg.3', 'Var', (97, 107))	('cancer', 'Disease', 'MESH:D009369', (132, 138))
479682	27519173	Furthermore, two additional isoforms are expressed at low levels in two cancer types (uc001qle.3 in BRCA and LUAD, and uc009zea.3 in BRCA).	('BRCA', 'Gene', '672', (100, 104))	('BRCA', 'Gene', '672', (133, 137))	('BRCA', 'Gene', (100, 104))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('uc001qle.3', 'Var', (86, 96))	('LUAD', 'Disease', (109, 113))	('uc009zea.3', 'Var', (119, 129))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('BRCA', 'Gene', (133, 137))	('cancer', 'Disease', (72, 78))
479690	27519173	In the given example, uc001qle.3 is a Type I candidate, as it is expressed at approximately 0.40 TPM in the tumor and is absent in the normal samples.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('uc001qle.3', 'Var', (22, 32))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('tumor', 'Disease', (108, 113))
479692	27519173	Likewise, uc001qlf.3 is a Type II candidate, because it is the major isoform only in cancer (66.4 %), while another isoform (uc009zeb.3) is the major isoform in the normal samples (77.6 %).	('cancer', 'Disease', (85, 91))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('uc001qlf.3', 'Var', (10, 20))
479700	27519173	In case 2, the coding region of the T >C variant of BTF3L4 is different (exon 3 vs. 4) when considering the major isoform (uc010onh.2) and the canonical isoform (uc001ctk.3).	('T >C', 'Var', (36, 40))	('BTF3L4', 'Gene', (52, 58))	('BTF3L4', 'Gene', '91408', (52, 58))
479701	27519173	While the former results in an amino acid change from Leu to Ser, the latter is interpreted as a synonymous mutation.	('Ser', 'MPA', (61, 64))	('Leu', 'Var', (54, 57))	('Leu', 'Chemical', 'MESH:D007930', (54, 57))	('results in', 'Reg', (17, 27))	('Ser', 'Chemical', 'MESH:D012694', (61, 64))
479702	27519173	In case 3, the G >A mutation in AMHR2 is interpreted as an Arg to Gln alteration in the canonical isoform (uc001scx.2), but it lies in the 3'-UTR region when the major isoform (uc009zmy.2) is considered.	('G >A', 'Var', (15, 19))	('AMHR2', 'Gene', '269', (32, 37))	('AMHR2', 'Gene', (32, 37))
479713	27519173	Among the four known isoforms, two isoforms showed dramatic expression shift: from uc011ava.2 to uc011avb.2 in nine cancer types (Fig.	('expression', 'MPA', (60, 70))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('uc011avb.2', 'Var', (97, 107))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))
479714	27519173	For the third example, CD44 is a cell surface glycoprotein that plays crucial roles in development as well as in cancer progression and metastasis, whose isoforms are known to be differentially expressed across tissues in many variant forms.	('CD44', 'Gene', '960', (23, 27))	('roles', 'Reg', (78, 83))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('CD44', 'Gene', (23, 27))	('cancer', 'Disease', (113, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('variant', 'Var', (227, 234))
479715	27519173	By contrast, one of three isoforms (uc001mvv.3, uc001mvw.3, or uc001mvx.3) was expressed as major type in tumor tissues (right chart of Fig.	('uc001mvw.3', 'Var', (48, 58))	('uc001mvv.3', 'Var', (36, 46))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('uc001mvx.3', 'Var', (63, 73))	('tumor', 'Disease', (106, 111))
479727	27519173	As reported by previous studies, cancer is closely associated with aberrant regulation of alternative splicing and therefore to the production of non-canonical and tumor-specific isoforms.	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('tumor', 'Disease', (164, 169))	('cancer', 'Disease', (33, 39))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('aberrant', 'Var', (67, 75))	('alternative splicing', 'MPA', (90, 110))	('associated', 'Reg', (51, 61))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('production', 'MPA', (132, 142))
479763	33626243	However, smokers with COPD are fourfold to sixfold as likely to develop LC as smokers without COPD [9], and the presence of emphysema in COPD predicts a higher LC risk adjusted for smoking status [10, 11].	('COPD', 'Disease', (94, 98))	('COPD', 'Disease', 'MESH:D029424', (137, 141))	('emphysema', 'Disease', (124, 133))	('emphysema', 'Disease', 'MESH:D004646', (124, 133))	('COPD', 'Disease', (22, 26))	('LC', 'Phenotype', 'HP:0100526', (72, 74))	('COPD', 'Disease', (137, 141))	('emphysema', 'Phenotype', 'HP:0002097', (124, 133))	('COPD', 'Phenotype', 'HP:0006510', (94, 98))	('presence', 'Var', (112, 120))	('LC', 'Phenotype', 'HP:0100526', (160, 162))	('COPD', 'Disease', 'MESH:D029424', (94, 98))	('COPD', 'Phenotype', 'HP:0006510', (137, 141))	('develop', 'PosReg', (64, 71))	('COPD', 'Phenotype', 'HP:0006510', (22, 26))	('COPD', 'Disease', 'MESH:D029424', (22, 26))
479848	33626243	High SPP1 expression in the tumour tissue was associated with inferior survival in a previous study with small sample size [24].	('SPP1', 'Gene', (5, 9))	('tumour', 'Phenotype', 'HP:0002664', (28, 34))	('High', 'Var', (0, 4))	('expression', 'MPA', (10, 20))	('tumour', 'Disease', 'MESH:D009369', (28, 34))	('inferior', 'NegReg', (62, 70))	('tumour', 'Disease', (28, 34))	('SPP1', 'Gene', '6696', (5, 9))
479855	33626243	Gene mutation has identified in squamous cell carcinoma and adenocarcinoma of lung [43, 44] and has led to resistance to chemotherapy, resulting in lower survival rates in small-cell LC [45].	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('led to', 'Reg', (100, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (46, 55))	('identified', 'Reg', (18, 28))	('LC', 'Phenotype', 'HP:0100526', (183, 185))	('small-cell LC', 'Disease', (172, 185))	('lower', 'NegReg', (148, 153))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (32, 55))	('adenocarcinoma of lung', 'Disease', (60, 82))	('squamous cell carcinoma', 'Disease', (32, 55))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (32, 55))	('adenocarcinoma of lung', 'Disease', 'MESH:D000077192', (60, 82))	('survival', 'MPA', (154, 162))	('mutation', 'Var', (5, 13))
479859	33626243	Small molecule inhibitors targeting both the IR and IGF1R or blockading beta-adrenergic receptor-mediated insulin-like growth factor receptor activation could reduce NSCLC cell proliferation and prevent LC [49, 50].	('LC', 'Phenotype', 'HP:0100526', (203, 205))	('IGF1R', 'Gene', '3480', (52, 57))	('LC [49', 'Disease', (203, 209))	('LC', 'Phenotype', 'HP:0100526', (169, 171))	('NSCLC', 'Disease', (166, 171))	('blockading', 'Var', (61, 71))	('insulin', 'Gene', (106, 113))	('prevent', 'NegReg', (195, 202))	('NSCLC', 'Disease', 'MESH:D002289', (166, 171))	('insulin', 'Gene', '3630', (106, 113))	('IGF1R', 'Gene', (52, 57))	('NSCLC', 'Phenotype', 'HP:0030358', (166, 171))	('reduce', 'NegReg', (159, 165))	('inhibitors', 'Var', (15, 25))
479877	33626243	Survival analysis showed that high expression of SPP1 was associated with shorter survival time.	('shorter', 'NegReg', (74, 81))	('survival time', 'CPA', (82, 95))	('high', 'Var', (30, 34))	('SPP1', 'Gene', '6696', (49, 53))	('SPP1', 'Gene', (49, 53))
479996	32517240	Even more, TEX were shown to reduce proliferation of CD8+ T cells and induce their apoptosis.	('CD8', 'Gene', (53, 56))	('CD8', 'Gene', '925', (53, 56))	('TEX', 'Chemical', '-', (11, 14))	('induce', 'Reg', (70, 76))	('TEX', 'Var', (11, 14))	('reduce proliferation of CD8+ T cells', 'Phenotype', 'HP:0005415', (29, 65))	('apoptosis', 'CPA', (83, 92))	('proliferation', 'CPA', (36, 49))	('reduce', 'NegReg', (29, 35))
480001	32517240	Further, TEX were shown to induce tumor innervation and angiogenesis through reprogramming of endothelial cells within the TME.	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('tumor', 'Disease', (34, 39))	('induce', 'PosReg', (27, 33))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('reprogramming', 'CPA', (77, 90))	('TEX', 'Chemical', '-', (9, 12))	('TEX', 'Var', (9, 12))	('angiogenesis', 'CPA', (56, 68))
480007	32517240	Overall, these observations emphasize that TEX-mediated modulation of the TME contributes to immune suppression, tumor growth, and metastasis in HNSCC.	('tumor', 'Disease', (113, 118))	('modulation', 'Var', (56, 66))	('HNSCC', 'Disease', (145, 150))	('immune suppression', 'CPA', (93, 111))	('metastasis', 'CPA', (131, 141))	('HNSCC', 'Phenotype', 'HP:0012288', (145, 150))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('TEX', 'Chemical', '-', (43, 46))
480012	32517240	The tumorigenic compound 4NQO causes intracellular oxidative stress followed by mutations and DNA strand breaks.	('tumor', 'Disease', (4, 9))	('4NQO', 'Chemical', 'MESH:D015112', (25, 29))	('mutations', 'CPA', (80, 89))	('oxidative stress', 'Phenotype', 'HP:0025464', (51, 67))	('DNA strand breaks', 'CPA', (94, 111))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('intracellular oxidative stress', 'MPA', (37, 67))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('4NQO', 'Var', (25, 29))
480020	32517240	HPV(+) tumors are generally more responsive to therapy and have a better prognosis and outcome with an approximately 60% reduced risk of death compared to HPV(-) tumors.	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('HPV', 'Species', '10566', (0, 3))	('HPV', 'Species', '10566', (155, 158))	('tumors', 'Disease', (7, 13))	('reduced', 'NegReg', (121, 128))	('tumors', 'Disease', 'MESH:D009369', (7, 13))	('tumors', 'Phenotype', 'HP:0002664', (7, 13))	('more', 'PosReg', (28, 32))	('tumors', 'Disease', (162, 168))	('tumors', 'Disease', 'MESH:D009369', (162, 168))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))	('HPV(+', 'Var', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
480024	32517240	Additionally, comparison of proteome profiles by mass spectrometry revealed differential content of protein cargos in HPV(+) and HPV(-) TEX.	('content of', 'MPA', (89, 99))	('protein', 'Protein', (100, 107))	('TEX', 'Chemical', '-', (136, 139))	('HPV', 'Species', '10566', (118, 121))	('HPV', 'Species', '10566', (129, 132))	('HPV', 'Var', (129, 132))
480100	32517240	Furthermore, the known EMT inducer TGF-beta was significantly reduced in exosomes after PDT.	('TGF-beta', 'Gene', '7039', (35, 43))	('TGF-beta', 'Gene', (35, 43))	('reduced', 'NegReg', (62, 69))	('PDT', 'Var', (88, 91))
480116	32517240	In another study, incorporation of paclitaxel in exosomes increased its cytotoxicity against multidrug-resistant cancer cells, indicating the possibility to overcome drug resistance by the use of exosome-encapsulated chemotherapeutics.	('increased', 'PosReg', (58, 67))	('cytotoxicity', 'Disease', 'MESH:D064420', (72, 84))	('incorporation', 'Var', (18, 31))	('paclitaxel', 'Chemical', 'MESH:D017239', (35, 45))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('cancer', 'Disease', (113, 119))	('drug resistance', 'Phenotype', 'HP:0020174', (166, 181))	('cytotoxicity', 'Disease', (72, 84))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
480120	32517240	Recent data showing that exosome-delivered miRNA-138 efficiently conferred its OSCC antitumor functions in vitro and in vivo support the presumption that exosomes have potential as delivery agents also in HNSCC.	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('OSCC', 'MPA', (79, 83))	('HNSCC', 'Phenotype', 'HP:0012288', (205, 210))	('miRNA-138', 'Var', (43, 52))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('miRNA-138', 'Chemical', '-', (43, 52))	('tumor', 'Disease', (88, 93))
480122	32517240	This approach is based on the mutant HIV-1 negative regulatory factor (Nefmut) protein, which remarkably incorporates into exosomes and acts as an exosome-anchoring protein upon fusion with heterologous proteins.	('HIV-1', 'Gene', (37, 42))	('mutant', 'Var', (30, 36))	('HIV-1', 'Species', '11676', (37, 42))
480130	31078526	Identification of cancer drivers at CTCF insulators in 1,962 whole-genomes Recent studies have shown that mutations at non-coding elements, such as promoters and enhancers, can act as cancer drivers.	('cancer', 'Disease', (184, 190))	('CTCF', 'Gene', '10664', (36, 40))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('CTCF', 'Gene', (36, 40))	('mutations', 'Var', (106, 115))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('cancer', 'Disease', (18, 24))	('cancer', 'Disease', 'MESH:D009369', (18, 24))
480133	31078526	In particular, mutations in an insulator in multiple cancer types, including 16% of melanoma samples, are associated with TGFB1 up-regulation.	('TGFB1', 'Gene', (122, 127))	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('up-regulation', 'PosReg', (128, 141))	('melanoma', 'Disease', 'MESH:D008545', (84, 92))	('mutations', 'Var', (15, 24))	('melanoma', 'Phenotype', 'HP:0002861', (84, 92))	('melanoma', 'Disease', (84, 92))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('TGFB1', 'Gene', '7040', (122, 127))
480134	31078526	Using CRISPR-Cas9, we find that alterations at two of the most frequently mutated regions in this insulator increase cell growth by 40-50%, supporting the role of this boundary element as a cancer driver.	('cancer', 'Disease', (190, 196))	('cancer', 'Disease', 'MESH:D009369', (190, 196))	('increase', 'PosReg', (108, 116))	('alterations', 'Var', (32, 43))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('cell growth', 'CPA', (117, 128))
480136	31078526	We developed a computational method that combines recurrence and functional impact of mutations to identify cancer drivers.	('mutations', 'Var', (86, 95))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
480138	31078526	In particular, mutations in an insulator on chr19 are associated with TGFB1 up-regulation and may point to a novel mechanism of TGF-beta signaling modulation in multiple cancer types.	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('TGFB1', 'Gene', '7040', (70, 75))	('TGF-beta', 'Gene', (128, 136))	('up-regulation', 'PosReg', (76, 89))	('cancer', 'Disease', (170, 176))	('mutations', 'Var', (15, 24))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('TGFB1', 'Gene', (70, 75))	('TGF-beta', 'Gene', '7039', (128, 136))
480139	31078526	Whole-genome sequencing (WGS) of tumors has revealed that most somatic mutations occur in non-coding regions.	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('mutations', 'Var', (71, 80))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('tumors', 'Disease', 'MESH:D009369', (33, 39))	('tumors', 'Disease', (33, 39))	('occur', 'Reg', (81, 86))
480140	31078526	Although most of these mutations do not impact tumor growth and are called passengers, some of them can act as cancer drivers by conferring growth advantage to promote tumorigenesis.	('promote', 'PosReg', (160, 167))	('tumor', 'Disease', (168, 173))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('growth', 'MPA', (140, 146))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('mutations', 'Var', (23, 32))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('tumor', 'Disease', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
480144	31078526	In other prominent examples, promoter and enhancer mutations in breast cancer can lead to FOXA1 and ESR1 overexpression, respectively.	('breast cancer', 'Phenotype', 'HP:0003002', (64, 77))	('enhancer', 'PosReg', (42, 50))	('mutations', 'Var', (51, 60))	('ESR1', 'Gene', (100, 104))	('overexpression', 'PosReg', (105, 119))	('FOXA1', 'Gene', (90, 95))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('breast cancer', 'Disease', 'MESH:D001943', (64, 77))	('ESR1', 'Gene', '2099', (100, 104))	('FOXA1', 'Gene', '3169', (90, 95))	('breast cancer', 'Disease', (64, 77))
480149	31078526	Disruption of the loop anchor regions, called CTCF/cohesin insulators (hereafter referred to as insulators), can lead to de novo enhancer-promoter interactions and the subsequent dysregulation of associated genes.	('lead to', 'Reg', (113, 120))	('CTCF', 'Gene', '10664', (46, 50))	('dysregulation', 'MPA', (179, 192))	('CTCF', 'Gene', (46, 50))	('enhancer-promoter interactions', 'MPA', (129, 159))	('Disruption', 'Var', (0, 10))
480152	31078526	Although the reasons for the high mutation rates are not completely understood, these studies noted that most of these mutations are likely passengers and do not drive tumor growth.	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('mutations', 'Var', (119, 128))	('tumor', 'Disease', (168, 173))
480153	31078526	found the CTCF insulators of DNA loops show recurrent deletions that alter the expression of LMO2 and TALI oncogenes in T cell acute lymphoblastic leukemia.	('CTCF', 'Gene', (10, 14))	('lymphoblastic leukemia', 'Disease', (133, 155))	('leukemia', 'Phenotype', 'HP:0001909', (147, 155))	('expression', 'MPA', (79, 89))	('deletions', 'Var', (54, 63))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (133, 155))	('LMO2', 'Gene', '4005', (93, 97))	('CTCF', 'Gene', '10664', (10, 14))	('alter', 'Reg', (69, 74))	('lymphoblastic leukemia', 'Disease', 'MESH:D054198', (133, 155))	('LMO2', 'Gene', (93, 97))	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (127, 155))	('T cell acute lymphoblastic leukemia', 'Phenotype', 'HP:0006727', (120, 155))
480154	31078526	Thus, some variants at insulators may have a functional role and drive the growth of cancer cells.	('variants', 'Var', (11, 19))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('drive', 'PosReg', (65, 70))	('cancer', 'Disease', (85, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
480158	31078526	Out of 5,042 insulators that show recurrent mutations (i.e., present in 2 or more samples) in 1,962 whole-genomes from 21 cancer types, our method identifies 21 putative drivers.	('cancer', 'Disease', (122, 128))	('mutations', 'Var', (44, 53))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))
480159	31078526	Functional validation of a predicted driver using CTCF ChIP-seq, 3C and CRISPR mutagenesis supports our computational predictions in human melanoma cells.	('mutagenesis', 'Var', (79, 90))	('melanoma', 'Phenotype', 'HP:0002861', (139, 147))	('melanoma', 'Disease', (139, 147))	('melanoma', 'Disease', 'MESH:D008545', (139, 147))	('CTCF', 'Gene', (50, 54))	('human', 'Species', '9606', (133, 138))	('CTCF', 'Gene', '10664', (50, 54))
480162	31078526	We analyzed the patterns of somatic single nucleotide variants (SNVs) in 1,962 genomes from 21 cancer types (Table S1) at constitutive insulators.	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('single nucleotide variants', 'Var', (36, 62))	('cancer', 'Disease', (95, 101))
480163	31078526	We identified the mutations predicted to disrupt CTCF binding by comparing the TF motif position weight matrix (PWM) score of the mutated vs. the reference sequence (Figure S2A and Table S14).	('CTCF', 'Gene', (49, 53))	('S14', 'Gene', '5714', (187, 190))	('CTCF', 'Gene', '10664', (49, 53))	('S14', 'Gene', (187, 190))	('binding', 'Interaction', (54, 61))	('mutations', 'Var', (18, 27))
480164	31078526	We observe significant enrichment of CTCF motifs predicted to be disrupted due to mutations in 15 out of 21 cancer types analyzed (Figure S2B).	('CTCF', 'Gene', '10664', (37, 41))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('mutations', 'Var', (82, 91))	('CTCF', 'Gene', (37, 41))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
480165	31078526	Next, we extracted the tri-nucleotide context of the mutations predicted to disrupt CTCF motifs and compared the distributions of the 96 possible contexts with known signatures of mutational processes in human cancer from COSMIC as a reference control using cosine similarity as the quantitative metric (Figures S2C and S2D).	('CTCF', 'Gene', '10664', (84, 88))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('mutations', 'Var', (53, 62))	('cancer', 'Disease', 'MESH:D009369', (210, 216))	('tri-nucleotide', 'Chemical', '-', (23, 37))	('human', 'Species', '9606', (204, 209))	('CTCF', 'Gene', (84, 88))	('cancer', 'Disease', (210, 216))
480166	31078526	We find that the tri-nucleotide distributions for CTCF motif-disrupting mutations vary considerably across cancer types and interestingly match the corresponding cancer-specific COSMIC mutational signatures in 9 cancer types (Figure S2D).	('mutations', 'Var', (72, 81))	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('tri-nucleotide', 'Chemical', '-', (17, 31))	('cancer', 'Disease', (162, 168))	('motif-disrupting', 'Reg', (55, 71))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('CTCF', 'Gene', (50, 54))	('cancer', 'Disease', (212, 218))	('cancer', 'Disease', 'MESH:D009369', (212, 218))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('CTCF', 'Gene', '10664', (50, 54))	('cancer', 'Disease', (107, 113))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))
480167	31078526	As seen in Figure S2B, these 9 cancer types are also enriched for CTCF motif disruption.	('disruption', 'Var', (77, 87))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('CTCF', 'Gene', (66, 70))	('CTCF', 'Gene', '10664', (66, 70))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('cancer', 'Disease', (31, 37))
480168	31078526	Thus, our results show that enrichment of CTCF motif disruption in multiple cancer types is likely due to neutral mutational processes operative in those cancers.	('disruption', 'Var', (53, 63))	('CTCF', 'Gene', (42, 46))	('cancers', 'Phenotype', 'HP:0002664', (154, 161))	('cancer', 'Disease', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('cancers', 'Disease', 'MESH:D009369', (154, 161))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('cancers', 'Disease', (154, 161))	('CTCF', 'Gene', '10664', (42, 46))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))
480169	31078526	For the remaining 6 cancer types that show enrichment of CTCF motif disruption, but do not closely match any single mutational signature identified in that cancer type, we expect the motif-disrupting mutations are likely either a combination of multiple signatures or may correspond to unknown signatures of longer sequence context.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('CTCF', 'Gene', '10664', (57, 61))	('motif disruption', 'Var', (62, 78))	('motif-disrupting', 'Reg', (183, 199))	('mutations', 'Var', (200, 209))	('cancer', 'Disease', (156, 162))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('cancer', 'Disease', 'MESH:D009369', (20, 26))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('cancer', 'Disease', (20, 26))	('CTCF', 'Gene', (57, 61))
480172	31078526	Our observations are consistent with those of Kaiser et al., who noted that enrichment of functional mutations at binding sites of CTCF and other TFs are likely due to neutral mutational processes, though they did not make a one-to-one comparison with the 30 mutational signatures from COSMIC.	('CTCF', 'Gene', (131, 135))	('CTCF', 'Gene', '10664', (131, 135))	('mutations', 'Var', (101, 110))
480173	31078526	Thus, these results demonstrate that in the computational models for cancer driver detection at CTCF insulators, there is a need to balance the higher functional impact of motif-disrupting mutations and their higher frequency (Figure S3) due to background mutational processes.	('CTCF', 'Gene', (96, 100))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('CTCF', 'Gene', '10664', (96, 100))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('mutations', 'Var', (189, 198))	('cancer', 'Disease', (69, 75))
480174	31078526	We report a novel computational method, CNCDriver, which combines the functional impact of mutations and their recurrence across multiple cancer samples to identify the elements that show signals of positive selection.	('cancer', 'Disease', (138, 144))	('mutations', 'Var', (91, 100))	('cancer', 'Disease', 'MESH:D009369', (138, 144))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))
480176	31078526	To identify the insulators under positive selection, CNCDriver also incorporates the ratio of CTCF motif-disrupting to motif-preserving mutations in the null model, thus balancing the opposite effects of predicted higher functional impact of these mutations with their higher frequency (Figure S3 and Methods).	('CTCF', 'Gene', (94, 98))	('CTCF', 'Gene', '10664', (94, 98))	('mutations', 'Var', (136, 145))
480181	31078526	We note that only 21 insulators are predicted to be under positive selection even though many insulators show high mutational frequencies (Figure S9: grey bars in circles for each cancer type).	('mutational', 'Var', (115, 125))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('cancer', 'Disease', (180, 186))	('cancer', 'Disease', 'MESH:D009369', (180, 186))
480189	31078526	To further interpret the tumorigenic role of mutations at insulator regions, we examined their clonality status.	('tumor', 'Disease', (25, 30))	('mutations', 'Var', (45, 54))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))
480190	31078526	We performed integrative analysis of tumor purity, copy number alterations and read depth at mutated loci using an approach similar to the one in previous studies (Figures S10A and S10B).	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('S10A', 'Var', (172, 176))	('copy number alterations', 'Var', (51, 74))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('S10B', 'Var', (181, 185))	('S10A', 'SUBSTITUTION', 'None', (172, 176))	('S10B', 'SUBSTITUTION', 'None', (181, 185))
480191	31078526	We find that the majority of mutations in both coding and non-coding drivers tend to be clonal, likely pointing to their roles during the early stages of tumor development (Figure S10C and S10D).	('S10C', 'Mutation', 'p.S10C', (180, 184))	('mutations', 'Var', (29, 38))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('S10D', 'Mutation', 'p.S10D', (189, 193))	('tumor', 'Disease', (154, 159))
480193	31078526	However, the fraction of clonal mutations in insulators (0.60) is significantly lower than that observed in promoters (0.79) (P value = 0.049, Fisher's exact test) suggesting the possibility that mutations at insulators may play a stronger role at later stages in cancer progression.	('cancer', 'Phenotype', 'HP:0002664', (264, 270))	('mutations', 'Var', (196, 205))	('mutations', 'Var', (32, 41))	('lower', 'NegReg', (80, 85))	('play', 'Reg', (224, 228))	('cancer', 'Disease', (264, 270))	('cancer', 'Disease', 'MESH:D009369', (264, 270))
480195	31078526	Based on previous studies, the majority (~80%) of the loop anchors bound by CTCF and cohesin contain CTCF motifs in convergent orientations (i.e.	('cohesin', 'Protein', (85, 92))	('CTCF', 'Gene', (76, 80))	('CTCF', 'Gene', (101, 105))	('CTCF', 'Gene', '10664', (101, 105))	('motifs', 'Var', (106, 112))	('CTCF', 'Gene', '10664', (76, 80))
480197	31078526	For example, in Figure 1C, mutations at the driver insulator with the reverse CTCF motif are predicted to weaken a constitutive loop (red), thereby strengthening an alternate constitutive loop (gray) and a predicted new loop (dotted) through the pairing of the forward CTCF motif with other reverse motifs in the vicinity.	('mutations', 'Var', (27, 36))	('CTCF', 'Gene', '10664', (78, 82))	('CTCF', 'Gene', '10664', (269, 273))	('CTCF', 'Gene', (269, 273))	('weaken', 'NegReg', (106, 112))	('strengthening', 'PosReg', (148, 161))	('constitutive loop', 'MPA', (175, 192))	('CTCF', 'Gene', (78, 82))
480198	31078526	Among these 76 genes, TGFB1, HES1, CUL1 and CDKN2A are involved in curated cancer pathways (Figures 1C, S11C, S11K and S11M).	('HES1', 'Gene', (29, 33))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('CDKN2A', 'Gene', (44, 50))	('TGFB1', 'Gene', (22, 27))	('cancer', 'Disease', (75, 81))	('involved', 'Reg', (55, 63))	('CUL1', 'Gene', (35, 39))	('S11K', 'Mutation', 'p.S11K', (110, 114))	('CDKN2A', 'Gene', '1029', (44, 50))	('HES1', 'Gene', '3280', (29, 33))	('S11M', 'Mutation', 'p.S11M', (119, 123))	('S11C', 'SUBSTITUTION', 'None', (104, 108))	('TGFB1', 'Gene', '7040', (22, 27))	('CUL1', 'Gene', '8454', (35, 39))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('S11C', 'Var', (104, 108))
480199	31078526	Next, we asked whether these 76 genes exhibit differential expression in patients with insulator mutations vs. those without.	('mutations', 'Var', (97, 106))	('expression', 'MPA', (59, 69))	('patients', 'Species', '9606', (73, 81))
480201	31078526	We found that the expression of two neighboring genes is associated with mutations in one insulator driver candidate: TGFB1 (in melanoma and pan-cancer analysis) and CYP2S1 (in melanoma) (Figure 1D and Figure S12A).	('cancer', 'Disease', (145, 151))	('CYP2S1', 'Gene', (166, 172))	('melanoma', 'Disease', 'MESH:D008545', (128, 136))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('S12A', 'SUBSTITUTION', 'None', (209, 213))	('melanoma', 'Disease', 'MESH:D008545', (177, 185))	('melanoma', 'Phenotype', 'HP:0002861', (177, 185))	('melanoma', 'Disease', (177, 185))	('S12A', 'Var', (209, 213))	('CYP2S1', 'Gene', '29785', (166, 172))	('TGFB1', 'Gene', '7040', (118, 123))	('expression', 'MPA', (18, 28))	('melanoma', 'Phenotype', 'HP:0002861', (128, 136))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('TGFB1', 'Gene', (118, 123))	('mutations', 'Var', (73, 82))	('associated', 'Reg', (57, 67))	('melanoma', 'Disease', (128, 136))
480203	31078526	The mutational frequency of candidate drivers is also lower in other cancer types relative to melanoma, which further decreases the statistical power to detect significant differences in gene expression.	('melanoma', 'Disease', 'MESH:D008545', (94, 102))	('melanoma', 'Phenotype', 'HP:0002861', (94, 102))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('melanoma', 'Disease', (94, 102))	('lower', 'NegReg', (54, 59))	('mutational frequency', 'Var', (4, 24))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Disease', (69, 75))
480204	31078526	For example, matched WGS and RNA-seq data is available for only 3 samples with mutations and 93 without for the candidate driver on chr12 in breast cancer, while it is available for 12 samples with mutations and 68 without for the candidate driver in melanoma.	('chr12', 'Gene', (132, 137))	('melanoma', 'Phenotype', 'HP:0002861', (251, 259))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('breast cancer', 'Disease', 'MESH:D001943', (141, 154))	('breast cancer', 'Disease', (141, 154))	('melanoma', 'Disease', 'MESH:D008545', (251, 259))	('breast cancer', 'Phenotype', 'HP:0003002', (141, 154))	('melanoma', 'Disease', (251, 259))	('mutations', 'Var', (79, 88))
480205	31078526	The driver candidate (chr19:41,767,305-41,771,623) identified in melanoma and in pan-cancer analysis where mutations are associated with TGFB1 up-regulation (Figures 1B, 1C, 1D and S12 and Table S13) is of particular interest.	('mutations', 'Var', (107, 116))	('TGFB1', 'Gene', (137, 142))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('S12', 'Gene', (181, 184))	('chr19:41,767,305-41,771,623', 'STRUCTURAL_ABNORMALITY', 'None', (22, 49))	('cancer', 'Disease', (85, 91))	('S12', 'Gene', '6268', (181, 184))	('melanoma', 'Phenotype', 'HP:0002861', (65, 73))	('up-regulation', 'PosReg', (143, 156))	('melanoma', 'Disease', (65, 73))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('TGFB1', 'Gene', '7040', (137, 142))	('melanoma', 'Disease', 'MESH:D008545', (65, 73))
480207	31078526	We find that the mutation frequency of this insulator is higher in metastatic (19%) relative to primary samples (12%) (Figure S12F), which is consistent with the known role of TGFB1 in melanoma metastasis.	('melanoma metastasis', 'Disease', (185, 204))	('S12F', 'Mutation', 'p.S12F', (126, 130))	('higher', 'Reg', (57, 63))	('mutation', 'Var', (17, 25))	('melanoma metastasis', 'Disease', 'MESH:D009362', (185, 204))	('metastatic', 'CPA', (67, 77))	('TGFB1', 'Gene', '7040', (176, 181))	('TGFB1', 'Gene', (176, 181))	('melanoma', 'Phenotype', 'HP:0002861', (185, 193))
480208	31078526	Furthermore, this trend is even stronger when analyzing the samples with recurrent mutations (since they are likely the ones under stronger positive selection than non-recurrent mutations), with mutation frequency of 17% for metastatic and 8% for primary melanoma samples (Figure S12F).	('mutations', 'Var', (83, 92))	('metastatic', 'Disease', (225, 235))	('melanoma', 'Phenotype', 'HP:0002861', (255, 263))	('S12F', 'Mutation', 'p.S12F', (280, 284))	('melanoma', 'Disease', (255, 263))	('melanoma', 'Disease', 'MESH:D008545', (255, 263))
480210	31078526	The mutations of this insulator in other cancer types (lung adenocarcinoma, endometrial carcinoma, prostate adenocarcinoma and liver hepatocellular carcinoma) and in particular the relatively high mutational frequency of 9% in colon cancer and 3% in esophageal adenocarcinoma may provide complementary mechanisms to the known genomic alterations (protein-coding mutations and copy number alterations) for modulation of TGF-beta signaling, especially in gastrointestinal cancers.	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('TGF-beta', 'Gene', (419, 427))	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (55, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('endometrial carcinoma, prostate adenocarcinoma', 'Disease', 'MESH:D016889', (76, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('cancer', 'Disease', (470, 476))	('colon cancer', 'Disease', 'MESH:D015179', (227, 239))	('cancer', 'Disease', (41, 47))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (55, 74))	('cancers', 'Phenotype', 'HP:0002664', (470, 477))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('liver hepatocellular carcinoma', 'Disease', 'MESH:D006528', (127, 157))	('cancer', 'Phenotype', 'HP:0002664', (470, 476))	('cancer', 'Disease', 'MESH:D009369', (233, 239))	('gastrointestinal cancers', 'Disease', 'MESH:D004067', (453, 477))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (76, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (148, 157))	('colon cancer', 'Disease', (227, 239))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (250, 275))	('cancer', 'Disease', 'MESH:D009369', (470, 476))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('mutations', 'Var', (4, 13))	('gastrointestinal cancers', 'Disease', (453, 477))	('esophageal adenocarcinoma', 'Disease', 'MESH:D000230', (250, 275))	('liver hepatocellular carcinoma', 'Disease', (127, 157))	('lung adenocarcinoma', 'Disease', (55, 74))	('esophageal adenocarcinoma', 'Disease', (250, 275))	('carcinoma', 'Phenotype', 'HP:0030731', (266, 275))	('cancer', 'Disease', (233, 239))	('TGF-beta', 'Gene', '7039', (419, 427))	('mutational', 'Var', (197, 207))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (133, 157))	('colon cancer', 'Phenotype', 'HP:0003003', (227, 239))
480218	31078526	Six out of 48 mutations in this insulator are located within the regions bound by CTCF (SNV4, 5, 19, 20, and 21 in Figure S12E), while 39 out of 48 mutations occur at the ChIP-seq peaks of other TFs.	('CTCF', 'Gene', '10664', (82, 86))	('S12E', 'Mutation', 'p.S12E', (122, 126))	('CTCF', 'Gene', (82, 86))	('mutations', 'Var', (14, 23))
480224	31078526	Many SNVs, including recurrent mutations (SNV8, 9, 11, 12, 14 and 18) are located at an YY1 ChIP-seq peak.	('mutations', 'Var', (31, 40))	('YY1', 'Gene', (88, 91))	('YY1', 'Gene', '7528', (88, 91))
480225	31078526	We find that the region spanned by SNV8 to SNV21 bound by many TFs also shows the highest mutational density in other cancer types aside from melanoma (Figure S12B).	('cancer', 'Disease', (118, 124))	('melanoma', 'Disease', 'MESH:D008545', (142, 150))	('S12B', 'Var', (159, 163))	('SNV21', 'Gene', (43, 48))	('TFs', 'Gene', (63, 66))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('mutational density', 'MPA', (90, 108))	('S12B', 'SUBSTITUTION', 'None', (159, 163))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('melanoma', 'Phenotype', 'HP:0002861', (142, 150))	('melanoma', 'Disease', (142, 150))
480230	31078526	We found increased proliferation in the SNV-edited melanoma cells : 139.8% +/- 7.3 for SNV4 and 149.8% +/- 1.7 for SNV8 : when compared to cells transduced with non-targeting guides (Figure 3D), suggesting that mutations in these regions confer a growth advantage in melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (267, 275))	('melanoma', 'Disease', (267, 275))	('mutations', 'Var', (211, 220))	('melanoma', 'Disease', 'MESH:D008545', (267, 275))	('growth advantage', 'CPA', (247, 263))	('melanoma', 'Phenotype', 'HP:0002861', (51, 59))	('melanoma', 'Disease', (51, 59))	('melanoma', 'Disease', 'MESH:D008545', (51, 59))
480231	31078526	This study presents a comprehensive analysis of CTCF/cohesin insulator mutations from WGS of 1,962 patients in 21 cancer types.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('CTCF', 'Gene', (48, 52))	('patients', 'Species', '9606', (99, 107))	('mutations', 'Var', (71, 80))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('CTCF', 'Gene', '10664', (48, 52))	('cancer', 'Disease', (114, 120))
480232	31078526	We find that background mutational processes in different cancers lead to differential enrichment of mutations predicted to disrupt CTCF motifs; the majority of which are likely to be passengers.	('mutations', 'Var', (101, 110))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('cancers', 'Phenotype', 'HP:0002664', (58, 65))	('CTCF', 'Gene', (132, 136))	('cancers', 'Disease', 'MESH:D009369', (58, 65))	('CTCF', 'Gene', '10664', (132, 136))	('cancers', 'Disease', (58, 65))
480233	31078526	Using the predicted functional impact of mutations, their frequency and the patterns of CTCF motif-disruption, we developed a computational approach (CNCDriver) to identify insulator regions under positive selection.	('mutations', 'Var', (41, 50))	('CTCF', 'Gene', (88, 92))	('CTCF', 'Gene', '10664', (88, 92))
480235	31078526	Mutations in one of these 21 candidates are associated with differential gene expression that may play a role in tumorigenesis by interfering with the TGF-beta pathway in melanoma and other cancers, especially gastrointestinal.	('tumor', 'Disease', (113, 118))	('TGF-beta', 'Gene', (151, 159))	('cancers', 'Phenotype', 'HP:0002664', (190, 197))	('cancers', 'Disease', (190, 197))	('TGF-beta', 'Gene', '7039', (151, 159))	('cancers', 'Disease', 'MESH:D009369', (190, 197))	('Mutations', 'Var', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('melanoma', 'Phenotype', 'HP:0002861', (171, 179))	('melanoma', 'Disease', (171, 179))	('interfering', 'NegReg', (130, 141))	('gastrointestinal', 'Disease', (210, 226))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('melanoma', 'Disease', 'MESH:D008545', (171, 179))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))
480236	31078526	Our hypothesis is supported by functional validation using CRISPR-Cas9 which shows that two of the most frequent mutations increase cell growth by 1.4- and 1.5-fold in melanoma cells.	('cell growth', 'CPA', (132, 143))	('increase', 'PosReg', (123, 131))	('mutations', 'Var', (113, 122))	('melanoma', 'Phenotype', 'HP:0002861', (168, 176))	('melanoma', 'Disease', (168, 176))	('melanoma', 'Disease', 'MESH:D008545', (168, 176))
480238	31078526	Thus, our study reveals several CTCF insulators as putative drivers and opens the door to multiple experimental validation and mechanistic studies of the tumorigenic impact of mutations in these elements.	('mutations', 'Var', (176, 185))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('CTCF', 'Gene', (32, 36))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('CTCF', 'Gene', '10664', (32, 36))	('tumor', 'Disease', (154, 159))
480242	31078526	In order to have sufficient statistical power to detect significant associations between gene expression and mutations, we estimate that we would need at least ~300 samples with matched RNA-seq data for the other cancer types in this study (Methods).	('cancer', 'Disease', 'MESH:D009369', (213, 219))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('cancer', 'Disease', (213, 219))	('mutations', 'Var', (109, 118))
480243	31078526	Finally, while we analyzed the impact of SNVs in insulators, CTCF-CTCF loops may also be perturbed by DNA methylation, small insertions or deletions, and structural variations at insulators.	('structural variations', 'Var', (154, 175))	('CTCF-CTCF', 'Gene', '10664', (61, 70))	('perturbed', 'Reg', (89, 98))	('insertions', 'Var', (125, 135))	('CTCF-CTCF', 'Gene', (61, 70))	('DNA methylation', 'Var', (102, 117))	('deletions', 'Var', (139, 148))
480272	31078526	We first define the orientation of CTCF motif (MA0139.1) from the JASPAR 2018 CORE vertebrate (MA0139.1) as CTCF forward direction and the reverse-complement model as CTCF reverse direction (Figure S2A).	('MA0139.1', 'Var', (47, 55))	('CTCF', 'Gene', '10664', (167, 171))	('CTCF', 'Gene', (108, 112))	('CTCF', 'Gene', (35, 39))	('CTCF', 'Gene', '10664', (108, 112))	('CTCF', 'Gene', '10664', (35, 39))	('CTCF', 'Gene', (167, 171))
480275	31078526	Our enhancer set is obtained by the union of TF binding peaks and DHSs from ENCODE, and Segway/ChromHMM-predicted enhancers, which were defined from histone marks (H3K4me1, H3K4me2 and H3K27ac).	('H3K4me1', 'Var', (164, 171))	('H3K4me2', 'Var', (173, 180))	('DHSs', 'Disease', (66, 70))	('DHSs', 'Disease', 'None', (66, 70))
480278	31078526	For pancreatic, kidney, ovarian, colon, esophageal, and prostate, we used the average replication timing signal from HepG2, MCF-7, GM12878, K562, BJ, IMR-90 and SK-N-SH.	('GM12878', 'Var', (131, 138))	('K562', 'CellLine', 'CVCL:0004', (140, 144))	('GM12878', 'Chemical', '-', (131, 138))	('MCF-7', 'CellLine', 'CVCL:0031', (124, 129))	('pancreatic, kidney, ovarian, colon', 'Disease', 'MESH:D010051', (4, 38))	('K562', 'Var', (140, 144))	('HepG2', 'CellLine', 'CVCL:0027', (117, 122))	('BJ', 'CellLine', 'CVCL:6573', (146, 148))
480279	31078526	We used ASCAT (ASCAT version 2.4.2 ) with default parameters to identify copy number alterations, ploidy and purity for the WGS samples in the ICGC MELA-AU project.	('copy number', 'Var', (73, 84))	('ploidy', 'Disease', 'None', (98, 104))	('ploidy', 'Disease', (98, 104))
480283	31078526	A375 cell line was obtained from Dr. Joan Massague (Memorial Sloan Kettering Cancer Center) and cultured in DMEM supplemented with L-glutamine (2mmol/L), penicillin (100U/ml), streptomycin (100ug/ml) and 10% heat-inactivated FBS.	('Cancer', 'Disease', (77, 83))	('A375', 'CellLine', 'CVCL:0132', (0, 4))	('100U/ml', 'Var', (166, 173))	('Cancer', 'Disease', 'MESH:D009369', (77, 83))	('streptomycin', 'Chemical', 'MESH:D013307', (176, 188))	('Cancer', 'Phenotype', 'HP:0002664', (77, 83))	('DMEM', 'Chemical', '-', (108, 112))	('penicillin', 'Chemical', 'MESH:D010406', (154, 164))	('L-glutamine', 'Chemical', 'MESH:D005973', (131, 142))	('100ug/ml', 'Var', (190, 198))
480308	31078526	To assess the enrichment of CTCF and other TF motif-disruption events within a specific cancer type, we performed a binomial test to compare the fraction of disrupted TF motifs to the corresponding proportion of the TF motifs abundance.	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('CTCF', 'Gene', (28, 32))	('motifs', 'Var', (170, 176))	('CTCF', 'Gene', '10664', (28, 32))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))
480309	31078526	To decipher the signatures of mutational processes operative in the TF binding site regions, we used the FunSeq2 annotation of the SNVs that disrupt TF motifs and computed their normalized tri-nucleotide distributions, which determined the motif-disruption signature for each TF for each cancer type (frequency of 96 mutation types equivalent to the six substitution changes and their immediate 5' and 3' sequence context).	('substitution changes', 'Var', (354, 374))	('tri-nucleotide', 'Chemical', '-', (189, 203))	('cancer', 'Disease', 'MESH:D009369', (288, 294))	('cancer', 'Disease', (288, 294))	('cancer', 'Phenotype', 'HP:0002664', (288, 294))
480312	31078526	In fact, liver cancers harbor five ubiquitous signatures (S1, S4, S5, S12, S16) with high mutation burden as has also been reported in Letouze et al..	('S1', 'Var', (58, 60))	('cancers', 'Phenotype', 'HP:0002664', (15, 22))	('S16', 'Gene', (75, 78))	('liver cancer', 'Phenotype', 'HP:0002896', (9, 21))	('S16', 'Gene', '6217', (75, 78))	('liver cancers', 'Phenotype', 'HP:0002896', (9, 22))	('S12', 'Gene', (70, 73))	('liver cancers', 'Disease', 'MESH:D006528', (9, 22))	('S12', 'Gene', '6268', (70, 73))	('liver cancers', 'Disease', (9, 22))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))
480313	31078526	In order to compute the rate of mutations predicted to cause CTCF motif-disruption within insulator regions, we considered the CTCF motif annotations from FunSeq2 within the flanking stretches of 2,500 nucleotides on both sides of the insulator mid-point.	('CTCF', 'Gene', '10664', (127, 131))	('CTCF', 'Gene', '10664', (61, 65))	('mutations', 'Var', (32, 41))	('CTCF', 'Gene', (127, 131))	('CTCF', 'Gene', (61, 65))
480314	31078526	The mutations that fall into CTCF binding sites were split into motif-disrupting or non-disrupting groups and overlapped with the insulator regions (5 kb windows).	('mutations', 'Var', (4, 13))	('fall', 'Phenotype', 'HP:0002527', (19, 23))	('CTCF', 'Gene', (29, 33))	('CTCF', 'Gene', '10664', (29, 33))
480316	31078526	The CTCF motif-disruption mutation rate of each randomly generated set of changes was computed as explained above and this procedure was repeated 100 times.	('CTCF', 'Gene', (4, 8))	('CTCF', 'Gene', '10664', (4, 8))	('changes', 'Var', (74, 81))
480317	31078526	Finally, the estimate of the expected rate of mutations predicted to cause CTCF motif-disruption was computed as the mean random mutation rate of every position within the windows of insulator regions.	('cause', 'Reg', (69, 74))	('mutations', 'Var', (46, 55))	('CTCF', 'Gene', (75, 79))	('CTCF', 'Gene', '10664', (75, 79))
480319	31078526	The same steps were used for mutations that are not predicted to disrupt CTCF motifs.	('CTCF', 'Gene', '10664', (73, 77))	('mutations', 'Var', (29, 38))	('CTCF', 'Gene', (73, 77))
480320	31078526	The clustering of mutations has been suggested to indicate signal of positive selection in cancer.	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('mutations', 'Var', (18, 27))
480322	31078526	To identify significantly mutated elements (CDS, promoters, enhancers, lincRNAs and CTCF insulators), we developed CNCDriver (Cornell Non-Coding Driver), which combines mutational recurrence and functional impact of variants to discern signals of positive selection.	('CTCF', 'Gene', (84, 88))	('CTCF', 'Gene', '10664', (84, 88))	('variants', 'Var', (216, 224))
480324	31078526	DHSs, histone modification marks, sensitive, ultra-sensitive, conserved, and highly occupied by transcription factor (HOT) regions) and the predicted impact of variants on TF binding.	('histone', 'MPA', (6, 13))	('binding', 'Interaction', (175, 182))	('DHSs', 'Disease', (0, 4))	('variants', 'Var', (160, 168))	('DHSs', 'Disease', 'None', (0, 4))
480325	31078526	While for promoters and enhancers, a variant's impact on TF binding is assessed for all TF motifs (549 TFs from ENCODE), only motifs for CTCF were used for variants in CTCF insulators.	('CTCF', 'Gene', (168, 172))	('CTCF', 'Gene', '10664', (137, 141))	('CTCF', 'Gene', '10664', (168, 172))	('variant', 'Var', (37, 44))	('CTCF', 'Gene', (137, 141))
480326	31078526	The probability of drawing a mutation is determined by its tri-nucleotide sequence probability across all samples in a given cancer type.	('mutation', 'Var', (29, 37))	('tri-nucleotide', 'Chemical', '-', (59, 73))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))
480330	31078526	For CTCF insulators, we also keep the same ratio of mutations predicted to disrupt CTCF motif or not during null background model generation.	('mutations', 'Var', (52, 61))	('CTCF', 'Gene', (4, 8))	('CTCF', 'Gene', (83, 87))	('CTCF', 'Gene', '10664', (4, 8))	('CTCF', 'Gene', '10664', (83, 87))
480333	31078526	noted that signature 9, which is observed in lymphoma, does not exhibit the mutational pattern of AID likely because the AID signal is obscured by mutations caused by the error-prone polymerase eta.	('lymphoma', 'Disease', 'MESH:D008223', (45, 53))	('mutations', 'Var', (147, 156))	('lymphoma', 'Phenotype', 'HP:0002665', (45, 53))	('lymphoma', 'Disease', (45, 53))
480334	31078526	to calculate enrichment of AID signature mutations in candidate elements,  where mutationsmotif is the number of mutations in the AID motif, mutationsC is the number of mutated cytosines, contextC is the total number of cytosines, and contextmotif is the total number of occurrences of the AID motif.	('mutations', 'Var', (41, 50))	('mutationsC', 'Var', (141, 151))	('cytosine', 'Chemical', 'MESH:D003596', (177, 185))	('mutationsmotif', 'Var', (81, 95))	('cytosine', 'Chemical', 'MESH:D003596', (220, 228))
480338	31078526	For a given mutation with alternative read counts (a), reference read counts (r) and total read depth (r + a), the probability of a given CCFi can be estimated from binomial distribution,   Then, for a given mutation with VAFobs, we computed the distribution of posterior probability P(CCFi) over 100 grid points of CCFi uniformly spanned between 0.01 to 1.	('CCF', 'Disease', (316, 319))	('CCF', 'Disease', 'MESH:D003025', (138, 141))	('CCF', 'Disease', (138, 141))	('CCF', 'Disease', 'MESH:D003025', (286, 289))	('CCF', 'Disease', (286, 289))	('VAFobs', 'Chemical', '-', (222, 228))	('mutation', 'Var', (12, 20))	('CCF', 'Disease', 'MESH:D003025', (316, 319))
480340	31078526	Mutations were classified as clonal if the maximum probability of CCFi is in the top quartile of cancer cell fraction (max(P(CCFi))>=0.75); otherwise mutations were classified as subclonal.	('cancer', 'Disease', (97, 103))	('cancer', 'Disease', 'MESH:D009369', (97, 103))	('CCF', 'Disease', (125, 128))	('CCF', 'Disease', 'MESH:D003025', (125, 128))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('Mutations', 'Var', (0, 9))	('CCF', 'Disease', (66, 69))	('CCF', 'Disease', 'MESH:D003025', (66, 69))
480345	31078526	In this study, 293 out of 462 mutations (63%) in the 21 insulators identified to be significantly mutated locate within CTCF ChIP-seq peaks.	('CTCF', 'Gene', '10664', (120, 124))	('mutations', 'Var', (30, 39))	('CTCF', 'Gene', (120, 124))
480346	31078526	Although we did not find CTCF M2 motif matched by FIMO (P value: 10-4) upstream of the core motif, 12 mutations are within the window that would bind other domains (ZF9-ZF11) (Supplementary Table S15).	('CTCF', 'Gene', (25, 29))	('S15', 'Gene', '6209', (196, 199))	('ZF9', 'Gene', '1316', (165, 168))	('CTCF', 'Gene', '10664', (25, 29))	('mutations', 'Var', (102, 111))	('ZF9', 'Gene', (165, 168))	('S15', 'Gene', (196, 199))
480347	31078526	Additionally, our major insulator candidate in melanoma has three mutated positions within the CTCF motif (SNV4, chr19:41,768,332 mutated in two patients; SNV10, chr19:41,768,799 in one patient and SNV11, chr19:41,769,800 in two patients, Figure S12E).	('patients', 'Species', '9606', (145, 153))	('patients', 'Species', '9606', (229, 237))	('SNV11', 'Var', (198, 203))	('CTCF', 'Gene', '10664', (95, 99))	('SNV10', 'Var', (155, 160))	('melanoma', 'Phenotype', 'HP:0002861', (47, 55))	('patient', 'Species', '9606', (145, 152))	('melanoma', 'Disease', (47, 55))	('mutated', 'Var', (130, 137))	('melanoma', 'Disease', 'MESH:D008545', (47, 55))	('patient', 'Species', '9606', (186, 193))	('patient', 'Species', '9606', (229, 236))	('S12E', 'Mutation', 'p.S12E', (246, 250))	('CTCF', 'Gene', (95, 99))
480360	31078526	The Wilcoxon rank-sum test was used to test the significance of the differential gene expression between tumor samples with insulator mutations vs. those without.	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('insulator', 'Gene', (124, 133))	('mutations', 'Var', (134, 143))	('tumor', 'Disease', (105, 110))
480362	31078526	We have also compared the expression of genes in tumor samples with insulator mutations versus normal samples, though we note that in melanoma, there is only one normal sample with RNA-seq data available.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor', 'Disease', (49, 54))	('mutations', 'Var', (78, 87))	('melanoma', 'Phenotype', 'HP:0002861', (134, 142))	('melanoma', 'Disease', (134, 142))	('melanoma', 'Disease', 'MESH:D008545', (134, 142))
480366	31078526	We were able to detect significant difference in gene expression when there were 12 samples with mutations vs. 68 samples without mutations for ~2-fold change (CYP2S1) and ~3-fold change (TGFB1) in melanoma.	('TGFB1', 'Gene', '7040', (188, 193))	('mutations', 'Var', (97, 106))	('CYP2S1', 'Gene', (160, 166))	('TGFB1', 'Gene', (188, 193))	('melanoma', 'Disease', 'MESH:D008545', (198, 206))	('melanoma', 'Phenotype', 'HP:0002861', (198, 206))	('melanoma', 'Disease', (198, 206))	('CYP2S1', 'Gene', '29785', (160, 166))
480368	31078526	Thus, given a mutation frequency is 3% and assuming a minimum number of mutated samples needed with matched WGS and RNA-seq data is 10, we will likely need ~300 samples with matched RNA-seq and WGS data to detect meaningful gene expression association in other cancer types with similar fold differences as observed for CYP2S1 and TGFB1.	('CYP2S1', 'Gene', '29785', (320, 326))	('TGFB1', 'Gene', '7040', (331, 336))	('cancer', 'Phenotype', 'HP:0002664', (261, 267))	('TGFB1', 'Gene', (331, 336))	('mutation', 'Var', (14, 22))	('cancer', 'Disease', (261, 267))	('cancer', 'Disease', 'MESH:D009369', (261, 267))	('CYP2S1', 'Gene', (320, 326))
480370	31078526	Enrichment of CTCF motif-disrupting mutations is associated with neutral signatures Novel computational method predicts 21 insulator drivers A predicted driver on chr19 is associated with TGFB1 up-regulation CTCF ChIP-seq, 3C and CRISPR-Cas9 support the computational predictions	('TGFB1', 'Gene', '7040', (188, 193))	('CTCF', 'Gene', (14, 18))	('TGFB1', 'Gene', (188, 193))	('mutations', 'Var', (36, 45))	('up-regulation', 'PosReg', (194, 207))	('CTCF', 'Gene', '10664', (14, 18))	('CTCF', 'Gene', (208, 212))	('CTCF', 'Gene', '10664', (208, 212))
480371	31620361	Genome-Wide Identification of a Novel Eight-lncRNA Signature to Improve Prognostic Prediction in Head and Neck Squamous Cell Carcinoma Objectives: LncRNAs are essential survival prognostic indicators with important biological functions in tumorigenesis and tumor progression.	('tumor', 'Disease', (257, 262))	('Neck Squamous Cell Carcinoma', 'Disease', (106, 134))	('tumor', 'Disease', 'MESH:D009369', (239, 244))	('LncRNAs', 'Var', (147, 154))	('Head and Neck Squamous Cell Carcinoma', 'Phenotype', 'HP:0012288', (97, 134))	('tumor', 'Phenotype', 'HP:0002664', (239, 244))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (111, 134))	('tumor', 'Disease', (239, 244))	('tumor', 'Disease', 'MESH:D009369', (257, 262))	('Carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('Neck Squamous Cell Carcinoma', 'Disease', 'MESH:C535575', (106, 134))	('tumor', 'Phenotype', 'HP:0002664', (257, 262))
480375	31620361	Results: Eight lncRNAs associated with survival in HNSCC patients, including AC010624.1, AC130456.4, LINC00608, LINC01300, MIR99AHG, AC008655.1, AC055758.2, and AC118553.1, were obtained by univariate regression, cox LASSO regression, and multivariate regression.	('HNSCC', 'Disease', 'MESH:C535575', (51, 56))	('LINC01300', 'Gene', (112, 121))	('cox', 'Gene', '1351', (213, 216))	('HNSCC', 'Disease', (51, 56))	('MIR99AHG', 'Gene', (123, 131))	('AC130456.4', 'Var', (89, 99))	('LINC00608', 'Gene', (101, 110))	('patients', 'Species', '9606', (57, 65))	('MIR99AHG', 'Gene', '388815', (123, 131))	('LINC00608', 'Gene', '151300', (101, 110))	('HNSCC', 'Phenotype', 'HP:0012288', (51, 56))	('LINC01300', 'Gene', '731779', (112, 121))	('cox', 'Gene', (213, 216))
480376	31620361	Functionally, patients with high signature scores had abnormal immune functions via GSEA.	('abnormal', 'Reg', (54, 62))	('immune functions', 'CPA', (63, 79))	('high', 'Var', (28, 32))	('patients', 'Species', '9606', (14, 22))	('GSEA', 'CPA', (84, 88))
480377	31620361	AC010624.1 and AC130456.4 may participate in epidermal cell differentiation and skin development, and MIR99AHG in the formation of cellular structures.	('MIR99AHG', 'Gene', (102, 110))	('participate', 'Reg', (30, 41))	('MIR99AHG', 'Gene', '388815', (102, 110))	('AC010624.1', 'Var', (0, 10))	('skin development', 'CPA', (80, 96))	('epidermal cell differentiation', 'CPA', (45, 75))	('AC130456.4', 'Var', (15, 25))
480400	31620361	We used the following formula to construct a prognostic risk score model: risk score = expGene1 x betaGene1+ expGene2 x betaGene2 + exp Genen x betaGenen (exp, prognostic gene expression level; beta, multivariate Cox regression model regression coefficients).	('Cox', 'Gene', '1351', (213, 216))	('Cox', 'Gene', (213, 216))	('expGene1', 'Var', (87, 95))
480408	31620361	There were T3-4 (72.8%) and M0 (97.4%) cases; median survival time was 28 months, and 72.9% of all individuals had no HPV infection.	('T3-4', 'Var', (11, 15))	('HPV infection', 'Disease', (118, 131))	('HPV infection', 'Disease', 'MESH:D007239', (118, 131))
480410	31620361	Multivariate Cox analysis based on the 28 lncRNAs finally identified 8 lncRNAs, including AC008655.1, AC010624.1, AC055758.2, AC118553.1, AC130456.4, LINC00608, LINC01300, and MIR99AHG.	('Cox', 'Gene', (13, 16))	('LINC01300', 'Gene', (161, 170))	('Cox', 'Gene', '1351', (13, 16))	('AC118553.1', 'Var', (126, 136))	('LINC00608', 'Gene', (150, 159))	('LINC01300', 'Gene', '731779', (161, 170))	('MIR99AHG', 'Gene', (176, 184))	('LINC00608', 'Gene', '151300', (150, 159))	('MIR99AHG', 'Gene', '388815', (176, 184))
480417	31620361	A co-expression network was constructed using GSE65858, including 269 HNSCC samples with complete clinical data.	('GSE65858', 'Var', (46, 54))	('HNSCC', 'Disease', 'MESH:C535575', (70, 75))	('HNSCC', 'Phenotype', 'HP:0012288', (70, 75))	('HNSCC', 'Disease', (70, 75))
480419	31620361	We found AC010624.1 and AC130456.4 in the black module, LINC00608 and LINC01300 in the blue module, MIR99AHG in the brown module, AC008655.1 in the tan module, and AC118553.1 in the magenta module.	('AC008655.1', 'Var', (130, 140))	('LINC00608', 'Gene', (56, 65))	('LINC01300', 'Gene', '731779', (70, 79))	('LINC00608', 'Gene', '151300', (56, 65))	('AC130456.4', 'Var', (24, 34))	('AC118553.1', 'Var', (164, 174))	('MIR99AHG', 'Gene', (100, 108))	('LINC01300', 'Gene', (70, 79))	('AC010624.1', 'Var', (9, 19))	('MIR99AHG', 'Gene', '388815', (100, 108))
480423	31620361	Using the mRNAs and lncRNAs selected after re-annotating the GSE65858 dataset of the GEO database, 8 prognosis-related lncRNAs including AC010624.1, AC130456.4, LINC00608, LINC01300, MIR99AHG, AC008655.1, AC055758.2, and AC118553.1 were obtained by univariate analysis, cox LASSO regression and multivariate analysis.	('LINC01300', 'Gene', (172, 181))	('cox', 'Gene', (270, 273))	('AC010624.1', 'Var', (137, 147))	('MIR99AHG', 'Gene', (183, 191))	('LINC01300', 'Gene', '731779', (172, 181))	('LINC00608', 'Gene', (161, 170))	('cox', 'Gene', '1351', (270, 273))	('MIR99AHG', 'Gene', '388815', (183, 191))	('LINC00608', 'Gene', '151300', (161, 170))
480425	31620361	The black module containing AC010624.1 and AC130456.4, the blue comprising LINC00608 and LINC01300, the brown containing MIR99AHG, the tan encompassing AC008655.1, and the magenta containing AC118553.1 were obtained.	('LINC01300', 'Gene', (89, 98))	('AC010624.1', 'Var', (28, 38))	('LINC01300', 'Gene', '731779', (89, 98))	('MIR99AHG', 'Gene', (121, 129))	('MIR99AHG', 'Gene', '388815', (121, 129))	('LINC00608', 'Gene', (75, 84))	('LINC00608', 'Gene', '151300', (75, 84))	('AC130456.4', 'Var', (43, 53))
480430	31620361	It can be inferred from the above signature that patients with high scores may benefit more from targeted drugs against the IL6/JAK/SATA3 pathway, which has a high guiding significance in future clinical applications.	('benefit', 'PosReg', (79, 86))	('IL6', 'Gene', '3569', (124, 127))	('IL6', 'Gene', (124, 127))	('high', 'Var', (63, 67))	('patients', 'Species', '9606', (49, 57))
480438	31620361	Our results showed AC010624.1 was negatively related with TMB, while LINC01300 was positively related with TMB (Figures S1G,H).	('TMB', 'Disease', (107, 110))	('AC010624.1', 'Var', (19, 29))	('LINC01300', 'Gene', (69, 78))	('TMB', 'Disease', (58, 61))	('LINC01300', 'Gene', '731779', (69, 78))	('negatively', 'NegReg', (34, 44))
480440	31620361	WGCNA results showed that the black module containing AC010624.1 and AC130456.4 was closely related to EGFR mutation in clinical phenotypes, while GO enrichment data indicated that these two lncRNAs may both participate in epidermal cell differentiation and skin development, which is consistent with the potential function of the black module.	('EGFR', 'Gene', '1956', (103, 107))	('AC010624.1', 'Var', (54, 64))	('EGFR', 'Gene', (103, 107))	('participate', 'Reg', (208, 219))	('skin development', 'CPA', (258, 274))	('epidermal cell differentiation', 'CPA', (223, 253))	('AC130456.4', 'Var', (69, 79))	('mutation', 'Var', (108, 116))
480442	31620361	Combining these findings, we hypothesized that AC010624.1 and AC130456.4 affect prognosis by participating in epidermal cell differentiation and skin development, which in turn affects EGFR mutation in patients with HNSCC.	('mutation', 'Var', (190, 198))	('affects', 'Reg', (177, 184))	('affect', 'Reg', (73, 79))	('AC010624.1', 'Var', (47, 57))	('EGFR', 'Gene', (185, 189))	('participating', 'Reg', (93, 106))	('AC130456.4', 'Var', (62, 72))	('patients', 'Species', '9606', (202, 210))	('HNSCC', 'Phenotype', 'HP:0012288', (216, 221))	('prognosis', 'MPA', (80, 89))	('HNSCC', 'Disease', 'MESH:C535575', (216, 221))	('skin development', 'CPA', (145, 161))	('epidermal cell differentiation', 'CPA', (110, 140))	('HNSCC', 'Disease', (216, 221))	('EGFR', 'Gene', '1956', (185, 189))
480443	31620361	Whether and how AC010624.1 and AC130456.4 affect EGFR mutations deserves further investigation by molecular biology experiments.	('affect', 'Reg', (42, 48))	('AC010624.1', 'Var', (16, 26))	('EGFR', 'Gene', '1956', (49, 53))	('EGFR', 'Gene', (49, 53))	('mutations', 'Var', (54, 63))	('AC130456.4', 'Var', (31, 41))
480444	31620361	Similarly, the brown module containing MIR99AHG was closely related to EGFR mutation in clinical phenotype.	('MIR99AHG', 'Gene', (39, 47))	('related', 'Reg', (60, 67))	('MIR99AHG', 'Gene', '388815', (39, 47))	('EGFR', 'Gene', '1956', (71, 75))	('mutation', 'Var', (76, 84))	('EGFR', 'Gene', (71, 75))
480458	31620361	In conclusion, we established an 8-lncRNA signature and a nomogram for predicting the prognosis of patients with HNSCC, and speculated that patients with a high signature score may have dysfunctional immune regulation, which may be a new direction of treatment for patients with HNSCC.	('HNSCC', 'Disease', 'MESH:C535575', (279, 284))	('HNSCC', 'Disease', (279, 284))	('HNSCC', 'Phenotype', 'HP:0012288', (279, 284))	('HNSCC', 'Phenotype', 'HP:0012288', (113, 118))	('patients', 'Species', '9606', (99, 107))	('patients', 'Species', '9606', (265, 273))	('dysfunctional immune regulation', 'MPA', (186, 217))	('patients', 'Species', '9606', (140, 148))	('HNSCC', 'Disease', 'MESH:C535575', (113, 118))	('HNSCC', 'Disease', (113, 118))	('high', 'Var', (156, 160))
480546	26663681	We examined the expression patterns of key factors in the above pathways in pLSCCs at week 24: the PI3K/mTOR signaling molecules PI3K, phospho-PDK1 (Ser241), phospho-mTOR (Ser2448), phospho-4EBP1 (Thr37/46), phospho-p70S6K (Thr421/Ser424), and HIF-1alpha; the NFE2L2/KEAP1/CUL3 signaling molecule Nrf2; and the CDKN2A/RB1 signaling molecule CDKN2A/p16 INK4A.	('PI3', 'Gene', '20702', (129, 132))	('HIF-1alpha', 'Gene', '15251', (244, 254))	('mTOR', 'Gene', '56717', (166, 170))	('PI3', 'Gene', (99, 102))	('p70S6K', 'Gene', (216, 222))	('mTOR', 'Gene', (104, 108))	('Nrf2', 'Gene', (297, 301))	('HIF-1alpha', 'Gene', (244, 254))	('p16', 'Gene', '12578', (348, 351))	('PI3', 'Gene', (129, 132))	('PDK1', 'Gene', '228026', (143, 147))	('mTOR', 'Gene', (166, 170))	('INK4A', 'Gene', (352, 357))	('Ser2448', 'Var', (172, 179))	('p16', 'Gene', (348, 351))	('Nrf2', 'Gene', '18024', (297, 301))	('p70S6K', 'Gene', '72508', (216, 222))	('PI3', 'Gene', '20702', (99, 102))	('mTOR', 'Gene', '56717', (104, 108))	('SCC', 'Gene', '6317', (78, 81))	('PDK1', 'Gene', (143, 147))	('4EBP1', 'Gene', '13685', (190, 195))	('4EBP1', 'Gene', (190, 195))	('INK4A', 'Gene', '12578', (352, 357))	('SCC', 'Gene', (78, 81))
480548	26663681	These findings indicate that while dysregulation of PI3K mTOR, NFE2L2/KEAP1/CUL3, and CDKN2A/RB1 signaling pathways might be involved in NTCU-induced pLSCCs, these pathways do not specifically contribute to deltaNp63posCD44vpos cancer cell proliferation.	('cancer', 'Disease', (228, 234))	('PI3', 'Gene', (52, 55))	('NTCU', 'Chemical', 'MESH:C572573', (137, 141))	('p63', 'Gene', '22061', (213, 216))	('SCC', 'Gene', (152, 155))	('SCC', 'Gene', '6317', (152, 155))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('mTOR', 'Gene', (57, 61))	('PI3', 'Gene', '20702', (52, 55))	('CD44', 'Gene', '12505', (219, 223))	('dysregulation', 'Var', (35, 48))	('CD44', 'Gene', (219, 223))	('mTOR', 'Gene', '56717', (57, 61))	('involved', 'Reg', (125, 133))	('p63', 'Gene', (213, 216))	('cancer', 'Disease', 'MESH:D009369', (228, 234))
480553	26663681	The EGFR- and CSF-1-mediated activation of STAT3 in tumor cells and tumor-associated immune cells is one of the key mechanisms by which TAMs provide support to tumors.32 Although expression of EGFR in the peripheral area of the pLSCCs was not different compared with the central area, phospho-EGFR (pY1068) and phospho-STAT3 (Tyr705) expression in the peripheral area of pLSCCs were higher than in the central area (Fig.	('TAMs', 'Chemical', '-', (136, 140))	('tumor', 'Disease', (52, 57))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('tumors', 'Disease', (160, 166))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('tumor', 'Disease', (68, 73))	('STAT3', 'Gene', '20848', (43, 48))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumors', 'Disease', 'MESH:D009369', (160, 166))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('SCC', 'Gene', '6317', (373, 376))	('SCC', 'Gene', '6317', (230, 233))	('STAT3', 'Gene', '20848', (319, 324))	('STAT3', 'Gene', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('tumor', 'Disease', (160, 165))	('SCC', 'Gene', (373, 376))	('higher', 'PosReg', (383, 389))	('SCC', 'Gene', (230, 233))	('pY1068', 'Var', (299, 305))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('CSF-1', 'Gene', (14, 19))	('STAT3', 'Gene', (319, 324))	('CSF-1', 'Gene', '12977', (14, 19))	('Tyr705', 'Chemical', '-', (326, 332))
480556	26663681	Our previous study showed that NTCU is a strong lung carcinogen capable of inducing SCCs in mice and that this NTCU-induced mouse SCC model is useful for analysis of the carcinogenic mechanism of lung SCC.24 In this study, we showed that NTCU-induced lung SCCs in mice were predominantly peripheral and resembled the characteristics of human pLSCC including histopathological location, differentiation grade, and growth pattern.	('SCC', 'Gene', '6317', (84, 87))	('NTCU-induced', 'Var', (238, 250))	('SCC', 'Gene', '6317', (201, 204))	('SCC', 'Gene', '6317', (344, 347))	('SCC', 'Gene', (84, 87))	('mice', 'Species', '10090', (92, 96))	('SCC', 'Gene', '6317', (256, 259))	('NTCU', 'Chemical', 'MESH:C572573', (111, 115))	('NTCU', 'Chemical', 'MESH:C572573', (238, 242))	('SCC', 'Gene', (201, 204))	('SCC', 'Gene', '6317', (130, 133))	('SCC', 'Gene', (344, 347))	('SCC', 'Gene', (256, 259))	('NTCU', 'Chemical', 'MESH:C572573', (31, 35))	('SCC', 'Gene', (130, 133))	('mouse', 'Species', '10090', (124, 129))	('mice', 'Species', '10090', (264, 268))	('carcinogenic mechanism of lung SCC', 'Disease', 'MESH:D006930', (170, 204))	('carcinogenic mechanism of lung SCC', 'Disease', (170, 204))	('human', 'Species', '9606', (336, 341))
480664	25329614	In vitro studies have demonstrated that alcohol enhances the mucosal penetration of the various carcinogens found in tobacco.	('alcohol', 'Chemical', 'MESH:D000438', (40, 47))	('alcohol', 'Var', (40, 47))	('mucosal penetration', 'CPA', (61, 80))	('tobacco', 'Species', '4097', (117, 124))	('enhances', 'PosReg', (48, 56))
480738	32785290	Recurrence-free survival and metastasis-free survival were decreased in patients with high numbers of CTLA-4+ cells in the parenchyma of the invasive front.	('decreased', 'NegReg', (59, 68))	('CTLA-4+', 'Gene', (102, 109))	('Recurrence-free survival', 'CPA', (0, 24))	('metastasis-free survival', 'CPA', (29, 53))	('high', 'Var', (86, 90))	('patients', 'Species', '9606', (72, 80))
480739	32785290	Our results indicate that FoxP3+ T-cells may exert site-specific anti-tumor effects but may not play an immunosuppressive role in OSCC.	('FoxP3+', 'Var', (26, 32))	('tumor', 'Disease', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))
480746	32785290	Patients with higher numbers of inherited defective genes in natural killer (NK) cells were reported to have a higher risk of developing cancer, and inherited defects were associated with tumor immune microenvironment subtypes, recruitment of tumor-infiltrating lymphocytes (TILs), immune checkpoint therapy response, and clinical outcomes.	('tumor', 'Disease', (188, 193))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('inherited defects', 'Disease', (149, 166))	('associated', 'Reg', (172, 182))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('tumor', 'Disease', 'MESH:D009369', (243, 248))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('Patients', 'Species', '9606', (0, 8))	('cancer', 'Disease', (137, 143))	('men', 'Species', '9606', (235, 238))	('inherited defective genes', 'Var', (32, 57))	('inherited defects', 'Disease', 'MESH:D030342', (149, 166))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('men', 'Species', '9606', (213, 216))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))	('tumor', 'Disease', (243, 248))
480747	32785290	Many studies on various human tumors have shown a significant association between the presence of TILs and patient survival.	('tumors', 'Disease', (30, 36))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('human', 'Species', '9606', (24, 29))	('presence', 'Var', (86, 94))	('patient survival', 'CPA', (107, 123))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('patient', 'Species', '9606', (107, 114))
480753	32785290	However, recent studies have challenged this notion, showing that FoxP3+ T-cells can improve the survival of patients with certain types of tumors.	('tumors', 'Disease', (140, 146))	('tumors', 'Disease', 'MESH:D009369', (140, 146))	('improve', 'PosReg', (85, 92))	('patients', 'Species', '9606', (109, 117))	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('survival', 'CPA', (97, 105))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('FoxP3+ T-cells', 'Var', (66, 80))
480754	32785290	Several studies have also shown that increased infiltration of FoxP3+ T-cells is associated with improved local/regional control and survival in patients with head and neck cancer; however, other studies have reported poor survival of patients with malignancies such as non-small cell lung cancer.	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('malignancies', 'Disease', (249, 261))	('improved', 'PosReg', (97, 105))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (274, 296))	('lung cancer', 'Disease', (285, 296))	('FoxP3+ T-cells', 'Var', (63, 77))	('survival', 'CPA', (133, 141))	('cancer', 'Disease', 'MESH:D009369', (290, 296))	('patients', 'Species', '9606', (235, 243))	('local/regional control', 'CPA', (106, 128))	('lung cancer', 'Disease', 'MESH:D008175', (285, 296))	('cancer', 'Disease', (173, 179))	('head and neck cancer', 'Phenotype', 'HP:0012288', (159, 179))	('lung cancer', 'Phenotype', 'HP:0100526', (285, 296))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('patients', 'Species', '9606', (145, 153))	('cancer', 'Disease', (290, 296))	('cancer', 'Phenotype', 'HP:0002664', (290, 296))	('malignancies', 'Disease', 'MESH:D009369', (249, 261))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (270, 296))
480762	32785290	FoxP3+ T-cells can inhibit inflammatory processes in the tumor microenvironment, favoring tumor progression.	('inhibit', 'NegReg', (19, 26))	('inflammatory processes', 'CPA', (27, 49))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('men', 'Species', '9606', (75, 78))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('favoring', 'PosReg', (81, 89))	('tumor', 'Disease', (57, 62))	('FoxP3+', 'Var', (0, 6))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
480763	32785290	Indeed, tumors of the head and neck are considered inflammatory, and use of a preclinical model has shown that the transfer of Tregs can delay the onset of an inflammation-linked cancer.	('transfer', 'Var', (115, 123))	('inflammation-linked cancer', 'Disease', 'MESH:D009369', (159, 185))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('delay', 'NegReg', (137, 142))	('inflammation-linked cancer', 'Disease', (159, 185))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('tumors', 'Disease', (8, 14))	('tumors', 'Disease', 'MESH:D009369', (8, 14))	('Tregs', 'Chemical', '-', (127, 132))	('tumors', 'Phenotype', 'HP:0002664', (8, 14))	('tumors of the head and neck', 'Phenotype', 'HP:0012288', (8, 35))
480782	32785290	We analyzed the prognostic role of the densities of FoxP3+ T-cells and CTLA-4+ cells for each of the four different tumor areas.	('FoxP3+', 'Var', (52, 58))	('tumor', 'Disease', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumor', 'Disease', 'MESH:D009369', (116, 121))
480809	32785290	Patients with OSCC and high density of FoxP3+ T-cells in the IF of tumor parenchyma showed significantly increased OS (91.7% vs. 73.8%, p = 0.006), DSS (95.8% vs. 84.6%, p = 0.02), RFS (73.6% vs. 50.8%, p = 0.008), and MFS (87.7% vs. 70.6%, p = 0.02).	('DSS', 'CPA', (148, 151))	('FoxP3+', 'Var', (39, 45))	('tumor parenchyma', 'Disease', (67, 83))	('MFS', 'CPA', (219, 222))	('tumor parenchyma', 'Disease', 'MESH:D010195', (67, 83))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('Patients', 'Species', '9606', (0, 8))	('DSS', 'Chemical', '-', (148, 151))	('increased', 'PosReg', (105, 114))	('OSCC', 'Disease', (14, 18))	('RFS', 'CPA', (181, 184))
480814	32785290	RFS was worse in patients with high numbers of CTLA-4+ cells in TCe stroma (52.9% vs. 73.1%, p = 0.01) and IF parenchyma (46.8% vs. 71.1%, p = 0.006).	('RFS', 'MPA', (0, 3))	('patients', 'Species', '9606', (17, 25))	('CTLA-4+', 'Var', (47, 54))
480818	32785290	Thus, the presence of FoxP3+ T-cells in the tumor microenvironment would indicate an unfavorable prognosis.	('men', 'Species', '9606', (62, 65))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('FoxP3+', 'Var', (22, 28))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('tumor', 'Disease', (44, 49))
480819	32785290	However, the prognostic value of FoxP3+ T-cells differs considerably with respect to different types of cancer.	('FoxP3+', 'Var', (33, 39))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))
480820	32785290	High FoxP3+ T-cell counts are associated with improved prognosis in patients with head and neck squamous cell carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('improved', 'PosReg', (46, 54))	('patients', 'Species', '9606', (68, 76))	('neck squamous cell carcinoma', 'Disease', (91, 119))	('High FoxP3+ T-cell counts', 'Var', (0, 25))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (96, 119))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (91, 119))
480821	32785290	Our results show that FoxP3+ T-cells in IF parenchyma indicated improved prognoses in patients with OSCC.	('patients', 'Species', '9606', (86, 94))	('OSCC', 'Disease', (100, 104))	('improved', 'PosReg', (64, 72))	('FoxP3+', 'Var', (22, 28))
480822	32785290	Our results also indicate that FoxP3+ T-cells may exert site-specific anti-tumor effects in patients with OSCC.	('patients', 'Species', '9606', (92, 100))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('OSCC', 'Disease', (106, 110))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('FoxP3+', 'Var', (31, 37))	('tumor', 'Disease', (75, 80))
480827	32785290	For example, in Treg-mediated cell therapy, in vivo expansion is used to suppress immune responses, while depletion or functional blockade of Tregs is used to enhance immune responses.	('suppress', 'NegReg', (73, 81))	('immune responses', 'CPA', (82, 98))	('depletion', 'Var', (106, 115))	('Treg', 'Chemical', '-', (16, 20))	('enhance', 'PosReg', (159, 166))	('Tregs', 'Chemical', '-', (142, 147))	('Treg', 'Chemical', '-', (142, 146))	('suppress immune responses', 'Phenotype', 'HP:0002721', (73, 98))	('immune responses', 'CPA', (167, 183))
480844	32785290	A recent study in mice has shown that CTLA-4+ cells are crucial for the suppressive function of FoxP3+ Tregs in vitro and in vivo.	('suppressive function', 'CPA', (72, 92))	('Tregs', 'Chemical', '-', (103, 108))	('mice', 'Species', '10090', (18, 22))	('FoxP3+', 'Var', (96, 102))
480858	32785290	Recurrence-free survival and metastasis-free survival were decreased in patients with high numbers of CTLA-4+ cells.	('decreased', 'NegReg', (59, 68))	('CTLA-4+', 'Gene', (102, 109))	('Recurrence-free survival', 'CPA', (0, 24))	('metastasis-free survival', 'CPA', (29, 53))	('high', 'Var', (86, 90))	('patients', 'Species', '9606', (72, 80))
480859	32785290	FoxP3+ T-cells may exert site-specific anti-tumor effects but may not play an immunosuppressive role in OSCC.	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('OSCC', 'Disease', (104, 108))	('FoxP3+', 'Var', (0, 6))	('tumor', 'Disease', (44, 49))
480889	31661124	In addition, the proliferation, cell cycle distribution and apoptosis of A549 and H1299 cells were determined by MTT assay and flow cytometry, respectively, following cell transfection to induce overexpression and knockdown of RFC3.	('A549', 'CellLine', 'CVCL:0023', (73, 77))	('RFC3', 'Gene', '5983', (227, 231))	('cell cycle distribution', 'CPA', (32, 55))	('knockdown', 'Var', (214, 223))	('apoptosis', 'CPA', (60, 69))	('overexpression', 'PosReg', (195, 209))	('RFC3', 'Gene', (227, 231))	('H1299', 'CellLine', 'CVCL:0060', (82, 87))	('MTT', 'Chemical', 'MESH:C022616', (113, 116))
480893	31661124	Furthermore, overexpression of RFC3 increased the invasion and migration of A549 cells, whereas knockdown of RFC3 significantly reduced the invasion and migration of H1299 cells.	('knockdown', 'Var', (96, 105))	('invasion', 'CPA', (50, 58))	('H1299', 'CellLine', 'CVCL:0060', (166, 171))	('reduced', 'NegReg', (128, 135))	('RFC3', 'Gene', '5983', (31, 35))	('RFC3', 'Gene', (31, 35))	('A549', 'CellLine', 'CVCL:0023', (76, 80))	('increased', 'PosReg', (36, 45))	('overexpression', 'PosReg', (13, 27))	('RFC3', 'Gene', '5983', (109, 113))	('RFC3', 'Gene', (109, 113))
480899	31661124	Although targeted drugs can be used in some cases to treat patients with mutations in genes such as epidermal growth factor receptor and anaplastic lymphoma kinase, the proportion of such patients is limited and drug resistance limits the long-term efficacy of targeted therapy.	('lymphoma', 'Phenotype', 'HP:0002665', (148, 156))	('drug resistance', 'Phenotype', 'HP:0020174', (212, 227))	('epidermal growth factor receptor', 'Gene', (100, 132))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (137, 156))	('patients', 'Species', '9606', (188, 196))	('lymphoma', 'Disease', (148, 156))	('patients', 'Species', '9606', (59, 67))	('mutations', 'Var', (73, 82))	('lymphoma', 'Disease', 'MESH:D008223', (148, 156))
480902	31661124	It was been reported that overactivation of beta-catenin in the pulmonary epithelium of genetically engineered mice could induce epithelial differentiation defects, promoting cell multiplication, basal cell amplification and lung tumorigenesis.	('tumor', 'Disease', (230, 235))	('basal cell amplification', 'CPA', (196, 220))	('cell multiplication', 'CPA', (175, 194))	('beta-catenin', 'Protein', (44, 56))	('mice', 'Species', '10090', (111, 115))	('tumor', 'Disease', 'MESH:D009369', (230, 235))	('overactivation', 'Var', (26, 40))	('epithelial differentiation defects', 'CPA', (129, 163))	('induce', 'Reg', (122, 128))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))	('promoting', 'PosReg', (165, 174))
480906	31661124	Mutations in beta-catenin or adenomatous polyposis coli, which represent the most universal mechanisms underlying abnormal activation of the Wnt/beta-catenin pathway, are infrequent in NSCLC.	('NSCLC', 'Disease', 'MESH:D002289', (185, 190))	('adenomatous polyposis coli', 'Phenotype', 'HP:0005227', (29, 55))	('Mutations', 'Var', (0, 9))	('NSCLC', 'Phenotype', 'HP:0030358', (185, 190))	('beta-catenin', 'Protein', (13, 25))	('adenomatous polyposis coli', 'Disease', 'MESH:D011125', (29, 55))	('adenomatous polyposis coli', 'Disease', (29, 55))	('NSCLC', 'Disease', (185, 190))
480939	31661124	Receiver operating characteristic curve analysis was performed to determine the cut-off scores for low or high RFC3 expression.	('expression', 'MPA', (116, 126))	('low', 'NegReg', (99, 102))	('high', 'Var', (106, 110))	('RFC3', 'Gene', '5983', (111, 115))	('RFC3', 'Gene', (111, 115))
480982	31661124	Kaplan-Meier analysis indicated that high RFC3 expression could lead to a poor prognosis in cases of lung adenocarcinoma; similar results were determined in analysis of disease-free survival (Fig.	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (101, 120))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (101, 120))	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('high', 'Var', (37, 41))	('RFC3', 'Gene', '5983', (42, 46))	('lung adenocarcinoma', 'Disease', (101, 120))	('RFC3', 'Gene', (42, 46))	('expression', 'MPA', (47, 57))
480991	31661124	In addition, a RFC3 siRNA was transfected into the H1299 cell line to knock down RFC3.	('knock down', 'Var', (70, 80))	('H1299', 'CellLine', 'CVCL:0060', (51, 56))	('RFC3', 'Gene', '5983', (15, 19))	('RFC3', 'Gene', (15, 19))	('RFC3', 'Gene', '5983', (81, 85))	('RFC3', 'Gene', (81, 85))
480992	31661124	S1, the proliferative ability of H1299 and A549 cells was not significantly affected by overexpression or knockdown of RFC3 compared with in the control groups (P>0.05).	('H1299', 'CellLine', 'CVCL:0060', (33, 38))	('knockdown', 'Var', (106, 115))	('proliferative ability', 'CPA', (8, 29))	('A549', 'CellLine', 'CVCL:0023', (43, 47))	('RFC3', 'Gene', '5983', (119, 123))	('RFC3', 'Gene', (119, 123))
480994	31661124	The proportion of H1299 cells in G0/G1 stage was increased when RFC3 was knocked down, whereas the proportion of S stage cells was decreased, indicating that more cells were arrested at G0/G1 stage after RFC3 was knocked down (P<0.05; Fig.	('arrest', 'Disease', (174, 180))	('increased', 'PosReg', (49, 58))	('knocked down', 'Var', (213, 225))	('RFC3', 'Gene', '5983', (204, 208))	('RFC3', 'Gene', (204, 208))	('knocked down', 'Var', (73, 85))	('H1299', 'Var', (18, 23))	('arrest', 'Disease', 'MESH:D006323', (174, 180))	('RFC3', 'Gene', '5983', (64, 68))	('RFC3', 'Gene', (64, 68))	('H1299', 'CellLine', 'CVCL:0060', (18, 23))
480996	31661124	In addition, more apoptotic cells were detected in the H1299 cell line when RFC3 was knocked down in comparison with the control group (P<0.01; Fig.	('H1299', 'CellLine', 'CVCL:0060', (55, 60))	('knocked down', 'Var', (85, 97))	('RFC3', 'Gene', '5983', (76, 80))	('RFC3', 'Gene', (76, 80))	('apoptotic cells', 'CPA', (18, 33))
480998	31661124	Conversely, when erlotinib was added to the H1299 cell line to induce apoptosis, more apoptotic cells were detected in the H1299 cell line when RFC3 was knocked down in comparison with the control group (P<0.05; Fig.	('erlotinib', 'Chemical', 'MESH:C400278', (17, 26))	('RFC3', 'Gene', (144, 148))	('RFC3', 'Gene', '5983', (144, 148))	('H1299', 'CellLine', 'CVCL:0060', (44, 49))	('H1299', 'CellLine', 'CVCL:0060', (123, 128))	('knocked down', 'Var', (153, 165))
481001	31661124	Conversely, after the knockdown of RFC3, the opposite result was observed in H1299 cells (P<0.05; Fig.	('knockdown', 'Var', (22, 31))	('H1299', 'CellLine', 'CVCL:0060', (77, 82))	('RFC3', 'Gene', '5983', (35, 39))	('RFC3', 'Gene', (35, 39))
481004	31661124	However, following RFC3 knockdown in H1299 cells, the expression levels of Wnt1, N-cadherin, beta-catenin, Vimentin, c-MYC and the ratio of p-GSK3-beta (Ser9)/GSK3-beta were decreased, whereas E-cadherin expression was increased.	('expression levels', 'MPA', (54, 71))	('increased', 'PosReg', (219, 228))	('Ser9', 'Chemical', 'MESH:C530429', (153, 157))	('beta-catenin', 'MPA', (93, 105))	('H1299', 'CellLine', 'CVCL:0060', (37, 42))	('RFC3', 'Gene', '5983', (19, 23))	('Wnt1', 'Gene', '7471', (75, 79))	('N-cadherin', 'Gene', (81, 91))	('decreased', 'NegReg', (174, 183))	('GSK3-beta', 'Gene', (142, 151))	('N-cadherin', 'Gene', '1000', (81, 91))	('E-cadherin', 'Gene', (193, 203))	('GSK3-beta', 'Gene', (159, 168))	('E-cadherin', 'Gene', '999', (193, 203))	('Vimentin', 'Gene', '7431', (107, 115))	('c-MYC', 'Gene', '4609', (117, 122))	('RFC3', 'Gene', (19, 23))	('expression', 'MPA', (204, 214))	('knockdown', 'Var', (24, 33))	('GSK3-beta', 'Gene', '2932', (142, 151))	('GSK3-beta', 'Gene', '2932', (159, 168))	('c-MYC', 'Gene', (117, 122))	('Wnt1', 'Gene', (75, 79))	('Vimentin', 'Gene', (107, 115))
481009	31661124	However, it has also been reported that RFC3 mutations in gastric and colorectal cancer result in downregulation of expression or loss of function.	('gastric', 'Disease', (58, 65))	('expression', 'MPA', (116, 126))	('mutations', 'Var', (45, 54))	('loss of function', 'NegReg', (130, 146))	('colorectal cancer', 'Disease', 'MESH:D015179', (70, 87))	('downregulation', 'NegReg', (98, 112))	('colorectal cancer', 'Phenotype', 'HP:0003003', (70, 87))	('colorectal cancer', 'Disease', (70, 87))	('RFC3', 'Gene', (40, 44))	('RFC3', 'Gene', '5983', (40, 44))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))
481024	31661124	Previous studies have observed changes in cell biological behavior after knocking down RFC3.	('RFC3', 'Gene', '5983', (87, 91))	('RFC3', 'Gene', (87, 91))	('knocking down', 'Var', (73, 86))	('cell biological behavior', 'CPA', (42, 66))	('changes', 'Reg', (31, 38))
481026	31661124	The proliferative abilities of A549 and H1299 cells were not significantly affected by overexpression or knockdown of RFC3 compared with in the control groups.	('A549', 'CellLine', 'CVCL:0023', (31, 35))	('proliferative abilities', 'CPA', (4, 27))	('knockdown', 'Var', (105, 114))	('RFC3', 'Gene', '5983', (118, 122))	('RFC3', 'Gene', (118, 122))	('H1299', 'CellLine', 'CVCL:0060', (40, 45))
481028	31661124	However, previous studies have reported that the proliferation curve is significantly decreased when RFC3 is knocked down in the following cell lines: Liver cancer SMMC-7721, ovarian cancer OVCAR-3, breast cancer MDA-MB-231 and MDA-MB-468, and esophageal cancer, OE33 and OE19.	('esophageal cancer', 'Disease', (244, 261))	('breast cancer', 'Disease', 'MESH:D001943', (199, 212))	('RFC3', 'Gene', '5983', (101, 105))	('breast cancer', 'Disease', (199, 212))	('MDA-MB-468', 'CellLine', 'CVCL:0419', (228, 238))	('cancer', 'Phenotype', 'HP:0002664', (255, 261))	('ovarian cancer', 'Disease', 'MESH:D010051', (175, 189))	('Liver cancer', 'Disease', (151, 163))	('Liver cancer', 'Disease', 'MESH:D006528', (151, 163))	('RFC3', 'Gene', (101, 105))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('Liver cancer', 'Phenotype', 'HP:0002896', (151, 163))	('decreased', 'NegReg', (86, 95))	('ovarian cancer', 'Disease', (175, 189))	('proliferation curve', 'CPA', (49, 68))	('knocked down', 'Var', (109, 121))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (213, 223))	('ovarian cancer', 'Phenotype', 'HP:0100615', (175, 189))	('esophageal cancer', 'Disease', 'MESH:D004938', (244, 261))	('breast cancer', 'Phenotype', 'HP:0003002', (199, 212))
481032	31661124	Notably, hepatocellular and ovarian cancer cell lines were arrested in S phase after RFC3 knockdown.	('RFC3', 'Gene', '5983', (85, 89))	('RFC3', 'Gene', (85, 89))	('hepatocellular and ovarian cancer', 'Disease', 'MESH:D010051', (9, 42))	('ovarian cancer', 'Phenotype', 'HP:0100615', (28, 42))	('knockdown', 'Var', (90, 99))	('arrest', 'Disease', (59, 65))	('S phase', 'CPA', (71, 78))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('arrest', 'Disease', 'MESH:D006323', (59, 65))
481033	31661124	Changes in some cell cycle regulatory proteins have been detected after RFC3 knockdown in hepatocellular carcinoma cell lines, which explains why the hepatocellular carcinoma cell cycle was arrested in S stage after RFC3 knockdown in this previous study.	('RFC3', 'Gene', '5983', (216, 220))	('RFC3', 'Gene', (216, 220))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (90, 114))	('cell', 'MPA', (16, 20))	('arrest', 'Disease', 'MESH:D006323', (190, 196))	('hepatocellular carcinoma', 'Disease', (90, 114))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (90, 114))	('knockdown', 'Var', (77, 86))	('RFC3', 'Gene', '5983', (72, 76))	('RFC3', 'Gene', (72, 76))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (150, 174))	('arrest', 'Disease', (190, 196))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (150, 174))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('carcinoma', 'Phenotype', 'HP:0030731', (165, 174))	('hepatocellular carcinoma', 'Disease', (150, 174))	('Changes', 'Reg', (0, 7))
481034	31661124	The present study demonstrated that upregulation of RFC3 or knockdown of RFC3 could result in corresponding changes in the downstream protein c-MYC in the Wnt/beta-catenin pathway.	('RFC3', 'Gene', '5983', (73, 77))	('c-MYC', 'Gene', (142, 147))	('RFC3', 'Gene', '5983', (52, 56))	('RFC3', 'Gene', (52, 56))	('upregulation', 'PosReg', (36, 48))	('RFC3', 'Gene', (73, 77))	('c-MYC', 'Gene', '4609', (142, 147))	('knockdown', 'Var', (60, 69))	('changes', 'Reg', (108, 115))	('Wnt/beta-catenin pathway', 'Pathway', (155, 179))
481036	31661124	Unlike the effects on hepatocellular carcinoma cells, in this study, the effects of RFC3 on the cell cycle progression of lung adenocarcinoma resulted in G1-S progression, not S-G2 progression.	('effects', 'Var', (73, 80))	('RFC3', 'Gene', (84, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('cell cycle progression', 'CPA', (96, 118))	('G1-S progression', 'CPA', (154, 170))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (122, 141))	('carcinoma', 'Phenotype', 'HP:0030731', (37, 46))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (22, 46))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (22, 46))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (122, 141))	('hepatocellular carcinoma', 'Disease', (22, 46))	('RFC3', 'Gene', '5983', (84, 88))	('resulted in', 'Reg', (142, 153))	('lung adenocarcinoma', 'Disease', (122, 141))
481040	31661124	Whether or not erlotinib was added to H1299 cells to induce apoptosis, knockdown of RFC3 resulted in a significant increase in apoptosis.	('knockdown', 'Var', (71, 80))	('increase', 'PosReg', (115, 123))	('apoptosis', 'CPA', (127, 136))	('erlotinib', 'Chemical', 'MESH:C400278', (15, 24))	('RFC3', 'Gene', '5983', (84, 88))	('RFC3', 'Gene', (84, 88))	('H1299', 'CellLine', 'CVCL:0060', (38, 43))
481047	31661124	When RFC3 was knocked down, the aforementioned effects of RFC3 overexpression were reversed.	('RFC3', 'Gene', '5983', (58, 62))	('RFC3', 'Gene', (58, 62))	('knocked down', 'Var', (14, 26))	('RFC3', 'Gene', '5983', (5, 9))	('RFC3', 'Gene', (5, 9))
481067	30050135	In this study, we found that the high expression of HDAC6 was associated with poor prognosis in esophageal squamous cell carcinoma (ESCC) tissues.	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (96, 130))	('high expression', 'Var', (33, 48))	('associated', 'Reg', (62, 72))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (107, 130))	('HDAC6', 'Gene', '10013', (52, 57))	('HDAC6', 'Gene', (52, 57))	('esophageal squamous cell carcinoma', 'Disease', (96, 130))
481068	30050135	Then, we identified that ACY-1215 significantly inhibited cellular proliferation in ESCC, and caused G2/M phase arrest and apoptosis.	('ACY-1215', 'Var', (25, 33))	('caused', 'Reg', (94, 100))	('apoptosis', 'CPA', (123, 132))	('G2/M phase arrest', 'CPA', (101, 118))	('inhibited', 'NegReg', (48, 57))	('cellular proliferation', 'CPA', (58, 80))	('ACY-1215', 'Chemical', 'MESH:C572255', (25, 33))
481073	30050135	Furthermore, the effects of ACY-1215 inhibited ESCC proliferation were validated in a mouse xenograft model in vivo.	('ACY-1215', 'Chemical', 'MESH:C572255', (28, 36))	('inhibited', 'NegReg', (37, 46))	('ACY-1215', 'Var', (28, 36))	('mouse', 'Species', '10090', (86, 91))	('ESCC proliferation', 'CPA', (47, 65))
481074	30050135	In conclusion, our study showed that ACY-1215 suppressed proliferation and promoted apoptosis in ESCC via miR-30d/PI3K/AKT/mTOR and ERK pathways and that ACY-1215 may be a promising antitumor agent in ESCC.	('ERK', 'Gene', (132, 135))	('tumor', 'Disease', (186, 191))	('mTOR', 'Gene', '2475', (123, 127))	('ESCC', 'Disease', (201, 205))	('miR-30d', 'Gene', (106, 113))	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('apoptosis', 'CPA', (84, 93))	('AKT', 'Gene', '207', (119, 122))	('ACY-1215', 'Chemical', 'MESH:C572255', (37, 45))	('ACY-1215', 'Var', (37, 45))	('ESCC', 'Disease', (97, 101))	('suppressed', 'NegReg', (46, 56))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('miR-30d', 'Gene', '407033', (106, 113))	('ACY-1215', 'Chemical', 'MESH:C572255', (154, 162))	('ACY-1215', 'Var', (154, 162))	('ERK', 'Gene', '5594', (132, 135))	('promoted', 'PosReg', (75, 83))	('proliferation', 'CPA', (57, 70))	('AKT', 'Gene', (119, 122))	('mTOR', 'Gene', (123, 127))
481086	30050135	ACY-1215 activates potent acetylation of alpha-tubulin and multiple stress-related mechanisms to induce tumor cell apoptosis.	('ACY-1215', 'Var', (0, 8))	('acetylation', 'MPA', (26, 37))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('activates', 'PosReg', (9, 18))	('tumor', 'Disease', (104, 109))	('induce', 'PosReg', (97, 103))	('alpha-tubulin', 'Protein', (41, 54))	('ACY-1215', 'Chemical', 'MESH:C572255', (0, 8))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
481087	30050135	Several clinical trials have tested the efficacy of ACY-1215 in malignancies, either as a single treatment or in combination with other agents.	('malignancies', 'Disease', 'MESH:D009369', (64, 76))	('ACY-1215', 'Chemical', 'MESH:C572255', (52, 60))	('malignancies', 'Disease', (64, 76))	('ACY-1215', 'Var', (52, 60))	('tested', 'Reg', (29, 35))
481088	30050135	A multicenter phase 1b clinical trial found that ACY-1215 is a safe and well tolerated selective HDAC6 inhibitor in combination with lenalidomide and dexamethasone in relapsed or refractory multiple myeloma.	('ACY-1215', 'Var', (49, 57))	('dexamethasone', 'Chemical', 'MESH:D003907', (150, 163))	('relapsed', 'Disease', (167, 175))	('multiple myeloma', 'Disease', 'MESH:D009101', (190, 206))	('HDAC6', 'Gene', '10013', (97, 102))	('multiple myeloma', 'Phenotype', 'HP:0006775', (190, 206))	('lenalidomide', 'Chemical', 'MESH:D000077269', (133, 145))	('multiple myeloma', 'Disease', (190, 206))	('HDAC6', 'Gene', (97, 102))	('ACY-1215', 'Chemical', 'MESH:C572255', (49, 57))
481090	30050135	In this study, we evaluated the efficacy and the potential mechanisms of ACY-1215 in ESCC.	('ACY-1215', 'Var', (73, 81))	('ACY-1215', 'Chemical', 'MESH:C572255', (73, 81))	('ESCC', 'Disease', (85, 89))
481092	30050135	ACY-1215 inhibited proliferation in ESCC, and caused G2/M phase arrest and apoptosis.	('inhibited', 'NegReg', (9, 18))	('ACY-1215', 'Var', (0, 8))	('apoptosis', 'CPA', (75, 84))	('caused', 'Reg', (46, 52))	('proliferation', 'CPA', (19, 32))	('ACY-1215', 'Chemical', 'MESH:C572255', (0, 8))	('G2/M phase arrest', 'CPA', (53, 70))
481094	30050135	Intriguingly, we further provided evidence that ACY-1215 triggered cell cycle arrest and apoptosis by directly affecting the miR-30d/PI3K/AKT/mTOR and ERK pathways.	('ACY-1215', 'Chemical', 'MESH:C572255', (48, 56))	('mTOR', 'Gene', (142, 146))	('mTOR', 'Gene', '2475', (142, 146))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (67, 84))	('miR-30d', 'Gene', (125, 132))	('AKT', 'Gene', (138, 141))	('ACY-1215', 'Var', (48, 56))	('apoptosis', 'CPA', (89, 98))	('ERK', 'Gene', '5594', (151, 154))	('miR-30d', 'Gene', '407033', (125, 132))	('affecting', 'Reg', (111, 120))	('cell cycle arrest', 'CPA', (67, 84))	('ERK', 'Gene', (151, 154))	('AKT', 'Gene', '207', (138, 141))
481098	30050135	The high expression of HDAC6 was associated with poor prognosis compared with low expression (p = 0.0011, Fig.	('HDAC6', 'Gene', (23, 28))	('high', 'Var', (4, 8))	('HDAC6', 'Gene', '10013', (23, 28))
481100	30050135	The MTT assay revealed that ACY-1215 inhibited cellular proliferation in a dose- and time-dependent manner (Fig.	('ACY-1215', 'Chemical', 'MESH:C572255', (28, 36))	('inhibited', 'NegReg', (37, 46))	('ACY-1215', 'Var', (28, 36))	('cellular proliferation', 'CPA', (47, 69))	('MTT', 'Chemical', 'MESH:C070243', (4, 7))
481104	30050135	The MTT assay revealed that ACY-1215 inhibited cellular proliferation in HUVEC is significantly less than ESCC cells (Fig.	('ACY-1215', 'Chemical', 'MESH:C572255', (28, 36))	('inhibited', 'NegReg', (37, 46))	('ACY-1215', 'Var', (28, 36))	('cellular proliferation', 'CPA', (47, 69))	('MTT', 'Chemical', 'MESH:C070243', (4, 7))	('less', 'NegReg', (96, 100))
481105	30050135	To clarify the mechanism of ACY-1215 in suppression of tumor cell proliferation, we examined the cell cycle progression and apoptosis in response to varying doses.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('ACY-1215', 'Chemical', 'MESH:C572255', (28, 36))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('ACY-1215', 'Var', (28, 36))	('tumor', 'Disease', (55, 60))
481111	30050135	To better understand the mechanism by which ACY-1215 caused tumor cell cycle arrest and apoptosis, western blot was carried out to explore the effect of ACY-1215 on its other targets.	('cell cycle arrest', 'Phenotype', 'HP:0011018', (66, 83))	('apoptosis', 'CPA', (88, 97))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('ACY-1215', 'Chemical', 'MESH:C572255', (153, 161))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('ACY-1215', 'Var', (44, 52))	('ACY-1215', 'Chemical', 'MESH:C572255', (44, 52))	('tumor', 'Disease', (60, 65))
481112	30050135	We demonstrated that ACY-1215 effectively reduced PI3K, P-AKT (S473), PRAS40, P-mTOR, and P-ERK1/2 protein levels and increased Rag C protein levels (Fig.	('reduced', 'NegReg', (42, 49))	('Rag C protein', 'Gene', (128, 141))	('AKT', 'Gene', (58, 61))	('mTOR', 'Gene', (80, 84))	('mTOR', 'Gene', '2475', (80, 84))	('PI3K', 'MPA', (50, 54))	('increased', 'PosReg', (118, 127))	('Rag C protein', 'Gene', '64121', (128, 141))	('AKT', 'Gene', '207', (58, 61))	('PRAS40', 'Gene', '84335', (70, 76))	('PRAS40', 'Gene', (70, 76))	('ACY-1215', 'Chemical', 'MESH:C572255', (21, 29))	('P-ERK1/2 protein levels', 'MPA', (90, 113))	('ACY-1215', 'Var', (21, 29))
481113	30050135	In addition, using GSK690693 (a pan-Akt inhibitor) combined with ACY-1215 treatment the ESCC cells, we detected that co-treatment with GSK690693 could further enhance the ACY-1215-inhibited cell proliferation (Fig.	('ACY-1215', 'Chemical', 'MESH:C572255', (65, 73))	('GSK690693', 'Chemical', 'MESH:C528328', (135, 144))	('GSK690693', 'Var', (135, 144))	('GSK690693', 'Chemical', 'MESH:C528328', (19, 28))	('Akt', 'Gene', (36, 39))	('enhance', 'PosReg', (159, 166))	('ACY-1215', 'Chemical', 'MESH:C572255', (171, 179))	('Akt', 'Gene', '207', (36, 39))
481114	30050135	GSK690693 increased P-AKT due to blocking a negative feedback loop downstream of AKT (PRAS40, Rag C, and P-mTOR) (Fig.	('mTOR', 'Gene', (107, 111))	('AKT', 'Gene', '207', (22, 25))	('AKT', 'Gene', '207', (81, 84))	('mTOR', 'Gene', '2475', (107, 111))	('Rag C', 'Gene', (94, 99))	('negative feedback loop', 'MPA', (44, 66))	('PRAS40', 'Gene', '84335', (86, 92))	('GSK690693', 'Var', (0, 9))	('AKT', 'Gene', (22, 25))	('AKT', 'Gene', (81, 84))	('Rag C', 'Gene', '64121', (94, 99))	('blocking', 'NegReg', (33, 41))	('GSK690693', 'Chemical', 'MESH:C528328', (0, 9))	('PRAS40', 'Gene', (86, 92))	('increased', 'PosReg', (10, 19))
481116	30050135	We found that the levels of Ac-H3K9 and Ac-H4K8 were increased after ACY-1215 treatment (Fig.	('ACY-1215', 'Chemical', 'MESH:C572255', (69, 77))	('levels', 'MPA', (18, 24))	('increased', 'PosReg', (53, 62))	('Ac-H3K9', 'MPA', (28, 35))	('Ac-H4K8', 'Var', (40, 47))
481117	30050135	Having confirmed that ACY-1215 was correlated with epigenetic effects, we used miRNA microarray assay to investigate those miRNAs whose expression was upgraded by ACY-1215 treatment.	('expression', 'MPA', (136, 146))	('ACY-1215', 'Chemical', 'MESH:C572255', (163, 171))	('upgraded', 'PosReg', (151, 159))	('ACY-1215', 'Var', (163, 171))	('ACY-1215', 'Chemical', 'MESH:C572255', (22, 30))
481120	30050135	To validate the results, we used quantitative real-time PCR analysis to demonstrate that miR-30d was significantly overexpressed after ACY-1215 treatment, while PIK3R2 expression decreased (Fig.	('decreased', 'NegReg', (179, 188))	('miR-30d', 'Gene', '407033', (89, 96))	('expression', 'MPA', (168, 178))	('PIK3R2', 'Gene', '5296', (161, 167))	('ACY-1215', 'Chemical', 'MESH:C572255', (135, 143))	('overexpressed', 'PosReg', (115, 128))	('ACY-1215', 'Var', (135, 143))	('miR-30d', 'Gene', (89, 96))	('PIK3R2', 'Gene', (161, 167))
481124	30050135	In summary, these data validated the conclusion that ACY-1215 suppresses proliferation and promotes apoptosis in ESCC by upregulating miR-30d and inhibiting PI3K/AKT/mTOR signaling pathways.	('suppresses', 'NegReg', (62, 72))	('promotes', 'PosReg', (91, 99))	('ESCC', 'Disease', (113, 117))	('AKT', 'Gene', '207', (162, 165))	('proliferation', 'CPA', (73, 86))	('mTOR', 'Gene', (166, 170))	('mTOR', 'Gene', '2475', (166, 170))	('AKT', 'Gene', (162, 165))	('miR-30d', 'Gene', (134, 141))	('upregulating', 'PosReg', (121, 133))	('ACY-1215', 'Var', (53, 61))	('ACY-1215', 'Chemical', 'MESH:C572255', (53, 61))	('inhibiting', 'NegReg', (146, 156))	('miR-30d', 'Gene', '407033', (134, 141))	('apoptosis', 'CPA', (100, 109))
481127	30050135	Following three cycles of therapy, the ACY-1215 treatment group led to a statistically significant tumor growth slower than those in the control group (Fig.	('slower', 'NegReg', (112, 118))	('tumor', 'Disease', (99, 104))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('ACY-1215', 'Var', (39, 47))	('ACY-1215', 'Chemical', 'MESH:C572255', (39, 47))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))
481128	30050135	These findingssuggested that ACY-1215 inhibited tumor growth in vivo.	('tumor', 'Disease', (48, 53))	('ACY-1215', 'Chemical', 'MESH:C572255', (29, 37))	('inhibited', 'NegReg', (38, 47))	('ACY-1215', 'Var', (29, 37))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
481129	30050135	Several new observations in this study may provide important insights into the efficacy of ACY-1215 and its underlying mechanisms in ESCC.	('ESCC', 'Disease', (133, 137))	('ACY-1215', 'Var', (91, 99))	('ACY-1215', 'Chemical', 'MESH:C572255', (91, 99))
481130	30050135	First of all, we identified a relationship between HDAC6 and ESCC: the high expression of HDAC6 was associated with poor prognosis.	('high', 'Var', (71, 75))	('HDAC6', 'Gene', '10013', (90, 95))	('HDAC6', 'Gene', '10013', (51, 56))	('HDAC6', 'Gene', (90, 95))	('HDAC6', 'Gene', (51, 56))
481132	30050135	Finally, we confirmed that ACY-1215 was correlated with epigenetic modulation in ESCC.	('ACY-1215', 'Var', (27, 35))	('epigenetic modulation', 'Var', (56, 77))	('ESCC', 'Gene', (81, 85))	('correlated', 'Reg', (40, 50))	('ACY-1215', 'Chemical', 'MESH:C572255', (27, 35))
481140	30050135	ACY-1215 is a first-in-class potent and selective HDAC6 inhibitor.	('HDAC6', 'Gene', '10013', (50, 55))	('ACY-1215', 'Var', (0, 8))	('ACY-1215', 'Chemical', 'MESH:C572255', (0, 8))	('HDAC6', 'Gene', (50, 55))
481143	30050135	ACY-1215 in combination with bortezomib can induce apoptosis by activation of endoplasmic reticulum (ER) stress and unfolded protein response in two xenograft mouse models.	('unfolded protein response', 'MPA', (116, 141))	('induce', 'PosReg', (44, 50))	('ACY-1215', 'Var', (0, 8))	('mouse', 'Species', '10090', (159, 164))	('activation', 'PosReg', (64, 74))	('bortezomib', 'Chemical', 'MESH:D000069286', (29, 39))	('apoptosis', 'CPA', (51, 60))	('ACY-1215', 'Chemical', 'MESH:C572255', (0, 8))
481144	30050135	In non-Hodgkin lymphoma cells, ACY-1215 acts synergistically with carfilzomib through multiple stress-related mechanisms, causing increases in DNA damage, G2/M arrest, and inducing mitochondrial injury and apoptosis.	('non-Hodgkin lymphoma', 'Phenotype', 'HP:0012539', (3, 23))	('lymphoma', 'Phenotype', 'HP:0002665', (15, 23))	('mitochondrial injury', 'Disease', (181, 201))	('ACY-1215', 'Var', (31, 39))	('inducing', 'PosReg', (172, 180))	('mitochondrial injury', 'Disease', 'MESH:D028361', (181, 201))	('Hodgkin lymphoma', 'Phenotype', 'HP:0012189', (7, 23))	('carfilzomib', 'Chemical', 'MESH:C524865', (66, 77))	('non-Hodgkin lymphoma', 'Disease', 'MESH:D008228', (3, 23))	('ACY-1215', 'Chemical', 'MESH:C572255', (31, 39))	('apoptosis', 'CPA', (206, 215))	('M arrest', 'Disease', 'MESH:D006323', (158, 166))	('M arrest', 'Disease', (158, 166))	('DNA damage', 'MPA', (143, 153))	('increases', 'PosReg', (130, 139))	('non-Hodgkin lymphoma', 'Disease', (3, 23))
481145	30050135	In glioblastoma, tumor cell growth is significantly inhibited by ACY-1215 through transforming growth factor beta receptor signaling, which induces SMAD2 phosphorylation and increased P21 expression.	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('P21', 'Gene', '644914', (184, 187))	('induces', 'PosReg', (140, 147))	('tumor', 'Disease', (17, 22))	('phosphorylation', 'MPA', (154, 169))	('transforming growth factor beta receptor signaling', 'MPA', (82, 132))	('expression', 'MPA', (188, 198))	('ACY-1215', 'Var', (65, 73))	('ACY-1215', 'Chemical', 'MESH:C572255', (65, 73))	('P21', 'Gene', (184, 187))	('SMAD2', 'Gene', (148, 153))	('SMAD2', 'Gene', '4087', (148, 153))	('glioblastoma', 'Disease', (3, 15))	('glioblastoma', 'Disease', 'MESH:D005909', (3, 15))	('inhibited', 'NegReg', (52, 61))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('glioblastoma', 'Phenotype', 'HP:0012174', (3, 15))	('increased', 'PosReg', (174, 183))
481146	30050135	In BRAF-mutant melanoma cells, ACY-1215 sensitizes vemurafenib-induced cell proliferation inhibition and apoptosis through induction of ER stress and inactivation of ERK.	('ERK', 'Gene', '5594', (166, 169))	('ACY-1215', 'Var', (31, 39))	('inactivation', 'Var', (150, 162))	('melanoma', 'Phenotype', 'HP:0002861', (15, 23))	('apoptosis', 'CPA', (105, 114))	('melanoma', 'Disease', (15, 23))	('ERK', 'Gene', (166, 169))	('melanoma', 'Disease', 'MESH:D008545', (15, 23))	('vemurafenib', 'Chemical', 'MESH:D000077484', (51, 62))	('vemurafenib-induced', 'Gene', (51, 70))	('cell proliferation inhibition', 'CPA', (71, 100))	('BRAF', 'Gene', '673', (3, 7))	('BRAF', 'Gene', (3, 7))	('ACY-1215', 'Chemical', 'MESH:C572255', (31, 39))
481147	30050135	In ESCC, we demonstrated that ACY-1215 inhibited cellular proliferation by inducing G2/M arrest and apoptosis.	('ACY-1215', 'Var', (30, 38))	('M arrest', 'Disease', (87, 95))	('inhibited', 'NegReg', (39, 48))	('ACY-1215', 'Chemical', 'MESH:C572255', (30, 38))	('M arrest', 'Disease', 'MESH:D006323', (87, 95))	('inducing', 'Reg', (75, 83))	('apoptosis', 'CPA', (100, 109))	('cellular proliferation', 'CPA', (49, 71))
481149	30050135	In addition to increasing apoptosis through the commonly activated caspase pathway, we also identified that ACY-1215 increased Bax and Bim protein expression and reduced Bcl2 protein levels.	('Bcl2', 'Gene', '596', (170, 174))	('Bax', 'Gene', '581', (127, 130))	('increased', 'PosReg', (117, 126))	('ACY-1215', 'Var', (108, 116))	('ACY-1215', 'Chemical', 'MESH:C572255', (108, 116))	('reduced', 'NegReg', (162, 169))	('Bcl2', 'Gene', (170, 174))	('Bax', 'Gene', (127, 130))	('Bim', 'Gene', (135, 138))	('Bim', 'Gene', '10018', (135, 138))
481150	30050135	To better understand the mechanism by which ACY-1215 caused tumor cell cycle arrest and apoptosis, we demonstrated that ACY-1215 not only effectively inhibited phosphorylation ERK, but also inhibited PI3K/AKT/mTOR signaling pathways.	('inhibited', 'NegReg', (190, 199))	('phosphorylation', 'MPA', (160, 175))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (66, 83))	('AKT', 'Gene', '207', (205, 208))	('ERK', 'Gene', (176, 179))	('ACY-1215', 'Chemical', 'MESH:C572255', (120, 128))	('inhibited', 'NegReg', (150, 159))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('AKT', 'Gene', (205, 208))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('ACY-1215', 'Var', (44, 52))	('ACY-1215', 'Chemical', 'MESH:C572255', (44, 52))	('mTOR', 'Gene', (209, 213))	('mTOR', 'Gene', '2475', (209, 213))	('tumor', 'Disease', (60, 65))	('ACY-1215', 'Var', (120, 128))	('ERK', 'Gene', '5594', (176, 179))
481151	30050135	GSK690693 (a pan-Akt inhibitor) combined with ACY-1215 treatment could further enhance the ACY-1215-inhibited cell proliferation.	('ACY-1215', 'Chemical', 'MESH:C572255', (46, 54))	('Akt', 'Gene', '207', (17, 20))	('ACY-1215', 'Chemical', 'MESH:C572255', (91, 99))	('enhance', 'PosReg', (79, 86))	('GSK690693', 'Var', (0, 9))	('GSK690693', 'Chemical', 'MESH:C528328', (0, 9))	('Akt', 'Gene', (17, 20))
481152	30050135	GSK690693 increased P-AKT due to blocking a negative feedback loop downstream of AKT (PRAS40, Rag C, and P-mTOR).	('mTOR', 'Gene', (107, 111))	('AKT', 'Gene', '207', (22, 25))	('AKT', 'Gene', '207', (81, 84))	('mTOR', 'Gene', '2475', (107, 111))	('Rag C', 'Gene', (94, 99))	('negative feedback loop', 'MPA', (44, 66))	('PRAS40', 'Gene', '84335', (86, 92))	('GSK690693', 'Var', (0, 9))	('AKT', 'Gene', (22, 25))	('AKT', 'Gene', (81, 84))	('Rag C', 'Gene', '64121', (94, 99))	('blocking', 'NegReg', (33, 41))	('GSK690693', 'Chemical', 'MESH:C528328', (0, 9))	('PRAS40', 'Gene', (86, 92))	('increased', 'PosReg', (10, 19))
481154	30050135	A recent study showed that ACY-1215 in combination with bendamustine leads to AKT pathway inactivation in lymphoma cells.	('ACY-1215', 'Var', (27, 35))	('lymphoma', 'Disease', (106, 114))	('bendamustine', 'Chemical', 'MESH:D000069461', (56, 68))	('AKT', 'Gene', '207', (78, 81))	('lymphoma', 'Disease', 'MESH:D008223', (106, 114))	('inactivation', 'NegReg', (90, 102))	('lymphoma', 'Phenotype', 'HP:0002665', (106, 114))	('ACY-1215', 'Chemical', 'MESH:C572255', (27, 35))	('AKT', 'Gene', (78, 81))
481155	30050135	The phosphorylation status of AKT, GSK3beta, mTOR, 4EBP1, p90RSK, and p70S6 kinase all declined under treatment with ACY-1215 in combination with bendamustine.	('bendamustine', 'Chemical', 'MESH:D000069461', (146, 158))	('4EBP1', 'Gene', '1978', (51, 56))	('ACY-1215', 'Var', (117, 125))	('4EBP1', 'Gene', (51, 56))	('mTOR', 'Gene', '2475', (45, 49))	('GSK3beta', 'Gene', '2932', (35, 43))	('p90RSK', 'Gene', '6195', (58, 64))	('AKT', 'Gene', '207', (30, 33))	('ACY-1215', 'Chemical', 'MESH:C572255', (117, 125))	('p70S6 kinase', 'MPA', (70, 82))	('phosphorylation status', 'MPA', (4, 26))	('AKT', 'Gene', (30, 33))	('p90RSK', 'Gene', (58, 64))	('declined', 'NegReg', (87, 95))	('GSK3beta', 'Gene', (35, 43))	('mTOR', 'Gene', (45, 49))
481156	30050135	In this study, we identified that ACY-1215 effectively reduced PI3K, P-AKT (S473), PRAS40, and P-mTOR protein levels in ESCC.	('ACY-1215', 'Var', (34, 42))	('AKT', 'Gene', '207', (71, 74))	('mTOR', 'Gene', '2475', (97, 101))	('reduced', 'NegReg', (55, 62))	('mTOR', 'Gene', (97, 101))	('PI3K', 'Pathway', (63, 67))	('PRAS40', 'Gene', '84335', (83, 89))	('AKT', 'Gene', (71, 74))	('PRAS40', 'Gene', (83, 89))	('ACY-1215', 'Chemical', 'MESH:C572255', (34, 42))
481157	30050135	Thus, the effective targeting of multiple downstream effectors suggests that ACY-1215 may be an effective anticancer agent for ESCC.	('ACY-1215', 'Chemical', 'MESH:C572255', (77, 85))	('cancer', 'Disease', (110, 116))	('ESCC', 'Disease', (127, 131))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('ACY-1215', 'Var', (77, 85))	('cancer', 'Disease', 'MESH:D009369', (110, 116))
481161	30050135	In the present study, we found that ACY-1215 not only triggered acetylation of lysine on histone H3K9 and histone H4K8, but also promoted miR-30d expression.	('lysine', 'Chemical', 'MESH:D008239', (79, 85))	('promoted', 'PosReg', (129, 137))	('miR-30d', 'Gene', (138, 145))	('histone H4', 'Gene', (106, 116))	('acetylation of lysine', 'MPA', (64, 85))	('histone', 'Protein', (89, 96))	('ACY-1215', 'Var', (36, 44))	('ACY-1215', 'Chemical', 'MESH:C572255', (36, 44))	('miR-30d', 'Gene', '407033', (138, 145))	('histone H4', 'Gene', '8294', (106, 116))
481166	30050135	Moreover, we demonstrated here that anti-miR-30d partially reversed the G2/M arrest and apoptosis and AKT signaling caused by ACY-1215 treatment, further indicating that ACY-1215 suppresses proliferation and promotes apoptosis in ESCC through miR-30d/PI3K/AKT/mTOR signaling pathways.	('AKT', 'Gene', '207', (256, 259))	('M arrest', 'Disease', (75, 83))	('proliferation', 'CPA', (190, 203))	('mTOR', 'Gene', '2475', (260, 264))	('ACY-1215', 'Chemical', 'MESH:C572255', (126, 134))	('AKT', 'Gene', (102, 105))	('miR-30d', 'Gene', (41, 48))	('apoptosis', 'MPA', (88, 97))	('miR-30d', 'Gene', '407033', (243, 250))	('ACY-1215', 'Chemical', 'MESH:C572255', (170, 178))	('miR-30d', 'Gene', '407033', (41, 48))	('ACY-1215', 'Var', (170, 178))	('apoptosis', 'CPA', (217, 226))	('AKT', 'Gene', '207', (102, 105))	('AKT', 'Gene', (256, 259))	('promotes', 'PosReg', (208, 216))	('M arrest', 'Disease', 'MESH:D006323', (75, 83))	('suppresses', 'NegReg', (179, 189))	('miR-30d', 'Gene', (243, 250))	('mTOR', 'Gene', (260, 264))
481168	30050135	A selective HDAC6 inhibitor, ACY-1215, inhibited proliferation in ESCC, and caused G2/M phase arrest and apoptosis via miR-30d/PI3K/AKT/mTOR and ERK pathways.	('ERK', 'Gene', (145, 148))	('AKT', 'Gene', '207', (132, 135))	('inhibited', 'NegReg', (39, 48))	('HDAC6', 'Gene', '10013', (12, 17))	('apoptosis', 'CPA', (105, 114))	('proliferation', 'CPA', (49, 62))	('caused', 'Reg', (76, 82))	('ACY-1215', 'Chemical', 'MESH:C572255', (29, 37))	('G2/M phase arrest', 'CPA', (83, 100))	('AKT', 'Gene', (132, 135))	('ACY-1215', 'Var', (29, 37))	('miR-30d', 'Gene', (119, 126))	('mTOR', 'Gene', (136, 140))	('ERK', 'Gene', '5594', (145, 148))	('mTOR', 'Gene', '2475', (136, 140))	('HDAC6', 'Gene', (12, 17))	('miR-30d', 'Gene', '407033', (119, 126))
481169	30050135	Altogether, these findings provide underlying molecular and cellular evidence that ACY-1215 may be a promising antitumor agent in ESCC.	('ACY-1215', 'Chemical', 'MESH:C572255', (83, 91))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('ACY-1215', 'Var', (83, 91))	('ESCC', 'Disease', (130, 134))	('tumor', 'Disease', (115, 120))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
481178	30050135	The following antibodies were purchased from Cell Signaling Technology (Danvers, MA): Survivin (dilution at 1:1000), P21 (1:1000), CDC2 (1:1000), P53 (1:1000), P-P53 (1:1000), CyclinA2 (1:1000), CyclinB1 (1:1000), Bax (1:1000), Bim (1:1000), Bcl2 (1:1000), Cleaved caspase3 (1:1000), Cleaved caspase 9 (1:1000), Cleaved PARP (1:1000), PI3K (1:1000), AKT (1:1000), P-AKT (1:1000), PRAS40 (1:1000), Rag C (1:1000), mTOR (1:1000), P-mTOR (1:1000), ERK1/2 (1:1000), P-ERK1/2 (1:1000).	('AKT', 'Gene', (366, 369))	('P21', 'Gene', (117, 120))	('P53', 'Gene', '7157', (162, 165))	('CyclinB1', 'Gene', '891', (195, 203))	('PRAS40', 'Gene', (380, 386))	('Rag C', 'Gene', (397, 402))	('CyclinB1', 'Gene', (195, 203))	('CyclinA2', 'Gene', (176, 184))	('Bim', 'Gene', (228, 231))	('mTOR', 'Gene', (430, 434))	('1:1000', 'Var', (453, 459))	('mTOR', 'Gene', (413, 417))	('AKT', 'Gene', '207', (366, 369))	('PARP', 'Gene', '1302', (320, 324))	('AKT', 'Gene', '207', (350, 353))	('Bcl2', 'Gene', (242, 246))	('CDC2', 'Gene', '983', (131, 135))	('CDC2', 'Gene', (131, 135))	('mTOR', 'Gene', '2475', (430, 434))	('PRAS40', 'Gene', '84335', (380, 386))	('Bcl2', 'Gene', '596', (242, 246))	('mTOR', 'Gene', '2475', (413, 417))	('Bax', 'Gene', (214, 217))	('caspase 9', 'Gene', (292, 301))	('P21', 'Gene', '644914', (117, 120))	('PARP', 'Gene', (320, 324))	('P53', 'Gene', (162, 165))	('Rag C', 'Gene', '64121', (397, 402))	('P53', 'Gene', (146, 149))	('Bax', 'Gene', '581', (214, 217))	('CyclinA2', 'Gene', '890', (176, 184))	('caspase 9', 'Gene', '842', (292, 301))	('Bim', 'Gene', '10018', (228, 231))	('AKT', 'Gene', (350, 353))	('P53', 'Gene', '7157', (146, 149))
481196	25506919	Additionally, knockdown of agrin and perlecan promoted a decrease on cell migration and adhesion, and on resistance of cells to cisplatin.	('decrease', 'NegReg', (57, 65))	('perlecan', 'Protein', (37, 45))	('agrin', 'Gene', '375790', (27, 32))	('resistance', 'MPA', (105, 115))	('agrin', 'Gene', (27, 32))	('cisplatin', 'Chemical', 'MESH:D002945', (128, 137))	('cell migration', 'CPA', (69, 83))	('adhesion', 'CPA', (88, 96))	('knockdown', 'Var', (14, 23))
481235	25506919	SCC-9, SCC-9 LN-1 or A431 cells, transfected with control siRNA (scramble, sc-44510, Santa Cruz) or specific siRNA against agrin (sc-29652, Santa Cruz) or perlecan (sc-44010, Santa Cruz), were submitted either to cell migration or adhesion assays.	('cell migration', 'CPA', (213, 227))	('adhesion assays', 'CPA', (231, 246))	('A431', 'CellLine', 'CVCL:0037', (21, 25))	('agrin', 'Gene', '375790', (123, 128))	('agrin', 'Gene', (123, 128))	('SCC-9 LN-1', 'CellLine', 'CVCL:L211', (7, 17))	('SCC-9', 'CellLine', 'CVCL:1685', (0, 5))	('SCC-9', 'CellLine', 'CVCL:1685', (7, 12))	('sc-29652', 'Var', (130, 138))
481268	25506919	We observed that targeted agrin knockdown decreased the adhesion of SCC-9 and SCC-9 LN-1 cells to the Matrigel (Fig.	('agrin', 'Gene', '375790', (26, 31))	('agrin', 'Gene', (26, 31))	('SCC-9 LN-1', 'CellLine', 'CVCL:L211', (78, 88))	('SCC-9', 'CellLine', 'CVCL:1685', (78, 83))	('decreased', 'NegReg', (42, 51))	('adhesion', 'MPA', (56, 64))	('knockdown', 'Var', (32, 41))	('SCC-9', 'CellLine', 'CVCL:1685', (68, 73))
481270	25506919	The knockdown of perlecan decreased the adhesion of SCC-9 LN-1 and A431 cells (Fig.	('SCC-9 LN-1', 'CellLine', 'CVCL:L211', (52, 62))	('perlecan', 'Protein', (17, 25))	('adhesion', 'MPA', (40, 48))	('A431', 'CellLine', 'CVCL:0037', (67, 71))	('knockdown', 'Var', (4, 13))	('decreased', 'NegReg', (26, 35))
481276	25506919	Cell viability was tested using MTT assay in the presence of 10% FBS, and we verified that SCC-9 and SCC-9 LN-1-agrin knockdown had a significant reduction in cell viability (Fig.	('SCC-9 LN-1', 'CellLine', 'CVCL:L211', (101, 111))	('SCC-9', 'CellLine', 'CVCL:1685', (101, 106))	('FBS', 'Disease', (65, 68))	('knockdown', 'Var', (118, 127))	('SCC-9', 'CellLine', 'CVCL:1685', (91, 96))	('FBS', 'Disease', 'MESH:D005198', (65, 68))	('cell viability', 'CPA', (159, 173))	('agrin', 'Gene', '375790', (112, 117))	('agrin', 'Gene', (112, 117))	('reduction', 'NegReg', (146, 155))	('MTT', 'Chemical', 'MESH:C070243', (32, 35))
481279	25506919	It was observed that the siRNA-knockdown of agrin promoted a reduction in the cisplatin cell resistance in all cell lines used in this study: SCC-9 (2.4 fold), SCC-9 LN-1 (3.8 fold) and A431 (1.7 fold) (S3 Figure).	('agrin', 'Gene', (44, 49))	('SCC-9 LN-1', 'CellLine', 'CVCL:L211', (160, 170))	('SCC-9', 'CellLine', 'CVCL:1685', (160, 165))	('reduction', 'NegReg', (61, 70))	('A431', 'CellLine', 'CVCL:0037', (186, 190))	('SCC-9', 'CellLine', 'CVCL:1685', (142, 147))	('cisplatin cell resistance', 'MPA', (78, 103))	('cisplatin', 'Chemical', 'MESH:D002945', (78, 87))	('siRNA-knockdown', 'Var', (25, 40))	('agrin', 'Gene', '375790', (44, 49))
481291	25506919	The disruption of GAGs modification by heparanase was shown to facilitate tumor cell invasion angiogenesis and metastasis.	('modification', 'Var', (23, 35))	('metastasis', 'CPA', (111, 121))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('facilitate', 'PosReg', (63, 73))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('heparanase', 'Protein', (39, 49))	('GAGs', 'Gene', (18, 22))	('GAG', 'Chemical', 'MESH:D006025', (18, 21))	('tumor', 'Disease', (74, 79))	('disruption', 'Var', (4, 14))
481299	25506919	Therapeutic PGs- and GAG-targeting modifications have been considered as anti-invasion and tumor-specific drug delivery potential approaches.	('modifications', 'Var', (35, 48))	('GAG', 'Chemical', 'MESH:D006025', (21, 24))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor', 'Disease', (91, 96))
481331	33202946	Consistent with the critical roles of ADME genes in metabolizing and clearing anticancer drugs and cancer-modulating compounds, numerous genetic polymorphisms (e.g., single nucleotide polymorphism, SNP) of ADME genes are known to be associated with carcinogenesis and drug response.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('carcinogenesis', 'Disease', (249, 263))	('associated', 'Reg', (233, 243))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('ADME', 'Gene', (206, 210))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', (99, 105))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('single nucleotide polymorphism', 'Var', (166, 196))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('carcinogenesis', 'Disease', 'MESH:D063646', (249, 263))
481347	33202946	Of the 298 ADME genes, 157 genes (52%) were expressed in all 21 cancers and only 12 genes (4%) (CYP11B1, CYP11B2, DHRS7C, GPX5, GPX6, GSTA3, GSTA5, LOC731356, PLGLB1, SLCO6A1, SULT1C1, UGT2B17) were not expressed in any of the 21 cancer types analysed (Table S1).	('CYP11B2', 'Gene', (105, 112))	('GPX6', 'Gene', (128, 132))	('LOC731356', 'Var', (148, 157))	('DHRS7C', 'Gene', '201140', (114, 120))	('PLGLB1', 'Gene', '5343', (159, 165))	('UGT2B17', 'Gene', '7367', (185, 192))	('GSTA3', 'Gene', '2940', (134, 139))	('GSTA5', 'Gene', (141, 146))	('SULT1C1', 'Gene', '6819', (176, 183))	('cancer', 'Disease', (64, 70))	('cancers', 'Phenotype', 'HP:0002664', (64, 71))	('GSTA3', 'Gene', (134, 139))	('cancers', 'Disease', (64, 71))	('cancer', 'Disease', (230, 236))	('SLCO6A1', 'Gene', '133482', (167, 174))	('PLGLB1', 'Gene', (159, 165))	('SLCO6A1', 'Gene', (167, 174))	('GSTA5', 'Gene', '221357', (141, 146))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('SULT1C1', 'Gene', (176, 183))	('CYP11B2', 'Gene', '1585', (105, 112))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('GPX5', 'Gene', (122, 126))	('UGT2B17', 'Gene', (185, 192))	('CYP11B1', 'Gene', '1584', (96, 103))	('DHRS7C', 'Gene', (114, 120))	('GPX5', 'Gene', '2880', (122, 126))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('cancers', 'Disease', 'MESH:D009369', (64, 71))	('cancer', 'Disease', 'MESH:D009369', (230, 236))	('GPX6', 'Gene', '257202', (128, 132))	('CYP11B1', 'Gene', (96, 103))
481362	33202946	A recent study reported frequent somatic DPYD mutations in SKCM and its upregulation in metastatic tumour.	('DPYD', 'Gene', '1806', (41, 45))	('upregulation', 'PosReg', (72, 84))	('mutations', 'Var', (46, 55))	('tumour', 'Disease', 'MESH:D009369', (99, 105))	('tumour', 'Disease', (99, 105))	('SKCM', 'Gene', (59, 63))	('DPYD', 'Gene', (41, 45))	('tumour', 'Phenotype', 'HP:0002664', (99, 105))
481364	33202946	Among the CYP genes, four (2C19, 2C8, 2C9, 3A5) showed significant associations with increased OS rates in liver cancer (LIHC); three showed correlation with reduced (2D6, E1) or increased (3A4) OS rates in kidney cancer (KIRC); CYP2D6 was also associated with increased OS rates in breast cancer (BRCA) (Figure 1).	('CYP', 'Gene', (229, 232))	('CYP2D6', 'Gene', (229, 235))	('liver cancer', 'Disease', 'MESH:D006528', (107, 119))	('kidney cancer', 'Disease', 'MESH:D007680', (207, 220))	('BRCA', 'Gene', '672', (298, 302))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('breast cancer', 'Phenotype', 'HP:0003002', (283, 296))	('liver cancer', 'Phenotype', 'HP:0002896', (107, 119))	('kidney cancer', 'Phenotype', 'HP:0009726', (207, 220))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('kidney cancer', 'Disease', (207, 220))	('CYP', 'Gene', '9360', (10, 13))	('liver cancer', 'Disease', (107, 119))	('reduced', 'NegReg', (158, 165))	('breast cancer', 'Disease', 'MESH:D001943', (283, 296))	('BRCA', 'Gene', (298, 302))	('breast cancer', 'Disease', (283, 296))	('CYP', 'Gene', (10, 13))	('CYP', 'Gene', '9360', (229, 232))	('2C19', 'Var', (27, 31))	('cancer', 'Phenotype', 'HP:0002664', (290, 296))	('CYP2D6', 'Gene', '1565', (229, 235))
481377	33202946	Among the three ABC transporters, high ABCB1 expression was associated with increased OS rates consistently across four different cancer types (HNSC, PAAD, SARC, SKCM) (Figure 4A); high ABCG2 expression was also correlated with increased OS rates in KIRC (Figure 4A), consistent with a recent report.	('ABC', 'Gene', (16, 19))	('ABCG2', 'Gene', (186, 191))	('increased', 'PosReg', (228, 237))	('ABCG2', 'Gene', '9429', (186, 191))	('OS rates', 'MPA', (86, 94))	('ABC', 'Gene', '10058', (39, 42))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('increased', 'PosReg', (76, 85))	('expression', 'MPA', (192, 202))	('high', 'Var', (181, 185))	('ABC', 'Gene', (39, 42))	('ABCB1', 'Gene', (39, 44))	('ABCB1', 'Gene', '5243', (39, 44))	('ABC', 'Gene', '10058', (186, 189))	('cancer', 'Disease', (130, 136))	('ABC', 'Gene', (186, 189))	('high', 'Var', (34, 38))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('ABC', 'Gene', '10058', (16, 19))
481378	33202946	By contrast, high ABCC2 levels showed associations with decreased OS rates in SKCM (Figure 4A).	('high', 'Var', (13, 17))	('SKCM', 'Disease', (78, 82))	('decreased', 'NegReg', (56, 65))	('ABCC2', 'Gene', (18, 23))	('ABCC2', 'Gene', '1244', (18, 23))
481384	33202946	The finding that high SLC15A2 expression associated with favourable OS in the TCGA-LUAD dataset (Figure 4B), was corroborated by the KM-LUAD analysis.	('SLC15A2', 'Gene', '6565', (22, 29))	('expression', 'MPA', (30, 40))	('high', 'Var', (17, 21))	('SLC15A2', 'Gene', (22, 29))	('KM-LUAD', 'Chemical', '-', (133, 140))
481385	33202946	Specifically, analysis of the KM-LUAD cohort using expression data from both of the SLC15A2 probe sets: 205316_at (Figure 5A) and 205317_s_at (Figure 5B), showed a similar association with OS.	('SLC15A2', 'Gene', '6565', (84, 91))	('205317_s_at', 'Var', (130, 141))	('SLC15A2', 'Gene', (84, 91))	('KM-LUAD', 'Chemical', '-', (30, 37))	('205316_at', 'Var', (104, 113))
481387	33202946	High UGT1A1 expression was associated with favourable OS rates in TCGA LUSC (Figure 3).	('UGT1A1', 'Gene', (5, 11))	('TCGA LUSC', 'Disease', (66, 75))	('High', 'Var', (0, 4))	('expression', 'MPA', (12, 22))	('UGT1A1', 'Gene', '54658', (5, 11))
481390	33202946	Of the six UGT1A1 probe sets, four (215125_s_at, 207126_x_at, 206094_x_at, 204532_x_at) target exon 5, one (208596_s_at) targets exons 3-5, and the sixth (221304_at) targets UGT1A8 exon 1.	('UGT1A8', 'Gene', '54576', (174, 180))	('UGT1A8', 'Gene', (174, 180))	('221304_at', 'Var', (155, 164))	('215125_s_at', 'Var', (36, 47))	('UGT1A1', 'Gene', '54658', (11, 17))	('UGT1A1', 'Gene', (11, 17))	('208596_s_at', 'Var', (108, 119))	('206094_x_at, 204532_x_at', 'Var', (62, 86))
481394	33202946	The exception was GSTM1, where higher expression was associated with favourable OS in KM-BRCA when analysed using data from both GSTM1 probe sets (215333_x_at, 204550_x_at) (Figure S4).	('GSTM1', 'Gene', '2944', (129, 134))	('BRCA', 'Gene', (89, 93))	('expression', 'MPA', (38, 48))	('GSTM1', 'Gene', (129, 134))	('GSTM1', 'Gene', '2944', (18, 23))	('215333_x_at', 'Var', (147, 158))	('GSTM1', 'Gene', (18, 23))	('BRCA', 'Gene', '672', (89, 93))
481395	33202946	Moreover, our finding that high CYP2D6 levels associated with favourable OS in the TCGA-BRCA dataset (Figure 1), was not corroborated by the KM-BRCA analysis when all three CYP2D6 probe sets were analysed (207498_s_at, 215809_at, 217468_at) (Table S3).	('CYP2D6', 'Gene', (173, 179))	('CYP2D6', 'Gene', (32, 38))	('BRCA', 'Gene', (144, 148))	('207498_s_at', 'Var', (206, 217))	('CYP2D6', 'Gene', '1565', (32, 38))	('BRCA', 'Gene', '672', (144, 148))	('CYP2D6', 'Gene', '1565', (173, 179))	('BRCA', 'Gene', '672', (88, 92))	('associated', 'Reg', (46, 56))	('BRCA', 'Gene', (88, 92))
481424	33202946	In BLCA, we showed an association of high UGT2B15 expression with favourable OS, consistent with a recent report.	('UGT2B15', 'Gene', (42, 49))	('high', 'Var', (37, 41))	('UGT2B15', 'Gene', '7366', (42, 49))	('favourable OS', 'Disease', (66, 79))	('expression', 'MPA', (50, 60))
481433	33202946	In LIHC, we showed the association of high CYP3A5 expression with favourable OS (Figure 1), which is consistent with the reported tumour suppressive activity of this enzyme.	('tumour', 'Disease', 'MESH:D009369', (130, 136))	('tumour', 'Disease', (130, 136))	('CYP3A5', 'Gene', (43, 49))	('high', 'Var', (38, 42))	('CYP3A5', 'Gene', '1577', (43, 49))	('favourable OS', 'Disease', (66, 79))	('tumour', 'Phenotype', 'HP:0002664', (130, 136))	('expression', 'MPA', (50, 60))
481451	33202946	We showed here that high ABCC2 expression was associated with unfavourable OS in melanoma (SKCM) (Figure 4A).	('melanoma', 'Disease', 'MESH:D008545', (81, 89))	('ABCC2', 'Gene', (25, 30))	('high', 'Var', (20, 24))	('melanoma', 'Disease', (81, 89))	('expression', 'MPA', (31, 41))	('ABCC2', 'Gene', '1244', (25, 30))	('melanoma', 'Phenotype', 'HP:0002861', (81, 89))	('associated', 'Reg', (46, 56))
481461	33202946	High ABCB1 expression was also associated with favourable OS in neuroblastoma.	('ABCB1', 'Gene', (5, 10))	('neuroblastoma', 'Disease', 'MESH:D009447', (64, 77))	('ABCB1', 'Gene', '5243', (5, 10))	('High', 'Var', (0, 4))	('favourable OS', 'Disease', (47, 60))	('expression', 'MPA', (11, 21))	('neuroblastoma', 'Disease', (64, 77))	('associated', 'Reg', (31, 41))	('neuroblastoma', 'Phenotype', 'HP:0003006', (64, 77))
481470	33202946	Most clinical trials of inhibitors targeting ABCB1 resulted in no benefit in survival.	('inhibitors', 'Var', (24, 34))	('ABCB1', 'Gene', '5243', (45, 50))	('ABCB1', 'Gene', (45, 50))
481509	33202946	Conflicting results were seen for some genes such as DPYD in KM-LUAD, where all three DPYD probe sets showed a Bonferroni-corrected p-value of < 0.05; however, one probe set (1554534_at) was associated with unfavourable OS but the two other probe sets (1554536_at, 204646_at) showed association with favourable OS (Table S3).	('1554536_at', 'Var', (253, 263))	('DPYD', 'Gene', (86, 90))	('DPYD', 'Gene', '1806', (86, 90))	('1554534_at', 'Var', (175, 185))	('unfavourable', 'Disease', (207, 219))	('DPYD', 'Gene', (53, 57))	('KM-LUAD', 'Chemical', '-', (61, 68))	('DPYD', 'Gene', '1806', (53, 57))	('associated', 'Reg', (191, 201))	('favourable OS', 'Disease', (300, 313))
481523	26430661	Optimal cut-off value of pretreatment and posttreatment SCC-Ag for predicting recurrence was 1.86 ng/mL (area under the curve, 0.663; P=0.000), and 0.9 ng/mL (area under the curve, 0.581; P=0.002), respectively.	('0.9 ng/mL', 'Var', (148, 157))	('SCC', 'Gene', (56, 59))	('SCC', 'Gene', '6317', (56, 59))
481582	26430661	reported that pretreatment serum SCC-Ag <7 ng/mL was associated with longer progression free survival and overall survival in the univariate analysis in patients with stage IB to IIIB disease who underwent neo-adjuvant chemotherapy followed by radical surgery.	('SCC', 'Gene', '6317', (33, 36))	('<7 ng/mL', 'Var', (40, 48))	('patients', 'Species', '9606', (153, 161))	('progression free survival', 'CPA', (76, 101))	('longer', 'PosReg', (69, 75))	('SCC', 'Gene', (33, 36))	('overall survival', 'CPA', (106, 122))
481588	26430661	In our study, posttreatment SCC-Ag >0.9 ng/mL was also associated with higher risk of recurrence in the multivariate analysis.	('SCC', 'Gene', (28, 31))	('SCC', 'Gene', '6317', (28, 31))	('>0.9', 'Var', (35, 39))
481611	24423612	In cell lines, genetic knockdown of SMO produced minor effects on cell survival, while GLI2 knockdown significantly reduced proliferation and induced extensive apoptosis.	('apoptosis', 'CPA', (160, 169))	('GLI2', 'Gene', (87, 91))	('GLI2', 'Gene', '2736', (87, 91))	('proliferation', 'CPA', (124, 137))	('knockdown', 'Var', (92, 101))	('SMO', 'Gene', '6608', (36, 39))	('SMO', 'Gene', (36, 39))	('reduced', 'NegReg', (116, 123))	('induced', 'Reg', (142, 149))
481612	24423612	Consistently, the SMO inhibitor GDC-0449 resulted in limited cytotoxicity in LSCC cells, whereas the GLI inhibitor GANT61 was very effective.	('GLI', 'Gene', (101, 104))	('GDC-0449', 'Var', (32, 40))	('cytotoxicity', 'Disease', (61, 73))	('SMO', 'Gene', '6608', (18, 21))	('LSCC', 'Phenotype', 'HP:0030359', (77, 81))	('SMO', 'Gene', (18, 21))	('GLI', 'Gene', '2735', (101, 104))	('cytotoxicity', 'Disease', 'MESH:D064420', (61, 73))	('limited', 'NegReg', (53, 60))	('GANT61', 'Chemical', 'MESH:C551027', (115, 121))	('GDC-0449', 'Chemical', 'MESH:C538724', (32, 40))
481620	24423612	SMO de-repression triggers a series of intracellular events, resulting in the activation of downstream target genes through the zinc-finger transcription factors GLI1, GLI2 and GLI3.	('GLI1', 'Gene', '2735', (162, 166))	('GLI1', 'Gene', (162, 166))	('SMO', 'Gene', '6608', (0, 3))	('de-repression', 'Var', (4, 17))	('activation', 'PosReg', (78, 88))	('GLI3', 'Gene', (177, 181))	('GLI3', 'Gene', '2737', (177, 181))	('GLI2', 'Gene', '2736', (168, 172))	('GLI2', 'Gene', (168, 172))	('SMO', 'Gene', (0, 3))
481627	24423612	Dysregulation of the HH pathway has been implicated in a variety of cancers.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('Dysregulation', 'Var', (0, 13))	('cancers', 'Phenotype', 'HP:0002664', (68, 75))	('cancers', 'Disease', (68, 75))	('cancers', 'Disease', 'MESH:D009369', (68, 75))	('HH pathway', 'Pathway', (21, 31))	('implicated', 'Reg', (41, 51))
481649	24423612	Antibodies: SHH, PTCH, SMO (Santa Cruz); GLI2, GAPDH (Abcam); GLI1 (Novus Biologicals); Cleaved Caspase-3, Cleaved PARP (Cell Signaling Technology); CCND1 (BD Biosciences).	('CCND1', 'Gene', (149, 154))	('PTCH', 'Gene', (17, 21))	('GLI1', 'Gene', (62, 66))	('GLI1', 'Gene', '2735', (62, 66))	('PTCH', 'Gene', '5727', (17, 21))	('SMO', 'Gene', '6608', (23, 26))	('SHH', 'Gene', (12, 15))	('GLI2', 'Gene', '2736', (41, 45))	('Cleaved', 'Var', (107, 114))	('GAPDH', 'Gene', '2597', (47, 52))	('PARP', 'Gene', (115, 119))	('CCND1', 'Gene', '595', (149, 154))	('GLI2', 'Gene', (41, 45))	('PARP', 'Gene', '1302', (115, 119))	('SMO', 'Gene', (23, 26))	('Cleaved', 'Var', (88, 95))	('SHH', 'Gene', '6469', (12, 15))	('GAPDH', 'Gene', (47, 52))
481690	24423612	SMO knockdown caused a moderate decrease of PTCH1 mRNA in NCI-H520 and NCI-H226 (Figure 3D), but no significant reduction of HHIP mRNA in any of four lines (Figure 3E).	('HHIP', 'Gene', '64399', (125, 129))	('PTCH1', 'Gene', (44, 49))	('HHIP', 'Gene', (125, 129))	('NCI-H226', 'CellLine', 'CVCL:1544', (71, 79))	('PTCH1', 'Gene', '5727', (44, 49))	('knockdown', 'Var', (4, 13))	('decrease', 'NegReg', (32, 40))	('SMO', 'Gene', '6608', (0, 3))	('SMO', 'Gene', (0, 3))
481692	24423612	Interestingly, loss of SMO did not reduce GLI2 mRNA level in three GLI-positive cell lines.	('GLI2', 'Gene', (42, 46))	('GLI2', 'Gene', '2736', (42, 46))	('GLI', 'Gene', (67, 70))	('GLI', 'Gene', '2735', (42, 45))	('GLI', 'Gene', '2735', (67, 70))	('loss', 'Var', (15, 19))	('SMO', 'Gene', '6608', (23, 26))	('reduce', 'NegReg', (35, 41))	('GLI', 'Gene', (42, 45))	('SMO', 'Gene', (23, 26))
481697	24423612	Loss of GLI2 also induced extensive apoptosis, demonstrated by elevated caspase 3/7 activity (Figure 3I), and the detection of cleaved caspase-3 and cleaved PARP (Figure 3G).	('caspase 3', 'Gene', (72, 81))	('PARP', 'Gene', '1302', (157, 161))	('cleaved caspase-3', 'MPA', (127, 144))	('caspase 3', 'Gene', '836', (72, 81))	('apoptosis', 'CPA', (36, 45))	('PARP', 'Gene', (157, 161))	('GLI2', 'Gene', (8, 12))	('GLI2', 'Gene', '2736', (8, 12))	('activity', 'MPA', (84, 92))	('elevated', 'PosReg', (63, 71))	('Loss', 'Var', (0, 4))
481701	24423612	Cells were treated in triplicate with either DMSO control, GDC-0449 or GANT61 for 96 hours, and then assayed for viability and caspase 3/7 activation.	('caspase 3', 'Gene', (127, 136))	('caspase 3', 'Gene', '836', (127, 136))	('GDC-0449', 'Chemical', 'MESH:C538724', (59, 67))	('DMSO', 'Chemical', 'MESH:D004121', (45, 49))	('GDC-0449', 'Var', (59, 67))	('GANT61', 'Chemical', 'MESH:C551027', (71, 77))
481702	24423612	As Figure 4A and 4B demonstrate, GDC-0449 showed limited growth inhibition and apoptosis induction only in NCI-H520 and NCI-H226 cells at 10 mumol/L despite the universal expression of SMO.	('SMO', 'Gene', '6608', (185, 188))	('GDC-0449', 'Chemical', 'MESH:C538724', (33, 41))	('SMO', 'Gene', (185, 188))	('growth inhibition', 'CPA', (57, 74))	('GDC-0449', 'Var', (33, 41))	('NCI-H226 cells', 'CellLine', 'CVCL:1544', (120, 134))	('apoptosis induction', 'CPA', (79, 98))	('limited growth', 'Phenotype', 'HP:0001510', (49, 63))
481703	24423612	Consistently, GDC-0449 only caused modest reduction of PTCH1 mRNA in NCI-H226 cells (Figure 5A).	('PTCH1', 'Gene', '5727', (55, 60))	('PTCH1', 'Gene', (55, 60))	('GDC-0449', 'Chemical', 'MESH:C538724', (14, 22))	('GDC-0449', 'Var', (14, 22))	('reduction', 'NegReg', (42, 51))	('NCI-H226 cells', 'CellLine', 'CVCL:1544', (69, 83))
481704	24423612	Among three GLI-positive cell lines, GDC-0449 led to slight decrease of GLI2 mRNA in NCI-H226 and SK-MES-1 (Figure 5B), again suggesting a minimal role of SMO in mediating HH-GLI signaling in LSCC.	('GLI', 'Gene', (12, 15))	('SMO', 'Gene', '6608', (155, 158))	('decrease', 'NegReg', (60, 68))	('GDC-0449', 'Chemical', 'MESH:C538724', (37, 45))	('GLI2', 'Gene', (72, 76))	('GDC-0449', 'Var', (37, 45))	('GLI2', 'Gene', '2736', (72, 76))	('SMO', 'Gene', (155, 158))	('GLI', 'Gene', '2735', (72, 75))	('GLI', 'Gene', '2735', (12, 15))	('SK-MES-1', 'Chemical', '-', (98, 106))	('GLI', 'Gene', (175, 178))	('LSCC', 'Phenotype', 'HP:0030359', (192, 196))	('GLI', 'Gene', '2735', (175, 178))	('NCI-H226', 'CellLine', 'CVCL:1544', (85, 93))	('GLI', 'Gene', (72, 75))
481709	24423612	SK-MES-1 displayed approximate 40% and 60% decrease in viability at 5 and 10 mumol/L, respectively.	('viability', 'MPA', (55, 64))	('SK-MES-1', 'Var', (0, 8))	('decrease', 'NegReg', (43, 51))	('SK-MES-1', 'Chemical', '-', (0, 8))
481714	24423612	Cleaved caspase-3 and cleaved PARP were detected in cells receiving GANT61 (Figure 5F).	('PARP', 'Gene', '1302', (30, 34))	('PARP', 'Gene', (30, 34))	('GANT61', 'Chemical', 'MESH:C551027', (68, 74))	('cleaved', 'Var', (22, 29))	('caspase-3', 'Protein', (8, 17))
481725	24423612	GANT61 led to a significant 40% reduction of tumor weight for both GLI-positive cell lines in comparison to solvent control, but had no effects on GLI-negative NCI-H2170 tumors (Figure 6D~F), suggesting specific anti-tumor efficacy of GANT61.	('GANT61', 'Var', (0, 6))	('tumor', 'Disease', (45, 50))	('GLI', 'Gene', '2735', (67, 70))	('tumor', 'Disease', (170, 175))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('GLI', 'Gene', '2735', (147, 150))	('tumor', 'Disease', (217, 222))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('tumor', 'Disease', 'MESH:D009369', (217, 222))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('GANT61', 'Chemical', 'MESH:C551027', (0, 6))	('NCI-H2170 tumors', 'CellLine', 'CVCL:1535', (160, 176))	('tumors', 'Phenotype', 'HP:0002664', (170, 176))	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('GLI', 'Gene', (67, 70))	('GLI', 'Gene', (147, 150))	('reduction', 'NegReg', (32, 41))	('GANT61', 'Chemical', 'MESH:C551027', (235, 241))
481727	24423612	Real-time PCR analysis confirmed that GANT61 reduced the mRNA level of GLI target genes PTCH1 and HHIP in NCI-H520 and NCI-H226 xenografts, but not in NCI-H2170 tumors (Figure 6G~I).	('HHIP', 'Gene', (98, 102))	('NCI-H2170 tumors', 'CellLine', 'CVCL:1535', (151, 167))	('reduced', 'NegReg', (45, 52))	('GANT61', 'Var', (38, 44))	('tumors', 'Phenotype', 'HP:0002664', (161, 167))	('GLI', 'Gene', (71, 74))	('GANT61', 'Chemical', 'MESH:C551027', (38, 44))	('PTCH1', 'Gene', '5727', (88, 93))	('NCI-H520', 'Var', (106, 114))	('HHIP', 'Gene', '64399', (98, 102))	('GLI', 'Gene', '2735', (71, 74))	('NCI-H226', 'CellLine', 'CVCL:1544', (119, 127))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('mRNA level', 'MPA', (57, 67))	('PTCH1', 'Gene', (88, 93))
481728	24423612	Aberrant HH signaling has been implicated in a diverse spectrum of human cancers.	('implicated', 'Reg', (31, 41))	('cancers', 'Disease', (73, 80))	('Aberrant', 'Var', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('human', 'Species', '9606', (67, 72))	('cancers', 'Disease', 'MESH:D009369', (73, 80))
481737	24423612	Genetic alterations, including loss of PTCH function, constitutively active SMO, and amplification of GLI1/GLI2 have been reported to activate downstream HH signaling independent of ligands in various cancers.	('cancers', 'Disease', 'MESH:D009369', (201, 208))	('cancers', 'Phenotype', 'HP:0002664', (201, 208))	('GLI2', 'Gene', (107, 111))	('activate', 'PosReg', (134, 142))	('loss', 'NegReg', (31, 35))	('cancers', 'Disease', (201, 208))	('GLI2', 'Gene', '2736', (107, 111))	('PTCH', 'Gene', (39, 43))	('PTCH', 'Gene', '5727', (39, 43))	('SMO', 'Gene', '6608', (76, 79))	('SMO', 'Gene', (76, 79))	('downstream HH signaling', 'MPA', (143, 166))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('amplification', 'Var', (85, 98))	('GLI1', 'Gene', '2735', (102, 106))	('GLI1', 'Gene', (102, 106))
481740	24423612	However, shRNAs knockdown of SMO showed only minor effects on LSCC cell survival and apoptosis, with little effect on HH downstream target gene expression.	('LSCC cell survival', 'CPA', (62, 80))	('apoptosis', 'CPA', (85, 94))	('knockdown', 'Var', (16, 25))	('SMO', 'Gene', '6608', (29, 32))	('SMO', 'Gene', (29, 32))	('LSCC', 'Phenotype', 'HP:0030359', (62, 66))
481741	24423612	Consistently, GDC-0449 produced limited cytotoxicity despite the universal expression of SMO, suggesting the existence of SMO-independent regulation of GLI signaling.	('cytotoxicity', 'Disease', (40, 52))	('GLI', 'Gene', (152, 155))	('GDC-0449', 'Var', (14, 22))	('GLI', 'Gene', '2735', (152, 155))	('cytotoxicity', 'Disease', 'MESH:D064420', (40, 52))	('GDC-0449', 'Chemical', 'MESH:C538724', (14, 22))	('SMO', 'Gene', '6608', (89, 92))	('SMO', 'Gene', (89, 92))	('SMO', 'Gene', '6608', (122, 125))	('SMO', 'Gene', (122, 125))
481750	24423612	ATO has been shown to inhibit HH signaling by inhibiting GLI2 ciliary accumulation and promoting its degradation, and inhibit tumor growth in cancers with known drug-resistant SMO mutations and in the context of GLI2 overexpression.	('inhibiting', 'NegReg', (46, 56))	('cancers', 'Disease', 'MESH:D009369', (142, 149))	('GLI2', 'Gene', (57, 61))	('GLI2', 'Gene', '2736', (57, 61))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('inhibit', 'NegReg', (118, 125))	('degradation', 'MPA', (101, 112))	('inhibit', 'NegReg', (22, 29))	('GLI2', 'Gene', (212, 216))	('GLI2', 'Gene', '2736', (212, 216))	('cancers', 'Phenotype', 'HP:0002664', (142, 149))	('mutations', 'Var', (180, 189))	('cancers', 'Disease', (142, 149))	('SMO', 'Gene', '6608', (176, 179))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('ATO', 'Chemical', 'MESH:D000077237', (0, 3))	('tumor', 'Disease', (126, 131))	('promoting', 'PosReg', (87, 96))	('SMO', 'Gene', (176, 179))	('tumor', 'Disease', 'MESH:D009369', (126, 131))
481755	24423612	PIK3CA copy number gains and loss of PTEN function are prevalent in the classical subtype of LSCC, where the activation of HH signaling was observed.	('prevalent', 'Reg', (55, 64))	('function', 'MPA', (42, 50))	('copy number gains', 'Var', (7, 24))	('loss', 'NegReg', (29, 33))	('PTEN', 'Gene', (37, 41))	('PIK3CA', 'Gene', (0, 6))	('PTEN', 'Gene', '5728', (37, 41))	('PIK3CA', 'Gene', '5290', (0, 6))	('LSCC', 'Disease', (93, 97))	('LSCC', 'Phenotype', 'HP:0030359', (93, 97))
481829	31961032	Not surprisingly, abnormal expression of JMJD6 may contribute to the development of many diseases, such as neuropathic pain, foot-and-mouth disease, gestational diabetes mellitus, hepatitis C and various types of cancer.	('gestational diabetes mellitus', 'Disease', 'MESH:D016640', (149, 178))	('expression', 'MPA', (27, 37))	('neuropathic pain', 'Disease', (107, 123))	('hepatitis C', 'Disease', (180, 191))	('foot-and-mouth disease', 'Disease', (125, 147))	('pain', 'Phenotype', 'HP:0012531', (119, 123))	('diabetes mellitus', 'Phenotype', 'HP:0000819', (161, 178))	('gestational diabetes', 'Phenotype', 'HP:0009800', (149, 169))	('cancer', 'Disease', (213, 219))	('contribute', 'Reg', (51, 61))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('gestational diabetes mellitus', 'Disease', (149, 178))	('hepatitis', 'Phenotype', 'HP:0012115', (180, 189))	('JMJD6', 'Gene', (41, 46))	('-mouth', 'Phenotype', 'HP:0010806', (133, 139))	('neuropathic pain', 'Disease', 'MESH:D009437', (107, 123))	('man', 'Species', '9606', (84, 87))	('abnormal', 'Var', (18, 26))	('cancer', 'Disease', 'MESH:D009369', (213, 219))	('foot-and-mouth disease', 'Disease', 'MESH:D005536', (125, 147))
481830	31961032	In the present review, we summarized the structure and functions of JMJD6, with particular emphasis on the role of JMJD6 in cancer progression.	('cancer', 'Disease', (124, 130))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('JMJD6', 'Gene', (68, 73))	('JMJD6', 'Var', (115, 120))	('cancer', 'Disease', 'MESH:D009369', (124, 130))
481832	31961032	In particular, we focused on the role of JMJD6 in cancer progression and candidate mechanisms in order to highlight that JMJD6 may represent an attractive target for a new generation of anticancer drugs.	('cancer', 'Disease', (190, 196))	('cancer', 'Disease', 'MESH:D009369', (190, 196))	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('JMJD6', 'Var', (121, 126))
481837	31961032	In the JMJD6 protein, the polyS domain may have a regulatory influence on its oligomeric structure.	('oligomeric structure', 'MPA', (78, 98))	('influence', 'Reg', (61, 70))	('JMJD6', 'Gene', (7, 12))	('polyS', 'Chemical', 'MESH:C027794', (26, 31))	('polyS domain', 'Var', (26, 38))
481847	31961032	In addition to its arginine demethylase activity, JMJD6 also has strong lysyl hydroxylase activity (Figure 2B).23, 51, 52 After incubation of U2 small nuclear ribonucleoprotein auxiliary factor 65-kilodalton subunit (U2AF65) with JMJD6, 2OG and iron, the results of liquid chromatography-mass spectrometry (LC-MS)/MS analysis showed that U2AF65 is a substrate of JMJD6 and JMJD6 executes lysine-specific hydroxylation of U2AF65 (from HeLa cells) at lysine K15 (hydroxylated:unhydroxylated, 1:100) and K276 (hydroxylated:unhydroxylated, 1:250) residues.23 Moreover, in HeLa cells, JMJD6 overexpression results in increased hydroxylation of U2AF65.23 No evidence of hydroxylation of lysyl residues in endogenous histones (H2A, H2B, H3 and H4) was accrued in this study.23 However, in 2013, another study developed an alternative method, namely amino acid composition analysis, to detect 5-hydroxylation of histone lysyl residues.51 This study reported that JMJD6 can hydroxylate multiple lysine residues of histone H3 and H4.51 It indicates that in addition to the only known lysyl hydroxylases, the procollagen lysyl hydroxylase (PLOD enzymes), JMJD6 also functions as a specialized lysyl hydroxylase.	('H2B, H3 and H4', 'Gene', '8349;126961;60675', (725, 739))	('U2AF65', 'Gene', '11338', (338, 344))	('U2AF65', 'Gene', '11338', (217, 223))	('U2AF65', 'Gene', (421, 427))	('U2AF65', 'Gene', '11338', (639, 645))	('arginine', 'Chemical', 'MESH:D001120', (19, 27))	('lysine', 'Chemical', 'MESH:D008239', (449, 455))	('demethylase', 'Gene', (28, 39))	('demethylase', 'Gene', '8932', (28, 39))	('lysine', 'Chemical', 'MESH:D008239', (986, 992))	('U2AF65', 'Gene', '11338', (421, 427))	('PLOD', 'Gene', '5351', (1129, 1133))	('U2AF65', 'Gene', (338, 344))	('PLOD', 'Gene', (1129, 1133))	('HeLa', 'CellLine', 'CVCL:0030', (568, 572))	('JMJD6', 'Var', (1144, 1149))	('HeLa', 'CellLine', 'CVCL:0030', (434, 438))	('U2AF65', 'Gene', (217, 223))	('U2AF65', 'Gene', (639, 645))	('lysine', 'Chemical', 'MESH:D008239', (388, 394))
481852	31961032	Jumonji domain-containing protein 6 regulates melanogenesis in melanoma cells because overexpression of JMJD6 promotes the expression of microphthalmia-associated transcription factor (MITF), a master regulator of melanogenesis.63 JMJD6 facilitates multiple cellular processes, including proliferation and invasion of melanoma cells in vitro, and promotes growth and metastasis of melanoma in vivo.63 At later stages of melanoma development in zebrafish, the expression of JMJD6 is elevated.64 Furthermore, JMJD6 is capable of enhancing blood vessel formation in melanoma.63  In human melanoma tissues, JMJD6 expressions were increased in both primary and metastatic melanomas than normal tissues, with higher expression of JMJD6 in metastatic melanoma.63 JMJD6 is closely correlated with lymph node involvement, distant metastases and more aggressive phenotypes, whereas depth of invasion is not correlated with the expression of JMJD6.63 Compared with patients with wild-type JMJD6, patients with mutation, amplification, deep deletion or multiple alteration of JMJD6 have an unfavourable prognosis.64 Collectively, JMJD6 plays an important role in the development and progression of melanoma.	('melanoma', 'Disease', 'MESH:D008545', (585, 593))	('melanoma', 'Phenotype', 'HP:0002861', (318, 326))	('melanoma', 'Disease', (318, 326))	('MITF', 'Gene', (185, 189))	('melanoma', 'Phenotype', 'HP:0002861', (381, 389))	('melanoma', 'Disease', (381, 389))	('metastases', 'Disease', (821, 831))	('melanoma', 'Phenotype', 'HP:0002861', (63, 71))	('melanoma', 'Disease', (667, 675))	('melanoma', 'Disease', (63, 71))	('melanoma', 'Disease', 'MESH:D008545', (1186, 1194))	('metastasis of melanoma', 'Disease', (367, 389))	('melanoma', 'Phenotype', 'HP:0002861', (420, 428))	('melanoma', 'Disease', (420, 428))	('microphthalmia-associated transcription factor', 'Gene', '30080', (137, 183))	('melanoma', 'Disease', (744, 752))	('zebrafish', 'Species', '7955', (444, 453))	('melanoma', 'Phenotype', 'HP:0002861', (563, 571))	('melanoma', 'Disease', (563, 571))	('melanomas', 'Disease', 'MESH:D008545', (667, 676))	('human', 'Species', '9606', (579, 584))	('melanoma', 'Disease', (585, 593))	('melanomas', 'Disease', (667, 676))	('melanoma', 'Disease', 'MESH:D008545', (318, 326))	('melanoma', 'Disease', 'MESH:D008545', (381, 389))	('melanoma', 'Disease', 'MESH:D008545', (667, 675))	('microphthalmia-associated transcription factor', 'Gene', (137, 183))	('JMJD6', 'Gene', (1118, 1123))	('melanoma', 'Disease', 'MESH:D008545', (63, 71))	('melanoma', 'Disease', (1186, 1194))	('patients', 'Species', '9606', (985, 993))	('deep deletion', 'Var', (1024, 1037))	('MITF', 'Gene', '30080', (185, 189))	('melanoma', 'Disease', 'MESH:D008545', (420, 428))	('patients', 'Species', '9606', (954, 962))	('melanoma', 'Disease', 'MESH:D008545', (744, 752))	('microphthalmia', 'Phenotype', 'HP:0000568', (137, 151))	('melanoma', 'Disease', 'MESH:D008545', (563, 571))	('metastasis of melanoma', 'Disease', 'MESH:D009362', (367, 389))	('melanomas', 'Phenotype', 'HP:0002861', (667, 676))	('metastases', 'Disease', 'MESH:D009362', (821, 831))
481860	31961032	Although hydroxylation of p53 protein has not been reported before this study, it was demonstrated that JMJD6 acts as a 2-OG- and Fe(II)-dependent lysyl hydroxylase and catalyses hydroxylation of p53 on lysine 382 (K382).	('hydroxylation', 'MPA', (179, 192))	('K382', 'Chemical', '-', (215, 219))	('p53', 'Gene', (196, 199))	('Fe(II)', 'Chemical', '-', (130, 136))	('p53', 'Gene', (26, 29))	('p53', 'Gene', '7157', (26, 29))	('lysine', 'Chemical', 'MESH:D008239', (203, 209))	('p53', 'Gene', '7157', (196, 199))	('JMJD6', 'Var', (104, 109))
481863	31961032	JMJD6 knock-down arrests cells in the G1 phase, induces cell apoptosis, makes cells sensitive to DNA damaging agents and represses p53-dependent colon cell proliferation and tumour development in a p53-dependent manner.	('tumour', 'Phenotype', 'HP:0002664', (174, 180))	('man', 'Species', '9606', (212, 215))	('cells', 'CPA', (25, 30))	('represses', 'NegReg', (121, 130))	('knock-down', 'Var', (6, 16))	('JMJD6', 'Gene', (0, 5))	('G1 phase', 'CPA', (38, 46))	('p53', 'Gene', (131, 134))	('colon cell proliferation and tumour', 'Disease', 'MESH:D003110', (145, 180))	('induces', 'Reg', (48, 55))	('p53', 'Gene', (198, 201))	('p53', 'Gene', '7157', (198, 201))	('p53', 'Gene', '7157', (131, 134))	('cell apoptosis', 'CPA', (56, 70))
481865	31961032	In addition to being hydroxylated, lysine 382 of p53 can also be acetylated by the acetyl transferase p300/CBP, which has been reported to enhance the transcriptional activity of p53.	('p53', 'Gene', (179, 182))	('lysine', 'Chemical', 'MESH:D008239', (35, 41))	('transcriptional activity', 'MPA', (151, 175))	('p53', 'Gene', (49, 52))	('p53', 'Gene', '7157', (179, 182))	('p53', 'Gene', '7157', (49, 52))	('CBP', 'Gene', '1387', (107, 110))	('CBP', 'Gene', (107, 110))	('lysine 382', 'Var', (35, 45))	('p300', 'Gene', '2033', (102, 106))	('acetylated', 'MPA', (65, 75))	('enhance', 'PosReg', (139, 146))	('p300', 'Gene', (102, 106))
481867	31961032	Together, these findings suggested that JMJD6 catalyses hydroxylation of p53 and downregulates its transcriptional activity, thereby inhibiting the tumour suppressor function of p53.	('transcriptional activity', 'MPA', (99, 123))	('tumour', 'Disease', (148, 154))	('hydroxylation', 'MPA', (56, 69))	('inhibiting', 'NegReg', (133, 143))	('JMJD6', 'Var', (40, 45))	('downregulates', 'NegReg', (81, 94))	('p53', 'Gene', (73, 76))	('p53', 'Gene', '7157', (73, 76))	('tumour', 'Phenotype', 'HP:0002664', (148, 154))	('p53', 'Gene', (178, 181))	('p53', 'Gene', '7157', (178, 181))	('tumour', 'Disease', 'MESH:D009369', (148, 154))
481868	31961032	Since Wnt signalling is critical for the activity of epithelial stem cells, it is not surprising that Wnt signalling is frequently upregulated in cancer.77 In glioma stem cells, cignal finder cancer 10-pathway reporter array was adopted to explore the signalling pathways involved in the association between JMJD6 and increased cell proliferation, migration and invasion.13 The results demonstrated that silencing of JMJD6 with JMJD6-shRNA suppresses Wnt signalling and activates p53 signalling.	('glioma', 'Disease', (159, 165))	('cancer', 'Disease', (146, 152))	('JMJD6', 'Gene', (417, 422))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('silencing', 'Var', (404, 413))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('p53', 'Gene', (480, 483))	('p53', 'Gene', '7157', (480, 483))	('cancer', 'Disease', (192, 198))	('cancer', 'Disease', 'MESH:D009369', (192, 198))	('glioma', 'Disease', 'MESH:D005910', (159, 165))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('glioma', 'Phenotype', 'HP:0009733', (159, 165))	('activates', 'PosReg', (470, 479))	('Wnt signalling', 'MPA', (451, 465))	('suppresses', 'NegReg', (440, 450))
481869	31961032	Further studies measured the expression of essential molecule T-cell factor/lymphoid enhancer factor (TCF/LEF) family protein Tcf7l2 in Wnt signalling and found that silencing of JMJD6 significantly reduces the Tcf7l2 expression.13 JMJD6 has also been demonstrated to interact with and depress TCF/LEF family protein Tcf7l1 (also known as Tcf3), a transcriptional repressor that inhibits transcription of Wnt target genes by recruiting Groucho-related transcriptional corepressors.78, 79 This study then showed that JMJD6 does enhance Wnt signalling.	('enhance', 'PosReg', (527, 534))	('Tcf7l1', 'Gene', (317, 323))	('Tcf7l2', 'Gene', '6934', (211, 217))	('Tcf7l2', 'Gene', (211, 217))	('Tcf3', 'Gene', '6929', (339, 343))	('TCF/LEF', 'Gene', '3172', (294, 301))	('TCF/LEF', 'Gene', '3172', (102, 109))	('TCF/LEF', 'Gene', (102, 109))	('TCF/LEF', 'Gene', (294, 301))	('Tcf7l2', 'Gene', (126, 132))	('Tcf7l1', 'Gene', '83439', (317, 323))	('Tcf7l2', 'Gene', '6934', (126, 132))	('Tcf3', 'Gene', (339, 343))	('JMJD6', 'Var', (516, 521))	('Wnt signalling', 'MPA', (535, 549))
481872	31961032	Myc plays an important role in multiple cellular processes that promote survival of cancer cells.86, 87 To curb cell cycle progression in response to increased Myc, increased Myc also induces p19ARF expression, thereby leading to cell apoptosis through the activation of p53.88, 89 Furthermore, p19ARF binds with Myc and prevents Myc-mediated tumorigenesis in a p53-independent manner.89 JMJD6 cooperates with Myc to enhance tumorigenesis through suppressing Myc-induced apoptosis.62 JMJD6 binds to the p19ARF promoter and demethylates Arg3 of histone H4, thereby repressing p19ARF and reducing p53 levels.	('Myc', 'Gene', (160, 163))	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('p53', 'Gene', '7157', (271, 274))	('p19ARF', 'Gene', '1029', (575, 581))	('Myc', 'Gene', (175, 178))	('Myc', 'Gene', (0, 3))	('p19ARF', 'Gene', (575, 581))	('p19ARF', 'Gene', '1029', (503, 509))	('Arg3', 'Protein', (536, 540))	('Myc', 'Gene', '4609', (313, 316))	('p19ARF', 'Gene', (503, 509))	('demethylates', 'Var', (523, 535))	('histone H4', 'Gene', '8294', (544, 554))	('p53', 'Gene', (271, 274))	('repressing', 'PosReg', (564, 574))	('Myc', 'Gene', (459, 462))	('Myc', 'Gene', (330, 333))	('p53', 'Gene', '7157', (595, 598))	('p19ARF', 'Gene', '1029', (295, 301))	('Myc', 'Gene', '4609', (160, 163))	('p19ARF', 'Gene', '1029', (192, 198))	('p19ARF', 'Gene', (295, 301))	('Myc', 'Gene', (410, 413))	('p19ARF', 'Gene', (192, 198))	('Myc', 'Gene', '4609', (175, 178))	('cancer', 'Disease', (84, 90))	('Myc', 'Gene', '4609', (0, 3))	('p53', 'Gene', (595, 598))	('reducing', 'NegReg', (586, 594))	('p53', 'Gene', '7157', (362, 365))	('Myc', 'Gene', (313, 316))	('JMJD6', 'Var', (484, 489))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('Myc', 'Gene', '4609', (459, 462))	('Myc', 'Gene', '4609', (330, 333))	('p53', 'Gene', (362, 365))	('man', 'Species', '9606', (378, 381))	('histone H4', 'Gene', (544, 554))	('binds', 'Interaction', (490, 495))	('Myc', 'Gene', '4609', (410, 413))
481873	31961032	Moreover, JMJD6 overexpression can induce epithelial-mesenchymal transformation and greatly enhance tumour growth and invasion.62  The transforming growth factor (TGF)-beta signalling is involved in diverse cellular processes, such as cell proliferation, differentiation, apoptosis and migration.90, 91 In the tumour development, TGF-beta signalling plays an environment-dependent role: during the early phases, TGF-beta primarily acts as a tumour suppressor, whereas in the later phases, TGF-beta signalling promotes invasion and metastases of tumour.92, 93, 94 TGF-beta activates cyclin-dependent kinase inhibitors, p15 and p21, and suppresses CDK2 (cyclin-dependent kinase 2) and cyclin E, thereby exerting anti-proliferative effects.95, 96 In breast cancer cell lines, the TGF-beta isoforms, especially TGF-beta2, are downregulated at both mRNA and protein levels when JMJD6 is overexpressed.12 Therefore, JMJD6 may mediate cellular proliferation in part by suppressing TGF-beta2.	('TGF-beta', 'Gene', (563, 571))	('breast cancer', 'Disease', 'MESH:D001943', (747, 760))	('TGF-beta', 'Gene', (330, 338))	('tumour', 'Phenotype', 'HP:0002664', (545, 551))	('TGF-beta', 'Gene', (412, 420))	('breast cancer', 'Disease', (747, 760))	('cyclin', 'Gene', (582, 588))	('tumour', 'Disease', 'MESH:D009369', (545, 551))	('tumour', 'Phenotype', 'HP:0002664', (100, 106))	('TGF-beta', 'Gene', '7039', (807, 815))	('tumour', 'Disease', (545, 551))	('cyclin', 'Gene', (652, 658))	('tumour', 'Disease', 'MESH:D009369', (100, 106))	('TGF-beta', 'Gene', (489, 497))	('CDK2', 'Gene', '1017', (646, 650))	('tumour', 'Disease', (100, 106))	('cyclin', 'Gene', (683, 689))	('TGF-beta2', 'Gene', (807, 816))	('TGF-beta2', 'Gene', (974, 983))	('tumour', 'Disease', 'MESH:D009369', (441, 447))	('JMJD6', 'Var', (910, 915))	('tumour', 'Phenotype', 'HP:0002664', (441, 447))	('p15', 'Gene', (618, 621))	('cellular proliferation', 'CPA', (928, 950))	('TGF-beta', 'Gene', (807, 815))	('CDK2', 'Gene', (646, 650))	('tumour', 'Disease', (441, 447))	('p21', 'Gene', (626, 629))	('metastases of tumour', 'Disease', (531, 551))	('p21', 'Gene', '644914', (626, 629))	('TGF-beta2', 'Gene', '7042', (974, 983))	('TGF-beta2', 'Gene', '7042', (807, 816))	('cancer', 'Phenotype', 'HP:0002664', (754, 760))	('cyclin-dependent kinase 2', 'Gene', '1017', (652, 677))	('p15', 'Gene', '1030', (618, 621))	('TGF-beta', 'Gene', '7039', (777, 785))	('cyclin-dependent kinase 2', 'Gene', (652, 677))	('tumour', 'Phenotype', 'HP:0002664', (310, 316))	('suppressing', 'NegReg', (962, 973))	('tumour', 'Disease', 'MESH:D009369', (310, 316))	('cyclin', 'Gene', '5111', (582, 588))	('breast cancer', 'Phenotype', 'HP:0003002', (747, 760))	('tumour', 'Disease', (310, 316))	('TGF-beta', 'Gene', (777, 785))	('TGF-beta', 'Gene', '7039', (974, 982))	('TGF-beta', 'Gene', '7039', (563, 571))	('metastases of tumour', 'Disease', 'MESH:D009362', (531, 551))	('cyclin', 'Gene', '5111', (652, 658))	('TGF-beta', 'Gene', '7039', (412, 420))	('TGF-beta', 'Gene', '7039', (330, 338))	('cyclin', 'Gene', '5111', (683, 689))	('TGF-beta', 'Gene', (974, 982))	('TGF-beta', 'Gene', '7039', (489, 497))
481875	31961032	Brd4 is a well-studied member of BET domain family of proteins which are characterized by two conserved N-terminal bromodomains (BD1 and BD2) and an extraterminal (ET) domain.97 Brd4 binds to acetylated lysine residues on histone tails and other nuclear proteins through bromodomains which have modest affinity for acetylated lysine in a range of polypeptide contexts, and recruits transcriptional regulators such as positive transcription elongation factor b (P-TEFb) via CTD (carboxyl-terminal domain) and mediator complex to influence gene expression.97, 98, 99, 100, 101 Cancer-associated genes seem to be selectively dependent on Brd4, which plays a key role in cancer development.102 In addition to regulating transcription, Brd4 also affects many processes like DNA damage repair and checkpoint activation or telomere homoeostasis.102  The interaction between ET domain of Brd4 and JMJD6 has been identified using proteomic analysis in the initial studies.103 ET domain recognizes the alpha6 helix of JMJD6.104 As one of the ET domain interactors, JMJD6 has been shown to be critical for P-TEFb-independent transcriptional activation of many target genes of Brd4.103 A subsequent study described more detailed investigations on the interaction between Brd4 and JMJD6, and indicated that the JmjC domains and amino-terminal of JMJD6 and the ET domain of Brd4 mediate this interaction.11 In particular, in the process of P-TEFb activation and promoter-proximal polymerase II (Pol II) pause release of a large numbers of genes, both JMJD6 and Brd4 are essential.11, 105 The pause release function of the JMJD6 and Brd4 is primarily based on their co-binding to distal enhancers, termed anti-pause enhancers (A-PEs).11, 73 In terms of mechanism, JMJD6 demethylates H4R3me2(s) (a repressive histone mark) and the methyl cap of 7SK snRNA (a "reader" for H4R3me2(s)), and causes dismissal of the inhibitory complex 7SK snRNA/HEXIM1, thus inducing the activation of P-TEFb, and permitting subsequent pause release for transcriptional elongation (Figure 4).11 It is noteworthy that either JMJD6 or Brd4 can function independently in promoter-proximal pause release for some transcription units.11  It has been demonstrated that JMJD6, independently of its catalytic activity, participates in the regulation of DNA damage response signalling in cells by interacting with Brd4.106 JMJD6 is recruited to DNA damage sites and limits the spreading of RNF168-catalysed histone ubiquitination around DNA double-strand breaks (DSBs).106 Furthermore, JMJD6 controls the subsequent recruitment of repair proteins, while the expressions of these proteins are not downregulated.	('RNF168', 'Gene', '165918', (2444, 2450))	('HEXIM1', 'Gene', '10614', (1925, 1931))	('lysine', 'Chemical', 'MESH:D008239', (326, 332))	('Brd4', 'Gene', (1165, 1169))	('Brd4', 'Gene', (1259, 1263))	('Brd4', 'Gene', '23476', (178, 182))	('man', 'Species', '9606', (1144, 1147))	('Brd4', 'Gene', '23476', (2096, 2100))	('cancer', 'Disease', (667, 673))	('lysine', 'Chemical', 'MESH:D008239', (203, 209))	('man', 'Species', '9606', (749, 752))	('Brd4', 'Gene', (1360, 1364))	('JMJD6', 'Var', (1749, 1754))	('HEXIM1', 'Gene', (1925, 1931))	('BD1', 'Gene', '1672', (129, 132))	('Brd4', 'Gene', '23476', (731, 735))	('cancer', 'Phenotype', 'HP:0002664', (667, 673))	('methyl cap', 'MPA', (1815, 1825))	('Brd4', 'Gene', (2368, 2372))	('Brd4', 'Gene', '23476', (635, 639))	('Brd4', 'Gene', '23476', (0, 4))	('Brd4', 'Gene', '23476', (1618, 1622))	('BD2', 'Gene', (137, 140))	('telomere homoeostasis', 'Disease', (816, 837))	('Brd4', 'Gene', '23476', (880, 884))	('Brd4', 'Gene', '23476', (1547, 1551))	('Brd4', 'Gene', (178, 182))	('Brd4', 'Gene', (2096, 2100))	('demethylates', 'NegReg', (1755, 1767))	('Cancer', 'Phenotype', 'HP:0002664', (575, 581))	('Brd4', 'Gene', (731, 735))	('cancer', 'Disease', 'MESH:D009369', (667, 673))	('Brd4', 'Gene', '23476', (1165, 1169))	('Brd4', 'Gene', (635, 639))	('Brd4', 'Gene', (0, 4))	('Brd4', 'Gene', '23476', (1259, 1263))	('H4R3me2', 'Protein', (1768, 1775))	('RNF168', 'Gene', (2444, 2450))	('Brd4', 'Gene', (1618, 1622))	('BD1', 'Gene', (129, 132))	('Brd4', 'Gene', '23476', (1360, 1364))	('Brd4', 'Gene', (880, 884))	('telomere homoeostasis', 'Disease', 'MESH:C536801', (816, 837))	('Brd4', 'Gene', '23476', (2368, 2372))	('Brd4', 'Gene', (1547, 1551))	('BD2', 'Gene', '1673', (137, 140))
481878	31961032	Abnormal splicing variants may contribute to the development of cancer in humans.	('Abnormal splicing variants', 'Var', (0, 26))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('humans', 'Species', '9606', (74, 80))	('contribute', 'Reg', (31, 41))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
481879	31961032	It was suggested that JMJD6 regulates the splicing of vascular endothelial growth factor receptor 1 (Flt1) and controls angiogenic sprouting.	('Flt1', 'Gene', (101, 105))	('JMJD6', 'Var', (22, 27))	('angiogenic sprouting', 'CPA', (120, 140))	('vascular endothelial growth factor receptor 1', 'Gene', (54, 99))	('controls', 'Reg', (111, 119))	('regulates', 'Reg', (28, 37))	('splicing', 'MPA', (42, 50))	('vascular endothelial growth factor receptor 1', 'Gene', '2321', (54, 99))	('Flt1', 'Gene', '2321', (101, 105))
481880	31961032	Downregulation of JMJD6 alters the splicing of Flt1 and increases the levels of its soluble form which binds to vascular endothelial growth factors (VEGF) and placental growth factor, thus inhibiting angiogenesis.50, 122, 123, 124 The role of JMJD6 in splicing regulation may be achieved by its interaction with RS domains (domains rich in alternating arginine and serine residues) of serine and arginine-rich (SR) proteins and SR-like splicing factors, especially the splicing factor U2AF65 (Figure 5).23 JMJD6 interacts with U2AF65 that binds to Flt1 mRNA.50 More recently, it was reported that JMJD6 and U2AF65 directly bind to pre-mRNA and coregulate a large set of alternative splicing events.125  In a recent study of triple-negative breast cancer, JMJD6 has been shown to have intrinsic tyrosine kinase activity.	('breast cancer', 'Disease', 'MESH:D001943', (740, 753))	('breast cancer', 'Disease', (740, 753))	('VEGF', 'Gene', '5228', (149, 153))	('VEGF', 'Gene', (149, 153))	('placental growth factor', 'Gene', (159, 182))	('U2AF65', 'Gene', (485, 491))	('U2AF65', 'Gene', '11338', (527, 533))	('Flt1', 'Gene', (47, 51))	('cancer', 'Phenotype', 'HP:0002664', (747, 753))	('U2AF65', 'Gene', '11338', (607, 613))	('Flt1', 'Gene', '2321', (548, 552))	('placental growth factor', 'Gene', '5228', (159, 182))	('U2AF65', 'Gene', '11338', (485, 491))	('arginine', 'Chemical', 'MESH:D001120', (352, 360))	('Flt1', 'Gene', '2321', (47, 51))	('JMJD6', 'Var', (755, 760))	('arginine', 'Chemical', 'MESH:D001120', (396, 404))	('U2AF65', 'Gene', (527, 533))	('breast cancer', 'Phenotype', 'HP:0003002', (740, 753))	('U2AF65', 'Gene', (607, 613))	('Flt1', 'Gene', (548, 552))	('intrinsic tyrosine kinase activity', 'MPA', (784, 818))
481891	31961032	We hypothesize that inhibition of JMJD6 as a monotherapy or in combination with other anti-tumour drugs may produce good anti-tumour effects in human cancer.	('tumour', 'Disease', 'MESH:D009369', (91, 97))	('tumour', 'Phenotype', 'HP:0002664', (126, 132))	('human', 'Species', '9606', (144, 149))	('inhibition', 'Var', (20, 30))	('tumour', 'Disease', 'MESH:D009369', (126, 132))	('tumour', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('tumour', 'Disease', (126, 132))	('cancer', 'Disease', (150, 156))	('JMJD6', 'Gene', (34, 39))	('tumour', 'Phenotype', 'HP:0002664', (91, 97))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
481913	32010126	A previous study showed that NKG2A promoted NK cell exhaustion and facilitated chronic hepatitis C virus infection in a mouse model.	('chronic hepatitis', 'Phenotype', 'HP:0200123', (79, 96))	('hepatitis', 'Phenotype', 'HP:0012115', (87, 96))	('facilitated', 'PosReg', (67, 78))	('chronic hepatitis C virus infection', 'Disease', 'MESH:D019698', (79, 114))	('NKG2A', 'Var', (29, 34))	('N', 'Chemical', 'MESH:D009584', (44, 45))	('hepatitis C virus infection', 'Phenotype', 'HP:0410371', (87, 114))	('promoted', 'PosReg', (35, 43))	('chronic hepatitis C virus infection', 'Disease', (79, 114))	('NK cell exhaustion', 'CPA', (44, 62))	('N', 'Chemical', 'MESH:D009584', (29, 30))	('mouse', 'Species', '10090', (120, 125))
481914	32010126	Recently, emerging evidence has demonstrated that the NKG2A blockade could promote both the NK and CD8+ T cell-mediated anti-tumor effect.	('blockade', 'Var', (60, 68))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('promote', 'PosReg', (75, 82))	('CD8', 'Gene', (99, 102))	('N', 'Chemical', 'MESH:D009584', (92, 93))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('N', 'Chemical', 'MESH:D009584', (54, 55))	('CD8', 'Gene', '925', (99, 102))	('tumor', 'Disease', (125, 130))	('NKG2A', 'Gene', (54, 59))
482010	32010126	In fact, our results show that both the proportion and number of NKG2A+ CD8+ T cells are significantly increased in human lung cancer.	('NKG2A+', 'Var', (65, 71))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('lung cancer', 'Disease', (122, 133))	('increased', 'PosReg', (103, 112))	('lung cancer', 'Phenotype', 'HP:0100526', (122, 133))	('CD8', 'Gene', (72, 75))	('lung cancer', 'Disease', 'MESH:D008175', (122, 133))	('CD8', 'Gene', '925', (72, 75))	('human', 'Species', '9606', (116, 121))
482018	32010126	Consistent with our study, there were two studies have shown that the NKG2A blockade could promote anti-tumor immunity by unleashing dysfunctional CD8+ T cells in tumors.	('promote', 'PosReg', (91, 98))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('CD8', 'Gene', (147, 150))	('NKG2A', 'Gene', (70, 75))	('tumor', 'Disease', (104, 109))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('CD8', 'Gene', '925', (147, 150))	('tumors', 'Disease', (163, 169))	('tumors', 'Disease', 'MESH:D009369', (163, 169))	('tumor', 'Disease', (163, 168))	('tumors', 'Phenotype', 'HP:0002664', (163, 169))	('unleashing', 'NegReg', (122, 132))	('blockade', 'Var', (76, 84))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
482029	32010126	In conclusion, our results elucidate that tumor-infiltrating NKG2A+ CD8+ T cells form the predominant subset of NKG2A+ lymphocytes in human lung cancer but not NK cells.	('lung cancer', 'Disease', (140, 151))	('human', 'Species', '9606', (134, 139))	('tumor', 'Disease', (42, 47))	('CD8', 'Gene', (68, 71))	('N', 'Chemical', 'MESH:D009584', (61, 62))	('lung cancer', 'Phenotype', 'HP:0100526', (140, 151))	('CD8', 'Gene', '925', (68, 71))	('N', 'Chemical', 'MESH:D009584', (112, 113))	('N', 'Chemical', 'MESH:D009584', (160, 161))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('NKG2A+', 'Var', (61, 67))	('lung cancer', 'Disease', 'MESH:D008175', (140, 151))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
482049	28114446	Acquired alterations to the cancer genome:including somatic single-nucleotide variants, insertions and deletions (indels), copy number variations (CNVs), and structural rearrangements:contribute to tumorigenesis by activating pathways involved in cell growth and proliferation, resistance to apoptosis, and immune cell invasion.	('contribute', 'Reg', (184, 194))	('C', 'Chemical', 'MESH:D003596', (147, 148))	('immune cell invasion', 'CPA', (307, 327))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('single-nucleotide variants', 'Var', (60, 86))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('deletions', 'Var', (103, 112))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('insertions', 'Var', (88, 98))	('copy number variations', 'Var', (123, 145))	('tumor', 'Disease', (198, 203))	('cancer', 'Disease', (28, 34))	('resistance to apoptosis', 'CPA', (278, 301))	('men', 'Species', '9606', (178, 181))	('activating', 'PosReg', (215, 225))
482050	28114446	Alterations in receptor tyrosine kinases (RTKs) such as EGFR, ALK, RET, and ROS1 are clinically important as they confer sensitivity to kinase inhibitors in lung adenocarcinomas.	('sensitivity', 'Reg', (121, 132))	('Alterations', 'Var', (0, 11))	('EGFR', 'Gene', '1956', (56, 60))	('ALK', 'Gene', (62, 65))	('RET', 'Gene', '5979', (67, 70))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (157, 176))	('carcinoma', 'Phenotype', 'HP:0030731', (167, 176))	('EGFR', 'Gene', (56, 60))	('ROS1', 'Gene', (76, 80))	('lung adenocarcinomas', 'Disease', (157, 177))	('carcinomas', 'Phenotype', 'HP:0030731', (167, 177))	('ALK', 'Gene', '238', (62, 65))	('ROS1', 'Gene', '6098', (76, 80))	('RET', 'Gene', (67, 70))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (157, 177))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (157, 177))
482052	28114446	We have shown that the frequency of acquired alterations in lung cancer driver genes are largely distinct between the 2 largest subclasses of non-small-cell lung cancer (NSCLC), lung adenocarcinoma, and lung squamous cell carcinoma.	('alterations', 'Var', (45, 56))	('lung cancer', 'Phenotype', 'HP:0100526', (60, 71))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (203, 231))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('lung squamous cell carcinoma', 'Disease', (203, 231))	('lung adenocarcinoma', 'Disease', (178, 197))	('lung cancer', 'Disease', (157, 168))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (222, 231))	('NSCLC', 'Disease', 'MESH:D002289', (170, 175))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (178, 197))	('lung cancer', 'Disease', (60, 71))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (178, 197))	('NSCLC', 'Disease', (170, 175))	('carcinoma', 'Phenotype', 'HP:0030731', (188, 197))	('lung cancer', 'Disease', 'MESH:D008175', (157, 168))	('NSCLC', 'Phenotype', 'HP:0030358', (170, 175))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (203, 231))	('lung cancer', 'Phenotype', 'HP:0100526', (157, 168))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (208, 231))	('lung cancer', 'Disease', 'MESH:D008175', (60, 71))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (142, 168))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (146, 168))
482053	28114446	In addition to histology, the frequency of acquired alterations in lung tumors can vary across sex, smoking status, and ancestral populations.	('lung tumors', 'Phenotype', 'HP:0100526', (67, 78))	('lung tumors', 'Disease', (67, 78))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('alterations', 'Var', (52, 63))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('lung tumors', 'Disease', 'MESH:D008175', (67, 78))	('lung tumor', 'Phenotype', 'HP:0100526', (67, 77))
482054	28114446	For example,EGFR kinase domain mutations occur at a significantly higher frequency in lung adenocarcinomas from women compared with men, never-smokers compared with smokers, and East Asian populations compared with non-Asian populations.	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (86, 106))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (86, 106))	('carcinomas', 'Phenotype', 'HP:0030731', (96, 106))	('women', 'Species', '9606', (112, 117))	('EGFR', 'Gene', (12, 16))	('men', 'Species', '9606', (114, 117))	('men', 'Species', '9606', (132, 135))	('EGFR', 'Gene', '1956', (12, 16))	('kinase domain mutations', 'Var', (17, 40))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (86, 105))	('lung adenocarcinomas', 'Disease', (86, 106))
482055	28114446	The higher rates of EGFR mutations in these populations have resulted in a corresponding higher rate of patients with clinical response to EGFR inhibitors.	('mutations', 'Var', (25, 34))	('EGFR', 'Gene', (20, 24))	('EGFR', 'Gene', '1956', (139, 143))	('higher', 'PosReg', (89, 95))	('EGFR', 'Gene', (139, 143))	('patients', 'Species', '9606', (104, 112))	('EGFR', 'Gene', '1956', (20, 24))
482058	28114446	Moving beyond EGFR, amore recent study examining a panel of known driver mutations across several hundred NSCLC samples found a lower overall frequency of mutations in any gene in tumors from black patients compared with white patients.	('NSCLC', 'Disease', 'MESH:D002289', (106, 111))	('EGFR', 'Gene', '1956', (14, 18))	('EGFR', 'Gene', (14, 18))	('mutations', 'Var', (155, 164))	('patients', 'Species', '9606', (198, 206))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('tumors', 'Phenotype', 'HP:0002664', (180, 186))	('patients', 'Species', '9606', (227, 235))	('NSCLC', 'Phenotype', 'HP:0030358', (106, 111))	('mutations', 'Var', (73, 82))	('tumors', 'Disease', (180, 186))	('tumors', 'Disease', 'MESH:D009369', (180, 186))	('lower', 'NegReg', (128, 133))	('NSCLC', 'Disease', (106, 111))
482073	28114446	Because we did not have paired normal tissue for these patients, we excluded variants found in exomes of noncancer tissue using the Exome Aggregation Consortium database (eFigure 1 in Supplement 1).	('variants', 'Var', (77, 85))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('men', 'Species', '9606', (190, 193))	('patients', 'Species', '9606', (55, 63))	('C', 'Chemical', 'MESH:D003596', (150, 151))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
482083	28114446	Various exogenous exposures or endogenous biological processes can contribute to the overall mutational load observed in lung tumors.	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('lung tumors', 'Disease', 'MESH:D008175', (121, 132))	('mutational', 'Var', (93, 103))	('lung tumor', 'Phenotype', 'HP:0100526', (121, 131))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('lung tumors', 'Phenotype', 'HP:0100526', (121, 132))	('lung tumors', 'Disease', (121, 132))	('contribute', 'Reg', (67, 77))
482105	28114446	We first examined the mutational profile of EGFR and observed 46 mutations across 41 tumors (Figure4A).	('tumors', 'Disease', 'MESH:D009369', (85, 91))	('EGFR', 'Gene', '1956', (44, 48))	('EGFR', 'Gene', (44, 48))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('mutations', 'Var', (65, 74))	('tumors', 'Disease', (85, 91))
482106	28114446	Five tumors had more than one EGFR mutation including p.V769M/p.ELREA746del, p.S768I/p.V769L, p.V769M/p.L858R, p.T790M/p.L858R, and p.G719A/p.L861Q.	('p.ELREA746del', 'Mutation', 'p.746delELREA', (62, 75))	('tumors', 'Disease', 'MESH:D009369', (5, 11))	('EGFR', 'Gene', (30, 34))	('p.V769L', 'Mutation', 'rs147149347', (85, 92))	('p.T790M', 'Mutation', 'rs121434569', (111, 118))	('p.S768I/p.V769L', 'Var', (77, 92))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('tumors', 'Phenotype', 'HP:0002664', (5, 11))	('EGFR', 'Gene', '1956', (30, 34))	('p.L858R', 'Mutation', 'rs121434568', (119, 126))	('p.V769M/p.L858R', 'Var', (94, 109))	('p.G719A/p.L861Q', 'Var', (132, 147))	('p.V769M', 'Mutation', 'rs147149347', (94, 101))	('p.T790M/p.L858R', 'Var', (111, 126))	('p.G719A', 'Mutation', 'rs121913428', (132, 139))	('p.V769M/p.ELREA746del', 'Var', (54, 75))	('tumors', 'Disease', (5, 11))	('p.V769M', 'Mutation', 'rs147149347', (54, 61))	('p.L858R', 'Mutation', 'rs121434568', (102, 109))	('p.L861Q', 'Mutation', 'rs121913444', (140, 147))	('p.S768I', 'Mutation', 'rs121913465', (77, 84))
482107	28114446	In-frame indels in exon 19 were observed in both men and women and did not show enrichment in black vs white women as has been previously reported (Fisher exact P = .80).	('indels', 'Var', (9, 15))	('men', 'Species', '9606', (49, 52))	('men', 'Species', '9606', (86, 89))	('men', 'Species', '9606', (111, 114))	('women', 'Species', '9606', (57, 62))	('exon 19', 'Gene', (19, 26))	('women', 'Species', '9606', (109, 114))	('men', 'Species', '9606', (59, 62))
482108	28114446	The overall frequency of activating EGFR mutations was not associated with ancestry (P = .51) (Figure 4B).	('mutations', 'Var', (41, 50))	('activating', 'PosReg', (25, 35))	('EGFR', 'Gene', (36, 40))	('EGFR', 'Gene', '1956', (36, 40))
482110	28114446	However, no significant association was observed between EGFR mutation status and ancestry (P = .35) (eFigure 8 in Supplement 1 and eTable 12 in Supplement 2).	('men', 'Species', '9606', (151, 154))	('men', 'Species', '9606', (121, 124))	('EGFR', 'Gene', '1956', (57, 61))	('mutation', 'Var', (62, 70))	('EGFR', 'Gene', (57, 61))
482111	28114446	To determine if the overall frequency of mutations from any gene in the pathway was associated with race, we designated lung adenocarcinomas that had a previously characterized activating somatic single-nucleotide variants, indel, amplification, or gene fusion in a known RTK/Ras/Raf driver as "oncogene positive" (n = 128) while the remaining lung adenocarcinomas were considered "oncogene negative" (n = 185).	('Raf', 'Gene', (280, 283))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (120, 139))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (120, 140))	('indel', 'Var', (224, 229))	('Raf', 'Gene', '22882', (280, 283))	('lung adenocarcinomas', 'Disease', (120, 140))	('single-nucleotide variants', 'Var', (196, 222))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (344, 364))	('amplification', 'Var', (231, 244))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (344, 363))	('carcinomas', 'Phenotype', 'HP:0030731', (354, 364))	('carcinoma', 'Phenotype', 'HP:0030731', (354, 363))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (344, 364))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('carcinomas', 'Phenotype', 'HP:0030731', (130, 140))	('gene fusion', 'Var', (249, 260))	('activating', 'PosReg', (177, 187))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (120, 140))	('lung adenocarcinomas', 'Disease', (344, 364))
482116	28114446	We examined variants in 504 genes from 313 lung adenocarcinomas and 138 lung squamous cell carcinomas and did not observe associations between ancestry and somatic genomic alterations within each histological subtype.	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (77, 101))	('lung squamous cell carcinomas', 'Disease', (72, 101))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (72, 100))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (43, 62))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (77, 100))	('examined', 'Reg', (3, 11))	('lung adenocarcinomas', 'Disease', (43, 63))	('variants', 'Var', (12, 20))	('genes', 'Gene', (28, 33))	('lung squamous cell carcinomas', 'Disease', 'MESH:D002294', (72, 101))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (53, 62))	('carcinomas', 'Phenotype', 'HP:0030731', (91, 101))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (43, 63))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (43, 63))	('carcinomas', 'Phenotype', 'HP:0030731', (53, 63))
482118	28114446	However, we were able to capture SNVs in the cancer genes likely to be inherited due to their relatively high frequency in nondisease tissue from the Exome Aggregation Consortium database.	('C', 'Chemical', 'MESH:D003596', (168, 169))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('SNVs', 'Var', (33, 37))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('cancer', 'Disease', (45, 51))
482120	28114446	We observed 4 mutational signatures that have been previously characterized in cancer including those related to smoke exposure, aberrant APOBEC activity, MMR deficiency or aging, and UV exposure.	('MMR deficiency', 'Disease', 'MESH:C536143', (155, 169))	('C', 'Chemical', 'MESH:D003596', (143, 144))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('MMR deficiency', 'Disease', (155, 169))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('aberrant', 'Var', (129, 137))	('APOBEC activity', 'Gene', (138, 153))
482121	28114446	Similar to 3 tumors from TCGA, we observed a single lung squamous cell carcinoma from a white male patient that had a pattern of UV-associated mutations often observed in skin cancers and may represent a metastasis to the lung.	('patient', 'Species', '9606', (99, 106))	('UV-associated', 'Gene', (129, 142))	('tumors', 'Disease', (13, 19))	('skin cancers', 'Disease', (171, 183))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (57, 80))	('skin cancers', 'Phenotype', 'HP:0008069', (171, 183))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (52, 80))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (52, 80))	('C', 'Chemical', 'MESH:D003596', (26, 27))	('skin cancers', 'Disease', 'MESH:D012878', (171, 183))	('lung squamous cell carcinoma', 'Disease', (52, 80))	('cancers', 'Phenotype', 'HP:0002664', (176, 183))	('mutations', 'Var', (143, 152))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
482124	28114446	Studies by Leidner et al and Yang et al reported statistically significant lower frequencies of EGFR mutations in black patients compared with white patients; Bauml et al reported lower frequencies in black female smokers compared with white female smokers; and Bollig-Fischer et al found higher rates of EGFR exon19 indels in black females compared with white females.	('EGFR', 'Gene', (305, 309))	('lower', 'NegReg', (75, 80))	('mutations', 'Var', (101, 110))	('patients', 'Species', '9606', (149, 157))	('EGFR', 'Gene', (96, 100))	('patients', 'Species', '9606', (120, 128))	('EGFR', 'Gene', '1956', (305, 309))	('exon19 indels', 'Var', (310, 323))	('EGFR', 'Gene', '1956', (96, 100))
482125	28114446	In contrast, Cote et al, Reinersman et al, Yamaguchi et al, and Araujo et al did not observe any association of EGFR mutations with race.	('EGFR', 'Gene', (112, 116))	('C', 'Chemical', 'MESH:D003596', (13, 14))	('mutations', 'Var', (117, 126))	('EGFR', 'Gene', '1956', (112, 116))
482126	28114446	Of the studies that did not reach statistical significance, Reinersman et al found a higher frequency of EGFR mutations in blacks, while the others found lower frequencies.	('EGFR', 'Gene', '1956', (105, 109))	('mutations', 'Var', (110, 119))	('EGFR', 'Gene', (105, 109))
482127	28114446	Overall, the frequency of EGFR mutations in black patients across all of these studies range from2%to 19%.	('EGFR', 'Gene', '1956', (26, 30))	('EGFR', 'Gene', (26, 30))	('mutations', 'Var', (31, 40))	('patients', 'Species', '9606', (50, 58))
482128	28114446	First, EGFR mutation frequency varies by both smoking history and by sex.	('EGFR', 'Gene', (7, 11))	('mutation', 'Var', (12, 20))	('EGFR', 'Gene', '1956', (7, 11))
482133	28114446	Araujo et al examined 38 SNVs across 8 genes as well as EGFR and ERBB2 indels and ALK translocations.	('indels', 'Var', (71, 77))	('ALK', 'Gene', (82, 85))	('EGFR', 'Gene', '1956', (56, 60))	('ERBB2', 'Gene', (65, 70))	('ERBB2', 'Gene', '2064', (65, 70))	('EGFR', 'Gene', (56, 60))	('ALK', 'Gene', '238', (82, 85))
482134	28114446	They did not find any significant differences in individual genes, but did observe an overall reduction in the frequency of tumors from black patients that had any driver alteration (P = .04).	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('reduction', 'NegReg', (94, 103))	('alteration', 'Var', (171, 181))	('tumors', 'Disease', 'MESH:D009369', (124, 130))	('tumors', 'Disease', (124, 130))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('patients', 'Species', '9606', (142, 150))
482141	28114446	In addition to the mutational frequencies of individual genes, we examined the differences in the frequency of previously curated Ras/Raf/RTK pathway alterations known to drive cellular transformation in lung adenocarcinoma.	('lung adenocarcinoma', 'Disease', (204, 223))	('carcinoma', 'Phenotype', 'HP:0030731', (214, 223))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (204, 223))	('Raf', 'Gene', (134, 137))	('alterations', 'Var', (150, 161))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (204, 223))	('Raf', 'Gene', '22882', (134, 137))
482179	32547220	NSCLC cell lines NCI-H1993 (H1993, LUAD) and NCI-H1581 (H2170, LUSC) were used in this study.	('NSCLC', 'Disease', 'MESH:D002289', (0, 5))	('H1993', 'CellLine', 'CVCL:1512', (28, 33))	('NCI-H1993', 'CellLine', 'CVCL:1512', (17, 26))	('LUSC', 'Phenotype', 'HP:0030359', (63, 67))	('H1993', 'CellLine', 'CVCL:1512', (21, 26))	('NCI-H1581', 'CellLine', 'CVCL:1479', (45, 54))	('NSCLC', 'Phenotype', 'HP:0030358', (0, 5))	('LUAD', 'Phenotype', 'HP:0030078', (35, 39))	('H2170', 'Var', (56, 61))	('NSCLC', 'Disease', (0, 5))	('H2170', 'CellLine', 'CVCL:1535', (56, 61))
482215	32547220	For instance, LEF1-AS1 is upregulated in oral cancer and its knockdown led to inhibited cancer progression through the Hippo signaling pathway.	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('upregulated', 'PosReg', (26, 37))	('inhibited', 'NegReg', (78, 87))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('cancer', 'Disease', (46, 52))	('LEF1-AS1', 'Gene', '641518', (14, 22))	('LEF1-AS1', 'Gene', (14, 22))	('knockdown', 'Var', (61, 70))	('Hippo signaling pathway', 'Pathway', (119, 142))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))
482236	32005243	Several known cancer genes with different mutations, including TP53 and KEAP1, were also detected.	('cancer', 'Disease', (14, 20))	('TP53', 'Gene', '7157', (63, 67))	('TP53', 'Gene', (63, 67))	('KEAP1', 'Gene', '9817', (72, 77))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('KEAP1', 'Gene', (72, 77))	('cancer', 'Disease', 'MESH:D009369', (14, 20))	('mutations', 'Var', (42, 51))
482240	32005243	The tumor with more neoantigens and no HLA LOH showed more infiltrating CD8+ T cells and more clonal TCRs, indicating a more active microenvironment.	('tumor', 'Disease', (4, 9))	('more', 'PosReg', (54, 58))	('neoantigens', 'Var', (20, 31))	('TCR', 'Gene', (101, 104))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('CD8', 'Gene', (72, 75))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('TCR', 'Gene', '6962', (101, 104))	('CD8', 'Gene', '925', (72, 75))
482266	32005243	Alterations in these pathways could result in the tumor proliferation, differentiation and inhibition of apoptosis.	('apoptosis', 'CPA', (105, 114))	('Alterations', 'Var', (0, 11))	('result in', 'Reg', (36, 45))	('inhibition', 'NegReg', (91, 101))	('differentiation', 'CPA', (71, 86))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Disease', (50, 55))
482267	32005243	A total of 81% genes in these pathways had CNVs, indicating chromosomal instability might occur in these early stage tumors.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('chromosomal instability', 'Phenotype', 'HP:0040012', (60, 83))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('C', 'Chemical', 'MESH:D002244', (43, 44))	('tumors', 'Disease', (117, 123))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('CNVs', 'Var', (43, 47))
482269	32005243	Tumors of P1 showed amplifications of oncogenes in ADC and SQCC, while tumors of P2 occurred deletions of tumor suppressor genes in ADC and SQCC (p < 0.05) (Fig.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Disease', (71, 77))	('amplifications', 'MPA', (20, 34))	('tumor', 'Disease', (106, 111))	('oncogenes', 'Protein', (38, 47))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumors', 'Disease', 'MESH:D009369', (71, 77))	('SQCC', 'Disease', (59, 63))	('ADC', 'Gene', '113451', (132, 135))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Disease', (71, 76))	('ADC', 'Gene', (132, 135))	('ADC', 'Gene', '113451', (51, 54))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('deletions', 'Var', (93, 102))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('ADC', 'Gene', (51, 54))
482276	32005243	Most of the mutations (93%) were clonal mutations, suggesting the potential role of the pathways during tumor initiation.	('mutations', 'Var', (12, 21))	('tumor', 'Disease', (104, 109))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
482277	32005243	The mutation spectra of SNVs were consistent across all the samples, with a preponderance of C > A, followed by C > T (Additional file 1: Figure S1).	('C > A', 'Var', (93, 98))	('C > T', 'Var', (112, 117))	('C', 'Chemical', 'MESH:D002244', (112, 113))	('C', 'Chemical', 'MESH:D002244', (93, 94))
482280	32005243	This signature exhibits a strong transcriptional strand bias for T > C mutations at ApTpN context and is observed in hepatocellular carcinomas.	('hepatocellular carcinomas', 'Phenotype', 'HP:0001402', (117, 142))	('C', 'Chemical', 'MESH:D002244', (69, 70))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('T > C mutations', 'Var', (65, 80))	('hepatocellular carcinomas', 'Disease', 'MESH:D006528', (117, 142))	('hepatocellular carcinomas', 'Disease', (117, 142))	('carcinomas', 'Phenotype', 'HP:0030731', (132, 142))
482284	32005243	Intriguingly, we found loss of heterogeneity (LOH) of human leukocyte antigen (HLA) in P1S and P2A (Fig.	('P2A', 'Var', (95, 98))	('heterogeneity', 'MPA', (31, 44))	('HLA', 'Gene', (79, 82))	('human', 'Species', '9606', (54, 59))	('P1S', 'Var', (87, 90))
482295	32005243	Meanwhile, P1S exhibited more non-immune infiltrating cells, including cancer-associated fibroblasts (CAFs) and endothelial cells, which were reported to contributed to the tumor progression (Fig.	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('non-immune infiltrating cells', 'CPA', (30, 59))	('CAF', 'Chemical', 'MESH:C035000', (102, 105))	('cancer', 'Disease', (71, 77))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumor', 'Disease', (173, 178))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('P1S', 'Var', (11, 14))
482305	32005243	Interestingly, copy number gains in oncogenes were more frequently in P1, while losses in tumor suppressor genes were more frequently in P2.	('losses', 'NegReg', (80, 86))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('copy number gains', 'Var', (15, 32))	('oncogenes', 'Protein', (36, 45))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
482306	32005243	Besides, several tumor suppressor genes, including TP53, KEAP1, FAT4 and HMCN1 were recurrently mutated in tumors with distinct mutated sites.	('tumor', 'Disease', (17, 22))	('KEAP1', 'Gene', (57, 62))	('tumor', 'Disease', (107, 112))	('TP53', 'Gene', (51, 55))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('mutated', 'Var', (128, 135))	('tumors', 'Disease', (107, 113))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('FAT4', 'Gene', (64, 68))	('tumors', 'Disease', 'MESH:D009369', (107, 113))	('FAT4', 'Gene', '79633', (64, 68))	('HMCN1', 'Gene', '83872', (73, 78))	('HMCN1', 'Gene', (73, 78))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('KEAP1', 'Gene', '9817', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('TP53', 'Gene', '7157', (51, 55))
482307	32005243	These indicated that tumors might alter the functions of the same oncogenic pathways through different approaches, such as mutation in the same genes, or copy number alterations in the same pathways.	('copy number alterations', 'Var', (154, 177))	('mutation', 'Var', (123, 131))	('tumors', 'Disease', (21, 27))	('tumors', 'Disease', 'MESH:D009369', (21, 27))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('alter', 'Reg', (34, 39))	('oncogenic pathways', 'Pathway', (66, 84))	('functions', 'MPA', (44, 53))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
482323	32005243	ADC Adenocarcinoma CAF Cancer-associated fibroblast CNV Copy number variation CP Checkpoints or immunomodulators EC Effector cells IPS Immunophenoscore LOH Loss of heterogeneity LUL Left upper lobe MHC Antigen processing MLC Multifocal lung cancer RML Right middle lobe RUL Right upper lobe SC Suppressor cells SNV Single-nucleotide variation SQCC Squamous cell carcinoma TCR T cell receptor TME Tumor microenvironment WES Whole exome sequencing Supplementary information accompanies this paper at 10.1186/s12920-020-0663-8.	('C', 'Chemical', 'MESH:D002244', (52, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (9, 18))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('Left upper lobe', 'Disease', (182, 197))	('C', 'Chemical', 'MESH:D002244', (345, 346))	('Adenocarcinoma', 'Disease', 'MESH:D000230', (4, 18))	('Tumor', 'Phenotype', 'HP:0002664', (396, 401))	('C', 'Chemical', 'MESH:D002244', (19, 20))	('Squamous cell carcinoma', 'Phenotype', 'HP:0002860', (348, 371))	('Multifocal lung cancer', 'Disease', (225, 247))	('TCR', 'Gene', '6962', (372, 375))	('Squamous cell carcinoma', 'Disease', (348, 371))	('middle lobe', 'Disease', 'MESH:D008878', (258, 269))	('CAF', 'Chemical', 'MESH:C035000', (19, 22))	('ADC', 'Gene', '113451', (0, 3))	('C', 'Chemical', 'MESH:D002244', (200, 201))	('C', 'Chemical', 'MESH:D002244', (114, 115))	('Squamous cell carcinoma', 'Disease', 'MESH:D002294', (348, 371))	('MHC', 'Gene', (198, 201))	('C', 'Chemical', 'MESH:D002244', (2, 3))	('Multifocal lung cancer', 'Disease', 'None', (225, 247))	('C', 'Chemical', 'MESH:D002244', (81, 82))	('ADC', 'Gene', (0, 3))	('C', 'Chemical', 'MESH:D002244', (223, 224))	('TCR', 'Gene', (372, 375))	('C', 'Chemical', 'MESH:D002244', (56, 57))	('Adenocarcinoma', 'Disease', (4, 18))	('C', 'Chemical', 'MESH:D002244', (23, 24))	('C', 'Chemical', 'MESH:D002244', (78, 79))	('MHC', 'Gene', '3107', (198, 201))	('Left upper lobe', 'Disease', 'MESH:D012141', (182, 197))	('Single-nucleotide variation', 'Var', (315, 342))	('C', 'Chemical', 'MESH:D002244', (292, 293))	('C', 'Chemical', 'MESH:D002244', (373, 374))	('lung cancer', 'Phenotype', 'HP:0100526', (236, 247))	('carcinoma', 'Phenotype', 'HP:0030731', (362, 371))	('Cancer', 'Phenotype', 'HP:0002664', (23, 29))	('C', 'Chemical', 'MESH:D002244', (346, 347))	('middle lobe', 'Disease', (258, 269))
482376	29463131	Rational Design for Cervical Cancer Therapeutics: Cellular and Non-Cellular Based Strategies on the Horizon for Recurrent, Metastatic or Refractory Cervical Cancer Though cervical cytology, HPV DNA testing, and pre-invasive disease management has significantly reduced the number new diagnoses of cervical cancer, women with persistent oncogenic HPV variants are at significant risk for developing invasive cervical cancer.	('variants', 'Var', (350, 358))	('HPV', 'Gene', (346, 349))	('cervical cancer', 'Disease', (297, 312))	('women', 'Species', '9606', (314, 319))	('cervical cancer', 'Disease', 'MESH:D002583', (297, 312))	('cervical cancer', 'Disease', 'MESH:D002583', (407, 422))	('cancer', 'Phenotype', 'HP:0002664', (416, 422))	('cancer', 'Phenotype', 'HP:0002664', (306, 312))	('HPV', 'Species', '10566', (190, 193))	('Cancer', 'Phenotype', 'HP:0002664', (157, 163))	('invasive cervical cancer', 'Disease', (398, 422))	('invasive cervical cancer', 'Disease', 'MESH:D002583', (398, 422))	('Cancer', 'Phenotype', 'HP:0002664', (29, 35))	('HPV', 'Species', '10566', (346, 349))
482394	29463131	These oncoproteins are important targets because it is universally known that although there are approximately 100-150 different genotypes of HPV, greater than 95% of cervical cancers are associated with HPV 16, 18, 31, 33, 37, and 3; with HPV 16 and 18 alone causing upwards of 70% of the cervical cancers.	('cervical cancers', 'Disease', (167, 183))	('associated', 'Reg', (188, 198))	('HPV', 'Species', '10566', (240, 243))	('HPV 16', 'Species', '333760', (204, 210))	('cervical cancers', 'Disease', 'MESH:D002583', (290, 306))	('HPV', 'Species', '10566', (142, 145))	('cervical cancers', 'Disease', 'MESH:D002583', (167, 183))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('cancer', 'Phenotype', 'HP:0002664', (299, 305))	('HPV', 'Species', '10566', (204, 207))	('cancers', 'Phenotype', 'HP:0002664', (299, 306))	('cancers', 'Phenotype', 'HP:0002664', (176, 183))	('HPV 16', 'Var', (204, 210))	('HPV 16', 'Species', '333760', (240, 246))	('cervical cancers', 'Disease', (290, 306))
482399	29463131	The patients had a surgical excision of their tumor that was at least 1cm3, the tumor cells were expanded with interleukin-2 (IL-2) and tumor-infiltrating T-cells (TILs) were preferentially selected based on their HPV 16 E6 and E7 reactivity (HPV-TILs).	('interleukin-2', 'Gene', '3558', (111, 124))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('interleukin-2', 'Gene', (111, 124))	('HPV', 'Species', '10566', (243, 246))	('IL-2', 'Gene', '3558', (126, 130))	('HPV', 'Var', (214, 217))	('patients', 'Species', '9606', (4, 12))	('tumor', 'Disease', (136, 141))	('HPV 16', 'Species', '333760', (214, 220))	('tumor', 'Disease', (46, 51))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('tumor', 'Disease', (80, 85))	('tumor', 'Disease', 'MESH:D009369', (46, 51))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('IL-2', 'Gene', (126, 130))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('E7 reactivity', 'Var', (228, 241))	('HPV', 'Species', '10566', (214, 217))
482420	29463131	Lm is a gram-positive bacterium that has the capability to escape the cellular phagosome, and thus it is able to transfect directly into the host cell, eliciting the macrophages and neutrophils for the innate immune response and the CD 4+ and CD8+ T-Cells for the adaptive immune response; an immunogenic cascade activated to overcome the immune tolerance to HPV.	('CD8', 'Gene', (243, 246))	('CD8', 'Gene', '925', (243, 246))	('transfect', 'Var', (113, 122))	('eliciting', 'Reg', (152, 161))	('HPV', 'Species', '10566', (359, 362))	('Lm', 'Species', '1639', (0, 2))
482421	29463131	AXAL has shown activity against multiple high-risk HPV variants.	('variants', 'Var', (55, 63))	('HPV', 'Gene', (51, 54))	('HPV', 'Species', '10566', (51, 54))	('activity', 'MPA', (15, 23))
482440	29463131	Checkpoint inhibition targets and impedes the inherent checkpoints, allowing for host T-cell activation and ensuing immune response to eliminate the tumor cells; essentially inhibiting the inhibition of the T-cells allowing for an appropriate host immune response to identify the tumor cells.	('inhibiting', 'NegReg', (174, 184))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('inhibition', 'MPA', (189, 199))	('tumor', 'Disease', 'MESH:D009369', (280, 285))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('tumor', 'Phenotype', 'HP:0002664', (280, 285))	('inhibition', 'Var', (11, 21))	('tumor', 'Disease', (149, 154))	('tumor', 'Disease', (280, 285))
482445	29463131	Consequently, inhibition of CTLA-4 allows for the stimulation of those T-cells to trigger a response in opposition to the tumor cells.	('stimulation', 'PosReg', (50, 61))	('response', 'MPA', (92, 100))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('inhibition', 'Var', (14, 24))	('tumor', 'Disease', (122, 127))	('CTLA-4', 'Gene', (28, 34))
482462	29463131	The carcinogen-induced disease involves the down regulation of p16 and p53 mutants, similar to vulvar squamous cancers, and with the viral-induced disease, it is associated with the HPV E6 and E7 oncoproteins and a subsequent upregulation of p16, similar to cervical and anal cancers.	('cancers', 'Disease', 'MESH:D009369', (111, 118))	('HPV', 'Gene', (182, 185))	('cancers', 'Disease', 'MESH:D009369', (276, 283))	('carcinogen-induced disease', 'Disease', (4, 30))	('p16', 'Gene', '1029', (242, 245))	('mutants', 'Var', (75, 82))	('cervical', 'Disease', (258, 266))	('down regulation', 'NegReg', (44, 59))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('p53', 'Gene', (71, 74))	('vulvar squamous cancers', 'Disease', (95, 118))	('cancers', 'Phenotype', 'HP:0002664', (111, 118))	('cancers', 'Phenotype', 'HP:0002664', (276, 283))	('cancers', 'Disease', (111, 118))	('cancers', 'Disease', (276, 283))	('p16', 'Gene', (63, 66))	('cancer', 'Phenotype', 'HP:0002664', (276, 282))	('upregulation', 'PosReg', (226, 238))	('vulvar squamous cancers', 'Disease', 'MESH:D014846', (95, 118))	('E7 oncoproteins', 'Protein', (193, 208))	('p16', 'Gene', '1029', (63, 66))	('HPV', 'Species', '10566', (182, 185))	('oncoproteins', 'Protein', (196, 208))	('p16', 'Gene', (242, 245))	('anal cancer', 'Phenotype', 'HP:0032186', (271, 282))
482507	29463131	REGN2810 is a high-affinity, hinge-stabilized IgG4 human anti-PD-1 antibody, obstructing the interaction between PD-1 and PD-L1.	('obstructing', 'NegReg', (77, 88))	('PD-1', 'Gene', '5133', (113, 117))	('PD-1', 'Gene', (62, 66))	('human', 'Species', '9606', (51, 56))	('interaction', 'Interaction', (93, 104))	('PD-1', 'Gene', '5133', (62, 66))	('REGN2810', 'Chemical', 'MESH:C000627974', (0, 8))	('REGN2810', 'Var', (0, 8))	('PD-1', 'Gene', (113, 117))
482544	29463131	PI3K/AKT/mTOR pathway is an intracellular pathway that regulates the cell cycles and it is known that treatment resistance to standard chemoradiation has been associated with alterations in this pathway and thus inhibitors to PI3K/AKT/mTOR have been developed in the hopes that it will improve the response to treatment.	('AKT', 'Gene', '207', (231, 234))	('mTOR', 'Gene', (9, 13))	('mTOR', 'Gene', (235, 239))	('associated', 'Reg', (159, 169))	('mTOR', 'Gene', '2475', (9, 13))	('mTOR', 'Gene', '2475', (235, 239))	('AKT', 'Gene', '207', (5, 8))	('AKT', 'Gene', (231, 234))	('improve', 'PosReg', (286, 293))	('AKT', 'Gene', (5, 8))	('alterations', 'Var', (175, 186))
482545	29463131	Pre-clinical studies supported this theory by exhibiting that AKT inhibitors did in fact block mTOR pathways and decreased cell viability, and additionally mTOR inhibitors have been shown to decrease the levels of the E7 oncoprotein associated with HPV-malignancies.	('block', 'NegReg', (89, 94))	('AKT', 'Gene', (62, 65))	('cell viability', 'CPA', (123, 137))	('levels', 'MPA', (204, 210))	('HPV-malignancies', 'Disease', (249, 265))	('mTOR', 'Gene', (156, 160))	('mTOR', 'Gene', '2475', (156, 160))	('HPV-malignancies', 'Disease', 'MESH:D030361', (249, 265))	('inhibitors', 'Var', (161, 171))	('AKT', 'Gene', '207', (62, 65))	('mTOR', 'Gene', (95, 99))	('mTOR', 'Gene', '2475', (95, 99))	('decreased', 'NegReg', (113, 122))	('decrease', 'NegReg', (191, 199))
482548	29463131	Findings from this study found that PI3K mutations were more common in patients with squamous cell cervical cancer, 48% versus the 14% found in those with adenocarcinoma.	('mutations', 'Var', (41, 50))	('PI3K', 'Gene', (36, 40))	('carcinoma', 'Phenotype', 'HP:0030731', (160, 169))	('patients', 'Species', '9606', (71, 79))	('squamous cell cervical cancer', 'Disease', (85, 114))	('adenocarcinoma', 'Disease', (155, 169))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('common', 'Reg', (61, 67))	('squamous cell cervical cancer', 'Disease', 'MESH:D002294', (85, 114))	('adenocarcinoma', 'Disease', 'MESH:D000230', (155, 169))
482550	29463131	In addition, those with adenocarcinoma and a PI3K mutation had an OS of 19.4 months (95% CI: 0 - 43.6).	('OS', 'Chemical', '-', (66, 68))	('PI3K mutation', 'Var', (45, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (29, 38))	('adenocarcinoma', 'Disease', (24, 38))	('adenocarcinoma', 'Disease', 'MESH:D000230', (24, 38))
482553	29463131	Poly (adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitors (PARPi) are agents that were initially created for cancers that harbor a deleterious BRCA mutation that are unable to repair double-strand breaks through homologous recombination.	('PARP', 'Gene', '142', (72, 76))	('mutation', 'Var', (161, 169))	('PARP', 'Gene', '142', (54, 58))	('BRCA', 'Gene', (156, 160))	('PARP', 'Gene', (72, 76))	('cancers', 'Disease', 'MESH:D009369', (122, 129))	('cancers', 'Phenotype', 'HP:0002664', (122, 129))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('cancers', 'Disease', (122, 129))	('PARPi', 'Chemical', '-', (72, 77))	('PARP', 'Gene', (54, 58))
482555	29463131	Nonetheless, the recent FDA approval of the PARPi in patients with advanced ovarian cancer was not only limited to those patients who have a BRCA-mutation or a homologous recombination deficiency, but to all patients with recurrent ovarian cancer, as they have shown to also be effective in those patients without such a mutation.	('ovarian cancer', 'Disease', (76, 90))	('patients', 'Species', '9606', (208, 216))	('patients', 'Species', '9606', (53, 61))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('BRCA-mutation', 'Gene', (141, 154))	('ovarian cancer', 'Disease', (232, 246))	('BRCA-mutation', 'Var', (141, 154))	('patients', 'Species', '9606', (297, 305))	('PARPi', 'Chemical', '-', (44, 49))	('ovarian cancer', 'Disease', 'MESH:D010051', (232, 246))	('ovarian cancer', 'Phenotype', 'HP:0100615', (76, 90))	('recurrent ovarian cancer', 'Phenotype', 'HP:0008209', (222, 246))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('ovarian cancer', 'Disease', 'MESH:D010051', (76, 90))	('ovarian cancer', 'Phenotype', 'HP:0100615', (232, 246))	('patients', 'Species', '9606', (121, 129))
482564	29463131	Even though there are over 100-150 different genotypic variants of HPV, the hope is that one day that at least the few oncogenic variants will be eradicated by prophylactic vaccines, and with improvements in screening, the number of patients with new diagnoses of cervical cancer as well as those with advanced and recurrent cervical cancer will be no longer, but until this end, more effective treatments are needed to treat this devastating disease.	('variants', 'Var', (55, 63))	('cervical cancer', 'Disease', (325, 340))	('cervical cancer', 'Disease', 'MESH:D002583', (325, 340))	('cancer', 'Phenotype', 'HP:0002664', (334, 340))	('HPV', 'Species', '10566', (67, 70))	('cancer', 'Phenotype', 'HP:0002664', (273, 279))	('HPV', 'Gene', (67, 70))	('patients', 'Species', '9606', (233, 241))	('cervical cancer', 'Disease', (264, 279))	('cervical cancer', 'Disease', 'MESH:D002583', (264, 279))	('variants', 'Var', (129, 137))
482568	29463131	Thus, it is evident that by targeting the breakdown of the host immune tolerance to the HPV specific oncoproteins, such as HPV E6 and E7, this will aid in the treatment of not only cervical cancer, but additionally the other HPV-related malignancies such as oropharyngeal, anal, vulvar and vaginal cancers.	('oropharyngeal', 'Disease', (258, 271))	('vulvar', 'Disease', (279, 285))	('HPV', 'Species', '10566', (123, 126))	('anal', 'Disease', (273, 277))	('malignancies', 'Disease', 'MESH:D009369', (237, 249))	('HPV', 'Species', '10566', (225, 228))	('vaginal cancers', 'Disease', 'MESH:D014625', (290, 305))	('cancers', 'Phenotype', 'HP:0002664', (298, 305))	('aid in', 'Reg', (148, 154))	('malignancies', 'Disease', (237, 249))	('HPV E6', 'Var', (123, 129))	('vaginal cancers', 'Disease', (290, 305))	('cervical cancer', 'Disease', (181, 196))	('cervical cancer', 'Disease', 'MESH:D002583', (181, 196))	('HPV', 'Species', '10566', (88, 91))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('cancer', 'Phenotype', 'HP:0002664', (298, 304))
482570	29463131	In fact, in May of 2017, there was the first ever FDA approval of a tissue-agnostic therapy, pembrolizumab, for the treatment of solid tumors with mismatch repair deficiencies or that are microsatellite instability high, focusing on biomarkers expressed rather than tumor type.	('solid tumors', 'Disease', (129, 141))	('pembrolizumab', 'Chemical', 'MESH:C582435', (93, 106))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('solid tumors', 'Disease', 'MESH:D009369', (129, 141))	('tumor', 'Disease', 'MESH:D009369', (266, 271))	('tumor', 'Disease', (135, 140))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))	('tumor', 'Phenotype', 'HP:0002664', (266, 271))	('tumor', 'Disease', (266, 271))	('mismatch repair deficiencies', 'Var', (147, 175))	('microsatellite', 'Var', (188, 202))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
482593	29159261	Furthermore, the signal intensity of bone marrow in T1- and T2-WI on MRI was markedly lower than that of an age-matched healthy woman.	('woman', 'Species', '9606', (128, 133))	('T2-WI', 'Var', (60, 65))	('signal intensity', 'MPA', (17, 33))	('lower', 'NegReg', (86, 91))	('T1-', 'Var', (52, 55))
482596	29159261	18F-Fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) showed the elevated uptake of FDG in the left ovarian tumor and para-aortic and pelvic lymph nodes.	('FDG', 'Chemical', 'MESH:D019788', (24, 27))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('FDG', 'Chemical', 'MESH:D019788', (117, 120))	('ovarian tumor', 'Phenotype', 'HP:0100615', (133, 146))	('elevated', 'PosReg', (98, 106))	('FDG', 'Var', (117, 120))	('left ovarian tumor', 'Disease', (128, 146))	('uptake', 'MPA', (107, 113))	('left ovarian tumor', 'Disease', 'MESH:D010051', (128, 146))
482626	29159261	These characteristic findings of MRI and 18F-FDG-PET/CT suggested increased bone marrow activity and may be useful in the diagnosis of G-CSF-producing tumors.	('FDG', 'Chemical', 'MESH:D019788', (45, 48))	('increased', 'PosReg', (66, 75))	('increased bone marrow', 'Phenotype', 'HP:0005528', (66, 87))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumors', 'Disease', (151, 157))	('tumors', 'Disease', 'MESH:D009369', (151, 157))	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('G-CSF', 'Gene', '1440', (135, 140))	('MRI', 'Var', (33, 36))	('bone marrow activity', 'CPA', (76, 96))	('G-CSF', 'Gene', (135, 140))	('18F-FDG-PET/CT', 'Var', (41, 55))
482637	26949921	Gene fusions were associated with significant up regulation of 16 genes (including EGFR and ERBB4) and down regulation of four genes (PTPRT, ZNF750, DLG2, SLCO5A1).	('EGFR', 'Gene', '1956', (83, 87))	('SLCO5A1', 'Gene', '81796', (155, 162))	('DLG2', 'Gene', '1740', (149, 153))	('ZNF750', 'Gene', '79755', (141, 147))	('ERBB4', 'Gene', (92, 97))	('Gene fusions', 'Var', (0, 12))	('EGFR', 'Gene', (83, 87))	('PTPRT', 'Gene', (134, 139))	('up regulation', 'PosReg', (46, 59))	('down regulation', 'NegReg', (103, 118))	('PTPRT', 'Gene', '11122', (134, 139))	('ZNF750', 'Gene', (141, 147))	('SLCO5A1', 'Gene', (155, 162))	('DLG2', 'Gene', (149, 153))	('ERBB4', 'Gene', '2066', (92, 97))
482647	26949921	HPV-positive tumors harbor significantly fewer mutations per tumor than HPV-negative tumors and have a genetic profile distinct from tobacco exposure related tumors.	('tumors', 'Phenotype', 'HP:0002664', (158, 164))	('tumor', 'Disease', (13, 18))	('tumor', 'Disease', (85, 90))	('tobacco', 'Species', '4097', (133, 140))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('tumors', 'Disease', (158, 164))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('mutations', 'Var', (47, 56))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('tumors', 'Disease', (85, 91))	('tumors', 'Disease', (13, 19))	('tumors', 'Disease', 'MESH:D009369', (158, 164))	('HPV-positive tumors', 'Disease', (0, 19))	('tumors', 'Disease', 'MESH:D009369', (85, 91))	('tumor', 'Disease', (158, 163))	('fewer', 'NegReg', (41, 46))	('HPV', 'Species', '10566', (0, 3))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('HPV-positive tumors', 'Disease', 'MESH:D030361', (0, 19))	('HPV', 'Species', '10566', (72, 75))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('tumor', 'Disease', (61, 66))
482651	26949921	While gene fusions have traditionally been associated with hematologic malignancies, their role is starting to be recognized in solid tumors.	('gene fusions', 'Var', (6, 18))	('solid tumors', 'Disease', 'MESH:D009369', (128, 140))	('hematologic malignancies', 'Disease', (59, 83))	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('solid tumors', 'Disease', (128, 140))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('associated', 'Reg', (43, 53))	('hematologic malignancies', 'Disease', 'MESH:D019337', (59, 83))
482652	26949921	In particular, the advancement of sequencing technologies has improved our ability to identify gene fusions in heterogeneous solid tumors.	('solid tumors', 'Disease', 'MESH:D009369', (125, 137))	('improved', 'PosReg', (62, 70))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('solid tumors', 'Disease', (125, 137))	('gene fusions', 'Var', (95, 107))
482653	26949921	In the head and neck region, a recurring MYB-NFIB gene fusion has been identified in adenoid cystic carcinoma as a prognostic marker and potential therapeutic target.	('NFIB', 'Gene', '4781', (45, 49))	('adenoid cystic carcinoma', 'Disease', 'MESH:D003528', (85, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('adenoid cystic carcinoma', 'Disease', (85, 109))	('fusion', 'Var', (55, 61))	('MYB', 'Gene', '4602', (41, 44))	('NFIB', 'Gene', (45, 49))	('MYB', 'Gene', (41, 44))
482658	26949921	Beyond the FGFR3-TACC3 fusion, no other known gene fusions that involve oncogenes were identified, although EGFR and FGFR3 were noted to occur in fusions with non-recurrent partners.	('TACC3', 'Gene', '10460', (17, 22))	('FGFR3', 'Gene', '2261', (117, 122))	('fusion', 'Var', (23, 29))	('FGFR3', 'Gene', '2261', (11, 16))	('EGFR', 'Gene', '1956', (108, 112))	('EGFR', 'Gene', (108, 112))	('TACC3', 'Gene', (17, 22))	('FGFR3', 'Gene', (11, 16))	('FGFR3', 'Gene', (117, 122))
482689	26949921	About half of the gene fusions identified (51.4%) involved a non-coding region (denoted as "NA") at either the donor or acceptor end of the fusion, and 38.3% of fusions involved two unique genes.	('involved', 'Reg', (169, 177))	('donor', 'Species', '9606', (111, 116))	('involved', 'Reg', (50, 58))	('fusions', 'Var', (23, 30))
482694	26949921	Expression of these genes was compared between tumors harboring a fusion involving the gene of interest and normal tissue.	('tumors', 'Disease', (47, 53))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('fusion', 'Var', (66, 72))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))
482695	26949921	The median ratio of gene expression in tumors with fusions compared to normal tissue was 1.24.	('tumors', 'Disease', (39, 45))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('fusions', 'Var', (51, 58))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))
482699	26949921	In fusions associated with over-expression, gene expression was uniformly higher in tumors with a fusion compared to median expression of tumors without a fusion.	('gene expression', 'MPA', (44, 59))	('fusion', 'Var', (98, 104))	('higher', 'PosReg', (74, 80))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('over-expression', 'MPA', (27, 42))	('tumors', 'Disease', (138, 144))	('tumors', 'Disease', 'MESH:D009369', (138, 144))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('tumors', 'Disease', (84, 90))	('tumors', 'Disease', 'MESH:D009369', (84, 90))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
482700	26949921	Similarly, in fusions associated with decreased gene expression, expression was 5-29 times lower in tumors with a fusion compared to the median expression of tumors without a fusion.	('lower', 'NegReg', (91, 96))	('tumors', 'Disease', (158, 164))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('decreased', 'NegReg', (38, 47))	('tumors', 'Phenotype', 'HP:0002664', (158, 164))	('tumors', 'Disease', 'MESH:D009369', (158, 164))	('tumors', 'Disease', (100, 106))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('expression', 'MPA', (65, 75))	('fusion', 'Var', (114, 120))	('gene expression', 'MPA', (48, 63))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))
482703	26949921	The TFG-GPR128 fusion was associated with increased expression of GPR128 (ratio of gene expression in tumor with fusion compared to median of normal: 580.5 in TCGA vs. 1004.1 in JHU cohort).	('fusion', 'Var', (15, 21))	('increased', 'PosReg', (42, 51))	('TFG', 'Gene', '10342', (4, 7))	('TFG', 'Gene', (4, 7))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('expression', 'MPA', (52, 62))	('GPR128', 'Gene', (66, 72))	('GPR128', 'Gene', '84873', (66, 72))	('GPR128', 'Gene', (8, 14))	('GPR128', 'Gene', '84873', (8, 14))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))
482706	26949921	However, the tumor with the KRT14-KRT16 fusion in the JHU cohort that showed increased expression of KRT14 also harbored an APAF1-KRT14 fusion, which was not identified in the TCGA cohort.	('fusion', 'Var', (40, 46))	('tumor', 'Disease', (13, 18))	('KRT16', 'Gene', (34, 39))	('APAF1', 'Gene', (124, 129))	('KRT16', 'Gene', '3868', (34, 39))	('KRT14', 'Gene', '3861', (130, 135))	('KRT14', 'Gene', (101, 106))	('APAF1', 'Gene', '317', (124, 129))	('KRT14', 'Gene', '3861', (28, 33))	('expression', 'MPA', (87, 97))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('KRT14', 'Gene', (130, 135))	('increased', 'PosReg', (77, 86))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('KRT14', 'Gene', (28, 33))	('KRT14', 'Gene', '3861', (101, 106))
482711	26949921	A similar comparison was performed on the four genes with down regulation in association with a fusion, and three genes (75%) showed statistically significant down regulation in tumors (Fig.	('down regulation', 'NegReg', (159, 174))	('tumors', 'Disease', (178, 184))	('tumors', 'Disease', 'MESH:D009369', (178, 184))	('tumors', 'Phenotype', 'HP:0002664', (178, 184))	('fusion', 'Var', (96, 102))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('down regulation', 'NegReg', (58, 73))
482712	26949921	Similarly, tumors with a fusion in a down regulated gene had the lowest gene expression of the cohort in 75% of the genes.	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('tumors', 'Phenotype', 'HP:0002664', (11, 17))	('fusion', 'Var', (25, 31))	('tumors', 'Disease', (11, 17))	('tumors', 'Disease', 'MESH:D009369', (11, 17))	('lowest', 'NegReg', (65, 71))	('gene expression', 'MPA', (72, 87))	('down regulated', 'NegReg', (37, 51))
482720	26949921	The TFG-GPR128 gene fusion was identified between the third exon of TFG and the second exon of GPR128, also reversing the order of the genes.	('TFG', 'Gene', '10342', (4, 7))	('TFG', 'Gene', (68, 71))	('fusion', 'Var', (20, 26))	('TFG', 'Gene', (4, 7))	('GPR128', 'Gene', '84873', (95, 101))	('GPR128', 'Gene', (8, 14))	('GPR128', 'Gene', '84873', (8, 14))	('TFG', 'Gene', '10342', (68, 71))	('GPR128', 'Gene', (95, 101))
482721	26949921	Lastly, the RALY-PTPRT gene fusion connected the first exon of RALY to the 7th intron of PTPRT, spanning a distance of 8 Mb across chromosome 20.	('RALY', 'Gene', (63, 67))	('PTPRT', 'Gene', (89, 94))	('fusion', 'Var', (28, 34))	('PTPRT', 'Gene', '11122', (89, 94))	('RALY', 'Gene', '22913', (63, 67))	('PTPRT', 'Gene', '11122', (17, 22))	('PTPRT', 'Gene', (17, 22))	('RALY', 'Gene', '22913', (12, 16))	('RALY', 'Gene', (12, 16))
482724	26949921	Gene fusions that result in activation of relevant oncogenes, such as those in protein kinases which were recently identified in several cancer types through TCGA, could represent potential therapeutic targets, as exemplified by the use of Imantinib to target the BCR-ABL1 fusion.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('BCR-ABL1', 'Gene', (264, 272))	('BCR-ABL1', 'Gene', '613;25', (264, 272))	('fusions', 'Var', (5, 12))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('activation', 'PosReg', (28, 38))	('cancer', 'Disease', (137, 143))	('Imantinib', 'Chemical', '-', (240, 249))
482725	26949921	For instance, the FGFR3-TACC3 gene fusion has been identified in multiple cancer types and has been shown to display oncogenic activity in in vivo models.	('oncogenic activity', 'CPA', (117, 135))	('FGFR3', 'Gene', '2261', (18, 23))	('TACC3', 'Gene', '10460', (24, 29))	('identified', 'Reg', (51, 61))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('TACC3', 'Gene', (24, 29))	('FGFR3', 'Gene', (18, 23))	('cancer', 'Disease', (74, 80))	('fusion', 'Var', (35, 41))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
482726	26949921	Additionally given that gene fusions are unique to tumors, they also have the potential to be utilized as biomarkers for noninvasive diagnosis or evaluation of prognosis.	('gene fusions', 'Var', (24, 36))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumors', 'Disease', (51, 57))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('tumors', 'Disease', 'MESH:D009369', (51, 57))
482732	26949921	These putative fusions could potentially represent undocumented splice variants, although 25 of these fusions were intra-chromasomal, 10 involved a strand switch, and 20 spanned a distance >1,000,000 bases.	('intra-chromasomal', 'Disease', 'MESH:D057072', (115, 132))	('intra-chromasomal', 'Disease', (115, 132))	('involved', 'Reg', (137, 145))	('fusions', 'Var', (102, 109))	('strand switch', 'MPA', (148, 161))
482737	26949921	These gene expression changes were augmented in the presence of a fusion, as tumors with a fusion had the highest level of gene expression among the tumor cohort in 81% of up-regulated genes and lowest expression in 75% of down-regulated genes.	('tumors', 'Disease', (77, 83))	('tumors', 'Disease', 'MESH:D009369', (77, 83))	('fusion', 'Var', (91, 97))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('up-regulated', 'PosReg', (172, 184))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Disease', (149, 154))	('level', 'MPA', (114, 119))	('tumor', 'Disease', (77, 82))
482738	26949921	The fusion may represent one mechanism of gene activation or suppression, where other tumors without a fusion may rely on other mechanisms to achieve gene expression changes, including transcriptional, genomic, and epigenetic alterations.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('tumors', 'Disease', (86, 92))	('epigenetic alterations', 'Var', (215, 237))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('genomic', 'Var', (202, 209))
482739	26949921	For instance, the gene PTPRT was seen to be down regulated in association with a gene fusion, but PTPRT was also significantly down regulated in tumors without a gene fusion.	('down regulated', 'NegReg', (44, 58))	('PTPRT', 'Gene', '11122', (98, 103))	('PTPRT', 'Gene', (98, 103))	('down regulated', 'NegReg', (127, 141))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumors', 'Disease', (145, 151))	('PTPRT', 'Gene', '11122', (23, 28))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('tumors', 'Disease', 'MESH:D009369', (145, 151))	('gene fusion', 'Var', (81, 92))	('PTPRT', 'Gene', (23, 28))
482741	26949921	Some particularly relevant genes appear in the list of genes that are affected by the presence of a gene fusion including EGFR, ERBB4, ZNF750 and PTPRT.	('ERBB4', 'Gene', (128, 133))	('ZNF750', 'Gene', '79755', (135, 141))	('presence', 'Var', (86, 94))	('ZNF750', 'Gene', (135, 141))	('ERBB4', 'Gene', '2066', (128, 133))	('PTPRT', 'Gene', '11122', (146, 151))	('PTPRT', 'Gene', (146, 151))	('EGFR', 'Gene', '1956', (122, 126))	('EGFR', 'Gene', (122, 126))
482745	26949921	ERBB4, or HER4, is another member of the epidermal growth factor tyrosine kinase receptor family, and the related ERBB2 is mutated in 4% of HNSCC tumors.	('ERBB4', 'Gene', '2066', (0, 5))	('tumors', 'Phenotype', 'HP:0002664', (146, 152))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('HER4', 'Gene', (10, 14))	('ERBB4', 'Gene', (0, 5))	('HNSCC tumors', 'Disease', (140, 152))	('HER4', 'Gene', '2066', (10, 14))	('HNSCC tumors', 'Disease', 'MESH:D000077195', (140, 152))	('mutated', 'Var', (123, 130))	('ERBB2', 'Gene', '2064', (114, 119))	('ERBB2', 'Gene', (114, 119))
482746	26949921	ZNF750 regulates late epidermal differentiation by inhibiting progenitor genes, and mutations were identified in 4% of the TCGA HNSCC cohort as well as in esophageal SCC.	('SCC', 'Gene', (130, 133))	('progenitor', 'CPA', (62, 72))	('ZNF750', 'Gene', (0, 6))	('SCC', 'Gene', '6317', (130, 133))	('SCC', 'Gene', (166, 169))	('mutations', 'Var', (84, 93))	('regulates', 'Reg', (7, 16))	('TCGA', 'Gene', (123, 127))	('inhibiting', 'NegReg', (51, 61))	('SCC', 'Gene', '6317', (166, 169))	('ZNF750', 'Gene', '79755', (0, 6))
482747	26949921	PTPRT is a negative regulator of STAT3 signaling, and inhibition of this gene has reported in HNSCC tumors through promoter hypermethylation in HNSCC tumors as well as inactivating mutations in both HNSCC and colorectal tumors.	('tumors', 'Phenotype', 'HP:0002664', (150, 156))	('STAT3', 'Gene', '6774', (33, 38))	('PTPRT', 'Gene', '11122', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('SCC', 'Gene', '6317', (201, 204))	('SCC', 'Gene', '6317', (146, 149))	('tumors', 'Phenotype', 'HP:0002664', (220, 226))	('SCC', 'Gene', (201, 204))	('SCC', 'Gene', (146, 149))	('inhibition', 'NegReg', (54, 64))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('SCC', 'Gene', '6317', (96, 99))	('HNSCC tumors', 'Disease', 'MESH:D000077195', (144, 156))	('inactivating mutations', 'Var', (168, 190))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('colorectal tumors', 'Disease', (209, 226))	('SCC', 'Gene', (96, 99))	('PTPRT', 'Gene', (0, 5))	('HNSCC tumors', 'Disease', (144, 156))	('HNSCC tumors', 'Disease', 'MESH:D000077195', (94, 106))	('STAT3', 'Gene', (33, 38))	('colorectal tumors', 'Disease', 'MESH:D015179', (209, 226))	('HNSCC tumors', 'Disease', (94, 106))
482751	26949921	This is supporting evidence that gene fusions in HPV-positive OPSCC may be one mechanism by which functionally relevant gene targets are altered.	('HPV', 'Species', '10566', (49, 52))	('SCC', 'Gene', '6317', (64, 67))	('gene fusions', 'Var', (33, 45))	('altered', 'Reg', (137, 144))	('SCC', 'Gene', (64, 67))
482782	27011654	On the left side, power was MRC grade 2/5 at shoulder joint, 2/5 at elbow joint, 3/5 at wrist extension, 4/5 at wrist flexion and hand grip weakness was noted.	('hand grip weakness', 'Phenotype', 'HP:0030237', (130, 148))	('wrist flexion', 'Phenotype', 'HP:0001239', (112, 125))	('MRC grade', 'Var', (28, 37))	('hand grip weakness', 'Disease', (130, 148))	('hand grip weakness', 'Disease', 'MESH:D018908', (130, 148))	('MRC', 'CellLine', 'CVCL:0440', (28, 31))	('hand grip', 'Phenotype', 'HP:0001188', (130, 139))
482837	27011654	Recently myeloradiculopathy with similar clinical presentation of bi-brachial weakness was reported in association with testicular malignancy and anti-Ma 2 antibody.	('anti-Ma', 'Var', (146, 153))	('antibody', 'Var', (156, 164))	('malignancy', 'Disease', 'MESH:D009369', (131, 141))	('bi-brachial weakness', 'Disease', (66, 86))	('malignancy', 'Disease', (131, 141))	('testicular malignancy', 'Phenotype', 'HP:0010788', (120, 141))	('myeloradiculopathy', 'Disease', 'MESH:D020818', (9, 27))	('bi-brachial weakness', 'Disease', 'MESH:D018908', (66, 86))	('myeloradiculopathy', 'Disease', (9, 27))
482858	24194897	Alterations in miRNA expression has been implicated in carcinogenesis and metastasis.	('Alterations', 'Var', (0, 11))	('metastasis', 'CPA', (74, 84))	('miRNA expression', 'Protein', (15, 31))	('implicated', 'Reg', (41, 51))	('carcinogenesis', 'Disease', 'MESH:D063646', (55, 69))	('carcinogenesis', 'Disease', (55, 69))
482891	24194897	Site-directed mutagenesis of the miR-129-5p target site in the APC-3'-UTR was used as a negative control and termed Mut-3'-UTR.	('miR-129-5p', 'Gene', '100302178', (33, 43))	('APC-3', 'Gene', '996', (63, 68))	('mutagenesis', 'Var', (14, 25))	('APC', 'Phenotype', 'HP:0005227', (63, 66))	('miR-129-5p', 'Gene', (33, 43))	('APC-3', 'Gene', (63, 68))	('S', 'Chemical', 'MESH:D013455', (0, 1))
482903	24194897	Seventy-two hours after transfection with lentivirus containing ASO sequences against miR-129-5p, 2x104 LSSC cells were resuspended in 200 microL of serum-free medium and plated in the upper compartment of the Boyden chambers.	('S', 'Chemical', 'MESH:D013455', (65, 66))	('ASO', 'Var', (64, 67))	('ASO', 'Chemical', 'MESH:D016376', (64, 67))	('S', 'Chemical', 'MESH:D013455', (105, 106))	('S', 'Chemical', 'MESH:D013455', (106, 107))	('miR-129-5p', 'Gene', '100302178', (86, 96))	('miR-129-5p', 'Gene', (86, 96))	('S', 'Chemical', 'MESH:D013455', (0, 1))
482952	24194897	Transfecting Hep-2 cells with the GFP-lentivirus caused no significant changes to the cell cycle progression at 72 h post-transfection compared to untransfected Hep-2 cells (P>0.05).	('cell cycle progression', 'CPA', (86, 108))	('Hep-2', 'CellLine', 'CVCL:1906', (13, 18))	('GFP-lentivirus', 'Var', (34, 48))	('Hep-2', 'CellLine', 'CVCL:1906', (161, 166))
482957	24194897	Furthermore, in the xenograft sections from the nude mice, morphological findings from transmission electron microscopy show typical signs of apoptosis such as nuclear condensation and fragmentation, marginalization of chromatin, cell shrinkage, and formation of cytoplasmic vacuoles in tumours treated with ASO-miR129-5p lentivirus (Fig.	('marginalization', 'CPA', (200, 215))	('fragmentation', 'CPA', (185, 198))	('tumours', 'Phenotype', 'HP:0002664', (287, 294))	('ASO-miR129-5p', 'Var', (308, 321))	('tumours', 'Disease', 'MESH:D009369', (287, 294))	('tumour', 'Phenotype', 'HP:0002664', (287, 293))	('5p', 'Chemical', '-', (319, 321))	('tumours', 'Disease', (287, 294))	('apoptosis', 'CPA', (142, 151))	('nuclear condensation', 'CPA', (160, 180))	('ASO', 'Chemical', 'MESH:D016376', (308, 311))	('p lentivirus', 'Species', '11648', (320, 332))	('cell shrinkage', 'CPA', (230, 244))	('nude mice', 'Species', '10090', (48, 57))
482958	24194897	No obvious apoptosis was observed in the tumours from the GFP-lentivirus group or the untreated group.	('tumour', 'Phenotype', 'HP:0002664', (41, 47))	('tumours', 'Phenotype', 'HP:0002664', (41, 48))	('GFP-lentivirus', 'Var', (58, 72))	('tumours', 'Disease', 'MESH:D009369', (41, 48))	('tumours', 'Disease', (41, 48))
482968	24194897	Additionally, miR-129-5p transfection did not reduce the luciferase activity of the reporter construct transfected with mutant 3'UTR of APC.	('APC', 'Phenotype', 'HP:0005227', (136, 139))	('APC', 'Gene', (136, 139))	('miR-129-5p', 'Gene', (14, 24))	('luciferase', 'Enzyme', (57, 67))	('APC', 'Gene', '324', (136, 139))	('activity', 'MPA', (68, 76))	('mutant', 'Var', (120, 126))	('miR-129-5p', 'Gene', '100302178', (14, 24))
482970	24194897	Moreover, negative control (NC) miRNA did not affect luciferase activity of reporters containing either the 3'UTR of APC or the mutant APC construct (Fig.5 B, C).	('APC', 'Gene', '324', (135, 138))	('luciferase', 'Enzyme', (53, 63))	('APC', 'Phenotype', 'HP:0005227', (117, 120))	('mutant', 'Var', (128, 134))	('activity', 'MPA', (64, 72))	('APC', 'Gene', (117, 120))	('APC', 'Phenotype', 'HP:0005227', (135, 138))	('APC', 'Gene', (135, 138))	('APC', 'Gene', '324', (117, 120))
482973	24194897	Down-regulation of miR-129-5p in Hep-2 cells transfected with the ASO-miR129-5p lentivirus led to higher levels of APC expression compared to cells transfected with the GFP-lentivirus or untransfected cells (P<0.05) (Fig.	('Hep-2', 'CellLine', 'CVCL:1906', (33, 38))	('p lentivirus', 'Species', '11648', (78, 90))	('ASO', 'Chemical', 'MESH:D016376', (66, 69))	('APC', 'Gene', '324', (115, 118))	('5p', 'Chemical', '-', (77, 79))	('levels', 'MPA', (105, 111))	('Down-regulation', 'NegReg', (0, 15))	('higher', 'PosReg', (98, 104))	('miR-129-5p', 'Gene', (19, 29))	('miR-129-5p', 'Gene', '100302178', (19, 29))	('APC', 'Phenotype', 'HP:0005227', (115, 118))	('APC', 'Gene', (115, 118))	('5p', 'Chemical', '-', (27, 29))	('ASO-miR129-5p', 'Var', (66, 79))
482975	24194897	Immunohistochemical staining showed greater levels of cytoplasmic APC in cells treated with the ASO-miR129-5p-lentivirus while cells in GFP-lentivirus group or untransfected group showed only weak expression (Fig.	('5p', 'Chemical', '-', (107, 109))	('APC', 'Phenotype', 'HP:0005227', (66, 69))	('APC', 'Gene', (66, 69))	('APC', 'Gene', '324', (66, 69))	('levels', 'MPA', (44, 50))	('p-lentivirus', 'Species', '11648', (108, 120))	('greater', 'PosReg', (36, 43))	('ASO', 'Chemical', 'MESH:D016376', (96, 99))	('ASO-miR129-5p-lentivirus', 'Var', (96, 120))
482990	24194897	It has been reported that miR-129 was methylated in more than 95% of esophageal squamous cell carcinoma (ESCC).	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (69, 103))	('miR-129', 'Gene', (26, 33))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (80, 103))	('methylated', 'Var', (38, 48))	('esophageal squamous cell carcinoma', 'Disease', (69, 103))	('S', 'Chemical', 'MESH:D013455', (106, 107))	('miR-129', 'Gene', '387148', (26, 33))
482991	24194897	Down-regulation of miR-129 through methylation was correlated with upregulation of the SRY-related high-mobility group box 4 (SOX4) in gastric cancers.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('miR-129', 'Gene', (19, 26))	('gastric cancers', 'Phenotype', 'HP:0012126', (135, 150))	('SRY-related high-mobility group box 4', 'Gene', '6659', (87, 124))	('miR-129', 'Gene', '387148', (19, 26))	('Down-regulation', 'NegReg', (0, 15))	('upregulation', 'PosReg', (67, 79))	('cancers', 'Phenotype', 'HP:0002664', (143, 150))	('methylation', 'Var', (35, 46))	('SOX4', 'Gene', (126, 130))	('SOX4', 'Gene', '6659', (126, 130))	('SRY-related high-mobility group box 4', 'Gene', (87, 124))	('gastric cancers', 'Disease', (135, 150))	('gastric cancers', 'Disease', 'MESH:D013274', (135, 150))
483003	24194897	Liu et al demonstrated that down-regulation of VCP by microRNA-129-5p could suppress the genesis and progression of hepatocellularcarcinoma.	('down-regulation', 'NegReg', (28, 43))	('hepatocellularcarcinoma', 'Disease', 'None', (116, 139))	('microRNA-129-5p', 'Var', (54, 69))	('suppress', 'NegReg', (76, 84))	('5p', 'Chemical', '-', (67, 69))	('VCP', 'Gene', (47, 50))	('VCP', 'Gene', '7415', (47, 50))	('genesis', 'CPA', (89, 96))	('hepatocellularcarcinoma', 'Disease', (116, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('progression', 'CPA', (101, 112))
483004	24194897	Epigenetic repression of microRNA-129-2 led to overexpression of SOX4 oncogene in endometrial cancer.	('endometrial cancer', 'Phenotype', 'HP:0012114', (82, 100))	('microRNA-129-2', 'Gene', (25, 39))	('Epigenetic repression', 'Var', (0, 21))	('overexpression', 'PosReg', (47, 61))	('endometrial cancer', 'Disease', 'MESH:D016889', (82, 100))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('endometrial cancer', 'Disease', (82, 100))	('SOX4', 'Gene', (65, 69))	('SOX4', 'Gene', '6659', (65, 69))
483034	33537094	ILT4 inhibition prevents TAM- and dysfunctional T cell-mediated immunosuppression and enhances the efficacy of anti-PD-L1 therapy in NSCLC with EGFR activation Rationale: Immune checkpoint inhibitors (ICIs) against the PD-1/PD-L1 pathway showed limited success in non-small cell lung cancer (NSCLC) patients, especially in those with activating epidermal growth factor receptor (EGFR) mutations.	('dysfunctional T', 'Disease', 'MESH:D009461', (34, 49))	('PD-1', 'Gene', (219, 223))	('NSCLC', 'Disease', 'MESH:D002289', (292, 297))	('ILT4', 'Gene', (0, 4))	('activating', 'PosReg', (334, 344))	('NSCLC', 'Disease', (133, 138))	('patients', 'Species', '9606', (299, 307))	('PD-L1', 'Gene', (224, 229))	('C', 'Chemical', 'MESH:D002244', (296, 297))	('lung cancer', 'Disease', 'MESH:D008175', (279, 290))	('C', 'Chemical', 'MESH:D002244', (202, 203))	('PD-L1', 'Gene', '29126', (224, 229))	('NSCLC', 'Phenotype', 'HP:0030358', (133, 138))	('NSCLC', 'Disease', (292, 297))	('dysfunctional T', 'Disease', (34, 49))	('EGFR', 'Gene', '1956', (379, 383))	('EGFR', 'Gene', '1956', (144, 148))	('lung cancer', 'Phenotype', 'HP:0100526', (279, 290))	('ILT4', 'Gene', '10288', (0, 4))	('C', 'Chemical', 'MESH:D002244', (137, 138))	('NSCLC', 'Phenotype', 'HP:0030358', (292, 297))	('PD-1', 'Gene', '6622', (219, 223))	('EGFR', 'Gene', (144, 148))	('C', 'Chemical', 'MESH:D002244', (135, 136))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (264, 290))	('PD-L1', 'Gene', (116, 121))	('TAM', 'Chemical', '-', (25, 28))	('C', 'Chemical', 'MESH:D002244', (294, 295))	('epidermal growth factor receptor', 'Gene', (345, 377))	('PD-L1', 'Gene', '29126', (116, 121))	('cancer', 'Phenotype', 'HP:0002664', (284, 290))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (268, 290))	('epidermal growth factor receptor', 'Gene', '1956', (345, 377))	('lung cancer', 'Disease', (279, 290))	('EGFR', 'Gene', (379, 383))	('NSCLC', 'Disease', 'MESH:D002289', (133, 138))	('mutations', 'Var', (385, 394))
483042	33537094	Tumor immunotherapy models targeting at paired Ig-like receptor B (PIR-B, an ortholog of ILT4 in mouse)/ILT4 and/or PD-L1 were established in C57BL/6 mice inoculated with stable EGFR- overexpressing Lewis lung carcinoma (LLC) cells and in humanized NSG mice inoculated with EGFR mutant, gefitinib-resistant PC9 (PC9-GR) or EGFR-overexpressing wild type H1299 cells.	('carcinoma', 'Phenotype', 'HP:0030731', (210, 219))	('mice', 'Species', '10090', (150, 154))	('C', 'Chemical', 'MESH:D002244', (313, 314))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('Lewis lung carcinoma', 'Disease', (199, 219))	('PC9', 'CellLine', 'CVCL:B260', (312, 315))	('ILT4', 'Gene', (89, 93))	('human', 'Species', '9606', (239, 244))	('ILT4', 'Gene', '10288', (104, 108))	('Lewis lung carcinoma', 'Disease', 'MESH:D018827', (199, 219))	('mutant', 'Var', (279, 285))	('ILT4', 'Gene', '10288', (89, 93))	('C', 'Chemical', 'MESH:D002244', (142, 143))	('C', 'Chemical', 'MESH:D002244', (223, 224))	('C', 'Chemical', 'MESH:D002244', (308, 309))	('H1299', 'CellLine', 'CVCL:0060', (353, 358))	('PC9', 'CellLine', 'CVCL:B260', (307, 310))	('PC9-GR', 'CellLine', 'CVCL:S706', (312, 318))	('paired Ig-like receptor B', 'Gene', (40, 65))	('ILT4', 'Gene', (104, 108))	('mouse', 'Species', '10090', (97, 102))	('paired Ig-like receptor B', 'Gene', '18733', (40, 65))	('gefitinib', 'Chemical', 'MESH:D000077156', (287, 296))	('EGFR', 'Gene', (274, 278))	('mice', 'Species', '10090', (253, 257))
483048	33537094	Overexpressed ILT4 in EGFR-activated tumor cells induced TAM recruitment and M2-like polarization, which impaired T cell function.	('Overexpressed', 'Var', (0, 13))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('impaired T cell function', 'Phenotype', 'HP:0005435', (105, 129))	('TAM recruitment', 'MPA', (57, 72))	('impaired T', 'Disease', (105, 115))	('impaired T', 'Disease', 'MESH:D060825', (105, 115))	('TAM', 'Chemical', '-', (57, 60))	('ILT4', 'Gene', (14, 18))	('M2-like polarization', 'CPA', (77, 97))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('induced', 'Reg', (49, 56))	('ILT4', 'Gene', '10288', (14, 18))
483050	33537094	In EGFR-activated cell lines in vitro and in wild-type EGFR-activated C57BL/6 and humanized NSG immunotherapy models in vivo, either ILT4 (PIR-B) or PD-L1 inhibition enhanced anti-tumor immunity and suppressed tumor progression by counteracting TAM- and dysfunctional T cell- induced immuno-suppressive TME; the combined inhibition of both molecules showed the most dramatic tumor retraction.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('TAM', 'Chemical', '-', (245, 248))	('suppressed', 'NegReg', (199, 209))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('ILT4', 'Gene', (133, 137))	('tumor', 'Disease', (210, 215))	('tumor', 'Disease', (375, 380))	('enhanced', 'PosReg', (166, 174))	('tumor', 'Disease', 'MESH:D009369', (210, 215))	('PD-L1', 'Gene', (149, 154))	('tumor', 'Disease', 'MESH:D009369', (375, 380))	('ILT4', 'Gene', '10288', (133, 137))	('dysfunctional T', 'Disease', 'MESH:D009461', (254, 269))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('tumor', 'Phenotype', 'HP:0002664', (375, 380))	('C', 'Chemical', 'MESH:D002244', (70, 71))	('tumor', 'Disease', (180, 185))	('dysfunctional T', 'Disease', (254, 269))	('inhibition', 'Var', (155, 165))	('human', 'Species', '9606', (82, 87))
483051	33537094	Surprisingly, in EGFR mutant, TKI resistant humanized NSG immunotherapy model, ILT4 inhibition alone rather than in combination with a PD-L1 inhibitor suppressed tumor growth and immune evasion.	('human', 'Species', '9606', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('inhibition', 'NegReg', (84, 94))	('immune evasion', 'MPA', (179, 193))	('tumor', 'Disease', (162, 167))	('ILT4', 'Gene', (79, 83))	('suppressed', 'NegReg', (151, 161))	('mutant', 'Var', (22, 28))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('ILT4', 'Gene', '10288', (79, 83))	('EGFR', 'Gene', (17, 21))
483054	33537094	Furthermore, ILT4 inhibition enhanced the efficacy of PD-L1 inhibitor in EGFR wild-type but not in EGFR mutant NSCLC.	('ILT4', 'Gene', (13, 17))	('NSCLC', 'Disease', (111, 116))	('PD-L1 inhibitor', 'Protein', (54, 69))	('NSCLC', 'Disease', 'MESH:D002289', (111, 116))	('ILT4', 'Gene', '10288', (13, 17))	('NSCLC', 'Phenotype', 'HP:0030358', (111, 116))	('inhibition', 'Var', (18, 28))	('efficacy', 'MPA', (42, 50))	('enhanced', 'PosReg', (29, 37))
483082	33537094	ILT4 inhibition prevented the immunosuppressive TME and tumor growth of EGFR-activated NSCLC both in vitro and in vivo.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('NSCLC', 'Disease', (87, 92))	('inhibition', 'Var', (5, 15))	('NSCLC', 'Disease', 'MESH:D002289', (87, 92))	('tumor', 'Disease', (56, 61))	('immunosuppressive TME', 'MPA', (30, 51))	('ILT4', 'Gene', (0, 4))	('ILT4', 'Gene', '10288', (0, 4))	('NSCLC', 'Phenotype', 'HP:0030358', (87, 92))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('prevented', 'NegReg', (16, 25))
483083	33537094	Furthermore, ILT4 blockade displayed synergy with the PD-L1 inhibitor in EGFR wild-type rather than EGFR mutant NSCLC in humanized mouse immunotherapy models.	('ILT4', 'Gene', (13, 17))	('NSCLC', 'Phenotype', 'HP:0030358', (112, 117))	('mouse', 'Species', '10090', (131, 136))	('EGFR', 'Gene', (73, 77))	('human', 'Species', '9606', (121, 126))	('ILT4', 'Gene', '10288', (13, 17))	('NSCLC', 'Disease', (112, 117))	('mutant', 'Var', (105, 111))	('NSCLC', 'Disease', 'MESH:D002289', (112, 117))
483086	33537094	Of the 80 samples, 28 were squamous cell carcinoma, and 52 were adenocarcinoma in which 38 harbored EGFR sensitizing mutations and 14 were EGFR wild-type.	('mutations', 'Var', (117, 126))	('squamous cell carcinoma', 'Disease', (27, 50))	('carcinoma', 'Phenotype', 'HP:0030731', (41, 50))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (27, 50))	('adenocarcinoma', 'Disease', (64, 78))	('EGFR', 'Gene', (100, 104))	('adenocarcinoma', 'Disease', 'MESH:D000230', (64, 78))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (27, 50))
483090	33537094	EGFR genotypes of NSCLC cell lines were as follows: PC9-exon 19 deletion, HCC827- exon 19 deletion, H1975-L858R and T790M mutations, A549 and H1299-EGFR wild-type.	('H1299', 'CellLine', 'CVCL:0060', (142, 147))	('deletion', 'Var', (90, 98))	('PC9', 'CellLine', 'CVCL:B260', (52, 55))	('NSCLC', 'Disease', (18, 23))	('H1975', 'CellLine', 'CVCL:1511', (100, 105))	('HCC827-', 'Gene', (74, 81))	('L858R', 'Mutation', 'rs121434568', (106, 111))	('NSCLC', 'Disease', 'MESH:D002289', (18, 23))	('T790M', 'Mutation', 'rs121434569', (116, 121))	('H1975-L858R', 'Var', (100, 111))	('PC9-exon', 'Gene', (52, 60))	('NSCLC', 'Phenotype', 'HP:0030358', (18, 23))	('T790M mutations', 'Var', (116, 131))	('A549', 'CellLine', 'CVCL:0023', (133, 137))	('HCC827', 'CellLine', 'CVCL:2063', (74, 80))
483102	33537094	For induction of TAMs, macrophages were seeded in 12-well plates and stimulated with 1ml mixture of CM and FBS-containing medium (1:1) for 24 h. Human naive T cells were first activated using anti-human CD3 (Biolegend; Cat No.317326) pre-coated 6-well plates and then cultured with RPMI-1640 containing 10% FBS, 1 mug/mL anti-human CD28 (Biolegend; Cat No.302914) and 100 IU/mL recombinant human IL-2 (Pepro Tech; Cat No.2000250).	('C', 'Chemical', 'MESH:D002244', (100, 101))	('CD3', 'Gene', (203, 206))	('IL-2', 'Gene', '3558', (396, 400))	('CD3', 'Gene', '28134', (203, 206))	('human', 'Species', '9606', (326, 331))	('C', 'Chemical', 'MESH:D002244', (414, 415))	('human', 'Species', '9606', (390, 395))	('CD28', 'Gene', (332, 336))	('IL-2', 'Gene', (396, 400))	('C', 'Chemical', 'MESH:D002244', (332, 333))	('human', 'Species', '9606', (197, 202))	('C', 'Chemical', 'MESH:D002244', (349, 350))	('TAMs', 'Chemical', '-', (17, 21))	('Human', 'Species', '9606', (145, 150))	('RPMI-1640', 'Chemical', '-', (282, 291))	('CD28', 'Gene', '940', (332, 336))	('C', 'Chemical', 'MESH:D002244', (219, 220))	('anti-human', 'Var', (321, 331))	('C', 'Chemical', 'MESH:D002244', (203, 204))
483125	33537094	HY-12031A), AKT1/2/3 inhibitor MK2206 (MCE; Cat No.	('AKT1/2/3', 'Gene', '207;208;10000', (12, 20))	('MK2206', 'Chemical', 'MESH:C548887', (31, 37))	('HY-12031A', 'Var', (0, 9))	('AKT1/2/3', 'Gene', (12, 20))	('C', 'Chemical', 'MESH:D002244', (40, 41))	('C', 'Chemical', 'MESH:D002244', (44, 45))
483143	33537094	Tumor cell lines upon EGFR overexpression/knockdown or EGF/TKI treatment were seeded on a chamber slide and fixed with 4% paraformaldehyde for 15 min.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('overexpression/knockdown', 'Var', (27, 51))	('EGF', 'Gene', '1950', (22, 25))	('paraformaldehyde', 'Chemical', 'MESH:C003043', (122, 138))	('EGF', 'Gene', (55, 58))	('overexpression/knockdown', 'PosReg', (27, 51))	('EGF', 'Gene', '1950', (55, 58))	('EGF', 'Gene', (22, 25))
483194	33537094	NSG mice were used to determine the efficacy of combined ILT4 and PD-L1 blockade in EGFR wild-type or mutant NSCLC.	('mutant', 'Var', (102, 108))	('NSCLC', 'Disease', 'MESH:D002289', (109, 114))	('ILT4', 'Gene', (57, 61))	('mice', 'Species', '10090', (4, 8))	('NSCLC', 'Phenotype', 'HP:0030358', (109, 114))	('ILT4', 'Gene', '10288', (57, 61))	('PD-L1 blockade', 'Gene', (66, 80))	('NSCLC', 'Disease', (109, 114))
483204	33537094	To explore whether ILT4 was upregulated by EGFR activation, we retrospectively analyzed ILT4 expression differences in EGFR wild-type and mutant tumor tissues from 80 NSCLC patients.	('ILT4', 'Gene', (19, 23))	('NSCLC', 'Disease', 'MESH:D002289', (167, 172))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('ILT4', 'Gene', '10288', (19, 23))	('patients', 'Species', '9606', (173, 181))	('NSCLC', 'Phenotype', 'HP:0030358', (167, 172))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('mutant', 'Var', (138, 144))	('ILT4', 'Gene', '10288', (88, 92))	('tumor', 'Disease', (145, 150))	('NSCLC', 'Disease', (167, 172))	('ILT4', 'Gene', (88, 92))
483206	33537094	Considering that EGFR can be activated in a ligand-dependent or -independent (i.e., activating EGFR mutation) manner in vivo, yielding phosphorylated EGFR (pEGFR), we determined the correlation of ILT4 expression with EGFR phosphorylation.	('ILT4', 'Gene', (197, 201))	('ILT4', 'Gene', '10288', (197, 201))	('mutation', 'Var', (100, 108))	('activating', 'PosReg', (84, 94))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('EGFR', 'Gene', (95, 99))
483207	33537094	We observed that in most NSCLC tissues (Figure 1A) and tumor cell lines (Figure S1B), high ILT4 expression was accompanied by increased pEGFR levels.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('ILT4', 'Gene', (91, 95))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('NSCLC', 'Disease', (25, 30))	('expression', 'MPA', (96, 106))	('tumor', 'Disease', (55, 60))	('pEGFR levels', 'MPA', (136, 148))	('NSCLC', 'Disease', 'MESH:D002289', (25, 30))	('ILT4', 'Gene', '10288', (91, 95))	('increased', 'PosReg', (126, 135))	('NSCLC', 'Phenotype', 'HP:0030358', (25, 30))	('high', 'Var', (86, 90))
483209	33537094	Analysis of patients' clinicopathological features with different ILT4 and pEGFR levels revealed that co-existence of ILT4 and pEGFR predicted more frequent pleural metastasis compared with double-negative patients (Table 1).	('ILT4', 'Gene', '10288', (66, 70))	('patients', 'Species', '9606', (12, 20))	('co-existence', 'Var', (102, 114))	('ILT4', 'Gene', '10288', (118, 122))	('pleural metastasis', 'Disease', 'MESH:D009362', (157, 175))	('ILT4', 'Gene', (66, 70))	('pEGFR', 'Var', (127, 132))	('patients', 'Species', '9606', (206, 214))	('pleural metastasis', 'Disease', (157, 175))	('ILT4', 'Gene', (118, 122))
483211	33537094	To further clarify the causative connection between ILT4 expression and EGFR activation, we first downregulated ILT4 expression using specific ILT4-knockdown lentivirus and detected EGFR and pEGFR levels in PC9 and H1975 cells with intrinsic exon 19 deletion and T790M mutation, respectively.	('downregulated', 'NegReg', (98, 111))	('ILT4', 'Gene', '10288', (52, 56))	('pEGFR levels', 'MPA', (191, 203))	('ILT4', 'Gene', (112, 116))	('ILT4', 'Gene', (143, 147))	('PC9', 'CellLine', 'CVCL:B260', (207, 210))	('T790M', 'Mutation', 'rs121434569', (263, 268))	('deletion', 'Var', (250, 258))	('expression', 'MPA', (117, 127))	('ILT4', 'Gene', '10288', (112, 116))	('EGFR', 'MPA', (182, 186))	('ILT4', 'Gene', '10288', (143, 147))	('ILT4', 'Gene', (52, 56))	('H1975', 'CellLine', 'CVCL:1511', (215, 220))	('T790M mutation', 'Var', (263, 277))
483215	33537094	We selected PC9, HCC827, and H1975 cells that harbor activating EGFR mutations, to manipulate EGFR activation using the first-generation TKI gefitinib or the third-generation TKI osimertinib.	('mutations', 'Var', (69, 78))	('PC9', 'CellLine', 'CVCL:B260', (12, 15))	('osimertinib', 'Chemical', '-', (179, 190))	('HCC827', 'CellLine', 'CVCL:2063', (17, 23))	('gefitinib', 'Chemical', 'MESH:D000077156', (141, 150))	('H1975', 'CellLine', 'CVCL:1511', (29, 34))	('activating', 'PosReg', (53, 63))	('EGFR', 'Gene', (64, 68))
483223	33537094	Similarly, when we upregulated the EGFR level by transfecting the EGFR overexpression plasmid in H1299 cells, EGFR phosphorylation and ILT4 expression were significantly elevated (Figure 1K, Figure S1O-R).	('phosphorylation', 'MPA', (115, 130))	('elevated', 'PosReg', (170, 178))	('upregulated', 'PosReg', (19, 30))	('overexpression', 'PosReg', (71, 85))	('ILT4', 'Gene', '10288', (135, 139))	('expression', 'MPA', (140, 150))	('transfecting', 'Var', (49, 61))	('EGFR', 'Gene', (110, 114))	('EGFR', 'Gene', (66, 70))	('H1299', 'CellLine', 'CVCL:0060', (97, 102))	('ILT4', 'Gene', (135, 139))
483238	33537094	To further examine the role of ILT4 in the pathogenesis of EGFR-activated NSCLC, we examined the proliferation and apoptosis of tumor cells upon ILT4 knockdown.	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('ILT4', 'Gene', '10288', (31, 35))	('NSCLC', 'Phenotype', 'HP:0030358', (74, 79))	('ILT4', 'Gene', '10288', (145, 149))	('knockdown', 'Var', (150, 159))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('NSCLC', 'Disease', (74, 79))	('ILT4', 'Gene', (31, 35))	('tumor', 'Disease', (128, 133))	('NSCLC', 'Disease', 'MESH:D002289', (74, 79))	('ILT4', 'Gene', (145, 149))
483239	33537094	As shown in Figure S2A-B, ILT4 knockdown inhibited the proliferation and Ki-67 expression of PC9 and H1975 cells but induced their apoptosis (Figure S2C-D).	('C', 'Chemical', 'MESH:D002244', (151, 152))	('ILT4', 'Gene', (26, 30))	('Ki-67 expression', 'CPA', (73, 89))	('proliferation', 'CPA', (55, 68))	('C', 'Chemical', 'MESH:D002244', (94, 95))	('H1975', 'CellLine', 'CVCL:1511', (101, 106))	('ILT4', 'Gene', '10288', (26, 30))	('inhibited', 'NegReg', (41, 50))	('apoptosis', 'CPA', (131, 140))	('induced', 'Reg', (117, 124))	('knockdown', 'Var', (31, 40))	('PC9', 'CellLine', 'CVCL:B260', (93, 96))
483245	33537094	We also found that the high ILT4 level predicted decreased CD4+ non-regulatory and CD8+ T cells (Figure S3D-F).	('high ILT4 level', 'Phenotype', 'HP:0032300', (23, 38))	('high', 'Var', (23, 27))	('ILT4', 'Gene', (28, 32))	('decreased', 'NegReg', (49, 58))	('CD8', 'Gene', (83, 86))	('CD8', 'Gene', '925', (83, 86))	('CD4+ non-regulatory', 'MPA', (59, 78))	('ILT4', 'Gene', '10288', (28, 32))
483247	33537094	Next, we stained ILT4 and CD68 (TAM marker) in sequential sections of 80 NSCLC tissues and found that patients with high ILT4 expression in tumor cells displayed markedly elevated CD68+ TAM infiltration (Figure 3A-B).	('patients', 'Species', '9606', (102, 110))	('elevated', 'PosReg', (171, 179))	('NSCLC', 'Disease', (73, 78))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('ILT4', 'Gene', '10288', (17, 21))	('CD68', 'Gene', (26, 30))	('NSCLC', 'Phenotype', 'HP:0030358', (73, 78))	('ILT4', 'Gene', '10288', (121, 125))	('CD68', 'Gene', '968', (180, 184))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('CD68', 'Gene', (180, 184))	('TAM', 'Chemical', '-', (186, 189))	('high', 'Var', (116, 120))	('TAM', 'Chemical', '-', (32, 35))	('ILT4', 'Gene', (17, 21))	('NSCLC', 'Disease', 'MESH:D002289', (73, 78))	('ILT4', 'Gene', (121, 125))	('CD68', 'Gene', '968', (26, 30))	('tumor', 'Disease', (140, 145))
483250	33537094	As expected, macrophages cultured with CM of both PC9 and H1975 cells showed enhanced migration ability compared with those cultured with normal medium, while ILT4 knockdown in tumor cells partially prevented TAM migration (Figure 3C-D).	('H1975', 'CellLine', 'CVCL:1511', (58, 63))	('TAM migration', 'CPA', (209, 222))	('enhanced', 'PosReg', (77, 85))	('C', 'Chemical', 'MESH:D002244', (51, 52))	('prevented', 'NegReg', (199, 208))	('ILT4', 'Gene', '10288', (159, 163))	('PC9', 'CellLine', 'CVCL:B260', (50, 53))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('C', 'Chemical', 'MESH:D002244', (232, 233))	('TAM', 'Chemical', '-', (209, 212))	('C', 'Chemical', 'MESH:D002244', (39, 40))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('knockdown', 'Var', (164, 173))	('migration ability', 'CPA', (86, 103))	('tumor', 'Disease', (177, 182))	('ILT4', 'Gene', (159, 163))
483253	33537094	But ILT4 knockdown significantly decreased the expression and secretion of CCL2 and CCL5 in both PC9 and H1975 cells (Figure S3G, Figure 3E-F).	('CCL2', 'Gene', (75, 79))	('ILT4', 'Gene', '10288', (4, 8))	('knockdown', 'Var', (9, 18))	('ILT4', 'Gene', (4, 8))	('secretion', 'MPA', (62, 71))	('H1975', 'CellLine', 'CVCL:1511', (105, 110))	('CCL5', 'Gene', (84, 88))	('CCL2', 'Gene', '6347', (75, 79))	('decreased', 'NegReg', (33, 42))	('PC9', 'CellLine', 'CVCL:B260', (97, 100))	('expression', 'MPA', (47, 57))	('CCL5', 'Gene', '6352', (84, 88))
483257	33537094	The M1 macrophages, with high levels of CD80, CD86, IL-12, and TNFalpha, were involved in the inflammatory response, pathogen clearance, and antitumor immunity.	('involved', 'Reg', (78, 86))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('TNFalpha', 'Gene', (63, 71))	('inflammatory response', 'CPA', (94, 115))	('IL-12', 'Gene', (52, 57))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('CD80', 'Var', (40, 44))	('TNFalpha', 'Gene', '7124', (63, 71))	('tumor', 'Disease', (145, 150))	('CD86', 'Gene', (46, 50))
483260	33537094	We investigated ILT4-regulated TAM polarization and found a markedly increased frequency of CD206+ (M2-like TAM marker) but decreased CD86+ (M1-like TAM marker) TAMs in patients with high ILT4 expression compared to those with low ILT4 levels (Figure 3I-J).	('ILT4', 'Gene', (16, 20))	('TAMs', 'Chemical', '-', (161, 165))	('patients', 'Species', '9606', (169, 177))	('ILT4', 'Gene', (188, 192))	('increased', 'PosReg', (69, 78))	('ILT4', 'Gene', '10288', (231, 235))	('CD86+', 'MPA', (134, 139))	('ILT4', 'Gene', '10288', (16, 20))	('decreased', 'NegReg', (124, 133))	('ILT4', 'Gene', '10288', (188, 192))	('TAM', 'Chemical', '-', (161, 164))	('high', 'Var', (183, 187))	('TAM', 'Chemical', '-', (31, 34))	('CD206+', 'MPA', (92, 98))	('TAM', 'Chemical', '-', (149, 152))	('TAM', 'Chemical', '-', (108, 111))	('ILT4', 'Gene', (231, 235))
483262	33537094	We observed that ILT4 knockdown in tumor cells decreased M2-like markers, including CD163, CD206, IL-10, and Arginase 1 but increased M1-like markers including CD80, CD86, IL-12, and TNFalphain TAMs (Figure 3K-L, Figure S3H).	('CD206', 'MPA', (91, 96))	('Arginase 1', 'Gene', '383', (109, 119))	('knockdown', 'Var', (22, 31))	('CD86', 'MPA', (166, 170))	('ILT4', 'Gene', '10288', (17, 21))	('TNFalphain TAMs', 'Disease', (183, 198))	('CD80', 'MPA', (160, 164))	('increased', 'PosReg', (124, 133))	('tumor', 'Disease', (35, 40))	('decreased', 'NegReg', (47, 56))	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('M2-like markers', 'MPA', (57, 72))	('IL-10', 'Gene', '3586', (98, 103))	('Arginase 1', 'Gene', (109, 119))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('IL-10', 'Gene', (98, 103))	('ILT4', 'Gene', (17, 21))	('TNFalphain TAMs', 'Disease', 'None', (183, 198))	('CD163', 'MPA', (84, 89))	('M1-like', 'MPA', (134, 141))
483265	33537094	The ILT4 knockdown in both tumor cell lines promoted TAM-mediated T cell proliferation (Figure 3M, Figure S3I) and IFN-gamma generation (Figure 3N, Figure S3J).	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('promoted', 'PosReg', (44, 52))	('knockdown', 'Var', (9, 18))	('tumor', 'Disease', (27, 32))	('TAM', 'Chemical', '-', (53, 56))	('ILT4', 'Gene', (4, 8))	('TAM-mediated T cell proliferation', 'CPA', (53, 86))	('IFN-gamma generation', 'MPA', (115, 135))	('ILT4', 'Gene', '10288', (4, 8))	('tumor', 'Disease', 'MESH:D009369', (27, 32))
483275	33537094	The results showed that ILT4 knockdown in tumor cells heightened the killing ability of T cells (Figure 4K).	('tumor', 'Disease', (42, 47))	('knockdown', 'Var', (29, 38))	('ILT4', 'Gene', (24, 28))	('killing ability of T cells', 'CPA', (69, 95))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('ILT4', 'Gene', '10288', (24, 28))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('heightened', 'PosReg', (54, 64))
483281	33537094	We found that CM from either anti-ILT4- or anti-PD-L1-pretreated tumor cells inhibited TAM migration while combined application of both antibodies showed the most dramatic inhibition (Figure S4A-B).	('anti-PD-L1-pretreated', 'Var', (43, 64))	('C', 'Chemical', 'MESH:D002244', (14, 15))	('tumor', 'Disease', (65, 70))	('inhibited', 'NegReg', (77, 86))	('TAM migration', 'CPA', (87, 100))	('ILT4', 'Gene', (34, 38))	('ILT4', 'Gene', '10288', (34, 38))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('TAM', 'Chemical', '-', (87, 90))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
483283	33537094	Meanwhile, CM from anti-ILT4- or anti-PD-L1-pretreated tumor cells decreased CD163 and CD206 levels in TAMs, and combined antibody group displayed the lowest CD163 and CD206 expression (Figure S4G-I).	('C', 'Chemical', 'MESH:D002244', (87, 88))	('C', 'Chemical', 'MESH:D002244', (168, 169))	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('CD163', 'MPA', (158, 163))	('expression', 'MPA', (174, 184))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('TAMs', 'Chemical', '-', (103, 107))	('ILT4', 'Gene', (24, 28))	('CD206', 'MPA', (168, 173))	('lowest', 'NegReg', (151, 157))	('tumor', 'Disease', (55, 60))	('C', 'Chemical', 'MESH:D002244', (77, 78))	('decreased', 'NegReg', (67, 76))	('ILT4', 'Gene', '10288', (24, 28))	('anti-PD-L1-pretreated', 'Var', (33, 54))	('C', 'Chemical', 'MESH:D002244', (158, 159))	('C', 'Chemical', 'MESH:D002244', (11, 12))
483284	33537094	These results suggested that anti-ILT4 and anti-PD-L1 had a synergistic impact on TAM recruitment and M2-like polarization.	('TAM recruitment', 'CPA', (82, 97))	('ILT4', 'Gene', (34, 38))	('TAM', 'Chemical', '-', (82, 85))	('anti-PD-L1', 'Var', (43, 53))	('M2-like polarization', 'CPA', (102, 122))	('ILT4', 'Gene', '10288', (34, 38))	('impact', 'Reg', (72, 78))
483286	33537094	As shown in Figure S4J-K, pretreatment of tumor cells using either anti-ILT4 or anti-PD-L1 promoted the proliferation of T cells co-cultured with these tumor cells, and combined antibodies yielded most significant improvement in T cell proliferation.	('T cell proliferation', 'CPA', (229, 249))	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('promoted', 'PosReg', (91, 99))	('ILT4', 'Gene', '10288', (72, 76))	('tumor', 'Disease', (42, 47))	('T cells', 'CPA', (121, 128))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('proliferation', 'CPA', (104, 117))	('anti-PD-L1', 'Var', (80, 90))	('tumor', 'Disease', (152, 157))	('ILT4', 'Gene', (72, 76))	('improvement', 'PosReg', (214, 225))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
483291	33537094	One is intrinsic activation caused by EGFR mutation, and the other is extrinsic activation by ligand engagement in EGFR wild-type patients.	('mutation', 'Var', (43, 51))	('EGFR', 'Gene', (38, 42))	('patients', 'Species', '9606', (130, 138))	('activation', 'PosReg', (17, 27))	('intrinsic', 'MPA', (7, 16))
483302	33537094	As shown in Figure 5A-B, pretreatment of PC9-GR with either anti-ILT4 or anti-PD-L1 dramatically inhibited TAM migration, while blockade of both molecules most significantly suppressed TAM migration.	('TAM migration', 'CPA', (185, 198))	('anti-PD-L1', 'Var', (73, 83))	('PC9-GR', 'CellLine', 'CVCL:S706', (41, 47))	('TAM migration', 'CPA', (107, 120))	('suppressed', 'NegReg', (174, 184))	('ILT4', 'Gene', (65, 69))	('TAM', 'Chemical', '-', (107, 110))	('inhibited', 'NegReg', (97, 106))	('TAM', 'Chemical', '-', (185, 188))	('ILT4', 'Gene', '10288', (65, 69))
483303	33537094	Similarly, EGF stimulation of H1299 cells remarkably increased the migration ability of TAMs, whereas the addition of either anti-ILT4 or anti-PD-L1 or combined antibodies markedly decreased TAM migration with the combination group showing the most significant inhibition (Figure 5A-B).	('TAM', 'Chemical', '-', (88, 91))	('ILT4', 'Gene', (130, 134))	('TAM', 'Chemical', '-', (191, 194))	('anti-PD-L1', 'Var', (138, 148))	('EGF', 'Gene', (11, 14))	('increased', 'PosReg', (53, 62))	('H1299', 'CellLine', 'CVCL:0060', (30, 35))	('ILT4', 'Gene', '10288', (130, 134))	('TAMs', 'Chemical', '-', (88, 92))	('EGF', 'Gene', '1950', (11, 14))	('TAM migration', 'CPA', (191, 204))	('migration ability of TAMs', 'CPA', (67, 92))	('decreased', 'NegReg', (181, 190))
483306	33537094	We also determined TAM phenotypes following ILT4 and PD-L1 blockade, in PC9-GR or EGF-H1299 and observed reduced M2-like markers (CD163 and CD206) in TAMs, and the reduction was highest with both antibody treatment (Figure 5G-I).	('ILT4', 'Gene', (44, 48))	('TAMs', 'Chemical', '-', (150, 154))	('PD-L1', 'Gene', (53, 58))	('TAM', 'Chemical', '-', (19, 22))	('EGF', 'Gene', (82, 85))	('TAM', 'Chemical', '-', (150, 153))	('ILT4', 'Gene', '10288', (44, 48))	('PC9-GR', 'CellLine', 'CVCL:S706', (72, 78))	('blockade', 'Var', (59, 67))	('reduced', 'NegReg', (105, 112))	('EGF', 'Gene', '1950', (82, 85))	('H1299', 'CellLine', 'CVCL:0060', (86, 91))
483307	33537094	These data suggested that combined ILT4 and PD-L1 blockade synergistically prevented recruitment and M2-like polarization of TAMs in both EGFR-TKI resistant and EGFR wild-type NSCLC and might cooperate to repress TAM-mediated tumor promotion.	('M2-like polarization', 'CPA', (101, 121))	('TAM', 'Chemical', '-', (125, 128))	('blockade', 'Var', (50, 58))	('ILT4', 'Gene', '10288', (35, 39))	('NSCLC', 'Disease', (176, 181))	('TAM', 'Chemical', '-', (213, 216))	('PD-L1', 'Gene', (44, 49))	('tumor', 'Disease', 'MESH:D009369', (226, 231))	('TAMs', 'Chemical', '-', (125, 129))	('recruitment', 'MPA', (85, 96))	('NSCLC', 'Disease', 'MESH:D002289', (176, 181))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('repress', 'NegReg', (205, 212))	('ILT4', 'Gene', (35, 39))	('NSCLC', 'Phenotype', 'HP:0030358', (176, 181))	('tumor', 'Disease', (226, 231))	('prevented', 'NegReg', (75, 84))
483310	33537094	Figure 5J-K shows that T cells co-cultured with anti-ILT4- or anti-PD-L1-pretreated tumor cells had higher proliferation rate than those cocultured with IgG-pretreated tumor cells, while pretreatment of tumor cells with combined antibodies led to most significant increase in T cell proliferation.	('ILT4', 'Gene', (53, 57))	('increase', 'PosReg', (264, 272))	('tumor', 'Disease', (203, 208))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('tumor', 'Disease', (168, 173))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('proliferation rate', 'CPA', (107, 125))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('ILT4', 'Gene', '10288', (53, 57))	('tumor', 'Disease', (84, 89))	('anti-PD-L1-pretreated', 'Var', (62, 83))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('higher', 'PosReg', (100, 106))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('T cell proliferation', 'CPA', (276, 296))
483311	33537094	In contrast, pretreatment of tumor cells with either anti-ILT4 or anti-PD-L1 antibodies yielded lower apoptosis of T cells compared with the control IgG group, and the combination treatment generated the least number of apoptotic T cells (Figure 5L-M).	('anti-PD-L1', 'Var', (66, 76))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('apoptosis', 'CPA', (102, 111))	('lower', 'NegReg', (96, 101))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumor', 'Disease', (29, 34))	('ILT4', 'Gene', (58, 62))	('ILT4', 'Gene', '10288', (58, 62))
483313	33537094	More importantly, the cytolytic ability of T cells was significantly improved when they were co-cultured with anti-ILT4- or anti-PD-L1- or both antibody-pretreated tumor cells, in which the combination group generated the strongest tumor eradication in response to T cells (Figure 5O).	('tumor', 'Disease', (164, 169))	('ILT4', 'Gene', '10288', (115, 119))	('improved', 'PosReg', (69, 77))	('tumor', 'Disease', 'MESH:D009369', (232, 237))	('anti-PD-L1-', 'Var', (124, 135))	('cytolytic ability', 'CPA', (22, 39))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('tumor', 'Disease', (232, 237))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('ILT4', 'Gene', (115, 119))
483314	33537094	Taken together, these results suggested that ILT4 blockade enhanced ICI activity in both TKI-resistant and EGFR wild-type NSCLC cells, affording a potential strategy to overcome ICI resistance in these patients.	('NSCLC', 'Disease', 'MESH:D002289', (122, 127))	('blockade', 'Var', (50, 58))	('C', 'Chemical', 'MESH:D002244', (69, 70))	('ILT4', 'Gene', (45, 49))	('C', 'Chemical', 'MESH:D002244', (124, 125))	('enhanced', 'PosReg', (59, 67))	('NSCLC', 'Phenotype', 'HP:0030358', (122, 127))	('patients', 'Species', '9606', (202, 210))	('C', 'Chemical', 'MESH:D002244', (179, 180))	('ILT4', 'Gene', '10288', (45, 49))	('NSCLC', 'Disease', (122, 127))	('C', 'Chemical', 'MESH:D002244', (126, 127))	('ICI activity', 'MPA', (68, 80))
483315	33537094	Our in vitro studies indicated that ILT4 led to the infiltration of M2-like TAMs and hypo-responsiveness of T cells, and blockade of ILT4 significantly curtailed these effects and enhanced the activity of the PD-L1 inhibitor.	('hypo-responsiveness of T cells', 'MPA', (85, 115))	('ILT4', 'Gene', (133, 137))	('infiltration', 'MPA', (52, 64))	('ILT4', 'Gene', '10288', (36, 40))	('M2-like', 'Protein', (68, 75))	('ILT4', 'Gene', '10288', (133, 137))	('activity', 'MPA', (193, 201))	('PD-L1 inhibitor', 'Enzyme', (209, 224))	('TAMs', 'Chemical', '-', (76, 80))	('enhanced', 'PosReg', (180, 188))	('blockade', 'Var', (121, 129))	('ILT4', 'Gene', (36, 40))	('curtailed', 'NegReg', (152, 161))
483316	33537094	We next explored whether combined ILT4 and PD-L1 blockade had a synergistic effect on controlling tumor development, M2-like TAM infiltration, and T cell dysfunction in vivo.	('TAM', 'Chemical', '-', (125, 128))	('T cell dysfunction', 'Phenotype', 'HP:0005435', (147, 165))	('ILT4', 'Gene', (34, 38))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('PD-L1', 'Gene', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('blockade', 'Var', (49, 57))	('ILT4', 'Gene', '10288', (34, 38))	('tumor', 'Disease', (98, 103))	('T cell dysfunction', 'CPA', (147, 165))
483320	33537094	After 7 days, anti-PD-L1 or control IgG were intraperitoneally injected into tumor-bearing mice every 4 days, and the tumor sizes were measured.	('mice', 'Species', '10090', (91, 95))	('anti-PD-L1', 'Var', (14, 24))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('tumor', 'Disease', (118, 123))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Disease', (77, 82))
483322	33537094	Figure 6A shows that both PIR-B knockdown and PD-L1 blockade slowed down tumor growth compared with the control group, while combined blockade of both molecules displayed a cooperative effect on tumor inhibition.	('PD-L1', 'Gene', (46, 51))	('slowed down', 'NegReg', (61, 72))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('tumor', 'Disease', (195, 200))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Disease', (73, 78))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('blockade', 'Var', (52, 60))
483330	33537094	We also analyzed the M2-like phenotype of TAMs by detecting CD206-positive cells in spleens and CD206/CD163/CD86/CD80-positive cells in tumor tissues.	('TAMs', 'Chemical', '-', (42, 46))	('CD206/CD163/CD86/CD80-positive', 'Var', (96, 126))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('tumor', 'Disease', (136, 141))	('CD206-positive', 'Var', (60, 74))
483332	33537094	Similarly, PIR-B or PD-L1 inhibition reduced the proportion of CD206+ and CD163+ TAMs but elevated that of CD86+ and CD80+ TAMs in tumor tissues with the most obvious alteration in the combined blockade group (Figure 6G-H, Figure S6D-G).	('elevated', 'PosReg', (90, 98))	('CD163+ TAMs', 'MPA', (74, 85))	('CD80+', 'Var', (117, 122))	('TAMs', 'Chemical', '-', (81, 85))	('CD206+', 'MPA', (63, 69))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumor', 'Disease', (131, 136))	('CD86+', 'MPA', (107, 112))	('PD-L1', 'Gene', (20, 25))	('reduced', 'NegReg', (37, 44))	('TAMs', 'Chemical', '-', (123, 127))
483334	33537094	However, blockade of either PIR-B or PD-L1 in tumors partially restored T cell infiltration and combined blockade almost totally restored T cell accumulation in spleens, blood, and tumor tissues (Figure 6I-J, Figure S6H).	('tumor', 'Disease', 'MESH:D009369', (46, 51))	('tumor', 'Disease', (181, 186))	('PD-L1', 'Gene', (37, 42))	('restored', 'NegReg', (129, 137))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('PIR-B', 'Gene', (28, 33))	('T cell infiltration', 'CPA', (72, 91))	('restored', 'PosReg', (63, 71))	('tumor', 'Disease', (46, 51))	('tumors', 'Disease', 'MESH:D009369', (46, 52))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('tumors', 'Disease', (46, 52))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('blockade', 'Var', (9, 17))
483341	33537094	We found that knockdown of PIR-B slowed down tumor growth compared with the control group (Figure 6M-O).	('slowed down', 'NegReg', (33, 44))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('PIR-B', 'Gene', (27, 32))	('tumor', 'Disease', (45, 50))	('knockdown', 'Var', (14, 23))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
483343	33537094	Collectively, these results indicated that PIR-B and PD-L1 blockade synergistically normalized the immunosuppressive TME and prevented tumor growth and immune escape in vivo, rationalizing the combination of ILT4 and PD-L1 blockade in lung cancer treatment.	('ILT4', 'Gene', (208, 212))	('PD-L1', 'Gene', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('normalized', 'NegReg', (84, 94))	('tumor', 'Disease', (135, 140))	('lung cancer', 'Disease', (235, 246))	('lung cancer', 'Disease', 'MESH:D008175', (235, 246))	('ILT4', 'Gene', '10288', (208, 212))	('prevented', 'NegReg', (125, 134))	('immunosuppressive TME', 'MPA', (99, 120))	('immune', 'CPA', (152, 158))	('blockade', 'Var', (59, 67))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('PIR-B', 'Gene', (43, 48))	('lung cancer', 'Phenotype', 'HP:0100526', (235, 246))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
483344	33537094	For NSCLC patients with TKI-resistant EGFR mutant, ICI resistance is still a challenge.	('C', 'Chemical', 'MESH:D002244', (52, 53))	('NSCLC', 'Disease', 'MESH:D002289', (4, 9))	('EGFR', 'Gene', (38, 42))	('C', 'Chemical', 'MESH:D002244', (8, 9))	('mutant', 'Var', (43, 49))	('NSCLC', 'Phenotype', 'HP:0030358', (4, 9))	('patients', 'Species', '9606', (10, 18))	('C', 'Chemical', 'MESH:D002244', (6, 7))	('NSCLC', 'Disease', (4, 9))
483346	33537094	We first established an immunotherapy model in immune-reconstructed NSG mice using the TKI-resistant EGFR mutant NSCLC cell line PC9-GR.	('mutant', 'Var', (106, 112))	('NSCLC', 'Disease', 'MESH:D002289', (113, 118))	('NSCLC', 'Phenotype', 'HP:0030358', (113, 118))	('EGFR', 'Gene', (101, 105))	('mice', 'Species', '10090', (72, 76))	('NSCLC', 'Disease', (113, 118))	('PC9-GR', 'CellLine', 'CVCL:S706', (129, 135))
483348	33537094	The efficiency of ILT4 knockdown in PC9-GR cells was confirmed at both mRNA and protein levels before tumor implantation (Figure S6M-N).	('knockdown', 'Var', (23, 32))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('ILT4', 'Gene', (18, 22))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('PC9-GR', 'CellLine', 'CVCL:S706', (36, 42))	('ILT4', 'Gene', '10288', (18, 22))
483351	33537094	Tumor growth in the ILT4 knockdown group was much slower than in the control group (Figure 7A).	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('ILT4', 'Gene', (20, 24))	('Tumor growth', 'CPA', (0, 12))	('ILT4', 'Gene', '10288', (20, 24))	('knockdown', 'Var', (25, 34))	('slower', 'NegReg', (50, 56))
483352	33537094	Surprisingly, PD-L1 blockade promoted rather than inhibited tumor growth in PC9-GR control and ILT4 knockdown groups (Figure 7A).	('promoted', 'PosReg', (29, 37))	('ILT4', 'Gene', (95, 99))	('PC9-GR', 'CellLine', 'CVCL:S706', (76, 82))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('blockade', 'Var', (20, 28))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('ILT4', 'Gene', '10288', (95, 99))	('PD-L1', 'Gene', (14, 19))	('tumor', 'Disease', (60, 65))	('inhibited', 'NegReg', (50, 59))
483357	33537094	As expected, ILT4 knockdown markedly elevated T cell infiltration in spleens (Figure 7D), blood (Figure 7E) and tumor tissues (Figure 7F-G).	('knockdown', 'Var', (18, 27))	('tumor', 'Disease', (112, 117))	('ILT4', 'Gene', (13, 17))	('elevated', 'PosReg', (37, 45))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('elevated T cell', 'Phenotype', 'HP:0100828', (37, 52))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('ILT4', 'Gene', '10288', (13, 17))	('T cell infiltration', 'CPA', (46, 65))
483359	33537094	Also, T cells in the ILT4 knockdown group rather than in the PD-L1 blockade or combination therapy group displayed increased IFN-gamma levels in blood, spleens and tumor tissues compared with the control group (Figure 7H-I).	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('tumor', 'Disease', (164, 169))	('increased', 'PosReg', (115, 124))	('ILT4', 'Gene', (21, 25))	('knockdown', 'Var', (26, 35))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('ILT4', 'Gene', '10288', (21, 25))	('IFN-gamma levels', 'MPA', (125, 141))
483361	33537094	Furthermore, ILT4 blockade augmented IFN-gamma expression in both CD4+ and CD8+ T cell subsets from mouse blood and spleens (Figure 7L-M).	('IFN-gamma expression', 'MPA', (37, 57))	('CD8', 'Gene', '925', (75, 78))	('ILT4', 'Gene', (13, 17))	('augmented', 'PosReg', (27, 36))	('mouse', 'Species', '10090', (100, 105))	('ILT4', 'Gene', '10288', (13, 17))	('blockade', 'Var', (18, 26))	('CD8', 'Gene', (75, 78))
483362	33537094	These results clearly indicated that ILT4 blockade might be an effective treatment strategy for EGFR mutant patients resistant to EGFR-TKI treatment.	('ILT4', 'Gene', (37, 41))	('EGFR', 'Gene', (96, 100))	('mutant', 'Var', (101, 107))	('ILT4', 'Gene', '10288', (37, 41))	('patients', 'Species', '9606', (108, 116))
483366	33537094	Since combined blockade of ILT4 and PD-L1 showed a synergistic effect on tumor inhibition in vitro, we explored whether combination therapy could increase ICI treatment potential in EGFR wild-type NSCLC in vivo.	('blockade', 'Var', (15, 23))	('ILT4', 'Gene', '10288', (27, 31))	('ICI treatment', 'MPA', (155, 168))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('increase', 'PosReg', (146, 154))	('NSCLC', 'Phenotype', 'HP:0030358', (197, 202))	('PD-L1', 'Gene', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('ILT4', 'Gene', (27, 31))	('C', 'Chemical', 'MESH:D002244', (201, 202))	('tumor', 'Disease', (73, 78))	('C', 'Chemical', 'MESH:D002244', (156, 157))	('NSCLC', 'Disease', (197, 202))	('NSCLC', 'Disease', 'MESH:D002289', (197, 202))	('C', 'Chemical', 'MESH:D002244', (199, 200))
483368	33537094	The efficiency of ILT4 knockdown in EGFR-H1299 cells was validated at both mRNA and protein levels before tumor injection (Figure S6O-P).	('H1299', 'CellLine', 'CVCL:0060', (41, 46))	('knockdown', 'Var', (23, 32))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('ILT4', 'Gene', (18, 22))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Disease', (106, 111))	('ILT4', 'Gene', '10288', (18, 22))
483372	33537094	As displayed in Figure 8D-E, either ILT4 or PD-L1 inhibition promoted T cell accumulation in these organs compared with the control group, while combination therapy yielded the highest T cell accumulation.	('T cell accumulation in these organs', 'CPA', (70, 105))	('inhibition', 'Var', (50, 60))	('ILT4', 'Gene', '10288', (36, 40))	('promoted', 'PosReg', (61, 69))	('PD-L1', 'Gene', (44, 49))	('ILT4', 'Gene', (36, 40))
483373	33537094	Moreover, IFN-gamma produced by these T cells was also markedly elevated by ILT4 and/or PD-L1 blockade and the combination blockade generated the highest IFN-gamma levels in spleens, blood and tumor tissues (Figure 8F-G).	('ILT4', 'Gene', '10288', (76, 80))	('PD-L1', 'Gene', (88, 93))	('elevated', 'PosReg', (64, 72))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('IFN-gamma produced', 'MPA', (10, 28))	('IFN-gamma levels', 'MPA', (154, 170))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('ILT4', 'Gene', (76, 80))	('tumor', 'Disease', (193, 198))	('blockade', 'Var', (94, 102))
483375	33537094	These results collectively revealed that ILT4 and PD-L1 blockade synergistically cooperated to inhibit tumor growth and immune evasion.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('PD-L1', 'Gene', (50, 55))	('tumor', 'Disease', (103, 108))	('inhibit', 'NegReg', (95, 102))	('ILT4', 'Gene', (41, 45))	('blockade', 'Var', (56, 64))	('ILT4', 'Gene', '10288', (41, 45))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('immune evasion', 'MPA', (120, 134))
483383	33537094	ILT4 blockade or knockdown prevented immunosuppression and tumor progression both in vitro and in vivo.	('blockade', 'Var', (5, 13))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Disease', (59, 64))	('immunosuppression', 'CPA', (37, 54))	('ILT4', 'Gene', (0, 4))	('prevented', 'NegReg', (27, 36))	('ILT4', 'Gene', '10288', (0, 4))	('knockdown', 'Var', (17, 26))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
483384	33537094	Significantly, using humanized murine immunotherapy models, we established ILT4 inhibition as an attractive approach for TKI-resistant EGFR-mutant NSCLC patients.	('NSCLC', 'Disease', (147, 152))	('inhibition', 'NegReg', (80, 90))	('patients', 'Species', '9606', (153, 161))	('NSCLC', 'Disease', 'MESH:D002289', (147, 152))	('ILT4', 'Gene', (75, 79))	('human', 'Species', '9606', (21, 26))	('EGFR-mutant', 'Var', (135, 146))	('EGFR-mutant', 'Gene', (135, 146))	('NSCLC', 'Phenotype', 'HP:0030358', (147, 152))	('ILT4', 'Gene', '10288', (75, 79))	('murine', 'Species', '10090', (31, 37))
483385	33537094	Furthermore, ILT4 inhibition substantially potentiated the anti-tumor activity of PD-L1 inhibitor in the EGFR wild-type NSCLC subtype.	('NSCLC', 'Disease', 'MESH:D002289', (120, 125))	('tumor', 'Disease', (64, 69))	('ILT4', 'Gene', (13, 17))	('potentiated', 'PosReg', (43, 54))	('NSCLC', 'Phenotype', 'HP:0030358', (120, 125))	('ILT4', 'Gene', '10288', (13, 17))	('PD-L1 inhibitor', 'Gene', (82, 97))	('inhibition', 'Var', (18, 28))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('NSCLC', 'Disease', (120, 125))
483406	33537094	Based on our results, it is plausible that blocking ILT4 might prevent TAM-mediated immunosuppression, improve infiltration and bioactivity of tumor-specific T cells, and break the hostile immune barrier in TME.	('ILT4', 'Gene', '10288', (52, 56))	('TAM-mediated immunosuppression', 'MPA', (71, 101))	('blocking', 'Var', (43, 51))	('TAM', 'Chemical', '-', (71, 74))	('tumor', 'Disease', (143, 148))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('hostile immune barrier', 'MPA', (181, 203))	('bioactivity', 'MPA', (128, 139))	('break', 'NegReg', (171, 176))	('ILT4', 'Gene', (52, 56))	('improve', 'PosReg', (103, 110))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('infiltration', 'MPA', (111, 123))
483407	33537094	Indeed, our in vitro and in vivo studies have demonstrated that ILT4 blockade decreased M2-like TAM accumulation and restored infiltration and tumoricidal function of T cells, thus inhibiting tumor growth.	('ILT4', 'Gene', (64, 68))	('tumor', 'Disease', (192, 197))	('tumor', 'Disease', (143, 148))	('inhibiting', 'NegReg', (181, 191))	('infiltration', 'MPA', (126, 138))	('restored', 'PosReg', (117, 125))	('ILT4', 'Gene', '10288', (64, 68))	('M2-like TAM accumulation', 'MPA', (88, 112))	('TAM', 'Chemical', '-', (96, 99))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('blockade', 'Var', (69, 77))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('decreased', 'NegReg', (78, 87))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
483408	33537094	EGFR mutations are the most common oncogenic drivers for NSCLC initiation and progression.	('EGFR', 'Gene', (0, 4))	('NSCLC initiation', 'Disease', (57, 73))	('NSCLC', 'Phenotype', 'HP:0030358', (57, 62))	('mutations', 'Var', (5, 14))	('NSCLC initiation', 'Disease', 'MESH:D007319', (57, 73))
483410	33537094	Activated EGFR signaling also induces the immunosuppressive TME through recruiting or reprogramming suppressive immunocytes, inhibiting MHC molecule levels, and upregulating inhibitory cytokines and metabolites.	('MHC', 'Gene', '3107', (136, 139))	('upregulating', 'PosReg', (161, 173))	('reprogramming', 'CPA', (86, 99))	('immunosuppressive TME', 'MPA', (42, 63))	('EGFR signaling', 'Gene', (10, 24))	('Activated', 'Var', (0, 9))	('inhibiting', 'NegReg', (125, 135))	('MHC', 'Gene', (136, 139))	('induces', 'Reg', (30, 37))
483414	33537094	We observed that in both cases, activated EGFR upregulated ILT4 expression and led to immunosuppression, suggesting that ILT4 blockade is pertinent in patients with EGFR mutant and wild-type forms.	('expression', 'MPA', (64, 74))	('led to', 'Reg', (79, 85))	('upregulated', 'PosReg', (47, 58))	('ILT4', 'Gene', (59, 63))	('EGFR', 'Gene', (42, 46))	('immunosuppression', 'MPA', (86, 103))	('patients', 'Species', '9606', (151, 159))	('mutant', 'Var', (170, 176))	('ILT4', 'Gene', '10288', (59, 63))	('ILT4', 'Gene', (121, 125))	('ILT4', 'Gene', '10288', (121, 125))
483415	33537094	Our in vivo study also verified that in both EGFR mutant and EGF-activated EGFR wild-type tumors, ILT4 inhibition was an appropriate approach for treating NSCLC.	('EGF', 'Gene', '1950', (45, 48))	('ILT4', 'Gene', (98, 102))	('EGF', 'Gene', (75, 78))	('EGF', 'Gene', (61, 64))	('EGF', 'Gene', '1950', (75, 78))	('NSCLC', 'Disease', (155, 160))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('ILT4', 'Gene', '10288', (98, 102))	('tumors', 'Disease', (90, 96))	('tumors', 'Disease', 'MESH:D009369', (90, 96))	('EGF', 'Gene', (45, 48))	('NSCLC', 'Disease', 'MESH:D002289', (155, 160))	('mutant', 'Var', (50, 56))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('EGF', 'Gene', '1950', (61, 64))	('NSCLC', 'Phenotype', 'HP:0030358', (155, 160))
483418	33537094	Specific inhibition of EGFR activity using EGFR-TKIs has become the preferred first-line therapy in NSCLC patients harboring EGFR mutation since the last decade.	('inhibition', 'NegReg', (9, 19))	('NSCLC', 'Disease', (100, 105))	('mutation', 'Var', (130, 138))	('NSCLC', 'Disease', 'MESH:D002289', (100, 105))	('EGFR', 'Gene', (125, 129))	('EGFR', 'Protein', (23, 27))	('patients', 'Species', '9606', (106, 114))	('NSCLC', 'Phenotype', 'HP:0030358', (100, 105))
483421	33537094	Our present study found that ILT4 inhibition reconfigured the immunosuppressive and tumor-promoting microenvironment, and repressed the progression of EGFR mutant NSCLC.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('reconfigured', 'Reg', (45, 57))	('EGFR', 'Gene', (151, 155))	('inhibition', 'Var', (34, 44))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('ILT4', 'Gene', '10288', (29, 33))	('NSCLC', 'Disease', (163, 168))	('tumor', 'Disease', (84, 89))	('NSCLC', 'Disease', 'MESH:D002289', (163, 168))	('mutant', 'Var', (156, 162))	('ILT4', 'Gene', (29, 33))	('NSCLC', 'Phenotype', 'HP:0030358', (163, 168))
483422	33537094	Using a humanized immunotherapy model of EGFR-resistant NSCLC, we elucidated that ILT4 inhibition could be used as the second-line therapy in EGFR mutant patients who acquire resistance to EGFR-TKI treatment.	('mutant', 'Var', (147, 153))	('ILT4', 'Gene', (82, 86))	('NSCLC', 'Disease', (56, 61))	('EGFR', 'Gene', (142, 146))	('patients', 'Species', '9606', (154, 162))	('NSCLC', 'Disease', 'MESH:D002289', (56, 61))	('ILT4', 'Gene', '10288', (82, 86))	('human', 'Species', '9606', (8, 13))	('NSCLC', 'Phenotype', 'HP:0030358', (56, 61))
483423	33537094	Since immunosuppressive TME, one of the major causes for ICI resistance in EGFR mutant patients, could be partially reversed by ILT4 inhibition, we speculated that ILT4 blockade might be effective to overcome the primary hypo-responsiveness of ICIs in this NSCLC subpopulation.	('ILT4', 'Gene', '10288', (128, 132))	('C', 'Chemical', 'MESH:D002244', (58, 59))	('NSCLC', 'Disease', (257, 262))	('C', 'Chemical', 'MESH:D002244', (261, 262))	('mutant', 'Var', (80, 86))	('NSCLC', 'Disease', 'MESH:D002289', (257, 262))	('C', 'Chemical', 'MESH:D002244', (245, 246))	('C', 'Chemical', 'MESH:D002244', (259, 260))	('ILT4', 'Gene', (164, 168))	('ILT4', 'Gene', (128, 132))	('NSCLC', 'Phenotype', 'HP:0030358', (257, 262))	('patients', 'Species', '9606', (87, 95))	('EGFR', 'Gene', (75, 79))	('ILT4', 'Gene', '10288', (164, 168))
483431	33537094	Herein, using a humanized murine immunotherapy model, we demonstrated that ILT4 antagonism enhanced the efficacy of PD-L1 inhibitor in EGFR wild-type NSCLC.	('NSCLC', 'Disease', 'MESH:D002289', (150, 155))	('ILT4', 'Gene', (75, 79))	('murine', 'Species', '10090', (26, 32))	('human', 'Species', '9606', (16, 21))	('NSCLC', 'Phenotype', 'HP:0030358', (150, 155))	('ILT4', 'Gene', '10288', (75, 79))	('antagonism', 'Var', (80, 90))	('NSCLC', 'Disease', (150, 155))	('efficacy', 'MPA', (104, 112))	('enhanced', 'PosReg', (91, 99))
483434	33537094	Furthermore, increased ILT4 and PD-L1 co-expression in human NSCLC tissues with wild-type EGFR suggested that the combination blockade of ILT4 and PD-L1 is clinically feasible for a broad spectrum of NSCLC patients.	('NSCLC', 'Phenotype', 'HP:0030358', (200, 205))	('co-expression', 'MPA', (38, 51))	('ILT4', 'Gene', (23, 27))	('PD-L1', 'Gene', (32, 37))	('NSCLC', 'Phenotype', 'HP:0030358', (61, 66))	('blockade', 'Var', (126, 134))	('human', 'Species', '9606', (55, 60))	('NSCLC', 'Disease', (200, 205))	('increased', 'PosReg', (13, 22))	('ILT4', 'Gene', '10288', (23, 27))	('ILT4', 'Gene', (138, 142))	('patients', 'Species', '9606', (206, 214))	('NSCLC', 'Disease', 'MESH:D002289', (200, 205))	('NSCLC', 'Disease', (61, 66))	('PD-L1', 'Gene', (147, 152))	('NSCLC', 'Disease', 'MESH:D002289', (61, 66))	('combination', 'Interaction', (114, 125))	('ILT4', 'Gene', '10288', (138, 142))
483439	33537094	ADC adenocarcinoma CCL chemokine (C-C motif) ligand CXCL chemokine (C-X-C motif) ligand CM conditioned medium CSF colony stimulating factor CTL cytotoxic T lymphocyte DAB 3,3'-diaminobenzidine solution DC dendritic cell E:T ratio effector target cell ratio EGF epidermal growth factor EGF-H1299 EGF-preactivated H1299 EGFR epidermal growth factor receptor ELISA enzyme linked immunosorbent assay FBS fetal bovine serum HRP streptavidin-conjugated horseradish peroxidase ICI immune checkpoint inhibitor IHC immunohistochemistry ILT4 immunoglobulin-like transcript 4 KEGG Kyoto Encyclopedia of Genes and Genomes LDH lactate dehydrogenase LLC Lewis lung carcinoma M-CSF macrophage colony stimulating factor MDSC myeloid-derived suppressor cell MHC major histocompatibility complex NSCLC non-small cell lung cancer PBMC peripheral blood mononuclear cell PC9-GR gefitinib-resistant PC9 pEGFR phosphorylated EGFR PIR-B paired Ig-like receptor B SCC squamous cell carcinoma siRNA small interfering RNA TAM tumor-associated macrophage TCGA The Cancer Genome Atlas TKI tyrosine kinase inhibitor TMB tumor mutation burden TME tumor microenvironment Treg regulatory T cell	('Cancer', 'Disease', (1036, 1042))	('C', 'Chemical', 'MESH:D002244', (52, 53))	('paired Ig-like receptor B', 'Gene', (913, 938))	('tyrosine kinase', 'Gene', (1060, 1075))	('cancer', 'Phenotype', 'HP:0002664', (804, 810))	('C', 'Chemical', 'MESH:D002244', (940, 941))	('tyrosine kinase', 'Gene', '7294', (1060, 1075))	('gefitinib', 'Chemical', 'MESH:D000077156', (857, 866))	('C', 'Chemical', 'MESH:D002244', (638, 639))	('Cancer', 'Disease', 'MESH:D009369', (1036, 1042))	('carcinoma', 'Phenotype', 'HP:0030731', (651, 660))	('M-CSF', 'Gene', (661, 666))	('EGF', 'Gene', (902, 905))	('C', 'Chemical', 'MESH:D002244', (72, 73))	('C', 'Chemical', 'MESH:D002244', (707, 708))	('tumor', 'Phenotype', 'HP:0002664', (1090, 1095))	('H1299', 'CellLine', 'CVCL:0060', (312, 317))	('mutation', 'Var', (1096, 1104))	('ADC', 'Chemical', '-', (0, 3))	('M-CSF', 'Gene', '1435', (661, 666))	('C', 'Chemical', 'MESH:D002244', (110, 111))	('C', 'Chemical', 'MESH:D002244', (878, 879))	('NSCLC', 'Disease', (778, 783))	('C', 'Chemical', 'MESH:D002244', (663, 664))	('C', 'Chemical', 'MESH:D002244', (140, 141))	('macrophage colony stimulating factor', 'Gene', (667, 703))	('EGF', 'Gene', (318, 321))	('paired Ig-like receptor B', 'Gene', '18733', (913, 938))	('EGF', 'Gene', (295, 298))	('NSCLC', 'Phenotype', 'HP:0030358', (778, 783))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (784, 810))	('EGF', 'Gene', '1950', (902, 905))	('C', 'Chemical', 'MESH:D002244', (851, 852))	('C', 'Chemical', 'MESH:D002244', (504, 505))	('tumor', 'Phenotype', 'HP:0002664', (999, 1004))	('DAB', 'Chemical', '-', (167, 170))	("3,3'-diaminobenzidine", 'Chemical', 'MESH:D015100', (171, 192))	('epidermal growth factor receptor', 'Gene', '1956', (323, 355))	('tumor', 'Phenotype', 'HP:0002664', (1116, 1121))	('EGF', 'Gene', '1950', (318, 321))	('TAM', 'Chemical', '-', (995, 998))	('lung cancer', 'Disease', 'MESH:D008175', (799, 810))	('EGF', 'Gene', '1950', (295, 298))	('PC9', 'CellLine', 'CVCL:B260', (877, 880))	('Cancer', 'Phenotype', 'HP:0002664', (1036, 1042))	('ILT4', 'Gene', (527, 531))	('C', 'Chemical', 'MESH:D002244', (54, 55))	('epidermal growth factor', 'Gene', '1950', (323, 346))	('macrophage colony stimulating factor', 'Gene', '1435', (667, 703))	('C', 'Chemical', 'MESH:D002244', (814, 815))	('C', 'Chemical', 'MESH:D002244', (1028, 1029))	('horseradish', 'Species', '3704', (447, 458))	('tumor', 'Disease', (1090, 1095))	('C', 'Chemical', 'MESH:D002244', (19, 20))	('C', 'Chemical', 'MESH:D002244', (36, 37))	('C', 'Chemical', 'MESH:D002244', (34, 35))	('MHC', 'Gene', '3107', (741, 744))	('C', 'Chemical', 'MESH:D002244', (782, 783))	('C', 'Chemical', 'MESH:D002244', (471, 472))	('PC9', 'CellLine', 'CVCL:B260', (850, 853))	('tumor', 'Disease', 'MESH:D009369', (1090, 1095))	('lung cancer', 'Disease', (799, 810))	('C', 'Chemical', 'MESH:D002244', (780, 781))	('C', 'Chemical', 'MESH:D002244', (2, 3))	('EGF', 'Gene', (257, 260))	('adenocarcinoma', 'Disease', (4, 18))	('tumor', 'Disease', (999, 1004))	('H1299', 'CellLine', 'CVCL:0060', (289, 294))	('lung cancer', 'Phenotype', 'HP:0100526', (799, 810))	('EGF', 'Gene', (882, 885))	('tumor', 'Disease', 'MESH:D009369', (999, 1004))	('C', 'Chemical', 'MESH:D002244', (1036, 1037))	('C', 'Chemical', 'MESH:D002244', (20, 21))	('squamous cell carcinoma', 'Disease', (943, 966))	('C', 'Chemical', 'MESH:D002244', (203, 204))	('PC9-GR', 'CellLine', 'CVCL:S706', (850, 856))	('C', 'Chemical', 'MESH:D002244', (941, 942))	('carcinoma', 'Phenotype', 'HP:0030731', (9, 18))	('C', 'Chemical', 'MESH:D002244', (743, 744))	('tumor', 'Disease', (1116, 1121))	('EGF', 'Gene', (285, 288))	('ILT4', 'Gene', '10288', (527, 531))	('EGF', 'Gene', '1950', (257, 260))	('C', 'Chemical', 'MESH:D002244', (68, 69))	('tumor', 'Disease', 'MESH:D009369', (1116, 1121))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (788, 810))	('C', 'Chemical', 'MESH:D002244', (88, 89))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (943, 966))	('epidermal growth factor receptor', 'Gene', (323, 355))	('Lewis lung carcinoma', 'Disease', (640, 660))	('EGF', 'Gene', '1950', (882, 885))	('epidermal growth factor', 'Gene', (261, 284))	('epidermal growth factor', 'Gene', '1950', (261, 284))	('carcinoma', 'Phenotype', 'HP:0030731', (957, 966))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (943, 966))	('Lewis lung carcinoma', 'Disease', 'MESH:D018827', (640, 660))	('NSCLC', 'Disease', 'MESH:D002289', (778, 783))	('EGF', 'Gene', '1950', (285, 288))	('Treg', 'Chemical', '-', (1139, 1143))	('TMB', 'Chemical', '-', (1086, 1089))	('MHC', 'Gene', (741, 744))	('adenocarcinoma', 'Disease', 'MESH:D000230', (4, 18))
483440	31452792	Mutations in exon 8 of TP53 are associated with shorter survival in patients with advanced lung cancer Currently, in clinical settings, all TP53 mutations have been considered equally.	('lung cancer', 'Phenotype', 'HP:0100526', (91, 102))	('TP53', 'Gene', (140, 144))	('survival', 'MPA', (56, 64))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('patients', 'Species', '9606', (68, 76))	('Mutations in exon', 'Var', (0, 17))	('shorter', 'NegReg', (48, 55))	('lung cancer', 'Disease', 'MESH:D008175', (91, 102))	('TP53', 'Gene', '7157', (23, 27))	('TP53', 'Gene', (23, 27))	('TP53', 'Gene', '7157', (140, 144))	('lung cancer', 'Disease', (91, 102))
483441	31452792	Such discrepancy can be partially due to the lack of unifying classification system for TP53 mutations.	('TP53', 'Gene', '7157', (88, 92))	('TP53', 'Gene', (88, 92))	('mutations', 'Var', (93, 102))
483442	31452792	In the present study, two of the most frequently used systems were compared, according to the location of the mutation or its functional effects on p53 protein and the impact of TP53 mutations on the overall survival (OS) time of 379 Chinese patients with advanced lung cancer was analyzed.	('advanced lung cancer', 'Disease', (256, 276))	('TP53', 'Gene', '7157', (178, 182))	('p53', 'Gene', (148, 151))	('TP53', 'Gene', (178, 182))	('p53', 'Gene', '7157', (148, 151))	('lung cancer', 'Phenotype', 'HP:0100526', (265, 276))	('OS', 'Chemical', '-', (218, 220))	('mutation', 'Var', (110, 118))	('advanced lung cancer', 'Disease', 'MESH:D008175', (256, 276))	('cancer', 'Phenotype', 'HP:0002664', (270, 276))	('patients', 'Species', '9606', (242, 250))
483444	31452792	The present results suggested that mutations occurring in exon 8 may be associated with shorter OS in tyrosine kinase inhibitor-naive patients (P=0.013) and in patients previously treated with one line of treatment (P=0.032).	('shorter', 'NegReg', (88, 95))	('patients', 'Species', '9606', (160, 168))	('patients', 'Species', '9606', (134, 142))	('OS', 'Chemical', '-', (96, 98))	('mutations', 'Var', (35, 44))	('tyrosine kinase inhibitor-naive', 'MPA', (102, 133))
483445	31452792	The results of the present study provided solid evidence that not all TP53 mutations were associated with a similar prognosis.	('TP53', 'Gene', '7157', (70, 74))	('TP53', 'Gene', (70, 74))	('mutations', 'Var', (75, 84))
483446	31452792	Mutations in exon 8 were found in a subgroup of patients with unfavorable prognosis across various treatment histories.	('found', 'Reg', (25, 30))	('Mutations in', 'Var', (0, 12))	('patients', 'Species', '9606', (48, 56))
483452	31452792	Mutations in TP53 have been revealed to result in the loss of tumor-suppressor function, thus leading to an unstable genome and downregulating apoptosis.	('TP53', 'Gene', (13, 17))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', (62, 67))	('loss', 'NegReg', (54, 58))	('downregulating', 'NegReg', (128, 142))	('Mutations', 'Var', (0, 9))	('apoptosis', 'CPA', (143, 152))	('unstable genome', 'MPA', (108, 123))	('TP53', 'Gene', '7157', (13, 17))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
483453	31452792	Accumulating evidence have suggested that, in addition to eliminating the tumor suppressor function, mutations in TP53 can also induce new functions, including gain-of-function mutations, which can accelerate tumor progression and metastasis.	('tumor', 'Disease', (209, 214))	('mutations', 'Var', (101, 110))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('TP53', 'Gene', '7157', (114, 118))	('tumor', 'Disease', (74, 79))	('tumor', 'Disease', 'MESH:D009369', (209, 214))	('TP53', 'Gene', (114, 118))	('accelerate', 'PosReg', (198, 208))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))	('gain-of-function', 'PosReg', (160, 176))
483454	31452792	TP53 mutation is observed in ~50% of patients with non-small cell lung cancer (NSCLC), with a higher prevalence in squamous-cell carcinoma of the lung compared with lung adenocarcinoma (38 vs. 12%).	('squamous-cell carcinoma of the lung', 'Disease', 'MESH:D002294', (115, 150))	('lung cancer', 'Phenotype', 'HP:0100526', (66, 77))	('carcinoma', 'Phenotype', 'HP:0030731', (175, 184))	('TP53', 'Gene', '7157', (0, 4))	('non-small cell lung cancer', 'Disease', (51, 77))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (165, 184))	('patients', 'Species', '9606', (37, 45))	('squamous-cell carcinoma of the lung', 'Disease', (115, 150))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (165, 184))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (51, 77))	('squamous-cell carcinoma of the lung', 'Phenotype', 'HP:0030359', (115, 150))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (55, 77))	('squamous-cell carcinoma', 'Phenotype', 'HP:0002860', (115, 138))	('TP53', 'Gene', (0, 4))	('NSCLC', 'Disease', 'MESH:D002289', (79, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (51, 77))	('carcinoma of the lung', 'Phenotype', 'HP:0100526', (129, 150))	('mutation', 'Var', (5, 13))	('NSCLC', 'Disease', (79, 84))	('lung adenocarcinoma', 'Disease', (165, 184))
483455	31452792	Unlike other tumor suppressor genes, such as APC, BRCA1 or RB transcriptional corepressor 1 (RB1) with truncating mutations being the major alteration type, the majority of TP53 alterations are missense mutations, accounting for more than 75% of alterations.	('tumor', 'Disease', (13, 18))	('BRCA1', 'Gene', (50, 55))	('BRCA1', 'Gene', '672', (50, 55))	('APC', 'Disease', 'MESH:D011125', (45, 48))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('APC', 'Disease', (45, 48))	('TP53', 'Gene', '7157', (173, 177))	('TP53', 'Gene', (173, 177))	('alterations', 'Var', (178, 189))	('RB transcriptional corepressor 1 (RB1', 'Gene', '5925', (59, 96))	('missense mutations', 'Var', (194, 212))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
483456	31452792	The majority of TP53 mutations occur in the DNA-binding region, in exons 5-8, spanning 540 nucleotides with numerous recurring hotspot mutations, leading to a stable protein with a significant loss of activity.	('activity', 'MPA', (201, 209))	('loss', 'NegReg', (193, 197))	('mutations', 'Var', (135, 144))	('TP53', 'Gene', '7157', (16, 20))	('TP53', 'Gene', (16, 20))	('mutations', 'Var', (21, 30))
483458	31452792	The prognostic and predictive values of TP53 mutations have been investigated, however results are conflicting; a previous study demonstrated that non-disruptive TP53 mutations are independently correlated with shorter OS in patients with advanced NSCLC, regardless of epidermal growth factor receptor (EGFR) and KRAS status.	('EGFR', 'Gene', '1956', (303, 307))	('OS', 'Chemical', '-', (219, 221))	('NSCLC', 'Disease', (248, 253))	('patients', 'Species', '9606', (225, 233))	('KRAS', 'Gene', '3845', (313, 317))	('shorter OS', 'Disease', (211, 221))	('EGFR', 'Gene', (303, 307))	('TP53', 'Gene', (162, 166))	('TP53', 'Gene', '7157', (162, 166))	('NSCLC', 'Disease', 'MESH:D002289', (248, 253))	('mutations', 'Var', (167, 176))	('epidermal growth factor receptor', 'Gene', (269, 301))	('TP53', 'Gene', '7157', (40, 44))	('TP53', 'Gene', (40, 44))	('epidermal growth factor receptor', 'Gene', '1956', (269, 301))	('KRAS', 'Gene', (313, 317))
483459	31452792	Another study revealed that a shorter OS was associated with adjuvant chemotherapy in patients presenting mutations in TP53 with NSCLC and completely resected tumors.	('OS', 'Chemical', '-', (38, 40))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('tumors', 'Disease', (159, 165))	('tumors', 'Phenotype', 'HP:0002664', (159, 165))	('NSCLC', 'Disease', (129, 134))	('tumors', 'Disease', 'MESH:D009369', (159, 165))	('mutations', 'Var', (106, 115))	('TP53', 'Gene', '7157', (119, 123))	('TP53', 'Gene', (119, 123))	('NSCLC', 'Disease', 'MESH:D002289', (129, 134))	('patients', 'Species', '9606', (86, 94))
483460	31452792	A previous study investigating clinical outcomes of patients with NSCLC with dual EGFR and TP53 mutations revealed lower response rates and shorter progression-free survival (PFS) in such patients compared with patients with EGFR mutations.	('TP53', 'Gene', (91, 95))	('EGFR', 'Gene', (82, 86))	('shorter', 'NegReg', (140, 147))	('patients', 'Species', '9606', (211, 219))	('NSCLC', 'Disease', (66, 71))	('progression-free survival', 'CPA', (148, 173))	('EGFR', 'Gene', '1956', (225, 229))	('NSCLC', 'Disease', 'MESH:D002289', (66, 71))	('patients', 'Species', '9606', (188, 196))	('lower', 'NegReg', (115, 120))	('EGFR', 'Gene', '1956', (82, 86))	('patients', 'Species', '9606', (52, 60))	('EGFR', 'Gene', (225, 229))	('TP53', 'Gene', '7157', (91, 95))	('response', 'MPA', (121, 129))	('mutations', 'Var', (96, 105))
483461	31452792	By contrast, other previous studies have revealed the lack of association between TP53 mutations and OS or response to treatment.	('TP53', 'Gene', '7157', (82, 86))	('TP53', 'Gene', (82, 86))	('OS', 'Chemical', '-', (101, 103))	('mutations', 'Var', (87, 96))
483463	31452792	A variety of criteria have been used to categorize TP53 mutations, including, but not limited to, functional effects on p53 (disruptive vs. non-disruptive) and location ('hotspot' exons vs. 'non-hotspot' exons).	('mutations', 'Var', (56, 65))	('TP53', 'Gene', (51, 55))	('p53', 'Gene', '7157', (120, 123))	('p53', 'Gene', (120, 123))	('TP53', 'Gene', '7157', (51, 55))
483466	31452792	Important functional differences among various mutant forms of p53 have been elucidated, including mutations in the amino-terminal (AT) domain, the oligomerization domain (OD) and the DNA-binding domain (DBD).	('oligomerization', 'MPA', (148, 163))	('p53', 'Gene', (63, 66))	('p53', 'Gene', '7157', (63, 66))	('DNA-binding', 'Interaction', (184, 195))	('mutations', 'Var', (99, 108))	('mutant', 'Var', (47, 53))	('AT', 'Disease', 'None', (132, 134))
483470	31452792	Mutations occurring in the OD, which is important for the tetramerization of p53, often behave as loss-of-function mutations.	('p53', 'Gene', (77, 80))	('Mutations', 'Var', (0, 9))	('p53', 'Gene', '7157', (77, 80))	('loss-of-function', 'NegReg', (98, 114))
483471	31452792	Patients harboring such mutations are less responsive to therapies that rely on p53-mediated cytotoxic effects.	('mutations', 'Var', (24, 33))	('p53', 'Gene', '7157', (80, 83))	('p53', 'Gene', (80, 83))	('Patients', 'Species', '9606', (0, 8))
483472	31452792	In total, ~80% of TP53 mutations affect the DBD, encoded by exons 5-8.	('TP53', 'Gene', '7157', (18, 22))	('affect', 'Reg', (33, 39))	('TP53', 'Gene', (18, 22))	('mutations', 'Var', (23, 32))	('DBD', 'MPA', (44, 47))
483473	31452792	In the present study, capture-based ultra-deep targeted sequencing was performed on the plasma samples of 379 Chinese patients with advanced lung cancer to investigate clinical outcomes associated with TP53 mutations.	('TP53', 'Gene', (202, 206))	('mutations', 'Var', (207, 216))	('advanced lung cancer', 'Disease', 'MESH:D008175', (132, 152))	('lung cancer', 'Phenotype', 'HP:0100526', (141, 152))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('advanced lung cancer', 'Disease', (132, 152))	('patients', 'Species', '9606', (118, 126))	('TP53', 'Gene', '7157', (202, 206))
483478	31452792	The inclusion criteria were: i) Patients diagnosed with advanced-stage lung cancer (stage IIIB-stage IV) of any histology harboring at least one classic NSCLC driver mutation; and ii) the patient was treated at any of the nine participating centers between September 2015 and October 2016.	('Patients', 'Species', '9606', (32, 40))	('patient', 'Species', '9606', (188, 195))	('advanced-stage lung cancer', 'Disease', (56, 82))	('NSCLC', 'Disease', (153, 158))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('NSCLC', 'Disease', 'MESH:D002289', (153, 158))	('mutation', 'Var', (166, 174))	('advanced-stage lung cancer', 'Disease', 'MESH:D008175', (56, 82))	('lung cancer', 'Phenotype', 'HP:0100526', (71, 82))
483485	31452792	The TP53 status of 379 patients with advanced lung cancer (Stage IIIB to IV) harboring at least one classic NSCLC driver mutation with various histological types was assessed in the present study.	('advanced lung cancer', 'Disease', (37, 57))	('TP53', 'Gene', (4, 8))	('patients', 'Species', '9606', (23, 31))	('NSCLC', 'Disease', (108, 113))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('mutation', 'Var', (121, 129))	('NSCLC', 'Disease', 'MESH:D002289', (108, 113))	('advanced lung cancer', 'Disease', 'MESH:D008175', (37, 57))	('TP53', 'Gene', '7157', (4, 8))	('lung cancer', 'Phenotype', 'HP:0100526', (46, 57))
483486	31452792	Among them, 294 patients had EGFR mutations, 24 had anaplastic lymphoma kinase (ALK) rearrangements, 14 had erb-b2 receptor tyrosine kinase 2 mutations, five had MET Proto-Oncogene (MET) mutations, two had B-raf proto-oncogene mutations, four had ROS proto-oncogene 1, receptor tyrosine kinase fusions, 11 had KRAS fusions and five had ret proto-oncogene fusions; the remaining 20 patients had dual driver mutations (Table I).	('anaplastic lymphoma kinase', 'Gene', '238', (52, 78))	('patients', 'Species', '9606', (16, 24))	('ROS proto-oncogene 1, receptor tyrosine kinase', 'Gene', '6098', (247, 293))	('anaplastic lymphoma kinase', 'Gene', (52, 78))	('mutations', 'Var', (142, 151))	('EGFR', 'Gene', '1956', (29, 33))	('lymphoma', 'Phenotype', 'HP:0002665', (63, 71))	('mutations', 'Var', (34, 43))	('rearrangements', 'Var', (85, 99))	('KRAS', 'Gene', '3845', (310, 314))	('ret', 'Gene', (336, 339))	('ret', 'Gene', '5979', (336, 339))	('erb-b2', 'Gene', (108, 114))	('KRAS', 'Gene', (310, 314))	('ALK', 'Gene', '238', (80, 83))	('patients', 'Species', '9606', (381, 389))	('EGFR', 'Gene', (29, 33))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (52, 71))	('ALK', 'Gene', (80, 83))
483494	31452792	A capture-based ultra-deep targeted sequencing analysis was performed as described in Materials and methods and on the plasma samples obtained from 379 patients with advanced lung cancer to investigate their TP53 status and the prognostic value of the TP53 mutations.	('mutations', 'Var', (257, 266))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('lung cancer', 'Phenotype', 'HP:0100526', (175, 186))	('TP53', 'Gene', '7157', (208, 212))	('advanced lung cancer', 'Disease', 'MESH:D008175', (166, 186))	('TP53', 'Gene', (208, 212))	('advanced lung cancer', 'Disease', (166, 186))	('TP53', 'Gene', '7157', (252, 256))	('TP53', 'Gene', (252, 256))	('patients', 'Species', '9606', (152, 160))
483495	31452792	The prevalence of TP53 mutations in the cohort was 49.9% (189/379), which is comparable to its prevalence in the western population.	('mutations', 'Var', (23, 32))	('TP53', 'Gene', '7157', (18, 22))	('TP53', 'Gene', (18, 22))
483496	31452792	Among them, 163 patients harbored mutations in hotspot exons: 48 Mutations were on exon 5, 31 on exon 6, 40 on exon 7 and 46 on exon 8 (Table I).	('Mutations', 'Var', (65, 74))	('patients', 'Species', '9606', (16, 24))	('mutations', 'Var', (34, 43))
483499	31452792	The distribution of TP53 mutations is also presented in Fig.	('mutations', 'Var', (25, 34))	('TP53', 'Gene', '7157', (20, 24))	('TP53', 'Gene', (20, 24))
483500	31452792	No association between TP53 mutations and smoking history was observed when all TP53 mutations were taken into consideration (data not shown).	('TP53', 'Gene', '7157', (80, 84))	('TP53', 'Gene', (80, 84))	('TP53', 'Gene', '7157', (23, 27))	('TP53', 'Gene', (23, 27))	('mutations', 'Var', (28, 37))
483502	31452792	The percentages of TP53 mutations were comparable in patients with adenocarcinoma (48.3%) and small cell lung cancer (48.4%) (data not shown).	('adenocarcinoma', 'Disease', (67, 81))	('lung cancer', 'Phenotype', 'HP:0100526', (105, 116))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('adenocarcinoma', 'Disease', 'MESH:D000230', (67, 81))	('patients', 'Species', '9606', (53, 61))	('small cell lung cancer', 'Disease', 'MESH:D055752', (94, 116))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (94, 116))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('TP53', 'Gene', '7157', (19, 23))	('small cell lung cancer', 'Disease', (94, 116))	('TP53', 'Gene', (19, 23))	('mutations', 'Var', (24, 33))
483503	31452792	All patients investigated in the present study with small cell lung cancer carried TP53 mutations, in line with previous studies, suggesting that a significant percentage of patients with small cell lung cancer have TP53 mutations.	('TP53', 'Gene', '7157', (83, 87))	('TP53', 'Gene', (216, 220))	('small cell lung cancer', 'Disease', 'MESH:D055752', (52, 74))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('mutations', 'Var', (221, 230))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (52, 74))	('small cell lung cancer', 'Disease', (188, 210))	('TP53', 'Gene', (83, 87))	('mutations', 'Var', (88, 97))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('small cell lung cancer', 'Disease', (52, 74))	('patients', 'Species', '9606', (174, 182))	('lung cancer', 'Phenotype', 'HP:0100526', (199, 210))	('lung cancer', 'Phenotype', 'HP:0100526', (63, 74))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (188, 210))	('patients', 'Species', '9606', (4, 12))	('TP53', 'Gene', '7157', (216, 220))	('small cell lung cancer', 'Disease', 'MESH:D055752', (188, 210))
483504	31452792	Next, the mutation spectra of patients with TP53 mutations were compared with patients without TP53 mutation (Fig.	('mutations', 'Var', (49, 58))	('patients', 'Species', '9606', (78, 86))	('patients', 'Species', '9606', (30, 38))	('TP53', 'Gene', '7157', (44, 48))	('TP53', 'Gene', '7157', (95, 99))	('TP53', 'Gene', (44, 48))	('TP53', 'Gene', (95, 99))
483506	31452792	In addition, a larger number of RB1 mutations and MET amplifications were present in patients with TP53 mutation (Fig.	('TP53', 'Gene', (99, 103))	('RB1', 'Gene', (32, 35))	('mutations', 'Var', (36, 45))	('patients', 'Species', '9606', (85, 93))	('mutation', 'Var', (104, 112))	('RB1', 'Gene', '5925', (32, 35))	('TP53', 'Gene', '7157', (99, 103))
483508	31452792	A positive correlation was identified between TP53 mutations and the TNM stage when all mutations were considered collectively.	('TP53', 'Gene', (46, 50))	('TNM stage', 'CPA', (69, 78))	('TP53', 'Gene', '7157', (46, 50))	('mutations', 'Var', (51, 60))
483509	31452792	Patients with TP53 mutations were more likely to have advanced N (P=0.004, r=0.161) and M (P=0.004, r=0.151) stages of the disease (Fig.	('Patients', 'Species', '9606', (0, 8))	('TP53', 'Gene', '7157', (14, 18))	('TP53', 'Gene', (14, 18))	('mutations', 'Var', (19, 28))
483510	31452792	A positive correlation was also identified between liver metastasis and TP53 mutations when all mutations were considered collectively (P=0.001, r=0.187).	('TP53', 'Gene', (72, 76))	('mutations', 'Var', (77, 86))	('TP53', 'Gene', '7157', (72, 76))	('liver metastasis', 'CPA', (51, 67))
483511	31452792	In the cohort, 67.9% patients (55/81) with TP53 mutations had liver metastasis; in contrast, 45.5% (127/279) of patients without a TP53 mutation had liver metastasis (P=0.001) (Fig.	('liver metastasis', 'CPA', (62, 78))	('liver metastasis', 'CPA', (149, 165))	('patients', 'Species', '9606', (112, 120))	('TP53', 'Gene', '7157', (131, 135))	('patients', 'Species', '9606', (21, 29))	('TP53', 'Gene', (131, 135))	('TP53', 'Gene', '7157', (43, 47))	('TP53', 'Gene', (43, 47))	('mutations', 'Var', (48, 57))
483513	31452792	When TP53 mutations were classified as disruptive or non-disruptive mutations, TP53 disruptive mutations exhibited a non-significant correlation with N (P=0.08) and M (P=0.1) stages.	('TP53', 'Gene', '7157', (79, 83))	('TP53', 'Gene', (79, 83))	('TP53', 'Gene', '7157', (5, 9))	('mutations', 'Var', (95, 104))	('TP53', 'Gene', (5, 9))
483514	31452792	A strong correlation was observed between liver metastasis and TP53 mutation, regardless of the classification system (P<0.001).	('TP53', 'Gene', (63, 67))	('TP53', 'Gene', '7157', (63, 67))	('mutation', 'Var', (68, 76))	('liver', 'Disease', (42, 47))
483518	31452792	The prognostic value of TP53 mutations was evaluated using the two aforementioned classification systems.	('TP53', 'Gene', (24, 28))	('mutations', 'Var', (29, 38))	('TP53', 'Gene', '7157', (24, 28))
483520	31452792	In the TKI-naive patients, 74 patients had TP53 mutations.	('patients', 'Species', '9606', (30, 38))	('patients', 'Species', '9606', (17, 25))	('TP53', 'Gene', '7157', (43, 47))	('TP53', 'Gene', (43, 47))	('mutations', 'Var', (48, 57))
483522	31452792	No association was observed between TP53 mutations and OS when all TP53 mutations were considered collectively or classified according to their location (hotspot exon vs. non-hotspot exon mutations) and functional effects on p53 protein (disruptive vs. non-disruptive; Fig.	('mutations', 'Var', (41, 50))	('mutations', 'Var', (72, 81))	('TP53', 'Gene', (36, 40))	('OS', 'Chemical', '-', (55, 57))	('p53', 'Gene', (225, 228))	('TP53', 'Gene', '7157', (36, 40))	('p53', 'Gene', '7157', (225, 228))	('TP53', 'Gene', '7157', (67, 71))	('protein', 'Protein', (229, 236))	('TP53', 'Gene', (67, 71))	('effects', 'Reg', (214, 221))
483523	31452792	Notably, mutations occurring on exon 8 were found to be associated with OS (P=0.013) when controlling for age, sex, stage and histology.	('OS', 'Chemical', '-', (72, 74))	('mutations', 'Var', (9, 18))	('associated with', 'Reg', (56, 71))
483524	31452792	A total of 14 patients with mutations in exon 8 had a shorter median OS compared with the remaining 91 patients who had no mutations in exon 8 (Fig.	('OS', 'Chemical', '-', (69, 71))	('shorter', 'NegReg', (54, 61))	('patients', 'Species', '9606', (103, 111))	('median OS', 'MPA', (62, 71))	('mutations in', 'Var', (28, 40))	('patients', 'Species', '9606', (14, 22))
483525	31452792	In patients previously treated with one line of TKI treatment (n=184), an analysis revealed that TP53 status, when all mutations were considered collectively, was found to be marginally associated with OS (P=0.05).	('OS', 'Chemical', '-', (202, 204))	('TP53', 'Gene', '7157', (97, 101))	('TP53', 'Gene', (97, 101))	('associated', 'Reg', (186, 196))	('patients', 'Species', '9606', (3, 11))	('mutations', 'Var', (119, 128))
483526	31452792	Patients with TP53 mutations had a shorter OS compared with patients with WT TP53 (Fig.	('TP53', 'Gene', '7157', (14, 18))	('TP53', 'Gene', (14, 18))	('patients', 'Species', '9606', (60, 68))	('shorter', 'NegReg', (35, 42))	('mutations', 'Var', (19, 28))	('Patients', 'Species', '9606', (0, 8))	('OS', 'Chemical', '-', (43, 45))	('TP53', 'Gene', '7157', (77, 81))	('TP53', 'Gene', (77, 81))
483527	31452792	A total of 26 patients had mutations in exon 8, including 22 missense, three frameshift and one nonsense mutation (Fig.	('mutations', 'Var', (27, 36))	('missense', 'Var', (61, 69))	('frameshift', 'Var', (77, 87))	('patients', 'Species', '9606', (14, 22))
483530	31452792	The impact of TP53 mutations on OS in osimertinib-treated patients was subsequently analyzed.	('TP53', 'Gene', '7157', (14, 18))	('osimertinib', 'Chemical', 'MESH:C000603933', (38, 49))	('TP53', 'Gene', (14, 18))	('mutations', 'Var', (19, 28))	('OS', 'Chemical', '-', (32, 34))	('patients', 'Species', '9606', (58, 66))
483531	31452792	In this cohort, 32 patients had WT TP53 and 67 patients had TP53 mutations (data not shown).	('patients', 'Species', '9606', (19, 27))	('TP53', 'Gene', '7157', (35, 39))	('patients', 'Species', '9606', (47, 55))	('TP53', 'Gene', (35, 39))	('TP53', 'Gene', '7157', (60, 64))	('TP53', 'Gene', (60, 64))	('mutations', 'Var', (65, 74))
483534	31452792	No association was observed between TP53 status and OS, regardless of classification system, in patients harboring EGFR L858R (data not shown).	('OS', 'Chemical', '-', (52, 54))	('L858R', 'Mutation', 'rs121434568', (120, 125))	('EGFR', 'Gene', '1956', (115, 119))	('TP53', 'Gene', '7157', (36, 40))	('EGFR', 'Gene', (115, 119))	('patients', 'Species', '9606', (96, 104))	('TP53', 'Gene', (36, 40))	('L858R', 'Var', (120, 125))
483535	31452792	In patients harboring EGFR 19 del concurrent to T790M treated with osimertinib, non-disruptive mutations (P=0.031) were found to be associated with OS (Fig.	('EGFR 19 del', 'Mutation', 'c.19delEGFR', (22, 33))	('OS', 'Chemical', '-', (148, 150))	('EGFR 19', 'Gene', (22, 29))	('patients', 'Species', '9606', (3, 11))	('T790M', 'Mutation', 'rs121434569', (48, 53))	('associated', 'Reg', (132, 142))	('osimertinib', 'Chemical', 'MESH:C000603933', (67, 78))	('T790M', 'Var', (48, 53))	('del concurrent to T790M', 'Var', (30, 53))
483536	31452792	A total of 14 patients with non-disruptive TP53 mutations exhibited a significantly shorter OS compared with patients with WT TP53.	('TP53', 'Gene', (126, 130))	('patients', 'Species', '9606', (109, 117))	('TP53', 'Gene', '7157', (126, 130))	('shorter', 'NegReg', (84, 91))	('OS', 'Chemical', '-', (92, 94))	('TP53', 'Gene', '7157', (43, 47))	('TP53', 'Gene', (43, 47))	('mutations', 'Var', (48, 57))	('patients', 'Species', '9606', (14, 22))
483537	31452792	All TP53 mutations (P=0.156), particularly disruptive mutations (P=0.690) as well as all hotspot exon mutations (P=0.128) including exon 8 (P=0.075) did not exhibit an association with OS (Fig.	('mutations', 'Var', (9, 18))	('OS', 'Chemical', '-', (185, 187))	('TP53', 'Gene', '7157', (4, 8))	('TP53', 'Gene', (4, 8))
483538	31452792	In patients treated with two lines of TKI, the analysis revealed that TP53 mutations, when considered collectively, were identified to be associated with OS (P=0.037; Fig.	('TP53', 'Gene', '7157', (70, 74))	('associated', 'Reg', (138, 148))	('TP53', 'Gene', (70, 74))	('patients', 'Species', '9606', (3, 11))	('mutations', 'Var', (75, 84))	('OS', 'Chemical', '-', (154, 156))
483539	31452792	Mutations occurring on exon 8 (P=0.079) as well as all hot exon mutations (P=0.052) also exhibited an association with OS (Fig.	('Mutations', 'Var', (0, 9))	('association', 'Interaction', (102, 113))	('OS', 'Chemical', '-', (119, 121))
483542	31452792	Furthermore, by comparing multiple TP53 mutation classification systems, it was identified that mutations in exon 8 may serve as prognostic biomarkers across all patients.	('patients', 'Species', '9606', (162, 170))	('TP53', 'Gene', '7157', (35, 39))	('TP53', 'Gene', (35, 39))	('mutations in', 'Var', (96, 108))
483543	31452792	In the present study, the association between TP53 mutations, analyzed using two classification methods (based on location and function), and OS was investigated in a large cohort of patients with advanced lung cancer.	('mutations', 'Var', (51, 60))	('OS', 'Chemical', '-', (142, 144))	('TP53', 'Gene', '7157', (46, 50))	('lung cancer', 'Phenotype', 'HP:0100526', (206, 217))	('TP53', 'Gene', (46, 50))	('advanced lung cancer', 'Disease', 'MESH:D008175', (197, 217))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('advanced lung cancer', 'Disease', (197, 217))	('patients', 'Species', '9606', (183, 191))
483545	31452792	The present results revealed that mutations occurring in exon 8 correlated with shorter OS in TKI-naive and patients previously treated with one line of TKI.	('patients', 'Species', '9606', (108, 116))	('OS', 'Chemical', '-', (88, 90))	('mutations', 'Var', (34, 43))	('shorter OS', 'MPA', (80, 90))
483546	31452792	Such mutations also exhibited a slight association, although not significant, with shorter OS in patients previously treated with two lines of treatment.	('shorter OS', 'Disease', (83, 93))	('OS', 'Chemical', '-', (91, 93))	('mutations', 'Var', (5, 14))	('patients', 'Species', '9606', (97, 105))
483547	31452792	Therefore, TP53 exon 8 mutations defined a distinct subset of patients with an unfavorable prognosis.	('TP53', 'Gene', '7157', (11, 15))	('mutations', 'Var', (23, 32))	('TP53', 'Gene', (11, 15))	('patients', 'Species', '9606', (62, 70))
483548	31452792	The association between OS and TP53 mutations categorized by function or considered collectively was not consistent across various treatment histories.	('TP53', 'Gene', '7157', (31, 35))	('TP53', 'Gene', (31, 35))	('mutations', 'Var', (36, 45))	('OS', 'Chemical', '-', (24, 26))
483549	31452792	In fact, TP53 mutations considered collectively were only associated with OS in patients who received a certain treatment.	('associated with', 'Reg', (58, 73))	('patients', 'Species', '9606', (80, 88))	('TP53', 'Gene', '7157', (9, 13))	('TP53', 'Gene', (9, 13))	('OS', 'Chemical', '-', (74, 76))	('mutations', 'Var', (14, 23))
483550	31452792	TP53 mutations were not associated with the prognosis in treatment-naive patients.	('TP53', 'Gene', '7157', (0, 4))	('patients', 'Species', '9606', (73, 81))	('TP53', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))
483551	31452792	Such inconsistencies could be attributed to the following reasons: i) Not all mutations occurring on hotspot exons (exons 5-8) are functional; ii) treatment history of treated patients may vary among patients; iii) the number of patients were significantly fewer in patients treated with >=2 lines of treatment; and iv) a number of studies have reported that TP53 can serve as a resistance mechanism against the function of EGFR inhibitors.	('fewer', 'NegReg', (257, 262))	('patients', 'Species', '9606', (176, 184))	('patients', 'Species', '9606', (229, 237))	('patients', 'Species', '9606', (266, 274))	('patients', 'Species', '9606', (200, 208))	('TP53', 'Gene', '7157', (359, 363))	('mutations', 'Var', (78, 87))	('TP53', 'Gene', (359, 363))	('EGFR', 'Gene', '1956', (424, 428))	('EGFR', 'Gene', (424, 428))
483552	31452792	Therefore, the impact of mutations in TP53 in patients treated with such inhibitors may be greater compared with patients treated with other therapies, such as chemotherapy.	('mutations', 'Var', (25, 34))	('patients', 'Species', '9606', (46, 54))	('TP53', 'Gene', (38, 42))	('patients', 'Species', '9606', (113, 121))	('TP53', 'Gene', '7157', (38, 42))
483553	31452792	Currently, all TP53 mutations are considered equally in clinical settings, as well as during the development of therapeutic strategies, which primarily focuses on the restoration of the WT activity of TP53.	('TP53', 'Gene', '7157', (201, 205))	('TP53', 'Gene', '7157', (15, 19))	('TP53', 'Gene', (201, 205))	('TP53', 'Gene', (15, 19))	('mutations', 'Var', (20, 29))
483554	31452792	Numerous studies investigating the prognostic value of TP53 mutations, when all mutations were considered collectively, identified either no or slight associations, which was subsequently lost in the multivariate analysis.	('mutations', 'Var', (60, 69))	('TP53', 'Gene', (55, 59))	('TP53', 'Gene', '7157', (55, 59))
483555	31452792	An increasing number of studies have been categorizing TP53 mutations based on the multiple biological effects produced by different mutant proteins.	('mutations', 'Var', (60, 69))	('TP53', 'Gene', (55, 59))	('TP53', 'Gene', '7157', (55, 59))
483556	31452792	Several previous studies categorized TP53 mutations and examined their prognostic value, presenting conflicting results, partially due to the lack of a unifying classification system.	('TP53', 'Gene', (37, 41))	('mutations', 'Var', (42, 51))	('TP53', 'Gene', '7157', (37, 41))
483559	31452792	Furthermore, mutations occurring on different parts of the gene have different biological functions such as the AT domain, DBD and oligomerization domain.	('oligomerization domain', 'Disease', (131, 153))	('mutations', 'Var', (13, 22))	('AT', 'Disease', 'None', (112, 114))	('DBD', 'Disease', (123, 126))
483560	31452792	Since a significant percentage of patients exhibiting mutations in EGFR have concurrent TP53 mutations, numerous studies have also assessed the impact of TP53 mutations on the clinical outcomes of patients with EGFR mutations treated with EGFR-TKIs.	('patients', 'Species', '9606', (197, 205))	('TP53', 'Gene', (154, 158))	('mutations', 'Var', (54, 63))	('EGFR', 'Gene', '1956', (211, 215))	('TP53', 'Gene', '7157', (88, 92))	('patients', 'Species', '9606', (34, 42))	('EGFR', 'Gene', '1956', (239, 243))	('EGFR', 'Gene', '1956', (67, 71))	('EGFR', 'Gene', (211, 215))	('EGFR', 'Gene', (67, 71))	('TP53', 'Gene', (88, 92))	('TP53', 'Gene', '7157', (154, 158))	('EGFR', 'Gene', (239, 243))
483561	31452792	A previous study revealed that the predictive and prognostic power of TP53 status to first-generation EGFR-TKI treatment are more reliable in patients harboring EGFR exon 19 deletion (19 del).	('19 del', 'Var', (184, 190))	('EGFR', 'Gene', (161, 165))	('TP53', 'Gene', '7157', (70, 74))	('exon', 'Var', (166, 170))	('TP53', 'Gene', (70, 74))	('patients', 'Species', '9606', (142, 150))	('EGFR', 'Gene', '1956', (102, 106))	('EGFR', 'Gene', '1956', (161, 165))	('EGFR', 'Gene', (102, 106))
483562	31452792	Since TP53 mutations have been confirmed as a primary resistance mechanism to EGFR-TKI, some studies reported diminished responses.	('mutations', 'Var', (11, 20))	('TP53', 'Gene', '7157', (6, 10))	('TP53', 'Gene', (6, 10))	('responses', 'MPA', (121, 130))	('EGFR', 'Gene', '1956', (78, 82))	('EGFR', 'Gene', (78, 82))
483563	31452792	Canale et al revealed that TP53 exon 8 mutations, especially in conjunction with EGFR 19 deletion, were associated with a significantly lower disease control rate.	('TP53', 'Gene', '7157', (27, 31))	('lower', 'NegReg', (136, 141))	('TP53', 'Gene', (27, 31))	('EGFR 19 del', 'Mutation', 'c.19delEGFR', (81, 92))	('mutations', 'Var', (39, 48))	('EGFR 19', 'Gene', (81, 88))	('disease control rate', 'CPA', (142, 162))
483564	31452792	Labbe et al reported a marginally lower response rate and shorter PFS in patients with concurrent EGFR and TP53 mutations, where all TP53 mutations were considered collectively.	('EGFR', 'Gene', (98, 102))	('shorter', 'NegReg', (58, 65))	('response', 'MPA', (40, 48))	('lower', 'NegReg', (34, 39))	('TP53', 'Gene', '7157', (107, 111))	('TP53', 'Gene', (107, 111))	('PFS', 'MPA', (66, 69))	('mutations', 'Var', (112, 121))	('EGFR', 'Gene', '1956', (98, 102))	('TP53', 'Gene', '7157', (133, 137))	('patients', 'Species', '9606', (73, 81))	('TP53', 'Gene', (133, 137))
483567	31452792	To the best of our knowledge, the present study is the first study to investigate, in a large cohort, the clinical relevance of TP53 mutations in Chinese patients with advanced lung cancer, who had received previous treatments.	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('TP53', 'Gene', '7157', (128, 132))	('TP53', 'Gene', (128, 132))	('advanced lung cancer', 'Disease', 'MESH:D008175', (168, 188))	('patients', 'Species', '9606', (154, 162))	('advanced lung cancer', 'Disease', (168, 188))	('mutations', 'Var', (133, 142))	('lung cancer', 'Phenotype', 'HP:0100526', (177, 188))
483568	31452792	Furthermore, to the best of our knowledge, the present study is also the first one to investigate the association between TP53 mutations and OS in patients treated with osimertinib, a TKI inhibitor.	('association', 'Interaction', (102, 113))	('TP53', 'Gene', (122, 126))	('OS', 'Chemical', '-', (141, 143))	('osimertinib', 'Chemical', 'MESH:C000603933', (169, 180))	('patients', 'Species', '9606', (147, 155))	('mutations', 'Var', (127, 136))	('TP53', 'Gene', '7157', (122, 126))
483569	31452792	It was revealed that the prognostic power of TP53 mutations only existed in patients with EGFR 19 del and T790M.	('patients', 'Species', '9606', (76, 84))	('TP53', 'Gene', (45, 49))	('EGFR 19', 'Gene', (90, 97))	('T790M', 'Mutation', 'rs121434569', (106, 111))	('T790M', 'Var', (106, 111))	('EGFR 19 del', 'Mutation', 'c.19delEGFR', (90, 101))	('TP53', 'Gene', '7157', (45, 49))
483570	31452792	In such patients, non-disruptive mutations were associated with shorter OS.	('shorter OS', 'Disease', (64, 74))	('OS', 'Chemical', '-', (72, 74))	('non-disruptive mutations', 'Var', (18, 42))	('patients', 'Species', '9606', (8, 16))
483571	31452792	The prognostic power was not statistically significant in patients harboring EGFR L858R.	('L858R', 'Mutation', 'rs121434568', (82, 87))	('EGFR', 'Gene', '1956', (77, 81))	('patients', 'Species', '9606', (58, 66))	('L858R', 'Var', (82, 87))	('EGFR', 'Gene', (77, 81))
483572	31452792	A previous study evaluated the impact of TP53 mutations on the outcomes of patients with EGFR mutations treated with one course of EGFR-TKI and revealed similar results.	('TP53', 'Gene', '7157', (41, 45))	('TP53', 'Gene', (41, 45))	('EGFR', 'Gene', (89, 93))	('mutations', 'Var', (94, 103))	('patients', 'Species', '9606', (75, 83))	('EGFR', 'Gene', '1956', (131, 135))	('EGFR', 'Gene', (131, 135))	('EGFR', 'Gene', '1956', (89, 93))
483573	31452792	Patients harboring concurrent mutations in the exon 8 of TP53 and EGFR 19 del were associated with a shorter PFS and OS.	('OS', 'Chemical', '-', (117, 119))	('EGFR 19', 'Gene', (66, 73))	('PFS', 'CPA', (109, 112))	('shorter', 'NegReg', (101, 108))	('Patients', 'Species', '9606', (0, 8))	('mutations in', 'Var', (30, 42))	('EGFR 19 del', 'Mutation', 'c.19delEGFR', (66, 77))	('TP53', 'Gene', '7157', (57, 61))	('TP53', 'Gene', (57, 61))
483574	31452792	The predictive and prognostic power was much weaker in subgroups containing patients with other EGFR mutations.	('EGFR', 'Gene', (96, 100))	('patients', 'Species', '9606', (76, 84))	('mutations', 'Var', (101, 110))	('EGFR', 'Gene', '1956', (96, 100))
483575	31452792	One major limitation associated with the present study is that it only included patients with classic NSCLC driver mutations.	('NSCLC', 'Disease', 'MESH:D002289', (102, 107))	('NSCLC', 'Disease', (102, 107))	('mutations', 'Var', (115, 124))	('patients', 'Species', '9606', (80, 88))
483580	31452792	Furthermore, to the best of our knowledge, the current study may be the first to reveal that the prognostic potential of TP53 mutations, in patients treated with osimertinib, only exists in patients with EGFR 19 del mutation.	('patients', 'Species', '9606', (190, 198))	('TP53', 'Gene', '7157', (121, 125))	('TP53', 'Gene', (121, 125))	('osimertinib', 'Chemical', 'MESH:C000603933', (162, 173))	('patients', 'Species', '9606', (140, 148))	('mutations', 'Var', (126, 135))	('EGFR 19 del', 'Mutation', 'c.19delEGFR', (204, 215))
483581	31452792	Further studies are required to elucidate why TP53 mutations determined significantly poor prognoses in patients harboring EGFR 19 del but not in patients presenting EGFR L858R.	('EGFR', 'Gene', (123, 127))	('mutations', 'Var', (51, 60))	('L858R', 'Mutation', 'rs121434568', (171, 176))	('EGFR 19 del', 'Mutation', 'c.19delEGFR', (123, 134))	('TP53', 'Gene', '7157', (46, 50))	('EGFR', 'Gene', '1956', (166, 170))	('EGFR', 'Gene', (166, 170))	('TP53', 'Gene', (46, 50))	('EGFR', 'Gene', '1956', (123, 127))	('patients', 'Species', '9606', (146, 154))	('patients', 'Species', '9606', (104, 112))
483679	32458638	Aberrant Expression of miR-103, miR-184, miR-378, miR-497 and miR-506 in Tumor Tissue from Patients with Oral Squamous Cell Carcinoma Regulates the Clinical Picture of the Patients This study aimed to evaluate the expression patterns of miR-103, miR-184, miR-378, miR497 and in squamous cell carcinoma (SCC) of the tongue and to be compared with normal peripheral tissues.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (278, 301))	('miR-184', 'Gene', '406960', (246, 253))	('miR-184', 'Gene', '406960', (32, 39))	('miR-103', 'Gene', (23, 30))	('Tumor', 'Phenotype', 'HP:0002664', (73, 78))	('SCC', 'Phenotype', 'HP:0002860', (303, 306))	('miR-378', 'Gene', '494327', (255, 262))	('miR-378', 'Gene', '494327', (41, 48))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (278, 301))	('miR-103', 'Chemical', '-', (237, 244))	('Patients', 'Species', '9606', (172, 180))	('Carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('miR-506', 'Gene', '574511', (62, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (292, 301))	('miR-103', 'Chemical', '-', (23, 30))	('squamous cell carcinoma', 'Disease', (278, 301))	('miR-184', 'Gene', (32, 39))	('miR497', 'Gene', '574456', (264, 270))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (110, 133))	('miR-184', 'Gene', (246, 253))	('miR-497', 'Gene', (50, 57))	('miR-497', 'Gene', '574456', (50, 57))	('Patients', 'Species', '9606', (91, 99))	('Oral Squamous Cell Carcinoma', 'Disease', 'MESH:D002294', (105, 133))	('miR-378', 'Gene', (255, 262))	('miR-378', 'Gene', (41, 48))	('Oral Squamous Cell Carcinoma', 'Disease', (105, 133))	('miR-506', 'Gene', (62, 69))	('miR497', 'Gene', (264, 270))	('miR-103', 'Var', (237, 244))
483681	32458638	After RNA extraction, expression level of miR-103, miR-184, miR-378, miR497, and miR506 was estimated using SYBR green master mix and real-time quantitative PCR.	('miR-378', 'Gene', '494327', (60, 67))	('miR-184', 'Gene', '406960', (51, 58))	('miR-103', 'Var', (42, 49))	('miR-184', 'Gene', (51, 58))	('miR-378', 'Gene', (60, 67))	('miR497', 'Gene', '574456', (69, 75))	('miR-103', 'Chemical', '-', (42, 49))	('expression', 'MPA', (22, 32))	('miR506', 'Gene', (81, 87))	('miR497', 'Gene', (69, 75))	('miR506', 'Gene', '574511', (81, 87))
483694	32458638	This study investigated aberrantly expressed miR-103, miR-184, miR-378, miR-497 and miR-506 in OSCC and evaluated attribution of these miRNAs' expression with the clinical outcomes of the patients with Iranian Azari society.	('miR-506', 'Gene', '574511', (84, 91))	('miR-506', 'Gene', (84, 91))	('SCC', 'Phenotype', 'HP:0002860', (96, 99))	('miR-497', 'Gene', '574456', (72, 79))	('patients', 'Species', '9606', (188, 196))	('miR-184', 'Gene', '406960', (54, 61))	('miR-184', 'Gene', (54, 61))	('miR-497', 'Gene', (72, 79))	('miR-103', 'Chemical', '-', (45, 52))	('miR-378', 'Gene', '494327', (63, 70))	('miR-378', 'Gene', (63, 70))	('miR-103', 'Var', (45, 52))
483706	32458638	We evaluated miR-103, miR-184, miR-378, miR-497 and miR-506 expression in 50 patients with tongue cancer samples and 50 paired noncancerous samples.	('cancerous', 'Disease', 'MESH:D009369', (130, 139))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('tongue cancer', 'Disease', (91, 104))	('miR-497', 'Gene', (40, 47))	('miR-506', 'Gene', '574511', (52, 59))	('tongue cancer', 'Disease', 'MESH:D014062', (91, 104))	('miR-103', 'Chemical', '-', (13, 20))	('cancerous', 'Disease', (130, 139))	('patients', 'Species', '9606', (77, 85))	('miR-378', 'Gene', '494327', (31, 38))	('miR-378', 'Gene', (31, 38))	('miR-184', 'Gene', '406960', (22, 29))	('miR-184', 'Gene', (22, 29))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('miR-103', 'Var', (13, 20))	('miR-506', 'Gene', (52, 59))	('miR-497', 'Gene', '574456', (40, 47))
483709	32458638	On the other hand, expression of miRNA-103 did not show any different in comparison with peripheral tumor-free tissues (p < 0.8786, shown in Figure 1).	('tumor', 'Disease', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('miRNA-103', 'Var', (33, 42))
483715	32458638	Among various miRNAs dysregulated in OSCC miR-103, miR-184, miR-375, miR-497, and miR-506; are several important miRNAs that contribute to the development and progression of OSCC.	('miR-184', 'Gene', '406960', (51, 58))	('SCC', 'Phenotype', 'HP:0002860', (175, 178))	('miR-103', 'Var', (42, 49))	('miR-184', 'Gene', (51, 58))	('miR-375', 'Gene', '494324', (60, 67))	('SCC', 'Phenotype', 'HP:0002860', (38, 41))	('miR-506', 'Gene', '574511', (82, 89))	('miR-506', 'Gene', (82, 89))	('miR-103', 'Chemical', '-', (42, 49))	('miR-497', 'Gene', (69, 76))	('miR-375', 'Gene', (60, 67))	('miR-497', 'Gene', '574456', (69, 76))	('OSCC', 'Disease', (174, 178))	('men', 'Species', '9606', (150, 153))	('contribute', 'Reg', (125, 135))
483731	30682845	The Risks and Benefits of Immune Checkpoint Blockade in Anti-AChR Antibody-Seropositive Non-Small Cell Lung Cancer Patients Background: Anti-programmed cell death 1 (PD-1) monoclonal antibodies (Abs) unleash an immune response to cancer.	('Lung Cancer', 'Phenotype', 'HP:0100526', (103, 114))	('PD-1', 'Gene', (166, 170))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('Small Cell Lung Cancer', 'Phenotype', 'HP:0030357', (92, 114))	('Non-Small Cell Lung Cancer', 'Phenotype', 'HP:0030358', (88, 114))	('cancer', 'Disease', (230, 236))	('cancer', 'Disease', 'MESH:D009369', (230, 236))	('Anti-programmed', 'Var', (136, 151))	('Antibody-Seropositive Non-Small Cell Lung Cancer', 'Disease', (66, 114))	('PD-1', 'Gene', '5133', (166, 170))	('unleash', 'Reg', (200, 207))	('Antibody-Seropositive Non-Small Cell Lung Cancer', 'Disease', 'MESH:D002289', (66, 114))	('Cancer', 'Phenotype', 'HP:0002664', (108, 114))
483752	30682845	A 72-year-old man was diagnosed with lung squamous cell carcinoma and had left upper lobectomy and lymph node resection (pathological T2aN2M0 stage IB, PD-L1 tumor proportion score >= 50%).	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (37, 65))	('lung squamous cell carcinoma', 'Disease', (37, 65))	('PD-L1 tumor', 'Disease', (152, 163))	('PD-L1 tumor', 'Disease', 'MESH:D010300', (152, 163))	('man', 'Species', '9606', (14, 17))	('T2aN2M0', 'Var', (134, 141))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (37, 65))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (42, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (56, 65))
483779	30682845	However, the disruption of immune checkpoint signaling can lead to imbalances in immunologic tolerance and result in an unfavorable immune response, which clinically manifest as irAEs.	('disruption', 'Var', (13, 23))	('imbalances', 'MPA', (67, 77))	('unfavorable', 'MPA', (120, 131))	('lead to', 'Reg', (59, 66))	('imbalances', 'Phenotype', 'HP:0002172', (67, 77))	('irAEs', 'Disease', (178, 183))	('man', 'Species', '9606', (166, 169))	('immunologic', 'MPA', (81, 92))	('result in', 'Reg', (107, 116))
483804	30682845	PD-1 expresses on activated B cells as well as activated T cells, which indicates that there is a potential risk of triggering B cell-mediated autoimmune disease such as MG by the blockade of the interaction between PD-1 and PD-L1.	('PD-L1', 'Gene', (225, 230))	('PD-1', 'Gene', (216, 220))	('interaction', 'Interaction', (196, 207))	('PD-1', 'Gene', (0, 4))	('PD-1', 'Gene', '5133', (216, 220))	('PD-1', 'Gene', '5133', (0, 4))	('autoimmune disease', 'Disease', (143, 161))	('autoimmune disease', 'Phenotype', 'HP:0002960', (143, 161))	('autoimmune disease', 'Disease', 'MESH:D001327', (143, 161))	('blockade', 'Var', (180, 188))
483805	30682845	The evidence suggests that blocking PD-1/PD-L1 signaling may shift the systemic immune balance from the T cell-mediated immune response (cellular immune response) to the B-cell mediated immune response (humoral immune response) which enhances pre-existing anti-AChR antibody, and may lead to the onset of MG as an irAE (Figure 5A).	('lead to', 'Reg', (284, 291))	('shift', 'Reg', (61, 66))	('blocking', 'Var', (27, 35))	('irAE', 'Disease', (314, 318))	('anti-AChR antibody', 'Protein', (256, 274))	('enhances', 'PosReg', (234, 242))	('systemic immune', 'MPA', (71, 86))	('PD-1', 'Gene', (36, 40))	('PD-1', 'Gene', '5133', (36, 40))
483827	30682845	Writing, review, and/or revision of the manuscript: K.S., R.S., S.N., Y.H., T.S., and Y.T.	('man', 'Species', '9606', (40, 43))	('T.S.', 'Var', (76, 80))	('R.S.', 'Disease', (58, 62))	('S.N.', 'Var', (64, 68))	('Y.H.', 'Var', (70, 74))	('K.S.', 'Var', (52, 56))
483830	33194642	KRAS mutant cancer cells suppress the anti-tumor T cell response.	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('cancer', 'Disease', (12, 18))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('mutant', 'Var', (5, 11))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('suppress', 'NegReg', (25, 33))	('tumor', 'Disease', (43, 48))	('KRAS', 'Gene', (0, 4))	('KRAS', 'Gene', '3845', (0, 4))
483836	33194642	Knock-down of mutant KRAS resulted in increased ACAA1 mRNA level in H1944 cells.	('ACAA1 mRNA level', 'MPA', (48, 64))	('KRAS', 'Gene', '3845', (21, 25))	('mutant', 'Var', (14, 20))	('H1944', 'CellLine', 'CVCL:1508', (68, 73))	('KRAS', 'Gene', (21, 25))	('increased', 'PosReg', (38, 47))
483837	33194642	ACAA1 mRNA level was significantly upregulated in H1944 after treatment with MAPK pathway inhibitor sorafenib, indicating that oncogenic KRAS may downregulate ACAA1 through MAPK signaling.	('sorafenib', 'Chemical', 'MESH:D000077157', (100, 109))	('H1944', 'CellLine', 'CVCL:1508', (50, 55))	('ACAA1', 'Gene', (159, 164))	('upregulated', 'PosReg', (35, 46))	('ACAA1 mRNA level', 'MPA', (0, 16))	('KRAS', 'Gene', (137, 141))	('downregulate', 'NegReg', (146, 158))	('KRAS', 'Gene', '3845', (137, 141))	('H1944', 'Var', (50, 55))
483845	33194642	Cancer cells with KRAS mutations can avoid being attacked by the immune system, facilitating immune evasion or immunosuppression phenotypes of the tumor.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('KRAS', 'Gene', (18, 22))	('KRAS', 'Gene', '3845', (18, 22))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('mutations', 'Var', (23, 32))	('immune evasion', 'MPA', (93, 107))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))
483848	33194642	Among these, the ability of KRAS mutant cells to convert CD4+ Th cells into functional Tregs is crucial to inhibit T cell activation and promote a tolerogenic microenvironment.	('inhibit', 'NegReg', (107, 114))	('KRAS', 'Gene', (28, 32))	('KRAS', 'Gene', '3845', (28, 32))	('T cell activation', 'MPA', (115, 132))	('promote', 'PosReg', (137, 144))	('mutant', 'Var', (33, 39))	('Tregs', 'Chemical', '-', (87, 92))
483851	33194642	By increasing the mutation burden of tumor cells, oncogenic KRAS also induces the production of a large number of neoantigens that may be recognized by CD8+ and CD4+ T cells.	('production of', 'MPA', (82, 95))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('neoantigens', 'MPA', (114, 125))	('induces', 'Reg', (70, 77))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('increasing', 'PosReg', (3, 13))	('KRAS', 'Gene', (60, 64))	('mutation', 'Var', (18, 26))	('KRAS', 'Gene', '3845', (60, 64))	('CD8', 'Gene', (152, 155))	('CD8', 'Gene', '925', (152, 155))
483858	33194642	In fact, MEK inhibition increases CD8+ T cell infiltration within the tumor, while combination of MEK and PD-1 inhibitors synergistically promotes tumor regression.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('MEK', 'Gene', (98, 101))	('increases', 'PosReg', (24, 33))	('MEK', 'Gene', '5609', (98, 101))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('CD8', 'Gene', (34, 37))	('inhibition', 'Var', (13, 23))	('tumor', 'Disease', (70, 75))	('promotes', 'PosReg', (138, 146))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('CD8', 'Gene', '925', (34, 37))	('MEK', 'Gene', (9, 12))	('MEK', 'Gene', '5609', (9, 12))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
483878	33194642	H1944 cells harbor KRAS mutation G13D.	('G13D', 'Var', (33, 37))	('H1944', 'CellLine', 'CVCL:1508', (0, 5))	('KRAS', 'Gene', (19, 23))	('G13D', 'Mutation', 'rs112445441', (33, 37))	('KRAS', 'Gene', '3845', (19, 23))
483896	33194642	(abbreviations: CHOL: Cholangiocarcinoma; COAD: colon adenocarcinoma ESCA: Esophageal Squamous Cell Carcinoma HNSC: Head-neck squamous cell carcinoma KICH: Kidney chromophobe KIRC: Kidney renal clear cell carcinoma KIRP: Kidney renal papillary cell carcinoma LIHC: Liver hepatocellular carcinoma LUAD: Lung adenocarcinoma LUSC: Lung squamous cell carcinoma READ: Rectum adenocarcinoma SKCM: skin cutaneous melanoma STAD: Stomach adenocarcinoma THCA: Thyroid carcinoma) To analyze how oncogenic KRAS regulates ACAA1 expression and the related upstream signaling pathway, we used lung adenocarcinoma cell line H1944, which harbors KRASG13D mutation.	('Cholangiocarcinoma', 'Phenotype', 'HP:0030153', (22, 40))	('colon adenocarcinoma ESCA', 'Disease', 'MESH:D003110', (48, 73))	('LUAD', 'Phenotype', 'HP:0030078', (296, 300))	('skin cutaneous melanoma STAD', 'Disease', 'MESH:C562393', (391, 419))	('Stomach adenocarcinoma THCA', 'Disease', 'MESH:D000230', (421, 448))	('COAD', 'Disease', (42, 46))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (396, 414))	('mutation', 'Var', (638, 646))	('melanoma', 'Phenotype', 'HP:0002861', (406, 414))	('Thyroid carcinoma', 'Phenotype', 'HP:0002890', (450, 467))	('Lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (328, 356))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (578, 597))	('colon adenocarcinoma ESCA', 'Disease', (48, 73))	('Cholangiocarcinoma', 'Disease', 'MESH:D018281', (22, 40))	('Cholangiocarcinoma', 'Disease', (22, 40))	('Kidney chromophobe KIRC', 'Disease', (156, 179))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (333, 356))	('Lung squamous cell carcinoma READ', 'Disease', (328, 361))	('CHOL', 'Disease', 'None', (16, 20))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (578, 597))	('skin cutaneous melanoma STAD', 'Disease', (391, 419))	('KRAS', 'Gene', '3845', (629, 633))	('Stomach adenocarcinoma THCA', 'Disease', (421, 448))	('Lung adenocarcinoma LUSC', 'Disease', 'MESH:D000077192', (302, 326))	('Kidney chromophobe KIRC', 'Disease', 'MESH:D000238', (156, 179))	('Kidney renal papillary cell carcinoma LIHC', 'Disease', 'MESH:C538614', (221, 263))	('Kidney renal clear cell carcinoma KIRP', 'Disease', 'MESH:C538614', (181, 219))	('Kidney renal clear cell carcinoma KIRP', 'Disease', (181, 219))	('Carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('renal papillary cell carcinoma', 'Phenotype', 'HP:0006766', (228, 258))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (126, 149))	('Head-neck squamous cell carcinoma KICH', 'Disease', 'MESH:D000077195', (116, 154))	('Lung squamous cell carcinoma READ', 'Disease', 'MESH:D002294', (328, 361))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (271, 295))	('carcinoma', 'Phenotype', 'HP:0030731', (31, 40))	('KRAS', 'Gene', (629, 633))	('CHOL', 'Disease', (16, 20))	('KRAS', 'Gene', '3845', (494, 498))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (86, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (205, 214))	('LUSC', 'Phenotype', 'HP:0030359', (322, 326))	('Squamous Cell Carcinoma HNSC', 'Disease', (86, 114))	('Liver hepatocellular carcinoma LUAD', 'Disease', (265, 300))	('Thyroid carcinoma', 'Disease', (450, 467))	('KRAS', 'Gene', (494, 498))	('carcinoma', 'Phenotype', 'HP:0030731', (59, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))	('Lung adenocarcinoma LUSC', 'Disease', (302, 326))	('COAD', 'Disease', 'MESH:D029424', (42, 46))	('Rectum adenocarcinoma SKCM', 'Disease', 'MESH:D012004', (363, 389))	('Thyroid carcinoma', 'Disease', 'MESH:D013964', (450, 467))	('Liver hepatocellular carcinoma LUAD', 'Disease', 'MESH:D006528', (265, 300))	('Rectum adenocarcinoma SKCM', 'Disease', (363, 389))	('lung adenocarcinoma', 'Disease', (578, 597))	('Squamous Cell Carcinoma HNSC', 'Disease', 'MESH:D002294', (86, 114))	('carcinoma', 'Phenotype', 'HP:0030731', (249, 258))	('H1944', 'CellLine', 'CVCL:1508', (608, 613))	('Lung adenocarcinoma', 'Phenotype', 'HP:0030078', (302, 321))	('Kidney renal papillary cell carcinoma LIHC', 'Disease', (221, 263))	('Head-neck squamous cell carcinoma KICH', 'Disease', (116, 154))
483897	33194642	Knock-down of mutant KRAS resulted in increased ACAA1 mRNA levels ( Figure 1D ).	('KRAS', 'Gene', '3845', (21, 25))	('mutant', 'Var', (14, 20))	('ACAA1 mRNA levels', 'MPA', (48, 65))	('KRAS', 'Gene', (21, 25))	('increased', 'PosReg', (38, 47))
483902	33194642	KRAS mutation is the second most prevalent mutation in lung cancer, and we observed that KRAS regulated the mRNA of ACAA1.	('ACAA1', 'Gene', (116, 121))	('KRAS', 'Gene', '3845', (0, 4))	('lung cancer', 'Disease', 'MESH:D008175', (55, 66))	('mRNA', 'MPA', (108, 112))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('lung cancer', 'Disease', (55, 66))	('lung cancer', 'Phenotype', 'HP:0100526', (55, 66))	('KRAS', 'Gene', (89, 93))	('KRAS', 'Gene', (0, 4))	('regulated', 'Reg', (94, 103))	('mutation', 'Var', (5, 13))	('KRAS', 'Gene', '3845', (89, 93))
483909	33194642	As lung cancers harboring KRAS mutation have high response rate to PD-1/PD-L1 blockade, KRAS mutation might be a potential driver of DNA instability and DNA damage repair defects, thereby leading to the production of more neoantigens.	('cancers', 'Phenotype', 'HP:0002664', (8, 15))	('KRAS', 'Gene', (26, 30))	('lung cancers', 'Disease', (3, 15))	('PD-1/PD-L1 blockade', 'Disease', 'MESH:D010300', (67, 86))	('production of', 'MPA', (203, 216))	('mutation', 'Var', (31, 39))	('lung cancer', 'Phenotype', 'HP:0100526', (3, 14))	('more', 'PosReg', (217, 221))	('KRAS', 'Gene', (88, 92))	('lung cancers', 'Disease', 'MESH:D008175', (3, 15))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('leading to', 'Reg', (188, 198))	('neoantigens', 'MPA', (222, 233))	('KRAS', 'Gene', '3845', (88, 92))	('lung cancers', 'Phenotype', 'HP:0100526', (3, 15))	('mutation', 'Var', (93, 101))	('KRAS', 'Gene', '3845', (26, 30))	('PD-1/PD-L1 blockade', 'Disease', (67, 86))
483911	33194642	Based on this, we propose that LUAD and LUSC harboring KRAS mutation probably recruit less CD4+ T cells by suppressing ACAA1 expression, providing tumors with an immunosuppressive microenvironment.	('KRAS', 'Gene', (55, 59))	('ACAA1', 'Gene', (119, 124))	('mutation', 'Var', (60, 68))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumors', 'Disease', (147, 153))	('tumors', 'Phenotype', 'HP:0002664', (147, 153))	('KRAS', 'Gene', '3845', (55, 59))	('LUAD', 'Phenotype', 'HP:0030078', (31, 35))	('tumors', 'Disease', 'MESH:D009369', (147, 153))	('LUSC', 'Phenotype', 'HP:0030359', (40, 44))	('expression', 'MPA', (125, 135))	('suppressing', 'NegReg', (107, 118))
483913	33194642	The TIMER database also provides a comparison of tumor infiltration levels among tumors with different somatic copy number alterations for a given gene.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumors', 'Disease', (81, 87))	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor', 'Disease', (49, 54))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('copy number alterations', 'Var', (111, 134))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('tumor', 'Disease', (81, 86))
483933	33194642	In our study, we did not observe that KRAS mutation increased PD-L1 expression ( Supplementary Figure 1C ), nor a solid correlation of ACAA1 with PD-L1 expression in cancer cells using GEPIA (TCGA datasets) ( Supplementary Figure 1D ).	('cancer', 'Disease', (166, 172))	('increased', 'PosReg', (52, 61))	('KRAS', 'Gene', '3845', (38, 42))	('PD-L1', 'Gene', '29126', (146, 151))	('expression', 'MPA', (68, 78))	('mutation', 'Var', (43, 51))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('PD-L1', 'Gene', '29126', (62, 67))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('increased PD', 'Phenotype', 'HP:0008151', (52, 64))	('PD-L1', 'Gene', (62, 67))	('PD-L1', 'Gene', (146, 151))	('KRAS', 'Gene', (38, 42))
483937	33194642	Recent studies indicated that NSCLC harboring KRAS mutation show higher clinical response rate to and efficacy of PD-1/PD-L1 blockade.	('NSCLC', 'Disease', 'MESH:D002289', (30, 35))	('KRAS', 'Gene', (46, 50))	('NSCLC', 'Phenotype', 'HP:0030358', (30, 35))	('KRAS', 'Gene', '3845', (46, 50))	('mutation', 'Var', (51, 59))	('clinical response rate', 'CPA', (72, 94))	('PD-1/PD-L1 blockade', 'Disease', (114, 133))	('higher', 'PosReg', (65, 71))	('PD-1/PD-L1 blockade', 'Disease', 'MESH:D010300', (114, 133))	('NSCLC', 'Disease', (30, 35))
483938	33194642	Our study suggests that oncogenic KRAS suppresses ACAA1 expression through MAPK signaling pathway.	('KRAS', 'Gene', '3845', (34, 38))	('suppresses', 'NegReg', (39, 49))	('oncogenic', 'Var', (24, 33))	('expression', 'MPA', (56, 66))	('ACAA1', 'Gene', (50, 55))	('KRAS', 'Gene', (34, 38))
483942	33194642	Moreover, NSCLC harboring KRAS mutation present a higher tumor mutation burden, leading to tumor immunogenicity.	('NSCLC', 'Disease', (10, 15))	('higher', 'PosReg', (50, 56))	('NSCLC', 'Disease', 'MESH:D002289', (10, 15))	('mutation', 'Var', (31, 39))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('NSCLC', 'Phenotype', 'HP:0030358', (10, 15))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('KRAS', 'Gene', (26, 30))	('tumor', 'Disease', (57, 62))	('tumor', 'Disease', (91, 96))	('KRAS', 'Gene', '3845', (26, 30))
483943	33194642	Copy number variation of ACAA1 also pointed to lower abundance of CD4+ in the tumor microenvironment.	('lower', 'NegReg', (47, 52))	('ACAA1', 'Gene', (25, 30))	('Copy number variation', 'Var', (0, 21))	('abundance of CD4+', 'MPA', (53, 70))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Disease', (78, 83))
483947	33194642	However, whether the occurring KRAS mutation simply coincides with other genetic mutations or is the direct cause of the downstream DNA instability remains unknown.	('KRAS', 'Gene', (31, 35))	('KRAS', 'Gene', '3845', (31, 35))	('mutation', 'Var', (36, 44))
483951	33194642	Consistently, FASN inhibition blocks cellular proliferation of KRAS-driven lung cancer cells.	('lung cancer', 'Disease', (75, 86))	('lung cancer', 'Phenotype', 'HP:0100526', (75, 86))	('KRAS', 'Gene', '3845', (63, 67))	('blocks', 'NegReg', (30, 36))	('inhibition', 'Var', (19, 29))	('cellular proliferation', 'CPA', (37, 59))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('FASN', 'Gene', (14, 18))	('FASN', 'Gene', '2194', (14, 18))	('lung cancer', 'Disease', 'MESH:D008175', (75, 86))	('KRAS', 'Gene', (63, 67))
483968	33194642	They found that, in mice, inhibition of acetyl-CoA acetyltransferase 1 (Acat1) in CD8+ T cells restores their antitumor effect and reduces cancer progression and metastasis.	('Acat1', 'Gene', (72, 77))	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('Acat1', 'Gene', '110446', (72, 77))	('CD8', 'Gene', (82, 85))	('restores', 'PosReg', (95, 103))	('CD8', 'Gene', '925', (82, 85))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('inhibition', 'Var', (26, 36))	('mice', 'Species', '10090', (20, 24))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('reduces', 'NegReg', (131, 138))	('tumor', 'Disease', (114, 119))	('acetyl-CoA acetyltransferase 1', 'Gene', (40, 70))	('acetyl-CoA acetyltransferase 1', 'Gene', '110446', (40, 70))	('cancer', 'Disease', (139, 145))
483971	33194642	Moreover, inhibitors targeting Acat1 could restore CD8+ cell function, and a combination of PD-1/PD-L1 antibody and Acat1 inhibitor demonstrated greater efficacy than the single agents.	('PD-1/PD-L1 antibody', 'Disease', (92, 111))	('restore', 'PosReg', (43, 50))	('Acat1', 'Gene', '110446', (31, 36))	('PD-1/PD-L1 antibody', 'Disease', 'MESH:D010300', (92, 111))	('CD8', 'Gene', (51, 54))	('Acat1', 'Gene', (116, 121))	('CD8', 'Gene', '925', (51, 54))	('Acat1', 'Gene', '110446', (116, 121))	('inhibitors', 'Var', (10, 20))	('Acat1', 'Gene', (31, 36))
484092	32657401	Most of the genes are cancer-related genes, and some of them have an explicit association with breast cancer and breast cancer patients' survival.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('genes', 'Var', (12, 17))	('breast cancer', 'Disease', 'MESH:D001943', (113, 126))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('breast cancer', 'Disease', (95, 108))	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('breast cancer', 'Disease', (113, 126))	('breast cancer', 'Phenotype', 'HP:0003002', (95, 108))	('breast cancer', 'Phenotype', 'HP:0003002', (113, 126))	('cancer', 'Disease', (22, 28))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('cancer', 'Disease', (102, 108))	('patients', 'Species', '9606', (127, 135))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('breast cancer', 'Disease', 'MESH:D001943', (95, 108))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('association', 'Interaction', (78, 89))
484093	32657401	The CDC20 gene is an essential component of cell division, and the high CDC20 expression is reported to be associated with the poor survival of breast cancer patients.	('CDC20', 'Gene', (72, 77))	('breast cancer', 'Disease', 'MESH:D001943', (144, 157))	('high', 'Var', (67, 71))	('expression', 'MPA', (78, 88))	('CDC20', 'Gene', '991', (72, 77))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('breast cancer', 'Disease', (144, 157))	('associated', 'Reg', (107, 117))	('breast cancer', 'Phenotype', 'HP:0003002', (144, 157))	('patients', 'Species', '9606', (158, 166))	('CDC20', 'Gene', (4, 9))	('CDC20', 'Gene', '991', (4, 9))
484098	32657401	The methylation of the KLHL17 gene is reported to be associated with early stage breast tumours and breast carcinogenesis.	('tumours', 'Phenotype', 'HP:0002664', (88, 95))	('KLHL17', 'Gene', '339451', (23, 29))	('methylation', 'Var', (4, 15))	('associated', 'Reg', (53, 63))	('breast tumours and breast carcinogenesis', 'Disease', 'MESH:D001943', (81, 121))	('KLHL17', 'Gene', (23, 29))	('tumour', 'Phenotype', 'HP:0002664', (88, 94))
484112	32657401	The performance of our VAECox model improved more when the transferred encoder weights were fine-tuned compared to when the weights of VAECox were randomly initialized.	('fine-tuned', 'Var', (92, 102))	('performance', 'MPA', (4, 15))	('Cox', 'Gene', '1351', (138, 141))	('improved', 'PosReg', (36, 44))	('Cox', 'Gene', (138, 141))	('Cox', 'Gene', '1351', (26, 29))	('Cox', 'Gene', (26, 29))
484113	32657401	The performance of VAECox was also higher when the transferred weights were fine-tuned than when transferring the encoder weights that were not fine-tuned.	('performance', 'MPA', (4, 15))	('Cox', 'Gene', '1351', (22, 25))	('fine-tuned', 'Var', (76, 86))	('higher', 'PosReg', (35, 41))	('Cox', 'Gene', (22, 25))
484152	28758927	Human diseases showing aberrant RNA splicing range from neurological pathologies to immunohematology disorders and malignancies.	('Human', 'Species', '9606', (0, 5))	('aberrant RNA splicing', 'Var', (23, 44))	('immunohematology disorders', 'Phenotype', 'HP:0001871', (84, 110))	('malignancies', 'Disease', 'MESH:D009369', (115, 127))	('malignancies', 'Disease', (115, 127))	('neurological pathologies to immunohematology disorders', 'Disease', 'MESH:D009422', (56, 110))
484153	28758927	For instance, a recent transcriptome sequencing study revealed aberrant alternative splicing in Huntington's disease through the identification of 593 differential alternative splicing events between pathological and control brains.	("Huntington's disease", 'Disease', (96, 116))	("Huntington's disease", 'Disease', 'MESH:D006816', (96, 116))	('aberrant', 'Var', (63, 71))	('alternative splicing', 'MPA', (72, 92))
484155	28758927	Besides, in cancer the splicing process is frequently disrupted thus appearing as one of the hallmarks of cancer; indeed, many cancer-specific splicing events, which are likely to contribute to disease progression, have been recently identified as the result either of mutations in splicing-regulatory elements or changes in components of the splicing machinery.	('changes', 'Reg', (314, 321))	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('mutations', 'Var', (269, 278))	('cancer', 'Disease', (12, 18))	('splicing', 'MPA', (143, 151))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('cancer', 'Disease', (106, 112))	('splicing-regulatory elements', 'Protein', (282, 310))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('cancer', 'Disease', (127, 133))	('contribute', 'Reg', (180, 190))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
484157	28758927	Moreover, RNA-Seq allows the analysis of allele-specific expression and the detection of fusion transcripts, which often occur in pathologies like cancer.	('cancer', 'Disease', (147, 153))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('fusion transcripts', 'Var', (89, 107))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))
484166	28758927	As for the other ncRNA, even the deregulation of numerous lncRNA has been observed in many human diseases, from cancer to cardiac pathologies or neurodegenerative disorders.	('cardiac pathologies', 'Disease', (122, 141))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('neurodegenerative disorders', 'Disease', 'MESH:D019636', (145, 172))	('neurodegenerative disorders', 'Phenotype', 'HP:0002180', (145, 172))	('observed', 'Reg', (74, 82))	('neurodegenerative disorders', 'Disease', (145, 172))	('deregulation', 'Var', (33, 45))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('cardiac pathologies', 'Disease', 'MESH:D006331', (122, 141))	('human', 'Species', '9606', (91, 96))
484176	28758927	Thus, it is not surprising that the deregulation of many circRNA has been found to have relevance in many human diseases, including cancer, cardiovascular, neurological and developmental disorders, among others.	('neurological and developmental disorders', 'Disease', 'MESH:D009422', (156, 196))	('cancer', 'Disease', (132, 138))	('human', 'Species', '9606', (106, 111))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('cardiovascular', 'Disease', (140, 154))	('relevance', 'Reg', (88, 97))	('deregulation', 'Var', (36, 48))	('cancer', 'Disease', 'MESH:D009369', (132, 138))
484213	33907270	TMB is the number of mutations per million bases in tumor tissue, including base substitutions, gene insertion, and gene coding and deletion errors.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumor', 'Disease', (52, 57))	('gene insertion', 'Var', (96, 110))	('TMB', 'Chemical', '-', (0, 3))	('deletion errors', 'Var', (132, 147))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('base substitutions', 'Var', (76, 94))
484230	33907270	Kaplan-Meier analysis was used to show the survival difference between high and low TMB expression groups.	('TMB expression', 'Protein', (84, 98))	('TMB', 'Chemical', '-', (84, 87))	('low', 'NegReg', (80, 83))	('high', 'Var', (71, 75))
484232	33907270	Gene Ontology (GO) enrichment analysis was used to reveal potential biological processes of TMB-associated DEGs in LUSC.	('DEGs', 'Var', (107, 111))	('LUSC', 'Phenotype', 'HP:0030359', (115, 119))	('LUSC', 'Disease', (115, 119))	('TMB-associated', 'Gene', (92, 106))	('TMB', 'Chemical', '-', (92, 95))
484241	33907270	30 DEGs (including CCL19, BPIFB1, SCGB1A1, PIGR, SELE, NR5A1, PIP) were sorted into low and high expression TMB groups: threshold  Log2 FC > 1.0, P value < 0.05 and FDR < 0.05 (in Table1; Fig.	('NR5A1', 'Gene', (55, 60))	('CCL19', 'Gene', (19, 24))	('PIP', 'Gene', '5304', (62, 65))	('FDR < 0.05', 'Var', (165, 175))	('BPIFB1', 'Gene', '92747', (26, 32))	('SELE', 'Gene', '6401', (49, 53))	('NR5A1', 'Gene', '2516', (55, 60))	('BPIFB1', 'Gene', (26, 32))	('TMB', 'Chemical', '-', (108, 111))	('SELE', 'Gene', (49, 53))	('PIGR', 'Gene', (43, 47))	('SCGB1A1', 'Gene', '7356', (34, 41))	('PIP', 'Gene', (62, 65))	('CCL19', 'Gene', '6363', (19, 24))	('SCGB1A1', 'Gene', (34, 41))	('PIGR', 'Gene', '5284', (43, 47))
484250	33907270	Low-TMB was mainly associated with B cell receptor, T cell receptor, and chemokine signaling pathways (Fig.	('associated', 'Reg', (19, 29))	('TMB', 'Chemical', '-', (4, 7))	('Low-TMB', 'Var', (0, 7))	('chemokine signaling pathways', 'Pathway', (73, 101))	('B cell receptor', 'Protein', (35, 50))
484271	33907270	found that the expression of FAM107A was reduced significantly in larynx squamous cell carcinoma (LSCC), and the recurrent inactivation of FAM107A may be involved LSCC development.	('reduced', 'NegReg', (41, 48))	('inactivation', 'Var', (123, 135))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (73, 96))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (73, 96))	('involved', 'Reg', (154, 162))	('squamous cell carcinoma', 'Disease', (73, 96))	('expression', 'MPA', (15, 25))	('FAM107A', 'Gene', '11170', (139, 146))	('FAM107A', 'Gene', '11170', (29, 36))	('FAM107A', 'Gene', (29, 36))	('FAM107A', 'Gene', (139, 146))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))
484275	33907270	IGLL1 Mutations can induce blood system disease.	('induce', 'Reg', (20, 26))	('blood system disease', 'Disease', 'MESH:D006402', (27, 47))	('blood system disease', 'Disease', (27, 47))	('Mutations', 'Var', (6, 15))	('IGLL1', 'Gene', '3543', (0, 5))	('IGLL1', 'Gene', (0, 5))
484309	32195055	In cancer tissues, heterogeneity means that cells with different gene mutations may have different biological characteristics.	('cancer', 'Disease', (3, 9))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('mutations', 'Var', (70, 79))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
484372	32195055	HELLS is a key epigenetic driver of hepatocellular carcinoma (HCC) and inhibits multiple tumor suppressor genes by promoting the occupancy of nucleosomes of NFR and enhancers to promote HCC progression.	('NFR', 'Protein', (157, 160))	('HCC', 'Disease', (62, 65))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (36, 60))	('HCC', 'Phenotype', 'HP:0001402', (62, 65))	('inhibits', 'NegReg', (71, 79))	('HCC', 'Disease', 'MESH:D006528', (186, 189))	('promoting', 'PosReg', (115, 124))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (36, 60))	('tumor', 'Disease', (89, 94))	('occupancy of nucleosomes', 'MPA', (129, 153))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('HCC', 'Disease', 'MESH:D006528', (62, 65))	('hepatocellular carcinoma', 'Disease', (36, 60))	('HELLS', 'Var', (0, 5))	('enhancers', 'PosReg', (165, 174))	('HCC', 'Disease', (186, 189))	('HCC', 'Phenotype', 'HP:0001402', (186, 189))	('promote', 'PosReg', (178, 185))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (51, 60))
484383	32195055	Other studies have shown that cannabinoid-induced ICAM-1 can increase LAK cell-mediated tumor cell killing ability in lung cancer, a novel antitumor mechanism of cannabinoids.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('tumor', 'Disease', (143, 148))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('lung cancer', 'Disease', 'MESH:D008175', (118, 129))	('cannabinoids', 'Chemical', 'MESH:D002186', (162, 174))	('ICAM-1', 'Var', (50, 56))	('LAK', 'Gene', '80216', (70, 73))	('lung cancer', 'Phenotype', 'HP:0100526', (118, 129))	('cannabinoid', 'Chemical', 'MESH:D002186', (162, 173))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('lung cancer', 'Disease', (118, 129))	('increase', 'PosReg', (61, 69))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('LAK', 'Gene', (70, 73))	('tumor', 'Disease', (88, 93))	('cannabinoid', 'Chemical', 'MESH:D002186', (30, 41))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
484437	31772786	showed the rate of presence of PAX-8 to be as high as 91% in PSCCTh.	('PSCCTh', 'Disease', 'MESH:D002294', (61, 67))	('PAX-8', 'Gene', (31, 36))	('presence', 'Var', (19, 27))	('PSCCTh', 'Disease', (61, 67))	('PAX-8', 'Gene', '7849', (31, 36))
484457	29464864	A further case study in breast invasive carcinoma (BRCA) found that DRCE expression was consistent with the drug response pattern and the aberrant expression of the two NEAT1-related DRCEs may lead to poor response to tamoxifen therapy for patients with TP53 mutations.	('poor', 'NegReg', (201, 205))	('BRCA', 'Gene', '672', (51, 55))	('tamoxifen', 'Chemical', 'MESH:D013629', (218, 227))	('TP53', 'Gene', '7157', (254, 258))	('TP53', 'Gene', (254, 258))	('breast invasive carcinoma', 'Phenotype', 'HP:0003002', (24, 49))	('breast invasive carcinoma', 'Disease', (24, 49))	('BRCA', 'Gene', (51, 55))	('mutations', 'Var', (259, 268))	('BRCA', 'Phenotype', 'HP:0003002', (51, 55))	('aberrant', 'Var', (138, 146))	('NEAT1', 'Gene', (169, 174))	('response to tamoxifen therapy', 'MPA', (206, 235))	('carcinoma', 'Phenotype', 'HP:0030731', (40, 49))	('patients', 'Species', '9606', (240, 248))	('NEAT1', 'Gene', '283131', (169, 174))	('breast invasive carcinoma', 'Disease', 'MESH:D018270', (24, 49))	('lead to', 'Reg', (193, 200))
484473	29464864	A patient-drug two-layer integrated network and a linear weighting method were used to predict drug responses, and the dysregulation of DRCE expression was inferred to trigger functions and pathways associated with differences in the response to drugs.	('DRCE', 'Gene', (136, 140))	('dysregulation', 'Var', (119, 132))	('patient', 'Species', '9606', (2, 9))
484543	29464864	Epidermal growth factor receptor (EGFR) mutations are prevalent and well characterized in lung cancer and were shown by Gazdar (2009) to be associated with sensitivity and resistance to lung cancer treatment.	('lung cancer', 'Disease', 'MESH:D008175', (90, 101))	('associated', 'Reg', (140, 150))	('EGFR', 'Gene', (34, 38))	('lung cancer', 'Disease', 'MESH:D008175', (186, 197))	('Epidermal growth factor receptor', 'Gene', (0, 32))	('lung cancer', 'Disease', (90, 101))	('mutations', 'Var', (40, 49))	('lung cancer', 'Phenotype', 'HP:0100526', (90, 101))	('Epidermal growth factor receptor', 'Gene', '1956', (0, 32))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('lung cancer', 'Disease', (186, 197))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('lung cancer', 'Phenotype', 'HP:0100526', (186, 197))	('EGFR', 'Gene', '1956', (34, 38))
484553	29464864	In addition, we compared the correlation of simvastatin's drug activities with the expression of DRCEs and non-DRCEs and found DRCEs had a significantly higher correlation with simvastatin's drug activities than non-DRCEs (t-test P < 0.001, Fig.	('simvastatin', 'Chemical', 'MESH:D019821', (44, 55))	('higher', 'PosReg', (153, 159))	('correlation', 'Interaction', (160, 171))	('DRCEs', 'Var', (127, 132))	('simvastatin', 'Chemical', 'MESH:D019821', (177, 188))
484596	29464864	TP53 mutation is the most frequent genetic alteration in BRCA, and in the 304 patients, ER and PR negative patients with a TP53 mutation had a high DRS to carboplatin, clodronic acid, and letrozole, indicating that the three drugs might be given treatment priority.	('patients', 'Species', '9606', (107, 115))	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('clodronic acid', 'Chemical', 'MESH:D004002', (168, 182))	('carboplatin', 'Chemical', 'MESH:D016190', (155, 166))	('patients', 'Species', '9606', (78, 86))	('BRCA', 'Phenotype', 'HP:0003002', (57, 61))	('PR', 'Gene', '5241', (95, 97))	('TP53', 'Gene', '7157', (123, 127))	('BRCA', 'Gene', '672', (57, 61))	('mutation', 'Var', (128, 136))	('ER', 'Gene', '2099', (88, 90))	('letrozole', 'Chemical', 'MESH:D000077289', (188, 197))	('BRCA', 'Gene', (57, 61))	('DRS to carboplatin', 'MPA', (148, 166))	('TP53', 'Gene', (123, 127))
484599	29464864	As tamoxifen can target TP53, previous studies found that TP53 mutation can result in tamoxifen resistance in BRCA (Elledge et al., 1995).	('BRCA', 'Phenotype', 'HP:0003002', (110, 114))	('BRCA', 'Gene', '672', (110, 114))	('TP53', 'Gene', '7157', (58, 62))	('TP53', 'Gene', (24, 28))	('TP53', 'Gene', (58, 62))	('BRCA', 'Gene', (110, 114))	('tamoxifen resistance', 'MPA', (86, 106))	('mutation', 'Var', (63, 71))	('tamoxifen', 'Chemical', 'MESH:D013629', (3, 12))	('tamoxifen', 'Chemical', 'MESH:D013629', (86, 95))	('result in', 'Reg', (76, 85))	('TP53', 'Gene', '7157', (24, 28))
484603	29464864	Consistent with this report, TP53 mutation triggered down-regulation of NEAT1 expression and resulted in poor response to tamoxifen (Fig.	('down-regulation', 'NegReg', (53, 68))	('tamoxifen', 'Chemical', 'MESH:D013629', (122, 131))	('mutation', 'Var', (34, 42))	('TP53', 'Gene', '7157', (29, 33))	('NEAT1', 'Gene', (72, 77))	('TP53', 'Gene', (29, 33))	('NEAT1', 'Gene', '283131', (72, 77))	('response to tamoxifen', 'MPA', (110, 131))
484611	29464864	The expression dysregulated DRCEs NEAT1_hsa-miR-130b_TP53INP1 and NEAT1_hsa-miR-18a_NBR1 are thus likely to lead to poor response to tamoxifen therapy for patients carrying TP53 mutations.	('NBR1', 'Gene', '4077', (84, 88))	('NEAT1', 'Gene', (34, 39))	('poor', 'NegReg', (116, 120))	('NEAT1', 'Gene', (66, 71))	('mutations', 'Var', (178, 187))	('lead to', 'Reg', (108, 115))	('patients', 'Species', '9606', (155, 163))	('TP53', 'Gene', (173, 177))	('hsa-miR-18a', 'Gene', '406953', (72, 83))	('response', 'MPA', (121, 129))	('TP53', 'Gene', (53, 57))	('tamoxifen', 'Chemical', 'MESH:D013629', (133, 142))	('hsa-miR-18a', 'Gene', (72, 83))	('NBR1', 'Gene', (84, 88))	('NEAT1', 'Gene', '283131', (34, 39))	('NEAT1', 'Gene', '283131', (66, 71))	('TP53', 'Gene', '7157', (53, 57))	('TP53', 'Gene', '7157', (173, 177))	('TP53INP1', 'Gene', '94241', (53, 61))	('miR-130b', 'Gene', (44, 52))	('miR-130b', 'Gene', '406920', (44, 52))	('TP53INP1', 'Gene', (53, 61))
484615	29464864	7D), indicating that NEAT1 expression could impact on drug response of BRCA patients.	('patients', 'Species', '9606', (76, 84))	('NEAT1', 'Gene', '283131', (21, 26))	('impact', 'Reg', (44, 50))	('NEAT1', 'Gene', (21, 26))	('BRCA', 'Phenotype', 'HP:0003002', (71, 75))	('BRCA', 'Gene', '672', (71, 75))	('expression', 'Var', (27, 37))	('drug', 'MPA', (54, 58))	('BRCA', 'Gene', (71, 75))
484623	29464864	Furthermore, we focused on cisplatin which is widely used to treat a variety of cancers and kills cells by directly or indirectly inducing apoptosis, DNA damage, and cell cycle arrest (Siddik, 2003).	('inducing', 'Reg', (130, 138))	('cisplatin', 'Chemical', 'MESH:D002945', (27, 36))	('cancers', 'Disease', 'MESH:D009369', (80, 87))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancers', 'Disease', (80, 87))	('cell cycle arrest', 'CPA', (166, 183))	('DNA damage', 'MPA', (150, 160))	('cisplatin', 'Var', (27, 36))	('apoptosis', 'CPA', (139, 148))	('cancers', 'Phenotype', 'HP:0002664', (80, 87))
484627	29464864	Two DRCEs, NEAT1_hsa-miR-130b_TP53INP1 and NEAT1_hsa-miR-18a_NBR1, were found that may modulate the effect of tamoxifen therapy in BRCA patients with TP53 mutation.	('TP53INP1', 'Gene', (30, 38))	('TP53', 'Gene', (150, 154))	('NEAT1', 'Gene', (43, 48))	('NBR1', 'Gene', '4077', (61, 65))	('BRCA', 'Phenotype', 'HP:0003002', (131, 135))	('NEAT1', 'Gene', (11, 16))	('hsa-miR-18a', 'Gene', '406953', (49, 60))	('TP53', 'Gene', (30, 34))	('BRCA', 'Gene', '672', (131, 135))	('hsa-miR-18a', 'Gene', (49, 60))	('TP53', 'Gene', '7157', (150, 154))	('tamoxifen', 'Chemical', 'MESH:D013629', (110, 119))	('NEAT1', 'Gene', '283131', (43, 48))	('NBR1', 'Gene', (61, 65))	('NEAT1', 'Gene', '283131', (11, 16))	('BRCA', 'Gene', (131, 135))	('miR-130b', 'Gene', '406920', (21, 29))	('TP53', 'Gene', '7157', (30, 34))	('miR-130b', 'Gene', (21, 29))	('modulate', 'Reg', (87, 95))	('TP53INP1', 'Gene', '94241', (30, 38))	('patients', 'Species', '9606', (136, 144))	('mutation', 'Var', (155, 163))
484709	26539827	This is intriguing since there are known links between glutathione and cancer as well as drug resistance in lung cancer, and it has been shown that inhibiting MCT1 disables glutathione synthesis and glycolysis in cancer cells.	('cancer', 'Disease', (113, 119))	('links', 'Reg', (41, 46))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('cancer', 'Disease', (71, 77))	('lung cancer', 'Disease', (108, 119))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('cancer', 'Disease', (213, 219))	('disables', 'NegReg', (164, 172))	('drug resistance', 'Phenotype', 'HP:0020174', (89, 104))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('glutathione', 'Chemical', 'MESH:D005978', (55, 66))	('inhibiting', 'Var', (148, 158))	('MCT1', 'Gene', (159, 163))	('glutathione', 'Chemical', 'MESH:D005978', (173, 184))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('lung cancer', 'Disease', 'MESH:D008175', (108, 119))	('cancer', 'Disease', 'MESH:D009369', (213, 219))	('glycolysis', 'MPA', (199, 209))	('lung cancer', 'Phenotype', 'HP:0100526', (108, 119))	('MCT1', 'Gene', '6566', (159, 163))	('glutathione synthesis', 'MPA', (173, 194))
484728	26539827	Elevated MCT1 is reported to be a hallmark of MYC-driven malignancies.	('MCT1', 'Gene', '6566', (9, 13))	('malignancies', 'Disease', 'MESH:D009369', (57, 69))	('malignancies', 'Disease', (57, 69))	('MYC', 'Gene', (46, 49))	('MCT1', 'Gene', (9, 13))	('Elevated', 'Var', (0, 8))	('MYC', 'Gene', '4609', (46, 49))
484737	26539827	Furthermore, this same study shows that high expression of both MCT1 and GLUT1 has a negative impact on survival in NSCLC patients.	('MCT1', 'Gene', (64, 68))	('NSCLC', 'Disease', 'MESH:D002289', (116, 121))	('survival', 'MPA', (104, 112))	('high expression', 'Var', (40, 55))	('negative', 'NegReg', (85, 93))	('MCT1', 'Gene', '6566', (64, 68))	('patients', 'Species', '9606', (122, 130))	('GLUT1', 'Gene', (73, 78))	('NSCLC', 'Disease', (116, 121))	('GLUT1', 'Gene', '6513', (73, 78))
484740	26539827	Intriguingly, high expression of MCT1 was not associated with poor survival in SCC patients (P = 0.9, HR = 0.98; CI = 0.78-1.25; n = 525; S2 Fig) but was in ADC patients (p = 5.3E-15, HR = 2.58, CI = 2.02-3.31, n = 719; Fig 5C).	('SCC', 'Gene', (79, 82))	('patients', 'Species', '9606', (83, 91))	('SCC', 'Gene', '6317', (79, 82))	('patients', 'Species', '9606', (161, 169))	('high expression', 'Var', (14, 29))	('MCT1', 'Gene', (33, 37))	('MCT1', 'Gene', '6566', (33, 37))
484741	26539827	Similarly, high expression of GLUT1 was not associated with poor survival in SCC patients (P = 0.063, HR = 1.25, CI = 0.99-1.59; n = 525; S3 Fig) but was in ADC patients (P = 4.8E-15, HR = 2.55, CI = 2-3.25, n = 719; Fig 5D).	('GLUT1', 'Gene', (30, 35))	('GLUT1', 'Gene', '6513', (30, 35))	('patients', 'Species', '9606', (81, 89))	('high expression', 'Var', (11, 26))	('patients', 'Species', '9606', (161, 169))	('SCC', 'Gene', (77, 80))	('SCC', 'Gene', '6317', (77, 80))
484748	26539827	Making sense of the variations between ADC and SCC can be a difficult task, but alterations in the genomes of these cancers ultimately get integrated and produce a cancer proteome that can be analyzed using modern proteomic tools.	('alterations', 'Var', (80, 91))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('SCC', 'Gene', '6317', (47, 50))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('cancer', 'Disease', (164, 170))	('cancers', 'Disease', 'MESH:D009369', (116, 123))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('cancers', 'Phenotype', 'HP:0002664', (116, 123))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cancers', 'Disease', (116, 123))	('SCC', 'Gene', (47, 50))
484771	24162015	DNA hypermethylation and low expression of IRF7, an interferon transcription factor, tracks with this signature particularly in LUSC.	('IRF7', 'Gene', '3665', (43, 47))	('expression', 'MPA', (29, 39))	('IRF7', 'Gene', (43, 47))	('hypermethylation', 'Var', (4, 20))
484774	24162015	We hypothesize that epigenetic therapy combined with blockade of immune checkpoints - in particular the PD-1/PD-L1 pathway - may augment response of NSCLC by shifting the balance between immune activation and immune inhibition, particularly in a subset of NSCLC with low expression of these pathways.	('NSCLC', 'Disease', 'MESH:D002289', (256, 261))	('PD-1/PD-L1', 'Gene', (104, 114))	('shifting', 'Reg', (158, 166))	('NSCLC', 'Disease', 'MESH:D002289', (149, 154))	('NSCLC', 'Disease', (149, 154))	('response', 'MPA', (137, 145))	('epigenetic therapy', 'Var', (20, 38))	('augment', 'PosReg', (129, 136))	('NSCLC', 'Disease', (256, 261))
484775	24162015	Our studies define a biomarker strategy for response in a recently initiated trial to examine the potential of epigenetic therapy to sensitize patients with NSCLC to PD-1 immune checkpoint blockade.	('NSCLC', 'Disease', (157, 162))	('epigenetic therapy', 'Var', (111, 129))	('NSCLC', 'Disease', 'MESH:D002289', (157, 162))	('patients', 'Species', '9606', (143, 151))
484787	24162015	With respect to sensitization potential of this drug for immune responses, such targeting of DNMT's is known to induce increased expression of promoter DNA hypermethylated cancer testes antigens and also is reported to up-regulate other individual facets of the tumor immune stimulating profile, including major histocompatibility antigens, and transcription factors IRF7 and IRF5.	('dual face', 'Phenotype', 'HP:0000324', (243, 252))	('DNMT', 'Gene', '1786', (93, 97))	('tumor', 'Phenotype', 'HP:0002664', (262, 267))	('up-regulate', 'PosReg', (219, 230))	('DNMT', 'Gene', (93, 97))	('expression', 'MPA', (129, 139))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('tumor', 'Disease', (262, 267))	('IRF5', 'Gene', '3663', (376, 380))	('cancer testes', 'Phenotype', 'HP:0010788', (172, 185))	('IRF5', 'Gene', (376, 380))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('IRF7', 'Gene', (367, 371))	('cancer', 'Disease', (172, 178))	('IRF7', 'Gene', '3665', (367, 371))	('targeting', 'Var', (80, 89))	('tumor', 'Disease', 'MESH:D009369', (262, 267))	('increased', 'PosReg', (119, 128))
484806	24162015	As recognized by others, AZA increases expression of multiple cancer testes antigens including multiple MAGE family genes, whose expression has been shown to be suppressed by promoter hypermethylation (Fig.	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('cancer testes', 'Phenotype', 'HP:0010788', (62, 75))	('AZA', 'Var', (25, 28))	('MAGE family genes', 'Gene', (104, 121))	('increases', 'PosReg', (29, 38))	('cancer', 'Disease', (62, 68))	('expression', 'MPA', (39, 49))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('AZA', 'Chemical', 'MESH:D001379', (25, 28))
484809	24162015	Importantly, mutations potentially contributing to immune evasion have been described in HLA-A in a small percentage of LUSC and of B2M and CD58 in other tumor types.	('CD58', 'Gene', '965', (140, 144))	('contributing', 'Reg', (35, 47))	('HLA-A', 'Gene', '3105', (89, 94))	('HLA-A', 'Gene', (89, 94))	('CD58', 'Gene', (140, 144))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('immune evasion', 'MPA', (51, 65))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('mutations', 'Var', (13, 22))	('tumor', 'Disease', (154, 159))
484830	24162015	From the standpoint of the present studies, the immune-related expression alterations in DKO versus wild type HCT116 are remarkably similar to the AZA induced changes in NSCLC cells (Fig.	('DKO', 'Var', (89, 92))	('expression', 'MPA', (63, 73))	('HCT116', 'Gene', (110, 116))	('NSCLC', 'Disease', (170, 175))	('NSCLC', 'Disease', 'MESH:D002289', (170, 175))	('HCT116', 'CellLine', 'CVCL:0291', (110, 116))	('AZA', 'Chemical', 'MESH:D001379', (147, 150))
484838	24162015	Examining H2170, the LUSC cell line with the greatest up-regulation of IRF7 we hypothesized that other genes highly up-regulated in this cell line might be targets of this transcription factor (Fig.	('up-regulation', 'PosReg', (54, 67))	('H2170', 'Var', (10, 15))	('IRF7', 'Gene', (71, 75))	('IRF7', 'Gene', '3665', (71, 75))	('up-regulated', 'PosReg', (116, 128))	('H2170', 'CellLine', 'CVCL:1535', (10, 15))
484848	24162015	Our data therefore suggest a mechanism by which epigenetic therapy might improve the outcome of treatment of patients with NSCLC with PD-1/PD-L1immune checkpoint blockade.	('NSCLC', 'Disease', (123, 128))	('patients', 'Species', '9606', (109, 117))	('NSCLC', 'Disease', 'MESH:D002289', (123, 128))	('improve', 'PosReg', (73, 80))	('epigenetic therapy', 'Var', (48, 66))
484851	24162015	In particular, because the inhibitory ligand PD-L1 is up-regulated by AZA in our cell lines, and subsets of primary tumors have concordant low-expression of AZA induced immune genes and PD-L1, we suggest that combination of epigenetic therapy and PD-1 pathway blockade might produce a synergistic anti-tumor response.	('epigenetic therapy', 'Var', (224, 242))	('tumor', 'Phenotype', 'HP:0002664', (302, 307))	('AZA', 'Chemical', 'MESH:D001379', (70, 73))	('tumor', 'Disease', (302, 307))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('primary tumors', 'Disease', (108, 122))	('up-regulated', 'PosReg', (54, 66))	('primary tumors', 'Disease', 'MESH:D009369', (108, 122))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('AZA', 'Chemical', 'MESH:D001379', (157, 160))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))	('tumor', 'Disease', (116, 121))	('PD-L1', 'Gene', (45, 50))	('tumor', 'Disease', 'MESH:D009369', (302, 307))
484855	24162015	Representative images demonstrating responses to therapy were obtained from computed tomography series employed in the assessment of patient responses to anti-PD1 or anti-PD-L1 directed immune-checkpoint therapy.	('patient', 'Species', '9606', (133, 140))	('PD1', 'Gene', '5133', (159, 162))	('PD1', 'Gene', (159, 162))	('anti-PD-L1', 'Var', (166, 176))
484873	24162015	The following antibodies were used: CD274 (12-5983-42 Ebiosciences), HLA abc (12-9983-42 Ebiosciences), CD276(331606 Biolegend), CD119(558934 BD), B2 microblogumin(551337BD), CD58(555921BD).	('CD58', 'Gene', '965', (175, 179))	('CD276', 'Gene', '80381', (104, 109))	('CD274', 'Gene', '29126', (36, 41))	('CD119', 'Gene', (129, 134))	('CD274', 'Gene', (36, 41))	('CD58', 'Gene', (175, 179))	('551337BD', 'Var', (164, 172))	('abc', 'Gene', (73, 76))	('CD119', 'Gene', '3459', (129, 134))	('CD276', 'Gene', (104, 109))	('abc', 'Gene', '10058', (73, 76))
484880	33663506	Through bioinformatics analysis, we screened a circRNA signature including four circRNAs (hsa_circ_0000005, hsa_circ_0007541, hsa_circ_0008199, hsa_circ_0077536) which can classify the ESCC patients into two groups with significantly different survival (log rank P < 0.001), and found its predictive performance was better than that of the TNM stage(0.84 vs. 0.66; 0.65 vs. 0.62).	('patients', 'Species', '9606', (190, 198))	('hsa_circ_0000005', 'Var', (90, 106))	('hsa_circ_0008199', 'Var', (126, 142))	('hsa_circ_0007541', 'Var', (108, 124))	('ESCC', 'Disease', (185, 189))	('hsa_circ_0077536', 'Var', (144, 160))
484889	33663506	found that the high expression of circRHOT1 was associated with poor prognosis of hepatocellular carcinoma (HCC), and confirmed that circRHOT1 promoted malignant progression of tumors, Liang et al.	('circRHOT1', 'Gene', (34, 43))	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('tumors', 'Phenotype', 'HP:0002664', (177, 183))	('expression', 'MPA', (20, 30))	('circRHOT1', 'Var', (133, 142))	('promoted', 'PosReg', (143, 151))	('tumors', 'Disease', 'MESH:D009369', (177, 183))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (82, 106))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (82, 106))	('tumors', 'Disease', (177, 183))	('hepatocellular carcinoma', 'Disease', (82, 106))
484893	33663506	Research on the pathogenetic and metastatic factor of colon cancer (CC) indicated that circPPP1R12A had a promoting effect and could be a therapeutic target for CC.	('colon cancer', 'Phenotype', 'HP:0003003', (54, 66))	('colon cancer', 'Disease', 'MESH:D015179', (54, 66))	('colon cancer', 'Disease', (54, 66))	('circPPP1R12A', 'Var', (87, 99))	('promoting', 'PosReg', (106, 115))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
484895	33663506	It was found that Hsa_circ_0000337, hsa_circ_0067934 and ciRS-7 were significantly upregulated in ESCC tissues, and may promote tumor cell proliferation, migration and invasion, suggesting that these circRNAs may become potential therapeutic targets for ESCC.	('hsa_circ_0067934', 'Var', (36, 52))	('ciRS-7', 'Gene', (57, 63))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('Hsa_circ_0000337', 'Var', (18, 34))	('promote', 'PosReg', (120, 127))	('ESCC', 'Disease', (98, 102))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('ciRS-7', 'Gene', '103611090', (57, 63))	('upregulated', 'PosReg', (83, 94))	('tumor', 'Disease', (128, 133))	('invasion', 'CPA', (168, 176))	('migration', 'CPA', (154, 163))
484944	29672706	Dissecting the sources of gene expression variation in a pan-cancer analysis identifies novel regulatory mutations Although the catalog of cancer-associated mutations in protein-coding regions is nearly complete for all major cancer types, an assessment of regulatory changes in cancer genomes and their clinical significance remain largely preliminary.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('cancer', 'Disease', (61, 67))	('cancer', 'Phenotype', 'HP:0002664', (279, 285))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))	('mutations', 'Var', (105, 114))	('cancer', 'Disease', (226, 232))	('cancer', 'Disease', 'MESH:D009369', (226, 232))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('cancer', 'Disease', (279, 285))	('cancer', 'Disease', 'MESH:D009369', (279, 285))	('cancer', 'Disease', (139, 145))
484945	29672706	Adopting bottom-up approach, we quantify the effects of different sources of gene expression variation in a cohort of 3899 samples from 10 cancer types.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('variation', 'Var', (93, 102))	('cancer', 'Disease', (139, 145))
484946	29672706	We find that copy number alterations, epigenetic changes, transcription factors and microRNAs collectively explain, on average, only 31-38% and 18-26% expression variation for cancer-associated and other genes, respectively, and that among these factors copy number alteration has the highest effect.	('copy number alterations', 'Var', (13, 36))	('expression', 'MPA', (151, 161))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('cancer', 'Disease', (176, 182))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('copy number alteration', 'Var', (254, 276))
484948	29672706	Integrating whole genome sequencing data and focusing on genes with systematic expression variation we identify novel, recurrent regulatory mutations affecting known cancer genes such as NKX2-1 and GRIN2D in multiple cancer types.	('cancer', 'Disease', (166, 172))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('GRIN2D', 'Gene', '2906', (198, 204))	('NKX2-1', 'Gene', (187, 193))	('cancer', 'Disease', (217, 223))	('cancer', 'Disease', 'MESH:D009369', (217, 223))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('mutations', 'Var', (140, 149))	('NKX2-1', 'Gene', '7080', (187, 193))	('GRIN2D', 'Gene', (198, 204))
484951	29672706	Gene expression in mammalian genomes is regulated at different levels; point mutations, copy number alterations, epigenetic modifications, and post-transcriptional (and post-translational) modifications can potentially regulate abundance of gene products.	('epigenetic modifications', 'Var', (113, 137))	('copy number alterations', 'Var', (88, 111))	('mammalian', 'Species', '9606', (19, 28))	('abundance of gene products', 'MPA', (228, 254))	('regulate', 'Reg', (219, 227))	('point mutations', 'Var', (71, 86))
484952	29672706	Most major cancer types have been systematically profiled for copy number, CpG methylation and transcriptomic changes.	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('copy number', 'Var', (62, 73))	('cancer', 'Disease', 'MESH:D009369', (11, 17))	('CpG methylation', 'Var', (75, 90))	('cancer', 'Disease', (11, 17))
484953	29672706	Even though detection of driver alterations in protein coding regions (reviewed in) has reached near saturation in all major types of cancer, our understanding of the prevalence of regulatory alterations and their significance remain largely preliminary, primarily due to lack of whole genome sequencing (WGS) data for cohorts of samples until recently.	('alterations', 'Var', (32, 43))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))
484955	29672706	The discovery of recurrent mutations in TERT promoter in multiple cancer types including melanoma advocated for a genome-wide scans to identify recurrent noncoding regulatory mutations.	('mutations', 'Var', (27, 36))	('TERT', 'Gene', '7015', (40, 44))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('TERT', 'Gene', (40, 44))	('melanoma', 'Phenotype', 'HP:0002861', (89, 97))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('melanoma', 'Disease', (89, 97))	('melanoma', 'Disease', 'MESH:D008545', (89, 97))	('cancer', 'Disease', (66, 72))
484957	29672706	identified a signature of accelerated somatic evolution marked by clusters of non-recurrent mutations in the promoters of cancer genes that had pathway-level consequences.	('accelerated', 'PosReg', (26, 37))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('mutations', 'Var', (92, 101))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('somatic evolution', 'CPA', (38, 55))
484958	29672706	in BCL2 promoter in lymphoma); but, in some cases, recurrent mutations had no apparent regulatory effects on downstream genes, and in some other cases, mutations with regulatory significance did not necessarily have a base-pair level recurrence.	('regulatory', 'MPA', (87, 97))	('lymphoma', 'Disease', (20, 28))	('BCL2', 'Gene', (3, 7))	('mutations', 'Var', (61, 70))	('lymphoma', 'Disease', 'MESH:D008223', (20, 28))	('lymphoma', 'Phenotype', 'HP:0002665', (20, 28))	('BCL2', 'Gene', '596', (3, 7))
484959	29672706	Other modes of gene expression modulation such as epigenetic deregulation and chromatin-level changes appear to be pervasive in multiple cancer types.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('epigenetic deregulation', 'Var', (50, 73))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('cancer', 'Disease', (137, 143))	('chromatin-level', 'MPA', (78, 93))
484961	29672706	Oncogenic copy number alterations are major drivers behind activity of cancer pathways.	('cancer', 'Disease', (71, 77))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('copy number alterations', 'Var', (10, 33))
484962	29672706	However, it remains unclear to what extent gene expression variation in cancer genomes could be attributed to these factors, including point mutations, and their combinations.	('cancer', 'Disease', (72, 78))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('point mutations', 'Var', (135, 150))
484963	29672706	Here we adopt a novel approach, complementary to the ongoing genome-centric efforts, to dissect the sources of gene expression variations in a cohort of 3899 samples from 10 cancer types, and then integrate whole genome sequencing data for a subset of the cases to identify novel, recurrent somatic mutations associated with altered expression of genes in cancer genomes.	('expression', 'MPA', (333, 343))	('cancer', 'Disease', 'MESH:D009369', (356, 362))	('cancer', 'Disease', (174, 180))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('cancer', 'Phenotype', 'HP:0002664', (356, 362))	('cancer', 'Disease', (356, 362))	('altered', 'Reg', (325, 332))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('mutations', 'Var', (299, 308))
484974	29672706	This identified 5164 point mutations and 17, 339 InDels across all cancer cohorts.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('point mutations', 'Var', (21, 36))	('cancer', 'Disease', (67, 73))
484986	29672706	Similarly, for known cancer genes such as RANBP17 (HNSC) and HOXA9 (BLCA), methylation could explain 53-60% of gene expression variation (Supplementary Table S2).	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('HOXA9', 'Gene', (61, 66))	('methylation', 'Var', (75, 86))	('RANBP17', 'Gene', (42, 49))	('RANBP17', 'Gene', '64901', (42, 49))	('cancer', 'Disease', (21, 27))	('cancer', 'Disease', 'MESH:D009369', (21, 27))	('HOXA9', 'Gene', '3205', (61, 66))	('gene expression', 'MPA', (111, 126))
484990	29672706	Overall, among the above factors, copy number alteration contributed a significantly greater proportion of PVE (Wilcoxon test; FDR adjusted P-value < 5e-2) in gene expression in cancer genomes across all major cancer types, except COAD.	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('COAD', 'Disease', 'MESH:D029424', (231, 235))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('cancer', 'Disease', (178, 184))	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('COAD', 'Disease', (231, 235))	('gene expression', 'MPA', (159, 174))	('cancer', 'Disease', 'MESH:D009369', (210, 216))	('greater', 'PosReg', (85, 92))	('cancer', 'Disease', (210, 216))	('copy number alteration', 'Var', (34, 56))	('PVE', 'Disease', (107, 110))
484992	29672706	For instance, E-box methylation in promoter of EGFR and CASP8 influences binding of the N-Myc transcription factor.	('influences', 'Reg', (62, 72))	('binding', 'Interaction', (73, 80))	('Myc', 'Gene', '4609', (90, 93))	('E-box methylation', 'Var', (14, 31))	('CASP8', 'Gene', (56, 61))	('methylation', 'Var', (20, 31))	('Myc', 'Gene', (90, 93))	('CASP8', 'Gene', '841', (56, 61))	('EGFR', 'Gene', '1956', (47, 51))	('EGFR', 'Gene', (47, 51))
484998	29672706	It was also noted that on average, copy number alteration is a major determinant (higher D2) of gene expression variation in all major cancer types, and in contrast, those genes for which overall expression variation explained is lower, tend to have miRNA as major contributor of expression variation, as seen in Figure 1B and separately shown in Supplementary Figure S5.	('expression', 'MPA', (280, 290))	('cancer', 'Disease', (135, 141))	('lower', 'NegReg', (230, 235))	('copy number alteration', 'Var', (35, 57))	('expression', 'MPA', (196, 206))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('cancer', 'Disease', 'MESH:D009369', (135, 141))	('variation', 'Var', (112, 121))
485009	29672706	In our dataset for BRCA samples, BRCA1 expression was significantly different among the samples with deletion, duplication compared to wild type BRCA1 (Wilcoxon test P-value: 5e-03/2.2e-16, Supplementary Figure S9A).	('BRCA', 'Gene', (33, 37))	('different', 'Reg', (68, 77))	('deletion', 'Var', (101, 109))	('BRCA', 'Gene', '672', (145, 149))	('BRCA1', 'Gene', '672', (145, 150))	('BRCA', 'Gene', '672', (19, 23))	('BRCA1', 'Gene', '672', (33, 38))	('BRCA', 'Gene', (145, 149))	('BRCA', 'Gene', '672', (33, 37))	('BRCA1', 'Gene', (145, 150))	('duplication', 'Var', (111, 122))	('expression', 'MPA', (39, 49))	('BRCA', 'Gene', (19, 23))	('BRCA1', 'Gene', (33, 38))
485010	29672706	We first used the somExVar pipeline to identify sources of variation in BRCA1 expression without including SCNA in the model and identified large systematic variation in the model residuals.	('BRCA1', 'Gene', '672', (72, 77))	('variation', 'Var', (59, 68))	('BRCA1', 'Gene', (72, 77))
485011	29672706	This was evident when the samples were grouped according to their BRCA1 copy number status and model residuals were compared (deletion/ duplication; Wilcoxon test P-value: 3.8e-16/2.5e-13, Supplementary Figure S9B).	('BRCA1', 'Gene', (66, 71))	('BRCA1', 'Gene', '672', (66, 71))	('deletion/ duplication', 'Var', (126, 147))
485013	29672706	This suggests that copy number alteration is by far the leading mechanism driving expression variation of BRCA1.	('BRCA1', 'Gene', '672', (106, 111))	('BRCA1', 'Gene', (106, 111))	('copy number alteration', 'Var', (19, 41))	('expression', 'MPA', (82, 92))
485014	29672706	As a second example, we analyzed SDHD, which has been reported to carry recurrent regulatory mutations driving its decreased expression in melanoma (Wilcoxon test P-value < 1e-03, Supplementary Figure S10A,).	('S10A', 'SUBSTITUTION', 'None', (201, 205))	('mutations', 'Var', (93, 102))	('SDHD', 'Gene', '6392', (33, 37))	('melanoma', 'Phenotype', 'HP:0002861', (139, 147))	('SDHD', 'Gene', (33, 37))	('melanoma', 'Disease', (139, 147))	('S10A', 'Var', (201, 205))	('decreased', 'NegReg', (115, 124))	('expression', 'MPA', (125, 135))	('melanoma', 'Disease', 'MESH:D008545', (139, 147))
485015	29672706	It is noteworthy that copy number alteration at the SDHD locus is also common.	('SDHD', 'Gene', (52, 56))	('SDHD', 'Gene', '6392', (52, 56))	('copy number alteration', 'Var', (22, 44))
485016	29672706	In case of SDHD promoter mutation, 7 out of 13 samples carrying the mutant allele also had copy number loss (CN log2 ratio  0.1) of SDHD locus (remaining were copy neutral, CN log2 ratio: -0.1 to 0.1).	('copy', 'MPA', (91, 95))	('number loss', 'Disease', 'MESH:D016388', (96, 107))	('SDHD', 'Gene', (132, 136))	('mutation', 'Var', (25, 33))	('SDHD', 'Gene', '6392', (132, 136))	('SDHD', 'Gene', '6392', (11, 15))	('mutant', 'Var', (68, 74))	('number loss', 'Disease', (96, 107))	('SDHD', 'Gene', (11, 15))
485017	29672706	Including only promoter methylation, tumor purity, transcription factor and miRNA expression, somExVar identified systematic difference in residuals among the samples carrying promoter mutations/SCNA and those that were wild type (Supplementary Figure S10B).	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('residuals', 'MPA', (139, 148))	('S10B', 'Var', (252, 256))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('promoter mutations/SCNA', 'Var', (176, 199))	('S10B', 'SUBSTITUTION', 'None', (252, 256))
485021	29672706	It is noteworthy that some cancer types such as prostate cancer (PRAD), that have a relatively limited number of identified driver mutations in coding regions on average show large expression variation, potentially suggestive of regulatory abnormalities.	('mutations', 'Var', (131, 140))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('prostate cancer', 'Disease', 'MESH:D011471', (48, 63))	('cancer', 'Disease', (57, 63))	('expression variation', 'MPA', (181, 201))	('prostate cancer', 'Phenotype', 'HP:0012125', (48, 63))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('cancer', 'Disease', (27, 33))	('cancer', 'Disease', 'MESH:D009369', (27, 33))	('prostate cancer', 'Disease', (48, 63))
485025	29672706	Dysregulation of ECM composition and structure is known to play a role in invasive cancer.	('Dysregulation', 'Var', (0, 13))	('invasive cancer', 'Disease', 'MESH:D009362', (74, 89))	('invasive cancer', 'Disease', (74, 89))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))
485036	29672706	When we grouped the samples from the BLCA cancer cohort (n = 144) into two modal populations by the model residuals of SLC1A6 expression, they had significant difference in N0 status for the extent of spread to lymph node (Chi-square test FDR adjusted P-value < 5e-03) and survival (P-value < 1e-03, Supplementary Figure S15) so that the patients with large SLC1A6 expression residuals had greater spread to lymph node as well as consistently poor survival.	('SLC1A6', 'Gene', (358, 364))	('residuals', 'Var', (376, 385))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('S15', 'Gene', (321, 324))	('SLC1A6', 'Gene', '6511', (358, 364))	('SLC1A6', 'Gene', (119, 125))	('survival', 'MPA', (448, 456))	('cancer', 'Disease', (42, 48))	('poor', 'NegReg', (443, 447))	('greater', 'PosReg', (390, 397))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('spread to lymph node', 'CPA', (398, 418))	('S15', 'Gene', '6209', (321, 324))	('patients', 'Species', '9606', (338, 346))	('SLC1A6', 'Gene', '6511', (119, 125))
485039	29672706	The average mutation density in whole genome was ~24 mutations/mb and 3.2 mutations/mb for substitutions and InDels respectively across the ten cancer types.	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('cancer', 'Disease', (144, 150))	('InDels', 'Var', (109, 115))	('substitutions', 'Var', (91, 104))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
485041	29672706	While transitions were more common in gene regions, transversions were more common in the upstream regions (Supplementary Figure S17).	('transitions', 'Var', (6, 17))	('S17', 'Gene', (129, 132))	('S17', 'Gene', '6218', (129, 132))	('transversions', 'Var', (52, 65))
485042	29672706	Towards this, we found 33 recurrent single nucleotide variations and 134 small InDels in 63 genes across all 10 cancers, which were predicted to have high regulatory potential (SNVs: Figure 5B, Indels: Supplementary Figure S18).	('genes', 'Gene', (92, 97))	('cancers', 'Phenotype', 'HP:0002664', (112, 119))	('S18', 'Gene', '6222', (223, 226))	('cancers', 'Disease', 'MESH:D009369', (112, 119))	('cancers', 'Disease', (112, 119))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('single nucleotide variations', 'Var', (36, 64))	('S18', 'Gene', (223, 226))
485043	29672706	Integrating whole genome sequencing data, we detected recurrent somatic mutations with regulatory potential in the NKX2-1 promoter within 230bp upstream of the transcription start site in the HNSC cohort (Figure 5C).	('NKX2-1', 'Gene', (115, 121))	('regulatory', 'MPA', (87, 97))	('NKX2-1', 'Gene', '7080', (115, 121))	('mutations', 'Var', (72, 81))
485046	29672706	Samples with a mutation at this position disrupt the binding site for SP3, and thus had significantly higher expression compared to wild type (P-value = 0.03, Wilcoxon rank sum test), Figure 5D.	('mutation', 'Var', (15, 23))	('binding site', 'Interaction', (53, 65))	('disrupt', 'NegReg', (41, 48))	('expression', 'MPA', (109, 119))	('higher', 'PosReg', (102, 108))	('SP3', 'Gene', (70, 73))	('SP3', 'Gene', '6670', (70, 73))
485047	29672706	According to our model, the inclusion of these somatic mutations led to a 7% increase in PVE for the expression level of the NKX2-1 gene.	('NKX2-1', 'Gene', (125, 131))	('mutations', 'Var', (55, 64))	('NKX2-1', 'Gene', '7080', (125, 131))	('increase', 'PosReg', (77, 85))	('PVE for the expression level', 'MPA', (89, 117))
485050	29672706	Using a similar approach, we detected additional novel recurrent somatic mutations [chr19:48894669], SNVs and InDels, (in 11 samples of HNSC and 9 more samples across different cancers) upstream of the GRIN2D locus.	('SNVs', 'Var', (101, 105))	('InDels', 'Var', (110, 116))	('cancers', 'Disease', 'MESH:D009369', (177, 184))	('cancers', 'Phenotype', 'HP:0002664', (177, 184))	('cancers', 'Disease', (177, 184))	('GRIN2D', 'Gene', (202, 208))	('GRIN2D', 'Gene', '2906', (202, 208))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('HNSC', 'Disease', (136, 140))
485051	29672706	The recurrent SNV overlaps with the binding motif for NFKB1, with the mutation disrupting the canonical motif.	('NFKB1', 'Gene', (54, 59))	('canonical motif', 'MPA', (94, 109))	('disrupting', 'NegReg', (79, 89))	('NFKB1', 'Gene', '4790', (54, 59))	('mutation', 'Var', (70, 78))
485054	29672706	Mutations in NKX2-1 and GRIN2D were predicted to have regulatory impact by both RegulomeDB, and Funseq2, which highlight the utility of our approach to complement the classic top-down approach.	('regulatory impact', 'MPA', (54, 71))	('NKX2-1', 'Gene', '7080', (13, 19))	('GRIN2D', 'Gene', (24, 30))	('Mutations', 'Var', (0, 9))	('GRIN2D', 'Gene', '2906', (24, 30))	('NKX2-1', 'Gene', (13, 19))
485055	29672706	For instance, SDHD expression was affected by promoter mutations in some samples and copy number alteration in some other samples (Supplementary Figure S4).	('copy number alteration', 'Var', (85, 107))	('expression', 'MPA', (19, 29))	('affected', 'Reg', (34, 42))	('SDHD', 'Gene', '6392', (14, 18))	('SDHD', 'Gene', (14, 18))	('promoter mutations', 'Var', (46, 64))
485057	29672706	It is noteworthy that these genes, apart from having regulatory mutations, also harbor copy number alterations and missense mutations that are known to affect their gene expression levels (Supplementary Figure S19).	('Supplementary Figure S19', 'Disease', 'MESH:D017034', (189, 213))	('affect', 'Reg', (152, 158))	('copy number alterations', 'Var', (87, 110))	('gene expression levels', 'MPA', (165, 187))	('missense mutations', 'Var', (115, 133))	('Supplementary Figure S19', 'Disease', (189, 213))
485058	29672706	Thus, for SDHD and other examples, point mutations are not the only modifiers of gene expression, and rather most of these genes experience expression changes via multiple mechanisms.	('expression', 'MPA', (140, 150))	('changes', 'Reg', (151, 158))	('point mutations', 'Var', (35, 50))	('SDHD', 'Gene', (10, 14))	('SDHD', 'Gene', '6392', (10, 14))
485059	29672706	In this study, we present an integrative approach to identify the major sources of gene expression variation in cancer genomes, and identify candidates with large unexplained variation in gene expression after accounting for the effects of different modes of regulation such as copy number alterations, epigenetic changes, transcription factors, and miRNAs.	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('copy number alterations', 'Var', (278, 301))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('epigenetic changes', 'Var', (303, 321))
485065	29672706	Our Pan-cancer analysis indicates that copy number alterations, epigenetic changes, and transcriptional and post-transcriptional regulatory factors collectively explain, on average, 18-26% expression variation at a genome-wide scale.	('Pan-cancer', 'Disease', (4, 14))	('epigenetic changes', 'Var', (64, 82))	('Pan-cancer', 'Disease', 'MESH:C537931', (4, 14))	('expression', 'MPA', (189, 199))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('copy number alterations', 'Var', (39, 62))
485069	29672706	For instance, the recurrent SDHD promoter mutation increased the variation explained in the model only by 1%.	('SDHD', 'Gene', (28, 32))	('SDHD', 'Gene', '6392', (28, 32))	('mutation', 'Var', (42, 50))
485070	29672706	Also, when incorporated in somExVar workflow, promoter mutations lead to 2-5% improvement in average PVE in general across different cancer types (Supplementary Figure S20 and Supplementary Table S9).	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('S20', 'Gene', '6224', (168, 171))	('S20', 'Gene', (168, 171))	('cancer', 'Disease', (133, 139))	('PVE', 'MPA', (101, 104))	('improvement', 'PosReg', (78, 89))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('promoter mutations', 'Var', (46, 64))
485075	28859123	Recently, co-expression of multiple receptor tyrosine kinases (RTKs) has been found to be associated with aggressive biological behavior and poor prognosis of several types of malignancy.	('malignancy', 'Disease', 'MESH:D009369', (176, 186))	('co-expression', 'Var', (10, 23))	('aggressive biological behavior', 'CPA', (106, 136))	('malignancy', 'Disease', (176, 186))	('associated', 'Reg', (90, 100))	('aggressive biological behavior', 'Phenotype', 'HP:0000718', (106, 136))
485080	28859123	Positivity for HER2 was significantly correlated with tumor size (P = 0.029).	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('HER2', 'Protein', (15, 19))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('Positivity', 'Var', (0, 10))	('tumor', 'Disease', (54, 59))	('correlated', 'Reg', (38, 48))
485092	28859123	Therefore, the presence of RTKs has been shown to be associated with aggressive biological behavior, poor prognosis and therapeutic resistance for several types of malignancy including cervical squamous cell carcinoma.	('cervical squamous cell carcinoma', 'Disease', 'MESH:D002294', (185, 217))	('aggressive biological behavior', 'Phenotype', 'HP:0000718', (69, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (208, 217))	('malignancy', 'Disease', (164, 174))	('RTKs', 'Gene', (27, 31))	('cervical squamous cell carcinoma', 'Disease', (185, 217))	('presence', 'Var', (15, 23))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (194, 217))	('associated', 'Reg', (53, 63))	('malignancy', 'Disease', 'MESH:D009369', (164, 174))
485093	28859123	Furthermore, co-overexpression of EGFR and HER2 has been reported to be associated with malignancy in several tumors including breast cancer, lung cancer, prostate cancer and urinary bladder cancer.	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('associated', 'Reg', (72, 82))	('breast cancer', 'Phenotype', 'HP:0003002', (127, 140))	('lung cancer', 'Disease', (142, 153))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('EGFR', 'Gene', (34, 38))	('breast cancer', 'Disease', 'MESH:D001943', (127, 140))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('breast cancer', 'Disease', (127, 140))	('tumors', 'Disease', (110, 116))	('urinary bladder cancer', 'Disease', (175, 197))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('bladder cancer', 'Phenotype', 'HP:0009725', (183, 197))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('co-overexpression', 'Var', (13, 30))	('lung cancer', 'Disease', 'MESH:D008175', (142, 153))	('malignancy', 'Disease', 'MESH:D009369', (88, 98))	('tumors', 'Disease', 'MESH:D009369', (110, 116))	('lung cancer', 'Phenotype', 'HP:0100526', (142, 153))	('urinary bladder cancer', 'Disease', 'MESH:D001749', (175, 197))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('prostate cancer', 'Disease', 'MESH:D011471', (155, 170))	('prostate cancer', 'Phenotype', 'HP:0012125', (155, 170))	('HER2', 'Protein', (43, 47))	('malignancy', 'Disease', (88, 98))	('prostate cancer', 'Disease', (155, 170))
485108	28859123	Surgical specimen staining patterns were scored as follows: score 0, no reactivity or membranous reactivity in less than 10% of tumor cells: score 1+, faint/almost no membranous reactivity in 10% or more of tumor cells; score 2+, weak to moderate complete or basolateral membranous reactivity in 10% or more tumor cells; and score 3+, moderate to strong complete or basolateral membranous reactivity in 10% or more of tumor cells.	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('tumor', 'Disease', (418, 423))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('score 2+', 'Var', (220, 228))	('tumor', 'Disease', 'MESH:D009369', (308, 313))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('tumor', 'Phenotype', 'HP:0002664', (308, 313))	('tumor', 'Disease', 'MESH:D009369', (418, 423))	('tumor', 'Disease', (128, 133))	('tumor', 'Disease', (207, 212))	('tumor', 'Disease', (308, 313))	('tumor', 'Phenotype', 'HP:0002664', (418, 423))
485116	28859123	Twenty (46%) of the 43 adenocarcinoma cases were positive for multiple RTKs, including 7 cases (16%) with EGFR+/HER2+/c-Met+, 4 cases (9%) with EGFR+/HER2+/c-Met-, 3 cases (7%) with EGFR+/HER2-/c-Met+, and 6 cases (14%) with EGFR-/HER2+/c-Met+.	('EGFR+/HER2+/c-Met', 'Gene', '1956', (144, 161))	('carcinoma', 'Phenotype', 'HP:0030731', (28, 37))	('adenocarcinoma', 'Disease', 'MESH:D000230', (23, 37))	('EGFR+/HER2+/c-Met', 'Gene', '1956', (106, 123))	('positive', 'Reg', (49, 57))	('EGFR+/HER2-/c-Met+', 'Var', (182, 200))	('EGFR+/HER2+/c-Met', 'Gene', (106, 123))	('EGFR+/HER2+/c-Met', 'Gene', (144, 161))	('adenocarcinoma', 'Disease', (23, 37))
485119	28859123	HER2 positivity was correlated only with tumor size (P = 0.0291).	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('positivity', 'Var', (5, 15))	('tumor', 'Disease', (41, 46))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('HER2', 'Protein', (0, 4))
485125	28859123	The presence of RTKs has been reported to be associated with accelerated tumor progression and therapeutic resistance for several types of malignancies, including cervical cancer.	('cervical cancer', 'Disease', (163, 178))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('malignancies', 'Disease', (139, 151))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('accelerated', 'PosReg', (61, 72))	('tumor', 'Disease', (73, 78))	('therapeutic resistance', 'CPA', (95, 117))	('presence', 'Var', (4, 12))	('malignancies', 'Disease', 'MESH:D009369', (139, 151))	('cervical cancer', 'Disease', 'MESH:D002583', (163, 178))	('RTKs', 'Gene', (16, 20))
485133	28859123	EGFR positivity was associated with lymph node metastasis and UICC stage of the patients, which may result from the well-known role of EGFR in proliferation, invasiveness and migration of tumor cells.	('invasiveness', 'CPA', (158, 170))	('tumor', 'Disease', (188, 193))	('positivity', 'Var', (5, 15))	('associated', 'Reg', (20, 30))	('EGFR', 'Gene', (0, 4))	('lymph node metastasis', 'CPA', (36, 57))	('patients', 'Species', '9606', (80, 88))	('UICC stage', 'CPA', (62, 72))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))
485136	28859123	Previous studies have shown that EGFR and HER2 co-expression was implicated in an increase in tumor aggressiveness and worse prognosis of several cancers, including cervical squamous cell carcinoma.	('aggressiveness', 'Phenotype', 'HP:0000718', (100, 114))	('carcinoma', 'Phenotype', 'HP:0030731', (188, 197))	('cancers', 'Disease', (146, 153))	('HER2', 'Protein', (42, 46))	('cancers', 'Disease', 'MESH:D009369', (146, 153))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('co-expression', 'Var', (47, 60))	('cervical squamous cell carcinoma', 'Disease', (165, 197))	('tumor aggressiveness', 'Disease', (94, 114))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (174, 197))	('increase', 'PosReg', (82, 90))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('EGFR', 'Gene', (33, 37))	('cervical squamous cell carcinoma', 'Disease', 'MESH:D002294', (165, 197))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (94, 114))	('cancers', 'Phenotype', 'HP:0002664', (146, 153))
485162	28122605	The differentially methylated CpG sites (DMCs) or regions (DMRs) identified from such analysis can be further associated with somatic mutations or gene expression regulation to enhance our understanding of cancer etiology.	('DMRs', 'Chemical', '-', (59, 63))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('DMCs', 'Chemical', '-', (41, 45))	('associated', 'Reg', (110, 120))	('cancer', 'Disease', (206, 212))	('differentially', 'Var', (4, 18))	('enhance', 'PosReg', (177, 184))	('cancer', 'Disease', 'MESH:D009369', (206, 212))
485172	28122605	With the continuous cost reduction of technology, large-scale, population level methylation studies have become increasingly prevalent for different types of cancers.	('cancers', 'Phenotype', 'HP:0002664', (158, 165))	('cancers', 'Disease', (158, 165))	('cancers', 'Disease', 'MESH:D009369', (158, 165))	('methylation', 'Var', (80, 91))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
485206	28122605	To compare our estimated purities with other methods, we obtained purity estimates for all cancer samples from, based on different methods including ABSOLUTE, ESTIMATE, a consensus measurement of purity estimation (CPE), image analysis of hematoxylin and eosin stain slides (IHC), and non-methylation of immune-specific CpG sites (LUMP).	('eosin', 'Chemical', 'MESH:D004801', (255, 260))	('non-methylation', 'Var', (285, 300))	('hematoxylin', 'Chemical', 'MESH:D006416', (239, 250))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('CPE', 'Gene', (215, 218))	('CPE', 'Gene', '1363', (215, 218))
485261	28122605	Figure 4a shows the number of significant (defined as false discovery rate (FDR) < 0.01) DMCs detected for all cancer types whenever data are available.	('DMCs', 'Var', (89, 93))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('DMCs', 'Chemical', '-', (89, 93))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))
485264	28122605	The gain in sensitivity could be significant, for example, the number of DMCs detected in THCA (thyroid carcinoma) is almost doubled compared to minfi.	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (96, 113))	('thyroid carcinoma', 'Disease', (96, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('DMCs', 'Var', (73, 77))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (96, 113))	('THCA', 'Disease', (90, 94))	('DMCs', 'Chemical', '-', (73, 77))
485279	28122605	Even though different cancer types have distinct etiologies, they also share many commonalities, such as the hyper-methylation in CpG islands and genic regions and global hypo-methylation in whole genomes especially for highly and moderately repeated DNA sequences.	('highly', 'Var', (220, 226))	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('cancer', 'Disease', (22, 28))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('hypo-methylation', 'Var', (171, 187))
485287	28122605	We further examined the enrichment of DMGs in pathways related to different cancer types (Additional file 2: Figure S13).	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('DMGs', 'Chemical', '-', (38, 42))	('DMGs', 'Var', (38, 42))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))
485318	28122605	Although copy number alteration is a characteristic of cancer cells and is also less variable than gene expression, cancer cells often have aberrant overall ploidy number compared with normal cells, which greatly affects copy number-based purity estimates.	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('affects', 'Reg', (213, 220))	('ploidy number', 'MPA', (157, 170))	('alteration', 'Var', (21, 31))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('cancer', 'Disease', (55, 61))	('copy', 'Var', (9, 13))
485338	28122605	It could have a great impact on many cancer data analyses including differential expression, copy number alteration, differential methylation, genome-wide association studies, and EWAS.	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('differential methylation', 'Var', (117, 141))	('copy number alteration', 'Var', (93, 115))	('impact', 'Reg', (22, 28))	('cancer', 'Disease', (37, 43))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))
485382	28122605	The residual variances are sigma i 2 and sigma i'2, respectively, for normal and cancer groups.	("sigma i'2", 'Var', (41, 50))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('cancer', 'Disease', (81, 87))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('sigma', 'Var', (27, 32))
485402	32762722	LUAD has frequent driver mutations in EGFR and ALK, which serve as molecular targets for tyrosine kinase inhibitor-targeted therapy; whereas, LUSC has diverse mutation profiles without any specific dominant mutations and has been rendered unresponsive to molecularly targeted drugs currently available.	('EGFR', 'Gene', '1956', (38, 42))	('mutations', 'Var', (25, 34))	('LUSC', 'Phenotype', 'HP:0030359', (142, 146))	('EGFR', 'Gene', (38, 42))	('ALK', 'Gene', (47, 50))	('ALK', 'Gene', '238', (47, 50))	('LUAD', 'Phenotype', 'HP:0030078', (0, 4))
485438	32762722	The majority of the tumors in the PDX models had genetic alterations similar to those of their parental patient tumors (Additional file 4.	('genetic alterations', 'Var', (49, 68))	('tumors', 'Disease', 'MESH:D009369', (20, 26))	('tumors', 'Disease', (20, 26))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('patient', 'Species', '9606', (104, 111))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('tumors', 'Disease', 'MESH:D009369', (112, 118))	('tumors', 'Disease', (112, 118))
485448	32762722	In the LUSC PDX models in this study, three PDX models, DP089, SP212, and SP448, which had upregulated expression of the FGFR3 gene, could be used as preclinical models to test in vivo the efficacy of FGFR-targeted drugs.	('upregulated', 'PosReg', (91, 102))	('LUSC', 'Phenotype', 'HP:0030359', (7, 11))	('FGFR3', 'Gene', '2261', (121, 126))	('test', 'Reg', (172, 176))	('expression', 'MPA', (103, 113))	('SP448', 'Var', (74, 79))	('FGFR3', 'Gene', (121, 126))
485477	32762722	Other groups also showed that the combination of treatments of FGFR inhibitors and conventional chemotherapy could enhance the drug response of patients with lung cancer using PDX models.	('lung cancer', 'Disease', (158, 169))	('lung cancer', 'Phenotype', 'HP:0100526', (158, 169))	('FGFR', 'Gene', (63, 67))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('inhibitors', 'Var', (68, 78))	('patients', 'Species', '9606', (144, 152))	('drug response', 'CPA', (127, 140))	('lung cancer', 'Disease', 'MESH:D008175', (158, 169))	('enhance', 'PosReg', (115, 122))
485508	32038497	We rated the claimed statistically significant (P < 0.05) associations between aspirin and cancer risk into four levels:strong, highly suggestive, suggestive, and weak according to the following criteria: P < 10-6, >1,000 cases, P < 0.05 of the largest study in the meta-analysis, I2 <50%, absence of small-study effects (P > 0.1 for Egger's test), the 95% PI excludes the null value, no excess significance bias (P > 0.1), and survived the 10% credibility ceiling (P < 0.05) for strong evidence; P < 10-6, >1,000 cases, P < 0.05 of the largest study in the meta-analysis for highly suggestive evidence; P < 10-3, >1,000 cases for suggestive evidence; and P < 0.05 for weak evidence.	('P <', 'Var', (604, 607))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('aspirin', 'Chemical', 'MESH:D001241', (79, 86))
485544	30426973	In the univariate analysis, low PNI (PNI<45) (p=0.001), large primary tumour (T4) (p=0.044) and advanced lymph node disease (N2b-N3) (p=0.025) were significantly associated with poorer OS in the validation cohort.	('primary tumour', 'Disease', 'MESH:D009369', (62, 76))	('poorer OS', 'Disease', (178, 187))	('PNI', 'Gene', (32, 35))	('lymph node disease', 'Phenotype', 'HP:0002733', (105, 123))	('tumour', 'Phenotype', 'HP:0002664', (70, 76))	('lymph node disease', 'Disease', 'MESH:D000072717', (105, 123))	('primary tumour', 'Disease', (62, 76))	('low', 'Var', (28, 31))	('lymph node disease', 'Disease', (105, 123))	('OS', 'Chemical', '-', (185, 187))
485565	30426973	As regards HNSCC a low PNI has been shown to be a predictor of poor survival, and it has been associated with severe radiotherapy-induced adverse events in a small series of patients.	('HNSCC', 'Phenotype', 'HP:0012288', (11, 16))	('PNI', 'MPA', (23, 26))	('low', 'Var', (19, 22))	('patients', 'Species', '9606', (174, 182))	('associated', 'Reg', (94, 104))	('poor', 'NegReg', (63, 67))
485599	30426973	The highest sensitivity and specificity for predicting poor OS were met for NLR >=2.6 and dNLR >=1.7 and were therefore selected as the optimal thresholds for these inflammation-based prognostic scores (IBP) in this scenario (table 2).	('dNLR', 'Var', (90, 94))	('inflammation', 'Disease', 'MESH:D007249', (165, 177))	('NLR', 'Gene', (76, 79))	('OS', 'Chemical', '-', (60, 62))	('inflammation', 'Disease', (165, 177))
485607	30426973	Patients with a low PNI score were more likely to have more advanced lymph node disease (p=0.038), more advanced TNM staging (p=0.012) and higher NLR and dNLR levels (p=0.007 and p=0.44, respectively).	('low', 'Var', (16, 19))	('PNI score', 'Gene', (20, 29))	('TNM', 'Gene', (113, 116))	('lymph node disease', 'Disease', 'MESH:D000072717', (69, 87))	('Patients', 'Species', '9606', (0, 8))	('lymph node disease', 'Disease', (69, 87))	('TNM', 'Gene', '10178', (113, 116))	('higher', 'PosReg', (139, 145))	('lymph node disease', 'Phenotype', 'HP:0002733', (69, 87))
485609	30426973	In the univariate analysis, low PNI (PNI <45) (p=0.001), large primary tumour (T4) (p=0.044) and advanced lymph node disease (N2b-N3) (p=0.025) were significantly associated with poorer OS.	('primary tumour', 'Disease', (63, 77))	('poorer OS', 'Disease', (179, 188))	('primary tumour', 'Disease', 'MESH:D009369', (63, 77))	('PNI', 'Gene', (32, 35))	('OS', 'Chemical', '-', (186, 188))	('lymph node disease', 'Phenotype', 'HP:0002733', (106, 124))	('tumour', 'Phenotype', 'HP:0002664', (71, 77))	('lymph node disease', 'Disease', 'MESH:D000072717', (106, 124))	('lymph node disease', 'Disease', (106, 124))	('low', 'Var', (28, 31))
485625	30426973	Third, subjects displaying an ongoing inflammatory response may be at an additional risk of chemotherapy-related toxicity because of inflammation-related alterations in drug pharmacokinetics such as modulation of cytochrome P450 metabolism as well as hypoalbuminaemia; it could be helpful to clarify criteria for induction chemotherapy that remains controversial.	('modulation', 'Var', (199, 209))	('toxicity', 'Disease', 'MESH:D064420', (113, 121))	('toxicity', 'Disease', (113, 121))	('cytochrome P450 metabolism', 'Enzyme', (213, 239))	('hypoalbuminaemia', 'Disease', (251, 267))	('inflammation', 'Disease', 'MESH:D007249', (133, 145))	('hypoalbuminaemia', 'Disease', 'None', (251, 267))	('inflammation', 'Disease', (133, 145))	('alterations', 'Reg', (154, 165))	('drug pharmacokinetics', 'MPA', (169, 190))	('hypoalbuminaemia', 'Phenotype', 'HP:0003073', (251, 267))
485633	28115635	However, epigenetic reprogramming in cancer often involves gene body hypomethylation with consequences on gene expression.	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('epigenetic', 'Var', (9, 19))	('cancer', 'Disease', (37, 43))	('involves', 'Reg', (50, 58))	('hypomethylation', 'Var', (69, 84))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('consequences', 'Reg', (90, 102))
485635	28115635	Furthermore, they are significantly more prone to cancer-associated hypomethylation and mutation.	('prone', 'Reg', (41, 46))	('mutation', 'Var', (88, 96))	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))
485636	28115635	Consequently, gene body hypomethylation represents an additional layer of epigenetic regulatory complexity, with implications on cancer-associated epigenetic reprogramming.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('hypomethylation', 'Var', (24, 39))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))
485642	28115635	In some cases, gene body hypomethylation has been directly and casually linked to the alterations of gene expression in cancer.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('hypomethylation', 'Var', (25, 40))	('linked', 'Reg', (72, 78))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))
485649	28115635	Moreover, hypomethylated genes in normal human tissues are significantly over-represented in those that undergo cancer-associated hypomethylation.	('over-represented', 'PosReg', (73, 89))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('human', 'Species', '9606', (41, 46))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('hypomethylation', 'Var', (130, 145))
485650	28115635	These results indicate that body-hypomethylated genes occupy a unique epigenetic niche within the human genome and that their regulation may share pathways involved in cancer-associated hypomethylation.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('cancer', 'Disease', (168, 174))	('regulation', 'MPA', (126, 136))	('body-hypomethylated', 'Var', (28, 47))	('human', 'Species', '9606', (98, 103))
485678	28115635	Most human genes ('other genes') harbor histone modifications associated with regions of active transcription, such as H3K36me3 and H3K9me3, in agreement with previous studies.	('H3K36me3', 'Var', (119, 127))	('histone', 'Protein', (40, 47))	('H3K9me3', 'Var', (132, 139))	('human', 'Species', '9606', (5, 10))
485679	28115635	Previous studies have documented the cancer-associated hypomethylation of gene bodies occurring in different tumor types.	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('cancer', 'Disease', (37, 43))	('hypomethylation', 'Var', (55, 70))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('gene', 'Protein', (74, 78))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumor', 'Disease', (109, 114))
485683	28115635	Second, hypomethylated genes are significantly more prone to be differentially methylated between tumor samples versus tissue-matched non-cancerous samples, which was found in 12 out of the 18 cancers analyzed (average enrichment of 3.65, P-value < 0.001 based on 1000 bootstraps, Supplementary Table S7).	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('cancer', 'Disease', (138, 144))	('cancers', 'Disease', 'MESH:D009369', (193, 200))	('cancers', 'Phenotype', 'HP:0002664', (193, 200))	('differentially methylated', 'MPA', (64, 89))	('hypomethylated', 'Var', (8, 22))	('cancers', 'Disease', (193, 200))	('cancer', 'Disease', (193, 199))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('tumor', 'Disease', (98, 103))	('cancer', 'Disease', 'MESH:D009369', (138, 144))
485686	28115635	We analyzed around two million somatic mutations considered pathogenic in cancer and identified in whole-genome and whole-exome sequencing projects and deposited in the COSMIC.	('cancer', 'Disease', (74, 80))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('mutations', 'Var', (39, 48))
485687	28115635	Hypomethylated genes harbor significantly higher number of cancerous mutations per base than other genes (P < 10-15, Wilcoxon test, Supplementary Figure S4A).	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('Hypomethylated', 'Var', (0, 14))
485688	28115635	For example, the gene with the highest number of per base pair mutations is a histone gene HIST1H3B, which is constitutively hypomethylated at its gene body, harboring 69 mutations total.	('mutations', 'Var', (63, 72))	('HIST1H3B', 'Gene', (91, 99))	('HIST1H3B', 'Gene', '8358', (91, 99))
485689	28115635	Therefore, gene body regions of hypomethylated genes seem to evolve under stronger selective constraints than other genes but they tend to accumulate higher number of pathogenic mutations than other genes during somatic cancerous processes.	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('hypomethylated', 'Var', (32, 46))	('accumulate', 'PosReg', (139, 149))	('cancer', 'Disease', 'MESH:D009369', (220, 226))	('cancer', 'Disease', (220, 226))	('mutations', 'Var', (178, 187))
485700	28115635	Hypomethylated genes tend to be short, harbor fewer exons than the rest of the genome, and they are guanine cytosine (GC)-rich.	('exons', 'MPA', (52, 57))	('guanine cytosine', 'Chemical', '-', (100, 116))	('fewer', 'NegReg', (46, 51))	('GC', 'Chemical', '-', (118, 120))	('Hypomethylated genes', 'Var', (0, 20))
485706	28115635	Furthermore, we show that genes hypomethylated in normal tissues are highly prone to cancer-associated hypomethylation and somatic mutations, irrespective of their tissue origins.	('mutations', 'Var', (131, 140))	('prone', 'Reg', (76, 81))	('hypomethylated', 'Var', (32, 46))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('cancer', 'Disease', (85, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
485707	28115635	Although the implications of cancer-associated hypomethylation of specific promoters (such as those of oncogenes) are well-recognized, the impact of cancer-associated gene body hypomethylation is less clear.	('cancer', 'Disease', (29, 35))	('hypomethylation', 'Var', (47, 62))	('cancer', 'Disease', (149, 155))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('cancer', 'Disease', 'MESH:D009369', (29, 35))	('cancer', 'Disease', 'MESH:D009369', (149, 155))
485710	25237374	Molecular Pathology of Lung Cancer: Current Status and Future Directions The rapid development of targeted therapies has enormously changed the clinical management of lung cancer patients over the past decade; therefore, molecular testing, such as epidermal growth factor receptor (EGFR) gene mutations or anaplastic lymphoma kinase (ALK) gene rearrangements, is now routinely used to predict the therapeutic responses in lung cancer patients.	('lung cancer', 'Disease', (167, 178))	('EGFR', 'Gene', (282, 286))	('anaplastic lymphoma kinase', 'Gene', '238', (306, 332))	('lung cancer', 'Disease', 'MESH:D008175', (422, 433))	('anaplastic lymphoma kinase', 'Gene', (306, 332))	('Lung Cancer', 'Disease', 'MESH:D008175', (23, 34))	('patients', 'Species', '9606', (434, 442))	('lung cancer', 'Phenotype', 'HP:0100526', (422, 433))	('Lung Cancer', 'Phenotype', 'HP:0100526', (23, 34))	('patients', 'Species', '9606', (179, 187))	('lung cancer', 'Disease', 'MESH:D008175', (167, 178))	('lymphoma', 'Phenotype', 'HP:0002665', (317, 325))	('EGFR', 'Gene', '1956', (282, 286))	('ALK', 'Gene', '238', (334, 337))	('lung cancer', 'Phenotype', 'HP:0100526', (167, 178))	('mutations', 'Var', (293, 302))	('cancer', 'Phenotype', 'HP:0002664', (427, 433))	('ALK', 'Gene', (334, 337))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('lung cancer', 'Disease', (422, 433))	('epidermal growth factor receptor', 'Gene', (248, 280))	('Lung Cancer', 'Disease', (23, 34))	('Cancer', 'Phenotype', 'HP:0002664', (28, 34))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (306, 325))	('epidermal growth factor receptor', 'Gene', '1956', (248, 280))
485716	25237374	The use of targeted agents in lung cancer patients harboring epidermal growth factor receptor (EGFR) gene mutations or anaplastic lymphoma kinase (ALK) gene rearrangements has been associated with dramatic response rates and improved progression-free survival (PFS), therefore, molecular testing is now routinely used to guide clinical care of lung cancer patients to predict one's therapeutic response.	('lung cancer', 'Disease', 'MESH:D008175', (344, 355))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('lymphoma', 'Phenotype', 'HP:0002665', (130, 138))	('patients', 'Species', '9606', (356, 364))	('EGFR', 'Gene', '1956', (95, 99))	('lung cancer', 'Phenotype', 'HP:0100526', (344, 355))	('ALK', 'Gene', '238', (147, 150))	('progression-free survival', 'CPA', (234, 259))	('lung cancer', 'Disease', (30, 41))	('ALK', 'Gene', (147, 150))	('rearrangements', 'Var', (157, 171))	('cancer', 'Phenotype', 'HP:0002664', (349, 355))	('epidermal growth factor receptor', 'Gene', (61, 93))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (119, 138))	('epidermal growth factor receptor', 'Gene', '1956', (61, 93))	('lung cancer', 'Disease', 'MESH:D008175', (30, 41))	('lung cancer', 'Disease', (344, 355))	('patients', 'Species', '9606', (42, 50))	('anaplastic lymphoma kinase', 'Gene', '238', (119, 145))	('EGFR', 'Gene', (95, 99))	('lung cancer', 'Phenotype', 'HP:0100526', (30, 41))	('anaplastic lymphoma kinase', 'Gene', (119, 145))	('improved', 'PosReg', (225, 233))	('mutations', 'Var', (106, 115))
485721	25237374	Although EGFR mutations and ALK fusions are well-characterized molecular targets in non-small cell lung cancer (NSCLC), activating alterations in a variety of potential oncogeneic driver genes have also been identified in NSCLC.	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (84, 110))	('ALK', 'Gene', '238', (28, 31))	('NSCLC', 'Phenotype', 'HP:0030358', (222, 227))	('non-small cell lung cancer', 'Disease', (84, 110))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('NSCLC', 'Phenotype', 'HP:0030358', (112, 117))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (88, 110))	('EGFR', 'Gene', '1956', (9, 13))	('ALK', 'Gene', (28, 31))	('EGFR', 'Gene', (9, 13))	('NSCLC', 'Disease', (222, 227))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (84, 110))	('NSCLC', 'Disease', (112, 117))	('NSCLC', 'Disease', 'MESH:D002289', (222, 227))	('mutations', 'Var', (14, 23))	('NSCLC', 'Disease', 'MESH:D002289', (112, 117))	('lung cancer', 'Phenotype', 'HP:0100526', (99, 110))
485725	25237374	Activating somatic mutations are present in exons 18-21 of the tyrosine-kinase domain and deletions in exon 19 and the L858R point mutation in exon 21 occur in 90% of all EGFR mutations.	('EGFR', 'Gene', (171, 175))	('Activating', 'PosReg', (0, 10))	('mutations', 'Var', (176, 185))	('L858R', 'Var', (119, 124))	('L858R', 'Mutation', 'rs121434568', (119, 124))	('EGFR', 'Gene', '1956', (171, 175))	('deletions', 'Var', (90, 99))
485727	25237374	EGFR mutations are primarily seen in adenocarcinoma.	('adenocarcinoma', 'Disease', (37, 51))	('EGFR', 'Gene', (0, 4))	('adenocarcinoma', 'Disease', 'MESH:D000230', (37, 51))	('mutations', 'Var', (5, 14))	('seen', 'Reg', (29, 33))	('EGFR', 'Gene', '1956', (0, 4))	('carcinoma', 'Phenotype', 'HP:0030731', (42, 51))
485728	25237374	Therefore, EGFR mutation analysis is the best predictive marker for the use of EGFR-TKI therapy in NSCLC with an adenocarcinoma component, but gender, ethnicity, and smoking status are unsuitable for use as triage for mutation analysis.	('mutation', 'Var', (16, 24))	('adenocarcinoma component', 'Disease', (113, 137))	('EGFR', 'Gene', '1956', (79, 83))	('EGFR', 'Gene', (79, 83))	('EGFR', 'Gene', '1956', (11, 15))	('EGFR', 'Gene', (11, 15))	('NSCLC', 'Phenotype', 'HP:0030358', (99, 104))	('adenocarcinoma component', 'Disease', 'MESH:D000230', (113, 137))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('NSCLC', 'Disease', (99, 104))	('NSCLC', 'Disease', 'MESH:D002289', (99, 104))
485729	25237374	The most common mechanism of resistance to EGFR-TKI is the T790M gatekeeper mutation, caused by a single-base substitution of C to T, at nucleotide 2369.	('C to T', 'Gene', (126, 132))	('caused by', 'Reg', (86, 95))	('C to T, at nucleotide 2369', 'Mutation', 'rs121434569', (126, 152))	('T790M', 'Mutation', 'rs121434569', (59, 64))	('EGFR', 'Gene', '1956', (43, 47))	('T790M', 'Var', (59, 64))	('EGFR', 'Gene', (43, 47))	('gatekeeper', 'Species', '111938', (65, 75))
485730	25237374	The rearrangement results from a short inversion in chromosome 2p, whereby ALK signaling is activated by the creation of oncogenic fusions of the intron 10 of ALK gene within an upstream partner intron 13 of echinoderm microtubule associated protein-like 4 (EML4).	('ALK', 'Gene', (75, 78))	('activated', 'PosReg', (92, 101))	('fusions', 'Var', (131, 138))	('ALK', 'Gene', '238', (159, 162))	('EML4', 'Gene', (258, 262))	('ALK', 'Gene', (159, 162))	('ALK', 'Gene', '238', (75, 78))	('echinoderm microtubule associated protein-like 4', 'Gene', '27436', (208, 256))	('EML4', 'Gene', '27436', (258, 262))	('echinoderm microtubule associated protein-like 4', 'Gene', (208, 256))
485731	25237374	More recently, less than 1% of ALK rearrangements cases have different partner genes including kinesin family member 5B (KIF5B), TFG, and KLC-1.	('ALK', 'Gene', '238', (31, 34))	('KLC-1', 'Gene', (138, 143))	('kinesin family member 5B', 'Gene', '3799', (95, 119))	('rearrangements', 'Var', (35, 49))	('KIF5B', 'Gene', (121, 126))	('kinesin family member 5B', 'Gene', (95, 119))	('ALK', 'Gene', (31, 34))	('KLC-1', 'Gene', '3831', (138, 143))	('KIF5B', 'Gene', '3799', (121, 126))	('TFG', 'Gene', '10342', (129, 132))	('TFG', 'Gene', (129, 132))
485732	25237374	ALK rearrangements occur in approximately 4% of lung adenocarcinoma patients, usually young, non-smokers with clinically advanced disease.	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (48, 67))	('rearrangements', 'Var', (4, 18))	('ALK', 'Gene', '238', (0, 3))	('patients', 'Species', '9606', (68, 76))	('ALK', 'Gene', (0, 3))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (48, 67))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))	('lung adenocarcinoma', 'Disease', (48, 67))
485735	25237374	ROS1 gene rearrangements are known oncogenic drivers in NSCLC, and several fusion partners have been identified, including CD74, SLC34A2/NaPi2b, and FIG.	('ROS1', 'Gene', (0, 4))	('rearrangements', 'Var', (10, 24))	('NSCLC', 'Disease', (56, 61))	('CD74', 'Gene', '972', (123, 127))	('ROS1', 'Gene', '6098', (0, 4))	('NSCLC', 'Disease', 'MESH:D002289', (56, 61))	('SLC34A2', 'Gene', '10568', (129, 136))	('CD74', 'Gene', (123, 127))	('SLC34A2', 'Gene', (129, 136))	('NSCLC', 'Phenotype', 'HP:0030358', (56, 61))
485736	25237374	ROS1 fusions are present in about 2% of NSCLC cases and are often seen in young, non-smokers with adenocarcinoma, a population similar to those with ALK-rearranged NSCLC.	('adenocarcinoma', 'Disease', (98, 112))	('NSCLC', 'Disease', (164, 169))	('adenocarcinoma', 'Disease', 'MESH:D000230', (98, 112))	('ROS1', 'Gene', (0, 4))	('NSCLC', 'Disease', 'MESH:D002289', (164, 169))	('ALK', 'Gene', '238', (149, 152))	('NSCLC', 'Phenotype', 'HP:0030358', (40, 45))	('fusions', 'Var', (5, 12))	('ROS1', 'Gene', '6098', (0, 4))	('ALK', 'Gene', (149, 152))	('NSCLC', 'Phenotype', 'HP:0030358', (164, 169))	('NSCLC', 'Disease', (40, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('NSCLC', 'Disease', 'MESH:D002289', (40, 45))
485737	25237374	There is in vitro and early clinical evidence that lung cancers with ROS1 rearrangements are sensitive to TKIs including crizotinib.	('lung cancers', 'Disease', (51, 63))	('ROS1', 'Gene', (69, 73))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('ROS1', 'Gene', '6098', (69, 73))	('lung cancer', 'Phenotype', 'HP:0100526', (51, 62))	('lung cancers', 'Disease', 'MESH:D008175', (51, 63))	('lung cancers', 'Phenotype', 'HP:0100526', (51, 63))	('crizotinib', 'Chemical', 'MESH:D000077547', (121, 131))	('cancers', 'Phenotype', 'HP:0002664', (56, 63))	('rearrangements', 'Var', (74, 88))
485739	25237374	Translocations resulting in fusions with several partners have been reported in lung cancer, including multiple variants of KIF5B-RET (the most common type), CCDC6-RET (PTC1), NCOA4-RET (PTC3), and TRIM33-RET.	('PTC1', 'Gene', '5727', (169, 173))	('NCOA4', 'Gene', (176, 181))	('NCOA4', 'Gene', '8031', (176, 181))	('RET', 'Gene', '5979', (182, 185))	('KIF5B', 'Gene', '3799', (124, 129))	('lung cancer', 'Disease', 'MESH:D008175', (80, 91))	('fusions', 'Interaction', (28, 35))	('Translocations', 'Var', (0, 14))	('PTC3', 'Gene', '8031', (187, 191))	('RET', 'Gene', (130, 133))	('RET', 'Gene', '5979', (205, 208))	('lung cancer', 'Phenotype', 'HP:0100526', (80, 91))	('KIF5B', 'Gene', (124, 129))	('PTC3', 'Gene', (187, 191))	('RET', 'Gene', '5979', (164, 167))	('PTC1', 'Gene', (169, 173))	('variants', 'Var', (112, 120))	('RET', 'Gene', (182, 185))	('CCDC6', 'Gene', (158, 163))	('CCDC6', 'Gene', '8030', (158, 163))	('TRIM33', 'Gene', (198, 204))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('RET', 'Gene', (205, 208))	('RET', 'Gene', (164, 167))	('TRIM33', 'Gene', '51592', (198, 204))	('lung cancer', 'Disease', (80, 91))	('reported', 'Reg', (68, 76))	('RET', 'Gene', '5979', (130, 133))
485742	25237374	In contrast to melanoma, about 50% of the mutations are non-V600E mutations such as L596R and G468A.	('melanoma', 'Phenotype', 'HP:0002861', (15, 23))	('G468A', 'Mutation', 'rs200729445', (94, 99))	('melanoma', 'Disease', (15, 23))	('non-V600E', 'Var', (56, 65))	('melanoma', 'Disease', 'MESH:D008545', (15, 23))	('L596R', 'Var', (84, 89))	('V600E', 'Mutation', 'rs113488022', (60, 65))	('L596R', 'Mutation', 'p.L596R', (84, 89))	('G468A', 'Var', (94, 99))
485743	25237374	It is unknown whether V600E BRAF mutations function as driver mutations and other mutations as passenger mutations.	('BRAF', 'Gene', (28, 32))	('BRAF', 'Gene', '673', (28, 32))	('V600E', 'Mutation', 'rs113488022', (22, 27))	('V600E', 'Var', (22, 27))
485744	25237374	Non-V600E mutations have been associated with current or former smokers, while V600E mutations appear to be more common in female, non-smokers.	('V600E', 'Var', (79, 84))	('associated', 'Reg', (30, 40))	('Non-V600E mutations', 'Var', (0, 19))	('V600E', 'Mutation', 'rs113488022', (4, 9))	('V600E', 'Mutation', 'rs113488022', (79, 84))
485747	25237374	Mutations in MET are rare, but a high MET gene copy number has been detected in 1-11% of NSCLC cases.	('NSCLC', 'Disease', 'MESH:D002289', (89, 94))	('MET', 'Gene', (13, 16))	('NSCLC', 'Phenotype', 'HP:0030358', (89, 94))	('Mutations', 'Var', (0, 9))	('detected', 'Reg', (68, 76))	('NSCLC', 'Disease', (89, 94))
485748	25237374	High gene copy numbers are more common in squamous cell carcinoma than adenocarcinoma and are often associated with high MET protein expression and poor prognosis.	('squamous cell carcinoma than adenocarcinoma', 'Disease', 'MESH:D002294', (42, 85))	('squamous cell carcinoma than adenocarcinoma', 'Disease', (42, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('High gene copy numbers', 'Var', (0, 22))	('associated', 'Reg', (100, 110))	('common', 'Reg', (32, 38))	('high MET protein expression', 'MPA', (116, 143))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (42, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (56, 65))
485752	25237374	HER2 mutations are detected mainly in exon 20 in approximately 1-2% of NSCLC cases, predominantly in adenocarcinomas in non-smoking women.	('carcinomas', 'Phenotype', 'HP:0030731', (106, 116))	('women', 'Species', '9606', (132, 137))	('NSCLC', 'Phenotype', 'HP:0030358', (71, 76))	('mutations', 'Var', (5, 14))	('HER2', 'Gene', '2064', (0, 4))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('HER2', 'Gene', (0, 4))	('adenocarcinomas', 'Disease', 'MESH:D000230', (101, 116))	('NSCLC', 'Disease', (71, 76))	('adenocarcinomas', 'Disease', (101, 116))	('NSCLC', 'Disease', 'MESH:D002289', (71, 76))
485755	25237374	FGFR1 amplification occurs more frequently in squamous cell carcinoma (21%) than in adenocarcinoma (3%).	('adenocarcinoma', 'Disease', 'MESH:D000230', (84, 98))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (46, 69))	('FGFR1', 'Gene', (0, 5))	('FGFR1', 'Gene', '2260', (0, 5))	('carcinoma', 'Phenotype', 'HP:0030731', (60, 69))	('squamous cell carcinoma', 'Disease', (46, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('amplification', 'Var', (6, 19))	('adenocarcinoma', 'Disease', (84, 98))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (46, 69))
485758	25237374	PIK3CA mutations mostly involve the catalytic domain and have been identified in approximately 1-3% of NSCLCs, particularly in squamous cell carcinomas.	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (127, 151))	('squamous cell carcinomas', 'Disease', (127, 151))	('NSCLC', 'Disease', (103, 108))	('carcinomas', 'Phenotype', 'HP:0030731', (141, 151))	('PIK3CA', 'Gene', (0, 6))	('NSCLC', 'Disease', 'MESH:D002289', (103, 108))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (127, 151))	('identified', 'Reg', (67, 77))	('PIK3CA', 'Gene', '5290', (0, 6))	('NSCLC', 'Phenotype', 'HP:0030358', (103, 108))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (127, 150))	('involve', 'Reg', (24, 31))	('mutations', 'Var', (7, 16))
485760	25237374	PTEN mutations and loss of PTEN protein expression are relatively common in squamous cell carcinoma.	('expression', 'MPA', (40, 50))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (76, 99))	('common', 'Reg', (66, 72))	('squamous cell carcinoma', 'Disease', (76, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('loss', 'NegReg', (19, 23))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (76, 99))	('mutations', 'Var', (5, 14))	('protein', 'Protein', (32, 39))	('PTEN', 'Gene', (27, 31))	('PTEN', 'Gene', (0, 4))	('PTEN', 'Gene', '5728', (27, 31))	('PTEN', 'Gene', '5728', (0, 4))
485763	25237374	Mutations of DDR2 gene occur in 3.8% of squamous cell carcinomas and are associated with oncogenic activity that may respond to dasatinib.	('carcinoma', 'Phenotype', 'HP:0030731', (54, 63))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (40, 64))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (40, 64))	('DDR2', 'Gene', '4921', (13, 17))	('associated', 'Reg', (73, 83))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (40, 63))	('DDR2', 'Gene', (13, 17))	('Mutations', 'Var', (0, 9))	('carcinomas', 'Phenotype', 'HP:0030731', (54, 64))	('dasatinib', 'Chemical', 'MESH:D000069439', (128, 137))	('oncogenic activity', 'CPA', (89, 107))	('squamous cell carcinomas', 'Disease', (40, 64))
485765	25237374	However, EGFR mutation testing and ALK rearrangement status are the only two molecular makers considered the standard-of-care of NSCLC treatment in daily practice currently.	('ALK', 'Gene', '238', (35, 38))	('NSCLC', 'Phenotype', 'HP:0030358', (129, 134))	('NSCLC', 'Disease', (129, 134))	('EGFR', 'Gene', '1956', (9, 13))	('EGFR', 'Gene', (9, 13))	('mutation testing', 'Var', (14, 30))	('ALK', 'Gene', (35, 38))	('NSCLC', 'Disease', 'MESH:D002289', (129, 134))
485776	25237374	Mutation analysis, using a validated method with sufficient performance characteristics, such as direct sequencing, pyrosequencing, and peptide nucleic acid polymerase chain reaction (PCR) clamping, is recommended for EGFR mutation testing.	('EGFR', 'Gene', '1956', (218, 222))	('mutation', 'Var', (223, 231))	('EGFR', 'Gene', (218, 222))
485777	25237374	A wide range of sample types, including cytology specimens and fixatives (formalin-fixed paraffin-embedded [FFPE], fresh, frozen, and alcohol) are allowable for EGFR mutation testing.	('paraffin', 'Chemical', 'MESH:D010232', (89, 97))	('EGFR', 'Gene', (161, 165))	('alcohol', 'Chemical', 'MESH:D000438', (134, 141))	('formalin', 'Chemical', 'MESH:D005557', (74, 82))	('EGFR', 'Gene', '1956', (161, 165))	('mutation', 'Var', (166, 174))
485781	25237374	It is applied to detect individual mutations in cancer-related genes that may assist in cancer diagnosis, have prognostic value, or be used for prediction of response to targeted therapy.	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('cancer', 'Disease', (48, 54))	('assist', 'Reg', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('mutations', 'Var', (35, 44))
485789	25237374	Exonic regions of the 183 adenocarcinoma cases contained 77,736 somatic variants corresponding to a median of 8.1 mutations/megabase (MB) and a mean of 11.9 mutations/MB (range, 0.04-117.4 mutations/MB), whereas a total of 48,690 non-silent mutations with a mean of 228 non-silent and 360 total exonic mutations per tumor, corresponding to a mean somatic mutation rate of 8.1 mutations/MB and media of 8.4/MB in squamous cell carcinoma.	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (412, 435))	('adenocarcinoma', 'Disease', (26, 40))	('mutations/megabase', 'Var', (114, 132))	('squamous cell carcinoma', 'Disease', (412, 435))	('tumor', 'Phenotype', 'HP:0002664', (316, 321))	('adenocarcinoma', 'Disease', 'MESH:D000230', (26, 40))	('tumor', 'Disease', (316, 321))	('mutations/MB', 'Var', (157, 169))	('variants', 'Var', (72, 80))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (412, 435))	('exonic mutations', 'Var', (295, 311))	('carcinoma', 'Phenotype', 'HP:0030731', (426, 435))	('carcinoma', 'Phenotype', 'HP:0030731', (31, 40))	('tumor', 'Disease', 'MESH:D009369', (316, 321))
485792	25237374	In total, 25 genes were shown to have a statistically significant number of mutations in lung adenocarcinoma.	('mutations', 'Var', (76, 85))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (89, 108))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('lung adenocarcinoma', 'Disease', (89, 108))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (89, 108))
485793	25237374	Unexpectedly, U2AF1, RBM10, and ARID1A mutations were identified.	('RBM10', 'Gene', '8241', (21, 26))	('RBM10', 'Gene', (21, 26))	('mutations', 'Var', (39, 48))	('ARID1A', 'Gene', '8289', (32, 38))	('U2AF1', 'Gene', (14, 19))	('ARID1A', 'Gene', (32, 38))	('U2AF1', 'Gene', '7307', (14, 19))
485795	25237374	U2AF1 mutation may confer tumorigenic capability independent of known proliferations-sustaining driver genes and patients with U2AF1 mutations had significantly reduced PFS.	('reduced', 'NegReg', (161, 168))	('U2AF1', 'Gene', (127, 132))	('patients', 'Species', '9606', (113, 121))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('mutation', 'Var', (6, 14))	('PFS', 'MPA', (169, 172))	('mutations', 'Var', (133, 142))	('U2AF1', 'Gene', '7307', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('U2AF1', 'Gene', '7307', (127, 132))	('U2AF1', 'Gene', (0, 5))
485796	25237374	RBM10, encoding an RNA-binding protein, was mutated in 7% of cases and its mutations co-occurred with those in known lung adenocarcinoma oncogenes.	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (117, 136))	('mutated', 'Var', (44, 51))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (117, 136))	('RBM10', 'Gene', '8241', (0, 5))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('RBM10', 'Gene', (0, 5))	('lung adenocarcinoma', 'Disease', (117, 136))
485797	25237374	ARID1A, encoding a key protein in the SW1/SNF chromatin-remodeling complex, was mutated in 8% of cases and showed a significant accumulation of nonsense substitutions and frameshift indels.	('nonsense substitutions', 'Var', (144, 166))	('ARID1A', 'Gene', '8289', (0, 6))	('mutated', 'Var', (80, 87))	('accumulation', 'PosReg', (128, 140))	('ARID1A', 'Gene', (0, 6))	('frameshift indels', 'Var', (171, 188))
485799	25237374	In total, 18 genes were shown to have a statistically significant number of mutations including mutation of TP53 in nearly all specimens.	('TP53', 'Gene', (108, 112))	('mutation', 'Var', (96, 104))	('TP53', 'Gene', '7157', (108, 112))
485800	25237374	Significantly altered pathways by mutation or somatic copy number alterations included NFE2L2/KEAP1 in 34%, SOX2/TP63/NOTCH1 pathways in 44%, one of three components of the PI3K/AKT pathway (PIK3CA, PTEN or AKT3) in 47%, and CDKN2A (a known tumor suppressor gene that encodes the INK4A/p16 and ARF/p14 proteins)/RB1 in 72% of cases, providing evidence of common dysfunction in response to oxidative stress, squamous cell differentiation, apoptotic signaling, and/or cell cycle control, respectively.	('PTEN', 'Gene', '5728', (199, 203))	('ARF/p14', 'Gene', '1029', (294, 301))	('RB1', 'Gene', '5925', (312, 315))	('TP63', 'Gene', '8626', (113, 117))	('NFE2L2', 'Gene', (87, 93))	('alterations', 'Var', (66, 77))	('NOTCH1', 'Gene', (118, 124))	('AKT', 'Gene', '207', (207, 210))	('PIK3CA', 'Gene', '5290', (191, 197))	('dysfunction', 'Disease', 'MESH:D006331', (362, 373))	('tumor', 'Disease', (241, 246))	('CDKN2A', 'Gene', (225, 231))	('mutation', 'Var', (34, 42))	('INK4A', 'Gene', '1029', (280, 285))	('tumor', 'Disease', 'MESH:D009369', (241, 246))	('NOTCH1', 'Gene', '4851', (118, 124))	('AKT', 'Gene', (178, 181))	('altered', 'Reg', (14, 21))	('AKT3', 'Gene', '10000', (207, 211))	('KEAP1', 'Gene', '9817', (94, 99))	('CDKN2A', 'Gene', '1029', (225, 231))	('INK4A', 'Gene', (280, 285))	('RB1', 'Gene', (312, 315))	('p16', 'Gene', (286, 289))	('KEAP1', 'Gene', (94, 99))	('PIK3CA', 'Gene', (191, 197))	('PTEN', 'Gene', (199, 203))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))	('p16', 'Gene', '1029', (286, 289))	('SOX2', 'Gene', '6657', (108, 112))	('AKT3', 'Gene', (207, 211))	('SOX2', 'Gene', (108, 112))	('TP63', 'Gene', (113, 117))	('dysfunction', 'Disease', (362, 373))	('ARF/p14', 'Gene', (294, 301))	('AKT', 'Gene', (207, 210))	('oxidative stress', 'Phenotype', 'HP:0025464', (389, 405))	('NFE2L2', 'Gene', '4780', (87, 93))	('AKT', 'Gene', '207', (178, 181))
485801	25237374	Previously unreported loss-of-function mutations were seen in the HLA-A class I major histocompatibility gene, suggesting a possible role for genotypic selection of patients for immunotherapies.	('loss-of-function', 'NegReg', (22, 38))	('patients', 'Species', '9606', (165, 173))	('HLA-A class I major histocompatibility gene', 'Gene', (66, 109))	('mutations', 'Var', (39, 48))
485804	25237374	As further studies with sensitive multigene assays are completed, one might expect that the data will provide a key comprehensive means of identifying somatic alterations in entire lung cancer genomes or exomes and will ultimately inform clinical decision-making.	('alterations', 'Var', (159, 170))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('lung cancer', 'Disease', (181, 192))	('inform', 'Reg', (231, 237))	('lung cancer', 'Phenotype', 'HP:0100526', (181, 192))	('lung cancer', 'Disease', 'MESH:D008175', (181, 192))
485820	33076489	Studies show that their aberrations are involved in growth and progression of different malignancies.	('malignancies', 'Disease', (88, 100))	('aberrations', 'Var', (24, 35))	('involved', 'Reg', (40, 48))	('malignancies', 'Disease', 'MESH:D009369', (88, 100))
485822	33076489	Overexpression of FGFR1 is one of the most frequent genetic aberrancies within the FGFR family in cancers.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('aberrancies', 'Disease', (60, 71))	('aberrancies', 'Disease', 'MESH:D002869', (60, 71))	('cancers', 'Phenotype', 'HP:0002664', (98, 105))	('frequent', 'Reg', (43, 51))	('cancers', 'Disease', 'MESH:D009369', (98, 105))	('FGFR1', 'Gene', (18, 23))	('cancers', 'Disease', (98, 105))	('Overexpression', 'Var', (0, 14))	('FGFR1', 'Gene', '2260', (18, 23))
485829	33076489	We show that peptibodyF2 utilizes receptor-mediated endocytosis for internalization into FGFR1-expressing cells, into both engineered (transfected with fgfr1 gene) and lung cancer cell lines with elevated levels of FGFR1 expression.	('internalization', 'MPA', (68, 83))	('FGFR1', 'Gene', (215, 220))	('fgfr1', 'Gene', '2260', (152, 157))	('gene', 'Var', (158, 162))	('lung cancer', 'Disease', (168, 179))	('FGFR1', 'Gene', '2260', (215, 220))	('lung cancer', 'Phenotype', 'HP:0100526', (168, 179))	('elevated levels of FGFR1 expression', 'Phenotype', 'HP:0030269', (196, 231))	('FGFR1', 'Gene', (89, 94))	('FGFR1', 'Gene', '2260', (89, 94))	('fgfr1', 'Gene', (152, 157))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('receptor-mediated endocytosis', 'MPA', (34, 63))	('lung cancer', 'Disease', 'MESH:D008175', (168, 179))
485873	33076489	A similar cytotoxic effect of peptibodyF2-MMAE was obtained for non-modified, FGFR1-positive NCH-H520 lung cancer cells (Figure 6C).	('FGFR1', 'Gene', (78, 83))	('lung cancer', 'Phenotype', 'HP:0100526', (102, 113))	('FGFR1', 'Gene', '2260', (78, 83))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('lung cancer', 'Disease', (102, 113))	('MMAE', 'Chemical', 'MESH:C495575', (42, 46))	('lung cancer', 'Disease', 'MESH:D008175', (102, 113))	('peptibodyF2-MMAE', 'Var', (30, 46))
485875	33076489	In general, cytotoxicity of peptibodyF2-MMAE correlated with the FGFR1 expression level on tested cell lines.	('peptibodyF2-MMAE', 'Var', (28, 44))	('cytotoxicity', 'Disease', 'MESH:D064420', (12, 24))	('FGFR1', 'Gene', (65, 70))	('expression level', 'MPA', (71, 87))	('FGFR1', 'Gene', '2260', (65, 70))	('cytotoxicity', 'Disease', (12, 24))	('MMAE', 'Chemical', 'MESH:C495575', (40, 44))
485885	33076489	Fusing to the Fc domain renders therapeutic peptides more stable, minimizes the immunological response and increases their affinity to the target due to the avidity effects.	('more', 'PosReg', (53, 57))	('increases', 'PosReg', (107, 116))	('minimizes', 'NegReg', (66, 75))	('affinity', 'MPA', (123, 131))	('immunological response', 'CPA', (80, 102))	('Fc', 'Chemical', '-', (14, 16))	('Fusing', 'Var', (0, 6))	('stable', 'MPA', (58, 64))
485891	33076489	Moreover, peptibodyF2 did not show induction of a long-term cellular response:it did not stimulate proliferation of NIH 3T3 cells (data not shown), which is a desired feature of the targeting molecule for cancer treatment.	('cancer', 'Disease', 'MESH:D009369', (205, 211))	('cancer', 'Disease', (205, 211))	('NIH 3T3', 'CellLine', 'CVCL:0594', (116, 123))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('not', 'NegReg', (85, 88))	('peptibodyF2', 'Var', (10, 21))
485894	33076489	We subsequently generated a cytotoxic conjugate of peptibodyF2 and verified its potency for targeted delivery of the cytotoxic drug into FGFR1-overexpressing cells.	('FGFR1', 'Gene', '2260', (137, 142))	('peptibodyF2', 'Var', (51, 62))	('FGFR1', 'Gene', (137, 142))
485908	33076489	Based on the shown here specific cytotoxicity, peptibodyF2-MMAE emerges as an attractive alternative to larger targeting molecules used in the anticancer therapy.	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('cytotoxicity', 'Disease', (33, 45))	('MMAE', 'Chemical', 'MESH:C495575', (59, 63))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('cytotoxicity', 'Disease', 'MESH:D064420', (33, 45))	('cancer', 'Disease', (147, 153))	('peptibodyF2-MMAE', 'Var', (47, 63))
485958	33076489	P.433329, describing the use of peptibodyF2 conjugates for selective elimination of FGFR1-expressing cells, has been filed to The Patent Office of the Republic of Poland by the University of Wroclaw.	('FGFR1', 'Gene', (84, 89))	('P.433329', 'Var', (0, 8))	('FGFR1', 'Gene', '2260', (84, 89))
485974	32571310	There is substantial evidence that COX-2 expression promotes tumor development and progression in multiple human cancers including cutaneous squamous cell carcinoma, urothelial carcinoma, and colorectal carcinoma.	('cutaneous squamous cell carcinoma', 'Disease', (131, 164))	('cancers', 'Phenotype', 'HP:0002664', (113, 120))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (166, 186))	('carcinoma', 'Phenotype', 'HP:0030731', (177, 186))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('cancers', 'Disease', (113, 120))	('cutaneous squamous cell carcinoma', 'Disease', 'MESH:D002294', (131, 164))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (141, 164))	('urothelial carcinoma', 'Disease', (166, 186))	('promotes', 'PosReg', (52, 60))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('cancers', 'Disease', 'MESH:D009369', (113, 120))	('colorectal carcinoma', 'Disease', (192, 212))	('expression', 'Var', (41, 51))	('cutaneous squamous cell carcinoma', 'Phenotype', 'HP:0006739', (131, 164))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (192, 212))	('carcinoma', 'Phenotype', 'HP:0030731', (203, 212))	('carcinoma', 'Phenotype', 'HP:0030731', (155, 164))	('COX-2', 'Gene', (35, 40))	('human', 'Species', '9606', (107, 112))	('progression', 'CPA', (83, 94))	('tumor', 'Disease', (61, 66))
485983	32571310	In specific malignancies, activation of EP2R most commonly induces angiogenesis and suppression of the antitumor immune response.	('EP2R', 'Protein', (40, 44))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('angiogenesis', 'CPA', (67, 79))	('induces', 'Reg', (59, 66))	('suppression', 'NegReg', (84, 95))	('malignancies', 'Disease', 'MESH:D009369', (12, 24))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('malignancies', 'Disease', (12, 24))	('activation', 'Var', (26, 36))
485988	32571310	Specifically, signaling through EP4R promotes immune evasion of cancer cells through suppression of natural killer cells and cytotoxic T-lymphocytes, and activation of myeloid derived suppressor cells and T-regulatory cells.	('EP4R', 'Gene', '5734', (32, 36))	('natural killer cells', 'CPA', (100, 120))	('EP4R', 'Gene', (32, 36))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('activation', 'PosReg', (154, 164))	('suppression', 'NegReg', (85, 96))	('signaling', 'Var', (14, 23))	('immune evasion', 'MPA', (46, 60))	('T-regulatory cells', 'CPA', (205, 223))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('promotes', 'PosReg', (37, 45))	('myeloid derived suppressor cells', 'CPA', (168, 200))
485994	32571310	In fact, antagonism of the EP1 and EP4 receptors has resulted in suppression of human tumor development and progression across tumor type including tongue squamous cell carcinoma, skin tumors, and colonic carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (169, 178))	('squamous cell carcinoma', 'Disease', (155, 178))	('suppression', 'NegReg', (65, 76))	('EP1', 'Gene', (27, 30))	('tumor', 'Disease', (185, 190))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('skin tumors', 'Disease', (180, 191))	('colonic carcinoma', 'Disease', (197, 214))	('colonic carcinoma', 'Disease', 'MESH:D003110', (197, 214))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('human', 'Species', '9606', (80, 85))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (155, 178))	('carcinoma', 'Phenotype', 'HP:0030731', (205, 214))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('progression', 'CPA', (108, 119))	('skin tumors', 'Disease', 'MESH:D012878', (180, 191))	('tongue squamous cell carcinoma', 'Phenotype', 'HP:0030413', (148, 178))	('antagonism', 'Var', (9, 19))	('EP1', 'Gene', '5731', (27, 30))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (155, 178))	('skin tumors', 'Phenotype', 'HP:0008069', (180, 191))	('tumor', 'Disease', (127, 132))	('tumor', 'Disease', (86, 91))	('tumors', 'Phenotype', 'HP:0002664', (185, 191))	('EP4', 'Gene', '5734', (35, 38))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('EP4', 'Gene', (35, 38))
486001	32571310	Multiple clinical, experimental, and epidemiological studies indicate that COX-2 inhibitors show therapeutic potential in canine malignancies.	('inhibitors', 'Var', (81, 91))	('malignancies', 'Disease', (129, 141))	('COX-2', 'Gene', (75, 80))	('canine', 'Species', '9615', (122, 128))	('malignancies', 'Disease', 'MESH:D009369', (129, 141))
486004	32571310	However, NSAIDs are not specific and attenuate the production of prostanoids other than PGE2 that are important in homeostasis.	('PGE2', 'Chemical', 'MESH:D015232', (88, 92))	('NSAIDs', 'Var', (9, 15))	('PGE2', 'Gene', (88, 92))	('production of prostanoids', 'MPA', (51, 76))	('prostanoids', 'Chemical', 'MESH:D011453', (65, 76))	('attenuate', 'NegReg', (37, 46))
486054	32571310	In a cell line model of human urothelial carcinoma, EP4R antagonists decreased cancer cell migration and viability, and enhanced the effects of a commonly used chemotherapeutic, cisplatin, implying the potential role of EP4R antagonists in the treatment of several human malignancies.	('EP4R', 'Gene', (52, 56))	('effects', 'MPA', (133, 140))	('malignancies', 'Disease', 'MESH:D009369', (271, 283))	('human', 'Species', '9606', (265, 270))	('malignancies', 'Disease', (271, 283))	('urothelial carcinoma', 'Disease', 'MESH:D014523', (30, 50))	('EP4R', 'Gene', '5734', (52, 56))	('carcinoma', 'Phenotype', 'HP:0030731', (41, 50))	('human', 'Species', '9606', (24, 29))	('enhanced', 'PosReg', (120, 128))	('urothelial carcinoma', 'Disease', (30, 50))	('cancer', 'Disease', (79, 85))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('decreased', 'NegReg', (69, 78))	('EP4R', 'Gene', (220, 224))	('EP4R', 'Gene', '5734', (220, 224))	('antagonists', 'Var', (57, 68))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('cisplatin', 'Chemical', 'MESH:D002945', (178, 187))
486058	32571310	The information gleaned from this study suggests that if the gene expression of EP4R correlates to protein expression, contributing to the development of malignancy, blockade of EP4R with a piprant drug, such as grapiprant, may be a therapeutic approach for multiple canine tumors.	('correlates', 'Reg', (85, 95))	('tumors', 'Disease', (274, 280))	('tumors', 'Disease', 'MESH:D009369', (274, 280))	('tumors', 'Phenotype', 'HP:0002664', (274, 280))	('contributing to', 'Reg', (119, 134))	('EP4R', 'Gene', (80, 84))	('canine', 'Species', '9615', (267, 273))	('multiple canine', 'Phenotype', 'HP:0012738', (258, 273))	('EP4R', 'Gene', '5734', (178, 182))	('EP4R', 'Gene', (178, 182))	('EP4R', 'Gene', '5734', (80, 84))	('tumor', 'Phenotype', 'HP:0002664', (274, 279))	('malignancy', 'Disease', 'MESH:D009369', (154, 164))	('blockade', 'Var', (166, 174))	('malignancy', 'Disease', (154, 164))
486060	32571310	Similarly, confirmation that EP4R is the major isoform in canine malignancy will need to be proven with evaluation of the expression of EP1R, EP2R, and EP3R.	('EP2R', 'Var', (142, 146))	('malignancy', 'Disease', 'MESH:D009369', (65, 75))	('EP3R', 'Var', (152, 156))	('EP1', 'Gene', (136, 139))	('EP4R', 'Gene', (29, 33))	('malignancy', 'Disease', (65, 75))	('canine', 'Species', '9615', (58, 64))	('EP4R', 'Gene', '5734', (29, 33))	('EP1', 'Gene', '5731', (136, 139))
486139	31131052	In this study, we fixed the pump beam at 802 nm center wavelength, and imaged at two time delays which correspond to two Raman frequencies of 2845 cm-1 and 2930 cm-1 for lipid/protein decomposition.	('2930 cm-1', 'Var', (156, 165))	('lipid/protein decomposition', 'MPA', (170, 197))	('lipid', 'Chemical', 'MESH:D008055', (170, 175))
486281	25663947	Several studies have reported the clinical value of FDG-PET or FDG PET/CT in patients with cervical cancer who have unexplained elevated levels of serum SCCAg or CEA during follow-up.	('CEA', 'Gene', '1048', (162, 165))	('FDG', 'Chemical', 'MESH:D019788', (63, 66))	('cervical cancer', 'Disease', (91, 106))	('cervical cancer', 'Disease', 'MESH:D002583', (91, 106))	('CEA', 'Gene', (162, 165))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('FDG-PET', 'Var', (52, 59))	('FDG', 'Chemical', 'MESH:D019788', (52, 55))	('patients', 'Species', '9606', (77, 85))	('FDG PET/CT', 'Var', (63, 73))
486457	33649798	Furthermore, using the cBioportal pan-cancer panel, the present study identified specific cancer types with a number of TMPRSS4 amplifications in LGG, LUAD, STAD, deep deletions in BRCA, HNSC, and shallow deletions in BLCA, BRCA, CESC, ESCA, LUAD, LUSC, OV and TGCT.	('ESCA', 'Disease', (236, 240))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('deep deletions', 'Var', (163, 177))	('BRCA', 'Gene', (181, 185))	('LGG', 'Gene', (146, 149))	('TMPRSS4', 'Gene', (120, 127))	('BRCA', 'Gene', (224, 228))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('BLCA', 'Gene', (218, 222))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('TMPRSS4', 'Gene', '56649', (120, 127))	('cancer', 'Disease', (38, 44))	('CESC', 'Disease', (230, 234))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('shallow deletions', 'Var', (197, 214))
486458	33649798	Furthermore, there were two datasets for thyroid cancers with a number of patients presenting diploid and not mutated versions of the gene, namely for THYM and THCA.	('THCA', 'Disease', (160, 164))	('diploid', 'Var', (94, 101))	('thyroid cancers', 'Disease', (41, 56))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('patients', 'Species', '9606', (74, 82))	('thyroid cancers', 'Disease', 'MESH:D013964', (41, 56))	('THYM', 'Disease', (151, 155))	('cancers', 'Phenotype', 'HP:0002664', (49, 56))
486459	33649798	Of note, in the majority of the studied cancers, the majority of the patients had deletions and partly some gains and amplifications (Fig.	('deletions', 'Var', (82, 91))	('cancers', 'Phenotype', 'HP:0002664', (40, 47))	('gains', 'PosReg', (108, 113))	('cancers', 'Disease', 'MESH:D009369', (40, 47))	('cancers', 'Disease', (40, 47))	('patients', 'Species', '9606', (69, 77))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))
486538	29220434	RP11-244M2.1 and RP11-120D5.1 for proliferation, LINC00704 and RP5-1158E12.3 for migration and RP11-132A1.4, RP11-20B24.4 and FOXD2-AS1 for possible associations with MYC) should be validated by means of wet lab experiments.	('migration', 'CPA', (81, 90))	('RP11', 'Gene', '26121', (0, 4))	('AS1', 'Gene', (132, 135))	('FOXD2', 'Gene', (126, 131))	('LINC00704', 'Gene', (49, 58))	('RP11', 'Gene', '26121', (109, 113))	('RP11', 'Gene', (17, 21))	('RP11', 'Gene', '26121', (95, 99))	('MYC', 'Gene', (167, 170))	('RP11', 'Gene', (0, 4))	('proliferation', 'CPA', (34, 47))	('AS1', 'Gene', '5729', (132, 135))	('MYC', 'Gene', '4609', (167, 170))	('RP11', 'Gene', (109, 113))	('LINC00704', 'Gene', '100216001', (49, 58))	('associations', 'Interaction', (149, 161))	('RP11', 'Gene', (95, 99))	('FOXD2', 'Gene', '2306', (126, 131))	('RP11', 'Gene', '26121', (17, 21))	('RP5-1158E12.3', 'Var', (63, 76))
486542	29220434	Among those are several gene sets related to H3K27 methylation that is induced by HOTAIR through recruitment of PRC2.	('H3K27', 'Protein', (45, 50))	('methylation', 'Var', (51, 62))	('HOTAIR', 'Gene', (82, 88))	('PRC2', 'Gene', (112, 116))	('HOTAIR', 'Gene', '100124700', (82, 88))
486548	29220434	As a third and final test to evaluate the decodeRNA functionality, we performed GSEA on a publically available RNA sequencing dataset obtained upon MALAT1 perturbation in lung cancer (GEO accession number GSE43830) and determined the overlap of the resulting gene sets (upon perturbation) with the ones obtained through decodeRNA for MALAT1 in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC).	('MALAT1', 'Gene', (334, 340))	('lung cancer', 'Phenotype', 'HP:0100526', (171, 182))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (375, 403))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (380, 403))	('lung squamous cell carcinoma', 'Disease', (375, 403))	('LUSC', 'Phenotype', 'HP:0030359', (405, 409))	('MALAT1', 'Gene', '378938', (334, 340))	('lung adenocarcinoma', 'Disease', (344, 363))	('LUAD', 'Phenotype', 'HP:0030078', (365, 369))	('GSEA', 'Chemical', '-', (80, 84))	('lung cancer', 'Disease', (171, 182))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (344, 363))	('MALAT1', 'Gene', (148, 154))	('carcinoma', 'Phenotype', 'HP:0030731', (394, 403))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (344, 363))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (375, 403))	('MALAT1', 'Gene', '378938', (148, 154))	('carcinoma', 'Phenotype', 'HP:0030731', (354, 363))	('lung cancer', 'Disease', 'MESH:D008175', (171, 182))	('perturbation', 'Var', (155, 167))
486549	29220434	Both for the LUAD and LUSC datasets, gene sets identified by decodeRNA significantly overlapped with those identified from the MALAT1 perturbation experiment (Fischer exact test, LUAD: P < 2.2e-16; LUSC: P = 0.003042).	('LUAD', 'Phenotype', 'HP:0030078', (179, 183))	('decodeRNA', 'Var', (61, 70))	('MALAT1', 'Gene', (127, 133))	('LUSC', 'Phenotype', 'HP:0030359', (198, 202))	('LUSC', 'Phenotype', 'HP:0030359', (22, 26))	('MALAT1', 'Gene', '378938', (127, 133))	('LUAD', 'Phenotype', 'HP:0030078', (13, 17))
486617	27606290	These molecular alterations (gene amplification or mutations), which have the driver/transforming capability or property, represent potentially an early event in carcinogenesis that fuels further sufficient genetic alterations that lead to malignant characteristics of cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (269, 275))	('alterations', 'Var', (215, 226))	('carcinogenesis', 'Disease', 'MESH:D063646', (162, 176))	('carcinogenesis', 'Disease', (162, 176))	('cancer', 'Disease', (269, 275))	('cancer', 'Disease', 'MESH:D009369', (269, 275))	('lead to', 'Reg', (232, 239))
486621	27606290	Small molecule tyrosine kinase inhibitors (TKIs) (gefitinib and erlotinib) which target a mutant epidermal growth factor receptor (EGFR) have been approved by the Food and Drug Administration (FDA) as first-line agents in the treatment of advanced NSCLC patients, who tested positive for the activating driver mutation.	('NSCLC', 'Disease', (248, 253))	('NSCLC', 'Disease', 'MESH:D002289', (248, 253))	('mutant', 'Var', (90, 96))	('EGFR', 'Gene', '1956', (131, 135))	('epidermal growth factor receptor', 'Gene', (97, 129))	('EGFR', 'Gene', (131, 135))	('men', 'Species', '9606', (231, 234))	('gefitinib', 'Chemical', 'MESH:D000077156', (50, 59))	('NSCLC', 'Phenotype', 'HP:0030358', (248, 253))	('erlotinib', 'Chemical', 'MESH:D000069347', (64, 73))	('patients', 'Species', '9606', (254, 262))	('epidermal growth factor receptor', 'Gene', '1956', (97, 129))
486622	27606290	These driver mutations occur in exons 18-21 of the EGFR, modifying the active site of the kinase domain in favor of increased activity (ligand-driven or constitutive activity).	('EGFR', 'Gene', (51, 55))	('active site of the kinase domain', 'MPA', (71, 103))	('modifying', 'Reg', (57, 66))	('increased', 'PosReg', (116, 125))	('mutations', 'Var', (13, 22))	('activity', 'MPA', (126, 134))	('EGFR', 'Gene', '1956', (51, 55))
486623	27606290	The earlier reporting from most Indian populations suggested an EGFR mutation rate varying between 22% and 51.8%, which possibly was an overestimation resulting from selection bias and small sample size.	('EGFR', 'Gene', (64, 68))	('mutation', 'Var', (69, 77))	('EGFR', 'Gene', '1956', (64, 68))
486624	27606290	from Triesta laboratories in Bengaluru, India, reported an EGFR mutation rate of 55% in 220 patient samples tested between January 2008 and July 2010.	('Triesta laboratories in Bengaluru', 'Disease', (5, 38))	('mutation', 'Var', (64, 72))	('EGFR', 'Gene', (59, 63))	('patient', 'Species', '9606', (92, 99))	('Triesta laboratories in Bengaluru', 'Disease', 'MESH:D007757', (5, 38))	('EGFR', 'Gene', '1956', (59, 63))
486625	27606290	However, these patients were possibly selected for EGFR mutation testing based on their clinicodemographic profile, and hence was likely to be an enriched population.	('mutation', 'Var', (56, 64))	('patients', 'Species', '9606', (15, 23))	('EGFR', 'Gene', '1956', (51, 55))	('EGFR', 'Gene', (51, 55))
486628	27606290	Of all the EGFR tyrosine kinase domain mutations, 50% were in-frame deletions in exon 19, 42% were missense mutations in exon 21, 7% of the mutations were in exon 18, and 3% in exon 20.	('EGFR', 'Gene', '1956', (11, 15))	('EGFR', 'Gene', (11, 15))	('mutations', 'Var', (39, 48))
486629	27606290	Two patients harbored a mutation in exon 20 along with exon 21.	('mutation in exon', 'Var', (24, 40))	('harbored', 'Reg', (13, 21))	('patients', 'Species', '9606', (4, 12))
486630	27606290	The overall frequency of EGFR mutations in the adenocarcinoma population was 26% as compared to 3.8% in squamous cell carcinomas (n = 103).	('carcinoma', 'Phenotype', 'HP:0030731', (52, 61))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (104, 127))	('EGFR', 'Gene', (25, 29))	('adenocarcinoma', 'Disease', 'MESH:D000230', (47, 61))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (104, 128))	('squamous cell carcinomas', 'Disease', (104, 128))	('carcinomas', 'Phenotype', 'HP:0030731', (118, 128))	('mutations', 'Var', (30, 39))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (104, 128))	('EGFR', 'Gene', '1956', (25, 29))	('adenocarcinoma', 'Disease', (47, 61))
486631	27606290	This EGFR mutation rate was less than that of East Asian patients (26-30%) and more than Western patients (10-15%).	('patients', 'Species', '9606', (57, 65))	('EGFR', 'Gene', '1956', (5, 9))	('mutation', 'Var', (10, 18))	('EGFR', 'Gene', (5, 9))	('patients', 'Species', '9606', (97, 105))
486632	27606290	Another retrospective analysis involving 500 patients treated at six different centers revealed a slightly higher EGFR mutation rate of 33%.	('EGFR', 'Gene', (114, 118))	('mutation', 'Var', (119, 127))	('patients', 'Species', '9606', (45, 53))	('EGFR', 'Gene', '1956', (114, 118))
486633	27606290	The PIONEER study was a prospective, multinational, epidemiological study of EGFR mutations which enrolled patients from Asia with newly diagnosed advanced lung adenocarcinoma.	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (156, 175))	('patients', 'Species', '9606', (107, 115))	('carcinoma', 'Phenotype', 'HP:0030731', (166, 175))	('lung adenocarcinoma', 'Disease', (156, 175))	('mutations', 'Var', (82, 91))	('EGFR', 'Gene', '1956', (77, 81))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (156, 175))	('EGFR', 'Gene', (77, 81))
486635	27606290	PIONEER reported a lower EGFR mutation frequency in patients from India (22.2%) compared with other areas (47.2-64.2%).	('EGFR', 'Gene', (25, 29))	('mutation', 'Var', (30, 38))	('lower', 'NegReg', (19, 24))	('EGFR', 'Gene', '1956', (25, 29))	('patients', 'Species', '9606', (52, 60))
486639	27606290	Progression-free survival (PFS) and overall survival (OS) were 10 months and 19 months, respectively, in patients with EGFR mutations compared to 2 months and 13 months, respectively, for EGFR mutation-negative patients.	('patients', 'Species', '9606', (105, 113))	('mutations', 'Var', (124, 133))	('patients', 'Species', '9606', (211, 219))	('EGFR', 'Gene', '1956', (188, 192))	('EGFR', 'Gene', '1956', (119, 123))	('EGFR', 'Gene', (188, 192))	('EGFR', 'Gene', (119, 123))
486642	27606290	The prevalence of EGFR mutation in this population was 39.6% with exon 19 mutation being the most common (80%); exon 21 mutation was seen in 17% and exon 18 in 3%.	('exon 21', 'Var', (112, 119))	('EGFR', 'Gene', '1956', (18, 22))	('mutation', 'Var', (23, 31))	('EGFR', 'Gene', (18, 22))	('exon 19', 'Var', (66, 73))
486643	27606290	The response rates were superior in the EGFR mutation-positive group compared to mutation-negative group (90.5% vs. 70.3%), with the best response noted in those treated upfront with oral TKI (93.3% vs. 88.8%).	('mutation-positive', 'Var', (45, 62))	('EGFR', 'Gene', '1956', (40, 44))	('EGFR', 'Gene', (40, 44))
486644	27606290	This retrospective series further demonstrated better PFS in the EGFR mutation-positive patients who received chemotherapy, followed by TKI, as compared with EGFR mutation-positive patients who received only TKIs, which could be contributory evidence in support of studies assessing the best way to sequence chemotherapy and oral TKI in EGFR mutation-positive lung cancer patients.	('EGFR', 'Gene', (158, 162))	('better', 'PosReg', (47, 53))	('EGFR', 'Gene', '1956', (65, 69))	('EGFR', 'Gene', (65, 69))	('EGFR', 'Gene', '1956', (337, 341))	('patients', 'Species', '9606', (88, 96))	('cancer', 'Phenotype', 'HP:0002664', (365, 371))	('lung cancer', 'Disease', (360, 371))	('EGFR', 'Gene', '1956', (158, 162))	('lung cancer', 'Phenotype', 'HP:0100526', (360, 371))	('EGFR', 'Gene', (337, 341))	('patients', 'Species', '9606', (181, 189))	('mutation-positive', 'Var', (70, 87))	('lung cancer', 'Disease', 'MESH:D008175', (360, 371))	('patients', 'Species', '9606', (372, 380))	('PFS', 'MPA', (54, 57))
486645	27606290	Our group at Tata Memorial Hospital, Mumbai, Maharashtra, India retrospectively analyzed the survival outcomes of 101 EGFR mutant patients with and without brain metastases.	('brain metastases', 'Disease', 'MESH:D009362', (156, 172))	('patients', 'Species', '9606', (130, 138))	('EGFR', 'Gene', '1956', (118, 122))	('brain metastases', 'Disease', (156, 172))	('EGFR', 'Gene', (118, 122))	('mutant', 'Var', (123, 129))
486649	27606290	Thus, even among the patients with EGFR driver mutation, the presence of brain metastases leads to an inferior outcome.	('brain metastases', 'Disease', 'MESH:D009362', (73, 89))	('brain metastases', 'Disease', (73, 89))	('mutation', 'Var', (47, 55))	('EGFR', 'Gene', '1956', (35, 39))	('EGFR', 'Gene', (35, 39))	('patients', 'Species', '9606', (21, 29))
486650	27606290	in an abstract form in ASCO 2013 showed that the awareness about the need for EGFR mutation testing and use of TKIs among medical oncologists is increasing in India.	('EGFR', 'Gene', (78, 82))	('mutation', 'Var', (83, 91))	('EGFR', 'Gene', '1956', (78, 82))
486652	27606290	The presence of ALK mutation is reported in approximately 3-7% of lung cancers, found more commonly in young patients with adenocarcinomas with a history of never or light smoking.	('cancers', 'Phenotype', 'HP:0002664', (71, 78))	('adenocarcinomas', 'Disease', (123, 138))	('patients', 'Species', '9606', (109, 117))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('mutation', 'Var', (20, 28))	('lung cancers', 'Disease', (66, 78))	('lung cancer', 'Phenotype', 'HP:0100526', (66, 77))	('carcinomas', 'Phenotype', 'HP:0030731', (128, 138))	('ALK', 'Gene', '238', (16, 19))	('lung cancers', 'Phenotype', 'HP:0100526', (66, 78))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('lung cancers', 'Disease', 'MESH:D008175', (66, 78))	('ALK', 'Gene', (16, 19))	('adenocarcinomas', 'Disease', 'MESH:D000230', (123, 138))
486654	27606290	In the majority of patients, ALK rearrangements are nonoverlapping with other oncogenic mutations.	('ALK', 'Gene', (29, 32))	('patients', 'Species', '9606', (19, 27))	('men', 'Species', '9606', (42, 45))	('rearrangements', 'Var', (33, 47))	('ALK', 'Gene', '238', (29, 32))
486656	27606290	Based on the impressive response rates attained in initial Phase I and Phase II trials with the dual ALK/MET TKI, crizotinib in patients harboring the ALK mutation, an international Phase III trial randomized patients with advanced lung cancer harboring ALK fusions to crizotinib versus standard chemotherapy after disease progression on first line treatment.	('ALK', 'Gene', '238', (254, 257))	('ALK', 'Gene', (101, 104))	('crizotinib', 'Chemical', 'MESH:D000077547', (114, 124))	('men', 'Species', '9606', (354, 357))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('ALK', 'Gene', (151, 154))	('lung cancer', 'Disease', 'MESH:D008175', (232, 243))	('ALK', 'Gene', '238', (101, 104))	('patients', 'Species', '9606', (128, 136))	('ALK', 'Gene', (254, 257))	('patients', 'Species', '9606', (209, 217))	('mutation', 'Var', (155, 163))	('lung cancer', 'Phenotype', 'HP:0100526', (232, 243))	('crizotinib', 'Chemical', 'MESH:D000077547', (269, 279))	('ALK', 'Gene', '238', (151, 154))	('lung cancer', 'Disease', (232, 243))	('fusions', 'Var', (258, 265))
486658	27606290	In treatment naive patients harboring ALK mutation, therapy with crizotinib resulted in an improved PFS, quality of life (QOL), and radiographic response rates.	('PFS', 'Disease', (100, 103))	('ALK', 'Gene', '238', (38, 41))	('patients', 'Species', '9606', (19, 27))	('quality of life', 'CPA', (105, 120))	('men', 'Species', '9606', (8, 11))	('mutation', 'Var', (42, 50))	('radiographic response', 'CPA', (132, 153))	('ALK', 'Gene', (38, 41))	('improved', 'PosReg', (91, 99))	('crizotinib', 'Chemical', 'MESH:D000077547', (65, 75))
486660	27606290	from Tata Memorial Hospital in Mumbai, Maharashtra, India, in their retrospective observational study provided the earliest literature of ALK mutations among Indian lung cancer patients.	('mutations', 'Var', (142, 151))	('lung cancer', 'Disease', (165, 176))	('ALK', 'Gene', '238', (138, 141))	('patients', 'Species', '9606', (177, 185))	('lung cancer', 'Phenotype', 'HP:0100526', (165, 176))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('ALK', 'Gene', (138, 141))	('lung cancer', 'Disease', 'MESH:D008175', (165, 176))
486665	27606290	A total of 500 patients were enrolled from six centers in India and tested for the EGFR mutations.	('EGFR', 'Gene', '1956', (83, 87))	('patients', 'Species', '9606', (15, 23))	('EGFR', 'Gene', (83, 87))	('mutations', 'Var', (88, 97))	('tested', 'Reg', (68, 74))
486667	27606290	ALK mutation testing was performed on the 336 tissue blocks which tested negative for the EGFR mutation.	('EGFR', 'Gene', '1956', (90, 94))	('mutation', 'Var', (95, 103))	('ALK', 'Gene', (0, 3))	('EGFR', 'Gene', (90, 94))	('ALK', 'Gene', '238', (0, 3))
486669	27606290	The overall incidence of ALK mutations was 3.0% (15/500).	('ALK', 'Gene', (25, 28))	('mutations', 'Var', (29, 38))	('ALK', 'Gene', '238', (25, 28))
486687	27606290	On multivariate analysis, V5 ipsi was most strongly correlated with the development of radiation pneumonitis.	('ipsi', 'Chemical', '-', (29, 33))	('men', 'Species', '9606', (79, 82))	('pneumonitis', 'Disease', (97, 108))	('V5 ipsi', 'Var', (26, 33))	('pneumonitis', 'Disease', 'MESH:D011014', (97, 108))	('correlated with', 'Reg', (52, 67))
486759	27606290	At a median follow-up of 7.2 months, there was no significant difference in median OS between the two groups in the overall population (5.6 months in the patients treated with gefitinib vs. 5.1 months in the placebo-treated patients, HR - 0.89, 95% CI - 0.77-1.02, P = 0.087) or in the adenocarcinoma patients, 6.3 versus 5.4 months, 0.84 (0.68-1.03), P = 0.089.	('gefitinib', 'Chemical', 'MESH:D000077156', (176, 185))	('patients', 'Species', '9606', (301, 309))	('patients', 'Species', '9606', (154, 162))	('carcinoma', 'Phenotype', 'HP:0030731', (291, 300))	('adenocarcinoma', 'Disease', (286, 300))	('patients', 'Species', '9606', (224, 232))	('adenocarcinoma', 'Disease', 'MESH:D000230', (286, 300))	('gefitinib', 'Var', (176, 185))
486767	27606290	Thirty-nine of the 111 patients had an activating EGFR mutation and the response rate to gefitinib in these EGFR-positive patients was 74% while the response rate in EGFR-wild-type patients was 5%.	('gefitinib', 'Chemical', 'MESH:D000077156', (89, 98))	('EGFR', 'Gene', '1956', (108, 112))	('patients', 'Species', '9606', (23, 31))	('EGFR', 'Gene', (108, 112))	('EGFR', 'Gene', '1956', (166, 170))	('EGFR', 'Gene', (166, 170))	('EGFR', 'Gene', '1956', (50, 54))	('patients', 'Species', '9606', (122, 130))	('patients', 'Species', '9606', (181, 189))	('activating', 'PosReg', (39, 49))	('EGFR', 'Gene', (50, 54))	('mutation', 'Var', (55, 63))	('response', 'MPA', (72, 80))
486776	27606290	In the patients with performance status 2-3, gefitinib led to a significantly longer PFS than chemotherapy (PFS of 10 months vs. 4 months, P = 0.017).	('PFS', 'MPA', (85, 88))	('longer', 'PosReg', (78, 84))	('gefitinib', 'Chemical', 'MESH:D000077156', (45, 54))	('gefitinib', 'Var', (45, 54))	('patients', 'Species', '9606', (7, 15))
486836	33847677	Some authors have suggested that 18F-FDG PET/CT yields good diagnostic performance in long-term surveillance and imparts added value to clinical assessment.	('diagnostic', 'MPA', (60, 70))	('18F-FDG', 'Var', (33, 40))	('18F-FDG', 'Chemical', 'MESH:D019788', (33, 40))
486856	33495453	Recently, consideration of transcript-level changes within protein coding genes has enabled comprehensive characterization of isoform switching across multiple cancers, and extensive evidence now suggests noncoding transcripts and driver mutations within noncoding regions have important and functional roles in cancer by diverse mechanisms.	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('cancers', 'Disease', 'MESH:D009369', (160, 167))	('cancers', 'Phenotype', 'HP:0002664', (160, 167))	('cancer', 'Disease', (160, 166))	('cancers', 'Disease', (160, 167))	('mutations', 'Var', (238, 247))	('multiple cancer', 'Disease', (151, 166))	('cancer', 'Disease', 'MESH:D009369', (312, 318))	('cancer', 'Disease', (312, 318))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('multiple cancer', 'Disease', 'MESH:D009369', (151, 166))	('cancer', 'Phenotype', 'HP:0002664', (312, 318))
486863	33495453	Likewise, PINT87aa is a circRNA-encoded small peptide, which partially controls cell proliferation and tumorigenesis in cancer cells, is expressed at a reduced level in glioblastoma tissue, and is correlated with tumor grade.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('cancer', 'Disease', (120, 126))	('PINT87aa', 'Var', (10, 18))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('N', 'Chemical', 'MESH:D009584', (12, 13))	('reduced', 'NegReg', (152, 159))	('cell proliferation', 'CPA', (80, 98))	('glioblastoma', 'Disease', 'MESH:D005909', (169, 181))	('tumor', 'Disease', (103, 108))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('tumor', 'Disease', (213, 218))	('glioblastoma', 'Disease', (169, 181))	('glioblastoma', 'Phenotype', 'HP:0012174', (169, 181))	('correlated', 'Reg', (197, 207))	('tumor', 'Disease', 'MESH:D009369', (213, 218))	('N', 'Chemical', 'MESH:D009584', (29, 30))	('controls', 'Reg', (71, 79))
486864	33495453	Cells over-expressing PINT87aa exhibit decreased tumorigenic potential in animal models.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('PINT87aa', 'Var', (22, 30))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor', 'Disease', (49, 54))	('N', 'Chemical', 'MESH:D009584', (24, 25))	('over-expressing', 'PosReg', (6, 21))	('decreased', 'NegReg', (39, 48))
486876	33495453	In addition, analysis of all the GWAS-associated variants and mutations in the Catalog of Somatic Mutations in Cancer (COSMIC) and Human Gene Mutation Database (HGMD) databases revealed that a significant proportion of variants and mutations map to apparent noncoding regions of the human genome (Fig.	('HGMD', 'Disease', 'None', (161, 165))	('map', 'Reg', (242, 245))	('variants', 'Var', (219, 227))	('variants', 'Var', (49, 57))	('HGMD', 'Disease', (161, 165))	('mutations', 'Var', (232, 241))	('Cancer', 'Disease', 'MESH:D009369', (111, 117))	('Cancer', 'Disease', (111, 117))	('Human', 'Species', '9606', (131, 136))	('human', 'Species', '9606', (283, 288))	('Cancer', 'Phenotype', 'HP:0002664', (111, 117))	('mutations', 'Var', (62, 71))
486878	33495453	2a-d shows the top ~20 examples of COSMIC or HGMD mutations mapped to sORFs, Denovogenes, and Pseudogenes, demonstrating that these regions do indeed harbor mutations.	('mutations', 'Var', (50, 59))	('HGMD', 'Disease', 'None', (45, 49))	('HGMD', 'Disease', (45, 49))	('COSMIC', 'Gene', (35, 41))
486910	33495453	This suggested many nORF transcripts may have prognostic value, particularly in kidney clear cell carcinoma.	('nORF', 'Gene', (20, 24))	('kidney clear cell carcinoma', 'Disease', 'MESH:C538614', (80, 107))	('kidney clear cell carcinoma', 'Disease', (80, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('transcripts', 'Var', (25, 36))
486912	33495453	For a subset of 33 nORF transcripts: (i) the transcript is reproducibly differentially expressed in cancer compared with NAT and GTEx normal tissue, (ii) transcript expression is associated with prognosis (adjusted p-value < 0.05) and (iii) transcripts up-regulated in cancer are associated with poor prognosis, and vice versa.	('poor prognosis', 'CPA', (296, 310))	('associated with', 'Reg', (179, 194))	('transcript', 'MPA', (154, 164))	('cancer', 'Phenotype', 'HP:0002664', (269, 275))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('transcripts', 'Var', (241, 252))	('up-regulated', 'PosReg', (253, 265))	('prognosis', 'Disease', (195, 204))	('N', 'Chemical', 'MESH:D009584', (121, 122))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('cancer', 'Disease', (269, 275))	('cancer', 'Disease', 'MESH:D009369', (269, 275))
486924	33495453	Methylation, glycosylation, and phosphorylation were found to be significantly enriched in some novel protein datasets and NeXtProt proteins, compared to their individual random controls (Fig.	('Methylation', 'Var', (0, 11))	('N', 'Chemical', 'MESH:D009584', (123, 124))	('glycosylation', 'MPA', (13, 26))	('enriched', 'Reg', (79, 87))	('phosphorylation', 'MPA', (32, 47))
486933	33495453	Figure 5b and c (left panel and right panel) show the number of unique COSMIC and HGMD mutations along with the disease origin of these mutations for sORFs (left panel) and undefined ORFs (right panel) that are conserved in the human genome.	('HGMD', 'Disease', 'None', (82, 86))	('HGMD', 'Disease', (82, 86))	('sORFs', 'Disease', (150, 155))	('mutations', 'Var', (136, 145))	('human', 'Species', '9606', (228, 233))	('mutations', 'Var', (87, 96))
486936	33495453	Figure 5d shows (a) predicted structure of a translated product from the undefined novel ORF in an intergenic region in chr 14, (b) predicted structure of an undefined novel ORF insertion in Rps3a1 ribosomal protein (cyan) with the inserted fragment (red), and (c) predicted structure of an undefined novel ORF product antisense to Raet1.	('Rps3a1', 'Gene', (191, 197))	('insertion', 'Var', (178, 187))	('Rps3a1', 'Gene', '20091', (191, 197))	('Raet1', 'Gene', (332, 337))	('Raet1', 'Gene', '19368', (332, 337))
486941	33495453	Encoded by the DOP1A gene (DOP1 leucine zipper like protein A; ENSG00000083097), ENST00000484282.1 is annotated as a processed transcript, and therefore, by definition does not contain an ORF.	('DOP1', 'Gene', (27, 31))	('zip', 'Gene', (40, 43))	('DOP1', 'Gene', '23033', (15, 19))	('N', 'Chemical', 'MESH:D009584', (82, 83))	('N', 'Chemical', 'MESH:D009584', (64, 65))	('DOP1', 'Gene', (15, 19))	('DOP1', 'Gene', '23033', (27, 31))	('zip', 'Gene', '1613', (40, 43))	('leucine', 'Chemical', 'MESH:D007930', (32, 39))	('ENST00000484282.1', 'Var', (81, 98))
487003	33495453	To investigate whether the novel protein regions could harbor disease-associated mutations, we mapped mutations from the COSMIC and HGMD databases to nORF peptides.	('HGMD', 'Disease', (132, 136))	('mutations', 'Var', (102, 111))	('HGMD', 'Disease', 'None', (132, 136))
487004	33495453	2 shows examples of COSMIC or HGMD mutations mapped to all human sORFs, Denovogenes, and Pseudogenes demonstrating that these regions do indeed harbor mutations.	('human', 'Species', '9606', (59, 64))	('HGMD', 'Disease', 'None', (30, 34))	('HGMD', 'Disease', (30, 34))	('mutations', 'Var', (35, 44))
487089	31238894	The tumours with strong TLR2nucl or TLR5 expression were mostly virus-negative or HPV-positive keratinizing squamous cell carcinomas, and the patients with these tumours were significantly older than those with mild or negative TLR2nucl/TLR5 expression.	('TLR5', 'Gene', (36, 40))	('tumours', 'Disease', 'MESH:D009369', (162, 169))	('TLR2nucl', 'Var', (24, 32))	('tumours', 'Disease', (162, 169))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (108, 131))	('tumour', 'Phenotype', 'HP:0002664', (4, 10))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (108, 132))	('tumours', 'Phenotype', 'HP:0002664', (4, 11))	('squamous cell carcinomas', 'Disease', (108, 132))	('carcinomas', 'Phenotype', 'HP:0030731', (122, 132))	('tumour', 'Phenotype', 'HP:0002664', (162, 168))	('tumours', 'Disease', 'MESH:D009369', (4, 11))	('tumours', 'Phenotype', 'HP:0002664', (162, 169))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (108, 132))	('patients', 'Species', '9606', (142, 150))	('HPV', 'Species', '10566', (82, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('tumours', 'Disease', (4, 11))
487090	31238894	In Kaplan-Meier analysis, the patients with strong TLR5 expression had worse survival compared to the patients with negative or mild TLR5 expression, but the results were linked to other patient and tumour characteristics.	('tumour', 'Phenotype', 'HP:0002664', (199, 205))	('patient', 'Species', '9606', (30, 37))	('patient', 'Species', '9606', (102, 109))	('patients', 'Species', '9606', (102, 110))	('tumour', 'Disease', 'MESH:D009369', (199, 205))	('worse', 'NegReg', (71, 76))	('tumour', 'Disease', (199, 205))	('patients', 'Species', '9606', (30, 38))	('patient', 'Species', '9606', (187, 194))	('TLR5', 'Gene', (51, 55))	('survival', 'MPA', (77, 85))	('expression', 'Var', (56, 66))
487091	31238894	In multivariable-adjusted Cox regression analysis, the patients with positive TLR7 tumour expression had better overall survival than those with no TLR7 expression.	('tumour', 'Disease', (83, 89))	('better', 'PosReg', (105, 111))	('TLR7', 'Gene', '51284', (148, 152))	('TLR7', 'Gene', (78, 82))	('patients', 'Species', '9606', (55, 63))	('positive', 'Var', (69, 77))	('TLR7', 'Gene', '51284', (78, 82))	('tumour', 'Phenotype', 'HP:0002664', (83, 89))	('tumour', 'Disease', 'MESH:D009369', (83, 89))	('overall survival', 'MPA', (112, 128))	('TLR7', 'Gene', (148, 152))	('Cox', 'Gene', '1351', (26, 29))	('Cox', 'Gene', (26, 29))
487113	31238894	In NPC, the importance of TLRs in tumour immunity has been demonstrated in studies from endemic areas, where certain sequence variants in TLR genes were associated with increased NPC risk.	('NPC', 'Gene', '4864', (3, 6))	('TLR', 'Gene', (138, 141))	('NPC', 'Gene', '4864', (179, 182))	('tumour', 'Disease', 'MESH:D009369', (34, 40))	('sequence variants', 'Var', (117, 134))	('tumour', 'Disease', (34, 40))	('associated with', 'Reg', (153, 168))	('NPC', 'Gene', (3, 6))	('NPC', 'Gene', (179, 182))	('NPC', 'Phenotype', 'HP:0100630', (3, 6))	('NPC', 'Phenotype', 'HP:0100630', (179, 182))	('tumour', 'Phenotype', 'HP:0002664', (34, 40))
487176	31238894	In addition, the patients with negative or mild TLR5 expression were younger than those with strong TLR5 expression with mean ages of 54.4, 55.5, and 63.4, respectively (p = 0.021 and p = 0.053).	('negative', 'NegReg', (31, 39))	('mild', 'Var', (43, 47))	('TLR5', 'Gene', (48, 52))	('patients', 'Species', '9606', (17, 25))
487185	31238894	In Kaplan-Meier analysis, the patients with strong TLR5 expression had worse OS than those with mild or negative TLR5 expression (Fig.	('patients', 'Species', '9606', (30, 38))	('expression', 'Var', (56, 66))	('OS', 'Chemical', '-', (77, 79))	('TLR5', 'Gene', (51, 55))
487189	31238894	In contrast, the patients with no TLR7 expression had worse OS and DSS than the patients with positive TLR7 staining (Fig.	('DSS', 'Gene', (67, 70))	('DSS', 'Gene', '5376', (67, 70))	('patients', 'Species', '9606', (80, 88))	('expression', 'Var', (39, 49))	('TLR7', 'Gene', (34, 38))	('TLR7', 'Gene', (103, 107))	('patients', 'Species', '9606', (17, 25))	('TLR7', 'Gene', '51284', (34, 38))	('OS', 'Chemical', '-', (60, 62))	('TLR7', 'Gene', '51284', (103, 107))
487191	31238894	The patients with negative TLR9 expression had worse OS compared to the patients with positive TLR9 expression, but the significance of this is limited by the presence of only four TLR9-negative cases.	('expression', 'Var', (32, 42))	('negative', 'NegReg', (18, 26))	('OS', 'Chemical', '-', (53, 55))	('TLR9', 'Gene', (27, 31))	('patients', 'Species', '9606', (4, 12))	('patients', 'Species', '9606', (72, 80))
487193	31238894	In multivariable-adjusted Cox regression analysis, positive TLR7 expression (mild, p = 0.018; moderate or strong, p = 0.038) compared to negative TLR7 expression was a significant prognostic factor for a better OS (Table 4).	('TLR7', 'Gene', '51284', (146, 150))	('TLR7', 'Gene', (60, 64))	('positive', 'Var', (51, 59))	('TLR7', 'Gene', '51284', (60, 64))	('OS', 'Chemical', '-', (211, 213))	('TLR7', 'Gene', (146, 150))	('better OS', 'Disease', (204, 213))	('Cox', 'Gene', '1351', (26, 29))	('Cox', 'Gene', (26, 29))
487194	31238894	When analyzing DSS in multivariable-adjusted Cox regression analysis, only mild TLR7 expression (p = 0.046) compared to negative TLR7 expression remained as a significant prognostic factor for a better DSS.	('DSS', 'Gene', (15, 18))	('TLR7', 'Gene', (129, 133))	('mild', 'Var', (75, 79))	('DSS', 'Gene', '5376', (15, 18))	('TLR7', 'Gene', '51284', (80, 84))	('Cox', 'Gene', '1351', (45, 48))	('TLR7', 'Gene', '51284', (129, 133))	('DSS', 'Gene', (202, 205))	('Cox', 'Gene', (45, 48))	('TLR7', 'Gene', (80, 84))	('DSS', 'Gene', '5376', (202, 205))
487195	31238894	In age-adjusted Cox regression analysis, positive TLR9 expression (mild, p = 0.004; strong, p = 0.034) compared to no expression was associated with a better OS.	('TLR9', 'Gene', (50, 54))	('better', 'Disease', (151, 157))	('positive', 'Var', (41, 49))	('Cox', 'Gene', '1351', (16, 19))	('Cox', 'Gene', (16, 19))	('OS', 'Chemical', '-', (158, 160))
487201	31238894	The present study demonstrated that the expression patterns of TLR2 and TLR5 were related to the viral status while both TLRs were expressed significantly less in EBV-positive than in HPV-positive or EBV/HPV-negative NPC.	('expression', 'MPA', (40, 50))	('TLR5', 'Gene', (72, 76))	('NPC', 'Phenotype', 'HP:0100630', (217, 220))	('EBV', 'Species', '10376', (163, 166))	('NPC', 'Gene', '4864', (217, 220))	('related', 'Reg', (82, 89))	('TLR2', 'Gene', (63, 67))	('EBV', 'Species', '10376', (200, 203))	('HPV', 'Species', '10566', (184, 187))	('HPV', 'Species', '10566', (204, 207))	('EBV-positive', 'Var', (163, 175))	('less', 'NegReg', (155, 159))	('NPC', 'Gene', (217, 220))
487205	31238894	The exact effects of TLR-mediation on tumour growth are not known, but several in vitro studies on other types of carcinomas have shown that activation of TLR5 can promote tumorigenesis.	('tumorigenesis', 'CPA', (172, 185))	('tumour', 'Phenotype', 'HP:0002664', (38, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('promote', 'PosReg', (164, 171))	('carcinomas', 'Phenotype', 'HP:0030731', (114, 124))	('tumour', 'Disease', 'MESH:D009369', (38, 44))	('carcinomas', 'Disease', (114, 124))	('carcinomas', 'Disease', 'MESH:D002277', (114, 124))	('activation', 'Var', (141, 151))	('tumour', 'Disease', (38, 44))	('TLR5', 'Gene', (155, 159))
487207	31238894	In contrast to TLR5, the patients with positive TLR7 expression had better DSS and OS than the patients with no TLR7 expression, and TLR7 was found to be a significant prognostic factor in multivariable Cox regression analysis.	('TLR7', 'Gene', '51284', (48, 52))	('DSS', 'Gene', (75, 78))	('expression', 'Var', (53, 63))	('better', 'PosReg', (68, 74))	('TLR7', 'Gene', (112, 116))	('TLR7', 'Gene', (133, 137))	('OS', 'Chemical', '-', (83, 85))	('patients', 'Species', '9606', (95, 103))	('Cox', 'Gene', '1351', (203, 206))	('DSS', 'Gene', '5376', (75, 78))	('Cox', 'Gene', (203, 206))	('TLR7', 'Gene', '51284', (133, 137))	('TLR7', 'Gene', '51284', (112, 116))	('patients', 'Species', '9606', (25, 33))	('TLR7', 'Gene', (48, 52))	('positive', 'Var', (39, 47))
487208	31238894	The finding that the patients with mild TLR7 expression had slightly better 5-year survival than the patients with strong TLR7 expression was not expected, but a similar result has been reported in patients with oral squamous cell carcinoma.	('patients', 'Species', '9606', (101, 109))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (212, 240))	('5-year survival', 'MPA', (76, 91))	('patients', 'Species', '9606', (198, 206))	('carcinoma', 'Phenotype', 'HP:0030731', (231, 240))	('TLR7', 'Gene', (122, 126))	('TLR7', 'Gene', '51284', (40, 44))	('patients', 'Species', '9606', (21, 29))	('oral squamous cell carcinoma', 'Disease', (212, 240))	('better', 'PosReg', (69, 75))	('TLR7', 'Gene', '51284', (122, 126))	('mild', 'Var', (35, 39))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (217, 240))	('expression', 'Var', (45, 55))	('TLR7', 'Gene', (40, 44))
487215	31238894	They suggested that genetic TLR polymorphisms, especially in X-chromosome-linked TLR8, affect the innate immune response and make certain populations and individuals more vulnerable to infection-related cancers.	('TLR8', 'Gene', (81, 85))	('polymorphisms', 'Var', (32, 45))	('TLR8', 'Gene', '51311', (81, 85))	('infection', 'Disease', (185, 194))	('innate immune', 'MPA', (98, 111))	('vulnerable', 'Reg', (171, 181))	('affect', 'Reg', (87, 93))	('infection', 'Disease', 'MESH:D007239', (185, 194))	('cancers', 'Phenotype', 'HP:0002664', (203, 210))	('cancers', 'Disease', 'MESH:D009369', (203, 210))	('make', 'Reg', (125, 129))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('cancers', 'Disease', (203, 210))
487246	31258777	Using receiver operating characteristic (ROC) curve, the diagnostic value of serum IGFBP7 was demonstrated.	('OC', 'Phenotype', 'HP:0100615', (42, 44))	('IGFBP7', 'Gene', '3490', (83, 89))	('serum', 'Var', (77, 82))	('IGFBP7', 'Gene', (83, 89))
487291	31258777	Since there was no statistic difference between serum IGFBP7 and the clinical data, serum IGFBP7 might be a relative stable marker not affected by the obtained factors but just related to the existence status of the ESCC.	('IGFBP7', 'Gene', '3490', (54, 60))	('IGFBP7', 'Gene', (90, 96))	('IGFBP7', 'Gene', '3490', (90, 96))	('serum', 'Var', (84, 89))	('IGFBP7', 'Gene', (54, 60))
487294	31258777	In addition, as an important parameter for a test used in early detection of cancer, the positive predictive value (PPV) would be 59.1%, 81.3% and 92.9% when standardize disease prevalence of 25%, 50%, and 75%, demonstrating that serum IGFBP7 is a promising marker in both low-risk and high-risk area.	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('IGFBP7', 'Gene', (236, 242))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('serum', 'Var', (230, 235))	('IGFBP7', 'Gene', '3490', (236, 242))
487301	31258777	As methylation causes gene silencing of IGFBP7, researchers tried to measure the relationship between IGFBP7 methylation and malignance of cancer, finding that the methylation gave permission to cancer cell proliferation and could develop the tumor.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('IGFBP7', 'Gene', '3490', (40, 46))	('methylation', 'Var', (164, 175))	('methylation', 'Var', (3, 14))	('cancer', 'Disease', (195, 201))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('IGFBP7', 'Gene', '3490', (102, 108))	('malignance of cancer', 'Disease', 'MESH:D009369', (125, 145))	('IGFBP7', 'Gene', (40, 46))	('cancer', 'Disease', (139, 145))	('gene', 'MPA', (22, 26))	('tumor', 'Disease', 'MESH:D009369', (243, 248))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('tumor', 'Phenotype', 'HP:0002664', (243, 248))	('IGFBP7', 'Gene', (102, 108))	('malignance of cancer', 'Disease', (125, 145))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('tumor', 'Disease', (243, 248))
487302	31258777	If there is a deletion of IGFBP7, it even promotes the hepatocellular carcinoma.	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (55, 79))	('IGFBP7', 'Gene', '3490', (26, 32))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('hepatocellular carcinoma', 'Disease', (55, 79))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (55, 79))	('promotes', 'PosReg', (42, 50))	('IGFBP7', 'Gene', (26, 32))	('deletion', 'Var', (14, 22))
487319	31138328	Our results show that ITH is associated with survival time in several cancer types and its effect can be modified by other covariates, such as mutation burden.	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('associated', 'Reg', (29, 39))	('cancer', 'Disease', (70, 76))	('ITH', 'Var', (22, 25))	('cancer', 'Disease', 'MESH:D009369', (70, 76))
487320	31138328	Somatic mutations, including somatic point mutations (SPMs; e.g., single nucleotide variants or indels) and somatic copy number alterations (SCNAs), are the underlying driving force for tumor growth.	('single nucleotide variants', 'Var', (66, 92))	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('tumor', 'Disease', (186, 191))
487332	31138328	An alternative metric to quantify ITH is mutant-allele tumor heterogeneity (MATH), which is defined as 100xMAD/median, where median is the median of the variant allele frequencies (VAFs) of all somatic point mutations within a sample, and MAD is the median absolute deviation of the VAFs.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('VAF', 'Chemical', '-', (283, 286))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Disease', (55, 60))	('VAF', 'Chemical', '-', (181, 184))	('mutant-allele', 'Var', (41, 54))
487344	31138328	This assumption implies that tumor evolution is consistent with a "perfect and persistent phylogeny" such that each subclone has only one parental subclone and all mutations of the parental subclone.	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumor', 'Disease', (29, 34))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('mutations', 'Var', (164, 173))
487347	31138328	We obtain SCNA-related information, including tumor purity, ploidy, and allele-specific copy numbers per SPM through ASCAT.	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('copy numbers', 'Var', (88, 100))	('tumor', 'Disease', (46, 51))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
487356	31138328	The linear tree is characterized by Q3=(q31,q32,q33), whereas a branching tree is characterized by Q4=(q31,q33,q34).	('ran', 'Gene', '5901', (65, 68))	('q31', 'Var', (103, 106))	('ran', 'Gene', (65, 68))
487399	31138328	On average with 100 mutations, SMASH ran in less than 5 min for ITH inference.	('ran', 'Gene', (37, 40))	('ran', 'Gene', '5901', (37, 40))	('mutations', 'Var', (20, 29))
487405	31138328	Before running PyClone, PhyloWGS, and SMASH, we applied a set of filters to the SPM data by retaining the base substitution SPMs that are located along autosomes and have at least seven reads supporting the alternative allele.	('eta', 'Gene', (93, 96))	('SPMs', 'Gene', (124, 128))	('eta', 'Gene', '1909', (93, 96))	('base substitution', 'Var', (106, 123))
487407	31138328	The relative ordering of tumor types by mutation rate is consistent with the results reported in an earlier study.	('mutation', 'Var', (40, 48))	('tumor', 'Disease', (25, 30))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))
487419	31138328	TP53 mutations have average cellular prevalences near 1.0 for all cancer types except KIRC, which was the same observation made by Morris et al.. IDH1 mutations were subclonal in GBM and clonal in LGG and SKCM.	('IDH1', 'Gene', (146, 150))	('TP53', 'Gene', '7157', (0, 4))	('SKCM', 'Disease', (205, 209))	('TP53', 'Gene', (0, 4))	('IDH1', 'Gene', '3417', (146, 150))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('LGG', 'Disease', (197, 200))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('mutations', 'Var', (151, 160))	('cancer', 'Disease', (66, 72))
487441	31138328	Total mutation burden (TMB) was statistically significant for 7 cancer types: BLCA, COAD, GBM, LGG, LUAD, OV, and STAD (Additional file 1: Figure S17).	('COAD', 'Disease', (84, 88))	('LUAD', 'Disease', (100, 104))	('mutation burden', 'Var', (6, 21))	('significant', 'Reg', (46, 57))	('COAD', 'Disease', 'MESH:D029424', (84, 88))	('GBM', 'Disease', (90, 93))	('BLCA', 'Disease', (78, 82))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('STAD', 'Disease', (114, 118))	('LGG', 'Disease', (95, 98))	('TMB', 'Chemical', '-', (23, 26))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
487442	31138328	Significant associations between gene-level mutation status and OS include TP53 for BLCA, GBM, HNSC, LIHC, LUSC and STAD, TTN for GBM and LUSC, and MUC16 for SKCM (Additional file 1: Table S6-S19).	('mutation', 'Var', (44, 52))	('MUC16', 'Gene', (148, 153))	('TTN', 'Gene', (122, 125))	('TTN', 'Gene', '7273', (122, 125))	('MUC16', 'Gene', '94025', (148, 153))	('TP53', 'Gene', '7157', (75, 79))	('TP53', 'Gene', (75, 79))
487446	31138328	Other tumor type-specific covariates associated with OS include PAM50 for BRCA, tumor grade for KIRC, and IDH/CNV status for LGG (Additional file 1: Table S6-S19).	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('IDH', 'Gene', '3417', (106, 109))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumor', 'Disease', (80, 85))	('tumor', 'Disease', 'MESH:D009369', (6, 11))	('PAM50', 'Var', (64, 69))	('BRCA', 'Gene', '672', (74, 78))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('BRCA', 'Gene', (74, 78))	('IDH', 'Gene', (106, 109))	('tumor', 'Disease', (6, 11))
487462	31138328	In most cancer types, when TMB is included in the final model, it is negatively associated with hazard, and thus higher mutation burden leads to longer survival time (Additional file 1: Figure S18).	('survival time', 'MPA', (152, 165))	('cancer', 'Disease', (8, 14))	('mutation burden', 'Var', (120, 135))	('TMB', 'Chemical', '-', (27, 30))	('negatively', 'NegReg', (69, 79))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('longer', 'PosReg', (145, 151))	('hazard', 'MPA', (96, 102))	('cancer', 'Disease', 'MESH:D009369', (8, 14))
487469	31138328	In LUSC, we also observed interaction between entropy and TP53 mutation.	('TP53', 'Gene', (58, 62))	('TP53', 'Gene', '7157', (58, 62))	('mutation', 'Var', (63, 71))	('interaction', 'Interaction', (26, 37))
487470	31138328	When TP53 is mutated, higher entropy is associated with longer survival time for both OS and PFS (Additional file 1: Figure S20).	('higher', 'PosReg', (22, 28))	('entropy', 'MPA', (29, 36))	('survival time', 'CPA', (63, 76))	('longer', 'PosReg', (56, 62))	('TP53', 'Gene', '7157', (5, 9))	('TP53', 'Gene', (5, 9))	('mutated', 'Var', (13, 20))
487474	31138328	ASCAT Allele-specific copy number analysis of tumors ITH Intra-tumor heterogeneity MATH Mutant-allele tumor heterogeneity SCNA Somatic copy number alterations SMASH Subclone multiplicity allocation and somatic heterogeneity SPMs Somatic point mutations TCGA The Cancer Genome Atlas TMB Tumor mutation burden VAF Variant allele frequencies WS and DYL conceived the study.	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('Tumor', 'Phenotype', 'HP:0002664', (286, 291))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (262, 281))	('VAF', 'Chemical', '-', (308, 311))	('TMB', 'Chemical', '-', (282, 285))	('tumors', 'Disease', (46, 52))	('Cancer Genome Atlas', 'Disease', (262, 281))	('tumor', 'Disease', (63, 68))	('WS', 'Disease', 'MESH:D018980', (339, 341))	('tumor', 'Disease', (46, 51))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('Cancer', 'Phenotype', 'HP:0002664', (262, 268))	('Variant', 'Var', (312, 319))	('tumor', 'Disease', (102, 107))	('tumor', 'Disease', 'MESH:D009369', (46, 51))	('tumors', 'Disease', 'MESH:D009369', (46, 52))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
487485	31011293	Overexpression of OTUD4 increases radiosensitivity of NSCLC cells exhibiting as impaired clonogenic formation ability, enhanced cell cycle arrest and increased cell apoptosis.	('increases', 'PosReg', (24, 33))	('arrest', 'Disease', 'MESH:D006323', (139, 145))	('cell apoptosis', 'CPA', (160, 174))	('radiosensitivity', 'MPA', (34, 50))	('impaired', 'NegReg', (80, 88))	('NSCLC', 'Phenotype', 'HP:0030358', (54, 59))	('increases radiosensitivity', 'Phenotype', 'HP:0010997', (24, 50))	('OTUD4', 'Gene', '54726', (18, 23))	('clonogenic formation ability', 'CPA', (89, 117))	('NSCLC', 'Disease', (54, 59))	('arrest', 'Disease', (139, 145))	('Overexpression', 'Var', (0, 14))	('increased', 'PosReg', (150, 159))	('OTUD4', 'Gene', (18, 23))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (128, 145))	('enhanced', 'PosReg', (119, 127))	('NSCLC', 'Disease', 'MESH:D002289', (54, 59))
487502	31011293	Moreover, knockdown of OTUD4 significantly increased the sensitivity of PC-3 and H23 tumor cells to methyl methanesulfonate, an alkylating agent which leads to DNA alkylation damage.	('tumor', 'Disease', (85, 90))	('knockdown', 'Var', (10, 19))	('OTUD4', 'Gene', '54726', (23, 28))	('methyl methanesulfonate', 'Chemical', 'MESH:D008741', (100, 123))	('H23', 'CellLine', 'CVCL:1547', (81, 84))	('OTUD4', 'Gene', (23, 28))	('PC-3', 'Gene', '3853', (72, 76))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('increased', 'PosReg', (43, 52))	('sensitivity', 'MPA', (57, 68))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('PC-3', 'Gene', (72, 76))
487523	31011293	The following antibodies were used: OTUD4 (#ABN477) was form Millipore; gamma-H2AX (#9718), p-CHK2 (#2661), p53 (#2524), p21 (#2947), p-ATM (#5883) and Caspase-3 (#9662) were form Cell Signaling Technology; ATM (A1106) and alpha-tubulin (T9026) were from Sigma-Aldrich; CHK2 (sc-17747) and GAPDH (sc-365062) were from Santa Cruz Biotechnology.	('#2661', 'Var', (100, 105))	('OTUD4', 'Gene', '54726', (36, 41))	('CHK2', 'Gene', '11200', (94, 98))	('Caspase-3', 'Gene', (152, 161))	('p21', 'Gene', (121, 124))	('T9026', 'Var', (238, 243))	('p21', 'Gene', '644914', (121, 124))	('ATM', 'Gene', (207, 210))	('GAPDH', 'Gene', (290, 295))	('CHK2', 'Gene', (270, 274))	('alpha-tubulin', 'Gene', (223, 236))	('T9026', 'CellLine', 'CVCL:3174', (238, 243))	('ATM', 'Gene', (136, 139))	('gamma-H2AX', 'Gene', (72, 82))	('gamma-H2AX', 'Gene', '3014', (72, 82))	('p53', 'Gene', '7157', (108, 111))	('CHK2', 'Gene', '11200', (270, 274))	('Caspase-3', 'Gene', '836', (152, 161))	('CHK2', 'Gene', (94, 98))	('p53', 'Gene', (108, 111))	('ATM', 'Gene', '472', (207, 210))	('alpha-tubulin', 'Gene', '10376', (223, 236))	('OTUD4', 'Gene', (36, 41))	('GAPDH', 'Gene', '2597', (290, 295))	('ATM', 'Gene', '472', (136, 139))
487551	31011293	2a), which suggested that promoter methylation might repressed OTUD4 expression.	('promoter methylation', 'Var', (26, 46))	('expression', 'MPA', (69, 79))	('repressed', 'NegReg', (53, 62))	('OTUD4', 'Gene', '54726', (63, 68))	('OTUD4', 'Gene', (63, 68))
487568	31011293	What's more, increased expression of phosphorylated H2AX, ATM and CHK2 were noticed in OTUD4 overexpressed cells (Fig.	('CHK2', 'Gene', '11200', (66, 70))	('ATM', 'Gene', '472', (58, 61))	('H2AX', 'Gene', (52, 56))	('expression', 'MPA', (23, 33))	('H2AX', 'Gene', '3014', (52, 56))	('ATM', 'Gene', (58, 61))	('CHK2', 'Gene', (66, 70))	('OTUD4', 'Gene', '54726', (87, 92))	('increased', 'PosReg', (13, 22))	('phosphorylated', 'Var', (37, 51))	('OTUD4', 'Gene', (87, 92))
487572	31011293	Comet assay showed that A549 and H460 cells with OTUD4 overexpressed had significantly higher residual DNA damage relative to control cells (Fig.	('OTUD4', 'Gene', (49, 54))	('A549', 'CellLine', 'CVCL:0023', (24, 28))	('overexpressed', 'Var', (55, 68))	('Comet', 'Species', '302767', (0, 5))	('OTUD4', 'Gene', '54726', (49, 54))	('H460', 'CellLine', 'CVCL:0459', (33, 37))	('higher', 'PosReg', (87, 93))
487581	31011293	As shown, overexpression of OTUD4 resulted in a significant reduction of the percentage of GFP-positive cells in the DR-GFP U2OS but not that in the EJ5-U2OS reporter cells (Fig.	('EJ5-U2OS', 'CellLine', 'CVCL:0042', (149, 157))	('U2OS', 'CellLine', 'CVCL:0042', (124, 128))	('reduction', 'NegReg', (60, 69))	('U2OS', 'Var', (124, 128))	('U2OS', 'CellLine', 'CVCL:0042', (153, 157))	('OTUD4', 'Gene', '54726', (28, 33))	('OTUD4', 'Gene', (28, 33))
487584	31011293	A previous study reported that OTUD4 homozygous mutation was found in patients with ataxia and hypogonadotropic hypogonadism.	('patients', 'Species', '9606', (70, 78))	('hypogonadotropic hypogonadism', 'Disease', 'MESH:D007006', (95, 124))	('homozygous mutation', 'Var', (37, 56))	('OTUD4', 'Gene', (31, 36))	('hypogonadotropic hypogonadism', 'Disease', (95, 124))	('hypogonadotropic hypogonadism', 'Phenotype', 'HP:0000044', (95, 124))	('hypogonadism', 'Phenotype', 'HP:0000135', (112, 124))	('found', 'Reg', (61, 66))	('ataxia', 'Phenotype', 'HP:0001251', (84, 90))	('ataxia', 'Disease', 'MESH:D001259', (84, 90))	('OTUD4', 'Gene', '54726', (31, 36))	('ataxia', 'Disease', (84, 90))
487586	31011293	Up to date, this is the only report about deregulated OTUD4 in a pathological condition.	('OTUD4', 'Gene', '54726', (54, 59))	('deregulated', 'Var', (42, 53))	('OTUD4', 'Gene', (54, 59))
487587	31011293	Here, we report for the first time that deregulated OTUD4 associate with NSCLC.	('deregulated', 'Var', (40, 51))	('OTUD4', 'Gene', (52, 57))	('NSCLC', 'Disease', (73, 78))	('OTUD4', 'Gene', '54726', (52, 57))	('NSCLC', 'Disease', 'MESH:D002289', (73, 78))	('NSCLC', 'Phenotype', 'HP:0030358', (73, 78))	('associate', 'Reg', (58, 67))
487602	31011293	According to a previous report, knockdown of OTUD4 increased the ubiquitination of XPC, which suggests the deubiquitinase activity of OTUD4 might be essential for NER.	('XPC', 'Gene', (83, 86))	('OTUD4', 'Gene', (45, 50))	('OTUD4', 'Gene', '54726', (134, 139))	('increased', 'PosReg', (51, 60))	('XPC', 'Gene', '7508', (83, 86))	('knockdown', 'Var', (32, 41))	('OTUD4', 'Gene', (134, 139))	('OTUD4', 'Gene', '54726', (45, 50))
487612	31011293	In conclusion, our data suggested that OTUD4 was downregulated in tissues and cells of NSCLC resulted from promoter hypermethylation.	('promoter hypermethylation', 'Var', (107, 132))	('NSCLC', 'Disease', (87, 92))	('OTUD4', 'Gene', (39, 44))	('NSCLC', 'Disease', 'MESH:D002289', (87, 92))	('downregulated', 'NegReg', (49, 62))	('NSCLC', 'Phenotype', 'HP:0030358', (87, 92))	('OTUD4', 'Gene', '54726', (39, 44))
487643	31437624	TARGET datasets include large-scale genomic data including gene-expression, copy number variation, epigenetics, along with annotated clinical information for a selected set of pediatric cancers (https://ocg.cancer.gov/programs/target/data-matrix).	('cancer', 'Disease', 'MESH:D009369', (207, 213))	('cancers', 'Disease', 'MESH:D009369', (186, 193))	('cancers', 'Phenotype', 'HP:0002664', (186, 193))	('cancer', 'Disease', (207, 213))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('cancers', 'Disease', (186, 193))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('copy number variation', 'Var', (76, 97))	('cancer', 'Disease', (186, 192))	('cancer', 'Disease', 'MESH:D009369', (186, 192))
487674	31437624	Using 39 pedigrees, researchers were able to determine that the most common cause of LFS is inherited mutations in the tumor suppressor gene TP53.	('tumor', 'Disease', (119, 124))	('TP53', 'Gene', '7157', (141, 145))	('LFS', 'Disease', 'MESH:D016864', (85, 88))	('TP53', 'Gene', (141, 145))	('mutations', 'Var', (102, 111))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('cause', 'Reg', (76, 81))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('LFS', 'Disease', (85, 88))
487694	31437624	analyzed the mutation landscape of 12 major cancer types and found that TP53 and PIK3CA were the most commonly mutated genes, ARID1A were frequently mutated in bladder urothelial carcinoma (BLCA), uterine corpus endometrial carcinoma (UCEC), lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC), and EGFR were frequently mutated in GBM and LUAD.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (278, 301))	('mutated', 'Var', (149, 156))	('PIK3CA', 'Gene', '5290', (81, 87))	('lung adenocarcinoma', 'Disease', (242, 261))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (212, 233))	('bladder urothelial carcinoma', 'Disease', (160, 188))	('LUAD', 'Phenotype', 'HP:0030078', (263, 267))	('EGFR', 'Gene', (314, 318))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (212, 233))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (273, 301))	('TP53', 'Gene', '7157', (72, 76))	('lung squamous cell carcinoma', 'Disease', (273, 301))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (160, 188))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('GBM', 'Phenotype', 'HP:0012174', (346, 349))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (242, 261))	('carcinoma', 'Phenotype', 'HP:0030731', (292, 301))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (242, 261))	('PIK3CA', 'Gene', (81, 87))	('LUAD', 'Phenotype', 'HP:0030078', (354, 358))	('ARID1A', 'Gene', (126, 132))	('carcinoma', 'Phenotype', 'HP:0030731', (252, 261))	('EGFR', 'Gene', '1956', (314, 318))	('carcinoma', 'Phenotype', 'HP:0030731', (179, 188))	('ARID1A', 'Gene', '8289', (126, 132))	('endometrial carcinoma', 'Disease', (212, 233))	('cancer', 'Disease', (44, 50))	('USC', 'Phenotype', 'HP:0002891', (304, 307))	('TP53', 'Gene', (72, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (224, 233))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
487695	31437624	In contrast, VHL and PBRM1 mutations were exclusive to kidney renal clear cell carcinoma (KIRC), and NPM1 and FLT3 mutations were exclusive to AML.	('mutations', 'Var', (27, 36))	('FLT3', 'Gene', (110, 114))	('NPM1', 'Gene', '4869', (101, 105))	('kidney renal clear cell carcinoma', 'Disease', (55, 88))	('kidney renal clear cell carcinoma', 'Disease', 'MESH:C538614', (55, 88))	('FLT3', 'Gene', '2322', (110, 114))	('PBRM1', 'Gene', (21, 26))	('VHL', 'Gene', (13, 16))	('PBRM1', 'Gene', '55193', (21, 26))	('AML', 'Disease', 'MESH:D015470', (143, 146))	('VHL', 'Gene', '7428', (13, 16))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('AML', 'Disease', (143, 146))	('NPM1', 'Gene', (101, 105))	('AML', 'Phenotype', 'HP:0004808', (143, 146))
487696	31437624	Numerous pan-cancer analyses have been performed, including pan-cancer analyses of copy number alteration, enhancer expression, oncogenic signaling pathways, and transcriptional metabolic dysregulation.	('copy number alteration', 'Var', (83, 105))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('enhancer', 'PosReg', (107, 115))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('cancer', 'Disease', (13, 19))	('cancer', 'Disease', 'MESH:D009369', (13, 19))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
487706	31437624	To illustrate the integrative clustering analysis, we analyzed 241 sarcoma tumor samples from the TCGA SARC study that had somatic mutation, copy number, methylation and mRNA expression data using the recently developed iClusterBayes software.	('sarcoma tumor', 'Disease', 'MESH:D012509', (67, 80))	('sarcoma tumor', 'Disease', (67, 80))	('sarcoma', 'Phenotype', 'HP:0100242', (67, 74))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('copy', 'Var', (141, 145))	('SARC', 'Phenotype', 'HP:0100242', (103, 107))	('mRNA expression', 'MPA', (170, 185))
487721	26468007	Patients in the cisplatin arm were more likely to experience neutropenia and thrombocytopenia, whereas patients in the paclitaxel arm had a higher frequency of neuropathy and alopecia.	('neuropathy', 'Phenotype', 'HP:0009830', (160, 170))	('alopecia', 'Phenotype', 'HP:0001596', (175, 183))	('neutropenia', 'Phenotype', 'HP:0001875', (61, 72))	('thrombocytopenia', 'Disease', (77, 93))	('neuropathy and alopecia', 'Disease', 'MESH:D000505', (160, 183))	('cisplatin', 'Var', (16, 25))	('Patients', 'Species', '9606', (0, 8))	('neutropenia', 'Disease', (61, 72))	('thrombocytopenia', 'Disease', 'MESH:D013921', (77, 93))	('thrombocytopenia', 'Phenotype', 'HP:0001873', (77, 93))	('cisplatin', 'Chemical', 'MESH:D002945', (16, 25))	('patients', 'Species', '9606', (103, 111))	('paclitaxel', 'Chemical', 'MESH:D017239', (119, 129))	('neutropenia', 'Disease', 'MESH:D009503', (61, 72))
487738	26468007	Patients were required to have at least one measurable metastatic lesion as defined by the Response Criteria in Solid Tumors (RECIST) v1.0, an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, a life expectancy of at least 3 months, and adequate hematologic (neutrophil count >= 1500/mm3, platelet count >= 100,000/mm3, hemoglobin >= 9.0 g/dl), renal (serum creatinine <= 1.5 mg/dl or creatinine clearance >= 50 ml/min) and liver function (bilirubin <= 1.5 mg/dl, AST/ALT <= 3 times the upper normal limit).	('Tumors', 'Phenotype', 'HP:0002664', (118, 124))	('AST', 'Gene', '26503', (483, 486))	('>= 1500/mm3', 'Var', (295, 306))	('Patients', 'Species', '9606', (0, 8))	('AST', 'Gene', (483, 486))	('liver function', 'CPA', (443, 457))	('Oncology', 'Phenotype', 'HP:0002664', (163, 171))
487832	27713130	Numerous genetic lesions are involved in cancer development, together with abnormalities in DNA methylation, histone modification, promoter accessibility and other genome-wide rewirings, which result in expression deregulation of many genes.	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('histone', 'Protein', (109, 116))	('abnormalities', 'Var', (75, 88))	('expression deregulation', 'MPA', (203, 226))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('involved', 'Reg', (29, 37))
487872	27713130	Genome instability is recognized as one of the hallmarks of cancer and multiple levels of gene regulations are dysfunctional due to genetic and epigenetic changes, which may increase the intrinsic noise of gene expression in cancers.	('intrinsic noise', 'MPA', (187, 202))	('cancers', 'Disease', 'MESH:D009369', (225, 232))	('cancer', 'Disease', 'MESH:D009369', (225, 231))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('epigenetic changes', 'Var', (144, 162))	('cancer', 'Disease', (225, 231))	('cancers', 'Disease', (225, 232))	('cancer', 'Disease', (60, 66))	('increase', 'PosReg', (174, 182))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('cancers', 'Phenotype', 'HP:0002664', (225, 232))
487905	25013473	To the best of our knowledge, this is the first study concerning the coexistence of BRAF and KRAS mutations in LSCC.	('KRAS', 'Gene', (93, 97))	('BRAF', 'Gene', '673', (84, 88))	('BRAF', 'Gene', (84, 88))	('KRAS', 'Gene', '3845', (93, 97))	('mutations', 'Var', (98, 107))	('LSCC', 'Phenotype', 'HP:0030359', (111, 115))
487911	25013473	Mutations in KRAS and BRAF are present at the low frequencies of 6 and 2%, respectively, in LSCC, mostly occurring in current or former smokers.	('LSCC', 'Disease', (92, 96))	('LSCC', 'Phenotype', 'HP:0030359', (92, 96))	('BRAF', 'Gene', '673', (22, 26))	('occurring', 'Reg', (105, 114))	('BRAF', 'Gene', (22, 26))	('Mutations', 'Var', (0, 9))	('KRAS', 'Gene', (13, 17))	('KRAS', 'Gene', '3845', (13, 17))
487913	25013473	The present study describes the case of a treatment-naive LSCC patient with coexisting BRAF V600E and oncogenic KRAS G12A mutations in the primary lung lesion and the peritoneum metastases, and with prominent manifestations of peritoneal carcinomatosis and an eosinophilic leukemoid reaction.	('metastases', 'Disease', 'MESH:D009362', (178, 188))	('eosinophilic leukemoid reaction', 'Disease', 'MESH:D007955', (260, 291))	('BRAF', 'Gene', '673', (87, 91))	('V600E', 'Mutation', 'rs113488022', (92, 97))	('peritoneal carcinomatosis', 'Disease', 'MESH:D010534', (227, 252))	('primary lung lesion', 'Disease', (139, 158))	('G12A', 'Mutation', 'rs121913529', (117, 121))	('primary lung lesion', 'Disease', 'MESH:D008171', (139, 158))	('carcinoma', 'Phenotype', 'HP:0030731', (238, 247))	('metastases', 'Disease', (178, 188))	('mutations', 'Var', (122, 131))	('KRAS', 'Gene', (112, 116))	('patient', 'Species', '9606', (63, 70))	('LSCC', 'Phenotype', 'HP:0030359', (58, 62))	('eosinophilic leukemoid reaction', 'Disease', (260, 291))	('KRAS', 'Gene', '3845', (112, 116))	('peritoneal carcinomatosis', 'Disease', (227, 252))	('BRAF', 'Gene', (87, 91))
487924	25013473	Additionally, more excessive phosphorylation of ERK protein compared with total ERK was observed in the aspiration samples than in primary lung lesions from LSCC with a single BRAF V600E or KRAS G12A mutation, when analyzed by immunohistochemistry and western blot analysis (Figs.	('ERK', 'Gene', (48, 51))	('phosphorylation', 'MPA', (29, 44))	('ERK', 'Gene', '5594', (80, 83))	('G12A', 'Mutation', 'rs121913529', (195, 199))	('aspiration', 'Phenotype', 'HP:0002835', (104, 114))	('primary lung lesion', 'Disease', (131, 150))	('KRAS', 'Gene', (190, 194))	('ERK', 'Gene', (80, 83))	('excessive', 'PosReg', (19, 28))	('KRAS', 'Gene', '3845', (190, 194))	('LSCC', 'Phenotype', 'HP:0030359', (157, 161))	('primary lung lesion', 'Disease', 'MESH:D008171', (131, 150))	('V600E', 'Mutation', 'rs113488022', (181, 186))	('BRAF', 'Gene', '673', (176, 180))	('ERK', 'Gene', '5594', (48, 51))	('V600E', 'Var', (181, 186))	('BRAF', 'Gene', (176, 180))
487927	25013473	The present study reports a noteworthy case of peritoneal carcinomatosis from LSCC, with coexisting BRAF V600E and oncogenic KRAS G12A mutations in the primary lung lesion and peritoneal metastases.	('LSCC', 'Gene', (78, 82))	('KRAS', 'Gene', (125, 129))	('metastases', 'Disease', (187, 197))	('V600E', 'Mutation', 'rs113488022', (105, 110))	('KRAS', 'Gene', '3845', (125, 129))	('mutations', 'Var', (135, 144))	('LSCC', 'Phenotype', 'HP:0030359', (78, 82))	('metastases', 'Disease', 'MESH:D009362', (187, 197))	('BRAF', 'Gene', '673', (100, 104))	('primary lung lesion', 'Disease', (152, 171))	('peritoneal carcinomatosis', 'Disease', (47, 72))	('primary lung lesion', 'Disease', 'MESH:D008171', (152, 171))	('BRAF', 'Gene', (100, 104))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))	('peritoneal carcinomatosis', 'Disease', 'MESH:D010534', (47, 72))	('G12A', 'Mutation', 'rs121913529', (130, 134))
487932	25013473	The patient of the present study primarily presented with combined somatic BRAF and KRAS mutations with an aggressive clinical history, unusual disease burden and poor prognosis.	('BRAF', 'Gene', '673', (75, 79))	('patient', 'Species', '9606', (4, 11))	('KRAS', 'Gene', (84, 88))	('BRAF', 'Gene', (75, 79))	('KRAS', 'Gene', '3845', (84, 88))	('mutations', 'Var', (89, 98))	('presented with', 'Reg', (43, 57))
487933	25013473	In animal experiments, oncogenic KRAS and activated BRAF mutations cooperate to accelerate the rapid onset of cancer.	('cancer', 'Disease', (110, 116))	('KRAS', 'Gene', (33, 37))	('rapid onset of', 'CPA', (95, 109))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('KRAS', 'Gene', '3845', (33, 37))	('accelerate', 'PosReg', (80, 90))	('mutations', 'Var', (57, 66))	('BRAF', 'Gene', '673', (52, 56))	('BRAF', 'Gene', (52, 56))	('cancer', 'Disease', 'MESH:D009369', (110, 116))
487937	25013473	The results showed that pERK expression, compared with total ERK, was strongly positive, and that it was more intense than the level in primary lung lesions from LSCC with a single BRAF V600E or KRAS G12A mutation.	('V600E', 'Mutation', 'rs113488022', (186, 191))	('pERK', 'Gene', (24, 28))	('ERK', 'Gene', (25, 28))	('intense', 'PosReg', (110, 117))	('primary lung lesion', 'Disease', (136, 155))	('pERK', 'Gene', '9451', (24, 28))	('primary lung lesion', 'Disease', 'MESH:D008171', (136, 155))	('V600E', 'Var', (186, 191))	('BRAF', 'Gene', (181, 185))	('ERK', 'Gene', '5594', (25, 28))	('G12A', 'Mutation', 'rs121913529', (200, 204))	('BRAF', 'Gene', '673', (181, 185))	('ERK', 'Gene', '5594', (61, 64))	('LSCC', 'Phenotype', 'HP:0030359', (162, 166))	('ERK', 'Gene', (61, 64))	('expression', 'MPA', (29, 39))	('KRAS', 'Gene', (195, 199))	('KRAS', 'Gene', '3845', (195, 199))
487938	25013473	BRAF V600E is activated 500-fold more than the wild-type BRAF and directly phosphorylates the ERK signaling protein in cells, which plays a dominant role in promoting angiogenesis during tumor development.	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('ERK', 'Gene', (94, 97))	('V600E', 'Mutation', 'rs113488022', (5, 10))	('BRAF', 'Gene', '673', (57, 61))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('BRAF', 'Gene', (57, 61))	('angiogenesis', 'CPA', (167, 179))	('V600E', 'Var', (5, 10))	('tumor', 'Disease', (187, 192))	('BRAF', 'Gene', '673', (0, 4))	('BRAF', 'Gene', (0, 4))	('promoting', 'PosReg', (157, 166))	('ERK', 'Gene', '5594', (94, 97))
487940	25013473	Furthermore, BRAF V600E binds, transphosphorylates and hyperactivates CRAF in the presence of oncogenic KRAS to augment MEK/ERK signaling activation.	('V600E', 'Var', (18, 23))	('augment', 'PosReg', (112, 119))	('MEK', 'Gene', (120, 123))	('ERK', 'Gene', (124, 127))	('KRAS', 'Gene', '3845', (104, 108))	('BRAF', 'Gene', '673', (13, 17))	('MEK', 'Gene', '5609', (120, 123))	('BRAF', 'Gene', (13, 17))	('CRAF', 'Gene', (70, 74))	('CRAF', 'Gene', '5894', (70, 74))	('hyperactivates', 'PosReg', (55, 69))	('V600E', 'Mutation', 'rs113488022', (18, 23))	('ERK', 'Gene', '5594', (124, 127))	('KRAS', 'Gene', (104, 108))	('binds', 'Interaction', (24, 29))
487945	25013473	The occurrence of carcinoma is a multistep procedure and the result of an accumulation of gene mutations or abnormal expression.	('carcinoma', 'Disease', 'MESH:D002277', (18, 27))	('carcinoma', 'Phenotype', 'HP:0030731', (18, 27))	('carcinoma', 'Disease', (18, 27))	('expression', 'MPA', (117, 127))	('gene mutations', 'Var', (90, 104))	('abnormal', 'Reg', (108, 116))	('accumulation', 'PosReg', (74, 86))
487953	25013473	Recently, certain studies have confirmed that single target inhibitors in a double BRAF-V600E and oncogenic RAS mutation accelerate tumor progression.	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('mutation', 'Var', (112, 120))	('V600E', 'Mutation', 'rs113488022', (88, 93))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('accelerate', 'PosReg', (121, 131))	('tumor', 'Disease', (132, 137))	('BRAF', 'Gene', '673', (83, 87))	('BRAF', 'Gene', (83, 87))
487957	31262303	Bioinformatics workflows for analyzing genomic data obtained from human tumors engrafted in a mouse host (i.e., Patient-Derived Xenografts; PDXs) must address challenges such as discriminating between mouse and human sequence reads and accurately identifying somatic mutations and copy number alterations when paired non-tumor DNA from the patient is not available for comparison.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('copy number alterations', 'Var', (281, 304))	('tumor', 'Disease', (72, 77))	('tumor', 'Disease', 'MESH:D009369', (321, 326))	('patient', 'Species', '9606', (340, 347))	('human', 'Species', '9606', (66, 71))	('tumors', 'Disease', (72, 78))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('mouse', 'Species', '10090', (94, 99))	('Patient', 'Species', '9606', (112, 119))	('human', 'Species', '9606', (211, 216))	('tumor', 'Phenotype', 'HP:0002664', (321, 326))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('tumor', 'Disease', (321, 326))	('mouse', 'Species', '10090', (201, 206))	('tumor', 'Disease', 'MESH:D009369', (72, 77))
487985	31262303	Because low sequence coverage leads to poor sensitivity in variant calling, samples with less than 75% of the target region covered at least at >=100X by human reads were excluded from further analysis.	('sensitivity', 'MPA', (44, 55))	('human', 'Species', '9606', (154, 159))	('variant', 'Var', (59, 66))
487988	31262303	In addition, we verified that these default thresholds were able to detect all the known mutations in the CTP samples.	('CTP', 'Chemical', '-', (106, 109))	('mutations', 'Var', (89, 98))	('detect', 'Reg', (68, 74))
487990	31262303	We further annotated each variant with 1) known or predicted gain or loss of protein function, 2) potential treatment approach for any cancer type and 3) drug sensitivity and resistance effects in clinical or preclinical studies, based on curated clinical information from the JAX clinical knowledge base (CKB, https://ckbhome.jax.org/) via direct integration of our internal database of PDX data with the JAX CKB database.	('cancer', 'Disease', (135, 141))	('loss', 'NegReg', (69, 73))	('variant', 'Var', (26, 33))	('CKB', 'Chemical', '-', (306, 309))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('protein', 'Protein', (77, 84))	('CKB', 'Chemical', '-', (410, 413))	('drug sensitivity', 'Phenotype', 'HP:0020174', (154, 170))	('cancer', 'Disease', 'MESH:D009369', (135, 141))	('gain', 'PosReg', (61, 65))
487993	31262303	Since normal samples from patients whose tumors were used to generate the PDX models were unavailable in most cases, we generated a dataset of putative human germline variants using data from several public resources: (i) dbSNP, (ii) 1000 Genomes Project, (iii) ExAC database with MAF >=1%, and (iv) a compendium of variants from 20 normal human blood samples available in JAX (Additional file 1: Text S1) that were prepped and sequenced on the CTP panel using the same protocol as the PDX samples, with a frequency of 2/20 in normal samples or 1/20 in normal samples and 2/20 in PDX models.	('CTP', 'Chemical', '-', (445, 448))	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('human', 'Species', '9606', (340, 345))	('variants', 'Var', (167, 175))	('MAF', 'Gene', '4094', (281, 284))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('MAF', 'Gene', (281, 284))	('variants', 'Var', (316, 324))	('tumors', 'Disease', (41, 47))	('tumors', 'Disease', 'MESH:D009369', (41, 47))	('patients', 'Species', '9606', (26, 34))	('human', 'Species', '9606', (152, 157))
487994	31262303	The variants identified via GATK and Pindel in the PDX model tumors were annotated as germline and filtered out of the model's somatic mutation calls if they were present in our aggregated dataset of putative germline variants and had allele frequencies between 40 to 60% or more than 90%.	('tumors', 'Disease', (61, 67))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('variants', 'Var', (4, 12))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))
487996	31262303	An exception to the germline and false positives exclusion process was made for variants from GATK that were annotated as clinically relevant in JAX CKB.	('CKB', 'Chemical', '-', (149, 152))	('JAX CKB', 'Disease', (145, 152))	('GATK', 'Gene', (94, 98))	('variants', 'Var', (80, 88))
487997	31262303	We rescued any filtered variants that were curated into the proprietary JAX-Clinical Knowledgebase (CKB, https://ckbhome.jax.org/) with 1) known or predicted gain or loss of protein function, 2) potential treatment approach for any cancer type and 3) drug sensitivity and resistance effects in clinical or preclinical studies.	('cancer', 'Disease', 'MESH:D009369', (232, 238))	('gain', 'PosReg', (158, 162))	('variants', 'Var', (24, 32))	('cancer', 'Disease', (232, 238))	('loss', 'NegReg', (166, 170))	('CKB', 'Chemical', '-', (100, 103))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('drug sensitivity', 'Phenotype', 'HP:0020174', (251, 267))	('protein', 'Protein', (174, 181))
487999	31262303	The datasets included 1) varying sequencing coverage, 2) spiked-in mutations representative of the different tumor types, and 3) different proportions of spiked-in mouse sequence contamination (Additional file 2: Table S1).	('mouse', 'Species', '10090', (164, 169))	('spiked-in', 'Reg', (57, 66))	('mutations', 'Var', (67, 76))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumor', 'Disease', (109, 114))
488023	31262303	We compiled a list of genes with focal copy number alterations that were significantly amplified (n = 273) or deleted (n = 820) in the 8 tumor types (Additional file 1: Fig.	('amplified', 'PosReg', (87, 96))	('tumor', 'Disease', (137, 142))	('deleted', 'Var', (110, 117))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('copy number alterations', 'Var', (39, 62))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
488039	31262303	A graphical overview of the workflow for calling somatic mutations and indels in PDX tumors is provided in Fig.	('indels', 'Var', (71, 77))	('PDX tumors', 'Disease', 'MESH:D009369', (81, 91))	('PDX tumors', 'Disease', (81, 91))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))
488047	31262303	Based on range of allele frequencies identified in sequences of normal human blood samples (Additional file 1: Text S1), the variants in each PDX tumor with an allele frequency of 40-60% or > 90%, and present in either public germline databases or our list of putative germline variants (Additional file 1: Table S3), were filtered out as germline variants.	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('tumor', 'Disease', (146, 151))	('variants', 'Var', (125, 133))	('human', 'Species', '9606', (71, 76))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
488048	31262303	Figure 3b shows that the germline filters reduced the estimated somatic mutational load in the PDX tumors (Additional file 1: Table S5) by about four-fold (Additional file 1: Table S4).	('somatic mutational load', 'MPA', (64, 87))	('reduced', 'NegReg', (42, 49))	('PDX tumors', 'Disease', 'MESH:D009369', (95, 105))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('PDX tumors', 'Disease', (95, 105))	('germline filters', 'Var', (25, 41))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))
488050	31262303	To detect these putative FPs, we filtered out the variants at loci that were recurrently mutated in >=25% (see Methods) of PDX tumors (Fig.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('PDX tumors', 'Disease', 'MESH:D009369', (123, 133))	('variants', 'Var', (50, 58))	('PDX tumors', 'Disease', (123, 133))
488051	31262303	The distribution of tumor types for each of these recurrently mutated positions (n = 52) was highly similar to the overall distribution of tumor types in the PDX resource with Pearson correlation coefficient > 0.9 (Additional file 1: Figure S2).	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('tumor', 'Disease', (20, 25))	('mutated', 'Var', (62, 69))
488052	31262303	This implies that these mutations were systematic errors and were not explicitly selected for in any tumor type, and thus, likely do not contribute to tumor biology or treatment response.	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('tumor', 'Disease', (151, 156))	('tumor', 'Disease', 'MESH:D009369', (151, 156))	('contribute', 'Reg', (137, 147))	('mutations', 'Var', (24, 33))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
488053	31262303	While there was a negligible reduction in the overall mutational load after filtering highly recurrent variants, the filtering impact was notable for several known cancer-related genes (e.g., ERBB4 and MUC16) (Fig.	('ERBB4', 'Gene', '2066', (192, 197))	('mutational load', 'MPA', (54, 69))	('MUC16', 'Gene', (202, 207))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('reduction', 'NegReg', (29, 38))	('MUC16', 'Gene', '94025', (202, 207))	('variants', 'Var', (103, 111))	('cancer', 'Disease', (164, 170))	('ERBB4', 'Gene', (192, 197))	('cancer', 'Disease', 'MESH:D009369', (164, 170))
488056	31262303	Almost all were initially filtered as germline events, as many well-known actionable cancer mutations (e.g., BRAF V600E and KRAS G12C) are present in the dbSNP database and occurred at frequencies that fell within our exclusion criteria.	('G12C', 'Mutation', 'c.12G>C', (129, 133))	('KRAS G12C', 'Var', (124, 133))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('V600E', 'Mutation', 'p.V600E', (114, 119))	('cancer', 'Disease', (85, 91))	('AF', 'Disease', 'MESH:D001281', (111, 113))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
488059	31262303	Although the estimated allele frequencies were lower than the true allele frequencies, this difference was marginal and could be attributed to the reads carrying the variants being classified as non-human reads by Xenome, or not mapped to the genome.	('Xenome', 'Chemical', '-', (214, 220))	('lower', 'NegReg', (47, 52))	('variants', 'Var', (166, 174))	('human', 'Species', '9606', (199, 204))
488060	31262303	Moreover, all (20 out of 20) clinically relevant mutations experimentally validated or clinically reported in the corresponding patient tumors were detected in the PDX tumors (Fig.	('tumors', 'Disease', (136, 142))	('tumors', 'Disease', 'MESH:D009369', (136, 142))	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('PDX tumors', 'Disease', (164, 174))	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('mutations', 'Var', (49, 58))	('tumors', 'Disease', (168, 174))	('tumors', 'Disease', 'MESH:D009369', (168, 174))	('detected', 'Reg', (148, 156))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('PDX tumors', 'Disease', 'MESH:D009369', (164, 174))	('patient', 'Species', '9606', (128, 135))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
488067	31262303	A graphical overview of the workflow for calling copy number alterations in PDX tumors is provided in Fig.	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('PDX tumors', 'Disease', (76, 86))	('copy number alterations', 'Var', (49, 72))	('PDX tumors', 'Disease', 'MESH:D009369', (76, 86))
488075	31262303	When the overall cancer genome ploidy was used as the baseline, we observed that a larger proportion of the significantly amplified and deleted genes were called as copy number gains and losses among the PDX samples respectively (Additional file 1: Figure S9).	('losses', 'NegReg', (187, 193))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('gains', 'PosReg', (177, 182))	('copy number', 'Var', (165, 176))	('cancer', 'Disease', (17, 23))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
488076	31262303	While the average ploidy might not be estimated consistently across the tumor samples for the same model, the copy number changes relative to overall cancer genome ploidy remained consistent (Fig.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Disease', (72, 77))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('cancer', 'Disease', (150, 156))	('copy', 'Var', (110, 114))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
488077	31262303	We observed that the estimated copy number gains and losses of known oncogenes (n = 23) and tumor suppressor genes (n = 40), relative to the average ploidy per PDX sample, generally results in expression changes in the same direction as the copy number change (Additional file 1: Table S8).	('oncogenes', 'Gene', (69, 78))	('changes', 'Reg', (204, 211))	('losses', 'NegReg', (53, 59))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('copy number', 'Var', (31, 42))	('gains', 'PosReg', (43, 48))	('tumor', 'Disease', (92, 97))	('expression', 'MPA', (193, 203))
488079	31262303	Most of these genes show significant over-expression with copy number gain and significant under-expression with copy number loss across the PDX samples (p < 0.05) (Fig.	('copy number loss', 'Disease', (113, 129))	('copy number loss', 'Disease', 'MESH:D016388', (113, 129))	('under-expression', 'NegReg', (91, 107))	('over-expression', 'PosReg', (37, 52))	('copy number gain', 'Var', (58, 74))
488080	31262303	These results support using overall cancer genome ploidy as the baseline to call copy number gain and loss.	('copy number', 'Var', (81, 92))	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('cancer', 'Disease', (36, 42))	('gain', 'PosReg', (93, 97))	('loss', 'NegReg', (102, 106))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))
488083	31262303	Despite the much smaller sample size for each PDX tumor type, we observed a higher mutational load in colorectal cancer and melanoma among other tumor types, which is consistent with TCGA.	('melanoma', 'Disease', 'MESH:D008545', (124, 132))	('colorectal cancer', 'Phenotype', 'HP:0003003', (102, 119))	('melanoma', 'Phenotype', 'HP:0002861', (124, 132))	('melanoma', 'Disease', (124, 132))	('colorectal cancer', 'Disease', (102, 119))	('mutational', 'Var', (83, 93))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor', 'Disease', (145, 150))	('colorectal cancer', 'Disease', 'MESH:D015179', (102, 119))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('higher', 'PosReg', (76, 82))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('tumor', 'Disease', (50, 55))
488084	31262303	Given that there were more samples in the TCGA cohorts, we compared the genes that were mutated at 5% frequency with genes that were mutated in at least one sample within the same tumor type in the PDX resource.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('mutated', 'Var', (88, 95))	('tumor', 'Disease', (180, 185))
488085	31262303	Almost all genes mutated at high frequencies in TCGA tumors were mutated in PDX tumors, with significant p-values (p < 1 x 10- 4) by Fisher's exact test (Fig.	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('PDX tumors', 'Disease', (76, 86))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('tumors', 'Disease', (80, 86))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('PDX tumors', 'Disease', 'MESH:D009369', (76, 86))	('tumors', 'Disease', (53, 59))	('mutated', 'Var', (65, 72))
488086	31262303	These results indicate that the key drivers by mutation within each cancer type are preserved in PDX tumors.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('PDX tumors', 'Disease', 'MESH:D009369', (97, 107))	('mutation', 'Var', (47, 55))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('cancer', 'Disease', (68, 74))	('PDX tumors', 'Disease', (97, 107))
488092	31262303	The frequency of genome-wide copy number alterations for each tumor type in the PDX resource (Additional file 1: Table S12 and Fig.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('copy number alterations', 'Var', (29, 52))	('tumor', 'Disease', (62, 67))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
488093	31262303	S12A) was similar to the primary tumors in TCGA (Additional file 1: Fig.	('primary tumors', 'Disease', (25, 39))	('S12A', 'SUBSTITUTION', 'None', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('S12A', 'Var', (0, 4))	('primary tumors', 'Disease', 'MESH:D009369', (25, 39))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))
488099	31262303	Genomic data analysis workflows designed to call somatic mutations (SNVs, indels), copy number alterations and gene expression from PDX sequencing or array data require balancing sensitivity and specificity, especially when paired normal samples for engrafted tumors are not available.	('tumors', 'Disease', 'MESH:D009369', (260, 266))	('tumors', 'Disease', (260, 266))	('copy', 'Var', (83, 87))	('tumor', 'Phenotype', 'HP:0002664', (260, 265))	('tumors', 'Phenotype', 'HP:0002664', (260, 266))
488100	31262303	Using genomic and transcriptomic data from models in the JAX PDX resource, we developed and tailored data analysis workflows to reliably identify true somatic mutations, copy number alterations, and expression changes using genomic and transcriptomic data from PDX tumors that lack paired non-tumor samples.	('tumor', 'Phenotype', 'HP:0002664', (265, 270))	('tumor', 'Disease', 'MESH:D009369', (293, 298))	('expression', 'MPA', (199, 209))	('PDX tumors', 'Disease', (261, 271))	('mutations', 'Var', (159, 168))	('tumor', 'Disease', (265, 270))	('tumor', 'Phenotype', 'HP:0002664', (293, 298))	('tumors', 'Phenotype', 'HP:0002664', (265, 271))	('tumor', 'Disease', (293, 298))	('copy number alterations', 'Var', (170, 193))	('PDX tumors', 'Disease', 'MESH:D009369', (261, 271))	('tumor', 'Disease', 'MESH:D009369', (265, 270))
488102	31262303	This "variant rescue" process will likely also reclaim germline variants that are associated with cancer susceptibility and treatment response which may be important for selecting PDX models for dosing studies.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('associated', 'Reg', (82, 92))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('cancer', 'Disease', (98, 104))	('variants', 'Var', (64, 72))
488105	31262303	Our major recommendations for data analysis workflows for calling somatic mutations for PDX tumors in the absence of paired-normal samples include the following: Normalize SNP array signal intensity with a large number of normal samples that correspond to the sex of the patient associated with the PDX model.	('PDX tumors', 'Disease', 'MESH:D009369', (88, 98))	('patient', 'Species', '9606', (271, 278))	('mutations', 'Var', (74, 83))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('PDX tumors', 'Disease', (88, 98))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))
488106	31262303	Estimate copy number gains and losses using copy number ratio relative to overall cancer genome ploidy We recommend using publicly available data sets to generate a proxy for sex-matched normal samples in order to estimate copy number alterations in an engrafted PDX tumors.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('copy number alterations', 'Var', (223, 246))	('PDX tumors', 'Disease', 'MESH:D009369', (263, 273))	('tumor', 'Phenotype', 'HP:0002664', (267, 272))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('PDX tumors', 'Disease', (263, 273))	('tumors', 'Phenotype', 'HP:0002664', (267, 273))	('losses', 'NegReg', (31, 37))
488124	31262303	As such, it is possible tumors from PDXs harbor more mutations due to a bias in engraftment success.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumors', 'Disease', 'MESH:D009369', (24, 30))	('tumors', 'Disease', (24, 30))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('engraftment', 'CPA', (80, 91))	('mutations', 'Var', (53, 62))
488127	31262303	CKB Clinical Knowledgebase CNA Copy number alterations CTP Cancer Treatment Profile EBV Epstein-Barr virus FP False positive Indels Insertions and deletions JAX The Jackson Laboratory PDX Patient-derived xenograft SNV Single nucleotide variations TCGA The Cancer Genome Atlas TP True positive X.Y.W, J.H.G and V.Y.	('Cancer', 'Phenotype', 'HP:0002664', (59, 65))	('Epstein-Barr virus', 'Disease', (88, 106))	('CKB', 'Chemical', '-', (0, 3))	('TP', 'Chemical', '-', (56, 58))	('Cancer', 'Phenotype', 'HP:0002664', (256, 262))	('Cancer Genome Atlas', 'Disease', (256, 275))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (256, 275))	('TP', 'Chemical', '-', (276, 278))	('deletions', 'Var', (147, 156))	('EBV', 'Species', '10376', (84, 87))	('Epstein-Barr virus', 'Disease', 'MESH:D020031', (88, 106))	('Patient', 'Species', '9606', (188, 195))	('CTP', 'Chemical', '-', (55, 58))	('Single nucleotide variations', 'Var', (218, 246))	('Insertions', 'Var', (132, 142))
488132	31080515	Quantifying local malignant adaptation in tissue-specific evolutionary trajectories by harnessing cancer's repeatability at the genetic level Cancer is a potentially lethal disease, in which patients with nearly identical genetic backgrounds can develop a similar pathology through distinct combinations of genetic alterations.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('patients', 'Species', '9606', (191, 199))	('genetic alterations', 'Var', (307, 326))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('Cancer', 'Phenotype', 'HP:0002664', (142, 148))	('cancer', 'Disease', (98, 104))	('Cancer', 'Disease', (142, 148))	('Cancer', 'Disease', 'MESH:D009369', (142, 148))
488141	31080515	This is further corroborated by the observation that most solid adult tumours harbour multiple "driver" alterations, that is those likely to functionally impact cell behaviour and push it towards malignancy (Zack et al., 2013).	('malignancy', 'Disease', 'MESH:D009369', (196, 206))	('solid adult tumours', 'Disease', 'MESH:D006528', (58, 77))	('alterations', 'Var', (104, 115))	('malignancy', 'Disease', (196, 206))	('tumour', 'Phenotype', 'HP:0002664', (70, 76))	('impact', 'Reg', (154, 160))	('push', 'PosReg', (180, 184))	('tumours', 'Phenotype', 'HP:0002664', (70, 77))	('solid adult tumours', 'Disease', (58, 77))	('cell behaviour', 'CPA', (161, 175))
488153	31080515	Our model highlights differences across tumour types regarding the interactivity between driver alterations and predicts that premalignant skin and colorectal lesions are adapted to their environment, yet not as much as invasive tumours.	('interactivity', 'Interaction', (67, 80))	('colorectal lesions', 'Disease', (148, 166))	('alterations', 'Var', (96, 107))	('colorectal lesions', 'Disease', 'MESH:D015179', (148, 166))	('tumour type', 'Disease', (40, 51))	('tumour type', 'Disease', 'MESH:D009369', (40, 51))	('premalignant skin', 'Disease', (126, 143))	('invasive tumours', 'Disease', (220, 236))	('invasive tumours', 'Disease', 'MESH:D009361', (220, 236))	('tumour', 'Phenotype', 'HP:0002664', (229, 235))	('tumour', 'Phenotype', 'HP:0002664', (40, 46))	('tumours', 'Phenotype', 'HP:0002664', (229, 236))
488155	31080515	We downloaded data for 2,742 samples from The Cancer Genome Atlas (TCGA), for which we could obtain both allelic frequencies for mutations and copy number alterations (CNAs).	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (46, 65))	('copy number alterations', 'Var', (143, 166))	('mutations', 'Var', (129, 138))	('Cancer Genome Atlas', 'Disease', (46, 65))	('Cancer', 'Phenotype', 'HP:0002664', (46, 52))
488164	31080515	Mutations were considered clonal in an entire adenoma when they were predicted as clonal in >=75% of the related samples.	('Mutations', 'Var', (0, 9))	('adenoma', 'Disease', (46, 53))	('adenoma', 'Disease', 'MESH:D000236', (46, 53))
488172	31080515	For each tumour type, 10 randomised matrices were generated by randomly reassigning the mutations of each patient.	('tumour type', 'Disease', (9, 20))	('tumour type', 'Disease', 'MESH:D009369', (9, 20))	('patient', 'Species', '9606', (106, 113))	('mutations', 'Var', (88, 97))	('tumour', 'Phenotype', 'HP:0002664', (9, 15))
488175	31080515	The selective advantage of each driver alteration was defined as the ratio between expectations and observations in a given tumour type, considering mutations and CNAs separately.	('tumour type', 'Disease', (124, 135))	('tumour type', 'Disease', 'MESH:D009369', (124, 135))	('alteration', 'Var', (39, 49))	('tumour', 'Phenotype', 'HP:0002664', (124, 130))
488177	31080515	For simplicity, all models rely on summing the contribution of each driver alteration to the adaptation of each individual sample, given its alteration load and tumour-type-specific context.	('tumour', 'Phenotype', 'HP:0002664', (161, 167))	('tumour', 'Disease', (161, 167))	('tumour', 'Disease', 'MESH:D009369', (161, 167))	('alteration', 'Var', (75, 85))
488189	31080515	To accurately reflect the genetic background of the clones that ultimately adapted to each environment, we only focused on clonal driver alterations (i.e., those present in all cells of a tumour).	('tumour', 'Disease', (188, 194))	('alterations', 'Var', (137, 148))	('tumour', 'Disease', 'MESH:D009369', (188, 194))	('tumour', 'Phenotype', 'HP:0002664', (188, 194))
488192	31080515	As expected given the recurrence of driver mutations, our results highlight a high parallelism within each tumour type (Figure 1a).	('mutations', 'Var', (43, 52))	('high parallelism within each tumour type', 'Disease', (78, 118))	('high parallelism within each tumour type', 'Disease', 'MESH:D001929', (78, 118))	('tumour', 'Phenotype', 'HP:0002664', (107, 113))
488198	31080515	Both selective advantage and self-sufficiency measures are specific to single driver alterations in a given tumour type.	('tumour type', 'Disease', (108, 119))	('self-sufficiency', 'Disease', 'MESH:D012652', (29, 45))	('tumour', 'Phenotype', 'HP:0002664', (108, 114))	('self-sufficiency', 'Disease', (29, 45))	('alterations', 'Var', (85, 96))	('tumour type', 'Disease', 'MESH:D009369', (108, 119))
488199	31080515	This indicates that they can provide distinct information on the impact of each alteration and that mutations highly selected for may still require numerous other alterations in order to induce full cancerous transformation.	('mutations', 'Var', (100, 109))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('cancerous transformation', 'Disease', 'MESH:D020518', (199, 223))	('induce', 'Reg', (187, 193))	('cancerous transformation', 'Disease', (199, 223))
488200	31080515	In this work, these interactions differ slightly from the traditional concept of epistasis and are entirely focused on cancerous development: the interaction between two genes can favour or hamper malignant transformation on the long term, without immediately impacting selective advantage during somatic development.	('interaction', 'Var', (146, 157))	('cancerous', 'Disease', 'MESH:D009369', (119, 128))	('hamper', 'NegReg', (190, 196))	('malignant transformation', 'CPA', (197, 221))	('cancerous', 'Disease', (119, 128))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('favour', 'PosReg', (180, 186))
488201	31080515	The most negative interaction was the one found between known antagonists BRAF and NRAS in melanoma (Curtin et al., 2005), while the most positive interactions included those between AURKA gain, APC and TP53 mutations in colorectal cancer (Figure 2d).	('mutations', 'Var', (208, 217))	('melanoma', 'Disease', 'MESH:D008545', (91, 99))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('colorectal cancer', 'Disease', 'MESH:D015179', (221, 238))	('TP53', 'Gene', (203, 207))	('colorectal cancer', 'Disease', (221, 238))	('NRAS', 'Gene', '4893', (83, 87))	('AURKA', 'Gene', '6790', (183, 188))	('melanoma', 'Phenotype', 'HP:0002861', (91, 99))	('melanoma', 'Disease', (91, 99))	('APC', 'Disease', 'MESH:D011125', (195, 198))	('AURKA', 'Gene', (183, 188))	('APC', 'Disease', (195, 198))	('negative', 'NegReg', (9, 17))	('TP53', 'Gene', '7157', (203, 207))	('BRAF', 'Gene', (74, 78))	('BRAF', 'Gene', '673', (74, 78))	('interaction', 'Interaction', (18, 29))	('colorectal cancer', 'Phenotype', 'HP:0003003', (221, 238))	('NRAS', 'Gene', (83, 87))
488202	31080515	Across cancers, CNAs tended to frequently co-occur with each other and TP53 mutations (Supporting Information Figure S4), in agreement with the role of TP53 in promoting genome instability, which then accelerates CNA acquisition (Martinez et al., 2018; Sansregret, Vanhaesebroeck, & Swanton, 2018).	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('CNA acquisition', 'MPA', (213, 228))	('mutations', 'Var', (76, 85))	('genome instability', 'MPA', (170, 188))	('TP53', 'Gene', '7157', (152, 156))	('promoting', 'PosReg', (160, 169))	('cancers', 'Disease', 'MESH:D009369', (7, 14))	('cancers', 'Phenotype', 'HP:0002664', (7, 14))	('TP53', 'Gene', (152, 156))	('cancers', 'Disease', (7, 14))	('TP53', 'Gene', '7157', (71, 75))	('TP53', 'Gene', (71, 75))	('accelerates', 'PosReg', (201, 212))
488239	31080515	This corresponds to a maximum of 32,767 unique combinations of driver alterations per tumour type.	('alterations', 'Var', (70, 81))	('tumour', 'Phenotype', 'HP:0002664', (86, 92))	('tumour type', 'Disease', (86, 97))	('tumour type', 'Disease', 'MESH:D009369', (86, 97))
488244	31080515	This is also reflected in how fast the maximum LMA score in the network is reached, with some tumour types displaying a log-like distribution with decreasing improvement with each additional alteration, while the maximum LMA of GBM increases exponentially (Figure 6c).	('alteration', 'Var', (191, 201))	('LMA', 'Chemical', '-', (47, 50))	('tumour', 'Phenotype', 'HP:0002664', (94, 100))	('tumour type', 'Disease', (94, 105))	('tumour type', 'Disease', 'MESH:D009369', (94, 105))	('LMA', 'Chemical', '-', (221, 224))	('GBM', 'Phenotype', 'HP:0012174', (228, 231))
488249	31080515	The number of drivers in these combinations was superior to the one observed in the actual sample, which was expected given that their LMA score had to be equal or higher than the data set's median (Figure 6d,e).	('higher', 'PosReg', (164, 170))	('combinations', 'Var', (31, 43))	('LMA', 'Chemical', '-', (135, 138))
488253	31080515	We built and optimised simple models to quantify LMA based on the presence of recurrent genetic alterations in nine cohorts corresponding to nine tumour types.	('LMA', 'Chemical', '-', (49, 52))	('genetic alterations', 'Var', (88, 107))	('LMA', 'Disease', (49, 52))	('tumour', 'Phenotype', 'HP:0002664', (146, 152))	('tumour type', 'Disease', (146, 157))	('tumour type', 'Disease', 'MESH:D009369', (146, 157))
488266	31080515	Interestingly, recent work on the somatic evolution of normal oesophagus suggests that alterations providing a competitive growth advantage in the normal tissue did not necessarily yield malignant phenotypes, as exemplified by the prevalence of NOTCH1 mutations in normal, but not in cancerous tissue (Martincorena et al., 2018).	('NOTCH1', 'Gene', '4851', (245, 251))	('NOTCH1', 'Gene', (245, 251))	('cancerous', 'Disease', (284, 293))	('mutations', 'Var', (252, 261))	('cancerous', 'Disease', 'MESH:D009369', (284, 293))	('cancer', 'Phenotype', 'HP:0002664', (284, 290))
488282	30808417	Moreover, knockdown of Derlin1 induced apoptosis and affected the expression of apoptosis-related proteins, including Bcl-2, Bax, Bim, caspase3 and caspase9.	('apoptosis', 'CPA', (39, 48))	('affected', 'Reg', (53, 61))	('Bax', 'Gene', (125, 128))	('Bim', 'Gene', (130, 133))	('caspase3', 'Gene', (135, 143))	('Bim', 'Gene', '10018', (130, 133))	('expression', 'MPA', (66, 76))	('Bcl-2', 'Gene', (118, 123))	('Derlin1', 'Gene', (23, 30))	('apoptosis-related proteins', 'Gene', (80, 106))	('Bax', 'Gene', '581', (125, 128))	('caspase9', 'Gene', (148, 156))	('Bcl-2', 'Gene', '596', (118, 123))	('caspase3', 'Gene', '836', (135, 143))	('induced', 'Reg', (31, 38))	('knockdown', 'Var', (10, 19))	('caspase9', 'Gene', '842', (148, 156))
488283	30808417	Further experiments showed that AKT/mTOR signal pathway might be involve in this processes that knockdown of Derlin1 inhibited the expression of p-AKT and p-mTOR.	('knockdown', 'Var', (96, 105))	('AKT', 'Gene', '207', (32, 35))	('mTOR', 'Gene', (36, 40))	('mTOR', 'Gene', '2475', (36, 40))	('Derlin1', 'Gene', (109, 116))	('AKT', 'Gene', (32, 35))	('expression', 'MPA', (131, 141))	('AKT', 'Gene', '207', (147, 150))	('inhibited', 'NegReg', (117, 126))	('mTOR', 'Gene', (157, 161))	('mTOR', 'Gene', '2475', (157, 161))	('AKT', 'Gene', (147, 150))
488284	30808417	Over-expression of Derlin1 in H8 cells promoted cell proliferation and migration via up-regulated the expression of p-AKT and p-mTOR.	('promoted', 'PosReg', (39, 47))	('mTOR', 'Gene', (128, 132))	('mTOR', 'Gene', '2475', (128, 132))	('AKT', 'Gene', '207', (118, 121))	('expression', 'MPA', (102, 112))	('Derlin1', 'Gene', (19, 26))	('cell proliferation', 'CPA', (48, 66))	('migration', 'CPA', (71, 80))	('AKT', 'Gene', (118, 121))	('Over-expression', 'Var', (0, 15))	('up-regulated', 'PosReg', (85, 97))
488293	30808417	Derlin1 antibodies inhibit tumor growth in a mouse model of colon cancer.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('colon cancer', 'Phenotype', 'HP:0003003', (60, 72))	('colon cancer', 'Disease', 'MESH:D015179', (60, 72))	('tumor', 'Disease', (27, 32))	('inhibit', 'NegReg', (19, 26))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('mouse', 'Species', '10090', (45, 50))	('colon cancer', 'Disease', (60, 72))	('Derlin1', 'Gene', (0, 7))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('antibodies', 'Var', (8, 18))
488294	30808417	Derlin1 knockdown in bladder cancer also has been confirmed to inhibit cell migration.	('bladder cancer', 'Phenotype', 'HP:0009725', (21, 35))	('knockdown', 'Var', (8, 17))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('bladder cancer', 'Disease', (21, 35))	('bladder cancer', 'Disease', 'MESH:D001749', (21, 35))	('Derlin1', 'Gene', (0, 7))	('cell migration', 'CPA', (71, 85))	('inhibit', 'NegReg', (63, 70))
488325	30808417	As expected, the high Derlin1 expression showed higher incidences of larger tumors sizes (p = 0.000953), lymph node metastasis (p  = 0.034982), high pathological grade (p  = 0.037635).	('expression', 'MPA', (30, 40))	('high', 'Var', (17, 21))	('lymph node metastasis', 'CPA', (105, 126))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('high pathological grade', 'CPA', (144, 167))	('Derlin1', 'Gene', (22, 29))	('tumors', 'Disease', (76, 82))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))
488330	30808417	Thus, human cervical cancer cell lines SiHa and C33A were used as a model in vitro, and siRNA were designed to knockdown the expression of Derlin1 in cells (Derlin1-KD).	('cervical cancer', 'Disease', 'MESH:D002583', (12, 27))	('SiHa', 'CellLine', 'CVCL:0032', (39, 43))	('human', 'Species', '9606', (6, 11))	('knockdown', 'Var', (111, 120))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('cervical cancer', 'Disease', (12, 27))	('Derlin1', 'Gene', (139, 146))	('expression', 'MPA', (125, 135))
488331	30808417	The results demonstrate that the knockdown of Derlin1 inhibits the proliferation of SiHa and C33A cells.	('knockdown', 'Var', (33, 42))	('Derlin1', 'Gene', (46, 53))	('proliferation', 'CPA', (67, 80))	('inhibits', 'NegReg', (54, 62))	('SiHa', 'CellLine', 'CVCL:0032', (84, 88))
488334	30808417	In summary, the knockdown of Derlin1 inhibits the proliferation and migration of SiHa and C33A cells, which suggest that Derlin1 may play an oncogenic role in CC.	('SiHa', 'CellLine', 'CVCL:0032', (81, 85))	('Derlin1', 'Gene', (29, 36))	('proliferation', 'CPA', (50, 63))	('knockdown', 'Var', (16, 25))	('CC', 'Phenotype', 'HP:0002664', (159, 161))	('inhibits', 'NegReg', (37, 45))
488336	30808417	2c-e, the expression of pro-apoptosis proteins, Bax, Bim, caspase3 and caspase9, were up-regulated after Derlin1-siRNA transfection; and the expression of anti-apoptosis protein Bcl-2 was down-regulated.	('Bim', 'Gene', (53, 56))	('transfection', 'Var', (119, 131))	('caspase3', 'Gene', (58, 66))	('caspase9', 'Gene', (71, 79))	('Bim', 'Gene', '10018', (53, 56))	('Bcl-2', 'Gene', '596', (178, 183))	('down-regulated', 'NegReg', (188, 202))	('up-regulated', 'PosReg', (86, 98))	('caspase3', 'Gene', '836', (58, 66))	('caspase9', 'Gene', '842', (71, 79))	('Bax', 'Gene', '581', (48, 51))	('expression', 'MPA', (10, 20))	('expression', 'MPA', (141, 151))	('Bax', 'Gene', (48, 51))	('Bcl-2', 'Gene', (178, 183))
488337	30808417	Taken together, the knockdown of Derlin1 induced the apoptosis of SiHa and C33A cells.	('apoptosis', 'CPA', (53, 62))	('Derlin1', 'Gene', (33, 40))	('SiHa', 'CellLine', 'CVCL:0032', (66, 70))	('induced', 'Reg', (41, 48))	('knockdown', 'Var', (20, 29))
488339	30808417	5, the p-AKT and p-mTOR levels were significantly decreased in Derlin1-KD cells compared to CON and NC cells; while the expression of AKT and mTOR weren't impacted.	('AKT', 'Gene', (134, 137))	('AKT', 'Gene', '207', (9, 12))	('mTOR', 'Gene', (142, 146))	('mTOR', 'Gene', '2475', (142, 146))	('mTOR', 'Gene', '2475', (19, 23))	('Derlin1-KD', 'Var', (63, 73))	('mTOR', 'Gene', (19, 23))	('decreased', 'NegReg', (50, 59))	('AKT', 'Gene', (9, 12))	('AKT', 'Gene', '207', (134, 137))
488340	30808417	These data suggest that Derlin1 knockdown influence the phosphorylation of AKT and mTOR in SiHa and C33A cells.	('Derlin1', 'Gene', (24, 31))	('mTOR', 'Gene', (83, 87))	('SiHa', 'CellLine', 'CVCL:0032', (91, 95))	('AKT', 'Gene', '207', (75, 78))	('knockdown', 'Var', (32, 41))	('AKT', 'Gene', (75, 78))	('influence', 'Reg', (42, 51))	('phosphorylation', 'MPA', (56, 71))	('mTOR', 'Gene', '2475', (83, 87))
488350	30808417	The survival rate of bladder cancer patients with Derlin1 positive expression is significantly shorter than that of negative patients.	('survival rate', 'CPA', (4, 17))	('patients', 'Species', '9606', (36, 44))	('bladder cancer', 'Phenotype', 'HP:0009725', (21, 35))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('Derlin1', 'Gene', (50, 57))	('bladder cancer', 'Disease', 'MESH:D001749', (21, 35))	('positive expression', 'Var', (58, 77))	('bladder cancer', 'Disease', (21, 35))	('shorter', 'NegReg', (95, 102))	('patients', 'Species', '9606', (125, 133))
488355	30808417	And knockdown of Derlin1 in SiHa and C33A cells inhibited cell proliferation and migration.	('cell proliferation', 'CPA', (58, 76))	('SiHa', 'CellLine', 'CVCL:0032', (28, 32))	('inhibited', 'NegReg', (48, 57))	('Derlin1', 'Gene', (17, 24))	('knockdown', 'Var', (4, 13))
488371	30808417	In addition, knockdown of Derlin1 in SiHa and C33A cells could inhibit the cell proliferation and migration, and promote apoptosis.	('SiHa', 'CellLine', 'CVCL:0032', (37, 41))	('promote', 'PosReg', (113, 120))	('Derlin1', 'Gene', (26, 33))	('knockdown', 'Var', (13, 22))	('apoptosis', 'CPA', (121, 130))	('inhibit', 'NegReg', (63, 70))
488423	29356357	In the training set, the median level of CATPIII/CXCL7 was 1302.80 (931.84, 1790.14) ng/mL in the patients with squamous cell carcinoma and 1217.14 (970.40, 1940.93) ng/mL in the patients with adenocarcinoma, all significantly higher than that in controls (840.96 (585.53, 1023.92); Fig.	('adenocarcinoma', 'Disease', 'MESH:D000230', (193, 207))	('1217.14', 'Var', (140, 147))	('CXCL7', 'Gene', (49, 54))	('CXCL7', 'Gene', '5473', (49, 54))	('carcinoma', 'Phenotype', 'HP:0030731', (198, 207))	('patients', 'Species', '9606', (98, 106))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (112, 135))	('higher', 'PosReg', (227, 233))	('patients', 'Species', '9606', (179, 187))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (112, 135))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('squamous cell carcinoma', 'Disease', (112, 135))	('adenocarcinoma', 'Disease', (193, 207))
488425	29356357	When the two sets were combined, the median level of CATPIII/CXCL7 was 1258.99 (928.46, 1857.90) ng/mL in the patients with squamous cell carcinoma and 1257.03 (922.68, 1838.55) ng/mL in the patients with adenocarcinoma, all significantly higher than that in controls (851.80 (632.44, 1023.92) ng/L; Fig.	('carcinoma', 'Phenotype', 'HP:0030731', (210, 219))	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('adenocarcinoma', 'Disease', 'MESH:D000230', (205, 219))	('patients', 'Species', '9606', (191, 199))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (124, 147))	('higher', 'PosReg', (239, 245))	('patients', 'Species', '9606', (110, 118))	('1257.03', 'Var', (152, 159))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (124, 147))	('squamous cell carcinoma', 'Disease', (124, 147))	('CXCL7', 'Gene', (61, 66))	('CXCL7', 'Gene', '5473', (61, 66))	('adenocarcinoma', 'Disease', (205, 219))
488431	29356357	In patients with squamous cell carcinoma, CATPIII/CXCL7 was 1346.49 (869.74, 1632.24) ng/mL, 1176.80 (793.33, 2571.07) ng/mL, 1355.38 (903.20, 1856.07) ng/mL, 1222.86(1023.39, 1715.38) ng/mL corresponding to disease stage I to IV, respectively.	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (17, 40))	('1355.38', 'Var', (126, 133))	('patients', 'Species', '9606', (3, 11))	('CXCL7', 'Gene', (50, 55))	('CXCL7', 'Gene', '5473', (50, 55))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (17, 40))	('carcinoma', 'Phenotype', 'HP:0030731', (31, 40))	('squamous cell carcinoma', 'Disease', (17, 40))
488436	29356357	For lung squamous cell carcinoma, Cyfra211 showed the highest AUC (Fig.	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (4, 32))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (4, 32))	('Cyfra211', 'Var', (34, 42))	('carcinoma', 'Phenotype', 'HP:0030731', (23, 32))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (9, 32))	('lung squamous cell carcinoma', 'Disease', (4, 32))	('AUC', 'MPA', (62, 65))
488440	29356357	Assuming 95% specificity in the training set, 1309.45 ng/mL was appropriate as the cut-off value of CTAPIII/CXCL7 in NSCLC diagnosis (training set: sensitivity 42.3%, specificity 95%; test set: sensitivity 45.9%, specificity 96.1%).	('NSCLC', 'Disease', (117, 122))	('NSCLC', 'Disease', 'MESH:D002289', (117, 122))	('CXCL7', 'Gene', (108, 113))	('CXCL7', 'Gene', '5473', (108, 113))	('1309.45 ng/mL', 'Var', (46, 59))	('CTAPIII', 'Gene', '5473', (100, 107))	('CTAPIII', 'Gene', (100, 107))
488443	29356357	The optimal cut-off value of Cyfra211was 2.36 ng/mL in NSCLC diagnosis (training set: sensitivity 40.9%, specificity 95%; test set: sensitivity 39.8%, specificity 96.1%).	('Cyfra211was', 'Var', (29, 40))	('NSCLC', 'Disease', 'MESH:D002289', (55, 60))	('NSCLC', 'Disease', (55, 60))
488457	29356357	CXC chemokines have been implicated in various biological processes, including angiogenesis, anti-angiogenesis, tumorigenesis, and metastasis, which are divided into two classes, ELR+ and ELR-, based on whether they have specific amino acid sequence (ELR, Glu-Leu-Arg) 12.	('tumor', 'Disease', (112, 117))	('metastasis', 'CPA', (131, 141))	('Arg', 'Chemical', 'MESH:D001120', (264, 267))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('Leu', 'Chemical', 'MESH:D007930', (260, 263))	('Glu', 'Chemical', 'MESH:D018698', (256, 259))	('angiogenesis', 'CPA', (79, 91))	('implicated', 'Reg', (25, 35))	('Glu-Leu-Arg', 'Var', (256, 267))
488474	29356357	As it turns out, Cyfra211 showed higher sensitivity (72.4-75.9%) in diagnosis of squamous cell carcinoma than SCCAg, CEA, and CTAPIII/CXCL-7, consistent with previous reports.	('CEA', 'Gene', (117, 120))	('CEA', 'Gene', '1084', (117, 120))	('CXCL-7', 'Gene', '5473', (134, 140))	('Cyfra211', 'Var', (17, 25))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('CXCL-7', 'Gene', (134, 140))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (81, 104))	('CTAPIII', 'Gene', '5473', (126, 133))	('CTAPIII', 'Gene', (126, 133))	('squamous cell carcinoma', 'Disease', (81, 104))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (81, 104))
488477	29356357	The results showed that the biomarker panel including CEA, SCCAg, Cyfra211 and CTAPIII/CXCL-7 had significantly higher diagnostic efficacy than any single biomarker.	('CXCL-7', 'Gene', (87, 93))	('higher', 'PosReg', (112, 118))	('CEA', 'Gene', (54, 57))	('CEA', 'Gene', '1084', (54, 57))	('Cyfra211', 'Var', (66, 74))	('diagnostic', 'MPA', (119, 129))	('CXCL-7', 'Gene', '5473', (87, 93))	('CTAPIII', 'Gene', '5473', (79, 86))	('CTAPIII', 'Gene', (79, 86))
488510	28865486	In addition, blockade of NLRP3 inflammasome can also delayed the tumor-burdened speed in SCCHN mice.	('mice', 'Species', '10090', (95, 99))	('tumor', 'Disease', (65, 70))	('blockade', 'Var', (13, 21))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('delayed', 'NegReg', (53, 60))	('NLRP3 inflammasome', 'Protein', (25, 43))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
488519	28865486	By contrast, chronic inflammation is associated with DNA and tissue damage, which includes genetic and epigenetic changes leading to cancer, such as SCCHN.	('chronic inflammation', 'Disease', 'MESH:D007249', (13, 33))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('chronic inflammation', 'Disease', (13, 33))	('SCCHN', 'Disease', (149, 154))	('cancer', 'Disease', (133, 139))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('epigenetic', 'Var', (103, 113))
488534	28865486	High IL-1beta secretion is associated with malignant phenotype in the cancer microenvironment, and IL-1beta may promote the inflammatory cycle in the cancer microenvironment that induces sterile inflammation and carcinogenesis.	('IL-1beta', 'Var', (99, 107))	('sterile', 'Disease', (187, 194))	('IL-1beta', 'Gene', (5, 13))	('inflammatory cycle', 'CPA', (124, 142))	('promote', 'PosReg', (112, 119))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('induces', 'Reg', (179, 186))	('carcinogenesis', 'Disease', 'MESH:D063646', (212, 226))	('secretion', 'MPA', (14, 23))	('cancer', 'Disease', (150, 156))	('carcinogenesis', 'Disease', (212, 226))	('inflammation', 'Disease', 'MESH:D007249', (195, 207))	('inflammation', 'Disease', (195, 207))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('cancer', 'Disease', (70, 76))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
488539	28865486	LPS, ATP and MCC950 (PZ0280) were purchased from Sigma-Aldrich and the treatment of LPS, ATP and MCC950 were carried out as previously described.	('ATP', 'Chemical', 'MESH:D000255', (5, 8))	('ATP', 'Chemical', 'MESH:D000255', (89, 92))	('LPS', 'Gene', (0, 3))	('MCC950', 'Chemical', 'MESH:C000597426', (97, 103))	('LPS', 'Gene', '21898', (84, 87))	('MCC950', 'Chemical', 'MESH:C000597426', (13, 19))	('LPS', 'Gene', (84, 87))	('PZ0280', 'Var', (21, 27))	('LPS', 'Gene', '21898', (0, 3))	('PZ0280', 'Chemical', '-', (21, 27))
488544	28865486	These tissue microarray (T12-412-1 and T12-412-2) slides included 64 confirmed cases of SCCHN, 38 normal oral mucosa and 12 oral epithelial dysplasia.	('T12-412-2', 'CellLine', 'CVCL:1V29', (39, 48))	('oral epithelial dysplasia', 'Disease', 'MESH:D017573', (124, 149))	('oral epithelial dysplasia', 'Disease', (124, 149))	('T12-412-2', 'Var', (39, 48))	('SCCHN', 'Disease', (88, 93))
488550	28865486	Tgfbr1/Pten 2cKO mice were baseline induced with 2 mg of tamoxifen for five consecutive days to delete Tgfbr1 and Pten.	('Tgfbr1', 'Gene', (103, 109))	('Pten', 'Gene', (114, 118))	('delete', 'Var', (96, 102))	('tamoxifen', 'Chemical', 'MESH:D013629', (57, 66))	('Pten', 'Gene', '19211', (114, 118))	('mice', 'Species', '10090', (17, 21))	('Pten', 'Gene', (7, 11))	('Pten', 'Gene', '19211', (7, 11))
488578	28865486	We previously reported that the loss of Tgfbr1 and Pten results in cellular senescence evasion, cancer-related inflammation, and expansion of the CSCs in the basilar epithelial layer in SCCHN of the Tgfbr1/Pten 2cKO mice.	('inflammation', 'Disease', 'MESH:D007249', (111, 123))	('inflammation', 'Disease', (111, 123))	('mice', 'Species', '10090', (216, 220))	('expansion', 'PosReg', (129, 138))	('Pten', 'Gene', '19211', (206, 210))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('CSCs in the', 'CPA', (146, 157))	('SCCHN', 'Disease', (186, 191))	('loss', 'Var', (32, 36))	('cellular senescence evasion', 'MPA', (67, 94))	('Pten', 'Gene', (206, 210))	('Pten', 'Gene', (51, 55))	('Tgfbr1', 'Gene', (40, 46))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('Pten', 'Gene', '19211', (51, 55))	('cancer', 'Disease', (96, 102))
488583	28865486	Moreover, MCC950 treatment caused no weight loss compared with the PBS treatment group (Fig.	('weight loss', 'Disease', (37, 48))	('MCC950', 'Chemical', 'MESH:C000597426', (10, 16))	('weight loss', 'Phenotype', 'HP:0001824', (37, 48))	('MCC950', 'Gene', (10, 16))	('treatment', 'Var', (17, 26))	('weight loss', 'Disease', 'MESH:D015431', (37, 48))	('PBS', 'Chemical', 'MESH:D007854', (67, 70))
488586	28865486	Our results from the Western blot analysis showed that the expression of NLRP3, Caspase-1, IL-1beta, IL-18, BMI1, ALDH1 and CD44 was also significantly downregulated by MCC950 treatment (Fig.	('IL-1beta', 'Gene', (91, 99))	('IL-18', 'Gene', (101, 106))	('ALDH1', 'Gene', (114, 119))	('MCC950', 'Var', (169, 175))	('MCC950', 'Chemical', 'MESH:C000597426', (169, 175))	('expression', 'MPA', (59, 69))	('Caspase-1', 'Gene', (80, 89))	('downregulated', 'NegReg', (152, 165))	('NLRP3', 'Gene', (73, 78))	('BMI1', 'Gene', (108, 112))	('CD44', 'Gene', (124, 128))
488595	28865486	MCC950 was used to further investigate whether CSCs could be reduced by blockade of NLRP3 inflammasome in SCCHN cell lines.	('MCC950', 'Chemical', 'MESH:C000597426', (0, 6))	('NLRP3 inflammasome', 'Protein', (84, 102))	('blockade', 'Var', (72, 80))	('CSCs', 'Disease', (47, 51))
488596	28865486	Contrary to other NLRP3 inflammasome inhibitors, MCC950 blocks ASC oligomerization to inhibit canonical and non-canonical NLRP3 inflammasome activation rather than by reducing NLRP3 protein expression.	('ASC oligomerization', 'Protein', (63, 82))	('MCC950', 'Chemical', 'MESH:C000597426', (49, 55))	('MCC950', 'Var', (49, 55))	('inhibit', 'NegReg', (86, 93))
488627	28865486	Moreover, inactivation of NLRP3 inflammasome by MCC950 could not reduce NLRP3, pro-Caspase-1 protein expression level in vitro, but we observed decreased expression of NLRP3 and pro-Caspase-1 in the MCC950 treated Tgfbr1/Pten 2cKO SCCHN mice model compared to control group.	('decreased', 'NegReg', (144, 153))	('inactivation', 'Var', (10, 22))	('NLRP3', 'Gene', (168, 173))	('mice', 'Species', '10090', (237, 241))	('MCC950', 'Var', (199, 205))	('MCC950', 'Chemical', 'MESH:C000597426', (48, 54))	('MCC950', 'Chemical', 'MESH:C000597426', (199, 205))	('expression', 'MPA', (154, 164))
488629	28865486	Given that blockade of NLRP3 inflammasome could delay tumorigenesis in SCCHN mice by reducing the production of IL-1beta, and the stimulation on NLRP3 inflammasome from early tumor is less than advanced tumor, which might account for the decreased expression of NLRP3 and pro-Caspase-1.	('mice', 'Species', '10090', (77, 81))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('tumor', 'Disease', (203, 208))	('tumor', 'Disease', (175, 180))	('delay', 'NegReg', (48, 53))	('production of IL-1beta', 'MPA', (98, 120))	('reducing', 'NegReg', (85, 93))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('NLRP3', 'Gene', (145, 150))	('blockade', 'Var', (11, 19))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('tumor', 'Disease', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('NLRP3', 'Gene', (23, 28))
488658	25992232	Prolonged exposure to carcinogens alters the state of the epithelium, making it susceptible to developing a multifocal carcinoma, which can also derive from independent mutations in the absence of any genetic influence.	('mutations', 'Var', (169, 178))	('alters', 'Reg', (34, 40))	('multifocal carcinoma', 'Phenotype', 'HP:0006625', (108, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('multifocal carcinoma', 'Disease', 'None', (108, 128))	('multifocal carcinoma', 'Disease', (108, 128))
488678	25992232	The process of carcinogenesis initiates from multiple genetic and epigenetic alterations in the mucosa which can lead to the clonal expansion of premalignant daughter cells in a particular field.	('epigenetic alterations', 'Var', (66, 88))	('carcinogenesis', 'Disease', (15, 29))	('lead to', 'Reg', (113, 120))	('clonal expansion', 'CPA', (125, 141))	('carcinogenesis', 'Disease', 'MESH:D063646', (15, 29))
488680	25992232	In the epithelium, there is a cluster of cells with cancer-related genetic alterations which can be demonstrated by TP53 immunostatining.	('TP53', 'Gene', (116, 120))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('genetic alterations', 'Var', (67, 86))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('TP53', 'Gene', '7157', (116, 120))
488682	25992232	When a stem cell develops a genetic alteration, the cells derived from it continue to carry the same clonal patch resulting in the formation of a cluster containing TP53 immunopositive cells.	('TP53', 'Gene', '7157', (165, 169))	('TP53', 'Gene', (165, 169))	('genetic alteration', 'Var', (28, 46))
488693	25992232	The process of carcinogenesis begins with a stem cell which develops one or more genetic and epigenetic alterations.	('carcinogenesis', 'Disease', (15, 29))	('carcinogenesis', 'Disease', 'MESH:D063646', (15, 29))	('epigenetic alterations', 'Var', (93, 115))
488695	25992232	The probability of developing cancer from a genetically altered stem cell depends on the nature of the affected stem cell itself and of additional hits.	('cancer', 'Disease', (30, 36))	('genetically altered', 'Var', (44, 63))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
488708	25992232	Currently p53 mutations are used as clonal markers for multiple primary tumors, as their expression has been observed in the normal tissue far from the tumor sites.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('p53', 'Gene', '7157', (10, 13))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('primary tumors', 'Disease', 'MESH:D009369', (64, 78))	('tumor', 'Disease', (72, 77))	('tumor', 'Disease', (152, 157))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('mutations', 'Var', (14, 23))	('p53', 'Gene', (10, 13))	('primary tumors', 'Disease', (64, 78))
488710	25992232	This suggests that allelic loss can precede the histological changes in head and neck cancer.	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('neck cancer', 'Disease', 'MESH:D006258', (81, 92))	('head and neck cancer', 'Phenotype', 'HP:0012288', (72, 92))	('neck cancer', 'Disease', (81, 92))	('allelic loss', 'Var', (19, 31))
488712	25992232	Nodal involvements are characterized by a deletion on chromosome 7q, 10q, 11p, 11q, 15q and 20p and an over representation of chromosomes 19q and 20q.	('deletion', 'Var', (42, 50))	('Nodal', 'Gene', '4838', (0, 5))	('over representation', 'PosReg', (103, 122))	('Nodal', 'Gene', (0, 5))
488716	25992232	The presence of genetically altered cells in a particular field acts as a risk factor for cancerization and has important consequences.	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('genetically altered', 'Var', (16, 35))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))
488723	25992232	The markers commonly used are loss of heterozygosity, microsatellite alterations, chromosomal instability, mutations in the p53 gene, which are generally detected by polymerase chain reaction, immunohistochemistry and in situ hybridization.	('p53', 'Gene', (124, 127))	('chromosomal instability', 'Phenotype', 'HP:0040012', (82, 105))	('mutations', 'Var', (107, 116))	('p53', 'Gene', '7157', (124, 127))	('chromosomal instability', 'CPA', (82, 105))	('microsatellite alterations', 'Var', (54, 80))	('loss', 'Var', (30, 34))
488728	25992232	The definition of field cancerization refers to a group of genetically altered clones of cells in multifocal patches, which are prone to the development of synchronous and metachronous tumors.	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('tumors', 'Phenotype', 'HP:0002664', (185, 191))	('cancer', 'Disease', (24, 30))	('cancer', 'Disease', 'MESH:D009369', (24, 30))	('metachronous tumors', 'Disease', 'MESH:D016609', (172, 191))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('genetically altered', 'Var', (59, 78))	('metachronous tumors', 'Disease', (172, 191))
488732	24132290	Mutational landscape and significance across 12 major cancer types The Cancer Genome Atlas (TCGA) has used the latest sequencing and analysis methods to identify somatic variants across thousands of tumours.	('tumour', 'Phenotype', 'HP:0002664', (199, 205))	('Cancer Genome Atlas', 'Disease', (71, 90))	('TC', 'Chemical', 'MESH:D013667', (92, 94))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (71, 90))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('tumours', 'Phenotype', 'HP:0002664', (199, 206))	('cancer', 'Disease', (54, 60))	('variants', 'Var', (170, 178))	('CG', 'Chemical', 'MESH:C028505', (93, 95))	('tumours', 'Disease', 'MESH:D009369', (199, 206))	('tumours', 'Disease', (199, 206))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('Cancer', 'Phenotype', 'HP:0002664', (71, 77))
488733	24132290	Here we present data and analytical results for point mutations and small insertions/deletions from 3,281 tumours across 12 tumour types as part of the TCGA Pan-Cancer effort.	('tumour', 'Phenotype', 'HP:0002664', (106, 112))	('tumours', 'Phenotype', 'HP:0002664', (106, 113))	('tumour type', 'Disease', (124, 135))	('tumour', 'Phenotype', 'HP:0002664', (124, 130))	('Cancer', 'Phenotype', 'HP:0002664', (161, 167))	('tumours', 'Disease', 'MESH:D009369', (106, 113))	('CG', 'Chemical', 'MESH:C028505', (153, 155))	('tumours', 'Disease', (106, 113))	('point mutations', 'Var', (48, 63))	('small insertions/deletions', 'Var', (68, 94))	('tumour type', 'Disease', 'MESH:D009369', (124, 135))	('TC', 'Chemical', 'MESH:D013667', (152, 154))
488737	24132290	Mutations in transcriptional factors/regulators show tissue specificity, whereas histone modifiers are often mutated across several cancer types.	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('cancer', 'Disease', (132, 138))	('Mutations', 'Var', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))
488744	24132290	We determined interactions among mutations and correlated mutations in BAP1, FBXW7 and TP53 with detrimental phenotypes across several cancer types.	('FBXW7', 'Gene', '55294', (77, 82))	('mutations', 'Var', (58, 67))	('cancer', 'Disease', (135, 141))	('TP53', 'Gene', '7157', (87, 91))	('FBXW7', 'Gene', (77, 82))	('TP53', 'Gene', (87, 91))	('interactions', 'Interaction', (14, 26))	('mutations', 'Var', (33, 42))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('BAP1', 'Gene', '8314', (71, 75))	('BAP1', 'Gene', (71, 75))	('cancer', 'Disease', 'MESH:D009369', (135, 141))
488745	24132290	The subclonal structure and transcription status of underlying somatic mutations reveal the trajectory of tumour progression in patients with cancer.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('tumour', 'Phenotype', 'HP:0002664', (106, 112))	('tumour', 'Disease', 'MESH:D009369', (106, 112))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('mutations', 'Var', (71, 80))	('tumour', 'Disease', (106, 112))	('patients', 'Species', '9606', (128, 136))	('reveal', 'Reg', (81, 87))	('cancer', 'Disease', (142, 148))
488752	24132290	Indeed, there is a significant correlation between high mutation frequency and DNA repair pathway genes (for example, PRKDC, TP53 and MSH6) (Supplementary Table 3c).	('MSH6', 'Gene', '2956', (134, 138))	('TP53', 'Gene', '7157', (125, 129))	('DNA', 'Gene', (79, 82))	('high mutation frequency', 'Var', (51, 74))	('PRKDC', 'Gene', '5591', (118, 123))	('TP53', 'Gene', (125, 129))	('PRKDC', 'Gene', (118, 123))	('MSH6', 'Gene', (134, 138))
488753	24132290	Notably, PRKDC mutations are associated with high frequency in BLCA, COAD/READ, LUAD and UCEC, whereas TP53 mutations are related with higher frequencies in AML, BLCA, BRCA, HNSC, LUAD, LUSC and UCEC (all P < 0.05).	('PRKDC', 'Gene', '5591', (9, 14))	('BRCA', 'Gene', (168, 172))	('PRKDC', 'Gene', (9, 14))	('COAD', 'Disease', 'MESH:D029424', (69, 73))	('TP53', 'Gene', '7157', (103, 107))	('mutations', 'Var', (15, 24))	('LUAD', 'Phenotype', 'HP:0030078', (80, 84))	('UCEC', 'Disease', (195, 199))	('BLCA', 'Disease', (162, 166))	('BRCA', 'Phenotype', 'HP:0003002', (168, 172))	('COAD', 'Disease', (69, 73))	('LUAD', 'Disease', (80, 84))	('LUSC', 'Disease', (186, 190))	('AML', 'Disease', 'MESH:D015470', (157, 160))	('LUAD', 'Phenotype', 'HP:0030078', (180, 184))	('AML', 'Disease', (157, 160))	('HNSC', 'Disease', (174, 178))	('BRCA', 'Gene', '672', (168, 172))	('LUSC', 'Phenotype', 'HP:0030359', (186, 190))	('TP53', 'Gene', (103, 107))	('LUAD', 'Disease', (180, 184))	('BLCA', 'Disease', (63, 67))	('UCEC', 'Disease', (89, 93))	('HNSC', 'Phenotype', 'HP:0012288', (174, 178))
488754	24132290	Mutations in POLQ and POLE associate with highfrequencies in multiple cancer types; POLE association in UCEC is consistent with previous observations.	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('Mutations', 'Var', (0, 9))	('UCEC', 'Disease', (104, 108))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('POLQ', 'Gene', (13, 17))	('POLQ', 'Gene', '10721', (13, 17))
488755	24132290	The frequency of thymine 1-bp (base pair) upstream of C>G transversions is markedly higher in BLCA, BRCA and HNSC than in other cancer types (Extended Data Fig.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('BLCA', 'Disease', (94, 98))	('BRCA', 'Gene', '672', (100, 104))	('HNSC', 'Phenotype', 'HP:0012288', (109, 113))	('thymine', 'Var', (17, 24))	('C>G transversions', 'Var', (54, 71))	('BRCA', 'Gene', (100, 104))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('HNSC', 'Disease', (109, 113))	('BRCA', 'Phenotype', 'HP:0003002', (100, 104))	('higher', 'PosReg', (84, 90))	('cancer', 'Disease', (128, 134))
488756	24132290	GBM, AML, COAD/READ and UCEC have similar contexts in that the proportions of guanine 1 base downstream of C>T transitions are between 59% and 67%, substantially higher than the approximately 40% in other cancer types.	('C>T transitions', 'Var', (107, 122))	('higher', 'PosReg', (162, 168))	('cancer', 'Disease', 'MESH:D009369', (205, 211))	('COAD', 'Disease', (10, 14))	('AML', 'Disease', 'MESH:D015470', (5, 8))	('cancer', 'Disease', (205, 211))	('guanine 1 base', 'MPA', (78, 92))	('AML', 'Disease', (5, 8))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('guanine', 'Chemical', 'MESH:D006147', (78, 85))	('COAD', 'Disease', 'MESH:D029424', (10, 14))
488757	24132290	Higher frequencies of transition mutations at CpG in gastrointestinal tumours, including colorectal, were previously reported.	('gastrointestinal tumours', 'Disease', 'MESH:D004067', (53, 77))	('CpG', 'Gene', (46, 49))	('gastrointestinal tumours', 'Disease', (53, 77))	('tumour', 'Phenotype', 'HP:0002664', (70, 76))	('colorectal', 'Disease', (89, 99))	('tumours', 'Phenotype', 'HP:0002664', (70, 77))	('transition mutations', 'Var', (22, 42))
488758	24132290	We found three additional cancer types (GBM, AML and UCEC) clustered in the C>T mutation at CpG, consistent with previous findings of aberrant DNA methylation in endometrial cancer and glioblastoma.	('endometrial cancer', 'Disease', (162, 180))	('additional cancer', 'Disease', 'MESH:D009369', (15, 32))	('glioblastoma', 'Disease', (185, 197))	('endometrial cancer', 'Phenotype', 'HP:0012114', (162, 180))	('glioblastoma', 'Disease', 'MESH:D005909', (185, 197))	('endometrial cancer', 'Disease', 'MESH:D016889', (162, 180))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('AML', 'Disease', 'MESH:D015470', (45, 48))	('glioblastoma', 'Phenotype', 'HP:0012174', (185, 197))	('additional cancer', 'Disease', (15, 32))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('C>T mutation', 'Var', (76, 88))	('AML', 'Disease', (45, 48))
488766	24132290	Notably, 3,053 out of 3,281 total samples (93%) across the Pan-Cancer collection had at least one non-synonymous mutation in at least one SMG.	('SMG', 'Gene', '23034', (138, 141))	('Cancer', 'Phenotype', 'HP:0002664', (63, 69))	('non-synonymous mutation', 'Var', (98, 121))	('SMG', 'Gene', (138, 141))
488767	24132290	The average number of point mutations and small indels in these genes varies across tumour types, with the highest (~6 mutations per tumour) in UCEC, LUAD and LUSC, and the lowest (~2 mutations per tumour) in AML, BRCA, KIRC and OV.	('tumour', 'Disease', (84, 90))	('tumour type', 'Disease', (84, 95))	('tumour', 'Phenotype', 'HP:0002664', (133, 139))	('tumour', 'Disease', 'MESH:D009369', (133, 139))	('tumour', 'Disease', (133, 139))	('point', 'Var', (22, 27))	('BRCA', 'Gene', (214, 218))	('LUSC', 'Phenotype', 'HP:0030359', (159, 163))	('LUAD', 'Phenotype', 'HP:0030078', (150, 154))	('BRCA', 'Phenotype', 'HP:0003002', (214, 218))	('tumour', 'Phenotype', 'HP:0002664', (198, 204))	('tumour', 'Disease', 'MESH:D009369', (198, 204))	('tumour', 'Disease', (198, 204))	('tumour type', 'Disease', 'MESH:D009369', (84, 95))	('AML', 'Disease', 'MESH:D015470', (209, 212))	('BRCA', 'Gene', '672', (214, 218))	('tumour', 'Phenotype', 'HP:0002664', (84, 90))	('AML', 'Disease', (209, 212))	('tumour', 'Disease', 'MESH:D009369', (84, 90))
488770	24132290	Its mutations predominate in serous ovarian (95%) and serous endometrial carcinomas (89%) (Fig.	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (61, 82))	('serous endometrial carcinomas', 'Phenotype', 'HP:0012887', (54, 83))	('serous endometrial carcinomas', 'Disease', 'MESH:D016889', (54, 83))	('serous ovarian', 'Disease', 'MESH:D010051', (29, 43))	('carcinomas', 'Phenotype', 'HP:0030731', (73, 83))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))	('serous ovarian', 'Disease', (29, 43))	('endometrial carcinomas', 'Phenotype', 'HP:0012114', (61, 83))	('mutations', 'Var', (4, 13))	('serous endometrial carcinomas', 'Disease', (54, 83))
488771	24132290	TP53 mutations are also associated with basal subtype breast tumours.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('associated', 'Reg', (24, 34))	('tumours', 'Phenotype', 'HP:0002664', (61, 68))	('mutations', 'Var', (5, 14))	('basal subtype breast tumours', 'Disease', 'MESH:D001943', (40, 68))	('basal subtype breast tumours', 'Disease', (40, 68))	('tumour', 'Phenotype', 'HP:0002664', (61, 67))
488773	24132290	PIK3CA mutations frequented UCEC (52%) and BRCA (33.6%), being specifically enriched in luminal subtype tumours.	('luminal subtype tumours', 'Disease', 'MESH:C535673', (88, 111))	('tumour', 'Phenotype', 'HP:0002664', (104, 110))	('PIK3CA', 'Gene', (0, 6))	('tumours', 'Phenotype', 'HP:0002664', (104, 111))	('PIK3CA', 'Gene', '5290', (0, 6))	('BRCA', 'Phenotype', 'HP:0003002', (43, 47))	('BRCA', 'Gene', '672', (43, 47))	('luminal subtype tumours', 'Disease', (88, 111))	('BRCA', 'Gene', (43, 47))	('mutations', 'Var', (7, 16))
488774	24132290	Tumours lacking PIK3CA mutations often had mutations in PIK3R1, with the highest occurrences in UCEC (31%) and GBM (11%) (Fig.	('PIK3CA', 'Gene', '5290', (16, 22))	('PIK3R1', 'Gene', '5295', (56, 62))	('GBM', 'Disease', (111, 114))	('PIK3R1', 'Gene', (56, 62))	('mutations', 'Var', (43, 52))	('occurrences', 'Reg', (81, 92))	('UCEC', 'Disease', (96, 100))	('PIK3CA', 'Gene', (16, 22))	('Tumours', 'Phenotype', 'HP:0002664', (0, 7))
488775	24132290	Many cancer types carried mutations in chromatin re-modelling genes.	('carried', 'Reg', (18, 25))	('cancer', 'Disease', 'MESH:D009369', (5, 11))	('cancer', 'Disease', (5, 11))	('mutations', 'Var', (26, 35))	('chromatin re-modelling genes', 'Gene', (39, 67))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))
488777	24132290	Mutations in ARID1A are frequent in BLCA, UCEC, LUAD and LUSC, whereas mutations in ARID5B predominate in UCEC (10%) (Fig.	('ARID5B', 'Gene', '84159', (84, 90))	('BLCA', 'Disease', (36, 40))	('ARID1A', 'Gene', '8289', (13, 19))	('LUAD', 'Phenotype', 'HP:0030078', (48, 52))	('ARID1A', 'Gene', (13, 19))	('LUAD', 'Disease', (48, 52))	('Mutations', 'Var', (0, 9))	('LUSC', 'Disease', (57, 61))	('frequent', 'Reg', (24, 32))	('LUSC', 'Phenotype', 'HP:0030359', (57, 61))	('UCEC', 'Disease', (42, 46))	('ARID5B', 'Gene', (84, 90))
488779	24132290	EGFR mutations are frequent in GBM (27%) and LUAD (11%).	('LUAD', 'Phenotype', 'HP:0030078', (45, 49))	('LUAD', 'Disease', (45, 49))	('EGFR', 'Gene', (0, 4))	('GBM', 'Disease', (31, 34))	('frequent', 'Reg', (19, 27))	('mutations', 'Var', (5, 14))	('EGFR', 'Gene', '1956', (0, 4))
488780	24132290	Recurrent, gain-of-function mutations in IDH1 (Arg 132) and/or IDH2 (Arg 172) typify GBM and AML (Supplementary Table 2 and Fig.	('Arg 172', 'Var', (69, 76))	('IDH2', 'Gene', '3418', (63, 67))	('Arg', 'Chemical', 'MESH:D001120', (69, 72))	('AML', 'Disease', (93, 96))	('Arg', 'Chemical', 'MESH:D001120', (47, 50))	('IDH1', 'Gene', (41, 45))	('GBM', 'Disease', (85, 88))	('IDH2', 'Gene', (63, 67))	('AML', 'Disease', 'MESH:D015470', (93, 96))	('gain-of-function', 'PosReg', (11, 27))	('Arg 132', 'Var', (47, 54))	('mutations', 'Var', (28, 37))	('IDH1', 'Gene', '3417', (41, 45))
488781	24132290	Although KRAS residues Gly 12 and Gly 13 are commonly mutated in LUAD, COAD/READ and UCEC, the proportion of Gly12Cys changes is significantly higher in lung cancer (P < 3.2 x 10-10), resulting from the high C>A transversion rate (Extended Data Fig.	('lung cancer', 'Disease', 'MESH:D008175', (153, 164))	('Gly', 'Chemical', 'MESH:D005998', (109, 112))	('Gly', 'Chemical', 'MESH:D005998', (23, 26))	('KRAS', 'Gene', (9, 13))	('COAD', 'Disease', 'MESH:D029424', (71, 75))	('LUAD', 'Phenotype', 'HP:0030078', (65, 69))	('Gly12Cys', 'Var', (109, 117))	('Gly', 'Chemical', 'MESH:D005998', (34, 37))	('lung cancer', 'Disease', (153, 164))	('Gly12Cys', 'Mutation', 'rs121913530', (109, 117))	('KRAS', 'Gene', '3845', (9, 13))	('lung cancer', 'Phenotype', 'HP:0100526', (153, 164))	('COAD', 'Disease', (71, 75))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
488783	24132290	Mutations to BAP1 (10%) and SETD2 (12%) are also most common in KIRC.	('BAP1', 'Gene', (13, 17))	('KIRC', 'Disease', (64, 68))	('Mutations', 'Var', (0, 9))	('SETD2', 'Gene', '29072', (28, 33))	('common', 'Reg', (54, 60))	('BAP1', 'Gene', '8314', (13, 17))	('SETD2', 'Gene', (28, 33))
488785	24132290	Predominant COAD/READ-specific mutations are those affecting APC (82%) and Wnt/beta-catenin signalling (93% of samples).	('mutations', 'Var', (31, 40))	('APC', 'Disease', 'MESH:D011125', (61, 64))	('COAD', 'Disease', 'MESH:D029424', (12, 16))	('beta-catenin', 'Gene', '1499', (79, 91))	('APC', 'Disease', (61, 64))	('affecting', 'Reg', (51, 60))	('COAD', 'Disease', (12, 16))	('beta-catenin', 'Gene', (79, 91))
488786	24132290	Several mutations occur exclusively in AML, including recurrent mutations in NPM1 (27%) and FLT3 (27%), and rare mutations affecting MIR142 (Fig.	('AML', 'Disease', 'MESH:D015470', (39, 42))	('FLT3', 'Gene', '2322', (92, 96))	('NPM1', 'Gene', (77, 81))	('NPM1', 'Gene', '4869', (77, 81))	('AML', 'Disease', (39, 42))	('MIR142', 'Gene', (133, 139))	('mutations', 'Var', (64, 73))	('FLT3', 'Gene', (92, 96))	('MIR142', 'Gene', '406934', (133, 139))
488787	24132290	Mutations of methylation and chromatin modifiers are also typical in AML, mostly affecting DNMT3A and TET2.	('AML', 'Disease', (69, 72))	('affecting', 'Reg', (81, 90))	('DNMT3A', 'Gene', (91, 97))	('DNMT3A', 'Gene', '1788', (91, 97))	('TET2', 'Gene', '54790', (102, 106))	('Mutations', 'Var', (0, 9))	('TET2', 'Gene', (102, 106))	('AML', 'Disease', 'MESH:D015470', (69, 72))
488788	24132290	BRCA-specific mutations include GATA3 and MAP3K1, whereas KEAP1 mutations predominate in lung cancer (LUAD 17%, LUSC 12%).	('KEAP1', 'Gene', '9817', (58, 63))	('MAP3K1', 'Gene', '4214', (42, 48))	('BRCA', 'Gene', (0, 4))	('lung cancer', 'Disease', (89, 100))	('lung cancer', 'Phenotype', 'HP:0100526', (89, 100))	('LUSC', 'Phenotype', 'HP:0030359', (112, 116))	('KEAP1', 'Gene', (58, 63))	('GATA3', 'Gene', (32, 37))	('BRCA', 'Phenotype', 'HP:0003002', (0, 4))	('MAP3K1', 'Gene', (42, 48))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('mutations', 'Var', (64, 73))	('GATA3', 'Gene', '2625', (32, 37))	('lung cancer', 'Disease', 'MESH:D008175', (89, 100))	('mutations', 'Var', (14, 23))	('LUAD', 'Phenotype', 'HP:0030078', (102, 106))	('BRCA', 'Gene', '672', (0, 4))
488790	24132290	Cluster analysis on mutations in SMGs (Fig.	('SMG', 'Gene', (33, 36))	('mutations', 'Var', (20, 29))	('SMG', 'Gene', '23034', (33, 36))
488793	24132290	Two major endometrial endometroid clusters were found, one having mutations in PIK3CA, PTEN and ARID1A, and the other containing mutations in two additional genes (PIK3R1 and CTNNB1).	('mutations', 'Var', (66, 75))	('PTEN', 'Gene', (87, 91))	('PIK3R1', 'Gene', '5295', (164, 170))	('PTEN', 'Gene', '5728', (87, 91))	('PIK3R1', 'Gene', (164, 170))	('CTNNB1', 'Gene', (175, 181))	('ARID1A', 'Gene', '8289', (96, 102))	('mutations', 'Reg', (129, 138))	('ARID1A', 'Gene', (96, 102))	('PIK3CA', 'Gene', (79, 85))	('CTNNB1', 'Gene', '1499', (175, 181))	('PIK3CA', 'Gene', '5290', (79, 85))
488794	24132290	Five major breast cancer clusters were observed, with mutations in CDH1, GATA3, MAP3K1, PIK3CA and TP53 as drivers for respective clusters.	('breast cancer clusters', 'Disease', (11, 33))	('TP53', 'Gene', (99, 103))	('GATA3', 'Gene', (73, 78))	('PIK3CA', 'Gene', '5290', (88, 94))	('mutations', 'Var', (54, 63))	('GATA3', 'Gene', '2625', (73, 78))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('TP53', 'Gene', '7157', (99, 103))	('MAP3K1', 'Gene', (80, 86))	('breast cancer', 'Phenotype', 'HP:0003002', (11, 24))	('CDH1', 'Gene', (67, 71))	('PIK3CA', 'Gene', (88, 94))	('CDH1', 'Gene', '999', (67, 71))	('MAP3K1', 'Gene', '4214', (80, 86))	('breast cancer clusters', 'Disease', 'MESH:D001943', (11, 33))
488796	24132290	The glioblastoma cluster is characterized by mutations in EGFR.	('EGFR', 'Gene', '1956', (58, 62))	('mutations', 'Var', (45, 54))	('glioblastoma cluster', 'Disease', (4, 24))	('EGFR', 'Gene', (58, 62))	('glioblastoma cluster', 'Disease', 'MESH:D005909', (4, 24))	('glioblastoma', 'Phenotype', 'HP:0012174', (4, 16))
488797	24132290	Two kidney clear cell cancer clusters were detected; both have VHL as the common driver and one has additional mutations in PBRM1 and/or BAP1 (refs).	('BAP1', 'Gene', (137, 141))	('mutations', 'Var', (111, 120))	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('cancer', 'Disease', (22, 28))	('VHL', 'Disease', 'MESH:D006623', (63, 66))	('VHL', 'Disease', (63, 66))	('PBRM1', 'Gene', (124, 129))	('BAP1', 'Gene', '8314', (137, 141))	('clear cell cancer', 'Phenotype', 'HP:0006770', (11, 28))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('PBRM1', 'Gene', '55193', (124, 129))
488798	24132290	PBRM1 and BAP1 mutations are mutually exclusive in KIRC (P = 0.006), consistent with previous reports.	('BAP1', 'Gene', (10, 14))	('mutations', 'Var', (15, 24))	('PBRM1', 'Gene', (0, 5))	('PBRM1', 'Gene', '55193', (0, 5))	('BAP1', 'Gene', '8314', (10, 14))
488799	24132290	AML has three major clusters represented by various combinations of DNMT3A, NPM1 and FLT3 mutations, and one cluster dominated by RUNX1 mutations.	('mutations', 'Var', (90, 99))	('NPM1', 'Gene', '4869', (76, 80))	('DNMT3A', 'Gene', (68, 74))	('DNMT3A', 'Gene', '1788', (68, 74))	('FLT3', 'Gene', '2322', (85, 89))	('RUNX1', 'Gene', (130, 135))	('AML', 'Disease', 'MESH:D015470', (0, 3))	('RUNX1', 'Gene', '861', (130, 135))	('FLT3', 'Gene', (85, 89))	('NPM1', 'Gene', (76, 80))	('AML', 'Disease', (0, 3))
488800	24132290	One cluster having APC and KRAS mutations was almost exclusively detected in COAD/READ.	('APC', 'Disease', 'MESH:D011125', (19, 22))	('KRAS', 'Gene', '3845', (27, 31))	('APC', 'Disease', (19, 22))	('COAD', 'Disease', 'MESH:D029424', (77, 81))	('mutations', 'Var', (32, 41))	('KRAS', 'Gene', (27, 31))	('COAD', 'Disease', (77, 81))
488802	24132290	TP53 and CDH1 are exclusive in BRCA, with mutations enriched in different subtypes, as are TP53 and CTNNB1 in UCEC.	('TP53', 'Gene', (91, 95))	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('BRCA', 'Phenotype', 'HP:0003002', (31, 35))	('BRCA', 'Gene', '672', (31, 35))	('BRCA', 'Gene', (31, 35))	('CDH1', 'Gene', (9, 13))	('CTNNB1', 'Gene', (100, 106))	('CDH1', 'Gene', '999', (9, 13))	('TP53', 'Gene', '7157', (91, 95))	('mutations', 'Var', (42, 51))	('CTNNB1', 'Gene', '1499', (100, 106))
488803	24132290	Cohort analysis identified pairs where at least one gene has mutations strongly associated (corrected P < 0.05) to one cancer type, and also identifies TP53 and PIK3CA with significant exclusivity (Extended Data Fig.	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('TP53', 'Gene', '7157', (152, 156))	('mutations', 'Var', (61, 70))	('PIK3CA', 'Gene', (161, 167))	('cancer', 'Disease', (119, 125))	('PIK3CA', 'Gene', '5290', (161, 167))	('associated', 'Reg', (80, 90))	('TP53', 'Gene', (152, 156))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
488806	24132290	Not surprisingly, many are associated (P < 0.05) with one cancer type (for example, VHL mutations in KIRC), demonstrating a strong relationship between exclusivity and tissue of origin.	('VHL', 'Disease', (84, 87))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('mutations', 'Var', (88, 97))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('cancer', 'Disease', (58, 64))	('VHL', 'Disease', 'MESH:D006623', (84, 87))
488813	24132290	Some findings are unsurprising, such as the correlation of TP53 mutations with generally unfavourable indicators, for example in tumour stage (P = 0.01, Fisher's exact test) and elapsed time to death (P = 0.006, Wilcoxon) in HNSC, age (P = 0.002, Wilcoxon rank test) and time to death (P = 0.09, Wilcoxon) in AML, and vital status in OV (P = 0.04, Fisher).	('tumour', 'Phenotype', 'HP:0002664', (129, 135))	('AML', 'Disease', (309, 312))	('TP53', 'Gene', (59, 63))	('HNSC', 'Phenotype', 'HP:0012288', (225, 229))	('tumour', 'Disease', 'MESH:D009369', (129, 135))	('tumour', 'Disease', (129, 135))	('AML', 'Disease', 'MESH:D015470', (309, 312))	('mutations', 'Var', (64, 73))	('TP53', 'Gene', '7157', (59, 63))
488814	24132290	In UCEC, mutations in several genes are correlated with the endometrioid rather than serous subtype: PTEN, CTNNB1, PIK3R1, KRAS, ARID1A, CTCF, RPL22 and ARID5B (all P < 0.03) (Supplementary Table 9).	('PTEN', 'Gene', (101, 105))	('endometrioid', 'Disease', (60, 72))	('mutations', 'Var', (9, 18))	('PIK3R1', 'Gene', (115, 121))	('CTNNB1', 'Gene', (107, 113))	('KRAS', 'Gene', (123, 127))	('CTCF', 'Gene', (137, 141))	('RPL22', 'Gene', '6146', (143, 148))	('ARID5B', 'Gene', '84159', (153, 159))	('ARID1A', 'Gene', (129, 135))	('PTEN', 'Gene', '5728', (101, 105))	('RPL22', 'Gene', (143, 148))	('ARID5B', 'Gene', (153, 159))	('ARID1A', 'Gene', '8289', (129, 135))	('PIK3R1', 'Gene', '5295', (115, 121))	('correlated', 'Reg', (40, 50))	('CTNNB1', 'Gene', '1499', (107, 113))	('CTCF', 'Gene', '10664', (137, 141))	('KRAS', 'Gene', '3845', (123, 127))
488815	24132290	We examined which genes correlate with survival using the Cox proportional hazards model, first analysing individual cancer types using age and gender as covariates; an average of 2 genes (range: 0-4) with mutation frequency >=2% were significant (P <= 0.05) in each type (Supplementary Table 10a and Extended Data Fig.	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('significant', 'Reg', (235, 246))	('mutation', 'Var', (206, 214))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('cancer', 'Disease', (117, 123))
488816	24132290	KDM6A and ARID1A mutations correlate with better survival in BLCA (P = 0.03, hazard ratio (HR) = 0.36, 95% confidence interval (CI): 0.14-0.92) and UCEC (P = 0.03, HR = 0.11, 95% CI: 0.01-0.84), respectively, but mutations in SETBP1, recently identified with worse prognosis in atypical chronic myeloid leukaemia (aCML), have a significant detrimental effect in HNSC (P = 0.006, HR = 3.21, 95% CI: 1.39-7.44).	('HNSC', 'Phenotype', 'HP:0012288', (362, 366))	('chronic myeloid leukaemia', 'Disease', 'MESH:D015464', (287, 312))	('chronic myeloid leukaemia', 'Phenotype', 'HP:0005506', (287, 312))	('SETBP1', 'Gene', (226, 232))	('HNSC', 'Disease', (362, 366))	('ARID1A', 'Gene', '8289', (10, 16))	('myeloid leukaemia', 'Phenotype', 'HP:0012324', (295, 312))	('ARID1A', 'Gene', (10, 16))	('KDM6A', 'Gene', '7403', (0, 5))	('detrimental', 'NegReg', (340, 351))	('chronic myeloid leukaemia', 'Disease', (287, 312))	('mutations', 'Var', (213, 222))	('SETBP1', 'Gene', '26040', (226, 232))	('KDM6A', 'Gene', (0, 5))
488818	24132290	Conversely, BRCA2 mutations (P = 0.02, HR = 0.31, 95% CI: 0.12-0.85) associate with better survival in ovarian cancer, consistent with previous reports; BRCA1 mutations showed positive correlation with better survival, but did not reach significance here.	('mutations', 'Var', (159, 168))	('BRCA2', 'Gene', (12, 17))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('BRCA1', 'Gene', '672', (153, 158))	('BRCA', 'Phenotype', 'HP:0003002', (153, 157))	('ovarian cancer', 'Phenotype', 'HP:0100615', (103, 117))	('BRCA', 'Phenotype', 'HP:0003002', (12, 16))	('ovarian cancer', 'Disease', 'MESH:D010051', (103, 117))	('BRCA2', 'Gene', '675', (12, 17))	('BRCA1', 'Gene', (153, 158))	('better', 'PosReg', (84, 90))	('ovarian cancer', 'Disease', (103, 117))	('mutations', 'Var', (18, 27))
488819	24132290	We extended our survival analysis across cancer types, restricting our attention to the subset of 97 SMGs whose mutations appeared in >=2% of patients having survival data in >=2 tumour types.	('SMG', 'Gene', (101, 104))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('SMG', 'Gene', '23034', (101, 104))	('tumour', 'Phenotype', 'HP:0002664', (179, 185))	('mutations', 'Var', (112, 121))	('tumour type', 'Disease', (179, 190))	('tumour type', 'Disease', 'MESH:D009369', (179, 190))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('patients', 'Species', '9606', (142, 150))
488821	24132290	In particular, BAP1 was highly significant (P = 0.00013, HR = 2.20, 95% CI: 1.47-3.29, more than 53 mutated tumours out of 888 total), with mutations associating with detrimental outcome in four tumour types and notable associations in KIRC (P = 0.00079), consistent with a recent report, and in UCEC (P = 0.066).	('tumours', 'Disease', (108, 115))	('associations', 'Interaction', (220, 232))	('KIRC', 'Disease', (236, 240))	('tumour type', 'Disease', (195, 206))	('detrimental', 'Reg', (167, 178))	('BAP1', 'Gene', '8314', (15, 19))	('tumour type', 'Disease', 'MESH:D009369', (195, 206))	('tumour', 'Phenotype', 'HP:0002664', (108, 114))	('tumours', 'Phenotype', 'HP:0002664', (108, 115))	('mutations', 'Var', (140, 149))	('tumours', 'Disease', 'MESH:D009369', (108, 115))	('UCEC', 'Disease', (296, 300))	('BAP1', 'Gene', (15, 19))	('tumour', 'Phenotype', 'HP:0002664', (195, 201))
488822	24132290	Mutations in several other genes are detrimental, including DNMT3A (HR = 1.59), previously identified with poor prognosis in AML, and KDM5C (HR = 1.63), FBXW7 (HR = 1.57) and TP53 (HR = 1.19).	('AML', 'Disease', 'MESH:D015470', (125, 128))	('FBXW7', 'Gene', (153, 158))	('TP53', 'Gene', (175, 179))	('AML', 'Disease', (125, 128))	('DNMT3A', 'Gene', (60, 66))	('KDM5C', 'Gene', (134, 139))	('DNMT3A', 'Gene', '1788', (60, 66))	('KDM5C', 'Gene', '8242', (134, 139))	('Mutations', 'Var', (0, 9))	('FBXW7', 'Gene', '55294', (153, 158))	('TP53', 'Gene', '7157', (175, 179))
488825	24132290	IDH1 mutations are associated with improved prognosis across the Pan-Cancer set (HR = 0.67, P = 0.16) and also in GBM (HR = 0.42, P = 0.09) (Supplementary Table 10a, b), consistent with previous work.	('prognosis', 'MPA', (44, 53))	('improved', 'PosReg', (35, 43))	('mutations', 'Var', (5, 14))	('Cancer', 'Phenotype', 'HP:0002664', (69, 75))	('IDH1', 'Gene', (0, 4))	('IDH1', 'Gene', '3417', (0, 4))
488826	24132290	To understand the temporal order of somatic events, we analysed the variant allele fraction (VAF) distribution of mutations in SMGs across AML, BRCA and UCEC (Fig.	('BRCA', 'Gene', (144, 148))	('AML', 'Disease', 'MESH:D015470', (139, 142))	('mutations', 'Var', (114, 123))	('SMG', 'Gene', (127, 130))	('AML', 'Disease', (139, 142))	('SMG', 'Gene', '23034', (127, 130))	('BRCA', 'Phenotype', 'HP:0003002', (144, 148))	('BRCA', 'Gene', '672', (144, 148))
488828	24132290	Mutations in TP53 have higher VAFs on average in all three cancer types, suggesting early appearance during tumorigenesis, although it is possible that a later mutation contributing to tumour cell expansion might have a high VAF.	('TP53', 'Gene', (13, 17))	('higher', 'PosReg', (23, 29))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('tumour', 'Phenotype', 'HP:0002664', (185, 191))	('Mutations', 'Var', (0, 9))	('tumour', 'Disease', 'MESH:D009369', (185, 191))	('VAFs', 'CPA', (30, 34))	('TP53', 'Gene', '7157', (13, 17))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('tumour', 'Disease', (185, 191))
488833	24132290	Conversely, KRAS and/or NRAS mutations tend to have lower VAFs in all three tumour types (Fig.	('NRAS', 'Gene', '4893', (24, 28))	('mutations', 'Var', (29, 38))	('lower', 'NegReg', (52, 57))	('tumour', 'Phenotype', 'HP:0002664', (76, 82))	('KRAS', 'Gene', (12, 16))	('KRAS', 'Gene', '3845', (12, 16))	('tumour type', 'Disease', 'MESH:D009369', (76, 87))	('tumour type', 'Disease', (76, 87))	('NRAS', 'Gene', (24, 28))	('VAFs', 'MPA', (58, 62))
488837	24132290	Using 50 AML WGS cases, sciClone (http://github.com/genome/sciclone) detected DNMT3A mutations in the founding clone for 100% (8 out of 8) of cases and NRAS mutations in the subclone for 75% (3 out of 4) of cases (Extended Data Fig.	('AML', 'Disease', 'MESH:D015470', (9, 12))	('NRAS', 'Gene', (152, 156))	('DNMT3A', 'Gene', (78, 84))	('DNMT3A', 'Gene', '1788', (78, 84))	('AML', 'Disease', (9, 12))	('NRAS', 'Gene', '4893', (152, 156))	('mutations', 'Var', (157, 166))	('mutations', 'Var', (85, 94))
488840	24132290	In BRCA, 95% (62 out of 65) of cases contained PIK3CA mutations in the founding clone, whereas 33% (3 out of 9) of cases had MLL3 mutations in the subclone.	('PIK3CA', 'Gene', (47, 53))	('contained', 'Reg', (37, 46))	('BRCA', 'Gene', (3, 7))	('BRCA', 'Gene', '672', (3, 7))	('PIK3CA', 'Gene', '5290', (47, 53))	('MLL3', 'Gene', '58508', (125, 129))	('mutations', 'Var', (54, 63))	('MLL3', 'Gene', (125, 129))	('BRCA', 'Phenotype', 'HP:0003002', (3, 7))
488841	24132290	Similar patterns were found in UCEC tumours, with 96% (65 out of 68) and 95% (62 out of 65) of tumours containing PIK3CA and PTEN mutations, respectively, in the founding clone, and 9% (2 out of 22) of KRAS and 14% (1 out of 7) of NRAS mutations in the subclone (Extended Data Fig.	('PIK3CA', 'Gene', '5290', (114, 120))	('tumours', 'Phenotype', 'HP:0002664', (36, 43))	('PTEN', 'Gene', (125, 129))	('tumours', 'Disease', 'MESH:D009369', (36, 43))	('UCEC tumours', 'Disease', (31, 43))	('tumour', 'Phenotype', 'HP:0002664', (36, 42))	('KRAS', 'Gene', (202, 206))	('NRAS', 'Gene', (231, 235))	('PTEN', 'Gene', '5728', (125, 129))	('tumours', 'Disease', (95, 102))	('PIK3CA', 'Gene', (114, 120))	('UCEC tumours', 'Disease', 'MESH:D009369', (31, 43))	('tumours', 'Phenotype', 'HP:0002664', (95, 102))	('tumours', 'Disease', 'MESH:D009369', (95, 102))	('mutations', 'Var', (236, 245))	('tumour', 'Phenotype', 'HP:0002664', (95, 101))	('tumours', 'Disease', (36, 43))	('NRAS', 'Gene', '4893', (231, 235))	('mutations', 'Var', (130, 139))	('KRAS', 'Gene', '3845', (202, 206))
488844	24132290	Although a common set of driver mutations exists in each cancer type, the combination of drivers within a cancer type and their distribution within the founding clone and subclones varies for individual patients.	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('cancer', 'Disease', (57, 63))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('patients', 'Species', '9606', (203, 211))	('mutations', 'Var', (32, 41))	('cancer', 'Disease', (106, 112))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
488851	24132290	Finally, the TCGA disease analysis working groups (AWGs) may optionally perform manual curation of the variant calls, in which false positives are removed and true negatives are recovered.	('TCGA', 'Disease', (13, 17))	('TC', 'Chemical', 'MESH:D013667', (13, 15))	('variant', 'Var', (103, 110))	('CG', 'Chemical', 'MESH:C028505', (14, 16))
488853	24132290	Complete standardization of sensitivity could not be attained, as it would have required a uniform variant calling and filtering workflow across all tumour-normal pairs.	('tumour', 'Disease', 'MESH:D009369', (149, 155))	('tumour', 'Phenotype', 'HP:0002664', (149, 155))	('variant', 'Var', (99, 106))	('tumour', 'Disease', (149, 155))
488860	24132290	We used correlation modules in the mutational significance in cancer (MuSiC) package to identify genes with mutations that are positively correlated with the number of mutations in the tumour sample.	('mutations', 'Var', (108, 117))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('tumour', 'Phenotype', 'HP:0002664', (185, 191))	('tumour', 'Disease', 'MESH:D009369', (185, 191))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('tumour', 'Disease', (185, 191))
488871	24132290	Tumours with zero detected somatic mutations were also excluded, resulting in mutations from 2,611 tumours for downstream clustering analysis.	('tumours', 'Phenotype', 'HP:0002664', (99, 106))	('tumours', 'Disease', 'MESH:D009369', (99, 106))	('mutations', 'Var', (78, 87))	('tumours', 'Disease', (99, 106))	('tumour', 'Phenotype', 'HP:0002664', (99, 105))	('Tumours', 'Phenotype', 'HP:0002664', (0, 7))
488872	24132290	For instance, eight LUAD and two LUSC tumours are in the solid colorectal cluster, largely owing to their KRAS mutations (Fig.	('tumours', 'Disease', (38, 45))	('mutations', 'Var', (111, 120))	('KRAS', 'Gene', '3845', (106, 110))	('LUAD', 'Phenotype', 'HP:0030078', (20, 24))	('solid colorectal cluster', 'Disease', (57, 81))	('tumour', 'Phenotype', 'HP:0002664', (38, 44))	('LUSC', 'Phenotype', 'HP:0030359', (33, 37))	('tumours', 'Phenotype', 'HP:0002664', (38, 45))	('KRAS', 'Gene', (106, 110))	('tumours', 'Disease', 'MESH:D009369', (38, 45))	('solid colorectal cluster', 'Disease', 'MESH:D015179', (57, 81))
488873	24132290	Three UCEC, two GBM, one OV and one HSNC samples are in the BRCA cluster courtesy of TP53 and PIK3CA mutations.	('TP53', 'Gene', (85, 89))	('mutations', 'Var', (101, 110))	('PIK3CA', 'Gene', (94, 100))	('BRCA', 'Phenotype', 'HP:0003002', (60, 64))	('BRCA', 'Gene', '672', (60, 64))	('TP53', 'Gene', '7157', (85, 89))	('BRCA', 'Gene', (60, 64))	('PIK3CA', 'Gene', '5290', (94, 100))
488878	24132290	From these 1,000 genes, we discarded the ones with mutations strongly associated (Bonferroni corrected P <= 0.05 by Fisher's exact test) with a cancer type, and this resulted in 600 genes for Dendrix analysis.	('mutations', 'Var', (51, 60))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('associated', 'Reg', (70, 80))	('cancer', 'Disease', (144, 150))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
488894	24132290	Notably, we observed at least a twofold increase of variant allele expressions in 3.9%, 12.9% and 5.9% of mutations from SMGs in AML (for example, TP53, STAG2 and SMC3), BRCA (for example, CDH1, TP53, GATA3 and MLL3), and UCEC (for example, ARID1A and FGFR2), respectively (Supplementary Table 11a).	('CDH1', 'Gene', '999', (189, 193))	('AML', 'Disease', 'MESH:D015470', (129, 132))	('GATA3', 'Gene', (201, 206))	('BRCA', 'Phenotype', 'HP:0003002', (170, 174))	('STAG2', 'Gene', (153, 158))	('ARID1A', 'Gene', (241, 247))	('MLL3', 'Gene', '58508', (211, 215))	('AML', 'Disease', (129, 132))	('FGFR2', 'Gene', '2263', (252, 257))	('SMG', 'Gene', '23034', (121, 124))	('TP53', 'Gene', (147, 151))	('CDH1', 'Gene', (189, 193))	('TP53', 'Gene', (195, 199))	('SMC3', 'Gene', '9126', (163, 167))	('BRCA', 'Gene', '672', (170, 174))	('ARID1A', 'Gene', '8289', (241, 247))	('MLL3', 'Gene', (211, 215))	('BRCA', 'Gene', (170, 174))	('TP53', 'Gene', '7157', (147, 151))	('TP53', 'Gene', '7157', (195, 199))	('SMG', 'Gene', (121, 124))	('SMC3', 'Gene', (163, 167))	('increase', 'PosReg', (40, 48))	('STAG2', 'Gene', '10735', (153, 158))	('GATA3', 'Gene', '2625', (201, 206))	('mutations', 'Var', (106, 115))	('FGFR2', 'Gene', (252, 257))
488895	24132290	We further compared expression level distributions across mutations from SMGs and non-SMGs.	('mutations', 'Var', (58, 67))	('compared', 'Reg', (11, 19))	('SMG', 'Gene', '23034', (73, 76))	('SMG', 'Gene', (86, 89))	('SMG', 'Gene', (73, 76))	('SMG', 'Gene', '23034', (86, 89))	('expression level', 'MPA', (20, 36))
488913	33592580	Research has demonstrated that the interaction between programmed cell death protein-1 (PD-1) and programmed cell death ligand-1 (PD-L1) is a critical immune checkpoint, and inhibiting PD-1 has been found to exhibit high treatment efficacy for melanoma and is now approved for the treatment of HNSC.	('melanoma', 'Disease', 'MESH:D008545', (244, 252))	('inhibiting', 'Var', (174, 184))	('programmed cell death protein-1', 'Gene', '100533201', (55, 86))	('PD-1', 'Gene', (185, 189))	('PD-L1', 'Gene', '574058', (130, 135))	('interaction', 'Interaction', (35, 46))	('programmed cell death protein-1', 'Gene', (55, 86))	('PD-L1', 'Gene', (130, 135))	('HNSC', 'Phenotype', 'HP:0012288', (294, 298))	('programmed cell death ligand-1', 'Gene', (98, 128))	('programmed cell death ligand-1', 'Gene', '574058', (98, 128))	('melanoma', 'Phenotype', 'HP:0002861', (244, 252))	('melanoma', 'Disease', (244, 252))
488941	33592580	Among them, cg12798052 in the promoter region, cg03030757 and cg18744234 in the gene enhancement region, and cg15267307 in the transcription region were detected with significant hypermethylation (Figure 7).	('cg18744234', 'Var', (62, 72))	('cg18744234', 'Chemical', '-', (62, 72))	('cg12798052', 'Var', (12, 22))	('cg12798052', 'Chemical', '-', (12, 22))	('cg15267307', 'Chemical', '-', (109, 119))	('cg03030757', 'Var', (47, 57))	('cg15267307', 'Var', (109, 119))	('cg03030757', 'Chemical', '-', (47, 57))
488943	33592580	We also observed that the hypermethylation status of cg09490277 was significantly positively correlated with the expression of FANCE, while no significant effect of methylation status at other five methylation sites on the expression of FANCE was observed.	('expression', 'MPA', (113, 123))	('FANCE', 'Gene', '2178', (127, 132))	('FA', 'Phenotype', 'HP:0001994', (127, 129))	('FANCE', 'Gene', '2178', (237, 242))	('correlated', 'Reg', (93, 103))	('FA', 'Phenotype', 'HP:0001994', (237, 239))	('hypermethylation', 'MPA', (26, 42))	('cg09490277', 'Chemical', '-', (53, 63))	('positively', 'PosReg', (82, 92))	('FANCE', 'Gene', (127, 132))	('FANCE', 'Gene', (237, 242))	('cg09490277', 'Var', (53, 63))
488983	33592580	Since FANCE was found to be closely related to the infiltration of a variety of cells in the immune microenvironment, we are interested in whether changes in FANCE expression can predict the prognosis of other cancers.	('FANCE', 'Gene', '2178', (158, 163))	('FA', 'Phenotype', 'HP:0001994', (6, 8))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('cancers', 'Phenotype', 'HP:0002664', (210, 217))	('changes', 'Var', (147, 154))	('FANCE', 'Gene', (6, 11))	('cancers', 'Disease', 'MESH:D009369', (210, 217))	('FANCE', 'Gene', (158, 163))	('cancers', 'Disease', (210, 217))	('predict', 'Reg', (179, 186))	('FA', 'Phenotype', 'HP:0001994', (158, 160))	('FANCE', 'Gene', '2178', (6, 11))
488984	33592580	As shown in Figure 15, in five types of tumors: cervical squamous cell carcinoma, esophageal squamous cell carcinoma, gastric cancer, lung squamous cell carcinoma, and rectal adenocarcinoma, high expression of FANCE predicts a good prognosis.	('esophageal squamous cell carcinoma', 'Disease', (82, 116))	('FA', 'Phenotype', 'HP:0001994', (210, 212))	('carcinoma', 'Phenotype', 'HP:0030731', (153, 162))	('adenocarcinoma', 'Disease', 'MESH:D000230', (175, 189))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumors', 'Disease', (40, 46))	('FANCE', 'Gene', (210, 215))	('gastric cancer', 'Disease', (118, 132))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('FANCE', 'Gene', '2178', (210, 215))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (82, 116))	('tumors', 'Disease', 'MESH:D009369', (40, 46))	('high expression', 'Var', (191, 206))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (134, 162))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (139, 162))	('carcinoma', 'Phenotype', 'HP:0030731', (180, 189))	('gastric cancer', 'Disease', 'MESH:D013274', (118, 132))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (93, 116))	('cervical squamous cell carcinoma', 'Disease', (48, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('adenocarcinoma', 'Disease', (175, 189))	('cervical squamous cell carcinoma', 'Disease', 'MESH:D002294', (48, 80))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (134, 162))	('lung squamous cell carcinoma', 'Disease', (134, 162))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (57, 80))	('gastric cancer', 'Phenotype', 'HP:0012126', (118, 132))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))
488987	33592580	However, in uterine corpus endometrial carcinoma, sarcoma, pheochromocytoma and paraganglioma, high expression of FANCE is significantly associated with poor prognosis.	('associated', 'Reg', (137, 147))	('FA', 'Phenotype', 'HP:0001994', (114, 116))	('glioma', 'Phenotype', 'HP:0009733', (87, 93))	('paraganglioma', 'Phenotype', 'HP:0002668', (80, 93))	('pheochromocytoma', 'Disease', 'MESH:D010673', (59, 75))	('FANCE', 'Gene', (114, 119))	('endometrial carcinoma', 'Disease', (27, 48))	('FANCE', 'Gene', '2178', (114, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (39, 48))	('pheochromocytoma', 'Disease', (59, 75))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (59, 75))	('high expression', 'Var', (95, 110))	('sarcoma', 'Disease', 'MESH:D012509', (50, 57))	('sarcoma', 'Disease', (50, 57))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (27, 48))	('paraganglioma', 'Disease', (80, 93))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (27, 48))	('paraganglioma', 'Disease', 'MESH:D010235', (80, 93))	('sarcoma', 'Phenotype', 'HP:0100242', (50, 57))
488990	33592580	We found that FANCE was highly expressed in HNSC, and hypomethylation of specific methylation sites could be an important reason for the up-regulation.	('FANCE', 'Gene', '2178', (14, 19))	('hypomethylation', 'Var', (54, 69))	('HNSC', 'Phenotype', 'HP:0012288', (44, 48))	('FA', 'Phenotype', 'HP:0001994', (14, 16))	('up-regulation', 'PosReg', (137, 150))	('FANCE', 'Gene', (14, 19))
488992	33592580	The expression of FANCE significantly suppressed the infiltration levels of CD4+ T cells, neutrophils, macrophages, and DCs, as well as the marker genes of subclasses of CD4+ T cells and M2 macrophage.	('age', 'Gene', '5973', (110, 113))	('FANCE', 'Gene', '2178', (18, 23))	('age', 'Gene', '5973', (197, 200))	('suppressed', 'NegReg', (38, 48))	('CD4', 'Gene', (76, 79))	('FA', 'Phenotype', 'HP:0001994', (18, 20))	('age', 'Gene', (110, 113))	('CD4', 'Gene', (170, 173))	('expression', 'Var', (4, 14))	('CD4', 'Gene', '920', (76, 79))	('CD4', 'Gene', '920', (170, 173))	('age', 'Gene', (197, 200))	('FANCE', 'Gene', (18, 23))
489007	33592580	Novel evidence demonstrated that mutation of FA genes predisposed to development of different cancers.	('cancers', 'Disease', 'MESH:D009369', (94, 101))	('mutation', 'Var', (33, 41))	('FA', 'Phenotype', 'HP:0001994', (45, 47))	('FA genes', 'Gene', (45, 53))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('predisposed', 'Reg', (54, 65))	('cancers', 'Phenotype', 'HP:0002664', (94, 101))	('cancers', 'Disease', (94, 101))
489008	33592580	Single nucleotide polymorphisms of FANCE in the DNA repair pathways have been associated with increased risk of esophageal cancer.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('associated', 'Reg', (78, 88))	('DNA repair pathways', 'Pathway', (48, 67))	('FANCE', 'Gene', (35, 40))	('Single nucleotide polymorphisms', 'Var', (0, 31))	('age', 'Gene', '5973', (117, 120))	('FANCE', 'Gene', '2178', (35, 40))	('FA', 'Phenotype', 'HP:0001994', (35, 37))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('cancer', 'Disease', (123, 129))	('age', 'Gene', (117, 120))
489009	33592580	The study by Bonache showed that FANCE was included in the gene set of 18 genes with loss-of-function variants in breast or ovarian cancer patients, three of which also carried pathogenic variants in known cancer genes.	('variants', 'Var', (102, 110))	('cancer', 'Disease', (132, 138))	('breast or ovarian cancer', 'Disease', 'MESH:D001943', (114, 138))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('patients', 'Species', '9606', (139, 147))	('loss-of-function', 'NegReg', (85, 101))	('FANCE', 'Gene', (33, 38))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('ovarian cancer', 'Phenotype', 'HP:0100615', (124, 138))	('FANCE', 'Gene', '2178', (33, 38))	('breast or ovarian cancer', 'Disease', (114, 138))	('FA', 'Phenotype', 'HP:0001994', (33, 35))	('cancer', 'Disease', (206, 212))	('cancer', 'Disease', 'MESH:D009369', (206, 212))	('cancer', 'Disease', 'MESH:D009369', (132, 138))
489011	33592580	An increased mutation load of variants in FANCE in HNSC patients was observed compared with population-level estimate by Chandrasekharappa.	('increased', 'PosReg', (3, 12))	('patients', 'Species', '9606', (56, 64))	('variants', 'Var', (30, 38))	('FANCE', 'Gene', '2178', (42, 47))	('FA', 'Phenotype', 'HP:0001994', (42, 44))	('mutation load', 'MPA', (13, 26))	('HNSC', 'Phenotype', 'HP:0012288', (51, 55))	('FANCE', 'Gene', (42, 47))
489014	33592580	Disruption of the FA pathway can explain the large chromosomal changes that are common in sporadic cancers.	('FA pathway', 'Pathway', (18, 28))	('cancers', 'Phenotype', 'HP:0002664', (99, 106))	('sporadic cancers', 'Disease', 'MESH:D009369', (90, 106))	('FA', 'Phenotype', 'HP:0001994', (18, 20))	('sporadic cancers', 'Disease', (90, 106))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('Disruption', 'Var', (0, 10))
489018	33592580	Among the 10 methylation sites of FANCE, cg12798052 located in the promoter region showed significant hypomethylation in HNSC patients, which is an important reason for the down-regulation of FANCE expression.	('FA', 'Phenotype', 'HP:0001994', (34, 36))	('cg12798052', 'Chemical', '-', (41, 51))	('HNSC', 'Phenotype', 'HP:0012288', (121, 125))	('FA', 'Phenotype', 'HP:0001994', (192, 194))	('hypomethylation', 'MPA', (102, 117))	('HNSC', 'Disease', (121, 125))	('patients', 'Species', '9606', (126, 134))	('FANCE', 'Gene', (192, 197))	('FANCE', 'Gene', (34, 39))	('cg12798052', 'Var', (41, 51))	('FANCE', 'Gene', '2178', (192, 197))	('FANCE', 'Gene', '2178', (34, 39))
489019	33592580	In addition, the methylation sites cg03030757, cg18744234 and cg15267307 located in the gene enhanced region were also found to be hypomethylated.	('cg15267307', 'Chemical', '-', (62, 72))	('cg15267307', 'Var', (62, 72))	('cg18744234', 'Chemical', '-', (47, 57))	('cg03030757', 'Var', (35, 45))	('cg03030757', 'Chemical', '-', (35, 45))	('cg18744234', 'Var', (47, 57))
489031	33592580	Analysis of CD4+T cell subclasses showed that Treg, Th1, Th2 and Th17 were significantly down-regulated in the group with high expression of FANCE.	('down-regulated', 'NegReg', (89, 103))	('FANCE', 'Gene', (141, 146))	('Th17', 'CPA', (65, 69))	('FANCE', 'Gene', '2178', (141, 146))	('FA', 'Phenotype', 'HP:0001994', (141, 143))	('Treg', 'CPA', (46, 50))	('high expression', 'Var', (122, 137))	('CD4', 'Gene', (12, 15))	('CD4', 'Gene', '920', (12, 15))	('Th1', 'CPA', (52, 55))	('Th2', 'CPA', (57, 60))
489050	33592580	However, Garbati's research suggests that abnormal FA protein function can lead to the pro-inflammatory state of macrophages and induce hematopoietic stem cell depletion.	('lead to', 'Reg', (75, 82))	('induce', 'PosReg', (129, 135))	('FA', 'Phenotype', 'HP:0001994', (51, 53))	('age', 'Gene', (120, 123))	('abnormal', 'Var', (42, 50))	('hematopoietic stem cell depletion', 'CPA', (136, 169))	('age', 'Gene', '5973', (120, 123))	('FA protein', 'Protein', (51, 61))
489054	33592580	Different studies have found that FANCE mutations in breast cancer, sarcoma, colorectal cancer, gastric cancer and esophageal cancer, but its impact on the prognosis of these malignancies has not been reported.	('FA', 'Phenotype', 'HP:0001994', (34, 36))	('cancer', 'Disease', (88, 94))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('age', 'Gene', '5973', (120, 123))	('colorectal cancer', 'Phenotype', 'HP:0003003', (77, 94))	('FANCE', 'Gene', (34, 39))	('cancer', 'Disease', (104, 110))	('gastric cancer', 'Disease', 'MESH:D013274', (96, 110))	('FANCE', 'Gene', '2178', (34, 39))	('breast cancer', 'Phenotype', 'HP:0003002', (53, 66))	('malignancies', 'Disease', 'MESH:D009369', (175, 187))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('sarcoma', 'Disease', 'MESH:D012509', (68, 75))	('cancer', 'Disease', (126, 132))	('mutations', 'Var', (40, 49))	('malignancies', 'Disease', (175, 187))	('breast cancer', 'Disease', 'MESH:D001943', (53, 66))	('sarcoma', 'Disease', (68, 75))	('breast cancer', 'Disease', (53, 66))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('gastric cancer', 'Phenotype', 'HP:0012126', (96, 110))	('colorectal cancer', 'Disease', 'MESH:D015179', (77, 94))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('sarcoma', 'Phenotype', 'HP:0100242', (68, 75))	('colorectal cancer', 'Disease', (77, 94))	('age', 'Gene', (120, 123))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('cancer', 'Disease', (60, 66))	('gastric cancer', 'Disease', (96, 110))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
489057	33592580	Mutations in FANCE cause damage to the FA pathway, thereby increasing cancer susceptibility.	('FANCE', 'Gene', '2178', (13, 18))	('FA', 'Phenotype', 'HP:0001994', (13, 15))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('age', 'Gene', (28, 31))	('Mutations', 'Var', (0, 9))	('increasing', 'PosReg', (59, 69))	('FA pathway', 'Pathway', (39, 49))	('FA', 'Phenotype', 'HP:0001994', (39, 41))	('FANCE', 'Gene', (13, 18))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('age', 'Gene', '5973', (28, 31))
489131	32189917	The tumor cells revealed strong positivity for pancytokeratin in both squamous and glandular component and a low Ki-67 index [Figures 7 and 8].	('tumor', 'Disease', (4, 9))	('low', 'NegReg', (109, 112))	('Ki-67', 'CPA', (113, 118))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('positivity', 'Var', (32, 42))	('pancytokeratin', 'Protein', (47, 61))
489161	31317661	Silencing of RAD51AP1 suppresses epithelial-mesenchymal transition and metastasis in non-small cell lung cancer Non-small cell lung cancer (NSCLC) is a major cause of cancer-related mortality and is frequently accompanied by metastasis.	('Non-small cell lung cancer', 'Disease', 'MESH:D002289', (112, 138))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', (167, 173))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('Silencing', 'Var', (0, 9))	('RAD51AP1', 'Gene', (13, 21))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (85, 111))	('NSCLC', 'Disease', 'MESH:D002289', (140, 145))	('Non-small cell lung cancer', 'Disease', (112, 138))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (89, 111))	('NSCLC', 'Disease', (140, 145))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('lung cancer', 'Phenotype', 'HP:0100526', (127, 138))	('Non-small cell lung cancer', 'Phenotype', 'HP:0030358', (112, 138))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('NSCLC', 'Phenotype', 'HP:0030358', (140, 145))	('RAD51AP1', 'Gene', '10635', (13, 21))	('cancer', 'Disease', (132, 138))	('suppresses', 'NegReg', (22, 32))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (116, 138))	('lung cancer', 'Phenotype', 'HP:0100526', (100, 111))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))
489168	31317661	An in vivo experiment also confirmed that silencing of RAD51AP1 could inhibit NSCLC tumor formation and growth.	('silencing', 'Var', (42, 51))	('RAD51AP1', 'Gene', (55, 63))	('growth', 'CPA', (104, 110))	('NSCLC', 'Phenotype', 'HP:0030358', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('NSCLC tumor', 'Disease', 'MESH:D009369', (78, 89))	('inhibit', 'NegReg', (70, 77))	('NSCLC tumor', 'Disease', (78, 89))	('men', 'Species', '9606', (17, 20))
489169	31317661	Our results revealed that RAD51AP1 silencing suppressed the EMT and metastasis of NSCLC, thereby highlighting its potential as a promising novel target for NSCLC treatment.	('NSCLC', 'Disease', (82, 87))	('silencing', 'Var', (35, 44))	('NSCLC', 'Phenotype', 'HP:0030358', (82, 87))	('NSCLC', 'Phenotype', 'HP:0030358', (156, 161))	('suppressed', 'NegReg', (45, 55))	('NSCLC', 'Disease', (156, 161))	('RAD51AP1', 'Gene', (26, 34))	('NSCLC', 'Disease', 'MESH:D002289', (156, 161))	('men', 'Species', '9606', (167, 170))	('NSCLC', 'Disease', 'MESH:D002289', (82, 87))
489172	31317661	Silencing of RAD51AP1 contributes to the suppression of cholangiocarcinoma cell growth.12 Based on the results of these previous studies, we hypothesized that RAD51AP1 may affect NSCLC development.	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('NSCLC', 'Disease', (179, 184))	('NSCLC', 'Disease', 'MESH:D002289', (179, 184))	('cholangiocarcinoma', 'Disease', (56, 74))	('NSCLC', 'Phenotype', 'HP:0030358', (179, 184))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (56, 74))	('men', 'Species', '9606', (192, 195))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (56, 74))	('RAD51AP1', 'Var', (159, 167))	('affect', 'Reg', (172, 178))
489176	31317661	The Gene Expression Omnibus (GEO) database (https://www.ncbi.nlm.nih.gov/geo/) was used to retrieve NSCLC-related microarray datasets, from which GSE19188, GSE101929, GSE33532, and GSE74706 were selected and used for the screening of differentially expressed genes (DEGs).	('GSE33532', 'Var', (167, 175))	('GSE101929', 'Var', (156, 165))	('NSCLC', 'Disease', (100, 105))	('GSE19188', 'Var', (146, 154))	('GSE74706', 'Var', (181, 189))	('NSCLC', 'Disease', 'MESH:D002289', (100, 105))	('NSCLC', 'Phenotype', 'HP:0030358', (100, 105))
489199	31317661	The membrane was then blocked using 5% bovine serum albumin at room temperature for one hour, and then incubated with the following diluted primary antibodies: rabbit polyclonal antibody to RAD51AP1 (1:1000, ab101321), E-cadherin (1:500, ab15148), occludin (1:1000, ab168986), CK (1:1000, ab9377), N-cadherin (1: 200, ab18203), vimentin (1:1000, ab137321), fibronectin (1:500, ab2413), MMP-2 (1:2000, ab37150), OPN (1:1000, ab8448), and CD62 (1:300, ab18981) (all from Abcam), and 2,4,4-trimethyl-2-pentene(TMP-2) (1:500, YJ70002149, Shanghai Yiji Industrial Co., Ltd., Shanghai, China) at 4 C overnight.	('OPN', 'Gene', (411, 414))	('E-cadherin', 'Gene', (219, 229))	('vimentin', 'Gene', '7431', (328, 336))	('E-cadherin', 'Gene', '999', (219, 229))	('vimentin', 'Gene', (328, 336))	('fibronectin', 'Gene', (357, 368))	('N-cadherin', 'Gene', (298, 308))	('MMP-2', 'Gene', '4313', (386, 391))	('N-cadherin', 'Gene', '1000', (298, 308))	('CD62', 'Gene', (437, 441))	('bovine', 'Species', '9913', (39, 45))	('OPN', 'Gene', '6696', (411, 414))	('occludin', 'Gene', '100506658', (248, 256))	('rabbit', 'Species', '9986', (160, 166))	('fibronectin', 'Gene', '2335', (357, 368))	('MMP-2', 'Gene', (386, 391))	('occludin', 'Gene', (248, 256))	('1:500', 'Var', (515, 520))	('CD62', 'Gene', '6403', (437, 441))
489233	31317661	As depicted in Figure 2, RAD51AP1 protein expression was observed in both the NSCLC tissues and adjacent normal lung tissues.	('NSCLC', 'Phenotype', 'HP:0030358', (78, 83))	('observed', 'Reg', (57, 65))	('NSCLC', 'Disease', (78, 83))	('RAD51AP1', 'Var', (25, 33))	('NSCLC', 'Disease', 'MESH:D002289', (78, 83))
489240	31317661	Conjointly, these data support the conclusion that RAD51AP1 is expressed at a high level in NSCLC.	('NSCLC', 'Phenotype', 'HP:0030358', (92, 97))	('RAD51AP1', 'Var', (51, 59))	('NSCLC', 'Disease', 'MESH:D002289', (92, 97))	('NSCLC', 'Disease', (92, 97))
489241	31317661	The aforementioned findings revealed an increased expression rate of the RAD51AP1 protein in NSCLC, with subsequent detection of messenger RNA (mRNA) and protein expression of RAD51AP1, EMT, and metastasis-related genes in NSCLC.	('NSCLC', 'Disease', (223, 228))	('NSCLC', 'Disease', (93, 98))	('RAD51AP1', 'Var', (176, 184))	('NSCLC', 'Disease', 'MESH:D002289', (223, 228))	('NSCLC', 'Disease', 'MESH:D002289', (93, 98))	('RAD51AP1', 'Gene', (73, 81))	('men', 'Species', '9606', (9, 12))	('expression rate', 'MPA', (50, 65))	('increased', 'PosReg', (40, 49))	('NSCLC', 'Phenotype', 'HP:0030358', (223, 228))	('NSCLC', 'Phenotype', 'HP:0030358', (93, 98))	('protein', 'Protein', (82, 89))
489243	31317661	From these findings, it can be concluded that RAD51AP1 is highly expressed, which facilitates EMT in NSCLC.	('facilitates', 'PosReg', (82, 93))	('RAD51AP1', 'Var', (46, 54))	('NSCLC', 'Disease', (101, 106))	('NSCLC', 'Disease', 'MESH:D002289', (101, 106))	('EMT in', 'CPA', (94, 100))	('NSCLC', 'Phenotype', 'HP:0030358', (101, 106))
489251	31317661	The results of RT-qPCR and Western blot analysis exhibited elevated mRNA and protein expression of MMP-2, OPN, CD62, and TMP-2 in A549 and H520 cell lines in response to RAD51AP1 overexpression (P < 0.05), whereas reduced expression was observed in A549 and H520 cell lines after sh-RAD51AP1 transfection (P < 0.05) (Fig 6).	('MMP-2', 'Gene', (99, 104))	('RAD51AP1', 'Var', (170, 178))	('OPN', 'Gene', (106, 109))	('overexpression', 'PosReg', (179, 193))	('MMP-2', 'Gene', '4313', (99, 104))	('CD62', 'Gene', (111, 115))	('A549', 'CellLine', 'CVCL:0023', (249, 253))	('elevated', 'PosReg', (59, 67))	('CD62', 'Gene', '6403', (111, 115))	('TMP-2', 'Gene', (121, 126))	('OPN', 'Gene', '6696', (106, 109))	('A549', 'CellLine', 'CVCL:0023', (130, 134))
489252	31317661	Thus, RAD51AP1 silencing suppresses the metastasis of NSCLC cells.	('NSCLC', 'Phenotype', 'HP:0030358', (54, 59))	('silencing', 'Var', (15, 24))	('suppresses', 'NegReg', (25, 35))	('NSCLC', 'Disease', (54, 59))	('metastasis of', 'CPA', (40, 53))	('NSCLC', 'Disease', 'MESH:D002289', (54, 59))	('RAD51AP1', 'Gene', (6, 14))
489253	31317661	Considering the regulation of RAD51AP1 in EMT markers and metastasis-related genes, the study focal point shifted to the potential effects of RAD51AP1 on A549 and H520 cellular behavior with RAD51AP1 overexpressed or silenced in A549 and H520 cells.	('A549', 'CellLine', 'CVCL:0023', (154, 158))	('RAD51AP1', 'Var', (191, 199))	('effects', 'Reg', (131, 138))	('overexpressed', 'PosReg', (200, 213))	('A549', 'CellLine', 'CVCL:0023', (229, 233))	('RAD51AP1', 'Var', (142, 150))
489254	31317661	The results of scratch testing and Transwell assay revealed stimulated cell migration and invasion after RAD51AP1 overexpression (P < 0.05), but repressed cell migration and invasion after sh-RAD51AP1 treatment (P < 0.05) (Fig 7).	('invasion', 'CPA', (174, 182))	('stimulated', 'PosReg', (60, 70))	('overexpression', 'Var', (114, 128))	('cell migration', 'CPA', (155, 169))	('men', 'Species', '9606', (206, 209))	('RAD51AP1', 'Gene', (105, 113))	('cell migration', 'CPA', (71, 85))	('invasion', 'CPA', (90, 98))
489256	31317661	The cell viability was remarkably elevated after RAD51AP1 overexpression (P < 0.05), while it was reduced after sh-RAD51AP1 treatment (P < 0.05).	('overexpression', 'Var', (58, 72))	('cell viability', 'CPA', (4, 18))	('men', 'Species', '9606', (129, 132))	('RAD51AP1 overexpression', 'Var', (49, 72))	('elevated', 'PosReg', (34, 42))	('reduced', 'NegReg', (98, 105))
489257	31317661	The results of cell colony formation assay (Fig 9b,c) illustrated an enhanced clone formation rate after RAD51AP1 overexpression (P < 0.05), and a decreased formation rate after sh-RAD51AP1 treatment (P < 0.05).	('formation', 'MPA', (157, 166))	('enhanced', 'PosReg', (69, 77))	('decreased', 'NegReg', (147, 156))	('overexpression', 'Var', (114, 128))	('RAD51AP1', 'Gene', (105, 113))	('clone formation rate', 'CPA', (78, 98))	('men', 'Species', '9606', (195, 198))
489261	31317661	The results showed increased tumor weight and volume in nude mice after RAD51AP1 overexpression (P < 0.05), while a reduction was observed after RAD51AP1 silencing (P < 0.05) (Fig 10).	('RAD51AP1', 'Var', (72, 80))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('overexpression', 'PosReg', (81, 95))	('increased', 'PosReg', (19, 28))	('reduction', 'NegReg', (116, 125))	('tumor', 'Disease', (29, 34))	('silencing', 'NegReg', (154, 163))	('nude mice', 'Species', '10090', (56, 65))
489262	31317661	The results suggest that silencing of RAD51AP1 could reduce tumor formation and growth in vivo.	('reduce', 'NegReg', (53, 59))	('RAD51AP1', 'Gene', (38, 46))	('silencing', 'Var', (25, 34))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('growth in vivo', 'CPA', (80, 94))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Disease', (60, 65))
489264	31317661	Collectively, the findings from this study demonstrate that downregulated RAD51AP1 prevents the development of NSCLC by attenuating EMT and metastasis in NSCLC cells.	('downregulated', 'Var', (60, 73))	('NSCLC', 'Disease', 'MESH:D002289', (154, 159))	('NSCLC', 'Disease', (111, 116))	('NSCLC', 'Phenotype', 'HP:0030358', (154, 159))	('men', 'Species', '9606', (103, 106))	('NSCLC', 'Disease', 'MESH:D002289', (111, 116))	('RAD51AP1', 'Gene', (74, 82))	('attenuating', 'NegReg', (120, 131))	('prevents', 'NegReg', (83, 91))	('NSCLC', 'Phenotype', 'HP:0030358', (111, 116))	('NSCLC', 'Disease', (154, 159))
489266	31317661	Previous research has reported elevated RAD51AP1 expression in lung cancer.9 Furthermore, recent evidence has demonstrated the correlation of high RAD51AP1 expression with poor survival in lung adenocarcinoma.10 RAD51B overexpression has been observed in male NSCLC patients with squamous cell carcinoma, EGFR mutation, and no KRAS mutation.22 Our findings are consistent with these results, speculating the involvement of RAD51AP1 in NSCLC.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('lung adenocarcinoma', 'Disease', (189, 208))	('lung cancer', 'Disease', (63, 74))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (280, 303))	('carcinoma', 'Phenotype', 'HP:0030731', (199, 208))	('RAD51B', 'Gene', '5890', (212, 218))	('NSCLC', 'Disease', 'MESH:D002289', (260, 265))	('EGFR', 'Gene', (305, 309))	('patients', 'Species', '9606', (266, 274))	('NSCLC', 'Disease', 'MESH:D002289', (435, 440))	('men', 'Species', '9606', (415, 418))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (189, 208))	('KRAS', 'Gene', '3845', (327, 331))	('carcinoma', 'Phenotype', 'HP:0030731', (294, 303))	('squamous cell carcinoma', 'Disease', (280, 303))	('NSCLC', 'Disease', (435, 440))	('NSCLC', 'Disease', (260, 265))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (189, 208))	('lung cancer', 'Disease', 'MESH:D008175', (63, 74))	('KRAS', 'Gene', (327, 331))	('NSCLC', 'Phenotype', 'HP:0030358', (435, 440))	('NSCLC', 'Phenotype', 'HP:0030358', (260, 265))	('lung cancer', 'Phenotype', 'HP:0100526', (63, 74))	('EGFR', 'Gene', '1956', (305, 309))	('RAD51B', 'Gene', (212, 218))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (280, 303))	('RAD51AP1', 'Var', (423, 431))
489269	31317661	Another significant finding of our study showed that RAD51AP1 silencing treatment resulted in a significant decline in NSCLC cell metastasis, which was indicated upon observation of the decreased expression of metastasis-related factors (MMP-2, OPN, CD62, and TMP-2) after the knockdown of RAD51AP1.	('NSCLC', 'Disease', 'MESH:D002289', (119, 124))	('CD62', 'Gene', '6403', (250, 254))	('CD62', 'Gene', (250, 254))	('TMP-2', 'Gene', (260, 265))	('decline', 'NegReg', (108, 115))	('RAD51AP1', 'Var', (290, 298))	('MMP-2', 'Gene', '4313', (238, 243))	('expression', 'MPA', (196, 206))	('OPN', 'Gene', '6696', (245, 248))	('men', 'Species', '9606', (77, 80))	('NSCLC', 'Phenotype', 'HP:0030358', (119, 124))	('decreased', 'NegReg', (186, 195))	('RAD51AP1', 'Gene', (53, 61))	('OPN', 'Gene', (245, 248))	('MMP-2', 'Gene', (238, 243))	('NSCLC', 'Disease', (119, 124))	('silencing', 'NegReg', (62, 71))
489270	31317661	The association between OPN (a secret phosphorylated glycoprotein) and MMPs has been highlighted with tumor metastasis in NSCLC.29 Downregulation of CDDC6 facilitates low expression of RAD51 and is strongly related to the production of lymph node metastasis in NSCLC.30 Additionally, our findings demonstrate that downregulation of RAD51AP1 can reduce proliferation, invasion, and migration, but also stimulates the apoptosis of NSCLC cells.	('RAD51', 'Gene', (185, 190))	('RAD51', 'Gene', '5888', (185, 190))	('tumor metastasis', 'Disease', (102, 118))	('MMPs', 'Gene', '4313', (71, 75))	('NSCLC', 'Disease', 'MESH:D002289', (261, 266))	('NSCLC', 'Phenotype', 'HP:0030358', (429, 434))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('OPN', 'Gene', '6696', (24, 27))	('MMPs', 'Gene', (71, 75))	('NSCLC', 'Disease', (261, 266))	('invasion', 'CPA', (367, 375))	('RAD51', 'Gene', (332, 337))	('reduce', 'NegReg', (345, 351))	('NSCLC', 'Phenotype', 'HP:0030358', (261, 266))	('RAD51', 'Gene', '5888', (332, 337))	('NSCLC', 'Disease', 'MESH:D002289', (122, 127))	('CDDC6', 'Gene', (149, 154))	('apoptosis', 'CPA', (416, 425))	('Downregulation', 'NegReg', (131, 145))	('NSCLC', 'Disease', (122, 127))	('expression', 'MPA', (171, 181))	('NSCLC', 'Disease', 'MESH:D002289', (429, 434))	('tumor metastasis', 'Disease', 'MESH:D009362', (102, 118))	('stimulates', 'PosReg', (401, 411))	('OPN', 'Gene', (24, 27))	('NSCLC', 'Phenotype', 'HP:0030358', (122, 127))	('downregulation', 'Var', (314, 328))	('NSCLC', 'Disease', (429, 434))
489271	31317661	RAD51 has been documented to be of key importance in poor survival of NSCLC patients and inhibition of NSCLC cell apoptosis.31 RAD51 is also highly expressed in NSCLC and could suppress tumor cell apoptosis.32 On the basis of the aforementioned evidence, it can be concluded that RAD51AP1 silencing can reduce metastasis, proliferation, invasion, and migration, but induce apoptosis of NSCLC cells.	('metastasis', 'CPA', (310, 320))	('NSCLC', 'Disease', (103, 108))	('tumor', 'Disease', (186, 191))	('apoptosis', 'CPA', (373, 382))	('NSCLC', 'Disease', 'MESH:D002289', (70, 75))	('NSCLC', 'Phenotype', 'HP:0030358', (103, 108))	('men', 'Species', '9606', (19, 22))	('RAD51', 'Gene', (280, 285))	('induce', 'Reg', (366, 372))	('invasion', 'CPA', (337, 345))	('RAD51', 'Gene', (0, 5))	('RAD51', 'Gene', '5888', (280, 285))	('RAD51', 'Gene', '5888', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('NSCLC', 'Disease', (70, 75))	('NSCLC', 'Disease', 'MESH:D002289', (386, 391))	('NSCLC', 'Phenotype', 'HP:0030358', (70, 75))	('RAD51', 'Gene', (127, 132))	('NSCLC', 'Disease', 'MESH:D002289', (161, 166))	('patients', 'Species', '9606', (76, 84))	('RAD51', 'Gene', '5888', (127, 132))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('NSCLC', 'Disease', (386, 391))	('NSCLC', 'Disease', (161, 166))	('migration', 'CPA', (351, 360))	('NSCLC', 'Phenotype', 'HP:0030358', (386, 391))	('silencing', 'Var', (289, 298))	('NSCLC', 'Phenotype', 'HP:0030358', (161, 166))	('NSCLC', 'Disease', 'MESH:D002289', (103, 108))	('men', 'Species', '9606', (235, 238))	('reduce', 'NegReg', (303, 309))
489289	29532460	With regard to upper gastrointestinal cancers specifically, mounting preclinical evidence suggests that androgens and androgen receptor-signalling may be important in their pathogenesis; testosterone supresses wound healing and castration in male rats has been shown to inhibit gastric carcinogenesis.	('gastric carcinogenesis', 'Disease', (278, 300))	('supresses wound healing', 'Phenotype', 'HP:0001058', (200, 223))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('rats', 'Species', '10116', (247, 251))	('gastric carcinogenesis', 'Disease', 'MESH:D063646', (278, 300))	('inhibit', 'NegReg', (270, 277))	('wound healing', 'CPA', (210, 223))	('upper gastrointestinal cancers', 'Disease', 'MESH:D004067', (15, 45))	('cancers', 'Phenotype', 'HP:0002664', (38, 45))	('upper gastrointestinal cancers', 'Disease', (15, 45))	('supresses', 'NegReg', (200, 209))	('castration', 'Var', (228, 238))	('testosterone', 'Chemical', 'MESH:D013739', (187, 199))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (21, 44))
489328	29532460	Fathering children was associated with a reduction in oesophageal squamous cell carcinoma in unadjusted analysis (HR 0.48, 95% CI 0.24, 0.97); however, after adjustment for potential confounders, results attenuated and became statistically non-significant (adjusted HR 0.56, 95% CI 0.27, 1.15).	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('oesophageal squamous cell carcinoma', 'Disease', 'MESH:D002294', (54, 89))	('children', 'Species', '9606', (10, 18))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (66, 89))	('oesophageal squamous cell carcinoma', 'Disease', (54, 89))	('Fathering children', 'Var', (0, 18))	('men', 'Species', '9606', (164, 167))	('reduction', 'NegReg', (41, 50))
489374	29532460	In conclusion, in the first prospective study to investigate a range of male hormonal factors and risk of oesophageal and gastric cancer, there was suggestive evidence that male pattern baldness may be associated with an increased gastric cancer risk.	('male pattern baldness', 'Phenotype', 'HP:0002292', (173, 194))	('male pattern', 'Var', (173, 185))	('gastric cancer', 'Disease', (231, 245))	('associated', 'Reg', (202, 212))	('gastric cancer', 'Disease', 'MESH:D013274', (231, 245))	('increased gastric', 'Phenotype', 'HP:0005207', (221, 238))	('gastric cancer', 'Disease', (122, 136))	('baldness', 'Disease', 'MESH:D000505', (186, 194))	('baldness', 'Phenotype', 'HP:0002293', (186, 194))	('gastric cancer', 'Disease', 'MESH:D013274', (122, 136))	('increased gastric cancer', 'Phenotype', 'HP:0006753', (221, 245))	('gastric cancer', 'Phenotype', 'HP:0012126', (231, 245))	('baldness', 'Disease', (186, 194))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('gastric cancer', 'Phenotype', 'HP:0012126', (122, 136))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))	('oesophageal and gastric cancer', 'Disease', 'MESH:D013274', (106, 136))
489377	29532460	In the first prospective study of a range of male hormonal and reproductive factors and upper gastrointestinal cancer risk, the authors found some evidence that male pattern baldness was associated with gastric cancer risk, particularly for frontal male pattern baldness.	('baldness', 'Disease', (174, 182))	('gastric cancer', 'Phenotype', 'HP:0012126', (203, 217))	('baldness', 'Disease', (262, 270))	('male pattern', 'Var', (161, 173))	('frontal male pattern baldness', 'Disease', 'MESH:D000505', (241, 270))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('gastric cancer', 'Disease', (203, 217))	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (94, 117))	('male pattern baldness', 'Phenotype', 'HP:0002292', (249, 270))	('frontal male pattern baldness', 'Disease', (241, 270))	('baldness', 'Disease', 'MESH:D000505', (174, 182))	('baldness', 'Disease', 'MESH:D000505', (262, 270))	('male pattern baldness', 'Phenotype', 'HP:0002292', (161, 182))	('upper gastrointestinal cancer', 'Disease', 'MESH:D004067', (88, 117))	('associated', 'Reg', (187, 197))	('gastric cancer', 'Disease', 'MESH:D013274', (203, 217))	('baldness', 'Phenotype', 'HP:0002293', (174, 182))	('upper gastrointestinal cancer', 'Disease', (88, 117))	('baldness', 'Phenotype', 'HP:0002293', (262, 270))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))
489387	28979723	The histopathological diagnosis was moderately differentiated squamous cell carcinoma with pT1bN0M0, Stage IA.	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (62, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('squamous cell carcinoma', 'Disease', (62, 85))	('pT1bN0M0', 'Var', (91, 99))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (62, 85))
489391	28979723	In the present case, we clinically diagnosed esophageal carcinoma with right cervical lymph nodes metastasis, T2N2M0, Stage IIIA preoperatively, but the stage was revised to pT1bN0M0, Stage IA on pathological diagnosis.	('esophageal carcinoma', 'Disease', (45, 65))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (45, 65))	('cervical lymph nodes metastasis', 'Phenotype', 'HP:0025289', (77, 108))	('T2N2M0', 'Var', (110, 116))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (45, 65))	('diagnosed', 'Reg', (35, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (56, 65))
489410	28979723	The final diagnosis was esophageal squamous cell carcinoma without lymph node metastasis, pT1bN0M0, Stage IA and CD of the cervical lymph nodes.	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (24, 58))	('pT1bN0M0', 'Var', (90, 98))	('esophageal squamous cell carcinoma', 'Disease', (24, 58))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (35, 58))
489413	28979723	A variant of the multicentric form was later found to be associated with human herpesvirus 8 (HHV-8), which is the same virus found in Kaposi's sarcoma.	('HHV-8', 'Gene', (94, 99))	('sarcoma', 'Phenotype', 'HP:0100242', (144, 151))	("Kaposi's sarcoma", 'Disease', 'MESH:D012514', (135, 151))	('variant', 'Var', (2, 9))	('HHV-8', 'Species', '37296', (94, 99))	("Kaposi's sarcoma", 'Phenotype', 'HP:0100726', (135, 151))	("Kaposi's sarcoma", 'Disease', (135, 151))	('human herpesvirus 8', 'Species', '37296', (73, 92))	('associated', 'Reg', (57, 67))
489430	28979723	In the present case, the preoperative clinical diagnosis was esophageal carcinoma T2N2M0, Stage IIIA, but the stage was revised to pT1bN0M0, Stage IA upon pathological diagnosis.	('esophageal carcinoma', 'Disease', (61, 81))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (61, 81))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (61, 81))	('T2N2M0', 'Var', (82, 88))
489496	26847061	Using the salivary expression of IL-8p as an anchor marker and applying the 2-marker fractional polynomial models, the combination of IL-8p and IL-1beta gave the highest AUC (AUC= 0.817) in distinguishing OSCC patients from controls.	('combination', 'Var', (119, 130))	('IL-8p', 'Gene', (33, 38))	('OSCC', 'Disease', (205, 209))	('IL-8p', 'Gene', (134, 139))	('AUC', 'MPA', (170, 173))	('IL-1beta', 'Gene', (144, 152))	('IL-1beta', 'Gene', '3553', (144, 152))	('IL-8p', 'Gene', '3576', (33, 38))	('patients', 'Species', '9606', (210, 218))	('IL-8p', 'Gene', '3576', (134, 139))
489572	25627119	Lymph nodes showing at least one of the following features on CT were defined as positive nodes: short axis >=10 mm, distribution in a cluster of lymph nodes, infiltrative margin, or central necrosis.	('short axis', 'CPA', (97, 107))	('necrosis', 'Disease', (191, 199))	('necrosis', 'Disease', 'MESH:D009336', (191, 199))	('>=10', 'Var', (108, 112))
489720	32308481	Our results from 41 patients with an available, specific tumor differentiation diagnosis showed that the MDP uptake of low- or poorly differentiated soft tissue tumors was higher than that of moderately or well-differentiated tumors, which suggested that the degree of neoplastic MDP uptake might be associated with tumor differentiation.	('MDP', 'Chemical', 'MESH:D013669', (105, 108))	('MDP', 'Chemical', 'MESH:D013669', (280, 283))	('tumors', 'Disease', (161, 167))	('tumors', 'Disease', 'MESH:D009369', (226, 232))	('tumor', 'Disease', 'MESH:D009369', (226, 231))	('low- or poorly differentiated', 'Var', (119, 148))	('tumor', 'Disease', (161, 166))	('tumor', 'Phenotype', 'HP:0002664', (316, 321))	('tumors', 'Disease', 'MESH:D009369', (161, 167))	('higher', 'PosReg', (172, 178))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('patients', 'Species', '9606', (20, 28))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('tumor', 'Disease', (57, 62))	('tumors', 'Phenotype', 'HP:0002664', (226, 232))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('MDP uptake', 'MPA', (105, 115))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('soft tissue tumor', 'Phenotype', 'HP:0031459', (149, 166))	('tumors', 'Phenotype', 'HP:0002664', (161, 167))	('tumors', 'Disease', (226, 232))	('soft tissue tumors', 'Phenotype', 'HP:0031459', (149, 167))	('tumor', 'Disease', (316, 321))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Disease', (226, 231))	('tumor', 'Disease', 'MESH:D009369', (316, 321))
489838	29976955	Interestingly, and for the first time, we also detected editing sites in the microRNA cargo of circulating exosomes, providing the potential to non-invasively discriminate between normal and tumor samples.	('microRNA cargo', 'MPA', (77, 91))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('editing sites', 'Var', (56, 69))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('tumor', 'Disease', (191, 196))
489847	29976955	It has been shown that deregulation of the ADARs can contribute to the pathogenesis of human diseases, including lung cancer.	('ADAR', 'Gene', (43, 47))	('lung cancer', 'Disease', (113, 124))	('contribute', 'Reg', (53, 63))	('lung cancer', 'Phenotype', 'HP:0100526', (113, 124))	('human', 'Species', '9606', (87, 92))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('ADAR', 'Gene', '103', (43, 47))	('lung cancer', 'Disease', 'MESH:D008175', (113, 124))	('deregulation', 'Var', (23, 35))
489850	29976955	It has been estimated that 10-20% of miRNAs undergo A-to-I editing at the pri-miRNA level.	('undergo', 'Reg', (44, 51))	('miR', 'Gene', '220972', (37, 40))	('miR', 'Gene', (37, 40))	('miR', 'Gene', '220972', (78, 81))	('miR', 'Gene', (78, 81))	('A-to-I', 'Var', (52, 58))
489851	29976955	While A-to-I pri- or pre-miRNA editing events may affect both the maturation and the expression of miRNAs, those occurring in the mature sequence, particularly in miRNA seed regions (MSRs), could drastically alter the spectrum of microRNA targets ("targetome") and consequently modify their function.	('expression', 'MPA', (85, 95))	('alter', 'Reg', (208, 213))	('function', 'MPA', (291, 299))	('miR', 'Gene', '220972', (99, 102))	('miR', 'Gene', (99, 102))	('MSR', 'Gene', '4552', (183, 186))	('miR', 'Gene', '220972', (25, 28))	('MSR', 'Gene', (183, 186))	('miR', 'Gene', (25, 28))	('affect', 'Reg', (50, 56))	('modify', 'Reg', (278, 284))	('miR', 'Gene', '220972', (163, 166))	('editing', 'Var', (31, 38))	('miR', 'Gene', (163, 166))	('maturation', 'MPA', (66, 76))
489871	29976955	Noteworthy, miR-6129-5p with a U-to-A ME in position 10, and miR-379-5p with A-to-G ME in position 5 are specific for LUAD and LUSC samples, respectively, while the remaining MEs have been detected in both cancer subtypes (Fig.	('MEs', 'Chemical', '-', (175, 178))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('miR-379', 'Gene', (61, 68))	('miR', 'Gene', '220972', (61, 64))	('miR', 'Gene', (61, 64))	('U-to-A ME', 'Var', (31, 40))	('miR-379', 'Gene', '494328', (61, 68))	('ME', 'Chemical', '-', (84, 86))	('ME', 'Chemical', '-', (175, 177))	('LUAD', 'Disease', (118, 122))	('cancer', 'Disease', (206, 212))	('cancer', 'Disease', 'MESH:D009369', (206, 212))	('miR', 'Gene', '220972', (12, 15))	('ME', 'Chemical', '-', (38, 40))	('miR', 'Gene', (12, 15))
489885	29976955	S3): (1) the modified miRNA becomes a new miRNA (based on its MSR); (2) the edited miRNA shares the same MSR of another known miRNA.	('miR', 'Gene', '220972', (22, 25))	('miR', 'Gene', '220972', (126, 129))	('miR', 'Gene', (126, 129))	('modified', 'Var', (13, 21))	('MSR', 'Gene', '4552', (105, 108))	('miR', 'Gene', '220972', (83, 86))	('MSR', 'Gene', (105, 108))	('miR', 'Gene', (83, 86))	('miR', 'Gene', (42, 45))	('miR', 'Gene', '220972', (42, 45))	('MSR', 'Gene', '4552', (62, 65))	('miR', 'Gene', (22, 25))	('MSR', 'Gene', (62, 65))
489918	29976955	As previously observed, a single modification event in the miRNA seed region can change the targetome of a miRNA and thus its function.	('modification', 'Var', (33, 45))	('change', 'Reg', (81, 87))	('targetome of', 'MPA', (92, 104))	('function', 'MPA', (126, 134))	('miR', 'Gene', '220972', (59, 62))	('miR', 'Gene', (59, 62))	('miR', 'Gene', '220972', (107, 110))	('miR', 'Gene', (107, 110))
489945	29976955	Such modifications have the potential to induce shifts in miRNA targets thus altering downstream signaling.	('altering', 'Reg', (77, 85))	('downstream signaling', 'MPA', (86, 106))	('miR', 'Gene', '220972', (58, 61))	('miR', 'Gene', (58, 61))	('induce shifts', 'Reg', (41, 54))	('modifications', 'Var', (5, 18))
489947	29976955	While still early, we would propose that post-transcriptional modifications in miRNAs within both tissues and circulation could both serve as potential novel biomarkers and provide additional insights into the pathogenesis of cancers.	('post-transcriptional modifications', 'Var', (41, 75))	('cancers', 'Phenotype', 'HP:0002664', (226, 233))	('insights', 'Reg', (192, 200))	('miR', 'Gene', '220972', (79, 82))	('miR', 'Gene', (79, 82))	('cancers', 'Disease', (226, 233))	('cancers', 'Disease', 'MESH:D009369', (226, 233))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
489957	29976955	The detection and quantification analysis of modification events from sRNAseq data were based on two principal phases: (1) detection of miRNA editing sites by applying the Alon-Eisenberg pipeline and (2) differential expression analysis of miRNA editing hotspots (see Results section).	('miR', 'Gene', '220972', (136, 139))	('sites', 'Var', (150, 155))	('miR', 'Gene', '220972', (240, 243))	('miR', 'Gene', (136, 139))	('miR', 'Gene', (240, 243))
489976	28720099	The presence of genomic deletion(s) in a number of genes (OR5J2, GOLGA6L7P, APBA2, GALNTL5, VN1R31P, PHKG1P2, SGCZ, ZNF658) and lincRNA genes (RP11-76I14.1, CTC-535 M15.2, RP11-73B2.2) were associated with higher risk [HR between 1.67 (CI 1.3-2.1) and 2.15 (CI 1.5-2.9) for different CNVs] for development of skin lesions independent of gender, age, and arsenic exposure.	('VN1R31P', 'Gene', '100312787', (92, 99))	('VN1R31P', 'Gene', (92, 99))	('GALNTL5', 'Gene', (83, 90))	('deletion', 'Var', (24, 32))	('PHKG1P2', 'Gene', '644032', (101, 108))	('RP11', 'Gene', '26121', (143, 147))	('RP11', 'Gene', (172, 176))	('GALNTL5', 'Gene', '168391', (83, 90))	('GOLGA6L7P', 'Gene', (65, 74))	('men', 'Species', '9606', (301, 304))	('OR5J2', 'Gene', (58, 63))	('APBA2', 'Gene', (76, 81))	('OR5J2', 'Gene', '282775', (58, 63))	('ZNF658', 'Gene', '26149', (116, 122))	('PHKG1P2', 'Gene', (101, 108))	('lincRNA', 'Chemical', '-', (128, 135))	('CTC-535 M15.2', 'Var', (157, 170))	('SGCZ', 'Gene', '137868', (110, 114))	('RP11', 'Gene', (143, 147))	('presence', 'Var', (4, 12))	('skin lesions', 'Disease', 'MESH:D012871', (309, 321))	('SGCZ', 'Gene', (110, 114))	('ZNF658', 'Gene', (116, 122))	('APBA2', 'Gene', '321', (76, 81))	('RP11', 'Gene', '26121', (172, 176))	('arsenic', 'Chemical', 'MESH:D001151', (354, 361))	('GOLGA6L7P', 'Gene', '728310', (65, 74))	('skin lesions', 'Disease', (309, 321))
489977	28720099	Some deletions had stronger effect in a specific gender (ZNF658 in males, SGCZ in females) and some had stronger effect in higher arsenic exposure (lincRNA CTD-3179P9.1) suggesting a possible gene-environment interaction.	('stronger', 'PosReg', (19, 27))	('SGCZ', 'Gene', (74, 78))	('higher arsenic exposure', 'MPA', (123, 146))	('SGCZ', 'Gene', '137868', (74, 78))	('stronger', 'PosReg', (104, 112))	('ZNF658', 'Gene', '26149', (57, 63))	('lincRNA', 'Chemical', '-', (148, 155))	('men', 'Species', '9606', (204, 207))	('arsenic', 'Chemical', 'MESH:D001151', (130, 137))	('ZNF658', 'Gene', (57, 63))	('deletions', 'Var', (5, 14))
489986	28720099	Previously, using case-control design in a Bangladeshi population, in the first genome wide association study (GWAS) in arsenic, our group found some single nucleotide polymorphisms (SNP) to be associated with arsenic metabolism.	('arsenic', 'Chemical', 'MESH:D001151', (120, 127))	('arsenic', 'Chemical', 'MESH:D001151', (210, 217))	('associated', 'Reg', (194, 204))	('arsenic metabolism', 'MPA', (210, 228))	('single nucleotide polymorphisms', 'Var', (150, 181))
489992	28720099	In a tumor tissue based study, DNA losses at chromosomes 1q21.1, 7p22.3, 9q12 and 19q13.31 have been reported in arsenic-related lung squamous cell carcinoma.	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (129, 157))	('lung squamous cell carcinoma', 'Disease', (129, 157))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('DNA losses', 'Var', (31, 41))	('reported', 'Reg', (101, 109))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (134, 157))	('tumor', 'Disease', (5, 10))	('arsenic', 'Chemical', 'MESH:D001151', (113, 120))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (129, 157))	('carcinoma', 'Phenotype', 'HP:0030731', (148, 157))
489993	28720099	In this study, we evaluate whether there is any association of CNVs in germ line DNA in the development of arsenic-induced skin lesion.	('skin lesion', 'Disease', (123, 134))	('arsenic', 'Chemical', 'MESH:D001151', (107, 114))	('men', 'Species', '9606', (99, 102))	('CNVs', 'Var', (63, 67))	('skin lesion', 'Disease', 'MESH:D012871', (123, 134))
490021	28720099	After obtaining the CN value for each locus, to identify the genomic regions with amplification, normal CN or deletion, we used a genomic segmentation algorithm.	('men', 'Species', '9606', (141, 144))	('deletion', 'Var', (110, 118))	('amplification', 'Var', (82, 95))
490024	28720099	We restricted the analysis for the autosomes only (2.8% of the segments had CN > 2.3, 22.12% had CN <1.7 and the 75.0% had a copy number between 1.7-2.3).	('CN >', 'Var', (76, 80))	('men', 'Species', '9606', (66, 69))	('CN <', 'Var', (97, 101))
490026	28720099	In this paper, we reported a genomic segment in a sample to have amplification (0:no amplification, 1:amplification) or deletion (0:no deletion, 1:deletion) only if it was at least 5 kb in size and the geometric mean of the CN within the genomic boundary of the segment for that particular sample was >2.3 or <1.7 respectively.	('amplification', 'MPA', (65, 78))	('deletion', 'Var', (120, 128))	('men', 'Species', '9606', (40, 43))	('men', 'Species', '9606', (265, 268))
490042	28720099	To test the association between copy number loss/deletion and development of arsenic-induced skin lesions, we dichotomized the CN status of a segment as 0: no deletion and 1: deletion.	('skin lesions', 'Disease', 'MESH:D012871', (93, 105))	('men', 'Species', '9606', (69, 72))	('men', 'Species', '9606', (145, 148))	('copy number loss/deletion', 'Var', (32, 57))	('arsenic', 'Chemical', 'MESH:D001151', (77, 84))	('skin lesions', 'Disease', (93, 105))
490046	28720099	vs. >median) and UACR (= < median 192 mug/g of creatinine vs. >median) as covariates to see if the association(s) between segmental deletion and risk of skin lesion was independent of the covariates.	('UACR', 'Chemical', '-', (17, 21))	('skin lesion', 'Disease', 'MESH:D012871', (153, 164))	('men', 'Species', '9606', (125, 128))	('skin lesion', 'Disease', (153, 164))	('segmental deletion', 'Var', (122, 140))	('creatinine', 'Chemical', 'MESH:D003404', (47, 57))
490048	28720099	We found a total of 24 segments covering 10 cytoband regions, deletion of which were significantly (Bonferroni p = <0.05) associated with higher risk of skin lesion development (HR ranging between 1.67 and 2.15 for different segments, see Table 1).	('associated', 'Reg', (122, 132))	('skin lesion', 'Disease', 'MESH:D012871', (153, 164))	('skin lesion', 'Disease', (153, 164))	('men', 'Species', '9606', (228, 231))	('men', 'Species', '9606', (26, 29))	('deletion', 'Var', (62, 70))	('men', 'Species', '9606', (172, 175))
490051	28720099	Interestingly, out of these 10 cytoband regions, 3 of them (2q12.1, 5q34 and 7q11.21 shown in bold font in the Table 1) cover known lincRNA suggesting the possible significance of deletion of lincRNA as a risk factor for arsenic-induced skin lesions.	('skin lesions', 'Disease', 'MESH:D012871', (237, 249))	('deletion', 'Var', (180, 188))	('risk', 'Reg', (205, 209))	('lincRNA', 'Chemical', '-', (192, 199))	('lincRNA', 'Chemical', '-', (132, 139))	('arsenic', 'Chemical', 'MESH:D001151', (221, 228))	('skin lesions', 'Disease', (237, 249))	('lincRNA', 'Gene', (192, 199))
490052	28720099	Our previous GWAS showed that two SNPs, rs9527 and rs11191659, were associated with arsenic metabolism.	('arsenic metabolism', 'MPA', (84, 102))	('rs11191659', 'Var', (51, 61))	('associated', 'Reg', (68, 78))	('rs9527', 'Mutation', 'rs9527', (40, 46))	('arsenic', 'Chemical', 'MESH:D001151', (84, 91))	('rs11191659', 'Mutation', 'rs11191659', (51, 61))	('rs9527', 'Var', (40, 46))
490056	28720099	In the next step, in Cox regression models, in addition to the previous covariates, we also entered an interaction term "segment x gender" to find out if the deletion of any of the segment(s) affected the risk of skin lesion differently in male and female subjects.	('skin lesion', 'Disease', 'MESH:D012871', (213, 224))	('skin lesion', 'Disease', (213, 224))	('Cox', 'Gene', '1351', (21, 24))	('men', 'Species', '9606', (124, 127))	('affected', 'Reg', (192, 200))	('Cox', 'Gene', (21, 24))	('men', 'Species', '9606', (184, 187))	('deletion', 'Var', (158, 166))
490063	28720099	In the next step, in Cox regression analysis, in addition to gender, age, UACR, we also included an interaction term "segment x UACR" as predictors to find out if the deletion of any of the segment(s) affected the risk of skin lesion differently in subjects with high and low arsenic exposure (the Gene-Environment interaction).	('Cox', 'Gene', '1351', (21, 24))	('men', 'Species', '9606', (121, 124))	('Cox', 'Gene', (21, 24))	('men', 'Species', '9606', (193, 196))	('men', 'Species', '9606', (310, 313))	('deletion', 'Var', (167, 175))	('UACR', 'Chemical', '-', (128, 132))	('arsenic', 'Chemical', 'MESH:D001151', (276, 283))	('affected', 'Reg', (201, 209))	('skin lesion', 'Disease', 'MESH:D012871', (222, 233))	('UACR', 'Chemical', '-', (74, 78))	('skin lesion', 'Disease', (222, 233))
490065	28720099	For example, among the group of individuals with high arsenic exposure (UACR > = median 192 mug/g of creatinine), those with deletion of 5q34 were at a 2.5 (CI 1.7-3.8) fold higher risk of skin lesion development compared to those without deletion.	('5q34', 'Gene', (137, 141))	('skin lesion', 'Disease', 'MESH:D012871', (189, 200))	('skin lesion', 'Disease', (189, 200))	('men', 'Species', '9606', (208, 211))	('UACR', 'Chemical', '-', (72, 76))	('arsenic', 'Chemical', 'MESH:D001151', (54, 61))	('creatinine', 'Chemical', 'MESH:D003404', (101, 111))	('deletion', 'Var', (125, 133))
490067	28720099	We tested if a deletion of any of these segments is associated with arsenic exposure.	('deletion', 'Var', (15, 23))	('associated', 'Reg', (52, 62))	('tested', 'Reg', (3, 9))	('men', 'Species', '9606', (43, 46))	('arsenic', 'Chemical', 'MESH:D001151', (68, 75))
490071	28720099	We also looked for if a copy number gain/amplification was associated with development of arsenic-induced skin lesions.	('arsenic', 'Chemical', 'MESH:D001151', (90, 97))	('associated', 'Reg', (59, 69))	('skin lesions', 'Disease', 'MESH:D012871', (106, 118))	('skin lesions', 'Disease', (106, 118))	('copy number gain/amplification', 'Var', (24, 54))	('men', 'Species', '9606', (82, 85))
490074	28720099	None of the segments with amplification showed significantly higher risk for development of arsenic-induced skin lesions after Bonferroni correction for multiple testing.	('skin lesions', 'Disease', (108, 120))	('amplification', 'Var', (26, 39))	('men', 'Species', '9606', (15, 18))	('men', 'Species', '9606', (84, 87))	('arsenic', 'Chemical', 'MESH:D001151', (92, 99))	('skin lesions', 'Disease', 'MESH:D012871', (108, 120))
490075	28720099	To our knowledge, this is the first large-scale genome-wide CN analysis to show from a prospectively followed-up cohort that the structural variation(s) in the germ line DNA may predispose an individual exposed to arsenic to develop arsenic-induced skin lesions.	('structural variation', 'Var', (129, 149))	('skin lesions', 'Disease', (249, 261))	('skin lesions', 'Disease', 'MESH:D012871', (249, 261))	('develop', 'PosReg', (225, 232))	('arsenic', 'Chemical', 'MESH:D001151', (214, 221))	('predispose', 'Reg', (178, 188))	('arsenic', 'Chemical', 'MESH:D001151', (233, 240))
490076	28720099	In tumor tissue, from arsenic-induced lung squamous cell carcinoma, deletion in chromosomal regions 1q21.1, 7p22.3, and 9q12 have been reported.	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (38, 66))	('tumor', 'Disease', (3, 8))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (38, 66))	('carcinoma', 'Phenotype', 'HP:0030731', (57, 66))	('deletion', 'Var', (68, 76))	('lung squamous cell carcinoma', 'Disease', (38, 66))	('tumor', 'Disease', 'MESH:D009369', (3, 8))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (43, 66))	('arsenic', 'Chemical', 'MESH:D001151', (22, 29))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))
490083	28720099	Previously, using case-control design, our group found some SNPs to be associated with arsenic metabolism.	('arsenic', 'Chemical', 'MESH:D001151', (87, 94))	('arsenic metabolism', 'MPA', (87, 105))	('associated', 'Reg', (71, 81))	('SNPs', 'Var', (60, 64))
490085	28720099	Now, we provide evidence that structural variation in the form of CN loss or deletion in certain genomic location(s) may have a role in the development of arsenic-induced skin lesions independent of gender, age, level of arsenic exposure and also independent of the SNPs related to arsenic metabolism.	('role', 'Reg', (128, 132))	('arsenic', 'Chemical', 'MESH:D001151', (155, 162))	('deletion', 'Var', (77, 85))	('skin lesions', 'Disease', (171, 183))	('arsenic', 'Chemical', 'MESH:D001151', (282, 289))	('arsenic', 'Chemical', 'MESH:D001151', (221, 228))	('skin lesions', 'Disease', 'MESH:D012871', (171, 183))	('men', 'Species', '9606', (147, 150))
490098	28720099	The structural variants, we are reporting in this paper to have significant association with the development of arsenic-induced skin lesions, have a frequency between 5% and 21% among the study population.	('association', 'Reg', (76, 87))	('skin lesions', 'Disease', (128, 140))	('men', 'Species', '9606', (104, 107))	('skin lesions', 'Disease', 'MESH:D012871', (128, 140))	('variants', 'Var', (15, 23))	('arsenic', 'Chemical', 'MESH:D001151', (112, 119))
490099	28720099	For example, the deletion in 7q11.21 region: the deletion frequency ranges from 1 in 29,084 in a case-control study for developmental delay using arrays to 35 in 2504 in a sequence-based study; amplification/gain was reported as high as 121/270.	('developmental delay', 'Phenotype', 'HP:0001263', (120, 139))	('developmental delay', 'Disease', (120, 139))	('deletion', 'Var', (17, 25))	('deletion', 'Var', (49, 57))	('men', 'Species', '9606', (127, 130))
490102	28720099	Our current study clearly suggests that there is some role of structural change in the genome (in the form of CN loss/deletion) in the development of arsenic-induced skin lesions, independent of the known clinical factors/parameters like age, sex, UACR level as well as the genotypes known to affect the arsenic metabolism.	('structural', 'Var', (62, 72))	('men', 'Species', '9606', (142, 145))	('skin lesions', 'Disease', 'MESH:D012871', (166, 178))	('skin lesions', 'Disease', (166, 178))	('clinical', 'Species', '191496', (205, 213))	('UACR', 'Chemical', '-', (248, 252))	('arsenic', 'Chemical', 'MESH:D001151', (150, 157))	('arsenic', 'Chemical', 'MESH:D001151', (304, 311))
490103	28720099	The HRs of deletion(s) of these genomic segments for skin lesions may be slightly lower than the HRs of age, sex, but are not negligible.	('skin lesions', 'Disease', 'MESH:D012871', (53, 65))	('skin lesions', 'Disease', (53, 65))	('men', 'Species', '9606', (43, 46))	('deletion', 'Var', (11, 19))	('lower', 'NegReg', (82, 87))
490105	28720099	We did not have the source of RNA samples for these individuals to run gene expression to confirm the effects of deletion of lincRNA regions in the genomic DNA samples.	('deletion', 'Var', (113, 121))	('lincRNA', 'Chemical', '-', (125, 132))	('lincRNA regions', 'Gene', (125, 140))
490109	27553089	Prognostic significance of the methylation of Wnt pathway antagonists:CXXC4, DACT2, and the inhibitors of sonic hedgehog signaling:ZIC1, ZIC4, and HHIP in head and neck squamous cell carcinomas Aberrations in Wnt and Shh signaling pathways are related to the pathogenesis of head and neck carcinomas, and their activation frequently results from epigenetic alterations.	('sonic hedgehog', 'Gene', (106, 120))	('ZIC1', 'Gene', '7545', (131, 135))	('HHIP', 'Gene', (147, 151))	('carcinoma', 'Phenotype', 'HP:0030731', (289, 298))	('carcinomas', 'Phenotype', 'HP:0030731', (289, 299))	('head and neck squamous cell carcinomas', 'Phenotype', 'HP:0012288', (155, 193))	('epigenetic alterations', 'Var', (346, 368))	('Aberrations', 'Var', (194, 205))	('HHIP', 'Gene', '64399', (147, 151))	('related', 'Reg', (244, 251))	('neck carcinomas', 'Disease', 'MESH:D006258', (284, 299))	('head and neck carcinomas', 'Phenotype', 'HP:0012288', (275, 299))	('ZIC1', 'Gene', (131, 135))	('neck squamous cell carcinomas', 'Disease', (164, 193))	('CXXC4', 'Gene', (70, 75))	('results from', 'Reg', (333, 345))	('carcinoma', 'Phenotype', 'HP:0030731', (183, 192))	('Shh', 'Gene', '6469', (217, 220))	('activation', 'PosReg', (311, 321))	('carcinomas', 'Phenotype', 'HP:0030731', (183, 193))	('neck carcinomas', 'Disease', (284, 299))	('neck squamous cell carcinomas', 'Disease', 'MESH:D000077195', (164, 193))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (169, 193))	('ZIC4', 'Gene', (137, 141))	('ZIC4', 'Gene', '84107', (137, 141))	('DACT2', 'Gene', (77, 82))	('head and neck carcinoma', 'Phenotype', 'HP:0012288', (275, 298))	('DACT2', 'Gene', '168002', (77, 82))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (169, 192))	('sonic hedgehog', 'Gene', '6469', (106, 120))	('CXXC4', 'Gene', '80319', (70, 75))	('Shh', 'Gene', (217, 220))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (155, 192))
490110	27553089	This study aimed to assess the frequency of methylation of negative regulators of Wnt signaling: CXXC4, DACT2, HDPR1, and FBXW11 and Shh signaling: HHIP, PTCH1, SUFU, ZIC1, and ZIC4 and correlate it with clinicopathological features in this group of patients.	('HHIP', 'Gene', '64399', (148, 152))	('HDPR1', 'Gene', (111, 116))	('SUFU', 'Gene', '51684', (161, 165))	('DACT2', 'Gene', (104, 109))	('FBXW11', 'Gene', (122, 128))	('Shh', 'Gene', (133, 136))	('ZIC1', 'Gene', '7545', (167, 171))	('CXXC4', 'Gene', '80319', (97, 102))	('DACT2', 'Gene', '168002', (104, 109))	('FBXW11', 'Gene', '23291', (122, 128))	('PTCH1', 'Gene', '5727', (154, 159))	('SUFU', 'Gene', (161, 165))	('methylation', 'Var', (44, 55))	('ZIC1', 'Gene', (167, 171))	('patients', 'Species', '9606', (250, 258))	('ZIC4', 'Gene', (177, 181))	('Shh', 'Gene', '6469', (133, 136))	('PTCH1', 'Gene', (154, 159))	('CXXC4', 'Gene', (97, 102))	('HDPR1', 'Gene', '51339', (111, 116))	('ZIC4', 'Gene', '84107', (177, 181))	('HHIP', 'Gene', (148, 152))
490115	27553089	Moreover, ZIC4 methylation correlated with lymph node involvement in oral cancer patients.	('methylation', 'Var', (15, 26))	('ZIC4', 'Gene', (10, 14))	('correlated with', 'Reg', (27, 42))	('patients', 'Species', '9606', (81, 89))	('oral cancer', 'Disease', 'MESH:D009062', (69, 80))	('lymph', 'Disease', (43, 48))	('ZIC4', 'Gene', '84107', (10, 14))	('oral cancer', 'Disease', (69, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
490116	27553089	Our findings corroborate that the activation of Wnt signaling in head and neck squamous cell carcinoma (HNSCC) is related to epigenetic silencing of its negative regulators.	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (79, 102))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (74, 102))	('HNSCC', 'Phenotype', 'HP:0012288', (104, 109))	('Wnt signaling', 'Pathway', (48, 61))	('activation', 'PosReg', (34, 44))	('epigenetic silencing', 'Var', (125, 145))	('neck squamous cell carcinoma', 'Disease', (74, 102))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (65, 102))
490118	27553089	The methylation of ZIC4 may be considered a new prognostic marker in oral cavity and oropharyngeal tumors.	('oropharyngeal tumors', 'Disease', (85, 105))	('ZIC4', 'Gene', '84107', (19, 23))	('oral cavity', 'Disease', (69, 80))	('oropharyngeal tumors', 'Phenotype', 'HP:0100638', (85, 105))	('oropharyngeal tumors', 'Disease', 'MESH:D009959', (85, 105))	('methylation', 'Var', (4, 15))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('ZIC4', 'Gene', (19, 23))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))
490119	27553089	Further investigations should determine the diagnostic significance of methylation of ZIC4, HHIP, and DACT2 in head and neck carcinomas.	('methylation', 'Var', (71, 82))	('neck carcinomas', 'Disease', 'MESH:D006258', (120, 135))	('DACT2', 'Gene', '168002', (102, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('head and neck carcinomas', 'Phenotype', 'HP:0012288', (111, 135))	('carcinomas', 'Phenotype', 'HP:0030731', (125, 135))	('HHIP', 'Gene', '64399', (92, 96))	('ZIC4', 'Gene', (86, 90))	('DACT2', 'Gene', (102, 107))	('head and neck carcinoma', 'Phenotype', 'HP:0012288', (111, 134))	('HHIP', 'Gene', (92, 96))	('ZIC4', 'Gene', '84107', (86, 90))	('neck carcinomas', 'Disease', (120, 135))
490125	27553089	Recently, aberrations in the function of sonic hedgehog (Shh) and canonical Wnt pathways have been also implicated in the development of HNSCC.	('Shh', 'Gene', '6469', (57, 60))	('implicated', 'Reg', (104, 114))	('canonical Wnt pathways', 'Pathway', (66, 88))	('aberrations in', 'Var', (10, 24))	('Shh', 'Gene', (57, 60))	('sonic hedgehog', 'Gene', '6469', (41, 55))	('sonic hedgehog', 'Gene', (41, 55))	('HNSCC', 'Phenotype', 'HP:0012288', (137, 142))	('HNSCC', 'Disease', (137, 142))
490133	27553089	The biological importance of Wnt dysregulation for the development of HNSCC is corroborated by the fact that the growth of tongue cancer cells is inhibited by the silencing of CTNNB1 gene which encodes beta-catenin.	('beta-catenin', 'Gene', (202, 214))	('CTNNB1', 'Gene', '1499', (176, 182))	('beta-catenin', 'Gene', '1499', (202, 214))	('tongue cancer', 'Disease', (123, 136))	('HNSCC', 'Phenotype', 'HP:0012288', (70, 75))	('silencing', 'Var', (163, 172))	('tongue cancer', 'Disease', 'MESH:D014062', (123, 136))	('inhibited', 'NegReg', (146, 155))	('CTNNB1', 'Gene', (176, 182))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('growth', 'CPA', (113, 119))
490137	27553089	Evidence for the implication of Shh pathway dysregulation in the pathogenesis of HNSCC has only recently started to accumulate.	('dysregulation', 'Var', (44, 57))	('Shh', 'Gene', (32, 35))	('Shh', 'Gene', '6469', (32, 35))	('HNSCC', 'Phenotype', 'HP:0012288', (81, 86))	('HNSCC', 'Disease', (81, 86))
490141	27553089	However, the molecular mechanisms leading to the activation of Shh in HNSCC have not been well studied although it is suggested that this may occur due to epigenetic changes.	('Shh', 'Gene', '6469', (63, 66))	('HNSCC', 'Phenotype', 'HP:0012288', (70, 75))	('epigenetic changes', 'Var', (155, 173))	('Shh', 'Gene', (63, 66))	('activation', 'PosReg', (49, 59))
490142	27553089	The association between the dysregulation of Wnt and Shh pathways and the pathogenesis of HNSCC implicates the possibility of therapeutic targeting HNSCC by modulating the activity of these pathways.	('activity', 'MPA', (172, 180))	('HNSCC', 'Disease', (90, 95))	('modulating', 'Reg', (157, 167))	('Shh', 'Gene', (53, 56))	('HNSCC', 'Phenotype', 'HP:0012288', (148, 153))	('HNSCC', 'Phenotype', 'HP:0012288', (90, 95))	('dysregulation', 'Var', (28, 41))	('Shh', 'Gene', '6469', (53, 56))
490144	27553089	Most importantly, epigenetic silencing of negative regulators of Wnt and Shh pathways may have diagnostic significance.	('Shh', 'Gene', '6469', (73, 76))	('epigenetic silencing', 'Var', (18, 38))	('Wnt', 'Pathway', (65, 68))	('Shh', 'Gene', (73, 76))
490145	27553089	Thus, the aim of the present study was to assess the frequency of methylation of the selected negative regulators of Wnt signaling: CXXC4, DACT2, HDPR1 (DACT1), and FBXW11 and Shh signaling: HHIP, PTCH1, SUFU, ZIC1, and ZIC4 which were either rarely or never under study in head and neck cancers previously and correlate it with clinicopathological features in a group of HNSCC patients.	('Shh', 'Gene', (176, 179))	('ZIC4', 'Gene', (220, 224))	('cancers', 'Phenotype', 'HP:0002664', (288, 295))	('head and neck cancers', 'Phenotype', 'HP:0012288', (274, 295))	('PTCH1', 'Gene', '5727', (197, 202))	('ZIC4', 'Gene', '84107', (220, 224))	('ZIC1', 'Gene', (210, 214))	('FBXW11', 'Gene', (165, 171))	('SUFU', 'Gene', (204, 208))	('CXXC4', 'Gene', '80319', (132, 137))	('cancer', 'Phenotype', 'HP:0002664', (288, 294))	('FBXW11', 'Gene', '23291', (165, 171))	('HDPR1', 'Gene', '51339', (146, 151))	('head and neck cancers', 'Disease', 'MESH:D006258', (274, 295))	('HHIP', 'Gene', (191, 195))	('Shh', 'Gene', '6469', (176, 179))	('patients', 'Species', '9606', (378, 386))	('DACT2', 'Gene', '168002', (139, 144))	('PTCH1', 'Gene', (197, 202))	('HHIP', 'Gene', '64399', (191, 195))	('HNSCC', 'Phenotype', 'HP:0012288', (372, 377))	('HDPR1', 'Gene', (146, 151))	('CXXC4', 'Gene', (132, 137))	('methylation', 'Var', (66, 77))	('SUFU', 'Gene', '51684', (204, 208))	('DACT1', 'Gene', '51339', (153, 158))	('DACT2', 'Gene', (139, 144))	('DACT1', 'Gene', (153, 158))	('ZIC1', 'Gene', '7545', (210, 214))
490181	27553089	However, the presence of ZIC4 methylation in oral tumors significantly correlated with lymph node invasion (p = 0.041).	('ZIC4', 'Gene', (25, 29))	('methylation', 'Var', (30, 41))	('oral tumors', 'Phenotype', 'HP:0100649', (45, 56))	('ZIC4', 'Gene', '84107', (25, 29))	('oral tumor', 'Phenotype', 'HP:0100649', (45, 55))	('presence', 'Var', (13, 21))	('oral tumors', 'Disease', 'MESH:D020820', (45, 56))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('lymph node invasion', 'CPA', (87, 106))	('tumors', 'Phenotype', 'HP:0002664', (50, 56))	('correlated with', 'Reg', (71, 86))	('oral tumors', 'Disease', (45, 56))
490183	27553089	4) although there was a trend for an association between ZIC4 methylation and shorter survival in OSCC patients (p = 0.09088).	('ZIC4', 'Gene', (57, 61))	('ZIC4', 'Gene', '84107', (57, 61))	('methylation', 'Var', (62, 73))	('OSCC', 'Disease', (98, 102))	('patients', 'Species', '9606', (103, 111))	('shorter', 'NegReg', (78, 85))
490189	27553089	Only recently, molecularly targeted therapies with EGFR (epithelial growth factor receptor) inhibitors have been applied with moderate outcomes in HNSCC indicating the need for the search of other therapeutic strategies.	('EGFR', 'Gene', (51, 55))	('inhibitors', 'Var', (92, 102))	('epithelial growth factor receptor', 'Gene', '1956', (57, 90))	('epithelial growth factor receptor', 'Gene', (57, 90))	('HNSCC', 'Disease', (147, 152))	('EGFR', 'Gene', '1956', (51, 55))	('HNSCC', 'Phenotype', 'HP:0012288', (147, 152))
490193	27553089	The hypermethylation of such negative regulators of Wnt pathway as SFRP1-5, DKK1-3, WIF1, DACH1, and PPP2R2B may significantly contribute to pathway activation and was frequently observed in HNSCC.	('WIF1', 'Gene', (84, 88))	('SFRP1-5', 'Gene', '6422;6423;2487;6424;6425', (67, 74))	('PPP2R2B', 'Gene', '5521', (101, 108))	('HNSCC', 'Disease', (191, 196))	('PPP2R2B', 'Gene', (101, 108))	('DKK1-3', 'Gene', (76, 82))	('SFRP1-5', 'Gene', (67, 74))	('pathway', 'CPA', (141, 148))	('contribute', 'Reg', (127, 137))	('DKK1-3', 'Gene', '22943;27123;27122', (76, 82))	('HNSCC', 'Phenotype', 'HP:0012288', (191, 196))	('DACH1', 'Gene', (90, 95))	('observed', 'Reg', (179, 187))	('WIF1', 'Gene', '11197', (84, 88))	('DACH1', 'Gene', '1602', (90, 95))	('activation', 'PosReg', (149, 159))	('hypermethylation', 'Var', (4, 20))
490197	27553089	On the other hand, HDPR1 (DACT1) was downregulated by DNA methylation in breast or hepatocellular carcinoma and its downregulation was associated with poor prognosis in gastric and non-small cell lung cancers.	('cancers', 'Phenotype', 'HP:0002664', (201, 208))	('breast or hepatocellular carcinoma', 'Disease', (73, 107))	('gastric', 'Disease', (169, 176))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('non-small cell lung cancers', 'Disease', (181, 208))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (83, 107))	('non-small cell lung cancers', 'Phenotype', 'HP:0030358', (181, 208))	('downregulation', 'NegReg', (116, 130))	('HDPR1', 'Gene', '51339', (19, 24))	('breast or hepatocellular carcinoma', 'Disease', 'MESH:D006528', (73, 107))	('HDPR1', 'Gene', (19, 24))	('methylation', 'Var', (58, 69))	('small cell lung cancers', 'Phenotype', 'HP:0030357', (185, 208))	('downregulated', 'NegReg', (37, 50))	('non-small cell lung cancers', 'Disease', 'MESH:D002289', (181, 208))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('DACT1', 'Gene', '51339', (26, 31))	('lung cancers', 'Phenotype', 'HP:0100526', (196, 208))	('DACT1', 'Gene', (26, 31))
490198	27553089	Recently, it has been reported that both DACT1 and DACT2 are methylated in oral squamous cell carcinoma.	('methylated', 'Var', (61, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('DACT2', 'Gene', (51, 56))	('oral squamous cell carcinoma', 'Disease', (75, 103))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (80, 103))	('DACT1', 'Gene', (41, 46))	('DACT2', 'Gene', '168002', (51, 56))	('DACT1', 'Gene', '51339', (41, 46))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (75, 103))
490200	27553089	Its epigenetic downregulation led to the activation of Wnt signaling and was associated with poor outcome in gastric cancer patients.	('gastric cancer', 'Phenotype', 'HP:0012126', (109, 123))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('gastric cancer', 'Disease', (109, 123))	('gastric cancer', 'Disease', 'MESH:D013274', (109, 123))	('Wnt signaling', 'Pathway', (55, 68))	('activation', 'PosReg', (41, 51))	('epigenetic', 'Var', (4, 14))	('patients', 'Species', '9606', (124, 132))
490204	27553089	On the other hand, we have observed that DACT2 is frequently methylated in both the cells lines and head and neck carcinomas while CXXC4 is methylated to a lesser extent.	('DACT2', 'Gene', (41, 46))	('methylated', 'Var', (61, 71))	('CXXC4', 'Gene', (131, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('carcinomas', 'Phenotype', 'HP:0030731', (114, 124))	('DACT2', 'Gene', '168002', (41, 46))	('neck carcinomas', 'Disease', (109, 124))	('CXXC4', 'Gene', '80319', (131, 136))	('head and neck carcinomas', 'Phenotype', 'HP:0012288', (100, 124))	('head and neck carcinoma', 'Phenotype', 'HP:0012288', (100, 123))	('neck carcinomas', 'Disease', 'MESH:D006258', (109, 124))
490207	27553089	HHIP inhibits Shh signaling by sequestering Hh ligands which then cannot activate the pathway, and its epigenetically mediated downregulation was observed in gastrointestinal, hepatocellular, and pancreatic tumors.	('sequestering', 'MPA', (31, 43))	('inhibits', 'NegReg', (5, 13))	('HHIP', 'Gene', (0, 4))	('pancreatic tumors', 'Phenotype', 'HP:0002894', (196, 213))	('Shh', 'Gene', '6469', (14, 17))	('epigenetically', 'Var', (103, 117))	('downregulation', 'NegReg', (127, 141))	('hepatocellular', 'Disease', (176, 190))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('tumors', 'Phenotype', 'HP:0002664', (207, 213))	('gastrointestinal', 'Disease', (158, 174))	('HHIP', 'Gene', '64399', (0, 4))	('Hh ligands', 'Protein', (44, 54))	('pancreatic tumors', 'Disease', 'MESH:D010190', (196, 213))	('Shh', 'Gene', (14, 17))	('pancreatic tumors', 'Disease', (196, 213))
490211	27553089	Previous studies have shown that ZIC1 is frequently methylated in colorectal, hepatocellular, and gastric cancers while the methylation of ZIC4 was observed in bladder cancer.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('hepatocellular', 'Disease', (78, 92))	('ZIC1', 'Gene', (33, 37))	('ZIC4', 'Gene', '84107', (139, 143))	('bladder cancer', 'Disease', 'MESH:D001749', (160, 174))	('ZIC1', 'Gene', '7545', (33, 37))	('gastric cancers', 'Disease', (98, 113))	('gastric cancers', 'Disease', 'MESH:D013274', (98, 113))	('gastric cancers', 'Phenotype', 'HP:0012126', (98, 113))	('bladder cancer', 'Phenotype', 'HP:0009725', (160, 174))	('methylated', 'Var', (52, 62))	('bladder cancer', 'Disease', (160, 174))	('cancers', 'Phenotype', 'HP:0002664', (106, 113))	('colorectal', 'Disease', 'MESH:D015179', (66, 76))	('ZIC4', 'Gene', (139, 143))	('gastric cancer', 'Phenotype', 'HP:0012126', (98, 112))	('colorectal', 'Disease', (66, 76))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
490213	27553089	The observed lack of methylation of PTCH1 is in contrast to a recent finding where restriction analysis of promoter methylation showed that this gene is methylated in many dysplastic lesions and nearly half of HNSCC cases.	('PTCH1', 'Gene', (36, 41))	('HNSCC', 'Disease', (210, 215))	('dysplastic lesions', 'Disease', 'MESH:D021782', (172, 190))	('HNSCC', 'Phenotype', 'HP:0012288', (210, 215))	('PTCH1', 'Gene', '5727', (36, 41))	('dysplastic lesions', 'Disease', (172, 190))	('methylated', 'Var', (153, 163))
490217	27553089	Importantly, ZIC4 methylation in tumors significantly correlated with lymph node invasion implicating that it might be considered a prognostic biomarker.	('ZIC4', 'Gene', (13, 17))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('ZIC4', 'Gene', '84107', (13, 17))	('lymph node invasion', 'CPA', (70, 89))	('correlated', 'Reg', (54, 64))	('tumors', 'Disease', 'MESH:D009369', (33, 39))	('methylation', 'Var', (18, 29))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('tumors', 'Disease', (33, 39))
490218	27553089	Assuming that ZIC4 methylation leads to the upregulation of Gli1 signaling, it may be hypothesized that it would contribute to the induction of epithelial-to-mesenchymal transition what subsequently results in increased cell motility and invasion.	('methylation', 'Var', (19, 30))	('increased', 'PosReg', (210, 219))	('ZIC4', 'Gene', (14, 18))	('cell motility', 'CPA', (220, 233))	('upregulation', 'PosReg', (44, 56))	('ZIC4', 'Gene', '84107', (14, 18))	('Gli1', 'Gene', (60, 64))	('invasion', 'CPA', (238, 246))	('Gli1', 'Gene', '2735', (60, 64))	('epithelial-to-mesenchymal transition', 'CPA', (144, 180))
490223	27553089	In line with this model, epigenetic changes were observed not only in tumor sections but also in macroscopically normal surgical margin.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', (70, 75))	('epigenetic changes', 'Var', (25, 43))	('observed', 'Reg', (49, 57))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
490224	27553089	In summary, we report that CXXC4, DACT2, HHIP, ZIC1, and ZIC4 are methylated in head and neck squamous cell carcinomas.	('ZIC4', 'Gene', (57, 61))	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('HHIP', 'Gene', (41, 45))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (94, 117))	('ZIC4', 'Gene', '84107', (57, 61))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (80, 117))	('ZIC1', 'Gene', (47, 51))	('carcinomas', 'Phenotype', 'HP:0030731', (108, 118))	('methylated', 'Var', (66, 76))	('DACT2', 'Gene', '168002', (34, 39))	('ZIC1', 'Gene', '7545', (47, 51))	('head and neck squamous cell carcinomas', 'Phenotype', 'HP:0012288', (80, 118))	('CXXC4', 'Gene', '80319', (27, 32))	('head and neck squamous cell carcinomas', 'Disease', 'MESH:D000077195', (80, 118))	('HHIP', 'Gene', '64399', (41, 45))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (94, 118))	('DACT2', 'Gene', (34, 39))	('CXXC4', 'Gene', (27, 32))
490226	27553089	In this regard, functional studies should follow to investigate whether epigenetic modulators may inhibit Wnt or Shh signaling due to the reactivation of expression of pathway antagonists.	('Wnt', 'Pathway', (106, 109))	('epigenetic modulators', 'Var', (72, 93))	('Shh', 'Gene', (113, 116))	('inhibit', 'NegReg', (98, 105))	('Shh', 'Gene', '6469', (113, 116))	('expression', 'MPA', (154, 164))
490228	27553089	Further investigations should determine the detailed diagnostic significance of methylation of ZIC4, HHIP, and DACT2 in head and neck carcinomas.	('HHIP', 'Gene', '64399', (101, 105))	('DACT2', 'Gene', (111, 116))	('ZIC4', 'Gene', (95, 99))	('head and neck carcinoma', 'Phenotype', 'HP:0012288', (120, 143))	('ZIC4', 'Gene', '84107', (95, 99))	('HHIP', 'Gene', (101, 105))	('DACT2', 'Gene', '168002', (111, 116))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('neck carcinomas', 'Disease', (129, 144))	('methylation', 'Var', (80, 91))	('head and neck carcinomas', 'Phenotype', 'HP:0012288', (120, 144))	('carcinomas', 'Phenotype', 'HP:0030731', (134, 144))	('neck carcinomas', 'Disease', 'MESH:D006258', (129, 144))
490233	29772705	Kaplan-Meier and Cox proportional hazards analysis indicated that high expression of B-Myb is significantly associated with poor prognosis in NSCLC patients.	('patients', 'Species', '9606', (148, 156))	('Cox', 'Gene', '1351', (17, 20))	('B-Myb', 'Protein', (85, 90))	('Cox', 'Gene', (17, 20))	('NSCLC', 'Disease', (142, 147))	('NSCLC', 'Disease', 'MESH:D002289', (142, 147))	('high', 'Var', (66, 70))
490235	29772705	Notably, B-Myb depletion also decreased NSCLC cell migration and invasion ability as well as colony-forming ability.	('depletion', 'Var', (15, 24))	('NSCLC', 'Disease', 'MESH:D002289', (40, 45))	('colony-forming ability', 'CPA', (93, 115))	('invasion ability', 'CPA', (65, 81))	('B-Myb', 'Protein', (9, 14))	('NSCLC', 'Disease', (40, 45))	('decreased', 'NegReg', (30, 39))
490236	29772705	Moreover, an in vivo study demonstrated that B-Myb depletion caused significant inhibition of tumor growth in a NSCLC xenograft nude mouse model.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('inhibition', 'NegReg', (80, 90))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Disease', (94, 99))	('B-Myb', 'Protein', (45, 50))	('mouse', 'Species', '10090', (133, 138))	('NSCLC', 'Disease', (112, 117))	('depletion', 'Var', (51, 60))	('NSCLC', 'Disease', 'MESH:D002289', (112, 117))
490257	29772705	A loss-of-function study demonstrated that knockdown of B-Myb significantly suppressed NSCLC cell growth, cell cycle progression, colony-forming ability, motility, and tumorigenesis in vivo.	('motility', 'CPA', (154, 162))	('colony-forming ability', 'CPA', (130, 152))	('NSCLC', 'Disease', (87, 92))	('tumor', 'Disease', (168, 173))	('NSCLC', 'Disease', 'MESH:D002289', (87, 92))	('knockdown', 'Var', (43, 52))	('suppressed', 'NegReg', (76, 86))	('B-Myb', 'Protein', (56, 61))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('cell cycle progression', 'CPA', (106, 128))	('loss-of-function', 'NegReg', (2, 18))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
490259	29772705	Moreover, we further demonstrated that IGFBP3 is an important downstream target gene of B-Myb, and that B-Myb activates extracellular signal-regulated kinases (ERK) and Akt signaling at least partially through inhibiting IGFBP3 in NSCLC cells.	('IGFBP3', 'Gene', '3486', (221, 227))	('extracellular signal-regulated kinases', 'Gene', (120, 158))	('activates', 'PosReg', (110, 119))	('Akt', 'Gene', (169, 172))	('ERK', 'Gene', '5594', (160, 163))	('IGFBP3', 'Gene', '3486', (39, 45))	('NSCLC', 'Disease', (231, 236))	('ERK', 'Gene', (160, 163))	('IGFBP3', 'Gene', (221, 227))	('inhibiting', 'NegReg', (210, 220))	('IGFBP3', 'Gene', (39, 45))	('B-Myb', 'Var', (104, 109))	('NSCLC', 'Disease', 'MESH:D002289', (231, 236))	('Akt', 'Gene', '207', (169, 172))	('extracellular signal-regulated kinases', 'Gene', '5594', (120, 158))
490263	29772705	As shown in Figure 1A, high expression of B-Myb was strongly associated with poor overall survival of lung cancer patients in the Nagoya University lung adenocarcinoma (ADC) cohort and Michigan University lung squamous cell carcinoma (SQCC) cohort (p < 0.05).	('high expression', 'Var', (23, 38))	('lung cancer', 'Phenotype', 'HP:0100526', (102, 113))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('poor', 'NegReg', (77, 81))	('lung adenocarcinoma', 'Disease', (148, 167))	('B-Myb', 'Protein', (42, 47))	('lung cancer', 'Disease', (102, 113))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (148, 167))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (205, 233))	('carcinoma', 'Phenotype', 'HP:0030731', (158, 167))	('lung cancer', 'Disease', 'MESH:D008175', (102, 113))	('overall', 'MPA', (82, 89))	('lung squamous cell carcinoma', 'Disease', (205, 233))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (205, 233))	('carcinoma', 'Phenotype', 'HP:0030731', (224, 233))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (148, 167))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (210, 233))	('patients', 'Species', '9606', (114, 122))
490266	29772705	To investigate the therapeutic potential of B-Myb in NSCLC, we depleted the B-Myb expression via small interfering RNA (siRNA)-mediated silencing in A549 lung cancer cell lines, and cell proliferation and cell cycle assays were subsequently performed.	('lung cancer', 'Phenotype', 'HP:0100526', (154, 165))	('expression', 'MPA', (82, 92))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('depleted', 'NegReg', (63, 71))	('A549 lung cancer', 'Disease', 'MESH:D008175', (149, 165))	('NSCLC', 'Disease', (53, 58))	('silencing', 'Var', (136, 145))	('B-Myb', 'Gene', (76, 81))	('NSCLC', 'Disease', 'MESH:D002289', (53, 58))	('A549 lung cancer', 'Disease', (149, 165))
490268	29772705	B-Myb depletion resulted in a significant growth retardation compared with control siRNA from a later time point (96 h) in A549 cells (Figure 2B).	('B-Myb', 'Protein', (0, 5))	('growth retardation', 'Disease', 'MESH:D006130', (42, 60))	('depletion', 'Var', (6, 15))	('growth retardation', 'Disease', (42, 60))	('A549', 'CellLine', 'CVCL:0023', (123, 127))	('growth retardation', 'Phenotype', 'HP:0001510', (42, 60))
490269	29772705	Cell cycle analysis revealed that silencing B-Myb expression caused a remarkable G1 arrest in A549 cells (Figure 2C).	('A549', 'CellLine', 'CVCL:0023', (94, 98))	('silencing', 'Var', (34, 43))	('B-Myb', 'Protein', (44, 49))	('G1 arrest', 'CPA', (81, 90))
490270	29772705	Moreover, our previous study showed that B-Myb depletion affects the cell cycle progression and inhibits proliferation in H1299 cells.	('inhibits', 'NegReg', (96, 104))	('depletion', 'Var', (47, 56))	('cell cycle progression', 'CPA', (69, 91))	('affects', 'Reg', (57, 64))	('B-Myb', 'Protein', (41, 46))	('proliferation', 'CPA', (105, 118))	('H1299', 'CellLine', 'CVCL:0060', (122, 127))
490271	29772705	These results suggested that B-Myb depletion mainly delays cell cycle progression and significantly inhibits proliferation in both A549 and H1299 cells.	('inhibits', 'NegReg', (100, 108))	('delays', 'NegReg', (52, 58))	('cell cycle progression', 'CPA', (59, 81))	('A549', 'CellLine', 'CVCL:0023', (131, 135))	('H1299', 'CellLine', 'CVCL:0060', (140, 145))	('proliferation', 'CPA', (109, 122))	('B-Myb', 'Protein', (29, 34))	('depletion', 'Var', (35, 44))
490276	29772705	As shown in Figure 4B,C, colony formation assays on plastic and soft agar revealed that B-Myb knockdown in H1299 cells significantly inhibited anchorage-dependent and -independent colony-forming ability compared with the control cells.	('inhibited', 'NegReg', (133, 142))	('H1299', 'CellLine', 'CVCL:0060', (107, 112))	('B-Myb', 'Protein', (88, 93))	('knockdown', 'Var', (94, 103))
490277	29772705	To examine whether silencing of B-Myb expression could inhibit tumorigenesis in vivo, we used A549 cells to establish stable cells with lentiviral particle B-Myb knockdown.	('tumor', 'Disease', (63, 68))	('silencing', 'Var', (19, 28))	('A549', 'CellLine', 'CVCL:0023', (94, 98))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('B-Myb', 'Protein', (32, 37))	('inhibit', 'NegReg', (55, 62))
490279	29772705	As shown in Figure 5D-F, stable knockdown of B-Myb expression remarkably suppressed the tumor growth in both tumor volume and tumor weight in the nude mice.	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('knockdown', 'Var', (32, 41))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('suppressed', 'NegReg', (73, 83))	('B-Myb', 'Gene', (45, 50))	('nude mice', 'Species', '10090', (146, 155))	('tumor', 'Disease', (88, 93))	('tumor', 'Disease', (109, 114))	('tumor', 'Disease', (126, 131))
490282	29772705	Using the Kyoto Encyclopedia of Genes and Genomes databases, the significant signaling pathways of the DEGs affected by B-Myb depletion included the MAPK signaling pathway, cytokine-cytokine receptor interaction, transcriptional regulation in cancer, and so forth (Table 2).	('B-Myb', 'Protein', (120, 125))	('MAPK signaling pathway', 'Pathway', (149, 171))	('depletion', 'Var', (126, 135))	('cancer', 'Disease', (243, 249))	('cancer', 'Disease', 'MESH:D009369', (243, 249))	('cancer', 'Phenotype', 'HP:0002664', (243, 249))
490293	29772705	Quantitative RT-PCR analysis validated the successful knockdown of IGFBP3 in cells (Figure 7C).	('IGFBP3', 'Gene', (67, 73))	('IGFBP3', 'Gene', '3486', (67, 73))	('knockdown', 'Var', (54, 63))
490295	29772705	Moreover, in the wound healing assay, IGFBP3 overexpression inhibited the migratory capacity of H1299 cells induced by the B-Myb overexpression (Figure 7E).	('migratory capacity of H1299 cells', 'CPA', (74, 107))	('H1299', 'CellLine', 'CVCL:0060', (96, 101))	('IGFBP3', 'Gene', (38, 44))	('overexpression', 'Var', (45, 59))	('overexpression', 'PosReg', (129, 143))	('B-Myb', 'Protein', (123, 128))	('inhibited', 'NegReg', (60, 69))	('IGFBP3', 'Gene', '3486', (38, 44))
490296	29772705	These results suggest that B-Myb promotes cell proliferation and migration by targeting IGFBP3 in H1299 cells.	('promotes', 'PosReg', (33, 41))	('targeting', 'Var', (78, 87))	('migration', 'CPA', (65, 74))	('IGFBP3', 'Gene', '3486', (88, 94))	('cell proliferation', 'CPA', (42, 60))	('H1299', 'CellLine', 'CVCL:0060', (98, 103))	('B-Myb', 'Protein', (27, 32))	('IGFBP3', 'Gene', (88, 94))
490300	29772705	On the other hand, IGFBP3 knockdown increased the levels of phosphorylated ERK and Akt, whereas B-Myb knockdown decreased the phosphorylated ERK and Akt.	('ERK', 'Gene', '5594', (75, 78))	('ERK', 'Gene', (141, 144))	('Akt', 'Gene', (149, 152))	('IGFBP3', 'Gene', '3486', (19, 25))	('Akt', 'Gene', (83, 86))	('ERK', 'Gene', (75, 78))	('increased', 'PosReg', (36, 45))	('levels', 'MPA', (50, 56))	('knockdown', 'Var', (26, 35))	('Akt', 'Gene', '207', (149, 152))	('Akt', 'Gene', '207', (83, 86))	('IGFBP3', 'Gene', (19, 25))	('decreased', 'NegReg', (112, 121))	('ERK', 'Gene', '5594', (141, 144))	('phosphorylated', 'MPA', (126, 140))
490306	29772705	In a sharp contrast to B-Myb overexpression, B-Myb depletion enhances luciferase activities driven by the IGFBP3-P2822 promoter (Figure 9C).	('IGFBP3', 'Gene', (106, 112))	('depletion', 'Var', (51, 60))	('IGFBP3', 'Gene', '3486', (106, 112))	('enhances', 'PosReg', (61, 69))	('B-Myb', 'Protein', (45, 50))	('luciferase', 'Enzyme', (70, 80))	('activities', 'MPA', (81, 91))
490314	29772705	In the present study, we firstly found prognostic significance of B-Myb in NSCLC, and a loss-of-function study demonstrated that downregulation of B-Myb significantly suppressed NSCLC cell growth, cell cycle progression, colony-forming ability, motility, and tumorigenesis in vivo.	('downregulation', 'Var', (129, 143))	('NSCLC', 'Disease', (178, 183))	('suppressed', 'NegReg', (167, 177))	('NSCLC', 'Disease', 'MESH:D002289', (178, 183))	('tumor', 'Disease', 'MESH:D009369', (259, 264))	('B-Myb', 'Protein', (147, 152))	('tumor', 'Phenotype', 'HP:0002664', (259, 264))	('colony-forming ability', 'CPA', (221, 243))	('motility', 'CPA', (245, 253))	('NSCLC', 'Disease', (75, 80))	('tumor', 'Disease', (259, 264))	('cell cycle progression', 'CPA', (197, 219))	('NSCLC', 'Disease', 'MESH:D002289', (75, 80))
490319	29772705	Aberrant B-Myb expression or amplification has been confirmed in different types of human cancers, verifying a role in tumorigenesis.	('tumor', 'Disease', (119, 124))	('cancers', 'Disease', (90, 97))	('amplification', 'Var', (29, 42))	('Aberrant', 'Var', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('B-Myb', 'Protein', (9, 14))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('human', 'Species', '9606', (84, 89))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('cancers', 'Disease', 'MESH:D009369', (90, 97))
490320	29772705	According to our recent observations, exogenous B-Myb overexpression in NSCLC promoted G1-S phase transition progression; caused transactivation of multiple downstream genes such as CCNA1, COL11A1, COL6A1, MMP2, NID1, and FLT4; and activated ERK and Akt signaling pathways.	('NSCLC', 'Disease', (72, 77))	('overexpression', 'PosReg', (54, 68))	('ERK', 'Gene', (242, 245))	('CCNA1', 'Gene', '8900', (182, 187))	('NID1', 'Gene', '4811', (212, 216))	('NID1', 'Gene', (212, 216))	('COL11A1', 'Gene', '1301', (189, 196))	('FLT4', 'Gene', (222, 226))	('FLT4', 'Gene', '2324', (222, 226))	('promoted', 'PosReg', (78, 86))	('B-Myb', 'Protein', (48, 53))	('Akt', 'Gene', (250, 253))	('COL6A1', 'Gene', (198, 204))	('COL6A1', 'Gene', '1291', (198, 204))	('Akt', 'Gene', '207', (250, 253))	('activated', 'PosReg', (232, 241))	('MMP2', 'Gene', (206, 210))	('COL11A1', 'Gene', (189, 196))	('exogenous', 'Var', (38, 47))	('CCNA1', 'Gene', (182, 187))	('ERK', 'Gene', '5594', (242, 245))	('NSCLC', 'Disease', 'MESH:D002289', (72, 77))	('MMP2', 'Gene', '4313', (206, 210))	('transactivation', 'MPA', (129, 144))	('G1-S phase transition progression', 'CPA', (87, 120))
490321	29772705	Moreover, RNA-seq analysis showed that knockdown of B-Myb leads to upregulation of different downstream genes such as IGFBP3 and downregulation of various downstream genes such as COL11A1, FLT4, SPARC, IDH2, and PDK3.	('PDK3', 'Gene', '5165', (212, 216))	('PDK3', 'Gene', (212, 216))	('SPARC', 'Gene', '6678', (195, 200))	('downregulation', 'NegReg', (129, 143))	('COL11A1', 'Gene', '1301', (180, 187))	('knockdown', 'Var', (39, 48))	('SPARC', 'Gene', (195, 200))	('IGFBP3', 'Gene', (118, 124))	('upregulation', 'PosReg', (67, 79))	('IDH2', 'Gene', (202, 206))	('FLT4', 'Gene', (189, 193))	('FLT4', 'Gene', '2324', (189, 193))	('B-Myb', 'Gene', (52, 57))	('COL11A1', 'Gene', (180, 187))	('IGFBP3', 'Gene', '3486', (118, 124))	('IDH2', 'Gene', '3418', (202, 206))
490324	29772705	It is worthwhile to mention that IGFBP3 overexpression suppresses the growth of NSCLC cells in vitro and in vivo, and leads to apoptosis in NSCLC cells by suppression of the signal transduction mechanism participating in cellular proliferation and survival.	('suppression', 'NegReg', (155, 166))	('NSCLC', 'Disease', 'MESH:D002289', (140, 145))	('growth', 'CPA', (70, 76))	('signal transduction mechanism', 'Pathway', (174, 203))	('NSCLC', 'Disease', (80, 85))	('apoptosis', 'CPA', (127, 136))	('leads to', 'Reg', (118, 126))	('IGFBP3', 'Gene', (33, 39))	('NSCLC', 'Disease', 'MESH:D002289', (80, 85))	('overexpression', 'Var', (40, 54))	('suppresses', 'NegReg', (55, 65))	('IGFBP3', 'Gene', '3486', (33, 39))	('NSCLC', 'Disease', (140, 145))
490351	29772705	H1299 cells of B-Myb overexpression or B-Myb knockdown were transfected with corresponding plasmids to overexpress or knock down IGFBP3 using Lipofectamine 2000 reagent according to the manufacturer's instructions, and incubated at 37  C for 48 h. The human IGFBP3 and (-2282 nucleotide (nt) to +56 nt)-luciferase promoters were gifted by Dr. T. Hanafusa (Okayama University, Okayama, Japan).	('IGFBP3', 'Gene', (258, 264))	('IGFBP3', 'Gene', '3486', (129, 135))	('IGFBP3', 'Gene', '3486', (258, 264))	('-2282', 'Var', (270, 275))	('H1299', 'CellLine', 'CVCL:0060', (0, 5))	('IGFBP3', 'Gene', (129, 135))	('Lipofectamine 2000', 'Chemical', 'MESH:C086724', (142, 160))	('human', 'Species', '9606', (252, 257))
490360	29772705	The Nagoya lung adenocarcinoma (ADC) and Michigan lung squamous cell carcinoma (SQCC) datasets were downloaded from the public gene expression omnibus (GEO) database (GSE4573 and GSE13213.	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (11, 30))	('lung squamous cell carcinoma', 'Disease', (50, 78))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (55, 78))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (11, 30))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (50, 78))	('GSE4573', 'Var', (167, 174))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (50, 78))	('carcinoma', 'Phenotype', 'HP:0030731', (21, 30))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))	('lung adenocarcinoma', 'Disease', (11, 30))
490373	29115564	Furthermore, knockdown of CDK4/BCAS2 coincided with the suppressive effects of miR-486 in esophageal cancer cells.	('BCAS2', 'Gene', (31, 36))	('miR-486', 'Gene', (79, 86))	('suppressive', 'NegReg', (56, 67))	('BCAS2', 'Gene', '10286', (31, 36))	('esophageal cancer', 'Disease', (90, 107))	('CDK4', 'Gene', (26, 30))	('CDK4', 'Gene', '1019', (26, 30))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('esophageal cancer', 'Disease', 'MESH:D004938', (90, 107))	('knockdown', 'Var', (13, 22))	('miR-486', 'Gene', '619554', (79, 86))
490383	29115564	It has been reported that mutations of several genes are associated with esophageal cancer, such as p53, FasL and EGFR.	('esophageal cancer', 'Disease', (73, 90))	('EGFR', 'Gene', '1956', (114, 118))	('mutations', 'Var', (26, 35))	('p53', 'Gene', '7157', (100, 103))	('esophageal cancer', 'Disease', 'MESH:D004938', (73, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('FasL', 'Gene', (105, 109))	('EGFR', 'Gene', (114, 118))	('FasL', 'Gene', '356', (105, 109))	('associated', 'Reg', (57, 67))	('p53', 'Gene', (100, 103))
490399	29115564	Three esophageal cell lines (KYSE150, EC9706 and TE-9) and human normal esophageal epithelial cell line Het-1A were purchased from the Cell Bank of Shanghai Institute of Cell Biology (Chinese Academy of Medical Sciences, Shanghai, China).	('EC9706', 'Var', (38, 44))	('KYSE150', 'Var', (29, 36))	('human', 'Species', '9606', (59, 64))	('EC9706', 'CellLine', 'CVCL:E307', (38, 44))
490409	29115564	The membranes were immunoblotted with the primary antibodies: CDK4 (1:500, ab108357; Abcam, Cambridge, UK), BCAS2 (1:500, ab151293; Abcam), GAPDH (1:500, ab8245; Abcam), p21 (1:500, ab109520; Abcam) and caspase-3 (1:300, ab2171; Abcam) overnight at 4 C. After being rinsed with TBST, the membranes were incubated with secondary antibodies (at a dilution of 1:5,000) conjugated to horseradish peroxidase.	('GAPDH', 'Gene', (140, 145))	('TBS', 'Chemical', 'MESH:D013725', (278, 281))	('CDK4', 'Gene', (62, 66))	('CDK4', 'Gene', '1019', (62, 66))	('BCAS2', 'Gene', (108, 113))	('caspase-3', 'Gene', '836', (203, 212))	('p21', 'Gene', (170, 173))	('horseradish', 'Species', '3704', (380, 391))	('1:500', 'Var', (115, 120))	('GAPDH', 'Gene', '2597', (140, 145))	('p21', 'Gene', '644914', (170, 173))	('caspase-3', 'Gene', (203, 212))	('BCAS2', 'Gene', '10286', (108, 113))
490450	29115564	After overexpression of miR-486 in EC9706 cells, the number of cells invading the basement membrane was significantly lower than that in the NC group (Fig.	('miR-486', 'Gene', '619554', (24, 31))	('EC9706', 'Var', (35, 41))	('EC9706', 'CellLine', 'CVCL:E307', (35, 41))	('overexpression', 'PosReg', (6, 20))	('miR-486', 'Gene', (24, 31))	('lower', 'NegReg', (118, 123))
490455	29115564	When the binding site was mutated, the interaction relationship disappeared and the expression of CDK4/BCAS2 returned to normal, which indicated that miR-486 may be a regulatory factor of the CDK4/BCAS2 sequence (Fig.	('BCAS2', 'Gene', (103, 108))	('miR-486', 'Gene', (150, 157))	('BCAS2', 'Gene', '10286', (197, 202))	('disappeared', 'NegReg', (64, 75))	('BCAS2', 'Gene', (197, 202))	('CDK4', 'Gene', (192, 196))	('miR-486', 'Gene', '619554', (150, 157))	('CDK4', 'Gene', (98, 102))	('mutated', 'Var', (26, 33))	('binding', 'Interaction', (9, 16))	('CDK4', 'Gene', '1019', (192, 196))	('CDK4', 'Gene', '1019', (98, 102))	('expression', 'MPA', (84, 94))	('interaction', 'Interaction', (39, 50))	('BCAS2', 'Gene', '10286', (103, 108))
490461	29115564	The cell cycle was arrested in the G0/G1 phase following the silencing of CDK4 or BCAS2, and could not enter the cell cycle normally (Fig.	('cell cycle', 'CPA', (4, 14))	('BCAS2', 'Gene', '10286', (82, 87))	('CDK4', 'Gene', '1019', (74, 78))	('CDK4', 'Gene', (74, 78))	('arrest', 'Disease', 'MESH:D006323', (19, 25))	('BCAS2', 'Gene', (82, 87))	('silencing', 'Var', (61, 70))	('arrest', 'Disease', (19, 25))
490463	29115564	The above results showed that the knockdown of target genes CDK4/BCAS2 can induce the apoptosis of esophageal cancer cells, but the apoptosis-related downstream proteins were not clear.	('esophageal cancer', 'Disease', 'MESH:D004938', (99, 116))	('CDK4', 'Gene', (60, 64))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('CDK4', 'Gene', '1019', (60, 64))	('BCAS2', 'Gene', '10286', (65, 70))	('BCAS2', 'Gene', (65, 70))	('knockdown', 'Var', (34, 43))	('induce', 'PosReg', (75, 81))	('apoptosis', 'CPA', (86, 95))	('esophageal cancer', 'Disease', (99, 116))
490465	29115564	The results showed that compared with the NC group, CDK4 and BCAS2 protein expression was decreased, and expression levels of apoptotic signaling molecules p21 and caspase-3 were also downregulated in the siCDK4 and siBCAS2 EC9706 cell groups (Fig.	('CDK4', 'Gene', (52, 56))	('CDK4', 'Gene', '1019', (207, 211))	('CDK4', 'Gene', (207, 211))	('BCAS2', 'Gene', '10286', (218, 223))	('caspase-3', 'Gene', '836', (164, 173))	('BCAS2', 'Gene', (218, 223))	('BCAS2', 'Gene', '10286', (61, 66))	('EC9706', 'CellLine', 'CVCL:E307', (224, 230))	('BCAS2', 'Gene', (61, 66))	('decreased', 'NegReg', (90, 99))	('p21', 'Gene', (156, 159))	('protein', 'Protein', (67, 74))	('caspase-3', 'Gene', (164, 173))	('p21', 'Gene', '644914', (156, 159))	('downregulated', 'NegReg', (184, 197))	('EC9706', 'Var', (224, 230))	('CDK4', 'Gene', '1019', (52, 56))
490466	29115564	After transfected for 48 h, the migration ability of the EC9706 cells following silencing of CDK4/BCAS2 was significantly lower than that noted in the NC group (both p<0.01), which indicated that knockdown of target genes CDK4/BCAS2 could inhibit the motility of esophageal cancer cells (Fig.	('migration ability', 'CPA', (32, 49))	('lower', 'NegReg', (122, 127))	('CDK4', 'Gene', '1019', (93, 97))	('silencing', 'Var', (80, 89))	('motility of', 'CPA', (251, 262))	('BCAS2', 'Gene', '10286', (98, 103))	('esophageal cancer', 'Disease', 'MESH:D004938', (263, 280))	('inhibit', 'NegReg', (239, 246))	('EC9706', 'CellLine', 'CVCL:E307', (57, 63))	('CDK4', 'Gene', (222, 226))	('BCAS2', 'Gene', (98, 103))	('CDK4', 'Gene', '1019', (222, 226))	('BCAS2', 'Gene', '10286', (227, 232))	('esophageal cancer', 'Disease', (263, 280))	('knockdown', 'Var', (196, 205))	('cancer', 'Phenotype', 'HP:0002664', (274, 280))	('CDK4', 'Gene', (93, 97))	('BCAS2', 'Gene', (227, 232))
490468	29115564	These results suggest that knockdown of target genes CDK4/BCAS2 can reduce the migration and invasion abilities of the esophageal cancer cells.	('knockdown', 'Var', (27, 36))	('esophageal cancer', 'Disease', 'MESH:D004938', (119, 136))	('CDK4', 'Gene', '1019', (53, 57))	('CDK4', 'Gene', (53, 57))	('reduce', 'NegReg', (68, 74))	('invasion abilities of the', 'CPA', (93, 118))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('BCAS2', 'Gene', '10286', (58, 63))	('BCAS2', 'Gene', (58, 63))	('esophageal cancer', 'Disease', (119, 136))
490474	29115564	miRNAs can function as oncogenes or as tumor-suppressor genes, which play an important role in angiogenesis and epithelial-mesenchymal transition and drug resistance in cancer.	('tumor-suppressor', 'Gene', '7248', (39, 55))	('cancer', 'Disease', (169, 175))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('tumor-suppressor', 'Gene', (39, 55))	('miRNAs', 'Var', (0, 6))	('drug resistance', 'Phenotype', 'HP:0020174', (150, 165))	('cancer', 'Disease', 'MESH:D009369', (169, 175))
490483	29115564	The expression of miR-486 was determined in three esophageal squamous carcinoma cell lines and that of EC9706 had a significantly lower level compared to Het-1A (human esophageal epithelial cell line).	('lower', 'NegReg', (130, 135))	('EC9706', 'Var', (103, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('miR-486', 'Gene', '619554', (18, 25))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (61, 79))	('EC9706', 'CellLine', 'CVCL:E307', (103, 109))	('human', 'Species', '9606', (162, 167))	('esophageal squamous carcinoma', 'Disease', 'MESH:D000077277', (50, 79))	('esophageal squamous carcinoma', 'Disease', (50, 79))	('esophageal squamous carcinoma', 'Phenotype', 'HP:0011459', (50, 79))	('miR-486', 'Gene', (18, 25))
490495	29115564	In the present study, we found that the proliferation and clone formation ability of esophageal cancer cells were inhibited after knockdown of CDK4 and BCAS2 genes, and the ability of migration and invasion was also reduced.	('reduced', 'NegReg', (216, 223))	('clone formation ability', 'CPA', (58, 81))	('BCAS2', 'Gene', (152, 157))	('esophageal cancer', 'Disease', 'MESH:D004938', (85, 102))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('knockdown', 'Var', (130, 139))	('CDK4', 'Gene', (143, 147))	('CDK4', 'Gene', '1019', (143, 147))	('esophageal cancer', 'Disease', (85, 102))	('BCAS2', 'Gene', '10286', (152, 157))	('inhibited', 'NegReg', (114, 123))
490497	29115564	In addition, p53 is also a target protein of BCAS2, while knockdown of BCAS2 can enhance p53-induced apoptosis.	('BCAS2', 'Gene', (45, 50))	('enhance', 'PosReg', (81, 88))	('BCAS2', 'Gene', '10286', (71, 76))	('BCAS2', 'Gene', (71, 76))	('p53', 'Gene', (89, 92))	('p53', 'Gene', (13, 16))	('BCAS2', 'Gene', '10286', (45, 50))	('p53', 'Gene', '7157', (89, 92))	('knockdown', 'Var', (58, 67))	('p53', 'Gene', '7157', (13, 16))
490499	29115564	After knockdown of CDK4, the level of p21 was detected but the specific regulatory mechanism between CDK4 and p21 warrant further research.	('CDK4', 'Gene', '1019', (101, 105))	('CDK4', 'Gene', (101, 105))	('CDK4', 'Gene', (19, 23))	('p21', 'Gene', (38, 41))	('p21', 'Gene', '644914', (38, 41))	('CDK4', 'Gene', '1019', (19, 23))	('p21', 'Gene', (110, 113))	('p21', 'Gene', '644914', (110, 113))	('knockdown', 'Var', (6, 15))
490511	28949095	Further statistical analysis indicated that dysregulation of AURKA, BIRC5, and LINC00094 indicated poor prognosis in lung SCC.	('SCC', 'Gene', (122, 125))	('SCC', 'Phenotype', 'HP:0002860', (122, 125))	('dysregulation', 'Var', (44, 57))	('lung SCC', 'Phenotype', 'HP:0030359', (117, 125))	('SCC', 'Gene', '6317', (122, 125))	('LINC00094', 'Gene', (79, 88))	('AURKA', 'Gene', '6790', (61, 66))	('BIRC5', 'Gene', '332', (68, 73))	('LINC00094', 'Gene', '266655', (79, 88))	('BIRC5', 'Gene', (68, 73))	('AURKA', 'Gene', (61, 66))
490520	28949095	The expression profile datasets were downloaded from the Gene Expression Omnibus (GEO; http://www.ncbi.nlm.nih.gov/geo/).13 We selected two gene expression profile datasets, GSE43346 and GSE50081.	('GSE', 'Chemical', '-', (174, 177))	('GSE', 'Chemical', '-', (187, 190))	('GSE50081', 'Var', (187, 195))	('GSE43346', 'Var', (174, 182))
490530	28949095	Functional analysis of GO annotation showed that the DEGs were associated with cell adhesion,, regulation of transcription, apoptotic process, and other cancer-related biological processes (Fig 2b).	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('apoptotic process', 'CPA', (124, 141))	('cell adhesion', 'CPA', (79, 92))	('cancer', 'Disease', (153, 159))	('associated', 'Reg', (63, 73))	('DEGs', 'Var', (53, 57))	('regulation of transcription', 'MPA', (95, 122))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))
490536	28949095	Because of the unique nature of lncRNA expression, differentially expressed lncRNAs may be a predictive biomarker of cancer.	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('lncRNAs', 'Gene', (76, 83))	('cancer', 'Disease', (117, 123))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('differentially', 'Var', (51, 65))
490562	28949095	It has been proven that when BIRC5 is disrupted, apoptosis increases, leading to a decrease in tumor growth.	('BIRC5', 'Gene', '332', (29, 34))	('BIRC5', 'Gene', (29, 34))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('decrease', 'NegReg', (83, 91))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('disrupted', 'Var', (38, 47))	('apoptosis', 'CPA', (49, 58))	('tumor', 'Disease', (95, 100))
490609	31102336	On subgroup analysis, PORT was shown to significantly improve OS for pT3-4N1M0 compared with the surgery alone, and five-year OS was 41.3% versus 23.5%, respectively (P < 0.001).	('OS', 'Chemical', '-', (62, 64))	('pT3', 'Gene', '7694', (69, 72))	('PORT', 'Var', (22, 26))	('pT3', 'Gene', (69, 72))	('OS', 'Chemical', '-', (126, 128))	('improve', 'PosReg', (54, 61))
490718	30131556	For example, one study reported that even after adjusting for smoking status and sex, race was still significantly associated with EGFR mutations.	('associated', 'Reg', (115, 125))	('EGFR', 'Gene', (131, 135))	('EGFR', 'Gene', '1956', (131, 135))	('mutations', 'Var', (136, 145))
490719	30131556	EGFR mutations were highly prevalent in Asians at 30% vs. 7% in Whites.	('prevalent', 'Reg', (27, 36))	('EGFR', 'Gene', '1956', (0, 4))	('EGFR', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))
490724	30131556	Studies have also reported notable genetic variation in cancers by stage.	('cancers', 'Disease', (56, 63))	('cancers', 'Disease', 'MESH:D009369', (56, 63))	('genetic variation', 'Var', (35, 52))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('cancers', 'Phenotype', 'HP:0002664', (56, 63))
490771	28059107	We compared the cell cycle status between cells derived from PDPN+ and PDPN- seeded cells by measuring the duration of the periods when each nucleus displayed red (G0/G1 phase) and green (S/G2/M phase) fluorescence.	('red', 'MPA', (159, 162))	('S/G2', 'Var', (188, 192))	('green', 'MPA', (181, 186))	('PDPN+', 'Gene', (61, 66))	('S/G2', 'SUBSTITUTION', 'None', (188, 192))	('PDPN-', 'Gene', '10630', (71, 76))	('PDPN+', 'Gene', '10630', (61, 66))	('PDPN-', 'Gene', (71, 76))
490776	28059107	The average G1 phase durations of PDPN+- and PDPN-- derived cells were 19.9 +- 0.5 h and 18.0 +- 0.7 h, respectively, whereas the respective average durations of S/G2/M phases were 17.2 +- 1.1 h and 20.9 +- 1.8 h. There was no statistically significant difference in average doubling time between A431 PDPN+- and PDPN-- derived cells (37.0 +- 0.9 h vs. 38.8 +- 1.6 h) (Fig.	('S/G2', 'Var', (162, 166))	('PDPN+', 'Gene', (34, 39))	('PDPN+', 'Gene', '10630', (34, 39))	('S/G2', 'SUBSTITUTION', 'None', (162, 166))	('PDPN-', 'Gene', '10630', (313, 318))	('PDPN-', 'Gene', '10630', (45, 50))	('PDPN-', 'Gene', (313, 318))	('PDPN+', 'Gene', (302, 307))	('PDPN+', 'Gene', '10630', (302, 307))	('PDPN-', 'Gene', (45, 50))	('A431', 'CellLine', 'CVCL:0037', (297, 301))
490788	28059107	The percentage of cells that created large colonies was higher in shLuc-transfected cells (14 +- 3%) compared to shPDPN1- (only 2 +- 2%) and shPDPN3- (4 +- 6%) transfected cells, while both differences were statistically significant (shLuc vs. shPDPN1, p = 0.006; shLuc vs. shPDPN3, p = 0.04).	('PDPN', 'Gene', '10630', (143, 147))	('cells', 'CPA', (18, 23))	('shLuc-transfected', 'Var', (66, 83))	('PDPN', 'Gene', '10630', (276, 280))	('PDPN', 'Gene', (276, 280))	('PDPN', 'Gene', (246, 250))	('PDPN', 'Gene', (115, 119))	('PDPN', 'Gene', '10630', (115, 119))	('higher', 'PosReg', (56, 62))	('PDPN', 'Gene', '10630', (246, 250))	('PDPN', 'Gene', (143, 147))
490825	28059107	Our data suggest that the inhibition of PDPN-ROCK signaling can suppress tumor formation itself.	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('inhibition', 'Var', (26, 36))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('suppress', 'NegReg', (64, 72))	('PDPN-', 'Gene', (40, 45))	('tumor', 'Disease', (73, 78))	('PDPN-', 'Gene', '10630', (40, 45))
490844	28059107	The suspension was stained with anti-podoplanin mouse IgG (gp36, clone 18H5, Abcam, Cambridge, UK) or control mouse IgG.	('podoplanin', 'Gene', '10630', (37, 47))	('podoplanin', 'Gene', (37, 47))	('mouse', 'Species', '10090', (48, 53))	('mouse', 'Species', '10090', (110, 115))	('gp36', 'Var', (59, 63))
490852	28059107	Cells at the G0/G1 phases displayed red nuclear fluorescence, due to the accumulation of the mCherry-hCdt1 fusion protein in the nucleus, whereas cells at the S/G2/M phages displayed green fluorescence, due to the accumulation of the mVenus-HGeminin protein during these phases.	('S/G2', 'Var', (159, 163))	('S/G2', 'SUBSTITUTION', 'None', (159, 163))	('accumulation', 'PosReg', (73, 85))	('mCherry-hCdt1', 'Gene', (93, 106))	('red nuclear fluorescence', 'MPA', (36, 60))	('accumulation', 'PosReg', (214, 226))
490890	33076303	In a colon cancer model, it was demonstrated that in tumors treated with antibodies targeting PD-1 receptors, anti-PD-1 antibodies that are bound to T-cells were acquired by PD-1 negative TAMs.	('colon cancer', 'Phenotype', 'HP:0003003', (5, 17))	('colon cancer', 'Disease', 'MESH:D015179', (5, 17))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('TAM', 'Chemical', '-', (188, 191))	('antibodies', 'Var', (73, 83))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('colon cancer', 'Disease', (5, 17))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('PD-1', 'Gene', (94, 98))	('tumors', 'Disease', (53, 59))
490922	33076303	Particularly, the rates of EGFR and KRAS mutations are affected by the race of patients in NSCLC.	('mutations', 'Var', (41, 50))	('EGFR', 'Gene', '1956', (27, 31))	('NSCLC', 'Disease', 'MESH:D002289', (91, 96))	('EGFR', 'Gene', (27, 31))	('NSCLC', 'Phenotype', 'HP:0030358', (91, 96))	('KRAS', 'Gene', (36, 40))	('affected', 'Reg', (55, 63))	('KRAS', 'Gene', '3845', (36, 40))	('patients', 'Species', '9606', (79, 87))	('SCLC', 'Phenotype', 'HP:0030357', (92, 96))	('NSCLC', 'Disease', (91, 96))
490923	33076303	EGFR mutations are more commonly found in Asian populations (32-57%) than other races, while African populations show a greater genetic diversity.	('EGFR', 'Gene', '1956', (0, 4))	('EGFR', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))
490924	33076303	In a recent study by Sugiyama et al., the tumor microenvironment (TME) of EGFR mutated LUADs showed increased Treg infiltration, and a combination treatment of anti PD-1 with EGFR tyrosine kinase inhibitor erlotinib showed better anti-tumor effects.	('tumor', 'Disease', (42, 47))	('increased', 'PosReg', (100, 109))	('EGFR', 'Gene', (175, 179))	('mutated', 'Var', (79, 86))	('tumor', 'Disease', 'MESH:D009369', (235, 240))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('men', 'Species', '9606', (152, 155))	('tumor', 'Disease', (235, 240))	('EGFR', 'Gene', '1956', (74, 78))	('men', 'Species', '9606', (60, 63))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('Treg', 'Chemical', '-', (110, 114))	('EGFR', 'Gene', '1956', (175, 179))	('EGFR', 'Gene', (74, 78))	('erlotinib', 'Chemical', 'MESH:D000069347', (206, 215))	('Treg infiltration', 'CPA', (110, 127))
490932	33076303	On the basis of this evidence, surrogate mutations associated with racial differences may tailor the TME, concomitantly affecting the CPI efficacy.	('mutations', 'Var', (41, 50))	('affecting', 'Reg', (120, 129))	('CPI', 'MPA', (134, 137))	('tailor', 'Reg', (90, 96))	('CPI', 'Chemical', '-', (134, 137))
490947	33076303	Patients with age >75 years did not demonstrate an improved survival rate when treated with the anti PD-1 antibody.	('anti', 'Var', (96, 100))	('PD-1', 'Gene', (101, 105))	('Patients', 'Species', '9606', (0, 8))
490971	33076303	summarized the published clinical data from 20 clinical trial consisting of 11,000 patients administered with anti-PD1 or anti-CTLA-4 therapy.	('patients', 'Species', '9606', (83, 91))	('anti-PD1', 'Var', (110, 118))	('CTLA-4', 'Gene', '1493', (127, 133))	('CTLA-4', 'Gene', (127, 133))
490982	33076303	Tobacco smoking is conducive for tumor growth by inducing mutations in the tumor, modifying the tumor microenvironment and promoting pro or anti-inflammatory signaling.	('promoting', 'PosReg', (123, 132))	('mutations', 'Var', (58, 67))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('inducing', 'Reg', (49, 57))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('men', 'Species', '9606', (114, 117))	('tumor', 'Disease', (96, 101))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('modifying', 'Reg', (82, 91))	('Tobacco', 'Species', '4097', (0, 7))	('pro or anti-inflammatory signaling', 'MPA', (133, 167))	('tumor', 'Disease', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('tumor', 'Disease', (75, 80))
490984	33076303	This improvement in outcome is mainly attributed to mutations in DNA, induced by carcinogens present in smoke, eliciting increased neoantigen burden in tumors leading to immunological recognition of tumor.	('mutations', 'Var', (52, 61))	('tumor', 'Disease', (199, 204))	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('neoantigen burden', 'MPA', (131, 148))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('tumors', 'Disease', 'MESH:D009369', (152, 158))	('DNA', 'Gene', (65, 68))	('increased', 'PosReg', (121, 130))	('men', 'Species', '9606', (12, 15))	('tumor', 'Disease', (152, 157))	('improvement', 'PosReg', (5, 16))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('tumors', 'Disease', (152, 158))	('tumors', 'Phenotype', 'HP:0002664', (152, 158))
490985	33076303	Furthermore, the faulty DNA damage repair pathway, which is frequently spotted in patients with smoking history, is associated with a higher mutational burden and neoantigen presentation in tumor cells.	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('patients', 'Species', '9606', (82, 90))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('higher', 'PosReg', (134, 140))	('faulty', 'Var', (17, 23))	('tumor', 'Disease', (190, 195))	('neoantigen presentation', 'MPA', (163, 186))	('mutational burden', 'MPA', (141, 158))
490987	33076303	While the presence of neoantigens attracts T cells to the tumor, it also elevates PDL-1 expression in tumor cells, yielding improved responsiveness to CPI.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('responsiveness to CPI', 'MPA', (133, 154))	('PDL-1', 'Gene', (82, 87))	('improved', 'PosReg', (124, 132))	('elevates', 'PosReg', (73, 81))	('expression', 'MPA', (88, 98))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('presence', 'Var', (10, 18))	('tumor', 'Disease', (102, 107))	('PDL-1', 'Gene', '29126', (82, 87))	('CPI', 'Chemical', '-', (151, 154))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))
490995	33076303	Immune desert tumors are marked by immunologic ignorance arising from either the absence of antigens or defects in antigen presentation by the loss of MHC I, B2 microglobulin or the loss of TAP-1 and TAP-2, which leads to death of functional T cells in the tumor stroma.	('loss', 'NegReg', (182, 186))	('TAP-1', 'Gene', '6890', (190, 195))	('tumor stroma', 'Disease', 'MESH:D009369', (257, 269))	('B2 microglobulin', 'Gene', '3135', (158, 174))	('tumors', 'Disease', (14, 20))	('tumor stroma', 'Disease', (257, 269))	('B2 microglobulin', 'Gene', (158, 174))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('TAP-1', 'Gene', (190, 195))	('TAP-2', 'Gene', (200, 205))	('MHC I', 'Gene', (151, 156))	('loss', 'Var', (143, 147))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('antigen presentation', 'MPA', (115, 135))	('TAP-2', 'Gene', '6891', (200, 205))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (257, 262))	('defects', 'Reg', (104, 111))
491012	33076303	On the other hand, crosstalk between smoking and HPV infection yielded a favorable outcome in HNSCC patients who received the anti PD-1/PD-L1 monotherapy.	('HNSCC', 'Disease', (94, 99))	('HPV infection', 'Disease', 'MESH:D030361', (49, 62))	('crosstalk', 'Var', (19, 28))	('HNSCC', 'Phenotype', 'HP:0012288', (94, 99))	('patients', 'Species', '9606', (100, 108))	('HPV infection', 'Disease', (49, 62))
491042	33076303	noted that in melanoma patients treated with anti PD-1 (nivolumab), serum IL-10 levels were higher in patients with an objective response rate.	('melanoma', 'Disease', (14, 22))	('higher', 'PosReg', (92, 98))	('IL-10', 'Gene', (74, 79))	('patients', 'Species', '9606', (23, 31))	('patients', 'Species', '9606', (102, 110))	('anti PD-1', 'Var', (45, 54))	('nivolumab', 'Chemical', 'MESH:D000077594', (56, 65))	('IL-10', 'Gene', '3586', (74, 79))	('melanoma', 'Disease', 'MESH:D008545', (14, 22))	('melanoma', 'Phenotype', 'HP:0002861', (14, 22))
491090	33076303	According to WHO specification, a BMI >= 30 is defined as being obese and can lead to other comorbidities such as hypertension, heart disease and cancer.	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('heart disease', 'Disease', 'MESH:D006331', (128, 141))	('lead to', 'Reg', (78, 85))	('obese', 'Disease', 'MESH:D009765', (64, 69))	('BMI >= 30', 'Var', (34, 43))	('hypertension', 'Disease', 'MESH:D006973', (114, 126))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('obese', 'Disease', (64, 69))	('heart disease', 'Disease', (128, 141))	('hypertension', 'Disease', (114, 126))	('hypertension', 'Phenotype', 'HP:0000822', (114, 126))
491105	33076303	Furthermore, this study also showed that high BMI was associated with a better survival outcome in lung, melanoma and ovarian cancer patients.	('lung', 'Disease', (99, 103))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('melanoma and ovarian cancer', 'Disease', 'MESH:D008545', (105, 132))	('melanoma', 'Phenotype', 'HP:0002861', (105, 113))	('BMI', 'MPA', (46, 49))	('patients', 'Species', '9606', (133, 141))	('high', 'Var', (41, 45))	('better', 'PosReg', (72, 78))	('survival', 'CPA', (79, 87))	('ovarian cancer', 'Phenotype', 'HP:0100615', (118, 132))
491114	33076303	A study by Eikawa et al., used syngeneic melanoma mice model to show that metformin, drug used for lowering the blood glucose level in diabetic patients, increases T cell infiltration into tumors and exerts antitumor immunity by directly enhancing T cell functionality and protecting them from exhaustion (154).	('blood glucose level', 'MPA', (112, 131))	('glucose', 'Chemical', 'MESH:D005947', (118, 125))	('lowering the blood glucose', 'Phenotype', 'HP:0001943', (99, 125))	('tumor', 'Disease', (211, 216))	('metformin', 'Var', (74, 83))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('enhancing', 'PosReg', (238, 247))	('increases', 'PosReg', (154, 163))	('metformin', 'Chemical', 'MESH:D008687', (74, 83))	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('T cell functionality', 'CPA', (248, 268))	('tumors', 'Phenotype', 'HP:0002664', (189, 195))	('mice', 'Species', '10090', (50, 54))	('diabetic', 'Disease', 'MESH:D003920', (135, 143))	('melanoma', 'Disease', 'MESH:D008545', (41, 49))	('diabetic', 'Disease', (135, 143))	('tumors', 'Disease', (189, 195))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('tumor', 'Disease', (189, 194))	('increases T cell', 'Phenotype', 'HP:0100828', (154, 170))	('T cell infiltration into', 'CPA', (164, 188))	('tumors', 'Disease', 'MESH:D009369', (189, 195))	('patients', 'Species', '9606', (144, 152))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('melanoma', 'Phenotype', 'HP:0002861', (41, 49))	('melanoma', 'Disease', (41, 49))
491117	33076303	Therefore, it can be speculated that high BMI diabetic patients may have better outcomes under CPI treatment.	('diabetic', 'Disease', (46, 54))	('men', 'Species', '9606', (104, 107))	('high BMI', 'Var', (37, 45))	('diabetic', 'Disease', 'MESH:D003920', (46, 54))	('CPI', 'Chemical', '-', (95, 98))	('patients', 'Species', '9606', (55, 63))
491157	32150102	Aberrant expression of SMAD have been found in various cancers, and may be regarded as prognostic indicator for some malignancies.	('cancers', 'Disease', 'MESH:D009369', (55, 62))	('Aberrant expression', 'Var', (0, 19))	('cancers', 'Phenotype', 'HP:0002664', (55, 62))	('SMAD', 'Gene', (23, 27))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('malignancies', 'Disease', 'MESH:D009369', (117, 129))	('malignancies', 'Disease', (117, 129))	('SMAD', 'Gene', '33529', (23, 27))	('found', 'Reg', (38, 43))	('cancers', 'Disease', (55, 62))
491160	32150102	The mRNA levels of SMAD6/7/9 in NSCLC were significantly down-regulated in NSCLC, and aberrant SMAD2/3/4/5/6/7/9 mRNA levels were all correlated with the prognosis of NSCLC.	('down-regulated', 'NegReg', (57, 71))	('mRNA levels', 'MPA', (4, 15))	('NSCLC', 'Disease', 'MESH:D002289', (167, 172))	('SMAD6/7/9', 'Gene', (19, 28))	('NSCLC', 'Phenotype', 'HP:0030358', (32, 37))	('NSCLC', 'Phenotype', 'HP:0030358', (75, 80))	('NSCLC', 'Phenotype', 'HP:0030358', (167, 172))	('correlated', 'Reg', (134, 144))	('NSCLC', 'Disease', (32, 37))	('SMAD2/3/4/5/6/7/9', 'Gene', '4087', (95, 112))	('aberrant', 'Var', (86, 94))	('NSCLC', 'Disease', (75, 80))	('SMAD2/3/4/5/6/7/9', 'Gene', (95, 112))	('mRNA levels', 'MPA', (113, 124))	('NSCLC', 'Disease', 'MESH:D002289', (32, 37))	('SMAD6/7/9', 'Gene', '4091;4092;4093', (19, 28))	('NSCLC', 'Disease', 'MESH:D002289', (75, 80))	('NSCLC', 'Disease', (167, 172))
491230	32150102	We also found that high expressions of SMAD5/9 were associated with favorable OS, FP and PPS in NSCLC patients.	('favorable OS', 'Disease', (68, 80))	('NSCLC', 'Disease', (96, 101))	('SMAD5/9', 'Gene', '4090;4093', (39, 46))	('patients', 'Species', '9606', (102, 110))	('NSCLC', 'Disease', 'MESH:D002289', (96, 101))	('associated', 'Reg', (52, 62))	('high expressions', 'Var', (19, 35))	('SMAD5/9', 'Gene', (39, 46))	('PPS', 'Disease', (89, 92))	('NSCLC', 'Phenotype', 'HP:0030358', (96, 101))
491237	32150102	Toyokawa et al reported that high expression of p-SMAD2 predicted poor prognosis in patients with clinical stage I to IIIA NSCLC.	('high', 'Var', (29, 33))	('NSCLC', 'Disease', (123, 128))	('patients', 'Species', '9606', (84, 92))	('NSCLC', 'Disease', 'MESH:D002289', (123, 128))	('p-SMAD2', 'Gene', (48, 55))	('NSCLC', 'Phenotype', 'HP:0030358', (123, 128))
491238	32150102	Additionally, the high expression of SMAD3 was associated with unfavorable survival in acute myeloid leukemia patients.	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (87, 109))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (87, 109))	('SMAD3', 'Gene', '4088', (37, 42))	('high', 'Var', (18, 22))	('leukemia', 'Phenotype', 'HP:0001909', (101, 109))	('acute myeloid leukemia', 'Disease', (87, 109))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (93, 109))	('associated', 'Reg', (47, 57))	('SMAD3', 'Gene', (37, 42))	('patients', 'Species', '9606', (110, 118))
491240	32150102	Unexpectedly, high SMAD2 expression was correlation to better OS in NSCLC, especially in LUAD patients and in clinical grades I or II NSCLC patients.	('NSCLC', 'Disease', 'MESH:D002289', (134, 139))	('NSCLC', 'Disease', 'MESH:D002289', (68, 73))	('patients', 'Species', '9606', (94, 102))	('NSCLC', 'Phenotype', 'HP:0030358', (134, 139))	('expression', 'MPA', (25, 35))	('high', 'Var', (14, 18))	('NSCLC', 'Phenotype', 'HP:0030358', (68, 73))	('better', 'PosReg', (55, 61))	('patients', 'Species', '9606', (140, 148))	('SMAD2', 'Gene', (19, 24))	('LUAD', 'Phenotype', 'HP:0030078', (89, 93))	('NSCLC', 'Disease', (134, 139))	('NSCLC', 'Disease', (68, 73))
491251	32150102	High SMAD6/7 mRNA levels were association with better FP, PPS, and OS, especially in LUAD and early stage tumor.	('LUAD', 'Disease', (85, 89))	('High', 'Var', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Disease', (106, 111))	('SMAD6/7', 'Gene', '4091;4092', (5, 12))	('mRNA levels', 'MPA', (13, 24))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('PPS', 'Disease', (58, 61))	('LUAD', 'Phenotype', 'HP:0030078', (85, 89))	('SMAD6/7', 'Gene', (5, 12))
491252	32150102	Genetic alterations of SMAD family members may be associated with pathogenesis and progression of carcinogenesis.	('Genetic alterations', 'Var', (0, 19))	('carcinogenesis', 'Disease', 'MESH:D063646', (98, 112))	('carcinogenesis', 'Disease', (98, 112))	('SMAD', 'Gene', (23, 27))	('SMAD', 'Gene', '33529', (23, 27))	('associated', 'Reg', (50, 60))
491253	32150102	We found relatively consistent low levels of alterations in each SMAD in NSCLC, but these alterations had no effect on OS or DFS, suggesting that these changes may not directly impact NSCLC prognosis.	('alterations', 'Var', (45, 56))	('NSCLC', 'Phenotype', 'HP:0030358', (184, 189))	('impact', 'Reg', (177, 183))	('SMAD', 'Gene', '33529', (65, 69))	('NSCLC', 'Disease', (184, 189))	('NSCLC', 'Disease', (73, 78))	('NSCLC', 'Disease', 'MESH:D002289', (184, 189))	('SMAD', 'Gene', (65, 69))	('NSCLC', 'Phenotype', 'HP:0030358', (73, 78))	('NSCLC', 'Disease', 'MESH:D002289', (73, 78))
491257	32150102	In summary, the mRNA levels of SMAD6/7/9 in NSCLC were significantly down-regulated in NSCLC, and aberrant SMAD2/3/4/5/6/7/9 mRNA levels were all correlated with the prognosis of NSCLC.	('NSCLC', 'Disease', 'MESH:D002289', (44, 49))	('SMAD2/3/4/5/6/7/9', 'Gene', '4087', (107, 124))	('aberrant', 'Var', (98, 106))	('NSCLC', 'Disease', (87, 92))	('SMAD2/3/4/5/6/7/9', 'Gene', (107, 124))	('correlated', 'Reg', (146, 156))	('NSCLC', 'Disease', 'MESH:D002289', (179, 184))	('mRNA levels', 'MPA', (16, 27))	('mRNA levels', 'MPA', (125, 136))	('SMAD6/7/9', 'Gene', '4091;4092;4093', (31, 40))	('NSCLC', 'Disease', 'MESH:D002289', (87, 92))	('NSCLC', 'Phenotype', 'HP:0030358', (44, 49))	('NSCLC', 'Phenotype', 'HP:0030358', (179, 184))	('down-regulated', 'NegReg', (69, 83))	('NSCLC', 'Phenotype', 'HP:0030358', (87, 92))	('SMAD6/7/9', 'Gene', (31, 40))	('NSCLC', 'Disease', (44, 49))	('NSCLC', 'Disease', (179, 184))
491271	31387639	Clinical studies have noted the association of high TMB with improved patient responses and survival benefit after ICI treatment either in a single cancer type (eg.	('improved', 'PosReg', (61, 69))	('cancer', 'Disease', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('TMB', 'Gene', (52, 55))	('high', 'Var', (47, 51))	('patient', 'Species', '9606', (70, 77))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('TMB', 'Chemical', '-', (52, 55))	('survival benefit', 'CPA', (92, 108))	('patient responses', 'CPA', (70, 87))
491284	31387639	The TMB was calculated as the number of non-synonymous somatic, coding, base substitution, and indel mutations per megabase (Mb) of genome examined, and 38 Mb was used as the estimate of the whole exome size.	('indel mutations', 'Var', (95, 110))	('base substitution', 'Var', (72, 89))	('TMB', 'Chemical', '-', (4, 7))
491287	31387639	Notably, for F1CDx and TSO500, synonymous mutations were also included in order to reduce sampling noise as the developers proposed.	('TSO500', 'Gene', (23, 29))	('F1CDx', 'Var', (13, 18))	('F1CDx', 'Chemical', '-', (13, 18))
491288	31387639	Previous studies have suggested that the inclusion of synonymous mutations could enhance the precision of panel-based TMB estimation.	('precision', 'MPA', (93, 102))	('synonymous mutations', 'Var', (54, 74))	('enhance', 'PosReg', (81, 88))	('TMB', 'Chemical', '-', (118, 121))
491406	29861866	As a result, we found that the disease-free survival rate was obviously, but not statistically, lower in patients with TRKBhigh OSCC compared with those with TRKBlow OSCC (P = 0.068) (Figure 2A).	('patients', 'Species', '9606', (105, 113))	('disease-free survival rate', 'CPA', (31, 57))	('lower', 'NegReg', (96, 101))	('OSCC', 'Chemical', '-', (128, 132))	('TRKBhigh OSCC', 'Var', (119, 132))	('OSCC', 'Chemical', '-', (166, 170))
491407	29861866	The survival rates were significantly lower in BDNFhigh, TRKBhigh/BDNFhigh, and MD/PD-OSCC compared to that in controls (P = 0.0015, 0.034, and 0.0036, respectively) (Figure 2B-2D).	('survival rates', 'CPA', (4, 18))	('lower', 'NegReg', (38, 43))	('MD/PD-OSCC', 'Disease', (80, 90))	('MD/PD-OSCC', 'Disease', 'MESH:D010300', (80, 90))	('BDNFhigh', 'Var', (47, 55))	('TRKBhigh/BDNFhigh', 'Var', (57, 74))
491408	29861866	These data show that TRKBhigh and/or BDNFhigh, as well as moderately/poorly differentiations, represent risk factors for OSCC recurrence and metastasis.	('metastasis', 'CPA', (141, 151))	('OSCC recurrence', 'Disease', (121, 136))	('BDNFhigh', 'Gene', (37, 45))	('TRKBhigh', 'Var', (21, 29))	('OSCC', 'Chemical', '-', (121, 125))
491456	29861866	BDNF induces phosphorylation of TRKB (Tyr 532), which requires TRKB activation, subsequent growth, and migration signal transduction.	('Tyr', 'Chemical', 'MESH:D014443', (38, 41))	('phosphorylation', 'MPA', (13, 28))	('TRKB', 'Protein', (32, 36))	('activation', 'PosReg', (68, 78))	('Tyr 532', 'Var', (38, 45))	('TRKB', 'Protein', (63, 67))
491465	29861866	In contrast, a significant dose-dependent reduction of growth was observed in HSC-3 cells in the presence of ANA-12.	('ANA-12', 'Chemical', '-', (109, 115))	('HSC-3', 'Gene', (78, 83))	('HSC-3', 'Gene', '150353', (78, 83))	('ANA-12', 'Var', (109, 115))	('reduction', 'NegReg', (42, 51))	('growth', 'MPA', (55, 61))
491467	29861866	The invasion of HSC-3 cells was upregulated by BDNF stimulation and the upregulation was dose-dependently suppressed by ANA-12 treatment, whereas that of HSC-4 cells was not affected by BDNF or ANA-12 treatment.	('ANA-12', 'Chemical', '-', (120, 126))	('HSC-3', 'Gene', (16, 21))	('men', 'Species', '9606', (132, 135))	('suppressed', 'NegReg', (106, 116))	('HSC-3', 'Gene', '150353', (16, 21))	('ANA-12', 'Chemical', '-', (194, 200))	('ANA-12', 'Var', (120, 126))	('men', 'Species', '9606', (206, 209))	('upregulated', 'PosReg', (32, 43))
491481	29861866	Our data support the idea that BDNF/TRKB signaling may regulate tumor progression in OSCC, especially PD-OSCC, and that high expression of these molecules may be an attractive prognostic marker for tumor aggressiveness, as well as a potential target for OSCC therapies.	('PD-OSCC', 'Disease', (102, 109))	('OSCC', 'Chemical', '-', (105, 109))	('aggressiveness', 'Phenotype', 'HP:0000718', (204, 218))	('tumor', 'Disease', (64, 69))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (198, 218))	('OSCC', 'Chemical', '-', (254, 258))	('high', 'Var', (120, 124))	('BDNF/TRKB', 'Protein', (31, 40))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('OSCC', 'Disease', (85, 89))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('regulate', 'Reg', (55, 63))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Disease', (198, 203))	('tumor aggressiveness', 'Disease', (198, 218))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('PD-OSCC', 'Chemical', '-', (102, 109))	('OSCC', 'Chemical', '-', (85, 89))
491489	29861866	Previously, in patients with neuroblastoma, a study showed that high expressions of TRKA or TRKC in the tumor had no influence on the quality of the prognosis, whereas poor prognosis was observed when high expressions of TRKB and/or BDNF occurred, which is consistent with our results.	('patients', 'Species', '9606', (15, 23))	('high', 'Var', (64, 68))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('neuroblastoma', 'Disease', (29, 42))	('tumor', 'Disease', (104, 109))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('neuroblastoma', 'Phenotype', 'HP:0003006', (29, 42))	('TRKA', 'Gene', (84, 88))	('TRKC', 'Gene', '4916', (92, 96))	('TRKC', 'Gene', (92, 96))	('neuroblastoma', 'Disease', 'MESH:D009447', (29, 42))
491495	29861866	From our study, the analysis of the relationship between 2-year disease-free survival and high expression of TRKB/BDNF showed significantly higher rates of tumor recurrence in patients with TRKBhigh and/or BDNFhigh OSCC than in those suffering from TRKBlow/BDNFlow OSCC (Figure 2).	('higher rates', 'PosReg', (140, 152))	('patients', 'Species', '9606', (176, 184))	('OSCC', 'Chemical', '-', (215, 219))	('TRKB/BDNF', 'Gene', (109, 118))	('TRKBhigh', 'Var', (190, 198))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('OSCC', 'Chemical', '-', (265, 269))	('tumor', 'Disease', (156, 161))	('BDNFhigh', 'Var', (206, 214))
491508	29861866	Given that TRKB is highly expressed in MD/PD-OSCC, TRKB selective blockage could efficiently suppress the growth of MD/PD-OSCC tumor, allowing for a better prognosis in patients with OSCC.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('OSCC', 'Chemical', '-', (122, 126))	('TRKB', 'Gene', (51, 55))	('suppress', 'NegReg', (93, 101))	('OSCC', 'Chemical', '-', (45, 49))	('patients', 'Species', '9606', (169, 177))	('MD/PD-OSCC', 'Disease', (39, 49))	('MD/PD-OSCC tumor', 'Disease', (116, 132))	('OSCC', 'Chemical', '-', (183, 187))	('MD/PD-OSCC tumor', 'Disease', 'MESH:D010300', (116, 132))	('growth', 'MPA', (106, 112))	('MD/PD-OSCC', 'Disease', (116, 126))	('MD/PD-OSCC', 'Disease', 'MESH:D010300', (39, 49))	('selective', 'Var', (56, 65))	('MD/PD-OSCC', 'Disease', 'MESH:D010300', (116, 126))	('OSCC', 'Disease', (183, 187))
491555	29861866	The invasion assay was designed using Matrigel (#356230, Corning Costar, Cambridge, MA, USA)-coated Transwell plates (#3422, Corning Costar) which were 6.5 mm in diameter with 8 mum pore filters.	('Corning Costar', 'Disease', (57, 71))	('#3422', 'Var', (118, 123))	('Corning Costar', 'Disease', 'MESH:D002145', (125, 139))	('mum', 'Gene', '56925', (178, 181))	('Corning Costar', 'Disease', 'MESH:D002145', (57, 71))	('mum', 'Gene', (178, 181))	('Corning Costar', 'Disease', (125, 139))	('#356230', 'Var', (48, 55))
491561	26091466	In addition, the identification of epidermal growth factor receptor (EGFR) mutations and the introduction of EGFR inhibitors to successfully treat EGFR mutated non-small cell lung cancers are breakthroughs for lung cancer treatment.	('lung cancer', 'Disease', 'MESH:D008175', (210, 221))	('EGFR', 'Gene', (147, 151))	('men', 'Species', '9606', (227, 230))	('small cell lung cancers', 'Phenotype', 'HP:0030357', (164, 187))	('EGFR', 'Gene', '1956', (109, 113))	('lung cancer', 'Phenotype', 'HP:0100526', (210, 221))	('EGFR', 'Gene', '1956', (69, 73))	('non-small cell lung cancers', 'Disease', 'MESH:D002289', (160, 187))	('lung cancer', 'Disease', 'MESH:D008175', (175, 186))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('EGFR', 'Gene', '1956', (147, 151))	('epidermal growth factor receptor', 'Gene', (35, 67))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('lung cancer', 'Phenotype', 'HP:0100526', (175, 186))	('lung cancer', 'Disease', (210, 221))	('lung cancers', 'Phenotype', 'HP:0100526', (175, 187))	('epidermal growth factor receptor', 'Gene', '1956', (35, 67))	('EGFR', 'Gene', (109, 113))	('cancers', 'Phenotype', 'HP:0002664', (180, 187))	('mutated', 'Var', (152, 159))	('EGFR', 'Gene', (69, 73))	('non-small cell lung cancers', 'Disease', (160, 187))	('mutations', 'Var', (75, 84))	('non-small cell lung cancers', 'Phenotype', 'HP:0030358', (160, 187))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (164, 186))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (160, 186))
491585	26091466	However, the prognosis of lung cancer became different after the introduction of EGFR inhibitors.	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('lung cancer', 'Disease', 'MESH:D008175', (26, 37))	('inhibitors', 'Var', (86, 96))	('lung cancer', 'Disease', (26, 37))	('EGFR', 'Gene', '1956', (81, 85))	('lung cancer', 'Phenotype', 'HP:0100526', (26, 37))	('EGFR', 'Gene', (81, 85))
491586	26091466	Lung cancers with EGFR mutations are more likely to be adenocarcinoma and occur more often in women, East Asians, and nonsmokers.	('women', 'Species', '9606', (94, 99))	('EGFR', 'Gene', '1956', (18, 22))	('cancers', 'Phenotype', 'HP:0002664', (5, 12))	('Lung cancers', 'Disease', 'MESH:D008175', (0, 12))	('Lung cancer', 'Phenotype', 'HP:0100526', (0, 11))	('EGFR', 'Gene', (18, 22))	('mutations', 'Var', (23, 32))	('Lung cancers', 'Phenotype', 'HP:0100526', (0, 12))	('carcinoma', 'Phenotype', 'HP:0030731', (60, 69))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))	('adenocarcinoma', 'Disease', (55, 69))	('Lung cancers', 'Disease', (0, 12))	('adenocarcinoma', 'Disease', 'MESH:D000230', (55, 69))
491587	26091466	Lung cancers with EGFR mutations have been associated with a more favorable clinical response to EGFR inhibitors.	('EGFR', 'Gene', '1956', (18, 22))	('cancers', 'Phenotype', 'HP:0002664', (5, 12))	('EGFR', 'Gene', '1956', (97, 101))	('Lung cancers', 'Disease', 'MESH:D008175', (0, 12))	('Lung cancer', 'Phenotype', 'HP:0100526', (0, 11))	('EGFR', 'Gene', (18, 22))	('EGFR', 'Gene', (97, 101))	('mutations', 'Var', (23, 32))	('Lung cancers', 'Phenotype', 'HP:0100526', (0, 12))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))	('Lung cancers', 'Disease', (0, 12))
491589	26091466	Furthermore, first-line EGFR inhibitors achieved good response and prolonged the survival of advanced lung cancer patients with EGFR mutations.	('EGFR', 'Gene', '1956', (24, 28))	('survival', 'CPA', (81, 89))	('lung cancer', 'Phenotype', 'HP:0100526', (102, 113))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('EGFR', 'Gene', (24, 28))	('EGFR', 'Gene', '1956', (128, 132))	('EGFR', 'Gene', (128, 132))	('lung cancer', 'Disease', (102, 113))	('mutations', 'Var', (133, 142))	('lung cancer', 'Disease', 'MESH:D008175', (102, 113))	('patients', 'Species', '9606', (114, 122))	('prolonged', 'PosReg', (67, 76))
491592	26091466	The survival of lung cancer patients has been significantly improved by EGFR inhibitors, particularly for Asian patients with lung cancer harboring specific EGFR mutations; however, most data published to date have been hospital-based or clinical trial-based and mostly on NSCLC.	('EGFR', 'Gene', '1956', (72, 76))	('EGFR', 'Gene', '1956', (157, 161))	('lung cancer', 'Disease', 'MESH:D008175', (16, 27))	('lung cancer', 'Disease', (126, 137))	('lung cancer', 'Phenotype', 'HP:0100526', (16, 27))	('patients', 'Species', '9606', (28, 36))	('NSCLC', 'Disease', 'MESH:D002289', (273, 278))	('survival', 'CPA', (4, 12))	('EGFR', 'Gene', (72, 76))	('NSCLC', 'Disease', (273, 278))	('improved', 'PosReg', (60, 68))	('lung cancer', 'Disease', 'MESH:D008175', (126, 137))	('EGFR', 'Gene', (157, 161))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('mutations', 'Var', (162, 171))	('NSCLC', 'Phenotype', 'HP:0030358', (273, 278))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('patients', 'Species', '9606', (112, 120))	('lung cancer', 'Phenotype', 'HP:0100526', (126, 137))	('lung cancer', 'Disease', (16, 27))
491602	26091466	For NET, we adopted the M codes used by Hauso et al  and included: 8240 (carcinoid tumor), 8241 (enterochromaffin cell carcinoid), 8242 (enterochromaffin-like cell tumors), 8243 (goblet cell carcinoid), 8244 (composite carcinoid), 8245 (adenocarcinoid), 8246 (neuroendocrine carcinoma), 8249 (atypical carcinoid), 8013 (large cell neuroendocrine carcinoma), and 8574 (adenocarcinoma with neuroendocrine differentiation).	('8013', 'Var', (314, 318))	('neuroendocrine carcinoma', 'Disease', 'MESH:D018278', (331, 355))	('carcinoid', 'Phenotype', 'HP:0100570', (219, 228))	('NET', 'Gene', (4, 7))	('neuroendocrine carcinoma', 'Phenotype', 'HP:0100634', (331, 355))	('carcinoid', 'Phenotype', 'HP:0100570', (242, 251))	('8249', 'Var', (287, 291))	('carcinoid', 'Phenotype', 'HP:0100570', (73, 82))	('tumors', 'Phenotype', 'HP:0002664', (164, 170))	('enterochromaffin cell carcinoid', 'Phenotype', 'HP:0002666', (97, 128))	('neuroendocrine carcinoma', 'Disease', (260, 284))	('carcinoma', 'Phenotype', 'HP:0030731', (373, 382))	('adenocarcinoid', 'Disease', 'MESH:C538230', (237, 251))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('carcinoid tumor', 'Disease', 'MESH:D002276', (73, 88))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('neuroendocrine carcinoma', 'Disease', (331, 355))	('enterochromaffin-like cell tumors', 'Phenotype', 'HP:0002666', (137, 170))	('large cell neuroendocrine carcinoma', 'Phenotype', 'HP:0030360', (320, 355))	('cell tumors', 'Disease', (159, 170))	('carcinoma', 'Phenotype', 'HP:0030731', (346, 355))	('NET', 'Gene', '2004', (4, 7))	('adenocarcinoid', 'Disease', (237, 251))	('carcinoid', 'Phenotype', 'HP:0100570', (191, 200))	('cell tumors', 'Disease', 'MESH:D005935', (159, 170))	('adenocarcinoma', 'Disease', (368, 382))	('carcinoid tumor', 'Disease', (73, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (275, 284))	('carcinoid', 'Phenotype', 'HP:0100570', (119, 128))	('neuroendocrine carcinoma', 'Disease', 'MESH:D018278', (260, 284))	('8574', 'Var', (362, 366))	('atypical carcinoid', 'Phenotype', 'HP:0030446', (293, 311))	('neuroendocrine carcinoma', 'Phenotype', 'HP:0100634', (260, 284))	('adenocarcinoma', 'Disease', 'MESH:D000230', (368, 382))
491732	26091466	This observation was later correlated with EGFR mutations.	('EGFR', 'Gene', (43, 47))	('EGFR', 'Gene', '1956', (43, 47))	('correlated', 'Reg', (27, 37))	('mutations', 'Var', (48, 57))
491733	26091466	In a large multinational series of NSCLC, the prevalence of EGFR mutation was 27% and 34% in Taiwanese and Japanese NSCLC patients, respectively, and only 14% and 7% in US and Australian NSCLC patients, respectively.	('NSCLC', 'Disease', 'MESH:D002289', (116, 121))	('patients', 'Species', '9606', (193, 201))	('NSCLC', 'Phenotype', 'HP:0030358', (187, 192))	('NSCLC', 'Disease', (35, 40))	('NSCLC', 'Phenotype', 'HP:0030358', (116, 121))	('NSCLC', 'Disease', (187, 192))	('patients', 'Species', '9606', (122, 130))	('EGFR', 'Gene', '1956', (60, 64))	('mutation', 'Var', (65, 73))	('NSCLC', 'Disease', 'MESH:D002289', (35, 40))	('NSCLC', 'Disease', 'MESH:D002289', (187, 192))	('NSCLC', 'Phenotype', 'HP:0030358', (35, 40))	('NSCLC', 'Disease', (116, 121))	('EGFR', 'Gene', (60, 64))
491734	26091466	A percentage of EGFR mutations as high as 61% was noted in Taiwanese samples from clinical trials.	('EGFR', 'Gene', '1956', (16, 20))	('EGFR', 'Gene', (16, 20))	('mutations', 'Var', (21, 30))
491735	26091466	EGFR inhibitors not only increased the response rate of lung cancers with EGFR mutations but also prolonged the progression-free survival and overall survival.	('prolonged', 'PosReg', (98, 107))	('lung cancers', 'Phenotype', 'HP:0100526', (56, 68))	('EGFR', 'Gene', (0, 4))	('increased', 'PosReg', (25, 34))	('lung cancers', 'Disease', (56, 68))	('response', 'CPA', (39, 47))	('overall survival', 'CPA', (142, 158))	('cancers', 'Phenotype', 'HP:0002664', (61, 68))	('EGFR', 'Gene', '1956', (74, 78))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('EGFR', 'Gene', '1956', (0, 4))	('lung cancers', 'Disease', 'MESH:D008175', (56, 68))	('progression-free survival', 'CPA', (112, 137))	('EGFR', 'Gene', (74, 78))	('lung cancer', 'Phenotype', 'HP:0100526', (56, 67))	('mutations', 'Var', (79, 88))
491737	26091466	Since November of 2007, the BNHI began to reimburse Gefitinib as a second-line treatment for adenocarcinoma and in June of 2011, the BNHI started to reimburse Gefitinib as a first-line treatment for lung adenocarcinoma with EGFR mutations.	('adenocarcinoma', 'Disease', 'MESH:D000230', (204, 218))	('adenocarcinoma', 'Disease', 'MESH:D000230', (93, 107))	('EGFR', 'Gene', (224, 228))	('mutations', 'Var', (229, 238))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (199, 218))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('men', 'Species', '9606', (84, 87))	('men', 'Species', '9606', (190, 193))	('adenocarcinoma', 'Disease', (204, 218))	('adenocarcinoma', 'Disease', (93, 107))	('Gefitinib', 'Chemical', 'MESH:D000077156', (52, 61))	('Gefitinib', 'Chemical', 'MESH:D000077156', (159, 168))	('lung adenocarcinoma', 'Disease', (199, 218))	('carcinoma', 'Phenotype', 'HP:0030731', (209, 218))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (199, 218))	('EGFR', 'Gene', '1956', (224, 228))
491739	26091466	The use of EGFR inhibitors for lung adenocarcinoma since 2004 may explain the improvement in the survival of adenocarcinoma patients from 2000-2004 to 2005-2008, particularly for women, with improvement of the 1-, 3- and 5-year survival from 46.24%, 20.86%, and 15.26% in 1996-1999 to 64.53%, 31.81% and 19.86% in 2005-2008, respectively.	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (31, 50))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (31, 50))	('improvement', 'PosReg', (78, 89))	('patients', 'Species', '9606', (124, 132))	('carcinoma', 'Phenotype', 'HP:0030731', (41, 50))	('inhibitors', 'Var', (16, 26))	('adenocarcinoma', 'Disease', (109, 123))	('EGFR', 'Gene', (11, 15))	('adenocarcinoma', 'Disease', (36, 50))	('adenocarcinoma', 'Disease', 'MESH:D000230', (109, 123))	('women', 'Species', '9606', (179, 184))	('men', 'Species', '9606', (85, 88))	('men', 'Species', '9606', (198, 201))	('men', 'Species', '9606', (181, 184))	('lung adenocarcinoma', 'Disease', (31, 50))	('EGFR', 'Gene', '1956', (11, 15))	('adenocarcinoma', 'Disease', 'MESH:D000230', (36, 50))	('improvement', 'PosReg', (191, 202))
491740	26091466	In a large molecular epidemiologic study of lung adenocarcinoma in Asian patients, including patients from Taiwan, women were found to have a significantly higher percentage of EGFR mutations than men (61.1% vs 44%).	('patients', 'Species', '9606', (93, 101))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (44, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (54, 63))	('men', 'Species', '9606', (117, 120))	('lung adenocarcinoma', 'Disease', (44, 63))	('men', 'Species', '9606', (197, 200))	('EGFR', 'Gene', '1956', (177, 181))	('mutations', 'Var', (182, 191))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (44, 63))	('patients', 'Species', '9606', (73, 81))	('EGFR', 'Gene', (177, 181))	('women', 'Species', '9606', (115, 120))
491741	26091466	The higher percentage of EGFR mutations among female patients with lung adenocarcinoma compared to men with lung adenocarcinoma may explain the better survival of lung adenocarcinoma in Taiwanese women, particularly after the introduction of EGFR inhibitors.	('lung adenocarcinoma', 'Disease', (108, 127))	('lung adenocarcinoma', 'Disease', (163, 182))	('lung adenocarcinoma', 'Disease', (67, 86))	('EGFR', 'Gene', (242, 246))	('EGFR', 'Gene', (25, 29))	('patients', 'Species', '9606', (53, 61))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (163, 182))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (108, 127))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (67, 86))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (108, 127))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (163, 182))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (67, 86))	('carcinoma', 'Phenotype', 'HP:0030731', (173, 182))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('EGFR', 'Gene', '1956', (242, 246))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('mutations', 'Var', (30, 39))	('women', 'Species', '9606', (196, 201))	('men', 'Species', '9606', (198, 201))	('EGFR', 'Gene', '1956', (25, 29))	('men', 'Species', '9606', (99, 102))
491757	31711545	The role of cigarette smoke-induced epigenetic alterations in inflammation Exposure to cigarette smoke (CS) is a major threat to human health worldwide.	('human', 'Species', '9606', (129, 134))	('inflammation', 'Disease', (62, 74))	('inflammation', 'Disease', 'MESH:D007249', (62, 74))	('epigenetic alterations', 'Var', (36, 58))
491763	31711545	The recognition of the molecular mechanisms of the epigenetic changes in abnormal inflammation is expected to contribute to the understanding of the pathophysiology of CS-related diseases such that novel epigenetic therapies may be identified in the near future.	('abnormal inflammation', 'Disease', 'MESH:D007249', (73, 94))	('epigenetic changes', 'Var', (51, 69))	('abnormal inflammation', 'Disease', (73, 94))	('contribute', 'Reg', (110, 120))	('CS-related', 'Disease', (168, 178))
491770	31711545	DNA hypermethylation always leads to transcriptional suppression and decreased gene expression, while DNA hypomethylation influences chromosome stability or enhanced aneuploidy.	('influences', 'Reg', (122, 132))	('enhanced', 'PosReg', (157, 165))	('methyl', 'Chemical', 'MESH:C031105', (9, 15))	('methyl', 'Chemical', 'MESH:C031105', (110, 116))	('decreased', 'NegReg', (69, 78))	('suppression', 'NegReg', (53, 64))	('aneuploidy', 'Disease', (166, 176))	('transcriptional', 'MPA', (37, 52))	('gene expression', 'MPA', (79, 94))	('chromosome stability', 'CPA', (133, 153))	('aneuploidy', 'Disease', 'MESH:D000782', (166, 176))	('hypermethylation', 'Var', (4, 20))
491776	31711545	Small RNAs include but are not limited to microRNAs (miRNAs), PIWI-interacting RNAs, small interfering RNAs, small nucleolar RNAs, and transfer RNAs.	('miR', 'Gene', '220972', (53, 56))	('PIWI', 'Gene', '9271', (62, 66))	('miR', 'Gene', (53, 56))	('PIWI', 'Gene', (62, 66))	('small', 'Var', (85, 90))
491778	31711545	It is very important to note that the changes caused by epigenetic modifications of DNA and/or histones and changes in ncRNA expression represent dynamitic information that is markedly influenced by environmental stimuli, such as CS, air pollution and dietary changes.	('ncRNA', 'Gene', (119, 124))	('histones', 'Protein', (95, 103))	('DNA', 'Protein', (84, 87))	('changes', 'Reg', (108, 115))	('ncRNA', 'Gene', '220202', (119, 124))	('epigenetic modifications', 'Var', (56, 80))
491781	31711545	Alterations in DNA methylation have recently been suggested to be one possible mechanism potentially mediating CS-induced diseases.	('DNA methylation', 'Protein', (15, 30))	('Alterations', 'Var', (0, 11))	('methyl', 'Chemical', 'MESH:C031105', (19, 25))	('CS-induced diseases', 'Disease', (111, 130))	('rat', 'Species', '10116', (4, 7))
491782	31711545	Several epigenome-wide association studies based on different sample sizes, races and areas have confirmed that the altered DNA methylation at multiple CpG sites is induced by CS (Table 1) and can lead to changes in gene transcription and increased susceptibility to diseases.	('methyl', 'Chemical', 'MESH:C031105', (128, 134))	('gene transcription', 'MPA', (216, 234))	('induced', 'Reg', (165, 172))	('methylation', 'Var', (128, 139))	('lead to changes', 'Reg', (197, 212))
491791	31711545	Five-hundred and fifty-seven differentially methylated regions were overrepresented in important regulatory regions, including those of enhancers.	('differentially methylated', 'Var', (29, 54))	('overrepresented', 'PosReg', (68, 83))	('methylate', 'Chemical', 'MESH:C098207', (44, 53))
491794	31711545	Furthermore, the inhibition of DNMT1 can restore the expression of genes that had been suppressed by a CS condensate through demethylation.	('DNMT1', 'Gene', '1786', (31, 36))	('restore', 'PosReg', (41, 48))	('inhibition', 'Var', (17, 27))	('expression of genes', 'MPA', (53, 72))	('DNMT1', 'Gene', (31, 36))	('methyl', 'Chemical', 'MESH:C031105', (127, 133))
491804	31711545	In contrast to that of other HDACs, cytoplasmic HDAC6 expression is elevated in the lung tissues of chronic smokers with COPD, partly due to hypomethylation by HDAC6.	('expression', 'MPA', (54, 64))	('HDAC', 'Gene', (48, 52))	('HDAC', 'Gene', '9734', (48, 52))	('methyl', 'Chemical', 'MESH:C031105', (145, 151))	('HDAC', 'Gene', (160, 164))	('HDAC', 'Gene', '9734', (160, 164))	('hypomethylation', 'Var', (141, 156))	('HDAC', 'Gene', (29, 33))	('COPD', 'Phenotype', 'HP:0006510', (121, 125))	('elevated', 'PosReg', (68, 76))	('HDAC', 'Gene', '9734', (29, 33))	('COPD', 'Disease', 'MESH:D029424', (121, 125))	('COPD', 'Disease', (121, 125))	('cytoplasmic', 'MPA', (36, 47))
491816	31711545	Both mono-and di-methylation of histone H3 residues (H3K27me2/3, H3K36me1/2, H3K56me2, and H3K79me1/2) and histone H4 residues (H4K20me1/2, H4R23me1, H4K31me2, H4R35me1/2, H4R36me1, H4R55me1 and H4K77me1) were increased in CS-exposed mouse lungs.	('H4R23me1', 'Var', (140, 148))	('H3K27me2/3', 'Var', (53, 63))	('H4', 'Chemical', 'MESH:D006859', (195, 197))	('H4', 'Chemical', 'MESH:D006859', (140, 142))	('H4K31me2', 'Var', (150, 158))	('H4', 'Chemical', 'MESH:D006859', (172, 174))	('H3', 'Chemical', 'MESH:C405983', (77, 79))	('H3', 'Chemical', 'MESH:C405983', (53, 55))	('mono-and', 'MPA', (5, 13))	('H4R35me1/2', 'Var', (160, 170))	('H4R36me1', 'Var', (172, 180))	('H3', 'Chemical', 'MESH:C405983', (91, 93))	('H4', 'Chemical', 'MESH:D006859', (115, 117))	('H3K56me2', 'Chemical', 'MESH:C024755', (77, 85))	('H4K20me1/2', 'Var', (128, 138))	('mouse', 'Species', '10090', (234, 239))	('increased', 'PosReg', (210, 219))	('H4', 'Chemical', 'MESH:D006859', (128, 130))	('methyl', 'Chemical', 'MESH:C031105', (17, 23))	('di-methylation', 'MPA', (14, 28))	('H4R23me1, H4K31me2', 'Chemical', 'MESH:C033990', (140, 158))	('H4', 'Chemical', 'MESH:D006859', (160, 162))	('H3K36me1/2', 'Var', (65, 75))	('H3', 'Chemical', 'MESH:C405983', (65, 67))	('H4R55me1', 'Chemical', 'MESH:C114505', (182, 190))	('H4', 'Chemical', 'MESH:D006859', (150, 152))	('H4', 'Chemical', 'MESH:D006859', (182, 184))	('H4K77me1', 'Var', (195, 203))	('H3K56me2', 'Var', (77, 85))	('H3K79me1/2', 'Var', (91, 101))	('H4R55me1', 'Var', (182, 190))	('H3', 'Chemical', 'MESH:C405983', (40, 42))
491818	31711545	PRMT6 is a nuclear enzyme that specially catalyzes di-methylation of R2 in histone H3 (H3R2me2a).	('PRMT6', 'Gene', (0, 5))	('H3', 'Chemical', 'MESH:C405983', (83, 85))	('H3', 'Chemical', 'MESH:C405983', (87, 89))	('di-methylation', 'Var', (51, 65))	('methyl', 'Chemical', 'MESH:C031105', (54, 60))	('H3R2me2a', 'Chemical', 'MESH:C405983', (87, 95))
491821	31711545	It was shown that CSE can enhance the expression of EZH2 and increase the level of H3K27me3, which epigenetically controlled gene transcription.	('H3', 'Chemical', 'MESH:C405983', (83, 85))	('expression', 'MPA', (38, 48))	('EZH2', 'Gene', (52, 56))	('EZH2', 'Gene', '2146', (52, 56))	('increase', 'PosReg', (61, 69))	('level of H3K27me3', 'MPA', (74, 91))	('CSE', 'Var', (18, 21))	('enhance', 'PosReg', (26, 33))
491838	31711545	Moreover, mice deficient in either MAFbx or MuRF1 were protected from muscle atrophy, whereas overexpressed MAFbx in myotubes induced atrophy.	('atrophy', 'Disease', 'MESH:D001284', (77, 84))	('mice', 'Species', '10090', (10, 14))	('MuRF1', 'Gene', (44, 49))	('atrophy', 'Disease', 'MESH:D001284', (134, 141))	('overexpressed', 'Var', (94, 107))	('atrophy', 'Disease', (77, 84))	('muscle atrophy', 'Disease', (70, 84))	('muscle atrophy', 'Phenotype', 'HP:0003202', (70, 84))	('atrophy', 'Disease', (134, 141))	('MAFbx', 'Gene', (35, 40))	('muscle atrophy', 'Disease', 'MESH:D009133', (70, 84))
491844	31711545	CS can noticeably elevate MUL1 expression and Akt ubiquitination, while knocking down MUL1 suppressed CS-induced Akt ubiquitination/degradation and inhibited the reduction in cytoplasmic Akt and p-Akt.	('Akt', 'Gene', (46, 49))	('Akt', 'Gene', (197, 200))	('MUL1', 'Gene', (86, 90))	('Akt', 'Gene', '207', (46, 49))	('Akt', 'Gene', '207', (197, 200))	('Akt', 'Gene', (187, 190))	('knocking down', 'Var', (72, 85))	('MUL1', 'Gene', '79594', (86, 90))	('Akt', 'Gene', '207', (187, 190))	('cytoplasmic', 'MPA', (175, 186))	('expression', 'MPA', (31, 41))	('Akt', 'Gene', (113, 116))	('suppressed', 'NegReg', (91, 101))	('Akt', 'Gene', '207', (113, 116))	('ubiquitination/degradation', 'MPA', (117, 143))	('MUL1', 'Gene', (26, 30))	('elevate', 'PosReg', (18, 25))	('inhibited', 'NegReg', (148, 157))	('MUL1', 'Gene', '79594', (26, 30))
491889	31711545	The abnormal expression of lncRNAs has been reported to affect the progression of many human diseases, including that of CS-related disorders.	('affect', 'Reg', (56, 62))	('progression', 'CPA', (67, 78))	('CS-related disorders', 'Disease', (121, 141))	('human', 'Species', '9606', (87, 92))	('abnormal expression', 'Var', (4, 23))	('ncRNA', 'Gene', (28, 33))	('ncRNA', 'Gene', '220202', (28, 33))
491896	31711545	Further statistical analysis indicated that dysregulation of lncRNA AURKA, BIRC5, and LINC00094 indicated poor prognosis for patient with lung squamous cell carcinoma.	('ncRNA', 'Gene', '220202', (62, 67))	('AURKA', 'Gene', (68, 73))	('dysregulation', 'Var', (44, 57))	('BIRC5', 'Gene', '332', (75, 80))	('BIRC5', 'Gene', (75, 80))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (138, 166))	('LINC00094', 'Gene', (86, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (157, 166))	('ncRNA', 'Gene', (62, 67))	('patient', 'Species', '9606', (125, 132))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (143, 166))	('lung squamous cell carcinoma', 'Disease', (138, 166))	('AURKA', 'Gene', '6790', (68, 73))	('LINC00094', 'Gene', '266655', (86, 95))
491902	31711545	Similarly, activated CCAT1 promotes an altered cell cycle transition during the malignant transformation of the HBE cells via epigenetic silencing of miR-218, suggesting a mechanism for lung cancer development.	('epigenetic silencing', 'Var', (126, 146))	('CCAT1', 'Gene', (21, 26))	('HBE', 'CellLine', 'CVCL:3285', (112, 115))	('lung cancer', 'Disease', 'MESH:D008175', (186, 197))	('lung cancer', 'Phenotype', 'HP:0100526', (186, 197))	('malignant transformation', 'CPA', (80, 104))	('promotes', 'Reg', (27, 35))	('miR-21', 'Gene', '406991', (150, 156))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('lung cancer', 'Disease', (186, 197))	('altered', 'Reg', (39, 46))	('CCAT1', 'Gene', '100507056', (21, 26))	('miR-21', 'Gene', (150, 156))	('cell cycle transition', 'CPA', (47, 68))
491908	31711545	In recent years, evidence has suggested that epigenetic modification mechanisms can possibly explain the link between CS exposure and inflammation.	('epigenetic modification', 'Var', (45, 68))	('inflammation', 'Disease', (134, 146))	('inflammation', 'Disease', 'MESH:D007249', (134, 146))
491911	31711545	Increased DNA methylation with the highest signal, at cg10636246 near Absent in melanoma 2 (AIM2) and involved in inflammasome response, was associated with lower expression of AIM2 and lower CRP levels.	('cg10636246', 'Var', (54, 64))	('Absent in melanoma 2', 'Gene', '9447', (70, 90))	('AIM2', 'Gene', '9447', (177, 181))	('AIM2', 'Gene', '9447', (92, 96))	('methyl', 'Chemical', 'MESH:C031105', (14, 20))	('Absent in melanoma 2', 'Gene', (70, 90))	('melanoma', 'Phenotype', 'HP:0002861', (80, 88))	('AIM2', 'Gene', (177, 181))	('AIM2', 'Gene', (92, 96))	('CRP', 'Gene', (192, 195))	('DNA methylation', 'MPA', (10, 25))	('lower', 'NegReg', (186, 191))	('expression', 'MPA', (163, 173))	('CRP', 'Gene', '1401', (192, 195))	('lower', 'NegReg', (157, 162))
491912	31711545	Hypomethylation at cg18181703 (suppressor of cytokine signaling 3, SOCS3), cg06126421 (tubulin beta, TUBB), and cg05575921 (aryl hydrocarbon receptor repressor, AHRR) was associated with higher CRP levels and increased risk of future CHD.	('CHD', 'Disease', 'None', (234, 237))	('CRP', 'Gene', '1401', (194, 197))	('suppressor of cytokine signaling 3', 'Gene', (31, 65))	('AHRR', 'Gene', '57491', (161, 165))	('TUBB', 'Gene', (101, 105))	('higher', 'PosReg', (187, 193))	('methyl', 'Chemical', 'MESH:C031105', (4, 10))	('AHRR', 'Gene', (161, 165))	('CRP', 'Gene', (194, 197))	('CHD', 'Disease', (234, 237))	('aryl hydrocarbon receptor repressor', 'Gene', '57491', (124, 159))	('cg18181703', 'Var', (19, 29))	('aryl hydrocarbon receptor repressor', 'Gene', (124, 159))	('SOCS3', 'Gene', (67, 72))	('TUBB', 'Gene', '203068', (101, 105))	('cg06126421', 'Var', (75, 85))	('suppressor of cytokine signaling 3', 'Gene', '9021', (31, 65))	('cg05575921', 'Var', (112, 122))	('SOCS3', 'Gene', '9021', (67, 72))
491914	31711545	in African Americans suggested that CS may increase serum IL-18 levels through a decrease in the DNA methylation levels of cg03636183 in the coagulation factor II (thrombin) receptor-like 3 gene.	('decrease', 'NegReg', (81, 89))	('DNA methylation levels', 'MPA', (97, 119))	('methyl', 'Chemical', 'MESH:C031105', (101, 107))	('coagulation factor II (thrombin) receptor-like 3', 'Gene', '9002', (141, 189))	('increase', 'PosReg', (43, 51))	('IL-18', 'Gene', '3606', (58, 63))	('cg03636183', 'Var', (123, 133))	('IL-18', 'Gene', (58, 63))
491927	31711545	found that TET2 might be a positive regulator of LPS-induced inflammatory response in human dental pulp cells by epigenetically regulating the transcription of the signal transduction molecule MyD88 in the NF-kappaB signaling pathway.	('transcription', 'MPA', (143, 156))	('LPS', 'Gene', '21898', (49, 52))	('epigenetically', 'Var', (113, 127))	('LPS', 'Gene', (49, 52))	('human', 'Species', '9606', (86, 91))	('MyD88', 'Gene', (193, 198))	('dental pulp', 'Phenotype', 'HP:0003771', (92, 103))	('regulating', 'Reg', (128, 138))	('MyD88', 'Gene', '4615', (193, 198))
491929	31711545	These findings indicate that DNA methylation regulates gene expression and may manipulate inflammatory genes to increase or decrease inflammation (Table 2).	('methylation', 'Var', (33, 44))	('inflammation', 'Disease', 'MESH:D007249', (133, 145))	('inflammatory genes', 'Gene', (90, 108))	('methyl', 'Chemical', 'MESH:C031105', (33, 39))	('manipulate', 'Reg', (79, 89))	('increase', 'PosReg', (112, 120))	('inflammation', 'Disease', (133, 145))	('gene expression', 'MPA', (55, 70))	('regulates', 'Reg', (45, 54))	('decrease', 'NegReg', (124, 132))
491933	31711545	These results indicate that inflammatory bowel disease-associated patterns of DNA methylation are a result of the inflammatory features of the disease and are less likely to contribute to the development or progression of the disease.	('DNA', 'Gene', (78, 81))	('inflammatory bowel disease', 'Phenotype', 'HP:0002037', (28, 54))	('inflammatory bowel disease', 'Disease', 'MESH:D015212', (28, 54))	('contribute', 'Reg', (174, 184))	('inflammatory bowel disease', 'Disease', (28, 54))	('patterns', 'Var', (66, 74))	('methyl', 'Chemical', 'MESH:C031105', (82, 88))
491935	31711545	They used genetic association analyses to investigate the potential relationships between BMI (a key measure of adiposity) and DNA methylation in blood and found that the alterations in DNA methylation are predominantly the consequence of adiposity, rather than the cause of it.	('methyl', 'Chemical', 'MESH:C031105', (131, 137))	('methyl', 'Chemical', 'MESH:C031105', (190, 196))	('rat', 'Species', '10116', (250, 253))	('methylation', 'MPA', (190, 201))	('rat', 'Species', '10116', (175, 178))	('DNA', 'Gene', (186, 189))	('alterations', 'Var', (171, 182))
491937	31711545	Future research into the identification of heritable epigenetic changes may assist in improving the current understanding of CS-related inflammatory diseases based on the expression of inflammatory markers and the interpretation of their methylation profiles.	('epigenetic changes', 'Var', (53, 71))	('CS-related', 'Disease', (125, 135))	('methyl', 'Chemical', 'MESH:C031105', (238, 244))	('inflammatory disease', 'Disease', (136, 156))	('inflammatory disease', 'Disease', 'MESH:D007249', (136, 156))
491944	31711545	The acetylation of the NF-kappaB p65 subunit at lysine 310 or lysine 221 increases the transcriptional activity or DNA-binding affinity of NF-kappaB, whereas acetylation at lysine 122 and lysine 123 facilitates the relocation of NF-kappaB from the nucleus.	('lysine 310', 'Var', (48, 58))	('acetyl', 'Chemical', 'MESH:C011632', (4, 10))	('DNA-binding affinity', 'Interaction', (115, 135))	('increases', 'PosReg', (73, 82))	('p65', 'Gene', (33, 36))	('lysine', 'Chemical', 'MESH:C114808', (173, 179))	('lysine 123', 'Var', (188, 198))	('facilitates', 'PosReg', (199, 210))	('relocation', 'MPA', (215, 225))	('lysine', 'Chemical', 'MESH:C114808', (188, 194))	('transcriptional activity', 'MPA', (87, 111))	('p65', 'Gene', '5970', (33, 36))	('lysine', 'Chemical', 'MESH:C114808', (62, 68))	('acetyl', 'Chemical', 'MESH:C011632', (158, 164))	('lysine', 'Chemical', 'MESH:C114808', (48, 54))	('acetylation', 'MPA', (4, 15))	('lysine 221', 'Var', (62, 72))
491949	31711545	CS increased the expression of pro-inflammatory mediators IL-8, TNF-alpha and matrix metalloproteinase 9 through HDAC1 depression in rat lungs and in macrophages, while knocking down HDAC1 increases the expression of these genes.	('increased', 'PosReg', (3, 12))	('TNF-alpha', 'Gene', (64, 73))	('increases', 'PosReg', (189, 198))	('depression', 'Disease', (119, 129))	('HDAC1', 'Gene', (113, 118))	('HDAC1', 'Gene', '297893', (183, 188))	('matrix metalloproteinase 9', 'Gene', (78, 104))	('expression', 'MPA', (203, 213))	('expression', 'MPA', (17, 27))	('matrix metalloproteinase 9', 'Gene', '81687', (78, 104))	('rat', 'Species', '10116', (133, 136))	('knocking down', 'Var', (169, 182))	('depression', 'Disease', 'MESH:D003866', (119, 129))	('IL-8', 'Gene', '3576', (58, 62))	('HDAC1', 'Gene', '297893', (113, 118))	('IL-8', 'Gene', (58, 62))	('HDAC1', 'Gene', (183, 188))	('depression', 'Phenotype', 'HP:0000716', (119, 129))
491961	31711545	It has been shown that HDAC6 inhibition confers protective effects against LPS-induced inflammation, as is demonstrated by the reduced production of the pro-inflammatory cytokines TNF-alpha, IL-1beta, and IL-6 and decreased leukocyte infiltration.	('decreased leukocyte', 'Phenotype', 'HP:0001882', (214, 233))	('inflammation', 'Disease', (87, 99))	('rat', 'Species', '10116', (114, 117))	('TNF-alpha', 'MPA', (180, 189))	('inflammation', 'Disease', 'MESH:D007249', (87, 99))	('HDAC6', 'Gene', (23, 28))	('LPS', 'Gene', '21898', (75, 78))	('production', 'MPA', (135, 145))	('leukocyte infiltration', 'CPA', (224, 246))	('LPS', 'Gene', (75, 78))	('decreased', 'NegReg', (214, 223))	('reduced', 'NegReg', (127, 134))	('inhibition', 'Var', (29, 39))	('rat', 'Species', '10116', (240, 243))
491964	31711545	Another study shows the opposite result: specific inhibition of HDAC8 reduces LPS-induced IL-1beta, TNF-alpha, IL-6 secretion.	('inhibition', 'Var', (50, 60))	('HDAC8', 'Gene', '55869', (64, 69))	('reduces', 'NegReg', (70, 77))	('HDAC8', 'Gene', (64, 69))	('LPS', 'Gene', '21898', (78, 81))	('TNF-alpha', 'MPA', (100, 109))	('LPS', 'Gene', (78, 81))
491972	31711545	Further studies have shown that knocking down SIRT1, 2 or 6 both in vivo and in vitro results in increased expression of NF-kappabeta and simultaneous overexpression of inflammatory cytokines.	('SIRT1', 'Gene', (46, 51))	('increased', 'PosReg', (97, 106))	('NF-kappabeta', 'Gene', (121, 133))	('NF-kappabeta', 'Gene', '4790', (121, 133))	('expression', 'MPA', (107, 117))	('knocking down', 'Var', (32, 45))	('overexpression', 'PosReg', (151, 165))	('SIRT1', 'Gene', '23411', (46, 51))
491974	31711545	SIRT3 overexpression could ameliorate the activation of Nod-like receptor protein 3 (NLRP3) inflammasome, while SIRT3 knockdown accelerates the induction of NLRP3 expression.	('Nod-like receptor protein 3', 'Gene', (56, 83))	('NLRP3', 'Gene', (157, 162))	('NLRP3', 'Gene', (85, 90))	('knockdown', 'Var', (118, 127))	('induction', 'MPA', (144, 153))	('rat', 'Species', '10116', (33, 36))	('activation', 'PosReg', (42, 52))	('expression', 'MPA', (163, 173))	('rat', 'Species', '10116', (134, 137))	('accelerates', 'PosReg', (128, 139))	('Nod-like receptor protein 3', 'Gene', '114548', (56, 83))
491978	31711545	showed that the absence of SIRT7 produces an increase in inflammation, illustrating that SIRT7 also functions to suppress inflammation.	('absence', 'Var', (16, 23))	('SIRT7', 'Gene', (89, 94))	('SIRT7', 'Gene', '51547', (27, 32))	('SIRT7', 'Gene', (27, 32))	('rat', 'Species', '10116', (77, 80))	('SIRT7', 'Gene', '51547', (89, 94))	('inflammation', 'Disease', 'MESH:D007249', (57, 69))	('suppress', 'NegReg', (113, 121))	('inflammation', 'Disease', 'MESH:D007249', (122, 134))	('inflammation', 'Disease', (57, 69))	('inflammation', 'Disease', (122, 134))	('increase', 'PosReg', (45, 53))
491985	31711545	EZH2 deficiency directly stimulates TRAF expression to enhance TNF-alpha-induced NF-kappaB signaling, thereby leading to uncontrolled inflammation.	('TNF-alpha-induced NF-kappaB signaling', 'MPA', (63, 100))	('leading to', 'Reg', (110, 120))	('deficiency', 'Var', (5, 15))	('EZH2', 'Gene', '2146', (0, 4))	('EZH2', 'Gene', (0, 4))	('TRAF', 'Gene', (36, 40))	('enhance', 'PosReg', (55, 62))	('stimulates', 'PosReg', (25, 35))	('inflammation', 'Disease', 'MESH:D007249', (134, 146))	('inflammation', 'Disease', (134, 146))
491993	31711545	Our previous mouse model and in vitro studies revealed that PRMT6 exerts a negative effect on CS-induced pulmonary inflammation through H3R2me2a, while overexpression of PRMT6 inhibits CS-induced inflammation.	('inflammation', 'Disease', 'MESH:D007249', (115, 127))	('negative', 'NegReg', (75, 83))	('H3R2me2a', 'Var', (136, 144))	('PRMT6', 'Gene', (60, 65))	('mouse', 'Species', '10090', (13, 18))	('inflammation', 'Disease', (115, 127))	('pulmonary inflammation', 'Disease', (105, 127))	('H3R2me2a', 'Chemical', 'MESH:C405983', (136, 144))	('pulmonary inflammation', 'Disease', 'MESH:D011014', (105, 127))	('inflammation', 'Disease', 'MESH:D007249', (196, 208))	('inflammation', 'Disease', (196, 208))
491999	31711545	It has been shown that the phosphorylation of histone H3 at Ser10 and Ser28 plays a critical role in promoting COX2 expression.	('histone H3', 'Protein', (46, 56))	('expression', 'MPA', (116, 126))	('Ser28', 'Var', (70, 75))	('promoting', 'PosReg', (101, 110))	('phosphorylation', 'MPA', (27, 42))	('Ser10', 'Var', (60, 65))	('Ser', 'Chemical', 'MESH:C530429', (70, 73))	('H3', 'Chemical', 'MESH:C405983', (54, 56))	('COX2', 'Gene', '5743', (111, 115))	('COX2', 'Gene', (111, 115))	('Ser', 'Chemical', 'MESH:C530429', (60, 63))
492000	31711545	Histone H3 phosphorylation at Ser10, which occurs at the promoters of the NF-kappaB-regulated cytokines, has been observed to increase the accessibility of NF-kappaB binding sides.	('binding sides', 'Interaction', (166, 179))	('NF-kappaB', 'Protein', (156, 165))	('H3', 'Chemical', 'MESH:C405983', (8, 10))	('Ser10', 'Var', (30, 35))	('increase', 'PosReg', (126, 134))	('Ser', 'Chemical', 'MESH:C530429', (30, 33))	('accessibility', 'MPA', (139, 152))
492002	31711545	It has been shown that MSK1 can induce p65 phosphorylation at Ser276, which in turn induces IL-8/CXCL8 release in thrombin-stimulated human lung epithelial cells.	('IL-8', 'Gene', '3576', (92, 96))	('Ser276', 'Var', (62, 68))	('thrombin', 'Gene', (114, 122))	('Ser', 'Chemical', 'MESH:C530429', (62, 65))	('phosphorylation', 'MPA', (43, 58))	('MSK1', 'Gene', (23, 27))	('IL-8', 'Gene', (92, 96))	('p65', 'Gene', (39, 42))	('human', 'Species', '9606', (134, 139))	('thrombin', 'Gene', '2147', (114, 122))	('CXCL8', 'Gene', '3576', (97, 102))	('CXCL8', 'Gene', (97, 102))	('p65', 'Gene', '5970', (39, 42))	('induce', 'Reg', (32, 38))	('induces', 'Reg', (84, 91))
492004	31711545	found that knocking down of MSK1 decreased the mRNA levels of IL-1beta, TNF-alpha, which was triggered by stimulation with CX3CL1 through the inactivation of NF-kappaB signaling pathway.	('mRNA levels of IL-1beta', 'MPA', (47, 70))	('knocking down', 'Var', (11, 24))	('inactivation', 'NegReg', (142, 154))	('NF-kappaB signaling pathway', 'Pathway', (158, 185))	('decreased', 'NegReg', (33, 42))	('MSK1', 'Gene', (28, 32))	('CX3CL1', 'Gene', '6376', (123, 129))	('CX3CL1', 'Gene', (123, 129))
492008	31711545	It has been shown that MSK1 and MSK2 are required for the induced expression of both IL-1Ra mRNA and protein, while knocking out MSK in mice was found to result in a decreased IL-1Ra production.	('MSK2', 'Gene', '56613', (32, 36))	('mice', 'Species', '10090', (136, 140))	('MSK', 'Gene', '150094', (32, 35))	('MSK', 'Gene', (32, 35))	('MSK2', 'Gene', (32, 36))	('decreased', 'NegReg', (166, 175))	('knocking out', 'Var', (116, 128))	('IL-1Ra production', 'MPA', (176, 193))	('MSK', 'Gene', '150094', (129, 132))	('MSK', 'Gene', (129, 132))	('IL-1Ra', 'Gene', (85, 91))	('MSK', 'Gene', '150094', (23, 26))	('MSK', 'Gene', (23, 26))
492018	31711545	NF-kappaB inhibition prevents CS-induced upregulation of MuRF1 and CS-induced reduction in the diameter and degradation of the MyHC-related C2 myotubes, suggesting that inflammation is responsible for CS-induced proteasomal degradation in skeletal muscle.	('diameter', 'MPA', (95, 103))	('degradation', 'MPA', (108, 119))	('MuRF1', 'Gene', (57, 62))	('inflammation', 'Disease', 'MESH:D007249', (169, 181))	('inflammation', 'Disease', (169, 181))	('C2 myotubes', 'Disease', 'OMIM:217000', (140, 151))	('reduction', 'NegReg', (78, 87))	('NF-kappaB', 'Protein', (0, 9))	('inhibition', 'Var', (10, 20))	('C2 myotubes', 'Disease', (140, 151))	('upregulation', 'PosReg', (41, 53))
492020	31711545	found that atrogin-1 overexpression markedly inhibits the expression of pro-inflammatory-related genes (including IL-1beta, IL-6, Ptgs2 and Serpinb2), while knocking down atrogin-1 by siRNA had the opposite effects.	('Ptgs2', 'Gene', '5743', (130, 135))	('Ptgs2', 'Gene', (130, 135))	('inhibits', 'NegReg', (45, 53))	('atrogin-1', 'Gene', (11, 20))	('expression', 'MPA', (58, 68))	('Serpinb2', 'Gene', (140, 148))	('overexpression', 'PosReg', (21, 35))	('atrogin-1', 'Gene', (171, 180))	('IL-1beta', 'Gene', (114, 122))	('knocking', 'Var', (157, 165))	('IL-6', 'Gene', (124, 128))	('Serpinb2', 'Gene', '5055', (140, 148))
492022	31711545	Studies have shown that the knocking down MUL1 with a combination of siRNA and shRNA results in potentiated activation of both the IFN-beta and NF-kB pathways.	('IFN-beta', 'Gene', (131, 139))	('knocking down', 'Var', (28, 41))	('MUL1', 'Gene', '79594', (42, 46))	('NF-kB pathways', 'Pathway', (144, 158))	('IFN-beta', 'Gene', '3456', (131, 139))	('MUL1', 'Gene', (42, 46))	('activation', 'PosReg', (108, 118))
492036	31711545	Knocking down miR-132 attenuates CS-induced inflammation in human monocyte-like cells by targeting the SOCS5, which acts to limit the duration of signaling responses.	('miR-132', 'Gene', (14, 21))	('SOCS5', 'Gene', '9655', (103, 108))	('targeting', 'Reg', (89, 98))	('inflammation', 'Disease', 'MESH:D007249', (44, 56))	('miR-132', 'Gene', '406921', (14, 21))	('duration', 'MPA', (134, 142))	('inflammation', 'Disease', (44, 56))	('rat', 'Species', '10116', (136, 139))	('attenuates', 'NegReg', (22, 32))	('human', 'Species', '9606', (60, 65))	('SOCS5', 'Gene', (103, 108))	('Knocking', 'Var', (0, 8))
492038	31711545	Knocking down miR-195 alleviates CS-induced lung injury and inflammatory cell infiltration, as well as production of TNF-alpha and IL-6, by regulating Akt signaling, indicating that miR-195 has a role in the promotion of inflammation.	('miR-195', 'Gene', (182, 189))	('inflammation', 'Disease', 'MESH:D007249', (221, 233))	('Knocking down', 'Var', (0, 13))	('inflammatory cell infiltration', 'CPA', (60, 90))	('miR-195', 'Gene', '406971', (182, 189))	('regulating', 'Reg', (140, 150))	('inflammation', 'Disease', (221, 233))	('miR-195', 'Gene', (14, 21))	('alleviates', 'NegReg', (22, 32))	('rat', 'Species', '10116', (84, 87))	('Akt', 'Gene', '207', (151, 154))	('miR-195', 'Gene', '406971', (14, 21))	('production', 'MPA', (103, 113))	('lung injury', 'Disease', 'MESH:D055370', (44, 55))	('lung injury', 'Disease', (44, 55))	('CS-induced', 'Disease', (33, 43))	('Akt', 'Gene', (151, 154))
492066	31711545	Benzo[a]pyrene, a constituent of CS, has been shown to promote inflammation pathways via TNF-alpha and NF-kappaB, leading to IL-6 upregulation, miRNA (let-7a, miR-21 and miR-29b) dysregulation and the activation of VEGF.	('miR-29b', 'Gene', (170, 177))	('miR', 'Gene', '220972', (170, 173))	('IL-6', 'Gene', (125, 129))	('miR', 'Gene', '220972', (159, 162))	('VEGF', 'Gene', '7422', (215, 219))	('promote', 'PosReg', (55, 62))	('Benzo[a]pyrene', 'Var', (0, 14))	('miR', 'Gene', (170, 173))	('miR-21', 'Gene', '406991', (159, 165))	('VEGF', 'Gene', (215, 219))	('TNF-alpha', 'Protein', (89, 98))	('miR-29b', 'Gene', '407024', (170, 177))	('miR', 'Gene', '220972', (144, 147))	('inflammation', 'Disease', 'MESH:D007249', (63, 75))	('miR', 'Gene', (159, 162))	('NF-kappaB', 'Protein', (103, 112))	('Benzo[a]pyrene', 'Chemical', 'MESH:D001564', (0, 14))	('miR-21', 'Gene', (159, 165))	('dysregulation', 'MPA', (179, 192))	('upregulation', 'PosReg', (130, 142))	('miR', 'Gene', (144, 147))	('inflammation', 'Disease', (63, 75))
492078	31711545	Several reports have demonstrated the dysregulation of lncRNAs in the pathogenesis of various inflammatory diseases.	('dysregulation', 'Var', (38, 51))	('inflammatory disease', 'Disease', 'MESH:D007249', (94, 114))	('inflammatory disease', 'Disease', (94, 114))	('ncRNA', 'Gene', (56, 61))	('rat', 'Species', '10116', (28, 31))	('ncRNA', 'Gene', '220202', (56, 61))
492086	31711545	; that is, IL-6, IL-1beta, COX2, and TNF-alpha protein levels are significantly depressed by silencing HOTAIR but are increased by upregulation of HOTAIR.	('silencing', 'Var', (93, 102))	('upregulation', 'PosReg', (131, 143))	('TNF-alpha protein levels', 'MPA', (37, 61))	('depressed', 'NegReg', (80, 89))	('increased', 'PosReg', (118, 127))	('COX2', 'Gene', (27, 31))	('COX2', 'Gene', '5743', (27, 31))	('IL-1beta', 'MPA', (17, 25))	('HOTAIR', 'Gene', (103, 109))
492090	31711545	In addition, these effects induced by CLP are reversed by knocking down MALAT1.	('MALAT1', 'Gene', '378938', (72, 78))	('knocking down', 'Var', (58, 71))	('CLP', 'Gene', '8048', (38, 41))	('MALAT1', 'Gene', (72, 78))	('CLP', 'Gene', (38, 41))
492092	31711545	Knocking down MALAT1 downregulates serum amyloid antigen 3 activation, subsequently reducing the RNA and protein expressions of key inflammatory mediators (IL-6 and TNF-alpha).	('MALAT1', 'Gene', '378938', (14, 20))	('Knocking down', 'Var', (0, 13))	('downregulates', 'NegReg', (21, 34))	('MALAT1', 'Gene', (14, 20))	('serum amyloid antigen 3 activation', 'MPA', (35, 69))	('reducing', 'NegReg', (84, 92))
492094	31711545	Knocking down MALAT1 can increase LPS-induced expression of TNF-alpha and IL-6.	('LPS', 'Gene', (34, 37))	('MALAT1', 'Gene', '378938', (14, 20))	('Knocking down', 'Var', (0, 13))	('increase LPS', 'Phenotype', 'HP:0003141', (25, 37))	('IL-6', 'Gene', (74, 78))	('TNF-alpha', 'Protein', (60, 69))	('MALAT1', 'Gene', (14, 20))	('increase', 'PosReg', (25, 33))	('LPS', 'Gene', '21898', (34, 37))
492105	31711545	A growing body of evidence supports the importance of epigenetic alterations in the initiation and development of CS-induced diseases.	('CS-induced diseases', 'Disease', (114, 133))	('epigenetic alterations', 'Var', (54, 76))	('rat', 'Species', '10116', (69, 72))
492106	31711545	CS-mediated alterations in DNA methylation, histone modification, and ncRNAs can affect a variety of molecular and cellular processes, such as inflammation, cell cycle arrest, apoptosis, senescence, and autophagy.	('cell cycle arrest', 'CPA', (157, 174))	('methyl', 'Chemical', 'MESH:C031105', (31, 37))	('histone', 'Protein', (44, 51))	('senescence', 'CPA', (187, 197))	('alterations', 'Var', (12, 23))	('rat', 'Species', '10116', (16, 19))	('methylation', 'Var', (31, 42))	('affect', 'Reg', (81, 87))	('inflammation', 'Disease', 'MESH:D007249', (143, 155))	('inflammation', 'Disease', (143, 155))	('ncRNA', 'Gene', '220202', (70, 75))	('apoptosis', 'CPA', (176, 185))	('autophagy', 'CPA', (203, 212))	('ncRNA', 'Gene', (70, 75))	('DNA', 'Protein', (27, 30))
492107	31711545	In particular, transcription regulation by NF-kappaB, a key pro-inflammatory molecule, appears to have a main function in CS-induced epigenetic changes in the mediation of inflammation.	('inflammation', 'Disease', (172, 184))	('NF-kappaB', 'Gene', (43, 52))	('transcription regulation', 'MPA', (15, 39))	('epigenetic changes', 'Var', (133, 151))	('inflammation', 'Disease', 'MESH:D007249', (172, 184))
492109	31711545	Different changes of epigenetic alterations may play a pro-inflammatory or an anti-inflammatory role through the regulation of target gene expression, thereby participating in the occurrence and development of CS-medicated inflammatory diseases.	('rat', 'Species', '10116', (36, 39))	('participating', 'Reg', (159, 172))	('inflammatory disease', 'Disease', 'MESH:D007249', (223, 243))	('inflammatory disease', 'Disease', (223, 243))	('epigenetic alterations', 'Var', (21, 43))	('expression', 'MPA', (139, 149))
492110	31711545	The recognition of the alterations in DNA methylation, histone modifications, and ncRNAs provides a better understanding of the molecular basis for CS-medicated inflammation.	('ncRNA', 'Gene', (82, 87))	('DNA', 'Gene', (38, 41))	('ncRNA', 'Gene', '220202', (82, 87))	('CS-medicated', 'Disease', (148, 160))	('methylation', 'Var', (42, 53))	('inflammation', 'Disease', 'MESH:D007249', (161, 173))	('rat', 'Species', '10116', (27, 30))	('alterations', 'Reg', (23, 34))	('inflammation', 'Disease', (161, 173))	('methyl', 'Chemical', 'MESH:C031105', (42, 48))
492113	29581789	Integrated Oncogenomic Profiling of Copy Numbers and Gene Expression in Lung Adenocarcinomas without EGFR Mutations or ALK Fusion Targeted therapies based on EGFR mutations or on the ALK fusion oncogene have become the standard treatment for certain patients with lung adenocarcinoma (LUAD).	('EGFR', 'Gene', '1956', (158, 162))	('LUAD', 'Phenotype', 'HP:0030078', (285, 289))	('EGFR', 'Gene', '1956', (101, 105))	('lung adenocarcinoma', 'Disease', (264, 283))	('ALK', 'Gene', '238', (183, 186))	('patients', 'Species', '9606', (250, 258))	('Lung Adenocarcinomas', 'Phenotype', 'HP:0030078', (72, 92))	('ALK', 'Gene', '238', (119, 122))	('Lung Adenocarcinomas', 'Disease', 'MESH:D000077192', (72, 92))	('ALK', 'Gene', (183, 186))	('EGFR', 'Gene', (158, 162))	('mutations', 'Var', (163, 172))	('ALK', 'Gene', (119, 122))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (264, 283))	('EGFR', 'Gene', (101, 105))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('Lung Adenocarcinomas', 'Disease', (72, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (274, 283))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (264, 283))	('men', 'Species', '9606', (233, 236))
492114	29581789	However, most LUAD patients have no EGFR mutation or ALK fusion, and their oncogenetic alterations remain to be characterized.	('LUAD', 'Disease', (14, 18))	('ALK', 'Gene', (53, 56))	('patients', 'Species', '9606', (19, 27))	('LUAD', 'Phenotype', 'HP:0030078', (14, 18))	('EGFR', 'Gene', '1956', (36, 40))	('mutation', 'Var', (41, 49))	('ALK', 'Gene', '238', (53, 56))	('EGFR', 'Gene', (36, 40))
492119	29581789	In addition, analysis of the copy number alterations of these 23 genes revealed correlations between EMSY/CCND1, EMSY/PIK3CA, CCND1/CDKN2A, and CCND1/PIK3CA.	('CDKN2A', 'Gene', (132, 138))	('PIK3CA', 'Gene', (150, 156))	('CCND1', 'Gene', '595', (126, 131))	('EMSY', 'Gene', (113, 117))	('CCND1', 'Gene', '595', (144, 149))	('correlations', 'Interaction', (80, 92))	('CDKN2A', 'Gene', '1029', (132, 138))	('PIK3CA', 'Gene', '5290', (150, 156))	('CCND1', 'Gene', (126, 131))	('EMSY', 'Gene', '56946', (101, 105))	('copy number alterations', 'Var', (29, 52))	('CCND1', 'Gene', (106, 111))	('PIK3CA', 'Gene', (118, 124))	('CCND1', 'Gene', (144, 149))	('EMSY', 'Gene', (101, 105))	('PIK3CA', 'Gene', '5290', (118, 124))	('EMSY', 'Gene', '56946', (113, 117))	('CCND1', 'Gene', '595', (106, 111))
492125	29581789	For example, LUAD patients with activating mutations of the epidermal growth factor receptor gene (EGFR) have a better response to EGFR tyrosine kinase inhibitors (TKIs) than those without EGFR mutations, and rearrangement of the anaplastic lymphoma kinase gene (ALK) is the best predictor of LUAD response to the ALK TKI crizotinib.	('anaplastic lymphoma kinase gene', 'Gene', (230, 261))	('crizotinib', 'Chemical', 'MESH:D000077547', (322, 332))	('EGFR', 'Gene', (131, 135))	('men', 'Species', '9606', (218, 221))	('activating', 'PosReg', (32, 42))	('lymphoma', 'Phenotype', 'HP:0002665', (241, 249))	('EGFR', 'Gene', (99, 103))	('EGFR', 'Gene', '1956', (189, 193))	('rearrangement', 'Var', (209, 222))	('response', 'MPA', (119, 127))	('LUAD', 'Phenotype', 'HP:0030078', (293, 297))	('ALK', 'Gene', '238', (314, 317))	('ALK', 'Gene', (314, 317))	('better', 'PosReg', (112, 118))	('LUAD', 'Phenotype', 'HP:0030078', (13, 17))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (230, 249))	('EGFR', 'Gene', '1956', (131, 135))	('ALK', 'Gene', '238', (263, 266))	('patients', 'Species', '9606', (18, 26))	('EGFR', 'Gene', '1956', (99, 103))	('ALK', 'Gene', (263, 266))	('EGFR', 'Gene', (189, 193))	('mutations', 'Var', (43, 52))	('anaplastic lymphoma kinase gene', 'Gene', '238', (230, 261))
492126	29581789	However, patients with EGFR mutations or ALK fusion account for only one-third of patients diagnosed with LUAD, which indicates the necessity of understanding of the genetic basis for LUAD without EGFR mutations or ALK fusion.	('ALK', 'Gene', (215, 218))	('patients', 'Species', '9606', (9, 17))	('LUAD', 'Disease', (106, 110))	('LUAD', 'Phenotype', 'HP:0030078', (106, 110))	('patients', 'Species', '9606', (82, 90))	('LUAD', 'Phenotype', 'HP:0030078', (184, 188))	('ALK', 'Gene', '238', (215, 218))	('LUAD', 'Disease', (184, 188))	('ALK', 'Gene', (41, 44))	('EGFR', 'Gene', '1956', (23, 27))	('EGFR', 'Gene', '1956', (197, 201))	('EGFR', 'Gene', (23, 27))	('ALK', 'Gene', '238', (41, 44))	('mutations', 'Var', (28, 37))	('EGFR', 'Gene', (197, 201))
492128	29581789	It is not known if LUAD patients with EGFR/ALT alterations harbor distinct genetic characteristics compared to those without such alterations.	('EGFR', 'Gene', '1956', (38, 42))	('EGFR', 'Gene', (38, 42))	('LUAD', 'Phenotype', 'HP:0030078', (19, 23))	('patients', 'Species', '9606', (24, 32))	('alterations', 'Var', (47, 58))
492129	29581789	Moreover, little is understood about the correlation of copy numbers and gene expression of top-ranked genes in lung cancer, especially for LUAD without EGFR mutations or ALK fusion.	('LUAD', 'Phenotype', 'HP:0030078', (140, 144))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('lung cancer', 'Disease', (112, 123))	('lung cancer', 'Phenotype', 'HP:0100526', (112, 123))	('ALK', 'Gene', (171, 174))	('EGFR', 'Gene', '1956', (153, 157))	('lung cancer', 'Disease', 'MESH:D008175', (112, 123))	('EGFR', 'Gene', (153, 157))	('mutations', 'Var', (158, 167))	('ALK', 'Gene', '238', (171, 174))
492134	29581789	The copy numbers of these candidate genes were further evaluated in ten micro-dissected LUADs without EGFR mutations or ALK fusion.	('mutations', 'Var', (107, 116))	('ALK', 'Gene', (120, 123))	('LUAD', 'Phenotype', 'HP:0030078', (88, 92))	('ALK', 'Gene', '238', (120, 123))	('EGFR', 'Gene', '1956', (102, 106))	('EGFR', 'Gene', (102, 106))
492135	29581789	This study revealed a concordant change of PTEN at both genomic DNA and mRNA levels in LUAD without EGFR mutation or ALK fusion.	('EGFR', 'Gene', '1956', (100, 104))	('mutation', 'Var', (105, 113))	('mRNA levels', 'MPA', (72, 83))	('ALK', 'Gene', '238', (117, 120))	('LUAD', 'Phenotype', 'HP:0030078', (87, 91))	('EGFR', 'Gene', (100, 104))	('PTEN', 'Gene', (43, 47))	('PTEN', 'Gene', '5728', (43, 47))	('ALK', 'Gene', (117, 120))	('change', 'Reg', (33, 39))
492147	29581789	Lung cancer specimens obtained from a clinical molecular diagnostic laboratory were tested for EGFR mutations and ALK fusion.	('mutations', 'Var', (100, 109))	('tested', 'Reg', (84, 90))	('ALK', 'Gene', '238', (114, 117))	('men', 'Species', '9606', (17, 20))	('Lung cancer', 'Phenotype', 'HP:0100526', (0, 11))	('Lung cancer', 'Disease', (0, 11))	('EGFR', 'Gene', '1956', (95, 99))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))	('ALK', 'Gene', (114, 117))	('Lung cancer', 'Disease', 'MESH:D008175', (0, 11))	('EGFR', 'Gene', (95, 99))
492149	29581789	Mutations in EGFR were assessed on genomic DNA, whereas ALK fusions were determined with total RNA.	('ALK', 'Gene', '238', (56, 59))	('Mutations', 'Var', (0, 9))	('ALK', 'Gene', (56, 59))	('EGFR', 'Gene', '1956', (13, 17))	('EGFR', 'Gene', (13, 17))
492151	29581789	ALK fusion variants were detected by multiplex One-step RT-PCR using Human ALK Gene Fusions Detection Kits (AmoyDx).	('ALK', 'Gene', (75, 78))	('variants', 'Var', (11, 19))	('Human', 'Species', '9606', (69, 74))	('ALK', 'Gene', (0, 3))	('ALK', 'Gene', '238', (75, 78))	('ALK', 'Gene', '238', (0, 3))
492152	29581789	RT-PCR was performed on a 7500 Real Time PCR System (Thermo Fisher Scientific, Waltham, MA, USA), and the absence of EGFR mutations and ALK fusion was verified by direct sequencing of PCR and RT-PCR products as previously reported.	('EGFR', 'Gene', '1956', (117, 121))	('EGFR', 'Gene', (117, 121))	('ALK', 'Gene', (136, 139))	('mutations', 'Var', (122, 131))	('ALK', 'Gene', '238', (136, 139))
492164	29581789	Data mining was accomplished using cBioPortal for Cancer Genomics (cBioPortal for Cancer Genomics), available at http://www.cbioportal.org, to measure the incidence of conditions that are associated with alterations in these genes.	('Cancer', 'Disease', 'MESH:D009369', (50, 56))	('Cancer', 'Disease', (50, 56))	('Cancer', 'Phenotype', 'HP:0002664', (50, 56))	('alterations', 'Var', (204, 215))	('conditions', 'Disease', (168, 178))	('Cancer', 'Disease', 'MESH:D009369', (82, 88))	('Cancer', 'Disease', (82, 88))	('Cancer', 'Phenotype', 'HP:0002664', (82, 88))
492170	29581789	Most of the cancer-associated genes affected by copy number alterations (CNAs) are genes in cancer-signaling pathways involved in carcinogenesis and tumor progression.	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('carcinogenesis', 'Disease', 'MESH:D063646', (130, 144))	('copy number alterations', 'Var', (48, 71))	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', (12, 18))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('carcinogenesis', 'Disease', (130, 144))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('tumor', 'Disease', (149, 154))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
492172	29581789	Data mining was accomplished with cBioPortal for Cancer Genomics (available at http://www.cbioportal.org) to measure the incidence of conditions that are associated with alterations in these genes.	('Cancer', 'Phenotype', 'HP:0002664', (49, 55))	('Cancer', 'Disease', 'MESH:D009369', (49, 55))	('Cancer', 'Disease', (49, 55))	('alterations', 'Var', (170, 181))
492173	29581789	Since the portal reduces molecular profiling data from cancer tissues and cell lines into readily understandable genetic, epigenetic, gene expression events, a graph representing a cross-cancer alteration (amplification, deletion, mutation and multiple alterations) for each gene was generated (Fig 1).	('deletion', 'Var', (221, 229))	('cancer', 'Disease', 'MESH:D009369', (187, 193))	('mutation', 'Var', (231, 239))	('cancer', 'Disease', (187, 193))	('cross-cancer', 'Disease', (181, 193))	('cross-cancer', 'Disease', 'MESH:C537866', (181, 193))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('cancer', 'Disease', (55, 61))
492174	29581789	The focus was on genes whose alterations predispose to susceptibility for lung cancers.	('lung cancer', 'Phenotype', 'HP:0100526', (74, 85))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('lung cancers', 'Disease', 'MESH:D008175', (74, 86))	('lung cancers', 'Phenotype', 'HP:0100526', (74, 86))	('alterations', 'Var', (29, 40))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('lung cancers', 'Disease', (74, 86))
492176	29581789	Almost half of the checked genes, including CCND1, CSMD1, EGFR, EMSY, MYC, PDGFRA, PIK3CA, PTPRD, RB1, REL, and ZNF217, displayed multiple alterations (amplification, deletion, and mutation occurring simultaneously).	('RB1', 'Gene', '5925', (98, 101))	('EMSY', 'Gene', (64, 68))	('deletion', 'Var', (167, 175))	('CCND1', 'Gene', (44, 49))	('EMSY', 'Gene', '56946', (64, 68))	('MYC', 'Gene', '4609', (70, 73))	('CSMD1', 'Gene', '64478', (51, 56))	('CSMD1', 'Gene', (51, 56))	('EGFR', 'Gene', (58, 62))	('PIK3CA', 'Gene', (83, 89))	('PDGFRA', 'Gene', (75, 81))	('PDGFRA', 'Gene', '5156', (75, 81))	('ZNF217', 'Gene', (112, 118))	('RB1', 'Gene', (98, 101))	('ZNF217', 'Gene', '7764', (112, 118))	('PTPRD', 'Gene', (91, 96))	('EGFR', 'Gene', '1956', (58, 62))	('PTPRD', 'Gene', '5789', (91, 96))	('MYC', 'Gene', (70, 73))	('mutation', 'Var', (181, 189))	('PIK3CA', 'Gene', '5290', (83, 89))	('CCND1', 'Gene', '595', (44, 49))
492179	29581789	In LUAD, the PTEN gene, which has rare gene amplification as a tumor suppressor, exhibited higher incidences of mutation and deletion.	('tumor', 'Disease', (63, 68))	('mutation', 'Var', (112, 120))	('LUAD', 'Phenotype', 'HP:0030078', (3, 7))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('PTEN', 'Gene', (13, 17))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('PTEN', 'Gene', '5728', (13, 17))	('deletion', 'Var', (125, 133))
492180	29581789	The VEGFA gene, whose up-regulation is associated with tumor progression and angiogenesis, had mutations only in LUSC.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('VEGFA', 'Gene', '7422', (4, 9))	('angiogenesis', 'CPA', (77, 89))	('tumor', 'Disease', (55, 60))	('up-regulation', 'PosReg', (22, 35))	('mutations', 'Var', (95, 104))	('VEGFA', 'Gene', (4, 9))
492186	29581789	All tumors from these patients were negative for EGFR mutations and ALK fusion.	('EGFR', 'Gene', '1956', (49, 53))	('ALK', 'Gene', (68, 71))	('EGFR', 'Gene', (49, 53))	('mutations', 'Var', (54, 63))	('tumors', 'Disease', (4, 10))	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('patients', 'Species', '9606', (22, 30))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('ALK', 'Gene', '238', (68, 71))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))
492214	29581789	Our results strengthen the rationale for and importance of developing approaches targeting PTEN and RB1 for treating LUAD without genomic alterations such as EGFR mutations and ALK fusion.	('RB1', 'Gene', (100, 103))	('EGFR', 'Gene', (158, 162))	('mutations', 'Var', (163, 172))	('LUAD', 'Disease', (117, 121))	('ALK', 'Gene', '238', (177, 180))	('RB1', 'Gene', '5925', (100, 103))	('LUAD', 'Phenotype', 'HP:0030078', (117, 121))	('PTEN', 'Gene', (91, 95))	('EGFR', 'Gene', '1956', (158, 162))	('PTEN', 'Gene', '5728', (91, 95))	('ALK', 'Gene', (177, 180))
492218	29581789	In view of the lower PTPRD expression in LUAD tumors of a few patients (30%, Fig 3D) and no correlation between the copy numbers and gene expression levels of PTPRD (Fig 4D), gene deletion of PTPRD (Figs 1 and 2) is unlikely to contribute to its expression.	('gene deletion', 'Var', (175, 188))	('LUAD', 'Phenotype', 'HP:0030078', (41, 45))	('PTPRD', 'Gene', '5789', (192, 197))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('PTPRD', 'Gene', (192, 197))	('PTPRD', 'Gene', '5789', (21, 26))	('PTPRD', 'Gene', (21, 26))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('expression', 'MPA', (27, 37))	('PTPRD', 'Gene', '5789', (159, 164))	('PTPRD', 'Gene', (159, 164))	('LUAD tumors', 'Disease', 'MESH:D009369', (41, 52))	('lower', 'NegReg', (15, 20))	('patients', 'Species', '9606', (62, 70))	('LUAD tumors', 'Disease', (41, 52))
492227	29581789	In human cancers, PIK3CA and PTEN, signaling components of the PI3-kinase pathway, are frequently mutated.	('cancers', 'Disease', 'MESH:D009369', (9, 16))	('cancers', 'Phenotype', 'HP:0002664', (9, 16))	('cancers', 'Disease', (9, 16))	('human', 'Species', '9606', (3, 8))	('PTEN', 'Gene', (29, 33))	('PTEN', 'Gene', '5728', (29, 33))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('PIK3CA', 'Gene', (18, 24))	('mutated', 'Var', (98, 105))	('PIK3CA', 'Gene', '5290', (18, 24))
492233	29581789	Furthermore, the methodology for quantitation of DNA copy numbers and mRNA levels cannot distinguish gene mutations, since the mutants, rather than deletions of some genes, such as RB1 (Fig 1), act in a dominant-negative manner and are involved in carcinogenesis.	('involved', 'Reg', (236, 244))	('RB1', 'Gene', (181, 184))	('carcinogenesis', 'Disease', (248, 262))	('RB1', 'Gene', '5925', (181, 184))	('carcinogenesis', 'Disease', 'MESH:D063646', (248, 262))	('mutants', 'Var', (127, 134))
492237	29581789	In conclusions, we conducted an analysis of public datasets to assess the genomic alterations of 23 lung cancer-associated genes and found clues to the etiology and pathogenesis of LUAD and LUSC.	('LUAD', 'Disease', (181, 185))	('LUSC', 'Disease', (190, 194))	('lung cancer', 'Phenotype', 'HP:0100526', (100, 111))	('lung cancer', 'Disease', (100, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('genomic alterations', 'Var', (74, 93))	('lung cancer', 'Disease', 'MESH:D008175', (100, 111))	('LUAD', 'Phenotype', 'HP:0030078', (181, 185))
492238	29581789	We also assessed the oncogenomic profiles of surgically resected tumors without EGFR mutations or ALK fusion and tumor-distant normal lung tissues from LUAD patients and evaluated possible associations between these candidate genes.	('tumor', 'Disease', (113, 118))	('tumor', 'Disease', (65, 70))	('ALK', 'Gene', (98, 101))	('associations', 'Interaction', (189, 201))	('EGFR', 'Gene', '1956', (80, 84))	('patients', 'Species', '9606', (157, 165))	('EGFR', 'Gene', (80, 84))	('tumors', 'Disease', (65, 71))	('mutations', 'Var', (85, 94))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('LUAD', 'Phenotype', 'HP:0030078', (152, 156))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('ALK', 'Gene', '238', (98, 101))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
492239	29581789	Our findings have implications for the molecular stratification and therapeutic targeting of LUAD without EGFR mutations or ALK fusion.	('mutations', 'Var', (111, 120))	('ALK', 'Gene', '238', (124, 127))	('LUAD', 'Disease', (93, 97))	('LUAD', 'Phenotype', 'HP:0030078', (93, 97))	('ALK', 'Gene', (124, 127))	('EGFR', 'Gene', '1956', (106, 110))	('EGFR', 'Gene', (106, 110))
492254	28281960	For example, miR-184 was overexpressed in SCC patients, and inhibition of miR-184 in the TSCC cell line reduced the cell proliferation rate and oncogene c-Myc expression.	('TSCC', 'Phenotype', 'HP:0030413', (89, 93))	('patients', 'Species', '9606', (46, 54))	('inhibition', 'Var', (60, 70))	('reduced', 'NegReg', (104, 111))	('c-Myc', 'Gene', '4609', (153, 158))	('miR-184', 'Gene', (13, 20))	('expression', 'MPA', (159, 169))	('c-Myc', 'Gene', (153, 158))	('miR-184', 'Gene', '406960', (74, 81))	('miR-184', 'Gene', '406960', (13, 20))	('miR-184', 'Gene', (74, 81))	('cell proliferation rate', 'CPA', (116, 139))	('oncogene', 'CPA', (144, 152))
492259	28281960	identified that a target of miR-183, programmed cell death 4 (PDCD4), could be modulated by the P13K/AKT signaling pathway, which is associated with cell proliferation and related to caspase 3 activation.	('AKT', 'Gene', '207', (101, 104))	('P13K', 'Var', (96, 100))	('programmed cell death 4', 'Gene', '27250', (37, 60))	('caspase 3', 'Gene', (183, 192))	('caspase 3', 'Gene', '836', (183, 192))	('AKT', 'Gene', (101, 104))	('P13K', 'SUBSTITUTION', 'None', (96, 100))	('PDCD4', 'Gene', '27250', (62, 67))	('PDCD4', 'Gene', (62, 67))	('programmed cell death 4', 'Gene', (37, 60))	('miR-183', 'Gene', (28, 35))	('modulated', 'Reg', (79, 88))	('miR-183', 'Gene', '406959', (28, 35))
492296	28281960	Results showed that the expression of activated caspase 3 and BCL-xL was remarkably up- and downregulated in miR-183 inhibitor-transfected cells (p < 0.05), respectively (Fig.	('caspase 3', 'Gene', (48, 57))	('caspase 3', 'Gene', '836', (48, 57))	('BCL-xL', 'Gene', (62, 68))	('expression', 'MPA', (24, 34))	('BCL-xL', 'Gene', '598', (62, 68))	('miR-183', 'Gene', '406959', (109, 116))	('miR-183', 'Gene', (109, 116))	('inhibitor-transfected', 'Var', (117, 138))	('up-', 'PosReg', (84, 87))	('downregulated', 'NegReg', (92, 105))
492300	28281960	Moreover, miR-183 inhibition significantly upregulated activated caspase 3 expression while downregulating BCL-xL expression.	('upregulated', 'PosReg', (43, 54))	('caspase 3', 'Gene', '836', (65, 74))	('BCL-xL', 'Gene', '598', (107, 113))	('BCL-xL', 'Gene', (107, 113))	('miR-183', 'Gene', '406959', (10, 17))	('activated', 'MPA', (55, 64))	('downregulating', 'NegReg', (92, 106))	('inhibition', 'Var', (18, 28))	('miR-183', 'Gene', (10, 17))	('expression', 'MPA', (75, 85))	('caspase 3', 'Gene', (65, 74))
492314	28281960	These demonstrated that inhibition of miR-183 contributed to the inhibition of cancer cell growth; thus, the inhibition of miR-183 might be explored as a therapeutic target for TSCC.	('inhibition', 'NegReg', (65, 75))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('inhibition', 'Var', (109, 119))	('miR-183', 'Gene', '406959', (38, 45))	('TSCC', 'Phenotype', 'HP:0030413', (177, 181))	('inhibition', 'Var', (24, 34))	('miR-183', 'Gene', '406959', (123, 130))	('miR-183', 'Gene', (123, 130))	('TSCC', 'Disease', (177, 181))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('miR-183', 'Gene', (38, 45))
492323	28281960	Also, miR-183 inhibition upregulated activated caspase 3 expression while decreasing BCL-xL expression.	('expression', 'MPA', (57, 67))	('BCL-xL', 'Gene', (85, 91))	('decreasing', 'NegReg', (74, 84))	('upregulated', 'PosReg', (25, 36))	('caspase 3', 'Gene', (47, 56))	('caspase 3', 'Gene', '836', (47, 56))	('miR-183', 'Gene', '406959', (6, 13))	('activated', 'MPA', (37, 46))	('miR-183', 'Gene', (6, 13))	('inhibition', 'Var', (14, 24))	('BCL-xL', 'Gene', '598', (85, 91))
492330	30747484	Analysis of patient data and quantitative estimation of Cdh23 in human tissues (normal and tumor) also indicated that Cdh23 is down-regulated via promoter methylation in lung adenocarcinoma (AD) and esophageal squamous cell carcinoma (SCC) cells; we also observed a clear inverse correlation between Cdh23 expression and cancer metastasis.	('human', 'Species', '9606', (65, 70))	('SCC', 'Gene', '6317', (235, 238))	('AD', 'Disease', (191, 193))	('SCC', 'Gene', (235, 238))	('cancer metastasis', 'Disease', (321, 338))	('tumor', 'Disease', (91, 96))	('AD', 'Disease', 'MESH:D000544', (191, 193))	('down-regulated', 'NegReg', (127, 141))	('esophageal squamous cell carcinoma', 'Disease', (199, 233))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('lung adenocarcinoma', 'Disease', (170, 189))	('cancer metastasis', 'Disease', 'MESH:D009362', (321, 338))	('promoter methylation', 'Var', (146, 166))	('carcinoma', 'Phenotype', 'HP:0030731', (180, 189))	('Cdh23', 'Gene', (300, 305))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (170, 189))	('inverse', 'NegReg', (272, 279))	('Cdh23', 'Gene', (118, 123))	('patient', 'Species', '9606', (12, 19))	('SCC', 'Phenotype', 'HP:0002860', (235, 238))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (210, 233))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (199, 233))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (170, 189))	('carcinoma', 'Phenotype', 'HP:0030731', (224, 233))	('cancer', 'Phenotype', 'HP:0002664', (321, 327))
492347	30747484	The genome-wide association studies of kidney function identified a strong association of Cdh23 with the estimated cross-sectional glomerular filtration rate, and its knockdown in zebrafish embryo resulted in severe edema, suggesting its essential role in normal kidney functions (Gorski et al., 2015).	('edema', 'Disease', (216, 221))	('knockdown', 'Var', (167, 176))	('Cdh23', 'Gene', (90, 95))	('zebrafish', 'Species', '7955', (180, 189))	('edema', 'Disease', 'MESH:D004487', (216, 221))	('edema', 'Phenotype', 'HP:0000969', (216, 221))	('resulted in', 'Reg', (197, 208))	('association', 'Interaction', (75, 86))
492408	30747484	Apart from the changes in the intensity-fluctuation profile, the overall pattern in the RSD values for varying experimental conditions (control, Cdh23-siRNA, GFP+, and siRNA-GFP+) remained the same.	('Cdh23-siRNA', 'Var', (145, 156))	('RSD', 'Disease', (88, 91))	('RSD', 'Disease', 'MESH:D012019', (88, 91))
492413	30747484	On Day 3, as the effect of siRNA progresses, we noticed a significant difference (P < 0.001) in the scrambled-transfected (15.98 +- 2.48) and Cdh23-siRNA-transfected (siRNA, 21.69 +- 3.72) GFP- cells with lower RSD for the latter, reconfirming that the silencing of the intrinsic Cdh23 inhibits cell aggregation (Fig.	('RSD', 'Disease', 'MESH:D012019', (211, 214))	('RSD', 'Disease', (211, 214))	('inhibits', 'NegReg', (286, 294))	('silencing', 'Var', (253, 262))	('Cdh23', 'Gene', (280, 285))
492414	30747484	Following a similar trend, the difference in the RSD between scrambled- (pCdh23, 7.21 +- 2.59) and Cdh23-siRNA-transfected (pCdh23 + siRNA, 19.13 +- 6.43) GFP+ cells was significantly increased (P < 0.01), further evidence that lack of Cdh23 resulted in decreased aggregation of cells (Fig.	('lack', 'Var', (228, 232))	('RSD', 'Disease', (49, 52))	('decreased', 'NegReg', (254, 263))	('pCdh23', 'Gene', '54798', (73, 79))	('pCdh23', 'Gene', (124, 130))	('Cdh23', 'Gene', (236, 241))	('pCdh23', 'Gene', (73, 79))	('aggregation of cells', 'CPA', (264, 284))	('pCdh23', 'Gene', '54798', (124, 130))	('RSD', 'Disease', 'MESH:D012019', (49, 52))
492416	30747484	Overall, the transwell assay and hanging-drop assay jointly indicated that silencing of Cdh23 expression resulted in decreased cell aggregation and enhanced cell migration.	('decreased cell aggregation', 'Disease', (117, 143))	('decreased cell aggregation', 'Disease', 'MESH:D020914', (117, 143))	('cell migration', 'CPA', (157, 171))	('decreased cell aggregation', 'Phenotype', 'HP:0003540', (117, 143))	('silencing', 'Var', (75, 84))	('enhanced', 'PosReg', (148, 156))	('Cdh23', 'Gene', (88, 93))
492432	30747484	In the case of LCTA, we observed a higher population of tissues (12-23% more) that are adjacent to primary tumor (adjacent lung tissue, 68.4%) and malignant (62.5-73.3%), falling in the low-Cdh23 group in comparison with normal lung tissue (50%).	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('primary tumor', 'Disease', 'MESH:D009369', (99, 112))	('LC', 'Phenotype', 'HP:0100526', (15, 17))	('LCTA', 'Chemical', '-', (15, 19))	('low-Cdh23', 'Var', (186, 195))	('falling', 'Phenotype', 'HP:0002527', (171, 178))	('primary tumor', 'Disease', (99, 112))
492436	30747484	Similar to our experimental observations, TCGA has also reported a higher percentage of patients with advanced lymph node status [> N1, LUAD, 74%; LUSC, 93%; ESCC (N1), 92%] and metastasis stage (M1, LUAD, 72%; LUSC, 71%, ESCC, 78%) in the low-Cdh23 expression group.	('AD', 'Disease', (138, 140))	('low-Cdh23 expression', 'Var', (240, 260))	('AD', 'Disease', (202, 204))	('patients', 'Species', '9606', (88, 96))	('SCC', 'Gene', (223, 226))	('SCC', 'Gene', (159, 162))	('SCC', 'Phenotype', 'HP:0002860', (223, 226))	('SCC', 'Phenotype', 'HP:0002860', (159, 162))	('metastasis stage', 'CPA', (178, 194))	('AD', 'Disease', 'MESH:D000544', (202, 204))	('SCC', 'Gene', '6317', (223, 226))	('SCC', 'Gene', '6317', (159, 162))	('advanced lymph node status', 'CPA', (102, 128))	('AD', 'Disease', 'MESH:D000544', (138, 140))
492437	30747484	Overall, in silico analysis and TMA analysis suggest that Cdh23 is decreased in cancer, which is further decreased in advance lymph node stages and metastatic stages, suggesting Cdh23 suppresses cancer cell metastasis.	('cancer', 'Disease', (80, 86))	('TMA', 'Disease', 'MESH:D000783', (32, 35))	('Cdh23', 'Gene', (58, 63))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('Cdh23', 'Var', (178, 183))	('cancer', 'Disease', (195, 201))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('decreased', 'NegReg', (67, 76))	('TMA', 'Disease', (32, 35))	('decreased', 'NegReg', (105, 114))	('suppresses', 'NegReg', (184, 194))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
492446	30747484	Further, zooming the promoter-region near the 'start' site of Cdh23 at chromosome 10 (73156164-73157954), we observed a CpG island (73156164-73575440) which showed higher methylation for LUAD tumor (n = 463, red) samples than the normal (n = 32, green) cases (Fig.	('methylation', 'MPA', (171, 182))	('Cdh23', 'Gene', (62, 67))	('LUAD tumor', 'Disease', 'MESH:D009369', (187, 197))	('LUAD tumor', 'Disease', (187, 197))	('73156164-73575440', 'Var', (132, 149))	('higher', 'PosReg', (164, 170))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))
492457	30747484	HeLa cells with the least expression of Cdh23 showed no significant change in the migration at 100 pmol (150.6 +- 10.03) or 200 pmol (154.4 +- 5.42) of Cdh23-siRNA compared with scrambled control (149.4 +- 4.86).	('HeLa', 'CellLine', 'CVCL:0030', (0, 4))	('Cdh23-siRNA', 'Var', (152, 163))	('Cdh23', 'Gene', (40, 45))
492459	30747484	5B) with respect to scrambled controls (L132, 152.9 +- 8.13; A549, 151.3 +- 4.8; WRL68, 135.4 +- 8.75), indicating increased cell migration with the silencing of Cdh23.	('increased', 'PosReg', (115, 124))	('cell migration', 'CPA', (125, 139))	('silencing', 'Var', (149, 158))	('Cdh23', 'Gene', (162, 167))	('A549', 'CellLine', 'CVCL:0023', (61, 65))
492462	30747484	As expected, no significant change in RSD was observed for HeLa cells when treated with 100 pmol (7.86 +- 2.59, P = 0.48) or 200 pmol (11.64 +- 2.72, P = 0.093) of Cdh23-siRNA compared with scrambled control (9.11 +- 2.10).	('HeLa', 'CellLine', 'CVCL:0030', (59, 63))	('RSD', 'Disease', (38, 41))	('Cdh23-siRNA', 'Var', (164, 175))	('RSD', 'Disease', 'MESH:D012019', (38, 41))
492463	30747484	L132 showed a decrease in RSD at both 100 pmol (16.62 +- 7.1, P = 0.28) and 200 pmol (15.50 +- 6.29, P = 0.23) compared with scrambled control (18.29 +- 3.15).	('RSD', 'Disease', 'MESH:D012019', (26, 29))	('L132', 'Var', (0, 4))	('decrease', 'NegReg', (14, 22))	('RSD', 'Disease', (26, 29))
492466	30747484	HeLa showed no change in the rate of healing with the silencing of Cdh23.	('silencing', 'Var', (54, 63))	('Cdh23', 'Gene', (67, 72))	('HeLa', 'CellLine', 'CVCL:0030', (0, 4))
492467	30747484	However, for L132 and A549, the rate of healing increased significantly with the increase in Cdh23-siRNA; for A549, there was a significant gap-closure on Day 3 for the Cdh23-siRNA sample treated with 200 pmol.	('increased', 'PosReg', (48, 57))	('healing', 'CPA', (40, 47))	('A549', 'CellLine', 'CVCL:0023', (110, 114))	('gap-closure', 'CPA', (140, 151))	('A549', 'Var', (110, 114))	('A549', 'CellLine', 'CVCL:0023', (22, 26))
492470	30747484	Similarly, RSD from hanging-drop assay showed no significant difference after Day 1 of silencing (Control, 7.83 +- 4.85; Cdh23-siRNA, 8.80 +- 2.37; Ecdh-shRNA, 12.15 +- 6.94; Cdh23 + Ecdh, 11.05 +- 6.56).	('silencing', 'Var', (87, 96))	('RSD', 'Disease', 'MESH:D012019', (11, 14))	('RSD', 'Disease', (11, 14))
492471	30747484	Although silencing of Cdh23 in cancer cells showed no effect on the canonical beta-catenin signal pathway, suggesting that its prevailing function was cell adhesion (Fig.	('cancer', 'Disease', (31, 37))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('silencing', 'Var', (9, 18))	('cell adhesion', 'CPA', (151, 164))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('beta-catenin', 'Gene', (78, 90))	('Cdh23', 'Gene', (22, 27))	('beta-catenin', 'Gene', '1499', (78, 90))
492474	30747484	We noticed a predominant expression of IS2 and IS5 in both protein and mRNA forms, in various cancer cell lines including A549 cells (Figs 6A,B and S9a-j).	('IS2', 'Var', (39, 42))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('IS5', 'Var', (47, 50))	('A549', 'CellLine', 'CVCL:0023', (122, 126))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
492476	30747484	Silencing Cdh23 with siRNA, targeting IS1-5, showed a reduced expression of these isoforms (Fig.	('Cdh23', 'Gene', (10, 15))	('IS1-5', 'Gene', (38, 43))	('expression', 'MPA', (62, 72))	('reduced', 'NegReg', (54, 61))	('IS1-5', 'Gene', '260402;282552;55636;100190785;100190985', (38, 43))	('Silencing', 'Var', (0, 9))
492499	30747484	Moreover, silencing of both Ecdh and Cdh23 resulted in increased cell migration and significant cell disaggregation, suggesting both can have a synergistic effect on cancer cell migration (Fig.	('cancer', 'Disease', (166, 172))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('cell disaggregation', 'CPA', (96, 115))	('increased', 'PosReg', (55, 64))	('cell migration', 'CPA', (65, 79))	('Cdh23', 'Gene', (37, 42))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('Ecdh', 'Gene', (28, 32))	('silencing', 'Var', (10, 19))
492506	30747484	Silencing of Cdh23 in A549 cell lines showed no significant effect on the canonical beta-catenin pathway (Fig.	('Cdh23', 'Gene', (13, 18))	('beta-catenin', 'Gene', (84, 96))	('Silencing', 'Var', (0, 9))	('beta-catenin', 'Gene', '1499', (84, 96))	('A549', 'CellLine', 'CVCL:0023', (22, 26))
492520	30745454	High mRNA expression of PIEZO channels was found to correlate with better overall survival (OS) for NSCLC patients, especially for patients with lung adenocarcinoma (LUAD), but not for patients with lung squamous cell carcinoma (LUSC).	('PIEZO', 'Gene', (24, 29))	('mRNA expression', 'MPA', (5, 20))	('better', 'PosReg', (67, 73))	('lung adenocarcinoma', 'Disease', (145, 164))	('High', 'Var', (0, 4))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (199, 227))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (204, 227))	('LUSC', 'Phenotype', 'HP:0030359', (229, 233))	('NSCLC', 'Disease', 'MESH:D002289', (100, 105))	('LUAD', 'Phenotype', 'HP:0030078', (166, 170))	('patients', 'Species', '9606', (131, 139))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (145, 164))	('NSCLC', 'Disease', (100, 105))	('LUAD', 'Disease', (166, 170))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (199, 227))	('lung squamous cell carcinoma', 'Disease', (199, 227))	('PIEZO', 'Gene', '34112', (24, 29))	('patients', 'Species', '9606', (106, 114))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (145, 164))	('patients', 'Species', '9606', (185, 193))	('carcinoma', 'Phenotype', 'HP:0030731', (155, 164))	('LC', 'Phenotype', 'HP:0100526', (103, 105))	('LUAD', 'Disease', 'None', (166, 170))	('carcinoma', 'Phenotype', 'HP:0030731', (218, 227))	('overall survival', 'MPA', (74, 90))	('OS', 'Chemical', '-', (92, 94))
492522	30745454	Knockdown of PIEZO1 or PIEZO2 in NSCLC cells significantly promoted cell migration in vitro and tumor growth in vivo.	('cell migration', 'CPA', (68, 82))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('PIEZO2', 'Var', (23, 29))	('tumor', 'Disease', (96, 101))	('promoted', 'PosReg', (59, 67))	('LC', 'Phenotype', 'HP:0100526', (36, 38))	('NSCLC', 'Disease', (33, 38))	('PIEZO1', 'Var', (13, 19))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('NSCLC', 'Disease', 'MESH:D002289', (33, 38))
492529	30745454	Research focussing on genetic reasons for NSCLC has demonstrated that epidermal growth factor receptor (EGFR) is the most commonly mutated protein that results in LC.	('NSCLC', 'Disease', (42, 47))	('results in', 'Reg', (152, 162))	('EGFR', 'Gene', (104, 108))	('NSCLC', 'Disease', 'MESH:D002289', (42, 47))	('mutated', 'Var', (131, 138))	('LC', 'Phenotype', 'HP:0100526', (163, 165))	('LC', 'Phenotype', 'HP:0100526', (45, 47))	('epidermal growth factor receptor', 'Gene', (70, 102))	('epidermal growth factor receptor', 'Gene', '1956', (70, 102))	('EGFR', 'Gene', '1956', (104, 108))
492530	30745454	Approximately 90% of EGFR mutations in LC are a result of deletion in exon 19 affecting either the conserved sequence LREA (delE746-A750) or Leucine to Arginine at 858 (L858R) .	('EGFR', 'Gene', '1956', (21, 25))	('L858R', 'Mutation', 'rs121434568', (169, 174))	('EGFR', 'Gene', (21, 25))	('affecting', 'Reg', (78, 87))	('LREA', 'Chemical', '-', (118, 122))	('delE746-A750', 'Var', (124, 136))	('LC', 'Phenotype', 'HP:0100526', (39, 41))	('mutations', 'Var', (26, 35))	('Leucine to Arginine', 'MPA', (141, 160))	('delE746', 'Mutation', 'p.746delE', (124, 131))	('Leucine to Arginine at 858', 'Mutation', 'rs121434568', (141, 167))
492535	30745454	More importantly, various genetic diseases caused by alteration of channel properties are associated with mutations in human PIEZO1 and PIEZO2 genes.	('PIEZO1', 'Gene', (125, 131))	('PIEZO2', 'Gene', (136, 142))	('genetic diseases', 'Disease', (26, 42))	('associated', 'Reg', (90, 100))	('genetic diseases', 'Disease', 'MESH:D030342', (26, 42))	('mutations', 'Var', (106, 115))	('human', 'Species', '9606', (119, 124))
492536	30745454	According to recent research, mutations in the PIEZO1 gene of humans contribute to anemia (dehydrated stomatocytosis) and generalized lymphatic dysplasia.	('anemia', 'Disease', 'MESH:D000740', (83, 89))	('stomatocytosis', 'Phenotype', 'HP:0004446', (102, 116))	('anemia', 'Phenotype', 'HP:0001903', (83, 89))	('dehydrated stomatocytosis', 'Disease', 'MESH:C566369', (91, 116))	('lymphatic dysplasia', 'Disease', (134, 153))	('mutations', 'Var', (30, 39))	('contribute', 'Reg', (69, 79))	('lymphatic dysplasia', 'Disease', 'MESH:D008206', (134, 153))	('humans', 'Species', '9606', (62, 68))	('PIEZO1', 'Gene', (47, 53))	('dehydrated stomatocytosis', 'Disease', (91, 116))	('anemia', 'Disease', (83, 89))
492537	30745454	In vitro experiments show that knockdown of PIEZO1 in lung epithelial cells promotes cell migration and reduces cell adherence, suggesting that lack of PIEZO1 expression may lead to cell migration and metastasis in lung tumors .	('metastasis in lung tumors', 'Disease', (201, 226))	('cell migration', 'CPA', (85, 99))	('cell adherence', 'CPA', (112, 126))	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('metastasis in lung tumors', 'Disease', 'MESH:D009362', (201, 226))	('cell migration', 'CPA', (182, 196))	('tumors', 'Phenotype', 'HP:0002664', (220, 226))	('lung tumors', 'Phenotype', 'HP:0100526', (215, 226))	('reduces', 'NegReg', (104, 111))	('lead to', 'Reg', (174, 181))	('lack', 'Var', (144, 148))	('lung tumor', 'Phenotype', 'HP:0100526', (215, 225))	('PIEZO1', 'Gene', (152, 158))	('promotes', 'PosReg', (76, 84))	('PIEZO1', 'Gene', (44, 50))
492538	30745454	PIEZO2 gene mutations are responsible for distal arthrogryposis and other diseases.	('arthrogryposis', 'Phenotype', 'HP:0002804', (49, 63))	('responsible', 'Reg', (26, 37))	('distal arthrogryposis', 'Phenotype', 'HP:0005684', (42, 63))	('arthrogryposis', 'Disease', (49, 63))	('arthrogryposis', 'Disease', 'MESH:D001176', (49, 63))	('mutations', 'Var', (12, 21))	('PIEZO2', 'Gene', (0, 6))
492539	30745454	PIEZO2 knockdown has been shown to promote anchorage-independent growth in premalignant human fibroblasts.	('anchorage-independent growth', 'CPA', (43, 71))	('PIEZO2', 'Gene', (0, 6))	('promote', 'PosReg', (35, 42))	('human', 'Species', '9606', (88, 93))	('knockdown', 'Var', (7, 16))
492543	30745454	The differentially expressed mRNA for PIEZO1 and 2 in NSCLC samples (GSE10072 and GSE19804) and adjacent non-tumor tissues were used for analysis.	('GSE', 'Chemical', '-', (69, 72))	('GSE', 'Chemical', '-', (82, 85))	('non-tumor', 'Disease', 'MESH:D009369', (105, 114))	('LC', 'Phenotype', 'HP:0100526', (57, 59))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('NSCLC', 'Disease', (54, 59))	('non-tumor', 'Disease', (105, 114))	('GSE19804', 'Var', (82, 90))	('GSE10072', 'Var', (69, 77))	('PIEZO1 and 2', 'Gene', '9780;63895', (38, 50))	('NSCLC', 'Disease', 'MESH:D002289', (54, 59))
492561	30745454	A549 cells cultured on six-well plates (50-60% confluence) were transiently transfected with Veh sh-RNA or sh-PIEZO1 or sh-PIEZO2 (3 microg/well) using a plasmid transfection kit (Qiagen, Inc., Gaithersburg, MD, U.S.A.) according to the manufacturer's instructions.	('sh-PIEZO2', 'Var', (120, 129))	('A549', 'CellLine', 'CVCL:0023', (0, 4))	('sh-PIEZO1', 'Var', (107, 116))
492577	30745454	As shown in Figure 1E-H, the mRNA (E,F) and protein (G,H) expression of PIEZO1 (Figure 1E,G) and PIEZO2 (Figure 1F,H) in cancer tissue from NSCLC patients were significantly lower than that in the adjacent non-cancer tissues.	('PIEZO2', 'Var', (97, 103))	('cancer', 'Disease', (210, 216))	('NSCLC', 'Disease', 'MESH:D002289', (140, 145))	('lower', 'NegReg', (174, 179))	('mRNA', 'MPA', (29, 33))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('PIEZO1', 'Gene', (72, 78))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('cancer', 'Disease', 'MESH:D009369', (210, 216))	('patients', 'Species', '9606', (146, 154))	('cancer', 'Disease', (121, 127))	('LC', 'Phenotype', 'HP:0100526', (143, 145))	('NSCLC', 'Disease', (140, 145))
492579	30745454	We found that there was a high deep deletion rate of PIEZO1 gene in NSCLC (Figure 2A), and a high gene mutation rate of the PIEZO2 gene in NSCLC (Figure 2B).	('deep deletion', 'Var', (31, 44))	('NSCLC', 'Disease', 'MESH:D002289', (68, 73))	('LC', 'Phenotype', 'HP:0100526', (142, 144))	('NSCLC', 'Disease', (139, 144))	('LC', 'Phenotype', 'HP:0100526', (71, 73))	('NSCLC', 'Disease', 'MESH:D002289', (139, 144))	('PIEZO1', 'Gene', (53, 59))	('PIEZO2', 'Gene', (124, 130))	('NSCLC', 'Disease', (68, 73))
492591	30745454	As shown in Table 1, the high expression of PIEZO1 and 2 was strongly correlated with better OS in non-smoking patients, but not in patients who smoked.	('PIEZO1 and 2', 'Gene', '9780;63895', (44, 56))	('OS', 'Chemical', '-', (93, 95))	('high expression', 'Var', (25, 40))	('better OS', 'Disease', (86, 95))	('patients', 'Species', '9606', (132, 140))	('patients', 'Species', '9606', (111, 119))
492596	30745454	As shown in Figure 5A,B,E, F, stable transfection of sh-PIEZO1 (Figure 5A,B) or sh-PIEZO2 (Figure 5E,F) significantly reduced the mRNA and protein expression of the target gene in A549 cells.	('sh-PIEZO2', 'Var', (80, 89))	('reduced', 'NegReg', (118, 125))	('A549', 'CellLine', 'CVCL:0023', (180, 184))
492597	30745454	In comparison with cells with transfection of Veh sh-RNA, cells with stable knockdown of PIEZO1 (Figure 5C,D) or PIEZO2 (Figure 5G,H) promoted cell migration in A549 cells.	('A549', 'CellLine', 'CVCL:0023', (161, 165))	('knockdown', 'Var', (76, 85))	('PIEZO2', 'Gene', (113, 119))	('promoted', 'PosReg', (134, 142))	('cell migration in A549 cells', 'CPA', (143, 171))	('PIEZO1', 'Gene', (89, 95))
492599	30745454	As shown in Figure 6A, the tumors derived after inoculation with sh-PIEZO1-transfected A549 cells grew faster and larger than the mice inoculated with Veh sh-RNA transfected A549 cells in vivo (Figure 6A).	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('mice', 'Species', '10090', (130, 134))	('A549', 'CellLine', 'CVCL:0023', (174, 178))	('A549', 'CellLine', 'CVCL:0023', (87, 91))	('larger', 'PosReg', (114, 120))	('faster', 'PosReg', (103, 109))	('sh-PIEZO1-transfected', 'Var', (65, 86))	('tumors', 'Disease', (27, 33))	('tumors', 'Disease', 'MESH:D009369', (27, 33))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))
492600	30745454	The qPCR data indicate that the xenografts from mice inoculated with A549 cells with stable knockdown of PIEZO1 showed a greatly decreased expression of human PIEZO1 in comparison with those xenografts grown from A549 cells with stable transfection of Veh sh-RNA (Figure 6B).	('A549', 'CellLine', 'CVCL:0023', (213, 217))	('knockdown', 'Var', (92, 101))	('mice', 'Species', '10090', (48, 52))	('PIEZO1', 'Gene', (159, 165))	('A549', 'CellLine', 'CVCL:0023', (69, 73))	('human', 'Species', '9606', (153, 158))	('expression', 'MPA', (139, 149))	('decreased', 'NegReg', (129, 138))	('PIEZO1', 'Gene', (105, 111))
492607	30745454	Furthermore, mutations in human PIEZO1 and PIEZO2 genes have been linked to various genetic diseases due to alterations in channel properties.	('PIEZO2', 'Gene', (43, 49))	('alterations', 'Reg', (108, 119))	('linked', 'Reg', (66, 72))	('genetic diseases', 'Disease', 'MESH:D030342', (84, 100))	('channel properties', 'MPA', (123, 141))	('genetic diseases', 'Disease', (84, 100))	('PIEZO1', 'Gene', (32, 38))	('mutations', 'Var', (13, 22))	('human', 'Species', '9606', (26, 31))
492613	30745454	Stiffness plays a key role in regulating the matricellular protein CCN1/CYR61 in endothelial cells during tumor metastasis, suggesting that target stiffness-induced changes is a potential mechanism to impair tumor metastasis.	('CYR61', 'Gene', (72, 77))	('CYR61', 'Gene', '3491', (72, 77))	('CCN1', 'Gene', (67, 71))	('tumor metastasis', 'Disease', 'MESH:D009362', (106, 122))	('tumor metastasis', 'Disease', (106, 122))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('CCN1', 'Gene', '3491', (67, 71))	('changes', 'Var', (165, 172))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('impair', 'NegReg', (201, 207))	('tumor metastasis', 'Disease', 'MESH:D009362', (208, 224))	('tumor metastasis', 'Disease', (208, 224))
492616	30745454	Human PIEZO1 gene mutations resulted in anemia and generalized lymphatic dysplasia, and PIEZO2 gene mutations were proved to cause distal arthrogryposis and other diseases.	('mutations', 'Var', (100, 109))	('Human', 'Species', '9606', (0, 5))	('arthrogryposis', 'Phenotype', 'HP:0002804', (138, 152))	('lymphatic dysplasia', 'Disease', 'MESH:D008206', (63, 82))	('arthrogryposis', 'Disease', (138, 152))	('PIEZO1', 'Gene', (6, 12))	('anemia', 'Disease', 'MESH:D000740', (40, 46))	('distal arthrogryposis', 'Phenotype', 'HP:0005684', (131, 152))	('anemia', 'Disease', (40, 46))	('arthrogryposis', 'Disease', 'MESH:D001176', (138, 152))	('cause', 'Reg', (125, 130))	('anemia', 'Phenotype', 'HP:0001903', (40, 46))	('resulted in', 'Reg', (28, 39))	('lymphatic dysplasia', 'Disease', (63, 82))	('PIEZO2', 'Gene', (88, 94))	('mutations', 'Var', (18, 27))
492617	30745454	A recent study has shown that PIEZO1 regulates epithelial restitution and cell mobility in gastric cancer cells through interaction with trefoil factor family 1 (TFF1), a member of the TFF-domain peptide family; and knockdown of PIEZO1 expression reduces cell migration in gastric cancer cell lines.	('interaction', 'Interaction', (120, 131))	('regulates', 'Reg', (37, 46))	('gastric cancer', 'Phenotype', 'HP:0012126', (91, 105))	('trefoil factor family 1', 'Gene', '7031', (137, 160))	('gastric cancer', 'Phenotype', 'HP:0012126', (273, 287))	('reduces', 'NegReg', (247, 254))	('TFF1', 'Gene', '7031', (162, 166))	('knockdown', 'Var', (216, 225))	('epithelial restitution', 'CPA', (47, 69))	('PIEZO1', 'Gene', (229, 235))	('TFF1', 'Gene', (162, 166))	('PIEZO1', 'Gene', (30, 36))	('cell mobility', 'CPA', (74, 87))	('gastric cancer', 'Disease', (91, 105))	('gastric cancer', 'Disease', (273, 287))	('trefoil factor family 1', 'Gene', (137, 160))	('gastric cancer', 'Disease', 'MESH:D013274', (91, 105))	('gastric cancer', 'Disease', 'MESH:D013274', (273, 287))	('cancer', 'Phenotype', 'HP:0002664', (281, 287))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
492627	30745454	For PIEZO1, gene expression shows high frequency of deep deletion in human LC tissue.	('PIEZO1', 'Gene', (4, 10))	('LC', 'Phenotype', 'HP:0100526', (75, 77))	('human', 'Species', '9606', (69, 74))	('deep deletion', 'Var', (52, 65))
492633	30745454	Our current study indicated that blocking the function of PIEZOs or knockout of the expression of PIEZOs promotes tumor formation, which may suggest that activators targetting PIEZOs would be a potential candidate for the treatment of NSCLC.	('promotes', 'PosReg', (105, 113))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('PIEZO', 'Gene', (58, 63))	('PIEZO', 'Gene', '34112', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('knockout', 'Var', (68, 76))	('tumor', 'Disease', (114, 119))	('PIEZO', 'Gene', (176, 181))	('NSCLC', 'Disease', (235, 240))	('PIEZO', 'Gene', '34112', (58, 63))	('function', 'MPA', (46, 54))	('LC', 'Phenotype', 'HP:0100526', (238, 240))	('NSCLC', 'Disease', 'MESH:D002289', (235, 240))	('PIEZO', 'Gene', '34112', (176, 181))	('PIEZO', 'Gene', (98, 103))
492640	28139702	However, the same 'actionable mutation' impacts distinct context-specific gene regulatory programs and signalling networks:and interacts with different genetic backgrounds of co-occurring alterations:in different cancers.	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('impacts', 'Reg', (40, 47))	('context-specific', 'MPA', (57, 73))	('mutation', 'Var', (30, 38))	('signalling networks', 'Pathway', (103, 122))	('cancers', 'Disease', 'MESH:D009369', (213, 220))	('cancers', 'Phenotype', 'HP:0002664', (213, 220))	('cancers', 'Disease', (213, 220))	('interacts', 'Reg', (127, 136))
492642	28139702	Our analysis predicts distinct dysregulated transcriptional regulators downstream of somatic alterations in different cancers, and we validate the context-specific differential activity of TFs associated to mutant PIK3CA in isogenic cancer cell line models.	('cancers', 'Disease', (118, 125))	('cancer', 'Disease', (118, 124))	('cancers', 'Disease', 'MESH:D009369', (118, 125))	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('cancer', 'Disease', (233, 239))	('mutant', 'Var', (207, 213))	('cancer', 'Disease', 'MESH:D009369', (233, 239))	('dysregulated transcriptional regulators', 'MPA', (31, 70))	('PIK3CA', 'Gene', (214, 220))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('cancers', 'Phenotype', 'HP:0002664', (118, 125))	('PIK3CA', 'Gene', '5290', (214, 220))
492645	28139702	Large-scale cancer genomics projects such as The Cancer Genome Atlas (TCGA) have generated a comprehensive catalogue of somatic mutations and copy number aberrations across many tumour types.	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('tumour', 'Phenotype', 'HP:0002664', (178, 184))	('mutations', 'Var', (128, 137))	('cancer', 'Disease', (12, 18))	('copy number aberrations', 'Var', (142, 165))	('tumour type', 'Disease', (178, 189))	('tumour type', 'Disease', 'MESH:D009369', (178, 189))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('Cancer', 'Phenotype', 'HP:0002664', (49, 55))
492650	28139702	To this end, we applied a computational strategy for exploiting parallel (phospho)proteomic and mRNA sequencing data for large tumour sets by linking the dysregulation of upstream signalling pathways with altered transcriptional response through the transcriptional circuitry.	('dysregulation', 'Var', (154, 167))	('tumour', 'Phenotype', 'HP:0002664', (127, 133))	('tumour', 'Disease', 'MESH:D009369', (127, 133))	('upstream signalling pathways', 'Pathway', (171, 199))	('transcriptional response', 'MPA', (213, 237))	('tumour', 'Disease', (127, 133))
492654	28139702	By stratifying tumours by inferred TF activities rather than gene expression patterns, we identified known and previously unlinked TFs that are differentially active in HPV(+) versus HPV(-) head and neck squamous cancer, and we uncovered a subtype of endometrioid uterine cancer harbouring mutant beta-catenin with altered TF activities.	('uterine cancer', 'Phenotype', 'HP:0010784', (264, 278))	('cancer', 'Phenotype', 'HP:0002664', (272, 278))	('squamous cancer', 'Phenotype', 'HP:0002860', (204, 219))	('neck squamous cancer', 'Disease', 'MESH:D006258', (199, 219))	('head and neck squamous cancer', 'Phenotype', 'HP:0012288', (190, 219))	('HPV', 'Species', '10566', (169, 172))	('cancer', 'Disease', 'MESH:D009369', (272, 278))	('activities', 'MPA', (326, 336))	('cancer', 'Disease', (213, 219))	('HPV', 'Disease', (169, 172))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('expression', 'Species', '29278', (66, 76))	('tumours', 'Disease', (15, 22))	('HPV', 'Species', '10566', (183, 186))	('neck squamous cancer', 'Disease', (199, 219))	('tumours', 'Phenotype', 'HP:0002664', (15, 22))	('tumours', 'Disease', 'MESH:D009369', (15, 22))	('cancer', 'Disease', 'MESH:D009369', (213, 219))	('beta-catenin', 'Gene', (297, 309))	('cancer', 'Disease', (272, 278))	('tumour', 'Phenotype', 'HP:0002664', (15, 21))	('mutant', 'Var', (290, 296))	('beta-catenin', 'Gene', '1499', (297, 309))
492656	28139702	This analysis identified key regulators associated with the major mutations in renal clear-cell carcinoma.	('mutations', 'Var', (66, 75))	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('renal clear-cell carcinoma', 'Phenotype', 'HP:0006770', (79, 105))	('renal clear-cell carcinoma', 'Disease', 'MESH:C538614', (79, 105))	('renal clear-cell carcinoma', 'Disease', (79, 105))
492658	28139702	In particular, we associated PIK3CA activating mutations with altered activities of distinct sets of TFs in different cancers.	('cancers', 'Disease', (118, 125))	('cancers', 'Phenotype', 'HP:0002664', (118, 125))	('cancers', 'Disease', 'MESH:D009369', (118, 125))	('activities', 'MPA', (70, 80))	('mutations', 'Var', (47, 56))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('TFs', 'Gene', (101, 104))	('PIK3CA', 'Gene', (29, 35))	('PIK3CA', 'Gene', '5290', (29, 35))	('activating', 'PosReg', (36, 46))
492659	28139702	Notably, in isogenic cell line models of breast cancer and head and neck cancer, we validated the altered activity of several TFs in the presence of mutant PIK3CA by measuring promoter occupancy and expression of target genes, confirming the context-specific predictions of our model.	('expression', 'Species', '29278', (199, 209))	('breast cancer', 'Disease', 'MESH:D001943', (41, 54))	('promoter occupancy', 'MPA', (176, 194))	('head and neck cancer', 'Phenotype', 'HP:0012288', (59, 79))	('expression', 'MPA', (199, 209))	('PIK3CA', 'Gene', '5290', (156, 162))	('breast cancer', 'Disease', (41, 54))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('mutant', 'Var', (149, 155))	('breast cancer', 'Phenotype', 'HP:0003002', (41, 54))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('head and neck cancer', 'Disease', 'MESH:D006258', (59, 79))	('activity', 'MPA', (106, 114))	('altered', 'Reg', (98, 105))	('PIK3CA', 'Gene', (156, 162))
492688	28139702	Head and neck squamous cancer is frequently associated with human papillomavirus (HPV) infection and mutations in TP53.	('associated', 'Reg', (44, 54))	('papillomavirus (HPV) infection', 'Disease', 'MESH:D030361', (66, 96))	('neck squamous cancer', 'Disease', (9, 29))	('mutations', 'Var', (101, 110))	('TP53', 'Gene', '7157', (114, 118))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('neck squamous cancer', 'Disease', 'MESH:D006258', (9, 29))	('TP53', 'Gene', (114, 118))	('squamous cancer', 'Phenotype', 'HP:0002860', (14, 29))	('human', 'Species', '9606', (60, 65))
492697	28139702	As described previously, mutant TP53 tends to be mutually exclusive with HPV(+) status, but inferred TP53 TF activity and inferred p53 protein activity were not significantly different between HPV(+) and HPV(-) patients (t-test P=0.477 and P=0.741, respectively).	('mutant', 'Var', (25, 31))	('patients', 'Species', '9606', (211, 219))	('TP53', 'Gene', '7157', (101, 105))	('TP53', 'Gene', '7157', (32, 36))	('HPV', 'Species', '10566', (73, 76))	('p53', 'Gene', (131, 134))	('HPV', 'Species', '10566', (193, 196))	('p53', 'Gene', '7157', (131, 134))	('HPV', 'Species', '10566', (204, 207))	('TP53', 'Gene', (101, 105))	('TP53', 'Gene', (32, 36))
492702	28139702	Serous-like endometrial tumours are hormone receptor negative, mostly copy number high, and harbour mutations in TP53, whereas endometrioid tumours are hormone receptor positive, copy number low, and have a high frequency of PI3K-AKT (phosphatidylinositol 3-kinase-AKT) pathway alterations.	('tumour', 'Phenotype', 'HP:0002664', (140, 146))	('AKT', 'Gene', (230, 233))	('alterations', 'Reg', (278, 289))	('tumours', 'Phenotype', 'HP:0002664', (140, 147))	('hormone receptor', 'Gene', (152, 168))	('hormone receptor', 'Gene', '3164', (36, 52))	('endometrioid tumours', 'Disease', 'MESH:D016889', (127, 147))	('AKT', 'Gene', '207', (230, 233))	('TP53', 'Gene', (113, 117))	('tumour', 'Phenotype', 'HP:0002664', (24, 30))	('endometrial tumours', 'Disease', (12, 31))	('AKT', 'Gene', (265, 268))	('tumours', 'Phenotype', 'HP:0002664', (24, 31))	('hormone receptor', 'Gene', (36, 52))	('endometrioid tumours', 'Disease', (127, 147))	('hormone receptor', 'Gene', '3164', (152, 168))	('mutations', 'Var', (100, 109))	('endometrial tumours', 'Disease', 'MESH:D016889', (12, 31))	('TP53', 'Gene', '7157', (113, 117))	('AKT', 'Gene', '207', (265, 268))
492704	28139702	Importantly, clustering by TF activities revealed subclasses of tumours within each histological subtype that sometimes correlated with mutation status.	('tumours', 'Phenotype', 'HP:0002664', (64, 71))	('mutation', 'Var', (136, 144))	('tumours', 'Disease', 'MESH:D009369', (64, 71))	('tumours', 'Disease', (64, 71))	('correlated', 'Reg', (120, 130))	('tumour', 'Phenotype', 'HP:0002664', (64, 70))
492705	28139702	In particular, endometrioid tumours with a CTNNB1 mutation form a distinct cluster based on inferred TF activity profiles that was not observed by clustering TF mRNA expression levels directly (Supplementary Fig.	('tumour', 'Phenotype', 'HP:0002664', (28, 34))	('endometrioid tumours', 'Disease', (15, 35))	('endometrioid tumours', 'Disease', 'MESH:D016889', (15, 35))	('mutation', 'Var', (50, 58))	('CTNNB1', 'Gene', '1499', (43, 49))	('tumours', 'Phenotype', 'HP:0002664', (28, 35))	('expression', 'Species', '29278', (166, 176))	('CTNNB1', 'Gene', (43, 49))
492706	28139702	Moreover, clustering based on inferred TF activity was better able to stratify patients by CTNNB1 mutation status (P<10-17, two-sided chi2 test for all tests) compared to reported TCGA mRNA clusters (P<0.01) and TCGA integrated clusters (P<10-6) (Supplementary Tables 9 and 10).	('CTNNB1', 'Gene', '1499', (91, 97))	('mutation', 'Var', (98, 106))	('patients', 'Species', '9606', (79, 87))	('CTNNB1', 'Gene', (91, 97))
492707	28139702	Significant inferred TF activity differences between CTNNB1 mutant and WT patients (satisfying FDR-corrected P<0.01, t-test) associated CTNNB1 mutant status with altered activity of TFs involved in WNT signalling, epithelial-mesenchymal transition and cancer stem cell transition including TCF4 (transcriptional factor 4), NFATC4, JUN, TP53, MAX, MYC, STAT3 and KLF12 (Fig.	('cancer', 'Disease', 'MESH:D009369', (252, 258))	('KLF12', 'Gene', (362, 367))	('STAT3', 'Gene', '6774', (352, 357))	('NFATC4', 'Gene', (323, 329))	('CTNNB1', 'Gene', '1499', (136, 142))	('KLF12', 'Gene', '11278', (362, 367))	('MYC', 'Gene', '4609', (347, 350))	('TP53', 'Gene', '7157', (336, 340))	('TCF4', 'Gene', '6925', (290, 294))	('TP53', 'Gene', (336, 340))	('mutant', 'Var', (143, 149))	('CTNNB1', 'Gene', (136, 142))	('cancer', 'Disease', (252, 258))	('patients', 'Species', '9606', (74, 82))	('CTNNB1', 'Gene', '1499', (53, 59))	('transcriptional factor 4', 'Gene', (296, 320))	('transcriptional factor 4', 'Gene', '6925', (296, 320))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('TCF4', 'Gene', (290, 294))	('epithelial-mesenchymal transition', 'CPA', (214, 247))	('MYC', 'Gene', (347, 350))	('activity', 'MPA', (170, 178))	('altered', 'Reg', (162, 169))	('STAT3', 'Gene', (352, 357))	('NFATC4', 'Gene', '4776', (323, 329))	('mutant', 'Var', (60, 66))	('CTNNB1', 'Gene', (53, 59))
492708	28139702	We confirmed these results in an independent data set of 203 endometrial RPPA profiles along with mutation and clinical data compiled by MDACC, using the UCEC TCGA-trained AR model to infer TF activities, and replicated many of the TFs associated with mutant CTNBB1 (P<10-5, Mann-Whitney test; Fig.	('CTNBB1', 'Gene', (259, 265))	('mutant', 'Var', (252, 258))	('P<10-5', 'Gene', (267, 273))	('P<10-5', 'Gene', '4790', (267, 273))
492709	28139702	Interestingly, another study performed customized consensus clustering on TCGA UCEC expression data and did identify a cluster enriched with beta-catenin mutations, and GSEA (gene set enrichment analysis) suggested an association with WNT signalling, consistent with our analysis.	('association', 'Interaction', (218, 229))	('WNT signalling', 'Pathway', (235, 249))	('beta-catenin', 'Gene', (141, 153))	('GSEA', 'Chemical', '-', (169, 173))	('beta-catenin', 'Gene', '1499', (141, 153))	('expression', 'Species', '29278', (84, 94))	('mutations', 'Var', (154, 163))
492710	28139702	Encouraged by our findings for mutant CTNBB1 endometrioid tumours, we developed a systematic statistical approach for modelling the impact of somatic alterations on regulator activity in each tumour type, with the eventual goal of deciphering cancer-specific downstream effects of targeted therapies and potentially discovering secondary targets for combination drug strategies.	('CTNBB1', 'Gene', (38, 44))	('cancer', 'Phenotype', 'HP:0002664', (243, 249))	('mutant', 'Var', (31, 37))	('tumour', 'Phenotype', 'HP:0002664', (192, 198))	('tumours', 'Phenotype', 'HP:0002664', (58, 65))	('tumour', 'Phenotype', 'HP:0002664', (58, 64))	('cancer', 'Disease', (243, 249))	('tumour type', 'Disease', (192, 203))	('tumour type', 'Disease', 'MESH:D009369', (192, 203))	('cancer', 'Disease', 'MESH:D009369', (243, 249))	('endometrioid tumours', 'Disease', (45, 65))	('endometrioid tumours', 'Disease', 'MESH:D016889', (45, 65))
492713	28139702	Combining these results identified a set of regulators predicted to be significantly dysregulated by each somatic alteration in each TCGA cancer study.	('cancer', 'Disease', (138, 144))	('TCGA', 'Disease', (133, 137))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('alteration', 'Var', (114, 124))	('cancer', 'Disease', 'MESH:D009369', (138, 144))
492714	28139702	Our model identified mutations in VHL (von Hippel-Lindau), PBMR1, BAP1, MTOR, ATM, SETD2, KDM5C and PTEN (phosphatase and tensin homolog), as well as copy number changes in MLH1, DUSP1 and RANDBP17 as significantly associated with various TF activity changes across tumours.	('PTEN', 'Gene', (100, 104))	('DUSP1', 'Gene', '1843', (179, 184))	('tumours', 'Disease', 'MESH:D009369', (266, 273))	('BAP1', 'Gene', (66, 70))	('SETD2', 'Gene', '29072', (83, 88))	('ATM', 'Gene', '472', (78, 81))	('tumour', 'Phenotype', 'HP:0002664', (266, 272))	('associated', 'Reg', (215, 225))	('PTEN', 'Gene', '5728', (100, 104))	('MLH1', 'Gene', (173, 177))	('KDM5C', 'Gene', '8242', (90, 95))	('von Hippel-Lindau', 'Gene', '7428', (39, 56))	('PBMR1', 'Gene', (59, 64))	('copy number changes', 'Var', (150, 169))	('DUSP1', 'Gene', (179, 184))	('MLH1', 'Gene', '4292', (173, 177))	('MTOR', 'Gene', (72, 76))	('ATM', 'Gene', (78, 81))	('activity', 'MPA', (242, 250))	('MTOR', 'Gene', '2475', (72, 76))	('VHL', 'Gene', (34, 37))	('mutations', 'Var', (21, 30))	('KDM5C', 'Gene', (90, 95))	('BAP1', 'Gene', '8314', (66, 70))	('tumours', 'Disease', (266, 273))	('RANDBP17', 'Gene', (189, 197))	('SETD2', 'Gene', (83, 88))	('von Hippel-Lindau', 'Gene', (39, 56))	('VHL', 'Gene', '7428', (34, 37))	('tumours', 'Phenotype', 'HP:0002664', (266, 273))
492715	28139702	KIRC is characterized by a high-frequency inactivating mutation in the VHL gene found in ~54% of tumours in TCGA and likely more prevalent.	('tumours', 'Disease', (97, 104))	('VHL', 'Gene', (71, 74))	('inactivating mutation', 'Var', (42, 63))	('VHL', 'Gene', '7428', (71, 74))	('tumour', 'Phenotype', 'HP:0002664', (97, 103))	('tumours', 'Phenotype', 'HP:0002664', (97, 104))	('tumours', 'Disease', 'MESH:D009369', (97, 104))
492716	28139702	Mutually exclusive mutations in PBRM1, a subunit of the PBAF SWI/SNF chromatin remodelling complex, and in histone deubiquitinase BAP1 define two genetic subtypes of KIRC, while recurrent mutations in the histone methyltransferase SETD2 also occur.	('PBRM1', 'Gene', (32, 37))	('BAP1', 'Gene', (130, 134))	('PBRM1', 'Gene', '55193', (32, 37))	('SETD2', 'Gene', (231, 236))	('mutations', 'Var', (19, 28))	('BAP1', 'Gene', '8314', (130, 134))	('SETD2', 'Gene', '29072', (231, 236))
492717	28139702	KIRC samples with PBMR1 and BAP1 mutations showed distinct patterns of TF and protein activities (Fig.	('BAP1', 'Gene', '8314', (28, 32))	('PBMR1', 'Gene', (18, 23))	('BAP1', 'Gene', (28, 32))	('mutations', 'Var', (33, 42))
492718	28139702	PBMR1 mutant tumours are associated with increased activity of TFs/(phospho)proteins that have roles in interleukin signalling and MYC, while regulators with increased activity in BAP1 mutant tumours are involved in DNA damage response, apoptosis, insulin signalling and mTOR signalling.	('TFs/', 'Protein', (63, 67))	('tumour', 'Phenotype', 'HP:0002664', (13, 19))	('MYC', 'Gene', (131, 134))	('tumours', 'Disease', (192, 199))	('mTOR', 'Gene', (271, 275))	('insulin', 'Gene', '3630', (248, 255))	('tumours', 'Phenotype', 'HP:0002664', (192, 199))	('BAP1', 'Gene', '8314', (180, 184))	('tumours', 'Disease', 'MESH:D009369', (192, 199))	('mTOR', 'Gene', '2475', (271, 275))	('MYC', 'Gene', '4609', (131, 134))	('tumour', 'Phenotype', 'HP:0002664', (192, 198))	('tumours', 'Disease', (13, 20))	('BAP1', 'Gene', (180, 184))	('insulin', 'Gene', (248, 255))	('activity', 'MPA', (51, 59))	('mutant', 'Var', (6, 12))	('increased', 'PosReg', (41, 50))	('tumours', 'Phenotype', 'HP:0002664', (13, 20))	('PBMR1', 'Gene', (0, 5))	('tumours', 'Disease', 'MESH:D009369', (13, 20))
492719	28139702	Notably, NFE2L2 TF activity was significantly higher in BAP1 mutant tumours than PBMR1 mutant tumours.	('tumours', 'Disease', (94, 101))	('tumour', 'Phenotype', 'HP:0002664', (68, 74))	('tumours', 'Phenotype', 'HP:0002664', (68, 75))	('higher', 'PosReg', (46, 52))	('BAP1', 'Gene', '8314', (56, 60))	('tumours', 'Disease', 'MESH:D009369', (68, 75))	('activity', 'MPA', (19, 27))	('tumours', 'Disease', (68, 75))	('BAP1', 'Gene', (56, 60))	('NFE2L2', 'Gene', '4780', (9, 15))	('mutant', 'Var', (61, 67))	('tumours', 'Phenotype', 'HP:0002664', (94, 101))	('tumour', 'Phenotype', 'HP:0002664', (94, 100))	('NFE2L2', 'Gene', (9, 15))	('tumours', 'Disease', 'MESH:D009369', (94, 101))
492721	28139702	Mutations in KEAP1, NFE2L2 (Nrf2), CUL3 or RBX1 are the most common mechanisms that impair KEAP1-mediated degradation of NFE2L2 and thereby activate the transcriptional effects of NFE2L2.	('KEAP1', 'Gene', (91, 96))	('NFE2L2', 'Gene', '4780', (20, 26))	('RBX1', 'Gene', '9978', (43, 47))	('Nrf2', 'Gene', (28, 32))	('impair', 'NegReg', (84, 90))	('NFE2L2', 'Gene', (180, 186))	('activate', 'PosReg', (140, 148))	('NFE2L2', 'Gene', '4780', (121, 127))	('NFE2L2', 'Gene', (20, 26))	('Mutations', 'Var', (0, 9))	('CUL3', 'Gene', (35, 39))	('RBX1', 'Gene', (43, 47))	('NFE2L2', 'Gene', (121, 127))	('degradation', 'MPA', (106, 117))	('KEAP1', 'Gene', '9817', (13, 18))	('transcriptional effects', 'MPA', (153, 176))	('KEAP1', 'Gene', (13, 18))	('Nrf2', 'Gene', '4780', (28, 32))	('NFE2L2', 'Gene', '4780', (180, 186))	('KEAP1', 'Gene', '9817', (91, 96))	('CUL3', 'Gene', '8452', (35, 39))
492722	28139702	Inferred TF activity of NFE2L2 was increased in mutant versus WT KEAP1 or NFE2L2 lung cancers; these differences are not observed at the gene expression level (Supplementary Fig.	('NFE2L2', 'Gene', '4780', (74, 80))	('increased', 'PosReg', (35, 44))	('mutant', 'Var', (48, 54))	('TF activity', 'MPA', (9, 20))	('NFE2L2', 'Gene', '4780', (24, 30))	('lung cancer', 'Phenotype', 'HP:0100526', (81, 92))	('KEAP1', 'Gene', (65, 70))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('lung cancers', 'Disease', 'MESH:D008175', (81, 93))	('NFE2L2', 'Gene', (24, 30))	('NFE2L2', 'Gene', (74, 80))	('lung cancers', 'Phenotype', 'HP:0100526', (81, 93))	('expression', 'Species', '29278', (142, 152))	('cancers', 'Phenotype', 'HP:0002664', (86, 93))	('lung cancers', 'Disease', (81, 93))	('KEAP1', 'Gene', '9817', (65, 70))
492723	28139702	In samples where VHL was comutated with PBMR1, SMAD1 (interaction P<0.0003) and KLF12 (interaction P<0.05) activity were significantly decreased.	('SMAD1', 'Gene', (47, 52))	('PBMR1', 'Gene', (40, 45))	('activity', 'MPA', (107, 115))	('comutated', 'Var', (25, 34))	('KLF12', 'Gene', '11278', (80, 85))	('VHL', 'Gene', (17, 20))	('decreased', 'NegReg', (135, 144))	('VHL', 'Gene', '7428', (17, 20))	('KLF12', 'Gene', (80, 85))	('SMAD1', 'Gene', '4086', (47, 52))
492725	28139702	The PI3K pathway controls proliferation, metabolism, survival and motility and is frequently activated in many cancers, often via mutations in PIK3CA, which encodes the alpha-isoform of the p110 catalytic subunit of PI3K (PI3Kalpha); loss of PTEN, which antagonizes PI3K function; and overexpression of membrane-bound receptor tyrosine kinase.	('cancers', 'Disease', 'MESH:D009369', (111, 118))	('cancers', 'Phenotype', 'HP:0002664', (111, 118))	('loss', 'Var', (234, 238))	('cancers', 'Disease', (111, 118))	('PI3Kalpha', 'Gene', (222, 231))	('PIK3CA', 'Gene', (143, 149))	('PTEN', 'Gene', (242, 246))	('motility', 'CPA', (66, 74))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('PTEN', 'Gene', '5728', (242, 246))	('expression', 'Species', '29278', (289, 299))	('PI3K pathway', 'Pathway', (4, 16))	('mutations', 'Var', (130, 139))	('PI3Kalpha', 'Gene', '5290', (222, 231))	('PIK3CA', 'Gene', '5290', (143, 149))	('activated', 'PosReg', (93, 102))	('proliferation', 'CPA', (26, 39))	('overexpression', 'PosReg', (285, 299))
492729	28139702	Mutations often occur in one of three hotspot locations (E545K, E542K and H1047) and promote constitutive signalling though the pathway.	('E542K', 'Mutation', 'rs121913273', (64, 69))	('E545K', 'Var', (57, 62))	('promote', 'PosReg', (85, 92))	('H1047', 'Var', (74, 79))	('E542K', 'Var', (64, 69))	('E545K', 'Mutation', 'rs104886003', (57, 62))	('constitutive signalling', 'MPA', (93, 116))
492730	28139702	In UCEC, ~66% of tumours have PTEN inactivating mutations, ~50% have PIK3CA activating mutations and ~35% have a comutation of PTEN and PIK3CA.	('PIK3CA', 'Gene', (136, 142))	('tumour', 'Phenotype', 'HP:0002664', (17, 23))	('tumours', 'Phenotype', 'HP:0002664', (17, 24))	('activating', 'PosReg', (76, 86))	('PIK3CA', 'Gene', '5290', (136, 142))	('PIK3CA', 'Gene', '5290', (69, 75))	('inactivating', 'NegReg', (35, 47))	('PIK3CA', 'Gene', (69, 75))	('tumours', 'Disease', (17, 24))	('tumours', 'Disease', 'MESH:D009369', (17, 24))	('PTEN', 'Gene', (127, 131))	('PTEN', 'Gene', (30, 34))	('comutation', 'Var', (113, 123))	('PTEN', 'Gene', '5728', (127, 131))	('PTEN', 'Gene', '5728', (30, 34))
492732	28139702	Notably, the number of TFs dysregulated by PI3K pathway alterations varied widely across different cancers (9 in HNSC, 65 in BRCA and 63 in UCEC), with striking changes in ErbB/MAPK, mTOR, HIF-1, VEGF and PI3K-Akt pathways.	('PI3K', 'Gene', (43, 47))	('BRCA', 'Gene', '672', (125, 129))	('HNSC', 'Disease', (113, 117))	('mTOR', 'Gene', (183, 187))	('cancers', 'Disease', 'MESH:D009369', (99, 106))	('BRCA', 'Gene', (125, 129))	('ErbB', 'Gene', '1956', (172, 176))	('Akt', 'Gene', (210, 213))	('HIF-1', 'Gene', (189, 194))	('mTOR', 'Gene', '2475', (183, 187))	('HIF-1', 'Gene', '29072', (189, 194))	('Akt', 'Gene', '207', (210, 213))	('VEGF', 'Gene', '7422', (196, 200))	('alterations', 'Var', (56, 67))	('cancers', 'Phenotype', 'HP:0002664', (99, 106))	('changes', 'Reg', (161, 168))	('cancers', 'Disease', (99, 106))	('VEGF', 'Gene', (196, 200))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('ErbB', 'Gene', (172, 176))
492733	28139702	Only ELK1, a TF downstream of the MAPK/ERK pathway, is dysregulated by PIK3CA or PTEN mutations in all three cancers.	('mutations', 'Var', (86, 95))	('PIK3CA', 'Gene', '5290', (71, 77))	('cancers', 'Disease', 'MESH:D009369', (109, 116))	('cancers', 'Phenotype', 'HP:0002664', (109, 116))	('PTEN', 'Gene', '5728', (81, 85))	('ELK1', 'Gene', (5, 9))	('cancers', 'Disease', (109, 116))	('ERK', 'Gene', '2048', (39, 42))	('ELK1', 'Gene', '2002', (5, 9))	('ERK', 'Gene', (39, 42))	('PTEN', 'Gene', (81, 85))	('dysregulated', 'Reg', (55, 67))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('PIK3CA', 'Gene', (71, 77))
492736	28139702	Interestingly, many TF activities were associated with mutant PTEN irrespective of PIK3CA status in endometrial cancer (Supplementary Fig.	('PTEN', 'Gene', (62, 66))	('PTEN', 'Gene', '5728', (62, 66))	('endometrial cancer', 'Disease', (100, 118))	('endometrial cancer', 'Phenotype', 'HP:0012114', (100, 118))	('mutant', 'Var', (55, 61))	('endometrial cancer', 'Disease', 'MESH:D016889', (100, 118))	('PIK3CA', 'Gene', (83, 89))	('associated', 'Reg', (39, 49))	('PIK3CA', 'Gene', '5290', (83, 89))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('activities', 'MPA', (23, 33))
492737	28139702	19), consistent with a recent preclinical study, while PIK3CA mutations were only significantly associated with a single TF, CREB1.	('CREB1', 'Gene', '1385', (125, 130))	('associated', 'Reg', (96, 106))	('CREB1', 'Gene', (125, 130))	('PIK3CA', 'Gene', (55, 61))	('PIK3CA', 'Gene', '5290', (55, 61))	('mutations', 'Var', (62, 71))
492738	28139702	Therefore, PTEN and PIK3CA appear to have distinct consequences for PI3K activation in UCEC.	('PTEN', 'Gene', (11, 15))	('activation', 'PosReg', (73, 83))	('PTEN', 'Gene', '5728', (11, 15))	('PIK3CA', 'Gene', (20, 26))	('PIK3CA', 'Gene', '5290', (20, 26))	('PI3K', 'Var', (68, 72))	('UCEC', 'Disease', (87, 91))
492739	28139702	PI3K pathway inhibition is known to alter STAT5 (ref.	('inhibition', 'Var', (13, 23))	('PI3K pathway', 'Pathway', (0, 12))	('STAT5', 'Gene', '6776', (42, 47))	('STAT5', 'Gene', (42, 47))
492743	28139702	We also examined protein microarray-based AKT1 kinase assay and SILAC-based phosphoproteomic data from isogenic knock-in breast cell lines harbouring mutations of PIK3CA (see Methods section).	('AKT1', 'Gene', '207', (42, 46))	('AKT1', 'Gene', (42, 46))	('PIK3CA', 'Gene', (163, 169))	('mutations', 'Var', (150, 159))	('PIK3CA', 'Gene', '5290', (163, 169))
492744	28139702	Of 11 TFs represented in the phosphoproteomic data and associated with mutant PIK3CA in BRCA, eight of them:ADD1, FOXO3, HMGA1, HSF1, JUND, NF1, POU2F1, STAT3:showed protein abundance change in isogenic cell line systems (see Methods section and Supplementary Table 12).	('PIK3CA', 'Gene', (78, 84))	('STAT3', 'Gene', '6774', (153, 158))	('ADD1', 'Gene', (108, 112))	('POU2F1', 'Gene', (145, 151))	('HMGA1', 'Gene', (121, 126))	('FOXO3', 'Gene', '2309', (114, 119))	('ADD1', 'Gene', '118', (108, 112))	('mutant', 'Var', (71, 77))	('HSF1', 'Gene', '3297', (128, 132))	('NF1', 'Gene', '4763', (140, 143))	('HSF1', 'Gene', (128, 132))	('HMGA1', 'Gene', '3159', (121, 126))	('JUND', 'Gene', (134, 138))	('PIK3CA', 'Gene', '5290', (78, 84))	('NF1', 'Gene', (140, 143))	('JUND', 'Gene', '3727', (134, 138))	('change', 'Reg', (184, 190))	('BRCA', 'Gene', '672', (88, 92))	('STAT3', 'Gene', (153, 158))	('POU2F1', 'Gene', '5451', (145, 151))	('FOXO3', 'Gene', (114, 119))	('BRCA', 'Gene', (88, 92))	('protein abundance', 'MPA', (166, 183))
492745	28139702	Moreover, of the six TFs represented in the AKT1 kinase assay and associated with mutant PIK3CA in BRCA, four of them:ETS1, ATF6, SOX9 and TEAD1:were identified as AKT substrates (Supplementary Table 13).	('PIK3CA', 'Gene', '5290', (89, 95))	('AKT1', 'Gene', '207', (44, 48))	('ETS1', 'Gene', (118, 122))	('mutant', 'Var', (82, 88))	('AKT', 'Gene', (164, 167))	('AKT', 'Gene', (44, 47))	('BRCA', 'Gene', '672', (99, 103))	('SOX9', 'Gene', (130, 134))	('AKT1', 'Gene', (44, 48))	('PIK3CA', 'Gene', (89, 95))	('ATF6', 'Gene', (124, 128))	('AKT', 'Gene', '207', (164, 167))	('TEAD1', 'Gene', (139, 144))	('BRCA', 'Gene', (99, 103))	('SOX9', 'Gene', '6662', (130, 134))	('AKT', 'Gene', '207', (44, 47))	('TEAD1', 'Gene', '7003', (139, 144))	('ETS1', 'Gene', '2113', (118, 122))	('ATF6', 'Gene', '22926', (124, 128))
492746	28139702	Our analysis associated mutant PIK3CA with ELK1 and TCF4 activity in both breast and head and neck cancer, and with FOXO1 activity in BRCA but not in head and neck cancer.	('BRCA', 'Gene', '672', (134, 138))	('head and neck cancer', 'Disease', 'MESH:D006258', (150, 170))	('ELK1', 'Gene', (43, 47))	('activity', 'MPA', (57, 65))	('mutant', 'Var', (24, 30))	('head and neck cancer', 'Phenotype', 'HP:0012288', (85, 105))	('FOXO1', 'Gene', '2308', (116, 121))	('BRCA', 'Gene', (134, 138))	('PIK3CA', 'Gene', '5290', (31, 37))	('FOXO1', 'Gene', (116, 121))	('TCF4', 'Gene', '6925', (52, 56))	('head and neck cancer', 'Disease', 'MESH:D006258', (85, 105))	('ELK1', 'Gene', '2002', (43, 47))	('breast', 'Disease', (74, 80))	('head and neck cancer', 'Phenotype', 'HP:0012288', (150, 170))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('TCF4', 'Gene', (52, 56))	('PIK3CA', 'Gene', (31, 37))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('activity', 'MPA', (122, 130))
492748	28139702	First, we used the parental MCF7 cell line carrying the PIK3CA E545K mutation and an MCF7 PIK3CA WT cell line in which the mutation was corrected using gene targeting.	('MCF7', 'CellLine', 'CVCL:0031', (28, 32))	('E545K', 'Mutation', 'rs104886003', (63, 68))	('E545K', 'Var', (63, 68))	('PIK3CA', 'Gene', (56, 62))	('PIK3CA', 'Gene', (90, 96))	('MCF7', 'CellLine', 'CVCL:0031', (85, 89))	('PIK3CA', 'Gene', '5290', (56, 62))	('PIK3CA', 'Gene', '5290', (90, 96))
492751	28139702	), WNK1, PAPLN, FOXP4 and DDX27 confirmed significant increases in mRNA levels in the parental PIK3CA mutant cells compared to PIK3CA WT cells, with the exception of PAPLN, where we observed a significant decrease (Fig.	('mutant', 'Var', (102, 108))	('PAPLN', 'Gene', (166, 171))	('WNK1', 'Gene', (3, 7))	('PIK3CA', 'Gene', (95, 101))	('DDX27', 'Gene', '55661', (26, 31))	('PAPLN', 'Gene', (9, 14))	('PIK3CA', 'Gene', '5290', (95, 101))	('DDX27', 'Gene', (26, 31))	('mRNA levels', 'MPA', (67, 78))	('PIK3CA', 'Gene', (127, 133))	('FOXP4', 'Gene', '116113', (16, 21))	('PIK3CA', 'Gene', '5290', (127, 133))	('increases', 'PosReg', (54, 63))	('FOXP4', 'Gene', (16, 21))	('WNK1', 'Gene', '65125', (3, 7))	('PAPLN', 'Gene', '89932', (166, 171))	('PAPLN', 'Gene', '89932', (9, 14))
492752	28139702	Moreover, ChIP-qPCR experiments confirmed that ELK1 binding to all five target gene promoters was significantly increased in the PIK3CA mutant MCF7 compared to WT cells, showing that mutant PIK3CA enhances ELK1 transcriptional activity in BRCA cells (Fig.	('enhances', 'PosReg', (197, 205))	('PIK3CA', 'Gene', '5290', (190, 196))	('PIK3CA', 'Gene', (129, 135))	('mutant', 'Var', (183, 189))	('PIK3CA', 'Gene', '5290', (129, 135))	('binding', 'Interaction', (52, 59))	('ELK1', 'Gene', (47, 51))	('transcriptional activity', 'MPA', (211, 235))	('increased', 'PosReg', (112, 121))	('ELK1', 'Gene', '2002', (47, 51))	('PIK3CA', 'Gene', (190, 196))	('BRCA', 'Gene', '672', (239, 243))	('MCF7', 'CellLine', 'CVCL:0031', (143, 147))	('ELK1', 'Gene', (206, 210))	('mutant', 'Var', (136, 142))	('ELK1', 'Gene', '2002', (206, 210))	('BRCA', 'Gene', (239, 243))
492753	28139702	Well-known TCF4 target genes such as WNT10B, APC, FBXW11 and PPP2R5E were differentially regulated by the PIK3CA E545K mutation in MCF7 cells (Fig.	('WNT10B', 'Gene', (37, 43))	('PPP2R5E', 'Gene', '5529', (61, 68))	('E545K', 'Mutation', 'rs104886003', (113, 118))	('E545K', 'Var', (113, 118))	('FBXW11', 'Gene', (50, 56))	('WNT10B', 'Gene', '7480', (37, 43))	('PIK3CA', 'Gene', (106, 112))	('PPP2R5E', 'Gene', (61, 68))	('TCF4', 'Gene', (11, 15))	('TCF4', 'Gene', '6925', (11, 15))	('MCF7', 'CellLine', 'CVCL:0031', (131, 135))	('PIK3CA', 'Gene', '5290', (106, 112))	('FBXW11', 'Gene', '23291', (50, 56))	('regulated', 'Reg', (89, 98))	('APC', 'Disease', 'MESH:D011125', (45, 48))	('APC', 'Disease', (45, 48))
492754	28139702	21b), and ChIP-qPCR analysis confirmed enhanced binding of TCF4 to their promoters in mutant PIK3CA cells (Fig.	('TCF4', 'Gene', (59, 63))	('TCF4', 'Gene', '6925', (59, 63))	('PIK3CA', 'Gene', '5290', (93, 99))	('mutant', 'Var', (86, 92))	('binding', 'Interaction', (48, 55))	('PIK3CA', 'Gene', (93, 99))	('enhanced', 'PosReg', (39, 47))
492756	28139702	mRNA confirmed that their mRNA levels were differentially regulated by the PIK3CA E545K mutation (Fig.	('PIK3CA', 'Gene', (75, 81))	('E545K', 'Var', (82, 87))	('PIK3CA', 'Gene', '5290', (75, 81))	('mRNA levels', 'MPA', (26, 37))	('regulated', 'Reg', (58, 67))	('E545K', 'Mutation', 'rs104886003', (82, 87))
492759	28139702	Control, PIK3CA WT or PIK3CA E545K vectors were overexpressed in Cal27, and ChIP-qPCR and RT-qPCR expression experiments were performed to investigate the activity of ELK1, TCF4 and FOXO1.	('PIK3CA', 'Gene', '5290', (22, 28))	('PIK3CA', 'Gene', '5290', (9, 15))	('FOXO1', 'Gene', (182, 187))	('FOXO1', 'Gene', '2308', (182, 187))	('ELK1', 'Gene', (167, 171))	('TCF4', 'Gene', '6925', (173, 177))	('ELK1', 'Gene', '2002', (167, 171))	('PIK3CA', 'Gene', (9, 15))	('Cal27', 'CellLine', 'CVCL:1107', (65, 70))	('expression', 'Species', '29278', (98, 108))	('TCF4', 'Gene', (173, 177))	('PIK3CA', 'Gene', (22, 28))	('E545K', 'Mutation', 'rs104886003', (29, 34))	('E545K', 'Var', (29, 34))
492761	28139702	Like in the MCF7 BRCA model, RT-qPCR analysis demonstrated an increase in the mRNA levels of four known ELK1 target genes, ACTR3, PSMB4, WNK1 and DDX27, in Cal27 cells transfected with PIK3CA E545K compared to Cal27 cells transfected with WT PIK3CA and control cells (Fig.	('E545K', 'Var', (192, 197))	('PIK3CA', 'Gene', '5290', (185, 191))	('PIK3CA', 'Gene', (242, 248))	('ELK1', 'Gene', (104, 108))	('increase', 'PosReg', (62, 70))	('PSMB4', 'Gene', (130, 135))	('MCF7', 'CellLine', 'CVCL:0031', (12, 16))	('ACTR3', 'Gene', (123, 128))	('BRCA', 'Gene', '672', (17, 21))	('Cal27', 'CellLine', 'CVCL:1107', (156, 161))	('mRNA levels', 'MPA', (78, 89))	('PIK3CA', 'Gene', (185, 191))	('WNK1', 'Gene', (137, 141))	('DDX27', 'Gene', (146, 151))	('PSMB4', 'Gene', '5692', (130, 135))	('ELK1', 'Gene', '2002', (104, 108))	('BRCA', 'Gene', (17, 21))	('E545K', 'Mutation', 'rs104886003', (192, 197))	('Cal27', 'CellLine', 'CVCL:1107', (210, 215))	('PIK3CA', 'Gene', '5290', (242, 248))	('ACTR3', 'Gene', '10096', (123, 128))	('WNK1', 'Gene', '65125', (137, 141))	('DDX27', 'Gene', '55661', (146, 151))
492762	28139702	Increased occupancy of ELK1 at target promoters was confirmed by ChIP-qPCR assays only when cells were transfected with the PIK3CA E545K vector (Fig.	('ELK1', 'Gene', (23, 27))	('PIK3CA', 'Gene', (124, 130))	('ELK1', 'Gene', '2002', (23, 27))	('E545K', 'Mutation', 'rs104886003', (131, 136))	('E545K', 'Var', (131, 136))	('PIK3CA', 'Gene', '5290', (124, 130))
492763	28139702	Thus, ELK1 transcriptional activity is enhanced by mutant PIK3CA in both head and neck and BRCA models.	('transcriptional activity', 'MPA', (11, 35))	('BRCA', 'Gene', (91, 95))	('mutant', 'Var', (51, 57))	('PIK3CA', 'Gene', (58, 64))	('PIK3CA', 'Gene', '5290', (58, 64))	('ELK1', 'Gene', (6, 10))	('BRCA', 'Gene', '672', (91, 95))	('ELK1', 'Gene', '2002', (6, 10))	('enhanced', 'PosReg', (39, 47))
492764	28139702	RT-qPCR analysis demonstrated an increase in the mRNA levels of four TCF4 target genes in Cal27 cells with PIK3CA E545K compared to WT Cal27 and control cells (Fig.	('mRNA levels of', 'MPA', (49, 63))	('Cal27', 'CellLine', 'CVCL:1107', (90, 95))	('Cal27', 'CellLine', 'CVCL:1107', (135, 140))	('TCF4', 'Gene', '6925', (69, 73))	('TCF4', 'Gene', (69, 73))	('increase', 'PosReg', (33, 41))	('PIK3CA', 'Gene', (107, 113))	('PIK3CA', 'Gene', '5290', (107, 113))	('E545K', 'Mutation', 'rs104886003', (114, 119))	('E545K', 'Var', (114, 119))
492765	28139702	Increased occupancy of TCF4 at the promoters of these genes was confirmed by ChIP assays only when cells were transfected with the PIK3CA E545K vector (Fig.	('E545K', 'Mutation', 'rs104886003', (138, 143))	('E545K', 'Var', (138, 143))	('PIK3CA', 'Gene', (131, 137))	('PIK3CA', 'Gene', '5290', (131, 137))	('TCF4', 'Gene', (23, 27))	('TCF4', 'Gene', '6925', (23, 27))
492766	28139702	Thus, mutant PIK3CA enhances TCF4 transcriptional activity in head and neck as well as BRCA models.	('mutant', 'Var', (6, 12))	('PIK3CA', 'Gene', (13, 19))	('BRCA', 'Gene', '672', (87, 91))	('transcriptional activity', 'MPA', (34, 58))	('BRCA', 'Gene', (87, 91))	('enhances', 'PosReg', (20, 28))	('PIK3CA', 'Gene', '5290', (13, 19))	('TCF4', 'Gene', (29, 33))	('TCF4', 'Gene', '6925', (29, 33))
492767	28139702	FOXO1 activity was not associated with mutant PIK3CA in our HNSC model.	('activity', 'MPA', (6, 14))	('PIK3CA', 'Gene', '5290', (46, 52))	('FOXO1', 'Gene', (0, 5))	('FOXO1', 'Gene', '2308', (0, 5))	('mutant', 'Var', (39, 45))	('PIK3CA', 'Gene', (46, 52))
492769	28139702	Further, no change in occupancy of FOXO1 at the promoters of TNFSF10 and RUNX1 was shown by ChIP assays when cells were transfected with the PIK3CA E545K vector (Fig.	('PIK3CA', 'Gene', '5290', (141, 147))	('RUNX1', 'Gene', (73, 78))	('occupancy', 'MPA', (22, 31))	('RUNX1', 'Gene', '861', (73, 78))	('FOXO1', 'Gene', '2308', (35, 40))	('PIK3CA', 'Gene', (141, 147))	('E545K', 'Mutation', 'rs104886003', (148, 153))	('E545K', 'Var', (148, 153))	('TNFSF10', 'Gene', (61, 68))	('FOXO1', 'Gene', (35, 40))	('TNFSF10', 'Gene', '8743', (61, 68))
492772	28139702	Our computational and experimental results suggest that a potential mechanism for ELK1 activation is through an activating PIK3CA mutation.	('activation', 'PosReg', (87, 97))	('mutation', 'Var', (130, 138))	('PIK3CA', 'Gene', (123, 129))	('PIK3CA', 'Gene', '5290', (123, 129))	('ELK1', 'Gene', (82, 86))	('ELK1', 'Gene', '2002', (82, 86))	('activating', 'PosReg', (112, 122))
492774	28139702	Our analyses confirm that TCF4 activation may result from an activating PIK3CA mutation.	('PIK3CA', 'Gene', (72, 78))	('mutation', 'Var', (79, 87))	('activation', 'PosReg', (31, 41))	('PIK3CA', 'Gene', '5290', (72, 78))	('TCF4', 'Gene', (26, 30))	('TCF4', 'Gene', '6925', (26, 30))	('activating', 'PosReg', (61, 71))
492776	28139702	Since we demonstrated altered transcriptional activity of TCF4 downstream of mutant PIK3CA in breast and head and neck cancer cells, targeting TCF4 might be new therapeutic strategy in PIK3CA mutant patients.	('PIK3CA', 'Gene', '5290', (84, 90))	('transcriptional activity', 'MPA', (30, 54))	('head and neck cancer', 'Disease', 'MESH:D006258', (105, 125))	('TCF4', 'Gene', (58, 62))	('TCF4', 'Gene', '6925', (58, 62))	('PIK3CA', 'Gene', (185, 191))	('altered', 'Reg', (22, 29))	('head and neck cancer', 'Phenotype', 'HP:0012288', (105, 125))	('PIK3CA', 'Gene', (84, 90))	('patients', 'Species', '9606', (199, 207))	('PIK3CA', 'Gene', '5290', (185, 191))	('mutant', 'Var', (77, 83))	('TCF4', 'Gene', (143, 147))	('TCF4', 'Gene', '6925', (143, 147))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
492779	28139702	Specifically, we showed that an activating PIK3CA mutation altered FOXO1 activity in the BRCA model but not in the head and neck cancer model, consistent with the context-specific predictions of our algorithm.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('FOXO1', 'Gene', (67, 72))	('FOXO1', 'Gene', '2308', (67, 72))	('PIK3CA', 'Gene', '5290', (43, 49))	('BRCA', 'Gene', (89, 93))	('activity', 'MPA', (73, 81))	('head and neck cancer', 'Disease', 'MESH:D006258', (115, 135))	('head and neck cancer', 'Phenotype', 'HP:0012288', (115, 135))	('BRCA', 'Gene', '672', (89, 93))	('activating', 'PosReg', (32, 42))	('mutation', 'Var', (50, 58))	('PIK3CA', 'Gene', (43, 49))
492780	28139702	This shows one example of how a clinically relevant 'actionable mutation' impacts regulatory programs in a cancer-specific manner, giving clues about druggability across tumour types.	('tumour type', 'Disease', 'MESH:D009369', (170, 181))	('tumour type', 'Disease', (170, 181))	('regulatory programs', 'MPA', (82, 101))	('impacts', 'Reg', (74, 81))	("mutation'", 'Var', (64, 73))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('tumour', 'Phenotype', 'HP:0002664', (170, 176))	('clues', 'Reg', (138, 143))	('cancer', 'Disease', (107, 113))
492782	28139702	For example, activating mutations and amplifications of PIK3CA are targetable by PI3K inhibitors, which are in active clinical assessment in combination therapies with RTK inhibitors and antioestrogen therapies in BRCA, antiandrogen therapy in PRAD and MEK inhibitors in many solid tumours.	('solid tumours', 'Disease', 'MESH:D009369', (276, 289))	('tumour', 'Phenotype', 'HP:0002664', (282, 288))	('amplifications', 'Var', (38, 52))	('activating', 'PosReg', (13, 23))	('solid tumours', 'Disease', (276, 289))	('MEK', 'Gene', '5604;5605', (253, 256))	('PIK3CA', 'Gene', (56, 62))	('BRCA', 'Gene', '672', (214, 218))	('tumours', 'Phenotype', 'HP:0002664', (282, 289))	('BRCA', 'Gene', (214, 218))	('MEK', 'Gene', (253, 256))	('PIK3CA', 'Gene', '5290', (56, 62))
492789	28139702	Linking mutant beta-catenin to putative downstream TF effectors could inform future mechanistic studies:for example, short hairpin RNA or CRISPR/Cas screening to identify TFs whose deletion/knockdown leads to changes in proliferation:to develop new therapeutic strategies.	('proliferation', 'MPA', (220, 233))	('changes', 'Reg', (209, 216))	('mutant', 'Var', (8, 14))	('beta-catenin', 'Gene', (15, 27))	('beta-catenin', 'Gene', '1499', (15, 27))	('deletion/knockdown', 'Var', (181, 199))
492790	28139702	Several recent studies have integrated TF binding site or occupancy data to identify cancer-associated TFs, for example, combining tumour-specific DNA methylation changes in distal enhancers, mRNA sequencing and cis-regulatory sequences mediating effects on target genes or integrating ENCODE TF ChIP-seq profiles with the pancancer TCGA expression data.	('changes', 'Var', (163, 170))	('tumour', 'Disease', (131, 137))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('cancer', 'Disease', 'MESH:D009369', (326, 332))	('expression', 'Species', '29278', (338, 348))	('cancer', 'Disease', (85, 91))	('tumour', 'Phenotype', 'HP:0002664', (131, 137))	('cancer', 'Disease', (326, 332))	('tumour', 'Disease', 'MESH:D009369', (131, 137))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('cancer', 'Phenotype', 'HP:0002664', (326, 332))
492804	28139702	We obtained SILAC-based quantitative phosphoproteomic data set of a spontaneously immortalized non-tumorigenic breast epithelial cell line MCF10A along with two isogenic derivatives generated by knock-in of mutant alleles:one bearing the E545K mutation and the other bearing the H1047R mutation of the PIK3CA gene:from the originally published Supplementary Data.	('MCF10A', 'CellLine', 'CVCL:0598', (139, 145))	('H1047R', 'Mutation', 'rs121913279', (279, 285))	('PIK3CA', 'Gene', (302, 308))	('PIK3CA', 'Gene', '5290', (302, 308))	('H1047R', 'Var', (279, 285))	('E545K', 'Var', (238, 243))	('E545K', 'Mutation', 'rs104886003', (238, 243))
492830	28139702	The BRCA cell line, MCF7, which has a PIK3CA E545K mutation, and the targeted correction of the E545K mutation to WT PIK3CA were obtained from the Lauring Lab.	('BRCA', 'Gene', '672', (4, 8))	('BRCA', 'Gene', (4, 8))	('PIK3CA', 'Gene', (38, 44))	('E545K mutation', 'Var', (45, 59))	('PIK3CA', 'Gene', (117, 123))	('E545K', 'Mutation', 'rs104886003', (96, 101))	('E545K', 'Var', (96, 101))	('PIK3CA', 'Gene', '5290', (38, 44))	('E545K', 'Mutation', 'rs104886003', (45, 50))	('PIK3CA', 'Gene', '5290', (117, 123))	('MCF7', 'CellLine', 'CVCL:0031', (20, 24))
492834	28139702	Cal27 cell lines were transfected with pbabe control vector, pbabe WT PIK3CA and pbabe E545K PIK3CA vectors (Addgene) using Lipofectamine 3000 according to the manufacturer's instructions.	('PIK3CA', 'Gene', '5290', (93, 99))	('E545K', 'Mutation', 'rs104886003', (87, 92))	('E545K', 'Var', (87, 92))	('PIK3CA', 'Gene', (70, 76))	('Cal27', 'CellLine', 'CVCL:1107', (0, 5))	('PIK3CA', 'Gene', (93, 99))	('PIK3CA', 'Gene', '5290', (70, 76))	('Lipofectamine', 'Chemical', 'MESH:C086724', (124, 137))
492839	28139702	Sheared chromatin was incubated overnight with 2 mug of rabbit monoclonal ChIP grade antibody to ELK1 (E277, ab32106; Abcam) as has been previously used by Zhang et al.	('rabbit', 'Species', '9986', (56, 62))	('ELK1', 'Gene', '2002', (97, 101))	('E277', 'Var', (103, 107))	('ELK1', 'Gene', (97, 101))
492850	26656462	Polymorphisms of BCL2 and BAX Genes Associate with Outcomes in Advanced Non-small cell lung cancer Patients treated with platinum-based Chemotherapy Single-nucleotide polymorphisms (SNP) of the gene belonging to the BCL2 family are thought to play a role in chemotherapy resistance.	('platinum', 'Chemical', 'MESH:D010984', (121, 129))	('BAX', 'Gene', '581', (26, 29))	('Associate with', 'Reg', (36, 50))	('Non-small cell lung cancer', 'Disease', (72, 98))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (76, 98))	('BCL2', 'Gene', (17, 21))	('Non-small cell lung cancer', 'Phenotype', 'HP:0030358', (72, 98))	('BCL2', 'Gene', (216, 220))	('Polymorphisms', 'Var', (0, 13))	('lung cancer', 'Phenotype', 'HP:0100526', (87, 98))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('Patients', 'Species', '9606', (99, 107))	('Single-nucleotide polymorphisms', 'Var', (149, 180))	('Non-small cell lung cancer', 'Disease', 'MESH:D002289', (72, 98))	('BCL2', 'Gene', '596', (17, 21))	('BCL2', 'Gene', '596', (216, 220))	('BAX', 'Gene', (26, 29))
492851	26656462	This study investigated the association of BCL2-938C>A(rs2279115) and BAX-248G>A(rs4645878) promoter region SNPs and the clinical responses and outcomes of 235 non-small cell lung cancer (NSCLC) patients treated with platinum-based chemotherapy.	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (160, 186))	('NSCLC', 'Disease', 'MESH:D002289', (188, 193))	('rs4645878', 'Mutation', 'rs4645878', (81, 90))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('platinum', 'Chemical', 'MESH:D010984', (217, 225))	('lung cancer', 'Phenotype', 'HP:0100526', (175, 186))	('rs2279115', 'Mutation', 'rs2279115', (55, 64))	('non-small cell lung cancer', 'Disease', (160, 186))	('BAX-248G>A', 'Var', (70, 80))	('patients', 'Species', '9606', (195, 203))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (164, 186))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (160, 186))	('BCL2-938C>A', 'Var', (43, 54))	('NSCLC', 'Disease', (188, 193))
492852	26656462	The data suggested that BAX-248GA and GA+AA genotype was associated with poor response [odds ratio (OR) 1.943, p = 0.039; OR 1.867, p = 0.038, respectively] to chemotherapy, and BCL2-938CA, CA+AA and BAX-248GA, AA and GA+AA were associated with poor progression-free survival (PFS) [hazard ratio (HR) 1.514, p = 0.004; HR 1.456, p = 0.009; HR 1.449, p = 0.013; HR 2.006, p = 0.010; HR 1.506, p = 0.003, respectively] and BCL2-938CA, AA and CA+AA and BAX-248GA, AA and GA+AA were associated with poor overall survival (OS) (HR 2.006, p < 0.001; HR 2.322, p < 0.001; HR 2.096, p < 0.001; HR 1.632, p = 0.001; HR 2.014, p = 0.010; HR 1.506, p < 0.001, respectively).	('BCL2', 'Gene', '596', (178, 182))	('BCL2', 'Gene', (178, 182))	('BAX', 'Gene', (24, 27))	('progression-free survival', 'CPA', (250, 275))	('BAX', 'Gene', (450, 453))	('BCL2', 'Gene', '596', (421, 425))	('BAX', 'Gene', '581', (450, 453))	('overall', 'MPA', (500, 507))	('BAX', 'Gene', '581', (24, 27))	('BCL2', 'Gene', (421, 425))	('BAX', 'Gene', '581', (200, 203))	('BAX', 'Gene', (200, 203))	('CA+AA', 'Var', (440, 445))	('poor', 'NegReg', (495, 499))
492853	26656462	Furthermore, combination of these two polymorphisms showed patients with 2-4 variant alleles of these two genes associated with poor PFS and OS (HR 1.637, p = 0.001; HR 2.365, p < 0.001).	('poor PFS', 'Disease', (128, 136))	('associated', 'Reg', (112, 122))	('patients', 'Species', '9606', (59, 67))	('variant', 'Var', (77, 84))
492854	26656462	The data from the current study provide evidence that BCL2-938C>A and BAX-248G>A polymorphisms may be useful in predicting clinical outcomes of patients with advanced inoperable NSCLC to platinum-based chemotherapy.	('NSCLC', 'Disease', (178, 183))	('platinum', 'Chemical', 'MESH:D010984', (187, 195))	('NSCLC', 'Disease', 'MESH:D002289', (178, 183))	('BAX-248G', 'Gene', (70, 78))	('patients', 'Species', '9606', (144, 152))	('BCL2-938C>A', 'Var', (54, 65))
492858	26656462	Chemotherapy resistance of NSCLC to platinum-based treatments is complex, but single-nucleotide polymorphisms (SNP) in apoptosis genes, particularly the BCL2 family, may play a critical role.	('apoptosis genes', 'Gene', (119, 134))	('NSCLC', 'Disease', (27, 32))	('BCL2', 'Gene', '596', (153, 157))	('platinum', 'Chemical', 'MESH:D010984', (36, 44))	('NSCLC', 'Disease', 'MESH:D002289', (27, 32))	('single-nucleotide polymorphisms', 'Var', (78, 109))	('BCL2', 'Gene', (153, 157))
492865	26656462	Thus, aberrant expression of Bcl-2 and/or BAX is thought to play a role in cancer development.	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('play', 'Reg', (60, 64))	('cancer', 'Disease', (75, 81))	('aberrant expression', 'Var', (6, 25))	('BAX', 'Gene', (42, 45))	('Bcl-2', 'Gene', (29, 34))	('role', 'Reg', (67, 71))	('Bcl-2', 'Gene', '596', (29, 34))	('BAX', 'Gene', '581', (42, 45))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))
492866	26656462	Additionally, SNPs in these genes have been reported to be associated with various human cancers such as head and neck squamous cell carcinoma, endometrial cancer, prostate cancer, breast cancer, acute lymphoblastic leukemia and glioma.	('acute lymphoblastic leukemia', 'Disease', (196, 224))	('breast cancer', 'Phenotype', 'HP:0003002', (181, 194))	('cancers', 'Phenotype', 'HP:0002664', (89, 96))	('endometrial cancer', 'Disease', 'MESH:D016889', (144, 162))	('acute lymphoblastic leukemia', 'Disease', 'MESH:D054198', (196, 224))	('cancers', 'Disease', (89, 96))	('SNPs', 'Var', (14, 18))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (119, 142))	('glioma', 'Phenotype', 'HP:0009733', (229, 235))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (196, 224))	('breast cancer', 'Disease', 'MESH:D001943', (181, 194))	('breast cancer', 'Disease', (181, 194))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (105, 142))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (119, 142))	('cancers', 'Disease', 'MESH:D009369', (89, 96))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (202, 224))	('prostate cancer', 'Disease', 'MESH:D011471', (164, 179))	('squamous cell carcinoma', 'Disease', (119, 142))	('prostate cancer', 'Phenotype', 'HP:0012125', (164, 179))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('leukemia', 'Phenotype', 'HP:0001909', (216, 224))	('endometrial cancer', 'Phenotype', 'HP:0012114', (144, 162))	('human', 'Species', '9606', (83, 88))	('associated', 'Reg', (59, 69))	('glioma', 'Disease', (229, 235))	('prostate cancer', 'Disease', (164, 179))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('endometrial cancer', 'Disease', (144, 162))	('glioma', 'Disease', 'MESH:D005910', (229, 235))
492867	26656462	Furthermore, high BCL2 expression has been associated with chemoresistance, and overexpression in cell lines has been observed to inhibit apoptosis.	('BCL2', 'Gene', '596', (18, 22))	('inhibit', 'NegReg', (130, 137))	('high', 'Var', (13, 17))	('BCL2', 'Gene', (18, 22))	('apoptosis', 'CPA', (138, 147))	('associated', 'Reg', (43, 53))	('chemoresistance', 'CPA', (59, 74))	('expression', 'MPA', (23, 33))
492869	26656462	Most studies of BCL2 and BAX SNPs have focused on the promoter regions of these two genes, BCL2-938C>A (rs2279115) and BAX-248G>A(rs4645878), because they have been reported to be associated with altered expression of BCL2 and BAX.	('BAX', 'Gene', (119, 122))	('BCL2', 'Gene', (218, 222))	('BCL2', 'Gene', (91, 95))	('BCL2', 'Gene', (16, 20))	('rs2279115', 'Var', (104, 113))	('rs4645878', 'Mutation', 'rs4645878', (130, 139))	('BAX', 'Gene', '581', (119, 122))	('BAX', 'Gene', (25, 28))	('BAX', 'Gene', '581', (25, 28))	('BAX', 'Gene', (227, 230))	('rs2279115', 'Mutation', 'rs2279115', (104, 113))	('BCL2', 'Gene', '596', (218, 222))	('BAX', 'Gene', '581', (227, 230))	('BCL2', 'Gene', '596', (16, 20))	('BCL2', 'Gene', '596', (91, 95))	('expression', 'MPA', (204, 214))
492870	26656462	The BCL2-938C>A A allele was associated with an increase in BCL-2 expression[14,27].	('BCL2-938C>A', 'Var', (4, 15))	('BCL-2', 'Gene', (60, 65))	('expression', 'MPA', (66, 76))	('BCL-2', 'Gene', '596', (60, 65))	('increase', 'PosReg', (48, 56))
492872	26656462	Hence, in this study, we hypothesized that BCL2 and BAX polymorphisms, located in the untranslated promoter regions, could be associated with treatment responses and clinical outcomes in advanced NSCLC treated with platinum-based chemotherapy.	('BCL2', 'Gene', (43, 47))	('NSCLC', 'Disease', (196, 201))	('associated with', 'Reg', (126, 141))	('treatment responses', 'CPA', (142, 161))	('NSCLC', 'Disease', 'MESH:D002289', (196, 201))	('platinum', 'Chemical', 'MESH:D010984', (215, 223))	('BAX', 'Gene', (52, 55))	('BCL2', 'Gene', '596', (43, 47))	('BAX', 'Gene', '581', (52, 55))	('polymorphisms', 'Var', (56, 69))
492873	26656462	To assess our hypothesis, we analyzed the responses and treatment outcomes of 235 patients with advanced NSCLC treated with platinum-based therapy and the association of treatment response and outcomes with BCL2 -938C>A) (rs2279115) and BAX -248G>A (rs4645878) SNP status.	('NSCLC', 'Disease', 'MESH:D002289', (105, 110))	('rs4645878', 'Var', (250, 259))	('platinum', 'Chemical', 'MESH:D010984', (124, 132))	('BAX', 'Gene', (237, 240))	('patients', 'Species', '9606', (82, 90))	('BAX', 'Gene', '581', (237, 240))	('BCL2', 'Gene', '596', (207, 211))	('-248G>A', 'Mutation', 'rs4645878', (241, 248))	('rs2279115', 'Var', (222, 231))	('BCL2', 'Gene', (207, 211))	('-938C>A', 'Mutation', 'rs2279115', (212, 219))	('NSCLC', 'Disease', (105, 110))	('rs2279115', 'Mutation', 'rs2279115', (222, 231))	('rs4645878', 'Mutation', 'rs4645878', (250, 259))
492893	26656462	Differences in response to treatment or grade 3/4 toxicities were analyzed between groups with different genotypes of these SNPs (variants vs. the wild-type) by calculation of p values using the Pearson chi2 test or the Fisher exact test.	('toxicities', 'Disease', (50, 60))	('variants', 'Var', (130, 138))	('toxicities', 'Disease', 'MESH:D064420', (50, 60))
492906	26656462	After adjusting for age, gender, ECOG PS, histology, tumor stage, smoking status, chemotherapy regimens, weight loss, BCL2-938C>A, and BAX-248G>A, the logistic regression model analysis showed that the following parameters were able to predict the treatment response: ECOG PS (adjusted OR 2.112, 95% CI 1.156-3.857, p = 0.015), tumor stage (adjusted OR 2.887, 95% CI 1.510-5.518, p = 0.001), smoking status (adjusted OR 2.446, 95% CI 1.140-5.247, p = 0.022) and BAX-248G>A (GG vs. GA, adjusted OR 1.943, 95% CI 1.035-3.648, p = 0.039; GG vs. GA+AA, adjusted OR 1.867, 95% CI 1.035-3.369, p = 0.038).	('BAX-248G>A', 'Var', (462, 472))	('weight loss', 'Phenotype', 'HP:0001824', (105, 116))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Disease', 'MESH:D009369', (328, 333))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('weight loss', 'Disease', 'MESH:D015431', (105, 116))	('tumor', 'Phenotype', 'HP:0002664', (328, 333))	('tumor', 'Disease', (53, 58))	('tumor', 'Disease', (328, 333))	('weight loss', 'Disease', (105, 116))
492909	26656462	Our SNP data showed that there was no significant association between risk of grade 3/4 hematologic toxicity or gastrointestinal toxicity and BCL2-938C>A (adjusted OR 1.006, 95% CI 0.680 ~ 1.490, p = 0.975; adjusted OR 0.927, 95% CI 0.572 ~ 1.500, p = 0.756) or BAX-248G>A (adjusted OR 0.726, 95% CI 0.464 ~ 1.490, p = 0.160; adjusted OR 0.976, 95% CI 0.576 ~ 1.655, p = 0.929) polymorphisms (Logistic regression model analysis).	('hematologic toxicity', 'Disease', (88, 108))	('gastrointestinal toxicity', 'Disease', 'MESH:D005767', (112, 137))	('BCL2-938C>A', 'Var', (142, 153))	('hematologic toxicity', 'Disease', 'MESH:D006402', (88, 108))	('BAX-248G>A', 'Var', (262, 272))	('gastrointestinal toxicity', 'Disease', (112, 137))
492915	26656462	Furthermore, in the univariate model (Table 4), the BCL2-938C>A polymorphism was significantly associated with OS, i.e., patients carrying the CC genotype had a longer median OS than patients carrying the CA, AA or CA+AA genotype (19 m vs. 12 m, p < 0.001; 19 m vs. 11 m, p < 0.001; 19 m vs. 12 m, p < 0.001; Log-rank test; respectively; Fig.	('associated', 'Reg', (95, 105))	('BCL2-938C>A', 'Var', (52, 63))	('patients', 'Species', '9606', (183, 191))	('patients', 'Species', '9606', (121, 129))
492918	26656462	The multivariate analysis showed that ECOG PS (HR 2.430, 95% CI 1.823-3.238, p < 0.001), BCL2-938C>A (CC vs. CA, HR 2.006, 95% CI 1.462-2.752, p < 0.001; CC vs. AA, HR 2.322, 95% CI 1.558-3.461, p < 0.001; CC vs. CA+AA, HR 2.096, 95% CI 1.555-2.824; p < 0.001), and BAX-248G>A (GG vs. GA, HR 1.632, 95% CI 1.210-2.199, p = 0.001; GG vs. AA, HR 2.014, 95% CI 1.188-3.425, p = 0.010; GG vs. GA+AA, HR 1.705, 95% CI 1.283-2.266, p < 0.001) were all independent predictors for OS of these NSCLC patients.	('BAX-248G>A', 'Var', (266, 276))	('NSCLC', 'Disease', (485, 490))	('NSCLC', 'Disease', 'MESH:D002289', (485, 490))	('patients', 'Species', '9606', (491, 499))
492919	26656462	After that, we combined these two BCL2-938C>A and BAX-248G>A polymorphisms for association with PFS and OS of patients.	('PFS', 'Disease', (96, 99))	('BAX-248G>A', 'Var', (50, 60))	('association', 'Interaction', (79, 90))	('BCL2-938C', 'Var', (34, 43))	('OS of', 'Disease', (104, 109))	('patients', 'Species', '9606', (110, 118))
492925	26656462	In this study, we investigated whether the occurrence of SNPs, located in the promoter regions of two apoptosis-related genes are associated with responses and/or outcomes in patients with advanced NSCLC that are treated with cisplatin-based chemotherapy.	('SNPs', 'Var', (57, 61))	('responses', 'MPA', (146, 155))	('apoptosis-related genes', 'Gene', (102, 125))	('patients', 'Species', '9606', (175, 183))	('NSCLC', 'Disease', (198, 203))	('cisplatin', 'Chemical', 'MESH:D002945', (226, 235))	('NSCLC', 'Disease', 'MESH:D002289', (198, 203))	('associated', 'Reg', (130, 140))
492928	26656462	Furthermore, patients with the BCL2-938C>A variant genotype (A allele) or BAX-248G>A variant genotype (A allele) associated with poor PFS and OS.	('BCL2-938C>A', 'Var', (31, 42))	('BAX-248G>A', 'Var', (74, 84))	('poor', 'NegReg', (129, 133))	('patients', 'Species', '9606', (13, 21))	('PFS', 'Disease', (134, 137))
492929	26656462	The combined BCL2-938C>A and BAX-248G>A were also associated with PFS and OS of the patients.	('BAX-248G>A', 'Var', (29, 39))	('PFS', 'Disease', (66, 69))	('patients', 'Species', '9606', (84, 92))	('associated', 'Reg', (50, 60))	('BCL2-938C>A', 'Var', (13, 24))
492930	26656462	The multivariate analysis showed that ECOG PS, BCL2-938C>A, and BAX-248G>A were all independent predictors for OS of these NSCLC patients.	('NSCLC', 'Disease', (123, 128))	('patients', 'Species', '9606', (129, 137))	('NSCLC', 'Disease', 'MESH:D002289', (123, 128))	('BAX-248G>A', 'Var', (64, 74))	('ECOG PS', 'Var', (38, 45))	('BCL2-938C>A', 'Var', (47, 58))
492931	26656462	To the best of our knowledge, this is the first study of this kind to demonstrate an association between the BAX-248G>A or the combination of BCL2-938C>A and BAX-248G>A with outcome of advanced NSCLC patients to cisplatin-based chemotherapy.	('BAX-248G>A', 'Var', (109, 119))	('patients', 'Species', '9606', (200, 208))	('BAX-248G>A', 'Var', (158, 168))	('NSCLC', 'Disease', (194, 199))	('BCL2-938C>A', 'Var', (142, 153))	('NSCLC', 'Disease', 'MESH:D002289', (194, 199))	('cisplatin', 'Chemical', 'MESH:D002945', (212, 221))	('association', 'Interaction', (85, 96))
492934	26656462	identified BCL2-938C>A(rs2279115) in P2 and Nuckel et al.	('BCL2-938C>A(rs2279115', 'Var', (11, 32))	('rs2279115', 'Var', (23, 32))	('tif', 'Gene', (4, 7))	('tif', 'Gene', '7301', (4, 7))	('rs2279115', 'Mutation', 'rs2279115', (23, 32))
492951	26656462	showed that p53 mutations developed cisplatin resistance in ovarian cancer as a consequence of the loss of p53 transactivation of BAX expression.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('ovarian cancer', 'Phenotype', 'HP:0100615', (60, 74))	('expression', 'MPA', (134, 144))	('BAX', 'Gene', (130, 133))	('cisplatin', 'Chemical', 'MESH:D002945', (36, 45))	('p53', 'Gene', (107, 110))	('BAX', 'Gene', '581', (130, 133))	('ovarian cancer', 'Disease', 'MESH:D010051', (60, 74))	('p53', 'Gene', '7157', (107, 110))	('transactivation', 'MPA', (111, 126))	('mutations', 'Var', (16, 25))	('p53', 'Gene', (12, 15))	('p53', 'Gene', '7157', (12, 15))	('ovarian cancer', 'Disease', (60, 74))	('loss', 'NegReg', (99, 103))	('cisplatin resistance', 'MPA', (36, 56))	('developed', 'Reg', (26, 35))
492955	26656462	Patients with more than 2 variant alleles had a much shorter median PFS and OS compared to those carrying 0-1 variant alleles.	('PFS', 'MPA', (68, 71))	('Patients', 'Species', '9606', (0, 8))	('variant', 'Var', (26, 33))	('shorter', 'NegReg', (53, 60))
492956	26656462	Although we showed that the BCL2-938C>A and BAX-248G>A SNPs significantly associated with platinum-based chemotherapy response, PFS and OS of patients with advanced NSCLC, we did not show the association of these SNPs with chemotherapy-related toxicities.	('BAX-248G>A', 'Var', (44, 54))	('PFS', 'Disease', (128, 131))	('NSCLC', 'Disease', 'MESH:D002289', (165, 170))	('platinum', 'Chemical', 'MESH:D010984', (90, 98))	('BCL2-938C>A', 'Var', (28, 39))	('platinum-based chemotherapy response', 'CPA', (90, 126))	('toxicities', 'Disease', (244, 254))	('toxicities', 'Disease', 'MESH:D064420', (244, 254))	('patients', 'Species', '9606', (142, 150))	('associated with', 'Reg', (74, 89))	('NSCLC', 'Disease', (165, 170))
492959	26656462	Do the polymorphisms actually affect the effectiveness of the regimen, or do they simply afford a better prognosis to patients?	('affect', 'Reg', (30, 36))	('effectiveness', 'MPA', (41, 54))	('patients', 'Species', '9606', (118, 126))	('polymorphisms', 'Var', (7, 20))
492960	26656462	Variation of BCL2 and BAX expression associates with an altered sensitivity and clinical outcome of NSCLC patients to chemotherapy.	('sensitivity', 'MPA', (64, 75))	('BCL2', 'Gene', (13, 17))	('NSCLC', 'Disease', (100, 105))	('altered', 'Reg', (56, 63))	('NSCLC', 'Disease', 'MESH:D002289', (100, 105))	('patients', 'Species', '9606', (106, 114))	('BCL2', 'Gene', '596', (13, 17))	('Variation', 'Var', (0, 9))	('BAX', 'Gene', (22, 25))	('BAX', 'Gene', '581', (22, 25))
492961	26656462	Polymorphisms of BCL2 and BAX Genes Associate with Outcomes in Advanced Non-small cell lung cancer Patients treated with platinum-based Chemotherapy.	('platinum', 'Chemical', 'MESH:D010984', (121, 129))	('BAX', 'Gene', '581', (26, 29))	('Associate with', 'Reg', (36, 50))	('Non-small cell lung cancer', 'Disease', (72, 98))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (76, 98))	('BCL2', 'Gene', (17, 21))	('Non-small cell lung cancer', 'Phenotype', 'HP:0030358', (72, 98))	('Polymorphisms', 'Var', (0, 13))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('Patients', 'Species', '9606', (99, 107))	('lung cancer', 'Phenotype', 'HP:0100526', (87, 98))	('Non-small cell lung cancer', 'Disease', 'MESH:D002289', (72, 98))	('BCL2', 'Gene', '596', (17, 21))	('BAX', 'Gene', (26, 29))
492969	28586036	In conclusion, these data provided evidence that epigenetic regulation of PTPRO impairs its tumor suppressor role in LSCC, and restoration of PTPRO may be a potential therapeutic strategy.	('PTPRO', 'Gene', (74, 79))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('LSCC', 'Disease', (117, 121))	('tumor', 'Disease', (92, 97))	('epigenetic regulation', 'Var', (49, 70))	('LSCC', 'Phenotype', 'HP:0030359', (117, 121))	('impairs', 'NegReg', (80, 87))
492976	28586036	For example, promoter methylation of RECK contributes to metastasis of osteosarcoma.	('RECK', 'Gene', (37, 41))	('metastasis of osteosarcoma', 'Disease', (57, 83))	('metastasis of osteosarcoma', 'Disease', 'MESH:D009362', (57, 83))	('RECK', 'Gene', '8434', (37, 41))	('contributes', 'Reg', (42, 53))	('promoter methylation', 'Var', (13, 33))	('osteosarcoma', 'Phenotype', 'HP:0002669', (71, 83))
492977	28586036	BRCA1 negatively mediates cell proliferation, and its mRNA levels were downregulated by methylation.	('downregulated', 'NegReg', (71, 84))	('methylation', 'Var', (88, 99))	('BRCA1', 'Gene', (0, 5))	('negatively', 'NegReg', (6, 16))	('BRCA1', 'Gene', '672', (0, 5))	('mRNA levels', 'MPA', (54, 65))	('mediates', 'Reg', (17, 25))	('cell proliferation', 'CPA', (26, 44))
492978	28586036	The epigenetically inactivated RASSF1A gene was associated with poor prognosis and advanced tumor stage.	('epigenetically inactivated', 'Var', (4, 30))	('associated', 'Reg', (48, 58))	('RASSF1A', 'Gene', (31, 38))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('RASSF1A', 'Gene', '11186', (31, 38))	('tumor', 'Disease', (92, 97))	('poor prognosis', 'CPA', (64, 78))
493000	28586036	As inactivation of tumor suppressor genes may occur via hypermethylation of CpG islands upstream of the transcription start site, the present study selected a target region spanning from -405 to -74 (containing 23 CpG sites) in the BSP analysis, and the primers for PTPRO (forward: 5'-GAGGTTGTTGTTATTTTATGGG-3'; reverse: 5'-TAAAACTACAACCTCAAACCCT-3') were used.	('BSP', 'Gene', '3381', (232, 235))	('BSP', 'Gene', (232, 235))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('inactivation', 'NegReg', (3, 15))	('hypermethylation', 'Var', (56, 72))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('tumor', 'Disease', (19, 24))
493031	28586036	To assess if a demethylation agent could restore transcriptional activity, LSCC cells were treated with 0, 2.5 or 5 microM 5-AZA for 72 h. The mRNA expression levels of PTPRO were significantly increased following 5-AZA treatment in all groups except the 2.5 microM treatment group in SK-MES-1 cells (Fig.	('men', 'Species', '9606', (271, 274))	('5-AZA', 'Var', (214, 219))	('PTPRO', 'Gene', (169, 174))	('5-AZA', 'Chemical', 'MESH:D000077209', (123, 128))	('LSCC', 'Phenotype', 'HP:0030359', (75, 79))	('mRNA expression levels', 'MPA', (143, 165))	('men', 'Species', '9606', (225, 228))	('increased', 'PosReg', (194, 203))	('5-AZA', 'Chemical', 'MESH:D000077209', (214, 219))	('SK-MES-1', 'CellLine', 'CVCL:0630', (285, 293))
493032	28586036	These data demonstrated that the CpG island of PTPRO exon 1 was hypermethylated in LSCC cells and tissues, suggesting that the epigenetic regulation of PTPRO may serve a role in LSCC tumorigenesis.	('PTPRO', 'Gene', (152, 157))	('serve', 'Reg', (162, 167))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('role', 'Reg', (170, 174))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('LSCC', 'Disease', (178, 182))	('PTPRO', 'Gene', (47, 52))	('tumor', 'Disease', (183, 188))	('LSCC', 'Phenotype', 'HP:0030359', (178, 182))	('LSCC', 'Phenotype', 'HP:0030359', (83, 87))	('epigenetic regulation', 'Var', (127, 148))
493038	28586036	Subsequently, the present study verified whether the methylation or expression of PTPRO was associated with clinicopathological features of patients.	('expression', 'MPA', (68, 78))	('PTPRO', 'Gene', (82, 87))	('patients', 'Species', '9606', (140, 148))	('associated', 'Reg', (92, 102))	('methylation', 'Var', (53, 64))
493041	28586036	Univariate analysis demonstrated that the high methylation of PTPRO, low PTPRO mRNA, smoking, advanced tumor stage, higher T stage and lymph node metastasis were predictors of poor prognosis for patients, whereas only mRNA expression levels of PTPRO (P=0.005) and higher TNM stage (P=0.001) were identified as significantly independent prognostic factors in multivariate analysis, with relative risks of 2.826 and 3.714, respectively (Table II).	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('PTPRO', 'Gene', (73, 78))	('TNM', 'Gene', '10178', (271, 274))	('tumor', 'Disease', (103, 108))	('methylation', 'Var', (47, 58))	('TNM', 'Gene', (271, 274))	('patients', 'Species', '9606', (195, 203))	('high methylation', 'Var', (42, 58))	('low', 'NegReg', (69, 72))	('PTPRO', 'Gene', (62, 67))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
493042	28586036	Taken together, these data suggested that epigenetically downregulated PTPRO may be involved in LSCC development and may be a potential prognostic marker.	('epigenetically downregulated', 'Var', (42, 70))	('men', 'Species', '9606', (108, 111))	('LSCC', 'Disease', (96, 100))	('PTPRO', 'Gene', (71, 76))	('LSCC', 'Phenotype', 'HP:0030359', (96, 100))	('involved', 'Reg', (84, 92))
493051	28586036	The initiation and progression of squamous cell carcinoma is a complex process involving the abnormalities of a variety of oncogenes and tumor suppressors.	('squamous cell carcinoma', 'Disease', (34, 57))	('abnormalities', 'Var', (93, 106))	('tumor', 'Disease', (137, 142))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (34, 57))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (34, 57))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('carcinoma', 'Phenotype', 'HP:0030731', (48, 57))
493053	28586036	It is well known that the cell tyrosine phosphorylation levels are co-regulated by PTP and protein tyrosine kinase (PTK); dysfunction of tyrosine phosphatase is closely associated with the occurrence of a variety of human tumors.	('tyrosine', 'Chemical', 'MESH:D014443', (31, 39))	('dysfunction', 'Var', (122, 133))	('tumors', 'Disease', 'MESH:D009369', (222, 228))	('human', 'Species', '9606', (216, 221))	('PTK', 'Gene', (116, 119))	('PTP', 'Gene', '26191', (83, 86))	('PTK', 'Gene', '2185', (116, 119))	('associated', 'Reg', (169, 179))	('tyrosine', 'Chemical', 'MESH:D014443', (137, 145))	('tyrosine', 'Chemical', 'MESH:D014443', (99, 107))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('tumors', 'Phenotype', 'HP:0002664', (222, 228))	('tumors', 'Disease', (222, 228))	('PTP', 'Gene', (83, 86))
493176	27316348	Pathological diagnosis of an incisional biopsy specimen indicated a moderately differentiated squamous cell carcinoma (SCC) (cT4aN0M0, stage IV).	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('moderately', 'Disease', (68, 78))	('cT4aN0M0', 'Var', (125, 133))	('SCC', 'Gene', '6317', (119, 122))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (94, 117))	('squamous cell carcinoma', 'Disease', (94, 117))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (94, 117))	('SCC', 'Gene', (119, 122))	('SCC', 'Phenotype', 'HP:0002860', (119, 122))
493224	33233641	miRNAs can either promote or repress cancer development and progression according to their target genes.	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('cancer', 'Disease', (37, 43))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('miRNAs', 'Var', (0, 6))	('promote', 'PosReg', (18, 25))	('repress', 'NegReg', (29, 36))
493230	33233641	Long-term smoking is well-known to be the main cause of lung cancer, while environmental effects (e.g., air pollution and particulate matters) and genetic variations (e.g., KRAS and EGFR mutations) can also cause lung cancer.	('cause', 'Reg', (207, 212))	('EGFR', 'Gene', '1956', (182, 186))	('lung cancer', 'Disease', 'MESH:D008175', (56, 67))	('EGFR', 'Gene', (182, 186))	('lung cancer', 'Phenotype', 'HP:0100526', (213, 224))	('lung cancer', 'Disease', (213, 224))	('KRAS', 'Gene', (173, 177))	('mutations', 'Var', (187, 196))	('KRAS', 'Gene', '3845', (173, 177))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('lung cancer', 'Disease', 'MESH:D008175', (213, 224))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('lung cancer', 'Disease', (56, 67))	('lung cancer', 'Phenotype', 'HP:0100526', (56, 67))
493237	33233641	Like normal single-stranded RNA molecules, pri-miRNA can form secondary structures in which part(s) of the pri-miRNA strand forms hairpin loops, stabilized by intramolecular hydrogen bonds.	('pri-miRNA', 'Var', (107, 116))	('hairpin loops', 'MPA', (130, 143))	('hydrogen', 'Chemical', 'MESH:D006859', (174, 182))
493241	33233641	Exportin 5 binds to stem-loop pre-miRNAs, and RanGTP binding triggers nuclear export of the pre-miRNA:exportin 5 complex.	('nuclear export', 'MPA', (70, 84))	('exportin 5', 'Gene', (102, 112))	('Exportin 5', 'Gene', '57510', (0, 10))	('triggers', 'Reg', (61, 69))	('Exportin 5', 'Gene', (0, 10))	('RanGTP binding', 'Var', (46, 60))	('exportin 5', 'Gene', '57510', (102, 112))	('RanGTP', 'Chemical', '-', (46, 52))
493248	33233641	For example, both miR-142-5p and miR-142-3p are downregulated in liver cancer possibly through promoter hypermethylation and synergistically suppress cancer cell migration by regulating actin cytoskeleton, adherens junctions, and focal adhesion.	('focal adhesion', 'CPA', (230, 244))	('hypermethylation', 'Var', (104, 120))	('miR-142', 'Gene', '406934', (18, 25))	('miR-142', 'Gene', '406934', (33, 40))	('cancer', 'Disease', (71, 77))	('liver cancer', 'Disease', 'MESH:D006528', (65, 77))	('downregulated', 'NegReg', (48, 61))	('cancer', 'Disease', (150, 156))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('adherens junctions', 'CPA', (206, 224))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('liver cancer', 'Phenotype', 'HP:0002896', (65, 77))	('miR-142', 'Gene', (18, 25))	('liver cancer', 'Disease', (65, 77))	('miR-142', 'Gene', (33, 40))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('regulating', 'Reg', (175, 185))	('suppress', 'NegReg', (141, 149))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('actin cytoskeleton', 'MPA', (186, 204))
493257	33233641	In addition, miRNAs have been shown to dissociate the eIF4A complex, thus inhibiting ribosome binding and scanning.	('inhibiting', 'NegReg', (74, 84))	('eIF4A', 'Gene', '1973;1974', (54, 59))	('ribosome', 'MPA', (85, 93))	('miRNAs', 'Var', (13, 19))	('eIF4A', 'Gene', (54, 59))	('scanning', 'MPA', (106, 114))
493259	33233641	Upregulation of oncogenic miR-21 in various types of cancer is associated with hypomethylation on the promoter region.	('Upregulation', 'PosReg', (0, 12))	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('miR-21', 'Gene', '406991', (26, 32))	('hypomethylation', 'Var', (79, 94))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('miR-21', 'Gene', (26, 32))
493260	33233641	In addition, histone modification on the promoter of miR-200b/200a/429 cluster causes silencing of miR-200 family members and promotes stemness of breast cancer cells.	('miR-200b', 'Gene', '406984', (53, 61))	('miR-200b', 'Gene', (53, 61))	('breast cancer', 'Phenotype', 'HP:0003002', (147, 160))	('promotes', 'PosReg', (126, 134))	('silencing', 'MPA', (86, 95))	('miR-200 family', 'Gene', (99, 113))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('stemness of breast cancer', 'Disease', (135, 160))	('stemness of breast cancer', 'Disease', 'MESH:D001943', (135, 160))	('histone modification', 'Var', (13, 33))
493263	33233641	ITGA1 mRNA functions as a sponge against miR-181b and relieves ADCY9 targeting.	('ITGA1', 'Gene', '3672', (0, 5))	('ITGA1', 'Gene', (0, 5))	('miR-181b', 'Var', (41, 49))	('ADCY9', 'Gene', (63, 68))	('relieves', 'NegReg', (54, 62))	('ADCY9', 'Gene', '115', (63, 68))
493287	33233641	Several studies have reported that HIF1alpha is also targeted by several miRNAs, such as miR-130a, miR-199a, and miR-200c.	('miR-130a', 'Gene', (89, 97))	('miR-200c', 'Gene', (113, 121))	('miR-200c', 'Gene', '406985', (113, 121))	('miR-130a', 'Gene', '406919', (89, 97))	('miR-199a', 'Var', (99, 107))	('HIF1alpha', 'Gene', (35, 44))	('targeted', 'Reg', (53, 61))	('HIF1alpha', 'Gene', '3091', (35, 44))
493305	33233641	miR-138, miR-140, and miR-142 have also been reported to target PD-L1.	('miR-140', 'Gene', '406932', (9, 16))	('miR-138', 'Chemical', '-', (0, 7))	('miR-138', 'Var', (0, 7))	('PD-L1', 'Gene', (64, 69))	('miR-142', 'Gene', '406934', (22, 29))	('miR-140', 'Gene', (9, 16))	('miR-142', 'Gene', (22, 29))	('PD-L1', 'Gene', '29126', (64, 69))
493310	33233641	Ectopic expression of miR-200 family members induces MET in highly metastatic lung cancer cells.	('lung cancer', 'Disease', (78, 89))	('lung cancer', 'Phenotype', 'HP:0100526', (78, 89))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('induces', 'Reg', (45, 52))	('Ectopic expression', 'Var', (0, 18))	('highly metastatic', 'CPA', (60, 77))	('lung cancer', 'Disease', 'MESH:D008175', (78, 89))	('miR-200', 'Gene', (22, 29))	('MET', 'Gene', '79811', (53, 56))	('MET', 'Gene', (53, 56))
493317	33233641	For example, activating mutations in epidermal growth factor receptor (EGFR) and mutations in anaplastic lymphoma kinase (ALK) fusion proteins usually occur in LUAD, but not in LUSC, rendering therapy targeted at these genes ineffective for LUSC.	('lymphoma', 'Phenotype', 'HP:0002665', (105, 113))	('activating', 'PosReg', (13, 23))	('epidermal growth factor receptor', 'Gene', '1956', (37, 69))	('ALK', 'Gene', (122, 125))	('EGFR', 'Gene', '1956', (71, 75))	('LUAD', 'Disease', (160, 164))	('epidermal growth factor receptor', 'Gene', (37, 69))	('anaplastic lymphoma kinase', 'Gene', '238', (94, 120))	('mutations', 'Var', (81, 90))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (94, 113))	('mutations', 'Var', (24, 33))	('anaplastic lymphoma kinase', 'Gene', (94, 120))	('EGFR', 'Gene', (71, 75))	('ALK', 'Gene', '238', (122, 125))
493319	33233641	In a previous report, four miRNAs (miR-205, miR-93, miR-221, and miR-30e) were shown to be highly expressed in LUSC, and five miRNAs (miR-29b, miR-29c, let-7e, miR-100, and miR-125a-5p) were highly expressed in LUAD.	('miR-100', 'Gene', '406892', (160, 167))	('miR-29b', 'Gene', (134, 141))	('miR-30e', 'Gene', (65, 72))	('miR-221', 'Gene', (52, 59))	('let-7e', 'Gene', '406887', (152, 158))	('miR-29b', 'Gene', '407024', (134, 141))	('miR-29c', 'Gene', (143, 150))	('miR-205', 'Gene', (35, 42))	('miR-100', 'Gene', (160, 167))	('let-7e', 'Gene', (152, 158))	('miR-29c', 'Gene', '407026', (143, 150))	('miR-30e', 'Gene', '407034', (65, 72))	('miR-125a-5p', 'Var', (173, 184))	('miR-205', 'Gene', '406988', (35, 42))	('miR-93', 'Gene', '407051', (44, 50))	('miR-221', 'Gene', '407006', (52, 59))	('miR-93', 'Gene', (44, 50))
493328	33233641	In a study with drug-resistant NSCLC cell lines, several markers were identified as being predictive of the degree of responsiveness to therapy, with miR-192, miR-194, miR-205, miR-30a, and miR-30c demonstrated to be predictive factors for a positive response to chemotherapy.	('miR-192', 'Gene', '406967', (150, 157))	('miR-30c', 'Gene', '407031', (190, 197))	('NSCLC', 'Disease', (31, 36))	('miR-30a', 'Gene', '407029', (177, 184))	('NSCLC', 'Disease', 'MESH:D002289', (31, 36))	('miR-194', 'Var', (159, 166))	('miR-205', 'Gene', (168, 175))	('SCLC', 'Phenotype', 'HP:0030357', (32, 36))	('miR-30a', 'Gene', (177, 184))	('miR-205', 'Gene', '406988', (168, 175))	('miR-30c', 'Gene', (190, 197))	('NSCLC', 'Phenotype', 'HP:0030358', (31, 36))	('miR-192', 'Gene', (150, 157))
493329	33233641	In an analysis of 148 LUAD patients who were negative for EGFR mutations or ALK translocations and who received maintenance treatment with pemetrexed, progression-free survival duration for patients expressing different levels of circulating miR-25, miR-145, and miR-210 were significantly different in the pemetrexed-treated group, suggesting these three miRNAs are predictors for the efficacy of maintenance treatment.	('mutations', 'Var', (63, 72))	('EGFR', 'Gene', '1956', (58, 62))	('miR-25', 'Gene', (242, 248))	('patients', 'Species', '9606', (190, 198))	('miR-145', 'Gene', (250, 257))	('EGFR', 'Gene', (58, 62))	('miR-210', 'Gene', (263, 270))	('miR-145', 'Gene', '406937', (250, 257))	('ALK', 'Gene', '238', (76, 79))	('miR-210', 'Gene', '406992', (263, 270))	('patients', 'Species', '9606', (27, 35))	('pemetrexed', 'Chemical', 'MESH:D000068437', (307, 317))	('ALK', 'Gene', (76, 79))	('miR-25', 'Gene', '407014', (242, 248))	('pemetrexed', 'Chemical', 'MESH:D000068437', (139, 149))	('different', 'Reg', (290, 299))
493331	33233641	In a comparative analysis between responders and non-responders to PD-1/PD-L1 inhibitors, miR-320 family members, such as miR-320d, miR-320c, and miR-320b, were identified as potential biomarkers for predicting the efficacy of immunotherapy in advanced NSCLC.	('miR-320b', 'Var', (146, 154))	('PD-1', 'Gene', (67, 71))	('SCLC', 'Phenotype', 'HP:0030357', (254, 258))	('PD-L1', 'Gene', '29126', (72, 77))	('NSCLC', 'Phenotype', 'HP:0030358', (253, 258))	('miR-320', 'Gene', (90, 97))	('miR-320c', 'Var', (132, 140))	('PD-1', 'Gene', '6622', (67, 71))	('NSCLC', 'Disease', (253, 258))	('miR-320d', 'Var', (122, 130))	('NSCLC', 'Disease', 'MESH:D002289', (253, 258))	('PD-L1', 'Gene', (72, 77))
493345	33233641	In in vivo lung cancer models for therapeutic applications, miR-15/16, miR-29b, miR-7, miR-34a, let-7, miR-200c, and miR-145 were tested using different delivery systems.	('miR-15/16', 'Var', (60, 69))	('miR-200c', 'Gene', (103, 111))	('miR-34a', 'Gene', '407040', (87, 94))	('miR-29b', 'Gene', (71, 78))	('miR-145', 'Gene', '406937', (117, 124))	('miR-200c', 'Gene', '406985', (103, 111))	('miR-7', 'Gene', (80, 85))	('miR-34a', 'Gene', (87, 94))	('lung cancer', 'Disease', (11, 22))	('lung cancer', 'Phenotype', 'HP:0100526', (11, 22))	('miR-7', 'Gene', '10859', (80, 85))	('miR-29b', 'Gene', '407024', (71, 78))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('miR-145', 'Gene', (117, 124))	('lung cancer', 'Disease', 'MESH:D008175', (11, 22))
493360	33233641	and by a grant from the National R&D Program for Cancer Control, Ministry of Health & Welfare, Republic of Korea (1720100 to Y.H.K.).	('Cancer', 'Phenotype', 'HP:0002664', (49, 55))	('Cancer', 'Disease', 'MESH:D009369', (49, 55))	('Cancer', 'Disease', (49, 55))	('of Korea', 'Var', (104, 112))
493537	32578965	Table 4 summarizes the response rates and OS in previous studies of EGFR inhibitors or cytotoxic chemotherapy for patients with advanced CSCC.	('CSCC', 'Phenotype', 'HP:0006739', (137, 141))	('EGFR', 'Gene', (68, 72))	('EGFR', 'Gene', '1956', (68, 72))	('patients', 'Species', '9606', (114, 122))	('inhibitors', 'Var', (73, 83))
493549	32578965	This retrospective study confirms the limited efficacy of cytotoxic chemotherapy and EGFR inhibitors in a real-world population that is twice as large as that of any prior study of these agents in the treatment of advanced CSCC.	('EGFR', 'Gene', (85, 89))	('CSCC', 'Phenotype', 'HP:0006739', (223, 227))	('EGFR', 'Gene', '1956', (85, 89))	('inhibitors', 'Var', (90, 100))	('men', 'Species', '9606', (206, 209))
493566	28533227	Several studies report loss of heterozygosity, chromosomal aneusomy, and aberrant methylation and protein expression in bronchial PMLs.	('chromosomal aneusomy', 'Disease', (47, 67))	('PML', 'Gene', '5371', (130, 133))	('chromosomal aneusomy', 'Disease', 'MESH:D002869', (47, 67))	('aberrant', 'Var', (73, 81))	('PML', 'Gene', (130, 133))	('loss', 'NegReg', (23, 27))	('protein', 'Protein', (98, 105))	('methylation', 'MPA', (82, 93))
493618	28533227	There was a greater reduction in OCR in PMLs immediately following oligomycin treatment (p<0.022) suggesting an increased dependence on OXPHOS for ATP production to meet energetic demands.	('OCR', 'MPA', (33, 36))	('oligomycin', 'Chemical', 'MESH:D009840', (67, 77))	('ATP', 'Chemical', 'MESH:D000255', (147, 150))	('PML', 'Gene', (40, 43))	('oligomycin', 'Var', (67, 77))	('dependence', 'MPA', (122, 132))	('reduction', 'NegReg', (20, 29))	('PML', 'Gene', '5371', (40, 43))
493686	25364428	For example, lung adenocarcinoma patients with an epidermal growth factor receptor (EGFR) mutation or with an ELM4-ALK fusion protein have been shown to respond well to the corresponding drugs.	('ALK', 'Gene', (115, 118))	('patients', 'Species', '9606', (33, 41))	('epidermal growth factor receptor', 'Gene', '1956', (50, 82))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (13, 32))	('carcinoma', 'Phenotype', 'HP:0030731', (23, 32))	('ALK', 'Gene', '238', (115, 118))	('EGFR', 'Gene', '1956', (84, 88))	('epidermal growth factor receptor', 'Gene', (50, 82))	('EGFR', 'Gene', (84, 88))	('mutation', 'Var', (90, 98))	('lung adenocarcinoma', 'Disease', (13, 32))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (13, 32))
493690	25364428	Silencing of the IGF2 gene was recently reported to result in apoptosis only for IGF2 LOI colorectal carcinomas.	('colorectal carcinomas', 'Disease', 'MESH:D015179', (90, 111))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('colorectal carcinomas', 'Disease', (90, 111))	('IGF2', 'Gene', '3481', (81, 85))	('IGF2', 'Gene', '3481', (17, 21))	('carcinomas', 'Phenotype', 'HP:0030731', (101, 111))	('apoptosis', 'CPA', (62, 71))	('IGF2', 'Gene', (17, 21))	('Silencing', 'Var', (0, 9))	('IGF2', 'Gene', (81, 85))	('LOI', 'Var', (86, 89))
493693	25364428	In the present study, the precise incidence of IGF2 LOI in lung carcinomas was examined using PCR-RFLP in combination with DNA sequencing of samples obtained by a laser capture microdissection (LCM) method, as reported previously.	('LOI', 'Var', (52, 55))	('lung carcinomas', 'Disease', (59, 74))	('IGF2', 'Gene', '3481', (47, 51))	('IGF2', 'Gene', (47, 51))	('lung carcinomas', 'Disease', 'MESH:D008175', (59, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))	('carcinomas', 'Phenotype', 'HP:0030731', (64, 74))
493713	25364428	Since a previous study concerning IGF2 LOI in lung adenocarcinoma refers to histological type, the association between the histological grade of the adenocarcinoma sample and LOI was also analyzed in the present study.	('adenocarcinoma', 'Disease', 'MESH:D000230', (149, 163))	('lung adenocarcinoma', 'Disease', (46, 65))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (46, 65))	('LOI', 'Var', (39, 42))	('IGF2', 'Gene', '3481', (34, 38))	('adenocarcinoma', 'Disease', (51, 65))	('adenocarcinoma', 'Disease', (149, 163))	('carcinoma', 'Phenotype', 'HP:0030731', (154, 163))	('adenocarcinoma', 'Disease', 'MESH:D000230', (51, 65))	('IGF2', 'Gene', (34, 38))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (46, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (56, 65))
493715	25364428	These results do not support the previous suggestion that IGF2 LOI occurs more frequently in poorly differentiated adenocarcinomas.	('IGF2', 'Gene', (58, 62))	('LOI', 'Var', (63, 66))	('adenocarcinomas', 'Disease', 'MESH:D000230', (115, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('IGF2', 'Gene', '3481', (58, 62))	('carcinomas', 'Phenotype', 'HP:0030731', (120, 130))	('adenocarcinomas', 'Disease', (115, 130))
493717	25364428	IGF2 LOI was found to increase IGF2 signaling by increasing the proliferation of expression-related genes.	('IGF2', 'Gene', (31, 35))	('proliferation of expression-related genes', 'MPA', (64, 105))	('LOI', 'Var', (5, 8))	('increase', 'PosReg', (22, 30))	('increase IGF2 signaling', 'Phenotype', 'HP:0030269', (22, 45))	('IGF2', 'Gene', '3481', (0, 4))	('increasing', 'PosReg', (49, 59))	('IGF2', 'Gene', '3481', (31, 35))	('IGF2', 'Gene', (0, 4))
493718	25364428	We hypothesize that IGF2 LOI leads to an increased the risk of malignant transformation.	('IGF2', 'Gene', (20, 24))	('malignant transformation', 'CPA', (63, 87))	('LOI', 'Var', (25, 28))	('IGF2', 'Gene', '3481', (20, 24))
493720	25364428	A number of adenocarcinoma-specific gene alterations are known, including EGFR, KRAS and BRAF, and these affect the gene products of the MAP kinase and PI3/AKT signaling pathways.	('KRAS', 'Gene', (80, 84))	('PI3', 'Gene', (152, 155))	('adenocarcinoma', 'Disease', 'MESH:D000230', (12, 26))	('affect', 'Reg', (105, 111))	('gene', 'MPA', (116, 120))	('KRAS', 'Gene', '3845', (80, 84))	('EGFR', 'Gene', '1956', (74, 78))	('BRAF', 'Gene', '673', (89, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (17, 26))	('BRAF', 'Gene', (89, 93))	('adenocarcinoma', 'Disease', (12, 26))	('EGFR', 'Gene', (74, 78))	('PI3', 'Gene', '5266', (152, 155))	('alterations', 'Var', (41, 52))
493723	25364428	The incidence of IGF2 LOI in adenocarcinoma (62%) appears high as compared with other adenocarcinoma-specific gene alterations.	('adenocarcinoma', 'Disease', 'MESH:D000230', (29, 43))	('LOI', 'Var', (22, 25))	('IGF2', 'Gene', '3481', (17, 21))	('adenocarcinoma', 'Disease', (86, 100))	('IGF2', 'Gene', (17, 21))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (34, 43))	('adenocarcinoma', 'Disease', (29, 43))	('adenocarcinoma', 'Disease', 'MESH:D000230', (86, 100))
493724	25364428	A previous study indicated that the most frequent gene alteration in lung adenocarcinomas in Japanese patients is the EGFR mutation, with an incidence of 38%, while the most frequent gene alteration in Caucasians is KRAS mutation, with an incidence of 30%.	('lung adenocarcinomas', 'Disease', (69, 89))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (69, 89))	('mutation', 'Var', (123, 131))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (69, 89))	('patients', 'Species', '9606', (102, 110))	('EGFR', 'Gene', '1956', (118, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('EGFR', 'Gene', (118, 122))	('KRAS', 'Gene', (216, 220))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (69, 88))	('carcinomas', 'Phenotype', 'HP:0030731', (79, 89))	('KRAS', 'Gene', '3845', (216, 220))
493725	25364428	The high incidence of the IGF2 mutation in the present study, as compared with the incidences of other genes detected in previous studies, suggests an important role for the IGF2 mutation in lung carcinogenesis.	('IGF2', 'Gene', '3481', (26, 30))	('mutation', 'Var', (31, 39))	('mutation', 'Var', (179, 187))	('IGF2', 'Gene', '3481', (174, 178))	('lung carcinogenesis', 'Disease', (191, 210))	('IGF2', 'Gene', (26, 30))	('lung carcinogenesis', 'Disease', 'MESH:D063646', (191, 210))	('IGF2', 'Gene', (174, 178))
493726	25364428	In the present study, IGF2 LOI was detected in approximately half of adenocarcinomas but not in any of the squamous cell carcinomas examined; thus, IGF2 LOI may be a marker of lung adenocarcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('carcinomas', 'Phenotype', 'HP:0030731', (121, 131))	('IGF2', 'Gene', (148, 152))	('adenocarcinomas', 'Disease', 'MESH:D000230', (69, 84))	('adenocarcinomas', 'Disease', (69, 84))	('IGF2', 'Gene', (22, 26))	('carcinomas', 'Phenotype', 'HP:0030731', (74, 84))	('lung adenocarcinoma', 'Disease', (176, 195))	('LOI', 'Var', (153, 156))	('IGF2', 'Gene', '3481', (148, 152))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (107, 131))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (176, 195))	('IGF2', 'Gene', '3481', (22, 26))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (107, 131))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (176, 195))	('carcinoma', 'Phenotype', 'HP:0030731', (186, 195))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (107, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('squamous cell carcinomas', 'Disease', (107, 131))
493729	25364428	In conclusion, in the present study, IGF2 LOI was observed to occur at a high frequency in lung adenocarcinoma, but was not observed in squamous cell carcinoma.	('LOI', 'Var', (42, 45))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (91, 110))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('IGF2', 'Gene', '3481', (37, 41))	('lung adenocarcinoma', 'Disease', (91, 110))	('carcinoma', 'Phenotype', 'HP:0030731', (150, 159))	('IGF2', 'Gene', (37, 41))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (136, 159))	('squamous cell carcinoma', 'Disease', (136, 159))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (91, 110))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (136, 159))
493732	31746315	Epidermal Growth Factor Receptor Mutations in Resectable Non-Small Cell Lung Cancer Patients and their Potential Role in the Immune Landscape The epidermal growth factor receptor (EGFR) is a therapeutic target for non-small cell lung cancer (NSCLC), but knowledge on gene mutations that contribute to NSCLC development and persistence is lacking.	('Lung Cancer', 'Phenotype', 'HP:0100526', (72, 83))	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (218, 240))	('NSCLC', 'Disease', (301, 306))	('Non-Small Cell Lung Cancer', 'Disease', (57, 83))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (214, 240))	('Mutations', 'Var', (33, 42))	('EGFR', 'Gene', '1956', (180, 184))	('Small Cell Lung Cancer', 'Phenotype', 'HP:0030357', (61, 83))	('Non-Small Cell Lung Cancer', 'Phenotype', 'HP:0030358', (57, 83))	('NSCLC', 'Disease', 'MESH:D002289', (242, 247))	('Epidermal Growth Factor Receptor', 'Gene', (0, 32))	('non-small cell lung cancer', 'Disease', (214, 240))	('epidermal growth factor receptor', 'Gene', (146, 178))	('NSCLC', 'Disease', (242, 247))	('epidermal growth factor receptor', 'Gene', '1956', (146, 178))	('lung cancer', 'Phenotype', 'HP:0100526', (229, 240))	('Epidermal Growth Factor Receptor', 'Gene', '1956', (0, 32))	('Patients', 'Species', '9606', (84, 92))	('Cancer', 'Phenotype', 'HP:0002664', (77, 83))	('EGFR', 'Gene', (180, 184))	('Non-Small Cell Lung Cancer', 'Disease', 'MESH:D002289', (57, 83))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (214, 240))	('NSCLC', 'Disease', 'MESH:D002289', (301, 306))
493735	31746315	EGFR mutation frequencies were 54.4% (180 of 331 patients) and 8.0% (83 of 1040 patients) in the clinical and TCGA cohorts, respectively.	('EGFR', 'Gene', (0, 4))	('patients', 'Species', '9606', (80, 88))	('clinical', 'Species', '191496', (97, 105))	('patients', 'Species', '9606', (49, 57))	('EGFR', 'Gene', '1956', (0, 4))	('mutation', 'Var', (5, 13))
493736	31746315	EGFR mutations were strongly associated with smoking and pathology (P<=0.05) in the clinical cohort, and with gender, smoking, and pathology (P=0.001, P<0.001, and P<0.001, respectively) in TCGA cohort.	('EGFR', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))	('clinical', 'Species', '191496', (84, 92))	('associated', 'Reg', (29, 39))	('EGFR', 'Gene', '1956', (0, 4))
493737	31746315	In cases of lung squamous carcinoma (LUSC), EGFR was overexpressed as a result of DNA amplification, but this amplified expression showed no association with the overall survival (OS) or progression-free survival of LUSC patients.	('patients', 'Species', '9606', (221, 229))	('lung squamous carcinoma', 'Phenotype', 'HP:0030359', (12, 35))	('LUSC', 'Disease', 'MESH:D002294', (216, 220))	('lung squamous carcinoma', 'Disease', (12, 35))	('LUSC', 'Disease', 'MESH:D002294', (37, 41))	('LUSC', 'Disease', (37, 41))	('carcinoma', 'Phenotype', 'HP:0030731', (26, 35))	('EGFR', 'Gene', '1956', (44, 48))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (17, 35))	('EGFR', 'Gene', (44, 48))	('overexpressed', 'PosReg', (53, 66))	('DNA amplification', 'Var', (82, 99))	('LUSC', 'Disease', (216, 220))	('lung squamous carcinoma', 'Disease', 'MESH:D002294', (12, 35))
493738	31746315	EGFR gene alterations were, however, associated with worse OS in lung adenocarcinoma (LUAD) patients.	('alterations', 'Var', (10, 21))	('EGFR', 'Gene', (0, 4))	('patients', 'Species', '9606', (92, 100))	('LUAD', 'Disease', (86, 90))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('LUAD', 'Disease', 'MESH:C538231', (86, 90))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (65, 84))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (65, 84))	('EGFR', 'Gene', '1956', (0, 4))	('lung adenocarcinoma', 'Disease', (65, 84))
493740	31746315	EGFR mutations resulted in a decline of immune infiltration or a lack of infiltrating immune cells in the NSCLC microenvironment.	('NSCLC', 'Disease', 'MESH:D002289', (106, 111))	('EGFR', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))	('immune infiltration', 'CPA', (40, 59))	('decline', 'NegReg', (29, 36))	('EGFR', 'Gene', '1956', (0, 4))	('NSCLC', 'Disease', (106, 111))
493743	31746315	A range of driver gene mutations have been implicated in lung cancer development including epidermal growth factor receptor (EGFR) and ROS1 mutations.	('epidermal growth factor receptor', 'Gene', '1956', (91, 123))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('EGFR', 'Gene', '1956', (125, 129))	('implicated', 'Reg', (43, 53))	('ROS1', 'Gene', '6098', (135, 139))	('lung cancer', 'Disease', 'MESH:D008175', (57, 68))	('EGFR', 'Gene', (125, 129))	('mutations', 'Var', (23, 32))	('epidermal growth factor receptor', 'Gene', (91, 123))	('mutations', 'Var', (140, 149))	('ROS1', 'Gene', (135, 139))	('lung cancer', 'Disease', (57, 68))	('lung cancer', 'Phenotype', 'HP:0100526', (57, 68))
493744	31746315	Precision therapy using tyrosine kinase inhibitors (TKIs) can improve prognosis in those patients harboring specific genetic alterations, producing response rates of up to 80% in non-small cell lung cancer (NSCLC) patients with TKI-sensitive EGFR mutations.	('lung cancer', 'Phenotype', 'HP:0100526', (194, 205))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (179, 205))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('patients', 'Species', '9606', (214, 222))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (183, 205))	('tyrosine', 'Chemical', 'None', (24, 32))	('alterations', 'Var', (125, 136))	('EGFR', 'Gene', '1956', (242, 246))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (179, 205))	('patients', 'Species', '9606', (89, 97))	('non-small cell lung cancer', 'Disease', (179, 205))	('EGFR', 'Gene', (242, 246))	('NSCLC', 'Disease', (207, 212))	('mutations', 'Var', (247, 256))	('NSCLC', 'Disease', 'MESH:D002289', (207, 212))	('TKI-sensitive', 'Gene', (228, 241))
493750	31746315	However, EGFR mutation profiles in resectable NSCLC are rare.	('NSCLC', 'Disease', (46, 51))	('EGFR', 'Gene', '1956', (9, 13))	('mutation', 'Var', (14, 22))	('EGFR', 'Gene', (9, 13))	('NSCLC', 'Disease', 'MESH:D002289', (46, 51))
493753	31746315	Inhibiting the PD1/PDL1 interaction is efficacious in NSCLC immunotherapy owing to immune cell effector reactivity on NSCLC.	('PDL1', 'Gene', (19, 23))	('Inhibiting', 'Var', (0, 10))	('interaction', 'Interaction', (24, 35))	('NSCLC', 'Disease', 'MESH:D002289', (118, 123))	('PDL1', 'Gene', '29126', (19, 23))	('PD1', 'Gene', (15, 18))	('PD1', 'Gene', '5133', (15, 18))	('NSCLC', 'Disease', (118, 123))	('NSCLC', 'Disease', (54, 59))	('NSCLC', 'Disease', 'MESH:D002289', (54, 59))
493761	31746315	For The Cancer Genome Atlas (TCGA) cohort, the enrollment criteria were: 1) pathologic diagnosis confirmed as NSCLC at stage I-IIIA; and 2) exon 18-21 mutations in EGFR.	('EGFR', 'Gene', (164, 168))	('Cancer', 'Phenotype', 'HP:0002664', (8, 14))	('NSCLC', 'Disease', (110, 115))	('NSCLC', 'Disease', 'MESH:D002289', (110, 115))	('exon 18-21 mutations', 'Var', (140, 160))	('EGFR', 'Gene', '1956', (164, 168))
493762	31746315	A total of 21 hotspot mutations in EGFR in exons 18-21 in the clinical cohort were subject to mutation-based amplification (CFDA #.	('EGFR', 'Gene', '1956', (35, 39))	('clinical', 'Species', '191496', (62, 70))	('mutations', 'Var', (22, 31))	('EGFR', 'Gene', (35, 39))
493769	31746315	Kaplan-Meier survival curves were used to assess the association between EGFR gene alterations and OS and progression-free survival (PFS) in LUAD and LUSC patients.	('EGFR', 'Gene', '1956', (73, 77))	('alterations', 'Var', (83, 94))	('LUAD', 'Disease', (141, 145))	('EGFR', 'Gene', (73, 77))	('LUAD', 'Disease', 'MESH:C538231', (141, 145))	('patients', 'Species', '9606', (155, 163))	('LUSC', 'Disease', 'MESH:D002294', (150, 154))	('LUSC', 'Disease', (150, 154))
493775	31746315	Mutation models were used to quantify the levels of immune cell infiltration according to somatic copy number alterations in EGFR according to the SCNA module.	('EGFR', 'Gene', '1956', (125, 129))	('EGFR', 'Gene', (125, 129))	('alterations', 'Var', (110, 121))	('copy number alterations', 'Var', (98, 121))
493776	31746315	EGFR mutations and clinical outcomes were compared using Fisher's or chi2 tests.	('EGFR', 'Gene', '1956', (0, 4))	('EGFR', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))	('clinical', 'Species', '191496', (19, 27))
493780	31746315	The presence of EGFR mutations was assessed by ARMS.	('EGFR', 'Gene', '1956', (16, 20))	('EGFR', 'Gene', (16, 20))	('mutations', 'Var', (21, 30))
493785	31746315	Gender, smoking, pathology, and differentiation were significantly associated with EGFR mutation frequency in the univariate analysis (Table 1, P=0.013, P<0.001, P<0.002, P<0.001, respectively).	('EGFR', 'Gene', '1956', (83, 87))	('mutation', 'Var', (88, 96))	('EGFR', 'Gene', (83, 87))	('associated', 'Reg', (67, 77))
493786	31746315	The multivariate logistic regression showed that smoking (P=0.009) and pathology (P=0.017) were 2 independent factors associated with the frequency of EGFR mutations.	('mutations', 'Var', (156, 165))	('EGFR', 'Gene', '1956', (151, 155))	('EGFR', 'Gene', (151, 155))
493791	31746315	The EGFR mutation frequency was 7.98% (83 of 1040 cases) in TCGA cohort.	('EGFR', 'Gene', (4, 8))	('TCGA', 'Disease', (60, 64))	('mutation', 'Var', (9, 17))	('EGFR', 'Gene', '1956', (4, 8))
493792	31746315	In the univariate analysis, gender, smoking, and pathology showed significant associations with the frequency of EGFR mutations (Table 2, P<0.001 for all).	('mutations', 'Var', (118, 127))	('EGFR', 'Gene', '1956', (113, 117))	('associations', 'Interaction', (78, 90))	('EGFR', 'Gene', (113, 117))
493793	31746315	The multivariate logistic regression showed that gender, smoking, and pathology were 3 independent factors associated with EGFR mutation frequency (Table 2, P=0.001, P<0.001, and P<0.001, respectively).	('EGFR', 'Gene', (123, 127))	('mutation', 'Var', (128, 136))	('EGFR', 'Gene', '1956', (123, 127))
493798	31746315	Figure 2C shows that EGFR mutations occurred in ~16% and ~9% of LUAD and LUSC cases, respectively.	('EGFR', 'Gene', '1956', (21, 25))	('EGFR', 'Gene', (21, 25))	('LUSC', 'Disease', 'MESH:D002294', (73, 77))	('occurred', 'Reg', (36, 44))	('LUSC', 'Disease', (73, 77))	('mutations', 'Var', (26, 35))	('LUAD', 'Disease', (64, 68))	('LUAD', 'Disease', 'MESH:C538231', (64, 68))
493799	31746315	EGFR amplification was predominant in both cancer types as revealed from the EGFR copy numbers (Figure 3A, 3B).	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('EGFR', 'Gene', (0, 4))	('copy', 'Var', (82, 86))	('cancer', 'Disease', (43, 49))	('amplification', 'Var', (5, 18))	('EGFR', 'Gene', '1956', (77, 81))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('EGFR', 'Gene', '1956', (0, 4))	('EGFR', 'Gene', (77, 81))
493804	31746315	LUAD patients with EGFR gene alterations had significantly worse OS (Figure 5A; P<0.01).	('worse', 'NegReg', (59, 64))	('LUAD', 'Disease', (0, 4))	('LUAD', 'Disease', 'MESH:C538231', (0, 4))	('patients', 'Species', '9606', (5, 13))	('EGFR', 'Gene', (19, 23))	('EGFR', 'Gene', '1956', (19, 23))	('alterations', 'Var', (29, 40))	('gene alterations', 'Var', (24, 40))
493805	31746315	However, there was no association of EGFR alterations with PFS in LUAD patients (Figure 5B).	('LUAD', 'Disease', (66, 70))	('alterations', 'Var', (42, 53))	('patients', 'Species', '9606', (71, 79))	('LUAD', 'Disease', 'MESH:C538231', (66, 70))	('EGFR', 'Gene', '1956', (37, 41))	('EGFR', 'Gene', (37, 41))	('PFS', 'Disease', (59, 62))
493806	31746315	By contrast, EGFR gene alterations did not prominently affect OS or PFS in LUSC patients (Figure 5C, 5D).	('affect', 'Reg', (55, 61))	('patients', 'Species', '9606', (80, 88))	('alterations', 'Var', (23, 34))	('LUSC', 'Disease', 'MESH:D002294', (75, 79))	('PFS', 'Disease', (68, 71))	('EGFR', 'Gene', '1956', (13, 17))	('EGFR', 'Gene', (13, 17))	('LUSC', 'Disease', (75, 79))
493817	31746315	In LUAD patients, those with mutated EGFR had significantly higher infiltration of B and dendritic cells (Figure 8).	('LUAD', 'Disease', (3, 7))	('LUAD', 'Disease', 'MESH:C538231', (3, 7))	('higher', 'PosReg', (60, 66))	('infiltration', 'MPA', (67, 79))	('EGFR', 'Gene', '1956', (37, 41))	('mutated', 'Var', (29, 36))	('EGFR', 'Gene', (37, 41))	('patients', 'Species', '9606', (8, 16))
493818	31746315	This implied that the immune response to LUAD in mutated and wild-type patients was disparate.	('LUAD', 'Disease', (41, 45))	('mutated', 'Var', (49, 56))	('LUAD', 'Disease', 'MESH:C538231', (41, 45))	('patients', 'Species', '9606', (71, 79))
493820	31746315	In different copy number subsets of EGFR mutations, the immune cell infiltration level decreased in deep deletion, arm-level deletion, arm-level gain, and high amplification mutations, as compared to diploid/normal, in both LUAD and LUSC patients (Figure 9).	('high amplification mutations', 'Var', (155, 183))	('mutations', 'Var', (41, 50))	('LUSC', 'Disease', (233, 237))	('LUSC', 'Disease', 'MESH:D002294', (233, 237))	('LUAD', 'Disease', (224, 228))	('decreased', 'NegReg', (87, 96))	('LUAD', 'Disease', 'MESH:C538231', (224, 228))	('deep', 'Disease', (100, 104))	('immune cell infiltration level', 'MPA', (56, 86))	('EGFR', 'Gene', '1956', (36, 40))	('gain', 'PosReg', (145, 149))	('EGFR', 'Gene', (36, 40))	('patients', 'Species', '9606', (238, 246))
493827	31746315	A larger number of EGFR mutations were observed in the clinical compared to TCGA cohort.	('clinical', 'Species', '191496', (55, 63))	('observed', 'Reg', (39, 47))	('EGFR', 'Gene', '1956', (19, 23))	('EGFR', 'Gene', (19, 23))	('mutations', 'Var', (24, 33))
493828	31746315	Tumor immune cell infiltrates in LUAD and LUSC were different, and EGFR mutations may cause the decline or lack of immune infiltration in the NSCLC microenvironment.	('mutations', 'Var', (72, 81))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('LUSC', 'Disease', 'MESH:D002294', (42, 46))	('LUSC', 'Disease', (42, 46))	('NSCLC', 'Disease', (142, 147))	('NSCLC', 'Disease', 'MESH:D002289', (142, 147))	('LUAD', 'Disease', (33, 37))	('EGFR', 'Gene', '1956', (67, 71))	('LUAD', 'Disease', 'MESH:C538231', (33, 37))	('EGFR', 'Gene', (67, 71))
493829	31746315	Compared with TCGA cohort, a larger number of EGFR mutations occurred in clinical samples.	('clinical samples', 'Species', '191496', (73, 89))	('mutations', 'Var', (51, 60))	('EGFR', 'Gene', '1956', (46, 50))	('occurred', 'Reg', (61, 69))	('EGFR', 'Gene', (46, 50))
493830	31746315	Both cohorts highlighted the relationship between smoking and pathology for EGFR mutations.	('EGFR', 'Gene', '1956', (76, 80))	('EGFR', 'Gene', (76, 80))	('mutations', 'Var', (81, 90))
493831	31746315	In our study, the EGFR mutation frequency in the clinical and TCGA cohorts had no relation with disease stage, indicating that EGFR mutations are likely to occur during the early stages of NSCLC development.	('clinical', 'Species', '191496', (49, 57))	('NSCLC', 'Disease', (189, 194))	('EGFR', 'Gene', '1956', (18, 22))	('NSCLC', 'Disease', 'MESH:D002289', (189, 194))	('mutations', 'Var', (132, 141))	('EGFR', 'Gene', (18, 22))	('EGFR', 'Gene', '1956', (127, 131))	('EGFR', 'Gene', (127, 131))
493834	31746315	Additionally, EGFR alterations in LUAD had an unfavorable influence on OS, but were not associated with changes in PFS.	('EGFR', 'Gene', '1956', (14, 18))	('LUAD', 'Disease', (34, 38))	('EGFR', 'Gene', (14, 18))	('LUAD', 'Disease', 'MESH:C538231', (34, 38))	('alterations', 'Var', (19, 30))
493835	31746315	Meanwhile, no significant relationship in LUSC was found between EGFR alterations and OS or PFS.	('alterations', 'Var', (70, 81))	('LUSC', 'Disease', 'MESH:D002294', (42, 46))	('LUSC', 'Disease', (42, 46))	('EGFR', 'Gene', '1956', (65, 69))	('EGFR', 'Gene', (65, 69))	('PFS', 'Disease', (92, 95))
493836	31746315	These results suggested that EGFR alterations might be a vital mechanism involved in long-term survival of LUAD patients.	('LUAD', 'Disease', (107, 111))	('patients', 'Species', '9606', (112, 120))	('LUAD', 'Disease', 'MESH:C538231', (107, 111))	('EGFR', 'Gene', '1956', (29, 33))	('EGFR', 'Gene', (29, 33))	('involved', 'Reg', (73, 81))	('alterations', 'Var', (34, 45))
493849	31746315	This trend was also demonstrated in B and dendritic cells of patients with mutated compared to wild-type EGFR (Figure 9), although the relationship did not reach statistical significance for CD4 T cells, CD8 T cells, macrophages, and neutrophils.	('CD8', 'Gene', '925', (204, 207))	('patients', 'Species', '9606', (61, 69))	('EGFR', 'Gene', '1956', (105, 109))	('CD4', 'Gene', (191, 194))	('mutated', 'Var', (75, 82))	('EGFR', 'Gene', (105, 109))	('CD4', 'Gene', '920', (191, 194))	('CD8', 'Gene', (204, 207))
493850	31746315	In addition, to determine the role of copy number alterations of EGFR in the immune cell infiltration level in LUAD and LUSC patients, further analyses revealed that the levels in deep deletion, arm-level deletion, arm-level gain, and high amplification mutation subtypes were decreased compared to diploid/normal.	('high amplification mutation', 'MPA', (235, 262))	('deep deletion', 'Var', (180, 193))	('EGFR', 'Gene', '1956', (65, 69))	('EGFR', 'Gene', (65, 69))	('LUAD', 'Disease', (111, 115))	('gain', 'PosReg', (225, 229))	('LUAD', 'Disease', 'MESH:C538231', (111, 115))	('LUSC', 'Disease', 'MESH:D002294', (120, 124))	('LUSC', 'Disease', (120, 124))	('decreased', 'NegReg', (277, 286))	('patients', 'Species', '9606', (125, 133))
493851	31746315	Overall, these findings indicate that mutations of EGFR might induce a decline or lack of immune cell infiltration in the tumor microenvironment, reducing the anticancer effect of immune cells.	('lack', 'NegReg', (82, 86))	('cancer', 'Disease', 'MESH:D009369', (163, 169))	('EGFR', 'Gene', (51, 55))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('immune cell infiltration in the', 'CPA', (90, 121))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('decline or lack of immune cell', 'Phenotype', 'HP:0002721', (71, 101))	('reducing', 'NegReg', (146, 154))	('mutations', 'Var', (38, 47))	('cancer', 'Disease', (163, 169))	('tumor', 'Disease', (122, 127))	('EGFR', 'Gene', '1956', (51, 55))
493854	31746315	However, the correlation between PDL1/PD1 expression and EGFR expression/mutation remains controversial.	('PDL1', 'Gene', (33, 37))	('PD1', 'Gene', (38, 41))	('EGFR', 'Gene', '1956', (57, 61))	('PDL1', 'Gene', '29126', (33, 37))	('expression/mutation', 'Var', (62, 81))	('EGFR', 'Gene', (57, 61))	('PD1', 'Gene', '5133', (38, 41))
493855	31746315	highlighted the association of elevated PDL1 levels with EGFR mutations by immunohistochemistry in 164 surgically resected NSCLC specimens.	('PDL1', 'Gene', (40, 44))	('NSCLC', 'Disease', (123, 128))	('NSCLC', 'Disease', 'MESH:D002289', (123, 128))	('EGFR', 'Gene', '1956', (57, 61))	('elevated', 'PosReg', (31, 39))	('PDL1', 'Gene', '29126', (40, 44))	('EGFR', 'Gene', (57, 61))	('mutations', 'Var', (62, 71))
493856	31746315	showed that PDL1 positivity was related to the occurrence of EGFR mutations.	('mutations', 'Var', (66, 75))	('PDL1', 'Gene', '29126', (12, 16))	('EGFR', 'Gene', '1956', (61, 65))	('EGFR', 'Gene', (61, 65))	('PDL1', 'Gene', (12, 16))
493857	31746315	highlighted a negative correlation between PDL1 and EGFR mutational status in 100 resected patients with primary LUAD, with higher rates of mutations occurring in those with low levels of PDL1 expression.	('PDL1', 'Gene', '29126', (43, 47))	('patients', 'Species', '9606', (91, 99))	('PDL1', 'Gene', (43, 47))	('PDL1', 'Gene', (188, 192))	('EGFR', 'Gene', (52, 56))	('EGFR', 'Gene', '1956', (52, 56))	('negative', 'NegReg', (14, 22))	('mutational', 'Var', (57, 67))	('LUAD', 'Disease', (113, 117))	('LUAD', 'Disease', 'MESH:C538231', (113, 117))	('PDL1', 'Gene', '29126', (188, 192))
493858	31746315	This was confirmed by a meta-analysis showing that wild-type EGFR NSCLC was more likely to be PDL1-positive compared to mutant EGFR NSCLC.	('NSCLC', 'Disease', (66, 71))	('PDL1', 'Gene', (94, 98))	('NSCLC', 'Disease', 'MESH:D002289', (66, 71))	('PDL1', 'Gene', '29126', (94, 98))	('NSCLC', 'Disease', (132, 137))	('EGFR', 'Gene', '1956', (61, 65))	('NSCLC', 'Disease', 'MESH:D002289', (132, 137))	('EGFR', 'Gene', '1956', (127, 131))	('EGFR', 'Gene', (127, 131))	('mutant', 'Var', (120, 126))	('EGFR', 'Gene', (61, 65))
493859	31746315	TKIs inhibiting EGFR activity can reduce PDL1 expression by inhibiting NF-kappaB in EGFR mutant NSCLC.	('inhibiting', 'NegReg', (60, 70))	('PDL1', 'Gene', '29126', (41, 45))	('NSCLC', 'Disease', (96, 101))	('NSCLC', 'Disease', 'MESH:D002289', (96, 101))	('reduce', 'NegReg', (34, 40))	('PDL1', 'Gene', (41, 45))	('EGFR', 'Gene', '1956', (84, 88))	('NF-kappaB', 'Protein', (71, 80))	('EGFR', 'Gene', '1956', (16, 20))	('EGFR', 'Gene', (84, 88))	('expression', 'MPA', (46, 56))	('mutant', 'Var', (89, 95))	('EGFR', 'Gene', (16, 20))
493864	31746315	First-line treatment with pembrolizumab (which blocks PD1) was ineffective in 10 patients with advanced NSCLC with mutated EGFR and positive PDL1 who did not receive TKI therapy in a phase II clinical trial.	('EGFR', 'Gene', (123, 127))	('EGFR', 'Gene', '1956', (123, 127))	('NSCLC', 'Disease', (104, 109))	('mutated', 'Var', (115, 122))	('patients', 'Species', '9606', (81, 89))	('PD1', 'Gene', '5133', (54, 57))	('PDL1', 'Gene', '29126', (141, 145))	('NSCLC', 'Disease', 'MESH:D002289', (104, 109))	('PD1', 'Gene', (54, 57))	('clinical', 'Species', '191496', (192, 200))	('PDL1', 'Gene', (141, 145))
493866	31746315	High PDL1 expression correlated with poor responses to TKI therapy in those harboring EGFR mutations, whilst higher PDL1 expression was associated with TKI resistance in advanced LUAD patients harboring EGFR mutations.	('associated', 'Reg', (136, 146))	('responses', 'MPA', (42, 51))	('LUAD', 'Disease', 'MESH:C538231', (179, 183))	('PDL1', 'Gene', (5, 9))	('EGFR', 'Gene', '1956', (203, 207))	('patients', 'Species', '9606', (184, 192))	('PDL1', 'Gene', (116, 120))	('EGFR', 'Gene', '1956', (86, 90))	('EGFR', 'Gene', (203, 207))	('expression', 'MPA', (121, 131))	('expression', 'MPA', (10, 20))	('EGFR', 'Gene', (86, 90))	('mutations', 'Var', (91, 100))	('PDL1', 'Gene', '29126', (5, 9))	('PDL1', 'Gene', '29126', (116, 120))	('LUAD', 'Disease', (179, 183))
493867	31746315	Despite the poor efficacy of TKI therapy in those with high PDL1 expression upon first-line treatment, the efficacy improved in third generation treatment and appeared unaffected by PDL1 expression.	('PDL1', 'Gene', (60, 64))	('PDL1', 'Gene', '29126', (182, 186))	('PDL1', 'Gene', (182, 186))	('expression', 'MPA', (65, 75))	('high', 'Var', (55, 59))	('PDL1', 'Gene', '29126', (60, 64))	('improved', 'PosReg', (116, 124))
493868	31746315	Given these findings, EGFR mutant and PDL1-positive patients should receive TKIs targeting the EGFR as a first-line therapy.	('PDL1', 'Gene', '29126', (38, 42))	('EGFR', 'Gene', (22, 26))	('mutant', 'Var', (27, 33))	('PDL1', 'Gene', (38, 42))	('EGFR', 'Gene', '1956', (22, 26))	('EGFR', 'Gene', '1956', (95, 99))	('patients', 'Species', '9606', (52, 60))	('EGFR', 'Gene', (95, 99))
493869	31746315	PDL1 immunohistochemical analysis was not performed in the clinical cohort, and the correlation of PDL1 and EGFR mutations in resectable NSCLC must be performed.	('PDL1', 'Gene', '29126', (99, 103))	('NSCLC', 'Disease', (137, 142))	('PDL1', 'Gene', '29126', (0, 4))	('EGFR', 'Gene', '1956', (108, 112))	('EGFR', 'Gene', (108, 112))	('NSCLC', 'Disease', 'MESH:D002289', (137, 142))	('PDL1', 'Gene', (99, 103))	('PDL1', 'Gene', (0, 4))	('mutations', 'Var', (113, 122))	('clinical', 'Species', '191496', (59, 67))
493872	31746315	This study demonstrated that EGFR mutations are frequent in resectable lung cancer and contribute to the long-term survival outcomes of LUAD patients.	('contribute', 'Reg', (87, 97))	('lung cancer', 'Disease', 'MESH:D008175', (71, 82))	('patients', 'Species', '9606', (141, 149))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('EGFR', 'Gene', '1956', (29, 33))	('EGFR', 'Gene', (29, 33))	('frequent', 'Reg', (48, 56))	('mutations', 'Var', (34, 43))	('LUAD', 'Disease', (136, 140))	('LUAD', 'Disease', 'MESH:C538231', (136, 140))	('lung cancer', 'Disease', (71, 82))	('lung cancer', 'Phenotype', 'HP:0100526', (71, 82))
493874	31746315	EGFR mutations decrease immune cell infiltration in the tumor microenvironment, decreasing the anticancer effect of immune cells.	('decreasing', 'NegReg', (80, 90))	('decrease', 'NegReg', (15, 23))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('EGFR', 'Gene', (0, 4))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('tumor', 'Disease', (56, 61))	('decrease immune cell', 'Phenotype', 'HP:0002721', (15, 35))	('mutations', 'Var', (5, 14))	('cancer', 'Disease', (99, 105))	('immune cell infiltration in the', 'CPA', (24, 55))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('EGFR', 'Gene', '1956', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
493918	30075545	The uptake of 18F-FDG is mainly related to Glut-1 (facilitative glucose transporter), which is highly expressed in malignant tumor cells.	('Glut-1', 'Gene', '6513', (43, 49))	('18F-FDG', 'Var', (14, 21))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('glucose', 'Chemical', 'MESH:D005947', (64, 71))	('malignant tumor', 'Disease', (115, 130))	('18F-FDG', 'Chemical', 'MESH:D019788', (14, 21))	('uptake', 'MPA', (4, 10))	('Glut-1', 'Gene', (43, 49))	('malignant tumor', 'Disease', 'MESH:D018198', (115, 130))
493939	30075545	There were more lesions with high-intake of FDG in benign nodules such as TB, inflammatory pseudotumor, pulmonary and cryptococcus, which leads to a large overlap of the SUVmax between benign and malignant nodules, and which is the reason for simple PET diagnosis being less effective.	('pulmonary', 'Disease', (104, 113))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('FDG', 'Gene', (44, 47))	('tumor', 'Disease', (97, 102))	('cryptococcus', 'Disease', (118, 130))	('high-intake', 'Var', (29, 40))
493953	28938570	This study demonstrated that PD-L1 expression is an independent prognostic factor for poor survival in NSCLC patients, especially those with non-squamous NSCLC.	('NSCLC', 'Disease', 'MESH:D002289', (154, 159))	('PD-L1', 'Gene', (29, 34))	('patients', 'Species', '9606', (109, 117))	('NSCLC', 'Disease', (103, 108))	('NSCLC', 'Phenotype', 'HP:0030358', (154, 159))	('NSCLC', 'Disease', 'MESH:D002289', (103, 108))	('expression', 'Var', (35, 45))	('NSCLC', 'Phenotype', 'HP:0030358', (103, 108))	('NSCLC', 'Disease', (154, 159))	('poor', 'NegReg', (86, 90))
493956	28938570	Preclinical and clinical data showed that monoclonal antibodies can significantly enhance the antitumor immunity of patients.	('patients', 'Species', '9606', (116, 124))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumor', 'Disease', (98, 103))	('monoclonal antibodies', 'Var', (42, 63))	('enhance', 'PosReg', (82, 89))
493962	28938570	The inhibition of the PD-1/PD-L1 pathway enhances antitumor immunity to prevent tumor cells from escaping from host immune responses, thus providing a promising strategy for specific tumor immunotherapy.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('tumor', 'Disease', (80, 85))	('inhibition', 'Var', (4, 14))	('PD-1/PD-L1', 'Gene', (22, 32))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumor', 'Disease', (183, 188))	('enhances', 'PosReg', (41, 49))	('tumor', 'Disease', (54, 59))
493965	28938570	However, several meta-analyses indicated that PD-L1 expression was associated with poor OS in NSCLC patients, yet the association of PD-L1 expression with clinicopathologic characteristics, especially histologic type, remained unclear.	('PD-L1', 'Gene', (46, 51))	('NSCLC', 'Phenotype', 'HP:0030358', (94, 99))	('NSCLC', 'Disease', (94, 99))	('poor OS', 'Disease', (83, 90))	('patients', 'Species', '9606', (100, 108))	('associated', 'Reg', (67, 77))	('NSCLC', 'Disease', 'MESH:D002289', (94, 99))	('expression', 'Var', (52, 62))	('OS', 'Chemical', '-', (88, 90))
493982	28938570	Interestingly, in the subgroup analysis of non-squamous cell carcinoma, OS was more favorable in those without PD-L1 expression than in those with PD-L1 expression (median OS: 113 months vs. 37 months, p < 0.001).	('OS', 'Chemical', '-', (172, 174))	('OS', 'Chemical', '-', (72, 74))	('non-squamous cell carcinoma', 'Disease', 'MESH:D002294', (43, 70))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (47, 70))	('expression', 'Var', (117, 127))	('PD-L1', 'Gene', (111, 116))	('non-squamous cell carcinoma', 'Disease', (43, 70))
493984	28938570	This study demonstrated that PD-L1 expression is an independent prognostic factor for poor OS in NSCLC patients, especially those with non-squamous NSCLC.	('PD-L1', 'Gene', (29, 34))	('NSCLC', 'Disease', (97, 102))	('poor OS', 'Disease', (86, 93))	('NSCLC', 'Disease', (148, 153))	('NSCLC', 'Disease', 'MESH:D002289', (148, 153))	('OS', 'Chemical', '-', (91, 93))	('NSCLC', 'Disease', 'MESH:D002289', (97, 102))	('patients', 'Species', '9606', (103, 111))	('NSCLC', 'Phenotype', 'HP:0030358', (97, 102))	('NSCLC', 'Phenotype', 'HP:0030358', (148, 153))	('expression', 'Var', (35, 45))
493986	28938570	Previous studies similarly reported that high PD-L1 expression was regarded as a poor prognostic biomarker in patients with lung cancer, renal cell carcinoma, breast cancer, malignant melanoma, hepatocellular carcinoma, gastric carcinoma, pancreatic cancer, and ovarian cancer.	('melanoma', 'Phenotype', 'HP:0002861', (184, 192))	('malignant melanoma', 'Disease', (174, 192))	('breast cancer', 'Disease', 'MESH:D001943', (159, 172))	('breast cancer', 'Disease', (159, 172))	('PD-L1', 'Gene', (46, 51))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('gastric carcinoma', 'Disease', 'MESH:D013274', (220, 237))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (239, 256))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (194, 218))	('renal cell carcinoma', 'Disease', (137, 157))	('gastric carcinoma', 'Disease', (220, 237))	('ovarian cancer', 'Disease', 'MESH:D010051', (262, 276))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (137, 157))	('lung cancer', 'Disease', (124, 135))	('cancer', 'Phenotype', 'HP:0002664', (270, 276))	('carcinoma', 'Phenotype', 'HP:0030731', (209, 218))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (220, 237))	('carcinoma', 'Phenotype', 'HP:0030731', (148, 157))	('malignant melanoma', 'Phenotype', 'HP:0002861', (174, 192))	('malignant melanoma', 'Disease', 'MESH:D008545', (174, 192))	('carcinoma', 'Phenotype', 'HP:0030731', (228, 237))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (194, 218))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('pancreatic cancer', 'Disease', 'MESH:D010190', (239, 256))	('ovarian cancer', 'Disease', (262, 276))	('lung cancer', 'Disease', 'MESH:D008175', (124, 135))	('ovarian cancer', 'Phenotype', 'HP:0100615', (262, 276))	('high', 'Var', (41, 45))	('hepatocellular carcinoma', 'Disease', (194, 218))	('pancreatic cancer', 'Disease', (239, 256))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (137, 157))	('lung cancer', 'Phenotype', 'HP:0100526', (124, 135))	('breast cancer', 'Phenotype', 'HP:0003002', (159, 172))	('patients', 'Species', '9606', (110, 118))
493991	28938570	Another randomized controlled trial, Keynote 001, reported that among patients with at least 50% of tumor cells expressing PD-L1 who received the anti-PD-1 monoclonal antibody pembrolizumab, the objective response rate was 45.3%, which means that nearly half of the patients had tumor shrinkage by at least 30%; however, in patients with less than 1% of tumor cells expressing PD-L1, the objective response rate was only 10.7%.	('patients', 'Species', '9606', (70, 78))	('patients', 'Species', '9606', (324, 332))	('tumor', 'Disease', 'MESH:D009369', (354, 359))	('patients', 'Species', '9606', (266, 274))	('tumor', 'Phenotype', 'HP:0002664', (279, 284))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('pembrolizumab', 'Chemical', 'MESH:C582435', (176, 189))	('tumor', 'Disease', (100, 105))	('tumor', 'Phenotype', 'HP:0002664', (354, 359))	('tumor', 'Disease', (279, 284))	('tumor', 'Disease', (354, 359))	('PD-L1', 'Var', (123, 128))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (279, 284))
494004	28938570	No significant difference in the proportion of squamous carcinoma was observed between the groups with and without PD-L1 expression, although this finding may have been different with longer follow-up or a larger sample size.	('squamous carcinoma', 'Phenotype', 'HP:0002860', (47, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (56, 65))	('expression', 'Var', (121, 131))	('squamous carcinoma', 'Disease', 'MESH:D002294', (47, 65))	('squamous carcinoma', 'Disease', (47, 65))	('PD-L1', 'Gene', (115, 120))
494044	28123534	The results of the present study suggested the importance of RYBP in HCC and its possible mechanism in the metastasis of HCC.	('HCC', 'Gene', '619501', (121, 124))	('HCC', 'Phenotype', 'HP:0001402', (121, 124))	('HCC', 'Phenotype', 'HP:0001402', (69, 72))	('HCC', 'Gene', (69, 72))	('HCC', 'Gene', (121, 124))	('RYBP', 'Var', (61, 65))	('HCC', 'Gene', '619501', (69, 72))
494058	28123534	In prostate cancer, abnormal RYBP is involved in transmembrane protease, serine 2-ETS-related gene fusion, and is associated with the prognosis of patients.	('prostate cancer', 'Phenotype', 'HP:0012125', (3, 18))	('abnormal', 'Var', (20, 28))	('RYBP', 'Gene', (29, 33))	('associated with', 'Reg', (114, 129))	('prostate cancer', 'Disease', (3, 18))	('patients', 'Species', '9606', (147, 155))	('serine', 'Chemical', 'MESH:D012694', (73, 79))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('involved', 'Reg', (37, 45))	('prostate cancer', 'Disease', 'MESH:D011471', (3, 18))
494080	28123534	The primers used for RT-qPCR analysis were purchased from Invitrogen (Thermo Fisher Scientific, Inc.) and were as follows: RYBP, forward 5'-TCGCAACTTCCATTGATT-3' and reverse 5'-TCACACTCAGTCATACCT-3'; GAPDH, forward 5'-TCGCAACTTCCATTGATT-3' and reverse 5'-TCACACTCAGTCATACCT-3'.	("forward 5'-TCGCAACTTCCATTGATT-3", 'Var', (207, 238))	('GAPDH', 'Gene', (200, 205))	('GAPDH', 'Gene', '2597', (200, 205))
494084	28123534	A DeltaCq value of 3.33 corresponds to a magnitude lower of gene expression compared with that of GAPDH.	('DeltaCq', 'Chemical', '-', (2, 9))	('gene expression', 'MPA', (60, 75))	('DeltaCq', 'Var', (2, 9))	('lower', 'NegReg', (51, 56))	('GAPDH', 'Gene', '2597', (98, 103))	('GAPDH', 'Gene', (98, 103))
494106	28123534	As shown in Table I, the negative expression of RYBP was significantly associated with tumor size (P=0.046) and metastasis (P=0.028), which suggested that the expression of RYBP was correlated with the diagnosis and prognosis of HCC.	('RYBP', 'Gene', (48, 52))	('expression', 'MPA', (34, 44))	('HCC', 'Gene', '619501', (229, 232))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('negative', 'NegReg', (25, 33))	('tumor', 'Disease', (87, 92))	('metastasis', 'CPA', (112, 122))	('HCC', 'Phenotype', 'HP:0001402', (229, 232))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('RYBP', 'Var', (173, 177))	('correlated', 'Reg', (182, 192))	('HCC', 'Gene', (229, 232))
494116	28123534	In patients with HCC, the group with high expression levels of ZEB1 had shorter survival rates, compared with the group expressing low levels of ZEB1.	('HCC', 'Gene', (17, 20))	('survival rates', 'CPA', (80, 94))	('shorter', 'NegReg', (72, 79))	('HCC', 'Gene', '619501', (17, 20))	('patients', 'Species', '9606', (3, 11))	('HCC', 'Phenotype', 'HP:0001402', (17, 20))	('ZEB1', 'Gene', (63, 67))	('high expression levels', 'Var', (37, 59))
494142	28123534	The knockdown of ZEB1 not only restores the expression of E-cadherin in dedifferentiated and metastatic tumors, but also causes the reconstruction of epithelial function, including tight junctions.	('expression', 'MPA', (44, 54))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('ZEB1', 'Gene', (17, 21))	('causes', 'Reg', (121, 127))	('tumors', 'Disease', (104, 110))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('E-cadherin', 'Gene', (58, 68))	('restores', 'PosReg', (31, 39))	('epithelial function', 'CPA', (150, 169))	('tight junctions', 'CPA', (181, 196))	('reconstruction', 'NegReg', (132, 146))	('E-cadherin', 'Gene', '999', (58, 68))	('knockdown', 'Var', (4, 13))
494143	28123534	In addition, mutation of ZEB1 has been shown to lead to loss of the mesenchymal marker vimentin in mouse mesenchymal cells, resulting in a variety of abnormal functions in mouse embryos.	('vimentin', 'Protein', (87, 95))	('abnormal functions', 'MPA', (150, 168))	('mouse', 'Species', '10090', (99, 104))	('loss', 'NegReg', (56, 60))	('mutation', 'Var', (13, 21))	('mouse', 'Species', '10090', (172, 177))	('ZEB1', 'Gene', (25, 29))
494160	25506199	In the current study, we devised a pipeline to predict novel alternative splicing (AS) variants from high-throughput transcriptome sequencing data and applied it to large sets of tumor transcriptomes from The Cancer Genome Atlas (TCGA).	('Cancer Genome Atlas', 'Disease', (209, 228))	('Cancer', 'Phenotype', 'HP:0002664', (209, 215))	('variants', 'Var', (87, 95))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (209, 228))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('tumor', 'Disease', (179, 184))
494161	25506199	We identified two novel tumor-associated splice variants of matriptase, a known cancer-associated gene, in the transcriptome data from epithelial-derived tumors but not normal tissue.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumors', 'Disease', (154, 160))	('tumors', 'Disease', 'MESH:D009369', (154, 160))	('tumors', 'Phenotype', 'HP:0002664', (154, 160))	('tumor', 'Disease', (24, 29))	('splice variants', 'Var', (41, 56))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('matriptase', 'Gene', (60, 70))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('matriptase', 'Gene', '19143', (60, 70))	('cancer', 'Disease', (80, 86))	('tumor', 'Disease', (154, 159))
494162	25506199	Most notably, these variants were found in 69% of lung squamous cell carcinoma (LUSC) samples studied.	('lung squamous cell carcinoma', 'Disease', (50, 78))	('variants', 'Var', (20, 28))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (55, 78))	('LUSC', 'Phenotype', 'HP:0030359', (80, 84))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (50, 78))	('found', 'Reg', (34, 39))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (50, 78))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))
494165	25506199	Our findings further implicate matriptase in contributing to oncogenic processes and suggest potential novel therapeutic uses for matriptase splice variants.	('matriptase', 'Gene', '19143', (130, 140))	('contributing', 'Reg', (45, 57))	('matriptase', 'Gene', (130, 140))	('matriptase', 'Gene', '19143', (31, 41))	('splice variants', 'Var', (141, 156))	('implicate', 'Reg', (21, 30))	('oncogenic processes', 'CPA', (61, 80))	('matriptase', 'Gene', (31, 41))
494168	25506199	Splice variants have been identified in a variety of cancers, suggesting that widespread aberrant and AS may be a common consequence or even a cause of cancer.	('cancers', 'Phenotype', 'HP:0002664', (53, 60))	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('cancers', 'Disease', (53, 60))	('cancer', 'Disease', (53, 59))	('Splice variants', 'Var', (0, 15))	('cancers', 'Disease', 'MESH:D009369', (53, 60))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('identified', 'Reg', (26, 36))
494170	25506199	However, a number of studies have demonstrated that cancer-associated splice variants can serve as diagnostic or prognostic markers, or predict sensitivity to certain drugs.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('splice variants', 'Var', (70, 85))	('predict', 'Reg', (136, 143))	('rat', 'Species', '10116', (41, 44))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('sensitivity', 'MPA', (144, 155))
494174	25506199	We identified two highly frequent novel tumor-associated splice variants of matriptase with restricted expression to epithelial-derived tumors.	('tumors', 'Disease', (136, 142))	('tumors', 'Disease', 'MESH:D009369', (136, 142))	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('matriptase', 'Gene', '19143', (76, 86))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('splice variants', 'Var', (57, 72))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('tumor', 'Disease', (136, 141))	('matriptase', 'Gene', (76, 86))
494182	25506199	Matriptase activity is tightly regulated via antagonism from HGF activator inhibitor-1 (HAI-1).	('HGF activator inhibitor-1', 'Gene', '6692', (61, 86))	('HAI-1', 'Gene', '6692', (88, 93))	('Matriptase', 'Gene', (0, 10))	('activity', 'MPA', (11, 19))	('Matriptase', 'Gene', '19143', (0, 10))	('antagonism', 'Var', (45, 55))	('HAI-1', 'Gene', (88, 93))	('HGF activator inhibitor-1', 'Gene', (61, 86))
494192	25506199	In addition to matriptase overexpression, an imbalance in the ratio of matriptase to HAI-1 has been reported in late-stage tumors leading to the proposal that uninhibited matriptase activity may contribute to the development of advanced disease.	('imbalance', 'Phenotype', 'HP:0002172', (45, 54))	('tumors', 'Disease', (123, 129))	('matriptase', 'Gene', (15, 25))	('reported', 'Reg', (100, 108))	('tumors', 'Disease', 'MESH:D009369', (123, 129))	('advanced disease', 'Disease', (228, 244))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('matriptase', 'Gene', (171, 181))	('matriptase', 'Gene', (71, 81))	('contribute', 'Reg', (195, 205))	('matriptase', 'Gene', '19143', (15, 25))	('HAI-1', 'Gene', '6692', (85, 90))	('matriptase', 'Gene', '19143', (71, 81))	('rat', 'Species', '10116', (62, 65))	('matriptase', 'Gene', '19143', (171, 181))	('HAI-1', 'Gene', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('imbalance', 'Var', (45, 54))
494198	25506199	Tumor association and the high frequency of matriptase splice variants within and across epithelial tumors suggest that these mutant matriptase transcripts may be of potential therapeutic value.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('matriptase', 'Gene', (133, 143))	('matriptase', 'Gene', (44, 54))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('epithelial tumors', 'Disease', (89, 106))	('epithelial tumors', 'Disease', 'MESH:D002277', (89, 106))	('matriptase', 'Gene', '19143', (133, 143))	('matriptase', 'Gene', '19143', (44, 54))	('mutant', 'Var', (126, 132))
494228	25506199	The exon 14 deletion (variant A3) was constructed the same way using the variant A3 forward primer (5'-AGCAGGGGTGCATGAACGTCGTCACTTGTACCAA-3') and the variant A3 reverse primer (5'-TGACGACGTTCATGCACCCCTGCTCGTCGCTGTT-3').	('GAA', 'Gene', '2548', (116, 119))	('variant', 'Var', (73, 80))	('GAA', 'Gene', (116, 119))
494230	25506199	The four transfections consisted of empty pTT5 vector alone, wild type plus HAI-1, variant A1 plus HAI-1, and variant A3 plus HAI-1.	('variant A1', 'Var', (83, 93))	('variant A3', 'Var', (110, 120))	('HAI-1', 'Gene', '6692', (126, 131))	('HAI-1', 'Gene', (76, 81))	('HAI-1', 'Gene', '6692', (99, 104))	('HAI-1', 'Gene', '6692', (76, 81))	('HAI-1', 'Gene', (126, 131))	('HAI-1', 'Gene', (99, 104))
494259	25506199	Matriptase variant A1 was found more frequent than A3 across all tumors studied (P = 0.01).	('Matriptase', 'Gene', (0, 10))	('Matriptase', 'Gene', '19143', (0, 10))	('frequent', 'Reg', (37, 45))	('tumors', 'Disease', (65, 71))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('variant A1', 'Var', (11, 21))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
494262	25506199	Analysis of predicted protein sequences revealed that both matriptase variants contain fully functional ORFs, suggesting the possibility of expressing two novel proteins (Supplementary Sequence S2).	('variants', 'Var', (70, 78))	('matriptase', 'Gene', (59, 69))	('matriptase', 'Gene', '19143', (59, 69))
494263	25506199	Protein domain prediction further demonstrated that matriptase variants A1 and A3 lack LDLRA1 and LDLRA3 domains, respectively.	('lack', 'NegReg', (82, 86))	('LDLRA1', 'MPA', (87, 93))	('variants', 'Var', (63, 71))	('matriptase', 'Gene', '19143', (52, 62))	('LDLRA3', 'MPA', (98, 104))	('rat', 'Species', '10116', (41, 44))	('matriptase', 'Gene', (52, 62))	('A1 and A3', 'Gene', '597', (72, 81))
494265	25506199	The A3 transcript encodes a protein of 817 amino acids, which is the result of skipping amino acids 524-562 followed by substitution of methionine (M) as a result of the formation of a novel exon-exon junction (Supplementary Sequence S3.2).	('substitution', 'Var', (120, 132))	('methionine', 'Chemical', 'MESH:D008715', (136, 146))	('skipping', 'Var', (79, 87))
494267	25506199	Our search did not find these novel matriptase variants.	('variants', 'Var', (47, 55))	('matriptase', 'Gene', (36, 46))	('matriptase', 'Gene', '19143', (36, 46))
494268	25506199	We only found three AS transcripts of matriptase, which are formed as a result of an intron retention event (Ensembl IDs: ENST00000530532, ENST00000524718, and ENST00000530376).	('matriptase', 'Gene', '19143', (38, 48))	('ENST00000524718', 'Var', (139, 154))	('ENST00000530532', 'Var', (122, 137))	('matriptase', 'Gene', (38, 48))	('ENST00000530376', 'Var', (160, 175))
494269	25506199	Furthermore, we did not detect the novel transcripts of matriptase in adjacent non-cancerous tissue from TCGA or in the transcriptome data available from the BodyMap 2.0 project, thus suggesting these variants are tumor associated.	('matriptase', 'Gene', '19143', (56, 66))	('cancerous', 'Disease', 'MESH:D009369', (83, 92))	('tumor', 'Disease', 'MESH:D009369', (214, 219))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('variants', 'Var', (201, 209))	('tumor', 'Disease', (214, 219))	('cancerous', 'Disease', (83, 92))	('matriptase', 'Gene', (56, 66))
494278	25506199	In fact, the majority of tissues in the normal tissue panel did not express matriptase A1 and A3 transcript variants at all, while a small number showed a much lower expression compared to tumor samples (Fig.	('tumor', 'Disease', (189, 194))	('matriptase', 'Gene', '19143', (76, 86))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('variants', 'Var', (108, 116))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('A1 and A3', 'Gene', '597', (87, 96))	('expression', 'MPA', (166, 176))	('matriptase', 'Gene', (76, 86))	('lower', 'NegReg', (160, 165))
494281	25506199	To address the question of whether matriptase A1 and A3 transcripts yield protein variants that are capable of being translocated to the cell surface, we transiently transfected CHO cells with cDNA encoding these genes followed by flow cytometric analysis of surface matriptase proteins (wild type, variant A1, and variant A3).	('CHO', 'CellLine', 'CVCL:0213', (178, 181))	('matriptase', 'Gene', (267, 277))	('matriptase', 'Gene', '19143', (35, 45))	('variant', 'Var', (315, 322))	('matriptase', 'Gene', '19143', (267, 277))	('A1 and A3', 'Gene', '597', (46, 55))	('variant A1', 'Var', (299, 309))	('matriptase', 'Gene', (35, 45))
494282	25506199	For this experiment, we used a human anti-matriptase antibody that binds to the catalytic domain of all three matriptase variants and is not variant specific.	('matriptase', 'Gene', '19143', (42, 52))	('variants', 'Var', (121, 129))	('matriptase', 'Gene', '19143', (110, 120))	('human', 'Species', '9606', (31, 36))	('matriptase', 'Gene', (42, 52))	('binds', 'Interaction', (67, 72))	('matriptase', 'Gene', (110, 120))
494283	25506199	Co-expression of the matriptase variants with HAI-1 resulted in a significant increase in the mean fluorescent intensity for wild type, variant A1, and variant A3 (P < 0.05; Fig.	('matriptase', 'Gene', '19143', (21, 31))	('mean fluorescent intensity', 'MPA', (94, 120))	('HAI-1', 'Gene', (46, 51))	('variant', 'Var', (136, 143))	('increase', 'PosReg', (78, 86))	('variants', 'Var', (32, 40))	('matriptase', 'Gene', (21, 31))	('HAI-1', 'Gene', '6692', (46, 51))
494284	25506199	5C-F), whereas expression of matriptase variants alone showed modest increases in surface expression (data not shown).	('increases', 'PosReg', (69, 78))	('matriptase', 'Gene', (29, 39))	('matriptase', 'Gene', '19143', (29, 39))	('variants', 'Var', (40, 48))	('surface expression', 'MPA', (82, 100))
494285	25506199	So to verify that the recombinant proteins detected by flow cytometry were the expected molecular weight for each variant, matriptase variants were immunoprecipitated from transfected CHO cells using the same human anti-matriptase antibody and analyzed by Western blot (Fig.	('human', 'Species', '9606', (209, 214))	('matriptase', 'Gene', '19143', (220, 230))	('variants', 'Var', (134, 142))	('matriptase', 'Gene', (123, 133))	('matriptase', 'Gene', (220, 230))	('CHO', 'CellLine', 'CVCL:0213', (184, 187))	('matriptase', 'Gene', '19143', (123, 133))
494287	25506199	These results support the assertion that proteins corresponding to the expected molecular weight of matriptase variants A1 and A3 are trafficked to the cell surface of transiently transfected cells, despite the deletion of the LDLRA domains.	('A1 and A3', 'Gene', '597', (120, 129))	('matriptase', 'Gene', (100, 110))	('matriptase', 'Gene', '19143', (100, 110))	('deletion', 'Var', (211, 219))
494294	25506199	The AS-detection pipeline allowed us to mine large sets of tumor transcriptomes to identify novel tumor-associated AS variants.	('tumor', 'Disease', (59, 64))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('variants', 'Var', (118, 126))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Disease', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
494295	25506199	Most notably, we identified two novel tumor- associated splicing variants of matriptase through analysis of more than 2,200 tumor transcriptome data available from TCGA.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('splicing variants', 'Var', (56, 73))	('matriptase', 'Gene', (77, 87))	('tumor', 'Disease', (124, 129))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('matriptase', 'Gene', '19143', (77, 87))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
494296	25506199	The variant designated A1 has an in-frame skipping of exon 12, and variant A3 is generated as a result of skipping exon 14.	('skipping', 'Var', (42, 50))	('rat', 'Species', '10116', (85, 88))	('skipping', 'Var', (106, 114))
494297	25506199	Our analysis revealed a high frequency of these variants across epithelial-derived tumors, which were absent or expressed at extremely low levels in transcriptomes derived from normal tissues.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('variants', 'Var', (48, 56))	('tumors', 'Disease', (83, 89))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('tumors', 'Disease', 'MESH:D009369', (83, 89))
494299	25506199	qRT-PCR confirmed mRNA expression of matriptase variants, and revealed differential higher expression of variant A1 in ovarian and lung tumor tissues and cell lines compared to low or no expression in normal samples.	('expression', 'MPA', (91, 101))	('matriptase', 'Gene', (37, 47))	('variants', 'Var', (48, 56))	('variant', 'Var', (105, 112))	('lung tumor', 'Phenotype', 'HP:0100526', (131, 141))	('ovarian and lung tumor', 'Disease', 'MESH:D010051', (119, 141))	('matriptase', 'Gene', '19143', (37, 47))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('mRNA', 'MPA', (18, 22))	('higher', 'PosReg', (84, 90))
494302	25506199	We observed no mRNA expression of matriptase variants in more than two-thirds of normal samples and a low level of expression in the remainder.	('matriptase', 'Gene', '19143', (34, 44))	('variants', 'Var', (45, 53))	('mRNA expression', 'MPA', (15, 30))	('matriptase', 'Gene', (34, 44))
494306	25506199	This analysis demonstrated the presence of these novel proteins on the surface of CHO cells, where wild-type matriptase surface expression predominated followed by variant A1 and then variant A3.	('CHO', 'CellLine', 'CVCL:0213', (82, 85))	('variant A3', 'Var', (184, 194))	('variant A1', 'Var', (164, 174))	('matriptase', 'Gene', (109, 119))	('rat', 'Species', '10116', (21, 24))	('matriptase', 'Gene', '19143', (109, 119))
494311	25506199	Point mutations at critical residues in this calcium cage have been found to potently inhibit the LDLRA ligand binding.	('Point mutations', 'Var', (0, 15))	('calcium', 'Chemical', 'MESH:D002118', (45, 52))	('LDLRA ligand binding', 'Interaction', (98, 118))	('inhibit', 'NegReg', (86, 93))
494312	25506199	Oberst et al showed that mutations in the Ca2+-binding motifs of any or all of the four LDLRA domains of matriptase prevent its activation.	('mutations', 'Var', (25, 34))	('prevent', 'NegReg', (116, 123))	('Ca2+', 'Chemical', 'MESH:D000069285', (42, 46))	('matriptase', 'Gene', (105, 115))	('activation', 'MPA', (128, 138))	('matriptase', 'Gene', '19143', (105, 115))
494313	25506199	Additional experiments are required to demonstrate the impact of deleting LDLRA1 and LDLRA3 domains as observed in the A1 and A3 variants.	('rat', 'Species', '10116', (46, 49))	('LDLRA3', 'Gene', (85, 91))	('A1 and A3', 'Gene', '597', (119, 128))	('deleting', 'Var', (65, 73))	('LDLRA1', 'Gene', (74, 80))
494314	25506199	Although these two deletions may have variable effects on matriptase activity, our results demonstrate that they do not affect the ability of their protein products to form a complex with HAI-1 and traffic to the cell surface.	('matriptase', 'Gene', '19143', (58, 68))	('activity', 'MPA', (69, 77))	('HAI-1', 'Gene', '6692', (188, 193))	('complex', 'Interaction', (175, 182))	('rat', 'Species', '10116', (98, 101))	('matriptase', 'Gene', (58, 68))	('effects', 'Reg', (47, 54))	('HAI-1', 'Gene', (188, 193))	('deletions', 'Var', (19, 28))
494315	25506199	We identified no splice-site mutation associated with skipping exons 12 and 14 of matriptase in TCGA mutation analysis data derived from matching whole-exome sequencing dataset.	('matriptase', 'Gene', (82, 92))	('matriptase', 'Gene', '19143', (82, 92))	('skipping exons', 'Var', (54, 68))
494316	25506199	We predicted RNA-binding proteins (RBPs) that possibly bind to matriptase mRNA using RBPmap online web server (Supplementary Table S7) and compared the expression of these RBPs according to the expression status of matriptase variants.	('bind', 'Interaction', (55, 59))	('variants', 'Var', (226, 234))	('matriptase', 'Gene', '19143', (63, 73))	('matriptase', 'Gene', (215, 225))	('matriptase', 'Gene', (63, 73))	('matriptase', 'Gene', '19143', (215, 225))
494317	25506199	We found no correlation between expression of matriptase variants and patient's survival time (P > 0.05, Supplementary Figs.	('matriptase', 'Gene', '19143', (46, 56))	('variants', 'Var', (57, 65))	('patient', 'Species', '9606', (70, 77))	('matriptase', 'Gene', (46, 56))
494322	25506199	This approach highlights high frequency of matriptase variants among patients with epithelial-derived tumors as well as low or no occurrence in normal tissue.	('matriptase', 'Gene', (43, 53))	('tumors', 'Disease', 'MESH:D009369', (102, 108))	('tumors', 'Disease', (102, 108))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('matriptase', 'Gene', '19143', (43, 53))	('patients', 'Species', '9606', (69, 77))	('variants', 'Var', (54, 62))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))
494323	25506199	In addition to gene expression data, our flow cytometric analysis confirmed protein expression of both matriptase variants on the surface of CHO cells, suggesting matriptase variants as potential biomarkers of tumor cells.	('variants', 'Var', (174, 182))	('matriptase', 'Gene', '19143', (103, 113))	('matriptase', 'Gene', (163, 173))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('CHO', 'CellLine', 'CVCL:0213', (141, 144))	('tumor', 'Disease', (210, 215))	('matriptase', 'Gene', '19143', (163, 173))	('variants', 'Var', (114, 122))	('matriptase', 'Gene', (103, 113))	('tumor', 'Disease', 'MESH:D009369', (210, 215))
494324	25506199	Clinical validation would prove valuable in confirming the utility of matriptase variants for therapeutic use.	('matriptase', 'Gene', '19143', (70, 80))	('matriptase', 'Gene', (70, 80))	('variants', 'Var', (81, 89))
494341	24405714	Many studies have shown that miRNAs are related to cell processes , , and the dysregulation of these events can lead to the occurrence of a number of diseases, such as lung cancer , prostate cancer , colorectal tumor , leukemia , and cervical cancer .	('miR', 'Gene', '220972', (29, 32))	('Man', 'Species', '9606', (0, 3))	('lung cancer', 'Disease', 'MESH:D008175', (168, 179))	('miR', 'Gene', (29, 32))	('lung cancer', 'Phenotype', 'HP:0100526', (168, 179))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('prostate cancer', 'Disease', 'MESH:D011471', (182, 197))	('prostate cancer', 'Phenotype', 'HP:0012125', (182, 197))	('leukemia', 'Phenotype', 'HP:0001909', (219, 227))	('colorectal tumor', 'Disease', 'MESH:D015179', (200, 216))	('cervical cancer', 'Disease', 'MESH:D002583', (234, 249))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('prostate cancer', 'Disease', (182, 197))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('cervical cancer', 'Disease', (234, 249))	('dysregulation', 'Var', (78, 91))	('colorectal tumor', 'Disease', (200, 216))	('lung cancer', 'Disease', (168, 179))	('leukemia', 'Disease', (219, 227))	('lead to', 'Reg', (112, 119))	('leukemia', 'Disease', 'MESH:D007938', (219, 227))	('cancer', 'Phenotype', 'HP:0002664', (243, 249))
494431	32979859	Overexpression of wild type or a Q311E mutant MB21D2 promotes a pro-oncogenic phenotype in HNSCC A novel cancer gene MB21D2, a known intracellular cadherin binder, was found to harbor Q311E recurrent mutation and to be overexpressed in head and neck cancer (HNSCC).	('overexpressed', 'PosReg', (219, 232))	('MB21D2', 'Gene', '151963', (46, 52))	('cancer', 'Disease', (105, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('head and neck cancer', 'Phenotype', 'HP:0012288', (236, 256))	('promotes', 'PosReg', (53, 61))	('cancer', 'Disease', 'MESH:D009369', (250, 256))	('Q311E', 'Mutation', 'rs988241015', (184, 189))	('Q311E', 'Mutation', 'rs988241015', (33, 38))	('cadherin', 'Gene', (147, 155))	('MB21D2', 'Gene', (117, 123))	('cadherin', 'Gene', '999;1002;1004', (147, 155))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('head and neck cancer', 'Disease', 'MESH:D006258', (236, 256))	('MB21D2', 'Gene', (46, 52))	('Q311E', 'Var', (184, 189))	('Q311E', 'Var', (33, 38))	('pro-oncogenic phenotype', 'MPA', (64, 87))	('cancer', 'Disease', (250, 256))	('MB21D2', 'Gene', '151963', (117, 123))	('HNSCC', 'Disease', (91, 96))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))
494432	32979859	Blockage of RAS could be used as a strategy for treating cancer with MB21D2 overexpression or mutation, particularly for tumors resistant to DNA-damaging drugs.	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('MB21D2', 'Gene', (69, 75))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('cancer', 'Disease', (57, 63))	('tumors', 'Disease', (121, 127))	('rat', 'Species', '10116', (37, 40))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('tumors', 'Disease', 'MESH:D009369', (121, 127))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('mutation', 'Var', (94, 102))	('overexpression', 'PosReg', (76, 90))
494434	32979859	Here, we screened mutational profiles of 312 annotated genes involved in cadherin binding in human squamous cell carcinomas and found MB21D2 to carry a unique recurrent Q311E mutation.	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (99, 123))	('human', 'Species', '9606', (93, 98))	('squamous cell carcinomas', 'Disease', (99, 123))	('Q311E', 'Mutation', 'rs988241015', (169, 174))	('cadherin', 'Gene', '999;1002;1004', (73, 81))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (99, 122))	('MB21D2', 'Gene', (134, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('carcinomas', 'Phenotype', 'HP:0030731', (113, 123))	('Q311E', 'Var', (169, 174))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (99, 123))	('cadherin', 'Gene', (73, 81))
494436	32979859	Cell-based characterizations revealed pro-oncogenic roles for MB21D2 wild-type (WT) and its Q311E mutant (Q311E) in cell proliferation, colony formation, sphere growth, and migration/invasion by promoting epithelial-mesenchymal transition.	('Q311E', 'Var', (92, 97))	('rat', 'Species', '10116', (176, 179))	('migration/invasion', 'CPA', (173, 191))	('sphere growth', 'CPA', (154, 167))	('colony formation', 'CPA', (136, 152))	('Q311E', 'Mutation', 'rs988241015', (92, 97))	('epithelial-mesenchymal transition', 'CPA', (205, 238))	('Q311E', 'Mutation', 'rs988241015', (106, 111))	('MB21D2', 'Gene', (62, 68))	('rat', 'Species', '10116', (128, 131))	('cell proliferation', 'CPA', (116, 134))	('promoting', 'PosReg', (195, 204))
494437	32979859	Conversely, MB21D2 knockdown in MB21D2-overexpressing cells resulted in cell growth arrest and apoptosis.	('cell growth arrest', 'Disease', (72, 90))	('cell growth arrest', 'Disease', 'MESH:D006323', (72, 90))	('knockdown', 'Var', (19, 28))	('apoptosis', 'CPA', (95, 104))	('MB21D2', 'Gene', (12, 18))	('growth arrest', 'Phenotype', 'HP:0001510', (77, 90))	('MB21D2-overexpressing', 'Gene', (32, 53))
494438	32979859	Xenograft tumor models with Q311E-expressing cells formed larger and more aggressive lesions, compared to models with WT-MB21D2-expressing cells or an empty vector.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('Q311E-expressing', 'Var', (28, 44))	('tumor', 'Disease', (10, 15))	('aggressive lesions', 'CPA', (74, 92))	('more', 'PosReg', (69, 73))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('Q311E', 'Mutation', 'rs988241015', (28, 33))
494442	32979859	Our study thus defined RAS signaling-dependent pro-oncogenic roles for MB21D2 overexpression and Q311E MB21D2 expression in HNSCC development.	('MB21D2', 'Gene', (103, 109))	('HNSCC', 'Disease', (124, 129))	('MB21D2', 'Gene', (71, 77))	('Q311E', 'Mutation', 'rs988241015', (97, 102))	('overexpression', 'PosReg', (78, 92))	('Q311E', 'Var', (97, 102))
494443	32979859	GEPIA gene expression profiling interactive analysis HNSCC head and neck squamous cell carcinoma KRAS Kirsten rat sarcoma viral oncogene homolog (KRAS proto-oncogene, GTPase) MB21D2 Mab-21-containing domain 2 PI3K phospho-inositol kinase 3 Q311E change in glutamine at the position 311 to glutamic acid SCCs squamous cell carcinoma(s TCGA The Cancer Genome Atlas WT in this study, wild-type MB21D2 Cadherin-mediated cell adhesion and migration play vital roles in controlling epithelial cell behaviors, and aberrations in the components of cadherin complex have been implicated in cancer development and invasion [1, 2].	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (73, 96))	('KRAS', 'Gene', '3845', (146, 150))	('cadherin', 'Gene', (540, 548))	('rat', 'Species', '10116', (437, 440))	('cancer', 'Phenotype', 'HP:0002664', (581, 587))	('Mab-21', 'Gene', (182, 188))	('cat', 'Gene', (572, 575))	('cadherin', 'Gene', '999;1002;1004', (540, 548))	('PI3', 'Gene', (209, 212))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (59, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))	('Q311E', 'Mutation', 'rs988241015', (240, 245))	('rat', 'Species', '10116', (110, 113))	('KRAS', 'Gene', (146, 150))	('Cancer', 'Phenotype', 'HP:0002664', (343, 349))	('KRAS', 'Gene', '3845', (97, 101))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (308, 331))	('glutamine', 'Chemical', 'MESH:D005973', (256, 265))	('cancer', 'Disease', 'MESH:D009369', (581, 587))	('cat', 'Gene', '847', (572, 575))	('aberrations', 'Var', (507, 518))	('sarcoma', 'Disease', 'MESH:D012509', (114, 121))	('Cancer', 'Disease', (343, 349))	('KRAS', 'Gene', (97, 101))	('sarcoma', 'Disease', (114, 121))	('glutamic acid', 'Chemical', 'MESH:D018698', (289, 302))	('carcinoma', 'Phenotype', 'HP:0030731', (322, 331))	('invasion', 'CPA', (604, 612))	('neck squamous cell carcinoma', 'Disease', (68, 96))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (68, 96))	('PI3', 'Gene', '5266', (209, 212))	('Cancer', 'Disease', 'MESH:D009369', (343, 349))	('sarcoma', 'Phenotype', 'HP:0100242', (114, 121))	('Mab-21', 'Gene', '175607', (182, 188))	('rat', 'Species', '10116', (511, 514))	('cancer', 'Disease', (581, 587))
494444	32979859	For instance, genetic loss or epigenetic silencing of E-cadherin (CDH1), which has been shown as a tumor suppressor, was frequently detected in cancers [2, 3, 4].	('detected', 'Reg', (132, 140))	('CDH1', 'Gene', (66, 70))	('E-cadherin', 'Gene', (54, 64))	('E-cadherin', 'Gene', '999', (54, 64))	('tumor suppressor', 'Gene', (99, 115))	('CDH1', 'Gene', '999', (66, 70))	('genetic loss', 'Disease', 'MESH:D030342', (14, 26))	('genetic loss', 'Disease', (14, 26))	('tumor suppressor', 'Gene', '7248', (99, 115))	('cancers', 'Phenotype', 'HP:0002664', (144, 151))	('cancers', 'Disease', (144, 151))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('cancers', 'Disease', 'MESH:D009369', (144, 151))	('epigenetic silencing', 'Var', (30, 50))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
494451	32979859	Because recurrent/hotspot mutations usually locate at functional domains of an oncogene, such substitutions suggest a mechanism for oncogene activation that mimics oncogene overexpression during cancer development.	('cat', 'Gene', (46, 49))	('substitutions', 'Var', (94, 107))	('cancer', 'Disease', (195, 201))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('mutations', 'Var', (26, 35))	('cat', 'Gene', '847', (46, 49))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
494452	32979859	Such activating mutations can contribute to clonal selection or expansion during cancer cell evolution, leading to oncogene addiction [14, 15].	('leading to', 'Reg', (104, 114))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('mutations', 'Var', (16, 25))	('cancer', 'Disease', (81, 87))	('oncogene addiction', 'Disease', (115, 133))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))
494453	32979859	The typical example would be PIK3CA recurrent mutations, which constitutively activate the catalytic subunit (p110) of PI3K [12, 16, 17], and in turn promotes dysregulated cell proliferation, uncontrolled motility, and evading apoptosis.	('uncontrolled motility', 'CPA', (192, 213))	('mutations', 'Var', (46, 55))	('PI3', 'Gene', '5266', (119, 122))	('promotes', 'PosReg', (150, 158))	('cat', 'Gene', (91, 94))	('rat', 'Species', '10116', (184, 187))	('evading apoptosis', 'CPA', (219, 236))	('PI3', 'Gene', (119, 122))	('dysregulated cell proliferation', 'CPA', (159, 190))	('cat', 'Gene', '847', (91, 94))	('PIK3CA', 'Gene', (29, 35))	('activate', 'PosReg', (78, 86))
494454	32979859	Several signaling molecules involved in oncogenesis, for example, RAS, RAF, and AKT, were also found to harbor recurrent/hotspot mutations at critical sites of the sequences in cancer lesions [18, 19].	('cancer lesions', 'Disease', 'MESH:D009369', (177, 191))	('AKT', 'Gene', '207', (80, 83))	('RAS', 'Gene', (66, 69))	('mutations', 'Var', (129, 138))	('RAF', 'Gene', '22882', (71, 74))	('AKT', 'Gene', (80, 83))	('RAF', 'Gene', (71, 74))	('cancer lesions', 'Disease', (177, 191))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))
494467	32979859	This finding suggests possible alterations in cellular signaling caused by the Q311E (neutral to negative charge) recurrent mutation which could be detected across squamous cell carcinomas.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (164, 187))	('Q311E', 'Mutation', 'rs988241015', (79, 84))	('squamous cell carcinomas', 'Disease', (164, 188))	('Q311E', 'Var', (79, 84))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (164, 188))	('cellular signaling', 'MPA', (46, 64))	('carcinomas', 'Phenotype', 'HP:0030731', (178, 188))	('carcinoma', 'Phenotype', 'HP:0030731', (178, 187))	('rat', 'Species', '10116', (35, 38))	('alterations', 'Reg', (31, 42))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (164, 188))
494468	32979859	In addition, advanced machine-learning-based studies suggest Q311E substitution in MB21D2 as a potent driver mutation in cancer worthy of a more detailed investigation [18, 38].	('Q311E', 'Var', (61, 66))	('MB21D2', 'Gene', (83, 89))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('Q311E', 'Mutation', 'rs988241015', (61, 66))	('cancer', 'Disease', (121, 127))
494469	32979859	In this study, we investigated the oncogenic roles of a novel gene named MB21D2 which harbors a recurrent Q311E mutation which is overexpressed in head and neck squamous cell carcinoma (HNSCC).	('MB21D2', 'Gene', (73, 79))	('Q311E', 'Var', (106, 111))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (161, 184))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (147, 184))	('carcinoma', 'Phenotype', 'HP:0030731', (175, 184))	('neck squamous cell carcinoma', 'Disease', (156, 184))	('Q311E', 'Mutation', 'rs988241015', (106, 111))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (156, 184))
494479	32979859	Based on the TCGA dataset of HNSCC (496 cases), high MB21D2 mRNA levels were found in 12.54% and somatic mutations in 2.15% of the cases, accounting for a total of 14.69 % of HNSCC with genetic alterations in MB21D2 (Fig.	('MB21D2', 'Gene', (53, 59))	('genetic alterations', 'Var', (186, 205))	('rat', 'Species', '10116', (198, 201))	('mRNA levels', 'MPA', (60, 71))	('high', 'PosReg', (48, 52))	('MB21D2', 'Gene', (209, 215))	('HNSCC', 'Disease', (175, 180))
494480	32979859	Upregulation of MB21D2 and Q311E mutation was found in 3 subtypes of HNSCC, which include cancers of oral cavity (high mRNA: 8.8%, Q311E: 1.1%, n = 200), oropharynx (high mRNA: 9.1%, Q311E: 6.1%, n = 39), and larynx (high mRNA: 22.8%, Q311E: 1.4%, n = 89) (Fig.	('Upregulation', 'PosReg', (0, 12))	('cancers', 'Disease', (90, 97))	('larynx', 'Disease', (209, 215))	('HNSCC', 'Disease', (69, 74))	('oropharynx', 'Disease', (154, 164))	('Q311E', 'Mutation', 'rs988241015', (27, 32))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('oral cavity', 'Disease', (101, 112))	('MB21D2', 'Gene', (16, 22))	('Q311E', 'Mutation', 'rs988241015', (131, 136))	('Q311E', 'Mutation', 'rs988241015', (235, 240))	('Q311E', 'Mutation', 'rs988241015', (183, 188))	('Q311E', 'Var', (27, 32))	('Q311E', 'Var', (131, 136))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('cancers', 'Disease', 'MESH:D009369', (90, 97))	('Q311E', 'Var', (235, 240))
494481	32979859	The average expression level of MB21D2 in tumors with Q311E mutation was found to be similar to that in tumors without mutation (Fig S1C).	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('Q311E', 'Var', (54, 59))	('tumors', 'Disease', (42, 48))	('tumors', 'Disease', 'MESH:D009369', (42, 48))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('MB21D2', 'Gene', (32, 38))	('tumors', 'Disease', (104, 110))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('Q311E', 'Mutation', 'rs988241015', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
494484	32979859	Furthermore, patients with MB21D2 overexpression showed lower p16 levels (Fig.	('patients', 'Species', '9606', (13, 21))	('p16', 'Gene', (62, 65))	('MB21D2', 'Var', (27, 33))	('overexpression', 'PosReg', (34, 48))	('lower', 'NegReg', (56, 61))	('p16', 'Gene', '1029', (62, 65))
494485	32979859	These data suggest a negative correlation between MB21D2 alterations and HPV infection in HNSCC.	('HNSCC', 'Disease', (90, 95))	('negative', 'NegReg', (21, 29))	('HPV infection', 'Disease', 'MESH:D030361', (73, 86))	('MB21D2', 'Gene', (50, 56))	('rat', 'Species', '10116', (61, 64))	('alterations', 'Var', (57, 68))	('HPV infection', 'Disease', (73, 86))
494486	32979859	These data suggest the involvement of MB21D2 overexpression and recurrent Q311E mutation in the development of human SCCs, particularly in HNSCC.	('Q311E', 'Var', (74, 79))	('HNSCC', 'Disease', (139, 144))	('human', 'Species', '9606', (111, 116))	('involvement', 'Reg', (23, 34))	('Q311E', 'Mutation', 'rs988241015', (74, 79))	('overexpression', 'PosReg', (45, 59))	('MB21D2', 'Gene', (38, 44))
494487	32979859	To determine the possible impact of MB21D2 overexpression and recurrent mutation on cellular behaviors, we performed transient expression study in HNSCC cells followed by validation with stable cell clones that constitutively express wild-type (WT) and the mutant (Q311E) MB21D2 (Fig.	('Q311E', 'Mutation', 'rs988241015', (265, 270))	('MB21D2', 'Gene', (272, 278))	('Q311E', 'Var', (265, 270))
494489	32979859	In transient expression experiments, cells with Q311E expression showed higher cell proliferation rate and formed bigger colonies as compared with cells with an empty vector (upper and lower left panels in Fig.	('Q311E', 'Mutation', 'rs988241015', (48, 53))	('rat', 'Species', '10116', (91, 94))	('cell proliferation rate', 'CPA', (79, 102))	('Q311E expression', 'Var', (48, 64))	('rat', 'Species', '10116', (98, 101))	('higher', 'PosReg', (72, 78))
494490	32979859	However, in stable CAL27 and TW206 cell clones, both WT- and Q311E-expressing cells exhibited increased proliferation rate than control cells (Fig.	('rat', 'Species', '10116', (111, 114))	('rat', 'Species', '10116', (118, 121))	('proliferation rate', 'CPA', (104, 122))	('CAL27', 'CellLine', 'CVCL:1107', (19, 24))	('increased', 'PosReg', (94, 103))	('TW206', 'CellLine', 'CVCL:F585', (29, 34))	('Q311E-expressing', 'Var', (61, 77))	('Q311E', 'Mutation', 'rs988241015', (61, 66))
494494	32979859	Our data indicate that the Q311E substitution may provide more survival advantages as compared to WT, leading to more aggressive phenotypes in HNSCC cells.	('HNSCC', 'Disease', (143, 148))	('Q311E', 'Mutation', 'rs988241015', (27, 32))	('cat', 'Gene', (13, 16))	('aggressive phenotypes', 'CPA', (118, 139))	('Q311E', 'Var', (27, 32))	('cat', 'Gene', '847', (13, 16))
494495	32979859	On the other hand, the results of our transient expression study support a point view that MB21D2-WT overexpression may serve as a selection barrier to enrich cell clones with tolerance to MB21D2-induced cell growth arrest/senescence.	('growth arrest', 'Phenotype', 'HP:0001510', (209, 222))	('cell growth arrest', 'Disease', 'MESH:D006323', (204, 222))	('cell growth arrest', 'Disease', (204, 222))	('MB21D2-induced', 'Var', (189, 203))
494496	32979859	Since the recurrent Q311E mutation showed the genetic feature of an oncogene and MB21D2 expression promoted clonal selection, we considered the possibility of MB21D2-induced addiction in cancer cells with MB21D2 overexpression.	('cancer', 'Disease', 'MESH:D009369', (187, 193))	('cancer', 'Disease', (187, 193))	('Q311E', 'Var', (20, 25))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('MB21D2', 'Gene', (81, 87))	('Q311E', 'Mutation', 'rs988241015', (20, 25))	('clonal selection', 'CPA', (108, 124))
494499	32979859	Annexin V staining further indicated increased cell death/apoptosis in cells transfected with anti-MB21D2 shRNAs as compared to control cells treated with scrambled shRNA (Fig.	('Annexin V', 'Gene', '308', (0, 9))	('Annexin V', 'Gene', (0, 9))	('cat', 'Gene', '847', (31, 34))	('death', 'Disease', 'MESH:D003643', (52, 57))	('death', 'Disease', (52, 57))	('increased', 'PosReg', (37, 46))	('cat', 'Gene', (31, 34))	('anti-MB21D2', 'Var', (94, 105))
494501	32979859	These results support our hypothesis that MB21D2 overexpression serves as a selective force to select and enrich cell clones with additional survival advantages, and the blockage of MB21D2 activity could be utilized as a strategy for treating cancer cells with MB21D2 overexpression.	('blockage', 'Var', (170, 178))	('cancer', 'Disease', (243, 249))	('cancer', 'Disease', 'MESH:D009369', (243, 249))	('cancer', 'Phenotype', 'HP:0002664', (243, 249))	('MB21D2', 'Gene', (182, 188))	('rat', 'Species', '10116', (223, 226))	('activity', 'MPA', (189, 197))
494502	32979859	Since MB21D2 is an annotated cadherin-binding protein, we next assessed the impact of MB21D2 overexpression and the Q311E recurrent mutation on cell migration and invasion which are cell-cell contact and cell-matrix adhesion-dependent processes.	('cell migration', 'CPA', (144, 158))	('cadherin', 'Gene', (29, 37))	('MB21D2', 'Gene', (86, 92))	('Q311E', 'Var', (116, 121))	('rat', 'Species', '10116', (152, 155))	('Q311E', 'Mutation', 'rs988241015', (116, 121))	('cadherin', 'Gene', '999;1002;1004', (29, 37))	('invasion', 'CPA', (163, 171))
494503	32979859	Wound-healing assay using stable cell clones revealed accelerated migration in cells expressing WT and Q311E (Fig.	('migration', 'CPA', (66, 75))	('Q311E', 'Mutation', 'rs988241015', (103, 108))	('accelerated', 'PosReg', (54, 65))	('rat', 'Species', '10116', (60, 63))	('Q311E', 'Var', (103, 108))	('rat', 'Species', '10116', (69, 72))
494504	32979859	S8C) revealed enhanced expression levels of some markers triggered by WT or Q311E for epithelial-mesenchymal transition (EMT), including vimentin, CD44, phospho-smad 2/3, Snail1, Twist 1/2 (in Q311E only), Bmi1 (WT only), and Slug (in Q311E only), in combination with downregulation of E-cadherin.	('Q311E', 'Mutation', 'rs988241015', (76, 81))	('vimentin', 'Gene', '7431', (137, 145))	('Snail1', 'Gene', '6615', (171, 177))	('expression levels', 'MPA', (23, 40))	('vimentin', 'Gene', (137, 145))	('Snail1', 'Gene', (171, 177))	('Q311E', 'Mutation', 'rs988241015', (193, 198))	('Q311E', 'Var', (76, 81))	('Slug', 'Gene', (226, 230))	('Bmi1', 'Gene', (206, 210))	('enhanced', 'PosReg', (14, 22))	('Twist 1/2', 'Gene', '7291;117581', (179, 188))	('Bmi1', 'Gene', '648', (206, 210))	('E-cadherin', 'Gene', (286, 296))	('E-cadherin', 'Gene', '999', (286, 296))	('CD44', 'Gene', '960', (147, 151))	('Q311E', 'Mutation', 'rs988241015', (235, 240))	('epithelial-mesenchymal transition', 'CPA', (86, 119))	('CD44', 'Gene', (147, 151))	('Twist 1/2', 'Gene', (179, 188))	('Slug', 'Gene', '6591', (226, 230))
494506	32979859	Both cellular and nuclear aspect ratios (major axis/minor axis) were significantly higher in CAL27 cells expressing WT and Q311E as compared with control cells with empty vector (Fig.	('Q311E', 'Mutation', 'rs988241015', (123, 128))	('rat', 'Species', '10116', (33, 36))	('Q311E', 'Var', (123, 128))	('higher', 'PosReg', (83, 89))	('CAL27', 'CellLine', 'CVCL:1107', (93, 98))
494508	32979859	In addition, the Transwell invasion study showed that CAL27 cells expressing Q311E gained more migrative/invasive phenotypes, followed by cells with WT expression, while the control cells with empty vector showed much less invasiveness (Fig.	('Q311E', 'Var', (77, 82))	('gained', 'PosReg', (83, 89))	('rat', 'Species', '10116', (98, 101))	('CAL27', 'CellLine', 'CVCL:1107', (54, 59))	('Q311E', 'Mutation', 'rs988241015', (77, 82))	('migrative/invasive phenotypes', 'CPA', (95, 124))
494510	32979859	4E and 4F, CAL27 cells expressing MB21D2 or its Q311E mutant showed higher stemness activity (WT: SFE: 47.5 % and CIC: 1/5.41; Q311E: SFE: 52.5 % and CIC: 1/9.35) than control cells expressing GFP (SFE: 5.0 %; CIC: 1/68.01).	('Q311E', 'Mutation', 'rs988241015', (48, 53))	('Q311E', 'Mutation', 'rs988241015', (127, 132))	('MB21D2', 'Var', (34, 40))	('higher', 'PosReg', (68, 74))	('Q311E', 'Var', (48, 53))	('stemness activity', 'CPA', (75, 92))	('CAL27', 'CellLine', 'CVCL:1107', (11, 16))
494511	32979859	These data suggest that long-term expression and selection of WT or Q311E MB21D2 trigger pro-oncogenic activities by promoting EMT/cancer stemness.	('cancer stemness', 'Disease', (131, 146))	('promoting', 'PosReg', (117, 126))	('Q311E', 'Var', (68, 73))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('MB21D2', 'Gene', (74, 80))	('cancer stemness', 'Disease', 'MESH:D009369', (131, 146))	('pro-oncogenic activities', 'MPA', (89, 113))	('Q311E', 'Mutation', 'rs988241015', (68, 73))
494512	32979859	To confirm that pro-oncogenic phenotypes are mediated by MB21D2 overexpression and Q311E mutation, we injected CAL27 (clones 1 and 2) and TW206 cells stably expressing MB21D2-WT and its Q311E mutant into nude mice.	('CAL27', 'CellLine', 'CVCL:1107', (111, 116))	('nude mice', 'Species', '10090', (204, 213))	('Q311E', 'Mutation', 'rs988241015', (83, 88))	('MB21D2-WT', 'Var', (168, 177))	('TW206', 'CellLine', 'CVCL:F585', (138, 143))	('Q311E', 'Mutation', 'rs988241015', (186, 191))	('MB21D2', 'Gene', (57, 63))	('Q311E', 'Var', (83, 88))	('Q311E', 'Var', (186, 191))
494514	32979859	Significantly, faster tumor growth and larger tumor sizes were observed in mice with Q311E expression in the xenografted tumors as compared to mice in WT and control groups (Figs.	('tumor', 'Disease', 'MESH:D009369', (46, 51))	('mice', 'Species', '10090', (75, 79))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('Q311E expression', 'Var', (85, 101))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('larger', 'PosReg', (39, 45))	('tumors', 'Disease', (121, 127))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('tumor', 'Disease', (46, 51))	('tumor', 'Disease', (121, 126))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('tumors', 'Disease', 'MESH:D009369', (121, 127))	('tumor', 'Disease', (22, 27))	('mice', 'Species', '10090', (143, 147))	('faster', 'PosReg', (15, 21))	('Q311E', 'Mutation', 'rs988241015', (85, 90))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
494515	32979859	Although tumor lesions in the WT group did not grow as fast as the Q311E tumors, they still showed more aggressiveness as compared to tumors in the control group (Fig.	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('Q311E', 'Mutation', 'rs988241015', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('tumors', 'Disease', (73, 79))	('tumors', 'Disease', (134, 140))	('tumor', 'Disease', (9, 14))	('aggressiveness', 'Disease', (104, 118))	('tumors', 'Disease', 'MESH:D009369', (73, 79))	('aggressiveness', 'Phenotype', 'HP:0000718', (104, 118))	('Q311E', 'Var', (67, 72))	('tumors', 'Disease', 'MESH:D009369', (134, 140))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('aggressiveness', 'Disease', 'MESH:D001523', (104, 118))	('tumor', 'Disease', (73, 78))	('tumor', 'Disease', (134, 139))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))
494516	32979859	Similar to the clone 1, the other CAL27 clone (clone 2) and TW206 stable cell lines with WT and Q311E expression are also more tumorigenic as compared to empty vector controls (Fig.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('Q311E', 'Mutation', 'rs988241015', (96, 101))	('TW206', 'CellLine', 'CVCL:F585', (60, 65))	('tumor', 'Disease', (127, 132))	('more', 'PosReg', (122, 126))	('Q311E', 'Var', (96, 101))	('CAL27', 'CellLine', 'CVCL:1107', (34, 39))	('tumor', 'Disease', 'MESH:D009369', (127, 132))
494517	32979859	IHC staining of tumor sections revealed stronger cancer stemness markers (anti-CD44, Twist, and Bmi1) and higher proliferative activity (anti-Ki67) in tumor lesions stably expressing WT or Q311E (Fig.	('Twist', 'Gene', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('Q311E', 'Var', (189, 194))	('rat', 'Species', '10116', (120, 123))	('stronger', 'PosReg', (40, 48))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('Bmi1', 'Gene', (96, 100))	('CD44', 'Gene', '960', (79, 83))	('CD44', 'Gene', (79, 83))	('Bmi1', 'Gene', '648', (96, 100))	('Twist', 'Gene', '7291', (85, 90))	('proliferative activity', 'CPA', (113, 135))	('cancer stemness', 'Disease', 'MESH:D009369', (49, 64))	('tumor', 'Disease', (16, 21))	('Q311E', 'Mutation', 'rs988241015', (189, 194))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('tumor', 'Disease', (151, 156))	('higher', 'PosReg', (106, 112))	('cancer stemness', 'Disease', (49, 64))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
494519	32979859	5D), suggesting genome instability triggered by WT or Q311E expression.	('genome instability', 'CPA', (16, 34))	('Q311E', 'Mutation', 'rs988241015', (54, 59))	('Q311E', 'Var', (54, 59))
494520	32979859	In particular, aberrant cell division can be frequently found in tumors with stable Q311E expression, which is relatively rare in the other two groups (Fig.	('Q311E', 'Mutation', 'rs988241015', (84, 89))	('tumors', 'Disease', (65, 71))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('found', 'Reg', (56, 61))	('Q311E', 'Var', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
494521	32979859	These data support the point of view that Q311E substitution in MB21D2 can trigger activation of pro-oncogenic signaling and may bypass stress-induced cell growth arrest/death, resulting in highly proliferative and genetically unstable cancer cells.	('bypass', 'NegReg', (129, 135))	('Q311E', 'Mutation', 'rs988241015', (42, 47))	('cancer', 'Disease', 'MESH:D009369', (236, 242))	('growth arrest', 'Phenotype', 'HP:0001510', (156, 169))	('cell growth arrest', 'Disease', 'MESH:D006323', (151, 169))	('cancer', 'Disease', (236, 242))	('rat', 'Species', '10116', (204, 207))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('Q311E', 'Var', (42, 47))	('MB21D2', 'Gene', (64, 70))	('death', 'Disease', (170, 175))	('death', 'Disease', 'MESH:D003643', (170, 175))	('pro-oncogenic signaling', 'MPA', (97, 120))	('cell growth arrest', 'Disease', (151, 169))	('activation', 'PosReg', (83, 93))
494523	32979859	To determine possible pathways involved in tumor aggressiveness induced by WT and Q311E, we first utilized mRNA expression data from the TCGA cohort to perform gene set enrichment analyses (GSEA) and determined which pathways could be correlated with MB21D2 overexpression.	('Q311E', 'Var', (82, 87))	('GSEA', 'Chemical', '-', (190, 194))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (43, 63))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('Q311E', 'Mutation', 'rs988241015', (82, 87))	('MB21D2', 'Gene', (251, 257))	('tumor aggressiveness', 'Disease', (43, 63))	('aggressiveness', 'Phenotype', 'HP:0000718', (49, 63))
494527	32979859	Our data showed positive enrichments of KRAS oncogenic signature commonly shared by both cell clones, either expressing WT or Q311E as compared to control cells (Fig.	('Q311E', 'Mutation', 'rs988241015', (126, 131))	('KRAS', 'Gene', (40, 44))	('Q311E', 'Var', (126, 131))	('KRAS', 'Gene', '3845', (40, 44))
494528	32979859	Of note, these pathways became much more significant in cells expressing Q311E as compared to cells expressing WT, including KRAS.50_UP.V1_UP (P = 0.025 for WT and P = 0.003 for Q311E) and KRAS.KIDNEY_UP.V1_UP (P = 0.038 for WT and P = 0.004 for Q311E), indicating a functional relevance of this Q311E recurrent mutation.	('KRAS', 'Gene', (189, 193))	('KRAS', 'Gene', '3845', (189, 193))	('KRAS', 'Gene', (125, 129))	('Q311E', 'Mutation', 'rs988241015', (296, 301))	('cat', 'Gene', '847', (258, 261))	('KRAS', 'Gene', '3845', (125, 129))	('Q311E', 'Mutation', 'rs988241015', (73, 78))	('Q311E', 'Var', (296, 301))	('significant', 'Reg', (41, 52))	('Q311E', 'Mutation', 'rs988241015', (246, 251))	('Q311E', 'Mutation', 'rs988241015', (178, 183))	('cat', 'Gene', (258, 261))	('Q311E', 'Var', (73, 78))
494530	32979859	As expected, elevated KRAS was found in cells with WT and Q311E expression as compared to empty vector controls (Fig.	('elevated', 'PosReg', (13, 21))	('Q311E expression', 'Var', (58, 74))	('KRAS', 'Gene', (22, 26))	('KRAS', 'Gene', '3845', (22, 26))	('Q311E', 'Mutation', 'rs988241015', (58, 63))
494532	32979859	Protein levels of PI3K and CREB were increased in WT and Q311E groups, which were associated with increased phosphorylation (Fig.	('Q311E', 'Var', (57, 62))	('CREB', 'Gene', (27, 31))	('CREB', 'Gene', '1385', (27, 31))	('increased', 'PosReg', (98, 107))	('increased', 'PosReg', (37, 46))	('phosphorylation', 'MPA', (108, 123))	('Q311E', 'Mutation', 'rs988241015', (57, 62))	('PI3', 'Gene', '5266', (18, 21))	('Protein levels', 'MPA', (0, 14))	('PI3', 'Gene', (18, 21))
494533	32979859	Though the protein levels of AKT were not changed by WT and Q311E expression, AKT was still activated by phosphorylation (Fig.	('Q311E', 'Var', (60, 65))	('activated', 'PosReg', (92, 101))	('AKT', 'Gene', '207', (29, 32))	('AKT', 'Gene', '207', (78, 81))	('Q311E', 'Mutation', 'rs988241015', (60, 65))	('AKT', 'Gene', (29, 32))	('AKT', 'Gene', (78, 81))
494534	32979859	Reversely, MB21D2 knockdown in FADU cells decreased total protein levels of KRAS and PI3K, along with dephosphorylation of PI3K, AKT, and CREB (Fig.	('MB21D2', 'Gene', (11, 17))	('knockdown', 'Var', (18, 27))	('PI3', 'Gene', '5266', (85, 88))	('decreased', 'NegReg', (42, 51))	('PI3', 'Gene', '5266', (123, 126))	('AKT', 'Gene', '207', (129, 132))	('KRAS', 'Gene', (76, 80))	('KRAS', 'Gene', '3845', (76, 80))	('PI3', 'Gene', (123, 126))	('CREB', 'Gene', (138, 142))	('PI3', 'Gene', (85, 88))	('CREB', 'Gene', '1385', (138, 142))	('protein levels', 'MPA', (58, 72))	('AKT', 'Gene', (129, 132))	('dephosphorylation', 'MPA', (102, 119))
494535	32979859	Cell line screening also showed that cells with high MB21D2 (FADU and HSC3 cells) expressed high levels of total and phosphorylated PI3K as compared to those with low MB21D2 expression (CAL27 and TW206 cells) (Fig.	('PI3', 'Gene', (132, 135))	('TW206', 'CellLine', 'CVCL:F585', (196, 201))	('CAL27', 'CellLine', 'CVCL:1107', (186, 191))	('PI3', 'Gene', '5266', (132, 135))	('HSC3', 'Gene', '150353', (70, 74))	('HSC3', 'Gene', (70, 74))	('MB21D2', 'Var', (53, 59))	('high MB21D2', 'Var', (48, 59))
494536	32979859	Since the KRAS-PI3K axis was shown to be enriched/upregulated by WT or Q311E expression, we endeavored to know whether KRAS or PI3K reduction could be utilized as a strategy against MB21D2.	('enriched/upregulated', 'PosReg', (41, 61))	('KRAS', 'Gene', '3845', (10, 14))	('PI3', 'Gene', '5266', (127, 130))	('PI3', 'Gene', (15, 18))	('KRAS', 'Gene', (119, 123))	('Q311E', 'Mutation', 'rs988241015', (71, 76))	('rat', 'Species', '10116', (167, 170))	('KRAS', 'Gene', '3845', (119, 123))	('Q311E expression', 'Var', (71, 87))	('PI3', 'Gene', (127, 130))	('PI3', 'Gene', '5266', (15, 18))	('KRAS', 'Gene', (10, 14))
494537	32979859	We treated OSCC cells with RAS (manumycin) and PI3K (wortmannin) inhibitors and found higher chemosensitivity in cells expressing high MB21D2 (HSC3 and FADU cells) as compared to cells with lower MB21D2 (CAL27 and TW206) (Fig.	('OSCC', 'CellLine', 'CVCL:L894', (11, 15))	('HSC3', 'Gene', '150353', (143, 147))	('CAL27', 'CellLine', 'CVCL:1107', (204, 209))	('PI3', 'Gene', '5266', (47, 50))	('high MB21D2', 'Var', (130, 141))	('HSC3', 'Gene', (143, 147))	('MB21D2', 'Var', (135, 141))	('wortmannin', 'Chemical', '-', (53, 63))	('PI3', 'Gene', (47, 50))	('higher', 'PosReg', (86, 92))	('TW206', 'CellLine', 'CVCL:F585', (214, 219))	('chemosensitivity', 'MPA', (93, 109))	('manumycin', 'Chemical', 'MESH:C054474', (32, 41))
494538	32979859	In the engineered CAL27 and TW206 cells, we also confirmed that the overexpression of MB21D2 and its Q311E mutant made cells more sensitive to RAS and PI3K inhibitors as compared to empty vector controls (Fig.	('TW206', 'CellLine', 'CVCL:F585', (28, 33))	('Q311E', 'Mutation', 'rs988241015', (101, 106))	('RAS', 'Protein', (143, 146))	('PI3', 'Gene', (151, 154))	('sensitive', 'MPA', (130, 139))	('PI3', 'Gene', '5266', (151, 154))	('overexpression', 'PosReg', (68, 82))	('more', 'PosReg', (125, 129))	('Q311E', 'Var', (101, 106))	('CAL27', 'CellLine', 'CVCL:1107', (18, 23))	('MB21D2', 'Gene', (86, 92))
494539	32979859	Through RAS inhibition, we can also see differential therapeutic effects on cells expressing WT or Q311E with limited effects on control cells (Fig.	('RAS', 'Protein', (8, 11))	('Q311E', 'Mutation', 'rs988241015', (99, 104))	('Q311E', 'Var', (99, 104))
494540	32979859	Our data suggest that WT MB21D2 overexpression and its Q311E mutation can positively influence the enrichment of KRAS to mediate aggressive cancer behavior.	('MB21D2', 'Gene', (25, 31))	('overexpression', 'PosReg', (32, 46))	('enrichment', 'MPA', (99, 109))	('Q311E', 'Mutation', 'rs988241015', (55, 60))	('influence', 'Reg', (85, 94))	('aggressive cancer', 'Disease', 'MESH:D009369', (129, 146))	('KRAS', 'Gene', (113, 117))	('Q311E', 'Var', (55, 60))	('mediate', 'Reg', (121, 128))	('aggressive cancer', 'Disease', (129, 146))	('KRAS', 'Gene', '3845', (113, 117))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))
494541	32979859	Anti-KRAS could be utilized as a good strategy to develop new methods for treating cancers with MB21D2 overexpression or its Q311E recurrent mutation.	('cancers', 'Disease', 'MESH:D009369', (83, 90))	('MB21D2', 'Gene', (96, 102))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('Q311E', 'Mutation', 'rs988241015', (125, 130))	('rat', 'Species', '10116', (40, 43))	('KRAS', 'Gene', (5, 9))	('KRAS', 'Gene', '3845', (5, 9))	('overexpression', 'PosReg', (103, 117))	('Q311E', 'Var', (125, 130))	('cancers', 'Phenotype', 'HP:0002664', (83, 90))	('cancers', 'Disease', (83, 90))
494546	32979859	We discovered a unique recurrent Q311E mutation in MB21D2 across human SCCs.	('Q311E', 'Mutation', 'rs988241015', (33, 38))	('Q311E', 'Var', (33, 38))	('human', 'Species', '9606', (65, 70))	('MB21D2', 'Gene', (51, 57))
494548	32979859	Cell-based assay revealed a significant increase in cell proliferation, migration, invasion, and in vivo tumorigenicity triggered by MB21D2 and its Q311E mutant by enrichment of KRAS signature that is known to subsequently activate the PI3K-AKT pathway [41, 42].	('migration', 'CPA', (72, 81))	('rat', 'Species', '10116', (64, 67))	('invasion', 'CPA', (83, 91))	('Q311E', 'Var', (148, 153))	('KRAS', 'Gene', '3845', (178, 182))	('tumor', 'Disease', (105, 110))	('PI3', 'Gene', '5266', (236, 239))	('KRAS', 'Gene', (178, 182))	('AKT', 'Gene', (241, 244))	('rat', 'Species', '10116', (75, 78))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('MB21D2', 'Gene', (133, 139))	('Q311E', 'Mutation', 'rs988241015', (148, 153))	('PI3', 'Gene', (236, 239))	('cell proliferation', 'CPA', (52, 70))	('activate', 'PosReg', (223, 231))	('increase', 'PosReg', (40, 48))	('AKT', 'Gene', '207', (241, 244))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))
494549	32979859	To our knowledge, this is the first report to show the functional relevance of MB21D2 overexpression and its Q311E mutant as pro-oncogenic proteins in HNSCC.	('MB21D2', 'Gene', (79, 85))	('HNSCC', 'Disease', (151, 156))	('Q311E', 'Var', (109, 114))	('Q311E', 'Mutation', 'rs988241015', (109, 114))	('overexpression', 'PosReg', (86, 100))
494551	32979859	Based on our study, MB21D2 overexpression and Q311E mutation correlated negatively with HPV infection, either by using E6/E7 viral marker or by using p16/CDKN2A host-cell marker (Fig.	('HPV infection', 'Disease', (88, 101))	('p16', 'Gene', (150, 153))	('negatively', 'NegReg', (72, 82))	('Q311E', 'Mutation', 'rs988241015', (46, 51))	('CDKN2A', 'Gene', (154, 160))	('p16', 'Gene', '1029', (150, 153))	('CDKN2A', 'Gene', '1029', (154, 160))	('MB21D2', 'Gene', (20, 26))	('HPV infection', 'Disease', 'MESH:D030361', (88, 101))	('Q311E', 'Var', (46, 51))	('overexpression', 'PosReg', (27, 41))
494553	32979859	Our data indicated that cells expressing MB21D2 and its Q311E form can survive better than the control cells and still proliferate in the presence of cisplatin (the newly added Fig.	('Q311E', 'Mutation', 'rs988241015', (56, 61))	('MB21D2', 'Var', (41, 47))	('cat', 'Gene', (13, 16))	('rat', 'Species', '10116', (126, 129))	('Q311E', 'Var', (56, 61))	('cisplatin', 'Chemical', 'MESH:D002945', (150, 159))	('proliferate', 'CPA', (119, 130))	('cat', 'Gene', '847', (13, 16))
494555	32979859	These data suggest that patients with MB21D2 overexpression and Q311E mutation may show less sensitivity toward DNA-damaging agents, such as cisplatin-based radiation therapy.	('sensitivity toward DNA-damaging agents', 'MPA', (93, 131))	('less', 'NegReg', (88, 92))	('Q311E', 'Var', (64, 69))	('cisplatin', 'Chemical', 'MESH:D002945', (141, 150))	('patients', 'Species', '9606', (24, 32))	('overexpression', 'PosReg', (45, 59))	('MB21D2', 'Gene', (38, 44))	('Q311E', 'Mutation', 'rs988241015', (64, 69))
494558	32979859	Oncogene-induced senescence could promote cancer initiation and development through combined alteration of downstream effectors and the microenvironment, such as senescence-associated inflammation [46].	('Oncogene-induced', 'Var', (0, 16))	('rat', 'Species', '10116', (97, 100))	('alteration', 'Reg', (93, 103))	('inflammation', 'Disease', 'MESH:D007249', (184, 196))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('development', 'CPA', (64, 75))	('inflammation', 'Disease', (184, 196))	('promote', 'PosReg', (34, 41))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))
494560	32979859	S11B) [27, 28], may further explain the clonal selection event, as fittest clone selection was previously observed in many cancers such as multiple myeloma [47].	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('S11B', 'Var', (0, 4))	('S11B', 'SUBSTITUTION', 'None', (0, 4))	('multiple myeloma', 'Phenotype', 'HP:0006775', (139, 155))	('cancers', 'Disease', 'MESH:D009369', (123, 130))	('multiple myeloma', 'Disease', 'MESH:D009101', (139, 155))	('cancers', 'Phenotype', 'HP:0002664', (123, 130))	('multiple myeloma', 'Disease', (139, 155))	('cancers', 'Disease', (123, 130))
494563	32979859	Prevalent hotspot mutations in BRAF (V600E), KRAS (G12D), and PIK3CA (E545K) are found in the functional domains [49] associated with oncogenic advantages.	('KRAS', 'Gene', '3845', (45, 49))	('V600E', 'Mutation', 'rs113488022', (37, 42))	('PIK3CA', 'Gene', (62, 68))	('E545K', 'Mutation', 'rs104886003', (70, 75))	('V600E', 'Var', (37, 42))	('E545K', 'Var', (70, 75))	('associated', 'Reg', (118, 128))	('BRAF', 'Gene', '673', (31, 35))	('oncogenic advantages', 'CPA', (134, 154))	('G12D', 'Mutation', 'rs121913529', (51, 55))	('KRAS', 'Gene', (45, 49))	('BRAF', 'Gene', (31, 35))
494564	32979859	Consistent oncogenic activity of Q311E supported by transient and stable expression studies suggests gain of function of this recurrent mutation.	('Q311E', 'Mutation', 'rs988241015', (33, 38))	('oncogenic activity', 'CPA', (11, 29))	('gain of function', 'PosReg', (101, 117))	('Q311E', 'Var', (33, 38))
494565	32979859	However, a recent study also suggested that the Q311E recurrent mutation might be the result of its position at the DNA stem-loop region, a favorable substrate for APOBEC3A [50, 51].	('Q311E', 'Mutation', 'rs988241015', (48, 53))	('APOBEC3A', 'Gene', '200315', (164, 172))	('Q311E', 'Var', (48, 53))	('rat', 'Species', '10116', (155, 158))	('APOBEC3A', 'Gene', (164, 172))
494570	32979859	MB21D1), the phosphorylation site (Y215) in Mab21 domain controls nuclear/cellular functions [52].	('Mab21', 'Gene', (44, 49))	('nuclear/cellular functions', 'MPA', (66, 92))	('Y215', 'Var', (35, 39))	('MB21D1', 'Gene', (0, 6))	('MB21D1', 'Gene', '115004', (0, 6))	('controls', 'Reg', (57, 65))
494571	32979859	Structural prediction also revealed a local conformational change from a helix to a beta-sheet connecting to a long loop by Q to E substitution (Fig.	('Q to E substitution', 'Var', (124, 143))	('conformational', 'MPA', (44, 58))	('a beta', 'Gene', '351', (82, 88))	('a beta', 'Gene', (82, 88))
494572	32979859	Thirdly, transcriptome analyses confirmed the enrichment of KRAS signaling in MB21D2-expressing cells and such oncogenic signaling became more enhanced in cells expressing Q311E mutation (Fig.	('Q311E', 'Mutation', 'rs988241015', (172, 177))	('enhanced', 'PosReg', (143, 151))	('oncogenic signaling', 'MPA', (111, 130))	('KRAS', 'Gene', (60, 64))	('Q311E', 'Var', (172, 177))	('KRAS', 'Gene', '3845', (60, 64))
494573	32979859	Higher oncogenic activities by Q311E mutation can also be found as compared to MB21D2-WT, including cell survival after transient transfection (Fig.	('Q311E', 'Mutation', 'rs988241015', (31, 36))	('cell survival', 'CPA', (100, 113))	('oncogenic activities', 'CPA', (7, 27))	('Higher', 'PosReg', (0, 6))	('Q311E', 'Var', (31, 36))
494575	32979859	Therefore, Q311E recurrent mutation should be functionally active that may mimic MB21D2 overexpression and possibly phosphorylation activation to enhance the downstream effectors involved in KRAS signaling.	('overexpression', 'PosReg', (88, 102))	('KRAS', 'Gene', (191, 195))	('phosphorylation', 'MPA', (116, 131))	('Q311E', 'Mutation', 'rs988241015', (11, 16))	('Q311E', 'Var', (11, 16))	('KRAS', 'Gene', '3845', (191, 195))	('enhance', 'PosReg', (146, 153))	('MB21D2', 'Gene', (81, 87))
494576	32979859	Our results suggest that the WT and or Q311E mutant may serve as an enrichment factor for KRAS which is known to be a positive regulator of PI3K, AKT, and CREB signaling molecules (Fig.	('Q311E', 'Var', (39, 44))	('AKT', 'Gene', '207', (146, 149))	('KRAS', 'Gene', (90, 94))	('KRAS', 'Gene', '3845', (90, 94))	('PI3', 'Gene', '5266', (140, 143))	('AKT', 'Gene', (146, 149))	('Q311E', 'Mutation', 'rs988241015', (39, 44))	('CREB', 'Gene', (155, 159))	('PI3', 'Gene', (140, 143))	('CREB', 'Gene', '1385', (155, 159))
494578	32979859	S12A and S12B), suggesting functional relevance between them.	('S12A', 'Var', (0, 4))	('S12B', 'SUBSTITUTION', 'None', (9, 13))	('S12B', 'Var', (9, 13))	('S12A', 'SUBSTITUTION', 'None', (0, 4))
494582	32979859	Thus, we consider that MB21D2 overexpression or its Q311E mutation can promote PI3K activation through KRAS signaling enrichment.	('KRAS', 'Gene', (103, 107))	('promote', 'PosReg', (71, 78))	('Q311E', 'Mutation', 'rs988241015', (52, 57))	('KRAS', 'Gene', '3845', (103, 107))	('activation', 'PosReg', (84, 94))	('overexpression', 'PosReg', (30, 44))	('PI3', 'Gene', '5266', (79, 82))	('Q311E', 'Var', (52, 57))	('MB21D2', 'Gene', (23, 29))	('PI3', 'Gene', (79, 82))
494583	32979859	Interestingly, MB21D2 upregulation correlated with PTEN downregulation signature (Table S4), which is more pronounced in Q311E as compared with WT.	('Q311E', 'Mutation', 'rs988241015', (121, 126))	('MB21D2', 'Gene', (15, 21))	('downregulation', 'NegReg', (56, 70))	('upregulation', 'PosReg', (22, 34))	('Q311E', 'Var', (121, 126))	('PTEN', 'Gene', (51, 55))
494588	32979859	Transcriptome analyses revealed upregulation of several transcription factors involved in cancer stemness/EMT, including Twist 1/2, Slug, Snail1, and Bmi1, by MB21D2 overexpression or its Q311E mutant (Fig.	('cancer stemness', 'Disease', (90, 105))	('Twist 1/2', 'Gene', '7291;117581', (121, 130))	('upregulation', 'PosReg', (32, 44))	('MB21D2', 'Gene', (159, 165))	('Bmi1', 'Gene', (150, 154))	('Twist 1/2', 'Gene', (121, 130))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('Q311E', 'Var', (188, 193))	('Slug', 'Gene', '6591', (132, 136))	('cancer stemness', 'Disease', 'MESH:D009369', (90, 105))	('Slug', 'Gene', (132, 136))	('Bmi1', 'Gene', '648', (150, 154))	('Q311E', 'Mutation', 'rs988241015', (188, 193))	('Snail1', 'Gene', (138, 144))	('Snail1', 'Gene', '6615', (138, 144))	('overexpression', 'PosReg', (166, 180))
494589	32979859	Some minor differences in transcriptional regulations on cancer stemness were found, such as Slug and Snail1 were enhanced only by Q311E, whereas Bmi1 was upregulated by WT-MB21D2 (Fig.	('Bmi1', 'Gene', '648', (146, 150))	('cancer stemness', 'Disease', (57, 72))	('Slug', 'Gene', '6591', (93, 97))	('Q311E', 'Mutation', 'rs988241015', (131, 136))	('Snail1', 'Gene', (102, 108))	('Bmi1', 'Gene', (146, 150))	('enhanced', 'PosReg', (114, 122))	('transcriptional regulations', 'MPA', (26, 53))	('upregulated', 'PosReg', (155, 166))	('Snail1', 'Gene', '6615', (102, 108))	('Q311E', 'Var', (131, 136))	('Slug', 'Gene', (93, 97))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('cancer stemness', 'Disease', 'MESH:D009369', (57, 72))
494590	32979859	The mechanisms that determine the differential downstream effects between MB21D2 and its Q311E are still unknown and need further study.	('MB21D2', 'Gene', (74, 80))	('Q311E', 'Var', (89, 94))	('Q311E', 'Mutation', 'rs988241015', (89, 94))
494591	32979859	In transgenic mice, PIK3CA-activating mutation is insufficient to initiate tumorigenesis, and additional genetic alterations are required to drive this process, such as TP53/PTEN alteration [55].	('rat', 'Species', '10116', (183, 186))	('rat', 'Species', '10116', (117, 120))	('PIK3CA-activating', 'Gene', (20, 37))	('TP53', 'Gene', '22059', (169, 173))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('TP53', 'Gene', (169, 173))	('mutation', 'Var', (38, 46))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('transgenic mice', 'Species', '10090', (3, 18))	('tumor', 'Disease', (75, 80))
494592	32979859	It is highly possible that MB21D2 overexpression or Q311E mutation serves as a secondary regulatory loop to control PI3K activity during cell transformation and cancer development through KRAS upregulation.	('Q311E', 'Mutation', 'rs988241015', (52, 57))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('upregulation', 'PosReg', (193, 205))	('Q311E mutation', 'Var', (52, 66))	('activity', 'MPA', (121, 129))	('PI3', 'Gene', '5266', (116, 119))	('overexpression', 'PosReg', (34, 48))	('KRAS', 'Gene', (188, 192))	('control', 'PosReg', (108, 115))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('cancer', 'Disease', (161, 167))	('PI3', 'Gene', (116, 119))	('KRAS', 'Gene', '3845', (188, 192))	('MB21D2', 'Gene', (27, 33))
494593	32979859	Currently, we are preparing to perform genome editing in a mouse model to introduce the Q311E mutation, which will enable us to further validate the oncogenic potentials of the Q311E mutation in cancer.	('Q311E', 'Var', (177, 182))	('Q311E', 'Var', (88, 93))	('mouse', 'Species', '10090', (59, 64))	('cancer', 'Disease', (195, 201))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('Q311E', 'Mutation', 'rs988241015', (88, 93))	('Q311E', 'Mutation', 'rs988241015', (177, 182))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
494594	32979859	Nevertheless, our study suggests that overexpression of wild-type MB21D2 and Q311E mutation mediates pro-oncogenic activities in HNSCC by positive enrichment of KRAS along with activation of PI3K-AKT, and EMT factors.	('AKT', 'Gene', (196, 199))	('PI3', 'Gene', (191, 194))	('pro-oncogenic activities', 'MPA', (101, 125))	('activation', 'PosReg', (177, 187))	('Q311E mutation', 'Var', (77, 91))	('HNSCC', 'Disease', (129, 134))	('Q311E', 'Mutation', 'rs988241015', (77, 82))	('AKT', 'Gene', '207', (196, 199))	('KRAS', 'Gene', (161, 165))	('PI3', 'Gene', '5266', (191, 194))	('MB21D2', 'Gene', (66, 72))	('KRAS', 'Gene', '3845', (161, 165))
494595	32979859	Finally, we recommend the use of RAS inhibition as a new strategy for treating HNSCC with Q311E mutation and overexpression in MB21D2.	('HNSCC', 'Disease', (79, 84))	('Q311E', 'Mutation', 'rs988241015', (90, 95))	('Q311E mutation', 'Var', (90, 104))	('rat', 'Species', '10116', (59, 62))	('MB21D2', 'Gene', (127, 133))
494631	32979859	GSEA was used to determine enrichment pathways in wild-type and Q311E mutant MB21D2 to determine common enriched pathways.	('Q311E', 'Var', (64, 69))	('GSEA', 'Chemical', '-', (0, 4))	('MB21D2', 'Gene', (77, 83))	('Q311E', 'Mutation', 'rs988241015', (64, 69))
494642	32979859	Overexpression of MB21D2 is correlated with shorter patient survival and promotes oncogenic advantages, such as cell proliferation, survival, and tumorigenicity based on vitro and nude mouse studies.	('rat', 'Species', '10116', (124, 127))	('cell proliferation', 'CPA', (112, 130))	('mouse', 'Species', '10090', (185, 190))	('MB21D2', 'Gene', (18, 24))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('patient survival', 'CPA', (52, 68))	('tumor', 'Disease', (146, 151))	('Overexpression', 'Var', (0, 14))	('oncogenic advantages', 'CPA', (82, 102))	('patient', 'Species', '9606', (52, 59))	('promotes', 'PosReg', (73, 81))	('survival', 'CPA', (132, 140))	('shorter', 'NegReg', (44, 51))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
494643	32979859	Further, MB21D2 (WT overexpression or its Q311E mutation) participates in migration/invasion as reflected in EMT upregulation and phosphorylation.	('Q311E', 'Mutation', 'rs988241015', (42, 47))	('rat', 'Species', '10116', (77, 80))	('MB21D2', 'Gene', (9, 15))	('upregulation', 'PosReg', (113, 125))	('migration/invasion', 'CPA', (74, 92))	('Q311E', 'Var', (42, 47))	('EMT', 'CPA', (109, 112))	('participates', 'Reg', (58, 70))	('phosphorylation', 'CPA', (130, 145))
494644	32979859	Consequently, we conclude that MB21D2 overexpression and its Q311E recurrent mutation play an important role in HNSCC by acting as an enrichment factor of KRAS-mediated signaling along with PI3K-AKT and CREB and EMT activation.	('AKT', 'Gene', (195, 198))	('EMT', 'CPA', (212, 215))	('Q311E', 'Var', (61, 66))	('MB21D2', 'Gene', (31, 37))	('PI3', 'Gene', '5266', (190, 193))	('KRAS', 'Gene', (155, 159))	('KRAS', 'Gene', '3845', (155, 159))	('PI3', 'Gene', (190, 193))	('CREB', 'Gene', (203, 207))	('CREB', 'Gene', '1385', (203, 207))	('overexpression', 'PosReg', (38, 52))	('HNSCC', 'Disease', (112, 117))	('AKT', 'Gene', '207', (195, 198))	('Q311E', 'Mutation', 'rs988241015', (61, 66))
494645	32979859	The negative association/correlation of MB21D2 with HPV may further explain the resistance of MB21D2 (WT or Q311E)-overexpressing cells to DNA-damaging drugs, such as cisplatin.	('MB21D2', 'Gene', (94, 100))	('cisplatin', 'Chemical', 'MESH:D002945', (167, 176))	('Q311E', 'Mutation', 'rs988241015', (108, 113))	('negative', 'NegReg', (4, 12))	('association/correlation', 'Interaction', (13, 36))	('Q311E', 'Var', (108, 113))
494671	32286489	A MAF file annotating mutations in the OCSCC TCGA cohort was downloaded from cbioportal (http://www.cbioportal.org/); whereas mutations present in the TCGA LUSC cohort were obtained from Campbell et al.. Mutations were considered impactful if their SIFT score was deleterious or their PolyPhen score was probably or possibly damaging.	('Mutations', 'Var', (204, 213))	('MAF', 'Gene', '4094', (2, 5))	('MAF', 'Gene', (2, 5))
494679	32286489	OCSCC tumors demonstrated a low mutational frequency in core metabolic genes (Supplementary Table 1; Supplementary Fig.	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('core', 'MPA', (56, 60))	('mutational', 'Var', (32, 42))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('tumors', 'Disease', (6, 12))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))
494681	32286489	However, there was a trend towards reduced survival in OCSCC patients with nuclear encoded mitochondrial gene mutations (MS = 20.73 months) compared to those without such alterations (MS = 53.91 months).	('mutations', 'Var', (110, 119))	('reduced', 'NegReg', (35, 42))	('patients', 'Species', '9606', (61, 69))	('survival', 'MPA', (43, 51))	('mitochondrial', 'Gene', (91, 104))
494683	32286489	4B), despite a trend for reduced survival in patients with impactful mutations in nuclear encoded mitochondrial genes.	('mutations', 'Var', (69, 78))	('patients', 'Species', '9606', (45, 53))	('reduced', 'NegReg', (25, 32))	('survival', 'MPA', (33, 41))
494684	32286489	Transketolase like 2 (TKTL2) had a mutational frequency above 5% in LUSC, but failed to reach statistical significance by MutSiq analysis (Q-value= 0.06) and demonstrated a random missense mutational pattern across the length of the gene (Supplementary Fig.	('mutational', 'Var', (35, 45))	('Transketolase like 2', 'Gene', (0, 20))	('Transketolase like 2', 'Gene', '84076', (0, 20))	('LUSC', 'Disease', (68, 72))	('TKTL2', 'Gene', '84076', (22, 27))	('TKTL2', 'Gene', (22, 27))
494751	32286489	A slight enrichment for increased mutations in KDM6a and KMT2B was found in OCSCC cluster 1 (Supplementary Table 20), but none of the other driver genes in either OCSCC or LUSC (not shown) had significantly different mutation frequencies between OXPHOG cluster 1 and other clusters (Supplementary Tables 21 and 22).	('KDM6a', 'Gene', '7403', (47, 52))	('KMT2B', 'Gene', '9757', (57, 62))	('KDM6a', 'Gene', (47, 52))	('KMT2B', 'Gene', (57, 62))	('OCSCC', 'Disease', (76, 81))	('mutations', 'Var', (34, 43))	('increased', 'PosReg', (24, 33))
494755	32286489	Over the last decade, our group along with other investigators have shifted focus toward modulation of mitochondrial activity to generate de novo anti-tumor activity, or to potentiate chemo-radiation effects in solid tumors.	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('tumor', 'Disease', (217, 222))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumors', 'Disease', (217, 223))	('tumors', 'Disease', 'MESH:D009369', (217, 223))	('tumors', 'Phenotype', 'HP:0002664', (217, 223))	('tumor', 'Disease', (151, 156))	('tumor', 'Disease', 'MESH:D009369', (151, 156))	('tumor', 'Disease', 'MESH:D009369', (217, 222))	('potentiate', 'PosReg', (173, 183))	('modulation', 'Var', (89, 99))	('mitochondrial', 'MPA', (103, 116))
494756	32286489	Although supported by preclinical studies and retrospective clinical data, inhibition of mitochondrial respiration to improve treatment response is somewhat counterintuitive, since high levels of mitochondrial activity are generally linked to improved clinical outcomes and indolent tumor behavior.	('inhibition', 'Var', (75, 85))	('clinical outcomes', 'CPA', (252, 269))	('tumor', 'Phenotype', 'HP:0002664', (283, 288))	('tumor behavior', 'Disease', 'MESH:D001523', (283, 297))	('improved', 'PosReg', (243, 251))	('tumor behavior', 'Disease', (283, 297))
494758	32286489	We found that OCSCC and LUSCC mutations in metabolic genes encoding enzymes and proteins involved in either glycolysis or oxidative phosphorylation are infrequent and likely to be random, unlike in other tumor types.	('OCSCC', 'Disease', (14, 19))	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('metabolic genes', 'Gene', (43, 58))	('tumor', 'Disease', (204, 209))	('mutations', 'Var', (30, 39))
494762	32286489	Previous investigations have linked mitochondrial copy number to cancer (non-SCC) survival.	('linked', 'Reg', (29, 35))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('mitochondrial copy number', 'Var', (36, 61))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))
494770	32286489	It is intriguing that that expression of OXPHOG genes generated a differential tumor immune microenvironment (TIME) imputed from gene expression analysis.	('expression', 'Var', (27, 37))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Disease', (79, 84))
494777	32076369	For instance, integrative analysis of ChIP-Seq and RNA-Seq data of head and neck squamous cell carcinoma (HNSCC) cell lines showed that cancer-specific histone marks, H3K4me3 and H3K27ac, are associated with transcriptional changes in HNSCC driver genes, epidermal growth factor receptor (EGFR), FGFR1, and FOXA1.	('associated', 'Reg', (192, 202))	('H3K4me3', 'Var', (167, 174))	('EGFR', 'Gene', (289, 293))	('cancer', 'Disease', (136, 142))	('H3K4me3', 'Chemical', 'MESH:C024755', (167, 174))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('H3K27ac', 'Var', (179, 186))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (67, 104))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('FGFR1', 'Gene', '2260', (296, 301))	('EGFR', 'Gene', '1956', (289, 293))	('FOXA1', 'Gene', '3169', (307, 312))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('FOXA1', 'Gene', (307, 312))	('transcriptional', 'MPA', (208, 223))	('epidermal growth factor receptor', 'Gene', (255, 287))	('HNSCC', 'Gene', (235, 240))	('epidermal growth factor receptor', 'Gene', '1956', (255, 287))	('neck squamous cell carcinoma', 'Disease', 'MESH:C535575', (76, 104))	('neck squamous cell carcinoma', 'Disease', (76, 104))	('FGFR1', 'Gene', (296, 301))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (81, 104))
494789	32076369	This initiative aims to generate, merge, analyze, and interpret the profiles of DNA, RNA, protein, and epigenetic changes in tumor samples along with the clinical and histological data.	('tumor', 'Disease', (125, 130))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('epigenetic changes', 'Var', (103, 121))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))
494801	32076369	Molecular Taxonomy of Breast Cancer International Consortium (METABRIC; http://molonc.bccrc.ca/aparicio-lab/research/metabric/) is a Canada-UK project that contains clinical traits, expression, single-nucleotide polymorphism (SNP), and CNV data derived from breast tumors.	('single-nucleotide', 'Var', (194, 211))	('breast tumors', 'Disease', 'MESH:D061325', (258, 271))	('tumor', 'Phenotype', 'HP:0002664', (265, 270))	('Cancer', 'Phenotype', 'HP:0002664', (29, 35))	('Breast Cancer', 'Disease', (22, 35))	('Breast Cancer', 'Disease', 'MESH:D001943', (22, 35))	('breast tumors', 'Phenotype', 'HP:0100013', (258, 271))	('tumors', 'Phenotype', 'HP:0002664', (265, 271))	('Breast Cancer', 'Phenotype', 'HP:0003002', (22, 35))	('breast tumors', 'Disease', (258, 271))
494808	32076369	Using TCGA data, previous reports identified distinct molecular subtypes of breast cancer by combining data from different layers such as CNV, mutation, DNA methylation, transcriptomics (mRNA expression and microRNA [miRNA] expression), and proteomics.	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('mutation', 'Var', (143, 151))	('breast cancer', 'Disease', (76, 89))	('breast cancer', 'Disease', 'MESH:D001943', (76, 89))	('breast cancer', 'Phenotype', 'HP:0003002', (76, 89))
494809	32076369	The integrative analysis produced a comprehensive catalog of genetic and epigenetic drivers of breast cancer subtypes.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('breast cancer', 'Disease', (95, 108))	('epigenetic', 'Var', (73, 83))	('breast cancer', 'Phenotype', 'HP:0003002', (95, 108))	('catalog of genetic', 'Disease', (50, 68))	('catalog of genetic', 'Disease', 'MESH:D030342', (50, 68))	('breast cancer', 'Disease', 'MESH:D001943', (95, 108))
494831	32076369	The subtype represented by cluster 1 showed an unevenly distributed profile of copy number alterations, hypermethylation of genes involved in brain development and neuronal differentiation, and a proneural expression profile.	('men', 'Species', '9606', (155, 158))	('copy number alterations', 'Var', (79, 102))	('hypermethylation', 'Var', (104, 120))	('proneural expression profile', 'MPA', (196, 224))
494832	32076369	The subtype shown as cluster 2 was characterized by association with EGFR alteration, gains of chromosome 19 and 20, methylation of homeobox genes, and enriched expression.	('EGFR', 'Gene', '1956', (69, 73))	('alteration', 'Var', (74, 84))	('EGFR', 'Gene', (69, 73))	('gains', 'Var', (86, 91))	('homeobox genes', 'Gene', (132, 146))	('methylation', 'Var', (117, 128))	('association', 'Interaction', (52, 63))
494838	32076369	Although many cell lines were majorly grouped by their cell-of-origin for few cancer types (eg, small-cell lung carcinoma [SCLC], hematopoietic and lymphoid tissue, and breast cancer), several other subgroups were also revealed that were not lineage-dependent and possibly were driven by a shared genetic alteration (eg, cluster 9 which belonged to both non-small-cell lung cancer [NSCLC] and pancreatic cancer cell lines showed prevalent KRAS mutations).	('pancreatic cancer', 'Phenotype', 'HP:0002894', (393, 410))	('cancer', 'Disease', 'MESH:D009369', (404, 410))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('cancer', 'Disease', (374, 380))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('small-cell lung carcinoma', 'Phenotype', 'HP:0030357', (96, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (358, 380))	('small-cell lung carcinoma', 'Disease', (96, 121))	('lung cancer', 'Phenotype', 'HP:0100526', (369, 380))	('cancer', 'Phenotype', 'HP:0002664', (374, 380))	('KRAS', 'Gene', '3845', (439, 443))	('mutations', 'Var', (444, 453))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (354, 380))	('pancreatic cancer', 'Disease', 'MESH:D010190', (393, 410))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('KRAS', 'Gene', (439, 443))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', (404, 410))	('cancer', 'Disease', 'MESH:D009369', (374, 380))	('NSCLC', 'Disease', 'MESH:D002289', (382, 387))	('pancreatic cancer', 'Disease', (393, 410))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('cancer', 'Phenotype', 'HP:0002664', (404, 410))	('breast cancer', 'Phenotype', 'HP:0003002', (169, 182))	('small-cell lung carcinoma', 'Disease', 'MESH:D055752', (96, 121))	('NSCLC', 'Disease', (382, 387))	('non-small-cell lung cancer', 'Disease', (354, 380))	('non-small-cell lung cancer', 'Disease', 'MESH:D002289', (354, 380))	('breast cancer', 'Disease', 'MESH:D001943', (169, 182))	('cancer', 'Disease', (176, 182))	('breast cancer', 'Disease', (169, 182))
494844	32076369	LRAcluster was used to classify TCGA data sets containing 11 different types of cancer using 4 different omics data, namely, mutation, CNV, DNA methylation, and gene expression (Table 2).	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('mutation', 'Var', (125, 133))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancer', 'Disease', (80, 86))
494882	32076369	Cluster 3 showed favorable prognosis and enriched for FAB M3 label which corresponds to acute promyelocytic leukemia (APL).	('FAB M3', 'Var', (54, 60))	('acute promyelocytic leukemia', 'Disease', (88, 116))	('leukemia', 'Phenotype', 'HP:0001909', (108, 116))	('APL', 'Disease', 'MESH:D015473', (118, 121))	('APL', 'Disease', (118, 121))	('acute promyelocytic leukemia', 'Phenotype', 'HP:0004836', (88, 116))	('acute promyelocytic leukemia', 'Disease', 'MESH:D015473', (88, 116))	('myelocytic leukemia', 'Phenotype', 'HP:0012324', (97, 116))
494918	32076369	Using the CCLE data (Table 2), a gene-centric integration in each cluster accurately identified known drivers in several cancer types, including MITF in melanoma, ERBB2 in breast cancer, EGFR and MET in LUAD, and MYCN in brain tumors.	('MITF', 'Gene', '4286', (145, 149))	('MYCN', 'Gene', (213, 217))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('melanoma', 'Phenotype', 'HP:0002861', (153, 161))	('melanoma', 'Disease', (153, 161))	('MITF', 'Gene', (145, 149))	('EGFR', 'Gene', '1956', (187, 191))	('tumors', 'Phenotype', 'HP:0002664', (227, 233))	('breast cancer', 'Phenotype', 'HP:0003002', (172, 185))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('brain tumors', 'Disease', 'MESH:D001932', (221, 233))	('brain tumors', 'Phenotype', 'HP:0030692', (221, 233))	('tumor', 'Phenotype', 'HP:0002664', (227, 232))	('breast cancer', 'Disease', 'MESH:D001943', (172, 185))	('MYCN', 'Gene', '4613', (213, 217))	('breast cancer', 'Disease', (172, 185))	('melanoma', 'Disease', 'MESH:D008545', (153, 161))	('ERBB2', 'Gene', (163, 168))	('MET', 'Var', (196, 199))	('brain tumors', 'Disease', (221, 233))	('EGFR', 'Gene', (187, 191))	('cancer', 'Disease', (179, 185))	('cancer', 'Disease', (121, 127))	('ERBB2', 'Gene', '2064', (163, 168))
494923	32076369	The first 2 major factors, factor 1 and factor 2, aligned with the 2 well-known and important clinical markers of CLL, IgHV mutation status and trisomy of chromosome 12, respectively, based on their loading weights in mutation data.	('trisomy', 'Var', (144, 151))	('IgHV', 'Gene', (119, 123))	('first 2 major factors, factor 1 and factor 2', 'Gene', '8458', (4, 48))	('mutation', 'Var', (124, 132))	('CLL', 'Gene', (114, 117))	('IgHV', 'Gene', '28402', (119, 123))
494947	32076369	Furthermore, associating the integrated clusters with the pharmacological profiles of 24 anticancer drug compounds revealed selective sensitivity to MEK inhibitors in a subset of hematopoietic cell lines, a potentially clinically important finding that a subgroup of hematological malignancies may benefit from MEK inhibitors.	('inhibitors', 'Var', (153, 163))	('hematological malignancies', 'Disease', 'MESH:D019337', (267, 293))	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('MEK', 'Gene', (149, 152))	('hematological malignancies', 'Phenotype', 'HP:0004377', (267, 293))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('MEK', 'Gene', '5609', (149, 152))	('MEK', 'Gene', (311, 314))	('benefit', 'PosReg', (298, 305))	('MEK', 'Gene', '5609', (311, 314))	('hematological malignancies', 'Disease', (267, 293))
494949	32076369	Chromosome 8q arm is well associated with disease progression in human cancers.	('human', 'Species', '9606', (65, 70))	('cancers', 'Disease', 'MESH:D009369', (71, 78))	('cancers', 'Phenotype', 'HP:0002664', (71, 78))	('cancers', 'Disease', (71, 78))	('Chromosome 8q arm', 'Var', (0, 17))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('associated', 'Reg', (26, 36))
494953	32076369	Using the TCGA GBM data of 50 patient samples (Table 2), CNAmet revealed a synergistic effect of DNA methylation and copy number alterations on gene expression for several known oncogenes (such as MDM2, EGFR, and PDGFRA) as well as novel candidate oncogenes.	('PDGFRA', 'Gene', (213, 219))	('EGFR', 'Gene', '1956', (203, 207))	('MDM2', 'Gene', '4193', (197, 201))	('patient', 'Species', '9606', (30, 37))	('MDM2', 'Gene', (197, 201))	('gene expression', 'MPA', (144, 159))	('copy number alterations', 'Var', (117, 140))	('EGFR', 'Gene', (203, 207))	('alterations', 'Var', (129, 140))	('methylation', 'Var', (101, 112))	('PDGFRA', 'Gene', '5156', (213, 219))
494954	32076369	It also showed that patients with hypomethylated EGFR had marginally better prognosis than patients with hypomethylated and amplified EGFR.	('EGFR', 'Gene', '1956', (49, 53))	('patients', 'Species', '9606', (91, 99))	('EGFR', 'Gene', (134, 138))	('EGFR', 'Gene', (49, 53))	('patients', 'Species', '9606', (20, 28))	('hypomethylated', 'Var', (34, 48))	('EGFR', 'Gene', '1956', (134, 138))
494979	32076369	For example, 13 patients associated with md-module 166 showed significantly poor survival outcome in which the genes were mostly associated with cell cycle checkpoints and nuclear division.	('cell cycle checkpoints', 'CPA', (145, 167))	('associated', 'Reg', (129, 139))	('patients', 'Species', '9606', (16, 24))	('nuclear division', 'CPA', (172, 188))	('md-module', 'Var', (41, 50))
494983	32076369	Using mutation, mRNA, and protein expression data of a hypermutated (due to MSH2 inactivation) hepatocellular carcinoma patient, they proposed a strategy to identify the driver genes of the disease in this patient.	('inactivation', 'Var', (81, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('patient', 'Species', '9606', (206, 213))	('patient', 'Species', '9606', (120, 127))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (95, 119))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (95, 119))	('MSH2', 'Gene', (76, 80))	('MSH2', 'Gene', '4436', (76, 80))	('hepatocellular carcinoma', 'Disease', (95, 119))
494985	32076369	Their strategy involved 3 criteria that help in identifying the driver genes: Near-saturation of the number of significantly mutated genes; Effect of mutation at mRNA/protein level; Causal implication of the genes in cancer development.	('mutation', 'Var', (150, 158))	('men', 'Species', '9606', (231, 234))	('cancer', 'Disease', (217, 223))	('cancer', 'Disease', 'MESH:D009369', (217, 223))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))
494993	32076369	By the integration of gene expression, miRNA expression, copy number alteration, and DNA methylation data, the model ranked 156 features to be highly associated with tumor recurrence.	('associated', 'Reg', (150, 160))	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('copy', 'Var', (57, 61))	('tumor', 'Disease', (166, 171))
495004	32076369	cBioPortal allows exploration, visualization, and analysis of cancer data containing genomic data, copy number alterations, gene expression, miRNA expression, methylation, and protein abundance data.	('miRNA expression', 'MPA', (141, 157))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('methylation', 'MPA', (159, 170))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('copy number alterations', 'Var', (99, 122))
495033	26094954	Oncogenic activity of BIRC2 and BIRC3 mutants independent of nuclear factor-kappaB-activating potential BIRC2 and BIRC3 are closely related members of the inhibitor of apoptosis (IAP) family of proteins and play pivotal roles in regulation of nuclear factor-kappaB (NF-kappaB) signaling and apoptosis.	('nuclear factor-kappaB', 'Gene', (243, 264))	('BIRC3', 'Gene', (114, 119))	('BIRC2', 'Gene', (22, 27))	('mutants', 'Var', (38, 45))	('BIRC2', 'Gene', '11797', (22, 27))	('BIRC3', 'Gene', (32, 37))	('BIRC3', 'Gene', '11796', (114, 119))	('Oncogenic activity', 'CPA', (0, 18))	('nuclear factor-kappaB', 'Gene', '18033', (61, 82))	('BIRC3', 'Gene', '11796', (32, 37))	('BIRC2', 'Gene', (104, 109))	('nuclear factor-kappaB', 'Gene', '18033', (243, 264))	('nuclear factor-kappaB', 'Gene', (61, 82))	('BIRC2', 'Gene', '11797', (104, 109))
495034	26094954	Copy number loss for and somatic mutation of BIRC2 and BIRC3 have been frequently detected in lymphoid malignancies, with such genetic alterations being thought to contribute to carcinogenesis through activation of the noncanonical NF-kappaB signaling pathway.	('Copy number loss', 'Var', (0, 16))	('activation', 'PosReg', (201, 211))	('BIRC3', 'Gene', (55, 60))	('lymphoid malignancies', 'Phenotype', 'HP:0002665', (94, 115))	('carcinogenesis', 'Disease', 'MESH:D063646', (178, 192))	('contribute', 'Reg', (164, 174))	('carcinogenesis', 'Disease', (178, 192))	('detected', 'Reg', (82, 90))	('noncanonical NF-kappaB signaling pathway', 'Pathway', (219, 259))	('BIRC2', 'Gene', (45, 50))	('lymphoid malignancies', 'Disease', 'MESH:D008223', (94, 115))	('BIRC2', 'Gene', '11797', (45, 50))	('lymphoid malignancies', 'Disease', (94, 115))
495035	26094954	Here we show that BIRC2 and BIRC3 mutations are also present in a wide range of epithelial tumors and that most such nonsense or frameshift mutations confer direct transforming potential.	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('epithelial tumors', 'Disease', (80, 97))	('transforming potential', 'CPA', (164, 186))	('epithelial tumors', 'Disease', 'MESH:D002277', (80, 97))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('BIRC2', 'Gene', (18, 23))	('BIRC3', 'Gene', (28, 33))	('BIRC2', 'Gene', '11797', (18, 23))	('mutations', 'Var', (34, 43))	('nonsense', 'Var', (117, 125))
495036	26094954	This oncogenic function of BIRC2/3 mutants is largely independent of their ability to activate NF-kappaB signaling.	('NF-kappaB', 'MPA', (95, 104))	('mutants', 'Var', (35, 42))	('BIRC2/3', 'Gene', (27, 34))	('activate', 'PosReg', (86, 94))	('BIRC2/3', 'Gene', '11797;11796', (27, 34))
495048	26094954	In contrast, BIRC2/3 are frequently inactivated by copy number loss or by nonsense or frameshift mutations in multiple myeloma.	('frameshift mutations', 'Var', (86, 106))	('BIRC2/3', 'Gene', (13, 20))	('multiple myeloma', 'Phenotype', 'HP:0006775', (110, 126))	('multiple myeloma', 'Disease', 'MESH:D009101', (110, 126))	('nonsense', 'Var', (74, 82))	('multiple myeloma', 'Disease', (110, 126))	('inactivated', 'Reg', (36, 47))	('BIRC2/3', 'Gene', '11797;11796', (13, 20))	('copy number loss', 'Disease', (51, 67))	('copy number loss', 'Disease', 'MESH:D016388', (51, 67))
495050	26094954	In these instances, BIRC2/3 mutations are loss-of-function, and are thought to contribute to carcinogenesis through activation of the noncanonical NF-kappaB signaling pathway.	('carcinogenesis', 'Disease', (93, 107))	('BIRC2/3', 'Gene', (20, 27))	('noncanonical NF-kappaB signaling pathway', 'Pathway', (134, 174))	('BIRC2/3', 'Gene', '11797;11796', (20, 27))	('activation', 'PosReg', (116, 126))	('loss-of-function', 'NegReg', (42, 58))	('carcinogenesis', 'Disease', 'MESH:D063646', (93, 107))	('mutations', 'Var', (28, 37))
495052	26094954	Somatic nonsense or insertion/deletion (indel) mutations that result in loss of the RING finger domain of BIRC3 were found to be present in a wide range of epithelial tumors and were also shown to be oncogenic.	('loss', 'NegReg', (72, 76))	('epithelial tumors', 'Disease', 'MESH:D002277', (156, 173))	('loss of the RING finger', 'Phenotype', 'HP:0009281', (72, 95))	('oncogenic', 'CPA', (200, 209))	('insertion/deletion', 'Var', (20, 38))	('BIRC3', 'Gene', (106, 111))	('RING finger domain', 'MPA', (84, 102))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('tumors', 'Phenotype', 'HP:0002664', (167, 173))	('epithelial tumors', 'Disease', (156, 173))	('nonsense', 'Var', (8, 16))
495053	26094954	Likewise, most oncogenic BIRC2 mutations found in cancer did not result in the activation of NF-kappaB.	('mutations', 'Var', (31, 40))	('NF-kappaB', 'Protein', (93, 102))	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('BIRC2', 'Gene', (25, 30))	('BIRC2', 'Gene', '11797', (25, 30))
495054	26094954	Our observations indicate that transforming mutants of BIRC2/3 exert their effects, at least in part, through an NF-kappaB-independent pathway that likely depends on the ubiquitylation of target molecules including NIK.	('NIK', 'Gene', (215, 218))	('NF-kappaB-independent pathway', 'Pathway', (113, 142))	('BIRC2/3', 'Gene', (55, 62))	('NIK', 'Gene', '53859', (215, 218))	('mutants', 'Var', (44, 51))	('BIRC2/3', 'Gene', '11797;11796', (55, 62))
495063	26094954	Most (n = 44) of the 56 mutations thus identified were found to be already reported in the public databases of cancer genome alterations including COSMIC version 61 (http://cancer.sanger.ac.uk/cancergenome/projects/cosmic), Cancer Cell Encyclopedia (CCE, http://www.broadinstitute.org/ccle/home), International Cancer Genome Consortium (ICGC, https://icgc.org), and The Cancer Genome Atlas (TCGA, http://cancergenome.nih.gov).	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('cancer', 'Disease', 'MESH:D009369', (404, 410))	('Cancer Cell Encyclopedia', 'Disease', (224, 248))	('Cancer', 'Disease', (370, 376))	('cancer', 'Disease', (193, 199))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('Cancer Cell Encyclopedia', 'Disease', 'MESH:C538614', (224, 248))	('cancer', 'Disease', (111, 117))	('mutations', 'Var', (24, 33))	('Cancer', 'Phenotype', 'HP:0002664', (311, 317))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('Cancer', 'Disease', 'MESH:D009369', (370, 376))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (370, 389))	('Cancer', 'Phenotype', 'HP:0002664', (224, 230))	('Cancer', 'Disease', (311, 317))	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('cancer', 'Disease', (173, 179))	('Cancer Genome Atlas', 'Disease', (370, 389))	('cancer', 'Disease', (404, 410))	('Cancer', 'Disease', (224, 230))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('cancer', 'Phenotype', 'HP:0002664', (404, 410))	('Cancer', 'Disease', 'MESH:D009369', (311, 317))	('Cancer', 'Phenotype', 'HP:0002664', (370, 376))	('Cancer', 'Disease', 'MESH:D009369', (224, 230))
495065	26094954	We thus tested if the identified BIRC3(E358*) has a direct contribution to carcinogenesis of NSCLC.	('tested', 'Reg', (8, 14))	('carcinogenesis of NSCLC', 'Disease', 'MESH:D063646', (75, 98))	('BIRC3', 'Gene', (33, 38))	('carcinogenesis of NSCLC', 'Disease', (75, 98))	('E358*', 'SUBSTITUTION', 'None', (39, 44))	('NSCLC', 'Phenotype', 'HP:0030358', (93, 98))	('E358*', 'Var', (39, 44))
495066	26094954	Interestingly, as shown in Figure1(a), BIRC3(E358*) clearly induced focus formation in 3T3 cells in culture, and also tumor formation in a nude mouse tumorigenicity assay, with the corresponding wild-type protein having no effects.	('mouse', 'Species', '10090', (144, 149))	('3T3', 'CellLine', 'CVCL:0594', (87, 90))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('induced', 'Reg', (60, 67))	('BIRC3', 'Gene', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('E358*', 'Var', (45, 50))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('E358*', 'SUBSTITUTION', 'None', (45, 50))	('tumor', 'Disease', (118, 123))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('focus formation', 'CPA', (68, 83))	('tumor', 'Disease', (150, 155))
495067	26094954	The E358* mutant of BIRC3 lacks the RING finger domain that confers ubiquitin ligase (E3) activity.	('lacks', 'NegReg', (26, 31))	('E358*', 'Var', (4, 9))	('E358*', 'SUBSTITUTION', 'None', (4, 9))	('activity', 'MPA', (90, 98))	('BIRC3', 'Gene', (20, 25))	('lacks the RING finger', 'Phenotype', 'HP:0009281', (26, 47))	('RING finger domain', 'MPA', (36, 54))
495068	26094954	Histidine-574 in the RING finger domain is a key residue for ubiquitin ligase activity of BIRC3, with substitution of this amino acid abolishing E3 activity.	('BIRC3', 'Gene', (90, 95))	('abolishing', 'NegReg', (134, 144))	('ubiquitin', 'MPA', (61, 70))	('activity', 'MPA', (148, 156))	('substitution', 'Var', (102, 114))	('Histidine', 'Chemical', 'MESH:D006639', (0, 9))	('activity', 'MPA', (78, 86))
495069	26094954	We thus generated the catalytic-null mutant BIRC3(H574A) and examined its transforming potential.	('BIRC3', 'Gene', (44, 49))	('H574A', 'Var', (50, 55))	('H574A', 'Mutation', 'p.H574A', (50, 55))
495070	26094954	As demonstrated in Figure1(a), oncogenic activity of BIRC3(H574A) was found to be similar to that of BIRC3(E358*) both in vitro and in vivo.	('oncogenic activity', 'CPA', (31, 49))	('E358*', 'SUBSTITUTION', 'None', (107, 112))	('E358*', 'Var', (107, 112))	('H574A', 'Mutation', 'p.H574A', (59, 64))	('BIRC3', 'Var', (53, 58))
495071	26094954	While the immunoblot band corresponding to BIRC3 or BIRC3(H574A) was broad compared to that to BIRC3(E358*) probably owing to ubiquitination of the proteins, a densitometric analysis of Figure S1 suggested that comparable amounts of the three proteins were expressed (1.23 arbitrary units for BIRC3, 1.25 for BIRC3(E358*) and 1.27 for BIRC3(H574A)).	('E358*', 'SUBSTITUTION', 'None', (315, 320))	('E358*', 'Var', (315, 320))	('E358*', 'SUBSTITUTION', 'None', (101, 106))	('E358*', 'Var', (101, 106))	('H574A', 'Mutation', 'p.H574A', (58, 63))	('H574A', 'Mutation', 'p.H574A', (341, 346))
495072	26094954	As shown in Figure1(b), abundance of p52 and RELB was profoundly increased in the nucleus of 3T3 cells expressing BIRC3(E358*) or BIRC3(H574A), which suggests activation of the noncanonical NF-kappaB pathway.	('E358*', 'Var', (120, 125))	('increased', 'PosReg', (65, 74))	('E358*', 'SUBSTITUTION', 'None', (120, 125))	('3T3', 'CellLine', 'CVCL:0594', (93, 96))	('RELB', 'Gene', '19698', (45, 49))	('noncanonical NF-kappaB pathway', 'Pathway', (177, 207))	('H574A', 'Mutation', 'p.H574A', (136, 141))	('p52', 'Gene', '18034', (37, 40))	('RELB', 'Gene', (45, 49))	('p52', 'Gene', (37, 40))	('BIRC3(H574A', 'Var', (130, 141))	('abundance', 'MPA', (24, 33))
495073	26094954	On the other hand, activation of the canonical NF-kappaB pathway was modest, demonstrated only by the BIRC3(H574A)-mediated increase in nuclear p50.	('canonical NF-kappaB pathway', 'Pathway', (37, 64))	('increase', 'PosReg', (124, 132))	('BIRC3', 'Var', (102, 107))	('p50', 'Gene', '18033', (144, 147))	('p50', 'Gene', (144, 147))	('H574A', 'Mutation', 'p.H574A', (108, 113))
495074	26094954	Figure1(c) demonstrates that BIRC3(E358*) was found to slightly upregulate the trans-activation activity of NF-kappaB in transfected HEK293T cells compared to the wild-type protein and that BIRC3(H574A) markedly induced an increase in NF-kappaB activity.	('increase', 'PosReg', (223, 231))	('NF-kappaB', 'Protein', (108, 117))	('HEK293T', 'CellLine', 'CVCL:0063', (133, 140))	('E358*', 'SUBSTITUTION', 'None', (35, 40))	('upregulate', 'PosReg', (64, 74))	('E358*', 'Var', (35, 40))	('NF-kappaB', 'Enzyme', (235, 244))	('activity', 'MPA', (245, 253))	('trans-activation activity', 'MPA', (79, 104))	('H574A', 'Mutation', 'p.H574A', (196, 201))	('BIRC3', 'Var', (190, 195))
495075	26094954	To investigate the relation between the ability of BIRC3 to promote oncogenesis and its NF-kappaB-activating potential, we generated a series of truncation mutants of BIRC3(H574A) by independently deleting the BIR1, BIR2, BIR3, ubiquitin-associated (UBA) domains or the caspase recruitment domain (CARD).	('H574A', 'Mutation', 'p.H574A', (173, 178))	('deleting', 'NegReg', (197, 205))	('BIR2', 'Protein', (216, 220))	('BIR3', 'Protein', (222, 226))	('mutants', 'Var', (156, 163))	('caspase recruitment domain', 'MPA', (270, 296))	('ubiquitin-associated', 'MPA', (228, 248))	('BIRC3', 'Gene', (167, 172))	('BIR1', 'Gene', (210, 214))	('BIR1', 'Gene', '16522', (210, 214))
495076	26094954	The BIR1 and UBA domains are required for homodimerization of and ubiquitin binding by BIRC3, respectively, and deletion of these domains attenuated the upregulation of NF-kappaB activity (Fig.1d and Suppl.	('BIRC3', 'Gene', (87, 92))	('activity', 'MPA', (179, 187))	('upregulation', 'PosReg', (153, 165))	('NF-kappaB', 'Protein', (169, 178))	('deletion', 'Var', (112, 120))	('attenuated', 'NegReg', (138, 148))	('homodimerization', 'MPA', (42, 58))	('binding', 'Interaction', (76, 83))	('ubiquitin', 'MPA', (66, 75))	('BIR1', 'Gene', (4, 8))	('BIR1', 'Gene', '16522', (4, 8))
495078	26094954	Deletion of the UBA domain, for instance, resulted in an increase in the transforming activity of BIRC3(H574A), suggesting that such activity is, at least in part, independent of NF-kappaB signaling.	('BIRC3', 'Protein', (98, 103))	('transforming activity', 'MPA', (73, 94))	('UBA', 'Gene', (16, 19))	('increase', 'PosReg', (57, 65))	('H574A', 'Mutation', 'p.H574A', (104, 109))	('Deletion', 'Var', (0, 8))
495080	26094954	In contrast, all missense mutations failed to manifest transforming activity, with the exception that BIRC3(C319Y) showed a low transformation potential in vitro but did not generate tumors in vivo.	('transformation potential', 'MPA', (128, 152))	('C319Y', 'Mutation', 'p.C319Y', (108, 113))	('tumors', 'Disease', 'MESH:D009369', (183, 189))	('C319Y', 'Var', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('BIRC3', 'Gene', (102, 107))	('tumors', 'Phenotype', 'HP:0002664', (183, 189))	('tumors', 'Disease', (183, 189))
495081	26094954	S2 and S5) revealed that some of the transformation-inducing mutants, including E368* and V395 fs*6, did not activate NF-kappaB.	('NF-kappaB', 'Protein', (118, 127))	('E368*', 'SUBSTITUTION', 'None', (80, 85))	('V395 fs*6', 'Var', (90, 99))	('activate', 'PosReg', (109, 117))	('E368*', 'Var', (80, 85))	('V395 fs', 'Mutation', 'p.V395fsX', (90, 97))
495082	26094954	We hypothesized that substrates for ubiquitylation by BIRC3 are likely mediators of BIRC3-driven transformation, with NIK in particular being a promising mediator given that it is directly ubiquitylated by BIRC3 and that cells that harbor BIRC3 mutations are dependent on NIK for survival.	('mutations', 'Var', (245, 254))	('NIK', 'Gene', '53859', (272, 275))	('BIRC3', 'Gene', (239, 244))	('NIK', 'Gene', '53859', (118, 121))	('NIK', 'Gene', (272, 275))	('NIK', 'Gene', (118, 121))
495085	26094954	Mouse 3T3 cells stably expressing the control or Nik shRNA were infected with retroviruses encoding wild-type or mutant forms of BIRC3 and then examined for malignant potential.	('Nik', 'Gene', (49, 52))	('BIRC3', 'Gene', (129, 134))	('Mouse', 'Species', '10090', (0, 5))	('mutant', 'Var', (113, 119))	('3T3', 'CellLine', 'CVCL:0594', (6, 9))	('Nik', 'Gene', '53859', (49, 52))
495089	26094954	The transforming activity of BIRC3(E358*) or BIRC3(H574A) was substantially, but not completely, attenuated in cells expressing Nik shRNA in both in vitro and in vivo (Fig.3b,c).	('Nik', 'Gene', '53859', (128, 131))	('transforming activity', 'MPA', (4, 25))	('Nik', 'Gene', (128, 131))	('E358*', 'SUBSTITUTION', 'None', (35, 40))	('E358*', 'Var', (35, 40))	('attenuated', 'NegReg', (97, 107))	('H574A', 'Mutation', 'p.H574A', (51, 56))
495090	26094954	Further, Nik knockdown suppressed BIRC3 mutant-mediated increase of p52 in the nucleus (Fig.1b).	('suppressed', 'NegReg', (23, 33))	('increase', 'PosReg', (56, 64))	('BIRC3 mutant-mediated', 'Gene', (34, 55))	('Nik', 'Gene', '53859', (9, 12))	('p52', 'Gene', '18034', (68, 71))	('Nik', 'Gene', (9, 12))	('knockdown', 'Var', (13, 22))	('p52', 'Gene', (68, 71))
495091	26094954	The residual transforming ability of the two BIRC3 mutants did not appear to be due to residual Nik protein, given that forced expression of an shRNA-sensitive form of mouse Nik in the cells expressing the Nik shRNA did not induce malignant transformation in vitro or in vivo.	('Nik', 'Gene', (174, 177))	('Nik', 'Gene', (206, 209))	('mutants', 'Var', (51, 58))	('mouse', 'Species', '10090', (168, 173))	('Nik', 'Gene', (96, 99))	('malignant transformation', 'CPA', (231, 255))	('Nik', 'Gene', '53859', (174, 177))	('Nik', 'Gene', '53859', (206, 209))	('Nik', 'Gene', '53859', (96, 99))	('BIRC3', 'Gene', (45, 50))
495093	26094954	Further, to confirm the presence of Nik-dependent but NF-kappaB-independent mechanism in the BIRC3-mediated transformation pathway, we examined if Nik knockdown attenuates focus formation of 3T3 by BIRC3(DeltaUBA/H574A) that does not have an ability to activate NF-kappaB (Fig.1d).	('Nik', 'Gene', (147, 150))	('attenuates', 'NegReg', (161, 171))	('3T3', 'CellLine', 'CVCL:0594', (191, 194))	('Nik', 'Gene', '53859', (36, 39))	('H574A', 'Mutation', 'p.H574A', (213, 218))	('focus formation of 3T3', 'MPA', (172, 194))	('Nik', 'Gene', (36, 39))	('Nik', 'Gene', '53859', (147, 150))	('knockdown', 'Var', (151, 160))
495094	26094954	As shown in Figure3(d), BIRC3(DeltaUBA/H574A)-driven transformation of 3T3 cells was significantly weakened by knockdown of the Nik messages.	('Nik', 'Gene', '53859', (128, 131))	('knockdown', 'Var', (111, 120))	('H574A', 'Mutation', 'p.H574A', (39, 44))	('Nik', 'Gene', (128, 131))	('3T3', 'CellLine', 'CVCL:0594', (71, 74))	('weakened', 'NegReg', (99, 107))
495096	26094954	With the exception of a frameshift mutation at Lys-19, all of the mutations rendered BIRC2 oncogenic in vitro (Fig.4b and Suppl.	('mutations', 'Var', (66, 75))	('BIRC2', 'Gene', (85, 90))	('BIRC2', 'Gene', '11797', (85, 90))	('oncogenic', 'CPA', (91, 100))	('Lys', 'Chemical', 'MESH:D008239', (47, 50))	('frameshift', 'Var', (24, 34))	('rendered', 'Reg', (76, 84))
495098	26094954	We also examined the various BIRC2 mutants for the ability to induce NF-kappaB activation.	('NF-kappaB', 'Protein', (69, 78))	('BIRC2', 'Gene', (29, 34))	('BIRC2', 'Gene', '11797', (29, 34))	('mutants', 'Var', (35, 42))	('activation', 'MPA', (79, 89))
495099	26094954	Whereas a frameshift mutation at Glu-440 and the artificial mutation at His-588 increased the ability of BIRC2 to activate NF-kappaB, such effect was marginal for some mutants and others even suppressed NF-kappaB (Fig.4c), indicative of an NF-kappaB-independent transformation mechanism for BIRC2 as for BIRC3.	('suppressed', 'NegReg', (192, 202))	('BIRC2', 'Gene', (291, 296))	('NF-kappaB', 'MPA', (203, 212))	('BIRC2', 'Gene', (105, 110))	('increased', 'PosReg', (80, 89))	('frameshift mutation at Glu-440', 'Var', (10, 40))	('BIRC2', 'Gene', '11797', (291, 296))	('BIRC2', 'Gene', '11797', (105, 110))	('activate', 'PosReg', (114, 122))	('His', 'Chemical', 'MESH:D006639', (72, 75))	('Glu', 'Chemical', 'MESH:D018698', (33, 36))	('NF-kappaB', 'Protein', (123, 132))
495103	26094954	We have here revealed a direct transforming potential of BIRC2 and BIRC3 mutants that is, at least in part, unrelated to the ability of these mutants to regulate NF-kappaB signaling.	('NF-kappaB signaling', 'MPA', (162, 181))	('BIRC2', 'Gene', (57, 62))	('BIRC3', 'Gene', (67, 72))	('mutants', 'Var', (73, 80))	('BIRC2', 'Gene', '11797', (57, 62))	('transforming', 'MPA', (31, 43))
495104	26094954	Given that knockdown of NIK mRNA suppresses the growth of mantle cell lymphoma cell lines in which the noncanonical NF-kappaB pathway is activated, and that NIK depletion markedly attenuated BIRC2/3 mutant-mediated 3T3 cell transformation, NIK is likely a major downstream effector of BIRC2/3 mutants in the induction of oncogenesis.	('NIK', 'Gene', '53859', (240, 243))	('NIK', 'Gene', (24, 27))	('noncanonical NF-kappaB pathway', 'Pathway', (103, 133))	('growth', 'CPA', (48, 54))	('suppresses', 'NegReg', (33, 43))	('NIK', 'Gene', '53859', (24, 27))	('mantle cell lymphoma', 'Disease', 'MESH:D020522', (58, 78))	('activated', 'PosReg', (137, 146))	('mantle cell lymphoma', 'Disease', (58, 78))	('3T3', 'CellLine', 'CVCL:0594', (215, 218))	('NIK', 'Gene', (157, 160))	('BIRC2/3', 'Gene', (191, 198))	('BIRC2/3', 'Gene', '11797;11796', (191, 198))	('NIK', 'Gene', '53859', (157, 160))	('attenuated', 'NegReg', (180, 190))	('cell lymphoma', 'Phenotype', 'HP:0012191', (65, 78))	('BIRC2/3', 'Gene', (285, 292))	('BIRC2/3', 'Gene', '11797;11796', (285, 292))	('lymphoma', 'Phenotype', 'HP:0002665', (70, 78))	('mutants', 'Var', (293, 300))	('NIK', 'Gene', (240, 243))
495106	26094954	NIK-mediated activation of the noncanonical NF-kappaB pathway (phosphorylation of IKKalpha and subsequent limited proteolysis of NFKB2) is not essential for the transformation mechanism, given that some BIRC2/3 mutants with full transforming potential failed to activate NF-kappaB.	('NFKB2', 'Gene', (129, 134))	('BIRC2/3', 'Gene', (203, 210))	('IKKalpha', 'Gene', (82, 90))	('mutants', 'Var', (211, 218))	('NFKB2', 'Gene', '18034', (129, 134))	('IKKalpha', 'Gene', '12675', (82, 90))	('BIRC2/3', 'Gene', '11797;11796', (203, 210))	('NIK', 'Gene', (0, 3))	('NIK', 'Gene', '53859', (0, 3))
495110	26094954	Mice expressing an IKKalpha mutant that cannot be phosphorylated by NIK were thus defective in NFKB2 processing but were found to have normal numbers of eosinophils.	('mutant', 'Var', (28, 34))	('processing', 'MPA', (101, 111))	('defective', 'NegReg', (82, 91))	('NFKB2', 'Gene', (95, 100))	('NIK', 'Gene', (68, 71))	('IKKalpha', 'Gene', (19, 27))	('IKKalpha', 'Gene', '12675', (19, 27))	('NFKB2', 'Gene', '18034', (95, 100))	('Mice', 'Species', '10090', (0, 4))	('NIK', 'Gene', '53859', (68, 71))
495114	26094954	Whereas little information is currently available on such targets, they may associate with the BIR1 or BIR3 domain, given that deletion of either of these domains attenuated the transforming ability of BIRC3(H574A).	('H574A', 'Mutation', 'p.H574A', (208, 213))	('transforming ability', 'CPA', (178, 198))	('attenuated', 'NegReg', (163, 173))	('deletion', 'Var', (127, 135))	('BIR1', 'Gene', (95, 99))	('BIR1', 'Gene', '16522', (95, 99))
495115	26094954	Nonsense or frameshift mutations of BIRC2/3 are frequently found in B cell malignancies, but they have also been detected in a wide range of epithelial tumors (Table S3).	('BIRC2/3', 'Gene', '11797;11796', (36, 43))	('epithelial tumors', 'Disease', 'MESH:D002277', (141, 158))	('Nonsense', 'Var', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('BIRC2/3', 'Gene', (36, 43))	('frameshift mutations', 'Var', (12, 32))	('B cell malignancies', 'Disease', (68, 87))	('found', 'Reg', (59, 64))	('detected', 'Reg', (113, 121))	('epithelial tumors', 'Disease', (141, 158))	('tumors', 'Phenotype', 'HP:0002664', (152, 158))
495116	26094954	Given that most such BIRC2/3 mutants lack the RING finger domain and therefore possess direct transforming ability, identification of the molecules that mediate BIRC2/3-driven carcinogenesis may provide a basis for the development of new targeted drugs for the treatment of such cancers.	('transforming', 'CPA', (94, 106))	('BIRC2/3', 'Gene', (21, 28))	('BIRC2/3', 'Gene', (161, 168))	('BIRC2/3', 'Gene', '11797;11796', (21, 28))	('BIRC2/3', 'Gene', '11797;11796', (161, 168))	('cancer', 'Phenotype', 'HP:0002664', (279, 285))	('mutants', 'Var', (29, 36))	('carcinogenesis', 'Disease', 'MESH:D063646', (176, 190))	('cancers', 'Phenotype', 'HP:0002664', (279, 286))	('lack', 'NegReg', (37, 41))	('cancers', 'Disease', (279, 286))	('carcinogenesis', 'Disease', (176, 190))	('cancers', 'Disease', 'MESH:D009369', (279, 286))	('RING finger domain', 'MPA', (46, 64))
495149	33614766	FMEC cells were grown in a 50/50 v/v mixture of DMEM and F12K (Ham's F-12K Nutrient Mixture, Kaighn's Modification with L-glutamine) with 10% FBS, 1% penicillin, and streptomycin, 1% non-essential amino acids (NEAA), and 10 ng/mL endothelial mitogen factor (MP Biomedicals, Fisher Scientific, Rockford, IL).	('NEAA', 'Chemical', '-', (210, 214))	('L-glutamine', 'Chemical', 'MESH:D005973', (120, 131))	('DMEM', 'Chemical', '-', (48, 52))	('streptomycin', 'Chemical', 'MESH:D013307', (166, 178))	('penicillin', 'Chemical', 'MESH:D010406', (150, 160))	('cat', 'Gene', '847', (108, 111))	('cat', 'Gene', (108, 111))	('F12K', 'SUBSTITUTION', 'None', (57, 61))	('F12K', 'Var', (57, 61))	('-essential amino acids', 'Chemical', 'MESH:D000601', (186, 208))
495320	32512671	One unit of increase in the stage of cancer (1-2/3a/3b/3c/4a/4b) increased the risk of survival decrement by 1.367-fold (Table 5, Figure 2, Figure 3).	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('cancer', 'Disease', (37, 43))	('1-2/3a/3b/3c/4a/4b', 'Var', (45, 63))	('increase', 'PosReg', (12, 20))	('men', 'Species', '9606', (101, 104))	('survival', 'CPA', (87, 95))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))
495329	32512671	With one unit of increase in the stage of cancer (1-2/3a/3b/3c/4a/4b), the risk increased significantly by 1.367-fold.	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('cancer', 'Disease', (42, 48))	('1-2/3a/3b/3c/4a/4b', 'Var', (50, 68))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))
495369	28830450	Levels of miR-218, IL-6R, JAK3 and phosphorylated STAT3 were compared in ALDH1A1 positive and ALDH1A1 negative cells.	('miR-218', 'Gene', '387214', (10, 17))	('positive', 'Var', (81, 89))	('ALDH1A1', 'Gene', (94, 101))	('STAT3', 'Gene', '6774', (50, 55))	('ALDH1A1', 'Gene', (73, 80))	('JAK3', 'Gene', (26, 30))	('IL-6R', 'Gene', '3570', (19, 24))	('STAT3', 'Gene', (50, 55))	('JAK3', 'Gene', '3718', (26, 30))	('ALDH1A1', 'Gene', '216', (94, 101))	('ALDH1A1', 'Gene', '216', (73, 80))	('IL-6R', 'Gene', (19, 24))	('miR-218', 'Gene', (10, 17))
495384	28830450	MicroRNAs (miRNAs) are a class of single-stranded, non-coding RNAs of 19-25 nucleotides that serve as negative regulators of gene expression by interacting with 3'untranslated regions (3'UTRs) of the target genes.Aberrant expression of miRNAs has been reported in different diseases including lung cancer, where they may act as oncogenes or tumor suppressors.	('miR', 'Gene', '220972', (236, 239))	('miR', 'Gene', (236, 239))	('tumor', 'Phenotype', 'HP:0002664', (341, 346))	('lung cancer', 'Disease', 'MESH:D008175', (293, 304))	('tumor', 'Disease', (341, 346))	('miR', 'Gene', '220972', (11, 14))	('miR', 'Gene', (11, 14))	('genes.Aberrant', 'Var', (207, 221))	('lung cancer', 'Disease', (293, 304))	('lung cancer', 'Phenotype', 'HP:0100526', (293, 304))	('reported', 'Reg', (252, 260))	('cancer', 'Phenotype', 'HP:0002664', (298, 304))	('expression', 'MPA', (222, 232))	('tumor', 'Disease', 'MESH:D009369', (341, 346))
495385	28830450	MiR-17-92, miR-21, and miR-221/miR-222 were reported to promote lung tumorigenesis, while let-7, miR-126, miR-16, miR-340, miR-145, andmiR-373 act as tumor suppressors.	('miR', 'Gene', (135, 138))	('miR', 'Gene', (23, 26))	('miR', 'Gene', '220972', (123, 126))	('miR-16', 'Gene', '51573', (106, 112))	('miR-340', 'Gene', (114, 121))	('miR', 'Gene', '220972', (11, 14))	('miR-340', 'Gene', '442908', (114, 121))	('miR', 'Gene', '220972', (114, 117))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('lung', 'Disease', (64, 68))	('miR-21', 'Gene', '406991', (11, 17))	('let-7', 'Var', (90, 95))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('miR', 'Gene', (123, 126))	('miR', 'Gene', '220972', (106, 109))	('miR', 'Gene', (11, 14))	('miR-221', 'Gene', (23, 30))	('miR-145', 'Gene', '406937', (123, 130))	('miR', 'Gene', (114, 117))	('MiR-17-92', 'Gene', (0, 9))	('promote', 'PosReg', (56, 63))	('miR-222', 'Gene', (31, 38))	('miR-126', 'Gene', (97, 104))	('MiR-17-92', 'Gene', '407975', (0, 9))	('miR', 'Gene', '220972', (97, 100))	('miR-221', 'Gene', '407006', (23, 30))	('miR', 'Gene', (106, 109))	('miR-21', 'Gene', (11, 17))	('miR', 'Gene', '220972', (31, 34))	('miR-145', 'Gene', (123, 130))	('miR', 'Gene', (97, 100))	('tumor', 'Disease', (150, 155))	('miR', 'Gene', '220972', (135, 138))	('miR', 'Gene', '220972', (23, 26))	('miR-16', 'Gene', (106, 112))	('tumor', 'Disease', (69, 74))	('miR-222', 'Gene', '407007', (31, 38))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('miR', 'Gene', (31, 34))	('miR-126', 'Gene', '406913', (97, 104))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
495405	28830450	Double-stranded oligonucleotides corresponding to the wild-type (WT 3'-UTR) or mutant (Mut 3'-UTR) miR-218 binding site in the 3'-UTR of IL-6R and JAK3 genes were synthesized and inserted into the PmeI and XbaI sites of the pmirGLO Vector (Promega, Madison, WI), respectively.	('IL-6R', 'Gene', (137, 142))	('miR-218', 'Gene', (99, 106))	('mutant', 'Var', (79, 85))	('JAK3', 'Gene', (147, 151))	('miR-218', 'Gene', '387214', (99, 106))	('IL-6R', 'Gene', '3570', (137, 142))	('JAK3', 'Gene', '3718', (147, 151))
495406	28830450	The sequences of the wild-type and mutated IL-6R gene 3'-UTR used were 5'-AAACTAGCGGCCGCTAGT CATGGTTCTGTCAAGCACCGCGT-3' and 5'-AAACTAGCGGCCGCTAGT CGCATCGTAGATGTCCACCGCT-3', respectively (miRNA targeted and mutated bases are underlined).The sequences of the wild-type and mutated JAK3 gene 3'-UTR were 5'-AAACTAGCGGCCGCTAGTATGGTTCCGTCAAGCACCATGG-3' and 5'-AAACTAGCGGCCGCTAGTACATCGTAGTCAAGCACCATGG-3', respectively (miRNA targeted and mutated bases are underlined).	('JAK3', 'Gene', '3718', (279, 283))	('miR', 'Gene', (414, 417))	('IL-6R', 'Gene', '3570', (43, 48))	('miR', 'Gene', (187, 190))	('miR', 'Gene', '220972', (187, 190))	('miR', 'Gene', '220972', (414, 417))	('JAK3', 'Gene', (279, 283))	('IL-6R', 'Gene', (43, 48))	('mutated', 'Var', (271, 278))
495407	28830450	The wild-type or mutant luciferase reporter constructs, together with the pRL-TK Vector (Promega, Madison, WI), were co-transfected into cells with miR-218 mimic or mimic-control by lipofectamine 2000 (Life Technologies, Grand Island, NY).	('miR-218', 'Gene', (148, 155))	('lipofectamine', 'Chemical', 'MESH:C086724', (182, 195))	('miR-218', 'Gene', '387214', (148, 155))	('luciferase', 'Enzyme', (24, 34))	('mutant', 'Var', (17, 23))
495409	28830450	Twenty-four hours after miR-218 mimic transfection, total RNA was isolated from H1975 and A549 cells using the miRNeasy Mini Kit (Qiagen, Valencia, CA) according to the manufacturer's protocol.	('miR-218', 'Gene', '387214', (24, 31))	('transfection', 'Var', (38, 50))	('A549', 'CellLine', 'CVCL:0023', (90, 94))	('H1975', 'CellLine', 'CVCL:1511', (80, 85))	('miR', 'Gene', '220972', (24, 27))	('miR', 'Gene', (24, 27))	('miR-218', 'Gene', (24, 31))	('miR', 'Gene', '220972', (111, 114))	('miR', 'Gene', (111, 114))
495410	28830450	Expression of the IL-6R or JAK3 gene was detected using RT2qPCR Primer Assays and RT2 SYBR Green Mastermixes (Qiagen, Valencia, CA) in an ABI 7900HT Sequence Detection System (Applied Biosystems, Foster City, CA).	('IL-6R', 'Gene', '3570', (18, 23))	('SYBR Green', 'Chemical', '-', (86, 96))	('IL-6R', 'Gene', (18, 23))	('JAK3', 'Gene', (27, 31))	('RT2', 'Var', (82, 85))	('JAK3', 'Gene', '3718', (27, 31))
495443	28830450	The results of cell proliferation showed that re-expression of miR-218 reduced cell proliferation (Fig.	('re-expression', 'Var', (46, 59))	('cell proliferation', 'CPA', (79, 97))	('miR-218', 'Gene', '387214', (63, 70))	('reduced', 'NegReg', (71, 78))	('miR-218', 'Gene', (63, 70))
495450	28830450	To determine whether the IL-6R and JAK3 mRNA expression is regulated by miR-218 through direct binding to their 3'-UTR regions, we used a dual-luciferase reporter system containing either the wild-type or the mutated 3'-UTR of IL-6R and JAK3.	('IL-6R', 'Gene', '3570', (227, 232))	('IL-6R', 'Gene', '3570', (25, 30))	('JAK3', 'Gene', (35, 39))	('mRNA expression', 'MPA', (40, 55))	('JAK3', 'Gene', '3718', (237, 241))	('miR-218', 'Gene', '387214', (72, 79))	('JAK3', 'Gene', '3718', (35, 39))	('IL-6R', 'Gene', (227, 232))	('IL-6R', 'Gene', (25, 30))	('regulated', 'Reg', (59, 68))	('mutated', 'Var', (209, 216))	('miR-218', 'Gene', (72, 79))	('binding', 'Interaction', (95, 102))	('JAK3', 'Gene', (237, 241))
495452	28830450	This suppressive effect was abolished by the mutations in the miR-218 targeted 3' UTR regions (Fig.	('miR-218', 'Gene', '387214', (62, 69))	('mutations', 'Var', (45, 54))	('miR-218', 'Gene', (62, 69))
495464	28830450	We confirmed the previous results (Additional file 1: Figure S1A) and found downregulation of EGFR decreased the levels of pSTAT3 more significantly in EGFR mutated cells (H1975) than in EGFR wild type cells (A549) (Additional file 1: Figure S1B).	('decreased', 'NegReg', (99, 108))	('levels of pSTAT3', 'MPA', (113, 129))	('EGFR', 'Gene', '1956', (94, 98))	('H1975', 'CellLine', 'CVCL:1511', (172, 177))	('EGFR', 'Gene', '1956', (187, 191))	('EGFR', 'Gene', '1956', (152, 156))	('EGFR', 'Gene', (94, 98))	('EGFR', 'Gene', (187, 191))	('EGFR', 'Gene', (152, 156))	('pSTAT3', 'Chemical', '-', (123, 129))	('mutated', 'Var', (157, 164))	('downregulation', 'NegReg', (76, 90))	('A549', 'CellLine', 'CVCL:0023', (209, 213))
495465	28830450	Similarly, downregulating of EGFR reduced cell viability more significantly in EGFR mutated cells (H1975) than in EGFR wild type cells (A549) (Additional file 1: Figure S1C).	('reduced', 'NegReg', (34, 41))	('cell viability', 'CPA', (42, 56))	('EGFR', 'Gene', '1956', (79, 83))	('EGFR', 'Gene', (79, 83))	('downregulating', 'NegReg', (11, 25))	('EGFR', 'Gene', '1956', (114, 118))	('mutated', 'Var', (84, 91))	('EGFR', 'Gene', '1956', (29, 33))	('EGFR', 'Gene', (29, 33))	('EGFR', 'Gene', (114, 118))	('A549', 'CellLine', 'CVCL:0023', (136, 140))	('H1975', 'CellLine', 'CVCL:1511', (99, 104))
495466	28830450	Overall, our data indicated that miR-218 negatively regulated STAT3 signaling through IL-6R and JAK3 in EGFR wild type cells and through IL-6R, JAK3, and EGFR in EGFR mutated cells.	('EGFR', 'Gene', (162, 166))	('JAK3', 'Gene', (144, 148))	('EGFR', 'Gene', (154, 158))	('STAT3', 'Gene', (62, 67))	('JAK3', 'Gene', '3718', (96, 100))	('EGFR', 'Gene', (104, 108))	('IL-6R', 'Gene', (137, 142))	('IL-6R', 'Gene', '3570', (137, 142))	('STAT3', 'Gene', '6774', (62, 67))	('JAK3', 'Gene', '3718', (144, 148))	('negatively', 'NegReg', (41, 51))	('EGFR', 'Gene', '1956', (162, 166))	('IL-6R', 'Gene', (86, 91))	('EGFR', 'Gene', '1956', (154, 158))	('EGFR', 'Gene', '1956', (104, 108))	('IL-6R', 'Gene', '3570', (86, 91))	('miR-218', 'Gene', (33, 40))	('mutated', 'Var', (167, 174))	('JAK3', 'Gene', (96, 100))	('miR-218', 'Gene', '387214', (33, 40))	('regulated', 'Reg', (52, 61))
495488	28830450	However, cancer cells display dysregulation of miRNA expression through different mechanisms, including abnormal transcription, epigenetic changes, amplification or deletion of miRNA host genes.	('epigenetic changes', 'CPA', (128, 146))	('cancer', 'Disease', (9, 15))	('miR', 'Gene', '220972', (47, 50))	('miR', 'Gene', (47, 50))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('dysregulation', 'MPA', (30, 43))	('deletion', 'Var', (165, 173))	('abnormal', 'Reg', (104, 112))	('miR', 'Gene', '220972', (177, 180))	('miR', 'Gene', (177, 180))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('amplification', 'Var', (148, 161))
495496	28830450	Studies involved in evaluating the role of miRNAs showed dysregulation of miRNA expression in NSCLC and postulated its important role toward malignancy.	('miR', 'Gene', (74, 77))	('NSCLC', 'Phenotype', 'HP:0030358', (94, 99))	('dysregulation', 'Var', (57, 70))	('miR', 'Gene', '220972', (43, 46))	('miR', 'Gene', (43, 46))	('miR', 'Gene', '220972', (74, 77))	('malignancy', 'Disease', 'MESH:D009369', (141, 151))	('malignancy', 'Disease', (141, 151))	('NSCLC', 'Disease', (94, 99))	('NSCLC', 'Disease', 'MESH:D002289', (94, 99))	('SCLC', 'Phenotype', 'HP:0030357', (95, 99))
495498	28830450	It is seen that the expression of miR-17, miR-18a, miR-19, miR-20a, miR-21, miR-31, miR-92a, and miR-224 is upregulated in lung cancer cells and inhibition of their expression can reduce cell growth and invasion capacities.	('miR', 'Gene', '220972', (84, 87))	('miR', 'Gene', '220972', (68, 71))	('miR-20a', 'Gene', (59, 66))	('lung cancer', 'Phenotype', 'HP:0100526', (123, 134))	('miR', 'Gene', '220972', (59, 62))	('miR', 'Gene', '220972', (51, 54))	('miR-20a', 'Gene', '406982', (59, 66))	('miR', 'Gene', '220972', (76, 79))	('reduce', 'NegReg', (180, 186))	('miR-21', 'Gene', '406991', (68, 74))	('miR-17', 'Gene', (34, 40))	('upregulated', 'PosReg', (108, 119))	('inhibition', 'Var', (145, 155))	('miR', 'Gene', (84, 87))	('miR', 'Gene', (68, 71))	('miR', 'Gene', '220972', (34, 37))	('miR', 'Gene', (59, 62))	('miR', 'Gene', (51, 54))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('miR', 'Gene', '220972', (42, 45))	('miR', 'Gene', (76, 79))	('miR', 'Gene', '220972', (97, 100))	('miR-21', 'Gene', (68, 74))	('miR-18a', 'Gene', (42, 49))	('lung cancer', 'Disease', (123, 134))	('invasion capacities', 'CPA', (203, 222))	('miR-31', 'Gene', (76, 82))	('miR', 'Gene', (34, 37))	('miR', 'Gene', (42, 45))	('miR', 'Gene', (97, 100))	('miR-224', 'Gene', '407009', (97, 104))	('miR-17', 'Gene', '406952', (34, 40))	('miR-224', 'Gene', (97, 104))	('cell growth', 'CPA', (187, 198))	('miR-18a', 'Gene', '406953', (42, 49))	('lung cancer', 'Disease', 'MESH:D008175', (123, 134))	('miR-31', 'Gene', '407035', (76, 82))
495506	28830450	Abnormalities in the IL-6/JAK/STAT3 pathway are also due to expression of a variety of oncogenes, such as Myc and VEGF, reportedly increased in lung cancer and other cancer types.	('expression', 'MPA', (60, 70))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('Abnormalities', 'Var', (0, 13))	('IL-6', 'Gene', (21, 25))	('lung cancer', 'Disease', 'MESH:D008175', (144, 155))	('increased', 'PosReg', (131, 140))	('lung cancer', 'Phenotype', 'HP:0100526', (144, 155))	('Myc', 'Gene', '4609', (106, 109))	('STAT3', 'Gene', (30, 35))	('VEGF', 'Gene', '7422', (114, 118))	('cancer', 'Disease', (149, 155))	('cancer', 'Disease', (166, 172))	('VEGF', 'Gene', (114, 118))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('STAT3', 'Gene', '6774', (30, 35))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('lung cancer', 'Disease', (144, 155))	('Myc', 'Gene', (106, 109))	('IL-6', 'Gene', '3569', (21, 25))	('cancer', 'Disease', 'MESH:D009369', (149, 155))
495511	28830450	In addition, in EGFR mutated lung cancer cells, miR-218 can also negatively regulate pSTAT3 signaling through targeting EGFR.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('miR-218', 'Gene', (48, 55))	('negatively regulate', 'NegReg', (65, 84))	('lung cancer', 'Disease', 'MESH:D008175', (29, 40))	('pSTAT3 signaling', 'MPA', (85, 101))	('miR-218', 'Gene', '387214', (48, 55))	('pSTAT3', 'Chemical', '-', (85, 91))	('EGFR', 'Gene', '1956', (16, 20))	('EGFR', 'Gene', '1956', (120, 124))	('targeting', 'Reg', (110, 119))	('mutated', 'Var', (21, 28))	('lung cancer', 'Disease', (29, 40))	('EGFR', 'Gene', (16, 20))	('lung cancer', 'Phenotype', 'HP:0100526', (29, 40))	('EGFR', 'Gene', (120, 124))
495533	26992219	DEPTOR promotes survival of cervical squamous cell carcinoma cells and its silencing induces apoptosis through downregulating PI3K/AKT and by up-regulating p38 MAP kinase DEPTOR is an endogenous inhibitor of mTOR complexes, de-regulated in cancers.	('AKT', 'Gene', '207', (131, 134))	('p38', 'Gene', (156, 159))	('DEPTOR', 'Gene', (171, 177))	('promotes', 'PosReg', (7, 15))	('cancers', 'Phenotype', 'HP:0002664', (240, 247))	('apoptosis', 'CPA', (93, 102))	('cancers', 'Disease', (240, 247))	('survival', 'CPA', (16, 24))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (37, 60))	('mTOR', 'Gene', (208, 212))	('up-regulating', 'PosReg', (142, 155))	('p38', 'Gene', '5594', (156, 159))	('DEPTOR', 'Gene', '64798', (0, 6))	('AKT', 'Gene', (131, 134))	('mTOR', 'Gene', '2475', (208, 212))	('silencing', 'Var', (75, 84))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (37, 60))	('DEPTOR', 'Gene', '64798', (171, 177))	('cancers', 'Disease', 'MESH:D009369', (240, 247))	('downregulating', 'NegReg', (111, 125))	('squamous cell carcinoma', 'Disease', (37, 60))	('DEPTOR', 'Gene', (0, 6))	('carcinoma', 'Phenotype', 'HP:0030731', (51, 60))
495535	26992219	DEPTOR was found to be overexpressed in both cervical SCC cells and tissues and it's silencing in cervical SCC cells induced apoptosis, mainly by up-regulation of p38 MAPK and by inhibiting PI3K/AKT pathway via a feed-back inhibition from mTORC1-S6K.	('p38', 'Gene', (163, 166))	('inhibiting', 'NegReg', (179, 189))	('S6K', 'Gene', (246, 249))	('apoptosis', 'CPA', (125, 134))	('SCC', 'Gene', '6317', (107, 110))	('MAPK', 'Gene', '5595;5594;5595', (167, 171))	('SCC', 'Gene', (107, 110))	('silencing', 'Var', (85, 94))	('p38', 'Gene', '5594', (163, 166))	('AKT', 'Gene', (195, 198))	('MAPK', 'Gene', (167, 171))	('DEPTOR', 'Gene', '64798', (0, 6))	('mTORC1', 'Gene', (239, 245))	('S6K', 'Gene', '6198', (246, 249))	('induced', 'Reg', (117, 124))	('mTORC1', 'Gene', '382056', (239, 245))	('SCC', 'Gene', '6317', (54, 57))	('up-regulation', 'PosReg', (146, 159))	('AKT', 'Gene', '207', (195, 198))	('SCC', 'Gene', (54, 57))	('DEPTOR', 'Gene', (0, 6))
495539	26992219	However pharmacological inhibition of p38 MAPK rescued the cells from apoptosis, indicating the major role of p38 MAPK in cell death induced by DEPTOR silencing.	('DEPTOR', 'Gene', '64798', (144, 150))	('p38', 'Gene', (110, 113))	('MAPK', 'Gene', '5595;5594;5595', (42, 46))	('MAPK', 'Gene', (42, 46))	('MAPK', 'Gene', '5595;5594;5595', (114, 118))	('inhibition', 'Var', (24, 34))	('DEPTOR', 'Gene', (144, 150))	('p38', 'Gene', '5594', (38, 41))	('apoptosis', 'CPA', (70, 79))	('MAPK', 'Gene', (114, 118))	('p38', 'Gene', '5594', (110, 113))	('p38', 'Gene', (38, 41))
495541	26992219	DEPTOR knockdown induced cell death in SiHa cells overexpressing the anti-apoptotic Bcl-2 and Bcl-xL, indicating strong survival role of DEPTOR in these cells.	('SiHa', 'CellLine', 'CVCL:0032', (39, 43))	('DEPTOR', 'Gene', '64798', (0, 6))	('Bcl-2', 'Gene', (84, 89))	('Bcl-2', 'Gene', '596', (84, 89))	('Bcl-xL', 'Gene', '598', (94, 100))	('cell death', 'CPA', (25, 35))	('DEPTOR', 'Gene', (137, 143))	('Bcl-xL', 'Gene', (94, 100))	('knockdown', 'Var', (7, 16))	('DEPTOR', 'Gene', (0, 6))	('DEPTOR', 'Gene', '64798', (137, 143))
495555	26992219	High-risk HPV E6 is also known to bind with several PDZ domain containing cellular proteins such as CBP/p300, BARD1, c-MYC, E6-BP/ERC 55, E6TPI, ORF-3, Mcm 7, Paxillin, hD1g, MAGI-1, MUPP-1, hScrib and NHERF1.	('E6-BP', 'Gene', '5955', (124, 129))	('NHERF1', 'Gene', '9368', (202, 208))	('E6TPI', 'Var', (138, 143))	('ERC 55', 'Gene', (130, 136))	('ERC 55', 'Gene', '5955', (130, 136))	('bind', 'Interaction', (34, 38))	('hScrib', 'Gene', (191, 197))	('CBP/p300', 'Gene', (100, 108))	('PDZ', 'Protein', (52, 55))	('BARD1', 'Gene', '580', (110, 115))	('MAGI-1', 'Gene', '9223', (175, 181))	('Mcm 7', 'Gene', (152, 157))	('MUPP-1', 'Gene', '8777', (183, 189))	('BARD1', 'Gene', (110, 115))	('MUPP-1', 'Gene', (183, 189))	('Paxillin', 'Gene', '5829', (159, 167))	('MAGI-1', 'Gene', (175, 181))	('CBP/p300', 'Gene', '1387;2033', (100, 108))	('c-MYC', 'Gene', '4609', (117, 122))	('ORF-3', 'Gene', '136991', (145, 150))	('c-MYC', 'Gene', (117, 122))	('ORF-3', 'Gene', (145, 150))	('HPV', 'Gene', (10, 13))	('NHERF1', 'Gene', (202, 208))	('Mcm 7', 'Gene', '4176', (152, 157))	('hScrib', 'Gene', '23513', (191, 197))	('Paxillin', 'Gene', (159, 167))	('E6-BP', 'Gene', (124, 129))
495564	26992219	To address the role of DEPTOR in cervical cancer cells, we knocked down DEPTOR in SiHa, ME-180 and HeLa cells (Figure 1A).	('DEPTOR', 'Gene', (72, 78))	('SiHa', 'CellLine', 'CVCL:0032', (82, 86))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('cervical cancer', 'Disease', (33, 48))	('DEPTOR', 'Gene', '64798', (72, 78))	('cervical cancer', 'Disease', 'MESH:D002583', (33, 48))	('HeLa', 'CellLine', 'CVCL:0030', (99, 103))	('DEPTOR', 'Gene', (23, 29))	('ME-180', 'CellLine', 'CVCL:1401', (88, 94))	('knocked', 'Var', (59, 66))	('DEPTOR', 'Gene', '64798', (23, 29))
495568	26992219	Nuclear condensation, a general aspect of apoptosis was also analyzed in SiHa and ME-180 cells using fluorescent microscopy and the DEPTOR silenced cells showed relatively high percentage of nuclear condensation in comparison to the respective controls (Figure 1C).	('ME-180', 'CellLine', 'CVCL:1401', (82, 88))	('DEPTOR', 'Gene', (132, 138))	('DEPTOR', 'Gene', '64798', (132, 138))	('SiHa', 'CellLine', 'CVCL:0032', (73, 77))	('nuclear condensation', 'CPA', (191, 211))	('silenced', 'Var', (139, 147))
495597	26992219	However mTOR can activate itself by auto phosphorylation at Ser 2481, which activates S6K and 4E-BP1.	('activates', 'PosReg', (76, 85))	('S6K', 'Gene', (86, 89))	('4E-BP1', 'Gene', (94, 100))	('Ser 2481', 'Var', (60, 68))	('mTOR', 'Gene', '2475', (8, 12))	('mTOR', 'Gene', (8, 12))	('S6K', 'Gene', '6198', (86, 89))	('4E-BP1', 'Gene', '1978', (94, 100))	('Ser', 'Chemical', 'MESH:D012694', (60, 63))
495626	26992219	Marked increase in the phosphorylated forms of both ERK1/2 (Thr202/Tyr204) and p38 MAPK (Thr180/Tyr182) in DEPTOR-silenced SiHa and ME-180 cells was evident in comparison to the control cells (Figure 6A).	('increase', 'PosReg', (7, 15))	('SiHa', 'CellLine', 'CVCL:0032', (123, 127))	('p38', 'Gene', (79, 82))	('ERK1/2', 'Gene', (52, 58))	('ERK1/2', 'Gene', '5595;5594', (52, 58))	('Thr202', 'Chemical', '-', (60, 66))	('Tyr182', 'Chemical', '-', (96, 102))	('DEPTOR', 'Gene', '64798', (107, 113))	('MAPK', 'Gene', '5595;5594;5595', (83, 87))	('Thr202/Tyr204', 'Var', (60, 73))	('MAPK', 'Gene', (83, 87))	('phosphorylated', 'MPA', (23, 37))	('p38', 'Gene', '5594', (79, 82))	('ME-180', 'CellLine', 'CVCL:1401', (132, 138))	('Thr180', 'Chemical', '-', (89, 95))	('Thr180/Tyr182', 'Var', (89, 102))	('Tyr204', 'Chemical', '-', (67, 73))	('DEPTOR', 'Gene', (107, 113))
495632	26992219	The SiHa cells were pretreated for 3 hours with 10muM PD98059 before DEPTOR silencing, along with proper control.	('DEPTOR', 'Gene', (69, 75))	('PD98059', 'Chemical', 'MESH:C093973', (54, 61))	('DEPTOR', 'Gene', '64798', (69, 75))	('SiHa', 'CellLine', 'CVCL:0032', (4, 8))	('PD98059', 'Var', (54, 61))
495640	26992219	The SiHa cells were pretreated for 3 hours with 10muM SB202190 before DEPTOR silencing, along with proper control.	('SiHa', 'CellLine', 'CVCL:0032', (4, 8))	('DEPTOR', 'Gene', '64798', (70, 76))	('SB202190', 'Chemical', 'MESH:C090942', (54, 62))	('DEPTOR', 'Gene', (70, 76))	('SB202190', 'Var', (54, 62))
495642	26992219	The annexin binding assay suggested the percentage of annexin positivity in cells treated with p38 MAPK inhibitor coupled with DEPTOR silencing is almost similar to the control cells with scramble siRNA silencing (Figure 6B), while the DEPTOR silenced cells showed approximately 7-10 times the annexin positivity in comparison to the control and p38 MAPK inhibitor pretreatment coupled with DEPTOR silencing.	('DEPTOR', 'Gene', '64798', (391, 397))	('p38', 'Gene', '5594', (95, 98))	('MAPK', 'Gene', '5595;5594;5595', (350, 354))	('DEPTOR', 'Gene', '64798', (127, 133))	('annexin', 'Protein', (54, 61))	('MAPK', 'Gene', (99, 103))	('MAPK', 'Gene', (350, 354))	('MAPK', 'Gene', '5595;5594;5595', (99, 103))	('p38', 'Gene', '5594', (346, 349))	('DEPTOR', 'Gene', (236, 242))	('p38', 'Gene', (95, 98))	('inhibitor', 'Var', (104, 113))	('DEPTOR', 'Gene', '64798', (236, 242))	('DEPTOR', 'Gene', (391, 397))	('DEPTOR', 'Gene', (127, 133))	('p38', 'Gene', (346, 349))
495646	26992219	HPV E6 contains a PDZ domain that is known to interact with PDZ domain of several host cellular proteins and high risk HPV E6 is known to activate the mTOR complex.	('interact', 'Interaction', (46, 54))	('activate', 'PosReg', (138, 146))	('HPV E6', 'Var', (119, 125))	('mTOR', 'Gene', (151, 155))	('mTOR', 'Gene', '2475', (151, 155))
495653	26992219	No reduction in the levels of DEPTOR was observed with E6/E7 silencing (Figure 7B).	('DEPTOR', 'Gene', (30, 36))	('DEPTOR', 'Gene', '64798', (30, 36))	('E6/E7 silencing', 'Var', (55, 70))
495654	26992219	All these data indicate a probable HPV E6/E7-independent mechanism of DEPTOR regulation in cervical SCC cells.	('SCC', 'Gene', (100, 103))	('DEPTOR', 'Gene', '64798', (70, 76))	('SCC', 'Gene', '6317', (100, 103))	('cervical', 'Disease', (91, 99))	('E6/E7-independent', 'Var', (39, 56))	('DEPTOR', 'Gene', (70, 76))
495658	26992219	To investigate whether silencing DEPTOR can induce cell death in cells overexpressing anti-apoptotic molecules Bcl-2 and Bcl-xL, we used SiHa cells overexpressing Bcl2, Bcl-xL and ER targeted Bcl-2, previously reported from our laboratories.	('Bcl-2', 'Gene', '596', (192, 197))	('SiHa', 'CellLine', 'CVCL:0032', (137, 141))	('Bcl-2', 'Gene', (111, 116))	('DEPTOR', 'Gene', (33, 39))	('Bcl-2', 'Gene', '596', (111, 116))	('Bcl-xL', 'Gene', '598', (121, 127))	('silencing', 'Var', (23, 32))	('Bcl-xL', 'Gene', (121, 127))	('Bcl2', 'Gene', (163, 167))	('DEPTOR', 'Gene', '64798', (33, 39))	('Bcl-xL', 'Gene', '598', (169, 175))	('Bcl2', 'Gene', '596', (163, 167))	('Bcl-2', 'Gene', (192, 197))	('Bcl-xL', 'Gene', (169, 175))
495668	26992219	As mTOR activation is reported to be the hall mark of several cancers, DEPTOR in general should act as tumor suppressor and its expression was reported to have growth suppression effects in pancreatic cancer cells.	('expression', 'Var', (128, 138))	('mTOR', 'Gene', '2475', (3, 7))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (190, 207))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('activation', 'PosReg', (8, 18))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('tumor', 'Disease', (103, 108))	('DEPTOR', 'Gene', (71, 77))	('cancers', 'Disease', (62, 69))	('pancreatic cancer', 'Disease', (190, 207))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('DEPTOR', 'Gene', '64798', (71, 77))	('pancreatic cancer', 'Disease', 'MESH:D010190', (190, 207))	('cancers', 'Disease', 'MESH:D009369', (62, 69))	('cancers', 'Phenotype', 'HP:0002664', (62, 69))	('growth suppression', 'CPA', (160, 178))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('mTOR', 'Gene', (3, 7))
495670	26992219	We started the present study with an aim to address the possible interaction/regulation between DEPTOR and HPV E6/E7, since HPV E6/E7 are known to interact with several host cellular proteins.	('HPV E6/E7', 'Gene', (107, 116))	('DEPTOR', 'Gene', '64798', (96, 102))	('interaction/regulation', 'Interaction', (65, 87))	('E6/E7', 'Var', (128, 133))	('interact', 'Interaction', (147, 155))	('DEPTOR', 'Gene', (96, 102))
495682	26992219	HPV 16 is known to activate the PI3K/AKT/mTOR pathway.	('HPV', 'Var', (0, 3))	('mTOR', 'Gene', (41, 45))	('AKT', 'Gene', '207', (37, 40))	('AKT', 'Gene', (37, 40))	('HPV 16', 'Species', '333760', (0, 6))	('activate', 'PosReg', (19, 27))	('mTOR', 'Gene', '2475', (41, 45))
495692	26992219	In our study, direct interaction between endogenous DEPTOR and ERK1/2 was not observed, however the clear activation of ERK and p38 MAPK by DEPTOR silencing suggests a positive input by mTORC1 activation.	('DEPTOR', 'Gene', '64798', (140, 146))	('DEPTOR', 'Gene', '64798', (52, 58))	('p38', 'Gene', (128, 131))	('ERK', 'Gene', '5594', (63, 66))	('ERK1/2', 'Gene', (63, 69))	('ERK1/2', 'Gene', '5595;5594', (63, 69))	('MAPK', 'Gene', '5595;5594;5595', (132, 136))	('mTORC1', 'Gene', '382056', (186, 192))	('DEPTOR', 'Gene', (140, 146))	('ERK', 'Gene', '5594', (120, 123))	('MAPK', 'Gene', (132, 136))	('p38', 'Gene', '5594', (128, 131))	('DEPTOR', 'Gene', (52, 58))	('ERK', 'Gene', (120, 123))	('activation', 'PosReg', (106, 116))	('ERK', 'Gene', (63, 66))	('mTORC1', 'Gene', (186, 192))	('silencing', 'Var', (147, 156))
495693	26992219	While there are reports citing that activated PI3K/AKT directly activates MAPK, the present study reveals that inhibition of PI3K/AKT, activates ERK.	('MAPK', 'Gene', (74, 78))	('ERK', 'Gene', (145, 148))	('AKT', 'Gene', (51, 54))	('activates', 'PosReg', (135, 144))	('AKT', 'Gene', '207', (130, 133))	('ERK', 'Gene', '5594', (145, 148))	('inhibition', 'Var', (111, 121))	('MAPK', 'Gene', '5595;5594;5595', (74, 78))	('AKT', 'Gene', '207', (51, 54))	('AKT', 'Gene', (130, 133))
495696	26992219	The results clearly indicate that p38 MAP kinase is responsible for the apoptosis under DEPOTR silencing, as cells pre-treated with p38 MAPK inhibitor attenuated the cell death caused by DEPTOR silencing (Figure 6B).	('MAPK', 'Gene', (136, 140))	('MAPK', 'Gene', '5595;5594;5595', (136, 140))	('attenuated', 'NegReg', (151, 161))	('DEPTOR', 'Gene', (187, 193))	('p38', 'Gene', (132, 135))	('p38', 'Gene', '5594', (34, 37))	('DEPTOR', 'Gene', '64798', (187, 193))	('silencing', 'Var', (95, 104))	('p38', 'Gene', '5594', (132, 135))	('p38', 'Gene', (34, 37))	('cell death', 'CPA', (166, 176))
495701	26992219	To our knowledge, this is the first study reporting the regulation of p38MAPK by DEPTOR.	('DEPTOR', 'Gene', '64798', (81, 87))	('p38MAPK', 'Var', (70, 77))	('DEPTOR', 'Gene', (81, 87))
495706	26992219	DEPTOR silencing in HPV-negative cervical cancer cell C33A likewise induced a strong apoptotic response similar to SiHa and ME-180 cells and HPV E6/E7 silencing in SiHa also showed no difference in DEPTOR protein levels when compared to the control silenced cells (Figure 7).	('apoptotic response', 'CPA', (85, 103))	('silencing', 'Var', (151, 160))	('DEPTOR', 'Gene', '64798', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('cervical cancer', 'Disease', (33, 48))	('DEPTOR', 'Gene', (198, 204))	('cervical cancer', 'Disease', 'MESH:D002583', (33, 48))	('induced', 'Reg', (68, 75))	('SiHa', 'CellLine', 'CVCL:0032', (164, 168))	('ME-180', 'CellLine', 'CVCL:1401', (124, 130))	('DEPTOR', 'Gene', '64798', (198, 204))	('SiHa', 'CellLine', 'CVCL:0032', (115, 119))	('DEPTOR', 'Gene', (0, 6))	('silencing', 'Var', (7, 16))
495707	26992219	A similar study on NEDD9, a focal adhesion scaffolding protein, proposed to promote migration and invasion of cervical cancer was found to be independent of any interaction with HPV E6/E7.	('promote', 'PosReg', (76, 83))	('cervical cancer', 'Disease', (110, 125))	('NEDD9', 'Gene', '4739', (19, 24))	('NEDD9', 'Gene', (19, 24))	('invasion', 'CPA', (98, 106))	('E6/E7', 'Var', (182, 187))	('migration', 'CPA', (84, 93))	('cervical cancer', 'Disease', 'MESH:D002583', (110, 125))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
495728	26992219	Rapamycin (Sigma, Germany) and Torin 2 (Tocris Biosciences, USA) inhibitors were used for the treatment of SiHa and ME-180 cells to assess their effects on signaling in comparison with DEPTOR silencing.	('Torin', 'Gene', '7001', (31, 36))	('Tocris Biosciences', 'Disease', 'None', (40, 58))	('DEPTOR', 'Gene', '64798', (185, 191))	('inhibitors', 'Var', (65, 75))	('Tocris Biosciences', 'Disease', (40, 58))	('SiHa', 'CellLine', 'CVCL:0032', (107, 111))	('ME-180', 'CellLine', 'CVCL:1401', (116, 122))	('DEPTOR', 'Gene', (185, 191))	('Torin', 'Gene', (31, 36))
495732	26992219	SB202190 and PD98059 (Sigma, Germany) were used as p38 MAPK and ERK inhibitors for delineating their respective roles in apoptosis induced by DEPTOR silencing.	('DEPTOR', 'Gene', (142, 148))	('SB202190', 'Chemical', 'MESH:C090942', (0, 8))	('p38', 'Gene', (51, 54))	('SB202190', 'Var', (0, 8))	('PD98059', 'Var', (13, 20))	('DEPTOR', 'Gene', '64798', (142, 148))	('PD98059', 'Chemical', 'MESH:C093973', (13, 20))	('ERK', 'Gene', '5594', (64, 67))	('MAPK', 'Gene', (55, 59))	('p38', 'Gene', '5594', (51, 54))	('MAPK', 'Gene', '5595;5594;5595', (55, 59))	('ERK', 'Gene', (64, 67))	('apoptosis', 'CPA', (121, 130))
495865	26622492	Development of squamous cell carcinoma in burn scar ulcers was reported to be associated with local Fas gene mutation and deletion.	('ulcers', 'Disease', (52, 58))	('local Fas gene', 'Gene', (94, 108))	('associated', 'Reg', (78, 88))	('ulcers', 'Disease', 'MESH:D014456', (52, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (29, 38))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (15, 38))	('deletion', 'Var', (122, 130))	('squamous cell carcinoma', 'Disease', (15, 38))	('scar', 'Phenotype', 'HP:0100699', (47, 51))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (15, 38))	('burn scar ulcer', 'Phenotype', 'HP:0200042', (42, 57))	('mutation', 'Var', (109, 117))
495880	26622492	Radiotherapy may also induce further carcinomatous change.	('Radiotherapy', 'Var', (0, 12))	('carcinoma', 'Phenotype', 'HP:0030731', (37, 46))	('carcinomatous change', 'Disease', (37, 57))	('induce', 'Reg', (22, 28))	('carcinomatous change', 'Disease', 'MESH:D055756', (37, 57))
495890	30530704	Activating Mutations in Pik3ca Contribute to Anal Carcinogenesis in the Presence or Absence of HPV-16 Oncogenes Over 95% of human anal cancers are etiologically associated with high-risk HPVs, with HPV type 16 (HPV16) the genotype most commonly found.	('HPV16', 'Species', '333760', (211, 216))	('Anal Carcinogenesis', 'Disease', (45, 64))	('cancers', 'Phenotype', 'HP:0002664', (135, 142))	('associated', 'Reg', (161, 171))	('cancers', 'Disease', (135, 142))	('cancers', 'Disease', 'MESH:D009369', (135, 142))	('HPV', 'Species', '10566', (187, 190))	('anal cancer', 'Phenotype', 'HP:0032186', (130, 141))	('HPV-16', 'Species', '333760', (95, 101))	('HPV', 'Species', '10566', (211, 214))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('human', 'Species', '9606', (124, 129))	('Pik3ca', 'Gene', (24, 30))	('Pik3ca', 'Gene', '18706', (24, 30))	('HPV', 'Species', '10566', (198, 201))	('HPV', 'Species', '10566', (95, 98))	('Mutations', 'Var', (11, 20))
495891	30530704	Activating mutations in the catalytic subunit of Phosphatidylinositol (3,4,5)-trisphosphate kinase (PI3K), encoded by the Pik3ca gene, are detected in approximately 20% of human anal cancers.	('mutations', 'Var', (11, 20))	('Activating', 'PosReg', (0, 10))	('cancers', 'Disease', (183, 190))	('human', 'Species', '9606', (172, 177))	('Pik3ca', 'Gene', (122, 128))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('detected', 'Reg', (139, 147))	('Phosphatidylinositol', 'Chemical', 'MESH:D010716', (49, 69))	('cancers', 'Phenotype', 'HP:0002664', (183, 190))	('anal cancer', 'Phenotype', 'HP:0032186', (178, 189))	('cancers', 'Disease', 'MESH:D009369', (183, 190))
495892	30530704	We asked if common activating mutations in Pik3ca contribute to anal carcinogenesis using an established mouse model for anal carcinogenesis in which mice are topically treated with the chemical carcinogen 7,12-Dimethylbenz(a)anthracene (DMBA).	('DMBA', 'Chemical', 'MESH:D015127', (238, 242))	('mice', 'Species', '10090', (150, 154))	('activating', 'PosReg', (19, 29))	('Pik3ca', 'Gene', (43, 49))	('carcinogenesis', 'Disease', 'MESH:D063646', (126, 140))	('carcinogenesis', 'Disease', (126, 140))	('anthracene', 'Chemical', 'MESH:C034020', (226, 236))	('mutations', 'Var', (30, 39))	('7,12-Dimethylbenz', 'Chemical', '-', (206, 223))	('carcinogenesis', 'Disease', 'MESH:D063646', (69, 83))	('mouse', 'Species', '10090', (105, 110))	('carcinogenesis', 'Disease', (69, 83))
495893	30530704	Mice expressing in their anal epithelium one of two activating mutations in Pik3ca genes, Pik3caH1047R or Pik3caE545K, were monitored for anal carcinogenesis in the presence or absence of transgenes expressing the HPV16 E6 and E7 oncogenes.	('E545K', 'Mutation', 'rs104886003', (112, 117))	('Pik3caH1047R', 'Var', (90, 102))	('HPV16', 'Species', '333760', (214, 219))	('carcinogenesis', 'Disease', 'MESH:D063646', (143, 157))	('H1047R', 'Mutation', 'rs121913279', (96, 102))	('carcinogenesis', 'Disease', (143, 157))	('Mice', 'Species', '10090', (0, 4))	('Pik3caE545K', 'Var', (106, 117))	('Pik3ca', 'Gene', (76, 82))
495894	30530704	Both mutant forms of Pik3ca increased susceptibility to anal carcinogenesis in the absence of HPV16 oncogenes, and cooperated with HPV16 oncogenes to induce the highest level and earliest onset of anal cancers.	('susceptibility', 'MPA', (38, 52))	('induce', 'PosReg', (150, 156))	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('anal cancer', 'Phenotype', 'HP:0032186', (197, 208))	('carcinogenesis', 'Disease', (61, 75))	('cancers', 'Phenotype', 'HP:0002664', (202, 209))	('mutant', 'Var', (5, 11))	('cancers', 'Disease', (202, 209))	('cancers', 'Disease', 'MESH:D009369', (202, 209))	('Pik3ca', 'Gene', (21, 27))	('HPV16', 'Species', '333760', (94, 99))	('HPV16', 'Species', '333760', (131, 136))	('carcinogenesis', 'Disease', 'MESH:D063646', (61, 75))
495895	30530704	The combination of HPV16 oncogenes and Pik3ca mutations led to anal cancers even in the absence of treatment with DMBA.	('anal cancer', 'Phenotype', 'HP:0032186', (63, 74))	('HPV16', 'Gene', (19, 24))	('HPV16', 'Species', '333760', (19, 24))	('led to', 'Reg', (56, 62))	('mutations', 'Var', (46, 55))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('Pik3ca', 'Gene', (39, 45))	('cancers', 'Phenotype', 'HP:0002664', (68, 75))	('cancers', 'Disease', (68, 75))	('cancers', 'Disease', 'MESH:D009369', (68, 75))	('DMBA', 'Chemical', 'MESH:D015127', (114, 118))
495897	30530704	These data demonstrate that activating mutations in Pik3ca drive anal carcinogenesis together with HPV16 oncogenes, and that the PI3K/mTOR pathway is a relevant target for therapeutic intervention.	('carcinogenesis', 'Disease', (70, 84))	('drive', 'Reg', (59, 64))	('activating', 'PosReg', (28, 38))	('HPV16', 'Species', '333760', (99, 104))	('mutations', 'Var', (39, 48))	('carcinogenesis', 'Disease', 'MESH:D063646', (70, 84))	('Pik3ca', 'Gene', (52, 58))
495903	30530704	Studies using this animal model led to the discoveries that HPV16 E7 is the more potent oncogene in anal carcinogenesis and that the mTOR ("mechanistic target of rapamycin" or "mammalian target of rapamycin") signaling pathway is activated in anal squamous cell carcinoma arising in HPV16 transgenic mice as well as in human anal cancers.	('HPV16', 'Species', '333760', (283, 288))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (248, 271))	('transgenic', 'Var', (289, 299))	('anal cancer', 'Phenotype', 'HP:0032186', (325, 336))	('cancers', 'Disease', 'MESH:D009369', (330, 337))	('human', 'Species', '9606', (319, 324))	('carcinoma', 'Phenotype', 'HP:0030731', (262, 271))	('mammalian target of rapamycin"', 'Gene', (177, 207))	('HPV16', 'Species', '333760', (60, 65))	('mammalian target of rapamycin"', 'Gene', '2475', (177, 207))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (248, 271))	('HPV16', 'Gene', (283, 288))	('carcinogenesis', 'Disease', (105, 119))	('squamous cell carcinoma', 'Disease', (248, 271))	('activated', 'PosReg', (230, 239))	('cancers', 'Phenotype', 'HP:0002664', (330, 337))	('cancers', 'Disease', (330, 337))	('transgenic mice', 'Species', '10090', (289, 304))	('carcinogenesis', 'Disease', 'MESH:D063646', (105, 119))	('cancer', 'Phenotype', 'HP:0002664', (330, 336))	('rapamycin', 'Chemical', 'MESH:D020123', (197, 206))	('HPV16', 'Gene', (60, 65))	('rapamycin', 'Chemical', 'MESH:D020123', (162, 171))
495906	30530704	Alterations in PI3K/AKT/mTOR signaling caused by hyper-activation of PI3K are thought to contribute to cancers including HPV-associated cancers.	('cancers', 'Disease', 'MESH:D009369', (103, 110))	('hyper-activation', 'PosReg', (49, 65))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('cancers', 'Phenotype', 'HP:0002664', (136, 143))	('Alterations', 'Var', (0, 11))	('cancers', 'Disease', (136, 143))	('contribute', 'Reg', (89, 99))	('HPV', 'Species', '10566', (121, 124))	('PI3K/AKT/mTOR signaling', 'Pathway', (15, 38))	('cancers', 'Disease', 'MESH:D009369', (136, 143))	('PI3K', 'Gene', (69, 73))	('cancers', 'Phenotype', 'HP:0002664', (103, 110))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('cancers', 'Disease', (103, 110))
495907	30530704	Recently, mutations that lead to increased PI3K signaling were found in 36% of 12 types of human cancers.	('cancers', 'Disease', 'MESH:D009369', (97, 104))	('cancers', 'Phenotype', 'HP:0002664', (97, 104))	('cancers', 'Disease', (97, 104))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('increased', 'PosReg', (33, 42))	('mutations', 'Var', (10, 19))	('PI3K signaling', 'Pathway', (43, 57))	('human', 'Species', '9606', (91, 96))
495908	30530704	Of these mutations causing activation of PI3K signaling, the most prevalent mutations occurred in the Pik3ca gene that encodes p110alpha, the catalytic subunit of PI3K.	('mutations', 'Var', (76, 85))	('p110alpha', 'Gene', '18706', (127, 136))	('occurred', 'Reg', (86, 94))	('mutations', 'Var', (9, 18))	('Pik3ca', 'Gene', (102, 108))	('activation', 'PosReg', (27, 37))	('p110alpha', 'Gene', (127, 136))
495909	30530704	Three hot-spot mutations in the Pik3ca gene, E542K and E545K (exon 9) in the helical domain and H1047R/L (exon 20) in the kinase domain of p110alpha, lead to the constitutive activation of PI3K signaling independent of the PI3K regulatory subunit p85.	('p85', 'Gene', (247, 250))	('PI3K signaling', 'Pathway', (189, 203))	('Pik3ca', 'Gene', (32, 38))	('p110alpha', 'Gene', (139, 148))	('activation', 'PosReg', (175, 185))	('E542K', 'Mutation', 'rs121913273', (45, 50))	('E545K', 'Mutation', 'rs104886003', (55, 60))	('p85', 'Gene', '21981', (247, 250))	('E545K', 'Var', (55, 60))	('p110alpha', 'Gene', '18706', (139, 148))	('E542K', 'Var', (45, 50))	('H1047R', 'SUBSTITUTION', 'None', (96, 102))	('H1047R', 'Var', (96, 102))
495910	30530704	Such mutations in Pik3ca arise in approximately 20% of human anal cancers, 90% of which are in exon 9.	('Pik3ca', 'Gene', (18, 24))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('human', 'Species', '9606', (55, 60))	('mutations', 'Var', (5, 14))	('arise in', 'Reg', (25, 33))	('anal cancer', 'Phenotype', 'HP:0032186', (61, 72))	('cancers', 'Phenotype', 'HP:0002664', (66, 73))	('cancers', 'Disease', (66, 73))	('cancers', 'Disease', 'MESH:D009369', (66, 73))
495912	30530704	Here, we asked if such activating mutations in Pik3ca contribute to anal carcinogenesis in the context of mice expressing or lacking HPV16 oncogenes, E6 and E7.	('HPV16', 'Species', '333760', (133, 138))	('carcinogenesis', 'Disease', (73, 87))	('mice', 'Species', '10090', (106, 110))	('Pik3ca', 'Gene', (47, 53))	('carcinogenesis', 'Disease', 'MESH:D063646', (73, 87))	('lacking', 'NegReg', (125, 132))	('mutations', 'Var', (34, 43))	('activating', 'PosReg', (23, 33))
495913	30530704	We generated mice expressing a mutant form of Pik3ca, either Pik3caH1047R or Pik3caE545K, +/- the HPV16 oncogenes, E6 and E7, and treated them topically in the anus with the chemical carcinogen DMBA.	('mice', 'Species', '10090', (13, 17))	('DMBA', 'Chemical', 'MESH:D015127', (194, 198))	('HPV16', 'Species', '333760', (98, 103))	('Pik3ca', 'Gene', (46, 52))	('Pik3caH1047R', 'Var', (61, 73))	('Pik3caE545K', 'Var', (77, 88))
495914	30530704	We found these activating mutations in Pik3ca to drive anal carcinogenesis, and their oncogenic potential was synergistic with HPV16 E6 and E7, even in the absence of DMBA.	('carcinogenesis', 'Disease', 'MESH:D063646', (60, 74))	('DMBA', 'Chemical', 'MESH:D015127', (167, 171))	('Pik3ca', 'Gene', (39, 45))	('oncogenic potential', 'CPA', (86, 105))	('mutations', 'Var', (26, 35))	('carcinogenesis', 'Disease', (60, 74))	('activating', 'PosReg', (15, 25))	('HPV16', 'Species', '333760', (127, 132))	('drive', 'PosReg', (49, 54))
495915	30530704	We also found that tumor spheres and tumor grafts derived from these anal tumors were inhibited in their growth by TAK-228 (also known as sapanisertib, INK-128 and MLN0128), an investigational drug that inhibits both TORC1 and TORC2.	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('TAK-228', 'Gene', (115, 122))	('tumor', 'Disease', (74, 79))	('tumor', 'Disease', (19, 24))	('TAK-228', 'Chemical', 'MESH:C572449', (115, 122))	('MLN0128', 'Var', (164, 171))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('TORC1', 'Gene', '382056', (217, 222))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('anal tumors', 'Disease', (69, 80))	('sapanisertib', 'Chemical', 'MESH:C572449', (138, 150))	('TORC1', 'Gene', (217, 222))	('growth', 'MPA', (105, 111))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('anal tumors', 'Disease', 'MESH:D001005', (69, 80))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('TORC2', 'Gene', '74343', (227, 232))	('TORC2', 'Gene', (227, 232))	('tumor', 'Disease', (37, 42))	('inhibited', 'NegReg', (86, 95))
495916	30530704	We conclude that activating mutations in Pik3ca contribute to anal carcinogenesis and that this pathway represents an important new target for therapeutic intervention.	('carcinogenesis', 'Disease', 'MESH:D063646', (67, 81))	('carcinogenesis', 'Disease', (67, 81))	('activating', 'PosReg', (17, 27))	('contribute', 'Reg', (48, 58))	('Pik3ca', 'Gene', (41, 47))	('mutations', 'Var', (28, 37))
495918	30530704	R26-Pik3caH1047R (heretofore referred to as Pik3caH1047R) and R26-Pik3caE545K (heretofore referred to as Pik3caE454K) mice were kindly provided by Dr. Dustin A Deming and described previously (The Jackson Laboratory; Stock Number 016977).	('R26-Pik3caE545K', 'Var', (62, 77))	('R26-Pik3caH1047R', 'Var', (0, 16))	('H1047R', 'Mutation', 'rs121913279', (10, 16))	('mice', 'Species', '10090', (118, 122))	('H1047R', 'Mutation', 'rs121913279', (50, 56))
495919	30530704	Details on the breeding schemes used to generate the various strains of mice used in this study, an ethics statement, and methods used to induce expression of the Pik3ca mutants and treat mice with DMBA are provided in supplemental information.	('Pik3ca', 'Gene', (163, 169))	('mice', 'Species', '10090', (188, 192))	('mutants', 'Var', (170, 177))	('expression', 'MPA', (145, 155))	('induce', 'PosReg', (138, 144))	('mice', 'Species', '10090', (72, 76))	('DMBA', 'Chemical', 'MESH:D015127', (198, 202))
495927	30530704	Anal tumors from 4-OHT treated K14E6/E7/Pik3caE545K: K14CreERtm mice were rubbed with 10% providone-iodine (CareFusion) and/or isopropyl alcohol, rinsed with sterile phosphate buffered saline (PBS), and excised with sterile instruments.	('phosphate buffered saline', 'Chemical', '-', (166, 191))	('Anal tumors', 'Disease', 'MESH:D001005', (0, 11))	('PBS', 'Chemical', '-', (193, 196))	('K14CreERtm', 'Var', (53, 63))	('isopropyl alcohol', 'Chemical', 'MESH:D019840', (127, 144))	('iodine', 'Chemical', 'MESH:D007455', (100, 106))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('K14E6', 'Chemical', '-', (31, 36))	('4-OHT', 'Chemical', 'MESH:C032278', (17, 22))	('E545K', 'Mutation', 'rs104886003', (46, 51))	('Anal tumors', 'Disease', (0, 11))	('K14CreERtm', 'Chemical', '-', (53, 63))	('tumors', 'Phenotype', 'HP:0002664', (5, 11))	('mice', 'Species', '10090', (64, 68))
495937	30530704	To determine whether activating mutations in Pik3ca found in human anal cancers contribute to anal carcinogenesis, we generated mice that conditionally express mutant forms of Pik3ca in anal, stratified squamous epithelium.	('cancers', 'Disease', 'MESH:D009369', (72, 79))	('carcinogenesis', 'Disease', 'MESH:D063646', (99, 113))	('anal cancer', 'Phenotype', 'HP:0032186', (67, 78))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('mice', 'Species', '10090', (128, 132))	('carcinogenesis', 'Disease', (99, 113))	('mutant', 'Var', (160, 166))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('cancers', 'Disease', (72, 79))	('human', 'Species', '9606', (61, 66))	('Pik3ca', 'Gene', (176, 182))
495939	30530704	To generate mice expressing this mutant form of Pik3ca in anal epithelium, K14CreERtm transgenic mice expressing the tamoxifen (or 4-hydroxy-tamoxifen: 4-OHT)-inducible CreERtm from the keratin14 (K14) promoter were bred to the Pik3caH1047R mice.	('keratin14', 'Gene', (186, 195))	('4-hydroxy-tamoxifen', 'Chemical', '-', (131, 150))	('K14', 'Gene', '16664', (197, 200))	('K14', 'Gene', (197, 200))	('K14', 'Gene', (75, 78))	('K14', 'Gene', '16664', (75, 78))	('mice', 'Species', '10090', (241, 245))	('keratin14', 'Gene', '16664', (186, 195))	('mice', 'Species', '10090', (97, 101))	('mutant', 'Var', (33, 39))	('tamoxifen', 'Chemical', 'MESH:D013629', (141, 150))	('K14CreERtm', 'Chemical', '-', (75, 85))	('mice', 'Species', '10090', (12, 16))	('tamoxifen', 'Chemical', 'MESH:D013629', (117, 126))	('4-OHT', 'Chemical', 'MESH:C032278', (152, 157))	('transgenic mice', 'Species', '10090', (86, 101))
495940	30530704	To assess the efficiency of expression of the mutant form of Pik3ca, p110alphaH1047R, through inducible Cre-recombination in anal epithelium from Pik3caH1047R: K14CreERtm and K14E6/E7/Pik3caH1047R:K14CreERtm mice, we performed western blot analysis to monitor levels of phospho S6 Ribosomal Protein (p-S6) in lysates from the anoderm of these mice.	('Pik3caH1047R', 'Var', (146, 158))	('K14E6', 'Chemical', '-', (175, 180))	('Pik3ca', 'Gene', (61, 67))	('p110alphaH1047R', 'Var', (69, 84))	('K14CreERtm', 'Chemical', '-', (160, 170))	('K14CreERtm', 'Chemical', '-', (197, 207))	('mice', 'Species', '10090', (208, 212))	('mice', 'Species', '10090', (343, 347))
495942	30530704	As previously described, activating mutations of Pik3ca lead to an increase in phosphorylation of AKT and subsequent phosphorylation of S6 and 4E-BP1.	('S6 and 4', 'Gene', '16898', (136, 144))	('activating', 'PosReg', (25, 35))	('AKT', 'Pathway', (98, 101))	('mutations', 'Var', (36, 45))	('phosphorylation', 'MPA', (117, 132))	('increase', 'PosReg', (67, 75))	('phosphorylation', 'MPA', (79, 94))	('Pik3ca', 'Gene', (49, 55))
495944	30530704	In lysates from both Pik3caH1047R:K14CreERtm and K14E6/E7/Pik3caH1047R, phosphorylation of S6 was increased over that seen in Pik3caH1047R mice (Figure 1A/B).	('H1047R', 'Mutation', 'rs121913279', (27, 33))	('1A/B', 'Var', (152, 156))	('1A/B', 'SUBSTITUTION', 'None', (152, 156))	('phosphorylation', 'MPA', (72, 87))	('Pik3caH1047R:K14CreERtm', 'Var', (21, 44))	('K14E6/E7/Pik3caH1047R', 'Var', (49, 70))	('H1047R', 'Mutation', 'rs121913279', (132, 138))	('K14E6', 'Chemical', '-', (49, 54))	('increased', 'PosReg', (98, 107))	('K14CreERtm', 'Var', (34, 44))	('mice', 'Species', '10090', (139, 143))	('H1047R', 'Mutation', 'rs121913279', (64, 70))	('K14CreERtm', 'Chemical', '-', (34, 44))
495945	30530704	Not surprisingly, phosphorylation of S6 was more significantly increased in K14E6/E7/Pik3caH1047R:K14CreERtm mice compared to the other groups, Pik3caH1047R:K14CreERtm and K14E6/E7/Pik3caH1047R.	('H1047R', 'Mutation', 'rs121913279', (150, 156))	('K14CreERtm', 'Chemical', '-', (157, 167))	('increased', 'PosReg', (63, 72))	('K14E6', 'Chemical', '-', (172, 177))	('K14E6', 'Chemical', '-', (76, 81))	('phosphorylation', 'MPA', (18, 33))	('H1047R', 'Mutation', 'rs121913279', (187, 193))	('K14CreERtm', 'Chemical', '-', (98, 108))	('mice', 'Species', '10090', (109, 113))	('H1047R', 'Mutation', 'rs121913279', (91, 97))	('K14E6/E7/Pik3caH1047R', 'Var', (76, 97))
495947	30530704	Using this experimental design, we observed that the activating mutation in Pik3ca present in the Pik3caH1047R:K14CreERtm mice caused anal cancers (Figure 2A).	('mice', 'Species', '10090', (122, 126))	('mutation', 'Var', (64, 72))	('cancers', 'Disease', 'MESH:D009369', (139, 146))	('cancers', 'Phenotype', 'HP:0002664', (139, 146))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('cancers', 'Disease', (139, 146))	('K14CreERtm', 'Chemical', '-', (111, 121))	('anal cancer', 'Phenotype', 'HP:0032186', (134, 145))	('caused', 'Reg', (127, 133))	('activating', 'PosReg', (53, 63))	('Pik3ca', 'Gene', (76, 82))
495950	30530704	All (n=14) of the Pik3caH1047R:K14CreERtm mice developed overt anal tumors with an average onset of 10.3 weeks after initial DMBA treatment, whereas none of the nontransgenic mice developed any overt tumors at this time point (Figure 2A).	('mice', 'Species', '10090', (175, 179))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('K14CreERtm', 'Chemical', '-', (31, 41))	('mice', 'Species', '10090', (42, 46))	('transgenic mice', 'Species', '10090', (164, 179))	('tumors', 'Phenotype', 'HP:0002664', (200, 206))	('overt tumors', 'Disease', 'MESH:D009369', (194, 206))	('overt tumors', 'Disease', (194, 206))	('anal tumors', 'Disease', 'MESH:D001005', (63, 74))	('Pik3caH1047R:K14CreERtm', 'Var', (18, 41))	('DMBA', 'Chemical', 'MESH:D015127', (125, 129))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('anal tumors', 'Disease', (63, 74))
495951	30530704	These observations indicate that the mutant form of Pik3ca, p110alphaH1047R, leads to increased susceptibility to anal tumors.	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('p110alphaH1047R', 'Var', (60, 75))	('susceptibility', 'Reg', (96, 110))	('anal tumors', 'Disease', 'MESH:D001005', (114, 125))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('Pik3ca', 'Gene', (52, 58))	('anal tumors', 'Disease', (114, 125))
495952	30530704	Next, we monitored the tumorigenic potential of the mutants of Pik3ca on anal carcinogenesis in context of HPV16 E6/E7 transgenic mice.	('carcinogenesis', 'Disease', 'MESH:D063646', (78, 92))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('carcinogenesis', 'Disease', (78, 92))	('mutants', 'Var', (52, 59))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('HPV16', 'Species', '333760', (107, 112))	('transgenic mice', 'Species', '10090', (119, 134))	('tumor', 'Disease', (23, 28))	('Pik3ca', 'Gene', (63, 69))
495954	30530704	K14CreERtm mice were bred to either Pik3caH1047R or Pik3caE545K mice and the resulting Pik3caH1047R: K14CreERtm or Pik3caE545K:K14CreERtm mice were crossed to K14E6 and K14E7 mice.	('K14', 'Gene', '16664', (169, 172))	('K14', 'Gene', '16664', (159, 162))	('K14CreERtm', 'Chemical', '-', (127, 137))	('K14CreERtm', 'Chemical', '-', (0, 10))	('K14', 'Gene', (101, 104))	('mice', 'Species', '10090', (138, 142))	('K14', 'Gene', '16664', (127, 130))	('K14', 'Gene', '16664', (0, 3))	('K14', 'Gene', (169, 172))	('Pik3caE545K', 'Var', (52, 63))	('E545K', 'Mutation', 'rs104886003', (58, 63))	('E545K', 'Mutation', 'rs104886003', (121, 126))	('K14E6', 'Chemical', '-', (159, 164))	('mice', 'Species', '10090', (11, 15))	('K14CreERtm', 'Chemical', '-', (101, 111))	('mice', 'Species', '10090', (64, 68))	('K14', 'Gene', (159, 162))	('mice', 'Species', '10090', (175, 179))	('K14', 'Gene', '16664', (101, 104))	('K14', 'Gene', (127, 130))	('K14', 'Gene', (0, 3))
495955	30530704	We generated 7 different groups of mice with the following genotypes: Pik3caH1047R, Pik3caE545K, Pik3caH1047R:K14CreERtm, Pik3caE545K:K14CreERtm, K14E6/E7/Pik3caH1047R, K14E6/E7/Pik3caH1047R:K14CreERtm, and K14E6/E7/Pik3caE545K:K14CreERtm.	('K14CreERtm', 'Var', (110, 120))	('K14CreERtm', 'Var', (228, 238))	('K14E6', 'Chemical', '-', (146, 151))	('Pik3caE545K:K14CreERtm', 'Var', (122, 144))	('K14CreERtm', 'Chemical', '-', (191, 201))	('K14CreERtm', 'Chemical', '-', (134, 144))	('Pik3caH1047R', 'Var', (70, 82))	('K14E6/E7/Pik3caE545K:K14CreERtm', 'Var', (207, 238))	('H1047R', 'Mutation', 'rs121913279', (76, 82))	('K14CreERtm', 'Chemical', '-', (110, 120))	('K14E6/E7/Pik3caH1047R:K14CreERtm', 'Var', (169, 201))	('Pik3caE545K', 'Var', (84, 95))	('K14CreERtm', 'Chemical', '-', (228, 238))	('K14E6', 'Chemical', '-', (169, 174))	('H1047R', 'Mutation', 'rs121913279', (184, 190))	('mice', 'Species', '10090', (35, 39))	('E545K', 'Mutation', 'rs104886003', (90, 95))	('K14E6', 'Chemical', '-', (207, 212))	('H1047R', 'Mutation', 'rs121913279', (161, 167))	('H1047R', 'Mutation', 'rs121913279', (103, 109))	('K14CreERtm', 'Var', (191, 201))	('K14CreERtm', 'Var', (134, 144))	('K14E6/E7/Pik3caH1047R', 'Var', (146, 167))	('E545K', 'Mutation', 'rs104886003', (128, 133))	('E545K', 'Mutation', 'rs104886003', (222, 227))	('Pik3caH1047R:K14CreERtm', 'Var', (97, 120))
495956	30530704	To assess the tumorigenic contributions of expressing p110alphaH1047R or p110alphaE545K in combination with HPV16 E6/E7 oncoproteins, we modified our prior protocol in terms of timing and method of delivery of tamoxifen to induce Cre-recombination and the duration of administration with DMBA.	('DMBA', 'Chemical', 'MESH:D015127', (288, 292))	('tumor', 'Disease', (14, 19))	('HPV16', 'Species', '333760', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('tamoxifen', 'Chemical', 'MESH:D013629', (210, 219))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('p110alphaH1047R', 'Var', (54, 69))	('Cre-recombination', 'CPA', (230, 247))	('p110alphaE545K', 'Var', (73, 87))
495957	30530704	Using our original protocol with systemically induced expression of p110alphaH1047R, we observed not only the early onset of tumors (Figure 2A), but also morbidity issues (tumors arising in other epithelial tissues, edema) in Pik3caH1047R:K14CreERtm (data not shown).	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('p110alphaH1047R', 'Var', (68, 83))	('edema', 'Disease', (216, 221))	('tumors', 'Disease', (172, 178))	('tumors', 'Disease', 'MESH:D009369', (172, 178))	('tumors', 'Phenotype', 'HP:0002664', (172, 178))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('Pik3caH1047R:K14CreERtm', 'Var', (226, 249))	('tumors', 'Disease', (125, 131))	('tumors', 'Disease', 'MESH:D009369', (125, 131))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('edema', 'Disease', 'MESH:D004487', (216, 221))	('K14CreERtm', 'Chemical', '-', (239, 249))	('edema', 'Phenotype', 'HP:0000969', (216, 221))
495960	30530704	None of Pik3caH1047R or Pik3caE545K mice developed overt anal tumors reflective of the short duration of DMBA treatment (Figure 2B).	('DMBA', 'Chemical', 'MESH:D015127', (105, 109))	('Pik3caE545K', 'Var', (24, 35))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('anal tumors', 'Disease', (57, 68))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('mice', 'Species', '10090', (36, 40))	('anal tumors', 'Disease', 'MESH:D001005', (57, 68))	('Pik3caH1047R', 'Var', (8, 20))
495961	30530704	In the K14E6/E7/Pik3caH1047R group, 11 out of 17 mice (64.7%) had overt tumors and these tumors arose between 11.5 and 26 weeks after initial administration with DMBA.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumors', 'Disease', (89, 95))	('overt tumors', 'Disease', 'MESH:D009369', (66, 78))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('overt tumors', 'Disease', (66, 78))	('K14E6', 'Chemical', '-', (7, 12))	('tumors', 'Disease', (72, 78))	('K14E6/E7/Pik3caH1047R', 'Var', (7, 28))	('mice', 'Species', '10090', (49, 53))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('DMBA', 'Chemical', 'MESH:D015127', (162, 166))	('H1047R', 'Mutation', 'rs121913279', (22, 28))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))
495962	30530704	17 out of 21 Pik3caH1047R:K14CreERtm mice (80.8%) had overt anal tumors with onset of anal tumors between 7 and 20.5 weeks.	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('anal tumors', 'Disease', 'MESH:D001005', (60, 71))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('Pik3caH1047R:K14CreERtm', 'Var', (13, 36))	('anal tumors', 'Disease', (60, 71))	('anal tumors', 'Disease', 'MESH:D001005', (86, 97))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('anal tumors', 'Disease', (86, 97))	('K14CreERtm', 'Chemical', '-', (26, 36))	('mice', 'Species', '10090', (37, 41))
495963	30530704	The onset of overt tumors in Pik3caH1047R:K14CreERtm mice was significantly earlier compared with that observed in K14E6/E7/Pik3caH1047R mice (Figure 2B, logrank sum test P (one-sided)=0.0231), though the incidence of overt anal tumor was not significantly different between the two groups.	('K14CreERtm', 'Chemical', '-', (42, 52))	('tumor', 'Disease', 'MESH:D009369', (229, 234))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('mice', 'Species', '10090', (137, 141))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('K14E6', 'Chemical', '-', (115, 120))	('tumor', 'Disease', (229, 234))	('overt tumors', 'Disease', 'MESH:D009369', (13, 25))	('tumor', 'Disease', (19, 24))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('Pik3caH1047R:K14CreERtm', 'Var', (29, 52))	('mice', 'Species', '10090', (53, 57))	('overt tumors', 'Disease', (13, 25))
495965	30530704	These results further demonstrate the oncogenic potential of these activating mutations in Pik3ca contributes to anal carcinogenesis in the absence of HPV oncogenes, even when the duration of treatment with DMBA was reduced.	('carcinogenesis', 'Disease', (118, 132))	('Pik3ca', 'Gene', (91, 97))	('mutations', 'Var', (78, 87))	('activating', 'PosReg', (67, 77))	('DMBA', 'Chemical', 'MESH:D015127', (207, 211))	('carcinogenesis', 'Disease', 'MESH:D063646', (118, 132))	('oncogenic', 'CPA', (38, 47))	('HPV', 'Species', '10566', (151, 154))
495966	30530704	Interestingly, both K14E6/E7/Pik3caH1047R:K14CreERtm and K14E6/E7/Pik3caE545K:K14CreERtm mice developed overt tumors significantly earlier compared with that seen in Pik3caH1047R:K14CreERtm (Figure 2B, log rank sum test P(two-sided) = 5.83 x 10-6), Pik3caE545K:K14CreERtm (P(two-sided) = 5.42x10-6) mice or K14E6/E7/Pik3caH1047R mice (P (two-sided) = 6.21 x 10-7, 5.92 x 10-7, respectively).	('K14E6', 'Chemical', '-', (20, 25))	('mice', 'Species', '10090', (299, 303))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('K14CreERtm', 'Var', (78, 88))	('K14E6', 'Chemical', '-', (307, 312))	('H1047R', 'Mutation', 'rs121913279', (322, 328))	('overt tumors', 'Disease', (104, 116))	('H1047R', 'Mutation', 'rs121913279', (172, 178))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('K14E6/E7/Pik3caE545K', 'Var', (57, 77))	('K14CreERtm', 'Chemical', '-', (261, 271))	('K14CreERtm', 'Chemical', '-', (179, 189))	('K14E6', 'Chemical', '-', (57, 62))	('K14CreERtm', 'Chemical', '-', (78, 88))	('mice', 'Species', '10090', (329, 333))	('H1047R', 'Mutation', 'rs121913279', (35, 41))	('earlier', 'PosReg', (131, 138))	('K14E6/E7/Pik3caH1047R', 'Var', (307, 328))	('overt tumors', 'Disease', 'MESH:D009369', (104, 116))	('K14CreERtm', 'Chemical', '-', (42, 52))	('mice', 'Species', '10090', (89, 93))	('E545K', 'Mutation', 'rs104886003', (255, 260))	('E545K', 'Mutation', 'rs104886003', (72, 77))
495967	30530704	The overt tumors in the K14E6/E7/Pik3caH1047R:K14CreERtm group arose between 5.5 and 9.5 weeks with an average age of onset of 6.7 weeks after DMBA treatment began.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('DMBA', 'Chemical', 'MESH:D015127', (143, 147))	('tumors', 'Phenotype', 'HP:0002664', (10, 16))	('K14E6', 'Chemical', '-', (24, 29))	('K14E6/E7/Pik3caH1047R', 'Var', (24, 45))	('K14CreERtm', 'Chemical', '-', (46, 56))	('overt tumors', 'Disease', 'MESH:D009369', (4, 16))	('overt tumors', 'Disease', (4, 16))
495968	30530704	Similarly, K14E6/E7/Pik3caE545K:K14CreERtm mice developed overt tumors between 5.5 and 11 weeks with an average onset of 7.0 weeks after DMBA treatment began.	('mice', 'Species', '10090', (43, 47))	('E545K', 'Mutation', 'rs104886003', (26, 31))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('overt tumors', 'Disease', (58, 70))	('DMBA', 'Chemical', 'MESH:D015127', (137, 141))	('developed', 'PosReg', (48, 57))	('K14E6', 'Chemical', '-', (11, 16))	('K14E6/E7/Pik3caE545K', 'Var', (11, 31))	('K14CreERtm', 'Chemical', '-', (32, 42))	('overt tumors', 'Disease', 'MESH:D009369', (58, 70))
495969	30530704	These observations indicate that both activating mutations in Pik3ca strongly drive anal tumorigenesis in the presence of HPV16 E6/E7, and that they show synergistic effects with the viral oncogenes on anal tumorigenesis.	('drive', 'PosReg', (78, 83))	('mutations', 'Var', (49, 58))	('activating', 'PosReg', (38, 48))	('HPV16', 'Species', '333760', (122, 127))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('E6/E7', 'Var', (128, 133))	('Pik3ca', 'Gene', (62, 68))	('tumor', 'Disease', (207, 212))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
495971	30530704	Both Pik3caH1047R:K14CreERtm and K14E6/E7:Pik3caH1047R:K14CreERtm mice were administered DMBA to their anus for 5 weeks.	('K14CreERtm', 'Var', (55, 65))	('Pik3caH1047R:K14CreERtm', 'Var', (5, 28))	('H1047R', 'Mutation', 'rs121913279', (11, 17))	('H1047R', 'Mutation', 'rs121913279', (48, 54))	('K14CreERtm', 'Chemical', '-', (18, 28))	('K14E6/E7:Pik3caH1047R:K14CreERtm', 'Var', (33, 65))	('mice', 'Species', '10090', (66, 70))	('K14CreERtm', 'Chemical', '-', (55, 65))	('DMBA', 'Chemical', 'MESH:D015127', (89, 93))	('K14E6', 'Chemical', '-', (33, 38))
495973	30530704	All of K14E6/E7/Pik3caH1047R:K14CreERtm mice developed anal tumors prior to 24 weeks (Figure 2C); whereas only 4 out of 12 Pik3caH1047R:K14CreERtm mice (33.4%) developed overt anal tumors.	('mice', 'Species', '10090', (147, 151))	('anal tumors', 'Disease', (176, 187))	('tumors', 'Phenotype', 'HP:0002664', (181, 187))	('K14E6', 'Chemical', '-', (7, 12))	('K14E6/E7/Pik3caH1047R', 'Var', (7, 28))	('K14CreERtm', 'Chemical', '-', (29, 39))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('anal tumors', 'Disease', 'MESH:D001005', (55, 66))	('anal tumors', 'Disease', 'MESH:D001005', (176, 187))	('mice', 'Species', '10090', (40, 44))	('K14CreERtm', 'Chemical', '-', (136, 146))	('anal tumors', 'Disease', (55, 66))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))
495974	30530704	K14E6/E7/Pik3caH1047R:K14CreERtm mice developed anal tumors significantly earlier compared with K14E6/E7/Pik3caH1047R mice or Pik3caH1047R:K14CreERtm mice (Figure 2C, log rank sum test P (two-sided) = 0.045, 8.06 x 10-6, respectively).	('earlier', 'PosReg', (74, 81))	('mice', 'Species', '10090', (150, 154))	('K14E6', 'Chemical', '-', (0, 5))	('K14E6', 'Chemical', '-', (96, 101))	('K14E6/E7/Pik3caH1047R', 'Var', (0, 21))	('H1047R', 'Mutation', 'rs121913279', (111, 117))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('H1047R', 'Mutation', 'rs121913279', (132, 138))	('anal tumors', 'Disease', 'MESH:D001005', (48, 59))	('K14CreERtm', 'Chemical', '-', (22, 32))	('K14CreERtm', 'Chemical', '-', (139, 149))	('H1047R', 'Mutation', 'rs121913279', (15, 21))	('mice', 'Species', '10090', (33, 37))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('mice', 'Species', '10090', (118, 122))	('anal tumors', 'Disease', (48, 59))
495975	30530704	These observations indicate that an activating mutation in Pik3ca accelerates anal carcinogenesis in the presence of HPV16 oncogenes, even when onset of its expression is delayed.	('mutation', 'Var', (47, 55))	('carcinogenesis', 'Disease', 'MESH:D063646', (83, 97))	('accelerates', 'PosReg', (66, 77))	('HPV16', 'Species', '333760', (117, 122))	('carcinogenesis', 'Disease', (83, 97))	('activating', 'PosReg', (36, 46))	('Pik3ca', 'Gene', (59, 65))
495976	30530704	HPV16 E6/E7 mice do not develop anal cancers without administration of DMBA.	('E6/E7', 'Var', (6, 11))	('DMBA', 'Chemical', 'MESH:D015127', (71, 75))	('HPV16', 'Species', '333760', (0, 5))	('cancers', 'Phenotype', 'HP:0002664', (37, 44))	('anal cancer', 'Phenotype', 'HP:0032186', (32, 43))	('cancers', 'Disease', (37, 44))	('HPV16', 'Gene', (0, 5))	('cancers', 'Disease', 'MESH:D009369', (37, 44))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('mice', 'Species', '10090', (12, 16))
495977	30530704	We asked if an activating mutation in Pik3ca, in the context of expression of these HPV16 oncogenes, drives anal carcinogenesis without treatment with DMBA.	('carcinogenesis', 'Disease', 'MESH:D063646', (113, 127))	('mutation', 'Var', (26, 34))	('HPV16', 'Species', '333760', (84, 89))	('DMBA', 'Chemical', 'MESH:D015127', (151, 155))	('carcinogenesis', 'Disease', (113, 127))	('activating', 'PosReg', (15, 25))	('Pik3ca', 'Gene', (38, 44))	('drives', 'PosReg', (101, 107))
495978	30530704	Pik3caH1047R:K14CreERtm and K14E6/E7/Pik3caH1047R:K14CreERtm mice were treated topically with 4-OHT on the anus for 5 consecutive days, but not treated with DMBA.	('mice', 'Species', '10090', (61, 65))	('K14E6', 'Chemical', '-', (28, 33))	('K14E6/E7/Pik3caH1047R:K14CreERtm', 'Var', (28, 60))	('DMBA', 'Chemical', 'MESH:D015127', (157, 161))	('K14CreERtm', 'Var', (50, 60))	('K14CreERtm', 'Chemical', '-', (50, 60))	('4-OHT', 'Chemical', 'MESH:C032278', (94, 99))	('K14CreERtm', 'Chemical', '-', (13, 23))
495980	30530704	Strikingly, 5 out of 10 K14E6/E7/Pik3caH1047R:K14CreERtm mice developed overt anal tumors without DMBA treatment; whereas, none of the Pik3caH1047R:K14CreERtm mice developed tumors (Figure 2D).	('mice', 'Species', '10090', (57, 61))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('anal tumors', 'Disease', 'MESH:D001005', (78, 89))	('DMBA', 'Chemical', 'MESH:D015127', (98, 102))	('tumors', 'Disease', (174, 180))	('tumors', 'Disease', 'MESH:D009369', (174, 180))	('anal tumors', 'Disease', (78, 89))	('K14E6/E7/Pik3caH1047R:K14CreERtm', 'Var', (24, 56))	('tumors', 'Disease', (83, 89))	('K14E6', 'Chemical', '-', (24, 29))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('tumors', 'Disease', 'MESH:D009369', (83, 89))	('K14CreERtm', 'Chemical', '-', (148, 158))	('mice', 'Species', '10090', (159, 163))	('K14CreERtm', 'Chemical', '-', (46, 56))	('tumors', 'Phenotype', 'HP:0002664', (174, 180))
495981	30530704	As seen previously with K14E6/E7 mice, the K14E6/E7/Pik3caH1047R mice did not develop anal tumors in the absence of DMBA treatment.	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('K14E6/E7/Pik3caH1047R', 'Var', (43, 64))	('DMBA', 'Chemical', 'MESH:D015127', (116, 120))	('mice', 'Species', '10090', (65, 69))	('K14E6', 'Chemical', '-', (24, 29))	('anal tumors', 'Disease', 'MESH:D001005', (86, 97))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('mice', 'Species', '10090', (33, 37))	('anal tumors', 'Disease', (86, 97))	('K14E6', 'Chemical', '-', (43, 48))
495982	30530704	The onset of overt tumors in K14E6/E7/Pik3caH1047R:K14CreERtm mice was significantly different than that observed in Pik3caH1047R:K14CreERtm (Figure 2D, log rank sum test P (two-sided)=0.0056) or in K14E6/E7/Pik3caH1047R mice.	('K14E6/E7/Pik3caH1047R', 'Var', (29, 50))	('H1047R', 'Mutation', 'rs121913279', (123, 129))	('K14E6', 'Chemical', '-', (199, 204))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('K14CreERtm', 'Chemical', '-', (51, 61))	('mice', 'Species', '10090', (62, 66))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('mice', 'Species', '10090', (221, 225))	('H1047R', 'Mutation', 'rs121913279', (214, 220))	('overt tumors', 'Disease', 'MESH:D009369', (13, 25))	('K14E6', 'Chemical', '-', (29, 34))	('H1047R', 'Mutation', 'rs121913279', (44, 50))	('K14CreERtm', 'Chemical', '-', (130, 140))	('overt tumors', 'Disease', (13, 25))
495983	30530704	These observations indicate that expression of an activating mutant form of Pik3ca in the presence of HPV16 oncogenes is sufficient to drive anal tumorigenesis in mice.	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('HPV16', 'Species', '333760', (102, 107))	('tumor', 'Disease', (146, 151))	('mice', 'Species', '10090', (163, 167))	('mutant', 'Var', (61, 67))	('tumor', 'Disease', 'MESH:D009369', (146, 151))	('drive', 'PosReg', (135, 140))	('activating', 'PosReg', (50, 60))	('Pik3ca', 'Gene', (76, 82))
495984	30530704	To determine whether the mutant forms of Pik3ca cause an increased severity of neoplastic disease in the anal region, we performed detailed histopathological analysis of the tissue harvested from 4-OHT and DMBA-treated mice.	('mutant', 'Var', (25, 31))	('mice', 'Species', '10090', (219, 223))	('neoplastic disease', 'Disease', (79, 97))	('DMBA', 'Chemical', 'MESH:D015127', (206, 210))	('4-OHT', 'Chemical', 'MESH:C032278', (196, 201))	('neoplastic disease', 'Phenotype', 'HP:0002664', (79, 97))	('Pik3ca', 'Gene', (41, 47))	('neoplastic disease', 'Disease', 'MESH:D009386', (79, 97))
495986	30530704	None of Pik3caH1047R mice developed a malignant disease, but did develop low-grade dysplasia.	('mice', 'Species', '10090', (21, 25))	('H1047R', 'Mutation', 'rs121913279', (14, 20))	('malignant disease', 'Disease', (38, 55))	('malignant disease', 'Disease', 'None', (38, 55))	('dysplasia', 'Disease', 'MESH:D015792', (83, 92))	('dysplasia', 'Disease', (83, 92))	('Pik3caH1047R', 'Var', (8, 20))
495987	30530704	In contrast, 7 out of 17 K14E6/E7/Pik3caH1047R mice (41.1%) had malignant anal tumors.	('K14E6', 'Chemical', '-', (25, 30))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('K14E6/E7/Pik3caH1047R', 'Var', (25, 46))	('malignant anal tumors', 'Disease', (64, 85))	('malignant anal tumors', 'Disease', 'MESH:D009369', (64, 85))	('mice', 'Species', '10090', (47, 51))	('H1047R', 'Mutation', 'rs121913279', (40, 46))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
495990	30530704	The incidence of cancer and severity of disease were significantly greater than for the Pik3caH1047R mice, but were not significantly different from the K14E6/E7/Pik3caH1047R mice.	('mice', 'Species', '10090', (175, 179))	('H1047R', 'Mutation', 'rs121913279', (168, 174))	('Pik3caH1047R', 'Var', (88, 100))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('mice', 'Species', '10090', (101, 105))	('cancer', 'Disease', (17, 23))	('H1047R', 'Mutation', 'rs121913279', (94, 100))	('K14E6', 'Chemical', '-', (153, 158))	('greater', 'PosReg', (67, 74))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
495993	30530704	Consistent with the observation of overt tumors in Figure 2B, all K14E6/E7/Pik3caH1047R:K14CreERtm mice had anal cancers, with half developing poorly-differentiated invasive squamous cell carcinomas.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('overt tumors', 'Disease', (35, 47))	('cancers', 'Phenotype', 'HP:0002664', (113, 120))	('cancers', 'Disease', (113, 120))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (174, 197))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('K14E6/E7/Pik3caH1047R:K14CreERtm', 'Var', (66, 98))	('K14E6', 'Chemical', '-', (66, 71))	('overt tumors', 'Disease', 'MESH:D009369', (35, 47))	('invasive squamous cell carcinomas', 'Disease', (165, 198))	('mice', 'Species', '10090', (99, 103))	('K14CreERtm', 'Var', (88, 98))	('anal cancer', 'Phenotype', 'HP:0032186', (108, 119))	('cancers', 'Disease', 'MESH:D009369', (113, 120))	('poorly-differentiated', 'CPA', (143, 164))	('invasive squamous cell carcinomas', 'Disease', 'MESH:D002294', (165, 198))	('carcinoma', 'Phenotype', 'HP:0030731', (188, 197))	('carcinomas', 'Phenotype', 'HP:0030731', (188, 198))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (174, 198))	('K14CreERtm', 'Chemical', '-', (88, 98))
495994	30530704	Incidence of cancer and severity of disease in K14E6/E7/Pik3caH1047R:K14CreERtm mice were significantly greater than in the Pik3caH1047R:K14CreERtm and K14E6/E7/Pik3caH1047R mice.	('K14E6', 'Chemical', '-', (47, 52))	('K14CreERtm', 'Chemical', '-', (137, 147))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('K14E6/E7/Pik3caH1047R', 'Var', (47, 68))	('mice', 'Species', '10090', (174, 178))	('greater', 'PosReg', (104, 111))	('K14CreERtm', 'Chemical', '-', (69, 79))	('cancer', 'Disease', (13, 19))	('cancer', 'Disease', 'MESH:D009369', (13, 19))	('K14E6', 'Chemical', '-', (152, 157))	('mice', 'Species', '10090', (80, 84))
495995	30530704	Similarly, 12 out of 13 K14E6/E7/Pik3caE545K:K14CreERtm mice developed malignant tumors.	('malignant tumors', 'Disease', (71, 87))	('K14CreERtm', 'Chemical', '-', (45, 55))	('E545K', 'Mutation', 'rs104886003', (39, 44))	('malignant tumors', 'Disease', 'MESH:D009369', (71, 87))	('K14E6', 'Chemical', '-', (24, 29))	('mice', 'Species', '10090', (56, 60))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('developed', 'PosReg', (61, 70))	('K14E6/E7/Pik3caE545K', 'Var', (24, 44))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))
495996	30530704	These data indicate that activating mutations in Pik3ca and expression of HPV16 E6/E7 synergize to increase the severity of anal carcinogenesis.	('HPV16', 'Species', '333760', (74, 79))	('HPV16', 'Gene', (74, 79))	('carcinogenesis', 'Disease', 'MESH:D063646', (129, 143))	('activating', 'PosReg', (25, 35))	('mutations', 'Var', (36, 45))	('carcinogenesis', 'Disease', (129, 143))	('E6/E7', 'Var', (80, 85))	('Pik3ca', 'Gene', (49, 55))	('increase', 'PosReg', (99, 107))
495997	30530704	We observed anal cancers from five genotypes: Pik3caH1047R:K14CreERtm, Pik3caE545K:K14CreERtm, K14E6/E7/Pik3caH1047R, K14E6/E7/Pik3caH1047R:K14CreERtm and K14E6/E7/Pik3caE545K:K14CreERtm.	('Pik3caH1047R', 'Var', (46, 58))	('cancers', 'Phenotype', 'HP:0002664', (17, 24))	('K14CreERtm', 'Var', (140, 150))	('cancers', 'Disease', (17, 24))	('K14E6', 'Chemical', '-', (155, 160))	('E545K', 'Mutation', 'rs104886003', (77, 82))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))	('E545K', 'Mutation', 'rs104886003', (170, 175))	('K14CreERtm', 'Var', (176, 186))	('K14CreERtm', 'Var', (59, 69))	('K14CreERtm', 'Chemical', '-', (140, 150))	('K14CreERtm', 'Var', (83, 93))	('K14E6/E7/Pik3caH1047R', 'Var', (95, 116))	('anal cancer', 'Phenotype', 'HP:0032186', (12, 23))	('cancers', 'Disease', 'MESH:D009369', (17, 24))	('K14E6/E7/Pik3caE545K:K14CreERtm', 'Var', (155, 186))	('K14E6', 'Chemical', '-', (95, 100))	('K14CreERtm', 'Chemical', '-', (59, 69))	('K14CreERtm', 'Chemical', '-', (176, 186))	('K14CreERtm', 'Chemical', '-', (83, 93))	('K14E6/E7/Pik3caH1047R:K14CreERtm', 'Var', (118, 150))	('K14E6', 'Chemical', '-', (118, 123))
496002	30530704	As expected, p-S6 was robustly detected in the cytoplasm of anal cancer cells.	('detected', 'Reg', (31, 39))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('anal cancer', 'Phenotype', 'HP:0032186', (60, 71))	('cancer', 'Disease', (65, 71))	('p-S6', 'Var', (13, 17))
496003	30530704	Similarly, half of the tumors (2 of 4) in Pik3caE545K:K14CreERtm mice were verrucous carcinoma and all of these tumors developed from below the recto-anal junction but still within the anus.	('verrucous carcinoma', 'Disease', (75, 94))	('tumors', 'Disease', (23, 29))	('tumors', 'Disease', 'MESH:D009369', (23, 29))	('half of the tumors', 'Disease', (11, 29))	('K14CreERtm', 'Chemical', '-', (54, 64))	('mice', 'Species', '10090', (65, 69))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('half of the tumors', 'Disease', 'MESH:D009369', (11, 29))	('verrucous carcinoma', 'Disease', 'MESH:D018289', (75, 94))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))	('tumors', 'Disease', 'MESH:D009369', (112, 118))	('Pik3caE545K:K14CreERtm', 'Var', (42, 64))	('tumors', 'Disease', (112, 118))
496004	30530704	In contrast, 3 out of 7 K14E6/E7/Pik3caH1047R mice (42.9 %) were scored to have squamous cell carcinoma, with 4 out of 9 tumors (44.5%) arising at the anorectal junction or above the junction, where HPV-associated anal cancer in human patients is commonly found (Supplemental Figure S1).	('HPV', 'Species', '10566', (199, 202))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (80, 103))	('patients', 'Species', '9606', (235, 243))	('squamous cell carcinoma', 'Disease', (80, 103))	('tumors', 'Disease', (121, 127))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('K14E6', 'Chemical', '-', (24, 29))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (80, 103))	('anal cancer', 'Phenotype', 'HP:0032186', (214, 225))	('K14E6/E7/Pik3caH1047R', 'Var', (24, 45))	('cancer', 'Disease', 'MESH:D009369', (219, 225))	('tumors', 'Disease', 'MESH:D009369', (121, 127))	('mice', 'Species', '10090', (46, 50))	('human', 'Species', '9606', (229, 234))	('cancer', 'Disease', (219, 225))
496005	30530704	In K14E6/E7/Pik3caH1047R mice, the expression of MCM7 was highly upregulated in suprabasal layer cells as well as basal cells (Supplemental Figure S2, third panel).	('mice', 'Species', '10090', (25, 29))	('K14E6', 'Chemical', '-', (3, 8))	('expression', 'MPA', (35, 45))	('MCM7', 'Gene', (49, 53))	('K14E6/E7/Pik3caH1047R', 'Var', (3, 24))	('upregulated', 'PosReg', (65, 76))	('MCM7', 'Gene', '17220', (49, 53))
496006	30530704	Consistent with the observation in epithelium (Figure 1C), p-S6 was detected in the cytoplasm of cancer cells (Supplemental Figure S2, fourth panel).	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('cancer', 'Disease', 'MESH:D009369', (97, 103))	('cancer', 'Disease', (97, 103))	('p-S6', 'Var', (59, 63))
496007	30530704	The cancer phenotypes from K14E6/E7/Pik3caH1047R:K14CreERtm and K14E6/E7/Pik3caE545K:K14CreERtm mice were more similar to that observed in the K14E6/E7/Pik3caH1047R than in the Pik3caH1047R:K14CreERtm mice.	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('K14CreERtm', 'Chemical', '-', (49, 59))	('K14CreERtm', 'Chemical', '-', (190, 200))	('K14CreERtm', 'Var', (85, 95))	('K14E6/E7/Pik3caH1047R', 'Var', (143, 164))	('K14E6/E7/Pik3caH1047R:K14CreERtm', 'Var', (27, 59))	('K14E6', 'Chemical', '-', (27, 32))	('mice', 'Species', '10090', (201, 205))	('K14E6/E7/Pik3caE545K:K14CreERtm', 'Var', (64, 95))	('cancer', 'Disease', 'MESH:D009369', (4, 10))	('K14CreERtm', 'Chemical', '-', (85, 95))	('mice', 'Species', '10090', (96, 100))	('H1047R', 'Mutation', 'rs121913279', (42, 48))	('K14CreERtm', 'Var', (49, 59))	('E545K', 'Mutation', 'rs104886003', (79, 84))	('K14E6', 'Chemical', '-', (64, 69))	('K14E6', 'Chemical', '-', (143, 148))	('H1047R', 'Mutation', 'rs121913279', (183, 189))	('cancer', 'Disease', (4, 10))	('H1047R', 'Mutation', 'rs121913279', (158, 164))
496008	30530704	Unlike the anal cancers in Pik3caH1047R:K14CreERtm mice, 12 out of 14 K14E6/E7/Pik3caH1047R:K14CreERtm mice (85.7%) developed invasive squamous cell carcinoma, and about half of the cancers (18 out of 35, 51.4%) originated at the anorectal junction or above the junction (Supplemental Figure S1).	('half of the cancers', 'Disease', 'MESH:D009369', (170, 189))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (135, 158))	('invasive squamous cell carcinoma', 'Disease', 'MESH:D002294', (126, 158))	('K14CreERtm', 'Chemical', '-', (40, 50))	('cancers', 'Phenotype', 'HP:0002664', (16, 23))	('cancers', 'Disease', (16, 23))	('mice', 'Species', '10090', (51, 55))	('cancers', 'Phenotype', 'HP:0002664', (182, 189))	('cancers', 'Disease', (182, 189))	('K14CreERtm', 'Chemical', '-', (92, 102))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('invasive squamous cell carcinoma', 'Disease', (126, 158))	('developed', 'PosReg', (116, 125))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('carcinoma', 'Phenotype', 'HP:0030731', (149, 158))	('half of the cancers', 'Disease', (170, 189))	('anal cancer', 'Phenotype', 'HP:0032186', (11, 22))	('cancers', 'Disease', 'MESH:D009369', (16, 23))	('mice', 'Species', '10090', (103, 107))	('K14E6/E7/Pik3caH1047R:K14CreERtm', 'Var', (70, 102))	('K14E6', 'Chemical', '-', (70, 75))	('cancers', 'Disease', 'MESH:D009369', (182, 189))
496009	30530704	Similarly, 11 out of 12 K14E6/E7/Pik3caE545K:K14CreERtm mice (91.7.%) developed invasive squamous cell carcinoma and 5 out of 13 tumors were found at the anorectal junction (Supplemental Figure S1).	('tumors', 'Disease', (129, 135))	('tumors', 'Disease', 'MESH:D009369', (129, 135))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('invasive squamous cell carcinoma', 'Disease', (80, 112))	('K14CreERtm', 'Chemical', '-', (45, 55))	('developed', 'PosReg', (70, 79))	('K14E6', 'Chemical', '-', (24, 29))	('invasive squamous cell carcinoma', 'Disease', 'MESH:D002294', (80, 112))	('mice', 'Species', '10090', (56, 60))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (89, 112))	('K14E6/E7/Pik3caE545K:K14CreERtm', 'Var', (24, 55))	('E545K', 'Mutation', 'rs104886003', (39, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))
496010	30530704	HPV16 E6/E7 induce DNA synthesis in the suprabasal compartment of anal epithelium as well as the skin, cervix and lingual/esophageal epithelium.	('E6/E7', 'Var', (6, 11))	('DNA synthesis', 'MPA', (19, 32))	('HPV16', 'Species', '333760', (0, 5))	('HPV16', 'Gene', (0, 5))	('induce', 'Reg', (12, 18))
496011	30530704	To determine whether activating mutations in Pik3ca induce DNA synthesis in anal epithelium, we analyzed by immunohistochemistry the frequency of BrdU-positive basal and suprabasal cells in sections of tissue from mice injected with this nucleoside analog 1 hour before sacrifice.	('nucleoside', 'Chemical', 'MESH:D009705', (238, 248))	('activating', 'PosReg', (21, 31))	('mutations', 'Var', (32, 41))	('DNA synthesis', 'MPA', (59, 72))	('BrdU', 'Chemical', 'MESH:D001973', (146, 150))	('Pik3ca', 'Gene', (45, 51))	('mice', 'Species', '10090', (214, 218))
496012	30530704	In both 4-OHT-treated Pik3caH1047R:K14CreERtm mice and Pik3caE545K:K14CreERtm mice, the frequency of basal cells supporting DNA synthesis was significantly higher than in the control group (Pik3caH1047R:K14CreERtm vs Pik3caH1047R and Pik3caE545K:K14CreERtm mice vs Pik3caE545K, P = 0.02857 and P = 0.05714, respectively) or K14E6/E7/Pik3ca mutant mice (Pik3caH1047R:K14CreERtm or Pik3caE545K:K14CreERtm vs K14E6/E7/Pik3caH1047R, P=0.03 for both comparisons).	('4-OHT', 'Chemical', 'MESH:C032278', (8, 13))	('basal cells supporting DNA synthesis', 'MPA', (101, 137))	('higher', 'PosReg', (156, 162))	('mice', 'Species', '10090', (257, 261))	('K14CreERtm', 'Chemical', '-', (203, 213))	('K14CreERtm', 'Chemical', '-', (35, 45))	('K14CreERtm', 'Chemical', '-', (392, 402))	('mice', 'Species', '10090', (347, 351))	('K14CreERtm', 'Var', (366, 376))	('K14E6', 'Chemical', '-', (324, 329))	('mice', 'Species', '10090', (46, 50))	('K14E6', 'Chemical', '-', (406, 411))	('K14CreERtm', 'Chemical', '-', (67, 77))	('K14CreERtm', 'Chemical', '-', (246, 256))	('mice', 'Species', '10090', (78, 82))	('K14CreERtm', 'Chemical', '-', (366, 376))
496014	30530704	Suprabasal DNA synthesis in Pik3caH1047R:K14CreERtm mice as well as Pik3caE545K:K14CreERtm mice also was significantly increased compared to the control group (Pik3caH1047R and Pik3caE545K, P = 0.01972 and P = 0.05714, respectively).	('mice', 'Species', '10090', (91, 95))	('H1047R', 'Mutation', 'rs121913279', (34, 40))	('K14CreERtm', 'Chemical', '-', (41, 51))	('K14CreERtm', 'Chemical', '-', (80, 90))	('mice', 'Species', '10090', (52, 56))	('E545K', 'Mutation', 'rs104886003', (183, 188))	('Pik3caE545K:K14CreERtm', 'Var', (68, 90))	('H1047R', 'Mutation', 'rs121913279', (166, 172))	('Pik3caH1047R:K14CreERtm', 'Var', (28, 51))	('E545K', 'Mutation', 'rs104886003', (74, 79))	('increased', 'PosReg', (119, 128))	('Suprabasal DNA synthesis', 'MPA', (0, 24))
496015	30530704	However, this induction of suprabasal DNA synthesis was significantly lower than that observed in K14E6/E7/Pik3ca mutant mice (Pik3caH1047R:K14CreERtm vs K14E6/E7/Pik3caH1047R, Pik3caE545K:K14CreERtm vs K14E6/E7/Pik3caE545K, P=0.02857, respectively).	('K14E6', 'Chemical', '-', (154, 159))	('K14CreERtm', 'Chemical', '-', (189, 199))	('K14E6', 'Chemical', '-', (203, 208))	('lower', 'NegReg', (70, 75))	('K14CreERtm', 'Var', (140, 150))	('mice', 'Species', '10090', (121, 125))	('K14CreERtm', 'Var', (189, 199))	('suprabasal DNA synthesis', 'MPA', (27, 51))	('K14E6', 'Chemical', '-', (98, 103))	('K14CreERtm', 'Chemical', '-', (140, 150))
496017	30530704	After isolating primary mouse anal tumors from K14E6/E7, K14E6/E7/Pik3caH1047R:K14CreERtm, and K14E6/E7/Pik3caE545K:K14CreERtm mice, tumor cells were combined with Matrigel and plated in 24 well plates, allowing us to culture these tumors as spheroids (Figure.	('mouse', 'Species', '10090', (24, 29))	('K14CreERtm', 'Chemical', '-', (79, 89))	('K14E6/E7', 'Var', (47, 55))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumors', 'Disease', 'MESH:D009369', (35, 41))	('tumors', 'Disease', 'MESH:D009369', (232, 238))	('K14E6/E7/Pik3caH1047R', 'Var', (57, 78))	('K14E6/E7/Pik3caE545K', 'Var', (95, 115))	('tumor', 'Disease', (35, 40))	('anal tumors', 'Disease', (30, 41))	('tumor', 'Disease', (232, 237))	('K14CreERtm', 'Chemical', '-', (116, 126))	('K14E6', 'Chemical', '-', (57, 62))	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('anal tumors', 'Disease', 'MESH:D001005', (30, 41))	('tumor', 'Disease', 'MESH:D009369', (232, 237))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('tumor', 'Disease', (133, 138))	('tumors', 'Phenotype', 'HP:0002664', (232, 238))	('mice', 'Species', '10090', (127, 131))	('K14E6', 'Chemical', '-', (47, 52))	('K14E6', 'Chemical', '-', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('tumors', 'Disease', (35, 41))	('tumors', 'Disease', (232, 238))
496020	30530704	All tumor spheroids treated with TAK-228 showed a significant reduction in growth compared to the control group not treated with the drug.	('tumor', 'Disease', (4, 9))	('TAK-228', 'Chemical', 'MESH:C572449', (33, 40))	('growth', 'MPA', (75, 81))	('TAK-228', 'Var', (33, 40))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('reduction', 'NegReg', (62, 71))
496021	30530704	Interestingly, spheroids from the K14E6/E7 mice treated with TAK-228 also showed significantly reduced cell growth, consistent with our prior observations and those shown above (Figure 1, Supplemental Figure S2) that mTOR pathway is activated in anal tumors arising in K14E6/E7 mice.	('anal tumors', 'Disease', 'MESH:D001005', (246, 257))	('TAK-228', 'Chemical', 'MESH:C572449', (61, 68))	('mice', 'Species', '10090', (43, 47))	('anal tumors', 'Disease', (246, 257))	('cell growth', 'CPA', (103, 114))	('tumors', 'Phenotype', 'HP:0002664', (251, 257))	('K14E6', 'Chemical', '-', (34, 39))	('mTOR pathway', 'Pathway', (217, 229))	('mice', 'Species', '10090', (278, 282))	('activated', 'PosReg', (233, 242))	('K14E6/E7', 'Var', (34, 42))	('K14E6', 'Chemical', '-', (269, 274))	('reduced', 'NegReg', (95, 102))	('TAK-228', 'Var', (61, 68))	('K14E6/E7', 'Var', (269, 277))	('tumor', 'Phenotype', 'HP:0002664', (251, 256))
496022	30530704	However, TAK228 caused a greater reduction in the growth of cells expressing a mutant form of Pik3ca.	('Pik3ca', 'Gene', (94, 100))	('growth', 'MPA', (50, 56))	('reduction', 'NegReg', (33, 42))	('TAK228', 'Chemical', 'MESH:C572449', (9, 15))	('mutant', 'Var', (79, 85))	('TAK228', 'Var', (9, 15))
496025	30530704	These data confirmed that TAK-228 efficiently restricts the activation of both the TORC1 (phosphorylation of both S6 and 4-EBP1) and the TORC2 (phosphorylation of AKT) pathways.	('EBP1', 'Gene', '18033', (123, 127))	('TORC2', 'Gene', (137, 142))	('S6 and 4', 'Gene', '16898', (114, 122))	('TORC1', 'Gene', '382056', (83, 88))	('TORC1', 'Gene', (83, 88))	('EBP1', 'Gene', (123, 127))	('TAK-228', 'Var', (26, 33))	('restricts', 'NegReg', (46, 55))	('TAK-228', 'Chemical', 'MESH:C572449', (26, 33))	('TORC2', 'Gene', '74343', (137, 142))
496028	30530704	For this reason, tumor grafts from anal tumors arising in K14E6/E7/Pik3caE545K:K14CreERtm mice were first established in NSG mice and verified by histology to be squamous cell carcinomas.	('K14CreERtm', 'Chemical', '-', (79, 89))	('carcinomas', 'Phenotype', 'HP:0030731', (176, 186))	('mice', 'Species', '10090', (125, 129))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('K14E6', 'Chemical', '-', (58, 63))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (162, 186))	('tumor', 'Disease', (17, 22))	('mice', 'Species', '10090', (90, 94))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (162, 186))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('tumor', 'Disease', (40, 45))	('anal tumors', 'Disease', (35, 46))	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (162, 185))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('squamous cell carcinomas', 'Disease', (162, 186))	('anal tumors', 'Disease', 'MESH:D001005', (35, 46))	('K14E6/E7/Pik3caE545K:K14CreERtm', 'Var', (58, 89))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('carcinoma', 'Phenotype', 'HP:0030731', (176, 185))
496039	30530704	Using the TUNEL assay, we observed a large number of cells with fragmented DNA indicative of apoptosis in the TAK-228-treated tumor grafts, whereas such cells were rarely detected in the vehicle-treated tumor grafts (Supplemental Figure S3).	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('tumor', 'Disease', (203, 208))	('TAK-228-treated', 'Gene', (110, 125))	('TAK-228', 'Chemical', 'MESH:C572449', (110, 117))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('fragmented', 'Var', (64, 74))	('tumor', 'Disease', (126, 131))
496042	30530704	These observations indicate that TAK-228 might also induce differentiation/maturation of anal tumor cells.	('TAK-228', 'Chemical', 'MESH:C572449', (33, 40))	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('differentiation/maturation', 'CPA', (59, 85))	('induce', 'PosReg', (52, 58))	('tumor', 'Disease', (94, 99))	('TAK-228', 'Var', (33, 40))
496043	30530704	In this study, we demonstrate the oncogenic potential of Pik3ca mutations in driving anal carcinogenesis in the presence or absence of HPV16 oncogenes, and show that an investigational dual TORC1/2 inhibitor now in clinical trials is effective at inhibiting the growth of tumor spheroids in vitro and tumor grafts in vivo.	('tumor', 'Phenotype', 'HP:0002664', (272, 277))	('Pik3ca', 'Gene', (57, 63))	('tumor', 'Disease', (272, 277))	('tumor', 'Disease', 'MESH:D009369', (301, 306))	('inhibiting', 'NegReg', (247, 257))	('tumor', 'Phenotype', 'HP:0002664', (301, 306))	('tumor', 'Disease', 'MESH:D009369', (272, 277))	('mutations', 'Var', (64, 73))	('carcinogenesis', 'Disease', 'MESH:D063646', (90, 104))	('tumor', 'Disease', (301, 306))	('HPV16', 'Species', '333760', (135, 140))	('carcinogenesis', 'Disease', (90, 104))
496045	30530704	Activating mutations in Pik3ca arise in 20~25% of human anal cancers, and 40~55% of HPV-positive human head and neck cancers.	('Activating', 'PosReg', (0, 10))	('mutations', 'Var', (11, 20))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('anal cancer', 'Phenotype', 'HP:0032186', (56, 67))	('human', 'Species', '9606', (97, 102))	('cancers', 'Disease', 'MESH:D009369', (61, 68))	('cancers', 'Phenotype', 'HP:0002664', (61, 68))	('cancers', 'Disease', (61, 68))	('human', 'Species', '9606', (50, 55))	('Pik3ca', 'Gene', (24, 30))	('head and neck cancers', 'Disease', 'MESH:D006258', (103, 124))	('cancers', 'Phenotype', 'HP:0002664', (117, 124))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('HPV', 'Species', '10566', (84, 87))	('arise', 'Reg', (31, 36))	('cancers', 'Disease', 'MESH:D009369', (117, 124))	('head and neck cancers', 'Phenotype', 'HP:0012288', (103, 124))	('cancers', 'Disease', (117, 124))
496046	30530704	The most frequent mutations are found in exon 9 (E542K, E545K) and are consistent with the hypothesis that HPV16 drives APOBEC ("apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like")-mediated mutagenesis by cytosine deamination.	('E542K', 'Var', (49, 54))	('APOBEC', 'Gene', (120, 126))	('E542K', 'Mutation', 'rs121913273', (49, 54))	('E545K', 'Mutation', 'rs104886003', (56, 61))	('catalytic polypeptide-like', 'MPA', (167, 193))	('E545K', 'Var', (56, 61))	('HPV16', 'Species', '333760', (107, 112))
496047	30530704	Cytidine deaminase activity of APOBEC family members is argued to cause oncogenic mutations in many types of cancers.	('cancers', 'Disease', 'MESH:D009369', (109, 116))	('cancers', 'Phenotype', 'HP:0002664', (109, 116))	('Cytidine deaminase', 'Gene', '72269', (0, 18))	('cancers', 'Disease', (109, 116))	('mutations', 'Var', (82, 91))	('APOBEC', 'Gene', (31, 37))	('cause', 'Reg', (66, 71))	('Cytidine deaminase', 'Gene', (0, 18))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))
496051	30530704	Thus HPV may drive the accumulation of certain activating mutations in Pik3ca through activation of APOBECs.	('mutations', 'Var', (58, 67))	('Pik3ca', 'Gene', (71, 77))	('APOBECs', 'Protein', (100, 107))	('HPV', 'Species', '10566', (5, 8))	('activation', 'PosReg', (86, 96))	('activating', 'PosReg', (47, 57))
496052	30530704	The Pik3caH1047R mutation is more oncogenic than the Pik3caE545K mutation in anal carcinogenesis in the absence of HPV oncogenes (Figure 2B and Table 1), as seen previously in a mouse mammary cancer model.	('oncogenic', 'CPA', (34, 43))	('mouse', 'Species', '10090', (178, 183))	('carcinogenesis', 'Disease', 'MESH:D063646', (82, 96))	('H1047R', 'Mutation', 'rs121913279', (10, 16))	('carcinogenesis', 'Disease', (82, 96))	('anal', 'Disease', (77, 81))	('cancer', 'Disease', (192, 198))	('cancer', 'Disease', 'MESH:D009369', (192, 198))	('HPV', 'Species', '10566', (115, 118))	('Pik3caH1047R', 'Var', (4, 16))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))
496054	30530704	This together with the fact that HPV drives APOBEC activity may explain why H1047R mutations are less common in HPV-positive human cancers.	('cancers', 'Disease', 'MESH:D009369', (131, 138))	('cancers', 'Phenotype', 'HP:0002664', (131, 138))	('cancers', 'Disease', (131, 138))	('H1047R', 'Mutation', 'rs121913279', (76, 82))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('human', 'Species', '9606', (125, 130))	('HPV', 'Species', '10566', (33, 36))	('HPV', 'Species', '10566', (112, 115))	('H1047R', 'Var', (76, 82))
496057	30530704	Our data clearly indicate that such mutations help drive anal carcinogenesis even in the presence of HPV16 oncogenes.	('mutations', 'Var', (36, 45))	('carcinogenesis', 'Disease', 'MESH:D063646', (62, 76))	('HPV16', 'Species', '333760', (101, 106))	('drive', 'PosReg', (51, 56))	('carcinogenesis', 'Disease', (62, 76))	('HPV16', 'Gene', (101, 106))
496058	30530704	The PI3K-AKT-mTOR signaling pathway was clearly enhanced when both an activating mutation in Pik3ca and HPV16 oncogenes were expressed (Figure 1) providing insight into why such activating mutations in Pik3ca contribute to HPV-associated anal cancers.	('anal cancer', 'Phenotype', 'HP:0032186', (238, 249))	('Pik3ca', 'Gene', (93, 99))	('HPV', 'Species', '10566', (104, 107))	('cancers', 'Phenotype', 'HP:0002664', (243, 250))	('activating', 'PosReg', (178, 188))	('HPV', 'Species', '10566', (223, 226))	('mutation', 'Var', (81, 89))	('enhanced', 'PosReg', (48, 56))	('cancers', 'Disease', 'MESH:D009369', (243, 250))	('Pik3ca', 'Gene', (202, 208))	('cancers', 'Disease', (243, 250))	('PI3K-AKT-mTOR signaling pathway', 'Pathway', (4, 35))	('HPV16', 'Species', '333760', (104, 109))	('cancer', 'Phenotype', 'HP:0002664', (243, 249))
496060	30530704	Disruption of the interaction of p110alpha with oncogenic Ras causes a defect in AKT activation and reduced transformation efficiency by H-Ras In this study, we observed that early onset expression of an activating mutant form of p110alpha together with HPV16 oncogenes drove anal carcinogenesis even in the absence of DMBA, a carcinogen known to drive initiation of carcinogenesis (Fig.	('AKT', 'Pathway', (81, 84))	('drove', 'PosReg', (270, 275))	('p110alpha', 'Gene', '18706', (230, 239))	('carcinogenesis', 'Disease', 'MESH:D063646', (281, 295))	('initiation of carcinogenesis', 'Disease', (353, 381))	('carcinogenesis', 'Disease', 'MESH:D063646', (367, 381))	('carcinogenesis', 'Disease', (281, 295))	('p110alpha', 'Gene', (33, 42))	('DMBA', 'Chemical', 'MESH:D015127', (319, 323))	('HPV16', 'Species', '333760', (254, 259))	('activating', 'PosReg', (204, 214))	('carcinogenesis', 'Disease', (367, 381))	('p110alpha', 'Gene', (230, 239))	('initiation of carcinogenesis', 'Disease', 'MESH:D063646', (353, 381))	('p110alpha', 'Gene', '18706', (33, 42))	('Disruption', 'Var', (0, 10))
496061	30530704	This leads us to hypothesize that activating mutations in Pik3ca contribute to the initiation phase of carcinogenesis, with HPV16 oncogenes contributing to the promotion phase, as we have clearly demonstrated previously.	('mutations', 'Var', (45, 54))	('activating', 'PosReg', (34, 44))	('carcinogenesis', 'Disease', 'MESH:D063646', (103, 117))	('Pik3ca', 'Gene', (58, 64))	('HPV16', 'Species', '333760', (124, 129))	('carcinogenesis', 'Disease', (103, 117))	('contribute', 'Reg', (65, 75))
496062	30530704	Consistent with this concept, activating mutations in Pik3ca have been shown to promote tumor initiation in breast and lung carcinogenesis and drive rapid onset of colon cancers.	('cancers', 'Phenotype', 'HP:0002664', (170, 177))	('colon cancers', 'Phenotype', 'HP:0003003', (164, 177))	('colon cancers', 'Disease', 'MESH:D015179', (164, 177))	('Pik3ca', 'Gene', (54, 60))	('activating mutations', 'Var', (30, 50))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor initiation in breast and lung carcinogenesis', 'Disease', 'MESH:D061325', (88, 138))	('colon cancers', 'Disease', (164, 177))	('promote', 'PosReg', (80, 87))
496063	30530704	Even when an activating mutation in Pik3ca is expressed late in the context of expression of HPV oncogenes, it led to rapid onset of anal carcinogenesis (Figure 2C), which is further evidence that such mutations are strong drivers of anal carcinogenesis regardless of when they arise.	('led to', 'Reg', (111, 117))	('carcinogenesis', 'Disease', 'MESH:D063646', (239, 253))	('activating', 'PosReg', (13, 23))	('Pik3ca', 'Gene', (36, 42))	('carcinogenesis', 'Disease', (239, 253))	('HPV', 'Species', '10566', (93, 96))	('mutation', 'Var', (24, 32))	('carcinogenesis', 'Disease', 'MESH:D063646', (138, 152))	('carcinogenesis', 'Disease', (138, 152))
496067	30530704	Human anal cancers are etiologically associated with human papillomaviruses (HPVs) however a large fraction contains mutations that activate the PI3K/AKT/mTOR signaling pathway.	('Human', 'Species', '9606', (0, 5))	('mutations', 'Var', (117, 126))	('human papillomavirus', 'Species', '10566', (53, 73))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('PI3K/AKT/mTOR signaling pathway', 'Pathway', (145, 176))	('activate', 'PosReg', (132, 140))	('HPV', 'Species', '10566', (77, 80))	('cancers', 'Phenotype', 'HP:0002664', (11, 18))	('cancers', 'Disease', (11, 18))	('cancers', 'Disease', 'MESH:D009369', (11, 18))	('anal cancer', 'Phenotype', 'HP:0032186', (6, 17))
496069	30530704	Herein we investigate the role in anal cancer of common, activating mutations in Pik3ca, which encodes the catalytic subunit of PI3K, using a mouse model for anal carcinogenesis.	('carcinogenesis', 'Disease', (163, 177))	('cancer', 'Disease', (39, 45))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('Pik3ca', 'Gene', (81, 87))	('mouse', 'Species', '10090', (142, 147))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('carcinogenesis', 'Disease', 'MESH:D063646', (163, 177))	('anal cancer', 'Phenotype', 'HP:0032186', (34, 45))	('mutations', 'Var', (68, 77))	('activating', 'PosReg', (57, 67))
496070	30530704	We find that these mutations make mice susceptible to anal cancers by themselves, and synergize with HPV16 oncogenes, E6 and E7, to drive rapid onset and highest severity of anal neoplastic disease.	('mice', 'Species', '10090', (34, 38))	('anal neoplastic disease', 'Disease', 'MESH:D001005', (174, 197))	('anal neoplastic disease', 'Phenotype', 'HP:0032186', (174, 197))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('mutations', 'Var', (19, 28))	('anal cancer', 'Phenotype', 'HP:0032186', (54, 65))	('neoplastic disease', 'Phenotype', 'HP:0002664', (179, 197))	('cancers', 'Disease', 'MESH:D009369', (59, 66))	('cancers', 'Phenotype', 'HP:0002664', (59, 66))	('HPV16', 'Species', '333760', (101, 106))	('cancers', 'Disease', (59, 66))	('anal neoplastic disease', 'Disease', (174, 197))
496081	30683132	Furthermore, deleting the PR domain from PRDM16 increased the transcriptional repression of MUC4 by exhibiting significant differences in histone modifications on its promoter.	('PRDM16', 'Gene', (41, 47))	('increased', 'PosReg', (48, 57))	('deleting', 'Var', (13, 21))	('differences', 'Reg', (123, 134))	('MUC4', 'Gene', '4585', (92, 96))	('histone modifications on', 'MPA', (138, 162))	('transcriptional repression', 'MPA', (62, 88))	('MUC4', 'Gene', (92, 96))
496082	30683132	Our findings demonstrate a critical interplay between transcriptional and epigenetic modifications during lung adenocarcinoma progression involving EMT of cancer cells and suggest that PRDM16 is a metastasis suppressor and potential therapeutic target for lung adenocarcinomas.	('epigenetic modifications', 'Var', (74, 98))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (106, 125))	('PRDM16', 'Gene', (185, 191))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (256, 275))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('carcinoma', 'Phenotype', 'HP:0030731', (266, 275))	('lung adenocarcinomas', 'Disease', (256, 276))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (106, 125))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (256, 275))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (256, 276))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (256, 276))	('carcinomas', 'Phenotype', 'HP:0030731', (266, 276))	('cancer', 'Disease', (155, 161))	('lung adenocarcinoma', 'Disease', (106, 125))	('cancer', 'Disease', 'MESH:D009369', (155, 161))
496099	30683132	In addition, deleting the PR domain increased the transcriptional repression of MUC4 by reducing enrichment of H3K9me1 and acetylation of histone 3 at lysine (H3K9ac) on its promoter.	('MUC4', 'Gene', '4585', (80, 84))	('deleting', 'Var', (13, 21))	('transcriptional repression', 'MPA', (50, 76))	('H3K9me1', 'Protein', (111, 118))	('acetylation', 'MPA', (123, 134))	('increased', 'PosReg', (36, 45))	('MUC4', 'Gene', (80, 84))	('lysine', 'Chemical', 'MESH:D008239', (151, 157))	('enrichment', 'MPA', (97, 107))	('reducing', 'NegReg', (88, 96))
496102	30683132	pCMV6-Myc-DDK (#PS100001) and pCMV6-Myc-DDK-PRDM16 (#RC214026) were from Origene (Rockville, MD, USA).	('Myc', 'Gene', '4609', (6, 9))	('Myc-DDK-PRDM16', 'Gene', '63976', (36, 50))	('Myc', 'Gene', (6, 9))	('#RC214026', 'Var', (52, 61))	('Myc-DDK-PRDM16', 'Gene', (36, 50))	('#PS100001', 'Var', (15, 24))	('Myc', 'Gene', '4609', (36, 39))	('Myc', 'Gene', (36, 39))
496103	30683132	PRDM16 deletion mutants were subcloned from pCMV6-Myc-DDK-PRDM16.	('Myc-DDK-PRDM16', 'Gene', '63976', (50, 64))	('PRDM16', 'Gene', (0, 6))	('deletion mutants', 'Var', (7, 23))	('Myc-DDK-PRDM16', 'Gene', (50, 64))
496126	30683132	Antibodies used were: Myc-tag (#2276, Cell Signaling Technology), PRDM16 (#ABE543, Millipore), H3K9me1 (#14186, Cell Signaling Technology), H3K9me2 (#4658, Cell Signaling Technology), H3K9me3 (#13969, Cell Signaling Technology), H3K9ac (#9649, Cell Signaling Technology).	('H3K9ac', 'Var', (229, 235))	('H3K9me2', 'Var', (140, 147))	('Myc', 'Gene', '4609', (22, 25))	('Myc', 'Gene', (22, 25))	('H3K9me3', 'Var', (184, 191))
496137	30683132	2a) or knocked down its expression in H1299 and Calu-1 cells (Fig.	('expression', 'MPA', (24, 34))	('knocked', 'Var', (7, 14))	('Calu-1', 'CellLine', 'CVCL:0608', (48, 54))	('H1299', 'CellLine', 'CVCL:0060', (38, 43))
496139	30683132	We found that PRDM16 overexpression inhibited and PRDM16 knockdown promoted the EMT progression of lung adenocarcinoma cells by regulating the expression of epithelial and mesenchymal markers (Fig.	('promoted', 'PosReg', (67, 75))	('inhibited', 'NegReg', (36, 45))	('expression', 'MPA', (143, 153))	('PRDM16', 'Gene', (14, 20))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (99, 118))	('knockdown', 'Var', (57, 66))	('EMT progression of', 'CPA', (80, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('lung adenocarcinoma', 'Disease', (99, 118))	('PRDM16', 'Gene', (50, 56))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (99, 118))	('regulating', 'Reg', (128, 138))
496149	30683132	Additionally, immunohistochemistry staining of E-cadherin, N-cadherin, Snail and Slug indicated a lower EMT status in cancer cells overexpressing PRDM16 compared to that in the control group, whereas the Ki67 staining was similar between the two groups (Fig.	('cancer', 'Disease', (118, 124))	('Snail', 'Gene', (71, 76))	('Snail', 'Gene', '6615', (71, 76))	('lower EMT', 'Phenotype', 'HP:0032198', (98, 107))	('E-cadherin', 'Gene', (47, 57))	('Slug', 'Gene', (81, 85))	('Ki67', 'Gene', (204, 208))	('EMT status', 'CPA', (104, 114))	('Slug', 'Gene', '6591', (81, 85))	('N-cadherin', 'Gene', (59, 69))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('E-cadherin', 'Gene', '999', (47, 57))	('Ki67', 'Gene', '17345', (204, 208))	('PRDM16', 'Var', (146, 152))	('N-cadherin', 'Gene', '1000', (59, 69))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('lower', 'NegReg', (98, 103))
496156	30683132	In addition, high MUC4 expression was associated with poor prognosis of lung adenocarcinoma patients (Fig.	('MUC4', 'Gene', '4585', (18, 22))	('lung adenocarcinoma', 'Disease', (72, 91))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (72, 91))	('high', 'Var', (13, 17))	('MUC4', 'Gene', (18, 22))	('patients', 'Species', '9606', (92, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (72, 91))	('expression', 'MPA', (23, 33))
496158	30683132	To validate this, we knocked down PRDM16 or overexpressed PRDM16 in a dose-dependent manner in H1299 and Calu-1 cells.	('PRDM16', 'Gene', (58, 64))	('knocked', 'Var', (21, 28))	('H1299', 'CellLine', 'CVCL:0060', (95, 100))	('Calu-1', 'CellLine', 'CVCL:0608', (105, 111))	('overexpressed', 'PosReg', (44, 57))	('PRDM16', 'Gene', (34, 40))
496159	30683132	As compared with the control group, MUC4 expression was upregulated by PRDM16 knockdown, and downregulated by PRDM16 overexpression in a dose-dependent manner (Fig.	('expression', 'MPA', (41, 51))	('MUC4', 'Gene', '4585', (36, 40))	('knockdown', 'Var', (78, 87))	('PRDM16', 'Gene', (71, 77))	('MUC4', 'Gene', (36, 40))	('downregulated', 'NegReg', (93, 106))	('upregulated', 'PosReg', (56, 67))
496161	30683132	Then, we knocked down or overexpressed MUC4 in H1299 and Calu-1.	('knocked', 'Var', (9, 16))	('overexpressed', 'PosReg', (25, 38))	('MUC4', 'Gene', '4585', (39, 43))	('H1299', 'CellLine', 'CVCL:0060', (47, 52))	('Calu-1', 'CellLine', 'CVCL:0608', (57, 63))	('MUC4', 'Gene', (39, 43))
496164	30683132	As expected, the suppression of E-cadherin and increased expression of N-cadherin, Snail and Slug induced by elevated MUC4 expression were restored by ectopic expression of PRDM16 (Fig.	('expression', 'MPA', (57, 67))	('E-cadherin', 'Gene', (32, 42))	('expression', 'MPA', (123, 133))	('elevated', 'PosReg', (109, 117))	('N-cadherin', 'Gene', '1000', (71, 81))	('E-cadherin', 'Gene', '999', (32, 42))	('Slug', 'Gene', '6591', (93, 97))	('MUC4', 'Gene', '4585', (118, 122))	('PRDM16', 'Gene', (173, 179))	('increased', 'PosReg', (47, 56))	('Snail', 'Gene', (83, 88))	('Snail', 'Gene', '6615', (83, 88))	('Slug', 'Gene', (93, 97))	('MUC4', 'Gene', (118, 122))	('suppression', 'NegReg', (17, 28))	('N-cadherin', 'Gene', (71, 81))	('ectopic expression', 'Var', (151, 169))
496167	30683132	The results indicated that PRDM16 bound to two regions of MUC4 promoter, Region 1 (- 2500 bp - -2189 bp) and Region 4 (- 1743 bp - -1442 bp) (Fig.	('PRDM16', 'Gene', (27, 33))	('MUC4', 'Gene', '4585', (58, 62))	('bound', 'Interaction', (34, 39))	('MUC4', 'Gene', (58, 62))	('- 1743 bp', 'Var', (119, 128))	('- 2500 bp', 'Var', (83, 92))
496168	30683132	To determine the domain(s) of PRDM16 that are responsible for transcriptional repression, we constructed a series of deletion mutants of PRDM16 and transfected full-length (wild-type, WT) and mutant PRDM16 plasmids into H1299 cells, and conducted luciferase reporter assays.	('H1299', 'CellLine', 'CVCL:0060', (220, 225))	('mutant', 'Var', (192, 198))	('mutants', 'Var', (126, 133))	('deletion mutants', 'Var', (117, 133))	('PRDM16', 'Gene', (137, 143))
496169	30683132	These mutants represent deletions of PR domain (DeltaPRD), DNA-binding domain 1 (DeltaDBD1), the proline-rich region (DeltaPRR), the C-terminal-binding protein (CtBP)-interacting domain (DeltaCID) and DNA-binding domain 2 (DeltaDBD2) (Fig.	('proline', 'Chemical', 'MESH:D011392', (97, 104))	('CID', 'Disease', (192, 195))	('CID', 'Disease', 'None', (192, 195))	('deletions', 'Var', (24, 33))
496170	30683132	Transcriptional repression was clearly reduced with PRDM16-DeltaCID and PRDM16-DeltaDBD2.	('PRDM16-DeltaDBD2', 'Var', (72, 88))	('Transcriptional repression', 'MPA', (0, 26))	('CID', 'Disease', (64, 67))	('CID', 'Disease', 'None', (64, 67))	('reduced', 'NegReg', (39, 46))
496172	30683132	To determine whether the increased transcriptional repression of MUC4 by PRDM16-DeltaPRD is associated with histone modifications, we overexpressed PRDM16-WT and PRDM16-DeltaPRD in H1299 cells.	('transcriptional', 'MPA', (35, 50))	('increased', 'PosReg', (25, 34))	('MUC4', 'Gene', (65, 69))	('PRDM16-DeltaPRD', 'Var', (73, 88))	('H1299', 'CellLine', 'CVCL:0060', (181, 186))	('MUC4', 'Gene', '4585', (65, 69))
496173	30683132	Compared with PRDM16-WT overexpressing cells, the expression of H3K9me1 and H3K9ac was reduced and di-methylation of histone 3 at lysine (H3K9me2) expression was increased in PRDM16-DeltaPRD overexpressing cells, whereas tri-methylation of histone 3 at lysine (H3K9me3) expression did not changed in this context (Fig.	('PRDM16-DeltaPRD', 'Var', (175, 190))	('increased', 'PosReg', (162, 171))	('expression', 'MPA', (147, 157))	('di-methylation', 'MPA', (99, 113))	('reduced', 'NegReg', (87, 94))	('lysine', 'Chemical', 'MESH:D008239', (130, 136))	('H3K9ac', 'Gene', (76, 82))	('lysine', 'Chemical', 'MESH:D008239', (253, 259))	('expression', 'MPA', (50, 60))
496174	30683132	As histone modifications are demonstrated to play an important role in transcriptional regulation, we further examined the enrichment of H3K9me1, H3K9me2, H3K9me3, and H3K9ac on the MUC4 promoter.	('H3K9me1', 'Var', (137, 144))	('MUC4', 'Gene', (182, 186))	('H3K9ac', 'Var', (168, 174))	('H3K9me3', 'Var', (155, 162))	('H3K9me2', 'Var', (146, 153))	('MUC4', 'Gene', '4585', (182, 186))
496175	30683132	Consistent with the pan-cellular western blot analysis, high PRDM16-DeltaPRD overexpression significantly reduced H3K9me1 and H3K9ac enrichment, and had little effect on H3K9me3 enrichment on the MUC4 promoter compared to that in PRDM16-WT overexpressing cells.	('PRDM16-DeltaPRD', 'Var', (61, 76))	('MUC4', 'Gene', (196, 200))	('high PRDM16-DeltaPRD', 'Var', (56, 76))	('H3K9ac', 'Protein', (126, 132))	('H3K9me1', 'Protein', (114, 121))	('MUC4', 'Gene', '4585', (196, 200))	('reduced', 'NegReg', (106, 113))
496176	30683132	However, we did not detect a significant difference in H3K9me2 enrichment on the MUC4 promoter between PRDM16-DeltaPRD and PRDM16-WT overexpressing cells (Fig.	('MUC4', 'Gene', (81, 85))	('PRDM16-DeltaPRD', 'Var', (103, 118))	('MUC4', 'Gene', '4585', (81, 85))
496177	30683132	As both H3K9me1 and H3K9ac tend to correlate with active promoters, these data may indicate that PRDM16-DeltaPRD increases transcriptional repression by reducing H3K9me1 and H3K9ac enrichment on MUC4 promoter.	('MUC4', 'Gene', (195, 199))	('H3K9me1', 'Protein', (162, 169))	('H3K9ac', 'Protein', (174, 180))	('PRDM16-DeltaPRD', 'Var', (97, 112))	('transcriptional repression', 'MPA', (123, 149))	('MUC4', 'Gene', '4585', (195, 199))	('reducing', 'NegReg', (153, 161))	('increases', 'PosReg', (113, 122))
496179	30683132	found that PR-lacking PRDM16, but not full-length PRDM16, repressed transforming growth factor beta (TGF beta)-mediated growth inhibition in adult T cell leukemia cells.	('leukemia', 'Phenotype', 'HP:0001909', (154, 162))	('leukemia', 'Disease', 'MESH:D007938', (154, 162))	('TGF beta', 'Gene', (101, 109))	('PR-lacking', 'Var', (11, 21))	('leukemia', 'Disease', (154, 162))	('transforming growth factor beta', 'Gene', (68, 99))	('growth inhibition', 'CPA', (120, 137))	('TGF beta', 'Gene', '7040', (101, 109))	('PRDM16', 'Gene', (22, 28))	('T cell leukemia', 'Phenotype', 'HP:0005517', (147, 162))	('transforming growth factor beta', 'Gene', '7040', (68, 99))
496182	30683132	Overexpression of full-length PRDM16 or PRDM16-DeltaPRD can suppress the transcription of MUC4 which is demonstrated to promote EMT in lung adenocarcinomas, suggesting full-length and PR-lacking PRDM16 exert similar effects on the metastatic ability of cancer cell in lung adenocarcinomas.	('carcinoma', 'Phenotype', 'HP:0030731', (145, 154))	('carcinomas', 'Phenotype', 'HP:0030731', (145, 155))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (135, 155))	('cancer', 'Disease', 'MESH:D009369', (253, 259))	('carcinoma', 'Phenotype', 'HP:0030731', (278, 287))	('PRDM16-DeltaPRD', 'Var', (40, 55))	('carcinomas', 'Phenotype', 'HP:0030731', (278, 288))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (268, 288))	('promote', 'PosReg', (120, 127))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (135, 155))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (268, 287))	('MUC4', 'Gene', '4585', (90, 94))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (268, 288))	('lung adenocarcinomas', 'Disease', (135, 155))	('MUC4', 'Gene', (90, 94))	('cancer', 'Disease', (253, 259))	('cancer', 'Phenotype', 'HP:0002664', (253, 259))	('lung adenocarcinomas', 'Disease', (268, 288))	('EMT', 'CPA', (128, 131))	('transcription', 'MPA', (73, 86))	('suppress', 'NegReg', (60, 68))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (135, 154))
496188	30683132	has reported that MUC4 plays a tumor-suppressor role in lung cancers, and high MUC4 expression was associated with a better overall survival in analysis of 29 patients with survival data.	('overall survival', 'MPA', (124, 140))	('MUC4', 'Gene', '4585', (18, 22))	('lung cancers', 'Phenotype', 'HP:0100526', (56, 68))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('lung cancer', 'Phenotype', 'HP:0100526', (56, 67))	('high', 'Var', (74, 78))	('lung cancers', 'Disease', (56, 68))	('MUC4', 'Gene', (79, 83))	('MUC4', 'Gene', (18, 22))	('tumor', 'Disease', (31, 36))	('cancers', 'Phenotype', 'HP:0002664', (61, 68))	('better', 'PosReg', (117, 123))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('expression', 'MPA', (84, 94))	('lung cancers', 'Disease', 'MESH:D008175', (56, 68))	('patients', 'Species', '9606', (159, 167))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('MUC4', 'Gene', '4585', (79, 83))
496190	30683132	reported that high MUC4 expression correlates with a poor survival rate in a cohort of 185 lung adenocarcinomas patients.	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (91, 110))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('expression', 'MPA', (24, 34))	('lung adenocarcinomas', 'Disease', (91, 111))	('poor', 'NegReg', (53, 57))	('patients', 'Species', '9606', (112, 120))	('MUC4', 'Gene', '4585', (19, 23))	('carcinomas', 'Phenotype', 'HP:0030731', (101, 111))	('high', 'Var', (14, 18))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (91, 111))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (91, 111))	('MUC4', 'Gene', (19, 23))	('survival', 'MPA', (58, 66))
496191	30683132	found that high MUC4 expression is significantly associated with vascular invasion in 338 lung adenocarcinomas, and patients with MUC4-positive tumors had worse prognoses.	('tumors', 'Disease', (144, 150))	('MUC4', 'Gene', (16, 20))	('tumors', 'Disease', 'MESH:D009369', (144, 150))	('patients', 'Species', '9606', (116, 124))	('associated with', 'Reg', (49, 64))	('MUC4', 'Gene', '4585', (130, 134))	('MUC4', 'Gene', (130, 134))	('vascular invasion', 'CPA', (65, 82))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (90, 110))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (90, 109))	('tumors', 'Phenotype', 'HP:0002664', (144, 150))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (90, 110))	('carcinomas', 'Phenotype', 'HP:0030731', (100, 110))	('expression', 'MPA', (21, 31))	('MUC4', 'Gene', '4585', (16, 20))	('high', 'Var', (11, 15))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('lung adenocarcinomas', 'Disease', (90, 110))
496193	30683132	But only lung adenocarcinoma patients with high MUC4 expression had shorter overall survival (Fig.	('patients', 'Species', '9606', (29, 37))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (9, 28))	('overall survival', 'MPA', (76, 92))	('high', 'Var', (43, 47))	('MUC4', 'Gene', (48, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (19, 28))	('lung adenocarcinoma', 'Disease', (9, 28))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (9, 28))	('MUC4', 'Gene', '4585', (48, 52))	('shorter', 'NegReg', (68, 75))
496199	30683132	reported that the transcriptional repressor activity of PR-lacking PRDM16 is mainly mediated by sumoylation and its interaction with CtBP through the CID, which contributes to the development of leukemia.	('mediated', 'Reg', (84, 92))	('leukemia', 'Phenotype', 'HP:0001909', (195, 203))	('leukemia', 'Disease', 'MESH:D007938', (195, 203))	('contributes', 'Reg', (161, 172))	('leukemia', 'Disease', (195, 203))	('CID', 'Disease', (150, 153))	('PR-lacking', 'Var', (56, 66))	('PRDM16', 'Gene', (67, 73))	('CID', 'Disease', 'None', (150, 153))	('sumoylation', 'MPA', (96, 107))	('transcriptional repressor activity', 'MPA', (18, 52))	('interaction', 'Interaction', (116, 127))
496203	30683132	In addition, we found that PRDM16-DeltaPRD increased the repression of MUC4 compared with full-length PRDM16 by reducing H3K9me1 and H3K9ac enrichment on the MUC4 promoter.	('reducing', 'NegReg', (112, 120))	('MUC4', 'Gene', (158, 162))	('H3K9ac', 'Protein', (133, 139))	('H3K9me1', 'Protein', (121, 128))	('PRDM16-DeltaPRD', 'Var', (27, 42))	('repression', 'MPA', (57, 67))	('MUC4', 'Gene', '4585', (71, 75))	('increased', 'PosReg', (43, 52))	('MUC4', 'Gene', '4585', (158, 162))	('MUC4', 'Gene', (71, 75))
496204	30683132	It is well known that aberrant epigenetic signatures are associated with abnormal developmental processes and diseases such as cancer.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('abnormal developmental processes', 'CPA', (73, 105))	('aberrant epigenetic signatures', 'Var', (22, 52))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('cancer', 'Disease', (127, 133))	('associated', 'Reg', (57, 67))
496206	30683132	Histone methylation, especially on the lysine residues in the N-terminal of histone 3, can either activate or repress gene transcription, depending on the site of lysine and the number of methyl groups.	('lysine', 'Chemical', 'MESH:D008239', (163, 169))	('Histone', 'Protein', (0, 7))	('repress', 'NegReg', (110, 117))	('lysine', 'Chemical', 'MESH:D008239', (39, 45))	('gene transcription', 'MPA', (118, 136))	('methylation', 'Var', (8, 19))	('activate', 'PosReg', (98, 106))
496207	30683132	Here, we found that the levels of H3K9me1/2/3 and H3K9ac in total cellular lysates and on MUC4 promoter were changed significantly in PRDM16-WT overexpressing cells compared with EV cells (Fig.	('H3K9me1/2/3', 'Var', (34, 45))	('MUC4', 'Gene', '4585', (90, 94))	('PRDM16-WT', 'Gene', (134, 143))	('MUC4', 'Gene', (90, 94))	('changed', 'Reg', (109, 116))	('EV', 'Chemical', '-', (179, 181))	('H3K9ac', 'Var', (50, 56))
496209	30683132	What we can make sure is that MUC4 transcription was significantly repressed in PRDM16 overexpressing cells compared with EV cells.	('MUC4', 'Gene', (30, 34))	('PRDM16', 'Gene', (80, 86))	('repressed', 'PosReg', (67, 76))	('EV', 'Chemical', '-', (122, 124))	('transcription', 'MPA', (35, 48))	('MUC4', 'Gene', '4585', (30, 34))	('overexpressing', 'Var', (87, 101))
496253	26739660	So, the low incidence rates of small intestine metastases are notable, and several associated mechanisms have been raised as follows: (1) the intestine has abundant immune protection with numerous lymphoid cells and large secretions of IgA in the mucosa and submucosa of the intestine; (2) a rapid refresh rate of small intestinal mucosa may inhibit the tumorigenesis; (3) liquefied chyme may cause less mucosal irritation, then reduces mechanical injury and inflammation.	('injury', 'Disease', 'MESH:D058186', (448, 454))	('tumor', 'Disease', 'MESH:D009369', (354, 359))	('mucosal irritation', 'Disease', (404, 422))	('liquefied', 'Var', (373, 382))	('numerous lymphoid', 'Disease', 'MESH:D008223', (188, 205))	('reduces', 'NegReg', (429, 436))	('tumor', 'Phenotype', 'HP:0002664', (354, 359))	('inflammation', 'Disease', 'MESH:D007249', (459, 471))	('inflammation', 'Disease', (459, 471))	('metastases', 'Disease', (47, 57))	('numerous lymphoid', 'Disease', (188, 205))	('inhibit', 'NegReg', (342, 349))	('tumor', 'Disease', (354, 359))	('mucosal irritation', 'Disease', 'MESH:D052016', (404, 422))	('metastases', 'Disease', 'MESH:D009362', (47, 57))	('injury', 'Disease', (448, 454))
496275	26317791	Depending on the type of malignancy, IKKalpha can provide both tumor-promoting and tumor-suppressive mechanisms that are in most instances cell autonomous.	('IKKalpha', 'Var', (37, 45))	('tumor', 'Disease', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('malignancy', 'Disease', 'MESH:D009369', (25, 35))	('tumor', 'Disease', (83, 88))	('malignancy', 'Disease', (25, 35))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
496276	26317791	Inhibition of IKKalpha prolongs survival and suppresses occurrence of metastatic diseases in models of mammary, prostate cancer and colorectal cancer.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('metastatic', 'CPA', (70, 80))	('prostate cancer', 'Phenotype', 'HP:0012125', (112, 127))	('colorectal cancer', 'Disease', 'MESH:D015179', (132, 149))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('prostate cancer', 'Disease', 'MESH:D011471', (112, 127))	('colorectal cancer', 'Phenotype', 'HP:0003003', (132, 149))	('prostate cancer', 'Disease', (112, 127))	('prolongs', 'PosReg', (23, 31))	('mammary', 'Disease', (103, 110))	('Inhibition', 'Var', (0, 10))	('colorectal cancer', 'Disease', (132, 149))	('suppresses', 'NegReg', (45, 55))	('survival', 'CPA', (32, 40))	('IKKalpha', 'Protein', (14, 22))
496279	26317791	In contrast, IKKalpha acts as a tumor suppressor in models of skin or lung squamous cell carcinoma (SCC), loss of IKKalpha enhances susceptibility to carcinogen-induced SCC in the skin and leads to the development of spontaneous lung SCC in mice.	('SCC', 'Gene', (100, 103))	('skin or lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (62, 98))	('SCC', 'Gene', '6317', (234, 237))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('SCC', 'Gene', '6317', (169, 172))	('SCC', 'Gene', (234, 237))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (70, 98))	('spontaneous', 'CPA', (217, 228))	('SCC', 'Gene', (169, 172))	('leads to', 'Reg', (189, 197))	('mice', 'Species', '10090', (241, 245))	('susceptibility', 'MPA', (132, 146))	('skin or lung squamous cell carcinoma', 'Disease', (62, 98))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (75, 98))	('tumor', 'Disease', (32, 37))	('loss', 'Var', (106, 110))	('enhances', 'PosReg', (123, 131))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('SCC', 'Gene', '6317', (100, 103))	('spontaneous lung SCC', 'Phenotype', 'HP:0002108', (217, 237))	('IKKalpha', 'Gene', (114, 122))
496280	26317791	Importantly, during development of lung SCC, IKKalpha kinase inactivation culminates in the recruitment of tumor-promoting inflammatory macrophages and depletion of macrophages prevents SCC formation.	('inactivation', 'Var', (61, 73))	('SCC', 'Gene', '6317', (186, 189))	('SCC', 'Gene', '6317', (40, 43))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('recruitment', 'MPA', (92, 103))	('SCC', 'Gene', (186, 189))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('IKKalpha', 'Gene', (45, 53))	('SCC', 'Gene', (40, 43))
496282	26317791	However, it is possible that spontaneous lung SCC initiated by inactivation of IKKalpha belongs to keratinizing carcinoma according to the results.	('inactivation', 'Var', (63, 75))	('carcinoma', 'Disease', (112, 121))	('carcinoma', 'Disease', 'MESH:D002277', (112, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('SCC', 'Gene', (46, 49))	('spontaneous lung SCC', 'Phenotype', 'HP:0002108', (29, 49))	('IKKalpha', 'Gene', (79, 87))	('SCC', 'Gene', '6317', (46, 49))
496318	26317791	The somatic conditional depletion of IKKalpha using keratin 5 or keratin 14 promoters leads to tumor progression.	('IKKalpha', 'Gene', (37, 45))	('keratin 14', 'Gene', '3861', (65, 75))	('keratin 14', 'Gene', (65, 75))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('conditional depletion', 'Var', (12, 33))	('leads to', 'Reg', (86, 94))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumor', 'Disease', (95, 100))
496339	25466476	Overexpression of S100A4 was significantly associated with the clinical stage, lymph node involvement, metastases, pattern of invasion and recurrence (p<0.05).	('metastases', 'Disease', 'MESH:D009362', (103, 113))	('clinical stage', 'CPA', (63, 77))	('Overexpression', 'Var', (0, 14))	('lymph node involvement', 'CPA', (79, 101))	('associated', 'Reg', (43, 53))	('S100A4', 'Gene', (18, 24))	('pattern of invasion', 'CPA', (115, 134))	('metastases', 'Disease', (103, 113))	('S100A4', 'Gene', '6275', (18, 24))
496439	25307233	Recently, accumulating evidence has shown that long non-coding RNAs (lncRNAs) may play critical roles in multiple cancers and may provide new insights into the molecular basis underlying the cancer subtypes.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('cancers', 'Disease', 'MESH:D009369', (114, 121))	('cancers', 'Phenotype', 'HP:0002664', (114, 121))	('cancer', 'Disease', (191, 197))	('cancer', 'Disease', 'MESH:D009369', (191, 197))	('cancers', 'Disease', (114, 121))	('play', 'Reg', (82, 86))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('long non-coding RNAs', 'Var', (47, 67))	('roles', 'Reg', (96, 101))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('cancer', 'Disease', (114, 120))
496446	25307233	The dysregulated lncRNAs in cancers suggest they are key components in biological network and may participate in tumorigenesis and metastasis.	('cancers', 'Disease', (28, 35))	('tumor', 'Disease', (113, 118))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('cancers', 'Disease', 'MESH:D009369', (28, 35))	('lncRNAs', 'Protein', (17, 24))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('cancers', 'Phenotype', 'HP:0002664', (28, 35))	('participate', 'Reg', (98, 109))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('dysregulated', 'Var', (4, 16))
496464	25307233	DSCAM is a member of the immunoglobulin superfamily of cell adhesion molecules, whose polymorphisms could influence overall survival in treatment of advanced NSCLC patients.	('NSCLC', 'Disease', (158, 163))	('NSCLC', 'Disease', 'MESH:D002289', (158, 163))	('influence', 'Reg', (106, 115))	('patients', 'Species', '9606', (164, 172))	('overall survival', 'MPA', (116, 132))	('NSCLC', 'Phenotype', 'HP:0030358', (158, 163))	('DSCAM', 'Gene', '1826', (0, 5))	('polymorphisms', 'Var', (86, 99))	('DSCAM', 'Gene', (0, 5))
496465	25307233	These differentially expressed antisense lncRNAs (such as NKX2-1-AS1 and DSCAM-AS1) might interact together with their host genes to fulfill functions in different subtypes of lung cancer.	('lung cancer', 'Phenotype', 'HP:0100526', (176, 187))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('lung cancer', 'Disease', 'MESH:D008175', (176, 187))	('DSCAM-AS1', 'Gene', (73, 82))	('NKX2-1-AS1', 'Gene', '100506237', (58, 68))	('DSCAM-AS1', 'Gene', '100506492', (73, 82))	('NKX2-1-AS1', 'Gene', (58, 68))	('lung cancer', 'Disease', (176, 187))	('interact', 'Reg', (90, 98))	('antisense', 'Var', (31, 40))
496500	25307233	Nevertheless, although amplification of TTF1 gene locus portends a remarkable event in lung adenocarcinoma, the mechanism accounting for their association remains unknown.	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('lung adenocarcinoma', 'Disease', (87, 106))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (87, 106))	('TTF1', 'Gene', (40, 44))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (87, 106))	('amplification', 'Var', (23, 36))	('TTF1', 'Gene', '7270', (40, 44))
496502	25307233	The amplification of 14q13.3 could influence the expression of both TTF1 and NKX2-1-AS1 gene, and the dysregulation of the sense-antisense pair could be an initiative event in the development of lung adenocarcinoma.	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (195, 214))	('TTF1', 'Gene', '7270', (68, 72))	('NKX2-1-AS1', 'Gene', '100506237', (77, 87))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (195, 214))	('expression', 'MPA', (49, 59))	('carcinoma', 'Phenotype', 'HP:0030731', (205, 214))	('NKX2-1-AS1', 'Gene', (77, 87))	('amplification', 'Var', (4, 17))	('lung adenocarcinoma', 'Disease', (195, 214))	('influence', 'Reg', (35, 44))	('TTF1', 'Gene', (68, 72))
496505	25307233	As we known, dysfunction of genes in cell junction, a form of cell adhesions structure, can lead to tumorigenesis, tumor development and metastasis.	('dysfunction', 'Var', (13, 24))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumor', 'Disease', (100, 105))	('lead to', 'Reg', (92, 99))	('tumor', 'Disease', (115, 120))	('metastasis', 'CPA', (137, 147))	('genes', 'Gene', (28, 33))	('cell junction', 'Protein', (37, 50))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (115, 120))
496516	25307233	Furthermore, previous study suggested that the variation in TERT (telomerase reverse transcriptase), a protein-coding gene that has important role in regulating telomerase and protect telomeres, is associated with ER negative breast cancer.	('associated with', 'Reg', (198, 213))	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('telomerase reverse transcriptase', 'Gene', (66, 98))	('breast cancer', 'Disease', (226, 239))	('TERT', 'Gene', '7015', (60, 64))	('breast cancer', 'Phenotype', 'HP:0003002', (226, 239))	('telomerase reverse transcriptase', 'Gene', '7015', (66, 98))	('breast cancer', 'Disease', 'MESH:D001943', (226, 239))	('variation', 'Var', (47, 56))	('TERT', 'Gene', (60, 64))
496519	25307233	The microarray data of 150 lung cancer and 306 breast cancer samples used in this study were obtained from the Gene Expression Omnibus (GEO) database and can be directly downloaded from the website (accession number: GSE43580 for lung cancer and GSE6532 for breast cancer).	('breast cancer', 'Disease', (47, 60))	('breast cancer', 'Phenotype', 'HP:0003002', (47, 60))	('breast cancer', 'Disease', 'MESH:D001943', (258, 271))	('lung cancer', 'Disease', (230, 241))	('lung cancer', 'Disease', (27, 38))	('lung cancer', 'Phenotype', 'HP:0100526', (230, 241))	('lung cancer', 'Phenotype', 'HP:0100526', (27, 38))	('cancer', 'Phenotype', 'HP:0002664', (265, 271))	('breast cancer', 'Disease', (258, 271))	('lung cancer', 'Disease', 'MESH:D008175', (230, 241))	('breast cancer', 'Phenotype', 'HP:0003002', (258, 271))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))	('GSE6532', 'Var', (246, 253))	('lung cancer', 'Disease', 'MESH:D008175', (27, 38))	('breast cancer', 'Disease', 'MESH:D001943', (47, 60))
496529	33787082	In addition, we demonstrated that miR-375 overexpression inhibited the luciferase activity of LUCAT1 wild-type and knockdown LUCAT1 promoted the miR-375 expression in TSCC cell.	('LUCAT1', 'Gene', (94, 100))	('miR-375', 'Gene', (145, 152))	('miR-375', 'Gene', (34, 41))	('LUCAT1', 'Gene', '100505994', (94, 100))	('luciferase', 'Enzyme', (71, 81))	('inhibited', 'NegReg', (57, 66))	('TSCC', 'Phenotype', 'HP:0030413', (167, 171))	('miR-375', 'Gene', '494324', (34, 41))	('activity', 'MPA', (82, 90))	('overexpression', 'PosReg', (42, 56))	('expression', 'MPA', (153, 163))	('miR-375', 'Gene', '494324', (145, 152))	('LUCAT1', 'Gene', '100505994', (125, 131))	('promoted', 'PosReg', (132, 140))	('LUCAT1', 'Gene', (125, 131))	('knockdown', 'Var', (115, 124))
496537	33787082	29 ,  30 ,  31 ,  32 ,  33  For example, Sun et al 33  indicated that LUCAT1 expression was overexpressed in lung tumour tissues and LUCAT1 knockdown suppressed the cell growth in vivo and in vitro.	('suppressed', 'NegReg', (150, 160))	('lung tumour', 'Phenotype', 'HP:0100526', (109, 120))	('tumour', 'Phenotype', 'HP:0002664', (114, 120))	('LUCAT1', 'Gene', '100505994', (133, 139))	('LUCAT1', 'Gene', (133, 139))	('lung tumour', 'Disease', (109, 120))	('lung tumour', 'Disease', 'MESH:D008175', (109, 120))	('knockdown', 'Var', (140, 149))	('LUCAT1', 'Gene', '100505994', (70, 76))	('cell growth', 'CPA', (165, 176))	('LUCAT1', 'Gene', (70, 76))
496564	33787082	Moreover, inhibition expression of LUCAT1 decreased the S phases in the SCC1 cell (Figure 2C).	('LUCAT1', 'Gene', (35, 41))	('S phases in the', 'CPA', (56, 71))	('SCC1', 'Gene', (72, 76))	('decreased', 'NegReg', (42, 51))	('SCC1', 'Gene', '5885', (72, 76))	('inhibition expression', 'Var', (10, 31))	('LUCAT1', 'Gene', '100505994', (35, 41))
496565	33787082	Wound scratch assay revealed that LUCAT1 silencing decreased the SCC1 cell migration (Figure 2D).	('SCC1', 'Gene', (65, 69))	('silencing', 'Var', (41, 50))	('decreased', 'NegReg', (51, 60))	('LUCAT1', 'Gene', '100505994', (34, 40))	('LUCAT1', 'Gene', (34, 40))	('SCC1', 'Gene', '5885', (65, 69))
496570	33787082	Furthermore, LUCAT1 silencing promoted the miR-375 expression in the SCC1 cell (Figure 3D).	('SCC1', 'Gene', (69, 73))	('miR-375', 'Gene', '494324', (43, 50))	('SCC1', 'Gene', '5885', (69, 73))	('promoted', 'PosReg', (30, 38))	('LUCAT1', 'Gene', '100505994', (13, 19))	('LUCAT1', 'Gene', (13, 19))	('expression', 'MPA', (51, 61))	('miR-375', 'Gene', (43, 50))	('silencing', 'Var', (20, 29))
496580	33787082	Wound scratch assay revealed that miR-375 silencing promoted the SCC1 cell migration (Figure 5D and E).	('silencing', 'Var', (42, 51))	('SCC1', 'Gene', (65, 69))	('miR-375', 'Gene', (34, 41))	('SCC1', 'Gene', '5885', (65, 69))	('miR-375', 'Gene', '494324', (34, 41))	('promoted', 'PosReg', (52, 60))
496582	33787082	As shown in Figure 6A, MTT assay indicated that LUCAT1 silencing suppressed SCC1 cells growth, whereas miR-375 silencing partially rescued the reduction of growth.	('miR-375', 'Gene', '494324', (103, 110))	('MTT', 'Chemical', 'MESH:C070243', (23, 26))	('SCC1', 'Gene', (76, 80))	('miR-375', 'Gene', (103, 110))	('silencing', 'Var', (55, 64))	('suppressed', 'NegReg', (65, 75))	('LUCAT1', 'Gene', '100505994', (48, 54))	('SCC1', 'Gene', '5885', (76, 80))	('LUCAT1', 'Gene', (48, 54))
496583	33787082	Moreover, knockdown expression of miR-375 partially reversed the cell cycle suppression of LUCAT1 knockdown (Figure 6B).	('miR-375', 'Gene', (34, 41))	('cell cycle suppression', 'CPA', (65, 87))	('knockdown', 'Var', (98, 107))	('LUCAT1', 'Gene', '100505994', (91, 97))	('LUCAT1', 'Gene', (91, 97))	('miR-375', 'Gene', '494324', (34, 41))
496584	33787082	Furthermore, wound scratch assay revealed that LUCAT1 silencing suppressed SCC1 cell migration, whereas miR-375 knockdown partially rescued the reduction of cell migration (Figure 6C and D).	('miR-375', 'Gene', (104, 111))	('cell migration', 'CPA', (157, 171))	('SCC1', 'Gene', '5885', (75, 79))	('silencing', 'Var', (54, 63))	('suppressed', 'NegReg', (64, 74))	('LUCAT1', 'Gene', '100505994', (47, 53))	('LUCAT1', 'Gene', (47, 53))	('SCC1', 'Gene', (75, 79))	('miR-375', 'Gene', '494324', (104, 111))
496587	33787082	11 ,  36 ,  37  Dysregulated expression of lncRNAs was found in a lot of human cancers using RNA sequencing and was correlated with tumour progression, survival and tumorigenesis in TSCC.	('cancers', 'Disease', (79, 86))	('TSCC', 'Phenotype', 'HP:0030413', (182, 186))	('tumour', 'Disease', (132, 138))	('Dysregulated', 'Var', (16, 28))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('correlated with', 'Reg', (116, 131))	('tumorigenesis', 'CPA', (165, 178))	('human', 'Species', '9606', (73, 78))	('survival', 'CPA', (152, 160))	('lncRNAs', 'Gene', (43, 50))	('tumour', 'Phenotype', 'HP:0002664', (132, 138))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('tumour', 'Disease', 'MESH:D009369', (132, 138))	('expression', 'MPA', (29, 39))	('cancers', 'Disease', 'MESH:D009369', (79, 86))
496592	33787082	LUCAT1 knockdown decreased the glioma cell invasion and proliferation partly through regulating the miR-375 expression.	('decreased', 'NegReg', (17, 26))	('miR-375', 'Gene', (100, 107))	('regulating', 'Reg', (85, 95))	('glioma', 'Disease', 'MESH:D005910', (31, 37))	('glioma', 'Phenotype', 'HP:0009733', (31, 37))	('LUCAT1', 'Gene', '100505994', (0, 6))	('expression', 'MPA', (108, 118))	('miR-375', 'Gene', '494324', (100, 107))	('knockdown', 'Var', (7, 16))	('LUCAT1', 'Gene', (0, 6))	('glioma', 'Disease', (31, 37))
496593	33787082	Han et al 31  showed that LUCAT1 expression was overexpressed in the methotrexate (MTX)-resistant cells and knockdown expression of LUCAT1 suppressed the osteosarcoma cell proliferation, tumour growth and invasion and some drug resistance-correlated genes (MRP5, MDR1LRP1) partly through sponging miR-200c expression.	('osteosarcoma', 'Phenotype', 'HP:0002669', (154, 166))	('LUCAT1', 'Gene', '100505994', (26, 32))	('LUCAT1', 'Gene', (26, 32))	('tumour', 'Phenotype', 'HP:0002664', (187, 193))	('tumour', 'Disease', 'MESH:D009369', (187, 193))	('tumour', 'Disease', (187, 193))	('methotrexate', 'Chemical', 'MESH:D008727', (69, 81))	('miR-200c', 'Gene', '406985', (297, 305))	('MTX', 'Chemical', 'MESH:D008727', (83, 86))	('MDR1LRP1', 'Gene', (263, 271))	('osteosarcoma', 'Disease', (154, 166))	('drug resistance', 'Phenotype', 'HP:0020174', (223, 238))	('miR-200c', 'Gene', (297, 305))	('osteosarcoma', 'Disease', 'MESH:D012516', (154, 166))	('sponging', 'Reg', (288, 296))	('suppressed', 'NegReg', (139, 149))	('invasion', 'CPA', (205, 213))	('LUCAT1', 'Gene', '100505994', (132, 138))	('knockdown expression', 'Var', (108, 128))	('LUCAT1', 'Gene', (132, 138))	('MRP5', 'Gene', '10057', (257, 261))	('MRP5', 'Gene', (257, 261))	('expression', 'MPA', (306, 316))
496605	33787082	Moreover, ectopic expression of miR-375 suppressed the LUCAT1 expression and LUCAT1 silencing promoted the miR-375 expression in the SCC1 cell.	('LUCAT1', 'Gene', (55, 61))	('miR-375', 'Gene', '494324', (32, 39))	('suppressed', 'NegReg', (40, 50))	('LUCAT1', 'Gene', '100505994', (55, 61))	('miR-375', 'Gene', (107, 114))	('expression', 'MPA', (62, 72))	('LUCAT1', 'Gene', (77, 83))	('silencing', 'Var', (84, 93))	('miR-375', 'Gene', (32, 39))	('LUCAT1', 'Gene', '100505994', (77, 83))	('expression', 'MPA', (115, 125))	('SCC1', 'Gene', (133, 137))	('miR-375', 'Gene', '494324', (107, 114))	('promoted', 'PosReg', (94, 102))	('SCC1', 'Gene', '5885', (133, 137))
496618	33194579	The analysis regarding let-7 family, specifically let-7a/b/e/f, revealed that downregulated expression of these transcripts predicts poor outcome for NSCLC patients [HR = 2.61, 95% CI = (1.58, 4.30), p < 0.001].	('patients', 'Species', '9606', (156, 164))	('NSCLC', 'Disease', 'MESH:D002289', (150, 155))	('let-7a/b/e/f', 'Var', (50, 62))	('NSCLC', 'Phenotype', 'HP:0030358', (150, 155))	('NSCLC', 'Disease', (150, 155))	('expression', 'MPA', (92, 102))	('downregulated', 'NegReg', (78, 91))
496622	33194579	The explanation would be that, independent to exogenous carcinogens, lung tumorigenesis is driven by genetic dysregulations of coding and non-codingRNAs.	('driven by', 'Reg', (91, 100))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('dysregulations', 'Var', (109, 123))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor', 'Disease', (74, 79))
496625	33194579	Mutations in epidermal growth factor receptor (EGFR), or other recombinant DNA processes in anaplastic lymphoma kinase (ALK) or c-ros oncogene 1 (ROS1) represent the main alterations that occur in patients diagnosed with NSCLC.	('patients', 'Species', '9606', (197, 205))	('anaplastic lymphoma kinase', 'Gene', (92, 118))	('NSCLC', 'Disease', (221, 226))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (92, 111))	('ROS1', 'Gene', '6098', (146, 150))	('EGFR', 'Gene', '1956', (47, 51))	('NSCLC', 'Phenotype', 'HP:0030358', (221, 226))	('epidermal growth factor receptor', 'Gene', (13, 45))	('epidermal growth factor receptor', 'Gene', '1956', (13, 45))	('Mutations', 'Var', (0, 9))	('lymphoma', 'Phenotype', 'HP:0002665', (103, 111))	('c-ros oncogene 1', 'Gene', (128, 144))	('ROS1', 'Gene', (146, 150))	('ALK', 'Gene', '238', (120, 123))	('EGFR', 'Gene', (47, 51))	('c-ros oncogene 1', 'Gene', '6098', (128, 144))	('ALK', 'Gene', (120, 123))	('NSCLC', 'Disease', 'MESH:D002289', (221, 226))	('anaplastic lymphoma kinase', 'Gene', '238', (92, 118))
496633	33194579	In NSCLC cells, let-7 family transfection considerably reduced proliferation rate, hence acting as tumor suppressor gene.	('tumor', 'Disease', (99, 104))	('NSCLC', 'Disease', (3, 8))	('let-7', 'Gene', (16, 21))	('reduced', 'NegReg', (55, 62))	('NSCLC', 'Disease', 'MESH:D002289', (3, 8))	('proliferation rate', 'CPA', (63, 81))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('NSCLC', 'Phenotype', 'HP:0030358', (3, 8))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('transfection', 'Var', (29, 41))
496642	33194579	The database was scrutinized using the following terms: "let-7*" OR "let7*" AND "lung cancer" for let-7 family, and "miR-21" OR "microRNA 21" AND "lung cancer" AND "patients" for miR-21.	('lung cancer', 'Disease', (81, 92))	('let7*', 'Var', (69, 74))	('lung cancer', 'Phenotype', 'HP:0100526', (81, 92))	('miR-21', 'Gene', (179, 185))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('lung cancer', 'Disease', (147, 158))	('miR-21', 'Gene', (117, 123))	('lung cancer', 'Phenotype', 'HP:0100526', (147, 158))	('lung cancer', 'Disease', 'MESH:D008175', (81, 92))	('patients', 'Species', '9606', (165, 173))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('miR-21', 'Gene', '406991', (117, 123))	('miR-21', 'Gene', '406991', (179, 185))	('lung cancer', 'Disease', 'MESH:D008175', (147, 158))
496661	33194579	Finally, 23 articles were identified as eligible for the present meta-analysis, of which two studies provided HR survival data for both miR-21 and let-7 (Figure 1).	('miR-21', 'Gene', '406991', (136, 142))	('let-7', 'Var', (147, 152))	('miR-21', 'Gene', (136, 142))
496668	33194579	The overall corrected hazard ratio for miR-21 is HR = 1.87, 95% CI = (1.41, 2.47) and statistically significant (Z = 4.43, p < 0.001), indicating that a high expression of miR-21 is associated with poor survival.	('miR-21', 'Gene', (172, 178))	('miR-21', 'Gene', '406991', (39, 45))	('miR-21', 'Gene', (39, 45))	('miR-21', 'Gene', '406991', (172, 178))	('high', 'Var', (153, 157))
496698	33194579	This means that in woman, the aberrant expression of miR-21 seems to be more consistent with its impact on patient survival.	('woman', 'Species', '9606', (19, 24))	('miR-21', 'Gene', '406991', (53, 59))	('aberrant', 'Var', (30, 38))	('miR-21', 'Gene', (53, 59))	('patient', 'Species', '9606', (107, 114))
496712	33194579	In this respect, for LUAD patients' mutations in TP53, STK11, ALK, EGFR genes are more common, unlike LUSC patients, which have more characteristic mutations in RB1, KEAP, NFE2L2 or NF1 genes.	('RB1', 'Gene', '5925', (161, 164))	('TP53', 'Gene', '7157', (49, 53))	('common', 'Reg', (87, 93))	('NFE2L2', 'Gene', '4780', (172, 178))	('NF1', 'Gene', (182, 185))	('EGFR', 'Gene', (67, 71))	('STK11', 'Gene', '6794', (55, 60))	('NFE2L2', 'Gene', (172, 178))	('LUSC', 'Phenotype', 'HP:0030359', (102, 106))	('patients', 'Species', '9606', (107, 115))	('LUAD', 'Phenotype', 'HP:0030078', (21, 25))	('TP53', 'Gene', (49, 53))	('EGFR', 'Gene', '1956', (67, 71))	('RB1', 'Gene', (161, 164))	('ALK', 'Gene', '238', (62, 65))	('ALK', 'Gene', (62, 65))	('mutations', 'Var', (36, 45))	('patients', 'Species', '9606', (26, 34))	('STK11', 'Gene', (55, 60))	('NF1', 'Gene', '4763', (182, 185))
496713	33194579	The literature mentions the efficacy of let-7b in NSCLC cell lines with TP53 and EGFR mutations as an adjuvant in the therapy with erlotinib in order to potentiate the effect of this therapeutic compound.	('mutations', 'Var', (86, 95))	('let-7b', 'Gene', '406884', (40, 46))	('erlotinib', 'Chemical', 'MESH:D000069347', (131, 140))	('let-7b', 'Gene', (40, 46))	('TP53', 'Gene', '7157', (72, 76))	('NSCLC', 'Phenotype', 'HP:0030358', (50, 55))	('men', 'Species', '9606', (15, 18))	('TP53', 'Gene', (72, 76))	('NSCLC', 'Disease', (50, 55))	('potentiate', 'PosReg', (153, 163))	('NSCLC', 'Disease', 'MESH:D002289', (50, 55))	('EGFR', 'Gene', '1956', (81, 85))	('EGFR', 'Gene', (81, 85))
496714	33194579	Besides, In NSCLC miR-21 was reported as being regulated by EGFR in non-smoker patients, its upregulation being correlated with EGFR mutations.	('upregulation', 'PosReg', (93, 105))	('regulated', 'MPA', (47, 56))	('miR-21', 'Gene', '406991', (18, 24))	('NSCLC', 'Phenotype', 'HP:0030358', (12, 17))	('EGFR', 'Gene', '1956', (128, 132))	('correlated', 'Reg', (112, 122))	('EGFR', 'Gene', (128, 132))	('miR-21', 'Gene', (18, 24))	('NSCLC', 'Disease', (12, 17))	('EGFR', 'Gene', '1956', (60, 64))	('mutations', 'Var', (133, 142))	('patients', 'Species', '9606', (79, 87))	('NSCLC', 'Disease', 'MESH:D002289', (12, 17))	('EGFR', 'Gene', (60, 64))
496725	33194579	In order to reinforce the importance and the utility of these two transcripts in non-smoker NSCLC patients, future studies focused exclusively on non-smoker patients should be conducted to investigate their roles and/or correlation with common mutations encountered also in non-smoking patients diagnosed with NSCLC, such as EGFR, ALK, KRAS, RET, etc..In this respect, a meta-analysis published in 2016 revealed that in the genes most frequently mutated in NSCLC, such as EGFR, KRAS, and ALK mutations are associated with patient characteristics, such gender, smoking status and histological type.	('patient', 'Species', '9606', (98, 105))	('NSCLC', 'Disease', (310, 315))	('ALK', 'Gene', '238', (331, 334))	('patients', 'Species', '9606', (157, 165))	('RET', 'Gene', '5979', (342, 345))	('EGFR', 'Gene', '1956', (325, 329))	('EGFR', 'Gene', (472, 476))	('NSCLC', 'Disease', 'MESH:D002289', (92, 97))	('KRAS', 'Gene', '3845', (336, 340))	('ALK', 'Gene', (331, 334))	('NSCLC', 'Phenotype', 'HP:0030358', (310, 315))	('mutations', 'Var', (492, 501))	('ALK', 'Gene', '238', (488, 491))	('NSCLC', 'Disease', 'MESH:D002289', (457, 462))	('KRAS', 'Gene', '3845', (478, 482))	('patient', 'Species', '9606', (522, 529))	('ALK', 'Gene', (488, 491))	('patient', 'Species', '9606', (286, 293))	('NSCLC', 'Disease', (92, 97))	('KRAS', 'Gene', (336, 340))	('KRAS', 'Gene', (478, 482))	('NSCLC', 'Disease', (457, 462))	('patient', 'Species', '9606', (157, 164))	('RET', 'Gene', (342, 345))	('NSCLC', 'Phenotype', 'HP:0030358', (92, 97))	('patients', 'Species', '9606', (98, 106))	('associated', 'Reg', (506, 516))	('EGFR', 'Gene', '1956', (472, 476))	('NSCLC', 'Phenotype', 'HP:0030358', (457, 462))	('EGFR', 'Gene', (325, 329))	('NSCLC', 'Disease', 'MESH:D002289', (310, 315))	('patients', 'Species', '9606', (286, 294))
496726	33194579	As already stated, in non-smokers, miR-21 appears to be regulated by EGFR, miR-21 overexpression being associated with EGFR mutations.	('EGFR', 'Gene', '1956', (69, 73))	('mutations', 'Var', (124, 133))	('associated', 'Reg', (103, 113))	('EGFR', 'Gene', (69, 73))	('miR-21', 'Gene', '406991', (75, 81))	('miR-21', 'Gene', (35, 41))	('overexpression', 'PosReg', (82, 96))	('EGFR', 'Gene', '1956', (119, 123))	('EGFR', 'Gene', (119, 123))	('miR-21', 'Gene', '406991', (35, 41))	('miR-21', 'Gene', (75, 81))
496729	33194579	Specifically, in A549 cells TGFB1 overexpression reduces cell proliferation and overexpression of miR-21 decreases TGFB1 levels, thus promoting aberrant cell proliferation and highlighting the function of miR-21 as an oncomiR in NSCLC.	('NSCLC', 'Disease', (229, 234))	('cell proliferation', 'CPA', (153, 171))	('aberrant cell proliferation', 'Phenotype', 'HP:0031377', (144, 171))	('miR-21', 'Gene', (205, 211))	('cell proliferation', 'CPA', (57, 75))	('overexpression', 'Var', (34, 48))	('TGFB1', 'Gene', '7040', (28, 33))	('NSCLC', 'Phenotype', 'HP:0030358', (229, 234))	('reduces', 'NegReg', (49, 56))	('TGFB1', 'Gene', (28, 33))	('TGFB1', 'Gene', '7040', (115, 120))	('TGFB1', 'Gene', (115, 120))	('miR-21', 'Gene', '406991', (98, 104))	('decreases', 'NegReg', (105, 114))	('miR-21', 'Gene', (98, 104))	('miR-21', 'Gene', '406991', (205, 211))	('NSCLC', 'Disease', 'MESH:D002289', (229, 234))	('promoting', 'PosReg', (134, 143))	('A549', 'CellLine', 'CVCL:0023', (17, 21))
496745	32547097	Loss of miR-204-5p Promotes Tumor Proliferation, Migration, and Invasion Through Targeting YWHAZ/PI3K/AKT Pathway in Esophageal Squamous Cell Carcinoma MicroRNAs dysregulation has been confirmed in multiple malignancies.	('Invasion', 'CPA', (64, 72))	('malignancies', 'Disease', (207, 219))	('miR-204-5p', 'Chemical', '-', (8, 18))	('Migration', 'CPA', (49, 58))	('Squamous Cell Carcinoma', 'Disease', (128, 151))	('Tumor', 'Phenotype', 'HP:0002664', (28, 33))	('miR-204-5p', 'Gene', (8, 18))	('YWHAZ', 'Gene', '7534', (91, 96))	('YWHAZ', 'Gene', (91, 96))	('AKT', 'Gene', '207', (102, 105))	('Tumor Proliferation', 'CPA', (28, 47))	('Carcinoma', 'Phenotype', 'HP:0030731', (142, 151))	('malignancies', 'Disease', 'MESH:D009369', (207, 219))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (128, 151))	('Loss', 'Var', (0, 4))	('Squamous Cell Carcinoma', 'Disease', 'MESH:D002294', (128, 151))	('AKT', 'Gene', (102, 105))	('Promotes', 'PosReg', (19, 27))
496746	32547097	This paper reported the molecular mechanism of miR-204-5p in esophageal squamous cell carcinoma (ESCC).	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (72, 95))	('esophageal squamous cell carcinoma', 'Disease', (61, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('miR-204-5p', 'Chemical', '-', (47, 57))	('miR-204-5p', 'Var', (47, 57))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (61, 95))
496750	32547097	Luciferase reporter gene assay and RNA-binding protein immunoprecipitation (RIP) were performed to verify the targeting relationship between miR-204-5p and YWHAZ.	('RIP', 'Gene', (76, 79))	('miR-204-5p', 'Var', (141, 151))	('RNA-binding protein immunoprecipitation', 'Gene', '3267', (35, 74))	('RNA-binding protein immunoprecipitation', 'Gene', (35, 74))	('RIP', 'Gene', '3267', (76, 79))	('YWHAZ', 'Gene', (156, 161))	('YWHAZ', 'Gene', '7534', (156, 161))	('miR-204-5p', 'Chemical', '-', (141, 151))
496755	32547097	Moreover, KYSE510 cells of miR-204-5p mimic group showed lower OD450 value, more cell percentage in G1 phase and less cell percentage in S phase, higher apoptosis percentage, and lower migration and invasion cell numbers than control.	('higher', 'PosReg', (146, 152))	('lower', 'NegReg', (179, 184))	('less', 'NegReg', (113, 117))	('G1 phase', 'CPA', (100, 108))	('miR-204-5p mimic', 'Var', (27, 43))	('OD450 value', 'Enzyme', (63, 74))	('miR-204-5p', 'Chemical', '-', (27, 37))	('KYSE510', 'CellLine', 'CVCL:1354', (10, 17))	('apoptosis percentage', 'CPA', (153, 173))	('lower', 'NegReg', (57, 62))
496756	32547097	YWHAZ was directly inhibited by miR-204-5p.	('inhibited', 'NegReg', (19, 28))	('miR-204-5p', 'Chemical', '-', (32, 42))	('miR-204-5p', 'Var', (32, 42))	('YWHAZ', 'Gene', (0, 5))	('YWHAZ', 'Gene', '7534', (0, 5))
496758	32547097	miR-204-5p up-regulation inhibited ESCC growth in vivo.	('up-regulation', 'PosReg', (11, 24))	('miR-204-5p', 'Chemical', '-', (0, 10))	('inhibited', 'NegReg', (25, 34))	('ESCC', 'Disease', (35, 39))	('miR-204-5p', 'Var', (0, 10))
496759	32547097	miR-204-5p inhibits ESCC progression by targeted inhibition of YWHAZ/PI3K/AKT.	('AKT', 'Gene', '207', (74, 77))	('inhibits', 'NegReg', (11, 19))	('ESCC', 'Disease', (20, 24))	('miR-204-5p', 'Chemical', '-', (0, 10))	('AKT', 'Gene', (74, 77))	('YWHAZ', 'Gene', (63, 68))	('inhibition', 'NegReg', (49, 59))	('miR-204-5p', 'Var', (0, 10))	('YWHAZ', 'Gene', '7534', (63, 68))
496766	32547097	MiRNAs have been shown to mediate post-transcriptional regulation of target genes through promoting RNA degradation or translational inhibition and participate in mediating various biological and pathological processes, including proliferation, apoptosis, differentiation, and carcinogenesis.	('participate', 'Reg', (148, 159))	('MiRNAs', 'Var', (0, 6))	('RNA degradation', 'MPA', (100, 115))	('apoptosis', 'CPA', (245, 254))	('carcinogenesis', 'Disease', 'MESH:D063646', (277, 291))	('carcinogenesis', 'Disease', (277, 291))	('promoting', 'PosReg', (90, 99))	('translational', 'MPA', (119, 132))	('differentiation', 'CPA', (256, 271))	('proliferation', 'CPA', (230, 243))
496771	32547097	miR-204-5p has been confirmed to involve in the regulation of multiple human malignant tumor progression, which was also verified to be tumor suppressor in some human tumors such as malignant melanoma and hepatocellular cancer.	('human', 'Species', '9606', (161, 166))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('malignant tumor', 'Disease', (77, 92))	('malignant melanoma and hepatocellular cancer', 'Disease', 'MESH:D006528', (182, 226))	('tumors', 'Disease', 'MESH:D009369', (167, 173))	('hepatocellular cancer', 'Phenotype', 'HP:0001402', (205, 226))	('miR-204-5p', 'Chemical', '-', (0, 10))	('malignant tumor', 'Disease', 'MESH:D009369', (77, 92))	('tumor', 'Disease', (136, 141))	('tumor', 'Disease', (167, 172))	('miR-204-5p', 'Var', (0, 10))	('human', 'Species', '9606', (71, 76))	('malignant melanoma', 'Phenotype', 'HP:0002861', (182, 200))	('involve', 'Reg', (33, 40))	('tumor', 'Disease', (87, 92))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('tumors', 'Phenotype', 'HP:0002664', (167, 173))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('tumors', 'Disease', (167, 173))
496772	32547097	Unfortunately, the function of miR-204-5p in ESCC has not been confirmed currently.	('miR-204-5p', 'Chemical', '-', (31, 41))	('ESCC', 'Disease', (45, 49))	('miR-204-5p', 'Var', (31, 41))
496773	32547097	We hypothesized that miR-204-5p might participate in the regulation of ESCC progression.	('ESCC', 'Disease', (71, 75))	('miR-204-5p', 'Var', (21, 31))	('participate', 'Reg', (38, 49))	('miR-204-5p', 'Chemical', '-', (21, 31))
496774	32547097	Meanwhile, we also noticed that miR-204-5p directly targeted YWHAZ.	('miR-204-5p', 'Chemical', '-', (32, 42))	('targeted', 'Reg', (52, 60))	('YWHAZ', 'Gene', (61, 66))	('miR-204-5p', 'Var', (32, 42))	('YWHAZ', 'Gene', '7534', (61, 66))
496776	32547097	Therefore, this article further investigated whether miR-204-5p regulated the progression of ESCC via interfering with YWHAZ expression.	('interfering', 'NegReg', (102, 113))	('miR-204-5p', 'Chemical', '-', (53, 63))	('miR-204-5p', 'Var', (53, 63))	('YWHAZ', 'Gene', (119, 124))	('YWHAZ', 'Gene', '7534', (119, 124))	('ESCC', 'Disease', (93, 97))
496818	32547097	After incubation of the primary antibody (YWHAZ, p-PI3K, pI3K, p-AKT, and AKT) and related secondary antibodies, streptomycin was used for the biotinylated HRP complex and placed at 37  C for 30 min.	('AKT', 'Gene', (65, 68))	('AKT', 'Gene', '207', (74, 77))	('streptomycin', 'Chemical', 'MESH:D013307', (113, 125))	('pI3K', 'Var', (57, 61))	('AKT', 'Gene', '207', (65, 68))	('AKT', 'Gene', (74, 77))	('YWHAZ', 'Gene', '7534', (42, 47))	('YWHAZ', 'Gene', (42, 47))	('p-PI3K', 'Var', (49, 55))
496833	32547097	The primer sequences used in this research were listed as follows: miR-204-5p-F, 5'-ACACTCCAGCTGGGTTCCCTTTGTCATCCTAT-3', miR-204-5p-R, 5'-CTCAACTGGTGTCGTGGA-3'.	('miR-204-5p-R', 'Var', (121, 133))	('miR-204-5p', 'Chemical', '-', (121, 131))	('miR-204-5p', 'Chemical', '-', (67, 77))	('miR-204-5p-F', 'Var', (67, 79))
496847	32547097	The expression of miR-204-5p in tumor and normal tissues of 97 ESCC patients was subsequently validated.	('miR-204-5p', 'Var', (18, 28))	('miR-204-5p', 'Chemical', '-', (18, 28))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('patients', 'Species', '9606', (68, 76))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('ESCC', 'Disease', (63, 67))	('tumor', 'Disease', (32, 37))
496848	32547097	It could be noted that relative to normal tissues, the expression of miR-204-5p was prominently reduced in ESCC tumor tissues (P< 0.0001) (Figure 1C).	('miR-204-5p', 'Var', (69, 79))	('expression', 'MPA', (55, 65))	('ESCC tumor', 'Disease', (107, 117))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('miR-204-5p', 'Chemical', '-', (69, 79))	('ESCC tumor', 'Disease', 'MESH:D004938', (107, 117))	('reduced', 'NegReg', (96, 103))
496850	32547097	As recorded in Table 1, low miR-204-5p expression was obviously associated with large tumor size and advanced tumor stage (P< 0.05).	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Disease', (86, 91))	('miR-204-5p expression', 'Var', (28, 49))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('low', 'NegReg', (24, 27))	('miR-204-5p', 'Chemical', '-', (28, 38))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
496851	32547097	Interestingly, patients with lower expression of miR-204-5p were always with short overall survival time (Figure 1D).	('short', 'NegReg', (77, 82))	('miR-204-5p', 'Var', (49, 59))	('patients', 'Species', '9606', (15, 23))	('overall', 'MPA', (83, 90))	('miR-204-5p', 'Chemical', '-', (49, 59))
496853	32547097	miR-204-5p expression was noticeably reduced in the 5 ESCC cell lines than that in Het-1A cell line (P< 0.01).	('reduced', 'NegReg', (37, 44))	('Het-1A', 'CellLine', 'CVCL:3702', (83, 89))	('miR-204-5p', 'Var', (0, 10))	('miR-204-5p', 'Chemical', '-', (0, 10))
496854	32547097	In the next study, the biological functions of miR-204-5p in ESCC were analyzed.	('miR-204-5p', 'Var', (47, 57))	('miR-204-5p', 'Chemical', '-', (47, 57))	('ESCC', 'Disease', (61, 65))
496855	32547097	Briefly, TE-1 cells with relatively high miR-204-5p expression were transfected by miR-204-5p inhibitor, whereas KYSE510 cells with relatively low miR-204-5p expression were transfected by miR-204-5p mimic.	('miR-204-5p', 'Chemical', '-', (83, 93))	('transfected', 'Reg', (68, 79))	('KYSE510', 'CellLine', 'CVCL:1354', (113, 120))	('miR-204-5p', 'Chemical', '-', (41, 51))	('miR-204-5p', 'Chemical', '-', (147, 157))	('miR-204-5p', 'Var', (41, 51))	('miR-204-5p', 'Chemical', '-', (189, 199))
496858	32547097	CCK-8 assay showed markedly higher OD450 value of TE-1 cells in miR-204-5p inhibitor group when compared with siNC group (P< 0.01), but remarkably lower OD450 value of KYSE510 cells in miR-204-5p mimic group compared to NC group (P< 0.01) (Figure 2C).	('OD450', 'MPA', (153, 158))	('siNC', 'Disease', (110, 114))	('lower', 'NegReg', (147, 152))	('higher', 'PosReg', (28, 34))	('miR-204-5p', 'Chemical', '-', (64, 74))	('miR-204-5p', 'Chemical', '-', (185, 195))	('KYSE510', 'CellLine', 'CVCL:1354', (168, 175))	('miR-204-5p', 'Var', (64, 74))	('siNC', 'Disease', 'None', (110, 114))	('OD450', 'MPA', (35, 40))
496859	32547097	Moreover, TE-1 cells of miR-204-5p inhibitor group exhibited less cell percentage in G1 phase and more cell percentage in S phase than siNC group (P< 0.05 or P< 0.01).	('more', 'PosReg', (98, 102))	('S phase', 'CPA', (122, 129))	('less', 'NegReg', (61, 65))	('siNC', 'Disease', (135, 139))	('miR-204-5p', 'Chemical', '-', (24, 34))	('miR-204-5p inhibitor', 'Var', (24, 44))	('cell percentage in G1 phase', 'CPA', (66, 93))	('siNC', 'Disease', 'None', (135, 139))
496860	32547097	However, relative to NC group, KYSE510 cells of miR-204-5p mimic group showed more cell percentage in G1 phase and less cell percentage in S phase (P< 0.05) (Figure 2D).	('less', 'NegReg', (115, 119))	('G1 phase', 'CPA', (102, 110))	('more', 'PosReg', (78, 82))	('miR-204-5p', 'Chemical', '-', (48, 58))	('miR-204-5p', 'Var', (48, 58))	('S phase', 'CPA', (139, 146))	('KYSE510', 'CellLine', 'CVCL:1354', (31, 38))
496861	32547097	Compared with siNC group, much lower apoptosis percentage and higher migration and invasion cell numbers were observed in miR-204-5p inhibitor group (P< 0.05 or P< 0.01).	('siNC', 'Disease', (14, 18))	('apoptosis percentage', 'CPA', (37, 57))	('lower', 'NegReg', (31, 36))	('miR-204-5p', 'Chemical', '-', (122, 132))	('higher', 'PosReg', (62, 68))	('miR-204-5p inhibitor', 'Var', (122, 142))	('siNC', 'Disease', 'None', (14, 18))
496863	32547097	The binding site of miR-204-5p and YWHAZ was predicted by TargetScan online software.	('YWHAZ', 'Gene', '7534', (35, 40))	('binding', 'Interaction', (4, 11))	('miR-204-5p', 'Chemical', '-', (20, 30))	('miR-204-5p', 'Var', (20, 30))	('YWHAZ', 'Gene', (35, 40))
496864	32547097	The results indicated that miR-204-5p was with the binding site to YWHAZ in the 3'-UTR region.	('binding', 'Interaction', (51, 58))	('YWHAZ', 'Gene', (67, 72))	('YWHAZ', 'Gene', '7534', (67, 72))	('miR-204-5p', 'Chemical', '-', (27, 37))	('miR-204-5p', 'Var', (27, 37))
496866	32547097	Results of the luciferase reporter gene assay showed that miR-204-5p overexpression significantly decreased the relative luciferase activity of YWHAZ-WT (P< 0.01) whereas no obvious effect was found in YWHAZ-Mut group (Figure 3B).	('overexpression', 'PosReg', (69, 83))	('activity', 'MPA', (132, 140))	('miR-204-5p', 'Chemical', '-', (58, 68))	('YWHAZ', 'Gene', '7534', (144, 149))	('YWHAZ', 'Gene', (144, 149))	('decreased', 'NegReg', (98, 107))	('luciferase', 'Enzyme', (121, 131))	('miR-204-5p', 'Var', (58, 68))	('YWHAZ', 'Gene', '7534', (202, 207))	('YWHAZ', 'Gene', (202, 207))
496867	32547097	Thus, YWHAZ expression was proved to be directly inhibited by miR-204-5p.	('YWHAZ', 'Gene', (6, 11))	('miR-204-5p', 'Chemical', '-', (62, 72))	('YWHAZ', 'Gene', '7534', (6, 11))	('inhibited', 'NegReg', (49, 58))	('miR-204-5p', 'Var', (62, 72))
496879	32547097	Western blot analysis was processed to detect the relative protein expression of p-PI3K/PI3K and p-AKT/AKT.	('AKT', 'Gene', '207', (103, 106))	('AKT', 'Gene', '207', (99, 102))	('AKT', 'Gene', (103, 106))	('AKT', 'Gene', (99, 102))	('p-PI3K/PI3K', 'Var', (81, 92))
496880	32547097	As the results shown in Figure 4F, relative protein expression of p-PI3K/PI3K and p-AKT/AKT was significantly higher in miR-inhibitor and miR-inhibitor+siCtrl than control, while siYWHAZ rescued the effect of miR-inhibitor.	('p-PI3K/PI3K', 'Var', (66, 77))	('miR', 'Gene', '220972', (120, 123))	('miR', 'Gene', '220972', (209, 212))	('miR', 'Gene', (120, 123))	('miR', 'Gene', (209, 212))	('AKT', 'Gene', '207', (88, 91))	('AKT', 'Gene', '207', (84, 87))	('miR', 'Gene', '220972', (138, 141))	('miR', 'Gene', (138, 141))	('AKT', 'Gene', (84, 87))	('siYWHAZ', 'Chemical', '-', (179, 186))	('AKT', 'Gene', (88, 91))	('higher', 'PosReg', (110, 116))	('protein expression', 'MPA', (44, 62))
496883	32547097	As shown in Figure 5A and B, both the tumor volume and weight of miR-204-5p mimic group were prominently lower than that of NC group on the 28th day after subcutaneous injection (P < 0.01).	('lower', 'NegReg', (105, 110))	('tumor', 'Disease', (38, 43))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('weight', 'CPA', (55, 61))	('miR-204-5p mimic', 'Var', (65, 81))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('miR-204-5p', 'Chemical', '-', (65, 75))
496885	32547097	As a result, tumor tissues of miR-204-5p mimic group exhibited much higher miR-204-5p expression and markedly lower YWHAZ expression than that of NC group (P< 0.01) (Figure 5C and D).	('tumor', 'Disease', (13, 18))	('miR-204-5p mimic', 'Var', (30, 46))	('miR-204-5p', 'Chemical', '-', (75, 85))	('higher', 'PosReg', (68, 74))	('miR-204-5p', 'Chemical', '-', (30, 40))	('lower', 'NegReg', (110, 115))	('YWHAZ', 'Gene', (116, 121))	('miR-204-5p expression', 'MPA', (75, 96))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('YWHAZ', 'Gene', '7534', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
496887	32547097	As shown in Figure 5E, the relative expression of YWHAZ, p-PI3K/PI3K, and p-AKT/AKT was significantly decreased after miR-204-5p mimic transfection.	('AKT', 'Gene', '207', (76, 79))	('AKT', 'Gene', '207', (80, 83))	('decreased', 'NegReg', (102, 111))	('miR-204-5p', 'Chemical', '-', (118, 128))	('YWHAZ', 'Gene', (50, 55))	('miR-204-5p mimic transfection', 'Var', (118, 147))	('AKT', 'Gene', (76, 79))	('AKT', 'Gene', (80, 83))	('YWHAZ', 'Gene', '7534', (50, 55))	('p-PI3K/PI3K', 'Var', (57, 68))	('expression', 'MPA', (36, 46))
496889	32547097	The abnormal expression of cancer-related genes will ultimately affect the development of tumors by inducing tumor growth, metastasis as well as a series of complex processes.	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('abnormal', 'Var', (4, 12))	('tumor', 'Disease', (109, 114))	('expression', 'MPA', (13, 23))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumors', 'Disease', (90, 96))	('tumors', 'Disease', 'MESH:D009369', (90, 96))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('cancer', 'Disease', (27, 33))	('cancer', 'Disease', 'MESH:D009369', (27, 33))	('affect', 'Reg', (64, 70))	('metastasis', 'CPA', (123, 133))	('inducing', 'PosReg', (100, 108))
496891	32547097	Regarding the mechanism, miR-204-5p inhibited ESCC progression in vitro and in vivo by targeting YWHAZ/PI3K/AKT.	('YWHAZ', 'Gene', (97, 102))	('AKT', 'Gene', '207', (108, 111))	('ESCC', 'Disease', (46, 50))	('inhibited', 'NegReg', (36, 45))	('YWHAZ', 'Gene', '7534', (97, 102))	('AKT', 'Gene', (108, 111))	('targeting', 'Reg', (87, 96))	('miR-204-5p', 'Chemical', '-', (25, 35))	('miR-204-5p', 'Var', (25, 35))
496892	32547097	The function of miR-204-5p in human malignancies has been reported in recent years.	('human', 'Species', '9606', (30, 35))	('malignancies', 'Disease', (36, 48))	('miR-204-5p', 'Var', (16, 26))	('miR-204-5p', 'Chemical', '-', (16, 26))	('malignancies', 'Disease', 'MESH:D009369', (36, 48))
496893	32547097	Previous research has reported that miR-204-5p expression was reduced in colorectal cancer.	('colorectal cancer', 'Disease', 'MESH:D015179', (73, 90))	('colorectal cancer', 'Phenotype', 'HP:0003003', (73, 90))	('miR-204-5p', 'Chemical', '-', (36, 46))	('miR-204-5p', 'Var', (36, 46))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('colorectal cancer', 'Disease', (73, 90))	('reduced', 'NegReg', (62, 69))
496894	32547097	After restoring the expression of miR-204-5p, migration and invasion abilities of the colorectal cancer cells were weakened and the sensitivity of tumor cells to chemotherapy was also enhanced.	('colorectal cancer', 'Disease', 'MESH:D015179', (86, 103))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumor', 'Disease', (147, 152))	('invasion abilities', 'CPA', (60, 78))	('expression', 'MPA', (20, 30))	('colorectal cancer', 'Phenotype', 'HP:0003003', (86, 103))	('colorectal cancer', 'Disease', (86, 103))	('miR-204-5p', 'Var', (34, 44))	('miR-204-5p', 'Chemical', '-', (34, 44))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('sensitivity', 'CPA', (132, 143))	('enhanced', 'PosReg', (184, 192))	('weakened', 'NegReg', (115, 123))
496895	32547097	The mechanism involved in this process was that miR-204-5p could directly inhibit RAB22A expression to exert its anti-tumor effect in colorectal cancer.	('expression', 'MPA', (89, 99))	('RAB22A', 'Gene', (82, 88))	('colorectal cancer', 'Disease', (134, 151))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('RAB22A', 'Gene', '57403', (82, 88))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('inhibit', 'NegReg', (74, 81))	('tumor', 'Disease', (118, 123))	('colorectal cancer', 'Disease', 'MESH:D015179', (134, 151))	('miR-204-5p', 'Var', (48, 58))	('miR-204-5p', 'Chemical', '-', (48, 58))	('colorectal cancer', 'Phenotype', 'HP:0003003', (134, 151))
496896	32547097	In papillary thyroid carcinoma, miR-204-5p possessed antitumor effect, which suppressed proliferation and induced apoptosis of papillary thyroid carcinoma cells by inhibiting the expression of IGFBP5.	('carcinoma', 'Phenotype', 'HP:0030731', (145, 154))	('inhibiting', 'NegReg', (164, 174))	('induced', 'Reg', (106, 113))	('papillary thyroid carcinoma', 'Phenotype', 'HP:0002895', (127, 154))	('IGFBP5', 'Gene', '3488', (193, 199))	('miR-204-5p', 'Chemical', '-', (32, 42))	('miR-204-5p', 'Var', (32, 42))	('papillary thyroid carcinoma', 'Disease', (127, 154))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (13, 30))	('tumor', 'Disease', (57, 62))	('papillary thyroid carcinoma', 'Disease', 'MESH:D000077273', (127, 154))	('suppressed', 'NegReg', (77, 87))	('IGFBP5', 'Gene', (193, 199))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (137, 154))	('carcinoma', 'Phenotype', 'HP:0030731', (21, 30))	('apoptosis', 'CPA', (114, 123))	('expression', 'MPA', (179, 189))	('papillary thyroid carcinoma', 'Phenotype', 'HP:0002895', (3, 30))	('papillary thyroid carcinoma', 'Disease', (3, 30))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('proliferation', 'CPA', (88, 101))	('papillary thyroid carcinoma', 'Disease', 'MESH:D000077273', (3, 30))
496898	32547097	miR-204-5p could inhibit hepatocellular cancer cells proliferation in vitro by regulating SIX1 and its downstream genes.	('hepatocellular cancer', 'Phenotype', 'HP:0001402', (25, 46))	('regulating', 'Reg', (79, 89))	('inhibit', 'NegReg', (17, 24))	('hepatocellular cancer', 'Disease', 'MESH:D006528', (25, 46))	('miR-204-5p', 'Chemical', '-', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('SIX1', 'Gene', '6495', (90, 94))	('hepatocellular cancer', 'Disease', (25, 46))	('SIX1', 'Gene', (90, 94))	('miR-204-5p', 'Var', (0, 10))
496899	32547097	Meanwhile, Wang et al reported that miR-204-5p was lower expressed in oral squamous cell carcinoma, and miR-204-5p acted as a  tumor suppressor in oral squamous cell carcinoma via targeting CXCR4.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('miR-204-5p', 'Chemical', '-', (104, 114))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (147, 175))	('CXCR4', 'Gene', (190, 195))	('miR-204-5p', 'Var', (104, 114))	('tumor', 'Disease', (127, 132))	('carcinoma', 'Phenotype', 'HP:0030731', (166, 175))	('miR-204-5p', 'Chemical', '-', (36, 46))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (70, 98))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (152, 175))	('lower', 'NegReg', (51, 56))	('oral squamous cell carcinoma', 'Disease', (147, 175))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (75, 98))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('CXCR4', 'Gene', '7852', (190, 195))	('oral squamous cell carcinoma', 'Disease', (70, 98))	('targeting', 'Reg', (180, 189))
496900	32547097	Therefore, most studies have suggested that miR-204-5p played as a tumor suppressor in multiple human malignant tumors, Similar to these studies, this research also illustrated that miR-204-5p acted as a tumor suppressor in ESCC.	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('human', 'Species', '9606', (96, 101))	('miR-204-5p', 'Chemical', '-', (44, 54))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('malignant tumors', 'Disease', (102, 118))	('malignant tumors', 'Disease', 'MESH:D009369', (102, 118))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumor', 'Disease', (204, 209))	('miR-204-5p', 'Chemical', '-', (182, 192))	('ESCC', 'Disease', (224, 228))	('tumor', 'Disease', (67, 72))	('tumor', 'Disease', (112, 117))	('miR-204-5p', 'Var', (182, 192))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))
496901	32547097	More importantly, this study demonstrated for the first time that miR-204-5p inhibited ESCC progression via regulating YWHAZ/PI3K/AKT.	('inhibited', 'NegReg', (77, 86))	('YWHAZ', 'Gene', (119, 124))	('ESCC', 'Disease', (87, 91))	('AKT', 'Gene', '207', (130, 133))	('YWHAZ', 'Gene', '7534', (119, 124))	('miR-204-5p', 'Var', (66, 76))	('miR-204-5p', 'Chemical', '-', (66, 76))	('AKT', 'Gene', (130, 133))
496902	32547097	These findings laid reliable theoretical basis for the application of miR-204-5p in the clinical target treatment of ESCC.	('ESCC', 'Disease', (117, 121))	('miR-204-5p', 'Chemical', '-', (70, 80))	('miR-204-5p', 'Var', (70, 80))
496909	32547097	This article proved for the first time that YWHAZ was directly inhibited by miR-204-5p in ESCC.	('YWHAZ', 'Gene', '7534', (44, 49))	('YWHAZ', 'Gene', (44, 49))	('inhibited', 'NegReg', (63, 72))	('miR-204-5p', 'Chemical', '-', (76, 86))	('miR-204-5p', 'Var', (76, 86))
496916	32547097	In this research, miR-204-5p inhibited the development of ESCC partially through suppressing the activation of YWHAZ/PI3K/AKT.	('YWHAZ', 'Gene', (111, 116))	('inhibited', 'NegReg', (29, 38))	('miR-204-5p', 'Var', (18, 28))	('suppressing', 'NegReg', (81, 92))	('miR-204-5p', 'Chemical', '-', (18, 28))	('development', 'CPA', (43, 54))	('YWHAZ', 'Gene', '7534', (111, 116))	('AKT', 'Gene', '207', (122, 125))	('ESCC', 'Disease', (58, 62))	('AKT', 'Gene', (122, 125))
496917	32547097	Collectively, this article discovered that miR-204-5p expression was reduced in ESCC and overexpression of miR-204-5p could inhibit the progression of ESCC by targeting YWHAZ/PI3K/AKT signaling.	('miR-204-5p', 'Var', (107, 117))	('expression', 'MPA', (54, 64))	('YWHAZ', 'Gene', (169, 174))	('progression', 'CPA', (136, 147))	('reduced', 'NegReg', (69, 76))	('miR-204-5p', 'Chemical', '-', (43, 53))	('YWHAZ', 'Gene', '7534', (169, 174))	('ESCC', 'Disease', (151, 155))	('miR-204-5p', 'Protein', (43, 53))	('AKT', 'Gene', (180, 183))	('AKT', 'Gene', '207', (180, 183))	('inhibit', 'NegReg', (124, 131))	('miR-204-5p', 'Chemical', '-', (107, 117))	('ESCC', 'Disease', (80, 84))	('targeting', 'Reg', (159, 168))
496918	32547097	Thus, miR-204-5p might be a novel potential target for the treatment of ESCC.	('miR-204-5p', 'Chemical', '-', (6, 16))	('miR-204-5p', 'Var', (6, 16))	('ESCC', 'Disease', (72, 76))
496920	32547097	(2) miR-204-5p overexpression suppressed ESCC development in vitro.	('miR-204-5p', 'Var', (4, 14))	('overexpression', 'PosReg', (15, 29))	('suppressed', 'NegReg', (30, 40))	('ESCC development', 'CPA', (41, 57))	('miR-204-5p', 'Chemical', '-', (4, 14))
496921	32547097	(3) YWHAZ was directly inhibited by miR-204-5p and was highly expressed in ESCC.	('inhibited', 'NegReg', (23, 32))	('miR-204-5p', 'Chemical', '-', (36, 46))	('miR-204-5p', 'Var', (36, 46))	('YWHAZ', 'Gene', '7534', (4, 9))	('YWHAZ', 'Gene', (4, 9))
496922	32547097	(4) miR-204-5p suppressed ESCC development by inhibiting YWHAZ/PI3K/AKT.	('inhibiting', 'NegReg', (46, 56))	('miR-204-5p', 'Var', (4, 14))	('ESCC development', 'CPA', (26, 42))	('YWHAZ', 'Gene', '7534', (57, 62))	('YWHAZ', 'Gene', (57, 62))	('AKT', 'Gene', '207', (68, 71))	('suppressed', 'NegReg', (15, 25))	('miR-204-5p', 'Chemical', '-', (4, 14))	('AKT', 'Gene', (68, 71))
496923	32547097	(5) miR-204-5p inhibited ESCC growth in vivo by suppressing YWHAZ expression.	('miR-204-5p', 'Var', (4, 14))	('inhibited', 'NegReg', (15, 24))	('YWHAZ', 'Gene', (60, 65))	('ESCC', 'Disease', (25, 29))	('YWHAZ', 'Gene', '7534', (60, 65))	('suppressing', 'NegReg', (48, 59))	('miR-204-5p', 'Chemical', '-', (4, 14))
496928	28757263	However, it is not clear what proportion of ESCC cells carry these epigenomic aberrations or how they contribute to tumor development.	('SCC', 'Gene', (45, 48))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('SCC', 'Gene', '6317', (45, 48))	('contribute', 'Reg', (102, 112))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('epigenomic aberrations', 'Var', (67, 89))	('tumor', 'Disease', (116, 121))
496934	28757263	Genomic analyses provide evidence for pervasive abnormalities in the ESCC epigenome: epigenetic regulators themselves are frequently altered by genetic changes.	('pervasive abnormalities', 'Disease', (38, 61))	('SCC', 'Gene', (70, 73))	('epigenetic regulators themselves', 'MPA', (85, 117))	('SCC', 'Gene', '6317', (70, 73))	('pervasive abnormalities', 'Disease', 'MESH:D002659', (38, 61))	('genetic changes', 'Var', (144, 159))	('altered', 'Reg', (133, 140))
496938	28757263	Several tumor types have genetic alterations that can be targeted therapeutically, such as HER2+ breast tumors, EGFR+ lung tumors, and BRAF+ melanomas, but such actionable alterations have not been identified in ESCCs.	('breast tumors', 'Disease', 'MESH:D001943', (97, 110))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('breast tumors', 'Phenotype', 'HP:0100013', (97, 110))	('genetic alterations', 'Var', (25, 44))	('BRAF', 'Gene', '673', (135, 139))	('melanomas', 'Phenotype', 'HP:0002861', (141, 150))	('tumor', 'Disease', (123, 128))	('BRAF', 'Gene', (135, 139))	('lung tumors', 'Disease', 'MESH:D008175', (118, 129))	('HER2', 'Gene', (91, 95))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('EGFR', 'Gene', '1956', (112, 116))	('lung tumors', 'Phenotype', 'HP:0100526', (118, 129))	('EGFR', 'Gene', (112, 116))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('SCC', 'Gene', '6317', (213, 216))	('tumor', 'Disease', (104, 109))	('tumor', 'Disease', (8, 13))	('SCC', 'Gene', (213, 216))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('lung tumors', 'Disease', (118, 129))	('melanomas', 'Disease', 'MESH:D008545', (141, 150))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('HER2', 'Gene', '2064', (91, 95))	('melanomas', 'Disease', (141, 150))	('breast tumors', 'Disease', (97, 110))
496942	28757263	The most frequent high-level amplifications and homozygous deletions involve 11q13.2-q13.3 and 9p21.3 (locus of CDKN2A and CDKN2B), respectively (Table 1).	('CDKN2A', 'Gene', (112, 118))	('CDKN2A', 'Gene', '1029', (112, 118))	('CDKN2B', 'Gene', (123, 129))	('CDKN2B', 'Gene', '1030', (123, 129))	('amplifications', 'Var', (29, 43))
496945	28757263	CCND1 is amplified by breakage fusion bridge cycles, which occurs under conditions of chromosomal instability.	('CCND1', 'Gene', (0, 5))	('chromosomal instability', 'Phenotype', 'HP:0040012', (86, 109))	('CCND1', 'Gene', '595', (0, 5))	('breakage', 'Var', (22, 30))
496946	28757263	This gene is often coamplified with its neighboring oncogene CTTN; its product promotes migration of ESCC cells.	('SCC', 'Gene', '6317', (102, 105))	('promotes', 'PosReg', (79, 87))	('CTTN', 'Gene', (61, 65))	('product', 'Var', (71, 78))	('CTTN', 'Gene', '2017', (61, 65))	('SCC', 'Gene', (102, 105))
496947	28757263	Additional recurrent focal amplifications in ESCC include those at 8p11.23 (FGFR1), 8q24.21 (MYC), 7p11.2 (EGFR), 12p12.1 (KRAS), 12q15 (MDM2), 3q26 (TP63 and PRKCI), 3q26.32-q26.33 (SOX2 and PIK3CA), and 14q13.3 (NKX2-1).	('EGFR', 'Gene', (107, 111))	('PIK3CA', 'Gene', '5290', (192, 198))	('KRAS', 'Gene', (123, 127))	('FGFR1', 'Gene', '2260', (76, 81))	('MYC', 'Gene', '4609', (93, 96))	('PRKCI', 'Gene', '5584', (159, 164))	('SOX2', 'Gene', '6657', (183, 187))	('SOX2', 'Gene', (183, 187))	('MDM2', 'Gene', (137, 141))	('7p11.2', 'Var', (99, 105))	('TP63', 'Gene', (150, 154))	('12p12.1', 'Var', (114, 121))	('3q26.32-q26.33', 'Var', (167, 181))	('NKX2-1', 'Gene', '7080', (214, 220))	('3q26', 'Var', (144, 148))	('EGFR', 'Gene', '1956', (107, 111))	('MDM2', 'Gene', '4193', (137, 141))	('PIK3CA', 'Gene', (192, 198))	('NKX2-1', 'Gene', (214, 220))	('TP63', 'Gene', '8626', (150, 154))	('FGFR1', 'Gene', (76, 81))	('SCC', 'Gene', '6317', (46, 49))	('PRKCI', 'Gene', (159, 164))	('MYC', 'Gene', (93, 96))	('SCC', 'Gene', (46, 49))	('KRAS', 'Gene', '3845', (123, 127))	('14q13.3', 'Var', (205, 212))
496948	28757263	Other frequent homozygous deletions contain 2q22.1-q22.2 (LRP1B), 9p24.1 (PTPRD), and 3p14.2 (FHIT).	('3p14.2', 'Var', (86, 92))	('LRP1B', 'Gene', (58, 63))	('2q22.1-q22.2', 'Var', (44, 56))	('PTPRD', 'Gene', '5789', (74, 79))	('PTPRD', 'Gene', (74, 79))	('9p24.1', 'Var', (66, 72))	('LRP1B', 'Gene', '53353', (58, 63))	('FHIT', 'Gene', (94, 98))	('FHIT', 'Gene', '2272', (94, 98))
496950	28757263	Recently, researchers also have performed high-resolution characterization of structural rearrangements in ESCCs, including intrachromosome insertions, inversions and duplications, and interchromosome translocations.	('SCC', 'Gene', (108, 111))	('inversions', 'Var', (152, 162))	('duplications', 'Var', (167, 179))	('interchromosome translocations', 'Var', (185, 215))	('SCC', 'Gene', '6317', (108, 111))
496952	28757263	Most structural rearrangements are not likely to have pathogenic potential, but a few recurrent ones might be candidate driver events, such as frequent structural breakpoints affecting the KCNB2 gene, or an in-frame fusion between TRAPPC9 and CLVS1.	('CLVS1', 'Gene', (243, 248))	('KCNB2', 'Gene', '9312', (189, 194))	('structural breakpoints', 'Var', (152, 174))	('TRAPPC9', 'Gene', '83696', (231, 238))	('CLVS1', 'Gene', '157807', (243, 248))	('KCNB2', 'Gene', (189, 194))	('TRAPPC9', 'Gene', (231, 238))
496955	28757263	Additional structural rearrangements involving potential oncogenes included MYBL2 duplication, fusions of RUNX1T1-PHACTR1, MAML2-TTC28, ASXL1-RNF170, and FGF19-SHANK2.	('RNF170', 'Gene', (142, 148))	('PHACTR1', 'Gene', (114, 121))	('MYBL2', 'Gene', '4605', (76, 81))	('duplication', 'Var', (82, 93))	('RUNX1T1', 'Gene', '862', (106, 113))	('FGF19', 'Gene', (154, 159))	('FGF19', 'Gene', '9965', (154, 159))	('RNF170', 'Gene', '81790', (142, 148))	('MAML2', 'Gene', (123, 128))	('ASXL1', 'Gene', '171023', (136, 141))	('PHACTR1', 'Gene', '221692', (114, 121))	('TTC28', 'Gene', '23331', (129, 134))	('SHANK2', 'Gene', '22941', (160, 166))	('MAML2', 'Gene', '84441', (123, 128))	('RUNX1T1', 'Gene', (106, 113))	('fusions', 'Var', (95, 102))	('MYBL2', 'Gene', (76, 81))	('ASXL1', 'Gene', (136, 141))	('TTC28', 'Gene', (129, 134))	('SHANK2', 'Gene', (160, 166))
496964	28757263	Like many other cancer types, ESCCs contain prevalent mutations in TP53.	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('SCC', 'Gene', (31, 34))	('cancer', 'Disease', 'MESH:D009369', (16, 22))	('cancer', 'Disease', (16, 22))	('mutations', 'Var', (54, 63))	('SCC', 'Gene', '6317', (31, 34))	('TP53', 'Gene', '7157', (67, 71))	('TP53', 'Gene', (67, 71))
496965	28757263	Other driver mutations are much less frequent in ESCCs (found in fewer than 20% of samples).	('SCC', 'Gene', '6317', (50, 53))	('mutations', 'Var', (13, 22))	('SCC', 'Gene', (50, 53))
496969	28757263	Mutations in FAM135B, EP300, and TET2 have been associated with shorter times of patient survival.	('EP300', 'Gene', (22, 27))	('TET2', 'Gene', '54790', (33, 37))	('FAM135B', 'Gene', (13, 20))	('patient', 'Species', '9606', (81, 88))	('TET2', 'Gene', (33, 37))	('Mutations', 'Var', (0, 9))	('FAM135B', 'Gene', '51059', (13, 20))	('EP300', 'Gene', '2033', (22, 27))	('shorter', 'NegReg', (64, 71))
496971	28757263	Specifically, studies of ESCCs typically sequenced the exomes of 100 to 150 tumor-germline pairs, whereas mathematical analysis estimated that 1000 to 2000 samples are needed to identify with confidence SMGs mutated in 2% to 3% of the population, taking into account the background mutational rate of ESCC.	('SCC', 'Gene', '6317', (26, 29))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('SCC', 'Gene', (302, 305))	('mutated', 'Var', (208, 215))	('SCC', 'Gene', '6317', (302, 305))	('SMG', 'Chemical', '-', (203, 206))	('SCC', 'Gene', (26, 29))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
496975	28757263	Signature 1 is characterized by C > T substitutions at NpCpG trinucleotides and is the most commonly observed signature in ESCC samples.	('substitutions', 'Var', (38, 51))	('NpCpG', 'Gene', (55, 60))	('SCC', 'Gene', (124, 127))	('SCC', 'Gene', '6317', (124, 127))	('C > T substitutions', 'Var', (32, 51))	('trinucleotides', 'Chemical', '-', (61, 75))
496977	28757263	Another clock-like mutation signature found in ESCC is Signature 5, which is characterized by transcriptional strand bias for T > C substitutions at ApTpN trinucleotides.	('SCC', 'Gene', (48, 51))	('trinucleotides', 'Chemical', '-', (155, 169))	('SCC', 'Gene', '6317', (48, 51))	('T > C substitutions', 'Var', (126, 145))	('ApTpN', 'Gene', (149, 154))
496981	28757263	Signature 4, characterized by transcription strand bias for C > A substitutions, is found in a small set of ESCC tissues.	('SCC', 'Gene', (109, 112))	('SCC', 'Gene', '6317', (109, 112))	('C > A substitutions', 'Var', (60, 79))
496985	28757263	Mutations in PIK3CA and ZNF750 were significantly enriched in ESCCs with signature 2 and signature 13, suggesting that elevated APOBEC activity may lead to acquisition of driver mutations in these ESCCs.	('ZNF750', 'Gene', (24, 30))	('SCC', 'Gene', '6317', (198, 201))	('PIK3CA', 'Gene', (13, 19))	('SCC', 'Gene', (63, 66))	('PIK3CA', 'Gene', '5290', (13, 19))	('Mutations', 'Var', (0, 9))	('SCC', 'Gene', '6317', (63, 66))	('ZNF750', 'Gene', '79755', (24, 30))	('SCC', 'Gene', (198, 201))
496987	28757263	Nevertheless, these approaches have identified many factors that contribute to esophageal carcinogenesis, such as epigenetic silencing of genes, super-enhancer activation, and RNA editing.	('super-enhancer', 'Var', (145, 159))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (79, 104))	('esophageal carcinogenesis', 'Disease', (79, 104))	('epigenetic silencing', 'Var', (114, 134))	('genes', 'Gene', (138, 143))
496989	28757263	These epigenomic aberrations each contribute to the pathogenesis of ESCC, through different mechanisms.	('SCC', 'Gene', (69, 72))	('SCC', 'Gene', '6317', (69, 72))	('epigenomic aberrations', 'Var', (6, 28))	('contribute', 'Reg', (34, 44))
496990	28757263	Promoter hypermethylation silences tumor suppressor genes such as CDKN2A, CDKN2B, DLC1, LRP1B, and RASSF1A (Table 3).	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('silences', 'NegReg', (26, 34))	('DLC1', 'Gene', (82, 86))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('RASSF1A', 'Gene', '11186', (99, 106))	('CDKN2B', 'Gene', (74, 80))	('LRP1B', 'Gene', '53353', (88, 93))	('tumor', 'Disease', (35, 40))	('CDKN2A', 'Gene', '1029', (66, 72))	('CDKN2B', 'Gene', '1030', (74, 80))	('RASSF1A', 'Gene', (99, 106))	('DLC1', 'Gene', '10395', (82, 86))	('CDKN2A', 'Gene', (66, 72))	('LRP1B', 'Gene', (88, 93))	('Promoter hypermethylation', 'Var', (0, 25))
496991	28757263	A few genes encoding microRNAs are also methylated and down-regulated in ESCCs, compared with nonmalignant tissues, including those with anti-proliferative functions, such as microRNA34a and micro-RNA375.	('methylated', 'Var', (40, 50))	('micro-RNA375', 'Gene', '494324', (191, 203))	('SCC', 'Gene', (74, 77))	('down-regulated', 'NegReg', (55, 69))	('micro-RNA375', 'Gene', (191, 203))	('SCC', 'Gene', '6317', (74, 77))
496994	28757263	In addition, hypermethylation of the APC and FHIT promoters was significantly associated with reduced survival times of patients with ESCC, so these might be prognostic factors.	('APC', 'Disease', (37, 40))	('reduced', 'NegReg', (94, 101))	('FHIT', 'Gene', (45, 49))	('SCC', 'Gene', (135, 138))	('FHIT', 'Gene', '2272', (45, 49))	('patients', 'Species', '9606', (120, 128))	('survival times', 'CPA', (102, 116))	('hypermethylation', 'Var', (13, 29))	('SCC', 'Gene', '6317', (135, 138))	('APC', 'Disease', 'MESH:D011125', (37, 40))
496999	28757263	Consistent genome-wide hypomethylation was observed in ESCCs from different cohorts.	('SCC', 'Gene', (56, 59))	('observed', 'Reg', (43, 51))	('SCC', 'Gene', '6317', (56, 59))	('hypomethylation', 'Var', (23, 38))
497000	28757263	LINE-1 hypomethylation was associated with increased chromosomal instability, TP53 mutation, lymph node metastasis, as well as a shorter survival times of patients.	('hypomethylation', 'Var', (7, 22))	('chromosomal instability', 'MPA', (53, 76))	('increased chromosomal instability', 'Phenotype', 'HP:0040012', (43, 76))	('mutation', 'Var', (83, 91))	('patients', 'Species', '9606', (155, 163))	('TP53', 'Gene', '7157', (78, 82))	('increased', 'PosReg', (43, 52))	('TP53', 'Gene', (78, 82))	('chromosomal instability', 'Phenotype', 'HP:0040012', (53, 76))	('lymph node metastasis', 'CPA', (93, 114))	('shorter', 'NegReg', (129, 136))	('LINE-1', 'Gene', (0, 6))
497002	28757263	In glioma cells, changes in DNA methylation reduced the binding of CTCF to its motif sequence, disrupting insulated genomic domains.	('CTCF', 'Gene', '10664', (67, 71))	('disrupting', 'NegReg', (95, 105))	('motif', 'Protein', (79, 84))	('CTCF', 'Gene', (67, 71))	('glioma', 'Disease', 'MESH:D005910', (3, 9))	('glioma', 'Phenotype', 'HP:0009733', (3, 9))	('changes', 'Var', (17, 24))	('binding', 'Interaction', (56, 63))	('insulated genomic domains', 'MPA', (106, 131))	('reduced', 'NegReg', (44, 51))	('glioma', 'Disease', (3, 9))	('DNA', 'MPA', (28, 31))
497003	28757263	Thus, the ESCC methylome awaits further characterization through sequence-based approaches, such as reduced representation bisulfite sequencing and whole-genome bisulfite sequencing, which detect methylation changes with high resolution and a high level of sensitivity.	('SCC', 'Gene', (11, 14))	('bisulfite', 'Chemical', 'MESH:C042345', (161, 170))	('SCC', 'Gene', '6317', (11, 14))	('methylation', 'Var', (196, 207))	('bisulfite', 'Chemical', 'MESH:C042345', (123, 132))
497005	28757263	Many mutations detected in ESCCs lie in genes encoding proteins that modify DNA/histone (EP300, CREBBP, and MLL2), genes that remove histone modifications (KDM6A and TET2), and proteins that remodel chromatin structures (ARID1A, ARID2, and SMARCC2).	('SMARCC2', 'Gene', (240, 247))	('SCC', 'Gene', '6317', (28, 31))	('TET2', 'Gene', '54790', (166, 170))	('DNA/histone', 'Protein', (76, 87))	('ARID2', 'Gene', '196528', (229, 234))	('SCC', 'Gene', (28, 31))	('MLL2', 'Gene', '8085', (108, 112))	('SMARCC2', 'Gene', '6601', (240, 247))	('histone modifications', 'MPA', (133, 154))	('CREBBP', 'Gene', (96, 102))	('modify', 'Reg', (69, 75))	('MLL2', 'Gene', (108, 112))	('EP300', 'Gene', '2033', (89, 94))	('KDM6A', 'Gene', '7403', (156, 161))	('mutations', 'Var', (5, 14))	('ARID2', 'Gene', (229, 234))	('ARID1A', 'Gene', (221, 227))	('EP300', 'Gene', (89, 94))	('CREBBP', 'Gene', '1387', (96, 102))	('TET2', 'Gene', (166, 170))	('ARID1A', 'Gene', '8289', (221, 227))	('KDM6A', 'Gene', (156, 161))
497008	28757263	Ectopic expression of EZH2 in ESCC cell lines elevated the overall level of H3K27me3.	('EZH2', 'Gene', (22, 26))	('elevated', 'PosReg', (46, 54))	('SCC', 'Gene', (31, 34))	('Ectopic expression', 'Var', (0, 18))	('SCC', 'Gene', '6317', (31, 34))	('H3K27me3', 'Gene', '126961', (76, 84))	('H3K27me3', 'Gene', (76, 84))	('EZH2', 'Gene', '2146', (22, 26))	('level', 'MPA', (67, 72))
497017	28757263	The ADAR1 gene was reported to be amplified and overexpressed in primary ESCC tissues, and ectopic expression of ADAR1 enhanced a malignant phenotype of ESCC cells.	('SCC', 'Gene', '6317', (154, 157))	('SCC', 'Gene', '6317', (74, 77))	('ADAR1', 'Gene', '103', (113, 118))	('ADAR1', 'Gene', (4, 9))	('malignant phenotype of', 'CPA', (130, 152))	('ectopic expression', 'Var', (91, 109))	('ADAR1', 'Gene', '103', (4, 9))	('SCC', 'Gene', (74, 77))	('SCC', 'Gene', (154, 157))	('enhanced', 'PosReg', (119, 127))	('ADAR1', 'Gene', (113, 118))
497031	28757263	ESCC1 was characterized by enriched genomic aberrations targeting the nuclear factor, erythroid 2 like 2 (NRF2) pathway (NFE2L2, KEAP1, CUL3, and ATG7), as well as amplifications of SOX2, TP63, and YAP1.	('ATG7', 'Gene', (146, 150))	('CUL3', 'Gene', '8452', (136, 140))	('NRF2', 'Gene', '4780', (106, 110))	('YAP1', 'Gene', '10413', (198, 202))	('nuclear factor, erythroid 2 like 2', 'Gene', '4780', (70, 104))	('NFE2L2', 'Gene', '4780', (121, 127))	('TP63', 'Gene', (188, 192))	('YAP1', 'Gene', (198, 202))	('SCC', 'Gene', '6317', (1, 4))	('NRF2', 'Gene', (106, 110))	('amplifications', 'Var', (164, 178))	('TP63', 'Gene', '8626', (188, 192))	('CUL3', 'Gene', (136, 140))	('SCC', 'Gene', (1, 4))	('ATG7', 'Gene', '10533', (146, 150))	('NFE2L2', 'Gene', (121, 127))	('SOX2', 'Gene', (182, 186))	('SOX2', 'Gene', '6657', (182, 186))	('KEAP1', 'Gene', '9817', (129, 134))	('KEAP1', 'Gene', (129, 134))
497032	28757263	ESCC2 was found to be devoid of these genetic alterations, but instead had more frequent mutations or deletions in SMGs such as KDM6A, MLL2, NOTCH1, and ZNF750.	('KDM6A', 'Gene', '7403', (128, 133))	('SMG', 'Chemical', '-', (115, 118))	('deletions', 'Var', (102, 111))	('MLL2', 'Gene', (135, 139))	('ZNF750', 'Gene', '79755', (153, 159))	('KDM6A', 'Gene', (128, 133))	('SCC', 'Gene', (1, 4))	('NOTCH1', 'Gene', '4851', (141, 147))	('mutations', 'Var', (89, 98))	('SMGs', 'Gene', (115, 119))	('MLL2', 'Gene', '8085', (135, 139))	('ZNF750', 'Gene', (153, 159))	('NOTCH1', 'Gene', (141, 147))	('SCC', 'Gene', '6317', (1, 4))
497033	28757263	The minor subtype, ESCC3, had SMARCA4 mutations and fewer CNAs than the ESCC1 or ESCC2 subtypes.	('fewer', 'NegReg', (52, 57))	('SCC', 'Gene', (20, 23))	('SCC', 'Gene', '6317', (82, 85))	('CNAs', 'Disease', (58, 62))	('SCC', 'Gene', (73, 76))	('SCC', 'Gene', '6317', (20, 23))	('SCC', 'Gene', '6317', (73, 76))	('mutations', 'Var', (38, 47))	('SCC', 'Gene', (82, 85))	('SMARCA4', 'Gene', (30, 37))	('SMARCA4', 'Gene', '6597', (30, 37))
497039	28757263	Importantly, 40% of driver mutations were spatially heterogeneous, meaning they could be detected only in some, but not all cancer cells from the same tumor.	('mutations', 'Var', (27, 36))	('cancer', 'Disease', (124, 130))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumor', 'Disease', (151, 156))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('cancer', 'Disease', 'MESH:D009369', (124, 130))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
497040	28757263	Mathematical reconstruction of tumor progression showed that these heterogeneous mutations were relatively late events in ESCC development, promoting the expansion of subclones of cancer cells.	('promoting', 'PosReg', (140, 149))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('SCC', 'Gene', '6317', (123, 126))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('tumor', 'Disease', (31, 36))	('mutations', 'Var', (81, 90))	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('cancer', 'Disease', (180, 186))	('SCC', 'Gene', (123, 126))
497042	28757263	Nevertheless, despite this tendency, several ESCC oncogenes, such as PIK3CA, MTOR, NFE2L2, and KIT, become mutated in a subclonal manner.	('mutated', 'Var', (107, 114))	('KIT', 'Gene', (95, 98))	('MTOR', 'Gene', (77, 81))	('NFE2L2', 'Gene', '4780', (83, 89))	('PIK3CA', 'Gene', (69, 75))	('SCC', 'Gene', (46, 49))	('MTOR', 'Gene', '2475', (77, 81))	('PIK3CA', 'Gene', '5290', (69, 75))	('NFE2L2', 'Gene', (83, 89))	('SCC', 'Gene', '6317', (46, 49))
497044	28757263	In a clinical trial, AZD4547, an inhibitor of fibroblast growth factor receptor (FGFR), reduced growth of only gastric tumors with clonal FGFR2 amplification, not those with subclonal amplification of this gene.	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('AZD4547', 'Chemical', 'MESH:C572463', (21, 28))	('FGFR2', 'Gene', (138, 143))	('FGFR2', 'Gene', '2263', (138, 143))	('gastric tumors', 'Phenotype', 'HP:0006753', (111, 125))	('FGFR', 'Gene', (81, 85))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('gastric tumors', 'Disease', (111, 125))	('gastric tumors', 'Disease', 'MESH:D013274', (111, 125))	('growth', 'MPA', (96, 102))	('amplification', 'Var', (144, 157))	('reduced', 'NegReg', (88, 95))	('AZD4547', 'Var', (21, 28))
497048	28757263	Other important genomic and epigenomic variations, including copy number and DNA methylation changes, contribute to the spatial diversity within single ESCC tumors.	('ESCC tumors', 'Disease', 'MESH:D004938', (152, 163))	('DNA', 'MPA', (77, 80))	('tumors', 'Phenotype', 'HP:0002664', (157, 163))	('copy number', 'Var', (61, 72))	('ESCC tumors', 'Disease', (152, 163))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))
497049	28757263	Degrees of intratumor heterogeneity and tumor evolution determined by DNA methylation recapitulate those determined by somatic mutations, indicating interactions between genomic and epigenomic events during development of ESCC.	('methylation', 'Var', (74, 85))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('SCC', 'Gene', (223, 226))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('tumor', 'Disease', (16, 21))	('SCC', 'Gene', '6317', (223, 226))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('interactions', 'Interaction', (149, 161))
497052	28757263	Using reduced representation bisulfite sequencing to profile chronic lymphocytic leukemia, Landau et al demonstrated that the degree of intratumor heterogeneity of methylation correlated with shorter time of relapse-free survival.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('leukemia', 'Phenotype', 'HP:0001909', (81, 89))	('shorter', 'NegReg', (192, 199))	('lymphocytic leukemia', 'Disease', 'MESH:D007945', (69, 89))	('lymphocytic leukemia', 'Disease', (69, 89))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('methylation', 'Var', (164, 175))	('tumor', 'Disease', (141, 146))	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (61, 89))	('bisulfite', 'Chemical', 'MESH:C042345', (29, 38))
497053	28757263	Intratumor heterogeneity of mutation and methylation also associate with outcomes of patients with hepatocellular carcinoma.	('associate with', 'Reg', (58, 72))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('methylation', 'Var', (41, 52))	('patients', 'Species', '9606', (85, 93))	('mutation', 'Var', (28, 36))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (99, 123))	('tumor', 'Disease', (5, 10))	('hepatocellular carcinoma', 'Disease', (99, 123))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (99, 123))
497071	28757263	Notably, however, several mutations associated with ESCC were also found in BCH samples, including those in TP53, NOTCH1, CDKN2A, EP300, and MLL2.	('SCC', 'Gene', '6317', (53, 56))	('BCH', 'Chemical', '-', (76, 79))	('MLL2', 'Gene', (141, 145))	('NOTCH1', 'Gene', (114, 120))	('EP300', 'Gene', (130, 135))	('TP53', 'Gene', '7157', (108, 112))	('TP53', 'Gene', (108, 112))	('CDKN2A', 'Gene', (122, 128))	('found', 'Reg', (67, 72))	('CDKN2A', 'Gene', '1029', (122, 128))	('mutations', 'Var', (26, 35))	('MLL2', 'Gene', '8085', (141, 145))	('SCC', 'Gene', (53, 56))	('NOTCH1', 'Gene', '4851', (114, 120))	('EP300', 'Gene', '2033', (130, 135))
497072	28757263	All these mutations were found in BCH, IEN, and ESCC tissues, so they might be early clonal events involved in development of ESCC.	('SCC', 'Gene', (127, 130))	('SCC', 'Gene', (49, 52))	('IEN', 'Phenotype', 'HP:0032187', (39, 42))	('SCC', 'Gene', '6317', (127, 130))	('SCC', 'Gene', '6317', (49, 52))	('BCH', 'Chemical', '-', (34, 37))	('mutations', 'Var', (10, 19))
497073	28757263	Independent studies also showed that TP53 mutations persisted from IEN to invasive cancer.	('invasive cancer', 'Disease', (74, 89))	('invasive cancer', 'Disease', 'MESH:D009362', (74, 89))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('IEN', 'Disease', (67, 70))	('TP53', 'Gene', '7157', (37, 41))	('TP53', 'Gene', (37, 41))	('IEN', 'Phenotype', 'HP:0032187', (67, 70))	('mutations', 'Var', (42, 51))
497074	28757263	It is not clear how these mutations promote esophageal tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('promote', 'PosReg', (36, 43))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Disease', (55, 60))	('mutations', 'Var', (26, 35))
497075	28757263	A model was proposed in which mutations in p53 and Kruppel-like factor 5 (KLF5, a zinc finger-containing transcription factor) contribute to transformation of esophageal squamous cells through de-regulation of the NOTCH1 pathway.	('NOTCH1', 'Gene', '4851', (214, 220))	('NOTCH1', 'Gene', (214, 220))	('Kruppel-like factor 5', 'Gene', '688', (51, 72))	('de-regulation', 'NegReg', (193, 206))	('esophageal squamous', 'Disease', 'MESH:D000077277', (159, 178))	('esophageal squamous', 'Disease', (159, 178))	('Kruppel-like factor 5', 'Gene', (51, 72))	('KLF5', 'Gene', (74, 78))	('mutations', 'Var', (30, 39))	('p53', 'Gene', (43, 46))	('p53', 'Gene', '7157', (43, 46))	('KLF5', 'Gene', '688', (74, 78))
497077	28757263	In dysplastic esophageal cells, with a TP53 mutation, KLF5 replaces p53 to maintain NOTCH1 transcription.	('mutation', 'Var', (44, 52))	('NOTCH1', 'Gene', (84, 90))	('dysplastic esophageal', 'Disease', 'MESH:D004941', (3, 24))	('KLF5', 'Gene', (54, 58))	('TP53', 'Gene', '7157', (39, 43))	('p53', 'Gene', (68, 71))	('p53', 'Gene', '7157', (68, 71))	('KLF5', 'Gene', '688', (54, 58))	('NOTCH1', 'Gene', '4851', (84, 90))	('TP53', 'Gene', (39, 43))	('dysplastic esophageal', 'Disease', (3, 24))
497081	28757263	Compared with BCH, LGIEN and HGIEN contain more genomic and epigenomic alterations, including CNAs, gene mutations, loss of heterozygosity, and regions of promoter hypermethylation.	('gene', 'MPA', (100, 104))	('genomic', 'CPA', (48, 55))	('CNAs', 'Disease', (94, 98))	('IEN', 'Phenotype', 'HP:0032187', (21, 24))	('IEN', 'Phenotype', 'HP:0032187', (31, 34))	('BCH', 'Chemical', '-', (14, 17))	('loss of heterozygosity', 'Var', (116, 138))
497085	28757263	In precancer lesions, amplification of 7p11.2 (locus of EGFR), 11q13.2-q13.3 (CCND1), 8q24.21 (MYC), and 3q26.32-q26.33 (SOX2 and PIK3CA) and homozygous deletion of 9p21.3 (CDKN2A) are the most frequently detected aberrations.	('PIK3CA', 'Gene', (130, 136))	('MYC', 'Gene', '4609', (95, 98))	('PIK3CA', 'Gene', '5290', (130, 136))	('CDKN2A', 'Gene', (173, 179))	('SOX2', 'Gene', (121, 125))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('SOX2', 'Gene', '6657', (121, 125))	('EGFR', 'Gene', '1956', (56, 60))	('CDKN2A', 'Gene', '1029', (173, 179))	('CCND1', 'Gene', (78, 83))	('amplification', 'Var', (22, 35))	('EGFR', 'Gene', (56, 60))	('cancer', 'Disease', 'MESH:D009369', (6, 12))	('MYC', 'Gene', (95, 98))	('CCND1', 'Gene', '595', (78, 83))	('3q26.32-q26.33', 'Var', (105, 119))	('cancer', 'Disease', (6, 12))
497089	28757263	Some driver genes were also mutated at similar frequencies in IEN compared with matched ESCC samples, including TP53, NOTCH1, CDKN2A, FAT1, PIK3CA, RB1, EP300, and MLL2.	('PIK3CA', 'Gene', (140, 146))	('TP53', 'Gene', '7157', (112, 116))	('NOTCH1', 'Gene', (118, 124))	('RB1', 'Gene', (148, 151))	('SCC', 'Gene', '6317', (89, 92))	('FAT1', 'Gene', '2195', (134, 138))	('EP300', 'Gene', '2033', (153, 158))	('SCC', 'Gene', (89, 92))	('NOTCH1', 'Gene', '4851', (118, 124))	('mutated', 'Var', (28, 35))	('MLL2', 'Gene', '8085', (164, 168))	('CDKN2A', 'Gene', (126, 132))	('PIK3CA', 'Gene', '5290', (140, 146))	('RB1', 'Gene', '5925', (148, 151))	('MLL2', 'Gene', (164, 168))	('EP300', 'Gene', (153, 158))	('TP53', 'Gene', (112, 116))	('IEN', 'Phenotype', 'HP:0032187', (62, 65))	('CDKN2A', 'Gene', '1029', (126, 132))	('FAT1', 'Gene', (134, 138))
497090	28757263	In a mathematical assessment, a large fraction of these mutations was detected as fully clonal in precancerous lesions, so they might provide the cell with a proliferative or survival advantage.	('mutations', 'Var', (56, 65))	('precancerous lesions', 'Disease', 'MESH:D011230', (98, 118))	('precancerous lesions', 'Disease', (98, 118))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('proliferative', 'CPA', (158, 171))	('survival advantage', 'CPA', (175, 193))
497091	28757263	Other alterations detected in dysplasia include hypermethylation at promoters of tumor suppressor genes (CDKN2A, CLDN3, and MT1G) and loss of heterozygosity of microsatellite markers.	('CLDN3', 'Gene', (113, 118))	('CDKN2A', 'Gene', (105, 111))	('microsatellite', 'Protein', (160, 174))	('hypermethylation', 'Var', (48, 64))	('MT1G', 'Gene', (124, 128))	('CDKN2A', 'Gene', '1029', (105, 111))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('CLDN3', 'Gene', '1365', (113, 118))	('MT1G', 'Gene', '4495', (124, 128))	('dysplasia', 'Disease', (30, 39))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('dysplasia', 'Disease', 'MESH:D004476', (30, 39))	('loss', 'Var', (134, 138))	('tumor', 'Disease', (81, 86))
497093	28757263	Several signaling pathways are dysregulated in ESCCs via genomic and epigenomic aberrations.	('dysregulated', 'Reg', (31, 43))	('SCC', 'Gene', (48, 51))	('SCC', 'Gene', '6317', (48, 51))	('epigenomic aberrations', 'Var', (69, 91))
497097	28757263	In ESCC samples, gain of function mutations and copy number gains activate NRF2, whereas loss-of-function mutations and copy number loss inhibit KEAP1 and CUL3.	('SCC', 'Gene', (4, 7))	('loss-of-function', 'NegReg', (89, 105))	('KEAP1', 'Gene', '9817', (145, 150))	('SCC', 'Gene', '6317', (4, 7))	('copy number', 'Var', (120, 131))	('gain of function', 'PosReg', (17, 33))	('NRF2', 'Gene', '4780', (75, 79))	('KEAP1', 'Gene', (145, 150))	('gains', 'PosReg', (60, 65))	('mutations', 'Var', (106, 115))	('CUL3', 'Gene', '8452', (155, 159))	('CUL3', 'Gene', (155, 159))	('copy number', 'Var', (48, 59))	('NRF2', 'Gene', (75, 79))	('mutations', 'Var', (34, 43))	('loss inhibit', 'NegReg', (132, 144))
497098	28757263	ATG7, a direct regulator of autophagy-mediated KEAP1 turnover, is also deleted in a subset of ESCCs.	('KEAP1', 'Gene', (47, 52))	('SCC', 'Gene', '6317', (95, 98))	('SCC', 'Gene', (95, 98))	('ATG7', 'Gene', '10533', (0, 4))	('deleted', 'Var', (71, 78))	('KEAP1', 'Gene', '9817', (47, 52))	('ATG7', 'Gene', (0, 4))
497099	28757263	Together, these genomic changes increase activity of the antioxidative pathway in ESCCs, as well as other SCCs (such as HNSCC, LUSC, and skin SCC).	('SCC', 'Gene', (122, 125))	('increase', 'PosReg', (32, 40))	('SCC', 'Gene', '6317', (106, 109))	('antioxidative pathway', 'Pathway', (57, 78))	('SCC', 'Gene', (83, 86))	('SCC', 'Gene', (142, 145))	('SCC', 'Gene', '6317', (122, 125))	('SCC', 'Gene', '6317', (83, 86))	('SCC', 'Gene', '6317', (142, 145))	('changes', 'Var', (24, 31))	('HNSCC', 'Phenotype', 'HP:0012288', (120, 125))	('LUSC', 'Disease', (127, 131))	('activity', 'MPA', (41, 49))	('SCC', 'Gene', (106, 109))
497107	28757263	SOX2 and TP63 are often coamplified, whereas NOTCH1, NOTCH3, and ZNF750 are frequently mutated in ESCCs and other SCCs.	('SOX2', 'Gene', '6657', (0, 4))	('TP63', 'Gene', '8626', (9, 13))	('mutated', 'Var', (87, 94))	('SCC', 'Gene', '6317', (99, 102))	('NOTCH3', 'Gene', '4854', (53, 59))	('TP63', 'Gene', (9, 13))	('SCC', 'Gene', (114, 117))	('ZNF750', 'Gene', '79755', (65, 71))	('ZNF750', 'Gene', (65, 71))	('SCC', 'Gene', '6317', (114, 117))	('NOTCH1', 'Gene', '4851', (45, 51))	('NOTCH1', 'Gene', (45, 51))	('SCC', 'Gene', (99, 102))	('SOX2', 'Gene', (0, 4))	('NOTCH3', 'Gene', (53, 59))
497109	28757263	Therefore, these genomic changes converge to dysregulate the differentiation program of squamous cells, which can have profound effects on the biology of ESCC.	('SCC', 'Gene', (155, 158))	('dysregulate', 'Reg', (45, 56))	('effects', 'Reg', (128, 135))	('differentiation program', 'CPA', (61, 84))	('SCC', 'Gene', '6317', (155, 158))	('changes', 'Var', (25, 32))
497111	28757263	Some of these dysregulate the cell cycle, such as mutations in TP53 and CDKN2A (as well as deletion and promoter hypermethylation of this gene) and amplifications of CCND1 and CDK6.	('deletion', 'Var', (91, 99))	('TP53', 'Gene', '7157', (63, 67))	('TP53', 'Gene', (63, 67))	('mutations', 'Var', (50, 59))	('CDKN2A', 'Gene', '1029', (72, 78))	('CDK6', 'Gene', '1021', (176, 180))	('dysregulate', 'Reg', (14, 25))	('CCND1', 'Gene', '595', (166, 171))	('amplifications', 'Var', (148, 162))	('CCND1', 'Gene', (166, 171))	('CDK6', 'Gene', (176, 180))	('CDKN2A', 'Gene', (72, 78))	('cell cycle', 'CPA', (30, 40))
497114	28757263	Palbociclib and abemaciclib (another small-molecule inhibitor of CDK4 and CDK6) are currently being tested in phase 2 trials of patients with stage 4 LUSC (NCT02785939 and NCT02450539).	('NCT02785939', 'Var', (156, 167))	('CDK6', 'Gene', (74, 78))	('CDK6', 'Gene', '1021', (74, 78))	('Palbociclib', 'Chemical', 'MESH:C500026', (0, 11))	('CDK4', 'Gene', '1019', (65, 69))	('CDK4', 'Gene', (65, 69))	('patients', 'Species', '9606', (128, 136))	('NCT02450539', 'Var', (172, 183))
497116	28757263	Many mutations detected in ESCCs affect receptor tyrosine kinase signaling pathways.	('affect', 'Reg', (33, 39))	('SCC', 'Gene', (28, 31))	('mutations', 'Var', (5, 14))	('receptor tyrosine kinase signaling pathways', 'Pathway', (40, 83))	('SCC', 'Gene', '6317', (28, 31))
497117	28757263	ESCCs contain amplifications in EGFR, FGFR1, and KRAS along with activating mutations in PIK3CA.	('KRAS', 'Gene', '3845', (49, 53))	('PIK3CA', 'Gene', (89, 95))	('EGFR', 'Gene', '1956', (32, 36))	('PIK3CA', 'Gene', '5290', (89, 95))	('amplifications', 'Var', (14, 28))	('FGFR1', 'Gene', (38, 43))	('FGFR1', 'Gene', '2260', (38, 43))	('SCC', 'Gene', (1, 4))	('EGFR', 'Gene', (32, 36))	('SCC', 'Gene', '6317', (1, 4))	('KRAS', 'Gene', (49, 53))
497118	28757263	In many ESCCs, PTEN is deleted or contains loss-of-function mutations.	('loss-of-function', 'NegReg', (43, 59))	('PTEN', 'Gene', (15, 19))	('SCC', 'Gene', (9, 12))	('PTEN', 'Gene', '5728', (15, 19))	('mutations', 'Var', (60, 69))	('SCC', 'Gene', '6317', (9, 12))
497119	28757263	Some ESCCs have mutations in ERBB2, ERBB4, MET, and MTOR (Table 4).	('ERBB2', 'Gene', (29, 34))	('MET', 'Gene', (43, 46))	('ERBB2', 'Gene', '2064', (29, 34))	('SCC', 'Gene', (6, 9))	('ERBB4', 'Gene', (36, 41))	('MTOR', 'Gene', '2475', (52, 56))	('mutations', 'Var', (16, 25))	('SCC', 'Gene', '6317', (6, 9))	('ERBB4', 'Gene', '2066', (36, 41))	('MTOR', 'Gene', (52, 56))
497120	28757263	Interestingly, even though these genes are not mutated at high prevalences in ESCCs, their products (ERBB2, MET, and MTOR) are frequently overexpressed, indicating epigenetic, posttranscriptional, or posttranslational alterations (Table 4).	('SCC', 'Gene', (79, 82))	('overexpressed', 'PosReg', (138, 151))	('MTOR', 'Gene', '2475', (117, 121))	('indicating', 'Reg', (153, 163))	('SCC', 'Gene', '6317', (79, 82))	('ERBB2', 'Gene', '2064', (101, 106))	('epigenetic', 'Var', (164, 174))	('ERBB2', 'Gene', (101, 106))	('MTOR', 'Gene', (117, 121))
497122	28757263	Genomic lesions that activate Wnt signaling to beta-catenin have been reported in ESCCs, including disruptions in FAT1 or AJUBA (their products control beta-catenin turnover) and amplification of YAP1 (its product promotes the transcription activity of beta-catenin).	('FAT1', 'Gene', '2195', (114, 118))	('activate', 'PosReg', (21, 29))	('AJUBA', 'Gene', '84962', (122, 127))	('beta-catenin', 'Gene', (152, 164))	('beta-catenin', 'Gene', '1499', (152, 164))	('SCC', 'Gene', '6317', (83, 86))	('AJUBA', 'Gene', (122, 127))	('amplification', 'Var', (179, 192))	('YAP1', 'Gene', '10413', (196, 200))	('SCC', 'Gene', (83, 86))	('beta-catenin', 'Gene', (47, 59))	('beta-catenin', 'Gene', (253, 265))	('beta-catenin', 'Gene', '1499', (253, 265))	('beta-catenin', 'Gene', '1499', (47, 59))	('YAP1', 'Gene', (196, 200))	('FAT1', 'Gene', (114, 118))	('transcription', 'MPA', (227, 240))	('disruptions', 'Var', (99, 110))	('Wnt signaling', 'MPA', (30, 43))
497125	28757263	Other pathways that are dysregulated in ESCCs include the nuclear exportin process (by mutations in XPO1) and homologous recombination pathway (by mutations in BRCA1 and BRCA2).	('BRCA1', 'Gene', (160, 165))	('mutations', 'Var', (147, 156))	('nuclear exportin process', 'Pathway', (58, 82))	('SCC', 'Gene', (41, 44))	('BRCA2', 'Gene', (170, 175))	('SCC', 'Gene', '6317', (41, 44))	('XPO1', 'Gene', (100, 104))	('BRCA2', 'Gene', '675', (170, 175))	('XPO1', 'Gene', '7514', (100, 104))	('BRCA1', 'Gene', '672', (160, 165))	('mutations', 'Var', (87, 96))	('homologous recombination pathway', 'Pathway', (110, 142))
497138	28757263	ADAR adenosine deaminases acting on RNA APOBEC apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like BCH basal cell hyperplasia CIS carcinoma in situ CNA copy number alteration ESCC esophageal squamous cell carcinoma FGFR fibroblast growth factor receptor HGIEN high-grade IEN HNSCC head and neck squamous cell carcinoma IEN intraepithelial neoplasia KLF5 Kruppel-like factor 5 LGIEN low-grade IEN LINE-1 long interspersed nuclear element-1 LUSC squamous cell carcinoma of the lung NRF2 nuclear factor, erythroid 2 like 2 SMG significantly mutated gene WES whole-exome sequencing.	('SCC', 'Gene', '6317', (290, 293))	('SCC', 'Gene', (189, 192))	('squamous cell carcinoma of the lung', 'Disease', 'MESH:D002294', (457, 492))	('IEN', 'Phenotype', 'HP:0032187', (284, 287))	('carcinoma of the lung', 'Phenotype', 'HP:0100526', (471, 492))	('KLF5', 'Gene', (362, 366))	('IEN', 'Phenotype', 'HP:0032187', (332, 335))	('intraepithelial neoplasia', 'Disease', 'MESH:D019048', (336, 361))	('neck squamous cell carcinoma', 'Disease', (303, 331))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (303, 331))	('SCC', 'Gene', (290, 293))	('squamous cell carcinoma of the lung', 'Phenotype', 'HP:0030359', (457, 492))	('esophageal squamous cell carcinoma', 'Disease', (193, 227))	('nuclear factor, erythroid 2 like 2', 'Gene', '4780', (498, 532))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (204, 227))	('CIS', 'Phenotype', 'HP:0030075', (139, 142))	('basal cell hyperplasia', 'Disease', (116, 138))	('NRF2', 'Gene', '4780', (493, 497))	('BCH', 'Chemical', '-', (112, 115))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (308, 331))	('neoplasia', 'Phenotype', 'HP:0002664', (352, 361))	('adenosine deaminases acting on RNA', 'Gene', (5, 39))	('intraepithelial neoplasia', 'Disease', (336, 361))	('carcinoma in situ', 'Disease', (143, 160))	('carcinoma', 'Phenotype', 'HP:0030731', (143, 152))	('Kruppel-like factor 5', 'Gene', '688', (367, 388))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (457, 480))	('basal cell hyperplasia', 'Disease', 'MESH:D002280', (116, 138))	('adenosine deaminases acting on RNA', 'Gene', '103', (5, 39))	('HNSCC', 'Phenotype', 'HP:0012288', (288, 293))	('ADAR', 'Gene', (0, 4))	('alteration', 'Var', (177, 187))	('Kruppel-like factor 5', 'Gene', (367, 388))	('IEN', 'Phenotype', 'HP:0032187', (391, 394))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (294, 331))	('carcinoma', 'Phenotype', 'HP:0030731', (322, 331))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (193, 227))	('NRF2', 'Gene', (493, 497))	('carcinoma in situ', 'Phenotype', 'HP:0030075', (143, 160))	('basal cell hyperplasia CIS carcinoma in situ', 'Phenotype', 'HP:0002671', (116, 160))	('SMG', 'Chemical', '-', (533, 536))	('KLF5', 'Gene', '688', (362, 366))	('carcinoma', 'Phenotype', 'HP:0030731', (218, 227))	('SCC', 'Gene', '6317', (189, 192))	('carcinoma in situ', 'Disease', 'MESH:D002278', (143, 160))	('IEN', 'Phenotype', 'HP:0032187', (405, 408))	('IEN', 'Phenotype', 'HP:0032187', (269, 272))	('intraepithelial neoplasia', 'Phenotype', 'HP:0032187', (336, 361))	('squamous cell carcinoma of the lung', 'Disease', (457, 492))	('carcinoma', 'Phenotype', 'HP:0030731', (471, 480))	('ADAR', 'Gene', '103', (0, 4))
497142	29430184	In this study, we evaluated diagnostic roles of serum miR-9-5p, 21-5p, 223-3p, 135b-5p, 339-5p, and 501-5p in patients with non-small-cell lung cancer (NSCLC) in Yunnan.	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('patients', 'Species', '9606', (110, 118))	('501-5p', 'Chemical', '-', (100, 106))	('NSCLC', 'Disease', (152, 157))	('non-small-cell lung cancer', 'Disease', (124, 150))	('NSCLC', 'Disease', 'MESH:D002289', (152, 157))	('non-small-cell lung cancer', 'Disease', 'MESH:D002289', (124, 150))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (124, 150))	('135b-5p', 'Var', (79, 86))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (128, 150))	('lung cancer', 'Phenotype', 'HP:0100526', (139, 150))	('miR-9-5p', 'Gene', (54, 62))	('miR-9-5p', 'Gene', '407052', (54, 62))
497150	29430184	The area under ROC curves (AUCs) of miR-9-5p, miR-21-5p, miR-223-3p, CEA, CYFRA21-1, and SCC were 0.706, 0.765, 0.744, 0.749, 0.735, and 0.616, respectively.	('miR-223', 'Gene', (57, 64))	('CEA', 'Gene', (69, 72))	('SCC', 'Gene', '6317', (89, 92))	('miR-21-5p', 'Gene', (46, 55))	('miR-223', 'Gene', '407008', (57, 64))	('miR-21-5p', 'Gene', '406997', (46, 55))	('CYFRA21-1', 'Var', (74, 83))	('CEA', 'Gene', '1048', (69, 72))	('miR-9-5p', 'Gene', (36, 44))	('miR-9-5p', 'Gene', '407052', (36, 44))	('SCC', 'Gene', (89, 92))
497172	29430184	Here, we intended to investigate whether serum miR-9-5p, 21-5p, 223-3p, 135b-5p, 339-5p, and 501-5p were suitable for use as diagnostic biomarkers for patients with non-small-cell lung cancer (NSCLC) in Yunnan.	('non-small-cell lung cancer', 'Disease', (165, 191))	('non-small-cell lung cancer', 'Disease', 'MESH:D002289', (165, 191))	('miR-9-5p', 'Gene', (47, 55))	('miR-9-5p', 'Gene', '407052', (47, 55))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (165, 191))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('135b-5p', 'Var', (72, 79))	('patients', 'Species', '9606', (151, 159))	('501-5p', 'Chemical', '-', (93, 99))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (169, 191))	('NSCLC', 'Disease', (193, 198))	('lung cancer', 'Phenotype', 'HP:0100526', (180, 191))	('NSCLC', 'Disease', 'MESH:D002289', (193, 198))
497178	29430184	We tested the expression level of serum miR-9-5p, 21-5p, 223-3p, 135b-5p, 339-5p, and 501-5p in NSCLC and cancer-free subjects.	('NSCLC', 'Disease', (96, 101))	('NSCLC', 'Disease', 'MESH:D002289', (96, 101))	('501-5p', 'Chemical', '-', (86, 92))	('tested', 'Reg', (3, 9))	('135b-5p', 'Var', (65, 72))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('cancer', 'Disease', (106, 112))	('miR-9-5p', 'Gene', (40, 48))	('miR-9-5p', 'Gene', '407052', (40, 48))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
497190	29430184	Primers of miR-9-5p (#CD201-0142), miR-21-5p (#CD201-0092), miR-223-3p (#CD201-0099), miR-135b-5p (#CD201-0213), miR-339-5p (#CD201-0360), and miR-501-5p (#CD201-0641) were obtained from Tiangen Biotech.	('miR-501', 'Gene', '574503', (143, 150))	('miR', 'Gene', '220972', (60, 63))	('miR-135b', 'Gene', '442891', (86, 94))	('miR-223', 'Gene', '407008', (60, 67))	('miR-9-5p', 'Gene', (11, 19))	('miR', 'Gene', '220972', (11, 14))	('miR', 'Gene', '220972', (35, 38))	('miR-135b', 'Gene', (86, 94))	('miR', 'Gene', '220972', (113, 116))	('miR', 'Gene', (60, 63))	('miR', 'Gene', (11, 14))	('miR', 'Gene', (35, 38))	('#CD201-0099', 'Var', (72, 83))	('#CD201-0142', 'Var', (21, 32))	('#CD201-0213', 'Var', (99, 110))	('miR', 'Gene', (113, 116))	('miR', 'Gene', '220972', (143, 146))	('miR', 'Gene', '220972', (86, 89))	('#CD201-0641', 'Var', (155, 166))	('miR-223', 'Gene', (60, 67))	('miR-21-5p', 'Gene', (35, 44))	('501-5p', 'Chemical', '-', (147, 153))	('miR', 'Gene', (143, 146))	('#CD201-0360', 'Var', (125, 136))	('miR-9-5p', 'Gene', '407052', (11, 19))	('miR', 'Gene', (86, 89))	('miR-21-5p', 'Gene', '406997', (35, 44))	('#CD201-0092', 'Var', (46, 57))	('miR-501', 'Gene', (143, 150))
497204	29430184	Furthermore, high miR-21 expression was associated with advanced stage (P=0.02) and T factor (P=0.028).	('advanced stage', 'CPA', (56, 70))	('miR-21', 'Gene', '406991', (18, 24))	('high', 'Var', (13, 17))	('expression', 'MPA', (25, 35))	('miR-21', 'Gene', (18, 24))	('T factor', 'CPA', (84, 92))
497209	29430184	Higher CEA, CYFRA21-1, and SCC levels were associated with positive lymphatic metastasis and distal metastasis.	('SCC', 'Gene', (27, 30))	('SCC', 'Gene', '6317', (27, 30))	('CYFRA21-1', 'Var', (12, 21))	('CEA', 'Gene', '1048', (7, 10))	('CEA', 'Gene', (7, 10))	('distal metastasis', 'CPA', (93, 110))
497216	29430184	The AUCs of CEA, CYFRA21-1, and SCC were 0.749, 0.735, and 0.616, with sensitivities of 54.81%, 64.42%, and 35.58% and specificities of 96.00%, 70.00%, and 92.00% for CEA (Figure 2C), CYFRA21-1 (Figure 2D), and SCC (Figure 2D), respectively.	('SCC', 'Gene', '6317', (211, 214))	('CEA', 'Gene', '1048', (12, 15))	('CEA', 'Gene', (12, 15))	('CYFRA21-1', 'Var', (184, 193))	('SCC', 'Gene', (32, 35))	('CEA', 'Gene', (167, 170))	('SCC', 'Gene', (211, 214))	('CEA', 'Gene', '1048', (167, 170))	('SCC', 'Gene', '6317', (32, 35))
497220	29430184	The combination of CEA, CYFRA21-1, and SCC produced higher diagnostic performance, with AUC of 0.846, sensitivity of 55.77%, and specificity of 92.00% (Figure 2E).	('CYFRA21-1', 'Var', (24, 33))	('SCC', 'Gene', '6317', (39, 42))	('diagnostic performance', 'MPA', (59, 81))	('CEA', 'Gene', (19, 22))	('CEA', 'Gene', '1048', (19, 22))	('higher', 'PosReg', (52, 58))	('SCC', 'Gene', (39, 42))
497224	29430184	The AUCs of miR-9-5p, miR-21-5p, miR-223-3p, CEA, CYFRA21-1, and SCC in Xuanwei subjects were 0.644, 0.718, 0.752, 0.790, 0.731, and 0.583, respectively.	('SCC', 'Gene', (65, 68))	('CEA', 'Gene', '1048', (45, 48))	('miR-223', 'Gene', '407008', (33, 40))	('CYFRA21-1', 'Var', (50, 59))	('SCC', 'Gene', '6317', (65, 68))	('miR-21-5p', 'Gene', (22, 31))	('miR-9-5p', 'Gene', (12, 20))	('miR-9-5p', 'Gene', '407052', (12, 20))	('miR-21-5p', 'Gene', '406997', (22, 31))	('miR-223', 'Gene', (33, 40))	('CEA', 'Gene', (45, 48))
497227	29430184	For early-stage NSCLC patients, the AUCs of miR-9-5p, miR-21-5p, miR-223-3p, CEA, CYFRA21-1, and SCC were 0.699, 0.732, 0.740, 0.774, 0.687, and 0.587, respectively.	('miR-9-5p', 'Gene', (44, 52))	('miR-9-5p', 'Gene', '407052', (44, 52))	('NSCLC', 'Disease', 'MESH:D002289', (16, 21))	('miR-223', 'Gene', (65, 72))	('CEA', 'Gene', (77, 80))	('CEA', 'Gene', '1048', (77, 80))	('miR-21-5p', 'Gene', (54, 63))	('SCC', 'Gene', (97, 100))	('miR-21-5p', 'Gene', '406997', (54, 63))	('0.740', 'Var', (120, 125))	('SCC', 'Gene', '6317', (97, 100))	('NSCLC', 'Disease', (16, 21))	('patients', 'Species', '9606', (22, 30))	('CYFRA21-1', 'Var', (82, 91))	('0.732', 'Var', (113, 118))	('miR-223', 'Gene', '407008', (65, 72))
497278	29430184	However, in the non-Xuanwei population, miR-21-5p and CYFRA21-1 had higher AUCs.	('AUCs', 'MPA', (75, 79))	('higher', 'PosReg', (68, 74))	('CYFRA21-1', 'Var', (54, 63))	('miR-21-5p', 'Gene', (40, 49))	('miR-21-5p', 'Gene', '406997', (40, 49))
497297	27313498	We found that increased galectin-1 attenuated apoptosis of SCC cells exposed to deguelin, while galectin-1 knockdown sensitized lung cancer cells to deguelin treatment.	('knockdown', 'Var', (107, 116))	('apoptosis', 'CPA', (46, 55))	('increased', 'PosReg', (14, 23))	('galectin-1', 'Protein', (24, 34))	('increased galectin-1', 'Phenotype', 'HP:0032205', (14, 34))	('SCC', 'Gene', (59, 62))	('lung cancer', 'Disease', 'MESH:D008175', (128, 139))	('attenuated', 'NegReg', (35, 45))	('SCC', 'Phenotype', 'HP:0002860', (59, 62))	('deguelin', 'Chemical', 'MESH:C107676', (149, 157))	('SCC', 'Gene', '6317', (59, 62))	('deguelin', 'Chemical', 'MESH:C107676', (80, 88))	('lung cancer', 'Disease', (128, 139))	('lung cancer', 'Phenotype', 'HP:0100526', (128, 139))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
497317	27313498	In the present study, we focused on the potential effects of deguelin on human lung SCC and identified that deguelin can be an apoptosis inducer for lung SCC cells.	('SCC', 'Gene', '6317', (84, 87))	('SCC', 'Gene', '6317', (154, 157))	('deguelin', 'Chemical', 'MESH:C107676', (108, 116))	('SCC', 'Phenotype', 'HP:0002860', (84, 87))	('human', 'Species', '9606', (73, 78))	('deguelin', 'Chemical', 'MESH:C107676', (61, 69))	('deguelin', 'Var', (108, 116))	('SCC', 'Gene', (84, 87))	('SCC', 'Gene', (154, 157))	('SCC', 'Phenotype', 'HP:0002860', (154, 157))
497365	27313498	Next, we performed western blotting to determine the effects of galectin-1 knockdown on apoptosis-related proteins after deguelin treatment.	('knockdown', 'Var', (75, 84))	('apoptosis-related', 'MPA', (88, 105))	('galectin-1', 'Gene', (64, 74))	('deguelin', 'Chemical', 'MESH:C107676', (121, 129))
497372	27313498	We found that galectin-1 knockdown led to decreased expression of H-Ras, p-Raf-1 and p-ERK1/2, while galectin-1 overexpression resulted in the activation of Ras/Raf/ERK pathway (Fig.	('ERK', 'Gene', (87, 90))	('Raf', 'Gene', '22882', (161, 164))	('Raf', 'Gene', (75, 78))	('decreased', 'NegReg', (42, 51))	('p-Raf-1', 'Gene', '64425', (73, 80))	('H-Ras', 'Gene', '3265', (66, 71))	('ERK', 'Gene', '5594', (165, 168))	('expression', 'MPA', (52, 62))	('Raf', 'Gene', (161, 164))	('activation', 'PosReg', (143, 153))	('Raf', 'Gene', '22882', (75, 78))	('knockdown', 'Var', (25, 34))	('galectin-1', 'Gene', (14, 24))	('ERK', 'Gene', (165, 168))	('p-Raf-1', 'Gene', (73, 80))	('H-Ras', 'Gene', (66, 71))	('ERK', 'Gene', '5594', (87, 90))
497374	27313498	7C, flow cytometry was applied and we observed a significant cell apoptosis in L779450 treatment group.	('L779450', 'Var', (79, 86))	('L779450', 'Chemical', 'MESH:C530671', (79, 86))	('cell apoptosis', 'CPA', (61, 75))
497392	27313498	In the present study, we found that deguelin could induce the apoptosis of lung SCC cells in vitro, which is consistent with the effect of deguelin performed in other cancer cells.	('SCC', 'Gene', '6317', (80, 83))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('cancer', 'Disease', (167, 173))	('apoptosis', 'CPA', (62, 71))	('induce', 'PosReg', (51, 57))	('deguelin', 'Chemical', 'MESH:C107676', (139, 147))	('deguelin', 'Chemical', 'MESH:C107676', (36, 44))	('SCC', 'Gene', (80, 83))	('SCC', 'Phenotype', 'HP:0002860', (80, 83))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('lung', 'Disease', (75, 79))	('deguelin', 'Var', (36, 44))
497400	27313498	recently reported that NSCLC patients showing high galectin-1 expression were evidenced to have a poorer clinical outcome.	('high', 'Var', (46, 50))	('patients', 'Species', '9606', (29, 37))	('NSCLC', 'Phenotype', 'HP:0030358', (23, 28))	('galectin-1', 'Protein', (51, 61))	('expression', 'MPA', (62, 72))	('NSCLC', 'Disease', (23, 28))	('NSCLC', 'Disease', 'MESH:D002289', (23, 28))
497402	27313498	Here, we explore the effect of deguelin on galectin-1 and put forward that deguelin can reduce the galectin-1 expression level both in vivo and in vitro.	('deguelin', 'Chemical', 'MESH:C107676', (31, 39))	('galectin-1 expression level', 'MPA', (99, 126))	('deguelin', 'Var', (75, 83))	('deguelin', 'Chemical', 'MESH:C107676', (75, 83))	('reduce', 'NegReg', (88, 94))
497405	27313498	After exposured to deguelin, we found that galectin-1 knockdown sensitized lung cancer cells to deguelin treatment, while galectin-1 overexpression cells were insensitive to deguelin compared with control cells in vitro.	('lung cancer', 'Disease', (75, 86))	('galectin-1', 'Gene', (43, 53))	('sensitized', 'Reg', (64, 74))	('deguelin', 'Chemical', 'MESH:C107676', (96, 104))	('lung cancer', 'Phenotype', 'HP:0100526', (75, 86))	('knockdown', 'Var', (54, 63))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('lung cancer', 'Disease', 'MESH:D008175', (75, 86))	('deguelin', 'Chemical', 'MESH:C107676', (19, 27))	('deguelin', 'Chemical', 'MESH:C107676', (174, 182))
497410	27313498	Besides, silencing of galectin-1 resulted in down-regulation of H-Ras, p-Raf-1 and p-ERK1/2 in both deguelin-treated NCI-H520 and SK-MES-1 cells, while galectin-1 overexpression could up-regulate H-Ras, p-Raf-1 and p-ERK1/2, indicating that galectin-1 can regulate the Ras/Raf/ERK pathway through the interaction with H-Ras.	('galectin-1', 'Gene', (22, 32))	('deguelin', 'Chemical', 'MESH:C107676', (100, 108))	('Raf', 'Gene', (273, 276))	('H-Ras', 'Gene', '3265', (318, 323))	('SK-MES-1', 'CellLine', 'CVCL:0630', (130, 138))	('Raf', 'Gene', (73, 76))	('ERK', 'Gene', '5594', (217, 220))	('p-Raf-1', 'Gene', '64425', (203, 210))	('H-Ras', 'Gene', (318, 323))	('up-regulate', 'PosReg', (184, 195))	('Raf', 'Gene', '22882', (273, 276))	('H-Ras', 'Gene', '3265', (64, 69))	('p-Raf-1', 'Gene', (203, 210))	('down-regulation', 'NegReg', (45, 60))	('ERK', 'Gene', (217, 220))	('Raf', 'Gene', (205, 208))	('Raf', 'Gene', '22882', (73, 76))	('ERK', 'Gene', '5594', (277, 280))	('ERK', 'Gene', '5594', (85, 88))	('p-Raf-1', 'Gene', '64425', (71, 78))	('H-Ras', 'Gene', (64, 69))	('H-Ras', 'Gene', '3265', (196, 201))	('p-Raf-1', 'Gene', (71, 78))	('silencing', 'Var', (9, 18))	('regulate', 'Reg', (256, 264))	('NCI-H520', 'CellLine', 'CVCL:1566', (117, 125))	('ERK', 'Gene', (85, 88))	('Raf', 'Gene', '22882', (205, 208))	('interaction', 'Interaction', (301, 312))	('ERK', 'Gene', (277, 280))	('H-Ras', 'Gene', (196, 201))
497428	29933065	These personalized therapies include epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) for lung cancers with EGFR activating mutations, anaplastic lymphoma kinase (ALK) TKIs for those with ALK translocations, and ROS1-TKIs for those with ROS1 translocations .	('ALK', 'Gene', (188, 191))	('tyrosine', 'Chemical', 'None', (77, 85))	('ROS1', 'Gene', (262, 266))	('lung cancers', 'Disease', (115, 127))	('EGFR', 'Gene', '1956', (71, 75))	('EGFR', 'Gene', '1956', (133, 137))	('lung cancer', 'Phenotype', 'HP:0100526', (115, 126))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('lung cancers', 'Phenotype', 'HP:0100526', (115, 127))	('ROS1', 'Gene', (237, 241))	('cancers', 'Phenotype', 'HP:0002664', (120, 127))	('epidermal growth factor receptor', 'Gene', (37, 69))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (160, 179))	('mutations', 'Var', (149, 158))	('epidermal growth factor receptor', 'Gene', '1956', (37, 69))	('ROS1', 'Gene', '6098', (262, 266))	('ALK', 'Gene', '238', (213, 216))	('EGFR', 'Gene', (71, 75))	('anaplastic lymphoma kinase', 'Gene', '238', (160, 186))	('EGFR', 'Gene', (133, 137))	('anaplastic lymphoma kinase', 'Gene', (160, 186))	('ALK', 'Gene', (213, 216))	('lymphoma', 'Phenotype', 'HP:0002665', (171, 179))	('ROS1', 'Gene', '6098', (237, 241))	('activating', 'PosReg', (138, 148))	('lung cancers', 'Disease', 'MESH:D008175', (115, 127))	('ALK', 'Gene', '238', (188, 191))
497442	29933065	Briefly, IMPACT takes sequence data as an input and outputs a VCF file containing predicted deleterious mutations.	('mutations', 'Var', (104, 113))	('VCF file', 'Disease', 'MESH:D004062', (62, 70))	('VCF file', 'Disease', (62, 70))
497444	29933065	SAMTools  and BCFtools (v1.1) were utilized to detect variants from the BAM file and create a VCF file output.	('VCF file', 'Disease', (94, 102))	('variants', 'Var', (54, 62))	('BCFtools', 'Chemical', 'None', (14, 22))	('VCF file', 'Disease', 'MESH:D004062', (94, 102))
497446	29933065	To understand the development of tumor evolution, we identified acquired somatic and deleterious mutations on reliably expressed genes in different legions.	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('mutations', 'Var', (97, 106))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumor', 'Disease', (33, 38))
497471	29933065	We next focused on the mutational analysis by evaluating a list of gene mutations that have been previously reported in NSCLCs by next-generation sequencing.	('mutations', 'Var', (72, 81))	('NSCLCs', 'Disease', (120, 126))	('NSCLCs', 'Disease', 'MESH:D002289', (120, 126))
497473	29933065	2C), while the other adenocarcinoma patient had trunk RICTOR and DUSP5 mutations, both of which may have the potential to be driver mutations (Supplementary Fig.	('DUSP5', 'Gene', '1847', (65, 70))	('adenocarcinoma', 'Disease', (21, 35))	('RICTOR', 'Gene', (54, 60))	('mutations', 'Var', (71, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (26, 35))	('RICTOR', 'Gene', '253260', (54, 60))	('adenocarcinoma', 'Disease', 'MESH:D000230', (21, 35))	('DUSP5', 'Gene', (65, 70))	('patient', 'Species', '9606', (36, 43))
497474	29933065	On the other hand, both of the squamous cell carcinoma patients harbored a trunk NFE2L2 mutation, which was reported as one of the hallmark mutations in squamous cell carcinomas related to oxidative stress response.	('NFE2L2', 'Gene', '4780', (81, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (45, 54))	('mutation', 'Var', (88, 96))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (31, 54))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (153, 177))	('squamous cell carcinoma', 'Disease', (31, 54))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (153, 176))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (31, 54))	('NFE2L2', 'Gene', (81, 87))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (153, 176))	('oxidative stress', 'Phenotype', 'HP:0025464', (189, 205))	('carcinoma', 'Phenotype', 'HP:0030731', (167, 176))	('carcinomas', 'Phenotype', 'HP:0030731', (167, 177))	('patients', 'Species', '9606', (55, 63))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (153, 177))	('squamous cell carcinomas', 'Disease', (153, 177))	('harbored', 'Reg', (64, 72))
497475	29933065	We also detected a trunk ITGB4 mutation in both of the squamous cell carcinoma patients.	('ITGB4', 'Gene', (25, 30))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (55, 78))	('ITGB4', 'Gene', '3691', (25, 30))	('squamous cell carcinoma', 'Disease', (55, 78))	('detected', 'Reg', (8, 16))	('mutation', 'Var', (31, 39))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (55, 78))	('patients', 'Species', '9606', (79, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))
497480	29933065	A TP53 mutation, as well as a PARP2 mutation, was identified as trunk mutation (Supplementary Fig.	('PARP2', 'Gene', '10038', (30, 35))	('PARP2', 'Gene', (30, 35))	('TP53', 'Gene', '7157', (2, 6))	('mutation', 'Var', (7, 15))	('TP53', 'Gene', (2, 6))
497503	29933065	For the other adenocarcinoma patient, we identified the RICTOR mutation  as one of the trunk mutations.	('patient', 'Species', '9606', (29, 36))	('RICTOR', 'Gene', '253260', (56, 62))	('carcinoma', 'Phenotype', 'HP:0030731', (19, 28))	('mutation', 'Var', (63, 71))	('adenocarcinoma', 'Disease', (14, 28))	('RICTOR', 'Gene', (56, 62))	('adenocarcinoma', 'Disease', 'MESH:D000230', (14, 28))
497504	29933065	In the analysis of squamous cell carcinoma patients, we identified the NFE2L2 mutation as a trunk mutation in both cases, suggesting its importance in squamous cell carcinomas.	('carcinomas', 'Phenotype', 'HP:0030731', (165, 175))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (151, 174))	('mutation', 'Var', (78, 86))	('NFE2L2', 'Gene', (71, 77))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (151, 175))	('squamous cell carcinomas', 'Disease', (151, 175))	('patients', 'Species', '9606', (43, 51))	('carcinoma', 'Phenotype', 'HP:0030731', (33, 42))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (19, 42))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (151, 175))	('importance', 'Reg', (137, 147))	('squamous cell carcinoma', 'Disease', (19, 42))	('carcinoma', 'Phenotype', 'HP:0030731', (165, 174))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (19, 42))	('NFE2L2', 'Gene', '4780', (71, 77))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (151, 174))
497505	29933065	Both patients also harbored a trunk ITGB4 mutation, however the collaborative role of these two mutated genes in squamous cell carcinomas is currently unclear.	('carcinomas', 'Phenotype', 'HP:0030731', (127, 137))	('patients', 'Species', '9606', (5, 13))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (113, 137))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (113, 137))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (113, 136))	('mutation', 'Var', (42, 50))	('ITGB4', 'Gene', (36, 41))	('ITGB4', 'Gene', '3691', (36, 41))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('harbored', 'Reg', (19, 27))	('squamous cell carcinomas', 'Disease', (113, 137))
497521	29375740	Core tip: We have found that positron emission tomography-computed tomography (PET-CT) in the setting of upper gastrointestinal cancer has a high sensitivity and negative predictive value, but has poor specificity and positive predictive value for the detection of malignant mediastinal lymph nodes.	('gastrointestinal cancer', 'Phenotype', 'HP:0007378', (111, 134))	('upper gastrointestinal cancer', 'Disease', 'MESH:D004067', (105, 134))	('upper gastrointestinal cancer', 'Disease', (105, 134))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('positron', 'Var', (29, 37))
497560	29375740	When all one hundred and eight cases were taken into consideration, EUS-FNA led directly to an alteration in clinical stage and subsequent clinical management in twenty seven (25%) patients.	('alteration', 'Reg', (95, 105))	('EUS-FNA', 'Var', (68, 75))	('patients', 'Species', '9606', (181, 189))	('clinical stage', 'CPA', (109, 123))
497603	29375740	The authors found that EUS-FNA resulted in altered tumour staging and subsequent management in 25% of cases included in this study.	('altered tumour', 'Disease', (43, 57))	('tumour', 'Phenotype', 'HP:0002664', (51, 57))	('altered tumour', 'Disease', 'MESH:D009369', (43, 57))	('EUS-FNA', 'Var', (23, 30))	('management', 'CPA', (81, 91))
497609	29029464	MiR-324-3p promotes tumor growth through targeting DACT1 and activation of Wnt/beta-catenin pathway in hepatocellular carcinoma Recently, it has been reported that miR-324-3p participates in regulation of the carcinogenesis and tumor progression in various cancers.	('miR-324-3p', 'Var', (164, 174))	('cancer', 'Phenotype', 'HP:0002664', (257, 263))	('tumor', 'Disease', 'MESH:D009369', (228, 233))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (103, 127))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('MiR-324', 'Gene', '442898', (0, 7))	('beta-catenin', 'Gene', (79, 91))	('beta-catenin', 'Gene', '1499', (79, 91))	('carcinogenesis', 'Disease', (209, 223))	('hepatocellular carcinoma', 'Disease', (103, 127))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('cancers', 'Disease', 'MESH:D009369', (257, 264))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('carcinogenesis', 'Disease', 'MESH:D063646', (209, 223))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('MiR-324', 'Gene', (0, 7))	('promotes', 'PosReg', (11, 19))	('DACT1', 'Gene', '51339', (51, 56))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (103, 127))	('DACT1', 'Gene', (51, 56))	('tumor', 'Disease', (228, 233))	('cancers', 'Phenotype', 'HP:0002664', (257, 264))	('cancers', 'Disease', (257, 264))	('tumor', 'Disease', (20, 25))
497610	29029464	However, the expression and function of miR-324-3p in hepatocellular carcinoma (HCC) remain unclear.	('HCC', 'Phenotype', 'HP:0001402', (80, 83))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (54, 78))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (54, 78))	('miR-324-3p', 'Var', (40, 50))	('hepatocellular carcinoma', 'Disease', (54, 78))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))
497611	29029464	HCC patients with high miR-324-3p level showed poor prognostic features and shorter overall survival and disease-free survival.	('high miR-324-3p level', 'Var', (18, 39))	('HCC', 'Phenotype', 'HP:0001402', (0, 3))	('overall survival', 'CPA', (84, 100))	('HCC', 'Disease', (0, 3))	('patients', 'Species', '9606', (4, 12))	('shorter', 'NegReg', (76, 83))	('disease-free survival', 'CPA', (105, 126))
497612	29029464	Further studies demonstrated that miR-324-3p could directly target DACT1 (dishevelled binding antagonist of beta catenin 1) and negatively regulated its expression in HCC cells.	('negatively regulated', 'NegReg', (128, 148))	('dishevelled', 'Gene', (74, 85))	('DACT1', 'Gene', '51339', (67, 72))	('dishevelled', 'Gene', '8215', (74, 85))	('expression', 'MPA', (153, 163))	('HCC', 'Phenotype', 'HP:0001402', (167, 170))	('miR-324-3p', 'Var', (34, 44))	('DACT1', 'Gene', (67, 72))
497613	29029464	And rescue experiments revealed that DACT1 could reverse the effects of miR-324-3p on HCC cells.	('HCC', 'Phenotype', 'HP:0001402', (86, 89))	('DACT1', 'Gene', '51339', (37, 42))	('miR-324-3p', 'Var', (72, 82))	('DACT1', 'Gene', (37, 42))
497614	29029464	Furthermore, the accumulation of both cytoplasmic and nuclear beta-catenin as well as its downstream targets including c-Myc and cyclin D1 could be positively regulated by miR-324-3p.	('beta-catenin', 'Gene', (62, 74))	('miR-324-3p', 'Var', (172, 182))	('cyclin D1', 'Gene', '595', (129, 138))	('accumulation', 'MPA', (17, 29))	('cyclin D1', 'Gene', (129, 138))	('beta-catenin', 'Gene', '1499', (62, 74))	('c-Myc', 'Gene', '4609', (119, 124))	('c-Myc', 'Gene', (119, 124))
497615	29029464	The regulatory effects of miR-324-3p on beta-catenin, c-Myc and cyclin D1 levels could be reversed by DACT1.	('DACT1', 'Gene', (102, 107))	('DACT1', 'Gene', '51339', (102, 107))	('beta-catenin', 'Gene', (40, 52))	('cyclin D1', 'Gene', '595', (64, 73))	('c-Myc', 'Gene', '4609', (54, 59))	('miR-324-3p', 'Var', (26, 36))	('beta-catenin', 'Gene', '1499', (40, 52))	('cyclin D1', 'Gene', (64, 73))	('c-Myc', 'Gene', (54, 59))
497616	29029464	Overall, we concluded that miR-324-3p could promote tumor growth through targeting DACT1 and activation of Wnt/beta-catenin pathway in HCC.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('activation', 'PosReg', (93, 103))	('HCC', 'Disease', (135, 138))	('miR-324-3p', 'Var', (27, 37))	('promote', 'PosReg', (44, 51))	('DACT1', 'Gene', (83, 88))	('tumor', 'Disease', (52, 57))	('beta-catenin', 'Gene', (111, 123))	('HCC', 'Phenotype', 'HP:0001402', (135, 138))	('beta-catenin', 'Gene', '1499', (111, 123))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('DACT1', 'Gene', '51339', (83, 88))
497623	29029464	reported that miR-324-3p could modulate cancer cell growth and apoptosis by targeting SMAD family member 7 (SMAD7) in nasopharyngeal carcinoma.	('SMAD', 'Gene', (86, 90))	('SMAD7', 'Gene', '4092', (108, 113))	('miR-324-3p', 'Var', (14, 24))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('nasopharyngeal carcinoma', 'Disease', 'MESH:D000077274', (118, 142))	('cancer', 'Disease', (40, 46))	('SMAD', 'Gene', '4092', (108, 112))	('SMAD', 'Gene', '4092', (86, 90))	('carcinoma', 'Phenotype', 'HP:0030731', (133, 142))	('nasopharyngeal carcinoma', 'Disease', (118, 142))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (118, 142))	('modulate', 'Reg', (31, 39))	('apoptosis', 'CPA', (63, 72))	('SMAD7', 'Gene', (108, 113))	('targeting', 'Reg', (76, 85))	('SMAD', 'Gene', (108, 112))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))
497624	29029464	demonstrated that up-regulated miR-324-3p expression was an independent prognostic predictor for early stage lung squamous cell carcinoma.	('stage lung squamous cell carcinoma', 'Disease', (103, 137))	('up-regulated', 'PosReg', (18, 30))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (114, 137))	('miR-324-3p', 'Var', (31, 41))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (109, 137))	('stage lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (103, 137))
497632	29029464	Here, we reported that miR-324-3p was up-regulated in HCC, and highly expressed miR-324-3p was significantly associated with the malignant clinicopathologic features and poor prognosis of HCC patients.	('associated', 'Reg', (109, 119))	('HCC', 'Disease', (54, 57))	('miR-324-3p', 'Var', (80, 90))	('patients', 'Species', '9606', (192, 200))	('HCC', 'Phenotype', 'HP:0001402', (54, 57))	('HCC', 'Disease', (188, 191))	('miR-324-3p', 'Gene', (23, 33))	('HCC', 'Phenotype', 'HP:0001402', (188, 191))	('up-regulated', 'PosReg', (38, 50))
497633	29029464	Furthermore, DACT1, an inhibitor of Wnt/beta-catenin signaling pathway, was determined as a direct target of miR-324-3p in HCC.	('HCC', 'Disease', (123, 126))	('beta-catenin', 'Gene', (40, 52))	('HCC', 'Phenotype', 'HP:0001402', (123, 126))	('DACT1', 'Gene', '51339', (13, 18))	('beta-catenin', 'Gene', '1499', (40, 52))	('miR-324-3p', 'Var', (109, 119))	('DACT1', 'Gene', (13, 18))
497634	29029464	And miR-324-3p could exert its oncogenic role possibly by activating Wnt/beta-catenin signaling pathway.	('beta-catenin', 'Gene', '1499', (73, 85))	('activating', 'PosReg', (58, 68))	('miR-324-3p', 'Var', (4, 14))	('beta-catenin', 'Gene', (73, 85))
497635	29029464	Taken together, elevated miR-324-3p expression promotes HCC growth by inhibiting the expression of DACT1 and subsequently activating Wnt/beta-catenin signaling pathway.	('expression', 'MPA', (85, 95))	('HCC', 'Disease', (56, 59))	('activating', 'PosReg', (122, 132))	('miR-324-3p expression', 'Var', (25, 46))	('beta-catenin', 'Gene', '1499', (137, 149))	('HCC', 'Phenotype', 'HP:0001402', (56, 59))	('promotes', 'PosReg', (47, 55))	('elevated', 'PosReg', (16, 24))	('DACT1', 'Gene', '51339', (99, 104))	('inhibiting', 'NegReg', (70, 80))	('beta-catenin', 'Gene', (137, 149))	('DACT1', 'Gene', (99, 104))
497638	29029464	Hep3B cells had the highest expression while SMMC-7721 showed the lowest expression of miR-324-3p (Figure 1C).	('SMMC-7721', 'CellLine', 'CVCL:0534', (45, 54))	('expression', 'MPA', (28, 38))	('Hep3B', 'CellLine', 'CVCL:0326', (0, 5))	('miR-324-3p', 'Var', (87, 97))
497640	29029464	As showed in Table 1, high expression of miR-324-3p was closely correlated with large tumor size(P = 0.003), multiple tumor nodules (P = 0.007) and advanced TNM tumor stage (P = 0.020).	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('miR-324-3p', 'Var', (41, 51))	('TNM tumor', 'Disease', (157, 166))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('TNM tumor', 'Disease', 'MESH:D009369', (157, 166))	('tumor', 'Disease', (86, 91))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('multiple tumor', 'Disease', (109, 123))	('tumor', 'Disease', (118, 123))	('multiple tumor', 'Disease', 'MESH:D009369', (109, 123))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('correlated', 'Reg', (64, 74))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('tumor', 'Disease', (161, 166))
497641	29029464	In addition, Kaplan-Meier survival curves suggested that HCC patients in high miR-324-3p group had obvious shorter 3-year overall survival (OS) and disease-free survival (DFS) (P < 0.05, Figure 2A and 2B) compared to those in low miR-324-3p group.	('high miR-324-3p', 'Var', (73, 88))	('patients', 'Species', '9606', (61, 69))	('HCC', 'Disease', (57, 60))	('shorter', 'NegReg', (107, 114))	('disease-free survival', 'CPA', (148, 169))	('HCC', 'Phenotype', 'HP:0001402', (57, 60))	('overall survival', 'CPA', (122, 138))
497642	29029464	In conclusion, these data suggested miR-324-3p as a predictive biomarker for the prognosis of HCC patients.	('HCC', 'Disease', (94, 97))	('miR-324-3p', 'Var', (36, 46))	('HCC', 'Phenotype', 'HP:0001402', (94, 97))	('patients', 'Species', '9606', (98, 106))
497644	29029464	Results of MTT assay, colony formation assay, EdU cell proliferation assay and cell cycle analysis revealed that up-regulation of miR-324-3p markedly promoted cell viability, colony formation, proliferation and cell cycle progression in SMMC-7721 cells (P < 0.05, Figure 3B-3F).	('colony formation', 'CPA', (175, 191))	('SMMC-7721', 'CellLine', 'CVCL:0534', (237, 246))	('MTT', 'Chemical', 'MESH:C070243', (11, 14))	('promoted', 'PosReg', (150, 158))	('cell viability', 'CPA', (159, 173))	('proliferation', 'CPA', (193, 206))	('cell cycle progression', 'CPA', (211, 233))	('miR-324-3p', 'Var', (130, 140))	('up-regulation', 'PosReg', (113, 126))
497645	29029464	In accordance, miR-324-3p knockdown inhibited these cellular processes of Hep3B cells (P < 0.05, Figure 3B-3F).	('miR-324-3p knockdown', 'Var', (15, 35))	('inhibited', 'NegReg', (36, 45))	('cellular processes of Hep3B cells', 'CPA', (52, 85))	('Hep3B', 'CellLine', 'CVCL:0326', (74, 79))
497647	29029464	The data showed that the tumor growth was markedly promoted in SMMC-7721-miR-324-3p group compared to the control group (P < 0.05, Figure 4A).	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumor', 'Disease', (25, 30))	('SMMC-7721-miR-324-3p', 'Var', (63, 83))	('SMMC-7721', 'CellLine', 'CVCL:0534', (63, 72))	('promoted', 'PosReg', (51, 59))	('tumor', 'Disease', 'MESH:D009369', (25, 30))
497648	29029464	In contrast, miR-324-3p silencing could dramatically inhibit the growth of Hep3B cells in vivo (P < 0.05, Figure 4B).	('miR-324-3p silencing', 'Var', (13, 33))	('inhibit', 'NegReg', (53, 60))	('Hep3B', 'CellLine', 'CVCL:0326', (75, 80))	('growth of Hep3B cells in vivo', 'CPA', (65, 94))
497650	29029464	As expected, the expression of Ki-67 in tumor tissues with overexpressed miR-324-3p was obviously higher than those in control group (P < 0.01, Figure 4C).	('overexpressed', 'Var', (59, 72))	('Ki-67', 'Gene', (31, 36))	('expression', 'MPA', (17, 27))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('miR-324-3p', 'Var', (73, 83))	('higher', 'PosReg', (98, 104))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('Ki-67', 'Gene', '17345', (31, 36))
497651	29029464	Meanwhile, the expression of Ki-67 was significantly reduced in tumor tissues with anti-miR-324-3p (P < 0.001, Figure 4D).	('tumor', 'Disease', (64, 69))	('Ki-67', 'Gene', '17345', (29, 34))	('anti-miR-324-3p', 'Var', (83, 98))	('Ki-67', 'Gene', (29, 34))	('reduced', 'NegReg', (53, 60))	('expression', 'MPA', (15, 25))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
497652	29029464	Thus, the data suggested that miR-324-3p could promote tumor growth in vivo.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('promote', 'PosReg', (47, 54))	('tumor', 'Disease', (55, 60))	('miR-324-3p', 'Var', (30, 40))
497656	29029464	In addition, a significant inverse correlation was revealed by Pearson's correlation analysis between the expression levels of miR-324-3p and DACT1 mRNA in HCC tissues (R = -0.8356, P < 0.001, Figure 5D).	('HCC', 'Phenotype', 'HP:0001402', (156, 159))	('DACT1', 'Gene', '51339', (142, 147))	('DACT1', 'Gene', (142, 147))	('miR-324-3p', 'Var', (127, 137))	('expression levels', 'MPA', (106, 123))	('mRNA', 'MPA', (148, 152))
497657	29029464	Consistently, miR-324-3p overexpression could notably reduce the mRNA and protein expression of DACT1 in SMMC-7721 cells, while miR-324-3p knockdown significantly increased DACT1 level in Hep3B cells (P < 0.05, Figure 5E and 5F).	('Hep3B', 'CellLine', 'CVCL:0326', (188, 193))	('SMMC-7721', 'CellLine', 'CVCL:0534', (105, 114))	('DACT1', 'Gene', '51339', (173, 178))	('miR-324-3p', 'Var', (14, 24))	('increased', 'PosReg', (163, 172))	('reduce', 'NegReg', (54, 60))	('DACT1', 'Gene', (96, 101))	('miR-324-3p', 'Var', (128, 138))	('DACT1', 'Gene', (173, 178))	('overexpression', 'PosReg', (25, 39))	('DACT1', 'Gene', '51339', (96, 101))
497658	29029464	Subsequently, dual luciferase reporter assay showed that miR-324-3p significantly suppressed the luciferase activity of reporter that carried wild type (WT) but not mutant (Mut) 3'-UTR of DACT1 (P < 0.001, Figure 5G).	('mutant', 'Var', (165, 171))	('luciferase', 'Enzyme', (97, 107))	('DACT1', 'Gene', (188, 193))	('activity', 'MPA', (108, 116))	('suppressed', 'NegReg', (82, 92))	('DACT1', 'Gene', '51339', (188, 193))	('miR-324-3p', 'Var', (57, 67))
497659	29029464	In conclusion, these data strongly suggested that DACT1 was a target of miR-324-3p in HCC.	('miR-324-3p', 'Var', (72, 82))	('DACT1', 'Gene', '51339', (50, 55))	('HCC', 'Disease', (86, 89))	('DACT1', 'Gene', (50, 55))	('HCC', 'Phenotype', 'HP:0001402', (86, 89))
497660	29029464	Next, we attempted to determine whether DACT1 could mediate the effects of miR-324-3p in HCC cells.	('HCC', 'Phenotype', 'HP:0001402', (89, 92))	('DACT1', 'Gene', '51339', (40, 45))	('miR-324-3p', 'Var', (75, 85))	('DACT1', 'Gene', (40, 45))
497661	29029464	As expected, MTT assay, colony formation assay, EdU cell proliferation assay and cell cycle analysis revealed that the promoting effects of miR-324-3p mimics on cell viability, colony formation, proliferation and cell cycle progression of SMMC-7721 cells could be largely reversed by DACT1 restoration (P < 0.05, Figure 6A-6D).	('proliferation', 'CPA', (195, 208))	('cell cycle progression', 'CPA', (213, 235))	('SMMC-7721', 'CellLine', 'CVCL:0534', (239, 248))	('MTT', 'Chemical', 'MESH:C070243', (13, 16))	('cell viability', 'CPA', (161, 175))	('DACT1', 'Gene', '51339', (284, 289))	('colony formation', 'CPA', (177, 193))	('DACT1', 'Gene', (284, 289))	('miR-324-3p', 'Var', (140, 150))	('promoting', 'PosReg', (119, 128))
497662	29029464	On the contrary, DACT1 siRNA could strongly rescue the effects of miR-324-3p on cell viability, colony formation, proliferation and cell cycle progression of Hep3B cells (P < 0.05, Figure 6A-6D).	('Hep3B', 'CellLine', 'CVCL:0326', (158, 163))	('miR-324-3p', 'Var', (66, 76))	('DACT1', 'Gene', (17, 22))	('cell viability', 'CPA', (80, 94))	('proliferation', 'CPA', (114, 127))	('colony formation', 'CPA', (96, 112))	('cell cycle progression', 'CPA', (132, 154))	('DACT1', 'Gene', '51339', (17, 22))	('rescue', 'PosReg', (44, 50))
497663	29029464	Then, we concluded that DACT1 mediated the effects of miR-324-3p in HCC cells.	('miR-324-3p', 'Var', (54, 64))	('DACT1', 'Gene', '51339', (24, 29))	('HCC', 'Phenotype', 'HP:0001402', (68, 71))	('DACT1', 'Gene', (24, 29))
497665	29029464	Next, we explored whether miR-324-3p could increase the accumulation of both cytoplasmic and nuclear beta-catenin in HCC cells.	('HCC', 'Phenotype', 'HP:0001402', (117, 120))	('beta-catenin', 'Gene', (101, 113))	('increase', 'PosReg', (43, 51))	('miR-324-3p', 'Var', (26, 36))	('beta-catenin', 'Gene', '1499', (101, 113))	('accumulation', 'MPA', (56, 68))
497666	29029464	As showed in Figure 7, the results of Western blot revealed that both cytoplasmic and nuclear beta-catenin expressions were increased in SMMC-7721 cells after miR-324-3p overexpression, while decreased in Hep3B cells with miR-324-3p knockdown (P < 0.05).	('miR-324-3p', 'Var', (159, 169))	('increased', 'PosReg', (124, 133))	('beta-catenin', 'Gene', (94, 106))	('cytoplasmic', 'MPA', (70, 81))	('beta-catenin', 'Gene', '1499', (94, 106))	('Hep3B', 'CellLine', 'CVCL:0326', (205, 210))	('SMMC-7721', 'CellLine', 'CVCL:0534', (137, 146))
497667	29029464	Furthermore, our results showed that modulating DACT1 expression by expression plasmid or siRNA obviously reversed cytoplasmic and nuclear beta-catenin expression in miR-324-3p overexpressing SMMC-7721 cells or miR-324-3p down-regulating Hep3B cells (P < 0.05, Figure 7).	('SMMC-7721', 'CellLine', 'CVCL:0534', (192, 201))	('DACT1', 'Gene', (48, 53))	('modulating', 'Var', (37, 47))	('DACT1', 'Gene', '51339', (48, 53))	('beta-catenin', 'Gene', (139, 151))	('miR-324-3p', 'Var', (166, 176))	('miR-324-3p', 'Var', (211, 221))	('down-regulating', 'NegReg', (222, 237))	('Hep3B', 'CellLine', 'CVCL:0326', (238, 243))	('beta-catenin', 'Gene', '1499', (139, 151))
497668	29029464	Meanwhile, c-Myc and cyclin D1, downstream targets of Wnt/beta-catenin pathway, were positively regulated by miR-324-3p and negatively modulated by DACT1 in HCC cells (P < 0.05, Figure 7).	('DACT1', 'Gene', '51339', (148, 153))	('beta-catenin', 'Gene', (58, 70))	('c-Myc', 'Gene', (11, 16))	('beta-catenin', 'Gene', '1499', (58, 70))	('DACT1', 'Gene', (148, 153))	('positively', 'PosReg', (85, 95))	('miR-324-3p', 'Var', (109, 119))	('HCC', 'Phenotype', 'HP:0001402', (157, 160))	('regulated', 'Reg', (96, 105))	('cyclin D1', 'Gene', '595', (21, 30))	('cyclin D1', 'Gene', (21, 30))	('c-Myc', 'Gene', '4609', (11, 16))
497669	29029464	Hence, miR-324-3p could enhanced Wnt/beta-catenin signaling pathway through decreasing DACT1 expression and increasing accumulation of both cytoplasmic and nuclear beta-catenin in HCC cells.	('accumulation', 'MPA', (119, 131))	('beta-catenin', 'Gene', (164, 176))	('miR-324-3p', 'Var', (7, 17))	('beta-catenin', 'Gene', '1499', (164, 176))	('HCC', 'Phenotype', 'HP:0001402', (180, 183))	('DACT1', 'Gene', (87, 92))	('enhanced', 'PosReg', (24, 32))	('beta-catenin', 'Gene', (37, 49))	('expression', 'MPA', (93, 103))	('decreasing', 'NegReg', (76, 86))	('increasing', 'PosReg', (108, 118))	('DACT1', 'Gene', '51339', (87, 92))	('beta-catenin', 'Gene', '1499', (37, 49))
497672	29029464	And a research revealed that miR-129-2 might serve as a prognostic indicator for HCC patients and exerted a tumor suppressive role by inhibiting high mobility group box 1 (HMGB1).What's more, miR-324-3p has been suggested to be involved in tumorigenesis and tumor development by acting as an oncogene or tumor suppressor in several cancers, such as nasopharyngeal carcinoma, colorectal cancer and lung squamous cell carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (416, 425))	('colorectal cancer', 'Disease', 'MESH:D015179', (375, 392))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (397, 425))	('tumor', 'Disease', (258, 263))	('tumor', 'Disease', (108, 113))	('cancers', 'Disease', 'MESH:D009369', (332, 339))	('colorectal cancer', 'Disease', (375, 392))	('tumor', 'Disease', (304, 309))	('nasopharyngeal carcinoma', 'Disease', (349, 373))	('tumor', 'Disease', 'MESH:D009369', (258, 263))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('miR-129-2', 'Gene', (29, 38))	('tumor', 'Disease', (240, 245))	('tumor', 'Disease', 'MESH:D009369', (304, 309))	('HMGB1', 'Gene', (172, 177))	('miR-129-2', 'Gene', '100302138', (29, 38))	('patients', 'Species', '9606', (85, 93))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (397, 425))	('HMGB1', 'Gene', '3146', (172, 177))	('nasopharyngeal carcinoma', 'Disease', 'MESH:D000077274', (349, 373))	('tumor', 'Disease', 'MESH:D009369', (240, 245))	('lung squamous cell carcinoma', 'Disease', (397, 425))	('carcinoma', 'Phenotype', 'HP:0030731', (364, 373))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (402, 425))	('miR-324-3p', 'Var', (192, 202))	('tumor', 'Phenotype', 'HP:0002664', (258, 263))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('colorectal cancer', 'Phenotype', 'HP:0003003', (375, 392))	('cancers', 'Phenotype', 'HP:0002664', (332, 339))	('tumor', 'Phenotype', 'HP:0002664', (304, 309))	('cancers', 'Disease', (332, 339))	('high mobility group box 1', 'Gene', (145, 170))	('tumor', 'Phenotype', 'HP:0002664', (240, 245))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (349, 373))	('high mobility group box 1', 'Gene', '3146', (145, 170))	('involved', 'Reg', (228, 236))	('cancer', 'Phenotype', 'HP:0002664', (332, 338))	('HCC', 'Phenotype', 'HP:0001402', (81, 84))	('cancer', 'Phenotype', 'HP:0002664', (386, 392))
497673	29029464	highlight that miR-324-3p is significantly overexpressed in the HBV-positive HCC patients compared with the HBV-positive cancer-free controls in both the training and validation sets.	('HCC', 'Disease', (77, 80))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('miR-324-3p', 'Var', (15, 25))	('HCC', 'Phenotype', 'HP:0001402', (77, 80))	('HBV-positive', 'Gene', (64, 76))	('patients', 'Species', '9606', (81, 89))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('overexpressed', 'PosReg', (43, 56))	('cancer', 'Disease', (121, 127))
497674	29029464	In addition, elevated miR-324-3p expression was closely associated with several growth-associated malignant clinicopathologic characteristics, including large tumor size, multiple tumor nodules, advanced TNM stage.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('TNM', 'Gene', (204, 207))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('elevated', 'PosReg', (13, 21))	('multiple tumor', 'Disease', (171, 185))	('tumor', 'Disease', (180, 185))	('associated', 'Reg', (56, 66))	('multiple tumor', 'Disease', 'MESH:D009369', (171, 185))	('tumor', 'Disease', (159, 164))	('miR-324-3p', 'Var', (22, 32))	('expression', 'MPA', (33, 43))	('TNM', 'Gene', '10178', (204, 207))	('tumor', 'Disease', 'MESH:D009369', (159, 164))
497675	29029464	HCC patients in high miR-324-3p group had shorter 3-year OS and DFS compared to those in low miR-324-3p group.	('shorter', 'NegReg', (42, 49))	('high miR-324-3p', 'Var', (16, 31))	('HCC', 'Disease', (0, 3))	('patients', 'Species', '9606', (4, 12))	('HCC', 'Phenotype', 'HP:0001402', (0, 3))	('DFS', 'CPA', (64, 67))
497676	29029464	Meanwhile, results from the subcutaneous nude mice models confirmed that miR-324-3p could promote tumor growth of HCC in vivo.	('HCC', 'Phenotype', 'HP:0001402', (114, 117))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('HCC', 'Disease', (114, 117))	('miR-324-3p', 'Var', (73, 83))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('promote', 'PosReg', (90, 97))	('tumor', 'Disease', (98, 103))	('nude mice', 'Species', '10090', (41, 50))
497680	29029464	Interestingly, a negative correlation between miR-324-3p and DACT1 was observed in HCC tissues.	('HCC', 'Phenotype', 'HP:0001402', (83, 86))	('negative', 'NegReg', (17, 25))	('DACT1', 'Gene', '51339', (61, 66))	('miR-324-3p', 'Var', (46, 56))	('HCC', 'Disease', (83, 86))	('DACT1', 'Gene', (61, 66))
497681	29029464	And miR-324-3p could negatively regulate the expression of DACT1 in HCC cells.	('regulate', 'Reg', (32, 40))	('negatively', 'NegReg', (21, 31))	('DACT1', 'Gene', (59, 64))	('miR-324-3p', 'Var', (4, 14))	('expression', 'MPA', (45, 55))	('DACT1', 'Gene', '51339', (59, 64))	('HCC', 'Phenotype', 'HP:0001402', (68, 71))
497682	29029464	In addition, dual luciferase reporter assay showed that miR-324-3p could bind to 3'-UTR of DACT1.	('miR-324-3p', 'Var', (56, 66))	('DACT1', 'Gene', (91, 96))	('DACT1', 'Gene', '51339', (91, 96))	('bind', 'Interaction', (73, 77))
497683	29029464	Then, we demonstrated that miR-324-3p could directly target DACT1 in HCC cells.	('target', 'Reg', (53, 59))	('miR-324-3p', 'Var', (27, 37))	('DACT1', 'Gene', '51339', (60, 65))	('HCC', 'Phenotype', 'HP:0001402', (69, 72))	('DACT1', 'Gene', (60, 65))
497684	29029464	Furthermore, the rescue experiments revealed that DACT1 could reverse the effects of miR-324-3p on cell viability, colony formation, proliferation and cell cycle progression of HCC cells.	('cell cycle progression', 'CPA', (151, 173))	('colony formation', 'CPA', (115, 131))	('HCC', 'Phenotype', 'HP:0001402', (177, 180))	('DACT1', 'Gene', '51339', (50, 55))	('proliferation', 'CPA', (133, 146))	('DACT1', 'Gene', (50, 55))	('miR-324-3p', 'Var', (85, 95))	('cell viability', 'CPA', (99, 113))
497685	29029464	Then, we demonstrate that DACT1 mediates the effects of miR-324-3p in HCC cells.	('miR-324-3p', 'Var', (56, 66))	('HCC', 'Phenotype', 'HP:0001402', (70, 73))	('DACT1', 'Gene', (26, 31))	('DACT1', 'Gene', '51339', (26, 31))
497688	29029464	Next, we observed that the accumulation of both cytoplasmic and nuclear beta-catenin as well as its downstream targets, c-Myc and cyclin D1, could be positively regulated by miR-324-3p in HCC cells.	('c-Myc', 'Gene', (120, 125))	('accumulation', 'MPA', (27, 39))	('beta-catenin', 'Gene', (72, 84))	('beta-catenin', 'Gene', '1499', (72, 84))	('cyclin D1', 'Gene', '595', (130, 139))	('regulated', 'Reg', (161, 170))	('c-Myc', 'Gene', '4609', (120, 125))	('cytoplasmic', 'MPA', (48, 59))	('HCC', 'Phenotype', 'HP:0001402', (188, 191))	('cyclin D1', 'Gene', (130, 139))	('miR-324-3p', 'Var', (174, 184))
497690	29029464	These data reveal that miR-324-3p activates Wnt/beta-catenin signaling pathway via targeting DACT1 in HCC cells.	('beta-catenin', 'Gene', (48, 60))	('DACT1', 'Gene', (93, 98))	('activates', 'PosReg', (34, 43))	('targeting', 'Reg', (83, 92))	('beta-catenin', 'Gene', '1499', (48, 60))	('HCC', 'Phenotype', 'HP:0001402', (102, 105))	('DACT1', 'Gene', '51339', (93, 98))	('miR-324-3p', 'Var', (23, 33))
497691	29029464	Taken together, our study report that miR-324-3p promotes tumor growth through targeting DACT1 and activation of Wnt/beta-catenin pathway in HCC.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('beta-catenin', 'Gene', (117, 129))	('DACT1', 'Gene', (89, 94))	('promotes', 'PosReg', (49, 57))	('beta-catenin', 'Gene', '1499', (117, 129))	('activation', 'PosReg', (99, 109))	('DACT1', 'Gene', '51339', (89, 94))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('HCC', 'Disease', (141, 144))	('HCC', 'Phenotype', 'HP:0001402', (141, 144))	('miR-324-3p', 'Var', (38, 48))
497703	29029464	Then, the above PVDF membranes were incubated with corresponding primary antibodies: DACT1 (1:1000, ab51260, Abcam, MA, USA), beta-catenin (1:1000, ab32572, Abcam), Cyclin D1 (1:1000, ab134175, Abcam), c-Myc (1:1000, ab32072, Abcam) and beta-actin (1:500, sc-130656, Santa Cruz, CA, USA).	('1:1000', 'Var', (209, 215))	('beta-catenin', 'Gene', '1499', (126, 138))	('c-Myc', 'Gene', (202, 207))	('c-Myc', 'Gene', '4609', (202, 207))	('Cyclin D1', 'Gene', '595', (165, 174))	('sc-130656', 'Var', (256, 265))	('DACT1', 'Gene', '51339', (85, 90))	('1:500', 'Var', (249, 254))	('PVDF', 'Chemical', 'MESH:C024865', (16, 20))	('Cyclin D1', 'Gene', (165, 174))	('beta-catenin', 'Gene', (126, 138))	('DACT1', 'Gene', (85, 90))
497729	28764725	Additionally, EGFR inhibitors induced squamous cell differentiation (defined as increased expression of involucrin and cytokeratin13) in epithelial-like but not mesenchymal-like cells.	('cytokeratin13', 'Gene', '3860', (119, 132))	('squamous', 'Disease', (38, 46))	('EGFR', 'Gene', (14, 18))	('induced', 'Reg', (30, 37))	('inhibitors', 'Var', (19, 29))	('cytokeratin13', 'Gene', (119, 132))
497730	28764725	Cetuximab consistently showed antitumor effects, and increased involucrin expression in TE-11R (epithelial-like)-derived xenograft tumors but not TE-8 (mesenchymal-like)-derived xenograft tumors.	('tumor', 'Disease', (188, 193))	('involucrin expression', 'MPA', (63, 84))	('xenograft tumors', 'Disease', (178, 194))	('TE-11R', 'Var', (88, 94))	('tumor', 'Disease', (131, 136))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('increased', 'PosReg', (53, 62))	('xenograft tumors', 'Disease', 'MESH:D009369', (178, 194))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('tumor', 'Disease', (34, 39))	('tumors', 'Phenotype', 'HP:0002664', (188, 194))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('Cetuximab', 'Chemical', 'MESH:D000068818', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('xenograft tumors', 'Disease', (121, 137))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('xenograft tumors', 'Disease', 'MESH:D009369', (121, 137))	('Cetuximab', 'Gene', (0, 9))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('TE-11R', 'Chemical', '-', (88, 94))
497733	28764725	EGFR inhibitors show antitumor effects on epithelial-like ESCC cells accompanied by promotion of squamous cell differentiation.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('SCC', 'Gene', (59, 62))	('EGFR', 'Gene', (0, 4))	('tumor', 'Disease', (25, 30))	('inhibitors', 'Var', (5, 15))	('SCC', 'Gene', '6317', (59, 62))	('promotion', 'PosReg', (84, 93))	('squamous cell differentiation', 'CPA', (97, 126))	('tumor', 'Disease', 'MESH:D009369', (25, 30))
497741	28764725	Recently, EGFR signaling blockade has been shown to promote squamous cell differentiation in skin keratinocytes as well as cutaneous SCCs.	('SCC', 'Gene', '6317', (133, 136))	('blockade', 'Var', (25, 33))	('squamous cell differentiation in skin', 'Phenotype', 'HP:0006739', (60, 97))	('EGFR signaling', 'Gene', (10, 24))	('cutaneous', 'Disease', (123, 132))	('SCC', 'Gene', (133, 136))	('promote', 'PosReg', (52, 59))
497747	28764725	Here, we postulate that the promotion of squamous cell differentiation by EGFR inhibitors may suppress the growth of ESCC cells, which would contribute to establishing "differentiation therapy" for ESCC.	('contribute', 'Reg', (141, 151))	('SCC', 'Gene', (199, 202))	('suppress', 'NegReg', (94, 102))	('SCC', 'Gene', (118, 121))	('inhibitors', 'Var', (79, 89))	('squamous cell differentiation', 'CPA', (41, 70))	('SCC', 'Gene', '6317', (199, 202))	('growth', 'MPA', (107, 113))	('SCC', 'Gene', '6317', (118, 121))	('EGFR', 'Gene', (74, 78))	('promotion', 'PosReg', (28, 37))
497749	28764725	Immortalized-human esophageal epithelial cells (EPC2-hTERT) and derivatives transformed by either EGFR and p53R175H (T-Epi) or SV40 large T antigen and Ha-RasV12 (T-Mes), fetal esophageal fibroblast cells (FEF3), and ESCC cells (HCE4, TE-1, TE-5, TE-8, and TE-11) were described previously.	('EGFR', 'Gene', (98, 102))	('p53R175H', 'Var', (107, 115))	('SCC', 'Gene', '6317', (218, 221))	('p53R175H', 'Mutation', 'p.R53,175H', (107, 115))	('human', 'Species', '9606', (13, 18))	('SV40', 'Var', (127, 131))	('T-Mes', 'Chemical', '-', (163, 168))	('HCE4', 'Chemical', '-', (229, 233))	('SCC', 'Gene', (218, 221))	('EPC2-hTERT', 'CellLine', 'CVCL:4361', (48, 58))
497752	28764725	These ESCC cells reportedly do not harbor an EGFR mutation.	('SCC', 'Gene', (7, 10))	('SCC', 'Gene', '6317', (7, 10))	('EGFR', 'Gene', (45, 49))	('mutation', 'Var', (50, 58))
497817	28764725	TE-1, TE-5, TE-11 and TE-11R cells exhibited high expression of E-cadherin and very low expression of vimentin, whereas TE-8 and HCE4 cells showed low expression of E-cadherin and high expression of vimentin (Fig.	('TE-11R', 'Var', (22, 28))	('TE-11', 'Var', (12, 17))	('HCE4', 'Chemical', '-', (129, 133))	('E-cadherin', 'Protein', (64, 74))	('expression', 'MPA', (88, 98))	('expression', 'MPA', (50, 60))	('TE-11R', 'Chemical', '-', (22, 28))
497818	28764725	Therefore, we classified TE-1, TE-5, TE-11, and TE-11R cells as epithelial-like ESCC cells, and TE-8 and HCE4 cells as mesenchymal-like ESCC cells.	('SCC', 'Gene', '6317', (81, 84))	('SCC', 'Gene', '6317', (137, 140))	('TE-11R', 'Chemical', '-', (48, 54))	('SCC', 'Gene', (81, 84))	('HCE4', 'Chemical', '-', (105, 109))	('TE-11R', 'Var', (48, 54))	('SCC', 'Gene', (137, 140))
497819	28764725	In agreement with the results of transformed-esophageal cells treated with EGFR inhibitors, the growth of epithelial-like ESCC cells (TE-1, TE-5, TE-11, and TE-11R) was significantly inhibited by treatment with erlotinib or cetuximab, but that of mesenchymal-like ESCC cells (TE-8 and HCE-4) was not affected (Fig.	('cetuximab', 'Chemical', 'MESH:D000068818', (224, 233))	('SCC', 'Gene', (265, 268))	('HCE', 'Chemical', 'MESH:C007907', (285, 288))	('SCC', 'Gene', '6317', (123, 126))	('growth', 'CPA', (96, 102))	('erlotinib', 'Chemical', 'MESH:D000069347', (211, 220))	('TE-11R', 'Chemical', '-', (157, 163))	('SCC', 'Gene', '6317', (265, 268))	('inhibited', 'NegReg', (183, 192))	('erlotinib', 'Var', (211, 220))	('SCC', 'Gene', (123, 126))
497830	28764725	Xenograft tumors generated from TE-11R and TE-8 were treated with cetuximab to investigate the antitumor effects of EGFR inhibitors on ESCC.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('tumor', 'Disease', (99, 104))	('cetuximab', 'Chemical', 'MESH:D000068818', (66, 75))	('SCC', 'Gene', (136, 139))	('TE-11R', 'Chemical', '-', (32, 38))	('tumor', 'Disease', (10, 15))	('tumors', 'Disease', (10, 16))	('SCC', 'Gene', '6317', (136, 139))	('tumors', 'Disease', 'MESH:D009369', (10, 16))	('tumors', 'Phenotype', 'HP:0002664', (10, 16))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('inhibitors', 'Var', (121, 131))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('EGFR', 'Gene', (116, 120))
497838	28764725	T-Epi cells are transformed by EGFR and p53R175H, and T-Mes cells by SV40 large T antigen and Ha-RasV12.	('T-Mes', 'Chemical', '-', (54, 59))	('p53R175H', 'Mutation', 'p.R53,175H', (40, 48))	('SV40 large T', 'Var', (69, 81))	('p53R175H', 'Var', (40, 48))
497840	28764725	In the present study, we showed that EGFR inhibitors promoted squamous cell differentiation in epithelial-like esophageal cells accompanied by increased expression of involucrin and CK13.	('increased', 'PosReg', (143, 152))	('promoted', 'PosReg', (53, 61))	('involucrin', 'Protein', (167, 177))	('CK13', 'Gene', '3860', (182, 186))	('inhibitors', 'Var', (42, 52))	('CK13', 'Gene', (182, 186))	('squamous cell differentiation', 'CPA', (62, 91))	('expression', 'MPA', (153, 163))	('EGFR', 'Gene', (37, 41))
497842	28764725	showing that EGFR inhibitors promoted cell differentiation in skin keratinocytes and cutaneous SCC cells via Notch signal activation.	('promoted', 'PosReg', (29, 37))	('SCC', 'Gene', '6317', (95, 98))	('Notch', 'Gene', (109, 114))	('activation', 'PosReg', (122, 132))	('cell differentiation in skin keratinocytes', 'CPA', (38, 80))	('SCC', 'Gene', (95, 98))	('Notch', 'Gene', '4851;4854', (109, 114))	('EGFR', 'Gene', (13, 17))	('inhibitors', 'Var', (18, 28))
497843	28764725	We suspect that the cell-cell contact induced by EGFR inhibitors might be involved in the promotion of squamous cell differentiation because it increases cell-cell interactions such as Notch signaling, which may help to promote squamous cell differentiation.	('Notch', 'Gene', '4851;4854', (185, 190))	('cell-cell interactions', 'CPA', (154, 176))	('cell-cell contact', 'CPA', (20, 37))	('increases', 'PosReg', (144, 153))	('squamous cell differentiation', 'CPA', (228, 257))	('Notch', 'Gene', (185, 190))	('inhibitors', 'Var', (54, 64))	('EGFR', 'Gene', (49, 53))	('squamous', 'Disease', (103, 111))	('promote', 'PosReg', (220, 227))
497844	28764725	In this study, EGFR inhibitors showed antitumor effects in epithelial-like ESCC cells but not in mesenchymal-like ESCC cells.	('tumor', 'Disease', (42, 47))	('SCC', 'Gene', (76, 79))	('inhibitors', 'Var', (20, 30))	('SCC', 'Gene', (115, 118))	('EGFR', 'Gene', (15, 19))	('SCC', 'Gene', '6317', (76, 79))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('SCC', 'Gene', '6317', (115, 118))
497848	28764725	Consistently, esophageal fibroblast cells, which are the mesenchymal cells, were not affected by treatment with EGFR inhibitors or rEGF (Additional file 5 Figure S5).	('EGFR', 'Gene', (112, 116))	('esophageal fibroblast cells', 'CPA', (14, 41))	('inhibitors', 'Var', (117, 127))	('rEGF', 'Gene', '25313', (131, 135))	('rEGF', 'Gene', (131, 135))
497858	28764725	Our findings provide novel, mechanistic insights into the effects of EGFR inhibitors on ESCC.	('SCC', 'Gene', '6317', (89, 92))	('inhibitors', 'Var', (74, 84))	('EGFR', 'Gene', (69, 73))	('SCC', 'Gene', (89, 92))
497906	24664352	While the conclusion is that oral transmucosal fentanyl citrate can be effective for the management of breakthrough cancer pain, clinicians should remember that genetic variation in the catechol-O-methyltransferase gene affects cancer patients' response to morphine, which might explain the non-responding patient.	('catechol-O-methyltransferase', 'Gene', '1312', (186, 214))	('catechol-O-methyltransferase', 'Gene', (186, 214))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('affects', 'Reg', (220, 227))	('response to morphine', 'MPA', (245, 265))	('patients', 'Species', '9606', (235, 243))	('breakthrough cancer pain', 'Disease', 'MESH:D059390', (103, 127))	('breakthrough cancer pain', 'Disease', (103, 127))	('fentanyl citrate', 'Chemical', 'MESH:D005283', (47, 63))	('morphine', 'Chemical', 'MESH:D009020', (257, 265))	('cancer', 'Disease', (228, 234))	('cancer', 'Disease', (116, 122))	('breakthrough cancer pain', 'Phenotype', 'HP:0032149', (103, 127))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('patient', 'Species', '9606', (235, 242))	('pain', 'Phenotype', 'HP:0012531', (123, 127))	('genetic variation', 'Var', (161, 178))	('patient', 'Species', '9606', (306, 313))	('cancer', 'Disease', 'MESH:D009369', (228, 234))
497983	24664352	AEA and FAAH inhibition affects calcium ion transduction, which the investigators measured in DRG neurons co-cultured with fibrosarcoma cells.	('coma', 'Phenotype', 'HP:0001259', (131, 135))	('AEA', 'Chemical', 'MESH:C078814', (0, 3))	('fibrosarcoma', 'Disease', (123, 135))	('inhibition', 'Var', (13, 23))	('FAAH', 'Gene', (8, 12))	('calcium', 'Chemical', 'MESH:D002118', (32, 39))	('sarcoma', 'Phenotype', 'HP:0100242', (128, 135))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (123, 135))	('calcium ion transduction', 'MPA', (32, 56))	('FAAH', 'Gene', '14073', (8, 12))	('fibrosarcoma', 'Disease', 'MESH:D005354', (123, 135))
498018	24664352	A317491, an antagonist of the P2X3 receptor, attenuates bone cancer pain when injected locally or intrathecally.	('bone cancer pain', 'Disease', (56, 72))	('rat', 'Species', '10116', (101, 104))	('bone cancer pain', 'Phenotype', 'HP:0002653', (56, 72))	('A317491', 'Chemical', 'MESH:C470346', (0, 7))	('attenuates', 'NegReg', (45, 55))	('pain', 'Phenotype', 'HP:0012531', (68, 72))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('A317491', 'Var', (0, 7))	('bone cancer pain', 'Disease', 'MESH:D001859', (56, 72))
498053	24664352	Interestingly disruption of the signaling leads to a decrease in cancer growth.	('decrease', 'NegReg', (53, 61))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('disruption', 'Var', (14, 24))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))
498071	24664352	In a bone cancer model inoculated with human cancer cells that express mutated alpha6 integrin, the mice show a decrease in bone fractures, a decrease in tumor cell migration within the bone and a decrease in cancer pain behavior.	('cancer pain behavior', 'Disease', 'MESH:D000072716', (209, 229))	('bone cancer', 'Disease', 'MESH:D001859', (5, 16))	('mice', 'Species', '10090', (100, 104))	('bone cancer', 'Disease', (5, 16))	('bone fractures', 'Disease', 'MESH:D050723', (124, 138))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('pain', 'Phenotype', 'HP:0012531', (216, 220))	('cancer', 'Disease', (10, 16))	('tumor', 'Disease', (154, 159))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('cancer', 'Disease', 'MESH:D009369', (209, 215))	('cancer pain behavior', 'Disease', (209, 229))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('human', 'Species', '9606', (39, 44))	('bone fractures', 'Disease', (124, 138))	('cancer', 'Disease', 'MESH:D009369', (10, 16))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('cancer', 'Disease', (45, 51))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('decrease', 'NegReg', (112, 120))	('mutated', 'Var', (71, 78))	('alpha6 integrin', 'Protein', (79, 94))	('decrease', 'NegReg', (142, 150))	('cancer', 'Disease', (209, 215))	('rat', 'Species', '10116', (168, 171))	('bone fractures', 'Phenotype', 'HP:0020110', (124, 138))	('decrease', 'NegReg', (197, 205))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
498094	24664352	Administration of H89, a PKA inhibitor, attenuates bone cancer pain in this model.	('H89', 'Var', (18, 21))	('rat', 'Species', '10116', (8, 11))	('pain', 'Phenotype', 'HP:0012531', (63, 67))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('bone cancer pain', 'Disease', 'MESH:D001859', (51, 67))	('H89', 'Chemical', 'MESH:C063509', (18, 21))	('bone cancer pain', 'Disease', (51, 67))	('bone cancer pain', 'Phenotype', 'HP:0002653', (51, 67))	('attenuates', 'NegReg', (40, 50))
498103	24664352	Spinal inhibition of the EphB1 receptor relieves bone cancer pain and restores morphine induced analgesia in this model; spinal cord neurochemical changes are also reversed.	('bone cancer pain', 'Disease', (49, 65))	('restores', 'PosReg', (70, 78))	('neurochemical changes', 'Phenotype', 'HP:0000707', (133, 154))	('EphB1', 'Gene', '270190', (25, 30))	('analgesia', 'Disease', 'MESH:D000699', (96, 105))	('analgesia', 'Disease', (96, 105))	('morphine', 'Chemical', 'MESH:D009020', (79, 87))	('relieves', 'NegReg', (40, 48))	('inhibition', 'Var', (7, 17))	('EphB1', 'Gene', (25, 30))	('bone cancer pain', 'Disease', 'MESH:D001859', (49, 65))	('pain', 'Phenotype', 'HP:0012531', (61, 65))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('bone cancer pain', 'Phenotype', 'HP:0002653', (49, 65))
498104	24664352	Descending modulation of serotonin-dependent spinal processing contributes to cancer-induced bone pain.	('modulation', 'Var', (11, 21))	('bone pain', 'Disease', 'MESH:D010146', (93, 102))	('serotonin-dependent spinal processing', 'MPA', (25, 62))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('bone pain', 'Disease', (93, 102))	('pain', 'Phenotype', 'HP:0012531', (98, 102))	('bone pain', 'Phenotype', 'HP:0002653', (93, 102))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('serotonin', 'Chemical', 'MESH:D012701', (25, 34))
498109	24664352	Blockade of WNT signaling in the spinal cord reduces neurochemical alterations consistent with mouse bone cancer pain.	('bone cancer pain', 'Disease', 'MESH:D001859', (101, 117))	('neurochemical alterations', 'Phenotype', 'HP:0000707', (53, 78))	('bone cancer pain', 'Disease', (101, 117))	('rat', 'Species', '10116', (71, 74))	('bone cancer pain', 'Phenotype', 'HP:0002653', (101, 117))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('Blockade', 'Var', (0, 8))	('reduces', 'NegReg', (45, 52))	('pain', 'Phenotype', 'HP:0012531', (113, 117))	('neurochemical alterations', 'MPA', (53, 78))	('mouse', 'Species', '10090', (95, 100))
498111	24664352	The cancer-induced molecular changes within the spinal cord result in electrophysiologic changes which are distinct relative to the changes induced by neuropathic or inflammatory pain (Figure 6).	('inflammatory pain', 'Disease', 'MESH:D010146', (166, 183))	('electrophysiologic changes', 'Phenotype', 'HP:0001311', (70, 96))	('electrophysiologic changes', 'MPA', (70, 96))	('neuropathic', 'Disease', (151, 162))	('changes', 'Var', (29, 36))	('molecular', 'MPA', (19, 28))	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('cancer', 'Disease', 'MESH:D009369', (4, 10))	('inflammatory pain', 'Disease', (166, 183))	('pain', 'Phenotype', 'HP:0012531', (179, 183))	('cancer', 'Disease', (4, 10))	('neuropathic', 'Disease', 'MESH:D012678', (151, 162))
498131	24664352	Subcutaneous injection of CBIO reduces the production of hydrogen peroxide in the spinal cord and reduces GFAP expression in the spinal cord; moreover, CBIO prevents morphine tolerance when the two drugs are used together.	('CBIO', 'Var', (152, 156))	('GFAP', 'Protein', (106, 110))	('CBIO', 'Chemical', '-', (152, 156))	('reduces', 'NegReg', (31, 38))	('morphine tolerance', 'CPA', (166, 184))	('prevents', 'NegReg', (157, 165))	('CBIO', 'Chemical', '-', (26, 30))	('morphine', 'Chemical', 'MESH:D009020', (166, 174))	('hydrogen peroxide', 'Chemical', 'MESH:D006861', (57, 74))	('production of hydrogen peroxide', 'MPA', (43, 74))	('reduces', 'NegReg', (98, 105))
498136	24664352	Intrathecal PPF relieves cancer-induced pain and inhibits activation of spinal glial cells and the expression of glia-associated pro-inflammatory cytokines, including IL-1beta, IL-6, and TNFalpha.	('expression', 'MPA', (99, 109))	('TNFalpha', 'Gene', '21926', (187, 195))	('PPF', 'Chemical', 'MESH:C032114', (12, 15))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('pain', 'Phenotype', 'HP:0012531', (40, 44))	('IL-6', 'Gene', (177, 181))	('inhibits', 'NegReg', (49, 57))	('IL-6', 'Gene', '16193', (177, 181))	('TNFalpha', 'Gene', (187, 195))	('PPF', 'Var', (12, 15))	('relieves', 'NegReg', (16, 24))	('pain', 'Disease', 'MESH:D010146', (40, 44))	('pain', 'Disease', (40, 44))	('cancer', 'Disease', 'MESH:D009369', (25, 31))	('rat', 'Species', '10116', (3, 6))	('cancer', 'Disease', (25, 31))	('activation', 'CPA', (58, 68))
498147	24664352	Systemic injections of inhibitors of JNK reduce cancer-related mechanical allodynia, heat hyperalgesia, and tumor growth both in vitro and in vivo.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('heat hyperalgesia', 'Disease', 'MESH:D006930', (85, 102))	('hyperalgesia', 'Phenotype', 'HP:0031005', (90, 102))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('inhibitors', 'Var', (23, 33))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('JNK', 'Gene', (37, 40))	('tumor', 'Disease', (108, 113))	('heat hyperalgesia', 'Disease', (85, 102))	('reduce', 'NegReg', (41, 47))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('mechanical allodynia', 'Disease', 'MESH:D006930', (63, 83))	('mechanical allodynia', 'Disease', (63, 83))	('allodynia', 'Phenotype', 'HP:0012533', (74, 83))
498210	32793792	Cervical cancer survivors may present to their primary care providers or emergency departments with symptomatic recurrences due to noncompliance with Gynecologic Oncology or discharge from the oncology practice after 5 years.	('noncompliance', 'Var', (131, 144))	('cancer', 'Disease', (9, 15))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('oncology', 'Phenotype', 'HP:0002664', (193, 201))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('Oncology', 'Phenotype', 'HP:0002664', (162, 170))
498225	29127119	We evaluated clinical and molecular characteristics of NSCLC with RASA1 mutations in comparison with NF1-mutated cases.	('RASA1', 'Gene', '5921', (66, 71))	('mutations', 'Var', (72, 81))	('NF1', 'Gene', (101, 104))	('RASA1', 'Gene', (66, 71))	('NSCLC', 'Disease', (55, 60))	('NF1', 'Gene', '4763', (101, 104))	('NSCLC', 'Disease', 'MESH:D002289', (55, 60))
498227	29127119	Functional studies were performed using immortalized human bronchial epithelial cells (HBECs) and NSCLC lines with RasGAP truncating mutations in RASA1, NF1, or both.	('RASA1', 'Gene', (146, 151))	('NF1', 'Gene', (153, 156))	('truncating mutations', 'Var', (122, 142))	('NF1', 'Gene', '4763', (153, 156))	('RasGAP', 'Gene', '5921', (115, 121))	('human', 'Species', '9606', (53, 58))	('NSCLC', 'Disease', (98, 103))	('RasGAP', 'Gene', (115, 121))	('NSCLC', 'Disease', 'MESH:D002289', (98, 103))	('RASA1', 'Gene', '5921', (146, 151))
498229	29127119	Unexpectedly, RASA1 truncating mutations had a strong tendency to co-occur with NF1 truncating mutations (p<0.001).	('co-occur', 'Interaction', (66, 74))	('RASA1', 'Gene', (14, 19))	('NF1', 'Gene', (80, 83))	('NF1', 'Gene', '4763', (80, 83))	('truncating mutations', 'Var', (20, 40))	('RASA1', 'Gene', '5921', (14, 19))
498230	29127119	Furthermore, all patients (16/16) with concurrent RASA1/NF1 truncating mutations lacked other known lung cancer drivers.	('NF1', 'Gene', '4763', (56, 59))	('truncating mutations', 'Var', (60, 80))	('RASA1', 'Gene', '5921', (50, 55))	('lung cancer', 'Phenotype', 'HP:0100526', (100, 111))	('lung cancer', 'Disease', (100, 111))	('RASA1', 'Gene', (50, 55))	('patients', 'Species', '9606', (17, 25))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('NF1', 'Gene', (56, 59))	('lung cancer', 'Disease', 'MESH:D008175', (100, 111))
498233	29127119	While growth of cell lines with inactivation of only one of these two RasGAPs showed moderate and variable sensitivity to inhibitors of MEK or PI3K, cells with concurrent RASA1/NF1 mutations were profoundly more sensitive (IC50: 0.040muM trametinib).	('NF1', 'Gene', (177, 180))	('trametinib', 'Chemical', 'MESH:C560077', (238, 248))	('NF1', 'Gene', '4763', (177, 180))	('MEK', 'Gene', (136, 139))	('MEK', 'Gene', '5609', (136, 139))	('sensitive', 'MPA', (212, 221))	('RasGAP', 'Gene', '5921', (70, 76))	('RASA1', 'Gene', '5921', (171, 176))	('mutations', 'Var', (181, 190))	('RasGAP', 'Gene', (70, 76))	('more', 'PosReg', (207, 211))	('RASA1', 'Gene', (171, 176))
498234	29127119	Finally, simultaneous genetic silencing of RASA1 and NF1 sensitized both HBECs and NSCLC cells to MEK inhibition.	('MEK', 'Gene', (98, 101))	('MEK', 'Gene', '5609', (98, 101))	('NSCLC', 'Disease', (83, 88))	('NF1', 'Gene', (53, 56))	('RASA1', 'Gene', '5921', (43, 48))	('genetic silencing', 'Var', (22, 39))	('NF1', 'Gene', '4763', (53, 56))	('NSCLC', 'Disease', 'MESH:D002289', (83, 88))	('RASA1', 'Gene', (43, 48))	('sensitized', 'Reg', (57, 67))
498235	29127119	Cancer genomic and functional data nominate concurrent RASA1/NF1 loss of function mutations as a strong mitogenic driver in NSCLC which may sensitize to trametinib.	('RASA1', 'Gene', '5921', (55, 60))	('RASA1', 'Gene', (55, 60))	('NSCLC', 'Disease', (124, 129))	('loss of function', 'NegReg', (65, 81))	('NF1', 'Gene', (61, 64))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('mutations', 'Var', (82, 91))	('NSCLC', 'Disease', 'MESH:D002289', (124, 129))	('NF1', 'Gene', '4763', (61, 64))	('trametinib', 'Chemical', 'MESH:C560077', (153, 163))
498237	29127119	It has become standard practice to profile non-small cell lung carcinomas (NSCLCs), especially adenocarcinomas, for recurrent targetable alterations such as mutant EGFR, MAP2K1, BRAF, NRAS, or rearranged ALK, RET, ROS1, NTRK1, NTRK2, NTRK3, or amplified ERBB2 or MET exon 14 skipping, which, as strong mitogenic drivers, are mutually exclusive.	('NTRK2', 'Gene', '4915', (227, 232))	('EGFR', 'Gene', (164, 168))	('NTRK1', 'Gene', (220, 225))	('rearranged', 'Var', (193, 203))	('RET', 'Gene', (209, 212))	('ALK', 'Gene', '238', (204, 207))	('ERBB2', 'Gene', (254, 259))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))	('ALK', 'Gene', (204, 207))	('ROS1', 'Gene', (214, 218))	('NRAS', 'Gene', (184, 188))	('ERBB2', 'Gene', '2064', (254, 259))	('small cell lung carcinomas', 'Phenotype', 'HP:0030357', (47, 73))	('NTRK2', 'Gene', (227, 232))	('MET exon 14 skipping', 'Gene', (263, 283))	('NTRK3', 'Gene', '4916', (234, 239))	('BRAF', 'Gene', '673', (178, 182))	('non-small cell lung carcinomas', 'Phenotype', 'HP:0030358', (43, 73))	('EGFR', 'Gene', '1956', (164, 168))	('carcinomas', 'Phenotype', 'HP:0030731', (63, 73))	('NTRK3', 'Gene', (234, 239))	('RET', 'Gene', '5979', (209, 212))	('NSCLCs', 'Phenotype', 'HP:0030358', (75, 81))	('non-small cell lung carcinomas (NSCLCs), especially adenocarcinomas', 'Disease', 'MESH:D002289', (43, 110))	('amplified', 'Var', (244, 253))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('mutant', 'Var', (157, 163))	('ROS1', 'Gene', '6098', (214, 218))	('MAP2K1', 'Gene', '5604', (170, 176))	('carcinomas', 'Phenotype', 'HP:0030731', (100, 110))	('NRAS', 'Gene', '4893', (184, 188))	('MAP2K1', 'Gene', (170, 176))	('BRAF', 'Gene', (178, 182))	('NTRK1', 'Gene', '4914', (220, 225))
498244	29127119	Accordingly, germline mutations of NF1 or RASA1 cause neurofibromatosis type I and capillary malformation-arteriovenous malformation, respectively.	('RASA1', 'Gene', (42, 47))	('capillary malformation-arteriovenous malformation', 'Disease', (83, 132))	('neurofibromatosis', 'Phenotype', 'HP:0001067', (54, 71))	('cause', 'Reg', (48, 53))	('neurofibromatosis type I', 'Disease', (54, 78))	('capillary malformation-arteriovenous malformation', 'Disease', 'MESH:C538115', (83, 132))	('arteriovenous malformation', 'Phenotype', 'HP:0100026', (106, 132))	('germline mutations', 'Var', (13, 31))	('capillary malformation', 'Phenotype', 'HP:0025104', (83, 105))	('neurofibromatosis type I', 'Disease', 'MESH:C537392', (54, 78))	('NF1', 'Gene', (35, 38))	('RASA1', 'Gene', '5921', (42, 47))	('NF1', 'Gene', '4763', (35, 38))
498246	29127119	With respect to lung cancer, NF1 inactivating mutations are enriched in NSCLCs lacking KRAS alterations; however, they are not completely mutually exclusive.	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('KRAS', 'Gene', (87, 91))	('KRAS', 'Gene', '3845', (87, 91))	('NSCLC', 'Disease', (72, 77))	('lung cancer', 'Disease', 'MESH:D008175', (16, 27))	('NF1', 'Gene', (29, 32))	('NSCLC', 'Disease', 'MESH:D002289', (72, 77))	('inactivating mutations', 'Var', (33, 55))	('NF1', 'Gene', '4763', (29, 32))	('NSCLCs', 'Phenotype', 'HP:0030358', (72, 78))	('lung cancer', 'Phenotype', 'HP:0100526', (16, 27))	('lung cancer', 'Disease', (16, 27))
498247	29127119	Furthermore, the clinical and molecular characteristics of NSCLC with RASA1 mutations have not been defined.	('RASA1', 'Gene', (70, 75))	('NSCLC', 'Disease', 'MESH:D002289', (59, 64))	('mutations', 'Var', (76, 85))	('RASA1', 'Gene', '5921', (70, 75))	('NSCLC', 'Disease', (59, 64))
498248	29127119	The Cancer Genome Atlas (TCGA) studies showed that RASA1 and NF1 mutations are frequently detected in both lung adenocarcinoma (1.7% for RASA1; 11% for NF1) and squamous cell carcinoma (4% for RASA1; 11% for NF1).	('NF1', 'Gene', (152, 155))	('RASA1', 'Gene', (51, 56))	('NF1', 'Gene', (208, 211))	('RASA1', 'Gene', (193, 198))	('Cancer', 'Phenotype', 'HP:0002664', (4, 10))	('carcinoma', 'Phenotype', 'HP:0030731', (175, 184))	('RASA1', 'Gene', (137, 142))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (161, 184))	('lung adenocarcinoma', 'Disease', (107, 126))	('NF1', 'Gene', '4763', (61, 64))	('squamous cell carcinoma', 'Disease', (161, 184))	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('detected', 'Reg', (90, 98))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (107, 126))	('NF1', 'Gene', (61, 64))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (4, 23))	('RASA1', 'Gene', '5921', (51, 56))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (107, 126))	('NF1', 'Gene', '4763', (152, 155))	('RASA1', 'Gene', '5921', (193, 198))	('NF1', 'Gene', '4763', (208, 211))	('RASA1', 'Gene', '5921', (137, 142))	('Cancer Genome Atlas', 'Disease', (4, 23))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (161, 184))	('mutations', 'Var', (65, 74))
498249	29127119	The link between RasGAPs and RAS signaling, and clinical genomic data suggest that RASA1 and NF1 loss of function mutations may be mitogenic drivers in NSCLCs.	('RASA1', 'Gene', (83, 88))	('NF1', 'Gene', '4763', (93, 96))	('mutations', 'Var', (114, 123))	('RasGAP', 'Gene', (17, 23))	('RasGAP', 'Gene', '5921', (17, 23))	('NSCLC', 'Disease', (152, 157))	('RAS', 'Chemical', 'MESH:D011883', (83, 86))	('NSCLC', 'Disease', 'MESH:D002289', (152, 157))	('loss of function', 'NegReg', (97, 113))	('RASA1', 'Gene', '5921', (83, 88))	('NSCLCs', 'Phenotype', 'HP:0030358', (152, 158))	('RAS', 'Chemical', 'MESH:D011883', (29, 32))	('NF1', 'Gene', (93, 96))
498250	29127119	Recent studies have demonstrated that inhibition of MAPK signaling can be effective in RAF/MAPK activated cancers, such as BRAF-mutant melanomas.	('RAF', 'Gene', '22882', (124, 127))	('melanomas', 'Disease', 'MESH:D008545', (135, 144))	('RAF', 'Gene', (124, 127))	('RAF', 'Gene', '22882', (87, 90))	('melanoma', 'Phenotype', 'HP:0002861', (135, 143))	('melanomas', 'Phenotype', 'HP:0002861', (135, 144))	('BRAF', 'Gene', (123, 127))	('RAF', 'Gene', (87, 90))	('BRAF', 'Gene', '673', (123, 127))	('cancers', 'Phenotype', 'HP:0002664', (106, 113))	('inhibition', 'Var', (38, 48))	('cancers', 'Disease', (106, 113))	('cancers', 'Disease', 'MESH:D009369', (106, 113))	('melanomas', 'Disease', (135, 144))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
498251	29127119	Trametinib, which acts downstream of RAS to suppress signaling through the MAPK cascade, is approved by the FDA for the treatment of BRAF V600E-mutant melanomas.	('Trametinib', 'Chemical', 'MESH:C560077', (0, 10))	('RAS', 'Chemical', 'MESH:D011883', (37, 40))	('BRAF', 'Gene', '673', (133, 137))	('V600E-mutant', 'Var', (138, 150))	('melanomas', 'Disease', (151, 160))	('MAPK cascade', 'Pathway', (75, 87))	('BRAF', 'Gene', (133, 137))	('melanoma', 'Phenotype', 'HP:0002861', (151, 159))	('V600E', 'Mutation', 'rs113488022', (138, 143))	('melanomas', 'Phenotype', 'HP:0002861', (151, 160))	('melanomas', 'Disease', 'MESH:D008545', (151, 160))
498253	29127119	Importantly, NSCLCs with RASA1 or NF1 inactivating mutations may also be sensitive to this strategy of downstream inhibition because of the negative regulation of RAS activity associated with RasGAPs.	('NSCLC', 'Disease', (13, 18))	('RASA1', 'Gene', (25, 30))	('inactivating mutations', 'Var', (38, 60))	('negative', 'NegReg', (140, 148))	('NSCLC', 'Disease', 'MESH:D002289', (13, 18))	('RAS', 'Chemical', 'MESH:D011883', (25, 28))	('RasGAP', 'Gene', '5921', (192, 198))	('NSCLCs', 'Phenotype', 'HP:0030358', (13, 19))	('RAS', 'Protein', (163, 166))	('RasGAP', 'Gene', (192, 198))	('RAS', 'Chemical', 'MESH:D011883', (163, 166))	('NF1', 'Gene', (34, 37))	('activity', 'MPA', (167, 175))	('RASA1', 'Gene', '5921', (25, 30))	('NF1', 'Gene', '4763', (34, 37))
498254	29127119	Here, we evaluate the clinical and molecular characteristics of NSCLCs with RASA1 mutations in comparison with NF1-mutated cases.	('NF1', 'Gene', (111, 114))	('NSCLC', 'Disease', 'MESH:D002289', (64, 69))	('RASA1', 'Gene', '5921', (76, 81))	('NSCLCs', 'Phenotype', 'HP:0030358', (64, 70))	('NF1', 'Gene', '4763', (111, 114))	('RASA1', 'Gene', (76, 81))	('mutations', 'Var', (82, 91))	('NSCLC', 'Disease', (64, 69))
498255	29127119	Our findings identify concurrent RASA1/NF1 loss of function mutations as a strong mitogenic driver in NSCLC, and suggest that therapeutic strategies for RAF/MAPK activated tumors may also have efficacy in patients whose tumors show this distinctive genotype.	('NSCLC', 'Disease', 'MESH:D002289', (102, 107))	('patients', 'Species', '9606', (205, 213))	('RASA1', 'Gene', (33, 38))	('NF1', 'Gene', '4763', (39, 42))	('RAF', 'Gene', '22882', (153, 156))	('NSCLC', 'Disease', (102, 107))	('loss of function', 'NegReg', (43, 59))	('tumors', 'Phenotype', 'HP:0002664', (172, 178))	('tumors', 'Phenotype', 'HP:0002664', (220, 226))	('NF1', 'Gene', (39, 42))	('RAF', 'Gene', (153, 156))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('tumors', 'Disease', (172, 178))	('tumors', 'Disease', (220, 226))	('RASA1', 'Gene', '5921', (33, 38))	('tumors', 'Disease', 'MESH:D009369', (172, 178))	('tumors', 'Disease', 'MESH:D009369', (220, 226))	('mutations', 'Var', (60, 69))
498274	29127119	Cell viability of HBEC3KT with RASA1 knock down or non-target control was assessed using a CellTiter-Blue  Cell Viability Assay (Promega).	('RASA1', 'Gene', (31, 36))	('RASA1', 'Gene', '5921', (31, 36))	('HBEC3KT', 'CellLine', 'CVCL:X491', (18, 25))	('knock down', 'Var', (37, 47))
498277	29127119	Genomic data from the MSK-IMPACT clinical cohort consisting of 2900 patients with NSCLC (data from 01/01/2014 to 9/24/2017) revealed truncating mutations of RASA1 and NF1 in 1.5% and 5% of cases, respectively (Figure 1a).	('truncating mutations', 'Var', (133, 153))	('NF1', 'Gene', (167, 170))	('patients', 'Species', '9606', (68, 76))	('RASA1', 'Gene', '5921', (157, 162))	('NF1', 'Gene', '4763', (167, 170))	('RASA1', 'Gene', (157, 162))	('NSCLC', 'Disease', (82, 87))	('to 9', 'Species', '1214577', (110, 114))	('NSCLC', 'Disease', 'MESH:D002289', (82, 87))
498278	29127119	Analysis performed through the cBioPortal demonstrated a statistically significant tendency toward co-occurrence of RASA1 and NF1 truncating mutations or homozygous deletion (p < 0.001; Figure 1c).	('truncating mutations', 'Var', (130, 150))	('co-occurrence', 'Interaction', (99, 112))	('NF1', 'Gene', (126, 129))	('RASA1', 'Gene', '5921', (116, 121))	('NF1', 'Gene', '4763', (126, 129))	('RASA1', 'Gene', (116, 121))
498279	29127119	In contrast, the presence of these two mutations, seen in 16/2900 patients (0.6%), was completely mutually exclusive with known activating EGFR or KRAS mutations (p<0.001 and 0.002, respectively; Figure 1c), as well as other common lung cancer mitogenic drivers such ALK/RET/ROS1 fusions, ERBB2 exon 20 insertions, BRAF mutations, and MET exon 14 skipping mutations (not shown).	('mutations', 'Var', (152, 161))	('lung cancer', 'Disease', 'MESH:D008175', (232, 243))	('ALK', 'Gene', '238', (267, 270))	('EGFR', 'Gene', (139, 143))	('ERBB2', 'Gene', '2064', (289, 294))	('KRAS', 'Gene', (147, 151))	('lung cancer', 'Phenotype', 'HP:0100526', (232, 243))	('MET exon 14', 'Var', (335, 346))	('ALK', 'Gene', (267, 270))	('ROS1', 'Gene', (275, 279))	('RET', 'Gene', (271, 274))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('BRAF', 'Gene', '673', (315, 319))	('EGFR', 'Gene', '1956', (139, 143))	('BRAF', 'Gene', (315, 319))	('ERBB2', 'Gene', (289, 294))	('lung cancer', 'Disease', (232, 243))	('patients', 'Species', '9606', (66, 74))	('skipping', 'NegReg', (347, 355))	('ROS1', 'Gene', '6098', (275, 279))	('RET', 'Gene', '5979', (271, 274))	('KRAS', 'Gene', '3845', (147, 151))
498280	29127119	Among other common lung cancer tumor suppressors, cases with RASA1 truncating mutations were significantly enriched for TP53 alterations (p<0.001) while STK11 and CDKN2A alterations were not over-represented (not shown).	('truncating mutations', 'Var', (67, 87))	('CDKN2A', 'Gene', '1029', (163, 169))	('STK11', 'Gene', '6794', (153, 158))	('lung cancer', 'Phenotype', 'HP:0100526', (19, 30))	('lung cancer tumor', 'Disease', 'MESH:D008175', (19, 36))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('alterations', 'Var', (125, 136))	('RASA1', 'Gene', '5921', (61, 66))	('RASA1', 'Gene', (61, 66))	('STK11', 'Gene', (153, 158))	('CDKN2A', 'Gene', (163, 169))	('TP53', 'Gene', '7157', (120, 124))	('TP53', 'Gene', (120, 124))	('lung cancer tumor', 'Disease', (19, 36))
498281	29127119	RASA1 and NF1 mutation rates were slightly higher in the TCGA combined squamous carcinoma and adenocarcinoma dataset (n = 1144 patients; Figure 1b), where truncating mutations (or homozygous deletions) were identified in 3% and 6% of NSCLC, respectively (Figure 1b), likely due to a higher proportion of squamous cell carcinoma (42% in the TCGA analysis vs 10% in the MSKCC cohort).	('truncating', 'MPA', (155, 165))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('NSCLC', 'Disease', (234, 239))	('squamous carcinoma and adenocarcinoma', 'Disease', 'MESH:D002294', (71, 108))	('NSCLC', 'Disease', 'MESH:D002289', (234, 239))	('higher', 'Reg', (43, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (318, 327))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (71, 89))	('patients', 'Species', '9606', (127, 135))	('mutation', 'Var', (14, 22))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('RASA1', 'Gene', '5921', (0, 5))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (304, 327))	('NF1', 'Gene', '4763', (10, 13))	('squamous cell carcinoma', 'Disease', (304, 327))	('NF1', 'Gene', (10, 13))	('RASA1', 'Gene', (0, 5))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (304, 327))
498284	29127119	The mutation details, smoking histories, and basic demographic and pathologic data for 24 patients (16 MSK-IMPACT, 8 TCGA) with co-inactivation of RASA1 and NF1 are provided in Table S2.	('RASA1', 'Gene', (147, 152))	('co-inactivation', 'Var', (128, 143))	('NF1', 'Gene', (157, 160))	('NF1', 'Gene', '4763', (157, 160))	('RASA1', 'Gene', '5921', (147, 152))	('patients', 'Species', '9606', (90, 98))
498286	29127119	We first analyzed the effect of RASA1 knockdown on the phosphorylation state of 43 proteins and total amounts of 2 related proteins using a human phospho-kinase array, which revealed a significant increase in the phosphorylation of proteins associated with MAPK and PI3K signaling in HBEC3KT cells (Figure 2a).	('human', 'Species', '9606', (140, 145))	('phosphorylation', 'MPA', (213, 228))	('increase', 'PosReg', (197, 205))	('RASA1', 'Gene', '5921', (32, 37))	('RASA1', 'Gene', (32, 37))	('proteins', 'Protein', (232, 240))	('knockdown', 'Var', (38, 47))	('HBEC3KT', 'CellLine', 'CVCL:X491', (284, 291))
498288	29127119	RASA1 knockdown activated downstream signaling of RAS via an increase in RAS-GTP (Figure 2b), which promoted cell growth in HBEC3KT cells (Figure 2c).	('RAS-GTP', 'Protein', (73, 80))	('RAS', 'Chemical', 'MESH:D011883', (0, 3))	('RAS-GTP', 'Chemical', '-', (73, 80))	('activated', 'PosReg', (16, 25))	('HBEC3KT', 'CellLine', 'CVCL:X491', (124, 131))	('cell growth', 'CPA', (109, 120))	('promoted', 'PosReg', (100, 108))	('RASA1', 'Gene', '5921', (0, 5))	('RAS', 'Chemical', 'MESH:D011883', (73, 76))	('increase', 'PosReg', (61, 69))	('knockdown', 'Var', (6, 15))	('RAS', 'Chemical', 'MESH:D011883', (50, 53))	('RASA1', 'Gene', (0, 5))
498289	29127119	Interestingly, there was more prominent elevation in pERK levels compared with pAKT upon RASA1 knockdown in HBEC3KT cells.	('pERK', 'Gene', '9451', (53, 57))	('elevation', 'PosReg', (40, 49))	('AKT', 'Gene', '207', (80, 83))	('HBEC3KT', 'CellLine', 'CVCL:X491', (108, 115))	('knockdown', 'Var', (95, 104))	('AKT', 'Gene', (80, 83))	('RASA1', 'Gene', '5921', (89, 94))	('RASA1', 'Gene', (89, 94))	('pERK', 'Gene', (53, 57))
498291	29127119	Only two cell lines exhibited no RASA1 expression, both of which harbored RASA1 truncating mutations (pE155* in EPLC272H cells and pL904fs in RERFLCKJ cells).	('RASA1', 'Gene', '5921', (74, 79))	('pE155*', 'Var', (102, 108))	('RASA1', 'Gene', '5921', (33, 38))	('RASA1', 'Gene', (74, 79))	('RASA1', 'Gene', (33, 38))	('pL904fs', 'Var', (131, 138))
498292	29127119	EPLC272H cell also contained an NF1 truncating mutation (pE2608*) and exhibited no NF1 expression (as did other cell lines with NF1 truncating mutations) (Figure 3a, b).	('NF1', 'Gene', '4763', (83, 86))	('NF1', 'Gene', '4763', (128, 131))	('NF1', 'Gene', (32, 35))	('NF1', 'Gene', '4763', (32, 35))	('EPLC272H', 'Var', (0, 8))	('NF1', 'Gene', (83, 86))	('NF1', 'Gene', (128, 131))
498293	29127119	To confirm a functional role for RASA1 inactivation in human lung cancers, we reintroduced RASA1 in two RASA1-null cell lines, EPLC272H, and RERFLCKJ.	('lung cancer', 'Phenotype', 'HP:0100526', (61, 72))	('RASA1', 'Gene', '5921', (104, 109))	('RASA1', 'Gene', '5921', (33, 38))	('RASA1', 'Gene', (104, 109))	('lung cancers', 'Disease', 'MESH:D008175', (61, 73))	('human', 'Species', '9606', (55, 60))	('RASA1', 'Gene', (33, 38))	('RASA1', 'Gene', '5921', (91, 96))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('lung cancers', 'Phenotype', 'HP:0100526', (61, 73))	('RASA1', 'Gene', (91, 96))	('cancers', 'Phenotype', 'HP:0002664', (66, 73))	('inactivation', 'Var', (39, 51))	('lung cancers', 'Disease', (61, 73))
498294	29127119	Ectopic RASA1 expression suppressed signaling through the MAPK and AKT pathways in RERFLCKJ cells; there were stronger reductions in pERK levels compared with pAKT levels.	('pERK', 'Gene', (133, 137))	('AKT', 'Gene', '207', (67, 70))	('signaling', 'MPA', (36, 45))	('AKT', 'Gene', '207', (160, 163))	('RASA1', 'Gene', '5921', (8, 13))	('AKT', 'Gene', (67, 70))	('RASA1', 'Gene', (8, 13))	('suppressed', 'NegReg', (25, 35))	('reductions', 'NegReg', (119, 129))	('Ectopic', 'Var', (0, 7))	('AKT', 'Gene', (160, 163))	('pERK', 'Gene', '9451', (133, 137))
498297	29127119	As expected, KRAS knockdown with 2 different shRNAs led to growth inhibition in both EPLC272 and RERFLCKJ cells (data not shown).	('knockdown', 'Var', (18, 27))	('KRAS', 'Gene', '3845', (13, 17))	('KRAS', 'Gene', (13, 17))	('growth', 'MPA', (59, 65))
498299	29127119	Specifically, to assess how RASA1 mutated NSCLC lines respond to the MEK inhibitor trametinib (GSK1120212), we analyzed effects of trametinib on the signaling of MAPK and PI3K/AKT pathways by Western blot in comparison with PI3K inhibitor (GDC0941).	('RASA1', 'Gene', (28, 33))	('NSCLC', 'Disease', (42, 47))	('MAPK', 'Pathway', (162, 166))	('RASA1', 'Gene', '5921', (28, 33))	('AKT', 'Gene', '207', (176, 179))	('GSK1120212', 'Chemical', 'MESH:C560077', (95, 105))	('NSCLC', 'Disease', 'MESH:D002289', (42, 47))	('GDC0941', 'Chemical', 'MESH:C532162', (240, 247))	('MEK', 'Gene', (69, 72))	('AKT', 'Gene', (176, 179))	('MEK', 'Gene', '5609', (69, 72))	('trametinib', 'Chemical', 'MESH:C560077', (83, 93))	('trametinib', 'Chemical', 'MESH:C560077', (131, 141))	('respond', 'Reg', (54, 61))	('mutated', 'Var', (34, 41))
498300	29127119	In both RASA1 mutated NSCLC lines (EPLC272H and RERFLCKJ), trametinib induced a potent dose-dependent decrease of pERK1/2 levels.	('RASA1', 'Gene', '5921', (8, 13))	('decrease', 'NegReg', (102, 110))	('RASA1', 'Gene', (8, 13))	('trametinib', 'Chemical', 'MESH:C560077', (59, 69))	('NSCLC', 'Disease', (22, 27))	('pERK', 'Gene', (114, 118))	('EPLC272H', 'Var', (35, 43))	('pERK', 'Gene', '9451', (114, 118))	('NSCLC', 'Disease', 'MESH:D002289', (22, 27))
498301	29127119	In contrast, GDC0941 reduced pAKT levels only at higher doses.	('reduced', 'NegReg', (21, 28))	('GDC0941', 'Chemical', 'MESH:C532162', (13, 20))	('AKT', 'Gene', '207', (30, 33))	('AKT', 'Gene', (30, 33))	('GDC0941', 'Var', (13, 20))
498304	29127119	This showed that combining trametinib and GDC0941 induced a dose-dependent decrease of both pERK and pAKT levels (Figure 4c).	('GDC0941', 'Var', (42, 49))	('pERK', 'Gene', '9451', (92, 96))	('decrease', 'NegReg', (75, 83))	('GDC0941', 'Chemical', 'MESH:C532162', (42, 49))	('trametinib', 'Chemical', 'MESH:C560077', (27, 37))	('AKT', 'Gene', '207', (102, 105))	('pERK', 'Gene', (92, 96))	('AKT', 'Gene', (102, 105))
498306	29127119	Since previous studies and our results show that loss of RasGAPs including RASA1 trigger activation of the MAPK and PI3K/AKT signaling through RAS, we next tested the sensitivity of RASA1 mutated NSCLC cells against variety of kinase inhibitors with in vitro cell growth inhibition assays.	('RasGAP', 'Gene', '5921', (57, 63))	('tested', 'Reg', (156, 162))	('RAS', 'Chemical', 'MESH:D011883', (182, 185))	('RASA1', 'Gene', (182, 187))	('NSCLC', 'Disease', (196, 201))	('loss', 'Var', (49, 53))	('AKT', 'Gene', (121, 124))	('RAS', 'Chemical', 'MESH:D011883', (143, 146))	('NSCLC', 'Disease', 'MESH:D002289', (196, 201))	('RAS', 'Chemical', 'MESH:D011883', (75, 78))	('RASA1', 'Gene', '5921', (75, 80))	('RASA1', 'Gene', (75, 80))	('activation', 'PosReg', (89, 99))	('mutated', 'Var', (188, 195))	('AKT', 'Gene', '207', (121, 124))	('RASA1', 'Gene', '5921', (182, 187))	('RasGAP', 'Gene', (57, 63))
498309	29127119	The panel included RASA1/NF1 co-mutated (EPLC272H), RASA1-mutated (RERFLCKJ), NF1-mutated (RERFLCAI, LCLC103H, H1838), KRAS mutated (H2030) and EGFR-mutated (H3255) NSCLC lines.	('RASA1', 'Gene', '5921', (52, 57))	('EGFR', 'Gene', (144, 148))	('NSCLC', 'Disease', 'MESH:D002289', (165, 170))	('RASA1', 'Gene', (52, 57))	('RASA1', 'Gene', '5921', (19, 24))	('RASA1', 'Gene', (19, 24))	('H3255', 'Var', (158, 163))	('NF1', 'Gene', (78, 81))	('H1838', 'Var', (111, 116))	('H2030', 'Var', (133, 138))	('KRAS', 'Gene', (119, 123))	('H3255', 'CellLine', 'CVCL:6831', (158, 163))	('NF1', 'Gene', '4763', (78, 81))	('NF1', 'Gene', (25, 28))	('KRAS', 'Gene', '3845', (119, 123))	('EGFR', 'Gene', '1956', (144, 148))	('NF1', 'Gene', '4763', (25, 28))	('NSCLC', 'Disease', (165, 170))
498311	29127119	EGFR mutated cells were moderately sensitive to combination of MEK and PI3K inhibitors, and sensitive to combined inhibition of MEK and EGFR, as expected.	('EGFR', 'Gene', (0, 4))	('PI3K', 'Gene', (71, 75))	('MEK', 'Gene', (63, 66))	('MEK', 'Gene', (128, 131))	('sensitive', 'Reg', (35, 44))	('MEK', 'Gene', '5609', (63, 66))	('MEK', 'Gene', '5609', (128, 131))	('mutated', 'Var', (5, 12))	('EGFR', 'Gene', '1956', (136, 140))	('EGFR', 'Gene', '1956', (0, 4))	('EGFR', 'Gene', (136, 140))	('combination', 'Interaction', (48, 59))
498312	29127119	NSCLC lines with only RASA1 or NF1 mutation (but not both) showed moderate and variable sensitivity to all inhibitors examined.	('NF1', 'Gene', '4763', (31, 34))	('NSCLC', 'Disease', 'MESH:D002289', (0, 5))	('RASA1', 'Gene', '5921', (22, 27))	('RASA1', 'Gene', (22, 27))	('mutation', 'Var', (35, 43))	('NF1', 'Gene', (31, 34))	('NSCLC', 'Disease', (0, 5))
498313	29127119	Surprisingly, RASA1/NF1 co-mutated cells showed profound sensitivity to the same inhibitors (IC50: 0.040muM trametinib; 0.036muM GDC0941; 0.0044muM combination of GSK1120201/GDC0941; 0.00089 muM combination of trametinib/afatinib) (Figure 5a).	('GDC0941', 'Chemical', 'MESH:C532162', (174, 181))	('RASA1', 'Gene', (14, 19))	('NF1', 'Gene', '4763', (20, 23))	('GDC0941', 'Chemical', 'MESH:C532162', (129, 136))	('trametinib', 'Chemical', 'MESH:C560077', (210, 220))	('trametinib', 'Chemical', 'MESH:C560077', (108, 118))	('NF1', 'Gene', (20, 23))	('sensitivity', 'MPA', (57, 68))	('afatinib', 'Chemical', 'MESH:D000077716', (221, 229))	('0.0044muM', 'Var', (138, 147))	('RASA1', 'Gene', '5921', (14, 19))
498317	29127119	cleaved PARP) after 72 hours in EPLC272H cells, but not in RERFLCKJ cells, suggesting that inhibition of MAPK signaling is sufficient to induce cell-cycle arrest and apoptosis in RASA1/NF1 co-mutated NSCLC lines, but not in RASA1-only mutated NSCLC lines.	('induce', 'Reg', (137, 143))	('RASA1', 'Gene', '5921', (224, 229))	('arrest', 'Disease', 'MESH:D006323', (155, 161))	('RASA1', 'Gene', (224, 229))	('inhibition', 'Var', (91, 101))	('NSCLC', 'Disease', 'MESH:D002289', (243, 248))	('NF1', 'Gene', '4763', (185, 188))	('RASA1', 'Gene', '5921', (179, 184))	('NSCLC', 'Disease', (200, 205))	('co-mutated', 'Var', (189, 199))	('arrest', 'Disease', (155, 161))	('NSCLC', 'Disease', 'MESH:D002289', (200, 205))	('PARP', 'Gene', '1302', (8, 12))	('NF1', 'Gene', (185, 188))	('PARP', 'Gene', (8, 12))	('apoptosis', 'CPA', (166, 175))	('RASA1', 'Gene', (179, 184))	('NSCLC', 'Disease', (243, 248))
498319	29127119	This showed that a number of apoptotic signaling proteins, such as cleaved caspase-3 are modulated following co-administration of trametinib and afatinib in both EPLC272H and RERFLCKJ cells (Figure S2a).	('caspase-3', 'Gene', '836', (75, 84))	('trametinib', 'Chemical', 'MESH:C560077', (130, 140))	('apoptotic', 'MPA', (29, 38))	('caspase-3', 'Gene', (75, 84))	('modulated', 'Reg', (89, 98))	('afatinib', 'Chemical', 'MESH:D000077716', (145, 153))	('EPLC272H', 'Var', (162, 170))
498323	29127119	Since our analysis of large cancer genomic datasets showed that RASA1 mutations tend to co-occur with NF1 mutations in NSCLCs, and our studies of native NSCLC cell lines showed that the RASA1/NF1 co-mutated EPLC272H cells are highly sensitive to MEK inhibition, we further investigated whether experimental inactivation of both RASA1 and NF1 confers sensitivity to trametinib in other cell lines.	('NSCLC', 'Disease', 'MESH:D002289', (119, 124))	('NF1', 'Gene', '4763', (102, 105))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('RASA1', 'Gene', '5921', (64, 69))	('NSCLC', 'Disease', (119, 124))	('NF1', 'Gene', '4763', (338, 341))	('NSCLCs', 'Phenotype', 'HP:0030358', (119, 125))	('NF1', 'Gene', (102, 105))	('RASA1', 'Gene', (64, 69))	('NF1', 'Gene', (338, 341))	('mutations', 'Var', (70, 79))	('RASA1', 'Gene', '5921', (186, 191))	('MEK', 'Gene', (246, 249))	('RASA1', 'Gene', '5921', (328, 333))	('NF1', 'Gene', '4763', (192, 195))	('NSCLC', 'Disease', 'MESH:D002289', (153, 158))	('MEK', 'Gene', '5609', (246, 249))	('cancer', 'Disease', (28, 34))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('RASA1', 'Gene', (186, 191))	('NSCLC', 'Disease', (153, 158))	('NF1', 'Gene', (192, 195))	('RASA1', 'Gene', (328, 333))	('mutations', 'Var', (106, 115))	('trametinib', 'Chemical', 'MESH:C560077', (365, 375))
498325	29127119	Trametinib treatment markedly reduced growth of HBEC3KT cells with both RASA1 and NF1 knockdown compared with cells with only RASA1 knockdown (Figure 5c).	('RASA1', 'Gene', '5921', (72, 77))	('Trametinib', 'Chemical', 'MESH:C560077', (0, 10))	('knockdown', 'Var', (86, 95))	('RASA1', 'Gene', (72, 77))	('NF1', 'Gene', (82, 85))	('growth', 'MPA', (38, 44))	('RASA1', 'Gene', '5921', (126, 131))	('NF1', 'Gene', '4763', (82, 85))	('HBEC3KT', 'CellLine', 'CVCL:X491', (48, 55))	('reduced', 'NegReg', (30, 37))	('RASA1', 'Gene', (126, 131))
498326	29127119	Furthermore, we found that trametinib could inhibit the growth of NF1 mutated NSCLC cells (RERFLCAI) when RASA1 is also knockdown (Figure 5c).	('inhibit', 'NegReg', (44, 51))	('trametinib', 'Chemical', 'MESH:C560077', (27, 37))	('RASA1', 'Gene', '5921', (106, 111))	('NF1', 'Gene', (66, 69))	('RASA1', 'Gene', (106, 111))	('NSCLC', 'Disease', (78, 83))	('NF1', 'Gene', '4763', (66, 69))	('growth', 'MPA', (56, 62))	('NSCLC', 'Disease', 'MESH:D002289', (78, 83))	('mutated', 'Var', (70, 77))
498328	29127119	Finally, we reviewed the characteristics of patients whose NSCLCs show co-inactivation of RASA1 and NF1.	('co-inactivation', 'Var', (71, 86))	('NSCLC', 'Disease', 'MESH:D002289', (59, 64))	('RASA1', 'Gene', '5921', (90, 95))	('patients', 'Species', '9606', (44, 52))	('RASA1', 'Gene', (90, 95))	('NSCLCs', 'Phenotype', 'HP:0030358', (59, 65))	('NF1', 'Gene', (100, 103))	('NF1', 'Gene', '4763', (100, 103))	('NSCLC', 'Disease', (59, 64))
498329	29127119	Patients with truncating mutations in both RASA1 and NF1 (or deep deletion of RASA1 and truncating mutation of NF1, n=1) had a mean and median age of 69 (range 46-81), 50% were female and consisted entirely of former or current heavy smokers (Table S3).	('NF1', 'Gene', (111, 114))	('NF1', 'Gene', '4763', (111, 114))	('NF1', 'Gene', (53, 56))	('RASA1', 'Gene', '5921', (43, 48))	('truncating mutation', 'Var', (88, 107))	('NF1', 'Gene', '4763', (53, 56))	('RASA1', 'Gene', '5921', (78, 83))	('RASA1', 'Gene', (43, 48))	('Patients', 'Species', '9606', (0, 8))	('truncating mutations', 'Var', (14, 34))	('RASA1', 'Gene', (78, 83))	('deep deletion', 'Var', (61, 74))
498330	29127119	RASA1-only mutated tumors were more often squamous cell carcinoma (63%; Chi-square p<0.0001) than tumors with NF1 alterations only which were predominantly adenocarcinomas (81%); 50% of tumors with RASA1/NF1 co-mutations were squamous.	('tumors', 'Disease', (19, 25))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (42, 65))	('tumors', 'Disease', (98, 104))	('NF1', 'Gene', '4763', (110, 113))	('RASA1', 'Gene', '5921', (198, 203))	('adenocarcinomas', 'Disease', 'MESH:D000230', (156, 171))	('adenocarcinomas', 'Disease', (156, 171))	('RASA1', 'Gene', (0, 5))	('carcinoma', 'Phenotype', 'HP:0030731', (56, 65))	('carcinomas', 'Phenotype', 'HP:0030731', (161, 171))	('NF1', 'Gene', (110, 113))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('squamous cell carcinoma', 'Disease', (42, 65))	('NF1', 'Gene', '4763', (204, 207))	('tumors', 'Disease', 'MESH:D009369', (98, 104))	('tumors', 'Phenotype', 'HP:0002664', (186, 192))	('RASA1', 'Gene', (198, 203))	('mutated', 'Var', (11, 18))	('NF1', 'Gene', (204, 207))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumors', 'Disease', (186, 192))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (42, 65))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('tumors', 'Disease', 'MESH:D009369', (186, 192))	('RASA1', 'Gene', '5921', (0, 5))	('carcinoma', 'Phenotype', 'HP:0030731', (161, 170))
498331	29127119	Focusing on patients with longer follow up data, survival analysis was performed on the first 109 MSK-IMPACT patients with inactivating alterations in one or both genes, a cohort with a median follow up of 13.3 months.	('patients', 'Species', '9606', (12, 20))	('MSK-IMPACT', 'Gene', (98, 108))	('inactivating alterations', 'Var', (123, 147))	('patients', 'Species', '9606', (109, 117))
498333	29127119	NSCLCs, particularly lung adenocarcinomas, have emerged as striking examples of cancers that have been molecularly redefined by the discovery of activating oncogene mutations that serve as strong mitogenic drivers and, as such, are largely mutually exclusive.	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (21, 41))	('NSCLC', 'Disease', 'MESH:D002289', (0, 5))	('oncogene', 'Gene', (156, 164))	('cancers', 'Disease', 'MESH:D009369', (80, 87))	('carcinomas', 'Phenotype', 'HP:0030731', (31, 41))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancers', 'Disease', (80, 87))	('activating', 'PosReg', (145, 155))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (21, 40))	('NSCLCs', 'Phenotype', 'HP:0030358', (0, 6))	('mutations', 'Var', (165, 174))	('lung adenocarcinomas', 'Disease', (21, 41))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (21, 41))	('NSCLC', 'Disease', (0, 5))	('carcinoma', 'Phenotype', 'HP:0030731', (31, 40))	('cancers', 'Phenotype', 'HP:0002664', (80, 87))
498334	29127119	While inactivating mutations in the NF1 and RASA1 tumor suppressors are expected to increase MAPK signaling and cell proliferation be mitogenic, it has been less clear how they fit into the "molecular pie chart" classification of lung adenocarcinoma as they are, individually, not as consistently mutually exclusive with strong mitogenic drivers such as EGFR and KRAS mutations.	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (230, 249))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (230, 249))	('cell proliferation', 'CPA', (112, 130))	('EGFR', 'Gene', '1956', (354, 358))	('NF1', 'Gene', '4763', (36, 39))	('increase', 'PosReg', (84, 92))	('tumor', 'Disease', (50, 55))	('NF1', 'Gene', (36, 39))	('RASA1', 'Gene', '5921', (44, 49))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('lung adenocarcinoma', 'Disease', (230, 249))	('KRAS', 'Gene', '3845', (363, 367))	('inactivating mutations', 'Var', (6, 28))	('MAPK signaling', 'MPA', (93, 107))	('EGFR', 'Gene', (354, 358))	('KRAS', 'Gene', (363, 367))	('RASA1', 'Gene', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('carcinoma', 'Phenotype', 'HP:0030731', (240, 249))
498335	29127119	Approximately 1.5% and 3% of NSCLCs harbor RASA1 truncating mutations in the MSK-IMPACT and TCGA cohorts, respectively.	('RASA1', 'Gene', '5921', (43, 48))	('RASA1', 'Gene', (43, 48))	('NSCLC', 'Disease', (29, 34))	('truncating mutations', 'Var', (49, 69))	('NSCLCs', 'Phenotype', 'HP:0030358', (29, 35))	('NSCLC', 'Disease', 'MESH:D002289', (29, 34))
498338	29127119	Thus, it is notable that a recent analysis of NSCLC evolution in 100 patients found that some RASA1 mutations occurred early in evolution, and one patient (1%) had both RASA1 and NF1 inactivation as early events in the absence of another strong driver.	('RASA1', 'Gene', '5921', (94, 99))	('mutations', 'Var', (100, 109))	('RASA1', 'Gene', (94, 99))	('RASA1', 'Gene', '5921', (169, 174))	('patient', 'Species', '9606', (147, 154))	('RASA1', 'Gene', (169, 174))	('NSCLC', 'Disease', (46, 51))	('patients', 'Species', '9606', (69, 77))	('NSCLC', 'Disease', 'MESH:D002289', (46, 51))	('patient', 'Species', '9606', (69, 76))	('NF1', 'Gene', (179, 182))	('NF1', 'Gene', '4763', (179, 182))
498339	29127119	Furthermore, there is also evidence for increased co-occurrence of NF1 mutations with alterations of other RasGAPs (including RASA1) and RasGEFs across a wide range of human cancers.	('NF1', 'Gene', (67, 70))	('human', 'Species', '9606', (168, 173))	('NF1', 'Gene', '4763', (67, 70))	('cancers', 'Phenotype', 'HP:0002664', (174, 181))	('cancers', 'Disease', (174, 181))	('RASA1', 'Gene', '5921', (126, 131))	('cancers', 'Disease', 'MESH:D009369', (174, 181))	('mutations', 'Var', (71, 80))	('RasGAP', 'Gene', (107, 113))	('RasGAP', 'Gene', '5921', (107, 113))	('RASA1', 'Gene', (126, 131))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))
498340	29127119	Finally, whereas T cell-lineage knockouts of NF1 or RASA1 show only a minor phenotype and do not result in T cell acute lymphoblastic leukemia/lymphoma (T-ALL), their combined deletion leads to the development of T-ALL, suggesting that, in some cellular settings, loss of both NF1 and RASA1 is needed to produce the high levels of signaling downstream of RAS necessary for malignant transformation.	('deletion', 'Var', (176, 184))	('leads to', 'Reg', (185, 193))	('lymphoblastic leukemia/lymphoma', 'Disease', 'MESH:D054198', (120, 151))	('NF1', 'Gene', '4763', (277, 280))	('T-ALL', 'Disease', (213, 218))	('NF1', 'Gene', '4763', (45, 48))	('RASA1', 'Gene', '5921', (285, 290))	('leukemia', 'Phenotype', 'HP:0001909', (134, 142))	('lymphoma', 'Phenotype', 'HP:0002665', (143, 151))	('RAS', 'Chemical', 'MESH:D011883', (285, 288))	('NF1', 'Gene', (277, 280))	('NF1', 'Gene', (45, 48))	('lymphoblastic leukemia/lymphoma', 'Disease', (120, 151))	('RASA1', 'Gene', '5921', (52, 57))	('loss', 'NegReg', (264, 268))	('RASA1', 'Gene', (285, 290))	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (114, 142))	('T cell acute lymphoblastic leukemia', 'Phenotype', 'HP:0006727', (107, 142))	('knockouts', 'Var', (32, 41))	('RAS', 'Chemical', 'MESH:D011883', (355, 358))	('RASA1', 'Gene', (52, 57))	('RAS', 'Chemical', 'MESH:D011883', (52, 55))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (120, 142))
498341	29127119	Such data, along with our analysis of the cancer genomic data nominate concurrent RASA1/NF1 truncating mutations as a strong mitogenic driver in NSCLC, a nomination for which we now provide functional data in NSCLC cell lines.	('NSCLC', 'Disease', 'MESH:D002289', (209, 214))	('NF1', 'Gene', (88, 91))	('truncating mutations', 'Var', (92, 112))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('NSCLC', 'Disease', (145, 150))	('NF1', 'Gene', '4763', (88, 91))	('RASA1', 'Gene', '5921', (82, 87))	('NSCLC', 'Disease', 'MESH:D002289', (145, 150))	('RASA1', 'Gene', (82, 87))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('NSCLC', 'Disease', (209, 214))
498342	29127119	We demonstrate that loss of RASA1 expression activates downstream signaling of RAS via an increase of RAS-GTP, which promotes cell growth in immortalized bronchial epithelial cells.	('activates', 'PosReg', (45, 54))	('RASA1', 'Gene', (28, 33))	('loss', 'Var', (20, 24))	('RAS', 'Chemical', 'MESH:D011883', (102, 105))	('increase', 'PosReg', (90, 98))	('RASA1', 'Gene', '5921', (28, 33))	('downstream signaling', 'MPA', (55, 75))	('RAS', 'Chemical', 'MESH:D011883', (28, 31))	('RAS', 'Chemical', 'MESH:D011883', (79, 82))	('promotes', 'PosReg', (117, 125))	('RAS-GTP', 'Chemical', '-', (102, 109))	('RAS-GTP', 'Protein', (102, 109))	('cell growth', 'CPA', (126, 137))
498343	29127119	Conversely, restoration of RASA1 expression reduces signaling through the MAPK and PI3K pathways in NSCLC lines harboring RASA1 truncating mutation.	('truncating mutation', 'Var', (128, 147))	('NSCLC', 'Disease', (100, 105))	('PI3K pathways', 'Pathway', (83, 96))	('signaling', 'MPA', (52, 61))	('NSCLC', 'Disease', 'MESH:D002289', (100, 105))	('RASA1', 'Gene', '5921', (122, 127))	('expression', 'MPA', (33, 43))	('RASA1', 'Gene', '5921', (27, 32))	('RASA1', 'Gene', (122, 127))	('reduces', 'NegReg', (44, 51))	('RASA1', 'Gene', (27, 32))
498344	29127119	Moreover, NSCLC lines with concurrent RASA1/NF1 mutations show more profound sensitivity to inhibitors of MEK, both in western blots and cell growth inhibition assays, as compared to only RASA1 mutated lines.	('NSCLC', 'Disease', (10, 15))	('NSCLC', 'Disease', 'MESH:D002289', (10, 15))	('NF1', 'Gene', (44, 47))	('MEK', 'Gene', (106, 109))	('MEK', 'Gene', '5609', (106, 109))	('NF1', 'Gene', '4763', (44, 47))	('sensitivity', 'MPA', (77, 88))	('RASA1', 'Gene', '5921', (188, 193))	('RASA1', 'Gene', '5921', (38, 43))	('mutations', 'Var', (48, 57))	('RASA1', 'Gene', (188, 193))	('RASA1', 'Gene', (38, 43))
498345	29127119	Likewise, simultaneous knockdown of RASA1 and NF1 enhances sensitivity to the MEK inhibitor trametinib, suggesting that more complete cellular loss of RasGAP function induced sensitivity to inhibitors which act downstream of RAS.	('MEK', 'Gene', (78, 81))	('enhances', 'PosReg', (50, 58))	('MEK', 'Gene', '5609', (78, 81))	('sensitivity', 'MPA', (175, 186))	('NF1', 'Gene', (46, 49))	('NF1', 'Gene', '4763', (46, 49))	('knockdown', 'Var', (23, 32))	('RasGAP', 'Gene', '5921', (151, 157))	('RASA1', 'Gene', '5921', (36, 41))	('RasGAP', 'Gene', (151, 157))	('loss', 'NegReg', (143, 147))	('RASA1', 'Gene', (36, 41))	('RAS', 'Chemical', 'MESH:D011883', (225, 228))	('RAS', 'Chemical', 'MESH:D011883', (36, 39))	('trametinib', 'Chemical', 'MESH:C560077', (92, 102))
498347	29127119	However, there was a significant difference seen in the histologic type observed in each cohort: RASA1 or NF1 truncating mutations were enriched among squamous cell carcinomas and adenocarcinomas, respectively, whereas RASA1/NF1 co-mutated tumors were more evenly distributed.	('RASA1', 'Gene', (97, 102))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (151, 175))	('tumors', 'Disease', (240, 246))	('adenocarcinomas', 'Disease', 'MESH:D000230', (180, 195))	('adenocarcinomas', 'Disease', (180, 195))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (151, 174))	('squamous cell carcinomas', 'Disease', (151, 175))	('tumors', 'Disease', 'MESH:D009369', (240, 246))	('RASA1', 'Gene', '5921', (219, 224))	('carcinoma', 'Phenotype', 'HP:0030731', (165, 174))	('NF1', 'Gene', '4763', (225, 228))	('NF1', 'Gene', '4763', (106, 109))	('truncating mutations', 'Var', (110, 130))	('tumor', 'Phenotype', 'HP:0002664', (240, 245))	('RASA1', 'Gene', (219, 224))	('RASA1', 'Gene', '5921', (97, 102))	('carcinomas', 'Phenotype', 'HP:0030731', (165, 175))	('NF1', 'Gene', (225, 228))	('tumors', 'Phenotype', 'HP:0002664', (240, 246))	('NF1', 'Gene', (106, 109))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (151, 175))	('carcinoma', 'Phenotype', 'HP:0030731', (185, 194))	('carcinomas', 'Phenotype', 'HP:0030731', (185, 195))
498349	29127119	This study indicates that inhibition of MEK in NSCLC lines harboring concurrent RASA1/NF1 truncating mutations dramatically inhibit cell growth in vitro.	('MEK', 'Gene', '5609', (40, 43))	('RASA1', 'Gene', '5921', (80, 85))	('RASA1', 'Gene', (80, 85))	('NF1', 'Gene', '4763', (86, 89))	('NSCLC', 'Disease', (47, 52))	('truncating mutations', 'Var', (90, 110))	('NF1', 'Gene', (86, 89))	('inhibit', 'NegReg', (124, 131))	('NSCLC', 'Disease', 'MESH:D002289', (47, 52))	('cell growth in vitro', 'CPA', (132, 152))	('MEK', 'Gene', (40, 43))
498350	29127119	Notably, these findings have potential therapeutic implications for patients with not only lung adenocarcinoma but also squamous cell carcinoma with concurrent RASA1/NF1 truncating mutations, providing a preclinical rationale for the evaluation of MEK inhibitors in this molecular subset of NSCLC that lacks other targetable alterations.	('NF1', 'Gene', '4763', (166, 169))	('RASA1', 'Gene', '5921', (160, 165))	('lung adenocarcinoma', 'Disease', (91, 110))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (120, 143))	('NSCLC', 'Disease', 'MESH:D002289', (291, 296))	('NF1', 'Gene', (166, 169))	('truncating mutations', 'Var', (170, 190))	('implications', 'Reg', (51, 63))	('patients', 'Species', '9606', (68, 76))	('RASA1', 'Gene', (160, 165))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (91, 110))	('NSCLC', 'Disease', (291, 296))	('squamous cell carcinoma', 'Disease', (120, 143))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (91, 110))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('MEK', 'Gene', '5609', (248, 251))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (120, 143))	('MEK', 'Gene', (248, 251))
498353	29127119	For instance, detailed genomic analysis of a bladder cancer patient with exceptional response to an mTORC1 inhibitor revealed nonsense mutations in TSC1 and NF2, both negative regulators of mTORC1.	('mTORC1', 'Gene', (190, 196))	('patient', 'Species', '9606', (60, 67))	('NF2', 'Gene', '4771', (157, 160))	('mutations', 'Var', (135, 144))	('bladder cancer', 'Phenotype', 'HP:0009725', (45, 59))	('mTORC1', 'Gene', (100, 106))	('mTORC1', 'Gene', '382056', (100, 106))	('mTORC1', 'Gene', '382056', (190, 196))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('NF2', 'Gene', (157, 160))	('TSC1', 'Gene', '7248', (148, 152))	('TSC1', 'Gene', (148, 152))	('bladder cancer', 'Disease', 'MESH:D001749', (45, 59))	('bladder cancer', 'Disease', (45, 59))
498354	29127119	Likewise, a recent analysis in malignant pleural mesothelioma identified a small subset with co-inactivation of LATS2 and NF2 that is associated with increased sensitivity to mTOR inhibition.	('NF2', 'Gene', (122, 125))	('LATS2', 'Gene', (112, 117))	('LATS2', 'Gene', '26524', (112, 117))	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (31, 61))	('NF2', 'Gene', '4771', (122, 125))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (41, 61))	('malignant pleural mesothelioma', 'Disease', (31, 61))	('mTOR', 'Gene', '2475', (175, 179))	('co-inactivation', 'Var', (93, 108))	('mTOR', 'Gene', (175, 179))
498355	29127119	Finally, a recent study found that cell lines with co-inactivation of ARID1A and RNF43, both alterations known to activate beta-catenin signaling, are exquisitely sensitive to aurora kinase inhibition.	('beta-catenin', 'Gene', '1499', (123, 135))	('RNF43', 'Gene', '54894', (81, 86))	('RNF43', 'Gene', (81, 86))	('ARID1A', 'Gene', '8289', (70, 76))	('activate', 'PosReg', (114, 122))	('ARID1A', 'Gene', (70, 76))	('beta-catenin', 'Gene', (123, 135))	('co-inactivation', 'Var', (51, 66))
498356	29127119	In summary, our cancer genomic and functional data nominate concurrent RASA1/NF1 loss of function mutations as a strong mitogenic driver in NSCLC.	('NSCLC', 'Disease', 'MESH:D002289', (140, 145))	('cancer', 'Disease', 'MESH:D009369', (16, 22))	('loss of function', 'NegReg', (81, 97))	('NF1', 'Gene', (77, 80))	('cancer', 'Disease', (16, 22))	('RASA1', 'Gene', '5921', (71, 76))	('NF1', 'Gene', '4763', (77, 80))	('mutations', 'Var', (98, 107))	('RASA1', 'Gene', (71, 76))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('NSCLC', 'Disease', (140, 145))
498358	29127119	Because of the relatively high background mutation rate of smoking-associated NSCLC, we have focused our data analyses on truncating mutations of RASA1 and NF1, reasoning that a high proportion of missense mutations in these two genes may be passenger mutations of uncertain functional significance and would add noise to the genomic data analysis.	('NF1', 'Gene', (156, 159))	('RASA1', 'Gene', (146, 151))	('NSCLC', 'Disease', 'MESH:D002289', (78, 83))	('NF1', 'Gene', '4763', (156, 159))	('NSCLC', 'Disease', (78, 83))	('missense mutations', 'Var', (197, 215))	('RASA1', 'Gene', '5921', (146, 151))
498359	29127119	However, it is likely that a subset of missense mutations in these genes, for instance in their RasGAP domains, may be functionally inactivating, potentially expanding the size of this small but targetable molecular subset of NSCLC.	('inactivating', 'NegReg', (132, 144))	('NSCLC', 'Disease', 'MESH:D002289', (226, 231))	('expanding', 'PosReg', (158, 167))	('RasGAP', 'Gene', (96, 102))	('RasGAP', 'Gene', '5921', (96, 102))	('NSCLC', 'Disease', (226, 231))	('missense mutations', 'Var', (39, 57))
498360	29127119	Finally, while targetable alterations are generally much more common in never-smokers, it is notable that patients whose NSCLC harbor concurrent RASA1/NF1 loss of function mutations, along with patients with MAP2K1 activating mutations, represent strongly smoking-associated subsets that are potentially targetable, opening new therapeutic avenues for some patients with smoking-induced NSCLC.	('mutations', 'Var', (172, 181))	('NSCLC', 'Disease', 'MESH:D002289', (387, 392))	('RASA1', 'Gene', '5921', (145, 150))	('patients', 'Species', '9606', (194, 202))	('MAP2K1', 'Gene', '5604', (208, 214))	('RASA1', 'Gene', (145, 150))	('loss of function', 'NegReg', (155, 171))	('NSCLC', 'Disease', (121, 126))	('MAP2K1', 'Gene', (208, 214))	('patients', 'Species', '9606', (357, 365))	('NF1', 'Gene', (151, 154))	('NSCLC', 'Disease', 'MESH:D002289', (121, 126))	('patients', 'Species', '9606', (106, 114))	('NF1', 'Gene', '4763', (151, 154))	('NSCLC', 'Disease', (387, 392))
498361	29127119	Approximately 2% of non-small cell lung carcinomas (NSCLCs) harbor RASA1 truncating mutations.	('non-small cell lung carcinomas', 'Phenotype', 'HP:0030358', (20, 50))	('NSCLC', 'Disease', (52, 57))	('non-small cell lung carcinomas', 'Disease', 'MESH:D002289', (20, 50))	('NSCLC', 'Disease', 'MESH:D002289', (52, 57))	('RASA1', 'Gene', '5921', (67, 72))	('NSCLCs', 'Phenotype', 'HP:0030358', (52, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (40, 49))	('RASA1', 'Gene', (67, 72))	('carcinomas', 'Phenotype', 'HP:0030731', (40, 50))	('non-small cell lung carcinomas', 'Disease', (20, 50))	('small cell lung carcinomas', 'Phenotype', 'HP:0030357', (24, 50))	('truncating mutations', 'Var', (73, 93))
498362	29127119	Here, we show that RASA1 truncating mutations have a strong tendency to co-occur with NF1 truncating mutations, and that alterations of these two negative regulators of RAS signaling, when concurrent, are mutually exclusive with other lung cancer mitogenic drivers.	('RAS', 'Chemical', 'MESH:D011883', (19, 22))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('RASA1', 'Gene', '5921', (19, 24))	('RASA1', 'Gene', (19, 24))	('truncating mutations', 'Var', (25, 45))	('lung cancer', 'Disease', 'MESH:D008175', (235, 246))	('NF1', 'Gene', (86, 89))	('truncating mutations', 'Var', (90, 110))	('RAS', 'Chemical', 'MESH:D011883', (169, 172))	('NF1', 'Gene', '4763', (86, 89))	('lung cancer', 'Disease', (235, 246))	('lung cancer', 'Phenotype', 'HP:0100526', (235, 246))
498363	29127119	This is notable because the major mitogenic drivers defined to date in NSCLC have been oncogenes activated by mutation or gene fusion, not tumor suppressors.	('gene fusion', 'Var', (122, 133))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('mutation', 'Var', (110, 118))	('NSCLC', 'Disease', (71, 76))	('NSCLC', 'Disease', 'MESH:D002289', (71, 76))
498364	29127119	NSCLC cells with concurrent RASA1/NF1 mutations show profound sensitivity to MEK inhibition.	('RASA1', 'Gene', (28, 33))	('RASA1', 'Gene', '5921', (28, 33))	('NSCLC', 'Disease', 'MESH:D002289', (0, 5))	('MEK', 'Gene', (77, 80))	('sensitivity', 'MPA', (62, 73))	('NF1', 'Gene', (34, 37))	('mutations', 'Var', (38, 47))	('MEK', 'Gene', '5609', (77, 80))	('NSCLC', 'Disease', (0, 5))	('NF1', 'Gene', '4763', (34, 37))
498365	29127119	Taken together, cancer genomic data and our functional data nominate concurrent RASA1/NF1 loss of function mutations as a strong mitogenic driver in NSCLCs.	('mutations', 'Var', (107, 116))	('cancer', 'Disease', 'MESH:D009369', (16, 22))	('RASA1', 'Gene', '5921', (80, 85))	('cancer', 'Disease', (16, 22))	('NSCLC', 'Disease', (149, 154))	('RASA1', 'Gene', (80, 85))	('loss of function', 'NegReg', (90, 106))	('NF1', 'Gene', (86, 89))	('NSCLCs', 'Phenotype', 'HP:0030358', (149, 155))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('NSCLC', 'Disease', 'MESH:D002289', (149, 154))	('NF1', 'Gene', '4763', (86, 89))
498380	32929263	Third we use VIPER (Virtual Inference of Protein activity by Enriched Regulon analysis) to associate the mutational state of a candidate upstream modulator protein with differential activity of the anchor protein or the mutational state of the latter with differential activity of its candidate downstream effectors.	('activity', 'MPA', (182, 190))	('mutational', 'Var', (105, 115))	('VIPER', 'Species', '31156', (13, 18))
498391	32929263	Consistent with these results, its VIPER-inferred activity is significantly affected by SETD2 and CTNNB1 mutations.	('CTNNB1', 'Gene', (98, 104))	('SETD2', 'Gene', (88, 93))	('mutations', 'Var', (105, 114))	('VIPER', 'Species', '31156', (35, 40))	('affected', 'Reg', (76, 84))	('CTNNB1', 'Gene', '1499', (98, 104))	('VIPER-inferred', 'CPA', (35, 49))
498433	32929263	MAP4Ks, such as MINK1 (MAP4K6, downstream) and MAP4K1 (upstream), are also implicated in vesicular trafficking through their association with Striatin family complexes, whose dysregulation leads to cancer.	('MAP4K1', 'Gene', (47, 53))	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('vesicular trafficking', 'MPA', (89, 110))	('dysregulation', 'Var', (175, 188))	('leads to', 'Reg', (189, 197))	('cancer', 'Disease', (198, 204))	('Striatin family complexes', 'Protein', (142, 167))	('association', 'Interaction', (125, 136))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))
498440	32929263	The significant overlap between these maps (R2LUSC/LUAD = 0.35, p < 10-267; and R2COAD/LUAD = 0.10, p < 10-165) suggests the existence of a core of context-independent physical/functional KRAS interactors (see Supplementary File 5).	('KRAS', 'Gene', (188, 192))	('KRAS', 'Gene', '3845', (188, 192))	('R2COAD/LUAD', 'Var', (80, 91))
498443	32929263	For instance, CSF1 (macrophage colony-stimulating factor 1, black) is a LUSC-specific, significant survival marker, while downregulation of RASAL2 (a Ras GTPase-activating protein, green) promotes metastatic progression in LUAD.	('LUAD', 'Disease', (223, 227))	('RASAL2', 'Gene', (140, 146))	('promotes', 'PosReg', (188, 196))	('GTP', 'Chemical', 'MESH:D006160', (154, 157))	('metastatic progression', 'CPA', (197, 219))	('downregulation', 'Var', (122, 136))
498448	32929263	While this may simply reflect stronger conservation of KRAS biology in these two tumors, PAAD analysis is challenging because most samples (>90%) harbor KRAS mutations and virtually all present significant KRAS pathway activity.	('KRAS', 'Gene', (55, 59))	('tumors', 'Disease', (81, 87))	('activity', 'MPA', (219, 227))	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('KRAS', 'Gene', '3845', (206, 210))	('harbor', 'Reg', (146, 152))	('KRAS', 'Gene', '3845', (55, 59))	('KRAS', 'Gene', (153, 157))	('KRAS', 'Gene', '3845', (153, 157))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('mutations', 'Var', (158, 167))	('KRAS', 'Gene', (206, 210))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))
498456	32929263	Furthermore, predictions were also highly enriched in 58 genes whose knockdown was shown to sensitize cells to EGFR-targeted inhibitors (p = 1.4 x 10-9).	('EGFR', 'Gene', '1956', (111, 115))	('EGFR', 'Gene', (111, 115))	('knockdown', 'Var', (69, 78))
498470	32929263	Thus, SigMaps may provide additional, pharmacologically accessible candidate targets for many mutated oncoproteins, including KRAS, thus providing a valuable resource for guiding hypothesis-based studies to validate their disease-related relevance.	('KRAS', 'Gene', '3845', (126, 130))	('mutated', 'Var', (94, 101))	('KRAS', 'Gene', (126, 130))
498475	32929263	aREA was used to assess the statistical significance of the co-segregation between nonsynonymous (missense) Single Nucleotide Polymorphisms in other genes and KRAS activity.	('KRAS', 'Gene', (159, 163))	('nonsynonymous', 'Var', (83, 96))	('KRAS', 'Gene', '3845', (159, 163))
498485	32929263	75 samples with KRAS knockdowns (KDs) in A549 cell lines were retrieved from The Library of Network-Based Cellular Signatures (LINCS) project (http://www.lincsproject.org/).	('A549', 'CellLine', 'CVCL:0023', (41, 45))	('knockdowns', 'Var', (21, 31))	('KRAS', 'Gene', (16, 20))	('KRAS', 'Gene', '3845', (16, 20))
498568	30411543	Recently, targeted therapy that is based on the mutation state of molecular biomarkers has been developed for the treatment of non-small-cell lung cancer.60 In fact, approximately 60%-80% of the patients whose tumor samples contain somatic mutations in the kinase domain of the epidermal growth factor receptor (EGFR) gene respond to EGFR tyrosine kinase inhibitors (TKIs).61 Mutated KRAS, v-erb-b2 erythroblastic leukemia viral oncogene homolog 2 (HER-2), and serine-threonine kinase BRAF are also involved in the development and progression of NSCLC.62, 63  Although the molecular status of EGFR in primary NSCLC has been extensively studied, the data on the molecular status of BM from NSCLC are limited.64, 65, 66, 67, 68, 69 Studies of molecular pathways that mediate brain metastases have shown that oncogenes play an important role and that the molecular statuses of these genes need to be further investigated because they can be part of the patient risk stratification.70  It has been reported that the epidermal growth factor receptor (EGFR) mutation status could have an influence on the central nervous system (CNS) progression of NSCLC.9, 39, 60, 69, 71, 72 The study by Li et al analyzed 110 patients with NSCLC whose EGFR status was detected in the primary tumors and brain metastases.	('patients', 'Species', '9606', (1206, 1214))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('NSCLC', 'Disease', 'MESH:D002289', (1143, 1148))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (127, 153))	('NSCLC', 'Disease', 'MESH:D002289', (546, 551))	('NSCLC', 'Disease', 'MESH:D002289', (1220, 1225))	('epidermal growth factor receptor', 'Gene', (278, 310))	('NSCLC', 'Disease', (689, 694))	('NSCLC', 'Disease', 'MESH:D002289', (609, 614))	('erythroblastic leukemia viral', 'Disease', (399, 428))	('N', 'Chemical', 'MESH:D009584', (1124, 1125))	('epidermal growth factor receptor', 'Gene', '1956', (278, 310))	('NSCLC', 'Disease', (1143, 1148))	('erythroblastic leukemia viral', 'Disease', 'MESH:D004915', (399, 428))	('NSCLC', 'Phenotype', 'HP:0030358', (689, 694))	('NSCLC', 'Disease', (1220, 1225))	('NSCLC', 'Disease', (546, 551))	('primary tumors', 'Disease', (1264, 1278))	('NSCLC', 'Disease', (609, 614))	('tumor', 'Disease', (210, 215))	('NSCLC', 'Phenotype', 'HP:0030358', (1143, 1148))	('patients', 'Species', '9606', (195, 203))	('tumor', 'Disease', (1272, 1277))	('N', 'Chemical', 'MESH:D009584', (1220, 1221))	('patient', 'Species', '9606', (1206, 1213))	('rat', 'Species', '10116', (965, 968))	('NSCLC', 'Phenotype', 'HP:0030358', (1220, 1225))	('NSCLC', 'Phenotype', 'HP:0030358', (546, 551))	('tumor', 'Disease', 'MESH:D009369', (210, 215))	('NSCLC', 'Phenotype', 'HP:0030358', (609, 614))	('non-small-cell lung cancer', 'Disease', (127, 153))	('patient', 'Species', '9606', (950, 957))	('tumor', 'Disease', 'MESH:D009369', (1272, 1277))	('epidermal growth factor receptor', 'Gene', (1012, 1044))	('non-small-cell lung cancer', 'Disease', 'MESH:D002289', (127, 153))	('HER-2', 'Gene', '2064', (449, 454))	('epidermal growth factor receptor', 'Gene', '1956', (1012, 1044))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (131, 153))	('primary tumors', 'Disease', 'MESH:D009369', (1264, 1278))	('HER-2', 'Gene', (449, 454))	('brain metastases', 'Disease', 'MESH:D009362', (1283, 1299))	('lung cancer', 'Phenotype', 'HP:0100526', (142, 153))	('brain metastases', 'Disease', (1283, 1299))	('tumors', 'Phenotype', 'HP:0002664', (1272, 1278))	('N', 'Chemical', 'MESH:D009584', (689, 690))	('b2 erythroblastic leukemia', 'Phenotype', 'HP:0004812', (396, 422))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('brain metastases', 'Disease', 'MESH:D009362', (773, 789))	('N', 'Chemical', 'MESH:D009584', (1143, 1144))	('brain metastases', 'Disease', (773, 789))	('patient', 'Species', '9606', (195, 202))	('tumor', 'Phenotype', 'HP:0002664', (1272, 1277))	('BRAF', 'Gene', (485, 489))	('BRAF', 'Gene', '673', (485, 489))	('leukemia', 'Phenotype', 'HP:0001909', (414, 422))	('NSCLC', 'Disease', 'MESH:D002289', (689, 694))	('N', 'Chemical', 'MESH:D009584', (546, 547))	('EGFR', 'Gene', (1046, 1050))	('mutation', 'Var', (1052, 1060))	('N', 'Chemical', 'MESH:D009584', (609, 610))
498569	30411543	The EGFR mutation rates in patients with and without brain metastases were 64% and 31%, respectively, suggesting that brain metastases were more common in patients with EGFR mutations.73 However, this study had small sample sizes, which may have limitations.	('rat', 'Species', '10116', (18, 21))	('mutations.73', 'Var', (174, 186))	('brain metastases', 'Disease', 'MESH:D009362', (118, 134))	('brain metastases', 'Disease', (118, 134))	('patients', 'Species', '9606', (27, 35))	('EGFR', 'Gene', (169, 173))	('patients', 'Species', '9606', (155, 163))	('brain metastases', 'Disease', 'MESH:D009362', (53, 69))	('brain metastases', 'Disease', (53, 69))
498570	30411543	In 2016, a retrospective study including 1522 consecutive NSCLC patients reported that patients with EGFR mutations at the time of diagnosis have a nearly twofold higher risk of brain metastases.74 The results above suggest that the EGFR mutation status could have an influence on the CNS progression of NSCLC.	('brain metastases', 'Disease', (178, 194))	('NSCLC', 'Disease', (58, 63))	('N', 'Chemical', 'MESH:D009584', (304, 305))	('NSCLC', 'Disease', 'MESH:D002289', (304, 309))	('patients', 'Species', '9606', (64, 72))	('NSCLC', 'Disease', 'MESH:D002289', (58, 63))	('EGFR', 'Gene', (233, 237))	('NSCLC', 'Phenotype', 'HP:0030358', (304, 309))	('patients', 'Species', '9606', (87, 95))	('CNS progression', 'CPA', (285, 300))	('N', 'Chemical', 'MESH:D009584', (58, 59))	('NSCLC', 'Phenotype', 'HP:0030358', (58, 63))	('NSCLC', 'Disease', (304, 309))	('influence', 'Reg', (268, 277))	('mutation', 'Var', (238, 246))	('brain metastases', 'Disease', 'MESH:D009362', (178, 194))	('N', 'Chemical', 'MESH:D009584', (286, 287))
498574	30411543	Italiano et al found that discordant EGFR expression can reach 33.3% in a cohort of 30 matched primary tumors and metastases.84  In conclusion, EGFR mutations play an important role in the metastasis of NSCLC and may support risk stratification, especially in East Asian patients, but the status of these mutations needs to be further investigated.	('primary tumors', 'Disease', (95, 109))	('support', 'Reg', (217, 224))	('metastases', 'Disease', (114, 124))	('EGFR', 'Gene', (144, 148))	('NSCLC', 'Disease', (203, 208))	('mutations', 'Var', (149, 158))	('rat', 'Species', '10116', (232, 235))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('primary tumors', 'Disease', 'MESH:D009369', (95, 109))	('NSCLC', 'Disease', 'MESH:D002289', (203, 208))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('metastases', 'Disease', 'MESH:D009362', (114, 124))	('patients', 'Species', '9606', (271, 279))	('NSCLC', 'Phenotype', 'HP:0030358', (203, 208))	('metastasis', 'CPA', (189, 199))
498575	30411543	The overall incidence rate of BM in patients withanaplastic lymphoma kinase (ALK)-positive NSCLC is high.85, 86, 87 Some studies have shown that patients with ALK overexpression mutations have stable or asymptomatic BM at the initial diagnosis or with progression.	('NSCLC', 'Disease', 'MESH:D002289', (91, 96))	('patients', 'Species', '9606', (145, 153))	('ALK', 'Gene', (77, 80))	('patients', 'Species', '9606', (36, 44))	('ALK', 'Gene', '238', (159, 162))	('NSCLC', 'Phenotype', 'HP:0030358', (91, 96))	('rat', 'Species', '10116', (22, 25))	('lymphoma', 'Phenotype', 'HP:0002665', (60, 68))	('NSCLC', 'Disease', (91, 96))	('ALK', 'Gene', '238', (77, 80))	('ALK', 'Gene', (159, 162))	('withanaplastic lymphoma', 'Disease', (45, 68))	('mutations', 'Var', (178, 187))	('withanaplastic lymphoma', 'Disease', 'MESH:D008223', (45, 68))	('overexpression', 'PosReg', (163, 177))
498576	30411543	In the study of 21 patients with NSCLC with mutated ALK by Deepa Rangachari,88 23.8% (5/21) of patients had BM at the initial diagnosis.	('NSCLC', 'Phenotype', 'HP:0030358', (33, 38))	('patients', 'Species', '9606', (19, 27))	('patients', 'Species', '9606', (95, 103))	('ALK', 'Gene', '238', (52, 55))	('mutated', 'Var', (44, 51))	('NSCLC', 'Disease', (33, 38))	('NSCLC', 'Disease', 'MESH:D002289', (33, 38))	('ALK', 'Gene', (52, 55))
498577	30411543	Although the clinical data were not enough to build a convincing conclusion, we can still find that the ALK mutations are associated with the incidence of BM in NSCLC.	('NSCLC', 'Disease', 'MESH:D002289', (161, 166))	('mutations', 'Var', (108, 117))	('ALK', 'Gene', '238', (104, 107))	('associated with', 'Reg', (122, 137))	('NSCLC', 'Phenotype', 'HP:0030358', (161, 166))	('ALK', 'Gene', (104, 107))	('NSCLC', 'Disease', (161, 166))
498589	30411543	EGFR mutations have been reported to be an independent risk factor for brain metastases.	('brain metastases', 'Disease', 'MESH:D009362', (71, 87))	('EGFR', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))	('brain metastases', 'Disease', (71, 87))
498610	26276745	In SWR/J mice, N-nitroso-tris-chloroethylurea (NTCU) induces premalignant lesions that progress to frank lung SCC.	('N-nitroso-tris-chloroethylurea', 'Var', (15, 45))	('N-nitroso-tris-chloroethylurea', 'Chemical', 'MESH:C572573', (15, 45))	('SCC', 'Gene', (110, 113))	('NTCU', 'Chemical', 'MESH:C572573', (47, 51))	('progress', 'PosReg', (87, 95))	('mice', 'Species', '10090', (9, 13))	('SCC', 'Gene', '6317', (110, 113))	('induces', 'Reg', (53, 60))
498628	26276745	It has been shown that vitamin D enhances the antimicrobial response to the respiratory pathogen, Mycobacterium tuberculosis.	('enhances', 'PosReg', (33, 41))	('vitamin', 'Var', (23, 30))	('Mycobacterium tuberculosis', 'Species', '1773', (98, 124))	('vitamin D', 'Chemical', '-', (23, 32))	('antimicrobial response to the respiratory pathogen', 'MPA', (46, 96))
498658	26276745	Primary antibodies were used at the following concentrations: (VDR, 1:250 MA1-710 (Affinity Bio); p63, 1:1500 SC-8431 (Santa Cruz); TTF-1, 1:400 M3675 (Dako); and F4/80, 1:100 AB6640 (Abcam).	('F4/80, 1:100 AB6640', 'Gene', '13733', (163, 182))	('TTF-1', 'Var', (132, 137))	('p63', 'Var', (98, 101))
498671	26276745	Primer probe sets IL-6 (Mm00446190_m1) and GAPDH (Mm99999915_g1) were used.	('Mm99999915_g1', 'Var', (50, 63))	('IL-6', 'Gene', (18, 22))	('GAPDH', 'Gene', '14433', (43, 48))	('Mm00446190_m1', 'Var', (24, 37))	('GAPDH', 'Gene', (43, 48))	('IL-6', 'Gene', '16193', (18, 22))
498686	26276745	It is unclear the mechanism(s) whereby NTCU induces SCC of the lung.	('NTCU', 'Chemical', 'MESH:C572573', (39, 43))	('SCC', 'Gene', (52, 55))	('NTCU', 'Var', (39, 43))	('SCC', 'Gene', '6317', (52, 55))	('induces', 'Reg', (44, 51))
498693	26276745	Dietary vitamin D3 supplementation resulted in ~50% reduction in the frequency of HGD after 15 mumol of NTCU: SN (43%) and SN+C (50%), compared to the DN group (100%)(p<0.05)(Table 2).	('SN+C', 'Chemical', '-', (123, 127))	('SN', 'Chemical', '-', (123, 125))	('DN', 'Chemical', '-', (151, 153))	('HGD', 'Disease', (82, 85))	('SN', 'Chemical', '-', (110, 112))	('SN+C', 'Var', (123, 127))	('frequency', 'MPA', (69, 78))	('vitamin D3', 'Chemical', 'MESH:D002762', (8, 18))	('NTCU', 'Chemical', 'MESH:C572573', (104, 108))	('reduction', 'NegReg', (52, 61))
498697	26276745	Calcitriol was also protective, as 58 % of mice in the DN+C group developed HGD after 15 mumol of NTCU, compared to 100% in the DN group (p<0.05)(Table 2).	('HGD', 'Disease', (76, 79))	('mice', 'Species', '10090', (43, 47))	('DN+C', 'Var', (55, 59))	('DN', 'Chemical', '-', (55, 57))	('NTCU', 'Chemical', 'MESH:C572573', (98, 102))	('Calcitriol', 'Chemical', 'MESH:D002117', (0, 10))	('DN', 'Chemical', '-', (128, 130))	('DN+C', 'Chemical', '-', (55, 59))
498699	26276745	In addition to reducing the frequency with which HGD occurred, the percentage of airway occupied by HGD lesions after treatment with 15 mumol of NTCU was significantly less in the SN (8.7%), SN+C (6.6%) and reduced in the DN+C (12.3%) groups compared to the DN (22.7%)(p<0.05) group (Table 3).	('SN+C', 'Var', (191, 195))	('NTCU', 'Chemical', 'MESH:C572573', (145, 149))	('DN', 'Chemical', '-', (258, 260))	('SN', 'Chemical', '-', (180, 182))	('DN+C', 'Chemical', '-', (222, 226))	('reduced', 'NegReg', (207, 214))	('SN+C', 'Chemical', '-', (191, 195))	('SN', 'Chemical', '-', (191, 193))	('NTCU', 'Gene', (145, 149))	('DN', 'Chemical', '-', (222, 224))	('less', 'NegReg', (168, 172))
498707	26276745	The expression of CK 5/6 and p63 were greater in the DN group compared to the SN group after treatment with 25 mumol of NTCU, consistent with our observation that deficient mice have more advanced squamous lesions (Fig.	('CK 5/6', 'Gene', (18, 24))	('greater', 'PosReg', (38, 45))	('expression', 'MPA', (4, 14))	('p63', 'Var', (29, 32))	('NTCU', 'Chemical', 'MESH:C572573', (120, 124))	('DN', 'Chemical', '-', (53, 55))	('mice', 'Species', '10090', (173, 177))	('squamous lesions', 'Disease', 'MESH:D002294', (197, 213))	('squamous lesions', 'Disease', (197, 213))	('SN', 'Chemical', '-', (78, 80))
498729	26276745	NTCU increases plasma IL-6 levels in DN mice compared to SN at each time point investigated (p<0.05) (Fig.	('IL-6', 'Gene', (22, 26))	('IL-6', 'Gene', '16193', (22, 26))	('increases', 'PosReg', (5, 14))	('DN', 'Chemical', '-', (37, 39))	('NTCU', 'Chemical', 'MESH:C572573', (0, 4))	('mice', 'Species', '10090', (40, 44))	('SN', 'Chemical', '-', (57, 59))	('NTCU', 'Var', (0, 4))
498730	26276745	These data suggest that NTCU elicits an enhanced inflammatory state in the DN mice.	('NTCU', 'Var', (24, 28))	('enhanced inflammatory state', 'Phenotype', 'HP:0012649', (40, 67))	('NTCU', 'Chemical', 'MESH:C572573', (24, 28))	('inflammatory', 'MPA', (49, 61))	('DN', 'Chemical', '-', (75, 77))	('enhanced', 'PosReg', (40, 48))	('mice', 'Species', '10090', (78, 82))
498731	26276745	Consistent with this idea, two weeks following NTCU treatment, the WBC count in the DN-80 mM group was markedly increased compared to all other groups (p<0.05).	('WBC count', 'CPA', (67, 76))	('DN-80 mM', 'Var', (84, 92))	('DN-80', 'Chemical', '-', (84, 89))	('NTCU', 'Chemical', 'MESH:C572573', (47, 51))	('increased', 'PosReg', (112, 121))
498733	26276745	Differential staining indicated that the increase in WBCs consisted predominately of neutrophils in the SN-80 mM group (p<0.01) and the DN-40 mM and DN-80 mM groups (p<0.05).	('WBCs', 'CPA', (53, 57))	('SN-80 mM', 'Var', (104, 112))	('DN', 'Chemical', '-', (149, 151))	('DN-80', 'Chemical', '-', (149, 154))	('SN-80', 'Chemical', '-', (104, 109))	('DN', 'Chemical', '-', (136, 138))	('increase', 'PosReg', (41, 49))
498735	26276745	The large increase in the number of WBCs in the DN-80 mM group consisted of neutrophils, monocytes and lymphocytes.	('DN-80', 'Chemical', '-', (48, 53))	('increase', 'PosReg', (10, 18))	('DN-80 mM', 'Var', (48, 56))
498742	26276745	The acute, pro-inflammatory effect of NTCU was enhanced in the deficient mice (p<0.01)(Fig.	('enhanced', 'PosReg', (47, 55))	('NTCU', 'Gene', (38, 42))	('mice', 'Species', '10090', (73, 77))	('deficient', 'Var', (63, 72))	('NTCU', 'Chemical', 'MESH:C572573', (38, 42))
498745	26276745	Cumulatively, these data suggest an association between increased inflammation and vitamin D deficiency, which correlates with enhanced disease progression.	('enhanced', 'PosReg', (127, 135))	('vitamin D', 'Gene', (83, 92))	('inflammation', 'Disease', (66, 78))	('increased', 'PosReg', (56, 65))	('vitamin D deficiency', 'Phenotype', 'HP:0100512', (83, 103))	('deficiency', 'Var', (93, 103))	('inflammation', 'Disease', 'MESH:D007249', (66, 78))	('vitamin D', 'Chemical', '-', (83, 92))
498780	26276745	Vitamin D deficiency was associated with increased proliferation as assessed by Ki-67 staining and increased progression of premalignant lesions.	('progression', 'CPA', (109, 120))	('Ki-67', 'Gene', '17345', (80, 85))	('increased', 'PosReg', (41, 50))	('premalignant lesions', 'CPA', (124, 144))	('Vitamin D', 'Gene', (0, 9))	('Ki-67', 'Gene', (80, 85))	('proliferation', 'CPA', (51, 64))	('Vitamin D', 'Chemical', '-', (0, 9))	('Vitamin D deficiency', 'Phenotype', 'HP:0100512', (0, 20))	('deficiency', 'Var', (10, 20))
498792	26276745	In summary, our studies suggest that inflammation, proliferation, and progression of premalignant are enhanced in mice with vitamin D deficiency.	('enhanced', 'PosReg', (102, 110))	('deficiency', 'Var', (134, 144))	('inflammation', 'Disease', 'MESH:D007249', (37, 49))	('vitamin D', 'Chemical', '-', (124, 133))	('inflammation', 'Disease', (37, 49))	('proliferation', 'CPA', (51, 64))	('vitamin D deficiency', 'Phenotype', 'HP:0100512', (124, 144))	('progression', 'CPA', (70, 81))	('mice', 'Species', '10090', (114, 118))	('premalignant', 'Disease', (85, 97))
498798	32350249	Targeting codon 158 p53-mutant cancers via the induction of p53 acetylation Gain of function (GOF) DNA binding domain (DBD) mutations of TP53 upregulate chromatin regulatory genes that promote genome-wide histone methylation and acetylation.	('p53', 'Gene', (20, 23))	('upregulate', 'PosReg', (142, 152))	('chromatin regulatory genes', 'Gene', (153, 179))	('histone methylation', 'MPA', (205, 224))	('mutations', 'Var', (124, 133))	('p53', 'Gene', '7157', (20, 23))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('acetylation', 'MPA', (229, 240))	('Gain of function', 'PosReg', (76, 92))	('acetylation', 'MPA', (64, 75))	('p53', 'Gene', (60, 63))	('promote', 'PosReg', (185, 192))	('TP53', 'Gene', '7157', (137, 141))	('p53', 'Gene', '7157', (60, 63))	('cancers', 'Phenotype', 'HP:0002664', (31, 38))	('cancers', 'Disease', (31, 38))	('cancers', 'Disease', 'MESH:D009369', (31, 38))	('TP53', 'Gene', (137, 141))
498800	32350249	Using high throughput compound screening and combination analyses, we uncover that acetylating mutp53R158G could render cancers susceptible to cisplatin-induced DNA stress.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('cisplatin', 'Chemical', 'MESH:D002945', (143, 152))	('render', 'Reg', (113, 119))	('mutp53R158G', 'Var', (95, 106))	('acetylating mutp53R158G', 'Var', (83, 106))	('p53R158G', 'Mutation', 'p.R53,158G', (98, 106))	('cancers', 'Phenotype', 'HP:0002664', (120, 127))	('cancers', 'Disease', (120, 127))	('cancers', 'Disease', 'MESH:D009369', (120, 127))	('susceptible to cisplatin-induced DNA stress', 'MPA', (128, 171))
498801	32350249	Acetylation of mutp53R158G alters DNA binding motifs and upregulates TRAIP, a RING domain-containing E3 ubiquitin ligase which dephosphorylates IkB and impedes nuclear translocation of RelA (p65), thus repressing oncogenic nuclear factor kappa-B (NF-kB) signaling and inducing apoptosis.	('DNA', 'Protein', (34, 37))	('apoptosis', 'CPA', (277, 286))	('upregulates', 'PosReg', (57, 68))	('mutp53R158G', 'Var', (15, 26))	('inducing', 'Reg', (268, 276))	('E3 ubiquitin ligase', 'Gene', (101, 120))	('p65', 'Gene', '5970', (191, 194))	('RelA', 'Gene', (185, 189))	('nuclear translocation', 'MPA', (160, 181))	('TRAIP', 'Gene', (69, 74))	('Acetylation', 'MPA', (0, 11))	('alters', 'Reg', (27, 33))	('RelA', 'Gene', '5970', (185, 189))	('p53R158G', 'Mutation', 'p.R53,158G', (18, 26))	('impedes', 'NegReg', (152, 159))	('repressing', 'PosReg', (202, 212))	('E3 ubiquitin ligase', 'Gene', '79594', (101, 120))	('p65', 'Gene', (191, 194))
498802	32350249	Given that this mechanism of cytotoxic vulnerability appears inapt in p53 wild-type (WT) or other hotspot GOF mutp53 cells, our work provides a therapeutic opportunity specific to Arg158-mutp53 tumors utilizing a regimen consisting of DNA-damaging agents and mutp53 acetylators, which is currently being pursued clinically.	('Arg158-mutp53', 'Var', (180, 193))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('tumors', 'Disease', 'MESH:D009369', (194, 200))	('tumors', 'Phenotype', 'HP:0002664', (194, 200))	('tumors', 'Disease', (194, 200))	('Arg158', 'Chemical', '-', (180, 186))
498803	32350249	Codon 158 gain-of-function mutant p53 (158-mutp53) promotes tumourigenesis in lung cancer.	('lung cancer', 'Disease', (78, 89))	('p53', 'Gene', (34, 37))	('lung cancer', 'Phenotype', 'HP:0100526', (78, 89))	('mutant', 'Var', (27, 33))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('gain-of-function', 'PosReg', (10, 26))	('promotes', 'PosReg', (51, 59))	('lung cancer', 'Disease', 'MESH:D008175', (78, 89))	('tumourigenesis', 'CPA', (60, 74))
498804	32350249	Here, the authors show that 158-mutp53 render cancers sensitive to cisplatin and p53 acetylation agents through a mechanism where acetylated mutant p53 upregulates TRAIP and inhibits NF-kB signaling.	('158-mutp53', 'Var', (28, 38))	('cancers', 'Disease', 'MESH:D009369', (46, 53))	('mutant', 'Var', (141, 147))	('p53', 'Gene', (148, 151))	('cancers', 'Phenotype', 'HP:0002664', (46, 53))	('cancers', 'Disease', (46, 53))	('upregulates', 'PosReg', (152, 163))	('TRAIP', 'MPA', (164, 169))	('NF-kB signaling', 'Pathway', (183, 198))	('cisplatin', 'Chemical', 'MESH:D002945', (67, 76))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('inhibits', 'NegReg', (174, 182))
498805	32350249	TP53 missense mutations are among the most common genetic lesions in tumors, which often coincide with the earlier onset of oncogenesis than patients with p53 loss.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('TP53', 'Gene', '7157', (0, 4))	('missense mutations', 'Var', (5, 23))	('TP53', 'Gene', (0, 4))	('genetic lesions', 'Disease', (50, 65))	('patients', 'Species', '9606', (141, 149))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('tumors', 'Disease', (69, 75))	('tumors', 'Disease', 'MESH:D009369', (69, 75))	('genetic lesions', 'Disease', 'MESH:D020022', (50, 65))
498806	32350249	A single nucleotide substitution at the DNA-binding domain (DBD) renders the protein defective in DNA-binding, loss of tumor suppressive properties and concomitantly prevents the negative feedback regulation through MDM2, leading to massive accumulation of full length mutant p53 (mutp53).	('tumor', 'Disease', (119, 124))	('loss', 'NegReg', (111, 115))	('MDM2', 'Gene', '4193', (216, 220))	('MDM2', 'Gene', (216, 220))	('mutant', 'Var', (269, 275))	('p53', 'Gene', (276, 279))	('negative feedback regulation', 'MPA', (179, 207))	('defective', 'NegReg', (85, 94))	('accumulation', 'PosReg', (241, 253))	('protein', 'Protein', (77, 84))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('full length', 'MPA', (257, 268))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('prevents', 'NegReg', (166, 174))	('single nucleotide substitution', 'Var', (2, 32))
498807	32350249	Depletion of mutp53 or inhibition of its co-activator have demonstrated strong cytotoxicity in tumor cells.	('cytotoxicity', 'Disease', 'MESH:D064420', (79, 91))	('cytotoxicity', 'Disease', (79, 91))	('mutp53', 'Var', (13, 19))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('Depletion', 'MPA', (0, 9))	('tumor', 'Disease', (95, 100))
498808	32350249	Proposed oncogenic mechanisms of hotspot p53 mutations include prolonged tumor necrosis factor alpha (TNF-alpha) signaling through the activation of NFkB (nuclear factor kappa-light-chain-enhancer of activated B cells), causing chronic tumor-associated inflammation, as well as altered structural interaction between mutated p53 and DNA that induces transcriptional perturbations to promote tumor-associated gene expression.	('TNF-alpha', 'Gene', (102, 111))	('tumor necrosis factor alpha', 'Gene', (73, 100))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Disease', 'MESH:D009369', (236, 241))	('inflammation', 'Disease', (253, 265))	('p53', 'Gene', (41, 44))	('tumor', 'Disease', (391, 396))	('altered', 'Reg', (278, 285))	('p53', 'Gene', (325, 328))	('tumor', 'Disease', 'MESH:D009369', (391, 396))	('tumor', 'Phenotype', 'HP:0002664', (236, 241))	('tumor necrosis factor alpha', 'Gene', '7124', (73, 100))	('activation', 'PosReg', (135, 145))	('tumor', 'Disease', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (391, 396))	('mutations', 'Var', (45, 54))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('inflammation', 'Disease', 'MESH:D007249', (253, 265))	('promote', 'PosReg', (383, 390))	('TNF-alpha', 'Gene', '7124', (102, 111))	('tumor', 'Disease', (236, 241))	('NFkB', 'Gene', (149, 153))
498810	32350249	In this study, we uncover a mechanism of activating mutp53-dependent apoptotic function in cancer cells through p53R158G acetylation, and demonstrate that TRAIP regulation of NFkB is the main molecular driver underpinning this observed sensitivity.	('p53R158G', 'Mutation', 'p.R53,158G', (112, 120))	('activating', 'PosReg', (41, 51))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('NFkB', 'Gene', (175, 179))	('apoptotic function', 'CPA', (69, 87))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('acetylation', 'MPA', (121, 132))	('p53R158G', 'Var', (112, 120))	('mutp53-dependent', 'Var', (52, 68))
498811	32350249	We further show in a high-throughput screen that acetylation of p53R158G can be achieved with several pharmacologic agents, providing a cogent basis for further clinical development.	('acetylation', 'MPA', (49, 60))	('p53R158G', 'Var', (64, 72))	('p53R158G', 'Mutation', 'p.R53,158G', (64, 72))
498812	32350249	Among the TP53 mutations found in ~50% of non-small cell lung cancer, p53R158G/H/L is one of the most common mutation hotspots according to multiple public databases (TCGA, COSMICS, IARC p53 Database), despite being reported in different frequencies.	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (42, 68))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('TP53', 'Gene', (10, 14))	('lung cancer', 'Phenotype', 'HP:0100526', (57, 68))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (46, 68))	('lung cancer', 'Disease', 'MESH:D008175', (57, 68))	('p53R158G/H/L', 'Var', (70, 82))	('p53R158G', 'Mutation', 'p.R53,158G', (70, 78))	('lung cancer', 'Disease', (57, 68))	('TP53', 'Gene', '7157', (10, 14))
498814	32350249	In addition, the frequency of codon 158 was found to be comparable to other hotspot mutp53 in both lung cancer subtypes (Supplementary Table 2).	('lung cancer', 'Disease', (99, 110))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('lung cancer', 'Disease', 'MESH:D008175', (99, 110))	('codon 158', 'Var', (30, 39))	('lung cancer', 'Phenotype', 'HP:0100526', (99, 110))
498817	32350249	To gain better insights into the p53R158G function, we generated isogenic cell-lines expressing either wild-type (p53wt) or mutant (p53R158G) p53 from homozygous deleted LUSC Calu-1 cells (p53-/-).	('p53R158G', 'Var', (132, 140))	('p53R158G', 'Mutation', 'p.R53,158G', (132, 140))	('p53R158G', 'Mutation', 'p.R53,158G', (33, 41))	('p53', 'Gene', (142, 145))
498819	32350249	As expected, expression of wild-type p53 (wtp53) increased transcription of MDM2, CDKN1A, PUMA, and PMAIP1 transcripts compared to p53-/- cells; in p53R158G cells, elevated CDKN1A showed partial preservation of p53 function, but reduced PMAIP1 transcription indicated gain of alternative function (Supplementary Fig.	('PMAIP1', 'Gene', '5366', (237, 243))	('PUMA', 'Gene', (90, 94))	('CDKN1A', 'Gene', '1026', (173, 179))	('PMAIP1', 'Gene', '5366', (100, 106))	('transcription', 'MPA', (244, 257))	('gain', 'PosReg', (268, 272))	('p53R158G', 'Var', (148, 156))	('CDKN1A', 'Gene', (82, 88))	('reduced', 'NegReg', (229, 236))	('PMAIP1', 'Gene', (237, 243))	('p53 function', 'MPA', (211, 223))	('PUMA', 'Gene', '27113', (90, 94))	('CDKN1A', 'Gene', '1026', (82, 88))	('MDM2', 'Gene', '4193', (76, 80))	('PMAIP1', 'Gene', (100, 106))	('p53R158G', 'Mutation', 'p.R53,158G', (148, 156))	('MDM2', 'Gene', (76, 80))	('CDKN1A', 'Gene', (173, 179))
498820	32350249	Functionally, mutp53R158G overexpression significantly increased cellular motility (Fig.	('mutp53R158G', 'Var', (14, 25))	('increased', 'PosReg', (55, 64))	('p53R158G', 'Mutation', 'p.R53,158G', (17, 25))	('cellular motility', 'CPA', (65, 82))
498821	32350249	1e, f); whereas invasiveness of H2170 cells could be reduced with TP53 knockdown (Fig.	('TP53', 'Gene', '7157', (66, 70))	('TP53', 'Gene', (66, 70))	('H2170', 'CellLine', 'CVCL:1535', (32, 37))	('invasiveness', 'CPA', (16, 28))	('knockdown', 'Var', (71, 80))	('reduced', 'NegReg', (53, 60))
498822	32350249	In contrast, overexpression of wtp53 exerted strong tumor suppressive effects in Calu-1 cells by reducing invasiveness (Fig.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('wtp53', 'Var', (31, 36))	('tumor', 'Disease', (52, 57))	('reducing', 'NegReg', (97, 105))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('invasiveness', 'CPA', (106, 118))
498823	32350249	Importantly, xenograft tumors derived from p53R158G cells demonstrated more aggressive growth relative to those from p53-/- and p53wt cells (Fig.	('tumors', 'Disease', (23, 29))	('tumors', 'Disease', 'MESH:D009369', (23, 29))	('more', 'PosReg', (71, 75))	('p53R158G', 'Mutation', 'p.R53,158G', (43, 51))	('aggressive growth', 'CPA', (76, 93))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))	('p53R158G', 'Var', (43, 51))
498824	32350249	Understanding the mechanisms underlying mutp53 GOF has allowed for anti-tumoral strategies aimed at inhibiting the oncogenic attributes of mutp53.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumoral', 'Disease', (72, 79))	('tumoral', 'Disease', 'MESH:D009369', (72, 79))	('mutp53', 'Var', (40, 46))
498825	32350249	We first selected for compounds that showed efficacy (> 50% growth inhibition) in at least one cell type (Supplementary Table 3), and identified inhibitors specific to p53-/-, p53wt, and p53R158G cell-lines (Fig.	('p53-/-', 'Var', (168, 174))	('p53R158G', 'Mutation', 'p.R53,158G', (187, 195))	('p53wt', 'Var', (176, 181))	('p53R158G', 'Var', (187, 195))
498827	32350249	Interestingly, 17 compounds demonstrated selective sensitivity in p53R158G cells compared with wtp53 and null cells (Fig.	('sensitivity', 'MPA', (51, 62))	('p53R158G', 'Var', (66, 74))	('p53R158G', 'Mutation', 'p.R53,158G', (66, 74))
498829	32350249	Consistent with previous reports, inhibitors of HSP90, histone deacetylase (HDAC) and polo-like kinase (PLK) demonstrated selective activity against mutp53 cells.	('mutp53', 'Var', (149, 155))	('PLK', 'Gene', '5347', (104, 107))	('HDAC', 'Gene', (76, 80))	('HDAC', 'Gene', '9734', (76, 80))	('HSP90', 'Gene', (48, 53))	('HSP90', 'Gene', '3320', (48, 53))	('histone deacetylase', 'Gene', '9734', (55, 74))	('polo-like kinase', 'Gene', (86, 102))	('polo-like kinase', 'Gene', '5347', (86, 102))	('PLK', 'Gene', (104, 107))	('histone deacetylase', 'Gene', (55, 74))
498830	32350249	HDAC inhibitors have demonstrated synergistic activities through epigenetic mechanisms with a variety of clinically approved agents in several cancers.	('HDAC', 'Gene', (0, 4))	('epigenetic', 'Var', (65, 75))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('HDAC', 'Gene', '9734', (0, 4))	('cancers', 'Disease', 'MESH:D009369', (143, 150))	('cancers', 'Phenotype', 'HP:0002664', (143, 150))	('cancers', 'Disease', (143, 150))
498834	32350249	In contrast, profound synergistic response was observed in p53R158G cells (Bliss value < 0) when combining belinostat (0.1 microM) with cisplatin (0.1-10 microM), indicating that the observed cell response was greater than the predicted values (Fig.	('cisplatin', 'Chemical', 'MESH:D002945', (136, 145))	('p53R158G', 'Var', (59, 67))	('p53R158G', 'Mutation', 'p.R53,158G', (59, 67))	('cell response', 'CPA', (192, 205))	('belinostat', 'Chemical', 'MESH:C487081', (107, 117))
498835	32350249	Concomitantly, while belinostat lowered cisplatin IC50 in mutp53R158G Calu-1 cells, it had little effect on cell-lines with wild-type or null p53 status (Fig.	('cisplatin IC50', 'MPA', (40, 54))	('p53R158G', 'Mutation', 'p.R53,158G', (61, 69))	('mutp53R158G', 'Var', (58, 69))	('cisplatin', 'Chemical', 'MESH:D002945', (40, 49))	('belinostat', 'Chemical', 'MESH:C487081', (21, 31))	('lowered', 'NegReg', (32, 39))
498838	32350249	Interestingly, similar observation was observed in other cancer types harboring Arg158 p53 mutations, including H441 (lung adenocarcinoma, p53R158L), H661 (lung large cell carcinoma, p53R158L), and H747 (colorectal carcinoma, p53R158L) (Fig.	('H747', 'Var', (198, 202))	('cancer', 'Disease', (57, 63))	('H661', 'CellLine', 'CVCL:1577', (150, 154))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (118, 137))	('carcinoma', 'Disease', 'MESH:D009369', (172, 181))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (118, 137))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('colorectal carcinoma', 'Disease', (204, 224))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (204, 224))	('carcinoma', 'Disease', (128, 137))	('H661', 'Var', (150, 154))	('carcinoma', 'Phenotype', 'HP:0030731', (215, 224))	('Arg158', 'Var', (80, 86))	('carcinoma', 'Disease', (215, 224))	('p53R158L', 'Mutation', 'p.R53,158L', (226, 234))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('p53', 'Gene', (87, 90))	('p53R158L', 'Mutation', 'p.R53,158L', (139, 147))	('carcinoma', 'Phenotype', 'HP:0030731', (172, 181))	('Arg158', 'Chemical', '-', (80, 86))	('large cell carcinoma', 'Phenotype', 'HP:0030360', (161, 181))	('carcinoma', 'Disease', 'MESH:D009369', (128, 137))	('p53R158L', 'Mutation', 'p.R53,158L', (183, 191))	('carcinoma', 'Disease', 'MESH:D009369', (215, 224))	('carcinoma', 'Disease', (172, 181))	('lung adenocarcinoma', 'Disease', (118, 137))
498839	32350249	On the contrary, cancer cells expressing other hotspot GOF p53 mutations, such as LUSC cells H596 (p53G245C) and ChaGo-k-1 (p53C275F); lung adenocarcinoma H1417 (p53R175L) and H1975 (p53R273H); breast carcinoma SK-BR-3 (p53R175H), HCC70 (p53R248Q), BT-549 (p53R249S) and MDA-MB-468 (p53R273H); pancreatic carcinoma MIA-Paca-2 (p53R248W) and PANC-1 (p53R273H); did not show increased in apoptotic markers when belinostat was combined with cisplatin (Fig.	('carcinoma', 'Phenotype', 'HP:0030731', (145, 154))	('HCC', 'Phenotype', 'HP:0001402', (231, 234))	('cisplatin', 'Chemical', 'MESH:D002945', (438, 447))	('H1417', 'CellLine', 'CVCL:1469', (155, 160))	('cancer', 'Disease', (17, 23))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))	('mutations', 'Var', (63, 72))	('BT-549', 'CellLine', 'CVCL:1092', (249, 255))	('breast carcinoma', 'Phenotype', 'HP:0003002', (194, 210))	('MIA-Paca-2', 'CellLine', 'CVCL:0428', (315, 325))	('pancreatic carcinoma', 'Disease', (294, 314))	('belinostat', 'Chemical', 'MESH:C487081', (409, 419))	('p53R273H', 'Mutation', 'p.R53,273H', (183, 191))	('p53R248W', 'Mutation', 'p.R53,248W', (327, 335))	('breast carcinoma', 'Disease', (194, 210))	('PANC-1', 'CellLine', 'CVCL:0480', (341, 347))	('p53R273H', 'Mutation', 'p.R53,273H', (349, 357))	('lung adenocarcinoma', 'Disease', (135, 154))	('p53R175L', 'Mutation', 'p.R53,175L', (162, 170))	('H1975', 'CellLine', 'CVCL:1511', (176, 181))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('p53R175H', 'Mutation', 'p.R53,175H', (220, 228))	('p53R248Q', 'Var', (238, 246))	('carcinoma', 'Phenotype', 'HP:0030731', (201, 210))	('SK-BR-3', 'CellLine', 'CVCL:0033', (211, 218))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (135, 154))	('R249S', 'Mutation', 'rs28934571', (260, 265))	('p53R248Q', 'Mutation', 'p.R53,248Q', (238, 246))	('pancreatic carcinoma', 'Disease', 'MESH:D010190', (294, 314))	('carcinoma', 'Phenotype', 'HP:0030731', (305, 314))	('MDA-MB-468', 'CellLine', 'CVCL:0419', (271, 281))	('p53R273H', 'Mutation', 'p.R53,273H', (283, 291))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (135, 154))	('breast carcinoma', 'Disease', 'MESH:D001943', (194, 210))
498840	32350249	Similar lack of synergism was observed in other lung cancer cells with p53 deletion (Calu-1), point-nonsense mutation (H520, SK-MES-1) and wild-type p53 (A549) (Fig.	('A549', 'CellLine', 'CVCL:0023', (154, 158))	('lung cancer', 'Disease', 'MESH:D008175', (48, 59))	('SK-MES-1', 'CellLine', 'CVCL:0630', (125, 133))	('point-nonsense mutation', 'Var', (94, 117))	('deletion', 'Var', (75, 83))	('p53', 'Gene', (71, 74))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('lung cancer', 'Disease', (48, 59))	('lung cancer', 'Phenotype', 'HP:0100526', (48, 59))
498841	32350249	These findings indicate specific mechanistic underpinnings of the observed synergy in Arg158 mutp53 cells.	('Arg158', 'Gene', (86, 92))	('mutp53', 'Var', (93, 99))	('Arg158', 'Chemical', '-', (86, 92))
498842	32350249	As HDAC inhibitors can acetylate histones and other cellular proteins, possible mechanisms that modulate mutp53 function include Lysine acetylation of histones affecting DNA configuration favoring mutp53 access to DNA-binding elements, or direct modification of mutp53 itself leading to alternative DNA binding.	('HDAC', 'Gene', (3, 7))	('HDAC', 'Gene', '9734', (3, 7))	('alternative DNA binding', 'Interaction', (287, 310))	('Lysine', 'Chemical', 'MESH:D008239', (129, 135))	('mutp53', 'Var', (197, 203))	('modification', 'Var', (246, 258))
498846	32350249	The dependence on mutp53R158G, functioning through active transcription regulation, was further substantiated by the positive p53-reporter-luciferase activity of combination drug-treatment (Supplementary Fig.	('p53R158G', 'Mutation', 'p.R53,158G', (21, 29))	('p53-reporter-luciferase', 'Enzyme', (126, 149))	('positive', 'PosReg', (117, 125))	('mutp53R158G', 'Var', (18, 29))	('activity', 'MPA', (150, 158))
498848	32350249	Consistently, depletion of p53 from H2170 parental cells with different short hairpin (shRNA) constructs or small interfering RNA (siRNA) reduced PARP and caspase 3 cleavage (Supplementary Fig.	('caspase 3', 'Gene', (155, 164))	('reduced', 'NegReg', (138, 145))	('small interfering RNA', 'Var', (108, 129))	('PARP', 'Gene', '1302', (146, 150))	('caspase 3', 'Gene', '836', (155, 164))	('PARP', 'Gene', (146, 150))	('H2170', 'CellLine', 'CVCL:1535', (36, 41))	('p53', 'Protein', (27, 30))	('depletion', 'MPA', (14, 23))
498849	32350249	Logically, destabilization and depletion of GOF mutp53 explains potent anti-tumor cytotoxicity, but paradoxically, we observed no reduction of mutp53R158G in H2170 cells despite robust apoptosis (Fig.	('tumor cytotoxicity', 'Disease', 'MESH:D064420', (76, 94))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor cytotoxicity', 'Disease', (76, 94))	('apoptosis', 'CPA', (185, 194))	('mutp53R158G', 'Var', (143, 154))	('H2170', 'CellLine', 'CVCL:1535', (158, 163))	('p53R158G', 'Mutation', 'p.R53,158G', (146, 154))
498855	32350249	4e); whereas, CDKN1A, PUMA, and BAX were induced post-treatment in mutp53 but not null cells (Fig.	('mutp53', 'Var', (67, 73))	('CDKN1A', 'Gene', (14, 20))	('induced', 'Reg', (41, 48))	('PUMA', 'Gene', (22, 26))	('PUMA', 'Gene', '27113', (22, 26))	('BAX', 'Gene', (32, 35))	('BAX', 'Gene', '581', (32, 35))	('CDKN1A', 'Gene', '1026', (14, 20))
498856	32350249	4f-i), implicating p53R158G in the synergistic pro-apoptotic effect.	('implicating', 'Reg', (7, 18))	('p53R158G', 'Var', (19, 27))	('p53R158G', 'Mutation', 'p.R53,158G', (19, 27))
498857	32350249	To investigate the role of p53 acetylation in mediating the pro-apoptotic function of mutp53, we first constructed p53R158G mutants by substituting the Lysine residues at the DBD (p53R158G(DBD, K-A)), C-terminal domain (p53R158G(CT, K-A)) or the whole protein (p53R158G(K20A)).	('p53R158G', 'Mutation', 'p.R53,158G', (115, 123))	('p53R158G', 'Var', (261, 269))	('Lysine', 'Chemical', 'MESH:D008239', (152, 158))	('p53R158G', 'Var', (220, 228))	('p53R158G', 'Var', (115, 123))	('p53R158G', 'Mutation', 'p.R53,158G', (261, 269))	('p53R158G', 'Mutation', 'p.R53,158G', (220, 228))	('K20A', 'Mutation', 'p.K20A', (270, 274))	('p53R158G', 'Mutation', 'p.R53,158G', (180, 188))
498859	32350249	Nonetheless, belinostat-induced synergy was abrogated in p53R158G(DBD, K-A) and p53R158G(K20A) cells (Fig.	('p53R158G', 'Mutation', 'p.R53,158G', (57, 65))	('K20A', 'Mutation', 'p.K20A', (89, 93))	('p53R158G', 'Var', (80, 88))	('belinostat', 'Chemical', 'MESH:C487081', (13, 23))	('abrogated', 'NegReg', (44, 53))	('p53R158G', 'Var', (57, 65))	('p53R158G', 'Mutation', 'p.R53,158G', (80, 88))
498860	32350249	4a, b, d), both cell types with impaired Lysine acetylation at the p53 DBD.	('impaired', 'NegReg', (32, 40))	('Lysine acetylation', 'MPA', (41, 59))	('p53', 'Var', (67, 70))	('Lysine', 'Chemical', 'MESH:D008239', (41, 47))
498862	32350249	4b), suggesting that C-terminal acetylation is not involved in mutp53-effected cytotoxicity.	('mutp53-effected', 'Var', (63, 78))	('cytotoxicity', 'Disease', 'MESH:D064420', (79, 91))	('cytotoxicity', 'Disease', (79, 91))
498865	32350249	Secondly, cisplatin but not belinostat treatment strongly increased the phosphorylated-p53-labelled cell population (Q3), and combination treatment had no effect on cells in Q3 (Supplementary Fig.	('phosphorylated-p53-labelled cell population', 'MPA', (72, 115))	('increased', 'PosReg', (58, 67))	('cisplatin', 'Var', (10, 19))	('belinostat', 'Chemical', 'MESH:C487081', (28, 38))	('cisplatin', 'Chemical', 'MESH:D002945', (10, 19))
498866	32350249	This data demonstrated the positive correlation of acetylated p53R158G with combination treatment, which significantly triggered cellular apoptosis.	('acetylated p53R158G', 'Var', (51, 70))	('p53R158G', 'Var', (62, 70))	('cellular apoptosis', 'CPA', (129, 147))	('p53R158G', 'Mutation', 'p.R53,158G', (62, 70))	('triggered', 'PosReg', (119, 128))
498869	32350249	4k), acetylation of p53R158G increased cleavage of PARP and caspase 3 (Fig.	('cleavage', 'MPA', (39, 47))	('caspase 3', 'Gene', '836', (60, 69))	('acetylation', 'MPA', (5, 16))	('PARP', 'Gene', '1302', (51, 55))	('p53R158G', 'Var', (20, 28))	('PARP', 'Gene', (51, 55))	('increased', 'PosReg', (29, 38))	('p53R158G', 'Mutation', 'p.R53,158G', (20, 28))	('caspase 3', 'Gene', (60, 69))
498870	32350249	Collectively, acetylation of the DBD is crucial to effecting apoptosis by mutp53R158G.	('p53R158G', 'Mutation', 'p.R53,158G', (77, 85))	('mutp53R158G', 'Var', (74, 85))	('effecting', 'Reg', (51, 60))
498871	32350249	We postulated that mutp53R158G binds to and activates a distinct spectrum of chromatin regulatory genes from wtp53, which may be significantly altered by drug-induced acetylation.	('mutp53R158G', 'Var', (19, 30))	('p53R158G', 'Mutation', 'p.R53,158G', (22, 30))	('chromatin regulatory genes', 'Gene', (77, 103))	('binds', 'Interaction', (31, 36))	('activates', 'PosReg', (44, 53))
498873	32350249	6A, C):that could likely disrupt key interactions between the DBD (K120, R280, R248) and DNA.	('disrupt', 'NegReg', (25, 32))	('K120', 'Var', (67, 71))	('K120', 'Chemical', '-', (67, 71))	('R280', 'Var', (73, 77))	('R248', 'Var', (79, 83))	('interactions', 'Interaction', (37, 49))
498874	32350249	Interestingly, acetylation of the Lysine residues within the DBD reduces the sidechain positive charges, resulting in structural and chemical alterations, which suggest restoration of the dimerization capacity of the core domain of mutp53R158G (Supplementary Fig.	('mutp53R158G', 'Var', (232, 243))	('p53R158G', 'Mutation', 'p.R53,158G', (235, 243))	('acetylation', 'MPA', (15, 26))	('reduces', 'NegReg', (65, 72))	('restoration', 'PosReg', (169, 180))	('Lysine', 'Chemical', 'MESH:D008239', (34, 40))	('dimerization capacity', 'MPA', (188, 209))	('sidechain positive charges', 'MPA', (77, 103))
498875	32350249	While the key interactions of K120 with the major groove of the DNA remain impaired in the acetylated R158G mutant, it is compensated for by the interactions between acetylated K201 and the minor groove (Supplementary Fig.	('R158G', 'Var', (102, 107))	('interactions', 'Interaction', (14, 26))	('impaired', 'NegReg', (75, 83))	('interactions', 'Interaction', (145, 157))	('K120', 'Var', (30, 34))	('K120', 'Chemical', '-', (30, 34))	('R158G', 'Mutation', 'rs770374782', (102, 107))
498876	32350249	The most intriguing alteration in the acetylated R158G mutant is an increase in the length of the dimerization helix H1 from R181 to D186:about 1.5 extra turns of a helix:that will promote the formation of a dimer that is more stable than the WT and is also associated with the introduction of two salt bridges across the dimer interface (E180 of each monomer forms a salt bridge with R181 of the second monomer; Supplementary Fig.	('more', 'PosReg', (222, 226))	('promote', 'PosReg', (181, 188))	('R158G', 'Var', (49, 54))	('stable', 'MPA', (227, 233))	('salt bridge', 'MPA', (368, 379))	('R158G', 'Mutation', 'rs770374782', (49, 54))
498878	32350249	This supports our earlier observations that conversions of these two Lysines to Alanines in the DBD (p53R158G(DBD,K-A)) resulted in attenuation of the pro-apoptotic activity seen in acetylated R158G (Fig.	('p53R158G', 'Mutation', 'p.R53,158G', (101, 109))	('R158G', 'Mutation', 'rs770374782', (104, 109))	('conversions', 'Var', (44, 55))	('Lysines', 'Chemical', 'MESH:D008239', (69, 76))	('pro-apoptotic activity', 'CPA', (151, 173))	('R158G', 'Mutation', 'rs770374782', (193, 198))	('p53R158G', 'Var', (101, 109))	('Alanines', 'Chemical', 'MESH:D000409', (80, 88))	('attenuation', 'NegReg', (132, 143))	('R158G', 'Var', (193, 198))
498880	32350249	Drug treatment led to marked increase in genomic binding in both p53R158G and p53wt cells, with higher signal intensity around the TSS-proximal regions (Fig.	('p53R158G', 'Var', (65, 73))	('genomic', 'MPA', (41, 48))	('increase', 'PosReg', (29, 37))	('p53R158G', 'Mutation', 'p.R53,158G', (65, 73))	('signal intensity', 'MPA', (103, 119))	('higher', 'PosReg', (96, 102))
498881	32350249	Importantly, predicted motif analysis for TSS-proximal peaks suggested that p53 consensus motifs were enriched not just in p53wt but also in p53R158G (motif similarity P = 0.029 and 0.039, TOMTOM match statistic; P = 1 x 10-16 and 1 x 10-265, HOMER statistic) (Fig.	('p53', 'Gene', (76, 79))	('p53R158G', 'Var', (141, 149))	('p53R158G', 'Mutation', 'p.R53,158G', (141, 149))	('p53wt', 'Var', (123, 128))
498885	32350249	These data collectively suggest that mutp53R158G partially retains wtp53 activity when cells are exposed to stress signal, which supports the induction of wtp53 response genes by the drug-induced transactivation of p53R158G in H2170 cells (Supplementary Fig.	('p53R158G', 'Mutation', 'p.R53,158G', (215, 223))	('p53R158G', 'Mutation', 'p.R53,158G', (40, 48))	('mutp53R158G', 'Var', (37, 48))	('transactivation', 'PosReg', (196, 211))	('p53R158G', 'Var', (215, 223))	('induction', 'MPA', (142, 151))	('H2170', 'CellLine', 'CVCL:1535', (227, 232))
498886	32350249	To identify the genes activated by acetylated p53R158G which are associated with the induction of apoptosis, we compared the treatment-induced perturbations of transcriptomic profiles (by Ampliseq RNA sequencing) between wild-type and mutant cells.	('p53R158G', 'Var', (46, 54))	('p53R158G', 'Mutation', 'p.R53,158G', (46, 54))	('acetylated p53R158G', 'Var', (35, 54))
498890	32350249	Two chromatin regulatory genes downstream of ETS2, KMT2D, and KAT6A, reported to be positively associated with hotspot GOF mutp53 (R175H, R248Q, R248W, R249S, or R273H), were neither transactivated nor upregulated in p53R158G (Fig.	('R248Q', 'Var', (138, 143))	('KAT6A', 'Gene', (62, 67))	('R249S', 'Mutation', 'rs28934571', (152, 157))	('R273H', 'Mutation', 'rs28934576', (162, 167))	('R175H', 'Mutation', 'rs28934578', (131, 136))	('upregulated', 'PosReg', (202, 213))	('R175H', 'Var', (131, 136))	('KMT2D', 'Gene', '8085', (51, 56))	('ETS2', 'Gene', '2114', (45, 49))	('R249S', 'Var', (152, 157))	('R273H', 'Var', (162, 167))	('R248W', 'Mutation', 'rs121912651', (145, 150))	('p53R158G', 'Var', (217, 225))	('chromatin regulatory genes', 'Gene', (4, 30))	('p53R158G', 'Mutation', 'p.R53,158G', (217, 225))	('KAT6A', 'Gene', '7994', (62, 67))	('R248W', 'Var', (145, 150))	('R248Q', 'Mutation', 'rs11540652', (138, 143))	('ETS2', 'Gene', (45, 49))	('KMT2D', 'Gene', (51, 56))
498893	32350249	However, combination-treated p53R158G cells did not demonstrate increased DNA damage response when compared to p53 loss or wtp53 cells, based on the analysis of induced-gammaH2AX (Fig.	('p53R158G', 'Mutation', 'p.R53,158G', (29, 37))	('DNA damage response', 'MPA', (74, 93))	('p53R158G', 'Var', (29, 37))
498894	32350249	Therefore, it is unlikely that the enhanced cytotoxicity in p53R158G is due to altered DNA damage signaling.	('cytotoxicity', 'Disease', 'MESH:D064420', (44, 56))	('p53R158G', 'Mutation', 'p.R53,158G', (60, 68))	('cytotoxicity', 'Disease', (44, 56))	('p53R158G', 'Var', (60, 68))
498896	32350249	We showed that TRAIP upregulation in p53R158G cells correlated with the IkB dephosphorylation and stabilization (Fig.	('p53R158G', 'Mutation', 'p.R53,158G', (37, 45))	('IkB', 'Protein', (72, 75))	('stabilization', 'MPA', (98, 111))	('dephosphorylation', 'MPA', (76, 93))	('upregulation', 'PosReg', (21, 33))	('TRAIP', 'Gene', (15, 20))	('p53R158G', 'Var', (37, 45))
498898	32350249	Accordingly, we hypothesize that acetylation of p53R158G may impede p65 activation through perturbation of the TRAIP-IkB-NFkB axis.	('perturbation', 'NegReg', (91, 103))	('acetylation', 'MPA', (33, 44))	('p53R158G', 'Var', (48, 56))	('p65', 'Gene', (68, 71))	('activation', 'MPA', (72, 82))	('impede', 'NegReg', (61, 67))	('p53R158G', 'Mutation', 'p.R53,158G', (48, 56))	('p65', 'Gene', '5970', (68, 71))
498902	32350249	Using ChIP-quantitative PCR (ChIP-qPCR), we validated the increased binding of p53R158G after belinostat/cisplatin treatment to the promoter region of the TRAIP gene (Supplementary Fig.	('binding', 'Interaction', (68, 75))	('increased', 'PosReg', (58, 67))	('belinostat', 'Chemical', 'MESH:C487081', (94, 104))	('p53R158G', 'Var', (79, 87))	('TRAIP', 'Gene', (155, 160))	('p53R158G', 'Mutation', 'p.R53,158G', (79, 87))	('cisplatin', 'Chemical', 'MESH:D002945', (105, 114))
498904	32350249	Collectively, these findings strengthened the concept that acetylation of p53R158G leads to the transactivation of TRAIP (Fig.	('p53R158G', 'Mutation', 'p.R53,158G', (74, 82))	('transactivation', 'MPA', (96, 111))	('TRAIP', 'Gene', (115, 120))	('acetylation', 'MPA', (59, 70))	('p53R158G', 'Var', (74, 82))
498907	32350249	In contrast, a reciprocal downregulation was observed in p53R158G cells, with a further reduction observed when combined with belinostat; whereas NFkB was unaffected in p53 deficient cells (Fig.	('p53R158G', 'Mutation', 'p.R53,158G', (57, 65))	('p53R158G', 'Var', (57, 65))	('belinostat', 'Chemical', 'MESH:C487081', (126, 136))	('downregulation', 'NegReg', (26, 40))
498910	32350249	In p53R158G cells, drug treatment reduced nuclear accumulation of p65; conversely, pronounced p65 nuclear translocation was observed in wild-type cells, in concordance with the increase in DNA-binding assays (Fig.	('p65', 'Gene', '5970', (66, 69))	('nuclear translocation', 'MPA', (98, 119))	('reduced', 'NegReg', (34, 41))	('p65', 'Gene', '5970', (94, 97))	('p53R158G', 'Var', (3, 11))	('p65', 'Gene', (66, 69))	('p53R158G', 'Mutation', 'p.R53,158G', (3, 11))	('p65', 'Gene', (94, 97))	('nuclear accumulation', 'MPA', (42, 62))
498912	32350249	In addition, we observed that basal nuclear NFkB is kept at levels lower in p53wt than in p53R158G or p53 null cells (Fig.	('p53R158G', 'Mutation', 'p.R53,158G', (90, 98))	('lower', 'NegReg', (67, 72))	('p53wt', 'Var', (76, 81))
498913	32350249	Together, our findings support the contention that increased transcription of TRAIP by acetylated p53R158G leads to inhibition of NFkB through blocking IkB phosphorylation and nuclear import of p65.	('p65', 'Gene', (194, 197))	('p53R158G', 'Mutation', 'p.R53,158G', (98, 106))	('increased', 'PosReg', (51, 60))	('phosphorylation', 'MPA', (156, 171))	('p65', 'Gene', '5970', (194, 197))	('NFkB', 'Gene', (130, 134))	('inhibition', 'NegReg', (116, 126))	('IkB', 'Protein', (152, 155))	('nuclear import', 'MPA', (176, 190))	('blocking', 'NegReg', (143, 151))	('p53R158G', 'Var', (98, 106))	('transcription', 'MPA', (61, 74))	('TRAIP', 'Gene', (78, 83))
498917	32350249	As previously described, ablation of TRAF2 reduced phosphorylation and degradation of IkB (Fig.	('IkB', 'Protein', (86, 89))	('TRAF2', 'Gene', (37, 42))	('degradation', 'MPA', (71, 82))	('phosphorylation', 'MPA', (51, 66))	('ablation', 'Var', (25, 33))	('reduced', 'NegReg', (43, 50))	('TRAF2', 'Gene', '7186', (37, 42))
498919	32350249	Importantly, exogenous TRAIP recapitulated p53R158G response to drug treatment in p53wt cells.	('p53R158G', 'Mutation', 'p.R53,158G', (43, 51))	('response to drug treatment', 'MPA', (52, 78))	('p53R158G', 'Var', (43, 51))
498920	32350249	Consistently, acetylation of p53R158G is associated with p21 upregulation, p-IkB suppression and elevated TRAIP transcript in H2170 cells (Supplementary Fig.	('elevated', 'PosReg', (97, 105))	('p-IkB', 'Protein', (75, 80))	('p53R158G', 'Mutation', 'p.R53,158G', (29, 37))	('TRAIP', 'Gene', (106, 111))	('upregulation', 'PosReg', (61, 73))	('H2170', 'CellLine', 'CVCL:1535', (126, 131))	('suppression', 'NegReg', (81, 92))	('p53R158G', 'Var', (29, 37))	('p21', 'Gene', '1026', (57, 60))	('p21', 'Gene', (57, 60))	('acetylation', 'MPA', (14, 25))
498923	32350249	Effective silencing of TRAIP markedly rescued cellular apoptosis in H2170 cells, as demonstrated by the reduced PARP and caspase 3 cleavage, by sustaining p-IkB without affecting p53 acetylation (Supplementary Fig.	('PARP', 'Gene', '1302', (112, 116))	('p-IkB', 'MPA', (155, 160))	('PARP', 'Gene', (112, 116))	('caspase 3', 'Gene', (121, 130))	('reduced', 'NegReg', (104, 111))	('caspase 3', 'Gene', '836', (121, 130))	('rescued', 'PosReg', (38, 45))	('TRAIP', 'Gene', (23, 28))	('H2170', 'CellLine', 'CVCL:1535', (68, 73))	('sustaining', 'PosReg', (144, 154))	('silencing', 'Var', (10, 19))	('cellular apoptosis', 'CPA', (46, 64))
498925	32350249	To further investigate the mechanisms of the TRAIP/TRAF2/NFkB axis, dominant negative IkBalpha mutants (IkBalpha- N, IkBalpha-S32A) were introduced to shut off NFkB activity.	('IkBalpha', 'Gene', (117, 125))	('activity', 'MPA', (165, 173))	('S32A', 'Mutation', 'p.S32A', (126, 130))	('TRAF2', 'Gene', (51, 56))	('shut off', 'NegReg', (151, 159))	('IkBalpha', 'Gene', (86, 94))	('TRAF2', 'Gene', '7186', (51, 56))	('mutants', 'Var', (95, 102))	('IkBalpha', 'Gene', '4792', (117, 125))	('IkBalpha', 'Gene', '4792', (104, 112))	('IkBalpha', 'Gene', (104, 112))	('IkBalpha', 'Gene', '4792', (86, 94))
498927	32350249	Surprisingly, transfection of IkBalpha mutants has little effect in p53-/- cells, and conversely, p65 was highly phosphorylated.	('p65', 'Gene', (98, 101))	('IkBalpha', 'Gene', '4792', (30, 38))	('IkBalpha', 'Gene', (30, 38))	('highly', 'PosReg', (106, 112))	('p65', 'Gene', '5970', (98, 101))	('mutants', 'Var', (39, 46))	('phosphorylated', 'MPA', (113, 127))
498928	32350249	Collectively, these data strongly suggest a direct role of TRAIP, expressed upon acetylation of mutp53R158G, in facilitating apoptosis through disruption of NFkB pathway signaling.	('NFkB pathway signaling', 'Pathway', (157, 179))	('facilitating', 'PosReg', (112, 124))	('p53R158G', 'Mutation', 'p.R53,158G', (99, 107))	('mutp53R158G', 'Var', (96, 107))	('apoptosis', 'CPA', (125, 134))	('disruption', 'NegReg', (143, 153))
498929	32350249	Further analyses of compounds found active against p53R158G cells revealed that eight out of the 10 compounds induced p53R158G acetylation (Supplementary Fig.	('p53R158G', 'Var', (118, 126))	('acetylation', 'MPA', (127, 138))	('p53R158G', 'Mutation', 'p.R53,158G', (51, 59))	('induced', 'Reg', (110, 117))	('p53R158G', 'Mutation', 'p.R53,158G', (118, 126))
498933	32350249	When applied in vivo, single agent cisplatin was effective in reducing tumor growth of p53R158G xenograft as compared to vehicle, with no efficacy observed in p53-/- and p53wt tumors (Supplementary Fig.	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('cisplatin', 'Chemical', 'MESH:D002945', (35, 44))	('tumor', 'Disease', (176, 181))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('p53R158G', 'Var', (87, 95))	('tumors', 'Disease', (176, 182))	('reducing', 'NegReg', (62, 70))	('tumors', 'Disease', 'MESH:D009369', (176, 182))	('tumors', 'Phenotype', 'HP:0002664', (176, 182))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumor', 'Disease', (71, 76))	('p53R158G', 'Mutation', 'p.R53,158G', (87, 95))	('tumor', 'Disease', 'MESH:D009369', (176, 181))
498934	32350249	Of note, efficacy of cisplatin in the p53R158G(K20A) tumors with defective acetylating mechanism was evidently reduced (Supplementary Fig.	('efficacy', 'MPA', (9, 17))	('cisplatin', 'Chemical', 'MESH:D002945', (21, 30))	('p53R158G', 'Var', (38, 46))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('reduced', 'NegReg', (111, 118))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('p53R158G', 'Mutation', 'p.R53,158G', (38, 46))	('acetylating mechanism', 'MPA', (75, 96))	('tumors', 'Disease', (53, 59))	('K20A', 'Mutation', 'p.K20A', (47, 51))
498935	32350249	Mechanistically, acetylation of mutp53R158G was accompanied by elevated TRAIP (Supplementary Fig.	('mutp53R158G', 'Var', (32, 43))	('TRAIP', 'CPA', (72, 77))	('acetylation', 'MPA', (17, 28))	('p53R158G', 'Mutation', 'p.R53,158G', (35, 43))	('elevated', 'PosReg', (63, 71))
498939	32350249	Scoring of TRAIP transcripts demonstrated a reciprocal inverse correlation with NFkB activity, for instance, a high basal score was associated with low p65 accumulation in p53wt tumors (Supplementary Fig.	('p53wt', 'Var', (172, 177))	('tumors', 'Disease', (178, 184))	('tumors', 'Disease', 'MESH:D009369', (178, 184))	('tumors', 'Phenotype', 'HP:0002664', (178, 184))	('p65', 'Gene', '5970', (152, 155))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('low', 'NegReg', (148, 151))	('p65', 'Gene', (152, 155))
498940	32350249	Further analyses of vehicle- and cisplatin-treated xenograft for drug-activity showed elevated TRAIP mRNA copies in p53R158G tumors, but decrease in wild-type tumors, validating the in vitro data (Supplementary Fig.	('elevated', 'PosReg', (86, 94))	('decrease', 'NegReg', (137, 145))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('p53R158G', 'Mutation', 'p.R53,158G', (116, 124))	('TRAIP mRNA copies', 'MPA', (95, 112))	('tumors', 'Disease', (125, 131))	('tumors', 'Disease', (159, 165))	('tumors', 'Disease', 'MESH:D009369', (125, 131))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('cisplatin', 'Chemical', 'MESH:D002945', (33, 42))	('tumors', 'Phenotype', 'HP:0002664', (159, 165))	('tumors', 'Disease', 'MESH:D009369', (159, 165))	('p53R158G', 'Var', (116, 124))
498942	32350249	Whereas volasertib demonstrated high toxicity in mice (died within days of administration), tolerable doses of JQ1 and topotecan were effective in suppressing growth of p53R158G tumors compared to the p53wt and p53-/- counterparts (Supplementary Fig.	('toxicity', 'Disease', (37, 45))	('volasertib', 'Chemical', 'MESH:C541363', (8, 18))	('p53R158G', 'Mutation', 'p.R53,158G', (169, 177))	('tumors', 'Disease', (178, 184))	('tumors', 'Disease', 'MESH:D009369', (178, 184))	('tumors', 'Phenotype', 'HP:0002664', (178, 184))	('suppressing', 'NegReg', (147, 158))	('mice', 'Species', '10090', (49, 53))	('topotecan', 'Chemical', 'MESH:D019772', (119, 128))	('growth', 'MPA', (159, 165))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('toxicity', 'Disease', 'MESH:D064420', (37, 45))	('p53R158G', 'Var', (169, 177))
498943	32350249	16I-K), providing direction for future development of p53-acetylating agents in p53R158G-positive tumors.	('tumors', 'Disease', (98, 104))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('acetylating agents', 'Chemical', '-', (58, 76))	('tumors', 'Disease', 'MESH:D009369', (98, 104))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('p53R158G-positive', 'Var', (80, 97))	('p53R158G', 'Mutation', 'p.R53,158G', (80, 88))
498944	32350249	Patient-derived xenograft (PDX) tumors of gastric cancer (GC; p53R158C) and hepatocellular carcinoma (HCC; p53R158H) harboring Arg158 mutp53 were selected for evaluation with p53-acetylators: cisplatin, JQ1 and topotecan.	('p53R158H', 'Mutation', 'p.R53,158H', (107, 115))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('topotecan', 'Chemical', 'MESH:D019772', (211, 220))	('cisplatin', 'Chemical', 'MESH:D002945', (192, 201))	('gastric cancer', 'Phenotype', 'HP:0012126', (42, 56))	('tumors of gastric', 'Phenotype', 'HP:0006753', (32, 49))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (76, 100))	('tumors of gastric cancer', 'Disease', (32, 56))	('HCC', 'Phenotype', 'HP:0001402', (102, 105))	('tumors of gastric cancer', 'Disease', 'MESH:D013274', (32, 56))	('p53R158C', 'Mutation', 'p.R53,158C', (62, 70))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (76, 100))	('Arg158', 'Var', (127, 133))	('GC', 'Phenotype', 'HP:0012126', (58, 60))	('hepatocellular carcinoma', 'Disease', (76, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('Arg158', 'Chemical', '-', (127, 133))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('Patient', 'Species', '9606', (0, 7))
498949	32350249	These findings suggest that, while the Arg158 p53 mutation is more prevalent in lung carcinomas, the mechanism conferring tumor cytotoxicity could be applied across cancer types harboring the same alteration.	('Arg158 p53', 'Var', (39, 49))	('Arg158', 'Chemical', '-', (39, 45))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('prevalent', 'Reg', (67, 76))	('lung carcinomas', 'Disease', (80, 95))	('carcinomas', 'Phenotype', 'HP:0030731', (85, 95))	('tumor cytotoxicity', 'Disease', 'MESH:D064420', (122, 140))	('cancer', 'Disease', (165, 171))	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('lung carcinomas', 'Disease', 'MESH:D008175', (80, 95))	('tumor cytotoxicity', 'Disease', (122, 140))
498953	32350249	Missense mutations in the DNA-binding domain constitute more than 70% of tumor-associated p53 mutations.	('p53', 'Gene', (90, 93))	('Missense mutations in', 'Var', (0, 21))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('mutations', 'Var', (94, 103))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Disease', (73, 78))
498954	32350249	These mutations alter DNA-binding capability of mutp53, concomitantly leading to a variable loss of p53 tumor suppressive functions, while mediating oncogenic GOF through transcriptional aberrations involving chromatin remodeling and interaction with transcription cofactors such as SREBP, ETS2, or NRF2.	('alter', 'Reg', (16, 21))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('NRF2', 'Gene', (299, 303))	('interaction', 'Interaction', (234, 245))	('ETS2', 'Gene', (290, 294))	('tumor', 'Disease', (104, 109))	('DNA-binding', 'Interaction', (22, 33))	('loss', 'NegReg', (92, 96))	('ETS2', 'Gene', '2114', (290, 294))	('NRF2', 'Gene', '4780', (299, 303))	('mutations', 'Var', (6, 15))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('p53', 'Gene', (100, 103))
498956	32350249	The complex crosstalk between p53 and NFkB has been described previously, with the suppression of p65 in wild-type cells a result of competitive interaction with p300 or glucocorticoid receptor; conversely mutp53 prolongs and enhances NFkB activation.	('glucocorticoid receptor', 'Gene', '2908', (170, 193))	('suppression', 'NegReg', (83, 94))	('p65', 'Gene', (98, 101))	('glucocorticoid receptor', 'Gene', (170, 193))	('NFkB', 'CPA', (235, 239))	('activation', 'MPA', (240, 250))	('p300', 'Gene', (162, 166))	('interaction', 'Interaction', (145, 156))	('enhances', 'PosReg', (226, 234))	('p65', 'Gene', '5970', (98, 101))	('mutp53', 'Var', (206, 212))	('prolongs', 'PosReg', (213, 221))	('p300', 'Gene', '2033', (162, 166))
498957	32350249	We propose here a mechanism for this divergent effect through acetylation of Arg158 mutp53, which alters its DNA-binding spectrum and upregulates TRAIP as key target gene, leading to NFkB suppression through TRAF2 degradation and culminating in cell death (Fig.	('DNA-binding spectrum', 'MPA', (109, 129))	('Arg158', 'Var', (77, 83))	('alters', 'Reg', (98, 104))	('Arg158', 'Chemical', '-', (77, 83))	('upregulates', 'PosReg', (134, 145))	('TRAF2', 'Gene', (208, 213))	('degradation', 'MPA', (214, 225))	('suppression', 'NegReg', (188, 199))	('TRAF2', 'Gene', '7186', (208, 213))	('cell death', 'CPA', (245, 255))	('NFkB', 'Gene', (183, 187))	('acetylation', 'Var', (62, 73))
498958	32350249	This p53 isoform appears to carry distinctive GOF mechanisms that does not involve the chromatin regulatory genes as observed in other DBD hotspot mutants; other hotspot p53 mutants, such as R175H and R273H, did not upregulate TRAIP in response to belinostat and cisplatin treatment.	('belinostat', 'Chemical', 'MESH:C487081', (248, 258))	('R273H', 'Mutation', 'rs28934576', (201, 206))	('p53', 'Gene', (170, 173))	('cisplatin', 'Chemical', 'MESH:D002945', (263, 272))	('R273H', 'Var', (201, 206))	('R175H', 'Mutation', 'rs28934578', (191, 196))	('R175H', 'Var', (191, 196))	('upregulate', 'PosReg', (216, 226))
498959	32350249	Given that a point mutation is sufficient to affect p53 transactivation, and that protein mis-folding regulated by zinc-binding could affect p53 transcriptional functions, it is possible that Arg158 mutp53 modulates site-specific DNA binding through aberrant Zinc2+ interaction which should be explored further.	('affect', 'Reg', (45, 51))	('DNA binding', 'Interaction', (230, 241))	('Zinc2+', 'Chemical', '-', (259, 265))	('Arg158 mutp53', 'Var', (192, 205))	('modulates', 'Reg', (206, 215))	('Zinc2+ interaction', 'Interaction', (259, 277))	('affect', 'Reg', (134, 140))	('Arg158', 'Chemical', '-', (192, 198))	('p53 transactivation', 'MPA', (52, 71))	('p53 transcriptional functions', 'MPA', (141, 170))
498960	32350249	Our expression analysis and ChIP-Seq findings concordantly demonstrated the retention of transcriptional activity of mutp53R158G, which has been described in other DBD variants.	('transcriptional activity', 'MPA', (89, 113))	('mutp53R158G', 'Var', (117, 128))	('p53R158G', 'Mutation', 'p.R53,158G', (120, 128))
498961	32350249	Exposure to cellular stress, such as cisplatin, could trigger a partial wild-type activity in mutp53R158G that induces p53-dependent pro-apoptotic signals, which is not seen in p53 null cells.	('p53R158G', 'Mutation', 'p.R53,158G', (97, 105))	('p53-dependent pro-apoptotic signals', 'MPA', (119, 154))	('activity', 'MPA', (82, 90))	('cisplatin', 'Chemical', 'MESH:D002945', (37, 46))	('induces', 'Reg', (111, 118))	('mutp53R158G', 'Var', (94, 105))
498962	32350249	However, the DNA-binding activity of mutp53R158G is distinct from p53wt, manifesting in GOF activity.	('mutp53R158G', 'Var', (37, 48))	('DNA-binding', 'Interaction', (13, 24))	('p53R158G', 'Mutation', 'p.R53,158G', (40, 48))	('GOF', 'MPA', (88, 91))
498963	32350249	Paradoxically, this DNA-binding ability is prerequisite for the induction of apoptosis as initiated through mutp53R158G acetylation, a key post-translational event closely associated with its transcriptional activity and stability.	('apoptosis', 'CPA', (77, 86))	('p53R158G', 'Mutation', 'p.R53,158G', (111, 119))	('acetylation', 'MPA', (120, 131))	('mutp53R158G', 'Var', (108, 119))
498965	32350249	These further refined the commonly held credence that targeting acetylation and eventual depletion of mutp53 is a plausible anti-tumor approach.	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('acetylation', 'MPA', (64, 75))	('mutp53', 'Var', (102, 108))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('depletion', 'MPA', (89, 98))	('tumor', 'Disease', (129, 134))
498966	32350249	Such findings are made therapeutically relevant by positive screen hits for compounds with pharmacological activity of p53R158G acetylation.	('acetylation', 'MPA', (128, 139))	('p53R158G', 'Mutation', 'p.R53,158G', (119, 127))	('p53R158G', 'Var', (119, 127))
498967	32350249	The selective cytotoxicity of these compounds in Arg158 mutp53 tumors, compared to wild-type and null tumors, is promising as a companion biomarker for selecting patients with greater potential to respond to the p53-acetylating agents.	('cytotoxicity', 'Disease', 'MESH:D064420', (14, 26))	('patients', 'Species', '9606', (162, 170))	('tumors', 'Disease', (102, 108))	('tumors', 'Disease', 'MESH:D009369', (102, 108))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('acetylating agents', 'Chemical', '-', (216, 234))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('tumors', 'Disease', (63, 69))	('cytotoxicity', 'Disease', (14, 26))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('Arg158 mutp53', 'Var', (49, 62))	('Arg158', 'Chemical', '-', (49, 55))
498969	32350249	For instance, the bromodomain (BRD) inhibitor JQ1 is currently in clinical development to target a rare genomic BRD-NUT fusion event in NUT midline carcinoma, and our data extends potential evaluation in Arg158 mutp53 tumors.	('Arg158', 'Chemical', '-', (204, 210))	('NUT midline carcinoma', 'Disease', (136, 157))	('NUT', 'Gene', '256646', (116, 119))	('NUT', 'Gene', '256646', (136, 139))	('tumors', 'Disease', 'MESH:D009369', (218, 224))	('tumors', 'Phenotype', 'HP:0002664', (218, 224))	('carcinoma', 'Phenotype', 'HP:0030731', (148, 157))	('NUT', 'Gene', (116, 119))	('NUT', 'Gene', (136, 139))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('NUT midline carcinoma', 'Disease', 'MESH:D009436', (136, 157))	('tumors', 'Disease', (218, 224))	('Arg158 mutp53', 'Var', (204, 217))
498970	32350249	Curated data from public databases (IARC TP53, COSMICs, ICGC, and cBioportal) reveal the presence of Arg158 mutp53 in multiple carcinomas; and the effectiveness of mutp53 acetylators in the PDX models of gastric and liver cancers further extends the applicability of these findings to other cancer types.	('TP53', 'Gene', '7157', (41, 45))	('Arg158', 'Var', (101, 107))	('carcinomas', 'Disease', (127, 137))	('cancer', 'Disease', 'MESH:D009369', (291, 297))	('liver cancers', 'Phenotype', 'HP:0002896', (216, 229))	('Arg158', 'Chemical', '-', (101, 107))	('cancer', 'Disease', (222, 228))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('carcinomas', 'Phenotype', 'HP:0030731', (127, 137))	('carcinomas', 'Disease', 'MESH:D009369', (127, 137))	('TP53', 'Gene', (41, 45))	('cancer', 'Disease', (291, 297))	('cancers', 'Phenotype', 'HP:0002664', (222, 229))	('mutp53', 'Var', (164, 170))	('cancer', 'Phenotype', 'HP:0002664', (291, 297))	('cancer', 'Disease', 'MESH:D009369', (222, 228))	('GC', 'Phenotype', 'HP:0012126', (58, 60))	('gastric and liver cancers', 'Disease', 'MESH:D013274', (204, 229))
498971	32350249	In conclusion, we provide evidence of a unique mechanism of p53 activation that is specific to Arg158 mutations, exposing a previously unrecognized therapeutic vulnerability and facilitating a biomarker-implemented approach directed against this GOF mutant.	('Arg158', 'Chemical', '-', (95, 101))	('Arg158', 'Gene', (95, 101))	('p53', 'Gene', (60, 63))	('mutations', 'Var', (102, 111))	('activation', 'PosReg', (64, 74))
498972	32350249	If validated in the clinic, this represents an advance in therapeutic treatment of tumors with mutated p53, particularly that of LUSC, in which Arg158 mutant is found to be prevalent.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('p53', 'Gene', (103, 106))	('Arg158 mutant', 'Var', (144, 157))	('tumors', 'Disease', (83, 89))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('Arg158', 'Chemical', '-', (144, 150))	('mutated', 'Var', (95, 102))	('tumors', 'Disease', 'MESH:D009369', (83, 89))
498974	32350249	Mutations found on TP53 genes and the corresponding protein change were extracted for analysis.	('Mutations', 'Var', (0, 9))	('TP53', 'Gene', '7157', (19, 23))	('TP53', 'Gene', (19, 23))
498975	32350249	Cancer cell-lines (Calu-1, ChaGo-k-1, HCC70, H441, H520, H596, H661, H747, H1417, H2170, MDA-MB-468, SK-BR-3, SK-MES-1) and lung fibroblast cells (MRC-5) were obtained directly from the American Type Culture Collection (ATCC), while others (A549, BT-549, H1975, MIA-Paca-2, PANC-1) were provided by Ashok Venkitaraman (MRC Cancer Unit, Cambridge, UK).	('MRC Cancer', 'Disease', (319, 329))	('A549', 'CellLine', 'CVCL:0023', (241, 245))	('PANC-1', 'CellLine', 'CVCL:0480', (274, 280))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('H1417', 'CellLine', 'CVCL:1469', (75, 80))	('Cancer', 'Disease', (323, 329))	('BT-549', 'CellLine', 'CVCL:1092', (247, 253))	('H2170', 'Var', (82, 87))	('H2170', 'CellLine', 'CVCL:1535', (82, 87))	('Cancer', 'Disease', 'MESH:D009369', (323, 329))	('HCC', 'Phenotype', 'HP:0001402', (38, 41))	('SK-MES-1', 'CellLine', 'CVCL:0630', (110, 118))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('MRC-5', 'CellLine', 'CVCL:0440', (147, 152))	('H1975', 'CellLine', 'CVCL:1511', (255, 260))	('MRC Cancer', 'Disease', 'MESH:D009369', (319, 329))	('SK-BR-3', 'CellLine', 'CVCL:0033', (101, 108))	('MDA-MB-468', 'CellLine', 'CVCL:0419', (89, 99))	('Cancer', 'Disease', (0, 6))	('H661', 'CellLine', 'CVCL:1577', (63, 67))	('MIA-Paca-2', 'CellLine', 'CVCL:0428', (262, 272))	('Cancer', 'Phenotype', 'HP:0002664', (323, 329))
498989	32350249	Bleomycin (S1214), AZD7762 (S1532), cladribine (S1199), topotecan (S1231), nocodazole (S2775), volasertib (S2235), BI-2536 (S1109), 17-AAG (S1141), belinostat (PXD101, S1085), bosutinib (S1014), MK-5108 (S2770), JQ1 (S7110), CX-6258 (S7041), alisertib (S1133), JNJ-26481585 (S1096), and M344 (S2779) were purchased from Selleckchem; oxamflatin was purchased from Sigma Aldrich (O3139).	('bosutinib', 'Chemical', 'MESH:C471992', (176, 185))	('S1014', 'Var', (187, 192))	('nocodazole', 'Chemical', 'MESH:D015739', (75, 85))	('topotecan', 'Chemical', 'MESH:D019772', (56, 65))	('volasertib', 'Chemical', 'MESH:C541363', (95, 105))	('AZD7762', 'Chemical', 'MESH:C532363', (19, 26))	('belinostat', 'Chemical', 'MESH:C487081', (148, 158))	('cladribine', 'Chemical', 'MESH:D017338', (36, 46))	('17-AAG', 'Chemical', 'MESH:C112765', (132, 138))	('S7041', 'Var', (234, 239))	('S1231', 'Var', (67, 72))	('S1133', 'Var', (253, 258))
498996	32350249	Antibodies used for immunoblotting include: PARP (#9542), cleaved PARP (#5625), caspase 3 (#9662), caspase 7 (#9492), acetyl-H3K23 (#9674), acetyl-H3K9K14 (#9677), total H3 (#9715), phospho-p53 Ser15 (#9286), acetyl-p53 Lys 382 (#2525), acetyl-p53 Lys379 (#2570), total p53 (#9282), p21 (#2947), gammaH2AX (#9718), phopho-IkB Ser32 (#2859), total IkB (#9247), total p65 (#8242), phoshph-TRAF2 Ser11 (#13908), total TRAF2 (#4724), c-IAP1 (#7065), c-IAP2 (#3130), alpha-tubulin (#2125), and horseradish peroxidase (HRP)-conjugated beta-actin (#5125) antibodies as well as secondary anti-mouse (#7076) and -rabbit (#7074) HRP-conjugated secondary antibodies were obtained from Cell Signaling Technologies; acetyl-H4 (#06-866) antibody was from Merck Millipore; TRAIP (#ab80170), TATA-box binding protein (#ab818) were from Abcam; DDK (#TA180144) antibody was from Origene.	('c-IAP2', 'Gene', '330', (446, 452))	('p65', 'Gene', '5970', (366, 369))	('c-IAP2', 'Gene', (446, 452))	('horseradish', 'Species', '3704', (489, 500))	('TRAF2', 'Gene', '7186', (415, 420))	('p21', 'Gene', '1026', (283, 286))	('alpha-tubulin', 'Gene', (462, 475))	('PARP', 'Gene', (44, 48))	('TATA-box binding protein', 'Gene', '21374', (776, 800))	('caspase 3', 'Gene', (80, 89))	('PARP', 'Gene', '1302', (66, 70))	('mouse', 'Species', '10090', (585, 590))	('TRAF2', 'Gene', (387, 392))	('caspase 3', 'Gene', '836', (80, 89))	('#ab80170', 'Var', (765, 773))	('#TA180144', 'Var', (832, 841))	('TRAF2', 'Gene', '7186', (387, 392))	('caspase 7', 'Gene', (99, 108))	('p65', 'Gene', (366, 369))	('PARP', 'Gene', (66, 70))	('p21', 'Gene', (283, 286))	('alpha-tubulin', 'Gene', '10376', (462, 475))	('c-IAP1', 'Gene', '329', (430, 436))	('caspase 7', 'Gene', '840', (99, 108))	('TATA-box binding protein', 'Gene', (776, 800))	('TRAF2', 'Gene', (415, 420))	('PARP', 'Gene', '1302', (44, 48))	('c-IAP1', 'Gene', (430, 436))
499025	32350249	Cultured cells were fixed with methanol for 30 min, and immunostained with acetyl-p53 (1:500, Cell Signaling, #2570), p-p53 (1:500, Cell Signaling, #9286), or NF-kappaB p65 (1:1000, Cell Signaling, #8242) for 4 hours at 4  C, followed by incubation with Alexa Fluor-488 or -594 secondary antibodies (1:1000, Molecular Probes, Life Technologies, A11034 and R37121) for 2 h at 25  C, and by Hoechst 33342 nuclear staining (1:2000, Sigma, #23491-52-3) for 15 min.	('1:1000', 'Var', (300, 306))	('R37121', 'Var', (356, 362))	('ethanol', 'Chemical', 'MESH:D000431', (32, 39))	('NF-kappaB p65', 'Gene', (159, 172))	('1:500', 'Var', (125, 130))	('NF-kappaB p65', 'Gene', '5970', (159, 172))	('A11034', 'Var', (345, 351))	('p-p53', 'Var', (118, 123))
499070	31992202	CKS1B is a lung cancer-related gene, knockdown of which results in a significant decrease in lung cancer cell proliferation, invasion and migration.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('CKS1B', 'Gene', '1163', (0, 5))	('lung cancer', 'Disease', 'MESH:D008175', (93, 104))	('CKS1B', 'Gene', (0, 5))	('knockdown', 'Var', (37, 46))	('lung cancer', 'Disease', (11, 22))	('lung cancer', 'Phenotype', 'HP:0100526', (11, 22))	('decrease in lung cancer', 'Disease', (81, 104))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('lung cancer', 'Phenotype', 'HP:0100526', (93, 104))	('decrease in lung cancer', 'Disease', 'MESH:D008175', (81, 104))	('lung cancer', 'Disease', 'MESH:D008175', (11, 22))
499088	31992202	TOP2A is an ideal candidate as miR-144-3p target in non-small cell lung cancer, while MiR-144-3p expression is significantly correlated with lymph node metastasis and vascular invasion.	('TOP2A', 'Gene', (0, 5))	('correlated', 'Reg', (125, 135))	('lymph node metastasis', 'CPA', (141, 162))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (56, 78))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (52, 78))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('MiR-144-3p', 'Var', (86, 96))	('TOP2A', 'Gene', '7153', (0, 5))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (52, 78))	('vascular invasion', 'CPA', (167, 184))	('lung cancer', 'Phenotype', 'HP:0100526', (67, 78))	('non-small cell lung cancer', 'Disease', (52, 78))
499121	31992202	The proposed method has been applied to six real datasets, i.e., the time-course dataset GSE2565 from NCBI GEO database (http://www.ncbi.nlm.nih.gov/geo) and five stage-course datasets LUSC, LUAD, STAD, THCA and COAD from TCGA database (http://cancergenome.nih.gov).	('LUSC', 'Disease', 'MESH:D002294', (185, 189))	('GSE2565', 'Var', (89, 96))	('LUSC', 'Disease', (185, 189))	('COAD', 'Disease', (212, 216))	('THCA', 'Disease', 'MESH:D013964', (203, 207))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('LUAD', 'Disease', (191, 195))	('LUAD', 'Disease', 'MESH:C538231', (191, 195))	('LUAD', 'Phenotype', 'HP:0030078', (191, 195))	('THCA', 'Phenotype', 'HP:0002890', (203, 207))	('COAD', 'Disease', 'MESH:D015179', (212, 216))	('THCA', 'Disease', (203, 207))	('STAD', 'Disease', 'MESH:D013274', (197, 201))	('STAD', 'Disease', (197, 201))	('cancer', 'Disease', (244, 250))	('cancer', 'Disease', 'MESH:D009369', (244, 250))
499133	27281369	The results of MTTs assay demonstrated that EEP, polyphenols and mixture of polyphenolic compounds were cytotoxic for CAL-27 cells in a dose dependent manner.	('MTTs', 'Chemical', 'MESH:C070243', (15, 19))	('polyphenolic compounds', 'Chemical', '-', (76, 98))	('cytotoxic', 'CPA', (104, 113))	('polyphenols', 'Chemical', 'MESH:D059808', (49, 60))	('CAL-27', 'CellLine', 'CVCL:1107', (118, 124))	('polyphenols', 'Var', (49, 60))
499145	27281369	In vitro/in vivo studies demonstrated that dietary compounds containing polyphenols are able to prevent carcinogenesis and might inhibit the growth of cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('inhibit', 'NegReg', (129, 136))	('polyphenols', 'Chemical', 'MESH:D059808', (72, 83))	('cancer', 'Disease', (151, 157))	('carcinogenesis', 'Disease', 'MESH:D063646', (104, 118))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('polyphenols', 'Var', (72, 83))	('carcinogenesis', 'Disease', (104, 118))
499147	27281369	Other evidences indicated that the methylated analogues of chrysin and apigenin inhibited the proliferation of human oral squamous cell carcinoma SCC-9.	('chrysin', 'Chemical', 'MESH:C043561', (59, 66))	('human', 'Species', '9606', (111, 116))	('proliferation', 'CPA', (94, 107))	('methylated', 'Var', (35, 45))	('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))	('SCC-9', 'CellLine', 'CVCL:1685', (146, 151))	('inhibited', 'NegReg', (80, 89))
499162	27281369	Primary antibodies anti caspase-3 (#559565), caspase-8 (#51-80851-N) and caspase-9 (#51-80861N), FITC Fluor-conjugated secondary antibody, (FITC goat anti-mouse IgG #554001, FITC goat anti-rabbit IgG #554020) were obtained from Becton Dickinson (New Jersey, USA).	('caspase-9', 'Gene', (73, 82))	('#51-80851-N', 'Var', (56, 67))	('FITC', 'Chemical', 'MESH:D016650', (97, 101))	('goat', 'Species', '9925', (145, 149))	('#559565', 'Var', (35, 42))	('caspase-3', 'Gene', '836', (24, 33))	('caspase-8', 'Gene', (45, 54))	('#51-80861N', 'Var', (84, 94))	('mouse', 'Species', '10090', (155, 160))	('caspase-9', 'Gene', '842', (73, 82))	('caspase-8', 'Gene', '841', (45, 54))	('goat', 'Species', '9925', (179, 183))	('FITC', 'Chemical', 'MESH:D016650', (140, 144))	('FITC', 'Chemical', 'MESH:D016650', (174, 178))	('caspase-3', 'Gene', (24, 33))	('FITC Fluor', 'Chemical', '-', (97, 107))	('rabbit', 'Species', '9986', (189, 195))
499173	27281369	The mass fragments (m/z) used for the quantitative analysis of the polyphenols were m/z 384, 383, and 311 for chrysin, m/z 471, 472 and 473 for galangin, m/z 192, 296 and 369 for pinobanksin, m/z 385, 386 and 457 for pinocembrin, 219, 396 and 397 for caffeic acid, 219, 293 and 308 for p-coumaric acid, 249, 323 and 338 for ferulic acid and 254, 269 and 284 for methyl syringate used as an internal standard (IS).	('caffeic acid', 'Chemical', 'MESH:C040048', (251, 263))	('galangin', 'Disease', 'None', (144, 152))	('ferulic acid', 'Chemical', 'MESH:C004999', (324, 336))	('m/z 471', 'Var', (119, 126))	('galangin', 'Disease', (144, 152))	('chrysin', 'Chemical', 'MESH:C043561', (110, 117))	('m/z 384', 'Var', (84, 91))	('m/z', 'Var', (154, 157))	('pinocembrin', 'Chemical', 'MESH:C016063', (217, 228))	('m/z', 'Var', (192, 195))	('polyphenols', 'Chemical', 'MESH:D059808', (67, 78))	('p-coumaric acid', 'Chemical', 'MESH:C495469', (286, 301))
499294	26170166	Prx1 & Prx2 knockout mice are reported to have some issue with erythropoiesis.	('Prx1', 'Gene', (0, 4))	('Prx2', 'Var', (7, 11))	('with', 'MPA', (58, 62))	('mice', 'Species', '10090', (21, 25))
499300	26170166	Biteau B et al (2003) identified how ATP-bound yeast Srx in the presence of Mg2+ approaches the hyperoxidized Prx, phosphorylates it and form thiosulfinate intermediate, which can be further reduced by other thiol reducing enzymes.	('Mg2+', 'Var', (76, 80))	('Mg2+', 'Chemical', '-', (76, 80))	('ATP', 'Chemical', 'MESH:D000255', (37, 40))	('thiol', 'Chemical', 'MESH:D013438', (208, 213))	('yeast', 'Species', '4932', (47, 52))	('thiosulfinate', 'Chemical', '-', (142, 155))	('thiosulfinate intermediate', 'MPA', (142, 168))	('yeast Srx', 'Enzyme', (47, 56))	('phosphorylates', 'MPA', (115, 129))
499305	26170166	The evolution of an ATP consuming process to reactivate Prx after deactivation of its peroxidase function by H2O2 have given a unique advantage to host organism where H2O2 and Srx acts as an On-Off switch for chaperone and peroxidase function of various Prxs.	('deactivation', 'NegReg', (66, 78))	('ATP', 'Chemical', 'MESH:D000255', (20, 23))	('H2O2', 'Chemical', 'MESH:D006861', (109, 113))	('H2O2', 'Var', (109, 113))	('peroxidase', 'Enzyme', (86, 96))	('H2O2', 'Chemical', 'MESH:D006861', (167, 171))
499306	26170166	The excess of H2O2 enhances the chaperone function and reduces the peroxidase function of Prx whereas excess of Srx reverses this process.	('enhances', 'PosReg', (19, 27))	('Prx', 'Enzyme', (90, 93))	('reduces', 'NegReg', (55, 62))	('peroxidase function', 'MPA', (67, 86))	('chaperone function', 'MPA', (32, 50))	('H2O2', 'Chemical', 'MESH:D006861', (14, 18))	('H2O2', 'Var', (14, 18))
499310	26170166	The glutathionylation of Cys83 of Prx1 favors formation of dimer over decamer, resulting in the loss of chaperone activity.	('formation of dimer over decamer', 'MPA', (46, 77))	('Prx1', 'Gene', (34, 38))	('favors', 'PosReg', (39, 45))	('glutathionylation', 'MPA', (4, 21))	('chaperone activity', 'MPA', (104, 122))	('Cys83', 'Chemical', '-', (25, 30))	('loss', 'NegReg', (96, 100))	('Cys83', 'Var', (25, 30))
499316	26170166	The Cys99 of human Srx is not involved in the Srx-Prx binding but it is directly involved in antioxidant as well as deglutathionylation functions of Srx.	('human', 'Species', '9606', (13, 18))	('deglutathionylation functions', 'MPA', (116, 145))	('involved', 'Reg', (81, 89))	('antioxidant', 'MPA', (93, 104))	('Cys99', 'Chemical', '-', (4, 9))	('Cys99', 'Var', (4, 9))
499318	26170166	Gly97, Gly98, His100 & Arg101 are considered to be supportive and are also important for the enzymatic activity of Srx.	('Gly98', 'Chemical', '-', (7, 12))	('Gly97', 'Var', (0, 5))	('Gly98', 'Var', (7, 12))	('Arg101', 'Chemical', '-', (23, 29))	('His100 &', 'Var', (14, 22))	('Gly97', 'Chemical', '-', (0, 5))	('His100', 'Chemical', '-', (14, 20))
499319	26170166	Pro52, Leu82, Phe96, Val118, Val127 and Tyr128 are amino acids that form a hydrophobic pocket in Srx that acts as the interface for Srx-Prx interaction.	('Val127', 'Var', (29, 35))	('Pro52', 'Chemical', '-', (0, 5))	('Tyr128', 'Chemical', '-', (40, 46))	('Tyr128', 'Var', (40, 46))	('Val127', 'Chemical', '-', (29, 35))	('Phe96', 'Chemical', '-', (14, 19))	('Leu82', 'Var', (7, 12))	('Val118', 'Chemical', '-', (21, 27))	('Phe96', 'Var', (14, 19))	('Leu82', 'Chemical', '-', (7, 12))	('Val118', 'Var', (21, 27))	('Pro52', 'Var', (0, 5))	('interaction', 'Interaction', (140, 151))
499325	26170166	For example, Cys83 of Prx1 mediates formation of decameric complex of Prx1 that differentiates the functions of Prx1 from Prx2.	('Prx1', 'Gene', (70, 74))	('Cys83', 'Chemical', '-', (13, 18))	('Cys83', 'Var', (13, 18))	('mediates', 'Reg', (27, 35))	('Prx1', 'Gene', (22, 26))	('functions', 'MPA', (99, 108))
499326	26170166	Despite of 78% sequence similarity, one individual cysteine (Cys83) of Prx1 plays such an important role which increases the efficiency of Prx1 to act as a chaperone.	('efficiency', 'MPA', (125, 135))	('increases', 'PosReg', (111, 120))	('Cys83', 'Chemical', '-', (61, 66))	('Cys83', 'Var', (61, 66))	('act', 'MPA', (147, 150))	('Prx1', 'Gene', (71, 75))	('cysteine', 'Chemical', 'MESH:D003545', (51, 59))
499327	26170166	Another report has indicated that the Cys83- Cys83 disulfide bond formation is not essential for rat Prx1 as it can form decameric structure through hydrophobic interactions and van der Waals bonds.	('rat', 'Species', '10116', (97, 100))	('Cys83', 'Chemical', '-', (45, 50))	('decameric structure', 'MPA', (121, 140))	('disulfide', 'Chemical', 'MESH:D004220', (51, 60))	('van der Waals', 'CPA', (178, 191))	('hydrophobic', 'Var', (149, 160))	('Cys83-', 'Var', (38, 44))	('Cys83', 'Chemical', '-', (38, 43))	('form', 'Reg', (116, 120))
499328	26170166	Glutathionylation of Cys83 has been reported to negatively affect the chaperone function of Prx1.	('negatively', 'NegReg', (48, 58))	('affect', 'Reg', (59, 65))	('chaperone function', 'MPA', (70, 88))	('Glutathionylation', 'MPA', (0, 17))	('Prx1', 'Gene', (92, 96))	('Cys83', 'Chemical', '-', (21, 26))	('Cys83', 'Var', (21, 26))
499347	26170166	In human typical 2-Cys Prxs, amino acids around the peroxidatic cysteine (i.e.	('peroxidatic cysteine', 'Chemical', '-', (52, 72))	('human', 'Species', '9606', (3, 8))	('peroxidatic cysteine', 'MPA', (52, 72))	('2-Cys', 'Chemical', '-', (17, 22))	('amino acids', 'Var', (29, 40))
499366	26170166	TAM67 is an N-terminal deletion mutant of c-Jun and it acts as a c-Jun antagonist.	('c-Jun', 'Gene', (42, 47))	('TAM67', 'Chemical', '-', (0, 5))	('deletion', 'Var', (23, 31))	('c-Jun', 'Gene', '3725', (65, 70))	('c-Jun', 'Gene', '3725', (42, 47))	('c-Jun', 'Gene', (65, 70))
499367	26170166	Therefore, TAM67 can negatively regulate Srx expression by inhibiting the activity of AP-1 complex.	('Srx', 'Gene', (41, 44))	('negatively', 'NegReg', (21, 31))	('TAM67', 'Var', (11, 16))	('TAM67', 'Chemical', '-', (11, 16))	('activity', 'MPA', (74, 82))	('inhibiting', 'NegReg', (59, 69))	('AP-1', 'Gene', '3725', (86, 90))	('AP-1', 'Gene', (86, 90))
499374	26170166	Aberrant expression of Srx in lung squamous cell carcinoma, lung adenocarcinoma, and pancreatic cancer is correlated with poor survival in those patients.	('lung squamous cell carcinoma', 'Disease', (30, 58))	('pancreatic cancer', 'Disease', (85, 102))	('Aberrant expression', 'Var', (0, 19))	('patients', 'Species', '9606', (145, 153))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (60, 79))	('pancreatic cancer', 'Disease', 'MESH:D010190', (85, 102))	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (85, 102))	('lung adenocarcinoma', 'Disease', (60, 79))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (60, 79))	('Srx', 'Gene', (23, 26))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (35, 58))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (30, 58))
499376	26170166	Srx expression is stimulated by TPA via MAPK/JNK (c-Jun N-terminal kinase) pathway in skin carcinogenesis and Srx depletion at least partially protects mice against DMBA(7,12-dimethylbenz[a]anthracene)/TPA-induced skin carcinogenesis.	('Srx', 'Gene', (0, 3))	('c-Jun', 'Gene', '3725', (50, 55))	('expression', 'MPA', (4, 14))	('skin carcinogenesis', 'Disease', (86, 105))	('c-Jun', 'Gene', (50, 55))	('TPA', 'Chemical', '-', (202, 205))	('dimethylbenz', 'Chemical', '-', (175, 187))	('MAPK', 'Gene', (40, 44))	('JNK', 'Gene', (45, 48))	('depletion', 'Var', (114, 123))	('JNK', 'Gene', '26419', (45, 48))	('DMBA', 'Chemical', 'MESH:C082386', (165, 169))	('MAPK', 'Gene', '5594', (40, 44))	('mice', 'Species', '10090', (152, 156))	('anthracene', 'Chemical', 'MESH:C034020', (190, 200))	('TPA', 'Chemical', '-', (32, 35))	('stimulated', 'PosReg', (18, 28))	('skin carcinogenesis', 'Disease', 'MESH:D063646', (214, 233))	('skin carcinogenesis', 'Disease', (214, 233))	('skin carcinogenesis', 'Disease', 'MESH:D063646', (86, 105))
499399	26170166	For this function, the Cys51 (peroxidatic cysteine) of Prx1 is essential as replacement of Cys51 by Ser nullifies such effects.	('Prx1', 'Gene', (55, 59))	('Cys51', 'Var', (91, 96))	('Cys51 by Ser', 'Mutation', 'p.C51S', (91, 103))	('replacement', 'Var', (76, 87))	('peroxidatic cysteine', 'Chemical', '-', (30, 50))	('Cys51', 'Chemical', '-', (23, 28))	('Cys51', 'Chemical', '-', (91, 96))	('nullifies', 'NegReg', (104, 113))
499403	26170166	On the other hand, oxidation of Prx1 will reduce the levels of ROS.	('ROS', 'Chemical', 'MESH:D017382', (63, 66))	('levels of ROS', 'MPA', (53, 66))	('Prx1', 'Gene', (32, 36))	('reduce', 'NegReg', (42, 48))	('oxidation', 'Var', (19, 28))
499406	26170166	Other possible explanations may be related with the single nucleotide polymorphism (SNPs) or allelic variants of Prx1 but none of these factors have been investigated in detail in the literature.	('rat', 'Species', '10116', (188, 191))	('single nucleotide polymorphism', 'Var', (52, 82))	('Prx1', 'Gene', (113, 117))
499411	26170166	Extensive methylation of CpG islands in the promoter region of the Prdx2 gene is one of the mechanisms to control Prx2 expression in melanoma.	('Prdx2', 'Gene', (67, 72))	('expression', 'MPA', (119, 129))	('control', 'PosReg', (106, 113))	('Prx2', 'Gene', (114, 118))	('melanoma', 'Phenotype', 'HP:0002861', (133, 141))	('melanoma', 'Disease', (133, 141))	('melanoma', 'Disease', 'MESH:D008545', (133, 141))	('methylation', 'Var', (10, 21))	('Prdx2', 'Gene', '7001', (67, 72))
499415	26170166	Nitrosylation of Tyr193 in the YF motif of Prx2 is an important post-translational modification that plays a critical role in the regulation of disulfide bond formation under oxidative stress conditions.	('Tyr193', 'Chemical', '-', (17, 23))	('Prx2', 'Gene', (43, 47))	('oxidative stress', 'Phenotype', 'HP:0025464', (175, 191))	('regulation', 'MPA', (130, 140))	('Nitrosylation', 'MPA', (0, 13))	('Tyr193', 'Var', (17, 23))	('disulfide', 'Chemical', 'MESH:D004220', (144, 153))	('disulfide bond formation', 'MPA', (144, 168))
499419	26170166	However, more studies are required to establish whether the alteration of Prx2 is a cause or effect of carcinogenesis.	('alteration', 'Var', (60, 70))	('Prx2', 'Gene', (74, 78))	('carcinogenesis', 'Disease', 'MESH:D063646', (103, 117))	('rat', 'Species', '10116', (64, 67))	('carcinogenesis', 'Disease', (103, 117))
499433	26170166	SNP RS7082598 of PRDX3 gene is correlated with a reduced risk of cervical cancer.	('reduced', 'NegReg', (49, 56))	('SNP RS7082598', 'Var', (0, 13))	('cervical cancer', 'Disease', (65, 80))	('PRDX3', 'Gene', '10935', (17, 22))	('PRDX3', 'Gene', (17, 22))	('cervical cancer', 'Disease', 'MESH:D002583', (65, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
499446	26170166	Moreover, Prx4 is a downstream mediator of Srx in lung cancer development, which is demonstrated by the recapitulation of reduced tumor phenotypes in Srx knockdown cells by knockdown of Prx4 (i.e.	('lung cancer', 'Disease', (50, 61))	('rat', 'Species', '10116', (91, 94))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('Prx4', 'Gene', (186, 190))	('knockdown', 'Var', (173, 182))	('lung cancer', 'Disease', 'MESH:D008175', (50, 61))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('lung cancer', 'Phenotype', 'HP:0100526', (50, 61))	('tumor', 'Disease', (130, 135))
499450	26170166	In prostate cancer, over-expressed Prx4 enhances the rate of cell proliferation.	('prostate cancer', 'Phenotype', 'HP:0012125', (3, 18))	('enhances', 'PosReg', (40, 48))	('Prx4', 'Gene', (35, 39))	('prostate cancer', 'Disease', 'MESH:D011471', (3, 18))	('rat', 'Species', '10116', (53, 56))	('over-expressed', 'Var', (20, 34))	('prostate cancer', 'Disease', (3, 18))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('rat', 'Species', '10116', (73, 76))
499451	26170166	In oral cavity squamous cell carcinoma, expression of Prx4 enhances cancer metastasis.	('cancer metastasis', 'Disease', 'MESH:D009362', (68, 85))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (29, 38))	('expression', 'Var', (40, 50))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (15, 38))	('squamous cell carcinoma', 'Disease', (15, 38))	('Prx4', 'Gene', (54, 58))	('cancer metastasis', 'Disease', (68, 85))	('enhances', 'PosReg', (59, 67))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (15, 38))
499452	26170166	In colorectal cancer, high expression of Prx4 is correlate with poor survival of patients.	('colorectal cancer', 'Phenotype', 'HP:0003003', (3, 20))	('high', 'Var', (22, 26))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('patients', 'Species', '9606', (81, 89))	('colorectal cancer', 'Disease', (3, 20))	('colorectal cancer', 'Disease', 'MESH:D015179', (3, 20))	('Prx4', 'Gene', (41, 45))
499479	33903614	Compared to other breast cancers, TNBC accounts for 15% of all breast cancers and is associated with stronger invasiveness, higher risk of early recurrence rate and inferior survival.	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('breast cancers', 'Phenotype', 'HP:0003002', (63, 77))	('TNBC', 'Var', (34, 38))	('breast cancers', 'Phenotype', 'HP:0003002', (18, 32))	('breast cancer', 'Phenotype', 'HP:0003002', (18, 31))	('breast cancer', 'Phenotype', 'HP:0003002', (63, 76))	('breast cancers', 'Disease', 'MESH:D001943', (18, 32))	('breast cancers', 'Disease', 'MESH:D001943', (63, 77))	('breast cancers', 'Disease', (18, 32))	('breast cancers', 'Disease', (63, 77))	('cancers', 'Phenotype', 'HP:0002664', (70, 77))	('cancers', 'Phenotype', 'HP:0002664', (25, 32))	('invasiveness', 'MPA', (110, 122))	('stronger', 'PosReg', (101, 109))
499527	33903614	The analysis showed that the ratio SCD5/SCD1 was significantly upregulated in low histological grade and early-stage breast cancer compared to high histological grade and late-stage breast cancer.	('SCD5', 'Gene', (35, 39))	('breast cancer', 'Disease', 'MESH:D001943', (182, 195))	('breast cancer', 'Disease', 'MESH:D001943', (117, 130))	('late-stage breast cancer', 'Disease', (171, 195))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('low', 'Var', (78, 81))	('late-stage breast cancer', 'Disease', 'MESH:D001943', (171, 195))	('SCD5', 'Gene', '79966', (35, 39))	('breast cancer', 'Disease', (117, 130))	('breast cancer', 'Phenotype', 'HP:0003002', (182, 195))	('upregulated', 'PosReg', (63, 74))	('breast cancer', 'Phenotype', 'HP:0003002', (117, 130))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))
499553	33903614	Thus, we speculated that high SCD5 expression characteristic was associated with unfavorable response to chemotherapy in breast cancer.	('breast cancer', 'Disease', 'MESH:D001943', (121, 134))	('associated', 'Reg', (65, 75))	('high', 'Var', (25, 29))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('breast cancer', 'Disease', (121, 134))	('SCD5', 'Gene', (30, 34))	('breast cancer', 'Phenotype', 'HP:0003002', (121, 134))	('SCD5', 'Gene', '79966', (30, 34))
499567	33903614	To further study the possible molecular functions and biological networks of SCD5, samples from GEO datasets (GSE25055 and GSE25065) were divided into two groups according to high SCD5 expression (top 20%) and low SCD5 expression (bottom 20%).	('SCD5', 'Gene', (180, 184))	('expression', 'MPA', (185, 195))	('expression', 'MPA', (219, 229))	('SCD5', 'Gene', (214, 218))	('GSE25065', 'Var', (123, 131))	('SCD5', 'Gene', (77, 81))	('SCD5', 'Gene', '79966', (180, 184))	('SCD5', 'Gene', '79966', (77, 81))	('SCD5', 'Gene', '79966', (214, 218))	('GSE25055', 'Var', (110, 118))
499583	33903614	Dysregulation of lipid metabolism is considered as a component of malignant transformation in many different cancers, including breast cancer.	('lipid', 'Chemical', 'MESH:D008055', (17, 22))	('Dysregulation', 'Var', (0, 13))	('cancers', 'Disease', 'MESH:D009369', (109, 116))	('cancers', 'Phenotype', 'HP:0002664', (109, 116))	('cancers', 'Disease', (109, 116))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('breast cancer', 'Disease', (128, 141))	('breast cancer', 'Disease', 'MESH:D001943', (128, 141))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('breast cancer', 'Phenotype', 'HP:0003002', (128, 141))
499590	33903614	Furthermore, we found that reduced SCD5 expression was correlated with some aggressive features, such as high histological grade, late stage, HER2 overexpression, BRAF, KRAS and CDKN2A mutations, and shorter RFS.	('reduced', 'NegReg', (27, 34))	('HER2', 'Gene', (142, 146))	('HER2', 'Gene', '2064', (142, 146))	('SCD5', 'Gene', (35, 39))	('high histological grade', 'CPA', (105, 128))	('KRAS', 'Var', (169, 173))	('CDKN2A', 'Gene', (178, 184))	('SCD5', 'Gene', '79966', (35, 39))	('overexpression', 'PosReg', (147, 161))	('mutations', 'Var', (185, 194))	('BRAF', 'Disease', (163, 167))
499599	33903614	The former research confirmed that monounsaturated fatty acid could suppress HER2 expression in breast cancer, which might explain the negative correlation between SCD5 and HER2 expression as well as the higher SCD5 expression in TNBC compared with other molecular subtypes.	('SCD5', 'Gene', '79966', (164, 168))	('monounsaturated fatty acid', 'Chemical', 'MESH:D005229', (35, 61))	('expression', 'MPA', (82, 92))	('HER2', 'Gene', (173, 177))	('SCD5', 'Gene', (211, 215))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('HER2', 'Gene', (77, 81))	('HER2', 'Gene', '2064', (173, 177))	('expression', 'MPA', (216, 226))	('breast cancer', 'Disease', 'MESH:D001943', (96, 109))	('HER2', 'Gene', '2064', (77, 81))	('SCD5', 'Gene', '79966', (211, 215))	('breast cancer', 'Disease', (96, 109))	('SCD5', 'Gene', (164, 168))	('suppress', 'NegReg', (68, 76))	('breast cancer', 'Phenotype', 'HP:0003002', (96, 109))	('monounsaturated', 'Var', (35, 50))	('higher', 'PosReg', (204, 210))
499605	33903614	Thus, we hypothesized that high SCD5 expression might induce cell cycle checkpoint arrest and lead to chemoresistance.	('arrest', 'Disease', 'MESH:D006323', (83, 89))	('SCD5', 'Gene', (32, 36))	('arrest', 'Disease', (83, 89))	('high', 'Var', (27, 31))	('SCD5', 'Gene', '79966', (32, 36))	('chemoresistance', 'CPA', (102, 117))	('lead to', 'Reg', (94, 101))	('induce', 'PosReg', (54, 60))
499692	33299129	Information includes mutations, variants, copy number, mRNA expression, protein expression, methylation and overall patient survival for 32 cancer types.	('patient', 'Species', '9606', (116, 123))	('protein expression', 'MPA', (72, 90))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('variants', 'Var', (32, 40))	('mRNA expression', 'MPA', (55, 70))	('copy number', 'Var', (42, 53))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('methylation', 'MPA', (92, 103))
499724	33299129	The relative comparison of IC50s between different cancer cell lines treated with FGFR1 inhibitor (AZD4547, FGFR3861, Foretinib, PD173074, Ponatinib) with a significant difference in primary and metastatic cell lines are shown (Fig.	('Foretinib', 'Chemical', 'MESH:C544831', (118, 127))	('FGFR1', 'Gene', (82, 87))	('Ponatinib', 'Chemical', 'MESH:C545373', (139, 148))	('PD173074', 'Var', (129, 137))	('FGFR3861', 'Var', (108, 116))	('PD173074', 'Chemical', 'MESH:C115711', (129, 137))	('FGFR1', 'Gene', '2260', (82, 87))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('AZD4547', 'Var', (99, 106))	('cancer', 'Disease', (51, 57))	('AZD4547', 'Chemical', 'MESH:C572463', (99, 106))
499748	33299129	The bar graph for copy number variation allows the user to investigate alterations such as deletions or amplifications of the gene of interest in a given cancer cohort.	('deletions', 'Var', (91, 100))	('cancer', 'Disease', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('amplifications', 'Var', (104, 118))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))
499756	33299129	This research was supported by CPRIT (RP160710/RP170172), NSF (15-597-1605817), NIH/NCI (R01CA200970, 2R01CA155243, and 5P30CA016672), and the Bowes Foundation, (to S.A.M.	('5P30CA016672', 'Var', (120, 132))	('NSF', 'Gene', (58, 61))	('15-597-1605817', 'Var', (63, 77))	('RP160710/RP170172', 'Var', (38, 55))	('R01CA200970', 'Var', (89, 100))	('NSF', 'Gene', '4905', (58, 61))
499805	31766478	The overall corrected hazard ratio is HR = 1.719, 95% CI = (1.402, 2.109) and statistically significant (Z = 5.198, p < 0.001), indicating that a high expression of miR-21 is associated with poor survival for patients diagnosed with HNSCC.	('HNSCC', 'Disease', (233, 238))	('poor', 'NegReg', (191, 195))	('miR-21', 'Gene', (165, 171))	('patients', 'Species', '9606', (209, 217))	('miR-21', 'Gene', '406991', (165, 171))	('high', 'Var', (146, 150))
499816	31766478	In one dataset, however, GEOD-32960, miR-21-5p was down-regulated in tumor tissue.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('GEOD-32960', 'Chemical', 'None', (25, 35))	('tumor', 'Disease', (69, 74))	('GEOD-32960', 'Var', (25, 35))	('down-regulated', 'NegReg', (51, 65))	('miR-21-5p', 'Gene', (37, 46))	('miR-21-5p', 'Gene', '406997', (37, 46))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
499831	31766478	Accumulating data suggest that aberrantly-expressed miR-21 is a mark of malignant phenotype in several cancers, including HNSCC, where, even if the pathologies forming this group are very different in terms of histology or anatomic site, this microRNA is upregulated in the vast majority of cases.	('cancers', 'Disease', 'MESH:D009369', (103, 110))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('miR-21', 'Gene', (52, 58))	('upregulated', 'PosReg', (255, 266))	('HNSCC', 'Disease', (122, 127))	('miR-21', 'Gene', '406991', (52, 58))	('cancers', 'Phenotype', 'HP:0002664', (103, 110))	('aberrantly-expressed', 'Var', (31, 51))	('cancers', 'Disease', (103, 110))
499836	31766478	We also found that the expression of miR-21 in the TCGA and GEO datasets is upregulated in the majority of cases, and that the underexpression of some of its targets is associated with worse outcome in terms of survival rates.	('miR-21', 'Gene', '406991', (37, 43))	('underexpression', 'Var', (127, 142))	('survival rates', 'CPA', (211, 225))	('miR-21', 'Gene', (37, 43))	('upregulated', 'PosReg', (76, 87))	('expression', 'MPA', (23, 33))
499851	31766478	Resistance to therapy is also mediated by miR-21, as, in tongue cancer, it was reported that in the Tca8113 and SCC-25 cell lines, transfection with miR-21 mimic resulted in enhanced chemoresistance capacity coupled with reduced apoptosis.	('enhanced', 'PosReg', (174, 182))	('tongue cancer', 'Disease', (57, 70))	('miR-21', 'Gene', '406991', (149, 155))	('miR-21', 'Gene', (42, 48))	('tongue cancer', 'Disease', 'MESH:D014062', (57, 70))	('mimic', 'Var', (156, 161))	('miR-21', 'Gene', (149, 155))	('reduced', 'NegReg', (221, 228))	('miR-21', 'Gene', '406991', (42, 48))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('SCC-25', 'CellLine', 'CVCL:1682', (112, 118))	('chemoresistance capacity', 'CPA', (183, 207))	('apoptosis', 'CPA', (229, 238))
499867	30866410	Epigenetic Suppression of the T-box Subfamily 2 (TBX2) in Human Non-Small Cell Lung Cancer (1) The TBX2 subfamily of transcription factors (TBXs 2, 3, 4 and 5) are markedly down-regulated in human non-small cell lung cancer (NSCLC) and exert tumor suppressor effects in lung malignancy.	('TBX2', 'Gene', (99, 103))	('lung malignancy', 'Phenotype', 'HP:0100526', (270, 285))	('TBX2', 'Gene', (49, 53))	('Non-Small Cell Lung Cancer', 'Disease', 'MESH:D002289', (64, 90))	('tumor', 'Disease', (242, 247))	('TBX2', 'Gene', '6909', (99, 103))	('lung malignancy', 'Disease', 'MESH:D009369', (270, 285))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (197, 223))	('SCLC', 'Phenotype', 'HP:0030357', (226, 230))	('Lung Cancer', 'Phenotype', 'HP:0100526', (79, 90))	('TBX2', 'Gene', '6909', (49, 53))	('tumor', 'Disease', 'MESH:D009369', (242, 247))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (201, 223))	('Epigenetic Suppression', 'Var', (0, 22))	('NSCLC', 'Disease', 'MESH:D002289', (225, 230))	('down-regulated', 'NegReg', (173, 187))	('human', 'Species', '9606', (191, 196))	('Non-Small Cell Lung Cancer', 'Disease', (64, 90))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (197, 223))	('NSCLC', 'Disease', (225, 230))	('tumor', 'Phenotype', 'HP:0002664', (242, 247))	('TBXs 2, 3, 4 and 5', 'Gene', '6909;6926;9496;6910', (140, 158))	('Small Cell Lung Cancer', 'Phenotype', 'HP:0030357', (68, 90))	('Non-Small Cell Lung Cancer', 'Phenotype', 'HP:0030358', (64, 90))	('Cancer', 'Phenotype', 'HP:0002664', (84, 90))	('T-box Subfamily 2', 'Gene', (30, 47))	('NSCLC', 'Phenotype', 'HP:0030358', (225, 230))	('lung cancer', 'Phenotype', 'HP:0100526', (212, 223))	('non-small cell lung cancer', 'Disease', (197, 223))	('Human', 'Species', '9606', (58, 63))	('lung malignancy', 'Disease', (270, 285))	('T-box Subfamily 2', 'Gene', '6909', (30, 47))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))
499878	30866410	Members of the subfamily were significantly hypermethylated in all tested NSCLC cell lines relative to normal alveolar cells.	('NSCLC', 'Phenotype', 'HP:0030358', (74, 79))	('hypermethylated', 'Var', (44, 59))	('NSCLC', 'Disease', (74, 79))	('NSCLC', 'Disease', 'MESH:D002289', (74, 79))	('SCLC', 'Phenotype', 'HP:0030357', (75, 79))
499880	30866410	Further, simultaneous knockdown of the four TBX genes markedly reduced anti-growth effects of Aza in NSCLC cells.	('NSCLC', 'Phenotype', 'HP:0030358', (101, 106))	('reduced', 'NegReg', (63, 70))	('NSCLC', 'Disease', (101, 106))	('knockdown', 'Var', (22, 31))	('NSCLC', 'Disease', 'MESH:D002289', (101, 106))	('TBX genes', 'Gene', (44, 53))	('SCLC', 'Phenotype', 'HP:0030357', (102, 106))	('anti-growth effects of', 'MPA', (71, 93))	('TBX', 'Chemical', '-', (44, 47))	('Aza', 'Chemical', 'MESH:D001374', (94, 97))
499881	30866410	(4) Our study sheds light on new epigenetic profiles in the molecular pathogenesis of human NSCLC.	('NSCLC', 'Phenotype', 'HP:0030358', (92, 97))	('SCLC', 'Phenotype', 'HP:0030357', (93, 97))	('human', 'Species', '9606', (86, 91))	('epigenetic profiles', 'Var', (33, 52))	('NSCLC', 'Disease', (92, 97))	('NSCLC', 'Disease', 'MESH:D002289', (92, 97))
499895	30866410	Here, we interrogated epigenetic silencing, namely hypermethylation, as a high-potential mechanism underlying suppressed expression of the TBX2 subfamily in human NSCLC.	('SCLC', 'Phenotype', 'HP:0030357', (164, 168))	('hypermethylation', 'Var', (51, 67))	('NSCLC', 'Disease', (163, 168))	('expression', 'MPA', (121, 131))	('NSCLC', 'Disease', 'MESH:D002289', (163, 168))	('TBX2', 'Gene', (139, 143))	('epigenetic silencing', 'Var', (22, 42))	('suppressed', 'NegReg', (110, 120))	('human', 'Species', '9606', (157, 162))	('NSCLC', 'Phenotype', 'HP:0030358', (163, 168))
499897	30866410	Here we sought to examine the role of epigenetic mediated suppression by hypermethylation of the four members of the TBX2 subfamily in human NSCLC.	('hypermethylation', 'Var', (73, 89))	('SCLC', 'Phenotype', 'HP:0030357', (142, 146))	('NSCLC', 'Disease', (141, 146))	('TBX2', 'Gene', (117, 121))	('human', 'Species', '9606', (135, 140))	('epigenetic mediated', 'Var', (38, 57))	('NSCLC', 'Disease', 'MESH:D002289', (141, 146))	('NSCLC', 'Phenotype', 'HP:0030358', (141, 146))	('suppression', 'NegReg', (58, 69))
499906	30866410	These data suggest that the four members of the TBX2 subfamily, particularly TBX4 and TBX5, are hypermethylated, while having reduced mRNA expression levels, in clinical human NSCLC samples.	('reduced', 'NegReg', (126, 133))	('TBX5', 'Gene', '6910', (86, 90))	('NSCLC', 'Disease', (176, 181))	('mRNA expression levels', 'MPA', (134, 156))	('TBX2', 'Gene', (48, 52))	('TBX4', 'Gene', (77, 81))	('NSCLC', 'Disease', 'MESH:D002289', (176, 181))	('TBX4', 'Gene', '9496', (77, 81))	('human', 'Species', '9606', (170, 175))	('hypermethylated', 'Var', (96, 111))	('SCLC', 'Phenotype', 'HP:0030357', (177, 181))	('NSCLC', 'Phenotype', 'HP:0030358', (176, 181))	('TBX5', 'Gene', (86, 90))
499907	30866410	These findings point to aberrant epigenetic silencing as a potential mechanism for suppressed expression of the TBX genes in human NSCLC.	('TBX', 'Chemical', '-', (112, 115))	('NSCLC', 'Disease', (131, 136))	('aberrant epigenetic silencing', 'Var', (24, 53))	('SCLC', 'Phenotype', 'HP:0030357', (132, 136))	('human', 'Species', '9606', (125, 130))	('NSCLC', 'Disease', 'MESH:D002289', (131, 136))	('TBX genes', 'Gene', (112, 121))	('expression', 'MPA', (94, 104))	('suppressed', 'NegReg', (83, 93))	('NSCLC', 'Phenotype', 'HP:0030358', (131, 136))
499911	30866410	These data suggest that hypermethylation of the TBX2 subfamily may be an early event since it is equally prevalent among early- and advanced-stage NSCLCs.	('hypermethylation', 'Var', (24, 40))	('NSCLC', 'Disease', (147, 152))	('NSCLC', 'Disease', 'MESH:D002289', (147, 152))	('SCLC', 'Phenotype', 'HP:0030357', (148, 152))	('TBX2', 'Gene', (48, 52))	('prevalent', 'Reg', (105, 114))	('NSCLC', 'Phenotype', 'HP:0030358', (147, 152))
499912	30866410	Similarly, there were no statistically significant differences in TBX2 subfamily methylation among NSCLCs by smoking, gender, age nor ethnicity, perhaps suggesting that hypermethylation of these transcription factors may be a prevalent and common feature in NSCLCs (Figure 2 and Figure S3).	('NSCLC', 'Disease', (258, 263))	('SCLC', 'Phenotype', 'HP:0030357', (100, 104))	('NSCLC', 'Disease', 'MESH:D002289', (258, 263))	('hypermethylation', 'Var', (169, 185))	('TBX2', 'Gene', (66, 70))	('NSCLC', 'Phenotype', 'HP:0030358', (99, 104))	('NSCLC', 'Phenotype', 'HP:0030358', (258, 263))	('SCLC', 'Phenotype', 'HP:0030357', (259, 263))	('NSCLC', 'Disease', (99, 104))	('NSCLC', 'Disease', 'MESH:D002289', (99, 104))
499913	30866410	These data raise the possible suggestion that hypermethylation of the TBX2 subfamily occurs early in the pathogenesis of NSCLC and is a common molecular event, and thus a potential marker, in this malignancy.	('NSCLC', 'Disease', (121, 126))	('TBX2', 'Gene', (70, 74))	('NSCLC', 'Disease', 'MESH:D002289', (121, 126))	('hypermethylation', 'Var', (46, 62))	('malignancy', 'Disease', 'MESH:D009369', (197, 207))	('SCLC', 'Phenotype', 'HP:0030357', (122, 126))	('malignancy', 'Disease', (197, 207))	('NSCLC', 'Phenotype', 'HP:0030358', (121, 126))
499922	30866410	We then probed the extent of epigenetic suppression by hypermethylation of the TBX genes in the NSCLC cell lines.	('NSCLC', 'Disease', (96, 101))	('hypermethylation', 'Var', (55, 71))	('epigenetic suppression', 'MPA', (29, 51))	('NSCLC', 'Disease', 'MESH:D002289', (96, 101))	('TBX', 'Chemical', '-', (79, 82))	('TBX', 'Gene', (79, 82))	('SCLC', 'Phenotype', 'HP:0030357', (97, 101))	('NSCLC', 'Phenotype', 'HP:0030358', (96, 101))
499928	30866410	These data suggest that, very synonymous to the clinical data above, hypermethylation of members of the TBX2 subfamily commonly occurs in NSCLC cell lines and is absent in normal alveolar epithelial cells.	('NSCLC', 'Disease', (138, 143))	('hypermethylation', 'Var', (69, 85))	('TBX2', 'Gene', (104, 108))	('NSCLC', 'Disease', 'MESH:D002289', (138, 143))	('SCLC', 'Phenotype', 'HP:0030357', (139, 143))	('NSCLC', 'Phenotype', 'HP:0030358', (138, 143))	('occurs', 'Reg', (128, 134))
499938	30866410	These results lend further evidence to hypermethylation of the TBX2 subfamily, particularly TBX4 and TBX5, in NSCLC cells.	('TBX5', 'Gene', (101, 105))	('NSCLC', 'Disease', (110, 115))	('TBX2', 'Gene', (63, 67))	('SCLC', 'Phenotype', 'HP:0030357', (111, 115))	('TBX4', 'Gene', '9496', (92, 96))	('NSCLC', 'Disease', 'MESH:D002289', (110, 115))	('TBX4', 'Gene', (92, 96))	('hypermethylation', 'Var', (39, 55))	('TBX5', 'Gene', '6910', (101, 105))	('NSCLC', 'Phenotype', 'HP:0030358', (110, 115))
499944	30866410	Drawing from our observations that all four members of the TBX2 subfamily were hypermethylated collectively in NSCLC cells, we surmised that individual knockdown of the TBX genes may not be sufficient to rescue cells from anti-growth effects of Aza.	('knockdown', 'Var', (152, 161))	('Aza', 'Chemical', 'MESH:D001374', (245, 248))	('anti-growth', 'MPA', (222, 233))	('NSCLC', 'Disease', (111, 116))	('TBX2', 'Gene', (59, 63))	('TBX', 'Chemical', '-', (59, 62))	('NSCLC', 'Disease', 'MESH:D002289', (111, 116))	('TBX', 'Chemical', '-', (169, 172))	('TBX', 'Gene', (169, 172))	('hypermethylated', 'Var', (79, 94))	('NSCLC', 'Phenotype', 'HP:0030358', (111, 116))	('SCLC', 'Phenotype', 'HP:0030357', (112, 116))
499945	30866410	Indeed, we found by further qRT-PCR analysis that the other three TBX2 subfamily members following TBX4 or TBX5 knockdown were still markedly induced by Aza treatment (Figure S6).	('TBX5', 'Gene', (107, 111))	('Aza', 'Chemical', 'MESH:D001374', (153, 156))	('TBX2', 'Gene', (66, 70))	('men', 'Species', '9606', (162, 165))	('induced', 'PosReg', (142, 149))	('knockdown', 'Var', (112, 121))	('TBX4', 'Gene', '9496', (99, 103))	('TBX4', 'Gene', (99, 103))	('TBX5', 'Gene', '6910', (107, 111))
499946	30866410	Given these observations, we next sought to assess the effects of simultaneous siRNA-mediated knockdown of all four members of the TBX2 subfamily on control- and Aza-treated cells.	('knockdown', 'Var', (94, 103))	('Aza', 'Chemical', 'MESH:D001374', (162, 165))	('TBX2', 'Gene', (131, 135))
499947	30866410	Combinatorial and simultaneous siRNA-mediated knockdown of the TBX2 subfamily (denoted by "Si Combo") efficaciously abrogated Aza-mediated induction of all four genes when compared with cells transfected with control/scrambled siRNAs (Figure 6A).	('knockdown', 'Var', (46, 55))	('TBX2', 'Gene', (63, 67))	('Aza', 'Chemical', 'MESH:D001374', (126, 129))	('abrogated', 'NegReg', (116, 125))	('Aza-mediated induction', 'MPA', (126, 148))
499948	30866410	Of note, combinatorial knockdown of all four members of the TBX2 subfamily markedly reduced the anti-proliferative (Figure 6B) and anti-growth (Figure 6C) effects of 1 microM Aza.	('anti-growth', 'CPA', (131, 142))	('knockdown', 'Var', (23, 32))	('Aza', 'Chemical', 'MESH:D001374', (175, 178))	('reduced', 'NegReg', (84, 91))	('TBX2', 'Gene', (60, 64))
499950	30866410	In this study, we interrogated the role of epigenetic silencing in suppressed expression of the TBX2 subfamily of transcription factors in NSCLC.	('NSCLC', 'Phenotype', 'HP:0030358', (139, 144))	('expression', 'MPA', (78, 88))	('TBX2', 'Gene', (96, 100))	('NSCLC', 'Disease', (139, 144))	('NSCLC', 'Disease', 'MESH:D002289', (139, 144))	('suppressed', 'NegReg', (67, 77))	('SCLC', 'Phenotype', 'HP:0030357', (140, 144))	('epigenetic silencing', 'Var', (43, 63))
499951	30866410	By in silico analysis of a cohort of NSCLCs and normal lung tissues, we first found that all four members of the TBX2 subfamily were, overall, hypermethylated, at both promoter regions and CpG islands, in clinical NSCLC samples compared to normal lung.	('NSCLC', 'Phenotype', 'HP:0030358', (37, 42))	('NSCLC', 'Phenotype', 'HP:0030358', (214, 219))	('SCLC', 'Phenotype', 'HP:0030357', (215, 219))	('hypermethylated', 'Var', (143, 158))	('NSCLC', 'Disease', (37, 42))	('NSCLC', 'Disease', (214, 219))	('NSCLC', 'Disease', 'MESH:D002289', (37, 42))	('TBX2', 'Gene', (113, 117))	('NSCLC', 'Disease', 'MESH:D002289', (214, 219))	('SCLC', 'Phenotype', 'HP:0030357', (38, 42))
499955	30866410	Lastly, we showed that simultaneous RNA-interference mediated knockdown of all four members of the TBX2 subfamily members markedly attenuated the anti-growth effects of Aza.	('Aza', 'Chemical', 'MESH:D001374', (169, 172))	('TBX2', 'Gene', (99, 103))	('RNA-interference', 'MPA', (36, 52))	('attenuated', 'NegReg', (131, 141))	('anti-growth effects', 'MPA', (146, 165))	('knockdown', 'Var', (62, 71))
499956	30866410	Our study provides new insights on therapeutically pliable and aberrant epigenetic mechanisms in the molecular pathogenesis of NSCLC involving prevalent hypermethylation of the TBX2 subfamily of evolutionarily conserved transcription factors.	('NSCLC', 'Disease', (127, 132))	('NSCLC', 'Disease', 'MESH:D002289', (127, 132))	('SCLC', 'Phenotype', 'HP:0030357', (128, 132))	('hypermethylation', 'Var', (153, 169))	('NSCLC', 'Phenotype', 'HP:0030358', (127, 132))	('TBX2', 'Gene', (177, 181))
499959	30866410	It is thus plausible that hypermethylation of the TBX2 subfamily occurs early on in the progression of NSCLC.	('SCLC', 'Phenotype', 'HP:0030357', (104, 108))	('NSCLC', 'Disease', (103, 108))	('NSCLC', 'Disease', 'MESH:D002289', (103, 108))	('hypermethylation', 'Var', (26, 42))	('TBX2', 'Gene', (50, 54))	('NSCLC', 'Phenotype', 'HP:0030358', (103, 108))
499961	30866410	It is not clear whether the epigenetic suppression of TBXs is conserved and found in mouse tumors, given that TBX2 subfamily members play crucial roles in development and organogenesis in mice.	('tumors', 'Disease', (91, 97))	('tumors', 'Disease', 'MESH:D009369', (91, 97))	('mice', 'Species', '10090', (188, 192))	('mouse', 'Species', '10090', (85, 90))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('TBXs', 'Chemical', '-', (54, 58))	('men', 'Species', '9606', (162, 165))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('epigenetic', 'Var', (28, 38))
499964	30866410	Nonetheless, given the pragmatic application of DNA methylation profiles as non-invasive biomarkers, our observations on the prevalence of TBX2 subfamily hypermethylation in NSCLC suggest that methylation of these genes may serve as a high-potential biomarker for early detection and/or diagnosis of lung cancer.	('methylation', 'Var', (193, 204))	('SCLC', 'Phenotype', 'HP:0030357', (175, 179))	('NSCLC', 'Disease', 'MESH:D002289', (174, 179))	('lung cancer', 'Disease', (300, 311))	('NSCLC', 'Phenotype', 'HP:0030358', (174, 179))	('TBX2', 'Gene', (139, 143))	('lung cancer', 'Phenotype', 'HP:0100526', (300, 311))	('cancer', 'Phenotype', 'HP:0002664', (305, 311))	('lung cancer', 'Disease', 'MESH:D008175', (300, 311))	('hypermethylation', 'Var', (154, 170))	('NSCLC', 'Disease', (174, 179))
499965	30866410	Using methylation-specific PCR analysis we showed that different members of the TBX2 subfamily were, overall, hypermethylated in all NSCLC cell lines examined relative to normal alveolar cells.	('NSCLC', 'Phenotype', 'HP:0030358', (133, 138))	('TBX2', 'Gene', (80, 84))	('NSCLC', 'Disease', (133, 138))	('NSCLC', 'Disease', 'MESH:D002289', (133, 138))	('SCLC', 'Phenotype', 'HP:0030357', (134, 138))	('hypermethylated', 'Var', (110, 125))
499967	30866410	Our study showing hypermethylation of members of the TBX2 subfamily is in line with previous studies underscoring specifically TBX5 methylation in lung tumors and sheds more light on the epigenome of NSCLC.	('NSCLC', 'Phenotype', 'HP:0030358', (200, 205))	('lung tumors', 'Disease', 'MESH:D008175', (147, 158))	('lung tumor', 'Phenotype', 'HP:0100526', (147, 157))	('hypermethylation', 'Var', (18, 34))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('SCLC', 'Phenotype', 'HP:0030357', (201, 205))	('TBX5', 'Gene', '6910', (127, 131))	('NSCLC', 'Disease', (200, 205))	('TBX5', 'Gene', (127, 131))	('lung tumors', 'Phenotype', 'HP:0100526', (147, 158))	('lung tumors', 'Disease', (147, 158))	('NSCLC', 'Disease', 'MESH:D002289', (200, 205))	('tumors', 'Phenotype', 'HP:0002664', (152, 158))	('methylation', 'Var', (132, 143))
499968	30866410	It is not clear whether hypermethylation of the TBX2 subfamily is specific to NSCLC or may be common to several tumor types.	('hypermethylation', 'Var', (24, 40))	('SCLC', 'Phenotype', 'HP:0030357', (79, 83))	('NSCLC', 'Phenotype', 'HP:0030358', (78, 83))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('TBX2', 'Gene', (48, 52))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('NSCLC', 'Disease', (78, 83))	('tumor', 'Disease', (112, 117))	('NSCLC', 'Disease', 'MESH:D002289', (78, 83))
499970	30866410	For instance, methylation of TBX2 and TBX3 were shown to be associated with prognosis and predict progression in bladder cancer.	('prognosis', 'CPA', (76, 85))	('bladder cancer', 'Phenotype', 'HP:0009725', (113, 127))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('bladder cancer', 'Disease', 'MESH:D001749', (113, 127))	('TBX3', 'Gene', '6926', (38, 42))	('methylation', 'Var', (14, 25))	('TBX3', 'Gene', (38, 42))	('bladder cancer', 'Disease', (113, 127))	('TBX2', 'Gene', (29, 33))	('associated with', 'Reg', (60, 75))
499971	30866410	TBX5 was also shown to be epigenetically inactivated by promoter methylation in colon cancer.	('epigenetically', 'Var', (26, 40))	('colon cancer', 'Disease', (80, 92))	('promoter methylation', 'Var', (56, 76))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('TBX5', 'Gene', '6910', (0, 4))	('TBX5', 'Gene', (0, 4))	('colon cancer', 'Phenotype', 'HP:0003003', (80, 92))	('colon cancer', 'Disease', 'MESH:D015179', (80, 92))
499972	30866410	It is important to mention that other mechanisms may account for epigenetic suppression of the TBX2 subfamily and underlie their reduced RNA expression levels (e.g., histone modifications).	('epigenetic', 'Var', (65, 75))	('TBX2', 'Gene', (95, 99))	('histone modifications', 'MPA', (166, 187))	('men', 'Species', '9606', (19, 22))	('reduced', 'NegReg', (129, 136))	('RNA expression levels', 'MPA', (137, 158))
499974	30866410	These observations lend further support to the supposition that the TBX2 subfamily is epigenetically suppressed by hypermethylation in NSCLC.	('suppressed', 'NegReg', (101, 111))	('hypermethylation', 'Var', (115, 131))	('NSCLC', 'Disease', (135, 140))	('NSCLC', 'Disease', 'MESH:D002289', (135, 140))	('SCLC', 'Phenotype', 'HP:0030357', (136, 140))	('TBX2', 'Gene', (68, 72))	('NSCLC', 'Phenotype', 'HP:0030358', (135, 140))
499976	30866410	We found that simultaneous knockdown by RNA interference of all four members of the TBX2 subfamily markedly decreased anti-growth effects of Aza treatment when compared with cells treated with the agent but transfected with scrambled siRNAs.	('knockdown', 'Var', (27, 36))	('RNA interference', 'MPA', (40, 56))	('anti-growth effects of Aza treatment', 'MPA', (118, 154))	('decreased', 'NegReg', (108, 117))	('men', 'Species', '9606', (150, 153))	('Aza', 'Chemical', 'MESH:D001374', (141, 144))	('TBX2', 'Gene', (84, 88))
499978	30866410	It is also conceivable that methylation status of the TBX2 subfamily may serve as a predictive marker for response of NSCLCs or other cancer types to the anti-tumor drug Aza.	('Aza', 'Chemical', 'MESH:D001374', (170, 173))	('NSCLC', 'Phenotype', 'HP:0030358', (118, 123))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('tumor', 'Disease', (159, 164))	('NSCLC', 'Disease', (118, 123))	('NSCLC', 'Disease', 'MESH:D002289', (118, 123))	('methylation', 'Var', (28, 39))	('SCLC', 'Phenotype', 'HP:0030357', (119, 123))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('TBX2', 'Gene', (54, 58))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
499986	30866410	Further, a genome-wide DNA methylation profiling study revealed that TBX5 methylation is a putative marker for LUSC.	('methylation', 'Var', (74, 85))	('LUSC', 'Disease', (111, 115))	('TBX5', 'Gene', '6910', (69, 73))	('TBX5', 'Gene', (69, 73))
499988	30866410	Further studies are warranted to fully scrutinize the impact of TBX4 and TBX5 epigenetic inactivation in early phases of NSCLC.	('NSCLC', 'Disease', (121, 126))	('TBX4', 'Gene', '9496', (64, 68))	('NSCLC', 'Disease', 'MESH:D002289', (121, 126))	('TBX4', 'Gene', (64, 68))	('TBX5', 'Gene', (73, 77))	('NSCLC', 'Phenotype', 'HP:0030358', (121, 126))	('SCLC', 'Phenotype', 'HP:0030357', (122, 126))	('TBX5', 'Gene', '6910', (73, 77))	('epigenetic inactivation', 'Var', (78, 101))
499997	30866410	Supporting this argument is our observation that simultaneous knockdown of all four members of the TBX2 subfamily, but not of individual TBXs, attenuated the anti-growth effects of the DNA methyltransferase and cancer drug 5-azacytidine.	('attenuated', 'NegReg', (143, 153))	('anti-growth effects', 'MPA', (158, 177))	('TBX2', 'Gene', (99, 103))	('cancer', 'Disease', 'MESH:D009369', (211, 217))	('5-azacytidine', 'Chemical', 'MESH:D001374', (223, 236))	('cancer', 'Disease', (211, 217))	('TBXs', 'Chemical', '-', (137, 141))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('men', 'Species', '9606', (20, 23))	('knockdown', 'Var', (62, 71))
500003	30866410	Thus, given the biology of these genes, it cannot be neglected that individual knockdown of one TBX gene, for instance in Aza-treated cells, could thus affect levels of expression of its linked and/or its cognate gene.	('levels of expression', 'MPA', (159, 179))	('TBX gene', 'Gene', (96, 104))	('TBX', 'Chemical', '-', (96, 99))	('affect', 'Reg', (152, 158))	('Aza', 'Chemical', 'MESH:D001374', (122, 125))	('knockdown', 'Var', (79, 88))
500004	30866410	This supposition may explain the effect of siRNA-mediated knockdown of either TBX4 or TBX5 in Aza-treated cells on the expression of the other three members (Figure S6).	('TBX5', 'Gene', '6910', (86, 90))	('expression', 'MPA', (119, 129))	('TBX4', 'Gene', '9496', (78, 82))	('TBX4', 'Gene', (78, 82))	('Aza', 'Chemical', 'MESH:D001374', (94, 97))	('knockdown', 'Var', (58, 67))	('TBX5', 'Gene', (86, 90))
500012	30866410	Human NSCLC cell lines used in this study included: H1299, H1693, H1792, H23, H460, H1650, HCC827 and H3255, originally obtained from the ATCC.	('Human', 'Species', '9606', (0, 5))	('NSCLC', 'Disease', 'MESH:D002289', (6, 11))	('H1792', 'CellLine', 'CVCL:1495', (66, 71))	('H460', 'CellLine', 'CVCL:0459', (78, 82))	('SCLC', 'Phenotype', 'HP:0030357', (7, 11))	('H3255', 'Var', (102, 107))	('NSCLC', 'Phenotype', 'HP:0030358', (6, 11))	('H1693', 'CellLine', 'CVCL:1488', (59, 64))	('H1299', 'Var', (52, 57))	('H1650', 'Var', (84, 89))	('NSCLC', 'Disease', (6, 11))	('H1299', 'CellLine', 'CVCL:0060', (52, 57))	('HCC827', 'CellLine', 'CVCL:2063', (91, 97))
500038	30866410	In conclusion, we demonstrated that the TBX2 subfamily of evolutionarily conserved transcription factors, particularly TBX4 and TBX5, are epigenetically suppressed by hypermethylation in human NSCLC.	('suppressed', 'NegReg', (153, 163))	('NSCLC', 'Phenotype', 'HP:0030358', (193, 198))	('TBX4', 'Gene', (119, 123))	('TBX2 subfamily', 'Gene', (40, 54))	('TBX4', 'Gene', '9496', (119, 123))	('human', 'Species', '9606', (187, 192))	('SCLC', 'Phenotype', 'HP:0030357', (194, 198))	('NSCLC', 'Disease', (193, 198))	('TBX5', 'Gene', '6910', (128, 132))	('hypermethylation', 'Var', (167, 183))	('NSCLC', 'Disease', 'MESH:D002289', (193, 198))	('TBX5', 'Gene', (128, 132))
500039	30866410	We also showed that TBX2 subfamily hypermethylation is a common attribute in NSCLC tumors and cell lines.	('hypermethylation', 'Var', (35, 51))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('TBX2', 'Gene', (20, 24))	('NSCLC', 'Phenotype', 'HP:0030358', (77, 82))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('NSCLC tumors', 'Disease', 'MESH:D009369', (77, 89))	('NSCLC tumors', 'Disease', (77, 89))	('SCLC', 'Phenotype', 'HP:0030357', (78, 82))
500040	30866410	We also found that members of the subfamily, particularly TBX4 and TBX5, are commonly suppressed and hypermethylated in human NSCLC cell lines.	('TBX4', 'Gene', '9496', (58, 62))	('human', 'Species', '9606', (120, 125))	('hypermethylated', 'Var', (101, 116))	('NSCLC', 'Disease', 'MESH:D002289', (126, 131))	('TBX5', 'Gene', '6910', (67, 71))	('TBX5', 'Gene', (67, 71))	('NSCLC', 'Phenotype', 'HP:0030358', (126, 131))	('suppressed', 'NegReg', (86, 96))	('SCLC', 'Phenotype', 'HP:0030357', (127, 131))	('NSCLC', 'Disease', (126, 131))	('TBX4', 'Gene', (58, 62))
500043	30866410	Our findings provide new insights into the molecular (epigenetic) pathogenesis of NSCLC and suggest that TBX2 subfamily methylation may serve as a potential biomarker for early detection and intervention of this morbid disease.	('NSCLC', 'Phenotype', 'HP:0030358', (82, 87))	('SCLC', 'Phenotype', 'HP:0030357', (83, 87))	('methylation', 'Var', (120, 131))	('NSCLC', 'Disease', (82, 87))	('TBX2', 'Gene', (105, 109))	('NSCLC', 'Disease', 'MESH:D002289', (82, 87))
500062	26273374	Present treatment methods include: antifolate chemotherapy drug Pemetrexed, which is only effective for treating lung adenocarcinoma (ADC); Bevacizumab, which should be avoided in lung squamous cell carcinoma (SQCC); epidermal growth factor receptor-tyrosine-kinase inhibitor (EGFR-TKI) therapy, which is only effective in treating lung ADC with EGFR gene mutations; and Crizotinib, which is only effective in treating patients with anaplastic lymphoma kinase (ALK) gene rearrangement.	('EGFR', 'Gene', (346, 350))	('anaplastic lymphoma kinase', 'Gene', '238', (433, 459))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (185, 208))	('SQCC', 'Phenotype', 'HP:0002860', (210, 214))	('ADC', 'Gene', (337, 340))	('anaplastic lymphoma kinase', 'Gene', (433, 459))	('EGFR', 'Gene', '1956', (277, 281))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (433, 452))	('patients', 'Species', '9606', (419, 427))	('carcinoma', 'Phenotype', 'HP:0030731', (199, 208))	('lung adenocarcinoma', 'Disease', (113, 132))	('EGFR', 'Gene', '1956', (346, 350))	('mutations', 'Var', (356, 365))	('ADC', 'Gene', '113451', (134, 137))	('epidermal growth factor receptor', 'Gene', (217, 249))	('lymphoma', 'Phenotype', 'HP:0002665', (444, 452))	('epidermal growth factor receptor', 'Gene', '1956', (217, 249))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (180, 208))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (113, 132))	('EGFR', 'Gene', (277, 281))	('men', 'Species', '9606', (13, 16))	('ADC', 'Gene', (134, 137))	('ALK', 'Gene', '238', (461, 464))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (113, 132))	('ADC', 'Gene', '113451', (337, 340))	('men', 'Species', '9606', (480, 483))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (180, 208))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('ALK', 'Gene', (461, 464))	('lung squamous cell carcinoma', 'Disease', (180, 208))
500110	26273374	Patients with high co-expression levels had better survival rates than those with low co-expression levels, and the difference was statistically significant (P = 0.002) (Fig 2d).	('Patients', 'Species', '9606', (0, 8))	('better', 'PosReg', (44, 50))	('survival rates', 'CPA', (51, 65))	('high co-expression levels', 'Var', (14, 39))
500120	26273374	TAp63 has a transactivation domain (TA) similar to that of p53, which regulates the expression of growth-suppressing genes; the DeltaNp63 isoform has an inactive DeltaN domain resulting from alternative splicing, which antagonizes the activity of TAp63 and p53.	('p63', 'Gene', (134, 137))	('p53', 'Gene', (59, 62))	('p63', 'Gene', '8626', (2, 5))	('alternative splicing', 'Var', (191, 211))	('p63', 'Gene', '8626', (249, 252))	('p53', 'Gene', '7157', (59, 62))	('p53', 'Gene', '7157', (257, 260))	('p63', 'Gene', '8626', (134, 137))	('p63', 'Gene', (2, 5))	('p53', 'Gene', (257, 260))	('p63', 'Gene', (249, 252))
500137	26273374	In addition, univariate analysis showed that patients with high levels of CK5/6 expression had better survival rates than those with low expression.	('high levels', 'Var', (59, 70))	('CK5/6', 'Gene', '3852', (74, 79))	('CK5/6', 'Gene', (74, 79))	('patients', 'Species', '9606', (45, 53))	('survival rates', 'CPA', (102, 116))	('better', 'PosReg', (95, 101))
500148	33276569	Pre-invasive lesions of adenocarcinoma (LUAD) and of squamous cell carcinoma (LUSC) can show impaired antigen presentation, loss of heterozygosity at the Human Leukocyte Antigen (HLA) region, neoantigen silencing, activation of immune checkpoints, altered TH1/TH2 cytokine ratios, and immune contexture evolution.	('impaired', 'NegReg', (93, 101))	('altered', 'Reg', (248, 255))	('LUAD', 'Phenotype', 'HP:0030078', (40, 44))	('adenocarcinoma', 'Disease', 'MESH:D000230', (24, 38))	('silencing', 'NegReg', (203, 212))	('TH1', 'Gene', '51497', (256, 259))	('loss', 'Var', (124, 128))	('neoantigen', 'MPA', (192, 202))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (53, 76))	('LUSC', 'Phenotype', 'HP:0030359', (78, 82))	('antigen presentation', 'MPA', (102, 122))	('activation', 'PosReg', (214, 224))	('carcinoma', 'Phenotype', 'HP:0030731', (29, 38))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (53, 76))	('Human', 'Species', '9606', (154, 159))	('adenocarcinoma', 'Disease', (24, 38))	('TH1', 'Gene', (256, 259))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('squamous cell carcinoma', 'Disease', (53, 76))
500156	33276569	Immunoediting in tumors with high tumor mutational burden (TMB) leads to the selection of neoplastic cells characterized by subclonal loss of heterozygosity at the HLA loci (HLA LOH) and to copy number loss or epigenetic silencing of genes containing neoantigenic mutations.	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('tumor', 'Disease', (17, 22))	('epigenetic silencing', 'Var', (210, 230))	('tumor', 'Disease', (34, 39))	('tumors', 'Disease', (17, 23))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('TMB', 'Chemical', '-', (59, 62))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('loss of', 'NegReg', (134, 141))	('loss', 'NegReg', (202, 206))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('copy number', 'Var', (190, 201))
500161	33276569	Some NSCLC molecular subsets show specific mechanisms that may promote resistance to immunotherapy due to the function of the genetic alterations that they harbor.	('resistance to immunotherapy', 'CPA', (71, 98))	('NSCLC', 'Disease', (5, 10))	('promote', 'PosReg', (63, 70))	('genetic alterations', 'Var', (126, 145))	('NSCLC', 'Disease', 'MESH:D002289', (5, 10))
500162	33276569	These include mutations of EGFR, fostering an uninflamed microenvironment, and of STK11/LKB1, associated with STING silencing and therefore with suppression of the intracellular DNA sensing pathway leading to type I IFN production.	('STK11', 'Gene', (82, 87))	('EGFR', 'Gene', '1956', (27, 31))	('EGFR', 'Gene', (27, 31))	('type I IFN production', 'MPA', (209, 230))	('suppression', 'NegReg', (145, 156))	('STK11', 'Gene', '6794', (82, 87))	('STING', 'Gene', '340061', (110, 115))	('fostering', 'Reg', (33, 42))	('intracellular DNA sensing pathway', 'Pathway', (164, 197))	('STING', 'Gene', (110, 115))	('associated', 'Reg', (94, 104))	('uninflamed microenvironment', 'MPA', (46, 73))	('mutations', 'Var', (14, 23))
500169	33276569	Total mutational burden, reflecting the accumulation of single nucleotide variants (SNVs), progressively increases from AAH to AIS and further to MIA and LUAD.	('LUAD', 'Phenotype', 'HP:0030078', (154, 158))	('single nucleotide variants', 'Var', (56, 82))	('AAH', 'Chemical', '-', (120, 123))	('mutational burden', 'MPA', (6, 23))	('increases', 'PosReg', (105, 114))
500171	33276569	Analysis of multifocal lesions at different stages showed higher TMB and higher proportion of clonal mutations in lesions at more advanced stages.	('TMB', 'MPA', (65, 68))	('clonal', 'Var', (94, 100))	('TMB', 'Chemical', '-', (65, 68))	('higher', 'PosReg', (58, 64))
500226	33276569	Collectively, these results indicated that the tumor microenvironment of early LUAD shows profound alterations of several immune compartments, including enrichment for PPARgammahiCD64hiCD14hiIL-6hi macrophages, CD1c+ DC, Tregs, and exhausted T cells and depletion of CD141+ DCs, CD16+ monocytes, NK cells, and granzyme B+ effector cells.	('Tregs', 'Chemical', '-', (221, 226))	('CD141', 'Gene', (267, 272))	('CD141', 'Gene', '7056', (267, 272))	('granzyme B', 'Gene', '3002', (310, 320))	('LUAD', 'Phenotype', 'HP:0030078', (79, 83))	('PPARgammahiCD64hiCD14hiIL-6hi', 'Var', (168, 197))	('granzyme B', 'Gene', (310, 320))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('Tregs', 'CPA', (221, 226))	('alterations', 'Reg', (99, 110))	('CD16', 'Gene', '2214', (279, 283))	('CD1c', 'Gene', '911', (211, 215))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('CD1c', 'Gene', (211, 215))	('tumor', 'Disease', (47, 52))	('CD16', 'Gene', (279, 283))
500235	33276569	Analysis of different NSCLC cohorts indicated a very low frequency of mutations predicted to disrupt antigen presentation or the MHC class I complex (5-8% of the tumors).	('disrupt', 'Reg', (93, 100))	('mutations', 'Var', (70, 79))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('NSCLC', 'Disease', (22, 27))	('tumors', 'Disease', (162, 168))	('tumors', 'Disease', 'MESH:D009369', (162, 168))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))	('antigen presentation', 'MPA', (101, 121))	('NSCLC', 'Disease', 'MESH:D002289', (22, 27))
500236	33276569	However, a computational tool (named "loss of heterozygosity in human leukocyte antigen", LOHHLA) allowed for the determination of HLA allele-specific copy number from sequencing data, indicated HLA LOH in 36/90 (40%) of NSCLCs, where either the maternal or paternal allele was lost, resulting in HLA homozygosity.	('human', 'Species', '9606', (64, 69))	('LOH', 'Var', (199, 202))	('NSCLCs', 'Disease', (221, 227))	('HLA', 'Gene', (195, 198))	('HLA', 'MPA', (297, 300))	('NSCLCs', 'Disease', 'MESH:D002289', (221, 227))
500238	33276569	No tumors exhibited homozygous deletion of HLA, in agreement with the hypothesis that maintaining one copy of HLA genes may avoid NK-mediated elimination.	('tumors', 'Phenotype', 'HP:0002664', (3, 9))	('avoid', 'NegReg', (124, 129))	('tumors', 'Disease', (3, 9))	('tumors', 'Disease', 'MESH:D009369', (3, 9))	('HLA', 'Gene', (43, 46))	('deletion', 'Var', (31, 39))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))
500239	33276569	In tumors with HLA LOH, there was a significant increase in the number of subclonal non-synonymous mutations (i.e., expressed only in a fraction of neoplastic cells), but not in the number of clonal mutations.	('tumors', 'Phenotype', 'HP:0002664', (3, 9))	('subclonal', 'Var', (74, 83))	('tumors', 'Disease', (3, 9))	('tumors', 'Disease', 'MESH:D009369', (3, 9))	('HLA', 'Var', (15, 18))	('non-synonymous mutations', 'Var', (84, 108))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))	('increase', 'PosReg', (48, 56))
500242	33276569	In agreement, the cytolytic activity score (level of expression of GZMA and PRF1), CD8+ and NK infiltrate were increased in tumors with HLA LOH.	('HLA', 'Var', (136, 139))	('increased', 'PosReg', (111, 120))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('GZMA', 'Gene', (67, 71))	('tumors', 'Disease', (124, 130))	('tumors', 'Disease', 'MESH:D009369', (124, 130))	('CD8', 'Gene', (83, 86))	('cytolytic activity score', 'MPA', (18, 42))	('NK infiltrate', 'MPA', (92, 105))	('GZMA', 'Gene', '3001', (67, 71))	('PRF1', 'Gene', (76, 80))	('CD8', 'Gene', '925', (83, 86))	('PRF1', 'Gene', '5551', (76, 80))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))
500277	33276569	showed that epigenetic silencing of genes harboring mutations that generate neoantigens is a mechanism of immune escape in NSCLC.	('mutations', 'Var', (52, 61))	('epigenetic silencing', 'Var', (12, 32))	('NSCLC', 'Disease', 'MESH:D002289', (123, 128))	('NSCLC', 'Disease', (123, 128))
500278	33276569	investigated the fraction of tumor cells harboring a mutation that leads to the generation of a putative neoantigen.	('mutation', 'Var', (53, 61))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumor', 'Disease', (29, 34))	('generation of a', 'MPA', (80, 95))	('leads to', 'Reg', (67, 75))	('neoantigen', 'MPA', (105, 115))
500282	33276569	Almost every tumor with a low neoantigen subclonal fraction (<5% subclonal) and high mutation burden (>=70, median clonal neoantigens of the cohort) demonstrated durable clinical benefit with anti-PD-1 therapy.	('tumor', 'Disease', (13, 18))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('anti-PD-1', 'Var', (192, 201))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
500286	33276569	Neoantigen loss occurred through the elimination of tumor subclones (i.e., by immunoediting of the tumor) or through deletion of chromosomal regions and LOH.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumor', 'Disease', (99, 104))	('loss', 'NegReg', (11, 15))	('chromosomal regions', 'Protein', (129, 148))	('tumor', 'Disease', (52, 57))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('Neoantigen', 'MPA', (0, 10))	('deletion', 'Var', (117, 125))
500288	33276569	LUAD with KRAS and p53 mutations shows a hot, T cell-infiltrated tumor microenvironment, higher TMB, and the expression of several molecules belonging to the immune checkpoint class.	('KRAS', 'Gene', '3845', (10, 14))	('TMB', 'Chemical', '-', (96, 99))	('tumor', 'Disease', (65, 70))	('LUAD', 'Phenotype', 'HP:0030078', (0, 4))	('mutations', 'Var', (23, 32))	('p53', 'Gene', (19, 22))	('p53', 'Gene', '7157', (19, 22))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('KRAS', 'Gene', (10, 14))
500289	33276569	In contrast, when KRAS mutations are associated with STK11/LKB1 deficiency, the tumor landscape is cold and associated with reduced PD-L1 expression.	('KRAS', 'Gene', (18, 22))	('reduced', 'NegReg', (124, 131))	('LKB1 deficiency, the tumor', 'Disease', 'MESH:D009369', (59, 85))	('STK11', 'Gene', '6794', (53, 58))	('KRAS', 'Gene', '3845', (18, 22))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('PD-L1', 'Protein', (132, 137))	('mutations', 'Var', (23, 32))	('expression', 'MPA', (138, 148))	('associated', 'Reg', (37, 47))	('reduced PD', 'Phenotype', 'HP:0032198', (124, 134))	('STK11', 'Gene', (53, 58))
500290	33276569	Co-mutations of KRAS and CDKN2A/B show a mixed immune profile.	('CDKN2A/B', 'Gene', (25, 33))	('Co-mutations', 'Var', (0, 12))	('KRAS', 'Gene', (16, 20))	('KRAS', 'Gene', '3845', (16, 20))	('CDKN2A/B', 'Gene', '1029;1030', (25, 33))
500292	33276569	Pathway enrichment identified neutrophil degranulation to be the signature most strongly associated with STK11 mutation, although neutrophils did not appear to be either specifically enriched or depleted in STK11 mutant tumors.	('STK11', 'Gene', (207, 212))	('associated', 'Reg', (89, 99))	('STK11', 'Gene', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('tumors', 'Phenotype', 'HP:0002664', (220, 226))	('STK11', 'Gene', '6794', (207, 212))	('STK11', 'Gene', '6794', (105, 110))	('tumors', 'Disease', (220, 226))	('tumors', 'Disease', 'MESH:D009369', (220, 226))	('mutation', 'Var', (111, 119))	('neutrophil degranulation', 'MPA', (30, 54))
500294	33276569	has shown that LKB1 inactivation is associated with neutrophil accumulation in the immune microenvironment and with overproduction of tumor-promoting cytokines.	('neutrophil', 'CPA', (52, 62))	('inactivation', 'Var', (20, 32))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('LKB1', 'Gene', (15, 19))	('associated', 'Reg', (36, 46))	('overproduction', 'PosReg', (116, 130))	('tumor', 'Disease', (134, 139))
500299	33276569	Therefore, LKB1 deficiency generates a powerful immune escape mechanism that blocks the generation of tumor immunity in the very early stages of the process.	('blocks', 'NegReg', (77, 83))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('LKB1', 'Gene', (11, 15))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('deficiency', 'Var', (16, 26))
500305	33276569	These results indicate that among LKB1 mutant tumors there is a range of immune profiles determined by distinct co-mutations (i.e., KRAS vs. p53).	('LKB1', 'Gene', (34, 38))	('p53', 'Gene', (141, 144))	('KRAS', 'Gene', (132, 136))	('p53', 'Gene', '7157', (141, 144))	('determined', 'Reg', (89, 99))	('immune profiles', 'MPA', (73, 88))	('KRAS', 'Gene', '3845', (132, 136))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('mutant', 'Var', (39, 45))	('tumors', 'Disease', (46, 52))	('tumors', 'Disease', 'MESH:D009369', (46, 52))
500306	33276569	The association of LKB1 deficiency with poor response to PD-1 blockade has been shown in 174 patients with KRAS mutant LUAD of the Stand Up To Cancer cohort (SU2C).	('KRAS', 'Gene', (107, 111))	('deficiency', 'Var', (24, 34))	('Cancer', 'Disease', (143, 149))	('KRAS', 'Gene', '3845', (107, 111))	('Cancer', 'Disease', 'MESH:D009369', (143, 149))	('Cancer', 'Phenotype', 'HP:0002664', (143, 149))	('LUAD', 'Phenotype', 'HP:0030078', (119, 123))	('LKB1', 'Gene', (19, 23))	('patients', 'Species', '9606', (93, 101))
500307	33276569	Objective response rates (ORRs) to PD-1 blockade were 7.4% in KRAS/LKB1 mutant tumors, 35.7% in KRAS/p53 mutant, and 28.6% in KRAS only tumors.	('tumors', 'Disease', (136, 142))	('KRAS', 'Gene', '3845', (126, 130))	('KRAS', 'Gene', (62, 66))	('tumors', 'Disease', 'MESH:D009369', (136, 142))	('KRAS', 'Gene', '3845', (96, 100))	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('KRAS', 'Gene', '3845', (62, 66))	('mutant', 'Var', (72, 78))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('p53', 'Gene', (101, 104))	('p53', 'Gene', '7157', (101, 104))	('tumors', 'Disease', (79, 85))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('KRAS', 'Gene', (126, 130))	('KRAS', 'Gene', (96, 100))
500309	33276569	In addition, in the SU2C cohort, KRAS/LKB1 mutant patients had shorter PFS and overall survival (OS) compared to KRASMUT/STK11/LKB1WT tumors.	('PFS', 'CPA', (71, 74))	('tumors', 'Disease', (134, 140))	('tumors', 'Disease', 'MESH:D009369', (134, 140))	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('SM', 'Chemical', '-', (116, 118))	('patients', 'Species', '9606', (50, 58))	('KRAS', 'Gene', (33, 37))	('shorter', 'NegReg', (63, 70))	('SM', 'Phenotype', 'HP:0002860', (116, 118))	('KRAS', 'Gene', '3845', (33, 37))	('KRAS', 'Gene', (113, 117))	('mutant', 'Var', (43, 49))	('STK11', 'Gene', (121, 126))	('KRAS', 'Gene', '3845', (113, 117))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('overall', 'CPA', (79, 86))	('STK11', 'Gene', '6794', (121, 126))
500311	33276569	This subset had WES data allowing for the identification of those with STK11 mutations (n = 33, 7.69%) and, interestingly, patients with or without STK11 mutations showed similar ORRs, PFS, and OS.	('STK11', 'Gene', (71, 76))	('STK11', 'Gene', '6794', (71, 76))	('patients', 'Species', '9606', (123, 131))	('STK11', 'Gene', (148, 153))	('mutations', 'Var', (77, 86))	('STK11', 'Gene', '6794', (148, 153))
500312	33276569	In addition, pembrolizumab resulted in improved outcomes compared to chemotherapy, regardless of STK11 mutation.	('STK11', 'Gene', '6794', (97, 102))	('outcomes', 'MPA', (48, 56))	('STK11', 'Gene', (97, 102))	('mutation', 'Var', (103, 111))	('improved', 'PosReg', (39, 47))	('pembrolizumab', 'Chemical', 'MESH:C582435', (13, 26))
500314	33276569	have assessed the impact of STK11 mutations in the Flatiron Health Clinico-Genomic Database (CGDB), a real-world data cohort including 2276 patients.	('STK11', 'Gene', (28, 33))	('mutations', 'Var', (34, 43))	('STK11', 'Gene', '6794', (28, 33))	('patients', 'Species', '9606', (140, 148))
500315	33276569	These authors found that STK11 mutations are prognostic rather than predictive and are associated with poor prognosis regardless of treatment.	('STK11', 'Gene', '6794', (25, 30))	('STK11', 'Gene', (25, 30))	('mutations', 'Var', (31, 40))
500317	33276569	Taken together, these studies suggest that the LKB1 deficiency is not necessarily associated with PD-1 resistance, in agreement with the evidence that such a mutation can be found even in tumors that do not have a STINGlow/immune "cold" profile.	('STING', 'Gene', '340061', (214, 219))	('associated', 'Reg', (82, 92))	('tumors', 'Disease', (188, 194))	('tumors', 'Disease', 'MESH:D009369', (188, 194))	('tumors', 'Phenotype', 'HP:0002664', (188, 194))	('deficiency', 'Var', (52, 62))	('STING', 'Gene', (214, 219))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('LKB1', 'Gene', (47, 51))
500318	33276569	An association between a specific molecular trait of the tumor and immune-cold microenvironment, that predisposes to resistance to immunotherapy, exists in EGFR mutant tumors (Table 1).	('mutant', 'Var', (161, 167))	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('tumor', 'Disease', (168, 173))	('EGFR', 'Gene', '1956', (156, 160))	('tumors', 'Disease', (168, 174))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumors', 'Disease', 'MESH:D009369', (168, 174))	('EGFR', 'Gene', (156, 160))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('tumor', 'Disease', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
500319	33276569	found that EGFR activation (due to, for example, exon-19 deletions, and L858R mutation) induced constitutive PD-L1 expression.	('constitutive', 'MPA', (96, 108))	('activation', 'PosReg', (16, 26))	('exon-19 deletions', 'Var', (49, 66))	('EGFR', 'Gene', '1956', (11, 15))	('EGFR', 'Gene', (11, 15))	('PD-L1', 'Gene', (109, 114))	('L858R mutation', 'Var', (72, 86))	('expression', 'MPA', (115, 125))	('L858R', 'Mutation', 'rs121434568', (72, 77))
500320	33276569	In other words, in EGFR mutant tumors, PD-L1 expression is not the result of an immune process (i.e., upregulation induced by IFN-gamma produced as result of an ongoing immune response), but is a mechanism of tumor immune escape.	('mutant', 'Var', (24, 30))	('PD-L1', 'Gene', (39, 44))	('tumor', 'Disease', (209, 214))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumors', 'Disease', (31, 37))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('tumor', 'Disease', (31, 36))	('IFN-gamma', 'Gene', '3458', (126, 135))	('EGFR', 'Gene', '1956', (19, 23))	('tumors', 'Disease', 'MESH:D009369', (31, 37))	('expression', 'MPA', (45, 55))	('upregulation', 'PosReg', (102, 114))	('tumor', 'Disease', 'MESH:D009369', (209, 214))	('EGFR', 'Gene', (19, 23))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('IFN-gamma', 'Gene', (126, 135))
500322	33276569	In a different study, patients with EGFR mutation showed a lack of T cell infiltration, a reduced proportion of PD-L1+/CD8+ TIL, and decreased tumor mutational burden.	('decreased tumor', 'Disease', 'MESH:D002303', (133, 148))	('lack', 'NegReg', (59, 63))	('reduced', 'NegReg', (90, 97))	('CD8', 'Gene', (119, 122))	('CD8', 'Gene', '925', (119, 122))	('patients', 'Species', '9606', (22, 30))	('EGFR', 'Gene', '1956', (36, 40))	('mutation', 'Var', (41, 49))	('EGFR', 'Gene', (36, 40))	('decreased tumor', 'Disease', (133, 148))	('T cell infiltration', 'CPA', (67, 86))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
500323	33276569	Analysis of data from four randomized trials also indicated that patients with EGFR mutation did not benefit from PD-1/PD-L1 inhibitors compared to patients with wild-type EGFR.	('EGFR', 'Gene', '1956', (172, 176))	('patients', 'Species', '9606', (148, 156))	('EGFR', 'Gene', '1956', (79, 83))	('EGFR', 'Gene', (79, 83))	('EGFR', 'Gene', (172, 176))	('patients', 'Species', '9606', (65, 73))	('mutation', 'Var', (84, 92))
500331	33276569	A recent proof of principle study (carried out in colorectal cancer and melanoma pre-clinical models) has shown that loss of B2M, a genetic alteration that abrogates MHC class I expression and prevents CD8-mediated tumor recognition, can be overcome by a therapy designed to activated NK cells.	('prevents', 'NegReg', (193, 201))	('melanoma', 'Disease', 'MESH:D008545', (72, 80))	('melanoma', 'Phenotype', 'HP:0002861', (72, 80))	('melanoma', 'Disease', (72, 80))	('colorectal cancer', 'Disease', 'MESH:D015179', (50, 67))	('abrogates', 'NegReg', (156, 165))	('loss', 'Var', (117, 121))	('expression', 'MPA', (178, 188))	('B2M', 'Gene', (125, 128))	('CD8', 'Gene', (202, 205))	('tumor', 'Disease', 'MESH:D009369', (215, 220))	('MHC class I', 'Protein', (166, 177))	('CD8', 'Gene', '925', (202, 205))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('colorectal cancer', 'Phenotype', 'HP:0003003', (50, 67))	('tumor', 'Disease', (215, 220))	('colorectal cancer', 'Disease', (50, 67))
500334	33276569	have shown that inhibition of EZH2, the catalytic component of PRC2, rescued MHC class I gene transcription in MHC class I-low tumors.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('EZH2', 'Gene', '2146', (30, 34))	('tumors', 'Disease', (127, 133))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('EZH2', 'Gene', (30, 34))	('MHC class I gene', 'Gene', (77, 93))	('tumors', 'Disease', 'MESH:D009369', (127, 133))	('rescued', 'PosReg', (69, 76))	('transcription', 'MPA', (94, 107))	('inhibition', 'Var', (16, 26))
500335	33276569	Topper et al., in NSCLC models, have shown that combination of the DNMTi azacytidine with histone deacetylase inhibitors (HDACis) can activate a type I IFN transcriptional program leading to the upregulation of HLA class I molecule expression.	('type I IFN transcriptional program', 'Pathway', (145, 179))	('activate', 'PosReg', (134, 142))	('NSCLC', 'Disease', (18, 23))	('azacytidine', 'Chemical', 'MESH:D001374', (73, 84))	('DNMTi azacytidine', 'Var', (67, 84))	('NSCLC', 'Disease', 'MESH:D002289', (18, 23))	('upregulation', 'PosReg', (195, 207))	('expression', 'MPA', (232, 242))	('HLA class I molecule', 'Protein', (211, 231))	('combination', 'Interaction', (48, 59))
500345	33276569	Furthermore, specific genetic changes and chromosomal alterations, as well as the interaction of neoantigen structure with adaptive immunity, concur to shape LUAD and LUSC immune evolution and to promote the resistance of different NSCLC subsets to immunotherapy targeting immune checkpoints.	('LUAD', 'Phenotype', 'HP:0030078', (158, 162))	('resistance', 'MPA', (208, 218))	('shape', 'Reg', (152, 157))	('changes', 'Var', (30, 37))	('promote', 'PosReg', (196, 203))	('NSCLC', 'Disease', (232, 237))	('alterations', 'Var', (54, 65))	('NSCLC', 'Disease', 'MESH:D002289', (232, 237))	('LUSC', 'Phenotype', 'HP:0030359', (167, 171))	('interaction', 'Interaction', (82, 93))
500385	32545409	further underscored this finding, as the authors demonstrated cases of CUP to have a high rate of HPV positivity (91%) as well a higher prevalence in a younger, male demographic.	('HPV', 'Species', '10566', (98, 101))	('HPV', 'Gene', (98, 101))	('CUP', 'Disease', (71, 74))	('positivity', 'Var', (102, 112))
500427	32545409	However, further investigations comparing cetuximab with cisplatin have shown HPV-positive OPSCC patients treated with cetuximab to have inferior overall and progression-free survival than those with cisplatin.	('overall', 'CPA', (146, 153))	('OPSCC', 'Disease', (91, 96))	('progression-free survival', 'CPA', (158, 183))	('cetuximab', 'Chemical', 'MESH:D000068818', (42, 51))	('inferior', 'NegReg', (137, 145))	('cisplatin', 'Chemical', 'MESH:D002945', (200, 209))	('cetuximab', 'Var', (119, 128))	('HPV-positive', 'Gene', (78, 90))	('cisplatin', 'Chemical', 'MESH:D002945', (57, 66))	('HPV', 'Species', '10566', (78, 81))	('cetuximab', 'Chemical', 'MESH:D000068818', (119, 128))	('patients', 'Species', '9606', (97, 105))
500442	32545409	concluded that PD-L1 expression of >=1% was associated with improved ORR; however, no association was seen based on HPV status.	('HPV', 'Species', '10566', (116, 119))	('PD-L1', 'Gene', (15, 20))	('expression', 'Var', (21, 31))	('improved', 'PosReg', (60, 68))	('ORR', 'Disease', (69, 72))
500458	32545409	Additional trials are improving risk stratification using pre-treatment (assessing tumor hypoxia burden, NCT03323463) or mid-treatment (assessing response to therapy) imaging characteristics (NCT03416153, NCT03215719, NCT03224000).	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('NCT03416153', 'Var', (192, 203))	('tumor hypoxia', 'Disease', 'MESH:D000860', (83, 96))	('tumor hypoxia', 'Disease', (83, 96))	('men', 'Species', '9606', (67, 70))	('NCT03224000', 'Var', (218, 229))	('men', 'Species', '9606', (130, 133))	('NCT03215719', 'Var', (205, 216))	('NCT03323463', 'Var', (105, 116))
500470	32545409	Ongoing clinical trials are investigating the efficacy of topical treatment options such as remetinostat, a histone deacetylase inhibitor, (NCT03180528) and of immune checkpoint inhibitors (ICIs) for patients who have progressed on HHIs or other systemic therapies (NCT03132636 and NCT03521830).	('HHIs', 'Disease', (232, 236))	('HHIs', 'Disease', 'None', (232, 236))	('NCT03132636', 'Var', (266, 277))	('patients', 'Species', '9606', (200, 208))	('men', 'Species', '9606', (71, 74))	('NCT03180528', 'Var', (140, 151))	('remetinostat', 'Chemical', '-', (92, 104))	('NCT03521830', 'Var', (282, 293))
500475	32545409	Additionally, poorer outcomes were often seen in T1/T2 classifications, whereas effective stratification would demonstrate worsening outcomes with the advancing stage of disease.	('age', 'Gene', '5973', (163, 166))	('age', 'Gene', (163, 166))	('T1/T2', 'Var', (49, 54))
500484	32545409	The impact of adjuvant immunotherapy with cemiplimab or pembrolizumab is currently under investigation for patients with high-risk cSCC after surgery and radiation therapy (NCT03833167 and NCT03969004).	('NCT03833167', 'Var', (173, 184))	('NCT03969004', 'Var', (189, 200))	('pembrolizumab', 'Chemical', 'MESH:C582435', (56, 69))	('cSCC', 'Disease', (131, 135))	('cemiplimab', 'Chemical', 'MESH:C000627974', (42, 52))	('patients', 'Species', '9606', (107, 115))
500489	32545409	Non-nodal regional disease, which includes in transit, satellite, and/or microsatellite metastases, is now incorporated into the N-classification criteria in combination with the numbers of lymph node involved.	('metastases', 'Disease', (88, 98))	('microsatellite', 'Var', (73, 87))	('nodal', 'Gene', '4838', (4, 9))	('metastases', 'Disease', 'MESH:D009362', (88, 98))	('nodal', 'Gene', (4, 9))
500499	32545409	These recommendations were based on reports describing intermediate Breslow thickness as a predictor for SLNB positivity in clinically node-negative (cN0) populations.	('SLNB', 'Gene', (105, 109))	('positivity', 'Var', (110, 120))	('men', 'Species', '9606', (11, 14))
500503	32545409	Roughly 50% of melanoma cases express a BRAF mutation (BRAF-MT) and may either be treated with a BRAF/MEK inhibitor combination or ICI therapy (Figure 2).	('BRAF', 'Gene', '673', (40, 44))	('MEK', 'Gene', '5609', (102, 105))	('melanoma', 'Phenotype', 'HP:0002861', (15, 23))	('BRAF', 'Gene', (40, 44))	('melanoma', 'Disease', (15, 23))	('melanoma', 'Disease', 'MESH:D008545', (15, 23))	('BRAF', 'Gene', (55, 59))	('mutation', 'Var', (45, 53))	('BRAF', 'Gene', '673', (55, 59))	('BRAF', 'Gene', '673', (97, 101))	('BRAF', 'Gene', (97, 101))	('MEK', 'Gene', (102, 105))
500526	32545409	Various T cell products under study include expanded tumor-infiltrating lymphocytes and T cells engineered with T cell receptors targeting E6 and E7 peptides associated with HPV (NCT02280811 and NCT02858310).	('HPV', 'Disease', (174, 177))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('NCT02858310', 'Var', (195, 206))	('E7 peptides', 'Var', (146, 157))	('NCT02280811', 'Var', (179, 190))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Disease', (53, 58))	('HPV', 'Species', '10566', (174, 177))
500532	32545409	Retrospective studies have shown an improvement in locoregional control with adaptive radiotherapy over standard RT.	('adaptive radiotherapy', 'Var', (77, 98))	('locoregional control', 'CPA', (51, 71))	('men', 'Species', '9606', (43, 46))	('improvement', 'PosReg', (36, 47))
500586	29743120	In addition, recent evidence demonstrates HPV-OSCC may also lead to atypical patterns of metastases.	('OSCC', 'Phenotype', 'HP:0012182', (46, 50))	('HPV', 'Species', '10566', (42, 45))	('HPV-OSCC', 'Var', (42, 50))	('lead to', 'Reg', (60, 67))	('metastases', 'Disease', (89, 99))	('metastases', 'Disease', 'MESH:D009362', (89, 99))
500588	29743120	However, HPV-OSCC has also resulted in atypical patterns, including dural metastasis, osseous metastases 11 years after initial treatment, and multiple brain metastases.	('metastases', 'Disease', (94, 104))	('osseous metastases', 'Disease', 'MESH:D009362', (86, 104))	('HPV-OSCC', 'Var', (9, 17))	('osseous metastases', 'Disease', (86, 104))	('metastases', 'Disease', 'MESH:D009362', (94, 104))	('resulted in', 'Reg', (27, 38))	('dural metastasis', 'CPA', (68, 84))	('metastases', 'Disease', (158, 168))	('HPV', 'Species', '10566', (9, 12))	('OSCC', 'Phenotype', 'HP:0012182', (13, 17))	('metastases', 'Disease', 'MESH:D009362', (158, 168))
500600	29743120	The patient was diagnosed with a cT4aN2c HPV-OSCC and referred to the institutional tumor board where a recommendation for definitive chemoradiation was made.	('HPV', 'Species', '10566', (41, 44))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('cT4aN2c', 'Var', (33, 40))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('patient', 'Species', '9606', (4, 11))	('tumor', 'Disease', (84, 89))	('OSCC', 'Phenotype', 'HP:0012182', (45, 49))
500642	29743120	Due to these anatomic relationships, lesions of the cavernous sinus may present with headache, chemosis, ophthalmoplegia, proptosis, miosis, diplopia, or sensory deficits in the ophthalmic and maxillary nerve distributions.	('headache', 'Disease', (85, 93))	('miosis', 'Phenotype', 'HP:0000616', (133, 139))	('ptosis', 'Disease', 'MESH:C564553', (125, 131))	('lesions', 'Var', (37, 44))	('diplopia', 'Disease', (141, 149))	('present', 'Reg', (72, 79))	('ophthalmoplegia', 'Disease', 'MESH:D009886', (105, 120))	('miosis', 'Disease', (133, 139))	('sensory deficits in the ophthalmic', 'Disease', 'MESH:D015417', (154, 188))	('ophthalmoplegia', 'Disease', (105, 120))	('chemosis', 'Phenotype', 'HP:0012375', (95, 103))	('chemosis', 'Disease', (95, 103))	('chemosis', 'Disease', 'None', (95, 103))	('headache', 'Disease', 'MESH:D006261', (85, 93))	('diplopia', 'Phenotype', 'HP:0000651', (141, 149))	('sensory deficits in the ophthalmic', 'Disease', (154, 188))	('ophthalmoplegia', 'Phenotype', 'HP:0000602', (105, 120))	('proptosis', 'Phenotype', 'HP:0000520', (122, 131))	('miosis', 'Disease', 'MESH:D015877', (133, 139))	('ptosis', 'Phenotype', 'HP:0000508', (125, 131))	('sensory deficits', 'Phenotype', 'HP:0003474', (154, 170))	('headache', 'Phenotype', 'HP:0002315', (85, 93))	('ptosis', 'Disease', (125, 131))	('diplopia', 'Disease', 'MESH:D004172', (141, 149))
500651	33067881	The panoramic picture of pepsinogen gene family with pan-cancer The panoramic picture of pepsinogen gene family with pan-cancer It is well known that pepsinogen (PGs), as an important precursor of pepsin performing digestive function, has a good correlation with the occurrence and development of gastric cancer and it is also known that ectopic PGs expression is related to the prognosis of some cancers.	('correlation', 'Reg', (246, 257))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('cancer', 'Disease', (57, 63))	('related', 'Reg', (364, 371))	('gastric cancer', 'Phenotype', 'HP:0012126', (297, 311))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('cancers', 'Phenotype', 'HP:0002664', (397, 404))	('cancers', 'Disease', (397, 404))	('cancer', 'Disease', (397, 403))	('cancer', 'Disease', 'MESH:D009369', (305, 311))	('PGs', 'Chemical', 'MESH:D010715', (346, 349))	('cancer', 'Phenotype', 'HP:0002664', (397, 403))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('PGs', 'Chemical', 'MESH:D010715', (162, 165))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('cancer', 'Phenotype', 'HP:0002664', (305, 311))	('gastric cancer', 'Disease', (297, 311))	('ectopic', 'Var', (338, 345))	('cancer', 'Disease', 'MESH:D009369', (397, 403))	('cancers', 'Disease', 'MESH:D009369', (397, 404))	('cancer', 'Disease', (305, 311))	('gastric cancer', 'Disease', 'MESH:D013274', (297, 311))	('cancer', 'Disease', (121, 127))
500653	33067881	This study focused on elucidating the expression profile, activated pathway, immune cells infiltration, mutation, and copy number variation of PGs and their potential role in human cancer.	('human', 'Species', '9606', (175, 180))	('copy number variation', 'Var', (118, 139))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('PGs', 'Chemical', 'MESH:D010715', (143, 146))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('PGs', 'Gene', (143, 146))	('cancer', 'Disease', (181, 187))
500654	33067881	Based on the next generation sequence data from TCGA, Oncomine, and CCLE, the molecular changes and clinical correlation of PGs in 33 tumor types were analyzed systematically by R language, including the expression, mutation, and copy number variation of PGs and their correlation with cancer-related signal transduction pathway, immune cell infiltration, and prognostic potential in different cancers.	('CCLE', 'Chemical', '-', (68, 72))	('cancer', 'Phenotype', 'HP:0002664', (394, 400))	('copy number variation', 'Var', (230, 251))	('cancer', 'Phenotype', 'HP:0002664', (286, 292))	('Oncomine', 'Chemical', '-', (54, 62))	('PGs', 'Chemical', 'MESH:D010715', (255, 258))	('cancer', 'Disease', 'MESH:D009369', (394, 400))	('cancers', 'Disease', 'MESH:D009369', (394, 401))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('cancer', 'Disease', (286, 292))	('PGs', 'Chemical', 'MESH:D010715', (124, 127))	('cancers', 'Phenotype', 'HP:0002664', (394, 401))	('cancer', 'Disease', (394, 400))	('cancers', 'Disease', (394, 401))	('PGs', 'Gene', (255, 258))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('tumor', 'Disease', (134, 139))	('cancer', 'Disease', 'MESH:D009369', (286, 292))
500659	33067881	PGs expression was significantly related to the activation or inhibition of many signal transduction pathways, in which PGC and PGA5 are more likely to be associated with cancer-related pathways.	('PGC', 'Gene', (120, 123))	('signal transduction pathways', 'Pathway', (81, 109))	('PGA5', 'Gene', (128, 132))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('PGs', 'Chemical', 'MESH:D010715', (0, 3))	('associated', 'Reg', (155, 165))	('cancer', 'Disease', (171, 177))	('PGs', 'Var', (0, 3))	('PGA5', 'Gene', '5222', (128, 132))	('activation', 'PosReg', (48, 58))	('PGC', 'Gene', '5225', (120, 123))	('inhibition', 'NegReg', (62, 72))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))
500665	33067881	Genetic variation analysis showed that PGC gene often mutated in uterine corpus endometrial carcinoma and stomach adenocarcinoma had extensive copy number amplification in various tumor types.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('tumor', 'Disease', (180, 185))	('PGC', 'Gene', '5225', (39, 42))	('mutated', 'Var', (54, 61))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (80, 101))	('copy number amplification', 'MPA', (143, 168))	('endometrial carcinoma and stomach adenocarcinoma', 'Disease', 'MESH:D016889', (80, 128))	('PGC', 'Gene', (39, 42))
500666	33067881	PGC expression was upregulated with the increase of copy number in cholangiocarcinoma, esophageal carcinoma, and kidney renal papillary cell carcinoma, while in stomach adenocarcinoma, PGC was upregulated regardless of whether the copy number was increased or decreased.	('renal papillary cell carcinoma', 'Phenotype', 'HP:0006766', (120, 150))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (67, 85))	('expression', 'MPA', (4, 14))	('esophageal carcinoma', 'Disease', (87, 107))	('cholangiocarcinoma', 'Disease', (67, 85))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (67, 85))	('PGC', 'Gene', (185, 188))	('kidney renal papillary cell carcinoma', 'Disease', (113, 150))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (87, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (174, 183))	('stomach adenocarcinoma', 'Disease', 'MESH:D000230', (161, 183))	('upregulated', 'PosReg', (193, 204))	('PGC', 'Gene', (0, 3))	('upregulated', 'PosReg', (19, 30))	('PGC', 'Gene', '5225', (185, 188))	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('stomach adenocarcinoma', 'Disease', (161, 183))	('PGC', 'Gene', '5225', (0, 3))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('increase', 'PosReg', (40, 48))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (87, 107))	('kidney renal papillary cell carcinoma', 'Disease', 'MESH:C538614', (113, 150))	('copy number', 'Var', (52, 63))
500670	33067881	The variation of copy number of PGC gene could affect the PGC expression.	('PGC', 'Gene', (58, 61))	('variation', 'Var', (4, 13))	('copy number', 'Var', (17, 28))	('expression', 'MPA', (62, 72))	('PGC', 'Gene', '5225', (32, 35))	('PGC', 'Gene', (32, 35))	('affect', 'Reg', (47, 53))	('PGC', 'Gene', '5225', (58, 61))
500672	33067881	Based on the next generation sequence data from TCGA and CCLE, the molecular changes and clinical correlation of PGs in 33 tumor types were analyzed systematically including the expression profiles, mutation and copy number variation of PGs and their correlation with cancer-related signal transduction pathway, immune cell infiltration and prognostic potential in different cancers.	('cancers', 'Phenotype', 'HP:0002664', (375, 382))	('cancer', 'Disease', (268, 274))	('PGs', 'Chemical', 'MESH:D010715', (113, 116))	('tumor', 'Disease', (123, 128))	('cancer', 'Disease', (375, 381))	('PGs', 'Chemical', 'MESH:D010715', (237, 240))	('copy number variation', 'Var', (212, 233))	('cancer', 'Disease', 'MESH:D009369', (375, 381))	('cancer', 'Phenotype', 'HP:0002664', (268, 274))	('cancer', 'Phenotype', 'HP:0002664', (375, 381))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('cancers', 'Disease', 'MESH:D009369', (375, 382))	('correlation', 'Reg', (251, 262))	('PGs', 'Gene', (237, 240))	('cancer', 'Disease', 'MESH:D009369', (268, 274))	('cancers', 'Disease', (375, 382))	('CCLE', 'Chemical', '-', (57, 61))
500692	33067881	In this study, by using the multilevel data from TCGA based Pan-Cancer Atlas, Oncomine and Cancer Cell Line Encyclopedia (CCLE), we focused on the elucidating expression profile, activated pathway, immune cells infiltration, mutation, and copy number variation of PGs and their prediction/diagnosis/prognosis potential in pan-cancer.	('Cancer', 'Disease', (91, 97))	('Cancer', 'Disease', (64, 70))	('Cancer', 'Disease', 'MESH:D009369', (91, 97))	('CCLE', 'Chemical', '-', (122, 126))	('Cancer', 'Disease', 'MESH:D009369', (64, 70))	('Cancer', 'Phenotype', 'HP:0002664', (91, 97))	('Cancer', 'Phenotype', 'HP:0002664', (64, 70))	('-cancer', 'Disease', 'MESH:D009369', (325, 332))	('-cancer', 'Disease', (325, 332))	('Oncomine', 'Chemical', '-', (78, 86))	('PGs', 'Chemical', 'MESH:D010715', (264, 267))	('copy number variation', 'Var', (239, 260))	('PGs', 'Gene', (264, 267))	('cancer', 'Phenotype', 'HP:0002664', (326, 332))
500693	33067881	We totally collected the information of 33 different kinds of tumors in TCGA database (http://cancergenome.nih.gov/), including the information of TPM (Transcripts Per Kilobase Million) expression, mutation, and copy number variation.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumors', 'Disease', (62, 68))	('tumors', 'Disease', 'MESH:D009369', (62, 68))	('copy number variation', 'Var', (212, 233))	('TPM', 'Gene', (147, 150))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))	('cancer', 'Disease', (94, 100))	('mutation', 'Var', (198, 206))
500698	33067881	CCLE database(https://portals.broadinstitute.org/ccle)was used to identify the PGs expression, mutation, and copy number variation in different cancer cell lines, including all 431 cell lines from six cancer types.	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('cancer', 'Disease', (201, 207))	('CCLE', 'Chemical', '-', (0, 4))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('cancer', 'Disease', (144, 150))	('PGs', 'Chemical', 'MESH:D010715', (79, 82))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('PGs', 'Gene', (79, 82))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('mutation', 'Var', (95, 103))
500711	33067881	The frequency of CNV in each cancer type and cell lines was calculated as the proportion of CNV amplification and deletion.	('cancer', 'Disease', (29, 35))	('cancer', 'Disease', 'MESH:D009369', (29, 35))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('deletion', 'Var', (114, 122))
500723	33067881	The results showed that in stomach adenocarcinoma and lung squamous cell carcinoma, high expression of PG is a protective factor, and high expression can reduce the risk of cancer.	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('cancer', 'Disease', (173, 179))	('reduce', 'NegReg', (154, 160))	('high expression', 'Var', (134, 149))	('stomach adenocarcinoma', 'Disease', 'MESH:D000230', (27, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('carcinoma', 'Phenotype', 'HP:0030731', (40, 49))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (54, 82))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (59, 82))	('stomach adenocarcinoma', 'Disease', (27, 49))	('lung squamous cell carcinoma', 'Disease', (54, 82))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (54, 82))
500734	33067881	The results show that PGs expression was significantly related to the activation or inhibition of many carcinogenic pathways (Figure 7A), in which PGC and PGA5 are more likely to be associated with carcinogenic processes.	('PGC', 'Gene', (147, 150))	('carcinogenic', 'Disease', 'MESH:D063646', (198, 210))	('associated', 'Reg', (182, 192))	('inhibition', 'NegReg', (84, 94))	('carcinogenic', 'Disease', (198, 210))	('expression', 'Var', (26, 36))	('PGA5', 'Gene', (155, 159))	('PGs', 'Gene', (22, 25))	('PGA5', 'Gene', '5222', (155, 159))	('carcinogenic', 'Disease', 'MESH:D063646', (103, 115))	('carcinogenic', 'Disease', (103, 115))	('activation', 'PosReg', (70, 80))	('related', 'Reg', (55, 62))	('PGs', 'Chemical', 'MESH:D010715', (22, 25))	('PGC', 'Gene', '5225', (147, 150))
500758	33067881	The results showed that PGC gene mutations frequently occurred in uterine corpus endometrial carcinoma and stomach adenocarcinoma (Figure 10A).	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('PGC', 'Gene', '5225', (24, 27))	('PGC', 'Gene', (24, 27))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (81, 102))	('endometrial carcinoma and stomach adenocarcinoma', 'Disease', 'MESH:D016889', (81, 129))	('mutations', 'Var', (33, 42))	('occurred', 'Reg', (54, 62))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))
500761	33067881	PGA3, PGA4, and PGA5 showed more copy number amplification in lung adenocarcinoma, esophageal carcinoma, kidney chromophobe, and copy number reduction in bladder urothelial carcinoma, lung squamous cell carcinoma, rectum adenocarcinoma, and cholangiocarcinoma.	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (62, 81))	('copy number', 'Var', (129, 140))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (184, 212))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (62, 81))	('PGA4', 'Gene', '643847', (6, 10))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (241, 259))	('PGA5', 'Gene', (16, 20))	('rectum adenocarcinoma', 'Disease', 'MESH:D012004', (214, 235))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('cholangiocarcinoma', 'Disease', (241, 259))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (241, 259))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (83, 103))	('copy', 'MPA', (33, 37))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (184, 212))	('lung squamous cell carcinoma', 'Disease', (184, 212))	('PGA5', 'Gene', '5222', (16, 20))	('kidney chromophobe', 'Disease', 'MESH:D000238', (105, 123))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (189, 212))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (173, 182))	('esophageal carcinoma', 'Disease', (83, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (226, 235))	('kidney chromophobe', 'Disease', (105, 123))	('PGA3', 'Chemical', '-', (0, 4))	('rectum adenocarcinoma', 'Disease', (214, 235))	('bladder urothelial carcinoma', 'Disease', (154, 182))	('carcinoma', 'Phenotype', 'HP:0030731', (203, 212))	('PGA4', 'Gene', (6, 10))	('lung adenocarcinoma', 'Disease', (62, 81))	('PGA3', 'Gene', (0, 4))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (83, 103))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (154, 182))
500762	33067881	In addition, CCLE database analysis revealed the mutation status of PGs in different human cancer cell lines, which showed that there were frequent mutations of PGs in colorectal cancer and gastric cancer cell lines (Figure 11).	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('colorectal cancer', 'Disease', 'MESH:D015179', (168, 185))	('gastric cancer', 'Disease', 'MESH:D013274', (190, 204))	('cancer', 'Disease', (198, 204))	('PGs', 'Chemical', 'MESH:D010715', (68, 71))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('colorectal cancer', 'Disease', (168, 185))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('PGs', 'Gene', (161, 164))	('CCLE', 'Chemical', '-', (13, 17))	('mutations', 'Var', (148, 157))	('PGs', 'Chemical', 'MESH:D010715', (161, 164))	('gastric cancer', 'Phenotype', 'HP:0012126', (190, 204))	('rectal cancer', 'Phenotype', 'HP:0100743', (172, 185))	('human', 'Species', '9606', (85, 90))	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('colorectal cancer', 'Phenotype', 'HP:0003003', (168, 185))	('cancer', 'Disease', (91, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('cancer', 'Disease', (179, 185))	('gastric cancer', 'Disease', (190, 204))
500763	33067881	In order to explore whether PGC self-variation affects its expression, we analyzed the correlation between PGs mutation, CNV, and PGs expression.	('PGs', 'Gene', (107, 110))	('PGC', 'Gene', '5225', (28, 31))	('PGC', 'Gene', (28, 31))	('PGs', 'Chemical', 'MESH:D010715', (130, 133))	('expression', 'MPA', (59, 69))	('PGs', 'Chemical', 'MESH:D010715', (107, 110))	('mutation', 'Var', (111, 119))
500764	33067881	The results showed that PGs mutations did not affect the PGs expression in all cancers.	('cancers', 'Disease', (79, 86))	('PGs', 'Chemical', 'MESH:D010715', (57, 60))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('PGs', 'Chemical', 'MESH:D010715', (24, 27))	('cancers', 'Disease', 'MESH:D009369', (79, 86))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('mutations', 'Var', (28, 37))	('PGs', 'Gene', (24, 27))
500767	33067881	In this study, we used the multilevel data of TCGA, Oncomine, and CCLE to reveal the expression and activated pathways, mutation, and copy number variation, prognostic potential of PGs in all 33 types of tumors and 431 cell lines, aiming to clarify the important role of PGs in tumorigenesis and development of cancers.	('Oncomine', 'Chemical', '-', (52, 60))	('tumors', 'Disease', 'MESH:D009369', (204, 210))	('tumor', 'Phenotype', 'HP:0002664', (278, 283))	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('copy number variation', 'Var', (134, 155))	('tumor', 'Disease', (278, 283))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('PGs', 'Chemical', 'MESH:D010715', (271, 274))	('CCLE', 'Chemical', '-', (66, 70))	('cancers', 'Disease', 'MESH:D009369', (311, 318))	('cancers', 'Phenotype', 'HP:0002664', (311, 318))	('cancers', 'Disease', (311, 318))	('tumor', 'Disease', (204, 209))	('PGs', 'Chemical', 'MESH:D010715', (181, 184))	('tumors', 'Disease', (204, 210))	('tumors', 'Phenotype', 'HP:0002664', (204, 210))	('tumor', 'Disease', 'MESH:D009369', (278, 283))	('cancer', 'Phenotype', 'HP:0002664', (311, 317))
500768	33067881	The results suggest that there was differential expression of PGs between many kinds of cancer tissues and corresponding normal tissues, which is related to the prognosis of patients; PGs expression was closely associated with the activation of cancer-related pathways and immune cell infiltration; the copy number variation of PGC could affect the gene expression.	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('gene expression', 'MPA', (349, 364))	('PGC', 'Gene', (328, 331))	('cancer', 'Disease', 'MESH:D009369', (245, 251))	('affect', 'Reg', (338, 344))	('cancer', 'Disease', (245, 251))	('immune cell infiltration', 'CPA', (273, 297))	('PGs', 'Chemical', 'MESH:D010715', (62, 65))	('copy number variation', 'Var', (303, 324))	('patients', 'Species', '9606', (174, 182))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('PGC', 'Gene', '5225', (328, 331))	('cancer', 'Phenotype', 'HP:0002664', (245, 251))	('associated', 'Reg', (211, 221))	('PGs', 'Chemical', 'MESH:D010715', (184, 187))
500787	33067881	The loss of pepsinogen in advanced esophageal squamous cell carcinoma indicates that pepsin is involved in the process of protein synthesis in the esophagus and causes esophageal carcinogenesis.	('pepsin', 'Var', (85, 91))	('esophageal carcinogenesis', 'Disease', 'MESH:D063646', (168, 193))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (35, 69))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (46, 69))	('causes', 'Reg', (161, 167))	('esophageal carcinogenesis', 'Disease', (168, 193))	('esophageal squamous cell carcinoma', 'Disease', (35, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (60, 69))	('loss', 'NegReg', (4, 8))	('pepsinogen', 'Protein', (12, 22))
500789	33067881	Both lung tissue and gastric mucosa have the same function of producing pepsinogen molecules, 11  and the injury of normal lung tissue could increase the synthesis of pepsinogen C. 22  Some studies have also suggested that the existence of pepsin in respiratory biological samples was caused by gastroesophageal reflux associated lung inhalation.	('increase', 'PosReg', (141, 149))	('gastroesophageal reflux', 'Phenotype', 'HP:0002020', (295, 318))	('pepsinogen C', 'Gene', '5225', (167, 179))	('injury', 'Var', (106, 112))	('pepsinogen C', 'Gene', (167, 179))	('gastroesophageal reflux', 'Disease', (295, 318))	('pepsin', 'Gene', (240, 246))	('synthesis', 'MPA', (154, 163))	('caused by', 'Reg', (285, 294))
500810	33067881	The results showed that the overall average mutation rate of PGs was 0%-5.3%, and the mutation rate of PGC was higher in stomach adenocarcinoma and endometrial carcinoma.	('higher', 'Reg', (111, 117))	('PGC', 'Gene', '5225', (103, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (160, 169))	('PGs', 'Chemical', 'MESH:D010715', (61, 64))	('PGC', 'Gene', (103, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (148, 169))	('mutation', 'Var', (86, 94))	('stomach adenocarcinoma and endometrial carcinoma', 'Disease', 'MESH:D016889', (121, 169))
500811	33067881	It is worth noticed that all PGC, PGA3, and PGA5 genes had a certain degree of mutation in endometrial carcinoma, which is a tumor with high global mutation rate.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('PGA3', 'Gene', (34, 38))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (91, 112))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumor', 'Disease', (125, 130))	('PGA3', 'Chemical', '-', (34, 38))	('PGA5', 'Gene', (44, 48))	('mutation', 'Var', (79, 87))	('PGC', 'Gene', '5225', (29, 32))	('PGC', 'Gene', (29, 32))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (91, 112))	('endometrial carcinoma', 'Disease', (91, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('PGA5', 'Gene', '5222', (44, 48))
500812	33067881	31  In addition, CCLE-based analysis of human cancer cell lines showed that most of the PGs mutations were found in colorectal adenocarcinoma and stomach adenocarcinoma cell lines, suggesting PGs mutation may be the key events in tumorigenesis and development of both gastric cancer and colorectal adenocarcinoma.	('CCLE', 'Chemical', '-', (17, 21))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('cancer', 'Disease', 'MESH:D009369', (276, 282))	('gastric cancer', 'Disease', (268, 282))	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (287, 312))	('carcinoma', 'Phenotype', 'HP:0030731', (159, 168))	('gastric cancer', 'Disease', 'MESH:D013274', (268, 282))	('colorectal adenocarcinoma', 'Disease', (116, 141))	('human', 'Species', '9606', (40, 45))	('tumor', 'Disease', (230, 235))	('cancer', 'Disease', (276, 282))	('cancer', 'Disease', (46, 52))	('PGs', 'Chemical', 'MESH:D010715', (192, 195))	('mutations', 'Var', (92, 101))	('PGs', 'Gene', (88, 91))	('cancer', 'Phenotype', 'HP:0002664', (276, 282))	('tumor', 'Disease', 'MESH:D009369', (230, 235))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('PGs', 'Chemical', 'MESH:D010715', (88, 91))	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (116, 141))	('gastric cancer', 'Phenotype', 'HP:0012126', (268, 282))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('colorectal adenocarcinoma and stomach adenocarcinoma', 'Disease', 'MESH:D000230', (116, 168))	('tumor', 'Phenotype', 'HP:0002664', (230, 235))	('carcinoma', 'Phenotype', 'HP:0030731', (303, 312))	('found', 'Reg', (107, 112))	('colorectal adenocarcinoma', 'Disease', (287, 312))
500813	33067881	In this study, we also found that there was extensive copy number amplification in various tumor types, which may be related to its widespread expression in various tissues.	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor', 'Disease', (91, 96))	('copy number amplification', 'Var', (54, 79))	('tumor', 'Disease', 'MESH:D009369', (91, 96))
500815	33067881	The results showed that there was no correlation between PGs mutation and PGs expression in cancer cells.	('PGs', 'Chemical', 'MESH:D010715', (74, 77))	('cancer', 'Disease', (92, 98))	('PGs', 'Chemical', 'MESH:D010715', (57, 60))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('mutation', 'Var', (61, 69))	('PGs', 'Gene', (57, 60))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
500816	33067881	However, previous studies in our lab have found that PGC gene insertion-deletion fragment polymorphism and single nucleotide polymorphism from human germline cells can affect PGC expression.	('PGC', 'Gene', (175, 178))	('human', 'Species', '9606', (143, 148))	('expression', 'MPA', (179, 189))	('insertion-deletion fragment polymorphism', 'Var', (62, 102))	('single nucleotide polymorphism', 'Var', (107, 137))	('PGC', 'Gene', '5225', (53, 56))	('PGC', 'Gene', (53, 56))	('affect', 'Reg', (168, 174))	('PGC', 'Gene', '5225', (175, 178))
500818	33067881	In cholangiocarcinoma, esophageal cancer, and kidney renal papillary cell carcinoma, PGC expression was upregulated with the increase of copy number, but in stomach adenocarcinoma, both increase and deletion of PGC copy number could lead to the up-regulation of PGC expression.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('expression', 'MPA', (266, 276))	('PGC', 'Gene', '5225', (211, 214))	('stomach adenocarcinoma', 'Disease', (157, 179))	('deletion', 'Var', (199, 207))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (3, 21))	('cholangiocarcinoma', 'Disease', (3, 21))	('copy number', 'Var', (215, 226))	('up-regulation', 'PosReg', (245, 258))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (3, 21))	('kidney renal papillary cell carcinoma', 'Disease', 'MESH:C538614', (46, 83))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('renal papillary cell carcinoma', 'Phenotype', 'HP:0006766', (53, 83))	('PGC', 'Gene', (262, 265))	('upregulated', 'PosReg', (104, 115))	('PGC', 'Gene', (85, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (170, 179))	('PGC', 'Gene', '5225', (262, 265))	('kidney renal papillary cell carcinoma', 'Disease', (46, 83))	('carcinoma', 'Phenotype', 'HP:0030731', (12, 21))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('PGC', 'Gene', (211, 214))	('cancer', 'Disease', (34, 40))	('PGC', 'Gene', '5225', (85, 88))	('stomach adenocarcinoma', 'Disease', 'MESH:D000230', (157, 179))
500874	32401928	Increased cellular levels of cleaved caspase-9 and cleaved PARP have been well-known as markers for the starting of cell apoptosis.	('PARP', 'Gene', '1302', (59, 63))	('cleaved', 'Var', (51, 58))	('PARP', 'Gene', (59, 63))	('cleaved', 'MPA', (29, 36))	('caspase-9', 'Gene', (37, 46))	('cellular levels', 'MPA', (10, 25))	('Increased', 'PosReg', (0, 9))	('caspase-9', 'Gene', '842', (37, 46))
500890	32401928	This study investigated the effects of EEA on proliferation and migration of HNSCC cells, and we found that EEA might inhibit proliferation and migration of SAS in a dose-dependent manner.	('inhibit', 'NegReg', (118, 125))	('EEA', 'Chemical', '-', (39, 42))	('EEA', 'Var', (108, 111))	('EEA', 'Chemical', '-', (108, 111))	('HNSCC', 'Phenotype', 'HP:0012288', (77, 82))
500900	32401928	Furthermore, recent articles revealed that EEA enhances chemo-sensitivity of several carcinomas, indicating that EEA can be used as adjuvant treatment combined with conventional chemotherapy.	('chemo-sensitivity', 'MPA', (56, 73))	('EEA', 'Var', (43, 46))	('enhances', 'PosReg', (47, 55))	('carcinomas', 'Phenotype', 'HP:0030731', (85, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('carcinomas', 'Disease', 'MESH:D009369', (85, 95))	('EEA', 'Chemical', '-', (43, 46))	('EEA', 'Chemical', '-', (113, 116))	('carcinomas', 'Disease', (85, 95))
500908	30619505	PIK3CA mutations are frequent in esophageal squamous cell carcinoma associated with chagasic megaesophagus and are associated with a worse patient outcome Chronic diseases such as chagasic megaesophagus (secondary to Chagas' disease) have been suggested as etiological factors for esophageal squamous cell carcinoma; however, the molecular mechanisms involved are poorly understood.	('esophageal squamous cell carcinoma', 'Disease', (281, 315))	("Chagas' disease", 'Disease', 'MESH:D014355', (217, 232))	('Chronic diseases', 'Disease', (155, 171))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (292, 315))	('esophageal squamous cell carcinoma', 'Disease', (33, 67))	('Chronic diseases', 'Disease', 'MESH:D002908', (155, 171))	('PIK3CA', 'Gene', '5290', (0, 6))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (281, 315))	('mutations', 'Var', (7, 16))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (33, 67))	('associated', 'Reg', (115, 125))	('frequent', 'Reg', (21, 29))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (44, 67))	('chagasic megaesophagus', 'Disease', (180, 202))	('carcinoma', 'Phenotype', 'HP:0030731', (306, 315))	('associated', 'Reg', (68, 78))	('chagasic megaesophagus', 'Disease', (84, 106))	("Chagas' disease", 'Disease', (217, 232))	('PIK3CA', 'Gene', (0, 6))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))	('patient', 'Species', '9606', (139, 146))
500909	30619505	We analyzed hotspot PIK3CA gene mutations in a series of esophageal squamous cell carcinomas associated or not with chagasic megaesophagus, as well as, in chagasic megaesophagus biopsies.	('PIK3CA', 'Gene', (20, 26))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('PIK3CA', 'Gene', '5290', (20, 26))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (68, 92))	('associated', 'Reg', (93, 103))	('mutations', 'Var', (32, 41))	('esophageal squamous cell carcinomas', 'Disease', (57, 92))	('esophageal squamous cell carcinomas', 'Disease', 'MESH:D000077277', (57, 92))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (68, 91))	('carcinomas', 'Phenotype', 'HP:0030731', (82, 92))
500912	30619505	PIK3CA hotspot mutations in exons 9 and 20 were evaluated by PCR followed by direct sequencing technique.	('PIK3CA', 'Gene', '5290', (0, 6))	('mutations', 'Var', (15, 24))	('PIK3CA', 'Gene', (0, 6))
500913	30619505	PIK3CA mutations were identified in 21.7% (5 out of 23) of CM/ESCC cases, in 10.5% (4 out of 38) of ESCC and in only 3.6% (1 case out of 28) of CM cases.	('CM', 'Disease', 'MESH:D009202', (144, 146))	('CM', 'Disease', 'MESH:D009202', (59, 61))	('PIK3CA', 'Gene', (0, 6))	('ESCC', 'Disease', (100, 104))	('identified', 'Reg', (22, 32))	('PIK3CA', 'Gene', '5290', (0, 6))	('mutations', 'Var', (7, 16))
500914	30619505	In the CM/ESCC group, PIK3CA mutations were significantly associated with lower survival (mean 5 months), when compared to wild-type patients (mean 2.0 years).	('CM', 'Disease', 'MESH:D009202', (7, 9))	('PIK3CA', 'Gene', '5290', (22, 28))	('patients', 'Species', '9606', (133, 141))	('mutations', 'Var', (29, 38))	('survival', 'MPA', (80, 88))	('lower', 'NegReg', (74, 79))	('PIK3CA', 'Gene', (22, 28))
500915	30619505	No other significant associations were observed between PIK3CA mutations and patients' clinical features or TP53 mutation profile.	('mutations', 'Var', (63, 72))	('TP53', 'Gene', '7157', (108, 112))	('TP53', 'Gene', (108, 112))	('PIK3CA', 'Gene', (56, 62))	('patients', 'Species', '9606', (77, 85))	('PIK3CA', 'Gene', '5290', (56, 62))
500916	30619505	This is the first report on the presence of PIK3CA mutations in esophageal cancer associated with chagasic megaesophagus.	('PIK3CA', 'Gene', (44, 50))	('mutations', 'Var', (51, 60))	('associated', 'Reg', (82, 92))	('PIK3CA', 'Gene', '5290', (44, 50))	('chagasic megaesophagus', 'Disease', (98, 120))	('presence', 'Reg', (32, 40))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('esophageal cancer', 'Disease', (64, 81))	('esophageal cancer', 'Disease', 'MESH:D004938', (64, 81))
500917	30619505	The detection of PIK3CA mutations in benign chagasic megaesophagus lesions suggests their putative role in esophageal squamous cell carcinoma development and opens new opportunities for targeted-therapies for these diseases.	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (107, 141))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('PIK3CA', 'Gene', (17, 23))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (118, 141))	('PIK3CA', 'Gene', '5290', (17, 23))	('esophageal squamous cell carcinoma', 'Disease', (107, 141))	('role', 'Reg', (99, 103))	('mutations', 'Var', (24, 33))
500927	30619505	Recently, our group showed the high frequency (13/32, 40.6%) of TP53 mutations in ESCC associated with chagasic megaesophagus.	('mutations', 'Var', (69, 78))	('associated', 'Reg', (87, 97))	('ESCC', 'Gene', (82, 86))	('TP53', 'Gene', '7157', (64, 68))	('TP53', 'Gene', (64, 68))	('chagasic megaesophagus', 'Disease', (103, 125))
500931	30619505	Recurrent PI3KCA oncogenic mutations were identified in several types of tumors, including colorectal, breast, ovary, gastric, and recently in ESSC.	('identified', 'Reg', (42, 52))	('mutations', 'Var', (27, 36))	('tumors', 'Disease', 'MESH:D009369', (73, 79))	('breast', 'Disease', (103, 109))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('PI3KCA', 'Gene', (10, 16))	('colorectal', 'Disease', (91, 101))	('ovary', 'Disease', (111, 116))	('gastric', 'Disease', (118, 125))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('tumors', 'Disease', (73, 79))	('ESSC', 'Disease', (143, 147))
500932	30619505	The mutations occur mainly in exons 9 (E542K and E545K) and 20 (H1047R).	('E542K', 'Var', (39, 44))	('H1047R', 'Var', (64, 70))	('E545K', 'Mutation', 'rs104886003', (49, 54))	('E545K', 'Var', (49, 54))	('E542K', 'Mutation', 'rs121913273', (39, 44))	('H1047R', 'Mutation', 'rs121913279', (64, 70))
500933	30619505	Recently, it was shown that PIK3CA mutations, namely H1047R, also disrupt cellular genetic stability, increasing the frequency of chromosomal errors and leading to tetraploidy.	('disrupt', 'NegReg', (66, 73))	('leading to', 'Reg', (153, 163))	('cellular genetic stability', 'CPA', (74, 100))	('PIK3CA', 'Gene', (28, 34))	('H1047R', 'Var', (53, 59))	('chromosomal errors', 'Disease', 'MESH:D012030', (130, 148))	('tetraploidy', 'CPA', (164, 175))	('increasing', 'PosReg', (102, 112))	('PIK3CA', 'Gene', '5290', (28, 34))	('H1047R', 'Mutation', 'rs121913279', (53, 59))	('chromosomal errors', 'Disease', (130, 148))
500934	30619505	Importantly, therapeutic strategies targeting the PIK3/Akt signaling pathway have been developed and could constitute effective treatment options for patients harboring PI3KCA mutations.	('Akt', 'Gene', (55, 58))	('mutations', 'Var', (176, 185))	('patients', 'Species', '9606', (150, 158))	('PIK3', 'Gene', (50, 54))	('PI3KCA', 'Gene', (169, 175))	('Akt', 'Gene', '207', (55, 58))	('PIK3', 'Gene', '5294', (50, 54))
500935	30619505	Therefore, in the current study we performed the mutation analysis of PIK3CA gene in patients with ESCC and chagasic megaesophagus associated or not with ESCC, and searched for associations between the mutation status and patients' clinical and pathological features.	('patients', 'Species', '9606', (222, 230))	('associated', 'Reg', (131, 141))	('ESCC', 'Disease', (99, 103))	('PIK3CA', 'Gene', (70, 76))	('patients', 'Species', '9606', (85, 93))	('mutation', 'Var', (49, 57))	('PIK3CA', 'Gene', '5290', (70, 76))
500952	30619505	The PIK3CA mutation analysis showed the presence of mutations in 21.7% of patients in CM/ESCC group, followed by 10.5% in ESCC group and 3.6% in CM group (Fig.	('mutations', 'Var', (52, 61))	('patients', 'Species', '9606', (74, 82))	('PIK3CA', 'Gene', (4, 10))	('CM', 'Disease', 'MESH:D009202', (86, 88))	('CM', 'Disease', 'MESH:D009202', (145, 147))	('PIK3CA', 'Gene', '5290', (4, 10))	('presence', 'Reg', (40, 48))
500953	30619505	With the exception of three variants (A1027D, K1030R and T1053K), all the other mutations have already been reported in the Catalogue of Somatic Mutations in Cancer database - COSMIC (http://cancer.sanger.ac.uk/cosmic) (Fig.	('T1053K', 'Mutation', 'p.T1053K', (57, 63))	('T1053K', 'Var', (57, 63))	('A1027D', 'Var', (38, 44))	('cancer', 'Disease', (191, 197))	('cancer', 'Disease', 'MESH:D009369', (191, 197))	('Cancer', 'Phenotype', 'HP:0002664', (158, 164))	('Cancer', 'Disease', (158, 164))	('Cancer', 'Disease', 'MESH:D009369', (158, 164))	('A1027D', 'Mutation', 'p.A1027D', (38, 44))	('K1030R', 'Mutation', 'rs778000986', (46, 52))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('K1030R', 'Var', (46, 52))
500955	30619505	Furthermore, we assessed the role of PIK3CA mutations on patients' overall survival in both groups affected by cancer (CM/ESCC and ESCC) (Fig.	('PIK3CA', 'Gene', '5290', (37, 43))	('CM', 'Disease', 'MESH:D009202', (119, 121))	('patients', 'Species', '9606', (57, 65))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('mutations', 'Var', (44, 53))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('PIK3CA', 'Gene', (37, 43))
500956	30619505	In CM/ESCC group, we observed that the presence of PIK3CA mutations was significantly associated with a lower survival rate from the diagnosis of cancer compared to wild-type patients (Fig.	('mutations', 'Var', (58, 67))	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('survival', 'MPA', (110, 118))	('CM', 'Disease', 'MESH:D009202', (3, 5))	('presence', 'Var', (39, 47))	('lower', 'NegReg', (104, 109))	('PIK3CA', 'Gene', (51, 57))	('patients', 'Species', '9606', (175, 183))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('PIK3CA', 'Gene', '5290', (51, 57))
500957	30619505	The mean patients' overall survival in cases from the CM/ESCC group mutated for the PIK3CA was 5 months, in comparison with 2.0 years for wild-type PIK3CA patients (Log-rank, p < 0.001) (Table 5).	('PIK3CA', 'Gene', '5290', (84, 90))	('PIK3CA', 'Gene', '5290', (148, 154))	('patients', 'Species', '9606', (9, 17))	('patients', 'Species', '9606', (155, 163))	('PIK3CA', 'Gene', (84, 90))	('PIK3CA', 'Gene', (148, 154))	('mutated', 'Var', (68, 75))	('CM', 'Disease', 'MESH:D009202', (54, 56))
500958	30619505	Additionally, we evaluated the association of PIK3CA and TP53 mutation status, and no association was found (Table 4).	('PIK3CA', 'Gene', '5290', (46, 52))	('association', 'Interaction', (31, 42))	('PIK3CA', 'Gene', (46, 52))	('TP53', 'Gene', '7157', (57, 61))	('TP53', 'Gene', (57, 61))	('mutation status', 'Var', (62, 77))
500961	30619505	In the present study, we investigated the frequency of PIK3CA mutations in regions of hotspot (exons 9 and 20) in patients with chagasic megaesophagus associated with esophageal squamous cell carcinoma (CM/ESCC) and compared with patients with esophageal squamous cell carcinoma without chagasic megaesophagus (ESCC) and patients with chagasic megaesophagus without esophageal squamous cell carcinoma (CM).	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (244, 278))	('CM', 'Disease', 'MESH:D009202', (203, 205))	('CM', 'Disease', 'MESH:D009202', (402, 404))	('carcinoma', 'Phenotype', 'HP:0030731', (192, 201))	('esophageal squamous cell carcinoma', 'Disease', (167, 201))	('esophageal squamous cell carcinoma', 'Disease', (366, 400))	('patients', 'Species', '9606', (321, 329))	('associated', 'Reg', (151, 161))	('PIK3CA', 'Gene', '5290', (55, 61))	('patients', 'Species', '9606', (114, 122))	('mutations', 'Var', (62, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (269, 278))	('esophageal squamous cell carcinoma', 'Disease', (244, 278))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (167, 201))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (366, 400))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (178, 201))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (377, 400))	('patients', 'Species', '9606', (230, 238))	('carcinoma', 'Phenotype', 'HP:0030731', (391, 400))	('PIK3CA', 'Gene', (55, 61))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (255, 278))
500963	30619505	This is the first report of PIK3CA mutation in ESCC that developed in the context of chagasic megaesophagus and the significant frequency of mutations (~ 22%) suggest that PIK3CA plays an important role in the carcinogenesis of CM/ESCC patients.	('PIK3CA', 'Gene', (28, 34))	('patients', 'Species', '9606', (236, 244))	('PIK3CA', 'Gene', (172, 178))	('CM', 'Disease', 'MESH:D009202', (228, 230))	('PIK3CA', 'Gene', '5290', (172, 178))	('PIK3CA', 'Gene', '5290', (28, 34))	('mutation', 'Var', (35, 43))
500964	30619505	Moreover, the presence of PIK3CA mutation in a benign lesion further supports the putative role of chagasic megaesophagus as an ESCC-related condition.	('mutation', 'Var', (33, 41))	('ESCC-related', 'Disease', (128, 140))	('PIK3CA', 'Gene', '5290', (26, 32))	('presence', 'Reg', (14, 22))	('chagasic megaesophagus', 'Disease', (99, 121))	('PIK3CA', 'Gene', (26, 32))
500965	30619505	The frequency of mutations identified in our study is in line with that reported in the literature for ESCC patients, with frequencies varying from 2.2 to 32.8% (Table 6).	('ESCC', 'Disease', (103, 107))	('mutations', 'Var', (17, 26))	('patients', 'Species', '9606', (108, 116))
500967	30619505	The PIK3CA gene is often mutated in several tumors types and most of its mutations occur in hotspot regions, such as E542K and E545A located in the helical domain (exon 9), and H1047R and H1047L in the kinase domain (exon 20).	('tumors', 'Disease', (44, 50))	('tumors', 'Disease', 'MESH:D009369', (44, 50))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('H1047R', 'Var', (177, 183))	('H1047L', 'Var', (188, 194))	('E542K', 'Mutation', 'rs121913273', (117, 122))	('PIK3CA', 'Gene', (4, 10))	('H1047R', 'Mutation', 'rs121913279', (177, 183))	('E545A', 'Mutation', 'rs121913274', (127, 132))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('PIK3CA', 'Gene', '5290', (4, 10))	('E545A', 'Var', (127, 132))	('E542K', 'Var', (117, 122))	('H1047L', 'Mutation', 'rs121913279', (188, 194))
500968	30619505	These mutations lead to the activation of the PIK3 pathway and have a great potential in oncogenic activities.	('PIK3', 'Gene', (46, 50))	('activation', 'PosReg', (28, 38))	('oncogenic activities', 'CPA', (89, 109))	('PIK3', 'Gene', '5294', (46, 50))	('mutations', 'Var', (6, 15))
500969	30619505	Interestingly, most of these mutations (E545A, H1047R and H1047L) occurred in patients in the CM/ESCC group and only one (E545A) in one patient in the ESCC group.	('patient', 'Species', '9606', (136, 143))	('patient', 'Species', '9606', (78, 85))	('occurred', 'Reg', (66, 74))	('H1047L', 'Mutation', 'rs121913279', (58, 64))	('H1047L', 'Var', (58, 64))	('CM', 'Disease', 'MESH:D009202', (94, 96))	('E545A', 'Mutation', 'rs121913274', (40, 45))	('H1047R', 'Var', (47, 53))	('patients', 'Species', '9606', (78, 86))	('E545A', 'Mutation', 'rs121913274', (122, 127))	('E545A', 'Var', (40, 45))	('H1047R', 'Mutation', 'rs121913279', (47, 53))
500970	30619505	We also identified other previously described important mutations (Table 3), the D549H mutation observed in the CM/ESCC group was reported in vulva and hepatocellular cancer; R524K mutation found in the ESCC group was reported in colorectal cancer; and the R555K mutation was reported in ovary cancer.	('vulva', 'Disease', (142, 147))	('R555K', 'Var', (257, 262))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('hepatocellular cancer', 'Phenotype', 'HP:0001402', (152, 173))	('hepatocellular cancer', 'Disease', 'MESH:D006528', (152, 173))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('colorectal cancer', 'Disease', 'MESH:D015179', (230, 247))	('reported', 'Reg', (218, 226))	('ovary cancer', 'Phenotype', 'HP:0100615', (288, 300))	('D549H', 'Var', (81, 86))	('D549H', 'Mutation', 'p.D549H', (81, 86))	('reported', 'Reg', (130, 138))	('R524K', 'Var', (175, 180))	('colorectal cancer', 'Disease', (230, 247))	('R555K', 'Mutation', 'rs104886000', (257, 262))	('R524K', 'Mutation', 'rs104885999', (175, 180))	('CM', 'Disease', 'MESH:D009202', (112, 114))	('cancer', 'Phenotype', 'HP:0002664', (294, 300))	('ovary cancer', 'Disease', (288, 300))	('colorectal cancer', 'Phenotype', 'HP:0003003', (230, 247))	('ovary cancer', 'Disease', 'MESH:D010051', (288, 300))	('hepatocellular cancer', 'Disease', (152, 173))
500971	30619505	Interestingly, it is important to note that we identified three mutations in exon 20 that have not yet been reported (A1027D and K1030R in CM/ESCC group; T1053K in CM group).	('K1030R', 'Var', (129, 135))	('K1030R', 'Mutation', 'rs778000986', (129, 135))	('T1053K', 'Var', (154, 160))	('T1053K', 'Mutation', 'p.T1053K', (154, 160))	('A1027D', 'Var', (118, 124))	('CM', 'Disease', 'MESH:D009202', (139, 141))	('A1027D', 'Mutation', 'p.A1027D', (118, 124))	('CM', 'Disease', 'MESH:D009202', (164, 166))
500972	30619505	All these mutations occurred in patients with chagasic megaesophagus whose mutational profile of PIK3CA was never reported.	('patients', 'Species', '9606', (32, 40))	('PIK3CA', 'Gene', (97, 103))	('chagasic megaesophagus', 'Disease', (46, 68))	('mutations', 'Var', (10, 19))	('occurred', 'Reg', (20, 28))	('PIK3CA', 'Gene', '5290', (97, 103))
500973	30619505	Importantly, we observed that CM/ESCC patients harboring PIK3CA mutations were associated with lower overall survival, suggesting its role as a prognostic biomarker in this group of patients.	('lower', 'NegReg', (95, 100))	('PIK3CA', 'Gene', '5290', (57, 63))	('overall survival', 'MPA', (101, 117))	('mutations', 'Var', (64, 73))	('patients', 'Species', '9606', (182, 190))	('patients', 'Species', '9606', (38, 46))	('CM', 'Disease', 'MESH:D009202', (30, 32))	('PIK3CA', 'Gene', (57, 63))
500974	30619505	Interestingly, the results of our analyzes of the survival of the mutated patients differ from those reported by others studies, especially in regions of some risk such as Asia, in which patients with ESCC with mutations of the PIK3CA gene had a favorable overall survival compared to patients wild-type.	('patients', 'Species', '9606', (187, 195))	('patients', 'Species', '9606', (74, 82))	('mutations', 'Var', (211, 220))	('overall', 'MPA', (256, 263))	('patients', 'Species', '9606', (285, 293))	('ESCC', 'Disease', (201, 205))	('PIK3CA', 'Gene', (228, 234))	('PIK3CA', 'Gene', '5290', (228, 234))
500975	30619505	Notably, inhibitors of the PIK3-Akt-mTOR pathway have been developed as cancer target therapy alternatives, and patients harboring PIK3CA gene mutations could be potential candidates for such therapeutic approach.	('Akt', 'Gene', '207', (32, 35))	('PIK3', 'Gene', (27, 31))	('mTOR', 'Gene', (36, 40))	('Akt', 'Gene', (32, 35))	('mTOR', 'Gene', '2475', (36, 40))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('PIK3', 'Gene', (131, 135))	('patients', 'Species', '9606', (112, 120))	('PIK3', 'Gene', '5294', (27, 31))	('PIK3', 'Gene', '5294', (131, 135))	('PIK3CA', 'Gene', (131, 137))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('PIK3CA', 'Gene', '5290', (131, 137))	('mutations', 'Var', (143, 152))	('cancer', 'Disease', (72, 78))
500978	30619505	Therefore, we can hypothesize that a subset of ESCC and CM/ESCC patients with PIK3CA mutations may benefit from these targeted-therapies and consequently improve their dismal survival.	('PIK3CA', 'Gene', (78, 84))	('improve', 'PosReg', (154, 161))	('patients', 'Species', '9606', (64, 72))	('CM', 'Disease', 'MESH:D009202', (56, 58))	('ESCC', 'Disease', (47, 51))	('PIK3CA', 'Gene', '5290', (78, 84))	('mutations', 'Var', (85, 94))	('benefit', 'PosReg', (99, 106))	('dismal survival', 'MPA', (168, 183))
500979	30619505	In conclusion, this is the first study that analyzed and identified PIK3CA activating mutations in patients with esophageal squamous cell carcinomas associated with chagasic megaesophagus (CM/ESCC), which were associated with a worse outcome.	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (124, 148))	('mutations', 'Var', (86, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (124, 147))	('PIK3CA', 'Gene', (68, 74))	('carcinomas', 'Phenotype', 'HP:0030731', (138, 148))	('CM', 'Disease', 'MESH:D009202', (189, 191))	('esophageal squamous cell carcinomas', 'Disease', 'MESH:D000077277', (113, 148))	('PIK3CA', 'Gene', '5290', (68, 74))	('associated', 'Reg', (149, 159))	('patients', 'Species', '9606', (99, 107))	('esophageal squamous cell carcinomas', 'Disease', (113, 148))	('chagasic megaesophagus', 'Disease', (165, 187))	('activating', 'PosReg', (75, 85))
500980	30619505	Moreover, the identification of mutations in benign chagasic megaesophagus suggests their putative role in the etiology of esophageal squamous cell carcinoma and opens new opportunities for the treatment of these neglected patients with targeted-therapies.	('carcinoma', 'Phenotype', 'HP:0030731', (148, 157))	('esophageal squamous cell carcinoma', 'Disease', (123, 157))	('mutations', 'Var', (32, 41))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (134, 157))	('patients', 'Species', '9606', (223, 231))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (123, 157))
500985	30514404	A population-based study We sought to expand upon preliminary data suggesting that metformin confers a survival benefit to patients with head and neck squamous cell carcinoma (HNSCC).	('survival benefit', 'CPA', (103, 119))	('patients', 'Species', '9606', (123, 131))	('metformin', 'Var', (83, 92))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (137, 174))	('neck squamous cell carcinoma', 'Disease', (146, 174))	('metformin', 'Chemical', 'MESH:D008687', (83, 92))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (146, 174))	('carcinoma', 'Phenotype', 'HP:0030731', (165, 174))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (151, 174))
501000	30514404	Combination novel therapeutics have also shown promise, for example, Monenisin - an animal antibiotic - has been shown to enhance the cytotoxicity of both erlotinib and lovastatin in vivo.	('erlotinib', 'Chemical', 'MESH:D000069347', (155, 164))	('enhance', 'PosReg', (122, 129))	('Monenisin', 'Chemical', '-', (69, 78))	('cytotoxicity', 'Disease', (134, 146))	('lovastatin', 'Chemical', 'MESH:D008148', (169, 179))	('Monenisin', 'Var', (69, 78))	('cytotoxicity', 'Disease', 'MESH:D064420', (134, 146))
501004	30514404	Additional downstream effects of AMPK target phosphorylation include inhibition of cellular growth and proliferation under stress conditions.	('AMPK', 'Gene', '5562', (33, 37))	('AMPK', 'Gene', (33, 37))	('proliferation', 'CPA', (103, 116))	('cellular growth', 'CPA', (83, 98))	('phosphorylation', 'Var', (45, 60))	('inhibition', 'NegReg', (69, 79))
501007	30514404	Several observational studies in humans have also supported an anti-tumorigenic effect of metformin, correlating metformin use in diabetics with decreased cancer incidence and mortality, and improved treatment response in colorectal and breast cancers.	('colorectal and breast cancers', 'Disease', 'MESH:D015179', (222, 251))	('decreased cancer', 'Disease', 'MESH:D009369', (145, 161))	('improved', 'PosReg', (191, 199))	('tumor', 'Disease', (68, 73))	('diabetics', 'Disease', (130, 139))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('treatment response', 'CPA', (200, 218))	('metformin', 'Chemical', 'MESH:D008687', (90, 99))	('metformin', 'Var', (113, 122))	('decreased cancer', 'Disease', (145, 161))	('metformin', 'Chemical', 'MESH:D008687', (113, 122))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('cancers', 'Phenotype', 'HP:0002664', (244, 251))	('diabetics', 'Disease', 'MESH:D003920', (130, 139))	('humans', 'Species', '9606', (33, 39))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('mortality', 'CPA', (176, 185))	('breast cancers', 'Phenotype', 'HP:0003002', (237, 251))
501008	30514404	In patients with cancer of the larynx, a recent single-centre study demonstrated improved survival in diabetics taking metformin compared with diabetics not on metformin.	('improved', 'PosReg', (81, 89))	('diabetics', 'Disease', 'MESH:D003920', (143, 152))	('metformin', 'Var', (119, 128))	('survival', 'MPA', (90, 98))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('diabetics', 'Disease', (102, 111))	('cancer of the larynx', 'Phenotype', 'HP:0012118', (17, 37))	('cancer', 'Disease', (17, 23))	('patients', 'Species', '9606', (3, 11))	('metformin', 'Chemical', 'MESH:D008687', (119, 128))	('diabetics', 'Disease', (143, 152))	('diabetics', 'Disease', 'MESH:D003920', (102, 111))	('metformin', 'Chemical', 'MESH:D008687', (160, 169))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
501025	30514404	Patients were classified as having undergone primary surgery if they underwent pharyngo-laryngectomy or "total excision" of the glottis, supraglottis, or larynx, defined by the following ICD10 Procedure codes - 1GA89, 1GB89, 1GE89, 1GE91 - and OHIP fee codes- M081, S068 - within 4 months of diagnosis.	('OHIP', 'Chemical', '-', (244, 248))	('1GB89', 'Var', (218, 223))	('pharyngo-laryngectomy', 'Disease', (79, 100))	('1GE89', 'Var', (225, 230))	('Patients', 'Species', '9606', (0, 8))
501093	30514404	The main indication for metformin treatment is diabetes and as such, comparing those on metformin to those not on metformin has the inherent difference that those patients on metformin will have underlying diabetes, contributing to a distinctly different disease state from those without.	('diabetes', 'Disease', (206, 214))	('metformin', 'Chemical', 'MESH:D008687', (114, 123))	('metformin', 'Var', (175, 184))	('disease', 'Disease', (255, 262))	('patients', 'Species', '9606', (163, 171))	('metformin', 'Chemical', 'MESH:D008687', (88, 97))	('diabetes', 'Disease', 'MESH:D003920', (47, 55))	('diabetes', 'Disease', 'MESH:D003920', (206, 214))	('metformin', 'Chemical', 'MESH:D008687', (175, 184))	('contributing to', 'Reg', (216, 231))	('metformin', 'Chemical', 'MESH:D008687', (24, 33))	('diabetes', 'Disease', (47, 55))
501101	26414444	Our improved understanding of this retaining enzyme will accelerate the design of retaining GT inhibitors that can modulate Notch activity in pathological situations where dysregulation of Notch is known to cause cancer or developmental disorders.	('Notch', 'Gene', '31293', (124, 129))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('cause', 'Reg', (207, 212))	('modulate', 'Reg', (115, 123))	('developmental disorders', 'Disease', 'MESH:D002658', (223, 246))	('Notch', 'Gene', (189, 194))	('cancer', 'Disease', 'MESH:D009369', (213, 219))	('Notch', 'Gene', '31293', (189, 194))	('dysregulation', 'Var', (172, 185))	('Notch', 'Gene', (124, 129))	('cancer', 'Disease', (213, 219))	('developmental disorders', 'Disease', (223, 246))	('activity', 'MPA', (130, 138))
501102	26414444	Notch signaling plays essential roles in development of all metazoans, and defects in the Notch pathway lead to a variety of human diseases including several cancers and developmental disorders.	('Notch', 'Gene', '31293', (90, 95))	('Notch', 'Gene', (0, 5))	('human diseases', 'Disease', (125, 139))	('cancers', 'Phenotype', 'HP:0002664', (158, 165))	('human', 'Species', '9606', (125, 130))	('defects', 'Var', (75, 82))	('developmental disorders', 'Disease', (170, 193))	('cancers', 'Disease', (158, 165))	('Notch', 'Gene', '31293', (0, 5))	('Notch', 'Gene', (90, 95))	('cancers', 'Disease', 'MESH:D009369', (158, 165))	('developmental disorders', 'Disease', 'MESH:D002658', (170, 193))	('lead to', 'Reg', (104, 111))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
501108	26414444	XXYLT1 belongs to glycosyltransferase family 8 (GT8) in the CAZY database, and is a retaining GT, i.e.	('glycosyltransferase family 8', 'Gene', '440138', (18, 46))	('GT8', 'Gene', '440138', (48, 51))	('XXYLT1', 'Var', (0, 6))	('glycosyltransferase family 8', 'Gene', (18, 46))	('GT8', 'Gene', (48, 51))
501122	26414444	As expected, XXYLT1 had a GT-A fold with the glycosyltransferase signature DXD motif (residues 225-227) coordinating a Mn2+ ion in the active site pocket (Supplementary Fig.	('Mn2+', 'Chemical', '-', (119, 123))	('Mn2+ ion', 'MPA', (119, 127))	('residues 225-227', 'Var', (86, 102))
501143	26414444	In the acceptor disaccharide region, the distal xylose formed four strong H-bonds with the enzyme, and the proximal glucose ring stacked against W358 and H326 and H-bonds with W359 of XXYLT1 (Fig.	('disaccharide', 'Chemical', 'MESH:D004187', (16, 28))	('W358', 'Var', (145, 149))	('W359', 'Chemical', '-', (176, 180))	('H-bonds', 'Protein', (74, 81))	('H326', 'CellLine', 'CVCL:D341', (154, 158))	('xylose', 'Chemical', 'MESH:D014994', (48, 54))	('glucose', 'Chemical', 'MESH:D005947', (116, 123))
501145	26414444	Because the EGF binding interface of XXYLT1 was rigid, as described above, the protruding helix-turn-helix motif (H362-Y364) forced the EGF to change its conformation in order to avoid the otherwise extensive steric clashes (Fig.	('EGF', 'Gene', (12, 15))	('conformation', 'MPA', (154, 166))	('EGF', 'Gene', '1950', (12, 15))	('change', 'Reg', (143, 149))	('EGF', 'Gene', (136, 139))	('EGF', 'Gene', '1950', (136, 139))	('H362-Y364', 'Var', (114, 123))
501149	26414444	The EGF conformation in the binary complex structure was unstable, because the hydrophobic residues P55 and Y69, a part of the core of the natively folded EGF, were exposed (Supplementary Movie 1).	('EGF', 'Gene', '1950', (155, 158))	('P55', 'Var', (100, 103))	('EGF', 'Gene', (4, 7))	('EGF', 'Gene', (155, 158))	('Y69', 'Var', (108, 111))	('EGF', 'Gene', '1950', (4, 7))
501150	26414444	This EGF conformation was stabilized by XXYLT1 via three H-bonds (EGF N54 with XXYLT1 H262, EGF C56 with XXYLT1 H262, and EGF S61 with XXYLT1 G325), as well as hydrophobic stacking between EGF L57 and W72 and XXYLT1 W265 (Fig.	('H262', 'Chemical', '-', (86, 90))	('EGF', 'Gene', (5, 8))	('EGF', 'Gene', (92, 95))	('EGF', 'Gene', '1950', (66, 69))	('EGF', 'Gene', '1950', (189, 192))	('EGF', 'Gene', (66, 69))	('EGF', 'Gene', (189, 192))	('EGF', 'Gene', (122, 125))	('W265', 'Chemical', '-', (216, 220))	('EGF', 'Gene', '1950', (5, 8))	('XXYLT1 H262', 'Var', (79, 90))	('EGF', 'Gene', '1950', (92, 95))	('EGF', 'Gene', '1950', (122, 125))	('H262', 'Chemical', '-', (112, 116))	('hydrophobic stacking', 'Var', (160, 180))	('W72', 'Var', (201, 204))	('XXYLT1 W265', 'Var', (209, 220))
501151	26414444	Therefore, the three XXYLT1 residues (H262, W265, and G325) appeared to be important for the enzyme activity.	('H262', 'Var', (38, 42))	('W265', 'Var', (44, 48))	('W265', 'Chemical', '-', (44, 48))	('G325', 'Var', (54, 58))	('H262', 'Chemical', '-', (38, 42))
501152	26414444	Substituting residues H262 and W265 with alanines in the acceptor-binding platform significantly reduced the XXYLT1 activity in vitro (Fig.	('W265', 'Chemical', '-', (31, 35))	('reduced', 'NegReg', (97, 104))	('H262', 'Chemical', '-', (22, 26))	('W265', 'Var', (31, 35))	('H262', 'Var', (22, 26))	('alanines', 'Chemical', 'MESH:D000409', (41, 49))	('XXYLT1', 'Enzyme', (109, 115))
501158	26414444	Sequence alignment with ClustalW showed that their EGF recognition surfaces were not conserved: H262, W265, and G325 in XXYLT1 are changed to G, N/S, and I, respectively, in GXYLT1/2 (Supplementary Fig.	('EGF', 'Gene', '1950', (51, 54))	('H262', 'Var', (96, 100))	('W265', 'Var', (102, 106))	('W265', 'Chemical', '-', (102, 106))	('EGF', 'Gene', (51, 54))	('G325', 'Var', (112, 116))	('H262', 'Chemical', '-', (96, 100))
501170	26414444	7a), but the space between the UDP and Q330 was tight, leading to further shift of pyrophosphate away from the active site.	('pyrophosphate', 'Chemical', 'MESH:C107241', (83, 96))	('Q330', 'Chemical', '-', (39, 43))	('Q330', 'Var', (39, 43))	('UDP', 'Chemical', 'MESH:D014530', (31, 34))	('shift', 'Reg', (74, 79))
501184	26414444	In the beginning complex, the donor sugar xylose was stabilized by interaction of its O2 hydroxyl with enzyme Q330 and its O3 hydroxyl with enzyme L327 backbone and S289 (Supplementary Fig.	('S289', 'Var', (165, 169))	('O2 hydroxyl', 'Chemical', '-', (86, 97))	('donor', 'Species', '9606', (30, 35))	('O3 hydroxyl', 'Chemical', '-', (123, 134))	('interaction', 'Interaction', (67, 78))	('stabilized', 'MPA', (53, 63))	('Q330', 'Chemical', '-', (110, 114))	('sugar xylose', 'Chemical', '-', (36, 48))
501196	26414444	We suggest that the beta-phosphate oxygen O3B is the most likely base to deprotonate the acceptor xylose O3 OH, as the O2 OH of the donor xylose and O1B of beta-phosphate oxygen are both involved in two hydrogen bonds, compromising their basicity.	('oxygen', 'Chemical', 'MESH:D010100', (171, 177))	('donor', 'Species', '9606', (132, 137))	('xylose', 'Chemical', 'MESH:D014994', (98, 104))	('beta-phosphate', 'Chemical', '-', (156, 170))	('oxygen', 'Chemical', 'MESH:D010100', (35, 41))	('hydrogen', 'Chemical', 'MESH:D006859', (203, 211))	('compromising', 'NegReg', (219, 231))	('involved', 'Reg', (187, 195))	('basicity', 'MPA', (238, 246))	('beta-phosphate', 'Chemical', '-', (20, 34))	('O1B', 'Var', (149, 152))	('xylose', 'Chemical', 'MESH:D014994', (138, 144))
501207	26414444	To investigate if XXYLT1 activity is sensitive to the active site composition, we substituted eight residues that make contact with the donor and/or acceptor with alanine and confirmed their protein expression and folding (Supplementary Fig.	('alanine', 'Chemical', 'MESH:D000409', (163, 170))	('confirmed', 'Reg', (175, 184))	('donor', 'Species', '9606', (136, 141))	('folding', 'MPA', (214, 221))	('protein expression', 'MPA', (191, 209))	('substituted', 'Var', (82, 93))
501208	26414444	We found by in vitro activity assay that xylose transfer activity was either abolished by Q330A and W359A substitutions, or profoundly reduced by E255A, H326A, W358A, and N384A substitutions, or reduced by Q257A, and S289A substitutions (Fig.	('N384A', 'Mutation', 'p.N384A', (171, 176))	('E255A', 'Var', (146, 151))	('Q257A', 'Var', (206, 211))	('E255A', 'Mutation', 'p.E255A', (146, 151))	('W359A', 'SUBSTITUTION', 'None', (100, 105))	('Q257A', 'Mutation', 'p.Q257A', (206, 211))	('H326A', 'Mutation', 'p.H326A', (153, 158))	('xylose', 'Chemical', 'MESH:D014994', (41, 47))	('N384A', 'Var', (171, 176))	('reduced', 'NegReg', (135, 142))	('W359A', 'Var', (100, 105))	('W358A', 'Var', (160, 165))	('H326A', 'Var', (153, 158))	('abolished', 'NegReg', (77, 86))	('W358A', 'SUBSTITUTION', 'None', (160, 165))	('S289A', 'Var', (217, 222))	('S289A', 'Mutation', 'p.S289A', (217, 222))	('xylose transfer activity', 'MPA', (41, 65))	('Q330A', 'Mutation', 'p.Q330A', (90, 95))	('Q330A', 'Var', (90, 95))
501209	26414444	The crucial role of Q330 was expected from the crystal structure, because it formed a strong H-bond (2.6 A) with the O2 OH of donor xylose, and a second H-bond with the O4 OH of acceptor xylose, bringing the two xylose rings together and orienting them for the transfer reaction (Supplementary Fig.	('xylose', 'Chemical', 'MESH:D014994', (132, 138))	('Q330', 'Var', (20, 24))	('orienting', 'Reg', (238, 247))	('donor', 'Species', '9606', (126, 131))	('xylose', 'Chemical', 'MESH:D014994', (212, 218))	('bringing', 'PosReg', (195, 203))	('Q330', 'Chemical', '-', (20, 24))	('xylose', 'Chemical', 'MESH:D014994', (187, 193))
501210	26414444	W359 was particularly important for the enzyme activity, perhaps because this residue formed a H-bond with the glucose of the acceptor disaccharide.	('formed', 'Reg', (86, 92))	('disaccharide', 'Chemical', 'MESH:D004187', (135, 147))	('glucose', 'Chemical', 'MESH:D005947', (111, 118))	('W359', 'Var', (0, 4))	('H-bond', 'MPA', (95, 101))	('W359', 'Chemical', '-', (0, 4))
501211	26414444	We further hypothesized that substituting residues that were close to but do not make contact with the donor xylose (for example, XXYLT1 D225 or D329) may not adversely affect the XXYLT1 activity.	('xylose', 'Chemical', 'MESH:D014994', (109, 115))	('affect', 'Reg', (169, 175))	('XXYLT1', 'Gene', (130, 136))	('XXYLT1', 'Enzyme', (180, 186))	('activity', 'MPA', (187, 195))	('D329', 'Var', (145, 149))	('D225', 'Var', (137, 141))	('donor', 'Species', '9606', (103, 108))
501212	26414444	We produced XXYLT1 with either D225N or D329A substitution, and found that these proteins had either similar (D225N) or even increased (D329A) in vitro activity compared to the wild type enzyme (Fig.	('D329A', 'Mutation', 'p.D329A', (40, 45))	('increased', 'PosReg', (125, 134))	('D329A', 'Mutation', 'p.D329A', (136, 141))	('D225N', 'Mutation', 'p.D225N', (31, 36))	('D225N', 'Mutation', 'p.D225N', (110, 115))	('D225N', 'Var', (31, 36))	('D329A', 'Var', (136, 141))	('D329A', 'Var', (40, 45))	('D225N', 'Var', (110, 115))
501215	26414444	Because XXYLT1 negatively regulates Notch, and Notch aberrations have been linked to myeloid cancers and squamous cell carcinoma of lung, head and neck squamous cell carcinoma, we wondered if the enzyme XXYLT1 is implicated in cancer.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (152, 175))	('cancer', 'Disease', 'MESH:D009369', (227, 233))	('Notch', 'Gene', (36, 41))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (166, 175))	('Notch', 'Gene', '31293', (47, 52))	('aberrations', 'Var', (53, 64))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('squamous cell carcinoma of lung', 'Disease', (105, 136))	('negatively', 'NegReg', (15, 25))	('myeloid cancers', 'Disease', (85, 100))	('cancer', 'Disease', (227, 233))	('myeloid cancers', 'Disease', 'MESH:D009369', (85, 100))	('Notch', 'Gene', (47, 52))	('cancers', 'Phenotype', 'HP:0002664', (93, 100))	('neck squamous cell carcinoma', 'Disease', (147, 175))	('cancer', 'Disease', (93, 99))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('Notch', 'Gene', '31293', (36, 41))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (147, 175))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('carcinoma of lung', 'Phenotype', 'HP:0100526', (119, 136))	('squamous cell carcinoma of lung', 'Disease', 'MESH:D002294', (105, 136))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (105, 128))	('linked', 'Reg', (75, 81))
501217	26414444	We also identified 22 cancer-associated missense mutations (Supplementary Table 3), although mutation occurred at a much lower frequency than amplification.	('missense mutations', 'Var', (40, 58))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('cancer', 'Disease', (22, 28))	('cancer', 'Disease', 'MESH:D009369', (22, 28))
501218	26414444	Four mutations (Q266K, D319N, R324S and G325S) were close to the bound EGF acceptor.	('EGF', 'Gene', (71, 74))	('D319N', 'SUBSTITUTION', 'None', (23, 28))	('R324S', 'Mutation', 'p.R324S', (30, 35))	('G325S', 'Var', (40, 45))	('EGF', 'Gene', '1950', (71, 74))	('D319N', 'Var', (23, 28))	('Q266K', 'Var', (16, 21))	('G325S', 'SUBSTITUTION', 'None', (40, 45))	('Q266K', 'Mutation', 'p.Q266K', (16, 21))	('R324S', 'Var', (30, 35))
501219	26414444	We found that Q266K and D319N retained the enzymatic activity while R324S and G325S reduced the activity by ~ 50-80 % (Fig.	('D319N', 'Var', (24, 29))	('R324S', 'Var', (68, 73))	('activity', 'MPA', (96, 104))	('Q266K', 'Var', (14, 19))	('Q266K', 'Mutation', 'p.Q266K', (14, 19))	('G325S', 'Var', (78, 83))	('reduced', 'NegReg', (84, 91))	('R324S', 'Mutation', 'p.R324S', (68, 73))	('enzymatic activity', 'MPA', (43, 61))	('G325S', 'SUBSTITUTION', 'None', (78, 83))	('D319N', 'SUBSTITUTION', 'None', (24, 29))
501220	26414444	Notably, the activity-reducing mutations occurred in cancers with much lower incidence of XXYLT1 amplification (Fig.	('cancers', 'Phenotype', 'HP:0002664', (53, 60))	('XXYLT1', 'Gene', (90, 96))	('mutations', 'Var', (31, 40))	('cancers', 'Disease', (53, 60))	('activity-reducing', 'MPA', (13, 30))	('cancers', 'Disease', 'MESH:D009369', (53, 60))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))
501228	26414444	During this process, an oxocarbenium ion character would likely develop, in which case the transient positive charge could be stabilized by the nearby Q330.	('Q330', 'Var', (151, 155))	('transient positive charge', 'MPA', (91, 116))	('Q330', 'Chemical', '-', (151, 155))	('oxocarbenium ion character', 'MPA', (24, 50))	('oxocarbenium', 'Chemical', '-', (24, 36))
501241	26414444	In most cases, aberrant Notch activation is oncogenic.	('Notch', 'Gene', (24, 29))	('activation', 'PosReg', (30, 40))	('Notch', 'Gene', '31293', (24, 29))	('aberrant', 'Var', (15, 23))
501242	26414444	However, in some cases such as squamous carcinomas derived from the epidermis, lung, and head and neck, and acute myeloid leukemia, inactivation of Notch signaling is oncogenic.	('acute myeloid leukemia', 'Disease', (108, 130))	('squamous carcinomas', 'Disease', 'MESH:D002294', (31, 50))	('leukemia', 'Phenotype', 'HP:0001909', (122, 130))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (108, 130))	('oncogenic', 'Reg', (167, 176))	('inactivation', 'Var', (132, 144))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (108, 130))	('Notch', 'Gene', (148, 153))	('carcinoma', 'Phenotype', 'HP:0030731', (40, 49))	('carcinomas', 'Phenotype', 'HP:0030731', (40, 50))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (114, 130))	('squamous carcinomas', 'Disease', (31, 50))	('Notch', 'Gene', '31293', (148, 153))
501244	26414444	R324S and G325S) caused reduced XXYLT1 activity, which may lead to enhanced Notch signaling, many more cancers show amplified XXYLT1, which would lead to reduced Notch signaling.	('cancers', 'Disease', 'MESH:D009369', (103, 110))	('Notch', 'Gene', (162, 167))	('Notch', 'Gene', (76, 81))	('enhanced', 'PosReg', (67, 75))	('amplified', 'PosReg', (116, 125))	('G325S', 'SUBSTITUTION', 'None', (10, 15))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('activity', 'MPA', (39, 47))	('cancers', 'Phenotype', 'HP:0002664', (103, 110))	('cancers', 'Disease', (103, 110))	('reduced', 'NegReg', (24, 31))	('R324S', 'Mutation', 'p.R324S', (0, 5))	('XXYLT1', 'Enzyme', (32, 38))	('G325S', 'Var', (10, 15))	('Notch', 'Gene', '31293', (162, 167))	('Notch', 'Gene', '31293', (76, 81))	('XXYLT1', 'Gene', (126, 132))	('reduced', 'NegReg', (154, 161))	('R324S', 'Var', (0, 5))
501263	26414444	Crystals of the XXYLT1:Xyl-Glc-EGF binary complex were obtained several days after setting up the hanging-drop vapor diffusion plates at 20 C using a reservoir solution containing 0.2 M Li2SO4, 0.1 M Bis-Tris, pH 6.5, and 21% PEG3350.	('EGF', 'Gene', '1950', (31, 34))	('Bis-Tris', 'Chemical', 'MESH:C026272', (200, 208))	('Li2SO4', 'Var', (186, 192))	('PEG3350', 'Chemical', 'MESH:C000595212', (226, 233))	('Xyl-Glc', 'Chemical', 'MESH:C061908', (23, 30))	('EGF', 'Gene', (31, 34))	('Li2SO4', 'Chemical', 'MESH:C054097', (186, 192))
501285	26414444	To determine if any of the mutations disturbed the folding of the protein, the spectra of the native tryptophan residues were recorded for both the wild type and each of the mutants.	('mutations', 'Var', (27, 36))	('folding', 'MPA', (51, 58))	('disturbed', 'Reg', (37, 46))	('tryptophan', 'Chemical', 'MESH:D014364', (101, 111))
501293	26414444	This suggests that these mutations had no significant effect on the solvent accessibility of tryptophan residues.	('mutations', 'Var', (25, 34))	('solvent accessibility of tryptophan residues', 'MPA', (68, 112))	('tryptophan', 'Chemical', 'MESH:D014364', (93, 103))
501306	33766047	The online version contains supplementary material available at 10.1186/s12967-021-02773-x For decades, cancer has been one of the leading causes of deaths worldwide, while the activating invasion is one of the six hallmark capabilities of the cancer and greatly worse the patients' prognosis.	('patients', 'Species', '9606', (273, 281))	('deaths', 'Disease', 'MESH:D003643', (149, 155))	('deaths', 'Disease', (149, 155))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('worse', 'Reg', (263, 268))	('activating invasion', 'Var', (177, 196))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('cancer', 'Disease', (244, 250))	('cancer', 'Disease', 'MESH:D009369', (244, 250))
501309	33766047	In recent years, pan-cancer analysis projects of specific function and biological pathway genes aimed at identifying the common molecular features across multiple tumor types have been increasingly reported and remarkably provided a multi-dimensional, in-depth, and comprehensive understanding of human cancer.	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('cancer', 'Disease', (303, 309))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('cancer', 'Phenotype', 'HP:0002664', (303, 309))	('tumor', 'Disease', (163, 168))	('cancer', 'Disease', (21, 27))	('cancer', 'Disease', 'MESH:D009369', (21, 27))	('human', 'Species', '9606', (297, 302))	('genes', 'Var', (90, 95))	('cancer', 'Disease', 'MESH:D009369', (303, 309))
501349	33766047	Patients in the high- and low-invasiveness groups showed distinct enrichment of the 24 genes in our signature (Additional file 7: Figure S2B), and high-invasiveness scores were consistently associated with worse prognosis in the majority of the 30 cancer types, including LUAD (hazard ratio [HR]: 1.73 (1.10-2.70), p = 0.015), LUSC (HR: 1.64 (1.02-2.63), p = 0.037), and esophageal carcinoma (ESCA; HR: 2.54 (1.23-5.25), p = 0.011; (Fig.	('cancer', 'Disease', (248, 254))	('esophageal carcinoma', 'Disease', (371, 391))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (371, 391))	('carcinoma', 'Phenotype', 'HP:0030731', (382, 391))	('LUAD', 'Disease', (272, 276))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (371, 391))	('cancer', 'Phenotype', 'HP:0002664', (248, 254))	('LUSC', 'Disease', (327, 331))	('Patients', 'Species', '9606', (0, 8))	('cancer', 'Disease', 'MESH:D009369', (248, 254))	('high-invasiveness', 'Var', (147, 164))
501355	33766047	Based on the invasiveness group determined by RNA-sequencing data, the 24-gene signature, which corresponds to 24 proteins, was also enriched in the high-invasiveness score group for both cancer types (FDR = 0.00261 for BRCA and 0.0021 for OV; Fig.	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('BRCA', 'Gene', (220, 224))	('0.0021', 'Var', (229, 235))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('OV; Fig', 'Disease', (240, 247))	('cancer', 'Disease', (188, 194))	('BRCA', 'Gene', '672', (220, 224))
501379	33766047	Overexpression of COL3A1 mRNA in 435 cell lines was linked to higher sensitivity to four anti-cancer drugs, including the ATM kinase inhibitor KU55933 (r = - 0.599).	('COL3A1', 'Gene', '1281', (18, 24))	('sensitivity', 'MPA', (69, 80))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('mRNA', 'Var', (25, 29))	('COL3A1', 'Gene', (18, 24))	('higher', 'PosReg', (62, 68))	('Overexpression', 'Var', (0, 14))	('KU55933', 'Chemical', 'MESH:C495818', (143, 150))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
501383	33766047	In terms of drugs, we identified the DNA-PK inhibitor NU7441, the GSK3 inhibitor SB216763, and KU55933 as three "core nodes" in the network since they were significantly correlated with the expression of 77, 91, and 110 invasiveness-related DEGs in our analysis (Fig.	('NU7441', 'Chemical', 'MESH:C499693', (54, 60))	('SB216763', 'Chemical', 'MESH:C417521', (81, 89))	('correlated', 'Reg', (170, 180))	('KU55933', 'Chemical', 'MESH:C495818', (95, 102))	('NU7441', 'Var', (54, 60))	('KU55933', 'Var', (95, 102))	('DNA-PK', 'Gene', (37, 43))	('expression', 'MPA', (190, 200))	('DNA-PK', 'Gene', '5591', (37, 43))
501387	33766047	Interestingly, we noticed that "response to hypoxia" [GO: 0001666] and a series of immune-related pathways like T cell activation (GO: 0050863) were also generally enriched across multiple tumor types (Fig.	('tumor', 'Disease', (189, 194))	('hypoxia', 'Disease', 'MESH:D000860', (44, 51))	('hypoxia', 'Disease', (44, 51))	('GO: 0050863', 'Var', (131, 142))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))
501394	33766047	DNA methylation was the first epigenetic abnormality recognized in human cancer and is a ubiquitous feature of carcinogenesis, where hypermethylation generally leads to gene silencing and hypomethylation results in overexpression.	('carcinogenesis', 'Disease', (111, 125))	('cancer', 'Disease', (73, 79))	('hypomethylation', 'Var', (188, 203))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('overexpression', 'PosReg', (215, 229))	('gene', 'MPA', (169, 173))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('carcinogenesis', 'Disease', 'MESH:D063646', (111, 125))	('human', 'Species', '9606', (67, 72))	('silencing', 'NegReg', (174, 183))	('hypermethylation', 'Var', (133, 149))
501397	33766047	The genes were classified into four groups based on the intersection between invasiveness-associated DMGs and DEGs: hypermethylated and upregulated (hyper-up), hypermethylated and downregulated (hyper-down), hypomethylated and upregulated (hypo-up), and hypomethylated and downregulated (hypo-down) (Fig.	('upregulated', 'PosReg', (136, 147))	('hypermethylated', 'Var', (160, 175))	('hypomethylated', 'Var', (208, 222))	('hypermethylated', 'Var', (116, 131))	('upregulated', 'PosReg', (227, 238))	('hypomethylated', 'Var', (254, 268))	('downregulated', 'NegReg', (180, 193))	('DMGs', 'Chemical', '-', (101, 105))	('downregulated', 'NegReg', (273, 286))
501410	33766047	For example, ADAM12, a biomarker of cancer stem cell phenotype which has been reported to promote esophageal squamous cell carcinomas invasion, was upregulated in high-invasiveness ESCA patients (logFC = 2.01, FDR = 2.92 x 10-22), and showed hypomethylation in the promoter region (logFC, or delta-beta = - 0.25, FDR = 0.0005).	('squamous cell carcinomas invasion', 'Disease', 'MESH:D002294', (109, 142))	('high-invasiveness ESCA', 'Disease', (163, 185))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (109, 133))	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('cancer', 'Disease', (36, 42))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (109, 132))	('carcinomas', 'Phenotype', 'HP:0030731', (123, 133))	('promote', 'PosReg', (90, 97))	('hypomethylation', 'Var', (242, 257))	('upregulated', 'PosReg', (148, 159))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('ADAM12', 'Gene', '8038', (13, 19))	('ADAM12', 'Gene', (13, 19))	('patients', 'Species', '9606', (186, 194))	('squamous cell carcinomas invasion', 'Disease', (109, 142))
501412	33766047	Three miRNAs that target the 3'-UTR regions of ADAM12 exhibited significant downregulation in the high-invasiveness score group (miR-130b-3p: logFC = - 0.535, FDR = 0.041; miR-130b-3p: logFC = - 0.509, FDR = 0.005; miR-502-3p: logFC = - 0.713, FDR = 1.554 x 10-04), and the miRNAs positively correlated with drug responses (resistance) which have negative correlations with ADAM12, such as miR-30b-5p with Imatinib and Docetaxel (r = 0.418 and r = 0.404, respectively) and miR-502-3p with Imatinib and Cisplatin (r = 0.484 and r = 0.470, respectively).	('Imatinib', 'Chemical', 'MESH:D000068877', (406, 414))	('miR-502-3p', 'Var', (473, 483))	('miR-130b-3p', 'Var', (172, 183))	('miR-30b', 'Gene', '407030', (390, 397))	('miR-30b', 'Gene', (390, 397))	('Docetaxel', 'Chemical', 'MESH:D000077143', (419, 428))	('ADAM12', 'Gene', '8038', (47, 53))	('ADAM12', 'Gene', '8038', (374, 380))	('ADAM12', 'Gene', (47, 53))	('downregulation', 'NegReg', (76, 90))	('ADAM12', 'Gene', (374, 380))	('Cisplatin', 'Chemical', 'MESH:D002945', (502, 511))	('Imatinib', 'Chemical', 'MESH:D000068877', (489, 497))	('drug responses', 'MPA', (308, 322))
501421	33766047	The interruption of any one or more of these steps could potentially inhibit the development of tumor invasiveness.	('tumor invasiveness', 'Disease', (96, 114))	('tumor invasiveness', 'Disease', 'MESH:D009361', (96, 114))	('interruption', 'Var', (4, 16))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('inhibit', 'NegReg', (69, 76))
501429	33766047	indicated that SULF1 normally functions as a negative regulator in HNSC and loss of it potentiates growth factor signaling, enhances motility, invasiveness and inhibits stress-induced apoptosis.	('invasiveness', 'CPA', (143, 155))	('potentiates', 'PosReg', (87, 98))	('loss', 'Var', (76, 80))	('growth factor signaling', 'MPA', (99, 122))	('SULF1', 'Gene', '23213', (15, 20))	('stress-induced apoptosis', 'CPA', (169, 193))	('SULF1', 'Gene', (15, 20))	('inhibits', 'NegReg', (160, 168))	('motility', 'CPA', (133, 141))	('enhances', 'PosReg', (124, 132))
501438	33766047	Another "core" drug, the DNA-PK inhibitor NU7441, has been demonstrated to increase cancer cell sensitivity to chemotherapy and radiotherapy.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('DNA-PK', 'Gene', (25, 31))	('cancer', 'Disease', (84, 90))	('NU7441', 'Chemical', 'MESH:C499693', (42, 48))	('DNA-PK', 'Gene', '5591', (25, 31))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('increase', 'PosReg', (75, 83))	('NU7441', 'Var', (42, 48))
501463	29625613	The unique cytomorphologic features of SCC variants lead to distinct treatment and outcomes.	('SCC', 'Gene', '6317', (39, 42))	('SCC', 'Gene', (39, 42))	('variants', 'Var', (43, 51))	('lead to', 'Reg', (52, 59))	('SCC', 'Phenotype', 'HP:0002860', (39, 42))
501466	29625613	The CD109 protein contains a 21 aa N-terminal leader peptide, a putative bait region (aa 651-683), a thioester binding site (aa 918-924), a thioester reactivity defining hexapeptide (aa1030-1035) and a C-terminal consensus GPI-anchor signal sequence with the cleavage predicted to occur after amino acid 1420 (Fig.	('GPI', 'Chemical', 'MESH:D017261', (223, 226))	('aa1030-1035', 'Var', (183, 194))	('amino acid 1420', 'Var', (293, 308))	('CD109', 'Gene', (4, 9))
501505	29625613	Furthermore, the expression pattern is validated on fresh surgical PSCC samples by immunofluorescence, qRT-PCR and western blotting, suggesting that CD109 may be a biomarker for PSCC.	('SCC', 'Phenotype', 'HP:0002860', (68, 71))	('SCC', 'Gene', '6317', (68, 71))	('SCC', 'Gene', (179, 182))	('SCC', 'Phenotype', 'HP:0002860', (179, 182))	('CD109', 'Var', (149, 154))	('SCC', 'Gene', '6317', (179, 182))	('SCC', 'Gene', (68, 71))
501507	29625613	Loss of function mutation in TGF-beta type II receptor is a frequent event for oral cavity SCC.	('mutation', 'Var', (17, 25))	('TGF-beta type II receptor', 'Gene', '7048', (29, 54))	('TGF-beta type II receptor', 'Gene', (29, 54))	('Loss of function', 'NegReg', (0, 16))	('SCC', 'Gene', (91, 94))	('SCC', 'Phenotype', 'HP:0002860', (91, 94))	('SCC', 'Gene', '6317', (91, 94))
501511	29625613	In addition, OSCC cell lines overexpressing CD109 exhibited accelerated cell growth in vitro, implicating that CD109 involves in the progression of OSCCs.	('involves', 'Reg', (117, 125))	('SCC', 'Gene', (149, 152))	('accelerated', 'PosReg', (60, 71))	('CD109', 'Var', (111, 116))	('SCC', 'Gene', (14, 17))	('SCC', 'Phenotype', 'HP:0002860', (14, 17))	('SCC', 'Phenotype', 'HP:0002860', (149, 152))	('SCC', 'Gene', '6317', (149, 152))	('SCC', 'Gene', '6317', (14, 17))	('cell growth in vitro', 'CPA', (72, 92))	('CD109', 'Var', (44, 49))
501516	29625613	As CD109 is distinctly expressed in malignant sqamous cells in gallbladder, CD109 may be a diagnostic marker for gallbladder SCCs and ASCs.	('CD109', 'Var', (76, 81))	('ASCs', 'Disease', (134, 138))	('SCC', 'Gene', (125, 128))	('CD109', 'Gene', (3, 8))	('SCC', 'Phenotype', 'HP:0002860', (125, 128))	('SCC', 'Gene', '6317', (125, 128))
501528	29625613	Dysregulation of the TGF-beta pathway has been implicated in multiple types of cancer.	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('Dysregulation', 'Var', (0, 13))	('implicated', 'Reg', (47, 57))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('TGF-beta', 'Gene', '7040', (21, 29))	('cancer', 'Disease', (79, 85))	('TGF-beta', 'Gene', (21, 29))
501530	29625613	Mutations in the TGF-betaR1 gene have also been found in SCCs of the skin, suggesting that the inactivation of TGF-beta leads to the initiation of SCCs.	('TGF-beta', 'Gene', (17, 25))	('TGF-beta', 'Gene', '7040', (111, 119))	('leads to', 'Reg', (120, 128))	('SCC', 'Gene', (147, 150))	('SCC', 'Gene', '6317', (57, 60))	('betaR1', 'Gene', '6373', (21, 27))	('SCC', 'Phenotype', 'HP:0002860', (57, 60))	('SCC', 'Phenotype', 'HP:0002860', (147, 150))	('TGF-beta', 'Gene', (111, 119))	('SCC', 'Gene', '6317', (147, 150))	('Mutations', 'Var', (0, 9))	('TGF-beta', 'Gene', '7040', (17, 25))	('found', 'Reg', (48, 53))	('betaR1', 'Gene', (21, 27))	('SCC', 'Gene', (57, 60))	('inactivation', 'Var', (95, 107))
501535	29625613	In addition, CD109 promotes localization of the TGF-beta receptors into the caveolar compartment in the presence of ligand and facilitates TGF-beta receptor degradation.	('CD109', 'Var', (13, 18))	('facilitates', 'PosReg', (127, 138))	('promotes', 'PosReg', (19, 27))	('TGF-beta', 'Gene', (48, 56))	('TGF-beta', 'Gene', '7040', (139, 147))	('localization', 'MPA', (28, 40))	('TGF-beta', 'Gene', (139, 147))	('TGF-beta', 'Gene', '7040', (48, 56))	('degradation', 'MPA', (157, 168))
501542	29625613	They demonstrate that ALK1 is expressed and co-localizes with CD109 in mouse keratinocytes and that mice overexpressing CD109 in the epidermis display enhanced ALK1-Smad1/5 signaling, but decreased ALK5-Smad2/3 signaling.	('decreased', 'NegReg', (188, 197))	('enhanced', 'PosReg', (151, 159))	('ALK5-Smad2/3 signaling', 'MPA', (198, 220))	('mice', 'Species', '10090', (100, 104))	('ALK1', 'Gene', (22, 26))	('ALK1-Smad1/5 signaling', 'MPA', (160, 182))	('mouse', 'Species', '10090', (71, 76))	('CD109', 'Var', (120, 125))
501545	29625613	In contrast, SCC cells with CD109 knockdown exhibited slower cell growth.	('slower', 'NegReg', (54, 60))	('SCC', 'Phenotype', 'HP:0002860', (13, 16))	('SCC', 'Gene', '6317', (13, 16))	('cell growth', 'CPA', (61, 72))	('CD109', 'Gene', (28, 33))	('knockdown', 'Var', (34, 43))	('SCC', 'Gene', (13, 16))
501546	29625613	A high level of CD109 expression inhibited Smad2 phosphorylation, thus attenuated TGF-beta1/Smad2 signaling and impairs TGF-beta1-mediated suppression of cell growth, CD109 knockdown increased Smad2 phosphorylation by TGF-beta1 stimulation.	('suppression', 'MPA', (139, 150))	('CD109', 'Gene', (167, 172))	('Smad2', 'Gene', '4087', (193, 198))	('knockdown', 'Var', (173, 182))	('Smad2', 'Gene', (43, 48))	('TGF-beta1', 'Gene', '7040', (218, 227))	('TGF-beta1', 'Gene', '7040', (82, 91))	('phosphorylation', 'MPA', (49, 64))	('TGF-beta1', 'Gene', (120, 129))	('CD109', 'Gene', (16, 21))	('phosphorylation', 'MPA', (199, 214))	('Smad2', 'Gene', (193, 198))	('attenuated', 'NegReg', (71, 81))	('TGF-beta1', 'Gene', '7040', (120, 129))	('inhibited', 'NegReg', (33, 42))	('Smad2', 'Gene', '4087', (92, 97))	('cell', 'CPA', (154, 158))	('Smad2', 'Gene', '4087', (43, 48))	('impairs', 'NegReg', (112, 119))	('increased', 'PosReg', (183, 192))	('Smad2', 'Gene', (92, 97))	('TGF-beta1', 'Gene', (218, 227))	('TGF-beta1', 'Gene', (82, 91))
501548	29625613	Together, CD109 facilitates the development of SCCs via inhibition of the TGF-beta-Smad2/3 pathway (Fig.	('inhibition', 'NegReg', (56, 66))	('CD109', 'Var', (10, 15))	('SCC', 'Phenotype', 'HP:0002860', (47, 50))	('SCC', 'Gene', '6317', (47, 50))	('TGF-beta', 'Gene', '7040', (74, 82))	('facilitates', 'PosReg', (16, 27))	('TGF-beta', 'Gene', (74, 82))	('SCC', 'Gene', (47, 50))
501551	29625613	In vitro, they found that transfection of CD109 siRNA down-regulates STAT3, release of CD109 from the cell surface of cultured human keratinocytes.	('down-regulates', 'NegReg', (54, 68))	('transfection', 'Var', (26, 38))	('human', 'Species', '9606', (127, 132))	('CD109', 'Gene', (42, 47))	('STAT3', 'MPA', (69, 74))	('release of CD109', 'MPA', (76, 92))
501553	29625613	reported that CD109 expression was dramatic upregulated in metastatic lung adenocarcinoma cells, and cells expressing a CD109 shRNA (shCD109) showed a dramatic reduction in STAT3 phosphorylation.	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('reduction', 'NegReg', (160, 169))	('expression', 'MPA', (20, 30))	('upregulated', 'PosReg', (44, 55))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (70, 89))	('CD109', 'Gene', (14, 19))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (70, 89))	('STAT3 phosphorylation', 'MPA', (173, 194))	('CD109', 'Var', (120, 125))	('lung adenocarcinoma', 'Disease', (70, 89))
501554	29625613	STAT3 knockdown greatly reduced metastases, and restoration of STAT3 activity increased the ability of shCD109-expressing cells to metastasize.	('activity', 'MPA', (69, 77))	('reduced', 'NegReg', (24, 31))	('metastases', 'Disease', (32, 42))	('increased', 'PosReg', (78, 87))	('metastases', 'Disease', 'MESH:D009362', (32, 42))	('knockdown', 'Var', (6, 15))	('STAT3', 'Gene', (0, 5))
501560	29625613	The discrepancy of the results from in vitro and in vivo studies might be caused by the systematic changes of microenvironment in the tissues of CD109 deficient mice.	('mice', 'Species', '10090', (161, 165))	('deficient', 'Var', (151, 160))	('CD109', 'Gene', (145, 150))
501561	29625613	Loss of CD109 in all the cells in mice might modify the subcutaneous microenvironment which activates STAT3 signaling in keratinocytes.	('mice', 'Species', '10090', (34, 38))	('STAT3 signaling', 'MPA', (102, 117))	('activates', 'PosReg', (92, 101))	('modify', 'Reg', (45, 51))	('Loss', 'Var', (0, 4))	('CD109', 'Gene', (8, 13))
501567	29625613	Mutations that lead to EGFR overexpression are detected in lung SCC, head and neck SCC, and esophagus SCC.	('lung SCC', 'Disease', 'MESH:D008171', (59, 67))	('SCC', 'Phenotype', 'HP:0002860', (102, 105))	('SCC', 'Gene', '6317', (102, 105))	('SCC', 'Gene', '6317', (64, 67))	('SCC', 'Gene', (83, 86))	('EGFR', 'Gene', '1956', (23, 27))	('Mutations', 'Var', (0, 9))	('SCC', 'Gene', '6317', (83, 86))	('SCC', 'Phenotype', 'HP:0002860', (83, 86))	('overexpression', 'PosReg', (28, 42))	('lung SCC', 'Disease', (59, 67))	('EGFR', 'Gene', (23, 27))	('SCC', 'Gene', (102, 105))	('SCC', 'Gene', (64, 67))	('SCC', 'Phenotype', 'HP:0002860', (64, 67))
501595	28849182	In vitro and in vivo antitumor effects of chloroquine on oral squamous cell carcinoma Chloroquine, which is a widely used antimalarial drug, has been reported to exert anticancer activity in some tumor types; however, its potential effects on oral squamous cell carcinoma (OSCC) remain unclear.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumor', 'Disease', (196, 201))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (248, 271))	('Chloroquine', 'Var', (86, 97))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (62, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (262, 271))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (248, 271))	('chloroquine', 'Chemical', 'MESH:D002738', (42, 53))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (62, 85))	('tumor', 'Disease', (25, 30))	('squamous cell carcinoma', 'Disease', (248, 271))	('cancer', 'Disease', (172, 178))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('Chloroquine', 'Chemical', 'MESH:D002738', (86, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('squamous cell carcinoma', 'Disease', (62, 85))
501602	28849182	In addition, chloroquine inhibited autophagy, and induced autophagosome and autolysosome accumulation in the cytoplasm, thus interfering with degradation; however, OSCC apoptosis was barely affected by chloroquine.	('induced', 'Reg', (50, 57))	('chloroquine', 'Chemical', 'MESH:D002738', (13, 24))	('degradation', 'MPA', (142, 153))	('chloroquine', 'Chemical', 'MESH:D002738', (202, 213))	('autophagosome', 'CPA', (58, 71))	('autophagy', 'CPA', (35, 44))	('chloroquine', 'Var', (13, 24))	('interfering', 'NegReg', (125, 136))	('autolysosome accumulation', 'CPA', (76, 101))	('inhibited', 'NegReg', (25, 34))
501606	28849182	Previous studies have suggested that chloroquine may be regarded as an effective anticancer drug, according to the 'old drugs-new uses' repositioning strategy, since chloroquine has been reported to exert numerous biological effects, including inhibiting cell growth and/or inducing cell death of various types of cancer cells, overcoming chemoresistance, increasing radiosensitivity and eliminating cancer stem cells.	('chloroquine', 'Chemical', 'MESH:D002738', (37, 48))	('cancer', 'Disease', (400, 406))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('increasing', 'PosReg', (356, 366))	('inhibiting', 'NegReg', (244, 254))	('chemoresistance', 'CPA', (339, 354))	('cancer', 'Phenotype', 'HP:0002664', (400, 406))	('cell growth', 'CPA', (255, 266))	('overcoming', 'PosReg', (328, 338))	('cancer', 'Disease', 'MESH:D009369', (314, 320))	('increasing radiosensitivity', 'Phenotype', 'HP:0010997', (356, 383))	('cancer', 'Disease', 'MESH:D009369', (400, 406))	('cancer', 'Disease', (85, 91))	('eliminating', 'NegReg', (388, 399))	('chloroquine', 'Chemical', 'MESH:D002738', (166, 177))	('inducing', 'Reg', (274, 282))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('cell death', 'CPA', (283, 293))	('chloroquine', 'Var', (166, 177))	('cancer', 'Disease', (314, 320))	('cancer', 'Phenotype', 'HP:0002664', (314, 320))	('radiosensitivity', 'CPA', (367, 383))
501646	28849182	The anti-LC3B (2775S) antibody produced two clear bands representing LC3-I (16 kDa) and LC3-II (14 kDa).	('LC3', 'Gene', '84557', (69, 72))	('LC3B', 'Gene', '81631', (9, 13))	('LC3', 'Gene', (69, 72))	('2775S', 'Var', (15, 20))	('LC3B', 'Gene', (9, 13))	('LC3', 'Gene', '84557', (9, 12))	('LC3', 'Gene', '84557', (88, 91))	('LC3', 'Gene', (9, 12))	('LC3', 'Gene', (88, 91))
501661	28849182	Results indicated a marked decrease in OSCC cell colony formation following treatment with chloroquine, in a dose-dependent manner (Fig.	('chloroquine', 'Chemical', 'MESH:D002738', (91, 102))	('OSCC cell colony formation', 'CPA', (39, 65))	('decrease', 'NegReg', (27, 35))	('chloroquine', 'Var', (91, 102))
501697	28849182	The results demonstrated that both OSCC cell lines treated with chloroquine exhibited a reduction in proliferation in a dose- and time-dependent manner.	('proliferation', 'CPA', (101, 114))	('reduction', 'NegReg', (88, 97))	('chloroquine', 'Chemical', 'MESH:D002738', (64, 75))	('chloroquine', 'Var', (64, 75))
501700	28849182	In addition, cyclin D1 polymorphism is associated with an increased susceptibility to OSCC.	('cyclin D1', 'Gene', (13, 22))	('OSCC', 'Disease', (86, 90))	('cyclin D1', 'Gene', '595', (13, 22))	('polymorphism', 'Var', (23, 35))
501727	28984774	From sequencing data, mutations in KRAS proto-oncogene, GTPase (KRAS), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), and tumor protein p53 (TP53) were found in the tumor biopsy of the patient.	('GTPase', 'Gene', (56, 62))	('p53', 'Gene', (170, 173))	('tumor', 'Disease', (156, 161))	('TP53', 'Gene', '7157', (175, 179))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha', 'Gene', '5290', (71, 141))	('KRAS', 'Gene', '3845', (35, 39))	('PIK3CA', 'Gene', '5290', (143, 149))	('KRAS', 'Gene', '3845', (64, 68))	('tumor', 'Disease', (199, 204))	('KRAS', 'Gene', (35, 39))	('patient', 'Species', '9606', (219, 226))	('KRAS', 'Gene', (64, 68))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('mutations', 'Var', (22, 31))	('TP53', 'Gene', (175, 179))	('PIK3CA', 'Gene', (143, 149))	('p53', 'Gene', '7157', (170, 173))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))
501744	28984774	The patient was diagnosed as T4N0M1b, stage IV left upper lobe lung SCC with metastases to the base of the tongue, according to the TNM staging system.	('TNM', 'Gene', (132, 135))	('SCC', 'Phenotype', 'HP:0002860', (68, 71))	('upper lobe lung SCC', 'Disease', 'MESH:D008171', (52, 71))	('upper lobe lung SCC', 'Disease', (52, 71))	('patient', 'Species', '9606', (4, 11))	('metastases', 'Disease', (77, 87))	('TNM', 'Gene', '10178', (132, 135))	('metastases', 'Disease', 'MESH:D009362', (77, 87))	('T4N0M1b', 'Var', (29, 36))
501767	28984774	Treatment of selected patients with advanced NSCLC that harbors specific oncogenic alterations, including epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) rearrangements, had been revolutionized.	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (160, 179))	('anaplastic lymphoma kinase', 'Gene', (160, 186))	('mutations', 'Var', (146, 155))	('EGFR', 'Gene', (140, 144))	('ALK', 'Gene', (188, 191))	('NSCLC', 'Phenotype', 'HP:0030358', (45, 50))	('NSCLC', 'Disease', (45, 50))	('patients', 'Species', '9606', (22, 30))	('epidermal growth factor receptor', 'Gene', '1956', (106, 138))	('lymphoma', 'Phenotype', 'HP:0002665', (171, 179))	('NSCLC', 'Disease', 'MESH:D002289', (45, 50))	('rearrangements', 'Var', (193, 207))	('ALK', 'Gene', '238', (188, 191))	('anaplastic lymphoma kinase', 'Gene', '238', (160, 186))	('EGFR', 'Gene', '1956', (140, 144))	('epidermal growth factor receptor', 'Gene', (106, 138))
501771	28984774	Immune checkpoint inhibitors, including monoclonal antibodies directed against cytotoxic T-lymphocyte-associated antigen-4 (such as ipilimumab and tremelimumab) and programmed cell death protein-1/programmed cell death ligand-1 pathway (such as nivolumab and pembrolizumab), have been shown to induce significant and prolonged clinical responses, with a manageable toxicity profile in patients with advanced NSCLC, for both SCC or adenocarcinoma, independently of any somatically activated oncogenes.	('adenocarcinoma', 'Disease', 'MESH:D000230', (431, 445))	('toxicity', 'Disease', 'MESH:D064420', (365, 373))	('SCC', 'Gene', '6317', (424, 427))	('nivolumab', 'Chemical', 'MESH:D000077594', (245, 254))	('SCC', 'Gene', (424, 427))	('patients', 'Species', '9606', (385, 393))	('toxicity', 'Disease', (365, 373))	('carcinoma', 'Phenotype', 'HP:0030731', (436, 445))	('NSCLC', 'Disease', 'MESH:D002289', (408, 413))	('monoclonal', 'Var', (40, 50))	('tremelimumab', 'Chemical', 'MESH:C520704', (147, 159))	('pembrolizumab', 'Chemical', 'MESH:C582435', (259, 272))	('man', 'Species', '9606', (354, 357))	('NSCLC', 'Disease', (408, 413))	('adenocarcinoma', 'Disease', (431, 445))	('clinical', 'MPA', (327, 335))	('ipilimumab', 'Chemical', 'MESH:D000074324', (132, 142))	('NSCLC', 'Phenotype', 'HP:0030358', (408, 413))	('SCC', 'Phenotype', 'HP:0002860', (424, 427))
501782	28984774	KRAS and PIK3CA are in pathways downstream of EGFR, and their mutations induce resistance to EGFR-TKI agents.	('EGFR', 'Gene', '1956', (93, 97))	('PIK3CA', 'Gene', '5290', (9, 15))	('induce', 'Reg', (72, 78))	('PIK3CA', 'Gene', (9, 15))	('EGFR', 'Gene', (93, 97))	('EGFR', 'Gene', '1956', (46, 50))	('EGFR', 'Gene', (46, 50))	('resistance', 'MPA', (79, 89))	('KRAS', 'Gene', (0, 4))	('mutations', 'Var', (62, 71))	('KRAS', 'Gene', '3845', (0, 4))
501783	28984774	Current research suggests that KRAS mutation is the main driver of poor prognosis in patients with NSCLC, and also may be a common cause of cancer recurrence, but unfortunately, no drugs are available that directly address KRAS mutation.	('KRAS', 'Gene', (31, 35))	('KRAS', 'Gene', (223, 227))	('KRAS', 'Gene', '3845', (223, 227))	('NSCLC', 'Phenotype', 'HP:0030358', (99, 104))	('KRAS', 'Gene', '3845', (31, 35))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('patients', 'Species', '9606', (85, 93))	('cause', 'Reg', (131, 136))	('NSCLC', 'Disease', (99, 104))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('mutation', 'Var', (36, 44))	('NSCLC', 'Disease', 'MESH:D002289', (99, 104))
501784	28984774	Mutations leading to the inactivation of Tp53 had also been shown to be frequent in human lung SCCs, and may lead to expansion of mutant stem cell clones.	('SCC', 'Gene', '6317', (95, 98))	('Tp53', 'Gene', (41, 45))	('lead to', 'Reg', (109, 116))	('inactivation', 'Var', (25, 37))	('Tp53', 'Gene', '7157', (41, 45))	('Mutations', 'Var', (0, 9))	('human', 'Species', '9606', (84, 89))	('SCC', 'Gene', (95, 98))	('SCC', 'Phenotype', 'HP:0002860', (95, 98))
501785	28984774	We expect that pharmacists can develop targeted drugs for new targets, such as KRAS mutation or inactivation of Tp53 in the near future, so that the treatment of lung cancer can have more choices.	('Tp53', 'Gene', (112, 116))	('Tp53', 'Gene', '7157', (112, 116))	('lung cancer', 'Disease', 'MESH:D008175', (162, 173))	('KRAS', 'Gene', '3845', (79, 83))	('inactivation', 'Var', (96, 108))	('lung cancer', 'Disease', (162, 173))	('lung cancer', 'Phenotype', 'HP:0100526', (162, 173))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('KRAS', 'Gene', (79, 83))	('mutation', 'Var', (84, 92))
501798	27670291	Thus, stathmin may be an attractive target for drug design as targeting this molecule could simultaneously inhibit several aspects of tumor progression.	('inhibit', 'NegReg', (107, 114))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('targeting', 'Var', (62, 71))	('tumor', 'Disease', (134, 139))
501822	27670291	Phosphoinositide 3-kinase PI3 K/mTOR/HSP90 is shown as a possible signal target for p-stathmin S38- high-endometrial cancer cases.	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('Phosphoinositide 3-kinase', 'Gene', (0, 25))	('mTOR', 'Gene', '2475', (32, 36))	('p-stathmin', 'Var', (84, 94))	('mTOR', 'Gene', (32, 36))	('Phosphoinositide 3-kinase', 'Gene', '5290', (0, 25))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('S38-', 'Var', (95, 99))	('cancer', 'Disease', (117, 123))	('HSP90', 'Gene', (37, 42))	('HSP90', 'Gene', '3320', (37, 42))	('endometrial cancer', 'Phenotype', 'HP:0012114', (105, 123))
501824	27670291	And low levels of Siva1 and Ser16-phosphorylated stathmin correlate with high metastatic states of human breast cancer cells.	('Ser16-phosphorylated', 'Var', (28, 48))	('Siva1', 'Gene', '10572', (18, 23))	('Siva1', 'Gene', (18, 23))	('high metastatic states', 'CPA', (73, 95))	('Ser16', 'Chemical', '-', (28, 33))	('breast cancer', 'Disease', 'MESH:D001943', (105, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('breast cancer', 'Disease', (105, 118))	('human', 'Species', '9606', (99, 104))	('breast cancer', 'Phenotype', 'HP:0003002', (105, 118))
501828	27670291	The inhibition of LMP1 expression attenuates the interaction of ERK with stathmin and promotes microtubule depolymerization.	('attenuates', 'NegReg', (34, 44))	('LMP1', 'Gene', (18, 22))	('ERK', 'Gene', '5594', (64, 67))	('interaction', 'Interaction', (49, 60))	('inhibition', 'Var', (4, 14))	('ERK', 'Gene', (64, 67))	('promotes', 'PosReg', (86, 94))	('LMP1', 'Gene', '9260', (18, 22))	('microtubule depolymerization', 'MPA', (95, 123))
501829	27670291	Stathmin depletion causes significant inhibition of HGF-induced WAVE2 transport and lamellipodia formation.	('WAVE2', 'Gene', '10163', (64, 69))	('Stathmin', 'Gene', (0, 8))	('WAVE2', 'Gene', (64, 69))	('HGF', 'Gene', (52, 55))	('inhibition', 'NegReg', (38, 48))	('lamellipodia formation', 'CPA', (84, 106))	('HGF', 'Gene', '3082', (52, 55))	('Stathmin', 'Gene', '3925', (0, 8))	('depletion', 'Var', (9, 18))
501831	27670291	Stathmin silencing also reduces the activity of CDC25, Aurora A and Plk1.	('Plk1', 'Gene', '5347', (68, 72))	('Stathmin', 'Gene', (0, 8))	('reduces', 'NegReg', (24, 31))	('silencing', 'Var', (9, 18))	('Aurora A', 'Gene', '6790', (55, 63))	('activity', 'MPA', (36, 44))	('Plk1', 'Gene', (68, 72))	('Aurora A', 'Gene', (55, 63))	('CDC25', 'Gene', (48, 53))	('CDC25', 'Gene', '995', (48, 53))	('Stathmin', 'Gene', '3925', (0, 8))
501833	27670291	Homo sapiens leucine rich repeat containing 4 (LRRC4) is epigenetically inactivated commonly in glioma.	('leucine rich repeat containing 4', 'Gene', (13, 45))	('LRRC4', 'Gene', (47, 52))	('LRRC4', 'Gene', '64101', (47, 52))	('glioma', 'Disease', 'MESH:D005910', (96, 102))	('glioma', 'Phenotype', 'HP:0009733', (96, 102))	('leucine rich repeat containing 4', 'Gene', '64101', (13, 45))	('epigenetically inactivated', 'Var', (57, 83))	('Homo sapiens', 'Species', '9606', (0, 12))	('glioma', 'Disease', (96, 102))
501844	27670291	Furthermore, silence of stathmin down-regulates the expression of Nf-kappaB (p65), which indicates that stathmin might play its oncogenic role by an interaction with Nf-kappaB pathway (Fig.	('stathmin', 'Gene', (24, 32))	('p65', 'Gene', (77, 80))	('Nf-kappaB', 'Gene', (66, 75))	('interaction', 'Interaction', (149, 160))	('expression', 'MPA', (52, 62))	('Nf-kappaB', 'Gene', (166, 175))	('p65', 'Gene', '5970', (77, 80))	('Nf-kappaB', 'Gene', '4790', (66, 75))	('Nf-kappaB', 'Gene', '4790', (166, 175))	('down-regulates', 'NegReg', (33, 47))	('silence', 'Var', (13, 20))
501845	27670291	Stathmin depletion suppresses the expression of hypoxia-induced factor-1alpha (HIF-1alpha) and VEGF, and impedes the phosphorylation of ribosomal protein S6 kinase 1 (S6 K) and Akt, which means stathmin play a critical role in the mTOR/HIF-1alpha/VEGF signally pathway.	('Stathmin', 'Gene', (0, 8))	('expression', 'MPA', (34, 44))	('HIF-1alpha', 'Gene', (236, 246))	('impedes', 'NegReg', (105, 112))	('VEGF', 'Gene', '7422', (247, 251))	('suppresses', 'NegReg', (19, 29))	('HIF-1alpha', 'Gene', '3091', (79, 89))	('phosphorylation', 'MPA', (117, 132))	('mTOR', 'Gene', (231, 235))	('VEGF', 'Gene', (247, 251))	('Stathmin', 'Gene', '3925', (0, 8))	('hypoxia', 'Disease', (48, 55))	('depletion', 'Var', (9, 18))	('Akt', 'Gene', (177, 180))	('mTOR', 'Gene', '2475', (231, 235))	('hypoxia', 'Disease', 'MESH:D000860', (48, 55))	('Akt', 'Gene', '207', (177, 180))	('HIF-1alpha', 'Gene', (79, 89))	('HIF-1alpha', 'Gene', '3091', (236, 246))	('VEGF', 'Gene', '7422', (95, 99))	('S6 K', 'Mutation', 'p.S6K', (167, 171))	('VEGF', 'Gene', (95, 99))
501849	27670291	Knockdown of stathmin promotes the effects of indoly-chalcones CITs (CIT-026, CIT-214, CIT-223) to bring down microtubule destabilization, result in cell death and decelerate cell proliferation.	('result in', 'Reg', (139, 148))	('cell proliferation', 'CPA', (175, 193))	('CIT-214', 'Var', (78, 85))	('decelerate', 'NegReg', (164, 174))	('bring', 'Reg', (99, 104))	('indoly-chalcones CITs', 'Chemical', '-', (46, 67))	('cell death', 'CPA', (149, 159))	('stathmin', 'Gene', (13, 21))	('microtubule destabilization', 'MPA', (110, 137))	('CIT-223', 'Var', (87, 94))
501851	27670291	And inhibition of Rlim (a Ring H2 zinc finger protein) increases the expression of stathmin, and leads to cell proliferation of human osteosarcoma cell lines.	('cell proliferation', 'CPA', (106, 124))	('osteosarcoma', 'Disease', (134, 146))	('osteosarcoma', 'Disease', 'MESH:D012516', (134, 146))	('Rlim', 'Gene', (18, 22))	('expression', 'MPA', (69, 79))	('inhibition', 'Var', (4, 14))	('increases', 'PosReg', (55, 64))	('leads to', 'Reg', (97, 105))	('human', 'Species', '9606', (128, 133))	('Rlim', 'Gene', '51132', (18, 22))	('stathmin', 'Gene', (83, 91))	('osteosarcoma', 'Phenotype', 'HP:0002669', (134, 146))
501856	27670291	Oxidative stress from menadione-generated superoxide induces JNK-dependent stathmin phosphorylation at Ser-16, Ser-25 and Ser-38 in hepatocytes.	('Ser', 'Chemical', 'MESH:D012694', (122, 125))	('Oxidative stress', 'Phenotype', 'HP:0025464', (0, 16))	('Ser', 'Chemical', 'MESH:D012694', (103, 106))	('stathmin phosphorylation', 'MPA', (75, 99))	('menadione', 'Chemical', 'MESH:D024483', (22, 31))	('JNK', 'Gene', (61, 64))	('Oxidative stress', 'MPA', (0, 16))	('Ser', 'Chemical', 'MESH:D012694', (111, 114))	('Ser-38', 'Var', (122, 128))	('superoxide', 'Chemical', 'MESH:D013481', (42, 52))	('JNK', 'Gene', '5599', (61, 64))
501859	27670291	And, stathmin knockdown improves the chemosensitivity of gastric cancer cells to docetaxel, making the percentage of cells at the sub-G1 stage increase and promote apoptosis.	('gastric cancer', 'Disease', (57, 71))	('chemosensitivity', 'MPA', (37, 53))	('gastric cancer', 'Disease', 'MESH:D013274', (57, 71))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('apoptosis', 'CPA', (164, 173))	('stathmin', 'Gene', (5, 13))	('gastric cancer', 'Phenotype', 'HP:0012126', (57, 71))	('knockdown', 'Var', (14, 23))	('improves', 'PosReg', (24, 32))	('increase', 'PosReg', (143, 151))	('docetaxel', 'Chemical', 'MESH:D000077143', (81, 90))	('promote', 'PosReg', (156, 163))
501860	27670291	Research shows paclitaxel reduces the expression of stathmin, and combination of stathmin silencing with paclitaxel treatment enhances microtubules polymerization and tumor cell apoptosis.	('expression', 'MPA', (38, 48))	('silencing', 'Var', (90, 99))	('paclitaxel', 'Chemical', 'MESH:D017239', (15, 25))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('enhances', 'PosReg', (126, 134))	('paclitaxel', 'Chemical', 'MESH:D017239', (105, 115))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('reduces', 'NegReg', (26, 33))	('stathmin', 'Gene', (81, 89))	('microtubules polymerization', 'MPA', (135, 162))	('tumor', 'Disease', (167, 172))
501862	27670291	The JAK2(V617F) mutation potentially leads to inhibition of stathmin activity via constitutive STAT3 phosphorylation.	('V617F', 'SUBSTITUTION', 'None', (9, 14))	('inhibition', 'NegReg', (46, 56))	('STAT3', 'Gene', '6774', (95, 100))	('V617F', 'Var', (9, 14))	('STAT3', 'Gene', (95, 100))	('stathmin', 'Enzyme', (60, 68))
501863	27670291	Therefore, combination of stathmin silencing and ruxolitinib treatment can reduce cell proliferation and clonal growth, and increase apoptosis induced by ruxolitinib (Fig.	('increase', 'PosReg', (124, 132))	('silencing', 'Var', (35, 44))	('clonal growth', 'CPA', (105, 118))	('reduce', 'NegReg', (75, 81))	('apoptosis', 'CPA', (133, 142))	('cell proliferation', 'CPA', (82, 100))	('ruxolitinib', 'Chemical', 'MESH:C540383', (49, 60))	('stathmin', 'Gene', (26, 34))	('ruxolitinib', 'Chemical', 'MESH:C540383', (154, 165))
501865	27670291	Research shows knockdown of stathmin inhibits the proliferation of glioma cells, induces apoptosis, arrests the cell cycle at G2/M phase in glioma stem cells (GSCs), and also suppresses the migration/invasion.	('cell cycle at G2/M phase', 'CPA', (112, 136))	('arrests', 'NegReg', (100, 107))	('glioma', 'Disease', 'MESH:D005910', (140, 146))	('glioma', 'Phenotype', 'HP:0009733', (140, 146))	('knockdown', 'Var', (15, 24))	('migration/invasion', 'CPA', (190, 208))	('glioma', 'Disease', (67, 73))	('suppresses', 'NegReg', (175, 185))	('apoptosis', 'CPA', (89, 98))	('induces', 'Reg', (81, 88))	('glioma', 'Disease', (140, 146))	('glioma', 'Disease', 'MESH:D005910', (67, 73))	('glioma', 'Phenotype', 'HP:0009733', (67, 73))	('inhibits', 'NegReg', (37, 45))	('stathmin', 'Gene', (28, 36))
501873	27670291	In addition, stathmin silencing significantly impedes cell proliferation and mobility of neuroblastoma cells, polyploidy of hepatoma cells and esophageal squamous cell carcinoma cells, and remarkably retards cell migration and invasion.	('carcinoma', 'Phenotype', 'HP:0030731', (168, 177))	('neuroblastoma', 'Phenotype', 'HP:0003006', (89, 102))	('cell proliferation', 'CPA', (54, 72))	('retards cell migration', 'Disease', 'MESH:D014085', (200, 222))	('esophageal squamous cell carcinoma', 'Disease', (143, 177))	('polyploidy of hepatoma', 'Disease', 'MESH:D011123', (110, 132))	('neuroblastoma', 'Disease', 'MESH:D009447', (89, 102))	('silencing', 'Var', (22, 31))	('polyploidy of hepatoma', 'Disease', (110, 132))	('stathmin', 'Gene', (13, 21))	('neuroblastoma', 'Disease', (89, 102))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (154, 177))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (143, 177))	('retards cell migration', 'Disease', (200, 222))	('impedes', 'NegReg', (46, 53))
501878	27670291	It is reported that the knockdown of proapoptotic protein SIVA activates the expression of stathmin, which promotes cell mobility and migration and the growth of xenotransplanted tumors, but silencing of ankyrin repeat and KH domain containing 1 protein (ANKHD1) plays an inverse function that leads to stathmin inactivation, inhibits cell migration and the growth of xenotransplanted, which possibly depends on the inhibition mechanism of SIVA/stathmin pathway.	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('ankyrin repeat and KH domain containing 1', 'Gene', '54882', (204, 245))	('xenotransplanted tumors', 'Disease', (162, 185))	('SIVA', 'Gene', (58, 62))	('tumors', 'Phenotype', 'HP:0002664', (179, 185))	('SIVA', 'Gene', (440, 444))	('silencing', 'Var', (191, 200))	('SIVA', 'Gene', '10572', (440, 444))	('xenotransplanted tumors', 'Disease', 'MESH:D009369', (162, 185))	('ANKHD1', 'Gene', '54882', (255, 261))	('cell migration', 'CPA', (335, 349))	('SIVA', 'Gene', '10572', (58, 62))	('ANKHD1', 'Gene', (255, 261))	('inhibits', 'NegReg', (326, 334))	('growth of xenotransplanted', 'CPA', (358, 384))	('stathmin', 'MPA', (303, 311))	('inactivation', 'NegReg', (312, 324))	('cell mobility', 'CPA', (116, 129))
501880	27670291	It is shown that MCPyV small tumor antigen enhances microtubule destabilization of the MCC cells by modulating the phosphorylation status of stathmin, which results in the motility, migration and metastasis of Merkel cell carcinoma (Fig.	('migration', 'CPA', (182, 191))	('MCPyV', 'Var', (17, 22))	('motility', 'CPA', (172, 180))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('phosphorylation status', 'MPA', (115, 137))	('modulating', 'Reg', (100, 110))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('enhances', 'PosReg', (43, 51))	('carcinoma', 'Phenotype', 'HP:0030731', (222, 231))	('MCPyV', 'Species', '493803', (17, 22))	('microtubule destabilization', 'MPA', (52, 79))	('tumor', 'Disease', (29, 34))	('metastasis of Merkel cell carcinoma', 'Disease', 'MESH:D015266', (196, 231))	('results in', 'Reg', (157, 167))	('metastasis of Merkel cell carcinoma', 'Disease', (196, 231))
501884	27670291	Evidence on the relation between MicroRNAs and malignant tumor has been suggested that some aberrant miRNA expressions promote the development of cancers, but the others play a negative function in tumorigenesis.	('cancers', 'Disease', (146, 153))	('aberrant', 'Var', (92, 100))	('cancers', 'Disease', 'MESH:D009369', (146, 153))	('malignant tumor', 'Disease', 'MESH:D018198', (47, 62))	('cancers', 'Phenotype', 'HP:0002664', (146, 153))	('promote', 'PosReg', (119, 126))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('tumor', 'Disease', (198, 203))	('tumor', 'Disease', (57, 62))	('malignant tumor', 'Disease', (47, 62))	('miR', 'Gene', '220972', (101, 104))	('miR', 'Gene', (101, 104))
501890	27670291	And study reveals that aberrant miR-223 contributes to aggressiveness of malignant pleural mesothelioma (MPM) by regulating stathmin and both are also in turn regulated by the JNK signally pathway (Fig.	('JNK', 'Gene', (176, 179))	('miR-223', 'Gene', '407008', (32, 39))	('aggressiveness of malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (55, 103))	('JNK', 'Gene', '5599', (176, 179))	('regulating', 'Reg', (113, 123))	('aggressiveness of malignant pleural mesothelioma', 'Disease', (55, 103))	('miR-223', 'Gene', (32, 39))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (83, 103))	('stathmin', 'MPA', (124, 132))	('aberrant', 'Var', (23, 31))	('aggressiveness', 'Phenotype', 'HP:0000718', (55, 69))
501893	27670291	It is suggested that long term colonization of Helicobacter pylori in gastric mucosa increases the risk of gastric cancer.	('gastric cancer', 'Phenotype', 'HP:0012126', (107, 121))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('Helicobacter pylori', 'Var', (47, 66))	('gastric cancer', 'Disease', (107, 121))	('Helicobacter pylori', 'Species', '210', (47, 66))	('gastric cancer', 'Disease', 'MESH:D013274', (107, 121))
501898	27670291	Interestingly, miR-101 expression inhibits the autophagy of hepatocellular carcinoma HepG2 cells by modulating the activity of stathmin, and enhances apoptosis of hepatocellular carcinoma cells by inhibition of autophagy.	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (163, 187))	('apoptosis', 'CPA', (150, 159))	('expression', 'Var', (23, 33))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (60, 84))	('autophagy', 'CPA', (47, 56))	('inhibition', 'NegReg', (197, 207))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (163, 187))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (60, 84))	('hepatocellular carcinoma', 'Disease', (163, 187))	('autophagy', 'CPA', (211, 220))	('HepG2', 'CellLine', 'CVCL:0027', (85, 90))	('hepatocellular carcinoma', 'Disease', (60, 84))	('miR', 'Gene', '220972', (15, 18))	('enhances', 'PosReg', (141, 149))	('inhibits', 'NegReg', (34, 42))	('modulating', 'Reg', (100, 110))	('activity', 'MPA', (115, 123))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (178, 187))	('miR', 'Gene', (15, 18))
501902	27670291	Research shows these biological effects of microRNAs on tumors are involved in stathmin signal, influencing the cell cycle control, proliferation, migration and drug resistance.	('cell cycle control', 'CPA', (112, 130))	('drug resistance', 'CPA', (161, 176))	('drug resistance', 'Phenotype', 'HP:0020174', (161, 176))	('migration', 'CPA', (147, 156))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('influencing', 'Reg', (96, 107))	('microRNAs', 'Var', (43, 52))	('tumors', 'Disease', (56, 62))	('proliferation', 'CPA', (132, 145))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))
501907	27670291	Meanwhile, ERK-mediated stathmin is involved in taxol resistance, because blockage of ERK signal improves the sensitivity of tumor cells to taxol.	('taxol', 'Chemical', 'MESH:D017239', (48, 53))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumor', 'Disease', (125, 130))	('blockage', 'Var', (74, 82))	('taxol', 'Chemical', 'MESH:D017239', (140, 145))	('ERK', 'Gene', '5594', (86, 89))	('ERK', 'Gene', '5594', (11, 14))	('ERK', 'Gene', (11, 14))	('improves', 'PosReg', (97, 105))	('ERK', 'Gene', (86, 89))
501908	27670291	Over-expression of antiapoptotic protein Bcl-2 has been shown to induce chemoresistance.	('Bcl-2', 'Gene', (41, 46))	('Bcl-2', 'Gene', '596', (41, 46))	('induce', 'PosReg', (65, 71))	('Over-expression', 'Var', (0, 15))	('chemoresistance', 'CPA', (72, 87))
501910	27670291	Dramatically, knockdown of stathmin combined with paclitaxel remarkably promotes the efficacy of inhibiting proliferation of esophageal squamous cell cancer, and leads to a significantly higher proportion of cells at G2/M phase, and this antiproliferative effect was accompanied by an increase in apoptosis rates and morphology changes.	('increase', 'PosReg', (285, 293))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('esophageal squamous cell cancer', 'Disease', 'MESH:D002294', (125, 156))	('apoptosis rates', 'CPA', (297, 312))	('paclitaxel', 'Chemical', 'MESH:D017239', (50, 60))	('proliferation', 'CPA', (108, 121))	('morphology changes', 'CPA', (317, 335))	('promotes', 'PosReg', (72, 80))	('knockdown', 'Var', (14, 23))	('esophageal squamous cell cancer', 'Disease', (125, 156))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (136, 156))	('inhibiting', 'NegReg', (97, 107))	('stathmin', 'Gene', (27, 35))	('higher', 'PosReg', (187, 193))	('cells at G2/M phase', 'CPA', (208, 227))
501911	27670291	After treated by paclitaxel or vincristine, esophageal squamous cell carcinoma (ESCC) cells of stathmin silencing are more likely to enter G2 but less likely to enter mitosis than control cells, suggesting that silencing of stathmin gene increases sensitivity of ESCC to paclitaxel and vincristine through G2/M phase block.	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (55, 78))	('ESCC', 'Disease', (263, 267))	('esophageal squamous cell carcinoma', 'Disease', (44, 78))	('silencing', 'Var', (104, 113))	('stathmin', 'Gene', (95, 103))	('vincristine', 'Chemical', 'MESH:D014750', (31, 42))	('sensitivity', 'MPA', (248, 259))	('silencing', 'Var', (211, 220))	('mitosis', 'Disease', (167, 174))	('increases', 'PosReg', (238, 247))	('G2/M phase block', 'CPA', (306, 322))	('mitosis', 'Disease', 'None', (167, 174))	('vincristine', 'Chemical', 'MESH:D014750', (286, 297))	('stathmin', 'Gene', (224, 232))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (44, 78))	('paclitaxel', 'Chemical', 'MESH:D017239', (17, 27))	('paclitaxel', 'Chemical', 'MESH:D017239', (271, 281))
501916	27670291	Research shows that stathmin silencing recovers the chemosensitivity of gastric cancer cells to docetaxel, arrests cells at the sub-G1 stage, induces apoptosis and inhibits the growth of transplantation tumor.	('stathmin', 'Gene', (20, 28))	('gastric cancer', 'Disease', 'MESH:D013274', (72, 86))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('tumor', 'Disease', (203, 208))	('arrests', 'NegReg', (107, 114))	('inhibits', 'NegReg', (164, 172))	('docetaxel', 'Chemical', 'MESH:D000077143', (96, 105))	('silencing', 'Var', (29, 38))	('induces', 'Reg', (142, 149))	('apoptosis', 'CPA', (150, 159))	('gastric cancer', 'Phenotype', 'HP:0012126', (72, 86))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('recovers', 'PosReg', (39, 47))	('cells at the sub-G1 stage', 'CPA', (115, 140))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('chemosensitivity', 'MPA', (52, 68))	('gastric cancer', 'Disease', (72, 86))
501918	27670291	Moreover, depletion of stathmin by antisense oligodeoxynucleotide promotes the antitumor effects of docetaxel to gastric cancer cells, and combination treatment of stathmin inhibition and docetaxel shows a synergistic effect.	('antisense oligodeoxynucleotide', 'Var', (35, 65))	('docetaxel', 'Chemical', 'MESH:D000077143', (188, 197))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('tumor', 'Disease', (83, 88))	('docetaxel', 'Chemical', 'MESH:D000077143', (100, 109))	('gastric cancer', 'Disease', (113, 127))	('gastric cancer', 'Phenotype', 'HP:0012126', (113, 127))	('gastric cancer', 'Disease', 'MESH:D013274', (113, 127))	('promotes', 'PosReg', (66, 74))	('oligodeoxynucleotide', 'Chemical', 'MESH:D009838', (45, 65))	('depletion', 'MPA', (10, 19))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
501920	27670291	Knock-down of stathmin enhances sensitivity to paclitaxel in endometrial carcinoma cells and also enhances the cytotoxic effect of paclitaxel to retinoblastoma.	('sensitivity to paclitaxel', 'MPA', (32, 57))	('paclitaxel', 'Chemical', 'MESH:D017239', (131, 141))	('endometrial carcinoma cells', 'Disease', 'MESH:D016889', (61, 88))	('retinoblastoma', 'Disease', 'MESH:D012175', (145, 159))	('retinoblastoma', 'Disease', (145, 159))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (61, 82))	('Knock-down', 'Var', (0, 10))	('enhances', 'PosReg', (98, 106))	('enhances', 'PosReg', (23, 31))	('endometrial carcinoma cells', 'Disease', (61, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))	('retinoblastoma', 'Phenotype', 'HP:0009919', (145, 159))	('cytotoxic effect', 'CPA', (111, 127))	('paclitaxel', 'Chemical', 'MESH:D017239', (47, 57))	('stathmin', 'Gene', (14, 22))
501922	27670291	Glioma stem cells (GSCs) are usually resistant to chemotherapy and radiotherapy, but silencing of stathmin can improve the sensitivity of glioma stem cells to temozolomide.	('sensitivity', 'MPA', (123, 134))	('glioma', 'Disease', (138, 144))	('temozolomide', 'Chemical', 'MESH:D000077204', (159, 171))	('Glioma', 'Phenotype', 'HP:0009733', (0, 6))	('glioma', 'Phenotype', 'HP:0009733', (138, 144))	('Glioma', 'Disease', 'MESH:D005910', (0, 6))	('stathmin', 'Gene', (98, 106))	('glioma', 'Disease', 'MESH:D005910', (138, 144))	('Glioma', 'Disease', (0, 6))	('silencing', 'Var', (85, 94))	('improve', 'PosReg', (111, 118))
501924	27670291	Surprisingly, down-regulation of stathmin significantly enhances the reversion of ADM resistance in MG63/dox by As2O3, and As2O3 also reverse ADM resistance in MG63/dox cells by down-regulation of stathmin.	('ADM', 'Gene', (142, 145))	('down-regulation', 'NegReg', (14, 29))	('As2O3', 'Chemical', 'MESH:D000077237', (123, 128))	('dox', 'Chemical', 'MESH:D004317', (165, 168))	('stathmin', 'Gene', (197, 205))	('ADM', 'Gene', '133', (142, 145))	('ADM', 'Gene', (82, 85))	('stathmin', 'Gene', (33, 41))	('As2O3', 'Var', (112, 117))	('down-regulation', 'NegReg', (178, 193))	('reversion', 'MPA', (69, 78))	('As2O3', 'Chemical', 'MESH:D000077237', (112, 117))	('dox', 'Chemical', 'MESH:D004317', (105, 108))	('ADM', 'Gene', '133', (82, 85))	('enhances', 'PosReg', (56, 64))	('As2O3', 'Var', (123, 128))
501925	27670291	In addition, 5-FU chemoresponse to the classical colorectal cancer can be improved by silencing of stathmin via a caspase-6 (CASP6)-dependent signal.	('5-FU', 'Chemical', 'MESH:D005472', (13, 17))	('silencing', 'Var', (86, 95))	('colorectal cancer', 'Phenotype', 'HP:0003003', (49, 66))	('caspase-6', 'Gene', (114, 123))	('CASP6', 'Gene', '839', (125, 130))	('caspase-6', 'Gene', '839', (114, 123))	('colorectal cancer', 'Disease', (49, 66))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('colorectal cancer', 'Disease', 'MESH:D015179', (49, 66))	('CASP6', 'Gene', (125, 130))	('stathmin', 'Gene', (99, 107))
501926	27670291	Interestingly, the function of stathmin is independent of p53 but requires phosphorylations at S25 or S38.	('p53', 'Gene', (58, 61))	('S38', 'Var', (102, 105))	('p53', 'Gene', '7157', (58, 61))	('S25', 'Var', (95, 98))
501930	27670291	For instance, knockdown of stathmin significantly reduces pancreatic cancer cell viability, colony formation, and even retards pancreatic tumor growth in nude mice.Although leukemia is not a solid tumor, stathmin silencing still reduces cell proliferation and clonogenicity of U937 and Namalwa leukemia cells.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (58, 75))	('leukemia', 'Disease', (294, 302))	('silencing', 'Var', (213, 222))	('leukemia', 'Disease', 'MESH:D007938', (294, 302))	('U937', 'CellLine', 'CVCL:0007', (277, 281))	('solid tumor', 'Disease', (191, 202))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('leukemia', 'Phenotype', 'HP:0001909', (173, 181))	('Namalwa leukemia', 'Disease', (286, 302))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('solid tumor', 'Disease', 'MESH:D009369', (191, 202))	('pancreatic cancer', 'Disease', 'MESH:D010190', (58, 75))	('cell proliferation', 'CPA', (237, 255))	('retards pancreatic tumor', 'Disease', 'MESH:D010190', (119, 143))	('retards pancreatic tumor', 'Disease', (119, 143))	('reduces', 'NegReg', (229, 236))	('leukemia', 'Disease', (173, 181))	('leukemia', 'Disease', 'MESH:D007938', (173, 181))	('pancreatic cancer', 'Disease', (58, 75))	('clonogenicity', 'CPA', (260, 273))	('Namalwa leukemia', 'Disease', 'MESH:D007938', (286, 302))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('stathmin', 'Gene', (204, 212))	('pancreatic tumor', 'Phenotype', 'HP:0002894', (127, 143))	('nude mice', 'Species', '10090', (154, 163))	('leukemia', 'Phenotype', 'HP:0001909', (294, 302))
501931	27670291	More widely, siRNA-mediated silencing of stathmin has been shown to suppress the proliferation, invasion and metastasis of nasopharyngeal carcinoma (NPC) cells, hepatoma, retinoblastoma, endometrial carcinoma, bladder cancer and glioma, and significantly induces the apoptosis of tumor cells.	('bladder cancer', 'Disease', 'MESH:D001749', (210, 224))	('bladder cancer', 'Disease', (210, 224))	('bladder cancer', 'Phenotype', 'HP:0009725', (210, 224))	('endometrial carcinoma', 'Disease', (187, 208))	('hepatoma', 'Disease', 'MESH:D006528', (161, 169))	('carcinoma', 'Phenotype', 'HP:0030731', (199, 208))	('glioma', 'Phenotype', 'HP:0009733', (229, 235))	('stathmin', 'Gene', (41, 49))	('retinoblastoma', 'Phenotype', 'HP:0009919', (171, 185))	('apoptosis', 'CPA', (267, 276))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (123, 147))	('metastasis of nasopharyngeal carcinoma', 'Disease', (109, 147))	('metastasis of nasopharyngeal carcinoma', 'Disease', 'MESH:D009362', (109, 147))	('retinoblastoma', 'Disease', (171, 185))	('invasion', 'CPA', (96, 104))	('silencing', 'Var', (28, 37))	('tumor', 'Disease', (280, 285))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (187, 208))	('tumor', 'Disease', 'MESH:D009369', (280, 285))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (187, 208))	('hepatoma', 'Disease', (161, 169))	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('NPC', 'Phenotype', 'HP:0100630', (149, 152))	('induces', 'Reg', (255, 262))	('glioma', 'Disease', (229, 235))	('retinoblastoma', 'Disease', 'MESH:D012175', (171, 185))	('tumor', 'Phenotype', 'HP:0002664', (280, 285))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('suppress', 'NegReg', (68, 76))	('glioma', 'Disease', 'MESH:D005910', (229, 235))	('proliferation', 'CPA', (81, 94))
501932	27670291	Adenovirus-mediated gene transfer of anti-stathmin ribozyme inhibits cell proliferation and clonogenicity in both ER-positive and ER-negative breast cancer cells and knockdown of stathmin can attenuate the miR-101-mediated enhancement of cell growth and metastasis.	('clonogenicity', 'CPA', (92, 105))	('knockdown', 'Var', (166, 175))	('attenuate', 'NegReg', (192, 201))	('breast cancer', 'Disease', 'MESH:D001943', (142, 155))	('miR', 'Gene', '220972', (206, 209))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('miR', 'Gene', (206, 209))	('cell proliferation', 'CPA', (69, 87))	('breast cancer', 'Disease', (142, 155))	('breast cancer', 'Phenotype', 'HP:0003002', (142, 155))	('inhibits', 'NegReg', (60, 68))
501934	27670291	To lung cancer cells, knockdown of stathmin results in a remarkable decrease in cellular proliferation and invasion, and monoclonal antibodies against stathmin also inhibit the proliferation of human lung carcinoma QG-56 cells, and even result in a significantly higher apoptosis rate.	('cellular proliferation', 'CPA', (80, 102))	('stathmin', 'Gene', (35, 43))	('lung cancer', 'Phenotype', 'HP:0100526', (3, 14))	('knockdown', 'Var', (22, 31))	('invasion', 'CPA', (107, 115))	('decrease', 'NegReg', (68, 76))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('inhibit', 'NegReg', (165, 172))	('stathmin', 'Gene', (151, 159))	('lung carcinoma', 'Disease', (200, 214))	('lung cancer', 'Disease', (3, 14))	('apoptosis rate', 'CPA', (270, 284))	('carcinoma', 'Phenotype', 'HP:0030731', (205, 214))	('higher', 'PosReg', (263, 269))	('QG-56', 'CellLine', 'CVCL:6943', (215, 220))	('human', 'Species', '9606', (194, 199))	('proliferation', 'CPA', (177, 190))	('lung cancer', 'Disease', 'MESH:D008175', (3, 14))	('lung carcinoma', 'Disease', 'MESH:D008175', (200, 214))
501935	27670291	The depletion of stathmin by antisense oligodeoxynucleotide significantly inhibits the proliferation of gastric cancer cells.	('gastric cancer', 'Disease', 'MESH:D013274', (104, 118))	('antisense oligodeoxynucleotide', 'Var', (29, 59))	('proliferation', 'CPA', (87, 100))	('oligodeoxynucleotide', 'Chemical', 'MESH:D009838', (39, 59))	('gastric cancer', 'Phenotype', 'HP:0012126', (104, 118))	('inhibits', 'NegReg', (74, 82))	('depletion', 'MPA', (4, 13))	('stathmin', 'Gene', (17, 25))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('gastric cancer', 'Disease', (104, 118))
501937	27670291	Bifunctional small hairpin RNAs (bi-shRNAs) is functional miRNA/siRNA composite; one study shows that a single intratumoral injection of pbi-sh-stathmin reduces growth of tumor xenograft derived from colorectal cancer CCL-247 cells, and also significantly inhibits the growth of tumorgrafts derived from primary melanoma and osteosarcoma xenograft.	('tumor', 'Phenotype', 'HP:0002664', (279, 284))	('colorectal cancer', 'Disease', 'MESH:D015179', (200, 217))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('miR', 'Gene', '220972', (58, 61))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('reduces', 'NegReg', (153, 160))	('pbi-sh-stathmin', 'Var', (137, 152))	('colorectal cancer', 'Disease', (200, 217))	('osteosarcoma', 'Phenotype', 'HP:0002669', (325, 337))	('miR', 'Gene', (58, 61))	('melanoma', 'Disease', 'MESH:D008545', (312, 320))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('osteosarcoma xenograft', 'Disease', 'MESH:D012516', (325, 347))	('osteosarcoma xenograft', 'Disease', (325, 347))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('CCL', 'Chemical', 'MESH:D002433', (218, 221))	('tumor', 'Disease', (279, 284))	('growth', 'CPA', (269, 275))	('growth', 'MPA', (161, 167))	('colorectal cancer', 'Phenotype', 'HP:0003003', (200, 217))	('tumor', 'Disease', 'MESH:D009369', (279, 284))	('melanoma', 'Phenotype', 'HP:0002861', (312, 320))	('melanoma', 'Disease', (312, 320))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('tumor', 'Disease', (171, 176))	('tumor', 'Disease', (116, 121))	('inhibits', 'NegReg', (256, 264))
501938	27670291	In human cancers, stathmin is usually overexpressed and anti-stathmin treatment usually reduces cell proliferation, clonal growth, cell motility, metastasis and increases apoptosis.	('cancers', 'Disease', 'MESH:D009369', (9, 16))	('cancers', 'Phenotype', 'HP:0002664', (9, 16))	('cancers', 'Disease', (9, 16))	('metastasis', 'CPA', (146, 156))	('reduces', 'NegReg', (88, 95))	('human', 'Species', '9606', (3, 8))	('apoptosis', 'CPA', (171, 180))	('anti-stathmin', 'Var', (56, 69))	('cell proliferation', 'CPA', (96, 114))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('clonal growth', 'CPA', (116, 129))	('cell motility', 'CPA', (131, 144))	('increases', 'PosReg', (161, 170))
501941	27670291	However, the abnormal expression of stathmin in tumor cells has provided to be a feasible approach for the development of stathmin-dependent molecular targeting therapy.	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('abnormal', 'Var', (13, 21))	('tumor', 'Disease', (48, 53))	('tumor', 'Disease', 'MESH:D009369', (48, 53))
501943	27670291	Stathmin expression has been found to be increased in a variety of cancers and high expression of stathmin can potentially promote cell proliferation, motility and metastasis of malignant tumors.	('cancers', 'Phenotype', 'HP:0002664', (67, 74))	('Stathmin', 'Gene', (0, 8))	('motility', 'CPA', (151, 159))	('tumors', 'Phenotype', 'HP:0002664', (188, 194))	('cancers', 'Disease', (67, 74))	('metastasis of malignant tumors', 'Disease', (164, 194))	('cancers', 'Disease', 'MESH:D009369', (67, 74))	('metastasis of malignant tumors', 'Disease', 'MESH:D009362', (164, 194))	('promote', 'PosReg', (123, 130))	('expression', 'MPA', (9, 19))	('cell proliferation', 'CPA', (131, 149))	('stathmin', 'Gene', (98, 106))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('high expression', 'Var', (79, 94))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('Stathmin', 'Gene', '3925', (0, 8))
501944	27670291	However, many target-specific anti-stathmin investigations have been demonstrated to reduce cell proliferation, clonal growth, cell motility and metastasis, and to increase apoptosis of malignant tumors.	('increase apoptosis of malignant tumors', 'Disease', (164, 202))	('tumors', 'Phenotype', 'HP:0002664', (196, 202))	('reduce', 'NegReg', (85, 91))	('clonal growth', 'CPA', (112, 125))	('increase apoptosis of malignant tumors', 'Disease', 'MESH:D018198', (164, 202))	('cell proliferation', 'CPA', (92, 110))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('anti-stathmin', 'Var', (30, 43))
501982	25092989	In addition, they successfully revealed the identity of the trans-acting factor governing the loading of miRNAs into exosomes, the heterogeneous nuclear ribonucleoprotein A2B1 (hnRNPA2B1), which after being sumoylated, specifically binds exosomal miRNAs through the recognition of these motifs and controls their loading (Figure 1).	('miR', 'Gene', (105, 108))	('miR', 'Gene', '220972', (247, 250))	('miR', 'Gene', (247, 250))	('loading', 'MPA', (313, 320))	('motifs', 'Var', (287, 293))	('heterogeneous nuclear ribonucleoprotein A2B1', 'Gene', (131, 175))	('heterogeneous nuclear ribonucleoprotein A2B1', 'Gene', '3181', (131, 175))	('hnRNPA2B1', 'Gene', (177, 186))	('binds', 'Interaction', (232, 237))	('hnRNPA2B1', 'Gene', '3181', (177, 186))	('controls', 'Reg', (298, 306))	('miR', 'Gene', '220972', (105, 108))
502061	25092989	More recently, the therapeutic potential of exosome-mediated siRNA delivery was demonstrated in vitro by the strong knockdown of RAD51, a prospective therapeutic target for cancer cells.	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('cancer', 'Disease', (173, 179))	('knockdown', 'Var', (116, 125))	('RAD51', 'Gene', (129, 134))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('RAD51', 'Gene', '5888', (129, 134))	('rat', 'Species', '10116', (87, 90))
502064	25092989	Moreover, Rab35 inactivation results in the intracellular accumulation of the vesicles and alters exosome secretion.	('exosome secretion', 'MPA', (98, 115))	('alters', 'Reg', (91, 97))	('inactivation', 'Var', (16, 28))	('Rab35', 'Gene', (10, 15))	('intracellular accumulation of the vesicles', 'MPA', (44, 86))	('Rab35', 'Gene', '11021', (10, 15))
502069	25092989	Indeed, Ohno et al recently reported that by engineering donor cells to produce modified exosomes with GE11, a peptide that binds to EGFR, expressed in their surfaces could efficiently deliver let-7a miRNA to EGFR-expressing breast cancer cells.	('miR', 'Gene', '220972', (200, 203))	('miR', 'Gene', (200, 203))	('GE11', 'Gene', (103, 107))	('EGFR', 'Gene', (209, 213))	('let-7a', 'Var', (193, 199))	('donor', 'Species', '9606', (57, 62))	('deliver', 'MPA', (185, 192))	('EGFR', 'Gene', (133, 137))	('EGFR', 'Gene', '1956', (133, 137))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('breast cancer', 'Disease', 'MESH:D001943', (225, 238))	('breast cancer', 'Phenotype', 'HP:0003002', (225, 238))	('EGFR', 'Gene', '1956', (209, 213))	('breast cancer', 'Disease', (225, 238))
502131	30558629	The operation time and blood loss were also similar in two groups, but the volume of chest drainage in VATS group was less than that in thoracotomy group (P = 0.019, power = 80.1%), although the duration of chest drainage was comparable.	('volume', 'MPA', (75, 81))	('less', 'NegReg', (118, 122))	('blood loss', 'Disease', 'MESH:D006473', (23, 33))	('VATS', 'Var', (103, 107))	('blood loss', 'Disease', (23, 33))
502158	28810546	Knockdown of EGFR induced a similar phenotype to that observed by the inhibition of EGFR.	('Knockdown', 'Var', (0, 9))	('EGFR', 'Gene', '1956', (84, 88))	('EGFR', 'Gene', (84, 88))	('EGFR', 'Gene', '1956', (13, 17))	('EGFR', 'Gene', (13, 17))
502159	28810546	Furthermore, in oral squamous cell carcinoma cells treated with high-dose EGFR inhibitor (50 microM), the small number of cells that survived formed cell-cell junctions that were positive for E-cadherin expression.	('carcinoma', 'Phenotype', 'HP:0030731', (35, 44))	('oral squamous cell carcinoma', 'Disease', (16, 44))	('cell-cell junctions', 'CPA', (149, 168))	('inhibitor', 'Var', (79, 88))	('EGFR', 'Gene', '1956', (74, 78))	('E-cadherin', 'Gene', (192, 202))	('E-cadherin', 'Gene', '999', (192, 202))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (16, 44))	('EGFR', 'Gene', (74, 78))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (21, 44))
502169	28810546	Loss of E-cadherin expression is typically observed in carcinomas, and in breast cancer, transfection with ectopic E-cadherin has been demonstrated to decrease the invasiveness of cancer cells.	('transfection', 'Var', (89, 101))	('carcinomas', 'Disease', (55, 65))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('rat', 'Species', '10116', (142, 145))	('E-cadherin', 'Gene', (115, 125))	('E-cadherin', 'Gene', '999', (115, 125))	('expression', 'MPA', (19, 29))	('Loss', 'NegReg', (0, 4))	('breast cancer', 'Phenotype', 'HP:0003002', (74, 87))	('carcinomas', 'Phenotype', 'HP:0030731', (55, 65))	('carcinomas', 'Disease', 'MESH:D002277', (55, 65))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('carcinoma', 'Phenotype', 'HP:0030731', (55, 64))	('breast cancer', 'Disease', 'MESH:D001943', (74, 87))	('E-cadherin', 'Gene', (8, 18))	('invasiveness of cancer', 'Disease', (164, 186))	('breast cancer', 'Disease', (74, 87))	('E-cadherin', 'Gene', '999', (8, 18))	('decrease', 'NegReg', (151, 159))	('ectopic', 'Var', (107, 114))	('invasiveness of cancer', 'Disease', 'MESH:D009362', (164, 186))
502179	28810546	The present study aimed to evaluate the effect of EGFR inhibition on OSCC cells, particularly on cell-cell junctions mediated by cadherin, by performing wound healing, E-cadherin immunostaining and transepithelial resistance assays in OSCC cells treated with EGFR inhibitor (AG1478) or EGFR small interfering RNA (siRNA).	('SCC', 'CellLine', 'CVCL:1R13', (70, 73))	('EGFR', 'Gene', '1956', (286, 290))	('E-cadherin', 'Gene', '999', (168, 178))	('EGFR', 'Gene', (259, 263))	('EGFR', 'Gene', '1956', (50, 54))	('EGFR', 'Gene', (286, 290))	('AG1478', 'Chemical', 'MESH:C101044', (275, 281))	('EGFR', 'Gene', '1956', (259, 263))	('SCC', 'CellLine', 'CVCL:1R13', (236, 239))	('E-cadherin', 'Gene', (168, 178))	('EGFR', 'Gene', (50, 54))	('small interfering RNA', 'Var', (291, 312))
502211	28810546	Previous studies have demonstrated that AG1478 (0-32 microM) inhibits cell growth in a dose-dependent manner, with lower concentrations of AG1478 (8 microM) having little inhibitory effect on cell growth.	('AG1478', 'Chemical', 'MESH:C101044', (40, 46))	('rat', 'Species', '10116', (29, 32))	('AG1478', 'Var', (40, 46))	('AG1478', 'Chemical', 'MESH:C101044', (139, 145))	('cell growth', 'CPA', (70, 81))	('rat', 'Species', '10116', (128, 131))	('inhibits', 'NegReg', (61, 69))
502212	28810546	A study using serial concentrations of AG1478 (0-40 microM) to treat human breast cancer cells treated with for 72 h also documented that 20 microh AG1478 did not induce significant apoptosis, relative to control cells, while 40 microM AG1478 induced significant apoptosis.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('breast cancer', 'Disease', (75, 88))	('breast cancer', 'Phenotype', 'HP:0003002', (75, 88))	('AG1478', 'Var', (148, 154))	('rat', 'Species', '10116', (28, 31))	('human', 'Species', '9606', (69, 74))	('AG1478', 'Chemical', 'MESH:C101044', (39, 45))	('AG1478', 'Chemical', 'MESH:C101044', (148, 154))	('AG1478', 'Chemical', 'MESH:C101044', (236, 242))	('breast cancer', 'Disease', 'MESH:D001943', (75, 88))
502214	28810546	To determine the optimal concentration of AG1478 for use in the current study, the growth of HSC-3 cells following treatment with AG1478 (0, 0.5, 2, 10 and 50 microM) for 24 h was assessed by cell counting.	('HSC-3', 'Gene', '150353', (93, 98))	('rat', 'Species', '10116', (32, 35))	('AG1478', 'Chemical', 'MESH:C101044', (42, 48))	('AG1478', 'Var', (130, 136))	('HSC-3', 'Gene', (93, 98))	('AG1478', 'Chemical', 'MESH:C101044', (130, 136))
502215	28810546	Analogous to previous reports, cytotoxic effects were observed in HSC-3 cells following treatment with 50 microM AG1478, while lower concentrations of AG1478 (0-10 microM) had little inhibitory effect on cell growth (data not shown).	('AG1478', 'Chemical', 'MESH:C101044', (113, 119))	('cytotoxic effects', 'CPA', (31, 48))	('HSC-3', 'Gene', '150353', (66, 71))	('AG1478', 'Chemical', 'MESH:C101044', (151, 157))	('AG1478', 'Var', (113, 119))	('rat', 'Species', '10116', (140, 143))	('HSC-3', 'Gene', (66, 71))
502217	28810546	Therefore, the current study evaluated the motility of HSC-3 cells following treatment with AG1478 (0.5 and 2 microM) for 12 and 24 h. In vitro wound healing assays indicated that AG1478 treatment (2 microM) suppressed the motility of the OSCC cell line, relative to untreated control cells (Fig.	('AG1478', 'Var', (180, 186))	('AG1478', 'Chemical', 'MESH:C101044', (92, 98))	('HSC-3', 'Gene', '150353', (55, 60))	('AG1478', 'Chemical', 'MESH:C101044', (180, 186))	('motility of the OSCC cell line', 'CPA', (223, 253))	('suppressed', 'NegReg', (208, 218))	('HSC-3', 'Gene', (55, 60))	('SCC', 'CellLine', 'CVCL:1R13', (240, 243))
502222	28810546	2B), and the higher concentration of AG1478 (2 microM) caused cells to adopt an epithelial-like squamous morphology (Fig.	('AG1478', 'Chemical', 'MESH:C101044', (37, 43))	('epithelial-like squamous morphology', 'CPA', (80, 115))	('AG1478', 'Var', (37, 43))	('rat', 'Species', '10116', (27, 30))
502223	28810546	Relative to all other concentrations of AG1478 investigated (0-50 microM), 2 microM AG1478 reduced the spaces between cells to the greatest extent.	('AG1478', 'Chemical', 'MESH:C101044', (40, 46))	('AG1478', 'Var', (84, 90))	('rat', 'Species', '10116', (29, 32))	('spaces between cells', 'CPA', (103, 123))	('reduced', 'NegReg', (91, 98))	('AG1478', 'Chemical', 'MESH:C101044', (84, 90))
502224	28810546	Immunostaining of cell-cell contacts demonstrated that AG1478 altered the expression of E-cadherin and the tight junction-associated cytoplasmic protein ZO-1, as a marker of cell junctions in various cell types, in a dose-dependent manner.	('ZO-1', 'Gene', (153, 157))	('expression', 'MPA', (74, 84))	('altered', 'Reg', (62, 69))	('E-cadherin', 'Gene', (88, 98))	('E-cadherin', 'Gene', '999', (88, 98))	('AG1478', 'Var', (55, 61))	('ZO-1', 'Gene', '7082', (153, 157))	('AG1478', 'Chemical', 'MESH:C101044', (55, 61))	('rat', 'Species', '10116', (44, 47))
502227	28810546	Treatment with the higher concentration of AG1478 (2 microM) led to the formation of continuous linear junctions, indicated by linear accumulations and co-expression of E-cadherin and ZO-1 (Fig.	('linear accumulations', 'MPA', (127, 147))	('ZO-1', 'Gene', (184, 188))	('E-cadherin', 'Gene', (169, 179))	('E-cadherin', 'Gene', '999', (169, 179))	('ZO-1', 'Gene', '7082', (184, 188))	('AG1478', 'Var', (43, 49))	('rat', 'Species', '10116', (33, 36))	('co-expression', 'Reg', (152, 165))	('AG1478', 'Chemical', 'MESH:C101044', (43, 49))
502229	28810546	It was observed that AG1478 (0.5 and 2 microM) increased TER in a dose-dependent manner (Fig.	('AG1478', 'Var', (21, 27))	('increased', 'PosReg', (47, 56))	('TER', 'MPA', (57, 60))	('AG1478', 'Chemical', 'MESH:C101044', (21, 27))
502230	28810546	Similar to AG1478 treatment, knockdown of EGFR flattened the fibroblastic morphology of HSC-3 cells (Fig.	('EGFR', 'Gene', '1956', (42, 46))	('knockdown', 'Var', (29, 38))	('HSC-3', 'Gene', (88, 93))	('AG1478', 'Chemical', 'MESH:C101044', (11, 17))	('EGFR', 'Gene', (42, 46))	('HSC-3', 'Gene', '150353', (88, 93))	('flattened', 'PosReg', (47, 56))
502232	28810546	High dose AG1478 caused a marked reduction in the number of HSC-3 cells, relative to untreated controls and cells treated with 2 microM AG1478.	('AG1478', 'Var', (10, 16))	('AG1478', 'Chemical', 'MESH:C101044', (136, 142))	('reduction', 'NegReg', (33, 42))	('HSC-3', 'Gene', (60, 65))	('AG1478', 'Chemical', 'MESH:C101044', (10, 16))	('HSC-3', 'Gene', '150353', (60, 65))
502242	28810546	In response to cell-matrix adhesion, a complex involving integrins and EGFR is formed, and EGFR is subsequently phosphorylated on tyrosines 845, 1068, 1086 and 1173, though not on 1148.	('tyrosines 845', 'Var', (130, 143))	('EGFR', 'Gene', (91, 95))	('complex', 'Interaction', (39, 46))	('tyrosines', 'Chemical', 'MESH:D014443', (130, 139))	('1086', 'Var', (151, 155))	('EGFR', 'Gene', '1956', (71, 75))	('1068', 'Var', (145, 149))	('EGFR', 'Gene', '1956', (91, 95))	('EGFR', 'Gene', (71, 75))
502243	28810546	Phosphorylation of EGFR at tyrosine 1173 has been associated with a poor prognosis in OSCC.	('SCC', 'CellLine', 'CVCL:1R13', (87, 90))	('Phosphorylation', 'Var', (0, 15))	('EGFR', 'Gene', '1956', (19, 23))	('EGFR', 'Gene', (19, 23))	('associated', 'Reg', (50, 60))	('tyrosine', 'Chemical', 'MESH:D014443', (27, 35))	('OSCC', 'Disease', (86, 90))
502246	28810546	Previous reports have demonstrated that inhibition of EGFR kinase activity with tyrosine kinase inhibitors typically leads to decreased cell proliferation without affecting cell survival, while targeted knockdown of the EGFR protein has been found to result in cell death.	('decreased', 'NegReg', (126, 135))	('rat', 'Species', '10116', (148, 151))	('EGFR', 'Gene', (220, 224))	('activity', 'MPA', (66, 74))	('tyrosine', 'Chemical', 'MESH:D014443', (80, 88))	('rat', 'Species', '10116', (29, 32))	('inhibition', 'NegReg', (40, 50))	('EGFR', 'Gene', '1956', (54, 58))	('EGFR', 'Gene', (54, 58))	('EGFR', 'Gene', '1956', (220, 224))	('knockdown', 'Var', (203, 212))	('cell proliferation', 'CPA', (136, 154))
502247	28810546	Cell death induced by EGFR knockdown may be due to autophagy and not typical apoptosis.	('knockdown', 'Var', (27, 36))	('autophagy', 'CPA', (51, 60))	('Cell death', 'CPA', (0, 10))	('EGFR', 'Gene', '1956', (22, 26))	('EGFR', 'Gene', (22, 26))
502249	28810546	Inhibition of tyrosine kinase activity alone has limited therapeutic efficacy, possibly due to the inhibitory effects of EGFR on autophagy in various cancer cell lines, which are potentially independent of its tyrosine kinase activity.	('EGFR', 'Gene', '1956', (121, 125))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('EGFR', 'Gene', (121, 125))	('cancer', 'Disease', (150, 156))	('Inhibition', 'Var', (0, 10))	('autophagy', 'CPA', (129, 138))	('tyrosine', 'Chemical', 'MESH:D014443', (210, 218))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('tyrosine', 'Chemical', 'MESH:D014443', (14, 22))
502251	28810546	In head and neck SCC cells overexpressing E-cadherin, it has also been documented that a reduction in E-cadherin expression may lead to an upregulation in EGFR transcription, suggesting that loss of E-cadherin may induce proliferation by activating EGFR.	('proliferation', 'CPA', (221, 234))	('EGFR', 'Gene', (155, 159))	('E-cadherin', 'Gene', (102, 112))	('E-cadherin', 'Gene', '999', (102, 112))	('EGFR', 'Gene', (249, 253))	('activating', 'PosReg', (238, 248))	('expression', 'MPA', (113, 123))	('rat', 'Species', '10116', (228, 231))	('induce', 'PosReg', (214, 220))	('E-cadherin', 'Gene', (42, 52))	('E-cadherin', 'Gene', '999', (42, 52))	('EGFR', 'Gene', '1956', (155, 159))	('E-cadherin', 'Gene', (199, 209))	('E-cadherin', 'Gene', '999', (199, 209))	('EGFR', 'Gene', '1956', (249, 253))	('reduction', 'NegReg', (89, 98))	('upregulation', 'PosReg', (139, 151))	('loss', 'Var', (191, 195))	('SCC', 'CellLine', 'CVCL:1R13', (17, 20))	('transcription', 'MPA', (160, 173))
502252	28810546	Furthermore, in pancreatic carcinoma cells, inhibitors of matrix metalloproteinases markedly reduced E-cadherin expression while suppressing EGFR activation, while upregulation of E-cadherin led to changes in cellular morphology, decreased cell motility and enhanced apoptotic sensitivity in response to chemotherapeutic treatment.	('E-cadherin', 'Gene', '999', (180, 190))	('carcinoma', 'Phenotype', 'HP:0030731', (27, 36))	('pancreatic carcinoma', 'Disease', 'MESH:C562463', (16, 36))	('expression', 'MPA', (112, 122))	('decreased', 'NegReg', (230, 239))	('changes', 'Reg', (198, 205))	('E-cadherin', 'Gene', (101, 111))	('EGFR', 'Gene', '1956', (141, 145))	('E-cadherin', 'Gene', '999', (101, 111))	('pancreatic carcinoma', 'Disease', (16, 36))	('apoptotic sensitivity', 'CPA', (267, 288))	('suppressing', 'NegReg', (129, 140))	('cell motility', 'CPA', (240, 253))	('activation', 'MPA', (146, 156))	('cellular morphology', 'CPA', (209, 228))	('upregulation', 'PosReg', (164, 176))	('inhibitors', 'Var', (44, 54))	('reduced', 'NegReg', (93, 100))	('EGFR', 'Gene', (141, 145))	('enhanced', 'PosReg', (258, 266))	('E-cadherin', 'Gene', (180, 190))
502268	28810546	In conclusion, treatment of OSCC cells with low concentrations of EGFR inhibitor led to the acquisition of epithelial properties, as indicated by E-cadherin-mediated cell junctions, suppression of cell motility and an increase in TER.	('TER', 'CPA', (230, 233))	('cell motility', 'CPA', (197, 210))	('E-cadherin', 'Gene', (146, 156))	('E-cadherin', 'Gene', '999', (146, 156))	('EGFR', 'Gene', '1956', (66, 70))	('EGFR', 'Gene', (66, 70))	('acquisition', 'PosReg', (92, 103))	('increase', 'PosReg', (218, 226))	('SCC', 'CellLine', 'CVCL:1R13', (29, 32))	('rat', 'Species', '10116', (55, 58))	('suppression', 'NegReg', (182, 193))	('epithelial properties', 'CPA', (107, 128))	('inhibitor', 'Var', (71, 80))
502272	28045062	Modifying effect of mouse double minute-2 promoter variants on risk of recurrence for patients with squamous cell carcinoma of oropharynx Functional mouse double minute-2 (MDM2) promoter variants may alter MDM2 expression and thus affect radiotherapy response and prognosis of squamous cell carcinoma of oropharynx (SCCOP).	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (100, 123))	('alter', 'Reg', (200, 205))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (100, 123))	('patients', 'Species', '9606', (86, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('squamous cell carcinoma', 'Disease', (100, 123))	('carcinoma', 'Phenotype', 'HP:0030731', (291, 300))	('variants', 'Var', (187, 195))	('affect', 'Reg', (231, 237))	('MDM2', 'Gene', (206, 210))	('mouse', 'Species', '10090', (149, 154))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (277, 300))	('radiotherapy response', 'CPA', (238, 259))	('squamous cell carcinoma', 'Disease', (277, 300))	('expression', 'MPA', (211, 221))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (277, 300))	('mouse', 'Species', '10090', (20, 25))
502273	28045062	The disease-free survival (DFS) of patients with MDM2rs2279744 TT or MDM2rs937283 AA genotypes was significantly reduced compared with that of patients with corresponding GT/GG or AG/GG genotypes.	('disease-free survival', 'CPA', (4, 25))	('patients', 'Species', '9606', (143, 151))	('rs2279744', 'Mutation', 'rs2279744', (53, 62))	('MDM2rs2279744', 'Var', (49, 62))	('patients', 'Species', '9606', (35, 43))	('reduced', 'NegReg', (113, 120))	('MDM2rs937283 AA', 'Var', (69, 84))
502278	28045062	Taken together, our findings suggest that MDM2 promoter variants individually, or more likely jointly, play a role in determining the risk of recurrence of SCCOP, particularly HPV-positive SCCOP.	('SCCOP', 'Disease', (156, 161))	('HPV', 'Species', '10566', (176, 179))	('variants', 'Var', (56, 64))	('MDM2', 'Gene', (42, 46))	('HPV-positive SCCOP', 'Disease', (176, 194))
502284	28045062	However, only a small proportion of individuals exposed to HPV eventually develop SCCOP, indicating that genetic susceptibility may contribute to an individual's SCCOP risk.	('HPV', 'Var', (59, 62))	('SCCOP', 'Disease', (82, 87))	('develop', 'Reg', (74, 81))	('HPV', 'Species', '10566', (59, 62))
502290	28045062	Genetic alterations in p53 have been found in most human cancers.	('Genetic alterations', 'Var', (0, 19))	('found', 'Reg', (37, 42))	('cancers', 'Phenotype', 'HP:0002664', (57, 64))	('cancers', 'Disease', (57, 64))	('human', 'Species', '9606', (51, 56))	('cancers', 'Disease', 'MESH:D009369', (57, 64))	('p53', 'Gene', (23, 26))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))
502292	28045062	Of the MDM2 promoter polymorphisms identified, 2 single nucleotide polymorphisms (SNPs) of MDM2, MDM2rs2279744 and MDM2rs937283, have been reported in the risk of SCCHN or HPV-associated oral cancer.	('HPV', 'Species', '10566', (172, 175))	('oral cancer', 'Disease', 'MESH:D009062', (187, 198))	('MDM2', 'Gene', (91, 95))	('SCCHN', 'Disease', (163, 168))	('MDM2rs937283', 'Var', (115, 127))	('MDM2rs2279744', 'Var', (97, 110))	('reported', 'Reg', (139, 147))	('oral cancer', 'Disease', (187, 198))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))
502293	28045062	To test our hypothesis, we used the log-rank test and multivariable Cox models to assess the association of 2 functional MDM2 promoter variants with recurrence risk in 1008 patients with incident SCCOP.	('Cox', 'Gene', (68, 71))	('patients', 'Species', '9606', (173, 181))	('variants', 'Var', (135, 143))	('association', 'Interaction', (93, 104))	('MDM2', 'Gene', (121, 125))	('Cox', 'Gene', '1351', (68, 71))
502316	28045062	The genotype distributions of the 2 MDM2 SNPs (MDM2rs2279744 and MDM2rs937283), the recurrence rates of patients with the SNPs, and the association results are presented in Table 2.	('MDM2', 'Gene', (36, 40))	('MDM2rs2279744', 'Var', (47, 60))	('rs2279744', 'Mutation', 'rs2279744', (51, 60))	('MDM2rs937283', 'Var', (65, 77))	('patients', 'Species', '9606', (104, 112))
502317	28045062	Kaplan-Meier analyses revealed that patients with the MDM2rs2279744 GT/GG and MDM2rs937283 AG/GG genotypes had significantly better DFS than patients with the corresponding TT and AA genotypes did (all log-rank P < 0.0001) (Fig.	('patients', 'Species', '9606', (36, 44))	('better', 'PosReg', (125, 131))	('MDM2rs2279744 GT/GG', 'Var', (54, 73))	('MDM2rs937283 AG/GG', 'Var', (78, 96))	('rs2279744', 'Mutation', 'rs2279744', (58, 67))	('DFS', 'MPA', (132, 135))	('patients', 'Species', '9606', (141, 149))
502320	28045062	Furthermore, after adjustment for several major confounders, including age, sex, ethnicity, smoking status, alcohol status, comorbidity, disease stage, and treatment, the multivariable Cox proportional hazards regression analysis showed that the patients with the MDM2rs2279744 TT and MDM2rs937283 AA genotypes had approximately 2- and 6-fold significantly increased risks of disease recurrence, respectively (aHR, 2.0, 95% CI, 1.5-2.8 and aHR, 6.2, 95% CI, 4.6-8.3, respectively).	('aHR', 'Gene', (410, 413))	('MDM2rs2279744 TT', 'Var', (264, 280))	('alcohol', 'Chemical', 'MESH:D000438', (108, 115))	('patients', 'Species', '9606', (246, 254))	('aHR', 'Gene', '196', (440, 443))	('Cox', 'Gene', '1351', (185, 188))	('Cox', 'Gene', (185, 188))	('aHR', 'Gene', '196', (410, 413))	('disease recurrence', 'CPA', (376, 394))	('aHR', 'Gene', (440, 443))	('MDM2rs937283 AA', 'Var', (285, 300))	('men', 'Species', '9606', (161, 164))	('men', 'Species', '9606', (25, 28))
502323	28045062	As expected, compared with patients with MDM2rs2279744 GG and MDM2rs937283 GG genotypes, the patients with MDM2rs2279744 TT and MDM2rs937283 AA genotypes had the highest risk of recurrence among all groups (aHR, 26.8; 95% CI, 10.3-48.7).	('rs2279744', 'Mutation', 'rs2279744', (111, 120))	('patients', 'Species', '9606', (93, 101))	('aHR', 'Gene', (207, 210))	('rs2279744', 'Mutation', 'rs2279744', (45, 54))	('MDM2rs2279744 TT', 'Var', (107, 123))	('aHR', 'Gene', '196', (207, 210))	('patients', 'Species', '9606', (27, 35))	('MDM2rs937283 AA', 'Var', (128, 143))	('recurrence', 'Disease', (178, 188))
502324	28045062	Additionally, although the patients with MDM2rs2279744 GT and MDM2rs937283 AG genotypes in the low-risk group, the risk for these patients was higher than those with MDM2rs2279744 TT and MDM2rs937283 GG genotypes in the medium-risk group.	('MDM2rs2279744 GT', 'Var', (41, 57))	('MDM2rs937283 AG', 'Var', (62, 77))	('patients', 'Species', '9606', (27, 35))	('patients', 'Species', '9606', (130, 138))	('higher', 'PosReg', (143, 149))
502327	28045062	2, patients with the MDM2rs2279744 GT/GG and MDM2rs937283 AG/GG genotypes had significantly better DFS than patients with the corresponding TT and AA genotypes did (all log-rank P < 0.0001).	('MDM2rs937283 AG/GG', 'Var', (45, 63))	('DFS', 'MPA', (99, 102))	('rs2279744', 'Mutation', 'rs2279744', (25, 34))	('patients', 'Species', '9606', (3, 11))	('MDM2rs2279744', 'Var', (21, 34))	('patients', 'Species', '9606', (108, 116))	('better', 'PosReg', (92, 98))
502328	28045062	Multivariable analysis with adjustment for several major confounders showed that the patients with the MDM2rs2279744 TT and MDM2rs937283 AA genotypes had approximately 4.5- and 24-fold significantly increased risks for recurrence compared with patients with the corresponding GT/GG and AG/GG genotypes (aHR, 4.4, 95% CI, 2.2-8.9 and aHR, 23.7, 95% CI, 11.5-48.8, respectively) (Table 4).	('MDM2rs2279744 TT', 'Var', (103, 119))	('aHR', 'Gene', '196', (303, 306))	('aHR', 'Gene', (333, 336))	('recurrence', 'CPA', (219, 229))	('patients', 'Species', '9606', (85, 93))	('aHR', 'Gene', (303, 306))	('aHR', 'Gene', '196', (333, 336))	('patients', 'Species', '9606', (244, 252))	('MDM2rs937283 AA', 'Var', (124, 139))	('increased', 'PosReg', (199, 208))	('men', 'Species', '9606', (34, 37))
502331	28045062	In previous studies, we found that the MDM2rs2279744 and MDM2rs937283 polymorphisms had an interactive effect on HPV-associated SCCOP; moreover, MDM2rs2279744 also modified the risk of lung cancer.	('MDM2rs937283', 'Var', (57, 69))	('lung cancer', 'Disease', 'MESH:D008175', (185, 196))	('MDM2rs2279744', 'Var', (39, 52))	('rs2279744', 'Mutation', 'rs2279744', (149, 158))	('HPV-associated SCCOP', 'Disease', (113, 133))	('rs2279744', 'Mutation', 'rs2279744', (43, 52))	('lung cancer', 'Disease', (185, 196))	('lung cancer', 'Phenotype', 'HP:0100526', (185, 196))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('MDM2rs2279744', 'Var', (145, 158))	('HPV', 'Species', '10566', (113, 116))	('modified', 'Reg', (164, 172))
502333	28045062	The present study revealed that both MDM2rs2279744 and MDM2rs937283 individually, or more likely jointly, significantly increase the risk of SCCOP recurrence after definitive radiotherapy, particularly in patients with HPV-positive tumors.	('rs2279744', 'Mutation', 'rs2279744', (41, 50))	('patients', 'Species', '9606', (205, 213))	('SCCOP recurrence', 'Disease', (141, 157))	('MDM2rs937283', 'Var', (55, 67))	('HPV-positive tumors', 'Disease', 'MESH:D030361', (219, 238))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('HPV-positive tumors', 'Disease', (219, 238))	('tumors', 'Phenotype', 'HP:0002664', (232, 238))	('increase', 'PosReg', (120, 128))	('MDM2rs2279744', 'Var', (37, 50))
502334	28045062	By inactivating p53, MDM2 overexpression can inhibit p53-mediated tumor-suppressing activities.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Disease', (66, 71))	('p53', 'Gene', (16, 19))	('p53-mediated', 'Protein', (53, 65))	('inhibit', 'NegReg', (45, 52))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('inactivating', 'Var', (3, 15))
502336	28045062	The 2 MDM2 SNPs we investigated in the present study have been found to modify cancer development, and our findings may provide some new evidence as to whether these 2 promoter variants of MDM2 affect recurrence risk among SCCOP patients.	('patients', 'Species', '9606', (229, 237))	('men', 'Species', '9606', (93, 96))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('affect', 'Reg', (194, 200))	('SCCOP', 'Disease', (223, 228))	('MDM2', 'Gene', (189, 193))	('variants', 'Var', (177, 185))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('modify', 'Reg', (72, 78))	('recurrence', 'CPA', (201, 211))
502338	28045062	In this study, the variant T allele was associated with increased risk of SCCOP recurrence, while others reported that individuals with the MDM2 G allele have a decreased risk of oral squamous cell carcinoma and leukemia.	('leukemia', 'Phenotype', 'HP:0001909', (212, 220))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (184, 207))	('carcinoma', 'Phenotype', 'HP:0030731', (198, 207))	('variant', 'Var', (19, 26))	('SCCOP recurrence', 'Disease', (74, 90))	('oral squamous cell carcinoma and leukemia', 'Disease', 'MESH:D002294', (179, 220))
502339	28045062	The molecular mechanisms underlying the effects that MDM2-rs2279744 and MDM2rs937283 genetic variations have on cancer development and progression remain elusive.	('men', 'Species', '9606', (126, 129))	('MDM2-rs2279744', 'Var', (53, 67))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('MDM2rs937283', 'Var', (72, 84))	('rs2279744', 'Mutation', 'rs2279744', (58, 67))
502340	28045062	The rs2279744 variant in the MDM2 promoter causes a T-to-G substitution at the 309 nucleotide site, which increases MDM2's binding affinity for the transcriptional activator SP1, thereby increasing MDM2 expression and thus enhancing p53 degradation.	('increasing', 'PosReg', (187, 197))	('MDM2', 'Gene', (29, 33))	('expression', 'MPA', (203, 213))	('enhancing', 'PosReg', (223, 232))	('binding affinity', 'Interaction', (123, 139))	('rs2279744', 'Mutation', 'rs2279744', (4, 13))	('increases', 'PosReg', (106, 115))	('MDM2', 'Protein', (198, 202))	('p53 degradation', 'MPA', (233, 248))	('rs2279744', 'Var', (4, 13))
502341	28045062	One recent meta-analysis investigating the association between positive MDM2 expression and clinicopathological characteristics in patients with esophageal squamous cell carcinoma found that high MDM2 expression was associated with early primary tumor stage and increased risk of regional, but not distant, lymph node metastasis, whereas another study showed that loss of MTBP (MDM2 binding protein) expression may be linked to worse survival in some patients with SCCHN.	('MTBP', 'Gene', (372, 376))	('associated', 'Reg', (216, 226))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('esophageal squamous cell carcinoma', 'Disease', (145, 179))	('expression', 'MPA', (201, 211))	('MDM2 binding protein', 'Gene', (378, 398))	('SCCHN', 'Disease', (465, 470))	('primary tumor', 'Disease', 'MESH:D009369', (238, 251))	('patients', 'Species', '9606', (131, 139))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (145, 179))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (156, 179))	('primary tumor', 'Disease', (238, 251))	('MDM2 binding protein', 'Gene', '27085', (378, 398))	('regional', 'CPA', (280, 288))	('MTBP', 'Gene', '27085', (372, 376))	('carcinoma', 'Phenotype', 'HP:0030731', (170, 179))	('MDM2', 'Gene', (196, 200))	('high', 'Var', (191, 195))	('patients', 'Species', '9606', (451, 459))
502343	28045062	reported that both MDM2rs2279744 and MDM2rs937283 may synergize with HPV16 L1 seropositivity to significantly increase the risk of oral squamous cell carcinoma, particularly SCCOP.	('increase', 'PosReg', (110, 118))	('MDM2rs2279744', 'Var', (19, 32))	('carcinoma', 'Phenotype', 'HP:0030731', (150, 159))	('SCCOP', 'Disease', (174, 179))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (131, 159))	('rs2279744', 'Mutation', 'rs2279744', (23, 32))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (136, 159))	('HPV16', 'Species', '333760', (69, 74))	('MDM2rs937283', 'Var', (37, 49))	('oral squamous cell carcinoma', 'Disease', (131, 159))
502346	28045062	Thus, compared with HPV-positive SCCOP patients, HPV-negative SCCOP patients generally have p53 mutations.	('HPV', 'Species', '10566', (20, 23))	('patients', 'Species', '9606', (39, 47))	('HPV', 'Species', '10566', (49, 52))	('patients', 'Species', '9606', (68, 76))	('p53', 'Gene', (92, 95))	('mutations', 'Var', (96, 105))
502348	28045062	In the present study, to minimize the confounding effect of tumor HPV status on SCCOP prognosis, we investigated the effects of MDM2rs2279744 and MDM2rs937283 variants on SCCOP recurrence among HPV-positive patients only.	('HPV', 'Species', '10566', (66, 69))	('patients', 'Species', '9606', (207, 215))	('rs2279744', 'Mutation', 'rs2279744', (132, 141))	('tumor HPV', 'Disease', 'MESH:D030361', (60, 69))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('MDM2rs937283', 'Var', (146, 158))	('HPV', 'Species', '10566', (194, 197))	('tumor HPV', 'Disease', (60, 69))	('MDM2rs2279744', 'Var', (128, 141))
502350	28045062	We speculate that the MDM2rs2279744 and MDM2rs937283 risk genotypes may cause p53 degradation, thereby reducing p53-induced apoptotic responses among patients with HPV16-positive tumors, which in turn lead to poor responses to definitive radiotherapy and subsequently an increased risk of disease recurrence.	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('MDM2rs2279744', 'Var', (22, 35))	('tumors', 'Phenotype', 'HP:0002664', (179, 185))	('HPV16-positive tumors', 'Disease', (164, 185))	('patients', 'Species', '9606', (150, 158))	('cause', 'Reg', (72, 77))	('p53 degradation', 'MPA', (78, 93))	('reducing', 'NegReg', (103, 111))	('lead to', 'Reg', (201, 208))	('HPV16-positive tumors', 'Disease', 'MESH:D009369', (164, 185))	('p53-induced', 'MPA', (112, 123))	('MDM2rs937283', 'Var', (40, 52))
502354	28045062	In conclusion, the genetic promoter variants MDM2rs2279744 and MDM2rs937283 may play important roles in MDM2 expression and p53-depenent apoptotic pathways, affect apoptotic capacity and radiotherapy response, and contribute to genetic susceptibility to SCCOP recurrence, particularly among SCCOP patients with HPV16-posiitve tumors who have received definitive radiotherapy.	('tumors', 'Phenotype', 'HP:0002664', (326, 332))	('HPV16-posiitve tumors', 'Disease', 'MESH:D009369', (311, 332))	('expression', 'MPA', (109, 119))	('susceptibility', 'Reg', (236, 250))	('HPV16-posiitve tumors', 'Disease', (311, 332))	('contribute', 'Reg', (214, 224))	('MDM2rs937283', 'Var', (63, 75))	('p53-depenent apoptotic pathways', 'Pathway', (124, 155))	('patients', 'Species', '9606', (297, 305))	('tumor', 'Phenotype', 'HP:0002664', (326, 331))	('MDM2rs2279744', 'Var', (45, 58))	('apoptotic capacity', 'CPA', (164, 182))	('MDM2', 'Gene', (104, 108))	('affect', 'Reg', (157, 163))	('radiotherapy response', 'CPA', (187, 208))	('SCCOP recurrence', 'Disease', (254, 270))	('play', 'Reg', (80, 84))
502355	28045062	Modifying effect of mouse double minute-2 promoter variants on risk of recurrence for patients with squamous cell carcinoma of oropharynx.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (100, 123))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (100, 123))	('Modifying effect', 'Reg', (0, 16))	('patients', 'Species', '9606', (86, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('squamous cell carcinoma', 'Disease', (100, 123))	('variants', 'Var', (51, 59))	('mouse', 'Species', '10090', (20, 25))
502361	27014069	Recent studies have reported differential expression and mutations of DDR1 and DDR2 in several cancer types and indicate clearly that these receptors have to be taken into account as new players in the different aspects of tumor progression, from non-malignant to highly malignant and invasive stages.	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('tumor', 'Disease', (223, 228))	('DDR1', 'Gene', (70, 74))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('cancer', 'Disease', (95, 101))	('mutations', 'Var', (57, 66))	('tumor', 'Disease', 'MESH:D009369', (223, 228))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('DDR2', 'Gene', (79, 83))
502386	27014069	While activation of DDRs is required for normal development, studies have reported differential expression and mutations of DDR1 and DDR2 in several cancers (Valiathan et al.,).	('mutations', 'Var', (111, 120))	('DDR', 'Gene', (133, 136))	('cancers', 'Disease', (149, 156))	('cancers', 'Phenotype', 'HP:0002664', (149, 156))	('DDR', 'Gene', (20, 23))	('DDR', 'Gene', '780;12305;25678;4921;478987;18214', (133, 136))	('DDR', 'Gene', '780;12305;25678;4921;478987;18214', (124, 127))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('DDR', 'Gene', (124, 127))	('DDR', 'Gene', '780;12305;25678;4921;478987;18214', (20, 23))	('cancers', 'Disease', 'MESH:D009369', (149, 156))
502407	27014069	For example, DDR1 inhibits cell migration in Madin-Darby canine kidney (MDCK) cells (Wang et al.,) whereas, in other cellular systems, DDR1 and DDR2 promote cell migration and/or invasion (Yoshida and Teramoto,).	('cell migration', 'CPA', (157, 171))	('rat', 'Species', '10116', (165, 168))	('cell migration', 'CPA', (27, 41))	('inhibits', 'NegReg', (18, 26))	('DDR1', 'Var', (13, 17))	('DDR1', 'Gene', (135, 139))	('canine', 'Species', '9615', (57, 63))	('invasion', 'CPA', (179, 187))	('DDR2', 'Gene', (144, 148))	('rat', 'Species', '10116', (35, 38))	('promote', 'PosReg', (149, 156))
502411	27014069	In the case of DDR2, these mutations are present in 3-4% of patients with lung squamous cell cancer (Hammerman et al.,) and have been reported in other cancers at comparable frequencies including lung adenocarcinoma, cervical carcinoma, gastric carcinoma, bladder carcinoma, melanoma, colorectal cancer, head, and neck cancer (Beauchamp et al.,).	('lung adenocarcinoma', 'Disease', (196, 215))	('mutations', 'Var', (27, 36))	('cancer', 'Phenotype', 'HP:0002664', (296, 302))	('colorectal cancer', 'Phenotype', 'HP:0003003', (285, 302))	('lung squamous cell cancer', 'Disease', 'MESH:D002294', (74, 99))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (256, 273))	('cancer', 'Phenotype', 'HP:0002664', (319, 325))	('neck cancer', 'Phenotype', 'HP:0012288', (314, 325))	('bladder carcinoma', 'Disease', 'MESH:D001749', (256, 273))	('cancers', 'Phenotype', 'HP:0002664', (152, 159))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (79, 99))	('cancers', 'Disease', (152, 159))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (196, 215))	('lung squamous cell cancer', 'Disease', (74, 99))	('patients', 'Species', '9606', (60, 68))	('gastric carcinoma', 'Disease', 'MESH:D013274', (237, 254))	('carcinoma', 'Phenotype', 'HP:0030731', (245, 254))	('cervical carcinoma', 'Disease', (217, 235))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (196, 215))	('gastric carcinoma', 'Disease', (237, 254))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('melanoma', 'Phenotype', 'HP:0002861', (275, 283))	('melanoma', 'Disease', (275, 283))	('colorectal cancer', 'Disease', 'MESH:D015179', (285, 302))	('bladder carcinoma', 'Disease', (256, 273))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (237, 254))	('carcinoma', 'Phenotype', 'HP:0030731', (206, 215))	('DDR2', 'Gene', (15, 19))	('neck cancer', 'Disease', 'MESH:D006258', (314, 325))	('neck cancer', 'Disease', (314, 325))	('cervical carcinoma', 'Disease', 'MESH:D002575', (217, 235))	('carcinoma', 'Phenotype', 'HP:0030731', (226, 235))	('colorectal cancer', 'Disease', (285, 302))	('lung squamous cell cancer', 'Phenotype', 'HP:0030359', (74, 99))	('cancers', 'Disease', 'MESH:D009369', (152, 159))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('melanoma', 'Disease', 'MESH:D008545', (275, 283))	('carcinoma', 'Phenotype', 'HP:0030731', (264, 273))
502412	27014069	Mutation known as I638F, has been shown to promote resistance to inhibitors of DDR2 kinase function (Hammerman et al.,; Figure 2).	('resistance to inhibitors', 'MPA', (51, 75))	('promote', 'PosReg', (43, 50))	('I638F', 'Var', (18, 23))	('I638F', 'Mutation', 'rs1057519789', (18, 23))	('DDR2', 'Gene', (79, 83))
502418	27014069	Upregulation of transforming growth factor beta 1 (TGFbeta1), following DDR1 silencing, is thought to induce tumor cell growth arrest (Rudra-Ganguly et al.,).	('Upregulation', 'PosReg', (0, 12))	('DDR1', 'Gene', (72, 76))	('induce', 'PosReg', (102, 108))	('silencing', 'Var', (77, 86))	('TGFbeta1', 'Gene', '7040', (51, 59))	('TGFbeta1', 'Gene', (51, 59))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumor cell growth arrest', 'Disease', (109, 133))	('tumor cell growth arrest', 'Disease', 'MESH:D006323', (109, 133))	('growth arrest', 'Phenotype', 'HP:0001510', (120, 133))	('transforming growth factor beta 1', 'Gene', '7040', (16, 49))	('transforming growth factor beta 1', 'Gene', (16, 49))
502419	27014069	Furthermore, inhibition of DDR1 in human colon carcinoma cells (Ongusaha et al.,), breast cancer cell lines (Ongusaha et al.,; Das et al.,) and collagen treated Hodgkin lymphoma cells (Cader et al.,) resulted in an increase in cell death in response to induced DNA damage (Ongusaha et al.,; Das et al.,; Cader et al.,).	('Hodgkin lymphoma', 'Disease', (161, 177))	('lymphoma', 'Phenotype', 'HP:0002665', (169, 177))	('colon carcinoma', 'Disease', 'MESH:D015179', (41, 56))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('colon carcinoma', 'Disease', (41, 56))	('breast cancer', 'Disease', 'MESH:D001943', (83, 96))	('inhibition', 'Var', (13, 23))	('increase', 'PosReg', (215, 223))	('human', 'Species', '9606', (35, 40))	('cell death', 'CPA', (227, 237))	('breast cancer', 'Disease', (83, 96))	('Hodgkin lymphoma', 'Disease', 'MESH:D006689', (161, 177))	('response to induced DNA damage', 'MPA', (241, 271))	('breast cancer', 'Phenotype', 'HP:0003002', (83, 96))	('Hodgkin lymphoma', 'Phenotype', 'HP:0012189', (161, 177))	('carcinoma', 'Phenotype', 'HP:0030731', (47, 56))	('DDR1', 'Gene', (27, 31))
502423	27014069	In the case of DDR2, mutations of the receptor were shown to promote cell growth in NIH3T3 mouse embryonic fibroblast cells [(Hammerman et al.,) section Supplementary Data, Figure S3-a].	('mutations', 'Var', (21, 30))	('DDR2', 'Gene', (15, 19))	('promote', 'PosReg', (61, 68))	('NIH3T3', 'CellLine', 'CVCL:0594', (84, 90))	('mouse', 'Species', '10090', (91, 96))	('cell growth', 'CPA', (69, 80))
502431	27014069	Indeed, Iwai and co-workers demonstrated that the mutation I638F in the kinase domain of DDR2, leads to an inhibition of SHP-2 phosphorylation and a loss of its cell growth suppression effect, whereas mutations L63V in the discoidin domain and G505S in the intracellular juxtamembrane region don't have any effect on SHP-2 phosphorylation (Iwai et al.,).	('L63V', 'Mutation', 'rs144594252', (211, 215))	('phosphorylation', 'MPA', (127, 142))	('loss', 'NegReg', (149, 153))	('SHP-2', 'Gene', (317, 322))	('rat', 'Species', '10116', (35, 38))	('I638F', 'Mutation', 'rs1057519789', (59, 64))	('SHP-2', 'Gene', (121, 126))	('I638F', 'Var', (59, 64))	('inhibition', 'NegReg', (107, 117))	('SHP-2', 'Gene', '5781', (317, 322))	('DDR2', 'Gene', (89, 93))	('cell growth suppression effect', 'CPA', (161, 191))	('G505S', 'Mutation', 'rs115169993', (244, 249))	('SHP-2', 'Gene', '5781', (121, 126))
502432	27014069	In addition, the mutation S131C in the DS domain of DDR2 was able to increase squamous cell lung cancer (SCC) proliferation in vitro and in vivo (Miao et al.,; Figure 2).	('S131C', 'Var', (26, 31))	('lung cancer', 'Phenotype', 'HP:0100526', (92, 103))	('rat', 'Species', '10116', (117, 120))	('increase', 'PosReg', (69, 77))	('squamous cell lung cancer', 'Disease', 'MESH:D002294', (78, 103))	('SCC', 'Phenotype', 'HP:0030359', (105, 108))	('squamous cell lung cancer', 'Phenotype', 'HP:0030359', (78, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('squamous cell lung cancer', 'Disease', (78, 103))	('S131C', 'Mutation', 'p.S131C', (26, 31))	('DDR2', 'Gene', (52, 56))
502437	27014069	Studies in A549 lung carcinoma cells showed that inhibiting the expression of DDR2 with siRNA is sufficient to alter activity of the NF-kappaB and the lymphoid enhancer-binding factor 1 (LEF-1) transcription factors and to inhibit EMT and cell migration induced by TGF-beta1 (Walsh et al.,).	('expression', 'MPA', (64, 74))	('activity', 'MPA', (117, 125))	('LEF-1', 'Gene', '51176', (187, 192))	('inhibiting', 'Var', (49, 59))	('A549 lung carcinoma', 'Disease', 'MESH:D008175', (11, 30))	('A549 lung carcinoma', 'Disease', (11, 30))	('TGF-beta1', 'Gene', '7040', (265, 274))	('DDR2', 'Gene', (78, 82))	('TGF-beta1', 'Gene', (265, 274))	('lymphoid enhancer-binding factor 1', 'Gene', '51176', (151, 185))	('LEF-1', 'Gene', (187, 192))	('NF-kappaB', 'Protein', (133, 142))	('rat', 'Species', '10116', (247, 250))	('lymphoid enhancer-binding factor 1', 'Gene', (151, 185))	('carcinoma', 'Phenotype', 'HP:0030731', (21, 30))	('alter', 'Reg', (111, 116))	('inhibit', 'NegReg', (223, 230))
502438	27014069	While in breast cancer cells, Zhang and co-workers showed that activation of DDR2 regulates SNAIL1 protein stability by stimulating ERK2 activity, in a Src-dependent manner.	('Src', 'Gene', '6714', (152, 155))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('ERK2', 'Gene', '5594', (132, 136))	('SNAIL1', 'Gene', (92, 98))	('regulates', 'MPA', (82, 91))	('SNAIL1', 'Gene', '6615', (92, 98))	('activation', 'Var', (63, 73))	('stimulating', 'PosReg', (120, 131))	('DDR2', 'Gene', (77, 81))	('activity', 'MPA', (137, 145))	('breast cancer', 'Disease', 'MESH:D001943', (9, 22))	('ERK2', 'Gene', (132, 136))	('Src', 'Gene', (152, 155))	('breast cancer', 'Disease', (9, 22))	('breast cancer', 'Phenotype', 'HP:0003002', (9, 22))
502442	27014069	While these studies suggest that acquisition of a more mesenchymal-like phenotype is associated with expression of DDR2, other studies suggest that, depending on the cell type, both DDRs can promote EMT.	('EMT', 'CPA', (199, 202))	('DDR', 'Gene', '780;12305;25678;4921;478987;18214', (115, 118))	('DDR', 'Gene', (182, 185))	('expression', 'Var', (101, 111))	('DDR', 'Gene', '780;12305;25678;4921;478987;18214', (182, 185))	('DDR', 'Gene', (115, 118))	('promote', 'PosReg', (191, 198))
502444	27014069	Indeed, overexpressing miR-199a-5p leads to a decrease in the expression of DDR1, matrix metalloproteinase-2 (MMP-2), N-cadherin, and vimentin, and an increase in E-cadherin expression in both LOVE1 and LOVO CRC cell lines.	('miR-199a-5p', 'Var', (23, 34))	('N-cadherin', 'Gene', '1000', (118, 128))	('E-cadherin', 'Gene', '999', (163, 173))	('expression', 'MPA', (174, 184))	('matrix metalloproteinase-2', 'Gene', (82, 108))	('DDR1', 'Gene', (76, 80))	('expression', 'MPA', (62, 72))	('matrix metalloproteinase-2', 'Gene', '4313', (82, 108))	('MMP-2', 'Gene', (110, 115))	('vimentin', 'Gene', '7431', (134, 142))	('CRC', 'Phenotype', 'HP:0003003', (208, 211))	('increase', 'PosReg', (151, 159))	('vimentin', 'Gene', (134, 142))	('N-cadherin', 'Gene', (118, 128))	('decrease', 'NegReg', (46, 54))	('E-cadherin', 'Gene', (163, 173))
502475	27014069	By contrast, DDR1 in pituitary adenoma cell line induced an increase in both MMP-2 and MMP-9 secretion (Yoshida and Teramoto,).	('MMP-9 secretion', 'MPA', (87, 102))	('pituitary adenoma', 'Disease', 'MESH:D010911', (21, 38))	('DDR1', 'Var', (13, 17))	('MMP-2', 'MPA', (77, 82))	('pituitary adenoma', 'Phenotype', 'HP:0002893', (21, 38))	('increase', 'PosReg', (60, 68))	('pituitary adenoma', 'Disease', (21, 38))
502479	27014069	In MDA-MB-231 breast cancer cells, type IV collagen induces MMP-2 and MMP-9 secretion and invasion through a DDR1 and Src-dependent pathway (Castro-Sanchez et al.,).	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('Src', 'Gene', '6714', (118, 121))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (3, 13))	('MMP-2', 'MPA', (60, 65))	('induces', 'PosReg', (52, 59))	('breast cancer', 'Disease', 'MESH:D001943', (14, 27))	('breast cancer', 'Disease', (14, 27))	('breast cancer', 'Phenotype', 'HP:0003002', (14, 27))	('Src', 'Gene', (118, 121))	('type IV', 'Var', (35, 42))	('invasion', 'CPA', (90, 98))
502495	27014069	In 2011, Hammerman and co-workers have shown that DDR2 is mutated in approximately 4% of lung squamous cell cancer and have reported data to suggest that these mutations induce a gain in DDRs function (Hammerman et al.,).	('gain', 'PosReg', (179, 183))	('DDR', 'Gene', '780;12305;25678;4921;478987;18214', (187, 190))	('lung squamous cell cancer', 'Disease', 'MESH:D002294', (89, 114))	('mutations', 'Var', (160, 169))	('DDR', 'Gene', '780;12305;25678;4921;478987;18214', (50, 53))	('lung squamous cell cancer', 'Phenotype', 'HP:0030359', (89, 114))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (94, 114))	('lung squamous cell cancer', 'Disease', (89, 114))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('DDR', 'Gene', (187, 190))	('DDR', 'Gene', (50, 53))
502496	27014069	The same group has also shown that cell lines harboring these mutations are sensitized to the multitargeted kinase inhibitor dasatinib (Hammerman et al.,; Bai et al.,).	('dasatinib', 'Chemical', 'MESH:D000069439', (125, 134))	('sensitized', 'Reg', (76, 86))	('mutations', 'Var', (62, 71))
502497	27014069	Indeed, dasatinib can efficiently inhibit the proliferation of DDR2- mutated SCC cell lines in vitro and in vivo, as well as cells ectopically expressing mutant DDR2 (Hammerman et al.,).	('dasatinib', 'Chemical', 'MESH:D000069439', (8, 17))	('SCC', 'Phenotype', 'HP:0030359', (77, 80))	('DDR2-', 'Gene', (63, 68))	('proliferation', 'CPA', (46, 59))	('rat', 'Species', '10116', (53, 56))	('inhibit', 'NegReg', (34, 41))	('DDR2', 'Gene', (161, 165))	('mutant', 'Var', (154, 160))
502499	27014069	However, inhibition of DDRs signaling pathways often activates secondary survival mechanisms (Beauchamp et al.,).	('DDR', 'Gene', (23, 26))	('activates', 'PosReg', (53, 62))	('secondary survival mechanisms', 'CPA', (63, 92))	('DDR', 'Gene', '780;12305;25678;4921;478987;18214', (23, 26))	('inhibition', 'Var', (9, 19))
502509	27014069	Furthermore, compounds 2a and 4b exhibited significant effect against the T654M gatekeeper mutant of DDR2 with IC50 values of 2.0 and 1.0 nM, respectively (Richters et al.,).	('DDR2', 'Gene', (101, 105))	('gatekeeper', 'Species', '111938', (80, 90))	('T654M', 'Var', (74, 79))	('T654M', 'Mutation', 'p.T654M', (74, 79))
502512	27014069	In vitro studies showed that DDR2 activity was highly inhibited by these molecules but in contrast to unselective inhibitors such as dasatinib, they were not able to inhibit proliferation of lung SCC cells harboring a mutant DDR2 (Murray et al.,).	('activity', 'MPA', (34, 42))	('inhibit', 'NegReg', (166, 173))	('dasatinib', 'Chemical', 'MESH:D000069439', (133, 142))	('DDR2', 'Gene', (225, 229))	('lung', 'Disease', (191, 195))	('SCC', 'Phenotype', 'HP:0030359', (196, 199))	('rat', 'Species', '10116', (181, 184))	('mutant', 'Var', (218, 224))	('DDR2', 'Enzyme', (29, 33))
502513	27014069	Finally, other ways to inhibit DDRs consist in the use of targeted delivery of miRNAs based therapeutics such as miR-199a-5p (Hu et al.,) or monoclonal antibodies including Fab 3E3 (Carafoli et al.,), 48B3 (Ram et al.,), and H-126 (Castro-Sanchez et al.,) that have been shown to bind to the DS-like domain of DDR1.	('Fab', 'Gene', (173, 176))	('miR-199a-5p', 'Var', (113, 124))	('DDR', 'Gene', '780;12305;25678;4921;478987;18214', (310, 313))	('inhibit', 'NegReg', (23, 30))	('DDR', 'Gene', (31, 34))	('Fab', 'Gene', '2187', (173, 176))	('DDR', 'Gene', (310, 313))	('DDR', 'Gene', '780;12305;25678;4921;478987;18214', (31, 34))
502519	27014069	Moreover, the role of DDR2 in the suppression of cell proliferation has been elegantly demonstrated using receptor mutants.	('rat', 'Species', '10116', (94, 97))	('rat', 'Species', '10116', (61, 64))	('cell proliferation', 'CPA', (49, 67))	('mutants', 'Var', (115, 122))	('DDR2', 'Gene', (22, 26))
502520	27014069	These mutations have been identified as novel drivers contributing to cell proliferation in vivo and consequently tumor progression.	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('cell proliferation', 'CPA', (70, 88))	('tumor', 'Disease', (114, 119))	('rat', 'Species', '10116', (82, 85))	('contributing', 'Reg', (54, 66))	('mutations', 'Var', (6, 15))
502525	27014069	However, mutations have been noted in several cancer specimens.	('cancer', 'Disease', (46, 52))	('mutations', 'Var', (9, 18))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))
502526	27014069	In the case of DDR2 mutations in squamous lung cell carcinoma, dasatinib showed particular efficacy.	('squamous lung cell carcinoma', 'Disease', (33, 61))	('carcinoma', 'Phenotype', 'HP:0030731', (52, 61))	('DDR2', 'Gene', (15, 19))	('dasatinib', 'Chemical', 'MESH:D000069439', (63, 72))	('squamous lung cell carcinoma', 'Phenotype', 'HP:0030359', (33, 61))	('squamous lung cell carcinoma', 'Disease', 'MESH:D002294', (33, 61))	('mutations', 'Var', (20, 29))
502527	27014069	Nevertheless, latest in vitro model studies have reported a second site mutation in DDR2 which was able to confer resistance to dasatinib.	('dasatinib', 'Chemical', 'MESH:D000069439', (128, 137))	('resistance to dasatinib', 'MPA', (114, 137))	('DDR2', 'Gene', (84, 88))	('mutation', 'Var', (72, 80))
502538	26833333	Cancer genomes harbor various somatic forms of genetic alterations spanning from nucleotide-level alterations (e.g., point mutations and small insertions/deletions) to large chromosomal events (e.g., structural variations and copy-number changes), some of which can contribute to tumor development.	('copy-number changes', 'Var', (226, 245))	('contribute', 'Reg', (266, 276))	('tumor', 'Disease', 'MESH:D009369', (280, 285))	('point mutations', 'Var', (117, 132))	('Cancer', 'Disease', (0, 6))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (280, 285))	('structural variations', 'Var', (200, 221))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('tumor', 'Disease', (280, 285))
502540	26833333	The main types of mechanisms known to cause SVs in human cancer include homologous recombination, nonreplicative nonhomologous repair, and replication-based mechanisms.	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('cancer', 'Disease', (57, 63))	('human', 'Species', '9606', (51, 56))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('homologous', 'Var', (72, 82))
502541	26833333	Generally, homologous recombination can occur by non-allelic homologous recombination (NAHR), and deficiency in homologous recombination is implicated as a major source of cancer genome instability.	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('non-allelic', 'Var', (49, 60))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('deficiency', 'Disease', (98, 108))	('cancer', 'Disease', (172, 178))	('deficiency', 'Disease', 'MESH:D007153', (98, 108))
502542	26833333	Recently, single catastrophic events causing genomic shattering followed by incorrect re-joining of the fragmented DNA, termed chromothripsis, is receiving greater attention as a major mechanism generating complex SVs in human cancer.	('chromothripsis', 'Disease', (127, 141))	('chromothripsis', 'Disease', 'MESH:D000072837', (127, 141))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('human', 'Species', '9606', (221, 226))	('cancer', 'Disease', 'MESH:D009369', (227, 233))	('cancer', 'Disease', (227, 233))	('genomic', 'Var', (45, 52))	('causing', 'Reg', (37, 44))
502543	26833333	It is well known that SVs have implications in treatment and prediction of individual's outcome because genome-scale rearrangements can play an unappreciated role in cancer through their ability to move blocks of adjacent genes simultaneously or form gene fusion, leading to concurrent oncogenic events.	('cancer', 'Disease', (166, 172))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('move', 'Reg', (198, 202))	('rearrangements', 'Var', (117, 131))	('oncogenic events', 'CPA', (286, 302))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))
502545	26833333	In addition, gene amplification, a selective copy-number increase of genomic segments through DNA rearrangements, is a clinically important form of genome instability in cancer, because gene amplification causes advanced tumors and acquired therapy resistance.	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('therapy resistance', 'CPA', (241, 259))	('cancer', 'Disease', (170, 176))	('tumors', 'Phenotype', 'HP:0002664', (221, 227))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('gene amplification', 'Var', (186, 204))	('tumors', 'Disease', 'MESH:D009369', (221, 227))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('tumors', 'Disease', (221, 227))	('causes', 'Reg', (205, 211))
502546	26833333	Continuous DNA breaks and rearrangements through chromothripsis, chromoplexy, or a breakage-fusion-bridge (BFB) cycle have been implicated as underlying mechanisms for gene amplification or fusion in human cancer.	('chromoplexy', 'CPA', (65, 76))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('chromothripsis', 'Disease', (49, 63))	('chromothripsis', 'Disease', 'MESH:D000072837', (49, 63))	('human', 'Species', '9606', (200, 205))	('cancer', 'Disease', (206, 212))	('cancer', 'Disease', 'MESH:D009369', (206, 212))	('rearrangements', 'Var', (26, 40))
502551	26833333	Unlike chromothripsis, which refers to an oncogenic mechanism operating on a global level and occurring in one or several chromosomes, kataegis has been found to operate locally, generating large numbers of mutations (or hotspots of hypermutations) in small regions of the genome.	('mutations', 'Var', (207, 216))	('chromothripsis', 'Disease', 'MESH:D000072837', (7, 21))	('chromothripsis', 'Disease', (7, 21))
502552	26833333	On the other hand, similar to chromothripsis, kataegis most likely causes a large number of substitution mutations to occur in a region of the genome at one time rather than accumulating in a step-wise fashion.	('chromothripsis', 'Disease', (30, 44))	('substitution mutations', 'Var', (92, 114))	('chromothripsis', 'Disease', 'MESH:D000072837', (30, 44))
502555	26833333	Our findings revealed different mutational mechanisms for the formation of amplification of cancer-associated genes in ESCC.	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('ESCC', 'Disease', (119, 123))	('amplification', 'Var', (75, 88))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
502562	26833333	verified the accuracy of Meerkat by applying it to two HapMap genomes (NA18507 and NA12878) that were sequenced at high coverage on the Illumina platform and for which complex deletions have been previously reported.	('Meerkat', 'Species', '37032', (25, 32))	('NA12878', 'Var', (83, 90))	('NA18507', 'Var', (71, 78))
502568	26833333	To assess the significance of SV enrichment on chromosomes, we required the number of locally arranged genomes to be more than 50 and clustered chromosomes to have a high SVs mutation rate per Mb exceeding three times the length of the interquartile range from the 75th percentile of the chromosome counts for each tumor.	('mutation', 'Var', (175, 183))	('SVs', 'Gene', (171, 174))	('tumor', 'Disease', 'MESH:D009369', (315, 320))	('tumor', 'Phenotype', 'HP:0002664', (315, 320))	('tumor', 'Disease', (315, 320))
502578	26833333	The primers used were designed against exon 18 of TRAPPC9 (MIM: 611966) forward (5'-CGGAATTCACCCTGGAAGCTGTCCTG-3') and exon 4 of CLVS1 (MIM: 611292) reverse (5'-CCCTCGAGCTGCAACCCTTCAATGGC-3') or against exon 1 of EIF3E (MIM: 602210) forward (5'-CGGAATTCATGGCGGAGTACG-3') and exon 5 of RAD51B (MIM: 602948) reverse (5'-CCCTCGAGCTTTCAGCACTAAATG-3').	('EIF3E', 'Gene', (213, 218))	('RAD51B', 'Gene', (285, 291))	('RAD51B', 'Gene', '5890', (285, 291))	('GC', 'Phenotype', 'HP:0012126', (185, 187))	('GC', 'Phenotype', 'HP:0012126', (168, 170))	('CLVS1', 'Gene', '157807', (129, 134))	('EIF3E', 'Gene', '3646', (213, 218))	('TRAPPC9', 'Gene', (50, 57))	('GC', 'Phenotype', 'HP:0012126', (101, 103))	('CLVS1', 'Gene', (129, 134))	('TRAPPC9', 'Gene', '83696', (50, 57))	('MIM: 602948', 'Var', (293, 304))	('GC', 'Phenotype', 'HP:0012126', (256, 258))	('GC', 'Phenotype', 'HP:0012126', (171, 173))
502581	26833333	Slides were stained with Cytocell enumeration probes against interesting genes FGFR1 (MIM: 136350)/CEN8 (Z-2072, Zytovision, German), CCND1 (MIM: 168461)/CEN11 (Z-2071, Zytovision, German), TRAPPC9, CLVS1, EIF3E, and RAD51B, conjugated with FITC or Cy3.5 (Rainbow Scientific).	('EIF3E', 'Gene', (206, 211))	('RAD51B', 'Gene', (217, 223))	('Cy3', 'Chemical', '-', (249, 252))	('CCND1', 'Gene', (134, 139))	('FGFR1', 'Gene', (79, 84))	('FITC', 'Chemical', 'MESH:D016650', (241, 245))	('TRAPPC9', 'Gene', (190, 197))	('MIM', 'Var', (141, 144))	('CLVS1', 'Gene', '157807', (199, 204))	('EIF3E', 'Gene', '3646', (206, 211))	('TRAPPC9', 'Gene', '83696', (190, 197))	('CLVS1', 'Gene', (199, 204))	('RAD51B', 'Gene', '5890', (217, 223))	('FGFR1', 'Gene', '2260', (79, 84))	('CCND1', 'Gene', '595', (134, 139))
502595	26833333	Three siRNAs targeting LETM2 and one negative control siRNA (NC) (Guangzhou RiboBio) were used to knock down LETM2 in ESCC cell lines (KYSE150 and ECA109).	('LETM2', 'Gene', '137994', (23, 28))	('knock down', 'Var', (98, 108))	('LETM2', 'Gene', (23, 28))	('LETM2', 'Gene', '137994', (109, 114))	('LETM2', 'Gene', (109, 114))
502596	26833333	Meanwhile, FGFR1 (siRNA #1: 5'-AGTGGCTTATTAATTCCGATA-3'; siRNA #2: 5'-GCTTGCCAATGGCGGACTCAA-3'; siRNA #3: 5'-GAATGAGTACGGCAGCATCAA-3') or WHSC1L1 (siRNA #1: 5'-CGAGAGTATAAAGGTCATAAA-3'; siRNA #2: 5'-CCATCATCAATCAGTGTGTAT-3'; siRNA #3: 5'-GCTTCCATTACGATGCACAAA-3') were knocked down in TE-1 and KYSE150 cells, respectively.	('GC', 'Phenotype', 'HP:0012126', (74, 76))	('GC', 'Phenotype', 'HP:0012126', (35, 37))	('GC', 'Phenotype', 'HP:0012126', (70, 72))	('WHSC1L1', 'Gene', (138, 145))	('GC', 'Phenotype', 'HP:0012126', (81, 83))	('FGFR1', 'Gene', (11, 16))	('knocked down', 'Var', (269, 281))	('FGFR1', 'Gene', '2260', (11, 16))	('WHSC1L1', 'Gene', '54904', (138, 145))	('GC', 'Phenotype', 'HP:0012126', (120, 122))
502611	26833333	We observed no homology at TDs within ESCC genomes, further supporting the underlying mechanism that requires no microhomology or existence of nonhomology-based mechanism to form TDs and complex deletions in tumor cells.	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('deletions', 'Var', (195, 204))	('tumor', 'Disease', (208, 213))	('tumor', 'Disease', 'MESH:D009369', (208, 213))
502612	26833333	Across 31 ESCC genomes, we found that 3,376 SVs occurred in the region of genes and were predicted to directly disrupt sequence of gene such as CDKN2A (MIM: 600160), NOTCH1 (MIM: 190198), NF1 (MIM: 613113), and FANCD2 (MIM: 613984), and 492 genes contained a breakpoint in two or more tumors.	('NOTCH1', 'Gene', '4851', (166, 172))	('MIM: 190198', 'Var', (174, 185))	('MIM: 600160', 'Var', (152, 163))	('tumor', 'Phenotype', 'HP:0002664', (285, 290))	('NOTCH1', 'Gene', (166, 172))	('NF1', 'Gene', (188, 191))	('CDKN2A', 'Gene', (144, 150))	('FANCD2', 'Gene', '2177', (211, 217))	('tumors', 'Disease', (285, 291))	('NF1', 'Gene', '4763', (188, 191))	('tumors', 'Disease', 'MESH:D009369', (285, 291))	('FANCD2', 'Gene', (211, 217))	('tumors', 'Phenotype', 'HP:0002664', (285, 291))	('CDKN2A', 'Gene', '1029', (144, 150))	('MIM', 'Var', (193, 196))	('MIM: 613984', 'Var', (219, 230))
502613	26833333	Specifically, 29 out of 31 ESCCs harbored CDKN2A deletion; of which, 13 ESCCs had supporting SVs responsible for CDKN2A deletion and 2 out of these 13 genomes demonstrated complex deletions (ESCC-14T and ESCC-28T) (Figures 1B and S1).	('ESCC-14T', 'Var', (191, 199))	('CDKN2A', 'Gene', (113, 119))	('CDKN2A', 'Gene', (42, 48))	('CDKN2A', 'Gene', '1029', (113, 119))	('CDKN2A', 'Gene', '1029', (42, 48))	('ESCC-28T', 'Var', (204, 212))
502614	26833333	Notably, all deletions from tumor genomes of these 13 ESCCs were homozygous deletion with both focal deletion and arm-level loss.	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('tumor', 'Disease', (28, 33))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('deletions', 'Var', (13, 22))
502616	26833333	In addition, we also found that NOTCH1 was directly disrupted by TDs in two ESCCs (Figure S2).	('TDs', 'Var', (65, 68))	('NOTCH1', 'Gene', '4851', (32, 38))	('NOTCH1', 'Gene', (32, 38))
502626	26833333	In addition to general transition between two copy number states, we found a high-level focal amplification (<500 kb, 38,155,351-38,570,827 Mb) rearranged by chromothripsis on chromosome 8p that corresponds to FGFR1 and LETM2 in this tumor.	('FGFR1', 'Gene', '2260', (210, 215))	('tumor', 'Disease', (234, 239))	('chromothripsis', 'Disease', 'MESH:D000072837', (158, 172))	('rearranged', 'Var', (144, 154))	('FGFR1', 'Gene', (210, 215))	('tumor', 'Disease', 'MESH:D009369', (234, 239))	('chromothripsis', 'Disease', (158, 172))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('LETM2', 'Gene', '137994', (220, 225))	('LETM2', 'Gene', (220, 225))
502627	26833333	Importantly, no breakpoints were observed within this amplified region, suggesting a strong positive selection of FGFR1 and LETM2 amplifications during ESCC progression/evolution.	('FGFR1', 'Gene', '2260', (114, 119))	('amplifications', 'Var', (130, 144))	('LETM2', 'Gene', (124, 129))	('LETM2', 'Gene', '137994', (124, 129))	('FGFR1', 'Gene', (114, 119))
502633	26833333	Further functional studies indicated that knockdown of FGFR1 dramatically suppressed cell proliferation, cell migration, and invasion in TE-1 and KYSE150 cells (Figures S5A-S5C).	('FGFR1', 'Gene', '2260', (55, 60))	('cell proliferation', 'CPA', (85, 103))	('suppressed', 'NegReg', (74, 84))	('FGFR1', 'Gene', (55, 60))	('cell migration', 'CPA', (105, 119))	('knockdown', 'Var', (42, 51))	('invasion', 'CPA', (125, 133))
502643	26833333	Our result showed that LETM2 knockdown prevented cell proliferation but had no statistical suppression of cell migration and invasion in KYSE150 and ECA109 cells (Figure 2F).	('prevented', 'NegReg', (39, 48))	('knockdown', 'Var', (29, 38))	('LETM2', 'Gene', '137994', (23, 28))	('LETM2', 'Gene', (23, 28))	('cell proliferation', 'CPA', (49, 67))	('suppression', 'NegReg', (91, 102))	('cell migration', 'CPA', (106, 120))
502646	26833333	This fusion variant was predicted to result in an in-frame fusion of the TRAPPC9 5' UTR and exon 1-18 with the CLVS1 exon 4-5 and 3' UTR (Figure 3A).	('variant', 'Var', (12, 19))	('TRAPPC9', 'Gene', '83696', (73, 80))	('CLVS1', 'Gene', (111, 116))	('result in', 'Reg', (37, 46))	('TRAPPC9', 'Gene', (73, 80))	('CLVS1', 'Gene', '157807', (111, 116))
502654	26833333	The first exon of EIF3E on chromosome 8, encoding the eukaryotic translation initiation factor 3 subunit, was predicted to join with the last two exons of RAD51B on chromosome 14, a protein that catalyzes repair of DSBs through the process of homologous recombination and are critical for genome stability (Figure 3D).	('RAD51B', 'Gene', '5890', (155, 161))	('RAD51B', 'Gene', (155, 161))	('EIF3E', 'Gene', (18, 23))	('EIF3E', 'Gene', '3646', (18, 23))	('DSBs', 'Var', (215, 219))
502659	26833333	Interestingly, translocation of RAD51B with other genes has been reported, for example, HMGA2-RAD51B in uterine leiomyoma.	('HMGA2', 'Gene', '8091', (88, 93))	('RAD51B', 'Gene', (94, 100))	('RAD51B', 'Gene', '5890', (94, 100))	('HMGA2', 'Gene', (88, 93))	('RAD51B', 'Gene', '5890', (32, 38))	('RAD51B', 'Gene', (32, 38))	('leiomyoma', 'Disease', (112, 121))	('uterine leiomyoma', 'Phenotype', 'HP:0000131', (104, 121))	('translocation', 'Var', (15, 28))	('leiomyoma', 'Disease', 'MESH:D007889', (112, 121))
502661	26833333	Since the N- and C-terminal domains of RAD51B were important to interact with other proteins to catalyze the repair of DNA double-strand breaks, we speculate that the in-frame fusions of EIF3E-RAD51B might cause disruption of EIF3E and RAD51B function, which could result in deregulated homologous recombination or translation initiation, contributing to the tumorigenesis of ESCC.	('deregulated', 'Reg', (275, 286))	('contributing', 'Reg', (339, 351))	('RAD51B', 'Gene', (193, 199))	('EIF3E', 'Gene', '3646', (226, 231))	('RAD51B', 'Gene', '5890', (236, 242))	('EIF3E', 'Gene', (187, 192))	('homologous recombination', 'MPA', (287, 311))	('ESCC', 'Disease', (376, 380))	('EIF3E', 'Gene', '3646', (187, 192))	('translation initiation', 'MPA', (315, 337))	('RAD51B', 'Gene', (39, 45))	('tumor', 'Disease', (359, 364))	('cause', 'Reg', (206, 211))	('tumor', 'Disease', 'MESH:D009369', (359, 364))	('RAD51B', 'Gene', '5890', (193, 199))	('RAD51B', 'Gene', (236, 242))	('function', 'MPA', (243, 251))	('fusions', 'Var', (176, 183))	('tumor', 'Phenotype', 'HP:0002664', (359, 364))	('RAD51B', 'Gene', '5890', (39, 45))	('disruption', 'NegReg', (212, 222))	('EIF3E', 'Gene', (226, 231))
502670	26833333	analyzed the mutational signatures of 21 breast cancers and identified kataegis, a distinct hypermutation phenomenon, in 61% of breast cancers, indicating a direct relevance to tumor initiation and progression.	('cancers', 'Phenotype', 'HP:0002664', (135, 142))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('breast cancers', 'Phenotype', 'HP:0003002', (41, 55))	('breast cancer', 'Phenotype', 'HP:0003002', (41, 54))	('breast cancers', 'Disease', 'MESH:D001943', (41, 55))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('breast cancers', 'Disease', (41, 55))	('tumor initiation', 'Disease', 'MESH:D009369', (177, 193))	('breast cancers', 'Phenotype', 'HP:0003002', (128, 142))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('kataegis', 'Var', (71, 79))	('breast cancers', 'Disease', 'MESH:D001943', (128, 142))	('breast cancers', 'Disease', (128, 142))	('breast cancer', 'Phenotype', 'HP:0003002', (128, 141))	('tumor initiation', 'Disease', (177, 193))	('cancers', 'Phenotype', 'HP:0002664', (48, 55))
502675	26833333	Notably, fold-back inversions on chromosome 11 enriched in a minor cluster around CCND1 locus (69,455,873-69,469,242 Mb) at 11q11.3 (Figure 5D).	('fold-back inversions', 'Var', (9, 29))	('CCND1', 'Gene', (82, 87))	('CCND1', 'Gene', '595', (82, 87))	('69,455,873-69,469,242', 'Var', (95, 116))
502679	26833333	Amplification of CCND1 has been reported in a variety of tumors and might contribute to tumorigenesis.	('Amplification', 'Var', (0, 13))	('CCND1', 'Gene', '595', (17, 22))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('contribute', 'Reg', (74, 84))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('reported', 'Reg', (32, 40))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('tumors', 'Disease', (57, 63))	('CCND1', 'Gene', (17, 22))	('tumor', 'Disease', (57, 62))	('tumor', 'Disease', (88, 93))	('tumors', 'Disease', 'MESH:D009369', (57, 63))
502682	26833333	Our results demonstrated that at least two mutational mechanisms, focal amplification via BFB cycles and inter-chromosomal translocations, result in CCND1 amplification in ESCC.	('amplification', 'Var', (155, 168))	('result in', 'Reg', (139, 148))	('CCND1', 'Gene', (149, 154))	('CCND1', 'Gene', '595', (149, 154))	('ESCC', 'Disease', (172, 176))
502683	26833333	Additionally, we observed that regions amplified by BFB cycles harbor oncogenes such as EGFR (MIM: 131550) (2/31), ERBB2 (MIM: 164870) (1/31), MMPs (1/31), and MYC (MIM: 190080) (1/31) (Figure 6), suggesting that BFB plays an important role in gene amplification in ESCC tumors.	('ESCC tumors', 'Disease', 'MESH:D004938', (266, 277))	('MIM: 164870', 'Var', (122, 133))	('tumor', 'Phenotype', 'HP:0002664', (271, 276))	('BFB', 'Gene', (52, 55))	('ERBB2', 'Gene', (115, 120))	('MYC', 'Gene', '4609', (160, 163))	('tumors', 'Phenotype', 'HP:0002664', (271, 277))	('MYC', 'Gene', (160, 163))	('EGFR', 'Gene', '1956', (88, 92))	('ERBB2', 'Gene', '2064', (115, 120))	('ESCC tumors', 'Disease', (266, 277))	('EGFR', 'Gene', (88, 92))
502685	26833333	EGFR is an established therapeutic target that is often overexpressed as a consequence of gene amplification in human cancers including ESCCs.	('cancers', 'Disease', (118, 125))	('cancers', 'Disease', 'MESH:D009369', (118, 125))	('EGFR', 'Gene', (0, 4))	('ESCCs', 'Disease', (136, 141))	('gene amplification', 'Var', (90, 108))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('human', 'Species', '9606', (112, 117))	('EGFR', 'Gene', '1956', (0, 4))	('cancers', 'Phenotype', 'HP:0002664', (118, 125))
502686	26833333	ERBB2 amplification was observed in breast, esophageal, and other types of cancer and has been a target of anticancer agents.	('esophageal', 'Disease', (44, 54))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('ERBB2', 'Gene', '2064', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('cancer', 'Disease', (75, 81))	('ERBB2', 'Gene', (0, 5))	('cancer', 'Disease', (111, 117))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('breast', 'Disease', (36, 42))	('amplification', 'Var', (6, 19))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('observed', 'Reg', (24, 32))
502690	26833333	Consistently, frequent arm-level changes were observed in ESCC, including frequent copy-number gains of 3q, 5p, 7p, 8q, 12p, 17p, 20p, and 20q and universal deletions affecting 3p, 4p, 4q, 5q, 10p, 13q, and 21q (Figure S9A).	('deletions', 'Var', (157, 166))	('17p', 'Chemical', 'MESH:D000077713', (125, 128))	('ESCC', 'Disease', (58, 62))	('gains', 'PosReg', (95, 100))	('13q', 'Chemical', '-', (198, 201))
502693	26833333	This analysis yielded 11 amplification peaks and 13 deletion peaks, including cancer genes EGFR, CDK6 (MIM: 603368), AKT1 (MIM: 164730), MYC, CCND1, CDKN2A, and others (Table S6).	('CCND1', 'Gene', (142, 147))	('CDKN2A', 'Gene', '1029', (149, 155))	('EGFR', 'Gene', (91, 95))	('CDK6', 'Gene', '1021', (97, 101))	('AKT1', 'Gene', '207', (117, 121))	('CCND1', 'Gene', '595', (142, 147))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('MIM: 164730', 'Var', (123, 134))	('MYC', 'Gene', '4609', (137, 140))	('AKT1', 'Gene', (117, 121))	('amplification', 'MPA', (25, 38))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('CDK6', 'Gene', (97, 101))	('CDKN2A', 'Gene', (149, 155))	('MYC', 'Gene', (137, 140))	('EGFR', 'Gene', '1956', (91, 95))
502698	26833333	Moreover, CDCA7 knockdown led to the decrease of phospho-ERK1/2, an essential downstream component of MAPK pathway regulating cell proliferation, whereas no significant effect was seen in AKT pathway (Figure 8A).	('decrease', 'NegReg', (37, 45))	('knockdown', 'Var', (16, 25))	('ERK1/2', 'Gene', (57, 63))	('AKT', 'Gene', '207', (188, 191))	('ERK1/2', 'Gene', '5595;5594', (57, 63))	('CDCA7', 'Gene', (10, 15))	('AKT', 'Gene', (188, 191))
502699	26833333	Indeed, we observed a positive and highly significant enrichment of the expression of cell proliferation or apoptosis-associated target genes, including FGF21 ([MIM: 609436] a MAPK pathway-related gene) and cell-apoptosis-associated genes TRAIL-R, CASP10 (MIM: 601762), IL1R1 (MIM: 147810), CASP7 (MIM: 601761), BCL2 (MIM: 151430), and CASP9 (MIM: 602234).	('MIM: 601761', 'Var', (298, 309))	('CASP10', 'Gene', '843', (248, 254))	('CASP9', 'Gene', '842', (336, 341))	('BCL2', 'Gene', (312, 316))	('MIM: 602234', 'Var', (343, 354))	('IL1R1', 'Gene', '3554', (270, 275))	('MIM: 147810', 'Var', (277, 288))	('FGF21', 'Gene', '26291', (153, 158))	('CASP7', 'Gene', '840', (291, 296))	('FGF21', 'Gene', (153, 158))	('CASP10', 'Gene', (248, 254))	('CASP9', 'Gene', (336, 341))	('MIM: 601762', 'Var', (256, 267))	('BCL2', 'Gene', '596', (312, 316))	('TRAIL-R', 'Gene', (239, 246))	('CASP7', 'Gene', (291, 296))	('IL1R1', 'Gene', (270, 275))	('MIM: 151430', 'Var', (318, 329))
502701	26833333	In addition, CDCA7 knockdown led to the increased expression levels of TRAIL-R, CASP10, IL1R1, and CASP7 and the decreased expression levels of BCL2 and CASP9 (Figure 8E and Table S8), indicating that these genes might be critical for CDCA7 to regulate cell apoptosis.	('expression levels', 'MPA', (123, 140))	('CASP7', 'Gene', (99, 104))	('IL1R1', 'Gene', '3554', (88, 93))	('knockdown', 'Var', (19, 28))	('BCL2', 'Gene', (144, 148))	('CASP9', 'Gene', (153, 158))	('expression levels', 'MPA', (50, 67))	('TRAIL-R', 'Gene', (71, 78))	('CASP10', 'Gene', (80, 86))	('increased', 'PosReg', (40, 49))	('CASP7', 'Gene', '840', (99, 104))	('CDCA7', 'Gene', (13, 18))	('CASP9', 'Gene', '842', (153, 158))	('IL1R1', 'Gene', (88, 93))	('decreased', 'NegReg', (113, 122))	('BCL2', 'Gene', '596', (144, 148))	('CASP10', 'Gene', '843', (80, 86))
502704	26833333	Furthermore, our data provide the potential mechanisms for oncogene amplification or fusion gene formation, which might be critical for tumorigenesis of ESCC.	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('oncogene amplification', 'Var', (59, 81))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('fusion gene formation', 'Var', (85, 106))	('tumor', 'Disease', (136, 141))	('ESCC', 'Disease', (153, 157))
502705	26833333	In studying SVs across ESCC genomes, we observed locally rearranged SVs with either limited (e.g., chromothripsis or kataegis) or substantial (e.g., BFB) copy-number states (Figure S3).	('chromothripsis', 'Disease', (99, 113))	('copy-number', 'Var', (154, 165))	('chromothripsis', 'Disease', 'MESH:D000072837', (99, 113))
502708	26833333	Besides copy-number alterations, translocations in chromothripsis led to gene fusions (e.g., TRAPPC9-CLVS1, EIF3E-RAD51B) (Figure S3).	('led to', 'Reg', (66, 72))	('CLVS1', 'Gene', '157807', (101, 106))	('chromothripsis', 'Disease', (51, 65))	('RAD51B', 'Gene', (114, 120))	('RAD51B', 'Gene', '5890', (114, 120))	('translocations', 'Var', (33, 47))	('TRAPPC9', 'Gene', '83696', (93, 100))	('CLVS1', 'Gene', (101, 106))	('EIF3E', 'Gene', (108, 113))	('TRAPPC9', 'Gene', (93, 100))	('chromothripsis', 'Disease', 'MESH:D000072837', (51, 65))	('EIF3E', 'Gene', '3646', (108, 113))	('gene fusions', 'MPA', (73, 85))
502723	26833333	Although TP53, which has been linked to chromothripsis in human cancers, was mutated at high frequency in both ESCC and EAC, we found that the frequency of chromothripsis tended to be lower in ESCC than in EAC.	('ESCC', 'Disease', (193, 197))	('human', 'Species', '9606', (58, 63))	('EAC', 'Phenotype', 'HP:0011459', (206, 209))	('EAC', 'Phenotype', 'HP:0011459', (120, 123))	('mutated', 'Var', (77, 84))	('cancers', 'Disease', 'MESH:D009369', (64, 71))	('TP53', 'Gene', '7157', (9, 13))	('cancers', 'Phenotype', 'HP:0002664', (64, 71))	('TP53', 'Gene', (9, 13))	('cancers', 'Disease', (64, 71))	('chromothripsis', 'Disease', (156, 170))	('lower', 'NegReg', (184, 189))	('chromothripsis', 'Disease', (40, 54))	('chromothripsis', 'Disease', 'MESH:D000072837', (156, 170))	('chromothripsis', 'Disease', 'MESH:D000072837', (40, 54))	('ESCC', 'Disease', (111, 115))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
502732	26833333	The whole-genome sequencing data of 31 pairs of tumors and matched normal tissues reported in this paper have been deposited to the European Genome-phenome Archive (EGA) under accession numbers EGAS00001001487 and EGAS00001000709.	('tumors', 'Disease', 'MESH:D009369', (48, 54))	('tumors', 'Disease', (48, 54))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('EGAS00001000709', 'Var', (214, 229))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
502734	25403850	In the present study, we developed a mouse model of inflammation-driven LSCC that was induced by N-nitroso-trischloroethylurea (NTCU) and enhanced by lipopolysaccharide (LPS), a potent proinflammatory agent contained in tobacco and tobacco smoke, and determined the chemopreventive effects of BioResponse diindolylmethane (DIM) in the same model.	('diindolylmethane', 'Chemical', 'MESH:C016392', (305, 321))	('inflammation', 'Disease', (52, 64))	('DIM', 'Chemical', 'MESH:C016392', (323, 326))	('LSCC', 'Phenotype', 'HP:0030359', (72, 76))	('N-nitroso-trischloroethylurea', 'Chemical', 'MESH:C572573', (97, 126))	('lipopolysaccharide', 'Chemical', 'MESH:D008070', (150, 168))	('enhanced', 'PosReg', (138, 146))	('tobacco', 'Species', '4097', (220, 227))	('LPS', 'Gene', '21898', (170, 173))	('mouse', 'Species', '10090', (37, 42))	('LSCC', 'Disease', (72, 76))	('LPS', 'Gene', (170, 173))	('N-nitroso-trischloroethylurea', 'Var', (97, 126))	('tobacco', 'Species', '4097', (232, 239))	('NTCU', 'Chemical', 'MESH:C572573', (128, 132))	('inflammation', 'Disease', 'MESH:D007249', (52, 64))
502810	25403850	The expression of COX-2, one of the downstream effectors of the NF-kappaB pathway known to catalyze the formation of cancer promoting prostaglandins, was significantly increased (about 5-fold) by the combination of NTCU and LPS.	('LPS', 'Gene', '21898', (224, 227))	('increased', 'PosReg', (168, 177))	('NTCU', 'Chemical', 'MESH:C572573', (215, 219))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('LPS', 'Gene', (224, 227))	('expression', 'MPA', (4, 14))	('NTCU', 'Var', (215, 219))	('COX-2', 'Gene', '17709', (18, 23))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('cancer', 'Disease', (117, 123))	('COX-2', 'Gene', (18, 23))	('prostaglandins', 'Chemical', 'MESH:D011453', (134, 148))
502853	25403850	One reason could be that p53 mutates in preneoplastic tissues and the mutant p53 gene gives rise to a stable mutant protein.	('p53', 'Gene', (25, 28))	('p53', 'Gene', '22060', (25, 28))	('mutant', 'Var', (70, 76))	('p53', 'Gene', (77, 80))	('p53', 'Gene', '22060', (77, 80))
502854	25403850	Mutant p53 proteins not only lose their tumor suppressive activities but often gain additional oncogenic functions that endow cells with growth and survival advantages.	('proteins', 'Protein', (11, 19))	('gain', 'PosReg', (79, 83))	('lose', 'NegReg', (29, 33))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('p53', 'Gene', '22060', (7, 10))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('oncogenic functions', 'CPA', (95, 114))	('Mutant', 'Var', (0, 6))	('tumor', 'Disease', (40, 45))	('p53', 'Gene', (7, 10))
502858	25403850	However, LPS-induced oxidative stress may also induce p53 mutation as has been reported in nontumorous colon tissue of subjects with ulcerative colitis.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('LPS', 'Gene', '21898', (9, 12))	('oxidative stress', 'Phenotype', 'HP:0025464', (21, 37))	('tumor', 'Disease', (94, 99))	('ulcerative colitis', 'Disease', (133, 151))	('mutation', 'Var', (58, 66))	('p53', 'Gene', (54, 57))	('colitis', 'Phenotype', 'HP:0002583', (144, 151))	('ulcerative colitis', 'Phenotype', 'HP:0100279', (133, 151))	('LPS', 'Gene', (9, 12))	('induce', 'Reg', (47, 53))	('p53', 'Gene', '22060', (54, 57))	('ulcerative colitis', 'Disease', 'MESH:D003093', (133, 151))
502880	32391558	MASPIN had a statistically negative correlation with NSCLC prognosis, functioning as an oncoprotein by hypomethylation and influencing specific pathways involving the 85 genes identified herein.	('influencing', 'Reg', (123, 134))	('NSCLC', 'Phenotype', 'HP:0030358', (53, 58))	('negative', 'NegReg', (27, 35))	('hypomethylation', 'Var', (103, 118))	('MASPIN', 'Gene', '5268', (0, 6))	('MASPIN', 'Gene', (0, 6))	('NSCLC', 'Disease', (53, 58))	('NSCLC', 'Disease', 'MESH:D002289', (53, 58))
502917	32391558	Next, OS was analyzed in NSCLC, LUAD, and LUSC related to SERPINB5 mRNA expression, and we found that NSCLC and LUAD patients with high expression of SERPINB5 mRNA had poorer prognosis (HR = 1.69, 95% CI = 1.47-1.95, P<0.001; HR = 1.88, 95% CI = 1.49-2.38, P<0.001; respectively, Figure 7A,B), and there was no statistically difference in LUSC patients (HR = 0.79, 95% CI = 0.61-1.03, P=0.081, Figure 7C).	('NSCLC', 'Disease', 'MESH:D002289', (102, 107))	('LUSC', 'Phenotype', 'HP:0030359', (42, 46))	('NSCLC', 'Disease', (25, 30))	('LUAD', 'Phenotype', 'HP:0030078', (32, 36))	('patients', 'Species', '9606', (117, 125))	('LUAD', 'Phenotype', 'HP:0030078', (112, 116))	('NSCLC', 'Disease', (102, 107))	('NSCLC', 'Phenotype', 'HP:0030358', (25, 30))	('SERPINB5', 'Gene', (150, 158))	('NSCLC', 'Phenotype', 'HP:0030358', (102, 107))	('SERPINB5', 'Gene', '5268', (58, 66))	('patients', 'Species', '9606', (344, 352))	('poorer', 'NegReg', (168, 174))	('prognosis', 'CPA', (175, 184))	('LUSC', 'Phenotype', 'HP:0030359', (339, 343))	('SERPINB5', 'Gene', '5268', (150, 158))	('NSCLC', 'Disease', 'MESH:D002289', (25, 30))	('high expression', 'Var', (131, 146))	('SERPINB5', 'Gene', (58, 66))
502948	32391558	About the treatment, resistance to osimertinib partially arises through MASPIN and a novel statistical methodology for detecting splicing changes in exon array data presented that SERPINB5 showed alternative splicing in NSCLC patients treated with bevacizumab/erlotinib.	('NSCLC', 'Disease', (220, 225))	('osimertinib', 'Chemical', 'MESH:C000596361', (35, 46))	('alternative splicing', 'Var', (196, 216))	('MASPIN', 'Gene', '5268', (72, 78))	('NSCLC', 'Disease', 'MESH:D002289', (220, 225))	('patients', 'Species', '9606', (226, 234))	('MASPIN', 'Gene', (72, 78))	('erlotinib', 'Chemical', 'MESH:D000069347', (260, 269))	('SERPINB5', 'Gene', '5268', (180, 188))	('NSCLC', 'Phenotype', 'HP:0030358', (220, 225))	('SERPINB5', 'Gene', (180, 188))	('bevacizumab', 'Chemical', 'MESH:D000068258', (248, 259))
502949	32391558	Online databases from MethHC showed that the underlying mechanism of MASPIN affecting NSCLC survival outcomes may be related to hypomethylation and this was following a previous study, and this difference may be critical for epigenetic regulation of radiosensitivity.	('NSCLC', 'Phenotype', 'HP:0030358', (86, 91))	('NSCLC', 'Disease', (86, 91))	('MethHC', 'Chemical', '-', (22, 28))	('NSCLC', 'Disease', 'MESH:D002289', (86, 91))	('hypomethylation', 'Var', (128, 143))	('affecting', 'Reg', (76, 85))	('MASPIN', 'Gene', '5268', (69, 75))	('MASPIN', 'Gene', (69, 75))
502951	32391558	Hypomethylated status means activation of gene expression, therefore, it is not difficult to infer that SERPINB5 methylation partially contributes to its increased expression and plays an important role in the occurrence and development in NSCLC.	('NSCLC', 'Disease', (240, 245))	('methylation', 'Var', (113, 124))	('expression', 'MPA', (164, 174))	('NSCLC', 'Disease', 'MESH:D002289', (240, 245))	('SERPINB5', 'Gene', '5268', (104, 112))	('role', 'Reg', (198, 202))	('SERPINB5', 'Gene', (104, 112))	('activation', 'PosReg', (28, 38))	('plays', 'Reg', (179, 184))	('NSCLC', 'Phenotype', 'HP:0030358', (240, 245))	('increased', 'PosReg', (154, 163))	('expression', 'MPA', (47, 57))
502957	32391558	In conclusion, our study demonstrated that MASPIN had a statistically negative correlation with NSCLC prognosis, functioning as an oncoprotein by hypomethylation and influencing specific pathways, which lays a foundation for MASPIN to develop into an independent prognostic factor for NSCLC patients.	('NSCLC', 'Disease', (96, 101))	('MASPIN', 'Gene', (43, 49))	('MASPIN', 'Gene', '5268', (225, 231))	('MASPIN', 'Gene', (225, 231))	('MASPIN', 'Gene', '5268', (43, 49))	('NSCLC', 'Disease', (285, 290))	('NSCLC', 'Disease', 'MESH:D002289', (96, 101))	('specific pathways', 'Pathway', (178, 195))	('negative', 'NegReg', (70, 78))	('patients', 'Species', '9606', (291, 299))	('hypomethylation', 'Var', (146, 161))	('NSCLC', 'Disease', 'MESH:D002289', (285, 290))	('influencing', 'Reg', (166, 177))	('NSCLC', 'Phenotype', 'HP:0030358', (96, 101))	('NSCLC', 'Phenotype', 'HP:0030358', (285, 290))
502961	32398949	The abnormality of m6A epigenetic modification in cancer has been increasingly attended.	('epigenetic modification', 'Var', (23, 46))	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('m6A', 'Gene', (19, 22))	('m6A', 'Gene', '56339', (19, 22))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))
502966	32398949	Besides, WTAP, RBM15, KIAA1429, YTHDF1, and YTHDF2 were all up expressed for TP53 mutation.	('KIAA1429', 'Gene', (22, 30))	('YTHDF1', 'Gene', '54915', (32, 38))	('RBM15', 'Gene', (15, 20))	('mutation', 'Var', (82, 90))	('YTHDF2', 'Gene', (44, 50))	('YTHDF1', 'Gene', (32, 38))	('KIAA1429', 'Gene', '25962', (22, 30))	('WTAP', 'Gene', '9589', (9, 13))	('WTAP', 'Gene', (9, 13))	('RBM15', 'Gene', '64783', (15, 20))	('TP53', 'Gene', '7157', (77, 81))	('TP53', 'Gene', (77, 81))	('YTHDF2', 'Gene', '51441', (44, 50))
502971	32398949	Conclusions: m6A epigenetic modification took part in the progression, and provided auxiliary diagnosis and prognosis of LUAD.	('LUAD', 'Phenotype', 'HP:0030078', (121, 125))	('epigenetic modification', 'Var', (17, 40))	('LUAD', 'Disease', (121, 125))	('m6A', 'Gene', (13, 16))	('m6A', 'Gene', '56339', (13, 16))
502975	32398949	However, with the rapid development of high-throughput sequencing technology, it is found that mRNA also undergo various modifications such as N6-methyladenosine (m6A), N1-methyladenosine (m1A) and pseudouridine methylation during the process of exon splicing, 5'-capping and 3'-tailing.	('pseudouridine', 'Chemical', 'MESH:D011560', (198, 211))	('N1-methyladenosine', 'Chemical', 'MESH:C002230', (169, 187))	('men', 'Species', '9606', (31, 34))	('m6A', 'Gene', (163, 166))	('N6-methyladenosine', 'Chemical', 'MESH:C010223', (143, 161))	('N6-methyladenosine', 'Var', (143, 161))	('N1-methyladenosine', 'Var', (169, 187))	('m1A', 'Chemical', '-', (189, 192))	('m6A', 'Gene', '56339', (163, 166))	('pseudouridine methylation', 'MPA', (198, 223))
502976	32398949	Researches on m6A epigenetic modification have been increasingly attended.	('m6A', 'Gene', '56339', (14, 17))	('epigenetic modification', 'Var', (18, 41))	('m6A', 'Gene', (14, 17))
502979	32398949	Similar to DNA and protein modification, the m6A methylation is dynamically and reversibly regulated by methyl-transferases ("writers"), binding proteins ("readers"), and demethylases ("erasers").	('methyl-transferases', 'Enzyme', (104, 123))	('demethylases', 'Var', (171, 183))	('m6A', 'Gene', '56339', (45, 48))	('regulated', 'Reg', (91, 100))	('binding proteins', 'Protein', (137, 153))	('m6A', 'Gene', (45, 48))
502984	32398949	At present, some diseases, such as obesity, diabetes, neuronal disease, infertility, autoimmune diseases, have been reported associated with m6A modification.	('m6A', 'Gene', (141, 144))	('infertility', 'Disease', 'MESH:D007247', (72, 83))	('autoimmune diseases', 'Disease', (85, 104))	('infertility', 'Phenotype', 'HP:0000789', (72, 83))	('m6A', 'Gene', '56339', (141, 144))	('obesity', 'Phenotype', 'HP:0001513', (35, 42))	('neuronal disease', 'Disease', 'MESH:D009410', (54, 70))	('infertility', 'Disease', (72, 83))	('associated', 'Reg', (125, 135))	('autoimmune diseases', 'Phenotype', 'HP:0002960', (85, 104))	('autoimmune diseases', 'Disease', 'MESH:D001327', (85, 104))	('neuronal disease', 'Disease', (54, 70))	('obesity', 'Disease', 'MESH:D009765', (35, 42))	('diabetes', 'Disease', (44, 52))	('modification', 'Var', (145, 157))	('obesity', 'Disease', (35, 42))	('diabetes', 'Disease', 'MESH:D003920', (44, 52))
502985	32398949	In addition, m6A methylation is likewise closely related to the tumor development.	('tumor', 'Disease', (64, 69))	('methylation', 'Var', (17, 28))	('men', 'Species', '9606', (77, 80))	('m6A', 'Gene', (13, 16))	('related', 'Reg', (49, 56))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('m6A', 'Gene', '56339', (13, 16))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
503001	32398949	GTEx and TCGA dataset were acted as training cohort, and GSE75037, GSE63459, GSE29013, GSE30219, GSE37745, and GSE50081 as validation cohort.	('GSE29013', 'Var', (77, 85))	('GSE30219', 'Var', (87, 95))	('GTEx', 'Chemical', '-', (0, 4))	('GSE63459', 'Var', (67, 75))	('GSE37745', 'Var', (97, 105))	('GSE75037', 'Var', (57, 65))
503021	32398949	These 13 m6A RNA methylation genes were mainly associated with RNA modification, dosage compensation by inactivation of X chromosome, and RNA destabilization (Figure 1C).	('m6A', 'Gene', (9, 12))	('inactivation', 'Var', (104, 116))	('m6A', 'Gene', '56339', (9, 12))	('RNA modification', 'Disease', (63, 79))	('associated', 'Reg', (47, 57))	('RNA methylation genes', 'Gene', (13, 34))
503030	32398949	Figure 2E and Figure S1B showed that the variation trends of HNRNPC, RBM15, YTHDF1, YTHDC1, FTO, and YTHDF2 of GSE75037 were accord with these in the training cohort.	('YTHDF1', 'Gene', (76, 82))	('HNRNPC', 'Gene', '3183', (61, 67))	('YTHDF2', 'Gene', (101, 107))	('HNRNPC', 'Gene', (61, 67))	('FTO', 'Gene', (92, 95))	('RBM15', 'Gene', '64783', (69, 74))	('YTHDC1', 'Gene', (84, 90))	('YTHDC1', 'Gene', '91746', (84, 90))	('GSE75037', 'Var', (111, 119))	('RBM15', 'Gene', (69, 74))	('FTO', 'Gene', '79068', (92, 95))	('YTHDF2', 'Gene', '51441', (101, 107))	('YTHDF1', 'Gene', '54915', (76, 82))
503032	32398949	For GSE63459, the trends of RBM15, WTAP, YTHDF1, FTO, and YTHDF2 were consistent with these in the training cohort (Figure 2H and Figure S1D).	('GSE63459', 'Var', (4, 12))	('RBM15', 'Gene', '64783', (28, 33))	('YTHDF2', 'Gene', '51441', (58, 64))	('FTO', 'Gene', '79068', (49, 52))	('WTAP', 'Gene', '9589', (35, 39))	('WTAP', 'Gene', (35, 39))	('RBM15', 'Gene', (28, 33))	('YTHDF2', 'Gene', (58, 64))	('FTO', 'Gene', (49, 52))	('YTHDF1', 'Gene', '54915', (41, 47))	('YTHDF1', 'Gene', (41, 47))
503037	32398949	For mutation, there was no correlation between m6A RNA methylation genes and KRAS or EGFR mutation (Figure S2).	('EGFR', 'Gene', (85, 89))	('KRAS', 'Gene', (77, 81))	('m6A', 'Gene', (47, 50))	('KRAS', 'Gene', '3845', (77, 81))	('EGFR', 'Gene', '1956', (85, 89))	('mutation', 'Var', (90, 98))	('m6A', 'Gene', '56339', (47, 50))
503038	32398949	For TP53 mutation, WTAP, RBM15, KIAA1429, YTHDF1, and YTHDF2 were all up expressed in mutation group (Figure 3G-H).	('mutation', 'Var', (9, 17))	('YTHDF2', 'Gene', '51441', (54, 60))	('up expressed', 'PosReg', (70, 82))	('YTHDF2', 'Gene', (54, 60))	('YTHDF1', 'Gene', (42, 48))	('TP53', 'Gene', (4, 8))	('KIAA1429', 'Gene', '25962', (32, 40))	('RBM15', 'Gene', '64783', (25, 30))	('WTAP', 'Gene', '9589', (19, 23))	('TP53', 'Gene', '7157', (4, 8))	('YTHDF1', 'Gene', '54915', (42, 48))	('WTAP', 'Gene', (19, 23))	('KIAA1429', 'Gene', (32, 40))	('RBM15', 'Gene', (25, 30))
503051	32398949	While in the multivariate Cox regression analysis, only the risk score was related with bad OS (HR: 2.181, 95%CI (1.594-2.984), P<0.001) (Figure 6B), indicating risk score was an independent risk factor of lung adenocarcinoma.	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (206, 225))	('bad OS', 'Disease', (88, 94))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (206, 225))	('risk score', 'Var', (161, 171))	('carcinoma', 'Phenotype', 'HP:0030731', (216, 225))	('lung adenocarcinoma', 'Disease', (206, 225))
503066	32398949	Recently, emerging evidence has indicated that the development of lung cancer is both affected by genetic variation and epigenetic variation.	('affected by', 'Reg', (86, 97))	('lung cancer', 'Disease', (66, 77))	('lung cancer', 'Disease', 'MESH:D008175', (66, 77))	('lung cancer', 'Phenotype', 'HP:0100526', (66, 77))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('genetic variation', 'Var', (98, 115))	('epigenetic variation', 'Var', (120, 140))	('men', 'Species', '9606', (58, 61))
503085	32398949	As we have demonstrated, for breast cancer cells, the repression of HNRNPC could inhibit cell proliferation and tumor growth.	('cell proliferation', 'CPA', (89, 107))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('inhibit', 'NegReg', (81, 88))	('HNRNPC', 'Gene', '3183', (68, 74))	('repression', 'Var', (54, 64))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('HNRNPC', 'Gene', (68, 74))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('breast cancer', 'Disease', 'MESH:D001943', (29, 42))	('tumor', 'Disease', (112, 117))	('breast cancer', 'Disease', (29, 42))	('breast cancer', 'Phenotype', 'HP:0003002', (29, 42))
503099	32398949	In spite of these indelible contributions, as the study went on, it was found that the above regulators exhibited no significant differential expression in KRAS and EGFR mutant LUAD.	('EGFR', 'Gene', (165, 169))	('KRAS', 'Gene', (156, 160))	('KRAS', 'Gene', '3845', (156, 160))	('mutant', 'Var', (170, 176))	('LUAD', 'Phenotype', 'HP:0030078', (177, 181))	('EGFR', 'Gene', '1956', (165, 169))
503100	32398949	In TP53 mutant LUAD, the regulators including WTAP, RBM15, KIAA1429, YTHDF1, and YTHDF2 all were highly expressed.	('YTHDF2', 'Gene', '51441', (81, 87))	('TP53', 'Gene', '7157', (3, 7))	('YTHDF1', 'Gene', (69, 75))	('TP53', 'Gene', (3, 7))	('YTHDF2', 'Gene', (81, 87))	('WTAP', 'Gene', '9589', (46, 50))	('mutant', 'Var', (8, 14))	('KIAA1429', 'Gene', (59, 67))	('RBM15', 'Gene', '64783', (52, 57))	('WTAP', 'Gene', (46, 50))	('YTHDF1', 'Gene', '54915', (69, 75))	('LUAD', 'Phenotype', 'HP:0030078', (15, 19))	('KIAA1429', 'Gene', '25962', (59, 67))	('RBM15', 'Gene', (52, 57))
503103	32398949	To the best of our knowledge, it was not clear yet that TP53 mutant impacted the expression of WTAP, RBM15, and KIAA1429, in which more evidences were required to elucidate their mechanistic correlation.	('RBM15', 'Gene', (101, 106))	('WTAP', 'Gene', (95, 99))	('impacted', 'Reg', (68, 76))	('KIAA1429', 'Gene', (112, 120))	('TP53', 'Gene', '7157', (56, 60))	('KIAA1429', 'Gene', '25962', (112, 120))	('WTAP', 'Gene', '9589', (95, 99))	('TP53', 'Gene', (56, 60))	('mutant', 'Var', (61, 67))	('RBM15', 'Gene', '64783', (101, 106))	('expression', 'MPA', (81, 91))
503113	26013599	Functional characterization of RAD52 as a lung cancer susceptibility gene in the 12p13.33 locus Recent genome-wide association studies have identified variations in the recombination repair gene, RAD52, that are associated with increased lung cancer risk, and particularly with the development of lung squamous cell carcinomas (LUSC).	('cancer', 'Phenotype', 'HP:0002664', (243, 249))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (302, 325))	('men', 'Species', '9606', (289, 292))	('lung cancer', 'Disease', 'MESH:D008175', (42, 53))	('lung cancer', 'Disease', 'MESH:D008175', (238, 249))	('RAD52', 'Gene', '19365', (31, 36))	('increased lung cancer', 'Disease', (228, 249))	('lung cancer', 'Phenotype', 'HP:0100526', (42, 53))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('lung cancer', 'Phenotype', 'HP:0100526', (238, 249))	('lung squamous cell carcinomas', 'Disease', 'MESH:D002294', (297, 326))	('carcinoma', 'Phenotype', 'HP:0030731', (316, 325))	('carcinomas', 'Phenotype', 'HP:0030731', (316, 326))	('RAD52', 'Gene', (31, 36))	('associated', 'Reg', (212, 222))	('RAD52', 'Gene', '19365', (196, 201))	('variations', 'Var', (151, 161))	('increased lung cancer', 'Disease', 'MESH:D008175', (228, 249))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (297, 325))	('RAD52', 'Gene', (196, 201))	('lung squamous cell carcinomas', 'Disease', (297, 326))	('lung cancer', 'Disease', (42, 53))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (302, 326))
503117	26013599	In addition, we report that amplification of the genomic region 12p13.33, which contains the RAD52 gene, is significantly associated with the development of LUSC in the TCGA database and that somatic overexpression of RAD52 was confirmed to be significant in LUSC tumors from our own patient cohort.	('tumor', 'Phenotype', 'HP:0002664', (264, 269))	('RAD52', 'Gene', (93, 98))	('LUSC tumors', 'Disease', 'MESH:D009369', (259, 270))	('men', 'Species', '9606', (149, 152))	('associated with', 'Reg', (122, 137))	('LUSC tumors', 'Disease', (259, 270))	('tumors', 'Phenotype', 'HP:0002664', (264, 270))	('LUSC', 'Disease', (157, 161))	('patient', 'Species', '9606', (284, 291))	('amplification', 'Var', (28, 41))
503118	26013599	Consistent with these genetic findings, we demonstrate that blockade of Rad52 slows cell growth and induces senescence in mouse bronchial epithelial cells.	('blockade', 'Var', (60, 68))	('senescence', 'CPA', (108, 118))	('cell growth', 'CPA', (84, 95))	('induces', 'Reg', (100, 107))	('slows', 'NegReg', (78, 83))	('Rad52', 'Gene', (72, 77))	('mouse', 'Species', '10090', (122, 127))
503128	26013599	Similarly, recent additions to the 1000 genomes project, including four genome-wide association studies of lung cancer in populations of European ancestry, identified large-effect genome-wide associations for squamous cell lung cancer with the rare variant of BRCA2-K3326X.	('lung cancer', 'Disease', 'MESH:D008175', (107, 118))	('lung cancer', 'Phenotype', 'HP:0100526', (223, 234))	('squamous cell lung cancer', 'Phenotype', 'HP:0030359', (209, 234))	('K3326X', 'Mutation', 'rs11571833', (266, 272))	('associations', 'Reg', (192, 204))	('BRCA2-K3326X', 'Var', (260, 272))	('squamous cell lung cancer', 'Disease', 'MESH:D002294', (209, 234))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('lung cancer', 'Disease', (107, 118))	('lung cancer', 'Phenotype', 'HP:0100526', (107, 118))	('lung cancer', 'Disease', 'MESH:D008175', (223, 234))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('squamous cell lung cancer', 'Disease', (209, 234))
503130	26013599	Upon RAD52 depletion, both the frequency of double-strand break-induced HR and ionizing radiation-induced RAD51 foci decreased significantly.	('RAD52', 'Gene', (5, 10))	('decreased', 'NegReg', (117, 126))	('RAD51', 'Gene', '19361', (106, 111))	('depletion', 'Var', (11, 20))	('RAD51', 'Gene', (106, 111))
503132	26013599	As well, inactivation of RAD52 in BRCA2 competent mouse ES cells did result in a modest reduction in HR.	('reduction', 'NegReg', (88, 97))	('inactivation', 'Var', (9, 21))	('RAD52', 'Gene', (25, 30))	('mouse', 'Species', '10090', (50, 55))
503135	26013599	Thus, in human cells deficient in the PALB2 or BRCA2 genes, RAD52 depletion may decrease cell survival by reducing rates of homologous recombination and by increasing damage-induced chromosomal abnormalities.	('cell survival', 'CPA', (89, 102))	('reducing', 'NegReg', (106, 114))	('chromosomal abnormalities', 'Disease', (182, 207))	('rates', 'MPA', (115, 120))	('BRCA2', 'Gene', (47, 52))	('human', 'Species', '9606', (9, 14))	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (182, 207))	('PALB2', 'Gene', '79728', (38, 43))	('depletion', 'Var', (66, 75))	('RAD52', 'Gene', (60, 65))	('PALB2', 'Gene', (38, 43))	('decrease', 'NegReg', (80, 88))	('increasing', 'PosReg', (156, 166))
503139	26013599	Thus, it fits that variation in this DNA repair gene would impact one's risk for lung cancer, suggestive of a potentially decreased ability to repair carcinogen-induced damage.	('lung cancer', 'Disease', (81, 92))	('lung cancer', 'Phenotype', 'HP:0100526', (81, 92))	('ability', 'MPA', (132, 139))	('repair carcinogen-induced damage', 'MPA', (143, 175))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('fits', 'Disease', 'MESH:D012640', (9, 13))	('lung cancer', 'Disease', 'MESH:D008175', (81, 92))	('impact', 'Reg', (59, 65))	('fits', 'Disease', (9, 13))	('variation', 'Var', (19, 28))	('decreased', 'NegReg', (122, 131))
503140	26013599	Surprisingly, our copy number variation (CNV) analysis of LUSC tumors revealed a copy number gain in the region of RAD52, resulting in a statistically significant level of amplification for RAD52 in lung squamous cell carcinoma patients.	('copy number', 'Var', (81, 92))	('RAD52', 'Gene', (190, 195))	('RAD52', 'Gene', (115, 120))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (204, 227))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (199, 227))	('amplification', 'MPA', (172, 185))	('patients', 'Species', '9606', (228, 236))	('gain', 'PosReg', (93, 97))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (199, 227))	('lung squamous cell carcinoma', 'Disease', (199, 227))	('LUSC tumors', 'Disease', 'MESH:D009369', (58, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (218, 227))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('LUSC tumors', 'Disease', (58, 69))
503142	26013599	In line with the statistical evidence portraying a role for RAD52 in developing lung cancer, we functionally demonstrate that upon Rad52 depletion, the rate of cell proliferation was attenuated and senescence was induced in non-tumorigenic bronchial epithelial mouse cells.	('lung cancer', 'Disease', 'MESH:D008175', (80, 91))	('depletion', 'Var', (137, 146))	('senescence', 'CPA', (198, 208))	('tumor', 'Disease', 'MESH:D009369', (228, 233))	('mouse', 'Species', '10090', (261, 266))	('induced', 'Reg', (213, 220))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('attenuated', 'NegReg', (183, 193))	('lung cancer', 'Disease', (80, 91))	('lung cancer', 'Phenotype', 'HP:0100526', (80, 91))	('tumor', 'Disease', (228, 233))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('Rad52', 'Gene', (131, 136))	('cell proliferation', 'CPA', (160, 178))
503143	26013599	We also show that loss of RAD52 slows cell proliferation while overexpression of RAD52 enhances proliferation in mouse lung cancer cells.	('cell proliferation', 'CPA', (38, 56))	('lung cancer', 'Disease', (119, 130))	('loss', 'Var', (18, 22))	('lung cancer', 'Phenotype', 'HP:0100526', (119, 130))	('proliferation', 'CPA', (96, 109))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('RAD52', 'Gene', (26, 31))	('slows', 'NegReg', (32, 37))	('lung cancer', 'Disease', 'MESH:D008175', (119, 130))	('mouse', 'Species', '10090', (113, 118))
503144	26013599	Additionally, in mouse tumor cell lines we demonstrate that depletion of RAD52 alters cell cycle distribution by decreasing the fraction of cells in G0/G1 and significantly increasing the fraction of cells in G2/M.	('increasing', 'PosReg', (173, 183))	('mouse', 'Species', '10090', (17, 22))	('RAD52', 'Gene', (73, 78))	('decreasing', 'NegReg', (113, 123))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('depletion', 'Var', (60, 69))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('alters', 'Reg', (79, 85))	('tumor', 'Disease', (23, 28))	('cell cycle distribution', 'CPA', (86, 109))
503145	26013599	Finally, we demonstrate that loss of Rad52 expression increases DNA damage accumulation in mouse normal bronchial and tumor cells.	('Rad52', 'Gene', (37, 42))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('loss', 'Var', (29, 33))	('tumor', 'Disease', (118, 123))	('increases', 'PosReg', (54, 63))	('DNA damage accumulation', 'MPA', (64, 87))	('mouse', 'Species', '10090', (91, 96))
503196	26013599	The first SNP, rs6413436, is significantly associated with LUSC in our GWAS cohort (p = 1.0x10-3 after multiple testing adjustment, odds ratio (OR) =1.06 for overall lung cancer (95% CIs: 1.024-1.10), n=28,998; p = 2.7x10-3, OR=1.09 for LUSC (95% CIs: 1.03-1.15), n=19,437).	('men', 'Species', '9606', (126, 129))	('rs6413436', 'Var', (15, 24))	('rs6413436', 'Mutation', 'rs6413436', (15, 24))	('lung cancer', 'Disease', 'MESH:D008175', (166, 177))	('associated', 'Reg', (43, 53))	('lung cancer', 'Disease', (166, 177))	('lung cancer', 'Phenotype', 'HP:0100526', (166, 177))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('LUSC', 'Disease', (59, 63))
503197	26013599	Although this SNP is not genotyped in our eQTL cohort of 70 lung tissues, it is in strong linkage disequilibrium (LD) (D'=1 and r2=0.82) with a nearby SNP, rs10744729, which we have genotyped in our eQTL cohort and found to be significantly associated with RAD52 gene expression (p = 0.01, n=70).	('RAD52', 'Gene', (257, 262))	('associated', 'Reg', (241, 251))	('expression', 'MPA', (268, 278))	('rs10744729', 'Mutation', 'rs10744729', (156, 166))	('rs10744729', 'Var', (156, 166))
503198	26013599	SNPs rs6413436 and rs10744729 are located in RAD52 intron 11 and intron 9, and the distance between them is relatively small, at about 1.9 kb.	('rs6413436', 'Var', (5, 14))	('RAD52', 'Gene', (45, 50))	('rs6413436', 'Mutation', 'rs6413436', (5, 14))	('rs10744729', 'Mutation', 'rs10744729', (19, 29))	('rs10744729', 'Var', (19, 29))
503200	26013599	The SNP rs10744729 also showed a significant association with LUSC in our GWAS study (p = 0.02 after multiple testing adjustment).	('rs10744729', 'Mutation', 'rs10744729', (8, 18))	('LUSC', 'Disease', (62, 66))	('men', 'Species', '9606', (124, 127))	('rs10744729', 'Var', (8, 18))	('association', 'Reg', (45, 56))
503201	26013599	And the linkage disequilibrium between rs10744729 and rs6413436 in our dataset is close to complete LD (r2 = 0.82).	('rs6413436', 'Mutation', 'rs6413436', (54, 63))	('rs6413436', 'Var', (54, 63))	('rs10744729', 'Var', (39, 49))	('rs10744729', 'Mutation', 'rs10744729', (39, 49))
503202	26013599	It is thus reasonable to conclude that rs10744729 is a proxy SNP for rs6413436.	('rs10744729', 'Var', (39, 49))	('rs6413436', 'Mutation', 'rs6413436', (69, 78))	('rs10744729', 'Mutation', 'rs10744729', (39, 49))	('rs6413436', 'Var', (69, 78))
503203	26013599	The significant association of both rs10744729 and rs6413436 with LUSC could be explained by the strong LD between these 2 SNPs.	('LUSC', 'Disease', (66, 70))	('rs10744729', 'Mutation', 'rs10744729', (36, 46))	('rs10744729', 'Var', (36, 46))	('rs6413436', 'Var', (51, 60))	('rs6413436', 'Mutation', 'rs6413436', (51, 60))
503204	26013599	This plus that rs10744729 was significantly associated with RAD52 expression in lung tissues suggest that these 2 SNPs were eQTL SNPs that associate with LUSC risk by influencing RAD52 gene expression.	('LUSC', 'Disease', (154, 158))	('rs10744729', 'Mutation', 'rs10744729', (15, 25))	('rs10744729', 'Var', (15, 25))	('expression', 'MPA', (190, 200))	('RAD52', 'Gene', (179, 184))	('influencing', 'Reg', (167, 178))
503205	26013599	Figure 1B demonstrates that the risk allele 'A' of rs10744729 (in LD with the lung cancer risk allele 'C' of rs6413436) is associated with increased expression of RAD52 in a dose-dependent manner (homozygous reference alleles 'CC' < heterozygous 'AC' < homozygous mutants 'AA').	('lung cancer', 'Disease', (78, 89))	('lung cancer', 'Phenotype', 'HP:0100526', (78, 89))	('rs10744729', 'Mutation', 'rs10744729', (51, 61))	('rs10744729', 'Var', (51, 61))	('RAD52', 'Gene', (163, 168))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('increased', 'PosReg', (139, 148))	('rs6413436', 'Mutation', 'rs6413436', (109, 118))	('lung cancer', 'Disease', 'MESH:D008175', (78, 89))	('expression', 'MPA', (149, 159))
503206	26013599	Thus, the eQTL for rs10744729 and its associated SNP, rs6413436, accounts for a small proportion of the variance in RAD52 expression in lung tissues, an observation consistent with the relatively modest genetic risk observed with these two variants for LUSC (OR=1.09).	('rs6413436', 'Var', (54, 63))	('expression', 'MPA', (122, 132))	('rs6413436', 'Mutation', 'rs6413436', (54, 63))	('RAD52', 'Gene', (116, 121))	('rs10744729', 'Mutation', 'rs10744729', (19, 29))	('rs10744729', 'Var', (19, 29))
503211	26013599	Gene expression levels of RAD52 are also positively correlated with somatic copy number gains in the RAD52 region in the TCGA LUSC samples (Supplementary Figure 1), suggesting that the somatic copy number gains in the LUSC tumors led to the corresponding increase in RAD52 expression.	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('tumors', 'Phenotype', 'HP:0002664', (223, 229))	('RAD52', 'Gene', (267, 272))	('men', 'Species', '9606', (146, 149))	('LUSC tumors', 'Disease', 'MESH:D009369', (218, 229))	('LUSC tumors', 'Disease', (218, 229))	('increase', 'PosReg', (255, 263))	('expression', 'MPA', (273, 283))	('copy number gains', 'Var', (193, 210))
503212	26013599	We identified a number of RAD52 SNPs which showed more significant P-values (P-values < 10-6 (Supplemental Table 2) for the associations with squamous cell lung cancer phenotype.	('SNPs', 'Var', (32, 36))	('men', 'Species', '9606', (100, 103))	('associations', 'Interaction', (124, 136))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('squamous cell lung cancer', 'Disease', (142, 167))	('RAD52', 'Gene', (26, 31))	('squamous cell lung cancer', 'Disease', 'MESH:D002294', (142, 167))	('squamous cell lung cancer', 'Phenotype', 'HP:0030359', (142, 167))	('lung cancer', 'Phenotype', 'HP:0100526', (156, 167))
503213	26013599	We replicated the significant association between RAD52 SNP rs6489769 and the risk of squamous cell carcinoma P = 9.4x10-7, (Supplemental Table 2) which was originally reported by Shi et al; however, this SNP does not show significant association with our RAD52 gene expression data, suggesting it may not be a cis-eQTL SNP in RAD52.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (86, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('rs6489769', 'Var', (60, 69))	('men', 'Species', '9606', (131, 134))	('RAD52', 'Gene', (50, 55))	('squamous cell carcinoma P', 'Disease', (86, 111))	('rs6489769', 'Mutation', 'rs6489769', (60, 69))
503214	26013599	did not find that the SNP rs6489769 was associated with RAD52 gene expression.	('RAD52', 'Gene', (56, 61))	('rs6489769', 'Var', (26, 35))	('rs6489769', 'Mutation', 'rs6489769', (26, 35))	('expression', 'MPA', (67, 77))	('associated', 'Reg', (40, 50))
503215	26013599	Current evidence suggests that rs6489769 may influence one's risk of developing LUSC via mechanisms other than RAD52 expression.	('rs6489769', 'Var', (31, 40))	('rs6489769', 'Mutation', 'rs6489769', (31, 40))	('developing LUSC', 'Disease', (69, 84))	('influence', 'Reg', (45, 54))
503219	26013599	This data suggests that RAD52 overexpression could contribute to LUSC etiology but not to LUAD carcinogenesis, which is consistent with our eQTL study showing that the identified eQTL SNPs in RAD52 are significantly associated with LUSC but not LUAD.	('LUSC', 'Disease', (65, 69))	('LUAD carcinogenesis', 'Disease', (90, 109))	('associated', 'Reg', (216, 226))	('LUAD carcinogenesis', 'Disease', 'MESH:D063646', (90, 109))	('RAD52', 'Gene', (192, 197))	('LUSC', 'Disease', (232, 236))	('contribute', 'Reg', (51, 61))	('SNPs', 'Var', (184, 188))
503224	26013599	The cells were cultured for 7-10 days post-infection before they stopped dividing, became morphologically round and flattened, and stained positive for senescence associated beta-galactosidase activity, indicating that loss of RAD52 resulted in senescence (Figure 4).	('loss', 'Var', (219, 223))	('RAD52', 'Gene', (227, 232))	('senescence', 'CPA', (245, 255))	('beta-galactosidase', 'Gene', (174, 192))	('beta-galactosidase', 'Gene', '12091', (174, 192))	('resulted', 'Reg', (233, 241))
503226	26013599	The role of gamma-H2AX foci in the DNA damage signaling pathway induced by double-strand breaks is to act as docking areas for the recruitment of repair factors and to bring the broken DNA ends closer so that DNA repair is accomplished.	('double-strand breaks', 'Var', (75, 95))	('gamma-H2AX', 'Gene', (12, 22))	('men', 'Species', '9606', (138, 141))	('DNA damage signaling pathway', 'Pathway', (35, 63))	('gamma-H2AX', 'Gene', '15270', (12, 22))
503232	26013599	Upon depletion of RAD52 in mouse lung epithelial cells, we observed the rate of cell proliferation begin to decrease around 96 hours post infection and 48 hours post completion of puromycin selection, prior to the appearance of a senescent phenotype.	('depletion', 'Var', (5, 14))	('puromycin', 'Chemical', 'MESH:D011691', (180, 189))	('mouse', 'Species', '10090', (27, 32))	('hours post infection', 'Disease', (127, 147))	('cell proliferation', 'CPA', (80, 98))	('hours post infection', 'Disease', 'MESH:D020178', (127, 147))	('decrease', 'NegReg', (108, 116))	('RAD52', 'Gene', (18, 23))
503233	26013599	Cellular proliferation in lung tumor cell lines (Spon2, Spon6 and CL25M) also decreased with depletion of RAD52 (Figure 4A).	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('depletion', 'Var', (93, 102))	('lung tumor', 'Disease', (26, 36))	('lung tumor', 'Disease', 'MESH:D008175', (26, 36))	('Cellular proliferation', 'CPA', (0, 22))	('decreased', 'NegReg', (78, 87))	('RAD52', 'Gene', (106, 111))	('lung tumor', 'Phenotype', 'HP:0100526', (26, 36))
503237	26013599	The E10 mouse bronchial epithelial cell line became senescent post-RAD52 knockdown, which prevented the acquisition of enough cells for flow cytometry.	('mouse', 'Species', '10090', (8, 13))	('post-RAD52', 'Gene', (62, 72))	('knockdown', 'Var', (73, 82))
503241	26013599	When DNA damage accumulates, a cell may either die because of excessive damage, or the cell may mechanistically sidestep the damage through modulation of other checkpoints or tumor suppressive proteins, leading to replication of the damaged cell and disease.	('excessive damage', 'Disease', (62, 78))	('tumor', 'Disease', (175, 180))	('excessive damage', 'Disease', 'MESH:D004194', (62, 78))	('disease', 'Disease', (250, 257))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('modulation', 'Var', (140, 150))	('leading to', 'Reg', (203, 213))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('replication', 'CPA', (214, 225))
503247	26013599	If unsuccessful in a critical repair process such as the DNA damage response, a cell may either undergo apoptosis or accumulate mutations that will ultimately evolve into genomic instability and cancer.	('genomic', 'MPA', (171, 178))	('mutations', 'Var', (128, 137))	('cancer', 'Disease', (195, 201))	('undergo', 'Reg', (96, 103))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('evolve', 'Reg', (159, 165))	('apoptosis', 'CPA', (104, 113))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
503249	26013599	Our research into the role of RAD52 in susceptibility to lung carcinogenesis emerged from prior findings implicating variation in RAD52 as a factor in LUSC development.	('men', 'Species', '9606', (163, 166))	('LUSC development', 'CPA', (151, 167))	('variation', 'Var', (117, 126))	('RAD52', 'Gene', (130, 135))	('factor', 'Reg', (141, 147))	('lung carcinogenesis', 'Disease', (57, 76))	('lung carcinogenesis', 'Disease', 'MESH:D063646', (57, 76))
503250	26013599	Here, we have identified two candidate regions in RAD52 where variations in the gene are associated with increased copy number as well as increased RAD52 expression in lung tumor tissue compared to normal.	('lung tumor', 'Phenotype', 'HP:0100526', (168, 178))	('increased', 'PosReg', (138, 147))	('RAD52', 'Gene', (148, 153))	('variations', 'Var', (62, 72))	('copy', 'MPA', (115, 119))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('RAD52', 'Gene', (50, 55))	('lung tumor', 'Disease', (168, 178))	('lung tumor', 'Disease', 'MESH:D008175', (168, 178))	('increased', 'PosReg', (105, 114))	('expression', 'MPA', (154, 164))
503255	26013599	Her group clearly demonstrated that by reducing homologous recombination through genetic deletion of the Rad52 gene, they were able to significantly decrease and delay the incidence of thymic tumors in Atm-/- mice: more than half of the Atm-/- mice developed tumors by 4 months of age compared to less than 20% of the Atm-/- Rad52-/- mice.	('thymic tumors', 'Disease', 'MESH:D013953', (185, 198))	('Atm', 'Gene', (202, 205))	('Rad52', 'Gene', (105, 110))	('mice', 'Species', '10090', (244, 248))	('tumors', 'Disease', (192, 198))	('delay', 'NegReg', (162, 167))	('tumors', 'Phenotype', 'HP:0002664', (259, 265))	('decrease', 'NegReg', (149, 157))	('genetic deletion', 'Var', (81, 97))	('tumors', 'Disease', 'MESH:D009369', (192, 198))	('tumor', 'Phenotype', 'HP:0002664', (259, 264))	('tumors', 'Disease', (259, 265))	('Atm', 'Gene', '11920', (202, 205))	('Atm', 'Gene', (318, 321))	('Atm', 'Gene', (237, 240))	('mice', 'Species', '10090', (209, 213))	('mice', 'Species', '10090', (334, 338))	('tumors', 'Disease', 'MESH:D009369', (259, 265))	('tumors', 'Phenotype', 'HP:0002664', (192, 198))	('Atm', 'Gene', '11920', (318, 321))	('Atm', 'Gene', '11920', (237, 240))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('thymic tumors', 'Disease', (185, 198))
503265	26013599	Furthermore, in mouse lung tumor cells, knockdown of Rad52 curbed proliferation and led to an accumulation of cells in the G2/M phase of the cell cycle (Figures 5,6).	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('cells in the G2/M phase of the cell cycle', 'CPA', (110, 151))	('curbed', 'NegReg', (59, 65))	('lung tumor', 'Disease', (22, 32))	('proliferation', 'CPA', (66, 79))	('knockdown', 'Var', (40, 49))	('lung tumor', 'Disease', 'MESH:D008175', (22, 32))	('mouse', 'Species', '10090', (16, 21))	('accumulation', 'PosReg', (94, 106))	('lung tumor', 'Phenotype', 'HP:0100526', (22, 32))	('Rad52', 'Gene', (53, 58))
503266	26013599	Little is known of the effects of variation in RAD52 in regards to susceptibility to lung cancer and tumor development.	('lung cancer', 'Disease', (85, 96))	('lung cancer', 'Phenotype', 'HP:0100526', (85, 96))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('men', 'Species', '9606', (114, 117))	('tumor', 'Disease', (101, 106))	('variation', 'Var', (34, 43))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('lung cancer', 'Disease', 'MESH:D008175', (85, 96))	('RAD52', 'Gene', (47, 52))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
503267	26013599	However, genetic variations that alter homologous recombination, coupled with a carcinogenic environment, may plausibly contribute to tumorigenesis.	('men', 'Species', '9606', (100, 103))	('genetic variations', 'Var', (9, 27))	('contribute', 'Reg', (120, 130))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('carcinogenic', 'Disease', 'MESH:D063646', (80, 92))	('carcinogenic', 'Disease', (80, 92))	('tumor', 'Disease', (134, 139))
503282	25653721	More than 80% of adenomas and carcinomas have mutations in various growth promoting developmental genes resulting in acquisition of a growth advantage phenomenon for maintenance and metastasis.	('growth advantage phenomenon', 'CPA', (134, 161))	('mutations', 'Var', (46, 55))	('growth promoting developmental genes', 'Gene', (67, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (30, 39))	('adenomas and carcinomas', 'Disease', 'MESH:D000236', (17, 40))	('carcinomas', 'Phenotype', 'HP:0030731', (30, 40))
503288	25653721	Evidence till date reveals that the genes that are helpful in occurrence and development of cancer are the targets of the Wnt/beta-catenin pathway and are usually upregulated as a consequence of the deregulation of the signalling molecules.	('deregulation', 'Var', (199, 211))	('beta-catenin', 'Gene', '1499', (126, 138))	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('upregulated', 'PosReg', (163, 174))	('beta-catenin', 'Gene', (126, 138))
503291	25653721	Telomere dysfunction leads to perturbation in various cell signalling pathways including the Wnt/beta-catenin pathway.	('cell signalling pathways', 'Pathway', (54, 78))	('beta-catenin', 'Gene', (97, 109))	('perturbation', 'Reg', (30, 42))	('beta-catenin', 'Gene', '1499', (97, 109))	('Telomere dysfunction', 'Var', (0, 20))
503298	25653721	Mutations in beta-catenin results in upregulation of hTert expression facilitating stabilization of the telomeres thus providing a significant hall mark for tumorigenesis.	('tumor', 'Disease', (157, 162))	('hTert', 'Gene', '7015', (53, 58))	('beta-catenin', 'Gene', '1499', (13, 25))	('hTert', 'Gene', (53, 58))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('upregulation', 'PosReg', (37, 49))	('Mutations', 'Var', (0, 9))	('stabilization', 'MPA', (83, 96))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('beta-catenin', 'Gene', (13, 25))
503358	25653721	Mutations in the wnt signalling pathway leads to alterations in the beta-catenin level in the cells.	('wnt signalling pathway', 'Pathway', (17, 39))	('alterations', 'Reg', (49, 60))	('Mutations', 'Var', (0, 9))	('beta-catenin', 'Gene', (68, 80))	('beta-catenin', 'Gene', '1499', (68, 80))	('wnt', 'Chemical', '-', (17, 20))
503397	33687144	Proliferation, migration, invasion and Western blotting were measured after treatment with overexpressed or knockdown FAM83A-AS1.	('knockdown', 'Var', (108, 117))	('FAM83A-AS1', 'Gene', (118, 128))	('migration', 'CPA', (15, 24))	('men', 'Species', '9606', (81, 84))	('FAM83A-AS1', 'Gene', '100131726', (118, 128))
503400	33687144	Functionally, high FAM83A-AS1 expression increased LUAD cell proliferation and metastasis, indicating that FAM83A-AS1 exerted its oncogenic functions.	('increased', 'PosReg', (41, 50))	('FAM83A-AS1', 'Gene', '100131726', (19, 29))	('FAM83A-AS1', 'Gene', '100131726', (107, 117))	('high', 'Var', (14, 18))	('FAM83A-AS1', 'Gene', (19, 29))	('metastasis', 'CPA', (79, 89))	('FAM83A-AS1', 'Gene', (107, 117))	('LUAD cell proliferation', 'CPA', (51, 74))
503427	33687144	The siRNA target sequences were as follows: si-NC 5'-CCCATAAGAGTAATAATAT-3'; si-FAM83A-AS1-1 (si-1) 5'-AGAGTAAGCAAGATAGAGAC-3'; si-FAM83A-AS1-2 (si-2) 5'-AGGCTAGTAAGCAGGTCACC-3'; si-FAM83A-1 5'-GCCGCCTTAGCAGCAGCAGT-3'; and si-FAM83A-2 5'-CCGCCTTAGCAGCAGCAGTG-3'.	('FAM83A-AS1', 'Gene', (131, 141))	('si-NC', 'Var', (44, 49))	('FAM83A', 'Gene', (131, 137))	('FAM83A', 'Gene', '84985', (131, 137))	('FAM83A-AS1', 'Gene', (80, 90))	('FAM83A-AS1', 'Gene', '100131726', (131, 141))	('FAM83A-AS1', 'Gene', '100131726', (80, 90))	('FAM83A', 'Gene', '84985', (226, 232))	('FAM83A', 'Gene', (226, 232))	('FAM83A', 'Gene', '84985', (182, 188))	('FAM83A', 'Gene', (182, 188))	('FAM83A', 'Gene', '84985', (80, 86))	('FAM83A', 'Gene', (80, 86))
503437	33687144	The blots were blocked using 5% skimmed milk and were incubated with antibodies against GAPDH (AM1020a, Abgent), FBL (66985-1-Ig, Proteintech), FAM83A (ab128245, Abcam), E-cadherin (610 181, BD), p-ERK (# 4370S, CST), and ERK (# 9107S, CST).	('FBL', 'Gene', '2091', (113, 116))	('GAPDH', 'Gene', '2597', (88, 93))	('FBL', 'Gene', (113, 116))	('CST', 'Gene', '106478911', (236, 239))	('GAPDH', 'Gene', (88, 93))	('CST', 'Gene', '106478911', (212, 215))	('E-cadherin', 'Gene', (170, 180))	('E-cadherin', 'Gene', '999', (170, 180))	('ERK', 'Gene', '5594', (198, 201))	('ERK', 'Gene', '5594', (222, 225))	('FAM83A', 'Gene', (144, 150))	('CST', 'Gene', (236, 239))	('CST', 'Gene', (212, 215))	('ab128245', 'Var', (152, 160))	('610 181', 'Var', (182, 189))	('ERK', 'Gene', (222, 225))	('FAM83A', 'Gene', '84985', (144, 150))	('ERK', 'Gene', (198, 201))	('# 4370S', 'Var', (203, 210))
503450	33687144	We used two siRNAs to knockdown FAM83A-AS1, and siRNA efficiency was detected using qRT-PCR (Figure 2f,g).	('knockdown', 'Var', (22, 31))	('FAM83A-AS1', 'Gene', (32, 42))	('FAM83A-AS1', 'Gene', '100131726', (32, 42))
503451	33687144	CCK-8 and transwell assays showed that NSCLC cell viability (Figure 2h,i) and metastatic abilities (Figure 2j,k) decreased after FAM83A-AS1 knockdown.	('metastatic abilities', 'CPA', (78, 98))	('NSCLC', 'Disease', 'MESH:D002289', (39, 44))	('FAM83A-AS1', 'Gene', (129, 139))	('NSCLC', 'Disease', (39, 44))	('knockdown', 'Var', (140, 149))	('decreased', 'NegReg', (113, 122))	('FAM83A-AS1', 'Gene', '100131726', (129, 139))
503452	33687144	WB showed that FAM83A-AS1 knockdown also significantly decreased FAM83A and ERK expression levels in NSCLC cell lines (Figure 2l).	('FAM83A', 'Gene', '84985', (65, 71))	('ERK', 'Gene', (76, 79))	('FAM83A-AS1', 'Gene', (15, 25))	('FAM83A', 'Gene', (15, 21))	('NSCLC', 'Disease', (101, 106))	('FAM83A-AS1', 'Gene', '100131726', (15, 25))	('FAM83A', 'Gene', '84985', (15, 21))	('decreased', 'NegReg', (55, 64))	('NSCLC', 'Disease', 'MESH:D002289', (101, 106))	('knockdown', 'Var', (26, 35))	('FAM83A', 'Gene', (65, 71))	('ERK', 'Gene', '5594', (76, 79))
503469	33687144	The RNase A enzyme digested the single-stranded RNA but did not digest the double-stranded RNA.	('RNase A', 'Gene', '6035', (4, 11))	('digested', 'Var', (19, 27))	('RNase A', 'Gene', (4, 11))
503475	33687144	After the knockdown of FBL, qRT-PCR was performed to confirm the relationship between FAM83A and FBL.	('FBL', 'Gene', '2091', (23, 26))	('FBL', 'Gene', (97, 100))	('FBL', 'Gene', (23, 26))	('FAM83A', 'Gene', (86, 92))	('knockdown', 'Var', (10, 19))	('FBL', 'Gene', '2091', (97, 100))	('FAM83A', 'Gene', '84985', (86, 92))
503481	33687144	reported that high lncRNA HOXA11-AS expression was correlated with the poor prognosis of glioma patients.	('glioma', 'Disease', 'MESH:D005910', (89, 95))	('glioma', 'Phenotype', 'HP:0009733', (89, 95))	('HOXA11', 'Gene', '3207', (26, 32))	('high', 'Var', (14, 18))	('glioma', 'Disease', (89, 95))	('patients', 'Species', '9606', (96, 104))	('HOXA11', 'Gene', (26, 32))
503511	29228709	Silence of HOTAIR in oral carcinomas stem cells (OCSC) significantly inhibited their cancer stemness, invasiveness and tumourigenicity in xenotransplantation models.	('cancer stemness', 'Disease', 'MESH:D009369', (85, 100))	('cancer stemness', 'Disease', (85, 100))	('oral carcinomas', 'Disease', (21, 36))	('tumourigenicity in xenotransplantation models', 'CPA', (119, 164))	('carcinoma', 'Phenotype', 'HP:0030731', (26, 35))	('carcinomas', 'Phenotype', 'HP:0030731', (26, 36))	('inhibited', 'NegReg', (69, 78))	('HOTAIR', 'Gene', (11, 17))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('Silence', 'Var', (0, 7))	('oral carcinomas', 'Disease', 'MESH:D020820', (21, 36))
503524	29228709	The expression level of HOTAIR was correlated with tumor size and clinical stage in OSCC and HOTAIR has been suggested as a prognosis factor for HNSCC.	('correlated', 'Reg', (35, 45))	('HNSCC', 'Disease', (145, 150))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('HNSCC', 'Phenotype', 'HP:0012288', (145, 150))	('clinical', 'Species', '191496', (66, 74))	('tumor', 'Disease', (51, 56))	('expression', 'MPA', (4, 14))	('OSCC', 'Disease', (84, 88))	('HOTAIR', 'Var', (93, 99))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
503529	29228709	We examined the cancer stemness and invasiveness in vitro and tumorigenicity in xenotransplantation model and demonstrated that modulation of HOTAIR could be considered for the development of CSC-targeted therapy in oral carcinogenesis.	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('modulation', 'Var', (128, 138))	('cancer stemness', 'Disease', (16, 31))	('tumor', 'Disease', (62, 67))	('invasiveness', 'CPA', (36, 48))	('oral carcinogenesis', 'Disease', 'MESH:D063646', (216, 235))	('oral carcinogenesis', 'Disease', (216, 235))	('tumor', 'Disease', 'MESH:D009369', (62, 67))	('cancer stemness', 'Disease', 'MESH:D009369', (16, 31))
503536	29228709	To further investigate whether HOTAIR plays a role in maintaining CSCs hallmarks, loss-of-function mutation was generated in GNM and Ca9-22 sphere-forming oral cancer stem cells using small hairpin RNA targeting HOTAIR (sh-HOTAIR-1 and sh-HOTAIR-2), and lentiviral vector expressing shRNA against luciferase (sh-Luc) was used as control.	('loss-of-function', 'NegReg', (82, 98))	('oral cancer', 'Disease', 'MESH:D009062', (155, 166))	('oral cancer', 'Disease', (155, 166))	('Ca9-22', 'CellLine', 'CVCL:1102', (133, 139))	('mutation', 'Var', (99, 107))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))
503548	29228709	Most importantly, Kaplan-Meier survival analysis of OSCC patients with high levels of HOTAIRshowed a reduced survival rate compared to low-expression subjects (Figure 6D) based on the Cancer Genome Atlas (TCGA) database.	('Cancer Genome Atlas', 'Disease', (184, 203))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (184, 203))	('HOTAIRshowed', 'Var', (86, 98))	('patients', 'Species', '9606', (57, 65))	('survival', 'MPA', (109, 117))	('reduced', 'NegReg', (101, 108))	('Cancer', 'Phenotype', 'HP:0002664', (184, 190))	('OSCC', 'Disease', (52, 56))
503550	29228709	It has been shown that HOTAIR contributes to chemoresistance through PI3K/AKT/MRP1, wnt/beta-catenin pathways or downregualtion of p21 in other carcinomas.	('carcinomas', 'Disease', (144, 154))	('carcinomas', 'Disease', 'MESH:D002277', (144, 154))	('HOTAIR', 'Var', (23, 29))	('p21', 'Gene', '1026', (131, 134))	('AKT', 'Gene', '207', (74, 77))	('MRP1', 'Gene', '928', (78, 82))	('carcinomas', 'Phenotype', 'HP:0030731', (144, 154))	('p21', 'Gene', (131, 134))	('downregualtion', 'NegReg', (113, 127))	('beta-catenin', 'Gene', (88, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('AKT', 'Gene', (74, 77))	('chemoresistance', 'CPA', (45, 60))	('MRP1', 'Gene', (78, 82))	('beta-catenin', 'Gene', '1499', (88, 100))
503553	29228709	Interestingly, a recent study has demonstrated that exosomal HOTAIR induces human colon cancer cell line to form more colonospheres.	('colon cancer', 'Phenotype', 'HP:0003003', (82, 94))	('colon cancer', 'Disease', 'MESH:D015179', (82, 94))	('human', 'Species', '9606', (76, 81))	('colon cancer', 'Disease', (82, 94))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('exosomal HOTAIR', 'Var', (52, 67))	('induces', 'PosReg', (68, 75))
503559	29228709	As for HOTAIR, it has been found that the expression of EZH2 was significantly decreased and the level of E-cadherin was enhanced in the HOTAIR knockdown OSCC cells.	('decreased', 'NegReg', (79, 88))	('expression', 'MPA', (42, 52))	('enhanced', 'PosReg', (121, 129))	('EZH2', 'Gene', '2146', (56, 60))	('E-cadherin', 'Gene', (106, 116))	('knockdown', 'Var', (144, 153))	('E-cadherin', 'Gene', '999', (106, 116))	('EZH2', 'Gene', (56, 60))
503560	29228709	They demonstrated that silence of HOTAIR reduced the binding of EZH2 on the promoter of E-cadherin.	('reduced', 'NegReg', (41, 48))	('E-cadherin', 'Gene', (88, 98))	('E-cadherin', 'Gene', '999', (88, 98))	('HOTAIR', 'Gene', (34, 40))	('silence', 'Var', (23, 30))	('binding', 'Interaction', (53, 60))	('EZH2', 'Gene', (64, 68))	('EZH2', 'Gene', '2146', (64, 68))
503564	29228709	Previously, it has been shown that increased HOTAIR expression promoted tumor sphere formation in non-small cell lung cancer cells via upregulation of the stem cell-associated markers, including Sox2, Nanog, Oct3/4, c-Myc, beta-catenin and Klf4.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('c-Myc', 'Gene', (216, 221))	('Klf4', 'Gene', (240, 244))	('promoted', 'PosReg', (63, 71))	('c-Myc', 'Gene', '4609', (216, 221))	('beta-catenin', 'Gene', (223, 235))	('lung cancer', 'Phenotype', 'HP:0100526', (113, 124))	('upregulation', 'PosReg', (135, 147))	('beta-catenin', 'Gene', '1499', (223, 235))	('Klf4', 'Gene', '9314', (240, 244))	('increased', 'Var', (35, 44))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (98, 124))	('Sox2', 'Gene', (195, 199))	('cancer', 'Disease', (118, 124))	('tumor', 'Disease', (72, 77))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (102, 124))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('Nanog', 'Gene', '79923', (201, 206))	('Oct3/4', 'Gene', '5460', (208, 214))	('Oct3/4', 'Gene', (208, 214))	('Sox2', 'Gene', '6657', (195, 199))	('Nanog', 'Gene', (201, 206))	('HOTAIR', 'Gene', (45, 51))	('cancer', 'Disease', 'MESH:D009369', (118, 124))
503595	27671334	AXL Inhibition Suppresses the DNA Damage Response and Sensitizes Cells to PARP Inhibition in Multiple Cancers Epithelial to mesenchymal transition (EMT) is associated with a wide range of changes in cancer cells, including stemness, chemo- and radio-resistance and metastasis.	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('Suppresses', 'NegReg', (15, 25))	('Inhibition', 'NegReg', (79, 89))	('Multiple Cancers', 'Disease', (93, 109))	('Cancers', 'Phenotype', 'HP:0002664', (102, 109))	('Multiple Cancers', 'Disease', 'MESH:D009369', (93, 109))	('PARP', 'Gene', '142', (74, 78))	('Cancer', 'Phenotype', 'HP:0002664', (102, 108))	('AXL', 'Gene', '558', (0, 3))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('DNA Damage Response', 'MPA', (30, 49))	('Epithelial to mesenchymal transition', 'CPA', (110, 146))	('cancer', 'Disease', (199, 205))	('Inhibition', 'Var', (4, 14))	('AXL', 'Gene', (0, 3))	('PARP', 'Gene', (74, 78))
503598	27671334	Since the DNA repair pathway is also altered in patient tumor specimens overexpressing AXL, it is hypothesized that modulation of AXL in cells that have undergone EMT will sensitize them to agents targeting the DNA repair pathway.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('DNA repair pathway', 'Pathway', (211, 229))	('tumor', 'Disease', (56, 61))	('patient', 'Species', '9606', (48, 55))	('DNA repair pathway', 'Pathway', (10, 28))	('sensitize', 'Reg', (172, 181))	('modulation', 'Var', (116, 126))	('altered', 'Reg', (37, 44))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
503605	27671334	AXL knockdown in mouse xenografts of A549 (non-small cell lung) and MDA-MB-231 (breast) cancer cell lines led to a modest decrease in tumor growth.	('cancer', 'Disease', (88, 94))	('AXL', 'Protein', (0, 3))	('A549', 'CellLine', 'CVCL:0023', (37, 41))	('mouse', 'Species', '10090', (17, 22))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (68, 78))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('decrease', 'NegReg', (122, 130))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('knockdown', 'Var', (4, 13))	('tumor', 'Disease', (134, 139))
503606	27671334	Additionally, AXL knockdown reduced lung metastasis in MDA-MB-231 cell lines and attenuated migration and anchorage-independent growth in other cancer types such as pancreatic cancer and hepatocellular carcinoma cell lines.	('reduced', 'NegReg', (28, 35))	('pancreatic cancer', 'Disease', 'MESH:D010190', (165, 182))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (187, 211))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('cancer', 'Disease', (144, 150))	('attenuated', 'NegReg', (81, 91))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('pancreatic cancer', 'Disease', (165, 182))	('lung metastasis', 'CPA', (36, 51))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (187, 211))	('cancer', 'Disease', (176, 182))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('knockdown', 'Var', (18, 27))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('hepatocellular carcinoma', 'Disease', (187, 211))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (165, 182))	('AXL', 'Protein', (14, 17))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (55, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (202, 211))
503615	27671334	Inhibition of AXL reversed lapatinib resistance in these cells.	('AXL', 'Protein', (14, 17))	('lapatinib', 'Chemical', 'MESH:D000077341', (27, 36))	('Inhibition', 'Var', (0, 10))	('lapatinib resistance', 'MPA', (27, 47))
503617	27671334	AXL overexpression also protected chronic myelogenous leukemia cell lines from growth inhibitory potential of imatinib (leading to drug resistance), while knockdown of AXL in these cells led to apoptosis of the resistant cell lines.	('myelogenous leukemia', 'Disease', (42, 62))	('knockdown', 'Var', (155, 164))	('leukemia cell lines', 'Disease', (54, 73))	('imatinib', 'Chemical', 'MESH:D000068877', (110, 118))	('chronic myelogenous leukemia', 'Phenotype', 'HP:0005506', (34, 62))	('growth inhibitory potential of imatinib', 'MPA', (79, 118))	('leukemia cell lines', 'Disease', 'MESH:D015458', (54, 73))	('leukemia', 'Phenotype', 'HP:0001909', (54, 62))	('myelogenous leukemia', 'Phenotype', 'HP:0012324', (42, 62))	('drug resistance', 'Phenotype', 'HP:0020174', (131, 146))	('myelogenous leukemia', 'Disease', 'MESH:D007951', (42, 62))	('drug resistance', 'MPA', (131, 146))
503618	27671334	Furthermore, AXL expression has been associated with primary or acquired resistance to DNA damaging therapies and may prevent normal DNA damage response (DDR) in a number of cancer types.	('AXL', 'Protein', (13, 16))	('resistance to DNA damaging therapies', 'MPA', (73, 109))	('cancer', 'Disease', (174, 180))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('normal DNA damage response', 'MPA', (126, 152))	('expression', 'Var', (17, 27))	('associated', 'Reg', (37, 47))	('prevent', 'NegReg', (118, 125))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))
503619	27671334	In esophageal cancer, high AXL expression was associated with in vitro resistance to cisplatin-induced apoptosis and prevented DNA damage induced cellular responses.	('AXL', 'Protein', (27, 30))	('cellular', 'CPA', (146, 154))	('esophageal cancer', 'Disease', (3, 20))	('high', 'Var', (22, 26))	('esophageal cancer', 'Disease', 'MESH:D004938', (3, 20))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('prevented', 'NegReg', (117, 126))	('resistance', 'CPA', (71, 81))	('cisplatin', 'Chemical', 'MESH:D002945', (85, 94))	('DNA damage induced', 'MPA', (127, 145))
503622	27671334	Collectively, these studies suggest that inhibition of AXL in multiple malignancies is likely to result in re-sensitization to targeted therapy, radiation and chemotherapy, possibly through enhancing/promoting DDR.	('multiple malignancies', 'Disease', (62, 83))	('DDR', 'MPA', (210, 213))	('AXL', 'Protein', (55, 58))	('inhibition', 'Var', (41, 51))	('multiple malignancies', 'Disease', 'MESH:D009369', (62, 83))	('enhancing/promoting', 'PosReg', (190, 209))
503662	27671334	Downregulation of AXL in both NSCLC and TNBC cell lines increased expression of apoptotic markers, cleaved PARP and cleaved caspase-7 (Fig.	('NSCLC', 'Disease', 'MESH:D002289', (30, 35))	('PARP', 'Gene', '142', (107, 111))	('increased', 'PosReg', (56, 65))	('Downregulation', 'NegReg', (0, 14))	('cleaved', 'MPA', (99, 106))	('NSCLC', 'Phenotype', 'HP:0030358', (30, 35))	('expression', 'MPA', (66, 76))	('caspase-7', 'Gene', (124, 133))	('caspase-7', 'Gene', '840', (124, 133))	('PARP', 'Gene', (107, 111))	('NSCLC', 'Disease', (30, 35))	('cleaved', 'Var', (116, 123))
503666	27671334	Additionally, AXL knockdown led to a reversal of the EMT phenotype, seen by an increase in E-cadherin protein levels and decrease in ZEB1 protein levels (Fig.	('increase', 'PosReg', (79, 87))	('knockdown', 'Var', (18, 27))	('E-cadherin', 'Gene', (91, 101))	('ZEB1', 'Gene', (133, 137))	('E-cadherin', 'Gene', '999', (91, 101))	('ZEB1', 'Gene', '6935', (133, 137))	('decrease', 'NegReg', (121, 129))
503673	27671334	To directly test this hypothesis, we measured the accumulation of DNA damage upon AXL inhibition and stable AXL knockdown across all three-cancer systems.	('AXL', 'Protein', (82, 85))	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('knockdown', 'Var', (112, 121))	('inhibition', 'NegReg', (86, 96))	('cancer', 'Disease', (139, 145))
503675	27671334	For example, we observed a significant increase in the percent cells exhibiting more than 10 gammaH2AX foci per cell following treatment with TP0903 in all cell lines examined.	('TP0903', 'Var', (142, 148))	('gammaH2AX', 'Gene', (93, 102))	('increase', 'PosReg', (39, 47))	('TP0903', 'Chemical', 'MESH:C000606144', (142, 148))	('gammaH2AX', 'Chemical', '-', (93, 102))
503676	27671334	Specifically, the percentage of cells exhibiting more than 10 foci/cell increased by 7 fold in HCC1806 (p<0.0001), 1.5 fold in SKLU1 cells (p<0.0001) and 6-fold in 584 (p<0.0001) (Fig.	('HCC1806', 'CellLine', 'CVCL:1258', (95, 102))	('SKLU1', 'CellLine', 'CVCL:0629', (127, 132))	('HCC1806', 'Var', (95, 102))	('increased', 'PosReg', (72, 81))
503679	27671334	For example, as early as 24 hours post TP0903 treatment, NSCLC cell lines showed a decrease in the protein levels of RAD50 (SKLU1) and RAD51 (Calu1), a protein directly involved in homologous recombination (HR) DNA repair (Fig.	('TP0903', 'Chemical', 'MESH:C000606144', (39, 45))	('RAD50', 'Gene', '10111', (117, 122))	('NSCLC', 'Phenotype', 'HP:0030358', (57, 62))	('RAD50', 'Gene', (117, 122))	('RAD51', 'Var', (135, 140))	('TP0903', 'Var', (39, 45))	('protein levels', 'MPA', (99, 113))	('decrease', 'NegReg', (83, 91))	('SKLU1', 'CellLine', 'CVCL:0629', (124, 129))	('NSCLC', 'Disease', (57, 62))	('NSCLC', 'Disease', 'MESH:D002289', (57, 62))
503680	27671334	In TNBCs, there was a consistent decrease in the protein levels of c-Myc (p<0.0001 HCC1806 and p<0.005 MDA-MB-231), which is involved in the transcription of DNA repair proteins such as RAD51 (Fig.	('DNA repair protein', 'Gene', '442459', (158, 176))	('decrease', 'NegReg', (33, 41))	('TNBCs', 'Var', (3, 8))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (103, 113))	('DNA repair protein', 'Gene', (158, 176))	('c-Myc', 'Gene', '4609', (67, 72))	('HCC1806', 'CellLine', 'CVCL:1258', (83, 90))	('c-Myc', 'Gene', (67, 72))	('protein levels', 'MPA', (49, 63))
503682	27671334	Furthermore, treatment of cells with TP0903 also resulted in cancer type dependent alteration of DNA repair proteins.	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('alteration', 'Reg', (83, 93))	('cancer', 'Disease', (61, 67))	('DNA repair protein', 'Gene', '442459', (97, 115))	('TP0903', 'Var', (37, 43))	('DNA repair protein', 'Gene', (97, 115))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('TP0903', 'Chemical', 'MESH:C000606144', (37, 43))	('resulted', 'Reg', (49, 57))
503684	27671334	Furthermore, knockdown of AXL in MDA-MB-157 (TNBC) and SKLU1 (NSCLC) cell lines resulted in a significant increase in gammaH2AX foci in both cell lines (MDA-MB-157: p<0.0001, SKLU1: p<0.001), verifying the accumulation of DNA damage upon AXL downregulation (Supp.	('NSCLC', 'Disease', (62, 67))	('gammaH2AX', 'Chemical', '-', (118, 127))	('NSCLC', 'Disease', 'MESH:D002289', (62, 67))	('SKLU1', 'CellLine', 'CVCL:0629', (175, 180))	('SKLU1', 'CellLine', 'CVCL:0629', (55, 60))	('MDA-MB-157', 'CellLine', 'CVCL:0618', (33, 43))	('MDA-MB-157', 'CellLine', 'CVCL:0618', (153, 163))	('NSCLC', 'Phenotype', 'HP:0030358', (62, 67))	('increase', 'PosReg', (106, 114))	('MDA-MB-157', 'Gene', (33, 43))	('knockdown', 'Var', (13, 22))	('downregulation', 'NegReg', (242, 256))	('gammaH2AX', 'Protein', (118, 127))
503687	27671334	Results revealed that the mRNA expression of key DNA repair proteins (RAD51, BRCA2, E2F1, RAD54L and BRCA1) decreased significantly at 48 hours post-treatment with 25 nM TP0903 in TNBC (MDA-MB-157, HCC1806), NSCLC (SKLU1) and HNSCC (584) cell lines (Fig.	('HCC1806', 'CellLine', 'CVCL:1258', (198, 205))	('NSCLC', 'Phenotype', 'HP:0030358', (208, 213))	('SKLU1', 'CellLine', 'CVCL:0629', (215, 220))	('mRNA expression', 'MPA', (26, 41))	('TP0903', 'Chemical', 'MESH:C000606144', (170, 176))	('RAD54L', 'Gene', '8438', (90, 96))	('MDA-MB-157', 'CellLine', 'CVCL:0618', (186, 196))	('RAD51', 'Gene', (70, 75))	('RAD54L', 'Gene', (90, 96))	('BRCA2', 'Gene', (77, 82))	('E2F1', 'Gene', (84, 88))	('DNA repair protein', 'Gene', '442459', (49, 67))	('NSCLC', 'Disease', 'MESH:D002289', (208, 213))	('BRCA1', 'Gene', '672', (101, 106))	('E2F1', 'Gene', '1869', (84, 88))	('TP0903', 'Var', (170, 176))	('DNA repair protein', 'Gene', (49, 67))	('decreased', 'NegReg', (108, 117))	('BRCA1', 'Gene', (101, 106))	('NSCLC', 'Disease', (208, 213))	('BRCA2', 'Gene', '675', (77, 82))
503692	27671334	To examine the specificity of TP0903 for AXL, we measured the RNA levels of RAD51, BRCA2, E2F and RAD54L in cell lines stably knocked down for AXL, which showed a decrease in expression of the DNA repair genes in all the cells lines examined (Fig.	('RAD54L', 'Gene', (98, 104))	('expression', 'MPA', (175, 185))	('BRCA2', 'Gene', '675', (83, 88))	('RAD54L', 'Gene', '8438', (98, 104))	('knocked', 'Var', (126, 133))	('BRCA2', 'Gene', (83, 88))	('decrease', 'NegReg', (163, 171))	('TP0903', 'Chemical', 'MESH:C000606144', (30, 36))	('RNA', 'MPA', (62, 65))
503694	27671334	BRCA2 showed more significant changes in gene expression such as 10 fold in SKLU1 (p<0.005), 3-fold in MDA-MB-157 (p<0.05) and 2.5-fold in HCC1806 (p<0.05), Calu1 (p<0.005), 584 (p<0.05) and 1386-LN (p<0.005) upon AXL knockdown.	('BRCA2', 'Gene', '675', (0, 5))	('MDA-MB-157', 'CellLine', 'CVCL:0618', (103, 113))	('changes', 'Reg', (30, 37))	('knockdown', 'Var', (218, 227))	('gene expression', 'MPA', (41, 56))	('SKLU1', 'CellLine', 'CVCL:0629', (76, 81))	('SKLU1', 'Gene', (76, 81))	('BRCA2', 'Gene', (0, 5))	('584', 'Var', (174, 177))	('HCC1806', 'CellLine', 'CVCL:1258', (139, 146))
503699	27671334	Results revealed that treatment of TNBC, NSCLC and HNSCC cell lines with the AXL inhibitor (25nM TP0903, 48 hours) led to 2-fold decrease in the efficiency of the cells to carry out HR-mediated DNA repair in MDA-MB-231 (p<0.005) and HCC1806 (p<0.05) cells and 2.5 fold decrease in SKLU1 and 584 (p<0.0001) cell lines (Fig.	('SKLU1', 'CellLine', 'CVCL:0629', (281, 286))	('NSCLC', 'Disease', (41, 46))	('decrease', 'NegReg', (129, 137))	('HR-mediated DNA repair', 'CPA', (182, 204))	('HCC1806', 'CellLine', 'CVCL:1258', (233, 240))	('TP0903', 'Var', (97, 103))	('NSCLC', 'Disease', 'MESH:D002289', (41, 46))	('TP0903', 'Chemical', 'MESH:C000606144', (97, 103))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (208, 218))	('NSCLC', 'Phenotype', 'HP:0030358', (41, 46))	('decrease', 'NegReg', (269, 277))
503703	27671334	Defects in HR-mediated DNA repair have been shown to sensitize cells to PARP inhibition, which interferes with single stranded DNA repair mechanism.	('PARP', 'Gene', '142', (72, 76))	('Defects', 'Var', (0, 7))	('sensitize', 'Reg', (53, 62))	('PARP', 'Gene', (72, 76))	('HR-mediated DNA repair', 'Protein', (11, 33))
503706	27671334	Treatment of TNBC, NSCLC and HNSCC mesenchymal cell lines with the combination of olaparib and TP0903 resulted in a significant growth inhibition (at TP0903 concentrations of 25nM or higher) compared to treatment with the single inhibitors alone (Fig.	('NSCLC', 'Phenotype', 'HP:0030358', (19, 24))	('olaparib', 'Chemical', 'MESH:C531550', (82, 90))	('TP0903', 'Var', (95, 101))	('NSCLC', 'Disease', (19, 24))	('growth inhibition', 'CPA', (128, 145))	('TP0903', 'Chemical', 'MESH:C000606144', (95, 101))	('NSCLC', 'Disease', 'MESH:D002289', (19, 24))	('TP0903', 'Chemical', 'MESH:C000606144', (150, 156))
503711	27671334	While treatment with olaparib alone resulted in little to no difference in cell numbers compared to control, treatment with AXL inhibitor (25nM TP0903) led to a 3-5 fold decrease in cell numbers.	('olaparib', 'Chemical', 'MESH:C531550', (21, 29))	('25nM', 'Var', (139, 143))	('decrease', 'NegReg', (170, 178))	('cell numbers', 'CPA', (182, 194))	('TP0903', 'Chemical', 'MESH:C000606144', (144, 150))
503717	27671334	Similar to TP0903, the combination of R428 and olaparib was also highly synergistic, yielding a combination index of <1 in MDA-MB-157 (TNBC) and SKLU1 (NSCLC) cell lines (Fig.	('olaparib', 'Chemical', 'MESH:C531550', (47, 55))	('MDA-MB-157', 'Gene', (123, 133))	('R428', 'Chemical', '-', (38, 42))	('MDA-MB-157', 'CellLine', 'CVCL:0618', (123, 133))	('TP0903', 'Chemical', 'MESH:C000606144', (11, 17))	('R428', 'Var', (38, 42))	('NSCLC', 'Disease', (152, 157))	('SKLU1', 'CellLine', 'CVCL:0629', (145, 150))	('NSCLC', 'Disease', 'MESH:D002289', (152, 157))	('combination index', 'MPA', (96, 113))	('NSCLC', 'Phenotype', 'HP:0030358', (152, 157))
503718	27671334	We next validated if the key DNA repair/damage proteins identified by RPPA from cells treated with single-agent TP0903 (Figure 2) were also modulated by the combination treatment with TP0903 and olaparib.	('olaparib', 'Chemical', 'MESH:C531550', (195, 203))	('TP0903', 'Chemical', 'MESH:C000606144', (184, 190))	('TP0903', 'Var', (112, 118))	('modulated', 'Reg', (140, 149))	('TP0903', 'Chemical', 'MESH:C000606144', (112, 118))
503719	27671334	Western blot analysis revealed that treatment of three cell lines, MDA-MB-157 (TNBC), SKLU1 (NSCLC) and 584 (HNSCC) with AXL inhibitor alone (25, 50 and 100 nM TP0903) led to a concentration-dependent decrease in protein levels of AXL, RAD51, MRE11, E2F1 and c-Myc.	('protein levels of AXL', 'MPA', (213, 234))	('MRE11', 'Gene', (243, 248))	('NSCLC', 'Disease', (93, 98))	('MRE11', 'Gene', '4361', (243, 248))	('TP0903', 'Var', (160, 166))	('c-Myc', 'Gene', '4609', (259, 264))	('SKLU1', 'CellLine', 'CVCL:0629', (86, 91))	('NSCLC', 'Disease', 'MESH:D002289', (93, 98))	('E2F1', 'Gene', '1869', (250, 254))	('E2F1', 'Gene', (250, 254))	('c-Myc', 'Gene', (259, 264))	('MDA-MB-157', 'CellLine', 'CVCL:0618', (67, 77))	('TP0903', 'Chemical', 'MESH:C000606144', (160, 166))	('NSCLC', 'Phenotype', 'HP:0030358', (93, 98))	('decrease', 'NegReg', (201, 209))	('RAD51', 'MPA', (236, 241))
503722	27671334	Since all pharmacologic agents can have off target effects, we examined the specificity of the synergism between AXL and PARP inhibitors by interrogating whether stable knockdown of AXL (in lieu of pharmacologic inhibition) was sufficient to sensitize cells to the PARP inhibitor.	('PARP', 'Gene', '142', (265, 269))	('PARP', 'Gene', '142', (121, 125))	('sensitize', 'Reg', (242, 251))	('knockdown', 'Var', (169, 178))	('PARP', 'Gene', (265, 269))	('PARP', 'Gene', (121, 125))
503723	27671334	Similar to the AXL inhibitors, cell counting assay showed that stable AXL knockdown sensitized cells to the PARP inhibitor across all the three cancer systems (HCC1806, SKLU1 and 584 cell lines) (p<0.05) (Fig.	('PARP', 'Gene', '142', (108, 112))	('HCC1806', 'CellLine', 'CVCL:1258', (160, 167))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('knockdown', 'Var', (74, 83))	('cancer', 'Disease', (144, 150))	('PARP', 'Gene', (108, 112))	('sensitized', 'Reg', (84, 94))	('SKLU1', 'CellLine', 'CVCL:0629', (169, 174))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
503724	27671334	Moreover, stable knockdown of AXL in MDA-MB-157 and SKLU1 cells, and AXL KD in combination with PARP inhibitor (1muM olaparib) treatment diminished protein levels of RAD51, E2F1 and MRE11, similar to TP0903 treatment (Supp.	('MRE11', 'Gene', (182, 187))	('protein levels', 'MPA', (148, 162))	('TP0903', 'Chemical', 'MESH:C000606144', (200, 206))	('PARP', 'Gene', (96, 100))	('SKLU1', 'CellLine', 'CVCL:0629', (52, 57))	('E2F1', 'Gene', (173, 177))	('olaparib', 'Chemical', 'MESH:C531550', (117, 125))	('E2F1', 'Gene', '1869', (173, 177))	('diminished', 'NegReg', (137, 147))	('RAD51', 'MPA', (166, 171))	('MDA-MB-157', 'CellLine', 'CVCL:0618', (37, 47))	('knockdown', 'Var', (17, 26))	('MRE11', 'Gene', '4361', (182, 187))	('PARP', 'Gene', '142', (96, 100))
503725	27671334	We next interrogated the biological effects of AXL (25 nM TP0903) and PARP inhibitors (0.5 uM olaparib) as single agents or in combination (TP0903+olaparib), by examining apoptosis using Annexin-V staining and cell cycle analysis.	('TP0903', 'Chemical', 'MESH:C000606144', (140, 146))	('PARP', 'Gene', '142', (70, 74))	('TP0903', 'Chemical', 'MESH:C000606144', (58, 64))	('25 nM TP0903', 'Var', (52, 64))	('olaparib', 'Chemical', 'MESH:C531550', (147, 155))	('Annexin-V', 'Gene', '308', (187, 196))	('Annexin-V', 'Gene', (187, 196))	('PARP', 'Gene', (70, 74))	('olaparib', 'Chemical', 'MESH:C531550', (94, 102))
503731	27671334	To validate the increase in apoptosis and cell cycle changes seen with the combination treatment, we used cells stably knocked down for AXL and treated them with olaparib.	('AXL', 'Protein', (136, 139))	('knocked down', 'Var', (119, 131))	('apoptosis', 'CPA', (28, 37))	('olaparib', 'Chemical', 'MESH:C531550', (162, 170))	('cell cycle changes', 'CPA', (42, 60))
503739	27671334	In lung squamous cell carcinoma (LUSC), positive correlations were seen with BRCA2, RAD51, E2F1 and X53BP1, which are shown to facilitate DNA repair (Fig.	('facilitate', 'PosReg', (127, 137))	('X53BP1', 'Var', (100, 106))	('BRCA2', 'Gene', '675', (77, 82))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (8, 31))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (3, 31))	('lung squamous cell carcinoma', 'Disease', (3, 31))	('BRCA2', 'Gene', (77, 82))	('E2F1', 'Gene', '1869', (91, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('RAD51', 'Var', (84, 89))	('E2F1', 'Gene', (91, 95))	('correlations', 'Interaction', (49, 61))
503740	27671334	With HNSCC, a consistent positive association was seen with RAD51, BRCA2, MRE11 and E2F1 (Fig.	('MRE11', 'Gene', '4361', (74, 79))	('E2F1', 'Gene', '1869', (84, 88))	('E2F1', 'Gene', (84, 88))	('MRE11', 'Gene', (74, 79))	('HNSCC', 'Disease', (5, 10))	('BRCA2', 'Gene', (67, 72))	('BRCA2', 'Gene', '675', (67, 72))	('RAD51', 'Var', (60, 65))
503742	27671334	This observation that high AXL expression is associated with increased expression of DNA repair genes across multiple tumor types is consistent with our in vitro results that indicate a direct role for AXL in regulating DNA repair.	('expression', 'MPA', (71, 81))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('DNA repair genes', 'Gene', (85, 101))	('AXL expression', 'MPA', (27, 41))	('high', 'Var', (22, 26))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('increased', 'PosReg', (61, 70))	('tumor', 'Disease', (118, 123))
503746	27671334	In these studies, inhibition of AXL in the mesenchymal cancer cells re-sensitized these cells to either chemotherapy or targeted therapy.	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('AXL', 'Protein', (32, 35))	('inhibition', 'Var', (18, 28))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('cancer', 'Disease', (55, 61))
503761	27671334	It is notable that c-Myc and E2F1 are known transcription factors that promote expression of genes involved in G2/M and S-phase transitions (DNA replication and repair) such as RAD51, RAD54L, CHK1 and RPA3.	('promote', 'PosReg', (71, 78))	('CHK1', 'Gene', (192, 196))	('expression', 'MPA', (79, 89))	('E2F1', 'Gene', '1869', (29, 33))	('RPA3', 'Gene', (201, 205))	('c-Myc', 'Gene', '4609', (19, 24))	('RAD54L', 'Gene', (184, 190))	('E2F1', 'Gene', (29, 33))	('CHK1', 'Gene', '1111', (192, 196))	('RPA3', 'Gene', '6119', (201, 205))	('RAD51', 'Var', (177, 182))	('RAD54L', 'Gene', '8438', (184, 190))	('c-Myc', 'Gene', (19, 24))
503766	27671334	Collectively, this study has opened up a possibility of a novel therapeutic strategy involving inhibitors that affect two different cellular pathways to which cancer cells are addicted for survival and to mediate drug resistance.	('cancer', 'Disease', (159, 165))	('drug resistance', 'Phenotype', 'HP:0020174', (213, 228))	('inhibitors', 'Var', (95, 105))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('mediate', 'Reg', (205, 212))
503800	33892664	There are a total of 426 DELs in the NSCLC group, 312 DELs in the LUAD group, 687 DELs in the LUSC group, and 197 common DELs in three groups (Fig.	('NSCLC', 'Phenotype', 'HP:0030358', (37, 42))	('LUSC', 'Phenotype', 'HP:0030359', (94, 98))	('LUAD', 'Phenotype', 'HP:0030078', (66, 70))	('NSCLC', 'Disease', (37, 42))	('NSCLC', 'Disease', 'MESH:D002289', (37, 42))	('DELs', 'Var', (82, 86))
503805	33892664	And there were 23 EGFR mutations in the 98 patients and 24 KRAS mutations in the 68 patients.	('KRAS', 'Gene', '3845', (59, 63))	('EGFR', 'Gene', '1956', (18, 22))	('patients', 'Species', '9606', (84, 92))	('patients', 'Species', '9606', (43, 51))	('EGFR', 'Gene', (18, 22))	('mutations', 'Var', (23, 32))	('KRAS', 'Gene', (59, 63))
503816	33892664	Our result indicated that the high-risk score of our risk model was related to age, male, smoking status, AJCC stage, and EGFR mutation with a statistical difference (P < 0.05).	('mutation', 'Var', (127, 135))	('EGFR', 'Gene', '1956', (122, 126))	('EGFR', 'Gene', (122, 126))	('AJCC stage', 'Disease', (106, 116))
503843	33892664	LINC01833 was demonstrated to promote the infiltration and metastasis of LUAD by adsorbing miR-519e-3p through a sponge and regulate S100A4 expression.	('metastasis', 'CPA', (59, 69))	('LINC01833', 'Chemical', '-', (0, 9))	('promote', 'PosReg', (30, 37))	('expression', 'MPA', (140, 150))	('LUAD', 'Phenotype', 'HP:0030078', (73, 77))	('regulate', 'Reg', (124, 132))	('LUAD', 'Disease', (73, 77))	('S100A4', 'Gene', (133, 139))	('S100A4', 'Gene', '6275', (133, 139))	('LINC01833', 'Var', (0, 9))	('infiltration', 'CPA', (42, 54))	('miR-519e-3p', 'Var', (91, 102))
503859	32990596	We validate a distinctive dependency on YAP1 and WWTR1 of the Hippo pathway, where the lost-of-fitness effect of one paralog can be compensated only in a subset of lines.	('WWTR1', 'Var', (49, 54))	('fitness', 'Disease', (95, 102))	('fitness', 'Disease', 'MESH:D012640', (95, 102))	('YAP1', 'Var', (40, 44))	('Hippo pathway', 'Pathway', (62, 75))
503897	32990596	For example, drugs targeting PIK3CA and CDK6 are already in clinical trials for HNSCC treatment [NCT01816984, NCT02537223, NCT03356223, NCT03356587].	('PIK3CA', 'Gene', '5290', (29, 35))	('NCT03356587]', 'Var', (136, 148))	('HNSCC', 'Disease', (80, 85))	('NCT02537223', 'Var', (110, 121))	('CDK6', 'Gene', '1021', (40, 44))	('PIK3CA', 'Gene', (29, 35))	('CDK6', 'Gene', (40, 44))	('NCT03356223', 'Var', (123, 134))
503898	32990596	We also examined the dependency profile of 44 cancer genes with driver mutations known to be associated with HNSCC (; Figure 2B) and found that more than half of these cancer genes were dispensable for OSCC survival.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('cancer', 'Disease', (46, 52))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('associated', 'Reg', (93, 103))	('mutations', 'Var', (71, 80))	('cancer', 'Disease', (168, 174))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('HNSCC', 'Disease', (109, 114))
503899	32990596	Dependencies on mutated PIK3CA were observed in four OSCC cell lines with a hotspot mutation in E545K (BICR10), Q546R (ORL-150) and H1047R (HSC-2), and to a lesser extent, in ORL-115 with H1047L mutation.	('H1047R', 'Var', (132, 138))	('PIK3CA', 'Gene', (24, 30))	('H1047L', 'Var', (188, 194))	('BICR10', 'Chemical', '-', (103, 109))	('Q546R', 'Mutation', 'rs397517201', (112, 117))	('Q546R', 'Var', (112, 117))	('E545K', 'Mutation', 'rs104886003', (96, 101))	('H1047R', 'Mutation', 'rs121913279', (132, 138))	('E545K', 'Var', (96, 101))	('PIK3CA', 'Gene', '5290', (24, 30))	('H1047L', 'Mutation', 'rs121913279', (188, 194))
503900	32990596	Intriguingly, HSC-4, which harbors the same E545K mutation as BICR10, did not show any dependency on the mutated PIK3CA, this is consistent with findings from Project Score.	('BICR10', 'Chemical', '-', (62, 68))	('E545K', 'Mutation', 'rs104886003', (44, 49))	('PIK3CA', 'Gene', (113, 119))	('E545K', 'Var', (44, 49))	('PIK3CA', 'Gene', '5290', (113, 119))
503901	32990596	A splice site driver mutation in PTEN co-occurred in HSC-4 and may have counteracted the oncogene addiction effect on the mutated PIK3CA, as suggested previously in breast cancer.	('splice', 'Var', (2, 8))	('PIK3CA', 'Gene', (130, 136))	('breast cancer', 'Disease', 'MESH:D001943', (165, 178))	('PIK3CA', 'Gene', '5290', (130, 136))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('breast cancer', 'Disease', (165, 178))	('co-occurred', 'Reg', (38, 49))	('breast cancer', 'Phenotype', 'HP:0003002', (165, 178))	('PTEN', 'Gene', (33, 37))	('mutation', 'Var', (21, 29))	('PTEN', 'Gene', '5728', (33, 37))
503903	32990596	Oncogene addiction is observed for Ho-1-u-1 with a hotspot mutation (E82D) in NFE2L2, that has been shown to enhance its transcriptional activity and promoting cell proliferation.	('enhance', 'PosReg', (109, 116))	('NFE2L2', 'Gene', (78, 84))	('transcriptional activity', 'MPA', (121, 145))	('E82D', 'Var', (69, 73))	('promoting', 'PosReg', (150, 159))	('E82D', 'Mutation', 'p.E82D', (69, 73))	('cell proliferation', 'CPA', (160, 178))	('NFE2L2', 'Gene', '4780', (78, 84))
503904	32990596	On the other hand, BICR10 harbors an inactivating mutation on KEAP1 (R320Q) a negative regulator of NFE2L2.	('inactivating mutation', 'Var', (37, 58))	('KEAP1', 'Gene', '9817', (62, 67))	('R320Q', 'Var', (69, 74))	('NFE2L2', 'Gene', '4780', (100, 106))	('KEAP1', 'Gene', (62, 67))	('R320Q', 'Mutation', 'p.R320Q', (69, 74))	('NFE2L2', 'Gene', (100, 106))	('BICR10', 'Chemical', '-', (19, 25))
503905	32990596	The R320Q mutation has been reported to stabilize NRF2 (encoded by NFE2L2) and enhances cell fitness as reported previously in lung cancer.	('NFE2L2', 'Gene', (67, 73))	('lung cancer', 'Disease', (127, 138))	('NRF2', 'Gene', '4780', (50, 54))	('R320Q', 'Mutation', 'p.R320Q', (4, 9))	('fitness', 'Disease', 'MESH:D012640', (93, 100))	('lung cancer', 'Phenotype', 'HP:0100526', (127, 138))	('stabilize', 'Reg', (40, 49))	('NRF2', 'Gene', (50, 54))	('NFE2L2', 'Gene', '4780', (67, 73))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('lung cancer', 'Disease', 'MESH:D008175', (127, 138))	('enhances', 'PosReg', (79, 87))	('R320Q', 'Var', (4, 9))	('fitness', 'Disease', (93, 100))
503909	32990596	In this study, several Asian-derived OSCC models that were associated with betel-quid chewing were included, and we had the opportunity to determine if there are differences in genetic dependencies between these OSCC (ORL-115, ORL-136, ORL-174, ORL-195, ORL-204, ORL-207, ORL-214) (n = 7), with those that are not associated with betel quid chewing (n = 14) (Figure 2D).	('ORL-204', 'Var', (254, 261))	('ORL-174', 'Var', (236, 243))	('betel', 'Chemical', '-', (75, 80))	('ORL-207', 'Var', (263, 270))	('associated', 'Reg', (59, 69))	('betel-quid chewing', 'Disease', (75, 93))	('ORL-214', 'Var', (272, 279))	('ORL-195', 'Var', (245, 252))	('ORL-115', 'Var', (218, 225))	('betel', 'Chemical', '-', (330, 335))
503921	32990596	HNSCC belongs to the 'C class' tumor, where the landscsape of genomic alterations is dominated by copy number alterations including recurrent chromosomal gains and losses.	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('chromosomal gains', 'Var', (142, 159))	('tumor', 'Disease', (31, 36))	('HNSCC', 'Disease', (0, 5))	('losses', 'NegReg', (164, 170))	('tumor', 'Disease', 'MESH:D009369', (31, 36))
503926	32990596	There were seven lines that were highly dependent on YAP1 (ORL-48, ORL-136, ORL-156, ORL-204, ORL-207, SAS, SCC-9), four highly dependent on WWTR1 (ORL-174, ORL-188, ORL-214, PE/CA-PJ15), while the other eight were not dependent on either (Figure 3A).	('ORL-214', 'Var', (166, 173))	('ORL-188', 'Var', (157, 164))	('SAS', 'Gene', (103, 106))	('SAS', 'Gene', '6302', (103, 106))
503929	32990596	This suggests that copy number amplification of WWTR1 may constitute to a functional oncogenic role of WWTR1 in OSCC, instead of being a passenger gene that is co-amplified with the canonical HNSCC oncogene, PIK3CA.	('PIK3CA', 'Gene', '5290', (208, 214))	('OSCC', 'Disease', (112, 116))	('copy number amplification', 'Var', (19, 44))	('PIK3CA', 'Gene', (208, 214))	('WWTR1', 'Gene', (103, 108))	('WWTR1', 'Gene', (48, 53))
503930	32990596	Notably, we also observed an enrichment of PIK3CA mutations (p=0.0003) among cell lines that are neither dependent on YAP1 or WWTR1, whereby five out of six such lines have PIK3CA hotspot mutations (BICR10, HSC-2, HSC-4, ORL-115, and ORL-150) (Figure 3A).	('PIK3CA', 'Gene', '5290', (173, 179))	('PIK3CA', 'Gene', '5290', (43, 49))	('mutations', 'Var', (50, 59))	('BICR10', 'Chemical', '-', (199, 205))	('PIK3CA', 'Gene', (173, 179))	('PIK3CA', 'Gene', (43, 49))
503931	32990596	Intriguingly, mutually exclusive copy number gains of chromosome 3q and 11q22 (where YAP1 is mapped to) have been reported in squamous cell carcinoma and consistently, YAP1 and WWTR1 amplification were also found to be mutually exclusive in HNSCC.	('HNSCC', 'Disease', (241, 246))	('copy number', 'Var', (33, 44))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (126, 149))	('gains', 'PosReg', (45, 50))	('squamous cell carcinoma', 'Disease', (126, 149))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (126, 149))
503937	32990596	On the other hand, the fraction of transduced cells in BICR10 and HSC-2 did not show any prominent changes upon knockout of either YAP1 or WWTR1.	('knockout', 'Var', (112, 120))	('YAP1', 'Gene', (131, 135))	('BICR10', 'Chemical', '-', (55, 61))
503940	32990596	Consistent with their known pro-survival properties, more substantial reduction of CTGF and CYR61 gene expression were seen only when the respective upstream fitness genes were knocked-out, as measured by qPCR (Figure 3D and Figure 3:figure supplement 4F).	('reduction', 'NegReg', (70, 79))	('CTGF', 'Gene', (83, 87))	('expression', 'MPA', (103, 113))	('CYR61', 'Gene', (92, 97))	('CYR61', 'Gene', '3491', (92, 97))	('fitness', 'Disease', (158, 165))	('knocked-out', 'Var', (177, 188))	('fitness', 'Disease', 'MESH:D012640', (158, 165))	('CTGF', 'Gene', '1490', (83, 87))
503941	32990596	Consistently, YAP1 depletion in ORL-48 resulted in significant reduction in viable cells, to a level comparable to the depletion of PLK1 (Figure 4A), and this was reflected in the increase in apoptotic cells (Figure 4B).	('PLK1', 'Gene', (132, 136))	('depletion', 'Var', (19, 28))	('apoptotic cells', 'CPA', (192, 207))	('YAP1', 'Gene', (14, 18))	('increase', 'PosReg', (180, 188))	('PLK1', 'Gene', '5347', (132, 136))	('viable cells', 'CPA', (76, 88))	('reduction', 'NegReg', (63, 72))
503945	32990596	To confirm our hypothesis, we knocked-out both YAP1 and WWTR1 simultaneously by co-transducing the cell lines with lentivirus carrying blue fluorescence protein (BFP)-tagged YAP1 sgRNA and mCherry-tagged WWTR1 sgRNA (Figure 5A).	('mul', 'Gene', '4591', (64, 67))	('mul', 'Gene', (64, 67))	('BFP', 'Gene', (162, 165))	('BFP', 'Gene', '7732', (162, 165))	('knocked-out', 'Var', (30, 41))
503946	32990596	The co-competition assays showed that the population of BICR10 and HSC-2 with the double knockout of both YAP1 and WWTR1 depleted drastically (Figure 5B) compared to when each gene was knocked-out individually (Figure 3C).	('YAP1', 'Gene', (106, 110))	('WWTR1', 'Gene', (115, 120))	('BICR10', 'Chemical', '-', (56, 62))	('double knockout', 'Var', (82, 97))	('depleted', 'NegReg', (121, 129))
503958	32990596	Notably, all three YAP1/WWTR1 compensable cell lines (BICR10, HSC-2 and HSC-4) harbor PIK3CA mutation, and that alterations in the PI3K signaling pathway have been linked to multiple metabolic dysregulations in cancer.	('harbor', 'Reg', (79, 85))	('mul', 'Gene', (174, 177))	('cancer', 'Disease', 'MESH:D009369', (211, 217))	('cancer', 'Disease', (211, 217))	('PIK3CA', 'Gene', (86, 92))	('mul', 'Gene', '4591', (174, 177))	('PI3K signaling pathway', 'Pathway', (131, 153))	('alterations', 'Reg', (112, 123))	('BICR10', 'Chemical', '-', (54, 60))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('PIK3CA', 'Gene', '5290', (86, 92))	('mutation', 'Var', (93, 101))	('linked', 'Reg', (164, 170))
503959	32990596	Specifically, WWTR1 but not YAP1 was shown to be essential for TH17 cell differentiation, and constitutively active WWTR1 (TAZ-S89A) was shown to induce PD-L1 expression to a much greater extent than YAP1 (YAP1-S127A).	('PD-L1', 'Gene', (153, 158))	('S127A', 'Mutation', 'rs762471803', (211, 216))	('PD-L1', 'Gene', '29126', (153, 158))	('expression', 'MPA', (159, 169))	('WWTR1', 'Var', (116, 121))	('induce', 'PosReg', (146, 152))	('S89A', 'Mutation', 'p.S89A', (127, 131))
503960	32990596	Using the stromal and immune signature defined previously, ssGSEA enrichment scores revealed that OSCC with high WWTR1 dependency signature score showed significantly lower stromal signature, but higher immune signature, when compared with OSCC of high YAP1 dependency or Compensable signature scores (Figure 6D).	('lower', 'NegReg', (167, 172))	('stromal signature', 'MPA', (173, 190))	('immune signature', 'MPA', (203, 219))	('higher', 'PosReg', (196, 202))	('WWTR1', 'Gene', (113, 118))	('GSEA', 'Chemical', '-', (61, 65))	('high', 'Var', (108, 112))
503967	32990596	qPCR results revealed strongest suppression of PD-L1 gene expression upon WWTR1 knockout, but remain largely unchanged when the other genes were knockout (PIK3CA, TP63, and SOX2) (Figure 6:figure supplement 3A).	('knockout', 'Var', (80, 88))	('TP63', 'Gene', (163, 167))	('TP63', 'Gene', '8626', (163, 167))	('PD-L1', 'Gene', (47, 52))	('expression', 'MPA', (58, 68))	('WWTR1', 'Gene', (74, 79))	('suppression', 'NegReg', (32, 43))	('SOX2', 'Gene', (173, 177))	('PIK3CA', 'Gene', (155, 161))	('SOX2', 'Gene', '6657', (173, 177))	('PD-L1', 'Gene', '29126', (47, 52))	('PIK3CA', 'Gene', '5290', (155, 161))
503969	32990596	However, genomics studies have shown that oncogenic mutations in OSCC are largely limited to PIK3CA and HRAS and even in these, mutations are only found in a small subset of patients.	('mutations', 'Var', (52, 61))	('PIK3CA', 'Gene', '5290', (93, 99))	('HRAS', 'Gene', (104, 108))	('patients', 'Species', '9606', (174, 182))	('PIK3CA', 'Gene', (93, 99))	('HRAS', 'Gene', '3265', (104, 108))	('OSCC', 'Gene', (65, 69))
503971	32990596	Adding to existing genomics datasets in OSCC, this approach identifies fitness genes required for the survival of cancer cells where targeting these will result in the killing of these cells.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('fitness', 'Disease', (71, 78))	('targeting', 'Var', (133, 142))	('fitness', 'Disease', 'MESH:D012640', (71, 78))	('result in', 'Reg', (154, 163))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('killing', 'CPA', (168, 175))	('cancer', 'Disease', (114, 120))
503984	32990596	However, upon analysing the dependency profiles on cancer genes that are commonly mutated in HNSCC and those with driver mutations among our 21 OSCC cell lines, we show that with the exception of some genes with driver mutations leading to oncogene addiction (PIK3CA, HRAS and NFE2L2), most other driver mutations did not confer preferential gene dependency and their value as a drug target remains unclear.	('HRAS', 'Gene', '3265', (268, 272))	('PIK3CA', 'Gene', (260, 266))	('NFE2L2', 'Gene', (277, 283))	('oncogene addiction', 'Disease', (240, 258))	('PIK3CA', 'Gene', '5290', (260, 266))	('HRAS', 'Gene', (268, 272))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('leading to', 'Reg', (229, 239))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('mutations', 'Var', (219, 228))	('cancer', 'Disease', (51, 57))	('NFE2L2', 'Gene', '4780', (277, 283))
503985	32990596	Given the propensity of copy number alterations in driving OSCC, a 'C' class tumor, we investigated the commonly amplified genomic regions to look for functionally important candidate genes.	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('copy number alterations', 'Var', (24, 47))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('driving OSCC', 'Disease', (51, 63))	('tumor', 'Disease', (77, 82))
503988	32990596	Using a tongue orthotopic mouse model with the deletion of MOB1A/B, provided strong evidence that YAP1 acted as a strong driver in OSCC tumor initiation and progression, whereby WWTR1 did not seems to play an equivalent role.	('YAP1', 'Gene', (98, 102))	('MOB1A/B', 'Gene', (59, 66))	('OSCC tumor initiation', 'Disease', (131, 152))	('OSCC tumor initiation', 'Disease', 'MESH:D009369', (131, 152))	('progression', 'CPA', (157, 168))	('deletion', 'Var', (47, 55))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('MOB1A/B', 'Gene', '232157', (59, 66))	('mouse', 'Species', '10090', (26, 31))
503990	32990596	The co-occurrence of amplifications in these genes that are part of the extended signaling network of the Hippo pathway underscores the critical role of the Hippo pathway in driving the OSCC tumorigenesis.	('OSCC', 'Disease', (186, 190))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('amplifications', 'Var', (21, 35))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('tumor', 'Disease', (191, 196))
503993	32990596	Intriguingly, while WWTR1 knockdown led to reduction of SOX2 mRNA and protein expression, this was not seen when YAP1 was knockdown in the HNSCC cells (Cal27 and Fadu).	('reduction', 'NegReg', (43, 52))	('SOX2', 'Gene', (56, 60))	('knockdown', 'Var', (26, 35))	('SOX2', 'Gene', '6657', (56, 60))
503999	32990596	Intriguingly, we also observed enrichment of PIK3CA mutant (p=0.0003) among OSCC lines that are compensable for YAP1 or WWTR1.	('PIK3CA', 'Gene', (45, 51))	('PIK3CA', 'Gene', '5290', (45, 51))	('mutant', 'Var', (52, 58))
504000	32990596	As recent studies have provided evidence that YAP1 and WWTR1 could mediate mutant PIK3CA-induced tumorigenesis andother studies also suggested crosstalk between these Hippo pathway effectors with the PI3K-Akt pathway, confirmatory and mechanistic studies will be needed to delineate why YAP1 and WWTR1 function can be compensated in these PIK3CA-mutated cell lines, while distinct dependencies on either paralog are observed in PIK3CA wild-type lines.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('Akt', 'Gene', '207', (205, 208))	('PIK3CA', 'Gene', (82, 88))	('PIK3CA', 'Gene', (339, 345))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('Akt', 'Gene', (205, 208))	('tumor', 'Disease', (97, 102))	('PIK3CA', 'Gene', '5290', (82, 88))	('PIK3CA', 'Gene', '5290', (339, 345))	('mutant', 'Var', (75, 81))	('PIK3CA', 'Gene', (428, 434))	('PIK3CA', 'Gene', '5290', (428, 434))
504001	32990596	The functional loss of mutated FAT1 has also been reported to be associated with YAP1 activation in head and neck cancer, however, no enrichment of FAT1 mutation was seen among the YAP1-dependent nor WWTR1-dependent models in this study.	('YAP1', 'Gene', (81, 85))	('FAT1', 'Gene', (31, 35))	('FAT1', 'Gene', (148, 152))	('head and neck cancer', 'Phenotype', 'HP:0012288', (100, 120))	('FAT1', 'Gene', '2195', (31, 35))	('loss', 'NegReg', (15, 19))	('mutated', 'Var', (23, 30))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('head and neck cancer', 'Disease', 'MESH:D006258', (100, 120))	('activation', 'PosReg', (86, 96))	('FAT1', 'Gene', '2195', (148, 152))
504007	32990596	This finding is consistent with the recent discovery that constitutively active WWTR1 induces PD-L1 expression, to a greater extent than YAP1, and that tumors with YAP1 amplifications have low T-cell infiltration.	('PD-L1', 'Gene', (94, 99))	('induces', 'PosReg', (86, 93))	('tumors', 'Disease', 'MESH:D009369', (152, 158))	('WWTR1', 'Gene', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('PD-L1', 'Gene', '29126', (94, 99))	('expression', 'MPA', (100, 110))	('amplifications', 'Var', (169, 183))	('low', 'NegReg', (189, 192))	('tumors', 'Disease', (152, 158))	('low T-cell', 'Phenotype', 'HP:0005403', (189, 199))	('tumors', 'Phenotype', 'HP:0002664', (152, 158))
504009	32990596	We acknowledge, however, that whilst the dependency observed in cell lines could be recapitulated in OSCC, OSCC tissues would be much more heterogenous and could harbor specific genetic abrogations that could be the dominant driver of tumorigenesis.	('OSCC', 'Disease', (101, 105))	('OSCC', 'Disease', (107, 111))	('tumor', 'Disease', 'MESH:D009369', (235, 240))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('tumor', 'Disease', (235, 240))	('abrogations', 'Var', (186, 197))
504011	32990596	The inactivation of the Hippo pathway through the loss of LATS1/2 was reported to cause the induction of anti-tumor immune response and inhibition of HNSCC tumor growth, via the hyperactivation of YAP1/WWTR1.	('induction', 'PosReg', (92, 101))	('LATS1/2', 'Gene', '9113;26524', (58, 65))	('tumor', 'Disease', 'MESH:D009369', (110, 115))	('HNSCC tumor', 'Disease', 'MESH:D000077195', (150, 161))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('HNSCC tumor', 'Disease', (150, 161))	('loss', 'Var', (50, 54))	('LATS1/2', 'Gene', (58, 65))	('inhibition', 'NegReg', (136, 146))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('Hippo pathway', 'Pathway', (24, 37))	('tumor', 'Disease', (156, 161))	('hyperactivation', 'PosReg', (178, 193))	('inactivation', 'NegReg', (4, 16))
504054	32990596	OSCC models with known betel quid chewing as the only risk habit were included in this analysis - (n = 7; ORL-115, ORL-136, ORL-174, ORL-195, ORL-204, ORL-207 and ORL-214), to compare with the other OSCCs not associated with betel quid chewing (n = 14; ORL-48, ORL-150, ORL-153, ORL-156, ORL-166, ORL-188, ORL-215, BICR10, Ho-1-u-1, HSC-2, HSC-4, SAS, SCC-9, PE/CA-PJ15).	('SAS', 'Gene', (347, 350))	('ORL-215', 'Var', (306, 313))	('betel', 'Chemical', '-', (23, 28))	('SAS', 'Gene', '6302', (347, 350))	('BICR10', 'Chemical', '-', (315, 321))	('betel', 'Chemical', '-', (225, 230))
504060	32990596	Following that, overnight ligation at 4 C was carried out using T4 ligase (NEB M0202S) and 10X ligase buffer (NEB M0202S).	('M0202S', 'Mutation', 'p.M0202S', (79, 85))	('T4 ligase', 'Protein', (64, 73))	('M0202S', 'Mutation', 'p.M0202S', (114, 120))	('M0202S', 'Var', (79, 85))
504113	32990596	(6) Besides papers cited by the authors, work relevant to the topic of this study includes Omori et al., 2020, for YAP1 as a driver, Saloura et al., 2019, showing YAP1 mutation is associated with a low CD8+ T cell inflamed phenotype, Martin et al., 2018, dissecting the Hippo pathway and demonstrating the targetability of YAP1 in head and neck cancer in a detailed Nat Comm paper, and an extensive review of the pathway at the end of 2019 by Santos-de-Frutos and colleagues.	('head and neck cancer', 'Disease', 'MESH:D006258', (331, 351))	('cancer', 'Phenotype', 'HP:0002664', (345, 351))	('CD8', 'Gene', (202, 205))	('CD8', 'Gene', '925', (202, 205))	('low CD8+ T cell', 'Phenotype', 'HP:0005415', (198, 213))	('mutation', 'Var', (168, 176))	('YAP1', 'Gene', (163, 167))	('head and neck cancer', 'Phenotype', 'HP:0012288', (331, 351))
504139	32990596	We agree that it would be important to show that the correlation between WWTR1-dependency gene signatures with the immune signatures are indeed specific to WWTR1, and not due to other co-amplified genes such as PIK3CA, TP63 and SOX2.	('PIK3CA', 'Gene', (211, 217))	('PIK3CA', 'Gene', '5290', (211, 217))	('SOX2', 'Gene', (228, 232))	('WWTR1', 'Var', (156, 161))	('SOX2', 'Gene', '6657', (228, 232))	('TP63', 'Gene', (219, 223))	('TP63', 'Gene', '8626', (219, 223))
504145	32990596	6) Besides papers cited by the authors, work relevant to the topic of this study includes Omori et al., 2020, for YAP1 as a driver, Saloura et al., 2019, showing YAP1 mutation is associated with a low CD8+ T cell inflamed phenotype, Martin et al., 2018, dissecting the Hippo pathway and demonstrating the targetability of YAP1 in head and neck cancer in a detailed Nat Comm paper, and an extensive review of the pathway at the end of 2019 by Santos-de-Frutos and colleagues.	('head and neck cancer', 'Phenotype', 'HP:0012288', (330, 350))	('mutation', 'Var', (167, 175))	('YAP1', 'Gene', (162, 166))	('cancer', 'Phenotype', 'HP:0002664', (344, 350))	('low CD8+ T cell', 'Phenotype', 'HP:0005415', (197, 212))	('CD8', 'Gene', (201, 204))	('CD8', 'Gene', '925', (201, 204))	('head and neck cancer', 'Disease', 'MESH:D006258', (330, 350))
504149	31991610	Novel Genetic Variants of ALG6 and GALNTL4 of the Glycosylation Pathway Predict Cutaneous Melanoma-Specific Survival Because aberrant glycosylation is known to play a role in the progression of melanoma, we hypothesize that genetic variants of glycosylation pathway genes are associated with the survival of cutaneous melanoma (CM) patients.	('CM', 'Phenotype', 'HP:0012056', (328, 330))	('melanoma', 'Phenotype', 'HP:0002861', (318, 326))	('melanoma', 'Disease', (318, 326))	('patients', 'Species', '9606', (332, 340))	('aberrant glycosylation', 'Phenotype', 'HP:0012345', (125, 147))	('CM', 'Disease', 'MESH:C562393', (328, 330))	('Variants', 'Var', (14, 22))	('Melanoma', 'Phenotype', 'HP:0002861', (90, 98))	('melanoma', 'Disease', 'MESH:D008545', (194, 202))	('GALNTL4', 'Gene', (35, 42))	('cutaneous melanoma', 'Disease', (308, 326))	('associated', 'Reg', (276, 286))	('ALG6', 'Gene', (26, 30))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (308, 326))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (308, 326))	('variants', 'Var', (232, 240))	('melanoma', 'Disease', 'MESH:D008545', (318, 326))	('ALG6', 'Gene', '29929', (26, 30))	('GALNTL4', 'Gene', '374378', (35, 42))	('melanoma', 'Phenotype', 'HP:0002861', (194, 202))	('melanoma', 'Disease', (194, 202))	('Cutaneous Melanoma-Specific Survival', 'Disease', 'MESH:C562393', (80, 116))	('Cutaneous Melanoma-Specific Survival', 'Disease', (80, 116))	('Cutaneous Melanoma', 'Phenotype', 'HP:0012056', (80, 98))
504150	31991610	To test this hypothesis, we used a Cox proportional hazards regression model in a single-locus analysis to evaluate associations between 34,096 genetic variants of 227 glycosylation pathway genes and CM disease-specific survival (CMSS) using genotyping data from two previously published genome-wide association studies.	('glycosylation', 'Gene', (168, 181))	('CM', 'Disease', 'MESH:C562393', (200, 202))	('CM', 'Phenotype', 'HP:0012056', (230, 232))	('variants', 'Var', (152, 160))	('CM', 'Phenotype', 'HP:0012056', (200, 202))	('associations', 'Interaction', (116, 128))	('CM', 'Disease', 'MESH:C562393', (230, 232))
504152	31991610	In the multivariable Cox regression analysis, we found that two novel single-nucleotide polymorphisms (SNPs) (ALG6 rs10889417 G>A and GALNTL4 rs12270446 G>C) predicted CMSS, with an adjusted hazards ratios of 0.60 (95% confidence interval = 0.44-0.83 and p = 0.002) and 0.66 (0.52-0.84 and 0.004), respectively.	('predicted', 'Reg', (158, 167))	('ALG6', 'Gene', (110, 114))	('GALNTL4', 'Gene', (134, 141))	('rs12270446', 'Mutation', 'rs12270446', (142, 152))	('CM', 'Phenotype', 'HP:0012056', (168, 170))	('N', 'Chemical', 'MESH:D009584', (137, 138))	('rs10889417 G>A', 'Var', (115, 129))	('rs10889417', 'Mutation', 'rs10889417', (115, 125))	('rs12270446 G>C', 'Var', (142, 156))	('GALNTL4', 'Gene', '374378', (134, 141))	('N', 'Chemical', 'MESH:D009584', (104, 105))	('CM', 'Disease', 'MESH:C562393', (168, 170))	('ALG6', 'Gene', '29929', (110, 114))
504153	31991610	Subsequent expression quantitative trait loci (eQTL) analysis revealed that ALG6 rs10889417 was associated with mRNA expression levels in the cultured skin fibroblasts and whole blood cells and that GALNTL4 rs12270446 was associated with mRNA expression levels in the skin tissues (all p < 0.05).	('N', 'Chemical', 'MESH:D009584', (114, 115))	('rs12270446', 'Mutation', 'rs12270446', (207, 217))	('ALG6', 'Gene', '29929', (76, 80))	('mRNA expression levels', 'MPA', (112, 134))	('associated', 'Reg', (96, 106))	('rs12270446', 'Var', (207, 217))	('GALNTL4', 'Gene', '374378', (199, 206))	('N', 'Chemical', 'MESH:D009584', (240, 241))	('ALG6', 'Gene', (76, 80))	('GALNTL4', 'Gene', (199, 206))	('rs10889417', 'Var', (81, 91))	('N', 'Chemical', 'MESH:D009584', (202, 203))	('mRNA expression levels', 'MPA', (238, 260))	('rs10889417', 'Mutation', 'rs10889417', (81, 91))
504154	31991610	Our findings suggest that, once validated by other large patient cohorts, these two novel SNPs in the glycosylation pathway genes may be useful prognostic biomarkers for CMSS, likely through modulating their gene expression.	('patient', 'Species', '9606', (57, 64))	('N', 'Chemical', 'MESH:D009584', (91, 92))	('glycosylation', 'Pathway', (102, 115))	('CM', 'Disease', 'MESH:C562393', (170, 172))	('modulating', 'Reg', (191, 201))	('CM', 'Phenotype', 'HP:0012056', (170, 172))	('SNPs', 'Var', (90, 94))
504158	31991610	Single-nucleotide polymorphisms (SNPs) are the common form of genetic variants that may affect gene expression and functions, likely leading to the development and progression of CM.	('gene expression', 'MPA', (95, 110))	('functions', 'MPA', (115, 124))	('affect', 'Reg', (88, 94))	('CM', 'Phenotype', 'HP:0012056', (179, 181))	('Single-nucleotide polymorphisms', 'Var', (0, 31))	('N', 'Chemical', 'MESH:D009584', (34, 35))	('leading to', 'Reg', (133, 143))	('CM', 'Disease', 'MESH:C562393', (179, 181))
504168	31991610	Thus, aberrant glycosylation and modification may affect the proliferation, apoptosis, invasion, metastasis, drug resistance, and immune escape of tumor cells.	('modification', 'Var', (33, 45))	('tumor', 'Disease', (147, 152))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('aberrant glycosylation', 'Phenotype', 'HP:0012345', (6, 28))	('aberrant', 'Var', (6, 14))	('metastasis', 'CPA', (97, 107))	('affect', 'Reg', (50, 56))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('invasion', 'CPA', (87, 95))	('drug resistance', 'CPA', (109, 124))	('apoptosis', 'CPA', (76, 85))	('drug resistance', 'Phenotype', 'HP:0020174', (109, 124))	('glycosylation', 'MPA', (15, 28))
504170	31991610	Since glycosylation may play an important role in the progression and metastasis of melanoma, we hypothesize that genetic variants of glycosylation pathway genes are associated with survival in CM patients.	('CM', 'Phenotype', 'HP:0012056', (194, 196))	('metastasis of melanoma', 'Disease', 'MESH:D009362', (70, 92))	('patients', 'Species', '9606', (197, 205))	('melanoma', 'Phenotype', 'HP:0002861', (84, 92))	('metastasis of melanoma', 'Disease', (70, 92))	('CM', 'Disease', 'MESH:C562393', (194, 196))	('associated with', 'Reg', (166, 181))	('genetic variants', 'Var', (114, 130))
504178	31991610	We first performed a single-locus analysis for associations of 4,770 genotyped and 29,326 imputed SNPs in the 227 glycosylation pathway genes with CMSS.	('CM', 'Disease', 'MESH:C562393', (147, 149))	('N', 'Chemical', 'MESH:D009584', (99, 100))	('SNPs', 'Var', (98, 102))	('227 glycosylation pathway', 'Pathway', (110, 135))	('CM', 'Phenotype', 'HP:0012056', (147, 149))	('associations', 'Interaction', (47, 59))
504179	31991610	We found that 1,564 SNPs were associated with CMSS (p < 0.05) in an additive genetic model.	('associated', 'Reg', (30, 40))	('SNPs', 'Var', (20, 24))	('CM', 'Disease', 'MESH:C562393', (46, 48))	('N', 'Chemical', 'MESH:D009584', (21, 22))	('CM', 'Phenotype', 'HP:0012056', (46, 48))
504180	31991610	After multiple test correction by Bayesian false discovery probability (BFDP) < 0.8, 1362 SNPs remained noteworthy; after subsequent replication in the NHS/HPFS dataset, 11 SNPs in five genes remained significantly associated with CMSS.	('CM', 'Phenotype', 'HP:0012056', (231, 233))	('BFDP', 'Chemical', '-', (72, 76))	('SNPs', 'Var', (173, 177))	('N', 'Chemical', 'MESH:D009584', (152, 153))	('N', 'Chemical', 'MESH:D009584', (91, 92))	('N', 'Chemical', 'MESH:D009584', (174, 175))	('CM', 'Disease', 'MESH:C562393', (231, 233))	('associated', 'Reg', (215, 225))
504183	31991610	We found that five SNPs (rs10889417, rs672748, rs13297246, rs12270446 and rs7287710) in five genes (ALG6; GALNT10 polypeptide N-acetylgalactosaminyltransferase 10; B4GALT1 beta-1,4-galactosyltransferase 1; GALNTL4; and LARGE LARGE xylosyl- and glucuronyltransferase 1) remained significantly associated with CMSS (p < 0.05).	('N', 'Chemical', 'MESH:D009584', (109, 110))	('rs10889417', 'Mutation', 'rs10889417', (25, 35))	('N', 'Chemical', 'MESH:D009584', (20, 21))	('B4GALT1', 'Gene', (164, 171))	('rs7287710', 'Var', (74, 83))	('GALNT10', 'Gene', '55568', (106, 113))	('GALNTL4', 'Gene', '374378', (206, 213))	('rs10889417', 'Var', (25, 35))	('associated', 'Reg', (292, 302))	('N', 'Chemical', 'MESH:D009584', (209, 210))	('rs672748', 'Mutation', 'rs672748', (37, 45))	('CM', 'Phenotype', 'HP:0012056', (308, 310))	('rs7287710', 'Mutation', 'rs7287710', (74, 83))	('rs12270446', 'Var', (59, 69))	('rs13297246', 'Var', (47, 57))	('rs672748', 'Var', (37, 45))	('CM', 'Disease', 'MESH:C562393', (308, 310))	('ALG6', 'Gene', (100, 104))	('GALNT10', 'Gene', (106, 113))	('N', 'Chemical', 'MESH:D009584', (126, 127))	('GALNTL4', 'Gene', (206, 213))	('rs12270446', 'Mutation', 'rs12270446', (59, 69))	('rs13297246', 'Mutation', 'rs13297246', (47, 57))	('ALG6', 'Gene', '29929', (100, 104))
504184	31991610	Then, we expanded the model by further including 40 previously reported significant survival-associated SNPs from the MDACC GWAS dataset; two of the newly identified SNPs (ALG6 rs10889417 and GALNTL4 rs12270446) remained independent and significantly associated with CMSS (Table 2).	('ALG6', 'Gene', '29929', (172, 176))	('ALG6', 'Gene', (172, 176))	('N', 'Chemical', 'MESH:D009584', (167, 168))	('rs12270446', 'Var', (200, 210))	('GALNTL4', 'Gene', (192, 199))	('associated', 'Reg', (251, 261))	('N', 'Chemical', 'MESH:D009584', (105, 106))	('CM', 'Phenotype', 'HP:0012056', (267, 269))	('N', 'Chemical', 'MESH:D009584', (195, 196))	('CM', 'Disease', 'MESH:C562393', (267, 269))	('GALNTL4', 'Gene', '374378', (192, 199))	('rs10889417', 'Var', (177, 187))	('rs10889417', 'Mutation', 'rs10889417', (177, 187))	('rs12270446', 'Mutation', 'rs12270446', (200, 210))
504185	31991610	Specifically, we observed a significant protective effect of the ALG6 rs10889417 A allele (Ptrend = 0.023) and the GALNTL4 rs12270446 C allele (Ptrend = 0.015) on CMSS.	('ALG6', 'Gene', (65, 69))	('rs12270446 C', 'Var', (123, 135))	('CM', 'Disease', 'MESH:C562393', (163, 165))	('rs12270446', 'Mutation', 'rs12270446', (123, 133))	('rs10889417 A', 'Var', (70, 82))	('GALNTL4', 'Gene', '374378', (115, 122))	('rs10889417', 'Mutation', 'rs10889417', (70, 80))	('CM', 'Phenotype', 'HP:0012056', (163, 165))	('ALG6', 'Gene', '29929', (65, 69))	('GALNTL4', 'Gene', (115, 122))
504187	31991610	Kaplan-Meier survival curves were plotted to visually show the associations between CMSS and the genotypes of ALG6 rs10889417 and GALNTL4 rs12270446, respectively (Figure 2 a-f).	('GALNTL4', 'Gene', (130, 137))	('ALG6', 'Gene', (110, 114))	('associations', 'Interaction', (63, 75))	('rs12270446', 'Var', (138, 148))	('CM', 'Disease', 'MESH:C562393', (84, 86))	('rs10889417', 'Var', (115, 125))	('GALNTL4', 'Gene', '374378', (130, 137))	('rs10889417', 'Mutation', 'rs10889417', (115, 125))	('CM', 'Phenotype', 'HP:0012056', (84, 86))	('rs12270446', 'Mutation', 'rs12270446', (138, 148))	('ALG6', 'Gene', '29929', (110, 114))
504192	31991610	To substantiate the associations between the genotypes of the two independent SNPs and CMSS, we combined the protective genotypes of ALG6 rs10889417 GA+AA and GALNTL4 rs12270446 GC+CC into one variable.	('rs12270446', 'Mutation', 'rs12270446', (167, 177))	('GALNTL4', 'Gene', '374378', (159, 166))	('rs10889417 GA+AA', 'Var', (138, 154))	('CM', 'Disease', 'MESH:C562393', (87, 89))	('N', 'Chemical', 'MESH:D009584', (79, 80))	('CM', 'Phenotype', 'HP:0012056', (87, 89))	('rs12270446 GC+CC', 'Var', (167, 183))	('ALG6', 'Gene', '29929', (133, 137))	('rs10889417', 'Mutation', 'rs10889417', (138, 148))	('GALNTL4', 'Gene', (159, 166))	('ALG6', 'Gene', (133, 137))	('N', 'Chemical', 'MESH:D009584', (162, 163))
504200	31991610	Compared with those with 0 NPG, patients with 1-2 NPG had a significantly better survival, particularly evident in the subgroups aged >60 years, female, regional/distant metastasis, Breslow thickness >1 mm, no ulceration, and mitotic rate >1 in the MDACC dataset and the subgroup aged >60 years in the NHS/HPFS dataset.	('regional/distant metastasis', 'CPA', (153, 180))	('better', 'PosReg', (74, 80))	('patients', 'Species', '9606', (32, 40))	('N', 'Chemical', 'MESH:D009584', (50, 51))	('Breslow', 'Var', (182, 189))	('mitotic rate', 'CPA', (226, 238))	('survival', 'MPA', (81, 89))	('N', 'Chemical', 'MESH:D009584', (302, 303))	('N', 'Chemical', 'MESH:D009584', (27, 28))
504204	31991610	With the online tools for predicting putative functions of genetic variants, we found that the rs10889417 A allele was significantly associated with increased expression levels of ALG6 mRNA in cultured skin fibroblasts (p = 0.015, Figure 2j) and whole blood cells (p = 0.001, Figure 2j).	('N', 'Chemical', 'MESH:D009584', (187, 188))	('ALG6', 'Gene', '29929', (180, 184))	('increased', 'PosReg', (149, 158))	('expression levels', 'MPA', (159, 176))	('ALG6', 'Gene', (180, 184))	('rs10889417 A', 'Var', (95, 107))	('rs10889417', 'Mutation', 'rs10889417', (95, 105))
504205	31991610	Besides, the GALNTL4 rs12270446 C allele was correlated with lower mRNA expression levels in normal tissue samples from 517 donors' suprapubic skin and 605 donors' sun-exposed lower leg skin from the genotype-tissue expression (GTEx) project (all p < 0.05, Figure 2k).	('mRNA expression levels', 'MPA', (67, 89))	('GALNTL4', 'Gene', '374378', (13, 20))	('lower', 'NegReg', (61, 66))	('lower leg', 'Phenotype', 'HP:0006385', (176, 185))	('N', 'Chemical', 'MESH:D009584', (16, 17))	('rs12270446 C', 'Var', (21, 33))	('GALNTL4', 'Gene', (13, 20))	('rs12270446', 'Mutation', 'rs12270446', (21, 31))	('N', 'Chemical', 'MESH:D009584', (69, 70))
504208	31991610	Based on experimental data from the ENCODE project available for the 227 glycosylation pathway genes (Table S5), the rs10889417 is located on the Pitx2 motif (Figure S6).	('Pitx2', 'Gene', '5308', (146, 151))	('N', 'Chemical', 'MESH:D009584', (37, 38))	('rs10889417', 'Var', (117, 127))	('rs10889417', 'Mutation', 'rs10889417', (117, 127))	('Pitx2', 'Gene', (146, 151))
504218	31991610	Considering that there are few mutations in these two genes, our results indicated that the functional SNPs in ALG6 may play relatively important roles in the dysregulated mRNA expression in tumor tissues, and the mutation may also play a role in the functional change and expression of GALNTL4 in addition to the causal SNPs.	('ALG6', 'Gene', '29929', (111, 115))	('mutation', 'Var', (214, 222))	('dysregulated mRNA expression in', 'MPA', (159, 190))	('N', 'Chemical', 'MESH:D009584', (322, 323))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('N', 'Chemical', 'MESH:D009584', (290, 291))	('GALNTL4', 'Gene', (287, 294))	('ALG6', 'Gene', (111, 115))	('functional', 'MPA', (251, 261))	('play', 'Reg', (232, 236))	('N', 'Chemical', 'MESH:D009584', (174, 175))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('tumor', 'Disease', (191, 196))	('SNPs', 'Var', (103, 107))	('N', 'Chemical', 'MESH:D009584', (104, 105))	('GALNTL4', 'Gene', '374378', (287, 294))	('expression', 'MPA', (273, 283))
504220	31991610	We found that two SNPs (i.e., ALG6 rs10889417G>A and GALNTL4 rs12270446G>C) were independently associated with the survival of CM patients.	('rs10889417G>A', 'Var', (35, 48))	('N', 'Chemical', 'MESH:D009584', (19, 20))	('rs10889417G>A', 'DBSNP_MENTION', 'None', (35, 48))	('CM', 'Phenotype', 'HP:0012056', (127, 129))	('GALNTL4', 'Gene', '374378', (53, 60))	('patients', 'Species', '9606', (130, 138))	('CM', 'Disease', 'MESH:C562393', (127, 129))	('ALG6', 'Gene', '29929', (30, 34))	('rs12270446G>C', 'Var', (61, 74))	('rs12270446G>C', 'DBSNP_MENTION', 'None', (61, 74))	('associated with', 'Reg', (95, 110))	('N', 'Chemical', 'MESH:D009584', (56, 57))	('GALNTL4', 'Gene', (53, 60))	('ALG6', 'Gene', (30, 34))
504221	31991610	In subsequent genotype-mRNA expression correlation analysis, we found that the low death-risk-associated rs10889417 A allele was associated with increase in ALG6 mRNA expression levels in cultured skin fibroblasts and whole blood cells and that the rs12270446 G allele was associated with decrease in GALNTL4 mRNA expression levels in skin tissues.	('N', 'Chemical', 'MESH:D009584', (304, 305))	('rs10889417', 'Mutation', 'rs10889417', (105, 115))	('ALG6', 'Gene', '29929', (157, 161))	('rs12270446', 'Mutation', 'rs12270446', (249, 259))	('increase', 'PosReg', (145, 153))	('N', 'Chemical', 'MESH:D009584', (311, 312))	('GALNTL4', 'Gene', '374378', (301, 308))	('rs10889417 A', 'Var', (105, 117))	('low', 'NegReg', (79, 82))	('N', 'Chemical', 'MESH:D009584', (25, 26))	('N', 'Chemical', 'MESH:D009584', (164, 165))	('decrease', 'NegReg', (289, 297))	('rs12270446 G', 'Var', (249, 261))	('ALG6', 'Gene', (157, 161))	('GALNTL4', 'Gene', (301, 308))
504224	31991610	One study has identified that integrin-reduced cell adhesion is the result of modification of N-acetylglucosaminyltransferase III, which is involved in the N-glycosylation process.	('N', 'Chemical', 'MESH:D009584', (156, 157))	('modification', 'Var', (78, 90))	('N-acetylglucosaminyltransferase III', 'Gene', (94, 129))	('N-acetylglucosaminyltransferase III', 'Gene', '4248', (94, 129))	('cell adhesion', 'CPA', (47, 60))	('N', 'Chemical', 'MESH:D009584', (94, 95))
504225	31991610	Although the present study suggested that the expression of ALG6 seemed not to have a significant effect on CM survival, a high ALG6 expression was associated with a better overall survival (OS) in colon adenocarcinoma and lung squamous cell carcinoma patients.	('expression', 'MPA', (133, 143))	('ALG6', 'Gene', '29929', (128, 132))	('colon adenocarcinoma and lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (198, 251))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (223, 251))	('ALG6', 'Gene', (128, 132))	('CM', 'Disease', 'MESH:C562393', (108, 110))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (228, 251))	('patients', 'Species', '9606', (252, 260))	('carcinoma', 'Phenotype', 'HP:0030731', (242, 251))	('overall survival', 'MPA', (173, 189))	('high', 'Var', (123, 127))	('ALG6', 'Gene', '29929', (60, 64))	('CM', 'Phenotype', 'HP:0012056', (108, 110))	('ALG6', 'Gene', (60, 64))	('better', 'PosReg', (166, 172))	('carcinoma', 'Phenotype', 'HP:0030731', (209, 218))
504226	31991610	In a previous animal study, however, we noted that knockdown of the mouse Alg6 gene increased melanoma lung metastasis without affecting primary tumor growth, which may lead to a shorter survival.	('mouse', 'Species', '10090', (68, 73))	('melanoma lung metastasis', 'Disease', (94, 118))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('shorter', 'NegReg', (179, 186))	('Alg6', 'Gene', (74, 78))	('survival', 'MPA', (187, 195))	('melanoma', 'Phenotype', 'HP:0002861', (94, 102))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumor', 'Disease', (145, 150))	('Alg6', 'Gene', '320438', (74, 78))	('increased', 'PosReg', (84, 93))	('melanoma lung metastasis', 'Disease', 'MESH:D009362', (94, 118))	('knockdown', 'Var', (51, 60))
504227	31991610	However, the gene expression profiles in tumor tissues are more likely affected by mutations in the driver genes commonly seen in tumor tissues.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('mutations', 'Var', (83, 92))	('tumor', 'Disease', (41, 46))	('gene expression profiles', 'MPA', (13, 37))	('affected', 'Reg', (71, 79))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('tumor', 'Disease', (130, 135))
504228	31991610	Mutations in ALG6 may lead to congenital disorders of glycosylation (CDG), called ALG6-CDG, of which missense mutations P. A333V and P. I299Del are the most common mutations.	('A333V', 'Mutation', 'rs121908443', (123, 128))	('lead to', 'Reg', (22, 29))	('P. A333V', 'Var', (120, 128))	('CDG', 'Disease', 'MESH:D018981', (69, 72))	('CDG', 'Disease', 'MESH:D018981', (87, 90))	('CDG', 'Disease', (69, 72))	('congenital disorders of glycosylation', 'Disease', (30, 67))	('CDG', 'Disease', (87, 90))	('Mutations', 'Var', (0, 9))	('ALG6', 'Gene', '29929', (13, 17))	('congenital disorders of glycosylation', 'Disease', 'MESH:D018981', (30, 67))	('ALG6', 'Gene', '29929', (82, 86))	('ALG6', 'Gene', (82, 86))	('ALG6', 'Gene', (13, 17))	('P. I299Del', 'Var', (133, 143))
504232	31991610	Although the ALG6 gene malfunction may play a role in the poor prognosis of melanoma, we also showed that the mutation rate of ALG6 in melanoma tissues was less than 2.56%, and thus the overall expression levels of ALG6 in melanoma tissues are more likely to be affected by SNPs.	('SNPs', 'Disease', (274, 278))	('affected', 'Reg', (262, 270))	('N', 'Chemical', 'MESH:D009584', (275, 276))	('melanoma', 'Phenotype', 'HP:0002861', (223, 231))	('melanoma', 'Disease', (223, 231))	('melanoma', 'Disease', 'MESH:D008545', (76, 84))	('melanoma', 'Phenotype', 'HP:0002861', (135, 143))	('melanoma', 'Disease', (135, 143))	('ALG6', 'Gene', (215, 219))	('melanoma tissues', 'Disease', 'MESH:D008545', (223, 239))	('ALG6', 'Gene', (127, 131))	('melanoma tissues', 'Disease', 'MESH:D008545', (135, 151))	('melanoma tissues', 'Disease', (223, 239))	('ALG6', 'Gene', '29929', (215, 219))	('melanoma tissues', 'Disease', (135, 151))	('ALG6', 'Gene', '29929', (127, 131))	('expression levels', 'MPA', (194, 211))	('mutation', 'Var', (110, 118))	('ALG6', 'Gene', (13, 17))	('melanoma', 'Phenotype', 'HP:0002861', (76, 84))	('melanoma', 'Disease', (76, 84))	('melanoma', 'Disease', 'MESH:D008545', (223, 231))	('melanoma', 'Disease', 'MESH:D008545', (135, 143))	('ALG6', 'Gene', '29929', (13, 17))
504233	31991610	Further supporting evidence is that ALG6 rs10889417 is located on the Pitx2 motif, indicating its potential regulatory roles in ALG6 mRNA expression.	('ALG6', 'Gene', '29929', (128, 132))	('ALG6', 'Gene', (128, 132))	('rs10889417', 'Var', (41, 51))	('ALG6', 'Gene', '29929', (36, 40))	('rs10889417', 'Mutation', 'rs10889417', (41, 51))	('ALG6', 'Gene', (36, 40))	('Pitx2', 'Gene', (70, 75))	('N', 'Chemical', 'MESH:D009584', (135, 136))	('Pitx2', 'Gene', '5308', (70, 75))
504234	31991610	Because of the close relationship established between ALG6 and N-linked glycosylation and melanoma cell activity, genetic variation in ALG6 is likely to play a role in CM progression and prognosis.	('ALG6', 'Gene', '29929', (135, 139))	('role', 'Reg', (160, 164))	('genetic variation', 'Var', (114, 131))	('play', 'Reg', (153, 157))	('N-linked glycosylation and melanoma', 'Disease', 'MESH:D008545', (63, 98))	('ALG6', 'Gene', '29929', (54, 58))	('CM', 'Phenotype', 'HP:0012056', (168, 170))	('ALG6', 'Gene', (135, 139))	('ALG6', 'Gene', (54, 58))	('CM', 'Disease', 'MESH:C562393', (168, 170))	('melanoma', 'Phenotype', 'HP:0002861', (90, 98))
504236	31991610	However, previous GWAS studies have shown an association between genetic variants of GALNTL4 and protective effects against differentiated thyroid cancer, and GALNTL4 SNPs are reportedly associated with the cisplatin sensitivity of urothelial cancer and the efficacy of gemcitabine combined with platinum in the chemo treatment of bladder urothelial carcinoma.	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('GALNTL4', 'Gene', (85, 92))	('GALNTL4', 'Gene', '374378', (159, 166))	('thyroid cancer', 'Disease', (139, 153))	('carcinoma', 'Phenotype', 'HP:0030731', (350, 359))	('N', 'Chemical', 'MESH:D009584', (162, 163))	('platinum', 'Chemical', 'MESH:D010984', (296, 304))	('genetic variants', 'Var', (65, 81))	('thyroid cancer', 'Disease', 'MESH:D013964', (139, 153))	('cisplatin', 'Chemical', 'MESH:D002945', (207, 216))	('GALNTL4', 'Gene', '374378', (85, 92))	('gemcitabine', 'Chemical', 'MESH:C056507', (270, 281))	('N', 'Chemical', 'MESH:D009584', (88, 89))	('thyroid cancer', 'Phenotype', 'HP:0002890', (139, 153))	('urothelial cancer', 'Disease', 'MESH:D014523', (232, 249))	('bladder urothelial carcinoma', 'Disease', (331, 359))	('N', 'Chemical', 'MESH:D009584', (168, 169))	('associated', 'Reg', (187, 197))	('cisplatin sensitivity', 'MPA', (207, 228))	('GALNTL4', 'Gene', (159, 166))	('urothelial cancer', 'Disease', (232, 249))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (331, 359))	('SNPs', 'Var', (167, 171))	('cancer', 'Phenotype', 'HP:0002664', (243, 249))
504237	31991610	In the present study, we showed that the rs12270446 G>A located in the intron of GALNTL4 was associated with CMSS.	('CM', 'Phenotype', 'HP:0012056', (109, 111))	('GALNTL4', 'Gene', (81, 88))	('associated', 'Reg', (93, 103))	('rs12270446', 'Mutation', 'rs12270446', (41, 51))	('CM', 'Disease', 'MESH:C562393', (109, 111))	('GALNTL4', 'Gene', '374378', (81, 88))	('rs12270446 G>A', 'Var', (41, 55))
504244	31991610	Lastly, we were not able to investigate the biological mechanisms to understand how ALG6 rs10889417 G>A and GALNTL4 rs12270446 G>C influence CMSS, which should be further investigated in the future.	('rs10889417 G>A', 'Var', (89, 103))	('rs10889417', 'Mutation', 'rs10889417', (89, 99))	('CM', 'Disease', 'MESH:C562393', (141, 143))	('GALNTL4', 'Gene', '374378', (108, 115))	('ALG6', 'Gene', '29929', (84, 88))	('rs12270446', 'Mutation', 'rs12270446', (116, 126))	('CM', 'Phenotype', 'HP:0012056', (141, 143))	('ALG6', 'Gene', (84, 88))	('GALNTL4', 'Gene', (108, 115))	('influence', 'Reg', (131, 140))	('rs12270446 G>C', 'Var', (116, 130))
504255	31991610	In the MDACC discovery analysis using a multivariable Cox proportional hazards regression model, we first assessed in a single-locus analysis the associations between selected SNPs in 227 glycosylation pathway genes and CMSS by calculating HR and its 95% CI using R software (GenABEL package).	('glycosylation pathway', 'Pathway', (188, 209))	('CM', 'Disease', 'MESH:C562393', (220, 222))	('N', 'Chemical', 'MESH:D009584', (177, 178))	('associations', 'Interaction', (146, 158))	('CM', 'Phenotype', 'HP:0012056', (220, 222))	('SNPs', 'Var', (176, 180))
504272	31991610	Two independent SNPs (i.e., ALG6 rs10889417G>A and GALNTL4 rs12270446G>C) were found to be significantly associated with CMSS in the MDACC discovery and NHS/HPFS replication datasets.	('N', 'Chemical', 'MESH:D009584', (153, 154))	('rs12270446G>C', 'DBSNP_MENTION', 'None', (59, 72))	('GALNTL4', 'Gene', '374378', (51, 58))	('rs10889417G>A', 'Var', (33, 46))	('CM', 'Disease', 'MESH:C562393', (121, 123))	('ALG6', 'Gene', (28, 32))	('N', 'Chemical', 'MESH:D009584', (54, 55))	('rs10889417G>A', 'DBSNP_MENTION', 'None', (33, 46))	('GALNTL4', 'Gene', (51, 58))	('CM', 'Phenotype', 'HP:0012056', (121, 123))	('N', 'Chemical', 'MESH:D009584', (17, 18))	('associated', 'Reg', (105, 115))	('ALG6', 'Gene', '29929', (28, 32))	('rs12270446G>C', 'Var', (59, 72))
504282	31991610	Figure S7: Kaplan-Meier analysis for cancer patients by expression levels of ALG6 and GALNTL4; and Figure S8: Mutation analysis of ALG6 and GALNTL4 gene in cutaneous melanoma tumor tissues by using public available data in the database of the cBioportal for Cancer Genomics .	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('ALG6', 'Gene', (131, 135))	('ALG6', 'Gene', '29929', (77, 81))	('ALG6', 'Gene', (77, 81))	('GALNTL4', 'Gene', '374378', (86, 93))	('melanoma', 'Phenotype', 'HP:0002861', (166, 174))	('patients', 'Species', '9606', (44, 52))	('ALG6', 'Gene', '29929', (131, 135))	('GALNTL4', 'Gene', (140, 147))	('cutaneous melanoma tumor', 'Disease', (156, 180))	('cancer', 'Disease', (37, 43))	('Mutation analysis', 'Var', (110, 127))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (156, 174))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('GALNTL4', 'Gene', '374378', (140, 147))	('Cancer', 'Phenotype', 'HP:0002664', (258, 264))	('GALNTL4', 'Gene', (86, 93))	('cutaneous melanoma tumor', 'Disease', 'MESH:C562393', (156, 180))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))
504284	31991610	The MD Anderson Study was supported by the National Institutes of Health/National Cancer Institute (R01 CA100264, 2P50CA093459 and R01CA133996) as well as by The University of Texas MD Anderson Cancer Centre Various Donors Melanoma and Skin Cancers Priority Program Fund; the Miriam and Jim Mulva Research Fund; the McCarthy Skin Cancer Research Fund and the Marit Peterson Fund for Melanoma Research.	('Skin Cancer', 'Phenotype', 'HP:0008069', (325, 336))	('Melanoma', 'Disease', 'MESH:D008545', (223, 231))	('Cancer', 'Phenotype', 'HP:0002664', (241, 247))	('Melanoma', 'Disease', (383, 391))	('Skin Cancer', 'Phenotype', 'HP:0008069', (236, 247))	('N', 'Chemical', 'MESH:D009584', (43, 44))	('McCarthy Skin Cancer', 'Disease', (316, 336))	('Cancer', 'Phenotype', 'HP:0002664', (82, 88))	('Melanoma', 'Disease', (223, 231))	('Melanoma', 'Phenotype', 'HP:0002861', (383, 391))	('Cancer', 'Phenotype', 'HP:0002664', (194, 200))	('McCarthy Skin Cancer', 'Disease', 'MESH:D012878', (316, 336))	('Skin Cancers', 'Phenotype', 'HP:0008069', (236, 248))	('Melanoma', 'Phenotype', 'HP:0002861', (223, 231))	('Cancers', 'Phenotype', 'HP:0002664', (241, 248))	('Texas MD Anderson Cancer', 'Disease', (176, 200))	('R01CA133996', 'Var', (131, 142))	('N', 'Chemical', 'MESH:D009584', (73, 74))	('Melanoma and Skin Cancers', 'Disease', 'MESH:D012878', (223, 248))	('Cancer', 'Phenotype', 'HP:0002664', (330, 336))	('Texas MD Anderson Cancer', 'Disease', 'MESH:D009369', (176, 200))	('Melanoma', 'Disease', 'MESH:D008545', (383, 391))	('R01 CA100264', 'Var', (100, 112))
504285	31991610	The Harvard NHS/HPFS Study was in part supported by National Institutes of Health/National Cancer Institute (R01 CA49449, P01 CA87969, UM1 CA186107 and UM1 CA167552).	('P01 CA87969', 'Var', (122, 133))	('N', 'Chemical', 'MESH:D009584', (12, 13))	('Cancer', 'Phenotype', 'HP:0002664', (91, 97))	('N', 'Chemical', 'MESH:D009584', (82, 83))	('N', 'Chemical', 'MESH:D009584', (52, 53))	('R01 CA49449', 'Var', (109, 120))	('UM1 CA186107', 'Var', (135, 147))
504311	31709182	By base-pairing to miRNA recognition elements (MERs) located in the 3'-untranslated regions (3' UTRs) of target mRNAs, mature miRNAs induce posttranslational repression or mRNA degradation of the target gene.	('posttranslational repression', 'MPA', (140, 168))	('miR', 'Gene', '220972', (19, 22))	('miR', 'Gene', (19, 22))	('miR', 'Gene', '220972', (126, 129))	('base-pairing', 'Var', (3, 15))	('miR', 'Gene', (126, 129))	('mRNA degradation', 'MPA', (172, 188))	('MERs', 'Species', '1335626', (47, 51))	('induce', 'Reg', (133, 139))
504370	31709182	The results showed that the patient survival rate was negatively correlated with high levels of miR-622 in breast cancer (BC, p = 2 x 10-6), cervical squamous cell carcinoma (CISCC, p = 0.0195), head and neck squamous cell carcinoma (HNSC, p = 0.0011), ovarian cancer (OV, p = 1.3 x 10-5), pancreatic ductal adenocarcinoma (PDAC, p = 0.0018), and uterine corpus endometrial carcinoma (UCEC, p = 4.5 x 10-4) (Supplementary Figure 1).	('BC', 'Phenotype', 'HP:0003002', (122, 124))	('high', 'Var', (81, 85))	('pancreatic ductal adenocarcinoma', 'Disease', (290, 322))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (150, 173))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (195, 232))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (362, 383))	('carcinoma', 'Phenotype', 'HP:0030731', (374, 383))	('breast cancer', 'Gene', '672', (107, 120))	('carcinoma', 'Phenotype', 'HP:0030731', (223, 232))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (290, 322))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (362, 383))	('breast cancer', 'Phenotype', 'HP:0003002', (107, 120))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (150, 173))	('ovarian cancer', 'Disease', 'MESH:D010051', (253, 267))	('cancer', 'Phenotype', 'HP:0002664', (261, 267))	('neck squamous cell carcinoma', 'Disease', 'MESH:C535575', (204, 232))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (209, 232))	('carcinoma', 'Phenotype', 'HP:0030731', (164, 173))	('neck squamous cell carcinoma', 'Disease', (204, 232))	('squamous cell carcinoma', 'Disease', (150, 173))	('carcinoma', 'Phenotype', 'HP:0030731', (313, 322))	('breast cancer', 'Gene', (107, 120))	('miR-622', 'Gene', (96, 103))	('ovarian cancer', 'Disease', (253, 267))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (290, 322))	('endometrial carcinoma', 'Disease', (362, 383))	('miR-622', 'Gene', '693207', (96, 103))	('patient', 'Species', '9606', (28, 35))	('negatively', 'NegReg', (54, 64))	('ovarian cancer', 'Phenotype', 'HP:0100615', (253, 267))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (209, 232))
504429	31709182	In addition, the cells were transfected with the miR-622 antagomir and the inhibitor N.C. in the breast cancer cell line MCF7 for Western blot detection.	('breast cancer', 'Gene', '672', (97, 110))	('MCF7', 'CellLine', 'CVCL:0031', (121, 125))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('breast cancer', 'Gene', (97, 110))	('N.C.', 'Var', (85, 89))	('miR-622', 'Gene', (49, 56))	('miR-622', 'Gene', '693207', (49, 56))	('breast cancer', 'Phenotype', 'HP:0003002', (97, 110))
504430	31709182	The results showed that the knockdown of miR-622 could upregulate the expression of RNF8 as well as the expression of the mesenchymal status marker Snail (by 0.65-fold, Figure 8A), while the epithelial status markers E-cadherin, ZO-1, and Claudin-1 were significantly decreased (by 0.65-fold, Figure 8A).	('RNF8', 'Gene', (84, 88))	('ZO-1', 'Gene', (229, 233))	('RNF8', 'Gene', '9025', (84, 88))	('ZO-1', 'Gene', '7082', (229, 233))	('Claudin-1', 'Gene', '9076', (239, 248))	('miR-622', 'Gene', (41, 48))	('decreased', 'NegReg', (268, 277))	('Claudin-1', 'Gene', (239, 248))	('expression', 'MPA', (70, 80))	('expression', 'MPA', (104, 114))	('Snail', 'Gene', (148, 153))	('E-cadherin', 'Gene', (217, 227))	('miR-622', 'Gene', '693207', (41, 48))	('knockdown', 'Var', (28, 37))	('Snail', 'Gene', '6615', (148, 153))	('E-cadherin', 'Gene', '999', (217, 227))	('upregulate', 'PosReg', (55, 65))
504438	31709182	The results showed that decreased miR-622 promoted the viability (Figure 8B, p < 0.001) and migration (Figures 8D,F, p < 0.001 and p < 0.01, respectively) capacities of breast cancer cells.	('breast cancer', 'Gene', '672', (169, 182))	('decreased', 'Var', (24, 33))	('miR-622', 'Gene', '693207', (34, 41))	('miR-622', 'Gene', (34, 41))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('migration', 'CPA', (92, 101))	('viability', 'CPA', (55, 64))	('breast cancer', 'Gene', (169, 182))	('promoted', 'PosReg', (42, 50))	('breast cancer', 'Phenotype', 'HP:0003002', (169, 182))
504441	31709182	To further test whether the miR-622-induced EMT process and EMT-related phenotype changes (for example, migration) of breast cancer cells are directly dependent on RNF8, an siRNA designed against RNF8 (siRNF8) and a miR-622-inhibitor (antagomir) were cotransfected to knock down the expression of RNF8 and miR-622 in breast cancer cell MCF7, respectively (Figure 9A).	('RNF8', 'Gene', (297, 301))	('breast cancer', 'Gene', '672', (118, 131))	('breast cancer', 'Phenotype', 'HP:0003002', (118, 131))	('knock down', 'Var', (268, 278))	('breast cancer', 'Gene', (317, 330))	('MCF7', 'CellLine', 'CVCL:0031', (336, 340))	('RNF8', 'Gene', '9025', (196, 200))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('cancer', 'Phenotype', 'HP:0002664', (324, 330))	('miR-622', 'Gene', (28, 35))	('RNF8', 'Gene', (196, 200))	('breast cancer', 'Gene', (118, 131))	('RNF8', 'Gene', '9025', (204, 208))	('miR-622', 'Gene', '693207', (28, 35))	('miR-622', 'Gene', (306, 313))	('breast cancer', 'Gene', '672', (317, 330))	('RNF8', 'Gene', (204, 208))	('miR-622', 'Gene', '693207', (306, 313))	('RNF8', 'Gene', '9025', (164, 168))	('miR-622', 'Gene', (216, 223))	('RNF8', 'Gene', (164, 168))	('miR-622', 'Gene', '693207', (216, 223))	('breast cancer', 'Phenotype', 'HP:0003002', (317, 330))	('RNF8', 'Gene', '9025', (297, 301))
504443	31709182	The results showed that the protein levels of RNF8 and Snail were significantly increased in the miR-622 antagomir-treated group (Figure 9B), while cell migration was largely increased, as determined by the Transwell assay.	('antagomir-treated', 'Var', (105, 122))	('increased', 'PosReg', (80, 89))	('increased', 'PosReg', (175, 184))	('RNF8', 'Gene', '9025', (46, 50))	('cell migration', 'CPA', (148, 162))	('miR-622', 'Gene', (97, 104))	('Snail', 'Gene', '6615', (55, 60))	('Snail', 'Gene', (55, 60))	('protein levels', 'MPA', (28, 42))	('miR-622', 'Gene', '693207', (97, 104))	('RNF8', 'Gene', (46, 50))
504483	31709182	Furthermore, we found that the overexpression of miR-622 in breast cancer cells can downregulate the expression of RNF8, while miR-622 knockdown by the antagomir could increase the protein level of RNF8, which verified the regulation of RNF8 by miR-622.	('increase', 'PosReg', (168, 176))	('RNF8', 'Gene', (115, 119))	('miR-622', 'Gene', (127, 134))	('breast cancer', 'Gene', '672', (60, 73))	('miR-622', 'Gene', '693207', (127, 134))	('miR-622', 'Gene', (245, 252))	('protein level', 'MPA', (181, 194))	('breast cancer', 'Phenotype', 'HP:0003002', (60, 73))	('miR-622', 'Gene', '693207', (245, 252))	('downregulate', 'NegReg', (84, 96))	('RNF8', 'Gene', '9025', (198, 202))	('RNF8', 'Gene', (198, 202))	('RNF8', 'Gene', '9025', (237, 241))	('breast cancer', 'Gene', (60, 73))	('RNF8', 'Gene', (237, 241))	('knockdown', 'Var', (135, 144))	('miR-622', 'Gene', (49, 56))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('miR-622', 'Gene', '693207', (49, 56))	('RNF8', 'Gene', '9025', (115, 119))	('expression', 'MPA', (101, 111))	('overexpression', 'PosReg', (31, 45))
504500	31660987	Targeting PKCiota-PAK1 signaling pathways in EGFR and KRAS mutant adenocarcinoma and lung squamous cell carcinoma p21-activated kinase 1 (PAK1) stimulates growth and metastasis in non-small cell lung cancer (NSCLC).	('NSCLC', 'Phenotype', 'HP:0030358', (208, 213))	('mutant', 'Var', (59, 65))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('lung cancer', 'Phenotype', 'HP:0100526', (195, 206))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (180, 206))	('PAK1', 'Gene', '5058', (138, 142))	('p21-activated kinase 1', 'Gene', '5058', (114, 136))	('PAK1', 'Gene', (18, 22))	('EGFR', 'Gene', '1956', (45, 49))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (184, 206))	('stimulates', 'PosReg', (144, 154))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('PAK1', 'Gene', '5058', (18, 22))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (85, 113))	('adenocarcinoma and lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (66, 113))	('PKCiota', 'Gene', '5584', (10, 17))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (180, 206))	('PKCiota', 'Gene', (10, 17))	('p21-activated kinase 1', 'Gene', (114, 136))	('KRAS', 'Gene', '3845', (54, 58))	('NSCLC', 'Disease', 'MESH:D002289', (208, 213))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (90, 113))	('non-small cell lung cancer', 'Disease', (180, 206))	('EGFR', 'Gene', (45, 49))	('KRAS', 'Gene', (54, 58))	('NSCLC', 'Disease', (208, 213))	('PAK1', 'Gene', (138, 142))
504503	31660987	The effect of IPA-3 (PAK1 inhibitor) plus auranofin (PKCiota inhibitor) combination was evaluated by cell viability assay, colony formation and western blotting assay, using three types of NSCLC cell lines: EGFR or KRAS mutant adenocarcinoma and squamous cell carcinoma with PAK1 amplification.	('NSCLC', 'Disease', (189, 194))	('NSCLC', 'Disease', 'MESH:D002289', (189, 194))	('mutant', 'Var', (220, 226))	('PKCiota', 'Gene', '5584', (53, 60))	('PAK1', 'Gene', (275, 279))	('PKCiota', 'Gene', (53, 60))	('adenocarcinoma', 'Disease', (227, 241))	('auranofin', 'Chemical', 'MESH:D001310', (42, 51))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (246, 269))	('squamous cell carcinoma', 'Disease', (246, 269))	('NSCLC', 'Phenotype', 'HP:0030358', (189, 194))	('carcinoma', 'Phenotype', 'HP:0030731', (232, 241))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (246, 269))	('carcinoma', 'Phenotype', 'HP:0030731', (260, 269))	('IPA', 'Chemical', 'MESH:C507406', (14, 17))	('adenocarcinoma', 'Disease', 'MESH:D000230', (227, 241))
504508	31660987	Combination of IPA-3 or OTSSP167 and auranofin was highly synergistic in EGFR or KRAS mutant adenocarcinoma and squamous cell carcinoma cell lines and decreased tumor volume in mice models.	('auranofin', 'Chemical', 'MESH:D001310', (37, 46))	('adenocarcinoma', 'Disease', 'MESH:D000230', (93, 107))	('IPA', 'Chemical', 'MESH:C507406', (15, 18))	('mutant', 'Var', (86, 92))	('mice', 'Species', '10090', (177, 181))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('EGFR', 'Gene', (73, 77))	('decreased', 'NegReg', (151, 160))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (112, 135))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('KRAS', 'Gene', (81, 85))	('adenocarcinoma', 'Disease', (93, 107))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (112, 135))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('squamous cell carcinoma', 'Disease', (112, 135))	('tumor', 'Disease', (161, 166))
504509	31660987	It is of interest to further test the targeting of PKCiota-PAK1 signaling pathways in EGFR mutant, KRAS mutant and squamous NSCLC patients.	('KRAS', 'Disease', (99, 103))	('NSCLC', 'Disease', (124, 129))	('EGFR', 'Gene', (86, 90))	('NSCLC', 'Disease', 'MESH:D002289', (124, 129))	('patients', 'Species', '9606', (130, 138))	('PKCiota', 'Gene', '5584', (51, 58))	('mutant', 'Var', (91, 97))	('PKCiota', 'Gene', (51, 58))	('NSCLC', 'Phenotype', 'HP:0030358', (124, 129))
504512	31660987	However, the effect of immunotherapy in patients with EGFR mutations is rather limited.	('patients', 'Species', '9606', (40, 48))	('EGFR', 'Gene', (54, 58))	('mutations', 'Var', (59, 68))
504513	31660987	A meta-analysis indicated that immuno-checkpoint inhibitors as second line treatment do not improve overall survival in comparison with docetaxel treatment in EGFR-mutant patients.	('docetaxel', 'Chemical', 'MESH:C067311', (136, 145))	('EGFR-mutant', 'Gene', (159, 170))	('EGFR-mutant', 'Var', (159, 170))	('patients', 'Species', '9606', (171, 179))
504514	31660987	We focus our research on the identification of recurrent pathways occurring in subclasses of NSCLC, including LUADs driven by KRAS or EGFR mutations, and SCC.	('NSCLC', 'Disease', (93, 98))	('LUAD', 'Disease', (110, 114))	('EGFR', 'Gene', (134, 138))	('mutations', 'Var', (139, 148))	('SCC', 'Disease', (154, 157))	('LUAD', 'Disease', 'MESH:C538231', (110, 114))	('NSCLC', 'Disease', 'MESH:D002289', (93, 98))	('LUAD', 'Phenotype', 'HP:0030078', (110, 114))	('SCC', 'Disease', 'MESH:D002294', (154, 157))	('NSCLC', 'Phenotype', 'HP:0030358', (93, 98))	('SCC', 'Phenotype', 'HP:0002860', (154, 157))	('KRAS', 'Gene', (126, 130))
504521	31660987	It is of interest that auranofin enhances ibrutinib activity in EGFR mutant LUAD by inhibiting the expression or phosphorylation of multiple key nodes in AKT/mTOR and MEK/ERK pathways.	('auranofin', 'Chemical', 'MESH:D001310', (23, 32))	('MEK', 'Gene', (167, 170))	('expression', 'MPA', (99, 109))	('MEK', 'Gene', '5609', (167, 170))	('phosphorylation', 'MPA', (113, 128))	('mutant', 'Var', (69, 75))	('enhances', 'PosReg', (33, 41))	('ibrutinib', 'Chemical', 'MESH:C551803', (42, 51))	('LUAD', 'Phenotype', 'HP:0030078', (76, 80))	('LUAD', 'Disease', (76, 80))	('ERK', 'Gene', '5594', (171, 174))	('LUAD', 'Disease', 'MESH:C538231', (76, 80))	('ERK', 'Gene', (171, 174))	('inhibiting', 'NegReg', (84, 94))	('EGFR', 'Gene', (64, 68))	('mTOR', 'Gene', (158, 162))	('ibrutinib activity', 'MPA', (42, 60))	('mTOR', 'Gene', '2475', (158, 162))
504524	31660987	PAK1 confers cisplatin resistance in NSCLC patients.	('cisplatin resistance', 'MPA', (13, 33))	('NSCLC', 'Phenotype', 'HP:0030358', (37, 42))	('patients', 'Species', '9606', (43, 51))	('PAK1', 'Var', (0, 4))	('NSCLC', 'Disease', (37, 42))	('NSCLC', 'Disease', 'MESH:D002289', (37, 42))	('cisplatin', 'Chemical', 'MESH:D002945', (13, 22))
504525	31660987	PAK1 signaling has been shown to cause resistance to MAPK kinase inhibitors in BRAF mutant melanomas.	('melanomas', 'Disease', (91, 100))	('resistance', 'MPA', (39, 49))	('melanomas', 'Phenotype', 'HP:0002861', (91, 100))	('mutant', 'Var', (84, 90))	('BRAF', 'Gene', '673', (79, 83))	('melanomas', 'Disease', 'MESH:D008545', (91, 100))	('BRAF', 'Gene', (79, 83))	('MAPK', 'Gene', (53, 57))	('MAPK', 'Gene', '5595;5594;5595', (53, 57))
504526	31660987	PAK1 mRNA expressing EGFR mutant tumors are resistant to EGFR tyrosine kinase inhibitors.	('EGFR', 'Gene', (21, 25))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumors', 'Disease', 'MESH:D009369', (33, 39))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('tyrosine', 'Chemical', 'None', (62, 70))	('N', 'Chemical', 'MESH:D009584', (7, 8))	('mutant', 'Var', (26, 32))	('resistant', 'MPA', (44, 53))	('tumors', 'Disease', (33, 39))
504528	31660987	Together with others, we have demonstrated that the combination of AKT and EGFR inhibitors could be of benefit in patients with EGFR mutations, however, even when blocking AKT, tumor regrowth could occur through the activation of other downstream regulators, via Src/FAK.	('AKT', 'Protein', (172, 175))	('FAK', 'Gene', '5747', (267, 270))	('Src', 'Gene', (263, 266))	('Src', 'Gene', '6714', (263, 266))	('FAK', 'Gene', (267, 270))	('EGFR', 'Gene', (128, 132))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('mutations', 'Var', (133, 142))	('patients', 'Species', '9606', (114, 122))	('tumor', 'Disease', (177, 182))
504529	31660987	We posit that different classes of LUADs, such as EGFR mutant LUADs, KRAS mutant LUADs and SCCs, could be sensitive to the inhibition of PKCiota with auranofin plus a PAK inhibitor.	('KRAS', 'Gene', (69, 73))	('SCC', 'Disease', (91, 94))	('auranofin', 'Chemical', 'MESH:D001310', (150, 159))	('LUAD', 'Disease', 'MESH:C538231', (62, 66))	('LUAD', 'Phenotype', 'HP:0030078', (35, 39))	('EGFR', 'Gene', (50, 54))	('LUAD', 'Phenotype', 'HP:0030078', (81, 85))	('LUAD', 'Disease', (35, 39))	('PKCiota', 'Gene', '5584', (137, 144))	('PAK', 'Gene', (167, 170))	('PKCiota', 'Gene', (137, 144))	('LUAD', 'Disease', (81, 85))	('PAK', 'Gene', '373103;5058;18479', (167, 170))	('LUAD', 'Phenotype', 'HP:0030078', (62, 66))	('mutant', 'Var', (55, 61))	('LUAD', 'Disease', 'MESH:C538231', (35, 39))	('SCC', 'Phenotype', 'HP:0002860', (91, 94))	('LUAD', 'Disease', 'MESH:C538231', (81, 85))	('LUAD', 'Disease', (62, 66))	('SCC', 'Disease', 'MESH:D002294', (91, 94))
504566	31660987	Western blotting experiments showed that OTSSP167 inhibited more PAK1 phosphorylated residues compared to IPA-3.	('OTSSP167', 'Var', (41, 49))	('PAK1', 'Protein', (65, 69))	('IPA', 'Chemical', 'MESH:C507406', (106, 109))	('inhibited', 'NegReg', (50, 59))
504573	31660987	The combination of OTSSP167 plus auranofin showed significant inhibition of tumor growth in the 3 mice model cell lines compared to single OTSSP167 or auranofin treatment (Fig.	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('auranofin', 'Chemical', 'MESH:D001310', (151, 160))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('OTSSP167', 'Var', (19, 27))	('inhibition', 'NegReg', (62, 72))	('auranofin', 'Chemical', 'MESH:D001310', (33, 42))	('mice', 'Species', '10090', (98, 102))
504574	31660987	Compared to vehicle group, mice body weight was significantly reduced in OTSSP167 plus auranofin and single OTSSP167 treatment in the 3 mice model cell lines.	('mice', 'Species', '10090', (136, 140))	('mice', 'Species', '10090', (27, 31))	('OTSSP167', 'Var', (73, 81))	('mice body weight', 'CPA', (27, 43))	('auranofin', 'Chemical', 'MESH:D001310', (87, 96))	('reduced', 'NegReg', (62, 69))
504579	31660987	EGFR TKIs result in loss of miR-21 and increase TNF mRNA stability, leading to EGFR TKI resistance in EGFR mutant NSCLC.	('N', 'Chemical', 'MESH:D009584', (114, 115))	('NSCLC', 'Phenotype', 'HP:0030358', (114, 119))	('mutant', 'Var', (107, 113))	('miR-21', 'Gene', (28, 34))	('TNF', 'Gene', (48, 51))	('N', 'Chemical', 'MESH:D009584', (54, 55))	('NSCLC', 'Disease', (114, 119))	('TNF', 'Gene', '7124', (48, 51))	('increase', 'PosReg', (39, 47))	('EGFR TKI', 'Gene', (79, 87))	('NSCLC', 'Disease', 'MESH:D002289', (114, 119))	('N', 'Chemical', 'MESH:D009584', (49, 50))	('loss', 'NegReg', (20, 24))	('miR-21', 'Gene', '406991', (28, 34))
504580	31660987	Therefore, it is tempting to speculate that an EGFR TKI, PAK inhibitor combination could serve as novel combinatory therapy for EGFR mutant NSCLC.	('PAK', 'Gene', '373103;5058;18479', (57, 60))	('NSCLC', 'Disease', 'MESH:D002289', (140, 145))	('EGFR', 'Gene', (128, 132))	('NSCLC', 'Phenotype', 'HP:0030358', (140, 145))	('PAK', 'Gene', (57, 60))	('mutant', 'Var', (133, 139))	('NSCLC', 'Disease', (140, 145))
504587	31660987	PAK1 inhibition induces exaggeration of calcium ion and arrhythmia.	('inhibition', 'Var', (5, 15))	('calcium ion', 'MPA', (40, 51))	('exaggeration', 'PosReg', (24, 36))	('calcium', 'Chemical', 'MESH:D002118', (40, 47))	('PAK1', 'Gene', (0, 4))	('arrhythmia', 'Disease', 'MESH:D001145', (56, 66))	('arrhythmia', 'Phenotype', 'HP:0011675', (56, 66))	('arrhythmia', 'Disease', (56, 66))
504604	31660987	The phosphosites, Ser21 or Thr423, also contribute towards PAK1 activation, although, Ser144 is the most critical for PAK kinase activity.	('Thr423', 'Chemical', 'MESH:C072935', (27, 33))	('PAK', 'Gene', (118, 121))	('Ser21', 'Var', (18, 23))	('PAK', 'Gene', '373103;5058;18479', (59, 62))	('PAK', 'Gene', '373103;5058;18479', (118, 121))	('activation', 'PosReg', (64, 74))	('Ser21', 'Chemical', 'MESH:C530429', (18, 23))	('Thr423', 'Var', (27, 33))	('Ser144', 'Var', (86, 92))	('Ser144', 'Chemical', 'MESH:C530429', (86, 92))	('PAK', 'Gene', (59, 62))
504605	31660987	Phosphorylated Ser144 on PAK1 was abrogated by IPA-3 plus auranofin, as well as by OTSSP167 plus auranofin.	('Ser144', 'Var', (15, 21))	('Phosphorylated', 'MPA', (0, 14))	('Ser144', 'Chemical', 'MESH:C530429', (15, 21))	('IPA', 'Chemical', 'MESH:C507406', (47, 50))	('auranofin', 'Chemical', 'MESH:D001310', (58, 67))	('auranofin', 'Chemical', 'MESH:D001310', (97, 106))	('abrogated', 'NegReg', (34, 43))
504613	31660987	Thus, PKCiota-PAK1 signaling is an important pathway in tumor genesis in EGFR mutant, KRAS mutant and SCC cell lines.	('SCC', 'Phenotype', 'HP:0002860', (102, 105))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('SCC', 'Disease', (102, 105))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('tumor', 'Disease', (56, 61))	('EGFR', 'Gene', (73, 77))	('PKCiota', 'Gene', '5584', (6, 13))	('SCC', 'Disease', 'MESH:D002294', (102, 105))	('mutant', 'Var', (78, 84))	('PKCiota', 'Gene', (6, 13))
504617	31660987	OTSSP167 suggested stronger PAK1 inhibition compared to IPA-3 in western blotting; phosphorylated PAK1 at Thr423/Ser144/Thr204 in HCC827 cell lines and Thr423 in H23 cell lines were inhibited by OTSSP167 alone, but not by IPA-3 alone.	('Thr423/Ser144/Thr204', 'Var', (106, 126))	('Thr423', 'Var', (152, 158))	('PAK1', 'Gene', (98, 102))	('Thr423', 'Chemical', 'MESH:C072935', (152, 158))	('Ser144', 'Chemical', 'MESH:C530429', (113, 119))	('IPA', 'Chemical', 'MESH:C507406', (222, 225))	('Thr204', 'Chemical', 'MESH:C003808', (120, 126))	('inhibited', 'NegReg', (182, 191))	('Thr423', 'Chemical', 'MESH:C072935', (106, 112))	('IPA', 'Chemical', 'MESH:C507406', (56, 59))
504619	31660987	Although mice body weight was significantly decreased in OTSSP167 alone, or OTSSP167 plus auranofin in all 3 cell lines, there was no significant difference between OTSSP167 alone, and OTSSP167 plus auranofin.	('OTSSP167', 'Var', (76, 84))	('auranofin', 'Chemical', 'MESH:D001310', (199, 208))	('OTSSP167', 'Var', (57, 65))	('mice', 'Species', '10090', (9, 13))	('auranofin', 'Chemical', 'MESH:D001310', (90, 99))	('mice body weight', 'CPA', (9, 25))	('decreased', 'NegReg', (44, 53))
504624	31660987	A Phase I study of OTSSP167 for solid tumors (NCT01910545) and a feasibility evaluation for healthy volunteers (NCT02768519) have been completed.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('N', 'Chemical', 'MESH:D009584', (46, 47))	('solid tumors', 'Disease', 'MESH:D009369', (32, 44))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('N', 'Chemical', 'MESH:D009584', (112, 113))	('NCT01910545', 'Var', (46, 57))	('OTSSP167', 'Gene', (19, 27))	('solid tumors', 'Disease', (32, 44))
504626	31660987	Targeting PKCiota-PAK1 signaling pathways is of interest to be further tested clinically in EGFR mutant, KRAS mutant, and squamous NSCLC patients.	('PKCiota', 'Gene', (10, 17))	('NSCLC', 'Disease', (131, 136))	('KRAS mutant', 'Disease', (105, 116))	('mutant', 'Var', (97, 103))	('patients', 'Species', '9606', (137, 145))	('PKCiota', 'Gene', '5584', (10, 17))	('NSCLC', 'Disease', 'MESH:D002289', (131, 136))	('EGFR', 'Gene', (92, 96))	('NSCLC', 'Phenotype', 'HP:0030358', (131, 136))
504628	31660987	It is warranted to further test the therapeutic strategy of targeting PKCiota-PAK1 signaling pathways in EGFR mutant, KRAS mutant and squamous NSCLC patients.	('patients', 'Species', '9606', (149, 157))	('KRAS', 'Disease', (118, 122))	('NSCLC', 'Disease', (143, 148))	('NSCLC', 'Disease', 'MESH:D002289', (143, 148))	('mutant', 'Var', (110, 116))	('NSCLC', 'Phenotype', 'HP:0030358', (143, 148))	('PKCiota', 'Gene', '5584', (70, 77))	('EGFR', 'Gene', (105, 109))	('PKCiota', 'Gene', (70, 77))
504656	30901831	MiRNA-329 and miRNA-410 have been shown to have an inverse correlation with Wnt-7b, a protein within the Wnt/beta-catenin pathway.	('miRNA-410', 'Var', (14, 23))	('Wnt-7b', 'Gene', (76, 82))	('correlation', 'Interaction', (59, 70))	('beta-catenin', 'Gene', (109, 121))	('inverse', 'NegReg', (51, 58))	('MiRNA-329', 'Var', (0, 9))	('Wnt-7b', 'Gene', '7477', (76, 82))	('beta-catenin', 'Gene', '1499', (109, 121))
504658	30901831	group identified miRNA-376c-3p as a tumor suppressor miRNA.	('miRNA-376c-3p', 'Var', (17, 30))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('tumor', 'Disease', (36, 41))	('tumor', 'Disease', 'MESH:D009369', (36, 41))
504660	30901831	were the first to associate the miRNA-365a-3p with laryngeal squamous cell carcinoma (LSCC).	('laryngeal squamous cell carcinoma', 'Disease', 'MESH:D002294', (51, 84))	('laryngeal squamous cell carcinoma', 'Disease', (51, 84))	('miRNA-365a-3p', 'Var', (32, 45))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (61, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('associate', 'Interaction', (18, 27))
504662	30901831	Fukumoto's group identified miRNA-26a/b, miRNA-29a/b/c, and miRNA-218 as direct inhibitors of Lysyl oxidase like 2 (LOXL2).	('LOXL2', 'Gene', (116, 121))	('miRNA-21', 'Gene', '406991', (60, 68))	('LOXL2', 'Gene', '4017', (116, 121))	('Lysyl oxidase like 2', 'Gene', '4017', (94, 114))	('miRNA-21', 'Gene', (60, 68))	('Lysyl oxidase like 2', 'Gene', (94, 114))	('miRNA-29a', 'Gene', '407021', (41, 50))	('miRNA-26a/b', 'Var', (28, 39))	('miRNA-29a', 'Gene', (41, 50))
504671	30901831	observed a correlation between the presence of miRNA-203 (in cooperation with other members of the miRNA-200 family) and the delay of EMT progression as monitored by downregulation of E-cadherin and upregulation of N-cadherin.	('N-cadherin', 'Gene', (215, 225))	('presence', 'Var', (35, 43))	('E-cadherin', 'Gene', (184, 194))	('E-cadherin', 'Gene', '999', (184, 194))	('miRNA-203', 'Gene', '406986', (47, 56))	('miRNA-203', 'Gene', (47, 56))	('N-cadherin', 'Gene', '1000', (215, 225))	('EMT progression', 'CPA', (134, 149))	('delay', 'NegReg', (125, 130))	('upregulation', 'PosReg', (199, 211))	('downregulation', 'NegReg', (166, 180))
504692	30901831	PTEN, a molecule that acts as an inhibitor to the PI3K pathway, is affected by miRNA-21, miRNA-214, miRNA-744-3p, and miRNA-205.	('miRNA-205', 'Var', (118, 127))	('miRNA-21', 'Gene', (89, 97))	('miRNA-21', 'Gene', (79, 87))	('affected', 'Reg', (67, 75))	('miRNA-214', 'Gene', (89, 98))	('PI3K pathway', 'Pathway', (50, 62))	('miRNA-21', 'Gene', '406991', (89, 97))	('miRNA-21', 'Gene', '406991', (79, 87))	('miRNA-744-3p', 'Var', (100, 112))	('miRNA-214', 'Gene', '406996', (89, 98))	('PTEN', 'Gene', (0, 4))	('PTEN', 'Gene', '5728', (0, 4))
504694	30901831	An additional array of four miRNAs in OSCC (miRNA-96-5p, miRNA-21-3p, miRNA-141-3p, and miRNA-130b-3p) were also implicated in decreased PTEN expression.	('decreased', 'NegReg', (127, 136))	('miRNA-141-3p', 'Var', (70, 82))	('miRNA-21', 'Gene', '406991', (57, 65))	('miRNA-96', 'Gene', (44, 52))	('PTEN', 'Gene', '5728', (137, 141))	('miRNA-96', 'Gene', '407053', (44, 52))	('PTEN', 'Gene', (137, 141))	('miRNA-130b-3p', 'Var', (88, 101))	('expression', 'MPA', (142, 152))	('miRNA-21', 'Gene', (57, 65))
504702	30901831	In this study, it was determined that variants of BRCA1 (rs12516) and RAD51 (rs7180135) had better disease-free survival and lower recurrence risk than those patients with the normal variant of the gene because these genes have roles in repairing the DSB that aid in creating malicious cancer cells.	('rs7180135', 'Mutation', 'rs7180135', (77, 86))	('patients', 'Species', '9606', (158, 166))	('cancer', 'Disease', (286, 292))	('recurrence', 'CPA', (131, 141))	('aid', 'Gene', (260, 263))	('rs7180135', 'Var', (77, 86))	('cancer', 'Phenotype', 'HP:0002664', (286, 292))	('aid', 'Gene', '57379', (260, 263))	('BRCA1', 'Gene', '672', (50, 55))	('BRCA1', 'Gene', (50, 55))	('RAD51', 'Gene', (70, 75))	('RAD51', 'Gene', '5888', (70, 75))	('rs12516', 'Mutation', 'rs12516', (57, 64))	('cancer', 'Disease', 'MESH:D009369', (286, 292))	('variants', 'Var', (38, 46))	('disease-free survival', 'CPA', (99, 120))	('lower', 'NegReg', (125, 130))	('rs12516', 'Var', (57, 64))	('better', 'PosReg', (92, 98))
504709	30901831	Transforming growth factor-beta (TGF-beta) controls cell growth and death through signaling with WWOX, and deficiency in this signaling facilitates cancer growth.	('signaling', 'MPA', (82, 91))	('cancer', 'Disease', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('death', 'Disease', 'MESH:D003643', (68, 73))	('death', 'Disease', (68, 73))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('deficiency', 'Var', (107, 117))	('TGF-beta', 'Gene', (33, 41))	('facilitates', 'PosReg', (136, 147))
504718	30901831	By knocking down miRNA-196b, migration and invasion was observed to decrease.	('miRNA-196b', 'Gene', '442920', (17, 27))	('decrease', 'NegReg', (68, 76))	('knocking down', 'Var', (3, 16))	('miRNA-196b', 'Gene', (17, 27))
504721	30901831	Other studies show that epigenetic regulation of miRNA-196b expression by more frequent hypomethylation of CpG islands upstream of the miRNA-196b gene promoted OSCC migration and invasion abilities.	('miRNA-196b', 'Gene', '442920', (135, 145))	('miRNA-196b', 'Gene', (49, 59))	('OSCC migration', 'CPA', (160, 174))	('miRNA-196b', 'Gene', (135, 145))	('promoted', 'PosReg', (151, 159))	('epigenetic regulation', 'Var', (24, 45))	('hypomethylation', 'Var', (88, 103))	('miRNA-196b', 'Gene', '442920', (49, 59))	('invasion abilities', 'CPA', (179, 197))
504722	30901831	Mice injected with miRNA-744-3p suppressed LSCC cells exhibited fewer metastatic cancer nodules when compared with the control group.	('LSCC cells', 'CPA', (43, 53))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('miRNA-744-3p', 'Var', (19, 31))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('cancer', 'Disease', (81, 87))	('Mice', 'Species', '10090', (0, 4))	('fewer', 'NegReg', (64, 69))	('suppressed', 'NegReg', (32, 42))
504723	30901831	To exert its effects, miRNA-744-3p targets PTEN and PDCD4.	('PTEN', 'Gene', (43, 47))	('miRNA-744-3p', 'Var', (22, 34))	('PDCD4', 'Gene', (52, 57))	('PTEN', 'Gene', '5728', (43, 47))	('PDCD4', 'Gene', '27250', (52, 57))
504728	30901831	As such, following miRNA-744-3p inhibition of PDCD4 and PTEN expression, MMP-9 is enhanced, leading to EMT and migration of LSCC.	('enhanced', 'PosReg', (82, 90))	('migration', 'CPA', (111, 120))	('EMT', 'CPA', (103, 106))	('PTEN', 'Gene', (56, 60))	('miRNA-744-3p', 'Var', (19, 31))	('PTEN', 'Gene', '5728', (56, 60))	('MMP-9', 'Gene', '4318', (73, 78))	('MMP-9', 'Gene', (73, 78))	('PDCD4', 'Gene', (46, 51))	('PDCD4', 'Gene', '27250', (46, 51))	('expression', 'MPA', (61, 71))
504734	30901831	In fact, FSCN1 knockdown also inhibited cell proliferation and increased cleavage of caspase-3.	('increased', 'PosReg', (63, 72))	('knockdown', 'Var', (15, 24))	('inhibited', 'NegReg', (30, 39))	('FSCN1', 'Gene', (9, 14))	('caspase-3', 'Gene', (85, 94))	('cleavage', 'MPA', (73, 81))	('cell proliferation', 'CPA', (40, 58))	('caspase-3', 'Gene', '836', (85, 94))
504736	30901831	Dysregulation of integrin expression may contribute to cancerous states, as is the case with integrin alpha3 (ITGA3), whose overexpression was confirmed in HNSCC specimens.	('expression', 'MPA', (26, 36))	('cancerous', 'Disease', (55, 64))	('ITGA3', 'Gene', (110, 115))	('Dysregulation', 'Var', (0, 13))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('integrin alpha3', 'Gene', (93, 108))	('cancerous', 'Disease', 'MESH:D009369', (55, 64))	('ITGA3', 'Gene', '3675', (110, 115))	('contribute', 'Reg', (41, 51))	('integrin alpha3', 'Gene', '3675', (93, 108))	('integrin', 'Protein', (17, 25))
504737	30901831	ITGA3 is directly regulated by all members of the miRNA-199 family, which includes miRNA-199a-5p, miRNA-199a-3p, miRNA-199b-5p, and miRNA-199b-3p.	('miRNA-199b-3p', 'Var', (132, 145))	('miRNA-199a-5p', 'Var', (83, 96))	('ITGA3', 'Gene', '3675', (0, 5))	('miRNA-199a-3p', 'Var', (98, 111))	('miRNA-199b-5p', 'Var', (113, 126))	('ITGA3', 'Gene', (0, 5))
504738	30901831	Restoration of miRNA-199 represses ITGA3 mRNA expression, which in turn inhibited HNSCC cell migration and invasion.	('ITGA3', 'Gene', (35, 40))	('represses', 'NegReg', (25, 34))	('Restoration', 'Var', (0, 11))	('miRNA-199', 'Gene', (15, 24))	('ITGA3', 'Gene', '3675', (35, 40))	('mRNA expression', 'MPA', (41, 56))	('inhibited', 'NegReg', (72, 81))
504742	30901831	Additionally, low levels of miRNA-203 was associated with LNM.	('associated', 'Reg', (42, 52))	('miRNA-203', 'Gene', '406986', (28, 37))	('low levels', 'Var', (14, 24))	('miRNA-203', 'Gene', (28, 37))	('LNM', 'Disease', (58, 61))
504744	30901831	By overexpressing miRNA-203 in HPC cells through transfection and downregulating PDPN, it was determined through wound-healing and invasion assays that these cells had slower cell migration and less cell invasion than control cells.	('downregulating', 'NegReg', (66, 80))	('cell invasion', 'CPA', (199, 212))	('HPC', 'Disease', 'MESH:C537262', (31, 34))	('less', 'NegReg', (194, 198))	('transfection', 'Var', (49, 61))	('slower', 'NegReg', (168, 174))	('HPC', 'Disease', (31, 34))	('miRNA-203', 'Gene', '406986', (18, 27))	('miRNA-203', 'Gene', (18, 27))	('overexpressing', 'PosReg', (3, 17))	('cell migration', 'CPA', (175, 189))	('PDPN', 'Gene', '10630', (81, 85))	('PDPN', 'Gene', (81, 85))
504746	30901831	When NUAK1 is transfected into OSCC cells, tumor invasion increased.	('increased', 'PosReg', (58, 67))	('NUAK1', 'Gene', '9891', (5, 10))	('transfected', 'Var', (14, 25))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('NUAK1', 'Gene', (5, 10))	('tumor', 'Disease', (43, 48))
504748	30901831	Restoration of miRNA-203 suppressed NUAK1, which decreased tumor invasion and LNM.	('miRNA-203', 'Gene', (15, 24))	('tumor', 'Disease', (59, 64))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('Restoration', 'Var', (0, 11))	('NUAK1', 'Gene', '9891', (36, 41))	('suppressed', 'NegReg', (25, 35))	('decreased', 'NegReg', (49, 58))	('LNM', 'CPA', (78, 81))	('NUAK1', 'Gene', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('miRNA-203', 'Gene', '406986', (15, 24))
504750	30901831	Similar to miRNA-203, mentioned above, miRNA-363 also targets PDPN.	('PDPN', 'Gene', (62, 66))	('targets', 'Reg', (54, 61))	('PDPN', 'Gene', '10630', (62, 66))	('miRNA-363', 'Var', (39, 48))	('miRNA-203', 'Gene', '406986', (11, 20))	('miRNA-363', 'Chemical', '-', (39, 48))	('miRNA-203', 'Gene', (11, 20))
504754	30901831	One common mechanism responsible for reduced or loss of miRNA expression is epigenetic silencing of miRNA genes by DNA methylation, a process that occurs early in tumorigenesis.	('loss', 'NegReg', (48, 52))	('epigenetic', 'Var', (76, 86))	('miRNA expression', 'MPA', (56, 72))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('tumor', 'Disease', (163, 168))	('miRNA genes', 'Gene', (100, 111))
504765	30901831	When comparing human cisplatin-sensitive tongue squamous cell carcinoma and cisplatin-resistant cell lines, there were significant increased levels of miRNA-23a, miRNA-214, miRNA-518c, miRNA-608, and the let-7 family of miRNAs.	('cisplatin', 'Chemical', 'MESH:D002945', (21, 30))	('carcinoma', 'Phenotype', 'HP:0030731', (62, 71))	('miRNA-23a', 'Gene', (151, 160))	('miRNA-518c', 'Var', (173, 183))	('increased', 'PosReg', (131, 140))	('tongue squamous cell carcinoma', 'Disease', (41, 71))	('miRNA-214', 'Gene', '406996', (162, 171))	('miRNA-608', 'MPA', (185, 194))	('cisplatin', 'Chemical', 'MESH:D002945', (76, 85))	('miRNA-214', 'Gene', (162, 171))	('miRNA-23a', 'Gene', '407010', (151, 160))	('human', 'Species', '9606', (15, 20))	('tongue squamous cell carcinoma', 'Phenotype', 'HP:0030413', (41, 71))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (48, 71))	('let-7', 'Gene', (204, 209))	('tongue squamous cell carcinoma', 'Disease', 'MESH:D002294', (41, 71))
504769	30901831	Transfection of OSCC cells with miRNA-125b enhanced radiosensitivity, likely through suppression of ICAM2, a protein that facilitates survival by activating the PI3K pathway.	('enhanced', 'PosReg', (43, 51))	('facilitates', 'PosReg', (122, 133))	('ICAM2', 'Gene', '3384', (100, 105))	('enhanced radiosensitivity', 'Phenotype', 'HP:0010997', (43, 68))	('survival', 'CPA', (134, 142))	('radiosensitivity', 'MPA', (52, 68))	('activating', 'Reg', (146, 156))	('PI3K pathway', 'Pathway', (161, 173))	('miRNA-125b', 'Chemical', '-', (32, 42))	('suppression', 'NegReg', (85, 96))	('ICAM2', 'Gene', (100, 105))	('miRNA-125b', 'Var', (32, 42))
504772	30901831	MiRNA-125b was also associated with N stage, metastasis, and death in HNSCC patients.	('metastasis', 'CPA', (45, 55))	('associated', 'Reg', (20, 30))	('patients', 'Species', '9606', (76, 84))	('death', 'Disease', 'MESH:D003643', (61, 66))	('death', 'Disease', (61, 66))	('MiRNA-125b', 'Var', (0, 10))	('N stage', 'CPA', (36, 43))
504777	30901831	They analyzed the miRNAs (let-7g-3p, miRNA-6508-5p, miRNA-210-5p, miRNA-4306, and miRNA-7161-3p) and divided the patients into high and low-risk groups based on their expression of these.	('miRNA-7161-3p', 'Var', (82, 95))	('let-7g', 'Gene', (26, 32))	('patients', 'Species', '9606', (113, 121))	('miRNA-21', 'Gene', (52, 60))	('let-7g', 'Gene', '406890', (26, 32))	('miRNA-4306', 'Var', (66, 76))	('miRNA-6508-5p', 'Var', (37, 50))	('miRNA-21', 'Gene', '406991', (52, 60))
504778	30901831	looked at a combination of four miRNAs (miRNA-21-3p, miRNA-21-5p, miRNA-96-5p, miRNA-429) in the area surrounding the tumor and its presence indicated higher risk of recurrence.	('miRNA-429', 'Var', (79, 88))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('presence', 'Var', (132, 140))	('miRNA-21', 'Gene', '406991', (53, 61))	('miRNA-21', 'Gene', '406991', (40, 48))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('miRNA-96', 'Gene', '407053', (66, 74))	('miRNA-21', 'Gene', (40, 48))	('tumor', 'Disease', (118, 123))	('miRNA-21', 'Gene', (53, 61))	('miRNA-96', 'Gene', (66, 74))
504781	30901831	The same group saw higher expression of four miRNAs (miRNA-96-5p, miRNA-21-3p, miRNA-141-3p, and miRNA-130b-3p) that predicted lower recurrence-free survival.	('expression', 'MPA', (26, 36))	('miRNA-141-3p', 'Var', (79, 91))	('recurrence-free survival', 'CPA', (133, 157))	('higher', 'PosReg', (19, 25))	('miRNA-96', 'Gene', (53, 61))	('lower', 'NegReg', (127, 132))	('miRNA-21', 'Gene', (66, 74))	('miRNA-130b-3p', 'Var', (97, 110))	('miRNA-96', 'Gene', '407053', (53, 61))	('miRNA-21', 'Gene', '406991', (66, 74))
504785	30901831	looked at 20 OSCC patients post-operatively, with a focus of three upregulated miRNAs (miRNA-148a-3p, miRNA-26a-5p and miRNA-21-5p) and three downregulated miRNAs (miRNA-375, miRNA-92b-3p and miRNA-486-5p).	('miRNA-486-5p', 'Var', (192, 204))	('miRNA-375', 'Gene', '494324', (164, 173))	('miRNA-26a-5p', 'Var', (102, 114))	('miRNA-21', 'Gene', '406991', (119, 127))	('miRNA-148a-3p', 'Var', (87, 100))	('downregulated', 'NegReg', (142, 155))	('patients', 'Species', '9606', (18, 26))	('miRNA-375', 'Gene', (164, 173))	('miRNA-92b-3p', 'Var', (175, 187))	('miRNA-21', 'Gene', (119, 127))	('upregulated', 'PosReg', (67, 78))
504786	30901831	The data showed a significant difference between the control group and the post-op group (9-12 months following surgery) for miRNA-486-5p, miRNA-375 and miRNA-92b-3p, with the downregulation of these indicating stronger OSCC recurrence.	('miRNA-375', 'Gene', (139, 148))	('stronger', 'PosReg', (211, 219))	('miRNA-92b-3p', 'Var', (153, 165))	('miRNA-375', 'Gene', '494324', (139, 148))	('miRNA-486-5p', 'Var', (125, 137))	('downregulation', 'NegReg', (176, 190))	('OSCC', 'Disease', (220, 224))
504788	30901831	lab identified miRNA-203 and miRNA-205 which were extremely sensitive markers for the detection of cervical lymph node metastases, even isolated cancer cells.	('miRNA-205', 'Var', (29, 38))	('cancer', 'Disease', (145, 151))	('cervical lymph node metastases', 'Phenotype', 'HP:0025289', (99, 129))	('miRNA-203', 'Gene', (15, 24))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('metastases', 'Disease', (119, 129))	('cervical lymph node', 'Disease', (99, 118))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('miRNA-203', 'Gene', '406986', (15, 24))	('metastases', 'Disease', 'MESH:D009362', (119, 129))
504791	30901831	In OSCC, tumors with low levels of miRNA-491-5p were more prone to develop LNM.	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('low levels', 'Var', (21, 31))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('tumors', 'Disease', (9, 15))	('develop LNM', 'CPA', (67, 78))	('miRNA-491-5p', 'Var', (35, 47))	('tumors', 'Disease', 'MESH:D009369', (9, 15))	('OSCC', 'Disease', (3, 7))
504792	30901831	Overexpression of miRNA-491-5p significantly inhibited migration and invasion of OSCC cells, and mice that were transfected with miRNA-491-5p experienced lung tumor areas that were reduced to 45% of the control.	('invasion of OSCC cells', 'CPA', (69, 91))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('miRNA-491-5p', 'Var', (129, 141))	('lung tumor', 'Disease', (154, 164))	('mice', 'Species', '10090', (97, 101))	('lung tumor', 'Disease', 'MESH:D008175', (154, 164))	('inhibited', 'NegReg', (45, 54))	('lung tumor', 'Phenotype', 'HP:0100526', (154, 164))
504797	30901831	In fact, miRNA-205 and miRNA-203, which was extensively discussed in Table 2, are capable of identifying all metastatic samples of HNSCC, regardless of the size of the metastatic deposit and the time of sample collection.	('miRNA-203', 'Gene', (23, 32))	('HNSCC', 'Disease', (131, 136))	('miRNA-203', 'Gene', '406986', (23, 32))	('miRNA-205', 'Var', (9, 18))
504802	30901831	Dysregulation of ATM function leads to upregulation of miRNA-16, miRNA-29b, miRNA-150, and miRNA-1254, while Let-7e is downregulated.	('miRNA-1254', 'Var', (91, 101))	('Dysregulation', 'Var', (0, 13))	('miRNA-150', 'Gene', (76, 85))	('miRNA-150', 'Gene', '406942', (76, 85))	('miRNA-16', 'Chemical', '-', (55, 63))	('Let-7e', 'Gene', (109, 115))	('upregulation', 'PosReg', (39, 51))	('ATM', 'Gene', (17, 20))	('miRNA-16', 'Gene', (55, 63))	('Let-7e', 'Gene', '406887', (109, 115))	('miRNA-29b', 'Gene', (65, 74))	('ATM', 'Gene', '472', (17, 20))
504804	30901831	Bcl-2 and MCL1, both anti-apoptotic factors, are regulated by miRNA-16 and miRNA-29b in leukemia and glioblastoma, respectively.	('glioblastoma', 'Disease', 'MESH:D005909', (101, 113))	('glioblastoma', 'Phenotype', 'HP:0012174', (101, 113))	('regulated', 'Reg', (49, 58))	('MCL1', 'Gene', '4170', (10, 14))	('miRNA-16', 'Var', (62, 70))	('miRNA-16', 'Chemical', '-', (62, 70))	('leukemia', 'Phenotype', 'HP:0001909', (88, 96))	('MCL1', 'Gene', (10, 14))	('miRNA-29b', 'Var', (75, 84))	('glioblastoma', 'Disease', (101, 113))	('Bcl-2', 'Gene', (0, 5))	('Bcl-2', 'Gene', '596', (0, 5))	('leukemia', 'Disease', (88, 96))	('leukemia', 'Disease', 'MESH:D007938', (88, 96))
504806	30901831	Another important miRNA, miRNA-196a, serves as an oncogenic miRNA in HNSCC, which is similar to the role of its family member, miRNA-196b, as mentioned in Table 1.	('HNSCC', 'Disease', (69, 74))	('miRNA-196a', 'Var', (25, 35))	('miRNA-196b', 'Gene', (127, 137))	('miRNA-196b', 'Gene', '442920', (127, 137))
504809	30901831	Further, miRNA-196a was found to directly suppress ANXA1.	('suppress', 'NegReg', (42, 50))	('miRNA-196a', 'Var', (9, 19))	('ANXA1', 'Gene', '301', (51, 56))	('ANXA1', 'Gene', (51, 56))
504811	30901831	Unsurprisingly, ANXA1 silencing induces the same effects in the HNSCC cell lines as that of miRNA-196a overexpression.	('silencing', 'Var', (22, 31))	('ANXA1', 'Gene', '301', (16, 21))	('ANXA1', 'Gene', (16, 21))
504812	30901831	Previously, it was determined that miRNA-125b enhances radiosensitivity in OSCC patients, but serves as a prognostic biomarker in metastatic HNSCC.	('enhances', 'PosReg', (46, 54))	('patients', 'Species', '9606', (80, 88))	('miRNA-125b', 'Chemical', '-', (35, 45))	('radiosensitivity', 'MPA', (55, 71))	('metastatic HNSCC', 'Disease', (130, 146))	('miRNA-125b', 'Var', (35, 45))	('OSCC', 'Disease', (75, 79))
504815	30901831	Laryngeal CSCs were initially determined to be resistant to cisplatin treatment, but overexpressing miRNA-125b enhanced cisplatin-induced cell death in the CSCs.	('miRNA-125b', 'Chemical', '-', (100, 110))	('death', 'Disease', 'MESH:D003643', (143, 148))	('death', 'Disease', (143, 148))	('miRNA-125b', 'Var', (100, 110))	('enhanced', 'PosReg', (111, 119))	('cisplatin-induced', 'MPA', (120, 137))	('cisplatin', 'Chemical', 'MESH:D002945', (120, 129))	('cisplatin', 'Chemical', 'MESH:D002945', (60, 69))
504825	31329578	Aberrant DNA methylation defines isoform usage in cancer, with functional implications Alternative transcript isoforms are common in tumors and act as potential drivers of cancer.	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('cancer', 'Disease', (50, 56))	('Aberrant', 'Var', (0, 8))	('tumors', 'Disease', (133, 139))	('tumors', 'Disease', 'MESH:D009369', (133, 139))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('cancer', 'Disease', (172, 178))
504830	31329578	Finally, methylation-correlated isoforms were enriched for oncogenes, tumor suppressors, and cancer-related pathways.	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', (70, 75))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('oncogenes', 'Gene', (59, 68))	('methylation-correlated', 'Var', (9, 31))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
504831	31329578	These findings provide new insights into the functional impact of dysregulated DNA methylation in cancer and highlight the relationship between the epigenome and transcriptome.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('DNA', 'Protein', (79, 82))	('dysregulated', 'Var', (66, 78))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('cancer', 'Disease', (98, 104))
504833	31329578	Given that dysregulation of DNA methylation is a cancer hallmark, we suspect the same regulation holds in cancer and contributes to cancer progression.	('cancer', 'Disease', (132, 138))	('DNA', 'Protein', (28, 31))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('cancer', 'Disease', (106, 112))	('dysregulation', 'Var', (11, 24))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('cancer', 'Disease', (49, 55))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
504841	31329578	To date, researchers seeking to learn more about the mechanisms underlying aberrant isoform activity in cancer have primarily focused on mutations in splicing regulatory sites or altered/deregulated splicing factors.	('splicing factor', 'Gene', (199, 214))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('mutations', 'Var', (137, 146))	('splicing factor', 'Gene', '10569', (199, 214))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))
504842	31329578	For example, we now know that mutations in the tumor suppressor gene BRCA1 cause inappropriate exon skipping and inactivation of BRCA1, whereas upregulation of NUMA1 splice isoforms in breast cancer cause increased cell proliferation.	('inactivation', 'MPA', (113, 125))	('increased', 'PosReg', (205, 214))	('BRCA1', 'Gene', '672', (129, 134))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('upregulation', 'PosReg', (144, 156))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('BRCA1', 'Gene', (129, 134))	('NUMA1', 'Gene', (160, 165))	('NUMA1', 'Gene', '4926', (160, 165))	('cell proliferation', 'CPA', (215, 233))	('breast cancer', 'Phenotype', 'HP:0003002', (185, 198))	('mutations', 'Var', (30, 39))	('tumor', 'Disease', (47, 52))	('exon', 'MPA', (95, 99))	('BRCA1', 'Gene', '672', (69, 74))	('breast cancer', 'Disease', 'MESH:D001943', (185, 198))	('breast cancer', 'Disease', (185, 198))	('BRCA1', 'Gene', (69, 74))	('tumor', 'Disease', 'MESH:D009369', (47, 52))
504846	31329578	Moreover, intragenic DNAm within exons or near exon boundaries can regulate alternative splicing outcomes by (1) preventing access of the DNA-binding protein CTCF, whose presence mediates local RNA polymerase II pausing for inclusion of weak exons or (2) facilitating access of the DNA-binding protein MeCP2, involved in inclusion of alternatively spliced exons.	('access', 'MPA', (124, 130))	('alternative splicing', 'MPA', (76, 96))	('regulate', 'Reg', (67, 75))	('CTCF', 'Gene', (158, 162))	('facilitating', 'PosReg', (255, 267))	('CTCF', 'Gene', '10664', (158, 162))	('DNAm', 'Var', (21, 25))	('MeCP2', 'Gene', '4204', (302, 307))	('preventing', 'NegReg', (113, 123))	('MeCP2', 'Gene', (302, 307))
504847	31329578	Affecting differential use of transcription termination sites, CGI methylation directs imprinting of murine H13 isoforms between paternal and maternal alleles.	('directs', 'Reg', (79, 86))	('murine', 'Species', '10090', (101, 107))	('imprinting', 'MPA', (87, 97))	('methylation', 'Var', (67, 78))
504849	31329578	In this study, recent advances in transcriptome sequencing and DNAm analysis, coupled with expansive collections of tumor samples, enabled us to test the hypothesis that DNAm dysregulation in cancers can disrupt isoform usage and contribute to tumorigenesis, as a common phenomenon.	('tumor', 'Phenotype', 'HP:0002664', (244, 249))	('DNAm', 'Gene', (170, 174))	('dysregulation', 'Var', (175, 188))	('tumor', 'Disease', (244, 249))	('isoform usage', 'MPA', (212, 225))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('cancers', 'Disease', 'MESH:D009369', (192, 199))	('cancers', 'Phenotype', 'HP:0002664', (192, 199))	('cancers', 'Disease', (192, 199))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('disrupt', 'NegReg', (204, 211))	('contribute', 'Reg', (230, 240))	('tumor', 'Disease', 'MESH:D009369', (244, 249))	('tumor', 'Disease', (116, 121))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))
504851	31329578	Based on a comprehensive analysis of data for 18 cancer types from The Cancer Genome Atlas (TCGA), we report that, within 11 cancer types, DNAm in the top 25% of variable methylated sites is associated with isoform switching, and this isoform switching is predicted to have functional consequences for tumorigenesis, involving 10-21% of genes.	('Cancer Genome Atlas', 'Disease', (71, 90))	('tumor', 'Phenotype', 'HP:0002664', (302, 307))	('tumor', 'Disease', 'MESH:D009369', (302, 307))	('Cancer', 'Phenotype', 'HP:0002664', (71, 77))	('isoform switching', 'MPA', (207, 224))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (71, 90))	('cancer', 'Disease', (125, 131))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('tumor', 'Disease', (302, 307))	('methylated sites', 'Var', (171, 187))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('associated', 'Reg', (191, 201))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('cancer', 'Disease', (49, 55))	('DNAm', 'Var', (139, 143))
504857	31329578	To further investigate the connection between DNAm and isoform usage, for each cancer type we identified methylation probes with the most variable values, which were most likely to behave differently across samples (i.e., those whose standard deviation across tumors fell within the top 25% for all sites).	('methylation', 'Var', (105, 116))	('tumors', 'Disease', 'MESH:D009369', (260, 266))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('tumors', 'Phenotype', 'HP:0002664', (260, 266))	('tumor', 'Phenotype', 'HP:0002664', (260, 265))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('tumors', 'Disease', (260, 266))
504866	31329578	We found negative correlations enriched among probes within OSRs, compared to other regions, in 9 out of 11 cancer types (#gene = 232) (Fig 1C) whereas the same enrichment was seen for CGIs in only 6 out of 11 cancer types, suggesting that TSS-correlated DNAm need not be confined to CGIs to impact transcription initiation.	('probes', 'Var', (46, 52))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('transcription initiation', 'MPA', (299, 323))	('impact', 'Reg', (292, 298))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (210, 216))	('negative', 'NegReg', (9, 17))	('cancer', 'Disease', (210, 216))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
504868	31329578	These findings suggest that, across most cancer types, DNAm at isoform positions > = exon 4 correlates with inclusion of distal exons in the gene body, indicative of transcriptional elongation.	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('DNAm', 'Var', (55, 59))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('cancer', 'Disease', (41, 47))
504873	31329578	For example, the very long terminal exon in BHLHE41 contains two internal methylation sites positively correlated with the inclusion of a long terminal exon but negatively correlated with the shorter isoform (Fig 3C).	('BHLHE41', 'Gene', '79365', (44, 51))	('negatively', 'NegReg', (161, 171))	('inclusion', 'Var', (123, 132))	('BHLHE41', 'Gene', (44, 51))	('correlated', 'Reg', (103, 113))
504887	31329578	To determine whether these subtype-discerning, isoform switching-linked DNAm alterations could impact tumorigenesis, we analyzed the functional outcomes of isoform switching among BRCA subtype samples, and also in normal breast tissue samples, using software designed for this purpose, IsoformSwitchAnalyzeR.	('impact', 'Reg', (95, 101))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('BRCA', 'Gene', (180, 184))	('alterations', 'Var', (77, 88))	('BRCA', 'Gene', '672', (180, 184))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))
504896	31329578	Nevertheless, the overrepresentation remained statistically significant across all n values (hypergeometric test; p < 1E-2) (S1 Table), suggesting DNAm-correlated isoform alterations may be positively selected in cancer-related genes, consistent with our hypothesis.	('cancer', 'Disease', 'MESH:D009369', (213, 219))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('alterations', 'Var', (171, 182))	('cancer', 'Disease', (213, 219))
504901	31329578	Thus, alteration of the DNAm of these genes may correspond to alteration of their functional domains and influence pathway functions in many types of cancer.	('influence', 'Reg', (105, 114))	('DNAm', 'MPA', (24, 28))	('pathway functions', 'CPA', (115, 132))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('functional domains', 'MPA', (82, 100))	('cancer', 'Disease', (150, 156))	('alteration', 'Var', (6, 16))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('alteration', 'Reg', (62, 72))
504905	31329578	Thus, this study shows that DNAm-correlated isoform usage alterations are common, could functionally contribute to cancer processes, and represent a new paradigm in the cancer epigenomic landscape.	('contribute', 'Reg', (101, 111))	('cancer', 'Disease', (115, 121))	('cancer', 'Disease', (169, 175))	('isoform usage', 'MPA', (44, 57))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('cancer', 'Disease', 'MESH:D009369', (169, 175))	('alterations', 'Var', (58, 69))
504907	31329578	These correlations suggest a potential blueprint for DNAm-regulated isoform activities worthy of further experimental elucidation while controlling for other isoform-regulating mechanisms such as aforementioned splicing factor alterations and recently reported regulation via miRNA binding at 3'UTRs.	('miRNA', 'Protein', (276, 281))	('alterations', 'Var', (227, 238))	('splicing factor', 'Gene', '10569', (211, 226))	('splicing factor', 'Gene', (211, 226))
504910	31329578	Thus, most cancer studies have focused on causal relationships between aberrant promoter hypermethylation and tumor suppressor gene silencing, paying less attention to the functional consequences of intragenic DNAm alterations.	('silencing', 'NegReg', (132, 141))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('promoter', 'MPA', (80, 88))	('paying less attention', 'Phenotype', 'HP:0000736', (143, 164))	('cancer', 'Disease', 'MESH:D009369', (11, 17))	('cancer', 'Disease', (11, 17))	('aberrant', 'Var', (71, 79))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
504913	31329578	Integrative analysis of these factors (using ChIP-Seq datasets, for example) coupled with exon-level expression data may provide insights into a mechanistic link between DNAm alterations and deleterious alternative splicing in cancer.	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('DNAm', 'MPA', (170, 174))	('cancer', 'Disease', (227, 233))	('cancer', 'Disease', 'MESH:D009369', (227, 233))	('alterations', 'Var', (175, 186))
504923	31329578	The following types of probes were removed from the analysis: (i) probes on the X and Y chromosomes, (ii) cross-reactive probes, (iii) probes near single nucleotide polymorphisms, and (iv) probes with missing rates >= 90% across all samples for a given cancer type.	('single nucleotide polymorphisms', 'Var', (147, 178))	('cancer', 'Disease', 'MESH:D009369', (253, 259))	('cancer', 'Disease', (253, 259))	('cancer', 'Phenotype', 'HP:0002664', (253, 259))	('probes', 'Var', (135, 141))
504931	30420492	 TP73 G4C14-A4T14 polymorphism and cancer susceptibility: evidence from 36 case-control studies G4C14-A4T14 polymorphism of TP73 gene has been reported with a potential association in cancer risks through affected cell homeostasis; however the results were not consistent.	('cancer', 'Disease', (184, 190))	('association', 'Reg', (169, 180))	('TP73', 'Gene', '7161', (124, 128))	('TP73', 'Gene', (124, 128))	('polymorphism', 'Var', (108, 120))	('G4C14-A4T14 polymorphism', 'Var', (96, 120))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('TP73', 'Gene', '7161', (1, 5))	('TP73', 'Gene', (1, 5))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('cancer', 'Disease', (35, 41))
504932	30420492	We performed a comprehensive meta-analysis to explore the associations between G4C14-A4T14 polymorphism and cancer susceptibility.	('associations', 'Interaction', (58, 70))	('G4C14-A4T14', 'Var', (79, 90))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
504935	30420492	The pooled results present a significantly higher risk of G4C14-A4T14 polymorphism in all the five genetic models, as well as in the subgroups of Caucasian, cervical cancer, colorectal cancer, H-B subgroup and comfort to Hardy-Weinberg equilibrium subgroup.	('G4C14-A4T14 polymorphism', 'Var', (58, 82))	('colorectal cancer', 'Phenotype', 'HP:0003003', (174, 191))	('higher', 'PosReg', (43, 49))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('polymorphism', 'Var', (70, 82))	('cervical cancer', 'Disease', 'MESH:D002583', (157, 172))	('colorectal cancer', 'Disease', (174, 191))	('cervical cancer', 'Disease', (157, 172))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('colorectal cancer', 'Disease', 'MESH:D015179', (174, 191))
504938	30420492	G4C14-A4T14 polymorphism might be a potential biomarker for judging the tumorigenesis of cervical cancer and colorectal cancer.	('colorectal cancer', 'Disease', (109, 126))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Disease', (72, 77))	('cervical cancer', 'Disease', 'MESH:D002583', (89, 104))	('colorectal cancer', 'Disease', 'MESH:D015179', (109, 126))	('cervical cancer', 'Disease', (89, 104))	('polymorphism', 'Var', (12, 24))	('G4C14-A4T14', 'Gene', (0, 11))	('colorectal cancer', 'Phenotype', 'HP:0003003', (109, 126))	('tumor', 'Disease', 'MESH:D009369', (72, 77))
504944	30420492	In the past decades, biological scientists have reported that environmental factors, genetic mutations and the multiple interactions between them mainly affect the process of tumorigenesis, and the new research results are also on the road, such as epigenetic control.	('tumor', 'Disease', (175, 180))	('interactions', 'Interaction', (120, 132))	('affect', 'Reg', (153, 159))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('genetic mutations', 'Var', (85, 102))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))
504948	30420492	G4A (rs2273953) and C14T (rs1801173), the two single-nucleotide polymorphisms (SNPs) of TP73 at positions 4 (G>A) and 14 (C>T), are incomplete linkage disequilibrium with each other, so we called it as G4C14-A4T14.	('C14T', 'Mutation', 'rs1801173', (20, 24))	('TP73', 'Gene', '7161', (88, 92))	('rs2273953', 'Var', (5, 14))	('rs1801173', 'Var', (26, 35))	('TP73', 'Gene', (88, 92))	('rs1801173', 'Mutation', 'rs1801173', (26, 35))	('14 (C>T)', 'Mutation', 'rs1801173', (118, 126))	('rs2273953', 'Mutation', 'rs2273953', (5, 14))	('G4A', 'Mutation', 'rs2273953', (0, 3))
504949	30420492	G4C14-A4T14 is located at the upstream of TP73 promoter in exon 2, it could influence the expression of TP73 through a stem-loop structure.	('TP73', 'Gene', '7161', (104, 108))	('TP73', 'Gene', (104, 108))	('G4C14-A4T14', 'Var', (0, 11))	('TP73', 'Gene', '7161', (42, 46))	('TP73', 'Gene', (42, 46))	('expression', 'MPA', (90, 100))	('influence', 'Reg', (76, 85))
504950	30420492	In recent years, G4C14-A4T14 polymorphism of TP73 was identified implicated in the tumorigenesis of a variety of cancer types, including breast cancer, colorectal cancer, lung cancer, cervical cancer, esophageal cancer and so on.	('cervical cancer', 'Disease', (184, 199))	('colorectal cancer', 'Disease', 'MESH:D015179', (152, 169))	('cervical cancer', 'Disease', 'MESH:D002583', (184, 199))	('cancer', 'Disease', (193, 199))	('tumor', 'Disease', (83, 88))	('lung cancer', 'Phenotype', 'HP:0100526', (171, 182))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('cancer', 'Disease', (113, 119))	('cancer', 'Disease', (144, 150))	('cancer', 'Disease', 'MESH:D009369', (212, 218))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('colorectal cancer', 'Disease', (152, 169))	('esophageal cancer', 'Disease', 'MESH:D004938', (201, 218))	('implicated in', 'Reg', (65, 78))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('cancer', 'Disease', 'MESH:D009369', (163, 169))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('TP73', 'Gene', '7161', (45, 49))	('esophageal cancer', 'Disease', (201, 218))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('TP73', 'Gene', (45, 49))	('breast cancer', 'Phenotype', 'HP:0003002', (137, 150))	('G4C14-A4T14 polymorphism', 'Var', (17, 41))	('lung cancer', 'Disease', (171, 182))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('colorectal cancer', 'Phenotype', 'HP:0003003', (152, 169))	('cancer', 'Disease', (212, 218))	('cancer', 'Disease', (163, 169))	('breast cancer', 'Disease', 'MESH:D001943', (137, 150))	('breast cancer', 'Disease', (137, 150))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('cancer', 'Disease', (176, 182))	('lung cancer', 'Disease', 'MESH:D008175', (171, 182))
504952	30420492	Therefore, we conducted a comprehensive meta-analysis to explore the association between G4C14-A4T14 polymorphism and cancer susceptibility.	('cancer', 'Disease', (118, 124))	('G4C14-A4T14', 'Gene', (89, 100))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('polymorphism', 'Var', (101, 113))	('cancer', 'Disease', 'MESH:D009369', (118, 124))
504954	30420492	The full-text of the remaining articles was further carefully inspected to determine whether to report the correlation of between G4C14-A4T14 polymorphism and cancer susceptibility.	('cancer', 'Disease', (159, 165))	('G4C14-A4T14', 'Gene', (130, 141))	('polymorphism', 'Var', (142, 154))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('cancer', 'Disease', 'MESH:D009369', (159, 165))
504955	30420492	All the eligible studies should fulfill the following inclusion criteria: (1) case-control studies focus on the correlation between G4C14-A4T14 polymorphism and cancer susceptibility; (2) genotype frequency of the cases and controls could be obtained directly or indirectly through calculation; and (3) articles in English or Chinese.	('polymorphism', 'Var', (144, 156))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('cancer', 'Disease', (161, 167))	('G4C14-A4T14', 'Gene', (132, 143))
504956	30420492	ORs with corresponding 95% CIs were performed to measure the strength of the relationship between G4C14-A4T14 polymorphism and cancer susceptibility.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('polymorphism', 'Var', (110, 122))	('G4C14-A4T14', 'Gene', (98, 109))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('cancer', 'Disease', (127, 133))
504962	30420492	After reviewing titles and abstracts, we excluded 1537 publications not investigating the association between TP73 G4C14-A4T14 polymorphism and cancer risk.	('polymorphism', 'Var', (127, 139))	('TP73', 'Gene', '7161', (110, 114))	('TP73', 'Gene', (110, 114))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('cancer', 'Disease', (144, 150))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
504965	30420492	Table 2 listed the main results of current meta-analysis work of polymorphisms in G4C14-A4T14 and risk of cancer.	('G4C14-A4T14', 'Gene', (82, 93))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('polymorphisms', 'Var', (65, 78))	('cancer', 'Disease', (106, 112))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
504966	30420492	The pooled results of the 36 included studies had shown that G4C14-A4T14 polymorphism conferred a significantly higher overall risk to cancer susceptibility in all the five genetic models, allelic contrast model (GC vs. AT: OR = 1.139, 95% CI = 1.048-1.238, P=0.002), homozygote comparison model (GC/GC vs. AT/AT: OR = 1.320, 95% CI = 1.071-1.627, P=0.009), heterozygote comparison model (GC/AT vs. AT/AT: OR = 1.123, 95% CI = 1.012-1.245, P=0.028), dominant comparison model (GC/GC+GC/AT vs. AT/AT: OR = 1.152, 95% CI = 1.044-1.272, P=0.005) and recessive comparison model (GC/GC vs. GC/AT+AT/AT: OR = 1.273, 95% CI = 1.038-1.563, P=0.021) (Table 2 and Figure 2).	('cancer', 'Disease', (135, 141))	('higher', 'PosReg', (112, 118))	('G4C14-A4T14 polymorphism', 'Var', (61, 85))	('polymorphism', 'Var', (73, 85))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('cancer', 'Disease', 'MESH:D009369', (135, 141))
504967	30420492	After overall pooled analysis, we also conducted stratification analysis by cancer type, in order to obtain more precise result about the G4C14-A4T14 polymorphism and cancer susceptibility.	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('cancer', 'Disease', (167, 173))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('G4C14-A4T14', 'Var', (138, 149))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))
504968	30420492	As shown in Table 2 and Figure 3, the subgroup analysis of six enrolled colorectal cancer related studies have shown that G4C14-A4T14 polymorphism was related to an increased cancer risk in allelic contrast model (GC vs. AT: OR = 1.204, 95% CI = 1.044-1.389, P=0.011), homozygote comparison model (GC/GC vs. AT/AT: OR = 1.820, 95% CI = 1.270-2.608, P=0.001) and recessive comparison model (GC/GC vs. GC/AT+AT/AT: OR = 1.760, 95% CI = 1.241-2.496, P=0.002).	('colorectal cancer', 'Disease', 'MESH:D015179', (72, 89))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('G4C14-A4T14 polymorphism', 'Var', (122, 146))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('cancer', 'Disease', (175, 181))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('colorectal cancer', 'Phenotype', 'HP:0003003', (72, 89))	('colorectal cancer', 'Disease', (72, 89))	('polymorphism', 'Var', (134, 146))	('cancer', 'Disease', (83, 89))
504970	30420492	The meta-analysis revealed an increasing risk of cancer caused by G4C14-A4T14 polymorphism in allelic contrast model (GC vs. AT: OR = 1.189, 95% CI = 1.016-1.392, P=0.031), heterozygote comparison model (GC/AT vs. AT/AT: OR = 1.413, 95% CI = 1.159-1.722, P=0.001) and dominant comparison model (GC/GC+GC/AT vs. AT/AT: OR = 1.338, 95% CI = 1.106-1.618, P=0.003) (Table 2, Figure 4).	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('G4C14-A4T14', 'Var', (66, 77))	('cancer', 'Disease', (49, 55))	('cancer', 'Disease', 'MESH:D009369', (49, 55))
504971	30420492	We also performed subgroup analysis of breast cancer, esophageal cancer, gastric cancer, lung cancer and squamous cell carcinoma of the head and neck, no significant association was found between G4C14-A4T14 polymorphism and these carcinomas in all five genetic models (Table 2 and Figures S1-S4).	('breast cancer', 'Phenotype', 'HP:0003002', (39, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (231, 240))	('breast cancer', 'Disease', 'MESH:D001943', (39, 52))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (105, 128))	('lung cancer', 'Disease', 'MESH:D008175', (89, 100))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('breast cancer', 'Disease', (39, 52))	('gastric cancer', 'Disease', 'MESH:D013274', (73, 87))	('lung cancer', 'Phenotype', 'HP:0100526', (89, 100))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('carcinomas', 'Phenotype', 'HP:0030731', (231, 241))	('carcinomas', 'Disease', 'MESH:D002277', (231, 241))	('squamous cell carcinoma', 'Disease', (105, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('gastric cancer', 'Phenotype', 'HP:0012126', (73, 87))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('polymorphism', 'Var', (208, 220))	('carcinoma of the head and neck', 'Phenotype', 'HP:0012288', (119, 149))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('esophageal cancer', 'Disease', 'MESH:D004938', (54, 71))	('lung cancer', 'Disease', (89, 100))	('G4C14-A4T14', 'Gene', (196, 207))	('esophageal cancer', 'Disease', (54, 71))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (105, 128))	('carcinomas', 'Disease', (231, 241))	('gastric cancer', 'Disease', (73, 87))
504973	30420492	The remarkable result shown a noticeable upgrade cancer risk of G4C14-A4T14 polymorphism of the hospital-based control subgroup in allelic contrast model (GC vs. AT: OR = 1.213, 95%CI = 1.079-1.365, P=0.001), homozygote comparison model (GC/GC vs. AT/AT: OR = 1.625, 95% CI = 1.210-2.183 P=0.001), dominant comparison model (GC/GC+GC/AT vs. AT/AT: OR = 1.204, 95% CI = 1.042-1.392, P=0.012) and recessive comparison model (GC/GC vs. GC/AT+AT/AT: OR = 1.545, 95% CI = 1.139-2.094, P=0.005), while there was no significant result of the heterozygote comparison model (GC/AT vs. AT/AT: OR = 1.134, 95% CI = 0.964-1.334, P=0.129).	('upgrade', 'PosReg', (41, 48))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('G4C14-A4T14', 'Var', (64, 75))	('cancer', 'Disease', (49, 55))
504975	30420492	As shown in Table 2 and Figure S7, the subgroup that conforms to HWE was uncovered responsible to the remarkable increasing cancer risk of G4C14-A4T14 polymorphism in allelic contrast model (GC vs. AT: OR = 1.138, 95%CI = 1.044-1.239, P=0.003), homozygote comparison model (GC/GC vs. AT/AT: OR = 1.342, 95% CI = 1.085-1.659, P=0.007), dominant comparison model (GC/GC+GC/AT vs. AT/AT: OR = 1.138, 95% CI = 1.032-1.255, P=0.010) and recessive comparison model (GC/GC vs. GC/AT+AT/AT: OR = 1.309, 95% CI = 1.063-1.613, P=0.011), whereas the other four case-control studies that do not conform to HWE did not influence the result in overall cancer (Table 2 and Figure S7).	('cancer', 'Disease', (124, 130))	('polymorphism', 'Var', (151, 163))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('cancer', 'Disease', (638, 644))	('cancer', 'Disease', 'MESH:D009369', (638, 644))	('G4C14-A4T14', 'Var', (139, 150))	('cancer', 'Disease', 'MESH:D009369', (124, 130))	('cancer', 'Phenotype', 'HP:0002664', (638, 644))
504987	30420492	In the past decades, almost 146 unique variations had been reported (shown in the Biomuta database), while numerous studies had probed into the relationship of G4C14-A4T14 polymorphism and cancer genomics.	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('variations', 'Var', (39, 49))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('G4C14-A4T14', 'Gene', (160, 171))	('cancer', 'Disease', (189, 195))
504988	30420492	G4A (rs2273953) and C14T (rs1801173) polymorphisms are located at position 4 (G to A) and 14 (C to T) of exon 2 5'-untranslated region, which might influence the initiating AUG codon through constructing a stem-loop.	('4 (G to A', 'Mutation', 'rs2273953', (75, 84))	('14 (C to T', 'Mutation', 'rs1801173', (90, 100))	('C14T', 'Mutation', 'rs1801173', (20, 24))	('influence', 'Reg', (148, 157))	('rs2273953', 'Var', (5, 14))	('rs1801173', 'Var', (26, 35))	('rs1801173', 'Mutation', 'rs1801173', (26, 35))	('G4A', 'Mutation', 'rs2273953', (0, 3))	('rs2273953', 'Mutation', 'rs2273953', (5, 14))
504989	30420492	reported that G4C14-A4T14 polymorphism was not associated with the cancer susceptibility of cervical cancer in Uighur and Japanese, respectively.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('cancer', 'Disease', (67, 73))	('cancer', 'Disease', (101, 107))	('cervical cancer', 'Disease', 'MESH:D002583', (92, 107))	('G4C14-A4T14 polymorphism', 'Var', (14, 38))	('cervical cancer', 'Disease', (92, 107))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('polymorphism', 'Var', (26, 38))
504990	30420492	revealed that G4C14-A4T14 polymorphism leads to an increasing risk of cervical cancer, as well as the newest study conducted by Feng et al..As colorectal cancer, Hamajima et al.	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('colorectal cancer', 'Disease', (143, 160))	('G4C14-A4T14 polymorphism', 'Var', (14, 38))	('colorectal cancer', 'Disease', 'MESH:D015179', (143, 160))	('cervical cancer', 'Disease', (70, 85))	('cervical cancer', 'Disease', 'MESH:D002583', (70, 85))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('colorectal cancer', 'Phenotype', 'HP:0003003', (143, 160))	('polymorphism', 'Var', (26, 38))
504991	30420492	reported that GC/AT and AT/AT genotypes were significantly associated with colorectal cancer risk in Korean population.	('colorectal cancer', 'Disease', (75, 92))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('colorectal cancer', 'Disease', 'MESH:D015179', (75, 92))	('AT/AT', 'Var', (24, 29))	('associated', 'Reg', (59, 69))	('colorectal cancer', 'Phenotype', 'HP:0003003', (75, 92))	('GC/AT', 'Var', (14, 19))
504992	30420492	also uncovered that no remarkable differences of genotype frequencies in cancers and controls, but they found that AT/AT genotype might cause the poor prognosis of colorectal cancer.	('cancers', 'Disease', (73, 80))	('colorectal cancer', 'Phenotype', 'HP:0003003', (164, 181))	('colorectal cancer', 'Disease', (164, 181))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('colorectal cancer', 'Disease', 'MESH:D015179', (164, 181))	('cancers', 'Disease', 'MESH:D009369', (73, 80))	('AT/AT genotype', 'Var', (115, 129))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
504994	30420492	indicated that both AT/AT and GC/AT variants were associated with a remarkable decreased risk for lung cancer, distinguishingly, Li et al.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('lung cancer', 'Disease', (98, 109))	('decreased', 'NegReg', (79, 88))	('lung cancer', 'Phenotype', 'HP:0100526', (98, 109))	('variants', 'Var', (36, 44))	('lung cancer', 'Disease', 'MESH:D008175', (98, 109))
504995	30420492	suggested that the AT/AT and GC/AT genotypes were related with a statistically significantly increased risk for lung cancer.	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('GC/AT', 'Var', (29, 34))	('lung cancer', 'Disease', (112, 123))	('lung cancer', 'Phenotype', 'HP:0100526', (112, 123))	('lung cancer', 'Disease', 'MESH:D008175', (112, 123))	('AT/AT', 'Var', (19, 24))
504997	30420492	Among these publications concerned about G4C14-A4T14 polymorphism and cancer risk, the result is not consistent.	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('G4C14-A4T14', 'Gene', (41, 52))	('polymorphism', 'Var', (53, 65))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))
504998	30420492	conducted a meta-analysis about G4C14-A4T14 polymorphism and cervical cancer, they only enrolled 5 studies, as well as Liu et al., they only enrolled 5 studies about lung cancer.	('G4C14-A4T14', 'Gene', (32, 43))	('cervical cancer', 'Disease', 'MESH:D002583', (61, 76))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('lung cancer', 'Disease', 'MESH:D008175', (166, 177))	('cervical cancer', 'Disease', (61, 76))	('polymorphism', 'Var', (44, 56))	('lung cancer', 'Disease', (166, 177))	('lung cancer', 'Phenotype', 'HP:0100526', (166, 177))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))
504999	30420492	All in all, our recent updated meta-analysis draws a comprehensive, precise and convincible result, which is that G4C14-A4T14 polymorphism of TP73 is strongly associated with the increasing cancer risk, especially for Caucasian, cervical cancer and colorectal cancer.	('colorectal cancer', 'Disease', (249, 266))	('TP73', 'Gene', '7161', (142, 146))	('cancer', 'Disease', 'MESH:D009369', (260, 266))	('cancer', 'Disease', (190, 196))	('cancer', 'Disease', (238, 244))	('cervical cancer', 'Disease', (229, 244))	('cervical cancer', 'Disease', 'MESH:D002583', (229, 244))	('TP73', 'Gene', (142, 146))	('associated with', 'Reg', (159, 174))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('G4C14-A4T14 polymorphism', 'Var', (114, 138))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('colorectal cancer', 'Phenotype', 'HP:0003003', (249, 266))	('cancer', 'Disease', (260, 266))	('cancer', 'Phenotype', 'HP:0002664', (260, 266))	('cancer', 'Disease', 'MESH:D009369', (190, 196))	('cancer', 'Disease', 'MESH:D009369', (238, 244))	('colorectal cancer', 'Disease', 'MESH:D015179', (249, 266))	('polymorphism', 'Var', (126, 138))
505000	30420492	Therefore, in the future, G4C14-A4T14 polymorphism might be a useful diagnostic marker for cervical cancer and colorectal cancer, especially in Caucasian population.	('polymorphism', 'Var', (38, 50))	('colorectal cancer', 'Disease', 'MESH:D015179', (111, 128))	('cervical cancer', 'Disease', (91, 106))	('cervical cancer', 'Disease', 'MESH:D002583', (91, 106))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('colorectal cancer', 'Phenotype', 'HP:0003003', (111, 128))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('colorectal cancer', 'Disease', (111, 128))	('G4C14-A4T14 polymorphism', 'Var', (26, 50))
505001	30420492	On the other hand, for researchers, other polymorphisms of TP73 should be focused on to assess whether they change cancer risks.	('TP73', 'Gene', '7161', (59, 63))	('cancer', 'Disease', (115, 121))	('TP73', 'Gene', (59, 63))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('polymorphisms', 'Var', (42, 55))	('change', 'Reg', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (115, 121))
505002	30420492	The current result about G4C14-A4T14 polymorphism and cancer risk should be cautiously interpreted, because there are some limitations.	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('cancer', 'Disease', (54, 60))	('G4C14-A4T14', 'Gene', (25, 36))	('polymorphism', 'Var', (37, 49))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
505005	30420492	In conclusion, our meta-analysis had successfully elaborated that TP73 G4C14-A4T14 polymorphism causes an upgrade cancer risk, especially in Caucasian population.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('TP73', 'Gene', '7161', (66, 70))	('TP73', 'Gene', (66, 70))	('polymorphism', 'Var', (83, 95))	('causes', 'Reg', (96, 102))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('cancer', 'Disease', (114, 120))
505017	26912435	In vivo PET imaging and ex vivo biodistribution studies in mice with breast, lung and esophageal cancer xenografts consistently showed enhanced 89Zr-ACKR3-mAb uptake in high ACKR3 expressing tumors.	('tumors', 'Phenotype', 'HP:0002664', (191, 197))	('high', 'Var', (169, 173))	('mice', 'Species', '10090', (59, 63))	('tumors', 'Disease', 'MESH:D009369', (191, 197))	('89Zr-ACKR3-mAb uptake', 'MPA', (144, 165))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('enhanced', 'PosReg', (135, 143))	('breast, lung and esophageal cancer', 'Disease', 'MESH:D004938', (69, 103))	('tumors', 'Disease', (191, 197))
505030	26912435	Attesting to this fact, small molecule ACKR3 inhibitors have been shown to limit tumor growth in syngenic mouse models of human breast cancer, B lymphoma and lung carcinoma mouse models.	('human', 'Species', '9606', (122, 127))	('ACKR3', 'Gene', (39, 44))	('breast cancer', 'Disease', (128, 141))	('breast cancer', 'Disease', 'MESH:D001943', (128, 141))	('lymphoma', 'Phenotype', 'HP:0002665', (145, 153))	('limit', 'NegReg', (75, 80))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('lung carcinoma', 'Disease', 'MESH:D008175', (158, 172))	('B lymphoma', 'Disease', (143, 153))	('mouse', 'Species', '10090', (173, 178))	('tumor', 'Disease', (81, 86))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('inhibitors', 'Var', (45, 55))	('B lymphoma', 'Phenotype', 'HP:0012191', (143, 153))	('mouse', 'Species', '10090', (106, 111))	('carcinoma', 'Phenotype', 'HP:0030731', (163, 172))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('lung carcinoma', 'Disease', (158, 172))	('breast cancer', 'Phenotype', 'HP:0003002', (128, 141))	('B lymphoma', 'Disease', 'MESH:D016393', (143, 153))
505033	26912435	Perhaps more important is that ACKR3 silencing results in reversal of TGF-beta1-induced changes on epithelial-mesenchymal transition, cancer cell invasion and migration.	('ACKR3', 'Gene', (31, 36))	('TGF-beta1', 'Gene', '7040', (70, 79))	('TGF-beta1', 'Gene', (70, 79))	('cancer', 'Disease', (134, 140))	('silencing', 'Var', (37, 46))	('migration', 'CPA', (159, 168))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('epithelial-mesenchymal transition', 'CPA', (99, 132))
505034	26912435	Patients with high ACKR3 and TGF-beta1 levels, however, exhibited worse prognosis and survival rates.	('survival rates', 'CPA', (86, 100))	('ACKR3', 'Gene', (19, 24))	('high', 'Var', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('TGF-beta1', 'Gene', '7040', (29, 38))	('TGF-beta1', 'Gene', (29, 38))
505057	26912435	ACKR3 Expression levels were evaluated by flow cytometry and were shown to be in the order of 231-ACKR3>MCF7>MDA-MB-231-CXCR4 (231-CXCR4)>KYSE520>HCC95>231 (Fig.	('CXCR4', 'Gene', (131, 136))	('CXCR4', 'Gene', '7852', (120, 125))	('CXCR4', 'Gene', (120, 125))	('KYSE520', 'Var', (138, 145))	('MDA-MB-231-CXCR4', 'CellLine', 'CVCL:0062', (109, 125))	('MCF7', 'CellLine', 'CVCL:0031', (104, 108))	('CXCR4', 'Gene', '7852', (131, 136))	('HCC95', 'CellLine', 'CVCL:5137', (146, 151))
505061	26912435	The highest 231-ACKR3 to 231 tumor ratio (5.1+-0.4) was observed with a 9MBq/100microg (250microCi/100microg) mAb dose per mouse (Fig.	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('mouse', 'Species', '10090', (123, 128))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumor', 'Disease', (29, 34))	('9MBq', 'Chemical', '-', (72, 76))	('9MBq/100microg', 'Var', (72, 86))
505062	26912435	PET-CT imaging of NOG mice baring 231-ACKR3 and 231 tumors over 120h indicated preferential uptake of 89Zr-ACKR3-mAb by 231-ACKR3, compared to 231, tumors (Fig.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('preferential', 'PosReg', (79, 91))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('231-ACKR3', 'Var', (120, 129))	('tumors', 'Disease', (52, 58))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('tumors', 'Disease', (148, 154))	('tumors', 'Disease', 'MESH:D009369', (148, 154))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('mice', 'Species', '10090', (22, 26))
505069	26912435	89Zr-ACKR3-mAb-PET successfully visualized ACKR3 overexpressing ER+ luminal A MCF-7 breast cancer xenografts in NOG mice (Fig.	('mice', 'Species', '10090', (116, 120))	('breast cancer', 'Phenotype', 'HP:0003002', (84, 97))	('MCF-7', 'CellLine', 'CVCL:0031', (78, 83))	('breast cancer', 'Disease', 'MESH:D001943', (84, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('ER+ luminal', 'Var', (64, 75))	('breast cancer', 'Disease', (84, 97))
505074	26912435	In KYSE520/231 xenografts, 89Zr-ACKR3-mAb was preferentially retained in high ACKR3 expressing KYSE520, compared to 231 control tumors (Fig.	('KYSE520', 'Var', (95, 102))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('preferentially', 'PosReg', (46, 60))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('tumors', 'Disease', (128, 134))	('tumors', 'Disease', 'MESH:D009369', (128, 134))
505075	26912435	Ex vivo biodistribution in these xenografts showed 10.7+-0.4%ID/g in KYSE520 and 5.9+-0.2%ID/g in 231 tumors, 48hrs post injection (Fig.	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('tumors', 'Disease', 'MESH:D009369', (102, 108))	('tumors', 'Disease', (102, 108))	('KYSE520', 'Var', (69, 76))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))
505076	26912435	ImmunoPET imaging following in vivo blocking, as well the corresponding in vivo image analysis, demonstrated a significant reduction (11.46+-3.47%ID/cc) in 89Zr-ACKR3-mAb uptake by KYSE520 tumors (Fig.	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('tumors', 'Disease', 'MESH:D009369', (189, 195))	('tumors', 'Disease', (189, 195))	('KYSE520', 'Var', (181, 188))	('tumors', 'Phenotype', 'HP:0002664', (189, 195))	('reduction', 'NegReg', (123, 132))	('89Zr-ACKR3-mAb uptake', 'MPA', (156, 177))
505077	26912435	This ACKR3-mediated uptake was also supported by enhanced ACKR3 immunoreactivity in excised KYSE520, compared to 231, tumors (Fig.	('KYSE520', 'Var', (92, 99))	('enhanced', 'PosReg', (49, 57))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('tumors', 'Disease', (118, 124))	('ACKR3 immunoreactivity', 'MPA', (58, 80))	('tumors', 'Disease', 'MESH:D009369', (118, 124))
505078	26912435	While 125I-ACKR3-mAb was initially non-specifically taken up by 231 tumors, preferential uptake and retention by 231-ACKR3 tumors was observed 120hrs post injection (Fig.	('tumors', 'Disease', 'MESH:D009369', (123, 129))	('tumors', 'Disease', (123, 129))	('tumors', 'Disease', (68, 74))	('tumors', 'Disease', 'MESH:D009369', (68, 74))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('preferential', 'PosReg', (76, 88))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('125I-ACKR3-mAb', 'Var', (6, 20))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
505079	26912435	Non-specific retention of 125I-ACKR3-mAb was observed in the thyroid (owing to in vivo de-iodination), liver, spleen, lungs, small intestines and kidneys.	('kidney', 'Disease', 'MESH:D007674', (146, 152))	('kidney', 'Disease', (146, 152))	('125I-ACKR3-mAb', 'Var', (26, 40))
505086	26912435	In addition, in agreement with the ACKR3 specificity shown for the 11G8 clone, our in vitro data also support preferential selectivity of 89Zr-ACKR3-mAb for ACKR3 over CXCR4.	('CXCR4', 'Gene', '7852', (168, 173))	('CXCR4', 'Gene', (168, 173))	('89Zr-ACKR3-mAb', 'Var', (138, 152))
505105	32410650	The overall survival (OS) of NACT group was significantly longer than that of conventional group when the pretreatment SCC antigen levels were >= 4.55 ng/mL.	('overall survival', 'CPA', (4, 20))	('SCC', 'Gene', '6317', (119, 122))	('NACT', 'Var', (29, 33))	('longer', 'PosReg', (58, 64))	('NACT', 'Chemical', '-', (29, 33))	('SCC', 'Gene', (119, 122))	('SCC', 'Phenotype', 'HP:0002860', (119, 122))
505106	32410650	The OS and progression-free survival rates of patients with SCC antigen levels < 2.7 ng/mL were longer than those >=2.7 ng/mL after the first chemotherapy.	('patients', 'Species', '9606', (46, 54))	('SCC', 'Gene', '6317', (60, 63))	('progression-free survival rates', 'CPA', (11, 42))	('longer', 'PosReg', (96, 102))	('< 2.7 ng/mL', 'Var', (79, 90))	('SCC', 'Gene', (60, 63))	('SCC', 'Phenotype', 'HP:0002860', (60, 63))
505115	32410650	In addition, NACT can decrease the size of preoperative tumors and reduce the risk of lymph node metastasis.	('reduce', 'NegReg', (67, 73))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('decrease', 'NegReg', (22, 30))	('lymph node metastasis', 'CPA', (86, 107))	('size', 'MPA', (35, 39))	('reduce the risk of lymph node metastasis', 'Phenotype', 'HP:0002732', (67, 107))	('tumors', 'Disease', (56, 62))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('NACT', 'Var', (13, 17))	('NACT', 'Chemical', '-', (13, 17))
505158	32410650	2, ROC curve analysis revealed that the area under the curve (AUC) values of FSCC (%) and TSCC (%) were 0.702 (0.572, 0.831) and 0.732 (0.609, 0.855), respectively, and the optimal cut-off values were 42.0 and 37.0%, respectively.	('SCC', 'Gene', '6317', (78, 81))	('SCC', 'Phenotype', 'HP:0002860', (78, 81))	('0.732', 'Var', (129, 134))	('SCC', 'Gene', (91, 94))	('SCC', 'Phenotype', 'HP:0002860', (91, 94))	('SCC', 'Gene', (78, 81))	('SCC', 'Gene', '6317', (91, 94))
505172	32410650	In the NACT group, the AUC values of ISCC, SSCC, OSCC, FSCC, and TSCC were 0.798 (0.679, 0.917), 0.803 (0.667, 0.940), 0.839 (0.730, 0.948), 0.738 (0.585, 0.891), and 0.677 (0.507, 0.846), respectively, and their cut-off values were 4.55, 2.70, 2.75, 2.80, and 1.35 ng/mL, respectively (Table 3).	('SCC', 'Gene', '6317', (44, 47))	('SCC', 'Gene', (38, 41))	('0.803', 'Var', (97, 102))	('0.738', 'Var', (141, 146))	('SCC', 'Gene', '6317', (66, 69))	('SCC', 'Gene', (44, 47))	('0.839', 'Var', (119, 124))	('0.677', 'Var', (167, 172))	('SCC', 'Gene', '6317', (50, 53))	('SCC', 'Gene', (66, 69))	('SCC', 'Phenotype', 'HP:0002860', (56, 59))	('SCC', 'Gene', (50, 53))	('SCC', 'Phenotype', 'HP:0002860', (38, 41))	('0.798', 'Var', (75, 80))	('SCC', 'Gene', '6317', (56, 59))	('SCC', 'Phenotype', 'HP:0002860', (44, 47))	('NACT', 'Chemical', '-', (7, 11))	('SCC', 'Phenotype', 'HP:0002860', (66, 69))	('SCC', 'Gene', (56, 59))	('SCC', 'Gene', '6317', (38, 41))	('SCC', 'Phenotype', 'HP:0002860', (50, 53))
505177	32410650	Furthermore, after the first chemotherapy, the OS and PFS of patients with SCC antigen levels < 2.7 ng/mL in the NACT group was longer than those >=2.7 ng/mL (chi2 = 10.869, P = 0.001; and chi2 = 13.954, P < 0.001) (Tables 4 and 5).	('PFS', 'CPA', (54, 57))	('NACT', 'Chemical', '-', (113, 117))	('SCC', 'Gene', '6317', (75, 78))	('< 2.7', 'Var', (94, 99))	('patients', 'Species', '9606', (61, 69))	('SCC', 'Gene', (75, 78))	('longer', 'PosReg', (128, 134))	('SCC', 'Phenotype', 'HP:0002860', (75, 78))
505205	32410650	Accumulating evidence has validated that the variation in SCC antigen levels during the treatment could influence the prognosis of patients who experienced recurrence Li et al.	('patients', 'Species', '9606', (131, 139))	('SCC', 'Gene', (58, 61))	('SCC', 'Phenotype', 'HP:0002860', (58, 61))	('SCC', 'Gene', '6317', (58, 61))	('variation', 'Var', (45, 54))	('influence', 'Reg', (104, 113))
505210	32410650	Moreover, our results showed that the OS and PFS of patients with SCC antigen levels < 2.7 ng/mL in the NACT group were significantly longer than that of patients with SCC antigen levels >=2.7 ng/mL after the first chemotherapy.	('SCC', 'Gene', (168, 171))	('SCC', 'Phenotype', 'HP:0002860', (168, 171))	('SCC', 'Gene', (66, 69))	('longer', 'PosReg', (134, 140))	('NACT', 'Chemical', '-', (104, 108))	('SCC', 'Gene', '6317', (168, 171))	('SCC', 'Phenotype', 'HP:0002860', (66, 69))	('SCC', 'Gene', '6317', (66, 69))	('patients', 'Species', '9606', (154, 162))	('PFS', 'CPA', (45, 48))	('< 2.7', 'Var', (85, 90))	('patients', 'Species', '9606', (52, 60))
505225	31769164	Motility of TSCC-derived cells was increased by deficiency of claudin-1, suggesting that the decrease in cell-surface claudin-1 promoted the cell migration.	('increased', 'PosReg', (35, 44))	('Motility', 'CPA', (0, 8))	('deficiency', 'Var', (48, 58))	('promoted', 'PosReg', (128, 136))	('cell migration', 'CPA', (141, 155))	('TSCC', 'Disease', 'MESH:D002294', (12, 16))	('TSCC', 'Phenotype', 'HP:0030413', (12, 16))	('decrease', 'NegReg', (93, 101))	('TSCC', 'Disease', (12, 16))	('claudin-1', 'Gene', (62, 71))
505239	31769164	The present study suggested that the ectopic, intracellular location of claudin-1 at the invasion front may be an additional and promising diagnostic marker of TSCC.	('ectopic', 'Var', (37, 44))	('TSCC', 'Disease', 'MESH:D002294', (160, 164))	('TSCC', 'Phenotype', 'HP:0030413', (160, 164))	('TSCC', 'Disease', (160, 164))	('claudin-1', 'Gene', (72, 81))
505268	31769164	The biotinylated claudin-1 that remained after stripping was considered to be endocytosed from the cell surface.	('biotinylated', 'Var', (4, 16))	('endocytosed', 'MPA', (78, 89))	('biotin', 'Chemical', 'MESH:D001710', (4, 10))
505272	31769164	However, immunofluorescence staining of claudin-1 in SAS cells revealed that the abundant intracellular staining of claudin-1 was suppressed in the presence of CPZ or IMP (Figure 5C).	('abundant intracellular staining', 'MPA', (81, 112))	('suppressed', 'NegReg', (130, 140))	('IMP', 'Chemical', 'MESH:D007099', (167, 170))	('CPZ', 'Chemical', 'MESH:D002746', (160, 163))	('claudin-1', 'Gene', (116, 125))	('SAS', 'CellLine', 'CVCL:1675', (53, 56))	('IMP', 'Var', (167, 170))
505275	31769164	For this purpose, we used the cell tracking method of recent studies.35, 36, 37 As shown in Figure 6 (Videos [Link], [Link], [Link]), total migrated distance was decreased by the addition of CPZ and IMP, suggesting that inhibition of endocytosis suppresses cell migration.	('CPZ', 'Chemical', 'MESH:D002746', (191, 194))	('suppresses', 'NegReg', (246, 256))	('CPZ', 'Var', (191, 194))	('IMP', 'Chemical', 'MESH:D007099', (199, 202))	('cell migration', 'CPA', (257, 271))	('decreased', 'NegReg', (162, 171))
505290	31769164	However, the deficiency of claudin-1 in SAS cells increased cell motility (Figure 7).	('claudin-1', 'Gene', (27, 36))	('deficiency', 'Var', (13, 23))	('increased', 'PosReg', (50, 59))	('SAS', 'CellLine', 'CVCL:1675', (40, 43))	('cell motility', 'CPA', (60, 73))
505301	31268159	Further analysis revealed that fascin-1 knockdown significantly decreased the invasion of cells under hypoxia and partially reversed hypoxia-induced MMP-2 expression under hypoxia in FaDu cells.	('MMP-2', 'Gene', '4313', (149, 154))	('invasion of cells under', 'CPA', (78, 101))	('hypoxia', 'Disease', 'MESH:D000860', (102, 109))	('knockdown', 'Var', (40, 49))	('hypoxia', 'Disease', (133, 140))	('expression', 'MPA', (155, 165))	('fascin-1', 'Gene', '14086', (31, 39))	('hypoxia', 'Disease', 'MESH:D000860', (133, 140))	('hypoxia', 'Disease', 'MESH:D000860', (172, 179))	('hypoxia', 'Disease', (102, 109))	('hypoxia', 'Disease', (172, 179))	('MMP-2', 'Gene', (149, 154))	('fascin-1', 'Gene', (31, 39))	('decreased', 'NegReg', (64, 73))
505398	31268159	The results revealed that fascin-1 knockdown downregulated MMP-2 expression in FaDu cells (Fig.	('knockdown', 'Var', (35, 44))	('MMP-2', 'Gene', (59, 64))	('fascin-1', 'Gene', '14086', (26, 34))	('fascin-1', 'Gene', (26, 34))	('expression', 'MPA', (65, 75))	('downregulated', 'NegReg', (45, 58))	('MMP-2', 'Gene', '4313', (59, 64))
505410	31268159	The results demonstrated that, with the upregulation of HIF-1alpha, fascin-1 expression was considerably increased in FaDu cells under CoCl2-induced hypoxia compared with under normoxia (Fig.	('expression', 'MPA', (77, 87))	('HIF-1alpha', 'Gene', (56, 66))	('fascin-1', 'Gene', '14086', (68, 76))	('upregulation', 'PosReg', (40, 52))	('HIF-1alpha', 'Gene', '3091', (56, 66))	('CoCl2-induced', 'Var', (135, 148))	('hypoxia', 'Disease', 'MESH:D000860', (149, 156))	('CoCl2', 'Chemical', 'MESH:C018021', (135, 140))	('fascin-1', 'Gene', (68, 76))	('increased', 'PosReg', (105, 114))	('hypoxia', 'Disease', (149, 156))
505416	31268159	Therefore, cells that underwent CoCl2-induced hypoxia for 48 h were transfected with HIF-1alpha siRNA.	('CoCl2', 'Chemical', 'MESH:C018021', (32, 37))	('hypoxia', 'Disease', (46, 53))	('hypoxia', 'Disease', 'MESH:D000860', (46, 53))	('HIF-1alpha', 'Gene', '3091', (85, 95))	('HIF-1alpha', 'Gene', (85, 95))	('transfected', 'Var', (68, 79))
505439	31268159	Zhao et al demonstrated that fascin-1 knockdown suppresses cell invasion and migration in non-small cell lung cancer.	('lung cancer', 'Phenotype', 'HP:0100526', (105, 116))	('non-small cell lung cancer', 'Disease', (90, 116))	('fascin-1', 'Gene', (29, 37))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (94, 116))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (90, 116))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('suppresses', 'NegReg', (48, 58))	('knockdown', 'Var', (38, 47))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (90, 116))	('fascin-1', 'Gene', '14086', (29, 37))
505455	31268159	A previous study demonstrated that HIF-1alpha knockdown markedly downregulates the expression of fascin under true hypoxia (1% O2), and fascin is a direct target gene of HIF-1alpha.	('hypoxia', 'Disease', 'MESH:D000860', (115, 122))	('HIF-1alpha', 'Gene', (35, 45))	('HIF-1alpha', 'Gene', '3091', (170, 180))	('fascin', 'Gene', (97, 103))	('knockdown', 'Var', (46, 55))	('fascin', 'Gene', '6624', (136, 142))	('fascin', 'Gene', (136, 142))	('downregulates', 'NegReg', (65, 78))	('fascin', 'Gene', '6624', (97, 103))	('HIF-1alpha', 'Gene', (170, 180))	('expression', 'MPA', (83, 93))	('O2', 'Chemical', 'MESH:D010100', (127, 129))	('HIF-1alpha', 'Gene', '3091', (35, 45))	('hypoxia', 'Disease', (115, 122))
505456	31268159	In line with this previous report, our further studies revealed that HIF-1alpha knockdown downregulated the expression of fascin-1 under CoCl2-induced hypoxia in FaDu cells.	('knockdown', 'Var', (80, 89))	('HIF-1alpha', 'Gene', (69, 79))	('CoCl2', 'Chemical', 'MESH:C018021', (137, 142))	('fascin-1', 'Gene', '14086', (122, 130))	('hypoxia', 'Disease', 'MESH:D000860', (151, 158))	('downregulated', 'NegReg', (90, 103))	('HIF-1alpha', 'Gene', '3091', (69, 79))	('hypoxia', 'Disease', (151, 158))	('expression', 'MPA', (108, 118))	('fascin-1', 'Gene', (122, 130))
505504	29285270	Several epidemiological and clinical studies have found that patients using metformin have decreased cancer incidences, as well as inhibited cancer survival and proliferation, in comparison with those using other antidiabetic medications.	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('metformin', 'Chemical', 'MESH:D008687', (76, 85))	('decreased', 'NegReg', (91, 100))	('cancer', 'Disease', (101, 107))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('patients', 'Species', '9606', (61, 69))	('metformin', 'Var', (76, 85))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('inhibited', 'NegReg', (131, 140))	('cancer', 'Disease', (141, 147))
505515	29285270	In a previous study, nickel accumulation increased cellular glycolytic activity, which is the foremost alteration of energy metabolism in tumorigenesis (the Warburg effect).	('increased', 'PosReg', (41, 50))	('nickel', 'Chemical', 'MESH:D009532', (21, 27))	('tumor', 'Disease', (138, 143))	('cellular glycolytic activity', 'MPA', (51, 79))	('nickel', 'Var', (21, 27))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
505523	29285270	The data indicated that NiCl2 stimulates AVO development in a dose-dependent manner in BEAS-2B cells (Figure 1D lower).	('stimulates', 'PosReg', (30, 40))	('BEAS-2B', 'CellLine', 'CVCL:0168', (87, 94))	('AVO development', 'CPA', (41, 56))	('NiCl2', 'Chemical', 'MESH:C022838', (24, 29))	('NiCl2', 'Var', (24, 29))
505564	29285270	The data revealed that blockade of endogenous LCN2, but not exogenous LCN2, represses autophagy in BEAS-2B cells (Figure 3F).	('LCN2', 'Gene', (70, 74))	('BEAS-2B', 'CellLine', 'CVCL:0168', (99, 106))	('blockade', 'Var', (23, 31))	('LCN2', 'Gene', (46, 50))	('represses', 'NegReg', (76, 85))	('autophagy', 'CPA', (86, 95))	('LCN2', 'Gene', '3934', (70, 74))	('LCN2', 'Gene', '3934', (46, 50))
505585	29285270	As shown in Figure 4F, there were no significant changes in the protein levels of p-AMPK and p-P70S6K after knockdown of HK2.	('HK2', 'Gene', (121, 124))	('knockdown', 'Var', (108, 117))	('P70S6K', 'Gene', '6198', (95, 101))	('HK2', 'Gene', '3099', (121, 124))	('P70S6K', 'Gene', (95, 101))	('p-AMPK', 'MPA', (82, 88))
505599	29285270	As shown in Figure 5E, the specific shRNA targeting LC3 was transfected into BEAS-2B cells with knockdown of the expression of LC3.	('knockdown', 'Var', (96, 105))	('LC3', 'Gene', (127, 130))	('BEAS-2B', 'CellLine', 'CVCL:0168', (77, 84))
505600	29285270	In comparison with BEAS-2B shGFP cells, NiCl2-induced cleavage of caspase 7 was blunted in BEAS-2B shLC3 cells.	('BEAS-2B', 'Var', (91, 98))	('BEAS-2B', 'CellLine', 'CVCL:0168', (19, 26))	('blunted', 'NegReg', (80, 87))	('NiCl2-induced cleavage', 'MPA', (40, 62))	('caspase 7', 'Gene', (66, 75))	('NiCl2', 'Chemical', 'MESH:C022838', (40, 45))	('caspase 7', 'Gene', '840', (66, 75))	('BEAS-2B', 'CellLine', 'CVCL:0168', (91, 98))
505601	29285270	Our results demonstrated that NiCl2-induced autophagy induces apoptosis.	('NiCl2-induced', 'Var', (30, 43))	('apoptosis', 'CPA', (62, 71))	('autophagy', 'CPA', (44, 53))	('NiCl2', 'Chemical', 'MESH:C022838', (30, 35))
505603	29285270	The presence or absence of HK2 and LC3B protein expressions was associated with tumor stage, T status and metastasis (Supplementary Table 2).	('associated', 'Reg', (64, 74))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('LC3B', 'Gene', '81631', (35, 39))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('T status', 'CPA', (93, 101))	('metastasis', 'CPA', (106, 116))	('tumor', 'Disease', (80, 85))	('LC3B', 'Gene', (35, 39))	('HK2', 'Gene', (27, 30))	('protein', 'Protein', (40, 47))	('HK2', 'Gene', '3099', (27, 30))	('presence', 'Var', (4, 12))	('absence', 'NegReg', (16, 23))
505611	29285270	Although nickel compounds have low mutagenic capabilities, previous studies have found that nickel accumulation in lung tissues contributes to incremental levels of EGFR and P53 mutations, which can reduce DNA repair activity and promote tumor invasion, leading to lung carcinogenesis.	('EGFR', 'Gene', (165, 169))	('tumor', 'Disease', 'MESH:D009369', (238, 243))	('P53', 'Gene', (174, 177))	('lung carcinogenesis', 'Disease', (265, 284))	('tumor', 'Phenotype', 'HP:0002664', (238, 243))	('promote', 'PosReg', (230, 237))	('reduce', 'NegReg', (199, 205))	('nickel', 'Chemical', 'MESH:D009532', (9, 15))	('lung carcinogenesis', 'Disease', 'MESH:D063646', (265, 284))	('tumor', 'Disease', (238, 243))	('P53', 'Gene', '7157', (174, 177))	('leading to', 'Reg', (254, 264))	('nickel', 'Chemical', 'MESH:D009532', (92, 98))	('DNA repair activity', 'MPA', (206, 225))	('mutations', 'Var', (178, 187))	('EGFR', 'Gene', '1956', (165, 169))
505617	29285270	Moreover, other miRNAs may be involved in the altered expression of HK2 in tumors, including miR-181b, miR-125b and miR-182.	('expression', 'MPA', (54, 64))	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('miR-182', 'Gene', (116, 123))	('HK2', 'Gene', (68, 71))	('HK2', 'Gene', '3099', (68, 71))	('miR-181b', 'Var', (93, 101))	('miR-182', 'Gene', '406958', (116, 123))	('miR-125b', 'Var', (103, 111))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumors', 'Disease', (75, 81))
505630	29285270	However, in contrast with normal tissues, inhibition of HK2 by 2-DG suppresses lung cancer cell growth through induction of cell apoptosis and autophagy.	('lung cancer', 'Disease', 'MESH:D008175', (79, 90))	('autophagy', 'CPA', (143, 152))	('suppresses', 'NegReg', (68, 78))	('inhibition', 'Var', (42, 52))	('lung cancer', 'Disease', (79, 90))	('lung cancer', 'Phenotype', 'HP:0100526', (79, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('2-DG', 'Chemical', 'MESH:D003847', (63, 67))	('HK2', 'Gene', '3099', (56, 59))	('cell apoptosis', 'CPA', (124, 138))	('HK2', 'Gene', (56, 59))
505638	29285270	It had been stated that DNA hypomethylation of proto-oncogene contribute to nickel-induced malignant transformation.	('nickel-induced', 'Disease', (76, 90))	('nickel', 'Chemical', 'MESH:D009532', (76, 82))	('proto-oncogene', 'Gene', (47, 61))	('contribute', 'Reg', (62, 72))	('DNA', 'Var', (24, 27))
505643	29285270	Studies have suggested that LCN2 upregulated by LPS is influenced via TLR4 signaling pathway.	('upregulated', 'PosReg', (33, 44))	('LCN2', 'Gene', (28, 32))	('TLR4', 'Gene', '7099', (70, 74))	('LPS', 'Chemical', 'MESH:D008070', (48, 51))	('LPS', 'Var', (48, 51))	('TLR4', 'Gene', (70, 74))	('LCN2', 'Gene', '3934', (28, 32))
505644	29285270	In this study, we demonstrated that NiCl2 induces autophagy induction via increment levels of HK2 and LCN2.	('LCN2', 'Gene', '3934', (102, 106))	('NiCl2', 'Chemical', 'MESH:C022838', (36, 41))	('NiCl2', 'Var', (36, 41))	('autophagy induction', 'CPA', (50, 69))	('LCN2', 'Gene', (102, 106))	('HK2', 'Gene', '3099', (94, 97))	('HK2', 'Gene', (94, 97))	('increment', 'PosReg', (74, 83))
505645	29285270	As shown in Figure 2F and Figure 3F, we used acridine orange stain to verify the role of HK2 and LCN2 in nickel-induced autophagy after HK2 and LCN2 gene silencing.	('gene silencing', 'Var', (149, 163))	('HK2', 'Gene', '3099', (136, 139))	('LCN2', 'Gene', (97, 101))	('HK2', 'Gene', (89, 92))	('HK2', 'Gene', '3099', (89, 92))	('acridine orange', 'Chemical', 'MESH:D000165', (45, 60))	('LCN2', 'Gene', '3934', (144, 148))	('LCN2', 'Gene', '3934', (97, 101))	('HK2', 'Gene', (136, 139))	('LCN2', 'Gene', (144, 148))	('nickel', 'Chemical', 'MESH:D009532', (105, 111))	('autophagy', 'CPA', (120, 129))
505667	29285270	In conclusion, the results of this study provide evidence that metformin alleviates NiCl2-stimulated autophagy via the inhibition of HK2 and LCN2 expressions (Figure 7).	('LCN2', 'Gene', (141, 145))	('autophagy', 'CPA', (101, 110))	('NiCl2', 'Chemical', 'MESH:C022838', (84, 89))	('metformin', 'Var', (63, 72))	('HK2', 'Gene', (133, 136))	('inhibition', 'NegReg', (119, 129))	('NiCl2-stimulated', 'MPA', (84, 100))	('expressions', 'MPA', (146, 157))	('metformin', 'Chemical', 'MESH:D008687', (63, 72))	('HK2', 'Gene', '3099', (133, 136))	('LCN2', 'Gene', '3934', (141, 145))	('alleviates', 'NegReg', (73, 83))
505692	29285270	Individual clones were identified by their unique TRC number: shGFP TRCN0000072178 (responding sequence: CAA CAG CCA CAA CGT CTA TAT) and shLuc TRCN0000072246 (responding sequence: CAA ATC ACA GAA TCG TCG TAT) for vector control; shHK2 (27) TRCN0000232927 (responding sequence: TGA CGA CAG CATC ATT GTT AA) and shHK2 (82) TRCN0000195582 (responding sequence: CCA AAG ACA TCT CAG ACA TTG) targeted to HK2; shLCN2 (89) TRCN0000060289 (responding sequence: CCA GCA TGC TAT GGT GTT CTT) and shLCN2 (90) TRCN0000060290 (responding sequence: GTA CTT CAA GAT CAC CCT CTA) targeted to LCN2; shLC3 (87) TRCN0000243387 (responding sequence: GGT GAT CAT CGA GCG CTA CAA) and shLC3 (91) TRCN0000243391 (responding sequence: AGC GAG TTG GTC AAG ATC ATC) targeted to LC3.	('LCN2', 'Gene', '3934', (407, 411))	('HK2', 'Gene', (313, 316))	('GAT', 'Gene', '10249', (635, 638))	('HK2', 'Gene', '3099', (313, 316))	('HK2', 'Gene', (232, 235))	('HK2', 'Gene', '3099', (232, 235))	('HK2', 'Gene', (400, 403))	('LCN2', 'Gene', (489, 493))	('HK2', 'Gene', '3099', (400, 403))	('LCN2', 'Gene', (407, 411))	('LCN2', 'Gene', '3934', (577, 581))	('shLC3 (87) TRCN0000243387', 'Var', (583, 608))	('GAT', 'Gene', (548, 551))	('GAT', 'Gene', '10249', (548, 551))	('LCN2', 'Gene', (577, 581))	('LCN2', 'Gene', '3934', (489, 493))	('GAT', 'Gene', (635, 638))
505702	29285270	Antibodies against HK2 (2867) and LC3B (3868) were obtained from Cell Signaling Technology.	('2867', 'Var', (24, 28))	('LC3B', 'Gene', (34, 38))	('HK2', 'Gene', (19, 22))	('HK2', 'Gene', '3099', (19, 22))	('LC3B', 'Gene', '81631', (34, 38))
505787	27512847	Yamashita et al  divided the tumors into 2 groups according to the diameter of blood vessels as big (>0.1 mm) group and small (0.02~0.1 mm) group; results showed that the correlation of small blood vessels of lung carcinomas was greater than large blood vessels (r = 0.77 and r = 0.59).	('lung carcinomas', 'Disease', 'MESH:D008175', (209, 224))	('carcinoma', 'Phenotype', 'HP:0030731', (214, 223))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('small', 'Var', (186, 191))	('tumors', 'Disease', 'MESH:D009369', (29, 35))	('carcinomas', 'Phenotype', 'HP:0030731', (214, 224))	('tumors', 'Disease', (29, 35))	('lung carcinomas', 'Disease', (209, 224))
505831	26944944	The standard molecular testing for lung cancer is to check for mutations of two molecules: epidermal growth factor receptor (EGFR) and rearrangement of anaplastic lymphoma kinase (ALK).	('mutations', 'Var', (63, 72))	('lymphoma', 'Phenotype', 'HP:0002665', (163, 171))	('lung cancer', 'Disease', 'MESH:D008175', (35, 46))	('epidermal growth factor receptor', 'Gene', '1956', (91, 123))	('EGFR', 'Gene', '1956', (125, 129))	('ALK', 'Gene', '238', (180, 183))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (152, 171))	('lung cancer', 'Disease', (35, 46))	('EGFR', 'Gene', (125, 129))	('lung cancer', 'Phenotype', 'HP:0100526', (35, 46))	('rearrangement', 'Var', (135, 148))	('anaplastic lymphoma kinase', 'Gene', '238', (152, 178))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('ALK', 'Gene', (180, 183))	('epidermal growth factor receptor', 'Gene', (91, 123))	('anaplastic lymphoma kinase', 'Gene', (152, 178))
505832	26944944	Each protein has mutations that lead to the development of lung cancer.	('lead to', 'Reg', (32, 39))	('lung cancer', 'Disease', 'MESH:D008175', (59, 70))	('lung cancer', 'Disease', (59, 70))	('lung cancer', 'Phenotype', 'HP:0100526', (59, 70))	('mutations', 'Var', (17, 26))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
505834	26944944	Similarly, ALK mutation occurs only in 6 % of tumors.	('mutation', 'Var', (15, 23))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumors', 'Phenotype', 'HP:0002664', (46, 52))	('tumors', 'Disease', 'MESH:D009369', (46, 52))	('ALK', 'Gene', (11, 14))	('tumors', 'Disease', (46, 52))	('ALK', 'Gene', '238', (11, 14))
505857	26944944	For instance, when using MDLPC we observed that the methylation site cg19782598 was discretized into two categories: methylated (>0.86) and unmethylated (<=0.86); while methylation site cg11693019 was discretized into three categories: methylated (>0.76), partially methylated (between 0.76 and 0.47), and unmethylated (<0.47).	('cg19782598', 'Var', (69, 79))	('cg19782598', 'Chemical', '-', (69, 79))	('cg11693019', 'Chemical', '-', (186, 196))	('cg11693019', 'Var', (186, 196))
505884	26944944	Rather, we suggest that the use of epigenomic changes could help in the small number of tumors which remain difficult to classify.	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('epigenomic changes', 'Var', (35, 53))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumors', 'Disease', (88, 94))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))
505927	24520272	The regulation of cell death may be a significant component in cancer as aberrantly regulated apoptotic cell death causes apoptotic diseases, including cancer.	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('apoptotic diseases', 'Disease', (122, 140))	('apoptotic cell death', 'CPA', (94, 114))	('causes', 'Reg', (115, 121))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('aberrantly regulated', 'Var', (73, 93))	('cancer', 'Disease', (63, 69))
505945	24520272	The cancer cells were cultured in RPMI-1640 medium (Welgene Inc., Daegu, Korea) supplemented with 10% fetal bovine serum (FBS) and 1% penicillin-streptomycin (Gibco Co., Grand Island, NY, USA) at 37oC in a humidified atmosphere containing 5% CO2 (incubator model 311 S/N29035; Forma, Waltham, MA, USA).	('S/N29035', 'SUBSTITUTION', 'None', (267, 275))	('FBS', 'Disease', (122, 125))	('streptomycin', 'Chemical', 'MESH:D013307', (145, 157))	('CO2', 'Chemical', '-', (242, 245))	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('FBS', 'Disease', 'MESH:D005198', (122, 125))	('penicillin', 'Chemical', 'MESH:D010406', (134, 144))	('Welgene', 'Chemical', '-', (52, 59))	('bovine', 'Species', '9913', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (4, 10))	('RPMI-1640', 'Chemical', '-', (34, 43))	('cancer', 'Disease', (4, 10))	('S/N29035', 'Var', (267, 275))
506015	24520272	Spontaneous and experimental metastasis to the liver decreased in mice that overexpressed TIMP1, and increased in mice that expressed antisense TIMP-1 mRNA.	('TIMP-1', 'Gene', (144, 150))	('increased', 'PosReg', (101, 110))	('overexpressed', 'PosReg', (76, 89))	('mice', 'Species', '10090', (66, 70))	('antisense', 'Var', (134, 143))	('TIMP1', 'Gene', '21857', (90, 95))	('mice', 'Species', '10090', (114, 118))	('decreased', 'NegReg', (53, 62))	('TIMP1', 'Gene', (90, 95))	('liver decreased', 'Phenotype', 'HP:0001410', (47, 62))
506030	32545367	Using a bioinformatics approach across non-small cell lung cancer (NSCLC) subtypes, we identified where patient sex, mutation of the major tumor suppressor gene, Tumour protein P53 (TP53), and immune signatures stratified outcomes in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC), among datasets of The Cancer Genome Atlas (TCGA).	('small cell lung cancer', 'Phenotype', 'HP:0030357', (43, 65))	('Tumour protein P53', 'Gene', (162, 180))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (265, 293))	('lung squamous cell carcinoma', 'Disease', (265, 293))	('tumor suppressor', 'Gene', '7248', (139, 155))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (270, 293))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('stratified outcomes', 'Reg', (211, 230))	('patient', 'Species', '9606', (104, 111))	('Cancer', 'Disease', 'MESH:D009369', (324, 330))	('lung adenocarcinoma', 'Disease', (234, 253))	('Tumour protein P53', 'Gene', '7157', (162, 180))	('carcinoma', 'Phenotype', 'HP:0030731', (284, 293))	('carcinoma', 'Phenotype', 'HP:0030731', (244, 253))	('NSCLC', 'Disease', 'MESH:D002289', (67, 72))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (234, 253))	('small cell lung cancer', 'Disease', 'MESH:D055752', (43, 65))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (234, 253))	('NSCLC', 'Disease', (67, 72))	('Cancer', 'Phenotype', 'HP:0002664', (324, 330))	('small cell lung cancer', 'Disease', (43, 65))	('Tumour', 'Phenotype', 'HP:0002664', (162, 168))	('lung cancer', 'Phenotype', 'HP:0100526', (54, 65))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (39, 65))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (265, 293))	('tumor suppressor', 'Gene', (139, 155))	('mutation', 'Var', (117, 125))	('Cancer', 'Disease', (324, 330))
506034	32545367	LUSC is dominated by male smokers with TP53 gene mutations, while a minor population of TCGA LC patients with wt TP53 genes unexpectedly had the poorest survival, suggestive of a separate etiology.	('TP53 gene', 'Gene', (39, 48))	('mutations', 'Var', (49, 58))	('poorest', 'NegReg', (145, 152))	('patients', 'Species', '9606', (96, 104))	('LUSC', 'Disease', (0, 4))
506044	32545367	One postulated explanation is that milder smoke composition prompts extended and deeper inhalation, with greater risk to more recessed distal lung cells that are more susceptible to adenocarcinoma.	('milder', 'Var', (35, 41))	('carcinoma', 'Phenotype', 'HP:0030731', (187, 196))	('adenocarcinoma', 'Disease', 'MESH:D000230', (182, 196))	('adenocarcinoma', 'Disease', (182, 196))
506046	32545367	We recently reported significant correlation between poor overall survival and mutation of the major tumor suppressor gene TP53 for the vast majority of US patients with spontaneous cancers of nonreproductive organs.	('patients', 'Species', '9606', (156, 164))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('tumor suppressor', 'Gene', (101, 117))	('tumor suppressor', 'Gene', '7248', (101, 117))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('cancers', 'Phenotype', 'HP:0002664', (182, 189))	('mutation', 'Var', (79, 87))	('cancers', 'Disease', (182, 189))	('cancers', 'Disease', 'MESH:D009369', (182, 189))	('TP53', 'Gene', (123, 127))
506047	32545367	Of particular relevance to lung cancer, we calculated that TP53 mutation risk is higher in NSCLC for males than females, in the US population.	('NSCLC', 'Disease', 'MESH:D002289', (91, 96))	('mutation', 'Var', (64, 72))	('TP53', 'Gene', (59, 63))	('lung cancer', 'Disease', (27, 38))	('lung cancer', 'Phenotype', 'HP:0100526', (27, 38))	('higher', 'Reg', (81, 87))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('NSCLC', 'Disease', (91, 96))	('lung cancer', 'Disease', 'MESH:D008175', (27, 38))
506048	32545367	Whether high incidence of TP53 mutation in men correlates with poor survival for LUAD and LUSC individually is particularly relevant due to the established link between smoking and TP53 mutation.	('TP53', 'Gene', (26, 30))	('mutation', 'Var', (31, 39))	('men', 'Species', '9606', (43, 46))	('poor', 'NegReg', (63, 67))
506050	32545367	In lung epithelia, a p53/microRNA-34(miR-34)/PD-L1 axis is reported to dictate immune detection, with p53 dysfunction tied to elevated PD-L1 expression and immune evasion in LUAD.	('dysfunction', 'Var', (106, 117))	('dictate', 'Reg', (71, 78))	('PD-L1', 'Protein', (135, 140))	('miR-34', 'Gene', (37, 43))	('immune detection', 'MPA', (79, 95))	('expression', 'MPA', (141, 151))	('elevated', 'PosReg', (126, 134))	('p53', 'Gene', (102, 105))	('miR-34', 'Gene', '407040', (37, 43))	('immune evasion', 'MPA', (156, 170))
506051	32545367	The TP53 mutation status of tumor cells can also profoundly influence the immune response in its surrounding microenvironment (reviewed in), by regulating inflammation.	('mutation', 'Var', (9, 17))	('tumor', 'Disease', (28, 33))	('TP53', 'Gene', (4, 8))	('men', 'Species', '9606', (121, 124))	('immune response', 'CPA', (74, 89))	('regulating', 'Reg', (144, 154))	('influence', 'Reg', (60, 69))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('inflammation', 'Disease', 'MESH:D007249', (155, 167))	('inflammation', 'Disease', (155, 167))
506052	32545367	While links between p53, mutation of its encoding gene TP53, and immune responses are emerging, a corresponding influence of patient sex on outcome is yet to be ascertained.	('p53', 'Gene', (20, 23))	('TP53', 'Gene', (55, 59))	('mutation', 'Var', (25, 33))	('links', 'Interaction', (6, 11))	('patient', 'Species', '9606', (125, 132))
506053	32545367	Motivated to investigate possible connections between TP53 mutation, patient sex, immunity, and disease outcomes in the two major NSCLC subtypes, we were prompted to explore for fate-determining engagements.	('NSCLC', 'Disease', 'MESH:D002289', (130, 135))	('NSCLC', 'Disease', (130, 135))	('men', 'Species', '9606', (201, 204))	('mutation', 'Var', (59, 67))	('patient', 'Species', '9606', (69, 76))	('TP53', 'Gene', (54, 58))
506057	32545367	Our recent findings demonstrate that for the vast majority of patients with nonreproductive cancers worse survival corresponds with TP53 mutation.	('mutation', 'Var', (137, 145))	('cancers', 'Phenotype', 'HP:0002664', (92, 99))	('TP53', 'Gene', (132, 136))	('worse', 'NegReg', (100, 105))	('cancers', 'Disease', 'MESH:D009369', (92, 99))	('cancers', 'Disease', (92, 99))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('patients', 'Species', '9606', (62, 70))
506061	32545367	Female LUAD patients with wt TP53 had the most extended overall survival compared with other LUAD patients (Figure 1D,E, p = 0.0034).	('patients', 'Species', '9606', (12, 20))	('overall survival', 'MPA', (56, 72))	('TP53', 'Var', (29, 33))	('patients', 'Species', '9606', (98, 106))	('extended', 'PosReg', (47, 55))
506062	32545367	In contrast, male survival did not significantly differ between patients with wt or mutant TP53 (Figure 1F, p = 0.11).	('mutant', 'Var', (84, 90))	('TP53', 'Gene', (91, 95))	('patients', 'Species', '9606', (64, 72))
506072	32545367	Analyses were performed separately for patients with wt TP53 and mutant TP53.	('TP53', 'Gene', (72, 76))	('mutant', 'Var', (65, 71))	('patients', 'Species', '9606', (39, 47))
506074	32545367	In contrast, in the mutant TP53 LUAD context, the findings were completely different, with enrichment in females only of the gene signature for the TGF-beta pathway and in males only of the wound healing signature (Figure 2F, Table S3).	('TP53', 'Gene', (27, 31))	('men', 'Species', '9606', (97, 100))	('TGF-beta', 'Gene', (148, 156))	('TGF-beta', 'Gene', '7039', (148, 156))	('mutant', 'Var', (20, 26))
506075	32545367	As extended survival was most significant among LUAD patients with wt TP53 and cancers were significant, we focused on GSEA analysis of the constituent immune gene networks of this group.	('cancers', 'Disease', (79, 86))	('patients', 'Species', '9606', (53, 61))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('wt TP53', 'Var', (67, 74))	('GSEA', 'Chemical', '-', (119, 123))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('cancers', 'Disease', 'MESH:D009369', (79, 86))
506079	32545367	The immunomodulator genes (Table S7) Major Histocompatibility Complex, Class II DR Beta 1 (HLA-DRB1), Interferon Alpha and Beta Receptor Subunit 2 (IFNAR2) and Tumour Necrosis Factor (TNF) are more highly expressed in wt TP53 LUAD in females, compared with their male counterparts, according to differential gene expression analysis comparison (Figure 3C, Table S8, TNF adjusted p = 0.021371, HLA-DRB1 adjusted p = 0.046451, and IFNAR2 adjusted p = 0.020318).	('Tumour', 'Phenotype', 'HP:0002664', (160, 166))	('HLA-DRB1', 'Gene', (393, 401))	('Tumour Necrosis Factor', 'Gene', '7124', (160, 182))	('TP53', 'Var', (221, 225))	('highly', 'PosReg', (198, 204))	('Interferon Alpha and Beta Receptor Subunit 2', 'Gene', '3455', (102, 146))	('IFNAR2', 'Gene', '3455', (429, 435))	('IFNAR2', 'Gene', (148, 154))	('TNF', 'Gene', (184, 187))	('Tumour Necrosis Factor', 'Gene', (160, 182))	('TNF', 'Gene', (366, 369))	('HLA-DRB1', 'Gene', '3123', (91, 99))	('IFNAR2', 'Gene', (429, 435))	('TNF', 'Gene', '7124', (184, 187))	('HLA-DRB1', 'Gene', '3123', (393, 401))	('TNF', 'Gene', '7124', (366, 369))	('HLA-DRB1', 'Gene', (91, 99))	('IFNAR2', 'Gene', '3455', (148, 154))	('S7', 'Gene', '6264', (33, 35))
506088	32545367	Significantly worse survival was evident among LUAD patients with high expression levels of the TGF-beta gene set (Figure S2E, p = 0.02) and wound healing genes (Figure S2F, p <= 0.0001).	('TGF-beta', 'Gene', (96, 104))	('worse', 'NegReg', (14, 19))	('TGF-beta', 'Gene', '7039', (96, 104))	('high', 'Var', (66, 70))	('expression levels', 'MPA', (71, 88))	('survival', 'MPA', (20, 28))	('patients', 'Species', '9606', (52, 60))
506094	32545367	Unexpectedly, patients with wt TP53 LUSC had significantly reduced survival compared with their mutant TP53 counterparts (Figure 5D, p < 0.0001).	('patients', 'Species', '9606', (14, 22))	('TP53', 'Var', (31, 35))	('reduced', 'NegReg', (59, 66))	('survival', 'MPA', (67, 75))
506095	32545367	This was the opposite outcome from LUAD, as we show here (Figure 1), and also to the overall survival in most nonreproductive cancers, where TP53 mutation corresponds with poorest survival.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('LUAD', 'Disease', (35, 39))	('TP53', 'Gene', (141, 145))	('cancers', 'Phenotype', 'HP:0002664', (126, 133))	('cancers', 'Disease', (126, 133))	('cancers', 'Disease', 'MESH:D009369', (126, 133))	('mutation', 'Var', (146, 154))
506098	32545367	Significantly higher levels of immune infiltrate were measured in LUSC from females than from males, for both wt and mutant TP53 (Figure 6C, p = 0.02; Figure 6D, p < 0.01) in contrast to LUAD, where significance was only seen for wt TP53 cancers (Figure 2C,D).	('cancers', 'Disease', (238, 245))	('cancers', 'Disease', 'MESH:D009369', (238, 245))	('mutant', 'Var', (117, 123))	('TP53', 'Gene', (124, 128))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('cancers', 'Phenotype', 'HP:0002664', (238, 245))	('higher', 'PosReg', (14, 20))
506100	32545367	The immune signatures in mutant TP53 LUSC are discriminated by patient sex, with females enriched in the signatures for IFN-gamma response (Figure 6E, Table S13, adjusted p = 0.00852, NES = 1.65420), lymphocyte infiltration (adjusted p = 0.00277, NES = 1.72073), and macrophage-monocytes (adjusted p = 0.00086, NES = 2.25607).	('mutant', 'Var', (25, 31))	('TP53', 'Gene', (32, 36))	('patient', 'Species', '9606', (63, 70))	('IFN-gamma', 'Gene', '3458', (120, 129))	('IFN-gamma', 'Gene', (120, 129))
506101	32545367	TGF-beta response and wound healing were more enriched in LUSC with mutant TP53 in males than females, but not to a significant level (Figure 6E, Table S13), as also observed for wt TP53 LUAD in men (Figure 2E).	('TGF-beta', 'Gene', '7039', (0, 8))	('wound healing', 'CPA', (22, 35))	('mutant', 'Var', (68, 74))	('TP53', 'Gene', (75, 79))	('men', 'Species', '9606', (195, 198))	('TGF-beta', 'Gene', (0, 8))
506105	32545367	Many immunomodulator genes were more highly expressed in mutant TP53 LUSC in females than males: C-X-C Motif Chemokine Ligand 9 (CXCL9), Major Histocompatibility Complex, Class II, DQ Beta 2 (HLA-DQB2), Major Histocompatibility Complex, Class II, DP Beta 1 (HLA-DPB1), T Cell Immunoreceptor With Ig and ITIM Domains (TIGIT), Major Histocompatibility Complex, Class II, DP Alpha 1 (HLA-DPA1), C-X-C Motif Chemokine Ligand 10 (CXCL10), Major Histocompatibility Complex, Class II, DQ Alpha 2 (HLA-DQA2), Major Histocompatibility Complex, Class II, DR Alpha (HLA-DRA), Indoleamine 2,3-Dioxygenase 1 (IDO-1), Programmed Cell Death 1 (PDCD1), Major Histocompatibility Complex, Class II, DQ Alpha 1 (HLA-DQA1), and CD40 Ligand (CD40LG) (Figure 7C, Table S16, CXCL9 adjusted p = 0.00061, HLA-DQB2 adjusted p = 0.00358, HLA-DPB1 adjusted p = 0.00572, TIGIT adjusted p = 0.01007, HLA-DPA1 adjusted p = 0.02358, CXCL10 adjusted p = 0.02949, HLA-DQA2 adjusted p = 0.03444, HLA-DRA adjusted p = 0.03941, IDO-1 adjusted p = 0.04007, PDCD1 adjusted p = 0.04071, HLA-DQA1 adjusted p = 0.04095, and CD40LG adjusted p = 0.04714).	('CD40', 'Gene', '958', (721, 725))	('Major Histocompatibility Complex, Class II, DQ Alpha 2', 'Gene', '3118', (434, 488))	('HLA-DRA', 'Gene', (555, 562))	('C-X-C Motif Chemokine Ligand 10', 'Gene', '3627', (392, 423))	('C-X-C Motif Chemokine Ligand 9', 'Gene', '4283', (97, 127))	('HLA-DQA2', 'Gene', '3118', (490, 498))	('HLA-DRA', 'Gene', (961, 968))	('HLA-DPA1', 'Gene', '3113', (381, 389))	('HLA-DQB2', 'Gene', '3120', (192, 200))	('CXCL9', 'Gene', (752, 757))	('Major Histocompatibility Complex, Class II, DP Beta 1', 'Gene', '3115', (203, 256))	('CXCL10', 'Gene', '3627', (901, 907))	('HLA-DRA', 'Gene', '3122', (961, 968))	('HLA-DPA1', 'Gene', (870, 878))	('HLA-DQA2', 'Gene', (490, 498))	('mutant', 'Var', (57, 63))	('Major Histocompatibility Complex, Class II, DQ Alpha 1', 'Gene', '3117', (637, 691))	('CD40LG', 'Gene', '959', (721, 727))	('CXCL10', 'Gene', (425, 431))	('HLA-DQB2', 'Gene', '3120', (780, 788))	('HLA-DPB1', 'Gene', (811, 819))	('CXCL9', 'Gene', '4283', (752, 757))	('HLA-DQA1', 'Gene', (1047, 1055))	('CD40', 'Gene', (1082, 1086))	('CXCL10', 'Gene', (901, 907))	('HLA-DQB2', 'Gene', (192, 200))	('CD40', 'Gene', (708, 712))	('CD40LG', 'Gene', (1082, 1088))	('C-X-C Motif Chemokine Ligand 10', 'Gene', (392, 423))	('HLA-DQA1', 'Gene', '3117', (693, 701))	('Major Histocompatibility Complex, Class II, DP Alpha 1', 'Gene', '3113', (325, 379))	('CXCL9', 'Gene', (129, 134))	('CD40', 'Gene', '958', (708, 712))	('HLA-DQB2', 'Gene', (780, 788))	('IDO-1', 'Gene', (596, 601))	('IDO-1', 'Gene', '3620', (596, 601))	('Major Histocompatibility Complex, Class II, DQ Beta 2', 'Gene', '3120', (137, 190))	('CD40', 'Gene', '958', (1082, 1086))	('HLA-DPA1', 'Gene', '3113', (870, 878))	('HLA-DQA2', 'Gene', '3118', (930, 938))	('HLA-DPB1', 'Gene', '3115', (258, 266))	('IDO-1', 'Gene', (991, 996))	('IDO-1', 'Gene', '3620', (991, 996))	('CD40LG', 'Gene', '959', (1082, 1088))	('Major Histocompatibility Complex, Class II, DR Alpha', 'Gene', '3122', (501, 553))	('CXCL9', 'Gene', '4283', (129, 134))	('HLA-DQA2', 'Gene', (930, 938))	('HLA-DQA1', 'Gene', '3117', (1047, 1055))	('S16', 'Gene', '6217', (747, 750))	('C-X-C Motif Chemokine Ligand 9', 'Gene', (97, 127))	('HLA-DPA1', 'Gene', (381, 389))	('CD40', 'Gene', (721, 725))	('CXCL10', 'Gene', '3627', (425, 431))	('Indoleamine 2,3-Dioxygenase 1', 'Gene', '3620', (565, 594))	('HLA-DPB1', 'Gene', '3115', (811, 819))	('HLA-DPB1', 'Gene', (258, 266))	('S16', 'Gene', (747, 750))	('CD40LG', 'Gene', (721, 727))	('HLA-DQA1', 'Gene', (693, 701))	('HLA-DRA', 'Gene', '3122', (555, 562))
506107	32545367	Two lymphocyte infiltration genes, CD3e Molecule (CD3E) and CD3d Molecule (CD3D), which encode protein components of the T cell receptor (TCR)-CD3 complex that is central to T cell activation and immune responses to foreign antigens (Table S18), were more highly expressed in mutant TP53 LUSC in females compared with their male counterparts (CD3E adjusted p = 0.05000 and CD3D adjusted p = 0.05588).	('CD3E', 'Gene', '916', (50, 54))	('CD3E', 'Gene', (343, 347))	('CD3e', 'Gene', (35, 39))	('CD3D', 'Gene', '915', (373, 377))	('CD3D', 'Gene', '915', (75, 79))	('CD3e', 'Gene', '916', (35, 39))	('S18', 'Gene', '6222', (240, 243))	('CD3E', 'Gene', '916', (343, 347))	('CD3D', 'Gene', (373, 377))	('CD3D', 'Gene', (75, 79))	('highly expressed', 'PosReg', (256, 272))	('mutant', 'Var', (276, 282))	('CD3E', 'Gene', (50, 54))	('CD3d', 'Gene', '915', (60, 64))	('S18', 'Gene', (240, 243))	('lymphocyte infiltration genes', 'Gene', (4, 33))	('TP53', 'Gene', (283, 287))	('CD3d', 'Gene', (60, 64))
506108	32545367	Overall survival was not affected by relative gene expression of the significant immune signatures in mutant TP53 LUSC (Figure S5B-E), marking a contrast to the instance of wt TP53 LUAD (Figure 2B-F).	('mutant', 'Var', (102, 108))	('S5B', 'Gene', '5711', (127, 130))	('TP53', 'Gene', (109, 113))	('S5B', 'Gene', (127, 130))
506112	32545367	Given the reported correlation between mutant TP53 and PD-L1 (CD274) expression in LUAD, we tested this also as a function of patient sex in both LUAD and LUSC.	('tested', 'Reg', (92, 98))	('LUAD', 'Disease', (83, 87))	('LUAD', 'Disease', (146, 150))	('patient', 'Species', '9606', (126, 133))	('expression', 'MPA', (69, 79))	('PD-L1 (CD274', 'Gene', (55, 67))	('TP53', 'Gene', (46, 50))	('mutant', 'Var', (39, 45))
506113	32545367	In LUAD patients, PD-L1 expression levels were higher in the context of mutant TP53 than wt TP53 (Figure 8C), but this did not prove to be significantly different across the sexes (data not shown).	('TP53', 'Gene', (79, 83))	('mutant', 'Var', (72, 78))	('higher', 'PosReg', (47, 53))	('PD-L1 expression levels', 'MPA', (18, 41))	('patients', 'Species', '9606', (8, 16))
506115	32545367	In LUSC, PD-1 was not differentially expressed between wt or mutant TP53 cancers (data not shown).	('cancers', 'Disease', (73, 80))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('mutant', 'Var', (61, 67))	('TP53', 'Gene', (68, 72))	('cancers', 'Disease', 'MESH:D009369', (73, 80))
506116	32545367	Expression of the ligands of cytotoxic T-Lymphocyte Associated Protein 4 (CTLA-4): CD80 molecule (CD80) and CD86 molecule (CD86) were not significantly altered between wt and mutant TP53 LUAD (data not shown); while, in contrast, in LUSC they were significantly higher in mutant TP53 compared with wt TP53 (Figure 9A, CD80 p = 0.0025 and Figure 9B, CD86 p = 0.00057).	('mutant', 'Var', (272, 278))	('TP53', 'Gene', (182, 186))	('CD80', 'Gene', '941', (98, 102))	('CD80', 'Gene', (83, 87))	('mutant', 'Var', (175, 181))	('CD86', 'Gene', '942', (349, 353))	('higher', 'PosReg', (262, 268))	('CD80', 'Gene', (98, 102))	('CD86', 'Gene', (349, 353))	('CD80', 'Gene', '941', (318, 322))	('CTLA-4', 'Gene', '1493', (74, 80))	('CTLA-4', 'Gene', (74, 80))	('CD80', 'Gene', (318, 322))	('CD86', 'Gene', '942', (108, 112))	('CD86', 'Gene', (108, 112))	('cytotoxic T-Lymphocyte Associated Protein 4', 'Gene', '1493', (29, 72))	('CD86', 'Gene', '942', (123, 127))	('CD86', 'Gene', (123, 127))	('cytotoxic T-Lymphocyte Associated Protein 4', 'Gene', (29, 72))	('CD80', 'Gene', '941', (83, 87))
506127	32545367	These pathways have clear roles in cancer defense, including: The role of INF-gamma in tumor clearance, beneficial lymphocyte infiltration, and the pro-inflammatory and anti-tumor effects associated with M1 macrophages.	('tumor', 'Disease', (174, 179))	('pro-inflammatory', 'CPA', (148, 164))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('beneficial lymphocyte infiltration', 'CPA', (104, 138))	('tumor', 'Disease', (87, 92))	('INF-gamma', 'Var', (74, 83))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('cancer', 'Disease', (35, 41))
506130	32545367	These findings predict that the survival advantage among females with wt TP53 LUAD results from a superior capacity to combat cancer through CD8+ T cells and Natural Killer (NK) cell mediated-killing, directed through MHCI and also by CD4+ T cells through MHCII.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('CD8', 'Gene', (141, 144))	('CD4', 'Gene', (235, 238))	('CD8', 'Gene', '925', (141, 144))	('survival advantage', 'CPA', (32, 50))	('CD4', 'Gene', '920', (235, 238))	('TP53', 'Var', (73, 77))
506132	32545367	This reduction appears to reflect the decreased rate of males smoking unfiltered cigarettes, where smoke carcinogens are a major cause of the high levels of TP53 mutations in this disease.	('TP53', 'Gene', (157, 161))	('smoke carcinogens', 'Disease', (99, 116))	('mutations', 'Var', (162, 171))	('smoke carcinogens', 'Disease', 'MESH:D000074607', (99, 116))
506133	32545367	In remarkable contrast to the findings in LUAD, it is the mutant TP53 LUSC females who have the advantageous immune signatures of IFN-gamma, lymphocyte infiltration, and TGF-beta, together with M1 macrophage signature (Figure 6E,F, respectively).	('mutant', 'Var', (58, 64))	('TGF-beta', 'Gene', '7039', (170, 178))	('TP53', 'Gene', (65, 69))	('TGF-beta', 'Gene', (170, 178))	('lymphocyte infiltration', 'CPA', (141, 164))	('IFN-gamma', 'Gene', '3458', (130, 139))	('IFN-gamma', 'Gene', (130, 139))
506135	32545367	In fact, the poorest survival for mutant TP53 LUAD corresponded with the highest PD-L1 expression levels among these patients (Figure 8D).	('TP53', 'Gene', (41, 45))	('patients', 'Species', '9606', (117, 125))	('highest', 'Reg', (73, 80))	('PD-L1 expression levels', 'MPA', (81, 104))	('poorest', 'NegReg', (13, 20))	('mutant', 'Var', (34, 40))
506137	32545367	In our studies, by correlating poor survival to TP53 mutation in patients with high PD-L1 expression, we defined a group predicted to benefit most advantageously from PD-L1 checkpoint inhibitor.	('patients', 'Species', '9606', (65, 73))	('TP53', 'Gene', (48, 52))	('mutation', 'Var', (53, 61))
506142	32545367	The rates of EGFR and KRAS Proto-Oncogene, GTPase (KRAS) mutations and ALK Receptor Tyrosine Kinase (ALK) rearrangements were very similar, regardless of whether TP53 was co-mutated or wild type (data not shown).	('ALK', 'Gene', (101, 104))	('ALK', 'Gene', (71, 74))	('KRAS', 'Gene', '3845', (51, 55))	('men', 'Species', '9606', (115, 118))	('ALK', 'Gene', '238', (101, 104))	('ALK', 'Gene', '238', (71, 74))	('mutations', 'Var', (57, 66))	('KRAS', 'Gene', (22, 26))	('KRAS', 'Gene', '3845', (22, 26))	('EGFR', 'Gene', '1956', (13, 17))	('EGFR', 'Gene', (13, 17))	('KRAS', 'Gene', (51, 55))
506148	32545367	For the TP53 gene, the mutation status of each patient sample was classified as either wildtype-TP53 (wt TP53) or mutant TP53.	('patient', 'Species', '9606', (47, 54))	('mutant TP53', 'Var', (114, 125))	('TP53', 'Gene', (8, 12))
506162	32545367	Using TCGA RNA-Seq normalized CPM, multiple groups were compared for differential gene expression: mutant TP53 tumors vs. wt TP53 tumors, female wt TP53 tumors vs. male wt TP53 tumors, and female Mt TP53 tumors vs. male mutant TP53 tumors.	('tumors', 'Disease', 'MESH:D009369', (130, 136))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumors', 'Disease', (111, 117))	('tumors', 'Phenotype', 'HP:0002664', (204, 210))	('tumors', 'Disease', 'MESH:D009369', (177, 183))	('tumors', 'Disease', 'MESH:D009369', (153, 159))	('tumors', 'Disease', 'MESH:D009369', (232, 238))	('tumors', 'Disease', (177, 183))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('tumors', 'Disease', 'MESH:D009369', (111, 117))	('tumors', 'Disease', (204, 210))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))	('TP53', 'Gene', (106, 110))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumors', 'Phenotype', 'HP:0002664', (153, 159))	('tumors', 'Disease', 'MESH:D009369', (204, 210))	('tumors', 'Phenotype', 'HP:0002664', (177, 183))	('tumors', 'Disease', (130, 136))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('tumors', 'Disease', (153, 159))	('mutant', 'Var', (99, 105))	('tumors', 'Disease', (232, 238))
506169	32545367	Patients were stratified based on sex, TP53 mutation status, immune infiltrate levels, and gene expression level.	('Patients', 'Species', '9606', (0, 8))	('mutation', 'Var', (44, 52))	('TP53', 'Gene', (39, 43))
506314	28504190	CDKN3 transcript variants and mutations have also been reported.	('CDKN3', 'Gene', '1033', (0, 5))	('mutations', 'Var', (30, 39))	('CDKN3', 'Gene', (0, 5))
506315	28504190	The mechanism of CDKN3 overexpression and the role of CDKN3 transcript variants in human cancer are not entirely clear.	('variants', 'Var', (71, 79))	('overexpression', 'PosReg', (23, 37))	('CDKN3', 'Gene', (17, 22))	('CDKN3', 'Gene', '1033', (54, 59))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('human', 'Species', '9606', (83, 88))	('cancer', 'Disease', (89, 95))	('CDKN3', 'Gene', '1033', (17, 22))	('CDKN3', 'Gene', (54, 59))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
506318	28504190	Aberrant CDKN3 transcripts were postulated to encode dominant-negative inhibitors of CDKN3 as an explanation for overexpression of the perceived tumor suppressor gene in human cancer.	('CDKN3', 'Gene', (85, 90))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('Aberrant', 'Var', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('CDKN3', 'Gene', '1033', (85, 90))	('overexpression', 'PosReg', (113, 127))	('CDKN3', 'Gene', (9, 14))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('CDKN3', 'Gene', '1033', (9, 14))	('tumor', 'Disease', (145, 150))	('human', 'Species', '9606', (170, 175))	('cancer', 'Disease', (176, 182))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('inhibitors', 'NegReg', (71, 81))
506328	28504190	In addition to the required interaction with cyclins that oscillate through cell cycle, CDK1/CDK2 Ser/Thr kinase activity is further regulated by phosphorylation at three residues; Thr-14 and Tyr-15 of both proteins and Thr-161 of CDK1 and Thr-160 of CDK2.	('Thr', 'Chemical', 'MESH:D013912', (102, 105))	('Thr', 'Chemical', 'MESH:D013912', (181, 184))	('Thr', 'Chemical', 'MESH:D013912', (220, 223))	('Thr-161', 'Var', (220, 227))	('cyclin', 'Gene', '5111', (45, 51))	('Thr-14', 'Var', (181, 187))	('Tyr', 'Chemical', 'MESH:D014443', (192, 195))	('Ser', 'Chemical', 'MESH:D012694', (98, 101))	('CDK1', 'Gene', (231, 235))	('CDK1', 'Gene', '983', (88, 92))	('CDK1', 'Gene', '983', (231, 235))	('CDK1', 'Gene', (88, 92))	('regulated', 'Reg', (133, 142))	('CDK2', 'Gene', '1017', (251, 255))	('Thr-160', 'Var', (240, 247))	('Thr', 'Chemical', 'MESH:D013912', (240, 243))	('cyclin', 'Gene', (45, 51))	('CDK2', 'Gene', '1017', (93, 97))	('CDK2', 'Gene', (251, 255))	('CDK2', 'Gene', (93, 97))	('activity', 'MPA', (113, 121))	('Tyr-15', 'Var', (192, 198))
506329	28504190	Phosphorylation at the dual Thr-14/Tyr-15 sites inhibits kinase activity and is regulated by the PKMYT1 (MYT1)/WEE1 kinase and the dual-specificity protein tyrosine phosphatase CDC25.	('PKMYT1', 'Gene', (97, 103))	('WEE1', 'Gene', (111, 115))	('WEE1', 'Gene', '7465', (111, 115))	('CDC25', 'Gene', (177, 182))	('inhibits', 'NegReg', (48, 56))	('MYT1', 'Gene', (99, 103))	('kinase activity', 'MPA', (57, 72))	('CDC25', 'Gene', '995', (177, 182))	('PKMYT1', 'Gene', '9088', (97, 103))	('Thr-14/Tyr', 'SUBSTITUTION', 'None', (28, 38))	('MYT1', 'Gene', '4661', (105, 109))	('Phosphorylation', 'MPA', (0, 15))	('Thr-14/Tyr', 'Var', (28, 38))	('MYT1', 'Gene', '4661', (99, 103))	('MYT1', 'Gene', (105, 109))
506332	28504190	Phosphorylation of Thr-160 in CDK2 increases its binding affinity for the kinase substrates, but has no effect on cyclin A binding.	('CDK2', 'Gene', (30, 34))	('Thr-160', 'Var', (19, 26))	('Thr', 'Chemical', 'MESH:D013912', (19, 22))	('increases', 'PosReg', (35, 44))	('binding', 'Interaction', (49, 56))	('Phosphorylation', 'MPA', (0, 15))	('CDK2', 'Gene', '1017', (30, 34))	('cyclin A', 'Gene', (114, 122))	('cyclin A', 'Gene', '890', (114, 122))
506342	28504190	Suppression of CDKN3 expression by antisense CDKN3 inhibited soft-agar colony growth of LNCaP cells and tumor xenograft growth of HeLa cells, suggesting that CDKN3 plays a tumorigenic role in these cells.	('CDKN3', 'Gene', (158, 163))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumor', 'Disease', (172, 177))	('HeLa', 'CellLine', 'CVCL:0030', (130, 134))	('Suppression', 'NegReg', (0, 11))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('CDKN3', 'Gene', '1033', (15, 20))	('CDKN3', 'Gene', (45, 50))	('CDKN3', 'Gene', '1033', (158, 163))	('inhibited', 'NegReg', (51, 60))	('antisense', 'Var', (35, 44))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('tumor', 'Disease', (104, 109))	('soft-agar colony growth of', 'CPA', (61, 87))	('CDKN3', 'Gene', '1033', (45, 50))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('LNCaP', 'CellLine', 'CVCL:0395', (88, 93))	('expression', 'MPA', (21, 31))	('CDKN3', 'Gene', (15, 20))
506344	28504190	Moreover, high CDKN3 mRNA levels have been associated with poor survival in glioma, cervical cancer, and lung adenocarcinoma.	('CDKN3', 'Gene', '1033', (15, 20))	('glioma', 'Disease', (76, 82))	('cervical cancer', 'Disease', 'MESH:D002583', (84, 99))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (105, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('cervical cancer', 'Disease', (84, 99))	('glioma', 'Disease', 'MESH:D005910', (76, 82))	('lung adenocarcinoma', 'Disease', (105, 124))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('glioma', 'Phenotype', 'HP:0009733', (76, 82))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (105, 124))	('CDKN3', 'Gene', (15, 20))	('poor', 'NegReg', (59, 63))	('high', 'Var', (10, 14))
506350	28504190	In the TCGA datasets, CDKN3 mRNA levels in acute myeloid leukemia, invasive breast carcinoma, and colorectal adenocarcinoma were not prognostic for overall survival, whereas high CDKN3 mRNA levels were associated with poor overall survival in low grade glioma and renal clear cell carcinoma (Fig.	('renal clear cell carcinoma', 'Disease', 'MESH:C538614', (264, 290))	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (98, 123))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('renal clear cell carcinoma', 'Disease', (264, 290))	('CDKN3', 'Gene', (22, 27))	('invasive breast carcinoma', 'Disease', 'MESH:D018270', (67, 92))	('CDKN3', 'Gene', (179, 184))	('glioma', 'Phenotype', 'HP:0009733', (253, 259))	('breast carcinoma', 'Phenotype', 'HP:0003002', (76, 92))	('poor', 'NegReg', (218, 222))	('high', 'Var', (174, 178))	('leukemia', 'Phenotype', 'HP:0001909', (57, 65))	('acute myeloid leukemia', 'Disease', (43, 65))	('invasive breast carcinoma', 'Disease', (67, 92))	('CDKN3', 'Gene', '1033', (22, 27))	('CDKN3', 'Gene', '1033', (179, 184))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))	('colorectal adenocarcinoma', 'Disease', (98, 123))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (43, 65))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (49, 65))	('glioma', 'Disease', (253, 259))	('carcinoma', 'Phenotype', 'HP:0030731', (281, 290))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (43, 65))	('glioma', 'Disease', 'MESH:D005910', (253, 259))
506351	28504190	In prostate adenocarcinoma, while the few deceased cases (2%) limited assessment of a correlation between CDKN3 levels and the overall survival, high CDKN3 mRNA expression was associated with poor disease-free survival (Fig.	('mRNA expression', 'MPA', (156, 171))	('prostate adenocarcinoma', 'Disease', 'MESH:D011471', (3, 26))	('disease-free survival', 'CPA', (197, 218))	('high', 'Var', (145, 149))	('CDKN3', 'Gene', '1033', (106, 111))	('CDKN3', 'Gene', '1033', (150, 155))	('poor', 'NegReg', (192, 196))	('carcinoma', 'Phenotype', 'HP:0030731', (17, 26))	('CDKN3', 'Gene', (150, 155))	('prostate adenocarcinoma', 'Disease', (3, 26))	('CDKN3', 'Gene', (106, 111))
506356	28504190	The exon 2-skip transcript results in a frameshift and encodes a short 23-amino acid residue peptide non-homologous to CDKN3.	('encodes', 'Reg', (55, 62))	('CDKN3', 'Gene', '1033', (119, 124))	('frameshift', 'Var', (40, 50))	('results in', 'Reg', (27, 37))	('CDKN3', 'Gene', (119, 124))
506361	28504190	These aberrant CDKN3 transcripts include nonsense mutations and deletions that resulted in truncated CDKN3 and CDKN3 with missense or internal deletion mutations.	('missense', 'Var', (122, 130))	('CDKN3', 'Gene', '1033', (15, 20))	('truncated', 'MPA', (91, 100))	('CDKN3', 'Gene', (111, 116))	('deletions', 'Var', (64, 73))	('CDKN3', 'Gene', (101, 106))	('internal deletion mutations', 'Var', (134, 161))	('CDKN3', 'Gene', (15, 20))	('CDKN3', 'Gene', '1033', (111, 116))	('CDKN3', 'Gene', '1033', (101, 106))
506362	28504190	Potentially, some of these aberrant transcripts may result in dominant-negative CDKN3 mutants that could interfere with normal CDKN3 function.	('CDKN3', 'Gene', (127, 132))	('mutants', 'Var', (86, 93))	('CDKN3', 'Gene', (80, 85))	('result', 'Reg', (52, 58))	('CDKN3', 'Gene', '1033', (127, 132))	('CDKN3', 'Gene', '1033', (80, 85))
506363	28504190	We found no CDKN3 mutations among 30 cases of hepatocellular carcinoma from Total Cancer Care  (TCC) data.	('CDKN3', 'Gene', '1033', (12, 17))	('Total Cancer', 'Disease', (76, 88))	('Total Cancer', 'Disease', 'MESH:D009369', (76, 88))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (46, 70))	('Cancer', 'Phenotype', 'HP:0002664', (82, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('hepatocellular carcinoma', 'Disease', (46, 70))	('CDKN3', 'Gene', (12, 17))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (46, 70))	('mutations', 'Var', (18, 27))
506364	28504190	Among 442 cases of hepatocellular carcinoma in TCGA and 231 cases of hepatocellular carcinoma reported by Ahn et al., there were two cases with missense mutations (I72T, E17K) (cbioportal.org).	('carcinoma', 'Phenotype', 'HP:0030731', (34, 43))	('E17K', 'Mutation', 'p.E17K', (170, 174))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (69, 93))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (69, 93))	('I72T', 'Var', (164, 168))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('hepatocellular carcinoma', 'Disease', (69, 93))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (19, 43))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (19, 43))	('E17K', 'Var', (170, 174))	('I72T', 'Mutation', 'rs1314092141', (164, 168))	('hepatocellular carcinoma', 'Disease', (19, 43))
506365	28504190	Therefore, the high incidence of CDKN3 missense and nonsense mutations reported by Yeh et al.	('nonsense mutations', 'Var', (52, 70))	('CDKN3', 'Gene', '1033', (33, 38))	('missense', 'Var', (39, 47))	('CDKN3', 'Gene', (33, 38))
506366	28504190	appeared inconsistent with genomic data in hepatocellular carcinoma from other laboratories, and some of the deletion mutations were probably generated post-transcriptionally via alternative splicing.	('deletion mutations', 'Var', (109, 127))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (43, 67))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (43, 67))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))	('hepatocellular carcinoma', 'Disease', (43, 67))
506371	28504190	These transcripts were generated from alternative splicing lacking internal exons or distal exons, but retaining exons 4, 6, 7, and/or 8 that encode CDK2 interacting regions of CDKN3.	('CDK2', 'Gene', '1017', (149, 153))	('CDKN3', 'Gene', '1033', (177, 182))	('internal exons', 'MPA', (67, 81))	('lacking', 'NegReg', (59, 66))	('CDK2', 'Gene', (149, 153))	('CDKN3', 'Gene', (177, 182))	('alternative splicing', 'Var', (38, 58))	('distal', 'MPA', (85, 91))
506372	28504190	Thus, proteins encoded by these aberrant transcripts are predicted to be able to interfere with the wildtype CDKN3 function.	('CDKN3', 'Gene', '1033', (109, 114))	('aberrant transcripts', 'Var', (32, 52))	('interfere', 'NegReg', (81, 90))	('function', 'MPA', (115, 123))	('CDKN3', 'Gene', (109, 114))	('proteins', 'Protein', (6, 14))
506377	28504190	Although we used RT-PCR primer pairs that were designed to detect potential alternative splicing in every exon of CDKN3, no aberrant alternative splicing or mutation was found in these 24 samples.	('CDKN3', 'Gene', (114, 119))	('CDKN3', 'Gene', '1033', (114, 119))	('alternative splicing', 'Var', (76, 96))
506378	28504190	The reasons that others detected minor aberrant CDKN3 transcripts in their samples and that we did not remain to be determined.	('aberrant', 'Var', (39, 47))	('CDKN3', 'Gene', (48, 53))	('CDKN3', 'Gene', '1033', (48, 53))	('transcripts', 'MPA', (54, 65))
506392	28504190	Elevated MPS1 results in overduplication of centrosomes that causes abnormal spindle assembly and interferes with cell division.	('cell division', 'CPA', (114, 127))	('MPS1', 'Gene', (9, 13))	('causes', 'Reg', (61, 67))	('spindle assembly', 'CPA', (77, 93))	('interferes', 'NegReg', (98, 108))	('centrosomes', 'Protein', (44, 55))	('overduplication', 'MPA', (25, 40))	('MPS1', 'Gene', '7272', (9, 13))	('Elevated', 'Var', (0, 8))
506399	28504190	Early studies attributed CDKN3 overexpression to dominant-negative protein, caused by either mutations or aberrant splicing transcripts.	('mutations', 'Var', (93, 102))	('CDKN3', 'Gene', (25, 30))	('protein', 'Protein', (67, 74))	('aberrant splicing transcripts', 'Var', (106, 135))	('CDKN3', 'Gene', '1033', (25, 30))	('overexpression', 'PosReg', (31, 45))	('caused by', 'Reg', (76, 85))
506400	28504190	However, recent cancer genomic data indicate that CDKN3 mutations are rare and likely non-disruptive.	('mutations', 'Var', (56, 65))	('cancer', 'Disease', 'MESH:D009369', (16, 22))	('CDKN3', 'Gene', '1033', (50, 55))	('cancer', 'Disease', (16, 22))	('CDKN3', 'Gene', (50, 55))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))
506407	28504190	While inactivating CDK1 to ensure mitotic exit may explain the need of a high level CDKN3 in the mitotic phase, the mechanisms of dynamic control of CDKN3 mRNA and protein expression during cell cycle remain to be investigated.	('CDKN3', 'Gene', '1033', (84, 89))	('CDK1', 'Gene', (19, 23))	('CDK1', 'Gene', '983', (19, 23))	('CDKN3', 'Gene', (149, 154))	('CDKN3', 'Gene', (84, 89))	('inactivating', 'Var', (6, 18))	('CDKN3', 'Gene', '1033', (149, 154))
506429	27840932	Evidence indicates that the loss of KEAP1 genes leads to NRF2 upregulation and expression of its downstream genes that encode cytoprotective proteins, including quinone oxidoreductase-1 (NQO-1) and heme oxygenase-1 (HO-1), which enhances cancer cell proliferation.	('KEAP1', 'Gene', (36, 41))	('cancer', 'Disease', (238, 244))	('loss', 'Var', (28, 32))	('cancer', 'Disease', 'MESH:D009369', (238, 244))	('enhances', 'PosReg', (229, 237))	('expression', 'MPA', (79, 89))	('HO-1', 'Gene', '3162', (216, 220))	('heme oxygenase-1', 'Gene', (198, 214))	('NQO-1', 'Gene', '1728', (187, 192))	('NRF2', 'Gene', '4780', (57, 61))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('KEAP1', 'Gene', '9817', (36, 41))	('NQO-1', 'Gene', (187, 192))	('NRF2', 'Gene', (57, 61))	('HO-1', 'Gene', (216, 220))	('heme oxygenase-1', 'Gene', '3162', (198, 214))	('upregulation', 'PosReg', (62, 74))
506430	27840932	Simultaneous knockdown of NRF2 genes produced the opposite results.	('NRF2', 'Gene', (26, 30))	('knockdown', 'Var', (13, 22))	('NRF2', 'Gene', '4780', (26, 30))
506504	27840932	NRF2 is a critical gene that with a core role in KEAP1/NRF2 system, and NRF2 expression is associated with poor prognosis in patients with cancer.	('patients', 'Species', '9606', (125, 133))	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('NRF2', 'Gene', (0, 4))	('NRF2', 'Gene', '4780', (72, 76))	('KEAP1', 'Gene', '9817', (49, 54))	('NRF2', 'Gene', (55, 59))	('expression', 'Var', (77, 87))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('NRF2', 'Gene', (72, 76))	('KEAP1', 'Gene', (49, 54))	('associated', 'Reg', (91, 101))	('NRF2', 'Gene', '4780', (0, 4))	('NRF2', 'Gene', '4780', (55, 59))	('cancer', 'Disease', (139, 145))
506515	27840932	This observation was verified in head and neck cancers and non-small cell lung carcinomas (NSCLC), in which nuclear NRF2 positivity was as high as 61.8% and its expression was statistically associated with higher KEAP1 expression.	('higher', 'PosReg', (206, 212))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('NRF2', 'Gene', (116, 120))	('small cell lung carcinomas', 'Phenotype', 'HP:0030357', (63, 89))	('carcinomas', 'Phenotype', 'HP:0030731', (79, 89))	('head and neck cancers', 'Phenotype', 'HP:0012288', (33, 54))	('non-small cell lung carcinomas', 'Phenotype', 'HP:0030358', (59, 89))	('expression', 'MPA', (161, 171))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('KEAP1', 'Gene', '9817', (213, 218))	('NSCLC', 'Disease', 'MESH:D002289', (91, 96))	('neck cancers', 'Disease', (42, 54))	('KEAP1', 'Gene', (213, 218))	('positivity', 'Var', (121, 131))	('non-small cell lung carcinomas', 'Disease', 'MESH:D002289', (59, 89))	('neck cancers', 'Disease', 'MESH:D006258', (42, 54))	('cancers', 'Phenotype', 'HP:0002664', (47, 54))	('non-small cell lung carcinomas', 'Disease', (59, 89))	('NSCLC', 'Disease', (91, 96))	('head and neck cancer', 'Phenotype', 'HP:0012288', (33, 53))	('NSCLC', 'Phenotype', 'HP:0030358', (91, 96))	('expression', 'MPA', (219, 229))	('NRF2', 'Gene', '4780', (116, 120))
506521	27840932	Various recent studies suggest that KEAP1 mutations lead to constitutive activation and the nuclear accumulation of NRF2, which enhances the expression of antioxidative and detoxifying enzymes.	('KEAP1', 'Gene', (36, 41))	('nuclear', 'MPA', (92, 99))	('activation', 'PosReg', (73, 83))	('NRF2', 'Gene', '4780', (116, 120))	('constitutive', 'MPA', (60, 72))	('expression', 'MPA', (141, 151))	('KEAP1', 'Gene', '9817', (36, 41))	('NRF2', 'Gene', (116, 120))	('mutations', 'Var', (42, 51))	('enhances', 'PosReg', (128, 136))
506522	27840932	Certain data demonstrated that KEAP1 mutations occur widely in solid cancers, irrespective of histological type.	('KEAP1', 'Gene', '9817', (31, 36))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('mutations', 'Var', (37, 46))	('KEAP1', 'Gene', (31, 36))	('solid cancers', 'Disease', (63, 76))	('cancers', 'Phenotype', 'HP:0002664', (69, 76))	('occur', 'Reg', (47, 52))	('solid cancers', 'Disease', 'MESH:D009369', (63, 76))
506585	26785356	In contrast, the M2 polarization is associated with wound healing, suppression of inflammation, and is considered to promote tumor growth.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('wound healing', 'CPA', (52, 65))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('suppression', 'NegReg', (67, 78))	('inflammation', 'Disease', 'MESH:D007249', (82, 94))	('tumor', 'Disease', (125, 130))	('inflammation', 'Disease', (82, 94))	('promote', 'PosReg', (117, 124))	('associated', 'Reg', (36, 46))	('M2 polarization', 'Var', (17, 32))
506781	32253638	Manipulating endosomal pH by epigenetic reprogramming, small molecules, or nanoparticles may offer promising new options in cancer therapy.	('epigenetic reprogramming', 'Var', (29, 53))	('cancer', 'Disease', (124, 130))	('pH', 'Gene', '5053', (23, 25))	('Manipulating', 'Var', (0, 12))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('cancer', 'Disease', 'MESH:D009369', (124, 130))
506783	32253638	Dysregulation of cellular pH is an established hallmark of malignancy.	('Dysregulation', 'Var', (0, 13))	('malignancy', 'Disease', (59, 69))	('pH', 'Gene', '5053', (26, 28))	('malignancy', 'Disease', 'MESH:D009369', (59, 69))
506826	32253638	Cl- flux is critical for endocytosis in renal tissue where defects in CLC-5 (gene name CLCN5) underlie Dent's disease characterized by proximal tubule dysfunction and low molecular weight proteinuria.	('tubule dysfunction', 'Disease', (144, 162))	('CLC-5', 'Gene', '1184', (70, 75))	('proteinuria', 'Disease', 'MESH:D011507', (188, 199))	('CLC-5', 'Gene', (70, 75))	('tubule dysfunction', 'Disease', 'MESH:D007673', (144, 162))	('proximal tubule dysfunction', 'Phenotype', 'HP:0000114', (135, 162))	('underlie', 'Reg', (94, 102))	('low molecular weight proteinuria', 'Phenotype', 'HP:0003126', (167, 199))	('CLCN5', 'Gene', '1184', (87, 92))	('CLCN5', 'Gene', (87, 92))	('proteinuria', 'Phenotype', 'HP:0000093', (188, 199))	("Dent's disease", 'Disease', 'MESH:C538212', (103, 117))	('proteinuria', 'Disease', (188, 199))	("Dent's disease", 'Disease', (103, 117))	('defects', 'Var', (59, 66))
506827	32253638	Consistent with their essential role in pH regulation, loss of function mutations in the chloride transporter isoform, CLC-7 (gene name CLCN7), phenocopy V-ATPase defects in the fatal disorder, osteopetrosis in which defective acidification by osteoclasts results in failure to remodel bone.	('CLC-7', 'Gene', '1186', (119, 124))	('mutations', 'Var', (72, 81))	('CLCN7', 'Gene', '1186', (136, 141))	('pH', 'Gene', '5053', (40, 42))	('defects', 'Var', (163, 170))	('defective', 'Var', (217, 226))	('defective acidification', 'Phenotype', 'HP:0031033', (217, 240))	('osteopetrosis', 'Disease', (194, 207))	('osteopetrosis', 'Disease', 'MESH:D010022', (194, 207))	('osteopetrosis', 'Phenotype', 'HP:0011002', (194, 207))	('acidification', 'MPA', (227, 240))	('fatal disorder', 'Disease', 'MESH:C535933', (178, 192))	('loss of function', 'NegReg', (55, 71))	('CLC-7', 'Gene', (119, 124))	('CLCN7', 'Gene', (136, 141))	('ATP', 'Chemical', 'MESH:D000255', (156, 159))	('fatal disorder', 'Disease', (178, 192))
506836	32253638	Similarly, NHE5 is a potent acidifier of recycling endosomes in rat pheochromocytoma PC12 cells, and attenuation of NHE5 expression via shRNA decreased the steady state level of Tropomyosin Receptor Kinase A (TrkA) on the plasma membrane.	('attenuation', 'Var', (101, 112))	('PC12', 'CellLine', 'CVCL:0481', (85, 89))	('Tropomyosin Receptor Kinase A', 'Gene', '59109', (178, 207))	('Tropomyosin Receptor Kinase A', 'Gene', (178, 207))	('pheochromocytoma', 'Disease', (68, 84))	('decreased', 'NegReg', (142, 151))	('TrkA', 'Gene', (209, 213))	('rat', 'Species', '10116', (64, 67))	('TrkA', 'Gene', '59109', (209, 213))	('pheochromocytoma', 'Phenotype', 'HP:0002666', (68, 84))	('pheochromocytoma', 'Disease', 'MESH:D010673', (68, 84))	('NHE5', 'Gene', (116, 120))
506841	32253638	This is consistent with the majority of studies, which report that NHE6, NHE7 and NHE9 alkalinize the compartmental lumen, in contrast to the "plasma membrane" subtype isoforms, NHE3 and NHE5 that acidify endosomal lumen.	('alkalinize', 'Reg', (87, 97))	('NHE6', 'Gene', (67, 71))	('NHE3', 'Gene', '6550', (178, 182))	('NHE7', 'Gene', '84679', (73, 77))	('NHE3', 'Gene', (178, 182))	('NHE6', 'Gene', '10479', (67, 71))	('NHE9', 'Var', (82, 86))	('NHE7', 'Gene', (73, 77))
506850	32253638	Along with the evolutionary selection of cancer-driving mutations, the acidic tumor microenvironment favors and drives cancer progression, particularly in local invasion and metastasis, genetic instability, cancer stem cells, epigenetic alterations, proliferation, and survival.	('favors', 'PosReg', (101, 107))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('epigenetic alterations', 'Var', (226, 248))	('cancer', 'Disease', (41, 47))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('cancer', 'Disease', (207, 213))	('cancer', 'Disease', (119, 125))	('local invasion', 'CPA', (155, 169))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('survival', 'CPA', (269, 277))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('rat', 'Species', '10116', (257, 260))	('proliferation', 'CPA', (250, 263))	('rat', 'Species', '10116', (241, 244))	('acidic tumor', 'Disease', 'MESH:D009369', (71, 83))	('genetic', 'Var', (186, 193))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (207, 213))	('acidic tumor', 'Disease', (71, 83))	('cancer', 'Disease', 'MESH:D009369', (119, 125))
506851	32253638	Acidic extracellular pH between 6.4 and 6.8 was found to increase lysosome size and promote anterograde trafficking to the cell periphery resulting in increased secretion of proteolytic enzymes.	('increased', 'PosReg', (151, 160))	('lysosome size', 'CPA', (66, 79))	('promote', 'PosReg', (84, 91))	('secretion of proteolytic enzymes', 'MPA', (161, 193))	('pH', 'Gene', '5053', (21, 23))	('Acidic', 'Var', (0, 6))	('increase', 'PosReg', (57, 65))	('anterograde trafficking to', 'CPA', (92, 118))
506853	32253638	In recent years, significant progress has been made towards elucidating the cellular processes and signaling pathways that link endosomal pH, and particularly dysregulated expression or activity of intracellular NHE isoforms to oncogenesis and chemoresistance.	('NHE', 'Gene', (212, 215))	('chemoresistance', 'CPA', (244, 259))	('dysregulated', 'Var', (159, 171))	('activity', 'MPA', (186, 194))	('NHE', 'Gene', '285335', (212, 215))	('pH', 'Gene', '5053', (138, 140))	('oncogenesis', 'CPA', (228, 239))
506863	32253638	found that silencing NHE6 but not NHE9 increased endosomal drug sequestration, even under normoxia.	('silencing', 'Var', (11, 20))	('NHE6', 'Gene', '10479', (21, 25))	('rat', 'Species', '10116', (71, 74))	('endosomal drug sequestration', 'MPA', (49, 77))	('NHE6', 'Gene', (21, 25))
506870	32253638	Consistent with high amplification of SLC9A9 (Figure 3), NHE9 was found to be a prognostic predictor for poor survival in esophageal squamous cell carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (147, 156))	('esophageal squamous cell carcinoma', 'Disease', (122, 156))	('SLC9A9', 'Gene', (38, 44))	('NHE9', 'Gene', (57, 61))	('high amplification', 'Var', (16, 34))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (133, 156))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (122, 156))	('SLC9A9', 'Gene', '285195', (38, 44))
506877	32253638	The increased chemoradiation resistance with NHE9 expression was also shown in xenograft model in mice.	('expression', 'Var', (50, 60))	('chemoradiation resistance', 'CPA', (14, 39))	('increased', 'PosReg', (4, 13))	('NHE9', 'Gene', (45, 49))	('mice', 'Species', '10090', (98, 102))
506880	32253638	showed that NHE9 increases anti-apoptotic and pro-survival pathways such as p-GSK3b, Bcl-2, beta-catenin, p-Akt and p-Src to inhibit cleavage of PARP or Caspase-3.	('GSK3b', 'Gene', '2932', (78, 83))	('anti-apoptotic', 'CPA', (27, 41))	('Caspase-3', 'Gene', (153, 162))	('Bcl-2', 'Gene', (85, 90))	('Src', 'Gene', (118, 121))	('Akt', 'Gene', (108, 111))	('PARP', 'Gene', '1302', (145, 149))	('Akt', 'Gene', '207', (108, 111))	('Src', 'Gene', '6714', (118, 121))	('Bcl-2', 'Gene', '596', (85, 90))	('inhibit', 'NegReg', (125, 132))	('increases', 'PosReg', (17, 26))	('GSK3b', 'Gene', (78, 83))	('NHE9', 'Var', (12, 16))	('Caspase-3', 'Gene', '836', (153, 162))	('beta-catenin', 'Gene', (92, 104))	('beta-catenin', 'Gene', '1499', (92, 104))	('PARP', 'Gene', (145, 149))	('cleavage', 'MPA', (133, 141))
506885	32253638	Using patient derived glioblastoma cell lines they demonstrated that up regulated expression of NHE9 significantly alkalinized endosomal lumen, to pH ~6.5.	('glioblastoma', 'Disease', (22, 34))	('patient', 'Species', '9606', (6, 13))	('glioblastoma', 'Disease', 'MESH:D005909', (22, 34))	('pH', 'Gene', '5053', (147, 149))	('expression', 'Var', (82, 92))	('glioblastoma', 'Phenotype', 'HP:0012174', (22, 34))	('rat', 'Species', '10116', (58, 61))	('up regulated', 'PosReg', (69, 81))	('alkalinized endosomal lumen', 'MPA', (115, 142))	('NHE9', 'Gene', (96, 100))
506887	32253638	Similarly, high levels of NHE9 expression correlated with increased metastasis and worse prognosis in colorectal cancer patients, where a positive correlation with EGFR signaling was also noted.	('colorectal cancer', 'Disease', (102, 119))	('increased', 'PosReg', (58, 67))	('NHE9', 'Protein', (26, 30))	('rectal cancer', 'Phenotype', 'HP:0100743', (106, 119))	('expression', 'MPA', (31, 41))	('colorectal cancer', 'Disease', 'MESH:D015179', (102, 119))	('patients', 'Species', '9606', (120, 128))	('metastasis', 'CPA', (68, 78))	('high', 'Var', (11, 15))	('colorectal cancer', 'Phenotype', 'HP:0003003', (102, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
506888	32253638	Post-translational oncogenic activation of EGFR was dependent on alkalinization of endosomal pH because autism-associated loss-of-function mutations, S438P and L236S, failed to phenocopy wild type NHE9 in glioblastoma cells.	('glioblastoma', 'Phenotype', 'HP:0012174', (205, 217))	('loss-of-function', 'NegReg', (122, 138))	('autism', 'Phenotype', 'HP:0000717', (104, 110))	('autism', 'Disease', 'MESH:D001321', (104, 110))	('L236S', 'Var', (160, 165))	('L236S', 'Mutation', 'rs113649536', (160, 165))	('S438P', 'Var', (150, 155))	('autism', 'Disease', (104, 110))	('S438P', 'Mutation', 'rs1181244744', (150, 155))	('glioblastoma', 'Disease', (205, 217))	('glioblastoma', 'Disease', 'MESH:D005909', (205, 217))	('pH', 'Gene', '5053', (93, 95))
506893	32253638	Functional restoration of miR-135a by ectopic expression in GBM cell lines resulted in down regulation of SLC9A9 transcript, acidification of endosomal pH and decreased GBM cell proliferation and migration.	('miR-135a', 'Gene', (26, 34))	('down regulation', 'NegReg', (87, 102))	('rat', 'Species', '10116', (16, 19))	('transcript', 'MPA', (113, 123))	('SLC9A9', 'Gene', (106, 112))	('ectopic expression', 'Var', (38, 56))	('decreased', 'NegReg', (159, 168))	('pH', 'Gene', '5053', (152, 154))	('rat', 'Species', '10116', (185, 188))	('rat', 'Species', '10116', (199, 202))	('SLC9A9', 'Gene', '285195', (106, 112))	('GBM cell proliferation', 'CPA', (169, 191))
506897	32253638	showed that NHE5 knockdown and treatment with the V-ATPase inhibitor bafilomycin had independent and additive effects in alkalinizing TfR-positive recycling endosomal compartments by small, but significant amounts of ~0.2-0.3 pH units.	('pH', 'Gene', '5053', (226, 228))	('NHE5', 'Gene', (12, 16))	('bafilomycin', 'Chemical', '-', (69, 80))	('TfR', 'Gene', (134, 137))	('ATP', 'Chemical', 'MESH:D000255', (52, 55))	('knockdown', 'Var', (17, 26))	('TfR', 'Gene', '64678', (134, 137))
506898	32253638	Surface levels of the receptor tyrosine kinase MET decreased with NHE5 knockdown, with concomitant reduction in downstream activation by hepatocyte growth factor (HGF) of PI3K/Akt pathway and activities of critical regulators of cytoskeleton remodelers such as the Rho family small GTPase protein, Rac1, and CDC42 (Figure 2D).	('Rac1', 'Gene', '363875', (298, 302))	('MET', 'Gene', '24553', (47, 50))	('decreased', 'NegReg', (51, 60))	('GTP', 'Chemical', 'MESH:D006160', (282, 285))	('activation', 'PosReg', (123, 133))	('NHE5', 'Gene', (66, 70))	('hepatocyte growth factor', 'Gene', '3082', (137, 161))	('Rac1', 'Gene', (298, 302))	('reduction', 'NegReg', (99, 108))	('hepatocyte growth factor', 'Gene', (137, 161))	('activities', 'MPA', (192, 202))	('CDC42', 'Gene', (308, 313))	('MET', 'Gene', (47, 50))	('receptor tyrosine kinase', 'Gene', '5979', (22, 46))	('CDC42', 'Gene', '998', (308, 313))	('Surface levels', 'MPA', (0, 14))	('HGF', 'Gene', '3082', (163, 166))	('Akt', 'Gene', (176, 179))	('knockdown', 'Var', (71, 80))	('receptor tyrosine kinase', 'Gene', (22, 46))	('HGF', 'Gene', (163, 166))	('Akt', 'Gene', '207', (176, 179))
506900	32253638	showed that NHE5 knockdown abrogated the recycling of MET receptor, but not Tfn receptors, whereas the endosome recycling inhibitor, primaquine, inhibited recycling of both MET and Tfn.	('abrogated', 'NegReg', (27, 36))	('MET', 'Gene', '24553', (54, 57))	('knockdown', 'Var', (17, 26))	('primaquine', 'Chemical', 'MESH:D011319', (133, 143))	('NHE5', 'Gene', (12, 16))	('MET', 'Gene', (173, 176))	('recycling', 'MPA', (155, 164))	('recycling', 'MPA', (41, 50))	('MET', 'Gene', (54, 57))	('MET', 'Gene', '24553', (173, 176))	('inhibited', 'NegReg', (145, 154))
506901	32253638	further showed that NHE5 increases the total level of EGFR and MET while abrogating the downstream signaling proteins' activation in C6 rat glioma cells.	('glioma', 'Disease', 'MESH:D005910', (140, 146))	('glioma', 'Phenotype', 'HP:0009733', (140, 146))	('EGFR', 'MPA', (54, 58))	('increases', 'PosReg', (25, 34))	('MET', 'Gene', (63, 66))	('MET', 'Gene', '24553', (63, 66))	('rat', 'Species', '10116', (136, 139))	("downstream signaling proteins' activation", 'MPA', (88, 129))	('glioma', 'Disease', (140, 146))	('NHE5', 'Var', (20, 24))	('abrogating', 'NegReg', (73, 83))
506915	32253638	Gene disruption of NHE8 causes mice to become more susceptible to spontaneous colitis, dysbiosis, and increased epithelial cell proliferation.	('epithelial cell proliferation', 'CPA', (112, 141))	('colitis', 'Disease', 'MESH:D003092', (78, 85))	('rat', 'Species', '10116', (135, 138))	('colitis', 'Phenotype', 'HP:0002583', (78, 85))	('dysbiosis', 'Disease', (87, 96))	('dysbiosis', 'Disease', 'MESH:D064806', (87, 96))	('Gene disruption', 'Var', (0, 15))	('NHE8', 'Gene', (19, 23))	('mice', 'Species', '10090', (31, 35))	('increased', 'PosReg', (102, 111))	('more', 'PosReg', (46, 50))	('colitis', 'Disease', (78, 85))
506930	32253638	In a comprehensive molecular characterization of human colon and rectal cancer, whole-genome sequencing of 276 samples revealed SLC9A9 was one of 7 most frequent targets of mutation in hypermutated cancers.	('cancer', 'Disease', (72, 78))	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('cancer', 'Disease', (198, 204))	('SLC9A9', 'Gene', '285195', (128, 134))	('cancers', 'Phenotype', 'HP:0002664', (198, 205))	('colon', 'Disease', 'MESH:D003110', (55, 60))	('human', 'Species', '9606', (49, 54))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('cancers', 'Disease', (198, 205))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('cancers', 'Disease', 'MESH:D009369', (198, 205))	('rectal cancer', 'Phenotype', 'HP:0100743', (65, 78))	('colon', 'Disease', (55, 60))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('SLC9A9', 'Gene', (128, 134))	('mutation', 'Var', (173, 181))
506937	32253638	Gene amplification events were more common in SLC9A9, especially in cervical, ovarian and head and neck cancers, and in lung squamous cell carcinoma (Figure 3).	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (125, 148))	('cervical', 'Disease', (68, 76))	('Gene amplification events', 'Var', (0, 25))	('SLC9A9', 'Gene', (46, 52))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (120, 148))	('lung squamous cell carcinoma', 'Disease', (120, 148))	('ovarian and head and neck cancers', 'Disease', 'MESH:D006258', (78, 111))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('carcinoma', 'Phenotype', 'HP:0030731', (139, 148))	('SLC9A9', 'Gene', '285195', (46, 52))	('common', 'Reg', (36, 42))	('cancers', 'Phenotype', 'HP:0002664', (104, 111))	('head and neck cancers', 'Phenotype', 'HP:0012288', (90, 111))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (120, 148))
506938	32253638	In contrast, majority of patients across all cancer types had shallow deletions in SLC9A6.	('SLC9A6', 'Gene', '10479', (83, 89))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('shallow deletions', 'Var', (62, 79))	('patients', 'Species', '9606', (25, 33))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('SLC9A6', 'Gene', (83, 89))	('cancer', 'Disease', (45, 51))
506939	32253638	For SLC9A9, gene amplification was observed in 14% of esophageal squamous cell carcinoma, 9% of cervical squamous cell carcinoma, and 6% of non-small cell lung cancer patients.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (65, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (140, 166))	('cervical squamous cell carcinoma', 'Disease', (96, 128))	('lung cancer', 'Disease', (155, 166))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (144, 166))	('esophageal squamous cell carcinoma', 'Disease', (54, 88))	('cervical squamous cell carcinoma', 'Disease', 'MESH:D002294', (96, 128))	('SLC9A9', 'Gene', '285195', (4, 10))	('gene amplification', 'Var', (12, 30))	('observed', 'Reg', (35, 43))	('lung cancer', 'Disease', 'MESH:D008175', (155, 166))	('patients', 'Species', '9606', (167, 175))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (105, 128))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (54, 88))	('lung cancer', 'Phenotype', 'HP:0100526', (155, 166))	('SLC9A9', 'Gene', (4, 10))
506940	32253638	On the other hand, the most frequently observed genetic alterations in SLC9A6 were gene mutations, reported in 7% of endometrial carcinoma, 3% of melanoma, and 2% of non-small cell lung cancer patients.	('melanoma', 'Phenotype', 'HP:0002861', (146, 154))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (117, 138))	('melanoma', 'Disease', (146, 154))	('patients', 'Species', '9606', (193, 201))	('melanoma', 'Disease', 'MESH:D008545', (146, 154))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (170, 192))	('endometrial carcinoma', 'Disease', (117, 138))	('lung cancer', 'Disease', 'MESH:D008175', (181, 192))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('lung cancer', 'Disease', (181, 192))	('SLC9A6', 'Gene', '10479', (71, 77))	('rat', 'Species', '10116', (60, 63))	('lung cancer', 'Phenotype', 'HP:0100526', (181, 192))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (166, 192))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (117, 138))	('genetic alterations', 'Var', (48, 67))	('SLC9A6', 'Gene', (71, 77))
506941	32253638	Thus, genetic alterations in SLC9A9 and SLC9A6 are cancer type-specific and isoform-specific, which should be taken into consideration when trying to target endosomal NHE in cancer.	('rat', 'Species', '10116', (18, 21))	('SLC9A6', 'Gene', (40, 46))	('SLC9A9', 'Gene', '285195', (29, 35))	('rat', 'Species', '10116', (128, 131))	('NHE', 'Gene', '285335', (167, 170))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('cancer', 'Disease', (174, 180))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('SLC9A6', 'Gene', '10479', (40, 46))	('cancer', 'Disease', (51, 57))	('SLC9A9', 'Gene', (29, 35))	('genetic alterations', 'Var', (6, 25))	('NHE', 'Gene', (167, 170))
506942	32253638	Recurring somatic mutations in cancer have been proposed to confer selective advantage, such as charge-changing mutations in pH sensing.	('charge-changing', 'Reg', (96, 111))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('advantage', 'PosReg', (77, 86))	('mutations', 'Var', (112, 121))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('pH', 'Gene', '5053', (125, 127))	('cancer', 'Disease', (31, 37))
506943	32253638	Despite the cancer-specific enrichment of mutation incidents in SLC9A6, the overall somatic mutation frequencies for both SLC9A9 and SLC9A6 were comparable at 1.5% and 1.1%, respectively (Figure 4).	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('SLC9A9', 'Gene', (122, 128))	('SLC9A6', 'Gene', (133, 139))	('cancer', 'Disease', (12, 18))	('SLC9A6', 'Gene', (64, 70))	('mutation', 'Var', (42, 50))	('SLC9A9', 'Gene', '285195', (122, 128))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('SLC9A6', 'Gene', '10479', (133, 139))	('SLC9A6', 'Gene', '10479', (64, 70))
506944	32253638	In SLC9A9, the most frequent mutation, S355L, was present in four uterine endometrioid carcinoma and one tubular stomach adenocarcinoma patients; Interestingly, according to the dbPTM database (http://dbptm.mbc.nctu.edu.tw/index.php), S355 residue is a potential phosphorylation site, which may influence the function and trafficking of NHE9.	('NHE9', 'Gene', (337, 341))	('influence', 'Reg', (295, 304))	('function', 'MPA', (309, 317))	('SLC9A9', 'Gene', (3, 9))	('tubular stomach adenocarcinoma', 'Disease', (105, 135))	('patients', 'Species', '9606', (136, 144))	('S355 residue', 'Var', (235, 247))	('trafficking', 'MPA', (322, 333))	('tubular stomach adenocarcinoma', 'Disease', 'MESH:D000230', (105, 135))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (74, 96))	('endometrioid carcinoma', 'Disease', 'MESH:D016889', (74, 96))	('S355L', 'Mutation', 'rs552019939', (39, 44))	('SLC9A9', 'Gene', '285195', (3, 9))	('endometrioid carcinoma', 'Disease', (74, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))
506945	32253638	Other post-translational modification sites that were mutated are N96Y, an N-glycosylation site, and Y631*, a tyrosine phosphorylation site.	('Y631*', 'Var', (101, 106))	('tyrosine', 'Chemical', 'MESH:D014443', (110, 118))	('N96Y', 'Mutation', 'p.N96Y', (66, 70))	('Y631*', 'SUBSTITUTION', 'None', (101, 106))	('N96Y', 'Var', (66, 70))
506946	32253638	Mutation at R468 in the predicted cytosolic domain of NHE6 was observed in four patients: R468Q in one head and neck squamous cell carcinoma patient, R468* in one rectal adenocarcinoma patient and one uterine endometrioid carcinoma patient, and R468L in one cutaneous melanoma patient.	('patients', 'Species', '9606', (80, 88))	('endometrioid carcinoma', 'Disease', 'MESH:D016889', (209, 231))	('patient', 'Species', '9606', (185, 192))	('R468Q', 'Var', (90, 95))	('NHE6', 'Gene', '10479', (54, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (175, 184))	('R468L', 'Var', (245, 250))	('neck squamous cell carcinoma', 'Disease', (112, 140))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (117, 140))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (112, 140))	('R468Q', 'Mutation', 'p.R468Q', (90, 95))	('endometrioid carcinoma', 'Disease', (209, 231))	('patient', 'Species', '9606', (141, 148))	('carcinoma', 'Phenotype', 'HP:0030731', (222, 231))	('R468*', 'Var', (150, 155))	('adenocarcinoma', 'Disease', (170, 184))	('patient', 'Species', '9606', (80, 87))	('melanoma', 'Phenotype', 'HP:0002861', (268, 276))	('melanoma', 'Disease', (268, 276))	('NHE6', 'Gene', (54, 58))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (258, 276))	('patient', 'Species', '9606', (277, 284))	('R468*', 'SUBSTITUTION', 'None', (150, 155))	('adenocarcinoma', 'Disease', 'MESH:D000230', (170, 184))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (209, 231))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('R468L', 'Mutation', 'p.R468L', (245, 250))	('patient', 'Species', '9606', (232, 239))	('melanoma', 'Disease', 'MESH:D008545', (268, 276))
506947	32253638	Overall, of gene alterations in SLC9A9, 81% were missense mutations, 14% truncating mutations, and 4% fusion events while, in SLC9A6, 84% were missense mutations and 16% were truncations (Figure 4).	('SLC9A9', 'Gene', (32, 38))	('missense', 'Var', (49, 57))	('SLC9A6', 'Gene', (126, 132))	('SLC9A9', 'Gene', '285195', (32, 38))	('SLC9A6', 'Gene', '10479', (126, 132))	('rat', 'Species', '10116', (21, 24))	('alterations', 'Var', (17, 28))
506948	32253638	While the pathogenicity of missense mutations remains to be assessed, truncating mutations within the conserved, transmembrane NHE coding region are likely to be detrimental to protein function and stability.	('missense mutations', 'Var', (27, 45))	('NHE', 'Gene', '285335', (127, 130))	('protein', 'Protein', (177, 184))	('stability', 'MPA', (198, 207))	('truncating mutations', 'Var', (70, 90))	('NHE', 'Gene', (127, 130))	('detrimental', 'NegReg', (162, 173))
506956	32253638	These findings suggest that the absence of NHE6 is related to tumor progression.	('NHE6', 'Gene', (43, 47))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('absence', 'Var', (32, 39))	('tumor', 'Disease', (62, 67))	('related', 'Reg', (51, 58))	('NHE6', 'Gene', '10479', (43, 47))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
507000	29348866	This study suggests that chromatin modifiers contribute to CD8+ T-cell exclusion and antigen presentation capacity of HPV-negative SCCHN, supporting that targeting of specific PMTs and/or PDMTs could enhance CD8+ T-cell infiltration and increase the proportion of patients that may benefit from immunotherapy.	('CD8', 'Gene', (208, 211))	('CD8', 'Gene', '925', (208, 211))	('increase', 'PosReg', (237, 245))	('PMTs', 'Gene', (176, 180))	('CD8', 'Gene', (59, 62))	('CD8', 'Gene', '925', (59, 62))	('PDMTs', 'Var', (188, 193))	('patients', 'Species', '9606', (264, 272))	('enhance', 'PosReg', (200, 207))
507006	29348866	Immune escape in SCCHN occurs through various mechanisms, including (1) exclusion/restriction of cytotoxic CD8+ T-cell trafficking in the tumor microenvironment, (2) suppression of anti-tumor immune response through activation of immune checkpoint molecules and their receptors, or infiltration of the tumor tissue by immune suppressive cells such as T-regulatory cells (Tregs), myeloid-derived suppressor cells (MDSCs) and M2 macrophages, (3) loss of tumor-associated antigens through somatic mutations or decreased expression of HLA or the antigen presenting machinery (APM) components, and (4) lack of or decreased expression of immune active tumor-associated antigens.	('tumor', 'Phenotype', 'HP:0002664', (302, 307))	('tumor', 'Disease', (138, 143))	('SCCHN', 'Disease', (17, 22))	('tumor', 'Disease', (186, 191))	('APM', 'Gene', (572, 575))	('tumor', 'Phenotype', 'HP:0002664', (452, 457))	('CD8', 'Gene', (107, 110))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('mutations', 'Var', (494, 503))	('expression', 'MPA', (517, 527))	('lack', 'NegReg', (597, 601))	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('tumor', 'Disease', (646, 651))	('decreased', 'NegReg', (507, 516))	('tumor', 'Disease', 'MESH:D009369', (646, 651))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('expression', 'MPA', (618, 628))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('tumor', 'Disease', (302, 307))	('HLA', 'Protein', (531, 534))	('tumor', 'Disease', (452, 457))	('CD8', 'Gene', '925', (107, 110))	('tumor', 'Disease', 'MESH:D009369', (302, 307))	('tumor', 'Phenotype', 'HP:0002664', (646, 651))	('decreased', 'NegReg', (608, 617))	('APM', 'Gene', '290', (572, 575))	('tumor', 'Disease', 'MESH:D009369', (452, 457))	('loss', 'NegReg', (444, 448))
507009	29348866	The Cancer Genome Atlas (TCGA) recently revealed a plethora of genetic alterations in chromatin modifiers in multiple cancer types, including SCCHN.	('genetic alterations', 'Var', (63, 82))	('SCCHN', 'Disease', (142, 147))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('multiple cancer', 'Disease', 'MESH:D009369', (109, 124))	('Cancer', 'Phenotype', 'HP:0002664', (4, 10))	('plethora', 'Phenotype', 'HP:0001050', (51, 59))	('Cancer Genome Atlas', 'Disease', (4, 23))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (4, 23))	('multiple cancer', 'Disease', (109, 124))
507011	29348866	More specifically, a recent study showed that the PMT enhancer of zeste homologue 2 (EZH2) and DNA-methyltransferase 1 (DNMT-1) transcriptionally repress Th1-type chemokines, CXCL9 and CXCL10, and that inhibition of both EZH2 and DNMT-1 increased CD8+ T-cell trafficking, reduced tumor growth and improved the efficacy of PD-L1 checkpoint blockade in a mouse ovarian cancer model.	('increased', 'PosReg', (237, 246))	('DNMT-1', 'Gene', '13433', (230, 236))	('inhibition', 'Var', (202, 212))	('PD-L1', 'Gene', '60533', (322, 327))	('Th1-type chemokines', 'MPA', (154, 173))	('ovarian cancer', 'Disease', 'MESH:D010051', (359, 373))	('cancer', 'Phenotype', 'HP:0002664', (367, 373))	('reduced', 'NegReg', (272, 279))	('CD8', 'Gene', (247, 250))	('DNMT-1', 'Gene', (120, 126))	('tumor', 'Disease', (280, 285))	('ovarian cancer', 'Disease', (359, 373))	('CXCL10', 'MPA', (185, 191))	('PD-L1', 'Gene', (322, 327))	('tumor', 'Disease', 'MESH:D009369', (280, 285))	('ovarian cancer', 'Phenotype', 'HP:0100615', (359, 373))	('DNMT-1', 'Gene', (230, 236))	('DNA-methyltransferase 1', 'Gene', '13433', (95, 118))	('efficacy', 'MPA', (310, 318))	('mouse', 'Species', '10090', (353, 358))	('DNMT-1', 'Gene', '13433', (120, 126))	('DNA-methyltransferase 1', 'Gene', (95, 118))	('CD8', 'Gene', '925', (247, 250))	('tumor', 'Phenotype', 'HP:0002664', (280, 285))	('improved', 'PosReg', (297, 305))
507028	29348866	In our analysis, we included PMTs and PDMTs that are known to induce not only repressive histone marks but also activating marks, as it is possible that activating marks may induce the expression of miRNAs that could silence specific chemokines, HLA class I or APM molecules.	('APM', 'Gene', (261, 264))	('induce', 'Reg', (174, 180))	('silence', 'NegReg', (217, 224))	('expression', 'MPA', (185, 195))	('specific', 'Protein', (225, 233))	('APM', 'Gene', '290', (261, 264))	('miRNAs', 'Var', (199, 205))	('HLA class I', 'Protein', (246, 257))
507036	29348866	Based on this preclinical evidence, SMYD3 has been under investigation as an anticancer target for the identification of specific drug compounds, and SMYD3 inhibitors that suppress the growth of SMYD3-overexpressing cancer cells were recently reported in the literature.	('inhibitors', 'Var', (156, 166))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('cancer', 'Disease', (81, 87))	('growth', 'MPA', (185, 191))	('cancer', 'Disease', (216, 222))	('cancer', 'Disease', 'MESH:D009369', (216, 222))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('SMYD3', 'Gene', (150, 155))	('suppress', 'NegReg', (172, 180))
507040	29348866	siRNA-mediated knockdown of SMYD3 led to upregulation of the mRNA transcripts of CD8+ T-cell attracting chemokines CXCL9, CXCL10 and CXCL11 in both HN-6 and HN-SCC-151 cell lines (Figure 4A).	('CD8', 'Gene', (81, 84))	('SMYD3', 'Gene', (28, 33))	('HN-6', 'Gene', (148, 152))	('knockdown', 'Var', (15, 24))	('CD8', 'Gene', '925', (81, 84))	('CXCL11', 'Gene', '6373', (133, 139))	('CXCL11', 'Gene', (133, 139))	('mRNA transcripts', 'MPA', (61, 77))	('HN-6', 'Gene', '100463482', (148, 152))	('CXCL10', 'MPA', (122, 128))	('upregulation', 'PosReg', (41, 53))	('HN-SCC-151', 'CellLine', 'CVCL:V279', (157, 167))
507042	29348866	SMYD3 knockdown resulted in a significant increase of CXCL9, CXCL10 and CXCL11 protein levels, compared with the siNC group (Figure 4B).	('CXCL9', 'MPA', (54, 59))	('SMYD3', 'Gene', (0, 5))	('CXCL11', 'Gene', '6373', (72, 78))	('CXCL11', 'Gene', (72, 78))	('knockdown', 'Var', (6, 15))	('increase', 'PosReg', (42, 50))
507043	29348866	Under similar experimental conditions, we also assessed the effect of siRNA-mediated knockdown of SMYD3 on the expression levels of HLA class I and APM molecules.	('APM', 'Gene', (148, 151))	('expression', 'MPA', (111, 121))	('HLA class I', 'Protein', (132, 143))	('knockdown', 'Var', (85, 94))	('SMYD3', 'Gene', (98, 103))	('APM', 'Gene', '290', (148, 151))
507044	29348866	SMYD3 knockdown downregulated tri-methylated H3K4 (H3K4me3) and resulted in the increase of TAP1 transcript and protein levels in HN-6 and HN-SCC-151 cell lines (Figure 4C, 4D).	('SMYD3', 'Gene', (0, 5))	('increase', 'PosReg', (80, 88))	('HN-6', 'Gene', '100463482', (130, 134))	('HN-SCC-151', 'CellLine', 'CVCL:V279', (139, 149))	('tri-methylated', 'MPA', (30, 44))	('TAP1', 'Gene', (92, 96))	('HN-6', 'Gene', (130, 134))	('knockdown', 'Var', (6, 15))	('downregulated', 'NegReg', (16, 29))
507050	29348866	previously demonstrated that the production of a subset of chemokines by melanoma cells was essential for the induction of T-cell infiltration in metastatic melanoma lesions and concordantly, the absence of expression of these chemokines was associated with a non-T-cell inflamed phenotype.	('melanoma', 'Disease', (73, 81))	('melanoma', 'Disease', 'MESH:D008545', (157, 165))	('melanoma', 'Disease', 'MESH:D008545', (73, 81))	('melanoma lesions', 'Disease', 'MESH:D008545', (157, 173))	('absence', 'Var', (196, 203))	('melanoma lesions', 'Disease', (157, 173))	('melanoma', 'Phenotype', 'HP:0002861', (157, 165))	('non-T-cell inflamed', 'Disease', (260, 279))	('melanoma', 'Disease', (157, 165))	('expression', 'MPA', (207, 217))	('melanoma', 'Phenotype', 'HP:0002861', (73, 81))
507055	29348866	Activating STAT3 mutations have been shown to block chemokine expression in melanoma cells and cause T-cell exclusion.	('melanoma', 'Disease', (76, 84))	('melanoma', 'Disease', 'MESH:D008545', (76, 84))	('cause', 'Reg', (95, 100))	('T-cell exclusion', 'CPA', (101, 117))	('block', 'NegReg', (46, 51))	('mutations', 'Var', (17, 26))	('melanoma', 'Phenotype', 'HP:0002861', (76, 84))	('STAT3', 'Gene', '6774', (11, 16))	('chemokine expression', 'MPA', (52, 72))	('STAT3', 'Gene', (11, 16))
507061	29348866	showed that DNA methyltransferase inhibitors upregulate the expression of endogenous retroviral genes, and that this triggers a type I IFN response and potentiates the antitumor effects of anti-CTLA4 treatment in a murine melanoma model.	('expression', 'MPA', (60, 70))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('CTLA4', 'Gene', '12477', (194, 199))	('murine', 'Species', '10090', (215, 221))	('tumor', 'Disease', (172, 177))	('potentiates', 'PosReg', (152, 163))	('inhibitors', 'Var', (34, 44))	('melanoma', 'Phenotype', 'HP:0002861', (222, 230))	('type I IFN response', 'MPA', (128, 147))	('melanoma', 'Disease', (222, 230))	('CTLA4', 'Gene', (194, 199))	('melanoma', 'Disease', 'MESH:D008545', (222, 230))	('triggers', 'Reg', (117, 125))	('tumor', 'Disease', 'MESH:D009369', (172, 177))	('upregulate', 'PosReg', (45, 55))
507064	29348866	PMTs and PDMTs, a large class of epigenetic modulators, are frequently genetically altered in a wide variety of cancer types and function through direct methylation of histone and non-histone proteins.	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('altered', 'Reg', (83, 90))	('histone', 'Protein', (168, 175))	('non-histone proteins', 'Protein', (180, 200))	('methylation', 'Var', (153, 164))	('PMTs', 'Gene', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))
507065	29348866	Other than the work performed by the Zou group showing that EZH2 produced by colon cancer cells mediates transcriptional silencing of Th1-type CXCL9 and CXCL10 chemokines, and causes subsequent CD8+ T-cell exclusion, no other studies have systematically explored the potential function of PMTs and PDMTs as one of the key factors of CD8+ T-cell exclusion or antigenicity in solid tumors.	('CXCL10 chemokines', 'MPA', (153, 170))	('CD8', 'Gene', (194, 197))	('CD8', 'Gene', '925', (194, 197))	('CD8', 'Gene', (333, 336))	('solid tumors', 'Disease', (374, 386))	('CD8', 'Gene', '925', (333, 336))	('colon cancer', 'Phenotype', 'HP:0003003', (77, 89))	('colon cancer', 'Disease', 'MESH:D015179', (77, 89))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('tumor', 'Phenotype', 'HP:0002664', (380, 385))	('EZH2', 'Var', (60, 64))	('causes', 'Reg', (176, 182))	('colon cancer', 'Disease', (77, 89))	('solid tumors', 'Disease', 'MESH:D009369', (374, 386))	('tumors', 'Phenotype', 'HP:0002664', (380, 386))	('silencing', 'NegReg', (121, 130))
507072	29348866	We further validated and functionally analyzed the negative correlation of one of these PMTs, SMYD3, with chemokines and APM components, by showing that siRNA-mediated knockdown of SMYD3 led to upregulation of the transcript and protein levels of CXCL9, CXCL10, CXCL11 and TAP1 in two HPV-negative SCCHN cell lines.	('SMYD3', 'Gene', (181, 186))	('APM', 'Gene', (121, 124))	('TAP1', 'MPA', (273, 277))	('upregulation', 'PosReg', (194, 206))	('CXCL9', 'MPA', (247, 252))	('CXCL11', 'Gene', (262, 268))	('CXCL11', 'Gene', '6373', (262, 268))	('knockdown', 'Var', (168, 177))	('CXCL10', 'MPA', (254, 260))	('APM', 'Gene', '290', (121, 124))
507075	29348866	Furthermore, it would be of paramount importance to determine whether PMTs affect tumor T-cell infiltration or tumor immunogenicity through direct methylation of substrates involved in these processes.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('PMTs', 'Var', (70, 74))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Disease', (111, 116))	('affect', 'Reg', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumor', 'Disease', (82, 87))
507083	29348866	The PMT/PDMTs were further sorted out based on the hypothesis that if these genes induce CD8+ T-cell exclusion, they should exhibit a significant negative correlation (P < 0.05) with CD8 mRNA.	('CD8', 'Gene', (89, 92))	('induce', 'PosReg', (82, 88))	('CD8', 'Gene', '925', (89, 92))	('negative', 'NegReg', (146, 154))	('CD8', 'Gene', (183, 186))	('genes', 'Var', (76, 81))	('CD8', 'Gene', '925', (183, 186))
507106	26538233	Targeting therapy to the epidermal growth factor receptor (EGFR) is a new and effective treatment for head and neck squamous cell carcinoma (HNSCC).	('epidermal growth factor receptor', 'Gene', (25, 57))	('EGFR', 'Gene', (59, 63))	('HNSCC', 'Phenotype', 'HP:0012288', (141, 146))	('neck squamous cell carcinoma', 'Disease', (111, 139))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (116, 139))	('epidermal growth factor receptor', 'Gene', '1956', (25, 57))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (102, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (111, 139))	('Targeting', 'Var', (0, 9))	('EGFR', 'Gene', '1956', (59, 63))
507127	26538233	In view of these findings, we proceeded to test whether the HER-3872-886 peptide itself could induce antigen-specific, tumor-reactive CD4 T cells.	('tumor', 'Disease', (119, 124))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('induce', 'PosReg', (94, 100))	('HER-3872-886 peptide', 'Var', (60, 80))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))
507130	26538233	The addition of an anti-HLA-DR antibody to the peptide stimulation assays resulted in the inhibition of IFN-gamma production by HER-3 reactive CD4 T cell lines indicating that peptide HER-3872-886 was recognized in the context of MHC class II molecules and specifically by HLA-DR since this antibody (L243) does not react with the HLA-DQ and -DP proteins (Fig.	('HLA', 'Gene', '3123', (331, 334))	('inhibition', 'NegReg', (90, 100))	('HLA', 'Gene', '3123', (273, 276))	('HLA', 'Gene', (331, 334))	('IFN-gamma', 'Gene', '3458', (104, 113))	('IFN-gamma', 'Gene', (104, 113))	('HLA', 'Gene', (273, 276))	('HLA', 'Gene', '3123', (24, 27))	('MHC', 'Gene', (230, 233))	('HLA', 'Gene', (24, 27))	('HER-3872-886', 'Var', (184, 196))	('MHC', 'Gene', '3107', (230, 233))
507132	26538233	To determine the HLA-DR alleles restricting the responses in these T cell lines, we used a panel of mouse fibroblasts expressing single HLA-DR molecules (L-DR4, L-DR9, L-DR53) as APCs.	('L-DR53', 'Var', (168, 174))	('DR4', 'Gene', (156, 159))	('mouse', 'Species', '10090', (100, 105))	('L-DR9', 'Var', (161, 166))	('HLA', 'Gene', '3123', (136, 139))	('HLA', 'Gene', '3123', (17, 20))	('DR4', 'Gene', '3126', (156, 159))	('HLA', 'Gene', (136, 139))	('HLA', 'Gene', (17, 20))
507134	26538233	Because the frequency of HLA-DR53-linked HLA-DR alleles has been reported to be 39% in the HNSCC patients, these results indicate that peptide HER-3872-886 is able to elicit CD4 responses in broad population of HNSCC patients.	('peptide HER-3872-886', 'Var', (135, 155))	('elicit', 'Reg', (167, 173))	('HER-3872-886', 'Var', (143, 155))	('HLA', 'Gene', '3123', (41, 44))	('HLA', 'Gene', '3123', (25, 28))	('CD4 responses', 'MPA', (174, 187))	('HNSCC', 'Phenotype', 'HP:0012288', (211, 216))	('HLA', 'Gene', (41, 44))	('HLA', 'Gene', (25, 28))	('HNSCC', 'Phenotype', 'HP:0012288', (91, 96))	('patients', 'Species', '9606', (217, 225))	('patients', 'Species', '9606', (97, 105))
507135	26538233	Although the HER-3 protein is expressed on tumor cells, presentation of the HER-3872-886 peptide on tumor cells through the endogenous antigen-processing machinery is required for CD4 T cell recognition.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Disease', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Disease', (43, 48))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('HER-3872-886', 'Var', (76, 88))
507148	26538233	We next determined whether the HER-3872-886 epitope can be processed from tumor lysates and efficiently presented by MHC class II molecules on DCs.	('MHC', 'Gene', (117, 120))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('MHC', 'Gene', '3107', (117, 120))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('HER-3872-886', 'Var', (31, 43))	('tumor', 'Disease', (74, 79))
507160	26538233	7, substantial T cell responses to HER-3872-886 were observed in two HNSCC patients and these responses were suppressed by anti-HLA-DR mAb suggesting that the responses were mediated through the MHC-II-peptide-T-cell receptor complexes.	('T cell', 'CPA', (15, 21))	('HLA', 'Gene', (128, 131))	('suppressed', 'NegReg', (109, 119))	('MHC', 'Gene', '3107', (195, 198))	('HNSCC', 'Phenotype', 'HP:0012288', (69, 74))	('patients', 'Species', '9606', (75, 83))	('HER-3872-886', 'Var', (35, 47))	('HLA', 'Gene', '3123', (128, 131))	('MHC', 'Gene', (195, 198))
507161	26538233	Taken together, HER-3872-886 has the potential to induce T cell responses not only in healthy donors but also in HNSCC patients.	('patients', 'Species', '9606', (119, 127))	('HNSCC', 'Phenotype', 'HP:0012288', (113, 118))	('HNSCC', 'Disease', (113, 118))	('induce', 'PosReg', (50, 56))	('T cell responses', 'CPA', (57, 73))	('HER-3872-886', 'Var', (16, 28))
507180	26538233	However, the antitumor effect of CD4 T cells is not only based on the direct cytotoxicity but also its interaction with other immune cells.	('tumor', 'Disease', (17, 22))	('CD4 T', 'Var', (33, 38))	('cytotoxicity', 'Disease', (77, 89))	('interaction', 'Interaction', (103, 114))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('cytotoxicity', 'Disease', 'MESH:D064420', (77, 89))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
507231	26538233	CD14 monocytes differentiated into dendritic cells (DCs) after 7 days of culture with GM-CSF (50 ng/ml) and IL-4 (1000 IU/ml) at 37  C in a humidified incubator with 5% CO2.	('50 ng/ml', 'Var', (94, 102))	('CD14', 'Gene', (0, 4))	('CD14', 'Gene', '929', (0, 4))	('GM-CSF', 'Gene', (86, 92))	('GM-CSF', 'Gene', '1437', (86, 92))	('IL-4', 'Gene', (108, 112))	('IL-4', 'Gene', '3565', (108, 112))	('CO2', 'Chemical', '-', (169, 172))
507293	25245383	It is reported that nuclear immunoreactivity of p53 is a good surrogate of TP53 mutations .	('p53', 'Gene', (48, 51))	('mutations', 'Var', (80, 89))	('p53', 'Gene', '7157', (48, 51))	('TP53', 'Gene', '7157', (75, 79))	('TP53', 'Gene', (75, 79))
507308	25245383	Overall survival ratio was significantly lower in the patients with synchronous MPMN than those with metachronous MPMN (adjusted hazard ratio 0.50, P <0.001).	('Overall survival', 'MPA', (0, 16))	('patients', 'Species', '9606', (54, 62))	('lower', 'NegReg', (41, 46))	('synchronous MPMN', 'Var', (68, 84))
507310	25245383	In particular, tobacco smoking causes cancers of the lung, oral cavity, naso-, oro-, and hypopharynx, nasal cavity and accessory sinuses, larynx, esophagus, stomach, pancreas, colorectum, liver, kidney (body and pelvis), ureter, urinary bladder, uterine cervix and ovary (mucinous), and myeloid leukemia .	('tobacco smoking', 'Var', (15, 30))	('tobacco', 'Species', '4097', (15, 22))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('cancers of the lung', 'Disease', (38, 57))	('myeloid leukemia', 'Disease', 'MESH:D007951', (287, 303))	('larynx', 'Disease', (138, 144))	('esophagus', 'Disease', (146, 155))	('pancreas', 'Disease', 'MESH:D010190', (166, 174))	('cancers of the lung', 'Disease', 'MESH:D008175', (38, 57))	('leukemia', 'Phenotype', 'HP:0001909', (295, 303))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (287, 303))	('colorectum', 'Disease', (176, 186))	('causes', 'Reg', (31, 37))	('pancreas', 'Disease', (166, 174))	('cancers', 'Phenotype', 'HP:0002664', (38, 45))	('myeloid leukemia', 'Disease', (287, 303))	('ureter', 'Disease', (221, 227))
507317	25245383	If the nature of the hereditary predisposition is similar to that of childhood cancers, i.e., an inherited mutation that reduces the subsequent number of mutations necessary in each cell of the target organ, then such individuals may have a high rate of spontaneous tumors and a unique sensitivity to environmental agents .	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('childhood cancers', 'Disease', 'MESH:C536928', (69, 86))	('childhood cancers', 'Disease', (69, 86))	('reduces', 'NegReg', (121, 128))	('tumors', 'Disease', 'MESH:D009369', (266, 272))	('tumor', 'Phenotype', 'HP:0002664', (266, 271))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('tumors', 'Phenotype', 'HP:0002664', (266, 272))	('mutation', 'Var', (107, 115))	('tumors', 'Disease', (266, 272))
507319	25245383	They found that tobacco habit and three genetic polymorphisms, including Tp53 (Arg72Arg), XRCC1 (Arg399His), and meH (Tyr113His), formed the best model for developing tobacco-associated MPMN .	('tobacco-associated MPMN', 'Disease', (167, 190))	('Arg72Arg', 'Var', (79, 87))	('Arg399His', 'Var', (97, 106))	('tobacco', 'Species', '4097', (167, 174))	('Tp53', 'Gene', (73, 77))	('Tyr113His', 'SUBSTITUTION', 'None', (118, 127))	('Tyr113His', 'Var', (118, 127))	('Tp53', 'Gene', '7157', (73, 77))	('Arg399His', 'SUBSTITUTION', 'None', (97, 106))	('tobacco', 'Species', '4097', (16, 23))
507324	25245383	In the present case, immunoreactivity of p53 in tumor cells was different among SCCs, suggesting that these cancers were polyclonal, although distinct genetic abnormalities including loss of heterogeneity, gene mutations, and influence of oncogenic viral infection may be necessary to definitely determine polyclonality.	('SCC', 'Gene', '6317', (80, 83))	('gene mutations', 'Var', (206, 220))	('p53', 'Gene', '7157', (41, 44))	('tumor', 'Disease', (48, 53))	('genetic abnormalities', 'Disease', 'MESH:D030342', (151, 172))	('oncogenic viral infection', 'Disease', 'MESH:D000074723', (239, 264))	('cancers', 'Phenotype', 'HP:0002664', (108, 115))	('p53', 'Gene', (41, 44))	('genetic abnormalities', 'Disease', (151, 172))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('SCC', 'Gene', (80, 83))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('oncogenic viral infection', 'Disease', (239, 264))	('cancers', 'Disease', 'MESH:D009369', (108, 115))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('cancers', 'Disease', (108, 115))	('heterogeneity', 'MPA', (191, 204))
507326	25245383	According to the report from the International Agency for Research on Cancer , high-grade UC is likely to have high level amplifications and TP53 mutations.	('amplifications', 'Var', (122, 136))	('high-grade UC', 'Disease', (79, 92))	('TP53', 'Gene', '7157', (141, 145))	('TP53', 'Gene', (141, 145))	('Cancer', 'Phenotype', 'HP:0002664', (70, 76))
507441	29552123	The dysregulation of autophagy is closely related with various pathological diseases, including cardiomyopathy, muscular diseases, neurodegenerative disorders, infection and cancer.	('cardiomyopathy', 'Disease', 'MESH:D009202', (96, 110))	('autophagy', 'CPA', (21, 30))	('dysregulation', 'Var', (4, 17))	('muscular diseases', 'Disease', (112, 129))	('muscular diseases', 'Disease', 'MESH:D009135', (112, 129))	('neurodegenerative disorders', 'Disease', (131, 158))	('neurodegenerative disorders', 'Disease', 'MESH:D019636', (131, 158))	('cardiomyopathy', 'Disease', (96, 110))	('neurodegenerative disorders', 'Phenotype', 'HP:0002180', (131, 158))	('infection and cancer', 'Disease', 'MESH:D009369', (160, 180))	('related', 'Reg', (42, 49))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('cardiomyopathy', 'Phenotype', 'HP:0001638', (96, 110))
507458	29552123	In addition, Ephrin type-B receptor 2 (EphB2) knockdown downregulated the gene expression of MMP1 and MMP13, which are associated with biological functions such as cell viability, migration and invasion of tumor cells.	('MMP1', 'Gene', (93, 97))	('EphB2', 'Gene', '2048', (39, 44))	('MMP1', 'Gene', '4312', (102, 106))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('knockdown', 'Var', (46, 55))	('EphB2', 'Gene', (39, 44))	('gene expression', 'MPA', (74, 89))	('tumor', 'Disease', (206, 211))	('Ephrin type-B receptor 2', 'Gene', (13, 37))	('MMP13', 'Gene', (102, 107))	('MMP1', 'Gene', (102, 106))	('downregulated', 'NegReg', (56, 69))	('MMP1', 'Gene', '4312', (93, 97))	('MMP13', 'Gene', '4322', (102, 107))	('Ephrin type-B receptor 2', 'Gene', '2048', (13, 37))	('tumor', 'Disease', 'MESH:D009369', (206, 211))
507459	29552123	Warren et al reported that alterations in the p53 pathway may be important in cSCC of head and neck (cSCCHN) with clinical PNI, but not in cSCCHN without PNI.	('cSCC', 'Phenotype', 'HP:0006739', (139, 143))	('cSCCHN', 'Chemical', '-', (101, 107))	('SCC', 'Gene', '6317', (102, 105))	('SCC', 'Gene', (79, 82))	('cSCC', 'Phenotype', 'HP:0006739', (78, 82))	('p53', 'Gene', (46, 49))	('SCC', 'Gene', '6317', (140, 143))	('p53', 'Gene', '7157', (46, 49))	('SCC', 'Gene', '6317', (79, 82))	('SCC', 'Gene', (102, 105))	('cSCC', 'Phenotype', 'HP:0006739', (101, 105))	('cSCCHN', 'Chemical', '-', (139, 145))	('alterations', 'Var', (27, 38))	('SCC', 'Gene', (140, 143))
507461	29552123	In addition, previous study from our research group has demonstrated that RAB23 knockdown repressed cell invasion, while RAB23 overexpression promoted cell invasion, depending on the GTP-bound form of RAB23.	('knockdown', 'Var', (80, 89))	('RAB23', 'Gene', (74, 79))	('overexpression promoted', 'PosReg', (127, 150))	('RAB23', 'Gene', (201, 206))	('RAB23', 'Gene', '51715', (74, 79))	('RAB23', 'Gene', '51715', (201, 206))	('cell invasion', 'CPA', (151, 164))	('cell invasion', 'CPA', (100, 113))	('GTP', 'Chemical', 'MESH:D006160', (183, 186))	('RAB23', 'Gene', (121, 126))	('RAB23', 'Gene', '51715', (121, 126))
507502	29552123	Notably, mTOR is the first key autophagy-related gene and repressed mTOR may activate the autophagy process.	('activate', 'PosReg', (77, 85))	('mTOR', 'Gene', (9, 13))	('mTOR', 'Gene', '2475', (9, 13))	('autophagy process', 'CPA', (90, 107))	('mTOR', 'Gene', '2475', (68, 72))	('mTOR', 'Gene', (68, 72))	('repressed', 'Var', (58, 67))
507505	29552123	Two studies have demonstrated that NVP-BEZ235 (both a PI3K and mTOR kinase inhibitor) can induce autophagy in cells, and combination treatment with autophagy inhibitors, NVP-BEZ235 and radiation increased cell death.	('mTOR', 'Gene', (63, 67))	('cell death', 'CPA', (205, 215))	('BEZ235', 'Chemical', 'MESH:C531198', (174, 180))	('NVP-BEZ235', 'Var', (35, 45))	('autophagy in', 'CPA', (97, 109))	('induce', 'PosReg', (90, 96))	('NVP-BEZ235', 'Var', (170, 180))	('increased', 'PosReg', (195, 204))	('combination', 'Interaction', (121, 132))	('BEZ235', 'Chemical', 'MESH:C531198', (39, 45))	('mTOR', 'Gene', '2475', (63, 67))
507511	29552123	In the oral squamous cell carcinoma cell line Tca8113, the HIF1A inhibitor PX-478 downregulated the expression levels of LC3-II/I and inhibited the autophagy process.	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (7, 35))	('downregulated', 'NegReg', (82, 95))	('Tca8113', 'Chemical', '-', (46, 53))	('PX-478', 'Var', (75, 81))	('expression levels', 'MPA', (100, 117))	('LC3', 'Gene', '84557', (121, 124))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (12, 35))	('HIF1A', 'Gene', (59, 64))	('inhibited', 'NegReg', (134, 143))	('autophagy process', 'CPA', (148, 165))	('oral squamous cell carcinoma', 'Disease', (7, 35))	('PX-478', 'Chemical', 'MESH:C492908', (75, 81))	('HIF1A', 'Gene', '3091', (59, 64))	('LC3', 'Gene', (121, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (26, 35))
507524	29552123	Recently, Zhang et al demonstrated that knockdown of RABl3 in lung cancer cells significantly increased cell death with autophagy induction, as demonstrated by an elevated level of LC3-II.	('lung cancer', 'Disease', 'MESH:D008175', (62, 73))	('elevated', 'PosReg', (163, 171))	('LC3', 'Gene', '84557', (181, 184))	('LC3', 'Gene', (181, 184))	('increased', 'PosReg', (94, 103))	('knockdown', 'Var', (40, 49))	('lung cancer', 'Phenotype', 'HP:0100526', (62, 73))	('lung cancer', 'Disease', (62, 73))	('level', 'MPA', (172, 177))	('RABl3', 'Gene', (53, 58))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('autophagy', 'CPA', (120, 129))	('cell death', 'CPA', (104, 114))	('RABl3', 'Gene', '285282', (53, 58))
507525	29552123	Interestingly, RABl3 knockdown was also associated with enhanced activation of MAPK8/9/10, except for MAPK11/12/13/14.	('MAPK11', 'Gene', '5600', (102, 108))	('RABl3', 'Gene', (15, 20))	('MAPK8', 'Gene', '5599', (79, 84))	('enhanced activation', 'PosReg', (56, 75))	('RABl3', 'Gene', '285282', (15, 20))	('knockdown', 'Var', (21, 30))	('MAPK11', 'Gene', (102, 108))	('MAPK8', 'Gene', (79, 84))
507526	29552123	Treatment withSP600125 (a MAPK8/9/10-specific inhibitor) significantly abolished RABl3 knockdown-induced LC3-II levels and autophagic cell death.	('withSP600125', 'Var', (10, 22))	('autophagic cell death', 'CPA', (123, 144))	('RABl3', 'Gene', '285282', (81, 86))	('knockdown-induced', 'Var', (87, 104))	('abolished', 'NegReg', (71, 80))	('LC3', 'Gene', '84557', (105, 108))	('MAPK8', 'Gene', '5599', (26, 31))	('MAPK8', 'Gene', (26, 31))	('RABl3', 'Gene', (81, 86))	('LC3', 'Gene', (105, 108))	('SP600125', 'Chemical', 'MESH:C432165', (14, 22))
507528	29552123	Following treatment with 30 mJ/cm2 UVB, wild-type RAB23 promotes the expression of LC3-II and Beclin1, while knockdown of RAB23 decreases the levels of LC3-II and Beclin 1.	('levels', 'MPA', (142, 148))	('RAB23', 'Gene', '51715', (50, 55))	('Beclin 1', 'Gene', (163, 171))	('RAB23', 'Gene', (50, 55))	('Beclin1', 'Gene', (94, 101))	('LC3', 'Gene', '84557', (83, 86))	('RAB23', 'Gene', '51715', (122, 127))	('decreases', 'NegReg', (128, 137))	('expression', 'MPA', (69, 79))	('RAB23', 'Gene', (122, 127))	('LC3', 'Gene', (83, 86))	('knockdown', 'Var', (109, 118))	('LC3', 'Gene', (152, 155))	('Beclin 1', 'Gene', '8678', (163, 171))	('LC3', 'Gene', '84557', (152, 155))	('promotes', 'PosReg', (56, 64))	('Beclin1', 'Gene', '8678', (94, 101))
507537	29552123	Knocking down myeloid cell leukemia sequence-1 (Mcl-1) sensitizes oral SCC cells to ABT-737 (a BH3 mimetic), which binds to BCL2L1 but not Mcl-1.	('sensitizes', 'Reg', (55, 65))	('Mcl-1', 'Gene', (139, 144))	('BCL2L1', 'Gene', '598', (124, 130))	('Mcl-1', 'Gene', '4170', (48, 53))	('leukemia', 'Phenotype', 'HP:0001909', (27, 35))	('myeloid cell leukemia', 'Phenotype', 'HP:0012324', (14, 35))	('myeloid cell leukemia sequence-1', 'Gene', (14, 46))	('binds', 'Interaction', (115, 120))	('Mcl-1', 'Gene', '4170', (139, 144))	('ABT-737', 'Chemical', 'MESH:C501332', (84, 91))	('Mcl-1', 'Gene', (48, 53))	('SCC', 'Gene', '6317', (71, 74))	('ABT-737', 'Gene', (84, 91))	('SCC', 'Gene', (71, 74))	('myeloid cell leukemia sequence-1', 'Gene', '4170', (14, 46))	('BCL2L1', 'Gene', (124, 130))	('Knocking', 'Var', (0, 8))	('BH3', 'Chemical', 'MESH:C006008', (95, 98))
507538	29552123	Dysregulation of autophagy contributes to the progression of cancer.	('autophagy', 'CPA', (17, 26))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('Dysregulation', 'Var', (0, 13))	('cancer', 'Disease', (61, 67))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))
507546	29552123	As far as clinical significance of these target genes is concerned, several pathway inhibitors have exhibited antitumor activity in vitro or in preclinical models, but this has not always provided meaningful benefits to patients with SCCHN.	('inhibitors', 'Var', (84, 94))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('SCC', 'Gene', (234, 237))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('SCC', 'Gene', '6317', (234, 237))	('tumor', 'Disease', (114, 119))	('patients', 'Species', '9606', (220, 228))
507550	26967383	In this study we aimed to determine the role of Nit1 in a transgenic mouse lung cancer model driven by a G12D Kras mutation.	('lung cancer', 'Disease', (75, 86))	('lung cancer', 'Phenotype', 'HP:0100526', (75, 86))	('G12D', 'Var', (105, 109))	('mouse', 'Species', '10090', (69, 74))	('G12D', 'Mutation', 'rs121913529', (105, 109))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('lung cancer', 'Disease', 'MESH:D008175', (75, 86))	('driven by', 'Reg', (93, 102))
507551	26967383	Nit1 knockout mice (Nit1-/-) were crossed with KrasG12D/+ mice to investigate whether a G12D Kras mutation and Nit1 inactivation interact to promote or inhibit the development of NSCLC.	('inhibit', 'NegReg', (152, 159))	('NSCLC', 'Disease', 'MESH:D002289', (179, 184))	('G12D', 'Var', (88, 92))	('mice', 'Species', '10090', (14, 18))	('G12D', 'Mutation', 'rs121913529', (51, 55))	('development of', 'CPA', (164, 178))	('mice', 'Species', '10090', (58, 62))	('G12D', 'Mutation', 'rs121913529', (88, 92))	('NSCLC', 'Phenotype', 'HP:0030358', (179, 184))	('promote', 'PosReg', (141, 148))	('Kras', 'Gene', (93, 97))	('Nit1', 'Gene', (111, 115))	('NSCLC', 'Disease', (179, 184))
507555	26967383	In addition, cisplatin response was enhanced in human lung cancer cells when Nit1 was knocked down and Nit1-/-:KrasG12D/+ tumors showed increased sensitivity to cisplatin in vivo.	('tumors', 'Disease', 'MESH:D009369', (122, 128))	('G12D', 'Mutation', 'rs121913529', (115, 119))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('sensitivity', 'MPA', (146, 157))	('Nit1-/-', 'Var', (103, 110))	('lung cancer', 'Disease', (54, 65))	('Nit1', 'Gene', (77, 81))	('human', 'Species', '9606', (48, 53))	('cisplatin response', 'MPA', (13, 31))	('tumors', 'Phenotype', 'HP:0002664', (122, 128))	('lung cancer', 'Disease', 'MESH:D008175', (54, 65))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('increased', 'PosReg', (136, 145))	('enhanced', 'PosReg', (36, 44))	('cisplatin', 'Chemical', 'MESH:D002945', (13, 22))	('tumors', 'Disease', (122, 128))	('lung cancer', 'Phenotype', 'HP:0100526', (54, 65))	('knocked down', 'Var', (86, 98))	('cisplatin', 'Chemical', 'MESH:D002945', (161, 170))
507559	26967383	Kras mutations, present in about 20-30% of NSCLCs, lead to the over activation of the mitogen-activated protein kinase (MAPK) pathway, which has diverse impacts on cellular proliferation.	('over activation', 'PosReg', (63, 78))	('NSCLC', 'Phenotype', 'HP:0030358', (43, 48))	('mutations', 'Var', (5, 14))	('Kras', 'Gene', (0, 4))	('NSCLC', 'Disease', (43, 48))	('NSCLCs', 'Phenotype', 'HP:0030358', (43, 49))	('impacts', 'Reg', (153, 160))	('NSCLC', 'Disease', 'MESH:D002289', (43, 48))
507560	26967383	Mutations in the Kras pathway have continually led cancer patients to decreased responses to chemotherapeutics and radiation therapy treatments.	('Kras pathway', 'Pathway', (17, 29))	('decreased', 'NegReg', (70, 79))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('responses to chemotherapeutics', 'MPA', (80, 110))	('Mutations', 'Var', (0, 9))	('patients', 'Species', '9606', (58, 66))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))
507561	26967383	The overall decreased response rates due to activating mutations in NSCLCs make it critically important to find new targets.	('response rates', 'MPA', (22, 36))	('activating', 'PosReg', (44, 54))	('NSCLC', 'Disease', 'MESH:D002289', (68, 73))	('mutations', 'Var', (55, 64))	('NSCLCs', 'Phenotype', 'HP:0030358', (68, 74))	('NSCLC', 'Phenotype', 'HP:0030358', (68, 73))	('decreased', 'NegReg', (12, 21))	('NSCLC', 'Disease', (68, 73))
507567	26967383	It was found that in plants, Nit1 is required to repress proliferation and in its absence causes cells to become polyploidy due to defects that occur in cytokinesis.	('polyploidy', 'Disease', 'MESH:D011123', (113, 123))	('defects', 'NegReg', (131, 138))	('causes', 'Reg', (90, 96))	('polyploidy', 'Disease', (113, 123))	('Nit1', 'Var', (29, 33))
507570	26967383	Although Nit1-deficient mice have a normal life cycle, reproduction, and do not develop spontaneous tumors, they are more sensitive to carcinogen-induced forestomach tumors; in addition, ectopic expression of Nit1 leads to caspase activation and apoptosis, and may play a role in DNA damage-induced apoptosis in cell models.	('play', 'Reg', (265, 269))	('apoptosis', 'CPA', (246, 255))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('Nit1-deficient', 'Disease', 'MESH:D007153', (9, 23))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))	('ectopic expression', 'Var', (187, 205))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('Nit1-deficient', 'Disease', (9, 23))	('tumors', 'Disease', (166, 172))	('forestomach tumors', 'Disease', (154, 172))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('activation', 'PosReg', (231, 241))	('tumors', 'Disease', (100, 106))	('Nit1', 'Gene', (209, 213))	('tumors', 'Disease', 'MESH:D009369', (166, 172))	('forestomach tumors', 'Disease', 'MESH:D013274', (154, 172))	('mice', 'Species', '10090', (24, 28))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('caspase', 'CPA', (223, 230))
507576	26967383	As shown in Figure 2A and 2B top, the number of pleural (p<0.001) or dissected tumor nodules (p<0.05) was significantly reduced in the Nit1-/-:KrasG12D/+ mice in comparison to Nit1+/+:KrasG12D/+ mice; in addition, the size of tumor nodules are much smaller in Nit1-/-:KrasG12D/+ mice (Figure 2A, 2B middle).	('G12D', 'Mutation', 'rs121913529', (272, 276))	('mice', 'Species', '10090', (195, 199))	('G12D', 'Mutation', 'rs121913529', (147, 151))	('mice', 'Species', '10090', (154, 158))	('tumor', 'Disease', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('Nit1-/-:KrasG12D/+', 'Var', (135, 153))	('mice', 'Species', '10090', (279, 283))	('G12D', 'Mutation', 'rs121913529', (188, 192))	('tumor', 'Disease', 'MESH:D009369', (226, 231))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('Nit1-/-:KrasG12D/+', 'Var', (260, 278))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('smaller', 'NegReg', (249, 256))	('reduced', 'NegReg', (120, 127))	('tumor', 'Disease', (226, 231))
507577	26967383	Next, we measured the weight of tumor-bearing lungs as well as dissected tumors from mice of the two genotypes and demonstrated that Nit1+/+:KrasG12D/+ mice have a heavier tumor load.	('mice', 'Species', '10090', (85, 89))	('tumors', 'Disease', 'MESH:D009369', (73, 79))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('heavier', 'PosReg', (164, 171))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Disease', (172, 177))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('Nit1+/+:KrasG12D/+', 'Var', (133, 151))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('tumor', 'Disease', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('mice', 'Species', '10090', (152, 156))	('tumors', 'Disease', (73, 79))	('tumor', 'Disease', (32, 37))	('tumor', 'Disease', 'MESH:D009369', (172, 177))
507579	26967383	As shown in Figure 2C, Nit1-/-:KrasG12D/+ mice have fewer and smaller lung lesions on CT with a 5-fold reduction of total tumor volume (median) compared with Nit1+/+:KrasG12D/+ mice (Figure 2D, p<0.01).	('G12D', 'Mutation', 'rs121913529', (170, 174))	('smaller', 'NegReg', (62, 69))	('mice', 'Species', '10090', (177, 181))	('mice', 'Species', '10090', (42, 46))	('G12D', 'Mutation', 'rs121913529', (35, 39))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('lung lesions', 'CPA', (70, 82))	('Nit1-/-:KrasG12D/+', 'Var', (23, 41))	('smaller lung', 'Phenotype', 'HP:0002089', (62, 74))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('reduction', 'NegReg', (103, 112))	('tumor', 'Disease', (122, 127))
507581	26967383	Remarkably, Nit1 deficient mice have a trend to live longer (Log-rank test for trend,   P<0.05) though the median survival has no difference in Nit1+/-:KrasG12D/+ vs Nit1+/+:KrasG12D/+, however, Nit1-/-:KrasG12D/+ mice have significantly elongated life spans when compared with wild-type controls (Mantel-Cox test, * P<0.05).	('life spans', 'CPA', (248, 258))	('G12D', 'Mutation', 'rs121913529', (156, 160))	('G12D', 'Mutation', 'rs121913529', (207, 211))	('mice', 'Species', '10090', (27, 31))	('KrasG12D/+', 'Var', (203, 213))	('Nit1-/-:KrasG12D/+', 'Var', (195, 213))	('mice', 'Species', '10090', (214, 218))	('elongated', 'PosReg', (238, 247))	('G12D', 'Mutation', 'rs121913529', (178, 182))
507584	26967383	Cross-sections of tumor-bearing lungs following H&E staining showed Nit1-/-:KrasG12D/+ mice have decreased tumor area (Figure 3A, 3C top) and or decreased tumor number (Figure 3A, 3C middle) compared with wild-type controls.	('decreased tumor', 'Disease', 'MESH:D009369', (145, 160))	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('have', 'NegReg', (92, 96))	('decreased tumor', 'Disease', 'MESH:D009369', (97, 112))	('tumor', 'Disease', (107, 112))	('tumor', 'Disease', (18, 23))	('decreased tumor', 'Disease', (145, 160))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('mice', 'Species', '10090', (87, 91))	('G12D', 'Mutation', 'rs121913529', (80, 84))	('decreased tumor', 'Disease', (97, 112))	('tumor', 'Disease', (155, 160))	('H&E', 'Chemical', 'MESH:D006371', (48, 51))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('showed Nit1-/-', 'Var', (61, 75))
507585	26967383	IHC staining of proliferation marker Ki67 indicated that tumor proliferation was suppressed significantly in Nit1-/-:KrasG12D/+ mice (Figure 3B, 3C bottom).	('suppressed', 'NegReg', (81, 91))	('Ki67', 'Gene', (37, 41))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('mice', 'Species', '10090', (128, 132))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Disease', (57, 62))	('Nit1-/-:KrasG12D/+', 'Var', (109, 127))	('Ki67', 'Gene', '17345', (37, 41))
507592	26967383	To determine whether lung cancer is dependent upon a high level of Nit1 expression, we tested lung cancer cell survival following Nit1 knockdown through siRNA using a specific siRNA smart pool.	('lung cancer', 'Disease', 'MESH:D008175', (94, 105))	('knockdown', 'Var', (135, 144))	('Nit1', 'Gene', (130, 134))	('lung cancer', 'Disease', (21, 32))	('lung cancer', 'Phenotype', 'HP:0100526', (21, 32))	('lung cancer', 'Disease', 'MESH:D008175', (21, 32))	('lung cancer', 'Disease', (94, 105))	('lung cancer', 'Phenotype', 'HP:0100526', (94, 105))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('tested', 'Reg', (87, 93))
507595	26967383	Knocking down of Nit1 or Nit2 in A549 lung cancer cells were validated by Western blotting as shown in the lower panel of Figure 5A.	('A549 lung cancer', 'Disease', (33, 49))	('Knocking down', 'Var', (0, 13))	('lung cancer', 'Phenotype', 'HP:0100526', (38, 49))	('Nit1', 'Gene', (17, 21))	('A549 lung cancer', 'Disease', 'MESH:D008175', (33, 49))	('Nit2', 'Gene', (25, 29))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))
507596	26967383	The upper panel of Figure 5A demonstrates that the survival reduction of most of the tested lung cancer cell lines is only observed in cells transfected with siRNA against Nit1, but not in cells transfected with control siRNA or siRNA against Nit2.	('lung cancer', 'Disease', (92, 103))	('lung cancer', 'Phenotype', 'HP:0100526', (92, 103))	('reduction', 'NegReg', (60, 69))	('survival', 'CPA', (51, 59))	('lung cancer', 'Disease', 'MESH:D008175', (92, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('siRNA against', 'Var', (158, 171))
507598	26967383	To determine the impact of Nit1 in mediating therapeutic effects against lung cancer, we knocked down Nit1 through siRNA and followed with cisplatin treatment on the relatively cisplatin resistant human lung cancer cell line A549.	('lung cancer', 'Disease', 'MESH:D008175', (73, 84))	('cisplatin', 'Chemical', 'MESH:D002945', (139, 148))	('lung cancer', 'Phenotype', 'HP:0100526', (203, 214))	('Nit1', 'Gene', (102, 106))	('knocked', 'Var', (89, 96))	('cisplatin', 'Chemical', 'MESH:D002945', (177, 186))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('lung cancer', 'Disease', (203, 214))	('lung cancer', 'Disease', (73, 84))	('A549', 'CellLine', 'CVCL:0023', (225, 229))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('human', 'Species', '9606', (197, 202))	('lung cancer', 'Phenotype', 'HP:0100526', (73, 84))	('lung cancer', 'Disease', 'MESH:D008175', (203, 214))
507599	26967383	As shown in Figure 6A, there was no significant decrease in cell survival after cisplatin treatment in Nit1 wild type (100% vs. 90%, p>0.05, left blue bars), while it was significantly decreased with Nit1 knockdown (60% vs. 40%, p<0.05, red bars).	('decreased', 'NegReg', (185, 194))	('cisplatin', 'Chemical', 'MESH:D002945', (80, 89))	('knockdown', 'Var', (205, 214))	('decrease', 'NegReg', (48, 56))	('Nit1', 'Gene', (103, 107))	('cell survival', 'CPA', (60, 73))	('Nit1', 'Gene', (200, 204))
507600	26967383	And the cisplatin response after Nit1 knockdown was remarkably increased (p<0.05, Figure 6A right).	('Nit1', 'Gene', (33, 37))	('increased', 'PosReg', (63, 72))	('cisplatin response', 'MPA', (8, 26))	('cisplatin', 'Chemical', 'MESH:D002945', (8, 17))	('knockdown', 'Var', (38, 47))
507602	26967383	To confirm this finding in vivo, we compared the cisplatin responses in Nit1-/-:KrasG12D/+ mice with their wild-type counterpart, since KrasG12D/+ mice easily acquire cisplatin resistance.	('mice', 'Species', '10090', (91, 95))	('mice', 'Species', '10090', (147, 151))	('cisplatin resistance', 'MPA', (167, 187))	('KrasG12D/+', 'Var', (136, 146))	('cisplatin', 'Chemical', 'MESH:D002945', (49, 58))	('acquire', 'Reg', (159, 166))	('cisplatin', 'Chemical', 'MESH:D002945', (167, 176))
507603	26967383	Before and after 4 doses of cisplatin treatment at 7.5 mg/kg every 3 days, tumor volumes were measured by the micro-CT. All tumor-bearing Nit1-/-:KrasG12D/+ mice demonstrated tumor shrinkage, whereas more than half of the Nit1 wild-type group had persistent tumor growth as shown by the waterfall plot (Figure 6C).	('cisplatin', 'Chemical', 'MESH:D002945', (28, 37))	('tumor', 'Phenotype', 'HP:0002664', (258, 263))	('tumor', 'Disease', (175, 180))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('mice', 'Species', '10090', (157, 161))	('tumor', 'Disease', (258, 263))	('Nit1-/-:KrasG12D/+', 'Var', (138, 156))	('tumor', 'Disease', (124, 129))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumor', 'Disease', 'MESH:D009369', (258, 263))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('tumor', 'Disease', (75, 80))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
507604	26967383	Representative CT images of tumor volume increasing in Nit1+/+:KrasG12D/+ mice (purple arrows), while decreasing in Nit1-/-:KrasG12D/+ mice (red arrows) were shown in Figure 6B.	('mice', 'Species', '10090', (74, 78))	('tumor', 'Disease', (28, 33))	('increasing', 'PosReg', (41, 51))	('decreasing', 'NegReg', (102, 112))	('mice', 'Species', '10090', (135, 139))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('Nit1+/+:KrasG12D/+', 'Var', (55, 73))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
507605	26967383	Increasing knowledge of activating driver mutations in NSCLCs has prompted the development of various targeted therapeutics.	('NSCLC', 'Disease', (55, 60))	('activating', 'PosReg', (24, 34))	('NSCLC', 'Disease', 'MESH:D002289', (55, 60))	('NSCLCs', 'Phenotype', 'HP:0030358', (55, 61))	('NSCLC', 'Phenotype', 'HP:0030358', (55, 60))	('mutations', 'Var', (42, 51))
507612	26967383	To investigate whether Nit1 deficiency may promote or inhibit the development of NSCLCs, we knocked out Nit1 in KrasG12D/+ mice lung cancer model background (Figure 1).	('lung cancer', 'Disease', 'MESH:D008175', (128, 139))	('inhibit', 'NegReg', (54, 61))	('promote', 'PosReg', (43, 50))	('NSCLC', 'Phenotype', 'HP:0030358', (81, 86))	('Nit1 deficiency', 'Disease', (23, 38))	('knocked out', 'Var', (92, 103))	('lung cancer', 'Disease', (128, 139))	('Nit1', 'Gene', (104, 108))	('lung cancer', 'Phenotype', 'HP:0100526', (128, 139))	('NSCLC', 'Disease', (81, 86))	('Nit1 deficiency', 'Disease', 'MESH:D007153', (23, 38))	('development of', 'CPA', (66, 80))	('NSCLC', 'Disease', 'MESH:D002289', (81, 86))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('mice', 'Species', '10090', (123, 127))	('NSCLCs', 'Phenotype', 'HP:0030358', (81, 87))
507613	26967383	Surprisingly, Nit1-/-:KrasG12D/+ mice showed significantly decreased tumor burden (lesions, volume, lung and tumor weight) and significant life extension compared with Nit1+/+:KrasG12D/+ (Figure 2 and 3).	('Nit1-/-:KrasG12D/+', 'Var', (14, 32))	('decreased tumor', 'Disease', (59, 74))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('KrasG12D/+', 'Var', (22, 32))	('tumor', 'Disease', (69, 74))	('G12D', 'Mutation', 'rs121913529', (180, 184))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('G12D', 'Mutation', 'rs121913529', (26, 30))	('life extension', 'CPA', (139, 153))	('mice', 'Species', '10090', (33, 37))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('decreased tumor', 'Disease', 'MESH:D009369', (59, 74))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('tumor', 'Disease', (109, 114))
507616	26967383	Our findings are consistent with the datasets of Oncomine, so we further investigated lung cancer cell survival post gene NIT1 knock down.	('Oncomine', 'Chemical', '-', (49, 57))	('investigated', 'Reg', (73, 85))	('lung cancer', 'Phenotype', 'HP:0100526', (86, 97))	('lung cancer', 'Disease', (86, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('lung cancer', 'Disease', 'MESH:D008175', (86, 97))	('NIT1', 'Gene', (122, 126))	('knock down', 'Var', (127, 137))
507617	26967383	Our data showed that knocking down NIT1, but not NIT2, can decrease cell viability in various lung cancer cell lines, and that it can be rescued after NIT1 expression levels were restored with recombinant human Nit1 adenovirus.	('cell viability', 'CPA', (68, 82))	('lung cancer', 'Disease', 'MESH:D008175', (94, 105))	('knocking down', 'Var', (21, 34))	('NIT2', 'Gene', (49, 53))	('NIT1', 'Gene', (35, 39))	('lung cancer', 'Disease', (94, 105))	('decrease', 'NegReg', (59, 67))	('lung cancer', 'Phenotype', 'HP:0100526', (94, 105))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('human', 'Species', '9606', (205, 210))	('NIT2', 'Gene', '52633', (49, 53))
507620	26967383	As shown in Figure 6A, significantly reduced cell survival post Nit1 knockdown combined with cisplatin treatment in resistant A549 indicated that Nit1 deficiency may sensitize cisplatin response in human lung cancer.	('A549', 'CellLine', 'CVCL:0023', (126, 130))	('cisplatin response', 'MPA', (176, 194))	('Nit1 deficiency', 'Disease', (146, 161))	('sensitize', 'Reg', (166, 175))	('cisplatin', 'Chemical', 'MESH:D002945', (176, 185))	('cell survival', 'CPA', (45, 58))	('cisplatin', 'Chemical', 'MESH:D002945', (93, 102))	('Nit1 deficiency', 'Disease', 'MESH:D007153', (146, 161))	('Nit1', 'Gene', (64, 68))	('lung cancer', 'Disease', 'MESH:D008175', (204, 215))	('lung cancer', 'Disease', (204, 215))	('human', 'Species', '9606', (198, 203))	('lung cancer', 'Phenotype', 'HP:0100526', (204, 215))	('reduced', 'NegReg', (37, 44))	('knockdown', 'Var', (69, 78))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
507623	26967383	The total tumor volume was decreased in some Nit1+/+:KrasG12D/+ mice, but more than half of them had persistent tumor growth, whereas all Nit1-/-:KrasG12D/+ mice demonstrated significant tumor shrinkage (Figure 6B, 6C).	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('tumor', 'Disease', 'MESH:D009369', (187, 192))	('mice', 'Species', '10090', (157, 161))	('tumor', 'Disease', (10, 15))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('decreased', 'NegReg', (27, 36))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('G12D', 'Mutation', 'rs121913529', (57, 61))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumor', 'Disease', (187, 192))	('Nit1+/+:KrasG12D/+', 'Var', (45, 63))	('G12D', 'Mutation', 'rs121913529', (150, 154))	('tumor', 'Disease', (112, 117))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('mice', 'Species', '10090', (64, 68))
507624	26967383	Despite the early descriptions of Nit1 potentially functioning like a tumor suppressor when overexpressed, our data showed that Nit1 knockdown could decrease cell viability in various lung cancer cell lines and lung tumorigenesis was significantly suppressed in Nit1 knockout KrasG12D/+ mice.	('suppressed', 'NegReg', (248, 258))	('decrease', 'NegReg', (149, 157))	('Nit1', 'Gene', (262, 266))	('tumor', 'Disease', (216, 221))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('lung cancer', 'Disease', 'MESH:D008175', (184, 195))	('lung tumor', 'Disease', 'MESH:D008175', (211, 221))	('tumor', 'Disease', 'MESH:D009369', (216, 221))	('lung cancer', 'Phenotype', 'HP:0100526', (184, 195))	('cell viability', 'CPA', (158, 172))	('Nit1', 'Gene', (128, 132))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('mice', 'Species', '10090', (287, 291))	('lung tumor', 'Disease', (211, 221))	('tumor', 'Disease', (70, 75))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('knockdown', 'Var', (133, 142))	('lung tumor', 'Phenotype', 'HP:0100526', (211, 221))	('lung cancer', 'Disease', (184, 195))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
507625	26967383	In addition, Nit1 knockdown has the ability to sensitize NSCLCs to cytotoxic agents (e.g.	('knockdown', 'Var', (18, 27))	('NSCLC', 'Phenotype', 'HP:0030358', (57, 62))	('sensitize', 'Reg', (47, 56))	('Nit1', 'Gene', (13, 17))	('NSCLC', 'Disease', (57, 62))	('NSCLCs', 'Phenotype', 'HP:0030358', (57, 63))	('NSCLC', 'Disease', 'MESH:D002289', (57, 62))
507628	26967383	recently showed that knockdown of Nit2 in colon cancer produced decreased levels of cellular proliferation.	('colon cancer', 'Disease', (42, 54))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('colon cancer', 'Phenotype', 'HP:0003003', (42, 54))	('colon cancer', 'Disease', 'MESH:D015179', (42, 54))	('Nit2', 'Gene', (34, 38))	('knockdown', 'Var', (21, 30))	('levels of cellular proliferation', 'MPA', (74, 106))	('decreased', 'NegReg', (64, 73))
507631	26967383	In the present study, we have shown the impact of knocking down Nit1 in vivo and in vitro in NSCLCs.	('NSCLC', 'Disease', (93, 98))	('NSCLC', 'Disease', 'MESH:D002289', (93, 98))	('Nit1', 'Gene', (64, 68))	('knocking down', 'Var', (50, 63))	('NSCLC', 'Phenotype', 'HP:0030358', (93, 98))	('NSCLCs', 'Phenotype', 'HP:0030358', (93, 99))
507646	26967383	Paired littermates of F2 (Nit1+/+:KrasG12D/+ and Nit1-/-:KrasG12D/+) were sacrificed at different time points ranging from ages 4 to 7 months because these mice develop lung tumors as early as 1 week after birth and do not usually survive >200 days.	('to 7', 'Species', '1214577', (130, 134))	('Nit1-/-', 'Var', (49, 56))	('develop', 'PosReg', (161, 168))	('KrasG12D/+', 'Var', (57, 67))	('lung tumors', 'Disease', 'MESH:D008175', (169, 180))	('lung tumor', 'Phenotype', 'HP:0100526', (169, 179))	('mice', 'Species', '10090', (156, 160))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('lung tumors', 'Disease', (169, 180))	('tumors', 'Phenotype', 'HP:0002664', (174, 180))	('lung tumors', 'Phenotype', 'HP:0100526', (169, 180))
507664	26967383	All siRNAs targeted to ORF region were bought from Dharmacon and included NIT1 mixture smart pool (L-020022-01-0005), NIT2 smart pool (L-017902-00-0005) and Non-targeting Pool (D-001810-10-20).	('D-001810-10-20', 'Var', (177, 191))	('NIT2', 'Gene', '52633', (118, 122))	('L-020022-01-0005', 'Var', (99, 115))	('NIT2', 'Gene', (118, 122))	('L-017902-00-0005', 'Var', (135, 151))
507786	33142921	It has also identified two major subsets of cells characterized by epithelial and stromal gene expression patterns attributable to the proliferation of genes, including genes associated with oxidative phosphorylation and MYC activity in ovarian cancer, as well as differences between isocitrate dehydrogenase mutants astrocytoma and oligodendroglioma in distinct tumor microenvironments and their signature genetic events.	('men', 'Species', '9606', (381, 384))	('ovarian cancer', 'Phenotype', 'HP:0100615', (237, 251))	('mutants', 'Var', (309, 316))	('tumor', 'Disease', 'MESH:D009369', (363, 368))	('ovarian cancer', 'Disease', 'MESH:D010051', (237, 251))	('tumor', 'Phenotype', 'HP:0002664', (363, 368))	('astrocytoma', 'Phenotype', 'HP:0009592', (317, 328))	('ovarian cancer', 'Disease', (237, 251))	('differences', 'Reg', (264, 275))	('cancer', 'Phenotype', 'HP:0002664', (245, 251))	('tumor', 'Disease', (363, 368))	('astrocytoma and oligodendroglioma', 'Disease', 'MESH:D009837', (317, 350))
507788	33142921	Moreover, for head and neck squamous cell carcinoma, subtypes are characterized by their malignant and stromal composition, and p-EMT has been established as an independent predictor of nodal metastasis, grade, and adverse pathologic features.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (28, 51))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (23, 51))	('p-EMT', 'Var', (128, 133))	('nodal metastasis', 'CPA', (186, 202))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (14, 51))	('carcinoma', 'Phenotype', 'HP:0030731', (42, 51))	('neck squamous cell carcinoma', 'Disease', (23, 51))
507809	33142921	The data were as follows: 0.162, 0.501, and 0.716 ng/muL for the 16-week control group; 0.126, 0.446, and 0.584 ng/muL for the 16-week experimental group; 0.132 and 3.100 ng/muL for the 29-week control group, and 0.288, 5.340, and 5.280 ng/muL for the 29-week experimental group.	('men', 'Species', '9606', (141, 144))	('muL', 'Gene', (53, 56))	('muL', 'Gene', '68729', (53, 56))	('muL', 'Gene', '68729', (174, 177))	('muL', 'Gene', (174, 177))	('muL', 'Gene', '68729', (240, 243))	('0.716', 'Var', (44, 49))	('0.132', 'Var', (155, 160))	('0.501', 'Var', (33, 38))	('men', 'Species', '9606', (266, 269))	('muL', 'Gene', (240, 243))	('0.446', 'Var', (95, 100))	('0.126', 'Var', (88, 93))	('muL', 'Gene', '68729', (115, 118))	('muL', 'Gene', (115, 118))
507855	33142921	It is known to have cytotoxicity and genotoxicity and induce mutations, which can cause histological or other biological changes.	('cytotoxicity and genotoxicity', 'Disease', 'MESH:D064420', (20, 49))	('cause', 'Reg', (82, 87))	('induce', 'Reg', (54, 60))	('mutations', 'Var', (61, 70))
507865	33142921	MYC mutations have been related to Burkitt's lymphoma and leukemia; they are activated through gene rearrangement and gene amplification, which affect other genes.	("Burkitt's lymphoma", 'Disease', (35, 53))	('MYC', 'Gene', (0, 3))	("Burkitt's lymphoma", 'Disease', 'MESH:D002051', (35, 53))	('leukemia', 'Disease', (58, 66))	('leukemia', 'Phenotype', 'HP:0001909', (58, 66))	('leukemia', 'Disease', 'MESH:D007938', (58, 66))	("Burkitt's lymphoma", 'Phenotype', 'HP:0030080', (35, 53))	('gene amplification', 'Var', (118, 136))	('lymphoma', 'Phenotype', 'HP:0002665', (45, 53))	('mutations', 'Var', (4, 13))	('men', 'Species', '9606', (109, 112))
507967	31217826	demonstrated that the expression of SLIT2 and ROBO1 was significantly associated with an increased metastatic risk and poorer overall survival in colorectal carcinoma patients.	('overall survival', 'CPA', (126, 142))	('poorer', 'NegReg', (119, 125))	('colorectal carcinoma', 'Disease', (146, 166))	('expression', 'Var', (22, 32))	('patients', 'Species', '9606', (167, 175))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (146, 166))	('associated', 'Reg', (70, 80))	('metastatic risk', 'CPA', (99, 114))	('rat', 'Species', '10116', (7, 10))	('carcinoma', 'Phenotype', 'HP:0030731', (157, 166))	('increased', 'PosReg', (89, 98))	('ROBO1', 'Gene', (46, 51))	('SLIT2', 'Gene', (36, 41))
507974	31217826	The SLIT2-Tg mice were found to develop significantly more skin tumors than wild-type mice, the skin tumors that occurred in SLIT2-Tg mice were significantly larger than those in the wild-type mice after 7,12-dimethylbenz[a]anthracene initiation until the end of the experiment.	('skin tumors', 'Disease', (96, 107))	('mice', 'Species', '10090', (13, 17))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('mice', 'Species', '10090', (134, 138))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('skin tumors', 'Disease', 'MESH:D012878', (59, 70))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('skin tumors', 'Disease', 'MESH:D012878', (96, 107))	('mice', 'Species', '10090', (86, 90))	('mice', 'Species', '10090', (193, 197))	('anthracene', 'Chemical', 'MESH:C034020', (224, 234))	('SLIT2-Tg', 'Var', (125, 133))	('larger', 'PosReg', (158, 164))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('skin tumors', 'Phenotype', 'HP:0008069', (59, 70))	('skin tumors', 'Phenotype', 'HP:0008069', (96, 107))	('skin tumors', 'Disease', (59, 70))
507992	31217826	Moreover, this effect can be attenuated by knockdown of Hakai.	('Hakai', 'Gene', '79872', (56, 61))	('Hakai', 'Gene', (56, 61))	('knockdown', 'Var', (43, 52))
507996	31217826	It has been shown that SLIT/ROBO pathway genes are frequently inactivated by promoter region's hypermethylation, resulting in downregulated gene expression in many human cancers.	('cancers', 'Phenotype', 'HP:0002664', (170, 177))	('inactivated', 'NegReg', (62, 73))	('gene expression', 'MPA', (140, 155))	('cancers', 'Disease', (170, 177))	('downregulated', 'NegReg', (126, 139))	('SLIT', 'Disease', (23, 27))	('human', 'Species', '9606', (164, 169))	('cancers', 'Disease', 'MESH:D009369', (170, 177))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('hypermethylation', 'Var', (95, 111))	('SLIT', 'Disease', 'None', (23, 27))
507997	31217826	SLIT2 was methylated in 71% (5/7) of glioma cell lines and in 59% (37/63) of other tumors and the SLIT2 expression was downregulated in methylated gliomas tumor samples, which indicated that SLIT2 was frequently inactivated by promoter region CpG island hypermethylation in gliomas and might be a good candidate for a glioma tumor suppressor gene.	('glioma tumor', 'Disease', (318, 330))	('glioma', 'Disease', (274, 280))	('gliomas', 'Disease', (274, 281))	('tumors', 'Disease', 'MESH:D009369', (83, 89))	('SLIT2', 'Gene', (191, 196))	('gliomas', 'Disease', (147, 154))	('glioma', 'Disease', (147, 153))	('tumor', 'Phenotype', 'HP:0002664', (325, 330))	('glioma', 'Phenotype', 'HP:0009733', (37, 43))	('glioma', 'Disease', 'MESH:D005910', (274, 280))	('hypermethylation', 'Var', (254, 270))	('glioma', 'Disease', (318, 324))	('glioma', 'Disease', 'MESH:D005910', (147, 153))	('gliomas', 'Disease', 'MESH:D005910', (274, 281))	('expression', 'MPA', (104, 114))	('gliomas tumor', 'Disease', (147, 160))	('glioma', 'Disease', 'MESH:D005910', (318, 324))	('gliomas', 'Disease', 'MESH:D005910', (147, 154))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('glioma', 'Phenotype', 'HP:0009733', (274, 280))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('downregulated', 'NegReg', (119, 132))	('glioma', 'Phenotype', 'HP:0009733', (147, 153))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('gliomas', 'Phenotype', 'HP:0009733', (274, 281))	('glioma', 'Phenotype', 'HP:0009733', (318, 324))	('gliomas', 'Phenotype', 'HP:0009733', (147, 154))	('SLIT2', 'Gene', (98, 103))	('inactivated', 'NegReg', (212, 223))	('glioma', 'Disease', (37, 43))	('tumors', 'Disease', (83, 89))	('gliomas tumor', 'Disease', 'MESH:D005910', (147, 160))	('glioma tumor', 'Disease', 'MESH:D005910', (318, 330))	('glioma', 'Disease', 'MESH:D005910', (37, 43))	('SLIT2', 'Gene', (0, 5))
507998	31217826	SLIT2 expression was reduced in CRC tissues because of hypermethylation of the SLIT2 gene in CRC cells, and SLIT2 could inhibit CRC cell migration that required USP33 by deubiquitinating and stabilizing ROBO1.	('reduced', 'NegReg', (21, 28))	('hypermethylation', 'Var', (55, 71))	('USP33', 'Gene', (161, 166))	('SLIT2', 'Gene', (79, 84))	('expression', 'MPA', (6, 16))	('CRC cell migration', 'CPA', (128, 146))	('stabilizing', 'MPA', (191, 202))	('inhibit', 'NegReg', (120, 127))	('SLIT2', 'Var', (108, 113))	('ROBO1', 'Gene', (203, 208))	('USP33', 'Gene', '23032', (161, 166))	('rat', 'Species', '10116', (140, 143))	('deubiquitinating', 'MPA', (170, 186))	('SLIT2', 'Gene', (0, 5))
508001	31217826	Furthermore, blocking SLIT/ROBO activity reduced apoptosis in both PEO-14 and SKOV-3 tumor cells.	('tumor', 'Disease', (85, 90))	('reduced', 'NegReg', (41, 48))	('blocking', 'Var', (13, 21))	('SLIT', 'Disease', 'None', (22, 26))	('SLIT', 'Disease', (22, 26))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('SKOV-3', 'CellLine', 'CVCL:0532', (78, 84))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('apoptosis', 'CPA', (49, 58))
508004	31217826	Silencing of SLIT3 induced EMT by downregulation of E-cadherin and upregulation of vimentin, and enhanced MMP2 and MMP9 expression, thus promoting proliferation, migration, and invasion of A549 cells.	('SLIT3', 'Gene', (13, 18))	('vimentin', 'Gene', (83, 91))	('enhanced', 'PosReg', (97, 105))	('E-cadherin', 'Gene', (52, 62))	('Silencing', 'Var', (0, 9))	('E-cadherin', 'Gene', '999', (52, 62))	('MMP2', 'Gene', (106, 110))	('expression', 'MPA', (120, 130))	('rat', 'Species', '10116', (165, 168))	('promoting', 'PosReg', (137, 146))	('proliferation', 'CPA', (147, 160))	('A549', 'CellLine', 'CVCL:0023', (189, 193))	('invasion', 'CPA', (177, 185))	('migration', 'CPA', (162, 171))	('rat', 'Species', '10116', (154, 157))	('downregulation', 'NegReg', (34, 48))	('MMP2', 'Gene', '4313', (106, 110))	('MMP9', 'Gene', '4318', (115, 119))	('MMP9', 'Gene', (115, 119))	('upregulation', 'PosReg', (67, 79))	('vimentin', 'Gene', '7431', (83, 91))
508013	31217826	The shRNA-mediated depletion of SLIT2 or ectopic expression of a soluble decoy ROBO enhance HGF-induced migration, matrix invasion, accompany with the upregulation of Cdc-42 and the downregulation of Rac-1 activities.	('HGF', 'Gene', (92, 95))	('depletion', 'Var', (19, 28))	('Cdc-42', 'Gene', (167, 173))	('activities', 'MPA', (206, 216))	('HGF', 'Gene', '3082', (92, 95))	('matrix invasion', 'CPA', (115, 130))	('Cdc-42', 'Gene', '998', (167, 173))	('Rac-1', 'Gene', '5879', (200, 205))	('downregulation', 'NegReg', (182, 196))	('SLIT2', 'Gene', (32, 37))	('upregulation', 'PosReg', (151, 163))	('Rac-1', 'Gene', (200, 205))	('enhance', 'PosReg', (84, 91))	('rat', 'Species', '10116', (107, 110))
508017	31217826	showed that loss of SLITs (SLIT2, SLIT3) or their ROBO1 receptor in murine mammary gland or human breast carcinoma cells resulted in coordinate upregulation of the CXCL12 and CXCR4 signaling axis, which was accompanied by hyperplastic changes in cells and desmoplastic alterations in the surrounding stroma.	('CXCL12', 'Gene', '6387', (164, 170))	('breast carcinoma', 'Disease', 'MESH:D001943', (98, 114))	('desmoplastic alterations', 'Disease', (256, 280))	('SLIT', 'Disease', (34, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('CXCL12', 'Gene', (164, 170))	('upregulation', 'PosReg', (144, 156))	('desmoplastic alterations', 'Disease', 'MESH:D018220', (256, 280))	('breast carcinoma', 'Phenotype', 'HP:0003002', (98, 114))	('breast carcinoma', 'Disease', (98, 114))	('SLIT', 'Disease', 'None', (20, 24))	('SLIT', 'Disease', 'None', (27, 31))	('murine', 'Species', '10090', (68, 74))	('loss', 'Var', (12, 16))	('human', 'Species', '9606', (92, 97))	('CXCR4', 'Gene', '7852', (175, 180))	('SLIT', 'Disease', 'None', (34, 38))	('SLIT', 'Disease', (27, 31))	('SLIT', 'Disease', (20, 24))	('CXCR4', 'Gene', (175, 180))
508021	31217826	It was also found that SLIT2 inhibited CXCL12-induced phosphatidylinositol 3-kinase (PI3K), p44/42 MAPK, and MMP-2 and MMP-9 activities, but it did not have an effect on JNK and p38 MAPK activities.	('inhibited', 'NegReg', (29, 38))	('MAPK', 'Gene', '5595;5594;5595', (99, 103))	('p44', 'Gene', (92, 95))	('MMP-2', 'Gene', '4313', (109, 114))	('p44', 'Gene', '10561', (92, 95))	('phosphatidylinositol 3-kinase', 'Gene', '5293', (54, 83))	('SLIT2', 'Var', (23, 28))	('MAPK', 'Gene', (99, 103))	('phosphatidylinositol 3-kinase', 'Gene', (54, 83))	('MMP-9', 'Gene', (119, 124))	('MMP-2', 'Gene', (109, 114))	('MAPK', 'Gene', '5595;5594;5595', (182, 186))	('CXCL12', 'Gene', '6387', (39, 45))	('JNK', 'Gene', (170, 173))	('MAPK', 'Gene', (182, 186))	('activities', 'MPA', (125, 135))	('CXCL12', 'Gene', (39, 45))	('JNK', 'Gene', '5599', (170, 173))	('MMP-9', 'Gene', '4318', (119, 124))
508032	31217826	Abl and Ena may bind CC2, which was partly responsible for ROBO repulsion in the midline, whereas Abl antagonized ROBO-mediated repulsion by phosphorylating a tyrosine residue in CC1.	('CC1', 'Gene', (179, 182))	('responsible', 'Reg', (43, 54))	('ROBO repulsion', 'MPA', (59, 73))	('CC2', 'Gene', (21, 24))	('phosphorylating', 'Var', (141, 156))	('antagonized', 'NegReg', (102, 113))	('CC2', 'Gene', '22088', (21, 24))	('tyrosine', 'Chemical', 'MESH:D014443', (159, 167))
508039	31217826	The study led by Zhang and Zhou demonstrated that downregulation of ROBO1 using small interfering RNA inhibited mesenchymal stem cell (MSC) proliferation.	('downregulation', 'NegReg', (50, 64))	('inhibited', 'NegReg', (102, 111))	('ROBO1', 'Gene', (68, 73))	('rat', 'Species', '10116', (39, 42))	('rat', 'Species', '10116', (147, 150))	('small interfering', 'Var', (80, 97))
508040	31217826	In addition, four miRNAs (miR), including miR-218, miR-29a, miR-146, and miR-148, inhibited the protein expression of ROBO1 in the MSCs, with miR-29 having the most marked effect.	('ROBO1', 'Gene', (118, 123))	('miR-146', 'Var', (60, 67))	('inhibited', 'NegReg', (82, 91))	('miR-29a', 'Gene', (51, 58))	('miR-29a', 'Gene', '407021', (51, 58))	('miR-218', 'Var', (42, 49))	('protein expression', 'MPA', (96, 114))	('miR-148', 'Var', (73, 80))
508045	31217826	In addition, miR-218 suppressed nasopharyngeal cancer progression through downregulating the SLIT2-ROBO1 pathway in a negative feedback loop manner.	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('miR-218', 'Var', (13, 20))	('cancer', 'Disease', (47, 53))	('suppressed', 'NegReg', (21, 31))	('SLIT2-ROBO1 pathway', 'Pathway', (93, 112))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('downregulating', 'NegReg', (74, 88))	('nasopharyngeal cancer', 'Phenotype', 'HP:0100630', (32, 53))
508059	31217826	suggested that SLIT2 could both positively and negatively regulate angiogenesis by binding to ROBO1 and ROBO4, respectively, and activation of ROBO4 blocked vascular endothelial growth factor (VEGF)-induced angiogenesis and vascular permeability.	('blocked', 'NegReg', (149, 156))	('activation', 'Var', (129, 139))	('VEGF', 'Gene', (193, 197))	('ROBO4', 'Gene', (104, 109))	('vascular endothelial growth factor', 'Gene', (157, 191))	('vascular endothelial growth factor', 'Gene', '7422', (157, 191))	('angiogenesis', 'CPA', (67, 79))	('binding', 'Interaction', (83, 90))	('VEGF', 'Gene', '7422', (193, 197))	('regulate', 'Reg', (58, 66))	('ROBO1', 'Gene', (94, 99))	('vascular permeability', 'CPA', (224, 245))	('negatively', 'NegReg', (47, 57))	('SLIT2', 'Gene', (15, 20))	('ROBO4', 'Gene', (143, 148))
508071	31217826	showed that disrupting SLIT2-ROBO signaling in PDAC might enhance metastasis and PDAC cells to neural invasion.	('enhance', 'PosReg', (58, 65))	('metastasis', 'CPA', (66, 76))	('PDAC', 'Phenotype', 'HP:0006725', (47, 51))	('PDAC', 'Phenotype', 'HP:0006725', (81, 85))	('SLIT2-ROBO', 'Protein', (23, 33))	('disrupting', 'Var', (12, 22))	('PDAC', 'Chemical', '-', (47, 51))	('PDAC', 'Chemical', '-', (81, 85))
508079	30634925	Although many explorations have revealed that high TMB may yield many neoantigens to incite antitumor immune response, a systematic exploration of the correlation between TMB and immune signatures in different cancer types is lacking.	('neoantigens', 'MPA', (70, 81))	('high', 'Var', (46, 50))	('incite', 'PosReg', (85, 91))	('TMB', 'Chemical', '-', (171, 174))	('TMB', 'Gene', (51, 54))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('TMB', 'Chemical', '-', (51, 54))	('tumor', 'Disease', (96, 101))	('cancer', 'Disease', 'MESH:D009369', (210, 216))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('cancer', 'Disease', (210, 216))
508083	30634925	Importantly, high TMB was associated with elevated expression of PD-L1 in diverse prevailing cancers.	('cancers', 'Disease', (93, 100))	('high', 'Var', (13, 17))	('cancers', 'Phenotype', 'HP:0002664', (93, 100))	('TMB', 'Chemical', '-', (18, 21))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('PD-L1', 'Gene', (65, 70))	('expression', 'MPA', (51, 61))	('cancers', 'Disease', 'MESH:D009369', (93, 100))	('elevated', 'PosReg', (42, 50))	('PD-L1', 'Gene', '29126', (65, 70))
508085	30634925	High TMB may inhibit immune cell infiltrations while promote CTAs expression and inflammatory response in cancer.	('CTAs expression', 'CPA', (61, 76))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('High TMB', 'Var', (0, 8))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('immune cell infiltrations', 'CPA', (21, 46))	('cancer', 'Disease', (106, 112))	('inhibit', 'NegReg', (13, 20))	('inflammatory response', 'CPA', (81, 102))	('TMB', 'Chemical', '-', (5, 8))	('promote', 'PosReg', (53, 60))
508087	30634925	Our data implicate that higher-TMB patients could gain a more favorable prognosis in diverse cancer types if treated with immunotherapy, otherwise would have a poorer prognosis compared to lower-TMB patients.	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('TMB', 'Chemical', '-', (195, 198))	('TMB', 'Chemical', '-', (31, 34))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('gain', 'PosReg', (50, 54))	('patients', 'Species', '9606', (199, 207))	('patients', 'Species', '9606', (35, 43))	('higher-TMB', 'Var', (24, 34))
508091	30634925	Some well-recognized molecular determinants include PD-L1 expression on tumor, DNA mismatch-repair deficiency, neoantigen load, and tumor-infiltrating lymphocytes.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('deficiency', 'Var', (99, 109))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('PD-L1', 'Gene', '29126', (52, 57))	('tumor', 'Disease', (72, 77))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('tumor', 'Disease', (132, 137))	('PD-L1', 'Gene', (52, 57))
508094	30634925	These studies demonstrated that higher nonsynonymous mutation burden in tumors is inclined to form more neoantigens that make tumors to have higher immunogenicity, and thus result to improved clinical response to immunotherapy.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumors', 'Disease', (126, 132))	('tumors', 'Disease', 'MESH:D009369', (126, 132))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('improved', 'PosReg', (183, 191))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumors', 'Disease', (72, 78))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('make tumors', 'Disease', (121, 132))	('higher', 'PosReg', (141, 147))	('clinical response', 'CPA', (192, 209))	('nonsynonymous mutation burden', 'Var', (39, 68))	('make tumors', 'Disease', 'MESH:C537705', (121, 132))	('immunogenicity', 'MPA', (148, 162))
508107	30634925	These results suggest that the relatedness between TMB and Treg cells infiltration degree depends on cancer types, whereas the lower-TMB subtype is likely to have stronger Treg cells infiltration than the higher-TMB subtype in diverse cancers.	('TMB', 'Chemical', '-', (133, 136))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('TMB', 'Chemical', '-', (212, 215))	('cancer', 'Disease', (235, 241))	('cancer', 'Disease', (101, 107))	('cancer', 'Disease', 'MESH:D009369', (235, 241))	('cancers', 'Disease', 'MESH:D009369', (235, 242))	('TMB', 'Chemical', '-', (51, 54))	('cancers', 'Phenotype', 'HP:0002664', (235, 242))	('cancers', 'Disease', (235, 242))	('Treg cells infiltration', 'CPA', (172, 195))	('lower-TMB', 'Var', (127, 136))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('stronger', 'PosReg', (163, 171))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))
508127	30634925	Again, this suggests that high TMB tends to inhibit immune cell infiltration in cancer.	('high', 'Var', (26, 30))	('inhibit', 'NegReg', (44, 51))	('TMB', 'Chemical', '-', (31, 34))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('immune cell infiltration', 'CPA', (52, 76))	('cancer', 'Disease', (80, 86))
508135	30634925	These results indicated that although the association between TMB and TILs infiltration was cancer type dependent, high TMB tended to inhibit TILs infiltration in various cancer types.	('high', 'Var', (115, 119))	('TILs infiltration', 'MPA', (142, 159))	('TMB', 'Chemical', '-', (120, 123))	('TMB', 'Chemical', '-', (62, 65))	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('inhibit', 'NegReg', (134, 141))	('association', 'Interaction', (42, 53))	('cancer', 'Disease', (171, 177))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('TMB', 'Gene', (120, 123))
508146	30634925	These results suggest that high TMB is associated with elevated expression of many CTAs in cancer.	('expression', 'MPA', (64, 74))	('CTAs', 'Disease', (83, 87))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('high', 'Var', (27, 31))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('TMB', 'Chemical', '-', (32, 35))	('elevated', 'PosReg', (55, 63))
508159	30634925	It suggests that high TMB may lead to depressed cytokine activity in diverse cancers.	('cancers', 'Disease', 'MESH:D009369', (77, 84))	('cancers', 'Phenotype', 'HP:0002664', (77, 84))	('depressed cytokine activity', 'Phenotype', 'HP:0031407', (38, 65))	('cancers', 'Disease', (77, 84))	('high', 'Var', (17, 21))	('TMB', 'Chemical', '-', (22, 25))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('cytokine', 'Gene', '943', (48, 56))	('cytokine', 'Gene', (48, 56))	('depressed', 'NegReg', (38, 47))
508178	30634925	However, the Treg cells, immune cell infiltrate, TILs, and CCR signatures were inclined to be upregulated in the lower-TMB subtype of various cancer types, suggesting that high TMB may inhibit immune cell infiltration in the TIM.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('lower-TMB', 'Disease', (113, 122))	('immune cell infiltration in the', 'CPA', (193, 224))	('TMB', 'Chemical', '-', (119, 122))	('high TMB', 'Var', (172, 180))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('TMB', 'Chemical', '-', (177, 180))	('upregulated', 'PosReg', (94, 105))	('inhibit', 'NegReg', (185, 192))	('cancer', 'Disease', (142, 148))
508179	30634925	In contrast, the CTA and pro-inflammatory signatures tended to be upregulated in the higher-TMB subtype of various cancer types, suggesting that high TMB may promote CTA expression and tumor inflammatory response.	('tumor', 'Disease', (185, 190))	('cancer', 'Disease', (115, 121))	('CTA', 'MPA', (17, 20))	('promote', 'PosReg', (158, 165))	('upregulated', 'PosReg', (66, 77))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('expression', 'MPA', (170, 180))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('CTA', 'Protein', (166, 169))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('TMB', 'Chemical', '-', (150, 153))	('TMB', 'Chemical', '-', (92, 95))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('high', 'Var', (145, 149))
508182	30634925	In fact, when we compared survival prognosis between the lower-TMB subtype and the higher-TMB subtype of cancers, we found that the lower-TMB subtype had better OS and/or DFS prognosis than the higher-TMB subtype in three of the four cancer types including HNSC, ACC, and LIHC (Fig.	('HNSC', 'Disease', (257, 261))	('cancers', 'Phenotype', 'HP:0002664', (105, 112))	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('cancer', 'Disease', (105, 111))	('cancers', 'Disease', (105, 112))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('LIHC', 'Disease', (272, 276))	('OS', 'Chemical', '-', (161, 163))	('better', 'PosReg', (154, 160))	('TMB', 'Chemical', '-', (90, 93))	('TMB', 'Chemical', '-', (138, 141))	('TMB', 'Chemical', '-', (201, 204))	('cancer', 'Disease', 'MESH:D009369', (234, 240))	('lower-TMB', 'Var', (132, 141))	('DFS', 'MPA', (171, 174))	('ACC', 'Gene', '31', (263, 266))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('cancers', 'Disease', 'MESH:D009369', (105, 112))	('ACC', 'Gene', (263, 266))	('TMB', 'Chemical', '-', (63, 66))	('cancer', 'Disease', (234, 240))
508184	30634925	Interestingly, we found that high TMB was associated with elevated pro-inflammatory immune activity while depressed immune cell infiltration in diverse cancers.	('high', 'Var', (29, 33))	('pro-inflammatory immune activity', 'MPA', (67, 99))	('cancers', 'Disease', (152, 159))	('cancers', 'Disease', 'MESH:D009369', (152, 159))	('TMB', 'Chemical', '-', (34, 37))	('depressed immune cell', 'Phenotype', 'HP:0002721', (106, 127))	('elevated', 'PosReg', (58, 66))	('immune cell infiltration', 'CPA', (116, 140))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('depressed', 'NegReg', (106, 115))	('TMB', 'Gene', (34, 37))	('cancers', 'Phenotype', 'HP:0002664', (152, 159))
508185	30634925	These findings appear to be contradictory and disagree with the established notion that high TMB may yield numerous neoantigens that incite anti-tumor immune response.	('high', 'Var', (88, 92))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('incite', 'PosReg', (133, 139))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumor', 'Disease', (145, 150))	('TMB', 'Chemical', '-', (93, 96))	('neoantigens', 'MPA', (116, 127))
508186	30634925	The possible explanations are that high TMB is often associated with genome instability that may inhibit anti-tumor immune response, and that the increased pro-inflammatory immune activity could be attributed to the higher percent of tumor necrosis component elicited by gene mutations in the higher-TMB cancer.	('pro-inflammatory immune activity', 'MPA', (156, 188))	('inhibit', 'NegReg', (97, 104))	('tumor', 'Disease', (234, 239))	('cancer', 'Disease', (304, 310))	('TMB', 'Chemical', '-', (300, 303))	('tumor', 'Disease', 'MESH:D009369', (234, 239))	('cancer', 'Phenotype', 'HP:0002664', (304, 310))	('gene mutations', 'Var', (271, 285))	('increased', 'PosReg', (146, 155))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('tumor necrosis', 'Disease', 'MESH:D009336', (234, 248))	('cancer', 'Disease', 'MESH:D009369', (304, 310))	('tumor necrosis', 'Disease', (234, 248))	('high', 'Disease', (35, 39))	('TMB', 'Chemical', '-', (40, 43))	('tumor', 'Disease', (110, 115))	('higher', 'PosReg', (216, 222))	('higher-TMB', 'Disease', (293, 303))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
508207	30634925	High TMB was associated with elevated expression of PD-L1 in diverse prevailing cancers.	('elevated', 'PosReg', (29, 37))	('High', 'Var', (0, 4))	('cancers', 'Disease', 'MESH:D009369', (80, 87))	('expression', 'MPA', (38, 48))	('PD-L1', 'Gene', '29126', (52, 57))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancers', 'Disease', (80, 87))	('TMB', 'Chemical', '-', (5, 8))	('PD-L1', 'Gene', (52, 57))	('cancers', 'Phenotype', 'HP:0002664', (80, 87))
508210	30634925	Consistent with a method we proposed previously, the TMB score of a tumor sample was calculated as follows:  total number of truncating mutations * 2.0 + total number of non-truncating mutations * 1.0  Nonsense, frame-shift deletion or insertion, and splice-site mutations were included in the truncating mutation category, and missense, in-frame deletion or insertion, and nonstop mutations were included in the non-truncating mutation category.	('tumor', 'Disease', (68, 73))	('missense', 'Var', (328, 336))	('frame-shift deletion', 'Var', (212, 232))	('insertion', 'Var', (236, 245))	('splice-site mutations', 'Var', (251, 272))	('Nonsense', 'Var', (202, 210))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('in-frame deletion', 'Var', (338, 355))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('TMB', 'Chemical', '-', (53, 56))
508217	24615916	There is increasing evidence that a mutator phenotype perpetuates the development of many human cancers.	('cancers', 'Phenotype', 'HP:0002664', (96, 103))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('human', 'Species', '9606', (90, 95))	('cancers', 'Disease', 'MESH:D009369', (96, 103))	('perpetuates', 'Reg', (54, 65))	('cancers', 'Disease', (96, 103))	('mutator', 'Var', (36, 43))
508219	24615916	Here, we discuss mechanisms that lead to mutation cluster formation, the biological consequences of their formation in cancer and evidence suggesting that APOBEC mutagenesis can also occur genome-wide.	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('mutation', 'Var', (41, 49))	('cancer', 'Disease', (119, 125))	('C', 'Chemical', 'MESH:D002244', (160, 161))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
508220	24615916	This raises the possibility that dysregulation of these enzymes may enable rapid malignant transformation by increasing mutation rates without the loss of fitness associated with permanent mutators.	('dysregulation', 'Var', (33, 46))	('loss of fitness', 'Disease', (147, 162))	('rapid malignant transformation', 'CPA', (75, 105))	('loss of fitness', 'Disease', 'MESH:D012640', (147, 162))	('increasing', 'PosReg', (109, 119))	('mutation rates', 'MPA', (120, 134))	('enable', 'PosReg', (68, 74))
508227	24615916	In addition, recent large scale sequencing of cancer genomes has indicated that many tumors have accumulated more mutations than would be expected from the spontaneous somatic mutation rate , supporting the hypothesis that many cancers acquire a mutator phenotype that facilitates their development.	('cancers', 'Phenotype', 'HP:0002664', (228, 235))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('cancers', 'Disease', (228, 235))	('cancer', 'Disease', (228, 234))	('tumors', 'Disease', 'MESH:D009369', (85, 91))	('mutations', 'Var', (114, 123))	('cancer', 'Disease', (46, 52))	('cancers', 'Disease', 'MESH:D009369', (228, 235))	('cancer', 'Disease', 'MESH:D009369', (228, 234))	('facilitates', 'PosReg', (269, 280))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('development', 'CPA', (287, 298))	('tumors', 'Disease', (85, 91))
508228	24615916	Somatically acquired alterations of DNA repair capacity and replication fidelity appear to be relatively rare causes of increased mutation rates, occurring primarily in a subset of colorectal and endometrial cancers.	('cancers', 'Phenotype', 'HP:0002664', (208, 215))	('alterations', 'Var', (21, 32))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('DNA repair', 'Protein', (36, 46))	('mutation rates', 'MPA', (130, 144))	('colorectal and endometrial cancers', 'Disease', 'MESH:D016889', (181, 215))
508230	24615916	closely-spaced base substitutions and single nucleotide insertions or deletions) can occur simultaneously, suggesting that transiently elevated mutation rates may play an important role in carcinogenesis.	('elevated', 'PosReg', (135, 143))	('base substitutions', 'Var', (15, 33))	('play', 'Reg', (163, 167))	('carcinogenesis', 'Disease', 'MESH:D063646', (189, 203))	('single nucleotide insertions', 'Var', (38, 66))	('carcinogenesis', 'Disease', (189, 203))	('deletions', 'Var', (70, 79))	('mutation rates', 'MPA', (144, 158))
508235	24615916	Exposure to UV light or the base alkylating agent methyl methanesulfonate (MMS) strongly increased CAN1 mutation frequencies near DSBs.	('CAN1', 'Gene', (99, 103))	('mutation', 'Var', (104, 112))	('MMS', 'Chemical', 'MESH:D008741', (75, 78))	('methyl methanesulfonate', 'Chemical', 'MESH:D008741', (50, 73))	('increased', 'PosReg', (89, 98))	('DSBs', 'Chemical', 'MESH:C007563', (130, 134))	('C', 'Chemical', 'MESH:D002244', (99, 100))
508236	24615916	Sequencing of UV-induced CAN1 mutations provided further support to the notion that lesions in ssDNA initiate hyper-mutability.	('ssDNA', 'Disease', (95, 100))	('mutations', 'Var', (30, 39))	('CAN1', 'Gene', (25, 29))	('C', 'Chemical', 'MESH:D002244', (25, 26))
508237	24615916	In this system, the UV light induced strand biased mutations occurring exclusively at pyrimidines 5' of the DSB and at purines 3' of the DSB.	('mutations', 'Var', (51, 60))	('pyrimidines', 'Var', (86, 97))	('pyrimidines', 'Chemical', 'MESH:D011743', (86, 97))	('DSB', 'Chemical', '-', (137, 140))	('purines', 'Chemical', 'MESH:D011687', (119, 126))	('DSB', 'Chemical', '-', (108, 111))
508239	24615916	MMS produced a similar switching of strand bias spectra (mutated cytosines 5' of the DSB and guanines 3' of the DSB), consistent with the mutations being induced by a single-strand-specific lesion, N3-methyl cytosine.	('DSB', 'Chemical', '-', (85, 88))	('N3-methyl', 'Var', (198, 207))	('MMS', 'Chemical', 'MESH:D008741', (0, 3))	('DSB', 'Chemical', '-', (112, 115))	('strand bias spectra', 'MPA', (36, 55))	('MMS', 'Var', (0, 3))	('guanines', 'Chemical', 'MESH:D006147', (93, 101))	('guanines', 'MPA', (93, 101))	('N3-methyl cytosine', 'Chemical', 'MESH:C036386', (198, 216))	('switching', 'Reg', (23, 32))	('cytosines', 'Chemical', 'MESH:D003596', (65, 74))
508241	24615916	Sub-telomeric locations prone to telomere uncapping and consequently single strandedness have been shown to be mutagenized by UV light, MMS, and even APOBEC3G cytidine deaminase in a manner consistent with lesion accumulation in the persisting DNA strand.	('MMS', 'Chemical', 'MESH:D008741', (136, 139))	('telomere', 'Protein', (33, 41))	('single', 'Var', (69, 75))	('mutagenized', 'Var', (111, 122))	('APOBEC3G', 'Gene', (150, 158))	('APOBEC3G', 'Gene', '60489', (150, 158))
508242	24615916	In mammalian B-cells, hypermutation of chromosomal DNA is strongly linked to ssDNA formed during transcription.	('DNA', 'Gene', (51, 54))	('hypermutation', 'Var', (22, 35))	('linked', 'Reg', (67, 73))	('ssDNA formed during', 'Disease', (77, 96))	('mammalian', 'Species', '9606', (3, 12))
508249	24615916	Other AID/APOBEC family members share AID's specificity for ssDNA , the ability to deaminate ssDNA in transcription bubbles in vitro, and the ability to damage nuclear DNA, hence leading to elevated mutation rates.	('deaminate', 'Var', (83, 92))	('C', 'Chemical', 'MESH:D002244', (15, 16))	('elevated', 'PosReg', (190, 198))	('damage', 'Reg', (153, 159))	('nuclear DNA', 'Protein', (160, 171))	('mutation rates', 'MPA', (199, 213))
508251	24615916	Selection of MMS-induced mutations in closely-spaced URA3 and CAN1 genes revealed large regions of hypermutation.	('C', 'Chemical', 'MESH:D002244', (62, 63))	('mutations', 'Var', (25, 34))	('URA3', 'Gene', (53, 57))	('MMS', 'Chemical', 'MESH:D008741', (13, 16))	('CAN1', 'Gene', (62, 66))
508252	24615916	Moreover, an excess of mutated C:G pairs in clusters compared to mutations in the rest of the genome also implied the contribution of the ssDNA-specific N3-methyl cytosine lesion in cluster formation.	('C', 'Chemical', 'MESH:D002244', (31, 32))	('C:G pairs', 'Protein', (31, 40))	('excess', 'PosReg', (13, 19))	('N3-methyl cytosine', 'Chemical', 'MESH:C036386', (153, 171))	('mutated', 'Var', (23, 30))
508253	24615916	One subset of clusters again identified homology-directed DSB repair as a likely source of ssDNA targeted for hyper-mutation and simultaneous mutations.	('DSB', 'Chemical', '-', (58, 61))	('mutations', 'Var', (142, 151))	('hyper-mutation', 'Var', (110, 124))	('ssDNA', 'Disease', (91, 96))
508256	24615916	However, the lengths of these mutation clusters imply that these repair processes occasionally generate ssDNA regions up to 100 kbps long, even without a genetic deficiency in homologous recombination, which are known to produce ssDNA regions tens of kbps long.	('ssDNA', 'Disease', (104, 109))	('mutation', 'Var', (30, 38))	('genetic deficiency', 'Disease', (154, 172))	('genetic deficiency', 'Disease', 'MESH:D030342', (154, 172))
508257	24615916	Along with DSB repair, MMS can also induce clustered mutations associated with destabilized replication forks.	('MMS', 'Var', (23, 26))	('DSB', 'Chemical', '-', (11, 14))	('clustered', 'MPA', (43, 52))	('MMS', 'Chemical', 'MESH:D008741', (23, 26))	('induce', 'Reg', (36, 42))
508258	24615916	Ablation of either TOF1 or CSM3, members of the replication fork protection complex, increased the frequency of strand-coordinated mutation clusters which additionally displayed mutational strand biases dependent on the direction of replication through the area where clusters were selected.	('CSM3', 'Gene', (27, 31))	('C', 'Chemical', 'MESH:D002244', (27, 28))	('displayed', 'Reg', (168, 177))	('TOF1', 'Gene', (19, 23))	('Ablation', 'Var', (0, 8))	('increased', 'PosReg', (85, 94))	('strand-coordinated', 'MPA', (112, 130))	('mutation', 'Var', (131, 139))
508264	24615916	found that several tumors contained multiple mutations in the LacZ gene.	('LacZ', 'Gene', (62, 66))	('tumors', 'Disease', (19, 25))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('mutations', 'Var', (45, 54))	('contained', 'Reg', (26, 35))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))
508266	24615916	Groups of 2 or more mutations whose spacing was unlikely based on random mutagenesis (Figure 3) have been found among multiple myeloma, prostate, head-and-neck cancers, and colorectal cancers.	('cancers', 'Phenotype', 'HP:0002664', (184, 191))	('head-and-neck cancers', 'Disease', 'MESH:D006258', (146, 167))	('cancers', 'Phenotype', 'HP:0002664', (160, 167))	('multiple myeloma', 'Disease', 'MESH:D009101', (118, 134))	('multiple myeloma', 'Phenotype', 'HP:0006775', (118, 134))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('prostate', 'Disease', (136, 144))	('multiple myeloma', 'Disease', (118, 134))	('head-and-neck cancers', 'Disease', (146, 167))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('colorectal cancers', 'Disease', 'MESH:D015179', (173, 191))	('colorectal cancers', 'Disease', (173, 191))	('mutations', 'Var', (20, 29))
508267	24615916	Further evaluation of mutation spectra, revealed these clusters existed in three classes based on stand-coordination (A- or T-coordinated, C- or G-coordinated, and non-coordinated), the non-coordinated class predominating.	('C- or G-coordinated', 'Var', (139, 158))	('C', 'Chemical', 'MESH:D002244', (139, 140))	('A-', 'Var', (118, 120))
508270	24615916	Supporting this, these clusters were composed primarily of mutated cytosines in the sequence context of WRC (all mutation contexts include the complementary sequence; mutated base is underlined; W = adenine or thymine; R = adenine or guanine) and mutated adenines in the context of WA.	('adenine', 'Chemical', 'MESH:D000225', (199, 206))	('adenine', 'Chemical', 'MESH:D000225', (255, 262))	('guanine', 'Chemical', 'MESH:D006147', (234, 241))	('C', 'Chemical', 'MESH:D002244', (106, 107))	('adenine', 'Chemical', 'MESH:D000225', (223, 230))	('cytosines', 'Chemical', 'MESH:D003596', (67, 76))	('thymine', 'Chemical', 'MESH:D013941', (210, 217))	('adenines', 'Chemical', 'MESH:D000225', (255, 263))	('mutated', 'Var', (247, 254))	('mutated', 'Var', (59, 66))
508271	24615916	We identified clustered mutations displaying C- or G-coordination in random locations of whole-genome sequenced tumors from four cancer types: multiple myeloma, prostate, head-and-neck, and colorectal cancers.	('cancers', 'Phenotype', 'HP:0002664', (201, 208))	('cancer', 'Disease', (201, 207))	('C', 'Chemical', 'MESH:D002244', (45, 46))	('cancer', 'Disease', (129, 135))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('mutations', 'Var', (24, 33))	('tumors', 'Disease', 'MESH:D009369', (112, 118))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('multiple myeloma', 'Disease', (143, 159))	('colorectal cancers', 'Disease', (190, 208))	('colorectal cancers', 'Disease', 'MESH:D015179', (190, 208))	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('multiple myeloma', 'Phenotype', 'HP:0006775', (143, 159))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('prostate', 'Disease', (161, 169))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('multiple myeloma', 'Disease', 'MESH:D009101', (143, 159))	('head-and-neck', 'Disease', (171, 184))	('tumors', 'Disease', (112, 118))
508272	24615916	This class of clustered mutations was composed almost exclusively of mutations occurring at the tri-nucleotide DNA sequence, TCW, suggesting that an enzymatic activity may be involved in this mutagenesis.	('mutations', 'Var', (69, 78))	('TCW', 'Gene', (125, 128))	('tri-nucleotide', 'Chemical', '-', (96, 110))	('mutations', 'Var', (24, 33))	('TCW', 'Chemical', '-', (125, 128))
508273	24615916	The nearly exclusive substitution of the mutated cytosine by either T or G, suggested that this mechanism may also involve error-prone trans-lesion synthesis past abasic sites , which can be generated by glycolytic removal of a damaged base.	('trans-lesion synthesis', 'MPA', (135, 157))	('cytosine', 'Chemical', 'MESH:D003596', (49, 57))	('substitution', 'Var', (21, 33))	('mutated', 'Var', (41, 48))
508280	24615916	These features all correlate with a potential role in mutagenizing ssDNA DSB repair intermediates.	('DSB', 'Chemical', '-', (73, 76))	('ssDNA DSB', 'Disease', (67, 76))	('mutagenizing', 'Var', (54, 66))
508281	24615916	Additional mechanistic studies further indicate that APOBEC cytidine deaminases indeed have the biological capacity to generate mutation clusters by targeting induced as well as naturally occurring ssDNA regions.	('mutation', 'Var', (128, 136))	('targeting', 'Reg', (149, 158))	('ssDNA', 'Disease', (198, 203))	('C', 'Chemical', 'MESH:D002244', (58, 59))
508284	24615916	The role of this processivity in generating the observed clustered TCW mutations in human cancer, however, is currently unclear as this feature appears to not be universal among APOBEC enzymes that target TCW sequences.	('TCW', 'Gene', (67, 70))	('C', 'Chemical', 'MESH:D002244', (206, 207))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('C', 'Chemical', 'MESH:D002244', (183, 184))	('mutations', 'Var', (71, 80))	('human', 'Species', '9606', (84, 89))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('TCW', 'Chemical', '-', (67, 70))	('cancer', 'Disease', (90, 96))	('C', 'Chemical', 'MESH:D002244', (68, 69))	('TCW', 'Chemical', '-', (205, 208))
508287	24615916	Expression of human APOBEC3G has been shown to induce multiple C to T and C to G mutations while excluding C to A transversions within regions of ssDNA through Ung1 mediated conversion of deoxyuridine to abasic sites and subsequent pol zeta and REV1 dependent error-prone trans-lesion synthesis.	('Ung1', 'Gene', (160, 164))	('C', 'Chemical', 'MESH:D002244', (107, 108))	('C to G', 'Gene', (74, 80))	('C to T', 'Disease', (63, 69))	('REV1', 'Gene', '51455', (245, 249))	('APOBEC3G', 'Gene', '60489', (20, 28))	('human', 'Species', '9606', (14, 19))	('REV1', 'Gene', (245, 249))	('Ung1', 'Gene', '7374', (160, 164))	('error-prone trans-lesion synthesis', 'MPA', (260, 294))	('induce', 'Reg', (47, 53))	('C', 'Chemical', 'MESH:D002244', (74, 75))	('deoxyuridine', 'Chemical', 'MESH:D003857', (188, 200))	('conversion', 'MPA', (174, 184))	('mutations', 'Var', (81, 90))	('APOBEC3G', 'Gene', (20, 28))	('C', 'Chemical', 'MESH:D002244', (63, 64))	('C', 'Chemical', 'MESH:D002244', (25, 26))
508288	24615916	Moreover, expressing hyper-active mutants of human AID and APOBEC3G and lamprey APOBEC  in yeast directly induces clustered strand-coordinated mutations.	('APOBEC3G', 'Gene', (59, 67))	('mutants', 'Var', (34, 41))	('induces', 'Reg', (106, 113))	('APOBEC3G', 'Gene', '60489', (59, 67))	('yeast', 'Species', '4932', (91, 96))	('clustered strand-coordinated mutations', 'MPA', (114, 152))	('human', 'Species', '9606', (45, 50))	('APOBEC', 'Gene', (80, 86))	('C', 'Chemical', 'MESH:D002244', (85, 86))	('C', 'Chemical', 'MESH:D002244', (64, 65))	('hyper-active', 'Phenotype', 'HP:0000752', (21, 33))
508290	24615916	reported similar strand-coordinated clustering of mutated cytosines among 21 whole-genome sequenced breast cancers.	('cytosines', 'Chemical', 'MESH:D003596', (58, 67))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('breast cancers', 'Phenotype', 'HP:0003002', (100, 114))	('breast cancers', 'Disease', 'MESH:D001943', (100, 114))	('mutated', 'Var', (50, 57))	('breast cancers', 'Disease', (100, 114))	('breast cancer', 'Phenotype', 'HP:0003002', (100, 113))	('cancers', 'Phenotype', 'HP:0002664', (107, 114))
508291	24615916	As with the clustered mutations observed in multiple myeloma, prostate, head-and-neck, and colorectal cancers, kataegis events were composed of strand-coordinated substitutions of cytosine to either thymine or guanine, primarily within the trinucleotide sequence of TpCpX (X = any nucleotide).	('cytosine', 'Chemical', 'MESH:D003596', (180, 188))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('colorectal cancers', 'Disease', (91, 109))	('trinucleotide', 'Chemical', '-', (240, 253))	('substitutions', 'Var', (163, 176))	('guanine', 'Chemical', 'MESH:D006147', (210, 217))	('head-and-neck', 'Disease', (72, 85))	('TpCpX', 'Chemical', '-', (266, 271))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))	('cytosine', 'Protein', (180, 188))	('thymine', 'Chemical', 'MESH:D013941', (199, 206))	('multiple myeloma', 'Phenotype', 'HP:0006775', (44, 60))	('multiple myeloma', 'Disease', 'MESH:D009101', (44, 60))	('multiple myeloma', 'Disease', (44, 60))	('colorectal cancers', 'Disease', 'MESH:D015179', (91, 109))
508292	24615916	Recent evaluation of 507 sequenced tumor genomes identified kataegis in lung adenocarcinoma, liver cancer, B-cell lymphoma, acute lymphoid leukemia, pancreatic cancer, chronic lymphoid leukemia, and medulloblastoma , indicating that while such events are rare in each sample, they are spread across a large variety of cancer types.	('cancer', 'Disease', (318, 324))	('liver cancer', 'Phenotype', 'HP:0002896', (93, 105))	('medulloblastoma', 'Disease', 'MESH:D008527', (199, 214))	('pancreatic cancer', 'Disease', 'MESH:D010190', (149, 166))	('cancer', 'Phenotype', 'HP:0002664', (318, 324))	('medulloblastoma', 'Phenotype', 'HP:0002885', (199, 214))	('liver cancer', 'Disease', (93, 105))	('medulloblastoma', 'Disease', (199, 214))	('lymphoid leukemia', 'Phenotype', 'HP:0005526', (130, 147))	('chronic lymphoid leukemia', 'Phenotype', 'HP:0005550', (168, 193))	('cancer', 'Disease', (160, 166))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('B-cell lymphoma', 'Disease', 'MESH:D016393', (107, 122))	('acute lymphoid leukemia', 'Disease', 'MESH:D054198', (124, 147))	('tumor', 'Disease', (35, 40))	('lymphoid leukemia', 'Phenotype', 'HP:0005526', (176, 193))	('pancreatic cancer', 'Disease', (149, 166))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('acute lymphoid leukemia', 'Phenotype', 'HP:0006721', (124, 147))	('kataegis', 'Var', (60, 68))	('acute lymphoid leukemia', 'Disease', (124, 147))	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('cancer', 'Disease', 'MESH:D009369', (318, 324))	('lung adenocarcinoma', 'Disease', (72, 91))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (107, 122))	('chronic lymphoid leukemia', 'Disease', 'MESH:D007945', (168, 193))	('leukemia', 'Phenotype', 'HP:0001909', (139, 147))	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (149, 166))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (72, 91))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('leukemia', 'Phenotype', 'HP:0001909', (185, 193))	('B-cell lymphoma', 'Disease', (107, 122))	('liver cancer', 'Disease', 'MESH:D006528', (93, 105))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('cancer', 'Disease', (99, 105))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (72, 91))	('lymphoma', 'Phenotype', 'HP:0002665', (114, 122))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('chronic lymphoid leukemia', 'Disease', (168, 193))
508293	24615916	Analysis of exome sequenced cancers has likewise identified strand-coordinated clustered TCW mutations within a wide variety of cancer types.	('cancers', 'Disease', (28, 35))	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('mutations', 'Var', (93, 102))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('TCW', 'Chemical', '-', (89, 92))	('TCW', 'Gene', (89, 92))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('cancers', 'Phenotype', 'HP:0002664', (28, 35))	('cancer', 'Disease', (28, 34))	('cancers', 'Disease', 'MESH:D009369', (28, 35))	('cancer', 'Disease', (128, 134))
508294	24615916	As seen in whole genome sequenced cancers, TCW clusters were identified in head-and-neck, prostate, and breast cancers among mutations from 2680 exome sequenced cancers, primarily from The Cancer Genome Atlas (TCGA).	('cancers', 'Disease', 'MESH:D009369', (111, 118))	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('cancers', 'Phenotype', 'HP:0002664', (161, 168))	('cancers', 'Phenotype', 'HP:0002664', (34, 41))	('cancers', 'Disease', (161, 168))	('head-and-neck', 'Disease', (75, 88))	('cancers', 'Disease', (34, 41))	('TCW', 'Chemical', '-', (43, 46))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (189, 208))	('cancers', 'Phenotype', 'HP:0002664', (111, 118))	('mutations', 'Var', (125, 134))	('TC', 'Chemical', 'MESH:D013667', (43, 45))	('cancers', 'Disease', (111, 118))	('breast cancers', 'Disease', 'MESH:D001943', (104, 118))	('Cancer Genome Atlas', 'Disease', (189, 208))	('breast cancers', 'Disease', (104, 118))	('cancers', 'Disease', 'MESH:D009369', (161, 168))	('TC', 'Chemical', 'MESH:D013667', (210, 212))	('cancers', 'Disease', 'MESH:D009369', (34, 41))	('breast cancers', 'Phenotype', 'HP:0003002', (104, 118))	('Cancer', 'Phenotype', 'HP:0002664', (189, 195))	('breast cancer', 'Phenotype', 'HP:0003002', (104, 117))	('prostate', 'Disease', (90, 98))
508296	24615916	Despite the widespread observation of C- or G-coordinated mutation clusters in 13 distinctly different tumor types, the frequency at which such events occur is heavily dependent upon cancer type: bladder, cervical, head-and-neck, breast, lung adenocarcinoma, and lung squamous cell carcinoma are clearly enriched in such clusters compared with other cancer types where these clusters appear to occur at a background level (Table 1).	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('breast', 'Disease', (230, 236))	('cancer', 'Disease', (350, 356))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (263, 291))	('bladder', 'Disease', (196, 203))	('cancer', 'Phenotype', 'HP:0002664', (350, 356))	('cancer', 'Disease', (183, 189))	('mutation', 'Var', (58, 66))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (263, 291))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (268, 291))	('lung squamous cell carcinoma', 'Disease', (263, 291))	('tumor', 'Disease', (103, 108))	('cancer', 'Disease', 'MESH:D009369', (350, 356))	('lung adenocarcinoma', 'Disease', (238, 257))	('head-and-neck', 'Disease', (215, 228))	('cervical', 'Disease', (205, 213))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('C', 'Chemical', 'MESH:D002244', (38, 39))	('cancer', 'Disease', 'MESH:D009369', (183, 189))	('carcinoma', 'Phenotype', 'HP:0030731', (282, 291))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (238, 257))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (238, 257))	('carcinoma', 'Phenotype', 'HP:0030731', (248, 257))
508297	24615916	The biological impact of clustered mutations, especially in terms of cancer development, is currently unknown.	('clustered', 'Var', (25, 34))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Disease', (69, 75))
508298	24615916	While multiple mutations are necessary to deregulate cell growth and proliferation, genes whose alterations are causative in cancer are distributed across the human genome.	('cell growth', 'CPA', (53, 64))	('mutations', 'Var', (15, 24))	('deregulate', 'Reg', (42, 52))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('human', 'Species', '9606', (159, 164))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))
508299	24615916	Consequently, the inactivation of multiple cancer drivers by a single mutation cluster is unlikely, and limits the potential carcinogenic roles of this type of transient hyper-mutation to 1) increasing the likelihood an individual tumor suppressor is inactivated by a single mutagenic event, 2) inducing multiple mutations jointly required for activating an oncogene, or 3) altering the functionally of regulatory sequences.	('tumor', 'Disease', 'MESH:D009369', (231, 236))	('increasing', 'PosReg', (191, 201))	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('cancer', 'Disease', (43, 49))	('altering', 'Reg', (374, 382))	('tumor', 'Disease', (231, 236))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('mutation', 'Var', (70, 78))	('carcinogenic', 'Disease', 'MESH:D063646', (125, 137))	('inducing', 'Reg', (295, 303))	('carcinogenic', 'Disease', (125, 137))
508300	24615916	Thus, damage to multiple, simultaneously occurring ssDNA regions may establish a global transient hypermutation, a subset of which may be synergistic mutational events that provide a significant growth advantage for cancer cells.	('damage', 'Var', (6, 12))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('transient hypermutation', 'MPA', (88, 111))	('cancer', 'Disease', (216, 222))	('cancer', 'Disease', 'MESH:D009369', (216, 222))	('growth advantage', 'CPA', (195, 211))
508301	24615916	The AID/APOBEC-induced mutations are prime candidates for generating genome-wide "mutation storms" that could initiate or promote cancer.	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('cancer', 'Disease', (130, 136))	('mutations', 'Var', (23, 32))	('promote', 'PosReg', (122, 129))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('initiate', 'PosReg', (110, 118))	('C', 'Chemical', 'MESH:D002244', (13, 14))
508302	24615916	Beyond commonly inducing clustered TCW mutations in a variety of human tumors, several AID/APOBEC family members have been shown to directly induce cancer.	('cancer', 'Disease', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('C', 'Chemical', 'MESH:D002244', (96, 97))	('human', 'Species', '9606', (65, 70))	('induce', 'Reg', (141, 147))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('mutations', 'Var', (39, 48))	('TCW', 'Chemical', '-', (35, 38))	('C', 'Chemical', 'MESH:D002244', (36, 37))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('tumors', 'Phenotype', 'HP:0002664', (71, 77))	('tumors', 'Disease', (71, 77))	('TCW', 'Gene', (35, 38))	('inducing', 'Reg', (16, 24))	('tumors', 'Disease', 'MESH:D009369', (71, 77))
508309	24615916	bladder, cervical, head-and-neck, breast, lung adenocarcinoma, and lung squamous cell carcinoma) also frequently display dramatic over-representation of scattered mutations occurring in the TCW motif.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (72, 95))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (42, 61))	('TCW', 'Chemical', '-', (190, 193))	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (52, 61))	('mutations', 'Var', (163, 172))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (42, 61))	('over-representation', 'PosReg', (130, 149))	('head-and-neck', 'Disease', (19, 32))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (67, 95))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (67, 95))	('lung squamous cell carcinoma', 'Disease', (67, 95))	('breast', 'Disease', (34, 40))	('lung adenocarcinoma', 'Disease', (42, 61))
508310	24615916	Moreover, this method highlighted the increased presence of TCW mutagenesis in one molecular subtype of breast cancer, HER2-enriched, suggesting that mutagenesis can be associated with specific features of tumor development.	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('TCW', 'Chemical', '-', (60, 63))	('tumor', 'Disease', (206, 211))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('breast cancer', 'Disease', 'MESH:D001943', (104, 117))	('associated', 'Reg', (169, 179))	('breast cancer', 'Disease', (104, 117))	('TCW mutagenesis', 'Var', (60, 75))	('breast cancer', 'Phenotype', 'HP:0003002', (104, 117))	('mutagenesis', 'Var', (64, 75))	('tumor', 'Disease', 'MESH:D009369', (206, 211))
508311	24615916	Complementary de novo pattern recognition analysis of mutations in 7042 tumors similarly identified APOBEC mutagenesis as a prominent mutation signature in 16 of 30 cancer types analyzed , including the 6 cancer types previously highlighted in the hypothesis-driven TCGA analyses; all together these works establish APOBEC enzymes as one of the most widespread mutational forces during cancer progression.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('cancer', 'Disease', 'MESH:D009369', (205, 211))	('tumors', 'Disease', (72, 78))	('C', 'Chemical', 'MESH:D002244', (321, 322))	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('cancer', 'Disease', 'MESH:D009369', (386, 392))	('mutations', 'Var', (54, 63))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('C', 'Chemical', 'MESH:D002244', (105, 106))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('TC', 'Chemical', 'MESH:D013667', (266, 268))	('mutagenesis', 'Var', (107, 118))	('cancer', 'Disease', (205, 211))	('cancer', 'Disease', (165, 171))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('cancer', 'Disease', (386, 392))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('APOBEC', 'Gene', (100, 106))	('C', 'Chemical', 'MESH:D002244', (267, 268))	('cancer', 'Phenotype', 'HP:0002664', (386, 392))
508312	24615916	Why specific cancer types display such strong mutagenesis at the TCW motif is currently unclear.	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('cancer', 'Disease', (13, 19))	('mutagenesis', 'Var', (46, 57))	('cancer', 'Disease', 'MESH:D009369', (13, 19))	('TCW', 'Chemical', '-', (65, 68))
508315	24615916	Importantly, this deaminase specifically targets cytidines in the TCW context, consistent with the over-representation of mutations in TCW within both mutation clusters and whole-exomes of some breast cancer samples.	('TCW', 'Gene', (135, 138))	('TCW', 'Chemical', '-', (66, 69))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('mutations', 'Var', (122, 131))	('TCW', 'Chemical', '-', (135, 138))	('breast cancer', 'Disease', 'MESH:D001943', (194, 207))	('breast cancer', 'Disease', (194, 207))	('cytidines', 'Chemical', 'MESH:D003562', (49, 58))	('breast cancer', 'Phenotype', 'HP:0003002', (194, 207))
508317	24615916	This relation implied that APOBEC3B is responsible for the overwhelming mutation of TCW in multiple cancer types and that its expression is one factor dictating the extent to which this mutation pattern occurs.	('TCW', 'Chemical', '-', (84, 87))	('TCW', 'Gene', (84, 87))	('responsible', 'Reg', (39, 50))	('APOBEC3B', 'Gene', (27, 35))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('APOBEC3B', 'Gene', '9582', (27, 35))	('mutation', 'Var', (72, 80))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))
508319	24615916	Expression of several APOBECs can correlate with the number of TCW mutations across multiple cancer samples (although lesser so than 3B)  and polymorphic deletion of APOBEC3B results in an increase in breast and liver cancers, suggesting a complicated relationship between the APOBEC enzymes, TCW mutagenesis and cancer incidence.	('liver cancer', 'Phenotype', 'HP:0002896', (212, 224))	('C', 'Chemical', 'MESH:D002244', (282, 283))	('cancers', 'Phenotype', 'HP:0002664', (218, 225))	('cancer', 'Phenotype', 'HP:0002664', (313, 319))	('increase', 'PosReg', (189, 197))	('cancer', 'Disease', 'MESH:D009369', (218, 224))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('C', 'Chemical', 'MESH:D002244', (27, 28))	('TCW', 'Gene', (63, 66))	('cancer', 'Disease', 'MESH:D009369', (313, 319))	('APOBEC3B', 'Gene', (166, 174))	('breast and liver cancers', 'Disease', 'MESH:D006528', (201, 225))	('TCW', 'Chemical', '-', (63, 66))	('C', 'Chemical', 'MESH:D002244', (294, 295))	('C', 'Chemical', 'MESH:D002244', (64, 65))	('TCW', 'Chemical', '-', (293, 296))	('liver cancers', 'Phenotype', 'HP:0002896', (212, 225))	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', (218, 224))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('mutations', 'Var', (67, 76))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('C', 'Chemical', 'MESH:D002244', (171, 172))	('polymorphic deletion', 'Var', (142, 162))	('cancer', 'Disease', (313, 319))	('APOBEC3B', 'Gene', '9582', (166, 174))
508328	24615916	APOBEC1 specificity for the C6666 of the apoB mRNA is enhanced by an auxiliary protein, ACF1; however the extent to which similar co-factors or post-translational modifications limit other APOBECs' access to chromosomal DNA is unknown.	('C', 'Chemical', 'MESH:D002244', (28, 29))	('C', 'Chemical', 'MESH:D002244', (194, 195))	('apoB', 'Gene', (41, 45))	('apoB', 'Gene', '338', (41, 45))	('C', 'Chemical', 'MESH:D002244', (5, 6))	('specificity', 'MPA', (8, 19))	('C6666', 'Var', (28, 33))	('APOBEC1', 'Gene', (0, 7))	('ACF1', 'Gene', (88, 92))	('C', 'Chemical', 'MESH:D002244', (89, 90))	('ACF1', 'Gene', '11177', (88, 92))	('enhanced', 'PosReg', (54, 62))
508337	24615916	An increased availability of ssDNA substrate is an additional parameter that may also contribute strongly to the number of TCW mutations in a sample.	('TCW', 'Gene', (123, 126))	('mutations', 'Var', (127, 136))	('TCW', 'Chemical', '-', (123, 126))
508338	24615916	The enrichment of both clustered and scattered TCW mutations near chromosome rearrangement breakpoints suggests that the formation of ssDNA, potentially during aberrant DNA DSB repair is likely a limiting factor for APOBEC-induced mutagenesis.	('C', 'Chemical', 'MESH:D002244', (48, 49))	('mutations', 'Var', (51, 60))	('C', 'Chemical', 'MESH:D002244', (221, 222))	('TCW', 'Chemical', '-', (47, 50))	('TCW', 'Gene', (47, 50))	('DSB', 'Chemical', '-', (173, 176))
508342	24615916	However, the number of segmental copy number alterations (a surrogate measure of the number of DSBs) failed to correlate with the total number of TCW mutations in 449 breast cancer samples, indicating that DSBs may be a minor source of the ssDNA target dictating the extent of genome-wide TCW mutagenesis.	('breast cancer', 'Disease', (167, 180))	('DSBs', 'Chemical', 'MESH:C007563', (206, 210))	('breast cancer', 'Phenotype', 'HP:0003002', (167, 180))	('mutagenesis', 'Var', (293, 304))	('TCW', 'Chemical', '-', (289, 292))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('TCW', 'Chemical', '-', (146, 149))	('breast cancer', 'Disease', 'MESH:D001943', (167, 180))	('DSBs', 'Chemical', 'MESH:C007563', (95, 99))
508343	24615916	Altered levels of transcription during tumor progression could either increase the amount of ssDNA or formation of stable R-loops and G-quadruplexes that can serve as AID/APOBEC substrates.	('increase', 'PosReg', (70, 78))	('G-quadruplexes', 'Var', (134, 148))	('C', 'Chemical', 'MESH:D002244', (176, 177))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('R-loops', 'Protein', (122, 129))	('Altered', 'Var', (0, 7))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumor', 'Disease', (39, 44))	('ssDNA', 'MPA', (93, 98))
508345	24615916	During normal replication, RPA may limit the ability of some APOBECs to induce mutations.	('RPA', 'Gene', (27, 30))	('C', 'Chemical', 'MESH:D002244', (66, 67))	('limit', 'NegReg', (35, 40))	('RPA', 'Gene', '6117', (27, 30))	('ability', 'MPA', (45, 52))	('APOBECs', 'Protein', (61, 68))	('mutations', 'Var', (79, 88))
508346	24615916	However in yeast, genetic perturbation of the replication fork increases both general mutagenesis, as well as the incidence of clustered mutations originating from damaged ssDNA.	('increases', 'PosReg', (63, 72))	('yeast', 'Species', '4932', (11, 16))	('clustered', 'Var', (127, 136))	('genetic perturbation', 'Var', (18, 38))	('general mutagenesis', 'MPA', (78, 97))
508347	24615916	APOBEC deamination of ssDNA during replication may have a profound impact on carcinogenesis.	('impact', 'Reg', (67, 73))	('carcinogenesis', 'Disease', 'MESH:D063646', (77, 91))	('carcinogenesis', 'Disease', (77, 91))	('deamination', 'Var', (7, 18))	('C', 'Chemical', 'MESH:D002244', (5, 6))
508348	24615916	The enhanced proliferation of cancer cells would itself increase the total APOBEC mutational load accumulated in cells by simply increasing the number of genome replications that have occurred.	('proliferation', 'CPA', (13, 26))	('increase', 'PosReg', (56, 64))	('APOBEC', 'Gene', (75, 81))	('increasing', 'PosReg', (129, 139))	('enhanced', 'PosReg', (4, 12))	('cancer', 'Disease', (30, 36))	('C', 'Chemical', 'MESH:D002244', (80, 81))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('mutational', 'Var', (82, 92))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
508351	24615916	The large amount of persistent ssDNA formed during this oncogene-induced senescent state would serve as an ideal target for APOBEC enzymes and could thereby lead to inactivation of multiple genes that contribute to the DNA damage barrier to tumorigenesis.	('genes', 'Gene', (190, 195))	('tumor', 'Disease', (241, 246))	('inactivation', 'Var', (165, 177))	('lead to', 'Reg', (157, 164))	('tumor', 'Disease', 'MESH:D009369', (241, 246))	('C', 'Chemical', 'MESH:D002244', (129, 130))	('tumor', 'Phenotype', 'HP:0002664', (241, 246))
508353	24615916	Specifically, databases of p53 mutations are statistically enriched in alterations at the sequence TC, and most TCW mutations occur late during breast cancer progression when a senescent barrier would likely be inactivated.	('mutations', 'Var', (31, 40))	('occur', 'Reg', (126, 131))	('breast cancer', 'Disease', 'MESH:D001943', (144, 157))	('p53', 'Gene', '7157', (27, 30))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('TCW', 'Chemical', '-', (112, 115))	('breast cancer', 'Disease', (144, 157))	('TC', 'Chemical', 'MESH:D013667', (112, 114))	('TC', 'Chemical', 'MESH:D013667', (99, 101))	('breast cancer', 'Phenotype', 'HP:0003002', (144, 157))	('TCW', 'Gene', (112, 115))	('alterations', 'Var', (71, 82))	('mutations', 'Var', (116, 125))	('p53', 'Gene', (27, 30))
508354	24615916	Moreover, tumor samples that have experienced significant TCW mutagenesis are frequent among cancer subtypes associated with amplification of the HER2 oncogene, which is known to induce an ATM dependent DNA damage response and senescence in mouse tumors.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('tumor', 'Phenotype', 'HP:0002664', (247, 252))	('cancer', 'Disease', (93, 99))	('amplification', 'Var', (125, 138))	('HER2 oncogene', 'Gene', (146, 159))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('tumors', 'Disease', (247, 253))	('tumors', 'Disease', 'MESH:D009369', (247, 253))	('tumor', 'Disease', (10, 15))	('tumor', 'Disease', (247, 252))	('mouse', 'Species', '10090', (241, 246))	('tumors', 'Phenotype', 'HP:0002664', (247, 253))	('TCW', 'Chemical', '-', (58, 61))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('tumor', 'Disease', 'MESH:D009369', (247, 252))
508356	24615916	We speculate that the impact of such mutational bursts in promoting tumorigenesis may differ from endogenous mutators caused by genetic defects.	('tumor', 'Disease', (68, 73))	('mutational', 'Var', (37, 47))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('genetic defects', 'Disease', 'MESH:D030342', (128, 143))	('genetic defects', 'Disease', (128, 143))
508357	24615916	APOBEC mutagenesis combines the features of an endogenous mutagen with those associated with momentary exposure to exogenous environmental agents or drugs.	('APOBEC', 'Gene', (0, 6))	('C', 'Chemical', 'MESH:D002244', (5, 6))	('mutagenesis', 'Var', (7, 18))
508358	24615916	Importantly, transient hypermutation may be more carcinogenic than the sustained mutagenesis associated with moderate permanent mutators.	('carcinogenic', 'Disease', 'MESH:D063646', (49, 61))	('transient hypermutation', 'Var', (13, 36))	('carcinogenic', 'Disease', (49, 61))
508359	24615916	While both types of mutagenesis would produce similar number of mutations over large periods of time, transient hypermutation can rapidly generate multiple mutations which can overcome multilayer growth control mechanisms and promote carcinogenic growth.	('ds', 'Chemical', 'MESH:D003903', (90, 92))	('carcinogenic growth', 'Disease', 'MESH:D006130', (234, 253))	('mutations', 'Var', (156, 165))	('promote', 'PosReg', (226, 233))	('carcinogenic growth', 'Disease', (234, 253))
508360	24615916	As opposed to permanent mutators, transient hypermutation also decreases the likelihood of subsequent deleterious mutations reducing any proliferative advantage a cancer cell may have acquired.	('decreases', 'NegReg', (63, 72))	('mutations', 'Var', (114, 123))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('proliferative advantage', 'CPA', (137, 160))	('reducing', 'NegReg', (124, 132))	('cancer', 'Disease', (163, 169))	('cancer', 'Disease', 'MESH:D009369', (163, 169))
508361	24615916	Moreover, along with increased mutations, permanent mutators, especially those associated with genetic disruption of DNA repair activities, elevate DNA damage loads that in turn can trigger apoptosis.	('elevate', 'PosReg', (140, 147))	('ds', 'Chemical', 'MESH:D003903', (162, 164))	('mutators', 'Var', (52, 60))	('trigger', 'Reg', (182, 189))	('DNA damage loads', 'MPA', (148, 164))	('apoptosis', 'CPA', (190, 199))
508362	24615916	Consequently, cells may be able to accumulate several cancer driving mutations during a transient exposure to DNA damage while initially escaping the p53 dependent genome surveillance machinery.	('mutations', 'Var', (69, 78))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('escaping', 'NegReg', (137, 145))	('cancer', 'Disease', (54, 60))	('p53', 'Gene', (150, 153))	('p53', 'Gene', '7157', (150, 153))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
508364	24615916	Transient hypermutation enables the induction of multiple mutations within a single cell generation without the establishment of a persistent mutator phenotype that may reduce a cell's fitness through accumulation of deleterious mutations.	('fitness', 'Disease', (185, 192))	('mutations', 'Var', (58, 67))	('fitness', 'Disease', 'MESH:D012640', (185, 192))	('reduce', 'NegReg', (169, 175))
508365	24615916	Recent efforts to sequence human tumors genomes have revealed that mutation clusters are surprisingly common during cancer development.	('mutation clusters', 'Var', (67, 84))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('human', 'Species', '9606', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumors', 'Disease', 'MESH:D009369', (33, 39))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('tumors', 'Disease', (33, 39))
508367	24615916	However, the incidence of clustered mutations at TCW correlates with frequent genome-wide hyper-mutation at the same DNA sequence, suggesting that the same mechanisms that induce mutation clusters may also create multiple mutations genome-wide.	('TCW', 'Gene', (49, 52))	('TCW', 'Chemical', '-', (49, 52))	('mutations', 'Var', (36, 45))
508369	24615916	This suggests that -- like clustered mutations -- scattered TCW mutations may accumulate over a short time- span.	('TCW', 'Chemical', '-', (60, 63))	('TCW', 'Gene', (60, 63))	('mutations', 'Var', (64, 73))
508370	24615916	Scattered simultaneous mutations have the potential to accelerate cancer progression through the inactivation of multiple tumor suppressor genes.	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('inactivation', 'NegReg', (97, 109))	('mutations', 'Var', (23, 32))	('accelerate', 'PosReg', (55, 65))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('tumor', 'Disease', (122, 127))	('cancer', 'Disease', (66, 72))
508371	24615916	Knowing whether scattered TCW mutations occur simultaneously or are accumulated through time will be critical not only to our understanding of the mutator phenotype that occurs in cancers, but also to how these cancers should be monitored and treated.	('TCW', 'Chemical', '-', (26, 29))	('cancers', 'Disease', 'MESH:D009369', (180, 187))	('cancers', 'Disease', 'MESH:D009369', (211, 218))	('cancers', 'Phenotype', 'HP:0002664', (180, 187))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('cancers', 'Disease', (180, 187))	('cancers', 'Disease', (211, 218))	('TCW', 'Gene', (26, 29))	('mutations', 'Var', (30, 39))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('cancers', 'Phenotype', 'HP:0002664', (211, 218))
508372	24615916	While analysis of allelic fractions may provide evidence regarding the timing of TCW mutations, sequencing of paired neoplasms, primary tumors, and re-growths or metastases may provide the best evidence to understand how genetic alterations are accumulated, the role of transient mutageneisis in cancer, and how tumors evolve during disease progression.	('tumors', 'Disease', (136, 142))	('tumors', 'Disease', (312, 318))	('metastases', 'Disease', (162, 172))	('cancer', 'Phenotype', 'HP:0002664', (296, 302))	('TCW', 'Gene', (81, 84))	('TCW', 'Chemical', '-', (81, 84))	('tumors', 'Disease', 'MESH:D009369', (136, 142))	('tumors', 'Disease', 'MESH:D009369', (312, 318))	('neoplasms', 'Disease', 'MESH:D009369', (117, 126))	('primary tumors', 'Disease', (128, 142))	('cancer', 'Disease', 'MESH:D009369', (296, 302))	('neoplasms', 'Disease', (117, 126))	('tumor', 'Phenotype', 'HP:0002664', (312, 317))	('mutations', 'Var', (85, 94))	('primary tumors', 'Disease', 'MESH:D009369', (128, 142))	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('tumors', 'Phenotype', 'HP:0002664', (312, 318))	('metastases', 'Disease', 'MESH:D009362', (162, 172))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('cancer', 'Disease', (296, 302))	('neoplasms', 'Phenotype', 'HP:0002664', (117, 126))
508375	24615916	APOBEC1, 3A, 3B, 3C, 3DE, 3F,and 3H) all capable to mutating TC and TCW motifs.	('C', 'Chemical', 'MESH:D002244', (62, 63))	('C', 'Chemical', 'MESH:D002244', (18, 19))	('C', 'Chemical', 'MESH:D002244', (69, 70))	('TC', 'Chemical', 'MESH:D013667', (61, 63))	('mutating', 'Var', (52, 60))	('TCW', 'Chemical', '-', (68, 71))	('TC', 'Chemical', 'MESH:D013667', (68, 70))	('3H', 'Chemical', 'MESH:D014316', (33, 35))	('C', 'Chemical', 'MESH:D002244', (5, 6))	('APOBEC1', 'Gene', (0, 7))	('TCW motifs', 'Gene', (68, 78))
508376	24615916	Current exome and whole-genome sequencing of tumors suggests that of AID/APOBEC family members, TC-specific APOBECs provide the most extensive mutagenesis of human cancers, with the enrichment of WRC mutations associated with AID being limited mainly to lymphoid cancers and little to no over-represented mutation of the CC dinucleotide associated with APOBEC3G (e.g.	('mutations', 'Var', (200, 209))	('APOBEC3G', 'Gene', (353, 361))	('dinucleotide', 'Chemical', 'MESH:D015226', (324, 336))	('C', 'Chemical', 'MESH:D002244', (321, 322))	('cancers', 'Disease', 'MESH:D009369', (164, 171))	('cancer', 'Phenotype', 'HP:0002664', (263, 269))	('lymphoid cancers', 'Disease', 'MESH:D009369', (254, 270))	('C', 'Chemical', 'MESH:D002244', (97, 98))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('cancers', 'Phenotype', 'HP:0002664', (263, 270))	('cancers', 'Disease', (263, 270))	('C', 'Chemical', 'MESH:D002244', (113, 114))	('C', 'Chemical', 'MESH:D002244', (0, 1))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('human', 'Species', '9606', (158, 163))	('tumors', 'Disease', (45, 51))	('C', 'Chemical', 'MESH:D002244', (358, 359))	('C', 'Chemical', 'MESH:D002244', (198, 199))	('cancers', 'Phenotype', 'HP:0002664', (164, 171))	('cancers', 'Disease', (164, 171))	('C', 'Chemical', 'MESH:D002244', (78, 79))	('APOBEC3G', 'Gene', '60489', (353, 361))	('lymphoid cancers', 'Disease', (254, 270))	('WRC', 'Gene', (196, 199))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('cancers', 'Disease', 'MESH:D009369', (263, 270))	('TC', 'Chemical', 'MESH:D013667', (96, 98))	('tumors', 'Disease', 'MESH:D009369', (45, 51))	('C', 'Chemical', 'MESH:D002244', (322, 323))
508380	24615916	the number of TCW TTW or TCW TGW; termed as "TCW mutations").	('TCW TGW', 'Var', (25, 32))	('TCW', 'Chemical', '-', (25, 28))	('TCW', 'Chemical', '-', (14, 17))	('TCW', 'Chemical', '-', (45, 48))	('TCW TTW', 'Var', (14, 21))
508382	24615916	TCW  TTW or  TGW mutations in cancers displaying APOBEC mutagenesis are often greater than 3-fold more abundant than expected by random mutagenesis, constituting up to 68% of total mutations identified in individual exome-sequenced samples and even 95% of mutations within one outstanding case of whole-genome sequenced breast cancer.	('cancers', 'Phenotype', 'HP:0002664', (30, 37))	('TGW', 'Gene', (13, 16))	('cancers', 'Disease', (30, 37))	('TCW', 'Chemical', '-', (0, 3))	('cancers', 'Disease', 'MESH:D009369', (30, 37))	('C', 'Chemical', 'MESH:D002244', (1, 2))	('cancer', 'Phenotype', 'HP:0002664', (327, 333))	('breast cancer', 'Disease', 'MESH:D001943', (320, 333))	('mutations', 'Var', (181, 190))	('C', 'Chemical', 'MESH:D002244', (54, 55))	('breast cancer', 'Disease', (320, 333))	('TTW', 'Gene', (5, 8))	('breast cancer', 'Phenotype', 'HP:0003002', (320, 333))	('mutations', 'Var', (17, 26))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
508405	32102460	Radon causes an estimated 3%-14% of lung cancer, depending on the average level of radon in the country and the smoking prevalence.	('lung cancer', 'Disease', (36, 47))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('lung cancer', 'Disease', 'MESH:D008175', (36, 47))	('Radon', 'Var', (0, 5))	('causes', 'Reg', (6, 12))	('lung cancer', 'Phenotype', 'HP:0100526', (36, 47))
508449	32102460	Adenocarcinoma was the second histological type associated with radon, but was the weakest associated with smoking, contrary to the results for squamous cell carcinoma.	('Adenocarcinoma', 'Disease', (0, 14))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (144, 167))	('radon', 'Var', (64, 69))	('Adenocarcinoma', 'Disease', 'MESH:D000230', (0, 14))	('carcinoma', 'Phenotype', 'HP:0030731', (5, 14))	('carcinoma', 'Phenotype', 'HP:0030731', (158, 167))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (144, 167))	('squamous cell carcinoma', 'Disease', (144, 167))
508461	32102460	The type of housing was underground, and the risk of lung cancer exposure to high radon was 2.03 times higher than that to low radon.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('high radon', 'Var', (77, 87))	('lung cancer', 'Disease', 'MESH:D008175', (53, 64))	('lung cancer', 'Disease', (53, 64))	('lung cancer', 'Phenotype', 'HP:0100526', (53, 64))
508485	29802376	In lung cancer, rearrangements of TrkA have been shown to be oncogenic and are drug-sensitive.	('lung cancer', 'Disease', (3, 14))	('lung cancer', 'Phenotype', 'HP:0100526', (3, 14))	('lung cancer', 'Disease', 'MESH:D008175', (3, 14))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('TrkA', 'Gene', '4914', (34, 38))	('TrkA', 'Gene', (34, 38))	('rearrangements', 'Var', (16, 30))	('oncogenic', 'CPA', (61, 70))
508580	29802376	In the nervous system, neurons responsive to NGF express TrkA and p75NTR and the stimulation of these receptors by NGF induces a cascade of intracellular signalings including SRC, AKT, PI3K, ERK and NFkB.	('NGF', 'Gene', '4803', (115, 118))	('induces', 'Reg', (119, 126))	('stimulation', 'PosReg', (81, 92))	('NGF', 'Gene', (115, 118))	('PI3K', 'Var', (185, 189))	('p75NTR', 'Gene', '4804', (66, 72))	('TrkA', 'Gene', '4914', (57, 61))	('ERK', 'Gene', (191, 194))	('TrkA', 'Gene', (57, 61))	('ERK', 'Gene', '2048', (191, 194))	('SRC', 'Gene', '6714', (175, 178))	('AKT', 'Gene', (180, 183))	('NGF', 'Gene', '4803', (45, 48))	('SRC', 'Gene', (175, 178))	('NGF', 'Gene', (45, 48))	('cascade of intracellular signalings', 'MPA', (129, 164))	('AKT', 'Gene', '207', (180, 183))	('p75NTR', 'Gene', (66, 72))
508591	29802376	The following primary antibodies were used at 1/500 dilution: anti-proNGF (#AB9040, Merck Millipore), anti-NGF (#ab52918, Abcam), anti-TrkA (#2508, Cell Signaling), anti-p75NTR (#4201, Cell Signaling), anti-sortilin (#ANT-009, Alomone Labs), anti-PGP9.5 (#ab15503, Abcam).	('sortilin', 'Gene', '6272', (207, 215))	('#ANT-009', 'Var', (217, 225))	('TrkA', 'Gene', '4914', (135, 139))	('TrkA', 'Gene', (135, 139))	('PGP9.5', 'Gene', (247, 253))	('#AB9040', 'Var', (75, 82))	('p75NTR', 'Gene', (170, 176))	('p75NTR', 'Gene', '4804', (170, 176))	('sortilin', 'Gene', (207, 215))	('#ab15503', 'Var', (255, 263))	('NGF', 'Gene', '4803', (70, 73))	('NGF', 'Gene', '4803', (107, 110))	('PGP9.5', 'Gene', '7345', (247, 253))	('NGF', 'Gene', (70, 73))	('NGF', 'Gene', (107, 110))
508603	29731998	Here, we report development of two novel mouse mAbs, KU42.33C and KU43.13A, against the human pancreatic cancer cell line BxPC-3.	('mAbs', 'Gene', '72935', (47, 51))	('mouse', 'Species', '10090', (41, 46))	('KU43.13A', 'Var', (66, 74))	('KU42.33C', 'Var', (53, 61))	('pancreatic cancer', 'Disease', (94, 111))	('mAbs', 'Gene', (47, 51))	('BxPC-3', 'CellLine', 'CVCL:0186', (122, 128))	('pancreatic cancer', 'Disease', 'MESH:D010190', (94, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('human', 'Species', '9606', (88, 93))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (94, 111))
508627	29731998	The results of ELISA screening showed that the antibodies secreted by two hybridomas, KU42.33C and KU43.13A, were against an antigen with high level of expression in some of the human pancreatic cell lines (e.g.	('human', 'Species', '9606', (178, 183))	('pancreatic', 'Disease', 'MESH:D010195', (184, 194))	('pancreatic', 'Disease', (184, 194))	('KU43.13A', 'Var', (99, 107))
508629	29731998	However, the target antigen recognised by mAbs KU42.33C and KU43.13A was found to be trypsin-sensitive and there was no binding when screened by flow cytometry (data not shown).	('mAbs', 'Gene', '72935', (42, 46))	('binding', 'Interaction', (120, 127))	('KU42.33C', 'Var', (47, 55))	('KU43.13A', 'Var', (60, 68))	('mAbs', 'Gene', (42, 46))
508630	29731998	Following optimisation, high level of expression of the target antigen was found with both mAbs KU42.33C and KU43.13A in some of the human pancreatic cancer cell lines including BxPC-3 (MFI=86 and 90), Capan-2 (MFI=19 and 16), MIA PaCa-2 (MFI=56 and 57), PANC-1 (MFI=45 and 56), CFPAC-1 (MFI=21 and 19) and FA-6 (MFI=39 and 36, respectively), compared to negative control (Figure 1, Supplementary Figure 2).	('pancreatic cancer', 'Phenotype', 'HP:0002894', (139, 156))	('expression', 'MPA', (38, 48))	('CFPAC-1', 'CellLine', 'CVCL:1119', (279, 286))	('MIA PaCa-2', 'CellLine', 'CVCL:0428', (227, 237))	('pancreatic cancer', 'Disease', (139, 156))	('Capan-2', 'CellLine', 'CVCL:0026', (202, 209))	('mAbs', 'Gene', '72935', (91, 95))	('mAbs', 'Gene', (91, 95))	('pancreatic cancer', 'Disease', 'MESH:D010190', (139, 156))	('KU43.13A', 'Var', (109, 117))	('KU42.33C', 'Var', (96, 104))	('human', 'Species', '9606', (133, 138))	('PANC-1', 'CellLine', 'CVCL:0480', (255, 261))	('BxPC-3', 'CellLine', 'CVCL:0186', (178, 184))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
508636	29731998	These results support that mAbs KU42.33C and KU43.13A recognise non-overlapping epitopes on the extracellular domain on the target antigen.	('epitopes', 'MPA', (80, 88))	('mAbs', 'Gene', (27, 31))	('KU43.13A', 'Var', (45, 53))	('mAbs', 'Gene', '72935', (27, 31))
508637	29731998	Both mAbs, KU42.33C and KU43.13A, immunoprecipitated a ~170 KDa protein identified as CD109 by mass spectrometry (Figure 3A and Table 1).	('KU43.13A', 'Var', (24, 32))	('mAbs', 'Gene', (5, 9))	('mAbs', 'Gene', '72935', (5, 9))	('CD109', 'Gene', (86, 91))	('KU42.33C', 'Var', (11, 19))
508638	29731998	However, in Western blot, only KU42.33C detected the CD109 bands of 170 KDa and 150 KDa, suggesting that KU43.13A is directed against a conformational epitope on CD109 antigen (Figures 3B).	('CD109 antigen', 'Gene', '135228', (162, 175))	('KU43.13A', 'Var', (105, 113))	('CD109 antigen', 'Gene', (162, 175))
508641	29731998	These results suggest that mAbs KU42.33C and KU43.13A are directed towards a sequential and a conformational epitope on CD109 antigen, respectively.	('KU42.33C', 'Var', (32, 40))	('KU43.13A', 'Var', (45, 53))	('CD109 antigen', 'Gene', '135228', (120, 133))	('CD109 antigen', 'Gene', (120, 133))	('mAbs', 'Gene', (27, 31))	('mAbs', 'Gene', '72935', (27, 31))
508643	29731998	At maximum concentration of 300 nM, mAbs KU42.33C and KU43.13A did not affect the growth of the human pancreatic cancer cell lines nor inhibited the migration of BxPC-3, AsPC-1 and CFPAC-1 cells (data not shown).	('mAbs', 'Gene', (36, 40))	('inhibited', 'NegReg', (135, 144))	('migration', 'CPA', (149, 158))	('human', 'Species', '9606', (96, 101))	('AsPC-1', 'CellLine', 'CVCL:0152', (170, 176))	('CFPAC-1', 'CellLine', 'CVCL:1119', (181, 188))	('BxPC-3', 'CellLine', 'CVCL:0186', (162, 168))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (102, 119))	('KU42.33C', 'Var', (41, 49))	('mAbs', 'Gene', '72935', (36, 40))	('KU43.13A', 'Var', (54, 62))	('pancreatic cancer', 'Disease', (102, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('pancreatic cancer', 'Disease', 'MESH:D010190', (102, 119))
508647	29731998	Our results showed that only mAb KU42.33C, which was found to be against a sequential epitope by Western blot analysis as described above, detected the antigen in formalin-fixed, paraffin-embedded tissue sections (Figure 5A and 5B).	('formalin', 'Chemical', 'MESH:D005557', (163, 171))	('detected', 'Reg', (139, 147))	('KU42.33C', 'Var', (33, 41))	('paraffin', 'Chemical', 'MESH:D010232', (179, 187))
508658	29731998	Here, we report the generation of two mAbs, KU42.33C and KU43.13A, against two distinct epitopes on the external domain of CD109, using the human pancreatic cancer cell line BxPC-3 as the source of tumour immunogen.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('tumour', 'Disease', (198, 204))	('human', 'Species', '9606', (140, 145))	('mAbs', 'Gene', '72935', (38, 42))	('CD109', 'Gene', (123, 128))	('KU42.33C', 'Var', (44, 52))	('pancreatic cancer', 'Disease', (146, 163))	('pancreatic cancer', 'Disease', 'MESH:D010190', (146, 163))	('tumour', 'Phenotype', 'HP:0002664', (198, 204))	('BxPC-3', 'CellLine', 'CVCL:0186', (174, 180))	('KU43.13A', 'Var', (57, 65))	('mAbs', 'Gene', (38, 42))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (146, 163))	('tumour', 'Disease', 'MESH:D009369', (198, 204))
508661	29731998	Interestingly, of the two antibodies, only mAb KU42.33C recognised the CD109 antigen by Western blot (Figure 3B), which suggests that both mAbs are directed against different epitopes of the same antigen (Figure 2).	('CD109 antigen', 'Gene', '135228', (71, 84))	('mAbs', 'Gene', (139, 143))	('KU42.33C', 'Var', (47, 55))	('CD109 antigen', 'Gene', (71, 84))	('mAbs', 'Gene', '72935', (139, 143))
508663	29731998	TGF-beta has been found to play a role in growth, differentiation and migration; dysregulation of TGF-beta signalling is associated with tissue fibrosis and cancer.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('fibrosis', 'Disease', 'MESH:D005355', (144, 152))	('fibrosis', 'Disease', (144, 152))	('dysregulation', 'Var', (81, 94))	('associated', 'Reg', (121, 131))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('TGF-beta', 'Gene', '7040', (98, 106))	('TGF-beta', 'Gene', '7040', (0, 8))	('cancer', 'Disease', (157, 163))	('TGF-beta', 'Gene', (98, 106))	('TGF-beta', 'Gene', (0, 8))
508683	29731998	Additionally, a significant association was observed between high CD109 expression and low 1-year survival in patients with diffuse large B-cell lymphoma.	('1-year survival', 'MPA', (91, 106))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (138, 153))	('patients', 'Species', '9606', (110, 118))	('high', 'Var', (61, 65))	('expression', 'MPA', (72, 82))	('CD109', 'Gene', (66, 71))	('low', 'NegReg', (87, 90))	('diffuse large B-cell lymphoma', 'Disease', (124, 153))	('lymphoma', 'Phenotype', 'HP:0002665', (145, 153))
508690	29731998	Finally, while TMAs are commonly employed in medical research, the heterogeneous nature of both tumour and stroma in patients with pancreatic cancer support the need for further investigations on the relative expression and prognostic significance of CD109 in a larger group of patients using the whole tumour sections or several TMA cores from the same tumours  In summary, our results suggest that high expression of CD109 is common in pancreatic cancer.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (131, 148))	('TMA', 'Chemical', 'MESH:C071868', (15, 18))	('tumour and stroma', 'Disease', 'MESH:D009369', (96, 113))	('cancer', 'Phenotype', 'HP:0002664', (449, 455))	('tumour', 'Phenotype', 'HP:0002664', (354, 360))	('tumour', 'Disease', 'MESH:D009369', (354, 360))	('patients', 'Species', '9606', (117, 125))	('TMA', 'Chemical', 'MESH:C071868', (330, 333))	('tumour', 'Disease', (354, 360))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (438, 455))	('CD109', 'Gene', (419, 424))	('pancreatic cancer', 'Disease', 'MESH:D010190', (131, 148))	('TMAs', 'Chemical', 'MESH:C071868', (15, 19))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('tumour', 'Phenotype', 'HP:0002664', (96, 102))	('tumour', 'Phenotype', 'HP:0002664', (303, 309))	('pancreatic cancer', 'Disease', (131, 148))	('tumour', 'Disease', 'MESH:D009369', (96, 102))	('pancreatic cancer', 'Disease', 'MESH:D010190', (438, 455))	('high', 'Var', (400, 404))	('tumour', 'Disease', 'MESH:D009369', (303, 309))	('tumour', 'Disease', (96, 102))	('tumour', 'Disease', (303, 309))	('tumours', 'Disease', (354, 361))	('common', 'Reg', (428, 434))	('pancreatic cancer', 'Disease', (438, 455))	('tumours', 'Phenotype', 'HP:0002664', (354, 361))	('patients', 'Species', '9606', (278, 286))	('tumours', 'Disease', 'MESH:D009369', (354, 361))
508694	29731998	anti-CD20, anti-CD30, anti-EGFR, anti-HER-2 mAbs) are the humanised/chimeric IgG1 version of the mouse mAbs due to their superior ADCC (antibody-dependent cell-mediated cytotoxicity) and/or CDC (complement-dependent cytotoxicity) functions, or conjugated to toxins and radioactive substances to deliver lethal doses of such agents to the tumour.	('mAbs', 'Gene', (103, 107))	('IgG1', 'Gene', '105243590', (77, 81))	('human', 'Species', '9606', (58, 63))	('tumour', 'Phenotype', 'HP:0002664', (338, 344))	('cytotoxicity', 'Disease', (216, 228))	('tumour', 'Disease', 'MESH:D009369', (338, 344))	('cytotoxicity', 'Disease', 'MESH:D064420', (216, 228))	('tumour', 'Disease', (338, 344))	('cytotoxicity', 'Disease', (169, 181))	('CD20', 'Gene', '12482', (5, 9))	('mAbs', 'Gene', (44, 48))	('cytotoxicity', 'Disease', 'MESH:D064420', (169, 181))	('mAbs', 'Gene', '72935', (103, 107))	('ADCC', 'CPA', (130, 134))	('CD30', 'Gene', (16, 20))	('CD30', 'Gene', '21941', (16, 20))	('anti-EGFR', 'Var', (22, 31))	('mouse', 'Species', '10090', (97, 102))	('mAbs', 'Gene', '72935', (44, 48))	('IgG1', 'Gene', (77, 81))	('CD20', 'Gene', (5, 9))
508720	29731998	Approximately 1x106 tumour cells were incubated with novel mouse mAbs KU42.33C or KU43.13A (10 mug/ml) or control (i.e.	('KU42.33C', 'Var', (70, 78))	('mAbs', 'Gene', '72935', (65, 69))	('mouse', 'Species', '10090', (59, 64))	('tumour', 'Disease', 'MESH:D009369', (20, 26))	('tumour', 'Phenotype', 'HP:0002664', (20, 26))	('tumour', 'Disease', (20, 26))	('KU43.13A', 'Var', (82, 90))	('mAbs', 'Gene', (65, 69))
508733	29731998	Cells were incubated with mAbs KU42.33C or KU43.13A (50 mug/ml), or negative control (i.e.	('KU43.13A', 'Var', (43, 51))	('mAbs', 'Gene', (26, 30))	('mAbs', 'Gene', '72935', (26, 30))
508746	29731998	Monoisotopic masses were obtained using a SNAP averaging algorithm (C 4.9384, N 1.3577, O 1.4773, S 0.0417, H 7.7583) and a S/N threshold of 2.	('C 4.9384', 'Var', (68, 76))	('O 1.4773', 'Var', (88, 96))	('H 7.7583', 'CellLine', 'CVCL:9772', (108, 116))	('S 0.0417', 'Var', (98, 106))
508747	29731998	The default calibration was used for MS/MS spectra, which were baseline-subtracted and smoothed (Savitsky-Golay, width 0.15 m/z, cycles 4); monoisotopic peak detection used a SNAP averaging algorithm (C 4.9384, N 1.3577, O 1.4773, S 0.0417, H 7.7583) with a minimum S/N of 6.	('C 4.9384', 'Var', (201, 209))	('H 7.7583', 'CellLine', 'CVCL:9772', (241, 249))	('N 1.3577', 'Var', (211, 219))
508749	29731998	Briefly, protein immunoprecipitated with novel mAbs KU42.33C and KU43.13A (5 mug) was analysed by SDS-PAGE under reducing conditions, prior to Western blotting.	('mAbs', 'Gene', '72935', (47, 51))	('SDS', 'Chemical', 'MESH:D012967', (98, 101))	('KU42.33C', 'Var', (52, 60))	('mAbs', 'Gene', (47, 51))
508761	33177840	SNHG3 Knockdown Suppresses Proliferation, Migration and Invasion, and Promotes Apoptosis in Non-Small Cell Lung Cancer Through Regulating miR-216a/ZEB1 Axis Tumour growth and development are dependent on many factors including long noncoding RNAs (lncRNAs).	('Knockdown', 'Var', (6, 15))	('SNHG3', 'Gene', (0, 5))	('Cancer', 'Phenotype', 'HP:0002664', (112, 118))	('miR-216a', 'Gene', '406998', (138, 146))	('Non-Small Cell Lung Cancer', 'Disease', 'MESH:D002289', (92, 118))	('Tumour', 'Phenotype', 'HP:0002664', (157, 163))	('ZEB1', 'Gene', (147, 151))	('Promotes', 'PosReg', (70, 78))	('Regulating', 'Reg', (127, 137))	('SNHG3', 'Gene', '8420', (0, 5))	('Invasion', 'CPA', (56, 64))	('Apoptosis', 'CPA', (79, 88))	('Proliferation', 'CPA', (27, 40))	('Non-Small Cell Lung Cancer', 'Disease', (92, 118))	('Migration', 'CPA', (42, 51))	('Lung Cancer', 'Phenotype', 'HP:0100526', (107, 118))	('Suppresses', 'NegReg', (16, 26))	('Non-Small Cell Lung Cancer', 'Phenotype', 'HP:0030358', (92, 118))	('ZEB1', 'Gene', '6935', (147, 151))	('Small Cell Lung Cancer', 'Phenotype', 'HP:0030357', (96, 118))	('miR-216a', 'Gene', (138, 146))
508765	33177840	Proliferation, migrations, invasion, and apoptosis of tumour cells were assessed using cell counting kit-8, transwell experiments, and flow cytometry after SNHG3 knockdown by small interfering RNAs.	('tumour', 'Disease', 'MESH:D009369', (54, 60))	('tumour', 'Disease', (54, 60))	('SNHG3', 'Gene', (156, 161))	('invasion', 'CPA', (27, 35))	('tumour', 'Phenotype', 'HP:0002664', (54, 60))	('migrations', 'CPA', (15, 25))	('knockdown', 'Var', (162, 171))
508768	33177840	SNHG3 silencing diminished the ability of NSCLC cells to proliferate, migrate, and invade and promoted apoptosis.	('diminished', 'NegReg', (16, 26))	('NSCLC', 'Disease', (42, 47))	('NSCLC', 'Disease', 'MESH:D002289', (42, 47))	('invade', 'CPA', (83, 89))	('SNHG3', 'Gene', (0, 5))	('apoptosis', 'CPA', (103, 112))	('NSCLC', 'Phenotype', 'HP:0030358', (42, 47))	('silencing', 'Var', (6, 15))	('promoted', 'PosReg', (94, 102))	('migrate', 'CPA', (70, 77))
508769	33177840	Furthermore, SNHG3 competed with endogenous RNA and enhanced the expression of ZEB1 by interfering with miR-216a.	('miR-216a', 'Gene', (104, 112))	('miR-216a', 'Gene', '406998', (104, 112))	('interfering', 'NegReg', (87, 98))	('enhanced', 'PosReg', (52, 60))	('expression', 'MPA', (65, 75))	('ZEB1', 'Gene', '6935', (79, 83))	('SNHG3', 'Var', (13, 18))	('ZEB1', 'Gene', (79, 83))
508771	33177840	Similar effects were observed in vivo where SNHG3 knockdown inhibited NSCLC tumour growth by reducing expression of miR-216a while increasing that of ZEB1.	('expression', 'MPA', (102, 112))	('knockdown', 'Var', (50, 59))	('NSCLC tumour', 'Disease', (70, 82))	('tumour', 'Phenotype', 'HP:0002664', (76, 82))	('inhibited', 'NegReg', (60, 69))	('reducing', 'NegReg', (93, 101))	('NSCLC tumour', 'Disease', 'MESH:D009369', (70, 82))	('miR-216a', 'Gene', (116, 124))	('ZEB1', 'Gene', (150, 154))	('SNHG3', 'Gene', (44, 49))	('ZEB1', 'Gene', '6935', (150, 154))	('increasing', 'PosReg', (131, 141))	('miR-216a', 'Gene', '406998', (116, 124))	('NSCLC', 'Phenotype', 'HP:0030358', (70, 75))
508782	33177840	Similar effects have been shown in papillary thyroid carcinoma where SNHG3 silencing dampened cell migration, invasion, proliferation, and colony formation by interfering with miR-214-3p, leading to upregulation of PSMD10.	('PSMD10', 'Gene', (215, 221))	('SNHG3', 'Gene', (69, 74))	('papillary thyroid carcinoma', 'Disease', 'MESH:D000077273', (35, 62))	('PSMD10', 'Gene', '5716', (215, 221))	('colony formation', 'CPA', (139, 155))	('interfering', 'NegReg', (159, 170))	('cell migration', 'CPA', (94, 108))	('papillary thyroid carcinoma', 'Phenotype', 'HP:0002895', (35, 62))	('carcinoma', 'Phenotype', 'HP:0030731', (53, 62))	('dampened', 'NegReg', (85, 93))	('silencing', 'Var', (75, 84))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (45, 62))	('invasion', 'CPA', (110, 118))	('upregulation', 'PosReg', (199, 211))	('papillary thyroid carcinoma', 'Disease', (35, 62))	('miR', 'Gene', '220972', (176, 179))	('miR', 'Gene', (176, 179))
508785	33177840	Moreover, knockdown of SNHG3 prevented tumour cells from proliferating, migrating, and invading and induced apoptosis.	('invading', 'CPA', (87, 95))	('tumour', 'Disease', (39, 45))	('SNHG3', 'Gene', (23, 28))	('migrating', 'CPA', (72, 81))	('tumour', 'Disease', 'MESH:D009369', (39, 45))	('induced', 'Reg', (100, 107))	('apoptosis', 'CPA', (108, 117))	('proliferating', 'CPA', (57, 70))	('tumour', 'Phenotype', 'HP:0002664', (39, 45))	('knockdown', 'Var', (10, 19))	('prevented', 'NegReg', (29, 38))
508786	33177840	Furthermore, SNHG3 competed with miR-216a, leading to enhanced ZEB1 expression and downstream oncogenic effects.	('oncogenic effects', 'CPA', (94, 111))	('expression', 'MPA', (68, 78))	('miR-216a', 'Gene', (33, 41))	('miR-216a', 'Gene', '406998', (33, 41))	('ZEB1', 'Gene', (63, 67))	('SNHG3', 'Var', (13, 18))	('ZEB1', 'Gene', '6935', (63, 67))	('enhanced', 'PosReg', (54, 62))
508800	33177840	Wildtype and mutant reporter plasmids of SNHG3 (SNHG3-WT and SNHG3-MUT, respectively) and ZEB1 3' UTR were individually synthesised by GenePharma (China) and were transfected into A549 and H1299 cells in conjunction with miR-control or miR-216a.	('mutant', 'Var', (13, 19))	('SNHG3', 'Gene', (41, 46))	('miR', 'Gene', (236, 239))	('miR', 'Gene', '220972', (236, 239))	('ZEB1', 'Gene', (90, 94))	('ZEB1', 'Gene', '6935', (90, 94))	('A549', 'CellLine', 'CVCL:0023', (180, 184))	('miR-216a', 'Gene', (236, 244))	('miR-216a', 'Gene', '406998', (236, 244))	('H1299', 'CellLine', 'CVCL:0060', (189, 194))	('miR', 'Gene', '220972', (221, 224))	('miR', 'Gene', (221, 224))
508811	33177840	Taken together, these results suggested that aberrantly increased SNHG3 expression is a contributor for developing NSCLC.	('SNHG3', 'Gene', (66, 71))	('aberrantly increased', 'Var', (45, 65))	('NSCLC', 'Disease', (115, 120))	('expression', 'MPA', (72, 82))	('NSCLC', 'Disease', 'MESH:D002289', (115, 120))	('NSCLC', 'Phenotype', 'HP:0030358', (115, 120))
508813	33177840	We observed that knocking SNHG3 by si-SNHG3 #2 or si-SNHG3 #3 led to an inhibition of A549 and H1299 proliferation (Figure 2B and C, Supplement Figure 1A and B).	('si-SNHG3 #2', 'Var', (35, 46))	('si-SNHG3 #3', 'Var', (50, 61))	('A549', 'CellLine', 'CVCL:0023', (86, 90))	('H1299', 'CellLine', 'CVCL:0060', (95, 100))	('inhibition', 'NegReg', (72, 82))
508814	33177840	In summary, SNHG3 silencing reduced proliferation, migration, and invasion of lung adenocarcinoma cell lines and promoted apoptosis.	('reduced', 'NegReg', (28, 35))	('silencing', 'Var', (18, 27))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (78, 97))	('migration', 'CPA', (51, 60))	('promoted', 'PosReg', (113, 121))	('apoptosis', 'CPA', (122, 131))	('SNHG3', 'Gene', (12, 17))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('lung adenocarcinoma', 'Disease', (78, 97))	('proliferation', 'CPA', (36, 49))	('invasion', 'CPA', (66, 74))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (78, 97))
508817	33177840	Conversely, knockdown of SNHG3 increased expression of miR-216a while SNHG3 overexpression resulted in the opposite effect (Figure 3D and E).	('miR-216a', 'Gene', (55, 63))	('SNHG3', 'Gene', (25, 30))	('miR-216a', 'Gene', '406998', (55, 63))	('increased', 'PosReg', (31, 40))	('expression', 'MPA', (41, 51))	('knockdown', 'Var', (12, 21))
508821	33177840	Our results indicated that miR-216a expression was remarkably reduced after anti-miR-216a transfection (Supplement Figure 2A).	('miR-216a', 'Gene', '406998', (27, 35))	('miR-216a', 'Gene', (81, 89))	('transfection', 'Var', (90, 102))	('miR-216a', 'Gene', (27, 35))	('expression', 'MPA', (36, 46))	('reduced', 'NegReg', (62, 69))	('miR-216a', 'Gene', '406998', (81, 89))
508823	33177840	Then, we transfected A549 and H1299 cell lines with si-SNHG3 #2 alone or si-SNHG3 #2 combined with anti-miR-216a to further investigate the relationship between SNHG3 and miR-216a.	('si-SNHG3', 'Var', (73, 81))	('A549', 'CellLine', 'CVCL:0023', (21, 25))	('si-SNHG3', 'Var', (52, 60))	('miR-216a', 'Gene', (104, 112))	('miR-216a', 'Gene', '406998', (104, 112))	('H1299', 'CellLine', 'CVCL:0060', (30, 35))	('miR-216a', 'Gene', (171, 179))	('miR-216a', 'Gene', '406998', (171, 179))
508832	33177840	Interestingly, blockade of miR-216a negated the inhibitory effects of si-SNHG3 on ZEB1 expression (Figure 5C and D).	('blockade', 'Var', (15, 23))	('si-SNHG3', 'Gene', (70, 78))	('miR-216a', 'Gene', '406998', (27, 35))	('ZEB1', 'Gene', '6935', (82, 86))	('negated', 'NegReg', (36, 43))	('ZEB1', 'Gene', (82, 86))	('inhibitory effects', 'MPA', (48, 66))	('miR-216a', 'Gene', (27, 35))
508834	33177840	Taken together, these results suggested that SNHG3 enhanced ZEB1 expression by interfering with miR-216a.	('miR-216a', 'Gene', '406998', (96, 104))	('SNHG3', 'Var', (45, 50))	('interfering', 'NegReg', (79, 90))	('ZEB1', 'Gene', (60, 64))	('enhanced', 'PosReg', (51, 59))	('ZEB1', 'Gene', '6935', (60, 64))	('miR-216a', 'Gene', (96, 104))
508835	33177840	We inoculated A549 cells that stably expressed Lenti-sh-SNHG3 or Lenti-sh-control into nude mice and found that SNHG3 knockdown caused a marked inhibition of tumour growth and reduced tumour volume and weight (Figure 6A and B).	('tumour', 'Phenotype', 'HP:0002664', (158, 164))	('A549', 'CellLine', 'CVCL:0023', (14, 18))	('knockdown', 'Var', (118, 127))	('Lenti-sh-SNHG3', 'Gene', (47, 61))	('tumour', 'Disease', 'MESH:D009369', (158, 164))	('reduced', 'NegReg', (176, 183))	('tumour', 'Phenotype', 'HP:0002664', (184, 190))	('SNHG3', 'Gene', (112, 117))	('tumour', 'Disease', (158, 164))	('Lenti-sh-SNHG3', 'Gene', '399101', (47, 61))	('inhibition', 'NegReg', (144, 154))	('nude mice', 'Species', '10090', (87, 96))	('tumour', 'Disease', 'MESH:D009369', (184, 190))	('tumour', 'Disease', (184, 190))
508837	33177840	Taken together, our in vivo experiments indicated that knockdown of SNHG3 inhibited tumour growth.	('knockdown', 'Var', (55, 64))	('tumour', 'Disease', (84, 90))	('inhibited', 'NegReg', (74, 83))	('tumour', 'Phenotype', 'HP:0002664', (84, 90))	('SNHG3', 'Gene', (68, 73))	('tumour', 'Disease', 'MESH:D009369', (84, 90))
508841	33177840	Our data suggested that SNHG3 increased proliferation, migration, and invasion of NSCLC cells, which was paired with a suppression of apoptosis.	('SNHG3', 'Var', (24, 29))	('NSCLC', 'Phenotype', 'HP:0030358', (82, 87))	('migration', 'CPA', (55, 64))	('increased', 'PosReg', (30, 39))	('NSCLC', 'Disease', (82, 87))	('proliferation', 'CPA', (40, 53))	('invasion', 'CPA', (70, 78))	('NSCLC', 'Disease', 'MESH:D002289', (82, 87))
508845	33177840	Similar observations have been made in hepatocellular carcinoma cells by Wu et al where SNHG3 disrupts miR-139-5p and elevates BMI1 expression.	('carcinoma', 'Phenotype', 'HP:0030731', (54, 63))	('elevates BMI1', 'Phenotype', 'HP:0030269', (118, 131))	('BMI1', 'Gene', (127, 131))	('elevates', 'PosReg', (118, 126))	('SNHG3', 'Var', (88, 93))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (39, 63))	('miR', 'Gene', '220972', (103, 106))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (39, 63))	('miR', 'Gene', (103, 106))	('BMI1', 'Gene', '648', (127, 131))	('disrupts', 'NegReg', (94, 102))	('expression', 'MPA', (132, 142))	('hepatocellular carcinoma', 'Disease', (39, 63))
508854	33177840	Moreover, the tumour suppressing effects of SNHG3 knockdown were negated by inhibiting miR-216a or overexpressing ZEB1.	('negated', 'NegReg', (65, 72))	('tumour', 'Disease', (14, 20))	('miR-216a', 'Gene', (87, 95))	('miR-216a', 'Gene', '406998', (87, 95))	('ZEB1', 'Gene', (114, 118))	('knockdown', 'Var', (50, 59))	('ZEB1', 'Gene', '6935', (114, 118))	('overexpressing', 'PosReg', (99, 113))	('inhibiting', 'NegReg', (76, 86))	('tumour', 'Phenotype', 'HP:0002664', (14, 20))	('SNHG3', 'Gene', (44, 49))	('tumour', 'Disease', 'MESH:D009369', (14, 20))
508855	33177840	In summary, SNHG3 contributed to the development of NSCLC tumours by modulating the miR-216a/ZEB1 axis.	('ZEB1', 'Gene', '6935', (93, 97))	('NSCLC tumours', 'Disease', (52, 65))	('tumours', 'Phenotype', 'HP:0002664', (58, 65))	('tumour', 'Phenotype', 'HP:0002664', (58, 64))	('miR-216a', 'Gene', (84, 92))	('modulating', 'Reg', (69, 79))	('miR-216a', 'Gene', '406998', (84, 92))	('SNHG3', 'Var', (12, 17))	('NSCLC', 'Phenotype', 'HP:0030358', (52, 57))	('NSCLC tumours', 'Disease', 'MESH:D009369', (52, 65))	('ZEB1', 'Gene', (93, 97))
508859	33177840	Stabilised p53 then further activates downstream targets including DINO, creating a positive feedback loop.	('p53', 'Gene', (11, 14))	('p53', 'Gene', '7157', (11, 14))	('Stabilised', 'Var', (0, 10))	('DINO', 'Gene', (67, 71))	('activates', 'PosReg', (28, 37))	('positive feedback loop', 'MPA', (84, 106))	('DINO', 'Gene', '108783646', (67, 71))
508860	33177840	In contrast to the functions reported in this study, SNHG3 appears to harbour tumour suppressive functions in papillary thyroid carcinoma where silencing SNHG3 promotes tumour formation in vivo via a pathway involving AKT, mTOR, and ERK.	('tumour', 'Disease', 'MESH:D009369', (78, 84))	('tumour', 'Disease', (78, 84))	('AKT', 'Gene', '207', (218, 221))	('ERK', 'Gene', (233, 236))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('papillary thyroid carcinoma', 'Phenotype', 'HP:0002895', (110, 137))	('tumour', 'Phenotype', 'HP:0002664', (169, 175))	('tumour', 'Disease', 'MESH:D009369', (169, 175))	('mTOR', 'Gene', (223, 227))	('papillary thyroid carcinoma', 'Disease', (110, 137))	('tumour', 'Disease', (169, 175))	('papillary thyroid carcinoma', 'Disease', 'MESH:D000077273', (110, 137))	('AKT', 'Gene', (218, 221))	('promotes', 'PosReg', (160, 168))	('mTOR', 'Gene', '2475', (223, 227))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (120, 137))	('ERK', 'Gene', '5594', (233, 236))	('silencing', 'Var', (144, 153))	('SNHG3', 'Gene', (154, 159))	('tumour', 'Phenotype', 'HP:0002664', (78, 84))
508861	33177840	In addition, SNHG3 upregulation has been shown to have a protective role in ischemia-induced injury in neonatal brains by sponging miR-196 in hippocampal cells, thus preventing expression of XIAP and CAAP1.	('preventing', 'NegReg', (166, 176))	('XIAP', 'Gene', (191, 195))	('CAAP1', 'Gene', '79886', (200, 205))	('XIAP', 'Gene', '331', (191, 195))	('upregulation', 'PosReg', (19, 31))	('miR', 'Gene', '220972', (131, 134))	('ischemia-induced injury in neonatal brains', 'Disease', 'MESH:D002545', (76, 118))	('ischemia-induced injury in neonatal brains', 'Disease', (76, 118))	('SNHG3', 'Gene', (13, 18))	('expression', 'MPA', (177, 187))	('CAAP1', 'Gene', (200, 205))	('miR', 'Gene', (131, 134))	('sponging', 'Var', (122, 130))
508862	33177840	However, in a similar setting, the sponging of miR-196 by SNHG3 in osteosarcoma leads to cell growth and subsequent poor outcomes.	('osteosarcoma', 'Disease', 'MESH:D012516', (67, 79))	('sponging', 'Var', (35, 43))	('SNHG3', 'Gene', (58, 63))	('miR', 'Gene', '220972', (47, 50))	('miR', 'Gene', (47, 50))	('cell growth', 'CPA', (89, 100))	('osteosarcoma', 'Disease', (67, 79))	('osteosarcoma', 'Phenotype', 'HP:0002669', (67, 79))
508870	32752094	Abnormalities in CNTN1 expression associate with cancer progression and poor prognosis.	('Abnormalities', 'Var', (0, 13))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('CNTN1', 'Gene', (17, 22))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('associate', 'Reg', (34, 43))	('cancer', 'Disease', (49, 55))
508877	32752094	Aberrant expression of CAMs has been shown to associate with invasive phenotype of tumour cells.	('tumour', 'Disease', (83, 89))	('Aberrant expression', 'Var', (0, 19))	('CAMs', 'Gene', (23, 27))	('associate', 'Reg', (46, 55))	('tumour', 'Phenotype', 'HP:0002664', (83, 89))	('tumour', 'Disease', 'MESH:D009369', (83, 89))
508894	32752094	Specifically, the CNTN1 mutants show an overt ataxia phenotype by day 10 which subsequently progresses to pronounced smaller size, emaciated appearance and uncontrolled movement by day 15.	('uncontrolled movement', 'Phenotype', 'HP:0007738', (156, 177))	('mutants', 'Var', (24, 31))	('CNTN1', 'Gene', (18, 23))	('ataxia', 'Phenotype', 'HP:0001251', (46, 52))	('ataxia', 'Disease', 'MESH:D001259', (46, 52))	('ataxia', 'Disease', (46, 52))
508901	32752094	The knockdown of CNTN1 via in utero electroporation resulted in significantly delayed radical migration mediated by RhoA activation, a Rho-GTPase critical for actin cytoskeletal reorganization.	('delayed', 'NegReg', (78, 85))	('RhoA', 'Gene', '387', (116, 120))	('CNTN1', 'Gene', (17, 22))	('RhoA', 'Gene', (116, 120))	('radical migration', 'CPA', (86, 103))	('knockdown', 'Var', (4, 13))
508903	32752094	A previous report also described a lethal form of congenital myopathy possibly caused by the loss of CNTN1 in the neuromuscular junction due to a familial mutation.	('myopathy', 'Phenotype', 'HP:0003198', (61, 69))	('congenital myopathy', 'Disease', 'MESH:D009224', (50, 69))	('loss', 'Var', (93, 97))	('caused by', 'Reg', (79, 88))	('CNTN1', 'Gene', (101, 106))	('congenital myopathy', 'Disease', (50, 69))
508911	32752094	Furthermore, NCAM localized in membrane compartments binds and stimulates fibroblast growth factor receptor 1 (FGFR1) through its fibronectin type III (F3) domains and activates MAPK-mediated cell migration in non-neural cells.	('NCAM', 'Var', (13, 17))	('FGFR1', 'Gene', '2260', (111, 116))	('fibronectin', 'Gene', '2335', (130, 141))	('fibroblast growth factor receptor 1', 'Gene', (74, 109))	('stimulates', 'PosReg', (63, 73))	('fibroblast growth factor receptor 1', 'Gene', '2260', (74, 109))	('fibronectin', 'Gene', (130, 141))	('FGFR1', 'Gene', (111, 116))	('MAPK-mediated cell migration in non-neural cells', 'CPA', (178, 226))	('activates', 'PosReg', (168, 177))
508913	32752094	Indeed, the correlation between deregulated NCAM expression and poor prognosis has been found in different cancer types including neuroblastoma, myeloma, acute myeloid leukemia, pancreatic cancer, and small cell lung cancer.	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (154, 176))	('neuroblastoma', 'Disease', 'MESH:D009447', (130, 143))	('leukemia', 'Phenotype', 'HP:0001909', (168, 176))	('myeloma', 'Disease', 'MESH:D009101', (145, 152))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (178, 195))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('NCAM', 'Gene', (44, 48))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (201, 223))	('expression', 'MPA', (49, 59))	('cancer', 'Disease', 'MESH:D009369', (217, 223))	('myeloma', 'Disease', (145, 152))	('deregulated', 'Var', (32, 43))	('pancreatic cancer', 'Disease', 'MESH:D010190', (178, 195))	('acute myeloid leukemia', 'Disease', (154, 176))	('cancer', 'Disease', (107, 113))	('cancer', 'Disease', (189, 195))	('pancreatic cancer', 'Disease', (178, 195))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('small cell lung cancer', 'Disease', 'MESH:D055752', (201, 223))	('lung cancer', 'Phenotype', 'HP:0100526', (212, 223))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('neuroblastoma', 'Disease', (130, 143))	('cancer', 'Disease', (217, 223))	('neuroblastoma', 'Phenotype', 'HP:0003006', (130, 143))	('small cell lung cancer', 'Disease', (201, 223))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (154, 176))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (160, 176))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))
508914	32752094	However, as the central nervous system was the only defective organ in CNTN1 deficient mice, the protein is not a major contributor to the development of other organs at least in mice.	('CNTN1', 'Gene', (71, 76))	('mice', 'Species', '10090', (87, 91))	('deficient', 'Var', (77, 86))	('mice', 'Species', '10090', (179, 183))
508919	32752094	Amplifications and gains of genomic materials are frequent in this region for malignant gliomas and astrocytoma.	('malignant gliomas', 'Disease', 'MESH:D005910', (78, 95))	('astrocytoma', 'Disease', 'MESH:D001254', (100, 111))	('gains', 'PosReg', (19, 24))	('astrocytoma', 'Disease', (100, 111))	('astrocytoma', 'Phenotype', 'HP:0009592', (100, 111))	('Amplifications', 'Var', (0, 14))	('gliomas', 'Phenotype', 'HP:0009733', (88, 95))	('glioma', 'Phenotype', 'HP:0009733', (88, 94))	('malignant gliomas', 'Disease', (78, 95))
508937	32752094	discovered that while the knockdown of CNTN1 did not influence lung cancer cell proliferation, it significantly reduced cancer cell's invasive abilities both in vitro and in xenograft model.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('lung cancer', 'Disease', 'MESH:D008175', (63, 74))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('invasive abilities', 'CPA', (134, 152))	('lung cancer', 'Disease', (63, 74))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('knockdown', 'Var', (26, 35))	('lung cancer', 'Phenotype', 'HP:0100526', (63, 74))	('cancer', 'Disease', (68, 74))	('reduced', 'NegReg', (112, 119))	('CNTN1', 'Gene', (39, 44))
508944	32752094	Similarly, CNTN1 expression was elevated in multidrug resistance (MDR) A549/cisplatin (A549/DDP) cells compared to its progenitor A549 lung cancer cells, and the silencing of CNTN1 rendered both cells higher cisplatin sensitivity and upregulated cisplatin-induced apoptosis, leading to inhibition of tumor invasion and metastasis.	('cisplatin', 'Chemical', 'MESH:D002945', (208, 217))	('lung cancer', 'Disease', (135, 146))	('tumor', 'Phenotype', 'HP:0002664', (300, 305))	('A549', 'CellLine', 'CVCL:0023', (87, 91))	('expression', 'MPA', (17, 27))	('upregulated', 'PosReg', (234, 245))	('cisplatin', 'Chemical', 'MESH:D002945', (246, 255))	('A549', 'CellLine', 'CVCL:0023', (71, 75))	('silencing', 'Var', (162, 171))	('elevated', 'PosReg', (32, 40))	('lung cancer', 'Disease', 'MESH:D008175', (135, 146))	('CNTN1', 'Gene', (11, 16))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('higher', 'PosReg', (201, 207))	('cisplatin sensitivity', 'MPA', (208, 229))	('lung cancer', 'Phenotype', 'HP:0100526', (135, 146))	('tumor', 'Disease', (300, 305))	('cisplatin', 'Chemical', 'MESH:D002945', (76, 85))	('CNTN1', 'Gene', (175, 180))	('tumor', 'Disease', 'MESH:D009369', (300, 305))	('A549', 'CellLine', 'CVCL:0023', (130, 134))	('inhibition', 'NegReg', (286, 296))
508945	32752094	This enhanced chemoresistance of lung cancer cells induced by CNTN1 overexpression was also found to be attributable to PI3K/AKT activated EMT enhancement (Figure 4).	('AKT', 'Gene', '207', (125, 128))	('lung cancer', 'Phenotype', 'HP:0100526', (33, 44))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('chemoresistance', 'CPA', (14, 29))	('AKT', 'Gene', (125, 128))	('lung cancer', 'Disease', 'MESH:D008175', (33, 44))	('CNTN1', 'Gene', (62, 67))	('enhanced', 'PosReg', (5, 13))	('enhancement', 'PosReg', (143, 154))	('overexpression', 'Var', (68, 82))	('lung cancer', 'Disease', (33, 44))
508955	32752094	Recent study has shown that a reduction in CNTN1 expression alone was sufficient to reverse the enhanced migration ability of esophageal cancer cells attributable to ectopic VEFGC expression in vitro.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('VEFGC', 'Gene', (174, 179))	('enhanced', 'PosReg', (96, 104))	('CNTN1', 'Gene', (43, 48))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('reduction', 'NegReg', (30, 39))	('cancer', 'Disease', (137, 143))	('migration ability', 'CPA', (105, 122))	('ectopic', 'Var', (166, 173))	('expression', 'Var', (180, 190))
508959	32752094	demonstrated that CNTN1 expression was directly regulated by Flt4 stimulation or inhibition, and this alteration was robustly associated with enhanced or reduced OSCC cell proliferation and migration correspondingly.	('OSCC cell proliferation', 'CPA', (162, 185))	('migration', 'CPA', (190, 199))	('expression', 'MPA', (24, 34))	('inhibition', 'Var', (81, 91))	('Flt4', 'Gene', (61, 65))	('CNTN1', 'Gene', (18, 23))	('stimulation', 'PosReg', (66, 77))	('Flt4', 'Gene', '2324', (61, 65))	('enhanced', 'PosReg', (142, 150))	('reduced', 'NegReg', (154, 161))	('regulated', 'Reg', (48, 57))
508962	32752094	The OSCC cells with CNTN1 knocked-down exhibits significant reduction in invasion but not proliferative properties, which is in line with previous findings demonstrating that CNTN1 may promote progression of cancer cells through exclusive activation of metastatic pathways.	('cancer', 'Disease', (208, 214))	('CNTN1', 'Gene', (175, 180))	('CNTN1', 'Gene', (20, 25))	('knocked-down', 'Var', (26, 38))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('reduction', 'NegReg', (60, 69))	('proliferative properties', 'CPA', (90, 114))	('activation', 'PosReg', (239, 249))	('promote', 'PosReg', (185, 192))	('invasion', 'CPA', (73, 81))	('metastatic', 'CPA', (253, 263))	('progression', 'CPA', (193, 204))	('cancer', 'Disease', 'MESH:D009369', (208, 214))
508973	32752094	Further analysis showed that silencing or knockdown of CNTN1 expression resulted in suppression of proliferation, invasion and migration capabilities in PC cells concurrent with a reduced PI3K/AKT signaling.	('AKT', 'Gene', '207', (193, 196))	('migration capabilities', 'CPA', (127, 149))	('silencing', 'Var', (29, 38))	('PC', 'CellLine', 'CVCL:0152', (153, 155))	('reduced', 'NegReg', (180, 187))	('AKT', 'Gene', (193, 196))	('suppression', 'NegReg', (84, 95))	('CNTN1', 'Gene', (55, 60))	('invasion', 'CPA', (114, 122))	('proliferation', 'CPA', (99, 112))	('knockdown', 'Var', (42, 51))
508974	32752094	CNTN1 inhibition also increased expression of E-cadherin while reduced N-cadherin and Vimentin, suggesting an inhibition of the EMT process pivotal in cancer metastases (Figure 4).	('inhibition', 'NegReg', (110, 120))	('Vimentin', 'Gene', (86, 94))	('reduced', 'NegReg', (63, 70))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('N-cadherin', 'Gene', '1000', (71, 81))	('cancer metastases', 'Disease', (151, 168))	('CNTN1', 'Gene', (0, 5))	('E-cadherin', 'Protein', (46, 56))	('Vimentin', 'Gene', '7431', (86, 94))	('increased', 'PosReg', (22, 31))	('EMT process', 'CPA', (128, 139))	('inhibition', 'Var', (6, 16))	('expression', 'MPA', (32, 42))	('N-cadherin', 'Gene', (71, 81))	('cancer metastases', 'Disease', 'MESH:D009362', (151, 168))
508976	32752094	Silencing of CNTN1 with short hairpin RNA (shRNA) inhibited cellular malignant phenotype and reduced expression of pluripotent markers such as CD44, octamer-binding transcription factor 4 (OCT-4), and Nanog.	('octamer-binding transcription factor 4', 'Gene', (149, 187))	('Nanog', 'Gene', '79923', (201, 206))	('CD44', 'Gene', '960', (143, 147))	('reduced', 'NegReg', (93, 100))	('CNTN1', 'Gene', (13, 18))	('OCT-4', 'Gene', '5460', (189, 194))	('CD44', 'Gene', (143, 147))	('OCT-4', 'Gene', (189, 194))	('cellular malignant phenotype', 'CPA', (60, 88))	('Nanog', 'Gene', (201, 206))	('octamer-binding transcription factor 4', 'Gene', '5460', (149, 187))	('expression', 'MPA', (101, 111))	('Silencing', 'Var', (0, 9))	('inhibited', 'NegReg', (50, 59))
508977	32752094	CNTN1 silencing sensitized Dox-resistant PC cells and inhibited PI3K/AKT signaling in vivo.	('inhibited', 'NegReg', (54, 63))	('PC', 'CellLine', 'CVCL:0152', (41, 43))	('Dox-resistant PC', 'Disease', (27, 43))	('AKT', 'Gene', (69, 72))	('CNTN1', 'Gene', (0, 5))	('Dox', 'Chemical', 'MESH:D000077143', (27, 30))	('AKT', 'Gene', '207', (69, 72))	('silencing', 'Var', (6, 15))
508979	32752094	In a study investigating breast cancer (BC), ectopic CNTN1 overexpression enhanced cell proliferation, invasion, migration as well as cell cycle progression from G1 to S phase in breast cancer cells in vitro.	('cell cycle progression from G1 to S phase', 'CPA', (134, 175))	('BC', 'Phenotype', 'HP:0003002', (40, 42))	('breast cancer', 'Disease', 'MESH:D001943', (179, 192))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('cell proliferation', 'CPA', (83, 101))	('breast cancer', 'Disease', 'MESH:D001943', (25, 38))	('breast cancer', 'Disease', (179, 192))	('breast cancer', 'Phenotype', 'HP:0003002', (179, 192))	('breast cancer', 'Disease', (25, 38))	('overexpression enhanced', 'PosReg', (59, 82))	('ectopic', 'Var', (45, 52))	('breast cancer', 'Phenotype', 'HP:0003002', (25, 38))	('migration', 'CPA', (113, 122))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('invasion', 'CPA', (103, 111))	('CNTN1', 'Gene', (53, 58))
508980	32752094	Notably, CNTN1 overexpression also enhanced breast cancer xenograft tumor growth in vivo in nude mice.	('tumor', 'Disease', (68, 73))	('breast cancer', 'Disease', 'MESH:D001943', (44, 57))	('breast cancer', 'Phenotype', 'HP:0003002', (44, 57))	('nude mice', 'Species', '10090', (92, 101))	('breast cancer', 'Disease', (44, 57))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('enhanced', 'PosReg', (35, 43))	('overexpression', 'Var', (15, 29))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('CNTN1', 'Gene', (9, 14))
508983	32752094	Among the 5 subtypes, we noticed a significant higher level of CNTN1 in HER2-E in a population consisting of 50 DNA microarray studies (n = 9254) and in the population of three RNA-seq investigation (n = 4712) (Figure 5).	('HER2', 'Gene', (72, 76))	('CNTN1', 'Var', (63, 68))	('higher', 'PosReg', (47, 53))	('HER2', 'Gene', '2064', (72, 76))
508988	32752094	In both positively correlated gene populations, enrichment in the terms of extracellular matrix organization (GO:0030198) and cell adhesion (GO:0007155) in Biological Process (BP) was observed in BC (All patients, Table 2).	('patients', 'Species', '9606', (204, 212))	('cell adhesion', 'CPA', (126, 139))	('GO:0007155', 'Var', (141, 151))	('BC', 'Phenotype', 'HP:0003002', (196, 198))	('extracellular matrix organization', 'CPA', (75, 108))
508991	32752094	As well, CNTN1 expression was found to be an independent prognostic factor for OS (hazard ratio 2.383, 95% confidence interval 1.262-4.503; p = 0.007) and DFS (disease free survival) (hazard ratio 2.356, 95% confidence interval 1.370-4.049; p = 0.002) in HCC patients.	('expression', 'Var', (15, 25))	('patients', 'Species', '9606', (259, 267))	('HCC', 'Disease', (255, 258))	('DFS', 'Disease', (155, 158))	('HCC', 'Phenotype', 'HP:0001402', (255, 258))	('CNTN1', 'Gene', (9, 14))	('DFS', 'Disease', 'None', (155, 158))
508992	32752094	RET/PTC3 (Ret proto-oncogene and Ret-activating protein ELE1) rearrangement is the most frequent genetic alteration in thyroid cancer and most functions of RET are mediated through pathways including ERK, JNK, and PI3K/AKT.	('thyroid cancer', 'Disease', 'MESH:D013964', (119, 133))	('Ret', 'Gene', (10, 13))	('mediated', 'Reg', (164, 172))	('thyroid cancer', 'Phenotype', 'HP:0002890', (119, 133))	('Ret', 'Gene', (33, 36))	('RET', 'Gene', '5979', (0, 3))	('ERK', 'Gene', '5594', (200, 203))	('ELE1', 'Gene', '8031', (56, 60))	('JNK', 'Gene', (205, 208))	('Ret', 'Gene', '5979', (10, 13))	('JNK', 'Gene', '5599', (205, 208))	('PTC3', 'Gene', '8031', (4, 8))	('Ret', 'Gene', '5979', (33, 36))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('AKT', 'Gene', (219, 222))	('ERK', 'Gene', (200, 203))	('PTC3', 'Gene', (4, 8))	('RET', 'Gene', (0, 3))	('RET', 'Gene', '5979', (156, 159))	('thyroid cancer', 'Disease', (119, 133))	('functions', 'MPA', (143, 152))	('rearrangement', 'Var', (62, 75))	('ELE1', 'Gene', (56, 60))	('AKT', 'Gene', '207', (219, 222))	('RET', 'Gene', (156, 159))
508998	32752094	Functionally, CNTN1 silencing in vitro restrained thyroid cancer cell migration and invasion abilities.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('thyroid cancer', 'Phenotype', 'HP:0002890', (50, 64))	('thyroid cancer', 'Disease', (50, 64))	('restrained', 'NegReg', (39, 49))	('CNTN1', 'Gene', (14, 19))	('invasion abilities', 'CPA', (84, 102))	('silencing', 'Var', (20, 29))	('thyroid cancer', 'Disease', 'MESH:D013964', (50, 64))
509003	32752094	The Notch signaling pathway is highly conserved, and its dysregulation is associated with many cancers.	('dysregulation', 'Var', (57, 70))	('cancers', 'Phenotype', 'HP:0002664', (95, 102))	('cancers', 'Disease', (95, 102))	('cancers', 'Disease', 'MESH:D009369', (95, 102))	('Notch signaling pathway', 'Pathway', (4, 27))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('associated', 'Reg', (74, 84))
509010	32752094	While these analyses support a positive association between high CNTN1 expression and poor OS in cancers, this association might be cancer-type specific at least at the level of mRNA; high CNTN1 expression displays a reverse association with poor OS in LGG (Figure 6c).	('cancers', 'Disease', 'MESH:D009369', (97, 104))	('expression', 'MPA', (71, 81))	('cancer', 'Disease', (132, 138))	('cancers', 'Phenotype', 'HP:0002664', (97, 104))	('cancers', 'Disease', (97, 104))	('cancer', 'Disease', (97, 103))	('cancer', 'Disease', 'MESH:D009369', (97, 103))	('CNTN1', 'Gene', (65, 70))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('CNTN1', 'Gene', (189, 194))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('high CNTN1', 'Gene', (60, 70))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('high', 'Var', (184, 188))	('poor OS in LGG', 'Disease', (242, 256))
509018	32752094	For example, a Cre-LoxP system can be explored in which mice carrying the transgene insertion of a strong translational and transcriptional termination (STOP) sequence flanked by loxP or FRT sites between the promoter sequence and CNTN1 which can be crossed with mice carrying tissue-specific promoters.	('mice', 'Species', '10090', (56, 60))	('mice', 'Species', '10090', (263, 267))	('transgene insertion', 'Var', (74, 93))	('CNTN1', 'Gene', (231, 236))	('insertion', 'Var', (84, 93))
509023	32752094	High CNTN1 expression was associated with biochemical recurrence following radical proctectomy in PC.	('CNTN1', 'Gene', (5, 10))	('High', 'Var', (0, 4))	('expression', 'MPA', (11, 21))	('biochemical recurrence', 'Disease', (42, 64))	('PC', 'CellLine', 'CVCL:0152', (98, 100))	('associated with', 'Reg', (26, 41))
509029	32752094	In view of the critical aspect of communications between cancer and stroma, proper adhesion is critical for cancer evolution or progression, targeting CNTN1 might thus be a useful option.	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('cancer', 'Disease', (57, 63))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('CNTN1', 'Gene', (151, 156))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('targeting', 'Var', (141, 150))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
509051	32752094	Indeed, silencing or inhibition of CNTN1 in experimental models have already highlighted its suitability as a potential target in lung, gastric, prostate, thyroid cancers, and oral squamous cell carcinoma.	('oral squamous cell carcinoma', 'Disease', (176, 204))	('thyroid cancer', 'Phenotype', 'HP:0002890', (155, 169))	('prostate', 'Disease', (145, 153))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (181, 204))	('silencing', 'Var', (8, 17))	('thyroid cancers', 'Disease', (155, 170))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (176, 204))	('gastric', 'Disease', (136, 143))	('thyroid cancers', 'Disease', 'MESH:D013964', (155, 170))	('CNTN1', 'Gene', (35, 40))	('carcinoma', 'Phenotype', 'HP:0030731', (195, 204))	('lung', 'Disease', (130, 134))	('inhibition', 'NegReg', (21, 31))	('cancers', 'Phenotype', 'HP:0002664', (163, 170))
509061	29290822	Conclusions: Collectively, our findings outlined a model whereby misregulated miR-31-5p-ACOX1 axis in tumor alters lipid metabolomes, consequently eliciting an intracellular signaling change to enhance cell motility.	('eliciting', 'Reg', (147, 156))	('alters', 'Reg', (108, 114))	('miR-31', 'Gene', '407035', (78, 84))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('cell motility', 'CPA', (202, 215))	('misregulated', 'Var', (65, 77))	('intracellular signaling change', 'MPA', (160, 190))	('lipid', 'Chemical', 'MESH:D008055', (115, 120))	('enhance', 'PosReg', (194, 201))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('lipid metabolomes', 'MPA', (115, 132))	('miR-31', 'Gene', (78, 84))
509064	29290822	Given their extensive involvement in many biological processes, including proliferation, apoptosis, differentiation, and metabolic homeostasis, mutations or mis-expression of miRNAs have been associated with the progression of various types of human cancers.	('mis-expression', 'Var', (157, 171))	('cancers', 'Disease', 'MESH:D009369', (250, 257))	('associated', 'Reg', (192, 202))	('human', 'Species', '9606', (244, 249))	('cancers', 'Phenotype', 'HP:0002664', (250, 257))	('rat', 'Species', '10116', (81, 84))	('cancers', 'Disease', (250, 257))	('miRNAs', 'Gene', (175, 181))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))	('mutations', 'Var', (144, 153))
509077	29290822	Interestingly, aside from oncogenic signaling and cell proliferation, an enrichment of predicted targets in fatty acid and peroxisome-associated metabolic pathways was evident, suggesting that distinct and hitherto unknown cellular changes may arise as a consequence of these OSCC-associated miRNA alterations.	('miRNA alterations', 'Var', (292, 309))	('fatty acid', 'Chemical', 'MESH:D005227', (108, 118))	('OSCC-associated', 'Disease', (276, 291))	('rat', 'Species', '10116', (62, 65))	('alterations', 'Var', (298, 309))	('rat', 'Species', '10116', (302, 305))
509090	29290822	ACOX1 deficiency is connected with a lethal human disease, called pseudoneonatal adrenoleukodystrophy (P-NALD).	('human', 'Species', '9606', (44, 49))	('ACOX1', 'Gene', (0, 5))	('pseudoneonatal adrenoleukodystrophy', 'Disease', 'MESH:C536662', (66, 101))	('P-NALD', 'Disease', 'MESH:D052919', (103, 109))	('connected', 'Reg', (20, 29))	('deficiency', 'Var', (6, 16))	('pseudoneonatal adrenoleukodystrophy', 'Disease', (66, 101))	('P-NALD', 'Disease', (103, 109))
509123	29290822	The luciferase reporter vectors for the wild-type or mutant ACOX1 3' UTR containing the miR-31-5p binding site were constructed into pMIR-REPORT luciferase system (Thermo Fisher Scientific).	('miR-31', 'Gene', '407035', (88, 94))	('miR-31', 'Gene', (88, 94))	('mutant', 'Var', (53, 59))	('ACOX1', 'Gene', (60, 65))
509124	29290822	Mutated ACOX1 3' UTR was generated by replacement of the target sequence UCUUGC to AAGCUU using two-step mutagenesis PCR.	('Mutated', 'Var', (0, 7))	('ACOX1', 'Gene', (8, 13))	('rat', 'Species', '10116', (29, 32))	('PC', 'Chemical', 'MESH:D010713', (117, 119))
509125	29290822	The vectors expressing firefly luciferase reporter fused with wild-type or mutant ACOX1 3' UTR were co-transfected with miR-31-5p antisense oligomers or scramble control into OSCC cells.	('miR-31', 'Gene', (120, 126))	('ACOX1', 'Gene', (82, 87))	('mutant', 'Var', (75, 81))	('miR-31', 'Gene', '407035', (120, 126))
509157	29290822	To confirm our findings, we also analyzed HNSCC and OSCC microRNA deep sequencing datasets from The Cancer Genome Atlas (TCGA) database, and subsequently identified 40 markedly up-regulated miRNAs (p-value < 0.05 and fold change > 2) in 43 HNSCC tissues (Figure 1A) and 47 over-expressed miRNAs (p-value < 0.05 and fold change > 4) in 28 OSCC subjects (Figure S2), as compared with their paired normal specimens.	('miRNAs', 'Var', (190, 196))	('up-regulated', 'PosReg', (177, 189))	('Cancer Genome Atlas', 'Disease', (100, 119))	('Cancer', 'Phenotype', 'HP:0002664', (100, 106))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (100, 119))	('over-expressed', 'PosReg', (273, 287))
509169	29290822	This expression profiling uncovered ACOX1, the first enzyme in peroxisomal lipid metabolism, as a possible target: depletion of miR-31-5p using antisense oligonucleotides increased both mRNA and protein levels of ACOX1 in various cultured OSCC cells (Figure 2C-2D and S5E) and also in a dose-dependent manner (Figure S5F).	('miR-31', 'Gene', '407035', (128, 134))	('miR-31', 'Gene', (128, 134))	('antisense', 'Var', (144, 153))	('oligonucleotides', 'Chemical', 'MESH:D009841', (154, 170))	('depletion', 'Var', (115, 124))	('increased', 'PosReg', (171, 180))	('ACOX1', 'Gene', (213, 218))	('lipid', 'Chemical', 'MESH:D008055', (75, 80))
509178	29290822	To test this hypothesis, we set out to assess various lipidomic features of cells in the context of miR-31-5p or ACOX1 mis-expression.	('mis-expression', 'Var', (119, 133))	('lipid', 'Chemical', 'MESH:D008055', (54, 59))	('miR-31', 'Gene', (100, 106))	('miR-31', 'Gene', '407035', (100, 106))	('ACOX1', 'Gene', (113, 118))
509179	29290822	First, a mass spectrometry-based, untargeted lipid metabolite analysis was conducted on SCC25 cells with miR-31-5p or ACOX1 knockdown (Figure 3A).	('knockdown', 'Var', (124, 133))	('SCC25', 'CellLine', 'CVCL:1682', (88, 93))	('miR-31', 'Gene', '407035', (105, 111))	('lipid', 'Chemical', 'MESH:D008055', (45, 50))	('ACOX1', 'Gene', (118, 123))	('miR-31', 'Gene', (105, 111))
509180	29290822	We found that several long chain fatty acids, including myristic acid (C14:0), palmitic acid (C16:0) and stearic acid (C18:0), were notably reduced upon inactivation of miR-31-5p in the cells (Figure 3B, left), whereas the levels of two C18 unsaturated fatty acids exhibited no significant change (Figure S6A, top).	('stearic acid', 'MPA', (105, 117))	('C16', 'Chemical', 'MESH:D019308', (94, 97))	('palmitic acid', 'Chemical', 'MESH:D019308', (79, 92))	('miR-31', 'Gene', '407035', (169, 175))	('myristic acid', 'Chemical', 'MESH:D019814', (56, 69))	('unsaturated fatty acids', 'Chemical', 'MESH:D005231', (241, 264))	('C18', 'Gene', '27241', (119, 122))	('C18', 'Gene', '27241', (237, 240))	('long chain fatty acids', 'Chemical', '-', (22, 44))	('myristic acid', 'MPA', (56, 69))	('C14', 'Chemical', 'MESH:D019814', (71, 74))	('palmitic acid', 'MPA', (79, 92))	('C18', 'Gene', (119, 122))	('inactivation', 'Var', (153, 165))	('stearic acid', 'Chemical', 'MESH:C031183', (105, 117))	('C18', 'Gene', (237, 240))	('miR-31', 'Gene', (169, 175))	('long chain fatty acids', 'MPA', (22, 44))	('reduced', 'NegReg', (140, 147))
509181	29290822	While the UPLC-MS data showed that reduced expression of ACOX1 did not affect the abundance of C14, C16 and C18 free fatty acids (Figure 3B, left), certain phospholipids and sphingolipids, especially those derived from free fatty acids with 16- or 18-carbon chain, underwent significant increases in the same knockdown culture (Figure 3B, right).	('ACOX1', 'Gene', (57, 62))	('phospholipids', 'Chemical', 'MESH:D010743', (156, 169))	('reduced', 'NegReg', (35, 42))	('C18', 'Gene', (108, 111))	('carbon', 'Chemical', 'MESH:D002244', (251, 257))	('C16', 'MPA', (100, 103))	('expression', 'Var', (43, 53))	('C16', 'Chemical', 'MESH:D019308', (100, 103))	('phospholipids', 'MPA', (156, 169))	('C14', 'Chemical', 'MESH:D019814', (95, 98))	('C18', 'Gene', '27241', (108, 111))	('free fatty acids', 'Chemical', 'MESH:D005230', (112, 128))	('sphingolipids', 'Chemical', 'MESH:D013107', (174, 187))	('increases', 'PosReg', (287, 296))	('free fatty acids', 'Chemical', 'MESH:D005230', (219, 235))	('C14', 'MPA', (95, 98))
509183	29290822	Notably, we discovered that several phosphatidylinositols (PI), phosphatidylglycerol (PG) and sphingomyelin were dramatically repressed upon ACOX1 depletion (Figure 3B and S6A), whereas the miR-31-5p inactivation exhibited a discernibly reverse outcome.	('miR-31', 'Gene', '407035', (190, 196))	('phosphatidylinositols', 'Chemical', 'MESH:D010716', (36, 57))	('phosphatidylglycerol', 'MPA', (64, 84))	('PG', 'Chemical', 'MESH:D010715', (86, 88))	('repressed', 'PosReg', (126, 135))	('miR-31', 'Gene', (190, 196))	('ACOX1', 'MPA', (141, 146))	('depletion', 'Var', (147, 156))	('phosphatidylinositols', 'MPA', (36, 57))	('sphingomyelin', 'Chemical', 'MESH:D013109', (94, 107))	('phosphatidylglycerol', 'Chemical', 'MESH:D010715', (64, 84))
509188	29290822	By contrast, there was a prominent accumulation of lipid droplets in the ACOX1 knockdown cells (Figure 3C-3D).	('lipid droplets', 'MPA', (51, 65))	('accumulation', 'PosReg', (35, 47))	('lipid', 'Chemical', 'MESH:D008055', (51, 56))	('ACOX1', 'Gene', (73, 78))	('knockdown', 'Var', (79, 88))
509191	29290822	Via transport into the extracellular space, intracellular PGE2 is also known to activate various pro-tumorigenesis signaling pathways.	('PGE2', 'Chemical', 'MESH:D015232', (58, 62))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('intracellular', 'Var', (44, 57))	('PGE2', 'Gene', (58, 62))	('activate', 'PosReg', (80, 88))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
509193	29290822	We found that siRNA abrogation of ACOX1 expression significantly enhanced the PGE2 levels in the CM (Figure 3E).	('ACOX1', 'Gene', (34, 39))	('enhanced', 'PosReg', (65, 73))	('PGE2 levels in', 'MPA', (78, 92))	('abrogation', 'Var', (20, 30))	('PGE2', 'Chemical', 'MESH:D015232', (78, 82))
509194	29290822	Conversely, inhibition of miR-31-5p reduced the concentration of PGE2.	('rat', 'Species', '10116', (55, 58))	('inhibition', 'Var', (12, 22))	('miR-31', 'Gene', '407035', (26, 32))	('PGE2', 'Chemical', 'MESH:D015232', (65, 69))	('reduced', 'NegReg', (36, 43))	('miR-31', 'Gene', (26, 32))	('concentration of PGE2', 'MPA', (48, 69))
509198	29290822	Toward this end, mis-expression of miR-31-5p did not influence the cell proliferation and colony formation capacity in three independent OSCC cell lines (Figure S7A-S7D).	('miR-31', 'Gene', (35, 41))	('mis-expression', 'Var', (17, 31))	('miR-31', 'Gene', '407035', (35, 41))	('rat', 'Species', '10116', (79, 82))	('cell proliferation', 'CPA', (67, 85))	('colony formation capacity', 'CPA', (90, 115))
509199	29290822	However, in vitro migratory assay showed that loss of miR-31-5p notably suppressed the migratory ability of OSCC cells, and that ectopic expression of miR-31-5p exhibited an adverse effect on cell migration (Figure 4A-4B and S7E).	('cell migration', 'CPA', (192, 206))	('miR-31', 'Gene', (151, 157))	('rat', 'Species', '10116', (200, 203))	('miR-31', 'Gene', '407035', (54, 60))	('migratory ability of OSCC cells', 'CPA', (87, 118))	('loss', 'Var', (46, 50))	('rat', 'Species', '10116', (21, 24))	('suppressed', 'NegReg', (72, 82))	('miR-31', 'Gene', '407035', (151, 157))	('miR-31', 'Gene', (54, 60))	('rat', 'Species', '10116', (90, 93))
509210	29290822	Our results revealed that this PGE2 treatment triggered the in vitro migratory and invasive activities of OSCC cells (Figure 5A).	('triggered', 'PosReg', (46, 55))	('treatment', 'Var', (36, 45))	('rat', 'Species', '10116', (72, 75))	('in vitro migratory', 'CPA', (60, 78))	('PGE2', 'Chemical', 'MESH:D015232', (31, 35))	('PGE2', 'Gene', (31, 35))	('invasive activities of OSCC cells', 'CPA', (83, 116))
509214	29290822	In contrast, levels of phospho-Akt (Thr308 or Ser473) were either invariable or undetectable, respectively (Figure 5B, top), indicating that AKT-associated signaling was not activated in PGE2-treated OSCC cells.	('Akt', 'Gene', (31, 34))	('Ser473', 'Var', (46, 52))	('AKT', 'Gene', (141, 144))	('Thr308', 'Var', (36, 42))	('Ser473', 'Chemical', '-', (46, 52))	('Akt', 'Gene', '207', (31, 34))	('PGE2', 'Chemical', 'MESH:D015232', (187, 191))	('AKT', 'Gene', '207', (141, 144))	('Thr308', 'Chemical', '-', (36, 42))
509215	29290822	Next, given that PGE2 up-regulates the expression of certain matrix metalloproteinases in immunocytes and cancer cells, we subsequently examined the mRNA expression levels of various MMP molecules, such as MMP1, MMP2, MMP3, MMP9 and MMP10, in PGE2-stimulated OSCC cells.	('PGE2', 'Chemical', 'MESH:D015232', (243, 247))	('MMP1', 'Gene', '4312', (233, 237))	('MMP2', 'Gene', '4313', (212, 216))	('cancer', 'Disease', (106, 112))	('MMP1', 'Gene', (233, 237))	('up-regulates', 'PosReg', (22, 34))	('PGE2', 'Chemical', 'MESH:D015232', (17, 21))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('MMP3', 'Gene', (218, 222))	('PGE2', 'Var', (17, 21))	('MMP1', 'Gene', '4312', (206, 210))	('expression', 'MPA', (39, 49))	('MMP1', 'Gene', (206, 210))	('matrix', 'Enzyme', (61, 67))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('MMP3', 'Gene', '4314', (218, 222))	('MMP10', 'Gene', '4319', (233, 238))	('MMP2', 'Gene', (212, 216))	('MMP9', 'Gene', '4318', (224, 228))	('MMP9', 'Gene', (224, 228))	('MMP10', 'Gene', (233, 238))
509216	29290822	We discovered that PGE2 treatment markedly triggered an increase in MMP9 relative to control but not the other MMPs, at both the mRNA (Figure 5C, top) and protein (Figure S9) levels.	('PGE2', 'Gene', (19, 23))	('increase', 'PosReg', (56, 64))	('treatment', 'Var', (24, 33))	('MMP9', 'Gene', '4318', (68, 72))	('PGE2', 'Chemical', 'MESH:D015232', (19, 23))	('MMP9', 'Gene', (68, 72))
509218	29290822	Our results showed that treatment with SC-51322 significantly antagonized the PGE2-induced cell migration and invasion (Figure 5A), ERK activation (Figure 5B, bottom) and MMP9 expression (Figure 5C, bottom and S9).	('SC-51322', 'Chemical', '-', (39, 47))	('ERK', 'Gene', '5594', (132, 135))	('MMP9', 'Gene', '4318', (171, 175))	('ERK', 'Gene', (132, 135))	('PGE2-induced', 'Gene', (78, 90))	('rat', 'Species', '10116', (99, 102))	('expression', 'MPA', (176, 186))	('activation', 'PosReg', (136, 146))	('antagonized', 'NegReg', (62, 73))	('cell migration', 'CPA', (91, 105))	('SC-51322', 'Var', (39, 47))	('MMP9', 'Gene', (171, 175))	('PGE2', 'Chemical', 'MESH:D015232', (78, 82))
509228	29290822	To this end, inhibiting the expression of miR-31-5p in OSCC cells significantly attenuated the level of ERK1/2 phosphorylation (Figure S10A-S10B).	('miR-31', 'Gene', (42, 48))	('inhibiting', 'NegReg', (13, 23))	('ERK1/2', 'Gene', (104, 110))	('S10A', 'SUBSTITUTION', 'None', (135, 139))	('ERK1/2', 'Gene', '5595;5594', (104, 110))	('expression', 'MPA', (28, 38))	('attenuated', 'NegReg', (80, 90))	('miR-31', 'Gene', '407035', (42, 48))	('S10A', 'Var', (135, 139))	('S10B', 'Var', (140, 144))	('S10B', 'SUBSTITUTION', 'None', (140, 144))
509229	29290822	By contrast, siRNA-mediated ACOX1 suppression in two OSCC cell lines activated the ERK pathway (Figure S10A-S10B).	('ACOX1', 'Gene', (28, 33))	('ERK', 'Gene', (83, 86))	('S10B', 'SUBSTITUTION', 'None', (108, 112))	('S10A', 'Var', (103, 107))	('ERK', 'Gene', '5594', (83, 86))	('activated', 'PosReg', (69, 78))	('suppression', 'NegReg', (34, 45))	('S10B', 'Var', (108, 112))	('S10A', 'SUBSTITUTION', 'None', (103, 107))
509234	29290822	Simultaneous knockdown of ACOX1 in the miR-31-5p-depleted cells antagonized the alterations exerted by single knockdown of miR-31-5p: the down-regulation of phospho-ERK and MMP9 was reversed upon co-treatment of ACOX1 siRNAs (Figure 6A-6C), and the reduced migration and invasiveness potential as a consequence of miR-31-5p knockdown was rescued by ACOX1 inactivation (Figure 6D).	('knockdown', 'Var', (324, 333))	('miR-31', 'Gene', '407035', (123, 129))	('inactivation', 'Var', (355, 367))	('reduced', 'NegReg', (249, 256))	('miR-31', 'Gene', (39, 45))	('rat', 'Species', '10116', (260, 263))	('MMP9', 'Gene', '4318', (173, 177))	('MMP9', 'Gene', (173, 177))	('miR-31', 'Gene', '407035', (39, 45))	('rat', 'Species', '10116', (84, 87))	('miR-31', 'Gene', (314, 320))	('ERK', 'Gene', '5594', (165, 168))	('miR-31', 'Gene', (123, 129))	('migration', 'CPA', (257, 266))	('down-regulation', 'NegReg', (138, 153))	('invasiveness potential', 'CPA', (271, 293))	('ERK', 'Gene', (165, 168))	('ACOX1', 'Gene', (349, 354))	('miR-31', 'Gene', '407035', (314, 320))
509239	29290822	Interestingly, we further discovered that the expression levels of ACOX1 were progressively decreased in HNSCC patients with higher-grade lymph node metastasis, in line with our observations that ACOX1 silencing raised the migratory and invasive potential of OSCC cells.	('ACOX1', 'Gene', (196, 201))	('expression levels', 'MPA', (46, 63))	('raised', 'PosReg', (212, 218))	('HNSCC', 'Disease', (105, 110))	('rat', 'Species', '10116', (226, 229))	('decreased', 'NegReg', (92, 101))	('silencing', 'Var', (202, 211))	('patients', 'Species', '9606', (111, 119))
509249	29290822	In contrast, its down-regulation in tumor has also been documented based on expression reduction in gastric cancer and prostate cancer, and homozygous deletion of miR-31-5p host gene (MIR31HG) in mesothelioma.	('MIR31HG', 'Gene', (184, 191))	('MIR31HG', 'Gene', '554202', (184, 191))	('gastric cancer', 'Phenotype', 'HP:0012126', (100, 114))	('homozygous', 'Var', (140, 150))	('tumor', 'Disease', (36, 41))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('gastric cancer', 'Disease', (100, 114))	('prostate cancer', 'Disease', 'MESH:D011471', (119, 134))	('prostate cancer', 'Phenotype', 'HP:0012125', (119, 134))	('miR-31', 'Gene', (163, 169))	('prostate cancer', 'Disease', (119, 134))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('reduction', 'NegReg', (87, 96))	('gastric cancer', 'Disease', 'MESH:D013274', (100, 114))	('mesothelioma', 'Disease', (196, 208))	('mesothelioma', 'Disease', 'MESH:D008654', (196, 208))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('expression', 'MPA', (76, 86))	('down-regulation', 'NegReg', (17, 32))	('miR-31', 'Gene', '407035', (163, 169))
509268	29290822	In this capacity, liver-specific miR-122-5p is reportedly associated with hepatic cholesterol and lipid metabolism, as miR-122-5p inactivation triggers down-regulation of plasma cholesterol and triglycerides in high-fat diet mice.	('miR-122-5p', 'Gene', '100188847', (33, 43))	('triglycerides', 'MPA', (194, 207))	('down-regulation', 'NegReg', (152, 167))	('inactivation', 'Var', (130, 142))	('associated', 'Reg', (58, 68))	('lipid', 'Chemical', 'MESH:D008055', (98, 103))	('cholesterol', 'Chemical', 'MESH:D002784', (82, 93))	('miR-122-5p', 'Gene', '100188847', (119, 129))	('miR-122-5p', 'Gene', (33, 43))	('cholesterol', 'Chemical', 'MESH:D002784', (178, 189))	('triglycerides', 'Chemical', 'MESH:D014280', (194, 207))	('hepatic', 'MPA', (74, 81))	('mice', 'Species', '10090', (225, 229))	('miR-122-5p', 'Gene', (119, 129))
509274	29290822	Given the critical roles of lipids in many cellular processes, dysregulation of lipid metabolism has been conceivably linked to cancer.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('lipids', 'Chemical', 'MESH:D008055', (28, 34))	('lipid', 'Chemical', 'MESH:D008055', (28, 33))	('linked', 'Reg', (118, 124))	('lipid', 'Chemical', 'MESH:D008055', (80, 85))	('dysregulation', 'Var', (63, 76))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('lipid metabolism', 'MPA', (80, 96))	('cancer', 'Disease', (128, 134))
509300	29290822	EP4 receptor might also contribute to metastatic behavior, as treatment with EP4 antagonists significantly inhibits breast cancer metastasis.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('EP4', 'Gene', '5734', (77, 80))	('breast cancer', 'Phenotype', 'HP:0003002', (116, 129))	('breast cancer metastasis', 'Disease', (116, 140))	('EP4', 'Gene', (77, 80))	('inhibits', 'NegReg', (107, 115))	('contribute', 'Reg', (24, 34))	('EP4', 'Gene', '5734', (0, 3))	('antagonists', 'Var', (81, 92))	('EP4', 'Gene', (0, 3))	('breast cancer metastasis', 'Disease', 'MESH:D009362', (116, 140))
509312	25254241	Moreover, LOXL2 modulates focal adhesions, tight junctions, and cell polarity complexes in basal breast carcinoma cells through activation of the FAK signaling pathway.	('LOXL2', 'Var', (10, 15))	('activation', 'PosReg', (128, 138))	('FAK signaling pathway', 'Pathway', (146, 167))	('focal adhesions', 'Protein', (26, 41))	('breast carcinoma', 'Phenotype', 'HP:0003002', (97, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('tight junctions', 'CPA', (43, 58))	('breast carcinoma', 'Disease', (97, 113))	('breast carcinoma', 'Disease', 'MESH:D001943', (97, 113))	('modulates', 'Reg', (16, 25))	('cell polarity complexes', 'CPA', (64, 87))
509324	25254241	These two PPI subnetworks indicated that overexpression of LOXL2-WT or LOXL2-e13 greatly perturbed the PPI network in ESCC cells due to DEGs interacting with hundreds and thousands of proteins to achieve the biological consequences of the LOX2 protein itself.	('LOX', 'Gene', '4015', (59, 62))	('LOX', 'Gene', (59, 62))	('PPI network', 'Pathway', (103, 114))	('DEGs', 'Var', (136, 140))	('proteins', 'Protein', (184, 192))	('LOX', 'Gene', '4015', (71, 74))	('LOX', 'Gene', '4015', (239, 242))	('perturbed', 'NegReg', (89, 98))	('LOX', 'Gene', (71, 74))	('interacting', 'Interaction', (141, 152))	('LOX', 'Gene', (239, 242))
509325	25254241	Other sequence feature annotations from PIR_SUPERFAMILY indicated LOXL2-e13-DEGs were characterized by "histone H2B," "chaperone HSP70," and "serpin," while LOXL2-WT-DEGs were annotated by "zinc finger protein ZFP-36."	('serpin', 'Protein', (142, 148))	('HSP70', 'Gene', (129, 134))	('HSP70', 'Gene', '3308', (129, 134))	('LOXL2-e13-DEGs', 'Var', (66, 80))
509327	25254241	As for LOXL2-WT-DEGs, four carcinoma-related KEGG pathways were found: "hsa04010:MAPK signaling pathway," "hsa04110:Cell cycle," "hsa04115:p53 signaling pathway," and "hsa05200:Pathways in cancer."	('hsa04110', 'Var', (107, 115))	('carcinoma', 'Disease', 'MESH:D002277', (27, 36))	('carcinoma', 'Phenotype', 'HP:0030731', (27, 36))	('Cell cycle', 'CPA', (116, 126))	('carcinoma', 'Disease', (27, 36))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('p53 signaling pathway', 'Pathway', (139, 160))	('MAPK signaling pathway', 'Pathway', (81, 103))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('cancer', 'Disease', (189, 195))
509332	25254241	Much evidence has indicated that splicing abnormalities are a hallmark of cancer.	('cancer', 'Disease', (74, 80))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('splicing abnormalities', 'Var', (33, 55))
509333	25254241	The potential roles for splice variants in cancer might involve cell migration, cell growth, hormone responsiveness, apoptosis, and response to chemotherapy.	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('cancer', 'Disease', (43, 49))	('splice variants', 'Var', (24, 39))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('cell migration', 'CPA', (64, 78))	('cell growth', 'CPA', (80, 91))
509337	25254241	This indicates that the expression of tumour-specific splice variants significantly affects many cellular events, critical for cancer biology, which are still far from being illustrated.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('splice variants', 'Var', (54, 69))	('affects', 'Reg', (84, 91))	('tumour', 'Phenotype', 'HP:0002664', (38, 44))	('tumour', 'Disease', 'MESH:D009369', (38, 44))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('cellular', 'MPA', (97, 105))	('cancer', 'Disease', (127, 133))	('tumour', 'Disease', (38, 44))
509343	25254241	Interference of SERPINB1 promotes migration and invasion of HCC cells, with an apparent increase in the level of active matrix metalloproteinase-2 (MMP2).	('promotes', 'PosReg', (25, 33))	('matrix metalloproteinase-2', 'Gene', (120, 146))	('SERPINB1', 'Gene', (16, 24))	('increase', 'PosReg', (88, 96))	('MMP2', 'Gene', (148, 152))	('HCC', 'CellLine', 'CVCL:0C54', (60, 63))	('MMP2', 'Gene', '4313', (148, 152))	('Interference', 'Var', (0, 12))	('SERPINB1', 'Gene', '1992', (16, 24))	('matrix metalloproteinase-2', 'Gene', '4313', (120, 146))	('invasion', 'CPA', (48, 56))	('migration', 'CPA', (34, 43))
509344	25254241	It is interesting to note that SERPINB1 is also decreased 1.58-fold upon LOXL2-e13 overexpression.	('LOXL2-e13', 'Var', (73, 82))	('decreased', 'NegReg', (48, 57))	('overexpression', 'PosReg', (83, 97))	('SERPINB1', 'Gene', (31, 39))	('SERPINB1', 'Gene', '1992', (31, 39))
509351	25254241	In support of this, we find VEGF is upregulated 1.68-fold in the e13-WT-DEGs.	('VEGF', 'Gene', '7422', (28, 32))	('upregulated', 'PosReg', (36, 47))	('VEGF', 'Gene', (28, 32))	('e13-WT-DEGs', 'Var', (65, 76))
509353	25254241	Loss of ITGA3 prevents skin tumor formation by promoting epidermal turnover and depletion of slow-cycling cells.	('epidermal turnover', 'CPA', (57, 75))	('skin tumor', 'Phenotype', 'HP:0008069', (23, 33))	('depletion of slow-cycling cells', 'MPA', (80, 111))	('skin tumor', 'Disease', (23, 33))	('ITGA3', 'Gene', (8, 13))	('skin tumor', 'Disease', 'MESH:D012878', (23, 33))	('prevents', 'NegReg', (14, 22))	('promoting', 'PosReg', (47, 56))	('Loss', 'Var', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
509356	25254241	So it is expected that LOXL2-e13 causes broad changes in mRNA expression profile, including some critical tumor-related genes, enabling LOXL2-e13 to play new and specific roles in ESCC compared to its wild-type counterpart.	('changes', 'Reg', (46, 53))	('mRNA expression profile', 'MPA', (57, 80))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('LOXL2-e13', 'Var', (23, 32))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('LOXL2-e13', 'Var', (136, 145))	('ESCC', 'Disease', (180, 184))	('tumor', 'Disease', (106, 111))
509366	31239772	The high density of neutrophils was associated with worse cancer-related survival time (p<0.001) and was an independent prognostic factor for OSCC, while the HPV-positive group was associated with better cancer-related survival time.	('OSCC', 'Disease', (142, 146))	('cancer', 'Disease', (204, 210))	('cancer', 'Disease', 'MESH:D009369', (204, 210))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('worse', 'NegReg', (52, 57))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('high density', 'Var', (4, 16))	('cancer', 'Disease', (58, 64))	('HPV', 'Species', '10566', (158, 161))
509368	31239772	Detection of cytokines and chemokines revealed that one of the chemotactic factors of neutrophils, IL-8, was exhibited relatively low expression by HPV-positive OSCC cells, whereas HPV-negative OSCC cells were found to drive an IL-8 secretion profile.	('IL-8', 'Gene', '3576', (228, 232))	('HPV', 'Species', '10566', (181, 184))	('expression', 'MPA', (134, 144))	('HPV-positive', 'Var', (148, 160))	('IL-8', 'Gene', (228, 232))	('IL-8', 'Gene', '3576', (99, 103))	('HPV', 'Species', '10566', (148, 151))	('low', 'NegReg', (130, 133))	('IL-8', 'Gene', (99, 103))
509422	31239772	cDNA was used for qRT-PCR analysis, and the mRNA expression of iL-8 in the three groups was detected after verifying the transfection efficiency of E7-HA-Flag.	('iL-8', 'Gene', (63, 67))	('iL-8', 'Gene', '3576', (63, 67))	('E7-HA-Flag', 'Var', (148, 158))
509446	31239772	In other words, high-density neutrophils were less infiltrated in the HPV (P16) positive expression group (21.74%, Figure 1C b), while high-density neutrophils were more infiltrated in the HPV (P16) negative group (55.17%, Figure 1C a).	('positive expression', 'Var', (80, 99))	('less', 'NegReg', (46, 50))	('HPV', 'Species', '10566', (189, 192))	('P16', 'Gene', '1029', (194, 197))	('P16', 'Gene', '1029', (75, 78))	('HPV', 'Species', '10566', (70, 73))	('P16', 'Gene', (194, 197))	('P16', 'Gene', (75, 78))
509455	31239772	By qRT-PCR (Figure 3A) and western blot analysis (Figure 3B and C), the expression of HPV18 E7 in the HPV18 E7 transfection group was significantly higher than that in the empty vector transfection group and the control group.	('HPV', 'Species', '10566', (86, 89))	('HPV18', 'Gene', (102, 107))	('expression', 'MPA', (72, 82))	('E7 transfection', 'Var', (108, 123))	('HPV18', 'Gene', (86, 91))	('HPV', 'Species', '10566', (102, 105))	('transfection', 'Var', (111, 123))	('higher', 'PosReg', (148, 154))
509485	31239772	It was noted that ROS of neutrophil origin, for example, MPO-mediated HOCl formation, had a relationship with point mutation and DNA damage.	('HOCl formation', 'CPA', (70, 84))	('MPO', 'Gene', '4353', (57, 60))	('point mutation', 'Var', (110, 124))	('HOCl', 'Chemical', 'MESH:D006997', (70, 74))	('ROS', 'Chemical', 'MESH:D017382', (18, 21))	('DNA damage', 'MPA', (129, 139))	('MPO', 'Gene', (57, 60))
509500	31239772	Furthermore, the results of our study explored that neutrophils were less infiltrated in the HPV (P16) expression positive group (Figure 1C a), while neutrophils were more infiltrated in the HPV (P16) expression negative group (Figure 1C b).	('P16', 'Gene', (98, 101))	('P16', 'Gene', (196, 199))	('HPV', 'Species', '10566', (93, 96))	('HPV', 'Species', '10566', (191, 194))	('neutrophils', 'CPA', (52, 63))	('P16', 'Gene', '1029', (196, 199))	('P16', 'Gene', '1029', (98, 101))	('positive', 'Var', (114, 122))	('less', 'NegReg', (69, 73))
509502	31239772	Based on this result, HPV-negative expression in OSCC affected neutrophil infiltration and location.	('OSCC', 'Gene', (49, 53))	('affected', 'Reg', (54, 62))	('neutrophil infiltration', 'CPA', (63, 86))	('HPV', 'Species', '10566', (22, 25))	('location', 'CPA', (91, 99))	('expression', 'Var', (35, 45))
509595	30925774	Similarly, blockade of both IL-6 and PD-L1 inhibits growth of hepatocellular carcinoma in the mouse model.	('hepatocellular carcinoma', 'Disease', (62, 86))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (62, 86))	('PD-L1', 'Gene', (37, 42))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('mouse', 'Species', '10090', (94, 99))	('growth', 'MPA', (52, 58))	('blockade', 'Var', (11, 19))	('inhibits', 'NegReg', (43, 51))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (62, 86))
509600	30925774	Macrophages are recruited to the tumour site by CCL-2-4, CCL-5, -7, -8, -12, VEGF-A, PDGF, M-CSF and IL-10.	('VEGF-A', 'Gene', '7422', (77, 83))	('M-CSF', 'Gene', (91, 96))	('VEGF-A', 'Gene', (77, 83))	('tumour', 'Disease', (33, 39))	('CCL-2-4', 'Gene', '6369;6347;6348;6351', (48, 55))	('IL-10', 'Gene', '3586', (101, 106))	('CCL-2-4', 'Gene', (48, 55))	('CCL-5', 'Gene', (57, 62))	('PDGF', 'Var', (85, 89))	('CCL-5', 'Gene', '6352', (57, 62))	('tumour', 'Phenotype', 'HP:0002664', (33, 39))	('M-CSF', 'Gene', '1435', (91, 96))	('tumour', 'Disease', 'MESH:D009369', (33, 39))	('IL-10', 'Gene', (101, 106))
509620	30925774	Concerning the target of anti-cancer immunity in HNSCC, the protein exhibiting genetic alterations, aberrantly expressed proteins such is MAGE-A4 antigen normally expressed in testicular cells or virus proteins were discussed.	('HNSCC', 'Phenotype', 'HP:0012288', (49, 54))	('alterations', 'Var', (87, 98))	('MAGE-A4', 'Gene', '4103', (138, 145))	('cancer', 'Disease', (30, 36))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('MAGE-A4', 'Gene', (138, 145))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
509625	30925774	Depletion of Treg lymphocytes in combination with immune checkpoint inhibitors, such as an antibody against CTLA-4, represent prospective anti-cancer therapy.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('antibody', 'Var', (91, 99))	('CTLA-4', 'Gene', (108, 114))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('CTLA-4', 'Gene', '1493', (108, 114))
509645	30925774	Normal primary keratinocytes consequently acquire an activated phenotype, including markers of epithelial-mesenchymal transition such as co-expression of vimentin and keratins and also transcription factor Snail.	('co-expression', 'Var', (137, 150))	('keratins', 'Protein', (167, 175))	('Snail', 'Gene', '6615', (206, 211))	('Snail', 'Gene', (206, 211))	('vimentin', 'Gene', '7431', (154, 162))	('vimentin', 'Gene', (154, 162))
509669	30925774	Modulation of intercellular signalling in the tumour microenvironment can be a valid and robust therapeutic modality.	('Modulation', 'Var', (0, 10))	('tumour', 'Disease', (46, 52))	('tumour', 'Phenotype', 'HP:0002664', (46, 52))	('tumour', 'Disease', 'MESH:D009369', (46, 52))
509859	26619011	Identifying recurrent mutations in cancer reveals widespread lineage diversity and mutational specificity Mutational hotspots indicate selective pressure across a population of tumor samples, but their prevalence within and across cancer types is incompletely characterized.	('cancer', 'Disease', 'MESH:D009369', (231, 237))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('cancer', 'Disease', (231, 237))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('mutations', 'Var', (22, 31))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('tumor', 'Disease', (177, 182))	('cancer', 'Disease', (35, 41))
509861	26619011	We applied the algorithm to 11,119 human tumors, spanning 41 cancer types, and identified 470 hotspot somatic substitutions in 275 genes.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('substitutions', 'Var', (110, 123))	('human', 'Species', '9606', (35, 40))	('cancer', 'Disease', (61, 67))	('tumors', 'Disease', (41, 47))	('tumors', 'Disease', 'MESH:D009369', (41, 47))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))
509862	26619011	We find that half of all human tumors possess one or more mutational hotspots with widespread lineage-, position-, and mutant allele-specific differences, many of which are likely functional.	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumors', 'Disease', (31, 37))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('human', 'Species', '9606', (25, 30))	('tumors', 'Disease', 'MESH:D009369', (31, 37))	('mutant', 'Var', (119, 125))
509870	26619011	Furthermore, not all driver alterations in a cancer gene have the same functional impact, and are therefore likely to have varying clinical significance.	('cancer', 'Disease', (45, 51))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('alterations', 'Var', (28, 39))
509871	26619011	However, emerging data indicate that different hotspot mutations in the same cancer gene can be functionally distinct in vitro and in vivo and display different clinical phenotypes and drug sensitivity.	('mutations', 'Var', (55, 64))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('drug sensitivity', 'Phenotype', 'HP:0020174', (185, 201))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))
509872	26619011	To date, studies of hotspot mutations in cancer have been limited to within individual tumor types or have focused on individual cancer genes across tumor types.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('tumor', 'Disease', (87, 92))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('tumor', 'Disease', (149, 154))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('mutations', 'Var', (28, 37))
509874	26619011	As broad-based clinical sequencing has begun to inform the care of individual cancer patients, this would begin to address one of the greatest challenges in the practice of genomically driven cancer medicine: interpreting the biological and clinical significance of mutations in even presumed actionable cancer genes as they arise in oncology clinics.	('cancer', 'Disease', 'MESH:D009369', (304, 310))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', (304, 310))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('patients', 'Species', '9606', (85, 93))	('oncology', 'Phenotype', 'HP:0002664', (334, 342))	('mutations', 'Var', (266, 275))	('cancer', 'Disease', (192, 198))	('cancer', 'Disease', 'MESH:D009369', (192, 198))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('cancer', 'Phenotype', 'HP:0002664', (304, 310))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))
509878	26619011	The repository consists of 2,007,694 somatic substitutions in protein-coding regions with a median of 57 mutations (25 and 125 mutations; 25th and 75th percentile respectively) per tumor-normal pair with significant variability in mutation rates among and between tumors and types.	('tumor', 'Phenotype', 'HP:0002664', (264, 269))	('tumor', 'Disease', (181, 186))	('tumor', 'Disease', (264, 269))	('tumors', 'Disease', (264, 270))	('tumors', 'Disease', 'MESH:D009369', (264, 270))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('tumors', 'Phenotype', 'HP:0002664', (264, 270))	('mutations', 'Var', (127, 136))	('tumor', 'Disease', 'MESH:D009369', (264, 269))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))
509880	26619011	1b, Table 1, Supplementary Table 2, and Methods) and 54.8% of all tumors assessed here possessed one or more hotspot mutations.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('mutations', 'Var', (117, 126))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('tumors', 'Disease', (66, 72))	('tumors', 'Disease', 'MESH:D009369', (66, 72))
509883	26619011	Moreover, the number of observed mutant amino acids at a given hotspot generally increases with its mutational frequency across tumors types (Supplementary Fig.	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('mutational', 'Var', (100, 110))	('mutant', 'Var', (33, 39))	('tumors', 'Disease', (128, 134))	('tumors', 'Disease', 'MESH:D009369', (128, 134))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('increases', 'PosReg', (81, 90))
509886	26619011	For instance, IDH1 R132 is most common in low-grade gliomas, glioblastomas, acute myeloid leukemias (AMLs), and cutaneous melanomas; but it is also present in 1 to 6 tumors in each of 11 additional cancer types.	('glioblastomas', 'Phenotype', 'HP:0012174', (61, 74))	('acute myeloid leukemias', 'Phenotype', 'HP:0004808', (76, 99))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('acute myeloid leukemias', 'Disease', (76, 99))	('myeloid leukemias', 'Phenotype', 'HP:0012324', (82, 99))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))	('cutaneous melanomas', 'Disease', (112, 131))	('gliomas', 'Disease', (52, 59))	('cancer', 'Disease', (198, 204))	('glioblastomas', 'Disease', (61, 74))	('IDH1 R132', 'Var', (14, 23))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('tumors', 'Disease', (166, 172))	('gliomas', 'Disease', 'MESH:D005910', (52, 59))	('glioblastomas', 'Disease', 'MESH:D005909', (61, 74))	('melanomas', 'Phenotype', 'HP:0002861', (122, 131))	('tumors', 'Disease', 'MESH:D009369', (166, 172))	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('leukemias', 'Phenotype', 'HP:0001909', (90, 99))	('gliomas', 'Phenotype', 'HP:0009733', (52, 59))	('common', 'Reg', (32, 38))	('cutaneous melanomas', 'Phenotype', 'HP:0012056', (112, 131))	('acute myeloid leukemias', 'Disease', 'MESH:D015470', (76, 99))	('cutaneous melanomas', 'Disease', 'MESH:C562393', (112, 131))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (112, 130))	('melanoma', 'Phenotype', 'HP:0002861', (122, 130))
509887	26619011	AKT1 E17K arises in greatest numbers in breast cancer, but also in 1 to 3 tumors of 10 additional cancer types.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('breast cancer', 'Disease', 'MESH:D001943', (40, 53))	('AKT1', 'Gene', '207', (0, 4))	('AKT1', 'Gene', (0, 4))	('breast cancer', 'Disease', (40, 53))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('breast cancer', 'Phenotype', 'HP:0003002', (40, 53))	('cancer', 'Disease', (47, 53))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('E17K', 'Mutation', 'rs121434592', (5, 9))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('cancer', 'Disease', (98, 104))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('E17K', 'Var', (5, 9))	('tumors', 'Disease', 'MESH:D009369', (74, 80))	('tumors', 'Disease', (74, 80))
509891	26619011	Of all hotspots, 81% arise in two or more tumor types, suggesting that many hotspot mutations may confer a growth advantage across diverse lineages.	('tumor', 'Disease', (42, 47))	('growth advantage', 'CPA', (107, 123))	('mutations', 'Var', (84, 93))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
509893	26619011	Thus, hotspot mutations that arise in a single tumor type may reflect organ-specific growth advantages but they represent only a small minority of all hotspot mutations in cancer.	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('cancer', 'Disease', (172, 178))	('mutations', 'Var', (14, 23))	('tumor', 'Disease', (47, 52))
509894	26619011	Twenty-seven hotspots (5.7%) were more frequently mutated in tumors of a squamous cell lineage (Supplementary Fig.	('tumors', 'Disease', (61, 67))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('mutated', 'Var', (50, 57))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))
509895	26619011	6), the most significant of which were MAPK1 E322 and EP300 D1399 (q-value = 6x10-13 and 1x10-11 respectively, chi2) and may potentially confer a squamous cell-type specific growth advantage.	('EP300 D1399', 'Var', (54, 65))	('MAPK1', 'Gene', '5594', (39, 44))	('E322', 'Var', (45, 49))	('MAPK1', 'Gene', (39, 44))	('squamous cell-type specific growth advantage', 'CPA', (146, 190))
509897	26619011	In some tumor types, a large proportion of tumors possess one or more hotspot mutations including a significant fraction of tumors with a hotspot in a candidate oncogene (Fig.	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('tumor', 'Disease', 'MESH:D009369', (124, 129))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Disease', (124, 129))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('mutations', 'Var', (78, 87))	('tumors', 'Disease', (124, 130))	('tumors', 'Disease', 'MESH:D009369', (124, 130))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Disease', (8, 13))	('tumors', 'Disease', (43, 49))	('tumor', 'Disease', (43, 48))	('tumors', 'Disease', 'MESH:D009369', (43, 49))
509899	26619011	Some of these differences are certainly attributable to the fact that hotspots are only one of many possible driver genomic aberrations, including specific gene fusions or focal amplifications and deletions.	('focal amplifications', 'Var', (172, 192))	('gene fusions', 'Var', (156, 168))	('deletions', 'Var', (197, 206))	('tri', 'Chemical', '-', (42, 45))
509903	26619011	Likewise, while papillary thyroid and high-grade pontine gliomas have mutations rates similar to nasopharyngeal tumors and neuroblastomas, the former far more commonly bear hotspot mutations (Fig.	('neuroblastomas', 'Disease', (123, 137))	('nasopharyngeal tumors', 'Phenotype', 'HP:0100630', (97, 118))	('mutations', 'Var', (70, 79))	('papillary thyroid', 'Disease', (16, 33))	('nasopharyngeal tumors', 'Disease', (97, 118))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('gliomas', 'Disease', 'MESH:D005910', (57, 64))	('neuroblastomas', 'Phenotype', 'HP:0003006', (123, 137))	('neuroblastomas', 'Disease', 'MESH:D009447', (123, 137))	('gliomas', 'Disease', (57, 64))	('gliomas', 'Phenotype', 'HP:0009733', (57, 64))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('nasopharyngeal tumors', 'Disease', 'MESH:D009304', (97, 118))
509904	26619011	For each of these hotspots, an associated transcript abnormality was identified from RNA sequencing of affected tumors (exon skipping, intron retention, in-frame deletions; Supplementary Fig.	('in-frame deletions', 'Var', (153, 171))	('tumors', 'Disease', (112, 118))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumors', 'Disease', 'MESH:D009369', (112, 118))	('intron', 'MPA', (135, 141))	('exon skipping', 'Var', (120, 133))
509905	26619011	7a), including two previously characterized in-frame activating mutations (MET D1010_splice and PIK3R1 M582_splice, both exon 14 skipping events).	('PIK3R1', 'Gene', (96, 102))	('PIK3R1', 'Gene', '5295', (96, 102))	('M582_splice', 'Var', (103, 114))	('MET D1010_splice', 'Var', (75, 91))
509906	26619011	While nonsense mutations scattered throughout a gene may reflect a pattern of loss-of-function consistent with tumor suppressor activity, a nonsense hotspot would appear to indicate the selection for the selective truncation of specific functional domains.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumor', 'Disease', (111, 116))	('nonsense mutations', 'Var', (6, 24))	('loss-of-function', 'NegReg', (78, 94))
509909	26619011	The majority of hotspot mutations arose in diverse tumor types and organ systems, yet widespread differences exist among individual residues and mutant amino acids in hotspots, genes, and tumor types (Fig.	('tumor', 'Disease', (188, 193))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('mutant', 'Var', (145, 151))	('tumor', 'Disease', (51, 56))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('mutations', 'Var', (24, 33))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
509911	26619011	We found that gastric cancers were more similar to multiple myeloma in the preponderance of non-G12 mutations compared to endometrial, lung, colorectal, and pancreas tumors (p-value = 5.3x10-18, Supplementary Table 4).	('pancreas tumors', 'Disease', 'MESH:D010190', (157, 172))	('colorectal', 'Disease', (141, 151))	('mutations', 'Var', (100, 109))	('tri', 'Chemical', '-', (17, 20))	('non-G12', 'Gene', (92, 99))	('multiple myeloma', 'Phenotype', 'HP:0006775', (51, 67))	('tri', 'Chemical', '-', (128, 131))	('cancers', 'Phenotype', 'HP:0002664', (22, 29))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('multiple myeloma', 'Disease', (51, 67))	('colorectal', 'Disease', 'MESH:D015179', (141, 151))	('gastric cancers', 'Disease', (14, 29))	('gastric cancers', 'Disease', 'MESH:D013274', (14, 29))	('pancreas tumors', 'Disease', (157, 172))	('gastric cancers', 'Phenotype', 'HP:0012126', (14, 29))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))	('multiple myeloma', 'Disease', 'MESH:D009101', (51, 67))
509913	26619011	Among KRAS G12 mutations, the abundance of G12C mutations are highest in lung adenocarcinomas (p-value = 4x10-42), an event that may be associated with prognostic differences compared with non-G12C KRAS mutations.	('KRAS', 'Gene', '3845', (6, 10))	('lung adenocarcinomas', 'Disease', (73, 93))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (73, 92))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (73, 93))	('mutations', 'Var', (15, 24))	('G12C', 'Mutation', 'rs121913530', (193, 197))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (73, 93))	('carcinomas', 'Phenotype', 'HP:0030731', (83, 93))	('KRAS', 'Gene', (198, 202))	('highest', 'Reg', (62, 69))	('G12C mutations', 'Var', (43, 57))	('KRAS', 'Gene', '3845', (198, 202))	('G12C', 'Mutation', 'rs121913530', (43, 47))	('KRAS', 'Gene', (6, 10))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))
509914	26619011	Such mutant amino acid specificity was also apparent in pancreas tumors, where KRAS G12R was more common than in any other tumor type (21% versus between 0 and 2.6%; chi2 p-value = 4.8x10-19).	('tumor', 'Disease', (123, 128))	('tumor', 'Disease', (65, 70))	('G12R', 'SUBSTITUTION', 'None', (84, 88))	('pancreas tumors', 'Disease', (56, 71))	('KRAS', 'Gene', '3845', (79, 83))	('G12R', 'Var', (84, 88))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('pancreas tumors', 'Disease', 'MESH:D010190', (56, 71))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('KRAS', 'Gene', (79, 83))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
509915	26619011	Gastric cancers, on the other hand, had the fewest G12V mutations among all KRAS G12-mutant tumor types, but the highest proportion of G12S (p-value = 0.007, Fig.	('cancers', 'Phenotype', 'HP:0002664', (8, 15))	('G12S', 'Mutation', 'rs121913530', (135, 139))	('Gastric cancers', 'Disease', (0, 15))	('Gastric cancers', 'Phenotype', 'HP:0012126', (0, 15))	('G12V mutations', 'Var', (51, 65))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('KRAS', 'Gene', (76, 80))	('KRAS', 'Gene', '3845', (76, 80))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('G12V', 'Mutation', 'rs121913529', (51, 55))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('tumor', 'Disease', (92, 97))	('G12S', 'Var', (135, 139))	('Gastric cancers', 'Disease', 'MESH:D013274', (0, 15))
509916	26619011	While papillary thyroid cancers nearly exclusively possessed codon Q61 mutations in HRAS and NRAS (p-value = 4x10-7), there was a higher prevalence of G12 and 13 codon mutations in these genes in AMLs, colorectal, bladder, and head and neck cancers, which together share few mutational processes in common (p-value = 4x10-10, Fig.	('papillary thyroid cancers', 'Phenotype', 'HP:0002895', (6, 31))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('codon Q61', 'Var', (61, 70))	('bladder', 'Disease', (214, 221))	('HRAS', 'Gene', '3265', (84, 88))	('HRAS', 'Gene', (84, 88))	('AMLs', 'Disease', (196, 200))	('neck cancers', 'Disease', (236, 248))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('neck cancers', 'Disease', 'MESH:D006258', (236, 248))	('papillary thyroid cancers', 'Disease', 'MESH:D000077273', (6, 31))	('NRAS', 'Gene', '4893', (93, 97))	('colorectal', 'Disease', 'MESH:D015179', (202, 212))	('cancers', 'Phenotype', 'HP:0002664', (24, 31))	('papillary thyroid cancers', 'Disease', (6, 31))	('NRAS', 'Gene', (93, 97))	('head and neck cancers', 'Phenotype', 'HP:0012288', (227, 248))	('cancers', 'Phenotype', 'HP:0002664', (241, 248))	('colorectal', 'Disease', (202, 212))
509918	26619011	V600E mutations describe nearly all BRAF hotspot mutations in melanoma, papillary thyroid, and colorectal carcinomas, whereas multiple myelomas are similar to lung adenocarcinoma in which non-V600E hotspots predominate (p-value = 1.9x-10-32).	('carcinoma', 'Phenotype', 'HP:0030731', (169, 178))	('colorectal carcinomas', 'Disease', (95, 116))	('colorectal carcinomas', 'Disease', 'MESH:D015179', (95, 116))	('myelomas', 'Disease', 'MESH:D009101', (135, 143))	('multiple myeloma', 'Disease', 'MESH:D009101', (126, 142))	('carcinomas', 'Phenotype', 'HP:0030731', (106, 116))	('mutations', 'Var', (49, 58))	('myelomas', 'Disease', (135, 143))	('BRAF', 'Gene', '673', (36, 40))	('melanoma', 'Phenotype', 'HP:0002861', (62, 70))	('melanoma', 'Disease', (62, 70))	('multiple myeloma', 'Disease', (126, 142))	('papillary thyroid', 'Disease', (72, 89))	('lung adenocarcinoma', 'Disease', (159, 178))	('BRAF', 'Gene', (36, 40))	('V600E', 'Mutation', 'rs113488022', (192, 197))	('V600E mutations', 'Var', (0, 15))	('V600E', 'Mutation', 'rs113488022', (0, 5))	('multiple myelomas', 'Phenotype', 'HP:0006775', (126, 143))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (159, 178))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (159, 178))	('multiple myeloma', 'Phenotype', 'HP:0006775', (126, 142))	('melanoma', 'Disease', 'MESH:D008545', (62, 70))
509920	26619011	ERBB2 followed a similar pattern, where extracellular domain mutations typified by S310F are far more common than are kinase domain mutations in bladder cancers compared to breast cancers (p-value = 0.006, Fig.	('bladder cancers', 'Disease', (145, 160))	('breast cancer', 'Phenotype', 'HP:0003002', (173, 186))	('cancers', 'Phenotype', 'HP:0002664', (180, 187))	('ERBB2', 'Gene', '2064', (0, 5))	('extracellular domain mutations', 'MPA', (40, 70))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('bladder cancers', 'Phenotype', 'HP:0009725', (145, 160))	('ERBB2', 'Gene', (0, 5))	('S310F', 'Var', (83, 88))	('bladder cancers', 'Disease', 'MESH:D001749', (145, 160))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('breast cancers', 'Phenotype', 'HP:0003002', (173, 187))	('breast cancers', 'Disease', 'MESH:D001943', (173, 187))	('common', 'Reg', (102, 108))	('breast cancers', 'Disease', (173, 187))	('cancers', 'Phenotype', 'HP:0002664', (153, 160))	('S310F', 'Mutation', 'rs1057519816', (83, 88))
509922	26619011	While bladder and cervical cancers are similar in their distribution of PIK3CA hotspot mutations, they vary significantly from breast cancers in the overall balance of helical to kinase domain mutations, possessing far fewer H1047R mutations among PIK3CA-mutated cases (p-value = 4.8x10-19).	('tri', 'Chemical', '-', (59, 62))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('breast cancers', 'Phenotype', 'HP:0003002', (127, 141))	('H1047R', 'Var', (225, 231))	('breast cancers', 'Disease', 'MESH:D001943', (127, 141))	('cancers', 'Phenotype', 'HP:0002664', (134, 141))	('breast cancers', 'Disease', (127, 141))	('bladder and cervical cancers', 'Disease', 'MESH:D001749', (6, 34))	('mutations', 'Var', (87, 96))	('PIK3CA', 'Gene', (72, 78))	('breast cancer', 'Phenotype', 'HP:0003002', (127, 140))	('cancers', 'Phenotype', 'HP:0002664', (27, 34))	('PIK3CA', 'Gene', (248, 254))	('PIK3CA', 'Gene', '5290', (72, 78))	('H1047R', 'Mutation', 'rs121913279', (225, 231))	('PIK3CA', 'Gene', '5290', (248, 254))	('fewer', 'NegReg', (219, 224))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
509923	26619011	Endometrial and colorectal cancers also have a similar pattern of PIK3CA hotspots, but both have a higher prevalence of R88Q mutations than any other tumor type (p-value = 1.3x10-11, Fig.	('colorectal cancers', 'Disease', (16, 34))	('tri', 'Chemical', '-', (6, 9))	('Endometrial', 'Disease', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('R88Q', 'Mutation', 'rs121913287', (120, 124))	('PIK3CA', 'Gene', (66, 72))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('R88Q mutations', 'Var', (120, 134))	('cancers', 'Phenotype', 'HP:0002664', (27, 34))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('PIK3CA', 'Gene', '5290', (66, 72))	('colorectal cancers', 'Disease', 'MESH:D015179', (16, 34))	('tumor', 'Disease', (150, 155))
509924	26619011	Such patterns extend beyond essential MAPK or PI3K signaling components, such as with SF3B1 K700 mutations that predominate in breast cancers and chronic lymphocytic leukemias whereas melanomas more frequently possess R625 mutations (p-value = 0.0001).	('leukemias', 'Phenotype', 'HP:0001909', (166, 175))	('melanoma', 'Phenotype', 'HP:0002861', (184, 192))	('breast cancers', 'Phenotype', 'HP:0003002', (127, 141))	('breast cancer', 'Phenotype', 'HP:0003002', (127, 140))	('chronic lymphocytic leukemias', 'Disease', (146, 175))	('melanomas', 'Disease', 'MESH:D008545', (184, 193))	('K700 mutations', 'Var', (92, 106))	('cancers', 'Phenotype', 'HP:0002664', (134, 141))	('R625 mutations', 'Var', (218, 232))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('melanomas', 'Disease', (184, 193))	('lymphocytic leukemias', 'Phenotype', 'HP:0005526', (154, 175))	('SF3B1', 'Gene', (86, 91))	('melanomas', 'Phenotype', 'HP:0002861', (184, 193))	('MAPK', 'Gene', (38, 42))	('breast cancers', 'Disease', 'MESH:D001943', (127, 141))	('breast cancers', 'Disease', (127, 141))	('chronic lymphocytic leukemias', 'Disease', 'MESH:D015451', (146, 175))	('chronic lymphocytic leukemias', 'Phenotype', 'HP:0005550', (146, 175))	('SF3B1', 'Gene', '23451', (86, 91))	('MAPK', 'Gene', '5594', (38, 42))
509925	26619011	The IDH1 R132H hotspot mutation predominated in multiple brain tumor types, but cysteine was the most common IDH1 R132 mutant amino acid in melanoma, which is unlikely to be exclusively related to UV light exposure, as this is also true in AMLs that lack a UV-driven etiology (p-value = 3.9x10-21).	('brain tumor', 'Disease', (57, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('cysteine', 'MPA', (80, 88))	('R132H', 'Mutation', 'rs201093943', (9, 14))	('brain tumor', 'Phenotype', 'HP:0030692', (57, 68))	('cysteine', 'Chemical', 'MESH:D003545', (80, 88))	('melanoma', 'Phenotype', 'HP:0002861', (140, 148))	('melanoma', 'Disease', (140, 148))	('melanoma', 'Disease', 'MESH:D008545', (140, 148))	('IDH1 R132', 'Gene', (109, 118))	('mutant', 'Var', (119, 125))	('brain tumor', 'Disease', 'MESH:D001932', (57, 68))
509926	26619011	Together, these results indicate that substantial mutant amino acid specificity exists among hotspot mutations across highly diverse tumor lineages.	('mutations', 'Var', (101, 110))	('tumor', 'Disease', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumor', 'Disease', 'MESH:D009369', (133, 138))
509927	26619011	Overall, mutations at hotspot residues more often resided in a greater fraction of tumor cells (see Methods) and were therefore earlier arising (presumptive clonal), than were non-hotspot mutations in the same genes (Fig.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('resided', 'Reg', (50, 57))	('tumor', 'Disease', (83, 88))	('mutations', 'Var', (9, 18))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
509928	26619011	So, while prior work has shown that driver genes in lung adenocarcinomas were enriched for clonal mutations, we found that this was true of hotspot mutations across a broad class of cancer genes and tumor types.	('tumor', 'Disease', (199, 204))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('carcinomas', 'Phenotype', 'HP:0030731', (62, 72))	('mutations', 'Var', (148, 157))	('carcinoma', 'Phenotype', 'HP:0030731', (62, 71))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (52, 72))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (52, 72))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (52, 71))	('cancer', 'Disease', (182, 188))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('lung adenocarcinomas', 'Disease', (52, 72))
509929	26619011	While colorectal and endometrial cancers have a similar pattern of PIK3CA hotspot mutations (Fig.	('PIK3CA', 'Gene', '5290', (67, 73))	('cancers', 'Phenotype', 'HP:0002664', (33, 40))	('endometrial cancers', 'Disease', 'MESH:D016889', (21, 40))	('endometrial cancers', 'Disease', (21, 40))	('colorectal', 'Disease', 'MESH:D015179', (6, 16))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('mutations', 'Var', (82, 91))	('PIK3CA', 'Gene', (67, 73))	('colorectal', 'Disease', (6, 16))
509930	26619011	3a) and share hypermutated subtypes of tumors driven by MSI and POLE exonuclease domain mutations, colorectal tumors were unique in the clonality of the E545 and H1047 mutations.	('colorectal tumors', 'Disease', (99, 116))	('H1047', 'Var', (162, 167))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('MSI', 'Disease', 'None', (56, 59))	('tumors', 'Disease', 'MESH:D009369', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('E545', 'Var', (153, 157))	('tumors', 'Disease', (110, 116))	('tumors', 'Disease', 'MESH:D009369', (110, 116))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('MSI', 'Disease', (56, 59))	('colorectal tumors', 'Disease', 'MESH:D015179', (99, 116))	('tumors', 'Disease', (39, 45))
509931	26619011	The majority of PIK3CA E545 helical domain mutations in colorectal cancers were subclonal, whereas H1047 kinase domain mutations were clonal, a difference that was not apparent in endometrial tumors, in which both are early clonal mutations (Fig.	('cancers', 'Phenotype', 'HP:0002664', (67, 74))	('PIK3CA', 'Gene', '5290', (16, 22))	('endometrial tumors', 'Disease', (180, 198))	('tumors', 'Phenotype', 'HP:0002664', (192, 198))	('E545 helical', 'Var', (23, 35))	('colorectal cancers', 'Disease', 'MESH:D015179', (56, 74))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('endometrial tumors', 'Disease', 'MESH:D016889', (180, 198))	('colorectal cancers', 'Disease', (56, 74))	('PIK3CA', 'Gene', (16, 22))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))
509932	26619011	This may be a function of the pattern of oncogenic co-mutation in these tumors as PIK3CA E545, but not H1047, mutations were significantly associated with KRAS mutations in these colorectal cancers (chi2 p-value = 0.0004) and in previous cohorts.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('cancers', 'Phenotype', 'HP:0002664', (190, 197))	('PIK3CA', 'Gene', (82, 88))	('mutations', 'Var', (110, 119))	('mutations', 'Var', (160, 169))	('KRAS', 'Gene', (155, 159))	('KRAS', 'Gene', '3845', (155, 159))	('colorectal cancers', 'Disease', (179, 197))	('tumors', 'Disease', (72, 78))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('PIK3CA', 'Gene', '5290', (82, 88))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('associated', 'Reg', (139, 149))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('colorectal cancers', 'Disease', 'MESH:D015179', (179, 197))	('E545', 'Var', (89, 93))
509934	26619011	Consistent with the so-called long tail of the frequency distribution of somatically mutated genes across cancer, we found that 85% of all hotspots identified here were mutated in less than 5% of tumors of all cancer types in which they were found (Fig.	('tumors', 'Phenotype', 'HP:0002664', (196, 202))	('tumors of all cancer', 'Disease', (196, 216))	('mutated', 'Var', (169, 176))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('tumors of all cancer', 'Disease', 'MESH:D009369', (196, 216))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('cancer', 'Disease', (106, 112))	('long tail', 'Phenotype', 'HP:0002831', (30, 39))	('cancer', 'Disease', 'MESH:D009369', (210, 216))	('tri', 'Chemical', '-', (60, 63))	('cancer', 'Disease', (210, 216))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
509938	26619011	This included 19 hotspots arising in only one sample of each affected cancer type such as U2AF1 I24, MYC T58, the hyperactivating MTOR I2500, PIK3CB D1067, EP300 H1451, and ERBB3 M60.	('I2500', 'Var', (135, 140))	('U2AF1', 'Gene', '7307', (90, 95))	('ERBB3', 'Gene', '2065', (173, 178))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('U2AF1', 'Gene', (90, 95))	('H1451', 'CellLine', 'CVCL:A495', (162, 167))	('MTOR', 'Gene', (130, 134))	('PIK3CB', 'Gene', (142, 148))	('PIK3CB', 'Gene', '5291', (142, 148))	('ERBB3', 'Gene', (173, 178))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('MTOR', 'Gene', '2475', (130, 134))	('EP300 H1451', 'Var', (156, 167))
509940	26619011	Conversely, population-level analysis, rather than by individual cancer type or organ system, allows identification of hotspots that arise as even private mutations in rare malignancies, for which additional broad-scale sequencing is most challenging.	('mutations', 'Var', (155, 164))	('malignancies', 'Disease', (173, 185))	('cancer', 'Disease', (65, 71))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('malignancies', 'Disease', 'MESH:D009369', (173, 185))	('cancer', 'Disease', 'MESH:D009369', (65, 71))
509942	26619011	Mutations in the Ras family of small GTPases occur widely in human cancers.	('cancers', 'Phenotype', 'HP:0002664', (67, 74))	('cancers', 'Disease', (67, 74))	('cancers', 'Disease', 'MESH:D009369', (67, 74))	('occur', 'Reg', (45, 50))	('Mutations', 'Var', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('human', 'Species', '9606', (61, 66))	('GTP', 'Chemical', 'MESH:D006160', (37, 40))
509944	26619011	Whereas G12, G13, and Q61 codon hotspots predominate in KRAS, NRAS, and HRAS, albeit at varying frequencies in different tumor types (Fig.	('G12', 'Var', (8, 11))	('NRAS', 'Gene', '4893', (62, 66))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('Q61 codon', 'Var', (22, 31))	('HRAS', 'Gene', '3265', (72, 76))	('KRAS', 'Gene', (56, 60))	('tumor', 'Disease', (121, 126))	('KRAS', 'Gene', '3845', (56, 60))	('HRAS', 'Gene', (72, 76))	('G13', 'Var', (13, 16))	('NRAS', 'Gene', (62, 66))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
509945	26619011	2a and 3a), we also identified GQ60GK, K117, and A146 hotspots in KRAS.	('GQ60GK', 'Var', (31, 37))	('KRAS', 'Gene', '3845', (66, 70))	('K117', 'Var', (39, 43))	('A146', 'Var', (49, 53))	('KRAS', 'Gene', (66, 70))
509946	26619011	Both K117 and A146 are known activating hotspots in the long tail, but we also identified a previously occult GQ60GK dinucleotide substitution (q-value = 2.3x10-6) in 11 tumors.	('tumors', 'Disease', (170, 176))	('dinucleotide', 'Chemical', 'MESH:D015226', (117, 129))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('GQ60GK', 'Var', (110, 116))	('tumors', 'Disease', 'MESH:D009369', (170, 176))	('K117', 'Var', (5, 9))	('tumors', 'Phenotype', 'HP:0002664', (170, 176))	('A146', 'Var', (14, 18))	('long tail', 'Phenotype', 'HP:0002831', (56, 65))
509947	26619011	This dinucleotide substitution results in a Q61K mutation accompanied by a G60 synonymous mutation that are present in cis (in concomitant RNA sequencing, Supplementary Fig.	('G60', 'Var', (75, 78))	('Q61K', 'Var', (44, 48))	('Q61K', 'Mutation', 'rs121913238', (44, 48))	('dinucleotide', 'Chemical', 'MESH:D015226', (5, 17))	('results in', 'Reg', (31, 41))
509948	26619011	Although Q>K mutations at codon 61 can result from 3'G>T single-nucleotide mutations in KRAS, 100% of these tumors harbored the dinucleotide substitution, a rare spontaneous event in human genomes.	('result', 'Reg', (39, 45))	("3'G>T single-nucleotide mutations", 'Var', (51, 84))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('dinucleotide substitution', 'Var', (128, 153))	('dinucleotide', 'Chemical', 'MESH:D015226', (128, 140))	('KRAS', 'Gene', (88, 92))	('Q>K mutations', 'Var', (9, 22))	('tumors', 'Disease', (108, 114))	('human', 'Species', '9606', (183, 188))	('KRAS', 'Gene', '3845', (88, 92))	('tumors', 'Disease', 'MESH:D009369', (108, 114))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))
509949	26619011	Overall, the distribution of codon 61 mutations in KRAS, NRAS, and HRAS are very different, with Q>K mutations occurring significantly less frequently in KRAS (p-value=0.016; Fig.	('KRAS', 'Gene', '3845', (154, 158))	('KRAS', 'Gene', '3845', (51, 55))	('NRAS', 'Gene', (57, 61))	('KRAS', 'Gene', (154, 158))	('HRAS', 'Gene', '3265', (67, 71))	('tri', 'Chemical', '-', (16, 19))	('HRAS', 'Gene', (67, 71))	('NRAS', 'Gene', '4893', (57, 61))	('codon 61', 'Gene', (29, 37))	('Q>K', 'Var', (97, 100))	('KRAS', 'Gene', (51, 55))
509951	26619011	4c) and converts the ACC codon at KRAS G60 to TCC, which is the sequence of the G60 codon in NRAS, in which Q61K mutations are far more common and arise nearly exclusively from single-nucleotide mutations.	('KRAS', 'Gene', '3845', (34, 38))	('Q61K', 'Mutation', 'rs121913238', (108, 112))	('Q61K mutations', 'Var', (108, 122))	('NRAS', 'Gene', '4893', (93, 97))	('G60 to TCC', 'Mutation', 'c.60G>TCC', (39, 49))	('single-nucleotide mutations', 'Var', (177, 204))	('KRAS', 'Gene', (34, 38))	('NRAS', 'Gene', (93, 97))
509955	26619011	GQ60GK is indeed present in diverse tumor types that all have well-established Ras-driven subsets (Supplementary Table 5).	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('tumor', 'Disease', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('GQ60GK', 'Var', (0, 6))
509956	26619011	Reasoning that if GQ60GK were a passenger mutation in Ras-driven tumors, alternative MAPK activating mutations may be present in these tumors.	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('MAPK', 'Gene', (85, 89))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('GQ60GK', 'Var', (18, 24))	('tumors', 'Disease', (65, 71))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('tumors', 'Disease', (135, 141))	('tumors', 'Disease', 'MESH:D009369', (135, 141))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))	('MAPK', 'Gene', '5594', (85, 89))
509957	26619011	Instead, we found that in every GQ60GK-mutant sample where another putative driver of MAPK signaling was present, that lesion was either 1) subclonal, defining a different clone than did GQ60GK; 2) low activity; or 3) a passenger mutation (Supplementary Table 5).	('MAPK', 'Gene', '5594', (86, 90))	('activity', 'MPA', (202, 210))	('MAPK', 'Gene', (86, 90))	('GQ60GK-mutant', 'Var', (32, 45))
509958	26619011	Also, despite the frequency of GA>TT, there was no evidence that a common underlying mutational process or exogenous mutagen was the source of GQ60GK.	('GA>TT', 'Var', (31, 36))	('GA', 'Chemical', 'MESH:D005708', (31, 33))	('GQ60GK', 'Var', (143, 149))
509960	26619011	Moreover, GQ60GK arose in both hypermutated (MSI-H colon lacking BRAF V600E) and non-hypermutated tumors.	('MSI-H colon', 'Disease', (45, 56))	('tumors', 'Disease', (98, 104))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('MSI-H colon', 'Disease', 'MESH:D015179', (45, 56))	('tumors', 'Disease', 'MESH:D009369', (98, 104))	('GQ60GK', 'Var', (10, 16))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('BRAF', 'Gene', '673', (65, 69))	('V600E', 'Mutation', 'rs113488022', (70, 75))	('BRAF', 'Gene', (65, 69))
509961	26619011	Finally, rare G60 missense mutations were evident in K- and HRAS in this dataset and in the literature (Supplementary Table 5).	('HRAS', 'Gene', '3265', (60, 64))	('HRAS', 'Gene', (60, 64))	('G60 missense mutations', 'Var', (14, 36))
509962	26619011	So, while we cannot exclude the possibility that the GQ60GK dinucleotide substitution is simply an alternative mechanism to achieve Q61K, the accompanying KRAS-specific G60 synonymous mutation may potentiate a different class of Q61-mutant tumors or cause signaling differences among Q61K-mutant tumors between K-N- or HRAS.	('KRAS', 'Gene', '3845', (155, 159))	('tumors', 'Disease', (240, 246))	('tumors', 'Disease', 'MESH:D009369', (296, 302))	('dinucleotide', 'Chemical', 'MESH:D015226', (60, 72))	('signaling', 'MPA', (256, 265))	('KRAS', 'Gene', (155, 159))	('Q61-mutant', 'Gene', (229, 239))	('Q61K', 'Mutation', 'rs121913238', (284, 288))	('tumors', 'Disease', 'MESH:D009369', (240, 246))	('G60', 'Var', (169, 172))	('Q61K', 'Mutation', 'rs121913238', (132, 136))	('tumors', 'Phenotype', 'HP:0002664', (296, 302))	('GQ60GK', 'Var', (53, 59))	('potentiate', 'PosReg', (197, 207))	('tumor', 'Phenotype', 'HP:0002664', (240, 245))	('HRAS', 'Gene', '3265', (319, 323))	('differences', 'Reg', (266, 277))	('tumor', 'Phenotype', 'HP:0002664', (296, 301))	('cause', 'Reg', (250, 255))	('HRAS', 'Gene', (319, 323))	('tumors', 'Phenotype', 'HP:0002664', (240, 246))	('tumors', 'Disease', (296, 302))
509963	26619011	Although further studies will need to explore the molecular properties of KRAS GQ60GK, this allele represents the most common dinucleotide substitution spanning two codons in human cancer and a mutation more common than other known hotspots in KRAS.	('human', 'Species', '9606', (175, 180))	('KRAS', 'Gene', '3845', (244, 248))	('dinucleotide', 'Chemical', 'MESH:D015226', (126, 138))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('GQ60GK', 'Var', (79, 85))	('KRAS', 'Gene', (74, 78))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('KRAS', 'Gene', '3845', (74, 78))	('cancer', 'Disease', (181, 187))	('KRAS', 'Gene', (244, 248))
509966	26619011	RAC1 P29S is an oncogenic hotspot in melanomas that we also identified in head and neck and endometrial cancers (Fig.	('melanomas', 'Disease', (37, 46))	('endometrial cancers', 'Disease', 'MESH:D016889', (92, 111))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('endometrial cancers', 'Disease', (92, 111))	('melanomas', 'Disease', 'MESH:D008545', (37, 46))	('melanoma', 'Phenotype', 'HP:0002861', (37, 45))	('melanomas', 'Phenotype', 'HP:0002861', (37, 46))	('RAC1', 'Gene', '5879', (0, 4))	('P29S', 'Var', (5, 9))	('cancers', 'Phenotype', 'HP:0002664', (104, 111))	('RAC1', 'Gene', (0, 4))	('P29S', 'Mutation', 'rs1057519874', (5, 9))
509970	26619011	Whereas activating KRAS A146T mutations arise predominantly in colorectal carcinomas (Supplementary Table 2), RAC1 A159V mutations are most common in head and neck cancers and were not present in any melanomas, despite the frequency of RAC1 P29S in this cancer type.	('RAC1', 'Gene', '5879', (236, 240))	('melanoma', 'Phenotype', 'HP:0002861', (200, 208))	('KRAS', 'Gene', '3845', (19, 23))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('cancer', 'Disease', (254, 260))	('activating', 'PosReg', (8, 18))	('carcinomas', 'Phenotype', 'HP:0030731', (74, 84))	('cancer', 'Phenotype', 'HP:0002664', (254, 260))	('melanomas', 'Disease', 'MESH:D008545', (200, 209))	('KRAS', 'Gene', (19, 23))	('A159V', 'Mutation', 'p.A159V', (115, 120))	('melanomas', 'Disease', (200, 209))	('RAC1', 'Gene', (110, 114))	('neck cancers', 'Disease', (159, 171))	('A146T', 'Mutation', 'rs121913527', (24, 29))	('head and neck cancers', 'Phenotype', 'HP:0012288', (150, 171))	('cancers', 'Phenotype', 'HP:0002664', (164, 171))	('cancer', 'Disease', 'MESH:D009369', (254, 260))	('cancer', 'Disease', (164, 170))	('P29S', 'Mutation', 'rs1057519874', (241, 245))	('mutations', 'Var', (30, 39))	('neck cancers', 'Disease', 'MESH:D006258', (159, 171))	('RAC1', 'Gene', '5879', (110, 114))	('colorectal carcinomas', 'Disease', (63, 84))	('melanomas', 'Phenotype', 'HP:0002861', (200, 209))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('RAC1', 'Gene', (236, 240))	('colorectal carcinomas', 'Disease', 'MESH:D015179', (63, 84))
509971	26619011	Moreover, similar to P29S mutations, we observed RAC1 A159V mutations in tumors that are both Ras/Raf wildtype and mutant (Fig.	('tumors', 'Disease', 'MESH:D009369', (73, 79))	('P29S', 'Mutation', 'rs1057519874', (21, 25))	('Raf', 'Gene', '22882', (98, 101))	('Raf', 'Gene', (98, 101))	('mutant', 'Var', (115, 121))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('A159V mutations', 'Var', (54, 69))	('tumors', 'Disease', (73, 79))	('RAC1', 'Gene', '5879', (49, 53))	('A159V', 'Mutation', 'p.A159V', (54, 59))	('RAC1', 'Gene', (49, 53))
509985	26619011	Beyond these hotspots, several less common RAC1 and RRAS2 mutations affect paralogous residues of highly recurrent alleles in KRAS (Fig.	('mutations', 'Var', (58, 67))	('KRAS', 'Gene', '3845', (126, 130))	('RAC1', 'Gene', '5879', (43, 47))	('RRAS2', 'Gene', (52, 57))	('RAC1', 'Gene', (43, 47))	('paralogous residues', 'MPA', (75, 94))	('RRAS2', 'Gene', '22800', (52, 57))	('affect', 'Reg', (68, 74))	('KRAS', 'Gene', (126, 130))
509986	26619011	Although we focus only on recurrent substitutions, we did find that while a subset of hotspots were prevalent in individual cancer types, most hotspots are present infrequently across many cancer types.	('cancer', 'Disease', (124, 130))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('substitutions', 'Var', (36, 49))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('cancer', 'Disease', 'MESH:D009369', (124, 130))	('cancer', 'Disease', (189, 195))
509990	26619011	New mutant alleles in established genes are likely to emerge faster than new cancer genes are identified, extending the long tail of the frequency distribution of somatic mutations.	('mutant', 'Var', (4, 10))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('long tail', 'Phenotype', 'HP:0002831', (120, 129))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('tri', 'Chemical', '-', (150, 153))
509992	26619011	Moreover, at present there are fewer actionable mutations in cancer than there are cancer genes.	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('cancer', 'Disease', (61, 67))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('mutations', 'Var', (48, 57))	('cancer', 'Disease', (83, 89))
509996	26619011	Genomic coordinates of variants from alignments to human reference assembly NCBI36 (hg18) were converted to GRCh37 using LiftOver with an Ensembl chain file (see URLs).	('variants', 'Var', (23, 31))	('hg18', 'Gene', (84, 88))	('human', 'Species', '9606', (51, 56))
509997	26619011	For any pair of tumors that shared greater than 80% mutational identity and identical or near-identical clinic-pathological characteristics (upon review of data from the source site/publication), a single tumor in the pair was chosen at random and removed from further analysis as a presumptive duplicate specimen.	('tumors', 'Disease', (16, 22))	('mutational', 'Var', (52, 62))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumor', 'Disease', (205, 210))	('tumor', 'Disease', (16, 21))	('tumors', 'Disease', 'MESH:D009369', (16, 22))
510002	26619011	For the purposes of this analysis, we first define a driver cancer gene as one in which a molecular abnormality leads to a fitness advantage for the affected cancer cell.	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('abnormality', 'Var', (100, 111))	('cancer', 'Disease', (60, 66))	('cancer', 'Disease', (158, 164))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('fitness advantage', 'CPA', (123, 140))
510009	26619011	Because a mutated codon in a given gene is comprised of mutations in any one of three trinucleotides that encode that codon, we estimate the mutability of a codon c in gene g as:  where nt,c is the number of mutations in the central position of trinucleotide t in codon c and nc is the number of mutations in codon c overall.	('trinucleotide t', 'Chemical', '-', (245, 260))	('trinucleotides', 'Chemical', '-', (86, 100))	('mutations', 'Var', (56, 65))	('mutations', 'Var', (208, 217))
510014	26619011	First, a presumptive true positive (pTPs) list of hotspots was predetermined as coding positions harboring substitutions in five or more tumor samples (from the August 2013 release of the cBioPortal) in one of 341 key cancer-associated genes sequenced as part of routine CLIA-certified sequencing of matched tumor and normal specimens at Memorial Sloan Kettering Cancer Center.	('cancer', 'Disease', 'MESH:D009369', (218, 224))	('Cancer', 'Disease', (363, 369))	('tumor', 'Disease', (137, 142))	('substitutions', 'Var', (107, 120))	('cancer', 'Disease', (218, 224))	('Cancer', 'Disease', 'MESH:D009369', (363, 369))	('Cancer', 'Phenotype', 'HP:0002664', (363, 369))	('tumor', 'Disease', 'MESH:D009369', (308, 313))	('tumor', 'Phenotype', 'HP:0002664', (308, 313))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('tumor', 'Disease', (308, 313))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
510019	26619011	Finally, we manually inspected the sequencing data contributing to the mutation call for select hotspots in a sampling of affected tumor and matched normal samples.	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('mutation', 'Var', (71, 79))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumor', 'Disease', (131, 136))	('tri', 'Chemical', '-', (54, 57))
510021	26619011	We downloaded BAM files of the aligned and unaligned sequencing reads corresponding to the tumor and matched normal exomes from each patient harboring one of the novel hotspots we discuss in detail in the manuscript (RAC1 A159; RRAS2 Q72; NUP93 E14 and Q15; MAX R60; and MAX H28) and reprocessed these from raw FASTQ to mutation calls with an independent sequence analysis pipeline.	('RAC1', 'Gene', (217, 221))	('E14', 'Gene', '4863', (245, 248))	('E14', 'Gene', (245, 248))	('RRAS2', 'Gene', '22800', (228, 233))	('patient', 'Species', '9606', (133, 140))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('Q15', 'Var', (253, 256))	('NUP93', 'Gene', '9688', (239, 244))	('NUP93', 'Gene', (239, 244))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('RAC1', 'Gene', '5879', (217, 221))	('tumor', 'Disease', (91, 96))	('RRAS2', 'Gene', (228, 233))
510023	26619011	Level-1 mutations are those not previously identified in human tumors or have been identified in an individual sample, but never described as a hotspot of recurrent mutation.	('Level-1', 'Gene', (0, 7))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('mutations', 'Var', (8, 17))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('tumors', 'Disease', (63, 69))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('human', 'Species', '9606', (57, 62))
510025	26619011	Level-2 hotspots are those mutations that have been reported previously in one tumor type that we also identified in the same, but also find mutated in one or more additional tumor types not previously described.	('mutations', 'Var', (27, 36))	('tumor', 'Disease', (175, 180))	('tumor', 'Disease', (79, 84))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
510026	26619011	Level-3 hotspots are those mutations that have been previously identified in one or more tumor types and have been assessed functionally in vitro or in vivo.	('mutations', 'Var', (27, 36))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))	('tumor', 'Disease', 'MESH:D009369', (89, 94))
510030	26619011	Hotspots mutated in at least one squamous tumor were examined and their statistical significance was assed with Fisher's exact test assuming the null hypothesis that squamous and non-squamous tumor samples are equally likely to possess a given hotspot.	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('mutated', 'Var', (9, 16))	('squamous tumor', 'Phenotype', 'HP:0002860', (183, 197))	('squamous tumor', 'Phenotype', 'HP:0002860', (33, 47))	('squamous tumor', 'Disease', 'MESH:D002294', (183, 197))	('squamous tumor', 'Disease', 'MESH:D002294', (33, 47))	('squamous tumor', 'Disease', (183, 197))	('squamous tumor', 'Disease', (33, 47))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
510066	31871210	Furthermore, ECM deposition enhances HCC chemotherapy resistance and offers protection against immune cells.	('HCC', 'Disease', (37, 40))	('HCC', 'Disease', 'MESH:D006528', (37, 40))	('ECM deposition', 'Var', (13, 27))	('enhances', 'PosReg', (28, 36))
510116	31871210	Most collagen family members in our network are regulated by the let-7 family and miR-29c, with a contribution of miR-335 and miR-338, while laminin gamma 1 (Lamc1) is targeted by miR-29c (Fig.	('let-7 family', 'Gene', (65, 77))	('regulated', 'Reg', (48, 57))	('miR-29c', 'Gene', (82, 89))	('miR-338', 'Var', (126, 133))	('miR-335', 'Var', (114, 121))	('Lamc1', 'Gene', '226519', (158, 163))	('laminin gamma 1', 'Gene', '226519', (141, 156))	('laminin gamma 1', 'Gene', (141, 156))	('Lamc1', 'Gene', (158, 163))	('miR-29c', 'Var', (180, 187))
510118	31871210	Components of the TGF- pathway (Tgfbr1 and Tgfbr2), the most potent positive regulator of fibrosis, are targeted by miR-335 and the let-7 family, while components of the PDGF pathway (Pdgfa and Pdgfb), responsible for induction of HSC proliferation, are targeted by miR-29c and miR-335.	('HSC', 'Gene', (231, 234))	('miR-29c', 'Var', (266, 273))	('miR-335', 'Var', (278, 285))	('Pdgfa', 'Gene', '18590', (184, 189))	('HSC', 'Gene', '2523', (231, 234))	('Pdgfb', 'Gene', '18591', (194, 199))	('Tgfbr2', 'Gene', (43, 49))	('Tgfbr1', 'Gene', '21812', (32, 38))	('Tgfbr1', 'Gene', (32, 38))	('Pdgfa', 'Gene', (184, 189))	('Pdgfb', 'Gene', (194, 199))	('fibrosis', 'Disease', 'MESH:D005355', (90, 98))	('fibrosis', 'Disease', (90, 98))	('Tgfbr2', 'Gene', '21813', (43, 49))	('miR-335', 'Var', (116, 123))
510135	31871210	First, we used miRNA mimics to overexpress miR-29c, miR-338, let-7a, let-7c, and let-7g.	('let-7g', 'Var', (81, 87))	('miR', 'Gene', (43, 46))	('let-7c', 'Gene', (69, 75))	('let-7c', 'Gene', '406885', (69, 75))	('miR', 'Gene', (52, 55))	('overexpress', 'PosReg', (31, 42))	('miR', 'Gene', '751537', (52, 55))	('miR', 'Gene', '751537', (15, 18))	('let-7a', 'Gene', (61, 67))	('let-7a', 'Gene', '387244', (61, 67))	('miR', 'Gene', '751537', (43, 46))	('miR', 'Gene', (15, 18))
510139	31871210	For validation, we mutated the miRNA binding sites and likewise assayed the mutant 3'-UTR constructs upon miRNA mimic or inhibitor transfection.	('miR', 'Gene', '751537', (106, 109))	('miR', 'Gene', (106, 109))	('mutant', 'Var', (76, 82))	('mutated', 'Var', (19, 26))	('miR', 'Gene', '751537', (31, 34))	('miR', 'Gene', (31, 34))
510140	31871210	The luciferase reporter containing wild-type 3'-UTR of Col1a1 showed significant down-regulation upon let-7a, let-7c, let-7g, or miR-29c mimic expression compared to scrambled mimic, while the mutant 3'-UTR construct retained comparable levels of expression upon specific miRNA and scrambled mimic transfection (SI Appendix, Figs.	('let-7a', 'Gene', '387244', (102, 108))	('miR', 'Gene', (129, 132))	('let-7c', 'Gene', (110, 116))	('miR', 'Gene', '751537', (272, 275))	('down-regulation', 'NegReg', (81, 96))	('let-7c', 'Gene', '406885', (110, 116))	('Col1a1', 'Gene', (55, 61))	('miR', 'Gene', (272, 275))	('let-7g', 'Var', (118, 124))	('luciferase', 'Enzyme', (4, 14))	('Col1a1', 'Gene', '12842', (55, 61))	('miR', 'Gene', '751537', (129, 132))	('let-7a', 'Gene', (102, 108))
510142	31871210	We observed a similar down-regulation of Pdgfa and Tgfbr1 constructs upon miR-29c and let-7a, let-7c, and let-7g mimics overexpression, respectively (Fig.	('miR-29c', 'Var', (74, 81))	('Tgfbr1', 'Gene', '21812', (51, 57))	('Pdgfa', 'Gene', '18590', (41, 46))	('let-7c', 'Gene', (94, 100))	('Tgfbr1', 'Gene', (51, 57))	('Pdgfa', 'Gene', (41, 46))	('overexpression', 'PosReg', (120, 134))	('down-regulation', 'NegReg', (22, 37))	('let-7a', 'Gene', (86, 92))	('let-7a', 'Gene', '387244', (86, 92))	('let-7c', 'Gene', '406885', (94, 100))
510143	31871210	S6C), as well as an up-regulation of the Tgfbr1 construct upon let-7g inhibitor transfection (SI Appendix, Fig.	('up-regulation', 'PosReg', (20, 33))	('S6C', 'Chemical', 'MESH:C012008', (0, 3))	('Tgfbr1', 'Gene', (41, 47))	('transfection', 'Var', (80, 92))	('Tgfbr1', 'Gene', '21812', (41, 47))	('let-7g inhibitor', 'Protein', (63, 79))
510144	31871210	The Adamts15 luciferase construct showed a significant down-regulation upon miR-338, let-7a, let-7c, let-7g, and miR-29c mimic transfection (SI Appendix, Figs.	('let-7a', 'Gene', '387244', (85, 91))	('miR-338', 'Var', (76, 83))	('Adamts15', 'Gene', '235130', (4, 12))	('miR-29c mimic transfection', 'Var', (113, 139))	('let-7c', 'Gene', (93, 99))	('let-7c', 'Gene', '406885', (93, 99))	('luciferase', 'Enzyme', (13, 23))	('let-7g', 'Var', (101, 107))	('Adamts15', 'Gene', (4, 12))	('down-regulation', 'NegReg', (55, 70))	('let-7a', 'Gene', (85, 91))
510147	31871210	We validated Lin28a overexpression relative to control and confirmed its inhibitory effect on let-7a, let-7c, and let-7g (SI Appendix, Fig.	('inhibitory effect', 'MPA', (73, 90))	('let-7c', 'Gene', '406885', (102, 108))	('let-7a', 'Gene', (94, 100))	('let-7a', 'Gene', '387244', (94, 100))	('overexpression', 'PosReg', (20, 34))	('let-7c', 'Gene', (102, 108))	('let-7g', 'Var', (114, 120))	('Lin28a', 'Gene', (13, 19))	('Lin28a', 'Gene', '83557', (13, 19))
510150	31871210	Additionally, we investigated the effect of let-7c, let-7g, and miR-29c up-regulation (SI Appendix, Fig.	('up-regulation', 'PosReg', (72, 85))	('miR-29c', 'Gene', (64, 71))	('let-7g', 'Var', (52, 58))	('let-7c', 'Gene', (44, 50))	('let-7c', 'Gene', '406885', (44, 50))
510153	31871210	While miR-29c and let-7c mediate significant inhibition of all their target genes with the exception of Col4a2 for let-7c (Fig.	('inhibition', 'NegReg', (45, 55))	('let-7c', 'Gene', (115, 121))	('let-7c', 'Gene', (18, 24))	('miR-29c', 'Var', (6, 13))	('let-7c', 'Gene', '406885', (115, 121))	('let-7c', 'Gene', '406885', (18, 24))	('Col4a2', 'Gene', (104, 110))	('Col4a2', 'Gene', '12827', (104, 110))
510168	31871210	In hHCC, most ECM-related genes are consistently targeted by let-7g and miR-29c, while Rho GTPase-related genes are targeted by miR-30e (SI Appendix, Fig.	('let-7g', 'Var', (61, 67))	('targeted', 'Reg', (49, 57))	('miR-29c', 'Var', (72, 79))	('HCC', 'Disease', 'MESH:D006528', (4, 7))	('HCC', 'Disease', (4, 7))	('miR-30e', 'Var', (128, 135))
510170	31871210	Similarly, let-7g and miR-29c consistently inhibit the majority of ECM-related genes in BRCA and LUAD samples.	('BRCA', 'Disease', (88, 92))	('ECM-related genes', 'Gene', (67, 84))	('inhibit', 'NegReg', (43, 50))	('let-7g', 'Var', (11, 17))	('LUAD', 'Disease', (97, 101))	('LUAD', 'Disease', 'MESH:C538231', (97, 101))	('miR-29c', 'Var', (22, 29))
510171	31871210	However, in these carcinomas, miR-335 and miR-338 additionally contribute to targeting of ECM genes, while Rho GTPase-related genes are primarily modulated by miR-30d and miR-338 (SI Appendix, Figs.	('carcinoma', 'Phenotype', 'HP:0030731', (18, 27))	('miR-30d', 'Var', (159, 166))	('carcinomas', 'Phenotype', 'HP:0030731', (18, 28))	('carcinomas', 'Disease', (18, 28))	('carcinomas', 'Disease', 'MESH:D002277', (18, 28))	('miR-338', 'Var', (171, 178))	('miR-335', 'Var', (30, 37))	('ECM genes', 'Gene', (90, 99))	('contribute', 'Reg', (63, 73))	('modulated', 'Reg', (146, 155))	('targeting', 'MPA', (77, 86))	('miR-338', 'Gene', (42, 49))
510174	31871210	A negative REC score of miRNA:mRNA pairs across fibrosis-facilitated carcinomas indicates that miR-29c, let-7g, let-7a, and miR-335 consistently regulate different collagens (SI Appendix, Fig.	('fibrosis-facilitated carcinomas', 'Disease', 'MESH:D005355', (48, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))	('miR', 'Gene', (95, 98))	('carcinomas', 'Phenotype', 'HP:0030731', (69, 79))	('fibrosis-facilitated carcinomas', 'Disease', (48, 79))	('let-7a', 'Gene', '387244', (112, 118))	('miR', 'Gene', '751537', (24, 27))	('collagens', 'Protein', (164, 173))	('miR', 'Gene', '751537', (124, 127))	('miR', 'Gene', (24, 27))	('let-7a', 'Gene', (112, 118))	('let-7g', 'Var', (104, 110))	('miR', 'Gene', (124, 127))	('miR', 'Gene', '751537', (95, 98))	('regulate', 'Reg', (145, 153))
510175	31871210	Adamts14 is regulated by miR-29c, let7a, and let-7g, while Adamts15 is targeted by let-7g and let-7c.	('Adamts15', 'Gene', (59, 67))	('regulated', 'Reg', (12, 21))	('let-7c', 'Gene', (94, 100))	('Adamts15', 'Gene', '235130', (59, 67))	('let7a', 'Gene', (34, 39))	('let-7g', 'Var', (45, 51))	('miR-29c', 'Var', (25, 32))	('Adamts14', 'Gene', (0, 8))	('let7a', 'Gene', '387244', (34, 39))	('let-7g', 'Var', (83, 89))	('Adamts14', 'Gene', '237360', (0, 8))	('let-7c', 'Gene', '406885', (94, 100))
510176	31871210	Loxl2 and Loxl4 are modulated by miR-29c and let-7c and let-7a, respectively.	('Loxl2', 'Gene', '94352', (0, 5))	('miR-29c', 'Var', (33, 40))	('Loxl2', 'Gene', (0, 5))	('Loxl4', 'Gene', '67573', (10, 15))	('let-7c', 'Gene', '406885', (45, 51))	('let-7a', 'Gene', (56, 62))	('let-7a', 'Gene', '387244', (56, 62))	('Loxl4', 'Gene', (10, 15))	('modulated', 'Reg', (20, 29))	('let-7c', 'Gene', (45, 51))
510177	31871210	Tgfbr1 is primarily regulated by miR-338, let-7a, and let-7c.	('Tgfbr1', 'Gene', (0, 6))	('let-7a', 'Gene', (42, 48))	('let-7a', 'Gene', '387244', (42, 48))	('miR-338', 'Var', (33, 40))	('let-7c', 'Gene', (54, 60))	('regulated', 'Reg', (20, 29))	('let-7c', 'Gene', '406885', (54, 60))	('Tgfbr1', 'Gene', '21812', (0, 6))
510187	31871210	To study how AF-miRNAs are regulated at the transcriptional level, we examined 2 major transcriptional regulation mechanisms: binding of potential transcription factors to the promoters of relevant miRNA-encoding genes and CpG methylation changes in promoters of miRNA-encoding genes upon HSC activation.	('HSC', 'Gene', '2523', (289, 292))	('miR', 'Gene', (198, 201))	('miR', 'Gene', (263, 266))	('binding', 'Interaction', (126, 133))	('changes', 'Reg', (239, 246))	('methylation', 'Var', (227, 238))	('HSC', 'Gene', (289, 292))	('miR', 'Gene', '751537', (16, 19))	('miR', 'Gene', (16, 19))	('miR', 'Gene', '751537', (198, 201))	('miR', 'Gene', '751537', (263, 266))
510198	31871210	This approach identified Ppar as a potential transcription regulator of mouse and human let-7a, let-7g, miR-338, miR-29c, miR-30e, and miR-30d genes.	('miR-29c', 'Var', (113, 120))	('miR-338', 'Gene', (104, 111))	('mouse', 'Species', '10090', (72, 77))	('let-7g', 'Gene', (96, 102))	('let-7a', 'Gene', (88, 94))	('Ppar', 'Gene', '19013', (25, 29))	('let-7a', 'Gene', '387244', (88, 94))	('miR-30d', 'Var', (135, 142))	('Ppar', 'Gene', (25, 29))	('miR-30e', 'Gene', (122, 129))	('human', 'Species', '9606', (82, 87))
510218	31871210	These data indicate that multiple fibrosis-associated genes of this network are:at least partially:regulated by Ppar-mediated expression of the AF-miRNAs miR-29c and let-7g.	('miR', 'Gene', (154, 157))	('miR', 'Gene', '751537', (147, 150))	('fibrosis', 'Disease', 'MESH:D005355', (34, 42))	('fibrosis', 'Disease', (34, 42))	('Ppar', 'Gene', '19013', (112, 116))	('regulated', 'Reg', (99, 108))	('miR', 'Gene', (147, 150))	('Ppar', 'Gene', (112, 116))	('miR', 'Gene', '751537', (154, 157))	('let-7g', 'Var', (166, 172))
510223	31871210	Also, modulation of AF-miRNA expression (let-7a, let-7c, let-7g, and miR-29c) causes anticorrelated expression of fibrosis-associated target genes.	('modulation', 'Var', (6, 16))	('miR', 'Gene', (23, 26))	('let-7a', 'Gene', (41, 47))	('let-7c', 'Gene', (49, 55))	('causes', 'Reg', (78, 84))	('let-7c', 'Gene', '406885', (49, 55))	('let-7a', 'Gene', '387244', (41, 47))	('miR', 'Gene', '751537', (69, 72))	('fibrosis', 'Disease', (114, 122))	('miR', 'Gene', (69, 72))	('fibrosis', 'Disease', 'MESH:D005355', (114, 122))	('anticorrelated expression', 'MPA', (85, 110))	('miR', 'Gene', '751537', (23, 26))	('let-7g', 'Var', (57, 63))
510224	31871210	In vitro luciferase assays experimentally confirm predicted targeting of Col1a1 by miR-29c, let-7a, let-7c, and let-7g; Pdgfa by miR-29c; Tgfbr1 by let-7a, let-7c, and let-7g; and Adamts15 by miR-29c, miR-338, let-7a, let-7c, and let-7g.	('Tgfbr1', 'Gene', '21812', (138, 144))	('miR-29c', 'Var', (129, 136))	('miR-29c', 'Var', (192, 199))	('Adamts15', 'Gene', (180, 188))	('let-7a', 'Gene', (148, 154))	('Adamts15', 'Gene', '235130', (180, 188))	('let-7a', 'Gene', '387244', (92, 98))	('Pdgfa', 'Gene', (120, 125))	('Col1a1', 'Gene', '12842', (73, 79))	('let-7c', 'Gene', (100, 106))	('let-7g', 'Var', (112, 118))	('Tgfbr1', 'Gene', (138, 144))	('let-7a', 'Gene', (210, 216))	('let-7g', 'Var', (168, 174))	('let-7c', 'Gene', (156, 162))	('let-7a', 'Gene', '387244', (148, 154))	('let-7c', 'Gene', (218, 224))	('men', 'Species', '9606', (33, 36))	('let-7c', 'Gene', '406885', (100, 106))	('let-7a', 'Gene', '387244', (210, 216))	('let-7g', 'Var', (230, 236))	('let-7c', 'Gene', '406885', (156, 162))	('let-7c', 'Gene', '406885', (218, 224))	('Pdgfa', 'Gene', '18590', (120, 125))	('miR-338', 'Var', (201, 208))	('miR-29c', 'Var', (83, 90))	('Col1a1', 'Gene', (73, 79))	('let-7a', 'Gene', (92, 98))
510230	31871210	We found key miRNA hubs of the network, i.e., miR-29c, miR-335, miR-338, let-7a, let-7c, let-7g, miR-30d, and miR-30e, to be down-regulated in the fibrosis-associated mHCC model, in 2 murine fibrosis models, and in 4 types of human carcinomas.	('miR', 'Gene', (46, 49))	('miR', 'Gene', (13, 16))	('fibrosis', 'Disease', (147, 155))	('fibrosis', 'Disease', 'MESH:D005355', (147, 155))	('carcinomas', 'Phenotype', 'HP:0030731', (232, 242))	('carcinomas', 'Disease', 'MESH:D002277', (232, 242))	('carcinoma', 'Phenotype', 'HP:0030731', (232, 241))	('let-7g', 'Var', (89, 95))	('HCC', 'Disease', 'MESH:D006528', (168, 171))	('down-regulated', 'NegReg', (125, 139))	('miR', 'Gene', '751537', (97, 100))	('fibrosis', 'Disease', 'MESH:D005355', (191, 199))	('fibrosis', 'Disease', (191, 199))	('miR', 'Gene', '751537', (64, 67))	('fibrosis models', 'Disease', (191, 206))	('miR', 'Gene', '751537', (55, 58))	('let-7c', 'Gene', (81, 87))	('let-7a', 'Gene', (73, 79))	('miR', 'Gene', '751537', (110, 113))	('carcinomas', 'Disease', (232, 242))	('fibrosis models', 'Disease', 'MESH:D005355', (191, 206))	('miR', 'Gene', '751537', (46, 49))	('murine', 'Species', '10090', (184, 190))	('miR', 'Gene', (97, 100))	('miR', 'Gene', '751537', (13, 16))	('human', 'Species', '9606', (226, 231))	('miR', 'Gene', (64, 67))	('HCC', 'Disease', (168, 171))	('let-7a', 'Gene', '387244', (73, 79))	('miR', 'Gene', (55, 58))	('let-7c', 'Gene', '406885', (81, 87))	('miR', 'Gene', (110, 113))
510231	31871210	miR-29c is a known modulator of fibrotic environments in nasopharyngeal carcinoma, shown to reduce mRNA levels of different collagens and LAMC1.	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('mRNA levels of different collagens', 'MPA', (99, 133))	('men', 'Species', '9606', (48, 51))	('reduce', 'NegReg', (92, 98))	('LAMC1', 'Gene', (138, 143))	('miR-29c', 'Var', (0, 7))	('carcinoma', 'Disease', (72, 81))	('carcinoma', 'Disease', 'MESH:D002277', (72, 81))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (57, 81))	('LAMC1', 'Gene', '226519', (138, 143))
510342	25620903	Chemotherapy may also cause fulminant hepatitis in patients who have a history of hepatitis B virus infection (negative for HBs antigen and positive for HBc antibody or HBs antibody).	('cause', 'Reg', (22, 27))	('hepatitis', 'Disease', (38, 47))	('hepatitis', 'Phenotype', 'HP:0012115', (38, 47))	('hepatitis', 'Disease', 'MESH:D056486', (82, 91))	('hepatitis B virus infection', 'Disease', 'MESH:D006509', (82, 109))	('hepatitis B virus infection', 'Disease', (82, 109))	('hepatitis', 'Disease', 'MESH:D056486', (38, 47))	('fulminant hepatitis', 'Phenotype', 'HP:0004787', (28, 47))	('hepatitis', 'Disease', (82, 91))	('negative', 'NegReg', (111, 119))	('HBs', 'Protein', (124, 127))	('Chemotherapy', 'Var', (0, 12))	('patients', 'Species', '9606', (51, 59))	('hepatitis', 'Phenotype', 'HP:0012115', (82, 91))	('HBc antibody', 'Phenotype', 'HP:0032146', (153, 165))
510399	25620903	Among these, [101] and [106-rec] lymph nodes belong to group 1, and [102], [104] and [105] lymph nodes belong to group 2 in cases of cervical esophageal carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (153, 162))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (142, 162))	('cervical esophageal carcinoma', 'Disease', 'MESH:D004938', (133, 162))	('cervical esophageal carcinoma', 'Disease', (133, 162))	('[102]', 'Var', (68, 73))
510497	25620903	At the time of revising the guidelines, the timing of adjuvant chemotherapy with cisplatin + 5-FU was examined in the JCOG9907 study (1999-2006), and it was found that neoadjuvant chemotherapy yielded significantly improved overall survival in comparison to postoperative chemotherapy.	('overall survival', 'MPA', (224, 240))	('5-FU', 'Chemical', 'MESH:D005472', (93, 97))	('neoadjuvant', 'Var', (168, 179))	('improved', 'PosReg', (215, 223))	('cisplatin', 'Chemical', 'MESH:D002945', (81, 90))
510506	25620903	According to a meta-analysis that addressed surgery preceded by neoadjuvant chemoradiotherapy vs. surgery alone, when the 3-year survival rate was used as an end point, neoadjuvant chemoradiotherapy (20-45 Gy) in patients with resectable carcinoma was associated with a significant increase in operation-related mortality within 90 postoperative days.	('carcinoma', 'Disease', 'MESH:D002277', (238, 247))	('neoadjuvant chemoradiotherapy', 'Var', (169, 198))	('operation-related mortality', 'MPA', (294, 321))	('carcinoma', 'Phenotype', 'HP:0030731', (238, 247))	('carcinoma', 'Disease', (238, 247))	('patients', 'Species', '9606', (213, 221))
510511	25620903	Postoperative chemotherapy: A randomized controlled trial (JCOG9204 study) comparing surgery with and without postoperative chemotherapy (cisplatin + 5-FU, 2 courses) carried out in Japan demonstrated that postoperative chemotherapy resulted in a significant increase in the disease-free survival rate as compared to surgery alone, although there was no significant difference in the overall survival rate.	('cisplatin', 'Chemical', 'MESH:D002945', (138, 147))	('5-FU', 'Chemical', 'MESH:D005472', (150, 154))	('disease-free survival rate', 'CPA', (275, 301))	('increase', 'PosReg', (259, 267))	('postoperative', 'Var', (206, 219))
510559	25620903	Concurrent chemoradiotherapy is indicated for patients with T1-4N0-3M0 carcinoma (UICC-TNM classification, 2009 edition) in good general condition and for those with locally advanced carcinoma up to metastasis to the supraclavicular lymph nodes (M1).	('patients', 'Species', '9606', (46, 54))	('carcinoma', 'Disease', 'MESH:D002277', (183, 192))	('carcinoma', 'Phenotype', 'HP:0030731', (183, 192))	('TNM', 'Gene', '10178', (87, 90))	('carcinoma', 'Disease', 'MESH:D002277', (71, 80))	('T1-4N0-3M0', 'Var', (60, 70))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('carcinoma', 'Disease', (183, 192))	('TNM', 'Gene', (87, 90))	('carcinoma', 'Disease', (71, 80))
510566	25620903	Definitive irradiation is the most suitable for cases with T1-4N0-3M0 carcinoma (UICC-TNM classification, 2009 edition) and cases with locally advanced disease up to metastasis to the supraclavicular nodes (M1).	('T1-4N0-3M0', 'Var', (59, 69))	('carcinoma', 'Disease', 'MESH:D002277', (70, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('TNM', 'Gene', '10178', (86, 89))	('carcinoma', 'Disease', (70, 79))	('TNM', 'Gene', (86, 89))
510609	25620903	In addition, irradiation of the cervical area may cause hypothyroidism a few years post-irradiation.	('cause', 'Reg', (50, 55))	('hypothyroidism', 'Phenotype', 'HP:0000821', (56, 70))	('hypothyroidism', 'Disease', (56, 70))	('irradiation', 'Var', (13, 24))	('hypothyroidism', 'Disease', 'MESH:D007037', (56, 70))
510617	25620903	Patients who can be the target of definitive chemoradiotherapy include T1-3N0-3M0 cases (UICC-TNM classification, 2009 edition), unresectable T4N0-3M0 cases, and cases with locally advanced disease up to metastasis to the supraclavicular nodes (M1).	('T4N0-3M0', 'Var', (142, 150))	('TNM', 'Gene', '10178', (94, 97))	('Patients', 'Species', '9606', (0, 8))	('TNM', 'Gene', (94, 97))	('T1-3N0-3M0', 'Var', (71, 81))
510622	25620903	In a randomized controlled trial of radiation monotherapy (64 Gy) and concurrent chemoradiotherapy (5-FU + cisplatin + radiation 50 Gy) for T1-4N0-1M0 esophageal carcinoma (corresponding to UICC-TNM classification, 2002 edition) carried out by the US Radiation Therapy Oncology Group (RTOG), the 5-year survival rate was 0 % for the former and 26 % for the latter; the latter treatment yielded significantly better results (p < 0.0001).	('Oncology', 'Phenotype', 'HP:0002664', (269, 277))	('esophageal carcinoma ', 'Gene', (151, 172))	('TNM', 'Gene', '10178', (195, 198))	('men', 'Species', '9606', (381, 384))	('cisplatin', 'Chemical', 'MESH:D002945', (107, 116))	('5-FU', 'Chemical', 'MESH:D005472', (100, 104))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (151, 171))	('TNM', 'Gene', (195, 198))	('T1-4N0-1M0', 'Var', (140, 150))	('esophageal carcinoma ', 'Gene', '259307', (151, 172))	('carcinoma', 'Phenotype', 'HP:0030731', (162, 171))
510624	25620903	In addition, a randomized controlled study (RTOG9405/INT0123) carried out succeedingly to RTOG 85-01 that compared chemoradiotherapy using standard-dose (50.4 Gy) and high-dose (64.8 Gy) radiation in patients with T1-4N0-1M0 esophageal carcinoma (corresponding to UICC-TNM classification, 2002 edition) revealed no superiority of high-dose radiation over standard-dose radiation in terms of the median survival time, the 2-year survival rate, and the local control rate, and concluded that the standard radiation dose for chemoradiotherapy using a combination of 5-FU plus cisplatin should be 50.4 Gy (1.8 Gy x 28 times).	('5-FU', 'Chemical', 'MESH:D005472', (563, 567))	('patients', 'Species', '9606', (200, 208))	('TNM', 'Gene', '10178', (269, 272))	('esophageal carcinoma ', 'Gene', '259307', (225, 246))	('T1-4N0-1M0', 'Var', (214, 224))	('carcinoma', 'Phenotype', 'HP:0030731', (236, 245))	('TNM', 'Gene', (269, 272))	('esophageal carcinoma ', 'Gene', (225, 246))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (225, 245))	('cisplatin', 'Chemical', 'MESH:D002945', (573, 582))
510637	25620903	Among other possible adverse events during chemoradiotherapy for esophageal carcinoma, special attention should be paid to the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) attributable to cisplatin and leukoencephalopathy attributable to 5-FU.	('cisplatin', 'Var', (211, 220))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('inappropriate secretion of antidiuretic hormone', 'Disease', 'MESH:D007177', (139, 186))	('esophageal carcinoma', 'Disease', (65, 85))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (65, 85))	('leukoencephalopathy', 'Disease', (225, 244))	('SIADH', 'Disease', (188, 193))	('5-FU', 'Chemical', 'MESH:D005472', (261, 265))	('cisplatin', 'Chemical', 'MESH:D002945', (211, 220))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (65, 85))	('leukoencephalopathy', 'Phenotype', 'HP:0002352', (225, 244))	('leukoencephalopathy', 'Disease', 'MESH:D056784', (225, 244))	('inappropriate secretion of antidiuretic hormone', 'Disease', (139, 186))	('SIADH', 'Disease', 'MESH:D007177', (188, 193))
510770	25620903	According to the NCCN guidelines, preoperative therapy is indicated for cases with T1b, N1, T2 to resectable T4, and resectable Stage IVA disease.	('T1b', 'Var', (83, 86))	('IVA disease', 'Disease', (134, 145))	('IVA disease', 'Disease', 'MESH:C538167', (134, 145))	('T2 to', 'Var', (92, 97))
510783	32751497	Epigenetic Silencing of LMX1A Contributes to Cancer Progression in Lung Cancer Cells Epigenetic modification is considered a major mechanism of the inactivation of tumor suppressor genes that finally contributes to carcinogenesis.	('carcinogenesis', 'Disease', 'MESH:D063646', (215, 229))	('tumor', 'Disease', (164, 169))	('Lung Cancer', 'Disease', (67, 78))	('Cancer', 'Disease', (45, 51))	('contributes', 'Reg', (200, 211))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('Cancer', 'Phenotype', 'HP:0002664', (72, 78))	('Lung Cancer', 'Disease', 'MESH:D008175', (67, 78))	('Epigenetic Silencing', 'Var', (0, 20))	('Cancer', 'Disease', 'MESH:D009369', (45, 51))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('Lung Cancer', 'Phenotype', 'HP:0100526', (67, 78))	('Epigenetic', 'MPA', (85, 95))	('Cancer', 'Disease', (72, 78))	('LMX1A', 'Gene', (24, 29))	('Contributes', 'Reg', (30, 41))	('carcinogenesis', 'Disease', (215, 229))	('Cancer', 'Phenotype', 'HP:0002664', (45, 51))	('LMX1A', 'Gene', '4009', (24, 29))	('Cancer', 'Disease', 'MESH:D009369', (72, 78))
510785	32751497	Recently, LMX1A was shown to be hypermethylated and functioned as a tumor suppressor in cervical cancer, ovarian cancer, and gastric cancer.	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('cancer', 'Disease', (113, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('gastric cancer', 'Disease', (125, 139))	('tumor', 'Disease', (68, 73))	('cancer', 'Disease', (97, 103))	('ovarian cancer', 'Disease', 'MESH:D010051', (105, 119))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('gastric cancer', 'Disease', 'MESH:D013274', (125, 139))	('LMX1A', 'Gene', (10, 15))	('hypermethylated', 'Var', (32, 47))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('ovarian cancer', 'Disease', (105, 119))	('cancer', 'Disease', (133, 139))	('LMX1A', 'Gene', '4009', (10, 15))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('ovarian cancer', 'Phenotype', 'HP:0100615', (105, 119))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('cancer', 'Disease', 'MESH:D009369', (97, 103))	('gastric cancer', 'Phenotype', 'HP:0012126', (125, 139))
510787	32751497	In this study, we used public databases, methylation-specific PCR (MSP), reverse transcription PCR (RT-PCR), and bisulfite genomic sequencing to show that LMX1A was downregulated or silenced due to promoter hypermethylation in lung cancers.	('silenced', 'NegReg', (182, 190))	('cancers', 'Phenotype', 'HP:0002664', (232, 239))	('lung cancers', 'Disease', (227, 239))	('downregulated', 'NegReg', (165, 178))	('LMX1A', 'Gene', (155, 160))	('promoter hypermethylation', 'Var', (198, 223))	('lung cancer', 'Phenotype', 'HP:0100526', (227, 238))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('lung cancers', 'Disease', 'MESH:D008175', (227, 239))	('LMX1A', 'Gene', '4009', (155, 160))	('lung cancers', 'Phenotype', 'HP:0100526', (227, 239))
510789	32751497	In the lung cancer cell lines H23 and H1299, overexpression of LMX1A did not affect cell proliferation but suppressed colony formation and invasion.	('invasion', 'CPA', (139, 147))	('overexpression', 'Var', (45, 59))	('lung cancer', 'Disease', (7, 18))	('lung cancer', 'Phenotype', 'HP:0100526', (7, 18))	('LMX1A', 'Gene', '4009', (63, 68))	('suppressed', 'NegReg', (107, 117))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('LMX1A', 'Gene', (63, 68))	('lung cancer', 'Disease', 'MESH:D008175', (7, 18))	('H1299', 'CellLine', 'CVCL:0060', (38, 43))
510792	32751497	NanoString gene expression analysis revealed that all aberrantly expressed genes were associated with processes related to cancer progression, including angiogenesis, extracellular matrix (ECM) remodeling, EMT, cancer metastasis, and hypoxia-related gene expression.	('EMT', 'CPA', (206, 209))	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('cancer', 'Disease', 'MESH:D009369', (211, 217))	('angiogenesis', 'CPA', (153, 165))	('cancer', 'Disease', (211, 217))	('aberrantly expressed', 'Var', (54, 74))	('associated', 'Reg', (86, 96))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('cancer metastasis', 'Disease', (211, 228))	('cancer', 'Disease', (123, 129))	('hypoxia', 'Disease', (234, 241))	('hypoxia', 'Disease', 'MESH:D000860', (234, 241))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('cancer metastasis', 'Disease', 'MESH:D009362', (211, 228))
510793	32751497	Taken together, these data demonstrated that LMX1A is inactivated through promoter hypermethylation and functions as a tumor suppressor.	('tumor', 'Disease', (119, 124))	('LMX1A', 'Gene', (45, 50))	('promoter hypermethylation', 'Var', (74, 99))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('LMX1A', 'Gene', '4009', (45, 50))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('inactivated', 'NegReg', (54, 65))
510798	32751497	Therefore, major efforts are being made to identify molecular markers, including aberrant DNA methylation, circulating cell-free tumor DNA, noncoding RNA, and proteomic markers, to facilitate early detection of lung cancer to improve prognosis and survival.	('lung cancer', 'Phenotype', 'HP:0100526', (211, 222))	('aberrant', 'Var', (81, 89))	('improve', 'PosReg', (226, 233))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('lung cancer', 'Disease', 'MESH:D008175', (211, 222))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('tumor', 'Disease', (129, 134))	('lung cancer', 'Disease', (211, 222))
510800	32751497	Recent research has demonstrated a promising advance in targeted therapy for lung cancers with epidermal growth factor (EGFR) mutations.	('lung cancer', 'Phenotype', 'HP:0100526', (77, 88))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('lung cancers', 'Disease', 'MESH:D008175', (77, 89))	('cancers', 'Phenotype', 'HP:0002664', (82, 89))	('lung cancers', 'Phenotype', 'HP:0100526', (77, 89))	('EGFR', 'Gene', '1950', (120, 124))	('mutations', 'Var', (126, 135))	('lung cancers', 'Disease', (77, 89))	('epidermal growth factor', 'Gene', (95, 118))	('epidermal growth factor', 'Gene', '1950', (95, 118))	('EGFR', 'Gene', (120, 124))
510802	32751497	In addition to genetic mutations, aberrant DNA methylation is another mechanism for inactivation of tumor suppressor genes to promote the occurrence and progression of lung cancer.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('lung cancer', 'Disease', (168, 179))	('tumor', 'Disease', (100, 105))	('aberrant', 'Var', (34, 42))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('promote', 'PosReg', (126, 133))	('lung cancer', 'Phenotype', 'HP:0100526', (168, 179))	('lung cancer', 'Disease', 'MESH:D008175', (168, 179))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('inactivation', 'Var', (84, 96))
510803	32751497	The identification of genetic mutations and epigenetic changes will further improve biomarker-driven precision treatment for lung cancer patients.	('lung cancer', 'Disease', 'MESH:D008175', (125, 136))	('epigenetic changes', 'Var', (44, 62))	('genetic mutations', 'Var', (22, 39))	('patients', 'Species', '9606', (137, 145))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('lung cancer', 'Disease', (125, 136))	('lung cancer', 'Phenotype', 'HP:0100526', (125, 136))	('improve', 'PosReg', (76, 83))
510809	32751497	Recently, LMX1A has been found to be hypermethylated in cervical cancer, gastric cancer, bladder cancer, ovarian cancer, and colorectal cancer.	('hypermethylated', 'Var', (37, 52))	('cancer', 'Disease', (81, 87))	('colorectal cancer', 'Phenotype', 'HP:0003003', (125, 142))	('cancer', 'Disease', (113, 119))	('bladder cancer', 'Disease', (89, 103))	('cancer', 'Disease', (136, 142))	('bladder cancer', 'Disease', 'MESH:D001749', (89, 103))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('cancer', 'Disease', (65, 71))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('gastric cancer', 'Disease', 'MESH:D013274', (73, 87))	('cancer', 'Disease', (97, 103))	('ovarian cancer', 'Disease', 'MESH:D010051', (105, 119))	('bladder cancer', 'Phenotype', 'HP:0009725', (89, 103))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('LMX1A', 'Gene', (10, 15))	('colorectal cancer', 'Disease', 'MESH:D015179', (125, 142))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('ovarian cancer', 'Disease', (105, 119))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('gastric cancer', 'Phenotype', 'HP:0012126', (73, 87))	('LMX1A', 'Gene', '4009', (10, 15))	('colorectal cancer', 'Disease', (125, 142))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('ovarian cancer', 'Phenotype', 'HP:0100615', (105, 119))	('cancer', 'Disease', 'MESH:D009369', (97, 103))	('gastric cancer', 'Disease', (73, 87))
510810	32751497	Moreover, LMX1A was reported to function as a tumor suppressor in cervical, gastric, and ovarian cancers, and its methylation was significantly associated with recurrence in bladder cancer and survival in stage I and II colorectal cancer patients.	('stage I', 'Disease', (205, 212))	('colorectal cancer', 'Phenotype', 'HP:0003003', (220, 237))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('gastric', 'Disease', (76, 83))	('cancers', 'Phenotype', 'HP:0002664', (97, 104))	('associated with', 'Reg', (144, 159))	('ovarian cancers', 'Phenotype', 'HP:0100615', (89, 104))	('cervical', 'Disease', (66, 74))	('recurrence in bladder', 'Phenotype', 'HP:0012786', (160, 181))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('bladder cancer', 'Disease', 'MESH:D001749', (174, 188))	('bladder cancer', 'Disease', (174, 188))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('LMX1A', 'Gene', (10, 15))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('bladder cancer', 'Phenotype', 'HP:0009725', (174, 188))	('II colorectal cancer', 'Disease', (217, 237))	('tumor', 'Disease', (46, 51))	('II colorectal cancer', 'Disease', 'MESH:D015179', (217, 237))	('LMX1A', 'Gene', '4009', (10, 15))	('methylation', 'Var', (114, 125))	('survival', 'CPA', (193, 201))	('patients', 'Species', '9606', (238, 246))	('ovarian cancer', 'Phenotype', 'HP:0100615', (89, 103))	('tumor', 'Disease', 'MESH:D009369', (46, 51))	('ovarian cancers', 'Disease', (89, 104))	('ovarian cancers', 'Disease', 'MESH:D010051', (89, 104))
510816	32751497	The data showed that LMX1A was frequently hypermethylated and downregulated in NSCLC cells.	('LMX1A', 'Gene', (21, 26))	('NSCLC', 'Disease', 'MESH:D002289', (79, 84))	('downregulated', 'NegReg', (62, 75))	('NSCLC', 'Phenotype', 'HP:0030358', (79, 84))	('LMX1A', 'Gene', '4009', (21, 26))	('hypermethylated', 'Var', (42, 57))	('NSCLC', 'Disease', (79, 84))
510846	32751497	Moreover, restoration of LMX1A significantly increased the expression of inhibitor of DNA-binding gene 2 (ID2) in H23 cells.	('LMX1A', 'Gene', (25, 30))	('restoration', 'Var', (10, 21))	('increased', 'PosReg', (45, 54))	('inhibitor of DNA-binding gene 2', 'Gene', '3398', (73, 104))	('ID2', 'Gene', '3398', (106, 109))	('expression', 'MPA', (59, 69))	('ID2', 'Gene', (106, 109))	('inhibitor of DNA-binding gene 2', 'Gene', (73, 104))	('LMX1A', 'Gene', '4009', (25, 30))
510854	32751497	All of the aberrantly expressed genes were related to processes involved in cancer progression, including angiogenesis, extracellular matrix (ECM) remodeling, cancer invasion, and cancer metastasis.	('cancer', 'Disease', (159, 165))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('cancer metastasis', 'Disease', (180, 197))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('related', 'Reg', (43, 50))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('angiogenesis', 'CPA', (106, 118))	('cancer metastasis', 'Disease', 'MESH:D009362', (180, 197))	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('aberrantly', 'Var', (11, 21))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('cancer', 'Disease', (180, 186))
510856	32751497	Lung carcinogenesis involves a multistage stepwise process with the accumulation of genetic and epigenetic alterations.	('Lung carcinogenesis', 'Disease', 'MESH:D063646', (0, 19))	('Lung carcinogenesis', 'Disease', (0, 19))	('epigenetic alterations', 'Var', (96, 118))
510857	32751497	Among them, aberrant DNA methylation-induced silencing of tumor suppressor genes is a hallmark and an early event in lung carcinogenesis.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('lung carcinogenesis', 'Disease', (117, 136))	('lung carcinogenesis', 'Disease', 'MESH:D063646', (117, 136))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('aberrant DNA methylation-induced', 'Var', (12, 44))	('silencing', 'NegReg', (45, 54))
510859	32751497	In this study, we found that LMX1A was methylation-silenced in non-small cell lung cancer (Figure 1, Figure 2 and Figure 3 and Figure S1).	('lung cancer', 'Phenotype', 'HP:0100526', (78, 89))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (67, 89))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (63, 89))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('LMX1A', 'Gene', (29, 34))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (63, 89))	('non-small cell lung cancer', 'Disease', (63, 89))	('methylation-silenced', 'Var', (39, 59))	('LMX1A', 'Gene', '4009', (29, 34))
510861	32751497	To our knowledge, there are no data reporting epigenetic regulation of LMX1A expression and its function in lung cancer.	('lung cancer', 'Disease', 'MESH:D008175', (108, 119))	('epigenetic regulation', 'Var', (46, 67))	('LMX1A', 'Gene', '4009', (71, 76))	('lung cancer', 'Disease', (108, 119))	('LMX1A', 'Gene', (71, 76))	('lung cancer', 'Phenotype', 'HP:0100526', (108, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
510862	32751497	DNA methylation is not only important in lung carcinogenesis but also serves as a biomarker for early lung cancer detection.	('lung cancer', 'Phenotype', 'HP:0100526', (102, 113))	('lung carcinogenesis', 'Disease', (41, 60))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('lung cancer', 'Disease', (102, 113))	('lung carcinogenesis', 'Disease', 'MESH:D063646', (41, 60))	('methylation', 'Var', (4, 15))	('lung cancer', 'Disease', 'MESH:D008175', (102, 113))
510863	32751497	We analyzed the data from The Cancer Genome Atlas (TCGA) database through the UALCAN  web portal and showed that methylation of LMX1A in non-small cell lung cancer occurred early in stage I patients and was then maintained throughout all the stages of non-small cell lung cancer (Figure S5).	('lung cancer', 'Phenotype', 'HP:0100526', (267, 278))	('cancer', 'Phenotype', 'HP:0002664', (272, 278))	('patients', 'Species', '9606', (190, 198))	('Cancer', 'Disease', (30, 36))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (137, 163))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (252, 278))	('Cancer', 'Disease', 'MESH:D009369', (30, 36))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (256, 278))	('non-small cell lung cancer', 'Disease', (137, 163))	('lung cancer', 'Phenotype', 'HP:0100526', (152, 163))	('maintained', 'Reg', (212, 222))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (252, 278))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (141, 163))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (137, 163))	('Cancer', 'Phenotype', 'HP:0002664', (30, 36))	('LMX1A', 'Gene', (128, 133))	('methylation', 'Var', (113, 124))	('non-small cell lung cancer', 'Disease', (252, 278))	('LMX1A', 'Gene', '4009', (128, 133))
510864	32751497	This result implied that LMX1A methylation could be used as a diagnostic biomarker for the early detection of lung cancer.	('lung cancer', 'Disease', 'MESH:D008175', (110, 121))	('LMX1A', 'Gene', (25, 30))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('lung cancer', 'Disease', (110, 121))	('lung cancer', 'Phenotype', 'HP:0100526', (110, 121))	('methylation', 'Var', (31, 42))	('LMX1A', 'Gene', '4009', (25, 30))
510867	32751497	Our research group has reported that LMX1A was methylation-silenced and that the expression of LIMX1A inhibited colony formation and invasion in cervical cancer.	('invasion', 'CPA', (133, 141))	('inhibited', 'NegReg', (102, 111))	('LMX1A', 'Gene', (37, 42))	('expression', 'Var', (81, 91))	('cancer', 'Disease', (154, 160))	('LIM', 'Gene', (95, 98))	('LIM', 'Gene', '10611', (95, 98))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('colony formation', 'CPA', (112, 128))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('LMX1A', 'Gene', '4009', (37, 42))
510870	32751497	In addition, Zhao and his colleagues found that methylation of LMX1A could be used as an early diagnostic biomarker and was associated with recurrence in bladder cancer.	('recurrence in bladder', 'Phenotype', 'HP:0012786', (140, 161))	('bladder cancer', 'Phenotype', 'HP:0009725', (154, 168))	('LMX1A', 'Gene', '4009', (63, 68))	('associated with', 'Reg', (124, 139))	('bladder cancer', 'Disease', 'MESH:D001749', (154, 168))	('bladder cancer', 'Disease', (154, 168))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('methylation', 'Var', (48, 59))	('LMX1A', 'Gene', (63, 68))
510871	32751497	Dong and his colleagues found that methylation-mediated inactivation of LMX1A and restoration of LMX1A induced cell apoptosis and suppressed anchorage-independent growth in gastric cancer.	('LMX1A', 'Gene', (72, 77))	('gastric cancer', 'Disease', (173, 187))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('suppressed', 'NegReg', (130, 140))	('gastric cancer', 'Disease', 'MESH:D013274', (173, 187))	('LMX1A', 'Gene', (97, 102))	('inactivation', 'NegReg', (56, 68))	('methylation-mediated', 'Var', (35, 55))	('gastric cancer', 'Phenotype', 'HP:0012126', (173, 187))	('anchorage-independent growth', 'CPA', (141, 169))	('LMX1A', 'Gene', '4009', (72, 77))	('cell apoptosis', 'CPA', (111, 125))	('restoration', 'Var', (82, 93))	('LMX1A', 'Gene', '4009', (97, 102))
510878	32751497	The methylation-induced silencing of LMX1A could be reversed after cells were treated with a DNA methylation inhibitor in the three cell lines (Figure 3B).	('silencing', 'NegReg', (24, 33))	('LMX1A', 'Gene', (37, 42))	('LMX1A', 'Gene', '4009', (37, 42))	('methylation-induced', 'Var', (4, 23))
510880	32751497	These data suggested that histone modifications are also involved in the epigenetic silencing of LMX1A in lung cancer cells.	('lung cancer', 'Disease', (106, 117))	('LMX1A', 'Gene', (97, 102))	('lung cancer', 'Phenotype', 'HP:0100526', (106, 117))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('epigenetic silencing', 'Var', (73, 93))	('histone modifications', 'MPA', (26, 47))	('lung cancer', 'Disease', 'MESH:D008175', (106, 117))	('LMX1A', 'Gene', '4009', (97, 102))	('involved', 'Reg', (57, 65))
510902	32751497	ID2 was significantly decreased by TGF-ss, and expression of ID2 was restored after treatment with a TGF-ss inhibitor.	('TGF-ss', 'Var', (35, 41))	('ID2', 'Gene', '3398', (61, 64))	('ID2', 'Gene', '3398', (0, 3))	('ID2', 'Gene', (61, 64))	('ID2', 'Gene', (0, 3))	('expression', 'MPA', (47, 57))	('decreased', 'NegReg', (22, 31))
510909	32751497	In brief, promoter methylation leads to the silencing of LMX1A and contributes to cancer progression.	('promoter methylation', 'Var', (10, 30))	('silencing', 'MPA', (44, 53))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('LMX1A', 'Gene', '4009', (57, 62))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('LMX1A', 'Gene', (57, 62))	('contributes to', 'Reg', (67, 81))
510925	32751497	Epigenetic inactivation of LMX1A abolishes the tumor suppressor function.	('LMX1A', 'Gene', (27, 32))	('abolishes', 'NegReg', (33, 42))	('tumor', 'Disease', (47, 52))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('LMX1A', 'Gene', '4009', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('Epigenetic inactivation', 'Var', (0, 23))
510926	32751497	Our data identified a methylation biomarker for lung cancer progression and suggest a potential combination of epigenetic drugs in future therapeutic approaches.	('lung cancer', 'Disease', 'MESH:D008175', (48, 59))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('lung cancer', 'Disease', (48, 59))	('lung cancer', 'Phenotype', 'HP:0100526', (48, 59))	('methylation', 'Var', (22, 33))
510937	32148531	Network Pharmacology Study on the Pharmacological Mechanism of Cinobufotalin Injection against Lung Cancer Cinobufotalin injection, extracted from the skin of Chinese giant salamander or black sable, has good clinical effect against lung cancer.	('lung cancer', 'Phenotype', 'HP:0100526', (233, 244))	('Cinobufotalin', 'Chemical', 'MESH:C063451', (63, 76))	('Cinobufotalin', 'Var', (107, 120))	('lung cancer', 'Disease', (233, 244))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('Cinobufotalin', 'Chemical', 'MESH:C063451', (107, 120))	('Lung Cancer', 'Phenotype', 'HP:0100526', (95, 106))	('Chinese giant salamander', 'Species', '141262', (159, 183))	('Cancer', 'Disease', 'MESH:D009369', (100, 106))	('Cancer', 'Disease', (100, 106))	('lung cancer', 'Disease', 'MESH:D008175', (233, 244))	('Cancer', 'Phenotype', 'HP:0002664', (100, 106))	('sable', 'Species', '36722', (193, 198))
511005	32148531	The researchers established a nude mouse model with xenograft transplantation of A549 tumor and confirmed that cinobufotalin inhibits tumor growth through regulation of the nonapoptotic death pathway of cyclophilin-D in lung cancer cells.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('lung cancer', 'Disease', 'MESH:D008175', (220, 231))	('cinobufotalin', 'Chemical', 'MESH:C063451', (111, 124))	('tumor', 'Disease', (86, 91))	('lung cancer', 'Disease', (220, 231))	('cyclophilin-D', 'Gene', '105675', (203, 216))	('mouse', 'Species', '10090', (35, 40))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('cinobufotalin', 'Var', (111, 124))	('inhibits', 'NegReg', (125, 133))	('lung cancer', 'Phenotype', 'HP:0100526', (220, 231))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('cyclophilin-D', 'Gene', (203, 216))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('nonapoptotic death pathway', 'Pathway', (173, 199))	('tumor', 'Disease', (134, 139))	('A549', 'CellLine', 'CVCL:0023', (81, 85))
511016	32148531	Enrichment analysis of 70 potential targets of cinobufacin injection against lung cancer found that cinobufacin injection exerted clinical efficacy against lung cancer through multiple targets and pathways, involving inhibition of cell proliferation, promotion of apoptosis, antiangiogenesis effect, and immune regulation, which are consistent with the results of studies on lung cancer pathogenesis.	('lung cancer', 'Disease', 'MESH:D008175', (375, 386))	('lung cancer', 'Phenotype', 'HP:0100526', (375, 386))	('lung cancer', 'Disease', (77, 88))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('injection', 'Var', (112, 121))	('lung cancer', 'Disease', (156, 167))	('cancer', 'Phenotype', 'HP:0002664', (380, 386))	('cell proliferation', 'CPA', (231, 249))	('lung cancer', 'Disease', 'MESH:D008175', (77, 88))	('lung cancer', 'Disease', (375, 386))	('apoptosis', 'CPA', (264, 273))	('inhibition', 'NegReg', (217, 227))	('antiangiogenesis effect', 'CPA', (275, 298))	('lung cancer', 'Phenotype', 'HP:0100526', (77, 88))	('promotion', 'PosReg', (251, 260))	('immune regulation', 'CPA', (304, 321))	('lung cancer', 'Disease', 'MESH:D008175', (156, 167))	('cinobufacin', 'Var', (100, 111))	('cinobufacin', 'Chemical', '-', (47, 58))	('lung cancer', 'Phenotype', 'HP:0100526', (156, 167))	('cinobufacin', 'Chemical', '-', (100, 111))
511017	32148531	In terms of cell cycle and proliferation, the clinical effects of cinobufotalin injection mainly involved the PI3K-Akt (hsa04151), p53 (hsa04115), and MAPK (hsa04010) signaling pathways.	('Akt', 'Gene', '207', (115, 118))	('cinobufotalin', 'Chemical', 'MESH:C063451', (66, 79))	('hsa04115', 'Var', (136, 144))	('proliferation', 'CPA', (27, 40))	('Akt', 'Gene', (115, 118))	('p53', 'Gene', (131, 134))	('p53', 'Gene', '7157', (131, 134))	('hsa04151', 'Var', (120, 128))	('involved', 'Reg', (97, 105))	('MAPK', 'Pathway', (151, 155))	('hsa04010', 'Var', (157, 165))
511019	32148531	Cinobufotalin injection blocks cancer cells in the G2/M phase, possibly by downregulating the expression of p-Akt, p-mTOR, and p-4E-BP, thus blocking the Akt/mTOR signaling pathway.	('mTOR', 'Gene', (117, 121))	('Akt', 'Gene', (110, 113))	('mTOR', 'Gene', '2475', (117, 121))	('Akt', 'Gene', '207', (154, 157))	('G2/M phase', 'CPA', (51, 61))	('Cinobufotalin', 'Chemical', 'MESH:C063451', (0, 13))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('blocking', 'NegReg', (141, 149))	('Akt', 'Gene', (154, 157))	('downregulating', 'NegReg', (75, 89))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('expression', 'MPA', (94, 104))	('cancer', 'Disease', (31, 37))	('Akt', 'Gene', '207', (110, 113))	('mTOR', 'Gene', (158, 162))	('mTOR', 'Gene', '2475', (158, 162))	('p-4E-BP', 'Var', (127, 134))
511021	32148531	In terms of immune inflammation, cinobufotalin injection plays anti-inflammatory and immunoregulatory roles, mainly, through the TNF (hsa04668), HIF-1 (hsa04066), and Toll-like receptor (hsa04620) signaling pathways.	('anti-inflammatory', 'CPA', (63, 80))	('HIF-1', 'Gene', '3091', (145, 150))	('hsa04066', 'Var', (152, 160))	('inflammation', 'Disease', 'MESH:D007249', (19, 31))	('cinobufotalin', 'Chemical', 'MESH:C063451', (33, 46))	('HIF-1', 'Gene', (145, 150))	('inflammation', 'Disease', (19, 31))	('TNF', 'Gene', (129, 132))	('hsa04668', 'Var', (134, 142))	('TNF', 'Gene', '7124', (129, 132))	('immunoregulatory', 'CPA', (85, 101))
511023	32148531	A recent study found that cinobufotalin injection promotes the enrichment of lymphocyte with CD3+, CD4+, and CD8+ in cancer and adjacent tissues and activates the proopiomelanocortin/beta-endorphin/mu-opioid receptor pathway by promoting the proliferation of immune cells to alleviate cancer pain and increase pain threshold in mice.	('promoting', 'PosReg', (228, 237))	('cancer pain', 'Disease', 'MESH:D009369', (285, 296))	('alleviate', 'PosReg', (275, 284))	('activates', 'PosReg', (149, 158))	('enrichment', 'CPA', (63, 73))	('increase pain', 'Disease', 'MESH:D010146', (301, 314))	('cinobufotalin', 'Chemical', 'MESH:C063451', (26, 39))	('immune cells', 'CPA', (259, 271))	('increase pain', 'Disease', (301, 314))	('cancer', 'Disease', (117, 123))	('cancer', 'Disease', (285, 291))	('promotes', 'PosReg', (50, 58))	('mice', 'Species', '10090', (328, 332))	('cancer pain', 'Disease', (285, 296))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('pain', 'Phenotype', 'HP:0012531', (310, 314))	('cancer', 'Phenotype', 'HP:0002664', (285, 291))	('proliferation', 'CPA', (242, 255))	('pain', 'Phenotype', 'HP:0012531', (292, 296))	('cinobufotalin', 'Var', (26, 39))	('CD8+', 'Var', (109, 113))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('cancer', 'Disease', 'MESH:D009369', (285, 291))
511025	32148531	treated nude mice model of pancreatic cancer with cinobufotalin injection, and the results showed that cinobufotalin injection inhibits the growth of primary pancreatic cancer and hepatic metastases by downregulating the expression of VEGF.	('inhibits', 'NegReg', (127, 135))	('cinobufotalin', 'Chemical', 'MESH:C063451', (50, 63))	('pancreatic cancer', 'Disease', 'MESH:D010190', (158, 175))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('hepatic metastases', 'Disease', (180, 198))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (27, 44))	('nude mice', 'Species', '10090', (8, 17))	('primary pancreatic cancer', 'Disease', 'MESH:D010190', (150, 175))	('cinobufotalin', 'Chemical', 'MESH:C063451', (103, 116))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('downregulating', 'NegReg', (202, 216))	('pancreatic cancer', 'Disease', 'MESH:D010190', (27, 44))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (158, 175))	('VEGF', 'Protein', (235, 239))	('expression', 'MPA', (221, 231))	('growth', 'CPA', (140, 146))	('primary pancreatic cancer', 'Disease', (150, 175))	('pancreatic cancer', 'Disease', (27, 44))	('cinobufotalin', 'Var', (103, 116))	('hepatic metastases', 'Disease', 'MESH:D009362', (180, 198))
511034	32148531	The survival time of patients with mutation or high expression of EGFR was significantly prolonged after treatment with small-molecule tyrosine kinase inhibitors.	('prolonged', 'PosReg', (89, 98))	('EGFR', 'Gene', '1956', (66, 70))	('EGFR', 'Gene', (66, 70))	('survival time', 'CPA', (4, 17))	('high expression', 'Var', (47, 62))	('tyrosine', 'Chemical', 'MESH:D014443', (135, 143))	('patients', 'Species', '9606', (21, 29))	('mutation', 'Var', (35, 43))
511037	32148531	Abnormal expression of this gene is associated with many cancers, such as lung, liver, and intestinal cancers.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('Abnormal expression', 'Var', (0, 19))	('intestinal cancers', 'Disease', 'MESH:D007414', (91, 109))	('cancers', 'Phenotype', 'HP:0002664', (57, 64))	('associated', 'Reg', (36, 46))	('cancers', 'Disease', (57, 64))	('intestinal cancers', 'Disease', (91, 109))	('cancers', 'Disease', 'MESH:D009369', (57, 64))	('cancers', 'Disease', 'MESH:D009369', (102, 109))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('cancers', 'Disease', (102, 109))	('liver', 'Disease', (80, 85))	('lung', 'Disease', (74, 78))
511071	27737660	Based on these findings, the patient was diagnosed with T3N0M0, stage IIA (according to the Union for International Cancer Control TNM classification of malignant tumors, 7th edition) ESCC.	('patient', 'Species', '9606', (29, 36))	('malignant tumors', 'Disease', (153, 169))	('SCC', 'Gene', (185, 188))	('malignant tumors', 'Disease', 'MESH:D018198', (153, 169))	('Cancer', 'Phenotype', 'HP:0002664', (116, 122))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('TNM', 'Gene', '10178', (131, 134))	('SCC', 'Gene', '6317', (185, 188))	('T3N0M0', 'Var', (56, 62))	('tumors', 'Phenotype', 'HP:0002664', (163, 169))	('TNM', 'Gene', (131, 134))
511091	27737660	An excess amount of aberrant production causes an inflammatory response such as fever and positive CRP, a kind of leukemoid reaction (leukocytosis >50,000 leukocytes/muL), and paraneoplastic syndrome in clinical oncology.	('muL', 'Gene', (166, 169))	('causes', 'Reg', (40, 46))	('fever', 'Disease', (80, 85))	('fever', 'Phenotype', 'HP:0001945', (80, 85))	('leukemoid reaction', 'Disease', (114, 132))	('oncology', 'Phenotype', 'HP:0002664', (212, 220))	('CRP', 'Gene', (99, 102))	('leukocytosis', 'Disease', 'MESH:D007964', (134, 146))	('leukocytosis', 'Phenotype', 'HP:0001974', (134, 146))	('inflammatory response', 'MPA', (50, 71))	('muL', 'Gene', '4591', (166, 169))	('paraneoplastic syndrome', 'Disease', (176, 199))	('leukemoid reaction', 'Disease', 'MESH:D007955', (114, 132))	('CRP', 'Gene', '1401', (99, 102))	('paraneoplastic syndrome', 'Disease', 'MESH:D010257', (176, 199))	('leukocytosis', 'Disease', (134, 146))	('aberrant production', 'Var', (20, 39))	('fever', 'Disease', 'MESH:D005334', (80, 85))
511185	26445608	used the Surveillance, Epidemiology, and End Results database to retrospectively evaluate the benefit of adjuvant RT in T3-4N0M0 or T1-4N1M0 esophageal cancer patients definitively treated with esophagectomy.	('esophageal cancer', 'Disease', (141, 158))	('T3-4N0M0', 'Var', (120, 128))	('esophageal cancer', 'Disease', 'MESH:D004938', (141, 158))	('T1-4N1M0', 'Var', (132, 140))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('patients', 'Species', '9606', (159, 167))
511187	26445608	For American Joint Committee on Cancer (AJCC) stage III esophageal carcinoma (T3N1M0 or T4N0-1M0), in which 346 patients had surgery alone and 231 patients received PORT, PORT significantly improved the median OS from 15 to 19 months and the three-year OS rate from 18.2% to 28.9% (P < 0.001).	('Cancer', 'Disease', (32, 38))	('Cancer', 'Disease', 'MESH:D009369', (32, 38))	('OS', 'Chemical', '-', (210, 212))	('esophageal carcinoma', 'Disease', (56, 76))	('patients', 'Species', '9606', (112, 120))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('patients', 'Species', '9606', (147, 155))	('improved', 'PosReg', (190, 198))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (56, 76))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (56, 76))	('T4N0-1M0', 'Var', (88, 96))	('T3N1M0', 'Var', (78, 84))	('OS', 'Chemical', '-', (253, 255))	('Cancer', 'Phenotype', 'HP:0002664', (32, 38))
511213	26445608	However, in the present study, we found that IMRT caused 3.1% gastrointestinal bleeding, which was higher than gastrointestinal bleeding rates of 1.1% and 1.0% reported previously.	('gastrointestinal bleeding', 'Phenotype', 'HP:0002239', (62, 87))	('gastrointestinal bleeding', 'Phenotype', 'HP:0002239', (111, 136))	('gastrointestinal bleeding', 'Disease', 'MESH:D006471', (62, 87))	('gastrointestinal bleeding', 'Disease', 'MESH:D006471', (111, 136))	('IMRT', 'Var', (45, 49))	('gastrointestinal bleeding', 'Disease', (62, 87))	('gastrointestinal bleeding', 'Disease', (111, 136))
511233	34003875	The high expression of LINC00958 has also been shown to promote the occurrence and development of certain cancers, including bladder cancer, oral cancer, pancreatic cancer, gastric cancer, cervical cancer and glioma.	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('cancers', 'Phenotype', 'HP:0002664', (106, 113))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (154, 171))	('high expression', 'Var', (4, 19))	('cancers', 'Disease', (106, 113))	('cancer', 'Disease', (106, 112))	('glioma', 'Disease', (209, 215))	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('gastric cancer', 'Disease', (173, 187))	('glioma', 'Disease', 'MESH:D005910', (209, 215))	('cancer', 'Disease', (198, 204))	('promote', 'PosReg', (56, 63))	('bladder cancer', 'Disease', 'MESH:D001749', (125, 139))	('bladder cancer', 'Disease', (125, 139))	('oral cancer', 'Disease', 'MESH:D009369', (141, 152))	('pancreatic cancer', 'Disease', 'MESH:D010190', (154, 171))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('glioma', 'Phenotype', 'HP:0009733', (209, 215))	('gastric cancer', 'Disease', 'MESH:D013274', (173, 187))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('cancer', 'Disease', (133, 139))	('bladder cancer', 'Phenotype', 'HP:0009725', (125, 139))	('cancer', 'Disease', (165, 171))	('cancers', 'Disease', 'MESH:D009369', (106, 113))	('cancer', 'Disease', (181, 187))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('pancreatic cancer', 'Disease', (154, 171))	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('LINC00958', 'Gene', '100506305', (23, 32))	('gastric cancer', 'Phenotype', 'HP:0012126', (173, 187))	('LINC00958', 'Gene', (23, 32))	('oral cancer', 'Disease', (141, 152))	('development', 'CPA', (83, 94))
511236	34003875	In addition, we verified miR-510-5p, a tumour suppressor to be a target miRNA of LINC00958, and suggested that the antitumor effect of miR-510-5p might be related to its target gene SPOCK1.	('tumor', 'Disease', (119, 124))	('miR-510-5p', 'Chemical', '-', (25, 35))	('tumour', 'Disease', (39, 45))	('miR-510-5p', 'Chemical', '-', (135, 145))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('LINC00958', 'Gene', '100506305', (81, 90))	('SPOCK1', 'Gene', (182, 188))	('miR-510-5p', 'Var', (135, 145))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('tumour', 'Phenotype', 'HP:0002664', (39, 45))	('LINC00958', 'Gene', (81, 90))	('tumour', 'Disease', 'MESH:D009369', (39, 45))	('SPOCK1', 'Gene', '6695', (182, 188))
511237	34003875	Three ESCC cell lines, EC109, EC9706 and KYSE180, and an immortal oesophageal epithelial cell line, Shantou Human Embryonic Oesophageal Epithelial (SHEE) cell line, were obtained from the Institute of Virology of the Chinese Academy of Preventive Medicine, Beijing, China.	('EC9706', 'CellLine', 'CVCL:E307', (30, 36))	('Human', 'Species', '9606', (108, 113))	('EC9706', 'Var', (30, 36))	('EC109', 'CellLine', 'CVCL:6898', (23, 28))	('KYSE180', 'Var', (41, 48))
511239	34003875	For the knockdown of LINC00958, siRNA-LINC00958-1 CCUUUGUUUCCAAAGGUUACC, siRNA-LINC00958-2 GCCUUAAAACUCACAUAGAGA and siRNA-LINC00958-3 GCGAAACUCCAUCUAAAAAAA (KeyGEN BioTECH, Nanjing, China) were designed and synthesised.	('BioTECH', 'Gene', '57449', (165, 172))	('LINC00958', 'Gene', (123, 132))	('LINC00958', 'Gene', (79, 88))	('LINC00958', 'Gene', (21, 30))	('LINC00958', 'Gene', (38, 47))	('knockdown', 'Var', (8, 17))	('LINC00958', 'Gene', '100506305', (123, 132))	('BioTECH', 'Gene', (165, 172))	('LINC00958', 'Gene', '100506305', (21, 30))	('LINC00958', 'Gene', '100506305', (38, 47))	('LINC00958', 'Gene', '100506305', (79, 88))
511247	34003875	The bioinformatics-based ENCORI (The Encyclopedia of RNA Interactomes) website (http://starbase.sysu.edu.cn/) was used to predict the binding site of LINC00958 and miR-510-5p.	('miR-510-5p', 'Var', (164, 174))	('LINC00958', 'Gene', '100506305', (150, 159))	('LINC00958', 'Gene', (150, 159))	('binding', 'Interaction', (134, 141))	('miR-510-5p', 'Chemical', '-', (164, 174))
511276	34003875	The results showed that the overexpression of LINC00958 promoted the proliferation of ESCC, which was detected using the xCELLigence RTCA DP system, while the knockdown of LINC00958 inhibited the proliferation of ESCC (Fig 2C and 2D).	('proliferation', 'CPA', (196, 209))	('LINC00958', 'Gene', '100506305', (46, 55))	('knockdown', 'Var', (159, 168))	('proliferation', 'CPA', (69, 82))	('LINC00958', 'Gene', (172, 181))	('ESCC', 'CPA', (86, 90))	('LINC00958', 'Gene', (46, 55))	('inhibited', 'NegReg', (182, 191))	('LINC00958', 'Gene', '100506305', (172, 181))	('promoted', 'PosReg', (56, 64))
511278	34003875	The knockdown of LINC00958 caused a significant increase in the number of cells in the G1 phase and a significant decrease in the number of cells in the S phase (Fig 2H and 2I).	('LINC00958', 'Gene', (17, 26))	('LINC00958', 'Gene', '100506305', (17, 26))	('decrease', 'NegReg', (114, 122))	('knockdown', 'Var', (4, 13))	('increase', 'PosReg', (48, 56))
511282	34003875	The knockdown of LINC00958 significantly inhibited the migration ability of ESCC, while the overexpression of LINC00958 significantly promoted the migration ability (Fig 3A-3C).	('LINC00958', 'Gene', (17, 26))	('LINC00958', 'Gene', '100506305', (110, 119))	('migration ability', 'CPA', (147, 164))	('promoted', 'PosReg', (134, 142))	('ESCC', 'CPA', (76, 80))	('LINC00958', 'Gene', (110, 119))	('migration ability', 'CPA', (55, 72))	('inhibited', 'NegReg', (41, 50))	('LINC00958', 'Gene', '100506305', (17, 26))	('knockdown', 'Var', (4, 13))
511284	34003875	After knockdown of LINC00958, the invasion ability of the EC109 cells was significantly reduced (Fig 3D).	('invasion ability of the EC109 cells', 'CPA', (34, 69))	('LINC00958', 'Gene', '100506305', (19, 28))	('EC109', 'CellLine', 'CVCL:6898', (58, 63))	('LINC00958', 'Gene', (19, 28))	('knockdown', 'Var', (6, 15))	('reduced', 'NegReg', (88, 95))
511289	34003875	To further study the function of LINC00958, we used the ENCORI website to predict the relationship between LINC00958 and miR-510-5p (Fig 4A).	('LINC00958', 'Gene', '100506305', (107, 116))	('LINC00958', 'Gene', '100506305', (33, 42))	('miR-510-5p', 'Chemical', '-', (121, 131))	('LINC00958', 'Gene', (107, 116))	('miR-510-5p', 'Var', (121, 131))	('LINC00958', 'Gene', (33, 42))
511290	34003875	A dual luciferase reporter gene experiment was used to verify that the miR-510-5p mimics significantly inhibited the luciferase activity of the PmirGLO-LINC00958 plasmid, but had no effect on the PmirGLO-NC plasmid (Fig 4B).	('activity', 'MPA', (128, 136))	('LINC00958', 'Gene', (152, 161))	('inhibited', 'NegReg', (103, 112))	('miR-510-5p', 'Chemical', '-', (71, 81))	('luciferase', 'Enzyme', (117, 127))	('miR-510-5p mimics', 'Var', (71, 88))	('LINC00958', 'Gene', '100506305', (152, 161))
511291	34003875	Subsequently, we used the TargetScan website to predict the downstream mRNA of miR-510-5p, and we focused on SPOCK1.	('miR-510-5p', 'Chemical', '-', (79, 89))	('SPOCK1', 'Gene', (109, 115))	('SPOCK1', 'Gene', '6695', (109, 115))	('miR-510-5p', 'Var', (79, 89))
511296	34003875	Compared with the control group, miR-510-5p significantly inhibited the expression of SPOCK1 (Fig 4H and 4I).	('miR-510-5p', 'Var', (33, 43))	('SPOCK1', 'Gene', '6695', (86, 92))	('expression', 'MPA', (72, 82))	('miR-510-5p', 'Chemical', '-', (33, 43))	('inhibited', 'NegReg', (58, 67))	('SPOCK1', 'Gene', (86, 92))
511310	34003875	To verify the function of LINC00958 in ESCC, we predicted that there was a targeting relationship between LINC00958 and miR-510-5p using the ENCORI website (S1 Fig).	('LINC00958', 'Gene', '100506305', (26, 35))	('LINC00958', 'Gene', '100506305', (106, 115))	('miR-510-5p', 'Chemical', '-', (120, 130))	('LINC00958', 'Gene', (106, 115))	('LINC00958', 'Gene', (26, 35))	('miR-510-5p', 'Var', (120, 130))
511311	34003875	Studies have reported that miR-510-5p acts as a tumour suppressor in renal cell carcinoma and, thus, inhibits cell proliferation and migration, and promotes cell apoptosis.	('miR-510-5p', 'Chemical', '-', (27, 37))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (69, 89))	('tumour', 'Phenotype', 'HP:0002664', (48, 54))	('miR-510-5p', 'Var', (27, 37))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (69, 89))	('cell apoptosis', 'CPA', (157, 171))	('tumour', 'Disease', 'MESH:D009369', (48, 54))	('inhibits', 'NegReg', (101, 109))	('tumour', 'Disease', (48, 54))	('promotes', 'PosReg', (148, 156))	('renal cell carcinoma', 'Disease', (69, 89))
511312	34003875	It can be speculated that miR-510-5p may act as a tumour suppressor in ESCC and play a similar role to that in renal cell carcinoma.	('miR-510-5p', 'Var', (26, 36))	('tumour', 'Disease', 'MESH:D009369', (50, 56))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (111, 131))	('tumour', 'Disease', (50, 56))	('ESCC', 'Disease', (71, 75))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (111, 131))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('tumour', 'Phenotype', 'HP:0002664', (50, 56))	('miR-510-5p', 'Chemical', '-', (26, 36))	('renal cell carcinoma', 'Disease', (111, 131))
511314	34003875	Through the TargetScan website, we predicted that there was a targeting relationship between miR-510-5p and SPOCK1.	('miR-510-5p', 'Chemical', '-', (93, 103))	('SPOCK1', 'Gene', '6695', (108, 114))	('miR-510-5p', 'Var', (93, 103))	('SPOCK1', 'Gene', (108, 114))
511315	34003875	Our experimental results showed that miR-510-5p is the upstream miRNA of SPOCK1.	('SPOCK1', 'Gene', (73, 79))	('miR-510-5p', 'Var', (37, 47))	('miR-510-5p', 'Chemical', '-', (37, 47))	('SPOCK1', 'Gene', '6695', (73, 79))
511322	34003875	reported that silencing of SPOCK1 by small interfering RNA inhibited ESCC cells migration and invasion Therefore, we suggested that LINC00958 might regulate the expression of SPOCK1 by its sponging of miR-510-5p, and involve proliferation, migration, invasion and EMT of ESCC.	('SPOCK1', 'Gene', '6695', (27, 33))	('silencing', 'Var', (14, 23))	('invasion', 'CPA', (94, 102))	('EMT', 'CPA', (264, 267))	('LINC00958', 'Gene', '100506305', (132, 141))	('expression', 'MPA', (161, 171))	('ESCC cells migration', 'CPA', (69, 89))	('ESCC', 'Disease', (271, 275))	('inhibited', 'NegReg', (59, 68))	('LINC00958', 'Gene', (132, 141))	('invasion', 'CPA', (251, 259))	('SPOCK1', 'Gene', (175, 181))	('proliferation', 'CPA', (225, 238))	('SPOCK1', 'Gene', '6695', (175, 181))	('miR-510-5p', 'Chemical', '-', (201, 211))	('SPOCK1', 'Gene', (27, 33))	('migration', 'CPA', (240, 249))	('regulate', 'Reg', (148, 156))
511335	34003875	Given the growing body of evidence implicating long noncoding RNAs in cancer development, this manuscript is of interest to the field of esophageal biology.	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('long noncoding RNAs', 'Var', (47, 66))
511336	34003875	Major concern: The data are too preliminary to support the central conclusion of this manuscript - that LINC00958-mediated 'sponging' of miR-510-5p results in elevated SPOCK1 expression, driving ESCC development.	('LINC00958', 'Gene', '100506305', (104, 113))	('expression', 'MPA', (175, 185))	('miR-510-5p', 'Var', (137, 147))	('driving', 'PosReg', (187, 194))	('LINC00958', 'Gene', (104, 113))	('ESCC development', 'CPA', (195, 211))	('SPOCK1', 'Gene', (168, 174))	('elevated', 'PosReg', (159, 167))	('SPOCK1', 'Gene', '6695', (168, 174))	('miR-510-5p', 'Chemical', '-', (137, 147))
511339	34003875	Does SPOCK1 overexpression rescue the oncogenic effects (growth, invasion, EMT) of LINC00958 silencing?	('silencing', 'Var', (93, 102))	('LINC00958', 'Gene', (83, 92))	('SPOCK1', 'Gene', (5, 11))	('oncogenic', 'MPA', (38, 47))	('SPOCK1', 'Gene', '6695', (5, 11))	('LINC00958', 'Gene', '100506305', (83, 92))	('invasion', 'CPA', (65, 73))
511341	34003875	The following questions need to be addressed in order to conclude that LINC00958 "sponging" of miR-510-5p is resulting in the SPOCK1-mediated oncogenic effects described in this manuscript: 1.	('LINC00958', 'Gene', '100506305', (71, 80))	('SPOCK1', 'Gene', (126, 132))	('SPOCK1', 'Gene', '6695', (126, 132))	('LINC00958', 'Gene', (71, 80))	('miR-510-5p', 'Chemical', '-', (95, 105))	('miR-510-5p', 'Var', (95, 105))	('oncogenic effects', 'CPA', (142, 159))
511342	34003875	Does overexpression of miR-510-5p reduce the oncogenic effects (growth, invasion, EMT) of LINC00958 overexpression?	('miR-510-5p', 'Var', (23, 33))	('LINC00958', 'Gene', '100506305', (90, 99))	('oncogenic effects', 'MPA', (45, 62))	('reduce', 'NegReg', (34, 40))	('LINC00958', 'Gene', (90, 99))	('miR-510-5p', 'Chemical', '-', (23, 33))	('invasion', 'CPA', (72, 80))
511343	34003875	Does miR-510-5p loss-of-function rescue the oncogenic effects (growth, invasion, EMT) of LINC00958 silencing?	('LINC00958', 'Gene', (89, 98))	('invasion', 'CPA', (71, 79))	('loss-of-function', 'NegReg', (16, 32))	('LINC00958', 'Gene', '100506305', (89, 98))	('silencing', 'Var', (99, 108))	('miR-510-5p', 'Chemical', '-', (5, 15))
511344	34003875	Additionally, more evidence must be given to conclude that miR-510-5p and LINC00958 interact.	('interact', 'Reg', (84, 92))	('miR-510-5p', 'Chemical', '-', (59, 69))	('LINC00958', 'Gene', '100506305', (74, 83))	('miR-510-5p', 'Var', (59, 69))	('LINC00958', 'Gene', (74, 83))
511351	34003875	Figure 4: More discussion is required to explain why miR-510-5p and SPOCK1 were evaluated in this manuscript.	('miR-510-5p', 'Var', (53, 63))	('miR-510-5p', 'Chemical', '-', (53, 63))	('SPOCK1', 'Gene', (68, 74))	('SPOCK1', 'Gene', '6695', (68, 74))
511359	34003875	The authors demonstrated a little effect on the ESCC cell proliferation by overexpression or knockdown of LINC00958 (Figure 2C-D) within 3 days.	('knockdown', 'Var', (93, 102))	('LINC00958', 'Gene', (106, 115))	('overexpression', 'PosReg', (75, 89))	('LINC00958', 'Gene', '100506305', (106, 115))	('ESCC', 'Disease', (48, 52))
511372	34003875	Then, we have predicted the competitive binding relationship between LINC00958 and miR-510-5p through the ENCORI website (Fig 4A).	('LINC00958', 'Gene', (69, 78))	('miR-510-5p', 'Chemical', '-', (83, 93))	('miR-510-5p', 'Var', (83, 93))	('LINC00958', 'Gene', '100506305', (69, 78))	('binding', 'Interaction', (40, 47))
511375	34003875	(CircRNA SCARB1 Promotes Renal Cell Carcinoma Progression Via Mir- 510-5p/SDC3 Axis) have reported that miR-510-5p acts as a tumor suppressor in renal cell carcinoma, inhibiting cell proliferation and migration, and promoting cell apoptosis.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('cell proliferation', 'CPA', (178, 196))	('miR-510-5p', 'Chemical', '-', (104, 114))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (145, 165))	('miR-510-5p', 'Var', (104, 114))	('Promotes Renal Cell Carcinoma', 'Disease', (16, 45))	('Renal Cell Carcinoma', 'Phenotype', 'HP:0005584', (25, 45))	('SDC3', 'Gene', (74, 78))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('SCARB1', 'Gene', (9, 15))	('promoting', 'PosReg', (216, 225))	('inhibiting', 'NegReg', (167, 177))	('carcinoma', 'Phenotype', 'HP:0030731', (156, 165))	('Carcinoma', 'Phenotype', 'HP:0030731', (36, 45))	('renal cell carcinoma', 'Disease', (145, 165))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (145, 165))	('SDC3', 'Gene', '9672', (74, 78))	('SCARB1', 'Gene', '949', (9, 15))	('Promotes Renal Cell Carcinoma', 'Disease', 'MESH:C538614', (16, 45))	('Mir- 510', 'Gene', '574515', (62, 70))	('Mir- 510', 'Gene', (62, 70))	('cell apoptosis', 'CPA', (226, 240))	('tumor', 'Disease', (125, 130))
511377	34003875	It can be speculated that miR-510-5p may act as a tumor suppressor in ESCC and play a similar role to that in renal cell carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('miR-510-5p', 'Var', (26, 36))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (110, 130))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (110, 130))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Disease', (50, 55))	('ESCC', 'Disease', (70, 74))	('miR-510-5p', 'Chemical', '-', (26, 36))	('renal cell carcinoma', 'Disease', (110, 130))
511378	34003875	Through the Target Scan website, we predicted the targeting relationship between miR-510-5p and SPOCK1, and the experimental results also showed that miR-510-5p was the upstream miRNA of SPOCK1.	('SPOCK1', 'Gene', '6695', (96, 102))	('miR-510-5p', 'Var', (150, 160))	('SPOCK1', 'Gene', (187, 193))	('SPOCK1', 'Gene', '6695', (187, 193))	('miR-510-5p', 'Chemical', '-', (81, 91))	('SPOCK1', 'Gene', (96, 102))	('miR-510-5p', 'Chemical', '-', (150, 160))
511386	34003875	The title is now changed to "LINC00958 upregulates SPOCK1 expression to promote the development of oesophageal squamous cell carcinoma by sponging miR-510-5p".	('SPOCK1', 'Gene', '6695', (51, 57))	('miR-510-5p', 'Chemical', '-', (147, 157))	('oesophageal squamous cell carcinoma', 'Disease', 'MESH:D002294', (99, 134))	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (111, 134))	('LINC00958', 'Gene', '100506305', (29, 38))	('expression', 'MPA', (58, 68))	('sponging', 'Var', (138, 146))	('LINC00958', 'Gene', (29, 38))	('promote', 'PosReg', (72, 79))	('upregulates', 'PosReg', (39, 50))	('SPOCK1', 'Gene', (51, 57))	('oesophageal squamous cell carcinoma', 'Disease', (99, 134))
511391	34003875	[Does SPOCK1 overexpression rescue the oncogenic effects (growth, invasion, EMT) of LINC00958 silencing?]	('SPOCK1', 'Gene', '6695', (6, 12))	('silencing', 'Var', (94, 103))	('LINC00958', 'Gene', '100506305', (84, 93))	('LINC00958', 'Gene', (84, 93))	('SPOCK1', 'Gene', (6, 12))	('invasion', 'CPA', (66, 74))
511392	34003875	Changes in the expression of LINC00958 will lead to changes in the expression of SPOCK1, which has been verified by western blot experiment (Fig 4D and E).	('LINC00958', 'Gene', '100506305', (29, 38))	('SPOCK1', 'Gene', (81, 87))	('LINC00958', 'Gene', (29, 38))	('Changes', 'Var', (0, 7))	('SPOCK1', 'Gene', '6695', (81, 87))	('expression', 'MPA', (67, 77))	('changes', 'Reg', (52, 59))
511401	34003875	According to our experimental results, overexpression of LINC00958 will promote the growth, migration, invasion and EMT of esophageal squamous cell carcinoma cells, while knocking down LINC00958 will get the opposite result (Page 12, lines 243-259).	('overexpression', 'PosReg', (39, 53))	('LINC00958', 'Gene', '100506305', (57, 66))	('carcinoma', 'Phenotype', 'HP:0030731', (148, 157))	('esophageal squamous cell carcinoma', 'Disease', (123, 157))	('invasion', 'CPA', (103, 111))	('growth', 'CPA', (84, 90))	('promote', 'PosReg', (72, 79))	('migration', 'CPA', (92, 101))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (123, 157))	('LINC00958', 'Gene', '100506305', (185, 194))	('LINC00958', 'Gene', (57, 66))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (134, 157))	('knocking down', 'Var', (171, 184))	('LINC00958', 'Gene', (185, 194))	('EMT', 'CPA', (116, 119))
511403	34003875	Therefore, the overexpression of miR-510-5p can reduce the oncogenic effect of LINC00958 through the competitive binding of LINC00958.	('LINC00958', 'Gene', (79, 88))	('LINC00958', 'Gene', '100506305', (124, 133))	('overexpression', 'PosReg', (15, 29))	('LINC00958', 'Gene', (124, 133))	('miR-510-5p', 'Chemical', '-', (33, 43))	('competitive binding', 'Interaction', (101, 120))	('reduce', 'NegReg', (48, 54))	('oncogenic effect', 'CPA', (59, 75))	('miR-510-5p', 'Var', (33, 43))	('LINC00958', 'Gene', '100506305', (79, 88))
511404	34003875	[Does miR-510-5p loss-of-function rescue the oncogenic effects (growth, invasion, EMT) of LINC00958 silencing?]	('LINC00958', 'Gene', '100506305', (90, 99))	('miR-510-5p', 'Chemical', '-', (6, 16))	('silencing', 'Var', (100, 109))	('loss-of-function', 'NegReg', (17, 33))	('LINC00958', 'Gene', (90, 99))	('invasion', 'CPA', (72, 80))
511405	34003875	(MicroRNA library screening identifies growth-suppressive microRNAs that regulate genes involved in cell cycle progression and apoptosis) have been identified that miR-510-5p has tumor suppressor function and can inhibit cell growth.	('cell growth', 'CPA', (221, 232))	('miR-510-5p', 'Var', (164, 174))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('inhibit', 'NegReg', (213, 220))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('miR-510-5p', 'Chemical', '-', (164, 174))	('tumor', 'Disease', (179, 184))
511407	34003875	Theoretically, when the function of miR-510-5p was lost, it could no longer combine with LINC00958 competitively.	('combine', 'Interaction', (76, 83))	('LINC00958', 'Gene', (89, 98))	('LINC00958', 'Gene', '100506305', (89, 98))	('miR-510-5p', 'Chemical', '-', (36, 46))	('miR-510-5p', 'Var', (36, 46))
511411	34003875	We paid attention to miR-510-5p that had an active relationship with LINC00958 (Figure 4A).	('miR-510-5p', 'Var', (21, 31))	('miR-510-5p', 'Chemical', '-', (21, 31))	('LINC00958', 'Gene', (69, 78))	('LINC00958', 'Gene', '100506305', (69, 78))
511412	34003875	After that, the dual luciferase experiment was used to verify that miR-510-5p mimics significantly inhibited the luciferase activity of PmirGLO-LINC00958, but had no effect on PmirGLO-NC (Fig 4B), indicating that miR-510-5p and LINC00958 indeed have an interaction relationship.	('miR-510-5p', 'Chemical', '-', (213, 223))	('inhibited', 'NegReg', (99, 108))	('activity', 'MPA', (124, 132))	('LINC00958', 'Gene', '100506305', (228, 237))	('luciferase', 'Enzyme', (113, 123))	('miR-510-5p', 'Chemical', '-', (67, 77))	('LINC00958', 'Gene', (228, 237))	('LINC00958', 'Gene', '100506305', (144, 153))	('miR-510-5p', 'Var', (67, 77))	('LINC00958', 'Gene', (144, 153))
511431	34003875	We focus on miR-510-5p, and have predicted the competitive binding relationship between LINC00958 and miR-510-5p through the ENCORI website (Fig 4A).We used TargetScan to predict the downstream mRNA of miR-510-5p, and we focused on SPOCK1.	('miR-510-5p', 'Chemical', '-', (202, 212))	('SPOCK1', 'Gene', (232, 238))	('LINC00958', 'Gene', '100506305', (88, 97))	('miR-510-5p', 'Var', (202, 212))	('SPOCK1', 'Gene', '6695', (232, 238))	('miR-510-5p', 'Chemical', '-', (12, 22))	('LINC00958', 'Gene', (88, 97))	('miR-510-5p', 'Chemical', '-', (102, 112))
511435	34003875	Compared with the control group, miR-510-5p significantly inhibited the expression of SPOCK1 (Fig 4H and 4I), so miR-510-5p and SPOCK1 were evaluated in our manuscript.	('miR-510-5p', 'Var', (33, 43))	('SPOCK1', 'Gene', '6695', (128, 134))	('SPOCK1', 'Gene', '6695', (86, 92))	('expression', 'MPA', (72, 82))	('miR-510-5p', 'Chemical', '-', (113, 123))	('miR-510-5p', 'Chemical', '-', (33, 43))	('inhibited', 'NegReg', (58, 67))	('SPOCK1', 'Gene', (128, 134))	('SPOCK1', 'Gene', (86, 92))
511436	34003875	In addition, we will conduct more specific experiments to explain the related functions of miR-510-5p and SPOCK1.	('SPOCK1', 'Gene', '6695', (106, 112))	('SPOCK1', 'Gene', (106, 112))	('miR-510-5p', 'Var', (91, 101))	('miR-510-5p', 'Chemical', '-', (91, 101))
511444	34003875	[The authors demonstrated a little effect on the ESCC cell proliferation by overexpression or knockdown of LINC00958 (Figure 2C-D) within 3 days.	('knockdown', 'Var', (94, 103))	('LINC00958', 'Gene', '100506305', (107, 116))	('LINC00958', 'Gene', (107, 116))	('ESCC', 'Disease', (49, 53))	('overexpression', 'PosReg', (76, 90))
511455	34003875	The authors would be required to demonstrate that SPOCK1 knockdown or overexpression rescue the phenotypes observed as result of LINC00958 knockdown or overexpression.	('overexpression', 'PosReg', (152, 166))	('LINC00958', 'Gene', '100506305', (129, 138))	('knockdown', 'Var', (139, 148))	('SPOCK1', 'Gene', (50, 56))	('SPOCK1', 'Gene', '6695', (50, 56))	('knockdown', 'Var', (57, 66))	('LINC00958', 'Gene', (129, 138))
511458	34003875	However, more work is needed to conclude that the observed decrease in migration following LINC00958 modulation is specifically by the EMT pathway.	('migration', 'CPA', (71, 80))	('LINC00958', 'Gene', '100506305', (91, 100))	('modulation', 'Var', (101, 111))	('decrease', 'NegReg', (59, 67))	('LINC00958', 'Gene', (91, 100))
511461	34003875	Given the growing interest in the tumor promoting role for long noncoding RNAs in ESCC, this manuscript is of interest to the field.	('tumor', 'Disease', (34, 39))	('ESCC', 'Disease', (82, 86))	('long noncoding RNAs', 'Var', (59, 78))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
511465	34003875	While the authors argue that changes in SPOCK1 have been well-studied in ESCC and are associated with proliferation and EMT, this evidence likely does not extend to the small changes in SPOCK1 expression observed during LINC00958 over or underexpression.	('LINC00958', 'Gene', (220, 229))	('changes', 'Var', (29, 36))	('SPOCK1', 'Gene', '6695', (186, 192))	('associated', 'Reg', (86, 96))	('SPOCK1', 'Gene', (40, 46))	('ESCC', 'Disease', (73, 77))	('SPOCK1', 'Gene', '6695', (40, 46))	('LINC00958', 'Gene', '100506305', (220, 229))	('EMT', 'CPA', (120, 123))	('SPOCK1', 'Gene', (186, 192))
511466	34003875	The authors need to address this discrepancy, ideally by determining if SPOCK1 knockdown or overexpression rescue the phenotypes observed by LINC00958 knockdown or overexpression.	('SPOCK1', 'Gene', '6695', (72, 78))	('LINC00958', 'Gene', (141, 150))	('knockdown', 'Var', (79, 88))	('LINC00958', 'Gene', '100506305', (141, 150))	('SPOCK1', 'Gene', (72, 78))	('knockdown', 'Var', (151, 160))
511495	34003875	The authors need to address this discrepancy, ideally by determining if SPOCK1 knockdown or overexpression rescue the phenotypes observed by LINC00958 knockdown or overexpression.]	('SPOCK1', 'Gene', '6695', (72, 78))	('LINC00958', 'Gene', (141, 150))	('knockdown', 'Var', (79, 88))	('LINC00958', 'Gene', '100506305', (141, 150))	('SPOCK1', 'Gene', (72, 78))	('knockdown', 'Var', (151, 160))
511509	34003875	10 May 2021  PONE-D-20-41067R2  LINC00958 promotes proliferation, migration, invasion, and Epithelial-Mesenchymal Transition of oesophageal squamous cell carcinoma cells  Dear Dr. Wang: I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE.	('Epithelial-Mesenchymal Transition', 'CPA', (91, 124))	('migration', 'CPA', (66, 75))	('invasion', 'CPA', (77, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (154, 163))	('proliferation', 'CPA', (51, 64))	('promotes', 'PosReg', (42, 50))	('oesophageal squamous cell carcinoma', 'Disease', (128, 163))	('LINC00958', 'Gene', '100506305', (32, 41))	('LINC00958', 'Gene', (32, 41))	('PONE-D-20-41067R2', 'Var', (13, 30))	('PONE-D-20-41067', 'Chemical', '-', (13, 28))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (140, 163))	('oesophageal squamous cell carcinoma', 'Disease', 'MESH:D002294', (128, 163))
511511	32326908	Here, we investigated the clinicopathologic implication of FGFR1 gene amplification and protein overexpression in hypopharyngeal and laryngeal SCC.	('SCC', 'Gene', (143, 146))	('SCC', 'Gene', '6317', (143, 146))	('FGFR1', 'Gene', (59, 64))	('FGFR1', 'Gene', '2260', (59, 64))	('overexpression', 'PosReg', (96, 110))	('amplification', 'Var', (70, 83))
511513	32326908	FGFR1 amplification observed in 8 (8/66, 12.1%; 6 hypopharynx and 2 larynx) patients and high FGFR1 expression in 21 (21/199, 10.6%) patients significantly correlated with lymph node metastasis and advanced pathological stages.	('FGFR1', 'Gene', '2260', (94, 99))	('patients', 'Species', '9606', (76, 84))	('lymph node metastasis', 'CPA', (172, 193))	('patients', 'Species', '9606', (133, 141))	('FGFR1', 'Gene', (0, 5))	('FGFR1', 'Gene', (94, 99))	('FGFR1', 'Gene', '2260', (0, 5))	('expression', 'MPA', (100, 110))	('amplification', 'Var', (6, 19))	('correlated with', 'Reg', (156, 171))
511514	32326908	FGFR1 amplification was also associated with worse disease-free survival in multivariate analysis (hazard ratio = 4.527, P = 0.032).	('disease-free survival', 'CPA', (51, 72))	('FGFR1', 'Gene', '2260', (0, 5))	('FGFR1', 'Gene', (0, 5))	('worse', 'NegReg', (45, 50))	('amplification', 'Var', (6, 19))
511516	32326908	FGFR1 amplification may serve as an independent prognostic factor for disease-free survival in hypopharyngeal and laryngeal SCC.	('SCC', 'Gene', '6317', (124, 127))	('FGFR1', 'Gene', (0, 5))	('FGFR1', 'Gene', '2260', (0, 5))	('SCC', 'Gene', (124, 127))	('amplification', 'Var', (6, 19))
511517	32326908	Aberrant FGFR signaling caused by FGFR1 gene amplification or protein overexpression may play a crucial role in the malignant evolution and progression of hypopharyngeal and laryngeal SCC, and offer novel therapeutic opportunities in patients with hypopharyngeal and laryngeal SCC that usually lack specific therapeutic targets.	('SCC', 'Gene', (277, 280))	('protein', 'Protein', (62, 69))	('hypopharyngeal', 'Disease', (155, 169))	('Aberrant', 'Var', (0, 8))	('SCC', 'Gene', '6317', (277, 280))	('FGFR1', 'Gene', (34, 39))	('malignant evolution', 'CPA', (116, 135))	('SCC', 'Gene', (184, 187))	('patients', 'Species', '9606', (234, 242))	('play', 'Reg', (89, 93))	('FGFR1', 'Gene', '2260', (34, 39))	('gene amplification', 'Var', (40, 58))	('FGFR signaling', 'MPA', (9, 23))	('SCC', 'Gene', '6317', (184, 187))	('overexpression', 'PosReg', (70, 84))	('amplification', 'Var', (45, 58))
511524	32326908	HPV-negative tumors are characterized with recurrent focal amplifications in receptor tyrosine kinases and fibroblast growth factor receptor 1 (FGFR1; 10% frequency) is the second most commonly observed gene after EGFR (15% frequency).	('HPV', 'Species', '10566', (0, 3))	('tumors', 'Disease', (13, 19))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('fibroblast growth factor receptor 1', 'Gene', '2260', (107, 142))	('FGFR1', 'Gene', (144, 149))	('EGFR', 'Gene', '1956', (214, 218))	('FGFR1', 'Gene', '2260', (144, 149))	('EGFR', 'Gene', (214, 218))	('fibroblast growth factor receptor 1', 'Gene', (107, 142))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('focal amplifications', 'Var', (53, 73))
511526	32326908	This gene is dysregulated by amplification, point mutation, translocation, and overexpression in various cancers.	('point mutation', 'Var', (44, 58))	('cancers', 'Phenotype', 'HP:0002664', (105, 112))	('cancers', 'Disease', (105, 112))	('cancers', 'Disease', 'MESH:D009369', (105, 112))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('translocation', 'Var', (60, 73))	('overexpression', 'PosReg', (79, 93))
511527	32326908	These aberrant FGFR1 alterations, in general, lead to gain-of-function characteristics and constitutively activate the downstream RAS/mitogen-activated protein kinase (MAPK), PI3K/protein kinase B (AKT), and Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathways.	('gain-of-function', 'PosReg', (54, 70))	('protein kinase B', 'Gene', (180, 196))	('activate', 'PosReg', (106, 114))	('FGFR1', 'Gene', '2260', (15, 20))	('AKT', 'Gene', '207', (198, 201))	('protein kinase B', 'Gene', '2185', (180, 196))	('characteristics', 'MPA', (71, 86))	('AKT', 'Gene', (198, 201))	('FGFR1', 'Gene', (15, 20))	('alterations', 'Var', (21, 32))
511528	32326908	In previous studies of HNSCC, FGFR1 amplification has been reported in 3 to 17% of cases, and FGFR1 protein overexpression has been identified in about 11-82% of cases.	('FGFR1', 'Gene', '2260', (94, 99))	('SCC', 'Gene', (25, 28))	('FGFR1', 'Gene', (30, 35))	('protein', 'Protein', (100, 107))	('FGFR1', 'Gene', '2260', (30, 35))	('SCC', 'Gene', '6317', (25, 28))	('amplification', 'Var', (36, 49))	('FGFR1', 'Gene', (94, 99))	('overexpression', 'PosReg', (108, 122))
511533	32326908	Recently, several nonselective or selective tyrosine kinase inhibitors suppressing FGFR1 expression, such as lucitanib (E3810), dovitinib (TKI258), ponatinib (AP24534), AZD4547, BGJ398, and TAS-120, have shown promising data or are currently being investigated in preclinical models and clinical trials on solid tumors, including HNSCC (NCT02706691, NCT02795156).	('tumors', 'Disease', (312, 318))	('FGFR1', 'Gene', '2260', (83, 88))	('TAS-120', 'Chemical', '-', (190, 197))	('dovitinib', 'Chemical', 'MESH:C500007', (128, 137))	('expression', 'MPA', (89, 99))	('tumors', 'Disease', 'MESH:D009369', (312, 318))	('AP24534', 'Chemical', 'MESH:C545373', (159, 166))	('E3810', 'Var', (120, 125))	('ponatinib', 'Chemical', 'MESH:C545373', (148, 157))	('E3810', 'Chemical', 'MESH:D064750', (120, 125))	('BGJ398', 'Chemical', 'MESH:C568950', (178, 184))	('tumor', 'Phenotype', 'HP:0002664', (312, 317))	('FGFR1', 'Gene', (83, 88))	('NCT02706691', 'Var', (337, 348))	('TKI258', 'Chemical', 'MESH:C500007', (139, 145))	('suppressing', 'NegReg', (71, 82))	('NCT02795156', 'Var', (350, 361))	('tumors', 'Phenotype', 'HP:0002664', (312, 318))	('lucitanib', 'Chemical', 'MESH:C000595232', (109, 118))	('SCC', 'Gene', '6317', (332, 335))	('AZD4547', 'Chemical', 'MESH:C572463', (169, 176))	('SCC', 'Gene', (332, 335))
511556	32326908	The chi-square, Fisher's exact, independent-samples t-tests, and bivariate correlation analysis were conducted to compare the clinicopathologic parameters among patients with FGFR1 gene amplification and other protein expression.	('patients', 'Species', '9606', (161, 169))	('FGFR1', 'Gene', (175, 180))	('gene amplification', 'Var', (181, 199))	('FGFR1', 'Gene', '2260', (175, 180))
511574	32326908	The mean FGFR1 copy number was 5.37 (range, 4.01 to 6.75) in the amplification group and 2.48 (range 1.85 to 4.86), in the non-amplification group.	('amplification', 'Var', (65, 78))	('FGFR1', 'Gene', '2260', (9, 14))	('FGFR1', 'Gene', (9, 14))
511576	32326908	The association of FGFR1 amplification with clinical and pathological factors is summarized in Table 2.	('FGFR1', 'Gene', '2260', (19, 24))	('amplification', 'Var', (25, 38))	('FGFR1', 'Gene', (19, 24))
511577	32326908	FGFR1 amplification was more frequent in hypopharyngeal SCC than in laryngeal SCC (6/42, 14.3% versus 2/24, 8.3%; P = 0.015) and showed a significant correlation with the presence of lymphovascular invasion (P = 0.031), more advanced pathological N-classification (P = 0.020), more advanced TNM tumor stage (P = 0.047), and more frequent recurrence rate (P = 0.042) than cases with no FGFR1 amplification.	('lymphovascular invasion', 'CPA', (183, 206))	('frequent', 'Reg', (29, 37))	('SCC', 'Gene', '6317', (78, 81))	('TNM tumor', 'Disease', 'MESH:D009369', (291, 300))	('SCC', 'Gene', (56, 59))	('FGFR1', 'Gene', (0, 5))	('FGFR1', 'Gene', '2260', (0, 5))	('correlation', 'Reg', (150, 161))	('FGFR1', 'Gene', (385, 390))	('SCC', 'Gene', '6317', (56, 59))	('tumor', 'Phenotype', 'HP:0002664', (295, 300))	('amplification', 'Var', (6, 19))	('recurrence', 'CPA', (338, 348))	('FGFR1', 'Gene', '2260', (385, 390))	('SCC', 'Gene', (78, 81))	('TNM tumor', 'Disease', (291, 300))
511578	32326908	Other factors were not significant according to FGFR1 amplification status.	('FGFR1', 'Gene', (48, 53))	('FGFR1', 'Gene', '2260', (48, 53))	('amplification status', 'Var', (54, 74))
511579	32326908	For the 8 cases with FGFR1 amplified squamous cell carcinoma, the clinicopathologic characteristics as well as detailed status FGFR1 gene and FGFR1 protein are summarized in Supplementary Table S1.	('amplified', 'Var', (27, 36))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (37, 60))	('FGFR1', 'Gene', (21, 26))	('FGFR1', 'Gene', (127, 132))	('FGFR1', 'Gene', '2260', (127, 132))	('FGFR1', 'Gene', (142, 147))	('squamous cell carcinoma', 'Disease', (37, 60))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (37, 60))	('FGFR1', 'Gene', '2260', (21, 26))	('FGFR1', 'Gene', '2260', (142, 147))	('carcinoma', 'Phenotype', 'HP:0030731', (51, 60))
511590	32326908	In comparison with no or low FGFR1 expression, high FGFR1 expression was associated with more advanced pathological N-classification (P = 0.003) and TNM stage (P = 0.001).	('FGFR1', 'Gene', '2260', (29, 34))	('expression', 'MPA', (58, 68))	('high', 'Var', (47, 51))	('TNM', 'Gene', '10178', (149, 152))	('FGFR1', 'Gene', (52, 57))	('FGFR1', 'Gene', '2260', (52, 57))	('TNM', 'Gene', (149, 152))	('FGFR1', 'Gene', (29, 34))
511592	32326908	Consistent with FGFR1 gene expression, high FGFR1 protein expression showed a marginal tendency to be related with gene amplification, although no statistical significance was observed (Fig.	('FGFR1', 'Gene', (44, 49))	('FGFR1', 'Gene', '2260', (16, 21))	('gene amplification', 'Var', (115, 133))	('FGFR1', 'Gene', '2260', (44, 49))	('protein', 'Protein', (50, 57))	('FGFR1', 'Gene', (16, 21))
511594	32326908	When comparing FGFR1 amplified SCC with non-amplified SCC, there were no statistically significant differences in Snail and Twist expression (P = 0.344 and P = 0.637, respectively; Supplementary Figure S2 and S3).	('amplified', 'Var', (21, 30))	('SCC', 'Gene', '6317', (54, 57))	('SCC', 'Gene', (31, 34))	('FGFR1', 'Gene', '2260', (15, 20))	('SCC', 'Gene', '6317', (31, 34))	('Twist', 'Gene', '7291', (124, 129))	('Snail', 'Gene', '6615', (114, 119))	('Snail', 'Gene', (114, 119))	('SCC', 'Gene', (54, 57))	('FGFR1', 'Gene', (15, 20))	('Twist', 'Gene', (124, 129))
511596	32326908	In the Kaplan-Meir analysis, patients with FGFR1 amplification were more associated with inferior DFS rate than those with no amplification (P = 0.010, Fig.	('amplification', 'Var', (49, 62))	('patients', 'Species', '9606', (29, 37))	('FGFR1', 'Gene', (43, 48))	('DFS rate', 'MPA', (98, 106))	('FGFR1', 'Gene', '2260', (43, 48))	('inferior', 'NegReg', (89, 97))
511598	32326908	In the univariate Cox proportional hazard analysis for DFS (Table 3), poorly differentiated histology (hazard ratio [HR] 3.803, P = 0.006), perineural invasion (HR 2.046, P = 0.039), pN-classification (N2; HR 5.415; P <  0.001, N3; HR 2.816; P = 0.005), pathologic stage (IV; HR 3.124; P = 0.007), and FGFR1 amplification (HR 4.204, P = 0.017) were significantly related to worse DFS.	('DFS', 'Disease', (380, 383))	('amplification', 'Var', (308, 321))	('perineural invasion', 'CPA', (140, 159))	('FGFR1', 'Gene', (302, 307))	('FGFR1', 'Gene', '2260', (302, 307))
511599	32326908	Of these, FGFR1 amplification was determined as an independent factor for poor DFS in multivariate analysis (HR 3.666, P = 0.049).	('FGFR1', 'Gene', (10, 15))	('FGFR1', 'Gene', '2260', (10, 15))	('amplification', 'Var', (16, 29))
511605	32326908	FGFR1 gene amplification was observed in about 12% tested hypopharyngeal and laryngeal SCC cases that was slightly more frequent in hypopharyngeal SCC (14.3%) than in laryngeal SCC (8.3%).	('SCC', 'Gene', (147, 150))	('SCC', 'Gene', (87, 90))	('FGFR1', 'Gene', (0, 5))	('SCC', 'Gene', (177, 180))	('SCC', 'Gene', '6317', (147, 150))	('FGFR1', 'Gene', '2260', (0, 5))	('SCC', 'Gene', '6317', (87, 90))	('SCC', 'Gene', '6317', (177, 180))	('amplification', 'Var', (11, 24))	('hypopharyngeal', 'Disease', (58, 72))
511606	32326908	FGFR1 amplification has been suggested as an oncogenic driver mutation in tobacco-associated cancers of the aerodigestive tract.	('cancers', 'Disease', (93, 100))	('tobacco', 'Species', '4097', (74, 81))	('cancers', 'Phenotype', 'HP:0002664', (93, 100))	('FGFR1', 'Gene', (0, 5))	('FGFR1', 'Gene', '2260', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('amplification', 'Var', (6, 19))	('cancers', 'Disease', 'MESH:D009369', (93, 100))
511607	32326908	Previous studies on FGFR1 in HNSCC have shown that FGFR1 amplification is more common in the SCC of hypopharynx and larynx than in that of oropharynx or oral cavity.	('common', 'Reg', (79, 85))	('SCC', 'Gene', (31, 34))	('hypopharynx', 'Disease', (100, 111))	('SCC', 'Gene', (93, 96))	('FGFR1', 'Gene', (20, 25))	('amplification', 'Var', (57, 70))	('SCC', 'Gene', '6317', (31, 34))	('FGFR1', 'Gene', '2260', (20, 25))	('FGFR1', 'Gene', (51, 56))	('larynx', 'Disease', (116, 122))	('SCC', 'Gene', '6317', (93, 96))	('FGFR1', 'Gene', '2260', (51, 56))
511609	32326908	All these findings are suggestive of the biological role of FGFR1 amplification in the tumorigenesis of these tobacco or alcohol-related cancers, hypopharyngeal and laryngeal SCCs, and may predict the role of targeted therapy for these tumors.	('predict', 'Reg', (189, 196))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Disease', 'MESH:D009369', (236, 241))	('cancers', 'Phenotype', 'HP:0002664', (137, 144))	('cancers', 'Disease', (137, 144))	('tumors', 'Phenotype', 'HP:0002664', (236, 242))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('hypopharyngeal', 'Disease', (146, 160))	('FGFR1', 'Gene', '2260', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (236, 241))	('tumors', 'Disease', (236, 242))	('amplification', 'Var', (66, 79))	('tumor', 'Disease', (87, 92))	('SCC', 'Gene', '6317', (175, 178))	('cancers', 'Disease', 'MESH:D009369', (137, 144))	('tumor', 'Disease', (236, 241))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('tumors', 'Disease', 'MESH:D009369', (236, 242))	('SCC', 'Gene', (175, 178))	('FGFR1', 'Gene', (60, 65))	('tobacco', 'Species', '4097', (110, 117))	('alcohol', 'Chemical', 'MESH:D000438', (121, 128))
511610	32326908	Considering the clinical implications of FGFR1 amplification, we observed significant association with poor prognostic factors, specifically, lymphovascular invasion and advanced stages of lymph node metastasis.	('lymphovascular invasion', 'CPA', (142, 165))	('association', 'Interaction', (86, 97))	('amplification', 'Var', (47, 60))	('FGFR1', 'Gene', (41, 46))	('FGFR1', 'Gene', '2260', (41, 46))
511611	32326908	This observation may be related to our findings that cases with FGFR1 amplification were closely associated with advanced TNM tumor stages and poorer DFS.	('TNM tumor', 'Disease', (122, 131))	('TNM tumor', 'Disease', 'MESH:D009369', (122, 131))	('FGFR1', 'Gene', (64, 69))	('FGFR1', 'Gene', '2260', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('associated', 'Reg', (97, 107))	('amplification', 'Var', (70, 83))
511612	32326908	In particular, FGFR1 amplification was determined as an independent factor for disease progression and thus, may be involved in the invasion, metastasis, and drug resistance of tumor cells during the development of treatment-resistant, aggressive, advanced hypopharyngeal and laryngeal SCCs.	('FGFR1', 'Gene', '2260', (15, 20))	('drug resistance', 'Phenotype', 'HP:0020174', (158, 173))	('involved', 'Reg', (116, 124))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('SCC', 'Gene', (286, 289))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('SCC', 'Gene', '6317', (286, 289))	('amplification', 'Var', (21, 34))	('tumor', 'Disease', (177, 182))	('FGFR1', 'Gene', (15, 20))
511613	32326908	Several studies have also shown that FGFR1 amplification plays a role in the invasion, metastasis, and drug resistance of various tumors.	('tumors', 'Disease', (130, 136))	('role', 'Reg', (65, 69))	('FGFR1', 'Gene', (37, 42))	('FGFR1', 'Gene', '2260', (37, 42))	('tumors', 'Disease', 'MESH:D009369', (130, 136))	('metastasis', 'CPA', (87, 97))	('amplification', 'Var', (43, 56))	('invasion', 'CPA', (77, 85))	('drug resistance', 'CPA', (103, 118))	('drug resistance', 'Phenotype', 'HP:0020174', (103, 118))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumors', 'Phenotype', 'HP:0002664', (130, 136))
511614	32326908	A recent study performed genomic profiling of HNSCC using targeted next-generation sequencing and identified FGFR1 amplification as an independent prognostic factor for OS, while it has been failed to impact on prognosis in other studies.	('amplification', 'Var', (115, 128))	('FGFR1', 'Gene', (109, 114))	('SCC', 'Gene', (48, 51))	('FGFR1', 'Gene', '2260', (109, 114))	('SCC', 'Gene', '6317', (48, 51))
511615	32326908	In our study, we failed to detect any association between FGFR1 amplification and OS.	('amplification', 'Var', (64, 77))	('FGFR1', 'Gene', (58, 63))	('FGFR1', 'Gene', '2260', (58, 63))
511616	32326908	Cases positive for FGFR1 amplification were relatively fewer in number in previous and present studies; therefore, its prognostic role warrants validation in future studies, including meta-analysis.	('FGFR1', 'Gene', '2260', (19, 24))	('amplification', 'Var', (25, 38))	('FGFR1', 'Gene', (19, 24))
511619	32326908	Considering the marginal association between high FGFR1 expression and FGFR1 amplification, gene amplification and the subsequent protein overexpression may be one of the related mechanisms underlying the invasion and metastasis of hypopharyngeal and laryngeal SCCs.	('FGFR1', 'Gene', (71, 76))	('FGFR1', 'Gene', (50, 55))	('SCC', 'Gene', (261, 264))	('FGFR1', 'Gene', '2260', (71, 76))	('metastasis', 'CPA', (218, 228))	('amplification', 'Var', (77, 90))	('FGFR1', 'Gene', '2260', (50, 55))	('expression', 'MPA', (56, 66))	('SCC', 'Gene', '6317', (261, 264))	('gene amplification', 'Var', (92, 110))	('overexpression', 'PosReg', (138, 152))
511626	32326908	Regarding the biologic implications of FGFR1 gene amplification or protein overexpression in hypopharyngeal and laryngeal SCC, we investigated a correlation of FGFR1 alteration with twist and snail, the well-known EMT markers, on the basis of previous studies showing that EMT is induced in tumors by abnormal activation of the FGFR signaling pathway in several types of cancers including HNSCC.	('cancers', 'Disease', 'MESH:D009369', (371, 378))	('twist', 'Gene', (182, 187))	('tumors', 'Phenotype', 'HP:0002664', (291, 297))	('FGFR1', 'Gene', (39, 44))	('FGFR1', 'Gene', (160, 165))	('SCC', 'Gene', '6317', (391, 394))	('SCC', 'Gene', '6317', (122, 125))	('tumor', 'Phenotype', 'HP:0002664', (291, 296))	('twist', 'Gene', '7291', (182, 187))	('tumors', 'Disease', (291, 297))	('SCC', 'Gene', (391, 394))	('SCC', 'Gene', (122, 125))	('activation', 'PosReg', (310, 320))	('snail', 'Gene', '6615', (192, 197))	('FGFR signaling pathway', 'Pathway', (328, 350))	('cancers', 'Phenotype', 'HP:0002664', (371, 378))	('cancers', 'Disease', (371, 378))	('tumors', 'Disease', 'MESH:D009369', (291, 297))	('cancer', 'Phenotype', 'HP:0002664', (371, 377))	('FGFR1', 'Gene', '2260', (39, 44))	('FGFR1', 'Gene', '2260', (160, 165))	('snail', 'Gene', (192, 197))	('alteration', 'Var', (166, 176))
511628	32326908	Therefore, further studies are needed to determine whether changes in FGFR1 affect EMT acquisition in hypopharyngeal and laryngeal SCC.	('affect', 'Reg', (76, 82))	('EMT acquisition', 'CPA', (83, 98))	('SCC', 'Gene', (131, 134))	('FGFR1', 'Gene', (70, 75))	('changes', 'Var', (59, 66))	('SCC', 'Gene', '6317', (131, 134))	('FGFR1', 'Gene', '2260', (70, 75))
511629	32326908	In addition, further in-depth studies should be followed for the underlying mechanisms of aberrant FGFR1 alterations in the tumorigenesis of hypopharyngeal and laryngeal SCC in the aspect of the known downstream signals of RAS/MAPK, PI3K/AKT, and JAK/STAT signaling pathways.	('hypopharyngeal', 'Disease', (141, 155))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('AKT', 'Gene', (238, 241))	('FGFR1', 'Gene', (99, 104))	('tumor', 'Disease', (124, 129))	('aberrant', 'Var', (90, 98))	('SCC', 'Gene', (170, 173))	('alterations', 'Var', (105, 116))	('FGFR1', 'Gene', '2260', (99, 104))	('SCC', 'Gene', '6317', (170, 173))	('AKT', 'Gene', '207', (238, 241))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
511632	32326908	Furthermore, FGFR1 amplification may not always cause protein overexpression alone, and may be affected by other closely related receptor tyrosine kinases (RTK).	('amplification', 'Var', (19, 32))	('FGFR1', 'Gene', (13, 18))	('cause', 'Reg', (48, 53))	('FGFR1', 'Gene', '2260', (13, 18))	('protein overexpression', 'MPA', (54, 76))	('affected', 'Reg', (95, 103))
511634	32326908	In summary, we report that FGFR1 gene amplification and protein overexpression occur in hypopharyngeal and laryngeal SCC with an incidence of 12.1 and 10.6%, respectively.	('occur', 'Reg', (79, 84))	('SCC', 'Gene', (117, 120))	('overexpression', 'PosReg', (64, 78))	('protein', 'Protein', (56, 63))	('hypopharyngeal', 'Disease', (88, 102))	('FGFR1', 'Gene', (27, 32))	('SCC', 'Gene', '6317', (117, 120))	('FGFR1', 'Gene', '2260', (27, 32))	('amplification', 'Var', (38, 51))
511636	32326908	In addition, FGFR1 amplification appeared as an independent prognostic factor for DFS and may serve as a prognostic biomarker.	('FGFR1', 'Gene', '2260', (13, 18))	('amplification', 'Var', (19, 32))	('FGFR1', 'Gene', (13, 18))	('DFS', 'Disease', (82, 85))
511649	31892232	Maintaining tissue-specific methylation patterns is of great importance to the normal function of many biological processes, as aberrant methylation has been implicated in the tumorigenesis of several types of cancer.	('aberrant methylation', 'Var', (128, 148))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('methylation', 'Var', (137, 148))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('tumor', 'Disease', (176, 181))	('implicated', 'Reg', (158, 168))	('cancer', 'Disease', 'MESH:D009369', (210, 216))	('cancer', 'Disease', (210, 216))	('tumor', 'Disease', 'MESH:D009369', (176, 181))
511650	31892232	Moreover, aberrant methylation patterns have been implicated in the carcinogenesis of cervical cancer and precancer specimens caused by high-risk HPV infection.	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('implicated', 'Reg', (50, 60))	('cancer', 'Disease', (109, 115))	('cancer', 'Disease', (95, 101))	('aberrant', 'Var', (10, 18))	('carcinogenesis of cervical cancer', 'Disease', 'MESH:D002583', (68, 101))	('methylation', 'MPA', (19, 30))	('carcinogenesis of cervical cancer', 'Disease', (68, 101))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('caused', 'Reg', (126, 132))
511656	31892232	The most enriched terms include the Dnase weak-normal human dermal fibroblast (NHDF) cell line, Dnase-fibrobalsts, Weak Enhancer-human umbilical vein endothelial cells (HUVEC), nuclear receptor subfamily 2 group F member 2 (NR2F2)-Endometrial Stromal Cell, and monomethylation of Histone H3 at lysine 4 (H3K4me1)-lymph node carcinoma of the prostate (LNCaP) cell line.	('human', 'Species', '9606', (54, 59))	('Histone H3', 'Protein', (280, 290))	('carcinoma of the prostate', 'Disease', (324, 349))	('LNCaP', 'CellLine', 'CVCL:0395', (351, 356))	('carcinoma', 'Phenotype', 'HP:0030731', (324, 333))	('carcinoma of the prostate', 'Disease', 'MESH:D011471', (324, 349))	('nuclear receptor subfamily 2 group F member 2', 'Gene', (177, 222))	('lysine', 'Chemical', 'MESH:D008239', (294, 300))	('human', 'Species', '9606', (129, 134))	('lymph node carcinoma', 'Phenotype', 'HP:0002665', (313, 333))	('nuclear receptor subfamily 2 group F member 2', 'Gene', '7026', (177, 222))	('monomethylation', 'Var', (261, 276))
511659	31892232	Not much is known about EXOC4 except that adjacent polymorphisms were associated with Type 2 diabetes.	('Type 2 diabetes', 'Phenotype', 'HP:0005978', (86, 101))	('Type 2 diabetes', 'Disease', 'MESH:D003924', (86, 101))	('associated', 'Reg', (70, 80))	('EXOC4', 'Gene', (24, 29))	('Type 2 diabetes', 'Disease', (86, 101))	('polymorphisms', 'Var', (51, 64))	('EXOC4', 'Gene', '60412', (24, 29))
511663	31892232	The reticulon 1 (RTN1) gene was the third most DM protein-coding gene in warts, with previous reports showing that RTN1 deficiency and isoforms were associated with senile plaque formation and kidney disease progression, respectively.	('RTN1', 'Gene', (115, 119))	('kidney disease', 'Phenotype', 'HP:0000112', (193, 207))	('senile plaque formation', 'Disease', (165, 188))	('RTN1', 'Gene', '6252', (115, 119))	('deficiency', 'Disease', 'None', (120, 130))	('warts', 'Phenotype', 'HP:0200043', (73, 78))	('reticulon 1', 'Gene', (4, 15))	('senile plaque', 'Phenotype', 'HP:0100256', (165, 178))	('RTN1', 'Gene', (17, 21))	('RTN1', 'Gene', '6252', (17, 21))	('kidney disease', 'Disease', (193, 207))	('associated with', 'Reg', (149, 164))	('wart', 'Phenotype', 'HP:0200043', (73, 77))	('isoforms', 'Var', (135, 143))	('deficiency', 'Disease', (120, 130))	('reticulon 1', 'Gene', '6252', (4, 15))	('kidney disease', 'Disease', 'MESH:D007674', (193, 207))
511664	31892232	In the context of viral infection, deletion of RTN1 in yeast cells led to a significant inhibition of viral replication.	('viral infection', 'Disease', 'MESH:D014777', (18, 33))	('inhibition', 'NegReg', (88, 98))	('RTN1', 'Gene', (47, 51))	('yeast', 'Species', '4932', (55, 60))	('RTN1', 'Gene', '6252', (47, 51))	('viral infection', 'Disease', (18, 33))	('deletion', 'Var', (35, 43))	('viral replication', 'CPA', (102, 119))
511670	31892232	Encoding an argonaute family protein, the piwi-like protein 4 (PIWIL4) gene was reported to be highly expressed in breast cancer cells, and its knockdown was found to lessen leukemic growth.	('piwi-like protein 4', 'Gene', '143689', (42, 61))	('PIWIL4', 'Gene', (63, 69))	('lessen', 'NegReg', (167, 173))	('leukemic', 'Disease', (174, 182))	('piwi-like protein 4', 'Gene', (42, 61))	('breast cancer', 'Disease', 'MESH:D001943', (115, 128))	('knockdown', 'Var', (144, 153))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('leukemic', 'Disease', 'MESH:D007938', (174, 182))	('breast cancer', 'Disease', (115, 128))	('breast cancer', 'Phenotype', 'HP:0003002', (115, 128))	('PIWIL4', 'Gene', '143689', (63, 69))
511676	31892232	Dysregulated ncRNA expression patterns have also been implicated in HPV-associated cancers caused by high-risk HPV infection.	('cancers', 'Disease', 'MESH:D009369', (83, 90))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('implicated', 'Reg', (54, 64))	('Dysregulated', 'Var', (0, 12))	('ncRNA expression patterns', 'MPA', (13, 38))	('cancers', 'Phenotype', 'HP:0002664', (83, 90))	('cancers', 'Disease', (83, 90))
511684	31892232	From among ENCODE's transcription factor binding sites, the c-Fos, STAT3, and c-Myc genes were the most hypermethylated in warts (Figure 7).	('c-Fos', 'Gene', (60, 65))	('wart', 'Phenotype', 'HP:0200043', (123, 127))	('STAT3', 'Gene', '6774', (67, 72))	('warts', 'Phenotype', 'HP:0200043', (123, 128))	('c-Myc', 'Gene', '4609', (78, 83))	('STAT3', 'Gene', (67, 72))	('warts', 'Disease', (123, 128))	('c-Fos', 'Gene', '2353', (60, 65))	('c-Myc', 'Gene', (78, 83))	('hypermethylated', 'Var', (104, 119))
511687	31892232	On the other hand, c-Fos expression was found to decrease keratinocyte growth by increasing sensitivity to apoptosis, but this state was reversed upon the addition of c-Jun.	('c-Jun', 'Gene', '3725', (167, 172))	('c-Fos', 'Gene', (19, 24))	('increasing', 'PosReg', (81, 91))	('c-Fos', 'Gene', '2353', (19, 24))	('sensitivity to apoptosis', 'MPA', (92, 116))	('decrease', 'NegReg', (49, 57))	('c-Jun', 'Gene', (167, 172))	('keratinocyte growth', 'CPA', (58, 77))	('expression', 'Var', (25, 35))
511693	31892232	Additionally, autocrine STAT3 activation is an integral part of HPV-mediated cervical cancer, and loss of STAT3 expression is detrimental to high-risk HPV infection of keratinocytes.	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('activation', 'PosReg', (30, 40))	('STAT3', 'Gene', '6774', (106, 111))	('STAT3', 'Gene', '6774', (24, 29))	('loss', 'Var', (98, 102))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('STAT3', 'Gene', (106, 111))	('STAT3', 'Gene', (24, 29))	('cancer', 'Disease', (86, 92))
511696	31892232	Alongside the SIN3 transcription regulator family member A (SIN3A) gene, c-Myc helps maintain tissue homeostasis in the skin, but epidermal cells deficient in c-Myc were found to be resistant to Ras-mediated tumorigenesis.	('resistant', 'NegReg', (182, 191))	('c-Myc', 'Gene', '4609', (159, 164))	('c-Myc', 'Gene', '4609', (73, 78))	('SIN3A', 'Gene', (60, 65))	('tissue homeostasis', 'MPA', (94, 112))	('SIN3', 'Gene', '25942', (14, 18))	('tumor', 'Disease', 'MESH:D009369', (208, 213))	('c-Myc', 'Gene', (159, 164))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('SIN3', 'Gene', (60, 64))	('c-Myc', 'Gene', (73, 78))	('tumor', 'Disease', (208, 213))	('deficient', 'Var', (146, 155))	('SIN3A', 'Gene', '25942', (60, 65))	('SIN3', 'Gene', '25942', (60, 64))	('SIN3', 'Gene', (14, 18))
511698	31892232	In warts, the AR, NR2F2, and AFF1 genes were among the most significantly hypomethylated in warts compared to normal skin (Figure 9).	('wart', 'Phenotype', 'HP:0200043', (92, 96))	('AFF1', 'Gene', (29, 33))	('wart', 'Phenotype', 'HP:0200043', (3, 7))	('warts', 'Phenotype', 'HP:0200043', (92, 97))	('hypomethylated', 'Var', (74, 88))	('NR2F2', 'Gene', (18, 23))	('AFF1', 'Gene', '4299', (29, 33))	('warts', 'Phenotype', 'HP:0200043', (3, 8))
511710	31892232	HDAC2 inhibition was found to stabilize tumor suppression and induce apoptosis in human keratinocyte cells infected with high-risk HPV.	('HDAC2', 'Gene', '3066', (0, 5))	('induce', 'PosReg', (62, 68))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('HDAC2', 'Gene', (0, 5))	('inhibition', 'Var', (6, 16))	('apoptosis', 'CPA', (69, 78))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('human', 'Species', '9606', (82, 87))
511711	31892232	Interestingly, in a cancer context, one study reported a novel epigenetic signature of HPV infection that was independent of the anatomic location in HPV-associated head and neck squamous cell carcinomas.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('head and neck squamous cell carcinomas', 'Phenotype', 'HP:0012288', (165, 203))	('infection', 'Var', (91, 100))	('epigenetic signature', 'MPA', (63, 83))	('carcinoma', 'Phenotype', 'HP:0030731', (193, 202))	('cancer', 'Disease', 'MESH:D009369', (20, 26))	('HPV', 'Gene', (87, 90))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (179, 203))	('cancer', 'Disease', (20, 26))	('carcinomas', 'Phenotype', 'HP:0030731', (193, 203))	('neck squamous cell carcinomas', 'Disease', (174, 203))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (179, 202))	('neck squamous cell carcinomas', 'Disease', 'MESH:C535575', (174, 203))
511762	25680671	A similar dichotomy exists for gastric cancer; case-control studies have associated red meat with gastric cancer, whereas cohort studies have not.	('red meat', 'Var', (84, 92))	('gastric cancer', 'Disease', (98, 112))	('gastric cancer', 'Phenotype', 'HP:0012126', (31, 45))	('gastric cancer', 'Disease', 'MESH:D013274', (98, 112))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('gastric cancer', 'Phenotype', 'HP:0012126', (98, 112))	('gastric cancer', 'Disease', 'MESH:D013274', (31, 45))	('gastric cancer', 'Disease', (31, 45))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
511816	25680671	In fact, there was some evidence that vitamin D was associated with increased risk of upper GI cancer in some subgroups.	('vitamin D', 'Chemical', 'MESH:D014807', (38, 47))	('GI cancer', 'Phenotype', 'HP:0007378', (92, 101))	('upper GI cancer', 'Disease', (86, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('vitamin', 'Var', (38, 45))	('upper GI cancer', 'Disease', 'MESH:D009369', (86, 101))
511823	25680671	Thirty of the case-control studies found that pickled vegetables significantly increased risk for gastric cancer, and 1 found that it significantly reduced risk.	('increased risk for gastric cancer', 'Phenotype', 'HP:0006753', (79, 112))	('pickled vegetables', 'Var', (46, 64))	('reduced', 'NegReg', (148, 155))	('gastric cancer', 'Disease', (98, 112))	('gastric cancer', 'Disease', 'MESH:D013274', (98, 112))	('gastric cancer', 'Phenotype', 'HP:0012126', (98, 112))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
511858	25680671	Many people of East Asian ancestry have polymorphisms that affect metabolism of ethanol, commonly known as the flushing response.163 Individuals with a single copy of a specific polymorphism in ALDH2 develop symptoms after consumption of ethanol, so they eliminate it from their diet.	('eliminate', 'NegReg', (255, 264))	('symptoms', 'MPA', (208, 216))	('flushing', 'Disease', 'MESH:D005483', (111, 119))	('single copy', 'Var', (152, 163))	('ethanol', 'Chemical', 'MESH:D000431', (238, 245))	('ethanol', 'Chemical', 'MESH:D000431', (80, 87))	('people', 'Species', '9606', (5, 11))	('develop', 'PosReg', (200, 207))	('flushing', 'Phenotype', 'HP:0031284', (111, 119))	('ALDH2', 'Gene', '217', (194, 199))	('polymorphism', 'Var', (178, 190))	('flushing', 'Disease', (111, 119))	('ALDH2', 'Gene', (194, 199))
511861	25680671	An analysis from the Barrett's and Esophageal Adenocarcinoma Consortium (BEACON) found no association between total alcoholic beverage consumption, even high doses (7 drinks/day) and esophageal adenocarcinoma.161 In most studies, adenocarcinomas of the stomach appear not to be associated with alcoholic beverage consumption, but there is some evidence for an adverse effect in subjects with genetic polymorphisms that alter metabolism of ethanol, similar to the effects of ALDH2 variants on esophageal cancer risk, although the current level of evidence is modest.165, 166 Heavier consumption of alcohol has been causally linked to cancers of colorectum, but with a more modest magnitude than for other types of GI cancers, such as esophageal squamous cell carcinoma.	('cancers', 'Disease', 'MESH:D009369', (633, 640))	('esophageal squamous cell carcinoma', 'Disease', (733, 767))	('modest.165', 'Var', (558, 568))	('ALDH2', 'Gene', '217', (474, 479))	('cancers', 'Phenotype', 'HP:0002664', (716, 723))	('alcohol', 'Chemical', 'MESH:D000438', (294, 301))	('cancers', 'Disease', (716, 723))	('cancer', 'Phenotype', 'HP:0002664', (716, 722))	('carcinoma', 'Phenotype', 'HP:0030731', (199, 208))	('adenocarcinomas of the stomach', 'Phenotype', 'HP:0006753', (230, 260))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (744, 767))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (733, 767))	('Esophageal Adenocarcinoma', 'Disease', 'MESH:D004938', (35, 60))	('cancers', 'Phenotype', 'HP:0002664', (633, 640))	('GI cancers', 'Disease', (713, 723))	('cancers', 'Disease', (633, 640))	('cancers', 'Disease', 'MESH:D009369', (716, 723))	('alcohol', 'Chemical', 'MESH:D000438', (116, 123))	('Esophageal Adenocarcinoma', 'Phenotype', 'HP:0011459', (35, 60))	('carcinoma', 'Phenotype', 'HP:0030731', (235, 244))	('esophageal cancer', 'Disease', 'MESH:D004938', (492, 509))	('ALDH2', 'Gene', (474, 479))	('ethanol', 'Chemical', 'MESH:D000431', (439, 446))	('cancer', 'Phenotype', 'HP:0002664', (633, 639))	('carcinoma', 'Phenotype', 'HP:0030731', (51, 60))	('Esophageal Adenocarcinoma', 'Disease', (35, 60))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (183, 208))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (183, 208))	('esophageal cancer', 'Disease', (492, 509))	('adenocarcinomas', 'Disease', 'MESH:D000230', (230, 245))	('adenocarcinomas', 'Disease', (230, 245))	('GI cancer', 'Phenotype', 'HP:0007378', (713, 722))	('linked', 'Reg', (623, 629))	('alcohol', 'Chemical', 'MESH:D000438', (597, 604))	('carcinomas', 'Phenotype', 'HP:0030731', (235, 245))	('GI cancers', 'Disease', 'MESH:D009369', (713, 723))	('cancer', 'Phenotype', 'HP:0002664', (503, 509))	('carcinoma', 'Phenotype', 'HP:0030731', (758, 767))	('esophageal adenocarcinoma', 'Disease', (183, 208))
511871	25680671	Trials can be helpful, but are not always possible, and negative results do not always quell the perception that modulating intake of certain foods or nutrients will lower risk for GI malignancies.	('GI malignancies', 'Disease', 'MESH:D009369', (181, 196))	('lower', 'NegReg', (166, 171))	('modulating', 'Var', (113, 123))	('GI malignancies', 'Disease', (181, 196))
511876	33008389	KIAA0101 and UbcH10 interact to regulate non-small cell lung cancer cell proliferation by disrupting the function of the spindle assembly checkpoint Chromosome mis-segregation caused by spindle assembly checkpoint (SAC) dysfunction during mitosis is an important pathogenic factor in cancer, and modulating SAC function has emerged as a potential novel therapy for non-small cell lung cancer (NSCLC).	('small cell lung cancer', 'Phenotype', 'HP:0030357', (45, 67))	('cancer', 'Disease', 'MESH:D009369', (284, 290))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('cancer', 'Phenotype', 'HP:0002664', (385, 391))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (369, 391))	('KIAA0101', 'Gene', '9768', (0, 8))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (41, 67))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (365, 391))	('lung cancer', 'Disease', 'MESH:D008175', (380, 391))	('cancer', 'Disease', 'MESH:D009369', (385, 391))	('NSCLC', 'Disease', 'MESH:D002289', (393, 398))	('non-small cell lung cancer', 'Disease', (41, 67))	('lung cancer', 'Phenotype', 'HP:0100526', (380, 391))	('lung cancer', 'Disease', 'MESH:D008175', (56, 67))	('non-small cell lung cancer', 'Disease', (365, 391))	('UbcH10', 'Gene', '11065', (13, 19))	('cancer', 'Disease', (284, 290))	('cancer', 'Disease', (61, 67))	('NSCLC', 'Disease', (393, 398))	('cancer', 'Phenotype', 'HP:0002664', (284, 290))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('lung cancer', 'Phenotype', 'HP:0100526', (56, 67))	('NSCLC', 'Phenotype', 'HP:0030358', (393, 398))	('UbcH10', 'Gene', (13, 19))	('KIAA0101', 'Gene', (0, 8))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (41, 67))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (365, 391))	('disrupting', 'NegReg', (90, 100))	('cancer', 'Disease', (385, 391))	('function', 'MPA', (105, 113))	('modulating', 'Var', (296, 306))
511881	33008389	Eventually, the effect of modulating UbcH10 and KIAA010 on tumor growth and its possible mechanisms were explored through in vivo tumor-bearing models.	('tumor', 'Disease', (59, 64))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('KIAA010', 'Gene', (48, 55))	('modulating', 'Var', (26, 36))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('UbcH10', 'Gene', (37, 43))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('KIAA010', 'Chemical', '-', (48, 55))	('tumor', 'Disease', (130, 135))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
511884	33008389	Moreover, tumor growth in vivo was significantly inhibited by silencing UbcH10 and KIAA0101 expression.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('silencing', 'Var', (62, 71))	('tumor', 'Disease', (10, 15))	('KIAA0101', 'Gene', (83, 91))	('UbcH10', 'Gene', (72, 78))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('inhibited', 'NegReg', (49, 58))	('expression', 'MPA', (92, 102))
511885	33008389	KIAA0101 and UbcH10 interact to cause SAC dysfunction, chromosomal instability and malignant proliferation in NSCLC, suggesting that UbcH10 and KIAA0101 are potential therapeutic targets for the treatment of NSCLC by ameliorating SAC function.	('malignant proliferation', 'CPA', (83, 106))	('UbcH10', 'Gene', (13, 19))	('KIAA0101', 'Var', (0, 8))	('NSCLC', 'Phenotype', 'HP:0030358', (208, 213))	('NSCLC', 'Disease', (110, 115))	('SAC dysfunction', 'Disease', 'MESH:D009461', (38, 53))	('NSCLC', 'Disease', 'MESH:D002289', (110, 115))	('chromosomal instability', 'Phenotype', 'HP:0040012', (55, 78))	('NSCLC', 'Disease', (208, 213))	('SAC dysfunction', 'Disease', (38, 53))	('NSCLC', 'Disease', 'MESH:D002289', (208, 213))	('cause', 'Reg', (32, 37))	('ameliorating', 'PosReg', (217, 229))	('chromosomal instability', 'CPA', (55, 78))	('NSCLC', 'Phenotype', 'HP:0030358', (110, 115))
511889	33008389	Aneuploidy caused by chromosome mis-segregation during mitosis is an important pathogenic factor in cancer.	('Aneuploidy', 'Disease', 'MESH:D000782', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('chromosome mis-segregation', 'Var', (21, 47))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('Aneuploidy', 'Disease', (0, 10))
511896	33008389	KIAA0101 is another appealing oncogene that was recently validated as an independent prognostic factor in NSCLC.	('NSCLC', 'Phenotype', 'HP:0030358', (106, 111))	('NSCLC', 'Disease', 'MESH:D002289', (106, 111))	('NSCLC', 'Disease', (106, 111))	('KIAA0101', 'Var', (0, 8))
511898	33008389	Based on the correlations between UbCH10, KIAA0101 and SAC function, we hypothesized that during the development of NSCLC, KIAA0101 may interact with UbcH10 to mediate SAC dysfunction and neoplastic transformation.	('NSCLC', 'Disease', 'MESH:D002289', (116, 121))	('KIAA0101', 'Var', (123, 131))	('interact', 'Reg', (136, 144))	('NSCLC', 'Phenotype', 'HP:0030358', (116, 121))	('UbCH10', 'Gene', (34, 40))	('SAC dysfunction', 'Disease', (168, 183))	('neoplastic transformation', 'CPA', (188, 213))	('SAC dysfunction', 'Disease', 'MESH:D009461', (168, 183))	('NSCLC', 'Disease', (116, 121))	('mediate', 'Reg', (160, 167))	('UbCH10', 'Gene', '11065', (34, 40))	('UbcH10', 'Gene', (150, 156))
511914	33008389	On the following day, the cells were infected with virus encoding UbcH10(Lv-UbcH10) or silencing KIAA0101(Lv-shRNA-KIAA0101 contains a siRNA sequence 5'-GACCTGAGGTATAAGCTCT-3') or control (Lv-control) at a multiplicity of infection (MOI) of 10.	('silencing', 'Var', (87, 96))	('infected', 'Disease', (37, 45))	('UbcH10', 'Var', (66, 72))	('KIAA0101', 'Gene', (97, 105))	('infected', 'Disease', 'MESH:D007239', (37, 45))	('infection', 'Disease', (222, 231))	('infection', 'Disease', 'MESH:D007239', (222, 231))
511938	33008389	The blots were probed with rabbit monoclonal antibodies against UbcH10 (1:200), KIAA0101 (1:500), BubR1 (1:600), Mad2 (1:250), CDC25(1:400), CDK1 (1:300), CDK7 (1:500), CyclinB (1:350) and beta-actin (1:1000) (Abcam, CA, USA), followed by incubation with secondary HRP-conjugated goat anti-rabbit antibody (Abcam, CA, USA).	('CDK7', 'Gene', (155, 159))	('CDK7', 'Gene', '1022', (155, 159))	('CDK1', 'Gene', '983', (141, 145))	('CDC25', 'Gene', (127, 132))	('1:1000', 'Var', (201, 207))	('CDC25', 'Gene', '995', (127, 132))	('beta-actin', 'Gene', '728378', (189, 199))	('CDK1', 'Gene', (141, 145))	('beta-actin', 'Gene', (189, 199))
511944	33008389	We then observed the spatial correlation of KIAA0101 and UbcH10 in SK-MES-1 cells in G2/M phase through an immunofluorescence assay and found that these two proteins were colocalized (Fig.	('SK-MES-1', 'CellLine', 'CVCL:0630', (67, 75))	('UbcH10', 'Gene', (57, 63))	('KIAA0101', 'Var', (44, 52))
511948	33008389	To further elucidate the correlation between UbcH10 and KIAA0101, we regulated UbcH10 and KIAA0101 in SK-MES-1 cells using lentiviral transfection.	('SK-MES-1', 'CellLine', 'CVCL:0630', (102, 110))	('KIAA0101', 'Var', (90, 98))	('UbcH10', 'Gene', (79, 85))
511951	33008389	We first investigated whether UbcH10 or KIAA0101 knockdown influences the SAC and cell cycle-related protein expression in SK-MES-1 cells.	('knockdown', 'Var', (49, 58))	('cell cycle-related protein expression', 'MPA', (82, 119))	('influences', 'Reg', (59, 69))	('SAC', 'MPA', (74, 77))	('SK-MES-1', 'CellLine', 'CVCL:0630', (123, 131))	('KIAA0101', 'Gene', (40, 48))	('UbcH10', 'Gene', (30, 36))
511952	33008389	The data showed that the suppression of either UbcH10 or KIAA0101 could downregulate BubR1, Mad2 and CyclinB, and upregulate CDC25, CDK1 and CDK7 proteins(p<0.05 compared to the control group), and KIAA0101 synergized with UbcH10 to affect the expression of these proteins, with a statistically significant difference between the dual and individual knockdown groups (p<0.01 compared to the control group) (Fig.	('UbcH10', 'Gene', (47, 53))	('CyclinB', 'MPA', (101, 108))	('CDK7', 'Gene', (141, 145))	('upregulate', 'PosReg', (114, 124))	('suppression', 'NegReg', (25, 36))	('BubR1', 'Protein', (85, 90))	('CDK1', 'Gene', '983', (132, 136))	('Mad2', 'Protein', (92, 96))	('CDK7', 'Gene', '1022', (141, 145))	('KIAA0101', 'Var', (57, 65))	('expression', 'MPA', (244, 254))	('CDK1', 'Gene', (132, 136))	('CDC25', 'Gene', (125, 130))	('downregulate', 'NegReg', (72, 84))	('affect', 'Reg', (233, 239))	('CDC25', 'Gene', '995', (125, 130))
511953	33008389	Six hours after the nocodazole treatment was stopped, the G2/M phase ratio was increased significantly among cells with UbcH10 or KIAA0101 knockdown (p<0.05 compared to the control group), and the G2/M phase ratio was significantly higher in the co-silenced group (p<0.01 compared to the control group) (Fig.	('UbcH10', 'Gene', (120, 126))	('increased', 'PosReg', (79, 88))	('KIAA0101', 'Gene', (130, 138))	('higher', 'PosReg', (232, 238))	('knockdown', 'Var', (139, 148))	('nocodazole', 'Chemical', 'MESH:D015739', (20, 30))	('G2/M phase', 'CPA', (197, 207))	('G2/M', 'MPA', (58, 62))
511954	33008389	We further evaluated the effects of UbcH10 and KIAA0101 knockdown on proliferation and found that A549 and SK-MES-1 cell proliferation was decreased in the UbcH10 shRNA group (p<0.05 compared to the control group at 72 h) and significantly decreased in the UbcH10 and KIAA0101 co-silenced group (p<0.01 compared to the control group at 72 h) (Fig.	('A549', 'CellLine', 'CVCL:0023', (98, 102))	('decreased', 'NegReg', (240, 249))	('decreased', 'NegReg', (139, 148))	('UbcH10', 'Var', (156, 162))	('SK-MES-1', 'CellLine', 'CVCL:0630', (107, 115))
511955	33008389	In summary, in NSCLC cells, UbcH10 and KIAA0101 may affect the expression of SAC-related proteins, regulate the cell cycle and promote tumor cell proliferation.	('KIAA0101', 'Var', (39, 47))	('NSCLC', 'Phenotype', 'HP:0030358', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('UbcH10', 'Gene', (28, 34))	('promote', 'PosReg', (127, 134))	('tumor', 'Disease', (135, 140))	('expression', 'MPA', (63, 73))	('regulate', 'Reg', (99, 107))	('NSCLC', 'Disease', (15, 20))	('SAC-related proteins', 'Protein', (77, 97))	('NSCLC', 'Disease', 'MESH:D002289', (15, 20))	('cell cycle', 'CPA', (112, 122))	('affect', 'Reg', (52, 58))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
511956	33008389	Silencing UbcH10 and KIAA0101 can restore SAC function, thus inhibiting the malignant proliferation of tumor cells.	('KIAA0101', 'Gene', (21, 29))	('inhibiting', 'NegReg', (61, 71))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor', 'Disease', (103, 108))	('UbcH10', 'Gene', (10, 16))	('SAC function', 'MPA', (42, 54))	('restore', 'PosReg', (34, 41))	('Silencing', 'Var', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
511958	33008389	Therefore, we hypothesized that KIAA0101 may cooperate with UbcH10 to regulate SAC function in a KEN box-dependent manner.	('KIAA0101', 'Var', (32, 40))	('KEN', 'Gene', (97, 100))	('regulate SAC function', 'MPA', (70, 91))	('KEN', 'Gene', '5116', (97, 100))
511962	33008389	By week 4, the tumor volume was significantly reduced in the UbcH10 and KIAA0101 shRNA groups (p<0.05 compared to the model group), and the co-silenced group showed a superior effect on tumor growth inhibition (p<0.01 compared to the model group) (Fig.	('UbcH10', 'Gene', (61, 67))	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumor', 'Disease', (186, 191))	('KIAA0101', 'Var', (72, 80))	('tumor', 'Disease', (15, 20))	('reduced', 'NegReg', (46, 53))
511963	33008389	We then quantified the expression of related proteins in tumor tissues and found that upon knockdown of UbcH10 and KIAA0101, the expression of the SAC components and cell cycle-associated proteins BubR1, Mad2 and CyclinB was effectively restored in tumor tissues (p<0.05 compared to the control group), and the co-silenced group showed a superior effect on these proteins (p<0.01 compared to the model group) (Fig.	('tumor', 'Disease', 'MESH:D009369', (249, 254))	('expression', 'MPA', (129, 139))	('BubR1', 'Gene', (197, 202))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (249, 254))	('knockdown', 'Var', (91, 100))	('UbcH10', 'Gene', (104, 110))	('restored', 'PosReg', (237, 245))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Disease', (249, 254))	('KIAA0101', 'Gene', (115, 123))	('tumor', 'Disease', (57, 62))
511964	33008389	The results indicated that UbcH10 silencing can restore SAC function to suppress tumor growth in a subcutaneously inoculated NSCLC model.	('suppress', 'NegReg', (72, 80))	('NSCLC', 'Disease', (125, 130))	('UbcH10', 'Gene', (27, 33))	('NSCLC', 'Disease', 'MESH:D002289', (125, 130))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('NSCLC', 'Phenotype', 'HP:0030358', (125, 130))	('SAC function', 'MPA', (56, 68))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('silencing', 'Var', (34, 43))	('tumor', 'Disease', (81, 86))
511970	33008389	In the present study, we demonstrated that by targeting UbcH10 and KIAA0101, SAC function could be effectively preserved, and tumor growth could be significantly inhibited, suggesting that UbcH10 and KIAA0101 are potential therapeutic targets in NSCLC that modulate SAC function.	('targeting', 'Var', (46, 55))	('NSCLC', 'Phenotype', 'HP:0030358', (246, 251))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('UbcH10', 'Gene', (56, 62))	('NSCLC', 'Disease', (246, 251))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('NSCLC', 'Disease', 'MESH:D002289', (246, 251))	('KIAA0101', 'Gene', (67, 75))	('inhibited', 'NegReg', (162, 171))	('tumor', 'Disease', (126, 131))
511974	33008389	found that in HeLa cells, UbcH10 caused the premature dissociation of Mad2 and BubR1 from the APC/C complex, and free Mad2 and BubR1 molecules could then be recognized by APC/C and degraded by the proteasome.	('premature dissociation', 'MPA', (44, 66))	('APC', 'Disease', 'MESH:D011125', (171, 174))	('degraded', 'NegReg', (181, 189))	('APC', 'Disease', (171, 174))	('APC', 'Disease', 'MESH:D011125', (94, 97))	('APC', 'Disease', (94, 97))	('HeLa', 'CellLine', 'CVCL:0030', (14, 18))	('UbcH10', 'Var', (26, 32))	('Mad2', 'Gene', (70, 74))
511977	33008389	These findings could be partly explained by the fact that in NSCLC, UbcH10 overexpression causes the SAC components Mad2 and BubR1 to prematurely dissociate from the APC/C complex and to be degraded by activated APC/C, which also degrades CyclinB, resulting in mitotic slippage, chromosomal instability and malignant proliferation.	('CyclinB', 'Protein', (239, 246))	('UbcH10', 'Gene', (68, 74))	('malignant proliferation', 'CPA', (307, 330))	('NSCLC', 'Disease', 'MESH:D002289', (61, 66))	('NSCLC', 'Phenotype', 'HP:0030358', (61, 66))	('APC', 'Disease', 'MESH:D011125', (212, 215))	('mitotic slippage', 'CPA', (261, 277))	('chromosomal instability', 'Phenotype', 'HP:0040012', (279, 302))	('APC', 'Disease', (212, 215))	('overexpression', 'Var', (75, 89))	('NSCLC', 'Disease', (61, 66))	('degrades', 'NegReg', (230, 238))	('degraded', 'NegReg', (190, 198))	('chromosomal instability', 'CPA', (279, 302))	('APC', 'Disease', 'MESH:D011125', (166, 169))	('APC', 'Disease', (166, 169))
511978	33008389	We also discovered that KIAA0101 and UbcH10 expression was spatially and temporally correlated and that KIAA0101 synergized with UbcH10 in regulating SAC function and tumorigenesis.	('UbcH10', 'Gene', (129, 135))	('KIAA0101', 'Var', (104, 112))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('UbcH10', 'Gene', (37, 43))	('SAC function', 'CPA', (150, 162))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('tumor', 'Disease', (167, 172))
511984	33008389	UbcH10 gene silencing and UbcH10 and KIAA0101 co-silencing effectively inhibited tumor growth in vivo, and the tumor suppressive effect of co-silencing was slightly better than that of UbcH10 alone, although the difference was not significant.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('inhibited', 'NegReg', (71, 80))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('better', 'PosReg', (165, 171))	('UbcH10', 'Gene', (0, 6))	('tumor', 'Disease', (111, 116))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('gene silencing', 'Var', (7, 21))	('co-silencing', 'Var', (46, 58))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('UbcH10', 'Gene', (26, 32))	('tumor', 'Disease', (81, 86))
511985	33008389	We attribute this outcome to the highly efficient tumor suppression by UbcH10 silencing.	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('silencing', 'Var', (78, 87))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('UbcH10', 'Gene', (71, 77))	('tumor', 'Disease', (50, 55))
511987	33008389	Based on the results we have already got, we supposed that KIAA0101 induced premature dissociation and degradation of BubR1 and Mad by competing for APC/C binding sites in KEN-box dependent manner, which in turn leads to SAC dysfunction and malignant proliferation.	('leads to', 'Reg', (212, 220))	('degradation', 'MPA', (103, 114))	('SAC dysfunction', 'Disease', (221, 236))	('KEN', 'Gene', (172, 175))	('BubR1', 'Gene', (118, 123))	('SAC dysfunction', 'Disease', 'MESH:D009461', (221, 236))	('KIAA0101', 'Var', (59, 67))	('Mad', 'Gene', '4084', (128, 131))	('KEN', 'Gene', '5116', (172, 175))	('Mad', 'Gene', (128, 131))	('APC', 'Disease', 'MESH:D011125', (149, 152))	('APC', 'Disease', (149, 152))	('malignant proliferation', 'CPA', (241, 264))	('competing', 'Interaction', (135, 144))	('dissociation', 'MPA', (86, 98))
511989	33008389	Therefore, we intend to use gene editing techniques to knock out the UbcH10 and KIAA0101 genes in a spontaneous tumor-forming model to further support our conclusions.	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('UbcH10', 'Gene', (69, 75))	('KIAA0101', 'Gene', (80, 88))	('tumor', 'Disease', (112, 117))	('knock out', 'Var', (55, 64))
511991	33008389	KIAA0101 and UbcH10 knockdown reduced the proliferation of NSCLC cells in vitro and suppressed tumor growth in vivo, suggesting that UbcH10 and KIAA0101 are potential therapeutic targets for the treatment of NSCLC by ameliorating SAC function.	('NSCLC', 'Disease', 'MESH:D002289', (59, 64))	('UbcH10', 'Gene', (13, 19))	('proliferation', 'CPA', (42, 55))	('NSCLC', 'Phenotype', 'HP:0030358', (208, 213))	('suppressed', 'NegReg', (84, 94))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('NSCLC', 'Phenotype', 'HP:0030358', (59, 64))	('NSCLC', 'Disease', (208, 213))	('reduced', 'NegReg', (30, 37))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('NSCLC', 'Disease', (59, 64))	('knockdown', 'Var', (20, 29))	('SAC', 'MPA', (230, 233))	('NSCLC', 'Disease', 'MESH:D002289', (208, 213))	('ameliorating', 'PosReg', (217, 229))	('tumor', 'Disease', (95, 100))
511995	30791227	Dysregulation, functional implications, and prognostic ability of the circadian clock across cancers It has been proposed that the circadian rhythm generally plays important roles in tumor suppression, but there is also evidence that disruption of the canonical circadian pathway has anticancer effects.	('cancers', 'Disease', (93, 100))	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('canonical circadian pathway', 'Pathway', (252, 279))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('cancers', 'Phenotype', 'HP:0002664', (93, 100))	('cancer', 'Disease', 'MESH:D009369', (288, 294))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('cancer', 'Disease', (288, 294))	('disruption', 'Var', (234, 244))	('tumor', 'Disease', (183, 188))	('clock', 'Gene', '9575', (80, 85))	('clock', 'Gene', (80, 85))	('cancer', 'Phenotype', 'HP:0002664', (288, 294))	('cancers', 'Disease', 'MESH:D009369', (93, 100))
512004	30791227	The 2017 Nobel Prize in Physiology or Medicine was awarded to Jeffrey C. Hall, Michael Rosbash and Michael W. Young for their leading discoveries of the molecular mechanisms controlling the circadian rhythm.1, 2 The circadian clock is critical for the normal physiological functions of cells, and disruption of the circadian system has been proposed to pose an important cancer risk.	('cancer', 'Phenotype', 'HP:0002664', (371, 377))	('clock', 'Gene', '9575', (226, 231))	('clock', 'Gene', (226, 231))	('cancer', 'Disease', (371, 377))	('cancer', 'Disease', 'MESH:D009369', (371, 377))	('disruption', 'Var', (297, 307))
512009	30791227	The results revealed that the circadian clock genes were most often dysregulated through DNA hypermethylation-based disruption of expression rather than mutations or copy number alterations.	('expression', 'MPA', (130, 140))	('DNA hypermethylation-based', 'Var', (89, 115))	('clock', 'Gene', (40, 45))	('clock', 'Gene', '9575', (40, 45))	('dysregulated', 'Reg', (68, 80))	('disruption', 'NegReg', (116, 126))	('hypermethylation-based', 'Var', (93, 115))
512019	30791227	The correlation between mutations of 375 driver genes40 and the CCI was analyzed by regression method, while cancer types and tumor mutation burden were adjusted.	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('tumor', 'Disease', (126, 131))	('cancer', 'Disease', (109, 115))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('mutations', 'Var', (24, 33))	('CCI', 'Chemical', '-', (64, 67))	('CCI', 'Disease', (64, 67))
512023	30791227	To test whether the mutational status of the driver genes40, 43 was significantly associated with the CCI, rank-transformed CCI was modeled via linear regression as a function of the gene's mutational status, and the rank-transformed mutation burden was used to diminish confounding effects.	('associated', 'Reg', (82, 92))	('CCI', 'Chemical', '-', (124, 127))	('genes40', 'Var', (52, 59))	('CCI', 'Chemical', '-', (102, 105))	('CCI', 'Disease', (102, 105))
512028	30791227	Thus, since the mutation rates of core clock genes were found to be low, the circadian rhythm system might not be disrupted by mutation in cancers.	('clock', 'Gene', '9575', (39, 44))	('cancers', 'Disease', 'MESH:D009369', (139, 146))	('cancers', 'Phenotype', 'HP:0002664', (139, 146))	('mutation', 'Var', (127, 135))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('cancers', 'Disease', (139, 146))	('mutation', 'MPA', (16, 24))	('clock', 'Gene', (39, 44))
512029	30791227	In general, PER1/2/3 exhibited the highest mutation frequencies among the core clock genes.	('PER1/2/3', 'Gene', '5187;8864;8863', (12, 20))	('PER1/2/3', 'Gene', (12, 20))	('mutation', 'Var', (43, 51))	('clock', 'Gene', (79, 84))	('clock', 'Gene', '9575', (79, 84))
512031	30791227	Furthermore, the mutation rates of other CCMCCs in cancer were also low (Figure S1 and S8).	('mutation', 'Var', (17, 25))	('low', 'NegReg', (68, 71))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))
512032	30791227	To further dissect the genomic alterations of circadian rhythm, the copy number variations of core clock genes were also analyzed (Figure 1B), and the results showed that the copy number alterations of core clock genes were limited, although both amplifications and deletions of core clock genes were observed.	('deletions', 'Var', (266, 275))	('clock', 'Gene', (284, 289))	('clock', 'Gene', '9575', (207, 212))	('clock', 'Gene', (99, 104))	('clock', 'Gene', '9575', (284, 289))	('clock', 'Gene', '9575', (99, 104))	('clock', 'Gene', (207, 212))
512035	30791227	To investigate aberrances in rhythmic genes across cancers, the mutations in the 1350 experimentally identified rhythmic genes curated from the CGDB were systematically analyzed in various cancers.	('CGDB', 'Gene', (144, 148))	('various cancers', 'Disease', 'MESH:D009369', (181, 196))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('various cancers', 'Disease', (181, 196))	('cancers', 'Phenotype', 'HP:0002664', (189, 196))	('analyzed', 'Reg', (169, 177))	('mutations', 'Var', (64, 73))	('cancers', 'Phenotype', 'HP:0002664', (51, 58))	('cancers', 'Disease', 'MESH:D009369', (189, 196))	('cancers', 'Disease', (51, 58))	('cancers', 'Disease', 'MESH:D009369', (51, 58))	('cancers', 'Disease', (189, 196))
512059	30791227	As the results shown in Figure 2D, the CCI was negatively correlated with mutations of driver genes including TP53 in BRCA, LIHC, and LUAD, XIRP2 in STAD, MUC4 in KIRC and FAM46C in HNSC, while negatively correlations were observed for RNF43 in CESC, PIK3CA in BRCA, FRG1 in HNSC, and EGFR in BLCA.	('EGFR', 'Gene', '1956', (285, 289))	('FAM46C', 'Gene', '54855', (172, 178))	('LUAD', 'Gene', (134, 138))	('PIK3CA', 'Gene', (251, 257))	('BRCA', 'Gene', '672', (261, 265))	('BRCA', 'Gene', '672', (118, 122))	('TP53', 'Gene', '7157', (110, 114))	('MUC4', 'Gene', '4585', (155, 159))	('RNF43', 'Gene', '54894', (236, 241))	('XIRP2', 'Gene', (140, 145))	('BRCA', 'Gene', (261, 265))	('MUC4', 'Gene', (155, 159))	('FRG1', 'Gene', '2483', (267, 271))	('BRCA', 'Gene', (118, 122))	('CCI', 'Chemical', '-', (39, 42))	('FRG1', 'Gene', (267, 271))	('LUAD', 'Phenotype', 'HP:0030078', (134, 138))	('EGFR', 'Gene', (285, 289))	('RNF43', 'Gene', (236, 241))	('PIK3CA', 'Gene', '5290', (251, 257))	('FAM46C', 'Gene', (172, 178))	('negatively', 'NegReg', (47, 57))	('CCI', 'Disease', (39, 42))	('TP53', 'Gene', (110, 114))	('BRCA', 'Phenotype', 'HP:0003002', (261, 265))	('mutations', 'Var', (74, 83))	('BRCA', 'Phenotype', 'HP:0003002', (118, 122))	('HNSC', 'Phenotype', 'HP:0012288', (275, 279))	('HNSC', 'Phenotype', 'HP:0012288', (182, 186))	('XIRP2', 'Gene', '129446', (140, 145))
512060	30791227	Furthermore, the expression and methylation of CCMCCs were analyzed, and the results presented in Figure S8 show that the expression of CCMCCs was disrupted in tumors and that hypermethylation contributed substantially to this disruption.	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('expression', 'MPA', (122, 132))	('hypermethylation', 'Var', (176, 192))	('CCMCCs', 'Gene', (136, 142))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('disrupted', 'NegReg', (147, 156))	('tumors', 'Disease', (160, 166))	('tumors', 'Disease', 'MESH:D009369', (160, 166))
512061	30791227	In tumor tissues, dysregulated circadian rhythm would disrupt the oscillatory expression of circadian genes; therefore, it was necessary to investigate the differential expression of rhythmic genes.	('dysregulated', 'Var', (18, 30))	('tumor', 'Disease', (3, 8))	('oscillatory expression', 'MPA', (66, 88))	('circadian genes', 'Gene', (92, 107))	('disrupt', 'NegReg', (54, 61))	('tumor', 'Disease', 'MESH:D009369', (3, 8))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))	('circadian', 'MPA', (31, 40))
512063	30791227	Enrichment analyses of DEGs in rhythmic genes across cancers were based on using a hypergeometric test.	('cancers', 'Phenotype', 'HP:0002664', (53, 60))	('cancers', 'Disease', (53, 60))	('cancers', 'Disease', 'MESH:D009369', (53, 60))	('DEGs', 'Var', (23, 27))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))
512071	30791227	Furthermore, CCI was positively correlated with a large number of metabolic pathways in LIHC (Figure S4A), which was consistent with the findings of previous studies.46, 47, 48, 49, 50  The circadian rhythm recently emerged as an important regulator of the immune system.51, 52 The GSEA results showed that a number of immune pathways were differentially activated in high- and low-CCI tumor tissues (Figure 3B).	('GSEA', 'Chemical', '-', (282, 286))	('high-', 'Var', (368, 373))	('low-CCI tumor', 'Disease', 'MESH:D009800', (378, 391))	('CCI', 'Chemical', '-', (382, 385))	('tumor', 'Phenotype', 'HP:0002664', (386, 391))	('low-CCI tumor', 'Disease', (378, 391))	('immune pathways', 'Pathway', (319, 334))	('CCI', 'Chemical', '-', (13, 16))	('activated', 'PosReg', (355, 364))
512073	30791227	Various pathways, including natural killer cell-mediated cytotoxicity, T- and B-cell receptor signaling pathways, Toll-like receptor signaling pathway, and primary immunodeficiency, were upregulated in high-CCI tumor tissues compared with low-CCI tumor tissues in BLCA and CESC.	('tumor', 'Phenotype', 'HP:0002664', (247, 252))	('Toll-like receptor signaling pathway', 'Pathway', (114, 150))	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('tumor', 'Disease', (247, 252))	('cytotoxicity', 'Disease', (57, 69))	('low-CCI tumor', 'Disease', (239, 252))	('primary immunodeficiency', 'Disease', (156, 180))	('tumor', 'Disease', 'MESH:D009369', (247, 252))	('immunodeficiency', 'Phenotype', 'HP:0002721', (164, 180))	('CCI', 'Chemical', '-', (207, 210))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('tumor', 'Disease', (211, 216))	('cytotoxicity', 'Disease', 'MESH:D064420', (57, 69))	('CCI', 'Chemical', '-', (243, 246))	('high-CCI', 'Var', (202, 210))	('low-CCI tumor', 'Disease', 'MESH:D009800', (239, 252))	('primary immunodeficiency', 'Disease', 'MESH:D007153', (156, 180))	('upregulated', 'PosReg', (187, 198))
512074	30791227	Fc gamma R-mediated phagocytosis was upregulated in high-CCI tumor tissues compared with low-CCI tumor tissues in BLCA and STAD.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('upregulated', 'PosReg', (37, 48))	('high-CCI', 'Var', (52, 60))	('low-CCI tumor', 'Disease', 'MESH:D009800', (89, 102))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('CCI', 'Chemical', '-', (93, 96))	('low-CCI tumor', 'Disease', (89, 102))	('Fc gamma R-mediated', 'Protein', (0, 19))	('tumor', 'Disease', (97, 102))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('CCI', 'Chemical', '-', (57, 60))	('tumor', 'Disease', (61, 66))
512075	30791227	The NOD-like receptor signaling pathway was upregulated in high-CCI tumor tissues compared with low-CCI tumor tissues in BLCA.	('tumor', 'Disease', (68, 73))	('CCI', 'Chemical', '-', (100, 103))	('NOD-like receptor signaling pathway', 'Pathway', (4, 39))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('upregulated', 'PosReg', (44, 55))	('tumor', 'Disease', (104, 109))	('low-CCI tumor', 'Disease', 'MESH:D009800', (96, 109))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('low-CCI tumor', 'Disease', (96, 109))	('CCI', 'Chemical', '-', (64, 67))	('high-CCI', 'Var', (59, 67))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
512076	30791227	In BLCA and THCA, antigen processing and presentation were upregulated and downregulated in high-CCI tumor tissues compared with low-CCI tumor tissues, respectively.	('CCI', 'Chemical', '-', (133, 136))	('THCA', 'Phenotype', 'HP:0002890', (12, 16))	('tumor', 'Disease', (137, 142))	('downregulated', 'NegReg', (75, 88))	('low-CCI tumor', 'Disease', (129, 142))	('tumor', 'Disease', (101, 106))	('presentation', 'MPA', (41, 53))	('CCI', 'Chemical', '-', (97, 100))	('high-CCI', 'Var', (92, 100))	('upregulated', 'PosReg', (59, 70))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('antigen processing', 'MPA', (18, 36))	('low-CCI tumor', 'Disease', 'MESH:D009800', (129, 142))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
512089	30791227	A previous study found that the circadian rhythm is associated with survival in colorectal cancer patients.8 For circadian rhythm is crucial to cell physiology and the core clock genes were dysregulated at mutation, SCNA, DNA methylation and expression levels, the prognostic ability of the circadian system in cancers should be investigated.	('colorectal cancer', 'Disease', 'MESH:D015179', (80, 97))	('cancers', 'Disease', 'MESH:D009369', (311, 318))	('cancers', 'Phenotype', 'HP:0002664', (311, 318))	('patients', 'Species', '9606', (98, 106))	('colorectal cancer', 'Phenotype', 'HP:0003003', (80, 97))	('cancers', 'Disease', (311, 318))	('mutation', 'Var', (206, 214))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('colorectal cancer', 'Disease', (80, 97))	('clock', 'Gene', '9575', (173, 178))	('clock', 'Gene', (173, 178))	('cancer', 'Phenotype', 'HP:0002664', (311, 317))
512095	30791227	The survival analysis with the best cutoff value showed that a high CCI predicted better survival in BRCA, CESC, KIRP, and LIHC (Figure 4B-E).	('CESC', 'Disease', (107, 111))	('high CCI', 'Var', (63, 71))	('better', 'PosReg', (82, 88))	('BRCA', 'Phenotype', 'HP:0003002', (101, 105))	('CCI', 'Var', (68, 71))	('BRCA', 'Gene', '672', (101, 105))	('KIRP', 'Disease', (113, 117))	('BRCA', 'Gene', (101, 105))	('CCI', 'Chemical', '-', (68, 71))
512102	30791227	For example, in KIRC, high expression level of FBXL3 predicted better survival, while RORB, CSNK1D, and CSNK1E significantly predicted poor survival (Figure S7).	('RORB', 'Gene', (86, 90))	('CSNK1E', 'Gene', (104, 110))	('high', 'Var', (22, 26))	('expression', 'MPA', (27, 37))	('CSNK1E', 'Gene', '1454', (104, 110))	('better', 'PosReg', (63, 69))	('RORB', 'Gene', '6096', (86, 90))	('survival', 'CPA', (70, 78))	('FBXL3', 'Gene', (47, 52))	('CSNK1D', 'Gene', (92, 98))	('CSNK1D', 'Gene', '1453', (92, 98))	('FBXL3', 'Gene', '26224', (47, 52))
512103	30791227	However, high expression of FBXL3 was related to poor survival in STAD (Figure S7).	('FBXL3', 'Gene', (28, 33))	('FBXL3', 'Gene', '26224', (28, 33))	('STAD', 'Disease', (66, 70))	('poor', 'NegReg', (49, 53))	('high', 'Var', (9, 13))
512109	30791227	reported that in hematologic malignancies ARNTL was transcriptionally silenced by the hypermethylation of its promoter CpG island.30 TCGA data showed that the expression of ARNTL was significantly lower in most solid tumors than in nontumor tissues; in addition, hypermethylation of ARNTL was also observed in PRAD (Figure 2A) and STAD, while the methylation status of ARNTL in other cancers was not available.	('lower', 'NegReg', (197, 202))	('ARNTL', 'Gene', '406', (42, 47))	('tumor', 'Disease', 'MESH:D009369', (235, 240))	('hypermethylation', 'Var', (263, 279))	('solid tumors', 'Disease', (211, 223))	('tumor', 'Disease', (217, 222))	('tumor', 'Phenotype', 'HP:0002664', (235, 240))	('cancers', 'Disease', 'MESH:D009369', (384, 391))	('expression', 'MPA', (159, 169))	('tumor', 'Disease', 'MESH:D009369', (217, 222))	('solid tumors', 'Disease', 'MESH:D009369', (211, 223))	('tumors', 'Phenotype', 'HP:0002664', (217, 223))	('ARNTL', 'Gene', (283, 288))	('ARNTL', 'Gene', '406', (173, 178))	('ARNTL', 'Gene', (173, 178))	('ARNTL', 'Gene', '406', (283, 288))	('hematologic malignancies', 'Disease', (17, 41))	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('ARNTL', 'Gene', '406', (369, 374))	('ARNTL', 'Gene', (369, 374))	('STAD', 'Disease', (331, 335))	('cancers', 'Phenotype', 'HP:0002664', (384, 391))	('cancers', 'Disease', (384, 391))	('tumor', 'Disease', (235, 240))	('hematologic malignancies', 'Disease', 'MESH:D019337', (17, 41))	('ARNTL', 'Gene', (42, 47))	('cancer', 'Phenotype', 'HP:0002664', (384, 390))
512111	30791227	Thus, the main cause of the lower expression levels of circadian clock genes might be hypermethylation of ARNTL and PER1/PER2/PER3, while the mechanisms for CLOCK and CRY1/CRY2 require further investigation.	('PER3', 'Gene', '8863', (126, 130))	('hypermethylation', 'Var', (86, 102))	('PER2', 'Gene', (121, 125))	('CRY2', 'Gene', (172, 176))	('lower', 'NegReg', (28, 33))	('clock', 'Gene', (65, 70))	('CRY1', 'Gene', (167, 171))	('PER2', 'Gene', '8864', (121, 125))	('PER3', 'Gene', (126, 130))	('clock', 'Gene', '9575', (65, 70))	('ARNTL', 'Gene', '406', (106, 111))	('CLOCK', 'Gene', '9575', (157, 162))	('ARNTL', 'Gene', (106, 111))	('CRY1', 'Gene', '1407', (167, 171))	('CRY2', 'Gene', '1408', (172, 176))	('CLOCK', 'Gene', (157, 162))	('expression levels', 'MPA', (34, 51))
512118	30791227	Thus, further detailed investigations should be performed to determine the mechanisms and functions of the dysregulation of the circadian clock in different cancer types.	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('clock', 'Gene', '9575', (138, 143))	('clock', 'Gene', (138, 143))	('cancer', 'Disease', (157, 163))	('dysregulation', 'Var', (107, 120))
512205	28946562	found that most breast cancers and most normal breast tissue samples expressed PTN mRNA as assessed by RT-PCR.	('PTN', 'Var', (79, 82))	('expressed', 'Reg', (69, 78))	('cancers', 'Phenotype', 'HP:0002664', (23, 30))	('breast cancers', 'Phenotype', 'HP:0003002', (16, 30))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('breast cancers', 'Disease', 'MESH:D001943', (16, 30))	('breast cancers', 'Disease', (16, 30))	('breast cancer', 'Phenotype', 'HP:0003002', (16, 29))
512226	29535388	Here we perform a comprehensive genomic (n = 60) and transcriptomic (n = 69) analysis of 75 LCNECs and identify two molecular subgroups: "type I LCNECs" with bi-allelic TP53 and STK11/KEAP1 alterations (37%), and "type II LCNECs" enriched for bi-allelic inactivation of TP53 and RB1 (42%).	('RB1', 'Gene', (279, 282))	('STK11', 'Gene', (178, 183))	('TP53', 'Gene', '7157', (169, 173))	('TP53', 'Gene', '7157', (270, 274))	('RB1', 'Gene', '5925', (279, 282))	('KEAP1', 'Gene', '9817', (184, 189))	('STK11', 'Gene', '6794', (178, 183))	('TP53', 'Gene', (169, 173))	('LCNEC', 'Chemical', '-', (145, 150))	('TP53', 'Gene', (270, 274))	('LCNEC', 'Chemical', '-', (222, 227))	('LCNEC', 'Chemical', '-', (92, 97))	('KEAP1', 'Gene', (184, 189))	('bi-allelic inactivation', 'Var', (243, 266))
512254	29535388	Early genomic profiling studies employing targeted sequencing of selected cancer-related genes aided in the identification of some prevalent mutations in LCNECs.	('LCNEC', 'Chemical', '-', (154, 159))	('mutations', 'Var', (141, 150))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('cancer', 'Disease', (74, 80))	('LCNECs', 'Disease', (154, 160))
512258	29535388	On average, LCNECs exhibited an exonic mutation rate of 8.6 non-synonymous mutations per million base pairs and a C:G > A:T transversion rate of 38.7% (Fig.	('LCNEC', 'Chemical', '-', (12, 17))	('C:G > A:T', 'Var', (114, 123))	('LCNECs', 'Disease', (12, 18))
512261	29535388	Analyses of chromosomal gene copy numbers revealed statistically significant amplifications of 1p34 (containing the MYCL1 gene, 12%), 8p12 (containing FGFR1, 7%), 8q24.21 (containing MYC, 5%), 13q33 (containing IRS2, 3%), and 14q13 (containing NKX2-1, also known as TTF-1, 10%) (Q < 0.01, Supplementary Fig.	('MYC', 'Gene', '4609', (183, 186))	('TTF-1', 'Gene', '7270', (266, 271))	('IRS2', 'Gene', '8660', (211, 215))	('p34', 'Gene', (96, 99))	('NKX2-1', 'Gene', (244, 250))	('MYCL1', 'Gene', '4610', (116, 121))	('MYC', 'Gene', (183, 186))	('8q24.21', 'Var', (163, 170))	('p34', 'Gene', '55379', (96, 99))	('MYC', 'Gene', '4609', (116, 119))	('IRS2', 'Gene', (211, 215))	('FGFR1', 'Gene', (151, 156))	('TTF-1', 'Gene', (266, 271))	('MYCL1', 'Gene', (116, 121))	('NKX2-1', 'Gene', '7080', (244, 250))	('FGFR1', 'Gene', '2260', (151, 156))	('MYC', 'Gene', (116, 119))
512262	29535388	Statistically significant deletions affected CDKN2A (9p21, 8%) and a putative fragile site at PTPRD (9p24, 7%).	('deletions', 'Var', (26, 35))	('PTPRD', 'Gene', '5789', (94, 99))	('PTPRD', 'Gene', (94, 99))	('CDKN2A', 'Gene', (45, 51))	('CDKN2A', 'Gene', '1029', (45, 51))
512263	29535388	While amplifications of NKX2-1 and FGFR1 frequently occur in lung adenocarcinomas and squamous cell carcinomas, respectively, MYCL1 amplifications are commonly found in SCLC.	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (86, 110))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (86, 109))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (61, 80))	('NKX2-1', 'Gene', '7080', (24, 30))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('carcinomas', 'Phenotype', 'HP:0030731', (71, 81))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (61, 81))	('NKX2-1', 'Gene', (24, 30))	('FGFR1', 'Gene', (35, 40))	('FGFR1', 'Gene', '2260', (35, 40))	('amplifications', 'Var', (6, 20))	('MYCL1', 'Gene', (126, 131))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (61, 81))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('carcinomas', 'Phenotype', 'HP:0030731', (100, 110))	('occur', 'Reg', (52, 57))	('SCLC', 'Gene', (169, 173))	('MYCL1', 'Gene', '4610', (126, 131))	('SCLC', 'Gene', '7864', (169, 173))	('lung adenocarcinomas', 'Disease', (61, 81))	('adenocarcinomas and squamous cell carcinomas', 'Disease', 'MESH:D002294', (66, 110))
512264	29535388	Thus, LCNECs harbor significant copy-number alterations that occur in different lung cancer subtypes.	('LCNEC', 'Chemical', '-', (6, 11))	('lung cancer', 'Disease', 'MESH:D008175', (80, 91))	('LCNECs', 'Disease', (6, 12))	('lung cancer', 'Disease', (80, 91))	('lung cancer', 'Phenotype', 'HP:0100526', (80, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('copy-number alterations', 'Var', (32, 55))
512265	29535388	TP53 was the most frequently mutated gene (92%), followed by inactivating somatic events in RB1 (42%); bi-allelic alterations in both genes, TP53 and RB1:a hallmark of SCLC:were found in 40% of the cases (Supplementary Fig.	('RB1', 'Gene', '5925', (92, 95))	('TP53', 'Gene', '7157', (0, 4))	('SCLC', 'Gene', '7864', (168, 172))	('TP53', 'Gene', (0, 4))	('SCLC', 'Gene', (168, 172))	('TP53', 'Gene', '7157', (141, 145))	('TP53', 'Gene', (141, 145))	('RB1', 'Gene', (150, 153))	('RB1', 'Gene', (92, 95))	('bi-allelic', 'Var', (103, 113))	('RB1', 'Gene', '5925', (150, 153))
512270	29535388	We furthermore identified:frequently deleterious:somatic alterations in functionally relevant domains of STK11 (30%) and KEAP1 (22%) (Fig.	('STK11', 'Gene', (105, 110))	('STK11', 'Gene', '6794', (105, 110))	('KEAP1', 'Gene', '9817', (121, 126))	('alterations', 'Var', (57, 68))	('KEAP1', 'Gene', (121, 126))
512271	29535388	Combined with loss-of-heterozygosity (LOH), bi-allelic alterations of STK11 and KEAP1 were found in 37% of the cases (Supplementary Fig.	('loss-of-heterozygosity', 'NegReg', (14, 36))	('found', 'Reg', (91, 96))	('bi-allelic alterations', 'Var', (44, 66))	('KEAP1', 'Gene', '9817', (80, 85))	('STK11', 'Gene', (70, 75))	('KEAP1', 'Gene', (80, 85))	('STK11', 'Gene', '6794', (70, 75))
512273	29535388	Altogether, somatic alterations of RB1 and STK11/KEAP1 were detected in 82% of the cases (n = 49) and occurred in a mutually exclusive fashion (P < 0.0001, Fisher's exact test, Fig.	('alterations', 'Var', (20, 31))	('STK11', 'Gene', (43, 48))	('RB1', 'Gene', (35, 38))	('KEAP1', 'Gene', '9817', (49, 54))	('RB1', 'Gene', '5925', (35, 38))	('STK11', 'Gene', '6794', (43, 48))	('detected', 'Reg', (60, 68))	('KEAP1', 'Gene', (49, 54))	('occurred', 'Reg', (102, 110))
512276	29535388	We additionally identified statistically significant mutations in the metalloproteinases ADAMTS2 (15%) and ADAMTS12 (20%), and in GAS7 (12%) and NTM (10%) (Q < 0.01, Methods section, Fig.	('GAS7', 'Gene', '8522', (130, 134))	('metalloproteinases', 'Enzyme', (70, 88))	('ADAMTS2', 'Gene', (89, 96))	('NTM', 'Gene', '50863', (145, 148))	('ADAMTS2', 'Gene', '9509', (89, 96))	('mutations', 'Var', (53, 62))	('GAS7', 'Gene', (130, 134))	('NTM', 'Gene', (145, 148))	('ADAMTS12', 'Gene', '81792', (107, 115))	('ADAMTS12', 'Gene', (107, 115))
512278	29535388	The mutations affected functionally important protein domains, which may suggest a relevant role in the tumorigenesis of LCNECs (Supplementary Fig.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('LCNECs', 'Disease', (121, 127))	('tumor', 'Disease', (104, 109))	('LCNEC', 'Chemical', '-', (121, 126))	('affected', 'Reg', (14, 22))	('protein', 'Protein', (46, 53))	('functionally important', 'MPA', (23, 45))	('mutations', 'Var', (4, 13))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
512280	29535388	4d, Supplementary Data 6) and found oncogenic mutations of RAS family genes (KRAS-G12V, -G12C, NRAS-D57E, HRAS-G13R), NFE2L2 (2 cases with G31V and 1 case with E79Q) and BRAF (V600E, and G469V).	('RAS family genes', 'Gene', (59, 75))	('HRAS-G13R', 'Var', (106, 115))	('G31V', 'Mutation', 'p.G31V', (139, 143))	('G13R', 'Mutation', 'p.G13R', (111, 115))	('NFE2L2', 'Gene', (118, 124))	('KRAS-G12V', 'Var', (77, 86))	('NRAS-D57E', 'Gene', (95, 104))	('V600E', 'Mutation', 'rs113488022', (176, 181))	('G31V', 'Var', (139, 143))	('G469V', 'Mutation', 'rs121913355', (187, 192))	('E79Q', 'Var', (160, 164))	('G469V', 'Var', (187, 192))	('BRAF', 'Gene', '673', (170, 174))	('E79Q', 'Mutation', 'rs1057519922', (160, 164))	('BRAF', 'Gene', (170, 174))	('V600E', 'Var', (176, 181))	('G12C', 'Mutation', 'rs1308981355', (89, 93))	('G12V', 'Mutation', 'p.G12V', (82, 86))	('NFE2L2', 'Gene', '4780', (118, 124))	('D57E', 'Mutation', 'p.D57E', (100, 104))
512283	29535388	Thus, LCNECs harbor alterations of oncogenes which are commonly found in lung adenocarcinomas, but usually absent in neuroendocrine tumors like SCLC.	('alterations', 'Var', (20, 31))	('SCLC', 'Gene', (144, 148))	('lung adenocarcinomas', 'Disease', (73, 93))	('LCNEC', 'Chemical', '-', (6, 11))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (73, 92))	('neuroendocrine tumors', 'Disease', 'MESH:D018358', (117, 138))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (73, 93))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (73, 93))	('carcinomas', 'Phenotype', 'HP:0030731', (83, 93))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (117, 138))	('tumors', 'Phenotype', 'HP:0002664', (132, 138))	('neuroendocrine tumors', 'Disease', (117, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))	('oncogenes', 'Gene', (35, 44))	('SCLC', 'Gene', '7864', (144, 148))
512288	29535388	Furthermore, all relevant and significant mutations were found to be clonal within the tumor, thus suggesting these alterations as early events during tumorigenesis (Fig.	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Disease', (151, 156))	('tumor', 'Disease', (87, 92))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('mutations', 'Var', (42, 51))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
512292	29535388	Our sequencing efforts have revealed genomic alterations in LCNECs that were previously known as canonical alterations in either, lung adenocarcinomas, squamous cell carcinomas, or SCLC.	('alterations', 'Var', (45, 56))	('SCLC', 'Gene', '7864', (181, 185))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (152, 176))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (130, 149))	('carcinoma', 'Phenotype', 'HP:0030731', (166, 175))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (152, 175))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (152, 176))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (130, 150))	('lung adenocarcinomas', 'Disease', (130, 150))	('carcinomas', 'Phenotype', 'HP:0030731', (166, 176))	('squamous cell carcinomas', 'Disease', (152, 176))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (130, 150))	('carcinomas', 'Phenotype', 'HP:0030731', (140, 150))	('SCLC', 'Gene', (181, 185))	('LCNEC', 'Chemical', '-', (60, 65))
512308	29535388	Although, LCNECs also harbored alterations commonly observed in adenocarcinomas and squamous cell carcinomas, even LCNECs with such alterations in KEAP1 or STK11 were primarily found in transcriptional subclasses shared with SCLC (Fig.	('alterations', 'Var', (31, 42))	('KEAP1', 'Gene', '9817', (147, 152))	('carcinomas', 'Phenotype', 'HP:0030731', (69, 79))	('adenocarcinomas and squamous cell carcinomas', 'Disease', 'MESH:D002294', (64, 108))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (84, 108))	('STK11', 'Gene', '6794', (156, 161))	('alterations', 'Var', (132, 143))	('LCNEC', 'Chemical', '-', (10, 15))	('KEAP1', 'Gene', (147, 152))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('SCLC', 'Gene', (225, 229))	('LCNEC', 'Chemical', '-', (115, 120))	('SCLC', 'Gene', '7864', (225, 229))	('carcinomas', 'Phenotype', 'HP:0030731', (98, 108))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (84, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))	('STK11', 'Gene', (156, 161))
512309	29535388	Therefore, this observation supports the view that despite the similarity in oncogenic mutations, LCNECs rather constitute their own biological class; and may not be considered as neuroendocrine versions of adenocarcinomas or squamous cell carcinomas.	('carcinomas', 'Phenotype', 'HP:0030731', (212, 222))	('LCNECs', 'Disease', (98, 104))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (226, 249))	('carcinomas', 'Phenotype', 'HP:0030731', (240, 250))	('adenocarcinomas or squamous cell carcinomas', 'Disease', 'MESH:D002294', (207, 250))	('carcinoma', 'Phenotype', 'HP:0030731', (212, 221))	('adenocarcinomas or squamous cell carcinomas', 'Disease', (207, 250))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (226, 250))	('carcinoma', 'Phenotype', 'HP:0030731', (240, 249))	('LCNEC', 'Chemical', '-', (98, 103))	('mutations', 'Var', (87, 96))
512317	29535388	Class I exclusively included LCNECs with STK11 or KEAP1 alterations; yet, a few cases with these alterations fell into class II that predominantly consisted of LCNECs with RB1 loss (Fig.	('RB1', 'Gene', (172, 175))	('KEAP1', 'Gene', (50, 55))	('loss', 'NegReg', (176, 180))	('alterations', 'Var', (56, 67))	('RB1', 'Gene', '5925', (172, 175))	('STK11', 'Gene', (41, 46))	('KEAP1', 'Gene', '9817', (50, 55))	('LCNEC', 'Chemical', '-', (29, 34))	('STK11', 'Gene', '6794', (41, 46))	('LCNEC', 'Chemical', '-', (160, 165))
512318	29535388	Some LCNECs, including tumors admixed with SCLC ("SCLC combined LCNECs"):clustered with the majority of SCLC tumors in the classes III and IV; similarly, some SCLC tumors were part of class II that included LCNECs bearing RB1 alterations (Fig.	('SCLC tumors', 'Disease', (159, 170))	('SCLC tumors', 'Disease', (104, 115))	('SCLC', 'Gene', '7864', (159, 163))	('SCLC', 'Gene', (159, 163))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('RB1', 'Gene', (222, 225))	('alterations', 'Var', (226, 237))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))	('tumors', 'Phenotype', 'HP:0002664', (164, 170))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('LCNEC', 'Chemical', '-', (207, 212))	('tumors', 'Disease', (109, 115))	('RB1', 'Gene', '5925', (222, 225))	('tumors', 'Disease', (23, 29))	('LCNEC', 'Chemical', '-', (64, 69))	('tumors', 'Disease', (164, 170))	('SCLC', 'Gene', '7864', (50, 54))	('SCLC', 'Gene', (50, 54))	('SCLC', 'Gene', '7864', (43, 47))	('LCNEC', 'Chemical', '-', (5, 10))	('SCLC', 'Gene', (43, 47))	('tumors', 'Disease', 'MESH:D009369', (109, 115))	('tumors', 'Disease', 'MESH:D009369', (23, 29))	('SCLC', 'Gene', (104, 108))	('SCLC', 'Gene', '7864', (104, 108))	('tumors', 'Disease', 'MESH:D009369', (164, 170))	('SCLC tumors', 'Disease', 'MESH:D018288', (104, 115))	('SCLC tumors', 'Disease', 'MESH:D018288', (159, 170))
512323	29535388	The transcriptional clustering heatmap pointed to a strong gene expression pattern shared by all LCNECs bearing STK11/KEAP1 alterations (Fig.	('STK11', 'Gene', '6794', (112, 117))	('alterations', 'Var', (124, 135))	('KEAP1', 'Gene', '9817', (118, 123))	('LCNEC', 'Chemical', '-', (97, 102))	('KEAP1', 'Gene', (118, 123))	('STK11', 'Gene', (112, 117))
512324	29535388	We therefore conducted a supervised analysis of the gene expression data, in which LCNECs with STK11/KEAP1 alterations were compared to tumors bearing RB1 alterations.	('tumors', 'Disease', (136, 142))	('tumors', 'Disease', 'MESH:D009369', (136, 142))	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('STK11', 'Gene', (95, 100))	('RB1', 'Gene', '5925', (151, 154))	('alterations', 'Var', (107, 118))	('KEAP1', 'Gene', '9817', (101, 106))	('LCNEC', 'Chemical', '-', (83, 88))	('STK11', 'Gene', '6794', (95, 100))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('KEAP1', 'Gene', (101, 106))	('RB1', 'Gene', (151, 154))
512329	29535388	2b), but which was less prominent in LCNECs and SCLC tumors with RB1 alterations (Fig.	('RB1', 'Gene', (65, 68))	('alterations', 'Var', (69, 80))	('SCLC tumors', 'Disease', (48, 59))	('RB1', 'Gene', '5925', (65, 68))	('SCLC tumors', 'Disease', 'MESH:D018288', (48, 59))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('LCNEC', 'Chemical', '-', (37, 42))	('LCNECs', 'Disease', (37, 43))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))
512332	29535388	12e; Supplementary Data 12), most LCNECs and some SCLC tumors with RB1 alterations in class II exhibited low levels of these genes (Fig.	('low', 'NegReg', (105, 108))	('LCNECs', 'Disease', (34, 40))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('LCNEC', 'Chemical', '-', (34, 39))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('RB1', 'Gene', (67, 70))	('alterations', 'Var', (71, 82))	('RB1', 'Gene', '5925', (67, 70))	('SCLC tumors', 'Disease', 'MESH:D018288', (50, 61))	('SCLC tumors', 'Disease', (50, 61))
512335	29535388	Given the strong enrichment of LCNECs with STK11 or KEAP1 alterations in cluster I, and the prominent lack of expression of key neuroendocrine genes in most tumors of class II, we termed LCNECs within this transcriptional class as "type II LCNECs".	('STK11', 'Gene', (43, 48))	('tumors', 'Phenotype', 'HP:0002664', (157, 163))	('KEAP1', 'Gene', '9817', (52, 57))	('LCNEC', 'Chemical', '-', (240, 245))	('tumors', 'Disease', (157, 163))	('STK11', 'Gene', '6794', (43, 48))	('tumors', 'Disease', 'MESH:D009369', (157, 163))	('LCNEC', 'Chemical', '-', (31, 36))	('KEAP1', 'Gene', (52, 57))	('LCNEC', 'Chemical', '-', (187, 192))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('alterations', 'Var', (58, 69))
512354	29535388	Type I and II LCNECs harbor key genomic alterations and oncogenic mutations, which are commonly found in SCLC, lung adenocarcinoma or squamous cell carcinoma (e.g., in RAS genes, BRAF, NFE2L2, as well as in STK11 and KEAP1 in the case of type I LCNECS, and RB1 losses in the case of type II LCNECs).	('mutations', 'Var', (66, 75))	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('KEAP1', 'Gene', '9817', (217, 222))	('STK11', 'Gene', '6794', (207, 212))	('KEAP1', 'Gene', (217, 222))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (111, 130))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (134, 157))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (111, 130))	('LCNEC', 'Chemical', '-', (245, 250))	('RB1', 'Gene', (257, 260))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (134, 157))	('carcinoma', 'Phenotype', 'HP:0030731', (148, 157))	('LCNEC', 'Chemical', '-', (14, 19))	('BRAF', 'Gene', '673', (179, 183))	('NFE2L2', 'Gene', '4780', (185, 191))	('SCLC', 'Gene', '7864', (105, 109))	('BRAF', 'Gene', (179, 183))	('SCLC', 'Gene', (105, 109))	('losses', 'NegReg', (261, 267))	('squamous cell carcinoma', 'Disease', (134, 157))	('RAS genes', 'Gene', (168, 177))	('LCNEC', 'Chemical', '-', (291, 296))	('STK11', 'Gene', (207, 212))	('RB1', 'Gene', '5925', (257, 260))	('lung adenocarcinoma', 'Disease', (111, 130))	('NFE2L2', 'Gene', (185, 191))
512358	29535388	Thus, the combinations of distinct sets of mutations with specific patterns of gene expression supports the view that LCNECs are not a variant of the other types of lung cancer, but represent a distinct subgroup within the spectrum of neuroendocrine lung tumors.	('lung tumors', 'Phenotype', 'HP:0100526', (250, 261))	('tumor', 'Phenotype', 'HP:0002664', (255, 260))	('lung cancer', 'Disease', (165, 176))	('lung cancer', 'Phenotype', 'HP:0100526', (165, 176))	('tumors', 'Phenotype', 'HP:0002664', (255, 261))	('LCNECs', 'Disease', (118, 124))	('mutations', 'Var', (43, 52))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('neuroendocrine lung tumors', 'Disease', (235, 261))	('LCNEC', 'Chemical', '-', (118, 123))	('neuroendocrine lung tumors', 'Disease', 'MESH:D018358', (235, 261))	('lung tumor', 'Phenotype', 'HP:0100526', (250, 260))	('lung cancer', 'Disease', 'MESH:D008175', (165, 176))
512359	29535388	In a more focused comparison with the most frequent neuroendocrine type of lung cancer, SCLC, type I LCNECs with STK11 and KEAP1 alterations exhibited a high degree of similarity with these carcinomas, as well as high expression of neuroendocrine genes and a profile of ASCL1high/DLL3high/NOTCHlow.	('lung cancer', 'Phenotype', 'HP:0100526', (75, 86))	('DLL3', 'Gene', (280, 284))	('KEAP1', 'Gene', (123, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (190, 199))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('carcinomas', 'Phenotype', 'HP:0030731', (190, 200))	('neuroendocrine genes', 'Gene', (232, 252))	('carcinomas', 'Disease', 'MESH:D002277', (190, 200))	('alterations', 'Var', (129, 140))	('DLL3', 'Gene', '105375808', (280, 284))	('neuroendocrine type of lung cancer', 'Disease', (52, 86))	('NOTCH', 'Gene', '4851;4853;4854', (289, 294))	('STK11', 'Gene', (113, 118))	('LCNEC', 'Chemical', '-', (101, 106))	('neuroendocrine type of lung cancer', 'Disease', 'MESH:D008175', (52, 86))	('NOTCH', 'Gene', (289, 294))	('carcinomas', 'Disease', (190, 200))	('SCLC', 'Gene', '7864', (88, 92))	('STK11', 'Gene', '6794', (113, 118))	('SCLC', 'Gene', (88, 92))	('expression', 'MPA', (218, 228))	('KEAP1', 'Gene', '9817', (123, 128))
512360	29535388	By contrast, type II LCNECs with RB1 alterations revealed reduced expression of neuroendocrine genes and a pattern of ASCL1low/DLL3low/NOTCHhigh.	('NOTCH', 'Gene', (135, 140))	('RB1', 'Gene', '5925', (33, 36))	('DLL3', 'Gene', '105375808', (127, 131))	('LCNEC', 'Chemical', '-', (21, 26))	('neuroendocrine genes', 'Gene', (80, 100))	('expression', 'MPA', (66, 76))	('DLL3', 'Gene', (127, 131))	('RB1', 'Gene', (33, 36))	('alterations', 'Var', (37, 48))	('reduced', 'NegReg', (58, 65))	('NOTCH', 'Gene', '4851;4853;4854', (135, 140))
512365	29535388	On the other hand, type II LCNECs with alterations in RB1 exhibited active Notch signaling (Fig.	('exhibited', 'Reg', (58, 67))	('LCNEC', 'Chemical', '-', (27, 32))	('RB1', 'Gene', (54, 57))	('alterations', 'Var', (39, 50))	('Notch', 'Gene', '4851;4853;4854', (75, 80))	('RB1', 'Gene', '5925', (54, 57))	('Notch', 'Gene', (75, 80))
512371	29535388	Our sequencing studies did not reveal any somatic events that may cause the transcriptional discrepancy observed in LCNEC and SCLC tumors with TP53 and RB1 alteration, which raises the question if all neuroendocrine tumors share the same cell of origin.	('TP53', 'Gene', (143, 147))	('alteration', 'Var', (156, 166))	('RB1', 'Gene', '5925', (152, 155))	('SCLC tumors', 'Disease', 'MESH:D018288', (126, 137))	('LCNEC', 'Disease', (116, 121))	('SCLC tumors', 'Disease', (126, 137))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('RB1', 'Gene', (152, 155))	('tumors', 'Phenotype', 'HP:0002664', (216, 222))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('neuroendocrine tumors', 'Disease', 'MESH:D018358', (201, 222))	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (201, 222))	('neuroendocrine tumors', 'Disease', (201, 222))	('TP53', 'Gene', '7157', (143, 147))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('LCNEC', 'Chemical', '-', (116, 121))	('transcriptional', 'MPA', (76, 91))
512393	29535388	The DNA of tumor and normal material was confirmed to originate from the same patient by short tandem repeat (STR) analysis which was conducted at the Institute of Legal Medicine at the University of Cologne (Cologne, Germany), or by subsequent Affymetrix 6.0 SNP array and sequencing analyses.	('tri', 'Chemical', '-', (251, 254))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('patient', 'Species', '9606', (78, 85))	('short tandem', 'Var', (89, 101))	('tumor', 'Disease', (11, 16))	('tumor', 'Disease', 'MESH:D009369', (11, 16))
512407	29535388	The clonal status of mutations was assessed by computing for every mutation the "cancer cell fraction" (CCF), which defines within a tumor the fraction of cancer cells harboring that particular mutation.	('mutation', 'Var', (67, 75))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('cancer', 'Disease', (81, 87))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumor', 'Disease', (133, 138))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('cancer', 'Disease', (155, 161))	('cancer', 'Disease', 'MESH:D009369', (155, 161))
512413	29535388	Single-base substitutions were classified into 96 types determined by the six possible substitutions (C:G > A:T, C:G > G:C, C:G > T:A, A:T > C:G, A:T > G:C, A:T > T:A) in their tri-nucleotides sequence context (16 combinations for each type of substitution).	('tri', 'Chemical', '-', (177, 180))	('C:G > G', 'Var', (113, 120))	('C:G > A:T', 'Var', (102, 111))	('A:T > C:G', 'Var', (135, 144))
512459	29535388	In brief, the BAC clone RP11-939M14 labeled centromeres with biotin (red signal) and CTD-3228E10 labeled telomeric sites with digoxigenin (green signal).	('RP11', 'Gene', '26121', (24, 28))	('digoxigenin', 'Chemical', 'MESH:D004076', (126, 137))	('CTD-3228E10', 'Var', (85, 96))	('RP11', 'Gene', (24, 28))	('biotin', 'MPA', (61, 67))	('biotin', 'Chemical', 'MESH:D001710', (61, 67))
512503	31781331	It is known that inflammation, oncogenic signals, DNA mutations, and dysfunction in the respiratory chain play an important role in inducing oxidative stress.	('oxidative stress', 'MPA', (141, 157))	('mutations', 'Var', (54, 63))	('dysfunction', 'Var', (69, 80))	('inflammation', 'Disease', 'MESH:D007249', (17, 29))	('oxidative stress', 'Phenotype', 'HP:0025464', (141, 157))	('inflammation', 'Disease', (17, 29))	('N', 'Chemical', 'MESH:D009584', (51, 52))
512579	31781331	Thus, CAT confers protection against the toxic effects of H2O2 without generating intermediate free radicals, and the resulting oxygen is utilized for other metabolic processes.	('H2O2', 'Var', (58, 62))	('H2O2', 'Chemical', 'MESH:D014867', (58, 62))	('oxygen', 'Chemical', 'MESH:D010100', (128, 134))	('CAT', 'Gene', '847', (6, 9))	('CAT', 'Gene', (6, 9))
512585	31781331	Previous studies suggested that the antioxidant activity is impaired in lung cancers, and the expression of GSH-related antioxidant enzymes creates an interindividual risk factor for lung cancer.	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('cancers', 'Phenotype', 'HP:0002664', (77, 84))	('GSH-related', 'Gene', (108, 119))	('GSH', 'Chemical', 'MESH:D005978', (108, 111))	('lung cancer', 'Disease', 'MESH:D008175', (183, 194))	('lung cancers', 'Disease', (72, 84))	('impaired', 'NegReg', (60, 68))	('lung cancers', 'Phenotype', 'HP:0100526', (72, 84))	('antioxidant activity', 'MPA', (36, 56))	('lung cancer', 'Phenotype', 'HP:0100526', (72, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('lung cancers', 'Disease', 'MESH:D008175', (72, 84))	('lung cancer', 'Disease', (183, 194))	('lung cancer', 'Phenotype', 'HP:0100526', (183, 194))	('lung cancer', 'Disease', 'MESH:D008175', (72, 83))	('expression', 'Var', (94, 104))
512630	26956891	Cox regression analysis indicated low expressions of SBP1 can be an independent prognostic factor for poor overall survival in LSCC patients (P = 0.002).	('expressions', 'MPA', (38, 49))	('Cox', 'Gene', (0, 3))	('SCC', 'Gene', (128, 131))	('Cox', 'Gene', '1351', (0, 3))	('LSCC', 'Phenotype', 'HP:0030359', (127, 131))	('overall', 'MPA', (107, 114))	('poor', 'NegReg', (102, 106))	('SCC', 'Phenotype', 'HP:0002860', (128, 131))	('SCC', 'Gene', '6317', (128, 131))	('low', 'Var', (34, 37))	('SBP1', 'Gene', (53, 57))	('patients', 'Species', '9606', (132, 140))	('SBP1', 'Gene', '8991', (53, 57))
512644	26956891	Selenium deficiency in diet can increase incidence of cancers, including liver, prostate, lung, and colorectal cancers.	('cancers', 'Disease', 'MESH:D009369', (111, 118))	('cancers', 'Phenotype', 'HP:0002664', (111, 118))	('prostate', 'Disease', (80, 88))	('Selenium', 'Chemical', 'MESH:D012643', (0, 8))	('cancers', 'Phenotype', 'HP:0002664', (54, 61))	('cancers', 'Disease', (111, 118))	('increase', 'PosReg', (32, 40))	('cancers', 'Disease', (54, 61))	('colorectal cancer', 'Phenotype', 'HP:0003003', (100, 117))	('cancers', 'Disease', 'MESH:D009369', (54, 61))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('Selenium deficiency', 'Var', (0, 19))	('colorectal cancers', 'Disease', 'MESH:D015179', (100, 118))	('lung', 'Disease', (90, 94))	('colorectal cancers', 'Disease', (100, 118))	('deficiency', 'Var', (9, 19))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('liver', 'Disease', (73, 78))
512700	26956891	The mean survival times of the patients with moderate and high expressions of SBP1 was 42.0 +- 16.2 months, which was higher than that of patients with low expression of SBP1 (26.1 +- 15.1 months, P < 0.01).	('higher', 'PosReg', (118, 124))	('high expressions', 'Var', (58, 74))	('survival times', 'CPA', (9, 23))	('SBP1', 'Gene', '8991', (170, 174))	('patients', 'Species', '9606', (31, 39))	('SBP1', 'Gene', (170, 174))	('SBP1', 'Gene', (78, 82))	('patients', 'Species', '9606', (138, 146))	('SBP1', 'Gene', '8991', (78, 82))
512721	26956891	In our previous studies, we found that knockdown of SBP1 in immortalized human bronchial epithelial cell line 16HBE cells significantly promoted cell proliferation, inhibited apoptosis, and increased the efficiency of B[a]P-induced cell transformation.	('B[a]P-induced cell transformation', 'CPA', (218, 251))	('apoptosis', 'CPA', (175, 184))	('knockdown', 'Var', (39, 48))	('inhibited', 'NegReg', (165, 174))	('increased', 'PosReg', (190, 199))	('SBP1', 'Gene', (52, 56))	('promoted', 'PosReg', (136, 144))	('SBP1', 'Gene', '8991', (52, 56))	('human', 'Species', '9606', (73, 78))	('cell proliferation', 'CPA', (145, 163))	('16HBE', 'CellLine', 'CVCL:0112', (110, 115))
512752	33712588	For instance, immuno-supportive phenotypes, which exhibit greater baseline antitumor immunity and improved immunotherapy response, have been linked to the presence of TILs and elevated expression of programmed death-ligand 1 (PD-L1) on tumor-associated immune cells.	('presence', 'Var', (155, 163))	('elevated', 'PosReg', (176, 184))	('programmed death-ligand 1', 'Gene', (199, 224))	('greater', 'PosReg', (58, 65))	('programmed death-ligand 1', 'Gene', '29126', (199, 224))	('tumor', 'Disease', (79, 84))	('expression', 'MPA', (185, 195))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('TIL', 'Gene', (167, 170))	('immunotherapy response', 'CPA', (107, 129))	('tumor', 'Disease', 'MESH:D009369', (236, 241))	('PD-L1', 'Gene', (226, 231))	('tumor', 'Phenotype', 'HP:0002664', (236, 241))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('improved', 'PosReg', (98, 106))	('tumor', 'Disease', (236, 241))	('TIL', 'Gene', '7096', (167, 170))	('PD-L1', 'Gene', '29126', (226, 231))
512833	33712588	Like the three other immune checkpoint proteins (PD-1, PD-L1, and CTLA-4), TIGIT expression was also associated with markers of tumor inflammation, including the count of cancer cells within 80 mum of lymphocytes (pan-cancer and BRCA), the total number of lymphocytes in CT + CAS (pan-cancer and BRCA), and the proportional count of lymphocytes to cancer cells within 80 mum of the CSI (LUAD) (Fig.	('tumor inflammation', 'Disease', (128, 146))	('cancer', 'Disease', 'MESH:D009369', (348, 354))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('TIGIT', 'Gene', (75, 80))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('CTLA-4', 'Gene', '1493', (66, 72))	('cancer', 'Disease', 'MESH:D009369', (218, 224))	('CTLA-4', 'Gene', (66, 72))	('BRCA', 'Phenotype', 'HP:0003002', (296, 300))	('PD-1', 'Gene', (49, 53))	('PD-1', 'Gene', '5133', (49, 53))	('PD-L1', 'Gene', (55, 60))	('cancer', 'Disease', (285, 291))	('cancer', 'Disease', (348, 354))	('LUAD', 'Phenotype', 'HP:0030078', (387, 391))	('PD-L1', 'Gene', '29126', (55, 60))	('BRCA', 'Phenotype', 'HP:0003002', (229, 233))	('expression', 'Var', (81, 91))	('cancer', 'Disease', (171, 177))	('cancer', 'Phenotype', 'HP:0002664', (285, 291))	('cancer', 'Phenotype', 'HP:0002664', (348, 354))	('associated', 'Reg', (101, 111))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('tumor inflammation', 'Disease', 'MESH:D007249', (128, 146))	('cancer', 'Disease', (218, 224))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('cancer', 'Disease', 'MESH:D009369', (285, 291))	('CAS', 'Gene', (276, 279))	('CAS', 'Gene', '9564', (276, 279))
512992	29213088	NSD1 inactivation defines an immune cold, DNA hypomethylated subtype in squamous cell carcinoma Chromatin modifying enzymes are frequently mutated in cancer, resulting in widespread epigenetic deregulation.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (72, 95))	('NSD1', 'Gene', (0, 4))	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('epigenetic deregulation', 'MPA', (182, 205))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (72, 95))	('squamous cell carcinoma', 'Disease', (72, 95))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('cancer', 'Disease', (150, 156))	('NSD1', 'Gene', '64324', (0, 4))	('inactivation', 'Var', (5, 17))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
512993	29213088	Recent reports indicate that inactivating mutations in the histone methyltransferase NSD1 define an intrinsic subtype of head and neck squamous cell carcinoma (HNSC) that features pronounced DNA hypomethylation.	('DNA', 'MPA', (191, 194))	('HNSC', 'Phenotype', 'HP:0012288', (160, 164))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (135, 158))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (121, 158))	('carcinoma', 'Phenotype', 'HP:0030731', (149, 158))	('NSD1', 'Gene', (85, 89))	('inactivating mutations', 'Var', (29, 51))	('neck squamous cell carcinoma', 'Disease', (130, 158))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (130, 158))
512994	29213088	Here, we describe a similar hypomethylated subtype of lung squamous cell carcinoma (LUSC) that is enriched for both inactivating mutations and deletions in NSD1.	('deletions', 'Var', (143, 152))	('NSD1', 'Gene', (156, 160))	('LUSC', 'Phenotype', 'HP:0030359', (84, 88))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (54, 82))	('inactivating mutations', 'Var', (116, 138))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (59, 82))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (54, 82))	('lung squamous cell carcinoma', 'Disease', (54, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
512995	29213088	The 'NSD1 subtypes' of HNSC and LUSC are highly correlated at the DNA methylation and gene expression levels, featuring ectopic expression of developmental transcription factors and genes that are also hypomethylated in Sotos syndrome, a congenital disorder caused by germline NSD1 mutations.	('a congenital disorder', 'Disease', (236, 257))	('Sotos syndrome', 'Disease', (220, 234))	('a congenital disorder', 'Disease', 'MESH:D000013', (236, 257))	('HNSC', 'Phenotype', 'HP:0012288', (23, 27))	('LUSC', 'Phenotype', 'HP:0030359', (32, 36))	('Sotos syndrome', 'Disease', 'MESH:D058495', (220, 234))	('mutations', 'Var', (282, 291))	('hypomethylated', 'Var', (202, 216))	('NSD1', 'Gene', (277, 281))
512997	29213088	Using an in vivo model, we demonstrate that NSD1 inactivation results in reduced T cell infiltration into the tumor microenvironment, implicating NSD1 as a tumor cell-intrinsic driver of an immune cold phenotype.	('reduced T cell', 'Phenotype', 'HP:0005403', (73, 87))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('reduced', 'NegReg', (73, 80))	('inactivation', 'Var', (49, 61))	('tumor', 'Disease', (110, 115))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumor', 'Disease', (156, 161))	('NSD1', 'Gene', (44, 48))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
512998	29213088	NSD1 inactivation therefore causes epigenetic deregulation across cancer sites, and has implications for immunotherapy.	('NSD1', 'Gene', (0, 4))	('epigenetic deregulation', 'MPA', (35, 58))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('causes', 'Reg', (28, 34))	('implications', 'Reg', (88, 100))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('inactivation', 'Var', (5, 17))	('cancer', 'Disease', (66, 72))
512999	29213088	Nuclear receptor binding SET domain protein 1 (NSD1) is frequently mutated in head and neck squamous cell carcinoma (HNSC), the sixth most common cancer by incidence, and a leading cause of cancer-related death.	('Nuclear receptor binding SET domain protein 1', 'Gene', (0, 45))	('cancer', 'Disease', (190, 196))	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (190, 196))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('HNSC', 'Phenotype', 'HP:0012288', (117, 121))	('neck squamous cell carcinoma', 'Disease', (87, 115))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (78, 115))	('mutated', 'Var', (67, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (92, 115))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (87, 115))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('Nuclear receptor binding SET domain protein 1', 'Gene', '64324', (0, 45))	('NSD1', 'Gene', (47, 51))	('death', 'Disease', 'MESH:D003643', (205, 210))	('death', 'Disease', (205, 210))
513000	29213088	NSD1 is also genetically or epigenetically deregulated (either inactivated or overexpressed) in several other cancer types.	('NSD1', 'Gene', (0, 4))	('cancer', 'Disease', (110, 116))	('epigenetically deregulated', 'Var', (28, 54))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('overexpressed', 'PosReg', (78, 91))	('cancer', 'Disease', 'MESH:D009369', (110, 116))
513004	29213088	reported that germline NSD1 mutations are associated with widespread perturbation (primarily loss) of DNA methylation, i.e., methylation of cytosine to form 5-methylcytosine at CpG dinucleotides.	('CpG dinucleotides', 'Chemical', 'MESH:C015772', (177, 194))	('DNA methylation', 'MPA', (102, 117))	('loss', 'NegReg', (93, 97))	('cytosine', 'Chemical', 'MESH:D003596', (140, 148))	('methylation of cytosine to form 5-methylcytosine', 'MPA', (125, 173))	('cytosine', 'Chemical', 'MESH:D003596', (165, 173))	('perturbation', 'NegReg', (69, 81))	('mutations', 'Var', (28, 37))	('5-methylcytosine', 'Chemical', 'MESH:D044503', (157, 173))	('NSD1', 'Gene', (23, 27))
513006	29213088	recently reported that a HNSC subtype featuring NSD1 mutations is defined by impairment of dimethylation (H3K36me2) and that NSD1 inactivation represents one of two mechanisms causing H3K36me2 impairment, the other being H3 K36M mutations.	('inactivation', 'NegReg', (130, 142))	('NSD1', 'Gene', (48, 52))	('NSD1', 'Gene', (125, 129))	('mutations', 'Var', (53, 62))	('impairment', 'NegReg', (193, 203))	('H3K36me2', 'MPA', (184, 192))	('impairment', 'NegReg', (77, 87))	('K36M', 'Mutation', 'p.K36M', (224, 228))	('HNSC', 'Phenotype', 'HP:0012288', (25, 29))
513007	29213088	These findings reveal NSD1 inactivation as one mechanism underlying deregulation of DNA methylation, a major cause of abnormal gene expression in virtually all cancers.	('DNA methylation', 'MPA', (84, 99))	('inactivation', 'Var', (27, 39))	('cancers', 'Disease', 'MESH:D009369', (160, 167))	('cancers', 'Phenotype', 'HP:0002664', (160, 167))	('cancers', 'Disease', (160, 167))	('deregulation', 'MPA', (68, 80))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('NSD1', 'Gene', (22, 26))
513016	29213088	We demonstrate that NSD1 inactivation induces immune cell exclusion from the tumor microenvironment using an in vivo mouse model of tumor immune infiltration, recapitulating the immune cold phenotype observed in the analysis of the TCGA data.	('immune cell exclusion', 'CPA', (46, 67))	('NSD1', 'Gene', (20, 24))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('inactivation', 'Var', (25, 37))	('mouse', 'Species', '10090', (117, 122))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('induces', 'Reg', (38, 45))	('tumor', 'Disease', (132, 137))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Disease', (77, 82))
513018	29213088	Fifty-seven percent (24/42) of patients within this HNSC subtype had NSD1 mutations, compared with 2-8% patients within the other subtypes.	('NSD1', 'Gene', (69, 73))	('mutations', 'Var', (74, 83))	('patients', 'Species', '9606', (31, 39))	('patients', 'Species', '9606', (104, 112))	('HNSC', 'Phenotype', 'HP:0012288', (52, 56))
513020	29213088	NSD1 deletions were significantly enriched among patients with NSD1 point mutations, as 21/33 (64%) of patients with NSD1 mutations had deletions, compared with 99/269 (0.34) of patients without mutations.	('NSD1', 'Gene', (0, 4))	('NSD1', 'Gene', (63, 67))	('deletions', 'Var', (136, 145))	('patients', 'Species', '9606', (178, 186))	('NSD1', 'Gene', (117, 121))	('mutations', 'Var', (122, 131))	('patients', 'Species', '9606', (49, 57))	('patients', 'Species', '9606', (103, 111))	('deletions', 'Var', (5, 14))
513021	29213088	Lowest NSD1 expression and mean methylation occurred in patients with high-level likely focal deletions but without mutations, and in patients with both NSD1 mutations and deletions, suggesting that tumors undergo positive selection for loss of both alleles, resulting in extreme hypomethylation.	('patients', 'Species', '9606', (56, 64))	('hypomethylation', 'MPA', (280, 295))	('NSD1', 'Gene', (7, 11))	('tumors', 'Disease', (199, 205))	('tumors', 'Disease', 'MESH:D009369', (199, 205))	('tumors', 'Phenotype', 'HP:0002664', (199, 205))	('patients', 'Species', '9606', (134, 142))	('methylation', 'MPA', (32, 43))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('NSD1', 'Gene', (153, 157))	('deletions', 'Var', (94, 103))	('Lowest', 'NegReg', (0, 6))	('expression', 'MPA', (12, 22))	('mutations', 'Var', (158, 167))
513022	29213088	Moreover, patients with low-level deletions (CNV = -1) had significantly lower mean DNA methylation than patients with normal copy number (CNV = 0), both in patients with and without NSD1 mutations, indicating that NSD1 deletions impair DNA methylation independent of mutations.	('DNA methylation', 'MPA', (84, 99))	('patients', 'Species', '9606', (105, 113))	('impair', 'NegReg', (230, 236))	('deletions', 'Var', (220, 229))	('deletions', 'Var', (34, 43))	('lower', 'NegReg', (73, 78))	('patients', 'Species', '9606', (157, 165))	('DNA methylation', 'MPA', (237, 252))	('NSD1', 'Gene', (215, 219))	('patients', 'Species', '9606', (10, 18))
513023	29213088	We investigated the possibility that NSD1 mutations affect DNA methylation in other cancers, focusing on cancers for which there were at least ten patients with NSD1 mutations and accompanying DNA methylation data within TCGA data.	('NSD1', 'Gene', (161, 165))	('cancers', 'Phenotype', 'HP:0002664', (105, 112))	('mutations', 'Var', (166, 175))	('cancers', 'Disease', 'MESH:D009369', (84, 91))	('cancers', 'Phenotype', 'HP:0002664', (84, 91))	('cancers', 'Disease', (105, 112))	('cancers', 'Disease', 'MESH:D009369', (105, 112))	('cancers', 'Disease', (84, 91))	('DNA methylation', 'MPA', (59, 74))	('patients', 'Species', '9606', (147, 155))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('NSD1', 'Gene', (37, 41))	('mutations', 'Var', (42, 51))	('affect', 'Reg', (52, 58))
513025	29213088	LUSC was the only of these cancers in which NSD1 mutations were significantly associated with DNA hypomethylation (p = 0.001) (Supplementary Figure 2).	('NSD1', 'Gene', (44, 48))	('associated', 'Reg', (78, 88))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('mutations', 'Var', (49, 58))	('LUSC', 'Phenotype', 'HP:0030359', (0, 4))	('LUSC', 'Disease', (0, 4))	('cancers', 'Phenotype', 'HP:0002664', (27, 34))	('cancers', 'Disease', 'MESH:D009369', (27, 34))	('DNA hypomethylation', 'MPA', (94, 113))	('cancers', 'Disease', (27, 34))
513027	29213088	This subtype included six of ten LUSC patients with NSD1 mutations, representing 17% of patients in this subtype (p = 0.005).	('patients', 'Species', '9606', (88, 96))	('NSD1', 'Gene', (52, 56))	('LUSC', 'Phenotype', 'HP:0030359', (33, 37))	('mutations', 'Var', (57, 66))	('patients', 'Species', '9606', (38, 46))
513028	29213088	This subtype was also enriched for NSD1 deletions, as 88/104 (84%) of patients within this subtype had deletions compared with 31-74% patients within other subtypes (p = 0.001).	('patients', 'Species', '9606', (70, 78))	('deletions', 'Var', (40, 49))	('patients', 'Species', '9606', (134, 142))	('deletions', 'Var', (103, 112))	('NSD1', 'Gene', (35, 39))
513035	29213088	These 'highly predictive' CpGs were all highly methylated in normal adjacent tissue and specifically hypomethylated in tumors of the NSD1 subtype, and are provided in Supplementary Table 3 (lines 185-188).	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('tumors', 'Disease', 'MESH:D009369', (119, 125))	('tumors', 'Disease', (119, 125))	('hypomethylated', 'Var', (101, 115))	('NSD1', 'Disease', (133, 137))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))
513037	29213088	Both patients with NSD1 deletions were within the group predicted as the NSD1 subtype.	('NSD1', 'Gene', (19, 23))	('patients', 'Species', '9606', (5, 13))	('deletions', 'Var', (24, 33))
513041	29213088	Moreover, NSD1 subtypes featured hypomethylation and overexpression of transcription factors that are normally expressed specifically in germline tissues or during development, for example, PIWIL2 , ELF5 , TBX6  and FOXH1 .	('TBX6', 'Gene', (206, 210))	('FOXH1', 'Gene', (216, 221))	('ELF5', 'Gene', '2001', (199, 203))	('FOXH1', 'Gene', '8928', (216, 221))	('NSD1', 'Gene', (10, 14))	('overexpression', 'PosReg', (53, 67))	('PIWIL2', 'Gene', '55124', (190, 196))	('ELF5', 'Gene', (199, 203))	('PIWIL2', 'Gene', (190, 196))	('TBX6', 'Gene', '6911', (206, 210))	('hypomethylation', 'Var', (33, 48))
513045	29213088	However, of 7,038 probes hypomethylated in Sotos syndrome, 117 were hypomethylated in the HNSC NSD1 subtype, and 161 were hypomethylated in the LUSC NSD1 subtypes, with 54 hypomethylated probes within 31 unique genes overlapping between Sotos syndrome, HNSC and LUSC (p < 2.2e-16) (Supplementary Table 1).	('HNSC', 'Phenotype', 'HP:0012288', (90, 94))	('LUSC', 'Phenotype', 'HP:0030359', (262, 266))	('Sotos syndrome', 'Disease', 'MESH:D058495', (43, 57))	('HNSC', 'Phenotype', 'HP:0012288', (253, 257))	('Sotos syndrome', 'Disease', (43, 57))	('Sotos syndrome', 'Disease', 'MESH:D058495', (237, 251))	('hypomethylated', 'Var', (68, 82))	('Sotos syndrome', 'Disease', (237, 251))	('LUSC', 'Phenotype', 'HP:0030359', (144, 148))
513050	29213088	Median levels of the Sotos syndrome overlap index, but not the random overlap index, increased incrementally with and increasing number of inactivating NSD1 lesions (Mutations and deletions) in both HNSC and LUSC (Supplementary Figure 5).	('inactivating', 'NegReg', (139, 151))	('lesions', 'Var', (157, 164))	('LUSC', 'Phenotype', 'HP:0030359', (208, 212))	('NSD1', 'Gene', (152, 156))	('Sotos syndrome', 'Disease', 'MESH:D058495', (21, 35))	('HNSC', 'Phenotype', 'HP:0012288', (199, 203))	('deletions', 'Var', (180, 189))	('Sotos syndrome', 'Disease', (21, 35))
513051	29213088	To formally test effect of NSD1 inactivation on the Sotos syndrome overlap index, we combined NSD1 mutations and deletions into a single 'NSD1 lesion score' (See methods for details) and tested for a linear association between this score and the Sotos syndrome overlap index.	('tested', 'Reg', (187, 193))	('Sotos syndrome', 'Disease', 'MESH:D058495', (246, 260))	('deletions', 'Var', (113, 122))	('NSD1', 'Gene', (94, 98))	('Sotos syndrome', 'Disease', (246, 260))	('mutations', 'Var', (99, 108))	('Sotos syndrome', 'Disease', 'MESH:D058495', (52, 66))	('Sotos syndrome', 'Disease', (52, 66))
513052	29213088	The Sotos syndrome overlap index increased with increasing number of inactivating NSD1 lesions in both HNSC and LUSC (Supplementary Figure 5a), and was higher in the NSD1 DNA methylation subtype compared with other subtypes in HNSC, though not in LUSC (Supplementary 6b).	('higher', 'PosReg', (152, 158))	('Sotos syndrome', 'Disease', (4, 18))	('LUSC', 'Phenotype', 'HP:0030359', (112, 116))	('NSD1', 'Var', (166, 170))	('LUSC', 'Phenotype', 'HP:0030359', (247, 251))	('lesions', 'Var', (87, 94))	('HNSC', 'Phenotype', 'HP:0012288', (103, 107))	('Sotos syndrome', 'Disease', 'MESH:D058495', (4, 18))	('inactivating', 'NegReg', (69, 81))	('HNSC', 'Phenotype', 'HP:0012288', (227, 231))	('NSD1', 'Gene', (82, 86))
513053	29213088	Overall, this analysis indicates similarity between the hypomethylation signatures associated with NSD1 inactivation in cancer and Sotos syndrome.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('Sotos syndrome', 'Disease', (131, 145))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('inactivation', 'Var', (104, 116))	('hypomethylation', 'Var', (56, 71))	('Sotos syndrome', 'Disease', 'MESH:D058495', (131, 145))	('NSD1', 'Gene', (99, 103))
513063	29213088	Consistent with recent reports that TAMs are reprogrammed to express PD-L1, M1 macrophage levels were also specifically correlated with expression of CD274 and PDCD1LG2 (Supplementary Figure 6).	('CD274', 'Gene', '29126', (150, 155))	('expression', 'Var', (136, 146))	('CD274', 'Gene', (150, 155))	('correlated', 'Reg', (120, 130))	('PDCD1LG2', 'Gene', '80380', (160, 168))	('TAMs', 'Chemical', '-', (36, 40))	('M1 macrophage levels', 'MPA', (76, 96))	('PDCD1LG2', 'Gene', (160, 168))
513065	29213088	Using NSD1 RNA expression as a measure of NSD1 proficiency, we next validated the correlation of NSD1 expression with tumor infiltrating T cell levels in three independent primary HNSC population data sets, including the aforementioned GSE33232 data set and two additional datasets: GSE65858 (n = 253) and GSE39366 (n = 138).	('HNSC', 'Phenotype', 'HP:0012288', (180, 184))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('GSE39366', 'Var', (306, 314))	('NSD1', 'Gene', (97, 101))	('tumor', 'Disease', (118, 123))
513070	29213088	There was a significantly lower number of T cells in the NSD1 knockdown tumors compared to the control transduced tumors established from the three sets of cell lines.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumors', 'Disease', (72, 78))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('tumors', 'Disease', (114, 120))	('tumors', 'Disease', 'MESH:D009369', (114, 120))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('NSD1', 'Gene', (57, 61))	('T cells', 'CPA', (42, 49))	('lower', 'NegReg', (26, 31))	('knockdown', 'Var', (62, 71))
513071	29213088	This points to a functional role of NSD1 inactivation in the exclusion of immune cells from the tumor microenvironment and is consistent with our observations of a correlation between NSD1 expression and T cell infiltration (Fig.	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('inactivation', 'Var', (41, 53))	('tumor', 'Disease', (96, 101))	('NSD1', 'Gene', (184, 188))	('NSD1', 'Gene', (36, 40))	('T cell infiltration', 'CPA', (204, 223))	('tumor', 'Disease', 'MESH:D009369', (96, 101))
513072	29213088	3c), consistent with the reduction in the number of infiltrating T cells in NSD1 knockdown tumors.	('tumors', 'Disease', (91, 97))	('reduction', 'NegReg', (25, 34))	('tumors', 'Disease', 'MESH:D009369', (91, 97))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('NSD1', 'Gene', (76, 80))	('knockdown', 'Var', (81, 90))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))
513074	29213088	An emerging consequence of cancer DNA hypomethylation is loss of epigenetic repression of developmental or germline tissue-specific genes, pushing cells to a more stem-like transcriptional profile.	('hypomethylation', 'Var', (38, 53))	('pushing', 'PosReg', (139, 146))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('epigenetic repression', 'MPA', (65, 86))	('more', 'PosReg', (158, 162))	('loss', 'NegReg', (57, 61))	('cancer', 'Disease', (27, 33))	('cancer', 'Disease', 'MESH:D009369', (27, 33))
513075	29213088	This is apparent in NSD1-inactivated squamous cell carcinoma subtypes, where concurrent hypomethylation and overexpression of developmental transcription factors such as PIWIL2 , ELF5 , TBX6 , and FOXH1  occurs.	('ELF5', 'Gene', (179, 183))	('ELF5', 'Gene', '2001', (179, 183))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (37, 60))	('TBX6', 'Gene', (186, 190))	('NSD1-inactivated squamous cell carcinoma subtypes', 'Disease', 'MESH:D002294', (20, 69))	('PIWIL2', 'Gene', '55124', (170, 176))	('NSD1-inactivated squamous cell carcinoma subtypes', 'Disease', (20, 69))	('FOXH1', 'Gene', '8928', (197, 202))	('PIWIL2', 'Gene', (170, 176))	('overexpression', 'PosReg', (108, 122))	('hypomethylation', 'Var', (88, 103))	('FOXH1', 'Gene', (197, 202))	('TBX6', 'Gene', '6911', (186, 190))	('carcinoma', 'Phenotype', 'HP:0030731', (51, 60))
513078	29213088	NSD1 inactivation likely deregulates DNA methylation indirectly through alteration of underlying chromatin marks, as is the case of mutations in SETD2 and MLL enzymes.	('NSD1', 'Gene', (0, 4))	('alteration', 'Reg', (72, 82))	('DNA methylation', 'MPA', (37, 52))	('chromatin marks', 'MPA', (97, 112))	('MLL', 'Gene', '4297', (155, 158))	('MLL', 'Gene', (155, 158))	('SETD2', 'Gene', '29072', (145, 150))	('inactivation', 'Var', (5, 17))	('SETD2', 'Gene', (145, 150))	('deregulates', 'Reg', (25, 36))
513079	29213088	NSD1 inactivation could deregulate DNA methylation by impairing H3K36 trimethylation (H3K36me3), a mark that regulates DNA methylation, as H3K36me1 and H3K36me2, the presumed methyltransferase products of NSD1, represent substrates for conversion to H3K36me3 by SETD2.	('NSD1', 'Gene', (0, 4))	('SETD2', 'Gene', (262, 267))	('deregulate', 'Reg', (24, 34))	('impairing', 'NegReg', (54, 63))	('H3K36', 'Protein', (64, 69))	('SETD2', 'Gene', '29072', (262, 267))	('DNA methylation', 'MPA', (35, 50))	('inactivation', 'Var', (5, 17))	('H3K36me2', 'Protein', (152, 160))
513080	29213088	Interestingly, SETD2 mutations, resulting in redistribution of H3K36me3, cause DNA hypermethylation at gene bodies in renal cell carcinoma, contrasting with widespread promoter hypomethylation in NSD1-inactivated cancers.	('SETD2', 'Gene', '29072', (15, 20))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('renal cell carcinoma', 'Disease', (118, 138))	('redistribution', 'PosReg', (45, 59))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (118, 138))	('SETD2', 'Gene', (15, 20))	('NSD1-inactivated cancers', 'Disease', (196, 220))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (118, 138))	('cancers', 'Phenotype', 'HP:0002664', (213, 220))	('DNA hypermethylation', 'MPA', (79, 99))	('H3K36me3', 'Protein', (63, 71))	('NSD1-inactivated cancers', 'Disease', 'MESH:D009369', (196, 220))	('cause', 'Reg', (73, 78))	('mutations', 'Var', (21, 30))
513082	29213088	Our analysis revealed a particularly striking correlation of the NSD1 subtypes between these two tumor types, postulating NSD1 inactivation as a driver of this novel molecular pan-cancer group.	('NSD1', 'Gene', (122, 126))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('inactivation', 'Var', (127, 139))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('tumor', 'Disease', (97, 102))	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('cancer', 'Disease', (180, 186))
513083	29213088	NSD1 genetic lesions represent one mechanism underlying impaired H3K36me; however, other mechanisms, such as H3K36 M mutations or those that impair NSD1 at the protein level, may account for H3K36me loss within the NSD1 wild type cancers within these subtypes.	('H3K36 M', 'Gene', (109, 116))	('mutations', 'Var', (117, 126))	('type cancers', 'Disease', 'MESH:D009369', (225, 237))	('lesions', 'Var', (13, 20))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('cancers', 'Phenotype', 'HP:0002664', (230, 237))	('type cancers', 'Disease', (225, 237))	('H3K36me', 'Var', (191, 198))	('loss', 'NegReg', (199, 203))
513090	29213088	We have found intriguing evidence that NSD1 inactivation promotes immune evasion by the exclusion of immune cell infiltration into the tumor microenvironment.	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('tumor', 'Disease', (135, 140))	('tumor', 'Disease', 'MESH:D009369', (135, 140))	('immune evasion', 'MPA', (66, 80))	('inactivation', 'Var', (44, 56))	('NSD1', 'Gene', (39, 43))	('promotes', 'PosReg', (57, 65))
513091	29213088	Using an in vivo model, we observed that the knockdown of NSD1 expression in HNSC tumors established in mice confers a decreased infiltration of CD8+ T cells compared to control tumors established in the same animals.	('decreased', 'NegReg', (119, 128))	('tumors', 'Disease', (82, 88))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('NSD1', 'Gene', (58, 62))	('tumors', 'Disease', (178, 184))	('tumors', 'Disease', 'MESH:D009369', (178, 184))	('HNSC tumors', 'Disease', 'MESH:D009369', (77, 88))	('tumors', 'Phenotype', 'HP:0002664', (178, 184))	('mice', 'Species', '10090', (104, 108))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('HNSC', 'Phenotype', 'HP:0012288', (77, 81))	('CD8', 'Gene', (145, 148))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('CD8', 'Gene', '925', (145, 148))	('HNSC tumors', 'Disease', (77, 88))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('knockdown', 'Var', (45, 54))
513093	29213088	Moreover, PRC2 mediated epigenetic silencing or chemokines, associated with concordant promoter H3K27me3 and DNA hypermethylation, precludes T cell infiltration in ovarian cancer.	('PRC2', 'Gene', (10, 14))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('precludes', 'NegReg', (131, 140))	('epigenetic silencing', 'Var', (24, 44))	('ovarian cancer', 'Phenotype', 'HP:0100615', (164, 178))	('ovarian cancer', 'Disease', 'MESH:D010051', (164, 178))	('T cell infiltration', 'CPA', (141, 160))	('ovarian cancer', 'Disease', (164, 178))
513094	29213088	There was a significant reduction in the expression of several key chemokines associated with knocking down NSD1 in HNSC cell lines, indicating that NSD1 contributes to the regulated expression of these genes in the tumor cells.	('tumor', 'Disease', (216, 221))	('expression of several key chemokines', 'MPA', (41, 77))	('NSD1', 'Gene', (108, 112))	('knocking down', 'Var', (94, 107))	('HNSC', 'Phenotype', 'HP:0012288', (116, 120))	('tumor', 'Disease', 'MESH:D009369', (216, 221))	('reduction', 'NegReg', (24, 33))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))
513100	29213088	MethylMix (Version 1.6.0) was applied to CpG cluster data to systematically identify regional CpG clusters that are abnormally methylated in cancer versus normal tissue, where DNA methylation is inversely associated with RNA expression of the corresponding gene, using beta-mixture models, as previously described.	('associated', 'Interaction', (205, 215))	('RNA expression', 'MPA', (221, 235))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('methylation', 'Var', (180, 191))	('cancer', 'Disease', (141, 147))
513115	29213088	the CpG probes within all hypomethylated genes (Genes with a hypomethylated tumor state, identified by MethylMix).	('probes', 'Var', (8, 14))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('CpG', 'Var', (4, 7))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
513119	29213088	Only patients for with estimation p-values less than 0.05 (n = 309 of 520 patients with RNA expression data), indicating high confidence TAL estimation, were included in downstream analyses.	('TAL', 'Gene', '6888', (137, 140))	('patients', 'Species', '9606', (5, 13))	('TAL', 'Gene', (137, 140))	('patients', 'Species', '9606', (74, 82))	('p-values', 'Var', (34, 42))
513149	29213088	Code used for analyses associated with this report are available as R scripts at: https://github.com/kevinbrennan/NSD1_10032017/blob/master/Code_Github_NSD1_paper.R  K.B., O.G., J.H.S., and J.B.S.	('O.G.', 'Disease', (172, 176))	('J.H.S.', 'Disease', (178, 184))	('J.H.S', 'CellLine', 'CVCL:M891', (178, 183))	('K.B.', 'Var', (166, 170))
513150	29213088	K.B., J.H.S., O.G., and J.B.S.	('J.B.S', 'Var', (24, 29))	('J.H.S.', 'Disease', (6, 12))	('J.H.S', 'CellLine', 'CVCL:M891', (6, 11))
513154	25180912	Several recent studies suggest that the leucine-rich repeats and immunoglobulin-like domains (LRIG) genes, transcripts, and proteins have prognostic implications in various cancer types.	('leucine-rich repeats', 'Var', (40, 60))	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('cancer', 'Disease', (173, 179))
513160	25180912	In early stage breast cancer, LRIG1 copy number was recently shown to predict early and late relapse in addition to overall survival; in nasopharyngeal carcinoma, loss of LRIG1 is also associated with poor survival.	('carcinoma', 'Phenotype', 'HP:0030731', (152, 161))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (137, 161))	('loss', 'Var', (163, 167))	('LRIG1', 'Protein', (171, 176))	('breast cancer', 'Disease', 'MESH:D001943', (15, 28))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('nasopharyngeal carcinoma', 'Disease', 'MESH:D000077274', (137, 161))	('breast cancer', 'Disease', (15, 28))	('breast cancer', 'Phenotype', 'HP:0003002', (15, 28))	('nasopharyngeal carcinoma', 'Disease', (137, 161))
513183	25180912	Furthermore, LRIG1 also appears to be able to regulate cytokine and bone morphogenetic protein (BMP) signaling; Lrig1-deficient cells show an increased responsiveness to interleukin-6, and SMA-10/LRIG mutant nematodes show impaired BMP signaling.	('BMP', 'Gene', (96, 99))	('increased', 'PosReg', (142, 151))	('BMP', 'Gene', '649', (232, 235))	('bone morphogenetic protein', 'Gene', (68, 94))	('bone morphogenetic protein', 'Gene', '649', (68, 94))	('mutant', 'Var', (201, 207))	('BMP', 'Gene', (232, 235))	('interleukin-6', 'Gene', (170, 183))	('BMP', 'Gene', '649', (96, 99))	('interleukin-6', 'Gene', '3569', (170, 183))	('Lrig1-deficient', 'Gene', (112, 127))	('increased responsiveness to interleukin-6', 'Phenotype', 'HP:0030783', (142, 183))	('impaired', 'NegReg', (223, 231))
513188	25180912	Recently, it was found that a subgroup of individuals with urofacial syndrome carries mutations in LRIG2.	('urofacial syndrome', 'Disease', 'MESH:C536480', (59, 77))	('mutations', 'Var', (86, 95))	('LRIG2', 'Gene', (99, 104))	('urofacial syndrome', 'Disease', (59, 77))
513193	25180912	In the amphibian Xenopus laevis, LRIG3 inhibits fibroblast growth factor (FGF) signaling.	('inhibits', 'NegReg', (39, 47))	('Xenopus laevis', 'Species', '8355', (17, 31))	('LRIG3', 'Var', (33, 38))
513209	25180912	In particular, dysregulated LRIG expression was found in cancers of the bladder, breast, uterine cervix, colorectum, head-and-neck, hematopoietic system, ovary, and prostate and also in glioma (Figure 1).	('glioma', 'Disease', (186, 192))	('LRIG expression', 'Protein', (28, 43))	('cancers of the bladder', 'Disease', 'MESH:D001749', (57, 79))	('head-and-neck', 'Disease', (117, 130))	('hematopoietic system', 'Disease', (132, 152))	('cancers', 'Phenotype', 'HP:0002664', (57, 64))	('uterine cervix', 'Disease', (89, 103))	('glioma', 'Disease', 'MESH:D005910', (186, 192))	('prostate', 'Disease', (165, 173))	('ovary', 'Disease', (154, 159))	('glioma', 'Phenotype', 'HP:0009733', (186, 192))	('dysregulated', 'Var', (15, 27))	('cancers of the bladder', 'Phenotype', 'HP:0009725', (57, 79))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('uterine cervix', 'Phenotype', 'HP:0030160', (89, 103))	('colorectum', 'Disease', (105, 115))	('breast', 'Disease', (81, 87))	('cancers of the bladder', 'Disease', (57, 79))
513211	25180912	The biological interpretation of dysregulated LRIG expression in cancer tissues is, however, complicated by the fact that expression is physiologically regulated and may be selected for (or against) during tumor evolution.	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('tumor', 'Disease', (206, 211))	('tumor', 'Disease', 'MESH:D009369', (206, 211))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('dysregulated', 'Var', (33, 45))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('LRIG', 'Protein', (46, 50))
513216	25180912	A recent study of gene copy number variation in 971 stage I/II breast tumors revealed that loss of the LRIG1 locus is an independent risk factor for early and late relapse and for death.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('II breast tumors', 'Disease', (60, 76))	('breast tumors', 'Phenotype', 'HP:0100013', (63, 76))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('II breast tumors', 'Disease', 'MESH:D001943', (60, 76))	('death', 'Disease', 'MESH:D003643', (180, 185))	('death', 'Disease', (180, 185))	('loss', 'Var', (91, 95))	('LRIG1', 'Gene', (103, 108))
513223	25180912	When low expression of LRIG1 and high expression of LRIG2 were combined, a subgroup of patients with a very poor prognosis was identified, which suggests that LRIG1 and LRIG2 could be useful prognostic markers in early stage uterine squamous cell carcinoma; it also suggests that LRIG1 and LRIG2 could have different and opposing functions in which LRIG1 suppresses cancer and LRIG2 promotes cancer.	('promotes', 'PosReg', (383, 391))	('cancer', 'Phenotype', 'HP:0002664', (366, 372))	('squamous cell carcinoma', 'Disease', (233, 256))	('cancer', 'Disease', (392, 398))	('cancer', 'Disease', 'MESH:D009369', (392, 398))	('LRIG2', 'Gene', (377, 382))	('cancer', 'Disease', 'MESH:D009369', (366, 372))	('cancer', 'Disease', (366, 372))	('cancer', 'Phenotype', 'HP:0002664', (392, 398))	('carcinoma', 'Phenotype', 'HP:0030731', (247, 256))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (233, 256))	('suppresses', 'NegReg', (355, 365))	('patients', 'Species', '9606', (87, 95))	('LRIG1', 'Var', (349, 354))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (233, 256))
513242	25180912	The finding that LRIG2 expression was associated with poor oligodendroglioma patient survival was further corroborated in an experimental study showing a correlation between Lrig2 gene dosage and the incidence and malignancy of PDGFB-induced glioma.	('glioma', 'Disease', (70, 76))	('LRIG2', 'Gene', (17, 22))	('associated', 'Reg', (38, 48))	('PDGFB', 'Gene', '5155', (228, 233))	('men', 'Species', '9606', (131, 134))	('glioma', 'Disease', 'MESH:D005910', (70, 76))	('Lrig2', 'Gene', (174, 179))	('glioma', 'Disease', (242, 248))	('expression', 'Var', (23, 33))	('malignancy', 'Disease', 'MESH:D009369', (214, 224))	('oligodendroglioma', 'Disease', 'MESH:D009837', (59, 76))	('glioma', 'Phenotype', 'HP:0009733', (70, 76))	('PDGFB', 'Gene', (228, 233))	('glioma', 'Disease', 'MESH:D005910', (242, 248))	('glioma', 'Phenotype', 'HP:0009733', (242, 248))	('patient', 'Species', '9606', (77, 84))	('malignancy', 'Disease', (214, 224))	('oligodendroglioma', 'Disease', (59, 76))
513243	25180912	Thus, in both cervical and oligodendroglial cancer, expression of LRIG2 predicts poor survival, emphasizing that the function of LRIG2 may be different from that of LRIG1.	('oligodendroglial cancer', 'Disease', 'MESH:D009369', (27, 50))	('oligodendroglial cancer', 'Disease', (27, 50))	('LRIG2', 'Gene', (66, 71))	('cervical', 'Disease', (14, 22))	('poor', 'NegReg', (81, 85))	('expression', 'Var', (52, 62))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
513246	25180912	In an immunohistochemical analysis of 347 non-small cell lung cancer cases, Kvarnbrink and co-workers found that high expression of LRIG1 was an independent prognostic factor that was correlated with good survival, particularly among patients with lung adenocarcinoma (Kvarnbrink et al., unpublished observation).	('high expression', 'Var', (113, 128))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (42, 68))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('lung cancer', 'Phenotype', 'HP:0100526', (57, 68))	('lung adenocarcinoma', 'Disease', (248, 267))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (46, 68))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (42, 68))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (248, 267))	('LRIG1', 'Gene', (132, 137))	('carcinoma', 'Phenotype', 'HP:0030731', (258, 267))	('patients', 'Species', '9606', (234, 242))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (248, 267))	('non-small cell lung cancer', 'Disease', (42, 68))	('correlated with', 'Reg', (184, 199))
513247	25180912	Intriguingly, in lung squamous cell carcinoma, expression of LRIG1 was not associated with survival if only the neoplastic cells were analyzed, whereas if the stromal and immune cells were also included in the analysis, high LRIG1 expression was correlated with a better survival.	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (17, 45))	('lung squamous cell carcinoma', 'Disease', (17, 45))	('LRIG1', 'Gene', (225, 230))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (22, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (36, 45))	('high', 'Var', (220, 224))	('LRIG1', 'Gene', (61, 66))	('better', 'PosReg', (264, 270))	('expression', 'MPA', (231, 241))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (17, 45))
513248	25180912	In the Oncomine database, which includes composite gene expression profiles of all cell types included in the respective tumor specimens, the expression of LRIG1 mRNA was associated with good survival in both lung adenocarcinoma and lung squamous cell carcinoma.	('expression', 'Var', (142, 152))	('Oncomine', 'Chemical', '-', (7, 15))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (209, 228))	('associated with', 'Reg', (171, 186))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (238, 261))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (233, 261))	('tumor', 'Disease', (121, 126))	('men', 'Species', '9606', (132, 135))	('carcinoma', 'Phenotype', 'HP:0030731', (252, 261))	('LRIG1', 'Gene', (156, 161))	('carcinoma', 'Phenotype', 'HP:0030731', (219, 228))	('lung adenocarcinoma and lung squamous cell carcinoma', 'Disease', 'MESH:D000077192', (209, 261))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
513254	25180912	In the Swedish cohort, the patients were followed via watchful waiting, and high expression of LRIG1 was an independent prognostic factor that was associated with worse overall and disease-specific survival.	('disease-specific survival', 'CPA', (181, 206))	('patients', 'Species', '9606', (27, 35))	('worse', 'NegReg', (163, 168))	('high expression', 'Var', (76, 91))	('LRIG1', 'Protein', (95, 100))
513255	25180912	The American cohort included patients who had undergone prostatectomy; in this group, the expression of LRIG1 was a positive prognostic factor for overall survival.	('overall', 'MPA', (147, 154))	('LRIG1', 'Protein', (104, 109))	('expression', 'Var', (90, 100))	('patients', 'Species', '9606', (29, 37))
513270	25180912	In a meta-analysis of gene expression and patient outcome in nine studies of breast, lung, and bladder cancer, glioma and melanoma, LRIG1 was identified as one of the four top genes that predicted survival across all of the data sets (the other genes were, KIF4A, HJURP, and ESPL1); the high expression of LRIG1 was associated with a better prognosis for these patients.	('KIF4A', 'Gene', '24137', (257, 262))	('patient', 'Species', '9606', (42, 49))	('high expression', 'Var', (287, 302))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('bladder cancer', 'Disease', 'MESH:D001749', (95, 109))	('bladder cancer', 'Disease', (95, 109))	('melanoma', 'Disease', 'MESH:D008545', (122, 130))	('bladder cancer', 'Phenotype', 'HP:0009725', (95, 109))	('HJURP', 'Gene', '55355', (264, 269))	('glioma', 'Disease', (111, 117))	('KIF4A', 'Gene', (257, 262))	('patients', 'Species', '9606', (361, 369))	('LRIG1', 'Gene', (306, 311))	('glioma', 'Disease', 'MESH:D005910', (111, 117))	('ESPL1', 'Gene', '9700', (275, 280))	('HJURP', 'Gene', (264, 269))	('glioma', 'Phenotype', 'HP:0009733', (111, 117))	('ESPL1', 'Gene', (275, 280))	('melanoma', 'Phenotype', 'HP:0002861', (122, 130))	('melanoma', 'Disease', (122, 130))	('patient', 'Species', '9606', (361, 368))
513274	25180912	Consistent with this finding, ectopic expression of LRIG1 increases the sensitivity of bladder cancer cells to cisplatin and of glioblastoma cells to cisplatin and temozolomide.	('cisplatin', 'Chemical', 'MESH:D002945', (150, 159))	('increases', 'PosReg', (58, 67))	('LRIG1', 'Gene', (52, 57))	('cisplatin', 'Chemical', 'MESH:D002945', (111, 120))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('temozolomide', 'Chemical', 'MESH:D000077204', (164, 176))	('sensitivity', 'MPA', (72, 83))	('bladder cancer', 'Phenotype', 'HP:0009725', (87, 101))	('ectopic expression', 'Var', (30, 48))	('bladder cancer', 'Disease', 'MESH:D001749', (87, 101))	('glioblastoma', 'Disease', (128, 140))	('glioblastoma', 'Disease', 'MESH:D005909', (128, 140))	('bladder cancer', 'Disease', (87, 101))	('glioblastoma', 'Phenotype', 'HP:0012174', (128, 140))
513309	24562618	PPS may be one of the factors reducing the OS benefit, but little is known regarding what factors other than PPS affect the association between OS and PFS.	('PPS', 'Chemical', '-', (109, 112))	('PPS', 'Var', (0, 3))	('association', 'Interaction', (124, 135))	('PPS', 'Chemical', '-', (0, 3))	('OS', 'Chemical', '-', (43, 45))	('OS', 'Chemical', '-', (144, 146))	('PFS', 'Disease', (151, 154))
513382	31827079	We can also predict many other key phenotypes, including intrinsic molecular subtypes, estrogen receptor status, and TP53 mutation.	('estrogen receptor', 'Gene', (87, 104))	('TP53', 'Gene', '7157', (117, 121))	('mutation', 'Var', (122, 130))	('estrogen receptor', 'Gene', '2099', (87, 104))	('TP53', 'Gene', (117, 121))
513395	31827079	We applied a panel of 543 published gene expression signatures measuring diverse tumor phenotypes including active signaling pathways, the aforementioned known prognostic clinical models, tumor microenvironment features (i.e., immune cells, fibroblasts), and features of DNA amplicons and deletions, onto 1038 breast cancers from the TCGA breast cancer project (Supplementary Fig.	('tumor', 'Disease', (188, 193))	('breast cancer', 'Disease', 'MESH:D001943', (339, 352))	('breast cancer', 'Disease', (339, 352))	('breast cancer', 'Phenotype', 'HP:0003002', (339, 352))	('breast cancers', 'Phenotype', 'HP:0003002', (310, 324))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('breast cancer', 'Phenotype', 'HP:0003002', (310, 323))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('breast cancers', 'Disease', 'MESH:D001943', (310, 324))	('breast cancers', 'Disease', (310, 324))	('breast cancer', 'Disease', 'MESH:D001943', (310, 323))	('cancer', 'Phenotype', 'HP:0002664', (317, 323))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('cancers', 'Phenotype', 'HP:0002664', (317, 324))	('cancer', 'Phenotype', 'HP:0002664', (346, 352))	('deletions', 'Var', (289, 298))	('tumor', 'Disease', (81, 86))
513402	31827079	For estrogen signaling signature, we identified many distinct luminal tumor DNA copy number changes including 16p gain and 16q loss (Fig.	('luminal', 'Chemical', 'MESH:D010634', (62, 69))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('16p', 'Var', (110, 113))	('16q', 'Var', (123, 126))	('tumor', 'Disease', (70, 75))	('gain', 'PosReg', (114, 118))	('loss', 'NegReg', (127, 131))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
513425	31827079	A distinct difference between these two subtypes is proliferation rate where Luminal B tumors generally have higher proliferation rate than Luminal A tumors; as might be expected, regions related to proliferation including 8q(MYC) amplification and RB1 deletion were only present in the Luminal B prediction model (Supplementary Fig.	('tumors', 'Disease', (150, 156))	('MYC', 'Gene', (226, 229))	('tumors', 'Disease', 'MESH:D009369', (150, 156))	('Luminal', 'Chemical', 'MESH:D010634', (287, 294))	('tumors', 'Phenotype', 'HP:0002664', (150, 156))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('Luminal', 'Chemical', 'MESH:D010634', (140, 147))	('deletion', 'Var', (253, 261))	('higher', 'PosReg', (109, 115))	('RB1', 'Gene', (249, 252))	('tumors', 'Disease', (87, 93))	('MYC', 'Gene', '4609', (226, 229))	('tumors', 'Phenotype', 'HP:0002664', (87, 93))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('proliferation rate', 'CPA', (116, 134))	('RB1', 'Gene', '5925', (249, 252))	('tumors', 'Disease', 'MESH:D009369', (87, 93))	('Luminal', 'Chemical', 'MESH:D010634', (77, 84))
513457	31827079	Not surprisingly, most of these signatures were amplicon signatures, however, two were related to TP53 mutation status and PTEN/PI3K pathway activity.	('PTEN', 'Gene', (123, 127))	('TP53', 'Gene', '7157', (98, 102))	('TP53', 'Gene', (98, 102))	('related', 'Reg', (87, 94))	('PTEN', 'Gene', '5728', (123, 127))	('mutation', 'Var', (103, 111))
513467	31827079	Lastly, amplicon signatures were universally predictable across tumor types that have high percentage of copy number altered genes.	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('copy number altered genes', 'Var', (105, 130))	('tumor', 'Disease', (64, 69))	('tumor', 'Disease', 'MESH:D009369', (64, 69))
513488	31827079	Consistent with our hypothesis, a variety of gene signatures besides amplicon signatures were predictable in tumor types that have many copy number changes.	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('copy', 'Var', (136, 140))	('tumor', 'Disease', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))
513510	31827079	For molecular subtype, clinical receptor status, cancer histology, and mutations that had binary outcomes, models were built to classify each outcome.	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('mutations', 'Var', (71, 80))	('cancer', 'Disease', (49, 55))	('cancer', 'Disease', 'MESH:D009369', (49, 55))
513519	31827079	Tumor labels were permuted 100 times for 16 representative phenotypes, namely RB-LOH signature, Basal signaling signature, estrogen signaling signature, HER1-C2 signature, ER/PR/HER2 IHC status, TP53 mutation, tumor mutation load and intrinsic molecular subtypes.	('PR', 'Gene', '5241', (175, 177))	('HER1', 'Gene', (153, 157))	('ER', 'Gene', '2099', (172, 174))	('ER', 'Gene', '2099', (179, 181))	('TP53', 'Gene', (195, 199))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (210, 215))	('HER2', 'Gene', '2064', (178, 182))	('RB-LOH', 'Chemical', '-', (78, 84))	('estrogen signaling', 'MPA', (123, 141))	('tumor', 'Disease', (210, 215))	('Basal signaling', 'MPA', (96, 111))	('HER1', 'Gene', '1956', (153, 157))	('HER2', 'Gene', (178, 182))	('TP53', 'Gene', '7157', (195, 199))	('ER', 'Gene', '2099', (154, 156))	('mutation', 'Var', (200, 208))	('tumor', 'Disease', 'MESH:D009369', (210, 215))
513534	31027181	Most lung adenocarcinomas harbor mutations in KRAS gene (32%) and epidermal growth factor receptor (EGFR) (11%), resulting in overactivation of the RAS-RAF-MEK-ERK pathway.	('EGFR', 'Gene', '1956', (100, 104))	('overactivation', 'PosReg', (126, 140))	('ERK', 'Gene', '5594', (160, 163))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (5, 24))	('carcinomas', 'Phenotype', 'HP:0030731', (15, 25))	('epidermal growth factor receptor', 'Gene', (66, 98))	('KRAS', 'Gene', (46, 50))	('EGFR', 'Gene', (100, 104))	('lung adenocarcinomas', 'Disease', (5, 25))	('mutations', 'Var', (33, 42))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (5, 25))	('ERK', 'Gene', (160, 163))	('KRAS', 'Gene', '3845', (46, 50))	('carcinoma', 'Phenotype', 'HP:0030731', (15, 24))	('epidermal growth factor receptor', 'Gene', '1956', (66, 98))
513575	31027181	Based on the changes of cell morphology and lack of anchorage, we compared gene expression profiles between DUSP6 silenced and control in H460 (NSCLC) cells by RNA sequencing.	('NSCLC', 'Disease', (144, 149))	('DUSP6', 'Gene', (108, 113))	('NSCLC', 'Disease', 'MESH:D002289', (144, 149))	('silenced', 'Var', (114, 122))	('DUSP6', 'Gene', '1848', (108, 113))
513578	31027181	Several of the regulatory pathways differentially regulated upon DUSP6 silencing were involved in cell-cell and cell-substrate adhesion, belonging to the focal and integrin-mediated adhesion gene family and actin cytoskeleton regulation (Figure 3B), in agreement with the observed increased motility in silenced cells (Figure 2B).	('DUSP6', 'Gene', '1848', (65, 70))	('silencing', 'Var', (71, 80))	('involved', 'Reg', (86, 94))	('rat', 'Species', '10116', (122, 125))	('DUSP6', 'Gene', (65, 70))
513594	31027181	Then, after serum depletion of H460shDUSP6 we seeded them in the plates that contained an extracellular matrix layer from H460, H460ns and H460shDUSP6 cells.	('H460shDUSP6', 'Gene', '1848', (31, 42))	('H460ns', 'Var', (128, 134))	('H460shDUSP6', 'Gene', (31, 42))	('H460shDUSP6', 'Gene', '1848', (139, 150))	('H460shDUSP6', 'Gene', (139, 150))
513602	31027181	Activation of EGFR is statistically significant and relevant after silencing of DUSP6 gene expression in NSCLC cells.	('NSCLC', 'Disease', 'MESH:D002289', (105, 110))	('EGFR', 'Gene', '1956', (14, 18))	('EGFR', 'Gene', (14, 18))	('DUSP6', 'Gene', (80, 85))	('DUSP6', 'Gene', '1848', (80, 85))	('silencing', 'Var', (67, 76))	('NSCLC', 'Disease', (105, 110))
513619	31027181	It has been published, that in LUAD, 15-20% mutations belonged to the EGFR pathway where DUSP6 plays an active role.	('belonged', 'Reg', (54, 62))	('EGFR', 'Gene', '1956', (70, 74))	('DUSP6', 'Gene', '1848', (89, 94))	('EGFR', 'Gene', (70, 74))	('mutations', 'Var', (44, 53))	('DUSP6', 'Gene', (89, 94))
513620	31027181	On the contrary in the carcinogenesis pathways implicated in LUSC, mutations occur in the cell cycle, p53 and the PI3K-Akt signaling pathway.	('occur', 'Reg', (77, 82))	('p53', 'Gene', '7157', (102, 105))	('PI3K-Akt signaling pathway', 'Pathway', (114, 140))	('mutations', 'Var', (67, 76))	('cell', 'Pathway', (90, 94))	('p53', 'Gene', (102, 105))
513633	31027181	CCND2 gene has been shown to be targeted by expression of mir-4317 and miR-671-3p and related to inhibition of cancer progression in NSCLC.	('mir-4317', 'Gene', '100422840', (58, 66))	('mir-4317', 'Gene', (58, 66))	('inhibition', 'NegReg', (97, 107))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('CCND2', 'Gene', (0, 5))	('NSCLC', 'Disease', (133, 138))	('miR-671-3p', 'Var', (71, 81))	('cancer', 'Disease', (111, 117))	('CCND2', 'Gene', '894', (0, 5))	('NSCLC', 'Disease', 'MESH:D002289', (133, 138))
513652	31027181	In contrast by the role of DUSP6 as a tumor suppressor that we describe here pharmacological inhibition of DUSP6, suppresses gastric cancer growth and metastasis and overcomes cisplatin resistance.	('gastric cancer', 'Disease', 'MESH:D013274', (125, 139))	('tumor', 'Disease', (38, 43))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('DUSP6', 'Gene', (107, 112))	('DUSP6', 'Gene', '1848', (107, 112))	('DUSP6', 'Gene', '1848', (27, 32))	('overcomes', 'NegReg', (166, 175))	('cisplatin', 'Chemical', 'MESH:D002945', (176, 185))	('gastric cancer', 'Phenotype', 'HP:0012126', (125, 139))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('cisplatin resistance', 'MPA', (176, 196))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('gastric cancer', 'Disease', (125, 139))	('suppresses', 'NegReg', (114, 124))	('DUSP6', 'Gene', (27, 32))	('inhibition', 'Var', (93, 103))
513660	31027181	GPZ Lentiviral vectors containing shRNAmir for human DUSP6 (RHS4430-99889522 and RHS4430-101132249) were purchased from Open Biosystems.	('DUSP6', 'Gene', (53, 58))	('RHS4430-99889522', 'Var', (60, 76))	('DUSP6', 'Gene', '1848', (53, 58))	('human', 'Species', '9606', (47, 52))	('RHS4430-101132249', 'Var', (81, 98))
513673	31027181	Primers used for amplification of the eight selected genes were purchased from Applied Biosystems as Taqman Gene Expression Assays as follows, Assay ID: DUSP6 Hs00737962m1, CCND2 Hs00153380_m1, COL3A1 Hs00943809_m1, FYN Hs00176628_m1, RUNX2 Hs01047973_m1, TNC Hs01115665_m1, BMP4 Hs03676628_s1, CAPN6 Hs00560073_m1, VAV3 Hs00916818_m1 and beta-ACTIN Hs01060665_g1.	('Hs01060665_g1', 'Var', (350, 363))	('VAV3', 'Gene', (316, 320))	('Hs01115665_m1', 'Var', (260, 273))	('Hs00560073_m1', 'Var', (301, 314))	('FYN', 'Gene', '2534', (216, 219))	('BMP4', 'Gene', '652', (275, 279))	('CAPN6', 'Gene', (295, 300))	('beta-ACTIN', 'Gene', '728378', (339, 349))	('CAPN6', 'Gene', '827', (295, 300))	('DUSP6', 'Gene', '1848', (153, 158))	('VAV3', 'Gene', '10451', (316, 320))	('beta-ACTIN', 'Gene', (339, 349))	('COL3A1', 'Gene', '1281', (194, 200))	('Hs03676628_s1', 'Var', (280, 293))	('DUSP6', 'Gene', (153, 158))	('Hs00916818_m1', 'Var', (321, 334))	('FYN', 'Gene', (216, 219))	('RUNX2', 'Gene', (235, 240))	('TNC', 'Gene', (256, 259))	('Hs00153380_m1', 'Var', (179, 192))	('CCND2', 'Gene', (173, 178))	('Hs00943809_m1', 'Var', (201, 214))	('RUNX2', 'Gene', '860', (235, 240))	('BMP4', 'Gene', (275, 279))	('CCND2', 'Gene', '894', (173, 178))	('TNC', 'Gene', '3371', (256, 259))	('COL3A1', 'Gene', (194, 200))
513686	31027181	The primary antibody was then added to the blocking buffer and the cells incubated overnight at 4  C. Primary antibodies: Mouse anti-gamma-catenin (610254, BD Transduction), mouse anti-p120 (P17920, BD Biosciences), mouse anti-alpha-tubulin (T9026, Sigma-Aldrich), and E-cadherin (ECCD2, Zymed laboratories).	('E-cadherin', 'Gene', '999', (269, 279))	('mouse', 'Species', '10090', (174, 179))	('mouse', 'Species', '10090', (216, 221))	('p120', 'Gene', '1500', (185, 189))	('rat', 'Species', '10116', (298, 301))	('T9026', 'CellLine', 'CVCL:3174', (242, 247))	('Mouse', 'Species', '10090', (122, 127))	('610254', 'Var', (148, 154))	('p120', 'Gene', (185, 189))	('E-cadherin', 'Gene', (269, 279))
513694	31027181	In order to satisfy statistical constraints, twenty-eight 6-week old mice were injected subcutaneously with one million H460ns or H460shDUSP6 cells embedded in matrigel in each flank.	('H460shDUSP6', 'Gene', (130, 141))	('mice', 'Species', '10090', (69, 73))	('H460ns', 'Var', (120, 126))	('H460shDUSP6', 'Gene', '1848', (130, 141))
513703	31027181	This work has been supported by PI17-01401 and PI18/00050 (Fondo de Investigaciones Sanitarias, Instituto de Salud Carlos III, Spain supported by FEDER funds), SAF2017-84183-R from the Spanish Ministry of Science, Innovation and Universities and Miguel Servet financial grant to Ibanez de Caceres, I (PI-717).	('PI18/00050', 'Var', (47, 57))	('PI17-01401', 'Var', (32, 42))	('SAF', 'Gene', (160, 163))	('Sanitarias', 'Disease', 'None', (84, 94))	('SAF', 'Gene', '100302740', (160, 163))	('Sanitarias', 'Disease', (84, 94))
513705	28881841	Efficacy of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) in targeted therapy of lung squamous cell carcinoma patients with EGFR mutation: a pooled analysis This pooled analysis aims to evaluate the efficacy of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) in lung squamous cell carcinoma with EGFR mutation.	('epidermal growth factor receptor', 'Gene', '1956', (239, 271))	('EGFR', 'Gene', '1956', (46, 50))	('carcinoma', 'Phenotype', 'HP:0030731', (335, 344))	('EGFR', 'Gene', (273, 277))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (316, 344))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('epidermal growth factor receptor', 'Gene', (12, 44))	('EGFR', 'Gene', (152, 156))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (109, 137))	('patients', 'Species', '9606', (138, 146))	('epidermal growth factor receptor', 'Gene', '1956', (12, 44))	('EGFR', 'Gene', (350, 354))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (321, 344))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (316, 344))	('lung squamous cell carcinoma', 'Disease', (316, 344))	('EGFR', 'Gene', (46, 50))	('EGFR', 'Gene', '1956', (273, 277))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (109, 137))	('lung squamous cell carcinoma', 'Disease', (109, 137))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (114, 137))	('EGFR', 'Gene', '1956', (152, 156))	('EGFR', 'Gene', '1956', (350, 354))	('mutation', 'Var', (355, 363))	('epidermal growth factor receptor', 'Gene', (239, 271))
513706	28881841	Advanced stage (IIIB/IV) lung squamous cell carcinoma patients with EGFR mutations treated with EGFR-TKIs were extracted from the publications searched from the databases of EMBASE, Medline (Ovid SP), Web of Science, Cochrane library, PubMed Publisher, ASCO meeting abstract and Google Scholar before August 2016, or identified from the database of Shanghai Chest Hospital from July 2014 to August 2016.	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (25, 53))	('EGFR', 'Gene', (96, 100))	('patients', 'Species', '9606', (54, 62))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (25, 53))	('lung squamous cell carcinoma', 'Disease', (25, 53))	('EGFR', 'Gene', '1956', (68, 72))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (30, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (44, 53))	('EGFR', 'Gene', (68, 72))	('mutations', 'Var', (73, 82))	('EGFR', 'Gene', '1956', (96, 100))
513707	28881841	The combined objective response rate, disease control rate and median progression-free survival were 31.6% (95%CI, 24.1%~40.2%), 72.0% (95% CI, 63.5%~79.2%) and 3.08 months (95% CI, 2.31-3.84 months) in lung squamous cell carcinoma patients with EGFR mutation.	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (203, 231))	('patients', 'Species', '9606', (232, 240))	('mutation', 'Var', (251, 259))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (203, 231))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (208, 231))	('carcinoma', 'Phenotype', 'HP:0030731', (222, 231))	('lung squamous cell carcinoma', 'Disease', (203, 231))	('EGFR', 'Gene', '1956', (246, 250))	('EGFR', 'Gene', (246, 250))
513708	28881841	The EGFR-TKIs had a modest response for EGFR mutated lung squamous cell carcinoma patients and might be a selective option for those patients.	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (53, 81))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('lung squamous cell carcinoma', 'Disease', (53, 81))	('EGFR', 'Gene', (4, 8))	('patients', 'Species', '9606', (82, 90))	('patients', 'Species', '9606', (133, 141))	('EGFR', 'Gene', '1956', (40, 44))	('EGFR', 'Gene', (40, 44))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (53, 81))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (58, 81))	('mutated', 'Var', (45, 52))	('EGFR', 'Gene', '1956', (4, 8))
513713	28881841	In the last decade, the FDA had approved targeted agents as initial treatment for patients with NSCLC, including gefitinib, erlotinib, and afatinib for the patients with EGFR mutations.	('patients', 'Species', '9606', (156, 164))	('erlotinib', 'Chemical', 'MESH:D000069347', (124, 133))	('NSCLC', 'Disease', (96, 101))	('EGFR', 'Gene', '1956', (170, 174))	('patients', 'Species', '9606', (82, 90))	('NSCLC', 'Disease', 'MESH:D002289', (96, 101))	('EGFR', 'Gene', (170, 174))	('mutations', 'Var', (175, 184))	('afatinib', 'Chemical', 'MESH:D000077716', (139, 147))	('gefitinib', 'Chemical', 'MESH:D000077156', (113, 122))
513715	28881841	Even it has been proved that EGFR-TKIs had a better response in EGFR mutation selected lung adenocarcinoma, whether the EGFR-mutated LSCC patients can benefit more from the EGFR-TKIs remains unclear.	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('lung adenocarcinoma', 'Disease', (87, 106))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (87, 106))	('LSCC', 'Phenotype', 'HP:0030359', (133, 137))	('mutation', 'Var', (69, 77))	('EGFR', 'Gene', '1956', (173, 177))	('EGFR', 'Gene', '1956', (29, 33))	('EGFR', 'Gene', (29, 33))	('EGFR', 'Gene', '1956', (64, 68))	('EGFR', 'Gene', '1956', (120, 124))	('EGFR', 'Gene', (64, 68))	('EGFR', 'Gene', (173, 177))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (87, 106))	('patients', 'Species', '9606', (138, 146))	('EGFR', 'Gene', (120, 124))
513716	28881841	However, former pooled frequency of LSCC patients with EGFR mutations was only about 5% both in Asian and non-Asian, which made it difficult to undergo a further investigation by big scale randomized clinical trials.	('EGFR', 'Gene', '1956', (55, 59))	('LSCC', 'Phenotype', 'HP:0030359', (36, 40))	('EGFR', 'Gene', (55, 59))	('patients', 'Species', '9606', (41, 49))	('mutations', 'Var', (60, 69))	('LSCC', 'Disease', (36, 40))
513719	28881841	In this study, we performed a pooled analysis to evaluate the efficacy of EGFR-TKIs in LSCC patients with EGFR mutations.	('mutations', 'Var', (111, 120))	('patients', 'Species', '9606', (92, 100))	('LSCC', 'Disease', (87, 91))	('EGFR', 'Gene', '1956', (74, 78))	('EGFR', 'Gene', '1956', (106, 110))	('LSCC', 'Phenotype', 'HP:0030359', (87, 91))	('EGFR', 'Gene', (74, 78))	('EGFR', 'Gene', (106, 110))
513720	28881841	One hundred and ten EGFR mutated LSCC patients with grouped data in the eight studies were assigned as the first-cohort (Table 1).	('LSCC', 'Phenotype', 'HP:0030359', (33, 37))	('EGFR', 'Gene', (20, 24))	('patients', 'Species', '9606', (38, 46))	('LSCC', 'Disease', (33, 37))	('mutated', 'Var', (25, 32))	('EGFR', 'Gene', '1956', (20, 24))
513721	28881841	Another forty-four EGFR mutated LSCC patients in 24 studies with individual data and six patients from the Shanghai Chest Hospital database were allocated as the second-cohort (Supplemental Table 1).	('LSCC', 'Phenotype', 'HP:0030359', (32, 36))	('mutated', 'Var', (24, 31))	('patients', 'Species', '9606', (37, 45))	('EGFR', 'Gene', '1956', (19, 23))	('patients', 'Species', '9606', (89, 97))	('EGFR', 'Gene', (19, 23))	('LSCC', 'Disease', (32, 36))
513722	28881841	In the first-cohort, data was extracted in eight retrospective studies (Table 1), including a total of 110 LSCC patients with EGFR mutation and 428 LSCC patients with EGFR wild type.	('LSCC', 'Phenotype', 'HP:0030359', (148, 152))	('patients', 'Species', '9606', (153, 161))	('EGFR', 'Gene', (126, 130))	('patients', 'Species', '9606', (112, 120))	('EGFR', 'Gene', '1956', (126, 130))	('EGFR', 'Gene', '1956', (167, 171))	('LSCC', 'Disease', (107, 111))	('LSCC', 'Phenotype', 'HP:0030359', (107, 111))	('EGFR', 'Gene', (167, 171))	('mutation', 'Var', (131, 139))
513723	28881841	Seven studies contained LSCC patients of the EGFR mutation group and EGFR wild type group.	('EGFR', 'Gene', '1956', (69, 73))	('patients', 'Species', '9606', (29, 37))	('EGFR', 'Gene', (45, 49))	('EGFR', 'Gene', (69, 73))	('LSCC', 'Disease', (24, 28))	('LSCC', 'Phenotype', 'HP:0030359', (24, 28))	('EGFR', 'Gene', '1956', (45, 49))	('mutation', 'Var', (50, 58))
513724	28881841	In the first-cohort, six studies reported the EGFR mutation status in a total of 86 LSCC patients with EGFR mutation.	('EGFR', 'Gene', '1956', (103, 107))	('LSCC', 'Phenotype', 'HP:0030359', (84, 88))	('EGFR', 'Gene', (103, 107))	('EGFR', 'Gene', '1956', (46, 50))	('patients', 'Species', '9606', (89, 97))	('EGFR', 'Gene', (46, 50))	('mutation', 'Var', (108, 116))	('LSCC', 'Disease', (84, 88))
513727	28881841	In the second-cohort (Supplemental Table 1), there were fifty LSCC patients harboring EGFR mutations.	('patients', 'Species', '9606', (67, 75))	('EGFR', 'Gene', '1956', (86, 90))	('LSCC', 'Disease', (62, 66))	('EGFR', 'Gene', (86, 90))	('mutations', 'Var', (91, 100))	('LSCC', 'Phenotype', 'HP:0030359', (62, 66))
513730	28881841	In the second-cohort, EGFR mutation were defined as exon 19 deletion (n = 19), exon 21 L858R (n = 13), other mutation type were exon18 G719S, Y727H, L692P, E711K, A702S, G721A, exon 20 A763V, N826S, A859T, Q787Q, V843I, K860E, E709K, co-mutation of exon 18 E709K+ exon 21 L858R, exon 19 del + exon 21 L858R, exon 20 T790M + exon 21 L858R, exon 21 L838P + E868G.	('G721A', 'Mutation', 'rs1407608935', (170, 175))	('E709K+ exon', 'Var', (257, 268))	('A859T', 'Mutation', 'c.859A>T', (199, 204))	('L838P', 'Mutation', 'p.L838P', (347, 352))	('E711K', 'Mutation', 'p.E711K', (156, 161))	('A763V', 'Mutation', 'rs1476693500', (185, 190))	('E868G', 'Mutation', 'p.E868G', (355, 360))	('L838P + E868G', 'Var', (347, 360))	('L858R', 'Var', (301, 306))	('L692P', 'Mutation', 'p.L692P', (149, 154))	('Y727H', 'Var', (142, 147))	('E709K', 'Mutation', 'rs727504256', (227, 232))	('L858R', 'Mutation', 'rs121434568', (272, 277))	('K860E', 'Mutation', 'p.K860E', (220, 225))	('EGFR', 'Gene', '1956', (22, 26))	('K860E', 'Var', (220, 225))	('del +', 'Var', (287, 292))	('T790M + exon 21 L858R', 'Var', (316, 337))	('E709K', 'Mutation', 'rs727504256', (257, 262))	('A702S', 'Mutation', 'p.A702S', (163, 168))	('L692P', 'Var', (149, 154))	('L858R', 'Mutation', 'rs121434568', (87, 92))	('Y727H', 'Mutation', 'p.Y727H', (142, 147))	('G719S', 'Var', (135, 140))	('E711K', 'Var', (156, 161))	('G719S', 'Mutation', 'rs28929495', (135, 140))	('L858R', 'Mutation', 'rs121434568', (301, 306))	('V843I', 'Mutation', 'rs146795390', (213, 218))	('N826S', 'Mutation', 'p.N826S', (192, 197))	('L858R', 'Mutation', 'rs121434568', (332, 337))	('T790M', 'Mutation', 'rs121434569', (316, 321))	('Q787Q', 'Mutation', 'rs1050171', (206, 211))	('EGFR', 'Gene', (22, 26))
513732	28881841	The ORR, DCR and median PFS were 34.78% (16/46), 73.91%(34/46), 3.0 months (Figure 2, n = 30, 95% CI, 2.525-3.425 months) in LSCC patients with EGFR mutation.	('EGFR', 'Gene', (144, 148))	('patients', 'Species', '9606', (130, 138))	('LSCC', 'Disease', (125, 129))	('EGFR', 'Gene', '1956', (144, 148))	('mutation', 'Var', (149, 157))	('LSCC', 'Phenotype', 'HP:0030359', (125, 129))
513734	28881841	The combined ORR was 31.6% (n = 127, 95% CI, 24.1%~40.2%; random-effect, Q statistic = 0.513, I2 < 0.001) in LSCC with EGFR mutation versus 7.5% (n = 147, 95% CI, 4.0%~13.7%, random-effect, Q statistic = 3.533, I2 = 0.000) in LSCC with EGFR wild type.	('LSCC', 'Phenotype', 'HP:0030359', (109, 113))	('LSCC', 'Phenotype', 'HP:0030359', (226, 230))	('EGFR', 'Gene', '1956', (236, 240))	('mutation', 'Var', (124, 132))	('EGFR', 'Gene', '1956', (119, 123))	('EGFR', 'Gene', (236, 240))	('LSCC', 'Disease', (109, 113))	('EGFR', 'Gene', (119, 123))
513735	28881841	The combined DCR were 72.0% (n = 127, 95% CI, 63.5%~79.2%, random-effect, Q statistic = 2.371, I2 < 0.001) in LSCC with EGFR mutation versus 45.8% (n = 107, 95% CI, 36.6%~55.3%, random-effect, Q statistic = 1.406, I2 < 0.001) in LSCC with EGFR wild type.	('EGFR', 'Gene', (239, 243))	('LSCC', 'Phenotype', 'HP:0030359', (229, 233))	('LSCC', 'Disease', (110, 114))	('LSCC', 'Phenotype', 'HP:0030359', (110, 114))	('EGFR', 'Gene', '1956', (239, 243))	('EGFR', 'Gene', '1956', (120, 124))	('mutation', 'Var', (125, 133))	('EGFR', 'Gene', (120, 124))
513736	28881841	The combined median PFS was 3.08 months (n = 129, 95% CI, 2.31-3.84 months, random-effect, Q statistic = 5.518, I2 = 9.391) in LSCC with EGFR mutation versus 1.85 months in wild type (n = 428, 95% CI, 1.72-1.97 months, fix-effect, Q statistic = 5.393, I2 < 0.001).	('EGFR', 'Gene', (137, 141))	('LSCC', 'Disease', (127, 131))	('LSCC', 'Phenotype', 'HP:0030359', (127, 131))	('EGFR', 'Gene', '1956', (137, 141))	('mutation', 'Var', (142, 150))
513738	28881841	Then, the phase III trial Lux-Lung 8 had shown hat afatinib versus erlotinib as second-line treatment of patients with EGFR mutation unselected advanced LSCC had significant improvements in PFS.	('LSCC', 'Phenotype', 'HP:0030359', (153, 157))	('patients', 'Species', '9606', (105, 113))	('afatinib', 'Chemical', 'MESH:D000077716', (51, 59))	('erlotinib', 'Chemical', 'MESH:D000069347', (67, 76))	('EGFR', 'Gene', '1956', (119, 123))	('mutation', 'Var', (124, 132))	('improvements', 'PosReg', (174, 186))	('EGFR', 'Gene', (119, 123))	('PFS', 'MPA', (190, 193))
513739	28881841	However, these trials did not answer that whether EGFR-TKI had a better efficacy in EGFR mutated LSCC patients compared with EGFR wild LSCC patients.	('LSCC', 'Phenotype', 'HP:0030359', (135, 139))	('EGFR', 'Gene', '1956', (125, 129))	('patients', 'Species', '9606', (102, 110))	('EGFR', 'Gene', '1956', (50, 54))	('EGFR', 'Gene', '1956', (84, 88))	('EGFR', 'Gene', (125, 129))	('LSCC', 'Disease', (97, 101))	('patients', 'Species', '9606', (140, 148))	('mutated', 'Var', (89, 96))	('EGFR', 'Gene', (50, 54))	('EGFR', 'Gene', (84, 88))	('LSCC', 'Phenotype', 'HP:0030359', (97, 101))
513740	28881841	This pooled analysis is by far the most updated and comprehensive analysis of EGFR-TKIs for EGFR mutated LSCC to answer this question.	('LSCC', 'Disease', (105, 109))	('LSCC', 'Phenotype', 'HP:0030359', (105, 109))	('mutated', 'Var', (97, 104))	('EGFR', 'Gene', '1956', (92, 96))	('EGFR', 'Gene', (78, 82))	('EGFR', 'Gene', (92, 96))	('EGFR', 'Gene', '1956', (78, 82))
513741	28881841	Takehito et al 2010 had revealed that the EGFR-TKI, gefitinib was less effective in non-adenocarcinoma NSCLC with EGFR mutation than lung adenocarcinoma (LADC) harboring EGFR mutation.	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('mutation', 'Var', (119, 127))	('EGFR', 'Gene', '1956', (42, 46))	('gefitinib', 'Chemical', 'MESH:D000077156', (52, 61))	('carcinoma', 'Phenotype', 'HP:0030731', (143, 152))	('LADC', 'Phenotype', 'HP:0030078', (154, 158))	('EGFR', 'Gene', '1956', (170, 174))	('EGFR', 'Gene', (42, 46))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (133, 152))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (133, 152))	('EGFR', 'Gene', '1956', (114, 118))	('non-adenocarcinoma NSCLC', 'Disease', (84, 108))	('EGFR', 'Gene', (170, 174))	('lung adenocarcinoma', 'Disease', (133, 152))	('EGFR', 'Gene', (114, 118))	('non-adenocarcinoma NSCLC', 'Disease', 'MESH:D000230', (84, 108))
513742	28881841	Our study found that EGFR mutated LSCC patients had prior response to EGFR-TKIs than EGFR wild type LSCC patients, with higher object response rate (31.6% vs. 11.7%), disease control rate (72.0% vs. 42.8%) and longer progression-free survival (3.08 vs. 1.85 months).	('EGFR', 'Gene', '1956', (21, 25))	('EGFR', 'Gene', (85, 89))	('disease control', 'CPA', (167, 182))	('EGFR', 'Gene', (21, 25))	('patients', 'Species', '9606', (105, 113))	('patients', 'Species', '9606', (39, 47))	('LSCC', 'Disease', (34, 38))	('EGFR', 'Gene', '1956', (70, 74))	('higher', 'PosReg', (120, 126))	('LSCC', 'Phenotype', 'HP:0030359', (34, 38))	('object response rate', 'CPA', (127, 147))	('mutated', 'Var', (26, 33))	('EGFR', 'Gene', (70, 74))	('LSCC', 'Phenotype', 'HP:0030359', (100, 104))	('EGFR', 'Gene', '1956', (85, 89))
513743	28881841	This modest priority highlighted that EGFR-TKI might be a better option for EGFR mutated LSCC patients than that with EGFR wild type.	('EGFR', 'Gene', '1956', (38, 42))	('patients', 'Species', '9606', (94, 102))	('EGFR', 'Gene', (38, 42))	('EGFR', 'Gene', '1956', (76, 80))	('LSCC', 'Disease', (89, 93))	('LSCC', 'Phenotype', 'HP:0030359', (89, 93))	('mutated', 'Var', (81, 88))	('EGFR', 'Gene', '1956', (118, 122))	('EGFR', 'Gene', (76, 80))	('EGFR', 'Gene', (118, 122))
513745	28881841	The mechanism of lower response of EGFR-TKI treatment in LSCC patients with EGFR mutation compared to LADC patients harboring EGFR mutation is under reveling.	('LADC', 'Phenotype', 'HP:0030078', (102, 106))	('LSCC', 'Disease', (57, 61))	('LSCC', 'Phenotype', 'HP:0030359', (57, 61))	('EGFR', 'Gene', (126, 130))	('lower', 'NegReg', (17, 22))	('EGFR', 'Gene', '1956', (76, 80))	('mutation', 'Var', (81, 89))	('EGFR', 'Gene', '1956', (35, 39))	('EGFR', 'Gene', (35, 39))	('EGFR', 'Gene', (76, 80))	('patients', 'Species', '9606', (62, 70))	('patients', 'Species', '9606', (107, 115))	('EGFR', 'Gene', '1956', (126, 130))
513749	28881841	Zhijie Wang et al reported that the resistance of LSCC harboring EGFR mutation to EGFR-TKI was due to the activation of BMP-BMPR-Smad1/5-p70S6K, and the combination of EGFR-TKI with inhibitors of BMP receptors signaling pathway overcame the resistance.	('EGFR', 'Gene', (82, 86))	('LSCC', 'Phenotype', 'HP:0030359', (50, 54))	('EGFR', 'Gene', '1956', (168, 172))	('EGFR', 'Gene', '1956', (65, 69))	('EGFR', 'Gene', (168, 172))	('EGFR', 'Gene', (65, 69))	('p70S6K', 'Gene', (137, 143))	('EGFR', 'Gene', '1956', (82, 86))	('p70S6K', 'Gene', '6198', (137, 143))	('mutation', 'Var', (70, 78))	('activation', 'PosReg', (106, 116))
513752	28881841	However, recent pooled analysis found that EGFR mutations and ALK rearrangements were associated with low response rates to PD-1 pathway blockade in NSCLC (mainly in lung adenocarcinoma).	('lung adenocarcinoma', 'Disease', (166, 185))	('PD-1 pathway', 'Pathway', (124, 136))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (166, 185))	('NSCLC', 'Disease', (149, 154))	('ALK', 'Gene', (62, 65))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (166, 185))	('EGFR', 'Gene', '1956', (43, 47))	('NSCLC', 'Disease', 'MESH:D002289', (149, 154))	('ALK', 'Gene', '238', (62, 65))	('EGFR', 'Gene', (43, 47))	('mutations', 'Var', (48, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (176, 185))
513754	28881841	However, whether it is the same in EGFR mutated LSCC patients remains unknown.	('patients', 'Species', '9606', (53, 61))	('EGFR', 'Gene', '1956', (35, 39))	('EGFR', 'Gene', (35, 39))	('LSCC', 'Disease', (48, 52))	('mutated', 'Var', (40, 47))	('LSCC', 'Phenotype', 'HP:0030359', (48, 52))
513755	28881841	Secondly, the very infrequency of EGFR mutation in LSCC patients had made the discovery so difficult that there were only scattered studies and reports found from the literature search, published in lower impact journals, lacking of crucial clinical information.	('patients', 'Species', '9606', (56, 64))	('mutation', 'Var', (39, 47))	('EGFR', 'Gene', (34, 38))	('LSCC', 'Disease', (51, 55))	('LSCC', 'Phenotype', 'HP:0030359', (51, 55))	('EGFR', 'Gene', '1956', (34, 38))
513756	28881841	In conclusion, our study had reveled that first generation EGFR-TKIs had a modest better efficacy for LSCC patients with EGFR mutation than EGFR wild type LSCC patients, and might be a selective option for those patients with EGFR mutation.	('patients', 'Species', '9606', (160, 168))	('EGFR', 'Gene', '1956', (121, 125))	('LSCC', 'Disease', (102, 106))	('EGFR', 'Gene', (59, 63))	('EGFR', 'Gene', (140, 144))	('mutation', 'Var', (126, 134))	('EGFR', 'Gene', (121, 125))	('patients', 'Species', '9606', (212, 220))	('LSCC', 'Phenotype', 'HP:0030359', (102, 106))	('EGFR', 'Gene', '1956', (226, 230))	('LSCC', 'Phenotype', 'HP:0030359', (155, 159))	('patients', 'Species', '9606', (107, 115))	('EGFR', 'Gene', '1956', (59, 63))	('EGFR', 'Gene', '1956', (140, 144))	('EGFR', 'Gene', (226, 230))
513758	28881841	Advanced stage (IIIB/IV) LSCC patients with EGFR mutations treated with EGFR-TKIs were identified in the database of Shanghai Chest Hospital from July 2014 to August 2016, or extracted from the publications searched from the online medicine databases.	('mutations', 'Var', (49, 58))	('EGFR', 'Gene', '1956', (72, 76))	('LSCC', 'Phenotype', 'HP:0030359', (25, 29))	('EGFR', 'Gene', (72, 76))	('patients', 'Species', '9606', (30, 38))	('EGFR', 'Gene', '1956', (44, 48))	('EGFR', 'Gene', (44, 48))
513760	28881841	Second, we identified the patients with EGFR mutated LSCC at the Shanghai Chest Hospital from July 2014 to August 2016 as Supplemental Table 1.	('LSCC', 'Phenotype', 'HP:0030359', (53, 57))	('patients', 'Species', '9606', (26, 34))	('EGFR', 'Gene', '1956', (40, 44))	('EGFR', 'Gene', (40, 44))	('mutated', 'Var', (45, 52))
513761	28881841	In the hospital database and searched publications, we extracted the baseline clinical characteristics included age at diagnosis, sex, tumor histology, EGFR mutation status, performance status (PS), smoking history and prior treatment regions.	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('EGFR', 'Gene', '1956', (152, 156))	('tumor', 'Disease', (135, 140))	('EGFR', 'Gene', (152, 156))	('performance', 'Disease', (174, 185))	('mutation status', 'Var', (157, 172))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
513769	32901882	The targeting of KIAA0101 by miR-216a-5p was verified by dual-luciferase reporter assays.	('miR-216a-5p', 'Var', (29, 40))	('miR-216a-5p', 'Chemical', '-', (29, 40))	('KIAA0101', 'Gene', (17, 25))
513771	32901882	miR-216a-5p was lowly expressed and inversely correlated with KIAA0101 protein expression in ESCC tissues and cell lines.	('expression', 'MPA', (79, 89))	('miR-216a-5p', 'Var', (0, 11))	('KIAA0101', 'Gene', (62, 70))	('correlated', 'Reg', (46, 56))	('protein', 'Protein', (71, 78))	('miR-216a-5p', 'Chemical', '-', (0, 11))
513773	32901882	miR-216a-5p negatively regulated KIAA0101 expression by directly targeting the 3'-untranslated region of the KIAA0101 mRNA.	('expression', 'MPA', (42, 52))	('miR-216a-5p', 'Var', (0, 11))	('miR-216a-5p', 'Chemical', '-', (0, 11))	('targeting', 'Reg', (65, 74))	('negatively', 'NegReg', (12, 22))	('KIAA0101', 'Gene', (33, 41))
513775	32901882	Meanwhile, KIAA0101 promoted ESCC migration and invasion, and its overexpression abolished the antitumor effects of miR-216a-5p mimics.	('tumor', 'Disease', (99, 104))	('KIAA0101', 'Var', (11, 19))	('promoted', 'PosReg', (20, 28))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('miR-216a-5p', 'Chemical', '-', (116, 127))	('invasion', 'CPA', (48, 56))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('ESCC migration', 'CPA', (29, 43))	('abolished', 'NegReg', (81, 90))
513776	32901882	As a tumor suppressor, miR-216a-5p targets KIAA0101 to inhibit the proliferation, migration, and invasion of ESCC.	('miR-216a-5p', 'Var', (23, 34))	('ESCC', 'Disease', (109, 113))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('migration', 'CPA', (82, 91))	('proliferation', 'CPA', (67, 80))	('miR-216a-5p', 'Chemical', '-', (23, 34))	('tumor', 'Disease', (5, 10))	('invasion', 'CPA', (97, 105))	('inhibit', 'NegReg', (55, 62))
513781	32901882	KIAA0101 (also referred to as NS5ATP9 or Paf15) is involved in multiple biological activities, including DNA repair, cell proliferation, cell cycle progression, and cell migration.	('cell cycle progression', 'CPA', (137, 159))	('Paf15', 'Gene', (41, 46))	('cell migration', 'CPA', (165, 179))	('KIAA0101', 'Var', (0, 8))	('NS5ATP9', 'Gene', '9768', (30, 37))	('cell proliferation', 'CPA', (117, 135))	('NS5ATP9', 'Gene', (30, 37))	('involved', 'Reg', (51, 59))	('Paf15', 'Gene', '9768', (41, 46))
513784	32901882	The overexpression of KIAA0101 was also found to enhance ESCC cell proliferation and to upregulate the expression of cyclins A and B, thus leading to a reduced percentage of cells in the G1 phase.	('cyclins A and B', 'Gene', '890', (117, 132))	('upregulate', 'PosReg', (88, 98))	('expression', 'MPA', (103, 113))	('enhance', 'PosReg', (49, 56))	('reduced', 'NegReg', (152, 159))	('ESCC cell proliferation', 'CPA', (57, 80))	('KIAA0101', 'Var', (22, 30))
513786	32901882	For example, miR-216a is significantly upregulated in hepatocellular carcinoma and was found to induce epithelial-mesenchymal transition (EMT) by suppressing the expression of PTEN, SMAD7, and TSLC1, thus contributing to carcinogenesis and recurrence.	('carcinogenesis', 'Disease', (221, 235))	('upregulated', 'PosReg', (39, 50))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (54, 78))	('TSLC1', 'Gene', '23705', (193, 198))	('SMAD7', 'Gene', '4092', (182, 187))	('carcinogenesis', 'Disease', 'MESH:D063646', (221, 235))	('induce', 'PosReg', (96, 102))	('hepatocellular carcinoma', 'Disease', (54, 78))	('suppressing', 'NegReg', (146, 157))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))	('PTEN', 'Gene', (176, 180))	('contributing', 'Reg', (205, 217))	('epithelial-mesenchymal transition', 'CPA', (103, 136))	('TSLC1', 'Gene', (193, 198))	('miR-216a', 'Var', (13, 21))	('PTEN', 'Gene', '5728', (176, 180))	('SMAD7', 'Gene', (182, 187))	('expression', 'MPA', (162, 172))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (54, 78))
513787	32901882	On the other hand, miR-216a displays a low expression in non-small cell lung cancer (NSCLC) and could inhibit the cell activity of NSCLC by directly targeting eIF4B and ZEB1.	('miR-216a', 'Var', (19, 27))	('lung cancer', 'Disease', 'MESH:D008175', (72, 83))	('NSCLC', 'Disease', 'MESH:D002289', (85, 90))	('ZEB1', 'Gene', '6935', (169, 173))	('NSCLC', 'Disease', 'MESH:D002289', (131, 136))	('inhibit', 'NegReg', (102, 109))	('lung cancer', 'Phenotype', 'HP:0100526', (72, 83))	('NSCLC', 'Disease', (85, 90))	('NSCLC', 'Disease', (131, 136))	('low', 'NegReg', (39, 42))	('NSCLC', 'Phenotype', 'HP:0030358', (85, 90))	('expression', 'MPA', (43, 53))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (57, 83))	('NSCLC', 'Phenotype', 'HP:0030358', (131, 136))	('ZEB1', 'Gene', (169, 173))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (61, 83))	('eIF4B', 'Gene', '1975', (159, 164))	('lung cancer', 'Disease', (72, 83))	('targeting', 'Reg', (149, 158))	('eIF4B', 'Gene', (159, 164))
513788	32901882	In addition, KIAA0101 enhanced resistance to cisplatin by upregulating cell mitosis.	('KIAA0101', 'Var', (13, 21))	('cisplatin', 'Chemical', 'MESH:D002945', (45, 54))	('upregulating', 'PosReg', (58, 70))	('cell mitosis', 'CPA', (71, 83))	('enhanced', 'PosReg', (22, 30))	('resistance to cisplatin', 'MPA', (31, 54))
513790	32901882	In the present study, we evaluated the expression level of miR-216a-5p in clinical specimens of ESCC and human ESCC cell lines and observed that lower expression of miR-216a-5p was associated with malignancy in comparison with the control tissues or cells.	('miR-216a-5p', 'Chemical', '-', (165, 176))	('miR-216a-5p', 'Var', (165, 176))	('expression', 'MPA', (151, 161))	('lower', 'NegReg', (145, 150))	('malignancy', 'Disease', 'MESH:D009369', (197, 207))	('human', 'Species', '9606', (105, 110))	('malignancy', 'Disease', (197, 207))	('miR-216a-5p', 'Chemical', '-', (59, 70))
513792	32901882	KIAA0101 was confirmed to be a downstream target of miR-216a-5p, and the in vitro experimental results demonstrated that miR-216a-5p inhibited tumor proliferation, migration, and invasion by directly decreasing the expression of KIAA0101 in ESCC.	('decreasing', 'NegReg', (200, 210))	('miR-216a-5p', 'Chemical', '-', (121, 132))	('tumor', 'Disease', (143, 148))	('miR-216a-5p', 'Var', (121, 132))	('miR-216a-5p', 'Chemical', '-', (52, 63))	('inhibited', 'NegReg', (133, 142))	('expression', 'MPA', (215, 225))	('invasion', 'CPA', (179, 187))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('KIAA0101', 'Gene', (229, 237))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('migration', 'CPA', (164, 173))
513793	32901882	Our study demonstrated a critical role of the miR216a-5p/KIAA0101 axis in the progression of ESCC.	('216a', 'Chemical', '-', (49, 53))	('ESCC', 'Disease', (93, 97))	('miR216a-5p/KIAA0101', 'Var', (46, 65))
513802	32901882	EC9706, EC109, KYSE150, KYSE450, TE1, and TE10 cells were cultured in RPMI-1640 medium (HyClone; GE Healthcare) containing 10% fetal bovine serum (FSB; HyClone; GE Healthcare) and 1% penicillin/streptomycin (Sigma-Aldrich; Merck KGaA).	('EC9706', 'Var', (0, 6))	('streptomycin', 'Chemical', 'MESH:D013307', (194, 206))	('EC9706', 'CellLine', 'CVCL:E307', (0, 6))	('KYSE150', 'Var', (15, 22))	('penicillin', 'Chemical', 'MESH:D010406', (183, 193))	('RPMI-1640 medium', 'Chemical', '-', (70, 86))
513812	32901882	The relative expression of miR-216a-5p was normalized against U6, while that of KIAA0101 was normalized to beta-actin, both using the 2-DeltaDeltaCq method.	('miR-216a-5p', 'Var', (27, 38))	('beta-actin', 'Gene', '728378', (107, 117))	('DeltaCq', 'Chemical', '-', (141, 148))	('beta-actin', 'Gene', (107, 117))	('miR-216a-5p', 'Chemical', '-', (27, 38))
513822	32901882	Following the manual of Gene Tailor Site-Directed Mutagenesis System (Invitrogen; Thermo Fisher Scientific, Inc.), the construct with mutations in the miR-216a-5p seed sequence (the sequence of TGAGATT at 357-363 bp was mutated to TCACAAT) was produced by the mutagenic oligonucleotide primers (forward: 5'-GTTGTATTTCACAATTGCTTAGATTGTTGTAC-3' and reverse: 5'-CTAAGCAATTGTGAAATACAACATACTTGTAA-3').	('miR-216a-5p', 'Chemical', '-', (151, 162))	('miR-216a-5p', 'Gene', (151, 162))	('mutations', 'Var', (134, 143))
513823	32901882	EC9706 and TE1 cells were co-transfected with 30 ng of pmiR-RB-KIAA0101 3'-UTR or their mutant constructs, 50 ng luciferase reporter, and 10 ng Renilla luciferase reporter using Lipofectamine 2000.	('EC9706', 'CellLine', 'CVCL:E307', (0, 6))	('Lipofectamine 2000', 'Chemical', 'MESH:C086724', (178, 196))	('mutant', 'Var', (88, 94))	('pmiR-RB-KIAA0101', 'Gene', (55, 71))
513828	32901882	A total of 1x105 EC9706 or TE1 cells were seeded in the upper chambers.	('TE1 cells', 'CPA', (27, 36))	('EC9706', 'CellLine', 'CVCL:E307', (17, 23))	('EC9706', 'Var', (17, 23))
513834	32901882	To explore the potential roles of miR-216a-5p in the pathogenesis and chemoresistance of ESCC, we first evaluated the binding site of miR-216a-5p to the 3'UTR of KIAA0101.	('ESCC', 'Disease', (89, 93))	('miR-216a-5p', 'Chemical', '-', (134, 145))	('binding', 'Interaction', (118, 125))	('miR-216a-5p', 'Chemical', '-', (34, 45))	('miR-216a-5p', 'Var', (134, 145))
513835	32901882	We found that miR-216a-5p could bind the 3'UTR of KIAA0101 (Fig.	('miR-216a-5p', 'Var', (14, 25))	('bind', 'Interaction', (32, 36))	('miR-216a-5p', 'Chemical', '-', (14, 25))
513838	32901882	RT-qPCR analysis demonstrated that compared with the adjacent normal tissues, the tumor tissues had significantly lower expression of miR-216a-5p (Fig.	('expression', 'MPA', (120, 130))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('miR-216a-5p', 'Chemical', '-', (134, 145))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('lower', 'NegReg', (114, 119))	('tumor', 'Disease', (82, 87))	('miR-216a-5p', 'Var', (134, 145))
513841	32901882	The miR-216a-5p expression levels in ESCC were not correlated with sex, age, pTNM stage, or preoperative CEA levels, but were correlated with histology (P=0.022), tumor depth (P=0.006), and lymph node metastasis (P=0.018; Table I).	('miR-216a-5p', 'Chemical', '-', (4, 15))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('miR-216a-5p', 'Var', (4, 15))	('lymph node metastasis', 'CPA', (190, 211))	('ESCC', 'Gene', (37, 41))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('CEA', 'Gene', (105, 108))	('correlated', 'Reg', (126, 136))	('CEA', 'Gene', '1084', (105, 108))	('tumor', 'Disease', (163, 168))
513842	32901882	In addition, the Cox regression analysis (Table II) revealed that the lymph node metastasis (P=0.001), pTNM stage (P<0.001), and miR-216a-5p levels (P<0.001) were independent risk factors for shorter overall survival in patients with ESCC.	('shorter', 'NegReg', (192, 199))	('overall survival', 'MPA', (200, 216))	('ESCC', 'Disease', (234, 238))	('miR-216a-5p', 'Chemical', '-', (129, 140))	('miR-216a-5p levels', 'Var', (129, 147))	('patients', 'Species', '9606', (220, 228))
513843	32901882	Furthermore, patients with ESCC and lower miR-216a-5p expression displayed reduced DFS (P<0.0001; Fig.	('lower', 'NegReg', (36, 41))	('miR-216a-5p', 'Chemical', '-', (42, 53))	('miR-216a-5p expression', 'Var', (42, 64))	('patients', 'Species', '9606', (13, 21))	('reduced', 'NegReg', (75, 82))	('ESCC', 'Disease', (27, 31))	('DFS', 'MPA', (83, 86))
513849	32901882	To ascertain whether miR-216a-5p functionally affects KIAA0101 expression, miR-216a-5p was overexpressed and knocked down by transfecting the ESCC cell lines EC9706 and TE1 with the miR-216a-5p mimics and miR-216a-5p inhibitor.	('EC9706', 'CellLine', 'CVCL:E307', (158, 164))	('affects', 'Reg', (46, 53))	('miR-216a-5p', 'Chemical', '-', (205, 216))	('knocked', 'Var', (109, 116))	('expression', 'MPA', (63, 73))	('miR-216a-5p', 'Chemical', '-', (75, 86))	('miR-216a-5p', 'Gene', (75, 86))	('miR-216a-5p', 'Chemical', '-', (182, 193))	('miR-216a-5p', 'Chemical', '-', (21, 32))
513856	32901882	Therefore, this finding revealed that miR-216a-5p could reduce the expression of KIAA0101 protein by directly binding to the 3'UTR of KIAA0101 and possible translation suppression.	('miR-216a-5p', 'Var', (38, 49))	('translation', 'MPA', (156, 167))	('protein', 'Protein', (90, 97))	('binding', 'Interaction', (110, 117))	('reduce', 'NegReg', (56, 62))	('miR-216a-5p', 'Chemical', '-', (38, 49))	('expression', 'MPA', (67, 77))	('KIAA0101', 'Gene', (81, 89))
513860	32901882	Overexpression of miR-216a-5p significantly suppressed the ESCC invasion and reduced the ESCC migration.	('suppressed', 'NegReg', (44, 54))	('ESCC migration', 'CPA', (89, 103))	('miR-216a-5p', 'Chemical', '-', (18, 29))	('ESCC invasion', 'CPA', (59, 72))	('miR-216a-5p', 'Var', (18, 29))	('reduced', 'NegReg', (77, 84))
513861	32901882	In contrast, the migration and invasion of ESCC cells increased when endogenous miR-216a-5p was inhibited (Fig.	('migration', 'CPA', (17, 26))	('miR-216a-5p', 'Chemical', '-', (80, 91))	('increased', 'PosReg', (54, 63))	('miR-216a-5p', 'Var', (80, 91))	('inhibited', 'NegReg', (96, 105))	('invasion of ESCC cells', 'CPA', (31, 53))
513864	32901882	5D) also demonstrated that KIAA0101 ectopic expression significantly attenuated the anti-proliferative effects of miR-216a-5p.	('miR-216a-5p', 'Chemical', '-', (114, 125))	('anti-proliferative effects', 'CPA', (84, 110))	('attenuated', 'NegReg', (69, 79))	('ectopic expression', 'Var', (36, 54))	('miR-216a-5p', 'Var', (114, 125))
513865	32901882	Meanwhile, additionally forced KIAA0101 expression in ESCC cells restored the migration and invasion inhibition induced by overexpression of miR-216a-5p (Fig.	('miR-216a-5p', 'Chemical', '-', (141, 152))	('miR-216a-5p', 'Var', (141, 152))	('restored', 'PosReg', (65, 73))	('invasion inhibition', 'CPA', (92, 111))	('migration', 'CPA', (78, 87))
513867	32901882	Collectively, overexpression of miR-216a-5p can inhibit the in vitro proliferation, migration, and invasion of ESCC cells through targeting the oncogene KIAA0101.	('in vitro proliferation', 'CPA', (60, 82))	('migration', 'CPA', (84, 93))	('miR-216a-5p', 'Chemical', '-', (32, 43))	('invasion', 'CPA', (99, 107))	('miR-216a-5p', 'Var', (32, 43))	('overexpression', 'PosReg', (14, 28))	('ESCC', 'Disease', (111, 115))	('inhibit', 'NegReg', (48, 55))
513870	32901882	In the present study, we identified that miR-216a-5p expression was significantly downregulated in primary human ESCC specimens and cell lines, and demonstrated an inverse correlation with KIAA0101 expression.	('downregulated', 'NegReg', (82, 95))	('miR-216a-5p', 'Var', (41, 52))	('human', 'Species', '9606', (107, 112))	('expression', 'MPA', (53, 63))	('miR-216a-5p', 'Chemical', '-', (41, 52))
513872	32901882	KIAA0101 was validated to be a direct downstream target of miR-216a-5p, and its expression in ESCC cells was regulated by miR-216a-5p at the translational level.	('miR-216a-5p', 'Var', (122, 133))	('miR-216a-5p', 'Var', (59, 70))	('regulated', 'Reg', (109, 118))	('expression', 'MPA', (80, 90))	('miR-216a-5p', 'Chemical', '-', (122, 133))	('miR-216a-5p', 'Chemical', '-', (59, 70))
513874	32901882	Our data demonstrated that the miR-216a-5p/KIAA0101 axis contributes to the progression of ESCC, and represents a valuable prognosis marker and therapeutic target for patients with ESCC.	('patients', 'Species', '9606', (167, 175))	('ESCC', 'Disease', (91, 95))	('miR-216a-5p/KIAA0101', 'Var', (31, 51))	('miR-216a-5p', 'Chemical', '-', (31, 42))
513876	32901882	In addition, KIAA0101 was found to enhance resistance to cisplatin by upregulating cell mitosis.	('cell mitosis', 'CPA', (83, 95))	('KIAA0101', 'Var', (13, 21))	('enhance', 'PosReg', (35, 42))	('upregulating', 'PosReg', (70, 82))	('cisplatin', 'Chemical', 'MESH:D002945', (57, 66))	('resistance to cisplatin', 'MPA', (43, 66))
513877	32901882	Herein we identified miR-216a-5p as an upstream regulator of KIAA0101 that was inversely correlated with KIAA0101.	('miR-216a-5p', 'Var', (21, 32))	('miR-216a-5p', 'Chemical', '-', (21, 32))	('KIAA0101', 'Gene', (61, 69))
513878	32901882	Consistent with the previous results, lower levels of miR-216a-5p in ESCC specimens corresponded to a higher level of KIAA0101 and less favorable prognosis for patients with ESCC.	('patients', 'Species', '9606', (160, 168))	('lower', 'NegReg', (38, 43))	('KIAA0101', 'MPA', (118, 126))	('higher', 'PosReg', (102, 108))	('ESCC', 'Disease', (174, 178))	('miR-216a-5p', 'Chemical', '-', (54, 65))	('ESCC', 'Disease', (69, 73))	('miR-216a-5p', 'Var', (54, 65))
513879	32901882	Our findings suggest that by repressing KIAA0101 protein, miR-216a-5p plays an essential role in suppressing the proliferation and metastasis of ESCC.	('miR-216a-5p', 'Var', (58, 69))	('protein', 'Protein', (49, 56))	('suppressing', 'NegReg', (97, 108))	('miR-216a-5p', 'Chemical', '-', (58, 69))	('ESCC', 'Disease', (145, 149))
513880	32901882	Evidence reveals that the abnormal expression of miR-216a is involved in tumorigenesis and cancer progression, but the specific role of miR-216a seems to be cell type-dependent.	('miR-216a', 'Gene', (49, 57))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('involved', 'Reg', (61, 69))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('expression', 'MPA', (35, 45))	('tumor', 'Disease', (73, 78))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('abnormal', 'Var', (26, 34))
513881	32901882	miR-216a has a low expression in NSCLC specimens and could inhibit cell activity of NSCLC, which was in accordance with observations in oral squamous cell carcinoma.	('NSCLC', 'Phenotype', 'HP:0030358', (33, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (155, 164))	('expression', 'MPA', (19, 29))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (136, 164))	('NSCLC', 'Phenotype', 'HP:0030358', (84, 89))	('NSCLC', 'Disease', (84, 89))	('oral squamous cell carcinoma', 'Disease', (136, 164))	('NSCLC', 'Disease', (33, 38))	('NSCLC', 'Disease', 'MESH:D002289', (84, 89))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (141, 164))	('inhibit', 'NegReg', (59, 66))	('NSCLC', 'Disease', 'MESH:D002289', (33, 38))	('miR-216a', 'Var', (0, 8))	('cell', 'CPA', (67, 71))
513882	32901882	In addition, Wang et al identified that miR-216a negatively regulated the progression of pancreatic cancer by direct interaction with JAK2.	('negatively regulated', 'NegReg', (49, 69))	('pancreatic cancer', 'Disease', 'MESH:D010190', (89, 106))	('progression', 'CPA', (74, 85))	('interaction', 'Interaction', (117, 128))	('JAK2', 'Gene', '3717', (134, 138))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (89, 106))	('JAK2', 'Gene', (134, 138))	('miR-216a', 'Var', (40, 48))	('pancreatic cancer', 'Disease', (89, 106))
513884	32901882	Nevertheless, miR-216a was also found to demonstrate a tumor-promoting role, and its expression affected the therapeutic effects of anticancer treatments.	('expression', 'MPA', (85, 95))	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('miR-216a', 'Var', (14, 22))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('affected', 'Reg', (96, 104))	('tumor', 'Disease', (55, 60))	('cancer', 'Disease', (136, 142))	('therapeutic effects', 'CPA', (109, 128))
513888	32901882	Link et al found that decreased expression of fecal miR-216a could be used as a non-invasive miRNA biomarker for pancreatic cancer.	('fecal miR-216a', 'Var', (46, 60))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (113, 130))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('pancreatic cancer', 'Disease', (113, 130))	('pancreatic cancer', 'Disease', 'MESH:D010190', (113, 130))	('expression', 'MPA', (32, 42))	('decreased', 'NegReg', (22, 31))
513890	32901882	In the present study, miR-216a-5p had lower expression in ESCC specimens and cell lines than in the normal control tissues and cells.	('expression', 'MPA', (44, 54))	('lower', 'NegReg', (38, 43))	('miR-216a-5p', 'Var', (22, 33))	('miR-216a-5p', 'Chemical', '-', (22, 33))	('ESCC', 'Disease', (58, 62))
513892	32901882	In addition, tectonic family member 1 (TCTN1) was proven to be another downstream target of miR-216a-5p in ESCC, and the restoration of TCTN expression reversed the effects of miR-216a-5p on cell proliferation and apoptosis.	('apoptosis', 'CPA', (214, 223))	('tectonic family member 1', 'Gene', '79600', (13, 37))	('TCTN1', 'Gene', (39, 44))	('restoration', 'Var', (121, 132))	('miR-216a-5p', 'Chemical', '-', (176, 187))	('miR-216a-5p', 'Chemical', '-', (92, 103))	('tectonic family member 1', 'Gene', (13, 37))	('cell proliferation', 'CPA', (191, 209))	('ESCC', 'Disease', (107, 111))	('TCTN', 'Gene', (136, 140))	('TCTN1', 'Gene', '79600', (39, 44))	('miR-216a-5p', 'Var', (92, 103))
513893	32901882	Therefore, further investigation of potential targets of miR-216a-5p is needed to fully elucidate the functions of miR-216a-5p in ESCC pathogenesis.	('ESCC', 'Disease', (130, 134))	('miR-216a-5p', 'Var', (115, 126))	('miR-216a-5p', 'Chemical', '-', (115, 126))	('miR-216a-5p', 'Chemical', '-', (57, 68))
513894	32901882	Its major strength is its novelty; to the best of our knowledge, this is the first report to unveil the critical role of the miR-216a-5p/KIAA0101 axis in ESCC pathogenesis.	('miR-216a-5p', 'Chemical', '-', (125, 136))	('ESCC', 'Disease', (154, 158))	('miR-216a-5p/KIAA0101', 'Var', (125, 145))
513898	32901882	Finally, miR-216a-5p has targets other than KIAA0101, and it is possible to modulate the expression of miR-216a-5p affecting ESCC proliferation through proteins other than KIAA0101.	('modulate', 'Reg', (76, 84))	('miR-216a-5p', 'Chemical', '-', (103, 114))	('miR-216a-5p', 'Chemical', '-', (9, 20))	('miR-216a-5p', 'Var', (103, 114))	('affecting', 'Reg', (115, 124))	('ESCC', 'Disease', (125, 129))
513899	32901882	In summary, this is the first report that reveals the targeting effect of miR-216a-5p on KIAA0101 expression in ESCC.	('miR-216a-5p', 'Chemical', '-', (74, 85))	('miR-216a-5p', 'Var', (74, 85))	('ESCC', 'Disease', (112, 116))
513900	32901882	Our results demonstrated the antitumor effects of miR-216a-5p and oncogenic effects of KIAA0101 in ESCC cells in terms of regulating cell proliferation, cell cycle progression, migration, and invasion.	('cell proliferation', 'CPA', (133, 151))	('regulating', 'Reg', (122, 132))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('KIAA0101', 'Gene', (87, 95))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('ESCC', 'Disease', (99, 103))	('invasion', 'CPA', (192, 200))	('migration', 'CPA', (177, 186))	('cell cycle progression', 'CPA', (153, 175))	('miR-216a-5p', 'Chemical', '-', (50, 61))	('tumor', 'Disease', (33, 38))	('miR-216a-5p', 'Var', (50, 61))
513912	29494516	The other ncRNA species are less studied, either due to their recent discovery, such as stable intronic sequence RNA (sisRNA), YRNA, miRNA-offset RNAs (moRNA), telomerase RNA component (TERC), natural antisense transcript (NAT), transcribed ultraconserved regions (T-UCR), and pseudogene transcript, or because they are still largely seen as non-coding transcripts with no relevance to pathogenesis.	('ncRNA', 'Gene', '54719', (10, 15))	('TERC', 'Gene', '7012', (186, 190))	('ncRNA', 'Gene', (10, 15))	('moR', 'Gene', (152, 155))	('moR', 'Gene', '4988', (152, 155))	('pseudogene transcript', 'Var', (277, 298))	('TERC', 'Gene', (186, 190))
513918	29494516	Squamous cell carcinoma is related to NOTCH1, PIK3CA and PTEN mutations, while esophageal cancer is related to high rates of KRAS mutations and HER2 amplification.	('carcinoma', 'Phenotype', 'HP:0030731', (14, 23))	('esophageal cancer', 'Disease', (79, 96))	('PIK3CA', 'Gene', '5290', (46, 52))	('KRAS', 'Gene', (125, 129))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('Squamous cell carcinoma', 'Phenotype', 'HP:0002860', (0, 23))	('KRAS', 'Gene', '3845', (125, 129))	('esophageal cancer', 'Disease', 'MESH:D004938', (79, 96))	('Squamous cell carcinoma', 'Disease', (0, 23))	('PTEN', 'Gene', (57, 61))	('HER2', 'Gene', (144, 148))	('PTEN', 'Gene', '5728', (57, 61))	('NOTCH1', 'Gene', '4851', (38, 44))	('NOTCH1', 'Gene', (38, 44))	('HER2', 'Gene', '2064', (144, 148))	('mutations', 'Var', (62, 71))	('Squamous cell carcinoma', 'Disease', 'MESH:D002294', (0, 23))	('PIK3CA', 'Gene', (46, 52))
513936	29494516	They can be sources of endogenous siRNA and miRNA, can sponge miRNAs or regulate gene expression through epigenetic modifications.	('gene', 'Gene', (81, 85))	('epigenetic modifications', 'Var', (105, 129))	('regulate', 'Reg', (72, 80))	('expression', 'Species', '29278', (86, 96))
513950	29494516	In H9 and HeLa cells, it was discovered that the sisRNA ci-ankrd52 can bind to the Pol II and stimulate the transcription of their own gene of origin.	('bind', 'Interaction', (71, 75))	('transcription', 'MPA', (108, 121))	('ci-ankrd52', 'Var', (56, 66))	('stimulate', 'PosReg', (94, 103))	('HeLa', 'CellLine', 'CVCL:0030', (10, 14))	('Pol II', 'Protein', (83, 89))
513961	29494516	In primary cell culture of macrophage from C57BL/6 J mice and THP.1 monocytes, RNY1 or RNY3 was related with the apoptosis activation through the cleavage of caspase-3 and NFkB signaling pathway.	('RNY3', 'Gene', '19874', (87, 91))	('apoptosis', 'CPA', (113, 122))	('RNY1', 'Var', (79, 83))	('caspase-3', 'Gene', '12367', (158, 167))	('NFkB signaling pathway', 'Pathway', (172, 194))	('RNY3', 'Gene', (87, 91))	('caspase-3', 'Gene', (158, 167))	('activation', 'PosReg', (123, 133))	('cleavage', 'MPA', (146, 154))	('mice', 'Species', '10090', (53, 57))	('THP.1', 'CellLine', 'CVCL:0006', (62, 67))
514015	29494516	At the tRNA 5' end, cleavage is catalyzed by the ubiquitous endoribonuclease RNase P, and tRNA 3' end cleavage is specific for RNase P. The cleaved fragments, that have poly-U repeats at the 3' end, are categorized as tRF-1.	('tRF-1', 'Gene', (218, 223))	('tRF-1', 'Gene', '7013', (218, 223))	('poly-U repeats', 'Var', (169, 183))
514016	29494516	The Dicer enzyme may further process the mature tRNA1 by a cut in the T loop and generate the tRF-3.	('tRF-3', 'Gene', (94, 99))	('tRF-3', 'Gene', '387332', (94, 99))	('T loop', 'Protein', (70, 76))	('cut', 'Var', (59, 62))
514023	29494516	Because of their length, pseudogene RNA are sometimes regarded as lncRNAs.	('ncRNA', 'Gene', '54719', (67, 72))	('pseudogene', 'Var', (25, 35))	('ncRNA', 'Gene', (67, 72))
514025	29494516	Through lentiviral transfection and restoration of the expression level of PTENP1, it was proven that, in vitro, the cells had decreased proliferation, invasion and migration capabilities, while, in vivo, they failed to form tumors.	('invasion', 'CPA', (152, 160))	('decreased', 'NegReg', (127, 136))	('tumor', 'Phenotype', 'HP:0002664', (225, 230))	('migration capabilities', 'CPA', (165, 187))	('expression', 'Species', '29278', (55, 65))	('tumors', 'Phenotype', 'HP:0002664', (225, 231))	('lentiviral', 'Var', (8, 18))	('expression', 'MPA', (55, 65))	('PTENP1', 'Gene', (75, 81))	('PTENP1', 'Gene', '11191', (75, 81))	('tumors', 'Disease', 'MESH:D009369', (225, 231))	('tumors', 'Disease', (225, 231))	('proliferation', 'CPA', (137, 150))
514039	29494516	The down-regulated T-UCRs, i.e., uc.214+, uc.328+, uc.329+ and uc.356+, and up-regulated T-UCRs, i.e., uc.202-, uc.223-, and uc.269-, were found to be associated with the carcinogenesis of this malignancy through tissue microarray analysis.	('carcinogenesis', 'Disease', 'MESH:D063646', (171, 185))	('uc.214+', 'Var', (33, 40))	('uc.202-', 'Var', (103, 110))	('carcinogenesis', 'Disease', (171, 185))	('up-regulated', 'PosReg', (76, 88))	('uc.269-', 'Var', (125, 132))	('malignancy', 'Disease', 'MESH:D009369', (194, 204))	('uc.223-', 'Var', (112, 119))	('uc.328+', 'Var', (42, 49))	('down-regulated', 'NegReg', (4, 18))	('malignancy', 'Disease', (194, 204))	('uc.329+', 'Var', (51, 58))	('uc.356+', 'Var', (63, 70))
514041	29494516	The pseudogene transcripts are dysregulated in the head and neck malignancies (Figure 3 and Table 2), suggesting that they can become valuable diagnostic, prognostic or even therapeutic markers.	('neck malignancies', 'Disease', (60, 77))	('neck malignancies', 'Disease', 'MESH:D009369', (60, 77))	('pseudogene', 'Var', (4, 14))	('head and neck malignancies', 'Phenotype', 'HP:0012288', (51, 77))
514055	29209433	In this setting, the cellular pathways contributing to the neoplastic phenotype, including cell cycle regulation, cell signaling, DNA repair, and apoptosis have been demonstrated to be potential targets of epigenetic alterations in OPSCC.	('SCC', 'Gene', (234, 237))	('SCC', 'Gene', '6317', (234, 237))	('OPSCC', 'Phenotype', 'HP:0012182', (232, 237))	('cell signaling', 'CPA', (114, 128))	('cellular pathways', 'Pathway', (21, 38))	('apoptosis', 'CPA', (146, 155))	('epigenetic alterations', 'Var', (206, 228))	('cell cycle', 'CPA', (91, 101))
514057	29209433	Epigenetic changes, including DNA methylation, histone modifications, and non-coding RNA expression, can be used as powerful and reliable tools for early diagnosis of OPSCC patients and improve prognostication.	('patients', 'Species', '9606', (173, 181))	('SCC', 'Gene', (169, 172))	('DNA methylation', 'Var', (30, 45))	('OPSCC', 'Phenotype', 'HP:0012182', (167, 172))	('SCC', 'Gene', '6317', (169, 172))	('histone modifications', 'Var', (47, 68))	('Epigenetic changes', 'Var', (0, 18))
514059	29209433	Thus, this review will focus on the main known epigenetic modifications that can occur in OPSCC and their exploitation as potential biomarkers and therapeutic targets.	('SCC', 'Gene', '6317', (92, 95))	('OPSCC', 'Phenotype', 'HP:0012182', (90, 95))	('epigenetic modifications', 'Var', (47, 71))	('SCC', 'Gene', (92, 95))
514060	29209433	Furthermore, we will address epigenetic alterations to OPSCC risk factors, with a particular focus on HPV infection, tobacco exposure, and heavy alcohol consumption.	('SCC', 'Gene', '6317', (57, 60))	('epigenetic', 'Var', (29, 39))	('OPSCC', 'Phenotype', 'HP:0012182', (55, 60))	('HPV infection', 'Disease', (102, 115))	('heavy alcohol consumption', 'Phenotype', 'HP:0030955', (139, 164))	('alcohol', 'Chemical', 'MESH:D000438', (145, 152))	('tobacco', 'Species', '4097', (117, 124))	('HPV infection', 'Disease', 'MESH:D030361', (102, 115))	('SCC', 'Gene', (57, 60))
514072	29209433	Besides genetic alterations, the accumulation of aberrant epigenetic events deeply influence OPSCC biology and may contribute, at least in part, to the differences between HPV-driven and non-HPV-driven OPSCC.	('SCC', 'Gene', '6317', (95, 98))	('HPV', 'Species', '10566', (172, 175))	('OPSCC', 'Phenotype', 'HP:0012182', (93, 98))	('aberrant epigenetic events', 'Var', (49, 75))	('HPV', 'Species', '10566', (191, 194))	('SCC', 'Gene', (204, 207))	('influence', 'Reg', (83, 92))	('SCC', 'Gene', (95, 98))	('SCC', 'Gene', '6317', (204, 207))	('biology', 'CPA', (99, 106))	('OPSCC', 'Phenotype', 'HP:0012182', (202, 207))
514074	29209433	Disruption of this complex epigenetic control mechanism can affect the structure and the integrity of the genome and alter the expression of genes critically involved in tumorigenesis.	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('integrity', 'MPA', (89, 98))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('expression of', 'MPA', (127, 140))	('tumor', 'Disease', (170, 175))	('alter', 'Reg', (117, 122))	('affect', 'Reg', (60, 66))	('structure', 'MPA', (71, 80))	('Disruption', 'Var', (0, 10))
514076	29209433	Based on these considerations, the primary objective of this review is to resume the common epigenetic events in OPSCC and to discuss their potential translational applications for the management of this disease.	('epigenetic events', 'Var', (92, 109))	('men', 'Species', '9606', (191, 194))	('SCC', 'Gene', (115, 118))	('OPSCC', 'Phenotype', 'HP:0012182', (113, 118))	('SCC', 'Gene', '6317', (115, 118))
514077	29209433	Any discussion in this review will also relate epigenetic alterations to OPSCC risk factors, with a particular focus on HPV infection, tobacco smoking, and excessive alcohol intake (Fig.	('tobacco', 'Species', '4097', (135, 142))	('SCC', 'Gene', '6317', (75, 78))	('OPSCC', 'Phenotype', 'HP:0012182', (73, 78))	('HPV infection', 'Disease', (120, 133))	('excessive alcohol', 'Phenotype', 'HP:0030955', (156, 173))	('epigenetic', 'Var', (47, 57))	('SCC', 'Gene', (75, 78))	('HPV infection', 'Disease', 'MESH:D030361', (120, 133))	('alcohol', 'Chemical', 'MESH:D000438', (166, 173))
514084	29209433	Patients with HPV-driven OPSCC are more likely to be younger, without a history of smoking and alcohol abuse, and have a higher socio-economic status and better performance status than those with non-HPV-driven OPSCC.	('SCC', 'Gene', (27, 30))	('OPSCC', 'Phenotype', 'HP:0012182', (25, 30))	('HPV', 'Species', '10566', (14, 17))	('SCC', 'Gene', '6317', (213, 216))	('alcohol abuse', 'Phenotype', 'HP:0030955', (95, 108))	('SCC', 'Gene', '6317', (27, 30))	('HPV', 'Species', '10566', (200, 203))	('Patients', 'Species', '9606', (0, 8))	('HPV-driven', 'Var', (14, 24))	('OPSCC', 'Phenotype', 'HP:0012182', (211, 216))	('alcohol abuse', 'Disease', (95, 108))	('SCC', 'Gene', (213, 216))	('alcohol abuse', 'Disease', 'MESH:D000437', (95, 108))
514087	29209433	Most environmental-induced cancers harbor inactivating mutations in the TP53 gene leading to the loss of tumor suppression activity.	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('inactivating mutations', 'Var', (42, 64))	('loss', 'NegReg', (97, 101))	('TP53', 'Gene', '7157', (72, 76))	('men', 'Species', '9606', (12, 15))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('TP53', 'Gene', (72, 76))	('cancers', 'Phenotype', 'HP:0002664', (27, 34))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('cancers', 'Disease', 'MESH:D009369', (27, 34))	('tumor', 'Disease', (105, 110))	('cancers', 'Disease', (27, 34))
514088	29209433	Furthermore, the p16INK4a-cyclin D1-RB axis is mainly deregulated by deletion or promoter hypermethylation of the CDKN2A gene encoding p16INK4a and/or by CCND1 amplification, which encodes cyclin D1, with both leading to a decrease in the growth-suppressive hypo-phosphorylated RB form.	('CCND1', 'Gene', '595', (154, 159))	('p16INK4a', 'Gene', (135, 143))	('CCND1', 'Gene', (154, 159))	('promoter hypermethylation', 'Var', (81, 106))	('cyclin D1', 'Gene', (26, 35))	('CDKN2A', 'Gene', (114, 120))	('RB', 'Chemical', 'MESH:D012413', (36, 38))	('p16INK4a', 'Gene', '1029', (135, 143))	('cyclin D1', 'Gene', '595', (26, 35))	('deletion', 'Var', (69, 77))	('cyclin D1', 'Gene', (189, 198))	('CDKN2A', 'Gene', '1029', (114, 120))	('p16INK4a', 'Gene', (17, 25))	('RB', 'Chemical', 'MESH:D012413', (278, 280))	('cyclin D1', 'Gene', '595', (189, 198))	('growth-suppressive hypo-phosphorylated RB form', 'MPA', (239, 285))	('deregulated', 'Reg', (54, 65))	('decrease', 'NegReg', (223, 231))	('p16INK4a', 'Gene', '1029', (17, 25))
514089	29209433	Conversely from environmental-related HNSCC and consistently with HPV-mediated carcinogenesis, cells from HPV-driven OPSCC rarely contain loss-of-function TP53 mutations or CDKN2A inactivation and show less genomic instability.	('mutations', 'Var', (160, 169))	('CDKN2A', 'Gene', '1029', (173, 179))	('loss-of-function', 'NegReg', (138, 154))	('HPV', 'Species', '10566', (66, 69))	('TP53', 'Gene', (155, 159))	('HPV', 'Species', '10566', (106, 109))	('SCC', 'Gene', '6317', (40, 43))	('SCC', 'Gene', '6317', (119, 122))	('men', 'Species', '9606', (23, 26))	('carcinogenesis', 'Disease', (79, 93))	('SCC', 'Gene', (40, 43))	('SCC', 'Gene', (119, 122))	('HNSCC', 'Phenotype', 'HP:0012288', (38, 43))	('OPSCC', 'Phenotype', 'HP:0012182', (117, 122))	('CDKN2A', 'Gene', (173, 179))	('TP53', 'Gene', '7157', (155, 159))	('genomic instability', 'CPA', (207, 226))	('carcinogenesis', 'Disease', 'MESH:D063646', (79, 93))	('inactivation', 'NegReg', (180, 192))
514096	29209433	Conversely, DNMT3A and DNMT3B are regarded as de novo DNMTs since they create new methylation patterns during embryogenesis and germ-cell development by methylating CpG dinucleotides previously unmethylated on both strands.	('DNMT3A', 'Gene', (12, 18))	('men', 'Species', '9606', (145, 148))	('DNMT', 'Gene', '1786', (12, 16))	('DNMT', 'Gene', '1786', (54, 58))	('DNMT3A', 'Gene', '1788', (12, 18))	('CpG dinucleotides', 'Chemical', 'MESH:C015772', (165, 182))	('methylating', 'Var', (153, 164))	('germ-cell development', 'CPA', (128, 149))	('methylation patterns', 'MPA', (82, 102))	('DNMT3B', 'Gene', '1789', (23, 29))	('DNMT', 'Gene', (12, 16))	('DNMT', 'Gene', (54, 58))	('DNMT', 'Gene', (23, 27))	('DNMT3B', 'Gene', (23, 29))	('DNMT', 'Gene', '1786', (23, 27))	('CpG', 'Protein', (165, 168))
514097	29209433	DNA methylation is associated with repression of genes involved in development and plays a crucial function in genomic imprinting and in X-chromosome inactivation.	('men', 'Species', '9606', (74, 77))	('repression', 'MPA', (35, 45))	('methylation', 'Var', (4, 15))
514098	29209433	Alterations in DNA methylation patterns have been extensively documented in cancer and appear to deeply contribute to its biology.	('contribute', 'Reg', (104, 114))	('men', 'Species', '9606', (66, 69))	('Alterations', 'Var', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('DNA', 'Protein', (15, 18))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))
514099	29209433	DNA hypermethylation acts as an alternate and/or complementary mechanism to gene mutation or deletion, resulting in the inactivation of specific gene expression and function of tumor suppressor genes (TSGs) that promote the acquisition of tumorigenic behaviors, such as increased proliferation, enhanced invasiveness, and escape from apoptosis.	('tumor suppressor', 'Gene', (177, 193))	('invasiveness', 'CPA', (304, 316))	('enhanced', 'PosReg', (295, 303))	('escape from apoptosis', 'CPA', (322, 343))	('tumor suppressor', 'Gene', '7248', (177, 193))	('tumor', 'Disease', (239, 244))	('deletion', 'Var', (93, 101))	('tumor', 'Disease', (177, 182))	('inactivation', 'NegReg', (120, 132))	('men', 'Species', '9606', (55, 58))	('tumor', 'Disease', 'MESH:D009369', (239, 244))	('mutation', 'Var', (81, 89))	('function', 'MPA', (165, 173))	('promote', 'PosReg', (212, 219))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('specific gene expression', 'MPA', (136, 160))	('tumor', 'Phenotype', 'HP:0002664', (239, 244))	('increased', 'PosReg', (270, 279))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))
514100	29209433	Besides DNA hypermethylation, the genome of cancer cells undergoes an overall decrease in the level of 5-methylcytosine.	('decrease', 'NegReg', (78, 86))	('5-methylcytosine', 'Chemical', 'MESH:D044503', (103, 119))	('cancer', 'Disease', (44, 50))	('hypermethylation', 'Var', (12, 28))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('level of 5-methylcytosine', 'MPA', (94, 119))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
514101	29209433	This genome-wide hypomethylation affects intergenic and intronic regions of the DNA, particularly repeat sequences and transposable elements, and is believed to facilitate chromosomal instability, loss of imprinting, and reactivation of endogenous parasitic sequences.	('facilitate', 'PosReg', (161, 171))	('hypomethylation', 'Var', (17, 32))	('imprinting', 'CPA', (205, 215))	('affects', 'Reg', (33, 40))	('chromosomal instability', 'Phenotype', 'HP:0040012', (172, 195))	('men', 'Species', '9606', (135, 138))	('loss', 'NegReg', (197, 201))	('chromosomal instability', 'CPA', (172, 195))
514102	29209433	The list of genes that are silenced by DNA methylation in OPSCC is growing rapidly and includes genes involved in several pathways, including apoptosis, cell cycle, DNA repair, and WNT signaling.	('OPSCC', 'Phenotype', 'HP:0012182', (58, 63))	('SCC', 'Gene', '6317', (60, 63))	('methylation', 'Var', (43, 54))	('cell cycle', 'CPA', (153, 163))	('SCC', 'Gene', (60, 63))
514105	29209433	Overall, while HPV-negative cancers are mainly characterized by genome-wide hypomethylation, the HPV-positive counterpart displays higher levels of promoter methylation (Table 1).	('cancers', 'Disease', (28, 35))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('HPV', 'Species', '10566', (97, 100))	('promoter methylation', 'MPA', (148, 168))	('hypomethylation', 'Var', (76, 91))	('HPV', 'Species', '10566', (15, 18))	('cancers', 'Phenotype', 'HP:0002664', (28, 35))	('cancers', 'Disease', 'MESH:D009369', (28, 35))	('higher', 'PosReg', (131, 137))
514106	29209433	Defects in the apoptotic pathways are essential for cancer development and progression, but also for resistance to chemotherapy and radiotherapy.	('men', 'Species', '9606', (66, 69))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('Defects', 'Var', (0, 7))	('apoptotic pathways', 'Pathway', (15, 33))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))
514108	29209433	The pro-apoptotic gene death-associated protein kinase (DAPK) is commonly hypermethylated in at least 20% of OPSCC independent of HPV status, indicating it is involved in both HPV-positive and HPV-negative OPSCC carcinogenesis.	('death-associated protein kinase', 'Gene', (23, 54))	('OPSCC', 'Phenotype', 'HP:0012182', (206, 211))	('death-associated protein kinase', 'Gene', '1612', (23, 54))	('HPV', 'Species', '10566', (176, 179))	('hypermethylated', 'Var', (74, 89))	('HPV', 'Species', '10566', (193, 196))	('carcinogenesis', 'Disease', 'MESH:D063646', (212, 226))	('involved', 'Reg', (159, 167))	('SCC', 'Gene', (111, 114))	('carcinogenesis', 'Disease', (212, 226))	('SCC', 'Gene', (208, 211))	('DAPK', 'Gene', (56, 60))	('DAPK', 'Gene', '1612', (56, 60))	('OPSCC', 'Phenotype', 'HP:0012182', (109, 114))	('SCC', 'Gene', '6317', (111, 114))	('HPV', 'Species', '10566', (130, 133))	('SCC', 'Gene', '6317', (208, 211))
514116	29209433	Interestingly, the hypermethylation of this region was associated with p16INK4A protein expression and correlated with an increased expression of p14ARF in OPSCC.	('SCC', 'Gene', '6317', (158, 161))	('p16INK4A', 'Gene', (71, 79))	('associated', 'Reg', (55, 65))	('expression', 'MPA', (88, 98))	('p14ARF', 'Gene', '1029', (146, 152))	('p16INK4A', 'Gene', '1029', (71, 79))	('protein', 'Protein', (80, 87))	('hypermethylation', 'Var', (19, 35))	('OPSCC', 'Phenotype', 'HP:0012182', (156, 161))	('increased', 'PosReg', (122, 131))	('expression', 'MPA', (132, 142))	('p14ARF', 'Gene', (146, 152))	('SCC', 'Gene', (158, 161))
514122	29209433	Aberrant methylation of the negative regulators of this pathway has been observed in HNSCC, including OPSCC.	('Aberrant', 'Var', (0, 8))	('SCC', 'Gene', '6317', (104, 107))	('SCC', 'Gene', (87, 90))	('SCC', 'Gene', (104, 107))	('HNSCC', 'Phenotype', 'HP:0012288', (85, 90))	('SCC', 'Gene', '6317', (87, 90))	('methylation', 'MPA', (9, 20))	('OPSCC', 'Phenotype', 'HP:0012182', (102, 107))	('observed', 'Reg', (73, 81))
514125	29209433	Of note, SFRP1 aberrant methylation occurred at a higher prevalence in both heavy and light drinkers, whereas SFRP4 promoter methylation was detected more frequently in never and former smokers and was also associated with HPV16 infection.	('aberrant methylation', 'Var', (15, 35))	('HPV16 infection', 'Disease', 'MESH:D007239', (223, 238))	('HPV16 infection', 'Disease', (223, 238))	('SFRP1', 'Gene', '6422', (9, 14))	('SFRP4', 'Gene', (110, 115))	('associated', 'Reg', (207, 217))	('SFRP1', 'Gene', (9, 14))
514126	29209433	Some genes, which are associated with the development of tumor radioresistance, are frequently hypermethylated in OPSCC (Table 1).	('SCC', 'Gene', (116, 119))	('men', 'Species', '9606', (49, 52))	('OPSCC', 'Phenotype', 'HP:0012182', (114, 119))	('hypermethylated', 'Var', (95, 110))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('SCC', 'Gene', '6317', (116, 119))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Disease', (57, 62))
514127	29209433	However, the molecular mechanism by which their inactivation may contribute to radiotherapy resistance in OPSCC is yet to be determined.	('radiotherapy resistance', 'CPA', (79, 102))	('SCC', 'Gene', (108, 111))	('inactivation', 'Var', (48, 60))	('SCC', 'Gene', '6317', (108, 111))	('OPSCC', 'Phenotype', 'HP:0012182', (106, 111))	('contribute', 'Reg', (65, 75))
514128	29209433	Among these, checkpoint with forkhead and RING finger domains protein (CHFR) was hypermethylated in 25% of HPV-negative OPSCC patients, while no promoter methylation of this gene was observed in HPV-positive group.	('SCC', 'Gene', (122, 125))	('HPV', 'Species', '10566', (195, 198))	('hypermethylated', 'Var', (81, 96))	('SCC', 'Gene', '6317', (122, 125))	('HPV', 'Species', '10566', (107, 110))	('patients', 'Species', '9606', (126, 134))	('OPSCC', 'Phenotype', 'HP:0012182', (120, 125))	('CHFR', 'Gene', '55743', (71, 75))	('CHFR', 'Gene', (71, 75))
514130	29209433	In contrast to gene-specific hypermethylation, which usually occurs in HPV-positive OPSCC, genome-wide and global hypomethylation are more frequently observed in HPV-negative tumors, likely leading to chromosomal instability.	('tumors', 'Disease', (175, 181))	('tumors', 'Disease', 'MESH:D009369', (175, 181))	('SCC', 'Gene', (86, 89))	('tumors', 'Phenotype', 'HP:0002664', (175, 181))	('HPV', 'Species', '10566', (162, 165))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('leading', 'Reg', (190, 197))	('SCC', 'Gene', '6317', (86, 89))	('hypomethylation', 'Var', (114, 129))	('OPSCC', 'Phenotype', 'HP:0012182', (84, 89))	('HPV', 'Species', '10566', (71, 74))	('observed', 'Reg', (150, 158))	('chromosomal instability', 'Phenotype', 'HP:0040012', (201, 224))	('chromosomal', 'MPA', (201, 212))
514133	29209433	This finding suggests that HPV16-infected cells may attempt to silence the virus by DNA methylation, which can result in increased methylation of LINE-1 repetitive elements.	('methylation', 'Var', (88, 99))	('increased', 'PosReg', (121, 130))	('HPV16', 'Species', '333760', (27, 32))	('methylation', 'MPA', (131, 142))	('men', 'Species', '9606', (167, 170))
514137	29209433	In addition, both DNMT1 and DNMT3a were found to be more highly expressed in cells from HPV-positive HNSCC than in those from HPV-negative tumors.	('DNMT1', 'Gene', '1786', (18, 23))	('HPV', 'Species', '10566', (126, 129))	('DNMT3a', 'Gene', (28, 34))	('HNSCC', 'Phenotype', 'HP:0012288', (101, 106))	('SCC', 'Gene', (103, 106))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('DNMT3a', 'Gene', '1788', (28, 34))	('HPV', 'Species', '10566', (88, 91))	('tumors', 'Disease', (139, 145))	('HPV-positive', 'Var', (88, 100))	('more highly', 'PosReg', (52, 63))	('DNMT1', 'Gene', (18, 23))	('SCC', 'Gene', '6317', (103, 106))	('tumors', 'Disease', 'MESH:D009369', (139, 145))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('expressed', 'MPA', (64, 73))
514138	29209433	Overall, the analysis of the methylation pattern of the integrate HPV16 and human host genome in cultured cells from HNSCC, including SCC from the base of the tongue, revealed that the methylation status of HPV16 is dramatically affected by the methylation status of the host DNA flanking the integration site with HPV16-DNA being highly methylated when integrated into intergenic highly methylated host genome sites, while remaining largely unmethylated when incorporated into poorly methylated intergenic regions.	('affected', 'Reg', (229, 237))	('HNSCC', 'Phenotype', 'HP:0012288', (117, 122))	('methylation', 'MPA', (185, 196))	('SCC', 'Gene', '6317', (119, 122))	('HPV16', 'Species', '333760', (207, 212))	('SCC', 'Gene', '6317', (134, 137))	('HPV16', 'Species', '333760', (315, 320))	('human', 'Species', '9606', (76, 81))	('HPV16', 'Species', '333760', (66, 71))	('HPV16-DNA', 'Var', (315, 324))	('SCC', 'Gene', (119, 122))	('SCC', 'Gene', (134, 137))
514143	29209433	HPV16 polymorphisms in the LCR may alter the oncogenic potential of the virus by enhancing p97 promoter activity.	('enhancing', 'PosReg', (81, 90))	('HPV16', 'Species', '333760', (0, 5))	('polymorphisms', 'Var', (6, 19))	('oncogenic potential', 'CPA', (45, 64))	('HPV16', 'Gene', (0, 5))	('p97', 'Gene', '4241', (91, 94))	('p97', 'Gene', (91, 94))	('alter', 'Reg', (35, 40))
514146	29209433	The functional significance of CpG methylation in the LCR may be indeed an attempt by the host cell to silence the expression of viral genes or a virus-induced strategy to shift from the productive stage of the viral life cycle towards the transforming phase of HPV infection.	('HPV infection', 'Disease', 'MESH:D030361', (262, 275))	('silence', 'NegReg', (103, 110))	('HPV infection', 'Disease', (262, 275))	('expression', 'MPA', (115, 125))	('methylation', 'Var', (35, 46))
514148	29209433	On the other hand, consistently with previous findings derived from cervical cancer, they found a CpG methylation enrichment at the boundary of the L1 and L2 viral gene.	('methylation', 'Var', (102, 113))	('cervical cancer', 'Disease', (68, 83))	('cervical cancer', 'Disease', 'MESH:D002583', (68, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('CpG methylation', 'Var', (98, 113))	('men', 'Species', '9606', (120, 123))
514152	29209433	In particular, at high concentration, E2 binds low-affinity E2BS3 and E2BS4 resulting in inhibition of the p97 promoter and thereby maintaining low levels of E6 and E7 (reviewed in).	('E2BS', 'Chemical', '-', (60, 64))	('p97', 'Gene', '4241', (107, 110))	('p97', 'Gene', (107, 110))	('inhibition', 'NegReg', (89, 99))	('E2BS4', 'Var', (70, 75))	('E2BS', 'Chemical', '-', (70, 74))	('E2BS3', 'Var', (60, 65))
514153	29209433	Thus, the transition towards a transforming HPV infection requires the inactivation of E2.	('HPV infection', 'Disease', 'MESH:D030361', (44, 57))	('HPV infection', 'Disease', (44, 57))	('inactivation', 'Var', (71, 83))
514155	29209433	In addition, viral integration in host genome may result in head-to-tail concatemers of full-length HPV16 genomes.	('result in', 'Reg', (50, 59))	('head-to-tail concatemers', 'MPA', (60, 84))	('HPV16', 'Species', '333760', (100, 105))	('viral integration', 'Var', (13, 30))	('HPV16', 'Gene', (100, 105))
514157	29209433	Methylation status of E2BSs was critical in maintaining the transformed phenotype in oral SCC cells, as demethylation of HPV16 LCR by 5-aza-2'-deoxycytidine (5-AZA-CdR) caused repression of E6 and E7 expression followed by cell cycle arrest at G2/M.	('HPV16', 'Species', '333760', (121, 126))	('SCC', 'Gene', '6317', (90, 93))	('arrest', 'Disease', (234, 240))	('SCC', 'Gene', (90, 93))	('E2BSs', 'Chemical', '-', (22, 27))	('5-AZA-CdR', 'Chemical', '-', (158, 167))	('expression', 'MPA', (200, 210))	("5-aza-2'-deoxycytidine", 'Chemical', 'MESH:D000077209', (134, 156))	('HPV16', 'Gene', (121, 126))	('arrest', 'Disease', 'MESH:D006323', (234, 240))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (223, 240))	('repression', 'NegReg', (176, 186))	('demethylation', 'Var', (104, 117))
514159	29209433	Tobacco smoke has been associated with both TSG promoter hypermethylation and genome-wide hypomethylation, especially in long-term tobacco users, along with prolonged alcohol consumption.	('promoter', 'MPA', (48, 56))	('hypomethylation', 'Var', (90, 105))	('alcohol', 'Chemical', 'MESH:D000438', (167, 174))	('genome-wide', 'MPA', (78, 89))	('TSG', 'Disease', (44, 47))	('Tobacco', 'Species', '4097', (0, 7))	('prolonged alcohol consumption', 'Phenotype', 'HP:0030955', (157, 186))	('associated', 'Reg', (23, 33))	('tobacco', 'Species', '4097', (131, 138))
514164	29209433	Although these evidences indicated that deficiencies of folate and vitamin B12 may be associated with increased risk of developing OPSCC, several CpG sites were found to be differentially methylated in HPV-negative OPSCC patients with the highest levels of both vitamin A and vitamin B12 intake.	('HPV', 'Species', '10566', (202, 205))	('patients', 'Species', '9606', (221, 229))	('B12', 'Gene', (284, 287))	('B12', 'Gene', (75, 78))	('B12', 'Gene', '4709', (75, 78))	('SCC', 'Gene', '6317', (133, 136))	('B12', 'Gene', '4709', (284, 287))	('OPSCC', 'Phenotype', 'HP:0012182', (131, 136))	('SCC', 'Gene', (217, 220))	('folate', 'Chemical', 'MESH:D005492', (56, 62))	('vitamin A', 'Chemical', 'MESH:D014801', (262, 271))	('OPSCC', 'Phenotype', 'HP:0012182', (215, 220))	('SCC', 'Gene', '6317', (217, 220))	('deficiencies', 'Var', (40, 52))	('SCC', 'Gene', (133, 136))
514174	29209433	Histone methylation, catalyzed by histone methyltransferases (HMTs), occurs at both arginine and lysine residues on the tails of histone proteins H3 and H4.	('HMT', 'Gene', '3176', (62, 65))	('lysine', 'Chemical', 'MESH:D008239', (97, 103))	('H3', 'Gene', '117579', (146, 148))	('occurs', 'Reg', (69, 75))	('arginine', 'Var', (84, 92))	('lysine residues', 'Var', (97, 112))	('HMT', 'Gene', (62, 65))	('arginine', 'Chemical', 'MESH:D001120', (84, 92))
514178	29209433	A whole-exome sequencing analysis identified inactivating mutations in MLL2 and MLL3 genes in both HPV-positive and HPV-negative OPSCC, indicating a tumor suppressor function.	('HPV', 'Species', '10566', (116, 119))	('tumor suppressor', 'Gene', (149, 165))	('inactivating mutations', 'Var', (45, 67))	('MLL', 'Gene', '4297', (71, 74))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('SCC', 'Gene', (131, 134))	('tumor suppressor', 'Gene', '7248', (149, 165))	('OPSCC', 'Phenotype', 'HP:0012182', (129, 134))	('HPV', 'Species', '10566', (99, 102))	('MLL', 'Gene', (80, 83))	('SCC', 'Gene', '6317', (131, 134))	('MLL', 'Gene', '4297', (80, 83))	('MLL', 'Gene', (71, 74))
514179	29209433	In the same study, the mutational spectrum of HPV-negative tumors resulted very similar to those observed in lung and esophageal squamous cell carcinomas and included mutations of the HMT nuclear-receptor-binding SET-domain-containing 1 (NSD1), which preferentially targets H3K36 methylation.	('carcinomas', 'Phenotype', 'HP:0030731', (143, 153))	('carcinoma', 'Phenotype', 'HP:0030731', (143, 152))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (129, 153))	('HMT', 'Gene', (184, 187))	('NSD1', 'Gene', '64324', (238, 242))	('HPV', 'Species', '10566', (46, 49))	('mutations', 'Var', (167, 176))	('esophageal squamous cell carcinomas', 'Disease', 'MESH:D000077277', (118, 153))	('tumors', 'Disease', (59, 65))	('tumors', 'Disease', 'MESH:D009369', (59, 65))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (129, 152))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('esophageal squamous cell carcinomas', 'Disease', (118, 153))	('H3', 'Gene', '117579', (274, 276))	('lung', 'Disease', (109, 113))	('NSD1', 'Gene', (238, 242))	('HMT', 'Gene', '3176', (184, 187))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
514181	29209433	have recently identified a DNA methylation cluster that exclusively contained samples carrying NSD1 mutations or H3K36 alterations.	('mutations', 'Var', (100, 109))	('NSD1', 'Gene', '64324', (95, 99))	('H3', 'Gene', '117579', (113, 115))	('alterations', 'Var', (119, 130))	('NSD1', 'Gene', (95, 99))
514182	29209433	Results were further validated in an independent cohort of OPSCC samples, in which the presence of H3K36 alterations associated to a drastic decrease in H3K36 methylation levels.	('presence', 'Var', (87, 95))	('OPSCC', 'Phenotype', 'HP:0012182', (59, 64))	('SCC', 'Gene', '6317', (61, 64))	('H3', 'Gene', '117579', (153, 155))	('alterations', 'Var', (105, 116))	('decrease', 'NegReg', (141, 149))	('H3', 'Gene', '117579', (99, 101))	('methylation levels', 'MPA', (159, 177))	('SCC', 'Gene', (61, 64))
514183	29209433	Altogether, these findings suggest that NSD1 mutations and/or H3K36 alterations may be associated with a genome-wide hypomethylation phenotype in OPSCC.	('H3', 'Gene', '117579', (62, 64))	('mutations', 'Var', (45, 54))	('OPSCC', 'Phenotype', 'HP:0012182', (146, 151))	('NSD1', 'Gene', '64324', (40, 44))	('associated', 'Reg', (87, 97))	('SCC', 'Gene', (148, 151))	('alterations', 'Var', (68, 79))	('NSD1', 'Gene', (40, 44))	('SCC', 'Gene', '6317', (148, 151))
514184	29209433	Among histone "variants," phosphorylated H2A.X (gammaH2A.X) variant represents a useful marker of DNA integrity and repair, because of its ability in recruiting DNA repair proteins at the site of the dysplastic tissue.	('H2A.X', 'Gene', '3014', (53, 58))	('recruiting', 'PosReg', (150, 160))	('variant', 'Var', (60, 67))	('H2A.X', 'Gene', (41, 46))	('dysplastic', 'Disease', 'MESH:D004416', (200, 210))	('gammaH2A', 'Chemical', '-', (48, 56))	('dysplastic', 'Disease', (200, 210))	('H2A.X', 'Gene', '3014', (41, 46))	('H2A.X', 'Gene', (53, 58))
514193	29209433	In HPV-driven cancers, histone modifications on targeted genes can mediate bidirectional effects on gene transcription.	('HPV-driven cancers', 'Disease', (3, 21))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('gene transcription', 'MPA', (100, 118))	('HPV-driven cancers', 'Disease', 'MESH:D030361', (3, 21))	('histone modifications', 'Var', (23, 44))	('cancers', 'Phenotype', 'HP:0002664', (14, 21))
514201	29209433	Polycomb silencers mediate the repression of key tumor-suppressor pathways and play a crucial role in suppressing genes required for differentiation and maintaining a cancer stem cell phenotype (reviewed in).	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('cancer', 'Disease', (167, 173))	('suppressing', 'NegReg', (102, 113))	('tumor', 'Disease', (49, 54))	('Polycomb', 'Var', (0, 8))	('genes', 'MPA', (114, 119))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('repression', 'NegReg', (31, 41))
514204	29209433	Furthermore, double immunofluorescence quantification of histone lysine methylation revealed that p16-positive OPSCC had global elevation of H3K27me3 and H4K20me1 that are both involved in generating a repressive gene environment through the formation of facultative heterochromatin.	('lysine', 'Chemical', 'MESH:D008239', (65, 71))	('H3', 'Gene', '117579', (141, 143))	('H4K20me1', 'Var', (154, 162))	('p16', 'Gene', (98, 101))	('SCC', 'Gene', '6317', (113, 116))	('OPSCC', 'Phenotype', 'HP:0012182', (111, 116))	('men', 'Species', '9606', (225, 228))	('p16', 'Gene', '1029', (98, 101))	('SCC', 'Gene', (113, 116))	('elevation', 'PosReg', (128, 137))
514206	29209433	Furthermore, a significant enrichment of highly methylated promoter regions of PRC2 targets together with a higher expression of DNMT3a was observed in cell lines from HPV-positive OPSCC compared to HPV-negative ones.	('HPV', 'Species', '10566', (199, 202))	('HPV-positive', 'Var', (168, 180))	('HPV', 'Species', '10566', (168, 171))	('DNMT3a', 'Gene', (129, 135))	('PRC2', 'Gene', (79, 83))	('DNMT3a', 'Gene', '1788', (129, 135))	('SCC', 'Gene', (183, 186))	('expression', 'MPA', (115, 125))	('men', 'Species', '9606', (33, 36))	('highly', 'PosReg', (41, 47))	('SCC', 'Gene', '6317', (183, 186))	('higher', 'PosReg', (108, 114))	('OPSCC', 'Phenotype', 'HP:0012182', (181, 186))
514208	29209433	While in environmental-related carcinomas the cyclin-dependent kinase inhibitor p16INK4a is usually downregulated mainly by gene mutation or deletion, it is frequently overexpressed in HPV-driven tumor and thus, it is considered a surrogate marker for active HPV involvement in OPSCC carcinogenesis.	('carcinomas', 'Disease', (31, 41))	('carcinogenesis', 'Disease', (284, 298))	('HPV', 'Species', '10566', (259, 262))	('SCC', 'Gene', '6317', (280, 283))	('carcinogenesis', 'Disease', 'MESH:D063646', (284, 298))	('HPV-driven tumor', 'Disease', (185, 201))	('cyclin', 'Gene', '5111', (46, 52))	('p16INK4a', 'Gene', '1029', (80, 88))	('men', 'Species', '9606', (16, 19))	('men', 'Species', '9606', (270, 273))	('SCC', 'Gene', (280, 283))	('carcinoma', 'Phenotype', 'HP:0030731', (31, 40))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('OPSCC', 'Phenotype', 'HP:0012182', (278, 283))	('deletion', 'Var', (141, 149))	('overexpressed', 'PosReg', (168, 181))	('HPV', 'Species', '10566', (185, 188))	('cyclin', 'Gene', (46, 52))	('carcinomas', 'Disease', 'MESH:D002277', (31, 41))	('carcinomas', 'Phenotype', 'HP:0030731', (31, 41))	('HPV-driven tumor', 'Disease', 'MESH:D030361', (185, 201))	('gene mutation', 'Var', (124, 137))	('downregulated', 'NegReg', (100, 113))	('p16INK4a', 'Gene', (80, 88))
514213	29209433	In lung cancer, mutations and deregulations of histone-modifying enzymes have been described in association with tobacco smoke condensate, and smoke-induced modifications in histone patterns have linked to aberrant gene expression in immune cells.	('tobacco', 'Species', '4097', (113, 120))	('lung cancer', 'Disease', (3, 14))	('aberrant gene expression', 'MPA', (206, 230))	('lung cancer', 'Phenotype', 'HP:0100526', (3, 14))	('mutations', 'Var', (16, 25))	('association', 'Interaction', (96, 107))	('histone-modifying enzymes', 'Enzyme', (47, 72))	('histone', 'Protein', (174, 181))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('lung cancer', 'Disease', 'MESH:D008175', (3, 14))	('deregulations', 'MPA', (30, 43))	('modifications', 'Var', (157, 170))	('linked to', 'Reg', (196, 205))
514225	29209433	Apart from miRNA machinery, single nucleotide polymorphisms in miRNA precursors may influence their maturation, and thereby modulate their expression as reported for miR-146, miR-149, miR-196, and miR-499.	('single nucleotide polymorphisms', 'Var', (28, 59))	('miR', 'Gene', (197, 200))	('miR', 'Gene', '220972', (11, 14))	('miR-499', 'Gene', (197, 204))	('miR-149', 'Gene', (175, 182))	('miR', 'Gene', (11, 14))	('miR', 'Gene', '220972', (184, 187))	('maturation', 'MPA', (100, 110))	('influence', 'Reg', (84, 93))	('miR', 'Gene', '220972', (175, 178))	('miR-149', 'Gene', '406941', (175, 182))	('miR', 'Gene', '220972', (63, 66))	('miR', 'Gene', '220972', (166, 169))	('miR', 'Gene', (184, 187))	('miR', 'Gene', '220972', (197, 200))	('miR', 'Gene', (175, 178))	('miR', 'Gene', (63, 66))	('expression', 'MPA', (139, 149))	('miR', 'Gene', (166, 169))	('miR-499', 'Gene', '574501', (197, 204))	('modulate', 'Reg', (124, 132))
514226	29209433	Polymorphisms in the immature form of these miRNAs were found to significantly increase the risk of HPV16-associated OPSCC, particularly in never smokers.	('increase', 'PosReg', (79, 87))	('miR', 'Gene', '220972', (44, 47))	('miR', 'Gene', (44, 47))	('OPSCC', 'Phenotype', 'HP:0012182', (117, 122))	('SCC', 'Gene', '6317', (119, 122))	('Polymorphisms', 'Var', (0, 13))	('HPV16-associated', 'Gene', (100, 116))	('HPV16', 'Species', '333760', (100, 105))	('SCC', 'Gene', (119, 122))
514227	29209433	Interestingly, miRNAs have been reported to be epigenetically silenced in laryngeal SCC, oral cavity SCC (OSCC), and OPSCC.	('SCC', 'Gene', '6317', (84, 87))	('OPSCC', 'Phenotype', 'HP:0012182', (117, 122))	('SCC', 'Gene', '6317', (119, 122))	('SCC', 'Gene', (107, 110))	('epigenetically silenced', 'Var', (47, 70))	('miR', 'Gene', '220972', (15, 18))	('SCC', 'Gene', (101, 104))	('SCC', 'Gene', '6317', (107, 110))	('SCC', 'Gene', (84, 87))	('SCC', 'Gene', (119, 122))	('SCC', 'Gene', '6317', (101, 104))	('miR', 'Gene', (15, 18))
514229	29209433	Furthermore, miR-9 ectopic expression led to PTEN upregulation, and a significant repression of HNSCC proliferation.	('HNSCC', 'Phenotype', 'HP:0012288', (96, 101))	('miR', 'Gene', '220972', (13, 16))	('ectopic expression', 'Var', (19, 37))	('miR', 'Gene', (13, 16))	('SCC', 'Gene', '6317', (98, 101))	('upregulation', 'PosReg', (50, 62))	('repression', 'NegReg', (82, 92))	('PTEN', 'Gene', (45, 49))	('PTEN', 'Gene', '5728', (45, 49))	('SCC', 'Gene', (98, 101))
514232	29209433	Along this line, miR-874 silencing by aberrant CpG promoter methylation has been frequently described in laryngeal SCC, OSCC, and OPSCC.	('aberrant', 'Var', (38, 46))	('miR-874', 'Gene', (17, 24))	('SCC', 'Gene', (121, 124))	('SCC', 'Gene', (132, 135))	('miR-874', 'Gene', '100126343', (17, 24))	('SCC', 'Gene', (115, 118))	('SCC', 'Gene', '6317', (132, 135))	('CpG promoter', 'Gene', (47, 59))	('OPSCC', 'Phenotype', 'HP:0012182', (130, 135))	('silencing', 'NegReg', (25, 34))	('SCC', 'Gene', '6317', (115, 118))	('SCC', 'Gene', '6317', (121, 124))
514246	29209433	In a study of Lajer et al., HPV-positive OPSCC showed a considerable upregulation of miR-363 expression, consistent with another report of Wald et al., in which HPV16 E6 knockdown was accompanied by a reduction of miR-363 levels in HNSCC, thus suggesting a possible role for miR-363 in HPV-positive OPSCC.	('miR', 'Gene', (85, 88))	('miR', 'Gene', (214, 217))	('SCC', 'Gene', '6317', (234, 237))	('miR', 'Gene', (275, 278))	('reduction', 'NegReg', (201, 210))	('knockdown', 'Var', (170, 179))	('SCC', 'Gene', (234, 237))	('HPV', 'Species', '10566', (28, 31))	('SCC', 'Gene', '6317', (43, 46))	('HPV16', 'Species', '333760', (161, 166))	('HNSCC', 'Phenotype', 'HP:0012288', (232, 237))	('SCC', 'Gene', (43, 46))	('SCC', 'Gene', '6317', (301, 304))	('HPV', 'Species', '10566', (161, 164))	('upregulation', 'PosReg', (69, 81))	('OPSCC', 'Phenotype', 'HP:0012182', (41, 46))	('SCC', 'Gene', (301, 304))	('miR', 'Gene', '220972', (85, 88))	('OPSCC', 'Phenotype', 'HP:0012182', (299, 304))	('miR', 'Gene', '220972', (214, 217))	('HPV16', 'Gene', (161, 166))	('HPV', 'Species', '10566', (286, 289))	('expression', 'MPA', (93, 103))	('miR', 'Gene', '220972', (275, 278))
514250	29209433	In a previous study of Jang et al., MALAT1 expression increased in oral keratinocytes transfected with HPV16 E6 and HPV E6/E7 oncoproteins, indicating HPV16 may promote cell proliferation by promoting MALAT1 upregulation.	('MALAT1', 'Gene', '378938', (201, 207))	('upregulation', 'PosReg', (208, 220))	('promote', 'PosReg', (161, 168))	('HPV16', 'Gene', (103, 108))	('cell proliferation', 'CPA', (169, 187))	('HPV', 'Species', '10566', (116, 119))	('HPV16', 'Var', (151, 156))	('HPV', 'Var', (116, 119))	('E6/E7', 'Gene', '1489078', (120, 125))	('HPV16', 'Species', '333760', (103, 108))	('MALAT1', 'Gene', (36, 42))	('HPV', 'Species', '10566', (151, 154))	('E6/E7', 'Gene', (120, 125))	('HPV', 'Species', '10566', (103, 106))	('increased', 'PosReg', (54, 63))	('MALAT1', 'Gene', '378938', (36, 42))	('MALAT1', 'Gene', (201, 207))	('promoting', 'PosReg', (191, 200))	('HPV16', 'Species', '333760', (151, 156))	('expression', 'MPA', (43, 53))
514260	29209433	The increasingly recognized role of aberrant epigenetic modifications in OPSCC biology strongly suggests for the opportunity to test epigenetic markers as potential indicators of disease prognosis and response to therapy.	('SCC', 'Gene', '6317', (75, 78))	('OPSCC', 'Phenotype', 'HP:0012182', (73, 78))	('aberrant epigenetic modifications', 'Var', (36, 69))	('SCC', 'Gene', (75, 78))
514261	29209433	The ability to determine epigenetic alterations in premalignant lesions, serum, and saliva may also provide valuable biomarkers for the early detection of OPSCC and for monitoring its recurrence.	('SCC', 'Gene', (157, 160))	('SCC', 'Gene', '6317', (157, 160))	('epigenetic alterations', 'Var', (25, 47))	('OPSCC', 'Phenotype', 'HP:0012182', (155, 160))
514262	29209433	Consistent with the increasing role of aberrant DNA methylation in HNSCC biology, different studies have reported the methylation of single genes/loci to have a potential in predicting OPSCC clinical outcome.	('SCC', 'Gene', (69, 72))	('SCC', 'Gene', (187, 190))	('SCC', 'Gene', '6317', (69, 72))	('HNSCC', 'Phenotype', 'HP:0012288', (67, 72))	('SCC', 'Gene', '6317', (187, 190))	('predicting', 'Reg', (174, 184))	('aberrant', 'Var', (39, 47))	('OPSCC', 'Phenotype', 'HP:0012182', (185, 190))
514266	29209433	In the last years, a number of studies have sought to establish a correlation between promoter methylation and improved survival rate in HPV-positive OPSCC.	('survival rate', 'CPA', (120, 133))	('improved', 'PosReg', (111, 119))	('SCC', 'Gene', (152, 155))	('OPSCC', 'Phenotype', 'HP:0012182', (150, 155))	('SCC', 'Gene', '6317', (152, 155))	('HPV-positive', 'Gene', (137, 149))	('promoter methylation', 'Var', (86, 106))	('HPV', 'Species', '10566', (137, 140))
514267	29209433	provided the evidence that the downregulation of the serine/threonine-protein kinase SMG-1 by promoter hypermethylation correlated with HPV-positive status and improved OPSCC patient survival, and also with enhanced response to radiotherapy in HPV-positive HNSCC cell lines.	('SCC', 'Gene', (171, 174))	('response to radiotherapy', 'CPA', (216, 240))	('SCC', 'Gene', '6317', (259, 262))	('HNSCC', 'Phenotype', 'HP:0012288', (257, 262))	('HPV', 'Species', '10566', (244, 247))	('patient', 'Species', '9606', (175, 182))	('promoter hypermethylation', 'Var', (94, 119))	('SMG', 'Gene', (85, 88))	('SCC', 'Gene', '6317', (171, 174))	('SMG', 'Gene', '23034', (85, 88))	('OPSCC', 'Phenotype', 'HP:0012182', (169, 174))	('HPV-positive status', 'Disease', (136, 155))	('enhanced', 'PosReg', (207, 215))	('SCC', 'Gene', (259, 262))	('improved', 'PosReg', (160, 168))	('downregulation', 'NegReg', (31, 45))	('HPV', 'Species', '10566', (136, 139))
514271	29209433	Interestingly, the association between smoking habits and LINE-1 hypomethylation was stronger in HPV16-negative OPSCC cases.	('stronger', 'Reg', (85, 93))	('SCC', 'Gene', (114, 117))	('hypomethylation', 'Var', (65, 80))	('OPSCC', 'Phenotype', 'HP:0012182', (112, 117))	('SCC', 'Gene', '6317', (114, 117))	('HPV16', 'Species', '333760', (97, 102))	('HPV16-negative', 'Gene', (97, 111))
514282	29209433	In this context, epigenetic drugs might represent an important therapeutic modality for the clinical management of OPSCC patients.	('men', 'Species', '9606', (107, 110))	('SCC', 'Gene', (117, 120))	('OPSCC', 'Phenotype', 'HP:0012182', (115, 120))	('SCC', 'Gene', '6317', (117, 120))	('epigenetic drugs', 'Var', (17, 33))	('patients', 'Species', '9606', (121, 129))
514287	29209433	Furthermore, an immunomodulatory activity of 5-AZA-CdR, which may ensure efficient therapeutic anti-tumor effects in HPV-positive malignancies, has been also shown in mice vaccinated with HPV DNA vaccines.	('5-AZA-CdR', 'Var', (45, 54))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('HPV-positive malignancies', 'Disease', 'MESH:D030361', (117, 142))	('tumor', 'Disease', (100, 105))	('HPV', 'Species', '10566', (117, 120))	('HPV-positive malignancies', 'Disease', (117, 142))	('5-AZA-CdR', 'Chemical', '-', (45, 54))	('HPV', 'Species', '10566', (188, 191))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('mice', 'Species', '10090', (167, 171))
514290	29209433	Epigenetic drugs have also been explored in combination with chemotherapeutics, indicating they may sensitize HNSCC cells to chemotherapy-induced apoptosis.	('sensitize', 'Reg', (100, 109))	('SCC', 'Gene', '6317', (112, 115))	('HNSCC', 'Phenotype', 'HP:0012288', (110, 115))	('Epigenetic drugs', 'Var', (0, 16))	('chemotherapy-induced apoptosis', 'CPA', (125, 155))	('SCC', 'Gene', (112, 115))
514291	29209433	For example, the combinations of 5-AZA-CdR or HDACi with cisplatin enhanced the cytotoxic effectiveness of this well-established chemotherapeutic in HNSCC treatment.	('combinations', 'Interaction', (17, 29))	('5-AZA-CdR', 'Chemical', '-', (33, 42))	('HDAC', 'Gene', (46, 50))	('SCC', 'Gene', '6317', (151, 154))	('5-AZA-CdR', 'Var', (33, 42))	('HNSCC', 'Phenotype', 'HP:0012288', (149, 154))	('HDAC', 'Gene', '9734', (46, 50))	('cytotoxic effectiveness', 'CPA', (80, 103))	('men', 'Species', '9606', (160, 163))	('cisplatin', 'Chemical', 'MESH:D002945', (57, 66))	('SCC', 'Gene', (151, 154))	('enhanced', 'PosReg', (67, 75))
514294	29209433	Based on these promising pre-clinical data, OPSCC clinical trials involving HDACi have been carried out or are on-going (NCT01064921, NCT01695122, NCT01249443, available at www.clinicaltrials.gov).	('HDAC', 'Gene', (76, 80))	('NCT01064921', 'Var', (121, 132))	('HDAC', 'Gene', '9734', (76, 80))	('SCC', 'Gene', (46, 49))	('OPSCC', 'Phenotype', 'HP:0012182', (44, 49))	('SCC', 'Gene', '6317', (46, 49))
514296	29209433	In this context, epigenetic inhibitors targeting the EZH2 pathway have recently shown effectiveness in suppressing OPSCC growth and survival, with a major effect in HPV-positive cell lines.	('HPV', 'Species', '10566', (165, 168))	('SCC', 'Gene', (117, 120))	('OPSCC', 'Phenotype', 'HP:0012182', (115, 120))	('epigenetic inhibitors', 'Var', (17, 38))	('SCC', 'Gene', '6317', (117, 120))	('suppressing', 'NegReg', (103, 114))	('EZH2', 'Gene', (53, 57))	('EZH2', 'Gene', '2146', (53, 57))
514300	29209433	Epigenetic alterations, including DNA methylation, histone modification, and ncRNAs, clearly impact on key pathways that are involved in OPSCC biology.	('Epigenetic alterations', 'Var', (0, 22))	('SCC', 'Gene', '6317', (139, 142))	('histone', 'MPA', (51, 58))	('ncRNA', 'Gene', (77, 82))	('ncRNA', 'Gene', '220202', (77, 82))	('DNA', 'MPA', (34, 37))	('SCC', 'Gene', (139, 142))	('key pathways', 'Pathway', (103, 115))	('impact', 'Reg', (93, 99))	('OPSCC', 'Phenotype', 'HP:0012182', (137, 142))
514302	29209433	HPV-positive and HPV-negative OPSCC have singular epigenetic drivers which may impact on different clinical behaviors and treatment response and strengthen the concept that HPV-driven OPSCC are biologically distinct from non-HPV-driven tumors.	('SCC', 'Gene', '6317', (186, 189))	('HPV', 'Species', '10566', (0, 3))	('OPSCC', 'Phenotype', 'HP:0012182', (184, 189))	('HPV', 'Species', '10566', (173, 176))	('HPV-driven tumors', 'Disease', (225, 242))	('men', 'Species', '9606', (127, 130))	('HPV-driven tumors', 'Disease', 'MESH:D030361', (225, 242))	('HPV', 'Species', '10566', (225, 228))	('epigenetic', 'Var', (50, 60))	('SCC', 'Gene', (32, 35))	('OPSCC', 'Phenotype', 'HP:0012182', (30, 35))	('SCC', 'Gene', (186, 189))	('tumor', 'Phenotype', 'HP:0002664', (236, 241))	('SCC', 'Gene', '6317', (32, 35))	('tumors', 'Phenotype', 'HP:0002664', (236, 242))	('impact', 'Reg', (79, 85))	('HPV', 'Species', '10566', (17, 20))
514307	28036263	Quantitative assessment of the diagnostic role of FHIT promoter methylation in non-small cell lung cancer Aberrant methylation of CpG islands acquired in promoter regions plays an important role in carcinogenesis.	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (79, 105))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (83, 105))	('Aberrant', 'Var', (106, 114))	('carcinogenesis', 'Disease', (198, 212))	('FHIT', 'Gene', '2272', (50, 54))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('cancer', 'Disease', (99, 105))	('methylation', 'MPA', (115, 126))	('lung cancer', 'Phenotype', 'HP:0100526', (94, 105))	('carcinogenesis', 'Disease', 'MESH:D063646', (198, 212))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('FHIT', 'Gene', (50, 54))
514308	28036263	Accumulated evidence demonstrates FHIT gene promoter hyper-methylation is involved in non-small cell lung cancer (NSCLC).	('non-small cell lung cancer', 'Disease', (86, 112))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (90, 112))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('FHIT gene', 'Gene', (34, 43))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (86, 112))	('NSCLC', 'Disease', (114, 119))	('NSCLC', 'Disease', 'MESH:D002289', (114, 119))	('promoter hyper-methylation', 'Var', (44, 70))	('lung cancer', 'Phenotype', 'HP:0100526', (101, 112))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (86, 112))	('involved', 'Reg', (74, 82))
514314	28036263	Lung cancer is a complicated disease involving genetic and epigenetic variation, and is one of the leading causes of cancer death all over the world.	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('Lung cancer', 'Phenotype', 'HP:0100526', (0, 11))	('Lung cancer', 'Disease', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))	('epigenetic variation', 'Var', (59, 79))	('cancer death', 'Disease', (117, 129))	('Lung cancer', 'Disease', 'MESH:D008175', (0, 11))	('cancer death', 'Disease', 'MESH:D003643', (117, 129))
514317	28036263	Hence, with the advantages like good chemical stability, non-invasive detection ability, quantitative signal, reasonable cost and low requirements for sample quality, DNA methylation could be a promising biomarker in early cancer detection.	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('methylation', 'Var', (171, 182))	('cancer', 'Disease', 'MESH:D009369', (223, 229))	('DNA methylation', 'Var', (167, 182))	('cancer', 'Disease', (223, 229))
514321	28036263	In addition, aberrant transcripts of FHIT have been found in other kinds of tumors, such as gastric, esophageal, and colon carcinomas.	('found', 'Reg', (52, 57))	('colon carcinomas', 'Disease', (117, 133))	('FHIT', 'Gene', (37, 41))	('colon carcinomas', 'Disease', 'MESH:D015179', (117, 133))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumors', 'Disease', (76, 82))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('transcripts', 'MPA', (22, 33))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('carcinomas', 'Phenotype', 'HP:0030731', (123, 133))	('gastric', 'Disease', (92, 99))	('esophageal', 'Disease', (101, 111))	('aberrant', 'Var', (13, 21))
514323	28036263	The FHIT -/- mice were more prone to develop carcinogen-induced tumors as well as the spontaneous tumors than wild type mice.	('mice', 'Species', '10090', (13, 17))	('tumors', 'Disease', (64, 70))	('tumors', 'Disease', (98, 104))	('mice', 'Species', '10090', (120, 124))	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('FHIT -/-', 'Var', (4, 12))	('tumors', 'Disease', 'MESH:D009369', (98, 104))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('develop', 'PosReg', (37, 44))
514326	28036263	In summary, FHIT is now considered as a cancer suppressor gene and the loss or aberrant transcripts of FHIT may be associated with carcinogenesis.	('carcinogenesis', 'Disease', (131, 145))	('aberrant transcripts', 'Var', (79, 99))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('cancer', 'Disease', (40, 46))	('associated', 'Reg', (115, 125))	('carcinogenesis', 'Disease', 'MESH:D063646', (131, 145))	('loss', 'NegReg', (71, 75))	('FHIT', 'Gene', (103, 107))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))
514333	28036263	The odd ratio (OR) for FHIT methylation in cancer group was 3.43 (95% CI: 1.85 - 6.36) in random effects model, and 2.03 (95% CI: 1.60 - 2.57) in fixed effects model, indicating a slight increase of methylation in lung cancer tissues (Figure 2).	('lung cancer', 'Phenotype', 'HP:0100526', (214, 225))	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('methylation', 'MPA', (199, 210))	('increase', 'PosReg', (187, 195))	('FHIT', 'Gene', (23, 27))	('cancer', 'Disease', (43, 49))	('cancer', 'Disease', 'MESH:D009369', (219, 225))	('lung cancer', 'Disease', 'MESH:D008175', (214, 225))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('cancer', 'Disease', (219, 225))	('methylation', 'Var', (28, 39))	('lung cancer', 'Disease', (214, 225))
514335	28036263	Both tissue and plasma groups showed significant association between FHIT methylation and NSCLC (OR = 3.68 and 3.89, respectively) (Figure 3D), which suggested that FHIT methylation test is a promising biomarker for NSCLC diagnosis with either tissue or plasma samples.	('NSCLC', 'Disease', (216, 221))	('methylation', 'Var', (74, 85))	('NSCLC', 'Disease', 'MESH:D002289', (216, 221))	('NSCLC', 'Disease', (90, 95))	('NSCLC', 'Disease', 'MESH:D002289', (90, 95))	('FHIT', 'Gene', (69, 73))
514337	28036263	The adjusted pooled OR after the trim and fill analysis was 2.09 (95% CI: 1.10 - 3.96, P = 0.024) in the random effects model indicating a significantly positive association between FHIT methylation and NSCLC (Supplementary Figure 2).	('NSCLC', 'Disease', (203, 208))	('positive', 'PosReg', (153, 161))	('NSCLC', 'Disease', 'MESH:D002289', (203, 208))	('methylation', 'Var', (187, 198))	('FHIT', 'Protein', (182, 186))
514342	28036263	Moreover, we downloaded GSE56044 with 124 NSCLC tissues and 12 adjacent normal tissues for further validation.	('NSCLC', 'Disease', 'MESH:D002289', (42, 47))	('GSE56044', 'Var', (24, 32))	('NSCLC', 'Disease', (42, 47))
514343	28036263	GSE56044 didn't have clinical information on the subtypes of NSCLC and thus we just utilized NSCLC tissues for subsequent comparison.	('NSCLC', 'Disease', (93, 98))	('NSCLC', 'Disease', 'MESH:D002289', (93, 98))	('NSCLC', 'Disease', (61, 66))	('NSCLC', 'Disease', 'MESH:D002289', (61, 66))	('GSE56044', 'Var', (0, 8))
514352	28036263	In addition, we also detected the methylation status of FHIT promoter in other kinds of cancers using TCGA datasets for further validation, and similar results were obtained and showed limited diagnostic ability (Supplementary Table 4).	('cancers', 'Disease', 'MESH:D009369', (88, 95))	('detected', 'Reg', (21, 29))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('cancers', 'Disease', (88, 95))	('FHIT promoter', 'Gene', (56, 69))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('methylation status', 'Var', (34, 52))
514354	28036263	Subgroup analysis showed that FHIT methylation is significantly relevant to NSCLC in Asians (OR = 3.50, 95% CI: 1.50 - 8.14) but not in Caucasian population (OR = 2.55, 95% CI: 0.86 - 7.57), indicating that aberrant methylation of FHIT can be a diagnostic biomarker for NSCLC in Asian population.	('aberrant methylation', 'Var', (207, 227))	('NSCLC', 'Disease', 'MESH:D002289', (270, 275))	('NSCLC', 'Disease', (76, 81))	('NSCLC', 'Disease', 'MESH:D002289', (76, 81))	('NSCLC', 'Disease', (270, 275))	('FHIT', 'Gene', (231, 235))
514356	28036263	The above consistencies and inconsistencies between the three studies implied the need to test the association between FHIT methylation and NSCLC with larger sample sizes and more advanced technology.	('NSCLC', 'Disease', 'MESH:D002289', (140, 145))	('methylation', 'Var', (124, 135))	('FHIT', 'Protein', (119, 123))	('NSCLC', 'Disease', (140, 145))
514364	28036263	And The GEO datasets including GSE39279, GSE52401 and GSE56044 were downloaded from Gene Expression Omnibus [ http://www.ncbi.nlm.nih.gov/geo/], including a sum of 568 NSCLC tissues and 256 adjacent or normal lung tissues.	('NSCLC', 'Disease', 'MESH:D002289', (168, 173))	('GSE56044', 'Var', (54, 62))	('NSCLC', 'Disease', (168, 173))
514443	33879658	Genetic variation in this family of genes can cause or contribute to a number of human disorders with Mendelian and complex inheritance.	('Genetic variation', 'Var', (0, 17))	('contribute to', 'Reg', (55, 68))	('human', 'Species', '9606', (81, 86))	('cause', 'Reg', (46, 51))	('human disorders', 'Disease', (81, 96))
514510	33879658	It has been concluded that miRNA-7 mediates SCLC chemoresistance by repressing ABCC1 expression, and might be a novel prognostic biomarker as well as therapeutic target.	('expression', 'MPA', (85, 95))	('SCLC', 'Disease', (44, 48))	('miRNA-7', 'Var', (27, 34))	('ABCC1', 'Gene', (79, 84))	('SCLC', 'Disease', 'MESH:D018288', (44, 48))	('ABCC1', 'Gene', '4363', (79, 84))	('repressing', 'NegReg', (68, 78))
514513	33879658	A study focusing on the genetic variants of ABCB1, ABCC2, and ABCG2 in colorectal cancer suggested that ABCB1 and ABCG2 haplotypes are associated with prognosis but ABCC2 is not.	('ABCB1', 'Gene', (44, 49))	('ABCB1', 'Gene', '5243', (44, 49))	('ABCC2', 'Gene', '1244', (51, 56))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('prognosis', 'MPA', (151, 160))	('ABCG2', 'Gene', (114, 119))	('colorectal cancer', 'Disease', 'MESH:D015179', (71, 88))	('ABCC2', 'Gene', (51, 56))	('variants', 'Var', (32, 40))	('ABCG2', 'Gene', '9429', (114, 119))	('ABCB1', 'Gene', (104, 109))	('ABCB1', 'Gene', '5243', (104, 109))	('colorectal cancer', 'Disease', (71, 88))	('ABCC2', 'Gene', '1244', (165, 170))	('haplotypes', 'Var', (120, 130))	('associated with', 'Reg', (135, 150))	('ABCG2', 'Gene', (62, 67))	('ABCG2', 'Gene', '9429', (62, 67))	('ABCC2', 'Gene', (165, 170))	('colorectal cancer', 'Phenotype', 'HP:0003003', (71, 88))
514519	33879658	Chen et al conducted a meta-analysis of polymorphisms of ABCB1 rs1128503, ABCC2 rs717620, and ABCC3 rs4148416 in osteosarcoma.	('osteosarcoma', 'Disease', 'MESH:D012516', (113, 125))	('ABCB1', 'Gene', (57, 62))	('rs4148416', 'Mutation', 'rs4148416', (100, 109))	('ABCB1', 'Gene', '5243', (57, 62))	('ABCC3', 'Gene', (94, 99))	('rs717620', 'Var', (80, 88))	('rs4148416', 'Var', (100, 109))	('ABCC2', 'Gene', '1244', (74, 79))	('rs717620', 'Mutation', 'rs717620', (80, 88))	('osteosarcoma', 'Disease', (113, 125))	('ABCC2', 'Gene', (74, 79))	('osteosarcoma', 'Phenotype', 'HP:0002669', (113, 125))	('rs1128503', 'Mutation', 'rs1128503', (63, 72))	('rs1128503', 'Var', (63, 72))
514520	33879658	They suggested that ABCC3 rs4148416 polymorphism is related to poor response in osteosarcoma and ABCB1 rs1128503 polymorphism to good response in Caucasians rather than Asians.	('rs1128503', 'Mutation', 'rs1128503', (103, 112))	('rs1128503', 'Var', (103, 112))	('ABCC3', 'Gene', (20, 25))	('osteosarcoma', 'Phenotype', 'HP:0002669', (80, 92))	('osteosarcoma', 'Disease', (80, 92))	('ABCB1', 'Gene', (97, 102))	('rs4148416', 'Mutation', 'rs4148416', (26, 35))	('ABCB1', 'Gene', '5243', (97, 102))	('rs4148416', 'Var', (26, 35))	('osteosarcoma', 'Disease', 'MESH:D012516', (80, 92))
514527	33879658	Targeted as target gene by miRNA-129-5p using bioinformatics and reporter gene assays, ABCB1, ABCC5, and ABCG1 were associated with chemoresistance of gastric cancer due to the potential significance of miRNA-129-5p as a therapeutic target.	('miRNA-129-5p', 'Var', (27, 39))	('associated with', 'Reg', (116, 131))	('ABCG1', 'Gene', '9619', (105, 110))	('chemoresistance', 'CPA', (132, 147))	('ABCC5', 'Gene', (94, 99))	('gastric cancer', 'Phenotype', 'HP:0012126', (151, 165))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('ABCB1', 'Gene', (87, 92))	('ABCB1', 'Gene', '5243', (87, 92))	('ABCC5', 'Gene', '10057', (94, 99))	('ABCG1', 'Gene', (105, 110))	('gastric cancer', 'Disease', (151, 165))	('gastric cancer', 'Disease', 'MESH:D013274', (151, 165))
514541	32635388	Methylation in HOX Clusters and Its Applications in Cancer Therapy HOX genes are commonly known for their role in embryonic development, defining the positional identity of most structures along the anterior-posterior axis.	('Methylation', 'Var', (0, 11))	('Cancer', 'Disease', 'MESH:D009369', (52, 58))	('Cancer', 'Phenotype', 'HP:0002664', (52, 58))	('Cancer', 'Disease', (52, 58))
514542	32635388	In postembryonic life, HOX gene aberrant expression can affect several processes involved in tumorigenesis such as proliferation, apoptosis, migration and invasion.	('affect', 'Reg', (56, 62))	('migration', 'CPA', (141, 150))	('HOX gene', 'Gene', (23, 31))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('apoptosis', 'CPA', (130, 139))	('tumor', 'Disease', (93, 98))	('proliferation', 'CPA', (115, 128))	('invasion', 'CPA', (155, 163))	('aberrant expression', 'Var', (32, 51))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
514543	32635388	Epigenetic modifications are implicated in gene expression deregulation, and it is accepted that methylation events affecting HOX gene expression play crucial roles in tumorigenesis.	('tumor', 'Disease', (168, 173))	('HOX gene', 'Gene', (126, 134))	('Epigenetic modifications', 'Var', (0, 24))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
514544	32635388	In fact, specific methylation profiles in the HOX gene sequence or in HOX-associated histones are recognized as potential biomarkers in several cancers, helping in the prediction of disease outcomes and adding information for decisions regarding the patient's treatment.	('methylation profiles', 'Var', (18, 38))	('helping', 'Reg', (153, 160))	('cancers', 'Phenotype', 'HP:0002664', (144, 151))	('cancers', 'Disease', (144, 151))	('cancers', 'Disease', 'MESH:D009369', (144, 151))	('patient', 'Species', '9606', (250, 257))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
514548	32635388	In the first stage of cancer research, great attention was paid to the description of mutations in oncogenes and tumor suppressor genes, and also to the functional characterization of genes and proteins.	('mutations', 'Var', (86, 95))	('tumor', 'Disease', (113, 118))	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('cancer', 'Disease', (22, 28))	('oncogenes', 'Gene', (99, 108))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))
514549	32635388	However, more recently, epigenetic modifications have emerged as a crucial mechanism for cancer onset, progression and metastasization.	('cancer', 'Disease', (89, 95))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('epigenetic modifications', 'Var', (24, 48))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
514553	32635388	Gene promoter regions frequently have CpG islands in which gene expression regulation can occur by methylation.. DNA methylation, leading to gene promoter hypermethylation and consequent transcriptional inhibition, has been observed in a wide variety of cancers with impact on their progression and aggressiveness (Figure 1).	('cancer', 'Phenotype', 'HP:0002664', (254, 260))	('hypermethylation', 'PosReg', (155, 171))	('transcriptional', 'MPA', (187, 202))	('aggressiveness', 'Disease', 'MESH:D001523', (299, 313))	('methylation', 'Var', (117, 128))	('aggressiveness', 'Disease', (299, 313))	('cancers', 'Phenotype', 'HP:0002664', (254, 261))	('aggressiveness', 'Phenotype', 'HP:0000718', (299, 313))	('observed', 'Reg', (224, 232))	('cancers', 'Disease', (254, 261))	('cancers', 'Disease', 'MESH:D009369', (254, 261))	('gene promoter', 'MPA', (141, 154))
514558	32635388	All these enzymes work in concert with ATP-dependent chromatin-remodeling complexes that recognize specific histone modifications, affecting the disassembly and assembly of nucleosomes and the movement of histone octamers along the DNA.	('disassembly', 'MPA', (145, 156))	('modifications', 'Var', (116, 129))	('histone', 'Protein', (205, 212))	('ATP', 'Chemical', 'MESH:D000255', (39, 42))	('movement', 'MPA', (193, 201))	('affecting', 'Reg', (131, 140))	('assembly of nucleosomes', 'MPA', (161, 184))
514559	32635388	Regarding the methylation pattern of histones, some methylations are features of active chromatin, such as the trimethylation of lysine 4 or 36 on histone H3 (H3K4me3 and H3K36me3), together with the hyperacetylation of histones H3 and H4 (H3ac, H4ac), while others are features of a silencing chromatin state, such as the trimethylation of lysines 9 and 27 on histone H3 (H3K9me3 and H3K27me3), together with the hypoacetylation of this histone.	('lysine', 'Chemical', 'MESH:D008239', (341, 347))	('H3', 'Gene', '126961', (229, 231))	('H3K27me3', 'Gene', '126961', (385, 393))	('H3', 'Gene', '126961', (373, 375))	('H3', 'Gene', '126961', (171, 173))	('lysines', 'Chemical', 'MESH:D008239', (341, 348))	('H3', 'Gene', '126961', (385, 387))	('H3', 'Gene', '126961', (240, 242))	('H3', 'Gene', '126961', (155, 157))	('hypoacetylation', 'MPA', (414, 429))	('H3', 'Gene', '126961', (159, 161))	('H3K27me3', 'Gene', (385, 393))	('lysine', 'Chemical', 'MESH:D008239', (129, 135))	('H3', 'Gene', '126961', (369, 371))	('methylations', 'Var', (52, 64))
514564	32635388	HOX gene mutations have been investigated in the past decade and found to increase cancer susceptibility, beyond being related to limb malformations, among other physiologic disorders.	('HOX', 'Gene', (0, 3))	('limb malformations', 'Phenotype', 'HP:0002813', (130, 148))	('mutations', 'Var', (9, 18))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('increase', 'PosReg', (74, 82))	('limb malformations', 'Disease', 'MESH:D000014', (130, 148))	('limb malformations', 'Disease', (130, 148))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('cancer', 'Disease', (83, 89))
514565	32635388	Interestingly, DNA methylation appears to be an important mechanism for HOX gene regulation, with a particular impact on cancer progression.	('methylation', 'Var', (19, 30))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('DNA', 'Var', (15, 18))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('impact', 'Reg', (111, 117))	('HOX gene', 'Gene', (72, 80))	('cancer', 'Disease', (121, 127))
514566	32635388	Therefore, the methylation status of a wide range of HOX genes is assuming increasing importance as a potential cancer prognostic marker.	('methylation', 'Var', (15, 26))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('HOX genes', 'Gene', (53, 62))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))
514567	32635388	In this review, we describe the state of knowledge of HOX gene methylation in cancer, clearly illustrating the remarkable potential of these epigenetic events for cancer prognostic marker discovery.	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('methylation', 'Var', (63, 74))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('cancer', 'Disease', (163, 169))	('cancer', 'Disease', 'MESH:D009369', (163, 169))	('HOX gene', 'Gene', (54, 62))
514572	32635388	Differential HOX gene methylation was also identified in neurofibroma, commonly a benign disease, and in endometrium with lower receptivity for embryo implantation.	('Differential HOX gene', 'Gene', (0, 21))	('benign disease', 'Disease', (82, 96))	('benign disease', 'Disease', 'MESH:D009369', (82, 96))	('identified', 'Reg', (43, 53))	('neurofibroma', 'Disease', (57, 69))	('neurofibroma', 'Phenotype', 'HP:0001067', (57, 69))	('neurofibroma', 'Disease', 'MESH:D009455', (57, 69))	('methylation', 'Var', (22, 33))
514574	32635388	The HOX gene hypermethylation is often linked to the silencing of HOX gene targets working as tumor-suppressor and/or apoptotic genes (Figure 1).	('HOX', 'Gene', (4, 7))	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Disease', (94, 99))	('linked', 'Reg', (39, 45))	('silencing', 'MPA', (53, 62))	('hypermethylation', 'Var', (13, 29))
514575	32635388	Interestingly, a recent study of DNA methylation profiles across the genome in normal and tumor tissues suggests an unexpected causal role of gene hypermethylation for HOX oncogene activation.	('HOX', 'Gene', (168, 171))	('hypermethylation', 'Var', (147, 163))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('activation', 'PosReg', (181, 191))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
514577	32635388	In this case, hypomethylation leads to HOXC10 overexpression, the downstream effects of which include increased of proliferation and the migration of cancer cells.	('leads to', 'Reg', (30, 38))	('HOXC10', 'Gene', (39, 45))	('overexpression', 'PosReg', (46, 60))	('hypomethylation', 'Var', (14, 29))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('cancer', 'Disease', (150, 156))	('increased', 'PosReg', (102, 111))	('HOXC10', 'Gene', '3226', (39, 45))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
514578	32635388	Genes from the HOXA cluster have a tendency for hypermethylation, and consequent downregulation, in most cancer types studied.	('cancer', 'Disease', (105, 111))	('hypermethylation', 'Var', (48, 64))	('HOXA', 'Gene', '3197', (15, 19))	('downregulation', 'NegReg', (81, 95))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('HOXA', 'Gene', (15, 19))
514579	32635388	It has been proposed that the methylation state of HOXA1, in combination with other genes, is a useful marker in the detection of malignant biliary obstruction, increasing the sensitivity of diagnoses by cytology and in the diagnosis of thyroid nodules.	('thyroid nodules', 'Disease', 'MESH:D016606', (237, 252))	('HOXA1', 'Gene', (51, 56))	('methylation', 'Var', (30, 41))	('malignant biliary obstruction', 'Disease', 'MESH:D009369', (130, 159))	('thyroid nodules', 'Phenotype', 'HP:0025388', (237, 252))	('HOXA1', 'Gene', '3198', (51, 56))	('malignant biliary obstruction', 'Disease', (130, 159))	('increasing', 'PosReg', (161, 171))	('thyroid nodules', 'Disease', (237, 252))	('biliary obstruction', 'Phenotype', 'HP:0005230', (140, 159))
514581	32635388	In gastric cancer, the aberrant HOXA1 methylation profile is associated with clinicopathological characteristics and clinical outcomes.	('HOXA1', 'Gene', '3198', (32, 37))	('gastric cancer', 'Phenotype', 'HP:0012126', (3, 17))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('HOXA1', 'Gene', (32, 37))	('methylation profile', 'Var', (38, 57))	('gastric cancer', 'Disease', (3, 17))	('associated', 'Reg', (61, 71))	('gastric cancer', 'Disease', 'MESH:D013274', (3, 17))	('aberrant', 'Var', (23, 31))
514584	32635388	It has been suggested that the HOXA2 methylation status, together with the methylation profile of other HOXA genes, may have prognostic value in laryngeal squamous cell carcinoma.	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (155, 178))	('methylation', 'Var', (37, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (169, 178))	('squamous cell carcinoma', 'Disease', (155, 178))	('HOXA2', 'Gene', (31, 36))	('HOXA', 'Gene', (104, 108))	('HOXA2', 'Gene', '3199', (31, 36))	('HOXA', 'Gene', (31, 35))	('HOXA', 'Gene', '3197', (104, 108))	('HOXA', 'Gene', '3197', (31, 35))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (155, 178))
514585	32635388	In addition, HOXA2 methylation analyses may work as a differential epigenetic biomarker between malignant and nonmalignant biliary and nasopharyngeal tissues.	('HOXA2', 'Gene', '3199', (13, 18))	('methylation', 'Var', (19, 30))	('HOXA2', 'Gene', (13, 18))
514589	32635388	In breast cancer, the increased DNA methylation of HOXA4 was proposed as a biomarker for early disease detection, and HOXA5 hypermethylation was identified specifically as part of the molecular portrait associated with high-grade ductal carcinoma in situ and Triple-negative breast cancer patients nonresponsive to neoadjuvant chemotherapy.	('ductal carcinoma', 'Disease', (230, 246))	('increased', 'PosReg', (22, 31))	('DNA', 'MPA', (32, 35))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('ductal carcinoma', 'Disease', 'MESH:D044584', (230, 246))	('breast cancer', 'Phenotype', 'HP:0003002', (275, 288))	('carcinoma', 'Phenotype', 'HP:0030731', (237, 246))	('patients', 'Species', '9606', (289, 297))	('HOXA4', 'Gene', '3201', (51, 56))	('hypermethylation', 'Var', (124, 140))	('associated', 'Reg', (203, 213))	('HOXA5', 'Gene', '3202', (118, 123))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('breast cancer', 'Disease', 'MESH:D001943', (275, 288))	('breast cancer', 'Disease', (275, 288))	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('HOXA4', 'Gene', (51, 56))	('cancer', 'Phenotype', 'HP:0002664', (282, 288))	('breast cancer', 'Disease', (3, 16))	('HOXA5', 'Gene', (118, 123))	('ductal carcinoma in situ', 'Phenotype', 'HP:0030075', (230, 254))
514591	32635388	The potential of HOX gene methylation profiles was also explored for the early detection of lung cancer in plasma and sputum, as HOXA7 and HOXA9 hypermethylation are part of the signature associated with this disease.	('lung cancer', 'Disease', (92, 103))	('lung cancer', 'Phenotype', 'HP:0100526', (92, 103))	('HOXA7', 'Gene', (129, 134))	('hypermethylation', 'Var', (145, 161))	('HOXA7', 'Gene', '3204', (129, 134))	('lung cancer', 'Disease', 'MESH:D008175', (92, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('HOXA9', 'Gene', '3205', (139, 144))	('HOXA9', 'Gene', (139, 144))
514592	32635388	The aberrant methylation of HOXA9 is characteristic of a wide variety of cancers, and is used as a biomarker for diagnoses and prognoses in distinct sample types.	('methylation', 'MPA', (13, 24))	('cancers', 'Disease', (73, 80))	('HOXA9', 'Gene', '3205', (28, 33))	('aberrant', 'Var', (4, 12))	('HOXA9', 'Gene', (28, 33))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('cancers', 'Disease', 'MESH:D009369', (73, 80))
514593	32635388	In serum, for example, the hypermethylation of HOXA9 was recently proposed as a marker to detect early epithelial ovarian cancer.	('hypermethylation', 'Var', (27, 43))	('epithelial ovarian cancer', 'Disease', (103, 128))	('HOXA9', 'Gene', (47, 52))	('epithelial ovarian cancer', 'Phenotype', 'HP:0025318', (103, 128))	('ovarian cancer', 'Phenotype', 'HP:0100615', (114, 128))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('HOXA9', 'Gene', '3205', (47, 52))	('epithelial ovarian cancer', 'Disease', 'MESH:D000077216', (103, 128))
514597	32635388	HOXA9 hypermethylation was also found to be a tool to identify advanced neck squamous cell carcinomas favoring tumor progression and metastasis, predict survival in breast cancer patients, together with HOXA10 hypermethylation, and detect early onset of endometrial cancer.	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (77, 101))	('endometrial cancer', 'Disease', 'MESH:D016889', (254, 272))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('breast cancer', 'Phenotype', 'HP:0003002', (165, 178))	('HOXA9', 'Gene', (0, 5))	('HOXA10', 'Gene', '3206', (203, 209))	('breast cancer', 'Disease', 'MESH:D001943', (165, 178))	('HOXA9', 'Gene', '3205', (0, 5))	('predict', 'Reg', (145, 152))	('breast cancer', 'Disease', (165, 178))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (77, 100))	('patients', 'Species', '9606', (179, 187))	('hypermethylation', 'Var', (6, 22))	('neck squamous cell carcinomas favoring tumor', 'Disease', (72, 116))	('neck squamous cell carcinomas favoring tumor', 'Disease', 'MESH:D000077195', (72, 116))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('endometrial cancer', 'Phenotype', 'HP:0012114', (254, 272))	('HOXA10', 'Gene', (203, 209))	('cancer', 'Phenotype', 'HP:0002664', (266, 272))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('carcinomas', 'Phenotype', 'HP:0030731', (91, 101))	('endometrial cancer', 'Disease', (254, 272))
514598	32635388	Knowledge of the downstream processes affected by HOXA gene deregulation, due to alterations in their methylation profile, is still incomplete for most cancers.	('HOXA', 'Gene', (50, 54))	('cancers', 'Disease', (152, 159))	('methylation profile', 'MPA', (102, 121))	('cancers', 'Disease', 'MESH:D009369', (152, 159))	('HOXA', 'Gene', '3197', (50, 54))	('alterations', 'Reg', (81, 92))	('deregulation', 'Var', (60, 72))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('cancers', 'Phenotype', 'HP:0002664', (152, 159))
514599	32635388	However, for HOXA10, for example, promoter hypermethylation favors miR-196b-5p-dependent cell proliferation and invasion in gastric cancer cells.	('gastric cancer', 'Disease', (124, 138))	('gastric cancer', 'Disease', 'MESH:D013274', (124, 138))	('invasion', 'CPA', (112, 120))	('miR-196b-5p-dependent', 'Gene', (67, 88))	('gastric cancer', 'Phenotype', 'HP:0012126', (124, 138))	('HOXA10', 'Gene', (13, 19))	('favors', 'PosReg', (60, 66))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('promoter hypermethylation', 'Var', (34, 59))	('HOXA10', 'Gene', '3206', (13, 19))
514600	32635388	In addition, in lung adenocarcinoma, HOXA11 hypermethylation seems to be related to cisplatin-resistance and to Akt/beta-catenin signaling activation, which occurs without interfering with the methylation status of HOXA11 antisense (HOXA11AS).	('activation', 'PosReg', (139, 149))	('Akt', 'Gene', '207', (112, 115))	('carcinoma', 'Phenotype', 'HP:0030731', (26, 35))	('HOXA11', 'Gene', (215, 221))	('HOXA11', 'Gene', (37, 43))	('HOXA11', 'Gene', '3207', (215, 221))	('HOXA11AS', 'Gene', '221883', (233, 241))	('HOXA11AS', 'Gene', (233, 241))	('cisplatin-resistance', 'MPA', (84, 104))	('HOXA11', 'Gene', '3207', (37, 43))	('lung adenocarcinoma', 'Disease', (16, 35))	('cisplatin', 'Chemical', 'MESH:D002945', (84, 93))	('hypermethylation', 'Var', (44, 60))	('beta-catenin', 'Gene', (116, 128))	('related', 'Reg', (73, 80))	('beta-catenin', 'Gene', '1499', (116, 128))	('HOXA11', 'Gene', (233, 239))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (16, 35))	('Akt', 'Gene', (112, 115))	('HOXA11', 'Gene', '3207', (233, 239))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (16, 35))
514601	32635388	Genes from the HOXB cluster (HOXB2, B3, B4, B9, B13) have been found to be hypermethylated in a variety of tumors.	('HOXB2', 'Gene', '3212', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('B3, B4, B9, B13', 'Gene', (36, 51))	('hypermethylated', 'Var', (75, 90))	('tumors', 'Disease', (107, 113))	('HOXB', 'Gene', '3210', (29, 33))	('HOXB', 'Gene', '3210', (15, 19))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('HOXB', 'Gene', (29, 33))	('HOXB', 'Gene', (15, 19))	('tumors', 'Disease', 'MESH:D009369', (107, 113))	('B3, B4, B9, B13)', 'Gene', '28908', (36, 52))	('HOXB2', 'Gene', (29, 34))
514602	32635388	The hypermethylation of HOXB2 was considered part of a signature exclusively found in the lymph node metastasis of the esophageal squamous cell carcinoma, serving as a possible biomarker for early diagnoses and prognoses.	('esophageal squamous cell carcinoma', 'Disease', (119, 153))	('HOXB2', 'Gene', (24, 29))	('HOXB2', 'Gene', '3212', (24, 29))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (130, 153))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (119, 153))	('hypermethylation', 'Var', (4, 20))
514604	32635388	HOXB3 and HOXB4 hypermethylation were identified as potential biomarkers in lung adenocarcinoma diagnosis.	('HOXB4', 'Gene', (10, 15))	('HOXB3', 'Gene', '3213', (0, 5))	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('lung adenocarcinoma', 'Disease', (76, 95))	('HOXB3', 'Gene', (0, 5))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (76, 95))	('HOXB4', 'Gene', '3214', (10, 15))	('hypermethylation', 'Var', (16, 32))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (76, 95))
514605	32635388	In addition, data from nearly 63,000 women of European ancestry suggest that HOXB3 hypermethylation is among the epigenetic modifications associated with epithelial ovarian cancer risk, and that HOXB4 is part of a multigene methylation signature found in circulating tumor cells from patients with metastatic breast cancer.	('patients', 'Species', '9606', (284, 292))	('tumor', 'Disease', 'MESH:D009369', (267, 272))	('breast cancer', 'Disease', 'MESH:D001943', (309, 322))	('breast cancer', 'Disease', (309, 322))	('epithelial ovarian cancer', 'Disease', 'MESH:D000077216', (154, 179))	('ovarian cancer', 'Phenotype', 'HP:0100615', (165, 179))	('tumor', 'Phenotype', 'HP:0002664', (267, 272))	('HOXB3', 'Gene', (77, 82))	('women', 'Species', '9606', (37, 42))	('cancer', 'Phenotype', 'HP:0002664', (316, 322))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('epithelial ovarian cancer', 'Phenotype', 'HP:0025318', (154, 179))	('HOXB4', 'Gene', (195, 200))	('HOXB3', 'Gene', '3213', (77, 82))	('hypermethylation', 'Var', (83, 99))	('HOXB4', 'Gene', '3214', (195, 200))	('breast cancer', 'Phenotype', 'HP:0003002', (309, 322))	('associated', 'Reg', (138, 148))	('tumor', 'Disease', (267, 272))	('epithelial ovarian cancer', 'Disease', (154, 179))
514609	32635388	Most genes from the HOXC cluster have been identified as hypermethylated in cancer (HOXC4, C5, C6, C8, C9).	('HOXC', 'Gene', '3220', (20, 24))	('hypermethylated', 'Var', (57, 72))	('HOXC', 'Gene', (20, 24))	('C5, C6, C8, C9', 'Gene', '727;729;3224', (91, 105))	('HOXC', 'Gene', '3220', (84, 88))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('HOXC4', 'Gene', '3221', (84, 89))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('HOXC', 'Gene', (84, 88))	('HOXC4', 'Gene', (84, 89))
514610	32635388	Methylated regions in a gene collection that includes HOXC4 were considered important in estimating cancer risk in urothelium and as part of a prognostic signature predicting survival in patients with oral squamous cell carcinoma.	('oral squamous cell carcinoma', 'Disease', (201, 229))	('patients', 'Species', '9606', (187, 195))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (206, 229))	('HOXC4', 'Gene', (54, 59))	('carcinoma', 'Phenotype', 'HP:0030731', (220, 229))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (201, 229))	('Methylated', 'Var', (0, 10))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('HOXC4', 'Gene', '3221', (54, 59))
514611	32635388	The role of HOXC8 in breast cancer, in which silencing seems to interfere with the self-renewal, differentiation and transformation of breast cancer stem cells, is also instigated by promoter hypermethylation.	('transformation', 'CPA', (117, 131))	('silencing', 'Var', (45, 54))	('HOXC8', 'Gene', '3224', (12, 17))	('HOXC8', 'Gene', (12, 17))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('breast cancer', 'Disease', 'MESH:D001943', (21, 34))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('differentiation', 'CPA', (97, 112))	('breast cancer', 'Disease', (21, 34))	('interfere', 'NegReg', (64, 73))	('breast cancer', 'Phenotype', 'HP:0003002', (21, 34))	('self-renewal', 'CPA', (83, 95))	('breast cancer', 'Disease', 'MESH:D001943', (135, 148))	('breast cancer', 'Disease', (135, 148))	('breast cancer', 'Phenotype', 'HP:0003002', (135, 148))
514614	32635388	HOXD1 hypermethylation is part of a signature helping to predict lymph node metastasis in gastric cancer.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('gastric cancer', 'Disease', 'MESH:D013274', (90, 104))	('hypermethylation', 'Var', (6, 22))	('HOXD1', 'Gene', (0, 5))	('gastric cancer', 'Phenotype', 'HP:0012126', (90, 104))	('HOXD1', 'Gene', '3231', (0, 5))	('lymph node metastasis', 'CPA', (65, 86))	('gastric cancer', 'Disease', (90, 104))
514615	32635388	Similarly, HOXD3 hypermethylation is part of a panel that includes HOXD8 methylation, which makes it possible to test the clinical significance of prostate cancer using urine samples, and is also considered to be among the prognostic indicators of late recurrence or of the need for hormone therapy after surgery in prostate cancer biopsies.	('HOXD3', 'Gene', '3232', (11, 16))	('prostate cancer', 'Disease', 'MESH:D011471', (147, 162))	('prostate cancer', 'Disease', 'MESH:D011471', (316, 331))	('prostate cancer', 'Phenotype', 'HP:0012125', (147, 162))	('HOXD3', 'Gene', (11, 16))	('prostate cancer', 'Phenotype', 'HP:0012125', (316, 331))	('prostate cancer', 'Disease', (147, 162))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('methylation', 'Var', (73, 84))	('HOXD8', 'Gene', (67, 72))	('HOXD8', 'Gene', '3234', (67, 72))	('cancer', 'Phenotype', 'HP:0002664', (325, 331))	('prostate cancer', 'Disease', (316, 331))
514616	32635388	Interestingly, the hypermethylation of HOXD3 is a feature of the most common male cancers worldwide (lung, prostate and colorectal cancers), but also a prognostic marker in renal cell and hepatocellular carcinomas.	('male cancers', 'Disease', 'MESH:D018567', (77, 89))	('cancers', 'Phenotype', 'HP:0002664', (131, 138))	('cancers', 'Phenotype', 'HP:0002664', (82, 89))	('male cancers', 'Disease', (77, 89))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('colorectal cancers', 'Disease', 'MESH:D015179', (120, 138))	('HOXD3', 'Gene', '3232', (39, 44))	('hepatocellular carcinomas', 'Disease', 'MESH:D006528', (188, 213))	('renal cell', 'Disease', (173, 183))	('HOXD3', 'Gene', (39, 44))	('lung', 'Disease', (101, 105))	('hepatocellular carcinomas', 'Phenotype', 'HP:0001402', (188, 213))	('prostate', 'Disease', (107, 115))	('colorectal cancer', 'Phenotype', 'HP:0003003', (120, 137))	('carcinoma', 'Phenotype', 'HP:0030731', (203, 212))	('carcinomas', 'Phenotype', 'HP:0030731', (203, 213))	('hepatocellular carcinomas', 'Disease', (188, 213))	('colorectal cancers', 'Disease', (120, 138))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('hypermethylation', 'Var', (19, 35))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (188, 212))
514617	32635388	Moreover, HOXD9 hypermethylation is a common epigenetic alteration in thymic carcinoma and one of the biomarkers that may help to differentiate cholangiocarcinoma from other biliary diseases using serum cell-free DNA analysis.	('cholangiocarcinoma', 'Disease', (144, 162))	('thymic carcinoma', 'Disease', (70, 86))	('biliary diseases', 'Disease', 'MESH:D001660', (174, 190))	('thymic carcinoma', 'Disease', 'MESH:D013953', (70, 86))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (144, 162))	('carcinoma', 'Phenotype', 'HP:0030731', (153, 162))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (144, 162))	('HOXD9', 'Gene', (10, 15))	('hypermethylation', 'Var', (16, 32))	('help', 'Reg', (122, 126))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('biliary diseases', 'Disease', (174, 190))	('HOXD9', 'Gene', '3235', (10, 15))
514619	32635388	In addition, it is a recognizable marker in papillary thyroid cancer patients, particularly among BRAFV600E mutation carriers.	('papillary thyroid cancer', 'Disease', (44, 68))	('papillary thyroid cancer', 'Disease', 'MESH:D000077273', (44, 68))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('papillary thyroid cancer', 'Phenotype', 'HP:0002895', (44, 68))	('thyroid cancer', 'Phenotype', 'HP:0002890', (54, 68))	('BRAFV600E', 'Mutation', 'rs113488022', (98, 107))	('mutation', 'Var', (108, 116))	('patients', 'Species', '9606', (69, 77))	('BRAFV600E', 'Gene', (98, 107))
514620	32635388	It has also been suggested that HOXD10 hypermethylation detection in the plasma, in combination with other genes, may be a useful biomarker for the early detection of gastric cancer and pre-cancerous lesions, and to distinguish lung cancer, pulmonary fibrosis and chronic obstructive lung disease.	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('cancerous lesions', 'Disease', 'MESH:D009369', (190, 207))	('gastric cancer', 'Disease', 'MESH:D013274', (167, 181))	('chronic obstructive lung disease', 'Disease', (264, 296))	('lung cancer', 'Disease', (228, 239))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('pulmonary fibrosis', 'Disease', (241, 259))	('HOXD10', 'Gene', (32, 38))	('pulmonary fibrosis', 'Phenotype', 'HP:0002206', (241, 259))	('chronic obstructive lung disease', 'Phenotype', 'HP:0006510', (264, 296))	('pulmonary fibrosis', 'Disease', 'MESH:D011658', (241, 259))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('hypermethylation', 'Var', (39, 55))	('gastric cancer', 'Phenotype', 'HP:0012126', (167, 181))	('chronic obstructive lung disease', 'Disease', 'MESH:D029424', (264, 296))	('lung cancer', 'Disease', 'MESH:D008175', (228, 239))	('lung disease', 'Phenotype', 'HP:0002088', (284, 296))	('HOXD10', 'Gene', '3236', (32, 38))	('cancerous lesions', 'Disease', (190, 207))	('lung cancer', 'Phenotype', 'HP:0100526', (228, 239))	('gastric cancer', 'Disease', (167, 181))	('obstructive lung disease', 'Phenotype', 'HP:0006536', (272, 296))
514621	32635388	However, epigenetic inactivation of HOXD10 has been associated with colon cancer, inhibiting RHOC/AKT/MAPK signaling, and with hepatocellular carcinoma, activating ERK signaling.	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (127, 151))	('colon cancer', 'Disease', 'MESH:D015179', (68, 80))	('AKT', 'Gene', '207', (98, 101))	('HOXD10', 'Gene', '3236', (36, 42))	('RHOC', 'Gene', (93, 97))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (142, 151))	('hepatocellular carcinoma', 'Disease', (127, 151))	('colon cancer', 'Disease', (68, 80))	('inhibiting', 'NegReg', (82, 92))	('associated', 'Reg', (52, 62))	('ERK', 'Gene', '5594', (164, 167))	('epigenetic inactivation', 'Var', (9, 32))	('AKT', 'Gene', (98, 101))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (127, 151))	('HOXD10', 'Gene', (36, 42))	('colon cancer', 'Phenotype', 'HP:0003003', (68, 80))	('activating', 'PosReg', (153, 163))	('RHOC', 'Gene', '389', (93, 97))	('ERK', 'Gene', (164, 167))
514622	32635388	HOXD13 hypermethylation has been particularly associated with breast cancer, as part of an epigenetic signature detectable in the serum and used for clinical diagnoses, and in lung adenocarcinoma, in which it is considered a potential prognostic biomarker.	('hypermethylation', 'Var', (7, 23))	('HOXD13', 'Gene', '3239', (0, 6))	('lung adenocarcinoma', 'Disease', (176, 195))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (176, 195))	('carcinoma', 'Phenotype', 'HP:0030731', (186, 195))	('HOXD13', 'Gene', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('breast cancer', 'Disease', 'MESH:D001943', (62, 75))	('breast cancer', 'Phenotype', 'HP:0003002', (62, 75))	('breast cancer', 'Disease', (62, 75))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (176, 195))	('associated', 'Reg', (46, 56))
514627	32635388	In acute myeloid leukemia, patients carrying a mutation in the sex combs-like 1 gene (ASXL1) often have genome-wide loss of H3K27me3, including in the HOXA cluster region.	('ASXL1', 'Gene', (86, 91))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (9, 25))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (3, 25))	('leukemia', 'Phenotype', 'HP:0001909', (17, 25))	('mutation', 'Var', (47, 55))	('H3K27me3', 'Gene', '126961', (124, 132))	('HOXA', 'Gene', (151, 155))	('patients', 'Species', '9606', (27, 35))	('acute myeloid leukemia', 'Disease', (3, 25))	('loss', 'NegReg', (116, 120))	('H3K27me3', 'Gene', (124, 132))	('HOXA', 'Gene', '3197', (151, 155))	('ASXL1', 'Gene', '171023', (86, 91))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (3, 25))
514631	32635388	The specific modulation of HOXB7 interferes with the AKT and MAPK pathways, impacting tumor growth.	('AKT', 'Gene', (53, 56))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Disease', (86, 91))	('HOXB7', 'Gene', (27, 32))	('interferes', 'NegReg', (33, 43))	('AKT', 'Gene', '207', (53, 56))	('impacting', 'Reg', (76, 85))	('modulation', 'Var', (13, 23))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('HOXB7', 'Gene', '3217', (27, 32))	('MAPK pathways', 'Pathway', (61, 74))
514635	32635388	Besides cancer, many other human diseases are associated with altered DNA or histone methylations.	('altered', 'Var', (62, 69))	('cancer', 'Disease', (8, 14))	('human', 'Species', '9606', (27, 32))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('histone methylations', 'MPA', (77, 97))	('associated', 'Reg', (46, 56))	('DNA', 'MPA', (70, 73))	('cancer', 'Disease', 'MESH:D009369', (8, 14))
514650	32635388	The deregulation of gene expression by epigenetic alterations is recognized as an important feature of cancer, and knowledge of epigenetic regulation is a useful tool for the understanding of carcinogenesis, as well as for the development of anti-epigenetic drugs.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('epigenetic alterations', 'Var', (39, 61))	('cancer', 'Disease', (103, 109))	('gene expression', 'MPA', (20, 35))	('deregulation', 'MPA', (4, 16))	('cancer', 'Disease', 'MESH:D009369', (103, 109))
514651	32635388	Targeting epigenetic modifications seems to be a novel approach contributing to precision medicine, although there are still limitations to be overcome before it reaches a clinical setting for treating cancer and other diseases.	('cancer', 'Disease', 'MESH:D009369', (202, 208))	('epigenetic modifications', 'Var', (10, 34))	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('cancer', 'Disease', (202, 208))
514652	32635388	The methylation of HOX genes or associated histones is recognized as a potential biomarker in several cancer types, facilitating predictions of disease outcome, and therefore, improving treatment decisions.	('improving', 'PosReg', (176, 185))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('HOX genes', 'Gene', (19, 28))	('histones', 'Protein', (43, 51))	('methylation', 'Var', (4, 15))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))
514653	32635388	The methylation of some HOX genes is also associated with therapy resistance, and thus, knowledge of its methylation profile may orientate the patients regarding treatment alternatives.	('therapy resistance', 'CPA', (58, 76))	('associated with', 'Reg', (42, 57))	('methylation', 'Var', (4, 15))	('patients', 'Species', '9606', (143, 151))	('orientate', 'Reg', (129, 138))	('HOX genes', 'Gene', (24, 33))
514658	32635388	This is justified by the high level of importance that the alteration of HOX gene expression has in cancer predisposition and development, and by the fact that the generalized effect of some epigenetic drugs may lead to secondary malignancies.	('malignancies', 'Disease', 'MESH:D009369', (230, 242))	('epigenetic drugs', 'Var', (191, 207))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('malignancies', 'Disease', (230, 242))	('lead to', 'Reg', (212, 219))	('development', 'CPA', (126, 137))	('alteration', 'Var', (59, 69))	('HOX gene', 'Gene', (73, 81))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))
514671	31888612	Actually, epigenetic modification plays an important role in the development of cancers.	('cancers', 'Disease', 'MESH:D009369', (80, 87))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancers', 'Disease', (80, 87))	('epigenetic modification', 'Var', (10, 33))	('cancers', 'Phenotype', 'HP:0002664', (80, 87))
514689	31888612	In this study, XML format files of pathways enriched by differentially methylated genes in each cancer type are obtained from KEGG database.	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('differentially methylated genes', 'Var', (56, 87))	('cancer', 'Disease', (96, 102))	('cancer', 'Disease', 'MESH:D009369', (96, 102))
514706	31888612	From the result of enrichment, we can see that differentially methylated genes in every cancer type are involved in various biological pathways and functions (Additional file 2: Figure S2, Additional file 3: Figure S3, Additional file 4: Figure S4, Additional file 5: Figure S5, Additional file 6: Figure S6, Additional file 7: Figure S7, Additional file 8: Figure S8).	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('involved', 'Reg', (104, 112))	('differentially methylated genes', 'Var', (47, 78))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('biological', 'CPA', (124, 134))
514711	31888612	Even within the same cancer type, differentially hypomethylated genes and hypermethylated could be involved in different pathways and functions.	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('involved', 'Reg', (99, 107))	('differentially hypomethylated genes', 'Var', (34, 69))	('cancer', 'Disease', (21, 27))	('cancer', 'Disease', 'MESH:D009369', (21, 27))
514717	31888612	The nodes in the network represent the genes in the pathways enriched by the differentially methylated genes in each type of cancer, and the edges represent the interaction between the two genes in the pathways.	('interaction', 'Interaction', (161, 172))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('cancer', 'Disease', (125, 131))	('differentially methylated', 'Var', (77, 102))
514722	31888612	We can learn from the graph that those genes are significantly enriched in cancer and multiple signaling pathways, as well as metabolic and biosynthetic pathways.	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('genes', 'Var', (39, 44))	('cancer', 'Disease', (75, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('metabolic', 'Pathway', (126, 135))
514729	31888612	Therefore, it is speculated that abnormalities in these genes may lead to dysregulation of related biological processes and pathways, thus inducing cancer.	('cancer', 'Disease', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('dysregulation', 'MPA', (74, 87))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('abnormalities', 'Var', (33, 46))	('lead to', 'Reg', (66, 73))	('inducing', 'Reg', (139, 147))
514742	31888612	In addition to genetic mutations, DNA methylation is an important epigenetic alteration that can modify gene expression and is commonly perturbed in cancers.	('cancers', 'Disease', (149, 156))	('modify', 'Reg', (97, 103))	('cancers', 'Phenotype', 'HP:0002664', (149, 156))	('methylation', 'Var', (38, 49))	('perturbed', 'Reg', (136, 145))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('gene expression', 'MPA', (104, 119))	('cancers', 'Disease', 'MESH:D009369', (149, 156))
514745	31888612	In cancer detection, DNA methylation also has several advantages over somatic mutation analysis, such as high clinical sensitivity and dynamic range.	('cancer', 'Phenotype', 'HP:0002664', (3, 9))	('cancer', 'Disease', (3, 9))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('DNA', 'Var', (21, 24))
514749	31888612	They discovered a potential tumorigenesis mechanism that involved of three pan-cancer differentially methylated CpG sites (PDMCs) and 62 PDMCs that are significantly associated with patient survival.	('tumor', 'Disease', (28, 33))	('differentially methylated', 'Var', (86, 111))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('patient', 'Species', '9606', (182, 189))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('associated', 'Reg', (166, 176))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))
514800	31335308	The ECM has an effect on tumor behavior; improper synthesis or degradation of any ECM molecule can change cell functioning and thus helps in the progression of disease.	('improper', 'Var', (41, 49))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('degradation', 'MPA', (63, 74))	('progression of disease', 'CPA', (145, 167))	('tumor', 'Disease', (25, 30))	('synthesis', 'MPA', (50, 59))	('cell functioning', 'CPA', (106, 122))	('helps in', 'Reg', (132, 140))	('tumor', 'Disease', 'MESH:D009369', (25, 30))	('change', 'Reg', (99, 105))
514915	30095656	Stratification exploratory subgroup analyses suggested that patients with ECOG PS score 0, PR as best treatment effect or treated with more than 4 courses of Endostar may achieve longer PFS than patients with the same condition in the DE group.	('PFS', 'CPA', (186, 189))	('men', 'Species', '9606', (107, 110))	('patients', 'Species', '9606', (60, 68))	('patients', 'Species', '9606', (195, 203))	('ECOG', 'Var', (74, 78))
514932	30142804	The expressions of CK19, CK20, and SCC-Ag in the experimental group before surgery were (0.0035 +- 0.0018), (1.06 +- 0.49), and (1.48 +- 0.46), respectively, and the positive rates were 32.1%, 33.3%, and 35.9%, respectively.	('CK19', 'Gene', (19, 23))	('0.0035 +- 0.0018', 'Var', (89, 105))	('SCC-Ag', 'Gene', (35, 41))	('CK20', 'Gene', '54474', (25, 29))	('CK19', 'Gene', '3880', (19, 23))	('1.48', 'Var', (129, 133))	('1.06 +- 0.49', 'Var', (109, 121))	('CK20', 'Gene', (25, 29))
514941	30142804	Animal experiments by Nishizaki et al have shown that surgical procedures can cause tumor cells to spread into the bloodstream, which increases the incidence of postoperative metastases.	('cause', 'Reg', (78, 83))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('surgical procedures', 'Var', (54, 73))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('postoperative metastases', 'Disease', (161, 185))	('postoperative metastases', 'Disease', 'MESH:D009362', (161, 185))	('tumor', 'Disease', (84, 89))	('increases', 'PosReg', (134, 143))
514949	30142804	Wang et al employed RT-PCR and IHC to detect the metastasis of sentinel lymph node (SLN) in early cervical cancer, the results showed that the positive detection rate of qRT-PCR test CK19 was 20%, and its sensitivity was significantly higher than that of immunohistochemistry.	('CK19', 'Gene', (183, 187))	('higher', 'PosReg', (235, 241))	('CK19', 'Gene', '3880', (183, 187))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('qRT-PCR', 'Var', (170, 177))	('cervical cancer', 'Disease', 'MESH:D002583', (98, 113))	('cervical cancer', 'Disease', (98, 113))
514979	30142804	The expression levels of CK19 in the experimental, positive, and negative control groups were (0.0035 +- 0.0018), (0.0011 +- 0.0009), and (0.0008 +- 0.0006), respectively, and there was statistical significance (P < .01).	('expression levels', 'MPA', (4, 21))	('0.0035 +- 0.0018', 'Var', (95, 111))	('CK19', 'Gene', '3880', (25, 29))	('0.0008 +- 0.0006', 'Var', (139, 155))	('0.0011 +- 0.0009', 'Var', (115, 131))	('CK19', 'Gene', (25, 29))
514987	30142804	The preoperative expression levels of peripheral blood CK19, CK19, and SCC-Ag in the laparoscopic group were (0.0034 +- 0.0016), (1.09 +- 0.45), and (1.53 +- 0.45), respectively, whereas the expression levels in the laparotomy group were (0.0037 +- 0.0020), (1.04 +- 0.52), and (1.49 +- 0.46), respectively, and there were no statistical significant differences between groups (P > .05).	('0.0034 +- 0.0016', 'Var', (110, 126))	('CK19', 'Gene', '3880', (55, 59))	('expression', 'MPA', (17, 27))	('CK19', 'Gene', (61, 65))	('SCC-Ag', 'Gene', (71, 77))	('1.09', 'Var', (130, 134))	('CK19', 'Gene', '3880', (61, 65))	('CK19', 'Gene', (55, 59))
514995	30142804	The expression of CK19, CK20 has already been used to assess the presence of CTCs from various types of cancer in many previous studies, however, the presence of its pseudogenes may lead to decreased specificity sensitivity of the assay.	('CK20', 'Gene', (24, 28))	('CK19', 'Gene', (18, 22))	('CK20', 'Gene', '54474', (24, 28))	('CK19', 'Gene', '3880', (18, 22))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('decreased', 'NegReg', (190, 199))	('specificity sensitivity', 'MPA', (200, 223))	('pseudogenes', 'Var', (166, 177))	('cancer', 'Disease', (104, 110))	('presence', 'Var', (150, 158))
515010	30142804	Some studies suggested that laparoscopic surgery needs CO2 pneumoperitoneum to create enough space for surgery, and CO2 causes acidic environment which can accelerate tumor cells entering into the blood, suggesting that laparoscopic surgery may accelerate the tumor cells entering into the blood and leading to the increase of occurrence rate of micrometastases.	('tumor', 'Disease', (260, 265))	('metastases', 'Disease', (351, 361))	('metastases', 'Disease', 'MESH:D009362', (351, 361))	('tumor', 'Disease', 'MESH:D009369', (260, 265))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('CO2', 'Chemical', '-', (116, 119))	('accelerate', 'PosReg', (245, 255))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('CO2', 'Var', (116, 119))	('tumor', 'Phenotype', 'HP:0002664', (260, 265))	('increase', 'PosReg', (315, 323))	('CO2', 'Chemical', '-', (55, 58))	('accelerate', 'PosReg', (156, 166))	('tumor', 'Disease', (167, 172))
515012	30142804	Our results showed that laparoscopic radical hysterectomy did not cause any more CTCs than traditional abdominal radical hysterectomy, and suggested that it did not increase the risk of metastases.	('laparoscopic', 'Var', (24, 36))	('metastases', 'Disease', 'MESH:D009362', (186, 196))	('metastases', 'Disease', (186, 196))
515027	30150714	A catalogue of somatic NRF2 gain-of-function mutations in cancer Identification and characterization of somatic mutations in cancer have important prognostication and treatment implications.	('mutations', 'Var', (45, 54))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('cancer', 'Disease', (125, 131))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('cancer', 'Disease', (58, 64))	('NRF2', 'Gene', '4780', (23, 27))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('gain-of-function', 'PosReg', (28, 44))	('NRF2', 'Gene', (23, 27))	('cancer', 'Disease', 'MESH:D009369', (125, 131))
515029	30150714	Despite its apparent significance, a comprehensive catalogue of somatic NRF2 mutations across different tumor types is still lacking.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('tumor', 'Disease', (104, 109))	('NRF2', 'Gene', (72, 76))	('mutations', 'Var', (77, 86))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
515030	30150714	Here, we catalogue NRF2 mutations in The Cancer Genome Atlas (TCGA) database.	('Cancer Genome Atlas', 'Disease', (41, 60))	('Cancer', 'Phenotype', 'HP:0002664', (41, 47))	('NRF2', 'Gene', (19, 23))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (41, 60))	('mutations', 'Var', (24, 33))
515032	30150714	NRF2 mutations were found in 21 out of the 33 tumor types.	('NRF2', 'Gene', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Disease', (46, 51))	('mutations', 'Var', (5, 14))	('found', 'Reg', (20, 25))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
515033	30150714	Notably, R34 and D29 mutations were overrepresented in bladder, lung, and uterine cancers.	('bladder', 'Disease', (55, 62))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('R34', 'Var', (9, 12))	('D29 mutations', 'Var', (17, 30))	('cancers', 'Phenotype', 'HP:0002664', (82, 89))	('cancers', 'Disease', (82, 89))	('cancers', 'Disease', 'MESH:D009369', (82, 89))	('lung', 'Disease', (64, 68))	('overrepresented', 'PosReg', (36, 51))	('uterine cancers', 'Phenotype', 'HP:0010784', (74, 89))
515034	30150714	Analyses of corresponding RNA sequencing data using a de novo derived gene expression classifier showed that the R34 mutations drive constitutive NRF2 activation with a selection pressure biased against the formation of R34L.	('mutations', 'Var', (117, 126))	('R34L', 'Mutation', 'p.R34L', (220, 224))	('R34', 'Gene', (113, 116))	('expression', 'Species', '29278', (75, 85))	('activation', 'PosReg', (151, 161))	('constitutive', 'MPA', (133, 145))
515035	30150714	Of all R34 mutants, R34L conferred the least degree of protein stabilization, suggesting a pro-tumor NRF2 half-life threshold.	('R34L', 'Mutation', 'p.R34L', (20, 24))	('least', 'NegReg', (39, 44))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('protein stabilization', 'MPA', (55, 76))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('R34L', 'Var', (20, 24))	('R34', 'Gene', (7, 10))	('tumor', 'Disease', (95, 100))
515036	30150714	Our findings offer a comprehensive catalogue of NRF2 mutations in cancer that can help prognostication and NRF2 research.	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('NRF2', 'Gene', (48, 52))	('mutations', 'Var', (53, 62))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('cancer', 'Disease', (66, 72))
515037	30150714	Several studies have shown that NRF2, together with its negative regulator KEAP1 (Kelch-like ECH-associated protein 1), are frequently mutated in cancer.	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('mutated', 'Var', (135, 142))	('NRF2', 'Gene', (32, 36))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))
515043	30150714	Accordingly, somatic NRF2 mutations in cancer mainly occurred within the ETGE and DLG motifs.	('NRF2', 'Gene', (21, 25))	('cancer', 'Disease', (39, 45))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('occurred', 'Reg', (53, 61))	('mutations', 'Var', (26, 35))	('ETGE', 'Chemical', '-', (73, 77))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))
515044	30150714	The focal nature of somatic NRF2 mutations presents an attractive genetic screening modality that could be used to identify cancers with constitutive NRF2 activation.	('NRF2', 'Gene', (28, 32))	('mutations', 'Var', (33, 42))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('cancers', 'Phenotype', 'HP:0002664', (124, 131))	('cancers', 'Disease', (124, 131))	('cancers', 'Disease', 'MESH:D009369', (124, 131))
515045	30150714	Moreover, the mutant forms of NRF2 are unique to cancer cells and therefore may be targeted as a treatment strategy.	('NRF2', 'Gene', (30, 34))	('mutant', 'Var', (14, 20))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('rat', 'Species', '10116', (109, 112))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('cancer', 'Disease', (49, 55))
515046	30150714	However, despite the focal nature of NRF2 mutation, a thorough cataloging of NRF2 mutation in cancer has yet to be reported, hampering the development of an easy NRF2 mutation screening method.	('hampering', 'NegReg', (125, 134))	('mutation', 'Var', (82, 90))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('mutation', 'Var', (42, 50))	('NRF2', 'Gene', (37, 41))	('NRF2', 'Gene', (77, 81))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
515047	30150714	Here we catalogue somatic NRF2 mutations in cancer cases reported in The Cancer Genome Atlas (TCGA).	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (73, 92))	('mutations', 'Var', (31, 40))	('Cancer', 'Phenotype', 'HP:0002664', (73, 79))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('NRF2', 'Gene', (26, 30))	('Cancer Genome Atlas', 'Disease', (73, 92))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
515048	30150714	By cross analyzing somatic mutations with gene expression analyses, we report NRF2 mutations that result in constitutive NRF2 activation.	('mutations', 'Var', (83, 92))	('NRF2', 'Gene', (121, 125))	('activation', 'PosReg', (126, 136))	('NRF2', 'Gene', (78, 82))	('expression', 'Species', '29278', (47, 57))
515050	30150714	There were a total of 226 cases of tumors with somatic NRF2 and 222 cases with somatic KEAP1 mutations.	('mutations', 'Var', (93, 102))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('NRF2', 'Gene', (55, 59))	('tumors', 'Phenotype', 'HP:0002664', (35, 41))	('KEAP1', 'Gene', (87, 92))	('tumors', 'Disease', (35, 41))	('tumors', 'Disease', 'MESH:D009369', (35, 41))
515051	30150714	Consistent with the literature, certain tumor subtypes show higher representation of either somatic NRF2 or KEAP1 mutations.	('NRF2', 'Gene', (100, 104))	('higher', 'PosReg', (60, 66))	('mutations', 'Var', (114, 123))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('tumor', 'Disease', (40, 45))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('KEAP1', 'Gene', (108, 113))	('rat', 'Species', '10116', (24, 27))
515052	30150714	Somatic NRF2 mutations were most frequently found in lung squamous cell carcinoma (LUSC), followed by esophageal carcinoma (ESCA) and uterine corpus endometrial carcinoma (UCEC) cancers (Fig.	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (53, 81))	('corpus endometrial carcinoma (UCEC) cancers', 'Disease', 'MESH:D016889', (142, 185))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (58, 81))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (102, 122))	('lung squamous cell carcinoma', 'Disease', (53, 81))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (102, 122))	('ESCA', 'Phenotype', 'HP:0011459', (124, 128))	('found', 'Reg', (44, 49))	('cancers', 'Phenotype', 'HP:0002664', (178, 185))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('NRF2', 'Gene', (8, 12))	('carcinoma', 'Phenotype', 'HP:0030731', (161, 170))	('mutations', 'Var', (13, 22))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (149, 170))	('esophageal carcinoma', 'Disease', (102, 122))
515053	30150714	Somatic KEAP1 mutations were most frequently found in lung adenocarcinoma (LUAD), followed by LUSC and liver hepatocellular carcinoma (LIHC) (Fig.	('KEAP1', 'Gene', (8, 13))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (54, 73))	('liver hepatocellular carcinoma', 'Disease', (103, 133))	('LIHC', 'Disease', (135, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('liver hepatocellular carcinoma', 'Disease', 'MESH:D006528', (103, 133))	('LIHC', 'Disease', 'None', (135, 139))	('LUSC', 'Disease', (94, 98))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (109, 133))	('lung adenocarcinoma', 'Disease', (54, 73))	('found', 'Reg', (45, 50))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (54, 73))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))	('mutations', 'Var', (14, 23))	('LUAD', 'Phenotype', 'HP:0030078', (75, 79))
515054	30150714	There is also a strong overlap among tumor types with somatic NRF2 or KEAP1 mutations, and many of these tumor types are associated with exposure to xenobiotics, suggesting carcinogen exposure as a selection pressure that selects for cells with sustained NRF2 activation phenotype.	('NRF2', 'Gene', (255, 259))	('mutations', 'Var', (76, 85))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('associated', 'Reg', (121, 131))	('NRF2', 'Gene', (62, 66))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('activation', 'PosReg', (260, 270))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('KEAP1', 'Gene', (70, 75))	('tumor', 'Disease', (105, 110))
515055	30150714	Many tumor types with NRF2 activation (either NRF2 or KEAP1 non-synonymous mutation) show increased frequency of mutations (Fig.	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('mutations', 'Var', (113, 122))	('tumor', 'Disease', (5, 10))	('activation', 'PosReg', (27, 37))	('NRF2', 'Gene', (22, 26))
515057	30150714	The significant correlation between NRF2 activation and carcinogen-associated transversion mutations is in agreement with the known correlation between NRF2 and KEAP1 mutations and cancer cases from smokers.	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('carcinogen-associated', 'Disease', (56, 77))	('transversion mutations', 'Var', (78, 100))	('NRF2', 'Gene', (36, 40))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('activation', 'PosReg', (41, 51))	('cancer', 'Disease', (181, 187))
515059	30150714	More recently, Orru and co-workers demonstrated that diethylnitrosamine, an alkylating agent, induced a high frequency of NRF2 gain-of-function mutations in a rat liver carcinogenesis model.	('liver carcinogenesis', 'Disease', (163, 183))	('rat', 'Species', '10116', (42, 45))	('gain-of-function', 'PosReg', (127, 143))	('rat', 'Species', '10116', (159, 162))	('liver carcinogenesis', 'Disease', 'MESH:D063646', (163, 183))	('mutations', 'Var', (144, 153))	('NRF2', 'Gene', (122, 126))	('diethylnitrosamine', 'Chemical', 'MESH:D004052', (53, 71))
515060	30150714	Moreover, they showed that NRF2 gain-of-function mutations were critical for the onset of hepatocellular carcinoma in the model.	('NRF2', 'Gene', (27, 31))	('gain-of-function', 'PosReg', (32, 48))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (90, 114))	('mutations', 'Var', (49, 58))	('hepatocellular carcinoma', 'Disease', (90, 114))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (90, 114))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))
515061	30150714	NRF2 protein consists of 605 amino acids, and mutations were mainly found within the NEH2 domain, where the ETGE and DLG motifs are located (Fig.	('found', 'Reg', (68, 73))	('NRF2', 'Gene', (0, 4))	('mutations', 'Var', (46, 55))	('ETGE', 'Chemical', '-', (108, 112))
515062	30150714	Several mutations outside of the DLG and ETGE motifs, including W24, Q26, R34, and D77, were found to be significantly overrepresented.	('D77', 'Var', (83, 86))	('R34', 'Var', (74, 77))	('ETGE', 'Chemical', '-', (41, 45))	('W24', 'Var', (64, 67))	('Q26', 'Var', (69, 72))	('overrepresented', 'PosReg', (119, 134))
515063	30150714	Tumor types distribution analysis showed R34 mutations were found in tumors of bladder, cervical, esophageal, head and neck, lung, and uterine origins (Fig.	('tumors of bladder', 'Disease', (69, 86))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('mutations', 'Var', (45, 54))	('tumors of bladder', 'Disease', 'MESH:D001749', (69, 86))	('tumors of bladder', 'Phenotype', 'HP:0009725', (69, 86))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('lung', 'Disease', (125, 129))	('esophageal', 'Disease', 'MESH:D004941', (98, 108))	('found', 'Reg', (60, 65))	('cervical', 'Disease', (88, 96))	('esophageal', 'Disease', (98, 108))	('R34', 'Gene', (41, 44))
515066	30150714	We focused our analysis on lung cancer, both LUSC and LUAD, since these are the tumor types with the most NRF2 and KEAP1 mutant cases.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('mutant', 'Var', (121, 127))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('lung cancer', 'Disease', 'MESH:D008175', (27, 38))	('lung cancer', 'Disease', (27, 38))	('lung cancer', 'Phenotype', 'HP:0100526', (27, 38))	('tumor', 'Disease', (80, 85))	('LUAD', 'Phenotype', 'HP:0030078', (54, 58))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('NRF2', 'Gene', (106, 110))
515068	30150714	These 12 NRF2 activated tumor cases consisted of 6 cases (3 LUSC and 3 LUAD) with NRF2 mutations and 6 cases (3 LUSC and 3 LUAD) with KEAP1 mutations.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumor', 'Disease', (24, 29))	('LUAD', 'Phenotype', 'HP:0030078', (123, 127))	('NRF2', 'Gene', (9, 13))	('LUAD', 'Phenotype', 'HP:0030078', (71, 75))	('NRF2', 'Gene', (82, 86))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('mutations', 'Var', (87, 96))
515069	30150714	The 6 NRF2 mutant cases were chosen based on mutation at the DLG or ETGE motifs, which are known to activate NRF2, while the 6 KEAP1 mutant cases were chosen based on low KEAP1 expression levels.	('mutant', 'Var', (11, 17))	('NRF2', 'Gene', (6, 10))	('ETGE', 'Chemical', '-', (68, 72))	('activate', 'PosReg', (100, 108))	('DLG', 'Gene', (61, 64))	('mutation', 'Var', (45, 53))	('expression', 'Species', '29278', (177, 187))	('NRF2', 'Gene', (109, 113))
515074	30150714	A handful of unique mutations appeared in both the NRF2-activated and NRF2-inactivated grouping; this may be caused by tumor heterogeneity between tissue sections used for exome and RNA sequencing.	('tumor', 'Disease', (119, 124))	('appeared', 'Reg', (30, 38))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('mutations', 'Var', (20, 29))
515076	30150714	We developed NRF2 expression constructs for the non-DLG and non-ETGE NRF2 mutants found in the activated signature, as well as the R34L NRF2 mutant.	('ETGE', 'Chemical', '-', (64, 68))	('R34L', 'Var', (131, 135))	('NRF2', 'Gene', (69, 73))	('expression', 'Species', '29278', (18, 28))	('R34L', 'Mutation', 'p.R34L', (131, 135))	('mutants', 'Var', (74, 81))
515077	30150714	As expected, KEAP1 expression ablated wild type NRF2 luciferase activity to <10% of its original level.	('NRF2 luciferase', 'Enzyme', (48, 63))	('ablated', 'NegReg', (30, 37))	('activity', 'MPA', (64, 72))	('KEAP1', 'Var', (13, 18))	('expression', 'Species', '29278', (19, 29))
515078	30150714	However, KEAP1 introduction reduced luciferase activation by NRF2-R34G, -R34P, -R34L, and -R34Q to only 60%; similarly, W24C, Q26R, Q26L, Q26P, D77G, and D77Y retained significant activity after KEAP1 expression.	('activation', 'MPA', (47, 57))	('reduced', 'NegReg', (28, 35))	('D77G', 'Mutation', 'p.D77G', (144, 148))	('R34L', 'Mutation', 'p.R34L', (80, 84))	('Q26R', 'Var', (126, 130))	('D77Y', 'Var', (154, 158))	('Q26R', 'Mutation', 'rs1168551006', (126, 130))	('W24C', 'Var', (120, 124))	('R34G', 'Mutation', 'p.R34G', (66, 70))	('R34Q', 'Mutation', 'p.R34Q', (91, 95))	('D77G', 'Var', (144, 148))	('Q26L', 'Mutation', 'p.Q26L', (132, 136))	('Q26P', 'Mutation', 'p.Q26P', (138, 142))	('NRF2-R34G', 'Gene', (61, 70))	('activity', 'MPA', (180, 188))	('luciferase', 'Enzyme', (36, 46))	('Q26L', 'Var', (132, 136))	('Q26P', 'Var', (138, 142))	('R34P', 'Mutation', 'p.R34P', (73, 77))	('expression', 'Species', '29278', (201, 211))	('W24C', 'SUBSTITUTION', 'None', (120, 124))	('D77Y', 'Mutation', 'p.D77Y', (154, 158))
515079	30150714	Activity of some mutants found in the signature (H107R, M235I, F289L, and L370V) was still repressed by KEAP1, indicating a possible secondary mechanism for NRF2 activation may be present in those tumors (Supplementary Fig.	('L370V', 'Mutation', 'p.L370V', (74, 79))	('tumors', 'Disease', 'MESH:D009369', (197, 203))	('M235I', 'Mutation', 'rs754094243', (56, 61))	('H107R', 'Mutation', 'p.H107R', (49, 54))	('H107R', 'Var', (49, 54))	('F289L', 'Var', (63, 68))	('tumors', 'Phenotype', 'HP:0002664', (197, 203))	('Activity', 'MPA', (0, 8))	('M235I', 'Var', (56, 61))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('F289L', 'Mutation', 'rs1416793394', (63, 68))	('L370V', 'Var', (74, 79))	('tumors', 'Disease', (197, 203))	('activation', 'PosReg', (162, 172))
515080	30150714	This demonstrates that many of the NRF2 and KEAP1 mutations identified in the NRF2-activating signature modulate NRF2 activity.	('rat', 'Species', '10116', (12, 15))	('NRF2 activity', 'MPA', (113, 126))	('NRF2-activating', 'Gene', (78, 93))	('mutations', 'Var', (50, 59))	('NRF2', 'Gene', (35, 39))	('modulate', 'Reg', (104, 112))
515081	30150714	Since mutation at the R34 position is the most frequently occurring NRF2 mutation and is located outside the ETGE and DLG sites known to be essential for KEAP1 binding, we sought to further evaluate mutational changes that are relevant to this position.	('NRF2', 'Gene', (68, 72))	('mutation at the R34', 'Var', (6, 25))	('ETGE', 'Chemical', '-', (109, 113))
515082	30150714	Thus, a single point mutation to this codon can result in either R34G, R34Q, R34P, or R34L amino acid change (Fig.	('R34L amino acid change', 'Var', (86, 108))	('R34P', 'Var', (77, 81))	('R34P', 'Mutation', 'p.R34P', (77, 81))	('R34G', 'Mutation', 'p.R34G', (65, 69))	('R34L', 'Mutation', 'p.R34L', (86, 90))	('R34Q', 'Mutation', 'p.R34Q', (71, 75))	('R34Q', 'Var', (71, 75))	('R34G', 'Var', (65, 69))	('result in', 'Reg', (48, 57))
515083	30150714	Upon evaluating the TCGA mutation database, we found that R34L was not represented in the 10,364 cases of tumors evaluated in this study, while R34G was significantly overrepresented (Fig.	('R34G', 'Mutation', 'p.R34G', (144, 148))	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('overrepresented', 'PosReg', (167, 182))	('tumors', 'Disease', (106, 112))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('R34L', 'Mutation', 'p.R34L', (58, 62))	('R34G', 'Var', (144, 148))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))
515084	30150714	The R34G mutation could be found in 5 of the 33 evaluated tumor types (Fig.	('R34G', 'Mutation', 'p.R34G', (4, 8))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('R34G', 'Var', (4, 8))
515085	30150714	To empirically evaluate the functional impact of each of these R34 mutants NRF2, we co-expressed each of these mutants with KEAP1 and found that all these mutations protect NRF2 against KEAP1-mediated degradation, with R34L showing the least protective effects among them (Fig.	('mutations', 'Var', (155, 164))	('R34L', 'Mutation', 'p.R34L', (219, 223))	('NRF2', 'Gene', (173, 177))	('KEAP1-mediated degradation', 'MPA', (186, 212))	('protect', 'Reg', (165, 172))	('R34L', 'Var', (219, 223))
515086	30150714	Fukutomi and co-workers have shown through in vitro binding assay between ETGE-deleted NEH2 domain of NRF2 and KEAP1 that R34Q mutation impairs the DLG-KEAP1 interaction.	('ETGE', 'Chemical', '-', (74, 78))	('impairs', 'NegReg', (136, 143))	('binding', 'Interaction', (52, 59))	('R34Q', 'Mutation', 'p.R34Q', (122, 126))	('NRF2', 'Gene', (102, 106))	('R34Q mutation', 'Var', (122, 135))	('DLG-KEAP1 interaction', 'Interaction', (148, 169))
515087	30150714	As binding at both DLG and ETGE motifs is required for ubiquitylation of NRF2, we assessed whether R34 mutants impaired KEAP1's ability to mediate NRF2 ubiquitylation.	('impaired', 'NegReg', (111, 119))	('R34 mutants', 'Var', (99, 110))	('mutants', 'Var', (103, 110))	('ETGE', 'Chemical', '-', (27, 31))	('ubiquitylation', 'MPA', (152, 166))
515088	30150714	To empirically determine the stability of the different NRF2 R34 mutants, we performed cycloheximide chase assays to determine the half-life (t1/2) of each mutant.	('R34', 'Gene', (61, 64))	('cycloheximide', 'Chemical', 'MESH:D003513', (87, 100))	('mutants', 'Var', (65, 72))	('NRF2 R34', 'Gene', (56, 64))
515092	30150714	The t1/2 of other NRF2-R34 mutants were in between 31 and 49 minutes, with R34L having the shortest half-life.	('mutants', 'Var', (27, 34))	('R34L', 'Var', (75, 79))	('NRF2-R34', 'Gene', (18, 26))	('R34L', 'Mutation', 'p.R34L', (75, 79))
515093	30150714	Thus, the absence of R34L in the cases analyzed may indicate that the increased stability conferred by R34L mutation does not pass the transcriptional reprogramming threshold to be positively selected during cancer development and progression.	('cancer', 'Disease', (208, 214))	('increased', 'PosReg', (70, 79))	('R34L', 'Mutation', 'p.R34L', (21, 25))	('R34L', 'Mutation', 'p.R34L', (103, 107))	('stability', 'MPA', (80, 89))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('mutation', 'Var', (108, 116))	('cancer', 'Disease', 'MESH:D009369', (208, 214))	('R34L', 'Gene', (103, 107))
515094	30150714	Activating the NRF2 transcription factor has long been recognized as a means to protect cells against chemical carcinogenesis and environmental insults.	('carcinogenesis', 'Disease', (111, 125))	('carcinogenesis', 'Disease', 'MESH:D063646', (111, 125))	('NRF2', 'Gene', (15, 19))	('Activating', 'Var', (0, 10))
515095	30150714	However, recent studies revealed that many tumors exhibit constitutive NRF2 activation driven by either somatic mutation to NRF2 itself or to its regulatory genes.	('mutation', 'Var', (112, 120))	('NRF2', 'Gene', (124, 128))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumors', 'Disease', (43, 49))	('NRF2', 'Gene', (71, 75))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('activation', 'PosReg', (76, 86))	('tumors', 'Disease', 'MESH:D009369', (43, 49))
515096	30150714	Importantly, tumors with constitutive NRF2 activation are more aggressive and are more resistant to most treatment modalities, prompting the need to identify tumor cases with NRF2 mutations for potential patients stratification and to develop NRF2 inhibitors.	('NRF2', 'Gene', (38, 42))	('tumor', 'Disease', (13, 18))	('tumor', 'Disease', (158, 163))	('NRF2', 'Gene', (175, 179))	('patients', 'Species', '9606', (204, 212))	('mutations', 'Var', (180, 189))	('tumors', 'Disease', (13, 19))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('activation', 'PosReg', (43, 53))	('rat', 'Species', '10116', (215, 218))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('aggressive', 'MPA', (63, 73))
515097	30150714	Given the role of NRF2 in protecting tissues against redox insults, exploiting NRF2 inhibition as a treatment strategy needs to be tumor selective as inhibiting NRF2 in normal cells may lead to increased cellular oxidative damage, increased cytotoxicity of chemotherapeutics, and increased susceptibility to malignant transformation.	('NRF2', 'Gene', (161, 165))	('cytotoxicity', 'Disease', 'MESH:D064420', (241, 253))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('susceptibility', 'Reg', (290, 304))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('increased', 'PosReg', (231, 240))	('increased', 'PosReg', (194, 203))	('tumor', 'Disease', (131, 136))	('rat', 'Species', '10116', (112, 115))	('cytotoxicity', 'Disease', (241, 253))	('cellular oxidative damage', 'MPA', (204, 229))	('inhibiting', 'Var', (150, 160))
515098	30150714	One strategy to target cancer specific proteins is with inhibitors that target the mutant variant of the protein: drugs such as gefitinib (against mutant EGFR) and vemurafenib (against BRAF V600E) have a good degree of success in cancer management.	('EGFR', 'Gene', (154, 158))	('mutant', 'Var', (147, 153))	('V600E', 'Mutation', 'rs113488022', (190, 195))	('rat', 'Species', '10116', (6, 9))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('cancer', 'Disease', (23, 29))	('cancer', 'Disease', 'MESH:D009369', (23, 29))	('gefitinib', 'Chemical', 'MESH:D000077156', (128, 137))	('cancer', 'Disease', (230, 236))	('cancer', 'Disease', 'MESH:D009369', (230, 236))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('vemurafenib', 'Chemical', 'MESH:D000077484', (164, 175))
515100	30150714	Thus, drug development efforts can concentrate on developing compounds that target the cancer specific variant, while leaving wild-type protein in normal cells untouched.	('cancer', 'Disease', (87, 93))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('variant', 'Var', (103, 110))	('rat', 'Species', '10116', (42, 45))
515101	30150714	This study demonstrates that somatic NRF2 mutations in cancer fulfill this criterion.	('rat', 'Species', '10116', (18, 21))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('NRF2', 'Gene', (37, 41))	('mutations', 'Var', (42, 51))	('cancer', 'Disease', (55, 61))
515104	30150714	Consistent with previous studies, our results also showed that somatic NRF2 mutations primarily occurred at the ETGE and the DLG motifs, which interfere with KEAP1 binding.	('mutations', 'Var', (76, 85))	('ETGE', 'Chemical', '-', (112, 116))	('NRF2', 'Gene', (71, 75))	('occurred', 'Reg', (96, 104))	('binding', 'Interaction', (164, 171))
515105	30150714	Several mutations outside the DLG/ETGE motifs to NRF2 were also frequently mutated (p < 0.05), including W24, Q25, D77, and R34.	('D77', 'Var', (115, 118))	('Q25', 'Var', (110, 113))	('NRF2', 'Gene', (49, 53))	('ETGE', 'Chemical', '-', (34, 38))	('W24', 'Var', (105, 108))	('mutated', 'Var', (75, 82))	('R34', 'Var', (124, 127))
515106	30150714	While a few isolated mutations to these locations have been reported and shown to mitigate NRF2-KEAP1 interactions, we focused on the R34 mutation and found it to be the most frequently mutated amino acid position and the only position significantly enriched across many tumor types.	('R34', 'Gene', (134, 137))	('tumor', 'Phenotype', 'HP:0002664', (271, 276))	('tumor', 'Disease', (271, 276))	('NRF2-KEAP1', 'Gene', (91, 101))	('mitigate', 'NegReg', (82, 90))	('tumor', 'Disease', 'MESH:D009369', (271, 276))	('mutations', 'Var', (21, 30))
515107	30150714	Upon evaluation of possible R34 mutations, there is a selection bias against R34L mutation.	('R34L', 'Var', (77, 81))	('R34L', 'Mutation', 'p.R34L', (77, 81))	('R34', 'Gene', (28, 31))
515108	30150714	Using ARE-Luciferase reporter assay, we found that R34L mutant could still evade KEAP1-mediated decrease in NRF2 transcriptional activity.	('R34L', 'Mutation', 'p.R34L', (51, 55))	('NRF2', 'Gene', (108, 112))	('evade', 'NegReg', (75, 80))	('R34L', 'Var', (51, 55))	('transcriptional activity', 'MPA', (113, 137))
515109	30150714	Half-life analysis showed that R34L mutation still stabilizes NRF2.	('R34L mutation', 'Var', (31, 44))	('stabilizes', 'Reg', (51, 61))	('R34L', 'Mutation', 'p.R34L', (31, 35))	('NRF2', 'Gene', (62, 66))
515110	30150714	However, it is the least stable among the NRF2 R34 mutants, indicating a potential minimal stability threshold for NRF2 to benefit cancer growth.	('cancer', 'Disease', (131, 137))	('benefit', 'PosReg', (123, 130))	('mutants', 'Var', (51, 58))	('NRF2', 'Gene', (42, 46))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('R34 mutants', 'Var', (47, 58))	('cancer', 'Disease', 'MESH:D009369', (131, 137))
515111	30150714	Although mechanistic underpinning behind the overrepresentation of longer half-life NRF2 mutants in cancer is still lacking, constitutive/sustained versus intermittent NRF2 activation has been proposed as the distinguishing feature that separate cancer prevention and cancer promotion properties of NRF2 activation.	('cancer', 'Disease', (268, 274))	('cancer', 'Disease', 'MESH:D009369', (246, 252))	('NRF2', 'Gene', (168, 172))	('cancer', 'Disease', (246, 252))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('cancer', 'Phenotype', 'HP:0002664', (268, 274))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))	('mutants', 'Var', (89, 96))	('NRF2', 'Gene', (84, 88))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('rat', 'Species', '10116', (241, 244))	('cancer', 'Disease', 'MESH:D009369', (268, 274))
515113	30150714	Apart from somatic NRF2 mutation, somatic mutations that activate NRF2 can range from direct loss-of-function KEAP1/CUL3 mutations, to KEAP1 gene silencing, to somatic mutations that lead to accumulation of oncometabolites, or ETGE/ETGE-like motifs containing proteins.	('KEAP1/CUL3', 'Gene', (110, 120))	('ETGE/ETGE-like', 'Protein', (227, 241))	('mutations', 'Var', (121, 130))	('ETGE', 'Chemical', '-', (232, 236))	('NRF2', 'Gene', (66, 70))	('proteins', 'Protein', (260, 268))	('oncometabolites', 'MPA', (207, 222))	('loss-of-function', 'NegReg', (93, 109))	('accumulation', 'PosReg', (191, 203))	('ETGE', 'Chemical', '-', (227, 231))	('activate', 'PosReg', (57, 65))	('mutations', 'Var', (42, 51))	('mutations', 'Var', (168, 177))	('silencing', 'NegReg', (146, 155))
515114	30150714	Intriguingly, our analysis revealed several KEAP1 mutations that were significantly enriched; some of these locations have been characterized, including KEAP1-G333C which has been shown to not bind NRF2 and subsequently not suppress NRF2-mediated transcription.	('G333C', 'Mutation', 'c.333G>C', (159, 164))	('not suppress', 'NegReg', (220, 232))	('bind', 'Interaction', (193, 197))	('NRF2-mediated transcription', 'MPA', (233, 260))	('KEAP1-G333C', 'Var', (153, 164))
515115	30150714	In contrast, KEAP1-R470C mutants have exhibited enhanced NRF2 binding: these "superbinder" mutants were shown to not suppress NRF2-mediated transcription, albeit through an unknown mechanism.	('NRF2', 'Protein', (57, 61))	('R470C', 'Mutation', 'p.R470C', (19, 24))	('binding', 'Interaction', (62, 69))	('enhanced', 'PosReg', (48, 56))	('KEAP1-R470C', 'Var', (13, 24))	('NRF2-mediated', 'MPA', (126, 139))
515118	30150714	AKR1B10 can be found in other NRF2-activation gene expression signatures, and its overexpression has been associated with lung cancers in particular.	('lung cancers', 'Disease', (122, 134))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('lung cancer', 'Phenotype', 'HP:0100526', (122, 133))	('associated', 'Reg', (106, 116))	('expression', 'Species', '29278', (86, 96))	('NRF2-activation', 'Gene', (30, 45))	('lung cancers', 'Disease', 'MESH:D008175', (122, 134))	('expression', 'Species', '29278', (51, 61))	('overexpression', 'PosReg', (82, 96))	('cancers', 'Phenotype', 'HP:0002664', (127, 134))	('lung cancers', 'Phenotype', 'HP:0100526', (122, 134))	('AKR1B10', 'Var', (0, 7))
515120	30150714	Apart from mutation sites and gene expression changes, the overrepresentation of NRF2 and KEAP1 mutations in tumor types with known association with carcinogen exposure provides a glimpse into the roles of NRF2 in cancer development and progression.	('cancer', 'Disease', (214, 220))	('tumor', 'Disease', (109, 114))	('expression', 'Species', '29278', (35, 45))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('KEAP1', 'Gene', (90, 95))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('overrepresentation', 'PosReg', (59, 77))	('NRF2', 'Gene', (81, 85))	('mutations', 'Var', (96, 105))	('cancer', 'Disease', 'MESH:D009369', (214, 220))
515121	30150714	We identified that tumors with NRF2 or KEAP1 mutations show higher frequencies of transversion mutations.	('tumors', 'Disease', (19, 25))	('KEAP1', 'Gene', (39, 44))	('mutations', 'Var', (45, 54))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('NRF2', 'Gene', (31, 35))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))	('transversion mutations', 'MPA', (82, 104))
515122	30150714	Many carcinogen-associated Michael acceptors, such as acrolein in cigarette smoke or quinone metabolites of polyaromatic hydrocarbons found in exhaust fumes, are known to cause both transversion mutations and NRF2 activation.	('quinone', 'Chemical', 'MESH:C004532', (85, 92))	('acrolein', 'Chemical', 'MESH:D000171', (54, 62))	('activation', 'PosReg', (214, 224))	('polyaromatic hydrocarbons', 'Chemical', '-', (108, 133))	('carcinogen-associated', 'Disease', (5, 26))	('transversion mutations', 'Var', (182, 204))	('NRF2', 'Gene', (209, 213))
515123	30150714	Indeed, recent work by Orru and co-workers showed that NRF2 activating mutations were acquired during early carcinogenesis in a rat carcinogenesis model using diethylnitrosamine (an alkylating agent) as the carcinogen.	('activating', 'PosReg', (60, 70))	('carcinogenesis', 'Disease', (132, 146))	('NRF2', 'Gene', (55, 59))	('diethylnitrosamine', 'Chemical', 'MESH:D004052', (159, 177))	('mutations', 'Var', (71, 80))	('carcinogenesis', 'Disease', 'MESH:D063646', (132, 146))	('carcinogenesis', 'Disease', 'MESH:D063646', (108, 122))	('rat', 'Species', '10116', (128, 131))	('carcinogenesis', 'Disease', (108, 122))
515124	30150714	However, we cannot rule out the possibility that NRF2-activating gene mutations contribute toward cancer progression rather than development.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('rat', 'Species', '10116', (117, 120))	('mutations', 'Var', (70, 79))	('NRF2-activating', 'Gene', (49, 64))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('cancer', 'Disease', (98, 104))	('contribute', 'Reg', (80, 90))
515125	30150714	This study provides an overview of NRF2 mutations in cancer in one of the largest curated datasets presented.	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('rat', 'Species', '10116', (84, 87))	('NRF2', 'Gene', (35, 39))	('mutations', 'Var', (40, 49))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))
515126	30150714	We identified four NRF2 mutation hotspots that fall outside the well-established DLG and ETGE motifs, and five KEAP1 mutation hotspots.	('ETGE', 'Chemical', '-', (89, 93))	('fall', 'Phenotype', 'HP:0002527', (47, 51))	('NRF2', 'Gene', (19, 23))	('mutation', 'Var', (24, 32))
515134	30150714	The 12 tumors in the training set consisted of 6 cases with either NRF2-DLG or -ETGE motif mutations (3 LUAD and 3 LUSC cases) and 6 cases with low relative KEAP1 expression amongst KEAP1 mutant cases (3 LUAD and 3 LUSC cases), while the 12 normal tissues were consisted of 6 cases of LUSC and 6 cases of LUAD normal tissues.	('NRF2-DLG', 'Gene', (67, 75))	('LUAD', 'Phenotype', 'HP:0030078', (305, 309))	('LUAD', 'Phenotype', 'HP:0030078', (104, 108))	('tumors', 'Disease', (7, 13))	('tumors', 'Disease', 'MESH:D009369', (7, 13))	('expression', 'Species', '29278', (163, 173))	('tumors', 'Phenotype', 'HP:0002664', (7, 13))	('mutations', 'Var', (91, 100))	('LUAD', 'Phenotype', 'HP:0030078', (204, 208))	('ETGE', 'Chemical', '-', (80, 84))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
515146	30150714	Site-directed mutagenesis was carried out on MYC3-NRF2 to generate NRF2 mutations.	('mutations', 'Var', (72, 81))	('MYC', 'Gene', (45, 48))	('NRF2', 'Gene', (67, 71))	('MYC', 'Gene', '4609', (45, 48))	('rat', 'Species', '10116', (62, 65))
515148	30150714	Site-directed mutagenesis was carried out on PCDNA3-KEAP1 to generate KEAP1 mutations.	('mutations', 'Var', (76, 85))	('KEAP1', 'Gene', (70, 75))	('rat', 'Species', '10116', (65, 68))
515149	30150714	To evaluate the role of KEAP1 in mediating the degradation of different NRF2 mutants, HEK293 cells were transfected with the different NRF2 mutant plasmids and either PCDNA3-KEAP1 or empty PCDNA3.1(+) using Attractene transfection reagent (Qiagen, Valencia, CA).	('NRF2', 'Gene', (72, 76))	('HEK293', 'CellLine', 'CVCL:0045', (86, 92))	('NRF2', 'Gene', (135, 139))	('mutants', 'Var', (77, 84))	('mutant', 'Var', (140, 146))
515163	28518145	We found that the expression of cytoplasmic RAP1 was significantly higher in high-grade NSCLC tissues than in low-grade NSCLC; compared with a normal pulmonary epithelial cell line, the A549 NSCLC cells exhibited more cytoplasmic RAP1 expression as well as increased NF-kappaB activity; cisplatin treatment resulted in a further increase of cytoplasmic RAP1 in A549 cells; overexpression of RAP1 desensitized the A549 cells to cisplatin, and conversely, RAP1 depletion in the NSCLC cells reduced their proliferation and increased their sensitivity to cisplatin, indicating that RAP1 is required for cell growth and has a key mediating role in the development of cisplatin resistance in NSCLC cells.	('reduced', 'NegReg', (488, 495))	('cisplatin', 'Chemical', 'MESH:D002945', (662, 671))	('NSCLC', 'Phenotype', 'HP:0030358', (88, 93))	('RAP1', 'Gene', (578, 582))	('RAP1', 'Gene', (44, 48))	('A549', 'CellLine', 'CVCL:0023', (413, 417))	('NSCLC', 'Phenotype', 'HP:0030358', (120, 125))	('RAP1', 'Gene', (353, 357))	('NSCLC', 'Disease', (191, 196))	('cisplatin', 'Chemical', 'MESH:D002945', (287, 296))	('NSCLC', 'Disease', (476, 481))	('RAP1', 'Gene', '54386', (230, 234))	('NSCLC', 'Phenotype', 'HP:0030358', (191, 196))	('NSCLC', 'Phenotype', 'HP:0030358', (476, 481))	('increased', 'PosReg', (520, 529))	('RAP1', 'Gene', (391, 395))	('RAP1', 'Gene', (454, 458))	('NSCLC', 'Disease', 'MESH:D002289', (686, 691))	('NF-kappaB', 'Gene', (267, 276))	('RAP1', 'Gene', '54386', (578, 582))	('RAP1', 'Gene', '54386', (44, 48))	('sensitivity to cisplatin', 'MPA', (536, 560))	('RAP1', 'Gene', '54386', (353, 357))	('cisplatin', 'Chemical', 'MESH:D002945', (427, 436))	('RAP1', 'Gene', (230, 234))	('NSCLC', 'Disease', (686, 691))	('NSCLC', 'Disease', 'MESH:D002289', (88, 93))	('NF-kappaB', 'Gene', '4790', (267, 276))	('depletion', 'Var', (459, 468))	('NSCLC', 'Disease', 'MESH:D002289', (120, 125))	('cisplatin', 'Chemical', 'MESH:D002945', (551, 560))	('proliferation', 'CPA', (502, 515))	('NSCLC', 'Phenotype', 'HP:0030358', (686, 691))	('A549', 'CellLine', 'CVCL:0023', (361, 365))	('A549', 'CellLine', 'CVCL:0023', (186, 190))	('NSCLC', 'Disease', (88, 93))	('RAP1', 'Gene', '54386', (391, 395))	('RAP1', 'Gene', '54386', (454, 458))	('NSCLC', 'Disease', 'MESH:D002289', (191, 196))	('NSCLC', 'Disease', 'MESH:D002289', (476, 481))	('NSCLC', 'Disease', (120, 125))
515166	28518145	Furthermore, in established cisplatin-resistant A549 cells, RAP1 depletion caused BCL2 depletion, caspase activation and dramatic lethality to the cells.	('cisplatin', 'Chemical', 'MESH:D002945', (28, 37))	('BCL2', 'Gene', (82, 86))	('RAP1', 'Gene', (60, 64))	('A549', 'CellLine', 'CVCL:0023', (48, 52))	('RAP1', 'Gene', '54386', (60, 64))	('depletion', 'Var', (65, 74))	('caspase', 'CPA', (98, 105))	('lethality', 'CPA', (130, 139))	('BCL2', 'Gene', '596', (82, 86))	('activation', 'PosReg', (106, 116))
515187	28518145	Meanwhile, we observed a synergistic effect between CP treatment and RAP1 deletion in tumor suppression.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Disease', (86, 91))	('deletion', 'Var', (74, 82))	('RAP1', 'Gene', (69, 73))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('RAP1', 'Gene', '54386', (69, 73))
515195	28518145	These analyses identify cytoplasmic RAP1 as an indicator of high-grade NSCLC, suggesting that it may have a critical role in cancer progression.	('RAP1', 'Gene', (36, 40))	('NSCLC', 'Phenotype', 'HP:0030358', (71, 76))	('cytoplasmic', 'Var', (24, 35))	('RAP1', 'Gene', '54386', (36, 40))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('cancer', 'Disease', (125, 131))	('NSCLC', 'Disease', (71, 76))	('NSCLC', 'Disease', 'MESH:D002289', (71, 76))
515203	28518145	RAP1 knockdown by shRAP1-1 or shRAP1-2 was evident both at the mRNA (Figure 2d) and protein levels in both cytoplasmic and nuclear fractions (Supplementary Figure S3b).	('RAP1', 'Gene', (32, 36))	('RAP1', 'Gene', '54386', (32, 36))	('knockdown', 'Var', (5, 14))	('RAP1', 'Gene', (0, 4))	('RAP1', 'Gene', (20, 24))	('RAP1', 'Gene', '54386', (0, 4))	('RAP1', 'Gene', '54386', (20, 24))
515211	28518145	To test this hypothesis, we detected the effect of RAP1 deletion on the activity of NF-kappaB signaling, a known downstream effector of cytoplasmic RAP1.	('deletion', 'Var', (56, 64))	('RAP1', 'Gene', (148, 152))	('NF-kappaB', 'Gene', '4790', (84, 93))	('NF-kappaB', 'Gene', (84, 93))	('activity', 'MPA', (72, 80))	('RAP1', 'Gene', (51, 55))	('RAP1', 'Gene', '54386', (51, 55))	('RAP1', 'Gene', '54386', (148, 152))
515213	28518145	Indeed, when RAP1 was deleted in A549 cells, we observed a decrease of phosphorylated p65 in the nuclear fraction (Figures 3a and b).	('p65', 'Gene', '5970', (86, 89))	('A549', 'CellLine', 'CVCL:0023', (33, 37))	('phosphorylated', 'MPA', (71, 85))	('RAP1', 'Gene', '54386', (13, 17))	('RAP1', 'Gene', (13, 17))	('p65', 'Gene', (86, 89))	('decrease', 'NegReg', (59, 67))	('deleted', 'Var', (22, 29))
515214	28518145	Phosphorylation of IkappaBalpha, which promotes NF-kappaB signaling, was also decreased with the deletion of RAP1 (Figure 3a and Supplementary Figure S5a).	('promotes', 'PosReg', (39, 47))	('S5a', 'Gene', '5710', (150, 153))	('RAP1', 'Gene', (109, 113))	('IkappaBalpha', 'Gene', '4792', (19, 31))	('S5a', 'Gene', (150, 153))	('NF-kappaB', 'Gene', '4790', (48, 57))	('RAP1', 'Gene', '54386', (109, 113))	('Phosphorylation', 'MPA', (0, 15))	('IkappaBalpha', 'Gene', (19, 31))	('decreased', 'NegReg', (78, 87))	('NF-kappaB', 'Gene', (48, 57))	('deletion', 'Var', (97, 105))
515215	28518145	Intriguingly, transcription of IkappaBalpha was significantly suppressed but the total IkappaBalpha protein was only moderately decreased after RAP1 deletion (Figures 3a and b), probably due to a positive feedback of NF-kappaB signaling.	('IkappaBalpha', 'Gene', (31, 43))	('deletion', 'Var', (149, 157))	('IkappaBalpha', 'Gene', (87, 99))	('transcription', 'MPA', (14, 27))	('NF-kappaB', 'Gene', '4790', (217, 226))	('IkappaBalpha', 'Gene', '4792', (31, 43))	('NF-kappaB', 'Gene', (217, 226))	('suppressed', 'NegReg', (62, 72))	('decreased', 'NegReg', (128, 137))	('RAP1', 'Gene', '54386', (144, 148))	('RAP1', 'Gene', (144, 148))	('IkappaBalpha', 'Gene', '4792', (87, 99))
515217	28518145	No significant changes in IKK protein levels or in its phosphorylation were observed upon RAP1 deletion (Supplementary Figures S5b and c).	('RAP1', 'Gene', (90, 94))	('deletion', 'Var', (95, 103))	('RAP1', 'Gene', '54386', (90, 94))	('phosphorylation', 'MPA', (55, 70))	('IKK protein', 'Protein', (26, 37))
515219	28518145	Clearly, RAP1 deletion led to the downregulation of these factors (Figure 3c).	('deletion', 'Var', (14, 22))	('downregulation', 'NegReg', (34, 48))	('RAP1', 'Gene', '54386', (9, 13))	('RAP1', 'Gene', (9, 13))
515227	28518145	Unexpectedly, when A549 cells were transduced to overexpress RAP1, they displayed only modest increase of growth (Figure 4b); however, a larger amount of CP was required to eliminate RAP1-overexpressed cells to an extent similar to that achievable with the control cells (Figure 4c).	('RAP1', 'Gene', '54386', (183, 187))	('overexpress', 'PosReg', (49, 60))	('transduced', 'Var', (35, 45))	('growth', 'MPA', (106, 112))	('RAP1', 'Gene', (61, 65))	('RAP1', 'Gene', '54386', (61, 65))	('A549', 'CellLine', 'CVCL:0023', (19, 23))	('RAP1', 'Gene', (183, 187))
515238	28518145	CP treatment slightly induced BCL-2 expression in cells transduced with control and RAP1-overexpression vectors, which might be a negative feedback of facilitated apoptosis (Figure 4e).	('RAP1', 'Gene', (84, 88))	('BCL-2', 'Gene', (30, 35))	('BCL-2', 'Gene', '596', (30, 35))	('induced', 'Reg', (22, 29))	('RAP1', 'Gene', '54386', (84, 88))	('vectors', 'Var', (104, 111))	('expression', 'MPA', (36, 46))
515256	28518145	As described above, RAP1 deletion increased the sensitivity of NSCLC cells to CP (Figure 5e), so we next evaluated the capability to target RAP1 in cells that have already established resistance.	('NSCLC', 'Disease', (63, 68))	('NSCLC', 'Disease', 'MESH:D002289', (63, 68))	('RAP1', 'Gene', '54386', (20, 24))	('sensitivity', 'MPA', (48, 59))	('deletion', 'Var', (25, 33))	('RAP1', 'Gene', (20, 24))	('RAP1', 'Gene', (140, 144))	('NSCLC', 'Phenotype', 'HP:0030358', (63, 68))	('RAP1', 'Gene', '54386', (140, 144))	('increased', 'PosReg', (34, 43))
515260	28518145	The BCL-2 expression was much higher in A549R cells compared with parental A549 cells, probably contributed by the continuous CP treatment in maintaining resistance (Figure 6d and Supplementary Figure S7c).	('BCL-2', 'Gene', '596', (4, 9))	('A549R', 'CellLine', 'CVCL:0023', (40, 45))	('higher', 'PosReg', (30, 36))	('BCL-2', 'Gene', (4, 9))	('A549R', 'Var', (40, 45))	('expression', 'MPA', (10, 20))	('resistance', 'MPA', (154, 164))	('A549', 'CellLine', 'CVCL:0023', (40, 44))	('A549', 'CellLine', 'CVCL:0023', (75, 79))
515261	28518145	Inspired by the effect described above that RAP1 deletion sensitizes cells to CP treatment, we sought to attenuate CP resistance in A549R cells through deleting RAP1.	('attenuate', 'NegReg', (105, 114))	('deleting', 'Var', (152, 160))	('RAP1', 'Gene', '54386', (44, 48))	('RAP1', 'Gene', (44, 48))	('RAP1', 'Gene', (161, 165))	('deletion', 'Var', (49, 57))	('RAP1', 'Gene', '54386', (161, 165))	('sensitizes', 'Reg', (58, 68))	('CP resistance', 'MPA', (115, 128))	('A549R', 'CellLine', 'CVCL:0023', (132, 137))
515263	28518145	To rule out the possibility that the CP used to maintain resistance might induce mortality, we cultured CP-resistant cells in CP-free media for 24 h before inducing RAP1 deletion.	('inducing', 'Reg', (156, 164))	('RAP1', 'Gene', '54386', (165, 169))	('RAP1', 'Gene', (165, 169))	('deletion', 'Var', (170, 178))
515267	28518145	Therefore, RAP1 deletion alone is sufficient to cause an overwhelming lethality in the A549R cells through hyperactivation of apoptosis, for which further CP treatment is no longer required.	('deletion', 'Var', (16, 24))	('hyperactivation', 'PosReg', (107, 122))	('apoptosis', 'CPA', (126, 135))	('cause', 'Reg', (48, 53))	('A549R', 'CellLine', 'CVCL:0023', (87, 92))	('RAP1', 'Gene', '54386', (11, 15))	('RAP1', 'Gene', (11, 15))
515271	28518145	The facilitating role of RAP1 in NSCLC progression is supported by our findings that shRNA-mediated RAP1 knockdown severely impairs the growth of lung adenocarcinoma and squamous carcinoma cell lines.	('squamous carcinoma', 'Phenotype', 'HP:0002860', (170, 188))	('NSCLC', 'Phenotype', 'HP:0030358', (33, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (156, 165))	('growth', 'MPA', (136, 142))	('lung adenocarcinoma', 'Disease', (146, 165))	('knockdown', 'Var', (105, 114))	('squamous carcinoma', 'Disease', 'MESH:D002294', (170, 188))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (146, 165))	('RAP1', 'Gene', (25, 29))	('carcinoma', 'Phenotype', 'HP:0030731', (179, 188))	('NSCLC', 'Disease', (33, 38))	('impairs', 'NegReg', (124, 131))	('RAP1', 'Gene', (100, 104))	('squamous carcinoma', 'Disease', (170, 188))	('NSCLC', 'Disease', 'MESH:D002289', (33, 38))	('RAP1', 'Gene', '54386', (25, 29))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (146, 165))	('RAP1', 'Gene', '54386', (100, 104))
515272	28518145	One might argue that RAP1 deletion targets not only the cytoplasmic fraction but also the nuclear fraction.	('RAP1', 'Gene', (21, 25))	('RAP1', 'Gene', '54386', (21, 25))	('deletion', 'Var', (26, 34))
515281	28518145	Interestingly, after RAP1 deletion, the transcription of IkappaBalpha, which was both an inhibitor and a downstream target of NF-kappaB, was remarkably decreased.	('transcription', 'MPA', (40, 53))	('NF-kappaB', 'Gene', '4790', (126, 135))	('deletion', 'Var', (26, 34))	('decreased', 'NegReg', (152, 161))	('IkappaBalpha', 'Gene', '4792', (57, 69))	('NF-kappaB', 'Gene', (126, 135))	('RAP1', 'Gene', '54386', (21, 25))	('RAP1', 'Gene', (21, 25))	('IkappaBalpha', 'Gene', (57, 69))
515283	28518145	The synergistic effect we found between RAP1 deletion and TNF-alpha treatment (Supplementary Figure S8) could further prove that targeting RAP1 is able to inhibit NF-kappaB activity, as TNF-alpha resistance is also correlated with NF-kappaB activity.	('TNF-alpha', 'Gene', '7124', (58, 67))	('NF-kappaB', 'Gene', (163, 172))	('NF-kappaB', 'Gene', (231, 240))	('RAP1', 'Gene', (139, 143))	('TNF-alpha', 'Gene', (58, 67))	('RAP1', 'Gene', (40, 44))	('targeting', 'Var', (129, 138))	('RAP1', 'Gene', '54386', (40, 44))	('RAP1', 'Gene', '54386', (139, 143))	('TNF-alpha', 'Gene', '7124', (186, 195))	('TNF-alpha', 'Gene', (186, 195))	('NF-kappaB', 'Gene', '4790', (163, 172))	('NF-kappaB', 'Gene', '4790', (231, 240))	('deletion', 'Var', (45, 53))	('inhibit', 'NegReg', (155, 162))
515288	28518145	We observed a very intriguing and potentially highly significant effect in the established CP-resistant NSCLC cells, where RAP1 deletion led to an almost complete elimination of the cells.	('NSCLC', 'Disease', (104, 109))	('RAP1', 'Gene', (123, 127))	('NSCLC', 'Disease', 'MESH:D002289', (104, 109))	('RAP1', 'Gene', '54386', (123, 127))	('NSCLC', 'Phenotype', 'HP:0030358', (104, 109))	('deletion', 'Var', (128, 136))
515289	28518145	It was hypothesized that the hyperactivated NF-kappaB in these cells will generate large amount of TNF-alpha, leading to the induction of apoptosis when the NF-kappaB signaling is disrupted by loss of RAP1.	('RAP1', 'Gene', (201, 205))	('NF-kappaB', 'Gene', '4790', (157, 166))	('leading to', 'Reg', (110, 120))	('NF-kappaB', 'Gene', '4790', (44, 53))	('RAP1', 'Gene', '54386', (201, 205))	('hyperactivated', 'PosReg', (29, 43))	('loss', 'Var', (193, 197))	('NF-kappaB', 'Gene', (157, 166))	('NF-kappaB', 'Gene', (44, 53))	('apoptosis', 'CPA', (138, 147))	('TNF-alpha', 'Gene', '7124', (99, 108))	('TNF-alpha', 'Gene', (99, 108))
515290	28518145	However, mortality still occurred when fresh media containing negligible amount of TNF-alpha was applied immediately after RAP1 deletion, suggesting that TNF-alpha is not the main reason for apoptosis induction.	('TNF-alpha', 'Gene', '7124', (83, 92))	('TNF-alpha', 'Gene', (154, 163))	('TNF-alpha', 'Gene', (83, 92))	('RAP1', 'Gene', (123, 127))	('RAP1', 'Gene', '54386', (123, 127))	('occurred', 'Reg', (25, 33))	('TNF-alpha', 'Gene', '7124', (154, 163))	('deletion', 'Var', (128, 136))
515291	28518145	One possible explanation is that the survival of CP-resistant cells becomes more dependent on the RAP1-NF-kappaB-BCL2 regulatory axis, making the deletion of any components of this pathway lethal to these cells.	('deletion', 'Var', (146, 154))	('NF-kappaB', 'Gene', '4790', (103, 112))	('RAP1', 'Gene', (98, 102))	('BCL2', 'Gene', '596', (113, 117))	('RAP1', 'Gene', '54386', (98, 102))	('NF-kappaB', 'Gene', (103, 112))	('BCL2', 'Gene', (113, 117))
515294	28518145	Upon RAP1 deletion, the no longer suppressed proapoptotic force would thus lead the cells toward programmed cell death.	('programmed cell death', 'CPA', (97, 118))	('lead', 'Reg', (75, 79))	('RAP1', 'Gene', '54386', (5, 9))	('RAP1', 'Gene', (5, 9))	('proapoptotic force', 'MPA', (45, 63))	('deletion', 'Var', (10, 18))
515295	28518145	Further examination of DNA damage in CP-resistant cells are needed to test the hypotheses mentioned above, but it is clear that targeting RAP1 directs the future approach against the resistant subset of NSCLC cells after CP treatment.	('NSCLC', 'Disease', (203, 208))	('RAP1', 'Gene', '54386', (138, 142))	('NSCLC', 'Disease', 'MESH:D002289', (203, 208))	('RAP1', 'Gene', (138, 142))	('NSCLC', 'Phenotype', 'HP:0030358', (203, 208))	('targeting', 'Var', (128, 137))
515296	28518145	On the other hand, RAP1 deletion also sensitizes NSCLC cells to CP, opening up new methods to combine RAP1-targeting strategy and cytotoxic chemotherapy.	('RAP1', 'Gene', (19, 23))	('NSCLC', 'Disease', (49, 54))	('RAP1', 'Gene', '54386', (19, 23))	('NSCLC', 'Disease', 'MESH:D002289', (49, 54))	('RAP1', 'Gene', (102, 106))	('deletion', 'Var', (24, 32))	('sensitizes', 'Reg', (38, 48))	('RAP1', 'Gene', '54386', (102, 106))	('NSCLC', 'Phenotype', 'HP:0030358', (49, 54))
515318	28356914	Specifically, aberrant activation of these pathways is implicated in modulation of cancer stem cells (CSCs), a small subset of cancer cells capable of self-renewal and differentiation into heterogeneous tumor cells.	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('tumor', 'Disease', (203, 208))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('activation', 'PosReg', (23, 33))	('aberrant', 'Var', (14, 22))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('cancer', 'Disease', (127, 133))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('cancer', 'Disease', (83, 89))
515332	28356914	For instance, in colorectal cancer, Wnt signaling deregulation is often associated with mutations in APC and beta-catenin genes.	('beta-catenin genes', 'Gene', (109, 127))	('APC', 'Disease', (101, 104))	('colorectal cancer', 'Phenotype', 'HP:0003003', (17, 34))	('Wnt signaling', 'Pathway', (36, 49))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('mutations', 'Var', (88, 97))	('associated', 'Reg', (72, 82))	('colorectal cancer', 'Disease', (17, 34))	('APC', 'Phenotype', 'HP:0005227', (101, 104))	('APC', 'Disease', 'MESH:D011125', (101, 104))	('colorectal cancer', 'Disease', 'MESH:D015179', (17, 34))	('deregulation', 'NegReg', (50, 62))
515333	28356914	Mutations in APC have been found in around 80% of all human colon tumors, and these mutations inactivate APC function resulting in Wnt signaling activation by preventing beta-catenin phosphorylation and subsequent beta-catenin degradation.	('Wnt signaling', 'MPA', (131, 144))	('beta-catenin phosphorylation', 'MPA', (170, 198))	('APC', 'Phenotype', 'HP:0005227', (13, 16))	('activation', 'PosReg', (145, 155))	('APC', 'Disease', 'MESH:D011125', (13, 16))	('APC', 'Disease', (13, 16))	('Mutations', 'Var', (0, 9))	('function', 'MPA', (109, 117))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('mutations', 'Var', (84, 93))	('colon tumors', 'Disease', 'MESH:D015179', (60, 72))	('APC', 'Phenotype', 'HP:0005227', (105, 108))	('APC', 'Disease', 'MESH:D011125', (105, 108))	('beta-catenin degradation', 'MPA', (214, 238))	('human', 'Species', '9606', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('APC', 'Disease', (105, 108))	('preventing', 'NegReg', (159, 169))	('colon tumors', 'Phenotype', 'HP:0100273', (60, 72))	('colon tumors', 'Disease', (60, 72))	('inactivate', 'NegReg', (94, 104))
515334	28356914	In addition, beta-catenin oncogenic mutations have been reported in approximately 10% of colorectal cancer patients, and these missense or deletion mutations are located at beta-catenin sites where GSK3beta normally phosphorylates beta-catenin, leading to stable beta-catenin translocation into the nucleus for Wnt activation.	('missense', 'Var', (127, 135))	('leading to', 'Reg', (245, 255))	('colorectal cancer', 'Phenotype', 'HP:0003003', (89, 106))	('deletion mutations', 'Var', (139, 157))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('colorectal cancer', 'Disease', (89, 106))	('mutations', 'Var', (36, 45))	('GSK3beta', 'Gene', (198, 206))	('GSK3beta', 'Gene', '2932', (198, 206))	('colorectal cancer', 'Disease', 'MESH:D015179', (89, 106))	('beta-catenin', 'Gene', (13, 25))	('patients', 'Species', '9606', (107, 115))
515337	28356914	For example, in an elegant study of squamous cell carcinomas, canonical Wnt signaling activation was shown to be critical in tumorigenesis of CD34+ bulge CSCs, and ablation of the beta-catenin gene resulted in depletion of CD34+ CSCs and complete tumor regression in mice.	('tumor', 'Phenotype', 'HP:0002664', (247, 252))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('depletion', 'MPA', (210, 219))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (36, 60))	('tumor', 'Disease', (247, 252))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (50, 59))	('tumor', 'Disease', 'MESH:D009369', (247, 252))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (36, 59))	('tumor', 'Disease', (125, 130))	('carcinomas', 'Phenotype', 'HP:0030731', (50, 60))	('CD34+ CSCs', 'MPA', (223, 233))	('ablation', 'Var', (164, 172))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (36, 60))	('squamous cell carcinomas', 'Disease', (36, 60))	('beta-catenin gene', 'Gene', (180, 197))	('mice', 'Species', '10090', (267, 271))
515341	28356914	One study showed that experimental knockdown of CD146 can dedifferentiate colorectal cancer cells to acquire a stem cell phenotype through inhibiting GSK-3beta which in turn promoted nuclear translocation of beta-catenin for Wnt signaling activation.	('knockdown', 'Var', (35, 44))	('CD146', 'Gene', '4162', (48, 53))	('CD146', 'Gene', (48, 53))	('colorectal cancer', 'Disease', 'MESH:D015179', (74, 91))	('promoted', 'PosReg', (174, 182))	('nuclear translocation', 'MPA', (183, 204))	('colorectal cancer', 'Phenotype', 'HP:0003003', (74, 91))	('dedifferentiate', 'NegReg', (58, 73))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('GSK-3beta', 'Gene', '2932', (150, 159))	('GSK-3beta', 'Gene', (150, 159))	('colorectal cancer', 'Disease', (74, 91))	('inhibiting', 'NegReg', (139, 149))
515342	28356914	Therefore, modifying Wnt signaling may be essential in the pursuit to curb colorectal cancer, specifically colorectal cancer stem cells.	('colorectal cancer', 'Disease', (75, 92))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('colorectal cancer', 'Phenotype', 'HP:0003003', (107, 124))	('colorectal cancer', 'Disease', 'MESH:D015179', (75, 92))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('modifying', 'Var', (11, 20))	('colorectal cancer', 'Disease', (107, 124))	('colorectal cancer', 'Phenotype', 'HP:0003003', (75, 92))	('colorectal cancer', 'Disease', 'MESH:D015179', (107, 124))
515363	28356914	In a murine CML model of study, deletion of SMO significantly reduced the CML CSCs, and conversely overexpression of SMO in a SMO-deficient mouse CML model dramatically enhanced CML CSCs 4-fold and significantly increased CML progression.	('CML CSCs', 'MPA', (74, 82))	('mouse', 'Species', '10090', (140, 145))	('deletion', 'Var', (32, 40))	('CML CSCs', 'MPA', (178, 186))	('CML', 'Phenotype', 'HP:0005506', (178, 181))	('CML', 'Phenotype', 'HP:0005506', (222, 225))	('CML', 'Phenotype', 'HP:0005506', (74, 77))	('murine', 'Species', '10090', (5, 11))	('CML progression', 'CPA', (222, 237))	('CML', 'Phenotype', 'HP:0005506', (12, 15))	('SMO', 'Gene', (44, 47))	('increased', 'PosReg', (212, 221))	('CML', 'Phenotype', 'HP:0005506', (146, 149))	('enhanced', 'PosReg', (169, 177))	('reduced', 'NegReg', (62, 69))
515366	28356914	For instance, Gli1 was shown to correlate with markers of EMT and highly express in the claudin-low breast CSCs, and knockdown of Gli1 resulted in reduced claudin-low breast CSC's viability, motility, clonogenicity, and self-renewal as well as tumor growth in orthotopic xenografts.	('Gli1', 'Gene', '2735', (130, 134))	("breast CSC's viability", 'Disease', 'MESH:D010144', (167, 189))	('tumor', 'Phenotype', 'HP:0002664', (244, 249))	('tumor', 'Disease', (244, 249))	('Gli1', 'Gene', '2735', (14, 18))	('self-renewal', 'CPA', (220, 232))	("breast CSC's viability", 'Disease', (167, 189))	('motility', 'CPA', (191, 199))	('clonogenicity', 'CPA', (201, 214))	('Gli1', 'Gene', (130, 134))	('tumor', 'Disease', 'MESH:D009369', (244, 249))	('reduced', 'NegReg', (147, 154))	('knockdown', 'Var', (117, 126))	('Gli1', 'Gene', (14, 18))
515367	28356914	have demonstrated that HH pathway and EMT are active in pancreatic cancer cells-derived tumorspheres that exhibit CSC properties, and inhibition of HH signaling by SMO knockdown blocks the self-renewal, EMT, invasion, chemoresistance, and tumorigenesis of pancreatic CSCs.	('pancreatic cancer', 'Disease', (56, 73))	('self-renewal', 'CPA', (189, 201))	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('SMO', 'Gene', (164, 167))	('pancreatic CSCs', 'Disease', (256, 271))	('blocks', 'NegReg', (178, 184))	('HH', 'Gene', '31680', (23, 25))	('tumor', 'Disease', (239, 244))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (56, 73))	('tumor', 'Disease', (88, 93))	('EMT', 'CPA', (203, 206))	('invasion', 'CPA', (208, 216))	('HH', 'Gene', '31680', (148, 150))	('rat', 'Species', '10116', (12, 15))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('inhibition', 'Var', (134, 144))	('tumor', 'Disease', 'MESH:D009369', (239, 244))	('chemoresistance', 'CPA', (218, 233))	('knockdown', 'Var', (168, 177))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('tumor', 'Phenotype', 'HP:0002664', (239, 244))	('pancreatic cancer', 'Disease', 'MESH:D010190', (56, 73))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumors', 'Disease', (88, 94))	('pancreatic CSCs', 'Disease', 'MESH:D010195', (256, 271))
515368	28356914	As evidenced above, HH signaling plays a critical role in CSC's self-renewal and regulation, and inhibition of the HH pathway disrupts CSC's stemness and induces CSC's differentiation which are desirable for cancer treatment.	('inhibition', 'Var', (97, 107))	('HH', 'Gene', '31680', (115, 117))	('cancer', 'Disease', (208, 214))	('induces', 'Reg', (154, 161))	('HH', 'Gene', '31680', (20, 22))	("disrupts CSC's stemness", 'Disease', 'MESH:D019958', (126, 149))	("disrupts CSC's stemness", 'Disease', (126, 149))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))	('CSC', 'CPA', (162, 165))	('differentiation', 'CPA', (168, 183))	('cancer', 'Disease', 'MESH:D009369', (208, 214))
515377	28356914	Currently, clinical trials of Vismodegib as a monotherapy or in combination with other therapeutic drugs are ongoing for various cancers including medulloblastoma, small cell lung cancer, metastatic pancreatic cancer, metastatic prostate cancer, intracranial meningioma, recurrent glioblastoma, and acute myeloid leukemia (NCT Numbers: NCT00833417, NCT01201915, NCT00739661, and NCT01088815).	('pancreatic cancer', 'Disease', (199, 216))	('metastatic prostate cancer', 'Disease', 'MESH:D011471', (218, 244))	('cancers', 'Phenotype', 'HP:0002664', (129, 136))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('NCT00739661', 'Var', (362, 373))	('cancers', 'Disease', (129, 136))	('metastatic prostate cancer', 'Disease', (218, 244))	('NCT01088815', 'Var', (379, 390))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('glioblastoma', 'Disease', 'MESH:D005909', (281, 293))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (199, 216))	('small cell lung cancer', 'Disease', 'MESH:D055752', (164, 186))	('acute myeloid leukemia', 'Disease', (299, 321))	('intracranial meningioma', 'Disease', 'MESH:D008577', (246, 269))	('intracranial meningioma', 'Phenotype', 'HP:0100009', (246, 269))	('glioblastoma', 'Disease', (281, 293))	('small cell lung cancer', 'Disease', (164, 186))	('medulloblastoma', 'Disease', 'MESH:D008527', (147, 162))	('cancers', 'Disease', 'MESH:D009369', (129, 136))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('lung cancer', 'Phenotype', 'HP:0100526', (175, 186))	('leukemia', 'Phenotype', 'HP:0001909', (313, 321))	('medulloblastoma', 'Phenotype', 'HP:0002885', (147, 162))	('glioblastoma', 'Phenotype', 'HP:0012174', (281, 293))	('NCT01201915', 'Var', (349, 360))	('intracranial meningioma', 'Disease', (246, 269))	('medulloblastoma', 'Disease', (147, 162))	('prostate cancer', 'Phenotype', 'HP:0012125', (229, 244))	('pancreatic cancer', 'Disease', 'MESH:D010190', (199, 216))	('meningioma', 'Phenotype', 'HP:0002858', (259, 269))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (299, 321))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (305, 321))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (299, 321))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (164, 186))
515383	28356914	Moreover, a few of HH signaling inhibitors that are actively being tested in clinical trials include additional SMO inhibitors (Saridegib, BMS-833923, Glasdegib, and PF-5274857) and GLI Inhibitor (arsenic trioxide).	('HH', 'Gene', '31680', (19, 21))	('GLI', 'Gene', (182, 185))	('arsenic trioxide', 'Chemical', 'MESH:D000077237', (197, 213))	('GLI', 'Gene', '2735', (182, 185))	('BMS-833923', 'Var', (139, 149))	('SMO', 'Gene', (112, 115))	('PF-5274857', 'Var', (166, 176))
515390	28356914	Fascin knockdown significantly reduced breast stem cell-like phenotype (downregulation of stem cell pluripotent genes such as Oct4, Nanog, Sox2, and Klf4), and the cells became less competent in forming colonies and tumorspheres.	('Sox2', 'Gene', '6657', (139, 143))	('tumors', 'Disease', (216, 222))	('less', 'NegReg', (177, 181))	('Fascin', 'Gene', '6624', (0, 6))	('tumors', 'Disease', 'MESH:D009369', (216, 222))	('Oct4', 'Gene', '5460', (126, 130))	('Nanog', 'Gene', '79923', (132, 137))	('reduced', 'NegReg', (31, 38))	('Fascin', 'Gene', (0, 6))	('breast stem cell-like phenotype', 'CPA', (39, 70))	('Klf4', 'Gene', (149, 153))	('Nanog', 'Gene', (132, 137))	('Sox2', 'Gene', (139, 143))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('Oct4', 'Gene', (126, 130))	('tumors', 'Phenotype', 'HP:0002664', (216, 222))	('downregulation', 'NegReg', (72, 86))	('knockdown', 'Var', (7, 16))	('stem cell pluripotent genes', 'Gene', (90, 117))	('Klf4', 'Gene', '9314', (149, 153))
515395	28356914	In a study of patient-derived pancreatic CSCs, Notch ligands Notch 1, Notch 3, Jag1, Jag2, and Notch target gene Hes1 were found to be highly expressed in the pancreatic CSCs, and an inhibitor of gamma-secretase (an important protease mediating Notch signaling by releasing the Notch ICD) significantly decreased the CSC's subpopulation and tumorsphere formation.	('Jag2', 'Gene', (85, 89))	('tumor', 'Phenotype', 'HP:0002664', (341, 346))	('decreased', 'NegReg', (303, 312))	('tumors', 'Disease', (341, 347))	('ICD', 'Disease', (284, 287))	('pancreatic CSCs', 'Disease', 'MESH:D010195', (159, 174))	('inhibitor', 'Var', (183, 192))	('Hes1', 'Gene', '3280', (113, 117))	('ICD', 'Disease', 'OMIM:252500', (284, 287))	('tumors', 'Disease', 'MESH:D009369', (341, 347))	('Jag2', 'Gene', '3714', (85, 89))	('pancreatic CSCs', 'Disease', (159, 174))	('pancreatic CSCs', 'Disease', 'MESH:D010195', (30, 45))	('Jag1', 'Gene', (79, 83))	('Hes1', 'Gene', (113, 117))	('Notch 1', 'Gene', '4851', (61, 68))	('patient', 'Species', '9606', (14, 21))	('Jag1', 'Gene', '182', (79, 83))	('CSC', 'Disease', (317, 320))	('pancreatic CSCs', 'Disease', (30, 45))	('tumors', 'Phenotype', 'HP:0002664', (341, 347))	('Notch 3', 'Gene', '4854', (70, 77))	('Notch 3', 'Gene', (70, 77))	('Notch 1', 'Gene', (61, 68))
515396	28356914	Moreover, activation of Notch signaling by delta/Serrate/Lag-2 peptide or inhibition of the signaling by knockdown of Hes1 enhanced or decreased pancreatic CSC's tumorsphere formation, respectively.	('enhanced', 'PosReg', (123, 131))	('Notch signaling', 'MPA', (24, 39))	('rat', 'Species', '10116', (52, 55))	('Hes1', 'Gene', (118, 122))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('Hes1', 'Gene', '3280', (118, 122))	('knockdown', 'Var', (105, 114))	('inhibition', 'NegReg', (74, 84))	('Lag-2', 'Gene', '10578', (57, 62))	("decreased pancreatic CSC's tumorsphere", 'Disease', 'MESH:D010195', (135, 173))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))	("decreased pancreatic CSC's tumorsphere", 'Disease', (135, 173))	('Lag-2', 'Gene', (57, 62))	('activation', 'PosReg', (10, 20))
515397	28356914	In addition, Notch signaling dysregulation has also been recognized in glioblastoma CSCs.	('dysregulation', 'Var', (29, 42))	('glioblastoma CSCs', 'Disease', (71, 88))	('glioblastoma CSCs', 'Disease', 'MESH:D005909', (71, 88))	('glioblastoma', 'Phenotype', 'HP:0012174', (71, 83))
515398	28356914	It was found that Protein Kinase C Iota (PKCi) was highly expressed in glioblastoma patient-derived CSCs, and silencing PKCi resulted in apoptosis and reduction of proliferation of the glioblastoma CSCs in vitro and tumor growth in vivo in a xenograft mouse model.	('PKCi', 'Gene', '5584', (120, 124))	('glioblastoma', 'Disease', (71, 83))	('glioblastoma CSCs', 'Disease', (185, 202))	('glioblastoma', 'Phenotype', 'HP:0012174', (71, 83))	('Protein Kinase C Iota', 'Gene', (18, 39))	('tumor', 'Disease', (216, 221))	('silencing', 'Var', (110, 119))	('glioblastoma', 'Disease', 'MESH:D005909', (185, 197))	('tumor', 'Disease', 'MESH:D009369', (216, 221))	('glioblastoma CSCs', 'Disease', 'MESH:D005909', (185, 202))	('mouse', 'Species', '10090', (252, 257))	('apoptosis', 'CPA', (137, 146))	('proliferation', 'CPA', (164, 177))	('glioblastoma', 'Disease', (185, 197))	('rat', 'Species', '10116', (171, 174))	('glioblastoma', 'Phenotype', 'HP:0012174', (185, 197))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('patient', 'Species', '9606', (84, 91))	('PKCi', 'Gene', (41, 45))	('glioblastoma', 'Disease', 'MESH:D005909', (71, 83))	('Protein Kinase C Iota', 'Gene', '5584', (18, 39))	('PKCi', 'Gene', '5584', (41, 45))	('PKCi', 'Gene', (120, 124))	('reduction', 'NegReg', (151, 160))
515403	28356914	In a preclinical study, a gamma-secretase inhibitor RO4929097 significantly suppressed Notch target genes Hes1, Hey1, and HeyL.	('Hey1', 'Gene', (112, 116))	('HeyL', 'Gene', (122, 126))	('Hey1', 'Gene', '23462', (112, 116))	('HeyL', 'Gene', '26508', (122, 126))	('Hes1', 'Gene', (106, 110))	('suppressed', 'NegReg', (76, 86))	('Hes1', 'Gene', '3280', (106, 110))	('RO4929097', 'Chemical', 'MESH:C545185', (52, 61))	('RO4929097', 'Var', (52, 61))
515404	28356914	Several phase I and phase II studies have been conducted in hopes of synergistically utilizing RO4929097 with other agents for cancer treatment.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('RO4929097', 'Chemical', 'MESH:C545185', (95, 104))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('RO4929097', 'Var', (95, 104))	('cancer', 'Disease', (127, 133))
515405	28356914	For instance, in a completed phase I trial, RO4929097 and Cediranib Maleate were used in tandem to determine the phase II dose and safety profile of RO4929097 in solid tumors (NCT Number: NCT01131234), and the clinical trial data shall be announced soon.	('Cediranib Maleate', 'Chemical', 'MESH:C500926', (58, 75))	('RO4929097', 'Var', (149, 158))	('solid tumors', 'Disease', 'MESH:D009369', (162, 174))	('RO4929097', 'Chemical', 'MESH:C545185', (149, 158))	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('RO4929097', 'Chemical', 'MESH:C545185', (44, 53))	('solid tumors', 'Disease', (162, 174))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
515426	28356914	showed that combination treatment with HH signaling inhibitor NVP-LDE225 and pI3/mTOR/Akt signaling inhibitor NVP-BEZ235 inhibited self-renewal capacity of pancreatic CSCs by suppressing the expression of pluripotency maintaining factors Nanog, Oct-4, Sox-2, and c-Myc and transcription of GLI.	('Akt', 'Gene', (86, 89))	('Oct-4', 'Gene', (245, 250))	('Nanog', 'Gene', '79923', (238, 243))	('Nanog', 'Gene', (238, 243))	('Akt', 'Gene', '207', (86, 89))	('GLI', 'Gene', '2735', (290, 293))	('c-Myc', 'Gene', (263, 268))	('NVP-LDE225', 'Var', (62, 72))	('Sox-2', 'Gene', (252, 257))	('Sox-2', 'Gene', '6657', (252, 257))	('c-Myc', 'Gene', '4609', (263, 268))	('pI3', 'Gene', (77, 80))	('mTOR', 'Gene', (81, 85))	('inhibited', 'NegReg', (121, 130))	('expression', 'MPA', (191, 201))	('NVP-BEZ235', 'Var', (110, 120))	('pancreatic CSCs', 'Disease', 'MESH:D010195', (156, 171))	('mTOR', 'Gene', '2475', (81, 85))	('pluripotency maintaining', 'MPA', (205, 229))	('transcription', 'MPA', (273, 286))	('GLI', 'Gene', (290, 293))	('suppressing', 'NegReg', (175, 186))	('Oct-4', 'Gene', '5460', (245, 250))	('BEZ235', 'Chemical', 'MESH:C531198', (114, 120))	('pI3', 'Gene', '5266', (77, 80))	('pancreatic CSCs', 'Disease', (156, 171))	('HH', 'Gene', '31680', (39, 41))
515432	27533083	Co-inhibition of pol theta and HR genes efficiently synergize with cisplatin to suppress cisplatin-resistant lung cancer cells survival Cisplatin exert its anticancer effect by creating intrastrand and interstrand DNA cross-links which block DNA replication and is a major drug used to treat lung cancer.	('lung cancer', 'Disease', (292, 303))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('cisplatin', 'Chemical', 'MESH:D002945', (89, 98))	('block', 'NegReg', (236, 241))	('lung cancer', 'Disease', (109, 120))	('cancer', 'Disease', 'MESH:D009369', (297, 303))	('cancer', 'Disease', (160, 166))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('lung cancer', 'Disease', 'MESH:D008175', (292, 303))	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('lung cancer', 'Phenotype', 'HP:0100526', (292, 303))	('lung cancer', 'Disease', 'MESH:D008175', (109, 120))	('DNA', 'MPA', (242, 245))	('cancer', 'Disease', (297, 303))	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('lung cancer', 'Phenotype', 'HP:0100526', (109, 120))	('Cisplatin', 'Chemical', 'MESH:D002945', (136, 145))	('cisplatin', 'Chemical', 'MESH:D002945', (67, 76))	('Cisplatin', 'Var', (136, 145))	('cancer', 'Phenotype', 'HP:0002664', (297, 303))	('cancer', 'Disease', (114, 120))
515437	27533083	Importantly, the sensitization effects to cisplatin and BMN673 in A549/DR cells by co-depleting BRCA2 and POLQ was stronger than those by co-depleting BRCA2 and other TLS factors including POLH, REV3, or REV1.	('cisplatin', 'Chemical', 'MESH:D002945', (42, 51))	('REV1', 'Gene', '51455', (204, 208))	('A549', 'CellLine', 'CVCL:0023', (66, 70))	('REV3', 'Gene', '5980', (195, 199))	('REV3', 'Gene', (195, 199))	('REV1', 'Gene', (204, 208))	('co-depleting', 'Var', (83, 95))	('POLQ', 'MPA', (106, 110))	('POLH', 'Chemical', '-', (189, 193))	('BRCA2', 'MPA', (96, 101))	('sensitization', 'MPA', (17, 30))	('BMN673', 'Chemical', 'MESH:C586365', (56, 62))	('stronger', 'PosReg', (115, 123))	('BMN673', 'Gene', (56, 62))
515455	27533083	But depletion of POLQ can sensitized mouse CH12B-lymphama cells to cisplatin and mitomycin (MMC).	('cisplatin', 'MPA', (67, 76))	('depletion', 'Var', (4, 13))	('MMC', 'Chemical', 'MESH:D016685', (92, 95))	('POLQ', 'Protein', (17, 21))	('mouse', 'Species', '10090', (37, 42))	('cisplatin', 'Chemical', 'MESH:D002945', (67, 76))	('mitomycin', 'Chemical', 'MESH:D016685', (81, 90))	('CH12B', 'CellLine', 'CVCL:6818', (43, 48))	('sensitized', 'Reg', (26, 36))
515456	27533083	The chaos 1 (a mutant allele of POLQ) mutant mice and cells derived from them exhibited no hypersensitivity to MMC, implying that POLQ does not participate in the repair of ICLs in vivo.	('mutant', 'Var', (38, 44))	('mice', 'Species', '10090', (45, 49))	('POLQ', 'Gene', (32, 36))	('chaos 1', 'Gene', (4, 11))	('hypersensitivity', 'Disease', (91, 107))	('hypersensitivity', 'Disease', 'MESH:D004342', (91, 107))	('MMC', 'Chemical', 'MESH:D016685', (111, 114))
515458	27533083	Mouse bone marrow cells deleted for POLQ are more sensitive than normal cells to ionizing radiation (IR) and bleomycin, both of which are known to produce DSBs.	('bleomycin', 'Chemical', 'MESH:D001761', (109, 118))	('sensitive', 'MPA', (50, 59))	('DSBs', 'Chemical', '-', (155, 159))	('deleted', 'Var', (24, 31))	('POLQ', 'Gene', (36, 40))	('Mouse', 'Species', '10090', (0, 5))
515459	27533083	Depleting of POLQ in human cancer cells caused an increase in IR-induced gammaH2AX foci and sensitized the cells to gamma-irradiation.	('POLQ', 'Protein', (13, 17))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('Depleting', 'Var', (0, 9))	('human', 'Species', '9606', (21, 26))	('H2AX', 'Gene', '3014', (78, 82))	('increase', 'PosReg', (50, 58))	('cancer', 'Disease', (27, 33))	('H2AX', 'Gene', (78, 82))	('cancer', 'Disease', 'MESH:D009369', (27, 33))	('IR-induced', 'MPA', (62, 72))
515476	27533083	By contrast, we found that POLH, REV3, or REV1 siRNA-transfected A549/DR cells exhibited greater sensitivity to cisplatin-induced cytotoxicity, although transfection of siRNA against POLQ also sensitize A549/DR cells to cisplatin (Figure 3B).	('cisplatin', 'Chemical', 'MESH:D002945', (220, 229))	('REV3', 'Gene', (33, 37))	('A549', 'CellLine', 'CVCL:0023', (203, 207))	('A549', 'CellLine', 'CVCL:0023', (65, 69))	('sensitize', 'Reg', (193, 202))	('cytotoxicity', 'Disease', (130, 142))	('POLH', 'Chemical', '-', (27, 31))	('sensitivity', 'MPA', (97, 108))	('REV3', 'Gene', '5980', (33, 37))	('cisplatin', 'Chemical', 'MESH:D002945', (112, 121))	('cytotoxicity', 'Disease', 'MESH:D064420', (130, 142))	('REV1', 'Gene', '51455', (42, 46))	('transfection', 'Var', (153, 165))	('REV1', 'Gene', (42, 46))
515477	27533083	Similarly, A549 cells depleting POLH, REV3 or REV1 were more sensitive to cisplatin compared to the cells depleted of POLQ (Figure 3C).	('REV1', 'Gene', '51455', (46, 50))	('sensitive', 'MPA', (61, 70))	('REV1', 'Gene', (46, 50))	('cisplatin', 'MPA', (74, 83))	('A549', 'CellLine', 'CVCL:0023', (11, 15))	('depleting POLH', 'Var', (22, 36))	('REV3', 'Gene', (38, 42))	('REV3', 'Gene', '5980', (38, 42))	('cisplatin', 'Chemical', 'MESH:D002945', (74, 83))	('POLH', 'Var', (32, 36))	('POLH', 'Chemical', '-', (32, 36))
515479	27533083	In addition, we examined the impact of TLS factors on sensitivity to PARP inhibitor in the lung cancer cells, and fond that knockdown of the four TLS factors slightly enhanced sensitivity of A549/DR and A549 cells to BMN (Figure 3D and 3E).	('knockdown', 'Var', (124, 133))	('PARP', 'Gene', '142', (69, 73))	('lung cancer', 'Phenotype', 'HP:0100526', (91, 102))	('TLS', 'Gene', (146, 149))	('A549', 'CellLine', 'CVCL:0023', (203, 207))	('enhanced', 'PosReg', (167, 175))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('A549', 'CellLine', 'CVCL:0023', (191, 195))	('lung cancer', 'Disease', 'MESH:D008175', (91, 102))	('PARP', 'Gene', (69, 73))	('sensitivity', 'MPA', (176, 187))	('lung cancer', 'Disease', (91, 102))
515482	27533083	Therefore, we measured the phosphorylation of ATM and ATR substrates (e.g., H2AX, CHK1 and CHK2) as surrogate markers for DSBs and replication stress as a result of deficient TLS, and examined whether depletion of POLQ, POLH, REV3 or REV1 in A549/DR and A549 cells lead to replication stalling and activations of ATM and ATR after cisplatin treatment.	('CHK1', 'Gene', (82, 86))	('ATR', 'Gene', '545', (321, 324))	('CHK2', 'Gene', (91, 95))	('H2AX', 'Gene', (76, 80))	('ATM', 'Gene', '472', (46, 49))	('deficient', 'Var', (165, 174))	('depletion', 'Var', (201, 210))	('activations', 'PosReg', (298, 309))	('replication stalling', 'CPA', (273, 293))	('H2AX', 'Gene', '3014', (76, 80))	('ATR', 'Gene', (54, 57))	('A549', 'CellLine', 'CVCL:0023', (254, 258))	('REV3', 'Gene', '5980', (226, 230))	('CHK1', 'Gene', '1111', (82, 86))	('POLH', 'Chemical', '-', (220, 224))	('CHK2', 'Gene', '11200', (91, 95))	('ATM', 'Gene', (46, 49))	('ATR', 'Gene', (321, 324))	('ATM', 'Gene', '472', (313, 316))	('REV3', 'Gene', (226, 230))	('cisplatin', 'Chemical', 'MESH:D002945', (331, 340))	('REV1', 'Gene', '51455', (234, 238))	('TLS', 'Gene', (175, 178))	('ATR', 'Gene', '545', (54, 57))	('DSBs', 'Chemical', '-', (122, 126))	('REV1', 'Gene', (234, 238))	('A549', 'CellLine', 'CVCL:0023', (242, 246))	('ATM', 'Gene', (313, 316))
515483	27533083	The results showed that knockdown of POLQ, POLH, REV3 or REV1 in the two cell lines strikingly increased the intensity of gammaH2AX in term of expression levels and the percentage of cells with 10 gammaH2AX foci following cisplatin treatment (Figure 4A to 4F, and Supplementary Figure S2A and S2B).	('expression levels', 'MPA', (143, 160))	('increased', 'PosReg', (95, 104))	('POLH', 'Gene', (43, 47))	('intensity', 'MPA', (109, 118))	('POLH', 'Chemical', '-', (43, 47))	('REV1', 'Gene', (57, 61))	('REV3', 'Gene', '5980', (49, 53))	('REV1', 'Gene', '51455', (57, 61))	('H2AX', 'Gene', '3014', (127, 131))	('REV3', 'Gene', (49, 53))	('H2AX', 'Gene', '3014', (202, 206))	('POLQ', 'Gene', (37, 41))	('H2AX', 'Gene', (127, 131))	('H2AX', 'Gene', (202, 206))	('knockdown', 'Var', (24, 33))	('cisplatin', 'Chemical', 'MESH:D002945', (222, 231))
515484	27533083	In line with the results of cell survival analysis, the increase of gammaH2AX foci formation in cells depleting REV3 or REV1 was more obvious compared with cells lacking POLQ or POLH (Figure 4A and 4B).	('H2AX', 'Gene', '3014', (73, 77))	('increase', 'PosReg', (56, 64))	('H2AX', 'Gene', (73, 77))	('REV3', 'Gene', (112, 116))	('REV3', 'Gene', '5980', (112, 116))	('REV1', 'Gene', (120, 124))	('POLH', 'Chemical', '-', (178, 182))	('REV1', 'Gene', '51455', (120, 124))	('depleting', 'Var', (102, 111))
515488	27533083	We found that knockdown of POLQ in A549/DR and A549 cells caused a remarkably increase of RAD51 in term of expression levels and number of cells with RAD51 foci (Figure 4C to 4G, and Supplementary Figure S2C and S2D).	('RAD51', 'Gene', '5888', (150, 155))	('POLQ', 'Gene', (27, 31))	('expression levels', 'MPA', (107, 124))	('RAD51', 'Gene', (90, 95))	('A549', 'CellLine', 'CVCL:0023', (35, 39))	('RAD51', 'Gene', '5888', (90, 95))	('increase', 'PosReg', (78, 86))	('knockdown', 'Var', (14, 23))	('RAD51', 'Gene', (150, 155))	('A549', 'CellLine', 'CVCL:0023', (47, 51))
515495	27533083	Also, the sensitization to BMN673 in A549/DR cells by co-depleting POLQ and BRCA2 or FANCD2 was more significant than those in A549 cells (Supplementary Figure S3B and Supplementary Table S1B).	('S3B', 'Gene', (160, 163))	('A549', 'CellLine', 'CVCL:0023', (37, 41))	('FA', 'Phenotype', 'HP:0001994', (85, 87))	('POLQ', 'MPA', (67, 71))	('BMN673', 'Var', (27, 33))	('S3B', 'Gene', '11778', (160, 163))	('co-depleting', 'Var', (54, 66))	('BMN673', 'Chemical', 'MESH:C586365', (27, 33))	('A549', 'CellLine', 'CVCL:0023', (127, 131))	('BRCA2', 'MPA', (76, 81))	('sensitization', 'MPA', (10, 23))
515499	27533083	A549 cells co-depleted of BRCA2 and POLQ did not show the sensitization effect like A549/DR cells to cisplatin and BNM673 (Supplementary Figure S3C and Supplementary Table S1C and S1D).	('sensitization', 'MPA', (58, 71))	('A549', 'CellLine', 'CVCL:0023', (0, 4))	('cisplatin', 'Chemical', 'MESH:D002945', (101, 110))	('BNM673', 'Var', (115, 121))	('A549', 'CellLine', 'CVCL:0023', (84, 88))
515500	27533083	Meanwhile, cell cycle analysis showed that double knockdown of BRCA2 and POLQ, or POLH, or REV3, or REV1 in A549/DR cells evoked prominent cisplatin-induced S/G2 arrest, but the cells co-depleted of BRCA2 and POLQ exhibited notably increased levels of death as reflected by emerging more Sub-G1 cells in response to cisplatin (Figure 5H).	('REV1', 'Gene', '51455', (100, 104))	('REV3', 'Gene', '5980', (91, 95))	('REV3', 'Gene', (91, 95))	('cisplatin-induced', 'MPA', (139, 156))	('cisplatin', 'Chemical', 'MESH:D002945', (316, 325))	('cisplatin', 'Chemical', 'MESH:D002945', (139, 148))	('A549', 'CellLine', 'CVCL:0023', (108, 112))	('POLH', 'Chemical', '-', (82, 86))	('S/G2', 'Var', (157, 161))	('BRCA2', 'Gene', (199, 204))	('BRCA2', 'Gene', (63, 68))	('S/G2', 'SUBSTITUTION', 'None', (157, 161))	('REV1', 'Gene', (100, 104))
515509	27533083	In addition, co-depletion of BRCA2 and POLQ also led to a significant elevation of chromatid gaps and breaks per metaphase in BMN673-treated A549/DR cells (Figure 6D and Supplementary Figure S4B).	('elevation of chromatid gaps', 'Phenotype', 'HP:0040012', (70, 97))	('POLQ', 'Var', (39, 43))	('BRCA2', 'Gene', (29, 34))	('A549', 'CellLine', 'CVCL:0023', (141, 145))	('BMN673', 'Chemical', 'MESH:C586365', (126, 132))	('elevation', 'PosReg', (70, 79))
515510	27533083	In line with a prominent increase of chromosome aberration, co-depletion of BRCA2 and POLQ resulted in notably enhanced gamma-H2AX staining by immunofluorescence post-treatment with BMN673 (Supplementary Figure S4C).	('co-depletion', 'Var', (60, 72))	('BRCA2', 'Gene', (76, 81))	('POLQ', 'Gene', (86, 90))	('increase of chromosome aberration', 'Phenotype', 'HP:0040012', (25, 58))	('enhanced', 'PosReg', (111, 119))	('H2AX', 'Gene', '3014', (126, 130))	('BMN673', 'Chemical', 'MESH:C586365', (182, 188))	('H2AX', 'Gene', (126, 130))
515516	27533083	The percentage of gammaH2AX foci positive A549/DR cells depleting POLQ was lower than the cells depleted of REV3 or REV1, although cells individually depleted of POLQ, POLH, REV3, or REV1 displayed similar and enhanced cell cycle checkpoint response, as measured by the phosphorylated H2AX, CHK1 and CHK2 kinase expression.	('CHK2', 'Gene', '11200', (300, 304))	('CHK1', 'Gene', '1111', (291, 295))	('REV3', 'Gene', '5980', (174, 178))	('A549', 'CellLine', 'CVCL:0023', (42, 46))	('POLH', 'Chemical', '-', (168, 172))	('REV3', 'Gene', '5980', (108, 112))	('POLQ', 'Var', (66, 70))	('REV1', 'Gene', (183, 187))	('lower', 'NegReg', (75, 80))	('REV3', 'Gene', (174, 178))	('REV3', 'Gene', (108, 112))	('H2AX', 'Gene', (285, 289))	('REV1', 'Gene', '51455', (116, 120))	('H2AX', 'Gene', (23, 27))	('cell cycle checkpoint response', 'CPA', (219, 249))	('CHK2', 'Gene', (300, 304))	('H2AX', 'Gene', '3014', (285, 289))	('depleting', 'NegReg', (56, 65))	('CHK1', 'Gene', (291, 295))	('enhanced', 'PosReg', (210, 218))	('H2AX', 'Gene', '3014', (23, 27))	('REV1', 'Gene', (116, 120))	('REV1', 'Gene', '51455', (183, 187))
515518	27533083	What is more, Polzeta and REV1 are necessary for the repair of cisplatin interstrand cross-links and DSBs caused by cisplatin, MMC or IR.	('caused', 'Reg', (106, 112))	('cisplatin', 'Chemical', 'MESH:D002945', (63, 72))	('DSBs', 'Chemical', '-', (101, 105))	('cisplatin', 'Var', (116, 125))	('REV1', 'Gene', '51455', (26, 30))	('MMC', 'Chemical', 'MESH:D016685', (127, 130))	('REV1', 'Gene', (26, 30))	('cisplatin', 'Chemical', 'MESH:D002945', (116, 125))	('MMC', 'Var', (127, 130))	('DSBs', 'Disease', (101, 105))
515536	27533083	Inhibition of the BER pathway, taken together with deficiency of HR, creates a synthetic lethality, which can be exacerbated when used in conjunction with suppression of alternative end-joining pathway or chemotherapy agents.	('synthetic lethality', 'MPA', (79, 98))	('deficiency of HR', 'Disease', 'MESH:D001919', (51, 67))	('deficiency of HR', 'Disease', (51, 67))	('Inhibition', 'Var', (0, 10))	('BER pathway', 'Pathway', (18, 29))
515537	27533083	Therefore our results may be interpreted by the notion that the combination of HR deficiency and Pol theta loss by siRNA transfection with suppression of PARP by PARPi can lead to a more potent effect of synthetic lethality.	('PARP', 'Gene', '142', (162, 166))	('loss', 'NegReg', (107, 111))	('PARP', 'Gene', (154, 158))	('HR deficiency', 'Disease', (79, 92))	('PARP', 'Gene', '142', (154, 158))	('PARP', 'Gene', (162, 166))	('synthetic', 'CPA', (204, 213))	('transfection', 'Var', (121, 133))	('Pol theta', 'Gene', (97, 106))	('HR deficiency', 'Disease', 'MESH:D001919', (79, 92))
515564	25877892	Although mutations in known driver genes typically occurred early in cancer evolution, we also identified later subclonal "actionable" mutations, including BRAF(V600E), IDH1(R132H), PIK3CA(E545K), EGFR(L858R), and KRAS(G12D), which may compromise the efficacy of targeted therapy approaches.	('E545K', 'Mutation', 'rs104886003', (189, 194))	('R132H', 'Mutation', 'rs121913500', (174, 179))	('V600E', 'Var', (161, 166))	('IDH1', 'Gene', (169, 173))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('PIK3CA', 'Gene', (182, 188))	('KRAS', 'Gene', (214, 218))	('G12D', 'Mutation', 'rs121913529', (219, 223))	('PIK3CA', 'Gene', '5290', (182, 188))	('IDH1', 'Gene', '3417', (169, 173))	('KRAS', 'Gene', '3845', (214, 218))	('L858R', 'Mutation', 'rs121434568', (202, 207))	('EGFR', 'Gene', '1956', (197, 201))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('V600E', 'SUBSTITUTION', 'None', (161, 166))	('EGFR', 'Gene', (197, 201))	('cancer', 'Disease', (69, 75))
515565	25877892	More than 20% of IDH1 mutations in glioblastomas, and 15% of mutations in genes in the PI3K(phosphatidylinositol 3-kinase)-AKT-mTOR (mammalian target of rapamycin) signaling axis across all tumor types were subclonal.	('glioblastomas', 'Disease', 'MESH:D005909', (35, 48))	('glioblastomas', 'Disease', (35, 48))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('phosphatidylinositol 3-kinase', 'Gene', '5290', (92, 121))	('mammalian target of rapamycin', 'Gene', (133, 162))	('mammalian target of rapamycin', 'Gene', '2475', (133, 162))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('AKT', 'Gene', '207', (123, 126))	('phosphatidylinositol 3-kinase', 'Gene', (92, 121))	('IDH1', 'Gene', (17, 21))	('tumor', 'Disease', (190, 195))	('mutations', 'Var', (22, 31))	('mTOR', 'Gene', (127, 131))	('mTOR', 'Gene', '2475', (127, 131))	('glioblastomas', 'Phenotype', 'HP:0012174', (35, 48))	('IDH1', 'Gene', '3417', (17, 21))	('glioblastoma', 'Phenotype', 'HP:0012174', (35, 47))	('AKT', 'Gene', (123, 126))
515566	25877892	Mutations in the RAS-MEK (mitogen-activated protein kinase kinase) signaling axis were less likely to be subclonal than mutations in genes associated with PI3K-AKT-mTORsignaling.	('AKT', 'Gene', '207', (160, 163))	('RAS-MEK', 'Gene', (17, 24))	('Mutations', 'Var', (0, 9))	('AKT', 'Gene', (160, 163))	('mTOR', 'Gene', (164, 168))	('mTOR', 'Gene', '2475', (164, 168))
515567	25877892	Analysis of late mutations revealed a link between APOBEC-mediated mutagenesis and the acquisition of subclonal driver mutations and uncovered putative cancer genes involved in subclonal expansions, including CTNNA2 and ATXN1.	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('ATXN1', 'Gene', '6310', (220, 225))	('CTNNA2', 'Gene', (209, 215))	('mutagenesis', 'Var', (67, 78))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('APOBEC-mediated', 'Gene', (51, 66))	('CTNNA2', 'Gene', '1496', (209, 215))	('ATXN1', 'Gene', (220, 225))
515569	25877892	The frequent presence of subclonal driver mutations suggests the need to stratify targeted therapy response according to the proportion of tumor cells in which the driver is identified.	('tumor', 'Disease', (139, 144))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('mutations', 'Var', (42, 51))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))
515575	25877892	The presence of subclonal mutations may reduce the clinical benefit of cancer therapies.	('subclonal mutations', 'Var', (16, 35))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('reduce', 'NegReg', (40, 46))	('cancer', 'Disease', (71, 77))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))
515576	25877892	For instance, in colorectal cancer, subclonal RAS mutations have been shown to precipitate resistance to cetuximab, and in glioblastomas, individual driver events can be present in distinct populations of cancer cells or subclones.	('cancer', 'Disease', 'MESH:D009369', (205, 211))	('precipitate', 'Reg', (79, 90))	('RAS', 'Gene', (46, 49))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('colorectal cancer', 'Disease', 'MESH:D015179', (17, 34))	('glioblastomas', 'Phenotype', 'HP:0012174', (123, 136))	('colorectal cancer', 'Disease', (17, 34))	('resistance to cetuximab', 'MPA', (91, 114))	('glioblastoma', 'Phenotype', 'HP:0012174', (123, 135))	('subclonal', 'Var', (36, 45))	('cancer', 'Disease', (205, 211))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('glioblastomas', 'Disease', (123, 136))	('cancer', 'Disease', (28, 34))	('colorectal cancer', 'Phenotype', 'HP:0003003', (17, 34))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('mutations', 'Var', (50, 59))	('glioblastomas', 'Disease', 'MESH:D005909', (123, 136))	('cetuximab', 'Chemical', 'MESH:D000068818', (105, 114))
515577	25877892	Furthermore, the use of targeted therapy against a subclonal driver present in a subset of cells within a tumor may lead to stimulation of wild-type subclones lacking the targeted mutation.	('targeted', 'Var', (24, 32))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('stimulation', 'PosReg', (124, 135))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Disease', (106, 111))
515579	25877892	However, although the clonal status of driver mutations has received attention in certain cancers, a broad understanding of the heterogeneity of driver genes, deciphering the clonal and subclonal frequencies, and the timing of mutational processes involved in tumor evolution is lacking.	('tumor', 'Disease', (260, 265))	('cancers', 'Disease', (90, 97))	('mutations', 'Var', (46, 55))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('tumor', 'Disease', 'MESH:D009369', (260, 265))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('tumor', 'Phenotype', 'HP:0002664', (260, 265))	('cancers', 'Disease', 'MESH:D009369', (90, 97))
515583	25877892	Mutations and copy number variants from TCGA were processed and filtered to obtain a pan-cancer data set representing 2694 tumors from nine major cancer types with both copy number and mutation data.	('cancer', 'Disease', (146, 152))	('tumors', 'Disease', (123, 129))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('tumors', 'Disease', 'MESH:D009369', (123, 129))	('TCGA', 'Gene', (40, 44))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('Mutations', 'Var', (0, 9))	('cancer', 'Disease', (89, 95))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
515584	25877892	To explore the relative timing of mutations, we first estimated the mutation copy number (the number of alleles harboring the mutation) and cancer cell fraction (the fraction of tumor cells with the mutation) of each single nucleotide variant.	('tumor', 'Disease', (178, 183))	('single nucleotide variant', 'Var', (217, 242))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))
515585	25877892	Mutations were classified as clonal (present in all tumor cells sequenced) if the upper band of the 95% cancer cell fraction confidence interval was >= 1, and subclonal otherwise.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('tumor', 'Disease', (52, 57))	('Mutations', 'Var', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))
515586	25877892	Mutations were then classified as "early" or "late" based on the cancer cell fraction and the mutation copy number.	('Mutations', 'Var', (0, 9))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))
515590	25877892	To explore the clonal status of mutations in established cancer genes, we first identified all nonsilent mutations that occurred in known cancer driver genes based on the recent pan-cancer analysis by Lawrence et al.	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('cancer', 'Disease', (138, 144))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('cancer', 'Disease', (57, 63))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('mutations', 'Var', (105, 114))	('cancer', 'Disease', (182, 188))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('cancer', 'Disease', 'MESH:D009369', (138, 144))
515591	25877892	In general, we observed a clear tendency for mutations in driver genes to be clonal compared to mutations in noncancer genes (Fig.	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('mutations', 'Var', (45, 54))	('cancer', 'Disease', (112, 118))
515592	25877892	In every cancer type, with the exception of KIRC, mutations in driver genes (considered in aggregate) were enriched to a statistically significant degree for clonal mutations, compared to mutations in nondriver genes (Fig.	('cancer', 'Disease', (9, 15))	('significant', 'Reg', (135, 146))	('mutations', 'Var', (50, 59))	('KIRC', 'Phenotype', 'HP:0005584', (44, 48))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('cancer', 'Disease', 'MESH:D009369', (9, 15))
515593	25877892	In KIRC, we found that VHL was the only cancer gene that had a significantly higher proportion of clonal mutations than the background rate representing all nonsilent mutations, consistent with multiregion sequencing results in KIRC and supporting our approach to distinguish clonal from subclonal somatic events (P= 0.0147; fig.	('VHL', 'Disease', (23, 26))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('KIRC', 'Phenotype', 'HP:0005584', (228, 232))	('cancer', 'Disease', (40, 46))	('mutations', 'Var', (105, 114))	('KIRC', 'Phenotype', 'HP:0005584', (3, 7))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('VHL', 'Disease', 'MESH:D006623', (23, 26))
515594	25877892	Within other cancer types, we found that mutations in specific cancer genes showed a tendency to be clonal (Fig.	('mutations', 'Var', (41, 50))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('cancer', 'Disease', (13, 19))	('cancer', 'Disease', 'MESH:D009369', (13, 19))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('cancer', 'Disease', (63, 69))
515595	25877892	For instance, in BRCA, mutations in CBFB were exclusively clonal, as were mutations in CDKN2A in LUSC and HNSC, and a similar trend was observed for mutations in ARID1A in BLCA.	('BRCA', 'Gene', (17, 21))	('CDKN2A', 'Gene', '1029', (87, 93))	('CBFB', 'Gene', '865', (36, 40))	('LUSC', 'Phenotype', 'HP:0030359', (97, 101))	('BRCA', 'Gene', '672', (17, 21))	('mutations', 'Var', (74, 83))	('HNSC', 'Phenotype', 'HP:0012288', (106, 110))	('mutations', 'Var', (23, 32))	('BLCA', 'Phenotype', 'HP:0009725', (172, 176))	('CBFB', 'Gene', (36, 40))	('ARID1A', 'Gene', '8289', (162, 168))	('BRCA', 'Phenotype', 'HP:0003002', (17, 21))	('ARID1A', 'Gene', (162, 168))	('CDKN2A', 'Gene', (87, 93))
515597	25877892	We also observed a significant enrichment of TP53 mutations in genome-doubled tumors (fig.	('genome-doubled', 'Disease', (63, 77))	('tumors', 'Disease', (78, 84))	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('TP53', 'Gene', (45, 49))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('mutations', 'Var', (50, 59))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('TP53', 'Gene', '7157', (45, 49))
515598	25877892	S4; P < 0.001, Fisher's exact test), and almost invariably (>90% cases), these mutations occurred before doubling, consistent with TP53 playing an important role in tolerance of genome doubling.	('TP53', 'Gene', (131, 135))	('occurred', 'Reg', (89, 97))	('mutations', 'Var', (79, 88))	('TP53', 'Gene', '7157', (131, 135))
515604	25877892	Mutations in PIK3R1 and MLL3 were frequently subclonal across cancer types, such that a higher proportion of subclonal mutations were observed in these genes compared to the background rate (fig.	('PIK3R1', 'Gene', '5295', (13, 19))	('MLL3', 'Gene', '58508', (24, 28))	('PIK3R1', 'Gene', (13, 19))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('Mutations', 'Var', (0, 9))	('MLL3', 'Gene', (24, 28))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))
515607	25877892	In GBM-28-2513, we identified two subclonal mutations in genes involved in the PI3K (phosphatidylinositol 3-kinase) signaling axis, with one mutation in PIK3R1 present in 54% of cancer cells and a mutation in PTEN present in only 36% of cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('phosphatidylinositol 3-kinase', 'Gene', '5290', (85, 114))	('cancer', 'Disease', (178, 184))	('PIK3R1', 'Gene', (153, 159))	('cancer', 'Disease', (237, 243))	('phosphatidylinositol 3-kinase', 'Gene', (85, 114))	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('cancer', 'Disease', 'MESH:D009369', (237, 243))	('PIK3R1', 'Gene', '5295', (153, 159))	('PTEN', 'Gene', (209, 213))	('mutation', 'Var', (141, 149))	('PTEN', 'Gene', '5728', (209, 213))
515609	25877892	In further support of parallel evolution, in general, we found that when multiple nonsilent mutations were identified in the same cancer gene within one tumor sample, these mutations exhibited a significantly lower cancer cell fraction compared to mutations in cancer genes occurring only once in a cancer sample (fig.	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('cancer', 'Disease', (215, 221))	('cancer', 'Disease', 'MESH:D009369', (215, 221))	('lower', 'NegReg', (209, 214))	('cancer', 'Disease', (130, 136))	('cancer', 'Phenotype', 'HP:0002664', (261, 267))	('cancer', 'Phenotype', 'HP:0002664', (299, 305))	('mutations', 'Var', (92, 101))	('mutations', 'Var', (173, 182))	('tumor', 'Disease', (153, 158))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('cancer', 'Disease', (261, 267))	('cancer', 'Disease', 'MESH:D009369', (261, 267))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('cancer', 'Disease', (299, 305))	('cancer', 'Disease', 'MESH:D009369', (299, 305))
515612	25877892	Signature 1A, reflecting a preponderance of C>T transitions at CpG sites, was identified in five cancer types (BLCA, BRCA, COAD, GBM, and HNSC).	('BRCA', 'Phenotype', 'HP:0003002', (117, 121))	('cancer', 'Disease', (97, 103))	('BRCA', 'Gene', (117, 121))	('BRCA', 'Gene', '672', (117, 121))	('COAD', 'Disease', 'MESH:D029424', (123, 127))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('GBM', 'Disease', (129, 132))	('BLCA', 'Phenotype', 'HP:0009725', (111, 115))	('BLCA', 'Disease', (111, 115))	('C>T', 'Var', (44, 47))	('HNSC', 'Phenotype', 'HP:0012288', (138, 142))	('COAD', 'Disease', (123, 127))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
515617	25877892	We also found a tendency for signature 2 to increase in frequency in later mutations in ER-negative BRCA (P= 0.0126), but not in ER-positive breast cancers (P= 0.597), highlighting the differences between these two subtypes of breast cancer.	('cancers', 'Phenotype', 'HP:0002664', (148, 155))	('BRCA', 'Gene', '672', (100, 104))	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('breast cancers', 'Phenotype', 'HP:0003002', (141, 155))	('BRCA', 'Gene', (100, 104))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('breast cancers', 'Disease', (141, 155))	('increase', 'PosReg', (44, 52))	('breast cancer', 'Disease', 'MESH:D001943', (141, 154))	('breast cancer', 'Disease', 'MESH:D001943', (227, 240))	('breast cancer', 'Phenotype', 'HP:0003002', (227, 240))	('breast cancers', 'Disease', 'MESH:D001943', (141, 155))	('breast cancer', 'Disease', (227, 240))	('breast cancer', 'Phenotype', 'HP:0003002', (141, 154))	('ER-negative', 'Var', (88, 99))	('BRCA', 'Phenotype', 'HP:0003002', (100, 104))
515618	25877892	These data suggest that the APOBEC mutational process may foster subclonal expansions across several tumor types.	('mutational', 'Var', (35, 45))	('APOBEC', 'Gene', (28, 34))	('tumor', 'Disease', (101, 106))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('subclonal expansions', 'MPA', (65, 85))	('foster', 'PosReg', (58, 64))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
515619	25877892	Notably, signature 2 was detected in both early and late mutations, albeit to a lesser degree in early mutations, suggesting that APOBEC activity is more than a transient event and does not simply represent a historical relic within the tumor genome, active at only one point in time during the disease course.	('mutations', 'Var', (57, 66))	('tumor', 'Disease', (237, 242))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))	('tumor', 'Disease', 'MESH:D009369', (237, 242))
515622	25877892	In SKCM, it is also worth noting that most samples were derived from metastatic sites; thus, many of the later mutations will likely have been acquired when tumor cells were no longer exposed to UV light.	('tumor', 'Disease', (157, 162))	('mutations', 'Var', (111, 120))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))
515624	25877892	In both LUAD and LUSC, we found that more than 30% of clonal nonsilent mutations in cancer genes were C>A transversions, which can be attributed to tobacco smoke; for example, more than 40% of clonal mutations in TP53 were C>A transversions.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('LUSC', 'Phenotype', 'HP:0030359', (17, 21))	('cancer', 'Disease', (84, 90))	('TP53', 'Gene', (213, 217))	('LUAD', 'Phenotype', 'HP:0030078', (8, 12))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('tobacco', 'Species', '4097', (148, 155))	('C>A', 'Var', (223, 226))	('TP53', 'Gene', '7157', (213, 217))
515628	25877892	Strikingly, in these cancers, more than 90% of subclonal mutations in PIK3CA occurred in an APOBEC context, and we also identified subclonal APOBEC mutations in multiple other cancer driver genes, including PTEN, EGFR, and TP53.	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('cancers', 'Disease', 'MESH:D009369', (21, 28))	('mutations', 'Var', (57, 66))	('cancer', 'Disease', 'MESH:D009369', (21, 27))	('EGFR', 'Gene', '1956', (213, 217))	('TP53', 'Gene', '7157', (223, 227))	('PIK3CA', 'Gene', '5290', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('mutations', 'Var', (148, 157))	('PTEN', 'Gene', (207, 211))	('cancers', 'Phenotype', 'HP:0002664', (21, 28))	('cancers', 'Disease', (21, 28))	('cancer', 'Disease', (21, 27))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('EGFR', 'Gene', (213, 217))	('TP53', 'Gene', (223, 227))	('PTEN', 'Gene', '5728', (207, 211))	('PIK3CA', 'Gene', (70, 76))	('occurred', 'Reg', (77, 85))	('cancer', 'Disease', (176, 182))
515630	25877892	Together, these data highlight the extent to which endogenous and exogenous mutational processes can fuel the acquisition of somatic events in cancer genes.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('mutational', 'Var', (76, 86))	('fuel', 'PosReg', (101, 105))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))
515631	25877892	Moreover, the dynamics of specific mutational processes may alter the subclonal architecture of a tumor by providing the mutational fuel upon which selection can act.	('mutational', 'Var', (35, 45))	('alter', 'Reg', (60, 65))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumor', 'Disease', (98, 103))
515632	25877892	Given the tendency for mutations in many known cancer genes to be clonal and the observation that many clonal mutations likely occur before tumorigenesis, we reasoned that it might be possible to identify drivers of subclonal expansions by focusing exclusively on late or subclonal mutations.	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('cancer', 'Disease', (47, 53))	('mutations', 'Var', (23, 32))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('tumor', 'Disease', (140, 145))
515636	25877892	Temporal dissection was required to uncover the cancer gene PIK3CA in HNSC, suggesting that mutations in this gene may often lead to, or be permissive for, subclonal expansions in this cancer type.	('lead to', 'Reg', (125, 132))	('HNSC', 'Phenotype', 'HP:0012288', (70, 74))	('PIK3CA', 'Gene', (60, 66))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('PIK3CA', 'Gene', '5290', (60, 66))	('mutations', 'Var', (92, 101))	('HNSC', 'Disease', (70, 74))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('cancer', 'Disease', (185, 191))
515639	25877892	CTNNA2 has previously been implicated in laryngeal cancer as a tumor suppressor, and its inactivation in HNSC cells is associated with migration and invasion advantages, consistent with it playing a role at later stages of tumor development.	('laryngeal cancer', 'Disease', (41, 57))	('tumor', 'Disease', (63, 68))	('invasion advantages', 'CPA', (149, 168))	('laryngeal cancer', 'Phenotype', 'HP:0012118', (41, 57))	('tumor', 'Disease', (223, 228))	('CTNNA2', 'Gene', '1496', (0, 6))	('HNSC', 'Phenotype', 'HP:0012288', (105, 109))	('inactivation', 'Var', (89, 101))	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('migration', 'CPA', (135, 144))	('CTNNA2', 'Gene', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('laryngeal cancer', 'Disease', 'MESH:D007822', (41, 57))	('tumor', 'Disease', 'MESH:D009369', (223, 228))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
515640	25877892	In LUAD, we also identified mutations in NRXN3 as a putative subclonal driver event.	('NRXN3', 'Gene', '9369', (41, 46))	('LUAD', 'Phenotype', 'HP:0030078', (3, 7))	('mutations', 'Var', (28, 37))	('NRXN3', 'Gene', (41, 46))
515641	25877892	A polymorphic site of this gene (rs10146997) has been associated with higher risk of breast cancer development, and low expression of NRXN3 is associated with poorer survival in lung cancer (fig.	('rs10146997', 'Var', (33, 43))	('breast cancer', 'Disease', 'MESH:D001943', (85, 98))	('expression', 'MPA', (120, 130))	('lung cancer', 'Disease', (178, 189))	('breast cancer', 'Disease', (85, 98))	('lung cancer', 'Phenotype', 'HP:0100526', (178, 189))	('rs10146997', 'Mutation', 'rs10146997', (33, 43))	('breast cancer', 'Phenotype', 'HP:0003002', (85, 98))	('low', 'NegReg', (116, 119))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('poorer', 'NegReg', (159, 165))	('NRXN3', 'Gene', '9369', (134, 139))	('NRXN3', 'Gene', (134, 139))	('lung cancer', 'Disease', 'MESH:D008175', (178, 189))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
515643	25877892	The ATXN1 protein family plays an important role in transcriptional control of extracellular matrix remodeling, and mutations in ATXN1 have been putatively linked to cancer metastasis, consistent with its occurrence as a later event in COAD.	('cancer metastasis', 'Disease', (166, 183))	('COAD', 'Disease', 'MESH:D029424', (236, 240))	('ATXN1', 'Gene', (129, 134))	('linked', 'Reg', (156, 162))	('ATXN1', 'Gene', '6310', (129, 134))	('mutations', 'Var', (116, 125))	('cancer metastasis', 'Disease', 'MESH:D009362', (166, 183))	('ATXN1', 'Gene', (4, 9))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('ATXN1', 'Gene', '6310', (4, 9))	('COAD', 'Disease', (236, 240))
515648	25877892	For instance, the presence of mutations that activate the PI3K-AKT-mTOR (mammalian target of rapamycin) pathway and contribute to carcinogenesis has engendered much interest in inhibitors of this signaling axis.	('AKT', 'Gene', (63, 66))	('carcinogenesis', 'Disease', 'MESH:D063646', (130, 144))	('contribute', 'Reg', (116, 126))	('carcinogenesis', 'Disease', (130, 144))	('activate', 'PosReg', (45, 53))	('mTOR', 'Gene', (67, 71))	('mTOR', 'Gene', '2475', (67, 71))	('mutations', 'Var', (30, 39))	('mammalian target of rapamycin', 'Gene', '2475', (73, 102))	('mammalian target of rapamycin', 'Gene', (73, 102))	('AKT', 'Gene', '207', (63, 66))
515650	25877892	More than 10%of all nonsilent PIK3CA mutations and more than 20% of all nonsilent mutations in PTEN were found to be subclonal, and more than 15% of mutations in genes in the PI3K-AKT-mTOR pathway overall were subclonal (Fig.	('PIK3CA', 'Gene', (30, 36))	('mutations', 'Var', (149, 158))	('mTOR', 'Gene', '2475', (184, 188))	('mTOR', 'Gene', (184, 188))	('PIK3CA', 'Gene', '5290', (30, 36))	('AKT', 'Gene', (180, 183))	('mutations', 'Var', (82, 91))	('mutations', 'Var', (37, 46))	('PTEN', 'Gene', (95, 99))	('PTEN', 'Gene', '5728', (95, 99))	('AKT', 'Gene', '207', (180, 183))
515651	25877892	In GBM, the use of IDH-targeted therapies has been proposed for tumors with IDH1 or IDH2 mutations, and yet, we observed that more than 20% of IDH1 mutations are subclonal in GBM (Fig.	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('IDH1', 'Gene', (143, 147))	('IDH1', 'Gene', '3417', (76, 80))	('IDH', 'Gene', '3417', (76, 79))	('IDH', 'Gene', '3417', (19, 22))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('IDH', 'Gene', (143, 146))	('tumors', 'Disease', (64, 70))	('IDH2', 'Gene', (84, 88))	('IDH2', 'Gene', '3418', (84, 88))	('IDH1', 'Gene', '3417', (143, 147))	('GBM', 'Disease', (175, 178))	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('mutations', 'Var', (148, 157))	('IDH', 'Gene', '3417', (143, 146))	('IDH', 'Gene', (84, 87))	('IDH1', 'Gene', (76, 80))	('IDH', 'Gene', (76, 79))	('IDH', 'Gene', (19, 22))	('IDH', 'Gene', '3417', (84, 87))
515652	25877892	On the other hand, all IDH1 mutations detected in SKCM were clonal.	('mutations', 'Var', (28, 37))	('IDH1', 'Gene', (23, 27))	('IDH1', 'Gene', '3417', (23, 27))
515653	25877892	In KIRC, mTOR inhibition is a common therapeutic option; however, we found that more than 30% of mutations in mTOR were subclonal within this disease type within single tumor samples.	('mTOR', 'Gene', (110, 114))	('mutations', 'Var', (97, 106))	('mTOR', 'Gene', '2475', (110, 114))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('mTOR', 'Gene', (9, 13))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('mTOR', 'Gene', '2475', (9, 13))	('tumor', 'Disease', (169, 174))	('KIRC', 'Phenotype', 'HP:0005584', (3, 7))
515656	25877892	Finally, we restricted our analysis to well-characterized mutations occurring in the database of curated mutations (DoCM; docm.genome.wustl.edu) and in at least three tumor samples within the cohort.	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('mutations', 'Var', (58, 67))	('tumor', 'Disease', (167, 172))	('tumor', 'Disease', 'MESH:D009369', (167, 172))
515657	25877892	For most of these mutations, we identified both clonal and subclonal mutations in at least one cancer type (fig.	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('cancer', 'Disease', (95, 101))	('mutations', 'Var', (18, 27))
515658	25877892	We identified tumor samples with subclonal mutations in known sites with therapeutic relevance such as NRAS(Q61K, Q61R, Q61L), BRAF (V600E), KRAS (G12C, G12D, G12V), PIK3CA (E542K, 545K, H1047R), and IDH1 (R132H), as well as many subclonal loss-of-function mutations in tumor suppressor genes such as PTEN (Fig.	('G12V', 'Var', (159, 163))	('IDH1', 'Gene', (200, 204))	('NRAS', 'Gene', '4893', (103, 107))	('KRAS', 'Gene', (141, 145))	('E542K', 'Mutation', 'rs121913273', (174, 179))	('BRAF', 'Gene', '673', (127, 131))	('BRAF', 'Gene', (127, 131))	('tumor', 'Phenotype', 'HP:0002664', (270, 275))	('V600E', 'Var', (133, 138))	('PTEN', 'Gene', '5728', (301, 305))	('E542K', 'Var', (174, 179))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('Q61R', 'Var', (114, 118))	('H1047R', 'Var', (187, 193))	('Q61R', 'Mutation', 'rs11554290', (114, 118))	('IDH1', 'Gene', '3417', (200, 204))	('G12D', 'Mutation', 'rs121913529', (153, 157))	('loss-of-function', 'NegReg', (240, 256))	('Q61L', 'Mutation', 'rs11554290', (120, 124))	('H1047R', 'Mutation', 'rs121913279', (187, 193))	('NRAS', 'Gene', (103, 107))	('545K', 'Var', (181, 185))	('G12C', 'Mutation', 'rs121913530', (147, 151))	('PIK3CA', 'Gene', '5290', (166, 172))	('R132H', 'Mutation', 'rs121913500', (206, 211))	('Q61L', 'Var', (120, 124))	('tumor', 'Disease', (270, 275))	('tumor', 'Disease', (14, 19))	('G12V', 'Mutation', 'rs121913529', (159, 163))	('KRAS', 'Gene', '3845', (141, 145))	('V600E', 'Mutation', 'rs113488022', (133, 138))	('tumor', 'Disease', 'MESH:D009369', (270, 275))	('PTEN', 'Gene', (301, 305))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('PIK3CA', 'Gene', (166, 172))	('Q61K', 'Mutation', 'rs121913254', (108, 112))
515659	25877892	Identified subclonal driver mutations often occurred in tumors where clonal mutations in established cancer genes were also present [Fig.	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('cancer', 'Disease', (101, 107))	('occurred', 'Reg', (44, 52))	('tumors', 'Disease', (56, 62))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('mutations', 'Var', (28, 37))
515660	25877892	For example, in patient HNSC-CV-7177, a PIK3CA (E545K) mutation in the highly conserved helical domain was estimated to be present in only 36% of cancer cells, whereas a mutation in TP53in the same tumor was found to be present in all cancer cells.	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('TP53', 'Gene', '7157', (182, 186))	('PIK3CA', 'Gene', (40, 46))	('TP53', 'Gene', (182, 186))	('HNSC', 'Phenotype', 'HP:0012288', (24, 28))	('cancer', 'Disease', (235, 241))	('cancer', 'Disease', 'MESH:D009369', (235, 241))	('PIK3CA', 'Gene', '5290', (40, 46))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('E545K', 'Mutation', 'rs104886003', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('mutation', 'Var', (55, 63))	('tumor', 'Disease', (198, 203))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))	('patient', 'Species', '9606', (16, 23))
515661	25877892	Similarly, patient SKCM-ER-A2NE exhibited a clonal mutation in NRAS(Q61K), whereas a PTEN mutation (Y178*) was present only in 13% of cells.	('NRAS', 'Gene', '4893', (63, 67))	('Y178*', 'SUBSTITUTION', 'None', (100, 105))	('Y178*', 'Var', (100, 105))	('Q61K', 'Mutation', 'rs121913254', (68, 72))	('patient', 'Species', '9606', (11, 18))	('PTEN', 'Gene', (85, 89))	('NRAS', 'Gene', (63, 67))	('PTEN', 'Gene', '5728', (85, 89))
515663	25877892	Moreover, these results demonstrate that known driver mutations do not only play a role in tumor initiation but also likely influence tumor behavior after tumor branching within distinct subclones.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('play', 'Reg', (76, 80))	('tumor branching', 'Disease', 'MESH:D009369', (155, 170))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('mutations', 'Var', (54, 63))	('tumor branching', 'Disease', (155, 170))	('tumor', 'Disease', (155, 160))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('tumor initiation', 'Disease', 'MESH:D009369', (91, 107))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('influence', 'Reg', (124, 133))	('tumor', 'Disease', (91, 96))	('tumor initiation', 'Disease', (91, 107))	('tumor', 'Disease', (134, 139))
515668	25877892	Our results demonstrate the presence of considerable intratumor heterogeneity in driver events, including known canonical hotspot mutations, such as IDH1 (R132H) and PIK3CA (E545K).	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('PIK3CA', 'Gene', '5290', (166, 172))	('R132H', 'Var', (155, 160))	('IDH1', 'Gene', (149, 153))	('E545K', 'Mutation', 'rs104886003', (174, 179))	('E545K', 'Var', (174, 179))	('R132H', 'Mutation', 'rs121913500', (155, 160))	('IDH1', 'Gene', '3417', (149, 153))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('PIK3CA', 'Gene', (166, 172))
515669	25877892	Strikingly, we find that almost every gene linked with a targeted therapy harbors subclonal mutations in at least one tumor within the cohort.	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumor', 'Disease', (118, 123))	('subclonal mutations', 'Var', (82, 101))	('tumor', 'Disease', 'MESH:D009369', (118, 123))
515675	25877892	Nevertheless, despite extensive heterogeneity, we also demonstrate that mutations in established driver genes have a tendency to be clonal compared to mutations in nondriver genes, suggesting that these mutational events may often be required as early events in tumorigenesis and might represent suitable candidates for cancer screening approaches.	('mutations', 'Var', (72, 81))	('tumor', 'Phenotype', 'HP:0002664', (262, 267))	('tumor', 'Disease', (262, 267))	('cancer', 'Phenotype', 'HP:0002664', (320, 326))	('cancer', 'Disease', 'MESH:D009369', (320, 326))	('tumor', 'Disease', 'MESH:D009369', (262, 267))	('cancer', 'Disease', (320, 326))
515683	25877892	We also found evidence linking APOBEC-mediated mutagenesis with the acquisition of subclonal driver events, highlighting how this mutational process can alter tumor evolutionary trajectories.	('alter', 'Reg', (153, 158))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('mutagenesis', 'Var', (47, 58))	('tumor', 'Disease', (159, 164))	('APOBEC-mediated', 'Gene', (31, 46))	('tumor', 'Disease', 'MESH:D009369', (159, 164))
515685	25877892	As recently demonstrated in KIRC as well as in LUAD and LUSC, mutations from single biopsies may give the illusion of clonality, that is, although a mutation appears to be present in every cell from one tumor biopsy, it can be entirely absent from other regions of the same tumor.	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('tumor', 'Disease', (203, 208))	('LUSC', 'Phenotype', 'HP:0030359', (56, 60))	('tumor', 'Disease', 'MESH:D009369', (274, 279))	('tumor', 'Phenotype', 'HP:0002664', (274, 279))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('KIRC', 'Phenotype', 'HP:0005584', (28, 32))	('LUAD', 'Phenotype', 'HP:0030078', (47, 51))	('tumor', 'Disease', (274, 279))	('mutation', 'Var', (149, 157))	('mutations', 'Var', (62, 71))
515689	25877892	This was an observational study using publicly available mutation and copy number data from nine cancer types to explore the clonal status of driver mutations (including those linked to targeted therapies), the dynamics of mutational processes over time, and whether we could identify additional cancer genes through temporal and clonal dissection (Fig.	('mutations', 'Var', (149, 158))	('cancer', 'Disease', (97, 103))	('cancer', 'Phenotype', 'HP:0002664', (296, 302))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('cancer', 'Disease', 'MESH:D009369', (296, 302))	('cancer', 'Disease', (296, 302))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
515697	25877892	To identify cancer genes, MutSigCV was applied separately to temporally and clonally dissected mutations within each cancer cohort (for details, see Supplementary Materials and Methods).	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('cancer', 'Disease', (12, 18))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('mutations', 'Var', (95, 104))	('cancer', 'Disease', (117, 123))
515703	33937015	In this era of precision oncology, there has been a rapid adoption of targeted therapy for detected driver mutations in non-small-cell lung cancer (NSCLC).	('mutations', 'Var', (107, 116))	('NSCLC', 'Disease', (148, 153))	('oncology', 'Phenotype', 'HP:0002664', (25, 33))	('lung cancer', 'Disease', 'MESH:D008175', (135, 146))	('NSCLC', 'Disease', 'MESH:D002289', (148, 153))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (124, 146))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('lung cancer', 'Disease', (135, 146))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (120, 146))	('lung cancer', 'Phenotype', 'HP:0100526', (135, 146))
515711	33937015	After lung cancer subtyping is complete, non LUSC are evaluated for targetable driver genomic alterations such as epidermal growth factor receptor (EGFR) mutations, anaplastic lymphoma kinase (ALK) rearrangements, c-Ros oncogene 1 (ROS1) rearrangements, and BRAF V600E mutation.	('c-Ros oncogene 1', 'Gene', (214, 230))	('ROS1', 'Gene', (232, 236))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('rearrangements', 'Var', (198, 212))	('rearrangements', 'Var', (238, 252))	('V600E mutation', 'Var', (263, 277))	('lymphoma', 'Phenotype', 'HP:0002665', (176, 184))	('EGFR', 'Gene', '1956', (148, 152))	('lung cancer', 'Disease', (6, 17))	('ALK', 'Gene', '238', (193, 196))	('ALK', 'Gene', (193, 196))	('ROS1', 'Gene', '6098', (232, 236))	('V600E', 'Mutation', 'rs113488022', (263, 268))	('c-Ros oncogene 1', 'Gene', '6098', (214, 230))	('epidermal growth factor receptor', 'Gene', (114, 146))	('BRAF', 'Gene', '673', (258, 262))	('epidermal growth factor receptor', 'Gene', '1956', (114, 146))	('BRAF', 'Gene', (258, 262))	('lung cancer', 'Disease', 'MESH:D008175', (6, 17))	('anaplastic lymphoma kinase', 'Gene', '238', (165, 191))	('EGFR', 'Gene', (148, 152))	('lung cancer', 'Phenotype', 'HP:0100526', (6, 17))	('anaplastic lymphoma kinase', 'Gene', (165, 191))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (165, 184))	('mutations', 'Var', (154, 163))
515721	33937015	It uses extremely small amounts of tissues and has been used successfully in precision oncology applications, including the detection of fusion genes in lung cancer cytology and molecular subtyping of diffuse large B-cell lymphoma.	('fusion genes', 'Var', (137, 149))	('lung cancer', 'Disease', 'MESH:D008175', (153, 164))	('lymphoma', 'Phenotype', 'HP:0002665', (222, 230))	('B-cell lymphoma', 'Disease', 'MESH:D016393', (215, 230))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (215, 230))	('lung cancer', 'Disease', (153, 164))	('oncology', 'Phenotype', 'HP:0002664', (87, 95))	('lung cancer', 'Phenotype', 'HP:0100526', (153, 164))	('B-cell lymphoma', 'Disease', (215, 230))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
515731	33937015	As demonstrated in  Figure 1 , as previously reported, knowledge about LUAD/LUSC subtyping related genes was learned from a meta-cohort (n = 490) microarray transcriptomics data extracted from public source [Gene Expression Omnibus: GSE10445, GSE4573, and GSE3141; the Director's Challenge Consortium for the Molecular Classification of Lung Adenocarcinoma ] and translated to a nanoString 67-gene panel for clinical use.	('carcinoma', 'Phenotype', 'HP:0030731', (347, 356))	('GSE3141', 'Chemical', '-', (256, 263))	('Lung Adenocarcinoma', 'Disease', (337, 356))	('GSE4573', 'Var', (243, 250))	('Lung Adenocarcinoma', 'Phenotype', 'HP:0030078', (337, 356))	('Lung Adenocarcinoma', 'Disease', 'MESH:D000077192', (337, 356))
515734	33937015	Four publicly available lung cancer cohorts were used for 67-gene panel construction, including the DUKE (n = 111, GEO: GSE3141), PARIS (n = 74, GEO: GSE10445), UM (n = 13, GEO: GSE4573), and the DC (n = 442, NCI caArray: Jacob-00182).	('PARIS', 'Gene', '155061', (130, 135))	('PARIS', 'Gene', (130, 135))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('GSE10445', 'Var', (150, 158))	('lung cancer', 'Disease', (24, 35))	('GSE3141', 'Chemical', '-', (120, 127))	('lung cancer', 'Phenotype', 'HP:0100526', (24, 35))	('GSE3141', 'Var', (120, 127))	('lung cancer', 'Disease', 'MESH:D008175', (24, 35))
515763	33937015	Another major future direction will be the incorporation of biomarkers representing the pathological and prognostic knowledge from different domains including genomic abnormalities such as EGFR and BRAF mutations, molecular subtypes such as LUSC and LUAD, immunotherapy markers such as PD-1/PD-L1 expression, and other transcriptomic and genomic signatures for precision oncology.	('EGFR', 'Gene', '1956', (189, 193))	('BRAF', 'Gene', '673', (198, 202))	('oncology', 'Phenotype', 'HP:0002664', (371, 379))	('LUSC', 'Disease', (241, 245))	('EGFR', 'Gene', (189, 193))	('BRAF', 'Gene', (198, 202))	('mutations', 'Var', (203, 212))	('LUAD', 'Disease', (250, 254))
515843	33664766	reported 115 cervical carcinoma-normal paired samples' whole-exome sequence analysis, 79 cases' transcriptome sequence, and 14 tumor-normal pairs' whole genome sequence and detected significantly recurrent somatic mutations in the mitogen-activated protein kinase 1 (MAPK1) gene among squamous cell cervical cancers and provided evidence of potential ERBB2 (also means HER2/neu) activation by somatic mutation, amplification, and HPV integration to combat cervical carcinoma.	('cervical carcinoma', 'Disease', (13, 31))	('ERBB2', 'Gene', '2064', (351, 356))	('squamous cell cervical cancers', 'Disease', (285, 315))	('mitogen-activated protein kinase 1', 'Gene', '5594', (231, 265))	('squamous cell cervical cancers', 'Disease', 'MESH:D002294', (285, 315))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('cervical carcinoma', 'Disease', 'MESH:D002583', (456, 474))	('HER2', 'Gene', (369, 373))	('mutations', 'Var', (214, 223))	('cervical carcinoma', 'Disease', (456, 474))	('neu', 'Gene', '2064', (374, 377))	('HPV', 'Species', '10566', (430, 433))	('carcinoma', 'Phenotype', 'HP:0030731', (465, 474))	('cancers', 'Phenotype', 'HP:0002664', (308, 315))	('mitogen-activated protein kinase 1', 'Gene', (231, 265))	('MAPK1', 'Gene', '5594', (267, 272))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('cancer', 'Phenotype', 'HP:0002664', (308, 314))	('activation', 'PosReg', (379, 389))	('tumor', 'Disease', (127, 132))	('HER2', 'Gene', '2064', (369, 373))	('amplification', 'Var', (411, 424))	('MAPK1', 'Gene', (267, 272))	('ERBB2', 'Gene', (351, 356))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('cervical carcinoma', 'Disease', 'MESH:D002583', (13, 31))	('neu', 'Gene', (374, 377))
515845	33664766	During the development of cancer, a large number of somatic mutations occur; however, only a handful of somatic mutations are expected to initiate and promote tumor growth, so-called driver mutations (Nehrt et al.,).	('cancer', 'Disease', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('mutations', 'Var', (112, 121))	('tumor', 'Disease', (159, 164))	('promote', 'PosReg', (151, 158))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('tumor', 'Disease', 'MESH:D009369', (159, 164))
515846	33664766	Several driver mutations have been identified as a subtype for specific cancer type or as a target in therapy.	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('mutations', 'Var', (15, 24))	('cancer', 'Disease', (72, 78))
515851	33664766	In the current study, we integrated somatic mutation, copy number variation (CNV), DNA methylation, and miRNA profile; depicted a comprehensive genomic landscape of cervical cancer; performed molecular classification; and finally identified driver genes.	('cervical cancer', 'Disease', (165, 180))	('cervical cancer', 'Disease', 'MESH:D002583', (165, 180))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('copy number', 'Var', (54, 65))
515867	33664766	Here, 233 patient samples (82.04%) have been detected to have somatic mutations, and a total number of 83,386 somatic mutations were obtained, including 50,644 missense mutations.	('missense mutations', 'Var', (160, 178))	('mutations', 'Var', (70, 79))	('patient', 'Species', '9606', (10, 17))
515868	33664766	SNV occurs predominantly in cervical cancer, with C > T being the most common type of mutation.	('occurs', 'Reg', (4, 10))	('C > T', 'Var', (50, 55))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('cervical cancer', 'Disease', 'MESH:D002583', (28, 43))	('cervical cancer', 'Disease', (28, 43))
515889	33664766	Previous studies have implicated somatic mutations in PIK3CA, TP53, STK11, EP300, FBXW7, and HLA-B in the pathogenesis of cervical carcinomas (Ojesina et al.,; Bager et al.,).	('EP300', 'Gene', (75, 80))	('mutations', 'Var', (41, 50))	('cervical carcinomas', 'Disease', 'MESH:D002583', (122, 141))	('HLA-B', 'Gene', (93, 98))	('FBXW7', 'Gene', (82, 87))	('EP300', 'Gene', '2033', (75, 80))	('TP53', 'Gene', '7157', (62, 66))	('STK11', 'Gene', (68, 73))	('HLA-B', 'Gene', '3106', (93, 98))	('PIK3CA', 'Gene', '5290', (54, 60))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('carcinomas', 'Phenotype', 'HP:0030731', (131, 141))	('TP53', 'Gene', (62, 66))	('implicated', 'Reg', (22, 32))	('STK11', 'Gene', '6794', (68, 73))	('FBXW7', 'Gene', '55294', (82, 87))	('cervical carcinomas', 'Disease', (122, 141))	('PIK3CA', 'Gene', (54, 60))
515890	33664766	As expected, in the current study, recurrent mutations in PIK3CA, EP300, and FBXW7 were presented in 32, 12, and 7% cervical patients, respectively, consistent with similar findings in previous reports (Ojesina et al.,).	('FBXW7', 'Gene', '55294', (77, 82))	('presented', 'Reg', (88, 97))	('mutations', 'Var', (45, 54))	('cervical', 'Disease', (116, 124))	('FBXW7', 'Gene', (77, 82))	('EP300', 'Gene', '2033', (66, 71))	('PIK3CA', 'Gene', (58, 64))	('EP300', 'Gene', (66, 71))	('PIK3CA', 'Gene', '5290', (58, 64))	('patients', 'Species', '9606', (125, 133))
515891	33664766	In addition, we found significantly recurrent mutations in TTN (33%), MUC4 (31%), and MUC16 (19%), here reported for the first time, to our knowledge, in cervical carcinomas.	('MUC16', 'Gene', (86, 91))	('mutations', 'Var', (46, 55))	('MUC4', 'Gene', '4585', (70, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (163, 172))	('carcinomas', 'Phenotype', 'HP:0030731', (163, 173))	('TTN', 'Gene', (59, 62))	('MUC4', 'Gene', (70, 74))	('MUC16', 'Gene', '94025', (86, 91))	('TTN', 'Gene', '7273', (59, 62))	('cervical carcinomas', 'Disease', 'MESH:D002583', (154, 173))	('cervical carcinomas', 'Disease', (154, 173))
515894	33664766	Missense mutation of TTN was detected in 85% lung squamous cell carcinoma and predicted a favorable prognosis of these diseases (Cheng et al.,).	('Missense mutation', 'Var', (0, 17))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (45, 73))	('TTN', 'Gene', (21, 24))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (50, 73))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (45, 73))	('lung squamous cell carcinoma', 'Disease', (45, 73))	('detected', 'Reg', (29, 37))	('TTN', 'Gene', '7273', (21, 24))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))
515895	33664766	More recently, TTN mutation was reported to predict an increased tumor mutational burden, a beneficial response to immune checkpoint blockade treatment, and a long survival among pan-solid tumors, including cervical cancer (Jia et al.,).	('cervical cancer', 'Disease', 'MESH:D002583', (207, 222))	('tumor', 'Disease', (189, 194))	('mutation', 'Var', (19, 27))	('TTN', 'Gene', '7273', (15, 18))	('tumor', 'Disease', (65, 70))	('cervical cancer', 'Disease', (207, 222))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('increased', 'PosReg', (55, 64))	('tumors', 'Disease', (189, 195))	('tumors', 'Disease', 'MESH:D009369', (189, 195))	('tumors', 'Phenotype', 'HP:0002664', (189, 195))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('TTN', 'Gene', (15, 18))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
515897	33664766	MUC4 was activated during the process of cervical squamous dysplastic transformation (Lopez-Ferrer et al.,), aberrantly expressed in cervical cancer (Munro et al.,), and associated with lymph node metastasis (Munro et al.,).	('activated', 'PosReg', (9, 18))	('lymph', 'Disease', (186, 191))	('MUC4', 'Gene', (0, 4))	('cervical cancer', 'Disease', 'MESH:D002583', (133, 148))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('cervical squamous dysplastic transformation', 'Disease', (41, 84))	('cervical squamous dysplastic transformation', 'Disease', 'MESH:D065309', (41, 84))	('cervical cancer', 'Disease', (133, 148))	('aberrantly', 'Var', (109, 119))	('associated with', 'Reg', (170, 185))	('MUC4', 'Gene', '4585', (0, 4))
515898	33664766	Abrogation of MUC4 expression reduces invasion and the mesenchymal properties of cervical cancer cells (Xu et al.,).	('Abrogation', 'Var', (0, 10))	('cervical cancer', 'Disease', 'MESH:D002583', (81, 96))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('MUC4', 'Gene', (14, 18))	('cervical cancer', 'Disease', (81, 96))	('invasion', 'CPA', (38, 46))	('mesenchymal properties of', 'CPA', (55, 80))	('reduces', 'NegReg', (30, 37))	('MUC4', 'Gene', '4585', (14, 18))
515899	33664766	We observed MUC16 mutation in our dataset, similar to recent reports in gastric cancers (Li et al.,).	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('MUC16', 'Gene', (12, 17))	('gastric cancers', 'Disease', 'MESH:D013274', (72, 87))	('gastric cancers', 'Disease', (72, 87))	('gastric cancers', 'Phenotype', 'HP:0012126', (72, 87))	('mutation', 'Var', (18, 26))	('MUC16', 'Gene', '94025', (12, 17))	('cancers', 'Phenotype', 'HP:0002664', (80, 87))
515900	33664766	Therefore, the recurrent site-specific TTN and MUC4 mutations and the known role of these genes in cancer suggest the possibility that mutant TTN and MUC4 may exert oncogenic activity in cervical cancer.	('MUC4', 'Gene', (47, 51))	('MUC4', 'Gene', (150, 154))	('cancer', 'Disease', 'MESH:D009369', (196, 202))	('TTN', 'Gene', '7273', (142, 145))	('TTN', 'Gene', '7273', (39, 42))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('mutant', 'Var', (135, 141))	('TTN', 'Gene', (142, 145))	('TTN', 'Gene', (39, 42))	('cervical cancer', 'Disease', (187, 202))	('cervical cancer', 'Disease', 'MESH:D002583', (187, 202))	('cancer', 'Disease', (196, 202))	('oncogenic activity', 'CPA', (165, 183))	('mutations', 'Var', (52, 61))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('MUC4', 'Gene', '4585', (47, 51))	('cancer', 'Disease', (99, 105))	('MUC4', 'Gene', '4585', (150, 154))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
515903	33664766	Previous study has described deficient DNA mismatch repair as a common phenomenon in the process of cervical cancer development (Nijhuis et al.,; Feng et al.,).	('cervical cancer', 'Disease', (100, 115))	('cervical cancer', 'Disease', 'MESH:D002583', (100, 115))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('DNA mismatch repair', 'MPA', (39, 58))	('deficient', 'Var', (29, 38))
515905	33664766	APOBEC activity served as a key driver of PIK3CA mutagenesis and HPV-induced transformation in head and neck squamous cell carcinomas (Henderson et al.,).	('head and neck squamous cell carcinomas', 'Disease', 'MESH:D000077195', (95, 133))	('mutagenesis', 'Var', (49, 60))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (109, 133))	('HPV', 'Species', '10566', (65, 68))	('PIK3CA', 'Gene', (42, 48))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (109, 132))	('PIK3CA', 'Gene', '5290', (42, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('carcinomas', 'Phenotype', 'HP:0030731', (123, 133))
515907	33664766	Our current results further support the concept that deficient DNA mismatch repair and APOBEC-mediated mutagenesis were carcinogenic in the cervix.	('APOBEC-mediated', 'Gene', (87, 102))	('deficient', 'Var', (53, 62))	('carcinogenic', 'Disease', 'MESH:D063646', (120, 132))	('carcinogenic', 'Disease', (120, 132))	('mutagenesis', 'Var', (103, 114))	('DNA mismatch repair', 'Protein', (63, 82))
515914	33664766	More recently, cervical cancer with Rb1 mutation is reported to be more sensitive to cisplatin through PI3K/AKT pathway.	('AKT', 'Gene', '207', (108, 111))	('mutation', 'Var', (40, 48))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('more', 'PosReg', (67, 71))	('cervical cancer', 'Disease', (15, 30))	('cervical cancer', 'Disease', 'MESH:D002583', (15, 30))	('sensitive to cisplatin', 'MPA', (72, 94))	('Rb1', 'Gene', (36, 39))	('AKT', 'Gene', (108, 111))	('Rb1', 'Gene', '5925', (36, 39))	('cisplatin', 'Chemical', 'MESH:D002945', (85, 94))
515915	33664766	Cluster 3 was characterized by poor CNV and poor methylation, most of which were squamous carcinoma.	('CNV', 'Var', (36, 39))	('squamous carcinoma', 'Disease', 'MESH:D002294', (81, 99))	('methylation', 'MPA', (49, 60))	('squamous carcinoma', 'Disease', (81, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('poor', 'NegReg', (44, 48))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (81, 99))
515980	31125107	Most of the individuals from the NCGG (2586 of 2670) were older than 60 years, and approximately half of them (1469 of 2670) were diagnosed as having dementia.	('diagnosed', 'Reg', (130, 139))	('dementia', 'Phenotype', 'HP:0000726', (150, 158))	('dementia', 'Disease', (150, 158))	('dementia', 'Disease', 'MESH:D003704', (150, 158))	('1469 of 2670', 'Var', (111, 123))
515985	31125107	The EC index was calculated as follows: (0.961037)*miR-8073+(-0.962054)*miR-6794-5p+(1.31647)*miR-3196+(-1.0132)*miR-6820-5p+(0.657628)*miR-744-5p+(-0.406723)*miR-6799-5p-9.799262.	('miR-6820', 'Gene', (113, 121))	('miR-6799', 'Gene', (159, 167))	('miR-6799', 'Gene', '102465479', (159, 167))	('miR-6794', 'Gene', (72, 80))	('miR-6820', 'Gene', '102465492', (113, 121))	('EC', 'Chemical', '-', (4, 6))	('miR-744', 'Gene', (136, 143))	('miR-8073', 'Gene', '102465872', (51, 59))	('miR-8073', 'Gene', (51, 59))	('miR-6794', 'Gene', '102466196', (72, 80))	('miR-3196', 'Gene', '100423014', (94, 102))	('miR-744', 'Gene', '100126313', (136, 143))	('0.961037', 'Var', (41, 49))	('miR-3196', 'Gene', (94, 102))
515995	31125107	The results showed that 7 miRNAs (miR-10a, miR-22, miR-100, miR-148b, miR-223, miR-133a, and miR-127-3p) were significantly upregulated in the serum of patients with ESCC compared with the control patients (the AUC for the 7 miRNAs ranged from 0.817 to 0.949).	('miR-127-3p', 'Gene', (93, 103))	('miR-100', 'Gene', (51, 58))	('patients', 'Species', '9606', (197, 205))	('miR-22', 'Gene', '407004', (43, 49))	('miR-22', 'Gene', (43, 49))	('upregulated', 'PosReg', (124, 135))	('SCC', 'Phenotype', 'HP:0002860', (167, 170))	('miR-223', 'Gene', (70, 77))	('miR-100', 'Gene', '406892', (51, 58))	('miR-10a', 'Gene', '406902', (34, 41))	('SCC', 'Gene', '6317', (167, 170))	('miR-148b', 'Gene', '442892', (60, 68))	('miR-148b', 'Gene', (60, 68))	('miR-133a', 'Var', (79, 87))	('miR-223', 'Gene', '407008', (70, 77))	('patients', 'Species', '9606', (152, 160))	('SCC', 'Gene', (167, 170))	('miR-22', 'Gene', '407004', (70, 76))	('miR-22', 'Gene', (70, 76))	('miR-127-3p', 'Gene', '100302165', (93, 103))	('miR-10a', 'Gene', (34, 41))
516043	30728900	Adding A-1210477 to ABT-263 (navitoclax) treatment resulted in an average 7-fold reduction in the required lethal dose of ABT-263 (navitoclax) when measured across all 8 cell lines.	('ABT-263', 'Chemical', 'MESH:C528561', (20, 27))	('A-1210477', 'Var', (7, 16))	('navitoclax', 'Chemical', 'MESH:C528561', (131, 141))	('A-1210477', 'Chemical', 'MESH:C000611392', (7, 16))	('navitoclax', 'Chemical', 'MESH:C528561', (29, 39))	('reduction', 'NegReg', (81, 90))	('ABT-263', 'Chemical', 'MESH:C528561', (122, 129))	('ABT-263', 'Gene', (122, 129))	('ABT-263', 'Gene', (20, 27))
516044	30728900	Synergistic activity was confirmed in PCI15B, Detroit 562, MDA686LN, and HN30 based on Bliss Independence analysis.	('MDA686LN', 'CellLine', 'CVCL:6984', (59, 67))	('MDA686LN', 'Var', (59, 67))	('PCI15B', 'Gene', (38, 44))
516055	30728900	Thus, disruption of apoptosis signaling plays a key role in the development of cancer, cancer cell survival, and resistance to therapy.	('cancer', 'Disease', (87, 93))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('cancer', 'Disease', (79, 85))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('apoptosis', 'MPA', (20, 29))	('disruption', 'Var', (6, 16))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('cancer', 'Disease', 'MESH:D009369', (79, 85))
516065	30728900	This led us to examine the efficacy of small-molecule targeting of BCL-xL in HNSCC.	('small-molecule', 'Var', (39, 53))	('SCC', 'Gene', (79, 82))	('SCC', 'Gene', '6317', (79, 82))	('BCL-xL', 'Gene', '598', (67, 73))	('BCL-xL', 'Gene', (67, 73))
516105	30728900	For example, HN30 showed an approximately 4-fold decrease in the cisplatin requirement to achieve the IC50 after treatment with 4muM of ABT-263 (2.92muM +-0.80muM vs. 0.72muM +-0.05muM), while Detroit562 showed no change in the IC50 (10.66muM +-0.40muM vs. 10.27muM +-0.41muM).	('cisplatin', 'Chemical', 'MESH:D002945', (65, 74))	('muM', 'Gene', (171, 174))	('ABT-263', 'Chemical', 'MESH:C528561', (136, 143))	('cisplatin requirement', 'MPA', (65, 86))	('muM', 'Gene', '56925', (249, 252))	('muM', 'Gene', '56925', (129, 132))	('muM', 'Gene', (249, 252))	('muM', 'Gene', '56925', (272, 275))	('muM', 'Gene', (129, 132))	('muM', 'Gene', '56925', (159, 162))	('ABT-263', 'Gene', (136, 143))	('muM', 'Gene', (272, 275))	('muM', 'Gene', (159, 162))	('muM', 'Gene', '56925', (239, 242))	('HN30', 'Var', (13, 17))	('muM', 'Gene', (239, 242))	('muM', 'Gene', '56925', (262, 265))	('muM', 'Gene', '56925', (149, 152))	('decrease', 'NegReg', (49, 57))	('muM', 'Gene', (262, 265))	('muM', 'Gene', (149, 152))	('IC50', 'MPA', (102, 106))	('muM', 'Gene', '56925', (181, 184))	('muM', 'Gene', (181, 184))	('muM', 'Gene', '56925', (171, 174))
516126	30728900	HNSCC cell lines were treated with 2.5muM and 5muM doses of A-1210477 to determine if this resulted in a dose reduction required to achieve the IC50 with ABT-263.	('muM', 'Gene', '56925', (38, 41))	('muM', 'Gene', (47, 50))	('A-1210477', 'Chemical', 'MESH:C000611392', (60, 69))	('muM', 'Gene', (38, 41))	('SCC', 'Gene', (2, 5))	('ABT-263', 'Chemical', 'MESH:C528561', (154, 161))	('A-1210477', 'Var', (60, 69))	('SCC', 'Gene', '6317', (2, 5))	('muM', 'Gene', '56925', (47, 50))
516128	30728900	The IC50 dose of ABT-263 was reduced on average 7-fold when combined with 5muM of A-1210477, ranging from 1.4-fold (HN5) to 22.3-fold (MDA686LN).	('HN5', 'Gene', (116, 119))	('A-1210477', 'Chemical', 'MESH:C000611392', (82, 91))	('MDA686LN', 'Var', (135, 143))	('MDA686LN', 'CellLine', 'CVCL:6984', (135, 143))	('ABT-263', 'Chemical', 'MESH:C528561', (17, 24))	('reduced', 'NegReg', (29, 36))	('ABT-263', 'Gene', (17, 24))	('muM', 'Gene', '56925', (75, 78))	('IC50 dose', 'MPA', (4, 13))	('HN5', 'Gene', '100463289', (116, 119))	('muM', 'Gene', (75, 78))
516129	30728900	It was suspected that the drug combination of ABT-263 and A-1210477 was synergistic based on results of the 8 cell line panel.	('A-1210477', 'Var', (58, 67))	('ABT-263', 'Gene', (46, 53))	('A-1210477', 'Chemical', 'MESH:C000611392', (58, 67))	('ABT-263', 'Chemical', 'MESH:C528561', (46, 53))
516143	30728900	Work by Bauer and colleagues demonstrated that patients with laryngeal SCC who express low levels of BCL-xL demonstrate better responses to chemotherapy and chemoradiation compared to patients with high BCL-xL expression, which was recapitulated in a HNSCC cell line model examining cisplatin-resistant cells.	('SCC', 'Gene', '6317', (253, 256))	('BCL-xL', 'Gene', '598', (203, 209))	('BCL-xL', 'Gene', (203, 209))	('better', 'PosReg', (120, 126))	('patients', 'Species', '9606', (184, 192))	('patients', 'Species', '9606', (47, 55))	('SCC', 'Gene', '6317', (71, 74))	('a HNSCC', 'CellLine', 'CVCL:5985', (249, 256))	('SCC', 'Gene', (71, 74))	('SCC', 'Gene', (253, 256))	('cisplatin', 'Chemical', 'MESH:D002945', (283, 292))	('BCL-xL', 'Gene', '598', (101, 107))	('BCL-xL', 'Gene', (101, 107))	('low', 'Var', (87, 90))	('responses', 'MPA', (127, 136))
516144	30728900	In a similar report, correlative studies from an organ-preservation trial demonstrated that high BCL-xL expression as a component of a biomarker panel was associated with poor outcomes.	('BCL-xL', 'Gene', '598', (97, 103))	('high', 'Var', (92, 96))	('BCL-xL', 'Gene', (97, 103))
516154	30728900	ABT-263 (navitoclax) has been studied in phase I and II trials, and the efficacy of ABT-263 (navitoclax) in solid tumors has been largely disappointing, both as a single agent and in combination with other chemotherapeutics, including gemcitabine, carboplatin/paclitaxel, irinotecan, and erlotinib.	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('ABT-263', 'Chemical', 'MESH:C528561', (84, 91))	('navitoclax', 'Chemical', 'MESH:C528561', (93, 103))	('navitoclax', 'Chemical', 'MESH:C528561', (9, 19))	('irinotecan', 'Chemical', 'MESH:D000077146', (272, 282))	('ABT-263', 'Var', (84, 91))	('solid tumors', 'Disease', (108, 120))	('paclitaxel', 'Chemical', 'MESH:D017239', (260, 270))	('erlotinib', 'Chemical', 'MESH:D000069347', (288, 297))	('carboplatin', 'Chemical', 'MESH:D016190', (248, 259))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('ABT-263', 'Chemical', 'MESH:C528561', (0, 7))	('gemcitabine', 'Chemical', 'MESH:C056507', (235, 246))	('solid tumors', 'Disease', 'MESH:D009369', (108, 120))
516158	30728900	(-)-Gossypol, a BH3-mimetic which inhibits BCL-xL and BCL-2, has been studied in HNSCC cell lines, and (-)-gossypol demonstrated improved efficacy compared to cisplatin and induced apoptosis in cisplatin resistant HNSCC lines.	('apoptosis', 'CPA', (181, 190))	('SCC', 'Gene', '6317', (83, 86))	('efficacy', 'MPA', (138, 146))	('(-)-gossypol', 'Chemical', 'MESH:D006072', (103, 115))	('SCC', 'Gene', (83, 86))	('SCC', 'Gene', '6317', (216, 219))	('cisplatin', 'Chemical', 'MESH:D002945', (159, 168))	('induced', 'Reg', (173, 180))	('BH3', 'Chemical', 'MESH:C006008', (16, 19))	('SCC', 'Gene', (216, 219))	('BCL-xL', 'Gene', '598', (43, 49))	('BCL-2', 'Gene', '596', (54, 59))	('BCL-2', 'Gene', (54, 59))	('inhibits', 'NegReg', (34, 42))	('(-)-Gossypol', 'Chemical', 'MESH:D006072', (0, 12))	('cisplatin', 'Chemical', 'MESH:D002945', (194, 203))	('-)-gossypol', 'Var', (104, 115))	('BCL-xL', 'Gene', (43, 49))	('improved', 'PosReg', (129, 137))
516188	30728900	Very recently a new MCL-1 inhibitor, S63845, was described and demonstrated both in vitro and in vivo efficacy against MCL-1 dependent myeloma, leukemia, and lymphoma cells.	('MCL-1 dependent myeloma, leukemia', 'Disease', 'MESH:C535516', (119, 152))	('leukemia', 'Phenotype', 'HP:0001909', (144, 152))	('lymphoma', 'Disease', (158, 166))	('MCL-1', 'Gene', '4170', (20, 25))	('lymphoma', 'Disease', 'MESH:D008223', (158, 166))	('S63845', 'Var', (37, 43))	('lymphoma', 'Phenotype', 'HP:0002665', (158, 166))	('MCL-1', 'Gene', (119, 124))	('MCL-1', 'Gene', (20, 25))	('MCL-1', 'Gene', '4170', (119, 124))
516190	30728900	Based on the data we have presented here, the combination of improved and clinically applicable MCL-1 inhibitors, such as S63845, with drugs targeting BCL-xL/BCL2, is a logical and potentially effective next step for in vivo studies of HNSCC.	('MCL-1', 'Gene', '4170', (96, 101))	('MCL-1', 'Gene', (96, 101))	('BCL-xL', 'Gene', (151, 157))	('BCL-xL', 'Gene', '598', (151, 157))	('BCL2', 'Gene', (158, 162))	('SCC', 'Gene', (238, 241))	('SCC', 'Gene', '6317', (238, 241))	('BCL2', 'Gene', '596', (158, 162))	('S63845', 'Var', (122, 128))
516193	30728900	MCL-1 expression correlated with radiation resistance in HNSCC cells, and inhibition of MCL-1 with A-1210477 enhanced response to ABT-263 (navitoclax).	('response to', 'MPA', (118, 129))	('inhibition', 'Var', (74, 84))	('SCC', 'Gene', (59, 62))	('radiation resistance', 'CPA', (33, 53))	('ABT-263', 'Chemical', 'MESH:C528561', (130, 137))	('expression', 'MPA', (6, 16))	('enhanced', 'PosReg', (109, 117))	('A-1210477', 'Chemical', 'MESH:C000611392', (99, 108))	('SCC', 'Gene', '6317', (59, 62))	('navitoclax', 'Chemical', 'MESH:C528561', (139, 149))	('MCL-1', 'Gene', '4170', (88, 93))	('MCL-1', 'Gene', (88, 93))	('MCL-1', 'Gene', '4170', (0, 5))	('A-1210477', 'Var', (99, 108))	('MCL-1', 'Gene', (0, 5))
516235	30728900	Cells were incubated with serial dilutions of ABT-263 (20 mM to 0.078 mM) and co-treated with A1210477 at the indicated concentrations.	('ABT-263', 'Gene', (46, 53))	('A1210477', 'Var', (94, 102))	('ABT-263', 'Chemical', 'MESH:C528561', (46, 53))
516284	33936200	The survival curve was downloaded from the following data links: TCGA CAARRAY GSE31210, GSE14814, GSE19188, GSE29013, GSE30219, GSE3141, GSE31908, GSE37745, GSE43580, GSE4573, GSE50081, GSE31908, and GSE8894.	('GSE4573', 'Chemical', '-', (167, 174))	('GSE31908', 'Var', (186, 194))	('GSE14814', 'Var', (88, 96))	('GSE31210', 'Var', (78, 86))	('GSE3141', 'Var', (128, 135))	('GSE3141', 'Chemical', '-', (128, 135))	('GSE31908', 'Var', (137, 145))	('GSE37745', 'Var', (147, 155))	('GSE29013', 'Var', (108, 116))	('GSE19188', 'Var', (98, 106))	('GSE30219', 'Var', (118, 126))	('GSE4573', 'Var', (167, 174))	('GSE43580', 'Var', (157, 165))	('GSE50081', 'Var', (176, 184))	('GSE8894', 'Chemical', '-', (200, 207))
516308	33936200	This may be because, under hypoxic conditions, the transcriptional instability of tumor cells may cause the activation of some cancer survival-related factors, resulting in the enhancement of tumor migration and invasion and promotion of cancer development.	('cancer', 'Disease', (238, 244))	('tumor', 'Disease', (192, 197))	('cancer', 'Disease', 'MESH:D009369', (238, 244))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('tumor', 'Phenotype', 'HP:0002664', (192, 197))	('enhancement', 'PosReg', (177, 188))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('promotion', 'PosReg', (225, 234))	('invasion', 'CPA', (212, 220))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumor', 'Disease', 'MESH:D009369', (192, 197))	('cancer', 'Disease', (127, 133))	('transcriptional instability', 'Var', (51, 78))	('tumor', 'Disease', (82, 87))	('activation', 'PosReg', (108, 118))
516317	33936200	Our results indicate that KxD1 is not only positively correlated with cancer invasion and metastasis, but also negatively correlated to nonoperational anticancer therapy resistance.	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('metastasis', 'CPA', (90, 100))	('positively', 'PosReg', (43, 53))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('negatively', 'NegReg', (111, 121))	('KxD1', 'Var', (26, 30))	('correlated', 'Reg', (54, 64))	('correlated', 'Reg', (122, 132))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('cancer', 'Disease', (155, 161))	('cancer', 'Disease', 'MESH:D009369', (155, 161))
516338	31959200	Several genetic alterations have been reported to be "drivers" of NSCLC progression, including mutations in epidermal growth factor receptor and mesenchymal-epidermal transition-related genes.	('mesenchymal-epidermal transition-related genes', 'Gene', (145, 191))	('NSCLC', 'Disease', (66, 71))	('alterations', 'Var', (16, 27))	('NSCLC', 'Disease', 'MESH:D002289', (66, 71))	('epidermal growth factor receptor', 'Gene', (108, 140))	('mutations', 'Var', (95, 104))	('epidermal growth factor receptor', 'Gene', '1956', (108, 140))	('NSCLC', 'Phenotype', 'HP:0030358', (66, 71))
516398	31959200	Kaplan-Meier survival analysis showed that the OS rates were lower for the high vs. low LINC01234 expression groups, which was supported by Kaplan-Meier Plotter analysis (www.kmplot.com) (Fig.	('lower', 'NegReg', (61, 66))	('LINC01234', 'Gene', (88, 97))	('high', 'Var', (75, 79))	('OS rates', 'MPA', (47, 55))	('LINC01234', 'Gene', '100506465', (88, 97))	('expression', 'MPA', (98, 108))
516400	31959200	We found that LINC01234 knockdown significantly decreased the migration and invasion ability of A549 and SPC-A1 cells compared with cells expressing si-NC, while overexpression of LINC01234 promoted A549 and SPC-A1 cells migration and invasion (Fig.	('migration', 'CPA', (62, 71))	('LINC01234', 'Gene', (180, 189))	('invasion', 'CPA', (235, 243))	('A549', 'CellLine', 'CVCL:0023', (199, 203))	('A549', 'CellLine', 'CVCL:0023', (96, 100))	('decreased', 'NegReg', (48, 57))	('LINC01234', 'Gene', '100506465', (14, 23))	('invasion ability', 'CPA', (76, 92))	('LINC01234', 'Gene', (14, 23))	('LINC01234', 'Gene', '100506465', (180, 189))	('knockdown', 'Var', (24, 33))	('promoted', 'PosReg', (190, 198))
516402	31959200	Consistent with the in vitro analyses, LINC01234 knockdown reduced the number of metastatic lung nodules compared with the control group.	('LINC01234', 'Gene', '100506465', (39, 48))	('knockdown', 'Var', (49, 58))	('LINC01234', 'Gene', (39, 48))	('reduced', 'NegReg', (59, 66))
516421	31959200	3d), from which we analyzed five with known tumor suppressor functions (miR-27b-3p, miR-340-5p, miR-490-3p, miR-100-5p, and miR-153-5p).	('miR-100-5p', 'Var', (108, 118))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('miR-27b', 'Gene', '407019', (72, 79))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('miR-340', 'Gene', (84, 91))	('miR-490-3p', 'Var', (96, 106))	('miR-340', 'Gene', '442908', (84, 91))	('miR-27b', 'Gene', (72, 79))	('miR-153-5p', 'Var', (124, 134))	('tumor', 'Disease', (44, 49))
516423	31959200	Mutation of the putative miR-27b-3p and miR-340-5p binding sites in LINC01234 abolished their ability to suppress luciferase expression, confirming that the miRNAs specifically interact with LINC01234 (Fig.	('LINC01234', 'Gene', (191, 200))	('suppress', 'NegReg', (105, 113))	('LINC01234', 'Gene', '100506465', (68, 77))	('Mutation', 'Var', (0, 8))	('expression', 'MPA', (125, 135))	('miR-27b', 'Gene', '407019', (25, 32))	('LINC01234', 'Gene', (68, 77))	('miR-340', 'Gene', '442908', (40, 47))	('miR-340', 'Gene', (40, 47))	('abolished', 'NegReg', (78, 87))	('miR-27b', 'Gene', (25, 32))	('luciferase', 'Enzyme', (114, 124))	('LINC01234', 'Gene', '100506465', (191, 200))
516425	31959200	Finally, miR-27b-3p and miR-340-5p levels in A549 and SPC-A1 cells were significantly increased and decreased by LINC01234 depletion and overexpression, respectively (Fig.	('increased', 'PosReg', (86, 95))	('miR-340', 'Gene', (24, 31))	('LINC01234', 'Gene', '100506465', (113, 122))	('miR-27b', 'Gene', (9, 16))	('miR-340', 'Gene', '442908', (24, 31))	('A549', 'CellLine', 'CVCL:0023', (45, 49))	('LINC01234', 'Gene', (113, 122))	('overexpression', 'PosReg', (137, 151))	('depletion', 'Var', (123, 132))	('decreased', 'NegReg', (100, 109))	('miR-27b', 'Gene', '407019', (9, 16))
516433	31959200	We cloned the wild-type 3'-untranslated region (3'UTR) of VAV3 (wt-VAV3) or one carrying mutations in the miR-27b-3p/miR-340-5p-binding sites (mut-VAV3) into the luciferase vector and co-transfected them with control miRNA or miR-27b-3p/miR-340-5p mimics into HEK293T cells.	('miR-340', 'Gene', (237, 244))	('VAV3', 'Gene', (147, 151))	('VAV3', 'Gene', '10451', (147, 151))	('miR-340', 'Gene', (117, 124))	('wt-VAV3', 'Gene', '10451', (64, 71))	('VAV3', 'Gene', (58, 62))	('miR-340', 'Gene', '442908', (117, 124))	('HEK293T', 'CellLine', 'CVCL:0063', (260, 267))	('miR-27b', 'Gene', '407019', (106, 113))	('miR-27b', 'Gene', '407019', (226, 233))	('VAV3', 'Gene', '10451', (58, 62))	('miR-27b', 'Gene', (226, 233))	('miR-27b', 'Gene', (106, 113))	('mutations', 'Var', (89, 98))	('VAV3', 'Gene', (67, 71))	('wt-VAV3', 'Gene', (64, 71))	('miR-340', 'Gene', '442908', (237, 244))	('VAV3', 'Gene', '10451', (67, 71))
516437	31959200	Additionally, E-cadherin was increased, whereas Vimentin was decreased, in VAV3 knockdown cells (Fig.	('Vimentin', 'Gene', (48, 56))	('knockdown', 'Var', (80, 89))	('E-cadherin', 'Gene', '999', (14, 24))	('VAV3', 'Gene', '10451', (75, 79))	('Vimentin', 'Gene', '7431', (48, 56))	('increased', 'PosReg', (29, 38))	('decreased', 'NegReg', (61, 70))	('E-cadherin', 'Gene', (14, 24))	('VAV3', 'Gene', (75, 79))
516446	31959200	Moreover, co-transfection with miR-27b-3p/miR-340-5p inhibitors partially reversed the inhibition of cell invasion induced by LINC01234 knockdown (Fig.	('inhibition', 'NegReg', (87, 97))	('miR-340', 'Gene', '442908', (42, 49))	('miR-340', 'Gene', (42, 49))	('LINC01234', 'Gene', '100506465', (126, 135))	('knockdown', 'Var', (136, 145))	('miR-27b', 'Gene', '407019', (31, 38))	('LINC01234', 'Gene', (126, 135))	('cell invasion', 'CPA', (101, 114))	('miR-27b', 'Gene', (31, 38))
516448	31959200	Inhibition of VAV3 significantly inhibited NSCLC cell invasion (Fig.	('VAV3', 'Gene', (14, 18))	('VAV3', 'Gene', '10451', (14, 18))	('NSCLC', 'Phenotype', 'HP:0030358', (43, 48))	('Inhibition', 'Var', (0, 10))	('NSCLC', 'Disease', (43, 48))	('inhibited', 'NegReg', (33, 42))	('NSCLC', 'Disease', 'MESH:D002289', (43, 48))
516454	31959200	BTG2 is of particular interest because of its remarkable expression fold change upon LINC01234 knockdown (Fig.	('expression', 'MPA', (57, 67))	('LINC01234', 'Gene', '100506465', (85, 94))	('LINC01234', 'Gene', (85, 94))	('knockdown', 'Var', (95, 104))	('BTG2', 'Gene', (0, 4))	('BTG2', 'Gene', '7832', (0, 4))
516455	31959200	Western blot analysis showed that knockdown of LINC01234 significantly increased BTG2 protein levels in NSCLC cells (Fig.	('LINC01234', 'Gene', '100506465', (47, 56))	('LINC01234', 'Gene', (47, 56))	('NSCLC', 'Disease', (104, 109))	('BTG2', 'Gene', (81, 85))	('NSCLC', 'Disease', 'MESH:D002289', (104, 109))	('increased', 'PosReg', (71, 80))	('BTG2', 'Gene', '7832', (81, 85))	('knockdown', 'Var', (34, 43))	('NSCLC', 'Phenotype', 'HP:0030358', (104, 109))
516474	31959200	Taken together, these findings demonstrate that LINC01234 affects NSCLC cell development and progression through the epigenetic repression of BTG2, at least in part.	('BTG2', 'Gene', '7832', (142, 146))	('NSCLC', 'Disease', (66, 71))	('NSCLC', 'Disease', 'MESH:D002289', (66, 71))	('affects', 'Reg', (58, 65))	('LINC01234', 'Gene', '100506465', (48, 57))	('men', 'Species', '9606', (84, 87))	('epigenetic repression', 'Var', (117, 138))	('LINC01234', 'Gene', (48, 57))	('BTG2', 'Gene', (142, 146))	('NSCLC', 'Phenotype', 'HP:0030358', (66, 71))	('progression', 'CPA', (93, 104))
516477	31959200	In addition, modulation of LINC01234 expression revealed its oncogenic activity through promotion of cell migration, invasion, supporting a potential role for LINC01234 dysregulation in NSCLC progression.	('NSCLC', 'Phenotype', 'HP:0030358', (186, 191))	('LINC01234', 'Gene', (159, 168))	('LINC01234', 'Gene', '100506465', (159, 168))	('NSCLC', 'Disease', (186, 191))	('cell migration', 'CPA', (101, 115))	('LINC01234', 'Gene', '100506465', (27, 36))	('promotion', 'PosReg', (88, 97))	('NSCLC', 'Disease', 'MESH:D002289', (186, 191))	('oncogenic activity', 'MPA', (61, 79))	('modulation', 'Var', (13, 23))	('LINC01234', 'Gene', (27, 36))	('invasion', 'CPA', (117, 125))
516487	31959200	In addition to these findings, our results showed that overexpression of miRNA-340 and miR-27b repressed NSCLC cell invasion by targeting VAV3 expression.	('overexpression', 'PosReg', (55, 69))	('NSCLC', 'Disease', 'MESH:D002289', (105, 110))	('miR-27b', 'Gene', (87, 94))	('NSCLC', 'Phenotype', 'HP:0030358', (105, 110))	('VAV3', 'Gene', (138, 142))	('VAV3', 'Gene', '10451', (138, 142))	('repressed', 'PosReg', (95, 104))	('miRNA-340', 'Var', (73, 82))	('miR-27b', 'Gene', '407019', (87, 94))	('NSCLC', 'Disease', (105, 110))	('targeting', 'Reg', (128, 137))
516490	31959200	Consistent with this, we also found that VAV3 was upregulated in NSCLC, and its knockdown inhibited NSCLC cell invasion.	('VAV3', 'Gene', (41, 45))	('knockdown', 'Var', (80, 89))	('upregulated', 'PosReg', (50, 61))	('NSCLC', 'Disease', (100, 105))	('VAV3', 'Gene', '10451', (41, 45))	('NSCLC', 'Disease', 'MESH:D002289', (65, 70))	('NSCLC', 'Disease', 'MESH:D002289', (100, 105))	('NSCLC', 'Phenotype', 'HP:0030358', (65, 70))	('inhibited', 'NegReg', (90, 99))	('NSCLC', 'Phenotype', 'HP:0030358', (100, 105))	('NSCLC', 'Disease', (65, 70))
516493	31959200	EZH2 and SUZ12 are core subunits of the Polycomb repressive complex 2 (PRC2), which suppresses gene transcription by trimethylating H3K27.	('trimethylating', 'Var', (117, 131))	('EZH2', 'Gene', '2146', (0, 4))	('suppresses', 'NegReg', (84, 94))	('H3K27', 'Protein', (132, 137))	('EZH2', 'Gene', (0, 4))	('SUZ12', 'Gene', '23512', (9, 14))	('SUZ12', 'Gene', (9, 14))	('gene transcription', 'MPA', (95, 113))
516494	31959200	In human melanoma cells, loss of EZH2 partially interfered with invasion capacity.	('invasion capacity', 'CPA', (64, 81))	('loss', 'Var', (25, 29))	('interfered', 'NegReg', (48, 58))	('melanoma', 'Phenotype', 'HP:0002861', (9, 17))	('melanoma', 'Disease', (9, 17))	('human', 'Species', '9606', (3, 8))	('melanoma', 'Disease', 'MESH:D008545', (9, 17))	('EZH2', 'Gene', '2146', (33, 37))	('EZH2', 'Gene', (33, 37))
516495	31959200	LSD1, one of the first discovered protein lysine demethylases, demethylates H3K4me2 to H3K4me1 or H3K4me0.	('LSD1', 'Gene', '23028', (0, 4))	('H3K4me1', 'Var', (87, 94))	('H3K4me0', 'Chemical', 'MESH:C024755', (98, 105))	('H3K4me2', 'Chemical', 'MESH:C024755', (76, 83))	('H3K4me1', 'Chemical', 'MESH:C024755', (87, 94))	('lysine', 'Chemical', 'MESH:C114808', (42, 48))	('H3K4me2', 'Protein', (76, 83))	('H3K4me0', 'Var', (98, 105))	('LSD1', 'Gene', (0, 4))
516527	30214570	At present, gene-targeted therapy provides a new approach for the treatment of lung cancer.	('lung cancer', 'Disease', 'MESH:D008175', (79, 90))	('gene-targeted therapy', 'Var', (12, 33))	('men', 'Species', '9606', (71, 74))	('lung cancer', 'Disease', (79, 90))	('lung cancer', 'Phenotype', 'HP:0100526', (79, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))
516600	30214570	The aforementioned results suggested that patients with high expression of CSDAP1 may have relatively poor prognosis.	('CSDAP1', 'Gene', '440359', (75, 81))	('men', 'Species', '9606', (9, 12))	('patients', 'Species', '9606', (42, 50))	('CSDAP1', 'Gene', (75, 81))	('high expression', 'Var', (56, 71))
516609	28469388	Significant Prognostic Features and Patterns of Somatic TP53 Mutations in Human Cancers TP53 is the most frequently altered gene in human cancers.	('Cancers', 'Disease', 'MESH:D009369', (80, 87))	('TP53', 'Gene', '7157', (56, 60))	('Mutations', 'Var', (61, 70))	('cancers', 'Phenotype', 'HP:0002664', (138, 145))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('TP53', 'Gene', (56, 60))	('TP53', 'Gene', '7157', (88, 92))	('Cancer', 'Phenotype', 'HP:0002664', (80, 86))	('human', 'Species', '9606', (132, 137))	('Human', 'Species', '9606', (74, 79))	('Cancers', 'Disease', (80, 87))	('TP53', 'Gene', (88, 92))	('cancers', 'Disease', (138, 145))	('Cancers', 'Phenotype', 'HP:0002664', (80, 87))	('cancers', 'Disease', 'MESH:D009369', (138, 145))
516610	28469388	Numerous retrospective studies have related its mutation and abnormal p53 protein expression to poor patient survival.	('patient', 'Species', '9606', (101, 108))	('p53', 'Gene', '7157', (70, 73))	('mutation', 'Var', (48, 56))	('p53', 'Gene', (70, 73))
516614	28469388	They include the following: (1) similar to previously reported cases in breast cancer, the mutations in exons 1 to 4 of TP53 were more lethal than those in exons 5 to 9 for the patients with lung adenocarcinomas; (2) TP53 mutants tended to be negatively selected in mammalian evolution, but the evolutionary conservation had various clinical implications for different cancers; (3) conserved correlation patterns (ie, consistent co-occurrence or consistent mutual exclusivity) between TP53 mutations and the alterations in several other cancer genes (ie, PIK3CA, PTEN, KRAS, APC, CDKN2A, and ATM) were present in several cancers in which prognosis was associated with TP53 status and/or the mutational characteristics; (4) among TP53-mutated tumors, the total mutation burden in other driver genes was a predictive signature (P < .05, false discovery rate <0.11) for better patient survival outcome in several cancer types, including glioblastoma multiforme.	('KRAS', 'Gene', '3845', (569, 573))	('TP53', 'Gene', '7157', (217, 221))	('cancers', 'Phenotype', 'HP:0002664', (369, 376))	('cancers', 'Disease', (369, 376))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (191, 211))	('TP53', 'Gene', '7157', (668, 672))	('carcinomas', 'Phenotype', 'HP:0030731', (201, 211))	('TP53', 'Gene', (729, 733))	('breast cancer', 'Disease', 'MESH:D001943', (72, 85))	('cancers', 'Phenotype', 'HP:0002664', (621, 628))	('breast cancer', 'Disease', (72, 85))	('cancer', 'Disease', 'MESH:D009369', (910, 916))	('cancer', 'Disease', (621, 627))	('cancers', 'Disease', (621, 628))	('to 9', 'Species', '1214577', (164, 168))	('TP53', 'Gene', '7157', (120, 124))	('KRAS', 'Gene', (569, 573))	('PTEN', 'Gene', '5728', (563, 567))	('cancer', 'Disease', 'MESH:D009369', (537, 543))	('TP53', 'Gene', '7157', (485, 489))	('cancer', 'Disease', 'MESH:D009369', (369, 375))	('glioblastoma', 'Phenotype', 'HP:0012174', (934, 946))	('patient', 'Species', '9606', (874, 881))	('lung adenocarcinomas', 'Disease', (191, 211))	('cancer', 'Phenotype', 'HP:0002664', (621, 627))	('PIK3CA', 'Gene', '5290', (555, 561))	('ATM', 'Gene', '472', (592, 595))	('tumors', 'Phenotype', 'HP:0002664', (742, 748))	('CDKN2A', 'Gene', (580, 586))	('better', 'PosReg', (867, 873))	('glioblastoma multiforme', 'Disease', (934, 957))	('cancer', 'Disease', (79, 85))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (934, 957))	('TP53', 'Gene', (485, 489))	('tumor', 'Phenotype', 'HP:0002664', (742, 747))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('TP53', 'Gene', (217, 221))	('tumors', 'Disease', (742, 748))	('cancers', 'Disease', 'MESH:D009369', (369, 376))	('TP53', 'Gene', '7157', (729, 733))	('CDKN2A', 'Gene', '1029', (580, 586))	('cancers', 'Disease', 'MESH:D009369', (621, 628))	('mammalian', 'Species', '9606', (266, 275))	('TP53', 'Gene', (668, 672))	('cancer', 'Disease', (910, 916))	('cancer', 'Disease', 'MESH:D009369', (621, 627))	('APC', 'Disease', 'MESH:D011125', (575, 578))	('APC', 'Disease', (575, 578))	('PIK3CA', 'Gene', (555, 561))	('TP53', 'Gene', (120, 124))	('ATM', 'Gene', (592, 595))	('cancer', 'Disease', (369, 375))	('cancer', 'Phenotype', 'HP:0002664', (910, 916))	('cancer', 'Disease', (537, 543))	('carcinoma', 'Phenotype', 'HP:0030731', (201, 210))	('patients', 'Species', '9606', (177, 185))	('patient', 'Species', '9606', (177, 184))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (191, 211))	('cancer', 'Phenotype', 'HP:0002664', (369, 375))	('cancer', 'Phenotype', 'HP:0002664', (537, 543))	('tumors', 'Disease', 'MESH:D009369', (742, 748))	('mutation', 'Var', (760, 768))	('breast cancer', 'Phenotype', 'HP:0003002', (72, 85))	('PTEN', 'Gene', (563, 567))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (191, 210))
516615	28469388	Among these findings, the fourth is of special significance as it suggested the potential existence of epistatic interaction effects among the mutations in different cancer driver genes on clinical outcomes.	('cancer', 'Disease', (166, 172))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('mutations', 'Var', (143, 152))
516618	28469388	Loss or disruption of p53 function due to a mutation can lead to uncontrolled cell proliferation and cancer.	('uncontrolled cell proliferation', 'CPA', (65, 96))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('mutation', 'Var', (44, 52))	('disruption', 'NegReg', (8, 18))	('function', 'MPA', (26, 34))	('cancer', 'Disease', (101, 107))	('p53', 'Gene', (22, 25))	('lead to', 'Reg', (57, 64))	('Loss', 'NegReg', (0, 4))	('p53', 'Gene', '7157', (22, 25))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))
516619	28469388	Some p53 mutants gain new functions, exhibit oncogenic properties, and exert a dominant negative effect by preventing wild-type (WT) p53 from binding to the promoter of its target genes.	('negative', 'NegReg', (88, 96))	('preventing', 'NegReg', (107, 117))	('oncogenic', 'CPA', (45, 54))	('p53', 'Gene', '7157', (133, 136))	('mutants', 'Var', (9, 16))	('p53', 'Gene', (5, 8))	('binding', 'Interaction', (142, 149))	('p53', 'Gene', '7157', (5, 8))	('functions', 'MPA', (26, 35))	('p53', 'Gene', (133, 136))	('gain', 'PosReg', (17, 21))
516620	28469388	Aberrations in TP53 could cause a burst of somatic mutations in tumor cells, disrupting the age-related accumulation patterns.	('disrupting', 'NegReg', (77, 87))	('cause', 'Reg', (26, 31))	('tumor', 'Disease', (64, 69))	('somatic mutations', 'MPA', (43, 60))	('age-related accumulation patterns', 'MPA', (92, 125))	('TP53', 'Gene', '7157', (15, 19))	('TP53', 'Gene', (15, 19))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('Aberrations', 'Var', (0, 11))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
516622	28469388	Most somatic TP53 mutations are single-base substitutions distributed throughout exons 5 to 8.	('TP53', 'Gene', '7157', (13, 17))	('TP53', 'Gene', (13, 17))	('mutations', 'Var', (18, 27))
516623	28469388	Notably, about 20% of these mutations alter 1 of 3 codons (175, 248, or 273) of the 393 amino acids in p53 protein.	('p53', 'Gene', '7157', (103, 106))	('p53', 'Gene', (103, 106))	('protein', 'Protein', (107, 114))	('alter', 'Reg', (38, 43))	('mutations', 'Var', (28, 37))
516625	28469388	Numerous retrospective studies have associated its mutation and abnormal p53 protein expression with poor patient survival.	('p53', 'Gene', (73, 76))	('p53', 'Gene', '7157', (73, 76))	('patient', 'Species', '9606', (106, 113))	('mutation', 'Var', (51, 59))
516629	28469388	Beyond the genotypes, more prognostic value of mutations in TP53 may be hidden in their tumor-specific characteristics as well as the interaction with other genomic aberrations.	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('mutations', 'Var', (47, 56))	('TP53', 'Gene', '7157', (60, 64))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor', 'Disease', (88, 93))	('TP53', 'Gene', (60, 64))
516630	28469388	Skaug et al and Huang et al showed that for patients with non-small cell lung cancer (NSCLC), mutations in exon 8 of the TP53 gene were more fatal than those in exons 5 and 7.	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (58, 84))	('patients', 'Species', '9606', (44, 52))	('NSCLC', 'Disease', (86, 91))	('mutations in exon 8', 'Var', (94, 113))	('TP53', 'Gene', '7157', (121, 125))	('TP53', 'Gene', (121, 125))	('NSCLC', 'Disease', 'MESH:D002289', (86, 91))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (58, 84))	('lung cancer', 'Phenotype', 'HP:0100526', (73, 84))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('non-small cell lung cancer', 'Disease', (58, 84))	('NSCLC', 'Phenotype', 'HP:0030358', (86, 91))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (62, 84))
516631	28469388	Molina-Vila et al found that nondisruptive p53 mutations, including in-frame deletions outside of the L2 and L3 loop domains and missense single-base substitutions, were associated with shorter survival in patients with NSCLC.	('deletions', 'Var', (77, 86))	('NSCLC', 'Disease', (220, 225))	('missense single-base substitutions', 'Var', (129, 163))	('survival', 'MPA', (194, 202))	('mutations', 'Var', (47, 56))	('NSCLC', 'Disease', 'MESH:D002289', (220, 225))	('patients', 'Species', '9606', (206, 214))	('shorter', 'NegReg', (186, 193))	('NSCLC', 'Phenotype', 'HP:0030358', (220, 225))	('p53', 'Gene', (43, 46))	('p53', 'Gene', '7157', (43, 46))
516632	28469388	Contrary to this finding in NSCLC, several studies on head and neck squamous cell carcinomas (HNSCs) showed that tumors containing mutations in the DNA-binding regions (L2, L3, and loop-sheet-helix domains) of TP53 led to a significantly worse prognosis and response to radiotherapy than tumors outside those regions.	('tumors', 'Disease', (113, 119))	('carcinomas', 'Phenotype', 'HP:0030731', (82, 92))	('tumors', 'Disease', 'MESH:D009369', (288, 294))	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('TP53', 'Gene', (210, 214))	('response to radiotherapy', 'CPA', (258, 282))	('NSCLC', 'Disease', 'MESH:D002289', (28, 33))	('HNSCs', 'Phenotype', 'HP:0012288', (94, 99))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (68, 92))	('NSCLC', 'Disease', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (288, 293))	('head and neck squamous cell carcinomas', 'Phenotype', 'HP:0012288', (54, 92))	('NSCLC', 'Phenotype', 'HP:0030358', (28, 33))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (68, 91))	('TP53', 'Gene', '7157', (210, 214))	('tumors', 'Phenotype', 'HP:0002664', (288, 294))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))	('mutations', 'Var', (131, 140))	('neck squamous cell carcinomas', 'Disease', (63, 92))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('neck squamous cell carcinomas', 'Disease', 'MESH:D000077195', (63, 92))	('worse', 'NegReg', (238, 243))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('tumors', 'Disease', (288, 294))
516633	28469388	A recent publication reported that the combination of TP53 mutation and loss of chromosome 3p associated with a remarkable decrease in short-period survival rates for patients with HNSC.	('HNSC', 'Disease', (181, 185))	('loss', 'NegReg', (72, 76))	('decrease', 'NegReg', (123, 131))	('short-period survival rates', 'CPA', (135, 162))	('patients', 'Species', '9606', (167, 175))	('TP53', 'Gene', '7157', (54, 58))	('mutation', 'Var', (59, 67))	('TP53', 'Gene', (54, 58))
516635	28469388	Our analysis was primarily focused on several less investigated features of the mutation spectra, such as the evolutionary selection of mutant alleles in TP53 during mammalian evolution, with an extension to the pan-cancer patterns of exclusivity and co-occurrence relationships between TP53 mutations and the alterations in other cancer driver genes.	('mutations', 'Var', (292, 301))	('cancer', 'Disease', (331, 337))	('TP53', 'Gene', (154, 158))	('cancer', 'Disease', 'MESH:D009369', (331, 337))	('mammalian', 'Species', '9606', (166, 175))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('TP53', 'Gene', '7157', (287, 291))	('cancer', 'Disease', (216, 222))	('cancer', 'Disease', 'MESH:D009369', (216, 222))	('cancer', 'Phenotype', 'HP:0002664', (331, 337))	('mutant', 'Var', (136, 142))	('TP53', 'Gene', '7157', (154, 158))	('TP53', 'Gene', (287, 291))
516642	28469388	The mutational association (or relationship) between TP53 and another gene was measured by the Yule phi coefficient (a Pearson correlation applied to dichotomous data) between the numbered genotypes (1 and 0 were assigned to mutant and WT, respectively).	('mutant', 'Var', (225, 231))	('TP53', 'Gene', '7157', (53, 57))	('TP53', 'Gene', (53, 57))
516644	28469388	Among the 33 cancer types with clinically annotated multiomic data available at TCGA database by April 24, 2015, 12 were studied in this work by considering the genetic diversity of patients and the prevalence of somatic TP53 mutations in these tumors.	('tumors', 'Phenotype', 'HP:0002664', (245, 251))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('TP53', 'Gene', '7157', (221, 225))	('tumors', 'Disease', 'MESH:D009369', (245, 251))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('cancer', 'Disease', (13, 19))	('cancer', 'Disease', 'MESH:D009369', (13, 19))	('TP53', 'Gene', (221, 225))	('patients', 'Species', '9606', (182, 190))	('mutations', 'Var', (226, 235))	('tumors', 'Disease', (245, 251))
516645	28469388	Each of the selected cancer types had at least 14 patients from a minority population (ie, black American or Asian) besides the dominant white Americans, and the ratio of samples with TP53 nonsynonymous mutations was more than 25% (Table 1).	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('patients', 'Species', '9606', (50, 58))	('nonsynonymous mutations', 'Var', (189, 212))	('TP53', 'Gene', '7157', (184, 188))	('TP53', 'Gene', (184, 188))	('cancer', 'Disease', (21, 27))	('cancer', 'Disease', 'MESH:D009369', (21, 27))
516649	28469388	In the modeling, TP53 (p53) status (ie, WT versus mutant) was treated as the stratification factor of primary interest and the patient age at the initial clinical date was included as a covariate.	('patient', 'Species', '9606', (127, 134))	('p53', 'Gene', (23, 26))	('mutant', 'Var', (50, 56))	('p53', 'Gene', '7157', (23, 26))	('TP53', 'Gene', '7157', (17, 21))	('TP53', 'Gene', (17, 21))
516650	28469388	The results demonstrated association between TP53 mutation and overall poor patient survival in 4 cancer types, namely, HNSC, LUAD, BRCA, and COAD (Supplementary Figure 1).	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('COAD', 'Disease', 'MESH:D029424', (142, 146))	('LUAD', 'Phenotype', 'HP:0030078', (126, 130))	('TP53', 'Gene', (45, 49))	('LUAD', 'Disease', (126, 130))	('TP53', 'Gene', '7157', (45, 49))	('BRCA', 'Gene', '672', (132, 136))	('poor', 'NegReg', (71, 75))	('BRCA', 'Phenotype', 'HP:0003002', (132, 136))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('BRCA', 'Gene', (132, 136))	('COAD', 'Disease', (142, 146))	('cancer', 'Disease', (98, 104))	('association', 'Reg', (25, 36))	('patient', 'Species', '9606', (76, 83))	('HNSC', 'Disease', (120, 124))	('mutation', 'Var', (50, 58))
516652	28469388	We depicted the physical distributions of TP53 mutations over the coding regions in Supplementary Figure 2.	('TP53', 'Gene', '7157', (42, 46))	('TP53', 'Gene', (42, 46))	('mutations', 'Var', (47, 56))
516654	28469388	Occasionally, mutations also occurred in exons 2, 3, and 9 in these cancer types.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('occurred', 'Reg', (29, 37))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('cancer', 'Disease', (68, 74))	('mutations', 'Var', (14, 23))
516656	28469388	Powell et al found that mutations within exon 4 were particularly associated with poor prognosis in breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('associated', 'Reg', (66, 76))	('breast cancer', 'Disease', 'MESH:D001943', (100, 113))	('breast cancer', 'Phenotype', 'HP:0003002', (100, 113))	('breast cancer', 'Disease', (100, 113))	('mutations', 'Var', (24, 33))
516658	28469388	The result showed that for patients with BRCA and LUAD, the mutations in exons 2 to 4 were more lethal than those in other exons (Figure 1).	('BRCA', 'Gene', (41, 45))	('lethal', 'Reg', (96, 102))	('LUAD', 'Disease', (50, 54))	('patients', 'Species', '9606', (27, 35))	('LUAD', 'Phenotype', 'HP:0030078', (50, 54))	('mutations', 'Var', (60, 69))	('BRCA', 'Phenotype', 'HP:0003002', (41, 45))	('BRCA', 'Gene', '672', (41, 45))
516659	28469388	In BRCA, the P values were less than 2 x 10-5 (Benjamini-Hochberg FDR <2 x 10-4) in the comparison of E2-4 vs WT and larger than 0.05 in the comparison of E5-9 vs WT.	('BRCA', 'Gene', '672', (3, 7))	('BRCA', 'Gene', (3, 7))	('E2-4', 'Var', (102, 106))	('E5-9', 'Gene', '22899', (155, 159))	('E5-9', 'Gene', (155, 159))	('BRCA', 'Phenotype', 'HP:0003002', (3, 7))
516663	28469388	Therefore, the TP53 mutations observed in human tumors could be subject to the natural selection mechanisms during mammalian evolution.	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('mammalian', 'Species', '9606', (115, 124))	('human', 'Species', '9606', (42, 47))	('tumors', 'Disease', (48, 54))	('tumors', 'Disease', 'MESH:D009369', (48, 54))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('TP53', 'Gene', '7157', (15, 19))	('TP53', 'Gene', (15, 19))	('mutations', 'Var', (20, 29))
516665	28469388	We found that cancer-related TP53 variants tended to be negatively selected in the evolution of mammals.	('cancer', 'Disease', (14, 20))	('variants', 'Var', (34, 42))	('negatively', 'NegReg', (56, 66))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('TP53', 'Gene', '7157', (29, 33))	('TP53', 'Gene', (29, 33))	('cancer', 'Disease', 'MESH:D009369', (14, 20))
516667	28469388	Second, of the DNA bases in which the somatic mutations arose, those with PhyloP scores more than 1.301 accounted for a large proportion consistently across the 12 cancer types.	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('cancer', 'Disease', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('mutations', 'Var', (46, 55))
516668	28469388	The ratio was ~40% higher than that of the entire base set of exons 4 to 9, in which more than 99% of the somatic mutations in tumors were located.	('to 9', 'Species', '1214577', (70, 74))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('tumors', 'Disease', (127, 133))	('mutations', 'Var', (114, 123))	('tumors', 'Disease', 'MESH:D009369', (127, 133))
516669	28469388	We were particularly interested in the potential prognostic implications of the evolutionary conservation of somatic TP53 mutants.	('TP53', 'Gene', '7157', (117, 121))	('mutants', 'Var', (122, 129))	('TP53', 'Gene', (117, 121))
516670	28469388	As such, based on the presence or absence of a negatively selected TP53 variant in mammalian evolution, we partitioned the TP53-mutated samples of each cancer type into 2 groups (Con and nCon) and then performed survival analysis with this classification as the stratification factor of primary interest.	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('TP53', 'Gene', '7157', (67, 71))	('TP53', 'Gene', '7157', (123, 127))	('TP53', 'Gene', (67, 71))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('variant', 'Var', (72, 79))	('mammalian', 'Species', '9606', (83, 92))	('TP53', 'Gene', (123, 127))
516678	28469388	We found that there existed a "conserved" pattern (Figure 5) in the mutual-exclusivity and co-occurrence relationships between TP53 mutations and the alterations of these genes.	('TP53', 'Gene', '7157', (127, 131))	('TP53', 'Gene', (127, 131))	('mutations', 'Var', (132, 141))
516679	28469388	That is, the mutational associations for a specific gene pair were always in the same category, co-occurrence or mutual-exclusivity, across the cancer types.	('cancer', 'Disease', (144, 150))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('mutational', 'Var', (13, 23))
516681	28469388	We further noted that these significant relationships were primarily present in several cancers where patient outcome was associated with TP53 status and/or the positional and evolutionary characteristics of the mutations, as shown in Supplementary Figure 1, Figure 1, and Figure 2.	('associated', 'Reg', (122, 132))	('TP53', 'Gene', '7157', (138, 142))	('patient', 'Species', '9606', (102, 109))	('cancers', 'Disease', 'MESH:D009369', (88, 95))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('TP53', 'Gene', (138, 142))	('cancers', 'Disease', (88, 95))	('mutations', 'Var', (212, 221))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))
516683	28469388	It is well known that most cancers, including those with mutated TP53, are driven by multiple genetic mutations.	('driven by', 'Reg', (75, 84))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('TP53', 'Gene', '7157', (65, 69))	('TP53', 'Gene', (65, 69))	('cancers', 'Phenotype', 'HP:0002664', (27, 34))	('cancers', 'Disease', 'MESH:D009369', (27, 34))	('mutated', 'Var', (57, 64))	('cancers', 'Disease', (27, 34))
516684	28469388	Therefore, a general TP53-involved co-occurrence mutation pattern (or model) can be expressed by [Mp53, Mother], where Mp53 is the genotype (ie, mutant and WT) of TP53 gene in a tumor and Mother is the number of mutations on other cancer driver genes.	('TP53', 'Gene', (21, 25))	('tumor', 'Disease', (178, 183))	('cancer', 'Disease', 'MESH:D009369', (231, 237))	('p53', 'Gene', '7157', (120, 123))	('mutant', 'Var', (145, 151))	('TP53', 'Gene', '7157', (163, 167))	('cancer', 'Disease', (231, 237))	('TP53', 'Gene', (163, 167))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('p53', 'Gene', '7157', (99, 102))	('p53', 'Gene', (99, 102))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('p53', 'Gene', (120, 123))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('TP53', 'Gene', '7157', (21, 25))
516687	28469388	Notably, this finding indicates that TP53 mutation is also related to the prognosis of OV tumors, whereas the relevance cannot be detected by directly analyzing the association between TP53 genotypes (and other mutational features) and the survival times of patients.	('TP53', 'Gene', (185, 189))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('TP53', 'Gene', '7157', (37, 41))	('OV', 'Phenotype', 'HP:0012887', (87, 89))	('OV tumors', 'Disease', 'MESH:D009369', (87, 96))	('mutation', 'Var', (42, 50))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('patients', 'Species', '9606', (258, 266))	('related', 'Reg', (59, 66))	('TP53', 'Gene', (37, 41))	('OV tumors', 'Disease', (87, 96))	('TP53', 'Gene', '7157', (185, 189))
516689	28469388	In this study, we found that the mutations in exons 2 to 4 of TP53 gene defined a poor prognosis group in BRCA and LUAD.	('BRCA', 'Gene', (106, 110))	('TP53', 'Gene', '7157', (62, 66))	('TP53', 'Gene', (62, 66))	('mutations in', 'Var', (33, 45))	('LUAD', 'Phenotype', 'HP:0030078', (115, 119))	('LUAD', 'Disease', (115, 119))	('BRCA', 'Phenotype', 'HP:0003002', (106, 110))	('BRCA', 'Gene', '672', (106, 110))
516691	28469388	Meanwhile, we noticed that prevalence of mutations in these exon regions was an important characteristic of several cancers, including HNSC, LUAD, LUSC, BRCA, and STAD, where drinking and smoking are 2 common risk factors.	('mutations', 'Var', (41, 50))	('LUAD', 'Phenotype', 'HP:0030078', (141, 145))	('BRCA', 'Phenotype', 'HP:0003002', (153, 157))	('LUSC', 'Phenotype', 'HP:0030359', (147, 151))	('LUAD', 'Disease', (141, 145))	('STAD', 'Disease', (163, 167))	('HNSC', 'Disease', (135, 139))	('BRCA', 'Gene', '672', (153, 157))	('cancers', 'Disease', 'MESH:D009369', (116, 123))	('cancers', 'Phenotype', 'HP:0002664', (116, 123))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cancers', 'Disease', (116, 123))	('BRCA', 'Gene', (153, 157))	('LUSC', 'Disease', (147, 151))
516692	28469388	Due to this finding, an interesting question worth further study is whether alcohol and/or tobacco is a specific mutagen responsible for the alterations in exons 2 to 4 of TP53 gene.	('alcohol', 'Chemical', 'MESH:D000438', (76, 83))	('tobacco', 'Species', '4097', (91, 98))	('alterations', 'Var', (141, 152))	('TP53', 'Gene', '7157', (172, 176))	('TP53', 'Gene', (172, 176))
516693	28469388	Our analysis shows that TP53 variants tend to be negatively selected in the evolution of mammals.	('TP53', 'Gene', (24, 28))	('negatively', 'NegReg', (49, 59))	('variants', 'Var', (29, 37))	('TP53', 'Gene', '7157', (24, 28))
516694	28469388	While being consistent with the existing knowledge that recurrent mutations in tumors can be differentiated from single mutations by the evolutionary conservation-based functional impact score, this observation cannot be sufficiently explained by the survival disadvantage that is exerted on the carrier of the mutations (in a specific species) by the increased risk of cancer.	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('cancer', 'Disease', 'MESH:D009369', (370, 376))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('tumors', 'Disease', (79, 85))	('cancer', 'Disease', (370, 376))	('mutations', 'Var', (311, 320))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('cancer', 'Phenotype', 'HP:0002664', (370, 376))
516696	28469388	As a result, the survival disadvantage of the individuals with a germline mutation burden in TP53 gene is not equivalent to a lower fitness in evolution.	('TP53', 'Gene', '7157', (93, 97))	('TP53', 'Gene', (93, 97))	('germline mutation burden', 'Var', (65, 89))
516697	28469388	In this regard, the negative selection of TP53 mutants may involve reproduction-related mechanisms that could be interrupted by the loss or disruption of p53 function in DNA repair.	('TP53', 'Gene', '7157', (42, 46))	('negative', 'NegReg', (20, 28))	('TP53', 'Gene', (42, 46))	('p53', 'Gene', (154, 157))	('p53', 'Gene', '7157', (154, 157))	('mutants', 'Var', (47, 54))
516698	28469388	This hypothesis is supported by the varied clinical implications of a TP53 mutation occurred in evolutionarily conserved DNA bases for different cancers (Figure 3).	('cancers', 'Disease', (145, 152))	('cancers', 'Phenotype', 'HP:0002664', (145, 152))	('TP53', 'Gene', '7157', (70, 74))	('mutation', 'Var', (75, 83))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('TP53', 'Gene', (70, 74))	('cancers', 'Disease', 'MESH:D009369', (145, 152))
516699	28469388	In particular, the favorable prognosis of the BLCA patients with mutations in conserved sites of TP53 sequence suggests that the lower evolutionary fitness of TP53 mutants cannot be simply attributed to the cancer-caused death.	('cancer', 'Disease', 'MESH:D009369', (207, 213))	('TP53', 'Gene', '7157', (97, 101))	('cancer', 'Disease', (207, 213))	('TP53', 'Gene', '7157', (159, 163))	('TP53', 'Gene', (97, 101))	('TP53', 'Gene', (159, 163))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('patients', 'Species', '9606', (51, 59))	('death', 'Disease', 'MESH:D003643', (221, 226))	('evolutionary fitness', 'CPA', (135, 155))	('mutants', 'Var', (164, 171))	('mutations in', 'Var', (65, 77))	('death', 'Disease', (221, 226))
516700	28469388	Mutual exclusivity and co-occurrence of genomic alterations have been heavily studied in the past years.. A proposed naive rule is that mutations in genes functioning in different pathways can occur in the same cancer, whereas those in genes functioning in the same pathway are rarely mutated in the same sample.	('cancer', 'Disease', 'MESH:D009369', (211, 217))	('cancer', 'Disease', (211, 217))	('mutations', 'Var', (136, 145))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('occur', 'Reg', (193, 198))
516701	28469388	Our work showed that the rule was systematically violated when the analysis was focused on the specific relationships between TP53 mutations and genetic alterations occurred in several other major cancer driver genes (ie, PIK3CA, PTEN, KRAS, APC, CDKN2A, and ATM).	('PIK3CA', 'Gene', (222, 228))	('mutations', 'Var', (131, 140))	('PTEN', 'Gene', '5728', (230, 234))	('cancer', 'Disease', 'MESH:D009369', (197, 203))	('TP53', 'Gene', (126, 130))	('PIK3CA', 'Gene', '5290', (222, 228))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('ATM', 'Gene', (259, 262))	('cancer', 'Disease', (197, 203))	('CDKN2A', 'Gene', (247, 253))	('ATM', 'Gene', '472', (259, 262))	('KRAS', 'Gene', (236, 240))	('CDKN2A', 'Gene', '1029', (247, 253))	('APC', 'Disease', 'MESH:D011125', (242, 245))	('KRAS', 'Gene', '3845', (236, 240))	('TP53', 'Gene', '7157', (126, 130))	('PTEN', 'Gene', (230, 234))	('APC', 'Disease', (242, 245))
516705	28469388	Another example, PIK3CA gene plays roles in the PI3K/ART pathway, which regulates cell proliferation and apoptosis in a different manner from the p53 pathway, but, our results showed that the alterations in PIK3CA and TP53 tended to occur in a mutually exclusive way within 4 cancers (ie, BRCA, STAT, COAD, and HNSC).	('BRCA', 'Phenotype', 'HP:0003002', (289, 293))	('occur', 'Reg', (233, 238))	('cancers', 'Disease', 'MESH:D009369', (276, 283))	('p53', 'Gene', (146, 149))	('man', 'Species', '9606', (130, 133))	('PIK3CA', 'Gene', '5290', (17, 23))	('COAD', 'Disease', 'MESH:D029424', (301, 305))	('STAT', 'Disease', (295, 299))	('PIK3CA', 'Gene', '5290', (207, 213))	('BRCA', 'Gene', '672', (289, 293))	('TP53', 'Gene', (218, 222))	('alterations', 'Var', (192, 203))	('COAD', 'Disease', (301, 305))	('cancers', 'Phenotype', 'HP:0002664', (276, 283))	('PIK3CA', 'Gene', (17, 23))	('BRCA', 'Gene', (289, 293))	('cancers', 'Disease', (276, 283))	('cancer', 'Phenotype', 'HP:0002664', (276, 282))	('PIK3CA', 'Gene', (207, 213))	('p53', 'Gene', '7157', (146, 149))	('TP53', 'Gene', '7157', (218, 222))
516707	28469388	Underlying this prognostic stratification are the intrinsic subtypes (within the same cancer) that are approximately determined by the mutations in TP53 and the other driver genes such as PIK3CA.	('PIK3CA', 'Gene', (188, 194))	('TP53', 'Gene', '7157', (148, 152))	('TP53', 'Gene', (148, 152))	('mutations', 'Var', (135, 144))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('PIK3CA', 'Gene', '5290', (188, 194))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('cancer', 'Disease', (86, 92))
516708	28469388	In most cancer types, an average tumor sample contains at least half of hundreds of nonsynonymous somatic alterations, including a few cancer driver mutations that are fixed by conferring the recipient cells' fitness advantage and numerous passenger mutations that are fixed by the Muller ratchet and hitchhiking.	('cancer', 'Disease', (135, 141))	('cancer', 'Disease', (8, 14))	('mutations', 'Var', (149, 158))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('cancer', 'Disease', 'MESH:D009369', (135, 141))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('tumor', 'Disease', (33, 38))	('fitness advantage', 'CPA', (209, 226))	('cancer', 'Disease', 'MESH:D009369', (8, 14))
516709	28469388	However, a recently emerging theory proposes that some passenger mutations could be deleterious to the host cells and their accumulation may build strength to alter cancer progression.	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('accumulation', 'PosReg', (124, 136))	('cancer', 'Disease', (165, 171))	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('alter', 'Reg', (159, 164))	('mutations', 'Var', (65, 74))
516710	28469388	Our previous analyses of TCGA data suggested that some passenger mutations would exert significant impacts on the resistance of cancer cells to the treatments in ovarian carcinomas.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('carcinoma', 'Phenotype', 'HP:0030731', (170, 179))	('impacts', 'Reg', (99, 106))	('ovarian carcinomas', 'Disease', (162, 180))	('ovarian carcinomas', 'Disease', 'MESH:D010051', (162, 180))	('resistance', 'CPA', (114, 124))	('ovarian carcinomas', 'Phenotype', 'HP:0025318', (162, 180))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('carcinomas', 'Phenotype', 'HP:0030731', (170, 180))	('mutations', 'Var', (65, 74))	('cancer', 'Disease', (128, 134))
516712	28469388	Significant interactive effects of cancer driver mutations and passenger mutations on the clinical outcome of patients was implied by another recent publication, which showed that high mutation number forecasted a remarkably favorable outcome in ovarian patients carrying mutations in BRCA1 and BRCA2 genes.	('mutations', 'Var', (272, 281))	('BRCA2', 'Gene', '675', (295, 300))	('BRCA1', 'Gene', '672', (285, 290))	('patients', 'Species', '9606', (110, 118))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('BRCA1', 'Gene', (285, 290))	('ovarian', 'Disease', (246, 253))	('BRCA2', 'Gene', (295, 300))	('ovarian', 'Disease', 'MESH:D010051', (246, 253))	('BRCA', 'Phenotype', 'HP:0003002', (295, 299))	('patients', 'Species', '9606', (254, 262))	('cancer', 'Disease', (35, 41))	('BRCA', 'Phenotype', 'HP:0003002', (285, 289))
516715	28469388	Second, for the first time (to our knowledge), it suggested the potential existence of epistatic effects between the mutations in different cancer driver genes on clinical outcomes.	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('mutations', 'Var', (117, 126))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))
516717	28469388	In summary, through an integrative analysis of the genomic and clinical data of 12 cancers generated by TCGA, we pinpointed a set of significant prognostic features and patterns of somatic TP53 mutations.	('cancers', 'Disease', 'MESH:D009369', (83, 90))	('TP53', 'Gene', '7157', (189, 193))	('cancers', 'Phenotype', 'HP:0002664', (83, 90))	('TP53', 'Gene', (189, 193))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('mutations', 'Var', (194, 203))	('TCGA', 'Gene', (104, 108))	('cancers', 'Disease', (83, 90))
516727	28118260	The optimal threshold percentage was determined from MTV20%~MTV60%, and was correlated with SUVmax.	('MTV20', 'Chemical', '-', (53, 58))	('MTV60', 'Chemical', '-', (60, 65))	('~MTV60%', 'Var', (59, 66))	('MTV20%', 'Var', (53, 59))
516771	28118260	The optimal threshold percentage was determined from MTV20%~MTV60%, defined by the smallest percentage difference between segmentations results and the GTV.	('MTV20', 'Chemical', '-', (53, 58))	('MTV60', 'Chemical', '-', (60, 65))	('~MTV60%', 'Var', (59, 66))	('MTV20%~MTV60%', 'Var', (53, 66))	('GTV', 'Chemical', '-', (152, 155))
516776	28118260	MTV20%, MTV30%, MTV40%, MTV50%, MTV60% and MTViterative adaptive were 23.01+-16.99, 14.86+-11.38, 10.21+-8.76, 7.12+-7.06, 4.86+-5.26, and 12.56+-10.60 cm3, respectively, and GTV was 12.35+-10.10 cm3.	('MTV60%', 'Var', (32, 38))	('MTV20%', 'Var', (0, 6))	('MTV', 'Chemical', '-', (24, 27))	('MTV20', 'Chemical', '-', (0, 5))	('MTV50', 'Chemical', '-', (24, 29))	('MTV', 'Chemical', '-', (8, 11))	('MTV30%', 'Var', (8, 14))	('GTV', 'Chemical', '-', (175, 178))	('MTV', 'Chemical', '-', (32, 35))	('MTV50%', 'Var', (24, 30))	('MTV', 'Chemical', '-', (16, 19))	('MTV60', 'Chemical', '-', (32, 37))	('MTV', 'Chemical', '-', (43, 46))	('MTV40%', 'Var', (16, 22))	('MTV', 'Chemical', '-', (0, 3))
516791	28118260	The results showed that the patients with MTV larger than 20 cm3 had a significantly reduced disease-free survival compared with those with MTV less than 20 cm3 (P=0.029), and the MTVs were significantly different among the groups according to the status of lymph node metastasis, parametrial invasion, tumor differentiation, and International Federation of Gynecology and Obstetrics stage (P<0.05).	('MTV', 'Chemical', '-', (140, 143))	('tumor', 'Disease', 'MESH:D009369', (303, 308))	('MTV', 'Chemical', '-', (42, 45))	('MTV larger than 20 cm3', 'Var', (42, 64))	('tumor', 'Phenotype', 'HP:0002664', (303, 308))	('tumor', 'Disease', (303, 308))	('MTV', 'Chemical', '-', (180, 183))	('different', 'Reg', (204, 213))	('disease-free survival', 'CPA', (93, 114))	('reduced', 'NegReg', (85, 92))	('parametrial invasion', 'CPA', (281, 301))	('patients', 'Species', '9606', (28, 36))
516796	28118260	evaluated the percentage SUVmax for non-small-cell lung cancer target volume delineation using pathologic GTV as the gold standard, they found that the optimal thresholds ranged from 20 to 42% (31+-11%) SUVmax, and there was no certain optimal threshold.	('lung cancer', 'Disease', 'MESH:D008175', (51, 62))	('non-small-cell', 'Disease', (36, 50))	('SUVmax', 'Var', (203, 209))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('GTV', 'Chemical', '-', (106, 109))	('lung cancer', 'Disease', (51, 62))	('lung cancer', 'Phenotype', 'HP:0100526', (51, 62))
516867	32448831	Furthermore, we assumed that, due to this transformation of squamous metaplasia, our patient had an increased number of tumour markers, such as the squamous cell carcinoma marker SCC antigen and other adenocarcinoma markers, including carcinoembryonic antigen (CEA), CA19-9, and CA15-5.	('adenocarcinoma', 'Disease', 'MESH:D000230', (201, 215))	('squamous metaplasia', 'Disease', 'MESH:D008679', (60, 79))	('squamous cell carcinoma', 'Disease', (148, 171))	('CEA', 'Gene', '1048', (261, 264))	('increased', 'PosReg', (100, 109))	('squamous metaplasia', 'Phenotype', 'HP:0002860', (60, 79))	('carcinoembryonic antigen', 'Gene', (235, 259))	('tumour', 'Phenotype', 'HP:0002664', (120, 126))	('patient', 'Species', '9606', (85, 92))	('squamous metaplasia', 'Disease', (60, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (206, 215))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (148, 171))	('tumour', 'Disease', 'MESH:D009369', (120, 126))	('tumour', 'Disease', (120, 126))	('adenocarcinoma', 'Disease', (201, 215))	('CA15-5', 'Var', (279, 285))	('carcinoma', 'Phenotype', 'HP:0030731', (162, 171))	('CEA', 'Gene', (261, 264))	('carcinoembryonic antigen', 'Gene', '1048', (235, 259))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (148, 171))
516877	30758105	We also found ANXA10 promoted the cell growth of ESCC cell lines via the phosphorylation of Akt and Erk1/2 pathways in vitro.	('Erk1/2', 'Gene', '5595;5594', (100, 106))	('ESCC', 'Disease', 'MESH:C562729', (49, 53))	('Akt', 'Gene', '207', (92, 95))	('promoted', 'PosReg', (21, 29))	('Erk1/2', 'Gene', (100, 106))	('cell growth', 'CPA', (34, 45))	('Akt', 'Gene', (92, 95))	('ESCC', 'Disease', (49, 53))	('phosphorylation', 'MPA', (73, 88))	('ANXA10', 'Var', (14, 20))
516883	30758105	The protein CD163 and CD204 have been used as markers of M2 macrophages.10, 11 TAMs induce angiogenesis in the tumor microenvironment, suppress antitumor immunity and directly stimulate tumor cell proliferation.	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumor', 'Disease', (186, 191))	('CD163', 'Gene', '9332', (12, 17))	('macrophages.10', 'Var', (60, 74))	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('CD204', 'Gene', '4481', (22, 27))	('CD204', 'Gene', (22, 27))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('CD163', 'Gene', (12, 17))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('suppress', 'NegReg', (135, 143))	('tumor', 'Disease', (111, 116))	('induce', 'PosReg', (84, 90))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('angiogenesis', 'CPA', (91, 103))	('TAM', 'Gene', (79, 82))	('tumor', 'Disease', (148, 153))	('TAM', 'Gene', '8205', (79, 82))	('stimulate', 'PosReg', (176, 185))	('tumor', 'Disease', 'MESH:D009369', (148, 153))
516898	30758105	The primers were as follows: CYP1A1 (Hs01054797_g1), DHRS3 (Hs00191073_m1), ANXA10 (Hs01105012_m1), KLK6 (Hs00160519_m1), CYP1B1 (Hs02382916_s1), AMTN (Hs00418384_m1), IGFL1 (Hs01651089_g1) and GAPDH (Hs02786624_g1).	('DHRS3', 'Gene', (53, 58))	('IGFL1', 'Gene', '374918', (168, 173))	('Hs01105012_m1', 'Var', (84, 97))	('KLK6', 'Gene', '5653', (100, 104))	('GAPDH', 'Gene', (194, 199))	('AMTN', 'Gene', (146, 150))	('KLK6', 'Gene', (100, 104))	('CYP1A1', 'Gene', (29, 35))	('Hs02382916_s1', 'Var', (130, 143))	('Hs00418384_m1', 'Var', (152, 165))	('AMTN', 'Gene', '401138', (146, 150))	('DHRS3', 'Gene', '9249', (53, 58))	('CYP1B1', 'Gene', '1545', (122, 128))	('Hs01651089_g1', 'Var', (175, 188))	('CYP1B1', 'Gene', (122, 128))	('Hs00191073_m1', 'Var', (60, 73))	('Hs00160519_m1', 'Var', (106, 119))	('CYP1A1', 'Gene', '1543', (29, 35))	('Hs01054797_g1', 'Var', (37, 50))	('GAPDH', 'Gene', '2597', (194, 199))	('Hs02786624_g1', 'Var', (201, 214))	('IGFL1', 'Gene', (168, 173))
516904	30758105	The tissue sections were then incubated with anti-ANXA10 rabbit polyclonal antibody (1:200, NBP190156SS, Novus Biologicals, Littleton, CO, USA), anti-CYB1B1 rabbit polyclonal antibody (1:50, sc-32882, Santa Cruz Biotechnology, Santa Cruz, CA, USA) and anti-KLK6 mouse monoclonal antibody (1:50, sc-374564, Santa Cruz) at 4 C in a moist chamber overnight.	('NBP190156SS', 'Chemical', 'MESH:C000592574', (92, 103))	('rabbit', 'Species', '9986', (57, 63))	('mouse', 'Species', '10090', (262, 267))	('CO', 'Chemical', 'MESH:D002245', (135, 137))	('1:200', 'Var', (85, 90))	('KLK6', 'Gene', '5653', (257, 261))	('KLK6', 'Gene', (257, 261))	('rabbit', 'Species', '9986', (157, 163))	('sc-374564', 'Chemical', 'MESH:D012538', (295, 304))
516921	30758105	We also observed that a high number of infiltrating CD68+ (P = 0.046) or CD204+ (P = 0.006) macrophages was significantly correlated with high expressions of ANXA10 in cancer cells (Table 2).	('CD204', 'Gene', (73, 78))	('CD68', 'Gene', (52, 56))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('CD68', 'Gene', '968', (52, 56))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('ANXA10', 'Gene', (158, 164))	('cancer', 'Disease', (168, 174))	('correlated', 'Reg', (122, 132))	('high', 'Var', (138, 142))	('CD204', 'Gene', '4481', (73, 78))
516922	30758105	The disease-free survival of the patients with a high expression of ANXA10 was significantly shorter compared to that of the patients with low ANXA10 by log-rank test (P = 0.0216) (Fig.	('patients', 'Species', '9606', (33, 41))	('disease-free survival', 'CPA', (4, 25))	('shorter', 'NegReg', (93, 100))	('high', 'Var', (49, 53))	('ANXA10', 'Gene', (68, 74))	('patients', 'Species', '9606', (125, 133))
516923	30758105	The overall survival of the patients and cancer-related survival was not significantly different between the low and high ANXA10 expression groups (Fig.	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('expression', 'MPA', (129, 139))	('ANXA10', 'Protein', (122, 128))	('cancer', 'Disease', (41, 47))	('high', 'Var', (117, 121))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('patients', 'Species', '9606', (28, 36))
516927	30758105	ANXA10 knockdown significantly inhibited the growth of both of these ESCC cell lines (Fig.	('ESCC', 'Disease', 'MESH:C562729', (69, 73))	('growth', 'MPA', (45, 51))	('ESCC', 'Disease', (69, 73))	('inhibited', 'NegReg', (31, 40))	('ANXA10', 'Gene', (0, 6))	('knockdown', 'Var', (7, 16))
516928	30758105	ANXA10 knockdown suppressed the phosphorylation status of p-Akt (Ser473 and Thr308) and p-Erk1/2 (Thr202/Tyr204) and inhibit the growth of the ESCC cell lines (Fig.	('Thr308', 'Var', (76, 82))	('Erk1/2', 'Gene', '5595;5594', (90, 96))	('Akt', 'Gene', '207', (60, 63))	('Ser', 'Chemical', 'MESH:C530429', (65, 68))	('ESCC', 'Disease', (143, 147))	('suppressed', 'NegReg', (17, 27))	('Thr202/Tyr204', 'Var', (98, 111))	('Akt', 'Gene', (60, 63))	('Thr308', 'Chemical', 'MESH:C015596', (76, 82))	('Erk1/2', 'Gene', (90, 96))	('phosphorylation status', 'MPA', (32, 54))	('ANXA10', 'Gene', (0, 6))	('ESCC', 'Disease', 'MESH:C562729', (143, 147))	('growth', 'CPA', (129, 135))	('inhibit', 'NegReg', (117, 124))	('knockdown', 'Var', (7, 16))
516930	30758105	ANXA10 overexpression increased the phosphorylation status of p-Akt (Ser473 and Thr308) and p-Erk1/2 (Thr202/Tyr204) and increased the growth induction of the ESCC cells (Fig.	('Thr308', 'Chemical', 'MESH:C015596', (80, 86))	('increased', 'PosReg', (121, 130))	('ESCC', 'Disease', (159, 163))	('Akt', 'Gene', '207', (64, 67))	('Erk1/2', 'Gene', '5595;5594', (94, 100))	('Ser', 'Chemical', 'MESH:C530429', (69, 72))	('increased', 'PosReg', (22, 31))	('ESCC', 'Disease', 'MESH:C562729', (159, 163))	('Thr202/Tyr204', 'Var', (102, 115))	('Akt', 'Gene', (64, 67))	('phosphorylation status', 'MPA', (36, 58))	('Erk1/2', 'Gene', (94, 100))	('ANXA10', 'Gene', (0, 6))	('growth induction', 'CPA', (135, 151))	('Thr308', 'Var', (80, 86))	('Ser473', 'Var', (69, 75))
516946	30758105	The results showed that ANXA10 knockdown significantly decreased cell growth by inhibiting Akt and Erk1/2 signaling pathways.	('Erk1/2', 'Gene', (99, 105))	('cell growth', 'CPA', (65, 76))	('Akt', 'Gene', '207', (91, 94))	('Erk1/2', 'Gene', '5595;5594', (99, 105))	('Akt', 'Gene', (91, 94))	('decreased', 'NegReg', (55, 64))	('inhibiting', 'NegReg', (80, 90))	('ANXA10', 'Gene', (24, 30))	('knockdown', 'Var', (31, 40))
516948	30758105	Our results are the first to indicate that ANXA10 might play an important role in the growth of ESCCs by activating both the Akt andErk1/2 signaling pathways.	('ANXA10', 'Var', (43, 49))	('Akt', 'Gene', (125, 128))	('ESCCs', 'Disease', 'MESH:C562729', (96, 101))	('Erk1/2', 'Gene', '5595;5594', (132, 138))	('Erk1/2', 'Gene', (132, 138))	('ESCCs', 'Disease', (96, 101))	('activating', 'PosReg', (105, 115))	('Akt', 'Gene', '207', (125, 128))
517037	30626875	Genetic abrogation or induction of Ldh activity in HFSC-mediated tumorigenesis shows no effect on tumorigenesis as measured by number, time to formation, proliferation, volume, epithelial to mesenchymal transition, gene expression, or immune response.	('Genetic abrogation', 'Var', (0, 18))	('epithelial to mesenchymal transition', 'CPA', (177, 213))	('abrogation', 'Var', (8, 18))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('tumor', 'Disease', (65, 70))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('HFSC-mediated', 'Gene', (51, 64))	('tumor', 'Disease', (98, 103))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('Ldh', 'Protein', (35, 38))
517046	30626875	Moreover, inhibition of Ldh activity, which reduces lactate production, has been shown to impair the growth of tumor cells in vitro.	('lactate', 'Chemical', 'MESH:D019344', (52, 59))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('activity', 'MPA', (28, 36))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('reduces lactate production', 'Phenotype', 'HP:0030086', (44, 70))	('impair', 'NegReg', (90, 96))	('tumor', 'Disease', (111, 116))	('inhibition', 'Var', (10, 20))	('reduces', 'NegReg', (44, 51))	('lactate production', 'MPA', (52, 70))	('Ldh', 'Protein', (24, 27))
517049	30626875	One study that used a model of lung carcinoma driven by oncogenic Ras coupled with deletion of Ldha showed a regression of tumors, suggesting a requirement of Ldh activity for maintenance of tumor cells.	('lung carcinoma', 'Disease', (31, 45))	('tumors', 'Disease', (123, 129))	('tumors', 'Disease', 'MESH:D009369', (123, 129))	('tumor', 'Disease', (123, 128))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('Ldha', 'Gene', (95, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (36, 45))	('regression', 'NegReg', (109, 119))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('tumor', 'Disease', (191, 196))	('deletion', 'Var', (83, 91))	('lung carcinoma', 'Disease', 'MESH:D008175', (31, 45))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
517070	30626875	To determine whether induction of lactate production in HFSCs is required for squamous cell carcinoma initiation, we induced tumorigenesis in HFSCs in the context of Ldha deletion.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('squamous cell carcinoma initiation', 'Disease', (78, 112))	('deletion', 'Var', (171, 179))	('squamous cell carcinoma initiation', 'Disease', 'MESH:D002294', (78, 112))	('tumor', 'Disease', (125, 130))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (78, 101))	('lactate', 'Chemical', 'MESH:D019344', (34, 41))	('induced', 'Reg', (117, 124))	('Ldha', 'Gene', (166, 170))
517071	30626875	For this purpose, we coupled conditional deletion of p53 and activation of constitutively active Kras (LSL-KrasG12D) with inducible deletion of floxed-Ldha with either K15CrePR- or Lgr5CreER-mediated recombination, which we previously showed effectively abrogates lactate production in HFSCs.	('LSL-KrasG12D', 'Gene', (103, 115))	('deletion', 'Var', (132, 140))	('Kras', 'Gene', '16653', (97, 101))	('K15', 'Gene', '16665', (168, 171))	('LSL-KrasG12D', 'Gene', '16653', (103, 115))	('Lgr5', 'Gene', (181, 185))	('deletion', 'Var', (41, 49))	('p53', 'Gene', (53, 56))	('K15', 'Gene', (168, 171))	('abrogates', 'NegReg', (254, 263))	('Kras', 'Gene', '16653', (107, 111))	('lactate', 'Chemical', 'MESH:D019344', (264, 271))	('Lgr5', 'Gene', '14160', (181, 185))	('Kras', 'Gene', (107, 111))	('Kras', 'Gene', (97, 101))	('lactate production', 'MPA', (264, 282))
517072	30626875	Contrary to numerous observations linking glycolysis and lactate production to tumorigenesis, KrasG12D-p53fl/fl-mediated SCC tumor formation from HFSCs was not affected by loss of Ldha (Fig.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('Kras', 'Gene', '16653', (94, 98))	('tumor', 'Disease', (79, 84))	('SCC tumor', 'Disease', 'MESH:D009369', (121, 130))	('loss', 'Var', (172, 176))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('lactate', 'Chemical', 'MESH:D019344', (57, 64))	('SCC', 'Phenotype', 'HP:0002860', (121, 124))	('tumor', 'Disease', (125, 130))	('SCC tumor', 'Disease', (121, 130))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('Kras', 'Gene', (94, 98))	('Ldha', 'Gene', (180, 184))
517073	30626875	Quantification of tumorigenesis showed that neither the timing, volume, nor number of tumors formed was affected by loss of Ldha (Fig.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Disease', (18, 23))	('tumor', 'Disease', (86, 91))	('tumors', 'Disease', (86, 92))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('Ldha', 'Gene', (124, 128))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('loss', 'Var', (116, 120))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
517076	30626875	DMBA/TPA tumors were stratified as null or mosaic for Ldha expression.	('Ldha expression', 'Protein', (54, 69))	('mosaic', 'Var', (43, 49))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumors', 'Disease', (9, 15))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('DMBA/TPA', 'Chemical', '-', (0, 8))	('tumors', 'Disease', 'MESH:D009369', (9, 15))
517085	30626875	There were no observed differences in hypoxia levels in tumors due to loss of Ldha (Supplementary Figure 3b).	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('Ldha', 'Gene', (78, 82))	('loss', 'Var', (70, 74))	('tumors', 'Disease', (56, 62))	('hypoxia', 'Disease', 'MESH:D000860', (38, 45))	('tumors', 'Disease', 'MESH:D009369', (56, 62))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('hypoxia', 'Disease', (38, 45))
517111	30626875	To test this hypothesis, we administered DMBA/TPA for several weeks until the first signs of tumorigenesis then deleted Ldha by Cre activation with Mifepristone in transgenic animals.	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Disease', (93, 98))	('Ldha', 'Gene', (120, 124))	('deleted', 'Var', (112, 119))	('Mifepristone', 'Chemical', 'MESH:D015735', (148, 160))	('DMBA/TPA', 'Chemical', '-', (41, 49))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
517113	30626875	Deletion of Ldha in the midst of tumor formation did not affect the timing or degree of tumorigenesis (Fig.	('Ldha', 'Gene', (12, 16))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor', 'Disease', (33, 38))	('tumor', 'Disease', (88, 93))	('Deletion', 'Var', (0, 8))
517116	30626875	For this purpose, we genetically induced lactate production through the deletion of mitochondrial pyruvate carrier (Mpc1), an obligate component of the mitochondrial pyruvate carrier.	('pyruvate', 'Chemical', 'MESH:D019289', (98, 106))	('induced', 'Reg', (33, 40))	('Mpc1', 'Gene', (116, 120))	('lactate', 'Chemical', 'MESH:D019344', (41, 48))	('Mpc1', 'Gene', '55951', (116, 120))	('pyruvate', 'Chemical', 'MESH:D019289', (166, 174))	('deletion', 'Var', (72, 80))	('lactate production', 'MPA', (41, 59))
517117	30626875	We and others previously showed that inhibiting the ability of pyruvate to enter the mitochondria leads to increased Ldh activity, and deleting Mpc1 with K15CrePR or Lgr5CreER-mediated recombination effectively increases lactate production specifically in HFSCs.	('Ldh', 'Protein', (117, 120))	('K15', 'Gene', '16665', (154, 157))	('lactate', 'Chemical', 'MESH:D019344', (221, 228))	('activity', 'MPA', (121, 129))	('increased', 'PosReg', (107, 116))	('Lgr5', 'Gene', '14160', (166, 170))	('pyruvate', 'Chemical', 'MESH:D019289', (63, 71))	('K15', 'Gene', (154, 157))	('Lgr5', 'Gene', (166, 170))	('lactate production', 'MPA', (221, 239))	('Mpc1', 'Gene', (144, 148))	('HFSCs', 'Disease', (256, 261))	('increases', 'PosReg', (211, 220))	('deleting', 'Var', (135, 143))	('Mpc1', 'Gene', '55951', (144, 148))	('inhibiting', 'NegReg', (37, 47))
517119	30626875	Deletion of Mpc1 in these tumors led to a two-fold increase in Ldh activity, (Fig.	('increase', 'PosReg', (51, 59))	('Mpc1', 'Gene', (12, 16))	('Ldh activity', 'MPA', (63, 75))	('Mpc1', 'Gene', '55951', (12, 16))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumors', 'Disease', (26, 32))	('Deletion', 'Var', (0, 8))
517120	30626875	However, as with Ldh deletion, Ldh activation failed to affect the timing or degree of tumorigenesis (Fig.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('tumor', 'Disease', (87, 92))	('deletion', 'Var', (21, 29))
517138	30626875	To determine whether loss of Ldh activity promotes glutamine metabolism, we measured glutaminase activity in tumor lysate.	('loss', 'Var', (21, 25))	('glutamine', 'Chemical', 'MESH:D005973', (51, 60))	('promotes', 'PosReg', (42, 50))	('activity', 'MPA', (33, 41))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('Ldh', 'Gene', (29, 32))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumor', 'Disease', (109, 114))	('glutamine metabolism', 'MPA', (51, 71))
517145	30626875	Based on decades of research showing that nearly all tumors display increased lactate production, our null hypothesis was that deletion of Ldha would block tumor formation from HFSCs.	('Ldha', 'Gene', (139, 143))	('increased lactate production', 'Phenotype', 'HP:0003128', (68, 96))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('lactate', 'Chemical', 'MESH:D019344', (78, 85))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('deletion', 'Var', (127, 135))	('tumor', 'Disease', (156, 161))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('lactate production', 'MPA', (78, 96))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('tumor', 'Disease', (53, 58))	('block', 'NegReg', (150, 155))	('increased', 'PosReg', (68, 77))	('tumors', 'Disease', (53, 59))
517146	30626875	In addition, Ldha deletion in a model of lung tumor formation caused tumors to regress.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('lung tumor', 'Phenotype', 'HP:0100526', (41, 51))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('Ldha', 'Gene', (13, 17))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('tumors', 'Disease', (69, 75))	('lung tumor', 'Disease', (41, 51))	('tumors', 'Disease', 'MESH:D009369', (69, 75))	('lung tumor', 'Disease', 'MESH:D008175', (41, 51))	('deletion', 'Var', (18, 26))
517147	30626875	Despite the fact that this lung model also used KrasG12D and floxed p53, the outcome was different than what was observed here in a model of cutaneous SCC.	('SCC', 'Phenotype', 'HP:0002860', (151, 154))	('SCC', 'Gene', '6317', (151, 154))	('Kras', 'Gene', (48, 52))	('Kras', 'Gene', '16653', (48, 52))	('floxed p53', 'Var', (61, 71))	('SCC', 'Gene', (151, 154))
517148	30626875	The difference could be due to performing the experiments in distinct tissues, but the lung study also used deletion of Ldha in the entire tissue, and deleted Ldha only after tumors were established.	('tumors', 'Disease', (175, 181))	('Ldha', 'Gene', (159, 163))	('tumors', 'Disease', 'MESH:D009369', (175, 181))	('tumors', 'Phenotype', 'HP:0002664', (175, 181))	('deleted', 'Var', (151, 158))	('Ldha', 'Gene', (120, 124))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('deletion', 'Var', (108, 116))
517154	30626875	It is interesting that after deletion of Ldha, cutaneous SCC still formed from HFSCs without compensation by Ldhb.	('deletion', 'Var', (29, 37))	('SCC', 'Phenotype', 'HP:0002860', (57, 60))	('SCC', 'Gene', '6317', (57, 60))	('Ldha', 'Gene', (41, 45))	('Ldhb', 'Gene', (109, 113))	('Ldhb', 'Gene', '16832', (109, 113))	('SCC', 'Gene', (57, 60))
517155	30626875	Furthermore, deletion of Ldha in SCC appeared to strongly abrogate total Ldh activity, demonstrating that Ldha is the dominant isoform in the skin model.	('SCC', 'Gene', '6317', (33, 36))	('deletion', 'Var', (13, 21))	('Ldha', 'Gene', (25, 29))	('SCC', 'Gene', (33, 36))	('Ldh', 'Enzyme', (73, 76))	('abrogate', 'NegReg', (58, 66))	('SCC', 'Phenotype', 'HP:0002860', (33, 36))
517156	30626875	Previous studies have shown LDHA expression predicts worse survival in clear cell renal cell carcinoma, cholangiocarcinoma, and breast cancer.	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('expression', 'Var', (33, 43))	('LDHA', 'Gene', (28, 32))	('clear cell renal cell carcinoma', 'Disease', (71, 102))	('cholangiocarcinoma', 'Disease', (104, 122))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (71, 102))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (104, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('worse', 'NegReg', (53, 58))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (82, 102))	('breast cancer', 'Disease', (128, 141))	('breast cancer', 'Disease', 'MESH:D001943', (128, 141))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (71, 102))	('breast cancer', 'Phenotype', 'HP:0003002', (128, 141))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (104, 122))
517160	30626875	In the current study, we found that deletion of Ldha neither before nor after tumor formation had an effect on the outcome, demonstrating that Ldh activity in cancer cells of origin is not required for tumor initiation or progression in SCC.	('cancer', 'Disease', (159, 165))	('SCC', 'Gene', (237, 240))	('deletion', 'Var', (36, 44))	('tumor', 'Disease', (202, 207))	('tumor initiation', 'Disease', (202, 218))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('SCC', 'Phenotype', 'HP:0002860', (237, 240))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('SCC', 'Gene', '6317', (237, 240))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('tumor', 'Disease', (78, 83))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('Ldha', 'Gene', (48, 52))	('tumor initiation', 'Disease', 'MESH:D009369', (202, 218))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))
517162	30626875	Indeed, if the Warburg nature of SCC is more a reflection of expansion of phenotype of the cell from which it arose (Supplementary Figure 3), this could explain why loss of Ldh activity had no significant effect on tumorigenesis.	('SCC', 'Gene', '6317', (33, 36))	('Ldh', 'Protein', (173, 176))	('tumor', 'Disease', 'MESH:D009369', (215, 220))	('activity', 'MPA', (177, 185))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('SCC', 'Gene', (33, 36))	('SCC', 'Phenotype', 'HP:0002860', (33, 36))	('tumor', 'Disease', (215, 220))	('loss', 'Var', (165, 169))
517173	30626875	It is tempting to speculate that the lactate produced by tumors is meant to act as a signal to alert the entire body to the presence of a metabolic disruption, and therefore loss of lactate production in SCCs would not affect the progression of the tumor in our murine model, but instead how the entire system may respond to tumor formation.	('SCC', 'Gene', (204, 207))	('tumor', 'Disease', (249, 254))	('lactate', 'Chemical', 'MESH:D019344', (182, 189))	('tumor', 'Phenotype', 'HP:0002664', (325, 330))	('tumors', 'Disease', 'MESH:D009369', (57, 63))	('loss', 'Var', (174, 178))	('murine', 'Species', '10090', (262, 268))	('tumor', 'Disease', 'MESH:D009369', (249, 254))	('tumor', 'Disease', (57, 62))	('lactate', 'MPA', (182, 189))	('lactate', 'Chemical', 'MESH:D019344', (37, 44))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (249, 254))	('tumors', 'Phenotype', 'HP:0002664', (57, 63))	('SCC', 'Phenotype', 'HP:0002860', (204, 207))	('tumor', 'Disease', (325, 330))	('tumor', 'Disease', 'MESH:D009369', (325, 330))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumors', 'Disease', (57, 63))	('SCC', 'Gene', '6317', (204, 207))
517175	30626875	However, the data demonstrate instead that while in vivo deletion of Ldha did affect the metabolism of the tumors formed, this did not affect cancer cell proliferation, survival, pathology, immune response etc.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('deletion', 'Var', (57, 65))	('affect', 'Reg', (135, 141))	('tumors', 'Disease', (107, 113))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('affect', 'Reg', (78, 84))	('tumors', 'Disease', 'MESH:D009369', (107, 113))	('Ldha', 'Gene', (69, 73))	('cancer', 'Disease', (142, 148))
517196	30626875	At the first visible sign of tumor formation, K15-CrePR and Lgr5-CreER mice were treated with mifepristone and tamoxifen, respectively to delete Ldha or Mpc1.	('K15', 'Gene', (46, 49))	('Ldha', 'Gene', (145, 149))	('mice', 'Species', '10090', (71, 75))	('Mpc1', 'Gene', (153, 157))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('delete', 'Var', (138, 144))	('Mpc1', 'Gene', '55951', (153, 157))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('Lgr5', 'Gene', '14160', (60, 64))	('mifepristone', 'Chemical', 'MESH:D015735', (94, 106))	('Lgr5', 'Gene', (60, 64))	('tumor', 'Disease', (29, 34))	('K15', 'Gene', '16665', (46, 49))	('tamoxifen', 'Chemical', 'MESH:D013629', (111, 120))
517202	30626875	Antigen retrieval was performed on formalin-fixed paraffin-embedded tumor sections with citrate or Tris-EDTA buffers for 30 min at 95  C with the following antibodies: Ki-67 (Abcam, ab16667, 1:50), p-S6 (Cell Signaling, CST2215, 1:50), Sox9 (Abcam, ab185230, 1:1,000), CD34 (Abcam ab81289, 1:1000), K14 (Covance, PRB-155P, 1:800), Fibronectin (Abcam, ab2413, 1:250), Tenascin C (Abcam ab108930, 1:500).	('Sox9', 'Gene', (236, 240))	('CD34', 'Gene', '12490', (269, 273))	('Tenascin C', 'Gene', (367, 377))	('Tris', 'Chemical', '-', (99, 103))	('Fibronectin', 'Gene', (331, 342))	('tumor', 'Disease', (68, 73))	('K14', 'Gene', (299, 302))	('Abcam', 'Var', (344, 349))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('paraffin', 'Chemical', 'MESH:D010232', (50, 58))	('Fibronectin', 'Gene', '14268', (331, 342))	('Sox9', 'Gene', '20682', (236, 240))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('K14', 'Gene', '16664', (299, 302))	('CD34', 'Gene', (269, 273))	('EDTA', 'Chemical', 'MESH:D004492', (104, 108))	('citrate', 'Chemical', 'MESH:D019343', (88, 95))	('formalin', 'Chemical', 'MESH:D005557', (35, 43))	('Tenascin C', 'Gene', '21923', (367, 377))
517226	30626875	For experiments with labeled isotope tracing ([U-13C6] glucose, [U-13C5] glutamine, and [U-13C3] lactate; Cambridge Isotope Laboratories Inc. CLM-1396-5, CLM-1822-H-0.1, CLM-1579-0.5), the labeled isotope was delivered by intraperitoneal injection (2 g/kg in PBS) 15 min prior to euthanasia.	('[U-13C6] glucose', 'Chemical', '-', (46, 62))	('[U-13C3] lactate', 'Chemical', '-', (88, 104))	('CLM', 'Chemical', '-', (142, 145))	('[U-13C6]', 'Var', (46, 54))	('CLM', 'Chemical', '-', (170, 173))	('CLM', 'Chemical', '-', (154, 157))	('[U-13C5] glutamine', 'Chemical', '-', (64, 82))	('[U-13C3', 'Var', (88, 95))
517252	27807177	An example is crizotinib for the treatment of patients with non-small-cell lung cancer (NSCLC) that carries an anaplastic lymphoma kinase (ALK) rearrangement.	('non-small-cell lung cancer', 'Disease', 'MESH:D002289', (60, 86))	('rearrangement', 'Var', (144, 157))	('patients', 'Species', '9606', (46, 54))	('lung cancer', 'Phenotype', 'HP:0100526', (75, 86))	('ALK', 'Gene', (139, 142))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (60, 86))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (64, 86))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (111, 130))	('anaplastic lymphoma kinase', 'Gene', '238', (111, 137))	('lymphoma', 'Phenotype', 'HP:0002665', (122, 130))	('ALK', 'Gene', '238', (139, 142))	('NSCLC', 'Disease', (88, 93))	('NSCLC', 'Disease', 'MESH:D002289', (88, 93))	('anaplastic lymphoma kinase', 'Gene', (111, 137))	('crizotinib', 'Chemical', 'MESH:D000077547', (14, 24))	('non-small-cell lung cancer', 'Disease', (60, 86))
517254	27807177	Moreover, when patients present with multiple actionable mutations, which is not uncommon for many cancers, it becomes difficult to select the "optimal" treatment regime that would yield the best clinical outcome for a particular patient, (i.e., prolonged survival) based on the available data.	('patient', 'Species', '9606', (15, 22))	('patients', 'Species', '9606', (15, 23))	('cancers', 'Disease', 'MESH:D009369', (99, 106))	('cancers', 'Phenotype', 'HP:0002664', (99, 106))	('patient', 'Species', '9606', (230, 237))	('cancers', 'Disease', (99, 106))	('mutations', 'Var', (57, 66))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
517268	27807177	For this study, patients treated with the targeted therapy tended to experience prolonged PFS times.	('PFS', 'MPA', (90, 93))	('patients', 'Species', '9606', (16, 24))	('prolonged', 'PosReg', (80, 89))	('targeted therapy', 'Var', (42, 58))
517298	27807177	This data set contained gene expressions for a total of 5,000 genes among 11 patients diagnosed with acute myelogenous leukemia (AML) and 27 patients diagnosed with acute lymphoblastic leukemia (ALL; 19 ALL-B and 8 ALL-T).	('AML', 'Disease', 'MESH:D015470', (129, 132))	('leukemia', 'Phenotype', 'HP:0001909', (185, 193))	('myelogenous leukemia', 'Phenotype', 'HP:0012324', (107, 127))	('acute lymphoblastic leukemia', 'Disease', (165, 193))	('acute myelogenous leukemia', 'Disease', 'MESH:D015470', (101, 127))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (171, 193))	('acute lymphoblastic leukemia', 'Disease', 'MESH:D054198', (165, 193))	('patients', 'Species', '9606', (77, 85))	('AML', 'Disease', (129, 132))	('acute myelogenous leukemia', 'Disease', (101, 127))	('acute myelogenous leukemia', 'Phenotype', 'HP:0004808', (101, 127))	('ALL-B', 'Var', (203, 208))	('patients', 'Species', '9606', (141, 149))	('leukemia', 'Phenotype', 'HP:0001909', (119, 127))	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (165, 193))
517318	27807177	Specifically, we matched 58 pairs of patients with the 30-day landmark using the R package of MatchIt (with the default settings); the resultant standardized differences were -0.037, 0.212, 0.000, and 0.028 for gender, age, tumor stage and IYPD, respectively.	('0.028', 'Var', (201, 206))	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('patients', 'Species', '9606', (37, 45))	('tumor', 'Disease', (224, 229))	('0.212', 'Var', (183, 188))	('0.000', 'Var', (190, 195))	('tumor', 'Disease', 'MESH:D009369', (224, 229))
517322	27807177	Similarly, we used Topi15 and Topi50 to indicate genes that are within the top 15 and 50 statistically significant gene-treatment interactions, respectively, and Topv100, Topv200 and Topv500 to respectively denote the top 100, 200 and 500 varied genes.	('Topv200', 'Var', (171, 178))	('Topv500', 'Var', (183, 190))	('Si', 'Chemical', 'MESH:D012825', (0, 2))	('Topv100', 'Var', (162, 169))
517323	27807177	We investigated a total of 10 signatures, including Topv100, Topv200, Topv500, Topi15, Topi50, Zun15, Sun50A (adenocarcinoma), Sun50S (squamous cell carcinoma), Kaufman13 (squamous cell carcinoma) and Kaufman16 (adenocarcinoma).	('squamous cell carcinoma', 'Disease', (172, 195))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (135, 158))	('adenocarcinoma', 'Disease', (110, 124))	('Topv500', 'Var', (70, 77))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (135, 158))	('adenocarcinoma', 'Disease', (212, 226))	('50S', 'Species', '1214577', (130, 133))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (172, 195))	('adenocarcinoma', 'Disease', 'MESH:D000230', (110, 124))	('Topv200', 'Var', (61, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (149, 158))	('squamous cell carcinoma', 'Disease', (135, 158))	('Sun50S', 'Var', (127, 133))	('adenocarcinoma', 'Disease', 'MESH:D000230', (212, 226))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (172, 195))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('Topi50', 'Var', (87, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (186, 195))	('carcinoma', 'Phenotype', 'HP:0030731', (217, 226))
517331	27807177	The survival curves for the signatures of Topi15 and Topi50 are well differentiated, indicating substantially improved clinical benefits for patients who received their recommended treatment when compared to those who did not.	('Topi15', 'Var', (42, 48))	('improved', 'PosReg', (110, 118))	('Topi50', 'Var', (53, 59))	('clinical benefits', 'CPA', (119, 136))	('patients', 'Species', '9606', (141, 149))
517383	27826618	However, several recent preclinical and clinical studies have demonstrated that irradiation induces an increase in invasiveness and metastatic potential of several cancer cell types, including glioma, colon, breast, and lung cancer.	('increase', 'PosReg', (103, 111))	('cancer', 'Disease', 'MESH:D009369', (225, 231))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('metastatic potential', 'CPA', (132, 152))	('glioma', 'Disease', (193, 199))	('cancer', 'Disease', (225, 231))	('invasiveness', 'CPA', (115, 127))	('lung cancer', 'Disease', (220, 231))	('irradiation', 'Var', (80, 91))	('lung cancer', 'Phenotype', 'HP:0100526', (220, 231))	('cancer', 'Disease', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('breast', 'Disease', (208, 214))	('glioma', 'Phenotype', 'HP:0009733', (193, 199))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('glioma', 'Disease', 'MESH:D005910', (193, 199))	('colon', 'Disease', (201, 206))	('lung cancer', 'Disease', 'MESH:D008175', (220, 231))
517390	27826618	Irradiation can cause many cellular effects, including apoptosis, senescence, and genomic instability, that may lead to cancer cell death.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('cancer cell death', 'Disease', 'MESH:D003643', (120, 137))	('lead to', 'Reg', (112, 119))	('Irradiation', 'Var', (0, 11))	('apoptosis', 'CPA', (55, 64))	('cancer cell death', 'Disease', (120, 137))	('genomic instability', 'CPA', (82, 101))	('senescence', 'CPA', (66, 76))
517391	27826618	Conversely, irradiation also foments an increase in extra- and intracellular levels of TGF-beta1 in patients and induces acceleration of metastatic cancer progression.	('cancer', 'Disease', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('men', 'Species', '9606', (31, 34))	('TGF-beta1', 'Gene', (87, 96))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('increase', 'PosReg', (40, 48))	('acceleration', 'PosReg', (121, 133))	('patients', 'Species', '9606', (100, 108))	('irradiation', 'Var', (12, 23))
517394	27826618	HDAC inhibitors induce cell cycle arrest, differentiation, and apoptosis in vitro and in vivo.	('HDAC', 'Gene', (0, 4))	('differentiation', 'CPA', (42, 57))	('HDAC', 'Gene', '9734', (0, 4))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (23, 40))	('inhibitors', 'Var', (5, 15))	('apoptosis', 'CPA', (63, 72))	('cell cycle arrest', 'CPA', (23, 40))
517439	27826618	We used primary antibodies against the following proteins: E-cadherin (1:500), vimentin (1:500), beta-catenin (1:1,000), TGF-beta1 (1:1,000), Smad2 (1:200), Smad3 (1:200), phosphorylated-Smad2 (p-Smad2) (1:200), p-Smad3 (1:200), Twist (1:200), Snail (1:200), Slug (1:200), pro-MMP-2 (1:200), pro-MMP-7 (1:200), pro-MMP-9 (1:200), and HIF-1alpha (1:500).	('Smad2', 'Gene', (187, 192))	('beta-catenin', 'Gene', (97, 109))	('MMP-7', 'Gene', (296, 301))	('beta-catenin', 'Gene', '1499', (97, 109))	('Smad2', 'Gene', '4087', (142, 147))	('Smad3', 'Gene', '4088', (214, 219))	('MMP-9', 'Gene', '4318', (315, 320))	('MMP-9', 'Gene', (315, 320))	('MMP-2', 'Gene', (277, 282))	('Smad3', 'Gene', '4088', (157, 162))	('Smad3', 'Gene', (214, 219))	('Smad3', 'Gene', (157, 162))	('Snail', 'Gene', '6615', (244, 249))	('HIF-1alpha', 'Gene', '3091', (334, 344))	('Smad2', 'Gene', (142, 147))	('E-cadherin', 'Gene', (59, 69))	('vimentin', 'Gene', '7431', (79, 87))	('Slug', 'Gene', (259, 263))	('MMP-7', 'Gene', '4316', (296, 301))	('vimentin', 'Gene', (79, 87))	('E-cadherin', 'Gene', '999', (59, 69))	('Smad2', 'Gene', '4087', (196, 201))	('1:200', 'Var', (265, 270))	('Smad2', 'Gene', '4087', (187, 192))	('HIF-1alpha', 'Gene', (334, 344))	('MMP-2', 'Gene', '4313', (277, 282))	('Snail', 'Gene', (244, 249))	('Slug', 'Gene', '6591', (259, 263))	('Smad2', 'Gene', (196, 201))	('1:200', 'Var', (303, 308))
517520	27826618	As shown in this study, VPA can also suppress radiation-induced EMT, leading to inhibition of invasion and metastasis, and reducing resistance to further chemoradiotherapy.	('reducing', 'NegReg', (123, 131))	('resistance to further chemoradiotherapy', 'CPA', (132, 171))	('radiation-induced EMT', 'CPA', (46, 67))	('inhibition', 'NegReg', (80, 90))	('VPA', 'Chemical', 'MESH:D014635', (24, 27))	('suppress', 'NegReg', (37, 45))	('VPA', 'Var', (24, 27))
517534	33423409	High mdig expression predicted poor overall survival in lung squamous cell carcinoma and female smokers.	('mdig', 'Gene', (5, 9))	('High', 'Var', (0, 4))	('overall survival', 'MPA', (36, 52))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (56, 84))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (61, 84))	('mdig', 'Gene', '84864', (5, 9))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (56, 84))	('lung squamous cell carcinoma', 'Disease', (56, 84))	('poor', 'NegReg', (31, 35))
517573	33423409	The following tissue microarray slides were utilized in this study: lung cancer tissue microarray LC2085c; lung carcinoma with matched lymph node metastasis tissue microarray LC817a, early-stage of lung cancer with lung tissue array LC820, and pulmonary interstitial fibrosis tissue microarray LC561.	('lung cancer', 'Disease', (198, 209))	('lung carcinoma', 'Disease', (107, 121))	('lung cancer', 'Disease', (68, 79))	('lung cancer', 'Phenotype', 'HP:0100526', (198, 209))	('lung cancer', 'Phenotype', 'HP:0100526', (68, 79))	('LC817a', 'Var', (175, 181))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('pulmonary interstitial fibrosis', 'Disease', 'MESH:D011658', (244, 275))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('lung cancer', 'Disease', 'MESH:D008175', (198, 209))	('lung cancer', 'Disease', 'MESH:D008175', (68, 79))	('interstitial fibrosis', 'Phenotype', 'HP:0005576', (254, 275))	('lung carcinoma', 'Disease', 'MESH:D008175', (107, 121))	('pulmonary interstitial fibrosis', 'Disease', (244, 275))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))
517596	33423409	The probe set 213189_at was used to detect the open-reading frame (ORF) of mdig mRNA, and this probe set was scored to be the best among the other probe sets available using the JetSet best probe detection tool.	('213189_at', 'Var', (14, 23))	('mdig', 'Gene', '84864', (75, 79))	('mdig', 'Gene', (75, 79))
517669	33423409	High mdig expression has been implicated to be a poor prognostic factor for several human cancers, including lung cancer.	('mdig', 'Gene', (5, 9))	('lung cancer', 'Disease', (109, 120))	('cancers', 'Disease', (90, 97))	('lung cancer', 'Phenotype', 'HP:0100526', (109, 120))	('High', 'Var', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('mdig', 'Gene', '84864', (5, 9))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('lung cancer', 'Disease', 'MESH:D008175', (109, 120))	('human', 'Species', '9606', (84, 89))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('cancers', 'Disease', 'MESH:D009369', (90, 97))
517688	33423409	Several factors, including but not limited to such as environmental exposure, epigenetic alterations, genetic susceptibility, and immune status, interact at some points during the life of an individual to predispose them for lung cancer development.	('lung cancer', 'Phenotype', 'HP:0100526', (225, 236))	('men', 'Species', '9606', (244, 247))	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('predispose', 'Reg', (205, 215))	('epigenetic alterations', 'Var', (78, 100))	('lung cancer', 'Disease', 'MESH:D008175', (225, 236))	('men', 'Species', '9606', (61, 64))	('interact', 'Reg', (145, 153))	('lung cancer', 'Disease', (225, 236))
517696	33423409	Evaluating the overall survival and mdig status in human lung cancer populations, it is interesting to note that high mdig predicts poor overall survival of smokers.	('high', 'Var', (113, 117))	('mdig', 'Gene', (36, 40))	('mdig', 'Gene', (118, 122))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('mdig', 'Gene', '84864', (118, 122))	('lung cancer', 'Disease', 'MESH:D008175', (57, 68))	('human', 'Species', '9606', (51, 56))	('overall survival', 'MPA', (137, 153))	('mdig', 'Gene', '84864', (36, 40))	('poor', 'NegReg', (132, 136))	('lung cancer', 'Disease', (57, 68))	('lung cancer', 'Phenotype', 'HP:0100526', (57, 68))
517701	33423409	For example, the AHRR gene is hypomethylated with smoking, and its hypomethylation is associated with future lung cancers after adjusting for smoking.	('cancers', 'Phenotype', 'HP:0002664', (114, 121))	('lung cancer', 'Phenotype', 'HP:0100526', (109, 120))	('lung cancers', 'Disease', 'MESH:D008175', (109, 121))	('lung cancers', 'Phenotype', 'HP:0100526', (109, 121))	('associated with', 'Reg', (86, 101))	('AHRR', 'Gene', '57491', (17, 21))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('lung cancers', 'Disease', (109, 121))	('hypomethylation', 'Var', (67, 82))	('AHRR', 'Gene', (17, 21))
517711	33423409	As mdig expression and DNA methylation are inversely correlated, it would be relevant to postulate that high mdig expression levels causes the demethylation/hypomethylation of significant cancer-associated genes in early-stage lung cancers.	('mdig', 'Gene', (109, 113))	('cancer', 'Disease', 'MESH:D009369', (232, 238))	('cancers', 'Phenotype', 'HP:0002664', (232, 239))	('lung cancers', 'Disease', (227, 239))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('cancer', 'Disease', (232, 238))	('lung cancer', 'Phenotype', 'HP:0100526', (227, 238))	('mdig', 'Gene', (3, 7))	('demethylation/hypomethylation', 'MPA', (143, 172))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('mdig', 'Gene', '84864', (109, 113))	('high', 'Var', (104, 108))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('lung cancers', 'Disease', 'MESH:D008175', (227, 239))	('cancer', 'Disease', (188, 194))	('causes', 'Reg', (132, 138))	('lung cancers', 'Phenotype', 'HP:0100526', (227, 239))	('mdig', 'Gene', '84864', (3, 7))
517712	33423409	In light of this phenomenon, it is important to note that hypomethylation of DNA sequences is often found during the early stages of tumor development or in abnormal non-neoplastic tissue lesions, such as in hyperplasia.	('hypomethylation', 'Var', (58, 73))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('neoplastic tissue', 'Phenotype', 'HP:0002664', (170, 187))	('hyperplasia', 'Disease', (208, 219))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('men', 'Species', '9606', (146, 149))	('men', 'Species', '9606', (22, 25))	('hyperplasia', 'Disease', 'MESH:D006965', (208, 219))	('tumor', 'Disease', (133, 138))	('DNA sequences', 'Gene', (77, 90))	('found', 'Reg', (100, 105))
517713	33423409	Additionally, hypomethylation and overexpression of some imprinted genes, such as IGF-II and H19 genes, are implicated in carcinogenesis.	('IGF-II', 'Gene', '3481', (82, 88))	('IGF-II', 'Gene', (82, 88))	('carcinogenesis', 'Disease', 'MESH:D063646', (122, 136))	('H19', 'Gene', (93, 96))	('hypomethylation', 'Var', (14, 29))	('carcinogenesis', 'Disease', (122, 136))	('H19', 'Gene', '283120', (93, 96))	('overexpression', 'PosReg', (34, 48))	('implicated', 'Reg', (108, 118))
517714	33423409	We have demonstrated earlier that mdig is highly capable of inducing the expression of H19 gene by downregulating the H3K9me3 and heterochromatin, thereby further corroborating that early-stage lung cancers with high mdig expression are prone to hypomethylation and de-repression of certain cancer-associated genes.	('lung cancers', 'Disease', 'MESH:D008175', (194, 206))	('mdig', 'Gene', '84864', (217, 221))	('cancer', 'Disease', 'MESH:D009369', (291, 297))	('lung cancers', 'Disease', (194, 206))	('cancer', 'Disease', (199, 205))	('lung cancer', 'Phenotype', 'HP:0100526', (194, 205))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('lung cancers', 'Phenotype', 'HP:0100526', (194, 206))	('H19', 'Gene', (87, 90))	('high', 'Var', (212, 216))	('mdig', 'Gene', (34, 38))	('expression', 'MPA', (73, 83))	('H3K9me3', 'Protein', (118, 125))	('mdig', 'Gene', (217, 221))	('cancers', 'Phenotype', 'HP:0002664', (199, 206))	('downregulating', 'NegReg', (99, 113))	('hypomethylation', 'MPA', (246, 261))	('de-repression', 'NegReg', (266, 279))	('cancer', 'Disease', (291, 297))	('H19', 'Gene', '283120', (87, 90))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('cancer', 'Phenotype', 'HP:0002664', (291, 297))	('inducing', 'PosReg', (60, 68))	('mdig', 'Gene', '84864', (34, 38))
517715	33423409	Predicting the overall survival of lung cancers based on the TNM staging, we found that high mdig expression predicts poor OS for T1 and T2 tumors but better OS for T3 lung cancers.	('high', 'Var', (88, 92))	('lung cancers', 'Disease', (35, 47))	('poor', 'NegReg', (118, 122))	('lung cancer', 'Phenotype', 'HP:0100526', (35, 46))	('lung cancers', 'Phenotype', 'HP:0100526', (35, 47))	('TNM', 'Gene', '10178', (61, 64))	('cancers', 'Phenotype', 'HP:0002664', (40, 47))	('tumors', 'Phenotype', 'HP:0002664', (140, 146))	('TNM', 'Gene', (61, 64))	('lung cancer', 'Phenotype', 'HP:0100526', (168, 179))	('lung cancers', 'Disease', 'MESH:D008175', (168, 180))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('cancers', 'Phenotype', 'HP:0002664', (173, 180))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('tumors', 'Disease', (140, 146))	('lung cancers', 'Disease', (168, 180))	('mdig', 'Gene', '84864', (93, 97))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('lung cancers', 'Phenotype', 'HP:0100526', (168, 180))	('tumors', 'Disease', 'MESH:D009369', (140, 146))	('lung cancers', 'Disease', 'MESH:D008175', (35, 47))	('mdig', 'Gene', (93, 97))	('expression', 'MPA', (98, 108))
517716	33423409	First, high mdig expression in the early-stage cancers is most likely to cause the hypomethylation/expression of the genes implicated in lung tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('mdig', 'Gene', (12, 16))	('tumor', 'Disease', (142, 147))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('cancers', 'Disease', 'MESH:D009369', (47, 54))	('cancers', 'Phenotype', 'HP:0002664', (47, 54))	('cancers', 'Disease', (47, 54))	('mdig', 'Gene', '84864', (12, 16))	('high', 'Var', (7, 11))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('cause', 'Reg', (73, 78))	('hypomethylation/expression', 'MPA', (83, 109))
517718	33423409	Most of the hypermethylated genes are the bona fide tumor suppressor genes and genes implicated in invasion and metastasis.	('tumor', 'Disease', (52, 57))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('hypermethylated', 'Var', (12, 27))
517720	33423409	This finding is in accordance with our previous report, where loss of mdig enhanced the migration and invasion of lung cancer cells.	('loss', 'Var', (62, 66))	('enhanced', 'PosReg', (75, 83))	('lung cancer', 'Disease', 'MESH:D008175', (114, 125))	('mdig', 'Gene', '84864', (70, 74))	('invasion', 'CPA', (102, 110))	('migration', 'CPA', (88, 97))	('lung cancer', 'Disease', (114, 125))	('lung cancer', 'Phenotype', 'HP:0100526', (114, 125))	('mdig', 'Gene', (70, 74))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
517726	33423409	Our recent CRISPR-Cas9-based gene editing of mdig in epithelial cells had indicated epigenetic silencing of mdig on collagen family genes and genes in the TGFbeta signaling pathway.	('collagen family genes', 'Gene', (116, 137))	('mdig', 'Gene', '84864', (108, 112))	('TGFbeta signaling pathway', 'Pathway', (155, 180))	('mdig', 'Gene', (45, 49))	('mdig', 'Gene', (108, 112))	('epigenetic silencing', 'Var', (84, 104))	('mdig', 'Gene', '84864', (45, 49))
517741	33691015	Using AeQTL, we discovered that aggregated rare germline truncations in cis exomic regions are significantly associated with the expression of BRCA1 and SLC25A39 in breast tumors.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('associated', 'Reg', (109, 119))	('BRCA1', 'Gene', '672', (143, 148))	('breast tumors', 'Phenotype', 'HP:0100013', (165, 178))	('expression', 'MPA', (129, 139))	('tumors', 'Phenotype', 'HP:0002664', (172, 178))	('BRCA1', 'Gene', (143, 148))	('SLC25A39', 'Gene', (153, 161))	('breast tumors', 'Disease', 'MESH:D001943', (165, 178))	('germline', 'Var', (48, 56))	('breast tumors', 'Disease', (165, 178))	('SLC25A39', 'Gene', '51629', (153, 161))
517742	33691015	In a somatic mutation pan-cancer analysis, aggregated mutations of those predicted to be missense versus truncations were differentially associated with gene expressions of cancer drivers, and somatic truncation eQTLs were further identified as a new multi-omic classifier of oncogenes versus tumor-suppressor genes.	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('associated', 'Reg', (137, 147))	('tumor', 'Disease', 'MESH:D009369', (293, 298))	('cancer', 'Disease', (173, 179))	('cancer', 'Disease', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('tumor', 'Phenotype', 'HP:0002664', (293, 298))	('mutations', 'Var', (54, 63))	('tumor', 'Disease', (293, 298))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('gene expressions', 'MPA', (153, 169))
517751	33691015	The expression of BRCA1 was significantly associated with aggregated rare truncations in the BRCA1 exomic region (P = 0.033) in the BRCA cohort, demonstrating that AeQTL could efficiently identify grouped genotype-expression association.	('BRCA1', 'Gene', '672', (18, 23))	('associated', 'Reg', (42, 52))	('BRCA1', 'Gene', '672', (93, 98))	('BRCA1', 'Gene', (18, 23))	('truncations', 'Var', (74, 85))	('BRCA1', 'Gene', (93, 98))
517753	33691015	Aside from germline variants, we also tested AeQTL on somatic truncations and missense mutations across 32 cancer types of the TCGA PanCancer cohort.	('Cancer', 'Disease', 'MESH:D009369', (135, 141))	('missense mutations', 'Var', (78, 96))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('Cancer', 'Phenotype', 'HP:0002664', (135, 141))	('Cancer', 'Disease', (135, 141))	('cancer', 'Disease', (107, 113))
517756	33691015	AeQTL identified 243 gene-cancer pairs with truncations and 77 gene-cancer pairs with missense mutations that were significantly associated with their respective gene expressions (FDR < 0.05, Fig.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('associated', 'Reg', (129, 139))	('cancer', 'Disease', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('truncations', 'Var', (44, 55))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('cancer', 'Disease', (68, 74))	('missense mutations', 'Var', (86, 104))
517757	33691015	The top-ranked gene-cancer pairs with truncations include the MET proto-oncogene from brain lower grade glioma (LGG), the calcium channel gene CACNA1A from lung adenocarcinoma (LUAD), and TP53 from BRCA; the top-ranked gene-cancer pairs with missense mutations include JAK2 from stomach adenocarcinoma (STAD), TP53 from lung squamous cell carcinoma (LUSC), and FGFR3 from bladder urothelial carcinoma (BLCA).	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (320, 348))	('cancer', 'Disease', 'MESH:D009369', (20, 26))	('lung adenocarcinoma', 'Disease', (156, 175))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (325, 348))	('lung squamous cell carcinoma', 'Disease', (320, 348))	('LUAD', 'Phenotype', 'HP:0030078', (177, 181))	('cancer', 'Disease', (224, 230))	('CACNA1A', 'Gene', (143, 150))	('MET', 'Gene', (62, 65))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('carcinoma', 'Phenotype', 'HP:0030731', (166, 175))	('TP53', 'Gene', '7157', (310, 314))	('bladder urothelial carcinoma', 'Disease', (372, 400))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (156, 175))	('JAK2', 'Gene', '3717', (269, 273))	('TP53', 'Gene', '7157', (188, 192))	('FGFR3', 'Gene', (361, 366))	('glioma', 'Disease', (104, 110))	('carcinoma', 'Phenotype', 'HP:0030731', (292, 301))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (156, 175))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (372, 400))	('FGFR3', 'Gene', '2261', (361, 366))	('glioma', 'Disease', 'MESH:D005910', (104, 110))	('cancer', 'Disease', (20, 26))	('cancer', 'Disease', 'MESH:D009369', (224, 230))	('carcinoma', 'Phenotype', 'HP:0030731', (339, 348))	('missense mutations', 'Var', (242, 260))	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('MET', 'Gene', '79811', (62, 65))	('JAK2', 'Gene', (269, 273))	('stomach adenocarcinoma', 'Disease', 'MESH:D000230', (279, 301))	('CACNA1A', 'Gene', '773', (143, 150))	('glioma', 'Phenotype', 'HP:0009733', (104, 110))	('TP53', 'Gene', (310, 314))	('carcinoma', 'Phenotype', 'HP:0030731', (391, 400))	('TP53', 'Gene', (188, 192))	('stomach adenocarcinoma', 'Disease', (279, 301))
517758	33691015	AeQTL identified 1,179 gene-cancer pairs with truncations and 3,241 gene-cancer pairs with missense mutations significantly associated with their respective gene expressions (FDR < 0.05).	('cancer', 'Disease', (73, 79))	('missense mutations', 'Var', (91, 109))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('truncations', 'Var', (46, 57))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('associated', 'Reg', (124, 134))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('cancer', 'Disease', (28, 34))
517759	33691015	For significant gene-cancer pairs with truncations, 156 overlapped with the likely driver genes.	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('truncations', 'Var', (39, 50))	('cancer', 'Disease', (21, 27))	('cancer', 'Disease', 'MESH:D009369', (21, 27))
517760	33691015	For significant gene-cancer pairs with missense mutations, 115 overlapped with the likely driver genes.	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('cancer', 'Disease', (21, 27))	('missense mutations', 'Var', (39, 57))	('cancer', 'Disease', 'MESH:D009369', (21, 27))
517761	33691015	The top-ranked somatic eQTL genes with truncations include OR8D1 in LUSC, SOX10 in head and neck squamous cell carcinoma (HNSC), and PSG7 in kidney renal clear cell carcinoma (KIRC).	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (92, 120))	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('SOX10', 'Gene', (74, 79))	('eQTL genes', 'Gene', (23, 33))	('SOX10', 'Gene', '6663', (74, 79))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (97, 120))	('truncations', 'Var', (39, 50))	('kidney renal clear cell carcinoma', 'Disease', (141, 174))	('kidney renal clear cell carcinoma', 'Disease', 'MESH:C538614', (141, 174))	('OR8D1', 'Gene', '283159', (59, 64))	('LUSC', 'Disease', (68, 72))	('OR8D1', 'Gene', (59, 64))	('carcinoma', 'Phenotype', 'HP:0030731', (165, 174))	('PSG7', 'Gene', '5676', (133, 137))	('neck squamous cell carcinoma', 'Disease', (92, 120))	('PSG7', 'Gene', (133, 137))
517762	33691015	The top-ranked somatic eQTL genes with missense mutations include USP29 in cholangiocarcinoma (CHOL) and AMELX, CNTN5, and OR1L3 in lymphoid neoplasm diffuse large B-cell lymphoma (DLBC).	('OR1L3', 'Gene', '26735', (123, 128))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (75, 93))	('neoplasm', 'Phenotype', 'HP:0002664', (141, 149))	('AMELX', 'Gene', (105, 110))	('cholangiocarcinoma', 'Disease', (75, 93))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (164, 179))	('missense mutations', 'Var', (39, 57))	('CHOL', 'Disease', 'None', (95, 99))	('OR1L3', 'Gene', (123, 128))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (75, 93))	('AMELX', 'Gene', '265', (105, 110))	('CNTN5', 'Gene', '53942', (112, 117))	('lymphoid neoplasm', 'Disease', (132, 149))	('B-cell lymphoma', 'Disease', (164, 179))	('eQTL genes', 'Gene', (23, 33))	('CHOL', 'Disease', (95, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('USP29', 'Gene', (66, 71))	('USP29', 'Gene', '57663', (66, 71))	('CHOL', 'Phenotype', 'HP:0030153', (95, 99))	('lymphoid neoplasm', 'Disease', 'MESH:D008223', (132, 149))	('CNTN5', 'Gene', (112, 117))	('lymphoid neoplasm', 'Phenotype', 'HP:0002665', (132, 149))	('lymphoma', 'Phenotype', 'HP:0002665', (171, 179))	('B-cell lymphoma', 'Disease', 'MESH:D016393', (164, 179))
517767	33691015	In the likely-driver-gene subset analysis, the genotype coefficients of truncations showed a strong association with their respective predicted classifications of oncogenes or TSGs.	('truncations', 'Var', (72, 83))	('TSG', 'Gene', '57045', (176, 179))	('association', 'Interaction', (100, 111))	('TSG', 'Gene', (176, 179))
517769	33691015	4a), demonstrating a polarized pattern of how truncations in oncogenes versus TSGs may affect their respective genes' expression in opposite directions.	('affect', 'Reg', (87, 93))	('truncations', 'Var', (46, 57))	('oncogenes', 'Gene', (61, 70))	('TSG', 'Gene', (78, 81))	('expression', 'MPA', (118, 128))	('TSG', 'Gene', '57045', (78, 81))
517771	33691015	In comparison, such a pattern was not recapitulated in the genotype coefficients of missense mutations, where both oncogene and TSG mutations were associated with increased gene expressions (Fig.	('TSG', 'Gene', (128, 131))	('increased', 'PosReg', (163, 172))	('mutations', 'Var', (132, 141))	('gene expressions', 'MPA', (173, 189))	('TSG', 'Gene', '57045', (128, 131))	('missense mutations', 'Var', (84, 102))
517772	33691015	Overall, genotype-expression analyses revealed distinct eQTL patterns associated with missenses versus truncations and oncogenes versus TSGs in cancer drivers.	('eQTL', 'Gene', (56, 60))	('TSG', 'Gene', '57045', (136, 139))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('associated', 'Reg', (70, 80))	('cancer', 'Disease', (144, 150))	('TSG', 'Gene', (136, 139))	('missenses', 'Var', (86, 95))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
517775	33691015	Further, neither SKAT nor SKAT-O provides a regression coefficient for regional genotype, which makes it difficult to understand the direction of variant's effect on gene expression and make discoveries such as the polarized eQTL patterns of oncogenes and TSGs.	('TSG', 'Gene', (256, 259))	('variant', 'Var', (146, 153))	('TSG', 'Gene', '57045', (256, 259))
517777	33691015	For real datasets, we used rare germline truncations in breast cancer to showcase that AeQTL can efficiently identify significant associations between grouped variants and gene expressions.	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('variants', 'Var', (159, 167))	('breast cancer', 'Disease', 'MESH:D001943', (56, 69))	('breast cancer', 'Phenotype', 'HP:0003002', (56, 69))	('breast cancer', 'Disease', (56, 69))
517778	33691015	Furthermore, we applied AeQTL to somatic mutations in a pan-cancer dataset and identified top-ranked gene-cancer pairs that were significantly associated with either truncations or missense mutations in their respective gene regions.	('associated', 'Reg', (143, 153))	('truncations', 'Var', (166, 177))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('missense mutations', 'Var', (181, 199))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('cancer', 'Disease', (60, 66))	('cancer', 'Disease', (106, 112))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
517784	33691015	In TSGs, truncations including nonsense variants or frameshift variants may introduce early stop-codons that likely have led to nonsense-mediated decay (NMD), thus abolishing gene transcripts.	('nonsense variants', 'Var', (31, 48))	('TSG', 'Gene', '57045', (3, 6))	('abolishing', 'NegReg', (164, 174))	('frameshift variants', 'Var', (52, 71))	('gene transcripts', 'MPA', (175, 191))	('nonsense-mediated decay', 'MPA', (128, 151))	('TSG', 'Gene', (3, 6))
517800	32581314	MetS is closely linked to cancer, as it increases cancer risk and cancer-related mortality.	('cancer', 'Disease', (50, 56))	('mortality', 'Disease', 'MESH:D003643', (81, 90))	('MetS', 'Var', (0, 4))	('cancer', 'Disease', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('mortality', 'Disease', (81, 90))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('increases', 'PosReg', (40, 49))	('cancer', 'Disease', (66, 72))
517844	32581314	MetS was associated with 9%, 27%, and 11% higher risk of developing oral, laryngeal, and esophageal cancers, respectively.	('esophageal cancers', 'Disease', (89, 107))	('MetS', 'Var', (0, 4))	('esophageal cancers', 'Disease', 'MESH:D004938', (89, 107))	('oral', 'Disease', (68, 72))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('laryngeal', 'Disease', (74, 83))	('cancers', 'Phenotype', 'HP:0002664', (100, 107))
517888	32581314	Oral, laryngeal, and esophageal cancers were defined as C00-C06, C32.0-32.9, and C15.0-C15.9, respectively.	('cancers', 'Phenotype', 'HP:0002664', (32, 39))	('esophageal cancers', 'Disease', (21, 39))	('Oral', 'Disease', (0, 4))	('esophageal cancers', 'Disease', 'MESH:D004938', (21, 39))	('laryngeal', 'Disease', (6, 15))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('C15.0-C15.9', 'Var', (81, 92))
517894	32581314	The measured BP was classified as normal SBP < 120 mmHg and DBP < 80 mmHg), prehypertension (SBP 120-139 mmHg or DBP 80-89 mmHg), or hypertension (SBP >= 140 mmHg or DBP >= 90 mmHg).	('hypertension', 'Disease', (133, 145))	('hypertension', 'Disease', 'MESH:D006973', (79, 91))	('hypertension', 'Phenotype', 'HP:0000822', (133, 145))	('hypertension', 'Disease', (79, 91))	('SBP 120-139 mmHg', 'Var', (93, 109))	('hypertension', 'Disease', 'MESH:D006973', (133, 145))	('hypertension', 'Phenotype', 'HP:0000822', (79, 91))
517903	32581314	According to this institution, patients with MetS should have three or more of the following five components: abdominal obesity (>= 90 cm for men and >= 85 cm for women), elevated blood pressure (systolic >= 130 and/or diastolic >= 85 mmHg), hyperglycemia (fasting plasma glucose >= 5.6 mmol/L (>= 100 mg/dL)), hypertriglyceridemia (triglycerides >= 1.7 mmol/L (>= 150 mg/dL)), and low HDL-cholesterol levels (1.0 mmol/L (< 40 mg/dL) for men and 1.3 mmol/L (< 50 mg/dL) for women).	('triglyceride', 'Chemical', 'MESH:D014280', (333, 345))	('elevated', 'PosReg', (171, 179))	('abdominal obesity', 'Disease', 'MESH:D056128', (110, 127))	('low', 'NegReg', (382, 385))	('cholesterol', 'Chemical', 'MESH:D002784', (390, 401))	('obesity', 'Phenotype', 'HP:0001513', (120, 127))	('hyperglycemia', 'Disease', (242, 255))	('men', 'Species', '9606', (476, 479))	('men', 'Species', '9606', (438, 441))	('women', 'Species', '9606', (474, 479))	('blood pressure', 'MPA', (180, 194))	('abdominal obesity', 'Phenotype', 'HP:0012743', (110, 127))	('hyperglycemia', 'Disease', 'MESH:D006943', (242, 255))	('>=', 'Var', (129, 131))	('hypertriglyceridemia', 'Disease', (311, 331))	('HDL-cholesterol levels', 'MPA', (386, 408))	('hypertriglyceridemia', 'Disease', 'MESH:D015228', (311, 331))	('triglyceride', 'Chemical', 'MESH:D014280', (316, 328))	('men', 'Species', '9606', (142, 145))	('low HDL-cholesterol', 'Phenotype', 'HP:0003233', (382, 401))	('elevated blood pressure', 'Phenotype', 'HP:0032263', (171, 194))	('men', 'Species', '9606', (165, 168))	('glucose', 'Chemical', 'MESH:D005947', (272, 279))	('women', 'Species', '9606', (163, 168))	('patients', 'Species', '9606', (31, 39))	('hyperglycemia', 'Phenotype', 'HP:0003074', (242, 255))	('abdominal obesity', 'Disease', (110, 127))	('hypertriglyceridemia', 'Phenotype', 'HP:0002155', (311, 331))
517921	32335823	IDH1 mutation was significantly associated with high-SST2 status.	('SST', 'Gene', '6750', (53, 56))	('associated', 'Reg', (32, 42))	('IDH1', 'Gene', (0, 4))	('SST', 'Gene', (53, 56))	('mutation', 'Var', (5, 13))	('IDH1', 'Gene', '3417', (0, 4))
517929	32335823	In particular, several radioligands targeting SST have been developed, such as 68Ga-DOTATOC and 68Ga-DOTATATE, which are now commonly used in the diagnosis of neuroendocrine tumors (NETs) via positron emission tomography (PET).	('neuroendocrine tumors', 'Disease', (159, 180))	('SST', 'Gene', '6750', (46, 49))	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (159, 180))	('68Ga-DOTATATE', 'Var', (96, 109))	('DOTATOC', 'Chemical', '-', (84, 91))	('NETs', 'Phenotype', 'HP:0100634', (182, 186))	('neuroendocrine tumors', 'Disease', 'MESH:D018358', (159, 180))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('SST', 'Gene', (46, 49))	('68Ga-DOTATATE', 'Chemical', 'MESH:C513399', (96, 109))	('tumors', 'Phenotype', 'HP:0002664', (174, 180))
517971	32335823	Mutational profiles were significantly associated with high-SST2 status in LGG, which showed the highest proportion of high-SST tumors, including isocitrate dehydrogenase 1 (IDH1), capicua transcriptional repressor (CIC), and far upstream element binding protein 1 (FUBP1) mutations.	('FUBP1', 'Gene', (266, 271))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('associated', 'Reg', (39, 49))	('tumors', 'Disease', (128, 134))	('CIC', 'Gene', '23152', (216, 219))	('isocitrate dehydrogenase 1', 'Gene', (146, 172))	('isocitrate dehydrogenase 1', 'Gene', '3417', (146, 172))	('SST', 'Gene', (124, 127))	('IDH1', 'Gene', (174, 178))	('tumors', 'Disease', 'MESH:D009369', (128, 134))	('capicua transcriptional repressor', 'Gene', '23152', (181, 214))	('FUBP1', 'Gene', '8880', (266, 271))	('far upstream element binding protein 1', 'Gene', '8880', (226, 264))	('SST', 'Gene', (60, 63))	('IDH1', 'Gene', '3417', (174, 178))	('CIC', 'Gene', (216, 219))	('SST', 'Gene', '6750', (124, 127))	('SST', 'Gene', '6750', (60, 63))	('capicua transcriptional repressor', 'Gene', (181, 214))	('mutations', 'Var', (273, 282))	('far upstream element binding protein 1', 'Gene', (226, 264))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))
517972	32335823	In contrast, epidermal growth factor receptor (EGFR), phosphatase and tensin homolog (PTEN), and tumor protein 53 (TP53) mutations were more common in low-SST2 tumors than in high-SST2 tumors (Fig.	('mutations', 'Var', (121, 130))	('PTEN', 'Gene', (86, 90))	('common', 'Reg', (141, 147))	('tumor protein 53', 'Gene', (97, 113))	('tumors', 'Disease', (185, 191))	('tumor protein 53', 'Gene', '7157', (97, 113))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('EGFR', 'Gene', '1956', (47, 51))	('tumors', 'Disease', (160, 166))	('epidermal growth factor receptor', 'Gene', (13, 45))	('PTEN', 'Gene', '5728', (86, 90))	('epidermal growth factor receptor', 'Gene', '1956', (13, 45))	('SST', 'Gene', (155, 158))	('tumors', 'Disease', 'MESH:D009369', (185, 191))	('SST', 'Gene', (180, 183))	('TP53', 'Gene', (115, 119))	('tumors', 'Disease', 'MESH:D009369', (160, 166))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('SST', 'Gene', '6750', (155, 158))	('EGFR', 'Gene', (47, 51))	('phosphatase and tensin homolog', 'Gene', '5728', (54, 84))	('SST', 'Gene', '6750', (180, 183))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumors', 'Phenotype', 'HP:0002664', (185, 191))	('tumors', 'Phenotype', 'HP:0002664', (160, 166))
517973	32335823	In pancreatic adenocarcinoma (PAAD), Kirsten rat sarcoma (KRAS) and TP53 mutations were associated with low-SST2 status.	('KRAS', 'Gene', (58, 62))	('sarcoma', 'Disease', 'MESH:D012509', (49, 56))	('SST', 'Gene', '6750', (108, 111))	('sarcoma', 'Phenotype', 'HP:0100242', (49, 56))	('KRAS', 'Gene', '24525', (58, 62))	('pancreatic adenocarcinoma', 'Disease', (3, 28))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D000230', (3, 28))	('carcinoma', 'Phenotype', 'HP:0030731', (19, 28))	('PAAD', 'Phenotype', 'HP:0006725', (30, 34))	('SST', 'Gene', (108, 111))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (3, 28))	('associated', 'Reg', (88, 98))	('TP53', 'Gene', (68, 72))	('mutations', 'Var', (73, 82))	('rat', 'Species', '10116', (45, 48))	('sarcoma', 'Disease', (49, 56))
517974	32335823	In uterine corpus endometrial carcinoma (UCEC), catenin beta 1 (CTNNB1) mutation showed an association with low-SST2 status.	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (18, 39))	('SST', 'Gene', (112, 115))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (18, 39))	('CTNNB1', 'Gene', (64, 70))	('catenin beta 1', 'Gene', (48, 62))	('endometrial carcinoma', 'Disease', (18, 39))	('SST', 'Gene', '6750', (112, 115))	('CTNNB1', 'Gene', '1499', (64, 70))	('carcinoma', 'Phenotype', 'HP:0030731', (30, 39))	('mutation', 'Var', (72, 80))	('catenin beta 1', 'Gene', '1499', (48, 62))	('association', 'Interaction', (91, 102))
517975	32335823	When high-SST2 tumors were defined with the expression level in PCPG as a reference value, SST2-based tumor subtypes were not significantly associated with gene alterations in other cancer subtypes, including BRCA, PCPG, and KIRC.	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('SST', 'Gene', '6750', (10, 13))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('BRCA', 'Phenotype', 'HP:0003002', (209, 213))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('KIRC', 'Disease', (225, 229))	('cancer', 'Disease', (182, 188))	('rat', 'Species', '10116', (165, 168))	('SST', 'Gene', (91, 94))	('tumors', 'Disease', (15, 21))	('BRCA', 'Gene', '672', (209, 213))	('alterations', 'Var', (161, 172))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('tumor', 'Disease', (15, 20))	('tumor', 'Disease', (102, 107))	('tumors', 'Disease', 'MESH:D009369', (15, 21))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('BRCA', 'Gene', (209, 213))	('SST', 'Gene', '6750', (91, 94))	('SST', 'Gene', (10, 13))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('PCPG', 'Disease', (215, 219))
517978	32335823	The SST2 level in G2 grade tumors was significantly higher than that in G3 grade tumors (Fig.	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumors', 'Disease', (81, 87))	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('G2 grade', 'Var', (18, 26))	('SST', 'Gene', (4, 7))	('tumors', 'Disease', (27, 33))	('tumors', 'Disease', 'MESH:D009369', (27, 33))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('higher', 'PosReg', (52, 58))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('SST', 'Gene', '6750', (4, 7))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))
517986	32335823	In addition, SST2 status showed prognostic impact in thymoma and glioblastoma when the level of expression in normal kidney tissue was defined as the reference (Supplementary fig.	('SST', 'Gene', (13, 16))	('impact', 'Reg', (43, 49))	('thymoma', 'Phenotype', 'HP:0100522', (53, 60))	('prognostic', 'Reg', (32, 42))	('SST', 'Gene', '6750', (13, 16))	('thymoma and glioblastoma', 'Disease', 'MESH:D013945', (53, 77))	('glioblastoma', 'Phenotype', 'HP:0012174', (65, 77))	('status', 'Var', (18, 24))
517992	32335823	Additionally, we revealed that fourteen of the 32 cancer subtypes had more than 5% of tumors with high-SST2 expression when SST2 expression in normal kidney tissue was used as the reference.	('SST', 'Gene', '6750', (124, 127))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('SST', 'Gene', '6750', (103, 106))	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('tumors', 'Disease', (86, 92))	('SST', 'Gene', (103, 106))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('SST', 'Gene', (124, 127))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('expression', 'Var', (108, 118))
518005	32335823	Several gene mutations were noted to have a correlation with SST2 expression in LGG.	('SST', 'Gene', (61, 64))	('SST', 'Gene', '6750', (61, 64))	('expression', 'MPA', (66, 76))	('correlation', 'Reg', (44, 55))	('mutations', 'Var', (13, 22))
518006	32335823	In particular, the IDH1 mutation was revealed to be associated with SST2 expression, which is supported by a previous study.	('IDH1', 'Gene', (19, 23))	('associated', 'Reg', (52, 62))	('IDH1', 'Gene', '3417', (19, 23))	('expression', 'MPA', (73, 83))	('SST', 'Gene', '6750', (68, 71))	('mutation', 'Var', (24, 32))	('SST', 'Gene', (68, 71))
518007	32335823	The close association between IDH1 mutation and SST2 expression was also verified by the association of high-SST2 with good prognosis in LGG.	('IDH1', 'Gene', '3417', (30, 34))	('IDH1', 'Gene', (30, 34))	('SST', 'Gene', (48, 51))	('SST', 'Gene', '6750', (109, 112))	('mutation', 'Var', (35, 43))	('SST', 'Gene', '6750', (48, 51))	('SST', 'Gene', (109, 112))	('LGG', 'Disease', (137, 140))	('association', 'Interaction', (89, 100))
518008	32335823	The presence of IDH1 mutation is the most common factor used to classify tumor subtypes in terms of disparate molecular pathogenesis and favorable prognosis.	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('rat', 'Species', '10116', (105, 108))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('mutation', 'Var', (21, 29))	('IDH1', 'Gene', (16, 20))	('tumor', 'Disease', (73, 78))	('IDH1', 'Gene', '3417', (16, 20))
518009	32335823	Additionally, not only IDH1 but also CIC and FUBP1 mutations demonstrated a positive association with SST2 expression.	('SST', 'Gene', (102, 105))	('mutations', 'Var', (51, 60))	('CIC', 'Gene', '23152', (37, 40))	('FUBP1', 'Gene', '8880', (45, 50))	('expression', 'MPA', (107, 117))	('IDH1', 'Gene', (23, 27))	('CIC', 'Gene', (37, 40))	('rat', 'Species', '10116', (68, 71))	('SST', 'Gene', '6750', (102, 105))	('FUBP1', 'Gene', (45, 50))	('IDH1', 'Gene', '3417', (23, 27))	('positive', 'PosReg', (76, 84))
518010	32335823	This finding is also consistent with previous studies that showed an association between IDH1, CIC, and FUBP1 mutations and a favorable prognosis.	('mutations', 'Var', (110, 119))	('CIC', 'Gene', '23152', (95, 98))	('FUBP1', 'Gene', '8880', (104, 109))	('CIC', 'Gene', (95, 98))	('IDH1', 'Gene', (89, 93))	('FUBP1', 'Gene', (104, 109))	('IDH1', 'Gene', '3417', (89, 93))
518011	32335823	In contrast, EGFR, PTEN, and TP53 mutations showed a negative association with SST2 expression.	('EGFR', 'Gene', (13, 17))	('SST', 'Gene', '6750', (79, 82))	('SST', 'Gene', (79, 82))	('PTEN', 'Gene', (19, 23))	('PTEN', 'Gene', '5728', (19, 23))	('TP53', 'Gene', (29, 33))	('expression', 'MPA', (84, 94))	('EGFR', 'Gene', '1956', (13, 17))	('negative', 'NegReg', (53, 61))	('mutations', 'Var', (34, 43))
518016	32335823	Considering the association between gene mutations and SST2 expression, a high level of SST2 expression can be deemed a strong alternative to favorable prognostic markers, such as IDH1 mutation or tumor grade.	('SST', 'Gene', (88, 91))	('mutations', 'Var', (41, 50))	('IDH1', 'Gene', (180, 184))	('tumor', 'Disease', 'MESH:D009369', (197, 202))	('IDH1', 'Gene', '3417', (180, 184))	('SST', 'Gene', '6750', (88, 91))	('mutation', 'Var', (185, 193))	('SST', 'Gene', (55, 58))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('SST', 'Gene', '6750', (55, 58))	('tumor', 'Disease', (197, 202))
518031	32335823	Despite IDH1 mutations and hormone receptor expression being good prognostic factors, recurrence of brain tumor patients with IDH1 mutations and breast cancer patients with hormone receptor expression is frequently observed in the clinical setting.	('IDH1', 'Gene', '3417', (126, 130))	('mutations', 'Var', (131, 140))	('IDH1', 'Gene', (8, 12))	('patients', 'Species', '9606', (112, 120))	('brain tumor', 'Disease', (100, 111))	('IDH1', 'Gene', '3417', (8, 12))	('breast cancer', 'Disease', 'MESH:D001943', (145, 158))	('IDH1', 'Gene', (126, 130))	('brain tumor', 'Disease', 'MESH:D001932', (100, 111))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('breast cancer', 'Disease', (145, 158))	('patients', 'Species', '9606', (159, 167))	('breast cancer', 'Phenotype', 'HP:0003002', (145, 158))	('brain tumor', 'Phenotype', 'HP:0030692', (100, 111))
518111	30867254	performed DNA methylation analyses in oral squamous cell carcinoma tissues, high-grade squamous intraepithelial lesions and corresponding normal contralateral mucosae, and found oral squamous cell carcinoma tissues and high-grade squamous intraepithelial lesions exhibited hypermethylation of LINC00599 in comparison with corresponding normal contralateral mucosae.	('squamous intraepithelial lesions', 'Disease', 'MESH:D000081483', (230, 262))	('LINC00599', 'Gene', '157627', (293, 302))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (183, 206))	('squamous intraepithelial lesions', 'Disease', (230, 262))	('LINC00599', 'Gene', (293, 302))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (38, 66))	('squamous intraepithelial lesions', 'Disease', (87, 119))	('oral squamous cell carcinoma', 'Disease', (178, 206))	('exhibited', 'Reg', (263, 272))	('squamous intraepithelial lesions', 'Disease', 'MESH:D000081483', (87, 119))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (43, 66))	('carcinoma', 'Phenotype', 'HP:0030731', (57, 66))	('carcinoma', 'Phenotype', 'HP:0030731', (197, 206))	('oral squamous cell carcinoma', 'Disease', (38, 66))	('hypermethylation', 'Var', (273, 289))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (178, 206))
518121	30867254	We analyzed the expression difference of LINC00599 in glioma cases, which were grouped according to age, gender, tumor size, and WHO grade, and found glioma tissues with WHO III-IV grade exhibited lower levels of LINC00599 expression than glioma tissues with I-II grade.	('lower', 'NegReg', (197, 202))	('glioma', 'Disease', 'MESH:D005910', (54, 60))	('glioma', 'Phenotype', 'HP:0009733', (54, 60))	('III-IV grade', 'Var', (174, 186))	('expression', 'MPA', (223, 233))	('tumor', 'Disease', (113, 118))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('glioma', 'Disease', (150, 156))	('glioma', 'Disease', (239, 245))	('LINC00599', 'Gene', (41, 50))	('LINC00599', 'Gene', '157627', (41, 50))	('glioma', 'Disease', 'MESH:D005910', (150, 156))	('glioma', 'Phenotype', 'HP:0009733', (239, 245))	('glioma', 'Disease', 'MESH:D005910', (239, 245))	('glioma', 'Disease', (54, 60))	('LINC00599', 'Gene', '157627', (213, 222))	('LINC00599', 'Gene', (213, 222))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('glioma', 'Phenotype', 'HP:0009733', (150, 156))
518135	30513726	Methods: We retrospectively analyzed the 161 patients with OTSCC treated with surgical resection, including 81 patients with high expression of Nox4 and 80 patients with low expression of Nox4.	('patients', 'Species', '9606', (156, 164))	('Nox4', 'Protein', (144, 148))	('patients', 'Species', '9606', (45, 53))	('high expression', 'Var', (125, 140))	('patients', 'Species', '9606', (111, 119))
518138	30513726	In addition, these cell lines were also treated with a Nox4 inhibitor (GKT-137831) and the results showed GKT-137831 could inhibit the proliferation of OTSCC tumor cells in a dose-dependent manner.	('tumor', 'Disease', (158, 163))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('GKT-137831', 'Chemical', 'MESH:C576694', (71, 81))	('proliferation', 'CPA', (135, 148))	('inhibit', 'NegReg', (123, 130))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('GKT-137831', 'Var', (106, 116))	('OTSCC', 'Disease', (152, 157))	('GKT-137831', 'Chemical', 'MESH:C576694', (106, 116))
518150	30513726	Growing evidence confirms that there is a close correlation of Nox4 with cancer development and progression and the inhibition of Nox4 suppresses tumor growth and leads to cancer cell death.	('suppresses', 'NegReg', (135, 145))	('cancer cell death', 'Disease', (172, 189))	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('inhibition', 'Var', (116, 126))	('men', 'Species', '9606', (87, 90))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('cancer cell death', 'Disease', 'MESH:D003643', (172, 189))	('tumor', 'Disease', (146, 151))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('leads to', 'Reg', (163, 171))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('cancer', 'Disease', (172, 178))	('Nox4', 'Gene', (130, 134))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
518198	30513726	These results showed GKT-137831 could inhibit the proliferation of tumor cells in a dose-dependent manner in SAS and SCC4 cell lines at 24th, 48th and 72nd hour after GKT-137831 treatment (Figure 2).	('men', 'Species', '9606', (183, 186))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('SCC4', 'Gene', '23383', (117, 121))	('GKT-137831', 'Chemical', 'MESH:C576694', (167, 177))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('SCC4', 'Gene', (117, 121))	('tumor', 'Disease', (67, 72))	('GKT-137831', 'Chemical', 'MESH:C576694', (21, 31))	('GKT-137831', 'Var', (21, 31))	('inhibit', 'NegReg', (38, 45))
518225	30513726	In a Chinese study, Nox4 expression was correlated with tumor size and poor prognosis in 90 patients with gastric cancer and knockdown of NOX4 expression blocked cell proliferation and the expression of Cyclin D1, BAX and so on in vitro.	('BAX', 'Gene', (214, 217))	('knockdown', 'Var', (125, 134))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('BAX', 'Gene', '581', (214, 217))	('tumor', 'Disease', (56, 61))	('NOX4', 'Gene', (138, 142))	('cell proliferation', 'CPA', (162, 180))	('blocked', 'NegReg', (154, 161))	('gastric cancer', 'Disease', 'MESH:D013274', (106, 120))	('expression', 'MPA', (189, 199))	('gastric cancer', 'Disease', (106, 120))	('Cyclin D1', 'Gene', '595', (203, 212))	('patients', 'Species', '9606', (92, 100))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('gastric cancer', 'Phenotype', 'HP:0012126', (106, 120))	('NOX4', 'Gene', '50507', (138, 142))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('Cyclin D1', 'Gene', (203, 212))
518226	30513726	Nox4 promoted cell proliferation via activation of the GLI1 pathway and overexpression of GLI1 reversed the suppression of tumor cell growth induced by silencing NOX4.	('promoted', 'PosReg', (5, 13))	('silencing', 'Var', (152, 161))	('tumor', 'Disease', (123, 128))	('GLI1', 'Gene', '2735', (90, 94))	('GLI1', 'Gene', (55, 59))	('GLI1', 'Gene', (90, 94))	('cell proliferation', 'CPA', (14, 32))	('NOX4', 'Gene', (162, 166))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('GLI1', 'Gene', '2735', (55, 59))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('NOX4', 'Gene', '50507', (162, 166))
518227	30513726	Furthermore, overexpression of Nox4 enhanced expression of GLI1 and knockdown of GLI1 expression reduced the effects induced by Nox4 overexpression.	('GLI1', 'Gene', (59, 63))	('GLI1', 'Gene', '2735', (81, 85))	('GLI1', 'Gene', '2735', (59, 63))	('expression', 'MPA', (45, 55))	('knockdown', 'Var', (68, 77))	('enhanced', 'PosReg', (36, 44))	('GLI1', 'Gene', (81, 85))
518228	30513726	A Japanese study, reported by Ito et al., also demonstrated that Nox4 was highly expressed in several oral squamous cell carcinoma cell lines and NOXs knockdown markedly suppressed cell viability and induced apoptosis; in addition, NOXs suppression significantly enhanced the cisplatin-induced cytotoxic effect.	('NOXs', 'Gene', (146, 150))	('NOXs', 'Enzyme', (232, 236))	('apoptosis', 'CPA', (208, 217))	('cisplatin-induced cytotoxic effect', 'CPA', (276, 310))	('suppression', 'NegReg', (237, 248))	('suppressed', 'NegReg', (170, 180))	('induced', 'Reg', (200, 207))	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (107, 130))	('cisplatin', 'Chemical', 'MESH:D002945', (276, 285))	('squamous cell carcinoma', 'Disease', (107, 130))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (107, 130))	('enhanced', 'PosReg', (263, 271))	('cell viability', 'CPA', (181, 195))	('knockdown', 'Var', (151, 160))
518232	30513726	The antitumor activity of EGFR inhibitors is suppressed by activation of Nox4-mediated pro-inflammatory pathways and knockdown of Nox4 reduced EGFR inhibitor-induced pro-inflammatory cytokine expression.	('EGFR', 'Gene', (26, 30))	('EGFR', 'Gene', (143, 147))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('suppressed', 'NegReg', (45, 55))	('Nox4-mediated pro-inflammatory pathways', 'Pathway', (73, 112))	('reduced', 'NegReg', (135, 142))	('EGFR', 'Gene', '1956', (26, 30))	('tumor', 'Disease', (8, 13))	('EGFR', 'Gene', '1956', (143, 147))	('Nox4', 'Gene', (130, 134))	('knockdown', 'Var', (117, 126))
518235	30513726	Suppression of Nox4 was found to revert the myofibroblastic-CAF phenotype, prevent myofibroblastic-CAF accumulation and slower tumor proliferation.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('revert', 'NegReg', (33, 39))	('myofibroblastic-CAF accumulation', 'CPA', (83, 115))	('tumor', 'Disease', (127, 132))	('Suppression', 'Var', (0, 11))	('Nox4', 'Gene', (15, 19))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('myofibroblastic-CAF', 'Disease', (44, 63))	('prevent', 'NegReg', (75, 82))
518250	32752229	The FFL network involved, comprised of miR-20b-5p, CCNB1, HMGA2, and E2F7.	('miR-20b-5p', 'Var', (39, 49))	('CCNB1', 'Gene', (51, 56))	('miR-20b-5p', 'Chemical', '-', (39, 49))
518277	32752229	Other causes include epigenetic modifications, genetic loss, and widespread transcriptional repression, all of which are also associated with aberrant regulation of miRNA levels in lung cancer.	('genetic loss', 'Disease', (47, 59))	('associated', 'Reg', (126, 136))	('genetic loss', 'Disease', 'MESH:D030342', (47, 59))	('epigenetic modifications', 'Var', (21, 45))	('miRNA levels', 'MPA', (165, 177))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('lung cancer', 'Disease', (181, 192))	('lung cancer', 'Phenotype', 'HP:0100526', (181, 192))	('widespread', 'CPA', (65, 75))	('lung cancer', 'Disease', 'MESH:D008175', (181, 192))
518278	32752229	miRNAs are also known to exert transcription repression effects mainly by inhibiting transcription factors (TFs).	('miRNAs', 'Var', (0, 6))	('TF', 'Gene', '2152', (108, 110))	('inhibiting', 'NegReg', (74, 84))	('transcription repression', 'MPA', (31, 55))
518318	32752229	miR-20b-5p targeted maximum number of hub genes (i.e., 4).	('miR-20b-5p', 'Chemical', '-', (0, 10))	('miR-20b-5p', 'Var', (0, 10))	('hub', 'Protein', (38, 41))
518321	32752229	The plots indicated that higher expression levels of HMGA2 (HR = 1.33; 95% CI = 1.17-1.52; p < 0.05) and E2F7 (HR = 1.75; 95% CI = 1.37-2.23; p < 0.05) were associated with shorter OS in NSCLC patients.	('patients', 'Species', '9606', (193, 201))	('NSCLC', 'Phenotype', 'HP:0030358', (187, 192))	('HMGA2', 'Gene', (53, 58))	('shorter OS', 'Disease', (173, 183))	('E2F7', 'Var', (105, 109))	('NSCLC', 'Disease', (187, 192))	('NSCLC', 'Disease', 'MESH:D002289', (187, 192))	('higher', 'PosReg', (25, 31))	('SCLC', 'Phenotype', 'HP:0030357', (188, 192))	('expression levels', 'MPA', (32, 49))
518327	32752229	Cancer type summary analysis displayed the overall alteration frequency of all hub genes as shown in Figure 6A i.e., 9.24% of 660 cases with a mutation frequency of 5% (33 cases), amplification frequency of 2.27% (15 cases), deep deletion frequency of 1.67% (11 cases), and multiple alterations with a frequency of 0.3% (2 cases) in case of LUAD.	('amplification', 'Var', (180, 193))	('deep deletion', 'Var', (225, 238))	('alteration', 'Reg', (51, 61))	('LUAD', 'Disease', (341, 345))	('mutation', 'Var', (143, 151))	('LUAD', 'Phenotype', 'HP:0030078', (341, 345))	('Cancer', 'Disease', (0, 6))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))
518329	32752229	Figure 6B shows genetic modification analysis of HMGA2 and E2F7 with an overall gene alteration frequency of both the TFs to be 6% (72 cases out of 1144) which can be further bifurcated into 8.03% of 660 cases of LUAD and 3.93% of 484 cases of LUSC.	('LUAD', 'Phenotype', 'HP:0030078', (213, 217))	('LUSC', 'Phenotype', 'HP:0030359', (244, 248))	('LUAD', 'Disease', (213, 217))	('E2F7', 'Gene', (59, 63))	('genetic modification', 'Var', (16, 36))	('HMGA2', 'Gene', (49, 54))	('TF', 'Gene', '2152', (118, 120))
518356	32752229	Also, a contemporary study has determined that the levels of anti-CCNB1 antibodies increase with histological grades and stages of cancer, supporting the importance of early-stage screening and recurrence follow-up in advanced stages of lung cancer.	('cancer', 'Disease', (131, 137))	('levels', 'MPA', (51, 57))	('increase', 'PosReg', (83, 91))	('cancer', 'Disease', (242, 248))	('cancer', 'Disease', 'MESH:D009369', (242, 248))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('lung cancer', 'Disease', (237, 248))	('lung cancer', 'Disease', 'MESH:D008175', (237, 248))	('lung cancer', 'Phenotype', 'HP:0100526', (237, 248))	('cancer', 'Phenotype', 'HP:0002664', (242, 248))	('anti-CCNB1', 'Var', (61, 71))	('cancer', 'Disease', 'MESH:D009369', (131, 137))
518357	32752229	Additionally, CCNB1 silencing inhibits cellular proliferation and induces cell senescence and apoptosis via P53 signaling pathway.	('P53', 'Gene', '7157', (108, 111))	('cellular proliferation', 'CPA', (39, 61))	('induces', 'Reg', (66, 73))	('cell senescence', 'CPA', (74, 89))	('P53', 'Gene', (108, 111))	('CCNB1', 'Gene', (14, 19))	('silencing', 'Var', (20, 29))	('apoptosis', 'CPA', (94, 103))	('inhibits', 'NegReg', (30, 38))
518364	32752229	A recent study has shown the in vitro and in vivo decrease in cellular proliferation, induction of G2/M cell cycle arrest and increased apoptosis of human breast cancer cells upon RNAi mediated silencing of KIF11.	('KIF11', 'Gene', '3832', (207, 212))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (104, 121))	('arrest', 'Disease', 'MESH:D006323', (115, 121))	('apoptosis', 'CPA', (136, 145))	('silencing', 'Var', (194, 203))	('arrest', 'Disease', (115, 121))	('breast cancer', 'Disease', 'MESH:D001943', (155, 168))	('human', 'Species', '9606', (149, 154))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('breast cancer', 'Disease', (155, 168))	('cellular proliferation', 'CPA', (62, 84))	('breast cancer', 'Phenotype', 'HP:0003002', (155, 168))	('increased', 'PosReg', (126, 135))	('KIF11', 'Gene', (207, 212))	('decrease', 'NegReg', (50, 58))
518368	32752229	Thus, upon inhibition of KIF11, ribosomes no longer bind to microtubules, leading to accumulation of polysomes in intact cells and finally resulting in defective elongation or termination during polypeptide synthesis.	('accumulation', 'PosReg', (85, 97))	('KIF11', 'Gene', (25, 30))	('termination during polypeptide synthesis', 'MPA', (176, 216))	('elongation', 'MPA', (162, 172))	('inhibition', 'Var', (11, 21))	('KIF11', 'Gene', '3832', (25, 30))	('defective', 'NegReg', (152, 161))	('polysomes', 'MPA', (101, 110))
518369	32752229	Moreover, to regulate spindle formation in mitotic cells, KIF11 has been found to be phosphorylated at Thr972 by CDK1, Aurora Kinase A (AURKA), and NIMA-related Kinase 6 (NEK6).	('spindle formation', 'CPA', (22, 39))	('Thr972', 'Var', (103, 109))	('CDK1', 'Gene', '983', (113, 117))	('Thr972', 'Chemical', '-', (103, 109))	('Aurora Kinase A', 'Gene', (119, 134))	('CDK1', 'Gene', (113, 117))	('NIMA-related Kinase 6', 'Gene', '10783', (148, 169))	('KIF11', 'Gene', (58, 63))	('NEK6', 'Gene', (171, 175))	('KIF11', 'Gene', '3832', (58, 63))	('NIMA-related Kinase 6', 'Gene', (148, 169))	('AURKA', 'Gene', '6790', (136, 141))	('NEK6', 'Gene', '10783', (171, 175))	('Aurora Kinase A', 'Gene', '6790', (119, 134))	('AURKA', 'Gene', (136, 141))
518374	32752229	Aneuploidy, abnormal chromosomal distribution, and spindle defects are consequences of aberrant expression of KIF20A and could also be probable causes of tumorigenesis.	('abnormal chromosomal', 'Var', (12, 32))	('tumor', 'Disease', (154, 159))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('KIF20A', 'Gene', (110, 116))	('causes', 'Reg', (144, 150))	('Aneuploidy', 'Disease', 'MESH:D000782', (0, 10))	('KIF20A', 'Gene', '10112', (110, 116))	('aberrant', 'Var', (87, 95))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('spindle defects', 'CPA', (51, 66))	('Aneuploidy', 'Disease', (0, 10))
518380	32752229	Studies have also shown that KIF20A knockdown reduced the proliferation, invasion, and migration of NSCLC cells via regulation of JNK signaling pathways.	('migration', 'CPA', (87, 96))	('JNK', 'Gene', '5599', (130, 133))	('JNK', 'Gene', (130, 133))	('proliferation', 'CPA', (58, 71))	('KIF20A', 'Gene', (29, 35))	('NSCLC', 'Disease', (100, 105))	('SCLC', 'Phenotype', 'HP:0030357', (101, 105))	('KIF20A', 'Gene', '10112', (29, 35))	('NSCLC', 'Disease', 'MESH:D002289', (100, 105))	('knockdown', 'Var', (36, 45))	('reduced', 'NegReg', (46, 53))	('invasion', 'CPA', (73, 81))	('NSCLC', 'Phenotype', 'HP:0030358', (100, 105))	('regulation', 'Reg', (116, 126))
518385	32752229	Studies involving siRNA mediated knockdown of KIF4A have resulted in suppression of NSCLC cell growth and its expression promotes cellular invasion.	('NSCLC', 'Phenotype', 'HP:0030358', (84, 89))	('cellular invasion', 'CPA', (130, 147))	('suppression', 'NegReg', (69, 80))	('knockdown', 'Var', (33, 42))	('KIF4A', 'Gene', (46, 51))	('NSCLC', 'Disease', (84, 89))	('promotes', 'PosReg', (121, 129))	('expression', 'MPA', (110, 120))	('KIF4A', 'Gene', '24137', (46, 51))	('NSCLC', 'Disease', 'MESH:D002289', (84, 89))	('SCLC', 'Phenotype', 'HP:0030357', (85, 89))
518386	32752229	Microarray studies have also demonstrated the decreased OS of NSCLC patients with overexpression of KIF4A.	('NSCLC', 'Disease', (62, 67))	('KIF4A', 'Gene', (100, 105))	('SCLC', 'Phenotype', 'HP:0030357', (63, 67))	('NSCLC', 'Disease', 'MESH:D002289', (62, 67))	('patients', 'Species', '9606', (68, 76))	('KIF4A', 'Gene', '24137', (100, 105))	('decreased', 'NegReg', (46, 55))	('NSCLC', 'Phenotype', 'HP:0030358', (62, 67))	('overexpression', 'Var', (82, 96))
518390	32752229	Despite, the molecular mechanisms behind its overexpression are not yet clarified, it is atypical cancer-testis antigens and scrupulous inhibition of KIF4A using molecular agents could be a promising therapeutic strategy against NSCLC.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('KIF4A', 'Gene', '24137', (150, 155))	('NSCLC', 'Phenotype', 'HP:0030358', (229, 234))	('cancer-testis', 'Disease', (98, 111))	('scrupulous', 'Var', (125, 135))	('cancer-testis', 'Disease', 'MESH:D013736', (98, 111))	('NSCLC', 'Disease', (229, 234))	('NSCLC', 'Disease', 'MESH:D002289', (229, 234))	('KIF4A', 'Gene', (150, 155))	('SCLC', 'Phenotype', 'HP:0030357', (230, 234))
518391	32752229	Nonetheless, one of a recent study has reported contradictory results where the loss of KIF4A lead to multiple mitotic defects such as spindle defects, chromosome misalignment and abnormal cytokinesis, which may lead to tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('chromosome misalignment', 'CPA', (152, 175))	('spindle defects', 'CPA', (135, 150))	('tumor', 'Disease', (220, 225))	('loss', 'Var', (80, 84))	('abnormal cytokinesis', 'CPA', (180, 200))	('lead to', 'Reg', (212, 219))	('KIF4A', 'Gene', (88, 93))	('lead to', 'Reg', (94, 101))	('tumor', 'Disease', 'MESH:D009369', (220, 225))	('KIF4A', 'Gene', '24137', (88, 93))	('mitotic defects', 'Disease', (111, 126))	('mitotic defects', 'Disease', 'MESH:C536987', (111, 126))
518401	32752229	HMGA2 and E2F7 are the two direct targets of miR-20b-5p.	('miR-20b-5p', 'Chemical', '-', (45, 55))	('HMGA2', 'Gene', (0, 5))	('miR-20b-5p', 'Var', (45, 55))	('E2F7', 'Gene', (10, 14))
518407	32752229	Chromosomal aberrations in the region 12q14-15, affecting HMGA2 are generally observed in a wide range of tumors.	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('Chromosomal aberrations', 'Var', (0, 23))	('tumors', 'Disease', (106, 112))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('Chromosomal aberrations', 'Phenotype', 'HP:0040012', (0, 23))	('observed', 'Reg', (78, 86))	('affecting', 'Reg', (48, 57))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('HMGA2', 'Gene', (58, 63))
518418	32752229	Overall, it can be speculated that genetic modifications could lead to an abrupt upregulation of HMGA2 and E2F7, which are involved in uncontrolled transition of the cells from G1 to S phase via CCNB1 and CDK1 mediated phosphorylation of Rb protein.	('Rb', 'Phenotype', 'HP:0009919', (238, 240))	('CDK1', 'Gene', (205, 209))	('upregulation', 'PosReg', (81, 93))	('E2F7', 'Gene', (107, 111))	('genetic modifications', 'Var', (35, 56))	('CDK1', 'Gene', '983', (205, 209))	('HMGA2', 'Gene', (97, 102))
518420	32752229	Furthermore, downregulation of miR-20b-5p worsens the OS of NSCLC patients, as demonstrated by Kaplan Meir Survival analysis (Figure 5), which is suggestive of the tumor-suppressive functions of miR-20b-5p.	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('tumor-suppressive', 'Disease', 'MESH:D009369', (164, 181))	('miR-20b-5p', 'Chemical', '-', (195, 205))	('NSCLC', 'Phenotype', 'HP:0030358', (60, 65))	('downregulation', 'NegReg', (13, 27))	('SCLC', 'Phenotype', 'HP:0030357', (61, 65))	('worsens', 'NegReg', (42, 49))	('miR-20b-5p', 'Chemical', '-', (31, 41))	('NSCLC', 'Disease', (60, 65))	('tumor-suppressive', 'Disease', (164, 181))	('miR-20b-5p', 'Var', (31, 41))	('patients', 'Species', '9606', (66, 74))	('NSCLC', 'Disease', 'MESH:D002289', (60, 65))
518421	32752229	Similarly, our study has found that mir-20b-5p targets both HMGA2 and E2F7 (both having a good frequency of genetic alterations in NSCLC, particularly in LUAD) and genetic alterations in HMGA2 and E2F7 may alter its 3'UTR site, consequently inhibiting miR-20b-5p mediated repression of HMGA2 and E2F7.	('miR-20b-5p', 'Chemical', '-', (252, 262))	('LUAD', 'Phenotype', 'HP:0030078', (154, 158))	('miR-20b-5p mediated repression', 'MPA', (252, 282))	('HMGA2', 'Gene', (187, 192))	("3'UTR site", 'MPA', (216, 226))	('NSCLC', 'Disease', (131, 136))	('SCLC', 'Phenotype', 'HP:0030357', (132, 136))	('inhibiting', 'NegReg', (241, 251))	('HMGA2', 'Gene', (60, 65))	('E2F7', 'Gene', (70, 74))	('NSCLC', 'Disease', 'MESH:D002289', (131, 136))	('alter', 'Reg', (206, 211))	('genetic alterations', 'Var', (164, 183))	('E2F7', 'Gene', (197, 201))	('NSCLC', 'Phenotype', 'HP:0030358', (131, 136))
518424	32752229	Therefore, upon overexpression of miR-20b-5p, the tumor-suppressive effects could be rescued back by regulating cell cycle and promoting apoptosis, which could prove to be an effective strategy of treatment of NSCLC.	('promoting', 'PosReg', (127, 136))	('apoptosis', 'CPA', (137, 146))	('overexpression', 'PosReg', (16, 30))	('tumor-suppressive', 'Disease', 'MESH:D009369', (50, 67))	('tumor-suppressive', 'Disease', (50, 67))	('miR-20b-5p', 'Chemical', '-', (34, 44))	('NSCLC', 'Disease', (210, 215))	('miR-20b-5p', 'Var', (34, 44))	('NSCLC', 'Disease', 'MESH:D002289', (210, 215))	('SCLC', 'Phenotype', 'HP:0030357', (211, 215))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('regulating', 'PosReg', (101, 111))	('cell cycle', 'CPA', (112, 122))	('NSCLC', 'Phenotype', 'HP:0030358', (210, 215))
518430	32752229	Overall, this study has identified certain novel molecules (miR-20b-5p, CCNB1, HMGA2, and E2F7), all of which could possess a great therapeutic and prognostic potential, which has not yet been identified in NSCLC.	('NSCLC', 'Phenotype', 'HP:0030358', (207, 212))	('miR-20b-5p', 'Chemical', '-', (60, 70))	('miR-20b-5p', 'Var', (60, 70))	('E2F7', 'Gene', (90, 94))	('SCLC', 'Phenotype', 'HP:0030357', (208, 212))	('HMGA2', 'Gene', (79, 84))	('NSCLC', 'Disease', (207, 212))	('NSCLC', 'Disease', 'MESH:D002289', (207, 212))	('CCNB1', 'Gene', (72, 77))
518431	32752229	Studies have reported that these targets are commonly involved in the deregulation of cell cycle because of genetic modifications, and escape from immunosurveillance, which are predominant hallmarks of cancer.	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('deregulation', 'MPA', (70, 82))	('cell cycle', 'CPA', (86, 96))	('cancer', 'Disease', 'MESH:D009369', (202, 208))	('cancer', 'Disease', (202, 208))	('genetic modifications', 'Var', (108, 129))	('involved', 'Reg', (54, 62))
518436	32752229	Moreover, genetic modification status of HMGA2 and E2F7 determines the involvement of epigenetic modifications in affecting miR-20b-5p mediated repression of these TFs, sequentially resulting in their upregulation.	('upregulation', 'PosReg', (201, 213))	('genetic modification', 'Var', (10, 30))	('E2F7', 'Gene', (51, 55))	('miR-20b-5p', 'Gene', (124, 134))	('TF', 'Gene', '2152', (164, 166))	('epigenetic modifications', 'Var', (86, 110))	('repression', 'NegReg', (144, 154))	('miR-20b-5p', 'Chemical', '-', (124, 134))
518438	32752229	Our findings contribute in providing an innovative comprehension into NSCLC via miR-20b-5p/CCNB1/HMGA2/E2F7.	('NSCLC', 'Disease', (70, 75))	('NSCLC', 'Disease', 'MESH:D002289', (70, 75))	('miR-20b-5p/CCNB1/HMGA2/E2F7', 'Var', (80, 107))	('SCLC', 'Phenotype', 'HP:0030357', (71, 75))	('miR-20b-5p', 'Chemical', '-', (80, 90))	('NSCLC', 'Phenotype', 'HP:0030358', (70, 75))
518440	32807223	Comprehensive analysis of the mechanism and treatment significance of Mucins in lung cancer Aberrant expression of mucin proteins has played a complex and essential role in cancer development and metastasis.	('Aberrant', 'Var', (92, 100))	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('men', 'Species', '9606', (49, 52))	('lung cancer', 'Disease', 'MESH:D008175', (80, 91))	('cancer', 'Disease', (173, 179))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('men', 'Species', '9606', (187, 190))	('mucin', 'Gene', '100508689', (115, 120))	('cancer', 'Disease', (85, 91))	('lung cancer', 'Disease', (80, 91))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('lung cancer', 'Phenotype', 'HP:0100526', (80, 91))	('expression', 'MPA', (101, 111))	('mucin', 'Gene', (115, 120))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
518464	32807223	summarized the MUC1 expression in lung cancer, which found high expression of MUC1 predicts poor survival in the majority of studies.	('MUC1', 'Gene', (15, 19))	('lung cancer', 'Disease', (34, 45))	('MUC1', 'Gene', '4582', (15, 19))	('lung cancer', 'Phenotype', 'HP:0100526', (34, 45))	('MUC1', 'Gene', (78, 82))	('MUC1', 'Gene', '4582', (78, 82))	('poor', 'NegReg', (92, 96))	('high', 'Var', (59, 63))	('lung cancer', 'Disease', 'MESH:D008175', (34, 45))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))
518473	32807223	It has recently reported that co-occurring genomic alterations as mediators of diverse NSCLC phenotypes impacted molecular stratification framework shave, which emerged as a major tenets of the molecular diversity of NSCLC.	('NSCLC', 'Disease', (217, 222))	('alterations', 'Var', (51, 62))	('NSCLC', 'Disease', (87, 92))	('NSCLC', 'Disease', 'MESH:D002289', (217, 222))	('NSCLC', 'Disease', 'MESH:D002289', (87, 92))	('impacted', 'Reg', (104, 112))	('molecular', 'CPA', (113, 122))	('NSCLC', 'Phenotype', 'HP:0030358', (217, 222))	('NSCLC', 'Phenotype', 'HP:0030358', (87, 92))
518479	32807223	demonstrated that knockdown MUC1 could activate apoptosis and inhibit cell proliferation and metastasis, as well as be sensitized to cisplatin treatment by modulating STAT3/Akt, SRC/FAK and Bcl-XL/Bcl-2 signaling pathways in NSCLC.	('Akt', 'Gene', (173, 176))	('STAT3', 'Gene', '6774', (167, 172))	('Bcl-2', 'Gene', (197, 202))	('inhibit', 'NegReg', (62, 69))	('Bcl-XL', 'Gene', '598', (190, 196))	('Akt', 'Gene', '207', (173, 176))	('Bcl-XL', 'Gene', (190, 196))	('Bcl-2', 'Gene', '596', (197, 202))	('NSCLC', 'Disease', 'MESH:D002289', (225, 230))	('cisplatin', 'Chemical', 'MESH:D002945', (133, 142))	('MUC1', 'Gene', (28, 32))	('MUC1', 'Gene', '4582', (28, 32))	('knockdown', 'Var', (18, 27))	('cell proliferation', 'CPA', (70, 88))	('NSCLC', 'Disease', (225, 230))	('FAK', 'Gene', (182, 185))	('SRC', 'Gene', '6714', (178, 181))	('modulating', 'Reg', (156, 166))	('NSCLC', 'Phenotype', 'HP:0030358', (225, 230))	('men', 'Species', '9606', (148, 151))	('SRC', 'Gene', (178, 181))	('FAK', 'Gene', '5747', (182, 185))	('STAT3', 'Gene', (167, 172))	('apoptosis', 'CPA', (48, 57))	('activate', 'PosReg', (39, 47))
518483	32807223	Another complex, MUC1/beta-catenin/TCF4 is directly bound to the MYC promoter and promotes the recruitment of p300 histone acetylase (EP300), which can induce histone H3 acetylation and MYC gene transcription, in turns downregulate MYC-target genes.	('EP300', 'Gene', (134, 139))	('histone', 'MPA', (159, 166))	('TCF4', 'Gene', (35, 39))	('MYC', 'Gene', (232, 235))	('MYC', 'Gene', (186, 189))	('MYC', 'Gene', (65, 68))	('p300', 'Var', (110, 114))	('downregulate', 'NegReg', (219, 231))	('induce', 'PosReg', (152, 158))	('MYC', 'Gene', '4609', (186, 189))	('transcription', 'MPA', (195, 208))	('MYC', 'Gene', '4609', (232, 235))	('MUC1', 'Gene', (17, 21))	('MUC1', 'Gene', '4582', (17, 21))	('beta-catenin', 'Gene', (22, 34))	('MYC', 'Gene', '4609', (65, 68))	('men', 'Species', '9606', (102, 105))	('beta-catenin', 'Gene', '1499', (22, 34))	('EP300', 'Gene', '2033', (134, 139))	('TCF4', 'Gene', '6925', (35, 39))
518488	32807223	demonstrated that knockout MUC1 could significantly increase the apophatic toxicity of displaying, doxorubicin and TRAIL induced anti-apoptotic lung cancer cells.	('toxicity', 'Disease', 'MESH:D064420', (75, 83))	('toxicity', 'Disease', (75, 83))	('lung cancer', 'Disease', (144, 155))	('lung cancer', 'Disease', 'MESH:D008175', (144, 155))	('doxorubicin', 'Chemical', 'MESH:D004317', (99, 110))	('lung cancer', 'Phenotype', 'HP:0100526', (144, 155))	('increase', 'PosReg', (52, 60))	('TRAIL', 'Gene', '8743', (115, 120))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('MUC1', 'Gene', (27, 31))	('TRAIL', 'Gene', (115, 120))	('knockout', 'Var', (18, 26))	('doxorubicin', 'MPA', (99, 110))	('MUC1', 'Gene', '4582', (27, 31))
518489	32807223	And miR-551b/catalase/ROS axis gives rise to MUC1 overexposure following EGFR-mediated activation of the cell survival cascade involving Akt/c-FLIP/COX-2.	('c-FLIP', 'Gene', '8837', (141, 147))	('c-FLIP', 'Gene', (141, 147))	('EGFR', 'Gene', '1956', (73, 77))	('COX-2', 'Gene', (148, 153))	('overexposure', 'PosReg', (50, 62))	('Akt', 'Gene', '207', (137, 140))	('EGFR', 'Gene', (73, 77))	('miR-551b/catalase/ROS', 'Var', (4, 25))	('cell survival', 'CPA', (105, 118))	('Akt', 'Gene', (137, 140))	('MUC1', 'Gene', (45, 49))	('MUC1', 'Gene', '4582', (45, 49))	('ROS', 'Chemical', 'MESH:D017382', (22, 25))	('COX-2', 'Gene', '4513', (148, 153))
518490	32807223	In PTX-resistant lung cancer cells, overexposure of MUC1 promotes proliferation, stemness by regulating PI3K/Akt signaling and cancer stemness biomarkers.	('PTX', 'Chemical', '-', (3, 6))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('overexposure', 'Var', (36, 48))	('Akt', 'Gene', '207', (109, 112))	('lung cancer', 'Disease', (17, 28))	('lung cancer', 'Phenotype', 'HP:0100526', (17, 28))	('stemness', 'CPA', (81, 89))	('proliferation', 'CPA', (66, 79))	('cancer stemness', 'Disease', 'MESH:D009369', (127, 142))	('Akt', 'Gene', (109, 112))	('cancer stemness', 'Disease', (127, 142))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('lung cancer', 'Disease', 'MESH:D008175', (17, 28))	('MUC1', 'Gene', '4582', (52, 56))	('MUC1', 'Gene', (52, 56))	('regulating', 'Reg', (93, 103))	('promotes', 'PosReg', (57, 65))
518492	32807223	MUC5AC interacts with integrin beta4 recruit phosphorylation of FAK (Y397) activated downstream signaling pathways, leading to lung cancer cell migration.	('MUC5AC', 'Gene', (0, 6))	('integrin beta4', 'Gene', '3691', (22, 36))	('lung cancer', 'Disease', (127, 138))	('lung cancer', 'Phenotype', 'HP:0100526', (127, 138))	('FAK', 'Gene', (64, 67))	('activated', 'PosReg', (75, 84))	('FAK', 'Gene', '5747', (64, 67))	('MUC5AC', 'Gene', '4586', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('leading to', 'Reg', (116, 126))	('integrin beta4', 'Gene', (22, 36))	('lung cancer', 'Disease', 'MESH:D008175', (127, 138))	('downstream signaling pathways', 'Pathway', (85, 114))	('phosphorylation', 'Var', (45, 60))
518495	32807223	MUC16 mutations are associated with MUC16 mRNA and protein up-regulation, furthermore promotes the proliferation, enhances migration and invasion and increases cisplatin resistance of lung cancer.	('cisplatin', 'Chemical', 'MESH:D002945', (160, 169))	('promotes', 'PosReg', (86, 94))	('cisplatin resistance', 'MPA', (160, 180))	('MUC16', 'Gene', '94025', (0, 5))	('enhances', 'PosReg', (114, 122))	('invasion', 'CPA', (137, 145))	('lung cancer', 'Disease', 'MESH:D008175', (184, 195))	('N', 'Chemical', 'MESH:D009584', (44, 45))	('MUC16', 'Gene', (36, 41))	('lung cancer', 'Phenotype', 'HP:0100526', (184, 195))	('mutations', 'Var', (6, 15))	('MUC16', 'Gene', (0, 5))	('migration', 'CPA', (123, 132))	('increases', 'PosReg', (150, 159))	('proliferation', 'CPA', (99, 112))	('up-regulation', 'PosReg', (59, 72))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('mRNA and', 'MPA', (42, 50))	('lung cancer', 'Disease', (184, 195))	('MUC16', 'Gene', '94025', (36, 41))
518522	32807223	Several studies have reported how G0-203 work in NSCLC.	('G0-203', 'Var', (34, 40))	('NSCLC', 'Phenotype', 'HP:0030358', (49, 54))	('NSCLC', 'Disease', 'MESH:D002289', (49, 54))	('NSCLC', 'Disease', (49, 54))
518523	32807223	GO-203 inhibits NSCLC cell growth and survival by preventing the integration between MUC1-C and PI3K-p85, and suppresses constitutive phosphorylation of Akt and its downstream effector, mTOR.	('suppresses', 'NegReg', (110, 120))	('Akt', 'Gene', '207', (153, 156))	('NSCLC', 'Disease', 'MESH:D002289', (16, 21))	('NSCLC', 'Phenotype', 'HP:0030358', (16, 21))	('mTOR', 'Gene', (186, 190))	('inhibits', 'NegReg', (7, 15))	('mTOR', 'Gene', '2475', (186, 190))	('GO-203', 'Var', (0, 6))	('Akt', 'Gene', (153, 156))	('integration', 'Interaction', (65, 76))	('p85', 'Gene', '5296', (101, 104))	('preventing', 'NegReg', (50, 60))	('NSCLC', 'Disease', (16, 21))	('MUC1', 'Gene', (85, 89))	('constitutive phosphorylation', 'MPA', (121, 149))	('MUC1', 'Gene', '4582', (85, 89))	('GO-203', 'Chemical', 'MESH:C582521', (0, 6))	('p85', 'Gene', (101, 104))
518525	32807223	Silencing MUC1-C in H1975/EGFR(L858R/T790M) cells suppresses AKT signaling pathway, and inhibits cell proliferation of lung cancer.	('EGFR', 'Gene', (26, 30))	('H1975', 'CellLine', 'CVCL:1511', (20, 25))	('T790M', 'Mutation', 'rs121434569', (37, 42))	('lung cancer', 'Disease', (119, 130))	('lung cancer', 'Phenotype', 'HP:0100526', (119, 130))	('L858R', 'SUBSTITUTION', 'None', (31, 36))	('suppresses', 'NegReg', (50, 60))	('L858R', 'Var', (31, 36))	('AKT', 'Gene', '207', (61, 64))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('cell proliferation of', 'CPA', (97, 118))	('inhibits', 'NegReg', (88, 96))	('lung cancer', 'Disease', 'MESH:D008175', (119, 130))	('EGFR', 'Gene', '1956', (26, 30))	('AKT', 'Gene', (61, 64))	('Silencing', 'Var', (0, 9))	('MUC1', 'Gene', (10, 14))	('MUC1', 'Gene', '4582', (10, 14))
518526	32807223	Combining GO-203 with afatinib work synergistically can inhibit the growth of NSCLC cells with EGFR(T790M) or EGFR (delE746-A750) mutants.	('delE746-A750', 'Var', (116, 128))	('EGFR', 'Gene', '1956', (110, 114))	('EGFR', 'Gene', (110, 114))	('NSCLC', 'Phenotype', 'HP:0030358', (78, 83))	('delE746', 'Mutation', 'p.746delE', (116, 123))	('NSCLC', 'Disease', (78, 83))	('GO-203', 'Chemical', 'MESH:C582521', (10, 16))	('EGFR', 'Gene', '1956', (95, 99))	('afatinib', 'Chemical', 'MESH:D000077716', (22, 30))	('T790M', 'Mutation', 'rs121434569', (100, 105))	('NSCLC', 'Disease', 'MESH:D002289', (78, 83))	('growth', 'CPA', (68, 74))	('inhibit', 'NegReg', (56, 63))	('EGFR', 'Gene', (95, 99))
518528	32807223	Silencing MUC1-C in KRAS(G12S) and KRAS(Q61H) mutated NSCLC cells results in downregulation of AKT and MEK signaling and represses ZEB1/miR-200c loop, thereby reverses the EMT phenotype, decreases self-renewal and attenuates the proliferation of KRAS mutant NSCLC cells.	('KRAS', 'Gene', '3845', (20, 24))	('ZEB1', 'Gene', '6935', (131, 135))	('MEK', 'Gene', (103, 106))	('proliferation', 'CPA', (229, 242))	('Silencing', 'Var', (0, 9))	('KRAS', 'Gene', (20, 24))	('NSCLC', 'Disease', 'MESH:D002289', (54, 59))	('downregulation', 'NegReg', (77, 91))	('NSCLC', 'Disease', 'MESH:D002289', (258, 263))	('AKT', 'Gene', '207', (95, 98))	('KRAS', 'Gene', '3845', (35, 39))	('G12S', 'Mutation', 'rs121913530', (25, 29))	('decreases', 'NegReg', (187, 196))	('NSCLC', 'Disease', (54, 59))	('Q61H', 'Mutation', 'rs17851045', (40, 44))	('NSCLC', 'Disease', (258, 263))	('KRAS', 'Gene', (35, 39))	('reverses', 'Reg', (159, 167))	('ZEB1', 'Gene', (131, 135))	('NSCLC', 'Phenotype', 'HP:0030358', (54, 59))	('represses', 'NegReg', (121, 130))	('NSCLC', 'Phenotype', 'HP:0030358', (258, 263))	('miR-200c', 'Gene', '406985', (136, 144))	('attenuates', 'NegReg', (214, 224))	('KRAS', 'Gene', '3845', (246, 250))	('MUC1', 'Gene', (10, 14))	('MUC1', 'Gene', '4582', (10, 14))	('EMT', 'Gene', (172, 175))	('EMT', 'Gene', '3702', (172, 175))	('KRAS', 'Gene', (246, 250))	('MEK', 'Gene', '5609', (103, 106))	('miR-200c', 'Gene', (136, 144))	('AKT', 'Gene', (95, 98))	('self-renewal', 'CPA', (197, 209))
518534	32807223	In Phase II study of TG4010, there were 65 patients with MUC1 positively treated with TG4010 in combination with cisplatin and vinorelbine as first-line chemotherapy.	('patients', 'Species', '9606', (43, 51))	('MUC1', 'Gene', (57, 61))	('MUC1', 'Gene', '4582', (57, 61))	('TG4010', 'Var', (86, 92))	('cisplatin', 'Chemical', 'MESH:D002945', (113, 122))	('vinorelbine', 'Chemical', 'MESH:D000077235', (127, 138))
518535	32807223	The 65 patients were divided into two groups: Group 1, a TG4010-chemotherapy combination; and Group 2, a sequential protocol in which TG4010 was first administered as monotherapy until got partial response then combined with chemotherapy.	('TG4010', 'Var', (134, 140))	('TG4010-chemotherapy', 'Var', (57, 76))	('patients', 'Species', '9606', (7, 15))
518536	32807223	(NCT00415818), 148 patients with advanced (stage IIIB or IV) NSCLC with MUC1 positively were enrolled in parallel groups, that patients in experiment treated were allocated to the combination therapy group, and received TG4010 plaque forming with TG4010 plus cisplatin and gemcitabine while the control group received the same chemotherapy alone.	('MUC1', 'Gene', (72, 76))	('men', 'Species', '9606', (145, 148))	('MUC1', 'Gene', '4582', (72, 76))	('N', 'Chemical', 'MESH:D009584', (61, 62))	('patients', 'Species', '9606', (19, 27))	('NSCLC', 'Phenotype', 'HP:0030358', (61, 66))	('cisplatin', 'Chemical', 'MESH:D002945', (259, 268))	('TG4010', 'Var', (247, 253))	('patients', 'Species', '9606', (127, 135))	('gemcitabine', 'Chemical', 'MESH:C056507', (273, 284))	('NSCLC', 'Disease', (61, 66))	('TG4010', 'Var', (220, 226))	('NSCLC', 'Disease', 'MESH:D002289', (61, 66))	('N', 'Chemical', 'MESH:D009584', (1, 2))
518538	32807223	Both of these studies demonstrated TG4010 plus chemotherapy improve PFS and OS outcome in MUC1-positive patients.	('MUC1', 'Gene', (90, 94))	('MUC1', 'Gene', '4582', (90, 94))	('PFS', 'Disease', (68, 71))	('TG4010', 'Var', (35, 41))	('patients', 'Species', '9606', (104, 112))	('improve', 'PosReg', (60, 67))
518539	32807223	Recently, a study of 78 patients which all coming from the TIME study carrying the HLA-A02*01 haplotype indicated TG4010 treatment broadens CD8 + T cell against responses to MUC1 as well as other non-targeted TAA.	('men', 'Species', '9606', (126, 129))	('CD8', 'Gene', (140, 143))	('CD8', 'Gene', '925', (140, 143))	('HLA-A', 'Gene', '3105', (83, 88))	('MUC1', 'Gene', (174, 178))	('TAA', 'Disease', 'None', (209, 212))	('MUC1', 'Gene', '4582', (174, 178))	('patients', 'Species', '9606', (24, 32))	('HLA-A', 'Gene', (83, 88))	('TG4010 treatment', 'Var', (114, 130))	('TAA', 'Disease', (209, 212))	('broadens', 'PosReg', (131, 139))
518541	32807223	Moreover, there are two clinical trials (NCT02823990 and NCT03353675) in studying about combing TG4010 and Nivolumab in NSCLC patients (Table 2).	('NCT03353675', 'Var', (57, 68))	('NSCLC', 'Disease', 'MESH:D002289', (120, 125))	('N', 'Chemical', 'MESH:D009584', (57, 58))	('N', 'Chemical', 'MESH:D009584', (120, 121))	('NSCLC', 'Phenotype', 'HP:0030358', (120, 125))	('TG4010', 'Gene', (96, 102))	('Nivolumab', 'Chemical', 'MESH:D000077594', (107, 116))	('patients', 'Species', '9606', (126, 134))	('N', 'Chemical', 'MESH:D009584', (107, 108))	('N', 'Chemical', 'MESH:D009584', (41, 42))	('NSCLC', 'Disease', (120, 125))	('NCT02823990', 'Var', (41, 52))
518544	32807223	conducted a Phase IIB Trial in stage IIIB or IV NSCLC patients, which patients were treated with either L-BLP25 plus best supportive care (BSC) or BSC alone.	('patients', 'Species', '9606', (70, 78))	('NSCLC', 'Disease', (48, 53))	('NSCLC', 'Phenotype', 'HP:0030358', (48, 53))	('patients', 'Species', '9606', (54, 62))	('NSCLC', 'Disease', 'MESH:D002289', (48, 53))	('L-BLP25', 'Var', (104, 111))
518545	32807223	The 3-year following up results demonstrated a median survival time was longer in patients treated with L-BLP25 plus BSC compared with BSC alone, and patients in stage IIIB LR disease showed the greatest difference.	('patients', 'Species', '9606', (82, 90))	('longer', 'PosReg', (72, 78))	('patients', 'Species', '9606', (150, 158))	('L-BLP25', 'Var', (104, 111))
518548	32807223	in Japanese unresectable Stage III NSCLC (NCT00960115) found that L-BLP25 has no greater treatment effect in individuals than those received primary concurrent chemoradiotherapy.	('NSCLC', 'Disease', (35, 40))	('men', 'Species', '9606', (94, 97))	('NSCLC', 'Disease', 'MESH:D002289', (35, 40))	('L-BLP25', 'Var', (66, 73))	('N', 'Chemical', 'MESH:D009584', (42, 43))	('N', 'Chemical', 'MESH:D009584', (35, 36))	('NSCLC', 'Phenotype', 'HP:0030358', (35, 40))
518561	32807223	This work was supported by the National Natural Science Foundations of China (No: 81773218, 81972838, 81472773 and 81703009) and The Natural Sciences Foundations of Hunan Province (No: 2017JJ3457).	('81703009', 'Var', (115, 123))	('N', 'Chemical', 'MESH:D009584', (78, 79))	('N', 'Chemical', 'MESH:D009584', (40, 41))	('N', 'Chemical', 'MESH:D009584', (133, 134))	('N', 'Chemical', 'MESH:D009584', (181, 182))	('81472773', 'Var', (102, 110))	('N', 'Chemical', 'MESH:D009584', (31, 32))	('81972838', 'Var', (92, 100))
518563	31737116	Prognostic Value of Survival of MicroRNAs Signatures in Non-small Cell Lung Cancer Introduction: Accumulating evidence showed that a large number of microRNAs (miRNAs) are abnormally expressed in lung cancer tissues and play critical roles in cancer development and progression.	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('cancer', 'Disease', (201, 207))	('lung cancer', 'Disease', (196, 207))	('microRNAs', 'Var', (149, 158))	('Non-small Cell Lung Cancer', 'Disease', (56, 82))	('Non-small Cell Lung Cancer', 'Disease', 'MESH:D002289', (56, 82))	('lung cancer', 'Phenotype', 'HP:0100526', (196, 207))	('cancer', 'Disease', (243, 249))	('cancer', 'Disease', 'MESH:D009369', (243, 249))	('Lung Cancer', 'Phenotype', 'HP:0100526', (71, 82))	('small Cell Lung Cancer', 'Phenotype', 'HP:0030357', (60, 82))	('Non-small Cell Lung Cancer', 'Phenotype', 'HP:0030358', (56, 82))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('play', 'Reg', (220, 224))	('roles', 'Reg', (234, 239))	('Cancer', 'Phenotype', 'HP:0002664', (76, 82))	('cancer', 'Phenotype', 'HP:0002664', (243, 249))	('lung cancer', 'Disease', 'MESH:D008175', (196, 207))
518573	31737116	Multiple evidence has demonstrated that miRNAs regulated various tumorigenesis processes including cell maturation, proliferation, apoptosis, motility, invasiveness, and autophagy.	('invasiveness', 'CPA', (152, 164))	('tumor', 'Disease', (65, 70))	('cell maturation', 'CPA', (99, 114))	('motility', 'CPA', (142, 150))	('regulated', 'Reg', (47, 56))	('autophagy', 'CPA', (170, 179))	('miRNAs', 'Var', (40, 46))	('proliferation', 'CPA', (116, 129))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('apoptosis', 'CPA', (131, 140))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
518619	31737116	The KEGG pathways were mainly enriched in miRNAs in cancer, PI3K-Akt signaling pathway, and other pathways in cancer.	('KEGG pathways', 'Pathway', (4, 17))	('cancer', 'Disease', (110, 116))	('Akt', 'Gene', (65, 68))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('Akt', 'Gene', '207', (65, 68))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('miRNAs', 'Var', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (110, 116))
518632	31737116	In recent years many studies have revealed that the aberrant expression of miRNA is closely related to tumorigenesis and is now an intense field of study.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor', 'Disease', (103, 108))	('related', 'Reg', (92, 99))	('aberrant expression', 'Var', (52, 71))	('miRNA', 'Gene', (75, 80))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
518642	31737116	To date, several studies had identified a number of miRNAs with prognostic values in NSCLC, such as miR-21, miR-200c, miR-125b, miR-148b, miR-365, miR-124, miR-32, miR-146a, and so on.	('miR-200c', 'Gene', (108, 116))	('NSCLC', 'Disease', (85, 90))	('miR-21', 'Gene', '406991', (100, 106))	('miR-146a', 'Gene', '406938', (164, 172))	('miR-200c', 'Gene', '406985', (108, 116))	('NSCLC', 'Disease', 'MESH:D002289', (85, 90))	('miR-124', 'Var', (147, 154))	('miR-32', 'Gene', (156, 162))	('miR-148b', 'Gene', '442892', (128, 136))	('miR-148b', 'Gene', (128, 136))	('miR-21', 'Gene', (100, 106))	('NSCLC', 'Phenotype', 'HP:0030358', (85, 90))	('miR-146a', 'Gene', (164, 172))	('SCLC', 'Phenotype', 'HP:0030357', (86, 90))	('miR-125b', 'Var', (118, 126))	('miR-365', 'Var', (138, 145))	('miR-32', 'Gene', '407036', (156, 162))
518648	31737116	The alteration of miR-375 in cancer is caused by a variety of mechanisms, including the dysregulation of transcription factors, aberrant promoter methylation and so on.	('promoter methylation', 'MPA', (137, 157))	('cancer', 'Disease', (29, 35))	('dysregulation', 'MPA', (88, 101))	('caused by', 'Reg', (39, 48))	('miR-375', 'Gene', (18, 25))	('aberrant', 'Var', (128, 136))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('alteration', 'Var', (4, 14))	('transcription factors', 'Protein', (105, 126))	('miR-375', 'Gene', '494324', (18, 25))	('cancer', 'Disease', 'MESH:D009369', (29, 35))
518658	31737116	However, high expression of miR-584 is associated with worse OS in LUAD patients.	('miR-584', 'Gene', (28, 35))	('worse OS', 'Disease', (55, 63))	('patients', 'Species', '9606', (72, 80))	('miR-584', 'Gene', '693169', (28, 35))	('associated', 'Reg', (39, 49))	('LUAD', 'Disease', (67, 71))	('LUAD', 'Disease', 'MESH:C538231', (67, 71))	('LUAD', 'Phenotype', 'HP:0030078', (67, 71))	('high', 'Var', (9, 13))
518664	31737116	However, in our study, we showed that high expression of miR-326 is associated with worse OS in LUSC patients.	('LUSC', 'Disease', 'MESH:D002294', (96, 100))	('LUSC', 'Disease', (96, 100))	('patients', 'Species', '9606', (101, 109))	('LUSC', 'Phenotype', 'HP:0030359', (96, 100))	('associated', 'Reg', (68, 78))	('high expression', 'Var', (38, 53))	('worse OS', 'Disease', (84, 92))	('miR-326', 'Gene', (57, 64))	('miR-326', 'Gene', '442900', (57, 64))
518707	31976112	Integrated computed tomography and 18F-2-deoxy-2-fluoro-D-glucose (FDG) positron emission tomography (PET/CT) showed uptake of FDG by a left pulmonary hilar lesion and both ipsilateral mediastinal and subcarinal lymph nodes, because of which lung cancer with metastasis to the lymph nodes was highly suspected (Figures 1(b)-1(d)).	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('FDG', 'Chemical', 'MESH:C554683', (67, 70))	('metastasis', 'Disease', 'MESH:D009362', (259, 269))	('metastasis', 'Disease', (259, 269))	('lung cancer', 'Disease', 'MESH:D008175', (242, 253))	('FDG', 'Var', (127, 130))	('FDG', 'Chemical', 'MESH:C554683', (127, 130))	('lung cancer', 'Disease', (242, 253))	('left pulmonary hilar lesion', 'Disease', (136, 163))	('left pulmonary hilar lesion', 'Disease', 'MESH:D008171', (136, 163))	('lung cancer', 'Phenotype', 'HP:0100526', (242, 253))	('18F-2-deoxy-2-fluoro-D-glucose', 'Chemical', 'MESH:C554683', (35, 65))
518749	30993736	For patients in different clinical stages, genes can have different effects on the Breslow thickness, which is a continuous variable and has been extensively used as a prognostic indicator for melanoma.	('Breslow thickness', 'CPA', (83, 100))	('melanoma', 'Disease', 'MESH:D008545', (193, 201))	('melanoma', 'Phenotype', 'HP:0002861', (193, 201))	('melanoma', 'Disease', (193, 201))	('genes', 'Var', (43, 48))	('patients', 'Species', '9606', (4, 12))	('effects', 'Reg', (68, 75))
518781	30993736	Moreover, it has been demonstrated that SEMA3A suppresses tumor growth and metastasis using multiple in vitro and in vivo approaches in mice melanoma models.	('melanoma', 'Phenotype', 'HP:0002861', (141, 149))	('tumor', 'Disease', (58, 63))	('melanoma', 'Disease', (141, 149))	('mice', 'Species', '10090', (136, 140))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('melanoma', 'Disease', 'MESH:D008545', (141, 149))	('suppresses', 'NegReg', (47, 57))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('SEMA3A', 'Var', (40, 46))
518798	30993736	It has been suggested that APOBEC-mediated mutagenesis is universal throughout cancer genomes, and a significant presence of the APOBEC mutation pattern has been found in breast, cervical, bladder, head, neck, and lung cancers.	('cervical', 'Disease', (179, 187))	('cancer', 'Disease', 'MESH:D009369', (219, 225))	('breast', 'Disease', (171, 177))	('found', 'Reg', (162, 167))	('bladder', 'Disease', (189, 196))	('APOBEC', 'Gene', (129, 135))	('cancer', 'Disease', (79, 85))	('lung cancers', 'Disease', 'MESH:D008175', (214, 226))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('mutation', 'Var', (136, 144))	('cancers', 'Phenotype', 'HP:0002664', (219, 226))	('cancer', 'Disease', (219, 225))	('lung cancers', 'Disease', (214, 226))	('lung cancer', 'Phenotype', 'HP:0100526', (214, 225))	('head', 'Disease', (198, 202))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('lung cancers', 'Phenotype', 'HP:0100526', (214, 226))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('presence', 'Reg', (113, 121))
518809	25578493	Aberrant expression and dysfunction of miR-93 are involved in many types of human tumours.	('tumour', 'Phenotype', 'HP:0002664', (82, 88))	('Aberrant expression', 'Var', (0, 19))	('tumours', 'Phenotype', 'HP:0002664', (82, 89))	('dysfunction', 'Var', (24, 35))	('human', 'Species', '9606', (76, 81))	('tumours', 'Disease', 'MESH:D009369', (82, 89))	('tumours', 'Disease', (82, 89))	('miR-93', 'Gene', '407051', (39, 45))	('miR-93', 'Gene', (39, 45))	('involved', 'Reg', (50, 58))
518815	25578493	Notably, high miR-93 expression was significantly associated with T classification, lymph node metastasis and clinical stage.	('lymph node metastasis', 'CPA', (84, 105))	('T classification', 'CPA', (66, 82))	('miR-93', 'Gene', '407051', (14, 20))	('clinical stage', 'CPA', (110, 124))	('expression', 'MPA', (21, 31))	('miR-93', 'Gene', (14, 20))	('associated', 'Reg', (50, 60))	('high', 'Var', (9, 13))
518816	25578493	Kaplan-Meier survival analysis demonstrated that patients with high miR-93 expression had poorer overall survival than patients with low miR-93 expression.	('miR-93', 'Gene', (137, 143))	('miR-93', 'Gene', (68, 74))	('overall survival', 'MPA', (97, 113))	('patients', 'Species', '9606', (119, 127))	('poorer', 'NegReg', (90, 96))	('high', 'Var', (63, 67))	('patients', 'Species', '9606', (49, 57))	('miR-93', 'Gene', '407051', (137, 143))	('miR-93', 'Gene', '407051', (68, 74))
518826	25578493	MiRNA-93-5p (miR-93) is from the miR-106b-25 cluster, a paralogue cluster of the miR-17-92 cluster.	('miR-93', 'Gene', '407051', (13, 19))	('miR-93', 'Gene', (13, 19))	('miR-106b', 'Gene', '406900', (33, 41))	('miR-17-92', 'Gene', '407975', (81, 90))	('MiRNA-93-5p', 'Var', (0, 11))	('miR-17-92', 'Gene', (81, 90))	('miR-106b', 'Gene', (33, 41))
518842	25578493	The clinical tumour stage distribution was stage I in 15 patients (T1N0M0 15 cases), stage II in 26 patients (T2N0M0 26 cases), stage III in 39 patients (T3N0M0 19 cases, T1N1M0 1 case, T2N1M0 5 cases and T3N1M0 14 cases) and stage IV in 23 patients (T2N2M0 5 cases, T3N2M0 7 cases, T3N3M0 1 case, T3N1M1 1 case, T4N0M0 4 cases, T4N1M0 3 cases and T4N2M0 2 cases).	('tumour', 'Phenotype', 'HP:0002664', (13, 19))	('T3N0M0', 'Var', (154, 160))	('T4N0M0', 'Var', (313, 319))	('patients', 'Species', '9606', (57, 65))	('tumour', 'Disease', 'MESH:D009369', (13, 19))	('T3N3M0', 'Var', (283, 289))	('patients', 'Species', '9606', (144, 152))	('tumour', 'Disease', (13, 19))	('patients', 'Species', '9606', (100, 108))	('T3N1M1', 'Var', (298, 304))	('T3N2M0', 'Var', (267, 273))	('T4N1M0', 'Var', (329, 335))	('patients', 'Species', '9606', (241, 249))	('T2N2M0', 'Var', (251, 257))
518884	25578493	For the overall survival curves using Kaplan-Meier analysis, patients in the high miR-93 expression group (33.3 %, 38.5 +- 3.4 months) had significantly poorer prognosis than those in the low miR-93 expression group (65.5 %, 51.8 +- 2.0 months) (log-rank test: chi 2 = 12.648, P < 0.001, Fig.	('miR-93', 'Gene', '407051', (192, 198))	('miR-93', 'Gene', (82, 88))	('miR-93', 'Gene', (192, 198))	('high', 'Var', (77, 81))	('patients', 'Species', '9606', (61, 69))	('poorer', 'NegReg', (153, 159))	('miR-93', 'Gene', '407051', (82, 88))
518905	25578493	Based on the Kaplan-Meier survival analysis and log-rank test, our data showed that the 5-year overall survival rate of patients with high miR-93 expression was significantly lower than that of patients with low miR-93 expression (33.3 vs. 65.5 %).	('miR-93', 'Gene', '407051', (212, 218))	('patients', 'Species', '9606', (194, 202))	('miR-93', 'Gene', (212, 218))	('lower', 'NegReg', (175, 180))	('high', 'Var', (134, 138))	('miR-93', 'Gene', '407051', (139, 145))	('miR-93', 'Gene', (139, 145))	('patients', 'Species', '9606', (120, 128))	('expression', 'MPA', (146, 156))
518914	25774687	High throughput DNA methylation analysis provides the possibility to comprehensively filter the epigenetics diversity across various cancers.	('epigenetics', 'Var', (96, 107))	('cancers', 'Phenotype', 'HP:0002664', (133, 140))	('cancers', 'Disease', (133, 140))	('cancers', 'Disease', 'MESH:D009369', (133, 140))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
518924	25774687	It has been revealed that CpG methylation plays an important role in biological processes including imprinting, retrotransposon silencing, X chromatin inactivation, DNA duplication, transcription, repair, even development of cancers and many other complex diseases.	('cancers', 'Disease', 'MESH:D009369', (225, 232))	('DNA duplication', 'Var', (165, 180))	('cancers', 'Disease', (225, 232))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('cancers', 'Phenotype', 'HP:0002664', (225, 232))
518925	25774687	Recent researches demonstrate that the methylation mechanism has strong effects within the cancer genes.	('effects', 'Reg', (72, 79))	('methylation', 'Var', (39, 50))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))
518927	25774687	There are many factors involved in cancers such as copy number alteration, differential expression, epigenetic aberration and so on, among which abnormal DNA methylation has been discovered in many cancers, including breast cancer, lung cancer and colorectal cancer.	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('discovered', 'Reg', (179, 189))	('lung cancer', 'Disease', 'MESH:D008175', (232, 243))	('cancers', 'Disease', 'MESH:D009369', (198, 205))	('colorectal cancer', 'Disease', (248, 265))	('lung cancer', 'Phenotype', 'HP:0100526', (232, 243))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('copy number alteration', 'Var', (51, 73))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('cancers', 'Disease', 'MESH:D009369', (35, 42))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('cancers', 'Phenotype', 'HP:0002664', (198, 205))	('colorectal cancer', 'Phenotype', 'HP:0003003', (248, 265))	('cancers', 'Disease', (198, 205))	('breast cancer', 'Phenotype', 'HP:0003002', (217, 230))	('cancer', 'Phenotype', 'HP:0002664', (259, 265))	('lung cancer', 'Disease', (232, 243))	('breast cancer', 'Disease', 'MESH:D001943', (217, 230))	('breast cancer', 'Disease', (217, 230))	('abnormal', 'Var', (145, 153))	('cancers', 'Phenotype', 'HP:0002664', (35, 42))	('colorectal cancer', 'Disease', 'MESH:D015179', (248, 265))	('cancers', 'Disease', (35, 42))
518928	25774687	Hypermethylation in promoter regions inhibits the expression of tumor suppressor genes.	('tumor', 'Disease', (64, 69))	('Hypermethylation', 'Var', (0, 16))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('inhibits', 'NegReg', (37, 45))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('expression', 'MPA', (50, 60))
518929	25774687	Global hypomethylation also plays an important feature in the process of carcinogenesis, increasing genomic and chromosomal instability.	('carcinogenesis', 'Disease', (73, 87))	('increasing', 'PosReg', (89, 99))	('Global hypomethylation', 'Var', (0, 22))	('carcinogenesis', 'Disease', 'MESH:D063646', (73, 87))	('chromosomal instability', 'Phenotype', 'HP:0040012', (112, 135))
518932	25774687	The hypermethylation of BRCA1/2 in promoter regions results in the inactivation of function and increases the risk of breast cancer.	('BRCA', 'Phenotype', 'HP:0003002', (24, 28))	('increases', 'PosReg', (96, 105))	('BRCA1/2', 'Gene', '672;675', (24, 31))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('function', 'MPA', (83, 91))	('breast cancer', 'Disease', 'MESH:D001943', (118, 131))	('BRCA1/2', 'Gene', (24, 31))	('breast cancer', 'Disease', (118, 131))	('inactivation', 'NegReg', (67, 79))	('breast cancer', 'Phenotype', 'HP:0003002', (118, 131))	('hypermethylation', 'Var', (4, 20))
518933	25774687	Similarly, the hypermethylation of AOX1 (aldehyde oxidase 1) and GSTP1 (Glutathione S-transferase 1) in prostate cancer also lead to the silence of gene expression.	('silence', 'NegReg', (137, 144))	('GSTP1', 'Gene', (65, 70))	('AOX1', 'Gene', (35, 39))	('aldehyde oxidase 1', 'Gene', '316', (41, 59))	('prostate cancer', 'Disease', 'MESH:D011471', (104, 119))	('aldehyde oxidase 1', 'Gene', (41, 59))	('hypermethylation', 'Var', (15, 31))	('prostate cancer', 'Phenotype', 'HP:0012125', (104, 119))	('GSTP1', 'Gene', '2950', (65, 70))	('prostate cancer', 'Disease', (104, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('gene expression', 'MPA', (148, 163))	('AOX1', 'Gene', '316', (35, 39))
518934	25774687	LINE-1 (long interspersed nucleotide element-1) is often regarded as a surrogate marker for global DNA methylation and the overexpression of LINE-1 induced by hypomethylation in promoters results in a poor prognosis in non-small cell lung cancer.	('hypomethylation', 'Var', (159, 174))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (219, 245))	('overexpression', 'PosReg', (123, 137))	('lung cancer', 'Phenotype', 'HP:0100526', (234, 245))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (219, 245))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (223, 245))	('non-small cell lung cancer', 'Disease', (219, 245))	('LINE-1', 'Gene', (141, 147))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))
518937	25774687	The hypermethylation of CDH1 in colorectal carcinogenesis reduces the gene expression and destroys the function of cell-cell adhesion system.	('reduces', 'NegReg', (58, 65))	('CDH1', 'Gene', (24, 28))	('colorectal carcinogenesis', 'Disease', (32, 57))	('CDH1', 'Gene', '999', (24, 28))	('destroys', 'NegReg', (90, 98))	('gene expression', 'MPA', (70, 85))	('function', 'MPA', (103, 111))	('colorectal carcinogenesis', 'Disease', 'MESH:D063646', (32, 57))	('hypermethylation', 'Var', (4, 20))
518938	25774687	Moreover the hypermethylation of CDH1 also disrupts the intercellular adhesion in gastric cancer, breast cancer and bladder cancer.	('breast cancer', 'Disease', 'MESH:D001943', (98, 111))	('gastric cancer', 'Phenotype', 'HP:0012126', (82, 96))	('breast cancer', 'Phenotype', 'HP:0003002', (98, 111))	('bladder cancer', 'Phenotype', 'HP:0009725', (116, 130))	('breast cancer', 'Disease', (98, 111))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('bladder cancer', 'Disease', 'MESH:D001749', (116, 130))	('bladder cancer', 'Disease', (116, 130))	('intercellular adhesion', 'CPA', (56, 78))	('CDH1', 'Gene', (33, 37))	('gastric cancer', 'Disease', 'MESH:D013274', (82, 96))	('gastric cancer', 'Disease', (82, 96))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('hypermethylation', 'Var', (13, 29))	('CDH1', 'Gene', '999', (33, 37))	('disrupts', 'NegReg', (43, 51))
518968	25774687	There were 509 genes showing differential methylation in BRCA, 591 genes in COAD, 130 genes in KIRC, 67 genes in KIRP, 53 genes in LUAD, 508 genes in LUSC and 701 genes in READ (S3 Table).	('COAD', 'Disease', 'MESH:D029424', (76, 80))	('COAD', 'Disease', (76, 80))	('LUAD', 'Phenotype', 'HP:0030078', (131, 135))	('BRCA', 'Phenotype', 'HP:0003002', (57, 61))	('BRCA', 'Gene', '672', (57, 61))	('methylation', 'Var', (42, 53))	('BRCA', 'Gene', (57, 61))	('LUSC', 'Phenotype', 'HP:0030359', (150, 154))
518972	25774687	Most of DMGs showed high methylation level in COAD and READ compared to other five cancer samples and normal samples, and about 11% in the DMGs displayed specific hypermethylation in COAD and READ respectively.	('COAD', 'Disease', 'MESH:D029424', (46, 50))	('methylation level', 'MPA', (25, 42))	('hypermethylation', 'Var', (163, 179))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('COAD', 'Disease', (183, 187))	('COAD', 'Disease', (46, 50))	('DMGs', 'Chemical', '-', (139, 143))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('DMGs', 'Chemical', '-', (8, 12))	('cancer', 'Disease', (83, 89))	('COAD', 'Disease', 'MESH:D029424', (183, 187))
518973	25774687	The result was supported that the tumors seemed to be hypermethylated more frequently and there were no significant differences which could distinguish colon and rectum cancers at methylation level.	('tumors', 'Disease', (34, 40))	('tumors', 'Disease', 'MESH:D009369', (34, 40))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('colon and rectum cancers', 'Disease', 'MESH:D012004', (152, 176))	('hypermethylated', 'Var', (54, 69))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('cancers', 'Phenotype', 'HP:0002664', (169, 176))
518983	25774687	These biological processes might be deregulated by the abnormal methylation of the differential genes, thus affecting the process of cancers.	('abnormal methylation', 'Var', (55, 75))	('methylation', 'Var', (64, 75))	('cancers', 'Phenotype', 'HP:0002664', (133, 140))	('deregulated', 'Reg', (36, 47))	('cancers', 'Disease', (133, 140))	('cancers', 'Disease', 'MESH:D009369', (133, 140))	('affecting', 'Reg', (108, 117))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('differential genes', 'Gene', (83, 101))
518993	25774687	The results suggested that these hypermethylated genes in cancer were cancer-related genes and could be regarded as the candidate biomarkers for the prognosis of cancers.	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('cancers', 'Disease', 'MESH:D009369', (162, 169))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('cancer', 'Disease', (162, 168))	('cancers', 'Disease', (162, 169))	('cancers', 'Phenotype', 'HP:0002664', (162, 169))	('hypermethylated', 'Var', (33, 48))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('cancer', 'Disease', (58, 64))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))
519003	25774687	There were 72 genes showing specific methylation in BRCA, 81 in COAD, 36 in KIRC, 7 in KIRP, 3 in LUAD, 48 in LUSC and 19 in READ in the network.	('BRCA', 'Phenotype', 'HP:0003002', (52, 56))	('LUSC', 'Phenotype', 'HP:0030359', (110, 114))	('methylation', 'Var', (37, 48))	('BRCA', 'Gene', (52, 56))	('BRCA', 'Gene', '672', (52, 56))	('COAD', 'Disease', 'MESH:D029424', (64, 68))	('LUAD', 'Phenotype', 'HP:0030078', (98, 102))	('COAD', 'Disease', (64, 68))
519004	25774687	The nodes in network were mainly classified into three categories including triple differential (TRI_D, 5 genes), double differential (DOU_D, 60 genes) and single differential (SIN_D, 266 genes).	('TRI_D', 'Gene', '8794', (97, 102))	('TRI_D', 'Gene', (97, 102))	('SIN', 'Disease', (177, 180))	('DOU_D', 'Var', (135, 140))	('triple', 'MPA', (76, 82))	('SIN', 'Disease', 'None', (177, 180))
519006	25774687	SLIT2 was usually regarded as a tumor suppressor gene and silenced both in colorectal cancer and breast cancer, whose silence was caused by the hypermethylation of its promoter regions and allelic loss.	('hypermethylation', 'Var', (144, 160))	('colorectal cancer', 'Disease', (75, 92))	('SLIT2', 'Gene', '9353', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('colorectal cancer', 'Disease', 'MESH:D015179', (75, 92))	('allelic loss', 'Var', (189, 201))	('breast cancer', 'Disease', 'MESH:D001943', (97, 110))	('breast cancer', 'Phenotype', 'HP:0003002', (97, 110))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('breast cancer', 'Disease', (97, 110))	('tumor', 'Disease', (32, 37))	('colorectal cancer', 'Phenotype', 'HP:0003003', (75, 92))	('silenced', 'NegReg', (58, 66))	('SLIT2', 'Gene', (0, 5))
519028	25774687	For example, MAP3K14 (Mitogen-activated protein kinase kinase kinase 14) hypermethylated in LUSC regulated the NF-kappaB activity pathway and took part in a NF-kappaB-inducing signaling to receptors of the tumor-necrosis/nerve-growth factor (TNF/NGF) family.	('tumor-necrosis', 'Disease', (206, 220))	('tumor-necrosis', 'Disease', 'MESH:D009336', (206, 220))	('Mitogen-activated protein kinase kinase kinase 14', 'Gene', '9020', (22, 71))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('MAP3K14', 'Gene', (13, 20))	('Mitogen-activated protein kinase kinase kinase 14', 'Gene', (22, 71))	('TNF', 'Gene', (242, 245))	('LUSC', 'Phenotype', 'HP:0030359', (92, 96))	('TNF', 'Gene', '7124', (242, 245))	('MAP3K14', 'Gene', '9020', (13, 20))	('NF-kappaB-inducing signaling', 'MPA', (157, 185))	('NF-kappaB activity pathway', 'Pathway', (111, 137))	('hypermethylated', 'Var', (73, 88))	('regulated', 'Reg', (97, 106))
519038	25774687	Aberrant DNA methylation on gene promoter regions are usually associated with cancers.	('Aberrant DNA methylation', 'Var', (0, 24))	('associated', 'Reg', (62, 72))	('cancers', 'Phenotype', 'HP:0002664', (78, 85))	('cancers', 'Disease', 'MESH:D009369', (78, 85))	('cancers', 'Disease', (78, 85))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))
519039	25774687	For example, aberrant DNA methylation of SIRT1 is frequently observed in different cancers and played an important role in carcinogenesis.	('cancers', 'Disease', 'MESH:D009369', (83, 90))	('DNA', 'MPA', (22, 25))	('carcinogenesis', 'Disease', 'MESH:D063646', (123, 137))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('role', 'Reg', (115, 119))	('observed', 'Reg', (61, 69))	('carcinogenesis', 'Disease', (123, 137))	('SIRT1', 'Gene', '23411', (41, 46))	('cancers', 'Phenotype', 'HP:0002664', (83, 90))	('SIRT1', 'Gene', (41, 46))	('cancers', 'Disease', (83, 90))	('aberrant', 'Var', (13, 21))
519040	25774687	Epigenetic inactivation of ST6GAL1 is indicated a tumor suppressive role in bladder carcinogenesis.	('bladder carcinogenesis', 'Disease', (76, 98))	('ST6GAL1', 'Gene', '6480', (27, 34))	('ST6GAL1', 'Gene', (27, 34))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Disease', (50, 55))	('bladder carcinogenesis', 'Disease', 'MESH:D063646', (76, 98))	('Epigenetic inactivation', 'Var', (0, 23))
519047	25774687	And the DMGs were mainly enriched in defense response, immune response, cell-cell signaling, cell adhesion and cell killing and other cancer-related KEGG pathways by function annotation analysis, suggesting that the damage of these biological processes activate the proliferation of cancer cells and inhibit protection of individuals.	('DMGs', 'Chemical', '-', (8, 12))	('cancer', 'Disease', 'MESH:D009369', (283, 289))	('cancer', 'Disease', (283, 289))	('damage', 'Var', (216, 222))	('cancer', 'Disease', (134, 140))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('protection of individuals', 'CPA', (308, 333))	('proliferation', 'CPA', (266, 279))	('cancer', 'Phenotype', 'HP:0002664', (283, 289))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('inhibit', 'NegReg', (300, 307))	('activate', 'PosReg', (253, 261))
519048	25774687	Additionally, the hypermethylated genes were mainly enriched in multiple cancer-related KEGG pathways compared to hypomethylated genes, and this finding supported previous study of the focal hypermethylation in tumorigenicity.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('tumor', 'Disease', (211, 216))	('enriched', 'Reg', (52, 60))	('hypermethylated', 'Var', (18, 33))
519065	33428594	The analysis of a cohort (GSE31210, N=204) of lung cancer patients demonstrated that high TSKU expression was strongly associated with poor overall survival (P =1.90E-05).	('poor', 'NegReg', (135, 139))	('TSKU', 'Gene', '25987', (90, 94))	('high', 'Var', (85, 89))	('TSKU', 'Gene', (90, 94))	('lung cancer', 'Disease', 'MESH:D008175', (46, 57))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('patients', 'Species', '9606', (58, 66))	('overall', 'MPA', (140, 147))	('lung cancer', 'Disease', (46, 57))	('expression', 'MPA', (95, 105))	('lung cancer', 'Phenotype', 'HP:0100526', (46, 57))
519066	33428594	The combination of high TSKU expression and low infiltration B cells identified a subtype of patients with poor survival in NSCLC.	('high', 'Var', (19, 23))	('TSKU', 'Gene', (24, 28))	('NSCLC', 'Disease', (124, 129))	('NSCLC', 'Disease', 'MESH:D002289', (124, 129))	('patients', 'Species', '9606', (93, 101))	('TSKU', 'Gene', '25987', (24, 28))	('NSCLC', 'Phenotype', 'HP:0030358', (124, 129))
519068	33428594	Overall, high TSKU expression combined with low infiltration of B cells may associate with a poor prognosis of NSCLC patients.	('expression', 'MPA', (19, 29))	('TSKU', 'Gene', (14, 18))	('NSCLC', 'Disease', (111, 116))	('NSCLC', 'Disease', 'MESH:D002289', (111, 116))	('low infiltration of B cells', 'Phenotype', 'HP:0010976', (44, 71))	('patients', 'Species', '9606', (117, 125))	('TSKU', 'Gene', '25987', (14, 18))	('NSCLC', 'Phenotype', 'HP:0030358', (111, 116))	('high', 'Var', (9, 13))
519095	33428594	TSKU expression has been significantly associated with the prognosis in some kinds of cancers, including lung, head and neck, breast, and soft tissue cancers (Figure 2A-2F).	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('cancers', 'Phenotype', 'HP:0002664', (150, 157))	('TSKU', 'Gene', (0, 4))	('soft tissue cancers', 'Disease', 'MESH:D009369', (138, 157))	('cancers', 'Disease', 'MESH:D009369', (86, 93))	('cancers', 'Disease', (150, 157))	('expression', 'Var', (5, 15))	('cancers', 'Disease', 'MESH:D009369', (150, 157))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('cancers', 'Phenotype', 'HP:0002664', (86, 93))	('associated', 'Reg', (39, 49))	('lung', 'Disease', (105, 109))	('cancers', 'Disease', (86, 93))	('soft tissue cancers', 'Disease', (138, 157))	('TSKU', 'Gene', '25987', (0, 4))	('breast', 'Disease', (126, 132))
519096	33428594	The cohort (GSE31210, N=204) of lung cancer patients in PrognoScan demonstrated Kaplan-Meier survival curves that showed patients in the high TSKU expression have poorer survival than those in low TSKU expression in overall survival (P =1.90E-05) and relapse-free survival (P =6.60E-05).	('TSKU', 'Gene', '25987', (142, 146))	('patients', 'Species', '9606', (44, 52))	('high', 'Var', (137, 141))	('TSKU', 'Gene', (142, 146))	('lung cancer', 'Disease', 'MESH:D008175', (32, 43))	('TSKU', 'Gene', '25987', (197, 201))	('poorer', 'NegReg', (163, 169))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('TSKU', 'Gene', (197, 201))	('overall survival', 'CPA', (216, 232))	('patients', 'Species', '9606', (121, 129))	('lung cancer', 'Disease', (32, 43))	('relapse-free survival', 'CPA', (251, 272))	('lung cancer', 'Phenotype', 'HP:0100526', (32, 43))
519097	33428594	High TSKU expression was strongly associated with poor overall survival of patients with lung cancer by multivariate Cox regression analysis, with HROS of 4.700 (95 % CI 2.360-9.360, P =1.10E-05) and HRRFS of 3.400 (95 % CI 2.030-5.810, P =4.00E-06), respectively.	('High', 'Var', (0, 4))	('poor', 'NegReg', (50, 54))	('RFS', 'Disease', (202, 205))	('lung cancer', 'Disease', (89, 100))	('lung cancer', 'Disease', 'MESH:D008175', (89, 100))	('lung cancer', 'Phenotype', 'HP:0100526', (89, 100))	('TSKU', 'Gene', '25987', (5, 9))	('overall', 'MPA', (55, 62))	('patients', 'Species', '9606', (75, 83))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('RFS', 'Disease', 'MESH:D005198', (202, 205))	('TSKU', 'Gene', (5, 9))
519098	33428594	In addition, the cohort (jacob-00182-HLM, N=79) of lung cancer patients with the high TSKU expression also showed poorer OS than those with low TSKU expression (P=0.029).	('lung cancer', 'Disease', 'MESH:D008175', (51, 62))	('TSKU', 'Gene', (144, 148))	('TSKU', 'Gene', '25987', (86, 90))	('high', 'Var', (81, 85))	('TSKU', 'Gene', (86, 90))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('lung cancer', 'Disease', (51, 62))	('HLM', 'Gene', '23762', (37, 40))	('lung cancer', 'Phenotype', 'HP:0100526', (51, 62))	('patients', 'Species', '9606', (63, 71))	('TSKU', 'Gene', '25987', (144, 148))	('HLM', 'Gene', (37, 40))
519101	33428594	Among the 14 types of combination meta-analysis, we found that high TSKU expression was significantly associated with poorer OS in lung cancer and poorer DFS in colorectal cancer.	('poorer', 'Disease', (118, 124))	('DFS', 'Disease', (154, 157))	('colorectal cancer', 'Disease', (161, 178))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('lung cancer', 'Disease', 'MESH:D008175', (131, 142))	('DFS', 'Disease', 'None', (154, 157))	('TSKU', 'Gene', '25987', (68, 72))	('colorectal cancer', 'Phenotype', 'HP:0003003', (161, 178))	('colorectal cancer', 'Disease', 'MESH:D015179', (161, 178))	('high', 'Var', (63, 67))	('lung cancer', 'Disease', (131, 142))	('lung cancer', 'Phenotype', 'HP:0100526', (131, 142))	('TSKU', 'Gene', (68, 72))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
519103	33428594	By further validating the association between TSKU expression and prognosis as determined by OS and DFS in 33 types of cancers from TCGA data via GEPIA (Gene Expression Profiling Interactive Analysis) (Supplementary Figure 2), we found that patients in the high TSKU expression showed poorer survival than those in the low TSKU expression in LUAD (P=0.004), ACC (adrenocortical carcinoma), KIRC, MESO (mesothelioma), PAAD (pancreatic adenocarcinoma), and THCA (thyroid carcinoma).	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (461, 478))	('adrenocortical carcinoma', 'Disease', (363, 387))	('mesothelioma', 'Disease', (402, 414))	('TSKU', 'Gene', (323, 327))	('pancreatic adenocarcinoma', 'Disease', (423, 448))	('carcinoma', 'Phenotype', 'HP:0030731', (469, 478))	('mesothelioma', 'Disease', 'MESH:D008654', (402, 414))	('DFS', 'Disease', 'None', (100, 103))	('TSKU', 'Gene', '25987', (262, 266))	('TSKU', 'Gene', '25987', (46, 50))	('cancers', 'Phenotype', 'HP:0002664', (119, 126))	('cancers', 'Disease', (119, 126))	('DFS', 'Disease', (100, 103))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D000230', (423, 448))	('TSKU', 'Gene', '25987', (323, 327))	('high', 'Var', (257, 261))	('carcinoma', 'Phenotype', 'HP:0030731', (378, 387))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (461, 478))	('adrenocortical carcinoma', 'Phenotype', 'HP:0006744', (363, 387))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (423, 448))	('patients', 'Species', '9606', (241, 249))	('thyroid carcinoma', 'Disease', (461, 478))	('TSKU', 'Gene', (262, 266))	('cancers', 'Disease', 'MESH:D009369', (119, 126))	('TSKU', 'Gene', (46, 50))	('poorer', 'NegReg', (285, 291))	('carcinoma', 'Phenotype', 'HP:0030731', (439, 448))	('adrenocortical carcinoma', 'Disease', 'MESH:D018268', (363, 387))
519110	33428594	Interestingly, while analyzing the relationships between TSKU expression and the marker genes of different immune cells, including CD8+ T cells, T cells (general), B cells, monocytes, TAMs, M1 and M2 macrophages, neutrophils, NK (natural killer) cells, DCs, exhausted T cells, and different subtypes of CD4+ T cells (T helper 1 (Th1) cells, T helper 2 (Th2) cells, follicular helper T (Tfh) cells, Th17 cells, and Tregs) in LUAD and LUSC (Table 1), we found that most of the gene markers of B cells and DCs significantly correlated with TSKU expression levels, especially CD19, CD20, CD21, and CD40L for B cells and HLA-DPB1, HLA-DQB1, HLA-DRA, and HLA-DPA1 for DCs (Figure 4A-4D).	('CD19', 'MPA', (572, 576))	('CD4', 'Gene', '920', (594, 597))	('TSKU', 'Gene', (537, 541))	('CD20', 'Var', (578, 582))	('TSKU', 'Gene', '25987', (57, 61))	('HLA-DQB1', 'Gene', '3119', (626, 634))	('CD8', 'Gene', (131, 134))	('CD40L', 'Gene', '959', (594, 599))	('CD4', 'Gene', (594, 597))	('HLA-DPB1', 'Gene', '3115', (616, 624))	('HLA-DPA1', 'Gene', '3113', (649, 657))	('TSKU', 'Gene', '25987', (537, 541))	('CD4', 'Gene', '920', (303, 306))	('expression levels', 'MPA', (542, 559))	('HLA-DPB1', 'Gene', (616, 624))	('TSKU', 'Gene', (57, 61))	('CD8', 'Gene', '925', (131, 134))	('CD40L', 'Gene', (594, 599))	('HLA-DQB1', 'Gene', (626, 634))	('CD4', 'Gene', (303, 306))	('correlated', 'Reg', (521, 531))	('CD21', 'Var', (584, 588))	('HLA-DRA', 'Gene', '3122', (636, 643))	('HLA-DRA', 'Gene', (636, 643))	('HLA-DPA1', 'Gene', (649, 657))
519114	33428594	Patients with high TSKU expression and low infiltrating B cell levels had poorer survival than those with low TSKU expression and high infiltrating B cell levels (HR=2.016; 95% CI, 1.330-3.057, Cox P=0.001) (Figure 4G).	('poorer', 'NegReg', (74, 80))	('survival', 'CPA', (81, 89))	('TSKU', 'Gene', (110, 114))	('TSKU', 'Gene', '25987', (19, 23))	('high', 'Var', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('TSKU', 'Gene', (19, 23))	('TSKU', 'Gene', '25987', (110, 114))
519115	33428594	Regardless of the disease subtype (LUAD or LUSC), patients with high TSKU expression and low infiltrating B cell levels presented a poorer survival than those with low TSKU expression and high infiltrating B cell levels.	('high', 'Var', (64, 68))	('patients', 'Species', '9606', (50, 58))	('Regardless of the disease', 'Disease', 'MESH:D003141', (0, 25))	('TSKU', 'Gene', (168, 172))	('low', 'NegReg', (89, 92))	('TSKU', 'Gene', (69, 73))	('survival', 'MPA', (139, 147))	('poorer', 'NegReg', (132, 138))	('Regardless of the disease', 'Disease', (0, 25))	('TSKU', 'Gene', '25987', (168, 172))	('TSKU', 'Gene', '25987', (69, 73))
519117	33428594	These data suggest that the combination of high TSKU expression and low infiltrating B cell levels may be associated with a poor prognosis in NSCLC patients.	('patients', 'Species', '9606', (148, 156))	('TSKU', 'Gene', '25987', (48, 52))	('high', 'Var', (43, 47))	('TSKU', 'Gene', (48, 52))	('NSCLC', 'Disease', (142, 147))	('low', 'NegReg', (68, 71))	('NSCLC', 'Disease', 'MESH:D002289', (142, 147))	('expression', 'MPA', (53, 63))	('NSCLC', 'Phenotype', 'HP:0030358', (142, 147))
519118	33428594	To clarify whether the aberrant methylation of the promoter affects gene expression, we evaluated the correlation between the TSKU methylation level in the promoter region and its expression.	('TSKU', 'Gene', (126, 130))	('affects', 'Reg', (60, 67))	('gene expression', 'MPA', (68, 83))	('TSKU', 'Gene', '25987', (126, 130))	('aberrant', 'Var', (23, 31))
519122	33428594	There were significant negative correlations between differential methylation and expression for some probes in the promoter region in LUAD, including cg20708135 (cor =-0.598, P <0.001) and cg20886049 (cor =-0.558, P <0.001) (Figure 5B, 5C).	('cg20886049', 'Var', (190, 200))	('cg20708135', 'Chemical', '-', (151, 161))	('expression', 'MPA', (82, 92))	('cg20886049', 'Chemical', '-', (190, 200))	('cg20708135', 'Var', (151, 161))	('negative', 'NegReg', (23, 31))
519123	33428594	In addition, a similar trend was observed in LUSC including the cg20708135 (cor =-0.329, P <0.05) and cg20886049 (cor =-0.374 P =0.004) probes (Figure 5E, 5F).	('cg20886049', 'Var', (102, 112))	('cg20886049', 'Chemical', '-', (102, 112))	('cg20708135', 'Chemical', '-', (64, 74))	('cg20708135', 'Var', (64, 74))
519127	33428594	We further evaluated the proportion of different TIICs between groups with higher and lower TSKU methylation levels in LUAD and LUSC samples from TCGA datasets (Figure 6E, 6F) and found that the proportion of B cells in cancer tissues with TSKU hypermethylation was higher than that in cancer tissues with TSKU hypomethylation.	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('TSKU', 'Gene', '25987', (306, 310))	('higher', 'PosReg', (266, 272))	('TSKU', 'Gene', (240, 244))	('cancer', 'Phenotype', 'HP:0002664', (286, 292))	('TSKU', 'Gene', '25987', (92, 96))	('hypermethylation', 'Var', (245, 261))	('TSKU', 'Gene', (306, 310))	('B cells', 'CPA', (209, 216))	('cancer', 'Disease', 'MESH:D009369', (220, 226))	('cancer', 'Disease', 'MESH:D009369', (286, 292))	('cancer', 'Disease', (220, 226))	('TSKU', 'Gene', (92, 96))	('TSKU', 'Gene', '25987', (240, 244))	('cancer', 'Disease', (286, 292))
519129	33428594	We found that low TSKU methylation was associated with poor prognosis in ACC, BRCA, KICH, LGG (brain lower grade glioma), and PAAD, while high TSKU methylation was associated with good prognosis in KIRC and UCEC (uterine corpus endometrial carcinoma).	('UCEC', 'Disease', (207, 211))	('glioma', 'Disease', 'MESH:D005910', (113, 119))	('TSKU', 'Gene', '25987', (18, 22))	('glioma', 'Phenotype', 'HP:0009733', (113, 119))	('ACC', 'Disease', (73, 76))	('BRCA', 'Disease', (78, 82))	('methylation', 'Var', (23, 34))	('TSKU', 'Gene', (18, 22))	('KICH', 'Disease', 'None', (84, 88))	('glioma', 'Disease', (113, 119))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (228, 249))	('TSKU', 'Gene', '25987', (143, 147))	('low', 'NegReg', (14, 17))	('carcinoma', 'Phenotype', 'HP:0030731', (240, 249))	('KICH', 'Disease', (84, 88))	('TSKU', 'Gene', (143, 147))	('endometrial carcinoma', 'Disease', (228, 249))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (228, 249))
519130	33428594	However, there was no significant association between TSKU methylation and prognosis in LUAD (HR=0.824, Cox P=0.240; HR=0.866, Cox P=0.420) and LUSC (HR=1.198, Cox P=0.360; HR=1.338, Cox P=0.150).	('LUSC', 'Disease', (144, 148))	('TSKU', 'Gene', '25987', (54, 58))	('methylation', 'Var', (59, 70))	('TSKU', 'Gene', (54, 58))	('LUAD', 'Disease', (88, 92))
519132	33428594	In addition, high TSKU expression combined with low tumor-infiltrating B cell levels may influence the prognosis of patients with NSCLC.	('NSCLC', 'Disease', 'MESH:D002289', (130, 135))	('low tumor', 'Disease', 'MESH:D009800', (48, 57))	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('TSKU', 'Gene', '25987', (18, 22))	('low tumor', 'Disease', (48, 57))	('influence', 'Reg', (89, 98))	('TSKU', 'Gene', (18, 22))	('high', 'Var', (13, 17))	('patients', 'Species', '9606', (116, 124))	('NSCLC', 'Phenotype', 'HP:0030358', (130, 135))	('NSCLC', 'Disease', (130, 135))	('expression', 'MPA', (23, 33))
519134	33428594	We further analyzed the association between TSKU expression and the prognosis of these cancers and found that, only in lung cancer, the high expression of TSKU was associated with a poor OS based on the above results of TSKU expression differential analysis (Figure 2A, 2B; Supplementary Figure 2A-2G).	('cancers', 'Disease', (87, 94))	('TSKU', 'Gene', '25987', (155, 159))	('lung cancer', 'Disease', (119, 130))	('TSKU', 'Gene', (220, 224))	('lung cancer', 'Phenotype', 'HP:0100526', (119, 130))	('high', 'Var', (136, 140))	('TSKU', 'Gene', '25987', (44, 48))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cancers', 'Phenotype', 'HP:0002664', (87, 94))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('TSKU', 'Gene', (155, 159))	('lung cancer', 'Disease', 'MESH:D008175', (119, 130))	('TSKU', 'Gene', (44, 48))	('TSKU', 'Gene', '25987', (220, 224))	('cancers', 'Disease', 'MESH:D009369', (87, 94))
519144	33428594	We further found that the combination of high TSKU expression and low B cell infiltration identified a group of patients with poor survival in NSCLC (Figure 4G).	('NSCLC', 'Disease', (143, 148))	('TSKU', 'Gene', '25987', (46, 50))	('NSCLC', 'Disease', 'MESH:D002289', (143, 148))	('patients', 'Species', '9606', (112, 120))	('high', 'Var', (41, 45))	('TSKU', 'Gene', (46, 50))	('NSCLC', 'Phenotype', 'HP:0030358', (143, 148))	('low B cell', 'Phenotype', 'HP:0010976', (66, 76))	('low B cell infiltration', 'Phenotype', 'HP:0010976', (66, 89))
519152	33428594	Nevertheless, the mechanisms behind high TSKU expression leading to poorer survival in NSCLC patients with low levels of infiltrating B cell need to be studied further.	('NSCLC', 'Disease', (87, 92))	('TSKU', 'Gene', (41, 45))	('poorer', 'NegReg', (68, 74))	('NSCLC', 'Disease', 'MESH:D002289', (87, 92))	('survival', 'MPA', (75, 83))	('NSCLC', 'Phenotype', 'HP:0030358', (87, 92))	('TSKU', 'Gene', '25987', (41, 45))	('patients', 'Species', '9606', (93, 101))	('high', 'Var', (36, 40))
519153	33428594	Another important aspect of this study was the significant negative correlation between differential methylation and expression in the promoter region (probes cg20708135 and cg20886049) of TSKU (Figures 5A-5F).	('TSKU', 'Gene', '25987', (189, 193))	('cg20886049', 'Chemical', '-', (174, 184))	('TSKU', 'Gene', (189, 193))	('cg20708135', 'Chemical', '-', (159, 169))	('expression', 'MPA', (117, 127))	('negative', 'NegReg', (59, 67))	('cg20886049', 'Var', (174, 184))
519154	33428594	However, we did not observe a significant association between TSKU methylation and prognosis in NSCLC (Supplementary Table 3).	('TSKU', 'Gene', '25987', (62, 66))	('NSCLC', 'Disease', (96, 101))	('TSKU', 'Gene', (62, 66))	('NSCLC', 'Disease', 'MESH:D002289', (96, 101))	('NSCLC', 'Phenotype', 'HP:0030358', (96, 101))	('methylation', 'Var', (67, 78))
519155	33428594	Other factors, including copy number alterations, transcription factor production and recruitment, histone modifications, and microRNA expression, may also play a role in regulating TSKU expression.	('regulating', 'Reg', (171, 181))	('TSKU', 'Gene', (182, 186))	('copy number alterations', 'Var', (25, 48))	('microRNA', 'MPA', (126, 134))	('expression', 'MPA', (187, 197))	('TSKU', 'Gene', '25987', (182, 186))
519158	33428594	Currently, our results preliminarily demonstrate that TSKU hypomethylation in the promoter region increases the expression levels of TSKU and worsens the clinical outcome of patients.	('clinical outcome of patients', 'CPA', (154, 182))	('hypomethylation', 'Var', (59, 74))	('patients', 'Species', '9606', (174, 182))	('TSKU', 'Gene', '25987', (54, 58))	('TSKU', 'Gene', '25987', (133, 137))	('TSKU', 'Gene', (54, 58))	('expression levels', 'MPA', (112, 129))	('increases', 'PosReg', (98, 107))	('worsens', 'NegReg', (142, 149))	('TSKU', 'Gene', (133, 137))
519163	33428594	TILs were identified as a favorable prognostic marker that plays a critical role in shaping tumor development and determining treatment responses in the tumor microenvironment.	('TILs', 'Var', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Disease', (153, 158))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (92, 97))
519169	33428594	Additionally, we should further validate whether TSKU methylation in the promoter affects the expression of TSKU and clinical outcome using large NSCLC patient sample sets.	('methylation', 'Var', (54, 65))	('TSKU', 'Gene', (49, 53))	('TSKU', 'Gene', (108, 112))	('NSCLC', 'Disease', (146, 151))	('affects', 'Reg', (82, 89))	('NSCLC', 'Disease', 'MESH:D002289', (146, 151))	('expression', 'MPA', (94, 104))	('NSCLC', 'Phenotype', 'HP:0030358', (146, 151))	('patient', 'Species', '9606', (152, 159))	('TSKU', 'Gene', '25987', (49, 53))	('TSKU', 'Gene', '25987', (108, 112))
519191	31190863	Results: The results showed that high expression of Nanog was significantly associated with poor overall survival (OS) (HR=1.95, 95% CI: 1.38-2.75, P=0.000).	('high', 'Var', (33, 37))	('Nanog', 'Gene', (52, 57))	('overall survival', 'MPA', (97, 113))	('OS', 'Chemical', '-', (115, 117))	('poor', 'NegReg', (92, 96))	('Nanog', 'Gene', '79923', (52, 57))
519192	31190863	Additionally, high Nanog expression was significantly correlated with tumor differentiation (OR=3.18, 95% CI: 1.69-5.98, P=0.000) and TNM stage (OR=1.78, 95% CI: 1.28-2.47, P=0.001).	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('TNM', 'Gene', '10178', (134, 137))	('Nanog', 'Gene', '79923', (19, 24))	('tumor', 'Disease', (70, 75))	('high', 'Var', (14, 18))	('TNM', 'Gene', (134, 137))	('Nanog', 'Gene', (19, 24))	('correlated', 'Reg', (54, 64))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
519194	31190863	Conclusion: High Nanog expression was associated with poor prognosis in patients with NSCLC, and Nanog may serve as a prognostic predictor in NSCLC.	('Nanog', 'Gene', (17, 22))	('Nanog', 'Gene', '79923', (97, 102))	('NSCLC', 'Disease', (86, 91))	('NSCLC', 'Disease', (142, 147))	('patients', 'Species', '9606', (72, 80))	('Nanog', 'Gene', (97, 102))	('NSCLC', 'Disease', 'MESH:D002289', (86, 91))	('NSCLC', 'Disease', 'MESH:D002289', (142, 147))	('Nanog', 'Gene', '79923', (17, 22))	('NSCLC', 'Phenotype', 'HP:0030358', (86, 91))	('High', 'Var', (12, 16))	('NSCLC', 'Phenotype', 'HP:0030358', (142, 147))	('expression', 'MPA', (23, 33))
519219	31190863	The analysis indicated that high Nanog expression was related to poor OS in NSCLC patients (HR=1.95, 95% CI: 1.38-2.75, P<0.01).	('OS', 'Chemical', '-', (70, 72))	('poor OS', 'Disease', (65, 72))	('Nanog', 'Gene', '79923', (33, 38))	('patients', 'Species', '9606', (82, 90))	('NSCLC', 'Disease', (76, 81))	('NSCLC', 'Disease', 'MESH:D002289', (76, 81))	('Nanog', 'Gene', (33, 38))	('high', 'Var', (28, 32))	('NSCLC', 'Phenotype', 'HP:0030358', (76, 81))
519230	31190863	In the subgroup analysis of ethnicity, high Nanog expression was associated with tumor differentiation for Chinese patients (OR=5.50, 95% CI: 2.53-11.92, P=0.000), but not for Korean or Greek patients.	('patients', 'Species', '9606', (115, 123))	('high', 'Var', (39, 43))	('Nanog', 'Gene', '79923', (44, 49))	('patients', 'Species', '9606', (192, 200))	('associated with', 'Reg', (65, 80))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('Nanog', 'Gene', (44, 49))	('tumor', 'Disease', (81, 86))
519242	31190863	Zhao et al found that high Nanog expression predicted a poor prognosis in solid tumors.	('Nanog', 'Gene', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('high', 'Var', (22, 26))	('solid tumors', 'Disease', 'MESH:D009369', (74, 86))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('Nanog', 'Gene', '79923', (27, 32))	('solid tumors', 'Disease', (74, 86))
519246	31190863	The results indicated that high Nanog expression was related to poor OS, tumor differentiation, and tumor TNM stage in NSCLC, but not correlated with gender, age, tumor size, or lymph node metastasis.	('NSCLC', 'Disease', 'MESH:D002289', (119, 124))	('tumor', 'Disease', (100, 105))	('Nanog', 'Gene', '79923', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('Nanog', 'Gene', (32, 37))	('tumor', 'Disease', (163, 168))	('poor OS', 'CPA', (64, 71))	('NSCLC', 'Disease', (119, 124))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('NSCLC', 'Phenotype', 'HP:0030358', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('TNM', 'Gene', '10178', (106, 109))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('high', 'Var', (27, 31))	('TNM', 'Gene', (106, 109))	('tumor', 'Disease', (73, 78))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('OS', 'Chemical', '-', (69, 71))
519248	31190863	However, Cheng et al also found that high Nanog expression was associated with tumor size and lymph node metastasis, which differed from our results.	('Nanog', 'Gene', (42, 47))	('lymph node metastasis', 'CPA', (94, 115))	('high', 'Var', (37, 41))	('tumor', 'Disease', (79, 84))	('associated', 'Reg', (63, 73))	('Nanog', 'Gene', '79923', (42, 47))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
519251	31190863	In this meta-analysis, five of the six studies analyzed found that high Nanog expression was correlated with poor OS.	('Nanog', 'Gene', '79923', (72, 77))	('high', 'Var', (67, 71))	('Nanog', 'Gene', (72, 77))	('OS', 'Chemical', '-', (114, 116))	('poor OS', 'Disease', (109, 116))
519260	31190863	However, the pooled analysis indicated that high Nanog expression was related to advanced TNM stage.	('high', 'Var', (44, 48))	('Nanog', 'Gene', (49, 54))	('TNM', 'Gene', '10178', (90, 93))	('related', 'Reg', (70, 77))	('TNM', 'Gene', (90, 93))	('Nanog', 'Gene', '79923', (49, 54))
519267	31190863	High Nanog expression was associated with poor prognosis in NSCLC patients, and Nanog may serve as a potential prognostic biomarker in NSCLC.	('High', 'Var', (0, 4))	('Nanog', 'Gene', '79923', (5, 10))	('Nanog', 'Gene', (80, 85))	('NSCLC', 'Disease', (135, 140))	('NSCLC', 'Phenotype', 'HP:0030358', (60, 65))	('Nanog', 'Gene', (5, 10))	('NSCLC', 'Disease', 'MESH:D002289', (135, 140))	('Nanog', 'Gene', '79923', (80, 85))	('NSCLC', 'Phenotype', 'HP:0030358', (135, 140))	('NSCLC', 'Disease', (60, 65))	('patients', 'Species', '9606', (66, 74))	('NSCLC', 'Disease', 'MESH:D002289', (60, 65))
519270	26555036	The close proximity of Arg/Lys amino acids and a proline two residues N-terminal to the phosphorylated residue both improve recognition of the substrate by CDK5.	('improve', 'PosReg', (116, 123))	('recognition of the substrate', 'MPA', (124, 152))	('proline', 'Chemical', 'MESH:D011392', (49, 56))	('Arg', 'Chemical', 'MESH:D001120', (23, 26))	('Arg/Lys amino acids', 'Var', (23, 42))	('Lys', 'Chemical', 'MESH:D008239', (27, 30))	('CDK5', 'Gene', (156, 160))
519271	26555036	In contrast the presence of a proline two residues C-terminal to the target residue dramatically reduces phosphorylation rate.	('proline', 'Chemical', 'MESH:D011392', (30, 37))	('phosphorylation rate', 'MPA', (105, 125))	('reduces', 'NegReg', (97, 104))	('presence', 'Var', (16, 24))
519272	26555036	Serine-522 of Collapsin Response Mediator-2 (CRMP2) is a validated CDK5 substrate with many of these structural criteria.	('Serine-522', 'Var', (0, 10))	('CRMP2', 'Gene', (45, 50))	('CRMP2', 'Gene', '1808', (45, 50))	('Serine', 'Chemical', 'MESH:D012694', (0, 6))
519274	26555036	In lung cancer the anti-phospho-Ser522 signal is positive in squamous cell carcinoma more frequently than adenocarcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('adenocarcinoma', 'Disease', (106, 120))	('lung cancer', 'Disease', (3, 14))	('lung cancer', 'Phenotype', 'HP:0100526', (3, 14))	('positive', 'Reg', (49, 57))	('adenocarcinoma', 'Disease', 'MESH:D000230', (106, 120))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (61, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('anti-phospho-Ser522', 'Var', (19, 38))	('Ser522', 'Chemical', '-', (32, 38))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (61, 84))	('squamous cell carcinoma', 'Disease', (61, 84))	('lung cancer', 'Disease', 'MESH:D008175', (3, 14))
519279	26555036	CDK5 is the catalytic subunit of an active heterodimeric complex consisting of CDK5 bound to either p35 or p39, two similar CDK5 cofactors encoded for by different genes (CDK5R1 and CDK5R2).	('CDK5R2', 'Gene', (182, 188))	('CDK5R1', 'Gene', (171, 177))	('CDK5R1', 'Gene', '8851', (171, 177))	('CDK5', 'Gene', (79, 83))	('p39', 'Var', (107, 110))	('p35', 'Var', (100, 103))	('CDK5R2', 'Gene', '8941', (182, 188))
519284	26555036	The p35 null mice exhibit increased susceptibility to seizures, while the p39 null mice have little apparent deficit, which may suggest that p35 is the more dominant regulator of CDK5 activity.	('mice', 'Species', '10090', (13, 17))	('seizures', 'Phenotype', 'HP:0001250', (54, 62))	('seizures', 'Disease', (54, 62))	('mice', 'Species', '10090', (83, 87))	('p35', 'Var', (4, 7))	('seizures', 'Disease', 'MESH:D012640', (54, 62))	('susceptibility', 'Reg', (36, 50))
519287	26555036	This alters the subcellular localization of the p25/p29 proteins, and the associated CDK5 catalytic subunit, since the N-terminal portion of p35/p39 that is lost contains a membrane localization domain.	('p25', 'Gene', '8851', (48, 51))	('alters', 'Reg', (5, 11))	('p25', 'Gene', (48, 51))	('p35/p39', 'Var', (141, 148))	('subcellular localization', 'MPA', (16, 40))	('p29', 'Gene', '25949', (52, 55))	('p29', 'Gene', (52, 55))	('membrane localization domain', 'MPA', (173, 201))
519294	26555036	These include; i) the phosphorylation of oncogenic proteins such as Rb, ATM, Bcl-2, p53, STAT3, and talin, ii) the observed dysregulation of CDK5 activity in leukaemia and pancreatic carcinoma cells, iii) a significant correlation between the expression of p35/CDK5 and the degree of differentiation and metastasis in non-small cell lung cancer, as well as increased expression and activity of CDK5 in human hepatocellular carcinoma (HCC), iv) an association between polymorphisms in the CDK5 promoter and lung cancer risk in a specific Korean population, v) the demonstration that CDK5 activation enhances medullary thyroid carcinoma (MTC) in a conditional mouse model, while inhibition of CDK5 activity reduces tumour growth, motility and metastasis in pancreatic cancer cells, and ablation/inhibition of CDK5 significantly decreased HCC cell proliferation.	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (318, 344))	('enhances', 'PosReg', (598, 606))	('tumour', 'Phenotype', 'HP:0002664', (713, 719))	('tumour', 'Disease', 'MESH:D009369', (713, 719))	('ATM', 'Gene', '472', (72, 75))	('tumour', 'Disease', (713, 719))	('STAT3', 'Gene', '6774', (89, 94))	('leukaemia', 'Disease', 'MESH:D007938', (158, 167))	('mouse', 'Species', '10090', (658, 663))	('medullary thyroid carcinoma', 'Phenotype', 'HP:0002865', (607, 634))	('Bcl-2', 'Gene', (77, 82))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (617, 634))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (408, 432))	('CDK5', 'Gene', (582, 586))	('non-small cell lung cancer', 'Disease', (318, 344))	('carcinoma', 'Phenotype', 'HP:0030731', (183, 192))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (755, 772))	('carcinoma', 'Phenotype', 'HP:0030731', (625, 634))	('decreased', 'NegReg', (826, 835))	('lung cancer', 'Disease', 'MESH:D008175', (333, 344))	('lung cancer', 'Disease', (506, 517))	('Bcl-2', 'Gene', '596', (77, 82))	('ATM', 'Gene', (72, 75))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (408, 432))	('lung cancer', 'Phenotype', 'HP:0100526', (333, 344))	('motility', 'CPA', (728, 736))	('reduces', 'NegReg', (705, 712))	('STAT3', 'Gene', (89, 94))	('metastasis', 'CPA', (741, 751))	('p53', 'Gene', '7157', (84, 87))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (318, 344))	('hepatocellular carcinoma', 'Disease', (408, 432))	('leukaemia', 'Disease', (158, 167))	('HCC cell proliferation', 'CPA', (836, 858))	('pancreatic cancer', 'Disease', 'MESH:D010190', (755, 772))	('human', 'Species', '9606', (402, 407))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (617, 634))	('ablation/inhibition', 'Var', (784, 803))	('pancreatic carcinoma', 'Disease', 'MESH:C562463', (172, 192))	('lung cancer', 'Disease', 'MESH:D008175', (506, 517))	('cancer', 'Phenotype', 'HP:0002664', (766, 772))	('cancer', 'Phenotype', 'HP:0002664', (338, 344))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (322, 344))	('p53', 'Gene', (84, 87))	('CDK5', 'Gene', (807, 811))	('thyroid carcinoma', 'Disease', (617, 634))	('lung cancer', 'Phenotype', 'HP:0100526', (506, 517))	('cancer', 'Phenotype', 'HP:0002664', (511, 517))	('carcinoma', 'Phenotype', 'HP:0030731', (423, 432))	('pancreatic cancer', 'Disease', (755, 772))	('pancreatic carcinoma', 'Disease', (172, 192))
519301	26555036	Active forms of the CMGC protein kinases were purchased from MRC Protein Phosphorylation Reagents, University of Dundee, except for p35/CDK5 and p25/CDK5 (Millipore UK Ltd, Herts, UK).	('p25', 'Gene', '8851', (145, 148))	('p25', 'Gene', (145, 148))	('MRC', 'CellLine', 'CVCL:0440', (61, 64))	('Pro', 'Chemical', 'MESH:D011392', (65, 68))	('p35/CDK5', 'Var', (132, 140))
519305	26555036	Expression constructs for CDK5, p35 and p25 were generated by Dr Margereta Nikolic, Imperial College, London.	('p25', 'Gene', (40, 43))	('p35', 'Var', (32, 35))	('CDK5', 'Gene', (26, 30))	('p25', 'Gene', '8851', (40, 43))
519334	26555036	GST-tau (0.5 muM) was incubated with either p25/CDK5 or p35/CDK5 and MgATP for 5, 20 or 60 mins.	('muM', 'Gene', (13, 16))	('p25', 'Gene', '8851', (44, 47))	('MgATP', 'Chemical', 'MESH:D000255', (69, 74))	('p35/CDK5', 'Var', (56, 64))	('p25', 'Gene', (44, 47))	('muM', 'Gene', '56925', (13, 16))
519348	26555036	For comparison of substrate phosphorylation following transfection of p35/CDK5 and p25/CDK5 with untransfected control, statistical analysis was performed by one-way analysis of variance (ANOVA) with Tukey's post hoc test as comparisons between each group.	('substrate phosphorylation', 'MPA', (18, 43))	('p35/CDK5', 'Var', (70, 78))	('p25', 'Gene', (83, 86))	('p25', 'Gene', '8851', (83, 86))
519350	26555036	As an initial assessment of the potential roles of CDK5 in human cancers, we interrogated Oncomine (https://www.oncomine.org/) and COSMIC (https://www.sanger.ac.uk/research/projects/cancergenome/) to search for evidence of differential expression or mutation of CDK5 and its two partners CDK5R1 (p35) and CDK5R2 (p39) in a range of cancer types.	('cancer', 'Disease', 'MESH:D009369', (332, 338))	('CDK5R1', 'Gene', (288, 294))	('oncomine', 'Chemical', '-', (112, 120))	('cancers', 'Phenotype', 'HP:0002664', (65, 72))	('cancer', 'Disease', (65, 71))	('cancers', 'Disease', (65, 72))	('mutation', 'Var', (250, 258))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('p39', 'Var', (313, 316))	('cancer', 'Disease', (182, 188))	('CDK5R1', 'Gene', '8851', (288, 294))	('CDK5', 'Gene', (262, 266))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('Oncomine', 'Chemical', '-', (90, 98))	('cancer', 'Disease', (332, 338))	('cancers', 'Disease', 'MESH:D009369', (65, 72))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('cancer', 'Phenotype', 'HP:0002664', (332, 338))	('human', 'Species', '9606', (59, 64))	('CDK5R2', 'Gene', '8941', (305, 311))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('CDK5R2', 'Gene', (305, 311))
519353	26555036	In the COSMIC database, mutations or copy number changes in any of these genes occurs very rarely (33/15583 for CDK5; 42/15259 for CDK5R1 and 30/15259 mutations for CDK5R2; all <0.3 %; accessed 3rd March, 2015).	('CDK5R1', 'Gene', (131, 137))	('CDK5R2', 'Gene', (165, 171))	('42/15259', 'Var', (118, 126))	('CDK5R1', 'Gene', '8851', (131, 137))	('CDK5', 'Gene', (112, 116))	('copy number changes', 'Var', (37, 56))	('30/15259 mutations', 'Var', (142, 160))	('CDK5R2', 'Gene', '8941', (165, 171))
519358	26555036	Therefore using peptide assays we re-investigated the importance of Arg/Lys residues around the substrate phosphorylation site for both p35/CDK5 and p25/CDK5.	('peptide', 'Chemical', 'MESH:D010455', (16, 23))	('p25', 'Gene', '8851', (149, 152))	('Arg/Lys', 'Var', (68, 75))	('p25', 'Gene', (149, 152))	('Lys', 'Chemical', 'MESH:D008239', (72, 75))	('p35/CDK5', 'Var', (136, 144))	('Arg', 'Chemical', 'MESH:D001120', (68, 71))
519359	26555036	Firstly we confirm that the presence of a Arg/Lys residue at +3 and/or +4 is a major enhancer of substrate recognition for both CDK5 complexes, at least in vitro (Fig.	('Arg', 'Chemical', 'MESH:D001120', (42, 45))	('substrate recognition', 'MPA', (97, 118))	('Lys', 'Chemical', 'MESH:D008239', (46, 49))	('enhancer', 'PosReg', (85, 93))	('Arg/Lys residue', 'Var', (42, 57))
519360	26555036	CDK5 isoforms phosphorylated a peptide containing the sequence TPKRR at a much higher rate than one with the sequence TPKAA (where the phosphorylated residue is underlined, Fig.	('higher rate', 'PosReg', (79, 90))	('peptide', 'Chemical', 'MESH:D010455', (31, 38))	('phosphorylated', 'MPA', (14, 28))	('TPKRR', 'Var', (63, 68))
519361	26555036	Indeed the latter peptide is an extremely poor substrate for both p35/CDK5 and p25/CDK5 (Vmax/Km <0.05, compared to 0.6-0.8 for TPKKR), suggesting for the first time that the presence of a single Arg/Lys residue at +2 is relatively poor at conferring CDK5 recognition (Fig.	('peptide', 'Chemical', 'MESH:D010455', (18, 25))	('p25', 'Gene', (79, 82))	('p25', 'Gene', '8851', (79, 82))	('Arg/Lys', 'Var', (196, 203))	('Lys', 'Chemical', 'MESH:D008239', (200, 203))	('Arg', 'Chemical', 'MESH:D001120', (196, 199))
519362	26555036	Indeed one can find examples of 4 different classes of CDK5 substrate, 1) Arg/Lys residues both N- and C-terminal to the phosphorylated residue (+-5), 2) Arg/Lys residues solely C-terminal, 3) Arg/Lys residues solely N-terminal and 4) no Arg/Lys residues either side of target residue.	('Arg/Lys', 'Var', (74, 81))	('Arg/Lys residues', 'Var', (154, 170))	('Arg', 'Chemical', 'MESH:D001120', (193, 196))	('Arg', 'Chemical', 'MESH:D001120', (238, 241))	('Lys', 'Chemical', 'MESH:D008239', (242, 245))	('Arg', 'Chemical', 'MESH:D001120', (74, 77))	('Arg/Lys residues', 'Var', (193, 209))	('Lys', 'Chemical', 'MESH:D008239', (197, 200))	('Arg', 'Chemical', 'MESH:D001120', (154, 157))	('Lys', 'Chemical', 'MESH:D008239', (158, 161))	('Lys', 'Chemical', 'MESH:D008239', (78, 81))
519375	26555036	This dramatic negative effect of a Pro substitution at +2 prompted us to investigate whether the presence of three Pro residues in close proximity to the phosphorylation site in peptide 1.3 worsened the rate of phosphorylation rather than the specific position.	('Pro', 'Chemical', 'MESH:D011392', (115, 118))	('worsened', 'NegReg', (190, 198))	('presence', 'Var', (97, 105))	('peptide', 'Chemical', 'MESH:D010455', (178, 185))	('Pro', 'Chemical', 'MESH:D011392', (35, 38))	('phosphorylation', 'MPA', (211, 226))
519382	26555036	1d), suggesting that substrates with a S/TPP sequence are likely to be better PICTAIRE targets than CDK5 (such as Mef2A and p53).	('TPP', 'Chemical', 'MESH:C016136', (41, 44))	('p53', 'Gene', (124, 127))	('p53', 'Gene', '7157', (124, 127))	('Mef2A', 'Gene', '4205', (114, 119))	('S/TPP sequence', 'Var', (39, 53))	('Mef2A', 'Gene', (114, 119))
519387	26555036	Both CDK5 complexes phosphorylate CRMP1, CRMP2 and CRMP4, and this is reduced by >75 % in the Ser522Ala mutant of each CRMP (Fig.	('CRMP', 'Chemical', '-', (34, 38))	('CRMP', 'Chemical', '-', (51, 55))	('CRMP4', 'Gene', (51, 56))	('reduced', 'NegReg', (70, 77))	('CRMP1', 'Gene', (34, 39))	('CRMP4', 'Gene', '1809', (51, 56))	('Ser522Ala', 'Var', (94, 103))	('CRMP', 'Chemical', '-', (119, 123))	('CRMP2', 'Gene', (41, 46))	('CRMP1', 'Gene', '1400', (34, 39))	('CRMP2', 'Gene', '1808', (41, 46))	('CRMP', 'Chemical', '-', (41, 45))	('Ser522Ala', 'SUBSTITUTION', 'None', (94, 103))
519389	26555036	Mass Fingerprinting found the major purvalanol A- and roscovitine-sensitive phosphorylation site on tau is Ser-235 (a class 1 site), with minor phosphorylation of Ser202/Thr205 (Additional file 2: Figure S1a).	('Ser202', 'Chemical', '-', (163, 169))	('Ser202/Thr205', 'Var', (163, 176))	('Ser', 'Chemical', 'MESH:D012694', (107, 110))	('Ser', 'Chemical', 'MESH:D012694', (163, 166))	('Ser-235', 'Var', (107, 114))	('Thr205', 'Chemical', '-', (170, 176))	('roscovitine', 'Chemical', 'MESH:D000077546', (54, 65))	('purvalanol A', 'Chemical', 'MESH:C471843', (36, 48))
519391	26555036	For example, Ser231 was reported as a CDK5 target and was not found in our studies, yet Ser231 was phosphorylated by GSK3 after tau phosphorylation at Ser235 by CDK5 (Additional file 2: Figure S1b).	('GSK3', 'Gene', (117, 121))	('Ser231', 'Var', (88, 94))	('GSK3', 'Gene', '56637', (117, 121))	('Ser231', 'Chemical', '-', (88, 94))	('Ser235', 'Chemical', '-', (151, 157))	('Ser231', 'Chemical', '-', (13, 19))
519392	26555036	Therefore phosphorylation at Ser235 turns tau into a substrate for GSK3 at Ser231 making this site look like a CDK5 site in cells.	('GSK3', 'Gene', (67, 71))	('GSK3', 'Gene', '56637', (67, 71))	('Ser235', 'Chemical', '-', (29, 35))	('Ser231', 'Chemical', '-', (75, 81))	('phosphorylation', 'Var', (10, 25))
519393	26555036	Importantly >80 % of the phosphate incorporation (at least after 60 min incubation with CDK5 in vitro) is accounted for by Ser235/Ser202/Thr205 phosphorylation.	('phosphate', 'Chemical', 'MESH:D010710', (25, 34))	('Ser202', 'Chemical', '-', (130, 136))	('Ser235', 'Chemical', '-', (123, 129))	('Ser235/Ser202/Thr205', 'Var', (123, 143))	('Thr205', 'Chemical', '-', (137, 143))	('phosphate incorporation', 'MPA', (25, 48))
519396	26555036	Human CRMP2 or CRMP4 was co-expressed with or without the CDK5 catalytic subunit and either p25 or p35 in HeLa cells (Additional file 2: Figure S2).	('Human', 'Species', '9606', (0, 5))	('CRMP4', 'Gene', (15, 20))	('CRMP2', 'Gene', (6, 11))	('p35', 'Var', (99, 102))	('CRMP2', 'Gene', '1808', (6, 11))	('HeLa', 'CellLine', 'CVCL:0030', (106, 110))	('CRMP4', 'Gene', '1809', (15, 20))	('p25', 'Gene', '8851', (92, 95))	('p25', 'Gene', (92, 95))
519403	26555036	These data support the hypothesis that an increase in CDK5 expression and/or activity associated with disease would alter the phosphorylation of CRMP2 (at Ser522) and tau (at Ser235 and Ser202/Thr205), and thus these substrates are potential biomarkers of aberrant CDK5 activity.	('at Ser235', 'Var', (172, 181))	('Ser202/Thr205', 'Var', (186, 199))	('CDK5', 'Gene', (54, 58))	('alter', 'Reg', (116, 121))	('CRMP2', 'Gene', (145, 150))	('Ser522', 'Chemical', '-', (155, 161))	('phosphorylation', 'MPA', (126, 141))	('Ser235', 'Chemical', '-', (175, 181))	('Ser202', 'Chemical', '-', (186, 192))	('Thr205', 'Chemical', '-', (193, 199))	('expression', 'MPA', (59, 69))	('activity', 'MPA', (77, 85))	('tau', 'Protein', (167, 170))	('CRMP2', 'Gene', '1808', (145, 150))	('increase', 'PosReg', (42, 50))
519406	26555036	CDK inhibition reduces CRMP2 phosphorylation at Ser522 but does not alter CRMP4 phosphorylation.	('CRMP2', 'Gene', (23, 28))	('CRMP2', 'Gene', '1808', (23, 28))	('Ser522', 'Chemical', '-', (48, 54))	('CRMP4', 'Gene', (74, 79))	('CDK', 'Protein', (0, 3))	('inhibition', 'Var', (4, 14))	('Ser522', 'Var', (48, 54))	('CRMP4', 'Gene', '1809', (74, 79))	('reduces', 'NegReg', (15, 22))
519407	26555036	Taken together with the CRMP and CDK5 co-expression data (Additional file 2: Figure S3) this indicates that Ser522 of CRMP2, but not CRMP4, is a physiological target for CDK5.	('CRMP2', 'Gene', (118, 123))	('CRMP', 'Chemical', '-', (24, 28))	('CRMP2', 'Gene', '1808', (118, 123))	('CRMP4', 'Gene', (133, 138))	('CRMP', 'Chemical', '-', (118, 122))	('Ser522', 'Chemical', '-', (108, 114))	('CRMP4', 'Gene', '1809', (133, 138))	('CRMP', 'Chemical', '-', (133, 137))	('Ser522', 'Var', (108, 114))
519409	26555036	Tau phosphorylation at Thr205 but not Ser202 is reduced by CDK inhibition (Fig.	('reduced', 'NegReg', (48, 55))	('Thr205', 'Chemical', '-', (23, 29))	('CDK', 'Protein', (59, 62))	('Ser202', 'Chemical', '-', (38, 44))	('Thr205', 'Var', (23, 29))	('inhibition', 'NegReg', (63, 73))	('Tau phosphorylation', 'MPA', (0, 19))
519416	26555036	Previous work had suggested that altered expression/phosphorylation of specific CRMP isoforms was associated with lung and breast cancer.	('breast cancer', 'Disease', 'MESH:D001943', (123, 136))	('expression/phosphorylation', 'MPA', (41, 67))	('CRMP', 'Chemical', '-', (80, 84))	('breast cancer', 'Disease', (123, 136))	('breast cancer', 'Phenotype', 'HP:0003002', (123, 136))	('CRMP', 'Gene', (80, 84))	('lung', 'Disease', (114, 118))	('altered', 'Var', (33, 40))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('associated', 'Reg', (98, 108))
519419	26555036	Interestingly this initial investigation suggested that immunopositive staining is more a feature of squamous cell carcinoma (8/11 with a score of 2 or 3, average score = 1.91) than adenocarcinoma (5 samples, none with score 3, average score = 1.8).	('immunopositive staining', 'Var', (56, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (101, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (187, 196))	('adenocarcinoma', 'Disease', (182, 196))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (101, 124))	('adenocarcinoma', 'Disease', 'MESH:D000230', (182, 196))	('squamous cell carcinoma', 'Disease', (101, 124))
519422	26555036	Consistent with the preliminary observation, Ser522 phosphorylated CRMP2 is predominantly localised in the nuclei of cancer cells and absent from healthy tissue, confirming the association of this phosphorylation with tumourigenesis and the unusual localisation of the CRMP2 (Fig.	('CRMP2', 'Gene', '1808', (269, 274))	('Ser522', 'Chemical', '-', (45, 51))	('CRMP2', 'Gene', (67, 72))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('tumour', 'Disease', (218, 224))	('CRMP2', 'Gene', '1808', (67, 72))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('association', 'Interaction', (177, 188))	('Ser522', 'Var', (45, 51))	('cancer', 'Disease', (117, 123))	('tumour', 'Phenotype', 'HP:0002664', (218, 224))	('CRMP2', 'Gene', (269, 274))	('tumour', 'Disease', 'MESH:D009369', (218, 224))
519423	26555036	CRMP2 phosphorylation at Ser522 has a higher intensity in squamous cell carcinoma compared to adenocarcinoma immunostaining.	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (58, 81))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('squamous cell carcinoma', 'Disease', (58, 81))	('Ser522', 'Chemical', '-', (25, 31))	('CRMP2', 'Gene', (0, 5))	('CRMP2', 'Gene', '1808', (0, 5))	('intensity', 'MPA', (45, 54))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('Ser522', 'Var', (25, 31))	('adenocarcinoma', 'Disease', (94, 108))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (58, 81))	('adenocarcinoma', 'Disease', 'MESH:D000230', (94, 108))
519426	26555036	In addition, there are no reported point mutants in CDK5R1 or CDK5R2 that result in significant increases in CDK5 activity.	('CDK5R2', 'Gene', (62, 68))	('increases', 'PosReg', (96, 105))	('point mutants', 'Var', (35, 48))	('CDK5R2', 'Gene', '8941', (62, 68))	('CDK5R1', 'Gene', (52, 58))	('CDK5', 'Enzyme', (109, 113))	('CDK5R1', 'Gene', '8851', (52, 58))
519427	26555036	Rather the ratio of p35 to its cleavage product p25 is proposed to alter subcellular location and potentially substrate selection.	('alter', 'Reg', (67, 72))	('p25', 'Gene', '8851', (48, 51))	('subcellular location', 'MPA', (73, 93))	('p25', 'Gene', (48, 51))	('p35', 'Var', (20, 23))
519429	26555036	However we have previously established that CRMP2 phosphorylation at Ser522 by CDK5 is a prerequisite for the subsequent sequential phosphorylation of CRMP2 at Ser518, Thr514 and finally Thr509 by GSK3.	('Thr509', 'Var', (187, 193))	('Thr509', 'Chemical', '-', (187, 193))	('Ser518', 'Var', (160, 166))	('Thr514', 'Var', (168, 174))	('CRMP2', 'Gene', (44, 49))	('Ser522', 'Chemical', '-', (69, 75))	('Ser518', 'Chemical', '-', (160, 166))	('CRMP2', 'Gene', '1808', (44, 49))	('GSK3', 'Gene', '56637', (197, 201))	('GSK3', 'Gene', (197, 201))	('CDK5', 'Gene', (79, 83))	('CRMP2', 'Gene', (151, 156))	('CRMP2', 'Gene', '1808', (151, 156))	('Thr514', 'Chemical', '-', (168, 174))	('Ser522', 'Var', (69, 75))
519433	26555036	Rather, increased CDK5 would also indirectly lead to enhanced phosphorylation of Th509/514 of CRMP2 subsequent to the increase in Ser522 phosphorylation.	('Th509/514', 'Var', (81, 90))	('CRMP2', 'Gene', '1808', (94, 99))	('increase', 'PosReg', (118, 126))	('Ser522 phosphorylation', 'MPA', (130, 152))	('Th509', 'Chemical', '-', (81, 86))	('phosphorylation', 'MPA', (62, 77))	('increased', 'PosReg', (8, 17))	('Ser522', 'Chemical', '-', (130, 136))	('CDK5', 'Protein', (18, 22))	('CRMP2', 'Gene', (94, 99))	('enhanced', 'PosReg', (53, 61))
519440	26555036	Previously Shimada and colleagues reported increased phosphorylation of Thr509 of CRMP2 in the nuclei of breast carcinoma and that this increased in proportion to the histological grade and triple-negative subtype.	('breast carcinoma', 'Disease', (105, 121))	('CRMP2', 'Gene', (82, 87))	('breast carcinoma', 'Phenotype', 'HP:0003002', (105, 121))	('CRMP2', 'Gene', '1808', (82, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('Thr509', 'Var', (72, 78))	('increased', 'PosReg', (43, 52))	('increased', 'PosReg', (136, 145))	('Thr509', 'Chemical', '-', (72, 78))	('phosphorylation', 'MPA', (53, 68))	('breast carcinoma', 'Disease', 'MESH:D001943', (105, 121))
519446	26555036	However this is the first indication that changes in CRMP2 phosphorylation, and by implication CDK5 regulation of CRMP2, are associated with B-lymphocyte biology, in health or disease.	('CRMP2', 'Gene', '1808', (114, 119))	('CRMP2', 'Gene', (53, 58))	('CRMP2', 'Gene', '1808', (53, 58))	('associated', 'Reg', (125, 135))	('phosphorylation', 'MPA', (59, 74))	('changes', 'Var', (42, 49))	('B-lymphocyte biology', 'CPA', (141, 161))	('CRMP2', 'Gene', (114, 119))
519448	26555036	As far as we are aware there is currently only one report proposing that phosphorylated CRMP2 is in the nucleus, with phospho-509/514 of CRMP2 being detected by immunofluorescence in the nucleus of breast cancer cells.	('breast cancer', 'Phenotype', 'HP:0003002', (198, 211))	('CRMP2', 'Gene', (88, 93))	('CRMP2', 'Gene', '1808', (88, 93))	('phospho-509/514', 'Var', (118, 133))	('CRMP2', 'Gene', (137, 142))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('CRMP2', 'Gene', '1808', (137, 142))	('breast cancer', 'Disease', 'MESH:D001943', (198, 211))	('breast cancer', 'Disease', (198, 211))
519461	26555036	Thus alternative splicing of CRMP2 regulates its nuclear localisation and it is specifically CRMP2A phosphorylation that is associated with lung, breast and lymphocyte tumour staining.	('CRMP2', 'Gene', (29, 34))	('CRMP2A', 'Gene', (93, 99))	('alternative splicing', 'Var', (5, 25))	('lung', 'Disease', (140, 144))	('CRMP2', 'Gene', '1808', (29, 34))	('tumour', 'Phenotype', 'HP:0002664', (168, 174))	('tumour', 'Disease', 'MESH:D009369', (168, 174))	('associated', 'Reg', (124, 134))	('breast', 'Disease', (146, 152))	('regulates', 'Reg', (35, 44))	('CRMP2', 'Gene', (93, 98))	('tumour', 'Disease', (168, 174))	('nuclear localisation', 'MPA', (49, 69))	('CRMP2', 'Gene', '1808', (93, 98))	('CRMP2A', 'Gene', '1808', (93, 99))
519465	26555036	Phosphorylation of CRMP2 by CDK5 is associated with altered function in neurons, however the role of phosphorylation of CRMPs by CDK5 in cancer has not yet been studied.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('CRMP2', 'Gene', (19, 24))	('CRMP2', 'Gene', '1808', (19, 24))	('Phosphorylation', 'Var', (0, 15))	('altered', 'Reg', (52, 59))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('CRMP', 'Chemical', '-', (19, 23))	('cancer', 'Disease', (137, 143))	('CDK5', 'Gene', (28, 32))	('CRMP', 'Chemical', '-', (120, 124))	('function', 'MPA', (60, 68))
519476	33927719	We firstly proved that TMB, PD-L1, and mutant-allele tumor heterogeneity (MATH) were independent biomarkers.	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('mutant-allele', 'Var', (39, 52))	('tumor', 'Disease', (53, 58))	('TMB', 'Chemical', '-', (23, 26))
519487	33927719	Another novel statistical value, mutant-allele tumor heterogeneity (MATH), has been documented that is not only as a measure of intratumor genetic heterogeneity but also can be used as a biomarker to predict the response of treatment for patients.	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumor', 'Disease', (133, 138))	('mutant-allele', 'Var', (33, 46))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('patients', 'Species', '9606', (238, 246))	('tumor', 'Disease', (47, 52))
519507	33927719	Somatic mutations were filtered with the following rules: (1) base quality value >=20; (2) mutation reads depth >=10; (3) variant allele frequency >=5%; (4) reads supporting variation <4 and frequency <2% in normal, tumor abundance/normal abundance >=8; (5) no strand bias (GATK parameter FS > 60 for SNP and FS >200 for indel); (6) discard synonymous mutations.	('tumor', 'Disease', (216, 221))	('FS >', 'Var', (309, 313))	('variant', 'Var', (122, 129))	('tumor', 'Disease', 'MESH:D009369', (216, 221))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))
519520	33927719	The patients with EGFR exon 18-21 mutations and ALK gene fusions were filtered to avoid make a disturbance for the analysis.	('EGFR', 'Gene', '1956', (18, 22))	('ALK', 'Gene', '238', (48, 51))	('EGFR', 'Gene', (18, 22))	('ALK', 'Gene', (48, 51))	('patients', 'Species', '9606', (4, 12))	('mutations', 'Var', (34, 43))
519530	33927719	A prior study has shown that co-mutation information of DNA damage response (DDR) pathway can be used as a predictor of response to immune checkpoint blockade, and the mutation of the DDR solved the problem of difficulty in determining an optimal TMB threshold.	('mutation', 'Var', (168, 176))	('TMB', 'Chemical', '-', (247, 250))	('DDR', 'Gene', (184, 187))
519532	33927719	The results showed that patients with mutations in any of six pathways had better survival than those without mutation ( Figure 2 ).	('mutations', 'Var', (38, 47))	('better', 'PosReg', (75, 81))	('survival', 'CPA', (82, 90))	('patients', 'Species', '9606', (24, 32))
519561	33927719	Previous studies have proven that CD8 cell play a central role in immunity to cancer through their capacity to kill malignant cells, EMT-related genes may contribute to tumor immune escape, and FGFR mutated cases have a more deserted immune phenotype than the wild type.	('mutated', 'Var', (199, 206))	('FGFR', 'Gene', (194, 198))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('CD8', 'Gene', (34, 37))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('EMT-related genes', 'Gene', (133, 150))	('CD8', 'Gene', '925', (34, 37))	('tumor', 'Disease', (169, 174))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('contribute', 'Reg', (155, 165))
519569	33927719	In LUAD cohort, the mutation ratio of KRAS, an oncogene which leads to immune escape in the tumor microenvironment, and PTPRD, which affects the tumor proliferation, were higher than LUSC also suggests the difference immune response mechanisms.	('PTPRD', 'Gene', '5789', (120, 125))	('PTPRD', 'Gene', (120, 125))	('KRAS', 'Gene', '3845', (38, 42))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('LUSC', 'Phenotype', 'HP:0030359', (183, 187))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('mutation', 'Var', (20, 28))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Disease', (145, 150))	('tumor', 'Disease', (92, 97))	('KRAS', 'Gene', (38, 42))
519581	32188929	Cancers can be caused by an accumulation of genetic mutations in oncogenes or tumor suppressors.	('caused by', 'Reg', (15, 24))	('Cancers', 'Disease', (0, 7))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('Cancers', 'Phenotype', 'HP:0002664', (0, 7))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('genetic mutations', 'Var', (44, 61))	('Cancers', 'Disease', 'MESH:D009369', (0, 7))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('tumor', 'Disease', (78, 83))	('oncogenes', 'Protein', (65, 74))
519582	32188929	These mutations are known as "driver" mutations and they are under positive selection; however, only a very small fraction of somatic mutations in a tumor sample are expected to be drivers.	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('tumor', 'Disease', (149, 154))	('mutations', 'Var', (134, 143))	('mutations', 'Var', (6, 15))
519586	32188929	For example, deleterious mutations in POLE, POLD1, and the MMR system defects may lead to a hypermutated phenotype.	('mutations', 'Var', (25, 34))	('POLE', 'Gene', (38, 42))	('lead to', 'Reg', (82, 89))	('hypermutated phenotype', 'MPA', (92, 114))	('system defects', 'Disease', 'MESH:D009421', (63, 77))	('system defects', 'Disease', (63, 77))	('POLD1', 'Gene', '5424', (44, 49))	('POLD1', 'Gene', (44, 49))
519591	32188929	Microsatellite instability (MSI) is a phenotype of an accumulation of deletions/insertions in repetitive DNA tracts, called microsatellites.	('Microsatellite instability', 'Disease', (0, 26))	('Microsatellite instability', 'Disease', 'MESH:D053842', (0, 26))	('deletions/insertions', 'Var', (70, 90))
519595	32188929	The major challenge is that even though the current well-accepted TMB measurement requires counting the non-synonymous somatic mutations in a paired tumor-normal sample using whole-exome sequencing (WES), current diagnostics based on sequencing technologies still rely heavily on targeted panel sequencing.	('TMB', 'Chemical', '-', (66, 69))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('tumor', 'Disease', (149, 154))	('mutations', 'Var', (127, 136))
519599	32188929	For example, Foundation Medicine used COSMIC to filter out driver mutations and added synonymous mutations to reach an agreement with WES-based TMB.	('mutations', 'Var', (66, 75))	('synonymous mutations', 'Var', (86, 106))	('TMB', 'Chemical', '-', (144, 147))
519611	32188929	The mutation predictions for MUC16 and TTN then became much closer to the observed values (Supplementary Fig.	('TTN', 'Gene', '7273', (39, 42))	('MUC16', 'Gene', (29, 34))	('mutation', 'Var', (4, 12))	('MUC16', 'Gene', '94025', (29, 34))	('TTN', 'Gene', (39, 42))
519612	32188929	In addition, the observed number of non-synonymous mutations in well-known cancer-specific driver genes, such as TP53, KRAS, and PIK3CA, were much higher than the predicted background ones due to positive selection (Supplementary Fig.	('PIK3CA', 'Gene', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('cancer', 'Disease', (75, 81))	('PIK3CA', 'Gene', '5290', (129, 135))	('TP53', 'Gene', '7157', (113, 117))	('KRAS', 'Gene', (119, 123))	('non-synonymous mutations', 'Var', (36, 60))	('higher', 'PosReg', (147, 153))	('KRAS', 'Gene', '3845', (119, 123))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('TP53', 'Gene', (113, 117))
519627	32188929	In contrast, ecTMB predictions, using both synonymous and non-synonymous mutations, not only improved correlation coefficients with WES-based TMB, but also reduced MSE, RMSE, sigma, and biases while keeping the slope close to 1.	('correlation coefficients', 'MPA', (102, 126))	('improved', 'PosReg', (93, 101))	('sigma', 'MPA', (175, 180))	('TMB', 'Chemical', '-', (142, 145))	('reduced', 'NegReg', (156, 163))	('RMSE', 'MPA', (169, 173))	('biases', 'MPA', (186, 192))	('TMB', 'Chemical', '-', (15, 18))	('mutations', 'Var', (73, 82))	('MSE', 'MPA', (164, 167))
519628	32188929	As an example, for the predictions of the TST170 panel, ecTMB improved R from 0.71 to 0.77, reduced MAE from 7.05 to 3.21, and decreased sigma from 6.04 to 4.13 if compared with the counting method without filtering (Fig.	('TMB', 'Chemical', '-', (58, 61))	('decreased', 'NegReg', (127, 136))	('improved', 'PosReg', (62, 70))	('sigma', 'MPA', (137, 142))	('ecTMB', 'Var', (56, 61))	('reduced', 'NegReg', (92, 99))	('MAE', 'MPA', (100, 103))
519630	32188929	These performance metrics demonstrated that TMB prediction by ecTMB has a higher agreement with WES-based TMB.	('tri', 'Chemical', '-', (20, 23))	('TMB', 'Chemical', '-', (64, 67))	('TMB', 'Chemical', '-', (106, 109))	('TMB', 'Disease', (44, 47))	('ecTMB', 'Var', (62, 67))	('TMB', 'Chemical', '-', (44, 47))
519635	32188929	ecTMB prediction had pretty good sensitivity and also high precision, leading to higher overall accuracy when comparing to the other 2 methods (Fig.	('ecTMB', 'Var', (0, 5))	('higher', 'PosReg', (81, 87))	('TMB', 'Chemical', '-', (2, 5))	('accuracy', 'MPA', (96, 104))
519643	32188929	We found that a large fraction (92%) of TMB-extreme samples possessed at least one non-synonymous mutation in POLE in aggregated colorectal, endometrial, and stomach cancer samples, among which we detected a high recurrence of 2 known POLE driver mutations (P286R and V411L) (Supplementary Fig.	('stomach cancer', 'Disease', (158, 172))	('P286R', 'Var', (258, 263))	('V411L', 'Mutation', 'rs1196350669', (268, 273))	('TMB-extreme', 'Gene', (40, 51))	('stomach cancer', 'Disease', 'MESH:D013274', (158, 172))	('TMB', 'Chemical', '-', (40, 43))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('V411L', 'Var', (268, 273))	('stomach cancer', 'Phenotype', 'HP:0012126', (158, 172))	('P286R', 'Mutation', 'p.P286R', (258, 263))	('tri', 'Chemical', '-', (147, 150))
519645	32188929	The comparison of non-synonymous mutations in seven MMR genes between TMB-high samples against the rest revealed 2 highly recurred mutations: N674lfs*6 in MLH3 and K383Rfs*32 in MSH3, which have not been reported as driver mutation before (Supplementary Fig.	('K383Rfs*32', 'Mutation', 'rs587776701', (164, 174))	('N674lfs*6', 'Var', (142, 151))	('TMB', 'Chemical', '-', (70, 73))	('MLH3', 'Gene', '27030', (155, 159))	('MSH3', 'Gene', (178, 182))	('K383Rfs*32', 'Var', (164, 174))	('MLH3', 'Gene', (155, 159))	('MSH3', 'Gene', '4437', (178, 182))
519646	32188929	We also found that TMB-high samples generally had a significantly higher fraction (~17%) of INDEL mutations than what was observed in both TMB-low (~5%) and TMB-extreme (~1%) samples (Fig.	('TMB', 'Chemical', '-', (157, 160))	('INDEL mutations', 'Var', (92, 107))	('higher', 'PosReg', (66, 72))	('TMB', 'Chemical', '-', (19, 22))	('TMB', 'Chemical', '-', (139, 142))
519647	32188929	These distinct mutation profiles suggest that defective MMR system could be the likely cause for TMB-high whereas mutated POLE system for TMB-extreme.	('TMB', 'Chemical', '-', (138, 141))	('TMB', 'Chemical', '-', (97, 100))	('TMB-high', 'Disease', (97, 105))	('MMR', 'Protein', (56, 59))	('defective', 'Var', (46, 55))
519658	32188929	First, ecTMB improves the consistency of TMB prediction among assays through systematic correction of panel design biases.	('consistency', 'MPA', (26, 37))	('TMB', 'Chemical', '-', (41, 44))	('improves', 'PosReg', (13, 21))	('ecTMB', 'Var', (7, 12))	('TMB', 'Chemical', '-', (9, 12))
519661	32188929	Although there are other factors influencing the consistency of TMB among assays, such as sequencing depth and choice of somatic mutation caller, we have demonstrated that ecTMB can help to improve the stability of TMB measurement when those factors are fixed.	('TMB', 'Chemical', '-', (64, 67))	('stability', 'MPA', (202, 211))	('TMB', 'MPA', (215, 218))	('ecTMB', 'Var', (172, 177))	('TMB', 'Chemical', '-', (215, 218))	('improve', 'PosReg', (190, 197))	('TMB', 'Chemical', '-', (174, 177))
519666	32188929	Although multiple studies have observed a better prognosis in MSI-H patients, we showed that TMB-extreme caused by dysfunctional POLE showed even better overall survival outcomes compared to TMB-high (MSI-H).	('patients', 'Species', '9606', (68, 76))	('dysfunctional POLE', 'Var', (115, 133))	('TMB', 'Chemical', '-', (93, 96))	('TMB-extreme', 'Disease', (93, 104))	('TMB', 'Chemical', '-', (191, 194))	('better', 'PosReg', (146, 152))
519667	32188929	Similar to our result, studies have reported that mutations in POLE proofreading domain are associated with improved prognosis in several cancer types, including high-grade glioma, lung adenocarcinoma, endometrial cancer, and colorectal cancer.	('cancer', 'Disease', (138, 144))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('glioma', 'Phenotype', 'HP:0009733', (173, 179))	('colorectal cancer', 'Phenotype', 'HP:0003003', (226, 243))	('cancer', 'Disease', (214, 220))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (181, 200))	('carcinoma', 'Phenotype', 'HP:0030731', (191, 200))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (181, 200))	('cancer', 'Disease', (237, 243))	('cancer', 'Disease', 'MESH:D009369', (138, 144))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('endometrial cancer', 'Phenotype', 'HP:0012114', (202, 220))	('improved', 'PosReg', (108, 116))	('colorectal cancer', 'Disease', 'MESH:D015179', (226, 243))	('endometrial cancer', 'Disease', (202, 220))	('cancer', 'Disease', 'MESH:D009369', (214, 220))	('colorectal cancer', 'Disease', (226, 243))	('mutations', 'Var', (50, 59))	('glioma', 'Disease', (173, 179))	('endometrial cancer', 'Disease', 'MESH:D016889', (202, 220))	('cancer', 'Disease', 'MESH:D009369', (237, 243))	('glioma', 'Disease', 'MESH:D005910', (173, 179))	('lung adenocarcinoma', 'Disease', (181, 200))
519669	32188929	The TMB-extreme subtype can also be potentially detected with an assay targeting only mutations in the POLE's proofreading domain.	('mutations', 'Var', (86, 95))	('TMB', 'Chemical', '-', (4, 7))	('TMB-extreme', 'Disease', (4, 15))	('detected', 'Reg', (48, 56))
519681	32188929	Different proportions of non-synonymous mutations can be used for TMB prediction.	('non-synonymous mutations', 'Var', (25, 49))	('TMB', 'Chemical', '-', (66, 69))	('TMB', 'Disease', (66, 69))
519682	32188929	In BLCA, SKCM, LUSC, and LUAD, which are known to harbor somatic mutations caused by environmental factors, the prediction accuracy increased as a higher proportion of non-synonymous mutations were included (Supplementary Fig.	('LUAD', 'Disease', (25, 29))	('SKCM', 'Disease', (9, 13))	('BLCA', 'Disease', 'MESH:D001749', (3, 7))	('LUSC', 'Disease', 'MESH:D002294', (15, 19))	('increased', 'PosReg', (132, 141))	('LUAD', 'Disease', 'MESH:D000077192', (25, 29))	('LUSC', 'Disease', (15, 19))	('BLCA', 'Disease', (3, 7))	('SKCM', 'Disease', 'MESH:C562393', (9, 13))	('non-synonymous mutations', 'Var', (168, 192))	('LUAD', 'Phenotype', 'HP:0030078', (25, 29))
519720	32160711	Research shows that single-nucleotide polymorphisms (SNPs) in miRNAs and their target sites can impact miRNA biology and affect cancer risk, as well as treatment response.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('affect', 'Reg', (121, 127))	('treatment response', 'CPA', (152, 170))	('miR', 'Gene', '220972', (62, 65))	('miR', 'Gene', (62, 65))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('single-nucleotide polymorphisms', 'Var', (20, 51))	('miR', 'Gene', '220972', (103, 106))	('impact', 'Reg', (96, 102))	('miR', 'Gene', (103, 106))	('cancer', 'Disease', (128, 134))
519825	31562203	Enhanced antigen presentation on the tumor cells by EZH2 inhibitors or CRISPR mediated EZH2 deficiency, increased antigen specific CD8+ T cell proliferation, IFNgamma production and tumor cell cytotoxicity.	('deficiency', 'Var', (92, 102))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('tumor', 'Disease', (182, 187))	('increased', 'PosReg', (104, 113))	('tumor cell cytotoxicity', 'Disease', 'MESH:D064420', (182, 205))	('CD8', 'Gene', '925', (131, 134))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('EZH2', 'Gene', (87, 91))	('IFNgamma production', 'MPA', (158, 177))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('antigen presentation', 'MPA', (9, 29))	('CD8', 'Gene', (131, 134))	('tumor cell cytotoxicity', 'Disease', (182, 205))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))	('Enhanced', 'PosReg', (0, 8))
519826	31562203	Mechanistically, EZH2 inhibition reduced the histone H3K27me3 modification on the beta-2-microglobulin (B2M) promoter.	('inhibition', 'Var', (22, 32))	('histone', 'MPA', (45, 52))	('EZH2', 'Gene', (17, 21))	('beta-2-microglobulin', 'Gene', '12010', (82, 102))	('reduced', 'NegReg', (33, 40))	('beta-2-microglobulin', 'Gene', (82, 102))
519847	31562203	In regulatory T cells (Tregs), disruption of EZH2 can enhance antitumor immunity by diminishing the suppressive activity of Tregs and enhancing T cell infiltration in the tumor.	('enhancing', 'PosReg', (134, 143))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Disease', (66, 71))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('EZH2', 'Gene', (45, 49))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('disruption', 'Var', (31, 41))	('diminishing', 'NegReg', (84, 95))	('enhance', 'PosReg', (54, 61))	('suppressive activity', 'CPA', (100, 120))	('tumor', 'Disease', (171, 176))	('tumor', 'Disease', 'MESH:D009369', (66, 71))
519850	31562203	In addition, EZH2 is also involved in natural killer cell mediated tumor eradication in hepatocellular carcinoma by silencing the expression of NK group 2D (NKG2D) ligands.	('expression', 'MPA', (130, 140))	('NKG2D', 'Gene', (157, 162))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('silencing', 'NegReg', (116, 125))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('EZH2', 'Var', (13, 17))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (88, 112))	('tumor', 'Disease', (67, 72))	('hepatocellular carcinoma', 'Disease', (88, 112))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (88, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('NKG2D', 'Gene', '27007', (157, 162))
519851	31562203	Very recently, diffuse large B-cell lymphoma showed a strong correlation between EHZ2 mutation enrichment and MHC class I and class II expression deficiency.	('deficiency', 'NegReg', (146, 156))	('MHC class I', 'Protein', (110, 121))	('lymphoma', 'Phenotype', 'HP:0002665', (36, 44))	('class II', 'Protein', (126, 134))	('B-cell lymphoma', 'Disease', (29, 44))	('B-cell lymphoma', 'Disease', 'MESH:D016393', (29, 44))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (29, 44))	('mutation', 'Var', (86, 94))	('EHZ2', 'Gene', (81, 85))
519852	31562203	EZH2 inhibition relieved suppression of NLRC5 and CIITA expression leading to increased expression but only in an EZH2 mutated background.	('suppression', 'NegReg', (25, 36))	('CIITA', 'Gene', (50, 55))	('CIITA', 'Gene', '12265', (50, 55))	('NLRC5', 'Gene', '434341', (40, 45))	('inhibition', 'Var', (5, 15))	('NLRC5', 'Gene', (40, 45))	('increased', 'PosReg', (78, 87))	('expression', 'MPA', (88, 98))
519854	31562203	In the present study, we hypothesized that inhibiting EZH2 function may improve the outcome of anti-PD-1 therapy by enhancing antigen presentation in HPV-negative HNSCC.	('EZH2', 'Gene', (54, 58))	('enhancing', 'PosReg', (116, 125))	('HNSCC', 'Phenotype', 'HP:0012288', (163, 168))	('antigen presentation', 'MPA', (126, 146))	('improve', 'PosReg', (72, 79))	('outcome', 'MPA', (84, 91))	('inhibiting', 'Var', (43, 53))	('HPV', 'Species', '10566', (150, 153))
519870	31562203	Mouse tumors were dissociated to single cell suspension with Tumor Dissociation Kit (130-096-730) and gentleMACS Dissociator (130-093-235) from Miltenyi Biotec.	('130-093-235', 'Var', (126, 137))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('tumors', 'Disease', (6, 12))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('Mouse', 'Species', '10090', (0, 5))	('Tumor', 'Phenotype', 'HP:0002664', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))
519872	31562203	Isolated T cells were cultured in RPMI 1640, supplemented with 10% heat inactivated FBS, 20 mM HEPES (15630080, Gibco), 1mM sodium pyruvate (11360070, Gibco), 0.05mM 2-mercaptoethanol, 2 mM L-glutamine (G7513, Sigma), and 100 U/ml penicillin streptomycin.	('2-mercaptoethanol', 'Chemical', 'MESH:D008623', (166, 183))	('penicillin', 'Chemical', 'MESH:D010406', (231, 241))	('HEPES', 'Chemical', 'MESH:D006531', (95, 100))	('sodium pyruvate', 'Chemical', '-', (124, 139))	('11360070', 'Var', (141, 149))	('streptomycin', 'Chemical', 'MESH:D013307', (242, 254))	('RPMI', 'Chemical', '-', (34, 38))	('15630080', 'Var', (102, 110))	('L-glutamine', 'Chemical', 'MESH:D005973', (190, 201))
519886	31562203	Cells were treated with increasing concentrations of GSK126, EPZ6438, or vehicle (DMSO) for 72 hours.	('EPZ6438', 'Var', (61, 68))	('DMSO', 'Chemical', 'MESH:D004121', (82, 86))	('EPZ6438', 'Chemical', 'MESH:C000593333', (61, 68))	('GSK126', 'Chemical', 'MESH:C577920', (53, 59))	('GSK126', 'Gene', (53, 59))
519888	31562203	TaqMan Real-time PCR Assays specific for mouse B2m (Mm00437762_m1), H2-K1 (Mm01612247_mH), Cxcl10 (Mm00445235_m1), Gapdh (Mm99999915_g1), human B2M (Hs00187842_m1), HLA-A (Hs01058806_g1), HLA-B (Hs00818803_g1), HLA-C (Hs00740298_g1), CXCL10 (Hs00171042_m1), and GAPDH (Hs02786624_g1) were purchased from Thermo Fisher and assays were performed on an ABI Step One Plus for quantifying gene expression levels.	('HLA-C', 'Gene', (211, 216))	('HLA-B', 'Gene', '3106', (188, 193))	('Cxcl10', 'Gene', '15945', (91, 97))	('HLA-C', 'Gene', '3107', (211, 216))	('mouse', 'Species', '10090', (41, 46))	('B2m', 'Gene', '12010', (47, 50))	('GAPDH', 'Gene', '2597', (262, 267))	('HLA-A', 'Gene', '3105', (165, 170))	('Gapdh', 'Gene', (115, 120))	('HLA-B', 'Gene', (188, 193))	('Hs00171042_m1', 'Var', (242, 255))	('GAPDH', 'Gene', (262, 267))	('Hs02786624_g1', 'Var', (269, 282))	('B2m', 'Gene', (47, 50))	('human', 'Species', '9606', (138, 143))	('Gapdh', 'Gene', '14433', (115, 120))	('HLA-A', 'Gene', (165, 170))	('Mm99999915_g1', 'Var', (122, 135))	('Cxcl10', 'Gene', (91, 97))
519910	31562203	Human HNSCC cell lines (CAL27, CAL33, SCC25, and SCC9) were treated with increasing concentrations of GSK126 or EPZ6438 to test the impact of EZH2 inhibition on cell viability.	('Human', 'Species', '9606', (0, 5))	('GSK126', 'Chemical', 'MESH:C577920', (102, 108))	('EPZ6438', 'Var', (112, 119))	('SCC9', 'Gene', (49, 53))	('EPZ6438', 'Chemical', 'MESH:C000593333', (112, 119))	('SCC9', 'Gene', '112207', (49, 53))	('CAL27', 'CellLine', 'CVCL:1107', (24, 29))	('HNSCC', 'Phenotype', 'HP:0012288', (6, 11))	('test', 'Reg', (123, 127))
519911	31562203	Based on the various sensitivities of these cell lines to EZH2 inhibitors, we selected the 10 muM concentration for both GSK126 and EPZ6438, at which neither inhibitor showed significant cell growth inhibition (Figure 2A).	('EPZ6438', 'Var', (132, 139))	('cell', 'CPA', (187, 191))	('GSK126', 'Chemical', 'MESH:C577920', (121, 127))	('EPZ6438', 'Chemical', 'MESH:C000593333', (132, 139))
519912	31562203	While GSK126 increased IFNgamma induced HLA expression in 3 of 4 lines tested, EPZ6438 increased both basal and IFNgamma induced HLA cell surface expression levels compared with DMSO control in all cell lines (Figure 2B).	('increased', 'PosReg', (87, 96))	('EPZ6438', 'Chemical', 'MESH:C000593333', (79, 86))	('GSK126', 'Chemical', 'MESH:C577920', (6, 12))	('IFNgamma induced HLA expression', 'MPA', (23, 54))	('GSK126', 'Var', (6, 12))	('DMSO', 'Chemical', 'MESH:D004121', (178, 182))	('EPZ6438', 'Var', (79, 86))	('increased', 'PosReg', (13, 22))
519925	31562203	We used 2 independent clones of CAS9 expressing MOC1-esc1 to knock out EZH2 with 2 different single guide RNAs (sgRNAs) to rule out clone specific or off-target effects.	('EZH2', 'Gene', (71, 75))	('knock out', 'Var', (61, 70))	('MOC1-esc1', 'Gene', (48, 57))	('esc1', 'CellLine', 'CVCL:9108', (53, 57))
519928	31562203	GSK126 or EPZ6438 treatment sensitized MOC1-esc1 cells to T cell-mediated killing (Figure 4B).	('sensitized', 'Reg', (28, 38))	('GSK126', 'Chemical', 'MESH:C577920', (0, 6))	('esc1', 'CellLine', 'CVCL:9108', (44, 48))	('EPZ6438', 'Var', (10, 17))	('T cell-mediated killing', 'CPA', (58, 81))	('EPZ6438', 'Chemical', 'MESH:C000593333', (10, 17))
519929	31562203	Genetic ablation of EZH2 dramatically sensitized tumor cells to T cell-mediated killing in both clones in comparison with their parental lines and ROSA26 targeting controls (Figure 4B and Supplementary Figure 6).	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('sensitized', 'Reg', (38, 48))	('EZH2', 'Gene', (20, 24))	('tumor', 'Disease', (49, 54))	('ROSA26', 'Gene', '14910', (147, 153))	('T cell-mediated killing', 'CPA', (64, 87))	('ROSA26', 'Gene', (147, 153))	('ablation', 'Var', (8, 16))
519930	31562203	Consistent with the inhibitor treatment experiment results, loss of EZH2 significantly increased MHC class I cell surface expression levels which again were enhanced in combination with IFNgamma without impacting PD-L1 (Figure 4C, D), indicating the specificity of this regulation on antigen presentation.	('EZH2', 'Gene', (68, 72))	('increased', 'PosReg', (87, 96))	('enhanced', 'PosReg', (157, 165))	('MHC class I cell surface expression levels', 'MPA', (97, 139))	('increased MHC class I cell surface expression', 'Phenotype', 'HP:0031391', (87, 132))	('increased MHC', 'Phenotype', 'HP:0025548', (87, 100))	('PD-L1', 'Gene', (213, 218))	('loss', 'Var', (60, 64))	('PD-L1', 'Gene', '60533', (213, 218))
519931	31562203	Therefore, targeting of EZH2 sensitized tumor cells to T cell-mediated killing.	('T cell-mediated killing', 'CPA', (55, 78))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('EZH2', 'Gene', (24, 28))	('sensitized', 'Reg', (29, 39))	('targeting', 'Var', (11, 20))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))
519932	31562203	To start to define the mechanism of EZH2 regulation of antigen presentation, we tested H3K27me3 levels in GSK126 or EPZ6438 treated cells.	('H3K27me3 levels', 'MPA', (87, 102))	('GSK126', 'Chemical', 'MESH:C577920', (106, 112))	('EPZ6438', 'Var', (116, 123))	('tested', 'Reg', (80, 86))	('EPZ6438', 'Chemical', 'MESH:C000593333', (116, 123))
519935	31562203	To test the hypothesis that EZH2 regulates H3K27me3 occupancy on the promoter region of B2M, MOC1-esc1 cells were treated with EPZ6438 or DMSO and subjected to chromatin immunoprecipitation (ChIP) with antibodies against EZH2, H3K27me3, or IgG control.	('EPZ6438', 'Var', (127, 134))	('esc1', 'CellLine', 'CVCL:9108', (98, 102))	('EPZ6438', 'Chemical', 'MESH:C000593333', (127, 134))	('DMSO', 'Chemical', 'MESH:D004121', (138, 142))	('H3K27me3', 'Var', (227, 235))
519937	31562203	Importantly, EPZ6438 treatment significantly reduced H3K27me3 enrichment on the B2M promoter region (Figure 5D).	('H3K27me3', 'Protein', (53, 61))	('EPZ6438', 'Chemical', 'MESH:C000593333', (13, 20))	('reduced', 'NegReg', (45, 52))	('EPZ6438', 'Var', (13, 20))
519947	31562203	In summary, enhanced antigen presentation induced by targeting of EZH2 promoted proliferation and IFNgamma production of antigen specific T cells and combination therapy of GSK126 and anti-PD-1 resulted in attenuation of tumor progression in an anti-PD-1 resistant mouse model of HNSCC.	('targeting', 'Var', (53, 62))	('promoted', 'PosReg', (71, 79))	('antigen presentation', 'MPA', (21, 41))	('proliferation', 'CPA', (80, 93))	('tumor', 'Disease', (221, 226))	('mouse', 'Species', '10090', (265, 270))	('EZH2', 'Gene', (66, 70))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('IFNgamma production', 'MPA', (98, 117))	('enhanced', 'PosReg', (12, 20))	('GSK126', 'Chemical', 'MESH:C577920', (173, 179))	('HNSCC', 'Phenotype', 'HP:0012288', (280, 285))	('attenuation', 'NegReg', (206, 217))	('tumor', 'Disease', 'MESH:D009369', (221, 226))
519950	31562203	Neither GSK126 monotherapy nor the combination of GSK126 and anti-PD-1 suppressed tumor growth (Figure 6H).	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('GSK126', 'Chemical', 'MESH:C577920', (8, 14))	('anti-PD-1', 'Gene', (61, 70))	('tumor', 'Disease', (82, 87))	('GSK126', 'Chemical', 'MESH:C577920', (50, 56))	('GSK126', 'Var', (50, 56))	('suppressed', 'NegReg', (71, 81))
519955	31562203	In order to define approaches to improve outcomes of anti-PD-1 therapy in HNSCCs, we identified that targeting the histone methyltransferase EZH2 enhanced antigen presentation in both human and mouse HNSCC lines.	('histone methyltransferase', 'Gene', '56979', (115, 140))	('HNSCC', 'Phenotype', 'HP:0012288', (200, 205))	('antigen presentation', 'MPA', (155, 175))	('histone methyltransferase', 'Gene', (115, 140))	('mouse', 'Species', '10090', (194, 199))	('HNSCC', 'Phenotype', 'HP:0012288', (74, 79))	('EZH2', 'Gene', (141, 145))	('enhanced', 'PosReg', (146, 154))	('human', 'Species', '9606', (184, 189))	('targeting', 'Var', (101, 110))
519956	31562203	The enhanced antigen presentation induced by targeting EZH2 sensitized tumor cells to T cell-mediated killing, resulted in higher T cell proliferation and IFNgamma production in vitro.	('antigen presentation', 'MPA', (13, 33))	('T cell-mediated killing', 'CPA', (86, 109))	('IFNgamma', 'MPA', (155, 163))	('enhanced', 'PosReg', (4, 12))	('T cell proliferation', 'CPA', (130, 150))	('higher', 'PosReg', (123, 129))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('EZH2', 'Gene', (55, 59))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('targeting', 'Var', (45, 54))	('tumor', 'Disease', (71, 76))
519957	31562203	These findings translated to a synergistic impact of combination GSK126 and anti-PD-1 in attenuating the tumor progression of an anti-PD-1 resistant model of HNSCC and showed that EZH2 inhibition can enhance tumor cell Class I expression in vivo including in highly resistant models.	('combination GSK126', 'Var', (53, 71))	('tumor', 'Disease', 'MESH:D009369', (208, 213))	('inhibition', 'Var', (185, 195))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('anti-PD-1', 'Gene', (76, 85))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('GSK126', 'Chemical', 'MESH:C577920', (65, 71))	('GSK126', 'Var', (65, 71))	('EZH2', 'Gene', (180, 184))	('tumor', 'Disease', (208, 213))	('attenuating', 'NegReg', (89, 100))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('enhance', 'PosReg', (200, 207))	('tumor', 'Disease', (105, 110))	('HNSCC', 'Phenotype', 'HP:0012288', (158, 163))
519958	31562203	EZH2 inhibition has been proposed as a therapeutic strategy in cancers with frequent gain of function mutation or over-expression of EZH2, including melanoma, ovarian cancer, and lymphoma to induce apoptotic cell death.	('melanoma, ovarian cancer', 'Disease', 'MESH:D008545', (149, 173))	('EZH2', 'Gene', (133, 137))	('apoptotic cell death', 'CPA', (198, 218))	('melanoma', 'Phenotype', 'HP:0002861', (149, 157))	('lymphoma', 'Disease', (179, 187))	('mutation', 'Var', (102, 110))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('over-expression', 'PosReg', (114, 129))	('gain of function', 'PosReg', (85, 101))	('lymphoma', 'Disease', 'MESH:D008223', (179, 187))	('ovarian cancer', 'Phenotype', 'HP:0100615', (159, 173))	('lymphoma', 'Phenotype', 'HP:0002665', (179, 187))	('cancers', 'Phenotype', 'HP:0002664', (63, 70))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('cancers', 'Disease', (63, 70))	('cancers', 'Disease', 'MESH:D009369', (63, 70))
519961	31562203	These previous studies highlighted EZH2 inhibition as a potential therapeutic target in HNSCC by modulating epigenetic silencing of genes involved in tumor progression.	('inhibition', 'Var', (40, 50))	('HNSCC', 'Disease', (88, 93))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('HNSCC', 'Phenotype', 'HP:0012288', (88, 93))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('modulating', 'Reg', (97, 107))	('tumor', 'Disease', (150, 155))	('epigenetic silencing', 'MPA', (108, 128))
519964	31562203	Thus, the present study provides a new line of evidence in support of EZH2 inhibition as a new combination immunotherapy target in promoting HNSCC antitumor immunity to overcome checkpoint blockade resistance.	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('inhibition', 'Var', (75, 85))	('HNSCC', 'Phenotype', 'HP:0012288', (141, 146))	('promoting', 'PosReg', (131, 140))	('tumor', 'Disease', (151, 156))	('EZH2', 'Gene', (70, 74))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
519965	31562203	Consistent with other studies, inhibition of EZH2 significantly induced the expression of CXCL10 in human HNSCC lines (Figure 2C).	('induced', 'Reg', (64, 71))	('EZH2', 'Gene', (45, 49))	('human', 'Species', '9606', (100, 105))	('expression', 'MPA', (76, 86))	('inhibition', 'Var', (31, 41))	('CXCL10', 'Gene', (90, 96))	('HNSCC', 'Phenotype', 'HP:0012288', (106, 111))
519971	31562203	Supporting the use of this approach, CRISPR-CAS9 knock out of B2M or PD-L1 in MOC1-esc1 resulted in resistance or sensitivity to T cell-mediated killing, respectively (data not shown).	('MOC1-esc1', 'Gene', (78, 87))	('B2M', 'Gene', (62, 65))	('resulted', 'Reg', (88, 96))	('resistance', 'CPA', (100, 110))	('T cell-mediated killing', 'CPA', (129, 152))	('sensitivity', 'MPA', (114, 125))	('knock out', 'Var', (49, 58))	('PD-L1', 'Gene', (69, 74))	('PD-L1', 'Gene', '60533', (69, 74))	('esc1', 'CellLine', 'CVCL:9108', (83, 87))
519974	31562203	Others have studied the contribution of EZH2 in augmenting tumor immunogenicity including antigen presentation regulation in melanoma and lymphoma, respectively.	('melanoma and lymphoma', 'Disease', 'MESH:D008545', (125, 146))	('melanoma', 'Phenotype', 'HP:0002861', (125, 133))	('tumor', 'Disease', (59, 64))	('EZH2', 'Var', (40, 44))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('antigen presentation regulation', 'MPA', (90, 121))	('lymphoma', 'Phenotype', 'HP:0002665', (138, 146))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('augmenting', 'PosReg', (48, 58))
519985	31505091	Aberrant expression of microRNAs is an important factor in lung cancer development and differs across different lung cancer expression subtypes.	('lung cancer', 'Disease', 'MESH:D008175', (59, 70))	('Aberrant expression', 'Var', (0, 19))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('lung cancer', 'Disease', (112, 123))	('lung cancer', 'Phenotype', 'HP:0100526', (112, 123))	('lung cancer', 'Disease', (59, 70))	('lung cancer', 'Phenotype', 'HP:0100526', (59, 70))	('lung cancer', 'Disease', 'MESH:D008175', (112, 123))	('microRNAs', 'Gene', (23, 32))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
519992	31505091	The TRUs are recognized with low mutational burden, but with distinct driver mutations such as EGFR mutations, ALK rearrangement, and ROS1 alterations.	('mutations', 'Var', (100, 109))	('ROS1', 'Gene', (134, 138))	('ALK', 'Gene', '238', (111, 114))	('alterations', 'Var', (139, 150))	('ROS1', 'Gene', '6098', (134, 138))	('EGFR', 'Gene', '1956', (95, 99))	('ALK', 'Gene', (111, 114))	('EGFR', 'Gene', (95, 99))
519993	31505091	The PI subtype is described with high immunological activity, high mutational burden, and high frequency of TP53 mutations.	('TP53', 'Gene', (108, 112))	('mutations', 'Var', (113, 122))	('TP53', 'Gene', '7157', (108, 112))
519994	31505091	High frequency of TP53 mutations is also found in the PP subtype in addition to KRAS and STK11 mutations.	('STK11', 'Gene', (89, 94))	('TP53', 'Gene', '7157', (18, 22))	('KRAS', 'Gene', (80, 84))	('TP53', 'Gene', (18, 22))	('STK11', 'Gene', '6794', (89, 94))	('mutations', 'Var', (23, 32))	('KRAS', 'Gene', '3845', (80, 84))
519999	31505091	Aberrant expression of microRNAs is well established as an important factor in lung cancer development, and dysregulation across different histological lung cancer subtypes is reported (Calin and Croce, 2006; Landi et al., 2010; Tran et al., 2018).	('lung cancer', 'Disease', 'MESH:D008175', (79, 90))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('Aberrant', 'Var', (0, 8))	('microRNAs', 'Protein', (23, 32))	('lung cancer', 'Disease', 'MESH:D008175', (152, 163))	('lung cancer', 'Disease', (79, 90))	('lung cancer', 'Phenotype', 'HP:0100526', (79, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('lung cancer', 'Phenotype', 'HP:0100526', (152, 163))	('lung cancer', 'Disease', (152, 163))
520038	31505091	Nevertheless, miR-142-3p, miR-142-5p, and miR 146-5p were highly expressed in T cells, whereas miR-140-3p and miR-221-5p were highly expressed in B cells.	('miR-221', 'Gene', (110, 117))	('miR-142', 'Gene', '406934', (14, 21))	('miR-140', 'Gene', '406932', (95, 102))	('miR-142', 'Gene', (14, 21))	('miR 146-5p', 'Var', (42, 52))	('miR-142', 'Gene', '406934', (26, 33))	('miR-221', 'Gene', '407006', (110, 117))	('miR-140', 'Gene', (95, 102))	('miR-142', 'Gene', (26, 33))
520040	31505091	This included 149-5p, miR-196a-5p, miR-200b-3p, miR-224-5p, miR-429, and miR-452-5p.	('miR-224', 'Gene', '407009', (48, 55))	('miR-429', 'Gene', (60, 67))	('miR-224', 'Gene', (48, 55))	('miR-196a-5p', 'Var', (22, 33))	('miR-429', 'Gene', '554210', (60, 67))	('miR-452-5p', 'Gene', '100616196', (73, 83))	('miR-200b', 'Gene', '406984', (35, 43))	('miR-200b', 'Gene', (35, 43))	('miR-452-5p', 'Gene', (73, 83))
520042	31505091	For AD PP, 11 predicted targets were identified for miR-101-3p and miR-140-3p within the gene set G2M checkpoint, and six predicted targets within inflammatory response were significantly anticorrelated with miR-200c-3p and miR-141-3p.	('miR-200c', 'Gene', (208, 216))	('miR-141', 'Gene', '406933', (224, 231))	('miR-200c', 'Gene', '406985', (208, 216))	('miR-140', 'Gene', '406932', (67, 74))	('miR-101-3p', 'Var', (52, 62))	('AD', 'Disease', 'MESH:D000230', (4, 6))	('miR-140', 'Gene', (67, 74))	('AD', 'Disease', (4, 6))	('miR-141', 'Gene', (224, 231))
520043	31505091	For SCC secretory subtype, predicted targets for miR-200a-3p, miR-200b-3p, miR-200c-3p, miR-141-3p, miR- 205-5p, miR-429, and miR-196-5p were identified within the gene sets inflammatory response (12 predicted targets), EMT (32 predicted targets), myogenesis (16 predicted targets), kras signaling up (13 predicted targets), il6-jak-stat3-signaling (four predicted targets), and/or coagulation (12 predicted targets).	('SCC', 'Disease', (4, 7))	('myogenesis', 'CPA', (248, 258))	('EMT', 'CPA', (220, 223))	('miR-429', 'Gene', (113, 120))	('miR-200c', 'Gene', '406985', (75, 83))	('miR-141', 'Gene', '406933', (88, 95))	('miR-200b', 'Gene', (62, 70))	('il6-jak-stat3-signaling', 'MPA', (325, 348))	('kras', 'Gene', '3845', (283, 287))	('miR-200c', 'Gene', (75, 83))	('miR-141', 'Gene', (88, 95))	('kras', 'Gene', (283, 287))	('inflammatory response', 'CPA', (174, 195))	('miR-429', 'Gene', '554210', (113, 120))	('miR-196-5p', 'Var', (126, 136))	('SCC', 'Phenotype', 'HP:0002860', (4, 7))	('miR-200a-3p', 'Var', (49, 60))	('miR-200b', 'Gene', '406984', (62, 70))	('coagulation', 'CPA', (382, 393))	('SCC', 'Disease', 'MESH:D002294', (4, 7))	('miR- 205-5p', 'Var', (100, 111))
520054	31505091	In the AD PP subtype, we found 11 predicted targets of miR-140-3p and miR-101-3p within the G2M checkpoint gene set indicating that upregulation of G2M checkpoint most likely is a result of repression of miR-140-3p and miR-101-3p.	('miR-140', 'Gene', '406932', (55, 62))	('miR-101-3p', 'Var', (219, 229))	('miR-140', 'Gene', '406932', (204, 211))	('miR-101-3p', 'Var', (70, 80))	('upregulation', 'PosReg', (132, 144))	('miR-140', 'Gene', (55, 62))	('AD', 'Disease', 'MESH:D000230', (7, 9))	('AD', 'Disease', (7, 9))	('G2M', 'MPA', (148, 151))	('miR-140', 'Gene', (204, 211))	('repression', 'NegReg', (190, 200))
520066	31505091	Interestingly, this was also consistent with the finding of a downregulation of immune response in the AD PP subtype, identified with upregulation of two of the same microRNAs (miR- 200c-3p and miR-141-3p) which were downregulated in the SCC secretory subtype.	('SCC', 'Disease', 'MESH:D002294', (238, 241))	('miR-141', 'Gene', (194, 201))	('miR- 200c-3p', 'Var', (177, 189))	('SCC', 'Phenotype', 'HP:0002860', (238, 241))	('downregulation', 'NegReg', (62, 76))	('AD', 'Disease', 'MESH:D000230', (103, 105))	('miR-141', 'Gene', '406933', (194, 201))	('AD', 'Disease', (103, 105))	('upregulation', 'PosReg', (134, 146))	('SCC', 'Disease', (238, 241))	('immune response', 'CPA', (80, 95))
520092	31489957	Although patients with LUAD who had high SUMO1 or SUMO1P3 expression had reduced RFS compared with low expression groups, univariate and multivariate analysis showed that only SUMO1P3 expression was independently associated reduced RFS (HR, 1.418; 95% CI, 1.041-1.930; p=0.027).	('SUMO1P3', 'Gene', '474338', (176, 183))	('reduced', 'NegReg', (224, 231))	('reduced', 'NegReg', (73, 80))	('SUMO1', 'Gene', '7341', (176, 181))	('LUAD', 'Phenotype', 'HP:0030078', (23, 27))	('high', 'Var', (36, 40))	('SUMO1', 'Gene', '7341', (50, 55))	('SUMO1', 'Gene', '7341', (41, 46))	('LUAD', 'Disease', (23, 27))	('SUMO1', 'Gene', (176, 181))	('patients', 'Species', '9606', (9, 17))	('SUMO1', 'Gene', (50, 55))	('SUMO1P3', 'Gene', (50, 57))	('RFS', 'MPA', (232, 235))	('RFS', 'MPA', (81, 84))	('SUMO1P3', 'Gene', '474338', (50, 57))	('SUMO1', 'Gene', (41, 46))	('LUAD', 'Disease', 'MESH:C538231', (23, 27))	('SUMO1P3', 'Gene', (176, 183))
520098	31489957	The high frequency of epidermal growth factor (EGFR) gene mutations and ALK-EML4 translocations have provided new targeted therapy for patients with LUAD, which are less effective for patients with LUSC.	('mutations', 'Var', (58, 67))	('EML4', 'Gene', '27436', (76, 80))	('patients', 'Species', '9606', (135, 143))	('patients', 'Species', '9606', (184, 192))	('ALK', 'Gene', '238', (72, 75))	('EGFR', 'Gene', (47, 51))	('LUAD', 'Phenotype', 'HP:0030078', (149, 153))	('EGFR', 'Gene', '1950', (47, 51))	('LUSC', 'Disease', 'MESH:D002294', (198, 202))	('translocations', 'Var', (81, 95))	('LUAD', 'Disease', (149, 153))	('LUSC', 'Disease', (198, 202))	('LUAD', 'Disease', 'MESH:C538231', (149, 153))	('LUSC', 'Phenotype', 'HP:0030359', (198, 202))	('EML4', 'Gene', (76, 80))	('epidermal growth factor', 'Gene', (22, 45))	('epidermal growth factor', 'Gene', '1950', (22, 45))	('ALK', 'Gene', (72, 75))
520107	31489957	SUMO1 dysregulation might be associated with chemosensitivity of NSCLC cells.	('SUMO1', 'Gene', '7341', (0, 5))	('NSCLC', 'Disease', 'MESH:D002289', (65, 70))	('SUMO1', 'Gene', (0, 5))	('dysregulation', 'Var', (6, 19))	('NSCLC', 'Phenotype', 'HP:0030358', (65, 70))	('associated', 'Reg', (29, 39))	('NSCLC', 'Disease', (65, 70))
520142	31489957	The patient group with high SUMO1 expression had a significantly reduced RFS (Figure 5B).	('reduced', 'NegReg', (65, 72))	('expression', 'MPA', (34, 44))	('high', 'Var', (23, 27))	('RFS', 'MPA', (73, 76))	('patient', 'Species', '9606', (4, 11))	('SUMO1', 'Gene', '7341', (28, 33))	('SUMO1', 'Gene', (28, 33))
520143	31489957	In contrast, the patient group with high SUMO1P3 expression had a significantly shorter OS (p=0.037) and RFS (p=0.007) compared with the group with low SUMO1P3 expression (Figure 5C, 5D).	('SUMO1P3', 'Gene', (152, 159))	('SUMO1P3', 'Gene', '474338', (41, 48))	('patient', 'Species', '9606', (17, 24))	('RFS', 'MPA', (105, 108))	('SUMO1P3', 'Gene', '474338', (152, 159))	('shorter', 'NegReg', (80, 87))	('SUMO1P3', 'Gene', (41, 48))	('high', 'Var', (36, 40))
520154	31489957	Also, although patients with LUAD with high SUMO1 or SUMO1P3 expression tended to have worse survival compared with the low expression group, the results of univariate and multivariate analysis indicated that only SUMO1P3 expression had independent prognostic value in terms of RFS (HR, 1.418; 95% CI, 1.041-1.930; p=0.027).	('SUMO1', 'Gene', (53, 58))	('patients', 'Species', '9606', (15, 23))	('survival', 'MPA', (93, 101))	('high', 'Var', (39, 43))	('SUMO1P3', 'Gene', (53, 60))	('RFS', 'MPA', (278, 281))	('SUMO1', 'Gene', (214, 219))	('SUMO1', 'Gene', '7341', (214, 219))	('SUMO1P3', 'Gene', (214, 221))	('worse', 'NegReg', (87, 92))	('SUMO1', 'Gene', '7341', (53, 58))	('SUMO1', 'Gene', (44, 49))	('SUMO1', 'Gene', '7341', (44, 49))	('LUAD', 'Disease', (29, 33))	('LUAD', 'Disease', 'MESH:C538231', (29, 33))	('LUAD', 'Phenotype', 'HP:0030078', (29, 33))	('SUMO1P3', 'Gene', '474338', (53, 60))	('SUMO1P3', 'Gene', '474338', (214, 221))
520163	31489957	Previous studies have shown that dysregulated SUMO1 expression is associated with chemoresistance of some tumors, including testicular germ cell tumors, osteosarcoma, and NSCLC.	('tumors', 'Disease', (106, 112))	('associated with', 'Reg', (66, 81))	('tumors', 'Disease', 'MESH:D009369', (145, 151))	('osteosarcoma', 'Phenotype', 'HP:0002669', (153, 165))	('NSCLC', 'Disease', 'MESH:D002289', (171, 176))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('germ cell tumors', 'Phenotype', 'HP:0100728', (135, 151))	('NSCLC', 'Disease', (171, 176))	('NSCLC', 'Phenotype', 'HP:0030358', (171, 176))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('dysregulated', 'Var', (33, 45))	('chemoresistance', 'CPA', (82, 97))	('osteosarcoma', 'Disease', (153, 165))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('SUMO1', 'Gene', '7341', (46, 51))	('osteosarcoma', 'Disease', 'MESH:D012516', (153, 165))	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumors', 'Disease', (145, 151))	('SUMO1', 'Gene', (46, 51))
520194	24952901	The relative predictive power of individual molecular datasets strongly depended on the cancer type: for example, the prognostic power was much higher for KIRC than for the other three cancer types.	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('KIRC', 'Var', (155, 159))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('prognostic power', 'MPA', (118, 134))	('higher', 'PosReg', (144, 150))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('cancer', 'Disease', (185, 191))
520207	24952901	Although up-regulation of miR-21, which has growth promoting activity, is associated with a worse prognosis, the remaining miRNAs (miR-192, miR-101, let-7a, let-7f and miR-143) suppress tumor growth, with higher expression being associated with a better prognosis (Fig.	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('let-7a', 'Var', (149, 155))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('miR-21', 'Gene', '406991', (26, 32))	('let-7f', 'Var', (157, 163))	('up-regulation', 'PosReg', (9, 22))	('expression', 'MPA', (212, 222))	('miR-143', 'Gene', '406935', (168, 175))	('tumor', 'Disease', (186, 191))	('suppress', 'NegReg', (177, 185))	('miR-143', 'Gene', (168, 175))	('miR-192', 'Gene', (131, 138))	('miR-21', 'Gene', (26, 32))	('miR-192', 'Gene', '406967', (131, 138))	('miR-101', 'Var', (140, 147))
520220	24952901	Finally, we assessed the therapeutic utility of TCGA data by analyzing somatic mutations and small insertion/deletions (indels) in 3,277 patients across 12 tumor types.	('small insertion/deletions', 'Var', (93, 118))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('patients', 'Species', '9606', (137, 145))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumor', 'Disease', (156, 161))
520222	24952901	In 89.4% (2,928/3,277) of the TCGA patient samples, 10,281 somatic non-synonymous alterations (1.62% of all alterations, synonymous or non-synonymous, in this combined cohort) in 121 clinically relevant cancer genes were observed (Fig.	('patient', 'Species', '9606', (35, 42))	('cancer', 'Disease', (203, 209))	('cancer', 'Disease', 'MESH:D009369', (203, 209))	('alterations', 'Var', (82, 93))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))
520229	24952901	Next, by combining mutation data from 12 tumor types, we observed a "tail" of low-frequency alterations in clinically relevant cancer genes that warrant clinical investigation but would not be apparent with smaller, single-tumor cohorts.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('tumor', 'Disease', (223, 228))	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('tumor', 'Disease', (41, 46))	('low-frequency', 'NegReg', (78, 91))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('alterations', 'Var', (92, 103))	('tumor', 'Disease', 'MESH:D009369', (223, 228))	('cancer', 'Disease', (127, 133))	('tumor', 'Disease', 'MESH:D009369', (41, 46))
520236	24952901	5i); a subset of these mutations may predict resistance to RAF and/or MEK inhibitors in specific clinical contexts.	('RAF', 'Gene', '22882', (59, 62))	('RAF', 'Gene', (59, 62))	('MEK', 'Gene', (70, 73))	('mutations', 'Var', (23, 32))	('predict', 'Reg', (37, 44))	('MEK', 'Gene', '5609', (70, 73))	('resistance', 'MPA', (45, 55))
520237	24952901	Critically, RAF and MEK inhibitors are currently being studied in numerous cancer types, so prospective knowledge of MEK1 status may impact treatment selection for patients with MEK1 mutations.	('MEK', 'Gene', (178, 181))	('MEK', 'Gene', '5609', (178, 181))	('numerous cancer', 'Disease', (66, 81))	('mutations', 'Var', (183, 192))	('MEK', 'Gene', (20, 23))	('impact', 'Reg', (133, 139))	('MEK', 'Gene', '5609', (20, 23))	('MEK', 'Gene', (117, 120))	('MEK', 'Gene', '5609', (117, 120))	('RAF', 'Gene', '22882', (12, 15))	('MEK1', 'Gene', '5604', (178, 182))	('numerous cancer', 'Disease', 'MESH:D009369', (66, 81))	('RAF', 'Gene', (12, 15))	('MEK1', 'Gene', (178, 182))	('MEK1', 'Gene', '5604', (117, 121))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('patients', 'Species', '9606', (164, 172))	('MEK1', 'Gene', (117, 121))
520254	24952901	As the number of identified clinically actionable cancer genes and alterations continues to rise, prospective genomic profiling may inform individualized treatment plans for patients with metastatic or localized disease, as these patients are guided toward genomically-driven clinical trials.	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('localized disease', 'Disease', (202, 219))	('alterations', 'Var', (67, 78))	('localized disease', 'Disease', 'MESH:D012594', (202, 219))	('patients', 'Species', '9606', (174, 182))	('patients', 'Species', '9606', (230, 238))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))
520255	24952901	Importantly, many of the alterations observed in clinically actionable cancer genes have either no known functional effect that may be consistent with a clinical action or even have the converse effect.	('alterations', 'Var', (25, 36))	('cancer', 'Disease', (71, 77))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))
520256	24952901	Through our cross-tumor analysis, we expect that many of these alterations will emerge in preclinical and clinical studies, thereby informing their relative impact in specific clinical settings from a predictive/prognostic standpoint when linked to relevant clinical outcomes.	('alterations', 'Var', (63, 74))	('cross-tumor', 'Disease', 'MESH:C537866', (12, 23))	('cross-tumor', 'Disease', (12, 23))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
520292	24952901	For the purpose of understanding the distribution of hotspot alterations in BRAF and PIK3CA, the following definitions were assigned: hotspot alterations in BRAF were defined as those leading to V600E, V600K, and V600R protein changes.	('V600K', 'Var', (202, 207))	('BRAF', 'Gene', (76, 80))	('BRAF', 'Gene', '673', (76, 80))	('V600R', 'Var', (213, 218))	('PIK3CA', 'Gene', (85, 91))	('V600K', 'Mutation', 'rs121913227', (202, 207))	('PIK3CA', 'Gene', '5290', (85, 91))	('BRAF', 'Gene', '673', (157, 161))	('V600E', 'Mutation', 'rs113488022', (195, 200))	('BRAF', 'Gene', (157, 161))	('V600R', 'Mutation', 'rs121913227', (213, 218))	('V600E', 'Var', (195, 200))	('protein', 'Protein', (219, 226))
520293	24952901	Similarly, hotspot alterations in PIK3CA were restricted to those that resulted in E545K and H1047R protein changes.	('PIK3CA', 'Gene', (34, 40))	('H1047R', 'Var', (93, 99))	('protein', 'Protein', (100, 107))	('E545K', 'Mutation', 'rs104886003', (83, 88))	('PIK3CA', 'Gene', '5290', (34, 40))	('H1047R', 'Mutation', 'rs121913279', (93, 99))	('E545K', 'Var', (83, 88))
520296	31708918	This review will summarize the features of costimulatory molecules (including CD137, OX40 as well as CD40) and coinhibitory molecules (including CTLA-4, PD-1, LAG3, and TIM3), analyze the underlying mechanism behind these molecules' regulation of the progression of HNSCC, and introduce the clinic application.	('CD40', 'Var', (101, 105))	('CTLA-4', 'Gene', (145, 151))	('HNSCC', 'Disease', 'MESH:C535575', (266, 271))	('HNSCC', 'Disease', (266, 271))	('HNSCC', 'Phenotype', 'HP:0012288', (266, 271))	('CTLA-4', 'Gene', '1493', (145, 151))
520312	31708918	Many costimulatory signaling molecules on the surface of immune cells, including CD137, OX40 and CD40, have now been found to play a vital role in HNSCC development.	('CD40', 'Var', (97, 101))	('HNSCC', 'Disease', 'MESH:C535575', (147, 152))	('CD137', 'Var', (81, 86))	('HNSCC', 'Disease', (147, 152))	('HNSCC', 'Phenotype', 'HP:0012288', (147, 152))
520321	31708918	found that agonists for CD137 in the HPV (+) HNSCC mouse model had a synergistic effect on inhibiting tumor growth compared to traditional single radiotherapy and chemotherapy.	('inhibiting', 'NegReg', (91, 101))	('HNSCC', 'Disease', 'MESH:C535575', (45, 50))	('agonists', 'Var', (11, 19))	('HNSCC', 'Disease', (45, 50))	('HNSCC', 'Phenotype', 'HP:0012288', (45, 50))	('mouse', 'Species', '10090', (51, 56))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('CD137', 'Gene', (24, 29))
520325	31708918	Two agonistic mAbs of CD137, urelumab (BMS-663513) and PF-05082566, have been developed for clinical use.	('PF-05082566', 'Chemical', 'MESH:D010977', (55, 66))	('BMS-663513', 'Chemical', 'MESH:C095300', (39, 49))	('CD137', 'Gene', (22, 27))	('PF-05082566', 'Var', (55, 66))
520327	31708918	On the other hand, CD137 agonist mAbs could enhance other mAbs' efficacy in HNSCC patients, such as cetuximab.	('HNSCC', 'Disease', (76, 81))	('efficacy', 'MPA', (64, 72))	('patients', 'Species', '9606', (82, 90))	('HNSCC', 'Disease', 'MESH:C535575', (76, 81))	('HNSCC', 'Phenotype', 'HP:0012288', (76, 81))	('CD137', 'Var', (19, 24))	('enhance', 'PosReg', (44, 51))
520331	31708918	In general, the ligand of OX40 (OX40L) on the surface of DCs or MCs binds directly to OX40.	('OX40', 'Var', (86, 90))	('OX40L', 'Gene', '7292', (32, 37))	('OX40L', 'Gene', (32, 37))	('binds', 'Interaction', (68, 73))
520333	31708918	OX40 activation could augment the downstream signaling of TCR mainly through the PI3-K/PKB pathway, accounting for T cell division, survival and cytokine production.	('downstream signaling', 'MPA', (34, 54))	('TCR', 'Gene', '6962', (58, 61))	('OX40 activation', 'Var', (0, 15))	('PKB', 'Gene', (87, 90))	('PKB', 'Gene', '207', (87, 90))	('augment', 'PosReg', (22, 29))	('TCR', 'Gene', (58, 61))
520334	31708918	Meanwhile, OX40 activated in conjunction with TCR signaling could increase calcium influx, promote nuclear factor of activated T cells (NFAT) activation and enhance several cytokines secretion, such as IL-2, IL-4, IL-5, and IFN-gamma.	('increase', 'PosReg', (66, 74))	('calcium influx', 'MPA', (75, 89))	('enhance', 'PosReg', (157, 164))	('nuclear factor', 'CPA', (99, 113))	('promote', 'PosReg', (91, 98))	('IL-4', 'Gene', '3565', (208, 212))	('TCR', 'Gene', (46, 49))	('calcium', 'Chemical', 'MESH:D002118', (75, 82))	('cytokines secretion', 'MPA', (173, 192))	('IFN-gamma', 'Gene', '3458', (224, 233))	('OX40', 'Var', (11, 15))	('TCR', 'Gene', '6962', (46, 49))	('activation', 'MPA', (142, 152))	('IL-5', 'Gene', (214, 218))	('IL-5', 'Gene', '3567', (214, 218))	('IL-4', 'Gene', (208, 212))	('IFN-gamma', 'Gene', (224, 233))
520336	31708918	An experiment on skin squamous carcinomas in vitro observed that there were more OX40 + Tregs in tumor tissues than in peripheral tissues, which could inhibit the function of effector T cells and the secretion of IFN-gamma.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('carcinoma', 'Phenotype', 'HP:0030731', (31, 40))	('carcinomas', 'Phenotype', 'HP:0030731', (31, 41))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('OX40 +', 'Var', (81, 87))	('tumor', 'Disease', (97, 102))	('function', 'MPA', (163, 171))	('skin squamous carcinomas', 'Disease', 'MESH:D002294', (17, 41))	('inhibit', 'NegReg', (151, 158))	('skin squamous carcinomas', 'Disease', (17, 41))	('IFN-gamma', 'Gene', '3458', (213, 222))	('IFN-gamma', 'Gene', (213, 222))
520337	31708918	Stimulated OX40 was found to not only obviously suppress the inhibition conducted by Tregs but also reduce the number of Tregs in tumor microenvironments by activating FccRs, finally inhibiting tumor growth.	('tumor', 'Disease', (130, 135))	('suppress', 'NegReg', (48, 56))	('activating', 'Reg', (157, 167))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('FccRs', 'Protein', (168, 173))	('OX40', 'Var', (11, 15))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumor', 'Disease', (194, 199))	('inhibition', 'MPA', (61, 71))	('reduce', 'NegReg', (100, 106))	('inhibiting', 'NegReg', (183, 193))
520339	31708918	OX40 could be expressed on the surface of T cells in HNSCC patients.	('HNSCC', 'Phenotype', 'HP:0012288', (53, 58))	('OX40', 'Var', (0, 4))	('HNSCC', 'Disease', 'MESH:C535575', (53, 58))	('HNSCC', 'Disease', (53, 58))	('patients', 'Species', '9606', (59, 67))
520340	31708918	Recent studies have found that the expression of OX40 on CD4(+) T cell surfaces in HNSCC patients was lower than in healthy people.	('lower', 'NegReg', (102, 107))	('HNSCC', 'Disease', (83, 88))	('CD4', 'Gene', '920', (57, 60))	('HNSCC', 'Phenotype', 'HP:0012288', (83, 88))	('people', 'Species', '9606', (124, 130))	('expression', 'MPA', (35, 45))	('OX40', 'Var', (49, 53))	('patients', 'Species', '9606', (89, 97))	('CD4', 'Gene', (57, 60))	('HNSCC', 'Disease', 'MESH:C535575', (83, 88))
520343	31708918	A series of pre-clinical experiments have shown that anti-OX40 dose-tolerant mAb could enhance the humoral and cellular immunity of cancer patients by amplifying the effector T cells and inhibiting the function of Tregs.	('cancer', 'Disease', (132, 138))	('function', 'CPA', (202, 210))	('patients', 'Species', '9606', (139, 147))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('effector T cells', 'CPA', (166, 182))	('enhance', 'PosReg', (87, 94))	('amplifying', 'PosReg', (151, 161))	('anti-OX40', 'Var', (53, 62))	('inhibiting', 'NegReg', (187, 197))	('Tregs', 'CPA', (214, 219))	('cancer', 'Disease', 'MESH:D009369', (132, 138))
520344	31708918	In a mouse ovarian tumor, the combined application of anti-PD-1/OX40 mAb had greatly improved the anti-tumor effect.	('ovarian tumor', 'Disease', 'MESH:D010051', (11, 24))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('improved', 'PosReg', (85, 93))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('mouse', 'Species', '10090', (5, 10))	('tumor', 'Disease', (103, 108))	('anti-PD-1/OX40', 'Var', (54, 68))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('ovarian tumor', 'Disease', (11, 24))	('tumor', 'Disease', (19, 24))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('ovarian tumor', 'Phenotype', 'HP:0100615', (11, 24))
520345	31708918	showed that, in tumor animal models, the overall survival could be effectively improved from 50% to 100% by combining anti-OX40 therapies after complete surgery or radiotherapy.	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('improved', 'PosReg', (79, 87))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('anti-OX40', 'Var', (118, 127))	('tumor', 'Disease', (16, 21))	('combining', 'Interaction', (108, 117))
520349	31708918	Binding with its ligand CD154, CD40 without enzymatic activity in the cytoplasmic domain recruits and interacts with TNF-receptor-associated factors (TRAFs), promoting the activation of the NF-kappaB signaling to maintain homeostasis and immunogenic pathogenic processes.	('NF-kappaB signaling', 'Pathway', (190, 209))	('homeostasis', 'MPA', (222, 233))	('TNF', 'Gene', (117, 120))	('TNF', 'Gene', '7124', (117, 120))	('interacts', 'Interaction', (102, 111))	('activation', 'PosReg', (172, 182))	('CD40', 'Var', (31, 35))	('promoting', 'PosReg', (158, 167))
520354	31708918	In mouse tumor models, high expression of CD40/CD154 had an anti-tumor effect, and a low level of CD40/CD154 was shown to promote tumor growth.	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('mouse', 'Species', '10090', (3, 8))	('tumor', 'Disease', (65, 70))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('promote', 'PosReg', (122, 129))	('tumor', 'Disease', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('CD40/CD154', 'Var', (42, 52))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('tumor', 'Disease', (130, 135))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
520375	31708918	The blocking of sCTLA-4 also activated the proliferation of CD8+ and CD4+ T cells and promoted the secretion of cytokines.	('activated', 'PosReg', (29, 38))	('CD4', 'Gene', (69, 72))	('blocking', 'Var', (4, 12))	('CD8', 'Gene', '925', (60, 63))	('CTLA-4', 'Gene', '1493', (17, 23))	('CTLA-4', 'Gene', (17, 23))	('CD4', 'Gene', '920', (69, 72))	('secretion of cytokines', 'MPA', (99, 121))	('proliferation', 'CPA', (43, 56))	('promoted', 'PosReg', (86, 94))	('CD8', 'Gene', (60, 63))
520390	31708918	There is a new viewpoint indicating that anti-CTLA-4 antibodies induce tumor recession by the selective depletion of Tregs in tumors rather than the blocking of B7-CTLA-4 interaction in lymphoid organs.	('CTLA-4', 'Gene', (164, 170))	('induce', 'PosReg', (64, 70))	('tumors', 'Disease', (126, 132))	('tumors', 'Disease', 'MESH:D009369', (126, 132))	('CTLA-4', 'Gene', '1493', (46, 52))	('tumors', 'Phenotype', 'HP:0002664', (126, 132))	('tumor', 'Disease', 'MESH:D009369', (71, 76))	('CTLA-4', 'Gene', (46, 52))	('Tregs', 'Protein', (117, 122))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('CTLA-4', 'Gene', '1493', (164, 170))	('tumor', 'Phenotype', 'HP:0002664', (71, 76))	('depletion', 'NegReg', (104, 113))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('tumor', 'Disease', (71, 76))	('antibodies', 'Var', (53, 63))	('tumor', 'Disease', (126, 131))
520396	31708918	On the other hand, the expression of PD-L1 on tumor cells could also be increased by activating intracellular signaling pathways, such as IFN-gamma/JAK2/IFN, ALK/STAT3, PI3K and MEK/ERK/STAT1.	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('intracellular', 'MPA', (96, 109))	('STAT1', 'Gene', '6772', (186, 191))	('IFN', 'Gene', (138, 141))	('IFN', 'Gene', '3439', (153, 156))	('MEK', 'Gene', '5609', (178, 181))	('JAK2', 'Gene', '3717', (148, 152))	('PI3K', 'Var', (169, 173))	('MEK', 'Gene', (178, 181))	('activating', 'PosReg', (85, 95))	('PD-L1', 'Gene', (37, 42))	('IFN-gamma', 'Gene', (138, 147))	('STAT3', 'Gene', (162, 167))	('IFN', 'Gene', (153, 156))	('IFN-gamma', 'Gene', '3458', (138, 147))	('tumor', 'Disease', (46, 51))	('PD-L1', 'Gene', '29126', (37, 42))	('ERK', 'Gene', (182, 185))	('ALK', 'Gene', '238', (158, 161))	('expression', 'MPA', (23, 33))	('STAT3', 'Gene', '6774', (162, 167))	('JAK2', 'Gene', (148, 152))	('tumor', 'Disease', 'MESH:D009369', (46, 51))	('increased', 'PosReg', (72, 81))	('ALK', 'Gene', (158, 161))	('STAT1', 'Gene', (186, 191))	('IFN', 'Gene', '3439', (138, 141))	('ERK', 'Gene', '2048', (182, 185))
520424	31708918	revealed that blocking LAG-3 could suppress tumor development, potentiate antitumor response of CD8+ T cells and reduce the population of immunosuppressive cells.	('LAG-3', 'Gene', (23, 28))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('reduce', 'NegReg', (113, 119))	('CD8', 'Gene', (96, 99))	('LAG-3', 'Gene', '16768', (23, 28))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('potentiate', 'PosReg', (63, 73))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('blocking', 'Var', (14, 22))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('population of immunosuppressive cells', 'MPA', (124, 161))	('CD8', 'Gene', '925', (96, 99))	('tumor', 'Disease', (78, 83))	('tumor', 'Disease', (44, 49))	('suppress', 'NegReg', (35, 43))
520442	31708918	However, blockade of TIM-3 induced a decrease of Tregs and promoted IFN-gamma production on CD8+ T cells.	('decrease', 'NegReg', (37, 45))	('CD8', 'Gene', (92, 95))	('TIM-3', 'Gene', (21, 26))	('blockade', 'Var', (9, 17))	('CD8', 'Gene', '925', (92, 95))	('promoted', 'PosReg', (59, 67))	('Tregs', 'CPA', (49, 54))	('IFN-gamma', 'Gene', '3458', (68, 77))	('IFN-gamma', 'Gene', (68, 77))
520443	31708918	The use of anti-TIM3 antibodies could not only reduce the expression of TIM-3 on the surface of T cells, but also decrease the number of MDSCs, inhibiting tumor growth.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('reduce', 'NegReg', (47, 53))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('inhibiting', 'NegReg', (144, 154))	('expression', 'MPA', (58, 68))	('TIM-3', 'Gene', (72, 77))	('anti-TIM3 antibodies', 'Var', (11, 31))	('tumor', 'Disease', (155, 160))	('antibodies', 'Var', (21, 31))	('anti-TIM3', 'Gene', (11, 20))	('MDSCs', 'Disease', (137, 142))	('decrease', 'NegReg', (114, 122))	('MDSCs', 'Disease', 'None', (137, 142))
520444	31708918	Moreover, the treatment of anti-TIM-3 monoclonal antibodies could restore the function of T cells to inhibit tumor growth.	('inhibit', 'NegReg', (101, 108))	('tumor', 'Disease', (109, 114))	('anti-TIM-3', 'Var', (27, 37))	('restore', 'PosReg', (66, 73))	('anti-TIM-3', 'Gene', (27, 37))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('function', 'MPA', (78, 86))
520463	31708918	In some tumor models, anti-TIM3 has almost the same effect as anti-PD-1 and anti-CTLA-4.	('CTLA-4', 'Gene', '1493', (81, 87))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('tumor', 'Disease', (8, 13))	('anti-TIM3', 'Var', (22, 31))	('CTLA-4', 'Gene', (81, 87))
520465	31708918	Similarly, antibodies against PD-L1, TIM3, or LAG3 could restore responses of HCC-derived T cells to tumor antigens, and combinations of those antibodies had additive effects.	('responses', 'MPA', (65, 74))	('restore', 'PosReg', (57, 64))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('PD-L1', 'Gene', (30, 35))	('TIM3', 'Gene', (37, 41))	('antibodies', 'Var', (11, 21))	('PD-L1', 'Gene', '29126', (30, 35))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('LAG3', 'Gene', (46, 50))
520466	31708918	Results displayed that HNSCC with a high T-cell inflamed phenotype (TCIP-H) were enriched in multiple immune checkpoints (particularly PD-L1, PD-L2, PD-1, TIM3, CEACAM1, LAG3, and CTLA4), had frequent mutations in CASP8, EP300, EPHA2, and HRAS, and frequent co-amplification of JAK2 and CD274.	('CTLA4', 'Gene', '1493', (180, 185))	('JAK2', 'Gene', '3717', (278, 282))	('CEACAM1', 'Gene', (161, 168))	('EPHA2', 'Gene', (228, 233))	('CASP8', 'Gene', '841', (214, 219))	('PD-L1', 'Gene', (135, 140))	('PD-L1', 'Gene', '29126', (135, 140))	('HNSCC', 'Disease', (23, 28))	('CTLA4', 'Gene', (180, 185))	('JAK2', 'Gene', (278, 282))	('CD274', 'Gene', '29126', (287, 292))	('CASP8', 'Gene', (214, 219))	('PD-L2', 'Gene', '80380', (142, 147))	('CEACAM1', 'Gene', '634', (161, 168))	('HNSCC', 'Phenotype', 'HP:0012288', (23, 28))	('EPHA2', 'Gene', '1969', (228, 233))	('HRAS', 'Gene', '3265', (239, 243))	('EP300', 'Gene', '2033', (221, 226))	('HRAS', 'Gene', (239, 243))	('PD-L2', 'Gene', (142, 147))	('mutations', 'Var', (201, 210))	('CD274', 'Gene', (287, 292))	('HNSCC', 'Disease', 'MESH:C535575', (23, 28))	('EP300', 'Gene', (221, 226))
520467	31708918	HNSCC tumors with a low T-cell inflamed phenotype (TCIP-L) were enriched in the WNT/beta-catenin and Hedgehog signaling pathways, had frequent NSD1 mutations, EGFR, YAP1 amplifications and CDKN2A deletions.	('EGFR', 'Gene', '1956', (159, 163))	('deletions', 'Var', (196, 205))	('NSD1', 'Gene', '64324', (143, 147))	('HNSCC', 'Disease', (0, 5))	('CDKN2A', 'Gene', '1029', (189, 195))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('YAP1', 'Gene', '10413', (165, 169))	('tumors', 'Phenotype', 'HP:0002664', (6, 12))	('HNSCC', 'Phenotype', 'HP:0012288', (0, 5))	('YAP1', 'Gene', (165, 169))	('mutations', 'Var', (148, 157))	('beta-catenin', 'Gene', (84, 96))	('tumors', 'Disease', (6, 12))	('EGFR', 'Gene', (159, 163))	('HNSCC', 'Disease', 'MESH:C535575', (0, 5))	('beta-catenin', 'Gene', '1499', (84, 96))	('NSD1', 'Gene', (143, 147))	('tumors', 'Disease', 'MESH:D009369', (6, 12))	('low T-cell', 'Phenotype', 'HP:0005403', (20, 30))	('Hedgehog signaling pathways', 'Pathway', (101, 128))	('CDKN2A', 'Gene', (189, 195))
520469	31708918	For HNSCC patients, immunotherapy for a single molecule cannot achieve full efficiency; for example, only 13.3% of the HNSCC patients responded to anti -PD-1.	('responded', 'Reg', (134, 143))	('HNSCC', 'Phenotype', 'HP:0012288', (119, 124))	('HNSCC', 'Disease', 'MESH:C535575', (4, 9))	('anti -PD-1', 'Var', (147, 157))	('HNSCC', 'Disease', 'MESH:C535575', (119, 124))	('HNSCC', 'Disease', (4, 9))	('HNSCC', 'Disease', (119, 124))	('HNSCC', 'Phenotype', 'HP:0012288', (4, 9))	('patients', 'Species', '9606', (10, 18))	('patients', 'Species', '9606', (125, 133))
520473	31708918	A study of mice using an OSCC model showed that TEX could suppress tumor immune response by inhibiting proliferation of both CD4+ and CD8+ T cells and reducing infiltration of T cells into tumors, thereby promoting the carcinogenesis of murine oral squamous cell carcinomas.	('proliferation', 'CPA', (103, 116))	('carcinoma', 'Phenotype', 'HP:0030731', (263, 272))	('carcinomas', 'Phenotype', 'HP:0030731', (263, 273))	('CD4', 'Gene', '920', (125, 128))	('murine', 'Species', '10090', (237, 243))	('promoting', 'PosReg', (205, 214))	('tumor', 'Disease', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('suppress', 'NegReg', (58, 66))	('reducing', 'NegReg', (151, 159))	('infiltration', 'CPA', (160, 172))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('CD8', 'Gene', '925', (134, 137))	('tumors', 'Phenotype', 'HP:0002664', (189, 195))	('CD4', 'Gene', (125, 128))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (249, 273))	('inhibiting', 'NegReg', (92, 102))	('tumors', 'Disease', (189, 195))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('mice', 'Species', '10090', (11, 15))	('carcinogenesis', 'CPA', (219, 233))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (249, 273))	('tumor', 'Disease', (189, 194))	('CD8', 'Gene', (134, 137))	('tumors', 'Disease', 'MESH:D009369', (189, 195))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (249, 272))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('TEX', 'Var', (48, 51))	('squamous cell carcinomas', 'Disease', (249, 273))
520494	30791396	An interesting observation was that the AXL inhibitor SGI7079 was more efficacious in the mesenchymal models.	('AXL', 'Gene', '558', (40, 43))	('SGI7079', 'Var', (54, 61))	('mesenchymal models', 'CPA', (90, 108))	('SGI7079', 'Chemical', '-', (54, 61))	('AXL', 'Gene', (40, 43))
520537	30791396	One such scenario is the treatment of metastatic NSCLC with exon 19 deletions or L858R mutations in EGFR.	('EGFR', 'Gene', '1956', (100, 104))	('exon 19 deletions', 'Var', (60, 77))	('NSCLC', 'Disease', (49, 54))	('L858R', 'Mutation', 'rs121434568', (81, 86))	('EGFR', 'Gene', (100, 104))	('NSCLC', 'Disease', 'MESH:D002289', (49, 54))	('NSCLC', 'Phenotype', 'HP:0030358', (49, 54))	('L858R', 'Var', (81, 86))
520538	30791396	Here, SOC therapy includes the tyrosine kinase (TKI) inhibitor erlotinib (EGFR inhibitor), to which resistance invariably develops, approximately half of which occurs through the acquisition of an additional T790M mutation in EGFR.	('T790M', 'Mutation', 'rs121434569', (208, 213))	('T790M', 'Var', (208, 213))	('erlotinib', 'Chemical', 'MESH:D000069347', (63, 72))	('EGFR', 'Gene', '1956', (74, 78))	('EGFR', 'Gene', '1956', (226, 230))	('EGFR', 'Gene', (74, 78))	('EGFR', 'Gene', (226, 230))
520539	30791396	A second generation EGFR inhibitor:osimertinib:is, however, effective in patients with EGFR T970M erlotinib-resistance mutations.	('EGFR', 'Gene', '1956', (87, 91))	('EGFR', 'Gene', (20, 24))	('erlotinib', 'Chemical', 'MESH:D000069347', (98, 107))	('T970M', 'Var', (92, 97))	('EGFR', 'Gene', (87, 91))	('osimertinib', 'Chemical', 'MESH:C000603933', (35, 46))	('T970M', 'Mutation', 'p.T970M', (92, 97))	('patients', 'Species', '9606', (73, 81))	('EGFR', 'Gene', '1956', (20, 24))
520540	30791396	Using response values to both erlotinib and osimertinib from a previous study, DISARM successfully identified osimertinib as a candidate for cell lines with T970M EGFR mutations (Figure 4A).	('EGFR', 'Gene', '1956', (163, 167))	('osimertinib', 'Chemical', 'MESH:C000603933', (110, 121))	('T970M', 'Var', (157, 162))	('EGFR', 'Gene', (163, 167))	('erlotinib', 'Chemical', 'MESH:D000069347', (30, 39))	('T970M', 'Mutation', 'p.T970M', (157, 162))	('osimertinib', 'Chemical', 'MESH:C000603933', (44, 55))
520544	30791396	The 26 candidate drugs with defined molecular targets, all of which had DISARM scores >=4.0 were then plotted using a DTECT map of their primary target, which revealed a number of common targets including PI3K, mTOR, and Aurora Kinase A (Figure 4B).	('mTOR', 'Gene', '2475', (211, 215))	('mTOR', 'Gene', (211, 215))	('DTECT', 'Chemical', '-', (118, 123))	('PI3K', 'Var', (205, 209))	('Aurora Kinase A', 'Gene', '6790', (221, 236))	('Aurora Kinase A', 'Gene', (221, 236))
520545	30791396	Comparing mRNA and protein expression data between cell lines identified as sensitive and resistant by DISARM, we identified low expression of the gene NKX2-1 and its protein (TTF1) as common markers of sensitivity to PI3K inhibitors (Figure 4C), in agreement with our proteomic subtyping of SCLC (Figure 2D).	('expression', 'MPA', (129, 139))	('SCLC', 'Disease', (292, 296))	('NKX2-1', 'Gene', (152, 158))	('TTF1', 'Gene', (176, 180))	('NKX2-1', 'Gene', '7080', (152, 158))	('PI3K', 'Var', (218, 222))	('TTF1', 'Gene', '7270', (176, 180))	('low', 'NegReg', (125, 128))	('SCLC', 'Disease', 'MESH:D018288', (292, 296))
520580	30693455	A number of genetic lesions, including mutations of the Son-of-Sevenless-1 (SOS1) gene have been associated with the isolated from of this condition.	('Son-of-Sevenless-1', 'Gene', (56, 74))	('genetic lesions', 'Disease', (12, 27))	('SOS1', 'Gene', '6654', (76, 80))	('mutations', 'Var', (39, 48))	('Son-of-Sevenless-1', 'Gene', '6654', (56, 74))	('isolated from', 'Disease', (117, 130))	('genetic lesions', 'Disease', 'MESH:D020022', (12, 27))	('associated', 'Reg', (97, 107))	('SOS1', 'Gene', (76, 80))
520735	28427144	HPV status was significantly associated with improved OS for lung adenocarcinoma patients (HR=0.69, 95% CI: 0.50-0.96), but was not significantly associated with OS for lung squamous cell carcinoma patients (HR=0.50, 95% CI: 0.23-1.12), non-small cell lung cancer patients (HR=0.92, 95% CI: 0.65-1.31) and lung cancer patients (HR=1.17, 95% CI: 0.68-2.03).	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (237, 263))	('HPV', 'Gene', (0, 3))	('patients', 'Species', '9606', (198, 206))	('cancer', 'Phenotype', 'HP:0002664', (257, 263))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (169, 197))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (61, 80))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (174, 197))	('lung squamous cell carcinoma', 'Disease', (169, 197))	('cancer', 'Phenotype', 'HP:0002664', (311, 317))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (241, 263))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (61, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('lung cancer', 'Disease', (306, 317))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (237, 263))	('improved', 'PosReg', (45, 53))	('lung cancer', 'Disease', 'MESH:D008175', (252, 263))	('status', 'Var', (4, 10))	('patients', 'Species', '9606', (264, 272))	('carcinoma', 'Phenotype', 'HP:0030731', (188, 197))	('non-small cell lung cancer', 'Disease', (237, 263))	('lung cancer', 'Disease', 'MESH:D008175', (306, 317))	('lung cancer', 'Phenotype', 'HP:0100526', (252, 263))	('HPV', 'Species', '10566', (0, 3))	('patients', 'Species', '9606', (318, 326))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (169, 197))	('patients', 'Species', '9606', (81, 89))	('lung adenocarcinoma', 'Disease', (61, 80))	('lung cancer', 'Phenotype', 'HP:0100526', (306, 317))
520736	28427144	When cancer cases were stratified by treatment method, HPV status was not significantly associated with improved OS for surgery only (HR=0.97, 95% CI: 0.73-1.28), but was significantly associated with better OS for other treatment methods (HR=0.72, 95% CI: 0.58-0.89).	('cancer', 'Disease', 'MESH:D009369', (5, 11))	('HPV', 'Species', '10566', (55, 58))	('cancer', 'Disease', (5, 11))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))	('status', 'Var', (59, 65))
520741	28427144	One previous study reported that HPV-positive HNSCCs was associated with a 54% reduction in overall mortality, in comparison to HPV-unrelated HNSCCs.	('HNSCC', 'Disease', (142, 147))	('HNSCC', 'Disease', (46, 51))	('HNSCC', 'Phenotype', 'HP:0012288', (142, 147))	('overall mortality', 'MPA', (92, 109))	('HPV', 'Species', '10566', (128, 131))	('HNSCC', 'Disease', 'MESH:D000077195', (142, 147))	('HNSCC', 'Phenotype', 'HP:0012288', (46, 51))	('HNSCC', 'Disease', 'MESH:D000077195', (46, 51))	('HPV-positive', 'Var', (33, 45))	('HPV', 'Species', '10566', (33, 36))	('reduction', 'NegReg', (79, 88))
520746	28427144	Besides, when stratified by treatment method, HPV status was not significantly associated with improved OS for surgery only patients, but significantly associated with improved OS for patients with other treatment methods, such as chemotherapy, radiotherapy, tyrosine kinase inhibitors and multiple therapies.	('status', 'Var', (50, 56))	('patients', 'Species', '9606', (184, 192))	('improved', 'PosReg', (168, 176))	('HPV', 'Species', '10566', (46, 49))	('associated', 'Reg', (152, 162))	('patients', 'Species', '9606', (124, 132))
520800	26738195	For example, the pan-cancer DE analysis identified several of the same proteins found by individual analysis for BRCA and HNSC, e.g., p_38_pT180_Y182 in BRCA and MAPK_pT202_Y204 in HNSC.	('cancer', 'Disease', 'MESH:D009369', (21, 27))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('p_38_pT180_Y182', 'Var', (134, 149))	('BRCA', 'Gene', '672', (153, 157))	('cancer', 'Disease', (21, 27))	('BRCA', 'Gene', '672', (113, 117))	('BRCA', 'Gene', (153, 157))	('BRCA', 'Gene', (113, 117))	('MAPK_pT202_Y204', 'Var', (162, 177))
520828	27410681	Lack of Correlation between Aberrant p16, RAR-beta2, TIMP3, ERCC1, and BRCA1 Protein Expression and Promoter Methylation in Squamous Cell Carcinoma Accompanying Candida albicans-Induced Inflammation Hyperplastic candidiasis is characterized by thickening of the mucosal epithelia with Candida albicans infection with occasional progression to squamous cell carcinoma (SCC).	('Squamous Cell Carcinoma', 'Disease', (124, 147))	('Candida albicans infection', 'Disease', 'MESH:C536777', (285, 311))	('Hyperplastic candidiasis', 'Disease', 'MESH:D002177', (199, 223))	('SCC', 'Gene', '6317', (368, 371))	('p16', 'Gene', '1029', (37, 40))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (343, 366))	('ERCC1', 'Gene', (60, 65))	('SCC', 'Gene', (368, 371))	('Candida albicans', 'Species', '5476', (161, 177))	('Carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('Candida albicans infection', 'Disease', (285, 311))	('carcinoma', 'Phenotype', 'HP:0030731', (357, 366))	('squamous cell carcinoma', 'Disease', (343, 366))	('Hyperplastic candidiasis', 'Disease', (199, 223))	('mucosal epithelia', 'Disease', (262, 279))	('BRCA1', 'Gene', '672', (71, 76))	('Squamous Cell Carcinoma', 'Disease', 'MESH:D002294', (124, 147))	('Candida albicans', 'Species', '5476', (285, 301))	('Inflammation Hyperplastic candidiasis', 'Phenotype', 'HP:0005411', (186, 223))	('BRCA1', 'Gene', (71, 76))	('TIMP3', 'Gene', '7078', (53, 58))	('TIMP3', 'Gene', (53, 58))	('SCC', 'Phenotype', 'HP:0002860', (368, 371))	('Aberrant', 'Var', (28, 36))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (124, 147))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (343, 366))	('mucosal epithelia', 'Disease', 'MESH:D052016', (262, 279))	('ERCC1', 'Gene', '2067', (60, 65))	('p16', 'Gene', (37, 40))
520831	27410681	In the present study, we investigate whether impaired DNA methylation and associated protein expression of tumor suppressor and DNA repair genes are involved in the SCC carcinogenesis process using this hyperplastic candidiasis model.	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('SCC carcinogenesis', 'Disease', (165, 183))	('SCC carcinogenesis', 'Disease', 'MESH:D063646', (165, 183))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('SCC', 'Phenotype', 'HP:0002860', (165, 168))	('impaired', 'Var', (45, 53))	('hyperplastic candidiasis', 'Phenotype', 'HP:0005411', (203, 227))	('involved', 'Reg', (149, 157))	('hyperplastic candidiasis', 'Disease', (203, 227))	('protein expression', 'MPA', (85, 103))	('hyperplastic candidiasis', 'Disease', 'MESH:D002177', (203, 227))
520837	27410681	These results suggest that aberrant p16, RAR-beta2, TIMP3, ERCC1, and BRCA1 expression might occur that is inconsistent with the respective gene promoter methylation status, and that this overexpression might serve to promote the inflammatory carcinogenesis caused by C. albicans infection.	('ERCC1', 'Gene', (59, 64))	('inflammatory carcinogenesis', 'Disease', 'MESH:D063646', (230, 257))	('aberrant', 'Var', (27, 35))	('promote', 'PosReg', (218, 225))	('BRCA1', 'Gene', '672', (70, 75))	('ERCC1', 'Gene', '2067', (59, 64))	('overexpression', 'PosReg', (188, 202))	('inflammatory carcinogenesis', 'Disease', (230, 257))	('BRCA1', 'Gene', (70, 75))	('infection', 'Disease', (280, 289))	('infection', 'Disease', 'MESH:D007239', (280, 289))	('RAR-beta2', 'Gene', (41, 50))	('p16', 'Gene', (36, 39))	('C. albicans', 'Species', '5476', (268, 279))
520851	27410681	Epigenetic changes such as nucleotide and histone modifications play a significant role in tumorigenesis in addition to genetic changes such as mutation and deletion.	('nucleotide', 'Var', (27, 37))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('deletion', 'Var', (157, 165))	('mutation', 'Var', (144, 152))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('histone', 'Protein', (42, 49))	('tumor', 'Disease', (91, 96))
520852	27410681	In oral SCC and gastric cancer, abnormal epigenetic changes are reportedly observed from the early stages of the multistep carcinogenesis process, which induce genetic abnormalities owing to the accumulation of a large number of epigenetic alterations.	('SCC', 'Gene', '6317', (8, 11))	('multistep carcinogenesis', 'Disease', (113, 137))	('multistep carcinogenesis', 'Disease', 'MESH:D063646', (113, 137))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('gastric cancer', 'Disease', (16, 30))	('epigenetic alterations', 'Var', (229, 251))	('gastric cancer', 'Disease', 'MESH:D013274', (16, 30))	('SCC', 'Gene', (8, 11))	('epigenetic changes', 'Var', (41, 59))	('SCC', 'Phenotype', 'HP:0002860', (8, 11))	('induce', 'Reg', (153, 159))	('genetic abnormalities', 'Disease', 'MESH:D030342', (160, 181))	('gastric cancer', 'Phenotype', 'HP:0012126', (16, 30))	('rat', 'Species', '10116', (244, 247))	('genetic abnormalities', 'Disease', (160, 181))
520853	27410681	The most commonly researched epigenetic mechanism in carcinogenesis studies is DNA methylation.	('carcinogenesis', 'Disease', 'MESH:D063646', (53, 67))	('DNA methylation', 'Var', (79, 94))	('methylation', 'Var', (83, 94))	('carcinogenesis', 'Disease', (53, 67))
520854	27410681	In SCC occurring in the esophagus, oral cavity, and lung, the DNA methylation of many tumor suppressor genes (p16, p15, CADM1, TIMP3, RAR-beta2, RASSF1A, DAPK1, and SOCS-3) and DNA repair genes (ERCC1, BRCA1, XRCC1, and MLH1) suppresses their protein expression and induces abnormal cell cycle and proliferative signaling leading to the accumulation of mutations.	('proliferative signaling', 'MPA', (298, 321))	('ERCC1', 'Gene', (195, 200))	('SCC', 'Gene', '6317', (3, 6))	('MLH1', 'Gene', (220, 224))	('suppresses', 'NegReg', (226, 236))	('SCC', 'Gene', (3, 6))	('protein expression', 'MPA', (243, 261))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('BRCA1', 'Gene', '672', (202, 207))	('BRCA1', 'Gene', (202, 207))	('MLH1', 'Gene', '4292', (220, 224))	('induces', 'Reg', (266, 273))	('rat', 'Species', '10116', (305, 308))	('abnormal cell cycle', 'Phenotype', 'HP:0011018', (274, 293))	('XRCC1', 'Gene', (209, 214))	('cell cycle', 'CPA', (283, 293))	('SCC', 'Phenotype', 'HP:0002860', (3, 6))	('ERCC1', 'Gene', '2067', (195, 200))	('tumor', 'Disease', (86, 91))	('mutations', 'Var', (353, 362))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
520857	27410681	In this study, we investigated the association of aberrant DNA methylation and protein expression of tumor suppressor and DNA repair genes with the process of multistep carcinogenesis using our animal model for hyperplastic candidiasis and determined the potential role such changes might play in the mechanism underlying SCC.	('hyperplastic candidiasis', 'Disease', 'MESH:D002177', (211, 235))	('hyperplastic candidiasis', 'Phenotype', 'HP:0005411', (211, 235))	('SCC', 'Gene', '6317', (322, 325))	('hyperplastic candidiasis', 'Disease', (211, 235))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('association', 'Interaction', (35, 46))	('multistep carcinogenesis', 'Disease', (159, 183))	('multistep carcinogenesis', 'Disease', 'MESH:D063646', (159, 183))	('aberrant', 'Var', (50, 58))	('SCC', 'Gene', (322, 325))	('SCC', 'Phenotype', 'HP:0002860', (322, 325))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
520895	27410681	The frequency of rats showing RAR-beta2 promoter methylation was 0% in normal epithelia and gradually increased in hyperplasia (27%) and hyperplasia adjacent to SCC (83%) but was rapidly lost in SCC (0%) (Fig 4A).	('rats', 'Species', '10116', (17, 21))	('SCC', 'Gene', (161, 164))	('SCC', 'Gene', (195, 198))	('hyperplasia', 'Disease', 'MESH:D006965', (137, 148))	('SCC', 'Phenotype', 'HP:0002860', (161, 164))	('SCC', 'Phenotype', 'HP:0002860', (195, 198))	('hyperplasia', 'Disease', (115, 126))	('epithelia', 'Disease', (78, 87))	('epithelia', 'Disease', 'None', (78, 87))	('SCC', 'Gene', '6317', (161, 164))	('SCC', 'Gene', '6317', (195, 198))	('RAR-beta2', 'Gene', (30, 39))	('hyperplasia', 'Disease', (137, 148))	('methylation', 'Var', (49, 60))	('increased', 'PosReg', (102, 111))	('hyperplasia', 'Disease', 'MESH:D006965', (115, 126))
520907	27410681	Hypermethylation of the p16 gene promoter is reported in many tumors such as oral, esophageal, and lung squamous cell carcinoma.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (104, 127))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('lung squamous cell carcinoma', 'Disease', (99, 127))	('reported', 'Reg', (45, 53))	('tumors', 'Disease', (62, 68))	('Hypermethylation', 'Var', (0, 16))	('oral', 'Disease', (77, 81))	('tumors', 'Disease', 'MESH:D009369', (62, 68))	('p16', 'Gene', (24, 27))	('tumors', 'Phenotype', 'HP:0002664', (62, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('esophageal', 'Disease', (83, 93))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (99, 127))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (99, 127))
520910	27410681	p16 protein overexpression reportedly occurs in cancer owing to mutation of the CDKN2A gene or feedback control caused by loss of the Rb gene.	('overexpression', 'PosReg', (12, 26))	('protein', 'Protein', (4, 11))	('mutation', 'Var', (64, 72))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('feedback', 'MPA', (95, 103))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('loss', 'NegReg', (122, 126))	('CDKN2A', 'Gene', (80, 86))	('p16 protein', 'Protein', (0, 11))
520911	27410681	In C. albicans-induced chronic inflammation-associated cancer, it is probable that p16 protein overexpression might be caused by alternative pathways such as CDKN2A gene mutation or loss of the Rb gene irrespective of p16 promoter hypermethylation.	('loss', 'NegReg', (182, 186))	('inflammation', 'Disease', (31, 43))	('protein', 'Protein', (87, 94))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('CDKN2A', 'Gene', (158, 164))	('overexpression', 'PosReg', (95, 109))	('C. albicans', 'Species', '5476', (3, 14))	('p16', 'Gene', (83, 86))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('inflammation', 'Disease', 'MESH:D007249', (31, 43))	('cancer', 'Disease', (55, 61))	('mutation', 'Var', (170, 178))
520913	27410681	TIMP3 promoter methylation is observed in many tumors such as esophageal, gastric, and thyroid cancer, and causes loss of TIMP3 protein expression.	('methylation', 'Var', (15, 26))	('tumors', 'Disease', (47, 53))	('expression', 'MPA', (136, 146))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('gastric', 'Disease', (74, 81))	('thyroid cancer', 'Disease', 'MESH:D013964', (87, 101))	('loss', 'NegReg', (114, 118))	('protein', 'Protein', (128, 135))	('TIMP3', 'Gene', (122, 127))	('TIMP3', 'Gene', (0, 5))	('esophageal', 'Disease', (62, 72))	('observed', 'Reg', (30, 38))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))	('thyroid cancer', 'Phenotype', 'HP:0002890', (87, 101))	('thyroid cancer', 'Disease', (87, 101))
520914	27410681	However, the down-regulation of TIMP3 protein not resulting from TIMP3 promoter hypermethylation has also been reported in pancreatic adenocarcinoma; this phenomenon is also known to be associated with microRNA and the loss of heterozygosity.	('pancreatic adenocarcinoma', 'Disease', 'MESH:D010190', (123, 148))	('pancreatic adenocarcinoma', 'Disease', (123, 148))	('TIMP3', 'Gene', (32, 37))	('carcinoma', 'Phenotype', 'HP:0030731', (139, 148))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (123, 148))	('hypermethylation', 'Var', (80, 96))	('down-regulation', 'NegReg', (13, 28))	('TIMP3', 'Gene', (65, 70))
520918	27410681	RAR-beta2 reportedly leads to the inhibition of cell growth and induction of apoptosis and its gene and mRNA expression disappears because of methylation of the DNA promoter region in SCC and dysplasia of the esophagus and oral mucosa.	('disappears', 'NegReg', (120, 130))	('cell growth', 'CPA', (48, 59))	('dysplasia of the esophagus', 'Disease', 'MESH:D004938', (192, 218))	('apoptosis', 'CPA', (77, 86))	('SCC', 'Phenotype', 'HP:0002860', (184, 187))	('RAR-beta2', 'Gene', (0, 9))	('dysplasia of the esophagus', 'Disease', (192, 218))	('SCC', 'Gene', (184, 187))	('inhibition', 'NegReg', (34, 44))	('gene', 'MPA', (95, 99))	('methylation', 'Var', (142, 153))	('mRNA expression', 'MPA', (104, 119))	('SCC', 'Gene', '6317', (184, 187))
520928	27410681	In this study, since its protein expression disappeared upon hyperplasia irrespective of promoter methylation, the underlying causative factor might involve gene mutation, degradation of the proteins by ROS, or epigenetic change other than promoter methylation.	('ROS', 'Chemical', '-', (203, 206))	('protein', 'Protein', (25, 32))	('disappeared', 'NegReg', (44, 55))	('hyperplasia', 'Disease', (61, 72))	('ROS', 'Protein', (203, 206))	('proteins', 'Protein', (191, 199))	('epigenetic change', 'Var', (211, 228))	('hyperplasia', 'Disease', 'MESH:D006965', (61, 72))	('degradation', 'MPA', (172, 183))
520930	27410681	Our findings suggest that an abnormality in the promoter region might enhance ERCC1 protein expression in C. albicans-induced cancer.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('enhance', 'PosReg', (70, 77))	('expression', 'MPA', (92, 102))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('C. albicans', 'Species', '5476', (106, 117))	('ERCC1', 'Gene', '2067', (78, 83))	('ERCC1', 'Gene', (78, 83))	('abnormality', 'Var', (29, 40))
520932	27410681	Gene mutation and loss of protein expression reportedly exist in breast and ovarian cancer and the loss and dysfunction of the BRCA1 protein induced by BRCA1 promoter hypermethylation have been identified in breast and ovarian cancer.	('protein', 'Protein', (133, 140))	('breast and ovarian cancer', 'Disease', 'MESH:D010051', (65, 90))	('loss', 'NegReg', (18, 22))	('BRCA1', 'Gene', '672', (127, 132))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('BRCA1', 'Gene', '672', (152, 157))	('ovarian cancer', 'Phenotype', 'HP:0100615', (219, 233))	('ovarian cancer', 'Phenotype', 'HP:0100615', (76, 90))	('BRCA1', 'Gene', (127, 132))	('breast and ovarian cancer', 'Disease', 'MESH:D010051', (208, 233))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('BRCA1', 'Gene', (152, 157))	('dysfunction', 'MPA', (108, 119))	('loss', 'NegReg', (99, 103))	('promoter hypermethylation', 'Var', (158, 183))	('protein', 'Protein', (26, 33))
520935	27410681	It is likely that BRCA1 inactivation might be related to the early stage of neoplastic transformation irrespective of promoter methylation status.	('inactivation', 'Var', (24, 36))	('BRCA1', 'Gene', '672', (18, 23))	('BRCA1', 'Gene', (18, 23))	('related', 'Reg', (46, 53))
520952	27410681	The present results suggest that aberrant protein expression of p16, RAR-beta2, TIMP3, BRCA1, and ERCC1 might occur regardless of promoter methylation and might promote the process of inflammatory carcinogenesis caused by C. albicans infection.	('TIMP3', 'Gene', (80, 85))	('p16', 'Gene', (64, 67))	('infection', 'Disease', (234, 243))	('inflammatory carcinogenesis', 'Disease', 'MESH:D063646', (184, 211))	('infection', 'Disease', 'MESH:D007239', (234, 243))	('protein', 'Protein', (42, 49))	('BRCA1', 'Gene', '672', (87, 92))	('C. albicans', 'Species', '5476', (222, 233))	('promote', 'PosReg', (161, 168))	('BRCA1', 'Gene', (87, 92))	('inflammatory carcinogenesis', 'Disease', (184, 211))	('aberrant', 'Var', (33, 41))	('ERCC1', 'Gene', '2067', (98, 103))	('ERCC1', 'Gene', (98, 103))	('RAR-beta2', 'Gene', (69, 78))
521000	33062455	An examination of this gene using the UCSC Xena Browser shows that there are 20 unique COL1A1 mutations in the TCGA, with a missense mutation being the most common (Fig.	('COL1A1', 'Gene', (87, 93))	('common (Fig', 'Species', '3494', (157, 168))	('mutations', 'Var', (94, 103))	('missense mutation', 'Var', (124, 141))	('COL1A1', 'Gene', '1277', (87, 93))	('common', 'Reg', (157, 163))
521001	33062455	While mutations in the COL1A1 gene may lead to other non-small cell lung cancers (e.g., large cell carcinomas and adenocarcinomas), it was nearly 2x as likely to mutated in squamous cell carcinomas (Fig.	('carcinomas', 'Disease', (119, 129))	('lead to', 'Reg', (39, 46))	('lung cancer', 'Phenotype', 'HP:0100526', (68, 79))	('lung cancers', 'Phenotype', 'HP:0100526', (68, 80))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (173, 197))	('non-small cell lung cancers', 'Phenotype', 'HP:0030358', (53, 80))	('COL1A1', 'Gene', '1277', (23, 29))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (173, 196))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('large cell carcinomas', 'Phenotype', 'HP:0030360', (88, 109))	('adenocarcinomas', 'Disease', 'MESH:D000230', (114, 129))	('adenocarcinomas', 'Disease', (114, 129))	('COL1A1', 'Gene', (23, 29))	('squamous cell carcinomas', 'Disease', (173, 197))	('carcinomas', 'Disease', (187, 197))	('carcinomas', 'Disease', 'MESH:D009369', (119, 129))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('carcinomas', 'Phenotype', 'HP:0030731', (119, 129))	('mutations', 'Var', (6, 15))	('carcinomas', 'Disease', (99, 109))	('small cell lung cancers', 'Phenotype', 'HP:0030357', (57, 80))	('mutated', 'Var', (162, 169))	('carcinomas', 'Disease', 'MESH:D009369', (187, 197))	('lung cancers', 'Disease', 'MESH:D008175', (68, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (187, 196))	('carcinomas', 'Phenotype', 'HP:0030731', (187, 197))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('carcinomas', 'Disease', 'MESH:D009369', (99, 109))	('carcinomas', 'Phenotype', 'HP:0030731', (99, 109))	('lung cancers', 'Disease', (68, 80))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (173, 197))
521006	33062455	In addition, high expression of the COL1A1 gene only resulted in a marginal decline in mortality (HR = 1.33).	('high expression', 'Var', (13, 28))	('mortality', 'Disease', 'MESH:D003643', (87, 96))	('COL1A1', 'Gene', '1277', (36, 42))	('COL1A1', 'Gene', (36, 42))	('decline', 'NegReg', (76, 83))	('mortality', 'Disease', (87, 96))
521035	33062455	COL1A1 is often found in connective tissues (e.g., bone and tendon) and thus its mutation is most closely associated with osteogenic diseases, specifically osteogenesis imperfecta.	('osteogenesis imperfecta', 'Disease', 'MESH:D010013', (156, 179))	('associated', 'Reg', (106, 116))	('osteogenic diseases', 'Disease', (122, 141))	('mutation', 'Var', (81, 89))	('osteogenesis imperfecta', 'Disease', (156, 179))	('COL1A1', 'Gene', '1277', (0, 6))	('COL1A1', 'Gene', (0, 6))	('osteogenic diseases', 'Disease', 'MESH:D012516', (122, 141))
521036	33062455	Dysregulation of COL1A1 has been identified in several different cancers including breast (, p. 1) and gastric (, p. 1).	('Dysregulation', 'Var', (0, 13))	('breast', 'Disease', (83, 89))	('gastric', 'Disease', (103, 110))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('identified', 'Reg', (33, 43))	('COL1A1', 'Gene', '1277', (17, 23))	('COL1A1', 'Gene', (17, 23))	('cancers', 'Disease', 'MESH:D009369', (65, 72))	('cancers', 'Phenotype', 'HP:0002664', (65, 72))	('cancers', 'Disease', (65, 72))
521039	33062455	In the present study, we found that not only does the expression of COL1A1 increase in NSCLC, but the presence is higher in LSCC than in other forms (Fig.	('NSCLC', 'Disease', (87, 92))	('higher', 'Reg', (114, 120))	('expression', 'Var', (54, 64))	('NSCLC', 'Disease', 'MESH:D002289', (87, 92))	('LSCC', 'Disease', (124, 128))	('increase', 'PosReg', (75, 83))	('COL1A1', 'Gene', '1277', (68, 74))	('COL1A1', 'Gene', (68, 74))	('NSCLC', 'Phenotype', 'HP:0030358', (87, 92))
521041	33062455	Since COL1A1 is a more fibrous protein, it is reasonable to assume that high expressions of it within the LSCC microenvironment increases density of the surrounding tissue.	('high expressions', 'Var', (72, 88))	('increases', 'PosReg', (128, 137))	('density of the surrounding tissue', 'CPA', (138, 171))	('COL1A1', 'Gene', '1277', (6, 12))	('COL1A1', 'Gene', (6, 12))
521047	33062455	Furthermore, these results suggest that specific inhibitors (e.g., Halofuginone) and gene silencing may be potential strategies for decreasing metastatic potential.	('Halofuginone', 'Chemical', 'MESH:C010176', (67, 79))	('decreasing', 'NegReg', (132, 142))	('gene silencing', 'Var', (85, 99))	('metastatic potential', 'CPA', (143, 163))
521048	29552201	VCAM1-targeted RNA interference inhibits the proliferation of human oral squamous carcinoma HN12 cells In the present study, RNA interference (RNAi) was used to investigate the effect of vascular cell adhesion molecule 1 (VCAM1) silencing on the proliferation of human oral squamous carcinoma HN12 cells.	('silencing', 'Var', (229, 238))	('oral squamous carcinoma', 'Disease', (68, 91))	('vascular cell adhesion molecule 1', 'Gene', '7412', (187, 220))	('VCAM1', 'Gene', (222, 227))	('human', 'Species', '9606', (263, 268))	('oral squamous carcinoma', 'Disease', 'MESH:D002294', (68, 91))	('VCAM1', 'Gene', '7412', (0, 5))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (274, 292))	('vascular cell adhesion molecule 1', 'Gene', (187, 220))	('squamous carcinoma', 'Disease', 'MESH:D002294', (274, 292))	('VCAM1', 'Gene', '7412', (222, 227))	('proliferation', 'CPA', (45, 58))	('human', 'Species', '9606', (62, 67))	('carcinoma', 'Phenotype', 'HP:0030731', (283, 292))	('HN12', 'CellLine', 'CVCL:5518', (293, 297))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (73, 91))	('oral squamous carcinoma', 'Disease', (269, 292))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('squamous carcinoma', 'Disease', 'MESH:D002294', (73, 91))	('oral squamous carcinoma', 'Disease', 'MESH:D002294', (269, 292))	('inhibits', 'NegReg', (32, 40))	('HN12', 'CellLine', 'CVCL:5518', (92, 96))	('VCAM1', 'Gene', (0, 5))
521060	29552201	Aberrant expression of VCAM1 frequently occurs in various types of cancer.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('Aberrant expression', 'Var', (0, 19))	('occurs', 'Reg', (40, 46))	('cancer', 'Disease', (67, 73))	('VCAM1', 'Gene', (23, 28))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))
521061	29552201	For example, abnormal expression of VCAM1 is associated with the metastasis of gastric carcinoma.	('metastasis', 'CPA', (65, 75))	('gastric carcinoma', 'Disease', 'MESH:D013274', (79, 96))	('associated with', 'Reg', (45, 60))	('gastric carcinoma', 'Disease', (79, 96))	('VCAM1', 'Gene', (36, 41))	('abnormal', 'Var', (13, 21))	('expression', 'MPA', (22, 32))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (79, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))
521068	29552201	However, there remain few studies on the effect of VCAM1 silencing on the proliferation of human oral squamous carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('oral squamous carcinoma', 'Disease', (97, 120))	('VCAM1', 'Gene', (51, 56))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (102, 120))	('silencing', 'Var', (57, 66))	('oral squamous carcinoma', 'Disease', 'MESH:D002294', (97, 120))	('human', 'Species', '9606', (91, 96))
521069	29552201	Therefore, to provide an experimental basis for the diagnosis and colorectal cancer treatment, the present study aimed to investigate the effect of VCAM1 silencing on the proliferation of human oral squamous carcinoma HN12 cells.	('human', 'Species', '9606', (188, 193))	('oral squamous carcinoma', 'Disease', 'MESH:D002294', (194, 217))	('carcinoma', 'Phenotype', 'HP:0030731', (208, 217))	('VCAM1', 'Gene', (148, 153))	('oral squamous carcinoma', 'Disease', (194, 217))	('colorectal cancer', 'Phenotype', 'HP:0003003', (66, 83))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (199, 217))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('colorectal cancer', 'Disease', (66, 83))	('silencing', 'Var', (154, 163))	('HN12', 'CellLine', 'CVCL:5518', (218, 222))	('colorectal cancer', 'Disease', 'MESH:D015179', (66, 83))
521092	29552201	However, a cytotoxic effect was observed with a MOI of 100, and the infection rate was >95% (Fig.	('infection', 'Disease', 'MESH:D007239', (68, 77))	('MOI of 100', 'Var', (48, 58))	('infection', 'Disease', (68, 77))
521096	29552201	To investigate the effect of VCAM1 silencing on cell proliferation, the HN12 cell growth inhibition rate was assayed using the CCK-8 method.	('VCAM1', 'Gene', (29, 34))	('HN12', 'CellLine', 'CVCL:5518', (72, 76))	('silencing', 'Var', (35, 44))
521101	29552201	In addition, the abnormal expression of VCAM1 is associated with the metastasis of gastric carcinoma.	('expression', 'MPA', (26, 36))	('gastric carcinoma', 'Phenotype', 'HP:0012126', (83, 100))	('metastasis', 'CPA', (69, 79))	('gastric carcinoma', 'Disease', 'MESH:D013274', (83, 100))	('associated with', 'Reg', (49, 64))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('VCAM1', 'Gene', (40, 45))	('gastric carcinoma', 'Disease', (83, 100))	('abnormal', 'Var', (17, 25))
521103	29552201	Nevertheless, the occurrence and development of oral squamous cell carcinoma is associated with the aberrant expression of multiple genes, as well as a variety of in vitro and in vivo factors.	('aberrant', 'Var', (100, 108))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (48, 76))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (53, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('associated', 'Reg', (80, 90))	('oral squamous cell carcinoma', 'Disease', (48, 76))
521105	29552201	Furthermore, anti-VCAM1 treatment is able to significantly decrease cancer-endothelial adhesion and block fusion.	('block fusion', 'CPA', (100, 112))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('anti-VCAM1', 'Var', (13, 23))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('decrease', 'NegReg', (59, 67))	('cancer', 'Disease', (68, 74))
521198	28163045	The multivariate-adjusted HR of metabolic syndrome was significant in male patients with TNM stage I or II (HR = 1.59; 95% CI: 1.05-2.41; P = 0.029) and positive regional LNM (N1-N3) (HR = 1.42; 95% CI: 1.10-1.83; P = 0.008) after adjusting for age, smoking and drinking, while no significance was noticed in females.	('patients', 'Species', '9606', (75, 83))	('positive regional LNM', 'Var', (153, 174))	('metabolic syndrome', 'Disease', 'MESH:D008659', (32, 50))	('TNM', 'Disease', (89, 92))	('metabolic syndrome', 'Disease', (32, 50))
521273	33396709	One study identified a copy number variant at the KITLG locus in animals with CDSCC, which may predispose them to develop this neoplasia.	('SCC', 'Phenotype', 'HP:0002860', (80, 83))	('neoplasia', 'Disease', 'MESH:D009369', (127, 136))	('neoplasia', 'Phenotype', 'HP:0002664', (127, 136))	('CDSCC', 'Disease', (78, 83))	('CDSCC', 'Chemical', '-', (78, 83))	('develop', 'PosReg', (114, 121))	('KITLG', 'Gene', (50, 55))	('predispose', 'Reg', (95, 105))	('copy number variant', 'Var', (23, 42))	('neoplasia', 'Disease', (127, 136))	('KITLG', 'Gene', '403507', (50, 55))
521342	33396709	In canine melanomas, postulated to be a potential human model, several copy number alterations and low numbers of single-nucleotide variations with non-UV-associated mutations were identified.	('melanomas', 'Disease', 'MESH:D008545', (10, 19))	('melanomas', 'Disease', (10, 19))	('melanoma', 'Phenotype', 'HP:0002861', (10, 18))	('melanomas', 'Phenotype', 'HP:0002861', (10, 19))	('human', 'Species', '9606', (50, 55))	('copy number alterations', 'Var', (71, 94))	('canine', 'Species', '9615', (3, 9))
521400	28246088	Excess body weight is associated with an increased risk of developing and dying from many diseases, including cancer, type 2 diabetes, and cardiovascular disease.	('cardiovascular disease', 'Disease', 'MESH:D002318', (139, 161))	('type 2 diabetes', 'Disease', 'MESH:D003924', (118, 133))	('cancer', 'Disease', (110, 116))	('type 2 diabetes', 'Phenotype', 'HP:0005978', (118, 133))	('Excess body', 'Var', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('type 2 diabetes', 'Disease', (118, 133))	('cardiovascular disease', 'Disease', (139, 161))	('cardiovascular disease', 'Phenotype', 'HP:0001626', (139, 161))	('Excess body weight', 'Phenotype', 'HP:0004324', (0, 18))
521411	28246088	Moreover, body mass index was associated with an increased risk of melanoma in men (relative risk per 5 kg/m2 1.17, 1.05 to 1.30) but not in women (0.96, 0.93 to 1.00).	('melanoma', 'Disease', 'MESH:D008545', (67, 75))	('melanoma', 'Phenotype', 'HP:0002861', (67, 75))	('body mass index', 'Var', (10, 25))	('melanoma', 'Disease', (67, 75))
521429	28246088	Two recent Mendelian randomisation studies found that body mass index was statistically significantly associated with an increased risk of squamous and small cell lung cancer but had a borderline significant inverse association with lung adenocarcinoma.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('associated', 'Reg', (102, 112))	('small cell lung cancer', 'Disease', 'MESH:D055752', (152, 174))	('carcinoma', 'Phenotype', 'HP:0030731', (243, 252))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (152, 174))	('lung cancer', 'Phenotype', 'HP:0100526', (163, 174))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (233, 252))	('squamous', 'Disease', (139, 147))	('body mass index', 'Var', (54, 69))	('lung adenocarcinoma', 'Disease', (233, 252))	('small cell lung cancer', 'Disease', (152, 174))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (233, 252))
521533	29663347	A TGF-beta1 genetic variant at the miRNA187 binding site significantly modifies risk of HPV16-associated oropharyngeal cancer TGF-beta1rs1982073 polymorphism at the miRNA-187 binding site may alter TGF-beta1 expression and function, and thereby this polymorphism (genotype CT/CC) increases cancer susceptibility.	('increases', 'PosReg', (280, 289))	('expression', 'MPA', (208, 218))	('TGF-beta1', 'Gene', (2, 11))	('miRNA-187', 'Gene', (165, 174))	('cancer', 'Disease', 'MESH:D009369', (290, 296))	('alter', 'Reg', (192, 197))	('modifies', 'Reg', (71, 79))	('cancer', 'Disease', (119, 125))	('function', 'MPA', (223, 231))	('TGF-beta1', 'Gene', (198, 207))	('TGF-beta1', 'Gene', '7040', (2, 11))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('TGF-beta1', 'Gene', (126, 135))	('miRNA-187', 'Gene', '406963', (165, 174))	('HPV16', 'Species', '333760', (88, 93))	('polymorphism', 'Var', (145, 157))	('TGF-beta1', 'Gene', '7040', (198, 207))	('TGF-beta1', 'Gene', '7040', (126, 135))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('cancer', 'Disease', (290, 296))	('cancer', 'Phenotype', 'HP:0002664', (290, 296))	('variant', 'Var', (20, 27))
521534	29663347	HPV16 L1 seropositivity is associated with the risk of oral squamous cell carcinoma (OSCC), including oropharyngeal squamous cell carcinoma (OPSCC) and oral cavity squamous cell carcinoma (OCSCC).	('HPV16 L1', 'Gene', (0, 8))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (164, 187))	('seropositivity', 'Var', (9, 23))	('HPV16', 'Species', '333760', (0, 5))	('oropharyngeal squamous cell carcinoma', 'Phenotype', 'HP:0012182', (102, 139))	('associated', 'Reg', (27, 37))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (55, 83))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (60, 83))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (116, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('squamous cell carcinoma', 'Disease', (116, 139))	('oral squamous cell carcinoma', 'Disease', (55, 83))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (60, 83))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (116, 139))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (164, 187))	('carcinoma', 'Phenotype', 'HP:0030731', (178, 187))	('squamous cell carcinoma', 'Disease', (164, 187))
521537	29663347	TGF-beta1rs1982073 polymorphism (CT/CC genotype) combined with HPV16 L1 seropositivity increased the risk of OSCC via joint effects, particularly in OPSCC subjects who were never-smokers (OR, 165.9; 95% CI, 28.6-960.4) or never-drinkers (OR, 196.0; 95% CI, 28.2-1000.0), respectively.	('increased', 'PosReg', (87, 96))	('OSCC', 'Disease', (109, 113))	('HPV16', 'Species', '333760', (63, 68))	('polymorphism', 'Var', (19, 31))	('TGF-beta1', 'Gene', '7040', (0, 9))	('TGF-beta1', 'Gene', (0, 9))
521547	29663347	The single nucleotide polymorphism (SNP) TGF-beta1rs1982073 (merged into NCBI SNP rs1800470; T869C; codon 10 of exon 1; encoding Leu10Pro) can significantly affect the serum expression level of TGF-beta1 and thereby increase the susceptibility to gastric and breast cancers .	('susceptibility', 'Reg', (229, 243))	('breast cancers', 'Phenotype', 'HP:0003002', (259, 273))	('TGF-beta1', 'Gene', '7040', (194, 203))	('breast cancer', 'Phenotype', 'HP:0003002', (259, 272))	('affect', 'Reg', (157, 163))	('T869C', 'Var', (93, 98))	('TGF-beta1', 'Gene', (41, 50))	('serum expression level', 'MPA', (168, 190))	('TGF-beta1', 'Gene', '7040', (41, 50))	('gastric and breast cancers', 'Disease', 'MESH:D013274', (247, 273))	('increase', 'PosReg', (216, 224))	('cancers', 'Phenotype', 'HP:0002664', (266, 273))	('rs1800470', 'Mutation', 'rs1800470', (82, 91))	('single nucleotide polymorphism', 'Var', (4, 34))	('T869C', 'Mutation', 'rs1800470', (93, 98))	('cancer', 'Phenotype', 'HP:0002664', (266, 272))	('TGF-beta1', 'Gene', (194, 203))	('Leu10Pro', 'Chemical', '-', (129, 137))	('Leu10Pro', 'Var', (129, 137))
521549	29663347	Therefore, this binding modification can alter miRNA gene regulation and TGF-beta1 expression and function and thereby affect the risk of cancer .	('cancer', 'Disease', (138, 144))	('TGF-beta1', 'Gene', '7040', (73, 82))	('miRNA gene regulation', 'MPA', (47, 68))	('TGF-beta1', 'Gene', (73, 82))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('modification', 'Var', (24, 36))	('alter', 'Reg', (41, 46))	('expression', 'MPA', (83, 93))	('affect', 'Reg', (119, 125))	('binding', 'Interaction', (16, 23))	('cancer', 'Disease', 'MESH:D009369', (138, 144))	('function', 'MPA', (98, 106))
521550	29663347	Polymorphism TGF-beta1rs1982073 has been associated with increased susceptibility to breast cancer  and prostate cancer , and our previous study identified the potential effects of TGF-beta1rs1982073 in OSCC subjects.	('TGF-beta1', 'Gene', '7040', (13, 22))	('breast cancer', 'Disease', 'MESH:D001943', (85, 98))	('Polymorphism', 'Var', (0, 12))	('TGF-beta1', 'Gene', (13, 22))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('prostate cancer', 'Disease', 'MESH:D011471', (104, 119))	('breast cancer', 'Disease', (85, 98))	('breast cancer', 'Phenotype', 'HP:0003002', (85, 98))	('prostate cancer', 'Phenotype', 'HP:0012125', (104, 119))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('prostate cancer', 'Disease', (104, 119))	('TGF-beta1', 'Gene', '7040', (181, 190))	('TGF-beta1', 'Gene', (181, 190))
521560	29663347	The criteria for determination of TGF-beta1 polymorphism have been previously described.	('TGF-beta1', 'Gene', (34, 43))	('polymorphism', 'Var', (44, 56))	('TGF-beta1', 'Gene', '7040', (34, 43))
521567	29663347	Stratified analyses of the joint effects of HPV16 serology and TGF-beta1rs1982073 polymorphism were further performed by taking into account smoking and drinking status and age.	('TGF-beta1', 'Gene', '7040', (63, 72))	('TGF-beta1', 'Gene', (63, 72))	('HPV16', 'Species', '333760', (44, 49))	('HPV16', 'Gene', (44, 49))	('polymorphism', 'Var', (82, 94))
521568	29663347	In addition, logistic regression analysis was performed to evaluate the association between the TGF-beta1rs1982073 polymorphism and HPV16 serological status and OSCC risk stratified by cancer site (OPSCC vs. OCSCC patients).	('patients', 'Species', '9606', (214, 222))	('HPV16', 'Gene', (132, 137))	('TGF-beta1', 'Gene', '7040', (96, 105))	('TGF-beta1', 'Gene', (96, 105))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('association', 'Interaction', (72, 83))	('OCSCC', 'Disease', (208, 213))	('OSCC', 'Disease', (161, 165))	('polymorphism', 'Var', (115, 127))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('cancer', 'Disease', (185, 191))	('HPV16', 'Species', '333760', (132, 137))
521575	29663347	The risk of OSCC was greatest among subjects with the CT/CC genotype and HPV16 L1 seropositivity (OR, 13.6; 95% CI, 7.1-26.2) (Table 2).	('HPV16 L1', 'Gene', (73, 81))	('OSCC', 'Disease', (12, 16))	('HPV16', 'Species', '333760', (73, 78))	('CT/CC', 'Var', (54, 59))
521577	29663347	In contrast, the risk of OCSCC was highest among subjects with the CT/CC genotype and negative HPV16 serology (OR, 4.4; 95% CI, 2.8-7.0).	('HPV16', 'Gene', (95, 100))	('HPV16', 'Species', '333760', (95, 100))	('CT/CC', 'Var', (67, 72))	('OCSCC', 'Disease', (25, 30))
521579	29663347	Table 3 shows that the joint effect of TGF-beta1rs1982073 polymorphism and HPV16 serology on risk of OSCC was more significant in never-smokers and never-drinkers than in ever-smokers and ever-drinkers, particularly for OPSCC patients.	('OSCC', 'Disease', (101, 105))	('significant', 'Reg', (115, 126))	('polymorphism', 'Var', (58, 70))	('HPV16', 'Gene', (75, 80))	('HPV16', 'Species', '333760', (75, 80))	('OPSCC', 'Disease', (220, 225))	('patients', 'Species', '9606', (226, 234))	('TGF-beta1', 'Gene', '7040', (39, 48))	('TGF-beta1', 'Gene', (39, 48))
521587	29663347	Moreover, the risk of OPSCC was 23.5-fold higher in the CT/CC genotype and HPV16 seropositive younger group and only 6.0-fold higher in the older group.	('CT/CC', 'Disease', (56, 61))	('HPV16', 'Gene', (75, 80))	('HPV16', 'Species', '333760', (75, 80))	('higher', 'PosReg', (42, 48))	('genotype', 'Var', (62, 70))	('OPSCC', 'Disease', (22, 27))
521590	29663347	These 40 patients were also genotyped for TGF-beta1rs1982073 polymorphisms.	('patients', 'Species', '9606', (9, 17))	('TGF-beta1', 'Gene', '7040', (42, 51))	('polymorphisms', 'Var', (61, 74))	('TGF-beta1', 'Gene', (42, 51))
521606	29663347	The TGF-beta1rs1982073 polymorphism increases the risk of HPV16 L1-seropositive OPSCC via miR-187 regulation due to this target SNP being located in the miRNA binding sites .	('TGF-beta1', 'Gene', (4, 13))	('HPV16', 'Species', '333760', (58, 63))	('polymorphism', 'Var', (23, 35))	('miR-187', 'Gene', '406963', (90, 97))	('HPV16', 'Gene', (58, 63))	('miR-187', 'Gene', (90, 97))	('increases', 'PosReg', (36, 45))	('TGF-beta1', 'Gene', '7040', (4, 13))
521607	29663347	The polymorphism of nucleotide C to T transition decreases the binding minimum free energy of the duplex of miR-187:: TGF-beta1-mRNA, thereby increasing the binding strength of that duplex.	('binding', 'Interaction', (157, 164))	('decreases', 'NegReg', (49, 58))	('miR-187', 'Gene', (108, 115))	('binding minimum free energy', 'MPA', (63, 90))	('miR-187', 'Gene', '406963', (108, 115))	('TGF-beta1', 'Gene', '7040', (118, 127))	('TGF-beta1', 'Gene', (118, 127))	('polymorphism', 'Var', (4, 16))	('increasing', 'PosReg', (142, 152))
521608	29663347	This suggests that the TT allele is protective, while the CT/CC allele increases the cancer risk.	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('cancer', 'Disease', (85, 91))	('increases', 'PosReg', (71, 80))	('CT/CC', 'Var', (58, 63))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
521610	29663347	TGF-beta1rs1982073 may also increase the risk of HPV16 L1seropositive OPSCC via the Leu10Pro signal peptide substitution that affects TGF-beta1 secretion, structure, and function.	('HPV16', 'Species', '333760', (49, 54))	('secretion', 'MPA', (144, 153))	('structure', 'MPA', (155, 164))	('affects', 'Reg', (126, 133))	('TGF-beta1', 'Gene', '7040', (134, 143))	('function', 'MPA', (170, 178))	('TGF-beta1', 'Gene', (134, 143))	('HPV16', 'Gene', (49, 54))	('Leu10Pro', 'Chemical', '-', (84, 92))	('TGF-beta1', 'Gene', '7040', (0, 9))	('Leu10Pro', 'Var', (84, 92))	('increase', 'PosReg', (28, 36))	('TGF-beta1', 'Gene', (0, 9))
521611	29663347	In cytomegalovirus (CMV)-transfected HeLa cell lines, CMV-Pro10 (CC genotype) had a 2.8-fold increase in TGF-beta1 secretion compared with CMV-Leu10 (TT genotype), and this increased secretion indicated that TGF-beta1rs1982073 (Pro10 homozygosity CC genotype) was associated with an increased risk of breast cancer .	('CMV-Pro10', 'Var', (54, 63))	('breast cancer', 'Disease', (301, 314))	('increase', 'PosReg', (93, 101))	('breast cancer', 'Phenotype', 'HP:0003002', (301, 314))	('HeLa', 'CellLine', 'CVCL:0030', (37, 41))	('TGF-beta1', 'Gene', '7040', (208, 217))	('TGF-beta1', 'Gene', (208, 217))	('secretion', 'MPA', (115, 124))	('TGF-beta1', 'Gene', '7040', (105, 114))	('cancer', 'Phenotype', 'HP:0002664', (308, 314))	('TGF-beta1', 'Gene', (105, 114))	('breast cancer', 'Disease', 'MESH:D001943', (301, 314))
521612	29663347	Likewise, in hepatoma cell lines (HepG2, SMMU7721, LX-2, and L02), cells transfected with CMV-Pro10 had higher capacity for TGF-beta1 secretion, greater anti-apoptosis effects, and stronger enhancement of cell proliferation compared with those transfected with CMV-Leu10 in vitro .	('secretion', 'MPA', (134, 143))	('hepatoma', 'Disease', 'MESH:D006528', (13, 21))	('greater', 'PosReg', (145, 152))	('enhancement', 'PosReg', (190, 201))	('TGF-beta1', 'Gene', '7040', (124, 133))	('TGF-beta1', 'Gene', (124, 133))	('hepatoma', 'Disease', (13, 21))	('anti-apoptosis effects', 'CPA', (153, 175))	('cell proliferation', 'CPA', (205, 223))	('HepG2', 'CellLine', 'CVCL:0027', (34, 39))	('higher', 'PosReg', (104, 110))	('CMV-Pro10', 'Var', (90, 99))
521617	29663347	Moreover, TGF-beta1/Smads and Wnt/beta-catenin are key morphogen pathways that coordinate to influence cell division and cell differentiation so that stem cells can ultimately transform into differentiated cells; however, disrupted coordination in this process can lead to tissue-specific cancers .	('TGF-beta1', 'Gene', '7040', (10, 19))	('cancers', 'Disease', 'MESH:D009369', (289, 296))	('TGF-beta1', 'Gene', (10, 19))	('beta-catenin', 'Gene', '1499', (34, 46))	('cancer', 'Phenotype', 'HP:0002664', (289, 295))	('cell differentiation', 'CPA', (121, 141))	('disrupted', 'Var', (222, 231))	('lead to', 'Reg', (265, 272))	('cancers', 'Phenotype', 'HP:0002664', (289, 296))	('influence', 'Reg', (93, 102))	('cell division', 'CPA', (103, 116))	('beta-catenin', 'Gene', (34, 46))	('cancers', 'Disease', (289, 296))
521634	29663347	Genetic alterations caused by TGF-beta1rs1982073 polymorphism and HPV16 may jointly facilitated OPSCC tumorigenesis .	('polymorphism', 'Var', (49, 61))	('HPV16', 'Gene', (66, 71))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('facilitated', 'PosReg', (84, 95))	('OPSCC', 'Disease', (96, 101))	('HPV16', 'Species', '333760', (66, 71))	('TGF-beta1', 'Gene', '7040', (30, 39))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('TGF-beta1', 'Gene', (30, 39))
521635	29663347	Our results show that HPV16 infection plays a major and independent role in OPSCC susceptibility, whereas OCSCC etiology is mainly associated with tobacco exposure and alcohol use .	('alcohol use', 'Phenotype', 'HP:0030955', (168, 179))	('HPV16', 'Species', '333760', (22, 27))	('HPV16', 'Gene', (22, 27))	('tobacco', 'Species', '4097', (147, 154))	('associated', 'Reg', (131, 141))	('alcohol', 'Chemical', 'MESH:D000438', (168, 175))	('infection', 'Var', (28, 37))	('OPSCC', 'Disease', (76, 81))
521656	30094028	The transbronchial biopsy and immunohistochemistry of the pulmonary nodule revealed well-differentiated squamous cell carcinoma with strong (80%-90%) positivity for PD-L1.	('positivity', 'Var', (150, 160))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (104, 127))	('squamous cell carcinoma', 'Disease', (104, 127))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (104, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('PD-L1', 'Gene', (165, 170))	('PD-L1', 'Gene', '29126', (165, 170))
521661	30094028	Laboratory testing revealed elevated levels of serum creatine phosphokinase (CK) (4361 IU/L; normal reference <265 IU/L), aldolase (134.8 IU/L; normal reference <7.5 IU/L), myoglobin (4572.0 ng/mL; normal reference <60 ng/mL), lactate dehydrogenase (580 IU/L; normal reference <228 IU/L), aspartate aminotransferase (269 IU/L; normal reference <37 IU/L), and alanine aminotransferase (222 IU/L; normal reference <45 IU/L), indicating myositis and hepatitis.	('hepatitis', 'Phenotype', 'HP:0012115', (447, 456))	('aspartate aminotransferase', 'MPA', (289, 315))	('myositis and hepatitis', 'Disease', 'MESH:D009220', (434, 456))	('222 IU/L', 'Var', (385, 393))	('myositis', 'Phenotype', 'HP:0100614', (434, 442))	('lactate dehydrogenase', 'MPA', (227, 248))	('alanine aminotransferase', 'MPA', (359, 383))	('myoglobin', 'MPA', (173, 182))	('aldolase', 'MPA', (122, 130))	('4572.0', 'Var', (184, 190))	('elevated', 'PosReg', (28, 36))
521682	30094028	Only five of these cases presented CPK elevation 4, 6, 9, 10 (reported as 10,386 IU/L, 4361 IU/L [our case], 2125 IU/L, 1200 IU/L, and "slightly elevated").	('2125 IU/L', 'Var', (109, 118))	('CPK', 'Gene', (35, 38))	('CPK elevation', 'Phenotype', 'HP:0003236', (35, 48))	('CPK', 'Gene', '5286', (35, 38))	('4361 IU/L', 'Var', (87, 96))
521697	29623202	High-risk human papillomavirus was significantly associated with oropharyngeal cancer (odds ratio = 13.44, 95% confidence interval = 1.6-114.8) but was nonsignificantly associated with oral cancer (odds ratio = 8.58, 95% confidence interval = 0.9-78.9).	('oropharyngeal cancer', 'Disease', 'MESH:D009959', (65, 85))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('associated', 'Reg', (49, 59))	('oral cancer', 'Disease', 'MESH:D009062', (185, 196))	('human papillomavirus', 'Species', '10566', (10, 30))	('oropharyngeal cancer', 'Disease', (65, 85))	('oral cancer', 'Disease', (185, 196))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('High-risk', 'Var', (0, 9))
521759	29623202	HPV type 16 was significantly associated with oropharyngeal squamous cell cancer (OR = 19.39, 95% CI = 1.02-367.4).	('associated', 'Reg', (30, 40))	('HPV', 'Species', '10566', (0, 3))	('oropharyngeal squamous cell cancer', 'Disease', (46, 80))	('oropharyngeal squamous cell cancer', 'Disease', 'MESH:D002294', (46, 80))	('HPV', 'Var', (0, 3))	('oropharyngeal squamous cell cancer', 'Phenotype', 'HP:0012182', (46, 80))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (60, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
521867	29515414	In particular, pembrolizumab is indicated for the treatment of patients with unresectable or metastatic solid tumors that have been identified as having one of the following biomarkers: MSI-H (microsatellite instability-high) or dMMR (deficient mismatch repair).	('unresectable', 'Disease', (77, 89))	('pembrolizumab', 'Chemical', 'MESH:C582435', (15, 28))	('MSI-H', 'Disease', 'MESH:D000848', (186, 191))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('solid tumors', 'Disease', (104, 116))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('patients', 'Species', '9606', (63, 71))	('dMMR', 'Var', (229, 233))	('MSI-H', 'Disease', (186, 191))	('dMMR', 'Chemical', '-', (229, 233))	('solid tumors', 'Disease', 'MESH:D009369', (104, 116))
521882	31252679	Moreover, the dataset of "The Cancer Genome Atlas" for head and neck cancer has suggested the genetic alterations of Akt1 and 2 tend to be associated with the utmost poor clinical outcome in oral cancer.	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('genetic alterations', 'Var', (94, 113))	('Cancer Genome Atlas', 'Disease', (30, 49))	('head and neck cancer', 'Phenotype', 'HP:0012288', (55, 75))	('Cancer', 'Phenotype', 'HP:0002664', (30, 36))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (30, 49))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('Akt1', 'Gene', (117, 121))	('oral cancer', 'Disease', 'MESH:D009062', (191, 202))	('associated', 'Reg', (139, 149))	('rat', 'Species', '10116', (106, 109))	('oral cancer', 'Disease', (191, 202))	('head and neck cancer', 'Disease', 'MESH:D006258', (55, 75))
521884	31252679	Akt1/2 silencing also reduced tobacco-induced aggressiveness by decreasing the clonogenic and migration potential of oral cancer cells.	('rat', 'Species', '10116', (97, 100))	('aggressiveness', 'Disease', (46, 60))	('tobacco', 'Species', '4097', (30, 37))	('oral cancer', 'Disease', 'MESH:D009062', (117, 128))	('aggressiveness', 'Phenotype', 'HP:0000718', (46, 60))	('decreasing', 'NegReg', (64, 74))	('oral cancer', 'Disease', (117, 128))	('reduced', 'NegReg', (22, 29))	('aggressiveness', 'Disease', 'MESH:D001523', (46, 60))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('Akt1/2', 'Gene', (0, 6))	('silencing', 'Var', (7, 16))
521885	31252679	Moreover, silencing of Akt1 and 2 isoforms was found to decrease the expression of proteins regulating cancer cell survival and proliferation such as cyclooxygenase-2, B-cell lymphoma 2 (Bcl-2), cyclin D1, and survivin.	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (168, 183))	('cyclooxygenase-2, B-cell lymphoma 2', 'Gene', '5743', (150, 185))	('proteins', 'Protein', (83, 91))	('survivin', 'Protein', (210, 218))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('rat', 'Species', '10116', (135, 138))	('Bcl-2', 'Gene', (187, 192))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('expression', 'MPA', (69, 79))	('Bcl-2', 'Gene', '596', (187, 192))	('lymphoma', 'Phenotype', 'HP:0002665', (175, 183))	('cyclin D1', 'Gene', '595', (195, 204))	('cyclin D1', 'Gene', (195, 204))	('cancer', 'Disease', (103, 109))	('decrease', 'NegReg', (56, 64))	('Akt1', 'Gene', (23, 27))	('silencing', 'Var', (10, 19))
521890	31252679	These factors result in numerous genetic and epigenetic changes that cause genomic instability and tumor development and progression.	('tumor', 'Disease', (99, 104))	('genomic instability', 'MPA', (75, 94))	('progression', 'CPA', (121, 132))	('cause', 'Reg', (69, 74))	('epigenetic changes', 'Var', (45, 63))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('result in', 'Reg', (14, 23))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))
521943	31252679	Next, we evaluated the effect of genetic alterations of Akt isoforms on the prognosis of the disease in terms of OS and DFS from the TCGA dataset.	('Akt', 'Gene', '207', (56, 59))	('Akt', 'Gene', (56, 59))	('rat', 'Species', '10116', (45, 48))	('genetic alterations', 'Var', (33, 52))
521954	31252679	The different types of genetic alterations such as DNA amplifications, mutations, and deletions in 504 patients with HNSCC were obtained and analyzed from TCGA datasets.	('HNSCC', 'Phenotype', 'HP:0012288', (117, 122))	('mutations', 'Var', (71, 80))	('deletions', 'Var', (86, 95))	('patients', 'Species', '9606', (103, 111))	('rat', 'Species', '10116', (35, 38))
521956	31252679	The detailed assessment of the heatmap against the cases harboring the genetic alterations showed the increased mRNA transcript level of Akt1 and 2 isoforms, while for Akt3 such observation was missing except in a few cases (Figure 2A-C).	('alterations', 'Var', (79, 90))	('Akt3', 'Gene', (168, 172))	('rat', 'Species', '10116', (83, 86))	('genetic alterations', 'Var', (71, 90))	('Akt3', 'Gene', '10000', (168, 172))	('increased', 'PosReg', (102, 111))
521957	31252679	On consideration of the univariate analysis for survival data of 504 HNSCC patients from TCGA datasets, it was observed that the increasing abundance of genetic alterations of the Akt2 isoform was associated with worst overall survival (OS) and disease-free survival (DFS) in comparison to Akt1 and 3.	('overall survival', 'CPA', (219, 235))	('Akt2', 'Gene', '208', (180, 184))	('HNSCC', 'Phenotype', 'HP:0012288', (69, 74))	('Akt1 and 3', 'Gene', '207;10000', (290, 300))	('genetic alterations', 'Var', (153, 172))	('Akt2', 'Gene', (180, 184))	('patients', 'Species', '9606', (75, 83))	('rat', 'Species', '10116', (165, 168))	('rat', 'Species', '10116', (10, 13))	('worst', 'NegReg', (213, 218))	('disease-free survival', 'CPA', (245, 266))
521958	31252679	The median OS and DFS of the patients with Akt2 genetic alteration were found to be reduced as 27.56 and 34.76 months, respectively, as compared to the cases with no alteration of the Akt2 gene (56.44 and 72.44 months).	('Akt2', 'Gene', (184, 188))	('patients', 'Species', '9606', (29, 37))	('DFS', 'CPA', (18, 21))	('Akt2', 'Gene', '208', (184, 188))	('Akt2', 'Gene', (43, 47))	('rat', 'Species', '10116', (170, 173))	('rat', 'Species', '10116', (60, 63))	('reduced', 'NegReg', (84, 91))	('genetic alteration', 'Var', (48, 66))	('Akt2', 'Gene', '208', (43, 47))
521959	31252679	Similarly, patients harboring Akt1 gene alteration were also found to have a reduced OS of 45.93 months compared to patients with unaltered Akt1 (56.44 months), while the data for DFS could not be obtained (Figure 2D-I).	('Akt1', 'Gene', (30, 34))	('Akt1', 'Gene', (140, 144))	('gene alteration', 'Var', (35, 50))	('patients', 'Species', '9606', (116, 124))	('Akt1', 'Gene', '207', (30, 34))	('rat', 'Species', '10116', (44, 47))	('Akt1', 'Gene', '207', (140, 144))	('reduced', 'NegReg', (77, 84))	('patients', 'Species', '9606', (11, 19))
521971	31252679	Finally, the clonogenic potential of nicotine-treated SAS cells was also found to be increased 1.3 times up to 0.5 muM concentration (Supplementary Materials Figure S2C), and it was also decreased after silencing the Akt1 and 2 isoform expression (Figure 5E-F).	('silencing', 'Var', (203, 212))	('clonogenic potential', 'CPA', (13, 33))	('nicotine', 'Chemical', 'MESH:D009538', (37, 45))	('muM', 'Gene', '56925', (115, 118))	('increased', 'PosReg', (85, 94))	('rat', 'Species', '10116', (126, 129))	('muM', 'Gene', (115, 118))	('decreased', 'NegReg', (187, 196))	('Akt1', 'Enzyme', (217, 221))
521972	31252679	The wound healing assay was performed to analyze the effect of silencing of the Akt1 and 2 isoforms on TE, BAP, and nicotine-induced migration of oral cancer cells.	('TE', 'Chemical', '-', (103, 105))	('BAP', 'Gene', (107, 110))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('migration of oral cancer', 'Disease', (133, 157))	('migration of oral cancer', 'Disease', 'MESH:D009062', (133, 157))	('nicotine', 'Chemical', 'MESH:D009538', (116, 124))	('Akt1', 'Gene', (80, 84))	('BAP', 'Gene', '11331', (107, 110))	('silencing', 'Var', (63, 72))
521976	31252679	It was found that the knockdown of Akt2 gene led to a reduction in the migration potential of oral cancer cells.	('Akt2', 'Gene', '208', (35, 39))	('reduction', 'NegReg', (54, 63))	('rat', 'Species', '10116', (74, 77))	('oral cancer', 'Disease', 'MESH:D009062', (94, 105))	('knockdown', 'Var', (22, 31))	('oral cancer', 'Disease', (94, 105))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('Akt2', 'Gene', (35, 39))
521977	31252679	However, silencing of Akt1 failed to decrease the migration potential of both tobacco-treated and untreated SAS cells (Figure 6A-C).	('decrease', 'NegReg', (37, 45))	('tobacco', 'Species', '4097', (78, 85))	('migration potential', 'CPA', (50, 69))	('silencing', 'Var', (9, 18))	('Akt1', 'Gene', '207', (22, 26))	('rat', 'Species', '10116', (53, 56))	('Akt1', 'Gene', (22, 26))
521978	31252679	Further, the western blot analysis of the Akt1 and 2 knockdown cells demonstrated a significant decrease in the expression of cyclin D1, Bcl-2, and survivin proteins only in Akt2 knockdown cells but no significant change was observed in Akt1 knockdown cells.	('rat', 'Species', '10116', (76, 79))	('survivin proteins', 'Protein', (148, 165))	('Akt1', 'Gene', (42, 46))	('Akt1', 'Gene', (237, 241))	('decrease', 'NegReg', (96, 104))	('Akt2', 'Gene', (174, 178))	('Akt2', 'Gene', '208', (174, 178))	('knockdown', 'Var', (179, 188))	('cyclin D1', 'Gene', '595', (126, 135))	('Akt1', 'Gene', '207', (237, 241))	('Akt1', 'Gene', '207', (42, 46))	('Bcl-2', 'Gene', (137, 142))	('cyclin D1', 'Gene', (126, 135))	('Bcl-2', 'Gene', '596', (137, 142))	('expression', 'MPA', (112, 122))
521979	31252679	However, both Akt1 and Akt2 knockdown was associated with decreased levels of Cox-2 protein expression (Figure 7E-H).	('Akt1', 'Gene', (14, 18))	('Akt2', 'Gene', (23, 27))	('decreased', 'NegReg', (58, 67))	('levels of', 'MPA', (68, 77))	('Cox-2', 'Gene', (78, 83))	('Akt1', 'Gene', '207', (14, 18))	('Akt2', 'Gene', '208', (23, 27))	('Cox-2', 'Gene', '5743', (78, 83))	('knockdown', 'Var', (28, 37))
521993	31252679	Regardless of the discrepancy in the association of the Akt isoforms in HNSCC and OSCC, only the genetic alteration associated with Akt1 and 2 isoforms were associated with poor OS and genetic alteration of Akt2 isoform was linked with poor DFS of HNSCC patients.	('Akt', 'Gene', '207', (207, 210))	('Akt', 'Gene', (56, 59))	('Akt', 'Gene', '207', (56, 59))	('HNSCC', 'Phenotype', 'HP:0012288', (248, 253))	('HNSCC', 'Disease', (72, 77))	('linked', 'Reg', (224, 230))	('rat', 'Species', '10116', (197, 200))	('Akt', 'Gene', (132, 135))	('poor DFS', 'Disease', (236, 244))	('rat', 'Species', '10116', (109, 112))	('Akt', 'Gene', '207', (132, 135))	('associated', 'Reg', (157, 167))	('HNSCC', 'Phenotype', 'HP:0012288', (72, 77))	('Akt2', 'Gene', (207, 211))	('Akt2', 'Gene', '208', (207, 211))	('Akt', 'Gene', (207, 210))	('genetic alteration', 'Var', (185, 203))	('OSCC', 'Disease', (82, 86))	('poor OS', 'Disease', (173, 180))	('patients', 'Species', '9606', (254, 262))
522007	31252679	Our preliminary study indicated that Akt1 and 2 are primarily overexpressed in oral cancer tissues and also the TCGA dataset revealed the genetic alteration associated with Akt1 and 2 isoforms increased the transcript level but not the Akt3 isoform.	('Akt3', 'Gene', (236, 240))	('Akt3', 'Gene', '10000', (236, 240))	('overexpressed', 'PosReg', (62, 75))	('transcript level', 'MPA', (207, 223))	('oral cancer', 'Disease', 'MESH:D009062', (79, 90))	('rat', 'Species', '10116', (150, 153))	('oral cancer', 'Disease', (79, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('Akt1', 'Gene', (173, 177))	('increased', 'PosReg', (193, 202))	('genetic alteration', 'Var', (138, 156))
522009	31252679	In our study, the silencing of Akt1 and 2 isoforms caused cell cycle arrest in the G2/M phase, and prior studies have also suggested the involvement of Akt in G2/M cell cycle arrest.	('Akt', 'Gene', (31, 34))	('silencing', 'Var', (18, 27))	('cell cycle arrest in the G2/M phase', 'CPA', (58, 93))	('Akt', 'Gene', (152, 155))	('Akt', 'Gene', '207', (31, 34))	('involvement', 'Reg', (137, 148))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (164, 181))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (58, 75))	('Akt', 'Gene', '207', (152, 155))
522014	31252679	In addition, silencing of Akt1 and 2 decreased the clonogenic efficiency of untreated and tobacco-treated cells.	('clonogenic efficiency', 'CPA', (51, 72))	('tobacco', 'Species', '4097', (90, 97))	('decreased', 'NegReg', (37, 46))	('Akt1', 'Gene', (26, 30))	('silencing', 'Var', (13, 22))
522022	31252679	In our study, the silencing of Akt2 reduced oral cancer cell migration, and a similar observation has been reported for breast cancer cells also.	('Akt2', 'Gene', '208', (31, 35))	('oral cancer', 'Disease', (44, 55))	('silencing', 'Var', (18, 27))	('breast cancer', 'Disease', (120, 133))	('breast cancer', 'Disease', 'MESH:D001943', (120, 133))	('oral cancer', 'Disease', 'MESH:D009062', (44, 55))	('breast cancer', 'Phenotype', 'HP:0003002', (120, 133))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('rat', 'Species', '10116', (64, 67))	('reduced', 'NegReg', (36, 43))	('Akt2', 'Gene', (31, 35))
522024	31252679	However, in lung cancer, a partial reduction in scratch wound healing migration was observed in Akt2 knockdown cells while the prominent effect was observed in Akt1 knockdown cells.	('lung cancer', 'Phenotype', 'HP:0100526', (12, 23))	('lung cancer', 'Disease', 'MESH:D008175', (12, 23))	('rat', 'Species', '10116', (50, 53))	('knockdown', 'Var', (101, 110))	('rat', 'Species', '10116', (73, 76))	('Akt1', 'Gene', (160, 164))	('Akt1', 'Gene', '207', (160, 164))	('lung cancer', 'Disease', (12, 23))	('Akt2', 'Gene', (96, 100))	('Akt2', 'Gene', '208', (96, 100))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))	('reduction', 'NegReg', (35, 44))	('scratch wound healing migration', 'CPA', (48, 79))
522025	31252679	In our analysis, we found that the silencing of Akt1 and 2 isoforms caused an increase in the percentage of cell death in oral cancer cells.	('oral cancer', 'Disease', 'MESH:D009062', (122, 133))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('silencing', 'Var', (35, 44))	('oral cancer', 'Disease', (122, 133))	('Akt1', 'Gene', (48, 52))
522027	31252679	Finally, we observed that silencing of Akt2 led to the decreased expression of proteins such as Cox-2, Cyclin D1, Bcl-2, and survivin, while silencing of Akt1 only led to a reduction in Cox-2 levels.	('proteins', 'Protein', (79, 87))	('Cox-2', 'Gene', '5743', (96, 101))	('Akt1', 'Gene', (154, 158))	('Cox-2', 'Gene', (96, 101))	('Akt2', 'Gene', (39, 43))	('Cox-2', 'Gene', '5743', (186, 191))	('survivin', 'Protein', (125, 133))	('Bcl-2', 'Gene', (114, 119))	('Cox-2', 'Gene', (186, 191))	('Akt2', 'Gene', '208', (39, 43))	('Bcl-2', 'Gene', '596', (114, 119))	('decreased', 'NegReg', (55, 64))	('Akt1', 'Gene', '207', (154, 158))	('expression', 'MPA', (65, 75))	('silencing', 'Var', (26, 35))	('Cyclin D1', 'Gene', '595', (103, 112))	('Cyclin D1', 'Gene', (103, 112))
522041	31252679	It was also suggested that the blockage of this pathway can help in proliferation and progression of tumor cells and thus can potentially help cancer patients in improving their quality of life and survival rates.	('improving', 'PosReg', (162, 171))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('proliferation', 'CPA', (68, 81))	('rat', 'Species', '10116', (207, 210))	('rat', 'Species', '10116', (75, 78))	('survival rates', 'CPA', (198, 212))	('tumor', 'Disease', (101, 106))	('help', 'PosReg', (60, 64))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('quality of life', 'CPA', (178, 193))	('patients', 'Species', '9606', (150, 158))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('help', 'Reg', (138, 142))	('blockage', 'Var', (31, 39))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
522044	31252679	In our study, we observed that the knockdown of both Akt1 and 2 isoforms led to the reduction of Cox-2 protein expression.	('reduction', 'NegReg', (84, 93))	('knockdown', 'Var', (35, 44))	('Cox-2', 'Gene', '5743', (97, 102))	('Cox-2', 'Gene', (97, 102))
522045	31252679	In line with our observation, the previous study has shown the link between decreased Cox-2 expression with silencing of Akt1 and 2 isoforms.	('Cox-2', 'Gene', '5743', (86, 91))	('silencing', 'Var', (108, 117))	('Cox-2', 'Gene', (86, 91))	('decreased', 'NegReg', (76, 85))	('Akt1', 'Protein', (121, 125))	('expression', 'MPA', (92, 102))
522050	31252679	In our study, we found that silencing of Akt2 led to the reduction of Cyclin D1 expression.	('Akt2', 'Gene', '208', (41, 45))	('Cyclin D1', 'Gene', (70, 79))	('reduction', 'NegReg', (57, 66))	('Akt2', 'Gene', (41, 45))	('expression', 'MPA', (80, 90))	('Cyclin D1', 'Gene', '595', (70, 79))	('silencing', 'Var', (28, 37))
522175	31031851	Although the treatment design was inconsistent, an increase in the median OS in patients treated with nimotuzumab (11.9 vs 6.5 months) and an increase of the 1-year survival rate (54.0% vs 21.9%) were observed.	('increase', 'PosReg', (51, 59))	('nimotuzumab', 'Var', (102, 113))	('increase', 'PosReg', (142, 150))	('patients', 'Species', '9606', (80, 88))	('nimotuzumab', 'Chemical', 'MESH:C501466', (102, 113))	('OS', 'Chemical', '-', (74, 76))
522213	29697365	Population-based statistical inference for temporal sequence of somatic mutations in cancer genomes It is well recognized that accumulation of somatic mutations in cancer genomes plays a role in carcinogenesis; however, the temporal sequence and evolutionary relationship of somatic mutations remain largely unknown.	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('carcinogenesis', 'Disease', 'MESH:D063646', (195, 209))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('carcinogenesis', 'Disease', (195, 209))	('cancer', 'Disease', (85, 91))	('cancer', 'Disease', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('mutations', 'Var', (151, 160))
522216	29697365	The most common ancestors identified in pairwise comparison of somatic mutations were TP53 mutations in breast, head/neck, and lung cancers.	('lung cancers', 'Disease', (127, 139))	('TP53', 'Gene', '7157', (86, 90))	('head/neck', 'Disease', (112, 121))	('lung cancers', 'Disease', 'MESH:D008175', (127, 139))	('breast', 'Disease', (104, 110))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('TP53', 'Gene', (86, 90))	('lung cancers', 'Phenotype', 'HP:0100526', (127, 139))	('mutations', 'Var', (91, 100))	('cancers', 'Phenotype', 'HP:0002664', (132, 139))
522217	29697365	The known relationship of KRAS to TP53 mutations in colorectal cancers was identified, as well as potential ancestors of TP53 mutation such as NOTCH1, EGFR, and PTEN mutations in head/neck, lung and endometrial cancers, respectively.	('head/neck', 'Disease', (179, 188))	('TP53', 'Gene', '7157', (121, 125))	('NOTCH1', 'Gene', (143, 149))	('mutations', 'Var', (166, 175))	('endometrial cancers', 'Disease', (199, 218))	('endometrial cancers', 'Disease', 'MESH:D016889', (199, 218))	('colorectal cancer', 'Phenotype', 'HP:0003003', (52, 69))	('mutations', 'Var', (39, 48))	('lung', 'Disease', (190, 194))	('NOTCH1', 'Gene', '4851', (143, 149))	('colorectal cancers', 'Disease', (52, 70))	('cancers', 'Phenotype', 'HP:0002664', (63, 70))	('PTEN', 'Gene', (161, 165))	('KRAS', 'Gene', '3845', (26, 30))	('TP53', 'Gene', (34, 38))	('EGFR', 'Gene', (151, 155))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('TP53', 'Gene', (121, 125))	('KRAS', 'Gene', (26, 30))	('PTEN', 'Gene', '5728', (161, 165))	('cancers', 'Phenotype', 'HP:0002664', (211, 218))	('colorectal cancers', 'Disease', 'MESH:D015179', (52, 70))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('TP53', 'Gene', '7157', (34, 38))	('EGFR', 'Gene', '1956', (151, 155))
522218	29697365	We also identified apoptosis-related genes enriched with ancestor mutations in lung cancers and a relationship between APC hotspot mutations and TP53 mutations in colorectal cancers.	('apoptosis-related genes', 'Gene', (19, 42))	('mutations', 'Var', (131, 140))	('lung cancers', 'Disease', (79, 91))	('APC', 'Disease', 'MESH:D011125', (119, 122))	('cancers', 'Phenotype', 'HP:0002664', (84, 91))	('cancers', 'Phenotype', 'HP:0002664', (174, 181))	('APC', 'Disease', (119, 122))	('TP53', 'Gene', '7157', (145, 149))	('TP53', 'Gene', (145, 149))	('colorectal cancer', 'Phenotype', 'HP:0003003', (163, 180))	('colorectal cancers', 'Disease', 'MESH:D015179', (163, 181))	('mutations', 'Var', (150, 159))	('lung cancers', 'Disease', 'MESH:D008175', (79, 91))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('lung cancers', 'Phenotype', 'HP:0100526', (79, 91))	('colorectal cancers', 'Disease', (163, 181))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))
522223	29697365	Recent advances in high-throughput sequencing technologies have enabled screening of cancer genomes for well-known cancer-related genomic aberrations such as somatic mutations, DNA copy number alterations, and chromosomal translocations.	('chromosomal translocations', 'Var', (210, 236))	('cancer', 'Disease', (115, 121))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('cancer', 'Disease', (85, 91))	('mi', 'Chemical', 'MESH:C011506', (134, 136))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('cancer', 'Disease', 'MESH:D009369', (115, 121))
522227	29697365	proposed a mathematical approach to determine the sequential order of APC, KRAS, and TP53 mutations in 70 colorectal cancer samples.	('TP53', 'Gene', (85, 89))	('mutations', 'Var', (90, 99))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('colorectal cancer', 'Disease', (106, 123))	('APC', 'Disease', 'MESH:D011125', (70, 73))	('KRAS', 'Gene', (75, 79))	('colorectal cancer', 'Disease', 'MESH:D015179', (106, 123))	('TP53', 'Gene', '7157', (85, 89))	('APC', 'Disease', (70, 73))	('colorectal cancer', 'Phenotype', 'HP:0003003', (106, 123))	('mi', 'Chemical', 'MESH:C011506', (41, 43))	('KRAS', 'Gene', '3845', (75, 79))
522242	29697365	The CCF is defined as the proportion of cancer cells harboring the mutations for each variant, and can be estimated using a method outlined by Landau et al..	('cancer', 'Disease', (40, 46))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('mutations', 'Var', (67, 76))
522253	29697365	A mean number of 120 somatic mutations (nonsilent SNVs; missense, nonsense and splice site mutations) were observed (1 to 1597 mutations per case; median of 59 mutations; Table 1).	('missense', 'Var', (56, 64))	('mi', 'Chemical', 'MESH:C011506', (56, 58))	('nonsense and splice site mutations', 'Var', (66, 100))
522257	29697365	The gene pairs with high SCORE-CO include TTN and MUC16 whose frequent mutations are largely due to their large gene size (36,800 and 14,500 amino acids, respectively) rather than their functional significance.	('mi', 'Chemical', 'MESH:C011506', (142, 144))	('MUC16', 'Gene', (50, 55))	('mutations', 'Var', (71, 80))	('TTN', 'Gene', (42, 45))	('TTN', 'Gene', '7273', (42, 45))	('MUC16', 'Gene', '94025', (50, 55))
522258	29697365	Thus, we focused on mutations in known cancer-related genes or the Cancer Gene Census (CGC) (Fig.	('Cancer', 'Disease', 'MESH:D009369', (67, 73))	('Cancer', 'Phenotype', 'HP:0002664', (67, 73))	('cancer', 'Disease', (39, 45))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('mutations', 'Var', (20, 29))	('Cancer', 'Disease', (67, 73))
522259	29697365	The co-occurring mutation gene pairs with high SCORE-CO were tumor type-specific, e.g., gene pairs of TP53 and PIK3CA were highly ranked in BLCA, BRCA, COADREAD, HNSC, LUSC, UCEC (SCORE-CO = 0.089 for 8 cases with the co-occurrence / total 90 patients, 0.055 for 40 cases, 0.085 for 21 cases, 0.083 for 22 cases, 0.085 for 10 cases, 0.106 for 18 cases, respectively) and to a lesser extent in LUAD (SCORE-CO =0.024 for 7 cases).	('LUSC', 'Phenotype', 'HP:0030359', (168, 172))	('TP53', 'Gene', (102, 106))	('BRCA', 'Phenotype', 'HP:0003002', (146, 150))	('BRCA', 'Gene', '672', (146, 150))	('patients', 'Species', '9606', (243, 251))	('PIK3CA', 'Gene', (111, 117))	('BRCA', 'Gene', (146, 150))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('BLCA', 'Disease', (140, 144))	('0.083', 'Var', (293, 298))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('UCEC', 'Disease', (174, 178))	('TP53', 'Gene', '7157', (102, 106))	('PIK3CA', 'Gene', '5290', (111, 117))	('tumor', 'Disease', (61, 66))
522261	29697365	LRP1B mutants frequently co-occurred with TP53 mutants in HNSC, LUAD and LUSC.	('TP53', 'Gene', '7157', (42, 46))	('mutants', 'Var', (6, 13))	('LUSC', 'Disease', (73, 77))	('LRP1B', 'Gene', (0, 5))	('HNSC', 'Disease', (58, 62))	('TP53', 'Gene', (42, 46))	('co-occurred', 'Reg', (25, 36))	('LRP1B', 'Gene', '53353', (0, 5))	('LUAD', 'Disease', (64, 68))	('mutants', 'Var', (47, 54))	('LUSC', 'Phenotype', 'HP:0030359', (73, 77))
522263	29697365	In addition, some of the mutation occurrences were tumor type-specific, e.g., PIK3CA mutations showed co-occurrence with FAT4 mutations with a high frequency in BLCA, but mainly co-occurred with PTEN mutations in UCEC.	('PIK3CA', 'Gene', (78, 84))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('FAT4', 'Gene', (121, 125))	('FAT4', 'Gene', '79633', (121, 125))	('tumor', 'Disease', (51, 56))	('PIK3CA', 'Gene', '5290', (78, 84))	('BLCA', 'Disease', (161, 165))	('co-occurrence', 'Reg', (102, 115))	('mutations', 'Var', (85, 94))	('mutations', 'Var', (126, 135))	('PTEN', 'Gene', (195, 199))	('PTEN', 'Gene', '5728', (195, 199))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
522271	29697365	For example, a frequently co-occurred mutation pair of TP53 and LRP1B (Fig.	('LRP1B', 'Gene', (64, 69))	('TP53', 'Gene', '7157', (55, 59))	('TP53', 'Gene', (55, 59))	('LRP1B', 'Gene', '53353', (64, 69))	('mutation', 'Var', (38, 46))	('co-occurred', 'Reg', (26, 37))
522273	29697365	In addition, KMT2C mutation was consistently observed as a descendant of TP53 mutations (TP53  KMT2C) in HNSC and LUAD (P value =3.0*10-5 and 5.0*10-5, respectively).	('TP53', 'Gene', '7157', (89, 93))	('TP53', 'Gene', '7157', (73, 77))	('TP53', 'Gene', (89, 93))	('TP53', 'Gene', (73, 77))	('mutations', 'Var', (78, 87))	('KMT2C', 'Gene', '58508', (95, 100))	('KMT2C', 'Gene', (95, 100))	('KMT2C', 'Gene', '58508', (13, 18))	('KMT2C', 'Gene', (13, 18))
522275	29697365	The hierarchy of the three genes (TP53  PIK3CA  CDH1) in BRCA suggests that TP53 mutations represent early events that are followed by subsequent PIK3CA mutations (P value =0.034), then CDH1 mutations (P value =3.0*10-5).	('PIK3CA', 'Gene', '5290', (146, 152))	('PIK3CA', 'Gene', (40, 46))	('TP53', 'Gene', (34, 38))	('CDH1', 'Gene', (48, 52))	('mutations', 'Var', (153, 162))	('PIK3CA', 'Gene', '5290', (40, 46))	('TP53', 'Gene', '7157', (76, 80))	('mutations', 'Var', (191, 200))	('CDH1', 'Gene', (186, 190))	('CDH1', 'Gene', '999', (48, 52))	('TP53', 'Gene', (76, 80))	('CDH1', 'Gene', '999', (186, 190))	('BRCA', 'Gene', '672', (57, 61))	('mutations', 'Var', (81, 90))	('BRCA', 'Phenotype', 'HP:0003002', (57, 61))	('PIK3CA', 'Gene', (146, 152))	('BRCA', 'Gene', (57, 61))	('TP53', 'Gene', '7157', (34, 38))
522276	29697365	This mutation sequence can be functionally interpreted as follows: genomic integrity is disrupted with TP53 mutations followed by cancer cell proliferation stimulated by PIK3CA mutations and the acquisition of later invasive/metastatic potential with CDH1 mutations.	('PIK3CA', 'Gene', '5290', (170, 176))	('TP53', 'Gene', '7157', (103, 107))	('invasive/metastatic potential', 'CPA', (216, 245))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('CDH1', 'Gene', '999', (251, 255))	('mutations', 'Var', (108, 117))	('disrupted', 'NegReg', (88, 97))	('cancer', 'Disease', (130, 136))	('TP53', 'Gene', (103, 107))	('mutations', 'Var', (177, 186))	('genomic integrity', 'CPA', (67, 84))	('mi', 'Chemical', 'MESH:C011506', (71, 73))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('PIK3CA', 'Gene', (170, 176))	('CDH1', 'Gene', (251, 255))
522279	29697365	The elevated mutation abundance (mean of 211 mutations per LUAD case vs. mean of 120 mutations for total cases) and the relatively large size of the cohort (290 cases) may explain this number, but only one mutation pair was observed in LUSC with similar mutation abundance (average 221 mutations per cases) and a smaller number of cohorts (118 cases).	('mutations', 'Var', (45, 54))	('mi', 'Chemical', 'MESH:C011506', (248, 250))	('elevated', 'PosReg', (4, 12))	('LUSC', 'Phenotype', 'HP:0030359', (236, 240))	('mutation abundance', 'MPA', (13, 31))
522280	29697365	TP53 mutation appeared as a hub in the 16 edge-based network of LUAD and was identified as ancestor in most mutation pairs.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('mutation', 'Var', (5, 13))
522281	29697365	TP53 mutations have been implicated in tumor development and progression across many tumor types.	('tumor', 'Disease', (85, 90))	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('mutations', 'Var', (5, 14))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('tumor', 'Disease', (39, 44))	('implicated', 'Reg', (25, 35))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))
522282	29697365	Our analysis also suggests that EGFR mutations may be earlier genomic events among the mutations in the LUAD pathogenesis.	('mutations', 'Var', (37, 46))	('EGFR', 'Gene', '1956', (32, 36))	('EGFR', 'Gene', (32, 36))	('mi', 'Chemical', 'MESH:C011506', (66, 68))
522283	29697365	A substantial fraction of EGFR mutations in LUAD are considered to be early addicted targets of targeted therapy, suggesting that they represent early genomic aberrations together with TP53 mutations.	('EGFR', 'Gene', (26, 30))	('mutations', 'Var', (31, 40))	('mi', 'Chemical', 'MESH:C011506', (155, 157))	('TP53', 'Gene', (185, 189))	('EGFR', 'Gene', '1956', (26, 30))	('TP53', 'Gene', '7157', (185, 189))
522285	29697365	In HNSC, NOTCH1 mutations may be earlier events than TP53 mutations.	('HNSC', 'Disease', (3, 7))	('TP53', 'Gene', (53, 57))	('mutations', 'Var', (16, 25))	('TP53', 'Gene', '7157', (53, 57))	('NOTCH1', 'Gene', '4851', (9, 15))	('NOTCH1', 'Gene', (9, 15))
522288	29697365	Colorectal carcinogenesis is one of the well-established stepwise cancer progression models and involves sequential acquisition of APC, KRAS, and TP53 mutations at colorectal dysplasia, adenoma, and carcinoma stages, respectively.	('colorectal dysplasia', 'Disease', 'MESH:D015179', (164, 184))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('Colorectal carcinogenesis', 'Disease', (0, 25))	('adenoma', 'Disease', 'MESH:D000236', (186, 193))	('carcinoma', 'Phenotype', 'HP:0030731', (199, 208))	('colorectal dysplasia', 'Disease', (164, 184))	('carcinoma', 'Disease', (199, 208))	('TP53', 'Gene', (146, 150))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('mutations', 'Var', (151, 160))	('KRAS', 'Gene', '3845', (136, 140))	('adenoma', 'Disease', (186, 193))	('Colorectal carcinogenesis', 'Disease', 'MESH:D063646', (0, 25))	('KRAS', 'Gene', (136, 140))	('APC', 'Disease', 'MESH:D011125', (131, 134))	('carcinoma', 'Disease', 'MESH:D002277', (199, 208))	('APC', 'Disease', (131, 134))	('TP53', 'Gene', '7157', (146, 150))	('cancer', 'Disease', (66, 72))
522289	29697365	Our inferred hierarchy from somatic mutations suggested that KRAS mutations were the earliest events in colorectal carcinogenesis.	('mutations', 'Var', (66, 75))	('events', 'Reg', (94, 100))	('colorectal carcinogenesis', 'Disease', 'MESH:D063646', (104, 129))	('KRAS', 'Gene', (61, 65))	('colorectal carcinogenesis', 'Disease', (104, 129))	('KRAS', 'Gene', '3845', (61, 65))
522290	29697365	Given that our statistical model only considered the SNV, tumor suppressors that can be inactivated by chromosomal deletions, such as APC, may not be adequately assessed for order of mutation.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('APC', 'Disease', 'MESH:D011125', (134, 137))	('APC', 'Disease', (134, 137))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('deletions', 'Var', (115, 124))
522298	29697365	For this tumor type, TP53 mutation was marked as a descendant for PIK3CA and PTEN mutations.	('TP53', 'Gene', (21, 25))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('mutation', 'Var', (26, 34))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('PIK3CA', 'Gene', (66, 72))	('PTEN', 'Gene', (77, 81))	('tumor', 'Disease', (9, 14))	('PTEN', 'Gene', '5728', (77, 81))	('PIK3CA', 'Gene', '5290', (66, 72))	('TP53', 'Gene', '7157', (21, 25))
522299	29697365	It was also noted that TP53 mutations were also observed as descendants of KRAS mutations in COADREAD.	('mutations', 'Var', (80, 89))	('KRAS', 'Gene', (75, 79))	('TP53', 'Gene', '7157', (23, 27))	('TP53', 'Gene', (23, 27))	('mutations', 'Var', (28, 37))	('KRAS', 'Gene', '3845', (75, 79))
522303	29697365	On C2cp gene sets (canonical pathway in MSigDB), the results for the positively ranked genes or functions enriched with high SCORE-AN were also obviously enriched for cancer-related functionalities (Additional file 7: Table S6) but no gene sets with statistical significance were observed for genes with low SCORE-AN (Additional file 8: Table S7).	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('cancer', 'Disease', (167, 173))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('high SCORE-AN', 'Var', (120, 133))
522304	29697365	It has been previously reported that APC mutations may initiate the process of colon cancer development as one of the earliest genomic aberrations, but we did not obtain clear results for the early occurrence of APC mutations in the gene-level experiments shown in the previous section.	('mutations', 'Var', (41, 50))	('colon cancer', 'Disease', (79, 91))	('mi', 'Chemical', 'MESH:C011506', (131, 133))	('APC', 'Disease', (37, 40))	('APC', 'Disease', 'MESH:D011125', (212, 215))	('colon cancer', 'Phenotype', 'HP:0003003', (79, 91))	('APC', 'Disease', (212, 215))	('colon cancer', 'Disease', 'MESH:D015179', (79, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('APC', 'Disease', 'MESH:D011125', (37, 40))
522306	29697365	The APC non-hotspot mutations showed relatively low CCF values compared with the APC hotspot mutations (Additional file 9: Figure S2(a)).	('CCF values', 'MPA', (52, 62))	('APC', 'Disease', (81, 84))	('APC', 'Disease', 'MESH:D011125', (4, 7))	('APC', 'Disease', (4, 7))	('low', 'NegReg', (48, 51))	('mutations', 'Var', (20, 29))	('APC', 'Disease', 'MESH:D011125', (81, 84))
522307	29697365	When we further examined four cases harboring both APC:Q1387 hotspot mutations and TP53 mutations, the APC:Q1387 hotspot mutations had higher CCF values compared with TP53 mutation, and it is reasonable to assume that the APC:Q1387 mutations would be an ancestor of the TP53 mutations in these cases (Additional file 9: Figure S2(b)).	('TP53', 'Gene', '7157', (83, 87))	('mutations', 'Var', (69, 78))	('APC', 'Disease', 'MESH:D011125', (222, 225))	('mutations', 'Var', (121, 130))	('TP53', 'Gene', (83, 87))	('APC', 'Disease', (222, 225))	('mutations', 'Var', (88, 97))	('TP53', 'Gene', '7157', (270, 274))	('mi', 'Chemical', 'MESH:C011506', (19, 21))	('APC', 'Disease', 'MESH:D011125', (51, 54))	('TP53', 'Gene', '7157', (167, 171))	('APC', 'Disease', (51, 54))	('APC', 'Disease', 'MESH:D011125', (103, 106))	('TP53', 'Gene', (270, 274))	('APC', 'Disease', (103, 106))	('higher', 'PosReg', (135, 141))	('CCF', 'MPA', (142, 145))	('TP53', 'Gene', (167, 171))
522310	29697365	Early- and late-occurring somatic mutations have different biological and clinical implications-the early addicted somatic mutations may serve as appropriate targets for therapeutic intervention while late-occurring cancer drivers have been associated with therapeutic resistance or disease progression.	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('mutations', 'Var', (123, 132))	('cancer', 'Disease', (216, 222))	('cancer', 'Disease', 'MESH:D009369', (216, 222))
522320	29697365	Among the tumor types examined, we identified TP53 mutations as a recurrently observed hub connected with other cancer-related genes, consistent with its prevalent and known roles in tumorigenesis across multiple cancer types.	('mi', 'Chemical', 'MESH:C011506', (25, 27))	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('mutations', 'Var', (51, 60))	('cancer', 'Disease', (112, 118))	('tumor', 'Disease', (10, 15))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('TP53', 'Gene', '7157', (46, 50))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('cancer', 'Disease', 'MESH:D009369', (213, 219))	('TP53', 'Gene', (46, 50))	('tumor', 'Disease', (183, 188))	('cancer', 'Disease', (213, 219))	('tumor', 'Disease', 'MESH:D009369', (10, 15))
522323	29697365	Inactivation of LRP1B increased the invasive potential in an in vitro setting, implicating a role of LRP1B mutations in the later stages of carcinogenesis.	('LRP1B', 'Gene', (16, 21))	('LRP1B', 'Gene', '53353', (101, 106))	('mutations', 'Var', (107, 116))	('carcinogenesis', 'Disease', 'MESH:D063646', (140, 154))	('LRP1B', 'Gene', '53353', (16, 21))	('carcinogenesis', 'Disease', (140, 154))	('increased', 'PosReg', (22, 31))	('LRP1B', 'Gene', (101, 106))	('Inactivation', 'Var', (0, 12))	('invasive potential', 'CPA', (36, 54))
522324	29697365	Whether the mutations in epigenetic modifiers are early or late events drivers is a subject of debate, with lines of evidence supporting early events for TET2 mutations or late events for SETD2 mutations.	('mutations', 'Var', (159, 168))	('mutations', 'Var', (194, 203))	('SETD2', 'Gene', '29072', (188, 193))	('TET2', 'Gene', '54790', (154, 158))	('SETD2', 'Gene', (188, 193))	('TET2', 'Gene', (154, 158))
522325	29697365	Our results suggest that KMT2C mutations are descendant genomic events relative to TP53 mutations in LUAD and HNSC, but further experimental validation in terms of multiregion sequencing or other method is required.	('TP53', 'Gene', '7157', (83, 87))	('mutations', 'Var', (31, 40))	('TP53', 'Gene', (83, 87))	('mi', 'Chemical', 'MESH:C011506', (60, 62))	('KMT2C', 'Gene', '58508', (25, 30))	('KMT2C', 'Gene', (25, 30))
522327	29697365	For example, USH2A mutation was frequently observed in several tumor types as shown in Fig.	('tumor', 'Disease', (63, 68))	('mutation', 'Var', (19, 27))	('USH2A', 'Gene', '7399', (13, 18))	('observed', 'Reg', (43, 51))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('USH2A', 'Gene', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
522329	29697365	In the case of COADREAD, the mutation pair of KRAS  APC was observed even though it is generally recognized that APC mutations occur early, before KRAS and TP53 mutations.	('APC', 'Disease', 'MESH:D011125', (113, 116))	('mutations', 'Var', (117, 126))	('KRAS', 'Gene', '3845', (147, 151))	('APC', 'Disease', (113, 116))	('KRAS', 'Gene', (46, 50))	('KRAS', 'Gene', '3845', (46, 50))	('TP53', 'Gene', '7157', (156, 160))	('TP53', 'Gene', (156, 160))	('APC', 'Disease', 'MESH:D011125', (52, 55))	('KRAS', 'Gene', (147, 151))	('APC', 'Disease', (52, 55))
522331	29697365	In the case of APC, chromosomal deletions or frameshifting indels may be also responsible for APC inactivation and our methods may not adequately evaluate the genetic hierarchy of tumor suppressors such as APC.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('APC', 'Disease', (15, 18))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('responsible', 'Reg', (78, 89))	('APC', 'Disease', 'MESH:D011125', (206, 209))	('tumor', 'Disease', (180, 185))	('APC', 'Disease', (206, 209))	('chromosomal deletions', 'Var', (20, 41))	('APC', 'Disease', 'MESH:D011125', (94, 97))	('APC', 'Disease', (94, 97))	('APC', 'Disease', 'MESH:D011125', (15, 18))	('frameshifting indels', 'Var', (45, 65))
522332	29697365	When we limit the APC mutations to those on a known mutation hotspot (APC:Q1387) accompanying TP53 mutations (four COADREAD cases), the CCF values of APC mutations were higher than those of TP53 mutations suggesting that APC mutation may have occurred earlier than TP53 mutation in those cases.	('APC', 'Disease', 'MESH:D011125', (150, 153))	('mi', 'Chemical', 'MESH:C011506', (10, 12))	('APC', 'Disease', (150, 153))	('TP53', 'Gene', '7157', (265, 269))	('TP53', 'Gene', (94, 98))	('APC', 'Disease', 'MESH:D011125', (221, 224))	('APC', 'Disease', (221, 224))	('TP53', 'Gene', '7157', (190, 194))	('APC', 'Disease', 'MESH:D011125', (70, 73))	('APC', 'Disease', (70, 73))	('TP53', 'Gene', '7157', (94, 98))	('CCF', 'MPA', (136, 139))	('TP53', 'Gene', (265, 269))	('higher', 'PosReg', (169, 175))	('mutations', 'Var', (99, 108))	('TP53', 'Gene', (190, 194))	('APC', 'Disease', 'MESH:D011125', (18, 21))	('APC', 'Disease', (18, 21))	('mutations', 'Var', (154, 163))
522338	29697365	Furthermore, the study on mutation hotspot information may be more robust in that the hotspot mutations represent functionally relevant cancer drivers as shown in the example of APC mutations in COADREAD.	('APC', 'Disease', 'MESH:D011125', (178, 181))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('mutations', 'Var', (94, 103))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('APC', 'Disease', (178, 181))	('cancer', 'Disease', (136, 142))	('mutations', 'Var', (182, 191))
522351	29371981	Recently, more and more evidence has shown that aberrant activation of Hh signaling pathway is involved in the formation of respiratory system malignance, gastrointestinal tumor and reproductive system cancers.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('system cancers', 'Disease', 'MESH:D009369', (195, 209))	('gastrointestinal tumor', 'Phenotype', 'HP:0007378', (155, 177))	('activation', 'PosReg', (57, 67))	('respiratory system malignance', 'Disease', (124, 153))	('system cancers', 'Disease', (195, 209))	('aberrant', 'Var', (48, 56))	('cancers', 'Phenotype', 'HP:0002664', (202, 209))	('Hh signaling pathway', 'Pathway', (71, 91))	('respiratory system malignance', 'Disease', 'MESH:D015619', (124, 153))	('gastrointestinal tumor', 'Disease', 'MESH:D004067', (155, 177))	('gastrointestinal tumor', 'Disease', (155, 177))	('involved', 'Reg', (95, 103))
522356	29371981	Functionally, Sufu knockdown prevents cervical cancer cell EMT in vitro.	('prevents', 'NegReg', (29, 37))	('Sufu', 'Gene', '51684', (14, 18))	('knockdown', 'Var', (19, 28))	('cervical cancer', 'Disease', 'MESH:D002583', (38, 53))	('Sufu', 'Gene', (14, 18))	('cervical cancer', 'Disease', (38, 53))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))
522358	29371981	To determine whether Sufu plays a positive role in carcinogenesis, we analyzed Sufu gene alteration using data from The Cancer Genomic Atlas (TCGA) database and the cBioPortal online tool (the cBioPortal for Cancer Genomics).	('Cancer', 'Disease', 'MESH:D009369', (208, 214))	('Sufu', 'Gene', '51684', (21, 25))	('Cancer', 'Disease', (120, 126))	('Sufu', 'Gene', '51684', (79, 83))	('Sufu', 'Gene', (21, 25))	('Cancer', 'Disease', 'MESH:D009369', (120, 126))	('Cancer', 'Phenotype', 'HP:0002664', (120, 126))	('Cancer Genomic Atlas', 'Disease', (120, 140))	('alteration', 'Var', (89, 99))	('Sufu', 'Gene', (79, 83))	('Cancer Genomic Atlas', 'Disease', 'MESH:D009369', (120, 140))	('carcinogenesis', 'Disease', 'MESH:D063646', (51, 65))	('Cancer', 'Phenotype', 'HP:0002664', (208, 214))	('Cancer', 'Disease', (208, 214))	('carcinogenesis', 'Disease', (51, 65))
522365	29371981	Interestingly, as shown in Figure 1E and Supplementary Figure 1, Sufu knockdown not only significantly inhibited the cell migration, but also reduced the cell invasion.	('cell invasion', 'CPA', (154, 167))	('knockdown', 'Var', (70, 79))	('Sufu', 'Gene', '51684', (65, 69))	('reduced', 'NegReg', (142, 149))	('cell migration', 'CPA', (117, 131))	('inhibited', 'NegReg', (103, 112))	('Sufu', 'Gene', (65, 69))
522369	29371981	As expected, in SiHa cell, western blot analysis showed that Sufu knockdown indeed up-regulated the E-cadherin protein level and down-regulated the Vimentin protein level, respectively (Figure 2A).	('Sufu', 'Gene', (61, 65))	('down-regulated', 'NegReg', (129, 143))	('Vimentin', 'Gene', (148, 156))	('up-regulated', 'PosReg', (83, 95))	('E-cadherin', 'Gene', '999', (100, 110))	('Vimentin', 'Gene', '7431', (148, 156))	('E-cadherin', 'Gene', (100, 110))	('knockdown', 'Var', (66, 75))	('Sufu', 'Gene', '51684', (61, 65))	('SiHa', 'CellLine', 'CVCL:0032', (16, 20))
522373	29371981	However, neither the mRNA levels of EMT markers nor the protein levels of EMT markers were altered by silencing Sufu in HeLa cells (Figure 2A, 2C).	('silencing', 'Var', (102, 111))	('Sufu', 'Gene', '51684', (112, 116))	('HeLa', 'CellLine', 'CVCL:0030', (120, 124))	('Sufu', 'Gene', (112, 116))
522374	29371981	Besides, our immunofluorescence (IF) experiment using anti-Vimentin and anti-E-cadherin antibody to detect endogenous Vimentin and E-cadherin showed that both of their protein levels were changed once Sufu knockdown in SiHa (Figure 2B).	('Vimentin', 'Gene', (59, 67))	('E-cadherin', 'Gene', '999', (131, 141))	('Vimentin', 'Gene', (118, 126))	('Vimentin', 'Gene', '7431', (59, 67))	('E-cadherin', 'Gene', (77, 87))	('E-cadherin', 'Gene', '999', (77, 87))	('Sufu', 'Gene', '51684', (201, 205))	('SiHa', 'CellLine', 'CVCL:0032', (219, 223))	('Vimentin', 'Gene', '7431', (118, 126))	('Sufu', 'Gene', (201, 205))	('changed', 'Reg', (188, 195))	('E-cadherin', 'Gene', (131, 141))	('protein levels', 'MPA', (168, 182))	('knockdown', 'Var', (206, 215))
522377	29371981	Using the online search tool 14-3-3-Pred (http://www.compbio.dundee.ac.uk/1433pred), we identified a sequence motif in Sufu (RAPS342RKDS346) that closely matches to the 14-3-3 binding consensus RX1-2SX2-3S.Moreover, the S342 and S346 sites were previously reported and required for Sufu stabilization and nuclear accumulation.	('Sufu', 'Gene', (119, 123))	('Sufu', 'Gene', '51684', (282, 286))	('S342', 'Var', (220, 224))	('Sufu', 'Gene', (282, 286))	('Sufu', 'Gene', '51684', (119, 123))	('S346', 'Var', (229, 233))
522381	29371981	Indeed, 14-3-3zeta knockdown abrogated Sufu protein (Figure 3B).	('Sufu', 'Gene', (39, 43))	('knockdown', 'Var', (19, 28))	('abrogated', 'NegReg', (29, 38))	('14-3-3zeta', 'Gene', (8, 18))	('Sufu', 'Gene', '51684', (39, 43))	('14-3-3zeta', 'Gene', '7534', (8, 18))
522386	29371981	To determine whether FoxM1 is regulated by 14-3-3zeta in cervical cancer cell line, knockdown 14-3-3zeta reduced FoxM1 protein level (Figure 3B, Supplementary Figure 4) rather than mRNA level (Figure 3E).	('cervical cancer', 'Disease', 'MESH:D002583', (57, 72))	('protein level', 'MPA', (119, 132))	('mRNA level', 'MPA', (181, 191))	('FoxM1', 'Gene', '2305', (113, 118))	('14-3-3zeta', 'Gene', '7534', (43, 53))	('cervical cancer', 'Disease', (57, 72))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('14-3-3zeta', 'Gene', (94, 104))	('knockdown', 'Var', (84, 93))	('14-3-3zeta', 'Gene', (43, 53))	('FoxM1', 'Gene', (113, 118))	('FoxM1', 'Gene', '2305', (21, 26))	('reduced', 'NegReg', (105, 112))	('FoxM1', 'Gene', (21, 26))	('14-3-3zeta', 'Gene', '7534', (94, 104))
522394	29371981	Since FoxM1 mRNA level was not altered by 14-3-3zeta knockdown (Figure 3E), but its protein level was decreased (Figure 3C).	('14-3-3zeta', 'Gene', (42, 52))	('FoxM1', 'Gene', '2305', (6, 11))	('knockdown', 'Var', (53, 62))	('14-3-3zeta', 'Gene', '7534', (42, 52))	('mRNA level', 'MPA', (12, 22))	('protein level', 'MPA', (84, 97))	('FoxM1', 'Gene', (6, 11))	('decreased', 'NegReg', (102, 111))
522405	29371981	Consequently, Sufu protein level dramatically decreased after transfected with FoxM1 siRNA (Figure 5E).	('Sufu', 'Gene', '51684', (14, 18))	('transfected', 'Var', (62, 73))	('FoxM1', 'Gene', '2305', (79, 84))	('Sufu', 'Gene', (14, 18))	('FoxM1', 'Gene', (79, 84))	('decreased', 'NegReg', (46, 55))
522411	29371981	In addition, knockdown of FOXM1 expression decreased the invasion of SiHa cells relative to that of control cells, and reconstitution of Sufu restored the invasion of these cells (Figure 6D, 6E).	('invasion', 'CPA', (57, 65))	('Sufu', 'Gene', (137, 141))	('SiHa', 'CellLine', 'CVCL:0032', (69, 73))	('FOXM1', 'Gene', '2305', (26, 31))	('FOXM1', 'Gene', (26, 31))	('invasion', 'CPA', (155, 163))	('Sufu', 'Gene', '51684', (137, 141))	('knockdown', 'Var', (13, 22))	('decreased', 'NegReg', (43, 52))
522419	29371981	Furthermore, the data from the TCGA database showed that alters of Sufu in cervical cancer have a certain proportion of the amplification (Figure 1A).	('alters', 'Var', (57, 63))	('cervical cancer', 'Disease', 'MESH:D002583', (75, 90))	('Sufu', 'Gene', (67, 71))	('cervical cancer', 'Disease', (75, 90))	('amplification', 'MPA', (124, 137))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('Sufu', 'Gene', '51684', (67, 71))
522421	29371981	Firstly, we transiently transfected Sufu small interfering RNA into cervical cancer cells (Figure1B) to perform EdU insertion experiments, however, we found no effect of silencing Sufu on cell proliferation (Figure 1C, 1D).	('silencing', 'Var', (170, 179))	('cervical cancer', 'Disease', (68, 83))	('cervical cancer', 'Disease', 'MESH:D002583', (68, 83))	('Sufu', 'Gene', '51684', (180, 184))	('Sufu', 'Gene', '51684', (36, 40))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('Sufu', 'Gene', (180, 184))	('Sufu', 'Gene', (36, 40))
522422	29371981	Then, we carried out transwell experiments to study the effect of Sufu on migration and invasion in SiHa cells, and Sufu knockdown slowed the motility and invasiveness of cervical squamous cell carcinoma SiHa cells (Figure 1E, 1F).	('knockdown', 'Var', (121, 130))	('Sufu', 'Gene', '51684', (116, 120))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (180, 203))	('motility', 'CPA', (142, 150))	('carcinoma', 'Phenotype', 'HP:0030731', (194, 203))	('Sufu', 'Gene', (116, 120))	('Sufu', 'Gene', '51684', (66, 70))	('SiHa', 'CellLine', 'CVCL:0032', (100, 104))	('Sufu', 'Gene', (66, 70))	('invasiveness of cervical squamous cell carcinoma SiHa', 'Disease', 'MESH:D002294', (155, 208))	('slowed', 'NegReg', (131, 137))	('SiHa', 'CellLine', 'CVCL:0032', (204, 208))
522427	29371981	We also found that Sufu knockdown reduced Hh downstream target genes Gli and Ptch1 (Figure 2C) in cervical squamous cell lines (SiHa and HCC94) rather than in adenocarcinoma cell line (HeLa) (Figure 3A, 3D).	('Gli', 'Gene', (69, 72))	('reduced', 'NegReg', (34, 41))	('Ptch1', 'Gene', '5727', (77, 82))	('Ptch1', 'Gene', (77, 82))	('Sufu', 'Gene', '51684', (19, 23))	('Gli', 'Gene', '2735', (69, 72))	('SiHa', 'CellLine', 'CVCL:0032', (128, 132))	('HCC94', 'CellLine', 'CVCL:6945', (137, 142))	('carcinoma', 'Phenotype', 'HP:0030731', (164, 173))	('adenocarcinoma', 'Disease', (159, 173))	('knockdown', 'Var', (24, 33))	('HeLa', 'CellLine', 'CVCL:0030', (185, 189))	('Sufu', 'Gene', (19, 23))	('adenocarcinoma', 'Disease', 'MESH:D000230', (159, 173))
522431	29371981	Maybe mutations are produced in Sufu or Gli, resulting in the interaction between them does not exist.	('interaction', 'Interaction', (62, 73))	('Sufu', 'Gene', '51684', (32, 36))	('Gli', 'Gene', (40, 43))	('Gli', 'Gene', '2735', (40, 43))	('Sufu', 'Gene', (32, 36))	('mutations', 'Var', (6, 15))
522433	29371981	Here, we consider the Sufu as a downstream target of 14-3-3zeta is based on three reasons: 1) 14-3-3zeta is highly expressed in many tumor types and binds to target proteins by a phosphorylation manner; 2) Sufu contains a conserved 14-3-3 binding motif, of which S342 and S346 sites have also been reported to be phosphorylated; 3) 14-3-3-Pred software predicts the two sites are the candidates of 14-3-3 binding sites.	('14-3-3zeta', 'Gene', '7534', (53, 63))	('Sufu', 'Gene', (22, 26))	('Sufu', 'Gene', '51684', (206, 210))	('S346', 'Var', (272, 276))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('Sufu', 'Gene', (206, 210))	('14-3-3zeta', 'Gene', (94, 104))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('14-3-3zeta', 'Gene', (53, 63))	('tumor', 'Disease', (133, 138))	('Sufu', 'Gene', '51684', (22, 26))	('14-3-3zeta', 'Gene', '7534', (94, 104))
522436	29371981	We consider this is likely because the wild type Sufu is hardly interacted with 14-3-3zeta, so we make use of sustained phosphorylated Sufu mutations (S342D, S346D, S342/6D) to carry out Co-IP experiment again, but we are unable to find any combination of signal (data not shown).	('S342D', 'Mutation', 'p.S342D', (151, 156))	('Sufu', 'Gene', '51684', (49, 53))	('S346D', 'Var', (158, 163))	('S342/6D', 'Var', (165, 172))	('14-3-3zeta', 'Gene', (80, 90))	('Sufu', 'Gene', '51684', (135, 139))	('Sufu', 'Gene', (49, 53))	('S346D', 'Mutation', 'p.S346D', (158, 163))	('S342D', 'Var', (151, 156))	('Sufu', 'Gene', (135, 139))	('14-3-3zeta', 'Gene', '7534', (80, 90))
522437	29371981	However, it is very interesting that when we knockdown 14-3-3zeta, Sufu mRNA and protein levels are both reduced, indicating that Sufu is a downstream target gene of 14-3-3zeta.	('14-3-3zeta', 'Gene', '7534', (166, 176))	('Sufu', 'Gene', (130, 134))	('Sufu', 'Gene', (67, 71))	('14-3-3zeta', 'Gene', (55, 65))	('14-3-3zeta', 'Gene', (166, 176))	('reduced', 'NegReg', (105, 112))	('Sufu', 'Gene', '51684', (67, 71))	('14-3-3zeta', 'Gene', '7534', (55, 65))	('Sufu', 'Gene', '51684', (130, 134))	('knockdown', 'Var', (45, 54))
522482	28361690	Cancer is a complex disease involving multiple hallmark processes, and aberrations in these processes are caused by SGAs that perturb pathways regulating these processes.	('caused', 'Reg', (106, 112))	('perturb', 'Reg', (126, 133))	('pathways', 'Pathway', (134, 142))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('SGAs', 'Disease', (116, 120))	('aberrations', 'Var', (71, 82))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))
522500	28361690	PolyPhen-2 was used to determine which single-nucleotide-substitution mutations in a tumor had a potential effect on protein function, where each tumor was a different cancer tumor.	('single-nucleotide-substitution mutations', 'Var', (39, 79))	('tumor', 'Disease', (85, 90))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('tumor', 'Disease', (175, 180))	('effect', 'Reg', (107, 113))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('cancer tumor', 'Disease', (168, 180))	('tumor', 'Disease', (146, 151))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('cancer tumor', 'Disease', 'MESH:D009369', (168, 180))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('protein function', 'MPA', (117, 133))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
522504	28361690	For each tumor, a gene that was either functionally mutated or affected by a copy number variation that resulted in an altered gene expression was considered an SGA event.	('copy number variation', 'Var', (77, 98))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumor', 'Disease', (9, 14))	('expression', 'MPA', (132, 142))
522506	28361690	The combined somatic mutation and copy number variation data resulted in datasets of the following sizes: BRCA with 779 samples and 15,517 genes; HNSC with 324 samples and 14,548 genes; LUAD with 398 samples and 11,851 genes; LUSC with 331 samples and 10,874 genes; and OV with 562 samples and 10,235 genes.	('BRCA', 'Gene', (106, 110))	('HNSC', 'Disease', (146, 150))	('LUAD', 'Phenotype', 'HP:0030078', (186, 190))	('copy', 'Var', (34, 38))	('BRCA', 'Gene', '672', (106, 110))
522513	28361690	In this way, the functional themes of the SGAs are presented in the document, and tumors with similar pathway alterations are similar even though they may host quite different SGAs.	('alterations', 'Var', (110, 121))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('tumors', 'Disease', (82, 88))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))
522551	27092882	The tumors of never-smokers were more often poorly differentiated (70.45% vs. 53.24%, P = 0.010) and more often contained oncogenic mutations (21.05% vs 11.05%, P = 0.023), particularly EGFR mutations (13.16% vs 3.40%, P = 0.001).	('contained', 'Reg', (112, 121))	('tumors', 'Disease', (4, 10))	('mutations', 'Var', (191, 200))	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('EGFR', 'Gene', '1956', (186, 190))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('EGFR', 'Gene', (186, 190))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('oncogenic', 'CPA', (122, 131))	('poorly differentiated', 'CPA', (44, 65))
522559	27092882	Among them are driver mutations within genes encoding signaling proteins critical for both the initiation and maintenance of lung malignancy, which have been identified in a series of molecular and translational studies.	('lung malignancy', 'Disease', (125, 140))	('lung malignancy', 'Disease', 'MESH:D009369', (125, 140))	('lung malignancy', 'Phenotype', 'HP:0100526', (125, 140))	('mutations', 'Var', (22, 31))
522560	27092882	Previous studies have shown that EGFR, KRAS, HER2 and BRAF contain recurrent driver mutations in ADC and that these mutations are seen particularly frequently in females, never-smokers and Asian patients.	('EGFR', 'Gene', (33, 37))	('BRAF', 'Gene', (54, 58))	('BRAF', 'Gene', '673', (54, 58))	('EGFR', 'Gene', '1956', (33, 37))	('mutations', 'Var', (84, 93))	('patients', 'Species', '9606', (195, 203))	('KRAS', 'Gene', (39, 43))	('HER2', 'Gene', (45, 49))	('ADC', 'Disease', (97, 100))	('KRAS', 'Gene', '3845', (39, 43))	('HER2', 'Gene', '2064', (45, 49))
522561	27092882	We were interested in whether SQCCs in never-smokers harbor the known EGFR and KRAS driver mutations.	('SQCC', 'Phenotype', 'HP:0002860', (30, 34))	('KRAS', 'Gene', '3845', (79, 83))	('EGFR', 'Gene', '1956', (70, 74))	('mutations', 'Var', (91, 100))	('EGFR', 'Gene', (70, 74))	('KRAS', 'Gene', (79, 83))
522562	27092882	Our findings provide important information that could be useful for selecting patients with specific driver mutations for future clinical trials of individualized therapies for SQCC.	('SQCC', 'Disease', (177, 181))	('SQCC', 'Phenotype', 'HP:0002860', (177, 181))	('patients', 'Species', '9606', (78, 86))	('mutations', 'Var', (108, 117))
522569	27092882	Among the 76 never-smokers, 16 harbored known oncogenic mutations, including 10 (13.16%) EGFR, 1 (1.32%) KRAS, 2 (2.63%) HER2, 1 (1.32%) BRAF, 2 (2.63%) PIK3CA and 2 (2.63%) FGFR fusion.	('HER2', 'Gene', '2064', (121, 125))	('mutations', 'Var', (56, 65))	('EGFR', 'Gene', (89, 93))	('KRAS', 'Gene', (105, 109))	('KRAS', 'Gene', '3845', (105, 109))	('BRAF, 2', 'Gene', '286494', (137, 144))	('PIK3CA and 2', 'Gene', '5290', (153, 165))	('EGFR', 'Gene', '1956', (89, 93))	('HER2', 'Gene', (121, 125))
522571	27092882	One patient harbored both EGFR and PIK3CA mutations, and another patient had both EGFR and FGFR mutations.	('EGFR', 'Gene', (26, 30))	('EGFR', 'Gene', (82, 86))	('FGFR', 'Gene', (91, 95))	('patient', 'Species', '9606', (4, 11))	('PIK3CA', 'Gene', (35, 41))	('patient', 'Species', '9606', (65, 72))	('PIK3CA', 'Gene', '5290', (35, 41))	('EGFR', 'Gene', '1956', (26, 30))	('EGFR', 'Gene', '1956', (82, 86))	('mutations', 'Var', (42, 51))
522572	27092882	Among 353 ever-smokers, 39 oncogenic mutations were detected, including 12 (3.40%) EGFR, 5 (1.42%) KRAS, 1 (0.28%) HER2, 1 (0.28%) AKT1, 11 (3.12%) PIK3CA and 11 (3.12%) FGFR fusion.	('EGFR', 'Gene', '1956', (83, 87))	('PIK3CA', 'Gene', '5290', (148, 154))	('HER2', 'Gene', (115, 119))	('oncogenic', 'CPA', (27, 36))	('HER2', 'Gene', '2064', (115, 119))	('EGFR', 'Gene', (83, 87))	('detected', 'Reg', (52, 60))	('AKT1', 'Gene', '207', (131, 135))	('mutations', 'Var', (37, 46))	('FGFR', 'Gene', (170, 174))	('PIK3CA', 'Gene', (148, 154))	('KRAS', 'Gene', (99, 103))	('AKT1', 'Gene', (131, 135))	('KRAS', 'Gene', '3845', (99, 103))
522574	27092882	One patient harbored both EGFR and PIK3CA mutations, and another patient had both KRAS and PIK3CA mutations.	('PIK3CA', 'Gene', (91, 97))	('EGFR', 'Gene', (26, 30))	('PIK3CA', 'Gene', '5290', (91, 97))	('patient', 'Species', '9606', (4, 11))	('PIK3CA', 'Gene', (35, 41))	('patient', 'Species', '9606', (65, 72))	('EGFR', 'Gene', '1956', (26, 30))	('PIK3CA', 'Gene', '5290', (35, 41))	('KRAS', 'Gene', (82, 86))	('KRAS', 'Gene', '3845', (82, 86))	('mutations', 'Var', (42, 51))
522575	27092882	As shown in Table 2, SQCCs in never-smokers harbored significantly more oncogenic mutations than those in ever-smokers (21.05% vs. 11.05%, P = 0.023), especially EGFR mutations (13.16% vs. 3.40%, P = 0.001).	('oncogenic mutations', 'CPA', (72, 91))	('SQCC', 'Phenotype', 'HP:0002860', (21, 25))	('EGFR', 'Gene', '1956', (162, 166))	('EGFR', 'Gene', (162, 166))	('mutations', 'Var', (167, 176))
522576	27092882	Among the 76 SQCCs from never-smokers, there were no statistically significant correlations with respect to gender, age, history of malignant diseases, tumor location, smoking status, pTNM stage or tumor differentiation between patients with EGFR wild-type and those with the mutant gene (Table 3).	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('SQCC', 'Phenotype', 'HP:0002860', (13, 17))	('TNM', 'Gene', '10178', (185, 188))	('malignant diseases', 'Disease', (132, 150))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('patients', 'Species', '9606', (228, 236))	('tumor', 'Disease', (152, 157))	('EGFR', 'Gene', '1956', (242, 246))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('TNM', 'Gene', (185, 188))	('mutant', 'Var', (276, 282))	('EGFR', 'Gene', (242, 246))	('tumor', 'Disease', (198, 203))	('malignant diseases', 'Disease', 'MESH:D009369', (132, 150))
522582	27092882	For lung ADCs, driver mutations to EGFR, KRAS, HER2, BRAF and AKT1 have been well reported, and considerable progress has been made in their treatment.	('KRAS', 'Gene', '3845', (41, 45))	('BRAF', 'Gene', '673', (53, 57))	('AKT1', 'Gene', '207', (62, 66))	('BRAF', 'Gene', (53, 57))	('HER2', 'Gene', (47, 51))	('AKT1', 'Gene', (62, 66))	('EGFR', 'Gene', (35, 39))	('EGFR', 'Gene', '1956', (35, 39))	('HER2', 'Gene', '2064', (47, 51))	('mutations', 'Var', (22, 31))	('KRAS', 'Gene', (41, 45))	('lung ADCs', 'Disease', (4, 13))
522585	27092882	Oncogenic mutations, especially EGFR mutations, occurred considerably more frequently in the never-smokers, which is consistent with findings from an earlier study.	('mutations', 'Var', (37, 46))	('Oncogenic', 'CPA', (0, 9))	('EGFR', 'Gene', '1956', (32, 36))	('EGFR', 'Gene', (32, 36))
522586	27092882	Controversy remains as to whether lung SQCCs actually harbor EGFR mutations.	('mutations', 'Var', (66, 75))	('SQCC', 'Phenotype', 'HP:0002860', (39, 43))	('harbor', 'Reg', (54, 60))	('EGFR', 'Gene', '1956', (61, 65))	('EGFR', 'Gene', (61, 65))	('lung SQCCs', 'Disease', (34, 44))
522587	27092882	In a study where lung SQCCs were identified based biomarker expression, EGFR mutations were absent, suggesting SQCCs found to contain EGFR mutations were actually misdiagnosed poorly differentiated ADCs or adenosquamous carcinoma.	('SQCC', 'Phenotype', 'HP:0002860', (22, 26))	('EGFR', 'Gene', (134, 138))	('mutations', 'Var', (139, 148))	('EGFR', 'Gene', '1956', (72, 76))	('poorly differentiated ADCs', 'Disease', (176, 202))	('SQCC', 'Phenotype', 'HP:0002860', (111, 115))	('EGFR', 'Gene', (72, 76))	('adenosquamous carcinoma', 'Disease', 'MESH:D018196', (206, 229))	('adenosquamous carcinoma', 'Disease', (206, 229))	('carcinoma', 'Phenotype', 'HP:0030731', (220, 229))	('EGFR', 'Gene', '1956', (134, 138))
522588	27092882	A previous study from our institution demonstrated that EGFR mutations were extremely rare or absent in patients with pure SQCC, whereas EGFR mutations occurred frequently in SQCCs with a minor glandular component (SQCC-mGC), and most SQCC-mGCs were diagnosed in never-smokers.	('EGFR', 'Gene', (137, 141))	('mutations', 'Var', (142, 151))	('SQCC', 'Phenotype', 'HP:0002860', (175, 179))	('EGFR', 'Gene', '1956', (56, 60))	('mutations', 'Var', (61, 70))	('EGFR', 'Gene', (56, 60))	('EGFR', 'Gene', '1956', (137, 141))	('SQCC', 'Phenotype', 'HP:0002860', (215, 219))	('SQCC', 'Phenotype', 'HP:0002860', (235, 239))	('patients', 'Species', '9606', (104, 112))	('SQCC', 'Phenotype', 'HP:0002860', (123, 127))
522589	27092882	That said, other studies showed that EGFR mutations were also present in pure SQCCs, especially in females and never-smokers.	('present', 'Reg', (62, 69))	('SQCCs', 'Disease', (78, 83))	('EGFR', 'Gene', '1956', (37, 41))	('EGFR', 'Gene', (37, 41))	('mutations', 'Var', (42, 51))	('SQCC', 'Phenotype', 'HP:0002860', (78, 82))
522590	27092882	showed that EGFR mutations were present in both adenocarcinomatous and squamous cell carcinomatous components of tumors, and were more commonly detected in never-smokers.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (71, 94))	('EGFR', 'Gene', '1956', (12, 16))	('present', 'Reg', (32, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (53, 62))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('adenocarcinomatous and squamous cell carcinomatous components of tumors', 'Disease', 'MESH:D002294', (48, 119))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('EGFR', 'Gene', (12, 16))	('mutations', 'Var', (17, 26))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
522591	27092882	In our present study, 7 of 10 (70.0%) SQCCs from never-smokers carried EGFR mutations, and 7 of 12 (58.3%) SQCCs with EGFR mutations from ever-smokers had minor glandular components.	('mutations', 'Var', (76, 85))	('SQCC', 'Phenotype', 'HP:0002860', (38, 42))	('SQCC', 'Phenotype', 'HP:0002860', (107, 111))	('EGFR', 'Gene', '1956', (71, 75))	('EGFR', 'Gene', '1956', (118, 122))	('EGFR', 'Gene', (118, 122))	('EGFR', 'Gene', (71, 75))
522592	27092882	This suggests a relation between the glandular component and EGFR mutations in lung SQCCs.	('mutations', 'Var', (66, 75))	('lung SQCCs', 'Disease', (79, 89))	('SQCC', 'Phenotype', 'HP:0002860', (84, 88))	('EGFR', 'Gene', '1956', (61, 65))	('EGFR', 'Gene', (61, 65))
522597	27092882	However, the impact of passive smoking on the incidence of SQCCs and EGFR mutations in never-smokers is not yet clear [30, 31].	('EGFR', 'Gene', '1956', (69, 73))	('SQCC', 'Phenotype', 'HP:0002860', (59, 63))	('EGFR', 'Gene', (69, 73))	('mutations', 'Var', (74, 83))	('SQCCs', 'Disease', (59, 64))
522598	27092882	In our study, two patients with EGFR mutations were treated with EGFR-TKIs, but the efficacy is unclear.	('EGFR', 'Gene', '1956', (65, 69))	('EGFR', 'Gene', (65, 69))	('EGFR', 'Gene', '1956', (32, 36))	('mutations', 'Var', (37, 46))	('EGFR', 'Gene', (32, 36))	('patients', 'Species', '9606', (18, 26))
522599	27092882	Consequently, determination of whether EGFR-TKIs are a useful treatment for SQCCs with EGFR mutations in never-smokers will require further study.	('SQCCs', 'Disease', (76, 81))	('EGFR', 'Gene', '1956', (87, 91))	('EGFR', 'Gene', (87, 91))	('mutations', 'Var', (92, 101))	('SQCC', 'Phenotype', 'HP:0002860', (76, 80))	('EGFR', 'Gene', '1956', (39, 43))	('EGFR', 'Gene', (39, 43))
522600	27092882	In sum, our study revealed SQCCs in never-smokers to be a distinct subtype that occurs disproportionally in females and is characterized by poor tumor differentiation and relatively high frequency of EGFR mutations along with other known oncogenic mutations.	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('SQCC', 'Phenotype', 'HP:0002860', (27, 31))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('mutations', 'Var', (205, 214))	('EGFR', 'Gene', '1956', (200, 204))	('EGFR', 'Gene', (200, 204))	('tumor', 'Disease', (145, 150))	('SQCCs', 'Disease', (27, 32))
522601	27092882	These features may help to identify patients with specific driver mutations for future clinical trials of individualized therapies for lung SQCC.	('mutations', 'Var', (66, 75))	('lung SQCC', 'Disease', (135, 144))	('SQCC', 'Phenotype', 'HP:0002860', (140, 144))	('patients', 'Species', '9606', (36, 44))
522603	27092882	Upon immunohistochemical staining for DeltaNp63 and TTF-1, a DeltaNp63-diffuse/TTF-1-negative profile supported SQCC, while double-positive staining in distinct cell populations supported bi-phenotypic differentiation (adenosquamous carcinoma).	('TTF-1', 'Gene', (79, 84))	('TTF-1', 'Gene', (52, 57))	('TTF-1', 'Gene', '7270', (79, 84))	('adenosquamous carcinoma', 'Disease', 'MESH:D018196', (219, 242))	('TTF-1', 'Gene', '7270', (52, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (233, 242))	('adenosquamous carcinoma', 'Disease', (219, 242))	('DeltaNp63', 'Var', (38, 47))	('SQCC', 'Disease', (112, 116))	('SQCC', 'Phenotype', 'HP:0002860', (112, 116))
522615	27092882	The amplified products were analyzed by direct dideoxynucleoside sequencing, after which Chromas Lite, version 2.4 (Technelysium Pty Ltd) and Vector NTI 11.0 (Life Technologies Corp) were used to detect mutations through comparison with standard gene sequences, as previous reported.	('Chromas Lite', 'Disease', 'None', (89, 101))	('dideoxynucleoside', 'Chemical', 'MESH:D015224', (47, 64))	('mutations', 'Var', (203, 212))	('Chromas Lite', 'Disease', (89, 101))
522627	26523280	The immunoexpression of iNOS is correlated with tumorigenesis and prognosis of OSCC and may serve as a prognostic marker.	('tumor', 'Disease', (48, 53))	('iNOS', 'Gene', (24, 28))	('OSCC', 'Chemical', '-', (79, 83))	('correlated', 'Reg', (32, 42))	('immunoexpression', 'Var', (4, 20))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('OSCC', 'Disease', (79, 83))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('iNOS', 'Gene', '4843', (24, 28))
522642	26523280	In contrast, the mutant p53 protein (mt-p53) loses its original tumor suppressor and becomes a tumor-promoting factor and promotes the process of tumor.	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('tumor', 'Disease', (64, 69))	('p53', 'Gene', (24, 27))	('p53', 'Gene', '7157', (24, 27))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('promotes', 'PosReg', (122, 130))	('protein', 'Protein', (28, 35))	('loses', 'NegReg', (45, 50))	('tumor', 'Disease', (146, 151))	('p53', 'Gene', (40, 43))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('p53', 'Gene', '7157', (40, 43))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('mutant', 'Var', (17, 23))	('tumor', 'Disease', (95, 100))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
522643	26523280	High frequency of mutation in TP53 gene has been shown in a variety of human tumors such as breast, brain, rectum, colon, esophagus, and lung cancers and OSCC.	('lung cancers', 'Disease', 'MESH:D008175', (137, 149))	('breast', 'Disease', (92, 98))	('rectum', 'Disease', (107, 113))	('colon', 'Disease', (115, 120))	('lung cancers', 'Disease', (137, 149))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('TP53', 'Gene', (30, 34))	('lung cancer', 'Phenotype', 'HP:0100526', (137, 148))	('lung cancers', 'Phenotype', 'HP:0100526', (137, 149))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('mutation', 'Var', (18, 26))	('cancers', 'Phenotype', 'HP:0002664', (142, 149))	('human', 'Species', '9606', (71, 76))	('tumors', 'Disease', (77, 83))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('TP53', 'Gene', '7157', (30, 34))	('brain', 'Disease', (100, 105))	('tumors', 'Disease', 'MESH:D009369', (77, 83))	('OSCC', 'Chemical', '-', (154, 158))	('shown', 'Reg', (49, 54))	('OSCC', 'Disease', (154, 158))	('esophagus', 'Disease', (122, 131))
522647	26523280	The majority of previous studies about iNOS and p53 focused on the expression and mutation of p53.	('p53', 'Gene', (48, 51))	('p53', 'Gene', (94, 97))	('p53', 'Gene', '7157', (94, 97))	('mutation', 'Var', (82, 90))	('p53', 'Gene', '7157', (48, 51))	('iNOS', 'Gene', '4843', (39, 43))	('iNOS', 'Gene', (39, 43))
522666	26523280	The Tca8113 cells of OSCC carry TP53 mutation.	('TP53', 'Gene', '7157', (32, 36))	('TP53', 'Gene', (32, 36))	('OSCC', 'Chemical', '-', (21, 25))	('mutation', 'Var', (37, 45))
522693	26523280	The overall survival of patients with positive iNOS expression at 5 years was 38.8%, whereas the overall survival of patients with negative iNOS expression was 80.1% (P < 0.01) (Figure 3(a)).	('iNOS', 'Gene', (140, 144))	('positive', 'Var', (38, 46))	('patients', 'Species', '9606', (117, 125))	('patients', 'Species', '9606', (24, 32))	('expression', 'Var', (52, 62))	('iNOS', 'Gene', (47, 51))	('iNOS', 'Gene', '4843', (47, 51))	('iNOS', 'Gene', '4843', (140, 144))
522696	26523280	Two siRNA sequences (si-1 and si-2) and a negative control (si-NC) of siRNA-iNOS were transfected into Tca8113 cells (Figure 4).	('si-1', 'Var', (21, 25))	('iNOS', 'Gene', (76, 80))	('iNOS', 'Gene', '4843', (76, 80))	('si-2', 'Var', (30, 34))
522699	26523280	However, the expression of p53 was significantly enhanced in response to the silencing of iNOS in Tca8113 cells (P < 0.05) (Figures 6(a) and 6(b)).	('p53', 'Gene', '7157', (27, 30))	('expression', 'MPA', (13, 23))	('enhanced', 'PosReg', (49, 57))	('iNOS', 'Gene', '4843', (90, 94))	('silencing', 'Var', (77, 86))	('iNOS', 'Gene', (90, 94))	('p53', 'Gene', (27, 30))
522700	26523280	Furthermore, the effect of iNOS silencing on Tca8113 cell proliferation was evaluated using Cell Counting Kit-8.	('silencing', 'Var', (32, 41))	('iNOS', 'Gene', (27, 31))	('iNOS', 'Gene', '4843', (27, 31))
522706	26523280	However, mutant p53 proteins gain oncogenic properties favoring the insurgence, the maintenance, and the spreading of malignant tumors.	('oncogenic properties', 'CPA', (34, 54))	('insurgence', 'CPA', (68, 78))	('maintenance', 'CPA', (84, 95))	('mutant', 'Var', (9, 15))	('p53', 'Gene', (16, 19))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('p53', 'Gene', '7157', (16, 19))	('gain', 'PosReg', (29, 33))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('malignant tumors', 'Disease', (118, 134))	('malignant tumors', 'Disease', 'MESH:D018198', (118, 134))	('proteins', 'Protein', (20, 28))
522711	26523280	In this study, we demonstrated for the first time that 5-year survival time of patients with positive iNOS expression was dramatically shorter than that of those with negative iNOS expression in OSCC.	('iNOS', 'Gene', (102, 106))	('OSCC', 'Chemical', '-', (195, 199))	('iNOS', 'Gene', '4843', (176, 180))	('survival time', 'CPA', (62, 75))	('iNOS', 'Gene', (176, 180))	('positive', 'Var', (93, 101))	('expression', 'Var', (107, 117))	('patients', 'Species', '9606', (79, 87))	('iNOS', 'Gene', '4843', (102, 106))	('shorter', 'NegReg', (135, 142))
522715	26523280	It is probably due to the mutation of p53 protein in the late stages of squamous cell carcinoma.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (72, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('p53', 'Gene', (38, 41))	('p53', 'Gene', '7157', (38, 41))	('mutation', 'Var', (26, 34))	('protein', 'Protein', (42, 49))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (72, 95))	('squamous cell carcinoma', 'Disease', (72, 95))
522718	26523280	iNOS is associated with the mutation of p53 in human esophageal squamous cell carcinoma.	('iNOS', 'Gene', '4843', (0, 4))	('iNOS', 'Gene', (0, 4))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('p53', 'Gene', (40, 43))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (53, 87))	('mutation', 'Var', (28, 36))	('associated', 'Reg', (8, 18))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (64, 87))	('p53', 'Gene', '7157', (40, 43))	('human', 'Species', '9606', (47, 52))	('esophageal squamous cell carcinoma', 'Disease', (53, 87))
522723	26523280	Previous studies showed that silencing of mutated p53 led to the decrease of the growth of human lung adenocarcinoma cells.	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (97, 116))	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('mutated', 'Var', (42, 49))	('silencing', 'Var', (29, 38))	('lung adenocarcinoma', 'Disease', (97, 116))	('growth of human', 'CPA', (81, 96))	('p53', 'Gene', (50, 53))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (97, 116))	('decrease', 'NegReg', (65, 73))	('p53', 'Gene', '7157', (50, 53))	('human', 'Species', '9606', (91, 96))
522724	26523280	There is still no report related to the expression of iNOS in response to the silencing of mutated p53, which will be our future objective.	('p53', 'Gene', (99, 102))	('silencing', 'NegReg', (78, 87))	('iNOS', 'Gene', '4843', (54, 58))	('mutated', 'Var', (91, 98))	('p53', 'Gene', '7157', (99, 102))	('iNOS', 'Gene', (54, 58))
522726	26523280	The interaction is not only related to the changes of gene and protein expression, but also to the changes of the nature and function of p53, such as activation and mutations.	('p53', 'Gene', '7157', (137, 140))	('activation', 'PosReg', (150, 160))	('changes', 'Reg', (43, 50))	('gene and', 'MPA', (54, 62))	('function', 'MPA', (125, 133))	('mutations', 'Var', (165, 174))	('p53', 'Gene', (137, 140))
522727	26523280	In the progression of OSCC tumor tissues, p53 expression is increased with the increased expression of iNOS because part of the p53 mutated and become mt-p53, which makes it a tumor-promoting factor.	('OSCC tumor', 'Disease', 'MESH:D009369', (22, 32))	('p53', 'Gene', '7157', (128, 131))	('p53', 'Gene', '7157', (42, 45))	('iNOS', 'Gene', (103, 107))	('p53', 'Gene', (42, 45))	('expression', 'MPA', (89, 99))	('p53', 'Gene', (128, 131))	('iNOS', 'Gene', '4843', (103, 107))	('tumor', 'Disease', (27, 32))	('tumor', 'Disease', (176, 181))	('mutated', 'Var', (132, 139))	('OSCC tumor', 'Disease', (22, 32))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('increased', 'PosReg', (60, 69))	('tumor', 'Disease', 'MESH:D009369', (176, 181))	('p53', 'Gene', '7157', (154, 157))	('expression', 'MPA', (46, 56))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('increased', 'PosReg', (79, 88))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('p53', 'Gene', (154, 157))
522735	26523280	Together, these data further support the concept of inhibiting iNOS as a therapeutic strategy for the treatment of OSCC.	('iNOS', 'Gene', '4843', (63, 67))	('iNOS', 'Gene', (63, 67))	('OSCC', 'Disease', (115, 119))	('inhibiting', 'Var', (52, 62))	('OSCC', 'Chemical', '-', (115, 119))
522741	33664747	Patients with high PDIA5 high-expression benefited from immunotherapies.	('PDIA5', 'Gene', '10954', (19, 24))	('immunotherapies', 'CPA', (56, 71))	('PDIA5', 'Gene', (19, 24))	('Patients', 'Species', '9606', (0, 8))	('high-expression', 'Var', (25, 40))
522764	33664747	Other research has found that PDI inhibition could impair tumorigenic T cells and enhance normal T cell function.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('inhibition', 'Var', (34, 44))	('PDI', 'Gene', (30, 33))	('PDI', 'Gene', '5034', (30, 33))	('impair', 'NegReg', (51, 57))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('enhance', 'PosReg', (82, 89))
522787	33664747	After antigen retrieval and blocking endogenous HRP activity, the slides were blocked with 10% normal goat serum and incubated with primary antibody (anti-PDIA5 antibody human reactivity (D225376, 1:200, Sangon Biotech, China), anti-CD68 E11 human reactivity (SC-17832, 1:400, Santa Cruz, US) at 4 C overnight.	('PDIA5', 'Gene', '10954', (155, 160))	('PDIA5', 'Gene', (155, 160))	('anti-CD68', 'Var', (228, 237))	('human', 'Species', '9606', (170, 175))	('human', 'Species', '9606', (242, 247))
522788	33664747	U251 VCT/PDIA5 and U251 siNC/siPDIA5 were co-cultured with HMC3 GFP in 3D condition.	('PDIA5', 'Gene', (31, 36))	('siNC', 'Disease', (24, 28))	('PDIA5', 'Gene', (9, 14))	('PDIA5', 'Gene', '10954', (9, 14))	('PDIA5', 'Gene', '10954', (31, 36))	('U251', 'Var', (19, 23))	('siNC', 'Disease', 'None', (24, 28))
522796	33664747	It is well-known that several molecular biomarkers, such as isocitrate dehydrogenase (IDH) mutation, 1p/19q codeletion status and O6-methylguanine DNA methyltransferase (MGMT) promoter methylation are related to the malignancy of gliomas.	('IDH', 'Gene', (86, 89))	('O6-methylguanine DNA methyltransferase', 'Gene', (130, 168))	('mutation', 'Var', (91, 99))	('isocitrate dehydrogenase', 'Gene', (60, 84))	('malignancy of gliomas', 'Disease', (216, 237))	('IDH', 'Gene', '3417', (86, 89))	('MGMT', 'Gene', '4255', (170, 174))	('O6-methylguanine DNA methyltransferase', 'Gene', '4255', (130, 168))	('glioma', 'Phenotype', 'HP:0009733', (230, 236))	('MGMT', 'Gene', (170, 174))	('isocitrate dehydrogenase', 'Gene', '3417', (60, 84))	('malignancy of gliomas', 'Disease', 'MESH:D005910', (216, 237))	('gliomas', 'Phenotype', 'HP:0009733', (230, 237))	('related', 'Reg', (201, 208))
522806	33664747	Furthermore, in the IVY GBM dataset, high PDIA5 level was enriched in hyperplastic blood vessels, microvascular proliferation, and peri-necrotic zones compared with other areas (Figure 1F).	('PDIA5', 'Gene', '10954', (42, 47))	('high', 'Var', (37, 41))	('microvascular proliferation', 'CPA', (98, 125))	('hyperplastic blood vessels', 'CPA', (70, 96))	('PDIA5', 'Gene', (42, 47))	('peri-necrotic zones', 'CPA', (131, 150))
522814	33664747	These findings revealed that high PDIA5 expression predicts poor clinical outcomes in multiple cancers.	('high', 'Var', (29, 33))	('expression', 'MPA', (40, 50))	('cancers', 'Phenotype', 'HP:0002664', (95, 102))	('cancers', 'Disease', (95, 102))	('cancers', 'Disease', 'MESH:D009369', (95, 102))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('PDIA5', 'Gene', '10954', (34, 39))	('PDIA5', 'Gene', (34, 39))
522817	33664747	Similarly, high PDIA5 expression was significantly associated with poor prognosis in the CGGA dataset (Supplementary Figure S2I).	('PDIA5', 'Gene', '10954', (16, 21))	('PDIA5', 'Gene', (16, 21))	('expression', 'MPA', (22, 32))	('high', 'Var', (11, 15))
522819	33664747	Regardless of whether IDH was mutated, 1p19q was co-deleted, and MGMT promoter was methylated, low PDIA5 expression was related to a favorable outcome (Supplementary Figures S3A-F), and the same results were obtained in the analysis of chemotherapy and radiotherapy (Supplementary Figures S3G-I).	('MGMT', 'Gene', (65, 69))	('low', 'NegReg', (95, 98))	('MGMT', 'Gene', '4255', (65, 69))	('IDH', 'Gene', (22, 25))	('IDH', 'Gene', '3417', (22, 25))	('PDIA5', 'Gene', (99, 104))	('PDIA5', 'Gene', '10954', (99, 104))	('1p19q', 'Var', (39, 44))	('expression', 'MPA', (105, 115))
522823	33664747	Amplification of chr7 and deletion of chr10 consistently appeared in gliomas with high PDIA5 expression.	('chr10', 'Gene', (38, 43))	('PDIA5', 'Gene', '10954', (87, 92))	('chr7', 'Gene', (17, 21))	('Amplification', 'Var', (0, 13))	('gliomas', 'Disease', (69, 76))	('appeared', 'Reg', (57, 65))	('gliomas', 'Disease', 'MESH:D005910', (69, 76))	('gliomas', 'Phenotype', 'HP:0009733', (69, 76))	('deletion', 'Var', (26, 34))	('glioma', 'Phenotype', 'HP:0009733', (69, 75))	('PDIA5', 'Gene', (87, 92))
522824	33664747	Additionally, 1p/19q codeletion more frequently occurred in gliomas with low PDIA5 expression (Supplementary Figure S4A), and 63 and 30 significant genomic events were discovered in the high and low PDIA5 groups respectively (Supplementary Figure S4B).	('occurred', 'Reg', (48, 56))	('1p/19q codeletion', 'Var', (14, 31))	('gliomas', 'Disease', 'MESH:D005910', (60, 67))	('gliomas', 'Phenotype', 'HP:0009733', (60, 67))	('gliomas', 'Disease', (60, 67))	('PDIA5', 'Gene', (77, 82))	('PDIA5', 'Gene', (199, 204))	('PDIA5', 'Gene', '10954', (77, 82))	('low', 'NegReg', (73, 76))	('PDIA5', 'Gene', '10954', (199, 204))	('glioma', 'Phenotype', 'HP:0009733', (60, 66))
522825	33664747	In the high PDIA5 group, focal amplification peaks, including driver oncogenes such as PIK3C2B (1q32.1), PDGFRA (4q12), EGFR (7p11.2), and CDK4 (12q14.1) were found accompanied by focal deletion peaks for tumor suppressor genes such as CHD5 (1p36.31), CDKN2A/CDKN2B (9p21.3), and PTEN (10q23.31).	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('PDIA5', 'Gene', '10954', (12, 17))	('CDKN2A', 'Gene', '1029', (252, 258))	('CHD5', 'Gene', (236, 240))	('PIK3C2B', 'Gene', '5287', (87, 94))	('CDKN2B', 'Gene', (259, 265))	('10q23.31', 'Var', (286, 294))	('CDK4', 'Gene', (139, 143))	('PTEN', 'Gene', (280, 284))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('EGFR', 'Gene', (120, 124))	('CDK4', 'Gene', '1019', (139, 143))	('CDKN2B', 'Gene', '1030', (259, 265))	('PTEN', 'Gene', '5728', (280, 284))	('PDGFRA', 'Gene', (105, 111))	('CHD5', 'Gene', '26038', (236, 240))	('deletion', 'Var', (186, 194))	('CDKN2A', 'Gene', (252, 258))	('PDIA5', 'Gene', (12, 17))	('tumor', 'Disease', (205, 210))	('EGFR', 'Gene', '1956', (120, 124))	('PIK3C2B', 'Gene', (87, 94))
522827	33664747	In regards to somatic mutations, mutation in TP53 (41%), TTN (25%), PTEN (23%), and EGFR (22%) were identified in the high PDIA5 group, while IDH1 (89%), CIC (45%), and FUBP1 (22%) were detected in the low PDIA5 group (Supplementary Figure S4C).	('TP53', 'Gene', (45, 49))	('TTN', 'Gene', '7273', (57, 60))	('PTEN', 'Gene', (68, 72))	('PDIA5', 'Gene', '10954', (123, 128))	('CIC', 'Disease', (154, 157))	('FUBP1', 'Gene', (169, 174))	('TTN', 'Gene', (57, 60))	('IDH', 'Gene', (142, 145))	('EGFR', 'Gene', '1956', (84, 88))	('PTEN', 'Gene', '5728', (68, 72))	('TP53', 'Gene', '7157', (45, 49))	('PDIA5', 'Gene', (206, 211))	('mutation', 'Var', (33, 41))	('CIC', 'Disease', 'None', (154, 157))	('FUBP1', 'Gene', '8880', (169, 174))	('IDH', 'Gene', '3417', (142, 145))	('PDIA5', 'Gene', '10954', (206, 211))	('EGFR', 'Gene', (84, 88))	('PDIA5', 'Gene', (123, 128))
522829	33664747	Moreover, in combination analysis of LGG and GBM, we observed PDIA5 expression was higher in the PDIA5 copy number gain group relative to the other two groups (Supplementary Figure S5B).	('PDIA5', 'Gene', '10954', (62, 67))	('PDIA5', 'Gene', (62, 67))	('PDIA5', 'Gene', '10954', (97, 102))	('PDIA5', 'Gene', (97, 102))	('expression', 'MPA', (68, 78))	('S5B', 'Gene', '5711', (181, 184))	('S5B', 'Gene', (181, 184))	('gain', 'PosReg', (115, 119))	('higher', 'PosReg', (83, 89))	('copy number', 'Var', (103, 114))
522851	33664747	Finally, patients with high PDIA5 and CD68, high combined expression of PDIA5 and CD68 group, and high ratio of PDIA5 to CD68 group experienced shorter OS (Supplementary Figures S8B-D).	('PDIA5', 'Gene', '10954', (28, 33))	('patients', 'Species', '9606', (9, 17))	('combined', 'Interaction', (49, 57))	('high', 'Var', (23, 27))	('shorter', 'NegReg', (144, 151))	('PDIA5', 'Gene', '10954', (72, 77))	('PDIA5', 'Gene', (112, 117))	('CD68', 'Var', (38, 42))	('PDIA5', 'Gene', '10954', (112, 117))	('CD68', 'Gene', (82, 86))	('PDIA5', 'Gene', (28, 33))	('PDIA5', 'Gene', (72, 77))
522866	33664747	Finally, the results of GO enrichment analysis (Supplementary Table S3, S4, S5) and KEGG pathway analysis (Supplementary Table S6, S7, S8) in regards to PDIA5 in neoplastic cells and macrophages is shown in Supplementary Figures S9D-F and S10D-F.	('KEGG pathway', 'Pathway', (84, 96))	('PDIA5', 'Gene', (153, 158))	('PDIA5', 'Gene', '10954', (153, 158))	('S9D-F', 'Var', (229, 234))	('S10D', 'Mutation', 'p.S10D', (239, 243))	('S10D-F', 'Var', (239, 245))
522874	33664747	Furthermore, knock-down PDIA5 presented the malignant behavior decreasing of glioma cells in immune cells exhausting.	('knock-down', 'Var', (13, 23))	('glioma', 'Phenotype', 'HP:0009733', (77, 83))	('malignant behavior', 'CPA', (44, 62))	('glioma', 'Disease', (77, 83))	('decreasing', 'NegReg', (63, 73))	('glioma', 'Disease', 'MESH:D005910', (77, 83))	('PDIA5', 'Gene', '10954', (24, 29))	('PDIA5', 'Gene', (24, 29))
522886	33664747	In the anti-PD-L1 cohort (IMvigor210), we observed that patients with high PDIA5 experienced significant clinical survival benefits (Figure 8A).	('patients', 'Species', '9606', (56, 64))	('PD-L1', 'Gene', (12, 17))	('clinical survival', 'CPA', (105, 122))	('benefits', 'PosReg', (123, 131))	('PD-L1', 'Gene', '29126', (12, 17))	('PDIA5', 'Gene', '10954', (75, 80))	('PDIA5', 'Gene', (75, 80))	('high', 'Var', (70, 74))
522888	33664747	In the anti-PD-L1 cohort, the percentages of complete response (CR) and progressive disease (PD) were 19.35 and 39.44% in the high PDIA5 group, respectively, and 6.7 and 58.64% in the low PDIA5 group, respectively.	('PD-L1', 'Gene', (12, 17))	('progressive disease', 'Disease', 'MESH:D018450', (72, 91))	('PDIA5', 'Gene', (131, 136))	('progressive disease', 'Disease', (72, 91))	('PDIA5', 'Gene', '10954', (131, 136))	('PD-L1', 'Gene', '29126', (12, 17))	('high', 'Var', (126, 130))	('PDIA5', 'Gene', (188, 193))	('PDIA5', 'Gene', '10954', (188, 193))	('complete', 'Disease', (45, 53))
522889	33664747	And the proportion of high PDIA5 expression in CR group and PD group were 35.93 and 11.56%, respectively.	('high', 'Var', (22, 26))	('PDIA5', 'Gene', '10954', (27, 32))	('PDIA5', 'Gene', (27, 32))	('expression', 'MPA', (33, 43))
522893	33664747	And the proportion of high PDIA5 expression in CR group, PD group, and PR group were 100, 84.35, and 94.84%, respectively (Figure 8I).	('high', 'Var', (22, 26))	('PDIA5', 'Gene', '10954', (27, 32))	('PDIA5', 'Gene', (27, 32))	('expression', 'MPA', (33, 43))
522899	33664747	Genomic alterations in gliomas are able to predict disease classification and prognosis.	('glioma', 'Phenotype', 'HP:0009733', (23, 29))	('gliomas', 'Disease', (23, 30))	('gliomas', 'Disease', 'MESH:D005910', (23, 30))	('gliomas', 'Phenotype', 'HP:0009733', (23, 30))	('Genomic alterations', 'Var', (0, 19))	('predict', 'Reg', (43, 50))
522902	33664747	These results suggest that high PDIA5 expression plays an important role in glioma infiltration.	('expression', 'MPA', (38, 48))	('glioma infiltration', 'Disease', 'MESH:D005910', (76, 95))	('high', 'Var', (27, 31))	('PDIA5', 'Gene', (32, 37))	('PDIA5', 'Gene', '10954', (32, 37))	('glioma', 'Phenotype', 'HP:0009733', (76, 82))	('glioma infiltration', 'Disease', (76, 95))
522926	33664747	Therefore, we deduced that high expression of PDIA5 may induce macrophage associated immunity, and contribute to M2 polarization of macrophage in gliomas.	('PDIA5', 'Gene', (46, 51))	('macrophage associated immunity', 'CPA', (63, 93))	('gliomas', 'Disease', 'MESH:D005910', (146, 153))	('gliomas', 'Phenotype', 'HP:0009733', (146, 153))	('gliomas', 'Disease', (146, 153))	('contribute', 'Reg', (99, 109))	('PDIA5', 'Gene', '10954', (46, 51))	('induce', 'PosReg', (56, 62))	('high expression', 'Var', (27, 42))	('glioma', 'Phenotype', 'HP:0009733', (146, 152))	('M2 polarization', 'MPA', (113, 128))
522946	33664747	Further predictive analysis based on the existing databases showed that patients with high PDIA5 had high anti-tumor immune activity and were more likely to benefit from immunotherapies in gliomas as well as other tumor types, indicating that inhibition of combined PDIA5 and these immune checkpoints could improve the clinical management of gliomas.	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('PDIA5', 'Gene', '10954', (91, 96))	('gliomas', 'Phenotype', 'HP:0009733', (342, 349))	('PDIA5', 'Gene', '10954', (266, 271))	('gliomas', 'Disease', 'MESH:D005910', (189, 196))	('glioma', 'Phenotype', 'HP:0009733', (189, 195))	('high', 'Var', (86, 90))	('gliomas', 'Phenotype', 'HP:0009733', (189, 196))	('tumor', 'Disease', (111, 116))	('tumor', 'Disease', (214, 219))	('gliomas', 'Disease', (342, 349))	('benefit', 'PosReg', (157, 164))	('high', 'PosReg', (101, 105))	('glioma', 'Phenotype', 'HP:0009733', (342, 348))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumor', 'Disease', 'MESH:D009369', (214, 219))	('PDIA5', 'Gene', (266, 271))	('PDIA5', 'Gene', (91, 96))	('gliomas', 'Disease', 'MESH:D005910', (342, 349))	('gliomas', 'Disease', (189, 196))	('patients', 'Species', '9606', (72, 80))
522950	33664747	Prior evidence implicated that high PD-L1 contributed to immunosuppression but enhanced the response rate to anti-PD-1 therapy in metastatic melanomas and breast cancer.	('melanoma', 'Phenotype', 'HP:0002861', (141, 149))	('breast cancer', 'Phenotype', 'HP:0003002', (155, 168))	('melanomas', 'Phenotype', 'HP:0002861', (141, 150))	('PD-1', 'Gene', '5133', (114, 118))	('PD-L1', 'Gene', (36, 41))	('immunosuppression', 'MPA', (57, 74))	('melanomas and breast cancer', 'Disease', 'MESH:D001943', (141, 168))	('enhanced', 'PosReg', (79, 87))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('PD-L1', 'Gene', '29126', (36, 41))	('high', 'Var', (31, 35))	('PD-1', 'Gene', (114, 118))	('response rate', 'MPA', (92, 105))
522962	29854282	LSCC SNP variant regulates SOX2 modulation of VDAC3 Lung squamous cell carcinoma (LSCC) is a genomically complex malignancy with no effective treatments.	('malignancy', 'Disease', (113, 123))	('variant', 'Var', (9, 16))	('Lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (52, 80))	('malignancy', 'Disease', 'MESH:D009369', (113, 123))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (57, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (57, 80))	('squamous cell carcinoma', 'Disease', (57, 80))	('SOX2', 'Gene', (27, 31))	('SOX2', 'Gene', '6657', (27, 31))
522965	29854282	To study the downstream mechanisms of SOX2, we employed expression quantitative trait loci (eQTLs) technology to investigate how the presence of SOX2 affects the expression of target genes.	('SOX2', 'Gene', (38, 42))	('affects', 'Reg', (150, 157))	('SOX2', 'Gene', (145, 149))	('SOX2', 'Gene', '6657', (145, 149))	('expression', 'MPA', (162, 172))	('presence', 'Var', (133, 141))	('SOX2', 'Gene', '6657', (38, 42))
522967	29854282	SNP rs798827 is within strong linkage disequilibrium (r2 = 1) to rs58163073, where rs58163073 [T] allele increases the binding affinity of SOX2 and allele [TA] decreases it.	('rs58163073 [', 'Var', (83, 95))	('SOX2', 'Gene', '6657', (139, 143))	('SOX2', 'Gene', (139, 143))	('decreases', 'NegReg', (160, 169))	('rs58163073', 'Mutation', 'rs58163073', (65, 75))	('rs58163073', 'Mutation', 'rs58163073', (83, 93))	('rs798827', 'Mutation', 'rs798827', (4, 12))	('increases', 'PosReg', (105, 114))	('binding', 'Interaction', (119, 126))
522968	29854282	In our analysis, SOX2 silencing downregulates VDAC3 in two LSCC cell lines.	('downregulates', 'NegReg', (32, 45))	('silencing', 'Var', (22, 31))	('SOX2', 'Gene', (17, 21))	('VDAC3', 'Gene', '7419', (46, 51))	('SOX2', 'Gene', '6657', (17, 21))	('VDAC3', 'Gene', (46, 51))
522969	29854282	Chromatin conformation capturing data indicates that this SNP is located within the same Topologically Associating Domain (TAD) of VDAC3, further suggesting SOX2's role in the regulation of VDAC3 through the binding of rs58163073.	('VDAC3', 'Gene', (131, 136))	('VDAC3', 'Gene', (190, 195))	('rs58163073', 'Mutation', 'rs58163073', (219, 229))	('VDAC3', 'Gene', '7419', (131, 136))	('VDAC3', 'Gene', '7419', (190, 195))	('SOX2', 'Gene', (157, 161))	('SOX2', 'Gene', '6657', (157, 161))	('binding', 'Interaction', (208, 215))	('rs58163073', 'Var', (219, 229))
522975	29854282	The most notable alteration is amplification of chromosome 3q, which contains the SOX2 locus.	('SOX2', 'Gene', (82, 86))	('amplification', 'Var', (31, 44))	('SOX2', 'Gene', '6657', (82, 86))
522980	29854282	Therefore, some SNPs, especially those located in SOX2 binding sequences, can alter SOX2's binding affinity to DNA.	('alter', 'Reg', (78, 83))	('SNPs', 'Var', (16, 20))	('SOX2', 'Gene', '6657', (50, 54))	('DNA', 'Protein', (111, 114))	('SOX2', 'Gene', '6657', (84, 88))	('SOX2', 'Gene', (50, 54))	('SOX2', 'Gene', (84, 88))	('binding', 'Interaction', (91, 98))
522988	29854282	Patients were first divided into two groups: SOX2-active and SOX2-inactive based on their gene expression, copy number variation, methylation of SOX2.	('methylation', 'Var', (130, 141))	('SOX2', 'Gene', (145, 149))	('SOX2', 'Gene', '6657', (145, 149))	('Patients', 'Species', '9606', (0, 8))	('copy number variation', 'Var', (107, 128))	('SOX2', 'Gene', (61, 65))	('SOX2', 'Gene', '6657', (61, 65))	('SOX2', 'Gene', '6657', (45, 49))	('SOX2', 'Gene', (45, 49))
522991	29854282	Patients with activated SOX2 met all three of the following criteria (Figure 2A-2C): 1) SOX2 expression values greater than the mean (log2expression values > 10.87797) 2) SOX2 copy number variation is duplicated compared to normal (segment means > 0.5) 3) SOX2 promoter region is hypomethylated (methylation beta-values <=0.4) Patients that did not meet all three criteria are considered as SOX2 inactive.	('SOX2', 'Gene', (24, 28))	('Patients', 'Species', '9606', (327, 335))	('SOX2', 'Gene', '6657', (256, 260))	('SOX2', 'Gene', '6657', (88, 92))	('hypomethylated', 'Var', (280, 294))	('Patients', 'Species', '9606', (0, 8))	('SOX2', 'Gene', '6657', (391, 395))	('SOX2', 'Gene', (88, 92))	('SOX2', 'Gene', (256, 260))	('SOX2', 'Gene', (171, 175))	('SOX2', 'Gene', '6657', (171, 175))	('SOX2', 'Gene', '6657', (24, 28))	('SOX2', 'Gene', (391, 395))
522993	29854282	Out of the 366 patients, 219 had high SOX2 expression, 212 had SOX2 copy number amplification, and 292 patients had SOX2 hypomethylation.	('SOX2', 'Gene', (63, 67))	('SOX2', 'Gene', (38, 42))	('high', 'MPA', (33, 37))	('patients', 'Species', '9606', (15, 23))	('SOX2', 'Gene', '6657', (63, 67))	('SOX2', 'Gene', (116, 120))	('SOX2', 'Gene', '6657', (116, 120))	('patients', 'Species', '9606', (103, 111))	('copy number amplification', 'Var', (68, 93))	('SOX2', 'Gene', '6657', (38, 42))
523001	29854282	Of the large number of SNP-gene pairs from our Matrix eQTL analysis, 8,546 SOX2-active and 8,956 SOX2-inactive pairs contained a gene that is downregulated upon silencing SOX2.	('SOX2', 'Gene', '6657', (97, 101))	('SOX2', 'Gene', (97, 101))	('SOX2', 'Gene', (171, 175))	('downregulated', 'NegReg', (142, 155))	('SOX2', 'Gene', (75, 79))	('silencing', 'Var', (161, 170))	('SOX2', 'Gene', '6657', (75, 79))	('SOX2', 'Gene', '6657', (171, 175))
523002	29854282	For example, patients with active SOX2, the genotypes for SNP rs798827 is significantly correlated with the expression of the gene VDAC3 (FDR p-value = 0.0034), where allele G is correlated with lower expression of VDAC3, and allele T is correlated with higher expression of VDAC3.	('VDAC3', 'Gene', (131, 136))	('VDAC3', 'Gene', '7419', (215, 220))	('correlated', 'Reg', (88, 98))	('VDAC3', 'Gene', (215, 220))	('lower', 'NegReg', (195, 200))	('patients', 'Species', '9606', (13, 21))	('higher', 'PosReg', (254, 260))	('rs798827', 'Var', (62, 70))	('expression', 'MPA', (261, 271))	('VDAC3', 'Gene', '7419', (275, 280))	('VDAC3', 'Gene', '7419', (131, 136))	('VDAC3', 'Gene', (275, 280))	('expression', 'MPA', (201, 211))	('SOX2', 'Gene', '6657', (34, 38))	('rs798827', 'Mutation', 'rs798827', (62, 70))	('SOX2', 'Gene', (34, 38))
523003	29854282	Not only that, but VDAC3 is downregulated upon SOX2 silencing in two LSCC cell lines.	('VDAC3', 'Gene', (19, 24))	('silencing', 'Var', (52, 61))	('downregulated', 'NegReg', (28, 41))	('SOX2', 'Gene', '6657', (47, 51))	('SOX2', 'Gene', (47, 51))	('VDAC3', 'Gene', '7419', (19, 24))
523006	29854282	Among the 16 SNP-gene pairs in SOX2 active patients that were not in SOX2 inactive patients, SNP rs798827 to gene VDAC3 pair caught our interest (Table 1).	('rs798827', 'Mutation', 'rs798827', (97, 105))	('SOX2', 'Gene', (69, 73))	('SOX2', 'Gene', (31, 35))	('SOX2', 'Gene', '6657', (69, 73))	('SOX2', 'Gene', '6657', (31, 35))	('patients', 'Species', '9606', (43, 51))	('SNP rs798827', 'Var', (93, 105))	('VDAC3', 'Gene', '7419', (114, 119))	('patients', 'Species', '9606', (83, 91))	('VDAC3', 'Gene', (114, 119))
523008	29854282	It was also found to be downregulated upon SOX2 silencing in two LSCC cell lines (Figure 3B).	('downregulated', 'NegReg', (24, 37))	('silencing', 'Var', (48, 57))	('SOX2', 'Gene', (43, 47))	('SOX2', 'Gene', '6657', (43, 47))
523009	29854282	Not only is the expression of VDAC3 significantly higher in SOX2 active patients when compared to SOX2 inactive patients (p = 0.0031), the expression of VDAC3 is also correlated with the genotype of SNP rs798827 in SOX2 active patients, but not in SOX2 inactive patients (ANOVA t-test p < 0.05) (Figure 4A and 4B).	('VDAC3', 'Gene', '7419', (30, 35))	('SOX2', 'Gene', '6657', (98, 102))	('rs798827', 'Var', (203, 211))	('SOX2', 'Gene', (98, 102))	('rs798827', 'Mutation', 'rs798827', (203, 211))	('VDAC3', 'Gene', (153, 158))	('SOX2', 'Gene', '6657', (248, 252))	('SOX2', 'Gene', (248, 252))	('SOX2', 'Gene', '6657', (215, 219))	('correlated', 'Reg', (167, 177))	('SOX2', 'Gene', (215, 219))	('VDAC3', 'Gene', '7419', (153, 158))	('expression', 'MPA', (16, 26))	('patients', 'Species', '9606', (227, 235))	('SNP', 'Var', (199, 202))	('higher', 'PosReg', (50, 56))	('VDAC3', 'Gene', (30, 35))	('patients', 'Species', '9606', (112, 120))	('SOX2', 'Gene', '6657', (60, 64))	('SOX2', 'Gene', (60, 64))	('expression', 'MPA', (139, 149))	('patients', 'Species', '9606', (262, 270))	('patients', 'Species', '9606', (72, 80))
523010	29854282	The T genotype of rs798827 correlated with a significantly higher expression of VDAC3 than the G genotype.	('expression', 'MPA', (66, 76))	('higher', 'PosReg', (59, 65))	('rs798827', 'Var', (18, 26))	('VDAC3', 'Gene', '7419', (80, 85))	('VDAC3', 'Gene', (80, 85))	('rs798827', 'Mutation', 'rs798827', (18, 26))
523020	29854282	The SNP from rs798827-VDAC3 pair is within a strong LD to SNP rs58163073.	('VDAC3', 'Gene', '7419', (22, 27))	('rs58163073', 'Var', (62, 72))	('VDAC3', 'Gene', (22, 27))	('rs798827', 'Mutation', 'rs798827', (13, 21))	('rs58163073', 'Mutation', 'rs58163073', (62, 72))
523021	29854282	The flanking sequences of LD SNP rs58163073 make up the SOX2 binding motif and the SNP genotype modified the position weight matrix score.	('SOX2', 'Gene', (56, 60))	('rs58163073', 'Var', (33, 43))	('rs58163073', 'Mutation', 'rs58163073', (33, 43))	('SOX2', 'Gene', '6657', (56, 60))
523023	29854282	The [T] allele of rs58163073 is linked to the [T] allele of rs798827 which is correlated with a higher expression of VDAC3.	('rs798827', 'Var', (60, 68))	('expression', 'MPA', (103, 113))	('rs58163073', 'Var', (18, 28))	('rs798827', 'Mutation', 'rs798827', (60, 68))	('VDAC3', 'Gene', '7419', (117, 122))	('rs58163073', 'Mutation', 'rs58163073', (18, 28))	('VDAC3', 'Gene', (117, 122))	('higher', 'PosReg', (96, 102))
523029	29854282	The location of VDAC3 and SNP rs58163073 are indicated.	('VDAC3', 'Gene', '7419', (16, 21))	('rs58163073', 'Var', (30, 40))	('VDAC3', 'Gene', (16, 21))	('rs58163073', 'Mutation', 'rs58163073', (30, 40))
523030	29854282	From analyzing Hi-C maps of lung cell lines (normal and cancer) and lung tissues, we have confirmed that VDAC3 and rs58163073 are located within the same TAD.	('VDAC3', 'Gene', '7419', (105, 110))	('VDAC3', 'Gene', (105, 110))	('rs58163073', 'Var', (115, 125))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('Hi-C', 'Chemical', '-', (15, 19))	('rs58163073', 'Mutation', 'rs58163073', (115, 125))	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))
523031	29854282	Minor allele frequencies (MAF) of rs798827 and rs58163073 varied by race, with Black or African Americans more likely to carry the minor alleles than Whites and Asians.	('rs798827', 'Var', (34, 42))	('rs58163073', 'Var', (47, 57))	('rs58163073', 'Mutation', 'rs58163073', (47, 57))	('rs798827', 'Mutation', 'rs798827', (34, 42))
523036	29854282	Patients with the minor allele had tumor more predominantly located on the right lungs (24 % left and 76% right, chi-square test 0.007461) Figure 8C.	('tumor', 'Disease', 'MESH:D009369', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('tumor', 'Disease', (35, 40))	('Patients', 'Species', '9606', (0, 8))	('minor', 'Var', (18, 23))
523039	29854282	First, LSCC patients were separated into two groups: SOX2-active and SOX2-inactive based on their SOX2 gene expression, copy number variation, and methylation.	('SOX2', 'Gene', (69, 73))	('patients', 'Species', '9606', (12, 20))	('copy number variation', 'Var', (120, 141))	('SOX2', 'Gene', '6657', (69, 73))	('methylation', 'Var', (147, 158))	('LSCC', 'Disease', (7, 11))	('SOX2', 'Gene', '6657', (53, 57))	('SOX2', 'Gene', '6657', (98, 102))	('SOX2', 'Gene', (53, 57))	('SOX2', 'Gene', (98, 102))
523044	29854282	The genotype of rs798827 is significantly correlated to the expression of VDAC3 in SOX2-active patients but not in SOX2-inactive patients.	('expression', 'MPA', (60, 70))	('SOX2', 'Gene', (83, 87))	('VDAC3', 'Gene', (74, 79))	('SOX2', 'Gene', '6657', (83, 87))	('patients', 'Species', '9606', (95, 103))	('rs798827', 'Var', (16, 24))	('patients', 'Species', '9606', (129, 137))	('SOX2', 'Gene', (115, 119))	('rs798827', 'Mutation', 'rs798827', (16, 24))	('SOX2', 'Gene', '6657', (115, 119))	('correlated', 'Reg', (42, 52))	('VDAC3', 'Gene', '7419', (74, 79))
523045	29854282	Since SOX2 is a transcription factor that binds to specific regions of the genome, variations in the binding sequences may alter the binding affinity of SOX2 to that region.	('SOX2', 'Gene', '6657', (6, 10))	('SOX2', 'Gene', '6657', (153, 157))	('SOX2', 'Gene', (153, 157))	('alter', 'Reg', (123, 128))	('variations', 'Var', (83, 93))	('binding affinity', 'Interaction', (133, 149))	('SOX2', 'Gene', (6, 10))
523046	29854282	We found that rs798827 is within strong LD to SNP rs58163073 and motif analysis indicates that SNP rs58163073 is located within the binding motif of SOX2.	('SNP rs58163073', 'Var', (95, 109))	('rs58163073', 'Mutation', 'rs58163073', (50, 60))	('SOX2', 'Gene', '6657', (149, 153))	('rs58163073', 'Mutation', 'rs58163073', (99, 109))	('SOX2', 'Gene', (149, 153))	('SNP', 'Gene', (46, 49))	('rs58163073', 'Var', (50, 60))	('rs798827', 'Var', (14, 22))	('rs798827', 'Mutation', 'rs798827', (14, 22))
523047	29854282	The [T] allele of SNP rs58163073 increased the position weight matrix score for SOX2 and the [TA] allele decreased it.	('SOX2', 'Gene', (80, 84))	('SOX2', 'Gene', '6657', (80, 84))	('position weight matrix score', 'MPA', (47, 75))	('increased', 'PosReg', (33, 42))	('rs58163073', 'Var', (22, 32))	('SNP rs58163073', 'Var', (18, 32))	('decreased', 'NegReg', (105, 114))	('rs58163073', 'Mutation', 'rs58163073', (22, 32))
523048	29854282	This SNP directly alter the binding sequence of SOX2 and the [T] allele increased its binding affinity.	('SOX2', 'Gene', '6657', (48, 52))	('SOX2', 'Gene', (48, 52))	('increased', 'PosReg', (72, 81))	('[T] allele', 'Var', (61, 71))	('binding', 'Interaction', (86, 93))	('binding', 'Interaction', (28, 35))	('alter', 'Reg', (18, 23))
523052	29854282	SNP rs58163073 and VDAC3 are also located within the same TAD in lung tissues, normal lung, and lung cancer cell lines.	('lung cancer', 'Disease', 'MESH:D008175', (96, 107))	('VDAC3', 'Gene', (19, 24))	('SNP rs58163073', 'Var', (0, 14))	('lung cancer', 'Disease', (96, 107))	('lung cancer', 'Phenotype', 'HP:0100526', (96, 107))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('rs58163073', 'Mutation', 'rs58163073', (4, 14))	('VDAC3', 'Gene', '7419', (19, 24))
523057	29854282	Deletion of VDAC3 significantly increases cell resistance to anti-tumor agent Erastin, which targets VDAC2 and VDAC3.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Disease', (66, 71))	('VDAC3', 'Gene', (12, 17))	('VDAC2', 'Gene', '7417', (101, 106))	('VDAC3', 'Gene', (111, 116))	('VDAC2', 'Gene', (101, 106))	('VDAC3', 'Gene', '7419', (111, 116))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('increases', 'PosReg', (32, 41))	('VDAC3', 'Gene', '7419', (12, 17))	('Deletion', 'Var', (0, 8))
523059	29854282	Collectively, these analyses support the notion that the SNP variant rs58163073 affects the binding of SOX2, which in turn affects SOX2's modulation of target genes such as VDAC3 (Figure 9).	('binding', 'Interaction', (92, 99))	('VDAC3', 'Gene', (173, 178))	('affects', 'Reg', (80, 87))	('SOX2', 'Gene', (103, 107))	('rs58163073', 'Var', (69, 79))	('SOX2', 'Gene', (131, 135))	('affects', 'Reg', (123, 130))	('SOX2', 'Gene', '6657', (131, 135))	('modulation', 'MPA', (138, 148))	('rs58163073', 'Mutation', 'rs58163073', (69, 79))	('VDAC3', 'Gene', '7419', (173, 178))	('SOX2', 'Gene', '6657', (103, 107))
523069	29854282	Only the SNP variants that overlapped the binding motif of SOX2 and changed the position weight matrix (PWM) score were considered.	('position weight matrix', 'MPA', (80, 102))	('variants', 'Var', (13, 21))	('SOX2', 'Gene', (59, 63))	('changed', 'Reg', (68, 75))	('SOX2', 'Gene', '6657', (59, 63))
523078	29854282	Hi-C heat maps resolutions are at 10 kb, 40 kb, 40 kb, and 40 kb respectively, and between 41000000 and 44000000 position on chromosome 8, which is where VDAC3 gene and associated SNPs are located.	('44000000', 'Var', (104, 112))	('VDAC3', 'Gene', '7419', (154, 159))	('Hi-C', 'Chemical', '-', (0, 4))	('VDAC3', 'Gene', (154, 159))
523197	24423398	The CD44+ cells were found to be tumorigenic and differentially expressed the stem cell marker gene BMI1, at both the RNA and protein levels.	('expressed', 'Reg', (64, 73))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('BMI1', 'Gene', '648', (100, 104))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('BMI1', 'Gene', (100, 104))	('tumor', 'Disease', (33, 38))	('CD44+', 'Var', (4, 9))
523200	24423398	OCT-4 is critically involved in the self-renewal of undifferentiated embryonic stem cells as evidenced by the fact that gene knockdown of OCT4 promotes differentiation in human embryonic stem cells.	('OCT4', 'Gene', (138, 142))	('promotes', 'PosReg', (143, 151))	('OCT-4', 'Gene', '5460', (0, 5))	('differentiation', 'CPA', (152, 167))	('OCT-4', 'Gene', (0, 5))	('gene knockdown', 'Var', (120, 134))	('human', 'Species', '9606', (171, 176))
523202	24423398	It is speculated that deregulation of Oct-4 gene may perturb the normal differentiation program and predispose to tumor formation.	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('predispose', 'Reg', (100, 110))	('normal differentiation program', 'CPA', (65, 95))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumor', 'Disease', (114, 119))	('Oct-4', 'Gene', '5460', (38, 43))	('Oct-4', 'Gene', (38, 43))	('perturb', 'NegReg', (53, 60))	('deregulation', 'Var', (22, 34))
523247	24423398	The crucial event in the activation of CREB is the phosphorylation of Ser133 in KID (kinase-inducible domain), which triggers the recruitment of transcriptional co-activators such as CBP and p300.	('p300', 'Gene', '2033', (191, 195))	('CREB', 'Gene', (39, 43))	('CREB', 'Gene', '1385', (39, 43))	('Ser133', 'Chemical', '-', (70, 76))	('recruitment', 'MPA', (130, 141))	('Ser133', 'Var', (70, 76))	('CBP', 'Gene', (183, 186))	('KID', 'Disease', (80, 83))	('CBP', 'Gene', '1387', (183, 186))	('p300', 'Gene', (191, 195))	('phosphorylation', 'MPA', (51, 66))	('KID', 'Disease', 'MESH:C536168', (80, 83))	('triggers', 'Reg', (117, 125))	('activation', 'PosReg', (25, 35))
523266	32516941	Herein, numerous biological facets of NSCLC are described involving driver genetic lesions, mutations ad fusions, PD-L1 glycosylation, ferroptosis and metabolic rewiring in NSCLC and lung adenocarcinoma (LUAD).	('NSCLC', 'Disease', (38, 43))	('PD-L1', 'Gene', (114, 119))	('NSCLC', 'Disease', 'MESH:D002289', (38, 43))	('lung adenocarcinoma', 'Disease', (183, 202))	('genetic lesions', 'Disease', (75, 90))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (183, 202))	('carcinoma', 'Phenotype', 'HP:0030731', (193, 202))	('mutations', 'Var', (92, 101))	('NSCLC', 'Disease', (173, 178))	('NSCLC', 'Disease', 'MESH:D002289', (173, 178))	('genetic lesions', 'Disease', 'MESH:D020022', (75, 90))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (183, 202))
523267	32516941	Novel concepts, such as immune-transmitters and the effect of neurotransmitters in immune evasion and tumor growth, the nascent relevance of necroptosis and pyroptosis, possible new biomarkers, such as gasdermin D and gasdermin E, the conundrum of K-Ras mutations in LUADs, with the growing recognition of liver kinase B1 (LKB1) and metabolic pathways, including others, are also commented.	('gasdermin D', 'Gene', '79792', (202, 213))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('N', 'Chemical', 'MESH:D009584', (0, 1))	('gasdermin D', 'Gene', (202, 213))	('LKB1', 'Gene', (323, 327))	('liver kinase B1', 'Gene', '6794', (306, 321))	('necroptosis and pyroptosis', 'Disease', 'None', (141, 167))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('mutations', 'Var', (254, 263))	('liver kinase B1', 'Gene', (306, 321))
523287	32516941	The recommendations are based on studies with clear information (Impower 130, KEYNOTE 189, KEYNOTE 142, Impower 150 and KEYNOTE 407).	('N', 'Chemical', 'MESH:D009584', (81, 82))	('N', 'Chemical', 'MESH:D009584', (123, 124))	('Impower 130', 'Var', (65, 76))	('Impower 150', 'Var', (104, 115))	('N', 'Chemical', 'MESH:D009584', (94, 95))
523292	32516941	For instance, KRAS mutations co-occur with other alterations and mutations, particularly in serine/threonine kinase 11 (STK11), also known as liver kinase B1 (LKB1), and Kelch-like ECH-associated protein 1 (KEAP1) (see below).	('liver kinase B1', 'Gene', '6794', (142, 157))	('serine/threonine kinase 11', 'Gene', (92, 118))	('STK11', 'Gene', (120, 125))	('liver kinase B1', 'Gene', (142, 157))	('Kelch-like ECH-associated protein 1', 'Gene', '9817', (170, 205))	('KRAS', 'Gene', '3845', (14, 18))	('mutations', 'Var', (19, 28))	('STK11', 'Gene', '6794', (120, 125))	('KEAP1', 'Gene', '9817', (207, 212))	('serine/threonine kinase 11', 'Gene', '6794', (92, 118))	('Kelch-like ECH-associated protein 1', 'Gene', (170, 205))	('KRAS', 'Gene', (14, 18))	('KEAP1', 'Gene', (207, 212))	('mutations', 'Var', (65, 74))
523293	32516941	TP53 mutations can co-occur, at different frequencies, with other driver alterations, including EGFR mutations, KRAS mutations, MET exon 14 skipping mutations, but also ALK and ROS1 rearrangements.	('MET exon', 'Var', (128, 136))	('TP53', 'Gene', '7157', (0, 4))	('ROS1', 'Gene', '6098', (177, 181))	('mutations', 'Var', (101, 110))	('TP53', 'Gene', (0, 4))	('EGFR', 'Gene', (96, 100))	('ALK', 'Gene', '238', (169, 172))	('mutations', 'Var', (5, 14))	('ALK', 'Gene', (169, 172))	('KRAS', 'Gene', (112, 116))	('KRAS', 'Gene', '3845', (112, 116))	('skipping mutations', 'Var', (140, 158))	('ROS1', 'Gene', (177, 181))
523295	32516941	Many attempts have been made with anti-PD-1 and anti-PD-L1 antibodies to improve the response and PFS in NSCLC patients with driver alterations.	('anti-PD-L1', 'Var', (48, 58))	('NSCLC', 'Disease', 'MESH:D002289', (105, 110))	('anti-PD-1', 'Var', (34, 43))	('improve', 'PosReg', (73, 80))	('response', 'MPA', (85, 93))	('NSCLC', 'Disease', (105, 110))	('patients', 'Species', '9606', (111, 119))
523300	32516941	Intriguingly, it has been seen that driver fusions in lung adenocarcinomas co-occur with SETD2 mutations (16% of cases) in contrast with lung adenocarcinomas with EGFR, KRAS, BRAF and MET mutations, where the frequency of SETD2 mutations is only 2%.	('lung adenocarcinomas', 'Disease', (137, 157))	('BRAF', 'Gene', (175, 179))	('BRAF', 'Gene', '673', (175, 179))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (54, 74))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (54, 73))	('KRAS', 'Gene', '3845', (169, 173))	('SETD2', 'Gene', (89, 94))	('mutations', 'Var', (95, 104))	('carcinoma', 'Phenotype', 'HP:0030731', (64, 73))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (54, 74))	('lung adenocarcinomas', 'Disease', (54, 74))	('SETD2', 'Gene', (222, 227))	('KRAS', 'Gene', (169, 173))	('SETD2', 'Gene', '29072', (89, 94))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (137, 157))	('SETD2', 'Gene', '29072', (222, 227))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (137, 156))	('carcinoma', 'Phenotype', 'HP:0030731', (147, 156))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (137, 157))
523302	32516941	SETD2 mutations partly explain the resistance to PD-1 and PD-L1 antibodies in lung adenocarcinomas driven by fusions, making the screening for SETD2 mutations advisable.	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (78, 97))	('SETD2', 'Gene', '29072', (0, 5))	('SETD2', 'Gene', '29072', (143, 148))	('lung adenocarcinomas', 'Disease', (78, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('SETD2', 'Gene', (0, 5))	('SETD2', 'Gene', (143, 148))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (78, 98))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (78, 98))	('mutations', 'Var', (6, 15))
523303	32516941	SETD2 directly methylates signal- transducer and activator of transcription 1 (STAT1) on K525, that is warranted for the activation of STAT1 and the interferon signaling pathway.	('STAT1', 'Gene', (79, 84))	('signal- transducer and activator of transcription 1', 'Gene', '6772', (26, 77))	('interferon', 'Gene', (149, 159))	('STAT1', 'Gene', '6772', (79, 84))	('K525', 'Var', (89, 93))	('SETD2', 'Gene', '29072', (0, 5))	('STAT1', 'Gene', (135, 140))	('STAT1', 'Gene', '6772', (135, 140))	('SETD2', 'Gene', (0, 5))	('methylates', 'Var', (15, 25))	('interferon', 'Gene', '3439', (149, 159))	('activation', 'PosReg', (121, 131))
523305	32516941	Moreover, the interferon signaling hyperactivation can also result in resistance to anti-PD-1 and anti-PD-L1 antibodies, as well as involving auto-immune disease, such as, systemic lupus erythematosus.	('systemic lupus erythematosus', 'Phenotype', 'HP:0002725', (172, 200))	('hyperactivation', 'PosReg', (35, 50))	('interferon', 'Gene', (14, 24))	('auto-immune disease', 'Phenotype', 'HP:0002960', (142, 161))	('anti-PD-1', 'Protein', (84, 93))	('result in', 'Reg', (60, 69))	('anti-PD-L1', 'Var', (98, 108))	('systemic lupus erythematosus', 'Disease', 'MESH:D008180', (172, 200))	('interferon', 'Gene', '3439', (14, 24))	('systemic lupus erythematosus', 'Disease', (172, 200))	('resistance', 'MPA', (70, 80))
523328	32516941	In this review the author explored the activity of many inhibitors, including those of the CME, such as, potassium depletion, hypertonic sucrose, cytosolic acidification, monodansylcadaverine andphenylarsine oxide (PAO).	('potassium depletion', 'MPA', (105, 124))	('cytosolic acidification', 'MPA', (146, 169))	('hypertonic sucrose', 'Disease', (126, 144))	('potassium', 'Chemical', 'MESH:D011188', (105, 114))	('hypertonic sucrose', 'Disease', 'MESH:D009122', (126, 144))	('oxide', 'Chemical', 'MESH:D010087', (208, 213))	('monodansylcadaverine', 'Var', (171, 191))	('PAO', 'Chemical', '-', (215, 218))	('monodansylcadaverine', 'Chemical', 'MESH:C008542', (171, 191))
523331	32516941	Dyngo4a also increases the expression of p-Akt, which is involved in mTOR phosphorylation of PRAS40, a powerful inhibitor of mTORC1 complex.	('increases', 'PosReg', (13, 22))	('mTOR', 'Gene', (69, 73))	('mTOR', 'Gene', '2475', (69, 73))	('mTOR', 'Gene', '2475', (125, 129))	('Akt', 'Gene', '207', (43, 46))	('mTOR', 'Gene', (125, 129))	('expression', 'MPA', (27, 37))	('mTORC1', 'Gene', '382056', (125, 131))	('Akt', 'Gene', (43, 46))	('Dyngo4a', 'Var', (0, 7))	('mTORC1', 'Gene', (125, 131))	('PRAS40', 'Gene', '84335', (93, 99))	('PRAS40', 'Gene', (93, 99))
523336	32516941	The lack of phosphorylation of Akt reduces the activity of Bcl-2/Bcl-X complex and NF-kappaB via apoptosis and gene transcription, respectively.	('Bcl-X', 'Gene', (65, 70))	('Akt', 'Gene', (31, 34))	('reduces', 'NegReg', (35, 42))	('NF-kappaB', 'Gene', '4790', (83, 92))	('gene transcription', 'CPA', (111, 129))	('Bcl-X', 'Gene', '598', (65, 70))	('Akt', 'Gene', '207', (31, 34))	('lack', 'Var', (4, 8))	('NF-kappaB', 'Gene', (83, 92))	('activity', 'MPA', (47, 55))	('Bcl-2', 'Gene', (59, 64))	('Bcl-2', 'Gene', '596', (59, 64))	('apoptosis', 'CPA', (97, 106))
523350	32516941	ID1 overexpression in NSCLC increases mRNA and protein expression of RIPK3 and MLKL.	('RIPK3', 'Gene', (69, 74))	('ID1', 'Gene', (0, 3))	('increases', 'PosReg', (28, 37))	('N', 'Chemical', 'MESH:D009584', (22, 23))	('MLKL', 'Gene', (79, 83))	('MLKL', 'Gene', '197259', (79, 83))	('overexpression', 'Var', (4, 18))	('RIPK3', 'Gene', '11035', (69, 74))	('N', 'Chemical', 'MESH:D009584', (40, 41))	('ID1', 'Gene', '3397', (0, 3))	('NSCLC', 'Disease', (22, 27))	('NSCLC', 'Disease', 'MESH:D002289', (22, 27))
523353	32516941	The loss of LKB1 causes SIK inactivation and the induction of CRTCs, leading to the upregulation of cAMP response element-binding protein (CREB).	('SIK', 'MPA', (24, 27))	('CREB', 'Gene', '1385', (139, 143))	('CRTCs', 'Gene', (62, 67))	('inactivation', 'NegReg', (28, 40))	('upregulation', 'PosReg', (84, 96))	('cAMP response element-binding protein', 'Gene', '1385', (100, 137))	('LKB1', 'Gene', (12, 16))	('cAMP response element-binding protein', 'Gene', (100, 137))	('CREB', 'Gene', (139, 143))	('loss', 'Var', (4, 8))
523357	32516941	It is tempting to speculate that gefitinib could be an ID1 inhibitor in LKB1 mutated KRAS NSCLC tumors (Table 2).	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('ID1', 'Gene', (55, 58))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('KRAS NSCLC tumors', 'Disease', (85, 102))	('mutated', 'Var', (77, 84))	('LKB1', 'Gene', (72, 76))	('gefitinib', 'Chemical', 'MESH:D000077156', (33, 42))	('ID1', 'Gene', '3397', (55, 58))	('KRAS NSCLC tumors', 'Disease', 'MESH:D009369', (85, 102))
523358	32516941	Patients with LKB1 mutations are resistant to PD-1 or PD-L1 monoclonal antibodies.	('LKB1', 'Gene', (14, 18))	('mutations', 'Var', (19, 28))	('Patients', 'Species', '9606', (0, 8))
523360	32516941	Interestingly, beta2-adrenergic receptor (beta2-AR) is activated by neurotransmitters, such as, norepinephrine, in EGFR mutant NSCLC.	('NSCLC', 'Disease', (127, 132))	('beta2-AR', 'Gene', '135', (42, 50))	('NSCLC', 'Disease', 'MESH:D002289', (127, 132))	('beta2-adrenergic receptor', 'Gene', (15, 40))	('beta2-adrenergic receptor', 'Gene', '154', (15, 40))	('EGFR', 'Gene', (115, 119))	('norepinephrine', 'Chemical', 'MESH:D009638', (96, 110))	('mutant', 'Var', (120, 126))	('activated', 'PosReg', (55, 64))	('beta2-AR', 'Gene', (42, 50))
523367	32516941	A gut microbiota-derived metabolite, phenylacetylglutamine (PAGln) was seen to increase the platelet activation and thrombosis.	('increase', 'PosReg', (79, 87))	('thrombosis', 'Disease', 'MESH:D013927', (116, 126))	('phenylacetylglutamine', 'Chemical', 'MESH:C003089', (37, 58))	('platelet activation', 'CPA', (92, 111))	('phenylacetylglutamine', 'Var', (37, 58))	('PAGln', 'Chemical', 'MESH:C003089', (60, 65))	('thrombosis', 'Disease', (116, 126))
523390	32516941	However, GPX4 inhibitors do not always cause cell death in cancer cell lines.	('cancer', 'Disease', (59, 65))	('inhibitors', 'Var', (14, 24))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))
523397	32516941	Furthermore, it has been shown that cGAMP induces autophagy for the clearance of DNA in viruses in the cytosol.	('clearance', 'MPA', (68, 77))	('N', 'Chemical', 'MESH:D009584', (82, 83))	('autophagy', 'CPA', (50, 59))	('cGAMP', 'Var', (36, 41))	('cGAMP', 'Chemical', 'MESH:C584311', (36, 41))
523411	32516941	The findings indicate that TGR5 can also provide information on the effect of anti-PD-1 and anti-PD-L1 monoclonal antibodies.	('TGR5', 'Gene', '151306', (27, 31))	('anti-PD-1', 'Var', (78, 87))	('TGR5', 'Gene', (27, 31))
523415	32516941	Dihydroartemisinin was previously shown to be a STAT3 inhibitor STAT3 is activated in mesenchymal cells, leading to promotion of DNA methyltransferases (DNMTs), which further methylate the promoter region of key molecules in antigen presentation machinery, such as, IRF1, PSMB8, PSMB9 and HLA molecules.	('STAT3', 'Gene', (48, 53))	('PSMB8', 'Gene', '5696', (272, 277))	('N', 'Chemical', 'MESH:D009584', (130, 131))	('PSMB9', 'Gene', '5698', (279, 284))	('STAT3', 'Gene', '6774', (48, 53))	('N', 'Chemical', 'MESH:D009584', (154, 155))	('methylate', 'Var', (175, 184))	('PSMB8', 'Gene', (272, 277))	('PSMB9', 'Gene', (279, 284))	('STAT3', 'Gene', '6774', (64, 69))	('promotion', 'PosReg', (116, 125))	('IRF1', 'Gene', '3659', (266, 270))	('STAT3', 'Gene', (64, 69))	('Dihydroartemisinin', 'Chemical', 'MESH:C039060', (0, 18))	('IRF1', 'Gene', (266, 270))
523418	32516941	We observed that high IFNgamma mRNA levels were an important marker of response to pembrolizumab in melanoma patients, and also an indicator of longer survival in NSCLC patients treated with nivolumab.	('nivolumab', 'Chemical', 'MESH:D000077594', (191, 200))	('patients', 'Species', '9606', (169, 177))	('N', 'Chemical', 'MESH:D009584', (33, 34))	('patients', 'Species', '9606', (109, 117))	('longer', 'PosReg', (144, 150))	('IFNgamma', 'Gene', (22, 30))	('NSCLC', 'Disease', (163, 168))	('high', 'Var', (17, 21))	('IFNgamma', 'Gene', '3458', (22, 30))	('N', 'Chemical', 'MESH:D009584', (24, 25))	('NSCLC', 'Disease', 'MESH:D002289', (163, 168))	('melanoma', 'Phenotype', 'HP:0002861', (100, 108))	('melanoma', 'Disease', (100, 108))	('melanoma', 'Disease', 'MESH:D008545', (100, 108))	('N', 'Chemical', 'MESH:D009584', (163, 164))	('pembrolizumab', 'Chemical', 'MESH:C582435', (83, 96))
523433	32516941	Therapy with elexacaftor-tezacaftor-ivacaftor for cystic fibrosis with CFTR mutations has provided benefit.	('tezacaftor', 'Chemical', 'MESH:C000625213', (25, 35))	('ivacaftor', 'Chemical', 'MESH:C545203', (36, 45))	('CFTR', 'Gene', (71, 75))	('mutations', 'Var', (76, 85))	('cystic fibrosis', 'Disease', (50, 65))	('elexacaftor', 'Chemical', 'MESH:C000629074', (13, 24))	('CFTR', 'Gene', '1080', (71, 75))	('cystic fibrosis', 'Disease', 'MESH:D003550', (50, 65))
523434	32516941	MUC1-C represses RAS association domain family IA (RASSF1A) expression and KRAS wild-type and mutant NSCLC.	('expression', 'MPA', (60, 70))	('RAS', 'Protein', (17, 20))	('NSCLC', 'Disease', (101, 106))	('RASSF1A', 'Gene', (51, 58))	('mutant', 'Var', (94, 100))	('NSCLC', 'Disease', 'MESH:D002289', (101, 106))	('RASSF1A', 'Gene', '11186', (51, 58))	('KRAS', 'Gene', (75, 79))	('MUC1', 'Gene', (0, 4))	('MUC1', 'Gene', '4582', (0, 4))	('KRAS', 'Gene', '3845', (75, 79))
523464	32516941	SHP2 is a critical regulator of RAS MAPK pathway and SHP2 inhibitors have activity in cancers with KRAS mutations and BRAF mutations.	('BRAF', 'Gene', '673', (118, 122))	('SHP2', 'Gene', (0, 4))	('BRAF', 'Gene', (118, 122))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('activity', 'MPA', (74, 82))	('cancers', 'Phenotype', 'HP:0002664', (86, 93))	('SHP2', 'Gene', (53, 57))	('KRAS', 'Gene', (99, 103))	('SHP2', 'Gene', '5781', (53, 57))	('cancers', 'Disease', 'MESH:D009369', (86, 93))	('KRAS', 'Gene', '3845', (99, 103))	('mutations', 'Var', (123, 132))	('cancers', 'Disease', (86, 93))	('SHP2', 'Gene', '5781', (0, 4))
523465	32516941	SHP2 inhibitors could target cancer cells, T lymphocytes, and macrophages simultaneously, and, thereby, could have significant activity in conjunction with anti-PD-1 and anti-PD-L1 antibodies (Table 2).	('SHP2', 'Gene', (0, 4))	('cancer', 'Disease', (29, 35))	('inhibitors', 'Var', (5, 15))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('cancer', 'Disease', 'MESH:D009369', (29, 35))	('activity', 'MPA', (127, 135))	('SHP2', 'Gene', '5781', (0, 4))
523478	32516941	Inhibition of EGF-mediated PD-L1 stabilization enhances the efficacy of PD-1 blockade, promoting tumor-infiltrating cytotoxic T cell immune response.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('promoting', 'PosReg', (87, 96))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('efficacy', 'MPA', (60, 68))	('PD-1', 'Protein', (72, 76))	('enhances', 'PosReg', (47, 55))	('tumor', 'Disease', (97, 102))	('EGF', 'Gene', (14, 17))	('Inhibition', 'Var', (0, 10))	('EGF', 'Gene', '1950', (14, 17))
523486	32516941	Breast and lung cancer patients who had high B3GNT3 expression have poor overall survival.	('high', 'Var', (40, 44))	('patients', 'Species', '9606', (23, 31))	('B3GNT3', 'Gene', '10331', (45, 51))	('lung cancer', 'Phenotype', 'HP:0100526', (11, 22))	('Breast and lung cancer', 'Disease', 'MESH:D001943', (0, 22))	('B3GNT3', 'Gene', (45, 51))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))
523499	32516941	For example, it has been reported that mutated KIT in GIST cell lines accumulated on the trans-side of the Golgi apparatus, where mutated KIT is phosphorylated on Y703, but not on the ER.	('KIT', 'Gene', (138, 141))	('Y703', 'Var', (163, 167))	('KIT', 'Gene', '3815', (47, 50))	('KIT', 'Gene', (47, 50))	('mutated', 'Var', (130, 137))	('Y703', 'Chemical', '-', (163, 167))	('KIT', 'Gene', '3815', (138, 141))
523502	32516941	KIT phosphorylated on Y703 almost completely disappeared from the Golgi apparatus, following the addition of HSP90 inhibitors.	('Y703', 'Chemical', '-', (22, 26))	('HSP90', 'Gene', (109, 114))	('HSP90', 'Gene', '3320', (109, 114))	('KIT', 'Gene', '3815', (0, 3))	('disappeared', 'NegReg', (45, 56))	('KIT', 'Gene', (0, 3))	('Y703', 'Var', (22, 26))
523513	32516941	xCT is highly expressed in different NSCLCs, such as A549, H520, and others, but not, for example, in H1869.	('A549', 'Var', (53, 57))	('NSCLCs', 'Disease', (37, 43))	('A549', 'CellLine', 'CVCL:0023', (53, 57))	('H520', 'Var', (59, 63))	('NSCLCs', 'Disease', 'MESH:D002289', (37, 43))
523521	32516941	Reinforcing the relevance of xCT, the combination of tumor cell xCT deletion with anti-CTLA, increased the frequency and durability of anti-tumor response.	('xCT', 'Gene', (64, 67))	('increased', 'PosReg', (93, 102))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('combination', 'Interaction', (38, 49))	('deletion', 'Var', (68, 76))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('tumor', 'Disease', (53, 58))	('tumor', 'Disease', (140, 145))
523525	32516941	We have noted that DHA can inhibit important downstream signaling nodes, such as, STAT3, YAP1, AKT, MEK, and several RTKs, including MET.	('AKT', 'Pathway', (95, 98))	('YAP1', 'Gene', (89, 93))	('MEK', 'Gene', (100, 103))	('YAP1', 'Gene', '10413', (89, 93))	('DHA', 'Chemical', 'MESH:C039060', (19, 22))	('DHA', 'Var', (19, 22))	('STAT3', 'Gene', '6774', (82, 87))	('MEK', 'Gene', '5609', (100, 103))	('STAT3', 'Gene', (82, 87))	('inhibit', 'NegReg', (27, 34))
523528	32516941	The sensitivity of ROS-induced ferroptosis is increased in p53-activated cells.	('ROS', 'Chemical', 'MESH:D017382', (19, 22))	('increased', 'PosReg', (46, 55))	('sensitivity', 'MPA', (4, 15))	('p53-activated', 'Var', (59, 72))
523543	32516941	Limiting asparagine by knockdown of asparagine synthetase (ASNS) treatment with L-asparaginase, or dietary asparagine restriction, reduces metastases.	('asparagine', 'Chemical', 'MESH:D001216', (107, 117))	('asparagine synthetase', 'Gene', '440', (36, 57))	('metastases', 'Disease', (139, 149))	('asparagine', 'Chemical', 'MESH:D001216', (9, 19))	('ASNS', 'Gene', '440', (59, 63))	('knockdown', 'Var', (23, 32))	('reduces', 'NegReg', (131, 138))	('ASNS', 'Gene', (59, 63))	('asparagine synthetase', 'Gene', (36, 57))	('asparagine', 'Chemical', 'MESH:D001216', (36, 46))	('metastases', 'Disease', 'MESH:D009362', (139, 149))
523544	32516941	Suppression of ASNS increases the potency of artemisinin in an NSCLC model in which artemisinin activates the ER-resident PERK, which reactivates ERK, phosphorylating ATF4, and nuclear ATF4 can enhance ASNS production.	('NSCLC', 'Disease', (63, 68))	('nuclear', 'Var', (177, 184))	('ERK', 'Gene', '5594', (146, 149))	('artemisinin', 'Chemical', 'MESH:C031327', (45, 56))	('ERK', 'Gene', (123, 126))	('artemisinin', 'Chemical', 'MESH:C031327', (84, 95))	('phosphorylating', 'MPA', (151, 166))	('ASNS', 'Gene', '440', (15, 19))	('ERK', 'Gene', (146, 149))	('ATF4', 'Gene', (185, 189))	('PERK', 'Gene', (122, 126))	('ATF4', 'Gene', '468', (185, 189))	('ASNS', 'Gene', (15, 19))	('ATF4', 'Gene', (167, 171))	('Suppression', 'Var', (0, 11))	('ASNS', 'Gene', '440', (202, 206))	('ATF4', 'Gene', '468', (167, 171))	('enhance', 'PosReg', (194, 201))	('PERK', 'Gene', '9451', (122, 126))	('NSCLC', 'Disease', 'MESH:D002289', (63, 68))	('ERK', 'Gene', '5594', (123, 126))	('potency', 'MPA', (34, 41))	('ASNS', 'Gene', (202, 206))	('reactivates', 'MPA', (134, 145))
523552	32516941	In EGFR mutant NSCLC cells, resistance to gefitinib is related to FASN, which produces 16-C saturated fatty acid palmitate (palmitoylation).	('EGFR', 'Gene', (3, 7))	('gefitinib', 'Chemical', 'MESH:D000077156', (42, 51))	('16-C saturated fatty acid palmitate', 'Chemical', '-', (87, 122))	('mutant', 'Var', (8, 14))	('FASN', 'Gene', (66, 70))	('NSCLC', 'Disease', (15, 20))	('FASN', 'Gene', '2194', (66, 70))	('NSCLC', 'Disease', 'MESH:D002289', (15, 20))	('16-C saturated fatty acid palmitate', 'MPA', (87, 122))
523554	32516941	Pharmacological inhibition of FASN by orlistat (Xenical) (an FDA-approved anti-obesity drug) inhibits EGFR palmitoylation, limiting tumor cell survival.	('FASN', 'Gene', (30, 34))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('FASN', 'Gene', '2194', (30, 34))	('obesity', 'Phenotype', 'HP:0001513', (79, 86))	('inhibits', 'NegReg', (93, 101))	('tumor', 'Disease', (132, 137))	('limiting', 'NegReg', (123, 131))	('obesity', 'Disease', 'MESH:D009765', (79, 86))	('EGFR palmitoylation', 'MPA', (102, 121))	('obesity', 'Disease', (79, 86))	('inhibition', 'Var', (16, 26))
523558	32516941	After depalmitoylation, KRAS4A loses affinity for the plasma membrane and gains affinity for endomembranes.	('KRAS4A', 'Gene', '3845', (24, 30))	('loses', 'NegReg', (31, 36))	('gains', 'PosReg', (74, 79))	('affinity for the plasma membrane', 'MPA', (37, 69))	('KRAS4A', 'Gene', (24, 30))	('affinity for endomembranes', 'MPA', (80, 106))	('depalmitoylation', 'Var', (6, 22))
523561	32516941	Therefore, KRAS4A palmitoylation inhibition could be a supplemental treatment for enhancing the effect of anti-PD1 or anti-PD-L1 antibodies.	('anti-PD1', 'Var', (106, 114))	('KRAS4A', 'Gene', '3845', (11, 17))	('anti-PD-L1', 'Var', (118, 128))	('enhancing', 'PosReg', (82, 91))	('palmitoylation inhibition', 'MPA', (18, 43))	('KRAS4A', 'Gene', (11, 17))
523562	32516941	Inhibiting cholesterol esterification in T cells by ablation or pharmacological inhibition of acetyl-CoA Acetyltransferase (ACAT1) augments the effector function and proliferation of CD8+ cells.	('ablation', 'Var', (52, 60))	('Inhibiting', 'Var', (0, 10))	('augments', 'PosReg', (131, 139))	('ACAT1', 'Gene', (124, 129))	('pharmacological', 'Var', (64, 79))	('ACAT1', 'Gene', '38', (124, 129))	('effector function', 'CPA', (144, 161))	('cholesterol', 'Chemical', 'MESH:D002784', (11, 22))	('CD8', 'Gene', (183, 186))	('CD8', 'Gene', '925', (183, 186))	('cholesterol esterification', 'MPA', (11, 37))
523566	32516941	Avasimibe monotherapy potentiates the effector function of both, PD-1high, and PD-1low, CD8+ T cells in the tumor microenvironment.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('CD8', 'Gene', '925', (88, 91))	('iron', 'Chemical', 'MESH:D007501', (122, 126))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('PD-1high', 'Var', (65, 73))	('potentiates', 'PosReg', (22, 33))	('effector function', 'MPA', (38, 55))	('tumor', 'Disease', (108, 113))	('PD-1low', 'Var', (79, 86))	('Avasimibe', 'Chemical', 'MESH:C423185', (0, 9))	('CD8', 'Gene', (88, 91))
523574	32516941	Moreover, in primary liver and lung cancer cell lines, it is noted that desaturate palmitate (fatty acid desaturation) to the unusual fatty acid sapienate, induces proliferation.	('proliferation', 'CPA', (164, 177))	('fatty acid', 'Chemical', 'MESH:D005227', (94, 104))	('desaturate', 'Var', (72, 82))	('liver and lung cancer', 'Disease', 'MESH:D008175', (21, 42))	('sapienate', 'Chemical', '-', (145, 154))	('lung cancer', 'Phenotype', 'HP:0100526', (31, 42))	('desaturate palmitate', 'Chemical', '-', (72, 92))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('fatty acid', 'Chemical', 'MESH:D005227', (134, 144))	('induces', 'Reg', (156, 163))
523583	32516941	Of great interest is the fact that PMN-MDSCs exclusively upregulate fatty acid transport protein 2 (FATP2).	('fatty acid transport protein 2', 'Gene', '11001', (68, 98))	('N', 'Chemical', 'MESH:D009584', (37, 38))	('PMN-MDSCs', 'Var', (35, 44))	('upregulate', 'PosReg', (57, 67))	('fatty acid transport protein 2', 'Gene', (68, 98))
523595	32516941	Inhibitors of ENNP1 can boost extracellular cGAMP concentration, immune infiltration and synergize with irradiation to delay tumor progression.	('extracellular cGAMP concentration', 'MPA', (30, 63))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('cGAMP', 'Chemical', 'MESH:C584311', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('Inhibitors', 'Var', (0, 10))	('tumor', 'Disease', (125, 130))	('ENNP1', 'Gene', (14, 19))	('immune infiltration', 'CPA', (65, 84))	('boost', 'PosReg', (24, 29))
523597	32516941	In E0771 orthotopic tumors in mice, neutralizing STING (to deplete extracellular cGAMP) significantly decreases the CD11c+ (dendritic cell) and CD103+CD11c+ (conventional type 1 dendritic cell, CDC1) populations.	('neutralizing', 'Var', (36, 48))	('CD11c', 'Gene', '3687', (116, 121))	('tumors', 'Disease', (20, 26))	('E0771', 'Var', (3, 8))	('CD11c', 'Gene', (116, 121))	('CD11c', 'Gene', (150, 155))	('CD11c', 'Gene', '3687', (150, 155))	('tumors', 'Disease', 'MESH:D009369', (20, 26))	('mice', 'Species', '10090', (30, 34))	('CD103', 'Gene', (144, 149))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('CD103', 'Gene', '3682', (144, 149))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('N', 'Chemical', 'MESH:D009584', (52, 53))	('decreases', 'NegReg', (102, 111))	('cGAMP', 'Chemical', 'MESH:C584311', (81, 86))
523611	32516941	Genetic knockout of SLC19A1, and inhibition of import with methotrexate, reduced pIRF3 signal by 50% in response to extracellular cGAMP.	('response to extracellular cGAMP', 'MPA', (104, 135))	('SLC19A1', 'Gene', '6573', (20, 27))	('methotrexate', 'Chemical', 'MESH:D008727', (59, 71))	('cGAMP', 'Chemical', 'MESH:C584311', (130, 135))	('import', 'MPA', (47, 53))	('SLC19A1', 'Gene', (20, 27))	('reduced', 'NegReg', (73, 80))	('inhibition', 'NegReg', (33, 43))	('Genetic knockout', 'Var', (0, 16))	('knockout', 'Var', (8, 16))	('IRF3', 'Gene', (82, 86))	('IRF3', 'Gene', '3661', (82, 86))
523613	32516941	Due to its key role in regulating anti-cancer immune responses, positive modulation of the cGAS-STING pathway signaling has been proposed as a potential therapeutic strategy to enhance tumor immunogenicity and sensitivity to a variety of immunotherapies, such as, cancer vaccine and immune checkpoint blockade.	('tumor', 'Disease', (185, 190))	('cancer', 'Disease', (39, 45))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('N', 'Chemical', 'MESH:D009584', (99, 100))	('cancer', 'Phenotype', 'HP:0002664', (264, 270))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('cGAS', 'Gene', (91, 95))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('positive modulation', 'Var', (64, 83))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('enhance', 'PosReg', (177, 184))	('cGAS', 'Gene', '115004', (91, 95))	('cancer', 'Disease', (264, 270))	('cancer', 'Disease', 'MESH:D009369', (264, 270))
523614	32516941	In several preclinical cancer models, pharmacological activation of STING has been shown to restrict tumor growth and enhance immunogenicity.	('STING', 'Gene', (68, 73))	('immunogenicity', 'MPA', (126, 140))	('pharmacological', 'Var', (38, 53))	('tumor', 'Disease', (101, 106))	('N', 'Chemical', 'MESH:D009584', (71, 72))	('cancer', 'Disease', (23, 29))	('cancer', 'Disease', 'MESH:D009369', (23, 29))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('enhance', 'PosReg', (118, 125))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('restrict', 'NegReg', (92, 100))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
523623	32516941	In the nucleus, cGAS is recruited to double-stranded breaks and interacts with PARP1.	('double-stranded', 'Var', (37, 52))	('cGAS', 'Gene', (16, 20))	('interacts', 'Interaction', (64, 73))	('recruited', 'PosReg', (24, 33))	('PARP1', 'Gene', '142', (79, 84))	('cGAS', 'Gene', '115004', (16, 20))	('PARP1', 'Gene', (79, 84))
523625	32516941	The phosphorylation of cGAS at Y215 by BLK maintains the cytosolic localization of cGAS, while stimulation with DNA damaging agents dephosphorylates cGAS shuttling cGAS to the nucleus.	('cytosolic localization', 'MPA', (57, 79))	('cGAS', 'Gene', '115004', (164, 168))	('cGAS', 'Gene', (149, 153))	('cGAS', 'Gene', '115004', (83, 87))	('N', 'Chemical', 'MESH:D009584', (113, 114))	('phosphorylation', 'MPA', (4, 19))	('cGAS', 'Gene', (23, 27))	('BLK', 'Gene', '640', (39, 42))	('cGAS', 'Gene', '115004', (149, 153))	('cGAS', 'Gene', (164, 168))	('BLK', 'Gene', (39, 42))	('cGAS', 'Gene', '115004', (23, 27))	('cGAS', 'Gene', (83, 87))	('at Y215', 'Var', (28, 35))	('shuttling', 'MPA', (154, 163))
523652	32516941	The NGF receptor TrkA (NTRK1) inhibition decreases YAP-driven transcription.	('YAP', 'Gene', (51, 54))	('inhibition', 'Var', (30, 40))	('decreases', 'NegReg', (41, 50))	('NTRK1', 'Gene', '4914', (23, 28))	('NGF', 'Gene', '4803', (4, 7))	('TrkA', 'Gene', '4914', (17, 21))	('TrkA', 'Gene', (17, 21))	('NGF', 'Gene', (4, 7))	('NTRK1', 'Gene', (23, 28))	('YAP', 'Gene', '10413', (51, 54))
523659	32516941	SR140333 (an NK-1R inhibitor) has demonstrated activity in the CML cell line, K562, and inhibits TNF-a, IL-1 and IL-6 expression in K562 cells.	('K562', 'CellLine', 'CVCL:0004', (78, 82))	('IL-1', 'Gene', '3552', (104, 108))	('IL-1', 'Gene', (104, 108))	('IL-6', 'Gene', (113, 117))	('IL-6', 'Gene', '3569', (113, 117))	('NK-1R', 'Gene', (13, 18))	('SR140333', 'Chemical', 'MESH:C085215', (0, 8))	('K562', 'CellLine', 'CVCL:0004', (132, 136))	('inhibits', 'NegReg', (88, 96))	('TNF-a', 'Gene', (97, 102))	('activity', 'MPA', (47, 55))	('expression', 'MPA', (118, 128))	('TNF-a', 'Gene', '7124', (97, 102))	('SR140333', 'Var', (0, 8))	('NK-1R', 'Gene', '6869', (13, 18))
523662	32516941	Both aprepitant and SR 140333 induced ER-mitochondrial calcium overload, with ROS accumulation and cell apoptosis.	('SR 140333', 'Var', (20, 29))	('ROS', 'Chemical', 'MESH:D017382', (78, 81))	('accumulation', 'PosReg', (82, 94))	('ER-mitochondrial calcium overload', 'MPA', (38, 71))	('induced', 'Reg', (30, 37))	('cell apoptosis', 'CPA', (99, 113))	('ROS', 'CPA', (78, 81))	('SR 140333', 'Chemical', 'MESH:C085215', (20, 29))	('calcium', 'Chemical', 'MESH:D002118', (55, 62))
523682	32516941	Upon apoptotic stimulation, cleavage of gasdermin E (GSDME/DFNA5) by caspase-3 produces GSDME-NT (-37kDa) forming pores on the plasma membrane, and, thereby, transforms apoptosis into pyroptosis/necrosis (Figure 3).	('apoptosis', 'Disease', (169, 178))	('necrosis', 'Disease', (195, 203))	('transforms', 'Reg', (158, 168))	('GSDME-NT', 'Chemical', '-', (88, 96))	('pores', 'MPA', (114, 119))	('caspase-3', 'Gene', '836', (69, 78))	('DFNA5', 'Gene', '1687', (59, 64))	('DFNA5', 'Gene', (59, 64))	('GSDME-NT (-37kDa', 'Var', (88, 104))	('cleavage', 'Var', (28, 36))	('necrosis', 'Disease', 'MESH:D009336', (195, 203))	('GSDME', 'Chemical', '-', (53, 58))	('GSDME', 'Chemical', '-', (88, 93))	('caspase-3', 'Gene', (69, 78))
523684	32516941	In BMDM, ATP induces rapid pyroptosis mediated by GDSMD cleavage, whereas, it induced delayed pyroptosis associated with GDSME cleavage when the canonical NLRP3 pathway is blocked (Figure 3).	('NLRP3', 'Gene', '114548', (155, 160))	('cleavage', 'Var', (56, 64))	('rapid pyroptosis', 'MPA', (21, 37))	('NLRP3', 'Gene', (155, 160))	('ATP', 'Chemical', 'MESH:D000255', (9, 12))
523695	32516941	Conversely, GSDME suppresses tumor growth by activating tumor-infiltrating NK and CD8+ T killer lymphocytes.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('CD8', 'Gene', (82, 85))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('N', 'Chemical', 'MESH:D009584', (75, 76))	('CD8', 'Gene', '925', (82, 85))	('GSDME', 'Var', (12, 17))	('tumor', 'Disease', (56, 61))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('activating', 'PosReg', (45, 55))	('tumor', 'Disease', (29, 34))	('GSDME', 'Chemical', '-', (12, 17))	('suppresses', 'NegReg', (18, 28))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
523697	32516941	It is noted that cancer cells develop epigenetic suppression of GSDME expression and LOF mutations to avoid GSDME-mediated tumor suppression.	('suppression', 'NegReg', (49, 60))	('tumor', 'Disease', (123, 128))	('GSDME', 'Chemical', '-', (64, 69))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('GSDME', 'Chemical', '-', (108, 113))	('LOF', 'NegReg', (85, 88))	('expression', 'MPA', (70, 80))	('cancer', 'Disease', (17, 23))	('GSDME', 'Gene', (64, 69))	('mutations', 'Var', (89, 98))	('epigenetic', 'Var', (38, 48))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
523698	32516941	Cancers with GDME mutations reduce pyroptosis, and mutations of D270, the shared granzyme B/caspase 3 cleavage site, enable tumors to evade tumor suppression by GSDME.	('mutations', 'Var', (51, 60))	('Cancers', 'Disease', (0, 7))	('Cancers', 'Phenotype', 'HP:0002664', (0, 7))	('tumor', 'Disease', (124, 129))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('GDME', 'Gene', (13, 17))	('granzyme B', 'Gene', (81, 91))	('D270', 'Gene', (64, 68))	('tumor', 'Disease', 'MESH:D009369', (124, 129))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('reduce', 'NegReg', (28, 34))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('pyroptosis', 'MPA', (35, 45))	('mutations', 'Var', (18, 27))	('GSDME', 'Chemical', '-', (161, 166))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('caspase 3', 'Gene', (92, 101))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancers', 'Disease', 'MESH:D009369', (0, 7))	('tumors', 'Disease', (124, 130))	('caspase 3', 'Gene', '836', (92, 101))	('evade', 'NegReg', (134, 139))	('granzyme B', 'Gene', '3002', (81, 91))	('tumors', 'Disease', 'MESH:D009369', (124, 130))	('nab', 'Chemical', '-', (118, 121))	('tumor', 'Disease', (140, 145))
523702	32516941	Both proteins are altered in K-Ras mutant NSCLC.	('NSCLC', 'Disease', (42, 47))	('NSCLC', 'Disease', 'MESH:D002289', (42, 47))	('altered', 'Reg', (18, 25))	('mutant', 'Var', (35, 41))	('K-Ras', 'Protein', (29, 34))
523717	32516941	ADORA1-ATF3-PD-L1 merits further scrutiny in K-Ras mutant NSCLC cell lines and patients.	('NSCLC', 'Disease', (58, 63))	('ADORA1', 'Gene', '134', (0, 6))	('NSCLC', 'Disease', 'MESH:D002289', (58, 63))	('ADORA1', 'Gene', (0, 6))	('mutant', 'Var', (51, 57))	('ATF3', 'Gene', '467', (7, 11))	('patients', 'Species', '9606', (79, 87))	('K-Ras', 'Gene', (45, 50))	('ATF3', 'Gene', (7, 11))
523721	32516941	HIF inhibitors could block the counter therapeutic effect of paclitaxel and other cytotoxic chemotherapy agents.	('paclitaxel', 'Chemical', 'MESH:D017239', (61, 71))	('counter therapeutic effect', 'MPA', (31, 57))	('block', 'NegReg', (21, 26))	('inhibitors', 'Var', (4, 14))
523723	32516941	Intriguingly, gemcitabine could be of benefit in K-Ras mutant NSCLC with LKB1nsm or deletion.	('NSCLC', 'Disease', (62, 67))	('LKB1nsm', 'Var', (73, 80))	('deletion', 'Var', (84, 92))	('gemcitabine', 'Chemical', 'MESH:C056507', (14, 25))	('NSCLC', 'Disease', 'MESH:D002289', (62, 67))	('mutant', 'Var', (55, 61))	('K-Ras mutant', 'Var', (49, 61))
523725	32516941	K-Ras mutant NSCLC with LKB1nsm or LKB1 loss has poor prognosis, as above commented.	('NSCLC', 'Disease', (13, 18))	('LKB1nsm', 'Var', (24, 31))	('NSCLC', 'Disease', 'MESH:D002289', (13, 18))	('loss', 'NegReg', (40, 44))	('LKB1', 'Gene', (35, 39))
523726	32516941	The loss of LKB1 in NSCLC leads to the dephosphorylation of CRT2 that displaces to the nucleus where it binds to CREB over the ID1 promoter and stimulates ID1 expression (Figure 4).	('CREB', 'Gene', (113, 117))	('CREB', 'Gene', '1385', (113, 117))	('ID1', 'Gene', (127, 130))	('NSCLC', 'Disease', 'MESH:D002289', (20, 25))	('ID1', 'Gene', (155, 158))	('displaces to the nucleus', 'MPA', (70, 94))	('binds', 'Interaction', (104, 109))	('stimulates', 'PosReg', (144, 154))	('ID1', 'Gene', '3397', (127, 130))	('expression', 'MPA', (159, 169))	('CRT2', 'Gene', '387700', (60, 64))	('CRT2', 'Gene', (60, 64))	('LKB1', 'Gene', (12, 16))	('dephosphorylation', 'MPA', (39, 56))	('ID1', 'Gene', '3397', (155, 158))	('NSCLC', 'Disease', (20, 25))	('loss', 'Var', (4, 8))
523729	32516941	K-Ras mutant pancreatic cancers with intact transforming growth factor-beta (TGF-beta) pathway drive tumor growth via ID1.	('ID1', 'Gene', '3397', (118, 121))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (13, 31))	('mutant', 'Var', (6, 12))	('TGF-beta', 'Gene', '7039', (77, 85))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('ID1', 'Gene', (118, 121))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('pancreatic cancers', 'Disease', 'MESH:D010190', (13, 31))	('pancreatic cancers', 'Disease', (13, 31))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (13, 30))	('cancers', 'Phenotype', 'HP:0002664', (24, 31))	('TGF-beta', 'Gene', (77, 85))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
523731	32516941	ID1 inhibits the activation of E12/E47.	('ID1', 'Gene', (0, 3))	('inhibits', 'NegReg', (4, 12))	('E12/E47', 'Var', (31, 38))	('ID1', 'Gene', '3397', (0, 3))
523733	32516941	The potential benefit of gefitinib in suppressing ID1 in K-Ras mutant NSCLC also warrants investigation.	('ID1', 'Gene', '3397', (50, 53))	('mutant', 'Var', (63, 69))	('suppressing', 'NegReg', (38, 49))	('gefitinib', 'Chemical', 'MESH:D000077156', (25, 34))	('NSCLC', 'Disease', (70, 75))	('NSCLC', 'Disease', 'MESH:D002289', (70, 75))	('ID1', 'Gene', (50, 53))
523746	32516941	Loss of MED12 or BAMBI induces an EMT-like phenotype in NSCLC, enhancing immunosuppressive effects.	('induces', 'Reg', (23, 30))	('MED12', 'Gene', (8, 13))	('MED12', 'Gene', '9968', (8, 13))	('enhancing', 'PosReg', (63, 72))	('NSCLC', 'Disease', (56, 61))	('BAMBI', 'Gene', '25805', (17, 22))	('immunosuppressive effects', 'MPA', (73, 98))	('NSCLC', 'Disease', 'MESH:D002289', (56, 61))	('Loss', 'Var', (0, 4))	('EMT-like', 'MPA', (34, 42))	('BAMBI', 'Gene', (17, 22))
523753	32516941	A TGF-beta signature predicts clinical outcomes to durvalumab in HIV-1 cancer patients  As previously commented, the overall survival of patients with LKB1nsm is extremely poor, as is confirmed in a large group of patients from Cologne, with median overall survival of 3.2 months versus 10 months for those with wild-type LKB1.	('HIV-1 cancer', 'Disease', 'MESH:D009369', (65, 77))	('TGF-beta', 'Gene', '7039', (2, 10))	('patients', 'Species', '9606', (214, 222))	('poor', 'NegReg', (172, 176))	('patients', 'Species', '9606', (78, 86))	('patients', 'Species', '9606', (137, 145))	('HIV-1 cancer', 'Disease', (65, 77))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('TGF-beta', 'Gene', (2, 10))	('LKB1nsm', 'Var', (151, 158))	('durvalumab', 'Chemical', 'MESH:C000613593', (51, 61))
523754	32516941	Metformin could serve as a potential adjunct therapy, as has been noted in EGFR mutant NSCLC patients receiving gefitinib plus metformin, versus gefitinib alone, in experimental gastric cancer models.	('NSCLC', 'Disease', (87, 92))	('mutant', 'Var', (80, 86))	('NSCLC', 'Disease', 'MESH:D002289', (87, 92))	('gefitinib', 'Chemical', 'MESH:D000077156', (112, 121))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('gefitinib', 'Chemical', 'MESH:D000077156', (145, 154))	('gastric cancer', 'Disease', (178, 192))	('metformin', 'Chemical', 'MESH:D008687', (127, 136))	('gastric cancer', 'Disease', 'MESH:D013274', (178, 192))	('Metformin', 'Chemical', 'MESH:D008687', (0, 9))	('patients', 'Species', '9606', (93, 101))	('gastric cancer', 'Phenotype', 'HP:0012126', (178, 192))	('EGFR', 'Gene', (75, 79))
523757	32516941	Selective response to phenformin was observed in K-Ras mouse models of NSCLC with LKB1 mutations, but not those with K-Ras and p53 mutations.	('LKB1', 'Gene', (82, 86))	('mouse', 'Species', '10090', (55, 60))	('NSCLC', 'Disease', (71, 76))	('phenformin', 'Chemical', 'MESH:D010629', (22, 32))	('mutations', 'Var', (87, 96))	('NSCLC', 'Disease', 'MESH:D002289', (71, 76))
523758	32516941	A synergistic effect was detected in a phase II trial of sorafenib (multi-kinase inhibitor) in K-Ras mutant NSCLC patients that were also receiving metformin.	('NSCLC', 'Disease', (108, 113))	('K-Ras', 'Gene', (95, 100))	('mutant', 'Var', (101, 107))	('NSCLC', 'Disease', 'MESH:D002289', (108, 113))	('sorafenib', 'Chemical', 'MESH:D000077157', (57, 66))	('patients', 'Species', '9606', (114, 122))	('metformin', 'Chemical', 'MESH:D008687', (148, 157))
523763	32516941	The combination was strongly suggested to be useful in the treatment of K-Ras mutant NSCLC  K-Ras/LKB1nsm cells express the urea cycle enzyme carbamoyl phosphate synthetase-1 (CSP1), which produces carbamoyl phosphate in the mitochondria from ammonia and bicarbonate, initiating nitrogen disposal.	('NSCLC', 'Disease', (85, 90))	('NSCLC', 'Disease', 'MESH:D002289', (85, 90))	('CSP1', 'Gene', (176, 180))	('nitrogen disposal', 'MPA', (279, 296))	('bicarbonate', 'Chemical', 'MESH:D001639', (255, 266))	('carbamoyl phosphate', 'Chemical', 'MESH:D002221', (142, 161))	('nitrogen', 'Chemical', 'MESH:D009584', (279, 287))	('ammonia', 'Chemical', 'MESH:D000641', (243, 250))	('carbamoyl phosphate', 'Chemical', 'MESH:D002221', (198, 217))	('mutant', 'Var', (78, 84))	('urea', 'Chemical', 'MESH:D014508', (124, 128))
523765	32516941	This primal study illustrates that metabolic alterations mediated by concurrent mutations of K-Ras and LKB1 render cells dependent on CPS1 for pyrimidine synthesis.	('mutations', 'Var', (80, 89))	('LKB1', 'Gene', (103, 107))	('CPS1', 'Gene', (134, 138))	('pyrimidine', 'Chemical', 'MESH:C030986', (143, 153))	('CPS1', 'Gene', '1373', (134, 138))	('metabolic alterations', 'MPA', (35, 56))	('K-Ras', 'Gene', (93, 98))
523766	32516941	It is supposed that the dependence on CPS1 is exacerbated by mutant K-Ras due to its action on glutamine metabolism.	('exacerbated', 'PosReg', (46, 57))	('CPS1', 'Gene', (38, 42))	('glutamine metabolism', 'MPA', (95, 115))	('K-Ras', 'Gene', (68, 73))	('mutant', 'Var', (61, 67))	('dependence', 'MPA', (24, 34))	('glutamine', 'Chemical', 'MESH:D005973', (95, 104))	('CPS1', 'Gene', '1373', (38, 42))	('action', 'Reg', (85, 91))
523781	32516941	Metformin-induced inactivation of mTORC1 subsequently inhibits growth through transcription of acyl-CoA dehydrogenase family member-10 (ACAD10).	('acyl-CoA dehydrogenase family member-10', 'Gene', (95, 134))	('acyl-CoA dehydrogenase family member-10', 'Gene', '80724', (95, 134))	('ACAD10', 'Gene', (136, 142))	('mTORC1', 'Gene', '382056', (34, 40))	('inactivation', 'Var', (18, 30))	('ACAD10', 'Gene', '80724', (136, 142))	('mTORC1', 'Gene', (34, 40))	('growth', 'MPA', (63, 69))	('inhibits', 'NegReg', (54, 62))	('Metformin', 'Chemical', 'MESH:D008687', (0, 9))	('transcription', 'MPA', (78, 91))
523784	32516941	In cancer cell lines, SMYD3-mediated methylation of MAP3K2 at lysine 260 enhances activation of the Ras/Raf/MEK/ERK signaling and SMYD3 depletion synergizes with a MEK inhibitor to block Ras-driven tumors.	('MEK', 'Gene', '5609', (164, 167))	('MEK', 'Gene', '5609', (108, 111))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('tumors', 'Disease', (198, 204))	('Raf', 'Gene', (104, 107))	('SMYD3', 'Gene', (22, 27))	('SMYD3', 'Gene', '64754', (22, 27))	('MEK', 'Gene', (164, 167))	('ERK', 'Gene', '5594', (112, 115))	('MEK', 'Gene', (108, 111))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('tumors', 'Disease', 'MESH:D009369', (198, 204))	('SMYD3', 'Gene', (130, 135))	('SMYD3', 'Gene', '64754', (130, 135))	('methylation', 'Var', (37, 48))	('MAP3K2', 'Gene', (52, 58))	('ERK', 'Gene', (112, 115))	('Raf', 'Gene', '673', (104, 107))	('enhances activation', 'PosReg', (73, 92))	('cancer', 'Disease', (3, 9))	('MAP3K2', 'Gene', '10746', (52, 58))	('tumors', 'Phenotype', 'HP:0002664', (198, 204))	('lysine', 'Chemical', 'MESH:D008239', (62, 68))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
523795	32516941	It is proposed that drugs targeting the heme pathway could be a therapeutic option in LUAD patients with dysregulation of KEAP-NRF2 pathway, often mutated in K-Ras mutant NSCLC.	('mutant', 'Var', (164, 170))	('patients', 'Species', '9606', (91, 99))	('heme', 'Chemical', 'MESH:D006418', (40, 44))	('KEAP', 'Chemical', '-', (122, 126))	('NRF2', 'Gene', '4780', (127, 131))	('NSCLC', 'Disease', (171, 176))	('NRF2', 'Gene', (127, 131))	('mutated', 'Var', (147, 154))	('NSCLC', 'Disease', 'MESH:D002289', (171, 176))
523800	32516941	Hence, drugs targeting the glutathione redox system (see ferroptosis) should be taken into account for the treatment of K-Ras mutant LUADs with NRF2, KEAP, BACH1 and FN3K, which are important predictive factors for ideal therapy (Figure 4, Table 2).	('NRF2', 'Gene', (144, 148))	('BACH1', 'Gene', '571', (156, 161))	('glutathione', 'Chemical', 'MESH:D005978', (27, 38))	('KEAP', 'Chemical', '-', (150, 154))	('FN3K', 'Gene', '64122', (166, 170))	('K-Ras', 'Gene', (120, 125))	('BACH1', 'Gene', (156, 161))	('NRF2', 'Gene', '4780', (144, 148))	('FN3K', 'Gene', (166, 170))	('mutant', 'Var', (126, 132))
523801	32516941	NRF2-KEAP alterations in K-Ras driven LUADs are also dependent on increased glutaminolysis, and offer another therapeutic opportunity through the inhibition of glutaminase.	('NRF2', 'Gene', (0, 4))	('increased', 'PosReg', (66, 75))	('alterations', 'Var', (10, 21))	('KEAP', 'Chemical', '-', (5, 9))	('glutaminolysis', 'MPA', (76, 90))	('glutaminase', 'Gene', '2744', (160, 171))	('NRF2', 'Gene', '4780', (0, 4))	('glutaminase', 'Gene', (160, 171))
523805	32516941	Mutations in NRF2 and KEAP1 were reported for the first time in 12 cell lines and 54 NSCLC samples.	('KEAP1', 'Gene', (22, 27))	('NSCLC', 'Disease', (85, 90))	('NSCLC', 'Disease', 'MESH:D002289', (85, 90))	('NRF2', 'Gene', '4780', (13, 17))	('Mutations', 'Var', (0, 9))	('KEAP1', 'Gene', '9817', (22, 27))	('NRF2', 'Gene', (13, 17))
523806	32516941	KEAP1 mutations were seen in 50% of cell lines and 19% of tumor specimens.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('KEAP1', 'Gene', (0, 5))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('KEAP1', 'Gene', '9817', (0, 5))	('mutations', 'Var', (6, 15))
523807	32516941	KEAP mutations are homozygous in A549, H460, H838, and H1435, and heterozygous in H1395 and H1993.	('H838', 'Var', (45, 49))	('H460', 'Var', (39, 43))	('A549', 'CellLine', 'CVCL:0023', (33, 37))	('KEAP', 'Chemical', '-', (0, 4))	('H460', 'CellLine', 'CVCL:0459', (39, 43))	('H1993', 'CellLine', 'CVCL:1512', (92, 97))	('H1435', 'Var', (55, 60))	('H1395', 'CellLine', 'CVCL:1467', (82, 87))	('A549', 'Var', (33, 37))
523808	32516941	In the A549, H838 and H1435, G-T transversions were probably induced by tobacco smoke.	('A549', 'CellLine', 'CVCL:0023', (7, 11))	('G-T transversions', 'CPA', (29, 46))	('induced', 'Reg', (61, 68))	('tobacco', 'Species', '4097', (72, 79))	('H838', 'Var', (13, 17))	('H1435', 'Var', (22, 27))
523813	32516941	Patients with high PALB2 mRNA have a response rate of 77% to cisplatin-docetaxel, compared with a response rate of 23% for those with low PALB2 mRNA expression (p = 0.04).	('PALB2', 'Gene', (19, 24))	('PALB2', 'Gene', '79728', (19, 24))	('high', 'Var', (14, 18))	('Patients', 'Species', '9606', (0, 8))	('docetaxel', 'Chemical', 'MESH:D000077143', (71, 80))	('cisplatin', 'Chemical', 'MESH:D002945', (61, 70))	('PALB2', 'Gene', '79728', (138, 143))	('cisplatin-docetaxel', 'MPA', (61, 80))	('N', 'Chemical', 'MESH:D009584', (27, 28))	('PALB2', 'Gene', (138, 143))	('N', 'Chemical', 'MESH:D009584', (146, 147))
523814	32516941	Knock-down of PALB2 in EBC1 and H1993 cells diminish the antiproliferative effect of docetaxel.	('Knock-down', 'Var', (0, 10))	('diminish', 'NegReg', (44, 52))	('H1993', 'CellLine', 'CVCL:1512', (32, 37))	('PALB2', 'Gene', '79728', (14, 19))	('antiproliferative effect', 'CPA', (57, 81))	('PALB2', 'Gene', (14, 19))	('docetaxel', 'Chemical', 'MESH:D000077143', (85, 94))
523815	32516941	Therefore, docetaxel could be a therapeutic tool in the treatment of K-Ras mutant NSCLC with KEAP mutations, and PALB2 mRNA expression could serve as a biomarker.	('docetaxel', 'Chemical', 'MESH:D000077143', (11, 20))	('N', 'Chemical', 'MESH:D009584', (82, 83))	('PALB2', 'Gene', (113, 118))	('PALB2', 'Gene', '79728', (113, 118))	('mutant', 'Var', (75, 81))	('N', 'Chemical', 'MESH:D009584', (121, 122))	('NSCLC', 'Disease', (82, 87))	('K-Ras', 'Gene', (69, 74))	('KEAP', 'Chemical', '-', (93, 97))	('NSCLC', 'Disease', 'MESH:D002289', (82, 87))
523820	32516941	Since the advent of IMT, translational research has gravitated around IMT, nevertheless, clinical outcomes are still meager and the recommendations for treatment of NSCLC relies on anti-PD-1 antibodies (pembrolizumab) or anti-PD-L1 antibodies (atezolizumab) with or without chemotherapy.	('anti-PD-1', 'Var', (181, 190))	('pembrolizumab', 'Chemical', 'MESH:C582435', (203, 216))	('NSCLC', 'Disease', 'MESH:D002289', (165, 170))	('atezolizumab', 'Chemical', 'MESH:C000594389', (244, 256))	('NSCLC', 'Disease', (165, 170))
523821	32516941	However, it is described that tumor cells express PD-1 and PD-L1, which inhibit tumor cell growth by impairing AKT and ERK1/2 pathways and preventing the interaction with PD-1-expressing T cells.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('impairing', 'NegReg', (101, 110))	('preventing', 'NegReg', (139, 149))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('tumor', 'Disease', (80, 85))	('ERK', 'Gene', '5594', (119, 122))	('ERK', 'Gene', (119, 122))	('PD-L1', 'Gene', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('inhibit', 'NegReg', (72, 79))	('PD-1', 'Var', (50, 54))	('tumor', 'Disease', (30, 35))	('interaction', 'Interaction', (154, 165))
523828	32516941	Moreover, murine tumor cells expressing PD-1 exhibit increased growth under PD-1 targeted antibody treatment both in vitro and in vivo, suggesting that tumor cell-intrinsic PD-1 plays an antitumor role in NSCLC.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('tumor', 'Disease', (17, 22))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('tumor', 'Disease', (152, 157))	('NSCLC', 'Disease', (205, 210))	('increased', 'PosReg', (53, 62))	('tumor', 'Disease', (191, 196))	('growth', 'MPA', (63, 69))	('murine', 'Species', '10090', (10, 16))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('NSCLC', 'Disease', 'MESH:D002289', (205, 210))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('PD-1', 'Var', (40, 44))
523841	32516941	The bacterial abundance and composition in the bronchoalveolar lavage fluid showed that the lungs from tumor-bearing KP (K-ras mutation and p53 loss) mice harbored unique commensal communities and depletion of commensal microbiota suppresses LUAD development.	('K-ras', 'Gene', (121, 126))	('K-ras', 'Gene', '16653', (121, 126))	('mice', 'Species', '10090', (150, 154))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('mutation', 'Var', (127, 135))	('tumor', 'Disease', (103, 108))	('depletion', 'MPA', (197, 206))	('suppresses', 'NegReg', (231, 241))	('LUAD development', 'CPA', (242, 258))	('p53', 'Gene', (140, 143))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('loss', 'NegReg', (144, 148))
523843	32516941	In vitro, the function of dendritic cells is repressed by EGFR exon 19 deletion in Lewis lung cancer.	('lung cancer', 'Disease', (89, 100))	('lung cancer', 'Phenotype', 'HP:0100526', (89, 100))	('EGFR', 'Gene', (58, 62))	('deletion', 'Var', (71, 79))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('lung cancer', 'Disease', 'MESH:D008175', (89, 100))
523844	32516941	Through exosome uptake, exosomes derived from the EGFR-19 deletion Lewis lung cancer cells could transfer EGFR-19 deletion to the surface of dendritic cells.	('lung cancer', 'Disease', 'MESH:D008175', (73, 84))	('EGFR-19', 'Gene', (50, 57))	('Thr', 'Chemical', 'MESH:D013912', (0, 3))	('EGFR-19', 'Gene', (106, 113))	('lung cancer', 'Disease', (73, 84))	('deletion', 'Var', (58, 66))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('lung cancer', 'Phenotype', 'HP:0100526', (73, 84))	('deletion', 'Var', (114, 122))
523845	32516941	The combination of gefitinib and GM-CSF treatment recover T cell infiltration in EGFR exon 19 deletion tumors.	('GM-CSF', 'Gene', (33, 39))	('GM-CSF', 'Gene', '1437', (33, 39))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('deletion', 'Var', (94, 102))	('T cell infiltration', 'CPA', (58, 77))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('EGFR exon 19', 'Gene', (81, 93))	('tumors', 'Disease', (103, 109))	('tumors', 'Disease', 'MESH:D009369', (103, 109))	('gefitinib', 'Chemical', 'MESH:D000077156', (19, 28))
523846	32516941	The assessment of EGFR mutations, for example, in plasma exosomes in NSCLC patients could further reveal the relevance of the experimental data.	('NSCLC', 'Disease', (69, 74))	('patients', 'Species', '9606', (75, 83))	('NSCLC', 'Disease', 'MESH:D002289', (69, 74))	('EGFR', 'Gene', (18, 22))	('mutations', 'Var', (23, 32))
523856	32516941	Clinical studies with TIM-3 or LAG-3 inhibitors, alone, or in combination with other drugs, including other immune checkpoint inhibitors, are ongoing.	('LAG-3', 'Gene', (31, 36))	('inhibitors', 'Var', (37, 47))	('TIM-3', 'Gene', (22, 27))	('LAG-3', 'Gene', '3902', (31, 36))	('TIM-3', 'Gene', '84868', (22, 27))
523860	32516941	Phase 2 studies with the anti-LAG-3 inhibitor, relatlimab, in association with nivolumab are ongoing in early stage and advanced-NSCLC (NCT04205552, NCT02750514).	('NCT04205552', 'Var', (136, 147))	('NCT02750514', 'Var', (149, 160))	('LAG-3', 'Gene', '3902', (30, 35))	('N', 'Chemical', 'MESH:D009584', (136, 137))	('N', 'Chemical', 'MESH:D009584', (129, 130))	('NSCLC', 'Disease', (129, 134))	('LAG-3', 'Gene', (30, 35))	('nivolumab', 'Chemical', 'MESH:D000077594', (79, 88))	('NSCLC', 'Disease', 'MESH:D002289', (129, 134))	('N', 'Chemical', 'MESH:D009584', (149, 150))
523861	32516941	Recent data suggest immunotherapy has favorable activity in patients with both BRAF V600E and non-V600E mutations.	('V600E', 'Mutation', 'rs113488022', (84, 89))	('patients', 'Species', '9606', (60, 68))	('V600E', 'Mutation', 'rs113488022', (98, 103))	('BRAF', 'Gene', '673', (79, 83))	('non-V600E', 'Var', (94, 103))	('BRAF', 'Gene', (79, 83))
523862	32516941	BRAF mutations were associated with high level of PD-L1 expression (42 to 50% of cases), low/intermediate TMB and microsatellite-stable status.	('TMB', 'Chemical', '-', (106, 109))	('microsatellite-stable', 'MPA', (114, 135))	('mutations', 'Var', (5, 14))	('BRAF', 'Gene', '673', (0, 4))	('expression', 'MPA', (56, 66))	('PD-L1', 'Protein', (50, 55))	('BRAF', 'Gene', (0, 4))
523865	32516941	Alterations in ARID1A gene, encoding for AT-Rich Interactive Domain-containing protein 1A involved in chromatin remodeling, have been shown to impair mismatch repair (MMR), which may in turn cause an increased mutation burden and drive responses to immune checkpoint inhibitors.	('ARID1A', 'Gene', (15, 21))	('AT-Rich Interactive Domain-containing protein 1A', 'Gene', (41, 89))	('impair', 'NegReg', (143, 149))	('drive', 'PosReg', (230, 235))	('Alterations', 'Var', (0, 11))	('increased', 'PosReg', (200, 209))	('mismatch repair', 'MPA', (150, 165))	('ARID1A', 'Gene', '8289', (15, 21))	('responses to', 'MPA', (236, 248))	('AT-Rich Interactive Domain-containing protein 1A', 'Gene', '8289', (41, 89))	('cause', 'Reg', (191, 196))	('mutation burden', 'MPA', (210, 225))
523866	32516941	In a recent study, ARID1A alterations assessed by tissue next-generation sequencing in different cancer types, including NSCLC, were significantly associated with longer PFS after checkpoint blockade, regardless of microsatellite instability or mutational burden, suggesting that the role of this biomarker need to be further explored in clinical setting.	('microsatellite instability', 'Disease', 'MESH:D053842', (215, 241))	('cancer', 'Disease', (97, 103))	('microsatellite instability', 'Disease', (215, 241))	('cancer', 'Disease', 'MESH:D009369', (97, 103))	('NSCLC', 'Disease', (121, 126))	('alterations', 'Var', (26, 37))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('NSCLC', 'Disease', 'MESH:D002289', (121, 126))	('longer', 'PosReg', (163, 169))	('ARID1A', 'Gene', '8289', (19, 25))	('ARID1A', 'Gene', (19, 25))	('PFS', 'MPA', (170, 173))
523868	32516941	Each entity, either with druggable driver mutations, or not, requires a more fundamental anti-cancer treatment and a profound re-formulation on the present view of treatment.	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('mutations', 'Var', (42, 51))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
523892	31261568	We identified patients with tongue cancer (International Classification of Diseases for Oncology, Third Edition [ICD-O-3], anatomic code C01.9, C02.0, C02.1, C02.2, C02.3, C02.4, C02.8, C02.9) for our study.	('C02.2', 'Var', (158, 163))	('Oncology', 'Phenotype', 'HP:0002664', (88, 96))	('C02.9', 'CellLine', 'CVCL:AX53', (186, 191))	('C02.4', 'Var', (172, 177))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('tongue cancer', 'Disease', (28, 41))	('C01.9', 'Var', (137, 142))	('C01.9', 'CellLine', 'CVCL:E303', (137, 142))	('tongue cancer', 'Disease', 'MESH:D014062', (28, 41))	('C02.1', 'Var', (151, 156))	('C02.3', 'Var', (165, 170))	('patients', 'Species', '9606', (14, 22))
523893	31261568	Patients were included when meeting the following criteria: diagnosed between 2004 and 2011; limited to squamous cell carcinoma (ICD-O-3, histologic code: 8050, 8051, 8052, 8070, 8071, 8072, 8073, 8074, 8075, 8076, 8081, 8082, 8083 and 8084); aged between 18 and 80 years old at diagnosis; diagnosed with AJCC TNM stage IV; receiving definite surgical treatment.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (104, 127))	('8050', 'Var', (155, 159))	('squamous cell carcinoma', 'Disease', (104, 127))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (104, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('Patients', 'Species', '9606', (0, 8))
523919	31261568	When it came to therapies, patients receiving radiotherapy had better OS and CSS than those without radiotherapy (receiving vs not, HR [hazard ratio] 0.612, 95% CI [confidence interval] 0.496-0.756, P < .001 for OS; HR 0.610, 95% CI 0.485-0.768, P < .001 for CSS).	('radiotherapy', 'Var', (46, 58))	('OS', 'Chemical', '-', (70, 72))	('patients', 'Species', '9606', (27, 35))	('CSS', 'Chemical', '-', (77, 80))	('better', 'PosReg', (63, 69))	('CSS', 'Chemical', '-', (259, 262))	('CSS', 'CPA', (77, 80))	('OS', 'Chemical', '-', (212, 214))
524047	29169318	Genome-wide DNA methylation profiling reveals novel epigenetic signatures in squamous cell lung cancer Epigenetic alterations are strongly associated with the development of cancer.	('associated with', 'Reg', (139, 154))	('lung cancer', 'Phenotype', 'HP:0100526', (91, 102))	('squamous cell lung cancer', 'Disease', 'MESH:D002294', (77, 102))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('epigenetic', 'Var', (52, 62))	('Epigenetic alterations', 'Var', (103, 125))	('squamous cell lung cancer', 'Phenotype', 'HP:0030359', (77, 102))	('cancer', 'Disease', (174, 180))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('cancer', 'Disease', (96, 102))	('squamous cell lung cancer', 'Disease', (77, 102))
524048	29169318	The aim of this study was to identify epigenetic pattern in squamous cell lung cancer (LUSC) on a genome-wide scale.	('squamous cell lung cancer', 'Disease', 'MESH:D002294', (60, 85))	('squamous cell lung cancer', 'Phenotype', 'HP:0030359', (60, 85))	('lung cancer', 'Phenotype', 'HP:0100526', (74, 85))	('epigenetic pattern', 'Var', (38, 56))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('squamous cell lung cancer', 'Disease', (60, 85))
524055	29169318	Collectively, these results suggest that DNA methylation plays critical roles in lung tumorigenesis and may potentially be proposed as a diagnostic biomarker.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Disease', (86, 91))	('methylation', 'Var', (45, 56))	('roles', 'Reg', (72, 77))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('DNA', 'Protein', (41, 44))
524067	29169318	Most importantly, DNA methylation can be detected by a wide range of sensitive and cost efficient techniques even in samples with low tumor purity.	('DNA', 'Var', (18, 21))	('low tumor', 'Disease', 'MESH:D009800', (130, 139))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('low tumor', 'Disease', (130, 139))	('detected', 'Reg', (41, 49))
524071	29169318	Of note, LUSC and adenocarcinoma shows distinct differences in DNA methylation, expression profiles and lesion location, although they are similarly treated in clinical practice due to the largely unknown underlying molecular mechanisms.	('adenocarcinoma', 'Disease', 'MESH:D000230', (18, 32))	('expression profiles', 'MPA', (80, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (23, 32))	('clinical', 'Species', '191496', (160, 168))	('DNA', 'MPA', (63, 66))	('adenocarcinoma', 'Disease', (18, 32))	('differences', 'Reg', (48, 59))	('methylation', 'Var', (67, 78))
524092	29169318	After integrating analysis of differentially methylated genes (DMGs) and differentially expressed genes (DEGs), we identified 449 aberrantly methylated genes accompanied with altered expression.	('aberrantly methylated', 'Var', (130, 151))	('expression', 'MPA', (183, 193))	('DMGs', 'Chemical', '-', (63, 67))
524094	29169318	Scatter plot demonstrated that these probes showed an inverse correlation of methylation with expression in tumor versus matched NTL, the Spearman correlation coefficient values for these ten genes were rRAPGEFL1 = -0.829, rCLDN1 = -0.564, rAKR1B10 = -0.709, rTP63 = -0.854, rTBX5 = -0.743, rTCF21 = -0.748, rADHFE1 = -0.685, rGATA6 = -0.831, rGPR87 = -0.749, and rHNF1B = -0.797, respectively (Fig.	('rHNF1B', 'Gene', (364, 370))	('rGATA6', 'Gene', '29300', (326, 332))	('tumor', 'Disease', (108, 113))	('rGPR87', 'Gene', (343, 349))	('rTP63', 'Gene', (259, 264))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('methylation', 'Var', (77, 88))	('rCLDN1', 'Gene', '65129', (223, 229))	('rAKR1B10', 'Gene', (240, 248))	('rADHFE1', 'Gene', '362474', (308, 315))	('rGPR87', 'Gene', '310443', (343, 349))	('rRAPGEFL1', 'Gene', (203, 212))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('rHNF1B', 'Gene', '25640', (364, 370))	('rCLDN1', 'Gene', (223, 229))	('expression', 'MPA', (94, 104))	('rRAPGEFL1', 'Gene', '303515', (203, 212))	('rTP63', 'Gene', '246334', (259, 264))	('rAKR1B10', 'Gene', '296972', (240, 248))	('rGATA6', 'Gene', (326, 332))	('rADHFE1', 'Gene', (308, 315))
524109	29169318	24 tumors were clearly divided into two independent categories: Cluster1 (n = 10) and Cluster 2 (n = 14), Cluster 1 tumors were significantly hypomethylated as compared with Cluster 2 tumors (Fig.	('tumors', 'Disease', (116, 122))	('tumors', 'Disease', 'MESH:D009369', (116, 122))	('Cluster 2 tumors', 'Disease', 'MESH:D003027', (174, 190))	('tumors', 'Phenotype', 'HP:0002664', (3, 9))	('hypomethylated', 'Var', (142, 156))	('tumors', 'Disease', (3, 9))	('tumors', 'Disease', 'MESH:D009369', (3, 9))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('Cluster 1 tumors', 'Disease', (106, 122))	('Cluster 1 tumors', 'Disease', 'MESH:D003027', (106, 122))	('tumors', 'Disease', (184, 190))	('tumors', 'Disease', 'MESH:D009369', (184, 190))	('tumors', 'Phenotype', 'HP:0002664', (184, 190))	('Cluster 2 tumors', 'Disease', (174, 190))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))
524125	29169318	According to current findings, WIF1 promoter methylation was a frequent event as an epigenetic field manner and could be considered as a useful prognostic marker for adenocarcinoma patients.	('promoter methylation', 'Var', (36, 56))	('WIF1', 'Gene', (31, 35))	('WIF1', 'Gene', '11197', (31, 35))	('patients', 'Species', '9606', (181, 189))	('carcinoma', 'Phenotype', 'HP:0030731', (171, 180))	('adenocarcinoma', 'Disease', (166, 180))	('adenocarcinoma', 'Disease', 'MESH:D000230', (166, 180))
524126	29169318	In agreement with this report, our results also showed that WIF1 expression was down-regulated by promoter hypermethylation in LUSC.	('expression', 'MPA', (65, 75))	('WIF1', 'Gene', (60, 64))	('down-regulated', 'NegReg', (80, 94))	('promoter hypermethylation', 'Var', (98, 123))	('WIF1', 'Gene', '11197', (60, 64))
524132	29169318	While our results suggested that hypomethylation might contribute to the upregulation of CLDN1 in LUSC and CLDN1 overexpression may play a role in the pathogenesis of LUSC.	('CLDN1', 'Gene', '65129', (107, 112))	('CLDN1', 'Gene', (89, 94))	('overexpression', 'PosReg', (113, 127))	('CLDN1', 'Gene', (107, 112))	('LUSC', 'Disease', (167, 171))	('CLDN1', 'Gene', '65129', (89, 94))	('LUSC', 'Disease', (98, 102))	('hypomethylation', 'Var', (33, 48))	('play', 'Reg', (132, 136))	('upregulation', 'PosReg', (73, 85))
524135	29169318	TCF21 hypermethylation and reduced protein expression are ubiquitous in NSCLC.	('TCF21', 'Gene', (0, 5))	('reduced', 'NegReg', (27, 34))	('hypermethylation', 'Var', (6, 22))	('NSCLC', 'Disease', (72, 77))	('NSCLC', 'Disease', 'MESH:D002289', (72, 77))	('protein expression', 'MPA', (35, 53))	('NSCLC', 'Phenotype', 'HP:0030358', (72, 77))
524138	29169318	The hypermethylation of ADHFE1 has recently been reported to be associated with colorectal cancer differentiation.	('associated', 'Reg', (64, 74))	('colorectal cancer', 'Disease', 'MESH:D015179', (80, 97))	('ADHFE1', 'Gene', (24, 30))	('colorectal cancer', 'Phenotype', 'HP:0003003', (80, 97))	('ADHFE1', 'Gene', '362474', (24, 30))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('colorectal cancer', 'Disease', (80, 97))	('hypermethylation', 'Var', (4, 20))
524140	29169318	Our results suggested that DNA methylation plays critical roles in lung tumorigenesis and may potentially be proposed as a diagnostic biomarker.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Disease', (72, 77))	('DNA', 'MPA', (27, 30))	('roles', 'Reg', (58, 63))	('methylation', 'Var', (31, 42))	('tumor', 'Disease', 'MESH:D009369', (72, 77))
524153	33922610	The benefit of adjuvant therapy diminished in patients with PD-L1 expression in more than 10% of tumor cells.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('patients', 'Species', '9606', (46, 54))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('PD-L1', 'Gene', (60, 65))	('tumor', 'Disease', (97, 102))	('expression', 'Var', (66, 76))	('PD-L1', 'Gene', '29126', (60, 65))	('diminished', 'NegReg', (32, 42))
524160	33922610	Five-year survival ranges from 50% in N1-positive to 30% or less in patients with N2-disease.	('patients', 'Species', '9606', (68, 76))	('less', 'NegReg', (60, 64))	('N1-positive', 'Var', (38, 49))
524219	33922610	Multivariate analysis in a subgroup of patients with adenocarcinoma histology and adjuvant treatment identified low tumor stage and positive PD-L1 expression as being independently associated with beneficial outcomes.	('adenocarcinoma', 'Disease', (53, 67))	('PD-L1', 'Gene', (141, 146))	('adenocarcinoma', 'Disease', 'MESH:D000230', (53, 67))	('patients', 'Species', '9606', (39, 47))	('PD-L1', 'Gene', '29126', (141, 146))	('expression', 'MPA', (147, 157))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('low tumor', 'Disease', 'MESH:D009800', (112, 121))	('positive', 'Var', (132, 140))	('low tumor', 'Disease', (112, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))	('subgroup', 'Species', '167159', (27, 35))
524237	33922610	included more than 10,000 surgical patients (stages I-III NSCLC), and high PD-L1 expression was associated with poor survival, statistically significant in adenocarcinoma, but not in squamous cell carcinoma.	('adenocarcinoma', 'Disease', (156, 170))	('NSCLC', 'Disease', (58, 63))	('adenocarcinoma', 'Disease', 'MESH:D000230', (156, 170))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (183, 206))	('NSCLC', 'Disease', 'MESH:D002289', (58, 63))	('PD-L1', 'Gene', (75, 80))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (183, 206))	('poor', 'NegReg', (112, 116))	('carcinoma', 'Phenotype', 'HP:0030731', (197, 206))	('squamous cell carcinoma', 'Disease', (183, 206))	('PD-L1', 'Gene', '29126', (75, 80))	('NSCLC', 'Phenotype', 'HP:0030358', (58, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (161, 170))	('patients', 'Species', '9606', (35, 43))	('high', 'Var', (70, 74))	('expression', 'MPA', (81, 91))
524239	33922610	Positive PD-L1-status showed a trend towards better outcomes in univariate analysis of our entire patient cohort.	('patient', 'Species', '9606', (98, 105))	('PD-L1', 'Gene', '29126', (9, 14))	('better', 'PosReg', (45, 51))	('Positive', 'Var', (0, 8))	('PD-L1', 'Gene', (9, 14))
524242	33922610	However, positive PD-L1 was predictive for improved survival after chemotherapy in multivariate analysis of patients with adenocarcinoma histology, but not squamous cell carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (170, 179))	('adenocarcinoma', 'Disease', (122, 136))	('survival', 'MPA', (52, 60))	('adenocarcinoma', 'Disease', 'MESH:D000230', (122, 136))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (156, 179))	('squamous cell carcinoma', 'Disease', (156, 179))	('positive', 'Var', (9, 17))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (156, 179))	('improved', 'PosReg', (43, 51))	('patients', 'Species', '9606', (108, 116))	('PD-L1', 'Gene', (18, 23))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('PD-L1', 'Gene', '29126', (18, 23))
524252	33922610	In this specific smoking-associated entity, the potential that accompanied smoking induced acquired somatic mutations along with oxidative stress that may result in the observed elevated expression of PD-L1 protein, thus leading to durable PD-1 antibody response in clinical studies.	('PD-L1', 'Gene', (201, 206))	('oxidative stress', 'Phenotype', 'HP:0025464', (129, 145))	('mutations', 'Var', (108, 117))	('leading to', 'Reg', (221, 231))	('elevated', 'PosReg', (178, 186))	('PD-L1', 'Gene', '29126', (201, 206))	('protein', 'Protein', (207, 214))	('expression', 'MPA', (187, 197))	('PD-1 antibody response', 'MPA', (240, 262))
524275	33922610	The observed trend towards better survival of PD-L1 positive patients in the entire cohort is assumed to be biased by the higher proportion of PD-L1 positive tumors in patients receiving chemotherapy, which was identified as a strong positive prognostic factor.	('PD-L1', 'Gene', (46, 51))	('tumors', 'Phenotype', 'HP:0002664', (158, 164))	('PD-L1 positive tumors', 'Disease', 'MESH:D010300', (143, 164))	('PD-L1', 'Gene', '29126', (46, 51))	('patients', 'Species', '9606', (61, 69))	('better', 'PosReg', (27, 33))	('PD-L1 positive tumors', 'Disease', (143, 164))	('PD-L1', 'Gene', (143, 148))	('patients', 'Species', '9606', (168, 176))	('positive', 'Var', (52, 60))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('PD-L1', 'Gene', '29126', (143, 148))
524292	32301195	3  Besides, ROS can damnify the vasculature of tumour parenchyma, resulting in blood supply deficiency, 4 ,  5  and further provoke the anti-tumour immune response further.	('tumour', 'Disease', 'MESH:D009369', (47, 53))	('provoke', 'PosReg', (124, 131))	('blood supply deficiency', 'Disease', (79, 102))	('tumour', 'Phenotype', 'HP:0002664', (141, 147))	('tumour', 'Disease', (47, 53))	('ROS', 'Var', (12, 15))	('tumour', 'Disease', 'MESH:D009369', (141, 147))	('tumour parenchyma', 'Disease', (47, 64))	('blood supply deficiency', 'Disease', 'MESH:D007022', (79, 102))	('ROS', 'Chemical', 'MESH:D017382', (12, 15))	('tumour', 'Disease', (141, 147))	('tumour', 'Phenotype', 'HP:0002664', (47, 53))	('tumour parenchyma', 'Disease', 'MESH:D010195', (47, 64))
524301	32301195	Wang and his co-workers 15  recently developed a nanosystem by combining chemotherapy with PDT for the targeted treatment of OTSCC, and they found that CAL-27 cells assimilated PEG linked haematoporphyrin (HP) and depicted high PDT efficiency through the target-peptide-mediated cell internalization.	('PDT', 'Enzyme', (228, 231))	('S', 'Chemical', 'MESH:D013455', (127, 128))	('PEG linked haematoporphyrin', 'Chemical', '-', (177, 204))	('PEG linked', 'Var', (177, 187))	('efficiency', 'MPA', (232, 242))	('CAL-27', 'CellLine', 'CVCL:1107', (152, 158))
524306	32301195	Moreover, by detecting the expression of apoptotic proteins, we also observed that the UM1 cells treated with S-CDs had higher expression levels of apoptotic proteins compared with those treated with classic photosensitizer 5-ALA at the same concentration (Figure 1), indicating the promising application prospect of the developed nano-photosensitizer in the PDT treatment for oral cancer treatment.	('cancer', 'Disease', 'MESH:D009369', (382, 388))	('cancer', 'Disease', (382, 388))	('expression levels', 'MPA', (127, 144))	('higher', 'PosReg', (120, 126))	('apoptotic proteins', 'MPA', (148, 166))	('cancer', 'Phenotype', 'HP:0002664', (382, 388))	('S-CDs', 'Var', (110, 115))	('5-ALA', 'Chemical', '-', (224, 229))	('S-CDs', 'Chemical', '-', (110, 115))
524331	32301195	When entering into cell and meet Ca2+, Fluo-4/AM would transfer to a strongly fluorescent compound.	('Fluo-4', 'Chemical', 'MESH:C409648', (39, 45))	('transfer', 'MPA', (55, 63))	('Fluo-4/AM', 'Var', (39, 48))	('Ca2+', 'Chemical', 'MESH:D000069285', (33, 37))
524354	32301195	Bright green fluorescence was observed in the UM1 cells receiving S-CD-mediated PDT, while no obvious green fluorescent signal was discovered in the groups receiving S-CDs or 5-ALA without light irradiation as well as the group that merely received culture medium (Figure 4A).	('5-ALA', 'Chemical', '-', (175, 180))	('S-CD', 'Gene', '6319', (166, 170))	('S-CD', 'Gene', '6319', (66, 70))	('S-CDs', 'Chemical', '-', (166, 171))	('S-CD', 'Gene', (66, 70))	('PDT', 'Var', (80, 83))	('S-CD', 'Gene', (166, 170))
524358	32301195	The bar chart presented the statistical analysis of the flow cytometry result and showed that the group receiving the S-CDs in the presence of light (green bar) had the highest average fluorescence intensity generated by ROS among the six groups, which was in line with the former flow cytometry results.	('S-CDs', 'Chemical', '-', (118, 123))	('fluorescence intensity generated', 'MPA', (185, 217))	('ROS', 'Chemical', 'MESH:D017382', (221, 224))	('ROS', 'Protein', (221, 224))	('S-CDs', 'Var', (118, 123))
524367	32301195	Firstly, as PDT treatment could raise the concentration of calcium (Ca2+) in cytoplasm, resulting in cell death, 33 ,  34  the alteration in Ca2+ level during light exposure was evaluated by using Fluo-4 AM (a Ca2+ probe).	('Ca2+', 'Chemical', 'MESH:D000069285', (210, 214))	('Fluo-4 AM', 'Chemical', '-', (197, 206))	('PDT', 'Gene', (12, 15))	('treatment', 'Var', (16, 25))	('death', 'Disease', (106, 111))	('death', 'Disease', 'MESH:D003643', (106, 111))	('raise', 'PosReg', (32, 37))	('Ca2+', 'Chemical', 'MESH:D000069285', (141, 145))	('calcium', 'Chemical', 'MESH:D002118', (59, 66))	('Ca2+', 'Chemical', 'MESH:D000069285', (68, 72))
524386	32301195	Firstly, the Fluo-4 AM analysis indicated that the green fluorescent signal of the S-CD-mediated PDT group was brighter than that of the 5-ALA-mediated PDT group, suggesting the high photosensitive oxidation capacity of nano-photosensitizer.	('S-CD', 'Gene', '6319', (83, 87))	('Fluo-4 AM', 'Chemical', '-', (13, 22))	('5-ALA', 'Chemical', '-', (137, 142))	('brighter', 'PosReg', (111, 119))	('PDT', 'Var', (97, 100))	('green fluorescent signal', 'MPA', (51, 75))	('S-CD', 'Gene', (83, 87))
524388	32301195	Therefore, we inferred that the minimum dosage S-CDs provoked apoptosis of UM1 cells via up-regulating the caspase-3 and Bax and decreasing the Bcl-2 level during the PDT.	('caspase-3', 'Gene', (107, 116))	('Bcl-2', 'Gene', '596', (144, 149))	('S-CDs', 'Chemical', '-', (47, 52))	('decreasing', 'NegReg', (129, 139))	('caspase-3', 'Gene', '836', (107, 116))	('Bax', 'Gene', '581', (121, 124))	('apoptosis', 'CPA', (62, 71))	('up-regulating', 'PosReg', (89, 102))	('Bax', 'Gene', (121, 124))	('S-CDs', 'Var', (47, 52))	('Bcl-2', 'Gene', (144, 149))
524391	32301195	Under the condition of light irradiation, the S-CDs may act as a more effective nano-weapon for anticancer therapy compared with traditional PS 5-ALA.	('S-CDs', 'Chemical', '-', (46, 51))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('S-CDs', 'Var', (46, 51))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('PS 5-ALA', 'Chemical', '-', (141, 149))
524414	31870427	We hypothesize that nonplacement of a cervical drainage tube leads to a noninferior postoperative anastomotic leakage rate, duration to oral intake, hospital stay, and less analgesic use compared with placement of a cervical drainage tube, which is the current standard of care.	('postoperative anastomotic leakage', 'Disease', (84, 117))	('analgesic use', 'MPA', (173, 186))	('nonplacement', 'Var', (20, 32))	('hospital stay', 'MPA', (149, 162))	('duration', 'MPA', (124, 132))	('postoperative anastomotic leakage', 'Disease', 'MESH:D057868', (84, 117))
524459	31870427	In the current study, we hypothesize that nonplacement of a cervical drainage tube will lead to a noninferior postoperative anastomotic leakage rate.	('nonplacement', 'Var', (42, 54))	('postoperative anastomotic leakage', 'Disease', 'MESH:D057868', (110, 143))	('postoperative anastomotic leakage', 'Disease', (110, 143))	('lead to', 'Reg', (88, 95))
524466	29793547	Long noncoding RNA AFAP1-AS1 predicts a poor prognosis and regulates non-small cell lung cancer cell proliferation by epigenetically repressing p21 expression Mounting evidence indicates that long noncoding RNAs (lncRNAs) could play a pivotal role in cancer biology.	('AFAP1', 'Gene', (19, 24))	('AFAP1', 'Gene', '60312', (19, 24))	('lung cancer', 'Phenotype', 'HP:0100526', (84, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (73, 95))	('p21', 'Gene', (144, 147))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('regulates', 'Reg', (59, 68))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (69, 95))	('cancer', 'Disease', (89, 95))	('AS1', 'Gene', (25, 28))	('cancer', 'Disease', 'MESH:D009369', (251, 257))	('expression', 'MPA', (148, 158))	('AS1', 'Gene', '5729', (25, 28))	('cancer', 'Disease', (251, 257))	('epigenetically', 'Var', (118, 132))	('p21', 'Gene', '1026', (144, 147))
524467	29793547	However, the role and molecular mechanism and global genes that were mediated by lncRNA AFAP1-AS1 in non-small cell lung cancer (NSCLC) remain largely unknown.	('cell lung cancer', 'Disease', 'MESH:D008175', (111, 127))	('AFAP1-AS1', 'Gene', '84740;60312;5729', (88, 97))	('lung cancer', 'Phenotype', 'HP:0100526', (116, 127))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (105, 127))	('AFAP1-AS1', 'Gene', (88, 97))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (101, 127))	('NSCLC', 'Disease', (129, 134))	('lncRNA', 'Var', (81, 87))	('NSCLC', 'Disease', 'MESH:D002289', (129, 134))	('cell lung cancer', 'Disease', (111, 127))
524470	29793547	RNA-seq assays were performed after knockdown AFAP1-AS1.	('knockdown', 'Var', (36, 45))	('AFAP1-AS1', 'Gene', '84740;60312;5729', (46, 55))	('AFAP1-AS1', 'Gene', (46, 55))
524475	29793547	RNA-seq revealed that knockdown of AFAP1-AS1 could induce the expression of p21.	('AFAP1-AS1', 'Gene', (35, 44))	('p21', 'Gene', '1026', (76, 79))	('expression', 'MPA', (62, 72))	('p21', 'Gene', (76, 79))	('knockdown', 'Var', (22, 31))	('induce', 'PosReg', (51, 57))	('AFAP1-AS1', 'Gene', '84740;60312;5729', (35, 44))
524476	29793547	Mechanistic investigations found that AFAP1-AS1 could interact with EZH2 and recruit EZH2 to the promoter regions of p21, thus epigenetically repressing p21 expression.	('EZH2', 'Gene', (68, 72))	('EZH2', 'Gene', '2146', (85, 89))	('expression', 'MPA', (157, 167))	('EZH2', 'Gene', (85, 89))	('p21', 'Gene', '1026', (117, 120))	('repressing', 'NegReg', (142, 152))	('p21', 'Gene', (117, 120))	('epigenetically', 'Var', (127, 141))	('p21', 'Gene', '1026', (153, 156))	('AFAP1-AS1', 'Gene', '84740;60312;5729', (38, 47))	('interact', 'Interaction', (54, 62))	('recruit', 'PosReg', (77, 84))	('EZH2', 'Gene', '2146', (68, 72))	('p21', 'Gene', (153, 156))	('AFAP1-AS1', 'Gene', (38, 47))
524483	29793547	In addition, an emerging paradigm of the aberrant lncRNAs has been found to participate in NSCLC development and progression.	('NSCLC', 'Disease', 'MESH:D002289', (91, 96))	('aberrant', 'Var', (41, 49))	('progression', 'CPA', (113, 124))	('NSCLC', 'Disease', (91, 96))	('participate', 'Reg', (76, 87))
524485	29793547	Elevated LINC00473 expression correlates with poor prognosis, and elevated LINC00473 serve as a robust biomarker for LKB1-inactivated NSCLC.	('expression', 'MPA', (19, 29))	('NSCLC', 'Disease', 'MESH:D002289', (134, 139))	('LINC00473', 'Gene', '90632', (75, 84))	('elevated', 'Var', (66, 74))	('LINC00473', 'Gene', (9, 18))	('LKB1', 'Gene', (117, 121))	('LINC00473', 'Gene', '90632', (9, 18))	('LINC00473', 'Gene', (75, 84))	('LKB1', 'Gene', '6794', (117, 121))	('NSCLC', 'Disease', (134, 139))
524490	29793547	These results indicate that AFAP1-AS1 may be necessary for development, and that its dysregulation may participate in human cancer progression.	('participate', 'Reg', (103, 114))	('cancer', 'Disease', (124, 130))	('dysregulation', 'Var', (85, 98))	('AFAP1-AS1', 'Gene', '84740;60312;5729', (28, 37))	('human', 'Species', '9606', (118, 123))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('human', 'CPA', (118, 123))	('AFAP1-AS1', 'Gene', (28, 37))	('cancer', 'Disease', 'MESH:D009369', (124, 130))
524491	29793547	found that knockdown of AFAP1-AS1 inhibits tumor cell growth and invasion in lung cancer.	('lung cancer', 'Phenotype', 'HP:0100526', (77, 88))	('AFAP1-AS1 inhibits tumor', 'Disease', 'OMIM:607277', (24, 48))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('lung cancer', 'Disease', 'MESH:D008175', (77, 88))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('invasion', 'CPA', (65, 73))	('AFAP1-AS1 inhibits tumor', 'Disease', (24, 48))	('knockdown', 'Var', (11, 20))	('lung cancer', 'Disease', (77, 88))
524517	29793547	Total RNA from the A549 cells with AFAP1-AS1 knockdown and control A549 cells were isolated and quantified.	('AFAP1-AS1', 'Gene', (35, 44))	('AFAP1-AS1', 'Gene', '84740;60312;5729', (35, 44))	('A549', 'CellLine', 'CVCL:0023', (19, 23))	('A549', 'CellLine', 'CVCL:0023', (67, 71))	('knockdown', 'Var', (45, 54))
524534	29793547	The median survival time for low AFAP1-AS1 expression groups was 43.989 +- 2.238 months, while that for high AFAP1-AS1 expression groups was only 30.505 +- 2.288 months.	('AFAP1-AS1', 'Gene', '84740;60312;5729', (109, 118))	('AFAP1-AS1', 'Gene', (33, 42))	('low', 'Var', (29, 32))	('AFAP1-AS1', 'Gene', (109, 118))	('AFAP1-AS1', 'Gene', '84740;60312;5729', (33, 42))
524547	29793547	Then BrdU assays demonstrated that AFAP1-AS1 knockdown had a significant repression on NSCLC cell proliferation (Fig.	('AFAP1-AS1', 'Gene', (35, 44))	('NSCLC', 'Disease', (87, 92))	('NSCLC', 'Disease', 'MESH:D002289', (87, 92))	('AFAP1-AS1', 'Gene', '84740;60312;5729', (35, 44))	('repression', 'NegReg', (73, 83))	('knockdown', 'Var', (45, 54))
524552	29793547	The results showed that tumors grown from AFAP1-AS1 stable knockdown cells were smaller than tumors grown from control cells (Fig.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumors', 'Disease', (24, 30))	('tumors', 'Disease', 'MESH:D009369', (24, 30))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('tumors', 'Disease', 'MESH:D009369', (93, 99))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('AFAP1-AS1', 'Gene', '84740;60312;5729', (42, 51))	('knockdown', 'Var', (59, 68))	('smaller', 'NegReg', (80, 87))	('tumors', 'Disease', (93, 99))	('AFAP1-AS1', 'Gene', (42, 51))
524558	29793547	A common set of 347 mRNAs showed >=2-fold increased expression in AFAP1-AS1-depleted cells and silencing AFAP1-AS1 also reduced the abundance (<= 2-fold) of 244 genes (Fig.	('increased', 'PosReg', (42, 51))	('AFAP1-AS1', 'Gene', (66, 75))	('AFAP1-AS1', 'Gene', '84740;60312;5729', (105, 114))	('expression', 'MPA', (52, 62))	('abundance', 'MPA', (132, 141))	('AFAP1-AS1', 'Gene', '84740;60312;5729', (66, 75))	('AFAP1-AS1', 'Gene', (105, 114))	('silencing', 'Var', (95, 104))	('reduced', 'NegReg', (120, 127))
524561	29793547	Enhancer of zeste homolog 2 (EZH2), the catalytic subunit of the PRC2, could epigenetically repress transcription of specific genes.	('repress', 'NegReg', (92, 99))	('Enhancer of zeste homolog 2', 'Gene', '2146', (0, 27))	('epigenetically', 'Var', (77, 91))	('transcription of specific genes', 'MPA', (100, 131))	('Enhancer of zeste homolog 2', 'Gene', (0, 27))	('EZH2', 'Gene', (29, 33))	('EZH2', 'Gene', '2146', (29, 33))
524562	29793547	In addition, aberrations in EZH2 are closely related to carcinogenesis.	('related', 'Reg', (45, 52))	('EZH2', 'Gene', '2146', (28, 32))	('EZH2', 'Gene', (28, 32))	('carcinogenesis', 'Disease', 'MESH:D063646', (56, 70))	('aberrations', 'Var', (13, 24))	('carcinogenesis', 'Disease', (56, 70))
524569	29793547	RNA-Seq found that knockdown of AFAP1-AS1 could significantly decrease a series of genes which promoting proliferation.	('AFAP1-AS1', 'Gene', '84740;60312;5729', (32, 41))	('knockdown', 'Var', (19, 28))	('proliferation', 'CPA', (105, 118))	('AFAP1-AS1', 'Gene', (32, 41))	('decrease', 'NegReg', (62, 70))	('promoting', 'PosReg', (95, 104))
524571	29793547	Importantly, aberrant methylation in promoter regions of p21 has been linked to downregulation of p21 in cancer cells.	('p21', 'Gene', '1026', (57, 60))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('methylation', 'MPA', (22, 33))	('p21', 'Gene', '1026', (98, 101))	('p21', 'Gene', (98, 101))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('p21', 'Gene', (57, 60))	('downregulation', 'NegReg', (80, 94))	('aberrant', 'Var', (13, 21))
524574	29793547	6a, western blot analysis showed that the protein expression levels of p21 after knockdown AFAP1-AS1.	('AFAP1-AS1', 'Gene', '84740;60312;5729', (91, 100))	('p21', 'Gene', '1026', (71, 74))	('knockdown', 'Var', (81, 90))	('AFAP1-AS1', 'Gene', (91, 100))	('p21', 'Gene', (71, 74))	('protein expression levels', 'MPA', (42, 67))
524575	29793547	Importantly, qRT-PCR and western blot analyses show that EZH2 knockdown could induce expression levels of p21 mRNA and protein (Fig.	('EZH2', 'Gene', (57, 61))	('expression levels', 'MPA', (85, 102))	('induce', 'PosReg', (78, 84))	('EZH2', 'Gene', '2146', (57, 61))	('p21', 'Gene', '1026', (106, 109))	('p21', 'Gene', (106, 109))	('knockdown', 'Var', (62, 71))
524577	29793547	The results showed that EZH2 could bind to the p21 promoter regions, and knockdown of AFAP1-AS1 reduced EZH2-mediated H3K27me3 trimethylation (Fig.	('AFAP1-AS1', 'Gene', (86, 95))	('reduced', 'NegReg', (96, 103))	('EZH2', 'Gene', '2146', (104, 108))	('EZH2', 'Gene', '2146', (24, 28))	('EZH2', 'Gene', (104, 108))	('EZH2', 'Gene', (24, 28))	('H3K27me3', 'Protein', (118, 126))	('AFAP1-AS1', 'Gene', '84740;60312;5729', (86, 95))	('p21', 'Gene', '1026', (47, 50))	('p21', 'Gene', (47, 50))	('knockdown', 'Var', (73, 82))
524580	29793547	These results suggest that AFAP1-AS1 could promote NSCLC cell growth partly through epigenetically silencing p21 transcription by binding to EZH2.	('AFAP1-AS1', 'Gene', (27, 36))	('promote', 'PosReg', (43, 50))	('NSCLC', 'Disease', (51, 56))	('EZH2', 'Gene', '2146', (141, 145))	('NSCLC', 'Disease', 'MESH:D002289', (51, 56))	('EZH2', 'Gene', (141, 145))	('p21', 'Gene', '1026', (109, 112))	('AFAP1-AS1', 'Gene', '84740;60312;5729', (27, 36))	('p21', 'Gene', (109, 112))	('epigenetically silencing', 'Var', (84, 108))	('binding', 'Interaction', (130, 137))
524582	29793547	To date, increasing evidence links dysregulation of lncRNAs to diverse human diseases especially in tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Disease', (100, 105))	('dysregulation', 'Var', (35, 48))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('lncRNAs', 'Protein', (52, 59))	('human', 'Species', '9606', (71, 76))
524589	29793547	Besides, knockdown of LncRNA AFAP1-AS1 in GBC cells inhibited EMT by upregulating the E-cadherin and downregulating the transcription factor Twist1 and Vimentin.	('knockdown', 'Var', (9, 18))	('Twist1', 'Gene', (141, 147))	('Vimentin', 'Gene', (152, 160))	('transcription factor', 'MPA', (120, 140))	('AFAP1-AS1', 'Gene', (29, 38))	('E-cadherin', 'Gene', '999', (86, 96))	('downregulating', 'NegReg', (101, 115))	('upregulating', 'PosReg', (69, 81))	('AFAP1-AS1', 'Gene', '84740;60312;5729', (29, 38))	('Vimentin', 'Gene', '7431', (152, 160))	('inhibited', 'NegReg', (52, 61))	('Twist1', 'Gene', '7291', (141, 147))	('E-cadherin', 'Gene', (86, 96))	('EMT', 'CPA', (62, 65))
524603	29793547	Notably, Our RNA-seq data found that p21 was significantly upregulated after AFAP1-AS1 knockdown.	('AFAP1-AS1', 'Gene', '84740;60312;5729', (77, 86))	('p21', 'Gene', '1026', (37, 40))	('upregulated', 'PosReg', (59, 70))	('AFAP1-AS1', 'Gene', (77, 86))	('p21', 'Gene', (37, 40))	('knockdown', 'Var', (87, 96))
524605	29793547	Our findings demonstrated that AFAP1-AS1 promotes lung cancer cell proliferation by epigenetically repressing p21 expression.	('lung cancer', 'Disease', (50, 61))	('AFAP1-AS1', 'Gene', (31, 40))	('p21', 'Gene', '1026', (110, 113))	('epigenetically repressing', 'Var', (84, 109))	('lung cancer', 'Disease', 'MESH:D008175', (50, 61))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('promotes', 'PosReg', (41, 49))	('p21', 'Gene', (110, 113))	('AFAP1-AS1', 'Gene', '84740;60312;5729', (31, 40))	('expression', 'MPA', (114, 124))	('lung cancer', 'Phenotype', 'HP:0100526', (50, 61))
524607	29793547	The loss of AFAP1-AS1 inhibited NSCLC cell proliferation in vitro and suppressed tumor growth in vivo.	('AFAP1-AS1', 'Gene', '84740;60312;5729', (12, 21))	('inhibited', 'NegReg', (22, 31))	('AFAP1-AS1', 'Gene', (12, 21))	('suppressed', 'NegReg', (70, 80))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('NSCLC', 'Disease', (32, 37))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('NSCLC', 'Disease', 'MESH:D002289', (32, 37))	('tumor', 'Disease', (81, 86))	('loss', 'Var', (4, 8))
524608	29793547	Furthermore, AFAP1-AS1-mediated oncogenic effects occurred partially through epigenetic suppression of p21 expression by binding to EZH2.	('p21', 'Gene', '1026', (103, 106))	('oncogenic effects', 'CPA', (32, 49))	('p21', 'Gene', (103, 106))	('expression', 'MPA', (107, 117))	('EZH2', 'Gene', '2146', (132, 136))	('epigenetic', 'Var', (77, 87))	('AFAP1-AS1', 'Gene', '84740;60312;5729', (13, 22))	('EZH2', 'Gene', (132, 136))	('binding', 'Interaction', (121, 128))	('AFAP1-AS1', 'Gene', (13, 22))
524679	30241031	However, if their levels are not tightly maintained, excess ROS lead to potentially cytotoxic oxidative stress.	('excess', 'Var', (53, 59))	('ROS', 'Protein', (60, 63))	('lead to', 'Reg', (64, 71))	('cytotoxic oxidative stress', 'MPA', (84, 110))	('oxidative stress', 'Phenotype', 'HP:0025464', (94, 110))	('ROS', 'Chemical', 'MESH:D017382', (60, 63))
524692	30241031	ROS have the potential to react with and damage all classes of macromolecules, so they are often viewed as cytotoxic.	('ROS', 'Var', (0, 3))	('damage', 'Reg', (41, 47))	('ROS', 'Chemical', 'MESH:D017382', (0, 3))	('classes', 'Protein', (52, 59))	('react', 'Interaction', (26, 31))
524696	30241031	In fact, many proteins that regulate angiogenesis, cell cycle progression, stem cell self-renewal, and differentiation are activated upon being oxidized by ROS.	('proteins', 'Protein', (14, 22))	('cell cycle progression', 'CPA', (51, 73))	('angiogenesis', 'CPA', (37, 49))	('differentiation', 'CPA', (103, 118))	('oxidized', 'Var', (144, 152))	('ROS', 'Chemical', 'MESH:D017382', (156, 159))	('activated', 'PosReg', (123, 132))	('ROS', 'Var', (156, 159))	('stem cell self-renewal', 'CPA', (75, 97))
524697	30241031	Thus, the role of cellular ROS is somewhat paradoxical: ROS can cause damage with potentially dire consequences, yet ROS are required as signaling molecules for normal development.	('ROS', 'Chemical', 'MESH:D017382', (27, 30))	('cause', 'Reg', (64, 69))	('ROS', 'Chemical', 'MESH:D017382', (117, 120))	('ROS', 'Var', (56, 59))	('ROS', 'Chemical', 'MESH:D017382', (56, 59))	('damage', 'MPA', (70, 76))
524707	30241031	ROS modification of KEAP1's cysteine residues decreases its ability to target NRF2 for ubiquitination so, as a consequence, NRF2 activity is increased by ROS.	('NRF2', 'Gene', '4780', (124, 128))	('cysteine', 'Chemical', 'MESH:D003545', (28, 36))	('ability', 'MPA', (60, 67))	('ROS', 'Chemical', 'MESH:D017382', (0, 3))	('KEAP1', 'Gene', (20, 25))	('increased', 'PosReg', (141, 150))	('NRF2', 'Gene', '4780', (78, 82))	('NRF2', 'Gene', (124, 128))	('modification', 'Var', (4, 16))	('decreases', 'NegReg', (46, 55))	('activity', 'MPA', (129, 137))	('NRF2', 'Gene', (78, 82))	('ROS', 'Chemical', 'MESH:D017382', (154, 157))	('KEAP1', 'Gene', '9817', (20, 25))	('ROS', 'Var', (154, 157))
524710	30241031	However, hypoxia triggers a paradoxical increase in ROS generation at the mitochondria, these hypoxia-induced ROS inhibit PHD activity and, therefore, increase HIF1alpha stability and activity.	('hypoxia', 'Disease', (9, 16))	('HIF1alpha', 'Gene', '3091', (160, 169))	('inhibit', 'NegReg', (114, 121))	('PHD', 'Disease', 'MESH:D011547', (122, 125))	('activity', 'MPA', (184, 192))	('increase', 'PosReg', (40, 48))	('increase', 'PosReg', (151, 159))	('PHD', 'Disease', (122, 125))	('ROS', 'Var', (110, 113))	('hypoxia', 'Disease', 'MESH:D000860', (9, 16))	('stability', 'MPA', (170, 179))	('ROS', 'Chemical', 'MESH:D017382', (110, 113))	('ROS', 'Chemical', 'MESH:D017382', (52, 55))	('hypoxia', 'Disease', 'MESH:D000860', (94, 101))	('HIF1alpha', 'Gene', (160, 169))	('hypoxia', 'Disease', (94, 101))	('ROS generation at the mitochondria', 'MPA', (52, 86))
524712	30241031	Because ROS can modify the activity of many TF networks, an unbiased genome-wide view of the transcriptional response to ROS has the potential to identify novel connections between redox-responsive TFs.	('connections', 'Interaction', (161, 172))	('modify', 'Reg', (16, 22))	('ROS', 'Var', (8, 11))	('ROS', 'Chemical', 'MESH:D017382', (121, 124))	('TF networks', 'Pathway', (44, 55))	('ROS', 'Chemical', 'MESH:D017382', (8, 11))	('activity', 'MPA', (27, 35))
524716	30241031	We confirmed these genomic findings in multiple cell lines, we identified a functional NRF2 binding site (i.e., an antioxidant response element, or ARE) approximately 32 kilobases upstream of HIF1A, and we found that oncogenic NRF2 mutations are associated with high HIF1A expression in multiple cancer types.	('NRF2', 'Gene', '4780', (87, 91))	('NRF2', 'Gene', '4780', (227, 231))	('NRF2', 'Gene', (87, 91))	('cancer', 'Phenotype', 'HP:0002664', (296, 302))	('multiple cancer', 'Disease', 'MESH:D009369', (287, 302))	('NRF2', 'Gene', (227, 231))	('mutations', 'Var', (232, 241))	('HIF1A', 'Gene', (267, 272))	('expression', 'MPA', (273, 283))	('multiple cancer', 'Disease', (287, 302))
524742	30241031	And, importantly, HIF1A expression has been linked to ROS in multiple settings: HIF1A mRNA is upregulated by ROS-inducing mutations in mouse lung carcinoma cells, by multiple sources of ROS in pulmonary artery smooth muscle cells, by chemotherapeutic-induced ROS, and by the ROS-inducer arsenite.	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('lung carcinoma cells', 'Disease', (141, 161))	('mRNA', 'MPA', (86, 90))	('ROS-inducing', 'Gene', (109, 121))	('arsenite', 'Chemical', 'MESH:C015001', (287, 295))	('ROS', 'Chemical', 'MESH:D017382', (275, 278))	('mouse', 'Species', '10090', (135, 140))	('lung carcinoma cells', 'Disease', 'MESH:D055752', (141, 161))	('upregulated', 'PosReg', (94, 105))	('mutations', 'Var', (122, 131))	('HIF1A', 'Gene', (80, 85))	('ROS', 'Chemical', 'MESH:D017382', (186, 189))	('ROS', 'Chemical', 'MESH:D017382', (259, 262))	('ROS', 'Chemical', 'MESH:D017382', (109, 112))	('ROS-inducing', 'Reg', (109, 121))	('ROS', 'Chemical', 'MESH:D017382', (54, 57))
524757	30241031	As expected, an unlabeled version of the NQO1 probe competes for binding with the labeled probe, and mutation of the NQO1 ARE sequence eliminates competition for binding; thus, this interaction is specific and ARE-dependent.	('NQO1', 'Gene', (117, 121))	('NQO1', 'Gene', '1728', (117, 121))	('binding', 'Interaction', (65, 72))	('competition', 'MPA', (146, 157))	('NQO1', 'Gene', (41, 45))	('binding', 'Interaction', (162, 169))	('eliminates', 'NegReg', (135, 145))	('mutation', 'Var', (101, 109))	('NQO1', 'Gene', '1728', (41, 45))
524762	30241031	4, menadione treatment led to a significant increase in HIF1AWT reporter activity in all three cell types, and this induction was eliminated by mutation of the ARE sequence (HIF1AMut).	('mutation', 'Var', (144, 152))	('increase', 'PosReg', (44, 52))	('HIF1AWT', 'Gene', (56, 63))	('menadione', 'Chemical', 'MESH:D024483', (3, 12))
524769	30241031	For example, NRF2 knockdown impairs hypoxia-mediated induction of HIF1alpha in both glioblastoma and colon cancer cells, and NRF2 overexpression drives HIF1alpha induction in multiple cancer cell lines.	('hypoxia', 'Disease', 'MESH:D000860', (36, 43))	('colon cancer', 'Disease', 'MESH:D015179', (101, 113))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('NRF2', 'Gene', (125, 129))	('multiple cancer', 'Disease', 'MESH:D009369', (175, 190))	('HIF1alpha', 'Gene', '3091', (66, 75))	('HIF1alpha', 'Gene', '3091', (152, 161))	('glioblastoma', 'Disease', (84, 96))	('glioblastoma', 'Phenotype', 'HP:0012174', (84, 96))	('colon cancer', 'Disease', (101, 113))	('overexpression', 'PosReg', (130, 144))	('HIF1alpha', 'Gene', (152, 161))	('HIF1alpha', 'Gene', (66, 75))	('impairs', 'NegReg', (28, 35))	('knockdown', 'Var', (18, 27))	('multiple cancer', 'Disease', (175, 190))	('NRF2', 'Gene', '4780', (13, 17))	('colon cancer', 'Phenotype', 'HP:0003003', (101, 113))	('NRF2', 'Gene', '4780', (125, 129))	('hypoxia', 'Disease', (36, 43))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('NRF2', 'Gene', (13, 17))	('glioblastoma', 'Disease', 'MESH:D005909', (84, 96))
524774	30241031	However, HIF1A was also induced by menadione in NRF2 knockout cells, but this induction was not as robust as that of control MDA-MB-231 cells (Fig.	('NRF2', 'Gene', '4780', (48, 52))	('menadione', 'Chemical', 'MESH:D024483', (35, 44))	('knockout', 'Var', (53, 61))	('NRF2', 'Gene', (48, 52))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (125, 135))	('HIF1A', 'Gene', (9, 14))
524782	30241031	This is useful because mutations that disrupt the interaction between NRF2 and its inhibitor KEAP1 are common in multiple cancer types - these mutations, which can occur in either NRF2 or KEAP1, drive constitutive NRF2 activity and provide cells with multiple oncogenic advantages.	('multiple cancer', 'Disease', (113, 128))	('activity', 'MPA', (219, 227))	('NRF2', 'Gene', '4780', (180, 184))	('KEAP1', 'Gene', '9817', (93, 98))	('NRF2', 'Gene', '4780', (70, 74))	('KEAP1', 'Gene', (188, 193))	('drive', 'PosReg', (195, 200))	('NRF2', 'Gene', (70, 74))	('NRF2', 'Gene', (180, 184))	('NRF2', 'Gene', '4780', (214, 218))	('oncogenic advantages', 'CPA', (260, 280))	('KEAP1', 'Gene', (93, 98))	('mutations', 'Var', (23, 32))	('NRF2', 'Gene', (214, 218))	('multiple cancer', 'Disease', 'MESH:D009369', (113, 128))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('mutations', 'Var', (143, 152))	('KEAP1', 'Gene', '9817', (188, 193))
524783	30241031	To test the impact of oncogenic NRF2 activity on downstream expression of HIF1A (and, for comparison, NQO1) we looked at the expression of both genes in the three cancer types where mutations in NRF2 or KEAP1 are most prevalent: bladder carcinoma (BLCA), lung squamous cell carcinoma (LUSC), and lung squamous cell carcinoma (LUAD).	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (296, 324))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (301, 324))	('lung squamous cell carcinoma', 'Disease', (296, 324))	('NQO1', 'Gene', (102, 106))	('cancer', 'Disease', 'MESH:D009369', (163, 169))	('NRF2', 'Gene', (195, 199))	('NRF2', 'Gene', '4780', (32, 36))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (255, 283))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (229, 246))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (260, 283))	('lung squamous cell carcinoma', 'Disease', (255, 283))	('bladder carcinoma', 'Disease', 'MESH:D001749', (229, 246))	('mutations', 'Var', (182, 191))	('carcinoma', 'Phenotype', 'HP:0030731', (237, 246))	('carcinoma', 'Phenotype', 'HP:0030731', (315, 324))	('NRF2', 'Gene', (32, 36))	('bladder carcinoma', 'Disease', (229, 246))	('cancer', 'Disease', (163, 169))	('KEAP1', 'Gene', '9817', (203, 208))	('KEAP1', 'Gene', (203, 208))	('prevalent', 'Reg', (218, 227))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('carcinoma', 'Phenotype', 'HP:0030731', (274, 283))	('NQO1', 'Gene', '1728', (102, 106))	('NRF2', 'Gene', '4780', (195, 199))
524784	30241031	For each cancer, we separated individual tumors into those with no mutation in NRF2 or KEAP1 (NRF2WT; KEAP1WT), those with a mutation in NRF2 (NRF2mut), and those with a mutation in KEAP1 (KEAP1mut); we then compared the expression of HIF1A and NQO1 across the three tumor classes for each cancer type (Fig.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('cancer', 'Disease', (9, 15))	('NQO1', 'Gene', (245, 249))	('tumor', 'Disease', 'MESH:D009369', (267, 272))	('tumors', 'Disease', (41, 47))	('NRF2', 'Gene', (94, 98))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('NRF2', 'Gene', '4780', (137, 141))	('KEAP1', 'Gene', '9817', (87, 92))	('cancer', 'Disease', 'MESH:D009369', (290, 296))	('tumors', 'Disease', 'MESH:D009369', (41, 47))	('KEAP1mut', 'Gene', '9817', (189, 197))	('KEAP1', 'Gene', (87, 92))	('compared', 'Reg', (208, 216))	('tumor', 'Phenotype', 'HP:0002664', (267, 272))	('NRF2', 'Gene', '4780', (143, 147))	('KEAP1', 'Gene', '9817', (102, 107))	('NRF2', 'Gene', '4780', (79, 83))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('NRF2', 'Gene', (137, 141))	('NRF2mut', 'Gene', '4780', (143, 150))	('KEAP1', 'Gene', '9817', (189, 194))	('KEAP1', 'Gene', (102, 107))	('KEAP1', 'Gene', '9817', (182, 187))	('tumor', 'Disease', (41, 46))	('KEAP1', 'Gene', (189, 194))	('KEAP1', 'Gene', (182, 187))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('NRF2', 'Gene', (143, 147))	('NRF2', 'Gene', '4780', (94, 98))	('NRF2', 'Gene', (79, 83))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('NQO1', 'Gene', '1728', (245, 249))	('KEAP1mut', 'Gene', (189, 197))	('cancer', 'Disease', (290, 296))	('tumor', 'Disease', (267, 272))	('NRF2mut', 'Gene', (143, 150))	('cancer', 'Phenotype', 'HP:0002664', (290, 296))	('mutation', 'Var', (125, 133))
524785	30241031	NQO1 upregulation in NRF2mut tumors was significant across all three cancer types, consistent with the idea that cancer-associated NRF2 mutations often lead to NRF2 hyperactivation; a similar, though less robust, pattern was seen for NQO1 expression in KEAP1mut tumors.	('NRF2', 'Gene', (21, 25))	('tumor', 'Phenotype', 'HP:0002664', (262, 267))	('NRF2', 'Gene', '4780', (131, 135))	('tumors', 'Phenotype', 'HP:0002664', (262, 268))	('cancer', 'Disease', (113, 119))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('NRF2 hyperactivation', 'Disease', (160, 180))	('mutations', 'Var', (136, 145))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('NRF2mut', 'Gene', (21, 28))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('NQO1', 'Gene', '1728', (234, 238))	('KEAP1mut', 'Gene', '9817', (253, 261))	('NRF2', 'Gene', '4780', (160, 164))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumors', 'Disease', (262, 268))	('NRF2', 'Gene', (131, 135))	('NQO1', 'Gene', (234, 238))	('tumors', 'Disease', (29, 35))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('upregulation', 'PosReg', (5, 17))	('NRF2', 'Gene', (160, 164))	('NRF2', 'Gene', '4780', (21, 25))	('KEAP1mut', 'Gene', (253, 261))	('tumors', 'Disease', 'MESH:D009369', (262, 268))	('tumors', 'Disease', 'MESH:D009369', (29, 35))	('lead to', 'Reg', (152, 159))	('NQO1', 'Gene', '1728', (0, 4))	('cancer', 'Disease', (69, 75))	('NRF2mut', 'Gene', '4780', (21, 28))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('NQO1', 'Gene', (0, 4))	('NRF2 hyperactivation', 'Disease', 'MESH:D011504', (160, 180))
524787	30241031	Thus, whereas NQO1 is almost always induced in tumors with presumed NRF2 hyperactivating mutations, NRF2-associated induction of HIF1A is limited to select cancer types (BLCA and LUSC).	('HIF1A', 'Gene', (129, 134))	('NRF2', 'Gene', (100, 104))	('tumors', 'Disease', (47, 53))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('cancer', 'Disease', (156, 162))	('cancer', 'Disease', 'MESH:D009369', (156, 162))	('NRF2', 'Gene', '4780', (68, 72))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('NQO1', 'Gene', (14, 18))	('mutations', 'Var', (89, 98))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('NRF2', 'Gene', (68, 72))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))	('NQO1', 'Gene', '1728', (14, 18))	('NRF2', 'Gene', '4780', (100, 104))
524789	30241031	Although oncogenic NRF2 mutations are rare in breast cancer, NRF2 can also be indirectly hyperactivated in many cancer types.	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('NRF2', 'Gene', '4780', (19, 23))	('NRF2', 'Gene', '4780', (61, 65))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('NRF2', 'Gene', (19, 23))	('hyperactivated', 'PosReg', (89, 103))	('breast cancer', 'Disease', 'MESH:D001943', (46, 59))	('mutations', 'Var', (24, 33))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('breast cancer', 'Disease', (46, 59))	('NRF2', 'Gene', (61, 65))	('breast cancer', 'Phenotype', 'HP:0003002', (46, 59))
524792	30241031	Overall, the gene expression patterns in clinical tumor samples are consistent with the regulatory strategies implied by the NRF2 knockout results: activation of NQO1 by oncogenic NRF2 was consistent across all four cancer types, whereas NRF2-associated activation of HIF1A was dependent on cancer type, and most robust in bladder and breast cancer.	('activation', 'PosReg', (148, 158))	('cancer', 'Disease', 'MESH:D009369', (291, 297))	('cancer', 'Disease', (342, 348))	('NRF2', 'Gene', (180, 184))	('NRF2', 'Gene', (125, 129))	('cancer', 'Disease', (216, 222))	('bladder and breast cancer', 'Disease', 'MESH:D001749', (323, 348))	('cancer', 'Phenotype', 'HP:0002664', (342, 348))	('NQO1', 'Gene', '1728', (162, 166))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('NQO1', 'Gene', (162, 166))	('tumor', 'Disease', (50, 55))	('cancer', 'Disease', 'MESH:D009369', (342, 348))	('NRF2', 'Gene', '4780', (238, 242))	('cancer', 'Disease', (291, 297))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('cancer', 'Disease', 'MESH:D009369', (216, 222))	('cancer', 'Phenotype', 'HP:0002664', (291, 297))	('NRF2', 'Gene', '4780', (180, 184))	('NRF2', 'Gene', '4780', (125, 129))	('breast cancer', 'Phenotype', 'HP:0003002', (335, 348))	('NRF2', 'Gene', (238, 242))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('oncogenic', 'Var', (170, 179))
524797	30241031	Additionally, we find that HIF1A expression is enhanced by oncogenic NRF2 mutations in certain cancer types.	('enhanced', 'PosReg', (47, 55))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('NRF2', 'Gene', (69, 73))	('mutations', 'Var', (74, 83))	('cancer', 'Disease', (95, 101))	('HIF1A', 'Gene', (27, 32))	('expression', 'MPA', (33, 43))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('NRF2', 'Gene', '4780', (69, 73))
524803	30241031	NRF2 can be directly activated in cancer via mutation in NRF2 or KEAP1, indirectly activated via additional oncogenic pathways, and possibly activated by ROS generated during hypoxia, which is common in solid tumors - downstream activation of HIF1A could be important in any of these tumorigenic conditions.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('KEAP1', 'Gene', (65, 70))	('tumors', 'Disease', 'MESH:D009369', (209, 215))	('tumor', 'Disease', 'MESH:D009369', (284, 289))	('activated', 'PosReg', (21, 30))	('tumor', 'Disease', (209, 214))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('NRF2', 'Gene', '4780', (57, 61))	('hypoxia', 'Disease', (175, 182))	('tumor', 'Phenotype', 'HP:0002664', (284, 289))	('tumor', 'Disease', 'MESH:D009369', (209, 214))	('NRF2', 'Gene', '4780', (0, 4))	('tumors', 'Phenotype', 'HP:0002664', (209, 215))	('hypoxia', 'Disease', 'MESH:D000860', (175, 182))	('NRF2', 'Gene', (57, 61))	('ROS', 'Chemical', 'MESH:D017382', (154, 157))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))	('tumors', 'Disease', (209, 215))	('NRF2', 'Gene', (0, 4))	('mutation', 'Var', (45, 53))	('cancer', 'Disease', (34, 40))	('tumor', 'Disease', (284, 289))	('KEAP1', 'Gene', '9817', (65, 70))
524822	30241031	Targeted disruption of NRF2's final exon resulted in a biallelic 1b deletion upstream of the basic leucine zipper domain, which was confirmed by Sanger sequencing; the deleted base coordinate is chromosome 2, position 178095987 (GRCh37/hg19 genome assembly).	('NRF2', 'Gene', '4780', (23, 27))	('deletion', 'Var', (68, 76))	('resulted in', 'Reg', (41, 52))	('NRF2', 'Gene', (23, 27))	('disruption', 'Var', (9, 19))
524845	30241031	Acquisition of the fluorescence signal was performed using the Dual Hydrolysis Probe setting for FAM (465-510 nm) and HEX/Yellow555 (533-580) dyes following the 65  C extension phase of each cycle.	('HEX', 'Gene', '3087', (118, 121))	('533-580', 'Var', (133, 140))	('HEX', 'Gene', (118, 121))
524852	30241031	The 32 gene signature is based on direct NRF2 target genes that are reliably upregulated by oncogenic NRF2 (Levings et al.)	('NRF2', 'Gene', (41, 45))	('upregulated', 'PosReg', (77, 88))	('NRF2', 'Gene', '4780', (102, 106))	('NRF2', 'Gene', '4780', (41, 45))	('NRF2', 'Gene', (102, 106))	('oncogenic', 'Var', (92, 101))
524855	30241031	Any sample with a mean expression above this 95th percentile was assigned to the high NRF2 group (N = 49), and any at or below this value was assigned normal NRF2 (N = 928).	('NRF2', 'Gene', (158, 162))	('NRF2', 'Gene', '4780', (86, 90))	('high', 'Var', (81, 85))	('NRF2', 'Gene', (86, 90))	('NRF2', 'Gene', '4780', (158, 162))	('expression', 'MPA', (23, 33))
524856	29072391	Analysis of ARID2 Gene Mutation in Oral Squamous Cell Carcinoma The ARID2 gene, encoding a sub unit of the chromatin remodelling complex, has a possible tumour suppressor function and has been found to be frequently mutated in various tumours, including gingivo buccal oral squamous cell carcinomas.	('tumours', 'Phenotype', 'HP:0002664', (235, 242))	('tumours', 'Disease', 'MESH:D009369', (235, 242))	('ARID2', 'Gene', (12, 17))	('carcinoma', 'Phenotype', 'HP:0030731', (288, 297))	('carcinomas', 'Phenotype', 'HP:0030731', (288, 298))	('tumour', 'Phenotype', 'HP:0002664', (235, 241))	('ARID2', 'Gene', (68, 73))	('tumour', 'Disease', 'MESH:D009369', (235, 241))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (274, 298))	('tumour', 'Disease', (235, 241))	('tumour', 'Phenotype', 'HP:0002664', (153, 159))	('gingivo buccal oral squamous cell carcinomas', 'Disease', 'MESH:D002294', (254, 298))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (40, 63))	('tumour', 'Disease', 'MESH:D009369', (153, 159))	('tumour', 'Disease', (153, 159))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (274, 297))	('gingivo buccal oral squamous cell carcinomas', 'Disease', (254, 298))	('mutated', 'Var', (216, 223))	('Oral Squamous Cell Carcinoma', 'Disease', 'MESH:D002294', (35, 63))	('Oral Squamous Cell Carcinoma', 'Disease', (35, 63))	('ARID2', 'Gene', '196528', (12, 17))	('tumours', 'Disease', (235, 242))	('ARID2', 'Gene', '196528', (68, 73))	('Carcinoma', 'Phenotype', 'HP:0030731', (54, 63))
524857	29072391	The present study was designed to analyse the presence of ARID2 gene mutations in the distinct genetic South Indian (Dravidian) population.	('mutations', 'Var', (69, 78))	('ARID2', 'Gene', '196528', (58, 63))	('ARID2', 'Gene', (58, 63))
524859	29072391	Our study yielded a 6% occurrence of mutations in the ARID2 gene among the thirty OSCC samples.	('mutations', 'Var', (37, 46))	('ARID2', 'Gene', '196528', (54, 59))	('ARID2', 'Gene', (54, 59))
524860	29072391	Two samples showed a C(5174)A nonsense mutation whereby the "C" nucleotide was substituted with an "A" nucleotide at position 5174, resulting in the conversion of serine amino acid at codon 1725 to a premature STOP codon.	('C(5174)A', 'Mutation', 'g.5174C>A', (21, 29))	('serine amino acid', 'Chemical', '-', (163, 180))	('conversion of serine amino acid at', 'MPA', (149, 183))	('C(5174', 'Var', (21, 27))
524861	29072391	Identification of ARID2 gene mutations in OSCCs in this distinct ethnic population reaffirms that aberrations in the chromatin remodelling complex could indeed also contribute to tumorigenesis, thus providing new insights for future research.	('ARID2', 'Gene', (18, 23))	('mutations', 'Var', (29, 38))	('tumorigenesis', 'CPA', (179, 192))	('contribute', 'Reg', (165, 175))	('ARID2', 'Gene', '196528', (18, 23))
524867	29072391	Genetic alterations predisposing to cancer are commonly detected in oncogenes, tumour suppressor genes and stability genes.	('Genetic alterations', 'Var', (0, 19))	('detected', 'Reg', (56, 64))	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('stability genes', 'Gene', (107, 122))	('cancer', 'Disease', (36, 42))	('tumour', 'Phenotype', 'HP:0002664', (79, 85))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('oncogenes', 'Gene', (68, 77))	('tumour', 'Disease', 'MESH:D009369', (79, 85))	('tumour', 'Disease', (79, 85))
524871	29072391	However ARID2 has been reported to be frequently mutated in various other cancers like hepatocellular carcinoma (HCC) such as HCV associated HCC, HBV associated HCC, alcohol associated HCC and HCC with no known etiology, malignant mesiothelioma, pancreatic cancer, primary urethral clear cell adenocarcinoma, microsatellite unstable colorectal cancer, non small cell lung carcinoma and malignant melanoma (Zhao et al., 2011; Biankin et al., 2012; Fujimoto et al., 2012; Hodis et al., 2012; Manceau et al., 2013; Cajuso et al., 2014; Duan et al., 2016).	('non small cell lung carcinoma', 'Disease', (352, 381))	('cancer', 'Phenotype', 'HP:0002664', (257, 263))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (87, 111))	('cancers', 'Phenotype', 'HP:0002664', (74, 81))	('malignant mesiothelioma', 'Phenotype', 'HP:0100001', (221, 244))	('cancer', 'Phenotype', 'HP:0002664', (344, 350))	('cancers', 'Disease', (74, 81))	('pancreatic cancer', 'Disease', (246, 263))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('alcohol', 'Chemical', 'MESH:D000438', (166, 173))	('HCV', 'Species', '11103', (126, 129))	('HCC', 'Phenotype', 'HP:0001402', (141, 144))	('malignant mesiothelioma', 'Disease', (221, 244))	('carcinoma', 'Phenotype', 'HP:0030731', (372, 381))	('melanoma', 'Phenotype', 'HP:0002861', (396, 404))	('ARID2', 'Gene', '196528', (8, 13))	('hepatocellular carcinoma', 'Disease', (87, 111))	('malignant mesiothelioma', 'Disease', 'MESH:D009369', (221, 244))	('non small cell lung carcinoma', 'Phenotype', 'HP:0030358', (352, 381))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('colorectal cancer', 'Disease', 'MESH:D015179', (333, 350))	('primary urethral clear cell adenocarcinoma', 'Disease', (265, 307))	('malignant melanoma', 'Disease', (386, 404))	('small cell lung carcinoma', 'Phenotype', 'HP:0030357', (356, 381))	('colorectal cancer', 'Disease', (333, 350))	('primary urethral clear cell adenocarcinoma', 'Disease', 'MESH:D008649', (265, 307))	('cancers', 'Disease', 'MESH:D009369', (74, 81))	('non small cell lung carcinoma', 'Disease', 'MESH:D002289', (352, 381))	('microsatellite unstable', 'Var', (309, 332))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (246, 263))	('ARID2', 'Gene', (8, 13))	('mutated', 'Var', (49, 56))	('HCC', 'Disease', (193, 196))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (87, 111))	('HCC', 'Phenotype', 'HP:0001402', (193, 196))	('HCC', 'Phenotype', 'HP:0001402', (113, 116))	('HCC', 'Phenotype', 'HP:0001402', (161, 164))	('malignant melanoma', 'Phenotype', 'HP:0002861', (386, 404))	('pancreatic cancer', 'Disease', 'MESH:D010190', (246, 263))	('carcinoma', 'Phenotype', 'HP:0030731', (298, 307))	('HCC', 'Phenotype', 'HP:0001402', (185, 188))	('malignant melanoma', 'Disease', 'MESH:D008545', (386, 404))	('colorectal cancer', 'Phenotype', 'HP:0003003', (333, 350))
524883	29072391	Sequence analysis identified a mutation C(5174)A within exon 19 of ARID2 in two OSCC samples from among the thirty study samples in this study yielding a 6% occurrence.	('C(5174)A', 'Var', (40, 48))	('C(5174)A', 'Mutation', 'g.5174C>A', (40, 48))	('ARID2', 'Gene', (67, 72))	('ARID2', 'Gene', '196528', (67, 72))
524884	29072391	The substitution of "C" nucleotide with "A" nucleotide at position 5174 causes substitution of serine amino acid at codon 1725 from TCA (coding for serine) to TAA (coding for a STOP codon) (Figure 1).	('serine', 'Chemical', 'MESH:D012694', (95, 101))	('causes', 'Reg', (72, 78))	('substitution', 'Var', (4, 16))	('substitution', 'Var', (79, 91))	('serine', 'Chemical', 'MESH:D012694', (148, 154))	('serine amino acid', 'Chemical', '-', (95, 112))	('serine amino acid', 'MPA', (95, 112))
524885	29072391	To the best of our knowledge, the role of ARID2 gene mutation in Oral squamous cell Carcinoma (OSCC) has not been elucidated in any other ethnic population other than the Indian population.	('Carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('ARID2', 'Gene', (42, 47))	('Oral squamous cell Carcinoma', 'Disease', 'MESH:D002294', (65, 93))	('mutation', 'Var', (53, 61))	('squamous cell Carcinoma', 'Phenotype', 'HP:0002860', (70, 93))	('ARID2', 'Gene', '196528', (42, 47))	('Oral squamous cell Carcinoma', 'Disease', (65, 93))
524889	29072391	Our study yielded a 6% occurrence of mutation in exon 19 of ARID2 gene from 30 study samples of OSCC which is comparably significant to the 10% occurrence from 50 GB OSCC samples from the previous study (IPT-ICGC, 2013).	('mutation', 'Var', (37, 45))	('ARID2', 'Gene', '196528', (60, 65))	('IPT', 'Chemical', '-', (204, 207))	('ARID2', 'Gene', (60, 65))
524890	29072391	Literature evidences quote mutations in ARID2 in similar strengths in some primary human cancers such as 5-8% of hepatocellular carcinomas (HCC), particularly HCCs that are related to hepatitis C virus (HCV) (14% of HCV-related cases compared with 2% of hepatitis B virus-related cases) (Zhao et al., 2011; Planchon et al., 2015), non-small cell lung cancer (7.3%) (Manceau et al., 2013) and melanoma (7%) (Hodis et al., 2012) to quote a few.	('mutations', 'Var', (27, 36))	('hepatitis C virus', 'Species', '11103', (184, 201))	('cancer', 'Phenotype', 'HP:0002664', (351, 357))	('cancers', 'Phenotype', 'HP:0002664', (89, 96))	('lung cancer', 'Phenotype', 'HP:0100526', (346, 357))	('hepatitis', 'Phenotype', 'HP:0012115', (184, 193))	('HCCs', 'Disease', (159, 163))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (331, 357))	('cancers', 'Disease', (89, 96))	('hepatocellular carcinomas', 'Phenotype', 'HP:0001402', (113, 138))	('hepatitis B virus', 'Species', '10407', (254, 271))	('hepatocellular carcinomas', 'Disease', (113, 138))	('hepatitis', 'Phenotype', 'HP:0012115', (254, 263))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('melanoma', 'Disease', 'MESH:D008545', (392, 400))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('ARID2', 'Gene', '196528', (40, 45))	('carcinomas', 'Phenotype', 'HP:0030731', (128, 138))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (113, 137))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (335, 357))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (331, 357))	('HCV', 'Species', '11103', (203, 206))	('cancers', 'Disease', 'MESH:D009369', (89, 96))	('ARID2', 'Gene', (40, 45))	('HCC', 'Phenotype', 'HP:0001402', (140, 143))	('HCV', 'Species', '11103', (216, 219))	('non-small cell lung cancer', 'Disease', (331, 357))	('melanoma', 'Phenotype', 'HP:0002861', (392, 400))	('melanoma', 'Disease', (392, 400))	('human', 'Species', '9606', (83, 88))	('hepatocellular carcinomas', 'Disease', 'MESH:D006528', (113, 138))	('HCC', 'Phenotype', 'HP:0001402', (159, 162))
524891	29072391	Complete loss of function of ARID2 by homozygous deletions or somatic mutations associated with a loss of heterozygosity, had been identified in these cancer types (Planchon et al., 2015).	('mutations', 'Var', (70, 79))	('ARID2', 'Gene', '196528', (29, 34))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('ARID2', 'Gene', (29, 34))	('cancer', 'Disease', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('homozygous deletions', 'Var', (38, 58))	('loss of function', 'NegReg', (9, 25))
524894	29072391	ARID2 gene mutation was one among the novel mutations uncovered in the Gingivo Buccal oral squamous cell carcinoma with a prevalence of 10% (IPT-ICGC, 2013), which hasn't been validated or replicated in any other varying ethnic population.	('mutation', 'Var', (11, 19))	('IPT', 'Chemical', '-', (141, 144))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (86, 114))	('ARID2', 'Gene', '196528', (0, 5))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (91, 114))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('oral squamous cell carcinoma', 'Disease', (86, 114))	('ARID2', 'Gene', (0, 5))
524950	29095823	FTH1P3 overexpression enhanced Rac1 expression in the MUM-2B cell (Fig 4B).	('overexpression', 'Var', (7, 21))	('FTH1P3', 'Gene', '2498', (0, 6))	('MUM-2', 'Gene', '58485', (54, 59))	('MUM-2', 'Gene', (54, 59))	('Rac1', 'Gene', '5879', (31, 35))	('enhanced', 'PosReg', (22, 30))	('Rac1', 'Gene', (31, 35))	('FTH1P3', 'Gene', (0, 6))
524990	29095823	In conclusion, we demonstrated that lncRNA FTH1P3 was commonly up-regulated in uveal melanoma cell lines and tissues and acted as an oncogene in uveal melanoma progression by inhibiting miR-224-5p expression.	('inhibiting', 'NegReg', (175, 185))	('uveal melanoma', 'Disease', 'MESH:C536494', (145, 159))	('uveal melanoma', 'Phenotype', 'HP:0007716', (145, 159))	('miR-224', 'Gene', (186, 193))	('FTH1P3', 'Gene', (43, 49))	('lncRNA', 'Var', (36, 42))	('uveal melanoma', 'Disease', (145, 159))	('miR-224', 'Gene', '407009', (186, 193))	('melanoma', 'Phenotype', 'HP:0002861', (151, 159))	('melanoma', 'Phenotype', 'HP:0002861', (85, 93))	('uveal melanoma', 'Disease', (79, 93))	('uveal melanoma', 'Disease', 'MESH:C536494', (79, 93))	('FTH1P3', 'Gene', '2498', (43, 49))	('uveal melanoma', 'Phenotype', 'HP:0007716', (79, 93))	('up-regulated', 'PosReg', (63, 75))
524994	29051489	The integrative analysis reveals two distinct tumor types: the mutator type is positively associated with potential response to immunotherapy, whereas the chromosome-instable type is negatively associated with it.	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Disease', (46, 51))	('mutator', 'Var', (63, 70))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
525002	29051489	As seen in earlier studies demonstrating that therapeutic targets were reliable predictive biomarkers, recent studies reported that tumor PD-L1 expression or its amplification was significantly associated with better response in patients undergoing anti-PD-1/PD-L1 therapies, although not all responders had high PD-L1 expression.	('patients', 'Species', '9606', (229, 237))	('PD-L1', 'Gene', (259, 264))	('PD-L1', 'Gene', '29126', (313, 318))	('amplification', 'Var', (162, 175))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('PD-1', 'Gene', (254, 258))	('PD-1', 'Gene', '5133', (254, 258))	('PD-L1', 'Gene', (313, 318))	('better', 'PosReg', (210, 216))	('PD-L1', 'Gene', '29126', (259, 264))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumor', 'Disease', (132, 137))	('response', 'MPA', (217, 225))	('PD-L1', 'Gene', (138, 143))	('PD-L1', 'Gene', '29126', (138, 143))
525049	29051489	Interestingly, a global analysis of all tumors showed a significant positive correlation between the non-synonymous mutation rate and the IS score (R 2 = 0.017, P < 0.001, Supplementary Fig.	('tumors', 'Phenotype', 'HP:0002664', (40, 46))	('positive', 'PosReg', (68, 76))	('IS score', 'MPA', (138, 146))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('non-synonymous mutation', 'Var', (101, 124))	('tumors', 'Disease', (40, 46))	('tumors', 'Disease', 'MESH:D009369', (40, 46))
525057	29051489	When two data sets were integrated, tumors were clearly separated into three major groups: tumors with high mutational burden and low CIN (mutator or M type), those with low mutational burden but high CIN (chromosome-instable or C type), and those not otherwise specified (NOS) (Fig.	('tumors', 'Disease', (91, 97))	('tumors', 'Disease', 'MESH:D009369', (91, 97))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('tumors', 'Disease', 'MESH:D009369', (36, 42))	('CIN', 'Disease', (134, 137))	('CIN', 'Phenotype', 'HP:0040012', (201, 204))	('CIN', 'Phenotype', 'HP:0040012', (134, 137))	('CIN', 'Disease', 'MESH:D007674', (134, 137))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('CIN', 'Disease', (201, 204))	('low CIN', 'Disease', (130, 137))	('low CIN', 'Disease', 'MESH:D009800', (130, 137))	('tumors', 'Disease', (36, 42))	('CIN', 'Disease', 'MESH:D007674', (201, 204))	('high mutational burden', 'Var', (103, 125))
525067	29051489	Interestingly, non-synonymous mutation rates were also modestly correlated with tumor purity, suggesting that the correlation was not specific to CIN scores.	('non-synonymous mutation', 'Var', (15, 38))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('CIN', 'Phenotype', 'HP:0040012', (146, 149))	('tumor', 'Disease', (80, 85))	('CIN', 'Disease', (146, 149))	('CIN', 'Disease', 'MESH:D007674', (146, 149))
525073	29051489	Not surprisingly, IS scores are positively correlated with high stromal fraction in tumor mass (Supplementary Fig.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('correlated', 'Reg', (43, 53))	('tumor', 'Disease', (84, 89))	('high', 'Var', (59, 63))
525075	29051489	In contrast to tumor antigens, some of the positively correlated mutations might be selected under host immunogenic pressure as part of cancer cells' mechanisms to evade immune surveillance.	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('cancer', 'Disease', (136, 142))	('tumor', 'Disease', (15, 20))	('mutations', 'Var', (65, 74))
525076	29051489	Mutations in HLA-A, -B, and -C, B2M, and CASP8 might fall into this category since CASP8 is an executor of ligand-mediated apoptosis and HLA-A, -B, and -C and B2M encode major antigen presenting machinery to immune cells.	('fall', 'Phenotype', 'HP:0002527', (53, 57))	('HLA-A, -B, and -C and B2M', 'Gene', '3105;3106;3107', (137, 162))	('CASP8', 'Gene', (41, 46))	('CASP8', 'Gene', (83, 88))	('CASP8', 'Gene', '841', (41, 46))	('Mutations', 'Var', (0, 9))	('CASP8', 'Gene', '841', (83, 88))	('HLA-A, -B, and -C, B2M', 'Gene', '3105;3106;3107', (13, 35))
525077	29051489	Any loss-of-function mutations would give a significant advantage to cancer cells to evade immune surveillance.	('loss-of-function', 'NegReg', (4, 20))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('evade', 'CPA', (85, 90))	('cancer', 'Disease', (69, 75))	('mutations', 'Var', (21, 30))
525078	29051489	In good agreement, tumors with mutations in these genes represent typical M type characteristics (Fig.	('tumors', 'Disease', (19, 25))	('tumors', 'Disease', 'MESH:D009369', (19, 25))	('mutations', 'Var', (31, 40))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('tumors', 'Phenotype', 'HP:0002664', (19, 25))
525080	29051489	3d), the amplification of ERBB2 (HER2) was significantly associated with low IS scores.	('amplification', 'Var', (9, 22))	('HER2', 'Gene', (33, 37))	('ERBB2', 'Gene', (26, 31))	('ERBB2', 'Gene', '2064', (26, 31))	('HER2', 'Gene', '2064', (33, 37))	('low', 'NegReg', (73, 76))	('associated', 'Reg', (57, 67))
525082	29051489	Importantly, recent study demonstrated that loss of PTEN is indeed significantly associated with resistant to immunotherapy with anti-PD-1 antibodies in melanoma, strongly suggesting that many of identified candidates might play key roles in host immunity to cancer cells.	('cancer', 'Disease', 'MESH:D009369', (259, 265))	('PTEN', 'Gene', (52, 56))	('PD-1', 'Gene', (134, 138))	('PTEN', 'Gene', '5728', (52, 56))	('melanoma', 'Phenotype', 'HP:0002861', (153, 161))	('PD-1', 'Gene', '5133', (134, 138))	('melanoma', 'Disease', (153, 161))	('resistant to immunotherapy', 'CPA', (97, 123))	('melanoma', 'Disease', 'MESH:D008545', (153, 161))	('cancer', 'Phenotype', 'HP:0002664', (259, 265))	('loss', 'Var', (44, 48))	('associated', 'Reg', (81, 91))	('cancer', 'Disease', (259, 265))
525083	29051489	Interestingly, expression of HLA-A, HLA-B, and HLA-C had a significant negative correlation with CIN scores in tumors with amplified genes or deleted genes (Fig.	('HLA-C', 'Gene', (47, 52))	('HLA-A', 'Gene', (29, 34))	('CIN', 'Disease', 'MESH:D007674', (97, 100))	('deleted genes', 'Var', (142, 155))	('HLA-C', 'Gene', '3107', (47, 52))	('CIN', 'Phenotype', 'HP:0040012', (97, 100))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumors', 'Disease', (111, 117))	('tumors', 'Disease', 'MESH:D009369', (111, 117))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('HLA-B', 'Gene', (36, 41))	('CIN', 'Disease', (97, 100))	('amplified genes', 'Var', (123, 138))	('expression', 'MPA', (15, 25))	('HLA-A', 'Gene', '3105', (29, 34))	('HLA-B', 'Gene', '3106', (36, 41))	('negative', 'NegReg', (71, 79))
525084	29051489	7c), suggesting that some of the copy number-altered genes might be involved in the suppression of antigen presentation in cancer cells either alone or in combination with other genes.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('antigen presentation', 'MPA', (99, 119))	('copy number-altered genes', 'Var', (33, 58))	('genes', 'Var', (53, 58))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('suppression', 'NegReg', (84, 95))	('cancer', 'Disease', (123, 129))
525091	29051489	First, IS scores reliably identified responders to immunotherapy in a mouse model treated with anti-CTLA-4 antibodies.	('mouse', 'Species', '10090', (70, 75))	('anti-CTLA-4', 'Gene', (95, 106))	('anti-CTLA-4', 'Var', (95, 106))
525105	29051489	In another study analyzing of samples from clinical trials with CTLA-4 and PD-1 blockade treatments, copy number loss is associated with resistance to immunotherapy.	('copy number loss', 'Var', (101, 117))	('PD-1', 'Gene', (75, 79))	('associated', 'Reg', (121, 131))	('PD-1', 'Gene', '5133', (75, 79))	('resistance to immunotherapy', 'CPA', (137, 164))
525106	29051489	A lack of neoantigen production due to low mutation rates may account for the insensitivity of C-type tumors to immunotherapy, however loss of key immune mediators is also likely to contribute.	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('mutation', 'Var', (43, 51))	('neoantigen production', 'MPA', (10, 31))	('loss', 'NegReg', (135, 139))	('C-type tumors', 'Disease', 'MESH:D019698', (95, 108))	('C-type tumors', 'Disease', (95, 108))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('lack', 'NegReg', (2, 6))
525109	29051489	M-type tumors have frequent mutations in genes involved in antigen presentation.	('M-type tumors', 'Disease', 'MESH:C566367', (0, 13))	('tumors', 'Phenotype', 'HP:0002664', (7, 13))	('M-type tumors', 'Disease', (0, 13))	('mutations', 'Var', (28, 37))	('tumor', 'Phenotype', 'HP:0002664', (7, 12))
525111	29051489	Likewise, mutations in CASP8, which is a key mediator of apoptosis, give an advantage to cancer cells to become insensitive to T-cell-mediated cell death.	('CASP8', 'Gene', (23, 28))	('advantage', 'PosReg', (76, 85))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('cancer', 'Disease', (89, 95))	('mutations', 'Var', (10, 19))	('CASP8', 'Gene', '841', (23, 28))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
525114	29051489	In good agreement with our analysis that identified PTEN as a key modulator of tumor immunity, recent study showed that PTEN play roles in T-cell activation and loss of PTEN is significantly associated with resistance of melanoma to immunotherapy.	('PTEN', 'Gene', (52, 56))	('tumor', 'Disease', (79, 84))	('melanoma', 'Phenotype', 'HP:0002861', (221, 229))	('melanoma', 'Disease', (221, 229))	('PTEN', 'Gene', '5728', (52, 56))	('PTEN', 'Gene', (169, 173))	('melanoma', 'Disease', 'MESH:D008545', (221, 229))	('PTEN', 'Gene', '5728', (169, 173))	('PTEN', 'Gene', '5728', (120, 124))	('PTEN', 'Gene', (120, 124))	('associated with', 'Reg', (191, 206))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('loss', 'Var', (161, 165))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
525132	29051489	In the current study, we showed that the potential benefit of immunotherapy highly varies across cancer lineages and revealed global subtypes of tumors and genomic alterations significantly associated with the potential benefit of immunotherapy.	('cancer', 'Disease', (97, 103))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('tumors', 'Disease', (145, 151))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('tumors', 'Disease', 'MESH:D009369', (145, 151))	('associated', 'Reg', (190, 200))	('alterations', 'Var', (164, 175))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
525151	29051489	For each cancer type, we performed logistic analysis with IS score as the independent variable, and dichotomized status in genomic data such as higher or lower than median mutation number or CIN scores as the dependent variables.	('cancer', 'Disease', (9, 15))	('lower', 'NegReg', (154, 159))	('mutation number', 'Var', (172, 187))	('CIN', 'Disease', 'MESH:D007674', (191, 194))	('CIN', 'Phenotype', 'HP:0040012', (191, 194))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('CIN', 'Disease', (191, 194))	('cancer', 'Disease', 'MESH:D009369', (9, 15))
525153	29051489	To estimate the significance of correlation in each cancer type, subgroup analysis of logistic regression was carried out to compute odds ratio (OR) of mutation rate or CIN score.	('CIN', 'Disease', 'MESH:D007674', (169, 172))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('CIN', 'Phenotype', 'HP:0040012', (169, 172))	('CIN', 'Disease', (169, 172))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('mutation', 'Var', (152, 160))
525182	28727782	Cell lines representative of relatively negative, low, moderate, and high expression (NSCLC cell lines, H460, H2122 H1975, and H226, respectively) were chosen for further characterization.	('NSCLC', 'Disease', (86, 91))	('H2122 H1975', 'CellLine', 'CVCL:1511', (110, 121))	('H2122 H1975', 'Var', (110, 121))	('NSCLC', 'Disease', 'MESH:D002289', (86, 91))
525308	28727782	It should be noted that in a recent study, patients with Her2 positivity in the tumor and in the CTC compartment demonstrated an improvement in PFS as compared to patients with Her2-positive tumors but no Her2 detected in the CTC compartment, indicating that information obtained from CTC analysis can help predict response.	('Her2', 'Gene', '2064', (205, 209))	('Her2', 'Gene', (177, 181))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('positivity', 'Var', (62, 72))	('Her2', 'Gene', (57, 61))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('tumors', 'Disease', (191, 197))	('Her2', 'Gene', (205, 209))	('tumors', 'Disease', 'MESH:D009369', (191, 197))	('patients', 'Species', '9606', (163, 171))	('patients', 'Species', '9606', (43, 51))	('tumor', 'Disease', (80, 85))	('tumor', 'Disease', (191, 196))	('improvement', 'PosReg', (129, 140))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('PFS', 'MPA', (144, 147))	('Her2', 'Gene', '2064', (57, 61))	('Her2', 'Gene', '2064', (177, 181))	('tumors', 'Phenotype', 'HP:0002664', (191, 197))
525309	28727782	There is a clinical trial currently underway (DETECT III, NCT01619111) to evaluate whether patients with Her2 positivity in the CTC compartment but undetectable Her2 in the tumor compartment may benefit from anti-Her2 therapy.	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('patients', 'Species', '9606', (91, 99))	('Her2', 'Gene', (105, 109))	('Her2', 'Gene', '2064', (105, 109))	('Her2', 'Gene', (161, 165))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumor', 'Disease', (173, 178))	('positivity', 'Var', (110, 120))	('Her2', 'Gene', (213, 217))	('benefit', 'Reg', (195, 202))	('Her2', 'Gene', '2064', (161, 165))	('Her2', 'Gene', '2064', (213, 217))
525320	28727782	59378191, NCI-H2122 (ATCC CRL-5985) Lot No.	('CRL', 'Gene', (26, 29))	('CRL', 'Gene', '133396', (26, 29))	('NCI-H2122', 'CellLine', 'CVCL:1531', (10, 19))	('59378191', 'Var', (0, 8))
525375	28727782	Human lung cancer cell lines were screened for 5T4 expression by IHC staining and 4 cell lines were identified with various expression levels: H460 (negative-low), H2122 (low), H1975 (medium), H226 (high).	('lung cancer', 'Disease', 'MESH:D008175', (6, 17))	('H460', 'Var', (143, 147))	('Human', 'Species', '9606', (0, 5))	('H2122', 'Var', (164, 169))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('H2122', 'CellLine', 'CVCL:1531', (164, 169))	('lung cancer', 'Disease', (6, 17))	('H1975', 'Var', (177, 182))	('lung cancer', 'Phenotype', 'HP:0100526', (6, 17))	('H1975', 'CellLine', 'CVCL:1511', (177, 182))	('5T4', 'Gene', (47, 50))	('5T4', 'Gene', '7162', (47, 50))	('H226', 'Var', (193, 197))
525382	28727782	Within a range of 0 (negative) to 300 (highly positive), the control cell lines produced the following H-scores: H460 = 58, H2122 = 102, H1975 = 201, H226 = 256.	('H226 = 256', 'Var', (150, 160))	('H460 = 58', 'Var', (113, 122))	('H1975 = 201', 'Var', (137, 148))	('H2122', 'CellLine', 'CVCL:1531', (124, 129))	('H2122 = 102', 'Var', (124, 135))	('H1975', 'CellLine', 'CVCL:1511', (137, 142))
525386	25541715	These analyses defined a signature of 50 genes differentially regulated between high and low TTP-expressing tumors.	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('low', 'NegReg', (89, 92))	('tumors', 'Disease', 'MESH:D009369', (108, 114))	('tumors', 'Disease', (108, 114))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('high', 'Var', (80, 84))
525389	25541715	TTP has documented roles in regulating mRNAs encoding inflammatory proteins, and pathway analysis identified several inflammatory pathways that are altered in tumors with low TTP expression.	('TTP', 'Gene', (175, 178))	('inflammatory pathways', 'Pathway', (117, 138))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('altered', 'Reg', (148, 155))	('tumors', 'Disease', (159, 165))	('low', 'Var', (171, 174))	('tumors', 'Phenotype', 'HP:0002664', (159, 165))	('tumors', 'Disease', 'MESH:D009369', (159, 165))	('mRNAs encoding', 'MPA', (39, 53))
525393	25541715	Even though specific anatomical and histological features have historically defined cancer, in this age of genomics it has become evident that genetic alterations in tumors even within a given subtype are unique from one patient to another, underscoring the need for personalized cancer therapies.	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('cancer', 'Disease', 'MESH:D009369', (280, 286))	('tumors', 'Disease', 'MESH:D009369', (166, 172))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('cancer', 'Disease', (84, 90))	('cancer', 'Disease', (280, 286))	('patient', 'Species', '9606', (221, 228))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('cancer', 'Phenotype', 'HP:0002664', (280, 286))	('tumors', 'Disease', (166, 172))	('genetic alterations', 'Var', (143, 162))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))
525396	25541715	Notably, genomic analysis has shown that at least 11% of all human genes contain AREs, and, pertinent to this study, all ten of the molecular mechanisms defined as the "Hallmarks of Cancer" include genes that contain AREs.	('Hallmarks of Cancer', 'Disease', (169, 188))	('Cancer', 'Phenotype', 'HP:0002664', (182, 188))	('Hallmarks of Cancer', 'Disease', 'MESH:D009369', (169, 188))	('AREs', 'Var', (81, 85))	('human', 'Species', '9606', (61, 66))
525404	25541715	However, enforcing TTP expression in Myc-expressing B cells doubles the lifespan of these tumor-prone mice and disables maintenance of Myc-driven lymphoma; thus, in this scenario TTP functions as tumor suppressor.	('disables', 'NegReg', (111, 119))	('mice', 'Species', '10090', (102, 106))	('tumor', 'Disease', (196, 201))	('tumor', 'Disease', 'MESH:D009369', (196, 201))	('maintenance', 'MPA', (120, 131))	('Myc', 'Gene', (135, 138))	('tumor', 'Disease', (90, 95))	('lymphoma', 'Disease', (146, 154))	('lymphoma', 'Disease', 'MESH:D008223', (146, 154))	('Myc', 'Gene', '17869', (135, 138))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('Myc', 'Gene', (37, 40))	('doubles', 'PosReg', (60, 67))	('lifespan', 'CPA', (72, 80))	('Myc', 'Gene', '17869', (37, 40))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('TTP expression', 'Var', (19, 33))	('lymphoma', 'Phenotype', 'HP:0002665', (146, 154))
525413	25541715	Unexpectedly, these analyses revealed that CREB target genes represent a significant proportion of the TTP-low tumor gene signature, suggesting that manipulating activity of the CREB pathway is a potential treatment option for patients with low TTP expressing tumors.	('tumor', 'Disease', (260, 265))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumors', 'Disease', 'MESH:D009369', (260, 266))	('CREB', 'Gene', '1385', (43, 47))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumor', 'Disease', 'MESH:D009369', (260, 265))	('manipulating activity', 'Var', (149, 170))	('tumors', 'Phenotype', 'HP:0002664', (260, 266))	('CREB', 'Gene', (178, 182))	('tumor', 'Disease', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (260, 265))	('CREB', 'Gene', '1385', (178, 182))	('patients', 'Species', '9606', (227, 235))	('tumors', 'Disease', (260, 266))	('CREB', 'Gene', (43, 47))
525426	25541715	Clinical data was analyzed for differences between tumors identified as having high TTP expression versus low TTP expression.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('TTP', 'MPA', (84, 87))	('tumors', 'Disease', 'MESH:D009369', (51, 57))	('tumors', 'Disease', (51, 57))	('high', 'Var', (79, 83))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))
525442	25541715	However, relapse-free survival data is available, and analysis of this data shows that breast cancer patients with low levels of TTP expression have a higher incidence of relapse than their TTP-high counterparts (Fig.	('patients', 'Species', '9606', (101, 109))	('breast cancer', 'Disease', 'MESH:D001943', (87, 100))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('relapse', 'CPA', (171, 178))	('breast cancer', 'Disease', (87, 100))	('low levels', 'Var', (115, 125))	('breast cancer', 'Phenotype', 'HP:0003002', (87, 100))
525443	25541715	This confirms previous findings suggesting that low TTP expression is a poor prognostic indicator in breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('breast cancer', 'Disease', 'MESH:D001943', (101, 114))	('TTP expression', 'MPA', (52, 66))	('breast cancer', 'Disease', (101, 114))	('low', 'Var', (48, 51))	('breast cancer', 'Phenotype', 'HP:0003002', (101, 114))
525446	25541715	However, there were no significant differences in survival rates of TTP-low versus TTP-high cohorts in lung squamous cell carcinoma or colon adenocarcinoma patients (Figs.	('patients', 'Species', '9606', (156, 164))	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('TTP-low', 'Var', (68, 75))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (108, 131))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (103, 131))	('colon adenocarcinoma', 'Disease', (135, 155))	('colon adenocarcinoma', 'Disease', 'MESH:D003110', (135, 155))	('lung squamous cell carcinoma', 'Disease', (103, 131))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (103, 131))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))
525454	25541715	Conversely, twice as many TTP-low breast cancers are HER2-positive (HER2+) compared to the TTP-high cohort, indicating that such patients might have an improved response to trastuzumab (Herceptin), which targets HER2.	('breast cancers', 'Phenotype', 'HP:0003002', (34, 48))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('breast cancers', 'Disease', 'MESH:D001943', (34, 48))	('breast cancers', 'Disease', (34, 48))	('patients', 'Species', '9606', (129, 137))	('HER2', 'Gene', (68, 72))	('HER2', 'Gene', (53, 57))	('HER2', 'Gene', '2064', (68, 72))	('Herceptin', 'Chemical', 'MESH:D000068878', (186, 195))	('improved', 'PosReg', (152, 160))	('response', 'MPA', (161, 169))	('trastuzumab', 'Chemical', 'MESH:D000068878', (173, 184))	('HER2', 'Gene', '2064', (53, 57))	('HER2', 'Gene', (212, 216))	('breast cancer', 'Phenotype', 'HP:0003002', (34, 47))	('cancers', 'Phenotype', 'HP:0002664', (41, 48))	('HER2', 'Gene', '2064', (212, 216))	('TTP-low', 'Var', (26, 33))
525455	25541715	Further, TTP-low breast cancers have approximately two times more triple-negative breast cancers (TNBCs) than TTP-high tumors.	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('breast cancer', 'Phenotype', 'HP:0003002', (82, 95))	('breast cancers', 'Disease', 'MESH:D001943', (82, 96))	('tumors', 'Disease', 'MESH:D009369', (119, 125))	('breast cancers', 'Disease', (82, 96))	('tumors', 'Disease', (119, 125))	('breast cancers', 'Disease', 'MESH:D001943', (17, 31))	('cancers', 'Phenotype', 'HP:0002664', (89, 96))	('breast cancers', 'Disease', (17, 31))	('breast cancer', 'Phenotype', 'HP:0003002', (17, 30))	('cancers', 'Phenotype', 'HP:0002664', (24, 31))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('breast cancers', 'Phenotype', 'HP:0003002', (82, 96))	('TTP-low', 'Var', (9, 16))	('breast cancers', 'Phenotype', 'HP:0003002', (17, 31))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
525457	25541715	EGFR mutations are more frequent in bronchioid tumors, whereas TP53, KRAS, and STK11 (the gene encoding the tumor suppressor LKB1) mutations are more frequent in magnoid tumors.	('KRAS', 'Gene', (69, 73))	('LKB1', 'Gene', (125, 129))	('tumor', 'Disease', (108, 113))	('tumor', 'Disease', (170, 175))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumors', 'Disease', 'MESH:D009369', (170, 176))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('tumors', 'Disease', (47, 53))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('TP53', 'Gene', '7157', (63, 67))	('frequent', 'Reg', (24, 32))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('EGFR', 'Gene', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('STK11', 'Gene', (79, 84))	('mutations', 'Var', (5, 14))	('LKB1', 'Gene', '6794', (125, 129))	('tumors', 'Phenotype', 'HP:0002664', (170, 176))	('EGFR', 'Gene', '1956', (0, 4))	('tumor', 'Disease', (47, 52))	('bronchioid tumors', 'Disease', 'MESH:D009369', (36, 53))	('KRAS', 'Gene', '3845', (69, 73))	('TP53', 'Gene', (63, 67))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('bronchioid tumors', 'Disease', (36, 53))	('STK11', 'Gene', '6794', (79, 84))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))	('tumors', 'Disease', (170, 176))
525458	25541715	TCGA clinical data was analyzed for mutations of these genes in TTP-high versus TTP-low lung adenocarcinomas (except for TP53, which was not included in this dataset).	('TP53', 'Gene', '7157', (121, 125))	('lung adenocarcinomas', 'Disease', (88, 108))	('TP53', 'Gene', (121, 125))	('mutations', 'Var', (36, 45))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (88, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (88, 108))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (88, 108))	('carcinomas', 'Phenotype', 'HP:0030731', (98, 108))
525460	25541715	However, the EGFR family member ERBB4 is less commonly mutated in TTP-low than TTP-high tumors (Fig.	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('ERBB4', 'Gene', (32, 37))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('TTP-low', 'Disease', (66, 73))	('mutated', 'Var', (55, 62))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('ERBB4', 'Gene', '2066', (32, 37))	('tumors', 'Disease', (88, 94))	('EGFR', 'Gene', '1956', (13, 17))	('EGFR', 'Gene', (13, 17))
525461	25541715	Similarly, KRAS and STK11 mutations are less frequent in low TTP-expressing lung adenocarcinomas than in the high TTP-expressing cohort.	('KRAS', 'Gene', (11, 15))	('lung adenocarcinomas', 'Disease', (76, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('STK11', 'Gene', (20, 25))	('carcinomas', 'Phenotype', 'HP:0030731', (86, 96))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (76, 96))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (76, 96))	('KRAS', 'Gene', '3845', (11, 15))	('STK11', 'Gene', '6794', (20, 25))	('mutations', 'Var', (26, 35))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (76, 95))
525462	25541715	Thus, even though the prognosis of patients having TTP-low expressing lung adenocarcinomas is worse (Fig.	('lung adenocarcinomas', 'Disease', (70, 90))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (70, 90))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (70, 90))	('carcinomas', 'Phenotype', 'HP:0030731', (80, 90))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (70, 89))	('patients', 'Species', '9606', (35, 43))	('TTP-low expressing', 'Var', (51, 69))
525465	25541715	Luminal A and luminal B are ER-positive (ER+) subtypes, and, in general, luminal B breast tumors are more aggressive and these patients have a worse prognosis versus patients with luminal A tumors.	('A tumors', 'Disease', 'MESH:D009369', (188, 196))	('ER', 'Gene', '2099', (41, 43))	('ER', 'Gene', '2099', (28, 30))	('breast tumors', 'Disease', 'MESH:D001943', (83, 96))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('breast tumors', 'Phenotype', 'HP:0100013', (83, 96))	('patients', 'Species', '9606', (127, 135))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('tumors', 'Phenotype', 'HP:0002664', (190, 196))	('luminal', 'Var', (73, 80))	('A tumors', 'Disease', (188, 196))	('patients', 'Species', '9606', (166, 174))	('breast tumors', 'Disease', (83, 96))
525470	25541715	In contrast, in TTP-low breast tumors, the percentage of luminal B (40%) and basal-like (19%) subtypes is much higher than in the TTP-high cohort (11% and 7%, respectively).	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('breast tumors', 'Phenotype', 'HP:0100013', (24, 37))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('luminal B', 'CPA', (57, 66))	('basal-like', 'CPA', (77, 87))	('higher', 'PosReg', (111, 117))	('breast tumors', 'Disease', (24, 37))	('breast tumors', 'Disease', 'MESH:D001943', (24, 37))	('TTP-low', 'Var', (16, 23))
525477	25541715	Finally, nearly twice as many TTP-low lung adenocarcinoma patients have Stage III or Stage IV tumors (27% combined) than TTP-high patients (14% combined) (Fig.	('TTP-low', 'Var', (30, 37))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('IV tumors', 'Disease', 'MESH:D009369', (91, 100))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (38, 57))	('IV tumors', 'Disease', (91, 100))	('patients', 'Species', '9606', (130, 138))	('Stage III', 'Disease', (72, 81))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('patients', 'Species', '9606', (58, 66))	('lung adenocarcinoma', 'Disease', (38, 57))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (38, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (48, 57))
525482	25541715	Importantly, the primitive subtype of lung squamous cell carcinoma are poorly differentiated and have the worse prognosis, and patients with low TTP expression have this detrimental form more often (23%) than individuals with high TTP expression (9%).	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (38, 66))	('TTP', 'Gene', (145, 148))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (38, 66))	('carcinoma', 'Phenotype', 'HP:0030731', (57, 66))	('patients', 'Species', '9606', (127, 135))	('lung squamous cell carcinoma', 'Disease', (38, 66))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (43, 66))	('low', 'Var', (141, 144))
525483	25541715	Finally, lung squamous cell carcinoma patients with low TTP levels have a higher percentage of Stage II, III and IV tumors (52% combined) than TTP-high patients (43% combined) (Fig.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (14, 37))	('lung squamous cell carcinoma', 'Disease', (9, 37))	('carcinoma', 'Phenotype', 'HP:0030731', (28, 37))	('TTP', 'MPA', (56, 59))	('Stage II', 'Disease', (95, 103))	('IV tumors', 'Disease', 'MESH:D009369', (113, 122))	('IV tumors', 'Disease', (113, 122))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (9, 37))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('patients', 'Species', '9606', (38, 46))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (9, 37))	('patients', 'Species', '9606', (152, 160))	('low', 'Var', (52, 55))
525495	25541715	Indeed, histological examination of tumor samples in the TCGA datasets revealed that TTP-low breast cancers and lung adenocarcinomas have significantly more tumor necrosis than TTP-high tumors (Fig.	('tumor', 'Disease', (186, 191))	('breast cancers', 'Disease', 'MESH:D001943', (93, 107))	('breast cancers', 'Disease', (93, 107))	('breast cancer', 'Phenotype', 'HP:0003002', (93, 106))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('tumor necrosis', 'Disease', 'MESH:D009336', (157, 171))	('more', 'PosReg', (152, 156))	('tumor', 'Disease', (36, 41))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (112, 132))	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('tumor necrosis', 'Disease', (157, 171))	('tumors', 'Phenotype', 'HP:0002664', (186, 192))	('lung adenocarcinomas', 'Disease', (112, 132))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('breast cancers', 'Phenotype', 'HP:0003002', (93, 107))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('tumors', 'Disease', (186, 192))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('cancers', 'Phenotype', 'HP:0002664', (100, 107))	('tumor', 'Disease', (157, 162))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (112, 131))	('TTP-low', 'Var', (85, 92))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('tumors', 'Disease', 'MESH:D009369', (186, 192))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (112, 132))	('carcinomas', 'Phenotype', 'HP:0030731', (122, 132))
525501	25541715	All 20 of the CREB targets were repressed, despite the fact that CREB expression was not significantly altered in TTP-low versus TTP-high tumors (Fig.	('CREB', 'Gene', (14, 18))	('CREB', 'Gene', (65, 69))	('tumors', 'Disease', (138, 144))	('CREB', 'Gene', '1385', (14, 18))	('CREB', 'Gene', '1385', (65, 69))	('tumors', 'Disease', 'MESH:D009369', (138, 144))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('TTP-low', 'Var', (114, 121))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
525505	25541715	Some splice variants of CREB family members function as dominant negative repressors of CREB activity.	('CREB', 'Gene', (88, 92))	('negative repressors', 'NegReg', (65, 84))	('activity', 'MPA', (93, 101))	('CREB', 'Gene', '1385', (88, 92))	('CREB', 'Gene', (24, 28))	('CREB', 'Gene', '1385', (24, 28))	('splice variants', 'Var', (5, 20))
525517	25541715	The analyses herein show that the TTP-low tumor gene signature is involved in inflammatory pathways, particularly innate immunity, and the increased necrosis in tumors classified as TTP-low supports this notion.	('tumor', 'Disease', (42, 47))	('tumors', 'Disease', (161, 167))	('tumors', 'Phenotype', 'HP:0002664', (161, 167))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('increased', 'PosReg', (139, 148))	('tumors', 'Disease', 'MESH:D009369', (161, 167))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('TTP-low', 'Var', (34, 41))	('necrosis', 'Disease', (149, 157))	('increased necrosis', 'Phenotype', 'HP:0010885', (139, 157))	('involved', 'Reg', (66, 74))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('inflammatory pathways', 'Pathway', (78, 99))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('necrosis', 'Disease', 'MESH:D009336', (149, 157))	('tumor', 'Disease', (161, 166))
525532	25541715	In addition, given that LKB1 functions in part to prevent CREB target gene activation, the decreased mutation frequency of STK11 (LKB1) in TTP-low lung adenocarcinomas compared to the TTP-high cohort corresponds with the observed decrease in CREB-target gene expression in TTP-low tumors.	('CREB', 'Gene', '1385', (242, 246))	('LKB1', 'Gene', '6794', (130, 134))	('CREB', 'Gene', '1385', (58, 62))	('STK11', 'Gene', (123, 128))	('LKB1', 'Gene', '6794', (24, 28))	('carcinoma', 'Phenotype', 'HP:0030731', (157, 166))	('TTP-low tumors', 'Disease', 'MESH:D011697', (273, 287))	('lung adenocarcinomas', 'Disease', (147, 167))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (147, 167))	('tumors', 'Phenotype', 'HP:0002664', (281, 287))	('LKB1', 'Gene', (130, 134))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (147, 166))	('tumor', 'Phenotype', 'HP:0002664', (281, 286))	('STK11', 'Gene', '6794', (123, 128))	('expression', 'MPA', (259, 269))	('CREB', 'Gene', (242, 246))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (147, 167))	('carcinomas', 'Phenotype', 'HP:0030731', (157, 167))	('LKB1', 'Gene', (24, 28))	('CREB', 'Gene', (58, 62))	('TTP-low tumors', 'Disease', (273, 287))	('mutation', 'Var', (101, 109))	('decreased', 'NegReg', (91, 100))
525592	33318305	For example, a very recent study reported that the expression level of ADAMTS9-AS2 is lower in esophageal cancer tissues and over-expressing it can suppress the development of esophageal cancer via inducing CDHS promoter methylation.	('CDHS promoter methylation', 'MPA', (207, 232))	('esophageal cancer', 'Disease', 'MESH:D004938', (95, 112))	('suppress', 'NegReg', (148, 156))	('esophageal cancer', 'Disease', (176, 193))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('ADAMTS9', 'Gene', (71, 78))	('lower', 'NegReg', (86, 91))	('development', 'CPA', (161, 172))	('esophageal cancer', 'Disease', 'MESH:D004938', (176, 193))	('inducing', 'PosReg', (198, 206))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('over-expressing', 'Var', (125, 140))	('esophageal cancer', 'Disease', (95, 112))	('ADAMTS9', 'Gene', '56999', (71, 78))	('expression level', 'MPA', (51, 67))
525662	29790669	We derived a weighted genetic risk score (wGRS) comprising 101 height-related single nucleotide polymorphisms (SNP) identified by previous genome-wide association studies (GWAS) in East Asian-ancestry populations and analyzed whether there is a causal relationship between height and risk of lung cancer.	('single nucleotide polymorphisms', 'Var', (78, 109))	('lung cancer', 'Disease', (292, 303))	('lung cancer', 'Phenotype', 'HP:0100526', (292, 303))	('cancer', 'Phenotype', 'HP:0002664', (297, 303))	('lung cancer', 'Disease', 'MESH:D008175', (292, 303))
525669	29790669	Two variants, rs234886 and rs12680655, were not available in our lung cancer GWAS data and were replaced by high linkage disequilibrium (LD) SNPs, rs2237886 and rs733254 (r 2 > 0.9 in 1000 Genomes Project Phase 3 East Asian population).	('lung cancer', 'Disease', 'MESH:D008175', (65, 76))	('rs2237886', 'Mutation', 'rs2237886', (147, 156))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('rs12680655', 'Mutation', 'rs12680655', (27, 37))	('rs234886', 'Mutation', 'rs234886', (14, 22))	('lung cancer', 'Disease', (65, 76))	('lung cancer', 'Phenotype', 'HP:0100526', (65, 76))	('rs2237886', 'Var', (147, 156))	('rs234886', 'Var', (14, 22))	('rs12680655', 'Var', (27, 37))	('rs733254', 'Var', (161, 169))	('rs733254', 'Mutation', 'rs733254', (161, 169))
525678	29790669	However, there were 15 SNPs in NJMU study and 13 SNPs in FLCCA study had nominally significant associations (P < 0.05), and only one SNP, rs174547, in NJMU study survived Bonferroni correction (P < 4.95 x 10-4).	('rs174547', 'Var', (138, 146))	('rs174547', 'Mutation', 'rs174547', (138, 146))	('associations', 'Interaction', (95, 107))
525680	29790669	As shown in Figure 1, the increasing wGRS was significantly associated with higher observed height in both male (r 2 = 0.014, P = 7.19 x 10-4) and female (r 2 = 0.021, P = 9.41 x 10-3) participants, the estimated effect was in the positive direction (male beta estimate = 2.37, female beta estimate = 2.92).	('participants', 'Species', '9606', (185, 197))	('higher', 'PosReg', (76, 82))	('wGRS', 'Var', (37, 41))	('observed height', 'MPA', (83, 98))
525683	29790669	When modeled as a tertile of height-associated wGRS, wGRS was significantly associated with an increased risk of all lung cancer (per tertile OR = 1.05, 95% CI = 1.01-1.09, trend P = 0.028) and lung squamous cell carcinoma (per tertile OR = 1.08, 95% CI = 1.01-1.17, trend P = 0.035); however, not significant in lung adenocarcinoma (per tertile OR = 1.04, 95% CI = 0.99-1.09, trend P = 0.094).	('carcinoma', 'Phenotype', 'HP:0030731', (323, 332))	('lung adenocarcinoma', 'Disease', (313, 332))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (313, 332))	('lung cancer', 'Disease', (117, 128))	('lung cancer', 'Phenotype', 'HP:0100526', (117, 128))	('wGRS', 'Var', (53, 57))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (194, 222))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (313, 332))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (199, 222))	('lung cancer', 'Disease', 'MESH:D008175', (117, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (213, 222))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (194, 222))	('lung squamous cell carcinoma', 'Disease', (194, 222))
525707	29790669	For the second assumption, it is possible that height-related genetic variants are associated with other risk factors that influence the cancer development.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('associated', 'Reg', (83, 93))	('genetic variants', 'Var', (62, 78))	('cancer', 'Disease', (137, 143))
525715	29790669	Our study suggests the biologic pathways that genetically determined adult height may also involve in the etiology of lung cancer.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('genetically', 'Var', (46, 57))	('involve', 'Reg', (91, 98))	('lung cancer', 'Disease', 'MESH:D008175', (118, 129))	('lung cancer', 'Disease', (118, 129))	('lung cancer', 'Phenotype', 'HP:0100526', (118, 129))
525759	33528895	Dysregulation of ferroptosis may involve in the development of non-small-cell lung cancer in Xuanwei area The Xuanwei area of Yunnan Province, China, is one of the regions suffering from the highest occurrence and mortality rate of lung cancer in the world.	('lung cancer', 'Disease', (78, 89))	('lung cancer', 'Phenotype', 'HP:0100526', (78, 89))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('involve', 'Reg', (33, 40))	('Dysregulation', 'Var', (0, 13))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('mortality', 'Disease', (214, 223))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (63, 89))	('lung cancer', 'Disease', 'MESH:D008175', (232, 243))	('lung cancer', 'Disease', 'MESH:D008175', (78, 89))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (67, 89))	('lung cancer', 'Disease', (232, 243))	('mortality', 'Disease', 'MESH:D003643', (214, 223))	('lung cancer', 'Phenotype', 'HP:0100526', (232, 243))
525766	33528895	Further experiments on the two differential proteins, thioredoxin 2 (TXN2) and haptoglobin (HP), showed that the change of their expressions could make the lung cancer cell lines more resistant to erastin or RSL-induced ferroptosis in vitro, and promote the growth of tumour in nude mice.	('erastin', 'Chemical', 'MESH:C477224', (197, 204))	('tumour', 'Phenotype', 'HP:0002664', (268, 274))	('tumour', 'Disease', 'MESH:D009369', (268, 274))	('nude mice', 'Species', '10090', (278, 287))	('RSL', 'Gene', (208, 211))	('thioredoxin 2', 'Gene', (54, 67))	('promote', 'PosReg', (246, 253))	('tumour', 'Disease', (268, 274))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('RSL', 'Gene', '110392', (208, 211))	('lung cancer', 'Disease', (156, 167))	('change', 'Var', (113, 119))	('haptoglobin', 'Gene', (79, 90))	('expressions', 'MPA', (129, 140))	('resistant', 'CPA', (184, 193))	('more', 'PosReg', (179, 183))	('lung cancer', 'Disease', 'MESH:D008175', (156, 167))	('thioredoxin 2', 'Gene', '56551', (54, 67))	('lung cancer', 'Phenotype', 'HP:0100526', (156, 167))	('haptoglobin', 'Gene', '15439', (79, 90))
525822	33528895	The chart indicated that the threshold of fold-change set in the current study can effectively separate the cancer and the para-carcinoma groups, and the data of each case from the 2 groups were reproducible.	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('fold-change', 'Var', (42, 53))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('para-carcinoma', 'Disease', 'MESH:D002277', (123, 137))	('para-carcinoma', 'Disease', (123, 137))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
525839	33528895	According to the survival analysis results from Kaplan-Meier plotter (http://kmplot.com/analysis/), the overall survival (OS) signature (high risk vs. low risk) of TXN2 (Affymetrix ID: 209078_s_at) presents high-TXN2-expression patients' overall survival time is shorter than that of low-expression NSCLC patients (hazard ratio [HR] 1.19; P = .0076), especially for LUAD (HR = 1.76, P = 2.7e-6) (Figure 4D,E).	('NSCLC', 'Disease', (299, 304))	('overall survival', 'MPA', (238, 254))	('NSCLC', 'Phenotype', 'HP:0030358', (299, 304))	('NSCLC', 'Disease', 'MESH:D002289', (299, 304))	('patients', 'Species', '9606', (228, 236))	('high-TXN2-expression', 'Var', (207, 227))	('patients', 'Species', '9606', (305, 313))	('shorter', 'NegReg', (263, 270))	('UA', 'Chemical', 'MESH:C005460', (367, 369))	('LUAD', 'Disease', (366, 370))
525840	33528895	In one of the above data sets (GSE31210, analysed with PrognoScan, http://dna00.bio.kyutech.ac.jp/PrognoScan/index.html), apart from the OS result in Figure 4F (PROBE ID: 209077_at) which was consistent with that in Figure 4D, high-TXN2-expression patients also exhibited lower RFS (relapse free survival) in Figure 4G (PROBE ID: 209077_at).	('lower', 'NegReg', (272, 277))	('high-TXN2-expression', 'Var', (227, 247))	('RFS', 'Disease', (278, 281))	('patients', 'Species', '9606', (248, 256))	('RFS', 'Disease', 'MESH:D005198', (278, 281))
525843	33528895	According to the survival analysis results from The Human Protein Atlas (https://www.proteinatlas.org/), low-HP-expression patients have a poorer overall survival in LUAD (Figure 5D) (cut-off = 0.81, P = .014), but quite in reverse, low-HP-expression patients have a better prognosis for LUSC (Figure 5E) (cut-off = 0.36, P = .002).	('Human', 'Species', '9606', (52, 57))	('LUAD', 'Disease', (166, 170))	('patients', 'Species', '9606', (123, 131))	('low-HP-expression', 'Var', (233, 250))	('poorer', 'NegReg', (139, 145))	('LUSC', 'Disease', (288, 292))	('patients', 'Species', '9606', (251, 259))	('UA', 'Chemical', 'MESH:C005460', (167, 169))	('low-HP-expression', 'Var', (105, 122))
525844	33528895	To further validate the role of HP in prognosis of NSCLC, we analysed the survival of patients with low or high HP expression using Kaplan-Meier plotter (http://kmplot.com/analysis/) that mainly contains GEO (gene expression omnibus) data sets.	('NSCLC', 'Disease', (51, 56))	('NSCLC', 'Disease', 'MESH:D002289', (51, 56))	('low', 'Var', (100, 103))	('NSCLC', 'Phenotype', 'HP:0030358', (51, 56))	('patients', 'Species', '9606', (86, 94))
525845	33528895	Against our prediction and the aforesaid result from TCGA, the low-HP-expression (Affymetrix ID: 206697_s_at) patients' overall survival was better, consistent with which, these patients showed longer time till first progression (Figure 5F,G).	('low-HP-expression', 'Var', (63, 80))	('patients', 'Species', '9606', (178, 186))	('better', 'PosReg', (141, 147))	('overall survival', 'CPA', (120, 136))	('longer', 'PosReg', (194, 200))	('patients', 'Species', '9606', (110, 118))
525863	33528895	In vitro, both knocking down of TXN2 and overexpression of HP were observed to modulate sensitivity of lung cancer cell lines to erastin and RSL.	('lung cancer', 'Disease', 'MESH:D008175', (103, 114))	('RSL', 'Gene', '110392', (141, 144))	('knocking down', 'Var', (15, 28))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('TXN2', 'Gene', (32, 36))	('RSL', 'Gene', (141, 144))	('lung cancer', 'Disease', (103, 114))	('erastin', 'Chemical', 'MESH:C477224', (129, 136))	('lung cancer', 'Phenotype', 'HP:0100526', (103, 114))	('modulate', 'Reg', (79, 87))	('sensitivity', 'MPA', (88, 99))
525886	33528895	27  The persistent activation of antioxidant systems and overexpression of thioredoxin via genetic alterations in Nrf2 and Keap1 also contributes to carcinogenesis.	('contributes', 'Reg', (134, 145))	('overexpression', 'PosReg', (57, 71))	('carcinogenesis', 'Disease', (149, 163))	('antioxidant systems', 'MPA', (33, 52))	('Nrf2', 'Gene', (114, 118))	('Keap1', 'Gene', (123, 128))	('thioredoxin', 'Gene', (75, 86))	('Keap1', 'Gene', '9817', (123, 128))	('activation', 'PosReg', (19, 29))	('genetic alterations', 'Var', (91, 110))	('carcinogenesis', 'Disease', 'MESH:D063646', (149, 163))	('thioredoxin', 'Gene', '7295', (75, 86))
525887	33528895	28  Moreover, a recent study reported genetic knockdown of TXN leads to accumulation of lipid ROS levels and induces an antioxidant response to cause ferroptosis, a potential pro-ferroptotic agent due to its inhibition of TXN would be an anti-cancer therapeutic strategy.	('TXN', 'Gene', (222, 225))	('ferroptosis', 'Disease', (150, 161))	('knockdown', 'Var', (46, 55))	('TXN', 'Gene', (59, 62))	('TXN', 'Gene', '7295', (222, 225))	('ROS', 'Chemical', 'MESH:D017382', (94, 97))	('cause', 'Reg', (144, 149))	('cancer', 'Disease', (243, 249))	('lipid ROS levels', 'MPA', (88, 104))	('cancer', 'Disease', 'MESH:D009369', (243, 249))	('accumulation', 'PosReg', (72, 84))	('TXN', 'Gene', '7295', (59, 62))	('lipid', 'Chemical', 'MESH:D008055', (88, 93))	('cancer', 'Phenotype', 'HP:0002664', (243, 249))	('antioxidant response', 'MPA', (120, 140))	('induces', 'Reg', (109, 116))
525890	33528895	31  HP polymorphism causes change in haemoglobin-bind capacity, antioxidant and iron-recycling activities, which may be important for effective oxidative stress response in lung cancer pathogenic process.	('polymorphism', 'Var', (7, 19))	('lung cancer', 'Disease', 'MESH:D008175', (173, 184))	('antioxidant', 'MPA', (64, 75))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('change', 'Reg', (27, 33))	('oxidative stress', 'Phenotype', 'HP:0025464', (144, 160))	('iron', 'Chemical', 'MESH:D007501', (80, 84))	('iron-recycling activities', 'MPA', (80, 105))	('haemoglobin-bind capacity', 'MPA', (37, 62))	('lung cancer', 'Disease', (173, 184))	('lung cancer', 'Phenotype', 'HP:0100526', (173, 184))
525896	33528895	Further experiments with overexpressed TXN2 or interfered with HP in lung cancer cell lines demonstrated that TXN2 overexpression and HP depletion promoted lung cancer resistance to erastin or RSL-induced cell death were through attenuating ferroptosis, whereas upregulating of HP but downregulating TXN2 increased the ferroptosis rate of lung cancer cells.	('erastin', 'Chemical', 'MESH:C477224', (182, 189))	('ferroptosis rate', 'CPA', (319, 335))	('RSL', 'Gene', '110392', (193, 196))	('cancer', 'Phenotype', 'HP:0002664', (344, 350))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('depletion', 'Var', (137, 146))	('lung cancer', 'Disease', (339, 350))	('attenuating', 'NegReg', (229, 240))	('lung cancer', 'Disease', (69, 80))	('increased', 'PosReg', (305, 314))	('death', 'Disease', 'MESH:D003643', (210, 215))	('lung cancer', 'Disease', (156, 167))	('promoted', 'PosReg', (147, 155))	('lung cancer', 'Disease', 'MESH:D008175', (339, 350))	('ferroptosis', 'CPA', (241, 252))	('lung cancer', 'Disease', 'MESH:D008175', (69, 80))	('lung cancer', 'Phenotype', 'HP:0100526', (339, 350))	('lung cancer', 'Disease', 'MESH:D008175', (156, 167))	('lung cancer', 'Phenotype', 'HP:0100526', (69, 80))	('RSL', 'Gene', (193, 196))	('death', 'Disease', (210, 215))	('lung cancer', 'Phenotype', 'HP:0100526', (156, 167))
525907	32937734	Results: The boosting estimation identified five CpGs with prognostic significance: EPHX3-24, EPHX3-26, ITGA4-3, ITGA4-4, and MiR193-3.	('MiR193-3', 'Var', (126, 134))	('EPHX3', 'Gene', (94, 99))	('ITGA4', 'Gene', (104, 109))	('EPHX3', 'Gene', (84, 89))	('ITGA4-4', 'Gene', (113, 120))	('ITGA4', 'Gene', '3676', (104, 109))	('ITGA4', 'Gene', (113, 118))	('ITGA4-4', 'Gene', '3676', (113, 120))	('ITGA4', 'Gene', '3676', (113, 118))	('EPHX3', 'Gene', '79852', (94, 99))	('EPHX3', 'Gene', '79852', (84, 89))
525916	32937734	Aberrant DNA methylation in these loci may contribute to cancer progression, leading to dysregulation of mRNA expression, an early and frequent event in tumors.	('contribute', 'Reg', (43, 53))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('dysregulation', 'MPA', (88, 101))	('Aberrant DNA methylation', 'Var', (0, 24))	('cancer', 'Disease', (57, 63))	('mRNA', 'Protein', (105, 109))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumors', 'Disease', (153, 159))	('tumors', 'Phenotype', 'HP:0002664', (153, 159))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('tumors', 'Disease', 'MESH:D009369', (153, 159))
525917	32937734	On the other side, DNA hypomethylation promotes tumorigenesis via transcriptional activation of oncogenes and chromosomal instability.	('transcriptional', 'MPA', (66, 81))	('promotes', 'PosReg', (39, 47))	('tumor', 'Disease', (48, 53))	('activation', 'PosReg', (82, 92))	('DNA hypomethylation', 'Var', (19, 38))	('chromosomal instability', 'Phenotype', 'HP:0040012', (110, 133))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('oncogenes', 'Gene', (96, 105))	('chromosomal instability', 'CPA', (110, 133))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('hypomethylation', 'Var', (23, 38))
525918	32937734	The loss of function of tumor-suppressor genes, which often occurs in tumors, has been ascribed more frequently to epigenetic silencing through methylation than to genetic mutations, supporting the hypothesis that epigenetic alterations have a significant role in every step of carcinogenesis.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('loss of function', 'NegReg', (4, 20))	('epigenetic silencing', 'MPA', (115, 135))	('methylation', 'Var', (144, 155))	('tumors', 'Disease', (70, 76))	('tumors', 'Disease', 'MESH:D009369', (70, 76))	('carcinogenesis', 'Disease', 'MESH:D063646', (278, 292))	('tumor-suppressor', 'Gene', '7248', (24, 40))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('carcinogenesis', 'Disease', (278, 292))	('tumor-suppressor', 'Gene', (24, 40))
525919	32937734	Previous studies, performed by our group, demonstrated the importance of epigenetic alterations and aberrant DNA methylation of specific genes to discriminate OSCC and its precursors lesions from benign oral mucosal lesions.	('epigenetic alterations', 'Var', (73, 95))	('OSCC', 'Disease', (159, 163))	('aberrant', 'Var', (100, 108))	('benign oral mucosal lesions', 'Disease', 'MESH:D009059', (196, 223))	('benign oral mucosal lesions', 'Disease', (196, 223))
525920	32937734	ROC analysis of all CpGs investigated allowed us to select the highest informative ones mapped within the following 13 genes: ZAP70, ITGA4, KIF1A, PARP15, EPHX3, NTM, LRRTM1, FLI1, MIR193, LINC00599, MIR296, TERT, and GP1BB.	('ZAP70', 'Gene', '7535', (126, 131))	('KIF1A', 'Gene', (140, 145))	('ITGA4', 'Gene', '3676', (133, 138))	('PARP15', 'Gene', (147, 153))	('NTM', 'Gene', (162, 165))	('FLI1', 'Gene', '2313', (175, 179))	('ITGA4', 'Gene', (133, 138))	('NTM', 'Gene', '50863', (162, 165))	('MIR296', 'Gene', (200, 206))	('GP1BB', 'Gene', (218, 223))	('KIF1A', 'Gene', '547', (140, 145))	('LRRTM1', 'Gene', (167, 173))	('MIR296', 'Gene', '407022', (200, 206))	('TERT', 'Gene', (208, 212))	('TERT', 'Gene', '7015', (208, 212))	('EPHX3', 'Gene', (155, 160))	('PARP15', 'Gene', '165631', (147, 153))	('MIR193', 'Var', (181, 187))	('LRRTM1', 'Gene', '347730', (167, 173))	('ZAP70', 'Gene', (126, 131))	('GP1BB', 'Gene', '2812', (218, 223))	('LINC00599', 'Gene', '157627', (189, 198))	('LINC00599', 'Gene', (189, 198))	('EPHX3', 'Gene', '79852', (155, 160))	('FLI1', 'Gene', (175, 179))
525933	32937734	Tumor size: the Mann-Whitney U test showed higher methylation levels of most CpG sites of LINC00599 (coordinates hg38: Chr8: 9903242-9903378) in T1-T2 tumors as compared to T3-T4 tumors, although results failed to achieve statistical significance at the 5%-level (Figure 2).	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('LINC00599', 'Gene', (90, 99))	('methylation levels', 'MPA', (50, 68))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('higher', 'PosReg', (43, 49))	('tumors', 'Disease', (151, 157))	('tumors', 'Disease', (179, 185))	('tumors', 'Disease', 'MESH:D009369', (151, 157))	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('tumors', 'Phenotype', 'HP:0002664', (179, 185))	('tumors', 'Disease', 'MESH:D009369', (179, 185))	('hg38', 'Gene', (113, 117))	('hg38', 'Gene', '8549', (113, 117))	('T1-T2', 'Var', (145, 150))	('LINC00599', 'Gene', '157627', (90, 99))
525936	32937734	The boosting estimation resulted in five non-zero regression coefficients associated with EPHX3-24, EPHX3-26, ITGA4-3, ITGA4-4, and MiR193-3.	('ITGA4', 'Gene', (110, 115))	('EPHX3', 'Gene', (90, 95))	('ITGA4-4', 'Gene', (119, 126))	('ITGA4', 'Gene', '3676', (110, 115))	('MiR193-3', 'Var', (132, 140))	('ITGA4', 'Gene', (119, 124))	('EPHX3', 'Gene', '79852', (100, 105))	('ITGA4-4', 'Gene', '3676', (119, 126))	('EPHX3', 'Gene', '79852', (90, 95))	('ITGA4', 'Gene', '3676', (119, 124))	('EPHX3', 'Gene', (100, 105))
525937	32937734	As shown in Table 2, EPHX3 was associated with worse prognostic outcomes in case of hypomethylation (HR < 1), while ITGA4 and MiR193 were associated with worse prognosis outcomes in case of hypermethylation (HR > 1).	('MiR193', 'Var', (126, 132))	('ITGA4', 'Gene', (116, 121))	('EPHX3', 'Gene', '79852', (21, 26))	('hypomethylation', 'Var', (84, 99))	('ITGA4', 'Gene', '3676', (116, 121))	('EPHX3', 'Gene', (21, 26))
525938	32937734	Removing the connection information from the boosting algorithm, results were quite stable (Table S2): the CpG sites retained in the final Cox model were EPHX3-23, EPHX3-24, ITGA4-4 and MiR193-3; the discriminative ability was virtually identical (C-index = 0.805; integrated AUC = 0.847), as well as the overall performance (integrated Brier score = 0.089).	('EPHX3-23', 'Gene', (154, 162))	('ITGA4-4', 'Gene', (174, 181))	('EPHX3', 'Gene', '79852', (154, 159))	('EPHX3-23', 'Gene', '79852;253152', (154, 162))	('MiR193-3', 'Var', (186, 194))	('EPHX3', 'Gene', '79852', (164, 169))	('EPHX3', 'Gene', (154, 159))	('EPHX3', 'Gene', (164, 169))	('Cox', 'Gene', '1351', (139, 142))	('Cox', 'Gene', (139, 142))	('ITGA4-4', 'Gene', '3676', (174, 181))
525944	32937734	As in other body sites (as lung or colon), OSCC molecular profile can give interesting information about tumor aggressiveness: Specifically, gene silencing by promoter methylation seems to play a crucial role in determining tumor aggressive potential.	('tumor aggressiveness', 'Disease', 'MESH:D001523', (105, 125))	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('colon', 'Disease', 'MESH:D003110', (35, 40))	('gene', 'Var', (141, 145))	('tumor', 'Disease', (224, 229))	('tumor', 'Disease', 'MESH:D009369', (105, 110))	('colon', 'Disease', (35, 40))	('tumor', 'Phenotype', 'HP:0002664', (105, 110))	('tumor aggressiveness', 'Disease', (105, 125))	('aggressiveness', 'Phenotype', 'HP:0000718', (111, 125))	('tumor', 'Disease', (105, 110))	('tumor', 'Disease', 'MESH:D009369', (224, 229))
525956	32937734	However, further studies and larger studies are needed to elucidate contribution LINC00599 methylation in oral carcinogenesis.	('methylation', 'Var', (91, 102))	('LINC00599', 'Gene', (81, 90))	('LINC00599', 'Gene', '157627', (81, 90))	('oral carcinogenesis', 'Disease', 'MESH:D063646', (106, 125))	('oral carcinogenesis', 'Disease', (106, 125))
525957	32937734	Similarly, there was a tendency toward hypomethylation for most CpG islands of EPHX3 in case of positive lymph-node status at the diagnosis.	('EPHX3', 'Gene', (79, 84))	('EPHX3', 'Gene', '79852', (79, 84))	('hypomethylation', 'Var', (39, 54))
525959	32937734	The boosting estimation resulted in five non-zero regression coefficients associated with EPHX3-24, EPHX3-26, ITGA4-3, ITGA4-4, and MiR193-3 significantly associated with the occurrence of loco regional adverse events.	('ITGA4', 'Gene', (110, 115))	('EPHX3', 'Gene', (90, 95))	('ITGA4-4', 'Gene', (119, 126))	('ITGA4', 'Gene', '3676', (110, 115))	('MiR193-3', 'Var', (132, 140))	('associated with', 'Reg', (155, 170))	('ITGA4', 'Gene', (119, 124))	('EPHX3', 'Gene', '79852', (100, 105))	('loco regional adverse events', 'Disease', (189, 217))	('ITGA4-4', 'Gene', '3676', (119, 126))	('EPHX3', 'Gene', '79852', (90, 95))	('ITGA4', 'Gene', '3676', (119, 124))	('EPHX3', 'Gene', (100, 105))
525960	32937734	Putative prognostic predictors methylation analysis showed that EPHX3 was associated with worse prognostic outcomes when hypomethylated (HR < 1), while ITGA4 and MiR193 were associated with worse prognosis outcomes in case of hypermethylation (HR > 1).	('MiR193', 'Var', (162, 168))	('ITGA4', 'Gene', (152, 157))	('ITGA4', 'Gene', '3676', (152, 157))	('EPHX3', 'Gene', '79852', (64, 69))	('EPHX3', 'Gene', (64, 69))	('hypomethylated', 'Var', (121, 135))
525975	32937734	Interestingly, when connection information from the boosting algorithm was removed, EPHX3-24, ITGA4-4, and MiR193-3 retained a strong predictive prognostic ability in the final Cox model.	('EPHX3', 'Gene', (84, 89))	('ITGA4-4', 'Gene', '3676', (94, 101))	('MiR193-3', 'Var', (107, 115))	('Cox', 'Gene', '1351', (177, 180))	('Cox', 'Gene', (177, 180))	('ITGA4-4', 'Gene', (94, 101))	('EPHX3', 'Gene', '79852', (84, 89))
526032	31860169	Further studies have found that GMDS-AS1 can act as a ceRNA to upregulate the expression level of CYLD by sponging miR-96-5p, which may be one of the mechanisms in LUAD.	('sponging', 'Var', (106, 114))	('LUAD', 'Disease', (164, 168))	('miR-96', 'Gene', '407053', (115, 121))	('LUAD', 'Disease', 'MESH:C538231', (164, 168))	('miR-96', 'Gene', (115, 121))	('expression level', 'MPA', (78, 94))	('GMDS-AS1', 'Gene', (32, 40))	('upregulate', 'PosReg', (63, 73))	('GMDS-AS1', 'Gene', '100508120', (32, 40))
526040	31860169	Luciferase reporter plasmids include wild type and mutant pGLO-GMDS-AS1, as well as wild type and mutant pGLO-CYLD 3'UTR, both constructed by Sangon Company.	('GMDS-AS1', 'Gene', '100508120', (63, 71))	('mutant', 'Var', (51, 57))	('GMDS-AS1', 'Gene', (63, 71))	('mutant', 'Var', (98, 104))
526051	31860169	Stable overexpressing cells were constructed in PC-9 cells using lentiviral overexpression plasmids Lenti-GMDS-AS1 and Lenti-NC.	('GMDS-AS1', 'Gene', '100508120', (106, 114))	('PC-9', 'Gene', (48, 52))	('GMDS-AS1', 'Gene', (106, 114))	('PC-9', 'Gene', '255738', (48, 52))	('Lenti-NC', 'Var', (119, 127))
526079	31860169	Based on the predicted binding sites, we designed the GMDS-AS1 reporter plasmid pGLO-GMDS-AS1 containing the wild-type binding sequence (WT) and the mutant binding sequence (Mut), respectively (Figure 4C).	('GMDS-AS1', 'Gene', '100508120', (85, 93))	('GMDS-AS1', 'Gene', (85, 93))	('mutant', 'Var', (149, 155))	('GMDS-AS1', 'Gene', '100508120', (54, 62))	('GMDS-AS1', 'Gene', (54, 62))
526099	31860169	The results of CCK-8 assay (Figure 5M,N) and colony formation assay (Figure 5O) showed that si-CYLD could reverse the inhibitory effect of anti-miR-96-5p on the proliferation of LUAD cells.	('LUAD', 'Disease', (178, 182))	('LUAD', 'Disease', 'MESH:C538231', (178, 182))	('si-CYLD', 'Var', (92, 99))	('miR-96', 'Gene', '407053', (144, 150))	('miR-96', 'Gene', (144, 150))
526124	31860169	In LUAD cells, GMDS-AS1 acts as a ceRNA, which promotes the expression of CYLD by sponging miR-96-5p, thereby inhibiting the proliferation of tumor cells and promoting apoptosis.	('expression', 'MPA', (60, 70))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('LUAD', 'Disease', (3, 7))	('LUAD', 'Disease', 'MESH:C538231', (3, 7))	('promotes', 'PosReg', (47, 55))	('tumor', 'Disease', (142, 147))	('miR-96', 'Gene', '407053', (91, 97))	('GMDS-AS1', 'Gene', '100508120', (15, 23))	('miR-96', 'Gene', (91, 97))	('inhibiting', 'NegReg', (110, 120))	('apoptosis', 'CPA', (168, 177))	('sponging', 'Var', (82, 90))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('promoting', 'PosReg', (158, 167))	('GMDS-AS1', 'Gene', (15, 23))	('CYLD', 'Gene', (74, 78))
526192	28195392	The trapped peptides were eluted onto the analytical column, (C18, 75 microm IDx50 cm, 2 microm, 100A, Dionex, Sunnyvale, CA).	('peptides', 'Chemical', 'MESH:D010455', (12, 20))	('IDx50 cm', 'Var', (77, 85))	('C18', 'Gene', '27241', (62, 65))	('C18', 'Gene', (62, 65))
526274	31660290	None of the cases showed drastic deterioration; therefore, the present case is the first to highlight that A. odontolyticus possibly produce drastically progressive lung cavity lesion.	('A. odontolyticus', 'Species', '1660', (107, 123))	('A. odontolyticus', 'Var', (107, 123))	('lung cavity lesion', 'Disease', (165, 183))	('lung cavity lesion', 'Disease', 'MESH:D008171', (165, 183))
526331	31660290	Further, it should be noted that A. odontolyticus may produce drastically progressive lung cavity lesion.	('produce', 'Reg', (54, 61))	('A. odontolyticus', 'Species', '1660', (33, 49))	('lung cavity lesion', 'Disease', (86, 104))	('A. odontolyticus', 'Var', (33, 49))	('lung cavity lesion', 'Disease', 'MESH:D008171', (86, 104))
526345	29777108	EGFR mutations and ALK translocations) in lung adenocarcinomas (LUAD) has led to the development of highly effective targeted therapies in these subsets of lung cancer.	('carcinoma', 'Phenotype', 'HP:0030731', (52, 61))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (42, 62))	('ALK', 'Gene', (19, 22))	('EGFR', 'Gene', (0, 4))	('EGFR', 'Gene', '13649', (0, 4))	('lung cancer', 'Phenotype', 'HP:0100526', (156, 167))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (42, 62))	('carcinomas', 'Phenotype', 'HP:0030731', (52, 62))	('lung cancer', 'Disease', 'MESH:D008175', (156, 167))	('translocations', 'Var', (23, 37))	('mutations', 'Var', (5, 14))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (42, 61))	('lung cancer', 'Disease', (156, 167))	('lung adenocarcinomas', 'Disease', (42, 62))	('ALK', 'Gene', '11682', (19, 22))
526348	29777108	In fact, several phase III clinical trials recently led to FDA approval of anti-PD1 antibodies in the first- and second-line treatment of LUSC, suggesting that LUSC may be suitable for additional examination of immune-oncology approaches.	('oncology', 'Phenotype', 'HP:0002664', (218, 226))	('LUSC', 'Disease', (138, 142))	('PD1', 'Gene', '5133', (80, 83))	('PD1', 'Gene', (80, 83))	('clinical', 'Species', '191496', (27, 35))	('antibodies', 'Var', (84, 94))
526385	29777108	Although CD14 is most highly expressed on IMs amongst leukocytes, it is possible that the poor survival associated with high CD14 expression is related to other CD14-expressing immune infiltrates, such as TAMs, DCs, myeloid-derived suppressor cells (MDSCs) or neutrophils.	('poor', 'NegReg', (90, 94))	('expression', 'MPA', (130, 140))	('high', 'Var', (120, 124))	('rat', 'Species', '10116', (190, 193))	('TAMs', 'Chemical', '-', (205, 209))	('CD14', 'Gene', (125, 129))
526394	29777108	Both sub-clones had significantly increased number and frequency of lymph node metastases; however, the LN4K1 sub-clone developed more distant metastases, while LN2-2-injected mice rapidly died from malignant pleural effusions (Supplementary Fig.	('metastases', 'Disease', 'MESH:D009362', (79, 89))	('metastases', 'Disease', 'MESH:D009362', (143, 153))	('pleural effusions', 'Phenotype', 'HP:0002202', (209, 226))	('malignant pleural effusions', 'Disease', (199, 226))	('mice', 'Species', '10090', (176, 180))	('malignant pleural effusions', 'Disease', 'MESH:D016066', (199, 226))	('metastases', 'Disease', (143, 153))	('metastases', 'Disease', (79, 89))	('LN4K1', 'Var', (104, 109))
526395	29777108	Although KLN205 and LN4K1 had similar intrinsic growth rates in vitro, LN4K1 tumors grew significantly faster in vivo (Supplementary Fig.	('tumors', 'Disease', (77, 83))	('tumors', 'Disease', 'MESH:D009369', (77, 83))	('KLN205', 'Chemical', '-', (9, 15))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('faster', 'PosReg', (103, 109))	('grew', 'CPA', (84, 88))	('KLN205', 'Var', (9, 15))	('LN4K1', 'Gene', (71, 76))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('rat', 'Species', '10116', (55, 58))
526398	29777108	To explore the molecular mechanisms underlying the metastatic properties of LN4K1, we compared the expression profiles of 3 cell lines: murine bronchial epithelial cells (MBEC) isolated from healthy adult DBA2 mice, KLN205, and LN4K1.	('mice', 'Species', '10090', (210, 214))	('LN4K1', 'Var', (228, 233))	('murine', 'Species', '10090', (136, 142))	('KLN205', 'Var', (216, 222))	('KLN205', 'Chemical', '-', (216, 222))
526404	29777108	Consistent with these findings, compared with KLN205, LN4K1 had markedly elevated TNFalpha and CCL2 expression levels and modest increases in CSF1 (Fig.	('CCL2', 'Gene', '20296', (95, 99))	('CSF1', 'Gene', '12977', (142, 146))	('KLN205', 'Chemical', '-', (46, 52))	('CCL2', 'Gene', (95, 99))	('expression levels', 'MPA', (100, 117))	('LN4K1', 'Var', (54, 59))	('TNFalpha', 'Gene', '21926', (82, 90))	('increases', 'PosReg', (129, 138))	('CSF1', 'Gene', (142, 146))	('elevated', 'PosReg', (73, 81))	('TNFalpha', 'Gene', (82, 90))
526408	29777108	Indeed, silencing p65 significantly decreased basal and exogenous TNFalpha-mediated stimulation of CCL2 in LN4K1 cells (Fig.	('CCL2', 'Gene', (99, 103))	('CCL2', 'Gene', '20296', (99, 103))	('TNFalpha', 'Gene', (66, 74))	('silencing', 'Var', (8, 17))	('p65', 'Gene', '19697', (18, 21))	('p65', 'Gene', (18, 21))	('TNFalpha', 'Gene', '21926', (66, 74))	('decreased', 'NegReg', (36, 45))
526409	29777108	Moreover, compared with KLN205, LN4K1 displayed increased activation of NFkappaB, and pharmacological inhibition of IKKbeta using Compound A (Cmpd A) significantly reduced the levels of phospho-p65 and CCL2 (Fig.	('CCL2', 'Gene', (202, 206))	('NFkappaB', 'Gene', '18033', (72, 80))	('p65', 'Gene', '19697', (194, 197))	('IKKbeta', 'Gene', (116, 123))	('CCL2', 'Gene', '20296', (202, 206))	('LN4K1', 'Var', (32, 37))	('p65', 'Gene', (194, 197))	('levels', 'MPA', (176, 182))	('KLN205', 'Chemical', '-', (24, 30))	('NFkappaB', 'Gene', (72, 80))	('activation', 'PosReg', (58, 68))	('reduced', 'NegReg', (164, 171))	('IKKbeta', 'Gene', '16150', (116, 123))
526411	29777108	The LN4K1 model promoted substantial increases in IM generation in the bone marrow (BM), leading to a significant increase in IMs in the blood and a non-significant increase in the spleen (Fig.	('increase', 'PosReg', (114, 122))	('LN4K1', 'Var', (4, 9))	('increases', 'PosReg', (37, 46))	('rat', 'Species', '10116', (57, 60))	('IM generation', 'MPA', (50, 63))	('IMs in the blood', 'MPA', (126, 142))
526418	29777108	4f), compared with the parental KLN205 cell line, LN4K1 was associated with marked increases in IM recruitment and rapid development of distant metastases (Supplementary Fig.	('increases', 'PosReg', (83, 92))	('LN4K1', 'Var', (50, 55))	('KLN205', 'Chemical', '-', (32, 38))	('IM recruitment', 'CPA', (96, 110))	('metastases', 'Disease', (144, 154))	('metastases', 'Disease', 'MESH:D009362', (144, 154))
526420	29777108	Indeed, the stable overexpression of CCL2 in KLN205 was sufficient to account for the enhanced metastatic properties of LN4K1, while the silencing of CCL2 in LN4K1 with two different shRNAs had the opposite effect, substantially decreasing metastatic properties (Fig.	('overexpression', 'PosReg', (19, 33))	('CCL2', 'Gene', (150, 154))	('metastatic properties', 'CPA', (240, 261))	('CCL2', 'Gene', '20296', (150, 154))	('decreasing', 'NegReg', (229, 239))	('KLN205', 'Var', (45, 51))	('enhanced', 'PosReg', (86, 94))	('KLN205', 'Chemical', '-', (45, 51))	('silencing', 'Var', (137, 146))	('CCL2', 'Gene', '20296', (37, 41))	('metastatic properties', 'CPA', (95, 116))	('CCL2', 'Gene', (37, 41))
526421	29777108	Additionally, consistent with the effects of CCL2 on metastasis and IM recruitment, CCL2 overexpression in KLN205 led to significantly shorter survival and increased IM infiltration in the lungs (Fig.	('CCL2', 'Gene', (45, 49))	('survival', 'CPA', (143, 151))	('CCL2', 'Gene', '20296', (45, 49))	('KLN205', 'Var', (107, 113))	('increased', 'PosReg', (156, 165))	('overexpression', 'PosReg', (89, 103))	('IM infiltration in the', 'CPA', (166, 188))	('KLN205', 'Chemical', '-', (107, 113))	('CCL2', 'Gene', (84, 88))	('rat', 'Species', '10116', (175, 178))	('shorter', 'NegReg', (135, 142))	('CCL2', 'Gene', '20296', (84, 88))
526429	29777108	While anti-CCL2 antibodies have shown initial promise in breast cancer, a rebound effect that accelerates metastasis has been observed upon drug cessation and this therapy is no longer being clinically developed.	('breast cancer', 'Disease', (57, 70))	('antibodies', 'Var', (16, 26))	('breast cancer', 'Phenotype', 'HP:0003002', (57, 70))	('CCL2', 'Gene', '20296', (11, 15))	('metastasis', 'CPA', (106, 116))	('clinical', 'Species', '191496', (191, 199))	('CCL2', 'Gene', (11, 15))	('accelerates', 'PosReg', (94, 105))	('breast cancer', 'Disease', 'MESH:D001943', (57, 70))	('rat', 'Species', '10116', (100, 103))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
526433	29777108	To assess the effects of PF-04136309 on established LUSC metastases, one week following tail vein injection of luciferase-labeled LN4K1 cells, mice were treated with vehicle or PF-04136309 and imaged one week later (Fig.	('PF-04136309', 'Var', (177, 188))	('PF-04136309', 'Chemical', 'MESH:C000620181', (25, 36))	('metastases', 'Disease', (57, 67))	('PF-04136309', 'Chemical', 'MESH:C000620181', (177, 188))	('metastases', 'Disease', 'MESH:D009362', (57, 67))	('mice', 'Species', '10090', (143, 147))
526434	29777108	Significant reduction in lung metastasis was observed with PF-04136309 treatment, consistent with significant reductions in both circulating and lung TME IMs (Fig.	('reductions', 'NegReg', (110, 120))	('PF-04136309', 'Chemical', 'MESH:C000620181', (59, 70))	('lung metastasis', 'Disease', (25, 40))	('reduction', 'NegReg', (12, 21))	('lung TME IMs', 'MPA', (145, 157))	('lung metastasis', 'Disease', 'MESH:D009362', (25, 40))	('PF-04136309', 'Var', (59, 70))
526436	29777108	In accordance with a prior study using CCR2 inhibition, 1 week of treatment did not significantly affect CD206High or CD206Low TAM subsets (Supplementary Fig.	('CCR2', 'Gene', (39, 43))	('TAM', 'Chemical', '-', (127, 130))	('CD206Low TAM', 'Var', (118, 130))	('CD206High', 'Var', (105, 114))	('CCR2', 'Gene', '12772', (39, 43))
526438	29777108	Additionally, CCR2 blockade with PF-04136309 significantly inhibited metastasis development when treatment was initiated on the day of cancer cell injection (Fig.	('metastasis development', 'CPA', (69, 91))	('cancer', 'Disease', (135, 141))	('CCR2', 'Gene', '12772', (14, 18))	('inhibited', 'NegReg', (59, 68))	('PF-04136309', 'Var', (33, 44))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('blockade', 'NegReg', (19, 27))	('CCR2', 'Gene', (14, 18))	('PF-04136309', 'Chemical', 'MESH:C000620181', (33, 44))	('cancer', 'Disease', 'MESH:D009369', (135, 141))
526443	29777108	Importantly, comparing the expression levels of F13a1 mRNA in CD206High and CD206Low TAM subsets revealed that TAMs express F13a1 levels that are similar to RMs (Supplementary Fig.	('CD206High', 'Var', (62, 71))	('F13a1', 'Gene', '74145', (48, 53))	('F13a1', 'Gene', (124, 129))	('TAM', 'Chemical', '-', (111, 114))	('F13a1', 'Gene', '74145', (124, 129))	('TAM', 'Chemical', '-', (85, 88))	('TAMs', 'Chemical', '-', (111, 115))	('F13a1', 'Gene', (48, 53))
526446	29777108	Furthermore, compared to tumors with low CD14 expression, F13a1 expression levels in CD14 high tumors were more than 2.5-fold higher (Supplementary Fig.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('CD14', 'Gene', (85, 89))	('tumors', 'Disease', (25, 31))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('higher', 'PosReg', (126, 132))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('tumors', 'Disease', 'MESH:D009369', (25, 31))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('expression levels', 'MPA', (64, 81))	('F13a1', 'Gene', (58, 63))	('high', 'Var', (90, 94))	('tumors', 'Disease', (95, 101))	('F13a1', 'Gene', '74145', (58, 63))
526456	29777108	Using a TMA of 96 surgically-resected LUSC tumors, we found that compared with low or intermediate staining, high staining of intra-tumoral fibrin cross-linking was associated with significantly worse recurrence-free survival (Fig.	('high staining', 'Var', (109, 122))	('worse', 'NegReg', (195, 200))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('LUSC tumors', 'Disease', 'MESH:D009369', (38, 49))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('intra-tumoral', 'Disease', 'MESH:D009369', (126, 139))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('intra-tumoral', 'Disease', (126, 139))	('LUSC tumors', 'Disease', (38, 49))	('recurrence-free survival', 'CPA', (201, 225))
526457	29777108	Consistent with this observation, LUSC tumors from the TCGA dataset expressing high F13a1 had significantly worse survival (Fig.	('survival', 'MPA', (114, 122))	('F13a1', 'Gene', (84, 89))	('LUSC tumors', 'Disease', 'MESH:D009369', (34, 45))	('F13a1', 'Gene', '74145', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('high', 'Var', (79, 83))	('worse', 'NegReg', (108, 113))	('LUSC tumors', 'Disease', (34, 45))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))
526458	29777108	Finally, to assess whether FXIIIA over-expressing monocytes are sufficient to enhance LUSC metastasis in vivo, we stably over-expressed or silenced FXIIIA in a THP1 monocyte model (Fig.	('enhance', 'PosReg', (78, 85))	('THP1', 'Gene', '2736', (160, 164))	('LUSC metastasis', 'CPA', (86, 101))	('FXIIIA', 'Gene', (148, 154))	('over-expressed', 'PosReg', (121, 135))	('THP1', 'Gene', (160, 164))	('silenced', 'Var', (139, 147))
526459	29777108	Genetically modified THP1 monocytes were infused into NSG mice daily for a total of 4 days following intravenous injection of LN4K1, and at 1 week the lungs were dissociated and micro-metastases were enumerated using FACS for EpCAM.	('metastases', 'Disease', (184, 194))	('FACS', 'Gene', (217, 221))	('FACS', 'Gene', '14081', (217, 221))	('rat', 'Species', '10116', (205, 208))	('metastases', 'Disease', 'MESH:D009362', (184, 194))	('mice', 'Species', '10090', (58, 62))	('LN4K1', 'Var', (126, 131))	('EpCAM', 'Gene', (226, 231))	('THP1', 'Gene', '2736', (21, 25))	('EpCAM', 'Gene', '17075', (226, 231))	('THP1', 'Gene', (21, 25))
526501	29777108	Lentiviral vectors for CCL2 knockdown in LN4K1 and KAL-LN2E1 cells were also purchased from GeneCopoeia: Cntrl shR (CSHCTR001-1-LVRU6H), CCL2 shR#1 (MSH030124-1-LVRU6H), CCL2 shR#2 (MSH030124-2-LVRU6H), CCL2 shR#3 (MSH030124-3-LVRU6H), and CCL2 shR#4 (MSH030124-4-LVRU6H).	('MSH030124-1-LVRU6H', 'Var', (149, 167))	('MSH030124-4-LVRU6H', 'Var', (252, 270))	('MSH030124-3-LVRU6H', 'Var', (215, 233))	('CCL2', 'Gene', '20296', (203, 207))	('CCL2', 'Gene', '20296', (240, 244))	('KAL', 'Gene', '13648', (51, 54))	('CCL2', 'Gene', (203, 207))	('CCL2', 'Gene', (240, 244))	('CCL2', 'Gene', '20296', (137, 141))	('CCL2', 'Gene', '20296', (23, 27))	('CCL2', 'Gene', '20296', (170, 174))	('CCL2', 'Gene', (170, 174))	('MSH030124-2-LVRU6H', 'Var', (182, 200))	('KAL', 'Gene', (51, 54))	('CCL2', 'Gene', (137, 141))	('CCL2', 'Gene', (23, 27))
526502	29777108	Lentiviral particles for Factor 13 overexpression and silencing in THP1 cells were purchased from GeneCopoeia: Factor 13 ORF (NM_028784.3), Factor 13 shR#1 (HSH005069-1-LVRU6H) and Factor 13 shR#2 (HSH005069-2-LVRU6H).	('THP1', 'Gene', '2736', (67, 71))	('HSH005069-2-LVRU6H', 'Var', (198, 216))	('HSH005069-1-LVRU6H', 'Var', (157, 175))	('THP1', 'Gene', (67, 71))
526509	29777108	Lung squamous KLN205, LN4K1 and KAL-LN2E1 cancer cells were injected either subcutaneously over the posterior flank (KLN205 and LN4K1: 1 x 105 cells in 100 microL HBSS), intravenously (LN4K1: 1 x 105 or 3 x 105 cells in 100 microL HBSS based on experiment) or by an intra-pulmonary technique [KLN205 and LN4K1: 2.5 x 104 cells and KAL-LN2E1: 5 x 105, in 100 microL 1:1 mixture of HBSS and BD Matrigel (BD Biosciences)].	('KLN205', 'Chemical', '-', (293, 299))	('KAL', 'Gene', (331, 334))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('KAL', 'Gene', (32, 35))	('LN4K1: 2.5', 'Var', (304, 314))	('KAL', 'Gene', '13648', (32, 35))	('KAL', 'Gene', '13648', (331, 334))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('KLN205', 'Chemical', '-', (117, 123))	('KLN205', 'Chemical', '-', (14, 20))
526522	29777108	For all the analyses based on RNA-Seq data, the only samples used were those having numerical data available (on January 2014) as for messenger RNA (mRNA), human methylation (HuMet), copy number variation (CNV) and micro-RNAs (miRNAs) (348 total), in order to exclude samples not sufficiently characterized by TCGA.	('human', 'Species', '9606', (156, 161))	('copy number variation', 'Var', (183, 204))	('messenger RNA', 'MPA', (134, 147))
526577	29777108	In the first procedure, genes are selected when (i) are differentially expressed between MBEC (4 replicates) and KLN205 (three replicates), or (ii) are differentially expressed between MBEC and the metastatic-derived cell line LN4K1 (three replicates) or (iii) fulfill both (i) and (ii).	('KLN205', 'Var', (113, 119))	('KLN205', 'Chemical', '-', (113, 119))	('MBEC', 'Gene', (89, 93))
526578	29777108	The second procedure allows defining which genes follow a gradient of expression (growth or reduction) going from MBEC to KLN205 parental to the sub-clone LN4K1 (hence moving from "normal" to "primary tumor" to "metastasis"), so that this expression gradient is sustained across all the replicates of the three experimental conditions.	('tumor', 'Disease', 'MESH:D009369', (201, 206))	('KLN205', 'Chemical', '-', (122, 128))	('reduction', 'NegReg', (92, 101))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('KLN205 parental', 'Var', (122, 137))	('tumor', 'Disease', (201, 206))
526580	29777108	The sub-pattern A-1 is based on the following requirements (which are extensively described for more easily allowing assessing the level of overlap with the sub-pattern A-2): (i) all the LN4K1 samples have a strictly greater expression than all the KLN205 samples; (ii) all the KLN205 samples have a strictly greater expression than all the MBEC samples; (iii) the average expression for the LN4K1 samples is strictly greater than the average expression for the KLN205 samples.	('A-1', 'Gene', '16627', (16, 19))	('greater', 'PosReg', (418, 425))	('KLN205', 'Chemical', '-', (462, 468))	('KLN205', 'Chemical', '-', (249, 255))	('expression', 'MPA', (373, 383))	('A-2', 'Gene', '14788', (169, 172))	('expression', 'MPA', (317, 327))	('KLN205', 'Chemical', '-', (278, 284))	('A-1', 'Gene', (16, 19))	('LN4K1', 'Var', (392, 397))	('expression', 'MPA', (225, 235))	('A-2', 'Gene', (169, 172))
526581	29777108	The sub-pattern A-2 is based on the following requirements: (i) the expression of each LN4K1 sample is strictly greater than the average expression across all the samples considered (10 = 4 + 3 + 3); (ii) the expression of each KLN205 sample is strictly lower than the average expression across all the samples considered; (iii) the expression of each MBEC sample is strictly lower than the average expression across all the samples considered.	('expression', 'MPA', (333, 343))	('expression', 'MPA', (209, 219))	('LN4K1', 'Gene', (87, 92))	('lower', 'NegReg', (254, 259))	('lower', 'NegReg', (376, 381))	('KLN205', 'Var', (228, 234))	('A-2', 'Gene', '14788', (16, 19))	('A-2', 'Gene', (16, 19))	('KLN205', 'Chemical', '-', (228, 234))
526583	29777108	The sub-pattern B-1 is based on the following requirements (extensively described, as for A-1): (i) all the LN4K1 samples have a strictly lower expression than all the KLN205 samples; (ii) all the KLN205 samples have a strictly lower expression than all the MBEC samples; (iii) the average expression for the LN4K1 samples is strictly lower than the average expression for the KLN205 samples.	('lower', 'NegReg', (335, 340))	('KLN205', 'Chemical', '-', (197, 203))	('expression', 'MPA', (144, 154))	('expression', 'MPA', (234, 244))	('KLN205', 'Var', (197, 203))	('lower', 'NegReg', (138, 143))	('A-1', 'Gene', (90, 93))	('KLN205', 'Chemical', '-', (168, 174))	('KLN205', 'Chemical', '-', (377, 383))	('lower', 'NegReg', (228, 233))	('expression', 'MPA', (290, 300))	('A-1', 'Gene', '16627', (90, 93))
526584	29777108	The sub-pattern B-2 is based on the following requirements: (i) the expression of each LN4K1 sample is strictly smaller than the average expression across all the samples considered; (ii) the expression of each KLN205 sample is strictly higher than the average expression across all the samples considered; (iii) the expression of each MBEC sample is strictly higher than the average expression across all the samples considered.	('smaller', 'NegReg', (112, 119))	('LN4K1', 'Gene', (87, 92))	('KLN205', 'Chemical', '-', (211, 217))	('expression', 'MPA', (68, 78))	('expression', 'MPA', (192, 202))	('higher', 'PosReg', (360, 366))	('higher', 'PosReg', (237, 243))	('expression', 'MPA', (317, 327))	('KLN205', 'Var', (211, 217))
526593	29777108	To assess secretion of CCL2 in vitro, 344SQ, KLN205, and LN4K1 were seeded at a density of 400,000 cells per well in 3 mL of media in 6-well plates.	('344SQ', 'Var', (38, 43))	('KLN205', 'Var', (45, 51))	('LN4K1', 'Var', (57, 62))	('344SQ', 'Chemical', '-', (38, 43))	('KLN205', 'Chemical', '-', (45, 51))	('CCL2', 'Gene', '20296', (23, 27))	('CCL2', 'Gene', (23, 27))
526602	29777108	LN4K1-GFP (50,000 cells) and bone marrow-derived IMs (100,000 cells) were mixed with 200 mug/mL Fibronectin, 2 mM CaCl2, and either 2 mg/mL unfractionated fibrinogen, Peak 1 fibrinogen or BD Matrigel (total final volume of 50 muL) on top of a Boyden 8 mum migration chamber.	('Fibronectin', 'Gene', '14268', (96, 107))	('Peak 1', 'Gene', (167, 173))	('CaCl2', 'Chemical', 'MESH:D002122', (114, 119))	('Peak 1', 'Gene', '244895', (167, 173))	('rat', 'Species', '10116', (259, 262))	('Fibronectin', 'Gene', (96, 107))	('LN4K1-GFP', 'Var', (0, 9))
526611	29777108	After probing with primary antibodies, membranes were washed three times in TBS-T and then probed with the appropriate horseradish peroxidase-conjugated secondary antibodies (anti-mouse (#115-035-003) or anti-rabbit (#111-035-003) from Jackson ImmunoResearch).	('#111-035-003', 'Var', (217, 229))	('mouse', 'Species', '10090', (180, 185))	('rabbit', 'Species', '9986', (209, 215))	('horseradish', 'Species', '3704', (119, 130))	('anti-mouse', 'Var', (175, 185))
526626	29777108	TaqMan Assays (Applied Biosystems) were used for TNFa expression (Mm00443258), and GAPDH (Mm99999915_g1) was used as a housekeeping gene.	('Mm99999915_g1', 'Var', (90, 103))	('GAPDH', 'Gene', (83, 88))	('TNFa', 'Gene', (49, 53))	('Mm00443258', 'Var', (66, 76))	('TNFa', 'Gene', '21926', (49, 53))	('GAPDH', 'Gene', '14433', (83, 88))
526646	29777108	For multiplexed staining, rabbit monoclonal antibody against CD14, clone EPR3653, # 114R-14 was from Cell Marque (Rocklin, California), mouse monoclonal antibodies were: anti-CCR2, clone 7A7, # ab176390, (Abcam, Cambridge, MA), anti-CK, clone AE1/AE3, # M3515 (Agilent Technologies/DAKO, Santa Clara, CA), anti-CD206, # ab64693, (Abcam, Cambridge, MA) and anti-D-Dimers (cross-linked fibrin), # A079 (Zedira GmbH, Darmstadt, Germany).	('AE3', 'Gene', (247, 250))	('anti-D-Dimers', 'Var', (356, 369))	('CCR2', 'Gene', '12772', (175, 179))	('anti-CD206', 'Var', (306, 316))	('CCR2', 'Gene', (175, 179))	('rabbit', 'Species', '9986', (26, 32))	('AE3', 'Gene', '20536', (247, 250))	('# ab64693', 'Var', (318, 327))	('# M3515', 'Var', (252, 259))	('AE1', 'Gene', (243, 246))	('mouse', 'Species', '10090', (136, 141))	('AE1', 'Gene', '20533', (243, 246))
526655	29777108	Nuclei were visualized in DAPI channel (blue), CD14 in AF 488 (green), CK in Cy3 (cyan) and CCR2 in Cy5 (red).	('CD14', 'Var', (47, 51))	('CCR2', 'Gene', (92, 96))	('DAPI', 'Chemical', 'MESH:C007293', (26, 30))	('AF', 'Disease', 'MESH:D001281', (55, 57))	('Cy5', 'Chemical', 'MESH:C085321', (100, 103))	('CCR2', 'Gene', '12772', (92, 96))
526674	31455821	In NSCLC, aberrant NRF2 stabilization is best understood through mutations in NRF2, KEAP1, or CUL3 that disrupt their interaction.	('CUL3', 'Gene', (94, 98))	('NSCLC', 'Disease', (3, 8))	('disrupt', 'NegReg', (104, 111))	('NSCLC', 'Disease', 'MESH:D002289', (3, 8))	('interaction', 'Interaction', (118, 129))	('NRF2', 'Gene', (78, 82))	('CUL3', 'Gene', '8452', (94, 98))	('NSCLC', 'Phenotype', 'HP:0030358', (3, 8))	('mutations', 'Var', (65, 74))
526678	31455821	Finally, we report that NRF2 protein expression in a NSCLC cohort exceeds the typical incidence of combined NRF2, KEAP1, and CUL3 mutations, and that NRF2 expression in this cohort is correlated with PIDD levels.	('PIDD', 'Chemical', '-', (200, 204))	('CUL3', 'Gene', '8452', (125, 129))	('NRF2', 'Gene', (150, 154))	('NSCLC', 'Phenotype', 'HP:0030358', (53, 58))	('correlated', 'Reg', (184, 194))	('NRF2', 'Gene', (24, 28))	('NRF2', 'Gene', (108, 112))	('PIDD levels', 'MPA', (200, 211))	('mutations', 'Var', (130, 139))	('NSCLC', 'Disease', (53, 58))	('protein', 'Protein', (29, 36))	('expression', 'MPA', (37, 47))	('CUL3', 'Gene', (125, 129))	('NSCLC', 'Disease', 'MESH:D002289', (53, 58))
526679	31455821	Our data identify PIDD as a new NRF2 regulator, and suggest that variations in PIDD levels contribute to differential chemosensitivities among NSCLC patients.	('PIDD', 'MPA', (79, 83))	('patients', 'Species', '9606', (149, 157))	('NSCLC', 'Disease', (143, 148))	('NSCLC', 'Disease', 'MESH:D002289', (143, 148))	('variations', 'Var', (65, 75))	('NSCLC', 'Phenotype', 'HP:0030358', (143, 148))	('PIDD', 'Chemical', '-', (79, 83))	('PIDD', 'Chemical', '-', (18, 22))
526689	31455821	Consistent with these molecular functions, high levels of NRF2 in NSCLC are associated with resistance to chemotherapy and poor prognosis.	('high levels', 'Var', (43, 54))	('NSCLC', 'Disease', (66, 71))	('NRF2', 'Gene', (58, 62))	('resistance to chemotherapy', 'CPA', (92, 118))	('NSCLC', 'Disease', 'MESH:D002289', (66, 71))	('associated', 'Reg', (76, 86))	('NSCLC', 'Phenotype', 'HP:0030358', (66, 71))
526690	31455821	In functional studies, the loss of Kelch-like ECH-associated protein 1 (KEAP1), a negative regulator of NRF2, increases nuclear accumulation and activation of NRF2 in NSCLC cell lines, and promotes growth and chemoresistance.	('loss', 'Var', (27, 31))	('NSCLC', 'Disease', 'MESH:D002289', (167, 172))	('NSCLC', 'Phenotype', 'HP:0030358', (167, 172))	('increases', 'PosReg', (110, 119))	('promotes', 'PosReg', (189, 197))	('Kelch-like ECH-associated protein 1', 'Gene', (35, 70))	('NRF2', 'Gene', (159, 163))	('KEAP1', 'Gene', (72, 77))	('activation', 'MPA', (145, 155))	('Kelch-like ECH-associated protein 1', 'Gene', '9817', (35, 70))	('nuclear accumulation', 'MPA', (120, 140))	('NSCLC', 'Disease', (167, 172))
526691	31455821	In addition, silencing of NRF2 through RNAi increases sensitivity to cisplatin in NSCLC cells.	('cisplatin', 'Chemical', 'MESH:D002945', (69, 78))	('NSCLC', 'Phenotype', 'HP:0030358', (82, 87))	('sensitivity to cisplatin', 'MPA', (54, 78))	('NRF2', 'Gene', (26, 30))	('NSCLC', 'Disease', (82, 87))	('increases', 'PosReg', (44, 53))	('silencing', 'Var', (13, 22))	('NSCLC', 'Disease', 'MESH:D002289', (82, 87))
526693	31455821	Upon exposure to oxidative stress or chemopreventive compounds like sulforaphane and curcumin, modification of the cysteine residues on KEAP1 imposes a conformational change that disrupts the binding between KEAP1 and NRF2, resulting in diminished NRF2 ubiquitination and increased NRF2 protein levels and target gene expression.	('NRF2 ubiquitination', 'MPA', (248, 267))	('modification', 'Var', (95, 107))	('increased', 'PosReg', (272, 281))	('sulforaphane', 'Chemical', 'MESH:C016766', (68, 80))	('disrupts', 'NegReg', (179, 187))	('oxidative stress', 'Phenotype', 'HP:0025464', (17, 33))	('cysteine', 'Chemical', 'MESH:D003545', (115, 123))	('diminished', 'NegReg', (237, 247))	('conformational change', 'MPA', (152, 173))	('curcumin', 'Chemical', 'MESH:D003474', (85, 93))	('expression', 'MPA', (318, 328))	('NRF2 protein levels', 'MPA', (282, 301))	('NRF2', 'Protein', (218, 222))	('binding', 'Interaction', (192, 199))
526694	31455821	The critical importance of this form of regulation to NRF2 activity is supported by the discovery of gain-of-function mutations in NRF2 that disrupt regulation by KEAP1-CUL3, and loss-of-function mutations in KEAP1 and CUL3 in several cancer types.	('regulation', 'MPA', (149, 159))	('loss-of-function', 'NegReg', (179, 195))	('cancer', 'Disease', (235, 241))	('cancer', 'Disease', 'MESH:D009369', (235, 241))	('mutations', 'Var', (118, 127))	('disrupt', 'NegReg', (141, 148))	('CUL3', 'Gene', '8452', (219, 223))	('NRF2', 'Gene', (131, 135))	('CUL3', 'Gene', '8452', (169, 173))	('CUL3', 'Gene', (219, 223))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))	('gain-of-function', 'PosReg', (101, 117))	('CUL3', 'Gene', (169, 173))
526701	31455821	Using the comprehensive TCGA data available through the cBioportal database (www.cBioportal.org), we examined DNA amplifications, deletions, and mutations in NRF2, KEAP1, and CUL3.	('NRF2', 'Gene', (158, 162))	('deletions', 'Var', (130, 139))	('mutations', 'Var', (145, 154))	('CUL3', 'Gene', '8452', (175, 179))	('CUL3', 'Gene', (175, 179))
526728	31455821	As observed in MGH7 cells, NRF2 shRNA2 reduced NRF2 and NQO1 protein levels in H1299-LV-PIDD cells, and importantly, without affecting PIDD expression (Fig.	('NQO1', 'Gene', (56, 60))	('NQO1', 'Gene', '1728', (56, 60))	('PIDD', 'Chemical', '-', (135, 139))	('PIDD', 'Chemical', '-', (88, 92))	('H1299-LV-PIDD', 'CellLine', 'CVCL:0060', (79, 92))	('MGH7', 'CellLine', 'CVCL:W786', (15, 19))	('NRF2', 'MPA', (47, 51))	('NRF2 shRNA2', 'Var', (27, 38))	('reduced', 'NegReg', (39, 46))
526740	31455821	Overall, these data indicate that as compared with low PIDD expression, high PIDD levels are associated with larger tumor size, lymph node metastasis, and higher stage.	('lymph node metastasis', 'CPA', (128, 149))	('tumor', 'Disease', (116, 121))	('PIDD', 'Chemical', '-', (77, 81))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('larger', 'PosReg', (109, 115))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('PIDD', 'Chemical', '-', (55, 59))	('higher stage', 'CPA', (155, 167))	('high', 'Var', (72, 76))
526741	31455821	Although not quite significant, Kaplan-Meier analysis indicated that there was a trend for high PIDD expression to also be associated with worse overall survival in this cohort that was treated with surgery alone (p = 0.075, Fig.	('PIDD', 'Chemical', '-', (96, 100))	('high', 'Var', (91, 95))	('overall survival', 'MPA', (145, 161))	('worse', 'NegReg', (139, 144))	('PIDD', 'Gene', (96, 100))	('expression', 'MPA', (101, 111))
526744	31455821	The poor prognosis of patients with tumors expressing high levels of NRF2 appears to relate to NRF2's ability to both enhance cancer cell proliferation and promote chemo and radio-resistance.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('tumors', 'Disease', 'MESH:D009369', (36, 42))	('NRF2', 'Gene', (69, 73))	('patients', 'Species', '9606', (22, 30))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('enhance', 'PosReg', (118, 125))	('tumors', 'Phenotype', 'HP:0002664', (36, 42))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('high levels', 'Var', (54, 65))	('tumors', 'Disease', (36, 42))	('NRF2', 'Gene', (95, 99))	('promote', 'PosReg', (156, 163))
526745	31455821	Although NRF2 stabilization through genomic alterations in NRF2, KEAP1, and CUL3 is well documented, additional mechanisms that increase NRF2 activity have remained enigmatic and may play an equal or even greater role in cancer progression.	('cancer', 'Disease', 'MESH:D009369', (221, 227))	('NRF2', 'Gene', (59, 63))	('activity', 'MPA', (142, 150))	('increase', 'PosReg', (128, 136))	('cancer', 'Disease', (221, 227))	('alterations', 'Var', (44, 55))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('CUL3', 'Gene', '8452', (76, 80))	('CUL3', 'Gene', (76, 80))
526754	31455821	Consistent with these findings, our functional studies using H1299 lung cancer cells also support PIDD expression promoting chemoresistance, and in cells that do not harbor KRAS mutations.	('chemoresistance', 'CPA', (124, 139))	('H1299 lung cancer', 'Disease', 'MESH:D008175', (61, 78))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('PIDD', 'Gene', (98, 102))	('PIDD', 'Chemical', '-', (98, 102))	('promoting', 'PosReg', (114, 123))	('H1299 lung cancer', 'Disease', (61, 78))	('expression', 'Var', (103, 113))	('lung cancer', 'Phenotype', 'HP:0100526', (67, 78))
526767	31455821	ML385 binds directly to NRF2 and enhances the cytotoxicity of platinum-based drugs on NSCLC cell lines.	('platinum', 'Chemical', 'MESH:D010984', (62, 70))	('ML385', 'Var', (0, 5))	('binds', 'Interaction', (6, 11))	('NSCLC', 'Disease', (86, 91))	('NRF2', 'Protein', (24, 28))	('enhances', 'PosReg', (33, 41))	('cytotoxicity', 'Disease', 'MESH:D064420', (46, 58))	('ML385', 'Chemical', '-', (0, 5))	('NSCLC', 'Disease', 'MESH:D002289', (86, 91))	('NSCLC', 'Phenotype', 'HP:0030358', (86, 91))	('cytotoxicity', 'Disease', (46, 58))
526820	29743817	Analysis of the role of rs2031920 and rs3813867 polymorphisms within the cytochrome P450 2E1 gene in the risk of squamous cell carcinoma To explore the genetic effect of rs2031920 and rs3813867 polymorphisms within the cytochrome P450 2E1 (CYP2E1) gene on the risk of squamous cell carcinoma (SCC), a meta-analysis was performed.	('rs3813867', 'Mutation', 'rs3813867', (38, 47))	('rs2031920', 'Mutation', 'rs2031920', (170, 179))	('squamous cell carcinoma', 'Disease', (268, 291))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (113, 136))	('cytochrome P450 2E1', 'Gene', '1571', (219, 238))	('cytochrome P450 2E1', 'Gene', (219, 238))	('rs3813867', 'Var', (184, 193))	('SCC', 'Phenotype', 'HP:0002860', (293, 296))	('CYP2E1', 'Gene', '1571', (240, 246))	('squamous cell carcinoma', 'Disease', (113, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('rs2031920', 'Mutation', 'rs2031920', (24, 33))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (268, 291))	('rs3813867', 'Mutation', 'rs3813867', (184, 193))	('rs2031920', 'Var', (170, 179))	('SCC', 'Gene', '6317', (293, 296))	('carcinoma', 'Phenotype', 'HP:0030731', (282, 291))	('rs3813867', 'Var', (38, 47))	('cytochrome P450 2E1', 'Gene', '1571', (73, 92))	('CYP2E1', 'Gene', (240, 246))	('SCC', 'Gene', (293, 296))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (268, 291))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (113, 136))	('cytochrome P450 2E1', 'Gene', (73, 92))	('rs2031920', 'Var', (24, 33))
526821	29743817	With regard to the rs2031920 C/T polymorphism, in comparison to controls, a reduced risk in cases of esophageal squamous cell carcinoma (ESCC) was detected for the models of allele T vs. allele C [P = 0.025, odds ratio (OR) = 0.67], carrier T vs. carrier C (P = 0.014, OR = 0.70), TT vs. CC (P = 0.029, OR = 0.65), CT vs. CC (P = 0.040, OR = 0.56), CT + TT vs. CC (P = 0.035, OR = 0.58).	('SCC', 'Gene', (138, 141))	('rs2031920 C/T', 'Var', (19, 32))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (101, 135))	('rs2031920', 'Mutation', 'rs2031920', (19, 28))	('CT + TT vs.', 'Var', (349, 360))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (112, 135))	('SCC', 'Gene', '6317', (138, 141))	('reduced', 'NegReg', (76, 83))	('SCC', 'Phenotype', 'HP:0002860', (138, 141))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('esophageal squamous cell carcinoma', 'Disease', (101, 135))
526822	29743817	Similarly, a decreased SCC risk was observed for the rs3813867 G/C polymorphism in the allele, carrier, homozygote, dominant, and recessive models of overall SCC meta-analysis and "ESCC" subgroup analysis (all P < 0.05, OR < 1) and in all genetic models of "Asian" and "population-based control (PB)" subgroup analysis (all P < 0.05, OR < 1).	('SCC', 'Gene', (182, 185))	('SCC', 'Phenotype', 'HP:0002860', (182, 185))	('decreased', 'NegReg', (13, 22))	('SCC', 'Gene', '6317', (23, 26))	('PB', 'Chemical', '-', (296, 298))	('SCC', 'Gene', '6317', (158, 161))	('SCC', 'Phenotype', 'HP:0002860', (158, 161))	('SCC', 'Gene', '6317', (182, 185))	('rs3813867 G/C', 'Var', (53, 66))	('rs3813867', 'Mutation', 'rs3813867', (53, 62))	('SCC', 'Gene', (23, 26))	('SCC', 'Phenotype', 'HP:0002860', (23, 26))	('SCC', 'Gene', (158, 161))
526823	29743817	Additionally, for the rs2031920/rs3813867 haplotype, a decreased SCC risk was also detected in the overall SCC meta-analysis under the allele, carrier, homozygote and dominant model (all P < 0.05, OR < 1) and the subgroup analysis of "PB" under the allele, carrier, and dominant models (all P < 0.05, OR < 1).	('SCC', 'Gene', (65, 68))	('PB', 'Chemical', '-', (235, 237))	('SCC', 'Gene', (107, 110))	('SCC', 'Phenotype', 'HP:0002860', (107, 110))	('SCC', 'Phenotype', 'HP:0002860', (65, 68))	('SCC', 'Gene', '6317', (65, 68))	('decreased', 'NegReg', (55, 64))	('rs2031920', 'Mutation', 'rs2031920', (22, 31))	('SCC', 'Gene', '6317', (107, 110))	('rs3813867', 'Mutation', 'rs3813867', (32, 41))	('rs2031920/rs3813867', 'Var', (22, 41))
526824	29743817	Our meta-analysis supports the "T" allele carrier of the CYP2E1 rs2031920 C/T polymorphism and "C" allele carrier of the rs3813867 G/C polymorphism as protective factors for ESCC patients, especially in Asian populations.	('SCC', 'Gene', (175, 178))	('SCC', 'Phenotype', 'HP:0002860', (175, 178))	('rs3813867', 'Mutation', 'rs3813867', (121, 130))	('rs2031920 C/T', 'Var', (64, 77))	('CYP2E1', 'Gene', '1571', (57, 63))	('SCC', 'Gene', '6317', (175, 178))	('CYP2E1', 'Gene', (57, 63))	('patients', 'Species', '9606', (179, 187))	('rs2031920', 'Mutation', 'rs2031920', (64, 73))
526827	29743817	Polymorphic variants, existing in the functional genes of the cytochrome P450 system, are associated with the pathogenesis of several clinical cancers.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('cytochrome P450', 'Gene', '4051', (62, 77))	('associated', 'Reg', (90, 100))	('cancers', 'Disease', 'MESH:D009369', (143, 150))	('cancers', 'Phenotype', 'HP:0002664', (143, 150))	('cancers', 'Disease', (143, 150))	('cytochrome P450', 'Gene', (62, 77))	('Polymorphic variants', 'Var', (0, 20))
526828	29743817	For example, rs2031920 C/T with an RsaI restriction enzyme site and rs3813867 C/T with a PstI restriction enzyme site are two common single nucleotide polymorphisms (SNP) within the 5'-flanking regions of the CYP2E1 gene.	('CYP2E1', 'Gene', (209, 215))	('PstI', 'Gene', '6690', (89, 93))	('rs2031920 C/T', 'Var', (13, 26))	('CYP2E1', 'Gene', '1571', (209, 215))	('rs2031920', 'Mutation', 'rs2031920', (13, 22))	('PstI', 'Gene', (89, 93))	('rs3813867 C/T', 'Var', (68, 81))	('rs3813867', 'Mutation', 'rs3813867', (68, 77))
526829	29743817	Three genotypes of c1/c1, c1/c2, c2/c2 were generated; rs2031920 and rs3813867 were in close linkage disequilibrium.	('rs3813867', 'Mutation', 'rs3813867', (69, 78))	('rs3813867', 'Var', (69, 78))	('rs2031920', 'Var', (55, 64))	('rs2031920', 'Mutation', 'rs2031920', (55, 64))	('c1/c1, c1/c2, c2/c2', 'Gene', '6966;717', (19, 38))
526830	29743817	Furthermore, CYP2E1 polymorphisms were reported to be linked to several cancers, such as nasopharyngeal carcinoma, urinary cancers and head and neck carcinoma, particularly in Asian populations.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('urinary cancers', 'Disease', 'MESH:D001749', (115, 130))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('cancers', 'Disease', (72, 79))	('head and neck carcinoma', 'Phenotype', 'HP:0012288', (135, 158))	('CYP2E1', 'Gene', (13, 19))	('nasopharyngeal carcinoma', 'Disease', (89, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('urinary cancers', 'Disease', (115, 130))	('cancers', 'Disease', 'MESH:D009369', (123, 130))	('nasopharyngeal carcinoma', 'Disease', 'MESH:D000077274', (89, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (149, 158))	('cancers', 'Disease', 'MESH:D009369', (72, 79))	('linked', 'Reg', (54, 60))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (89, 113))	('polymorphisms', 'Var', (20, 33))	('cancers', 'Phenotype', 'HP:0002664', (123, 130))	('neck carcinoma', 'Disease', (144, 158))	('CYP2E1', 'Gene', '1571', (13, 19))	('neck carcinoma', 'Disease', 'MESH:D006258', (144, 158))	('cancers', 'Disease', (123, 130))
526833	29743817	Living habits (e.g., smoking, drinking), viral infection [e.g., human papillomavirus (HPV)], immune system, and polymorphic variants with many genes may be related to the risk of different SCC diseases.	('human papillomavirus', 'Species', '10566', (64, 84))	('related', 'Reg', (156, 163))	('HPV', 'Disease', 'MESH:D030361', (86, 89))	('SCC diseases', 'Disease', (189, 201))	('SCC', 'Phenotype', 'HP:0002860', (189, 192))	('viral infection', 'Disease', (41, 56))	('HPV', 'Disease', (86, 89))	('human papillomavirus', 'Disease', (64, 84))	('SCC diseases', 'Disease', 'MESH:D004194', (189, 201))	('polymorphic variants', 'Var', (112, 132))	('viral infection', 'Disease', 'MESH:D001102', (41, 56))
526834	29743817	Previously, we conducted an updated meta-analysis to explore the impact of MDM2 (MDM2 Proto-Oncogene) polymorphisms on SCC susceptibility and found that the GG genotype of MDM2 rs2279744 polymorphism may be associated with an increased risk of esophageal SCC in Asian populations.	('SCC', 'Gene', (255, 258))	('SCC', 'Gene', '6317', (119, 122))	('esophageal SCC', 'Disease', (244, 258))	('SCC', 'Phenotype', 'HP:0002860', (255, 258))	('MDM2', 'Gene', '4193', (75, 79))	('MDM2', 'Gene', '4193', (81, 85))	('SCC', 'Gene', '6317', (255, 258))	('MDM2', 'Gene', (75, 79))	('MDM2', 'Gene', (81, 85))	('esophageal SCC', 'Disease', 'MESH:D004941', (244, 258))	('rs2279744', 'Mutation', 'rs2279744', (177, 186))	('rs2279744', 'Var', (177, 186))	('MDM2', 'Gene', '4193', (172, 176))	('MDM2', 'Gene', (172, 176))	('SCC', 'Gene', (119, 122))	('SCC', 'Phenotype', 'HP:0002860', (119, 122))
526835	29743817	We observed a different conclusion regarding the role of rs2031920 and rs3813867 polymorphisms within the CYP2E1 gene in the risk of SCC.	('CYP2E1', 'Gene', (106, 112))	('SCC', 'Gene', '6317', (133, 136))	('rs2031920', 'Mutation', 'rs2031920', (57, 66))	('rs3813867', 'Mutation', 'rs3813867', (71, 80))	('CYP2E1', 'Gene', '1571', (106, 112))	('rs2031920', 'Var', (57, 66))	('rs3813867', 'Var', (71, 80))	('SCC', 'Gene', (133, 136))	('SCC', 'Phenotype', 'HP:0002860', (133, 136))
526836	29743817	Thus, we are very interested in investigating the role of the rs2031920 and rs3813867 polymorphisms within the CYP2E1 gene in the susceptibility to SCC, considering the lack of publications of specific meta-analyses.	('rs2031920', 'Var', (62, 71))	('rs2031920', 'Mutation', 'rs2031920', (62, 71))	('CYP2E1', 'Gene', (111, 117))	('rs3813867', 'Mutation', 'rs3813867', (76, 85))	('SCC', 'Gene', (148, 151))	('SCC', 'Phenotype', 'HP:0002860', (148, 151))	('rs3813867', 'Var', (76, 85))	('CYP2E1', 'Gene', '1571', (111, 117))	('SCC', 'Gene', '6317', (148, 151))
526841	29743817	A meta-analysis of rs2031920 and SCC risk was conducted on the allele model (allele T vs. allele C), carrier model (carrier T vs. carrier C), homozygote model (TT vs. CC), heterozygote model (CT vs. CC), dominant model (CT + TT vs. CC), and recessive model (TT vs. CC + CT).	('SCC', 'Gene', '6317', (33, 36))	('rs2031920', 'Mutation', 'rs2031920', (19, 28))	('rs2031920', 'Var', (19, 28))	('SCC', 'Gene', (33, 36))	('SCC', 'Phenotype', 'HP:0002860', (33, 36))
526844	29743817	As shown in Table 2, in comparison with controls, a reduced ESCC risk was observed in the models of allele T vs. allele C (P = 0.025, OR = 0.67), carrier T vs. carrier C (P = 0.014, OR = 0.70), TT vs. CC (P = 0.029, OR = 0.65), CT vs. CC (P = 0.040, OR = 0.56), CT + TT vs. CC (P = 0.035, OR = 0.58), but not TT vs. CC + CT (P = 0.770).	('CT + TT vs. CC', 'Var', (262, 276))	('carrier T vs.', 'Var', (146, 159))	('SCC', 'Phenotype', 'HP:0002860', (61, 64))	('SCC', 'Gene', '6317', (61, 64))	('reduced', 'NegReg', (52, 59))	('SCC', 'Gene', (61, 64))
526846	29743817	The "T" allele carrier of the rs2031920 polymorphism within the CYP2E1 gene seems to be linked to ESCC risk.	('SCC', 'Gene', '6317', (99, 102))	('CYP2E1', 'Gene', '1571', (64, 70))	('linked', 'Reg', (88, 94))	('rs2031920', 'Var', (30, 39))	('rs2031920', 'Mutation', 'rs2031920', (30, 39))	('SCC', 'Gene', (99, 102))	('SCC', 'Phenotype', 'HP:0002860', (99, 102))	('CYP2E1', 'Gene', (64, 70))
526847	29743817	We also conducted the overall and subgroup meta-analysis of rs3813867 and SCC risk under the allele (10 case-control studies), carrier (10 case-control studies), homozygote (6 case-control studies), heterozygote (10 case-control studies), dominant (11 case-control studies), and recessive (6 case-control studies) models.	('rs3813867', 'Var', (60, 69))	('SCC', 'Gene', (74, 77))	('rs3813867', 'Mutation', 'rs3813867', (60, 69))	('SCC', 'Phenotype', 'HP:0002860', (74, 77))	('SCC', 'Gene', '6317', (74, 77))
526848	29743817	The positive results regarding the association between CYP2E1 rs3813867 and SCC risk were detected in the overall SCC meta-analysis and subgroup analysis of "ESCC" and "Y" (P value of Hardy-Weinberg equilibrium > 0.05) under all genetic models (Table 3, all P < 0.05, OR < 1), only apart from the heterozygote model (P = 0.150).	('rs3813867', 'Mutation', 'rs3813867', (62, 71))	('SCC', 'Gene', (114, 117))	('SCC', 'Gene', (159, 162))	('SCC', 'Gene', (76, 79))	('rs3813867', 'Var', (62, 71))	('SCC', 'Phenotype', 'HP:0002860', (159, 162))	('CYP2E1', 'Gene', (55, 61))	('association', 'Interaction', (35, 46))	('SCC', 'Phenotype', 'HP:0002860', (114, 117))	('SCC', 'Gene', '6317', (114, 117))	('SCC', 'Gene', '6317', (159, 162))	('SCC', 'Gene', '6317', (76, 79))	('SCC', 'Phenotype', 'HP:0002860', (76, 79))	('CYP2E1', 'Gene', '1571', (55, 61))
526851	29743817	The "C" allele carrier of CYP2E1 rs3813867 polymorphism may be associated with the risk of SCC, especially the ESCC cases in Asian populations.	('SCC', 'Phenotype', 'HP:0002860', (112, 115))	('SCC', 'Gene', '6317', (91, 94))	('CYP2E1', 'Gene', '1571', (26, 32))	('SCC', 'Gene', '6317', (112, 115))	('associated', 'Reg', (63, 73))	('rs3813867', 'Mutation', 'rs3813867', (33, 42))	('SCC', 'Gene', (91, 94))	('rs3813867', 'Var', (33, 42))	('CYP2E1', 'Gene', (26, 32))	('SCC', 'Phenotype', 'HP:0002860', (91, 94))	('SCC', 'Gene', (112, 115))
526852	29743817	The results of overall and subgroup meta-analysis of the rs2031920/rs3813867 haplotype and SCC risk under the allele (five case-control studies), carrier (five studies), homozygote (three studies), heterozygote (five studies), dominant (seven studies), and recessive (three studies) models are shown in Table 4.	('rs2031920', 'Mutation', 'rs2031920', (57, 66))	('SCC', 'Gene', (91, 94))	('rs3813867', 'Mutation', 'rs3813867', (67, 76))	('rs2031920/rs3813867', 'Var', (57, 76))	('SCC', 'Phenotype', 'HP:0002860', (91, 94))	('SCC', 'Gene', '6317', (91, 94))
526854	29743817	These results suggested a potential link between the c1/c2 or c2/c2 of rs2031920/rs3813867 haplotype and SCC risk, which still requires more case-control studies.	('link', 'Reg', (36, 40))	('c1/c2', 'Gene', '6966', (53, 58))	('rs2031920', 'Mutation', 'rs2031920', (71, 80))	('c1/c2', 'Gene', (53, 58))	('SCC', 'Gene', (105, 108))	('SCC', 'Phenotype', 'HP:0002860', (105, 108))	('rs2031920/rs3813867', 'Var', (71, 90))	('rs3813867', 'Mutation', 'rs3813867', (81, 90))	('SCC', 'Gene', '6317', (105, 108))
526856	29743817	The fixed model was used for the allele, carrier, homozygote and recessive models of rs3813867 (Table 5, all I2 < 50.0%, P value of heterogeneity > 0.05); and the allele, carrier, homozygote, dominant, and recessive models of the rs2031920/rs3813867 haplotype (Table 5, all I2 < 50.0%, P value of heterogeneity > 0.05).	('rs3813867', 'Var', (85, 94))	('rs3813867', 'Mutation', 'rs3813867', (240, 249))	('rs2031920/rs3813867', 'Var', (230, 249))	('rs2031920', 'Mutation', 'rs2031920', (230, 239))	('rs3813867', 'Mutation', 'rs3813867', (85, 94))
526858	29743817	Figures 2b and 3b show the Egger's publication bias plot of rs2031920 and rs3813867 under the allele model, respectively.	('rs2031920', 'Mutation', 'rs2031920', (60, 69))	('rs3813867', 'Mutation', 'rs3813867', (74, 83))	('rs3813867', 'Var', (74, 83))	('rs2031920', 'Var', (60, 69))
526861	29743817	CYP2E1 rs2031920 was related to the risk of ESCC in a high-incidence region (Kashmir, India).	('rs2031920', 'Var', (7, 16))	('SCC', 'Gene', (45, 48))	('CYP2E1', 'Gene', (0, 6))	('SCC', 'Phenotype', 'HP:0002860', (45, 48))	('SCC', 'Gene', '6317', (45, 48))	('CYP2E1', 'Gene', '1571', (0, 6))	('rs2031920', 'Mutation', 'rs2031920', (7, 16))
526862	29743817	We did not observe published meta-analyses specific for the genetic relationship between CYP2E1 rs2031920, rs3813867 SNP and ESCC risk.	('rs2031920', 'Var', (96, 105))	('rs2031920', 'Mutation', 'rs2031920', (96, 105))	('SCC', 'Phenotype', 'HP:0002860', (126, 129))	('SCC', 'Gene', '6317', (126, 129))	('rs3813867', 'Mutation', 'rs3813867', (107, 116))	('rs3813867 SNP', 'Var', (107, 120))	('CYP2E1', 'Gene', '1571', (89, 95))	('CYP2E1', 'Gene', (89, 95))	('SCC', 'Gene', (126, 129))
526863	29743817	In this study, we provide evidence that the "T" allele carrier of the rs2031920 polymorphism and the "C" allele carrier of the CYP2E1 rs3813867 polymorphism may be associated with a decreased risk of ESCC, especially in Asian populations because most of the included case-control studies were from China or India.	('CYP2E1', 'Gene', (127, 133))	('decreased', 'NegReg', (182, 191))	('rs2031920', 'Var', (70, 79))	('SCC', 'Gene', (201, 204))	('rs2031920', 'Mutation', 'rs2031920', (70, 79))	('SCC', 'Phenotype', 'HP:0002860', (201, 204))	('SCC', 'Gene', '6317', (201, 204))	('rs3813867', 'Mutation', 'rs3813867', (134, 143))	('CYP2E1', 'Gene', '1571', (127, 133))	('rs3813867', 'Var', (134, 143))
526864	29743817	selected 21 case-control studies for a meta-analysis in 2010 and investigated the potential effect of CYP2E1 rs2031920 and rs3813867 in the risk of head and neck cancer; they found that the homozygote genotype of CYP2E1 rs2031920/rs3813867 may be linked to the risk of head and neck cancer, especially in Asian populations.	('CYP2E1', 'Gene', (213, 219))	('CYP2E1', 'Gene', (102, 108))	('rs2031920/rs3813867', 'Var', (220, 239))	('rs2031920', 'Mutation', 'rs2031920', (220, 229))	('neck cancer', 'Disease', 'MESH:D006258', (278, 289))	('neck cancer', 'Disease', (278, 289))	('head and neck cancer', 'Phenotype', 'HP:0012288', (269, 289))	('head and neck cancer', 'Phenotype', 'HP:0012288', (148, 168))	('rs3813867', 'Mutation', 'rs3813867', (123, 132))	('CYP2E1', 'Gene', '1571', (213, 219))	('CYP2E1', 'Gene', '1571', (102, 108))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('neck cancer', 'Disease', 'MESH:D006258', (157, 168))	('rs2031920', 'Mutation', 'rs2031920', (109, 118))	('cancer', 'Phenotype', 'HP:0002664', (283, 289))	('rs3813867', 'Mutation', 'rs3813867', (230, 239))	('linked', 'Reg', (247, 253))	('neck cancer', 'Disease', (157, 168))
526865	29743817	performed another meta-analysis containing 43 case-control studies in 2016 and reported a positive association between CYP2E1 rs2031920/rs3813867 and head and neck cancer risk under the homozygote model.	('neck cancer', 'Disease', (159, 170))	('CYP2E1', 'Gene', (119, 125))	('rs2031920/rs3813867', 'Var', (126, 145))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('CYP2E1', 'Gene', '1571', (119, 125))	('positive', 'PosReg', (90, 98))	('rs3813867', 'Mutation', 'rs3813867', (136, 145))	('head and neck cancer', 'Phenotype', 'HP:0012288', (150, 170))	('rs2031920', 'Mutation', 'rs2031920', (126, 135))	('neck cancer', 'Disease', 'MESH:D006258', (159, 170))
526867	29743817	In our meta-analysis, we failed to observe the statistical relationship between CYP2E1 rs2031920 SNP, rs3813867 SNP, rs2031920/rs3813867 haplotype and HNSCC risk.	('rs3813867', 'Mutation', 'rs3813867', (127, 136))	('rs2031920/rs3813867', 'Var', (117, 136))	('rs3813867 SNP', 'Var', (102, 115))	('rs2031920', 'Mutation', 'rs2031920', (87, 96))	('SCC', 'Gene', '6317', (153, 156))	('rs2031920', 'Mutation', 'rs2031920', (117, 126))	('rs2031920 SNP', 'Var', (87, 100))	('CYP2E1', 'Gene', (80, 86))	('SCC', 'Gene', (153, 156))	('SCC', 'Phenotype', 'HP:0002860', (153, 156))	('rs3813867', 'Mutation', 'rs3813867', (102, 111))	('CYP2E1', 'Gene', '1571', (80, 86))
526868	29743817	selected 17 case-control studies with 2639 cases and 3450 controls for a meta-analysis of the association between CYP2E1 rs3813867 and the risk of lung cancer in the Chinese population in 2014, and showed a potential link between the "C" allele carriers of CYP2E1 rs3813867 and a decreased risk of lung cancer.	('CYP2E1', 'Gene', '1571', (114, 120))	('CYP2E1', 'Gene', (257, 263))	('rs3813867', 'Mutation', 'rs3813867', (121, 130))	('lung cancer', 'Disease', (298, 309))	('rs3813867', 'Mutation', 'rs3813867', (264, 273))	('lung cancer', 'Phenotype', 'HP:0100526', (298, 309))	('lung cancer', 'Disease', (147, 158))	('rs3813867', 'Var', (121, 130))	('lung cancer', 'Phenotype', 'HP:0100526', (147, 158))	('CYP2E1', 'Gene', (114, 120))	('association', 'Interaction', (94, 105))	('rs3813867', 'Var', (264, 273))	('cancer', 'Phenotype', 'HP:0002664', (303, 309))	('decreased', 'NegReg', (280, 289))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('lung cancer', 'Disease', 'MESH:D008175', (298, 309))	('CYP2E1', 'Gene', '1571', (257, 263))	('lung cancer', 'Disease', 'MESH:D008175', (147, 158))
526869	29743817	In our meta-analysis, very limited data were included after our strict selection; thus, no statistical evidence regarding the role of CYP2E1 rs3813867 in LSCC risk was provided.	('rs3813867', 'Mutation', 'rs3813867', (141, 150))	('SCC', 'Gene', (155, 158))	('SCC', 'Phenotype', 'HP:0002860', (155, 158))	('CYP2E1', 'Gene', '1571', (134, 140))	('rs3813867', 'Var', (141, 150))	('SCC', 'Gene', '6317', (155, 158))	('CYP2E1', 'Gene', (134, 140))
526870	29743817	However, we enrolled five case-control studies in our subgroup analysis of "LSCC" for CYP2E1 rs2031920 and found a negative genetic relationship, which was partly in line with the previous data from LSCC subgroup analysis.	('SCC', 'Gene', '6317', (200, 203))	('CYP2E1', 'Gene', '1571', (86, 92))	('CYP2E1', 'Gene', (86, 92))	('rs2031920', 'Var', (93, 102))	('rs2031920', 'Mutation', 'rs2031920', (93, 102))	('SCC', 'Gene', (77, 80))	('SCC', 'Gene', (200, 203))	('SCC', 'Phenotype', 'HP:0002860', (200, 203))	('negative', 'NegReg', (115, 123))	('SCC', 'Phenotype', 'HP:0002860', (77, 80))	('SCC', 'Gene', '6317', (77, 80))
526871	29743817	The close linkage disequilibrium between rs2031920 and rs3813867 for the CYP2E1 gene was reported.	('CYP2E1', 'Gene', '1571', (73, 79))	('rs2031920', 'Var', (41, 50))	('rs2031920', 'Mutation', 'rs2031920', (41, 50))	('rs3813867', 'Mutation', 'rs3813867', (55, 64))	('CYP2E1', 'Gene', (73, 79))	('rs3813867', 'Var', (55, 64))
526873	29743817	Thus, we performed a meta-analysis of rs2031920 and rs3813867, respectively; then, we analyzed the role of the rs2031920/rs3813867 haplotype based on the available data.	('rs3813867', 'Mutation', 'rs3813867', (121, 130))	('rs3813867', 'Mutation', 'rs3813867', (52, 61))	('rs2031920', 'Mutation', 'rs2031920', (111, 120))	('rs3813867', 'Var', (52, 61))	('rs2031920/rs3813867', 'Var', (111, 130))	('rs2031920', 'Var', (38, 47))	('rs2031920', 'Mutation', 'rs2031920', (38, 47))
526876	29743817	Only one case-control study was included in the "cervical SCC" subgroup analysis of rs2031920 under the allele, carrier, homozygote, heterozygote, and recessive models.	('SCC', 'Gene', (58, 61))	('SCC', 'Phenotype', 'HP:0002860', (58, 61))	('SCC', 'Gene', '6317', (58, 61))	('rs2031920', 'Mutation', 'rs2031920', (84, 93))	('rs2031920', 'Var', (84, 93))
526877	29743817	Only one case-control study was enrolled in the "lung SCC" subgroup analysis of rs3813867 under all genetic models.	('SCC', 'Gene', '6317', (54, 57))	('rs3813867', 'Mutation', 'rs3813867', (80, 89))	('rs3813867', 'Var', (80, 89))	('SCC', 'Gene', (54, 57))	('SCC', 'Phenotype', 'HP:0002860', (54, 57))
526878	29743817	Only two studies were enrolled in the "ESCC" subgroup analysis of the rs2031920/rs3813867 haplotype.	('SCC', 'Gene', '6317', (40, 43))	('rs2031920/rs3813867', 'Var', (70, 89))	('rs2031920', 'Mutation', 'rs2031920', (70, 79))	('rs3813867', 'Mutation', 'rs3813867', (80, 89))	('SCC', 'Gene', (40, 43))	('SCC', 'Phenotype', 'HP:0002860', (40, 43))
526879	29743817	In this study, we focused on the genetic role of two polymorphisms within the CYP2E1 gene in our meta-analysis, and we still cannot rule out the potential genetic effect of other CYP2E1 polymorphisms (e.g., rs6413432 T/A) and the variant combination between CYP2E1 and other related genes (e.g., MDM2).	('rs6413432', 'Mutation', 'rs6413432', (207, 216))	('CYP2E1', 'Gene', (258, 264))	('CYP2E1', 'Gene', (179, 185))	('CYP2E1', 'Gene', '1571', (78, 84))	('MDM2', 'Gene', '4193', (296, 300))	('rs6413432 T/A', 'Var', (207, 220))	('MDM2', 'Gene', (296, 300))	('CYP2E1', 'Gene', '1571', (258, 264))	('CYP2E1', 'Gene', '1571', (179, 185))	('CYP2E1', 'Gene', (78, 84))
526889	29743817	In conclusion, our meta-analysis data demonstrated that the CYP2E1 rs2031920 and rs3813867 polymorphisms may be associated with the risk of ESCC.	('rs3813867', 'Var', (81, 90))	('SCC', 'Gene', (141, 144))	('SCC', 'Phenotype', 'HP:0002860', (141, 144))	('CYP2E1', 'Gene', '1571', (60, 66))	('SCC', 'Gene', '6317', (141, 144))	('rs2031920', 'Var', (67, 76))	('rs2031920', 'Mutation', 'rs2031920', (67, 76))	('CYP2E1', 'Gene', (60, 66))	('associated', 'Reg', (112, 122))	('rs3813867', 'Mutation', 'rs3813867', (81, 90))
526896	29599774	We found that CCL4 increased VEGF-C expression and promoted lymphangiogenesis in oral cancer cells in vitro and in vivo.	('VEGF-C', 'Protein', (29, 35))	('oral cancer', 'Disease', (81, 92))	('increased VEGF-', 'Phenotype', 'HP:0030269', (19, 34))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('increased', 'PosReg', (19, 28))	('lymphangiogenesis', 'CPA', (60, 77))	('promoted', 'PosReg', (51, 59))	('CCL4', 'Var', (14, 18))	('expression', 'MPA', (36, 46))	('oral cancer', 'Disease', 'MESH:D009062', (81, 92))
526904	29599774	Serum concentrations of CCL4 have been found to be significantly higher in patients with head and neck squamous cell carcinoma compared with controls, and we have previously reported that CCL4 polymorphisms may enhance susceptibility to oral cancer.	('polymorphisms', 'Var', (193, 206))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (98, 126))	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (103, 126))	('oral cancer', 'Disease', 'MESH:D009062', (237, 248))	('patients', 'Species', '9606', (75, 83))	('Serum concentrations', 'MPA', (0, 20))	('CCL4', 'Gene', (188, 192))	('oral cancer', 'Disease', (237, 248))	('cancer', 'Phenotype', 'HP:0002664', (242, 248))	('higher', 'PosReg', (65, 71))	('enhance', 'PosReg', (211, 218))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (89, 126))	('neck squamous cell carcinoma', 'Disease', (98, 126))	('CCL4', 'Gene', (24, 28))
526907	29599774	Inhibition of cancer-mediated lymphangiogenesis has therefore been considered to be an effective means of preventing the spread of cancer.	('cancer', 'Disease', (14, 20))	('cancer', 'Disease', (131, 137))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('Inhibition', 'Var', (0, 10))	('cancer', 'Disease', 'MESH:D009369', (14, 20))	('cancer', 'Disease', 'MESH:D009369', (131, 137))
526914	29599774	Findings suggest that the deregulated expression of miRNAs may modulate tumor angiogenesis and lymphangiogenesis through the targeting of VEGF-C.	('deregulated', 'Var', (26, 37))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('expression', 'MPA', (38, 48))	('tumor', 'Disease', (72, 77))	('VEGF-C', 'Gene', (138, 144))	('miRNAs', 'Protein', (52, 58))	('lymphangiogenesis', 'CPA', (95, 112))	('modulate', 'Reg', (63, 71))	('tumor', 'Disease', 'MESH:D009369', (72, 77))
526916	29599774	Notably, aberrant miRNA expression associated with tumor progression, nodal metastasis, and blood vessel density has been observed in OSCC.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('blood vessel density', 'CPA', (92, 112))	('associated', 'Reg', (35, 45))	('tumor', 'Disease', (51, 56))	('nodal metastasis', 'CPA', (70, 86))	('N', 'Chemical', 'MESH:D009584', (0, 1))	('OSCC', 'Disease', (134, 138))	('aberrant', 'Var', (9, 17))	('N', 'Chemical', 'MESH:D009584', (21, 22))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('miRNA', 'Protein', (18, 23))
526917	29599774	In this study, we show that CCL4 induces VEGF-C expression in OSCC by activating the JAK2/STAT3 signaling pathway.	('STAT3', 'Gene', '6774', (90, 95))	('JAK2', 'Gene', '3717', (85, 89))	('STAT3', 'Gene', (90, 95))	('activating', 'PosReg', (70, 80))	('expression', 'MPA', (48, 58))	('JAK2', 'Gene', (85, 89))	('CCL4', 'Var', (28, 32))	('induces', 'PosReg', (33, 40))	('VEGF-C', 'Gene', (41, 47))
526960	29599774	Our previous study demonstrated the involvement of CCL4 gene polymorphisms in oral cancer development.	('polymorphisms', 'Var', (61, 74))	('oral cancer', 'Disease', (78, 89))	('men', 'Species', '9606', (97, 100))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('involvement', 'Reg', (36, 47))	('men', 'Species', '9606', (43, 46))	('oral cancer', 'Disease', 'MESH:D009062', (78, 89))	('CCL4', 'Gene', (51, 55))
526989	29599774	In addition, CCL4 significantly increased phosphorylation of STAT3 (Figure 4E).	('STAT3', 'Gene', '6774', (61, 66))	('phosphorylation', 'MPA', (42, 57))	('CCL4', 'Var', (13, 17))	('STAT3', 'Gene', (61, 66))	('increased', 'PosReg', (32, 41))
526990	29599774	CCL4 appears to enhance VEGF-C expression and lymphangiogenesis in OSCC cells through the JAK2/STAT3 signaling pathway.	('JAK2', 'Gene', (90, 94))	('lymphangiogenesis', 'CPA', (46, 63))	('expression', 'MPA', (31, 41))	('enhance', 'PosReg', (16, 23))	('STAT3', 'Gene', '6774', (95, 100))	('CCL4', 'Var', (0, 4))	('VEGF-C', 'Protein', (24, 30))	('JAK2', 'Gene', '3717', (90, 94))	('STAT3', 'Gene', (95, 100))
526994	29599774	To explore whether miR-195-3p regulates the 3'-UTR of VEGF-C, we constructed luciferase reporter vectors harboring either the wild-type 3'-UTR of VEGF-C mRNA (WT VEGF-C-3'-UTR) or mismatches in the predicted miR-195-3p binding site (MUT VEGF-C-3'-UTR) and transfected them into both SAS and SCC4 cell lines.	('mismatches', 'Var', (180, 190))	('SCC4', 'Gene', (291, 295))	('binding', 'Interaction', (219, 226))	('miR-195', 'Gene', '406971', (19, 26))	('SCC4', 'Gene', '23383', (291, 295))	('miR-195', 'Gene', (19, 26))	('miR-195', 'Gene', (208, 215))	('miR-195', 'Gene', '406971', (208, 215))	('N', 'Chemical', 'MESH:D009584', (155, 156))
526998	29599774	In vitro data demonstrated that transfecting human OSCC cells with CCL4-shRNA suppressed LEC tube formation and migration (Figure S4 in Supplementary Material).	('LEC', 'Gene', (89, 92))	('men', 'Species', '9606', (142, 145))	('N', 'Chemical', 'MESH:D009584', (75, 76))	('suppressed', 'NegReg', (78, 88))	('human', 'Species', '9606', (45, 50))	('CCL4-shRNA', 'Var', (67, 77))	('LEC', 'Gene', '6360', (89, 92))
527002	29599774	IHC staining of murine tissue revealed substantially lower levels of LYVE-1 expression from sh-CCL4 mice compared with controls.	('levels', 'MPA', (59, 65))	('murine', 'Species', '10090', (16, 22))	('mice', 'Species', '10090', (100, 104))	('expression', 'MPA', (76, 86))	('sh-CCL4', 'Var', (92, 99))	('LYVE-1', 'Gene', (69, 75))	('lower', 'NegReg', (53, 58))
527003	29599774	Similarly, sh-CCL4 mice had lower levels of CCL4 and VEGF-C tissue expression compared with control mice (Figures 6B,D,E).	('lower', 'NegReg', (28, 33))	('mice', 'Species', '10090', (100, 104))	('VEGF-C', 'Gene', (53, 59))	('levels of CCL4', 'MPA', (34, 48))	('sh-CCL4', 'Var', (11, 18))	('mice', 'Species', '10090', (19, 23))
527015	29599774	We also observed that CCL4 increases VEGF-C production by downregulating miR-195-3p via the JAK2 and STAT3 signaling pathways in OSCC cells, which indicates that CCL4 could serve as a novel therapeutic target in OSCC lymphangiogenesis.	('downregulating', 'NegReg', (58, 72))	('STAT3', 'Gene', '6774', (101, 106))	('STAT3', 'Gene', (101, 106))	('VEGF-C production', 'MPA', (37, 54))	('increases', 'PosReg', (27, 36))	('miR-195', 'Gene', (73, 80))	('JAK2', 'Gene', (92, 96))	('CCL4', 'Var', (22, 26))	('miR-195', 'Gene', '406971', (73, 80))	('OSCC', 'Disease', (212, 216))	('JAK2', 'Gene', '3717', (92, 96))
527018	29599774	Two main allelic variants of CCL4L exist: the originally described variant, CCL4L1, and a second allelic variant with a nucleotide change in the intron 2 acceptor splice site, CCL4L2.	('CCL4L1', 'Gene', '388372', (76, 82))	('CCL4L', 'Gene', (29, 34))	('CCL4L', 'Gene', '388372', (176, 181))	('nucleotide change in', 'Var', (120, 140))	('CCL4L', 'Gene', '388372', (76, 81))	('CCL4L', 'Gene', (176, 181))	('CCL4L', 'Gene', '388372', (29, 34))	('CCL4L2', 'Gene', '9560', (176, 182))	('CCL4L1', 'Gene', (76, 82))	('CCL4L', 'Gene', (76, 81))	('CCL4L2', 'Gene', (176, 182))
527026	29599774	In this study, CM from CCL4-treated OSCC cells promoted tube formation and migration in LECs, indicating that CCL4 enhances lymphangiogenesis in OSCC cells.	('lymphangiogenesis', 'CPA', (124, 141))	('tube formation', 'CPA', (56, 70))	('promoted', 'PosReg', (47, 55))	('LEC', 'Gene', '6360', (88, 91))	('CCL4', 'Var', (110, 114))	('migration', 'CPA', (75, 84))	('LEC', 'Gene', (88, 91))	('enhances', 'PosReg', (115, 123))
527028	29599774	In our study, CCR5 knockdown dramatically suppressed VEGF-C-induced lymphangiogenesis.	('CCR5', 'Gene', '1234', (14, 18))	('CCR5', 'Gene', (14, 18))	('VEGF-C-induced', 'Gene', (53, 67))	('knockdown', 'Var', (19, 28))	('suppressed', 'NegReg', (42, 52))	('lymphangiogenesis', 'CPA', (68, 85))
527059	26560875	Functional studies further demonstrate that FPN is post-transcriptionally regulated by miR-20a in non-small cell lung cancer (NSCLC) cells and that overexpression or knockdown of miR-20a or FPN affects NSCLC proliferation and colony formation.	('knockdown', 'Var', (166, 175))	('NSCLC', 'Disease', 'MESH:D002289', (126, 131))	('NSCLC', 'Disease', (202, 207))	('lung cancer', 'Phenotype', 'HP:0100526', (113, 124))	('affects', 'Reg', (194, 201))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (98, 124))	('NSCLC', 'Disease', 'MESH:D002289', (202, 207))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (102, 124))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('miR-20a', 'Gene', (87, 94))	('FPN', 'Gene', (44, 47))	('non-small cell lung cancer', 'Disease', (98, 124))	('colony formation', 'CPA', (226, 242))	('NSCLC', 'Phenotype', 'HP:0030358', (126, 131))	('NSCLC', 'Phenotype', 'HP:0030358', (202, 207))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (98, 124))	('NSCLC', 'Disease', (126, 131))
527063	26560875	Low FPN expression stimulates proliferation and colony formation of non-small cell lung cancer (NSCLC) cells, possibly by increasing iron availability for cancer cell proliferation.	('colony formation', 'CPA', (48, 64))	('cancer', 'Disease', (88, 94))	('NSCLC', 'Disease', (96, 101))	('lung cancer', 'Phenotype', 'HP:0100526', (83, 94))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('non-small cell lung cancer', 'Disease', (68, 94))	('NSCLC', 'Phenotype', 'HP:0030358', (96, 101))	('iron', 'Chemical', 'MESH:D007501', (133, 137))	('cancer', 'Disease', 'MESH:D009369', (155, 161))	('stimulates', 'PosReg', (19, 29))	('Low', 'Var', (0, 3))	('FPN', 'Gene', (4, 7))	('proliferation', 'CPA', (30, 43))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (68, 94))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (72, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('increasing', 'PosReg', (122, 132))	('iron availability', 'MPA', (133, 150))	('cancer', 'Disease', (155, 161))	('expression', 'Var', (8, 18))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('NSCLC', 'Disease', 'MESH:D002289', (96, 101))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (68, 94))
527072	26560875	The miR-17 family (miR-17 and miR-20a) triggers rapid proliferation by repressing the cell cycle inhibitors p21 (CDKN1A) and p57 (CDKN1C) as well as by directly targeting the proapoptotic protein Bim (BCL211) and the tumor suppressor gene phosphatase and tensin homolg (PTEN).	('p21', 'Gene', '1026', (108, 111))	('CDKN1C', 'Gene', (130, 136))	('Bim', 'Gene', '10018', (196, 199))	('p57', 'Gene', '1028', (125, 128))	('cell', 'CPA', (86, 90))	('miR-17', 'Gene', (4, 10))	('tumor', 'Disease', (217, 222))	('CDKN1A', 'Gene', (113, 119))	('Bim', 'Gene', (196, 199))	('targeting', 'Reg', (161, 170))	('repressing', 'PosReg', (71, 81))	('CDKN1A', 'Gene', '1026', (113, 119))	('miR-17', 'Gene', (19, 25))	('tumor', 'Disease', 'MESH:D009369', (217, 222))	('rapid proliferation', 'CPA', (48, 67))	('p21', 'Gene', (108, 111))	('PTEN', 'Gene', (270, 274))	('p57', 'Gene', (125, 128))	('CDKN1C', 'Gene', '1028', (130, 136))	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('miR-17', 'Gene', '406952', (4, 10))	('PTEN', 'Gene', '5728', (270, 274))	('miR-20a', 'Var', (30, 37))	('BCL211', 'Gene', (201, 207))	('miR-17', 'Gene', '406952', (19, 25))
527090	26560875	Overexpression or knockdown of miR-20a in the non-small cell lung cancer cell lines (NSCLC) H1299 and H1650 significantly affects FPN expression post-transcriptionally.	('NSCLC', 'Disease', (85, 90))	('knockdown', 'Var', (18, 27))	('H1650', 'Var', (102, 107))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (46, 72))	('lung cancer', 'Phenotype', 'HP:0100526', (61, 72))	('expression', 'MPA', (134, 144))	('NSCLC', 'Disease', 'MESH:D002289', (85, 90))	('H1650', 'CellLine', 'CVCL:1483', (102, 107))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('NSCLC', 'Phenotype', 'HP:0030358', (85, 90))	('H1299', 'CellLine', 'CVCL:0060', (92, 97))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (50, 72))	('affects', 'Reg', (122, 129))	('miR-20a', 'Gene', (31, 38))	('non-small cell lung cancer', 'Disease', (46, 72))	('FPN', 'Gene', (130, 133))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (46, 72))
527091	26560875	Importantly, low FPN expression stimulates proliferation and colony formation of NSCLC cells, possibly by increasing iron availability for cancer cell proliferation.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('iron availability', 'MPA', (117, 134))	('NSCLC', 'Phenotype', 'HP:0030358', (81, 86))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('iron', 'Chemical', 'MESH:D007501', (117, 121))	('colony formation', 'CPA', (61, 77))	('low', 'Var', (13, 16))	('increasing', 'PosReg', (106, 116))	('NSCLC', 'Disease', (81, 86))	('proliferation', 'CPA', (43, 56))	('FPN', 'Gene', (17, 20))	('NSCLC', 'Disease', 'MESH:D002289', (81, 86))	('stimulates', 'PosReg', (32, 42))	('cancer', 'Disease', (139, 145))
527122	26560875	miR-20a target sequences within the human FPN-3'UTR are located at nt 1108-1114, nt 1132-1138, and nt 1166-1172 (Fig.	('nt 1108-1114', 'Var', (67, 79))	('nt 1166-1172', 'Var', (99, 111))	('miR-20a', 'Gene', (0, 7))	('nt 1132-1138', 'Var', (81, 93))	('human', 'Species', '9606', (36, 41))
527129	26560875	Upon miR-20a overexpression, luciferase activity from cells transfected with the positive control plasmids pMIR-20+ and pMIR-HIF1A was strongly reduced whereas luciferase activity was unaffected from cells transfected with the negative control plasmids pMIR-20-, pMIR-HIF1A-MUT, or pMIR-RPL19 (Fig.	('miR-20a', 'Gene', (5, 12))	('reduced', 'NegReg', (144, 151))	('luciferase', 'Enzyme', (29, 39))	('HIF1A', 'Gene', '3091', (125, 130))	('RPL19', 'Gene', '6143', (287, 292))	('pMIR-20+', 'Var', (107, 115))	('HIF1A', 'Gene', (268, 273))	('HIF1A', 'Gene', '3091', (268, 273))	('activity', 'MPA', (40, 48))	('HIF1A', 'Gene', (125, 130))	('RPL19', 'Gene', (287, 292))	('overexpression', 'Var', (13, 27))
527147	26560875	Analysis of FPN mRNA and miR-20a expression in the H1299 and H160 cell lines showed that expression of FPN mRNA in H1650 was significantly higher compared to H1299 (Fig.	('H1299', 'CellLine', 'CVCL:0060', (51, 56))	('expression', 'MPA', (89, 99))	('H1299', 'CellLine', 'CVCL:0060', (158, 163))	('H1650', 'Var', (115, 120))	('H160', 'CellLine', 'CVCL:U058', (61, 65))	('H1650', 'CellLine', 'CVCL:1483', (115, 120))	('higher', 'PosReg', (139, 145))
527159	26560875	We show that inhibition of miR-20a in H1299 cells represses cell proliferation (F(6,28) = 4.157; P = 0.0041) (Fig.	('cell proliferation', 'CPA', (60, 78))	('inhibition', 'Var', (13, 23))	('miR-20a', 'Gene', (27, 34))	('represses', 'NegReg', (50, 59))	('H1299', 'CellLine', 'CVCL:0060', (38, 43))
527164	26560875	Reduced FPN expression decreases the capacity for iron export and causes cellular iron retention.	('cellular iron retention', 'MPA', (73, 96))	('FPN', 'Gene', (8, 11))	('causes', 'Reg', (66, 72))	('iron', 'Chemical', 'MESH:D007501', (50, 54))	('decreases', 'NegReg', (23, 32))	('capacity for iron export', 'MPA', (37, 61))	('Reduced', 'Var', (0, 7))	('iron', 'Chemical', 'MESH:D007501', (82, 86))
527174	26560875	Two miR-17-5p target sites at nt 1132-1138 and nt 1116-1172 within the FPN-3'UTR were predicted by a recent study, but the functionality was not proven.	('nt 1116-1172', 'Var', (47, 59))	('nt 1132-1138', 'Var', (30, 42))	('miR-17-5p', 'Gene', '406952', (4, 13))	('miR-17-5p', 'Gene', (4, 13))
527178	26560875	Here, we demonstrate for the first time that elevated miR-20a levels suppress expression of endogenous FPN mRNA in cell lines (e.g., Huh7 and H1650) (Fig.	('Huh7', 'Gene', '284424', (133, 137))	('expression', 'MPA', (78, 88))	('H1650', 'Var', (142, 147))	('H1650', 'CellLine', 'CVCL:1483', (142, 147))	('suppress', 'NegReg', (69, 77))	('Huh7', 'Gene', (133, 137))
527190	26560875	Furthermore, the oncogenic miR-20a may control iron metabolism indirectly, e.g., by modulating the expression levels of the transcription factor HIF1A (Fig.	('expression levels', 'MPA', (99, 116))	('control', 'Reg', (39, 46))	('miR-20a', 'Gene', (27, 34))	('HIF1A', 'Gene', (145, 150))	('oncogenic', 'Var', (17, 26))	('modulating', 'Reg', (84, 94))	('iron metabolism', 'MPA', (47, 62))	('HIF1A', 'Gene', '3091', (145, 150))	('iron', 'Chemical', 'MESH:D007501', (47, 51))
527198	26560875	It is of note that miR-20a is significantly higher expressed compared to miR-485 in lung cancer (Fig.	('lung cancer', 'Disease', (84, 95))	('miR-485', 'Gene', '574436', (73, 80))	('lung cancer', 'Phenotype', 'HP:0100526', (84, 95))	('miR-485', 'Gene', (73, 80))	('higher', 'PosReg', (44, 50))	('miR-20a', 'Var', (19, 26))	('lung cancer', 'Disease', 'MESH:D008175', (84, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
527199	26560875	This may suggest that miR-485 and miR-20a cooperate in regulating FPN levels in lung cancer, but that the regulatory effect of miR-20a on FPN may dominate over the one of miR-485 due to its low expression level.	('regulating FPN levels', 'MPA', (55, 76))	('lung cancer', 'Disease', 'MESH:D008175', (80, 91))	('miR-485', 'Gene', '574436', (22, 29))	('miR-485', 'Gene', (22, 29))	('lung cancer', 'Disease', (80, 91))	('lung cancer', 'Phenotype', 'HP:0100526', (80, 91))	('expression', 'MPA', (194, 204))	('miR-485', 'Gene', '574436', (171, 178))	('miR-20a', 'Var', (127, 134))	('miR-485', 'Gene', (171, 178))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
527201	26560875	Previous findings showed that changes in FPN expression affect the labile iron pool (LIP) and thus will influence intracellular availability of this important nutrient.	('affect', 'Reg', (56, 62))	('changes', 'Var', (30, 37))	('LIP', 'Disease', (85, 88))	('LIP', 'Disease', 'MESH:C536528', (85, 88))	('iron', 'Chemical', 'MESH:D007501', (74, 78))	('influence', 'Reg', (104, 113))	('FPN', 'Gene', (41, 44))
527204	26560875	Taken together, these findings suggest that manipulation of FPN expression may cause changes in intracellular iron availability in NSCLC cells that influence the rate of cell proliferation.	('manipulation', 'Var', (44, 56))	('changes', 'Reg', (85, 92))	('rate of cell proliferation', 'CPA', (162, 188))	('NSCLC', 'Disease', (131, 136))	('iron', 'Chemical', 'MESH:D007501', (110, 114))	('NSCLC', 'Disease', 'MESH:D002289', (131, 136))	('FPN', 'Gene', (60, 63))	('influence', 'Reg', (148, 157))	('NSCLC', 'Phenotype', 'HP:0030358', (131, 136))	('intracellular iron availability', 'MPA', (96, 127))
527212	24941347	In the present study, we found that TC-1 is highly expressed in NSCLC and that its aberrant expression is strongly associated with NSCLC cell proliferation.	('TC-1', 'Gene', (36, 40))	('NSCLC', 'Disease', 'MESH:D002289', (64, 69))	('NSCLC', 'Disease', (131, 136))	('NSCLC', 'Phenotype', 'HP:0030358', (131, 136))	('NSCLC', 'Disease', (64, 69))	('aberrant', 'Var', (83, 91))	('NSCLC', 'Disease', 'MESH:D002289', (131, 136))	('NSCLC', 'Phenotype', 'HP:0030358', (64, 69))	('TC-1', 'Gene', '56892', (36, 40))	('associated with', 'Reg', (115, 130))
527214	24941347	The knockdown of TC-1, however, inhibits NSCLC cell proliferation, cycle transition, and apoptosis resistance.	('TC-1', 'Gene', '56892', (17, 21))	('NSCLC', 'Disease', (41, 46))	('cycle transition', 'CPA', (67, 83))	('apoptosis resistance', 'CPA', (89, 109))	('NSCLC', 'Disease', 'MESH:D002289', (41, 46))	('TC-1', 'Gene', (17, 21))	('inhibits', 'NegReg', (32, 40))	('knockdown', 'Var', (4, 13))	('NSCLC', 'Phenotype', 'HP:0030358', (41, 46))
527215	24941347	Furthermore, we also demonstrated that PD173074, which functions as an inhibitor of the TC-1 in NSCLC, decreases the expression of TC-1 and inhibits TC-1 overexpression mediated cell proliferation in vitro and in vivo.	('inhibits', 'NegReg', (140, 148))	('TC-1', 'Gene', (131, 135))	('PD173074', 'Var', (39, 47))	('NSCLC', 'Disease', (96, 101))	('TC-1', 'Gene', (88, 92))	('PD173074', 'Chemical', 'MESH:C115711', (39, 47))	('decreases', 'NegReg', (103, 112))	('expression', 'MPA', (117, 127))	('NSCLC', 'Disease', 'MESH:D002289', (96, 101))	('TC-1', 'Gene', '56892', (149, 153))	('TC-1', 'Gene', '56892', (131, 135))	('TC-1', 'Gene', '56892', (88, 92))	('NSCLC', 'Phenotype', 'HP:0030358', (96, 101))	('TC-1', 'Gene', (149, 153))
527216	24941347	Nevertheless, the inhibition function of PD173074 on NSCLC cell proliferation was eliminated in cells with TC-1 knockdown.	('NSCLC', 'Phenotype', 'HP:0030358', (53, 58))	('eliminated', 'NegReg', (82, 92))	('PD173074', 'Chemical', 'MESH:C115711', (41, 49))	('PD173074', 'Var', (41, 49))	('TC-1', 'Gene', '56892', (107, 111))	('NSCLC', 'Disease', (53, 58))	('NSCLC', 'Disease', 'MESH:D002289', (53, 58))	('TC-1', 'Gene', (107, 111))
527217	24941347	These results suggest that PD173074 plays a significant role in TC-1 overexpression mediated NSCLC cell proliferation and may be a potential intervention target for the prevention of cell proliferation in NSCLC.	('overexpression', 'PosReg', (69, 83))	('NSCLC', 'Disease', (93, 98))	('NSCLC', 'Phenotype', 'HP:0030358', (205, 210))	('TC-1', 'Gene', (64, 68))	('PD173074', 'Chemical', 'MESH:C115711', (27, 35))	('NSCLC', 'Disease', 'MESH:D002289', (93, 98))	('PD173074', 'Var', (27, 35))	('NSCLC', 'Disease', (205, 210))	('NSCLC', 'Phenotype', 'HP:0030358', (93, 98))	('NSCLC', 'Disease', 'MESH:D002289', (205, 210))	('TC-1', 'Gene', '56892', (64, 68))
527226	24941347	An increasing number of studies have demonstrated that TC-1 is highly expressed in several carcinomas, and its aberrant expression was implicated in the proliferation of normal and cancer cells.	('implicated', 'Reg', (135, 145))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('TC-1', 'Gene', '56892', (55, 59))	('proliferation', 'CPA', (153, 166))	('aberrant', 'Var', (111, 119))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('carcinomas', 'Phenotype', 'HP:0030731', (91, 101))	('cancer', 'Disease', (181, 187))	('carcinomas', 'Disease', (91, 101))	('carcinomas', 'Disease', 'MESH:D002277', (91, 101))	('TC-1', 'Gene', (55, 59))
527231	24941347	reported that the selective fibroblast growth factor receptor (FGFR) inhibitor PD173074 blocks the proliferation and clonogenic growth of two small cell lung cancer cell lines (H69 and H510) in a dose-dependent manner and prevents FGF-2-induced chemoresistance.	('FGF-2', 'Gene', (231, 236))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('lung cancer', 'Disease', 'MESH:D008175', (153, 164))	('H69', 'CellLine', 'CVCL:8121', (177, 180))	('prevents', 'NegReg', (222, 230))	('FGFR', 'Gene', (63, 67))	('clonogenic growth', 'CPA', (117, 134))	('PD173074', 'Var', (79, 87))	('lung cancer', 'Disease', (153, 164))	('FGF-2', 'Gene', '2247', (231, 236))	('PD173074', 'Chemical', 'MESH:C115711', (79, 87))	('lung cancer', 'Phenotype', 'HP:0100526', (153, 164))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (142, 164))	('blocks', 'NegReg', (88, 94))	('proliferation', 'CPA', (99, 112))
527232	24941347	Surprisingly, in H510 xenografts, tumor growth was impaired with PD173074 treatment, resulting in an increase in the median survival compared with control sham-treated animals, similarly to the effect observed with the single-agent administration of cisplatin; in H69 xenografts, PD173074 induced a complete response that lasted at least 6 months in 50% of the mice.	('PD173074', 'Var', (280, 288))	('H69', 'CellLine', 'CVCL:8121', (264, 267))	('PD173074', 'Chemical', 'MESH:C115711', (280, 288))	('tumor', 'Disease', (34, 39))	('increase', 'PosReg', (101, 109))	('PD173074', 'Var', (65, 73))	('mice', 'Species', '10090', (361, 365))	('PD173074', 'Chemical', 'MESH:C115711', (65, 73))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('cisplatin', 'Chemical', 'MESH:D002945', (250, 259))	('impaired', 'NegReg', (51, 59))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
527233	24941347	In addition, the effect of cisplatin was significantly potentiated by its coadministration with PD173074.	('PD173074', 'Var', (96, 104))	('potentiated', 'PosReg', (55, 66))	('cisplatin', 'Chemical', 'MESH:D002945', (27, 36))	('PD173074', 'Chemical', 'MESH:C115711', (96, 104))
527234	24941347	These effects were explained by the finding that PD173074 treatment decreased intratumoral proliferation and increased cell apoptosis with a high appearance of the apoptotic cell death marker caspase-3.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('decreased', 'NegReg', (68, 77))	('caspase-3', 'Gene', '836', (192, 201))	('tumor', 'Disease', (83, 88))	('cell apoptosis', 'CPA', (119, 133))	('PD173074', 'Chemical', 'MESH:C115711', (49, 57))	('PD173074', 'Var', (49, 57))	('increased', 'PosReg', (109, 118))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('caspase-3', 'Gene', (192, 201))
527235	24941347	These encouraging findings promote further investigation of the effect of PD173074 on NSCLC cells.	('PD173074', 'Var', (74, 82))	('PD173074', 'Chemical', 'MESH:C115711', (74, 82))	('NSCLC', 'Disease', (86, 91))	('NSCLC', 'Disease', 'MESH:D002289', (86, 91))	('NSCLC', 'Phenotype', 'HP:0030358', (86, 91))
527279	24941347	For the tumorigenicity assay, 4- to 6-week-old BALB/c athymic nude mice (Experimental Animal Center, The Forth Military Medical University, Xi'an, China) were subcutaneously administered 5x106 A549- pLenti-shRNA1, A549- pLenti-NSRNA, NCI-H520-pLenti-TC-1, or NCI-H520-pLenti-LacZ cells.	('TC-1', 'Gene', (250, 254))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('nude mice', 'Species', '10090', (62, 71))	('A549', 'CellLine', 'CVCL:0023', (193, 197))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('NCI-H520', 'CellLine', 'CVCL:1566', (259, 267))	('tumor', 'Disease', (8, 13))	('A549', 'CellLine', 'CVCL:0023', (214, 218))	('5x106', 'Var', (187, 192))	('NCI-H520', 'CellLine', 'CVCL:1566', (234, 242))	('TC-1', 'Gene', '56892', (250, 254))
527285	24941347	When the tumors became measurable, 50 mg/kg PD173074/mice or an equivalent volume of buffer alone was administered daily for a total of 28 days.	('PD173074', 'Chemical', 'MESH:C115711', (44, 52))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('PD173074/mice', 'Var', (44, 57))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('tumors', 'Disease', (9, 15))	('tumors', 'Disease', 'MESH:D009369', (9, 15))	('mice', 'Species', '10090', (53, 57))
527303	24941347	Notably, in the MTT assay, the transfection of pLenti-TC1 transfection enhanced the proliferation of NCI-H520 cells compared with the control cells.	('TC1', 'Gene', '56892', (54, 57))	('enhanced', 'PosReg', (71, 79))	('NCI-H520', 'CellLine', 'CVCL:1566', (101, 109))	('transfection', 'Var', (58, 70))	('proliferation', 'CPA', (84, 97))	('TC1', 'Gene', (54, 57))	('MTT', 'Chemical', 'MESH:C070243', (16, 19))
527304	24941347	Alternatively, TC1 knockdown using TC1-shRNA1 showed significant downregulation of proliferation in A549-pLenti-shRNA1 cells compared with NSRNA-transfected cells (Fig.	('A549', 'CellLine', 'CVCL:0023', (100, 104))	('proliferation', 'CPA', (83, 96))	('knockdown', 'Var', (19, 28))	('TC1', 'Gene', (35, 38))	('TC1', 'Gene', '56892', (35, 38))	('downregulation', 'NegReg', (65, 79))	('TC1', 'Gene', (15, 18))	('TC1', 'Gene', '56892', (15, 18))
527305	24941347	Furthermore, the colony numbers of the pLenti-TC-1 and pLenti-NS RNA groups were higher than those obtained for the pLenti-LacZ and pLenti-shRNA1 groups, respectively (Fig.	('higher', 'PosReg', (81, 87))	('TC-1', 'Gene', '56892', (46, 50))	('colony numbers', 'CPA', (17, 31))	('pLenti-NS RNA', 'Var', (55, 68))	('TC-1', 'Gene', (46, 50))
527317	24941347	To test whether the addition of PD173074 influences the expression of TC-1 in NSCLC, A549 and A549-pLenti-shRNA1 cells in SITA were treated with PD173074.	('A549', 'CellLine', 'CVCL:0023', (85, 89))	('PD173074', 'Var', (145, 153))	('NSCLC', 'Disease', 'MESH:D002289', (78, 83))	('NSCLC', 'Phenotype', 'HP:0030358', (78, 83))	('SITA', 'Disease', (122, 126))	('TC-1', 'Gene', '56892', (70, 74))	('A549', 'CellLine', 'CVCL:0023', (94, 98))	('expression', 'MPA', (56, 66))	('SITA', 'Disease', 'None', (122, 126))	('NSCLC', 'Disease', (78, 83))	('PD173074', 'Chemical', 'MESH:C115711', (145, 153))	('PD173074', 'Chemical', 'MESH:C115711', (32, 40))	('TC-1', 'Gene', (70, 74))
527318	24941347	The results of RT-PCR and western blotting showed that the expression level of TC-1 decreased with an increase in the concentration of PD173074 and levels out when the concentration of PD173074 reaches 1 microMu (Fig.	('TC-1', 'Gene', '56892', (79, 83))	('PD173074', 'Var', (185, 193))	('PD173074', 'Chemical', 'MESH:C115711', (185, 193))	('increase', 'PosReg', (102, 110))	('TC-1', 'Gene', (79, 83))	('PD173074', 'Var', (135, 143))	('decreased', 'NegReg', (84, 93))	('PD173074', 'Chemical', 'MESH:C115711', (135, 143))	('expression level', 'MPA', (59, 75))
527320	24941347	6A, PD173074 treatment has a marked influence on the cell growth curves of the untransfected cells, as illustrated by the difference between the A549+PD173074 group and the A549 group, but has little influence on the cell growth curves of the transfected cells, as indicated by the difference between the A549-pLenti-shRNA1+PD173074 group and the A549-pLenti-shRNA1 group.	('cell growth curves', 'CPA', (53, 71))	('influence', 'Reg', (36, 45))	('PD173074', 'Chemical', 'MESH:C115711', (150, 158))	('PD173074', 'Var', (4, 12))	('PD173074', 'Chemical', 'MESH:C115711', (4, 12))	('A549', 'CellLine', 'CVCL:0023', (347, 351))	('A549', 'CellLine', 'CVCL:0023', (145, 149))	('A549', 'CellLine', 'CVCL:0023', (173, 177))	('A549', 'CellLine', 'CVCL:0023', (305, 309))	('PD173074', 'Chemical', 'MESH:C115711', (324, 332))
527321	24941347	A similar result was observed in the plate colony formation assay: there was a significant difference in the colony formation rate between the A549+PD173074 group and the A549 group, but only slight differences in the colony formation rate were observed between the A549-pLenti-shRNA1+PD173074 group and the A549-pLenti-shRNA1 group (Fig.	('A549', 'CellLine', 'CVCL:0023', (171, 175))	('PD173074', 'Chemical', 'MESH:C115711', (148, 156))	('colony formation rate', 'CPA', (109, 130))	('A549+PD173074', 'Var', (143, 156))	('A549', 'CellLine', 'CVCL:0023', (308, 312))	('PD173074', 'Chemical', 'MESH:C115711', (285, 293))	('A549', 'CellLine', 'CVCL:0023', (266, 270))	('A549', 'CellLine', 'CVCL:0023', (143, 147))
527322	24941347	6C, the percentages of cells in the S phase in the populations of PD173074-treated A549 cells, A549 cells, PD173074-treated A549-pLenti-shRNA1 cells, and A549-pLenti-shRNA1 cells were 29.47+-0.62%, 49.5+-1.89%, 28.02+-0.97%, and 29.5+-1.02%, respectively.	('A549', 'CellLine', 'CVCL:0023', (154, 158))	('PD173074-treated', 'Var', (66, 82))	('PD173074-treated', 'Var', (107, 123))	('A549', 'CellLine', 'CVCL:0023', (124, 128))	('A549', 'CellLine', 'CVCL:0023', (83, 87))	('PD173074', 'Chemical', 'MESH:C115711', (107, 115))	('PD173074', 'Chemical', 'MESH:C115711', (66, 74))	('S phase', 'CPA', (36, 43))	('A549', 'CellLine', 'CVCL:0023', (95, 99))
527324	24941347	6D, the apoptotic rates of the PD173074-treated A549 cells were significantly higher than that of the A549 cells; however, there was no marked difference in the apoptotic rate between the PD173074-treated A549-pLenti-shRNA1 cells and A549-pLenti-shRNA1 cells.	('A549', 'CellLine', 'CVCL:0023', (234, 238))	('PD173074', 'Chemical', 'MESH:C115711', (188, 196))	('PD173074', 'Chemical', 'MESH:C115711', (31, 39))	('A549', 'CellLine', 'CVCL:0023', (48, 52))	('A549', 'CellLine', 'CVCL:0023', (205, 209))	('apoptotic rates', 'CPA', (8, 23))	('PD173074-treated', 'Var', (188, 204))	('A549', 'CellLine', 'CVCL:0023', (102, 106))
527325	24941347	Taken together, these data indicate that PD173074 inhibits TC-1-mediated cell proliferation, cell cycle transition, and cell apoptosis resistance when TC-1 is highly or moderately expressed but not when it is lowly expressed.	('TC-1', 'Gene', '56892', (59, 63))	('TC-1', 'Gene', '56892', (151, 155))	('PD173074', 'Chemical', 'MESH:C115711', (41, 49))	('PD173074', 'Var', (41, 49))	('cell cycle transition', 'CPA', (93, 114))	('TC-1', 'Gene', (59, 63))	('TC-1', 'Gene', (151, 155))	('cell apoptosis resistance', 'CPA', (120, 145))	('inhibits', 'NegReg', (50, 58))
527329	24941347	In fact, PD173074 alone was as efficient as cisplatin in reducing the tumor growth rate and prolonging the survival of tumor-bearing animal compared with the Mock group.	('PD173074', 'Chemical', 'MESH:C115711', (9, 17))	('tumor', 'Disease', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (70, 75))	('tumor', 'Disease', (70, 75))	('prolonging', 'PosReg', (92, 102))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('cisplatin', 'Chemical', 'MESH:D002945', (44, 53))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('reducing', 'NegReg', (57, 65))	('PD173074', 'Var', (9, 17))
527331	24941347	These results also indicate that PD173074 plays a role in the regulation of TC-1-induced proliferation when TC-1 is highly or moderately expressed.	('proliferation', 'CPA', (89, 102))	('PD173074', 'Var', (33, 41))	('PD173074', 'Chemical', 'MESH:C115711', (33, 41))	('TC-1', 'Gene', '56892', (108, 112))	('TC-1', 'Gene', '56892', (76, 80))	('TC-1', 'Gene', (108, 112))	('TC-1', 'Gene', (76, 80))
527332	24941347	In this case, the effects caused by PD173074 alone were equivalent to the effects of cisplatin, and the combination of PD173074 with cisplatin may improve the chemotherapy effectiveness of cisplatin in NSCLC.	('PD173074', 'Chemical', 'MESH:C115711', (119, 127))	('cisplatin', 'Chemical', 'MESH:D002945', (189, 198))	('NSCLC', 'Disease', (202, 207))	('improve', 'PosReg', (147, 154))	('PD173074', 'Var', (119, 127))	('chemotherapy effectiveness', 'CPA', (159, 185))	('NSCLC', 'Disease', 'MESH:D002289', (202, 207))	('cisplatin', 'Chemical', 'MESH:D002945', (133, 142))	('NSCLC', 'Phenotype', 'HP:0030358', (202, 207))	('cisplatin', 'Chemical', 'MESH:D002945', (85, 94))	('PD173074', 'Chemical', 'MESH:C115711', (36, 44))
527337	24941347	Moreover, further analysis found that the expression level of TC-1 in the Ki>10% group was higher than that in the Ki<=10% group in both the squamous cell carcinoma and adenocarcinoma samples.	('carcinoma', 'Phenotype', 'HP:0030731', (155, 164))	('adenocarcinoma', 'Disease', 'MESH:D000230', (169, 183))	('expression level', 'MPA', (42, 58))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (141, 164))	('adenocarcinoma', 'Disease', (169, 183))	('higher', 'PosReg', (91, 97))	('squamous cell carcinoma', 'Disease', (141, 164))	('TC-1', 'Gene', '56892', (62, 66))	('Ki>10%', 'Var', (74, 80))	('TC-1', 'Gene', (62, 66))	('carcinoma', 'Phenotype', 'HP:0030731', (174, 183))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (141, 164))
527343	24941347	An important finding of our study is that PD173074 inhibits TC-1 overexpression mediated cell proliferation in NSCLC.	('TC-1', 'Gene', (60, 64))	('cell proliferation', 'CPA', (89, 107))	('inhibits', 'NegReg', (51, 59))	('NSCLC', 'Disease', (111, 116))	('NSCLC', 'Disease', 'MESH:D002289', (111, 116))	('PD173074', 'Var', (42, 50))	('PD173074', 'Chemical', 'MESH:C115711', (42, 50))	('overexpression', 'PosReg', (65, 79))	('TC-1', 'Gene', '56892', (60, 64))	('NSCLC', 'Phenotype', 'HP:0030358', (111, 116))
527344	24941347	PD173074, a small-molecular-weight pharmacological tyrosine kinase inhibitor, has reportedly shown powerful inhibitory effects on cell proliferation.	('PD173074', 'Chemical', 'MESH:C115711', (0, 8))	('PD173074', 'Var', (0, 8))	('cell proliferation', 'CPA', (130, 148))	('inhibitory', 'NegReg', (108, 118))
527345	24941347	In breast cancer, PD173074 treatment markedly reduces proliferation and promotes apoptosis in MKN45 cells.	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('apoptosis', 'CPA', (81, 90))	('breast cancer', 'Disease', (3, 16))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('PD173074', 'Var', (18, 26))	('promotes', 'PosReg', (72, 80))	('proliferation', 'CPA', (54, 67))	('PD173074', 'Chemical', 'MESH:C115711', (18, 26))	('reduces', 'NegReg', (46, 53))
527346	24941347	Moreover, the effects of the combination of PD173074 and 5-fluorouracil in inhibiting proliferation, increasing apoptosis were superior to these effects following the single agent treatments.	('increasing', 'PosReg', (101, 111))	('PD173074', 'Var', (44, 52))	('inhibiting', 'NegReg', (75, 85))	('apoptosis', 'CPA', (112, 121))	('PD173074', 'Chemical', 'MESH:C115711', (44, 52))	('5-fluorouracil', 'Chemical', 'MESH:D005472', (57, 71))	('proliferation', 'CPA', (86, 99))
527347	24941347	showed that treatment with PD173074 results in cell cycle arrest and induction of cell death in endometrial cancer cells with activating mutations in FGFR2.	('endometrial cancer', 'Disease', (96, 114))	('arrest', 'Disease', (58, 64))	('cell death', 'CPA', (82, 92))	('PD173074', 'Chemical', 'MESH:C115711', (27, 35))	('PD173074', 'Var', (27, 35))	('endometrial cancer', 'Disease', 'MESH:D016889', (96, 114))	('FGFR2', 'Gene', '2263', (150, 155))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (47, 64))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('endometrial cancer', 'Phenotype', 'HP:0012114', (96, 114))	('FGFR2', 'Gene', (150, 155))	('arrest', 'Disease', 'MESH:D006323', (58, 64))	('activating', 'PosReg', (126, 136))
527349	24941347	In bladder cancer, PD173074 markedly suppresses cell proliferation in two cell lines (UM-UC-14 and MGHU3) that express the mutated FGFR3 protein in vitro and in vivo, and further analysis revealed that the growth inhibitory effect of PD173074 is associated with arrest at G1-S transition and induction apoptosis in a dose-dependent manner.	('PD173074', 'Var', (19, 27))	('PD173074', 'Chemical', 'MESH:C115711', (19, 27))	('suppresses', 'NegReg', (37, 47))	('arrest', 'Disease', 'MESH:D006323', (262, 268))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('bladder cancer', 'Phenotype', 'HP:0009725', (3, 17))	('PD173074', 'Chemical', 'MESH:C115711', (234, 242))	('arrest', 'Disease', (262, 268))	('cell proliferation', 'CPA', (48, 66))	('growth inhibitory effect', 'CPA', (206, 230))	('PD173074', 'Var', (234, 242))	('FGFR3', 'Gene', '2261', (131, 136))	('bladder cancer', 'Disease', 'MESH:D001749', (3, 17))	('bladder cancer', 'Disease', (3, 17))	('FGFR3', 'Gene', (131, 136))	('mutated', 'Var', (123, 130))
527350	24941347	PD173074 inhibits the MAPK pathway, which regulates the activity of AP-1 and induces the mesenchymal-epithelial transition (MET), and this induction of MET likely suppresses head and neck squamous cell carcinoma cell proliferation and invasion.	('suppresses', 'NegReg', (163, 173))	('MAPK', 'Gene', (22, 26))	('AP-1', 'Gene', (68, 72))	('invasion', 'CPA', (235, 243))	('activity', 'MPA', (56, 64))	('PD173074', 'Var', (0, 8))	('MAPK', 'Gene', '5595;5594;5595', (22, 26))	('PD173074', 'Chemical', 'MESH:C115711', (0, 8))	('mesenchymal-epithelial transition', 'CPA', (89, 122))	('neck squamous cell carcinoma', 'Disease', (183, 211))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (183, 211))	('inhibits', 'NegReg', (9, 17))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (188, 211))	('induces', 'PosReg', (77, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (202, 211))	('AP-1', 'Gene', '3726', (68, 72))
527351	24941347	Lamont FR et al found that the small molecule FGF receptor inhibitor PD173074 block FGFR-dependent urothelial carcinoma growth in vitro and in vivo .	('urothelial carcinoma', 'Disease', 'MESH:D014526', (99, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('urothelial carcinoma', 'Disease', (99, 119))	('PD173074', 'Var', (69, 77))	('PD173074', 'Chemical', 'MESH:C115711', (69, 77))	('block', 'NegReg', (78, 83))	('FGFR-dependent', 'Gene', (84, 98))
527352	24941347	Moreover, in SCLC, PD173074 inhibits H-510 and H-69 cell proliferation and prevents FGF-2-induced chemoresistance.	('PD173074', 'Var', (19, 27))	('FGF-2', 'Gene', (84, 89))	('PD173074', 'Chemical', 'MESH:C115711', (19, 27))	('inhibits', 'NegReg', (28, 36))	('prevents', 'NegReg', (75, 83))	('SCLC', 'Disease', (13, 17))	('SCLC', 'Disease', 'MESH:D018288', (13, 17))	('chemoresistance', 'CPA', (98, 113))	('H-69', 'CellLine', 'CVCL:8121', (47, 51))	('FGF-2', 'Gene', '2247', (84, 89))
527353	24941347	In the current study, we treated A549 and A549-pLenti-shRNA1 cells with different concentrations of PD173074, qRT-PCR and western blotting showed that the expression level of TC-1 decreased significantly until the concentration of PD173074 reached 1 microMu, which suggests that PD173074 inhibits the expression of TC-1 in a dose-dependent fashion over a certain range.	('expression level', 'MPA', (155, 171))	('TC-1', 'Gene', '56892', (315, 319))	('A549', 'CellLine', 'CVCL:0023', (42, 46))	('TC-1', 'Gene', (175, 179))	('PD173074', 'Var', (100, 108))	('decreased', 'NegReg', (180, 189))	('PD173074', 'Var', (279, 287))	('TC-1', 'Gene', (315, 319))	('PD173074', 'Chemical', 'MESH:C115711', (100, 108))	('PD173074', 'Chemical', 'MESH:C115711', (279, 287))	('inhibits', 'NegReg', (288, 296))	('TC-1', 'Gene', '56892', (175, 179))	('A549', 'CellLine', 'CVCL:0023', (33, 37))	('PD173074', 'Var', (231, 239))	('expression', 'MPA', (301, 311))	('PD173074', 'Chemical', 'MESH:C115711', (231, 239))
527356	24941347	Furthermore, we found that PD173074 dramatically blocks cell proliferation, suppresses cell cycle transition, and promotes cell apoptosis in A549 cells but not in A549- pLenti-shRNA1 cells in vitro; consistently, PD173074 treatment exerted a marked inhibitory effect against the proliferation of A549 cells but a slight effect in A549- pLenti-shRNA1 cells in vivo, which reveals that the inhibitory effect of PD173074 in NSCLC is related to the TC-1 expression levels.	('TC-1', 'Gene', (445, 449))	('NSCLC', 'Phenotype', 'HP:0030358', (421, 426))	('TC-1', 'Gene', '56892', (445, 449))	('A549', 'CellLine', 'CVCL:0023', (330, 334))	('PD173074', 'Chemical', 'MESH:C115711', (27, 35))	('PD173074', 'Var', (213, 221))	('A549', 'CellLine', 'CVCL:0023', (296, 300))	('cell cycle transition', 'CPA', (87, 108))	('PD173074', 'Var', (409, 417))	('expression', 'MPA', (450, 460))	('PD173074', 'Chemical', 'MESH:C115711', (213, 221))	('A549', 'CellLine', 'CVCL:0023', (141, 145))	('PD173074', 'Chemical', 'MESH:C115711', (409, 417))	('cell proliferation', 'CPA', (56, 74))	('A549', 'CellLine', 'CVCL:0023', (163, 167))	('NSCLC', 'Disease', (421, 426))	('suppresses', 'NegReg', (76, 86))	('NSCLC', 'Disease', 'MESH:D002289', (421, 426))
527357	24941347	Thus, cell lines with TC-1 knockdown were unresponsive to PD173074, whereas cell lines that overexpression of TC-1 were highly sensitive to this inhibitor in NSCLC.	('TC-1', 'Gene', '56892', (22, 26))	('NSCLC', 'Disease', (158, 163))	('knockdown', 'Var', (27, 36))	('NSCLC', 'Disease', 'MESH:D002289', (158, 163))	('TC-1', 'Gene', (22, 26))	('TC-1', 'Gene', '56892', (110, 114))	('PD173074', 'Var', (58, 66))	('PD173074', 'Chemical', 'MESH:C115711', (58, 66))	('NSCLC', 'Phenotype', 'HP:0030358', (158, 163))	('TC-1', 'Gene', (110, 114))
527358	24941347	In addition, there was an encouraging in vivo result: PD173074 as a single agent was as efficient as cisplatin at inhibiting cell proliferation and prolonging the survival of A549 tumor-bearing nude mice, and the combination of the inhibitor with cisplatin exerted an improved effect.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('PD173074', 'Chemical', 'MESH:C115711', (54, 62))	('A549', 'CellLine', 'CVCL:0023', (175, 179))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('nude mice', 'Species', '10090', (194, 203))	('cisplatin', 'Chemical', 'MESH:D002945', (101, 110))	('prolonging', 'PosReg', (148, 158))	('tumor', 'Disease', (180, 185))	('cell proliferation', 'CPA', (125, 143))	('inhibiting', 'NegReg', (114, 124))	('survival', 'CPA', (163, 171))	('cisplatin', 'Chemical', 'MESH:D002945', (247, 256))	('PD173074', 'Var', (54, 62))
527359	24941347	This result was consistent with the previous research and suggests that the inhibition of TC-1-induced proliferation by PD173074 may provide a powerful therapeutic strategy for NSCLC treatment in a clinical setting (at least by improve the chemotherapeutic effect of cisplatin in NSCLC patient with TC-1 overexpression).	('inhibition', 'NegReg', (76, 86))	('NSCLC', 'Phenotype', 'HP:0030358', (177, 182))	('TC-1', 'Gene', '56892', (299, 303))	('PD173074', 'Var', (120, 128))	('NSCLC', 'Phenotype', 'HP:0030358', (280, 285))	('PD173074', 'Chemical', 'MESH:C115711', (120, 128))	('NSCLC', 'Disease', 'MESH:D002289', (177, 182))	('TC-1', 'Gene', '56892', (90, 94))	('cisplatin', 'Chemical', 'MESH:D002945', (267, 276))	('NSCLC', 'Disease', (177, 182))	('patient', 'Species', '9606', (286, 293))	('TC-1', 'Gene', (299, 303))	('NSCLC', 'Disease', (280, 285))	('improve', 'PosReg', (228, 235))	('TC-1', 'Gene', (90, 94))	('NSCLC', 'Disease', 'MESH:D002289', (280, 285))
527360	24941347	Of course, further studies need to be performed in the future to confirm our results, including the exact mechanisms of TC-1, PD173074 and the relationships between TC-1 and the FGFR family, which has been demonstrated to be susceptible to the inhibitor.	('TC-1', 'Gene', '56892', (120, 124))	('TC-1', 'Gene', '56892', (165, 169))	('PD173074', 'Var', (126, 134))	('PD173074', 'Chemical', 'MESH:C115711', (126, 134))	('TC-1', 'Gene', (120, 124))	('TC-1', 'Gene', (165, 169))
527363	24941347	Furthermore, the role of TC-1 overexpression in cell proliferation, cell cycle transition, and apoptosis resistance can be blocked by PD173074.	('apoptosis resistance', 'CPA', (95, 115))	('TC-1', 'Gene', '56892', (25, 29))	('PD173074', 'Var', (134, 142))	('overexpression', 'PosReg', (30, 44))	('cell proliferation', 'CPA', (48, 66))	('TC-1', 'Gene', (25, 29))	('PD173074', 'Chemical', 'MESH:C115711', (134, 142))	('cell cycle transition', 'CPA', (68, 89))
527364	24941347	The inhibition effect of PD173074 is mechanistically linked to the expression level of TC-1.	('TC-1', 'Gene', '56892', (87, 91))	('PD173074', 'Var', (25, 33))	('expression level', 'MPA', (67, 83))	('PD173074', 'Chemical', 'MESH:C115711', (25, 33))	('TC-1', 'Gene', (87, 91))	('inhibition', 'NegReg', (4, 14))
527393	33047888	Inclusion criteria were: (a) primary OTSCC (International Classification of Disease-10 diagnosis codes: C02.0, C02.1, C02.2, and C02.3); (b) age above 18 years; (c) no human papilloma virus (HPV) infection (assessed using HPV 16-specific fluorescence in situ hybridization and p16Ink4a-specific immunohistochemistry); (d) follow-up data of at least 3 years for alive patients.	('papilloma virus (HPV) infection', 'Disease', 'MESH:D030361', (174, 205))	('primary OTSCC', 'Disease', (29, 42))	('C02.0', 'Var', (104, 109))	('p16Ink4a', 'Gene', '1029', (277, 285))	('HPV 16', 'Species', '333760', (222, 228))	('patients', 'Species', '9606', (367, 375))	('papilloma', 'Phenotype', 'HP:0012740', (174, 183))	('p16Ink4a', 'Gene', (277, 285))	('C02.2', 'Var', (118, 123))	('C02.3)', 'Var', (129, 135))	('C02.1', 'Var', (111, 116))
527444	33047888	38  Among other TILs subpopulations, a high Th17/Treg ratio was found to be associated with better outcomes in OSCC.	('high', 'Var', (39, 43))	('TIL', 'Gene', '7096', (16, 19))	('Treg', 'Chemical', '-', (49, 53))	('TIL', 'Gene', (16, 19))	('OSCC', 'Disease', (111, 115))
527445	33047888	45  Taken together, these results suggest that high densities of CD3+ (pan T cell marker), CD4+ (T helper cell marker), and CD8+ (T cytotoxic cell marker) TILs are independent factors for favorable prognosis.	('TIL', 'Gene', '7096', (155, 158))	('CD4', 'Gene', (91, 94))	('CD8', 'Gene', (124, 127))	('CD8', 'Gene', '925', (124, 127))	('TIL', 'Gene', (155, 158))	('CD3+', 'Var', (65, 69))	('CD4', 'Gene', '920', (91, 94))
527496	31717887	Cancer cell lines have been cultured in vitro for a long time, leading to the acquisition of additional genetic aberrations and epigenetic modifications that can dramatically differ from the original cancers.	('pig', 'Species', '9823', (129, 132))	('genetic aberrations', 'Var', (104, 123))	('cancers', 'Disease', 'MESH:D009369', (200, 207))	('cancers', 'Phenotype', 'HP:0002664', (200, 207))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('cancers', 'Disease', (200, 207))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('epigenetic modifications', 'Var', (128, 152))	('Cancer', 'Disease', (0, 6))	('rat', 'Species', '10116', (116, 119))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))
527518	31717887	Recent developments in and convergence of cancer biology, "-omics" technologies, computational biology and drug development are revolutionizing targeted therapy and leading to a new level of precision cancer medicine in which cancer treatment is designed to target the underlying genetic and epigenetic alterations of individual cancers.	('cancer', 'Phenotype', 'HP:0002664', (329, 335))	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('cancer', 'Disease', (201, 207))	('cancers', 'Phenotype', 'HP:0002664', (329, 336))	('cancers', 'Disease', (329, 336))	('cancer', 'Disease', (329, 335))	('cancer', 'Disease', 'MESH:D009369', (329, 335))	('cancers', 'Disease', 'MESH:D009369', (329, 336))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', (226, 232))	('pig', 'Species', '9823', (293, 296))	('cancer', 'Disease', 'MESH:D009369', (226, 232))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('epigenetic alterations', 'Var', (292, 314))	('rat', 'Species', '10116', (307, 310))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
527520	31717887	For example, response rates of approximately 70% were observed when targeted therapies are used against epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) gene fusion in those patients, compared to less than 30% for cytotoxic chemotherapy.	('ALK', 'Gene', '238', (185, 188))	('patients', 'Species', '9606', (211, 219))	('EGFR', 'Gene', '1956', (138, 142))	('rat', 'Species', '10116', (22, 25))	('anaplastic lymphoma kinase', 'Gene', (157, 183))	('epidermal growth factor receptor', 'Gene', (104, 136))	('EGFR', 'Gene', (138, 142))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (157, 176))	('lymphoma', 'Phenotype', 'HP:0002665', (168, 176))	('ALK', 'Gene', (185, 188))	('epidermal growth factor receptor', 'Gene', '1956', (104, 136))	('mutations', 'Var', (144, 153))	('anaplastic lymphoma kinase', 'Gene', '238', (157, 183))
527525	31717887	Little efficacy was observed when a PI3K inhibitor is used in treating lung squamous cell carcinoma carrying PI3K activation mutations.	('mutations', 'Var', (125, 134))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (76, 99))	('PI3K', 'Gene', (109, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (71, 99))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (71, 99))	('lung squamous cell carcinoma', 'Disease', (71, 99))
527547	31717887	The culture method can rapidly convert normal and tumor cells to a state of "reprogrammed stem-like" in which the cells are highly proliferative and maintain their original karyotypes; moreover, the removal of these conditions restores the capacity for cell differentiation.	('rat', 'Species', '10116', (138, 141))	('removal', 'Var', (199, 206))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('cell differentiation', 'CPA', (253, 273))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('restores', 'PosReg', (227, 235))	('tumor', 'Disease', (50, 55))
527561	31717887	The patient was 60-year-old white female, with pathologic T3N0 squamous cell carcinoma of the left tongue, non-smoker, non-drinker.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (63, 86))	('squamous cell carcinoma', 'Disease', (63, 86))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (63, 86))	('patient', 'Species', '9606', (4, 11))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('T3N0', 'Var', (58, 62))
527566	31717887	Karyotypic analysis of the CRCs performed at early passages resulted in a diploid karyotype (46, XX) with no apparent chromosomal alterations in the non-malignant line (Figure 1B).	('rat', 'Species', '10116', (134, 137))	('resulted in', 'Reg', (60, 71))	('46, XX', 'Var', (93, 99))
527567	31717887	In contrast, the malignant line revealed a highly aneuploid karyotype with near-triploid clone and a modal number of chromosomes of 74 displaying aberrations in the majority of the chromosomes with variations that included number: trisomy 4, 5, 10, 12, 18, 20, 21, 22 and X; tetrasomy 2, 3, 6, 7, 11, 16, 17, 19 and pentasomy 1; as well as structural abnormalities such as fusions in chromosomes 3, 10, 18 (Figure 1B).	('trisomy', 'Var', (231, 238))	('aneuploid', 'Disease', (50, 59))	('pentasomy', 'Disease', (316, 325))	('structural abnormalities', 'Disease', 'MESH:C566527', (340, 364))	('rat', 'Species', '10116', (150, 153))	('aneuploid', 'Disease', 'MESH:D000782', (50, 59))	('fusions', 'Var', (373, 380))	('variations', 'Var', (198, 208))	('structural abnormalities', 'Disease', (340, 364))
527621	31717887	For example, CR cells identified LA-12 enhanced cell death by TRAIL, and combinational treatment of TRAIL with cisplatin/LA-12 killed prostate cancer cells more effectively.	('death', 'Disease', 'MESH:D003643', (53, 58))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('death', 'Disease', (53, 58))	('cisplatin', 'Chemical', 'MESH:D002945', (111, 120))	('TRAIL', 'Gene', '8743', (62, 67))	('TRAIL', 'Gene', '8743', (100, 105))	('prostate cancer', 'Disease', (134, 149))	('LA-12', 'Chemical', '-', (121, 126))	('TRAIL', 'Gene', (62, 67))	('TRAIL', 'Gene', (100, 105))	('LA-12', 'Chemical', '-', (33, 38))	('prostate cancer', 'Disease', 'MESH:D011471', (134, 149))	('prostate cancer', 'Phenotype', 'HP:0012125', (134, 149))	('LA-12', 'Var', (33, 38))	('enhanced', 'PosReg', (39, 47))
527628	31717887	For instance, CRISPR-Cas9 genetic editing of CR cells revealed the pro-inflammatory effects of MUC18 in airway epithelial cells and the role of the NLRP1 Inflammasome in UVB sensing in human primary keratinocytes.	('rat', 'Species', '10116', (201, 204))	('pro-inflammatory effects', 'MPA', (67, 91))	('NLRP1', 'Gene', (148, 153))	('human', 'Species', '9606', (185, 190))	('MUC18', 'Gene', (95, 100))	('MUC18', 'Gene', '4162', (95, 100))	('genetic', 'Var', (26, 33))	('NLRP1', 'Gene', '22861', (148, 153))
527657	31717887	identified that an anticancer candidate IDF-11774 interacted with ATP6V0C and synergized with the ATP6V0C inhibitor, bafilomycin A1, to inhibit CR colorectal cancer cells with low Bcl-2 expression, potentiating IDF-11774 for further clinical trials.	('colorectal cancer', 'Phenotype', 'HP:0003003', (147, 164))	('Bcl-2', 'Gene', (180, 185))	('colorectal cancer', 'Disease', (147, 164))	('ATP6V0C', 'Gene', (98, 105))	('Bcl-2', 'Gene', '596', (180, 185))	('inhibit', 'NegReg', (136, 143))	('IDF-11774', 'Var', (40, 49))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('ATP6V0C', 'Gene', (66, 73))	('cancer', 'Disease', (23, 29))	('cancer', 'Disease', 'MESH:D009369', (23, 29))	('cancer', 'Disease', (158, 164))	('ATP6V0C', 'Gene', '527', (98, 105))	('colorectal cancer', 'Disease', 'MESH:D015179', (147, 164))	('bafilomycin A1', 'Chemical', 'MESH:C040929', (117, 131))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('ATP6V0C', 'Gene', '527', (66, 73))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
527679	29190949	The binding of PD-1 to its ligand, programmed cell death-ligand 1, induces apoptosis or exhaustion in activated T cells, and inhibition of this interaction enhances the antitumor activity of T cells.	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('enhances', 'PosReg', (156, 164))	('binding', 'Interaction', (4, 11))	('apoptosis', 'CPA', (75, 84))	('exhaustion', 'MPA', (88, 98))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumor', 'Disease', (173, 178))	('induces', 'Reg', (67, 74))	('inhibition', 'Var', (125, 135))	('PD-1', 'Gene', (15, 19))
527706	29190949	The median number of CD3+, CD4+, and CD8+ TILs were 50 (range: 0-383), 21 (range: 0-186), and 36 (range: 0-347), respectively; these values were used to discriminate patients with high or low TIL density.	('CD8', 'Gene', (37, 40))	('CD4', 'Gene', (27, 30))	('CD4', 'Gene', '920', (27, 30))	('CD8', 'Gene', '925', (37, 40))	('CD3+', 'Var', (21, 25))	('patients', 'Species', '9606', (166, 174))
527714	29190949	In contrast, CD3+ or CD8+ TIL density was significantly correlated with HLA class I expression (p = 0.020 and p = 0.020, respectively).	('CD8', 'Gene', (21, 24))	('CD3+', 'Var', (13, 17))	('HLA class I', 'Protein', (72, 83))	('CD8', 'Gene', '925', (21, 24))	('expression', 'MPA', (84, 94))	('correlated', 'Reg', (56, 66))
527719	29190949	HLA class I expression was not included in the multivariate analysis because it was significantly correlated with PD-L1 expression, CD3+ TIL density, or CD8+ TIL density (p = 0.030, 0.020, and 0.020, respectively).	('CD8', 'Gene', (153, 156))	('PD-L1', 'Gene', (114, 119))	('expression', 'MPA', (120, 130))	('CD3+ TIL density', 'Var', (132, 148))	('CD8', 'Gene', '925', (153, 156))	('CD3+ TIL', 'Chemical', '-', (132, 140))	('correlated', 'Reg', (98, 108))
527723	29190949	A Kaplan-Meier analysis was performed to evaluate whether PD-L1 or HLA class I expression and CD3+, CD4+, or CD8+ TIL density were associated with PFS or OS (Figure 2).	('PF', 'Chemical', 'MESH:C002997', (147, 149))	('CD3+', 'Var', (94, 98))	('CD8', 'Gene', (109, 112))	('CD4', 'Gene', (100, 103))	('CD8', 'Gene', '925', (109, 112))	('associated', 'Reg', (131, 141))	('HLA class I expression', 'Protein', (67, 89))	('CD4', 'Gene', '920', (100, 103))	('OS', 'Chemical', '-', (154, 156))	('PFS', 'Disease', (147, 150))	('PD-L1', 'Protein', (58, 63))
527725	29190949	Although the differences were not significant, patients with higher numbers of CD3+ TILs tended to have a longer PFS (high vs. low: median NR vs. 10.4 months; p = 0.062), but not OS (high vs. low: median NR vs. 28.4 months; p = 0.181).	('PFS', 'MPA', (113, 116))	('CD3+ TIL', 'Chemical', '-', (79, 87))	('patients', 'Species', '9606', (47, 55))	('PF', 'Chemical', 'MESH:C002997', (113, 115))	('CD3+ TILs', 'Var', (79, 88))	('OS', 'Chemical', '-', (179, 181))
527767	29190949	Based on our finding that the PD-L1-/CD8high group tended to have a better prognosis than the PD-L1+/CD8high group, it may be possible that PD-L1 expression could induce more efficient immune suppression than other immune escape mechanisms.	('CD8', 'Gene', '925', (101, 104))	('CD8', 'Gene', (37, 40))	('CD8', 'Gene', '925', (37, 40))	('PD-L1 expression', 'Var', (140, 156))	('CD8', 'Gene', (101, 104))	('immune suppression', 'CPA', (185, 203))
527769	29190949	The anti-PD-L1 antibody MPDL3280A has been reported to elicit improved clinical responses in patients with tumors that express high levels of PD-L1 and contain higher numbers of tumor-infiltrating immune cells.	('tumor', 'Disease', (178, 183))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('PD-L1', 'Protein', (142, 147))	('tumor', 'Disease', (107, 112))	('improved', 'PosReg', (62, 70))	('MPDL3280A', 'Var', (24, 33))	('tumors', 'Disease', (107, 113))	('tumors', 'Phenotype', 'HP:0002664', (107, 113))	('tumors', 'Disease', 'MESH:D009369', (107, 113))	('MPDL3280A', 'Chemical', 'MESH:C000594389', (24, 33))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('patients', 'Species', '9606', (93, 101))	('clinical responses', 'CPA', (71, 89))
527770	29190949	Similarly, it has been suggested that patients with tumor cells expressing PD-L1, as well as a high density of CD8+ TILs may achieve better outcomes via an anti-PD-1 blocking antibody.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumor', 'Disease', (52, 57))	('PD-L1', 'Var', (75, 80))	('anti-PD-1', 'Protein', (156, 165))	('patients', 'Species', '9606', (38, 46))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('CD8', 'Gene', (111, 114))	('CD8', 'Gene', '925', (111, 114))
527788	29190949	All patient samples for PD-L1 expression were divided into groups based on the TPS of < 1%, 1%-49%, and >= 50%, as detailed previously.	('1%-49%', 'Var', (92, 98))	('PD-L1', 'Gene', (24, 29))	('patient', 'Species', '9606', (4, 11))
527792	29190949	We determined the median values of CD3+, CD4+, and CD8+ TILs to define the cut-off value for TIL density.	('CD3+', 'Var', (35, 39))	('CD4', 'Gene', (41, 44))	('CD4', 'Gene', '920', (41, 44))	('CD8', 'Gene', (51, 54))	('CD8', 'Gene', '925', (51, 54))
527800	28069571	However, extreme CIN correlates with improved cancer outcome, suggesting that karyotypic diversity required to adapt to selection pressures might be balanced in tumors against the risk of excessive instability.	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('tumors', 'Disease', (161, 167))	('extreme', 'Var', (9, 16))	('CIN', 'Disease', (17, 20))	('cancer', 'Disease', (46, 52))	('tumors', 'Phenotype', 'HP:0002664', (161, 167))	('tumors', 'Disease', 'MESH:D009369', (161, 167))	('CIN', 'Disease', 'MESH:D007674', (17, 20))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('improved', 'PosReg', (37, 45))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('CIN', 'Phenotype', 'HP:0040012', (17, 20))
527804	28069571	Finally, CRISPR-mediated introduction of cancer somatic mutations in the APC/C subunit cancer driver gene CDC27 reduces chromosome segregation errors, whereas reversal of an APC/C subunit nonsense mutation increases CIN.	('CIN', 'Phenotype', 'HP:0040012', (216, 219))	('cancer', 'Disease', (87, 93))	('mutations', 'Var', (56, 65))	('APC', 'Gene', (174, 177))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('APC', 'Gene', '324', (174, 177))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('APC', 'Gene', (73, 76))	('CDC27', 'Gene', '996', (106, 111))	('chromosome segregation', 'CPA', (120, 142))	('increases CIN', 'Disease', 'MESH:D019586', (206, 219))	('cancer', 'Disease', (41, 47))	('increases CIN', 'Disease', (206, 219))	('CDC27', 'Gene', (106, 111))	('APC', 'Gene', '324', (73, 76))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('reduces', 'NegReg', (112, 119))
527806	28069571	We report a mechanism whereby cancers balance the evolutionary advantages associated with CIN against the fitness costs caused by excessive genome instability, providing insight into the consequence of CDC27 APC/C subunit driver mutations in cancer.	('APC', 'Gene', '324', (208, 211))	('cancer', 'Disease', (242, 248))	('cancer', 'Disease', 'MESH:D009369', (242, 248))	('CIN', 'Phenotype', 'HP:0040012', (90, 93))	('cancers', 'Phenotype', 'HP:0002664', (30, 37))	('CDC27', 'Gene', (202, 207))	('mutations', 'Var', (229, 238))	('cancer', 'Disease', (30, 36))	('cancers', 'Disease', (30, 37))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('cancers', 'Disease', 'MESH:D009369', (30, 37))	('cancer', 'Phenotype', 'HP:0002664', (242, 248))	('CIN against the fitness costs', 'Disease', 'MESH:D012640', (90, 119))	('CIN against the fitness costs', 'Disease', (90, 119))	('CDC27', 'Gene', '996', (202, 207))	('APC', 'Gene', (208, 211))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
527808	28069571	Chromosome missegregation leads to abrupt changes in gene expression and protein stoichiometry that result in a strong negative selection pressure when occurring in most diploid cell types, but which are tolerated in aneuploid cancer cells (reviewed in).	('negative', 'NegReg', (119, 127))	('Chromosome missegregation', 'Var', (0, 25))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('aneuploid cancer', 'Disease', (217, 233))	('aneuploid cancer', 'Disease', 'MESH:D000782', (217, 233))	('missegregation', 'Var', (11, 25))	('selection pressure', 'MPA', (128, 146))	('changes', 'Reg', (42, 49))
527812	28069571	Although CIN has been generally associated with poor prognosis, patient stratification based on the degree of CIN has revealed that extremes of CIN are associated with improved prognosis, lending credence to the "just-right" threshold of genomic instability sufficient for tumor adaptation proposed by Cahill and colleagues.	('CIN', 'Phenotype', 'HP:0040012', (144, 147))	('CIN', 'Disease', 'MESH:D007674', (9, 12))	('patient', 'Species', '9606', (64, 71))	('CIN', 'Phenotype', 'HP:0040012', (110, 113))	('improved', 'PosReg', (168, 176))	('tumor', 'Disease', 'MESH:D009369', (273, 278))	('CIN', 'Disease', (144, 147))	('CIN', 'Disease', 'MESH:D007674', (110, 113))	('CIN', 'Phenotype', 'HP:0040012', (9, 12))	('CIN', 'Disease', (110, 113))	('CIN', 'Disease', 'MESH:D007674', (144, 147))	('tumor', 'Phenotype', 'HP:0002664', (273, 278))	('tumor', 'Disease', (273, 278))	('prognosis', 'MPA', (177, 186))	('extremes', 'Var', (132, 140))	('CIN', 'Disease', (9, 12))
527814	28069571	Hence, selection could favor the attenuation of CIN in human cancer to prevent excessive genome instability while ensuring sufficient karyotypic instability to foster adaptation to a changing environment.	('CIN', 'Phenotype', 'HP:0040012', (48, 51))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('karyotypic', 'MPA', (134, 144))	('attenuation', 'Var', (33, 44))	('cancer', 'Disease', (61, 67))	('human', 'Species', '9606', (55, 60))	('CIN', 'Disease', (48, 51))	('CIN', 'Disease', 'MESH:D007674', (48, 51))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('genome instability', 'MPA', (89, 107))
527821	28069571	Reversine increased the error rate per chromosome pair per division in a dose-dependent manner, from 0.00027 in DMSO-treated cells (approximately 1 error per 165 divisions, assuming a diploid karyotype with equal error rates for all chromosomes) to 0.021 in 250 nmol/L (1 error per 2 divisions), 0.055 in 500 nmol/L (1.3 chromosome errors per division on average), 0.183 in 750 nmol/L (4.2 chromosomes per division), and 0.232 in 1 mumol/L reversine (5.3 chromosomes per division; Fig.	('Reversine', 'Chemical', 'MESH:C484369', (0, 9))	('DMSO', 'Chemical', 'MESH:D004121', (112, 116))	('0.021', 'Var', (249, 254))	('0.183', 'Var', (365, 370))	('reversine', 'Chemical', 'MESH:C484369', (440, 449))	('0.055', 'Var', (296, 301))	('error', 'MPA', (24, 29))	('0.232', 'Var', (421, 426))
527827	28069571	TP53 disruption provided a clear proliferative advantage in low concentrations of reversine (150-250 nmol/L) over a 72-hour period, but this difference was less pronounced when CIN levels were further increased (300-500 nmol/L; Fig.	('CIN', 'Disease', 'MESH:D007674', (177, 180))	('proliferative advantage', 'CPA', (33, 56))	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('disruption', 'Var', (5, 15))	('CIN', 'Phenotype', 'HP:0040012', (177, 180))	('CIN', 'Disease', (177, 180))	('reversine', 'Chemical', 'MESH:C484369', (82, 91))
527828	28069571	In a long-term assay, TP53 disruption enabled colony formation in 200 nmol/L reversine, whereas 500 nmol/L reversine severely impaired colony formation in both cell lines (Fig.	('enabled', 'PosReg', (38, 45))	('reversine', 'Chemical', 'MESH:C484369', (77, 86))	('colony formation', 'CPA', (46, 62))	('colony formation', 'CPA', (135, 151))	('disruption', 'Var', (27, 37))	('impaired', 'NegReg', (126, 134))	('TP53', 'Gene', '7157', (22, 26))	('reversine', 'Chemical', 'MESH:C484369', (107, 116))	('TP53', 'Gene', (22, 26))
527833	28069571	The screen identified seven subunits of the anaphase-promoting complex/cyclosome (APC/C) E3 ligase complex (CDC16, CDC23, CDC27, ANAPC1, ANAPC4, ANAPC5, ANAPC10), along with one of its E2 ligases UBE2C (UBCH10) whose knockdown conferred a proliferative advantage in reversine (Fig.	('ANAPC1', 'Gene', '64682', (153, 159))	('APC', 'Gene', (82, 85))	('UBE2C', 'Gene', (196, 201))	('CDC23', 'Gene', (115, 120))	('ANAPC1', 'Gene', '64682', (129, 135))	('APC', 'Gene', '324', (155, 158))	('CDC27', 'Gene', (122, 127))	('UBE2C', 'Gene', '11065', (196, 201))	('UBCH10', 'Gene', '11065', (203, 209))	('UBCH10', 'Gene', (203, 209))	('APC', 'Gene', '324', (147, 150))	('knockdown', 'Var', (217, 226))	('CDC16', 'Gene', '8881', (108, 113))	('APC', 'Gene', '324', (131, 134))	('APC', 'Gene', '324', (139, 142))	('ANAPC5', 'Gene', '51433', (145, 151))	('ANAPC5', 'Gene', (145, 151))	('APC', 'Gene', '324', (82, 85))	('ANAPC4', 'Gene', '29945', (137, 143))	('APC', 'Gene', (155, 158))	('ANAPC1', 'Gene', (153, 159))	('proliferative advantage in reversine', 'CPA', (239, 275))	('ANAPC10', 'Gene', (153, 160))	('ANAPC1', 'Gene', (129, 135))	('CDC23', 'Gene', '8697', (115, 120))	('reversine', 'Chemical', 'MESH:C484369', (266, 275))	('APC', 'Gene', (147, 150))	('ANAPC4', 'Gene', (137, 143))	('CDC27', 'Gene', '996', (122, 127))	('APC', 'Gene', (131, 134))	('CDC16', 'Gene', (108, 113))	('APC', 'Gene', (139, 142))	('ANAPC10', 'Gene', '10393', (153, 160))
527837	28069571	Of note, complete pharmacologic inhibition of the APC/C or genetic ablation of the co-activator CDC20 robustly arrests cells at metaphase, indicating that the RNAi conditions used here result in partial APC/C loss of function.	('CDC20', 'Gene', '991', (96, 101))	('APC', 'Gene', '324', (50, 53))	('arrests', 'NegReg', (111, 118))	('ablation', 'Var', (67, 75))	('APC', 'Gene', (203, 206))	('APC', 'Gene', '324', (203, 206))	('cells at metaphase', 'CPA', (119, 137))	('APC', 'Gene', (50, 53))	('CDC20', 'Gene', (96, 101))
527847	28069571	Depending on the cancer type, 0.7% to 22.9% of tumors harbored a nonsynonymous mutation in an APC/C subunit (median, 6%; average, 8%; Supplementary Table S3).	('tumors', 'Disease', (47, 53))	('tumors', 'Disease', 'MESH:D009369', (47, 53))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('APC', 'Gene', (94, 97))	('cancer', 'Disease', (17, 23))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('APC', 'Gene', '324', (94, 97))	('nonsynonymous mutation', 'Var', (65, 87))	('harbored', 'Reg', (54, 62))	('tumors', 'Phenotype', 'HP:0002664', (47, 53))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
527850	28069571	It is unusual to observe recurrent frameshift mutations such as the deletion creating L454Hfs*9, which may reflect an alignment error in the TCGA pipeline.	('L454Hfs*9', 'Mutation', 'p.L454HfsX9', (86, 95))	('L454Hfs*9', 'Gene', (86, 95))	('deletion', 'Var', (68, 76))
527853	28069571	Truncating mutations are also predicted to have a clear detrimental impact on APC/C complex structural integrity based on the atomic structure (see details below), and heterozygous mutations could lead to fewer active complexes in the cell.	('APC', 'Gene', (78, 81))	('Truncating mutations', 'Var', (0, 20))	('detrimental impact', 'Disease', 'MESH:D004834', (56, 74))	('active complexes', 'MPA', (211, 227))	('APC', 'Gene', '324', (78, 81))	('detrimental impact', 'Disease', (56, 74))	('fewer', 'NegReg', (205, 210))	('mutations', 'Var', (181, 190))
527854	28069571	In order to test if CDC27 truncating mutations confer a selective advantage during the onset of CIN, we used CRISPR/Cas9 to engineer three RPE1 populations carrying CDC27 frameshift mutations by infecting cells with a lentiCRISPR vector at a low multiplicity of infection (MOI; Fig.	('CDC27', 'Gene', (20, 25))	('CDC27', 'Gene', (165, 170))	('CIN', 'Disease', (96, 99))	('CDC27', 'Gene', '996', (20, 25))	('CDC27', 'Gene', '996', (165, 170))	('CIN', 'Disease', 'MESH:D007674', (96, 99))	('frameshift mutations', 'Var', (171, 191))	('CIN', 'Phenotype', 'HP:0040012', (96, 99))
527861	28069571	To further explore if CDC27 mutations found in cancer disrupt APC/C activity, we took advantage of the sequence similarity between human and Schizosaccharomyces pombe (fission yeast) proteins, and the possibility to assay mutations in a haploid context.	('fission yeast', 'Species', '4896', (168, 181))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('Schizosaccharomyces pombe', 'Species', '4896', (141, 166))	('APC', 'Gene', (62, 65))	('CDC27', 'Gene', '996', (22, 27))	('cancer', 'Disease', (47, 53))	('disrupt', 'Reg', (54, 61))	('APC', 'Gene', '324', (62, 65))	('human', 'Species', '9606', (131, 136))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('CDC27', 'Gene', (22, 27))	('mutations', 'Var', (28, 37))
527862	28069571	We tested a subset of mutations for which a homologous residue is found in S. pombe (NUC2 for CDC27), and assayed their ability to rescue lethality of NUC2 deletion in haploid spores (Supplementary Fig.	('CDC27', 'Gene', '996', (94, 99))	('rescue', 'PosReg', (131, 137))	('CDC27', 'Gene', (94, 99))	('NUC2', 'Gene', (151, 155))	('NUC2', 'Gene', (85, 89))	('NUC2', 'Gene', '996', (85, 89))	('lethality', 'MPA', (138, 147))	('NUC2', 'Gene', '996', (151, 155))	('S. pombe', 'Species', '4896', (75, 83))	('deletion', 'Var', (156, 164))
527863	28069571	Truncating NUC2 at position E600, which corresponds to one of the most C-terminal CDC27 nonsense mutations in human cancers (E736*), did not support growth (Fig.	('NUC2', 'Gene', '996', (11, 15))	('E736*', 'Var', (125, 130))	('CDC27', 'Gene', '996', (82, 87))	('human', 'Species', '9606', (110, 115))	('cancers', 'Disease', 'MESH:D009369', (116, 123))	('cancers', 'Phenotype', 'HP:0002664', (116, 123))	('CDC27', 'Gene', (82, 87))	('E736*', 'SUBSTITUTION', 'None', (125, 130))	('cancers', 'Disease', (116, 123))	('NUC2', 'Gene', (11, 15))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))
527864	28069571	Similarly, substituting the homologous residue in NUC2 to mimic CDC27 G506E caused lethality, whereas the R629K mutation resulted in slow growth with delayed cyclin B degradation in mitosis (Fig.	('delayed', 'NegReg', (150, 157))	('slow', 'NegReg', (133, 137))	('G506E', 'Var', (70, 75))	('NUC2', 'Gene', '996', (50, 54))	('cyclin B degradation', 'MPA', (158, 178))	('G506E', 'Mutation', 'p.G506E', (70, 75))	('CDC27', 'Gene', '996', (64, 69))	('R629K', 'Var', (106, 111))	('mitosis', 'Disease', (182, 189))	('mitosis', 'Disease', 'None', (182, 189))	('R629K', 'Mutation', 'rs1378929700', (106, 111))	('slow growth', 'Phenotype', 'HP:0001510', (133, 144))	('NUC2', 'Gene', (50, 54))	('CDC27', 'Gene', (64, 69))
527866	28069571	Examination of the human APC/C atomic structure revealed that the CDC27 G506E mutation would disrupt the IR tail binding site required for the interaction with the coactivators (CDH1 and CDC20) and with APC10.	('APC10', 'Gene', '10393', (203, 208))	('CDH1', 'Gene', (178, 182))	('G506E', 'Var', (72, 77))	('CDC27', 'Gene', '996', (66, 71))	('APC', 'Gene', (25, 28))	('CDH1', 'Gene', '999', (178, 182))	('disrupt', 'NegReg', (93, 100))	('CDC20', 'Gene', (187, 192))	('CDC27', 'Gene', (66, 71))	('CDC20', 'Gene', '991', (187, 192))	('APC', 'Gene', (203, 206))	('G506E', 'Mutation', 'p.G506E', (72, 77))	('APC', 'Gene', '324', (203, 206))	('APC', 'Gene', '324', (25, 28))	('IR tail binding site required for', 'MPA', (105, 138))	('human', 'Species', '9606', (19, 24))	('APC10', 'Gene', (203, 208))	('interaction', 'Interaction', (143, 154))
527867	28069571	In addition, truncating CDC27 at E736 would also reduce contact with the IR tail and WD40 domain of APC/C coactivators, with the IR tail of APC10, and with the CDC16 subunit.	('CDC16', 'Gene', (160, 165))	('CDC27', 'Gene', (24, 29))	('CDC16', 'Gene', '8881', (160, 165))	('APC', 'Gene', (140, 143))	('truncating', 'Var', (13, 23))	('APC', 'Gene', (100, 103))	('APC', 'Gene', '324', (140, 143))	('APC10', 'Gene', (140, 145))	('APC', 'Gene', '324', (100, 103))	('APC10', 'Gene', '10393', (140, 145))	('contact', 'Interaction', (56, 63))	('CDC27', 'Gene', '996', (24, 29))	('reduce', 'NegReg', (49, 55))
527868	28069571	E736* and any upstream CDC27 truncating mutations often found in cancer would therefore severely impair APC/C activity and likely behave as null alleles, in line with the lethality of NUC2 E600* in S. pombe.	('NUC2', 'Gene', '996', (184, 188))	('E736*', 'SUBSTITUTION', 'None', (0, 5))	('E600*', 'SUBSTITUTION', 'None', (189, 194))	('CDC27', 'Gene', '996', (23, 28))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('APC', 'Gene', (104, 107))	('E600*', 'Var', (189, 194))	('CDC27', 'Gene', (23, 28))	('APC', 'Gene', '324', (104, 107))	('S. pombe', 'Species', '4896', (198, 206))	('impair', 'NegReg', (97, 103))	('E736*', 'Var', (0, 5))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('NUC2', 'Gene', (184, 188))
527870	28069571	2B using three new CDC27 lentiCRISPR populations, including two that targeted the region around residue E736 and one designed to disrupt CDC27 near E468 (Fig.	('CDC27', 'Gene', (137, 142))	('E736', 'Var', (104, 108))	('CDC27', 'Gene', '996', (19, 24))	('CDC27', 'Gene', (19, 24))	('CDC27', 'Gene', '996', (137, 142))	('disrupt', 'NegReg', (129, 136))
527871	28069571	We found that truncating human CDC27 near E736 was just as efficient in conferring resistance to prolonged reversine treatment as upstream truncating mutations (Supplementary Fig.	('CDC27', 'Gene', '996', (31, 36))	('CDC27', 'Gene', (31, 36))	('human', 'Species', '9606', (25, 30))	('near E736', 'Var', (37, 46))	('reversine', 'Chemical', 'MESH:C484369', (107, 116))	('truncating', 'Var', (14, 24))	('resistance to prolonged reversine treatment', 'MPA', (83, 126))
527872	28069571	This confirms that all CDC27 truncating mutations reported in TCGA are likely to be functionally relevant (except Q793*, which has not been tested).	('truncating mutations', 'Var', (29, 49))	('CDC27', 'Gene', '996', (23, 28))	('CDC27', 'Gene', (23, 28))	('Q793*', 'SUBSTITUTION', 'None', (114, 119))	('Q793*', 'Var', (114, 119))
527874	28069571	Deleterious mutations in CDC27 and other APC/C subunits can therefore be selected for in cancer and impair APC/C activity.	('CDC27', 'Gene', (25, 30))	('APC', 'Gene', (41, 44))	('mutations', 'Var', (12, 21))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('APC', 'Gene', (107, 110))	('impair', 'NegReg', (100, 106))	('APC', 'Gene', '324', (41, 44))	('cancer', 'Disease', (89, 95))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('APC', 'Gene', '324', (107, 110))	('CDC27', 'Gene', '996', (25, 30))
527875	28069571	To examine the consequence of a CDC27 truncating mutation in unperturbed conditions, we engineered RPE1 cells in which one allele contained the single base deletion that creates the L454Hfs*9 truncation (Fig.	('CDC27', 'Gene', '996', (32, 37))	('truncation', 'MPA', (192, 202))	('L454Hfs*9', 'Mutation', 'p.L454HfsX9', (182, 191))	('CDC27', 'Gene', (32, 37))	('L454Hfs*9', 'Var', (182, 191))
527877	28069571	To gain further insight into the consequence of APC/C missense mutations, we analyzed the published APC/C structure to assess the impact of a subset of mutations on the structural integrity of the complex (Supplementary Table S5).	('missense mutations', 'Var', (54, 72))	('APC', 'Gene', (100, 103))	('APC', 'Gene', (48, 51))	('APC', 'Gene', '324', (100, 103))	('APC', 'Gene', '324', (48, 51))
527879	28069571	A total of 132 missense mutations were examined in various subunits, 93 of which affected residues that could be mapped onto the APC/C structure (; Supplementary Table S5).	('APC', 'Gene', '324', (129, 132))	('affected', 'Reg', (81, 89))	('residues', 'MPA', (90, 98))	('missense mutations', 'Var', (15, 33))	('APC', 'Gene', (129, 132))
527880	28069571	In total, 40 mutations are predicted to disrupt the structural integrity of the APC/C (Supplementary Table S5).	('APC', 'Gene', (80, 83))	('APC', 'Gene', '324', (80, 83))	('structural', 'MPA', (52, 62))	('disrupt', 'NegReg', (40, 47))	('mutations', 'Var', (13, 22))
527881	28069571	In summary, potentially deleterious missense mutations in several APC/C subunits are found in cancer.	('missense mutations', 'Var', (36, 54))	('APC', 'Gene', (66, 69))	('APC', 'Gene', '324', (66, 69))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('found', 'Reg', (85, 90))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
527882	28069571	The pharmacologic induction of CIN has been proposed as a therapeutic approach to target cancer cells, and several MPS1 inhibitors have been developed for this purpose, some of which are currently in drug development (clinicaltrials.gov identifiers NCT02366949, NCT02138812, and NCT02792465).	('NCT02792465', 'Var', (279, 290))	('NCT02138812', 'Var', (262, 273))	('CIN', 'Phenotype', 'HP:0040012', (31, 34))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('CIN', 'Disease', (31, 34))	('cancer', 'Disease', (89, 95))	('CIN', 'Disease', 'MESH:D007674', (31, 34))	('MPS1', 'Gene', '7272', (115, 119))	('MPS1', 'Gene', (115, 119))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
527883	28069571	In a previous study, recovery of HCT116 clones resistant to a lethal dose of the MPS1 inhibitor Compound-5 (Cpd-5) led to the identification of mutations in the MPS1 kinase domain that conferred resistance to various MPS1 inhibitors.	('MPS1', 'Gene', '7272', (81, 85))	('MPS1', 'Gene', '7272', (217, 221))	('MPS1', 'Gene', '7272', (161, 165))	('MPS1', 'Gene', (161, 165))	('MPS1', 'Gene', (81, 85))	('MPS1', 'Gene', (217, 221))	('resistance', 'MPA', (195, 205))	('conferred', 'Reg', (185, 194))	('HCT116', 'CellLine', 'CVCL:0291', (33, 39))	('mutations', 'Var', (144, 153))
527885	28069571	Here, we performed targeted exon sequencing of these six clones for TTK, TP53, UBE2C, and all APC/C subunits and found two of the six clones carried a CDC16R136H heterozygous mutation, which is a highly conserved arginine residue.	('CDC16R136H', 'Var', (151, 161))	('TP53', 'Gene', '7157', (73, 77))	('carried', 'Reg', (141, 148))	('UBE2C', 'Gene', '11065', (79, 84))	('UBE2C', 'Gene', (79, 84))	('TP53', 'Gene', (73, 77))	('arginine', 'Chemical', 'MESH:D001120', (213, 221))	('APC', 'Gene', (94, 97))	('APC', 'Gene', '324', (94, 97))	('TTK', 'Gene', (68, 71))	('TTK', 'Gene', '7272', (68, 71))
527886	28069571	Interestingly, R136H clones displayed a longer mitotic duration while grown in Cpd-5 compared with untreated parental cells, and Cpd-5 washout prolonged NEBD-anaphase duration, suggestive of disrupted APC/C activity (Fig.	('longer', 'PosReg', (40, 46))	('prolonged', 'PosReg', (143, 152))	('R136H', 'Mutation', 'p.R136H', (15, 20))	('R136H', 'Var', (15, 20))	('APC', 'Gene', (201, 204))	('NEBD-anaphase duration', 'CPA', (153, 175))	('prolonged NEBD', 'Phenotype', 'HP:0410246', (143, 157))	('mitotic duration', 'CPA', (47, 63))	('APC', 'Gene', '324', (201, 204))
527887	28069571	In contrast, as expected, mitotic duration was unchanged with or without Cpd-5 in a clone bearing a mutation in the MPS1 kinase domain (I531M, Fig.	('MPS1', 'Gene', '7272', (116, 120))	('I531M', 'Mutation', 'rs1483341123', (136, 141))	('I531M', 'Var', (136, 141))	('MPS1', 'Gene', (116, 120))	('mitotic duration', 'CPA', (26, 42))	('mutation in', 'Var', (100, 111))
527890	28069571	Genome doubling constitutes a precursor of CIN in several cancer types, and experimental models have also shown that genome-doubled (tetraploid) cells are tumorigenic and prone to CIN.	('tumor', 'Disease', 'MESH:D009369', (155, 160))	('CIN', 'Disease', 'MESH:D007674', (180, 183))	('genome-doubled', 'Var', (117, 131))	('CIN', 'Disease', (43, 46))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('CIN', 'Disease', 'MESH:D007674', (43, 46))	('CIN', 'Phenotype', 'HP:0040012', (180, 183))	('tumor', 'Disease', (155, 160))	('prone', 'Reg', (171, 176))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('CIN', 'Phenotype', 'HP:0040012', (43, 46))	('cancer', 'Disease', (58, 64))	('CIN', 'Disease', (180, 183))
527891	28069571	We found that APC/C subunit nonsynonymous point mutations occurred significantly more frequently in genome-doubled compared with non-genome-doubled tumors (58%; P = 0.005, Fisher exact test; Fig.	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('genome-doubled', 'Var', (100, 114))	('nonsynonymous point mutations', 'Var', (28, 57))	('APC', 'Gene', (14, 17))	('tumors', 'Disease', (148, 154))	('tumors', 'Disease', 'MESH:D009369', (148, 154))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('APC', 'Gene', '324', (14, 17))
527894	28069571	If uncorrected, merotely may result in lagging chromosomes during chromosome separation and is considered to constitute a major cause of CIN in cancer.	('merotely', 'Var', (16, 24))	('result in', 'Reg', (29, 38))	('CIN in cancer', 'Disease', (137, 150))	('CIN', 'Phenotype', 'HP:0040012', (137, 140))	('cause', 'Reg', (128, 133))	('lagging chromosomes during chromosome separation', 'CPA', (39, 87))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('CIN in cancer', 'Disease', 'MESH:D009369', (137, 150))
527896	28069571	Because cell-cycle progression beyond G1 is limited by p53 after tetraploidization, we performed these experiments in RPE1 cells where TP53 was disrupted using CRISPR/Cas9 (Supplementary Fig.	('p53', 'Gene', (55, 58))	('p53', 'Gene', '7157', (55, 58))	('TP53', 'Gene', '7157', (135, 139))	('disrupted', 'Var', (144, 153))	('TP53', 'Gene', (135, 139))	('cell-cycle', 'CPA', (8, 18))
527918	28069571	A larger proportion of APC/C-mutated than APC/C-wild-type tumors also carry a TP53 mutation in the cohort of nine cancer types analyzed (39% vs. 28%, P = 0.004; Fig.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumors', 'Disease', (58, 64))	('APC', 'Gene', '324', (23, 26))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('APC', 'Gene', (42, 45))	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('mutation', 'Var', (83, 91))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('TP53', 'Gene', '7157', (78, 82))	('TP53', 'Gene', (78, 82))	('APC', 'Gene', '324', (42, 45))	('APC', 'Gene', (23, 26))	('cancer', 'Disease', (114, 120))
527923	28069571	Similar results were obtained in two RPE1-independent p53-null populations following drug adaptation and washout using 2 mumol/L AZ3146, an MPS1 inhibitor structurally unrelated to reversine (Supplementary Fig.	('reversine', 'Chemical', 'MESH:C484369', (181, 190))	('MPS1', 'Gene', '7272', (140, 144))	('p53', 'Gene', (54, 57))	('MPS1', 'Gene', (140, 144))	('p53', 'Gene', '7157', (54, 57))	('AZ3146', 'Var', (129, 135))	('AZ3146', 'Chemical', '-', (129, 135))
527927	28069571	Targeted exon sequencing on the RPE1/p53-/- adapted population did not reveal the clonal expansion of an APC/C subunit mutation, suggesting APC/C attenuation through parallel pathways that may involve transcriptional or epigenetic deregulation.	('mutation', 'Var', (119, 127))	('APC', 'Gene', '324', (105, 108))	('APC', 'Gene', (140, 143))	('APC', 'Gene', '324', (140, 143))	('p53', 'Gene', (37, 40))	('p53', 'Gene', '7157', (37, 40))	('APC', 'Gene', (105, 108))	('attenuation', 'NegReg', (146, 157))
527930	28069571	To test whether partial APC/C inhibition could reduce the frequency of naturally occurring segregation errors in cancer cell lines, we chose three cell lines with a high frequency of anaphase lagging chromosomes (H2030 lung adenocarcinoma, U251 glioblastoma, and SW480 colon carcinoma).	('carcinoma', 'Phenotype', 'HP:0030731', (275, 284))	('glioblastoma', 'Disease', (245, 257))	('glioblastoma', 'Disease', 'MESH:D005909', (245, 257))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('H2030 lung adenocarcinoma', 'Disease', (213, 238))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('APC', 'Gene', (24, 27))	('SW480 colon carcinoma', 'Disease', 'MESH:D015179', (263, 284))	('glioblastoma', 'Phenotype', 'HP:0012174', (245, 257))	('carcinoma', 'Phenotype', 'HP:0030731', (229, 238))	('cancer', 'Disease', (113, 119))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (219, 238))	('APC', 'Gene', '324', (24, 27))	('SW480 colon carcinoma', 'Disease', (263, 284))	('H2030 lung adenocarcinoma', 'Disease', 'MESH:D000077192', (213, 238))	('U251', 'Var', (240, 244))
527933	28069571	These results suggest that impairing APC/C function can also reduce the rate of endogenous segregation errors in established CIN cancer cell lines.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('reduce', 'NegReg', (61, 67))	('APC', 'Gene', '324', (37, 40))	('CIN', 'Phenotype', 'HP:0040012', (125, 128))	('impairing', 'Var', (27, 36))	('APC', 'Gene', (37, 40))	('endogenous segregation errors', 'MPA', (80, 109))	('CIN cancer', 'Disease', 'MESH:D009369', (125, 135))	('CIN cancer', 'Disease', (125, 135))
527934	28069571	To substantiate this finding, we generated H2030 cells bearing a frameshift mutation in one allele of CDC27 (Fig.	('CDC27', 'Gene', '996', (102, 107))	('frameshift mutation', 'Var', (65, 84))	('H2030', 'CellLine', 'CVCL:1517', (43, 48))	('CDC27', 'Gene', (102, 107))
527938	28069571	6D guide 7, having demonstrated previously that all CDC27 truncating mutations disrupt APC/C activity).	('disrupt', 'Reg', (79, 86))	('CDC27', 'Gene', (52, 57))	('APC', 'Gene', (87, 90))	('truncating mutations', 'Var', (58, 78))	('APC', 'Gene', '324', (87, 90))	('CDC27', 'Gene', '996', (52, 57))
527939	28069571	Disruption of a single CDC27 allele significantly delayed mitosis compared with three wild-type clones isolated in parallel, and was also associated with a significant reduction in lagging chromosomes (Fig.	('CDC27', 'Gene', '996', (23, 28))	('lagging chromosomes', 'CPA', (181, 200))	('mitosis', 'Disease', (58, 65))	('CDC27', 'Gene', (23, 28))	('delayed', 'NegReg', (50, 57))	('mitosis', 'Disease', 'None', (58, 65))	('reduction', 'NegReg', (168, 177))	('Disruption', 'Var', (0, 10))
527940	28069571	Monoallelic disruption of an APC/C subunit is therefore sufficient to reduce naturally occurring chromosome segregation errors.	('APC', 'Gene', '324', (29, 32))	('chromosome segregation errors', 'CPA', (97, 126))	('Monoallelic disruption', 'Var', (0, 22))	('reduce', 'NegReg', (70, 76))	('APC', 'Gene', (29, 32))
527941	28069571	Finally, we took advantage of the CIN colorectal cancer cell line HT29, which carries an endogenous heterozygous nonsense mutation in the APC/C subunit CDC23 (also known as ANAPC8, amino acid position E245; Fig.	('HT29', 'CellLine', 'CVCL:0320', (66, 70))	('nonsense mutation', 'Var', (113, 130))	('E245', 'Var', (201, 205))	('APC', 'Gene', (175, 178))	('colorectal cancer', 'Phenotype', 'HP:0003003', (38, 55))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('APC', 'Gene', '324', (175, 178))	('ANAPC8', 'Gene', '8697', (173, 179))	('ANAPC8', 'Gene', (173, 179))	('CDC23', 'Gene', (152, 157))	('APC', 'Gene', (138, 141))	('APC', 'Gene', '324', (138, 141))	('CDC23', 'Gene', '8697', (152, 157))	('CIN colorectal cancer', 'Disease', 'MESH:D015179', (34, 55))	('CIN colorectal cancer', 'Disease', (34, 55))	('CIN', 'Phenotype', 'HP:0040012', (34, 37))
527943	28069571	Correction of the CDC23 E245* truncating mutation back to wild-type caused a modest decrease in mitotic duration, and a significant increase in the frequency of lagging chromosomes compared with three clones bearing a monoallelic E245* mutation (+/E245*; Fig.	('decrease', 'NegReg', (84, 92))	('mitotic duration', 'CPA', (96, 112))	('E245*', 'Var', (24, 29))	('increase', 'PosReg', (132, 140))	('CDC23', 'Gene', (18, 23))	('E245*', 'Var', (248, 253))	('truncating', 'MPA', (30, 40))	('CDC23', 'Gene', '8697', (18, 23))	('E245*', 'SUBSTITUTION', 'None', (230, 235))	('E245*', 'SUBSTITUTION', 'None', (24, 29))	('E245*', 'SUBSTITUTION', 'None', (248, 253))	('E245*', 'Var', (230, 235))
527944	28069571	Taken together, the mutational status of APC/C subunits can therefore directly affect chromosome segregation fidelity in cancer cells.	('affect', 'Reg', (79, 85))	('APC', 'Gene', (41, 44))	('chromosome segregation fidelity', 'CPA', (86, 117))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('APC', 'Gene', '324', (41, 44))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('mutational', 'Var', (20, 30))	('cancer', 'Disease', (121, 127))
527952	28069571	Mutations in APC/C subunits that would otherwise have very mild consequences on overall proliferation (in the range of 3 to 15 minutes over an 18- to 24-hour cell cycle) might thus efficiently reduce segregation errors following cellular perturbations that have been recognized as some of the most potent CIN-inducing defects, such as genome-doubling, merotelic attachment errors, and SAC dysfunction.	('reduce', 'NegReg', (193, 199))	('attachment error', 'Disease', 'MESH:D019962', (362, 378))	('APC', 'Gene', (13, 16))	('CIN', 'Disease', 'MESH:D007674', (305, 308))	('APC', 'Gene', '324', (13, 16))	('C dysfunction', 'Disease', 'MESH:C537418', (387, 400))	('Mutations', 'Var', (0, 9))	('genome-doubling', 'CPA', (335, 350))	('CIN', 'Phenotype', 'HP:0040012', (305, 308))	('segregation', 'MPA', (200, 211))	('attachment error', 'Disease', (362, 378))	('C dysfunction', 'Disease', (387, 400))	('CIN', 'Disease', (305, 308))
527955	28069571	In addition, we provide functional evidence for the role of truncating mutations in the colorectal cancer driver CDC27 in rescuing cells from excessive CIN when segregation errors are experimentally elevated using MPS1 inhibitors.	('MPS1', 'Gene', (214, 218))	('excessive CIN', 'Disease', 'MESH:D015835', (142, 155))	('colorectal cancer', 'Disease', (88, 105))	('truncating mutations', 'Var', (60, 80))	('colorectal cancer', 'Disease', 'MESH:D015179', (88, 105))	('CIN', 'Phenotype', 'HP:0040012', (152, 155))	('CDC27', 'Gene', '996', (113, 118))	('excessive CIN', 'Disease', (142, 155))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('colorectal cancer', 'Phenotype', 'HP:0003003', (88, 105))	('CDC27', 'Gene', (113, 118))	('MPS1', 'Gene', '7272', (214, 218))
527956	28069571	Importantly, monoallelic truncation of CDC27 in the CIN cell line H2030 significantly reduced the frequency of lagging chromosomes.	('CIN', 'Disease', 'MESH:D007674', (52, 55))	('reduced', 'NegReg', (86, 93))	('H2030', 'CellLine', 'CVCL:1517', (66, 71))	('CIN', 'Phenotype', 'HP:0040012', (52, 55))	('CDC27', 'Gene', '996', (39, 44))	('CDC27', 'Gene', (39, 44))	('CIN', 'Disease', (52, 55))	('monoallelic truncation', 'Var', (13, 35))
527957	28069571	Conversely, restoring the heterozygous CDC23 E245* mutation naturally occurring in the CIN colorectal cell line HT29 back to wild-type caused an increase in lagging chromosomes, further indicating that APC/C mutations have a direct impact on chromosome segregation fidelity in cells with CIN.	('CIN', 'Disease', 'MESH:D007674', (288, 291))	('E245*', 'Var', (45, 50))	('CDC23', 'Gene', '8697', (39, 44))	('impact', 'Reg', (232, 238))	('CIN', 'Phenotype', 'HP:0040012', (87, 90))	('APC', 'Gene', '324', (202, 205))	('E245*', 'SUBSTITUTION', 'None', (45, 50))	('CIN', 'Disease', 'MESH:D007674', (87, 90))	('CIN', 'Disease', (288, 291))	('CIN colorectal', 'Disease', (87, 101))	('HT29', 'CellLine', 'CVCL:0320', (112, 116))	('chromosome segregation fidelity', 'CPA', (242, 273))	('CDC23', 'Gene', (39, 44))	('CIN colorectal', 'Disease', 'MESH:D015179', (87, 101))	('lagging chromosomes', 'CPA', (157, 176))	('APC', 'Gene', (202, 205))	('increase', 'PosReg', (145, 153))	('CIN', 'Phenotype', 'HP:0040012', (288, 291))	('CIN', 'Disease', (87, 90))
527958	28069571	Our detailed analysis of cancer-derived APC/C mutations suggests that although the mutation frequency of the complex as a whole is not higher than would be expected by chance, many mutations are very likely to have a functional impact.	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('APC', 'Gene', '324', (40, 43))	('cancer', 'Disease', 'MESH:D009369', (25, 31))	('mutations', 'Var', (181, 190))	('cancer', 'Disease', (25, 31))	('APC', 'Gene', (40, 43))	('impact', 'Reg', (228, 234))
527959	28069571	Limiting CIN might also be important to facilitate long-term survival in genetic backgrounds permissive for CIN, such as in TP53-disrupted cells, a relevant observation because 39% of tumors with an APC/C mutation also carry a TP53 mutation.	('CIN', 'Disease', 'MESH:D007674', (9, 12))	('TP53', 'Gene', '7157', (227, 231))	('TP53', 'Gene', '7157', (124, 128))	('mutation', 'Var', (232, 240))	('CIN', 'Phenotype', 'HP:0040012', (108, 111))	('carry', 'Reg', (219, 224))	('APC', 'Gene', (199, 202))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('TP53', 'Gene', (124, 128))	('TP53', 'Gene', (227, 231))	('tumors', 'Disease', (184, 190))	('tumors', 'Disease', 'MESH:D009369', (184, 190))	('CIN', 'Phenotype', 'HP:0040012', (9, 12))	('tumors', 'Phenotype', 'HP:0002664', (184, 190))	('CIN', 'Disease', (108, 111))	('APC', 'Gene', '324', (199, 202))	('CIN', 'Disease', 'MESH:D007674', (108, 111))	('CIN', 'Disease', (9, 12))
527961	28069571	We propose that genetic and epigenetic alterations affecting the expression or integrity of several APC/C subunits could affect the complex processivity, offering parallel avenues to select for impaired activity following the onset of CIN.	('affect', 'Reg', (121, 127))	('complex processivity', 'MPA', (132, 152))	('CIN', 'Disease', 'MESH:D007674', (235, 238))	('APC', 'Gene', (100, 103))	('APC', 'Gene', '324', (100, 103))	('CIN', 'Phenotype', 'HP:0040012', (235, 238))	('genetic', 'Var', (16, 23))	('CIN', 'Disease', (235, 238))	('epigenetic alterations', 'Var', (28, 50))	('activity', 'MPA', (203, 211))
527963	28069571	A number of cancer drugs targeting mitotic processes, including paclitaxel, can lead to extreme CIN and cell death, raising the possibility that APC/C mutations might also be a resistance mechanism to other anticancer drugs that function by precipitating chromosome segregation errors.	('lead to', 'Reg', (80, 87))	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('cancer', 'Disease', 'MESH:D009369', (211, 217))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('cancer', 'Disease', (12, 18))	('cancer', 'Disease', (211, 217))	('CIN', 'Disease', (96, 99))	('APC', 'Gene', (145, 148))	('CIN', 'Phenotype', 'HP:0040012', (96, 99))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('paclitaxel', 'Chemical', 'MESH:D017239', (64, 74))	('CIN', 'Disease', 'MESH:D007674', (96, 99))	('cell death', 'CPA', (104, 114))	('mutations', 'Var', (151, 160))	('APC', 'Gene', '324', (145, 148))
527966	28069571	DNA-repair processes are upregulated in choroid plexus carcinoma, a type of brain tumor harboring extensive somatic DNA copy-number alterations, and focal amplification of syntenic genes with roles in DNA repair found to be important for tumor maintenance was proposed to help stabilize cancer cells following the acquisition of extensive rearrangements.	('cancer', 'Disease', (287, 293))	('tumor', 'Phenotype', 'HP:0002664', (238, 243))	('choroid plexus carcinoma', 'Disease', (40, 64))	('cancer', 'Phenotype', 'HP:0002664', (287, 293))	('tumor', 'Disease', (82, 87))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('choroid plexus carcinoma', 'Phenotype', 'HP:0030392', (40, 64))	('cancer', 'Disease', 'MESH:D009369', (287, 293))	('carcinoma', 'Phenotype', 'HP:0030731', (55, 64))	('upregulated', 'PosReg', (25, 36))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumor', 'Disease', (238, 243))	('focal amplification', 'Var', (149, 168))	('DNA-repair', 'MPA', (0, 10))	('brain tumor', 'Phenotype', 'HP:0030692', (76, 87))	('choroid plexus carcinoma', 'Disease', 'MESH:D020288', (40, 64))	('tumor', 'Disease', 'MESH:D009369', (238, 243))	('brain tumor', 'Disease', (76, 87))	('brain tumor', 'Disease', 'MESH:D001932', (76, 87))
527971	28069571	All cell lines used in this study were obtained from the ATCC unless stated otherwise and reauthenticated by the London Research Institute's Cell Services core facility (now Francis Crick Institute) by short tandem repeat DNA profiling (hTERT-RPE-1, June 2015; HCT116 from ECACC, February 2015; HCT116 wild-type (+/+) and p53-/-, June 2010, a generous gift from Bert Vogelstein; H2030, October 2015; U251, January 2015; SW480, October 2015; HT29, June 2016) and regularly tested to confirm absence of Mycoplasma.	('HCT116', 'CellLine', 'CVCL:0291', (295, 301))	('absence of Mycoplasma', 'Disease', (490, 511))	('HT29', 'CellLine', 'CVCL:0320', (441, 445))	('absence of Mycoplasma', 'Disease', 'MESH:D004832', (490, 511))	('H2030', 'CellLine', 'CVCL:1517', (379, 384))	('HCT116', 'CellLine', 'CVCL:0291', (261, 267))	('H2030', 'Var', (379, 384))	('hTERT-RPE-1', 'CellLine', 'CVCL:4388', (237, 248))	('p53', 'Gene', '7157', (322, 325))	('p53', 'Gene', (322, 325))	('SW480', 'CellLine', 'CVCL:0546', (420, 425))
527996	28069571	For precise genome editing, CDC27 guide 7 or the CDC23 gRNA below was cloned into eSpCas9(1.1) (gift from Feng Zhang, Addgene #71814) which expresses a mutant Cas9 with improved specificity compared with wild-type Cas9.	('Cas9', 'Gene', (159, 163))	('CDC27', 'Gene', (28, 33))	('specificity', 'MPA', (178, 189))	('CDC23', 'Gene', (49, 54))	('mutant', 'Var', (152, 158))	('CDC23', 'Gene', '8697', (49, 54))	('improved', 'PosReg', (169, 177))	('CDC27', 'Gene', '996', (28, 33))
528007	28069571	Ninety-three of the 132 APC/C subunit mutations affected residues that were resolved on the APC/C atomic structure (PDB: 4UI9).	('APC', 'Gene', (92, 95))	('APC', 'Gene', (24, 27))	('APC', 'Gene', '324', (92, 95))	('affected', 'Reg', (48, 56))	('APC', 'Gene', '324', (24, 27))	('mutations', 'Var', (38, 47))
528009	28069571	The heterozygous NUC2 deletion strain was derived from the Bioneer collection.	('deletion', 'Var', (22, 30))	('NUC2', 'Gene', (17, 21))	('NUC2', 'Gene', '996', (17, 21))
528049	26538877	Nagy et al., contended that since alteration in the oral microflora demographics consequently led to local and systemic infections in patients suffering from oral neoplasms, an investigative study on the inhibition of biofilm present on the surfaces of oral squamous cell carcinomas (OSCC's) was warranted.	('neoplasms', 'Phenotype', 'HP:0002664', (163, 172))	('oral neoplasms', 'Disease', (158, 172))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (258, 281))	('led to', 'Reg', (94, 100))	('alteration', 'Var', (34, 44))	('oral neoplasms', 'Disease', 'MESH:D009062', (158, 172))	('oral squamous cell carcinomas', 'Disease', 'MESH:D002294', (253, 282))	('patients', 'Species', '9606', (134, 142))	('oral squamous cell carcinomas', 'Disease', (253, 282))	('neoplasm', 'Phenotype', 'HP:0002664', (163, 171))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (258, 282))	('systemic infections', 'Disease', 'MESH:D034721', (111, 130))	('carcinoma', 'Phenotype', 'HP:0030731', (272, 281))	('systemic infections', 'Disease', (111, 130))	('carcinomas', 'Phenotype', 'HP:0030731', (272, 282))
528060	26538877	The authors state that alterations in tumor-cell receptors could change the adhesion of some species of bacteria.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('adhesion', 'MPA', (76, 84))	('change', 'Reg', (65, 71))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('alterations', 'Var', (23, 34))
528111	26538877	They maintained that certain strains of HPV have been shown to be etiologically related to the development of uterine cervical and other genital cancers, but their plausible involvement in the development of malignancies at other sites is still a question mark.	('related', 'Reg', (80, 87))	('malignancies', 'Disease', (208, 220))	('strains', 'Var', (29, 36))	('genital cancers', 'Disease', (137, 152))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('genital cancers', 'Disease', 'MESH:D009369', (137, 152))	('uterine cervical', 'Disease', (110, 126))	('HPV', 'Species', '10566', (40, 43))	('malignancies', 'Disease', 'MESH:D009369', (208, 220))	('etiologically', 'Reg', (66, 79))	('cancers', 'Phenotype', 'HP:0002664', (145, 152))	('HPV', 'Gene', (40, 43))
528151	26538877	They further postulated that the progression of the activated cell into a tumorigenic cell might be linked to the amplification and over-expression of oncogenes.	('oncogenes', 'Protein', (151, 160))	('amplification', 'Var', (114, 127))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('linked', 'Reg', (100, 106))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('over-expression', 'PosReg', (132, 147))	('tumor', 'Disease', (74, 79))
528155	26538877	Thus, it can be postulated that C. albicans in association with tobacco will enhance the process of carcinogenesis.	('carcinogenesis', 'Disease', (100, 114))	('tobacco', 'Species', '4097', (64, 71))	('enhance', 'PosReg', (77, 84))	('C. albicans', 'Species', '5476', (32, 43))	('carcinogenesis', 'Disease', 'MESH:D063646', (100, 114))	('C. albicans', 'Var', (32, 43))
528190	33637109	In our previous work, we have shown that the methylation status of two genes, ASC/TMS1/PYCARD (apoptosis-associated speck-like protein containing a caspase recruitment domain) and MyD88 (Myeloid differentiation primary response protein 88), could be considered as a promising biomarker in non-small cell lung cancer (NSCLC) in distinguishing healthy from tumor tissue.	('NSCLC', 'Disease', (317, 322))	('MyD88', 'Gene', (180, 185))	('NSCLC', 'Phenotype', 'HP:0030358', (317, 322))	('lung cancer', 'Phenotype', 'HP:0100526', (304, 315))	('ASC', 'Gene', '29108', (78, 81))	('tumor', 'Phenotype', 'HP:0002664', (355, 360))	('non-small cell lung cancer', 'Disease', (289, 315))	('TMS1', 'Gene', '29108', (82, 86))	('methylation', 'Var', (45, 56))	('PYCARD', 'Gene', (87, 93))	('ASC', 'Gene', (78, 81))	('tumor', 'Disease', 'MESH:D009369', (355, 360))	('TMS1', 'Gene', (82, 86))	('cancer', 'Phenotype', 'HP:0002664', (309, 315))	('MyD88', 'Gene', '4615', (180, 185))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (289, 315))	('PYCARD', 'Gene', '29108', (87, 93))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (293, 315))	('tumor', 'Disease', (355, 360))	('NSCLC', 'Disease', 'MESH:D002289', (317, 322))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (289, 315))
528191	33637109	We found that both genes are hypomethylated in tumor tissue when compared to adjacent non-tumor tissue.	('hypomethylated', 'Var', (29, 43))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('tumor', 'Disease', (47, 52))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
528192	33637109	Furthermore, we found that the methylation status of tested genes in tumor tissue could be used as a potential prognostic biomarker in patients with early-stage NSCLC because hypomethylation of specific CpG sites in ASC/TMS1/PYCARD gene was associated with reduced overall survival.	('NSCLC', 'Disease', 'MESH:D002289', (161, 166))	('hypomethylation', 'Var', (175, 190))	('patients', 'Species', '9606', (135, 143))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('ASC', 'Gene', (216, 219))	('reduced', 'NegReg', (257, 264))	('TMS1', 'Gene', (220, 224))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('tumor', 'Disease', (69, 74))	('PYCARD', 'Gene', '29108', (225, 231))	('ASC', 'Gene', '29108', (216, 219))	('NSCLC', 'Phenotype', 'HP:0030358', (161, 166))	('TMS1', 'Gene', '29108', (220, 224))	('NSCLC', 'Disease', (161, 166))	('overall survival', 'MPA', (265, 281))	('PYCARD', 'Gene', (225, 231))
528202	33637109	Locations of the tested CpG sites in the ASC/TMS1/PYCARD gene are as follows: CpG1 + 52; CpG2 + 49; CpG3 + 33; CpG4-134; CpG5-129; CpG6-76; CpG7-71; CpG8-65.	('CpG5-129', 'Var', (121, 129))	('CpG2 + 49', 'Var', (89, 98))	('CpG7-71; CpG8-65', 'Var', (140, 156))	('ASC', 'Gene', (41, 44))	('PYCARD', 'Gene', '29108', (50, 56))	('TMS1', 'Gene', (45, 49))	('CpG6-76', 'Var', (131, 138))	('CpG4-134', 'Var', (111, 119))	('CpG1 + 52', 'Var', (78, 87))	('TMS1', 'Gene', '29108', (45, 49))	('ASC', 'Gene', '29108', (41, 44))	('CpG8-65', 'Var', (149, 156))	('CpG3 + 33', 'Var', (100, 109))	('PYCARD', 'Gene', (50, 56))
528203	33637109	Locations of the tested CpG sites in the MyD88 gene are as follows: CpG1-253; CpG2-256; CpG3-267; CpG4-278; CpG5-210; CpG6-216; CpG7-222; CpG8-146; CpG9-151; CpG10-167.	('CpG7-222', 'Var', (128, 136))	('CpG4-278', 'Var', (98, 106))	('MyD88', 'Gene', (41, 46))	('CpG8-146', 'Var', (138, 146))	('CpG2-256', 'Var', (78, 86))	('CpG6-216', 'Var', (118, 126))	('MyD88', 'Gene', '4615', (41, 46))	('CpG1-253', 'Var', (68, 76))	('CpG3-267', 'Var', (88, 96))	('CpG5-210', 'Var', (108, 116))	('CpG9-151; CpG10-167', 'Var', (148, 167))	('CpG10-167', 'Var', (158, 167))
528206	33637109	We have shown that ASC/TMS1/PYCARD_CpG8 (located - 65 upstream) is significantly hypermethylated in primary HNSCC (11.47%) in comparison to LuSCC (4.65%) (p < 0.0001) (Fig.	('ASC', 'Gene', '29108', (19, 22))	('PYCARD', 'Gene', (28, 34))	('hypermethylated', 'Var', (81, 96))	('TMS1', 'Gene', '29108', (23, 27))	('HNSCC', 'Phenotype', 'HP:0012288', (108, 113))	('LuSCC', 'Phenotype', 'HP:0030359', (140, 145))	('PYCARD', 'Gene', '29108', (28, 34))	('ASC', 'Gene', (19, 22))	('TMS1', 'Gene', (23, 27))	('primary HNSCC', 'Disease', (100, 113))
528221	33514352	Molecular alterations such as cancer driver gene mutational status and expression signatures have been implicated in LC prognosis; meanwhile, there have been emerging evidence that support the prognostic value of epigenetic alterations, which remains to be fully elucidated.	('LC', 'Phenotype', 'HP:0100526', (117, 119))	('cancer', 'Disease', (30, 36))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('epigenetic alterations', 'Var', (213, 235))	('implicated', 'Reg', (103, 113))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
528227	33514352	In total, 193 and 46 mutations were detected in 75 (68%) LC patients and 33 (42%) BLN plasma cfDNA, respectively (Supplementary Fig.	('LC', 'Phenotype', 'HP:0100526', (57, 59))	('patients', 'Species', '9606', (60, 68))	('detected', 'Reg', (36, 44))	('mutations', 'Var', (21, 30))
528228	33514352	Since some variants might derive from clonal hematopoiesis (CH) and confound the mutational analysis, genomic DNA (gDNA) of white blood cell (WBC) from cfDNA mutation-positive participants was also sequenced.	('variants', 'Var', (11, 19))	('hematopoiesis', 'Disease', (45, 58))	('participants', 'Species', '9606', (176, 188))	('hematopoiesis', 'Disease', 'MESH:C536227', (45, 58))
528229	33514352	Non-synonymous variants were detected in WBC of 73 (97%) LC patients and 33 (100%) BLN patients respectively (Supplementary Fig.	('Non-synonymous variants', 'Var', (0, 23))	('patients', 'Species', '9606', (60, 68))	('detected', 'Reg', (29, 37))	('LC', 'Phenotype', 'HP:0100526', (57, 59))	('patients', 'Species', '9606', (87, 95))
528230	33514352	Among WBC-shared cfDNA variants, the most frequently mutated genes included TP53, CBL, APOB, and CSMD3 for LC plasma, and CBL, CSMD3, and STAT3 for BLN plasma (Supplementary Fig.	('CSMD3', 'Gene', (127, 132))	('CSMD3', 'Gene', '114788', (127, 132))	('STAT3', 'Gene', (138, 143))	('CBL', 'Gene', '867', (82, 85))	('CBL', 'Gene', (122, 125))	('CSMD3', 'Gene', (97, 102))	('CBL', 'Gene', '867', (122, 125))	('CSMD3', 'Gene', '114788', (97, 102))	('TP53', 'Gene', '7157', (76, 80))	('LC', 'Phenotype', 'HP:0100526', (107, 109))	('cfDNA', 'Gene', (17, 22))	('APOB', 'Gene', '338', (87, 91))	('APOB', 'Gene', (87, 91))	('TP53', 'Gene', (76, 80))	('variants', 'Var', (23, 31))	('STAT3', 'Gene', '6774', (138, 143))	('CBL', 'Gene', (82, 85))
528231	33514352	Notably, a number of these mutations were hotspot mutations of cancer driver genes (Supplementary Fig.	('mutations', 'Var', (27, 36))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('cancer', 'Disease', (63, 69))	('cancer', 'Disease', 'MESH:D009369', (63, 69))
528236	33514352	These results revealed that, in contrast to common belief, plasma cfDNA from BLN patients also carried genomic sequence alterations including mutations in cancer driver genes, albeit less frequently.	('mutations', 'Var', (142, 151))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('patients', 'Species', '9606', (81, 89))	('genomic', 'MPA', (103, 110))	('carried', 'Reg', (95, 102))	('cancer', 'Disease', (155, 161))	('cancer', 'Disease', 'MESH:D009369', (155, 161))
528240	33514352	To quantify the cfDNA mutational burden, we constructed a mutation score for each cfDNA sample as either a simple summation of the allele fractions of all variants identified (SUMAF), or a weighted sum of the allele fractions, weighting more on TCGA hotspot cancer driver mutations and COSMIC hotspot mutations (weighted SUMAF, or wSUMAF; see Methods for details).	('mutations', 'Var', (272, 281))	('cancer', 'Phenotype', 'HP:0002664', (258, 264))	('variants', 'Var', (155, 163))	('TCGA', 'Gene', (245, 249))	('cancer', 'Disease', 'MESH:D009369', (258, 264))	('cancer', 'Disease', (258, 264))
528241	33514352	Our work obtained from a larger sample size (128 LC and 94 BLN plasma) suggested that genomic sequence alterations in cancer driver genes carried by BLN cfDNA might be more prevalent than previously thought, therefore limiting the utility of mutation-based diagnostic assays.	('cancer', 'Disease', (118, 124))	('LC', 'Phenotype', 'HP:0100526', (49, 51))	('prevalent', 'Reg', (173, 182))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('BLN', 'Var', (149, 152))	('cfDNA', 'Gene', (153, 158))	('limiting', 'NegReg', (218, 226))	('cancer', 'Disease', 'MESH:D009369', (118, 124))
528258	33514352	The multi-omics predictive models based on the combination of wSUMAF mutation score, regional methylation ratio of 54 selected DMRs, and the serum CEA level achieved an AUC of 0.78, with 76.9% sensitivity and 58.3% specificity (Fig.	('CEA', 'Gene', '1084', (147, 150))	('mutation', 'Var', (69, 77))	('wSUMAF', 'Gene', (62, 68))	('DMRs', 'Chemical', '-', (127, 131))	('CEA', 'Gene', (147, 150))
528267	33514352	Patients with a high mutational burden and a high MPS were categorized as the high prognosis score group, which had a significantly worse OS than the low prognosis score group in the testing set (Fig.	('MPS', 'Disease', 'MESH:D009084', (50, 53))	('high mutational burden', 'Var', (16, 38))	('MPS', 'Disease', (50, 53))	('Patients', 'Species', '9606', (0, 8))
528268	33514352	Finally, to avoid information loss due to categorization, we modeled both mutation score and MPS continuously in two multivariate Cox proportional hazard models on wSUMAF only, as well as in combination with MPS.	('mutation', 'Var', (74, 82))	('MPS', 'Disease', 'MESH:D009084', (208, 211))	('MPS', 'Disease', (93, 96))	('MPS', 'Disease', (208, 211))	('MPS', 'Disease', 'MESH:D009084', (93, 96))
528270	33514352	We found that the combination of genetic and epigenetic features of cfDNA along with serum protein marker CEA showed the best classification capability to differentiate the malignant vs. benign cases.	('cfDNA', 'Disease', (68, 73))	('CEA', 'Gene', '1084', (106, 109))	('CEA', 'Gene', (106, 109))	('epigenetic', 'Var', (45, 55))
528271	33514352	Also, an integrated model that combined cfDNA mutational status and methylation-based prognostic markers has potential to improve prediction for lung cancer survival.	('lung cancer', 'Disease', 'MESH:D008175', (145, 156))	('improve', 'PosReg', (122, 129))	('mutational', 'Var', (46, 56))	('lung cancer', 'Disease', (145, 156))	('lung cancer', 'Phenotype', 'HP:0100526', (145, 156))	('cfDNA', 'Gene', (40, 45))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
528415	31212608	We did not find any studies about TAFI expression and H&N cancer; however, it has been shown that some polymorphisms of the TAFI gene can have a protective effect for OSCC.	('SCC', 'Gene', (168, 171))	('TAFI', 'Gene', '1361', (124, 128))	('SCC', 'Phenotype', 'HP:0002860', (168, 171))	('H&N cancer', 'Disease', (54, 64))	('the', 'Gene', (120, 123))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('for', 'Disease', (163, 166))	('SCC', 'Gene', '6317', (168, 171))	('TAFI', 'Gene', (34, 38))	('some', 'Var', (98, 102))	('TAFI', 'Gene', (124, 128))	('TAFI', 'Gene', '1361', (34, 38))	('H&N cancer', 'Disease', 'MESH:D009369', (54, 64))
528436	31212608	Thus, aggressive H&N cancer with high podoplanin expression can be associated with an elevated associated thrombosis risk.	('thrombosis', 'Disease', (106, 116))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('aggressive H&N cancer', 'Disease', 'MESH:D009369', (6, 27))	('aggressive H&N cancer', 'Disease', (6, 27))	('high', 'Gene', (33, 37))	('thrombosis', 'Disease', 'MESH:D013927', (106, 116))	('with', 'Var', (28, 32))	('podoplanin', 'Gene', '10630', (38, 48))	('associated', 'Disease', (95, 105))	('podoplanin', 'Gene', (38, 48))
528526	29893918	However, only a small fraction of differential methylation events target genes with a defined role in cancer, raising the question of how aberrant DNA methylation contributes to carcinogenesis.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('aberrant', 'Var', (138, 146))	('carcinogenesis', 'Disease', 'MESH:D063646', (178, 192))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('contributes', 'Reg', (163, 174))	('carcinogenesis', 'Disease', (178, 192))
528529	29893918	The extent of hypomethylation was stronger in cancer, but in both ageing and cancer it was proportional to the replication timing of the region and the cell division rate of the tissue.	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('cancer', 'Disease', (46, 52))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('hypomethylation', 'Var', (14, 29))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))
528530	29893918	Moreover, cancer patients who displayed more hypomethylation in late-replicating, lamina-associated domains had higher expression of cell division genes.	('expression', 'MPA', (119, 129))	('cell division genes', 'Gene', (133, 152))	('higher', 'PosReg', (112, 118))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('hypomethylation', 'Var', (45, 60))	('patients', 'Species', '9606', (17, 25))	('cancer', 'Disease', 'MESH:D009369', (10, 16))	('cancer', 'Disease', (10, 16))
528533	29893918	Specifically, differential DNA methylation in cancer has been studied extensively and is the epigenetic mechanism for which the most data are available.	('cancer', 'Disease', (46, 52))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('differential', 'Var', (14, 26))
528537	29893918	Specifically, transcriptional silencing of tumour suppressor genes by hypermethylation of their promoters has been observed in cancer and initially proposed as one of the main epigenetic contributors to carcinogenesis.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('transcriptional', 'MPA', (14, 29))	('observed', 'Reg', (115, 123))	('hypermethylation', 'Var', (70, 86))	('tumour', 'Disease', (43, 49))	('carcinogenesis', 'Disease', 'MESH:D063646', (203, 217))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('carcinogenesis', 'Disease', (203, 217))	('cancer', 'Disease', (127, 133))	('tumour', 'Phenotype', 'HP:0002664', (43, 49))	('tumour', 'Disease', 'MESH:D009369', (43, 49))
528541	29893918	In conclusion, defining causes and consequences of aberrant methylation in cancer development is not straightforward, complicating interpretation of available data.	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('methylation', 'Var', (60, 71))	('cancer', 'Disease', (75, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('aberrant methylation', 'Var', (51, 71))
528542	29893918	The aberrant methylation landscape in cancer shares common features with that in ageing.	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('aberrant', 'Var', (4, 12))	('cancer', 'Disease', (38, 44))
528547	29893918	We first determined which genes were affected by differential methylation in cancer, but only a small number of these genes had been previously linked to carcinogenesis.	('differential methylation', 'Var', (49, 73))	('carcinogenesis', 'Disease', 'MESH:D063646', (154, 168))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('carcinogenesis', 'Disease', (154, 168))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))
528555	29893918	Our findings provide insights into tissue-specific methylation in cancer and provide another link between the intrinsic nature of different cell types and their propensity for carcinogenesis.	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('methylation', 'Var', (51, 62))	('carcinogenesis', 'Disease', 'MESH:D063646', (176, 190))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('carcinogenesis', 'Disease', (176, 190))	('cancer', 'Disease', (66, 72))
528558	29893918	These were GSE32146 (colon), GSE40360 (brain, frontal lobe), GSE49149 (pancreas), GSE51954 (skin), GSE61107 (brain, frontal cortex), GSE77954 (colon), GSE88890 (brain, cortex), GSE89702 (brain, cerebellum), GSE89703 (brain, hippocampus), GSE89705 (brain, striatum), GSE90124 (skin).	('pancreas', 'Disease', (71, 79))	('GSE40360', 'Var', (29, 37))	('GSE89705', 'Var', (238, 246))	('GSE51954', 'Var', (82, 90))	('GSE90124', 'Var', (266, 274))	('GSE89702', 'Var', (177, 185))	('GSE89703', 'Var', (207, 215))	('GSE88890', 'Var', (151, 159))	('pancreas', 'Disease', 'MESH:D010190', (71, 79))	('GSE32146', 'Var', (11, 19))	('GSE77954', 'Var', (133, 141))	('GSE61107', 'Var', (99, 107))	('GSE49149', 'Var', (61, 69))
528560	29893918	To look at phenotypes which display abnormalities in nuclear envelope structure, we downloaded data from senescent cells (GSE56719, GSE69046) and patients with progeria (GSE42865).	('GSE42865', 'Var', (170, 178))	('GSE56719', 'Var', (122, 130))	('patients', 'Species', '9606', (146, 154))	('GSE69046', 'Var', (132, 140))
528562	29893918	Before proceeding with further analyses, we excluded the possibility of copy number aberrations confounding the beta-values obtained from tumour samples.	('tumour', 'Phenotype', 'HP:0002664', (138, 144))	('tumour', 'Disease', 'MESH:D009369', (138, 144))	('copy number aberrations', 'Var', (72, 95))	('tumour', 'Disease', (138, 144))
528578	29893918	For the correlations, we considered only genes that were significantly affected by methylation changes in cancer.	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('cancer', 'Disease', (106, 112))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('methylation changes', 'Var', (83, 102))
528583	29893918	We considered separately the 6605 probes located in regions defined as Human Enhancers by the FANTOM5 Enhancer Atlas because enhancers have previously been shown to be targeted by aberrant methylation in cancer in a manner different from other intergenic regions.	('cancer', 'Disease', (204, 210))	('cancer', 'Disease', 'MESH:D009369', (204, 210))	('aberrant methylation', 'Var', (180, 200))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('methylation', 'Var', (189, 200))	('Human', 'Species', '9606', (71, 76))
528596	29893918	To validate the results obtained using array data, we downloaded bisulphite sequencing data for three patients from whom an adjacent normal tissue sample was available:TCGA-A7-A0CE (BRCA), TCGA-AA-3518 (COAD), TCGA-AX-A1CI (UCEC).	('BRCA', 'Gene', '672', (182, 186))	('BRCA', 'Gene', (182, 186))	('COAD', 'Disease', (203, 207))	('COAD', 'Disease', 'MESH:D029424', (203, 207))	('patients', 'Species', '9606', (102, 110))	('TCGA-A7-A0CE', 'Var', (168, 180))	('TCGA-AX-A1CI', 'Var', (210, 222))	('TCGA-AA-3518', 'Var', (189, 201))	('bisulphite', 'Chemical', 'MESH:C042345', (65, 75))	('BRCA', 'Phenotype', 'HP:0003002', (182, 186))
528598	29893918	Both dividing and non-dividing cells contribute to the final contingency table proportionally to their fraction: Which simplifies to: The resulting expected odds ratio would therefore be:  DNA methylation has been initially believed to contribute to cancer development through modifying the expression of specific cancer driver genes.	('expression', 'MPA', (291, 301))	('methylation', 'Var', (193, 204))	('contribute', 'Reg', (236, 246))	('cancer', 'Disease', (314, 320))	('cancer', 'Disease', 'MESH:D009369', (250, 256))	('cancer', 'Disease', (250, 256))	('modifying', 'Reg', (277, 286))	('cancer', 'Phenotype', 'HP:0002664', (314, 320))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))	('cancer', 'Disease', 'MESH:D009369', (314, 320))
528601	29893918	Having observed that hypermethylation is associated with lower gene expression in a weak but consistent manner across tissues, we asked whether we can identify traces of selection acting on methylation during cancer development.	('hypermethylation', 'Var', (21, 37))	('cancer', 'Disease', 'MESH:D009369', (209, 215))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))	('cancer', 'Disease', (209, 215))	('gene expression', 'MPA', (63, 78))	('lower', 'NegReg', (57, 62))
528602	29893918	This was in agreement with our previous observation that genes without paralogs are more strongly protected from damaging point mutations during cancer progression.	('cancer', 'Disease', (145, 151))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('point mutations', 'Var', (122, 137))
528606	29893918	Affected tumour suppressors did not display a preference for hypermethylation or hypomethylation (P-value >= 0.08; t-test), but affected oncogenes were preferentially hypermethylated (P-values < 0.0006; t-test).	('tumour', 'Disease', (9, 15))	('preferentially', 'PosReg', (152, 166))	('oncogenes', 'Gene', (137, 146))	('hypermethylated', 'Var', (167, 182))	('tumour', 'Phenotype', 'HP:0002664', (9, 15))	('tumour', 'Disease', 'MESH:D009369', (9, 15))
528617	29893918	We determined the overlap in all ageing-associated methylation events across all tissues and all cancer-associated methylation events across all tissues in our collection.	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('methylation', 'Var', (51, 62))	('cancer', 'Disease', (97, 103))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
528623	29893918	We then compared the enrichment of hypermethylated or hypomethylated probes in each of these categories between cancer and ageing.	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('hypomethylated', 'Var', (54, 68))	('hypermethylated', 'Var', (35, 50))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))
528624	29893918	Although there was no consistent pattern across all cohorts, hypermethylation in cancer was significantly enriched in enhancer regions for all cohorts excluding COAD and THCA, in the 5' untranslated region in five cohorts, and in the first exon in five cohorts (Figure 4A, for all P-values see Supplementary Table S3).	('COAD', 'Disease', (161, 165))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('enhancer', 'PosReg', (118, 126))	('cancer', 'Disease', (81, 87))	('COAD', 'Disease', 'MESH:D029424', (161, 165))	('hypermethylation', 'Var', (61, 77))	('THCA', 'Phenotype', 'HP:0002890', (170, 174))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))
528625	29893918	Hypomethylation in cancer was predominantly enriched in intergenic regions (Figure 4B, for all P-values see Supplementary Table S3).	('Hypomethylation', 'Var', (0, 15))	('cancer', 'Disease', (19, 25))	('cancer', 'Disease', 'MESH:D009369', (19, 25))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))
528626	29893918	Because only a small fraction of methylation events in cancer were associated with differential gene expression, we asked whether the observed methylation patterns could be influenced by factors other than functional selection on the gene level.	('differential gene expression', 'MPA', (83, 111))	('methylation', 'Var', (33, 44))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('cancer', 'Disease', (55, 61))
528630	29893918	Finally, we observed an association between cancer-associated hypermethylation, H3K27me3 and repressed Polycomb.	('hypermethylation', 'Var', (62, 78))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('repressed Polycomb', 'Disease', (93, 111))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('H3K27me3', 'Protein', (80, 88))
528631	29893918	By contrast, cancer-associated hypomethylation predominantly occurred in transcriptionally inactive stretches of the chromatin (Figure 4D, for all P-values see Supplementary Table S4).	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('hypomethylation', 'Var', (31, 46))	('cancer', 'Disease', (13, 19))	('cancer', 'Disease', 'MESH:D009369', (13, 19))	('occurred', 'Reg', (61, 69))
528633	29893918	In conclusion, hypermethylation and hypomethylation were associated with different features of chromatin organization and might therefore be linked to cancer development in different ways.	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('linked', 'Reg', (141, 147))	('hypermethylation', 'Var', (15, 31))	('cancer', 'Disease', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('hypomethylation', 'Var', (36, 51))	('associated', 'Reg', (57, 67))
528635	29893918	The enrichment of hypomethylation in constitutive LADs was higher in cancer when compared to that in ageing (Figure 5A).	('higher', 'Reg', (59, 65))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('hypomethylation', 'Var', (18, 33))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Disease', (69, 75))
528637	29893918	In three cancer patients (one from the BRCA, one from the COAD, and one from the UCEC cohort) from whom bisulphite sequencing data were available, we also confirmed enrichment of hypomethylation in LADs (Supplementary Figure S3B).	('BRCA', 'Gene', (39, 43))	('cancer', 'Disease', (9, 15))	('hypomethylation', 'Var', (179, 194))	('BRCA', 'Gene', '672', (39, 43))	('patients', 'Species', '9606', (16, 24))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('COAD', 'Disease', (58, 62))	('BRCA', 'Phenotype', 'HP:0003002', (39, 43))	('COAD', 'Disease', 'MESH:D029424', (58, 62))	('bisulphite', 'Chemical', 'MESH:C042345', (104, 114))	('cancer', 'Disease', 'MESH:D009369', (9, 15))
528638	29893918	In cancer, the enrichment of hypomethylated probes gradually increased from early- to late-replicating regions (Figure 5B, top).	('hypomethylated probes', 'Var', (29, 50))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('increased', 'PosReg', (61, 70))	('cancer', 'Disease', (3, 9))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))
528641	29893918	The enrichment of hypomethylation in constitutive LADs in cancer positively correlated with the mitotic index (r = 0.66, P-value = 0.007; Pearson correlation) (Figure 5C).	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('hypomethylation', 'Var', (18, 33))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('mitotic index', 'CPA', (96, 109))	('cancer', 'Disease', (58, 64))	('correlated', 'Reg', (76, 86))
528650	29893918	We performed a GSEA to identify pathways enriched among genes whose expression was correlated with the degree of hypomethylation in LADs in patients.	('hypomethylation', 'Var', (113, 128))	('GSEA', 'Chemical', '-', (15, 19))	('patients', 'Species', '9606', (140, 148))	('expression', 'MPA', (68, 78))
528653	29893918	We concluded that the association between the extent of LAD hypomethylation and the expression of genes participating in cell division within the same cancer type could be a proxy for variation in cell division rates.	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('cancer', 'Disease', (151, 157))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('association', 'Interaction', (22, 33))	('hypomethylation', 'Var', (60, 75))	('expression', 'MPA', (84, 94))
528655	29893918	We could think of three scenarios to explain the loss of methylation in LADs in cancer (Figure 6A).	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('methylation', 'Var', (57, 68))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancer', 'Disease', (80, 86))
528657	29893918	In eight tissues (BRCA, COAD, HNSC, LIHC, LUAD, LUSC, PRAD and UCEC), the observed LAD hypomethylation enrichment was higher for the HT1080A, HT1080B1 and constitutive LAD definitions (Figure 5A, Supplementary Figure S3).	('higher', 'PosReg', (118, 124))	('BRCA', 'Phenotype', 'HP:0003002', (18, 22))	('LUAD', 'Phenotype', 'HP:0030078', (42, 46))	('COAD', 'Disease', (24, 28))	('LUSC', 'Phenotype', 'HP:0030359', (48, 52))	('HT1080B1', 'Var', (142, 150))	('LIHC', 'Disease', (36, 40))	('BRCA', 'Gene', '672', (18, 22))	('LIHC', 'Disease', 'None', (36, 40))	('HT1080A', 'CellLine', 'CVCL:0317', (133, 140))	('BRCA', 'Gene', (18, 22))	('HT1080A', 'Var', (133, 140))	('HNSC', 'Phenotype', 'HP:0012288', (30, 34))	('LAD hypomethylation enrichment', 'MPA', (83, 113))	('COAD', 'Disease', 'MESH:D029424', (24, 28))	('HT1080B1', 'CellLine', 'CVCL:0317', (142, 150))
528662	29893918	The enrichment of hypomethylation in late-replicating regions in cancer was comparable to the values found for different definitions of LADs (Supplementary Figure S7A).	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('hypomethylation', 'Var', (18, 33))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))
528664	29893918	Progeria, a premature aging disorder, is known to be caused by a mutation in lamin A.	('premature aging disorder', 'Disease', 'MESH:D019588', (12, 36))	('caused by', 'Reg', (53, 62))	('premature aging disorder', 'Phenotype', 'HP:0007495', (12, 36))	('lamin A', 'Gene', (77, 84))	('mutation', 'Var', (65, 73))	('premature aging disorder', 'Disease', (12, 36))	('Progeria', 'Disease', (0, 8))
528666	29893918	Having observed an association between hypomethylation in cancer, structural reorganisation of the genome, replication timing and cell division rates, we went back to the original output from our cancer linear regression models.	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('cancer', 'Disease', 'MESH:D009369', (196, 202))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('cancer', 'Disease', (196, 202))	('cancer', 'Disease', (58, 64))	('hypomethylation', 'Var', (39, 54))
528667	29893918	In addition, pairwise differential methylation correlations between different tissues in cancer were higher for probes located in constitutive LADs compared to probes located outside LADs (Figure 6C).	('higher', 'PosReg', (101, 107))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('cancer', 'Disease', (89, 95))	('probes located', 'Var', (112, 126))	('methylation correlations', 'MPA', (35, 59))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
528669	29893918	Moreover, considering ~30% of the hypomethylated probes were located in LADs according to at least one LAD definition, these rearrangements contribute to the similarity across tissues and cancer types and are associated to the differences in cell division rates of healthy tissues and cancer cells.	('associated', 'Reg', (209, 219))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('contribute', 'Reg', (140, 150))	('differences', 'Reg', (227, 238))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('cell division rates', 'CPA', (242, 261))	('cancer', 'Phenotype', 'HP:0002664', (285, 291))	('hypomethylated', 'Var', (34, 48))	('cancer', 'Disease', (188, 194))	('cancer', 'Disease', (285, 291))	('cancer', 'Disease', 'MESH:D009369', (285, 291))
528671	29893918	Our observations suggested that functional selection for changes in methylation of cancer genes could only be associated with a small fraction of the methylation events in cancer.	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('changes', 'Var', (57, 64))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('cancer', 'Disease', (172, 178))	('cancer', 'Disease', (83, 89))
528677	29893918	Finally, genes associated with cell division were upregulated in patients displaying more hypomethylation in LADs.	('upregulated', 'PosReg', (50, 61))	('hypomethylation', 'Var', (90, 105))	('patients', 'Species', '9606', (65, 73))	('genes', 'Gene', (9, 14))	('cell division', 'CPA', (31, 44))
528678	29893918	Taken together, our results suggested that the aberrant methylation landscape in cancer is partially the result of structural reorganisation of the genome with respect to the nuclear lamina that is enhanced by the fast division rates of cancer cells.	('aberrant', 'Var', (47, 55))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('cancer', 'Disease', (81, 87))	('methylation', 'MPA', (56, 67))	('cancer', 'Disease', 'MESH:D009369', (237, 243))	('enhanced', 'PosReg', (198, 206))	('cancer', 'Disease', (237, 243))
528682	29893918	Studies where this association was observed, however, heavily focused on methylation in colon, the tissue in which we observed the highest similarity between cancer and ageing.	('colon', 'Disease', (88, 93))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('cancer', 'Disease', (158, 164))	('methylation', 'Var', (73, 84))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
528689	29893918	By contrast, we found that hypomethylation in cancer was not as strongly associated with chromatin states potentially affecting gene expression.	('gene', 'MPA', (128, 132))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('hypomethylation', 'Var', (27, 42))	('cancer', 'Disease', (46, 52))	('associated', 'Reg', (73, 83))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))
528691	29893918	The same was true for heterochromatin and H3K9me3, which were previously linked to elevated mutation rates and copy number aberrations in cancer.	('cancer', 'Disease', (138, 144))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('H3K9me3', 'Var', (42, 49))	('cancer', 'Disease', 'MESH:D009369', (138, 144))	('heterochromatin', 'Var', (22, 37))
528702	29893918	Specifically, we excluded that copy number variations contributed to the variation in methylation and that LAD hypomethylation was associated with the hypoxia levels of the tumour.	('tumour', 'Disease', (173, 179))	('methylation', 'MPA', (86, 97))	('associated', 'Reg', (131, 141))	('hypoxia', 'Disease', 'MESH:D000860', (151, 158))	('copy number', 'Var', (31, 42))	('tumour', 'Phenotype', 'HP:0002664', (173, 179))	('hypomethylation', 'Var', (111, 126))	('hypoxia', 'Disease', (151, 158))	('tumour', 'Disease', 'MESH:D009369', (173, 179))
528704	29893918	In conclusion, we associated the amount of hypomethylation in LADs to cell division both on the level of different tissues and cancer types and the level of individuals within the same cancer type.	('hypomethylation', 'Var', (43, 58))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('associated', 'Reg', (18, 28))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('cancer', 'Disease', (127, 133))	('cancer', 'Disease', (185, 191))	('cell division', 'CPA', (70, 83))
528708	29893918	Recently, the average levels of CpG island methylation in a tissue have also been shown to correlate with the tissue's risk to develop cancer.	('cancer', 'Disease', (135, 141))	('methylation', 'Var', (43, 54))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('CpG island', 'Protein', (32, 42))	('cancer', 'Disease', 'MESH:D009369', (135, 141))
528709	29893918	Therefore, methylation changes could also contribute to the accumulation of mutations in faster dividing cells prior to cancer development.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('methylation', 'MPA', (11, 22))	('mutations', 'Var', (76, 85))	('changes', 'Reg', (23, 30))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('contribute', 'Reg', (42, 52))
528828	30678439	An ICC study of fine needle aspiration of a liver tumor showed Hep Par-1 positivity combined with Ber-EP4 negativity was exclusively observed in hepatocellular carcinoma (Onofre et al., 2007).	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (145, 169))	('Hep', 'CellLine', 'CVCL:1906', (63, 66))	('carcinoma', 'Phenotype', 'HP:0030731', (160, 169))	('hepatocellular carcinoma', 'Disease', (145, 169))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (145, 169))	('liver tumor', 'Disease', 'MESH:D008113', (44, 55))	('observed', 'Reg', (133, 141))	('liver tumor', 'Phenotype', 'HP:0002896', (44, 55))	('liver tumor', 'Disease', (44, 55))	('positivity', 'Var', (73, 83))	('Par-1', 'Gene', '145624', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('Par-1', 'Gene', (67, 72))	('aspiration', 'Phenotype', 'HP:0002835', (28, 38))
528850	30290038	Some lung adenocarcinoma patients show EML4-ALK rearrangement, KRAS (KRAS proto-oncogene, GTPase) mutations, and epidermal growth factor receptor (EGFR) overexpression or mutations,4, 5, 6, 7 and these alterations have been used as biomarkers in lung cancer patients.	('KRAS', 'Gene', (69, 73))	('EML4', 'Gene', (39, 43))	('EGFR', 'Gene', (147, 151))	('EML4', 'Gene', '27436', (39, 43))	('ALK', 'Gene', '238', (44, 47))	('lung adenocarcinoma', 'Disease', (5, 24))	('ALK', 'Gene', (44, 47))	('carcinoma', 'Phenotype', 'HP:0030731', (15, 24))	('lung cancer', 'Disease', 'MESH:D008175', (246, 257))	('patients', 'Species', '9606', (258, 266))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (5, 24))	('EGFR', 'Gene', '1956', (147, 151))	('lung cancer', 'Phenotype', 'HP:0100526', (246, 257))	('overexpression', 'PosReg', (153, 167))	('KRAS', 'Gene', '3845', (63, 67))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (5, 24))	('rearrangement', 'Var', (48, 61))	('patients', 'Species', '9606', (25, 33))	('epidermal growth factor receptor', 'Gene', (113, 145))	('KRAS', 'Gene', (63, 67))	('GTPase', 'Gene', (90, 96))	('KRAS', 'Gene', '3845', (69, 73))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('epidermal growth factor receptor', 'Gene', '1956', (113, 145))	('mutations', 'Var', (98, 107))	('lung cancer', 'Disease', (246, 257))
528856	30290038	Information regarding LOC723809 (LHFPL3-AS2), LOC150622 (LINC01105), NCRNA00092 (LINC00092), LOC284276 (LINC00908), and LOC100131726 (FAM83A-AS1) expression in lung adenocarcinoma tissues was downloaded and normalized using a Z score analysis.	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (160, 179))	('LOC723809', 'Var', (22, 31))	('LINC00092', 'Gene', '100188953', (81, 90))	('LHFPL3-AS2', 'Gene', (33, 43))	('LOC284276', 'Var', (93, 102))	('LHFPL3-AS2', 'Gene', '723809', (33, 43))	('LINC00908', 'Gene', '284276', (104, 113))	('LOC100131726', 'Var', (120, 132))	('FAM83A-AS1', 'Gene', '100131726', (134, 144))	('NCRNA00092', 'Gene', (69, 79))	('LINC00908', 'Gene', (104, 113))	('LINC01105', 'Gene', (57, 66))	('FAM83A-AS1', 'Gene', (134, 144))	('LINC00092', 'Gene', (81, 90))	('NCRNA00092', 'Gene', '100188953', (69, 79))	('LINC01105', 'Gene', '150622', (57, 66))	('carcinoma', 'Phenotype', 'HP:0030731', (170, 179))	('lung adenocarcinoma tissues', 'Disease', (160, 187))	('lung adenocarcinoma tissues', 'Disease', 'MESH:D000077192', (160, 187))
528868	30290038	The expression of LOC100131726 (FAM83A-AS1) was negatively correlated with that of LOC723809 (LHFPL3-AS2), whereas the expression levels of LOC723809 (LHFPL3-AS2), LOC150622 (LINC01105), LOC284736 (LINC00908), and NCRNA00092 (LINC00092) were positively correlated with each other (Figure 1A).	('NCRNA00092', 'Gene', (214, 224))	('LOC723809', 'Var', (140, 149))	('LINC00092', 'Gene', (226, 235))	('LOC723809', 'Var', (83, 92))	('LOC100131726', 'Var', (18, 30))	('NCRNA00092', 'Gene', '100188953', (214, 224))	('LOC150622', 'Var', (164, 173))	('FAM83A-AS1', 'Gene', '100131726', (32, 42))	('LINC00908', 'Gene', '284276', (198, 207))	('negatively', 'NegReg', (48, 58))	('LHFPL3-AS2', 'Gene', (151, 161))	('FAM83A-AS1', 'Gene', (32, 42))	('LOC284736', 'Var', (187, 196))	('LHFPL3-AS2', 'Gene', (94, 104))	('LINC00092', 'Gene', '100188953', (226, 235))	('LINC00908', 'Gene', (198, 207))	('LINC01105', 'Gene', (175, 184))	('LHFPL3-AS2', 'Gene', '723809', (151, 161))	('LHFPL3-AS2', 'Gene', '723809', (94, 104))	('LINC01105', 'Gene', '150622', (175, 184))
528869	30290038	Four of the lncRNAs (LOC723809 [LHFPL3-AS2], LOC150622 [LINC01105], NCRNA00092 [LINC00092], and LOC284276 [LINC00908]) were expressed at a lower level and one (LOC100131726 [FAM83A-AS1]) was overexpressed in adenocarcinoma tissues (P < .0001; Figure 1C).	('LINC01105', 'Gene', (56, 65))	('adenocarcinoma', 'Disease', 'MESH:D000230', (208, 222))	('LINC00092', 'Gene', '100188953', (80, 89))	('LINC00908', 'Gene', (107, 116))	('LINC00092', 'Gene', (80, 89))	('LINC00908', 'Gene', '284276', (107, 116))	('LHFPL3-AS2', 'Gene', '723809', (32, 42))	('LINC01105', 'Gene', '150622', (56, 65))	('NCRNA00092', 'Gene', '100188953', (68, 78))	('LHFPL3-AS2', 'Gene', (32, 42))	('FAM83A-AS1', 'Gene', (174, 184))	('NCRNA00092', 'Gene', (68, 78))	('LOC723809', 'Var', (21, 30))	('carcinoma', 'Phenotype', 'HP:0030731', (213, 222))	('adenocarcinoma', 'Disease', (208, 222))	('FAM83A-AS1', 'Gene', '100131726', (174, 184))
528870	30290038	It is clear from Figure 1D that the expression pattern of LOC100131726 (FAM83A-AS1) is different from the other 4 lncRNAs.	('FAM83A-AS1', 'Gene', '100131726', (72, 82))	('LOC100131726', 'Var', (58, 70))	('FAM83A-AS1', 'Gene', (72, 82))
528871	30290038	Finally, the alterations in their DNA copy number were investigated in 7,589 adenocarcinoma samples.29 The LOC723809 (LHFPL3-AS2) and LOC150622 (LINC01105) genomic loci were not frequently lost.	('LOC723809', 'Var', (107, 116))	('LOC150622', 'Var', (134, 143))	('LINC01105', 'Gene', (145, 154))	('adenocarcinoma', 'Disease', 'MESH:D000230', (77, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('LHFPL3-AS2', 'Gene', '723809', (118, 128))	('LHFPL3-AS2', 'Gene', (118, 128))	('LINC01105', 'Gene', '150622', (145, 154))	('adenocarcinoma', 'Disease', (77, 91))
528872	30290038	The NCRNA00092 (LINC00092) locus was deleted in 10%-15% of the patients, whereas the LOC284276 (LINC00908) locus was deleted in 30%-45% of the samples, and LOC100131726 (FAM83A-AS1) was amplified in 30%-40% of the patients (Figure 1E).	('patients', 'Species', '9606', (214, 222))	('LINC00908', 'Gene', (96, 105))	('FAM83A-AS1', 'Gene', (170, 180))	('LOC100131726', 'Var', (156, 168))	('LINC00908', 'Gene', '284276', (96, 105))	('LINC00092', 'Gene', '100188953', (16, 25))	('FAM83A-AS1', 'Gene', '100131726', (170, 180))	('patients', 'Species', '9606', (63, 71))	('LINC00092', 'Gene', (16, 25))	('NCRNA00092', 'Gene', '100188953', (4, 14))	('NCRNA00092', 'Gene', (4, 14))
528878	30290038	Low LOC100131726 (FAM83A-AS1) expression and high LOC723809 (LHFPL3-AS2), LOC150622 (LINC01105), NCRNA00092 (LINC00092), and LOC284276 (LINC00908) expression were associated with survival (Figure 2D).	('LINC00908', 'Gene', (136, 145))	('FAM83A-AS1', 'Gene', (18, 28))	('LOC284276', 'Var', (125, 134))	('Low LOC100131726', 'Var', (0, 16))	('LINC01105', 'Gene', '150622', (85, 94))	('NCRNA00092', 'Gene', '100188953', (97, 107))	('FAM83A-AS1', 'Gene', '100131726', (18, 28))	('NCRNA00092', 'Gene', (97, 107))	('survival', 'Disease', (179, 187))	('associated', 'Reg', (163, 173))	('LHFPL3-AS2', 'Gene', '723809', (61, 71))	('LINC00092', 'Gene', '100188953', (109, 118))	('LHFPL3-AS2', 'Gene', (61, 71))	('LINC00092', 'Gene', (109, 118))	('high LOC723809', 'Var', (45, 59))	('LINC01105', 'Gene', (85, 94))	('LINC00908', 'Gene', '284276', (136, 145))	('LOC150622', 'Var', (74, 83))
528880	30290038	High LOC100131726 (FAM83A-AS1) expression and low LOC723809 (LHFPL3-AS2), LOC150622 (LINC01105), NCRNA00092 (LINC00092), and LOC284276 (LINC00908) expression were associated with death (Figure 2E).	('LINC00908', 'Gene', (136, 145))	('LOC284276', 'Var', (125, 134))	('LINC01105', 'Gene', '150622', (85, 94))	('LOC150622', 'Var', (74, 83))	('death', 'Disease', (179, 184))	('NCRNA00092', 'Gene', '100188953', (97, 107))	('NCRNA00092', 'Gene', (97, 107))	('associated', 'Reg', (163, 173))	('FAM83A-AS1', 'Gene', (19, 29))	('LOC100131726', 'Var', (5, 17))	('LHFPL3-AS2', 'Gene', '723809', (61, 71))	('LINC00092', 'Gene', '100188953', (109, 118))	('LHFPL3-AS2', 'Gene', (61, 71))	('LINC00092', 'Gene', (109, 118))	('FAM83A-AS1', 'Gene', '100131726', (19, 29))	('LINC01105', 'Gene', (85, 94))	('LINC00908', 'Gene', '284276', (136, 145))	('low LOC723809', 'Var', (46, 59))
528884	30290038	To further confirm the prognostic value of these 5 lncRNAs, we investigated the relationship between the expression of each lncRNA and cancer risk in 255 lung adenocarcinoma patients (ID: Lung Adenocarcinoma TCGA) included in the SurvExpress database and found that high LOC100131726 (FAM83A-AS1) expression and low LOC723809 (LHFPL3-AS2), LOC150622 (LINC01105), NCRNA00092 (LINC00092), and LOC284276 (LINC00908) expression were correlated with poor survival (Figure 4A).	('LINC00908', 'Gene', (402, 411))	('LOC150622', 'Var', (340, 349))	('LINC00092', 'Gene', '100188953', (375, 384))	('lung adenocarcinoma', 'Disease', (154, 173))	('Adenocarcinoma', 'Disease', 'MESH:D000230', (193, 207))	('cancer', 'Disease', (135, 141))	('poor survival', 'CPA', (445, 458))	('low LOC723809', 'Var', (312, 325))	('carcinoma', 'Phenotype', 'HP:0030731', (198, 207))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('LHFPL3-AS2', 'Gene', (327, 337))	('NCRNA00092', 'Gene', (363, 373))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (154, 173))	('LINC01105', 'Gene', (351, 360))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (154, 173))	('LINC00092', 'Gene', (375, 384))	('FAM83A-AS1', 'Gene', '100131726', (285, 295))	('LHFPL3-AS2', 'Gene', '723809', (327, 337))	('LINC01105', 'Gene', '150622', (351, 360))	('NCRNA00092', 'Gene', '100188953', (363, 373))	('LOC284276', 'Var', (391, 400))	('Adenocarcinoma', 'Disease', (193, 207))	('carcinoma', 'Phenotype', 'HP:0030731', (164, 173))	('cancer', 'Disease', 'MESH:D009369', (135, 141))	('FAM83A-AS1', 'Gene', (285, 295))	('LINC00908', 'Gene', '284276', (402, 411))	('high LOC100131726', 'Var', (266, 283))	('Lung Adenocarcinoma', 'Phenotype', 'HP:0030078', (188, 207))	('patients', 'Species', '9606', (174, 182))
528902	30290038	In contrast to the finding in lung adenocarcinoma patients, LOC723809 (LHFPL3-AS2) and LOC284276 (LINC00908) were not associated with survival in lung squamous cell carcinoma patients (P > .05; Figure 6A).	('LOC284276', 'Var', (87, 96))	('patients', 'Species', '9606', (50, 58))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (30, 49))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (146, 174))	('LHFPL3-AS2', 'Gene', '723809', (71, 81))	('patients', 'Species', '9606', (175, 183))	('carcinoma', 'Phenotype', 'HP:0030731', (40, 49))	('LOC723809', 'Var', (60, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (165, 174))	('lung adenocarcinoma', 'Disease', (30, 49))	('lung squamous cell carcinoma', 'Disease', (146, 174))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (146, 174))	('LINC00908', 'Gene', '284276', (98, 107))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (30, 49))	('LINC00908', 'Gene', (98, 107))	('LHFPL3-AS2', 'Gene', (71, 81))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (151, 174))
528903	30290038	However, low LOC150622 (LINC01105) and NCRNA00092 (LINC00092) expression increased the risk of death, and low LOC100131726 (FAM83A-AS1) expression was associated with a low risk of death.	('LINC00092', 'Gene', '100188953', (51, 60))	('FAM83A-AS1', 'Gene', (124, 134))	('NCRNA00092', 'Gene', '100188953', (39, 49))	('low LOC100131726', 'Var', (106, 122))	('LINC00092', 'Gene', (51, 60))	('NCRNA00092', 'Gene', (39, 49))	('FAM83A-AS1', 'Gene', '100131726', (124, 134))	('LINC01105', 'Gene', '150622', (24, 33))	('LINC01105', 'Gene', (24, 33))
528904	30290038	Although LOC723809 (LHFPL3-AS2) and LOC284276 (LINC00908) showed no differences in expression between low- and high-risk patients, a Cox regression analysis indicated that the overall expression pattern of all 5 lncRNAs as a group (Figure 6B) is still a better prognostic marker of lung squamous cell carcinoma than the expression pattern of only the three lncRNAs that showed differential expression between the different risk groups (Figure 6C).	('LHFPL3-AS2', 'Gene', (20, 30))	('Cox', 'Gene', (133, 136))	('Cox', 'Gene', '1351', (133, 136))	('LOC723809', 'Var', (9, 18))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (282, 310))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (287, 310))	('LOC284276', 'Var', (36, 45))	('carcinoma', 'Phenotype', 'HP:0030731', (301, 310))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (282, 310))	('lung squamous cell carcinoma', 'Disease', (282, 310))	('LINC00908', 'Gene', (47, 56))	('LHFPL3-AS2', 'Gene', '723809', (20, 30))	('patients', 'Species', '9606', (121, 129))	('LINC00908', 'Gene', '284276', (47, 56))
528905	30290038	It is possible that we did not observe differential LOC723809 (LHFPL3-AS2) and LOC284276 (LINC00908) expression between the low- and high-risk patients because the number of patients was too low.	('LHFPL3-AS2', 'Gene', '723809', (63, 73))	('LHFPL3-AS2', 'Gene', (63, 73))	('LINC00908', 'Gene', (90, 99))	('patients', 'Species', '9606', (143, 151))	('patients', 'Species', '9606', (174, 182))	('LINC00908', 'Gene', '284276', (90, 99))	('LOC284276', 'Var', (79, 88))	('LOC723809', 'Var', (52, 61))
528910	30290038	Four of the lncRNAs (LOC723809 [LHFPL3-AS2], LOC150622 [LINC01105], NCRNA00092 [LINC00092], and LOC284276 [LINC00908]) were expressed at significantly lower levels in the lymph node-positive group than in the lymph node-negative group (Figure 7C).	('LINC01105', 'Gene', (56, 65))	('LINC00092', 'Gene', '100188953', (80, 89))	('LINC00908', 'Gene', (107, 116))	('LINC00092', 'Gene', (80, 89))	('LINC00908', 'Gene', '284276', (107, 116))	('lymph', 'Disease', (171, 176))	('LHFPL3-AS2', 'Gene', '723809', (32, 42))	('LINC01105', 'Gene', '150622', (56, 65))	('NCRNA00092', 'Gene', '100188953', (68, 78))	('LHFPL3-AS2', 'Gene', (32, 42))	('NCRNA00092', 'Gene', (68, 78))	('LOC723809', 'Var', (21, 30))
528911	30290038	Twenty-two rules demonstrated that high LOC100131726 (FAM83A-AS1) expression and low LOC723809 (LHFPL3-AS2), LOC150622 (LINC01105), NCRNA00092 (LINC00092), and LOC284276 (LINC00908) expression were associated with the occurrence of lymph node metastasis (Figure 7D).	('LINC00908', 'Gene', '284276', (171, 180))	('LOC150622', 'Var', (109, 118))	('LHFPL3-AS2', 'Gene', '723809', (96, 106))	('LINC01105', 'Gene', '150622', (120, 129))	('NCRNA00092', 'Gene', '100188953', (132, 142))	('LOC284276', 'Var', (160, 169))	('LHFPL3-AS2', 'Gene', (96, 106))	('lymph', 'Disease', (232, 237))	('low LOC723809', 'Var', (81, 94))	('NCRNA00092', 'Gene', (132, 142))	('FAM83A-AS1', 'Gene', (54, 64))	('LOC100131726', 'Var', (40, 52))	('LINC01105', 'Gene', (120, 129))	('LINC00092', 'Gene', '100188953', (144, 153))	('FAM83A-AS1', 'Gene', '100131726', (54, 64))	('LINC00908', 'Gene', (171, 180))	('LINC00092', 'Gene', (144, 153))
528915	30290038	Multigene expression signatures focusing on lncRNAs, miRNAs, and protein-coding genes have been used for predicting risk and survival.30, 31, 32, 33, 34, 35, 36 In this study, we report the prognostic value of 5 lncRNAs (LOC723809 [LHFPL3-AS2], LOC150622 [LINC01105], NCRNA00092 [LINC00092], LOC284276 [LINC00908], and LOC100131726 [FAM83A-AS1]) in lung adenocarcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (359, 368))	('LINC01105', 'Gene', '150622', (256, 265))	('LINC00908', 'Gene', (303, 312))	('LINC00092', 'Gene', '100188953', (280, 289))	('LINC00908', 'Gene', '284276', (303, 312))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (349, 368))	('LHFPL3-AS2', 'Gene', '723809', (232, 242))	('LINC00092', 'Gene', (280, 289))	('FAM83A-AS1', 'Gene', '100131726', (333, 343))	('LINC01105', 'Gene', (256, 265))	('FAM83A-AS1', 'Gene', (333, 343))	('NCRNA00092', 'Gene', '100188953', (268, 278))	('lung adenocarcinoma', 'Disease', (349, 368))	('LHFPL3-AS2', 'Gene', (232, 242))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (349, 368))	('LOC100131726', 'Var', (319, 331))	('NCRNA00092', 'Gene', (268, 278))
528916	30290038	LOC150622 (LINC01105) is a stage-specific biomarker in lung adenocarcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('LINC01105', 'Gene', (11, 20))	('LOC150622', 'Var', (0, 9))	('lung adenocarcinoma', 'Disease', (55, 74))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (55, 74))	('LINC01105', 'Gene', '150622', (11, 20))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (55, 74))
528917	30290038	It is also highly expressed in neuroblastoma tissue, where it affects cellular proliferation and apoptosis.37, 38 Methylation of the LOC284276 (LINC00908) gene is negatively associated with birth weight.39 NCRNA00092 (LINC00092) acts in cancer-associated fibroblasts to drive glycolysis and progression of ovarian cancer.40 No studies have investigated the biological functions of LOC723809 (LHFPL3-AS2) or LOC100131726 (FAM83A-AS1).	('LHFPL3-AS2', 'Gene', '723809', (392, 402))	('NCRNA00092', 'Gene', (206, 216))	('cancer', 'Disease', 'MESH:D009369', (314, 320))	('ovarian cancer', 'Disease', (306, 320))	('LINC00908', 'Gene', '284276', (144, 153))	('LINC00092', 'Gene', (218, 227))	('LOC100131726', 'Var', (407, 419))	('FAM83A-AS1', 'Gene', '100131726', (421, 431))	('NCRNA00092', 'Gene', '100188953', (206, 216))	('cancer', 'Disease', (237, 243))	('LINC00908', 'Gene', (144, 153))	('neuroblastoma', 'Disease', (31, 44))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('neuroblastoma', 'Phenotype', 'HP:0003006', (31, 44))	('FAM83A-AS1', 'Gene', (421, 431))	('neuroblastoma', 'Disease', 'MESH:D009447', (31, 44))	('cancer', 'Disease', (314, 320))	('LHFPL3-AS2', 'Gene', (392, 402))	('LINC00092', 'Gene', '100188953', (218, 227))	('cancer', 'Phenotype', 'HP:0002664', (314, 320))	('cancer', 'Disease', 'MESH:D009369', (237, 243))	('ovarian cancer', 'Disease', 'MESH:D010051', (306, 320))	('LOC723809', 'Var', (381, 390))
528918	30290038	In addition, 4 of these lncRNAs (LOC723809 [LHFPL3-AS2], LOC150622 [LINC01105], NCRNA00092 [LINC00092], and LOC284276 [LINC00908]) are expressed at low levels, whereas LOC100131726 (FAM83A-AS1) is expressed at a high level in lung adenocarcinoma tissue.	('FAM83A-AS1', 'Gene', '100131726', (182, 192))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (226, 245))	('NCRNA00092', 'Gene', '100188953', (80, 90))	('LINC00908', 'Gene', '284276', (119, 128))	('LINC00908', 'Gene', (119, 128))	('LINC01105', 'Gene', '150622', (68, 77))	('NCRNA00092', 'Gene', (80, 90))	('LOC723809', 'Var', (33, 42))	('LINC00092', 'Gene', '100188953', (92, 101))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (226, 245))	('carcinoma', 'Phenotype', 'HP:0030731', (236, 245))	('LHFPL3-AS2', 'Gene', '723809', (44, 54))	('LINC00092', 'Gene', (92, 101))	('LHFPL3-AS2', 'Gene', (44, 54))	('lung adenocarcinoma', 'Disease', (226, 245))	('FAM83A-AS1', 'Gene', (182, 192))	('LINC01105', 'Gene', (68, 77))
528921	30290038	In lung adenocarcinoma, abnormal expression of this group of lncRNAs was found to be associated with poor prognosis.	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (3, 22))	('abnormal', 'Var', (24, 32))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (3, 22))	('expression', 'MPA', (33, 43))	('carcinoma', 'Phenotype', 'HP:0030731', (13, 22))	('lung adenocarcinoma', 'Disease', (3, 22))
528923	30290038	In addition, LOC723809 (LHFPL3-AS2) and LOC100131726 (FAM83A-AS1) might negatively regulate each other.	('LHFPL3-AS2', 'Gene', (24, 34))	('negatively', 'NegReg', (72, 82))	('FAM83A-AS1', 'Gene', (54, 64))	('LOC100131726', 'Var', (40, 52))	('LOC723809', 'Var', (13, 22))	('FAM83A-AS1', 'Gene', '100131726', (54, 64))	('LHFPL3-AS2', 'Gene', '723809', (24, 34))
528929	30290038	A correlation analysis between their expression and the lymph node metastasis status also revealed that high LOC100131726 (FAM83A-AS1) expression and low LOC723809 (LHFPL3-AS2), LOC150622 (LINC01105), NCRNA00092 (LINC00092), and LOC284276 (LINC00908) expression were associated with lymph node positivity.	('LINC01105', 'Gene', (189, 198))	('LHFPL3-AS2', 'Gene', '723809', (165, 175))	('LINC00092', 'Gene', (213, 222))	('NCRNA00092', 'Gene', '100188953', (201, 211))	('LOC284276', 'Var', (229, 238))	('LINC00908', 'Gene', '284276', (240, 249))	('LINC01105', 'Gene', '150622', (189, 198))	('FAM83A-AS1', 'Gene', (123, 133))	('lymph node positivity', 'Disease', (283, 304))	('high LOC100131726', 'Var', (104, 121))	('LINC00908', 'Gene', (240, 249))	('LOC723809', 'Var', (154, 163))	('LINC00092', 'Gene', '100188953', (213, 222))	('LOC150622', 'Var', (178, 187))	('LOC100131726', 'Var', (109, 121))	('LHFPL3-AS2', 'Gene', (165, 175))	('NCRNA00092', 'Gene', (201, 211))	('low LOC723809', 'Var', (150, 163))	('FAM83A-AS1', 'Gene', '100131726', (123, 133))
528937	29675925	Pathway abnormalities enhance the reactive oxygen species scavenging ability of cancer cells; thus the pathway is involved in carcinogenesis and resistance to chemoradiotherapy (CRT).	('reactive oxygen species scavenging', 'MPA', (34, 68))	('carcinogenesis', 'Disease', 'MESH:D063646', (126, 140))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('abnormalities', 'Var', (8, 21))	('carcinogenesis', 'Disease', (126, 140))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (34, 57))	('involved', 'Reg', (114, 122))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('enhance', 'PosReg', (22, 29))	('cancer', 'Disease', (80, 86))
528944	29675925	As a core transcription factor, Nrf2 is bound to Keap1 in cytoplasm and degrades in a proteasome-dependent manner under homeostatic conditions.19 Oxidative stress results in conformational change of the Keap1-Nrf2 complex, allowing Nrf2 to be translocated into the nucleus and activating the transcription of target antioxidant and redox genes.20, 21, 22, 23 Aberrant signaling via the Keap1-Nrf2 pathway frequently occurs in cancer cells, leading to the over-activation of Nrf2 and elevation of ROS scavenging ability, facilitating the initiation and development of malignant cells that produce ROS during rapid proliferation.24, 25, 26, 27, 28, 29, 30 On the other hand, ROS are also indispensable for the therapeutic effect of platinum complexes, fluorouracil, and X-ray, which means that Nrf2 over-activation could also help cancer cells survive chemotherapy and irradiation and subsequently relapse.9, 11, 12, 13, 14, 26, 31  The promoting role of aberrant Keap1-Nrf2 signaling in carcinogenesis and therapy resistance has been well demonstrated in vivo and animal models;7, 13, 17, 25, 29, 31, 32 however, relevant clinical studies remain inadequate.	('promoting', 'PosReg', (935, 944))	('aberrant', 'Var', (953, 961))	('cancer', 'Disease', (829, 835))	('cancer', 'Phenotype', 'HP:0002664', (426, 432))	('platinum', 'Chemical', 'MESH:D010984', (730, 738))	('carcinogenesis', 'Disease', 'MESH:D063646', (986, 1000))	('cancer', 'Phenotype', 'HP:0002664', (829, 835))	('ROS', 'Chemical', 'MESH:D017382', (673, 676))	('cancer', 'Disease', (426, 432))	('cancer', 'Disease', 'MESH:D009369', (426, 432))	('ROS', 'Chemical', 'MESH:D017382', (596, 599))	('Oxidative stress', 'Phenotype', 'HP:0025464', (146, 162))	('elevation of ROS scavenging ability', 'Phenotype', 'HP:0025464', (483, 518))	('therapy resistance', 'CPA', (1005, 1023))	('carcinogenesis', 'Disease', (986, 1000))	('ROS', 'Chemical', 'MESH:D017382', (496, 499))	('cancer', 'Disease', 'MESH:D009369', (829, 835))
528977	29675925	The promoting role of aberrant Keap1-Nrf2 signaling in carcinogenesis was proven in a clinical setting.	('carcinogenesis', 'Disease', 'MESH:D063646', (55, 69))	('aberrant', 'Var', (22, 30))	('Keap1-Nrf2', 'Gene', (31, 41))	('carcinogenesis', 'Disease', (55, 69))
529017	24786473	We uncovered 186 downregulated genes harboring cancer specific promoter methylation including PAX1 and PAX5 and we identified 10 key tumor suppressor genes (GABRB3, HOXC12, PARP15, SLCO4C1, CDKN2A, PAX1, PIK3AP1, HOXC6, PLCB1, and ZIC4) inactivated by both promoter methylation and/or somatic mutation.	('SLCO4C1', 'Gene', '353189', (181, 188))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('PAX1', 'Gene', '5075', (94, 98))	('GABRB3', 'Gene', (157, 163))	('cancer', 'Disease', (47, 53))	('downregulated', 'NegReg', (17, 30))	('PAX5', 'Gene', (103, 107))	('PARP15', 'Gene', '165631', (173, 179))	('PAX1', 'Gene', (198, 202))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('HOXC12', 'Gene', '3228', (165, 171))	('HOXC6', 'Gene', '3223', (213, 218))	('promoter methylation', 'Var', (257, 277))	('CDKN2A', 'Gene', (190, 196))	('SLCO4C1', 'Gene', (181, 188))	('PAX1', 'Gene', (94, 98))	('GABRB3', 'Gene', '2562', (157, 163))	('PAX5', 'Gene', '5079', (103, 107))	('tumor', 'Disease', (133, 138))	('ZIC4', 'Gene', (231, 235))	('PIK3AP1', 'Gene', '118788', (204, 211))	('HOXC6', 'Gene', (213, 218))	('ZIC4', 'Gene', '84107', (231, 235))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('CDKN2A', 'Gene', '1029', (190, 196))	('tumor', 'Disease', 'MESH:D009369', (133, 138))	('HOXC12', 'Gene', (165, 171))	('PARP15', 'Gene', (173, 179))	('PLCB1', 'Gene', '23236', (220, 225))	('PLCB1', 'Gene', (220, 225))	('PAX1', 'Gene', '5075', (198, 202))	('genes', 'Gene', (31, 36))	('PIK3AP1', 'Gene', (204, 211))
529018	24786473	Among the novel tumor suppressor genes discovered with dual mechanisms of inactivation, we found a high frequency of genomic and epigenomic alterations in the PAX gene family of transcription factors, which selectively impact canonical NOTCH and TP53 pathways to determine cell fate, cell survival, and genome maintenance.	('PAX', 'Chemical', '-', (159, 162))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('PAX', 'Gene', (159, 162))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('impact', 'Reg', (219, 225))	('TP53', 'Gene', '7157', (246, 250))	('cell survival', 'CPA', (284, 297))	('alterations', 'Var', (140, 151))	('tumor', 'Disease', (16, 21))	('genome maintenance', 'CPA', (303, 321))	('determine', 'Reg', (263, 272))	('TP53', 'Gene', (246, 250))	('cell fate', 'CPA', (273, 282))
529019	24786473	Our results highlight the importance of assessing TSGs at the genomic and epigenomic level to identify key pathways in HNSCC, deregulated by simultaneous promoter methylation and somatic mutations.	('TSG', 'Gene', (50, 53))	('promoter methylation', 'Var', (154, 174))	('TSG', 'Gene', '57045', (50, 53))	('HNSCC', 'Phenotype', 'HP:0012288', (119, 124))	('HNSCC', 'Disease', (119, 124))
529021	24786473	Two groups that independently studied the genetic origins of HNSCC reported inactivating mutations in NOTCH1.	('inactivating mutations', 'Var', (76, 98))	('NOTCH1', 'Gene', '4851', (102, 108))	('HNSCC', 'Phenotype', 'HP:0012288', (61, 66))	('NOTCH1', 'Gene', (102, 108))	('HNSCC', 'Disease', (61, 66))
529022	24786473	This was the first strong evidence of NOTCH1 mutations in solid tumors; analysis of the mutations suggested that NOTCH1 might act as a tumor suppressor gene (TSG) in HNSCC.	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('TSG', 'Gene', '57045', (158, 161))	('tumor', 'Disease', (64, 69))	('HNSCC', 'Phenotype', 'HP:0012288', (166, 171))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('HNSCC', 'Disease', (166, 171))	('solid tumors', 'Disease', (58, 70))	('mutations', 'Var', (88, 97))	('tumor', 'Disease', (135, 140))	('NOTCH1', 'Gene', (113, 119))	('NOTCH1', 'Gene', '4851', (113, 119))	('NOTCH1', 'Gene', '4851', (38, 44))	('NOTCH1', 'Gene', (38, 44))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('TSG', 'Gene', (158, 161))	('solid tumors', 'Disease', 'MESH:D009369', (58, 70))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
529024	24786473	TP53 was again identified as the most commonly mutated gene in HNSCC and, while mutant TP53 has been associated with poor survival, the most important biologic consequences of this alteration have been elusive.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', '7157', (87, 91))	('TP53', 'Gene', (0, 4))	('mutant', 'Var', (80, 86))	('TP53', 'Gene', (87, 91))	('HNSCC', 'Disease', (63, 68))	('HNSCC', 'Phenotype', 'HP:0012288', (63, 68))
529028	24786473	HNSCCs also exhibit many chromosomal abnormalities, including amplifications of the 11q13 region containing the cyclin D1 gene and the 7p11 region encoding EGFR, which lead to proto-oncogene activation.	('EGFR', 'Gene', '1956', (156, 160))	('amplifications', 'Var', (62, 76))	('activation', 'PosReg', (191, 201))	('cyclin D1', 'Gene', '595', (112, 121))	('chromosomal abnormalities', 'Disease', (25, 50))	('EGFR', 'Gene', (156, 160))	('cyclin D1', 'Gene', (112, 121))	('lead to', 'Reg', (168, 175))	('proto-oncogene', 'Protein', (176, 190))	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (25, 50))	('HNSCC', 'Phenotype', 'HP:0012288', (0, 5))
529029	24786473	Aberrant DNA methylation of CpGs in the proximity of predicted transcription start sites (TSS) often leads to alterations in gene function and pathway deregulation in human cancer.	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('cancer', 'Disease', (173, 179))	('Aberrant DNA methylation', 'Var', (0, 24))	('leads to alterations', 'Reg', (101, 121))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('gene function', 'MPA', (125, 138))	('human', 'Species', '9606', (167, 172))	('pathway deregulation', 'CPA', (143, 163))
529030	24786473	Epigenetic events linked to TSG inactivation through promoter methylation, are more frequent events than somatic mutations in cancer, and may be driving tumorigenic initiation and progression.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('TSG', 'Gene', '57045', (28, 31))	('Epigenetic events', 'Var', (0, 17))	('cancer', 'Disease', (126, 132))	('tumor', 'Disease', (153, 158))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('promoter', 'MPA', (53, 61))	('inactivation', 'Var', (32, 44))	('TSG', 'Gene', (28, 31))
529033	24786473	We tested the hypothesis that TSG promoter methylation predominantly occurs in genes or pathways with well-known somatic mutations and/or deletions in most HNSCC tumors, including TP53, CDK2NA, and, more recently, NOTCH1 and FAT1, as well as in recently described genes with low frequency mutations.	('HNSCC tumors', 'Disease', (156, 168))	('NOTCH1', 'Gene', '4851', (214, 220))	('NOTCH1', 'Gene', (214, 220))	('FAT1', 'Gene', '2195', (225, 229))	('mutations', 'Var', (121, 130))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('FAT1', 'Gene', (225, 229))	('HNSCC tumors', 'Disease', 'MESH:D000077195', (156, 168))	('TP53', 'Gene', '7157', (180, 184))	('TP53', 'Gene', (180, 184))	('TSG', 'Gene', '57045', (30, 33))	('TSG', 'Gene', (30, 33))	('occurs', 'Reg', (69, 75))	('CDK2', 'Gene', (186, 190))	('deletions', 'Var', (138, 147))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))	('HNSCC', 'Phenotype', 'HP:0012288', (156, 161))	('CDK2', 'Gene', '1017', (186, 190))
529039	24786473	HPV tumor status was also determined by E6/E7 PCR primer amplification.	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('HPV tumor', 'Disease', (0, 9))	('HPV tumor', 'Disease', 'MESH:D030361', (0, 9))	('E6/E7 PCR', 'Var', (40, 49))
529051	24786473	discovered and mapped mutations in HNSCC, comprising ten patients and ten frequency matched normal controls (uvulopalatopharyngoplasty tissue samples [UPPP]).	('uvulopalatopharyngoplasty', 'Disease', 'None', (109, 134))	('HNSCC', 'Phenotype', 'HP:0012288', (35, 40))	('patients', 'Species', '9606', (57, 65))	('uvulopalatopharyngoplasty', 'Disease', (109, 134))	('mutations', 'Var', (22, 31))	('HNSCC', 'Gene', (35, 40))
529056	24786473	186 methylated genes were found to harbor methylation and downregulation; PAX1 and PAX5 exhibited the greatest expression loss (Fig.	('downregulation', 'NegReg', (58, 72))	('expression', 'MPA', (111, 121))	('PAX5', 'Gene', (83, 87))	('PAX1', 'Gene', '5075', (74, 78))	('PAX5', 'Gene', '5079', (83, 87))	('methylation', 'Var', (42, 53))	('PAX1', 'Gene', (74, 78))
529057	24786473	Table S4B shows the relationship between methylation frequency of the significantly downregulated candidate genes with FC < -2 and the expression levels of these candidate genes for the 16 tumor samples queried with mRNA arrays in the Discovery cohort.	('downregulated', 'NegReg', (84, 97))	('tumor', 'Disease', (189, 194))	('expression levels', 'MPA', (135, 152))	('methylation', 'Var', (41, 52))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))
529059	24786473	CDKN2A (p16), one of the most frequently altered tumor suppressor genes in human cancer by mutation, methylation, and/or deletion was confirmed on this list.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('mutation', 'Var', (91, 99))	('p16', 'Gene', '1029', (8, 11))	('human', 'Species', '9606', (75, 80))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('cancer', 'Disease', (81, 87))	('tumor', 'Disease', (49, 54))	('p16', 'Gene', (8, 11))	('CDKN2A', 'Gene', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('methylation', 'Var', (101, 112))	('deletion', 'Var', (121, 129))	('CDKN2A', 'Gene', '1029', (0, 6))
529064	24786473	PAX1 was also methylated in most patients with a history of tobacco exposure (71%), while only 33% of patients without tobacco exposure history exhibited PAX1 methylation.	('tobacco', 'Species', '4097', (60, 67))	('tobacco', 'Species', '4097', (119, 126))	('PAX1', 'Gene', '5075', (0, 4))	('PAX1', 'Gene', (0, 4))	('patients', 'Species', '9606', (33, 41))	('PAX1', 'Gene', '5075', (154, 158))	('patients', 'Species', '9606', (102, 110))	('methylated', 'Var', (14, 24))	('PAX1', 'Gene', (154, 158))
529068	24786473	Patients with TP53 mutations also had PAX1 promoter methylation, history of tobacco exposure, and were HPV negative.	('tobacco', 'Species', '4097', (76, 83))	('TP53', 'Gene', '7157', (14, 18))	('TP53', 'Gene', (14, 18))	('PAX1', 'Gene', '5075', (38, 42))	('PAX1', 'Gene', (38, 42))	('mutations', 'Var', (19, 28))	('Patients', 'Species', '9606', (0, 8))
529069	24786473	Most (83%) of the patients with TP53 mutations had evidence of PAX5 methylation (Fig.	('TP53', 'Gene', '7157', (32, 36))	('mutations', 'Var', (37, 46))	('PAX5', 'Gene', '5079', (63, 67))	('PAX5', 'Gene', (63, 67))	('TP53', 'Gene', (32, 36))	('patients', 'Species', '9606', (18, 26))
529072	24786473	PAX1 was methylated in 68% of the cancer cases, ZIC4 in 80% and PLCB1 in 52%.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('PAX1', 'Gene', (0, 4))	('PAX1', 'Gene', '5075', (0, 4))	('PLCB1', 'Gene', '23236', (64, 69))	('ZIC4', 'Gene', (48, 52))	('PLCB1', 'Gene', (64, 69))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('cancer', 'Disease', (34, 40))	('methylated', 'Var', (9, 19))	('ZIC4', 'Gene', '84107', (48, 52))
529074	24786473	PAX5 was methylated in 77% of the HNSCC cases in the validation cohort, a number very similar to the 70% methylation frequency identified in the discovery set.	('PAX5', 'Gene', '5079', (0, 4))	('PAX5', 'Gene', (0, 4))	('methylated', 'Var', (9, 19))	('HNSCC', 'Phenotype', 'HP:0012288', (34, 39))	('HNSCC', 'Disease', (34, 39))
529075	24786473	We found that PAX1 (P < 0.0001), ZIC4 (P < 0.0001), PLCB1 (P < 0.001), and PAX5 (P < 0.0001) methylation distinguished tumor from UPPP samples (Figs.	('tumor', 'Disease', (119, 124))	('PAX1', 'Gene', (14, 18))	('ZIC4', 'Gene', '84107', (33, 37))	('PAX5', 'Gene', (75, 79))	('PAX5', 'Gene', '5079', (75, 79))	('PAX1', 'Gene', '5075', (14, 18))	('PLCB1', 'Gene', '23236', (52, 57))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('ZIC4', 'Gene', (33, 37))	('PLCB1', 'Gene', (52, 57))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('methylation', 'Var', (93, 104))
529077	24786473	A chi-square test of independence revealed an association between methylation in PLCB1 and tumor site, P < 0.01.	('PLCB1', 'Gene', (81, 86))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('methylation', 'Var', (66, 77))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor', 'Disease', (91, 96))	('PLCB1', 'Gene', '23236', (81, 86))
529078	24786473	Tumors of the oral cavity and oropharynx were the most frequently methylated.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('methylated', 'Var', (66, 76))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))
529079	24786473	All samples harboring CDKN2A mutations had PAX1 methylation (P < 0.0001) as did most of TP53 mutated samples (P < 0.01).	('methylation', 'MPA', (48, 59))	('mutations', 'Var', (29, 38))	('CDKN2A', 'Gene', (22, 28))	('CDKN2A', 'Gene', '1029', (22, 28))	('TP53', 'Gene', '7157', (88, 92))	('PAX1', 'Gene', '5075', (43, 47))	('PAX1', 'Gene', (43, 47))	('TP53', 'Gene', (88, 92))
529080	24786473	More than half of NOTCH1 (61.5%, P < 0.0001) mutated samples also exhibited PAX1 promoter methylation.	('NOTCH1', 'Gene', (18, 24))	('exhibited', 'Reg', (66, 75))	('PAX1', 'Gene', (76, 80))	('PAX1', 'Gene', '5075', (76, 80))	('NOTCH1', 'Gene', '4851', (18, 24))	('promoter methylation', 'MPA', (81, 101))	('mutated', 'Var', (45, 52))
529081	24786473	All the samples with mutations in FBXW7 (P < 0.0001), and most of the samples with mutations in TP53 (79%, P < 0.0001), and NOTCH1 (92%, P < 0.0001) were methylated in the PAX5 promoter even after controlling for HPV-status and history of tobacco use (Table S8A).	('mutations', 'Var', (83, 92))	('NOTCH1', 'Gene', (124, 130))	('methylated', 'Var', (154, 164))	('FBXW7', 'Gene', '55294', (34, 39))	('tobacco', 'Species', '4097', (239, 246))	('TP53', 'Gene', (96, 100))	('FBXW7', 'Gene', (34, 39))	('PAX5', 'Gene', (172, 176))	('PAX5', 'Gene', '5079', (172, 176))	('NOTCH1', 'Gene', '4851', (124, 130))	('TP53', 'Gene', '7157', (96, 100))	('mutations', 'Var', (21, 30))
529083	24786473	PAX5 promoter methylation was associated with TP53 mutations (P = 0.02), while PAX1 promoter methylation was associated with NOTCH1 mutations (P < 0.0001), even after controlling for HPV-status and tobacco use.	('associated', 'Reg', (30, 40))	('associated', 'Reg', (109, 119))	('mutations', 'Var', (51, 60))	('PAX1', 'Gene', (79, 83))	('tobacco', 'Species', '4097', (198, 205))	('mutations', 'Var', (132, 141))	('TP53', 'Gene', '7157', (46, 50))	('PAX1', 'Gene', '5075', (79, 83))	('PAX5', 'Gene', (0, 4))	('PAX5', 'Gene', '5079', (0, 4))	('TP53', 'Gene', (46, 50))	('NOTCH1', 'Gene', '4851', (125, 131))	('NOTCH1', 'Gene', (125, 131))
529084	24786473	This evidence suggests a frequent occurrence of previously unreported interactions between PAX1 and PAX5 promoter methylation and exonic mutations in NOTCH1 and TP53 in HNSCC, respectively (Table S8B).	('PAX1', 'Gene', '5075', (91, 95))	('TP53', 'Gene', (161, 165))	('TP53', 'Gene', '7157', (161, 165))	('NOTCH1', 'Gene', '4851', (150, 156))	('HNSCC', 'Phenotype', 'HP:0012288', (169, 174))	('PAX5', 'Gene', '5079', (100, 104))	('HNSCC', 'Disease', (169, 174))	('NOTCH1', 'Gene', (150, 156))	('interactions', 'Interaction', (70, 82))	('PAX5', 'Gene', (100, 104))	('methylation', 'Var', (114, 125))	('exonic mutations', 'Var', (130, 146))	('PAX1', 'Gene', (91, 95))
529092	24786473	After gene set enrichment analysis revealed that concurrent promoter methylation, mutations, and differential gene expression impacted cell differentiation, proliferation, growth and renewal pathways we performed a review study of the most important, potentially impacted cancer pathways in HNSCC.	('cancer', 'Phenotype', 'HP:0002664', (272, 278))	('impacted', 'Reg', (126, 134))	('HNSCC', 'Phenotype', 'HP:0012288', (291, 296))	('cancer', 'Disease', 'MESH:D009369', (272, 278))	('mutations', 'Var', (82, 91))	('cell differentiation', 'CPA', (135, 155))	('HNSCC', 'Disease', (291, 296))	('promoter methylation', 'Var', (60, 80))	('cancer', 'Disease', (272, 278))
529093	24786473	We found evidence of a strong interplay between somatic mutations in p53 and NOTCH1 and gene downregulation associated to PAX1 and PAX5 promoter methylation in HNSCC.	('PAX1', 'Gene', '5075', (122, 126))	('mutations', 'Var', (56, 65))	('p53', 'Gene', (69, 72))	('p53', 'Gene', '7157', (69, 72))	('NOTCH1', 'Gene', '4851', (77, 83))	('NOTCH1', 'Gene', (77, 83))	('PAX5', 'Gene', '5079', (131, 135))	('PAX5', 'Gene', (131, 135))	('HNSCC', 'Disease', (160, 165))	('HNSCC', 'Phenotype', 'HP:0012288', (160, 165))	('downregulation', 'NegReg', (93, 107))	('PAX1', 'Gene', (122, 126))
529103	24786473	revealed inactivating mutations in NOTCH1 gene, depicting its importance in HNSCC, proposing also a tumor suppressor function in this particular type of tumors.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('HNSCC', 'Disease', (76, 81))	('tumor', 'Disease', (100, 105))	('HNSCC', 'Phenotype', 'HP:0012288', (76, 81))	('inactivating mutations', 'Var', (9, 31))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('tumors', 'Disease', (153, 159))	('tumors', 'Phenotype', 'HP:0002664', (153, 159))	('NOTCH1', 'Gene', '4851', (35, 41))	('NOTCH1', 'Gene', (35, 41))	('tumors', 'Disease', 'MESH:D009369', (153, 159))
529105	24786473	Preliminary data in cell lines showed that downregulation of NOTCH1 in NOTCH1 mutant cell lines leads to a modest effect of cell cycle acceleration and anti-NOTCH1 agents are only effective in NOTCH1 wild type cell lines.	('NOTCH1', 'Gene', (193, 199))	('NOTCH1', 'Gene', (71, 77))	('downregulation', 'NegReg', (43, 57))	('NOTCH1', 'Gene', '4851', (61, 67))	('NOTCH1', 'Gene', (61, 67))	('cell cycle acceleration', 'CPA', (124, 147))	('NOTCH1', 'Gene', '4851', (157, 163))	('NOTCH1', 'Gene', (157, 163))	('mutant', 'Var', (78, 84))	('NOTCH1', 'Gene', '4851', (193, 199))	('NOTCH1', 'Gene', '4851', (71, 77))
529112	24786473	The main focus of this paper was to identify the number of tumor suppressor genes differentially methylated in the greater promoter region and mutated in HNSCC, and examine their combined impact in expression downregulation.	('tumor', 'Disease', (59, 64))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('mutated', 'Var', (143, 150))	('HNSCC', 'Phenotype', 'HP:0012288', (154, 159))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
529118	24786473	We observed interesting relationships among the most commonly mutated and methylated genes in HNSCC: 61.5% of the NOTCH1 mutated samples also exhibited PAX1 methylation and 79% of the samples carrying TP53 mutations were also methylated in the PAX5 gene promoter.	('mutations', 'Var', (206, 215))	('exhibited', 'Reg', (142, 151))	('NOTCH1', 'Gene', (114, 120))	('TP53', 'Gene', '7157', (201, 205))	('PAX5', 'Gene', '5079', (244, 248))	('HNSCC', 'Phenotype', 'HP:0012288', (94, 99))	('PAX1', 'Gene', (152, 156))	('mutated', 'Var', (121, 128))	('methylation', 'Var', (157, 168))	('PAX5', 'Gene', (244, 248))	('TP53', 'Gene', (201, 205))	('PAX1', 'Gene', '5075', (152, 156))	('NOTCH1', 'Gene', '4851', (114, 120))
529119	24786473	Combined, this evidence suggests the frequent occurrence of previously unreported interactions between PAX1 and PAX5 promoter methylation and exonic mutations in NOTCH1 and TP53 in HNSCC.	('interactions', 'Interaction', (82, 94))	('PAX5', 'Gene', '5079', (112, 116))	('NOTCH1', 'Gene', '4851', (162, 168))	('NOTCH1', 'Gene', (162, 168))	('exonic mutations', 'Var', (142, 158))	('PAX5', 'Gene', (112, 116))	('PAX1', 'Gene', (103, 107))	('PAX1', 'Gene', '5075', (103, 107))	('TP53', 'Gene', '7157', (173, 177))	('TP53', 'Gene', (173, 177))	('HNSCC', 'Phenotype', 'HP:0012288', (181, 186))	('HNSCC', 'Disease', (181, 186))
529129	24786473	Loss of NuOTCH1 function due to mutation, or mutation/methylation-dependent silencing of downstream genes, such as PAX1 or the HOX family genes, is likely to abrogate normal cell differentiation.	('silencing', 'NegReg', (76, 85))	('normal cell differentiation', 'CPA', (167, 194))	('NuOTCH1', 'Gene', (8, 15))	('Loss', 'NegReg', (0, 4))	('mutation/methylation-dependent', 'Var', (45, 75))	('PAX1', 'Gene', (115, 119))	('PAX1', 'Gene', '5075', (115, 119))	('abrogate', 'NegReg', (158, 166))	('mutation', 'Var', (32, 40))	('function', 'MPA', (16, 24))
529130	24786473	Clinically, TP53 mutation has been shown time and again to be among the worst molecular alterations in patients with HNSCC.	('HNSCC', 'Phenotype', 'HP:0012288', (117, 122))	('HNSCC', 'Disease', (117, 122))	('mutation', 'Var', (17, 25))	('TP53', 'Gene', '7157', (12, 16))	('patients', 'Species', '9606', (103, 111))	('TP53', 'Gene', (12, 16))
529132	24786473	We confirmed a high frequency of PAX methylated tumors in 279 HNSCC tumor samples from the TCGA cohort and found that tumors which already harbor a p53 mutation, also harbor PAX5 promoter methylation.	('tumors', 'Disease', (48, 54))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('tumors', 'Disease', 'MESH:D009369', (48, 54))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('HNSCC tumor', 'Disease', 'MESH:D000077195', (62, 73))	('tumors', 'Disease', (118, 124))	('mutation', 'Var', (152, 160))	('p53', 'Gene', '7157', (148, 151))	('PAX5', 'Gene', (174, 178))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('tumors', 'Disease', 'MESH:D009369', (118, 124))	('HNSCC', 'Phenotype', 'HP:0012288', (62, 67))	('p53', 'Gene', (148, 151))	('PAX5', 'Gene', '5079', (174, 178))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('PAX', 'Chemical', '-', (33, 36))	('PAX', 'Chemical', '-', (174, 177))	('HNSCC tumor', 'Disease', (62, 73))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
529164	24786473	A chi-square test of independence was applied to test whether each Functional Gene Set (FGS) was over-represented in any of the gene list associated with any of the investigated contrasts/conditions (e.g., gene associated with methylated promoters in HNSCC).	('HNSCC', 'Phenotype', 'HP:0012288', (251, 256))	('over-represented', 'PosReg', (97, 113))	('FGS', 'Disease', 'MESH:C537923', (88, 91))	('methylated', 'Var', (227, 237))	('FGS', 'Disease', (88, 91))
529167	24786473	AFA was used to compare biological themes enriched in the following gene lists: (1) mutated genes; (2) genes with hyper-methylated promoters; (3) genes showing hyper-methylation outside the greater promoter region; (4) genes upregulated in cancer when compared with normal; and (5) genes downregulated in cancer when compared with normal.	('upregulated', 'PosReg', (225, 236))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('hyper-methylation', 'Var', (160, 177))	('cancer', 'Disease', (305, 311))	('cancer', 'Disease', 'MESH:D009369', (305, 311))	('cancer', 'Disease', 'MESH:D009369', (240, 246))	('cancer', 'Disease', (240, 246))	('cancer', 'Phenotype', 'HP:0002664', (305, 311))
529168	24786473	qMSP was used for validation in a Prevalence cohort of 76 tumors in which we had previously identified somatic mutations in TP53, NOTCH1, CDKN2A, PIK3CA, FBXW7, and HRAS and in 19 UPPP normal control tissue samples.	('mutations', 'Var', (111, 120))	('CDKN2A', 'Gene', (138, 144))	('PIK3CA', 'Gene', '5290', (146, 152))	('CDKN2A', 'Gene', '1029', (138, 144))	('HRAS', 'Gene', (165, 169))	('TP53', 'Gene', '7157', (124, 128))	('tumors', 'Disease', (58, 64))	('NOTCH1', 'Gene', (130, 136))	('FBXW7', 'Gene', (154, 159))	('NOTCH1', 'Gene', '4851', (130, 136))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('TP53', 'Gene', (124, 128))	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('HRAS', 'Gene', '3265', (165, 169))	('PIK3CA', 'Gene', (146, 152))	('FBXW7', 'Gene', '55294', (154, 159))
529173	24786473	Contingency tables were used to examine the association between exonic mutations of TP53, CDKN2A, HRAS, FBXW7, and NOTCH1 and promoter methylation of ZIC4, PAX1, PAX5, and PLCB1.	('ZIC4', 'Gene', (150, 154))	('PAX1', 'Gene', '5075', (156, 160))	('ZIC4', 'Gene', '84107', (150, 154))	('PAX5', 'Gene', '5079', (162, 166))	('TP53', 'Gene', (84, 88))	('CDKN2A', 'Gene', (90, 96))	('FBXW7', 'Gene', (104, 109))	('exonic mutations', 'Var', (64, 80))	('HRAS', 'Gene', '3265', (98, 102))	('HRAS', 'Gene', (98, 102))	('association', 'Interaction', (44, 55))	('NOTCH1', 'Gene', (115, 121))	('CDKN2A', 'Gene', '1029', (90, 96))	('TP53', 'Gene', '7157', (84, 88))	('PAX1', 'Gene', (156, 160))	('FBXW7', 'Gene', '55294', (104, 109))	('NOTCH1', 'Gene', '4851', (115, 121))	('promoter methylation', 'MPA', (126, 146))	('PLCB1', 'Gene', '23236', (172, 177))	('PLCB1', 'Gene', (172, 177))	('PAX5', 'Gene', (162, 166))
529181	24786473	Pax5 knockdown in 22B cells showed a modest increase in cell proliferation compared with the control.	('Pax5', 'Gene', (0, 4))	('knockdown', 'Var', (5, 14))	('increase', 'PosReg', (44, 52))	('cell proliferation', 'CPA', (56, 74))	('Pax5', 'Gene', '5079', (0, 4))
529187	33462277	Moreover, we designed an effective nanoparticle system for the doxorubicin (DOX) delivery targeting the oral squamous cell carcinoma (OSCC) by mediating the HN-1 (TSPLNIHNGQKL) through hydrogen and pi-pi bonds.	('HN-1', 'Var', (157, 161))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (104, 132))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (109, 132))	('hydrogen', 'Chemical', 'MESH:D006859', (185, 193))	('DOX', 'Chemical', 'MESH:D004317', (76, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('doxorubicin', 'Chemical', 'MESH:D004317', (63, 74))	('oral squamous cell carcinoma', 'Disease', (104, 132))
529188	33462277	DOX@NGO-PEG-HN-1 showed significantly higher cellular uptakes and cytotoxicity in OSCC cells (CAL-27 and SCC-25), compared to free DOX.	('CAL', 'Chemical', '-', (94, 97))	('DOX', 'Chemical', 'MESH:D004317', (0, 3))	('cytotoxicity', 'Disease', 'MESH:D064420', (66, 78))	('NGO-PEG', 'Chemical', '-', (4, 11))	('DOX', 'Chemical', 'MESH:D004317', (131, 134))	('higher', 'PosReg', (38, 44))	('cytotoxicity', 'Disease', (66, 78))	('NGO-PEG-HN-1', 'Var', (4, 16))	('cellular uptakes', 'CPA', (45, 61))	('SCC-25', 'CellLine', 'CVCL:1682', (105, 111))
529197	33462277	EPR effect is the enhanced permeability and retention effect is that the small size of nanocarriers (20-200 nm) penetrate through the leaky tumor vessels and finally gather in the tumor interstitial space.	('leaky tumor', 'Disease', (134, 145))	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('leaky tumor', 'Disease', 'MESH:C535298', (134, 145))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('20-200 nm', 'Var', (101, 110))	('permeability', 'MPA', (27, 39))	('tumor', 'Disease', (180, 185))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('tumor', 'Disease', (140, 145))
529220	33462277	However, DOX@NGO-PEG-HN-1 represents obvious wrinkles and curls (Fig.	('wrinkles', 'CPA', (45, 53))	('DOX@NGO-PEG-HN-1', 'Var', (9, 25))	('DOX', 'Chemical', 'MESH:D004317', (9, 12))	('NGO-PEG', 'Chemical', '-', (13, 20))	('curls', 'CPA', (58, 63))
529236	33462277	This showed that the NGO was indeed apromising drug carrier materials.	('NGO', 'Chemical', '-', (21, 24))	('drug carrier', 'MPA', (47, 59))	('apromising', 'NegReg', (36, 46))	('NGO', 'Var', (21, 24))
529243	33462277	It exactly proved that the PEG conjunction could enhance the biocompatibility and stability of NGO.	('stability', 'CPA', (82, 91))	('PEG', 'Var', (27, 30))	('enhance', 'PosReg', (49, 56))	('biocompatibility', 'MPA', (61, 77))	('NGO', 'Chemical', '-', (95, 98))	('PEG', 'Chemical', 'MESH:D011092', (27, 30))
529256	33462277	11, the cell viability of the NGO-PEG-HN-1 group is nearly 100% in three kinds of cells.	('NGO-PEG', 'Chemical', '-', (30, 37))	('NGO-PEG-HN-1', 'Var', (30, 42))	('cell viability', 'CPA', (8, 22))
529259	33462277	11 that DOX@NGO-PEG-HN-1 had a greater cytotoxic effect than free DOX.	('cytotoxic effect', 'CPA', (39, 55))	('DOX@NGO-PEG-HN-1', 'Var', (8, 24))	('NGO-PEG', 'Chemical', '-', (12, 19))	('DOX', 'Chemical', 'MESH:D004317', (66, 69))	('DOX', 'Chemical', 'MESH:D004317', (8, 11))
529266	33462277	Achieving the DOX@NGO-PEG-HN-1 at tumor tissue, the DOX can be quickly released from the system as a result of the weakened hydrogen bonding interaction and pi-pi conjugation between GO and DOX.	('GO', 'Chemical', 'MESH:C000628730', (19, 21))	('tumor', 'Disease', (34, 39))	('hydrogen', 'Interaction', (124, 132))	('DOX', 'Chemical', 'MESH:D004317', (14, 17))	('DOX', 'Chemical', 'MESH:D004317', (52, 55))	('NGO-PEG', 'Chemical', '-', (18, 25))	('GO', 'Chemical', 'MESH:C000628730', (183, 185))	('pi-pi conjugation', 'Var', (157, 174))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('DOX', 'Chemical', 'MESH:D004317', (190, 193))	('hydrogen', 'Chemical', 'MESH:D006859', (124, 132))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('weakened', 'NegReg', (115, 123))
529267	33462277	The experimental findings of the cytotoxicity prove that the DOX@NGO-PEG-HN-1 can be simply absorbed by tumor cells and exhibited a collaboration effect.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('cytotoxicity', 'Disease', (33, 45))	('tumor', 'Disease', (104, 109))	('DOX@NGO-PEG-HN-1', 'Var', (61, 77))	('cytotoxicity', 'Disease', 'MESH:D064420', (33, 45))	('NGO-PEG', 'Chemical', '-', (65, 72))	('exhibited', 'Reg', (120, 129))	('DOX', 'Chemical', 'MESH:D004317', (61, 64))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
529272	33462277	Organ tissue section analysis, blood routine, and biochemical indicators indicated that NGO-PEG had no significant damage to liver and kidney functions in mice.	('NGO-PEG', 'Var', (88, 95))	('NGO-PEG', 'Chemical', '-', (88, 95))	('mice', 'Species', '10090', (155, 159))	('liver', 'MPA', (125, 130))
529294	33462277	The concentrations of NGO, NGO-PEG, DOX@NGO-PEG-HN-1 were 1.0 mg/mL in water and serum-containing solution.	('water', 'Chemical', 'MESH:D014867', (71, 76))	('NGO-PEG', 'Chemical', '-', (40, 47))	('NGO', 'Var', (22, 25))	('NGO', 'Chemical', '-', (22, 25))	('NGO', 'Chemical', '-', (40, 43))	('DOX', 'Chemical', 'MESH:D004317', (36, 39))	('NGO-PEG', 'Chemical', '-', (27, 34))	('NGO', 'Chemical', '-', (27, 30))	('NGO-PEG', 'Var', (27, 34))
529318	32932638	showed that local recurrence was higher with muscle invasion than DOI, although the positive predictive value of muscle invasion in regards to nodal status was slightly less than DOI.	('muscle invasion', 'Var', (45, 60))	('higher', 'PosReg', (33, 39))	('nodal', 'Gene', (143, 148))	('local recurrence', 'CPA', (12, 28))	('nodal', 'Gene', '4838', (143, 148))
529360	32932638	To reinforce the idea that like smooth muscle invasion, neoplastic invasion of skeletal muscle is associated with worsened cancer prognosis, Beunk et al.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('neoplastic', 'Var', (56, 66))	('cancer', 'Disease', (123, 129))	('worsened', 'PosReg', (114, 122))
529371	32932638	These authors found that in patients with low tumor budding grade, considered (histological) morphometric findings of invasiveness, the presence of podoplanin was a significant predictor of neck lymph node metastasis.	('low tumor', 'Disease', 'MESH:D009800', (42, 51))	('podoplanin', 'Gene', '10630', (148, 158))	('podoplanin', 'Gene', (148, 158))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('low tumor', 'Disease', (42, 51))	('neck lymph node metastasis', 'CPA', (190, 216))	('patients', 'Species', '9606', (28, 36))	('presence', 'Var', (136, 144))	('predictor', 'Reg', (177, 186))
529374	32932638	showed that local recurrence was higher with muscle invasion than DOI, although the positive predictive value of muscle invasion regarding nodal status was slightly less than DOI.	('muscle invasion', 'Var', (45, 60))	('higher', 'PosReg', (33, 39))	('nodal', 'Gene', (139, 144))	('nodal', 'Gene', '4838', (139, 144))	('local recurrence', 'CPA', (12, 28))
529393	31182116	Tumor DNA isolated from LXY30-enriched plasma exosomes might be used to detect driver oncogenic mutations in patients with metastatic NSCLC.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('NSCLC', 'Disease', 'MESH:D002289', (134, 139))	('LXY30', 'Chemical', '-', (24, 29))	('patients', 'Species', '9606', (109, 117))	('NSCLC', 'Phenotype', 'HP:0030358', (134, 139))	('metastatic', 'Disease', (123, 133))	('NSCLC', 'Disease', (134, 139))	('mutations', 'Var', (96, 105))
529394	31182116	LXY30 only enriches tumor cells but not neutrophils, macrophages, or monocytes in the malignant pleural effusion of NSCLC patients for detecting genomic alterations by next-generation sequencing.	('LXY30', 'Chemical', '-', (0, 5))	('LXY30', 'Var', (0, 5))	('pleural effusion', 'Phenotype', 'HP:0002202', (96, 112))	('malignant pleural effusion of NSCLC', 'Disease', (86, 121))	('NSCLC', 'Phenotype', 'HP:0030358', (116, 121))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('patients', 'Species', '9606', (122, 130))	('malignant pleural effusion of NSCLC', 'Disease', 'MESH:D016066', (86, 121))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('tumor', 'Disease', (20, 25))
529395	31182116	LXY30 detected increased alpha3beta1 integrin expression on the EGFR-mutant NSCLC cells with acquired resistance to erlotinib compared to parental erlotinib-sensitive EGFR-mutant NSCLC cells.	('beta1 integrin', 'Gene', '3688', (31, 45))	('LXY30', 'Chemical', '-', (0, 5))	('NSCLC', 'Disease', 'MESH:D002289', (179, 184))	('beta1 integrin', 'Gene', (31, 45))	('erlotinib', 'Chemical', 'MESH:D000069347', (147, 156))	('NSCLC', 'Disease', (76, 81))	('NSCLC', 'Phenotype', 'HP:0030358', (76, 81))	('increased', 'PosReg', (15, 24))	('EGFR-mutant', 'Var', (64, 75))	('erlotinib', 'Chemical', 'MESH:D000069347', (116, 125))	('NSCLC', 'Disease', 'MESH:D002289', (76, 81))	('NSCLC', 'Phenotype', 'HP:0030358', (179, 184))	('expression', 'MPA', (46, 56))	('EGFR-mutant', 'Gene', (64, 75))	('NSCLC', 'Disease', (179, 184))
529396	31182116	We further showed that LXY30 modulated the EGFR signaling pathway independently from another peptide ligand LXW64 targeting alphavbeta3 integrin in erlotinib-resistant, EGFR-mutant H1975 cells.	('EGFR-mutant', 'Var', (169, 180))	('peptide', 'Chemical', 'MESH:D010455', (93, 100))	('LXW64', 'Chemical', '-', (108, 113))	('alphavbeta3 integrin', 'Protein', (124, 144))	('modulated', 'Reg', (29, 38))	('LXY30', 'Chemical', '-', (23, 28))	('H1975', 'CellLine', 'CVCL:1511', (181, 186))	('EGFR signaling pathway', 'Pathway', (43, 65))	('erlotinib', 'Chemical', 'MESH:D000069347', (148, 157))
529398	31182116	LXY30-biotin/streptavidin-Cy5.5 complex had higher uptakes in the subcutaneous and intracranial xenografts of various alpha3beta1 integrin-expressing lung adenocarcinoma and patient-derived lung squamous cell carcinoma xenografts while sparing the surrounding normal tissues.	('beta1 integrin', 'Gene', '3688', (124, 138))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (150, 169))	('patient', 'Species', '9606', (174, 181))	('LXY30-biotin', 'Chemical', '-', (0, 12))	('higher', 'PosReg', (44, 50))	('carcinoma', 'Phenotype', 'HP:0030731', (160, 169))	('Cy5', 'Chemical', 'MESH:C085321', (26, 29))	('LXY30-biotin/streptavidin-Cy5.5', 'Var', (0, 31))	('beta1 integrin', 'Gene', (124, 138))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (190, 218))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (195, 218))	('lung adenocarcinoma', 'Disease', (150, 169))	('carcinoma', 'Phenotype', 'HP:0030731', (209, 218))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (150, 169))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (190, 218))	('lung squamous cell carcinoma', 'Disease', (190, 218))	('uptakes', 'MPA', (51, 58))
529399	31182116	LXY30 is a promising peptide for the cancer diagnosis and in vivo targeted delivery of imaging agents and cancer drugs in NSCLC, independent of histology and tumor genotype.	('NSCLC', 'Disease', 'MESH:D002289', (122, 127))	('tumor', 'Disease', (158, 163))	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('LXY30', 'Chemical', '-', (0, 5))	('LXY30', 'Var', (0, 5))	('cancer', 'Disease', (37, 43))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('NSCLC', 'Phenotype', 'HP:0030358', (122, 127))	('cancer', 'Disease', (106, 112))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('peptide', 'Chemical', 'MESH:D010455', (21, 28))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('NSCLC', 'Disease', (122, 127))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
529406	31182116	Abnormal integrin expression has been reported in many cancer types including NSCLC.	('reported', 'Reg', (38, 46))	('NSCLC', 'Phenotype', 'HP:0030358', (78, 83))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('integrin', 'Protein', (9, 17))	('expression', 'MPA', (18, 28))	('Abnormal', 'Var', (0, 8))	('NSCLC', 'Disease', (78, 83))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('NSCLC', 'Disease', 'MESH:D002289', (78, 83))	('cancer', 'Disease', (55, 61))
529411	31182116	Overexpression of alpha3beta1 integrin has been detected in multiple tumor types and associated with poor prognosis, tumorigenesis, invasion, metastasis, and resistance to cancer treatment in several cancer types, including NSCLC.	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('NSCLC', 'Disease', (224, 229))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('Overexpression', 'Var', (0, 14))	('NSCLC', 'Phenotype', 'HP:0030358', (224, 229))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('beta1 integrin', 'Gene', (24, 38))	('metastasis', 'CPA', (142, 152))	('beta1 integrin', 'Gene', '3688', (24, 38))	('cancer', 'Disease', 'MESH:D009369', (200, 206))	('associated', 'Reg', (85, 95))	('cancer', 'Disease', (172, 178))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('detected', 'Reg', (48, 56))	('tumor', 'Disease', (69, 74))	('tumor', 'Disease', (117, 122))	('poor prognosis', 'CPA', (101, 115))	('NSCLC', 'Disease', 'MESH:D002289', (224, 229))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('cancer', 'Disease', (200, 206))	('invasion', 'CPA', (132, 140))
529415	31182116	Among them, LXY30 was bound to alpha3 integrin on the surface of a panel of NSCLC cell lines with variable affinities.	('LXY30', 'Var', (12, 17))	('NSCLC', 'Disease', (76, 81))	('NSCLC', 'Disease', 'MESH:D002289', (76, 81))	('LXY30', 'Chemical', '-', (12, 17))	('bound', 'Interaction', (22, 27))	('alpha3 integrin', 'Protein', (31, 46))	('NSCLC', 'Phenotype', 'HP:0030358', (76, 81))
529416	31182116	As integrin alpha3 subunit only forms a heterodimer with the integrin beta1 subunit, LXY30 is a promising peptide ligand for in vivo targeting alpha3beta1 integrin in NSCLC.	('NSCLC', 'Disease', 'MESH:D002289', (167, 172))	('beta1 integrin', 'Gene', '3688', (149, 163))	('LXY30', 'Chemical', '-', (85, 90))	('NSCLC', 'Phenotype', 'HP:0030358', (167, 172))	('heterodimer', 'MPA', (40, 51))	('integrin beta1', 'Gene', (61, 75))	('LXY30', 'Var', (85, 90))	('integrin alpha3', 'Gene', '3675', (3, 18))	('integrin beta1', 'Gene', '3688', (61, 75))	('beta1 integrin', 'Gene', (149, 163))	('peptide', 'Chemical', 'MESH:D010455', (106, 113))	('NSCLC', 'Disease', (167, 172))	('integrin alpha3', 'Gene', (3, 18))
529425	31182116	H3255 R#2 is the best-characterized resistant clone mimicking the acquired resistance model of EGFR-mutant NSCLC to first-generation EGFR TKI erlotinib.	('NSCLC', 'Disease', (107, 112))	('H3255 R', 'Mutation', 'p.H3255R', (0, 7))	('NSCLC', 'Disease', 'MESH:D002289', (107, 112))	('EGFR-mutant', 'Var', (95, 106))	('EGFR-mutant', 'Gene', (95, 106))	('NSCLC', 'Phenotype', 'HP:0030358', (107, 112))	('erlotinib', 'Chemical', 'MESH:D000069347', (142, 151))
529436	31182116	To determine the binding sensitivity of LXY30, A549 cells or malignant pleural effusion (PE) was subjected to a serial dilution (1:105 or 1:103, respectively) using 1 mL of supernatant of malignant pleural effusion from NSCLC patients, followed by incubation with ~ 250 TentaGel (90 mum, 0.26 mmol/g) (Rapp Polymere GmbH, Tupsilonbingen, Germany) beads coated with LXY30 or scrambled-LXY30 (S-LXY30) for 2 h before examination under microscope.	('malignant pleural effusion', 'Disease', 'MESH:D016066', (61, 87))	('malignant pleural effusion', 'Disease', 'MESH:D016066', (188, 214))	('NSCLC', 'Disease', (220, 225))	('LXY30', 'Chemical', '-', (384, 389))	('TentaGel', 'Chemical', 'MESH:C101297', (270, 278))	('NSCLC', 'Disease', 'MESH:D002289', (220, 225))	('PE', 'Phenotype', 'HP:0002202', (89, 91))	('pleural effusion', 'Phenotype', 'HP:0002202', (71, 87))	('LXY30', 'Chemical', '-', (40, 45))	('malignant pleural effusion', 'Disease', (188, 214))	('patients', 'Species', '9606', (226, 234))	('LXY30', 'Chemical', '-', (393, 398))	('malignant pleural effusion', 'Disease', (61, 87))	('LXY30', 'Chemical', '-', (365, 370))	('NSCLC', 'Phenotype', 'HP:0030358', (220, 225))	('LXY30', 'Var', (365, 370))	('pleural effusion', 'Phenotype', 'HP:0002202', (198, 214))	('A549', 'CellLine', 'CVCL:0023', (47, 51))
529437	31182116	For the exosome-bead binding assay, 1.5 mug/muL A549, H1975, or patient tumor-derived exosomes in 200 muL were added into 1.5 mL tube followed by 100 TentaGel beads coated with LXY30 or S-LXY30 at 37  C for 60 min, respectively.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('S-LXY30', 'Var', (186, 193))	('LXY30', 'Var', (177, 182))	('LXY30', 'Chemical', '-', (188, 193))	('patient', 'Species', '9606', (64, 71))	('tumor', 'Disease', (72, 77))	('A549', 'CellLine', 'CVCL:0023', (48, 52))	('TentaGel', 'Chemical', 'MESH:C101297', (150, 158))	('H1975', 'CellLine', 'CVCL:1511', (54, 59))	('LXY30', 'Chemical', '-', (177, 182))	('tumor', 'Disease', 'MESH:D009369', (72, 77))
529440	31182116	Next, A549 exosome-bead and H1975 exosome-bead binding were visualized under a LSM710 confocal fluorescence microscope (Zeiss, Germany).	('H1975', 'Var', (28, 33))	('H1975', 'CellLine', 'CVCL:1511', (28, 33))	('A549', 'CellLine', 'CVCL:0023', (6, 10))	('binding', 'Interaction', (47, 54))
529445	31182116	Thirty micrograms of lysates or exosome samples was separated by electrophoresis on 10% SDS-PAGE gels, transferred to nitrocellulose membranes, and probed with the following primary antibodies at 1:400 dilution: pEGFR Y1068, EGFR, pAKT S473, AKT (40D4), pMEK1/2 S217/221, MEK1/2 47E6, pSTAT3 Y705, and STAT3 124H6 (all from Cell Signaling Technology, Danvers, MA); CD63 (Santa sc-365604), integrin alpha3 (sc-374242), integrin beta1 (sc-59829), integrin alphaV (sc-9969), and beta-actin (sc-47778) (Santa Cruz Biotech).	('STAT3', 'Gene', (302, 307))	('AKT', 'Gene', '207', (232, 235))	('STAT3', 'Gene', (286, 291))	('sc-374242', 'Var', (406, 415))	('MEK1/2 47E6', 'Gene', (272, 283))	('STAT3', 'Gene', '6774', (302, 307))	('STAT3', 'Gene', '6774', (286, 291))	('beta-actin', 'Gene', '728378', (476, 486))	('MEK1/2 47E6', 'Gene', '5604', (272, 283))	('AKT', 'Gene', (242, 245))	('CD63', 'Gene', (365, 369))	('integrin beta1', 'Gene', '3688', (418, 432))	('AKT', 'Gene', (232, 235))	('sc-59829', 'Var', (434, 442))	('integrin alpha3', 'Gene', '3675', (389, 404))	('AKT', 'Gene', '207', (242, 245))	('CD63', 'Gene', '967', (365, 369))	('integrin alpha3', 'Gene', (389, 404))	('beta-actin', 'Gene', (476, 486))	('integrin beta1', 'Gene', (418, 432))	('SD', 'Disease', 'MESH:D029461', (88, 90))
529449	31182116	Female athymic nude mice (nu/nu), obtained from Harlan (Indianapolis, IN) at 5-6 weeks of age, were injected with 5 x 106 of H3255, H1975, or A549 cells subcutaneously in the right flank.	('nude mice', 'Species', '10090', (15, 24))	('A549', 'CellLine', 'CVCL:0023', (142, 146))	('H1975', 'Var', (132, 137))	('H1975', 'CellLine', 'CVCL:1511', (132, 137))	('H3255', 'CellLine', 'CVCL:6831', (125, 130))	('H3255', 'Var', (125, 130))
529465	31182116	We previously reported that LXY30 binds to the alpha3 integrin on the surface of a panel of live NSCLC cell lines with variable affinities and entered the cells via endocytosis.	('entered', 'Reg', (143, 150))	('binds', 'Interaction', (34, 39))	('NSCLC', 'Disease', (97, 102))	('LXY30', 'Chemical', '-', (28, 33))	('LXY30', 'Var', (28, 33))	('alpha3 integrin', 'Protein', (47, 62))	('NSCLC', 'Disease', 'MESH:D002289', (97, 102))	('endocytosis', 'MPA', (165, 176))	('NSCLC', 'Phenotype', 'HP:0030358', (97, 102))
529467	31182116	1, A549 cells are specifically bound to LXY30-FITC (Fig.	('LXY30-FITC', 'Chemical', '-', (40, 50))	('A549', 'CellLine', 'CVCL:0023', (3, 7))	('bound', 'Interaction', (31, 36))	('LXY30-FITC', 'Var', (40, 50))
529471	31182116	We further showed that LXY30 but not S-LXY30 is specifically bound to alpha3 integrin-expressing exosomes from the supernatant of NSCLC cell lines or patient's biofluids (malignant pleural or pericardial effusion or plasma) in 9 out of 10 (90%) patients (Table 1).	('NSCLC', 'Disease', 'MESH:D002289', (130, 135))	('LXY30', 'Var', (23, 28))	('patient', 'Species', '9606', (150, 157))	('malignant pleural or pericardial effusion', 'Disease', 'MESH:D016066', (171, 212))	('patients', 'Species', '9606', (245, 253))	('malignant pleural or pericardial effusion', 'Disease', (171, 212))	('NSCLC', 'Phenotype', 'HP:0030358', (130, 135))	('pericardial effusion', 'Phenotype', 'HP:0001698', (192, 212))	('LXY30', 'Chemical', '-', (23, 28))	('LXY30', 'Chemical', '-', (39, 44))	('NSCLC', 'Disease', (130, 135))	('alpha3 integrin-expressing', 'Protein', (70, 96))	('patient', 'Species', '9606', (245, 252))	('bound', 'Interaction', (61, 66))
529473	31182116	The expression of alpha3 and beta1 integrin subunits was found in exosomes isolated from the supernatant of 4 lung adenocarcinoma cell lines A549, H1975, H3255, and H1650 and a patient pericardial effusion by Western blots using exosomal (CD63) and cellular-specific (beta-actin) markers (Fig.	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (110, 129))	('CD63', 'Gene', (239, 243))	('lung adenocarcinoma cell lines A549', 'Disease', (110, 145))	('H3255', 'Var', (154, 159))	('pericardial effusion', 'Disease', 'MESH:D010490', (185, 205))	('beta-actin', 'Gene', '728378', (268, 278))	('pericardial effusion', 'Phenotype', 'HP:0001698', (185, 205))	('H1975', 'Var', (147, 152))	('pericardial effusion', 'Disease', (185, 205))	('H1975', 'CellLine', 'CVCL:1511', (147, 152))	('H3255', 'CellLine', 'CVCL:6831', (154, 159))	('CD63', 'Gene', '967', (239, 243))	('beta1 integrin', 'Gene', (29, 43))	('H1650', 'Var', (165, 170))	('beta1 integrin', 'Gene', '3688', (29, 43))	('lung adenocarcinoma cell lines A549', 'Disease', 'MESH:D000077192', (110, 145))	('beta-actin', 'Gene', (268, 278))	('patient', 'Species', '9606', (177, 184))
529475	31182116	While there was no significant difference between the yield of DNA isolated from S-LXY30-enriched and LXY30-enriched EVs (4.0 +- 0.7 vs 3.0 +- 1.2 ng/muL, p = 0.074), the yield of DNA was 3.4-fold higher in LXY30-enriched exosomes than in S-LXY30-enriched exosomes (3.4 +- 0.7 vs 1.0 +- 0.2 ng/muL, p = 0.014).	('LXY30', 'Chemical', '-', (102, 107))	('higher', 'PosReg', (197, 203))	('LXY30', 'Chemical', '-', (241, 246))	('LXY30', 'Chemical', '-', (83, 88))	('LXY30-enriched', 'Var', (207, 221))	('LXY30', 'Chemical', '-', (207, 212))
529476	31182116	The same driven mutations (KRAS G12S in A549, EGFR L858R and T790 M in H1975) were detected in the DNA isolated from LXY30-enriched exosomes and tumor cells by polymerase chain reaction (PCR) and Sanger sequencing (Fig.	('T790 M', 'Mutation', 'rs121434569', (61, 67))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('KRAS G12S', 'Var', (27, 36))	('G12S', 'Mutation', 'p.G12S', (32, 36))	('T790 M', 'Var', (61, 67))	('A549', 'Gene', (40, 44))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('L858R', 'Var', (51, 56))	('LXY30', 'Chemical', '-', (117, 122))	('tumor', 'Disease', (145, 150))	('H1975', 'CellLine', 'CVCL:1511', (71, 76))	('A549', 'CellLine', 'CVCL:0023', (40, 44))	('L858R', 'Mutation', 'rs121434568', (51, 56))
529477	31182116	Using 10 patient samples with known plasma EGFR mutations by a clinical next-generation sequencing assay, we could detect the same EGFR mutations in LXY30-enriched exosomes using Sanger sequencing when the mutation allelic frequency (MAF) was high (> 50%) but not low (< 10%) although the threshold was not determined.	('MAF', 'Gene', '4094', (234, 237))	('MAF', 'Gene', (234, 237))	('EGFR', 'Gene', (131, 135))	('mutations', 'Var', (136, 145))	('patient', 'Species', '9606', (9, 16))	('LXY30', 'Chemical', '-', (149, 154))	('mutations', 'Var', (48, 57))
529479	31182116	Figure 3 illustrates that representative tumor cells are isolated from malignant pleural effusion from a NSCLC patient using TentaGel beads coated with LXY30 but not S-LXY30 after 2- and 5-h incubation (Fig.	('NSCLC', 'Disease', 'MESH:D002289', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('pleural effusion', 'Phenotype', 'HP:0002202', (81, 97))	('NSCLC', 'Phenotype', 'HP:0030358', (105, 110))	('tumor', 'Disease', (41, 46))	('TentaGel', 'Chemical', 'MESH:C101297', (125, 133))	('LXY30', 'Chemical', '-', (168, 173))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('LXY30', 'Chemical', '-', (152, 157))	('malignant pleural effusion', 'Disease', (71, 97))	('patient', 'Species', '9606', (111, 118))	('LXY30', 'Var', (152, 157))	('NSCLC', 'Disease', (105, 110))	('malignant pleural effusion', 'Disease', 'MESH:D016066', (71, 97))
529480	31182116	LXY30 did not bind the inflammatory cells in the pleural effusion, such as macrophage and monocytes.	('LXY30', 'Chemical', '-', (0, 5))	('LXY30', 'Var', (0, 5))	('pleural effusion', 'Disease', 'MESH:D010996', (49, 65))	('pleural effusion', 'Disease', (49, 65))	('pleural effusion', 'Phenotype', 'HP:0002202', (49, 65))
529481	31182116	Also, peripheral mononuclear blood cells (PBMCs) isolated from the same patients (N = 8) did not bind to TentaGel beads coated with either LXY30 or S-LXY30 (Fig.	('LXY30', 'Var', (139, 144))	('LXY30', 'Chemical', '-', (150, 155))	('bind', 'Interaction', (97, 101))	('TentaGel', 'Chemical', 'MESH:C101297', (105, 113))	('LXY30', 'Chemical', '-', (139, 144))	('S-LXY30', 'Var', (148, 155))	('patients', 'Species', '9606', (72, 80))
529484	31182116	On average, LXY30 could enriched malignant tumor cells by twofolds in these 8 patients tested (Fig.	('malignant tumor', 'Disease', 'MESH:D018198', (33, 48))	('LXY30', 'Var', (12, 17))	('patients', 'Species', '9606', (78, 86))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('malignant tumor', 'Disease', (33, 48))	('LXY30', 'Chemical', '-', (12, 17))
529488	31182116	Figure 4a illustrates that EGFR-mutant H3255 cells are bound to integrin ligand LXY30 (for alpha3beta1 integrin) and LXW64 (for alphavbeta3 integrin) with high affinity but not to LLP2A (for alpha4beta1 integrin) using the whole-cell binding assay.	('H3255', 'CellLine', 'CVCL:6831', (39, 44))	('EGFR-mutant H3255', 'Gene', (27, 44))	('beta1 integrin', 'Gene', '3688', (197, 211))	('beta1 integrin', 'Gene', '3688', (97, 111))	('H3255', 'Gene', (39, 44))	('bound', 'Interaction', (55, 60))	('beta1 integrin', 'Gene', (97, 111))	('LXY30', 'Chemical', '-', (80, 85))	('LXW64', 'Var', (117, 122))	('beta1 integrin', 'Gene', (197, 211))	('LXW64', 'Chemical', '-', (117, 122))
529491	31182116	As LLP2A could also bind to activated lymphocytes in PBMCs from cancer patients in clinical remission (data not shown), we further characterized the function of LXY30 and LXW64 in NSCLC in this study.	('LXY30', 'Chemical', '-', (161, 166))	('LXY30', 'Var', (161, 166))	('NSCLC', 'Disease', (180, 185))	('patients', 'Species', '9606', (71, 79))	('cancer', 'Disease', (64, 70))	('LXW64', 'Var', (171, 176))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('NSCLC', 'Disease', 'MESH:D002289', (180, 185))	('LXW64', 'Chemical', '-', (171, 176))	('NSCLC', 'Phenotype', 'HP:0030358', (180, 185))	('bind', 'Interaction', (20, 24))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
529493	31182116	LXY30 and LXW64 bind to the alpha3beta1 and alphavbeta3 integrins, respectively, and activate EGFR and downstream signaling molecules (Fig.	('LXY30', 'Chemical', '-', (0, 5))	('LXY30', 'Var', (0, 5))	('activate', 'PosReg', (85, 93))	('EGFR', 'Pathway', (94, 98))	('bind', 'Interaction', (16, 20))	('LXW64', 'Var', (10, 15))	('LXW64', 'Chemical', '-', (10, 15))	('alpha3beta1', 'Protein', (28, 39))	('alphavbeta3 integrins', 'Protein', (44, 65))
529494	31182116	Compared to the untreated cells, LXY30 and LXY64 bind to erlotinib-resistant H1975 cells and activate the expression of alpha3, beta1, and alphav integrins; EGFR; and downstream signaling molecules either independently or in concert (Fig.	('EGFR', 'Gene', (157, 161))	('beta1', 'Protein', (128, 133))	('expression', 'MPA', (106, 116))	('LXY64', 'Var', (43, 48))	('erlotinib', 'Chemical', 'MESH:D000069347', (57, 66))	('activate', 'PosReg', (93, 101))	('alpha3', 'Protein', (120, 126))	('H1975', 'CellLine', 'CVCL:1511', (77, 82))	('LXY30', 'Chemical', '-', (33, 38))	('alphav integrins', 'Protein', (139, 155))	('LXY30', 'Var', (33, 38))
529495	31182116	The effect of LXY30 and/or LXW64 on the growth and proliferation of H1975 cells is shown by morphology (Additional file 2: Figure S2A) and cell counts (Additional file 2: Figure S2B) at 8 h, 48 h, and 72 h. Studies on other NSCLC cell lines revealed that the effect of LXY30 and LXW64 might be cell line dependent (Table 1), although the underlying mechanisms remain to be defined.	('LXW64', 'Chemical', '-', (279, 284))	('LXY30', 'Chemical', '-', (14, 19))	('NSCLC', 'Disease', (224, 229))	('NSCLC', 'Disease', 'MESH:D002289', (224, 229))	('LXY30', 'Chemical', '-', (269, 274))	('LXY30', 'Var', (269, 274))	('LXW64', 'Var', (279, 284))	('LXW64', 'Chemical', '-', (27, 32))	('H1975', 'CellLine', 'CVCL:1511', (68, 73))	('NSCLC', 'Phenotype', 'HP:0030358', (224, 229))
529496	31182116	The in vivo tumor-targeting effect of LXY30 was evaluated in a subcutaneous and intracranial mouse models generated from EGFR-mutant lung adenocarcinoma H3255 cells by optical imaging (Fig.	('H3255', 'CellLine', 'CVCL:6831', (153, 158))	('carcinoma', 'Phenotype', 'HP:0030731', (143, 152))	('EGFR-mutant', 'Gene', (121, 132))	('mouse', 'Species', '10090', (93, 98))	('LXY30', 'Chemical', '-', (38, 43))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (133, 152))	('EGFR-mutant', 'Var', (121, 132))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('lung adenocarcinoma', 'Disease', (133, 152))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (133, 152))	('tumor', 'Disease', (12, 17))
529498	31182116	In both subcutaneous and intracranial xenografts, there was about twofold higher uptakes of SA-Cy5.5 dye with LXY30 complexed compared to those without LXY30 in the imaging complex (Fig.	('SA-Cy5.5', 'Chemical', '-', (92, 100))	('complexed', 'Var', (116, 125))	('LXY30 complexed', 'Var', (110, 125))	('higher', 'PosReg', (74, 80))	('uptakes', 'MPA', (81, 88))	('LXY30', 'Chemical', '-', (110, 115))	('LXY30', 'Chemical', '-', (152, 157))
529501	31182116	The in vivo targeting effect of LXY30 was also shown in subcutaneous xenograft models of H1975 (EGFR L858R/T790 M mutations) and A549 (KRAS G12S mutation) (Fig.	('L858R', 'SUBSTITUTION', 'None', (101, 106))	('G12S', 'Mutation', 'p.G12S', (140, 144))	('T790 M', 'Mutation', 'rs121434569', (107, 113))	('L858R', 'Var', (101, 106))	('LXY30', 'Chemical', '-', (32, 37))	('H1975', 'Var', (89, 94))	('A549', 'CellLine', 'CVCL:0023', (129, 133))	('H1975', 'CellLine', 'CVCL:1511', (89, 94))
529505	31182116	High ITGA3 expression was associated with poorer prognosis in LUSC (Fig.	('LUSC', 'Disease', (62, 66))	('High', 'Var', (0, 4))	('expression', 'MPA', (11, 21))	('ITGA3', 'Gene', (5, 10))	('ITGA3', 'Gene', '3675', (5, 10))
529508	31182116	The LXY30-biotin-streptavidin (SA)-Cy5.5 dye complex had significantly increased uptake compared to SA-Cy5.5 dye complex in tumor xenografts as shown in in vivo (Fig.	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('SA)-Cy5', 'Chemical', '-', (31, 38))	('uptake', 'MPA', (81, 87))	('LXY30-biotin', 'Chemical', '-', (4, 16))	('tumor', 'Disease', (124, 129))	('SA-Cy5.5', 'Chemical', '-', (100, 108))	('LXY30-biotin-streptavidin', 'Var', (4, 29))	('increased', 'PosReg', (71, 80))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
529513	31182116	Compared to the natural integrin ligands that have low binding affinity to integrins, these integrin-specific peptide ligands contain l-amino acids, d-amino acids, cyclic structure, and organic moieties, rendering them resistant to proteolysis.	('cyclic', 'MPA', (164, 170))	('d-amino acids', 'Chemical', '-', (149, 162))	('l-amino acids', 'Chemical', 'MESH:D000596', (134, 147))	('d-amino', 'MPA', (149, 156))	('l-amino acids', 'Var', (134, 147))	('peptide', 'Chemical', 'MESH:D010455', (110, 117))
529514	31182116	Among all the peptide ligands that we have generated to date, LXY30 targeting alpha3(beta1) integrin, LXW64 targeting alphavbeta3 integrin, and LLP2A targeting alpha4beta1 integrin are the most potent ligands for the respective integrin and have a broad-spectrum binding to multiple epithelial tumor types including NSCLC.	('tumor', 'Disease', (294, 299))	('beta1 integrin', 'Gene', '3688', (166, 180))	('NSCLC', 'Disease', (316, 321))	('LXW64', 'Var', (102, 107))	('epithelial tumor', 'Phenotype', 'HP:0031492', (283, 299))	('LXY30', 'Chemical', '-', (62, 67))	('NSCLC', 'Disease', 'MESH:D002289', (316, 321))	('alpha3(beta1) integrin', 'Protein', (78, 100))	('beta1 integrin', 'Gene', (166, 180))	('tumor', 'Disease', 'MESH:D009369', (294, 299))	('LLP2A', 'Var', (144, 149))	('LXY30', 'Var', (62, 67))	('integrin', 'Protein', (228, 236))	('LXW64', 'Chemical', '-', (102, 107))	('peptide', 'Chemical', 'MESH:D010455', (14, 21))	('NSCLC', 'Phenotype', 'HP:0030358', (316, 321))	('binding', 'Interaction', (263, 270))	('tumor', 'Phenotype', 'HP:0002664', (294, 299))
529520	31182116	In a patient with less than 5% tumor cells present in malignant pleural effusion, LXY30 was able to enrich the malignant tumor cells to over 20% for successful detection of genomic alterations.	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('LXY30', 'Gene', (82, 87))	('patient', 'Species', '9606', (5, 12))	('malignant pleural effusion', 'Disease', 'MESH:D016066', (54, 80))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('pleural effusion', 'Phenotype', 'HP:0002202', (64, 80))	('tumor', 'Disease', (31, 36))	('tumor', 'Disease', (121, 126))	('malignant tumor', 'Disease', (111, 126))	('malignant pleural effusion', 'Disease', (54, 80))	('malignant tumor', 'Disease', 'MESH:D018198', (111, 126))	('genomic', 'Var', (173, 180))	('LXY30', 'Chemical', '-', (82, 87))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
529522	31182116	However, the sensitivity of the current FDA-approved companion diagnostics using plasma ctDNA for EGFR T790 M is 70-82% with a specificity of >= 95%.	('EGFR', 'Gene', (98, 102))	('T790 M', 'Var', (103, 109))	('T790 M', 'Mutation', 'rs121434569', (103, 109))
529530	31182116	The presence of gain-of-function somatic mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) gene defines the first molecular subset of metastatic NSCLC patients whose tumors have 60-84% response rate to first-line EGFR tyrosine kinase inhibitors (TKIs; i.e., erlotinib, gefitinib, afatinib, osimertinib).	('mutations', 'Var', (41, 50))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('NSCLC', 'Disease', (182, 187))	('tumors', 'Disease', (203, 209))	('tumors', 'Disease', 'MESH:D009369', (203, 209))	('epidermal growth factor receptor', 'Gene', '1956', (88, 120))	('NSCLC', 'Disease', 'MESH:D002289', (182, 187))	('afatinib', 'Chemical', 'MESH:D000077716', (317, 325))	('gefitinib', 'Chemical', 'MESH:D000077156', (306, 315))	('tumors', 'Phenotype', 'HP:0002664', (203, 209))	('patients', 'Species', '9606', (188, 196))	('erlotinib', 'Chemical', 'MESH:D000069347', (295, 304))	('osimertinib', 'Chemical', 'MESH:C000603933', (327, 338))	('NSCLC', 'Phenotype', 'HP:0030358', (182, 187))	('epidermal growth factor receptor', 'Gene', (88, 120))	('EGFR', 'Gene', (122, 126))	('gain-of-function', 'PosReg', (16, 32))
529533	31182116	Consistent with the report that the expression of alpha3beta1 integrin was increased in erlotinib-resistant NSCLC tumors, we found that LXY30 was the most prevalent and potent integrin ligand for binding to live EGFR-mutant lung cancer.	('beta1 integrin', 'Gene', '3688', (56, 70))	('LXY30', 'Chemical', '-', (136, 141))	('binding', 'Interaction', (196, 203))	('NSCLC tumors', 'Disease', (108, 120))	('EGFR-mutant', 'Gene', (212, 223))	('LXY30', 'Var', (136, 141))	('lung cancer', 'Disease', 'MESH:D008175', (224, 235))	('NSCLC', 'Phenotype', 'HP:0030358', (108, 113))	('beta1 integrin', 'Gene', (56, 70))	('erlotinib', 'Chemical', 'MESH:D000069347', (88, 97))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('lung cancer', 'Disease', (224, 235))	('lung cancer', 'Phenotype', 'HP:0100526', (224, 235))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('NSCLC tumors', 'Disease', 'MESH:D009369', (108, 120))	('increased', 'PosReg', (75, 84))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('expression', 'MPA', (36, 46))
529536	31182116	LXY30 activates the EGFR signaling pathway via different downstream signaling molecules independently from other integrins such as alphavbeta3 integrin.	('EGFR signaling pathway', 'Pathway', (20, 42))	('LXY30', 'Chemical', '-', (0, 5))	('activates', 'PosReg', (6, 15))	('LXY30', 'Var', (0, 5))
529540	31182116	LXY30 could also target PDX of lung squamous cell carcinoma.	('LXY30', 'Chemical', '-', (0, 5))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (31, 59))	('LXY30', 'Var', (0, 5))	('carcinoma', 'Phenotype', 'HP:0030731', (50, 59))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (36, 59))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (31, 59))	('lung squamous cell carcinoma', 'Disease', (31, 59))
529543	31182116	Second, LXY30 could be used for sensitive detection of metastatic tumors or enrichment of the tumor cells in patient's biofluids, and thus potentially increase the success rate on the molecular diagnosis of NSCLC.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('NSCLC', 'Phenotype', 'HP:0030358', (207, 212))	('patient', 'Species', '9606', (109, 116))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Disease', (66, 71))	('tumors', 'Disease', (66, 72))	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('tumor', 'Disease', (94, 99))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('NSCLC', 'Disease', (207, 212))	('increase', 'PosReg', (151, 159))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('LXY30', 'Chemical', '-', (8, 13))	('NSCLC', 'Disease', 'MESH:D002289', (207, 212))	('LXY30', 'Var', (8, 13))
529545	31182116	Finally, the fact that LXY30-biotin/streptavidin-Cy5.5 complex with over 80,000 Da can target intracranially implanted xenografts suggests that LXY30 is an excellent cancer-specific ligand for guiding in vivo drug delivery to metastatic tumors in the brain.	('cancer', 'Disease', (166, 172))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('LXY30', 'Chemical', '-', (144, 149))	('tumors', 'Disease', (237, 243))	('tumors', 'Disease', 'MESH:D009369', (237, 243))	('LXY30', 'Var', (144, 149))	('tumors', 'Phenotype', 'HP:0002664', (237, 243))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('LXY30', 'Chemical', '-', (23, 28))	('Cy5', 'Chemical', 'MESH:C085321', (49, 52))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))	('LXY30-biotin', 'Chemical', '-', (23, 35))
529547	31182116	LXY30 can modulate the activity of the EGFR signaling pathway.	('LXY30', 'Chemical', '-', (0, 5))	('LXY30', 'Var', (0, 5))	('activity', 'MPA', (23, 31))	('modulate', 'Reg', (10, 18))	('EGFR signaling pathway', 'Pathway', (39, 61))
529548	31182116	LXY30-biotin/streptavidin-Cy5.5 conjugate had preferentially higher uptakes in the subcutaneous and intracranial xenografts of various alpha3beta1 integrin-expressing NSCLC and patient-derived NSCLC xenograft models compared to the surrounding normal tissues.	('NSCLC', 'Disease', 'MESH:D002289', (167, 172))	('beta1 integrin', 'Gene', '3688', (141, 155))	('NSCLC', 'Phenotype', 'HP:0030358', (193, 198))	('LXY30-biotin', 'Chemical', '-', (0, 12))	('NSCLC', 'Phenotype', 'HP:0030358', (167, 172))	('higher', 'PosReg', (61, 67))	('beta1 integrin', 'Gene', (141, 155))	('Cy5', 'Chemical', 'MESH:C085321', (26, 29))	('LXY30-biotin/streptavidin-Cy5.5', 'Var', (0, 31))	('uptakes', 'MPA', (68, 75))	('NSCLC', 'Disease', (193, 198))	('patient', 'Species', '9606', (177, 184))	('NSCLC', 'Disease', (167, 172))	('NSCLC', 'Disease', 'MESH:D002289', (193, 198))
529549	31182116	Further studies are warranted to use LXY30 to increase the sensitivity of cancer detection, molecular diagnosis, and in vivo targeted delivery of imaging dye and cancer drugs in alpha3beta1 integrin-expression NSCLC.	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('LXY30', 'Var', (37, 42))	('beta1 integrin', 'Gene', '3688', (184, 198))	('increase', 'PosReg', (46, 54))	('cancer', 'Disease', (162, 168))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('NSCLC', 'Disease', (210, 215))	('beta1 integrin', 'Gene', (184, 198))	('cancer', 'Disease', (74, 80))	('NSCLC', 'Disease', 'MESH:D002289', (210, 215))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('LXY30', 'Chemical', '-', (37, 42))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('NSCLC', 'Phenotype', 'HP:0030358', (210, 215))
529552	31182116	This work was supported by the University of California Cancer Research Coordinating Committee grants and Personalized Cancer Therapy Gift Fund (TL), R01CA115483 (KL), and R21 CA135345 (RL).	('R21 CA135345', 'Var', (172, 184))	('California Cancer', 'Disease', (45, 62))	('Cancer', 'Phenotype', 'HP:0002664', (119, 125))	('R01CA115483', 'Var', (150, 161))	('California Cancer', 'Disease', 'MESH:D004670', (45, 62))	('Cancer', 'Phenotype', 'HP:0002664', (56, 62))
529553	29891994	Airway brushing as a new experimental methodology to detect airway gene expression signatures in mouse lung squamous cell carcinoma As a consequence of exposure to environmental toxicants, a "field cancerization" effect occurs in the lung, resulting in the development of a field of initiated, but morphologically normal appearing cells within a damaged epithelium containing mutations in oncogene or tumor suppressor genes.	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('mutations', 'Var', (376, 385))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (108, 131))	('cancer', 'Disease', (198, 204))	('field', 'MPA', (274, 279))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (103, 131))	('tumor', 'Disease', 'MESH:D009369', (401, 406))	('oncogene', 'Gene', (389, 397))	('mouse', 'Species', '10090', (97, 102))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (103, 131))	('lung squamous cell carcinoma', 'Disease', (103, 131))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('tumor', 'Phenotype', 'HP:0002664', (401, 406))	('tumor', 'Disease', (401, 406))
529564	29891994	Prolonged exposure to cigarette smoke or other carcinogens creates a field of injury in the cytologically normal epithelium that lines the respiratory tract, reflecting processes associated with the precancerous disease state, such as mutations in oncogenes or tumor suppressor genes induced by inhaled environmental toxicants.	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('precancerous disease', 'Disease', 'MESH:D011230', (199, 219))	('tumor', 'Phenotype', 'HP:0002664', (261, 266))	('tumor', 'Disease', (261, 266))	('mutations', 'Var', (235, 244))	('precancerous disease', 'Disease', (199, 219))	('oncogenes', 'Gene', (248, 257))	('tumor', 'Disease', 'MESH:D009369', (261, 266))
529575	29891994	Intervention of these important pathways with small molecule inhibitors or genetic modulation with IkBalpha super-repressor is sufficient in preventing lung SCC progression.	('SCC', 'Gene', (157, 160))	('SCC', 'Phenotype', 'HP:0002860', (157, 160))	('SCC', 'Gene', '6317', (157, 160))	('genetic modulation', 'Var', (75, 93))	('IkBalpha', 'Gene', (99, 107))
529629	29891994	After addition of doxycycline (dox), expression of IkBalpha-DN in the lungs of these transgenic mice has been shown to block NFkB activation.	('block', 'NegReg', (119, 124))	('dox', 'Chemical', 'MESH:D004318', (31, 34))	('expression', 'Var', (37, 47))	('doxycycline', 'Chemical', 'MESH:D004318', (18, 29))	('dox', 'Chemical', 'MESH:D004318', (18, 21))	('IkBalpha-DN', 'Gene', (51, 62))	('IkBalpha-DN', 'Chemical', '-', (51, 62))	('NFkB', 'Gene', '18033', (125, 129))	('transgenic mice', 'Species', '10090', (85, 100))	('NFkB', 'Gene', (125, 129))	('activation', 'MPA', (130, 140))
529630	29891994	To investigate the impact of NFkB pathway on the development of lung squamous cell carcinoma, we bred IkBalpha-DN (Swiss background over nine generations) with CCSP-rtTA mice (A/J background) mice.	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (64, 92))	('mice', 'Species', '10090', (192, 196))	('NFkB', 'Gene', (29, 33))	('IkBalpha-DN', 'Var', (102, 113))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (69, 92))	('lung squamous cell carcinoma', 'Disease', (64, 92))	('NFkB', 'Gene', '18033', (29, 33))	('CCSP', 'Gene', '22287', (160, 164))	('CCSP', 'Gene', (160, 164))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (64, 92))	('mice', 'Species', '10090', (170, 174))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))	('IkBalpha-DN', 'Chemical', '-', (102, 113))
529632	29891994	NTCU induced lung SCC in all control mice, the distributions of lesions were analyzed as we previously published .	('SCC', 'Gene', (18, 21))	('induced', 'Reg', (5, 12))	('SCC', 'Phenotype', 'HP:0002860', (18, 21))	('SCC', 'Gene', '6317', (18, 21))	('NTCU', 'Chemical', 'MESH:C572573', (0, 4))	('NTCU', 'Var', (0, 4))	('mice', 'Species', '10090', (37, 41))
529681	29715309	Dysregulated lncRNAs have been implicated in many complex diseases, such as cardiovascular disease, breast cancer, and pancreatic cancer.	('implicated', 'Reg', (31, 41))	('pancreatic cancer', 'Disease', (119, 136))	('cardiovascular disease', 'Disease', (76, 98))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('cardiovascular disease', 'Phenotype', 'HP:0001626', (76, 98))	('breast cancer', 'Disease', 'MESH:D001943', (100, 113))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (119, 136))	('breast cancer', 'Phenotype', 'HP:0003002', (100, 113))	('ncRNA', 'Gene', (14, 19))	('Dysregulated', 'Var', (0, 12))	('cardiovascular disease', 'Disease', 'MESH:D002318', (76, 98))	('breast cancer', 'Disease', (100, 113))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('ncRNA', 'Gene', '54719', (14, 19))	('pancreatic cancer', 'Disease', 'MESH:D010190', (119, 136))
529683	29715309	A large number of studies have suggested that miRNAs participate in many important biological processes and that the aberrant expression of miRNAs might cause diseases such as breast cancer and lung cancer.	('lung cancer', 'Phenotype', 'HP:0100526', (194, 205))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('expression', 'MPA', (126, 136))	('miRNAs', 'Gene', (140, 146))	('aberrant', 'Var', (117, 125))	('lung cancer', 'Disease', 'MESH:D008175', (194, 205))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('breast cancer', 'Disease', 'MESH:D001943', (176, 189))	('breast cancer', 'Phenotype', 'HP:0003002', (176, 189))	('breast cancer', 'Disease', (176, 189))	('cause', 'Reg', (153, 158))	('lung cancer', 'Disease', (194, 205))
529729	29715309	Because the number of RNA molecules involved in the 155653 miRNA-lncRNA interactions is inhomogeneous, we propose the Activity Scores to further analyze the miRNAs involved in the candidate miRNA-lncRNA pairs.	('ncRNA', 'Gene', '54719', (66, 71))	('ncRNA', 'Gene', (197, 202))	('155653', 'Var', (52, 58))	('ncRNA', 'Gene', '54719', (197, 202))	('ncRNA', 'Gene', (66, 71))
529735	29715309	First, we constructed a reference regulatory background network of 155653 miRNA-lncRNA associations using the expression profiles of 84 adjacent non-tumor samples.	('155653', 'Var', (67, 73))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('ncRNA', 'Gene', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('tumor', 'Disease', (149, 154))	('ncRNA', 'Gene', '54719', (81, 86))
529787	29715309	Mature mir-34a of the mir-34 family is a part of the p53 tumor suppressor network; thus, dysregulated mir-34 is involved in the development of some cancers.	('cancers', 'Disease', 'MESH:D009369', (148, 155))	('involved', 'Reg', (112, 120))	('mir-34', 'Gene', (102, 108))	('mir-34', 'Gene', '407040', (102, 108))	('cancers', 'Phenotype', 'HP:0002664', (148, 155))	('cancers', 'Disease', (148, 155))	('mir-34', 'Gene', '407040', (7, 13))	('mir-34', 'Gene', (7, 13))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('p53', 'Gene', (53, 56))	('p53', 'Gene', '7157', (53, 56))	('mir-34', 'Gene', (22, 28))	('tumor', 'Disease', (57, 62))	('mir-34', 'Gene', '407040', (22, 28))	('dysregulated', 'Var', (89, 101))
529817	29061560	Gene ontology and pathway analyses revealed a signature of biological processes including "immune system process" that is significantly dysregulated in 4-NQO-induced oral cancer.	('dysregulated', 'Reg', (136, 148))	('4-NQO', 'Chemical', 'MESH:D015112', (152, 157))	('oral cancer', 'Disease', 'MESH:D009062', (166, 177))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('oral cancer', 'Disease', (166, 177))	('4-NQO-induced', 'Var', (152, 165))
529827	29061560	In this model, immunocompetent mice treated with 4-NQO develop invasive squamous cell carcinoma of the oral cavity with near 100% penetrance.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (72, 95))	('invasive squamous cell carcinoma', 'Disease', (63, 95))	('4-NQO', 'Var', (49, 54))	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('invasive squamous cell carcinoma', 'Disease', 'MESH:D002294', (63, 95))	('4-NQO', 'Chemical', 'MESH:D015112', (49, 54))	('develop', 'PosReg', (55, 62))	('carcinoma of the oral cavity', 'Phenotype', 'HP:0100649', (86, 114))	('mice', 'Species', '10090', (31, 35))	('squamous cell carcinoma of the oral cavity', 'Phenotype', 'HP:0030413', (72, 114))
529829	29061560	4-NQO is a synthetic, water soluble carcinogen, which mimics the chronic tobacco consumption effect by promoting DNA adduct formation, A-G nucleotide substitution and intracellular oxidative stress, resulting in histological and molecular alterations similar to human oral carcinogenesis.	('oral carcinogenesis', 'Disease', (268, 287))	('water', 'Chemical', 'MESH:D014867', (22, 27))	('promoting', 'PosReg', (103, 112))	('human', 'Species', '9606', (262, 267))	('oxidative stress', 'Phenotype', 'HP:0025464', (181, 197))	('DNA adduct formation', 'MPA', (113, 133))	('tobacco', 'Species', '4097', (73, 80))	('intracellular oxidative stress', 'MPA', (167, 197))	('4-NQO', 'Chemical', 'MESH:D015112', (0, 5))	('A-G nucleotide substitution', 'Var', (135, 162))	('oral carcinogenesis', 'Disease', 'MESH:D063646', (268, 287))
529834	29061560	We recently observed that BME augments NK-cell-mediated HNSCC killing activity and reduces the Th17 cell population in the tumor, implicating an immunomodulatory role in a syngeneic mouse model.	('tumor', 'Disease', (123, 128))	('augments', 'NegReg', (30, 38))	('BME', 'Chemical', '-', (26, 29))	('BME', 'Var', (26, 29))	('mouse', 'Species', '10090', (182, 187))	('HNSCC', 'Phenotype', 'HP:0012288', (56, 61))	('reduces', 'NegReg', (83, 90))	('NK-cell-mediated HNSCC killing activity', 'CPA', (39, 78))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
529851	29061560	Gene expression of S100a9 (Mm 00656925_m1), IL23a (Mm 00518984_m1), IL1b (Mm 00434228_m1), PDCD1 (Mm 01285676_m1) and MMP9 (Mm 00442991_m1) was carried out by real-time PCR using the Taqman gene expression assay (Thermo Fisher Scientific).	('Mm 01285676_m1', 'Var', (98, 112))	('S100a9', 'Gene', '20202', (19, 25))	('S100a9', 'Gene', (19, 25))	('Mm 00656925_m1', 'Var', (27, 41))	('Mm 00518984_m1', 'Var', (51, 65))	('Mm 00434228_m1', 'Var', (74, 88))
529862	29061560	The body weight of the mice was lower in 4-NQO treated group as compared to BME-fed group after 18 weeks (Fig.	('BME', 'Chemical', '-', (76, 79))	('4-NQO', 'Chemical', 'MESH:D015112', (41, 46))	('4-NQO treated', 'Var', (41, 54))	('body weight', 'CPA', (4, 15))	('mice', 'Species', '10090', (23, 27))	('lower', 'NegReg', (32, 37))
529863	29061560	Macroscopic lesions were more prominent in 4-NQO treated group as compared to BME-fed group (Fig.	('4-NQO', 'Chemical', 'MESH:D015112', (43, 48))	('Macroscopic lesions', 'CPA', (0, 19))	('BME', 'Chemical', '-', (78, 81))	('4-NQO', 'Var', (43, 48))
529876	29061560	In contrast, "inflammatory response", "extracellular space", "cytokine activity", "immune response", "structural molecule activity", and "cell chemotaxis" were significantly downregulated in the 4-NQO-induced cancer group as compared to normal samples (Fig.	('downregulated', 'NegReg', (174, 187))	('cancer', 'Disease', 'MESH:D009369', (209, 215))	('4-NQO-induced', 'Var', (195, 208))	('cancer', 'Disease', (209, 215))	('cell chemotaxis', 'CPA', (138, 153))	('4-NQO', 'Chemical', 'MESH:D015112', (195, 200))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
529880	29061560	For both comparisons, significantly enriched (P= 2.2X10-16) GO categories were "signal transduction (GO:0007165)", "apoptosis process (GO: 0006915)", "metabolic process (GO: 0008152)", "cell adhesion (GO:0007155)", "lipid metabolism (GO:0006629)", "immune system process (GO: 0002376)", "angiogenesis (GO: 0001525)", "ossification (GO: 0001503)", and "G1/S transition of mitotic cell cycle (GO: 0000082)" (Fig.	('lipid', 'Chemical', 'MESH:D008055', (216, 221))	('G1/S transition of mitotic cell cycle', 'CPA', (352, 389))	('angiogenesis', 'CPA', (288, 300))	('GO: 0002376', 'Var', (272, 283))	('GO: 0001525', 'Var', (302, 313))	('GO: 0000082', 'Var', (391, 402))	('GO: 0001503', 'Var', (332, 343))
529883	29061560	Further, HNSCC has been intensively studied as an immunosuppressive disease, and we focussed our analysis here in immune modulation We compared the mRNA expression change of selected individual genes of the significantly enriched immune system processes between the 4-NQO induced cancer group and BME-fed experimental group.	('BME', 'Chemical', '-', (297, 300))	('cancer', 'Disease', 'MESH:D009369', (280, 286))	('HNSCC', 'Phenotype', 'HP:0012288', (9, 14))	('cancer', 'Disease', (280, 286))	('4-NQO induced', 'Var', (266, 279))	('cancer', 'Phenotype', 'HP:0002664', (280, 286))	('4-NQO', 'Chemical', 'MESH:D015112', (266, 271))
529889	29061560	Similar to the RNA-Seq data, significant up-regulation of s100a9, IL23a, IL1b and PDCD1 were observed in 4-NQO induced cancer tongue tissues as compared to normal tongue tissues (Fig.	('IL23a', 'Gene', (66, 71))	('s100a9', 'Gene', (58, 64))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('4-NQO', 'Var', (105, 110))	('cancer', 'Disease', (119, 125))	('IL1b', 'Gene', (73, 77))	('4-NQO', 'Chemical', 'MESH:D015112', (105, 110))	('up-regulation', 'PosReg', (41, 54))	('PDCD1', 'Gene', (82, 87))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
529903	29061560	Our pilot study using limited number of mice suggested that BME feeding with 4-NQO delayed tumor initiation (~11th week of treatment) in mouse tongue (data not shown), suggesting the chemopreventive implication of BME.	('mouse', 'Species', '10090', (137, 142))	('BME', 'Chemical', '-', (60, 63))	('BME', 'Chemical', '-', (214, 217))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('delayed', 'NegReg', (83, 90))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('4-NQO', 'Var', (77, 82))	('mice', 'Species', '10090', (40, 44))	('4-NQO', 'Chemical', 'MESH:D015112', (77, 82))	('tumor', 'Disease', (91, 96))
529922	29061560	Thus, modulation of these pathways may be an important chemoprevention mechanism by BME with respect to oral cancer.	('modulation', 'Var', (6, 16))	('oral cancer', 'Disease', 'MESH:D009062', (104, 115))	('BME', 'Chemical', '-', (84, 87))	('oral cancer', 'Disease', (104, 115))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))
529927	29061560	It is possible that s100a9 may have anti- or pro-tumor responses depending on the intracellular milieu.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('s100a9', 'Var', (20, 26))	('anti-', 'CPA', (36, 41))	('tumor', 'Disease', (49, 54))
529949	29459674	The further functional enrichment on 889 genes with frequent copy number gains (CNGs) revealed that these genes were significantly associated with cancer pathways including regulation of cell cycle, cell differentiation and mitogen-activated protein kinase (MAPK) cascade.	('copy number', 'Var', (61, 72))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('associated', 'Reg', (131, 141))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('cell cycle', 'CPA', (187, 197))	('cancer', 'Disease', (147, 153))	('cell differentiation', 'CPA', (199, 219))
529953	29459674	This study provides the first observation of CNV in prognosis-related genes across pan-cancer.	('cancer', 'Disease', (87, 93))	('prognosis-related genes', 'Gene', (52, 75))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('CNV', 'Var', (45, 48))	('cancer', 'Disease', 'MESH:D009369', (87, 93))
529956	29459674	Examples of prognostic biomarkers are Prostate-Specific Antigen (PSA) in prostate cancer and the phosphatidylinositol 3-kinase (PIK3CA) mutation status of tumours - which are associated with human epidermal growth factor receptor 2 (HER2) in women with positive metastatic breast cancer.	('Prostate-Specific Antigen', 'Gene', (38, 63))	('tumour', 'Phenotype', 'HP:0002664', (155, 161))	('cancer', 'Phenotype', 'HP:0002664', (280, 286))	('PIK3CA', 'Gene', '5290', (128, 134))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('prostate cancer', 'Disease', 'MESH:D011471', (73, 88))	('prostate cancer', 'Phenotype', 'HP:0012125', (73, 88))	('HER2', 'Gene', (233, 237))	('human', 'Species', '9606', (191, 196))	('prostate cancer', 'Disease', (73, 88))	('breast cancer', 'Phenotype', 'HP:0003002', (273, 286))	('mutation', 'Var', (136, 144))	('PIK3CA', 'Gene', (128, 134))	('breast cancer', 'Disease', 'MESH:D001943', (273, 286))	('epidermal growth factor receptor 2', 'Gene', '2064', (197, 231))	('breast cancer', 'Disease', (273, 286))	('tumours', 'Disease', (155, 162))	('women', 'Species', '9606', (242, 247))	('Prostate-Specific Antigen', 'Gene', '354', (38, 63))	('tumours', 'Phenotype', 'HP:0002664', (155, 162))	('tumours', 'Disease', 'MESH:D009369', (155, 162))	('HER2', 'Gene', '2064', (233, 237))	('epidermal growth factor receptor 2', 'Gene', (197, 231))
529964	29459674	Cancer progression involves a series of genetic alterations involving mutations and copy number of variants (CNVs) in human genomes.	('mutations', 'Var', (70, 79))	('copy number of variants', 'Var', (84, 107))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('human', 'Species', '9606', (118, 123))
529973	29459674	Cancer results from a single somatic cell that has accumulated multiple DNA mutations and result in cell proliferation caused by mutations in genes that control proliferation and the cell cycle.	('mutations', 'Var', (76, 85))	('mutations', 'Var', (129, 138))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('cell proliferation', 'CPA', (100, 118))	('caused by', 'Reg', (119, 128))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('result in', 'Reg', (90, 99))
529978	29459674	Overexpression of BCL-2 and related anti-apoptotic proteins has been demonstrated to inhibit cell death induced by growth factor deprivation, hypoxia and oxidative stress.	('BCL-2', 'Gene', '596', (18, 23))	('growth', 'CPA', (115, 121))	('oxidative stress', 'Phenotype', 'HP:0025464', (154, 170))	('inhibit', 'NegReg', (85, 92))	('BCL-2', 'Gene', (18, 23))	('Overexpression', 'Var', (0, 14))	('hypoxia', 'Disease', 'MESH:D000860', (142, 149))	('hypoxia', 'Disease', (142, 149))	('cell death', 'CPA', (93, 103))
529983	29459674	For example, the frequency of genetic alterations in TCGA oesophageal carcinoma that exhibited at least one copy number change for each gene was the highest with 157 cases (85.3%).	('oesophageal carcinoma', 'Phenotype', 'HP:0011459', (58, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('genetic alterations', 'Var', (30, 49))	('oesophageal carcinoma', 'Disease', (58, 79))	('oesophageal carcinoma', 'Disease', 'MESH:D005764', (58, 79))
529986	29459674	More than 80.0% of oesophagus-stomach cancer patients involved gene amplifications.	('oesophagus-stomach cancer', 'Disease', 'MESH:D013274', (19, 44))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('patients', 'Species', '9606', (45, 53))	('stomach cancer', 'Phenotype', 'HP:0012126', (30, 44))	('gene amplifications', 'Var', (63, 82))	('oesophagus-stomach cancer', 'Disease', (19, 44))	('involved', 'Reg', (54, 62))
529987	29459674	The same proportion of copy number changes in both CNGs and CNLs with more than 60.0% cases were identified in 14 cancer datasets from six types of cancer, including breast cancer, head and neck squamous cell carcinoma, lung cancer, bladder urothelial carcinoma, sarcoma and uterine carcinosarcoma.	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('carcinosarcoma', 'Disease', (283, 297))	('head and neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (181, 218))	('cancer', 'Disease', (225, 231))	('breast cancer', 'Disease', 'MESH:D001943', (166, 179))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('breast cancer', 'Disease', (166, 179))	('carcinosarcoma', 'Disease', 'MESH:D002296', (283, 297))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('sarcoma', 'Phenotype', 'HP:0100242', (263, 270))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('sarcoma', 'Disease', 'MESH:D012509', (290, 297))	('lung cancer', 'Disease', (220, 231))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (195, 218))	('sarcoma', 'Disease', (290, 297))	('carcinoma', 'Phenotype', 'HP:0030731', (209, 218))	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('cancer', 'Disease', 'MESH:D009369', (225, 231))	('cancer', 'Disease', (173, 179))	('copy number changes', 'Var', (23, 42))	('carcinoma', 'Phenotype', 'HP:0030731', (252, 261))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (275, 297))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('sarcoma', 'Phenotype', 'HP:0100242', (290, 297))	('bladder urothelial carcinoma', 'Disease', (233, 261))	('cancer', 'Disease', (148, 154))	('lung cancer', 'Disease', 'MESH:D008175', (220, 231))	('sarcoma', 'Disease', 'MESH:D012509', (263, 270))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('lung cancer', 'Phenotype', 'HP:0100526', (220, 231))	('sarcoma', 'Disease', (263, 270))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (233, 261))	('breast cancer', 'Phenotype', 'HP:0003002', (166, 179))	('cancer', 'Disease', (114, 120))
529990	29459674	In addition to the sample analysis, we explored the genomic alterations in multiple genes across several tumour samples to further elaborate the prognosis-related genes (Fig.	('tumour', 'Disease', 'MESH:D009369', (105, 111))	('genomic alterations', 'Var', (52, 71))	('tumour', 'Disease', (105, 111))	('tumour', 'Phenotype', 'HP:0002664', (105, 111))
530021	29459674	Most studies show that the KRAS gene mutations are poor prognostic factors but that the upregulation of metadherin (MTDH) is associated with tumour progression in female reproductive system cancers.	('cancers', 'Phenotype', 'HP:0002664', (190, 197))	('KRAS', 'Gene', '3845', (27, 31))	('MTDH', 'Gene', (116, 120))	('tumour', 'Phenotype', 'HP:0002664', (141, 147))	('system cancers', 'Disease', (183, 197))	('system cancers', 'Disease', 'MESH:D009369', (183, 197))	('metadherin', 'Gene', '92140', (104, 114))	('upregulation', 'PosReg', (88, 100))	('mutations', 'Var', (37, 46))	('metadherin', 'Gene', (104, 114))	('tumour', 'Disease', 'MESH:D009369', (141, 147))	('MTDH', 'Gene', '92140', (116, 120))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('tumour', 'Disease', (141, 147))	('KRAS', 'Gene', (27, 31))
530046	29459674	The frequency of the oncogenes with CNGs and overexpression across the tumour samples suggested that this could be a common mechanism in cancer development.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('tumour', 'Disease', (71, 77))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('CNGs', 'Var', (36, 40))	('cancer', 'Disease', (137, 143))	('oncogenes', 'Gene', (21, 30))	('tumour', 'Phenotype', 'HP:0002664', (71, 77))	('overexpression', 'PosReg', (45, 59))	('tumour', 'Disease', 'MESH:D009369', (71, 77))
530047	29459674	Using cBioPortal, the overall survival rates of patients in these cancer types was compared between tumour samples with or without alterations in each gene, and those which contained the highest number of tumour samples (Fig.	('tumour', 'Disease', 'MESH:D009369', (205, 211))	('tumour', 'Disease', (205, 211))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('tumour', 'Phenotype', 'HP:0002664', (100, 106))	('alterations', 'Var', (131, 142))	('tumour', 'Disease', 'MESH:D009369', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('tumour', 'Disease', (100, 106))	('patients', 'Species', '9606', (48, 56))	('tumour', 'Phenotype', 'HP:0002664', (205, 211))	('cancer', 'Disease', (66, 72))
530048	29459674	Those patients with TCGA uterine corpus endometrial carcinoma had significant overall survival rates with p-value 1.930e-6.	('endometrial carcinoma', 'Disease', (40, 61))	('carcinoma', 'Phenotype', 'HP:0030731', (52, 61))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (40, 61))	('patients', 'Species', '9606', (6, 14))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (40, 61))	('TCGA', 'Var', (20, 24))
530049	29459674	We observed that TCGA uterine corpus endometrial carcinoma patients with genetic alterations in BIRC5 had significantly better overall survival rates when compared to TCGA sarcoma and ovarian serous cystadenocarcinoma patients with gene amplification in BIRC5 and EZH2.	('endometrial carcinoma', 'Disease', (37, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (208, 217))	('EZH2', 'Gene', (264, 268))	('EZH2', 'Gene', '2146', (264, 268))	('sarcoma', 'Disease', 'MESH:D012509', (172, 179))	('ovarian serous cystadenocarcinoma', 'Disease', (184, 217))	('sarcoma', 'Disease', (172, 179))	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (37, 58))	('genetic alterations', 'Var', (73, 92))	('patients', 'Species', '9606', (59, 67))	('ovarian serous cystadenocarcinoma', 'Disease', 'MESH:D018284', (184, 217))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (37, 58))	('overall', 'MPA', (127, 134))	('better', 'PosReg', (120, 126))	('sarcoma', 'Phenotype', 'HP:0100242', (172, 179))	('patients', 'Species', '9606', (218, 226))	('BIRC5', 'Gene', '332', (254, 259))	('BIRC5', 'Gene', '332', (96, 101))	('BIRC5', 'Gene', (254, 259))	('BIRC5', 'Gene', (96, 101))	('serous cystadenocarcinoma', 'Phenotype', 'HP:0012887', (192, 217))
530050	29459674	The median month survival for sarcoma patients with genetic alterations was 32.13 while that of patients without genetic alterations was 76.35.	('genetic alterations', 'Var', (52, 71))	('sarcoma', 'Disease', 'MESH:D012509', (30, 37))	('sarcoma', 'Disease', (30, 37))	('patients', 'Species', '9606', (96, 104))	('patients', 'Species', '9606', (38, 46))	('sarcoma', 'Phenotype', 'HP:0100242', (30, 37))
530059	29459674	The desired Affymetrix was valid: 202666_s_at (ACTL6A), 226463_at (ATP6V1C1), 203140_at (BCL6), 204274_at (EBAG9), 204010_s_at (KRAS), 212248_at (MTDH), 216071_x_at (OPA1) and 213184_at (SENP5).	('203140_at', 'Var', (78, 87))	('EBAG9', 'Gene', '9166', (107, 112))	('EBAG9', 'Gene', (107, 112))	('204010_s_at', 'Var', (115, 126))	('MTDH', 'Gene', (146, 150))	('202666_s_at', 'Var', (34, 45))	('SENP5', 'Gene', (187, 192))	('MTDH', 'Gene', '92140', (146, 150))	('ATP6V1C1', 'Gene', '528', (67, 75))	('ACTL6A', 'Gene', (47, 53))	('KRAS', 'Gene', '3845', (128, 132))	('BCL6', 'Gene', '604', (89, 93))	('212248_at', 'Var', (135, 144))	('ACTL6A', 'Gene', '86', (47, 53))	('OPA1', 'Gene', '4976', (166, 170))	('KRAS', 'Gene', (128, 132))	('ATP6V1C1', 'Gene', (67, 75))	('OPA1', 'Gene', (166, 170))	('226463_at', 'Var', (56, 65))	('213184_at', 'Var', (176, 185))	('204274_at', 'Var', (96, 105))	('216071_x_at', 'Var', (153, 164))	('SENP5', 'Gene', '205564', (187, 192))	('BCL6', 'Gene', (89, 93))
530062	29459674	Interestingly, we identified that MTDH was not statistically associated with RFS in ovarian cancer (P = 0.59); however, the high expression of MTDH was associated with a poor prognosis in other three cancer types - breast (P = 3.5e-10), lung (P = 2.1e-06) and gastric (P = 3.5e-10; Sup Fig.	('ovarian cancer', 'Disease', (84, 98))	('MTDH', 'Gene', (34, 38))	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('lung', 'Disease', (237, 241))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('gastric', 'Disease', (260, 267))	('MTDH', 'Gene', '92140', (143, 147))	('ovarian cancer', 'Disease', 'MESH:D010051', (84, 98))	('ovarian cancer', 'Phenotype', 'HP:0100615', (84, 98))	('MTDH', 'Gene', '92140', (34, 38))	('breast', 'Disease', (215, 221))	('cancer', 'Disease', 'MESH:D009369', (200, 206))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('cancer', 'Disease', (200, 206))	('high', 'Var', (124, 128))	('MTDH', 'Gene', (143, 147))
530074	29459674	The cases with more than 40.0% genetic alterations and including both CNLs and CNGs were identified in six cancer datasets from four cancer types: ovarian serous cystadenocarcinoma, lung squamous cell carcinoma, oesophageal carcinoma and uterine carcinosarcoma.	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (238, 260))	('sarcoma', 'Phenotype', 'HP:0100242', (253, 260))	('oesophageal carcinoma', 'Phenotype', 'HP:0011459', (212, 233))	('genetic alterations', 'Var', (31, 50))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (187, 210))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (182, 210))	('lung squamous cell carcinoma', 'Disease', (182, 210))	('cancer', 'Disease', (133, 139))	('serous cystadenocarcinoma', 'Phenotype', 'HP:0012887', (155, 180))	('carcinoma', 'Phenotype', 'HP:0030731', (171, 180))	('oesophageal carcinoma', 'Disease', 'MESH:D005764', (212, 233))	('cancer', 'Disease', (107, 113))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('carcinosarcoma', 'Disease', (246, 260))	('carcinoma', 'Phenotype', 'HP:0030731', (201, 210))	('carcinoma', 'Phenotype', 'HP:0030731', (224, 233))	('ovarian serous cystadenocarcinoma', 'Disease', (147, 180))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('oesophageal carcinoma', 'Disease', (212, 233))	('carcinosarcoma', 'Disease', 'MESH:D002296', (246, 260))	('ovarian serous cystadenocarcinoma', 'Disease', 'MESH:D018284', (147, 180))
530075	29459674	For example, the TCGA ovarian serous cystadenocarcinoma patients had more than 60.0% (360 cases) genetic alteration in CNGs.	('serous cystadenocarcinoma', 'Phenotype', 'HP:0012887', (30, 55))	('patients', 'Species', '9606', (56, 64))	('ovarian serous cystadenocarcinoma', 'Disease', 'MESH:D018284', (22, 55))	('carcinoma', 'Phenotype', 'HP:0030731', (46, 55))	('ovarian serous cystadenocarcinoma', 'Disease', (22, 55))	('genetic alteration', 'Var', (97, 115))
530077	29459674	The median month survival for ovarian serous cystadenocarcinoma patients with genetic alterations was 48.72, while that of patients without genetic mutation was 39.55.	('serous cystadenocarcinoma', 'Phenotype', 'HP:0012887', (38, 63))	('patients', 'Species', '9606', (64, 72))	('ovarian serous cystadenocarcinoma', 'Disease', (30, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (54, 63))	('patients', 'Species', '9606', (123, 131))	('genetic alterations', 'Var', (78, 97))	('ovarian serous cystadenocarcinoma', 'Disease', 'MESH:D018284', (30, 63))
530079	29459674	This study has revealed some significant somatic mutational characteristics of prognosis-related genes in multiple cancer types, particularly with respect to the CNVs and their effects on gene expression.	('mutational', 'Var', (49, 59))	('multiple cancer', 'Disease', (106, 121))	('prognosis-related genes', 'Gene', (79, 102))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('effects', 'Reg', (177, 184))	('multiple cancer', 'Disease', 'MESH:D009369', (106, 121))
530096	32296033	We previously reported that the p38 MAPK, through its downstream effectors MK2 and HSP27, suppressed CSC properties by downregulating the expression of transcription factors that mediate stemness in non-small-cell lung cancer (NSCLC) cells, and that despite unaltered total expression of total p38 proteins, the levels of activated p38 were reduced in NSCLC tissues.	('HSP27', 'Gene', (83, 88))	('NSCLC', 'Phenotype', 'HP:0030358', (352, 357))	('levels', 'MPA', (312, 318))	('CSC', 'Disease', (101, 104))	('expression', 'MPA', (138, 148))	('lung cancer', 'Disease', (214, 225))	('NSCLC', 'Disease', 'MESH:D002289', (227, 232))	('MK2', 'Gene', '9261', (75, 78))	('HSP27', 'Gene', '3315', (83, 88))	('NSCLC', 'Disease', (227, 232))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (203, 225))	('reduced', 'NegReg', (341, 348))	('lung cancer', 'Disease', 'MESH:D008175', (214, 225))	('NSCLC', 'Disease', 'MESH:D002289', (352, 357))	('NSCLC', 'Phenotype', 'HP:0030358', (227, 232))	('lung cancer', 'Phenotype', 'HP:0100526', (214, 225))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('p38', 'Var', (32, 35))	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (199, 225))	('NSCLC', 'Disease', (352, 357))	('MK2', 'Gene', (75, 78))	('suppressed', 'NegReg', (90, 100))	('downregulating', 'NegReg', (119, 133))
530103	32296033	These studies have identified the WIP1-p38-MK2-HSP27 cascade as a novel signaling pathway that, when altered, promotes CSC properties in NSCLC development, and have defined novel mechanisms underlying the oncogenic activity of WIP1 and the anticancer efficacy of WIP1 inhibitors.	('NSCLC', 'Disease', (137, 142))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('NSCLC', 'Disease', 'MESH:D002289', (137, 142))	('altered', 'Var', (101, 108))	('NSCLC', 'Phenotype', 'HP:0030358', (137, 142))	('MK2', 'Gene', '9261', (43, 46))	('CSC properties', 'CPA', (119, 133))	('promotes', 'PosReg', (110, 118))	('HSP27', 'Gene', '3315', (47, 52))	('HSP27', 'Gene', (47, 52))	('MK2', 'Gene', (43, 46))	('cancer', 'Disease', (244, 250))	('cancer', 'Disease', 'MESH:D009369', (244, 250))
530113	32296033	p38 is a tumor suppressor in the lungs, as p38 deletion in adult mice promotes K-RasG12V-induced lung cancer, but the mechanism underlying this observation and those underlying the tumor-suppressing activity of p38 in general are not completely understood.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('tumor', 'Disease', (181, 186))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('lung cancer', 'Disease', 'MESH:D008175', (97, 108))	('K-RasG12V-induced', 'Disease', (79, 96))	('promotes', 'PosReg', (70, 78))	('mice', 'Species', '10090', (65, 69))	('K-RasG12V', 'Chemical', '-', (79, 88))	('deletion', 'Var', (47, 55))	('tumor', 'Disease', (9, 14))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('p38', 'Gene', (43, 46))	('lung cancer', 'Disease', (97, 108))	('lung cancer', 'Phenotype', 'HP:0100526', (97, 108))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))
530114	32296033	We recently reported that p38, especially the gamma and delta isoforms of p38, suppresses the expression and reduces the stability of the stemness-related proteins SOX2, OCT4, NANOG, KLF4, and c-Myc and CSC properties via MK2-mediated HSP27 phosphorylation in NSCLC cells.	('MK2', 'Gene', '9261', (222, 225))	('c-Myc', 'Gene', (193, 198))	('NSCLC', 'Disease', 'MESH:D002289', (260, 265))	('c-Myc', 'Gene', '4609', (193, 198))	('stability', 'MPA', (121, 130))	('NANOG', 'Gene', '79923', (176, 181))	('suppresses', 'NegReg', (79, 89))	('NANOG', 'Gene', (176, 181))	('HSP27', 'Gene', '3315', (235, 240))	('KLF4', 'Gene', '9314', (183, 187))	('NSCLC', 'Disease', (260, 265))	('OCT4', 'Gene', '5460', (170, 174))	('p38', 'Var', (26, 29))	('NSCLC', 'Phenotype', 'HP:0030358', (260, 265))	('expression', 'MPA', (94, 104))	('MK2', 'Gene', (222, 225))	('reduces', 'NegReg', (109, 116))	('OCT4', 'Gene', (170, 174))	('phosphorylation', 'MPA', (241, 256))	('HSP27', 'Gene', (235, 240))	('CSC', 'CPA', (203, 206))	('KLF4', 'Gene', (183, 187))	('SOX2', 'Gene', (164, 168))	('SOX2', 'Gene', '6657', (164, 168))
530118	32296033	WIP1 has multiple substrates, including p38, p53, MDM2, and DNA damage response mediators (ATM, Chk1, and Chk2).	('p53', 'Gene', (45, 48))	('MDM2', 'Gene', (50, 54))	('p38', 'Var', (40, 43))	('p53', 'Gene', '7157', (45, 48))	('Chk2', 'Gene', '11200', (106, 110))	('ATM', 'Gene', (91, 94))	('Chk2', 'Gene', (106, 110))	('ATM', 'Gene', '472', (91, 94))	('Chk1', 'Gene', (96, 100))	('Chk1', 'Gene', '1111', (96, 100))	('MDM2', 'Gene', '4193', (50, 54))
530123	32296033	Further studies demonstrated that WIP1 indeed induced stemless-related proteins and CSC properties by inhibiting p38 in NSCLC cells in vitro and in vivo, and that the WIP1 inhibitor GSK283071 activated p38 and suppressed stemness-related protein expression and CSC properties in a p38-dependent manner in NSCLC cells.	('activated', 'PosReg', (192, 201))	('GSK283071', 'Chemical', '-', (182, 191))	('NSCLC', 'Disease', 'MESH:D002289', (120, 125))	('stemless-related', 'CPA', (54, 70))	('CSC properties', 'CPA', (84, 98))	('p38', 'CPA', (202, 205))	('inhibiting', 'NegReg', (102, 112))	('NSCLC', 'Phenotype', 'HP:0030358', (305, 310))	('NSCLC', 'Phenotype', 'HP:0030358', (120, 125))	('stemness-related protein', 'CPA', (221, 245))	('suppressed', 'NegReg', (210, 220))	('GSK283071', 'Var', (182, 191))	('induced', 'PosReg', (46, 53))	('NSCLC', 'Disease', (305, 310))	('p38', 'Protein', (113, 116))	('NSCLC', 'Disease', (120, 125))	('CSC properties', 'CPA', (261, 275))	('NSCLC', 'Disease', 'MESH:D002289', (305, 310))
530124	32296033	These studies revealed novel genetic alterations, along with the associated signaling pathway, that promote CSC properties in NSCLC development, and identified novel mechanisms underlying the oncogenic activity of WIP1 and the anticancer efficacy of WIP1 inhibitors, which may expand the therapeutic application of WIP1 inhibitors.	('NSCLC', 'Disease', 'MESH:D002289', (126, 131))	('CSC properties', 'CPA', (108, 122))	('genetic alterations', 'Var', (29, 48))	('cancer', 'Disease', 'MESH:D009369', (231, 237))	('cancer', 'Disease', (231, 237))	('NSCLC', 'Phenotype', 'HP:0030358', (126, 131))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('alterations', 'Var', (37, 48))	('promote', 'PosReg', (100, 107))	('WIP1', 'Gene', (250, 254))	('NSCLC', 'Disease', (126, 131))
530125	32296033	Inactivation of the p38 pathway promotes cancer development in mice.	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('p38 pathway', 'Pathway', (20, 31))	('mice', 'Species', '10090', (63, 67))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('promotes', 'PosReg', (32, 40))	('Inactivation', 'Var', (0, 12))
530131	32296033	The results showed that the level of p-p38 was significantly lower in the tumor tissue specimens than in the normal tissue specimens (Fig.	('lower', 'NegReg', (61, 66))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('level', 'MPA', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('p-p38', 'Var', (37, 42))	('tumor', 'Disease', (74, 79))
530135	32296033	We compared the expression of WIP1 and p-p38 in three NSCLC cell lines (H1299, A549, and H460) by Western blotting.	('H460', 'CellLine', 'CVCL:0459', (89, 93))	('A549', 'CellLine', 'CVCL:0023', (79, 83))	('NSCLC', 'Phenotype', 'HP:0030358', (54, 59))	('p-p38', 'Var', (39, 44))	('NSCLC', 'Disease', (54, 59))	('NSCLC', 'Disease', 'MESH:D002289', (54, 59))	('H1299', 'CellLine', 'CVCL:0060', (72, 77))
530139	32296033	We previously demonstrated that reduced p-p38 levels correlated with increased SOX2 levels in NSCLC tissues, and that activated p38 suppressed CSC properties in NSCLC cell lines.	('NSCLC', 'Disease', 'MESH:D002289', (161, 166))	('SOX2', 'Gene', '6657', (79, 83))	('p-p38 levels', 'MPA', (40, 52))	('NSCLC', 'Phenotype', 'HP:0030358', (94, 99))	('increased', 'PosReg', (69, 78))	('p38', 'Gene', (128, 131))	('suppressed', 'NegReg', (132, 142))	('reduced', 'NegReg', (32, 39))	('NSCLC', 'Disease', (94, 99))	('NSCLC', 'Phenotype', 'HP:0030358', (161, 166))	('NSCLC', 'Disease', 'MESH:D002289', (94, 99))	('activated', 'Var', (118, 127))	('NSCLC', 'Disease', (161, 166))	('CSC properties', 'CPA', (143, 157))	('SOX2', 'Gene', (79, 83))
530142	32296033	The analysis revealed associations between high WIP1 expression and increased levels of ALDH1A1 and ALDH1-A2 (Fig.	('ALDH1-A2', 'Gene', (100, 108))	('high', 'Var', (43, 47))	('ALDH1A1', 'Gene', '216', (88, 95))	('WIP1', 'Gene', (48, 52))	('levels', 'MPA', (78, 84))	('ALDH1A1', 'Gene', (88, 95))	('expression', 'MPA', (53, 63))	('ALDH1-A2', 'Gene', '8854', (100, 108))	('increased', 'PosReg', (68, 77))
530148	32296033	In addition, the overexpression of WIP1 in H460 cells effectively reduced the phosphorylation of MAPKAPK-2 (MK2) at Thr222 and Thr334, and the phosphorylation of HSP27 at Ser82 (Fig.	('reduced', 'NegReg', (66, 73))	('H460', 'CellLine', 'CVCL:0459', (43, 47))	('phosphorylation', 'MPA', (78, 93))	('HSP27', 'Gene', (162, 167))	('HSP27', 'Gene', '3315', (162, 167))	('phosphorylation', 'MPA', (143, 158))	('MK2', 'Gene', '9261', (108, 111))	('MK2', 'Gene', (108, 111))	('Ser82', 'Chemical', '-', (171, 176))	('MAPKAPK-2', 'Gene', (97, 106))	('Thr334', 'Chemical', '-', (127, 133))	('MAPKAPK-2', 'Gene', '9261', (97, 106))	('overexpression', 'PosReg', (17, 31))	('Thr334', 'Var', (127, 133))	('Thr222', 'Chemical', '-', (116, 122))
530149	32296033	2b), which was consistent with our previous report showing that p38 suppresses the expression of stemness-related proteins through MK2-dependent phosphorylation of HSP27.	('HSP27', 'Gene', '3315', (164, 169))	('stemness-related proteins', 'Gene', (97, 122))	('suppresses', 'NegReg', (68, 78))	('p38', 'Var', (64, 67))	('MK2', 'Gene', '9261', (131, 134))	('expression', 'MPA', (83, 93))	('MK2', 'Gene', (131, 134))	('HSP27', 'Gene', (164, 169))
530152	32296033	Compared with vector control treatment, ectopic expression of WIP1 led to a higher side population percentage in H1299 and H460 cells (Fig.	('H460', 'CellLine', 'CVCL:0459', (123, 127))	('side population percentage', 'CPA', (83, 109))	('ectopic expression', 'Var', (40, 58))	('H1299', 'CellLine', 'CVCL:0060', (113, 118))	('higher', 'PosReg', (76, 82))
530155	32296033	Our results showed that knocking down WIP1 expression upregulated the levels of p38, reduced the levels of the stemness-related proteins SOX2, OCT4, and NANOG, and the CSC marker ALDH1A1, as determined by Western blot analysis (Fig.	('levels', 'MPA', (70, 76))	('NANOG', 'Gene', (153, 158))	('knocking down', 'Var', (24, 37))	('upregulated', 'PosReg', (54, 65))	('p38', 'MPA', (80, 83))	('WIP1', 'Gene', (38, 42))	('ALDH1A1', 'Gene', '216', (179, 186))	('SOX2', 'Gene', '6657', (137, 141))	('NANOG', 'Gene', '79923', (153, 158))	('OCT4', 'Gene', '5460', (143, 147))	('SOX2', 'Gene', (137, 141))	('OCT4', 'Gene', (143, 147))	('reduced', 'NegReg', (85, 92))	('ALDH1A1', 'Gene', (179, 186))
530160	32296033	We analyzed the effect of WIP1 overexpression in H460 cells in which p38 was constitutively activated by an active mutant of MKK3 (MKK3E), and the effect of WIP1 knockdown in H460 cells in which p38 was inhibited by a dominant-negative mutant of MKK6 (MKK6A).	('H460', 'CellLine', 'CVCL:0459', (175, 179))	('MKK6', 'Gene', (246, 250))	('MKK6', 'Gene', (252, 256))	('activated', 'PosReg', (92, 101))	('MKK6', 'Gene', '5608', (252, 256))	('H460', 'CellLine', 'CVCL:0459', (49, 53))	('mutant', 'Var', (115, 121))	('MKK3E', 'Gene', (131, 136))	('MKK6A', 'Gene', (252, 257))	('MKK6A', 'Gene', '5608', (252, 257))	('inhibited', 'NegReg', (203, 212))	('MKK3E', 'Gene', '5606', (131, 136))	('MKK3', 'Gene', '5606', (125, 129))	('MKK3', 'Gene', '5606', (131, 135))	('MKK3', 'Gene', (125, 129))	('MKK3', 'Gene', (131, 135))	('MKK6', 'Gene', '5608', (246, 250))	('p38', 'Gene', (69, 72))
530165	32296033	In contrast, H460 cells with abrogation of the WIP1 knockdown-induced activation of p38 by MKK6A exhibited increases in SOX2, OCT4, and NANOG expression (Fig.	('NANOG', 'Gene', '79923', (136, 141))	('H460', 'CellLine', 'CVCL:0459', (13, 17))	('increases', 'PosReg', (107, 116))	('abrogation', 'Var', (29, 39))	('NANOG', 'Gene', (136, 141))	('p38', 'Gene', (84, 87))	('MKK6A', 'Gene', (91, 96))	('MKK6A', 'Gene', '5608', (91, 96))	('OCT4', 'Gene', '5460', (126, 130))	('SOX2', 'Gene', (120, 124))	('SOX2', 'Gene', '6657', (120, 124))	('activation', 'PosReg', (70, 80))	('WIP1', 'Gene', (47, 51))	('OCT4', 'Gene', (126, 130))
530170	32296033	In cells with ectopic expression of both WIP1 and MKK3E, the p38 phosphorylation status depends on the balance of signaling strength between these two proteins with opposite effects on p38.	('WIP1', 'Var', (41, 45))	('depends', 'Reg', (88, 95))	('phosphorylation status', 'MPA', (65, 87))	('MKK3E', 'Gene', (50, 55))	('balance of signaling strength', 'MPA', (103, 132))	('MKK3E', 'Gene', '5606', (50, 55))
530173	32296033	Indeed, WIP1 inhibitors, including GSK2830371 (GSK), are currently being pursued as anticancer drugs based on their ability to reactivate p53.	('cancer', 'Disease', (88, 94))	('p53', 'Gene', (138, 141))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('reactivate', 'MPA', (127, 137))	('p53', 'Gene', '7157', (138, 141))	('GSK2830371', 'Chemical', 'MESH:C587624', (35, 45))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('GSK2830371', 'Var', (35, 45))
530176	32296033	Furthermore, GSK reduced SOX2, OCT4, and NANOG protein levels, the expression levels of the CSC marker ALDH1A1 (Fig.	('OCT4', 'Gene', '5460', (31, 35))	('GSK', 'Var', (13, 16))	('OCT4', 'Gene', (31, 35))	('ALDH1A1', 'Gene', (103, 110))	('SOX2', 'Gene', (25, 29))	('NANOG', 'Gene', '79923', (41, 46))	('ALDH1A1', 'Gene', '216', (103, 110))	('expression levels', 'MPA', (67, 84))	('NANOG', 'Gene', (41, 46))	('SOX2', 'Gene', '6657', (25, 29))	('reduced', 'NegReg', (17, 24))
530177	32296033	We also found that treatment with GSK promoted the phosphorylation of the p38 downstream targets MK2 (Thr222 and Thr334) and HSP27 (Ser82) in H460 cells (Fig.	('Ser82', 'Chemical', '-', (132, 137))	('Ser82', 'Var', (132, 137))	('Thr222', 'Chemical', '-', (102, 108))	('HSP27', 'Gene', '3315', (125, 130))	('HSP27', 'Gene', (125, 130))	('Thr334', 'Chemical', '-', (113, 119))	('MK2', 'Gene', '9261', (97, 100))	('MK2', 'Gene', (97, 100))	('Thr222', 'Var', (102, 108))	('p38', 'Gene', (74, 77))	('phosphorylation', 'MPA', (51, 66))	('H460', 'CellLine', 'CVCL:0459', (142, 146))	('promoted', 'PosReg', (38, 46))	('Thr334', 'Var', (113, 119))
530178	32296033	Moreover, in addition to producing these effects on A549 and H460 cells with the wild-type TP53 gene, GSK also reduced the expression levels of SOX2, OCT4, NANOG, and the CSC marker ALDH1A1 in H1299 cells with homozygous deletion of the TP53 gene (Fig.	('deletion', 'Var', (221, 229))	('TP53', 'Gene', (91, 95))	('TP53', 'Gene', '7157', (237, 241))	('expression levels', 'MPA', (123, 140))	('H460', 'CellLine', 'CVCL:0459', (61, 65))	('NANOG', 'Gene', (156, 161))	('A549', 'CellLine', 'CVCL:0023', (52, 56))	('TP53', 'Gene', (237, 241))	('ALDH1A1', 'Gene', '216', (182, 189))	('TP53', 'Gene', '7157', (91, 95))	('reduced', 'NegReg', (111, 118))	('H1299', 'CellLine', 'CVCL:0060', (193, 198))	('OCT4', 'Gene', '5460', (150, 154))	('SOX2', 'Gene', (144, 148))	('OCT4', 'Gene', (150, 154))	('NANOG', 'Gene', '79923', (156, 161))	('SOX2', 'Gene', '6657', (144, 148))	('ALDH1A1', 'Gene', (182, 189))
530181	32296033	We thus measured the effect of WIP1 and the WIP1 inhibitor GSK2830371 on the tumor-initiating ability of H460 cells in mouse xenograft models using a limiting dilution assay performed by injecting varying amounts of cells into nude mice.	('nude mice', 'Species', '10090', (227, 236))	('mouse', 'Species', '10090', (119, 124))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('GSK2830371', 'Chemical', 'MESH:C587624', (59, 69))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Disease', (77, 82))	('GSK2830371', 'Var', (59, 69))	('H460', 'CellLine', 'CVCL:0459', (105, 109))
530182	32296033	We found that at multiple cell concentrations (e.g., 1 x 105 and 6 x 104), ectopic expression of WIP1 increased the frequency of tumor formation by H460 cells (Fig.	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('ectopic expression', 'Var', (75, 93))	('WIP1', 'Gene', (97, 101))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('H460', 'CellLine', 'CVCL:0459', (148, 152))	('increased', 'PosReg', (102, 111))	('tumor', 'Disease', (129, 134))
530184	32296033	S5, Supplementary Table S1), and inactivation of p38 by MKK6A reversed the inhibitory effect of GSK on tumor initiation (Fig.	('MKK6A', 'Gene', '5608', (56, 61))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('p38', 'Protein', (49, 52))	('tumor initiation', 'Disease', (103, 119))	('tumor initiation', 'Disease', 'MESH:D009369', (103, 119))	('inactivation', 'Var', (33, 45))	('MKK6A', 'Gene', (56, 61))
530197	32296033	Despite the tumor-suppressing functions of the p38 MAPK, mutations in p38 and altered p38 expression are rare in cancer.	('p38', 'Gene', (86, 89))	('p38', 'Gene', (70, 73))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('cancer', 'Disease', (113, 119))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('mutations', 'Var', (57, 66))	('expression', 'MPA', (90, 100))	('tumor', 'Disease', (12, 17))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
530205	32296033	WIP1 also dephosphorylates and inactivates ATM, Chk1, and Chk2, which are upstream kinase activators of p53 that function in response to DNA damage.	('p53', 'Gene', (104, 107))	('ATM', 'Gene', (43, 46))	('inactivates', 'Var', (31, 42))	('p53', 'Gene', '7157', (104, 107))	('Chk2', 'Gene', '11200', (58, 62))	('ATM', 'Gene', '472', (43, 46))	('Chk1', 'Gene', (48, 52))	('Chk2', 'Gene', (58, 62))	('Chk1', 'Gene', '1111', (48, 52))
530207	32296033	Importantly, this new oncogenic activity of WIP1 seems to be p53 independent, as WIP1 inhibited p38 phosphorylation and enhanced stemness-related protein expression and CSC properties, and the WIP1 inhibitor GSK2830371 reduced the expression of stemness-related transcription factors and the cancer stemness marker ALDH1 in H1299 cells with homozygous deletion of the TP53 gene (Figs.	('deletion', 'Var', (352, 360))	('stemness-related', 'CPA', (129, 145))	('p38', 'MPA', (96, 99))	('cancer stemness', 'Disease', (292, 307))	('ALDH1', 'Gene', (315, 320))	('enhanced', 'PosReg', (120, 128))	('H1299', 'CellLine', 'CVCL:0060', (324, 329))	('CSC properties', 'CPA', (169, 183))	('TP53', 'Gene', (368, 372))	('ALDH1', 'Gene', '216', (315, 320))	('GSK2830371', 'Chemical', 'MESH:C587624', (208, 218))	('expression', 'MPA', (231, 241))	('cancer', 'Phenotype', 'HP:0002664', (292, 298))	('p53', 'Gene', '7157', (61, 64))	('reduced', 'NegReg', (219, 226))	('TP53', 'Gene', '7157', (368, 372))	('cancer stemness', 'Disease', 'MESH:D009369', (292, 307))	('inhibited', 'NegReg', (86, 95))	('p53', 'Gene', (61, 64))
530208	32296033	WIP1 inhibitors, such as GSK2830371, are currently under development as anticancer drugs, based on their abilities to inhibit tumor growth and sensitize cancer cells to chemotherapy by reactivating p53.	('inhibit', 'NegReg', (118, 125))	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('cancer', 'Disease', (153, 159))	('GSK2830371', 'Chemical', 'MESH:C587624', (25, 35))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('GSK2830371', 'Var', (25, 35))	('p53', 'Gene', (198, 201))	('p53', 'Gene', '7157', (198, 201))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('reactivating', 'PosReg', (185, 197))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('tumor', 'Disease', (126, 131))
530210	32296033	Our findings on the ability of WIP1 to promote CSC properties and that of a WIP1 inhibitor to suppress these properties in p53-deficient NSCLC cells have defined a new mechanism underlying the therapeutic efficacy of WIP1 inhibitors, and suggest that these inhibitors may have effects beyond p53, and be effective regardless of the p53 status in NSCLC patients with either wild-type or mutant p53.	('NSCLC', 'Disease', (137, 142))	('promote', 'PosReg', (39, 46))	('p53', 'Gene', '7157', (292, 295))	('p53', 'Gene', (393, 396))	('p53', 'Gene', '7157', (393, 396))	('patients', 'Species', '9606', (352, 360))	('NSCLC', 'Disease', 'MESH:D002289', (137, 142))	('NSCLC', 'Phenotype', 'HP:0030358', (346, 351))	('NSCLC', 'Phenotype', 'HP:0030358', (137, 142))	('mutant', 'Var', (386, 392))	('CSC', 'MPA', (47, 50))	('p53', 'Gene', (123, 126))	('NSCLC', 'Disease', (346, 351))	('p53', 'Gene', '7157', (123, 126))	('p53', 'Gene', (332, 335))	('p53', 'Gene', '7157', (332, 335))	('NSCLC', 'Disease', 'MESH:D002289', (346, 351))	('p53', 'Gene', (292, 295))
530236	32296033	To evaluate the expression of WIP1, p-p38, SOX2, and ALDH1 in normal or tumor tissue samples, staining scores were evaluated by multiplying the positive staining area (scored as 1: 0-25%; 2: 26-50%; 3: 51-75%; 4: 76-100%) with the staining intensity (scored as 1: weak; 2: moderate; 3: strong; 4: very strong).	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Disease', (72, 77))	('ALDH1', 'Gene', (53, 58))	('SOX2', 'Gene', (43, 47))	('ALDH1', 'Gene', '216', (53, 58))	('SOX2', 'Gene', '6657', (43, 47))	('p-p38', 'Var', (36, 41))	('tumor', 'Disease', 'MESH:D009369', (72, 77))
530239	32296033	To determine the effects of GSK2830371 on tumor initiation and growth, mice injected with H460-BH or H460-MKK6A cells were randomly divided into two groups, one treated with a DMSO control and the other treated with 25 mg/kg GSK2830371 by intraperitoneal (i.p.)	('tumor initiation', 'Disease', 'MESH:D009369', (42, 58))	('mice', 'Species', '10090', (71, 75))	('GSK2830371', 'Var', (225, 235))	('tumor initiation', 'Disease', (42, 58))	('GSK2830371', 'Chemical', 'MESH:C587624', (28, 38))	('MKK6A', 'Gene', (106, 111))	('MKK6A', 'Gene', '5608', (106, 111))	('H460', 'CellLine', 'CVCL:0459', (90, 94))	('H460', 'CellLine', 'CVCL:0459', (101, 105))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('GSK2830371', 'Chemical', 'MESH:C587624', (225, 235))	('DMSO', 'Chemical', 'MESH:D004121', (176, 180))
530270	31159745	The study reported the importance of alterations in the genes encoding RNA binding proteins and that they trigger common and specific AS events in various solid tumors.	('tumors', 'Phenotype', 'HP:0002664', (161, 167))	('solid tumors', 'Disease', (155, 167))	('trigger', 'Reg', (106, 113))	('RNA binding proteins', 'Protein', (71, 91))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('alterations', 'Var', (37, 48))	('solid tumors', 'Disease', 'MESH:D009369', (155, 167))
530273	31159745	An important finding that abnormal RNA splicing, characterized by widespread IR events, is common across cancers was marked by a study performed by Dvinge and Bradley on 40 HNC patients data downloaded from CGHub.	('cancers', 'Phenotype', 'HP:0002664', (105, 112))	('cancers', 'Disease', (105, 112))	('patients', 'Species', '9606', (177, 185))	('cancers', 'Disease', 'MESH:D009369', (105, 112))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('abnormal RNA splicing', 'Var', (26, 47))
530275	31159745	Moreover, crosstalk between RNA splicing events and epigenetics may be associated with a diverse spectrum of mutations to RNA processing defects in cancer.	('cancer', 'Disease', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('crosstalk', 'Reg', (10, 19))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('mutations', 'Var', (109, 118))	('defects', 'Var', (137, 144))	('associated', 'Reg', (71, 81))
530278	31159745	used RNA-Seq data to analyze AS variants in sicontrol and siCELF1 transfected OC cells.	('variants', 'Var', (32, 40))	('CELF1', 'Gene', '10658', (60, 65))	('sicontrol', 'Gene', (44, 53))	('CELF1', 'Gene', (60, 65))
530282	31159745	Therefore, the rest of the data still remains to be studied for other mechanisms influenced by deregulation of CELF1 in HNSCC.	('HNSCC', 'Disease', (120, 125))	('deregulation', 'Var', (95, 107))	('CELF1', 'Gene', (111, 116))	('CELF1', 'Gene', '10658', (111, 116))
530289	31159745	Alternative splicing of genes is believed to be associated with the initiation, progression, and metastasis of cancer.	('metastasis of cancer', 'Disease', 'MESH:D009362', (97, 117))	('metastasis of cancer', 'Disease', (97, 117))	('associated', 'Reg', (48, 58))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('Alternative splicing', 'Var', (0, 20))
530297	31159745	Recurrent mutations in MLL3 have been reported in HNC in addition to several other cancers, including pancreatic, breast and gastric.	('cancers', 'Disease', 'MESH:D009369', (83, 90))	('cancers', 'Phenotype', 'HP:0002664', (83, 90))	('MLL3', 'Gene', (23, 27))	('reported', 'Reg', (38, 46))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('breast', 'Disease', (114, 120))	('pancreatic', 'Disease', 'MESH:D010195', (102, 112))	('MLL3', 'Gene', '58508', (23, 27))	('gastric', 'Disease', (125, 132))	('HNC', 'Disease', (50, 53))	('mutations', 'Var', (10, 19))	('pancreatic', 'Disease', (102, 112))	('cancers', 'Disease', (83, 90))
530302	31159745	Inhibition of RPS9 activates p53 activity, it is suggested to be an efficient method to induce apoptosis in tumor cells.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('RPS9', 'Gene', (14, 18))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('RPS9', 'Gene', '6203', (14, 18))	('activates', 'PosReg', (19, 28))	('tumor', 'Disease', (108, 113))	('p53', 'Gene', (29, 32))	('activity', 'MPA', (33, 41))	('Inhibition', 'Var', (0, 10))	('p53', 'Gene', '7157', (29, 32))
530330	30606157	The overall survival rates of patients with SPC were lower than those for patients without SPC, especially those with SPC in the esophagus or lungs.	('patients', 'Species', '9606', (74, 82))	('SPC', 'Var', (44, 47))	('lower', 'NegReg', (53, 58))	('patients', 'Species', '9606', (30, 38))
530343	30606157	This record includes information about patients' sex, age at diagnosis, sequential order of cancer incidence, histological type of cancer, and cancer site categorized according to the third edition of the International Classification of Diseases for Oncology (ICD-O-3), such as mouth/pharynx (C00-14), esophagus (C15), larynx (C32), and lung (C33, C34).	('patients', 'Species', '9606', (39, 47))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('mouth', 'Disease', (278, 283))	('type of cancer', 'Disease', 'MESH:D009369', (123, 137))	('mouth', 'Disease', 'MESH:D009059', (278, 283))	('C15', 'Gene', '51316', (313, 316))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('C32', 'Gene', (327, 330))	('larynx', 'Disease', (319, 325))	('esophagus', 'Disease', (302, 311))	('C15', 'Gene', (313, 316))	('cancer', 'Disease', (143, 149))	('C32', 'Gene', '51192', (327, 330))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('cancer', 'Disease', (92, 98))	('C00-14', 'Var', (293, 299))	('C33', 'Gene', (343, 346))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('cancer', 'Disease', (131, 137))	('type of cancer', 'Disease', (123, 137))	('Oncology', 'Phenotype', 'HP:0002664', (250, 258))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('lung', 'Disease', (337, 341))	('C33', 'Gene', '3732', (343, 346))	('cancer', 'Disease', 'MESH:D009369', (143, 149))
530416	29872701	Aberrant accumulation of polyamines is associated with various pathological consequences, including cancer.	('Aberrant', 'Var', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('polyamines', 'Chemical', 'MESH:D011073', (25, 35))	('accumulation', 'PosReg', (9, 21))	('associated', 'Reg', (39, 49))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('polyamines', 'Protein', (25, 35))
530434	29872701	Our results showed that knocking down ODC expression with shODC significantly increased total apoptosis of both KYSE450 and KYSE510 cell lines (Fig.	('knocking down', 'Var', (24, 37))	('increased', 'PosReg', (78, 87))	('apoptosis', 'CPA', (94, 103))	('ODC', 'Gene', (38, 41))	('KYSE510', 'CellLine', 'CVCL:1354', (124, 131))
530442	29872701	Our data showed that shMock-infected KYSE450 cells formed markedly larger xenograft tumors in nude mice compared to the shODC-infected groups (p < 0.01, Fig.	('nude mice', 'Species', '10090', (94, 103))	('xenograft tumors', 'Disease', (74, 90))	('larger', 'PosReg', (67, 73))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('shMock-infected', 'Var', (21, 36))	('tumors', 'Phenotype', 'HP:0002664', (84, 90))	('xenograft tumors', 'Disease', 'MESH:D009369', (74, 90))
530445	29872701	These results confirmed that inhibiting ODC expression in ESCC cells suppresses proliferation and induces apoptosis, leading to attenuation of ESCC tumorigenesis.	('attenuation', 'NegReg', (128, 139))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('induces', 'Reg', (98, 105))	('tumor', 'Disease', (148, 153))	('ODC expression', 'Protein', (40, 54))	('apoptosis', 'CPA', (106, 115))	('ESCC', 'Disease', (143, 147))	('proliferation', 'CPA', (80, 93))	('inhibiting', 'Var', (29, 39))	('suppresses', 'NegReg', (69, 79))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('rat', 'Species', '10116', (87, 90))
530451	29872701	Western blot analysis showed that DFMO induced an increased expression of Bax, p53, p21, p27, phosphorylation of CDK1 (Tyr15), cleavage of caspase 3 and PARP and suppressed expression of PCNA, Bcl-2 and cyclin B1.	('expression', 'MPA', (60, 70))	('PCNA', 'Gene', '5111', (187, 191))	('Tyr15', 'Chemical', '-', (119, 124))	('Bax', 'Gene', (74, 77))	('p21', 'Gene', '1026', (84, 87))	('DFMO', 'Chemical', 'MESH:D000518', (34, 38))	('DFMO', 'Var', (34, 38))	('p53', 'Gene', '7157', (79, 82))	('CDK1', 'Gene', '983', (113, 117))	('cyclin B1', 'Gene', '891', (203, 212))	('cyclin B1', 'Gene', (203, 212))	('CDK1', 'Gene', (113, 117))	('increased', 'PosReg', (50, 59))	('caspase 3', 'Protein', (139, 148))	('phosphorylation', 'MPA', (94, 109))	('p53', 'Gene', (79, 82))	('PARP', 'Gene', '142', (153, 157))	('cleavage', 'MPA', (127, 135))	('Bcl-2', 'Gene', (193, 198))	('suppressed', 'NegReg', (162, 172))	('expression', 'MPA', (173, 183))	('p21', 'Gene', (84, 87))	('PCNA', 'Gene', (187, 191))	('PARP', 'Gene', (153, 157))	('p27', 'Gene', '3429', (89, 92))	('p27', 'Gene', (89, 92))	('Bcl-2', 'Gene', '596', (193, 198))
530456	29872701	Results indicated that over 33 days of treatment, DFMO had no effect on mouse body weight compared with the vehicle-treated group.	('mouse', 'Species', '10090', (72, 77))	('DFMO', 'Chemical', 'MESH:D000518', (50, 54))	('mouse body weight', 'CPA', (72, 89))	('DFMO', 'Var', (50, 54))
530473	29872701	Studies focusing on transgenic mouse models have shown an essential role of polyamines in the early promotion of tumorigenesis.	('tumor', 'Disease', (113, 118))	('mouse', 'Species', '10090', (31, 36))	('polyamines', 'Chemical', 'MESH:D011073', (76, 86))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('transgenic', 'Species', '10090', (20, 30))	('polyamines', 'Var', (76, 86))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))
530476	29872701	Our data showed that when ODC expression in ESCC cells was knocked down, both proliferation and anchorage-independent growth of ESCC cells were significantly suppressed (Fig.	('suppressed', 'NegReg', (158, 168))	('rat', 'Species', '10116', (85, 88))	('anchorage-independent growth', 'CPA', (96, 124))	('knocked', 'Var', (59, 66))	('ODC expression', 'Protein', (26, 40))
530479	29872701	reported that polyamine depletion prevented apoptosis of rat intestinal epithelial cells by decreasing caspase 3 and 9 activities, as well as the translocation of Bax to mitochondria, thus diminishing cytochrome c release.	('diminishing', 'NegReg', (189, 200))	('decreasing', 'NegReg', (92, 102))	('polyamine depletion', 'Var', (14, 33))	('cytochrome c', 'Gene', (201, 213))	('polyamine', 'Chemical', 'MESH:D011073', (14, 23))	('depletion', 'Var', (24, 33))	('cytochrome c', 'Gene', '54205', (201, 213))	('caspase', 'Protein', (103, 110))	('rat', 'Species', '10116', (57, 60))	('diminishing cytochrome c', 'Phenotype', 'HP:0003514', (189, 213))	('translocation', 'MPA', (146, 159))	('activities', 'MPA', (119, 129))
530485	29872701	The homodimerization of Bcl-2 leads to anti-apoptosis signaling and Bax can heterodimerize with Bcl-2 to induce apoptosis.	('induce', 'PosReg', (105, 111))	('Bcl-2', 'Gene', (96, 101))	('heterodimerize', 'Var', (76, 90))	('Bcl-2', 'Gene', '596', (96, 101))	('apoptosis', 'CPA', (112, 121))	('homodimerization', 'MPA', (4, 20))	('anti-apoptosis signaling', 'MPA', (39, 63))	('Bcl-2', 'Gene', (24, 29))	('Bcl-2', 'Gene', '596', (24, 29))
530493	29872701	ODC activity displays two peaks during the entire cell cycle process, one associated with the G1/S transition and the other associated with the S/G2 and G2/M phases, suggesting that polyamines also play key roles in cell cycle progression.	('polyamines', 'Chemical', 'MESH:D011073', (182, 192))	('G1/S', 'Disease', (94, 98))	('S/G2', 'Var', (144, 148))	('S/G2', 'SUBSTITUTION', 'None', (144, 148))	('associated', 'Reg', (74, 84))
530495	29872701	Other effects, including arrest at the S or G2/M phase, have been reported in different cell lines, suggesting that polyamine depletion affects the cell cycle in a cell-type specific manner.	('cell cycle', 'CPA', (148, 158))	('affects', 'Reg', (136, 143))	('polyamine', 'Chemical', 'MESH:D011073', (116, 125))	('polyamine', 'Var', (116, 125))
530499	29872701	Our results showed that polyamine depletion increased the expression of wildtype p53, which in turn directly down-regulated the transcription of cyclin B1 mRNA and inactivated the CDK1/cyclin B1 complex by phosphorylation of CDK1.	('CDK1', 'Gene', (180, 184))	('expression', 'MPA', (58, 68))	('p53', 'Gene', (81, 84))	('transcription', 'MPA', (128, 141))	('CDK1', 'Gene', '983', (225, 229))	('CDK1', 'Gene', (225, 229))	('polyamine', 'Chemical', 'MESH:D011073', (24, 33))	('phosphorylation', 'MPA', (206, 221))	('depletion', 'Var', (34, 43))	('increased', 'PosReg', (44, 53))	('cyclin B1', 'Gene', '891', (185, 194))	('cyclin B1', 'Gene', (185, 194))	('down-regulated', 'NegReg', (109, 123))	('cyclin B1', 'Gene', '891', (145, 154))	('cyclin B1', 'Gene', (145, 154))	('polyamine depletion', 'Var', (24, 43))	('inactivated', 'NegReg', (164, 175))	('p53', 'Gene', '7157', (81, 84))	('CDK1', 'Gene', '983', (180, 184))
530507	29872701	However, DFMO is generally cytostatic in mammalian cells, causing a reduction in the rate of proliferation in the absence of cell death.	('mammalian', 'Species', '9606', (41, 50))	('rate', 'MPA', (85, 89))	('rat', 'Species', '10116', (85, 88))	('DFMO', 'Chemical', 'MESH:D000518', (9, 13))	('DFMO', 'Var', (9, 13))	('reduction', 'NegReg', (68, 77))	('rat', 'Species', '10116', (100, 103))
530516	29872701	Moreover, IHC results reconfirmed that DFMO not only suppressed proliferation, but also induced apoptosis in ESCC cells, leading to the inhibition of ESCC progression.	('induced', 'Reg', (88, 95))	('rat', 'Species', '10116', (71, 74))	('ESCC', 'Disease', (150, 154))	('inhibition', 'NegReg', (136, 146))	('apoptosis', 'CPA', (96, 105))	('DFMO', 'Var', (39, 43))	('proliferation', 'CPA', (64, 77))	('DFMO', 'Chemical', 'MESH:D000518', (39, 43))	('suppressed', 'NegReg', (53, 63))
530519	29872701	Our study also demonstrated that polyamine depletion not only suppressed proliferation, but also induced apoptosis of ESCC cells.	('induced', 'Reg', (97, 104))	('polyamine depletion', 'Var', (33, 52))	('apoptosis', 'CPA', (105, 114))	('proliferation', 'CPA', (73, 86))	('rat', 'Species', '10116', (80, 83))	('rat', 'Species', '10116', (22, 25))	('suppressed', 'NegReg', (62, 72))	('polyamine', 'Chemical', 'MESH:D011073', (33, 42))
530530	29872701	5625), phosphorylated ERKs (T202/Y204; Catalog No.	('ERKs', 'Gene', '5595;5594;5595', (22, 26))	('ERKs', 'Gene', (22, 26))	('T202/Y204;', 'Var', (28, 38))
530533	29872701	2524), phosphorylated CDK1 (Tyr15; Catalog No.	('CDK1', 'Gene', (22, 26))	('Tyr15', 'Chemical', '-', (28, 33))	('Tyr15;', 'Var', (28, 34))	('CDK1', 'Gene', '983', (22, 26))
530537	29872701	Human ESCC cell lines (KYSE450, KYSE510) and the human embryonic kidney cell line (HEK293T) were purchased from American Type Culture Collection (ATCC; Manassas, VA).	('Human', 'Species', '9606', (0, 5))	('KYSE510', 'CellLine', 'CVCL:1354', (32, 39))	('embryonic kidney', 'Disease', (55, 71))	('human', 'Species', '9606', (49, 54))	('KYSE510', 'Var', (32, 39))	('embryonic kidney', 'Disease', 'MESH:D007674', (55, 71))	('HEK293T', 'CellLine', 'CVCL:0063', (83, 90))
530576	29725249	Single nucleotide polymorphisms and haplotypes of carbonic anhydrase 9 can predict invasive squamous cell carcinoma of uterine cervix This study aimed to explore the involvement of carbonic anhydrase 9 (CA9) single nucleotide polymorphisms (SNPs) in the development of invasive cancer of uterine cervix for Taiwanese women.	('carbonic anhydrase 9', 'Gene', '768', (181, 201))	('carbonic anhydrase 9', 'Gene', (50, 70))	('CA9', 'Gene', '768', (203, 206))	('uterine cervix', 'Phenotype', 'HP:0030160', (119, 133))	('squamous cell carcinoma', 'Disease', (92, 115))	('women', 'Species', '9606', (317, 322))	('cancer', 'Phenotype', 'HP:0002664', (278, 284))	('carcinoma of uterine', 'Phenotype', 'HP:0010784', (106, 126))	('single nucleotide polymorphisms', 'Var', (208, 239))	('cancer of uterine', 'Phenotype', 'HP:0010784', (278, 295))	('carbonic anhydrase 9', 'Gene', '768', (50, 70))	('carbonic anhydrase 9', 'Gene', (181, 201))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (92, 115))	('invasive cancer', 'Disease', (269, 284))	('invasive cancer', 'Disease', 'MESH:D009362', (269, 284))	('CA9', 'Gene', (203, 206))	('uterine cervix', 'Phenotype', 'HP:0030160', (288, 302))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (92, 115))
530578	29725249	Two CA9 SNPs in exons, including rs2071676 (+201, G/A) in exon 1 and rs3829078 (+1081, A/G) in exon 7, rs1048638 (+1584, C/A) in 3'-untranslated region of exon 11, as well as an 18-base pair deletion/insertion (376deltion393) in exon 1 were selected and their genotypic distributions were determined by real-time polymerase chain reaction.	('rs2071676', 'Mutation', 'rs2071676', (33, 42))	('CA9', 'Gene', (4, 7))	('+201, G/A', 'Mutation', 'rs2071676', (44, 53))	('CA9', 'Gene', '768', (4, 7))	('rs3829078', 'Mutation', 'rs3829078', (69, 78))	('+1081, A/G', 'Mutation', 'rs3829078', (80, 90))	('376deltion393', 'Var', (211, 224))	('rs1048638', 'Mutation', 'rs1048638', (103, 112))	('+1584, C/A', 'Mutation', 'rs1048638', (114, 124))
530579	29725249	Haplotype was then constructed with rs2071676, 376del393, rs3829078 and rs1048638 in order.	('rs3829078', 'Var', (58, 67))	('376del393', 'Var', (47, 56))	('rs2071676', 'Mutation', 'rs2071676', (36, 45))	('rs3829078', 'Mutation', 'rs3829078', (58, 67))	('rs1048638', 'Var', (72, 81))	('376del393', 'Mutation', 'c.376del393', (47, 56))	('rs2071676', 'Var', (36, 45))	('rs1048638', 'Mutation', 'rs1048638', (72, 81))
530580	29725249	The results revealed that Taiwanese women with genotypes CA or CA/AA in CA9 SNP rs1048638 displayed a more risk in developing cervical invasive cancer, assigning wild genotype CC as a reference.	('rs1048638', 'Mutation', 'rs1048638', (80, 89))	('cervical invasive cancer', 'Disease', 'MESH:D002583', (126, 150))	('cervical invasive cancer', 'Disease', (126, 150))	('CA9', 'Gene', (72, 75))	('women', 'Species', '9606', (36, 41))	('CA9', 'Gene', '768', (72, 75))	('rs1048638', 'Var', (80, 89))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
530581	29725249	AA in SNP rs2071676 tended to increase the risk of developing cervical invasive cancer, using GG/GA as a reference.	('cervical invasive cancer', 'Disease', 'MESH:D002583', (62, 86))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cervical invasive cancer', 'Disease', (62, 86))	('rs2071676', 'Mutation', 'rs2071676', (10, 19))	('increase', 'PosReg', (30, 38))	('SNP rs2071676', 'Var', (6, 19))
530582	29725249	When women had the diplotypes, carrying at least one haplotype A1AA (one mutant allele A in rs2071676, no deletion in 376del393, no mutant allele A in rs3829078 and one mutant allele A in rs1048638), they were significantly susceptible to cervical invasive cancer.	('cervical invasive cancer', 'Disease', 'MESH:D002583', (239, 263))	('rs3829078', 'Var', (151, 160))	('cancer', 'Phenotype', 'HP:0002664', (257, 263))	('cervical invasive cancer', 'Disease', (239, 263))	('women', 'Species', '9606', (5, 10))	('376del393', 'Mutation', 'c.376del393', (118, 127))	('rs2071676', 'Mutation', 'rs2071676', (92, 101))	('rs3829078', 'Mutation', 'rs3829078', (151, 160))	('rs1048638', 'Mutation', 'rs1048638', (188, 197))	('susceptible', 'Reg', (224, 235))	('A1AA', 'Mutation', 'c.1A>AA', (63, 67))	('rs2071676', 'Var', (92, 101))
530583	29725249	In conclusion, CA9 SNP rs1048638 and haplotype A1AA are associated with the susceptibility of cervical invasive squamous cell carcinoma for Taiwanese women.	('rs1048638', 'Var', (23, 32))	('A1AA', 'Mutation', 'c.1A>AA', (47, 51))	('cervical invasive squamous cell carcinoma', 'Disease', 'MESH:D002294', (94, 135))	('rs1048638', 'Mutation', 'rs1048638', (23, 32))	('cervical invasive squamous cell carcinoma', 'Disease', (94, 135))	('associated', 'Reg', (56, 66))	('women', 'Species', '9606', (150, 155))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (112, 135))	('CA9', 'Gene', '768', (15, 18))	('CA9', 'Gene', (15, 18))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))
530598	29725249	SNPs of CA9 gene may have an impact on the expression of CA9 and then disease development via influencing the promoter area, exon and 3'-untranslated region (3'-UTR).	('CA9', 'Gene', '768', (57, 60))	('influencing', 'Reg', (94, 105))	('CA9', 'Gene', (8, 11))	("3'-untranslated", 'MPA', (134, 149))	('SNPs', 'Var', (0, 4))	('exon', 'MPA', (125, 129))	('CA9', 'Gene', '768', (8, 11))	('promoter area', 'MPA', (110, 123))	('expression', 'MPA', (43, 53))	('impact', 'Reg', (29, 35))	('CA9', 'Gene', (57, 60))
530599	29725249	To date, few studies correlate CA9 genetic polymorphisms with uterine cervical cancer.	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('CA9', 'Gene', (31, 34))	('CA9', 'Gene', '768', (31, 34))	('cervical cancer', 'Disease', (70, 85))	('cervical cancer', 'Disease', 'MESH:D002583', (70, 85))	('genetic polymorphisms', 'Var', (35, 56))
530600	29725249	However, our previous study found that the CA/AA frequency of CA9 SNP rs1048638 is higher in patients with cervical cancer, as compared to control women in Taiwan.	('cervical cancer', 'Disease', (107, 122))	('CA9', 'Gene', (62, 65))	('rs1048638', 'Mutation', 'rs1048638', (70, 79))	('patients', 'Species', '9606', (93, 101))	('CA9', 'Gene', '768', (62, 65))	('women', 'Species', '9606', (147, 152))	('cervical cancer', 'Disease', 'MESH:D002583', (107, 122))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('rs1048638', 'Var', (70, 79))	('higher', 'PosReg', (83, 89))
530613	29725249	rs1048638 (+1584, C/A), as well as an 18-base pair deletion/insertion 376deltion393 (376del393) in exon 1 according to the studies of Chien et al., de Martino et al., and Chinese HapMap (Han Chinese in Beijing, China) data.	('+1584', 'Var', (11, 16))	('rs1048638', 'Mutation', 'rs1048638', (0, 9))	('376deltion393', 'Var', (70, 83))	('+1584, C/A', 'Mutation', 'rs1048638', (11, 21))	('376del393', 'Mutation', 'c.376del393', (85, 94))
530615	29725249	The genotypic frequencies of the CA9 SNPs rs2071676 (+201, G/A) (C_25472146_10), rs3829078 (+1081, A/G) (C_27507259_10) and rs1048638 (+1584, C/A) (C_1294917_10) were detected by the ABI StepOne Real-Time PCR System (Applied Biosystems, Foster City, CA, USA).	('CA9', 'Gene', '768', (33, 36))	('rs3829078', 'Mutation', 'rs3829078', (81, 90))	('+1584, C/A', 'Mutation', 'rs1048638', (135, 145))	('+201, G/A', 'Mutation', 'rs2071676', (53, 62))	('C_1294917_10', 'Var', (148, 160))	('C_27507259_10', 'Var', (105, 118))	('C_25472146_10', 'Var', (65, 78))	('rs2071676', 'Mutation', 'rs2071676', (42, 51))	('+1081, A/G', 'Mutation', 'rs3829078', (92, 102))	('CA9', 'Gene', (33, 36))	('rs1048638', 'Mutation', 'rs1048638', (124, 133))
530621	29725249	Chi-square or Fisher's exact tests were used to examine the relationships among frequencies of CA9 gene SNPs, allele and incidence of cervical neoplasia (including invasive cancer and preinvasive lesions).	('neoplasia', 'Phenotype', 'HP:0002664', (143, 152))	('cervical neoplasia', 'Disease', 'MESH:D018290', (134, 152))	('lesion', 'Disease', (196, 202))	('invasive cancer', 'Disease', (164, 179))	('invasive cancer', 'Disease', 'MESH:D009362', (164, 179))	('lesion', 'Disease', 'MESH:D051437', (196, 202))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('CA9', 'Gene', (95, 98))	('cervical neoplasia', 'Phenotype', 'HP:0032241', (134, 152))	('SNPs', 'Var', (104, 108))	('CA9', 'Gene', '768', (95, 98))	('cervical neoplasia', 'Disease', (134, 152))
530624	29725249	The age distribution of each SNP genotype for each CA9 SNP was not different (p=0.246 for rs2071676, p=0.675 for rs3829078, p=0.434 for rs1048638, p=0.359 for 376deletion393).	('rs1048638', 'Var', (136, 145))	('rs3829078', 'Mutation', 'rs3829078', (113, 122))	('CA9', 'Gene', (51, 54))	('rs1048638', 'Mutation', 'rs1048638', (136, 145))	('rs2071676', 'Var', (90, 99))	('CA9', 'Gene', '768', (51, 54))	('376deletion393', 'Var', (159, 173))	('rs3829078', 'Var', (113, 122))	('rs2071676', 'Mutation', 'rs2071676', (90, 99))
530625	29725249	Genotypic distributions of SNPs rs2071676, rs3829078 and rs1048638 conformed to Hardy-Weinberg equilibrium (p=0.505, chi2 value: 0.445; p=0.753, chi2 value: 0.100; and p=0.330, chi2 value: 0.948, respectively).	('rs1048638', 'Var', (57, 66))	('rs1048638', 'Mutation', 'rs1048638', (57, 66))	('rs2071676', 'Mutation', 'rs2071676', (32, 41))	('rs2071676', 'Var', (32, 41))	('rs3829078', 'Var', (43, 52))	('rs3829078', 'Mutation', 'rs3829078', (43, 52))
530626	29725249	A significant difference was only found in the distribution of CA9 gene SNP rs1048638 (p=0.019) between women with cervical neoplasia and normal women (Table 1).	('rs1048638', 'Mutation', 'rs1048638', (76, 85))	('cervical neoplasia', 'Phenotype', 'HP:0032241', (115, 133))	('cervical neoplasia', 'Disease', (115, 133))	('CA9', 'Gene', '768', (63, 66))	('CA9', 'Gene', (63, 66))	('neoplasia', 'Phenotype', 'HP:0002664', (124, 133))	('rs1048638', 'Var', (76, 85))	('women', 'Species', '9606', (145, 150))	('cervical neoplasia', 'Disease', 'MESH:D018290', (115, 133))	('women', 'Species', '9606', (104, 109))
530627	29725249	No such difference was present in rs2071676, rs3829078 and 376deletion393.	('rs2071676', 'Var', (34, 43))	('rs3829078', 'Var', (45, 54))	('rs3829078', 'Mutation', 'rs3829078', (45, 54))	('rs2071676', 'Mutation', 'rs2071676', (34, 43))	('376deletion393', 'Var', (59, 73))
530628	29725249	Genotypes CA/AA of CA9 SNP rs1048638 were found to be differently distributed between patients with cervical neoplasia and control women while assigning wild genotype CC as a reference (p=0.016).	('CA9', 'Gene', '768', (19, 22))	('women', 'Species', '9606', (131, 136))	('cervical neoplasia', 'Phenotype', 'HP:0032241', (100, 118))	('cervical neoplasia', 'Disease', (100, 118))	('cervical neoplasia', 'Disease', 'MESH:D018290', (100, 118))	('rs1048638', 'Var', (27, 36))	('neoplasia', 'Phenotype', 'HP:0002664', (109, 118))	('rs1048638', 'Mutation', 'rs1048638', (27, 36))	('CA9', 'Gene', (19, 22))	('patients', 'Species', '9606', (86, 94))
530629	29725249	Women with genotype CA/AA still tended to have a more risk (AOR: 1.72, 95% CI: 1.00-2.94) in developing cervical neoplasia using CC as a reference after controlling for age.	('Women', 'Species', '9606', (0, 5))	('cervical neoplasia', 'Phenotype', 'HP:0032241', (104, 122))	('cervical neoplasia', 'Disease', (104, 122))	('genotype CA/AA', 'Var', (11, 25))	('cervical neoplasia', 'Disease', 'MESH:D018290', (104, 122))	('neoplasia', 'Phenotype', 'HP:0002664', (113, 122))
530630	29725249	After cervical neoplasia group was categorized into subgroups of invasive cancer and preinvasive lesions, a significant difference was revealed in the distribution of AA using GG/GA as a reference in CA9 SNP rs2071676 (p=0.035) among patients with invasive cancer or preinvasive lesions and control women (Table 2).	('cancer', 'Phenotype', 'HP:0002664', (257, 263))	('CA9', 'Gene', (200, 203))	('lesion', 'Disease', 'MESH:D051437', (279, 285))	('rs2071676', 'Var', (208, 217))	('lesion', 'Disease', 'MESH:D051437', (97, 103))	('cervical neoplasia', 'Phenotype', 'HP:0032241', (6, 24))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('rs2071676', 'Mutation', 'rs2071676', (208, 217))	('invasive cancer', 'Disease', (248, 263))	('patients', 'Species', '9606', (234, 242))	('invasive cancer', 'Disease', (65, 80))	('lesion', 'Disease', (279, 285))	('women', 'Species', '9606', (299, 304))	('CA9', 'Gene', '768', (200, 203))	('lesion', 'Disease', (97, 103))	('invasive cancer', 'Disease', 'MESH:D009362', (65, 80))	('invasive cancer', 'Disease', 'MESH:D009362', (248, 263))	('cervical neoplasia', 'Disease', 'MESH:D018290', (6, 24))	('neoplasia', 'Phenotype', 'HP:0002664', (15, 24))	('cervical neoplasia', 'Disease', (6, 24))
530631	29725249	However, AA in SNP rs2071676 increased the risk of developing cervical invasive cancer (OR: 1.65, 95% CI: 1.01-2.70) but did not increase the risk of preinvasive lesions (OR: 0.71, 95% CI: 0.39-1.30) using GG/GA as a reference.	('rs2071676', 'Mutation', 'rs2071676', (19, 28))	('cervical invasive cancer', 'Disease', 'MESH:D002583', (62, 86))	('lesion', 'Disease', (162, 168))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cervical invasive cancer', 'Disease', (62, 86))	('SNP', 'Gene', (15, 18))	('rs2071676', 'Var', (19, 28))	('lesion', 'Disease', 'MESH:D051437', (162, 168))
530633	29725249	Furthermore, women with CA or CA/AA displayed more risk to have cervical invasive cancer while assigning wild homozygote CC as a reference (OR: 2.57, 95% CI: 1.42-4.66 and OR: 2.42, 95% CI: 1.23-4.37, respectively; Table 2) but did not carry more risk of preinvasive lesions (OR: 1.38, 95% CI: 0.68-2.81 and OR: 1.30, 95% CI: 0.65-2.63, respectively) in CA9 SNP rs1048638.	('cervical invasive cancer', 'Disease', 'MESH:D002583', (64, 88))	('lesion', 'Disease', (267, 273))	('lesion', 'Disease', 'MESH:D051437', (267, 273))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('cervical invasive cancer', 'Disease', (64, 88))	('rs1048638', 'Mutation', 'rs1048638', (362, 371))	('CA9', 'Gene', '768', (354, 357))	('CA9', 'Gene', (354, 357))	('women', 'Species', '9606', (13, 18))	('rs1048638', 'Var', (362, 371))
530634	29725249	Even after controlling for the age, CA or CA/AA still displayed more risk of invasive cancer (AOR: 2.23, 95% CI: 1.13-4.39 and AOR: 2.15, 95% CI: 1.09-4.20, respectively; Table 2).	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('CA/AA', 'Var', (42, 47))	('invasive cancer', 'Disease', (77, 92))	('invasive cancer', 'Disease', 'MESH:D009362', (77, 92))
530635	29725249	However, no significant difference was found for genotypic distribution in rs3829078 and 376deletion393 among patients with invasive cancer or preinvasive lesions and controls.	('rs3829078', 'Mutation', 'rs3829078', (75, 84))	('376deletion393', 'Var', (89, 103))	('lesion', 'Disease', 'MESH:D051437', (155, 161))	('invasive cancer', 'Disease', (124, 139))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('lesion', 'Disease', (155, 161))	('rs3829078', 'Var', (75, 84))	('invasive cancer', 'Disease', 'MESH:D009362', (124, 139))	('patients', 'Species', '9606', (110, 118))
530636	29725249	The minor allelic frequencies of CA9 SNPs defined from control women in this study were 0.50 for rs2071676, 0.05 for rs3829078 and 0.06 for rs1048638, which were similar to those in HCB based on NCBI, dbSNP.	('0.06', 'Var', (131, 135))	('CA9', 'Gene', '768', (33, 36))	('rs3829078', 'Var', (117, 126))	('rs2071676', 'Var', (97, 106))	('rs3829078', 'Mutation', 'rs3829078', (117, 126))	('rs1048638', 'Var', (140, 149))	('women', 'Species', '9606', (63, 68))	('rs1048638', 'Mutation', 'rs1048638', (140, 149))	('CA9', 'Gene', (33, 36))	('rs2071676', 'Mutation', 'rs2071676', (97, 106))	('0.05', 'Var', (108, 112))
530637	29725249	Mutant allele A in CA9 SNP rs1048638 was the only one that increased the risk of cervical invasive cancer (AOR: 1.93, 95% CI: 1.02-3.64; Table 3).	('CA9', 'Gene', '768', (19, 22))	('cervical invasive cancer', 'Disease', (81, 105))	('rs1048638', 'Var', (27, 36))	('rs1048638', 'Mutation', 'rs1048638', (27, 36))	('CA9', 'Gene', (19, 22))	('cervical invasive cancer', 'Disease', 'MESH:D002583', (81, 105))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
530640	29725249	Based on PHASE program, we constructed the phased haplotypes of four points (rs2071676, 376del393, rs3829078 and rs1048638) in CA9 gene.	('rs3829078', 'Mutation', 'rs3829078', (99, 108))	('376del393', 'Var', (88, 97))	('CA9', 'Gene', '768', (127, 130))	('rs2071676', 'Mutation', 'rs2071676', (77, 86))	('rs1048638', 'Var', (113, 122))	('376del393', 'Mutation', 'c.376del393', (88, 97))	('rs1048638', 'Mutation', 'rs1048638', (113, 122))	('rs3829078', 'Var', (99, 108))	('rs2071676', 'Var', (77, 86))	('CA9', 'Gene', (127, 130))
530641	29725249	The haplotypes were showed rs2071676, 376del393, rs3829078 and rs1048638 in order.	('rs2071676', 'Mutation', 'rs2071676', (27, 36))	('rs2071676', 'Var', (27, 36))	('rs3829078', 'Var', (49, 58))	('rs1048638', 'Var', (63, 72))	('rs3829078', 'Mutation', 'rs3829078', (49, 58))	('376del393', 'Var', (38, 47))	('rs1048638', 'Mutation', 'rs1048638', (63, 72))	('376del393', 'Mutation', 'c.376del393', (38, 47))
530642	29725249	We found that only haplotype A1AA tended to increase the risk of cervical invasive cancer (p=0.053; AOR: 2.01, 95% CI: 0.99-4.07; Table 4), assigning G1AC as a reference.	('A1AA', 'Mutation', 'c.1A>AA', (29, 33))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('increase', 'PosReg', (44, 52))	('cervical invasive cancer', 'Disease', (65, 89))	('cervical invasive cancer', 'Disease', 'MESH:D002583', (65, 89))	('haplotype A1AA', 'Var', (19, 33))
530643	29725249	Therefore, we compared the risk of CA9 diplotypes carrying at least one A1AA with other types of diplotypes to assess the risk of cervical cancer.	('A1AA', 'Var', (72, 76))	('cervical cancer', 'Disease', (130, 145))	('cervical cancer', 'Disease', 'MESH:D002583', (130, 145))	('CA9', 'Gene', '768', (35, 38))	('CA9', 'Gene', (35, 38))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('A1AA', 'Mutation', 'c.1A>AA', (72, 76))
530644	29725249	We found that diplotypes carrying at least one A1AA significantly increase the risk of cervical invasive cancer in comparison with other diplotypes (p=0.035; AOR: 2.10, 95% CI: 1.05-4.20; Table 5).	('increase', 'PosReg', (66, 74))	('A1AA', 'Mutation', 'c.1A>AA', (47, 51))	('A1AA', 'Var', (47, 51))	('cervical invasive cancer', 'Disease', 'MESH:D002583', (87, 111))	('cervical invasive cancer', 'Disease', (87, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))
530647	29725249	However, mutant homozygote AA tended to increase the susceptibility of Taiwanese women to cervical invasive cancer using GG/GA as a reference in rs2071676.	('rs2071676', 'Mutation', 'rs2071676', (145, 154))	('women', 'Species', '9606', (81, 86))	('mutant', 'Var', (9, 15))	('increase', 'PosReg', (40, 48))	('cervical invasive cancer', 'Disease', 'MESH:D002583', (90, 114))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('cervical invasive cancer', 'Disease', (90, 114))
530648	29725249	The dominant promoting risk effect of invasive cancer from CA/AA in CA9 rs1048638 was supported by the analysis of allelic frequency.	('promoting', 'PosReg', (13, 22))	('CA9', 'Gene', '768', (68, 71))	('invasive cancer', 'Disease', (38, 53))	('rs1048638', 'Var', (72, 81))	('invasive cancer', 'Disease', 'MESH:D009362', (38, 53))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('rs1048638', 'Mutation', 'rs1048638', (72, 81))	('CA9', 'Gene', (68, 71))
530649	29725249	Only one mutant allele A was strong enough to increase the risk of cervical invasive cancer in CA9 SNP rs1048638.	('increase', 'PosReg', (46, 54))	('rs1048638', 'Var', (103, 112))	('cervical invasive cancer', 'Disease', 'MESH:D002583', (67, 91))	('CA9', 'Gene', (95, 98))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('rs1048638', 'Mutation', 'rs1048638', (103, 112))	('CA9', 'Gene', '768', (95, 98))	('cervical invasive cancer', 'Disease', (67, 91))
530654	29725249	Although moderate/strong CA9 expression was associated with squamous cell carcinoma of uterine cervix, no study relates the CA9 genetic polymorphisms to cervical invasive cancer.	('associated', 'Reg', (44, 54))	('CA9', 'Gene', (25, 28))	('cervical invasive cancer', 'Disease', (153, 177))	('carcinoma of uterine', 'Phenotype', 'HP:0010784', (74, 94))	('CA9', 'Gene', '768', (25, 28))	('CA9', 'Gene', (124, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('CA9', 'Gene', '768', (124, 127))	('moderate/strong', 'Var', (9, 24))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (60, 83))	('cervical invasive cancer', 'Disease', 'MESH:D002583', (153, 177))	('uterine cervix', 'Phenotype', 'HP:0030160', (87, 101))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (60, 83))	('expression', 'MPA', (29, 39))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('squamous cell carcinoma', 'Disease', (60, 83))
530655	29725249	In agreement with our finding for cancer, the CA9 SNP rs1048638 was demonstrated to be able to predict the susceptibility of urothelial cell carcinoma in Taiwan.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('rs1048638', 'Mutation', 'rs1048638', (54, 63))	('urothelial cell carcinoma', 'Disease', 'MESH:C538614', (125, 150))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('CA9', 'Gene', (46, 49))	('cancer', 'Disease', (34, 40))	('CA9', 'Gene', '768', (46, 49))	('rs1048638', 'Var', (54, 63))	('urothelial cell carcinoma', 'Disease', (125, 150))
530658	29725249	Bioinformatics analysis reveals that microRNAs may bind the 3'-UTR where the CA9 SNP rs1048638 locates based on the TargetScanHuman prediction server.	('CA9', 'Gene', '768', (77, 80))	('rs1048638', 'Var', (85, 94))	('rs1048638', 'Mutation', 'rs1048638', (85, 94))	('CA9', 'Gene', (77, 80))
530660	29725249	A nucleotide from cytosine to mutant adenine may affect the mircoRNA/target duplexes interaction and further exerts an impact on the expression of CA9 protein.	('CA9', 'Gene', (147, 150))	('mircoRNA/target', 'Protein', (60, 75))	('expression', 'MPA', (133, 143))	('affect', 'Reg', (49, 55))	('CA9', 'Gene', '768', (147, 150))	('impact', 'Reg', (119, 125))	('adenine', 'Gene', (37, 44))	('adenine', 'Chemical', 'MESH:D000225', (37, 44))	('interaction', 'Interaction', (85, 96))	('cytosine', 'Chemical', 'MESH:D003596', (18, 26))	('mutant', 'Var', (30, 36))
530661	29725249	In addition to CA9 SNP rs1048638, Chien et al.	('rs1048638', 'Var', (23, 32))	('rs1048638', 'Mutation', 'rs1048638', (23, 32))	('CA9', 'Gene', '768', (15, 18))	('CA9', 'Gene', (15, 18))
530662	29725249	also found that rs2071676 has potential to predict oral carcinogenesis significantly in Taiwan.	('predict', 'Reg', (43, 50))	('rs2071676', 'Mutation', 'rs2071676', (16, 25))	('carcinogenesis', 'Disease', 'MESH:D063646', (56, 70))	('rs2071676', 'Var', (16, 25))	('carcinogenesis', 'Disease', (56, 70))
530663	29725249	Similar to our finding, the guanine replaced by adenine in CA9 SNP rs2071676 was found in 59% of tumors in patients who had renal cell carcinoma with distant metastasis.	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (124, 144))	('guanine replaced', 'Var', (28, 44))	('guanine', 'Chemical', 'MESH:D006147', (28, 35))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (124, 144))	('CA9', 'Gene', '768', (59, 62))	('CA9', 'Gene', (59, 62))	('adenine', 'Chemical', 'MESH:D000225', (48, 55))	('rs2071676', 'Mutation', 'rs2071676', (67, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('found', 'Reg', (81, 86))	('tumors', 'Disease', (97, 103))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('rs2071676', 'Var', (67, 76))	('tumors', 'Disease', 'MESH:D009369', (97, 103))	('patients', 'Species', '9606', (107, 115))	('renal cell carcinoma', 'Disease', (124, 144))
530664	29725249	The CA9 SNP rs2071676 (+201, G/A) is located on exon 1 in chromosome 9p13.3 and changing the encoded amino acids from valine to methionine may lead to a nonsynonymous function via a nucleotide from G to mutant A in a coding sequence.	('mutant', 'Var', (203, 209))	('CA9', 'Gene', (4, 7))	('valine', 'Chemical', 'MESH:D014633', (118, 124))	('rs2071676', 'Mutation', 'rs2071676', (12, 21))	('changing', 'Var', (80, 88))	('CA9', 'Gene', '768', (4, 7))	('lead to', 'Reg', (143, 150))	('nonsynonymous function', 'MPA', (153, 175))	('methionine', 'Chemical', 'MESH:D008715', (128, 138))	('nucleotide', 'Var', (182, 192))	('+201', 'Var', (23, 27))	('+201, G/A', 'Mutation', 'rs2071676', (23, 32))
530665	29725249	The region, where the C A9 SNP rs2071676 is located, is concerned with the signal peptide of CA9 and probably affects its function.	('function', 'MPA', (122, 130))	('rs2071676', 'Var', (31, 40))	('CA9', 'Gene', '768', (93, 96))	('CA9', 'Gene', (93, 96))	('signal peptide', 'MPA', (75, 89))	('affects', 'Reg', (110, 117))	('rs2071676', 'Mutation', 'rs2071676', (31, 40))
530666	29725249	Haplotypes have important and clinically relevant associations with diseases such as Parkinson's disease and schizophrenia.	('schizophrenia', 'Disease', (109, 122))	("Parkinson's disease", 'Disease', (85, 104))	('schizophrenia', 'Disease', 'MESH:D012559', (109, 122))	('associations', 'Interaction', (50, 62))	("Parkinson's disease", 'Disease', 'MESH:D010300', (85, 104))	('schizophrenia', 'Phenotype', 'HP:0100753', (109, 122))	('Haplotypes', 'Var', (0, 10))
530667	29725249	We found that haplotype A1AA tends to increase the risk of cervical invasive cancer.	('increase', 'PosReg', (38, 46))	('A1AA', 'Mutation', 'c.1A>AA', (24, 28))	('haplotype A1AA', 'Var', (14, 28))	('cervical invasive cancer', 'Disease', (59, 83))	('cervical invasive cancer', 'Disease', 'MESH:D002583', (59, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))
530668	29725249	Taiwanese women with ditplotypes, which carried at least one A1AA, were significantly susceptible to cervical invasive cancer.	('ditplotypes', 'Var', (21, 32))	('A1AA', 'Mutation', 'c.1A>AA', (61, 65))	('women', 'Species', '9606', (10, 15))	('cervical invasive cancer', 'Disease', 'MESH:D002583', (101, 125))	('susceptible', 'Reg', (86, 97))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('cervical invasive cancer', 'Disease', (101, 125))
530670	29725249	Secondly, we utilize the CA9 haplotypes and diplotypes, in addition to CA9 SNPs, to strengthen the roles of CA9 genetic polymorphisms in the formation of cervical squamous cell carcinoma.	('CA9', 'Gene', (25, 28))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (163, 186))	('CA9', 'Gene', '768', (25, 28))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (163, 186))	('polymorphisms', 'Var', (120, 133))	('CA9', 'Gene', (108, 111))	('carcinoma', 'Phenotype', 'HP:0030731', (177, 186))	('squamous cell carcinoma', 'Disease', (163, 186))	('CA9', 'Gene', '768', (108, 111))	('CA9', 'Gene', '768', (71, 74))	('CA9', 'Gene', (71, 74))
530676	29725249	In conclusion, Taiwanese women with genotypes CA or CA/AA in CA9 SNP rs1048638 display a more risk in developing invasive squamous cell carcinoma of uterine cervix, using wild genotype CC as a reference.	('CA9', 'Gene', '768', (61, 64))	('CA9', 'Gene', (61, 64))	('uterine cervix', 'Phenotype', 'HP:0030160', (149, 163))	('SNP', 'Gene', (65, 68))	('carcinoma of uterine', 'Phenotype', 'HP:0010784', (136, 156))	('CA/AA', 'Var', (52, 57))	('rs1048638', 'Var', (69, 78))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (122, 145))	('invasive squamous cell carcinoma', 'Disease', (113, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('invasive squamous cell carcinoma', 'Disease', 'MESH:D002294', (113, 145))	('rs1048638', 'Mutation', 'rs1048638', (69, 78))	('women', 'Species', '9606', (25, 30))
530677	29725249	Importantly, when they have the diplotypes, carrying at least one A1AA, they are significantly susceptible to cervical invasive squamous cell carcinoma.	('cervical invasive squamous cell carcinoma', 'Disease', 'MESH:D002294', (110, 151))	('A1AA', 'Var', (66, 70))	('susceptible', 'Reg', (95, 106))	('cervical invasive squamous cell carcinoma', 'Disease', (110, 151))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (128, 151))	('A1AA', 'Mutation', 'c.1A>AA', (66, 70))	('carcinoma', 'Phenotype', 'HP:0030731', (142, 151))
530697	28725009	H. pylori (gastric cancer) or Salmonella typhi (gallbladder cancer).	('Salmonella', 'Var', (30, 40))	('cancer', 'Disease', 'MESH:D009369', (19, 25))	('H. pylori', 'Species', '210', (0, 9))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('cancer', 'Disease', (19, 25))	('gastric cancer', 'Phenotype', 'HP:0012126', (11, 25))	('cancer', 'Disease', (60, 66))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('Salmonella typhi', 'Species', '90370', (30, 46))
530761	28725009	These substances can induce mutations of tumour suppressor genes and proto-oncogenes, as well as alter pathways that control cell proliferation and/or survival.	('tumour', 'Phenotype', 'HP:0002664', (41, 47))	('induce', 'Reg', (21, 27))	('survival', 'CPA', (151, 159))	('tumour', 'Disease', 'MESH:D009369', (41, 47))	('pathways', 'Pathway', (103, 111))	('alter', 'Reg', (97, 102))	('cell proliferation', 'CPA', (125, 143))	('proto-oncogenes', 'Gene', (69, 84))	('tumour', 'Disease', (41, 47))	('mutations', 'Var', (28, 37))
530768	28725009	Although alcohol itself is not known to be carcinogenic, acetaldehyde (its first metabolite) can cause genomic damage that might influence carcinogenesis.	('carcinogenesis', 'Disease', (139, 153))	('alcohol', 'Chemical', 'MESH:D000438', (9, 16))	('acetaldehyde', 'Chemical', 'MESH:D000079', (57, 69))	('influence', 'Reg', (129, 138))	('carcinogenic', 'Disease', 'MESH:D063646', (43, 55))	('carcinogenic', 'Disease', (43, 55))	('acetaldehyde', 'Var', (57, 69))	('carcinogenesis', 'Disease', 'MESH:D063646', (139, 153))	('cause', 'Reg', (97, 102))	('genomic damage', 'CPA', (103, 117))
530798	25018652	The progression-free survival after treatment with a BRAF inhibitor is modest, however, and BRAF inhibitors induce cutaneous toxicity, likely due to paradoxical activation of the mitogen-activated protein kinase pathway.	('mitogen-activated protein kinase pathway', 'Pathway', (179, 219))	('RAF', 'Gene', '22882', (93, 96))	('RAF', 'Gene', (93, 96))	('RAF', 'Gene', '22882', (54, 57))	('induce', 'Reg', (108, 114))	('RAF', 'Gene', (54, 57))	('toxicity', 'Disease', 'MESH:D064420', (125, 133))	('toxicity', 'Disease', (125, 133))	('activation', 'PosReg', (161, 171))	('inhibitors', 'Var', (97, 107))
530829	25018652	Mutations in the BRAF oncogene may be an example of this.	('RAF', 'Gene', (18, 21))	('Mutations', 'Var', (0, 9))	('RAF', 'Gene', '22882', (18, 21))
530830	25018652	BRAF mutations have been characterized to constitute up to approximately 60% of the driver lesions in cutaneous melanoma, and they have also been observed in several other tumor types.	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('tumor', 'Disease', (172, 177))	('mutations', 'Var', (5, 14))	('RAF', 'Gene', '22882', (1, 4))	('melanoma', 'Phenotype', 'HP:0002861', (112, 120))	('RAF', 'Gene', (1, 4))	('cutaneous melanoma', 'Disease', (102, 120))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (102, 120))	('cutaneous melanoma', 'Disease', 'MESH:C562393', (102, 120))	('tumor', 'Disease', 'MESH:D009369', (172, 177))
530831	25018652	More specifically, BRAF mutations have been characterized in 10%-15% of colorectal carcinomas, 3 % of lung adenocarcinomas and breast cancers, 20%-50% of serous ovarian cancers, and 29%-69% of papillary thyroid cancers.	('breast cancers', 'Phenotype', 'HP:0003002', (127, 141))	('RAF', 'Gene', (20, 23))	('carcinomas', 'Phenotype', 'HP:0030731', (83, 93))	('papillary thyroid cancers', 'Disease', (193, 218))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('breast cancer', 'Phenotype', 'HP:0003002', (127, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('carcinomas', 'Phenotype', 'HP:0030731', (112, 122))	('mutations', 'Var', (24, 33))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (102, 122))	('cancers', 'Phenotype', 'HP:0002664', (134, 141))	('ovarian cancers', 'Phenotype', 'HP:0100615', (161, 176))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (102, 122))	('serous ovarian cancers', 'Disease', (154, 176))	('serous ovarian cancers', 'Disease', 'MESH:D010051', (154, 176))	('papillary thyroid cancers', 'Phenotype', 'HP:0002895', (193, 218))	('lung adenocarcinomas', 'Disease', (102, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))	('cancers', 'Phenotype', 'HP:0002664', (211, 218))	('RAF', 'Gene', '22882', (20, 23))	('breast cancers', 'Disease', 'MESH:D001943', (127, 141))	('breast cancers', 'Disease', (127, 141))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('colorectal carcinomas', 'Disease', (72, 93))	('papillary thyroid cancers', 'Disease', 'MESH:D000077273', (193, 218))	('colorectal carcinomas', 'Disease', 'MESH:D015179', (72, 93))	('cancers', 'Phenotype', 'HP:0002664', (169, 176))
530832	25018652	In addition, BRAF mutations may confer a worse clinical prognosis in several of these tumor types compared with cancers without the BRAF mutation.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('RAF', 'Gene', (14, 17))	('RAF', 'Gene', '22882', (14, 17))	('tumor', 'Disease', (86, 91))	('cancers', 'Phenotype', 'HP:0002664', (112, 119))	('cancers', 'Disease', 'MESH:D009369', (112, 119))	('cancers', 'Disease', (112, 119))	('RAF', 'Gene', '22882', (133, 136))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('RAF', 'Gene', (133, 136))	('mutations', 'Var', (18, 27))
530833	25018652	In melanoma, the presence of BRAF mutation in the primary lesion has not been shown to impact on disease-free interval (time to metastasis) or overall survival.	('mutation', 'Var', (34, 42))	('RAF', 'Gene', '22882', (30, 33))	('RAF', 'Gene', (30, 33))	('melanoma', 'Disease', (3, 11))	('impact', 'Reg', (87, 93))	('melanoma', 'Disease', 'MESH:D008545', (3, 11))	('melanoma', 'Phenotype', 'HP:0002861', (3, 11))
530834	25018652	However, after the development of metastatic melanoma, the median survival of patients with BRAF mutations has been described as shorter relative to patients with wild-type BRAF tumors, although this appears no longer to be the case given the development of selective BRAF inhibitors.	('mutations', 'Var', (97, 106))	('patients', 'Species', '9606', (149, 157))	('RAF', 'Gene', '22882', (269, 272))	('BRAF tumors', 'Disease', (173, 184))	('tumors', 'Phenotype', 'HP:0002664', (178, 184))	('RAF', 'Gene', (269, 272))	('RAF', 'Gene', '22882', (93, 96))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('patients', 'Species', '9606', (78, 86))	('RAF', 'Gene', (93, 96))	('RAF', 'Gene', '22882', (174, 177))	('melanoma', 'Phenotype', 'HP:0002861', (45, 53))	('BRAF tumors', 'Disease', 'MESH:D009369', (173, 184))	('melanoma', 'Disease', (45, 53))	('RAF', 'Gene', (174, 177))	('melanoma', 'Disease', 'MESH:D008545', (45, 53))	('shorter', 'NegReg', (129, 136))
530836	25018652	These mechanisms include acquired NRAS mutations, activation of non-MAPK growth pathways such as phosphatidylinositol 3-kinase/AKT via receptor tyrosine kinases (ie, platelet-derived growth factor receptor-beta), overexpression of COT kinase, mutation of MEK, development of RAS-independent BRAFV600E isoform splice variants, BRAF amplification, and overexpression of hepatocyte growth factor/activation of MET.	('RAF', 'Gene', '22882', (292, 295))	('amplification', 'Var', (331, 344))	('RAF', 'Gene', (292, 295))	('MEK', 'Gene', (255, 258))	('mutation', 'Var', (243, 251))	('MEK', 'Gene', '5609', (255, 258))	('activation', 'PosReg', (50, 60))	('RAF', 'Gene', (327, 330))	('mutations', 'Var', (39, 48))	('overexpression', 'PosReg', (213, 227))	('RAF', 'Gene', '22882', (327, 330))	('AKT', 'Gene', '207', (127, 130))	('BRAFV600E', 'Mutation', 'rs113488022', (291, 300))	('NRAS', 'Gene', (34, 38))	('MAPK', 'Gene', '5594', (68, 72))	('NRAS', 'Gene', '4893', (34, 38))	('AKT', 'Gene', (127, 130))	('MAPK', 'Gene', (68, 72))
530838	25018652	Mechanisms of resistance to treatment with BRAF inhibitors have recently been published in larger cohorts demonstrating approximately 50%-70% as harboring MAPK reactivating changes, with RAS mutations, amplification of BRAF, and BRAF splice variants being the most common.	('RAF', 'Gene', '22882', (220, 223))	('RAF', 'Gene', (230, 233))	('RAF', 'Gene', (220, 223))	('MAPK', 'Gene', '5594', (155, 159))	('mutations', 'Var', (191, 200))	('rat', 'Species', '10116', (113, 116))	('RAS', 'Gene', (187, 190))	('MAPK', 'Gene', (155, 159))	('RAF', 'Gene', '22882', (44, 47))	('RAF', 'Gene', (44, 47))	('amplification', 'Var', (202, 215))	('changes', 'Var', (173, 180))	('RAF', 'Gene', '22882', (230, 233))
530839	25018652	Mutations not previously described but thought likely to reactivate MAPK were also discovered, and include MAP2K2, MITF, and NF1, as well as mutations with less clear relevance to MAPK, such as HOXD8 and RAC1.	('NF1', 'Gene', (125, 128))	('MITF', 'Gene', '4286', (115, 119))	('RAC1', 'Gene', '5879', (204, 208))	('MAP2K2', 'Gene', (107, 113))	('NF1', 'Gene', '4763', (125, 128))	('MAPK', 'Gene', '5594', (180, 184))	('HOXD8', 'Gene', (194, 199))	('RAC1', 'Gene', (204, 208))	('Mutations', 'Var', (0, 9))	('MAPK', 'Gene', (180, 184))	('HOXD8', 'Gene', '3234', (194, 199))	('MAPK', 'Gene', '5594', (68, 72))	('MAP2K2', 'Gene', '5605', (107, 113))	('MITF', 'Gene', (115, 119))	('MAPK', 'Gene', (68, 72))
530847	25018652	These data are consistent with models of molecular resistance which suggest that upon removal of inhibition of the primary oncogenic kinase pathway (such as BRAF in melanoma), patients experience a tumor fare as the kinase is reactivated.	('patients', 'Species', '9606', (176, 184))	('removal', 'Var', (86, 93))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('melanoma', 'Phenotype', 'HP:0002861', (165, 173))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('tumor', 'Disease', (198, 203))	('RAF', 'Gene', '22882', (158, 161))	('melanoma', 'Disease', (165, 173))	('RAF', 'Gene', (158, 161))	('melanoma', 'Disease', 'MESH:D008545', (165, 173))
530848	25018652	The molecular biology of mutant RAF signaling is complex, and significant efforts have been made to elucidate it.	('RAF', 'Gene', '22882', (32, 35))	('mutant', 'Var', (25, 31))	('RAF', 'Gene', (32, 35))
530852	25018652	In contrast, mutated BRAF exists as a monomer and signals in constitutive fashion independent of upstream activation by receptor tyrosine kinase and RAS.	('RAF', 'Gene', (22, 25))	('mutated', 'Var', (13, 20))	('RAF', 'Gene', '22882', (22, 25))
530853	25018652	Vemurafenib blocks this activation of mutant BRAF but "paradoxically" can also lead to downstream MEK activation in physiologic MAPK (non-BRAF-mutated cells) cells through ARAF or CRAF homodimerization and heterodimerization.	('heterodimerization', 'Interaction', (206, 224))	('CRAF', 'Gene', (180, 184))	('RAF', 'Gene', (139, 142))	('ARAF', 'Gene', '369', (172, 176))	('ARAF', 'Gene', (172, 176))	('MAPK', 'Gene', (128, 132))	('RAF', 'Gene', '22882', (173, 176))	('RAF', 'Gene', '22882', (46, 49))	('CRAF', 'Gene', '5894', (180, 184))	('mutant', 'Var', (38, 44))	('RAF', 'Gene', '22882', (181, 184))	('MEK', 'Gene', '5609', (98, 101))	('MAPK', 'Gene', '5594', (128, 132))	('RAF', 'Gene', (173, 176))	('RAF', 'Gene', (46, 49))	('Vemurafenib', 'Chemical', 'MESH:D000077484', (0, 11))	('MEK', 'Gene', (98, 101))	('RAF', 'Gene', (181, 184))	('homodimerization', 'Interaction', (185, 201))	('activation', 'PosReg', (102, 112))	('RAF', 'Gene', '22882', (139, 142))
530857	25018652	Further, it is now apparent that upstream activation of RAS, predominantly by HRAS mutation, significantly promotes this effect in non-BRAF-mutant tissues.	('RAF', 'Gene', '22882', (136, 139))	('HRAS', 'Gene', '3265', (78, 82))	('mutation', 'Var', (83, 91))	('activation', 'PosReg', (42, 52))	('RAS', 'Protein', (56, 59))	('RAF', 'Gene', (136, 139))	('HRAS', 'Gene', (78, 82))
530860	25018652	Further, combined BRAF-MEK inhibition has been shown to induce greater cell killing and to allow a longer time to development of resistance than treatment with a BRAF or MEK inhibitor alone in naive BRAFV600E-mutant melanoma models.	('BRAFV600E', 'Mutation', 'rs113488022', (199, 208))	('cell killing', 'CPA', (71, 83))	('RAF', 'Gene', '22882', (163, 166))	('greater', 'PosReg', (63, 70))	('RAF', 'Gene', (163, 166))	('RAF', 'Gene', (200, 203))	('inhibition', 'Var', (27, 37))	('RAF', 'Gene', '22882', (200, 203))	('RAF', 'Gene', '22882', (19, 22))	('melanoma', 'Phenotype', 'HP:0002861', (216, 224))	('melanoma', 'Disease', (216, 224))	('RAF', 'Gene', (19, 22))	('melanoma', 'Disease', 'MESH:D008545', (216, 224))	('MEK', 'Gene', (170, 173))	('MEK', 'Gene', (23, 26))	('MEK', 'Gene', '5609', (170, 173))	('MEK', 'Gene', '5609', (23, 26))
530867	25018652	In three of five samples from patients who had become resistant to the combination, a novel mutation in MEK2 (Q60P) was observed, while two previously described mechanisms to single-agent BRAF inhibitor, BRAF splice variant and BRAF amplification, were observed.	('RAF', 'Gene', '22882', (189, 192))	('RAF', 'Gene', (189, 192))	('Q60P', 'Mutation', 'rs1057519808', (110, 114))	('MEK2', 'Gene', (104, 108))	('RAF', 'Gene', (205, 208))	('RAF', 'Gene', '22882', (229, 232))	('MEK2', 'Gene', '5605', (104, 108))	('Q60P', 'Var', (110, 114))	('RAF', 'Gene', (229, 232))	('patients', 'Species', '9606', (30, 38))	('RAF', 'Gene', '22882', (205, 208))
530886	25018652	Dabrafenib is an ATP-competitive, selective inhibitor of RAF kinases, with the strongest effect being on mutant BRAFV600 relative to wild-type BRAF or CRAF.	('RAF', 'Gene', '22882', (57, 60))	('RAF', 'Gene', (144, 147))	('CRAF', 'Gene', (151, 155))	('CRAF', 'Gene', '5894', (151, 155))	('RAF', 'Gene', '22882', (144, 147))	('RAF', 'Gene', '22882', (152, 155))	('ATP', 'Chemical', 'MESH:D000255', (17, 20))	('RAF', 'Gene', (152, 155))	('Dabrafenib', 'Chemical', 'MESH:C561627', (0, 10))	('RAF', 'Gene', '22882', (113, 116))	('mutant', 'Var', (105, 111))	('RAF', 'Gene', (57, 60))	('RAF', 'Gene', (113, 116))
530891	25018652	An initial Phase I study of patients with solid tumors harboring BRAFV600E/K mutations examined escalating doses of dabrafenib in 184 patients.	('BRAFV600E', 'Mutation', 'rs113488022', (65, 74))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('tumors', 'Phenotype', 'HP:0002664', (48, 54))	('BRAFV600E/K', 'Var', (65, 76))	('solid tumors', 'Disease', (42, 54))	('dabrafenib', 'Chemical', 'MESH:C561627', (116, 126))	('patients', 'Species', '9606', (134, 142))	('patients', 'Species', '9606', (28, 36))	('solid tumors', 'Disease', 'MESH:D009369', (42, 54))
530897	25018652	A Phase II study (known as BREAK-MB, ClinicalTrials.gov identifier NCT01266967) evaluated the use of dabrafenib in patients with BRAFV600E/K-mutant melanoma who were previously untreated or had been locally treated only for brain metastases.	('patients', 'Species', '9606', (115, 123))	('metastases', 'Disease', 'MESH:D009362', (230, 240))	('melanoma', 'Disease', 'MESH:D008545', (148, 156))	('melanoma', 'Phenotype', 'HP:0002861', (148, 156))	('melanoma', 'Disease', (148, 156))	('dabrafenib', 'Chemical', 'MESH:C561627', (101, 111))	('BRAFV600E', 'Mutation', 'rs113488022', (129, 138))	('BRAFV600E/K-mutant', 'Var', (129, 147))	('metastases', 'Disease', (230, 240))
530913	25018652	Among the population of patients with tumors harboring BRAF mutations, the response rate and median progression-free survival were found to be 33% and 5.7 months, respectively.	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumors', 'Disease', (38, 44))	('tumors', 'Phenotype', 'HP:0002664', (38, 44))	('RAF', 'Gene', '22882', (56, 59))	('rat', 'Species', '10116', (84, 87))	('RAF', 'Gene', (56, 59))	('tumors', 'Disease', 'MESH:D009369', (38, 44))	('patients', 'Species', '9606', (24, 32))	('mutations', 'Var', (60, 69))
530935	25018652	All patients in this study had advanced melanoma harboring mutations in BRAFV600E/K.	('BRAFV600E', 'Mutation', 'rs113488022', (72, 81))	('melanoma', 'Disease', 'MESH:D008545', (40, 48))	('melanoma', 'Phenotype', 'HP:0002861', (40, 48))	('melanoma', 'Disease', (40, 48))	('mutations', 'Var', (59, 68))	('patients', 'Species', '9606', (4, 12))	('BRAFV600E/K', 'Gene', (72, 83))
530964	25018652	Further, combination approaches using existing immunotherapies (anti-CTLA4 plus anti-PD1) and potentially other novel approaches (eg, anti-KIR, anti-LAG3, anti-OX40) have the potential to increase the response rate and durable disease control rates even further.	('KIR', 'Gene', '3805', (139, 142))	('LAG3', 'Gene', '3902', (149, 153))	('CTLA4', 'Gene', '1493', (69, 74))	('disease control', 'CPA', (227, 242))	('KIR', 'Gene', (139, 142))	('anti-OX40', 'Var', (155, 164))	('rat', 'Species', '10116', (243, 246))	('CTLA4', 'Gene', (69, 74))	('LAG3', 'Gene', (149, 153))	('PD1', 'Gene', '5133', (85, 88))	('increase', 'PosReg', (188, 196))	('PD1', 'Gene', (85, 88))	('rat', 'Species', '10116', (210, 213))	('response', 'CPA', (201, 209))
530973	25018652	It is also worth noting that other BRAF-MEK inhibitor combinations, as well as "paradox-breaker" RAF inhibitors that both block mutant BRAF and mitigate physiologic signaling through other RAF isoforms, are in clinical development.	('block', 'NegReg', (122, 127))	('MEK', 'Gene', '5609', (40, 43))	('RAF', 'Gene', '22882', (136, 139))	('RAF', 'Gene', '22882', (189, 192))	('RAF', 'Gene', (189, 192))	('RAF', 'Gene', (97, 100))	('RAF', 'Gene', '22882', (97, 100))	('RAF', 'Gene', '22882', (36, 39))	('mutant', 'Var', (128, 134))	('RAF', 'Gene', (36, 39))	('mitigate', 'NegReg', (144, 152))	('physiologic signaling', 'MPA', (153, 174))	('RAF', 'Gene', (136, 139))	('MEK', 'Gene', (40, 43))
530996	33076306	In addition, the amplification of genes such as EMS1, FGFR1, and CCND1 is also related to clinical outcome.	('CCND1', 'Gene', '595', (65, 70))	('FGFR1', 'Gene', (54, 59))	('FGFR1', 'Gene', '2260', (54, 59))	('EMS1', 'Gene', (48, 52))	('EMS1', 'Gene', '2017', (48, 52))	('CCND1', 'Gene', (65, 70))	('amplification', 'Var', (17, 30))	('related', 'Reg', (79, 86))
530997	33076306	Moreover, a recent study performed by computational analysis revealed the mutational profile of TP53 would be a predictive factor for prognosis.	('TP53', 'Gene', '7157', (96, 100))	('mutational profile', 'Var', (74, 92))	('TP53', 'Gene', (96, 100))
531006	33076306	Theoretically, tumor cells with PD-L1 expression tend to be more sensitive to PD-1/PD-L1 blockade treatment than PD-L1-negative tumor cells.	('more', 'PosReg', (60, 64))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('PD-L1 expression', 'Var', (32, 48))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('PD-L1-negative tumor', 'Disease', (113, 133))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('PD-L1-negative tumor', 'Disease', 'MESH:D010300', (113, 133))	('tumor', 'Disease', (15, 20))	('sensitive', 'MPA', (65, 74))	('tumor', 'Disease', (128, 133))
531008	33076306	In R/M HNSCC trials, a higher response rate and better survival in patients with high PD-L1 expression were also observed in the subgroup analysis of some ICI trials, including KEYNOTE-040 and KEYNOTE-048.	('HNSCC', 'Phenotype', 'HP:0012288', (7, 12))	('patients', 'Species', '9606', (67, 75))	('expression', 'Var', (92, 102))	('better', 'PosReg', (48, 54))	('high', 'Var', (81, 85))	('higher', 'PosReg', (23, 29))	('SCC', 'Phenotype', 'HP:0002860', (9, 12))	('PD-L1', 'Gene', (86, 91))	('survival', 'MPA', (55, 63))
531021	33076306	Subgroup analysis showed that patients with PD-L1 expression >= 1% had a better median OS (8.7 vs. 4.6 months, HR: 0.36-0.83) than patients who received standard therapy, but the significance was not observed across all cut-off values.	('patients', 'Species', '9606', (131, 139))	('patients', 'Species', '9606', (30, 38))	('PD-L1', 'Gene', (44, 49))	('expression >= 1%', 'Var', (50, 66))
531026	33076306	Regarding OS, patients with PD-L1 expression >=1% and >=5% had significantly better outcomes than patients in the standard therapy group.	('better', 'PosReg', (77, 83))	('expression >=1%', 'Var', (34, 49))	('>=5%', 'Var', (54, 58))	('patients', 'Species', '9606', (98, 106))	('PD-L1', 'Gene', (28, 33))	('patients', 'Species', '9606', (14, 22))	('>=1%', 'Var', (45, 49))
531027	33076306	Recently, a comment from the Society for Immunotherapy of Cancer indicated that tumor PD-L1 expression is generally correlated with a better response in R/M HNSCC patients who receive anti-PD-1/PD-L1 ICI treatment.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('patients', 'Species', '9606', (163, 171))	('better', 'PosReg', (134, 140))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('SCC', 'Phenotype', 'HP:0002860', (159, 162))	('Cancer', 'Phenotype', 'HP:0002664', (58, 64))	('tumor', 'Disease', (80, 85))	('R/M HNSCC', 'Disease', (153, 162))	('Cancer', 'Disease', (58, 64))	('anti-PD-1/PD-L1', 'Var', (184, 199))	('Cancer', 'Disease', 'MESH:D009369', (58, 64))	('HNSCC', 'Phenotype', 'HP:0012288', (157, 162))	('PD-L1', 'Gene', (86, 91))	('expression', 'MPA', (92, 102))
531037	33076306	HPV+ tumors had higher CTLA-4 expression and Treg infiltration and a higher Treg/CD8 T cell ratio than HPV-negative tumors.	('tumors', 'Disease', 'MESH:D009369', (5, 11))	('higher', 'PosReg', (16, 22))	('HPV-negative tumors', 'Disease', 'MESH:D030361', (103, 122))	('HPV+', 'Var', (0, 4))	('HPV-negative tumors', 'Disease', (103, 122))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))	('CD8', 'Gene', (81, 84))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumors', 'Phenotype', 'HP:0002664', (5, 11))	('higher', 'PosReg', (69, 75))	('tumors', 'Disease', (116, 122))	('tumors', 'Disease', 'MESH:D009369', (116, 122))	('tumors', 'Disease', (5, 11))	('expression', 'MPA', (30, 40))	('HPV', 'Species', '10566', (0, 3))	('CD8', 'Gene', '925', (81, 84))	('HPV', 'Species', '10566', (103, 106))	('CTLA-4', 'Gene', '1493', (23, 29))	('Treg infiltration', 'CPA', (45, 62))	('CTLA-4', 'Gene', (23, 29))
531043	33076306	For example, a higher response rate was observed in HPV+ patients treated with durvalumab than in HPV-negative patients treated with durvalumab (29.4% vs. 10.8%), while no difference was observed in the atezolizumab trial (15% vs. 17%).	('HPV+', 'Disease', (52, 56))	('higher', 'PosReg', (15, 21))	('durvalumab', 'Chemical', 'MESH:C000613593', (133, 143))	('patients', 'Species', '9606', (57, 65))	('response', 'MPA', (22, 30))	('HPV', 'Species', '10566', (52, 55))	('atezolizumab', 'Chemical', 'MESH:C000594389', (203, 215))	('durvalumab', 'Var', (79, 89))	('durvalumab', 'Chemical', 'MESH:C000613593', (79, 89))	('HPV', 'Species', '10566', (98, 101))	('patients', 'Species', '9606', (111, 119))
531046	33076306	Apolipoprotein-B mRNA editing enzyme catalytic polypeptide-like (APOBEC) enzymes, a family that catalyzes the deamination of cytosine bases, have been linked to mutagenesis in HPV-positive HNSCC.	('HNSCC', 'Phenotype', 'HP:0012288', (189, 194))	('cytosine', 'Chemical', 'MESH:D003596', (125, 133))	('Apolipoprotein-B mRNA editing', 'Protein', (0, 29))	('HPV', 'Species', '10566', (176, 179))	('mutagenesis', 'Var', (161, 172))	('SCC', 'Phenotype', 'HP:0002860', (191, 194))	('linked', 'Reg', (151, 157))
531048	33076306	A recent study evaluating whole-exome and RNA sequencing data from the TCGA dataset demonstrated that the APOBEC mutational burden was closely correlated with tumor-specific neoantigens, a marker suggesting a better response to ICI immunotherapy.	('mutational burden', 'Var', (113, 130))	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('APOBEC', 'Gene', (106, 112))	('tumor', 'Disease', (159, 164))	('correlated', 'Reg', (143, 153))	('tumor', 'Disease', 'MESH:D009369', (159, 164))
531051	33076306	Theoretically, a higher missense mutation number is correlated with a higher number of tumor neoantigens, which may induce a more significant immune response and increase the response to ICI treatment.	('induce', 'PosReg', (116, 122))	('missense mutation number', 'Var', (24, 48))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('increase', 'PosReg', (162, 170))	('tumor', 'Disease', (87, 92))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('more', 'PosReg', (125, 129))	('immune response', 'CPA', (142, 157))	('response to ICI treatment', 'MPA', (175, 200))
531057	33076306	HNSCC patients with TMB >= 10 mutations/Mb had a longer median survival than patients with TMB >= 5 mutations/Mb (20.0 versus 6.0 months, p = 0.01).	('TMB >= 10 mutations/Mb', 'Var', (20, 42))	('TMB', 'Chemical', '-', (20, 23))	('patients', 'Species', '9606', (77, 85))	('patients', 'Species', '9606', (6, 14))	('longer', 'PosReg', (49, 55))	('HNSCC', 'Disease', (0, 5))	('TMB', 'Chemical', '-', (91, 94))	('HNSCC', 'Phenotype', 'HP:0012288', (0, 5))	('SCC', 'Phenotype', 'HP:0002860', (2, 5))
531062	33076306	A randomized, open-label, phase three EAGLE trial (NCT02369874) evaluated plasma-based tumor mutational burden (bTMB) as a predictor for survival in 247 R/M HNSCC patients.	('247 R/M', 'SUBSTITUTION', 'None', (149, 156))	('patients', 'Species', '9606', (163, 171))	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('tumor', 'Disease', (87, 92))	('SCC', 'Phenotype', 'HP:0002860', (159, 162))	('HNSCC', 'Phenotype', 'HP:0012288', (157, 162))	('tumor', 'Disease', 'MESH:D009369', (87, 92))	('247 R/M', 'Var', (149, 156))	('bTMB', 'Chemical', '-', (112, 116))
531063	33076306	OS and PFS were significantly improved for immunotherapy (monotherapy or combined therapy) vs. chemotherapy in patients with high bTMB (>=16 mut/Mb) vs. low (<16 mut/Mb).	('bTMB', 'Chemical', '-', (130, 134))	('PFS', 'MPA', (7, 10))	('improved', 'PosReg', (30, 38))	('high', 'Var', (125, 129))	('>=16 mut/Mb', 'Var', (136, 147))	('patients', 'Species', '9606', (111, 119))
531076	33076306	The expression of T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3), T cell immunoreceptor with Ig and lymphocyte-activating gene 3 (LAG-3) and ITIM domains (TIGIT) on T cells is associated with impaired T cell immune response.	('TIM-3', 'Gene', (79, 84))	('TIGIT', 'Gene', (176, 181))	('ITIM domains', 'Var', (162, 174))	('TIM-3', 'Gene', '84868', (79, 84))	('lymphocyte-activating gene 3', 'Gene', (121, 149))	('impaired T cell immune', 'Phenotype', 'HP:0002843', (213, 235))	('impaired T', 'Disease', 'MESH:D060825', (213, 223))	('impaired T', 'Disease', (213, 223))	('impaired T cell immune response', 'Phenotype', 'HP:0031402', (213, 244))	('T cell immunoglobulin and mucin domain-containing protein 3', 'Gene', '84868', (18, 77))	('associated', 'Reg', (197, 207))	('TIGIT', 'Gene', '201633', (176, 181))	('lymphocyte-activating gene 3', 'Gene', '3902', (121, 149))
531079	33076306	A subgroup analysis of the CHECKMATE-141 trial evaluated nivolumab treatment beyond disease progression and showed that responders had PD1+ Tregs numbers on day 43 of treatment that were significantly lower than baseline levels and the levels in nonresponders, suggesting that circulating exhausted T cells could be a predictor of ICI treatment.	('circulating exhausted T cells', 'Phenotype', 'HP:0031514', (277, 306))	('PD1+', 'Var', (135, 139))	('nivolumab', 'Chemical', 'MESH:D000077594', (57, 66))	('lower', 'NegReg', (201, 206))
531090	33076306	An analysis from sequencing data of HNSCC samples revealed that a high mutational smoking signature was associated with lower levels of immune infiltration, cytolytic activity, and IFNgamma pathway signaling than a low signature.	('levels of immune infiltration', 'MPA', (126, 155))	('lower', 'NegReg', (120, 125))	('SCC', 'Phenotype', 'HP:0002860', (38, 41))	('cytolytic activity', 'MPA', (157, 175))	('high mutational', 'Var', (66, 81))	('HNSCC', 'Phenotype', 'HP:0012288', (36, 41))	('IFNgamma', 'Gene', '3458', (181, 189))	('IFNgamma', 'Gene', (181, 189))	('lower levels of immune infiltration', 'Phenotype', 'HP:0002721', (120, 155))
531094	33076306	Previous studies have suggested that tumors with more mutations affecting the DNA damage response, such as high microsatellite instability (MSI-H) or mismatch repair deficiency (dMMR) tumors, were associated with higher TMB and were more sensitive to ICIs than tumors with mutations affecting other pathways, leading to FDA approval of ICI treatment (pembrolizumab) for patients with dMMR or MSI-H tumors regardless of histology.	('MSI-H tumors regardless', 'Disease', 'MESH:D009369', (392, 415))	('pembrolizumab', 'Chemical', 'MESH:C582435', (351, 364))	('tumors', 'Disease', (398, 404))	('TMB', 'Chemical', '-', (220, 223))	('higher', 'PosReg', (213, 219))	('deficiency (dMMR) tumors', 'Disease', 'MESH:D009369', (166, 190))	('tumors', 'Disease', 'MESH:D009369', (184, 190))	('tumors', 'Phenotype', 'HP:0002664', (261, 267))	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('sensitive', 'MPA', (238, 247))	('tumor', 'Phenotype', 'HP:0002664', (261, 266))	('tumors', 'Disease', 'MESH:D009369', (398, 404))	('mutations', 'Var', (54, 63))	('tumors', 'Disease', (261, 267))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('patients', 'Species', '9606', (370, 378))	('tumors', 'Disease', (37, 43))	('MSI-H tumors regardless', 'Disease', (392, 415))	('tumors', 'Disease', 'MESH:D009369', (261, 267))	('dMMR', 'Chemical', '-', (384, 388))	('dMMR', 'Chemical', '-', (178, 182))	('tumors', 'Phenotype', 'HP:0002664', (184, 190))	('tumors', 'Disease', 'MESH:D009369', (37, 43))	('TMB', 'MPA', (220, 223))	('tumors', 'Phenotype', 'HP:0002664', (398, 404))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('tumors', 'Disease', (184, 190))	('tumor', 'Phenotype', 'HP:0002664', (398, 403))
531106	33076306	A study evaluating the saliva of HNSCC patients and healthy individuals revealed distinct microbiota compositions, and the presence of certain bacteria was related to a lower risk of HNSCC.	('patients', 'Species', '9606', (39, 47))	('SCC', 'Phenotype', 'HP:0002860', (185, 188))	('SCC', 'Phenotype', 'HP:0002860', (35, 38))	('HNSCC', 'Phenotype', 'HP:0012288', (183, 188))	('HNSCC', 'Phenotype', 'HP:0012288', (33, 38))	('HNSCC', 'Disease', (183, 188))	('presence', 'Var', (123, 131))	('lower', 'NegReg', (169, 174))
531292	31877856	Additionally, multidrug resistance tumours pose a severe threat and have been responsible for numerous cancer-related deaths.	('tumours', 'Disease', (35, 42))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('responsible', 'Reg', (78, 89))	('tumour', 'Phenotype', 'HP:0002664', (35, 41))	('tumours', 'Phenotype', 'HP:0002664', (35, 42))	('tumours', 'Disease', 'MESH:D009369', (35, 42))	('drug resistance', 'Phenotype', 'HP:0020174', (19, 34))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('multidrug resistance', 'Var', (14, 34))
531294	31877856	For instance, combination therapy that targets different pathways exhibit significantly lower toxicity towards normal cells compared to mono-therapy.	('combination', 'Var', (14, 25))	('lower', 'NegReg', (88, 93))	('toxicity', 'Disease', 'MESH:D064420', (94, 102))	('toxicity', 'Disease', (94, 102))
531319	31877856	The five steps of the honokiol synthesis pathway includes bromination, Suzuki coupling, allylation, one-pot Claisen's rearrangement, and demethylation, eventually resulting in a 32% overall yield.	('demethylation', 'Var', (137, 150))	('allylation', 'MPA', (88, 98))	('bromination', 'MPA', (58, 69))	('honokiol', 'Chemical', 'MESH:C005499', (22, 30))
531325	31877856	Through the alteration of the top and bottom rings by changing the substitution pattern at its bottom ring and replacing the hydroxyl group in the top ring with a methoxy group, six different analogues were produced, as shown in Figure 2.	('rat', 'Species', '10116', (16, 19))	('substitution', 'Var', (67, 79))	('changing', 'Reg', (54, 62))	('hydroxyl', 'Chemical', 'MESH:D017665', (125, 133))
531327	31877856	The two hydroxyl group substituted analogues (3'-Bromo-3,5'-dy-allyl-2'hydroxyl-4-methoxy-1,1'-biphenyl and 3,3'-Diallyl-4-methoxy-4'-hydroxy-1,1'-biphenyl) have induced G0/G1 phase cell cycle arrest and a swift decrement in Cdk1 and cyclin B1 protein levels, similarly to the parental honokiol compound.	('hydroxyl', 'Chemical', 'MESH:D017665', (71, 79))	('Cdk1', 'Gene', (225, 229))	('G0/G1 phase cell cycle arrest', 'CPA', (170, 199))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (182, 199))	('hydroxyl', 'Chemical', 'MESH:D017665', (8, 16))	("3'-Bromo-3,5'-dy-allyl-2'hydroxyl-4-methoxy-1,1'-biphenyl", 'Var', (46, 103))	('honokiol', 'Chemical', 'MESH:C005499', (286, 294))	('decrement', 'NegReg', (212, 221))	('Cdk1', 'Gene', '983', (225, 229))	('induced', 'Reg', (162, 169))	('cyclin B1', 'Gene', '891', (234, 243))	('cyclin B1', 'Gene', (234, 243))
531328	31877856	Overall, obstruction of the potential oxidation of the phenolic hydroxyl group in the biphenyl group skeleton of honokiol improved its anti-cancer effect.	('honokiol', 'Chemical', 'MESH:C005499', (113, 121))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('obstruction', 'Var', (9, 20))	('hydroxyl', 'Chemical', 'MESH:D017665', (64, 72))	('improved', 'PosReg', (122, 130))
531341	31877856	's study, they have shown that honokiol has enhanced the in vitro cytotoxicity of paclitaxel against human cervix cancer cell lines.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('cytotoxicity', 'Disease', 'MESH:D064420', (66, 78))	('honokiol', 'Chemical', 'MESH:C005499', (31, 39))	('human', 'Species', '9606', (101, 106))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('honokiol', 'Var', (31, 39))	('cytotoxicity', 'Disease', (66, 78))	('paclitaxel', 'Chemical', 'MESH:D017239', (82, 92))	('cervix cancer', 'Phenotype', 'HP:0030079', (107, 120))	('enhanced', 'PosReg', (44, 52))	('cancer', 'Disease', (114, 120))
531353	31877856	The tumour volume for Lipo-HNK treated mice was 408 +- 165 mm3 compared to liposome-treated mice and control mice were 2575 +- 701 mm3 and 2828 +- 796 mm3 respectively after 21 days.	('tumour', 'Phenotype', 'HP:0002664', (4, 10))	('mice', 'Species', '10090', (92, 96))	('tumour', 'Disease', 'MESH:D009369', (4, 10))	('tumour', 'Disease', (4, 10))	('Lipo-HNK', 'Var', (22, 30))	('mice', 'Species', '10090', (39, 43))	('mice', 'Species', '10090', (109, 113))
531354	31877856	In addition, Lipo-HNK was also shown to prolong survival and induce intra-tumoral apoptosis in vivo.	('Lipo-HNK', 'Var', (13, 21))	('induce', 'PosReg', (61, 67))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('intra-tumoral apoptosis', 'Disease', 'MESH:D009369', (68, 91))	('prolong', 'PosReg', (40, 47))	('survival', 'CPA', (48, 56))	('intra-tumoral apoptosis', 'Disease', (68, 91))
531359	31877856	Honokiol reduced U-87 MG human glioma/glioblastoma cell proliferation and migration in zebrafish yolk sac and in vivo xenograft nude mouse model.	('rat', 'Species', '10116', (77, 80))	('zebrafish', 'Species', '7955', (87, 96))	('glioma', 'Disease', 'MESH:D005910', (31, 37))	('glioblastoma', 'Disease', (38, 50))	('human', 'Species', '9606', (25, 30))	('glioma', 'Phenotype', 'HP:0009733', (31, 37))	('migration', 'CPA', (74, 83))	('reduced', 'NegReg', (9, 16))	('Honokiol', 'Chemical', 'MESH:C005499', (0, 8))	('glioblastoma', 'Disease', 'MESH:D005909', (38, 50))	('mouse', 'Species', '10090', (133, 138))	('U-87', 'Var', (17, 21))	('glioblastoma', 'Phenotype', 'HP:0012174', (38, 50))	('rat', 'Species', '10116', (63, 66))	('glioma', 'Disease', (31, 37))
531374	31877856	Other than intrinsic and extrinsic pathways, honokiol can also induce apoptosis by the endoplasmic reticulum (ER) stress-induced mechanism.	('apoptosis', 'CPA', (70, 79))	('honokiol', 'Var', (45, 53))	('induce', 'PosReg', (63, 69))	('honokiol', 'Chemical', 'MESH:C005499', (45, 53))
531377	31877856	found that honokiol also led to an increase in ER stress activity in melanoma cell lines B16F10 (mouse), human malignant melanoma, and human metastatic melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (121, 129))	('melanoma', 'Phenotype', 'HP:0002861', (152, 160))	('melanoma', 'Disease', (121, 129))	('melanoma', 'Disease', (152, 160))	('melanoma', 'Disease', 'MESH:D008545', (69, 77))	('B16F10', 'CellLine', 'CVCL:0159', (89, 95))	('human', 'Species', '9606', (105, 110))	('honokiol', 'Var', (11, 19))	('malignant melanoma', 'Phenotype', 'HP:0002861', (111, 129))	('human', 'Species', '9606', (135, 140))	('malignant melanoma', 'Disease', 'MESH:D008545', (111, 129))	('honokiol', 'Chemical', 'MESH:C005499', (11, 19))	('ER stress activity', 'MPA', (47, 65))	('melanoma', 'Phenotype', 'HP:0002861', (69, 77))	('melanoma', 'Disease', (69, 77))	('increase', 'PosReg', (35, 43))	('melanoma', 'Disease', 'MESH:D008545', (121, 129))	('melanoma', 'Disease', 'MESH:D008545', (152, 160))	('mouse', 'Species', '10090', (97, 102))	('malignant melanoma', 'Disease', (111, 129))
531384	31877856	The phosphorylation of Ser727 STAT3 induces translocation towards the mitochondria followed by ROS production, ultimately leading to the induction of necrosis.	('Ser727', 'Var', (23, 29))	('Ser727', 'Chemical', '-', (23, 29))	('ROS production', 'MPA', (95, 109))	('necrosis', 'Disease', 'MESH:D009336', (150, 158))	('ROS', 'Chemical', '-', (95, 98))	('translocation towards the mitochondria', 'MPA', (44, 82))	('phosphorylation', 'Var', (4, 19))	('induces', 'Reg', (36, 43))	('necrosis', 'Disease', (150, 158))
531394	31877856	The inhibition of mTORC1 complex will concurrently activate Unc-51-like autophagy-activating kinase (ULK) complex, inducing localisation to the phagophore and followed by class III PI3K activation.	('mTORC1', 'Gene', (18, 24))	('localisation', 'MPA', (124, 136))	('activate', 'PosReg', (51, 59))	('inducing', 'PosReg', (115, 123))	('inhibition', 'Var', (4, 14))	('mTORC1', 'Gene', '382056', (18, 24))
531400	31877856	This LC3 translocation was considered as a reliable hallmark of autophagy.	('LC3', 'Gene', '84557', (5, 8))	('LC3', 'Gene', (5, 8))	('translocation', 'Var', (9, 22))
531405	31877856	Several studies have highlighted the potential of honokiol to induce cell death via autophagy in human prostate cancer cells, human glioma cells, NSCLC cells, and human thyroid cancer cells.	('glioma', 'Disease', (132, 138))	('honokiol', 'Var', (50, 58))	('human', 'Species', '9606', (97, 102))	('glioma', 'Disease', 'MESH:D005910', (132, 138))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('honokiol', 'Chemical', 'MESH:C005499', (50, 58))	('thyroid cancer', 'Disease', (169, 183))	('NSCLC', 'Disease', 'MESH:D002289', (146, 151))	('autophagy', 'CPA', (84, 93))	('glioma', 'Phenotype', 'HP:0009733', (132, 138))	('human', 'Species', '9606', (126, 131))	('prostate cancer', 'Disease', 'MESH:D011471', (103, 118))	('induce', 'PosReg', (62, 68))	('NSCLC', 'Disease', (146, 151))	('prostate cancer', 'Phenotype', 'HP:0012125', (103, 118))	('thyroid cancer', 'Disease', 'MESH:D013964', (169, 183))	('prostate cancer', 'Disease', (103, 118))	('thyroid cancer', 'Phenotype', 'HP:0002890', (169, 183))	('human', 'Species', '9606', (163, 168))	('cell death', 'CPA', (69, 79))
531408	31877856	Similarly, the expression of autophagosomal marker LC3-II was also increased in Kirsten rat sarcoma viral oncogene homolog (KRAS) mutated cell lines of non-small cell lung cancer (NSCLC).	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('NSCLC', 'Disease', (180, 185))	('lung cancer', 'Phenotype', 'HP:0100526', (167, 178))	('LC3', 'Gene', '84557', (51, 54))	('autophagosomal', 'CPA', (29, 43))	('non-small cell lung cancer', 'Disease', (152, 178))	('LC3', 'Gene', (51, 54))	('rat', 'Species', '10116', (88, 91))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (156, 178))	('sarcoma', 'Disease', 'MESH:D012509', (92, 99))	('increased', 'PosReg', (67, 76))	('expression', 'MPA', (15, 25))	('sarcoma', 'Disease', (92, 99))	('mutated', 'Var', (130, 137))	('NSCLC', 'Disease', 'MESH:D002289', (180, 185))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (152, 178))	('sarcoma', 'Phenotype', 'HP:0100242', (92, 99))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (152, 178))
531409	31877856	Other signalling pathways are also found to be involved in honokiol-induced autophagy including the involvement of AMPK-mTOR signalling pathway which leads to autophagocytosis through the coordinated phosphorylation of Ulk1 in Kirsten rat sarcoma viral oncogene homolog (KRAS) mutant lung cancer and melanoma cells.	('leads to', 'Reg', (150, 158))	('lung cancer', 'Disease', (284, 295))	('lung cancer', 'Phenotype', 'HP:0100526', (284, 295))	('melanoma', 'Phenotype', 'HP:0002861', (300, 308))	('melanoma', 'Disease', (300, 308))	('sarcoma', 'Disease', 'MESH:D012509', (239, 246))	('melanoma', 'Disease', 'MESH:D008545', (300, 308))	('cancer', 'Phenotype', 'HP:0002664', (289, 295))	('rat', 'Species', '10116', (235, 238))	('lung cancer', 'Disease', 'MESH:D008175', (284, 295))	('autophagocytosis', 'CPA', (159, 175))	('sarcoma', 'Disease', (239, 246))	('phosphorylation', 'MPA', (200, 215))	('Ulk1', 'Gene', (219, 223))	('honokiol', 'Chemical', 'MESH:C005499', (59, 67))	('sarcoma', 'Phenotype', 'HP:0100242', (239, 246))	('mutant', 'Var', (277, 283))	('Ulk1', 'Gene', '360827', (219, 223))
531449	31877856	The overexpression of MMP-2 and MMP-9 are associated with pro-oncogenic events such as neovascularisation, tumour cell proliferation, and metastasis because it can degrade the extracellular matrix, basement membranes, and adhesion molecules (intercellular adhesion molecule, ICAM, and vascular cell adhesion molecule) and become invasive.	('metastasis', 'CPA', (138, 148))	('degrade', 'NegReg', (164, 171))	('tumour', 'Phenotype', 'HP:0002664', (107, 113))	('MMP-9', 'Var', (32, 37))	('neovascularisation', 'CPA', (87, 105))	('basement', 'Protein', (198, 206))	('tumour', 'Disease', 'MESH:D009369', (107, 113))	('rat', 'Species', '10116', (126, 129))	('adhesion', 'MPA', (222, 230))	('MMP-2', 'Gene', (22, 27))	('tumour', 'Disease', (107, 113))	('extracellular matrix', 'CPA', (176, 196))
531485	31877856	Furthermore, honokiol has also been shown to inhibit the TNF-alpha-induced phosphorylation and degradation of the cytosolic NFkappaB inhibitor IkappaBa and suppression of IKK activation.	('IKK activation', 'Pathway', (171, 185))	('TNF-alpha', 'Gene', (57, 66))	('IkappaBa', 'Protein', (143, 151))	('honokiol', 'Var', (13, 21))	('honokiol', 'Chemical', 'MESH:C005499', (13, 21))	('suppression', 'NegReg', (156, 167))	('TNF-alpha', 'Gene', '7124', (57, 66))	('degradation', 'MPA', (95, 106))	('NFkappaB', 'Gene', (124, 132))	('inhibit', 'NegReg', (45, 52))	('NFkappaB', 'Gene', '4790', (124, 132))	('phosphorylation', 'MPA', (75, 90))
531486	31877856	In addition, honokiol was also found to inhibit the nuclear translocation and phosphorylation of p65 subunit of NFkappaB.	('phosphorylation', 'MPA', (78, 93))	('inhibit', 'NegReg', (40, 47))	('NFkappaB', 'Gene', (112, 120))	('p65', 'Gene', '5970', (97, 100))	('nuclear translocation', 'MPA', (52, 73))	('honokiol', 'Var', (13, 21))	('honokiol', 'Chemical', 'MESH:C005499', (13, 21))	('NFkappaB', 'Gene', '4790', (112, 120))	('p65', 'Gene', (97, 100))
531494	31877856	Furthermore, another study indicated that honokiol induces apoptosis in human glioblastoma cell line U87 through suppressing the phosphorylation of STAT3 (Tyr705), down-regulating survivin, and upregulating cleaved caspase-3 expression.	('glioblastoma', 'Disease', (78, 90))	('cleaved', 'MPA', (207, 214))	('phosphorylation', 'MPA', (129, 144))	('suppressing', 'NegReg', (113, 124))	('U87', 'Gene', (101, 104))	('glioblastoma', 'Disease', 'MESH:D005909', (78, 90))	('Tyr705', 'Chemical', '-', (155, 161))	('survivin', 'Protein', (180, 188))	('glioblastoma', 'Phenotype', 'HP:0012174', (78, 90))	('human', 'Species', '9606', (72, 77))	('U87', 'Gene', '641648', (101, 104))	('honokiol', 'Chemical', 'MESH:C005499', (42, 50))	('down-regulating', 'NegReg', (164, 179))	('honokiol', 'Var', (42, 50))	('expression', 'MPA', (225, 235))	('upregulating', 'PosReg', (194, 206))
531499	31877856	Apart from that, honokiol suppressed metastasis and proliferation in both brain metastatic lung cancer cell lines PC9-BrM3 and H2030- BrM3 by inhibiting STAT3 phosphorylation.	('lung cancer', 'Phenotype', 'HP:0100526', (91, 102))	('brain metastatic lung cancer', 'Disease', 'MESH:D008175', (74, 102))	('proliferation', 'CPA', (52, 65))	('suppressed', 'NegReg', (26, 36))	('brain metastatic lung cancer', 'Disease', (74, 102))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('H2030- BrM3', 'Var', (127, 138))	('PC9-BrM3', 'CellLine', 'CVCL:9W71', (114, 122))	('metastasis', 'CPA', (37, 47))	('honokiol', 'Chemical', 'MESH:C005499', (17, 25))	('rat', 'Species', '10116', (59, 62))	('STAT3 phosphorylation', 'MPA', (153, 174))	('inhibiting', 'NegReg', (142, 152))
531502	31877856	Besides that, honokiol can induce necrosis and apoptosis in transformed Barrett's and oesophageal adenocarcinoma cells through the inhibition of the STAT3 signalling pathway.	('necrosis', 'Disease', (34, 42))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (87, 112))	('oesophageal adenocarcinoma', 'Disease', 'MESH:D000230', (86, 112))	('apoptosis', 'CPA', (47, 56))	('necrosis', 'Disease', 'MESH:D009336', (34, 42))	('honokiol', 'Chemical', 'MESH:C005499', (14, 22))	('oesophageal adenocarcinoma', 'Disease', (86, 112))	('STAT3 signalling pathway', 'Pathway', (149, 173))	('honokiol', 'Var', (14, 22))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('inhibition', 'NegReg', (131, 141))
531505	31877856	The overexpression or activating mutations in EGFR results in increased cell proliferation, abnormal metabolism, and cell survival through the activation of the downstream mitogen-activated protein kinase (MAPK) and v-akt murine thymoma viral oncogene homolog 1 (AKT) signalling pathways, as well as phosphatidyl-inositol 3-kinase (PI3K)/Akt, and STAT3 signalling pathways.	('increased', 'PosReg', (62, 71))	('STAT3 signalling pathways', 'Pathway', (347, 372))	('mutations', 'Var', (33, 42))	('AKT', 'Gene', '11651', (263, 266))	('cell proliferation', 'CPA', (72, 90))	('overexpression', 'PosReg', (4, 18))	('activating', 'PosReg', (22, 32))	('MAPK', 'Gene', (206, 210))	('rat', 'Species', '10116', (84, 87))	('v-akt murine thymoma viral oncogene homolog 1', 'Gene', (216, 261))	('phosphatidyl-inositol 3-kinase', 'Gene', (300, 330))	('EGFR', 'Gene', (46, 50))	('activation', 'PosReg', (143, 153))	('MAPK', 'Gene', '5595;5594;26413;5595;26417', (206, 210))	('phosphatidyl-inositol 3-kinase', 'Gene', '18708', (300, 330))	('abnormal metabolism', 'CPA', (92, 111))	('v-akt murine thymoma viral oncogene homolog 1', 'Gene', '207', (216, 261))	('cell survival', 'CPA', (117, 130))	('thymoma', 'Phenotype', 'HP:0100522', (229, 236))	('abnormal metabolism', 'Phenotype', 'HP:0032245', (92, 111))	('AKT', 'Gene', (263, 266))
531511	31877856	Overall, honokiol has been proven to be a promising candidate to suppress the development and progression of lung tumours driven by EGFR deregulation.	('deregulation', 'Var', (137, 149))	('lung tumours', 'Disease', (109, 121))	('honokiol', 'Chemical', 'MESH:C005499', (9, 17))	('development', 'CPA', (78, 89))	('lung tumour', 'Phenotype', 'HP:0100526', (109, 120))	('EGFR', 'Gene', (132, 136))	('tumour', 'Phenotype', 'HP:0002664', (114, 120))	('progression', 'CPA', (94, 105))	('lung tumours', 'Disease', 'MESH:D008175', (109, 121))	('tumours', 'Phenotype', 'HP:0002664', (114, 121))	('suppress', 'NegReg', (65, 73))
531517	31877856	Besides that, inhibition of HER-2 signalling by specific human epidermal growth receptor 1/HER-2 (EGFR/HER-2) kinase inhibitor lapatinib synergistically enhanced the anti-cancer effects of honokiol in HER-2 over-expressed breast cancer cells.	('lapatinib', 'Chemical', 'MESH:D000077341', (127, 136))	('breast cancer', 'Phenotype', 'HP:0003002', (222, 235))	('cancer', 'Disease', 'MESH:D009369', (229, 235))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('enhanced', 'PosReg', (153, 161))	('breast cancer', 'Disease', 'MESH:D001943', (222, 235))	('human', 'Species', '9606', (57, 62))	('breast cancer', 'Disease', (222, 235))	('HER-2', 'Gene', '2064', (28, 33))	('HER-2', 'Gene', (28, 33))	('cancer', 'Disease', (229, 235))	('HER-2', 'Gene', '2064', (91, 96))	('cancer', 'Disease', (171, 177))	('HER-2', 'Gene', (91, 96))	('over-expressed', 'PosReg', (207, 221))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('HER-2', 'Gene', '2064', (201, 206))	('HER-2', 'Gene', (201, 206))	('honokiol', 'Chemical', 'MESH:C005499', (189, 197))	('HER-2', 'Gene', '2064', (103, 108))	('inhibition', 'Var', (14, 24))	('HER-2', 'Gene', (103, 108))
531518	31877856	The treatment of HNSCC cells with honokiol also decreased the expression of total EGFR as well as p-EGFR and its downstream target, mTOR.	('EGFR', 'Gene', (82, 86))	('expression', 'MPA', (62, 72))	('honokiol', 'Chemical', 'MESH:C005499', (34, 42))	('decreased', 'NegReg', (48, 57))	('p-EGFR', 'Var', (98, 104))
531528	31877856	Furthermore, it was proven that honokiol was able to attenuate PI3K/Akt/mTOR signalling via the down-regulation of Akt phosphorylation and upregulation of PTEN expression in breast cancer cells (MCF-7, MCF-7/adr, and BT-474 cell lines).	('PI3K/Akt/mTOR signalling', 'Pathway', (63, 87))	('expression', 'MPA', (160, 170))	('breast cancer', 'Disease', 'MESH:D001943', (174, 187))	('honokiol', 'Var', (32, 40))	('PTEN', 'Gene', (155, 159))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('MCF-7', 'CellLine', 'CVCL:0031', (195, 200))	('breast cancer', 'Disease', (174, 187))	('PTEN', 'Gene', '5728', (155, 159))	('MCF-7', 'CellLine', 'CVCL:0031', (202, 207))	('upregulation', 'PosReg', (139, 151))	('breast cancer', 'Phenotype', 'HP:0003002', (174, 187))	('Akt phosphorylation', 'Pathway', (115, 134))	('down-regulation', 'NegReg', (96, 111))	('attenuate', 'NegReg', (53, 62))	('honokiol', 'Chemical', 'MESH:C005499', (32, 40))
531530	31877856	Other studies have also shown that honokiol induces autophagy in PC-3 and LNCaP prostate cancer cells via the suppression of mTOR and Akt phosphorylation.	('suppression', 'NegReg', (110, 121))	('autophagy', 'CPA', (52, 61))	('PC-3', 'Gene', '3853', (65, 69))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('LNCaP', 'CellLine', 'CVCL:0395', (74, 79))	('prostate cancer', 'Disease', 'MESH:D011471', (80, 95))	('mTOR', 'Pathway', (125, 129))	('prostate cancer', 'Phenotype', 'HP:0012125', (80, 95))	('honokiol', 'Chemical', 'MESH:C005499', (35, 43))	('honokiol', 'Var', (35, 43))	('PC-3', 'Gene', (65, 69))	('prostate cancer', 'Disease', (80, 95))	('Akt', 'Pathway', (134, 137))
531536	31877856	Recent studies suggest that transcriptional adaptation to hypoxia involves epigenetic changes in histone methylation.	('hypoxia', 'Disease', 'MESH:D000860', (58, 65))	('hypoxia', 'Disease', (58, 65))	('histone methylation', 'MPA', (97, 116))	('epigenetic changes', 'Var', (75, 93))
531540	31877856	In KRAS mutant lung cancer cells, it was discovered that Sirt3 was significantly up-regulated in honokiol-treated KRAS mutant lung cancer cells, leading to the destabilisation of its target gene Hif-1alpha and induction of G1 arrest and apoptosis.	('Sirt3', 'Gene', (57, 62))	('Hif-1alpha', 'Gene', (195, 205))	('induction', 'Reg', (210, 219))	('apoptosis', 'CPA', (237, 246))	('G1 arrest', 'CPA', (223, 232))	('lung cancer', 'Disease', (15, 26))	('lung cancer', 'Disease', (126, 137))	('honokiol', 'Chemical', 'MESH:C005499', (97, 105))	('mutant', 'Var', (119, 125))	('Sirt3', 'Gene', '23410', (57, 62))	('destabilisation', 'MPA', (160, 175))	('KRAS', 'Gene', (114, 118))	('lung cancer', 'Disease', 'MESH:D008175', (15, 26))	('lung cancer', 'Disease', 'MESH:D008175', (126, 137))	('lung cancer', 'Phenotype', 'HP:0100526', (15, 26))	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('Hif-1alpha', 'Gene', '3091', (195, 205))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('lung cancer', 'Phenotype', 'HP:0100526', (126, 137))	('up-regulated', 'PosReg', (81, 93))
531542	31877856	In mammals, the Notch receptor family comprises of four receptors (Notch-1, Notch-2, Notch-3, and Notch-4) and five ligands (Delta-like-1, Delta-like-3, Delta-like-4, Jagged-1, and Jagged-2).	('Notch-3', 'Gene', (85, 92))	('Delta-like-3', 'Gene', '10683', (139, 151))	('Notch-2', 'Gene', '4853', (76, 83))	('Jagged-1', 'Gene', (167, 175))	('Notch-4', 'Gene', (98, 105))	('Jagged-1', 'Gene', '182', (167, 175))	('Delta-like-4', 'Var', (153, 165))	('Delta-like-3', 'Gene', (139, 151))	('Notch-1', 'Gene', (67, 74))	('Notch-3', 'Gene', '4854', (85, 92))	('Notch-4', 'Gene', '4855', (98, 105))	('Jagged-2', 'Gene', '3714', (181, 189))	('Notch-2', 'Gene', (76, 83))	('Delta-like-1', 'Var', (125, 137))	('Jagged-2', 'Gene', (181, 189))	('Notch-1', 'Gene', '4851', (67, 74))
531600	31877856	PEGylated (polyethylene glycol coated) liposomal honokiol was shown to enhance the serum honokiol concentration and decrease clearance.	('PEGylated', 'Var', (0, 9))	('polyethylene glycol', 'Chemical', 'MESH:D011092', (11, 30))	('decrease clearance', 'Phenotype', 'HP:0012213', (116, 134))	('rat', 'Species', '10116', (105, 108))	('decrease', 'NegReg', (116, 124))	('PE', 'Chemical', 'MESH:C483858', (0, 2))	('honokiol', 'Chemical', 'MESH:C005499', (89, 97))	('honokiol', 'Chemical', 'MESH:C005499', (49, 57))	('clearance', 'MPA', (125, 134))	('enhance', 'PosReg', (71, 78))	('serum honokiol concentration', 'MPA', (83, 111))
531601	31877856	The pharmacokinetic analysis of PEGylated liposomal honokiol showed a two-fold increase in elimination t1/2 value as compared to that of free honokiol when being injected through the i.v.	('increase', 'PosReg', (79, 87))	('PEGylated', 'Var', (32, 41))	('honokiol', 'Chemical', 'MESH:C005499', (52, 60))	('honokiol', 'Chemical', 'MESH:C005499', (142, 150))	('PE', 'Chemical', 'MESH:C483858', (32, 34))	('elimination t1/2 value', 'MPA', (91, 113))
531603	31877856	Moreover, the AUC0   (mean concentration of drug in plasma) of PEGylated liposomal honokiol was about 1.85-fold higher than free honokiol.	('higher', 'PosReg', (112, 118))	('honokiol', 'Chemical', 'MESH:C005499', (129, 137))	('PEGylated', 'Var', (63, 72))	('PE', 'Chemical', 'MESH:C483858', (63, 65))	('honokiol', 'Chemical', 'MESH:C005499', (83, 91))	('rat', 'Species', '10116', (34, 37))
531617	31877856	Moreover, ATNH significantly inhibited tumour growth, metabolism, proliferation, micro-vessel generation, and caused cell-cycle arrest at the G1 phase.	('inhibited', 'NegReg', (29, 38))	('micro-vessel generation', 'CPA', (81, 104))	('tumour', 'Disease', (39, 45))	('caused', 'Reg', (110, 116))	('ATNH', 'Chemical', '-', (10, 14))	('rat', 'Species', '10116', (98, 101))	('metabolism', 'CPA', (54, 64))	('tumour', 'Phenotype', 'HP:0002664', (39, 45))	('ATNH', 'Var', (10, 14))	('tumour', 'Disease', 'MESH:D009369', (39, 45))	('cell-cycle arrest at the G1 phase', 'CPA', (117, 150))	('rat', 'Species', '10116', (73, 76))
531619	31877856	Furthermore, CE-HK NPs (40 mg/kg) inhibited tumour growth by 83.55% (p < 0.05), which was far higher than the 30.15% inhibition of free honokiol (40 mg/kg).	('CE-HK NPs', 'Var', (13, 22))	('NPs', 'Var', (19, 22))	('tumour', 'Disease', 'MESH:D009369', (44, 50))	('inhibited', 'NegReg', (34, 43))	('tumour', 'Disease', (44, 50))	('honokiol', 'Chemical', 'MESH:C005499', (136, 144))	('tumour', 'Phenotype', 'HP:0002664', (44, 50))	('HK', 'Chemical', 'MESH:C005499', (16, 18))
531624	31877856	HK-PDA-FA-NPs have better targeting ability to 4T1 cells than normal HK-NPs.	('4T1', 'CellLine', 'CVCL:0125', (47, 50))	('HK', 'Chemical', 'MESH:C005499', (0, 2))	('targeting ability', 'MPA', (26, 43))	('HK', 'Chemical', 'MESH:C005499', (69, 71))	('HK-PDA-FA-NPs', 'Var', (0, 13))	('HK-PDA-FA', 'Chemical', '-', (0, 9))
531640	31877856	Increased apoptosis and antiangiogenic effects were observed in HNK-NM groups compared to HNK-FD and untreated control mice.	('HNK-NM', 'Var', (64, 70))	('antiangiogenic effects', 'CPA', (24, 46))	('mice', 'Species', '10090', (119, 123))	('apoptosis', 'CPA', (10, 19))
531642	31877856	Both the cytotoxicity and the cellular uptake of P-H/M were increased in 4T1 cells, and P-H/M induced more apoptosis than PTX-loaded micelles or HK-loaded micelles.	('mice', 'Species', '10090', (133, 137))	('cytotoxicity', 'Disease', 'MESH:D064420', (9, 21))	('P-H/M', 'Var', (88, 93))	('apoptosis', 'CPA', (107, 116))	('mice', 'Species', '10090', (155, 159))	('PTX', 'Chemical', 'MESH:D017239', (122, 125))	('4T1', 'CellLine', 'CVCL:0125', (73, 76))	('HK', 'Chemical', 'MESH:C005499', (145, 147))	('cytotoxicity', 'Disease', (9, 21))	('increased', 'PosReg', (60, 69))	('cellular uptake', 'CPA', (30, 45))
531643	31877856	Furthermore, the antitumor effect of P-H/M was significantly improved compared with PTX-loaded micelles or HK-loaded micelles in vivo (Female Balb/c mice and female Balb/c nude mice treated with intravenous injection).	('improved', 'PosReg', (61, 69))	('mice', 'Species', '10090', (95, 99))	('P-H/M', 'Var', (37, 42))	('tumor', 'Disease', (21, 26))	('PTX', 'Chemical', 'MESH:D017239', (84, 87))	('mice', 'Species', '10090', (117, 121))	('mice', 'Species', '10090', (149, 153))	('HK', 'Chemical', 'MESH:C005499', (107, 109))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('mice', 'Species', '10090', (177, 181))	('nude mice', 'Species', '10090', (172, 181))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
531644	31877856	P-H/M were more effective in inhibiting tumour proliferation, inducing tumour apoptosis, and decreasing the density of microvasculature accumulated more in tumour tissues compared to the free drug.	('tumour', 'Disease', 'MESH:D009369', (156, 162))	('tumour proliferation', 'Disease', 'MESH:C565054', (40, 60))	('tumour', 'Disease', (71, 77))	('tumour apoptosis', 'Disease', (71, 87))	('tumour', 'Disease', 'MESH:D009369', (40, 46))	('tumour', 'Disease', (156, 162))	('tumour', 'Disease', (40, 46))	('inducing', 'Reg', (62, 70))	('tumour apoptosis', 'Disease', 'MESH:D009369', (71, 87))	('P-H/M', 'Var', (0, 5))	('tumour proliferation', 'Disease', (40, 60))	('tumour', 'Phenotype', 'HP:0002664', (71, 77))	('tumour', 'Phenotype', 'HP:0002664', (156, 162))	('inhibiting', 'NegReg', (29, 39))	('tumour', 'Phenotype', 'HP:0002664', (40, 46))	('density', 'MPA', (108, 115))	('decreasing', 'NegReg', (93, 103))	('tumour', 'Disease', 'MESH:D009369', (71, 77))
531652	31877856	created liposomal honokiol and tested it on cisplatin-sensitive (A2780s) and -resistant (A2780cp) human ovarian cancer models.	('ovarian cancer', 'Disease', (104, 118))	('ovarian cancer', 'Phenotype', 'HP:0100615', (104, 118))	('A2780s', 'Var', (65, 71))	('A2780cp', 'Var', (89, 96))	('tested', 'Reg', (31, 37))	('ovarian cancer', 'Disease', 'MESH:D010051', (104, 118))	('honokiol', 'Chemical', 'MESH:C005499', (18, 26))	('cisplatin', 'Chemical', 'MESH:D002945', (44, 53))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('human', 'Species', '9606', (98, 103))
531653	31877856	The administration of liposomal honokiol resulted in significant inhibition (84-88% maximum inhibition relative to controls) in the growth of A2780s and A2780cp tumour xenografts and prolonged the survival of the treated mice (treated twice weekly with intravenous administration).	('inhibition', 'NegReg', (65, 75))	('A2780cp', 'Var', (153, 160))	('rat', 'Species', '10116', (12, 15))	('tumour', 'Phenotype', 'HP:0002664', (161, 167))	('tumour', 'Disease', 'MESH:D009369', (161, 167))	('growth', 'CPA', (132, 138))	('rat', 'Species', '10116', (273, 276))	('mice', 'Species', '10090', (221, 225))	('tumour', 'Disease', (161, 167))	('A2780s', 'Var', (142, 148))	('prolonged', 'PosReg', (183, 192))	('survival', 'CPA', (197, 205))	('honokiol', 'Chemical', 'MESH:C005499', (32, 40))
531657	31877856	A similar result was observed in murine CT26 colon cancer models, where the systemic administration of liposomal honokiol with cisplatin resulted in the inhibition of subcutaneous tumour growth beyond the effects observed with either liposomal honokiol or cisplatin alone due to elevated levels of apoptosis and reduced endothelial cell density significantly.	('apoptosis', 'MPA', (298, 307))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('reduced', 'NegReg', (312, 319))	('cisplatin', 'Chemical', 'MESH:D002945', (256, 265))	('colon cancer', 'Disease', (45, 57))	('subcutaneous tumour', 'Phenotype', 'HP:0001482', (167, 186))	('honokiol', 'Chemical', 'MESH:C005499', (113, 121))	('elevated', 'PosReg', (279, 287))	('liposomal', 'Var', (103, 112))	('CT26', 'CellLine', 'CVCL:7254', (40, 44))	('cisplatin', 'Chemical', 'MESH:D002945', (127, 136))	('rat', 'Species', '10116', (93, 96))	('colon cancer', 'Phenotype', 'HP:0003003', (45, 57))	('endothelial cell density', 'CPA', (320, 344))	('inhibition', 'NegReg', (153, 163))	('murine', 'Species', '10090', (33, 39))	('tumour', 'Phenotype', 'HP:0002664', (180, 186))	('tumour', 'Disease', 'MESH:D009369', (180, 186))	('levels', 'MPA', (288, 294))	('colon cancer', 'Disease', 'MESH:D015179', (45, 57))	('honokiol', 'Chemical', 'MESH:C005499', (244, 252))	('tumour', 'Disease', (180, 186))
531741	31475114	Evidence also suggests that lung adenocarcinoma and lung squamous cell carcinoma differ in the composition of genes and molecular characteristics, such as EGFR gene mutations.	('EGFR', 'Gene', '1956', (155, 159))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (52, 80))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (57, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('EGFR', 'Gene', (155, 159))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (28, 47))	('mutations', 'Var', (165, 174))	('carcinoma', 'Phenotype', 'HP:0030731', (38, 47))	('lung adenocarcinoma and lung squamous cell carcinoma', 'Disease', 'MESH:D000077192', (28, 80))
531748	31475114	In our new modified staging system, cases of patients with T1N1M0 adenocarcinoma will now be classified as stage IB, reflecting their better outcomes than those of cases involving tumors that remain in stage IIB.	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('tumors', 'Phenotype', 'HP:0002664', (180, 186))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('adenocarcinoma', 'Disease', (66, 80))	('tumors', 'Disease', 'MESH:D009369', (180, 186))	('tumors', 'Disease', (180, 186))	('patients', 'Species', '9606', (45, 53))	('adenocarcinoma', 'Disease', 'MESH:D000230', (66, 80))	('T1N1M0', 'Var', (59, 65))
531749	31475114	Similarly, the category T1N2M0, T2N1M0, and T3N0M0 of adenocarcinoma will move from IIB or IIIA to IIA.	('adenocarcinoma', 'Disease', (54, 68))	('T3N0M0', 'Var', (44, 50))	('adenocarcinoma', 'Disease', 'MESH:D000230', (54, 68))	('T2N1M0', 'Var', (32, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (59, 68))
531750	31475114	In addition, cases of T4N0M0 of adenocarcinoma, T3-4N1M0 of adenocarcinoma, and T2N2M0 of adenocarcinoma will now be classified as IIB, not IIIA, as was the case previously.	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('T4N0M0', 'Var', (22, 28))	('adenocarcinoma', 'Disease', (60, 74))	('adenocarcinoma', 'Disease', 'MESH:D000230', (32, 46))	('T2N2M0', 'Var', (80, 86))	('carcinoma', 'Phenotype', 'HP:0030731', (37, 46))	('adenocarcinoma', 'Disease', 'MESH:D000230', (60, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (95, 104))	('adenocarcinoma', 'Disease', (90, 104))	('adenocarcinoma', 'Disease', 'MESH:D000230', (90, 104))	('T3-4N1M0', 'Var', (48, 56))	('adenocarcinoma', 'Disease', (32, 46))
531751	31475114	In addition, T3-4N2M0 of adenocarcinoma and T2-4N3M0 of adenocarcinoma would also shift from IIIC to IIIB, IIIB to IIIA, and from IIIA to IIB.	('T3-4N2M0', 'Var', (13, 21))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('T2-4N3M0', 'Var', (44, 52))	('adenocarcinoma', 'Disease', (25, 39))	('adenocarcinoma', 'Disease', (56, 70))	('carcinoma', 'Phenotype', 'HP:0030731', (30, 39))	('adenocarcinoma', 'Disease', 'MESH:D000230', (25, 39))	('adenocarcinoma', 'Disease', 'MESH:D000230', (56, 70))
531752	31475114	However, cases of T1-2N0M0 of squamous cell carcinoma would now move from IA to IB, IB to IIA, and from IIA to IIB, which reflect their worse outcome than that of cases involving tumors that remain in the original stage.	('tumors', 'Disease', (179, 185))	('tumors', 'Phenotype', 'HP:0002664', (179, 185))	('tumors', 'Disease', 'MESH:D009369', (179, 185))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (30, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (44, 53))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('T1-2N0M0', 'Var', (18, 26))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (30, 53))	('squamous cell carcinoma', 'Disease', (30, 53))
531769	31221981	The cancer driver genes IDH1/2, JARID1C/ KDM5C, and UTX/ KDM6A: crosstalk between histone demethylation and hypoxic reprogramming in cancer metabolism Cancer driver genes involved in epigenetics Among the 299 driver genes mentioned by Bailey et al., only the epigenetics-related pathways have been sorted out a20/20+: Classifies genes as an oncogene, tumor suppressor gene, or as a nondriver gene using Random Forests, http://2020plus.readthedocs.org bBLCA (bladder urothelial carcinoma), BRCA (breast invasive carcinoma), CESC (cervical squamous cell carcinoma and endocervical adenocarcinoma), CHOL (cholangiocarcinoma), DLBC (lymphoid neoplasm diffuse large B-cell lymphoma), ESCA (esophageal carcinoma), GBM (glioblastoma multiforme), HNSC (head and neck squamous cell carcinoma), KIRC (kidney renal clear cell carcinoma), KIRP (kidney renal papillary cell carcinoma), LAML (acute myeloid leukemia), LGG (brain lower grade glioma), LIHC (liver hepatocellular carcinoma), LUAD (lung adenocarcinoma), LUSC (lung squamous cell carcinoma), MESO (mesothelioma), PAAD (pancreatic adenocarcinoma), PANCAN (Pan-cancer), PRAD (prostate adenocarcinoma), SKCM (skin cutaneous melanoma), THCA (thyroid carcinoma), UCEC (uterine corpus endometrial carcinoma) Recent studies on mutations in cancer genomes have distinguished driver mutations from passenger mutations, which occur as byproducts of cancer development.	('melanoma', 'Phenotype', 'HP:0002861', (1169, 1177))	('cancer', 'Phenotype', 'HP:0002664', (1281, 1287))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (948, 972))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (981, 1000))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (1227, 1248))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (1014, 1037))	('tumor', 'Disease', (351, 356))	('lung squamous cell carcinoma', 'Disease', (1009, 1037))	('JARID1C', 'Gene', (32, 39))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (713, 736))	('AML', 'Phenotype', 'HP:0004808', (874, 877))	('tumor', 'Disease', 'MESH:D009369', (351, 356))	('carcinoma', 'Phenotype', 'HP:0030731', (611, 620))	('LAML', 'Disease', (873, 877))	('breast invasive carcinoma', 'Disease', 'MESH:D018270', (495, 520))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (879, 901))	('UTX', 'Gene', '7403', (52, 55))	('Cancer', 'Phenotype', 'HP:0002664', (151, 157))	('mesothelioma', 'Disease', (1046, 1058))	('LAML', 'Disease', 'None', (873, 877))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D010190', (1067, 1092))	('mutations', 'Var', (1322, 1331))	('mesothelioma', 'Disease', 'MESH:D008654', (1046, 1058))	('cancer', 'Phenotype', 'HP:0002664', (1107, 1113))	('lymphoid neoplasm', 'Disease', (629, 646))	('cholangiocarcinoma', 'Disease', 'MESH:D018281', (602, 620))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (1009, 1037))	('cancer', 'Disease', (4, 10))	('glioblastoma', 'Phenotype', 'HP:0012174', (713, 725))	('glioma', 'Phenotype', 'HP:0009733', (927, 933))	('lymphoid neoplasm', 'Disease', 'MESH:D008223', (629, 646))	('KDM6A', 'Gene', (57, 62))	('thyroid carcinoma', 'Disease', (1186, 1203))	('hypoxic', 'Disease', 'MESH:D000860', (108, 115))	('glioblastoma multiforme', 'Disease', (713, 736))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (1067, 1092))	('B-cell lymphoma', 'Disease', 'MESH:D016393', (661, 676))	('cancer', 'Disease', 'MESH:D009369', (1281, 1287))	('breast invasive carcinoma', 'Phenotype', 'HP:0003002', (495, 520))	('BRCA', 'Gene', (489, 493))	('cervical squamous cell carcinoma and endocervical adenocarcinoma', 'Disease', 'MESH:D002294', (529, 593))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (1186, 1203))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (759, 782))	('leukemia', 'Phenotype', 'HP:0001909', (893, 901))	('LIHC', 'Disease', (936, 940))	('cancer', 'Disease', (133, 139))	('esophageal carcinoma', 'Disease', (685, 705))	('carcinoma', 'Phenotype', 'HP:0030731', (584, 593))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (745, 782))	('pancreatic adenocarcinoma', 'Disease', (1067, 1092))	('IDH1/2', 'Gene', '3417;3418', (24, 30))	('KDM6A', 'Gene', '7403', (57, 62))	('liver hepatocellular carcinoma', 'Disease', (942, 972))	('glioma', 'Disease', 'MESH:D005910', (927, 933))	('kidney renal papillary cell carcinoma', 'Disease', (833, 870))	('breast invasive carcinoma', 'Disease', (495, 520))	('cancer', 'Disease', (1281, 1287))	('head and neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (745, 782))	('skin cutaneous melanoma', 'Disease', (1154, 1177))	('LUAD', 'Disease', 'None', (975, 979))	('KDM5C', 'Gene', (41, 46))	('JARID1C', 'Gene', '8242', (32, 39))	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('cancer', 'Disease', 'MESH:D009369', (1387, 1393))	('BRCA', 'Gene', '672', (489, 493))	('acute myeloid leukemia', 'Disease', (879, 901))	('renal papillary cell carcinoma', 'Phenotype', 'HP:0006766', (840, 870))	('cutaneous melanoma', 'Phenotype', 'HP:0012056', (1159, 1177))	('lymphoma', 'Phenotype', 'HP:0002665', (668, 676))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (885, 901))	('Pan-cancer', 'Disease', (1103, 1113))	('KDM5C', 'Gene', '8242', (41, 46))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (458, 486))	('cancer', 'Disease', (1387, 1393))	('carcinoma', 'Phenotype', 'HP:0030731', (552, 561))	('glioma', 'Disease', (927, 933))	('LUAD', 'Disease', (975, 979))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('tumor', 'Phenotype', 'HP:0002664', (351, 356))	('LIHC', 'Disease', 'None', (936, 940))	('cholangiocarcinoma', 'Disease', (602, 620))	('IDH1/2', 'Gene', (24, 30))	('lung adenocarcinoma', 'Disease', (981, 1000))	('kidney renal clear cell carcinoma', 'Disease', (791, 824))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (685, 705))	('Cancer', 'Disease', 'MESH:D009369', (151, 157))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (981, 1000))	('CHOL', 'Disease', (596, 600))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (1227, 1248))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (1186, 1203))	('kidney renal papillary cell carcinoma', 'Disease', 'MESH:D007681', (833, 870))	('prostate adenocarcinoma', 'Disease', (1122, 1145))	('neoplasm', 'Phenotype', 'HP:0002664', (638, 646))	('carcinoma', 'Phenotype', 'HP:0030731', (477, 486))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (1009, 1037))	('cancer', 'Disease', 'MESH:D009369', (1107, 1113))	('liver hepatocellular carcinoma', 'Disease', 'MESH:D006528', (942, 972))	('hypoxic', 'Disease', (108, 115))	('bladder urothelial carcinoma', 'Disease', (458, 486))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (538, 561))	('cancer', 'Disease', 'MESH:D009369', (4, 10))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (879, 901))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (685, 705))	('prostate adenocarcinoma', 'Disease', 'MESH:D011471', (1122, 1145))	('UTX', 'Gene', (52, 55))	('kidney renal clear cell carcinoma', 'Disease', 'MESH:C538614', (791, 824))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (661, 676))	('cancer', 'Phenotype', 'HP:0002664', (1387, 1393))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (602, 620))	('cancer', 'Disease', (1107, 1113))	('Pan-cancer', 'Disease', 'MESH:C537931', (1103, 1113))	('skin cutaneous melanoma', 'Disease', 'MESH:C562393', (1154, 1177))	('endometrial carcinoma', 'Disease', (1227, 1248))	('B-cell lymphoma', 'Disease', (661, 676))	('Cancer', 'Disease', (151, 157))	('CHOL', 'Disease', 'None', (596, 600))	('carcinoma', 'Phenotype', 'HP:0030731', (511, 520))
531772	31221981	Furthermore, gain-of-function mutations in genes encoding metabolic enzymes, such as isocitrate dehydrogenases (IDH)1/2, drive tumor progression by producing an oncometabolite, D-2-hydroxyglutarate (D-2HG), which is a competitive inhibitor of alpha-ketoglutarate, O2-dependent dioxygenases such as Jumonji domain-containing histone demethylases, and DNA demethylases.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('IDH)1/2', 'Gene', '3417;3418', (112, 119))	('O2', 'Chemical', 'MESH:D010100', (264, 266))	('hydroxyglutarate', 'Chemical', '-', (181, 197))	('tumor', 'Disease', (127, 132))	('gain-of-function', 'PosReg', (13, 29))	('oxygen', 'Chemical', 'MESH:D010100', (279, 285))	('alpha-ketoglutarate', 'Chemical', 'MESH:D007656', (243, 262))	('mutations', 'Var', (30, 39))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('isocitrate', 'Chemical', 'MESH:C034219', (85, 95))
531774	31221981	We have also discussed mutations in other isoforms such as the JARID1A, 1B, 1D of KDM5 subfamilies and the JMJD3/KDM6B of KDM6 subfamilies, which play opposing roles in tumor progression as oncogenes or tumor suppressors depending on the cancer cell type.	('JARID1A, 1B', 'Gene', '10765', (63, 74))	('cancer', 'Disease', (238, 244))	('tumor', 'Disease', (203, 208))	('KDM6B', 'Gene', (113, 118))	('JMJD3', 'Gene', '23135', (107, 112))	('cancer', 'Disease', 'MESH:D009369', (238, 244))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('mutations', 'Var', (23, 32))	('tumor', 'Disease', (169, 174))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('KDM6B', 'Gene', '23135', (113, 118))	('JMJD3', 'Gene', (107, 112))
531778	31221981	The mechanisms through which changes in histone methylation affect the expression of genes involved in tumor progression remain unknown.	('expression', 'MPA', (71, 81))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('changes', 'Var', (29, 36))	('tumor', 'Disease', (103, 108))	('affect', 'Reg', (60, 66))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
531788	31221981	The sensitivities of each histone demethylase to oncometabolites such as D(R)-2-hydroxyglutarate (HG) and L(S)-2HG vary, suggesting that histone methylation can be differently altered in response to IDH mutations and the presence of oncometabolites (Table 3).	('IDH', 'Gene', '3417', (199, 202))	('histone methylation', 'MPA', (137, 156))	('altered', 'Reg', (176, 183))	('D(R)-2-hydroxyglutarate', 'Chemical', '-', (73, 96))	('mutations', 'Var', (203, 212))	('IDH', 'Gene', (199, 202))
531792	31221981	Although several studies showed that hypoxia itself, hypoxia-induced metabolic reprogramming, and IDH mutations increase the total abundance of methylated histones in different cancer cells, the mechanism through which the increased level of histone methylation is related to cellular heterogeneity, cancer resistance, and progression remains unknown.	('hypoxia', 'Disease', (53, 60))	('hypoxia', 'Disease', 'MESH:D000860', (53, 60))	('cancer', 'Disease', (177, 183))	('cancer', 'Disease', 'MESH:D009369', (177, 183))	('hypoxia', 'Disease', (37, 44))	('hypoxia', 'Disease', 'MESH:D000860', (37, 44))	('cancer', 'Phenotype', 'HP:0002664', (300, 306))	('abundance of methylated', 'MPA', (131, 154))	('increase', 'PosReg', (112, 120))	('mutations', 'Var', (102, 111))	('cancer', 'Phenotype', 'HP:0002664', (177, 183))	('IDH', 'Gene', (98, 101))	('IDH', 'Gene', '3417', (98, 101))	('cancer', 'Disease', 'MESH:D009369', (300, 306))	('cancer', 'Disease', (300, 306))
531793	31221981	This review introduces recent observations regarding (i) metabolic reprogramming of the alpha-KG balance by IDH mutation and hypoxia in cancers, (ii) the tumor-suppressive functions of the cancer driver genes JARID1C/KDM5C and UTX/KDM6A, and (iii) mutations in genes encoding other isoforms in various cancers, namely, JARID1A, 1B, 1D, and JMJD3/KDM6B of the KDM5 and KDM6 subfamilies.	('mutations', 'Var', (248, 257))	('cancers', 'Phenotype', 'HP:0002664', (136, 143))	('hypoxia in cancers', 'Disease', (125, 143))	('cancers', 'Disease', (136, 143))	('cancer', 'Disease', (136, 142))	('KDM6A', 'Gene', (231, 236))	('cancers', 'Phenotype', 'HP:0002664', (302, 309))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('cancers', 'Disease', (302, 309))	('KDM5C', 'Gene', '8242', (217, 222))	('cancer', 'Disease', (302, 308))	('tumor', 'Disease', (154, 159))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('cancer', 'Phenotype', 'HP:0002664', (302, 308))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('IDH', 'Gene', (108, 111))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('cancers', 'Disease', 'MESH:D009369', (136, 143))	('alpha-KG', 'Chemical', 'MESH:D007656', (88, 96))	('cancer', 'Disease', 'MESH:D009369', (302, 308))	('KDM5C', 'Gene', (217, 222))	('cancers', 'Disease', 'MESH:D009369', (302, 309))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('KDM6A', 'Gene', '7403', (231, 236))	('JMJD3', 'Gene', '23135', (340, 345))	('hypoxia in cancers', 'Disease', 'MESH:D000860', (125, 143))	('cancer', 'Disease', (189, 195))	('KDM6B', 'Gene', (346, 351))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('IDH', 'Gene', '3417', (108, 111))	('JMJD3', 'Gene', (340, 345))	('JARID1A, 1B', 'Gene', '10765', (319, 330))	('KDM6B', 'Gene', '23135', (346, 351))
531795	31221981	Cancer genomic analyses have identified that an abnormal increase in the D-2HG level is associated with mutations in either IDH1 or IDH2.	('mutations', 'Var', (104, 113))	('IDH2', 'Gene', '3418', (132, 136))	('D-2HG level', 'MPA', (73, 84))	('IDH1', 'Gene', '3417', (124, 128))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('increase', 'PosReg', (57, 65))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('IDH1', 'Gene', (124, 128))	('IDH2', 'Gene', (132, 136))
531798	31221981	In several tumors, including glioma, AML, chondrosarcoma, intrahepatic cholangiocarcinoma, and thyroid carcinoma (Table 1), missense mutations of arginine residues in the active sites of both IDH1 and IDH2 (IDH1R123H, IDH2R140Q, or IDH2R172K) result in new activities that further convert alpha-KG to D-2HG.	('IDH1', 'Gene', (207, 211))	('chondrosarcoma', 'Phenotype', 'HP:0006765', (42, 56))	('tumors', 'Disease', 'MESH:D009369', (11, 17))	('IDH1R123H', 'Gene', '3418', (207, 216))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (95, 112))	('glioma', 'Phenotype', 'HP:0009733', (29, 35))	('IDH1', 'Gene', '3417', (192, 196))	('arginine', 'Chemical', 'MESH:D001120', (146, 154))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('alpha-KG', 'Chemical', 'MESH:D007656', (289, 297))	('activities', 'MPA', (257, 267))	('intrahepatic cholangiocarcinoma', 'Disease', 'MESH:D018281', (58, 89))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('intrahepatic cholangiocarcinoma', 'Disease', (58, 89))	('IDH1', 'Gene', '3417', (207, 211))	('convert alpha-KG', 'MPA', (281, 297))	('IDH2', 'Gene', (201, 205))	('cholangiocarcinoma', 'Phenotype', 'HP:0030153', (71, 89))	('IDH2', 'Gene', '3418', (201, 205))	('tumors', 'Phenotype', 'HP:0002664', (11, 17))	('IDH2', 'Gene', (218, 222))	('IDH2', 'Gene', '3418', (218, 222))	('missense mutations', 'Var', (124, 142))	('chondrosarcoma', 'Disease', (42, 56))	('chondrosarcoma', 'Disease', 'MESH:D002813', (42, 56))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('glioma', 'Disease', (29, 35))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (95, 112))	('result', 'Reg', (243, 249))	('IDH2', 'Gene', (232, 236))	('AML', 'Disease', 'MESH:D015470', (37, 40))	('tumors', 'Disease', (11, 17))	('AML', 'Phenotype', 'HP:0004808', (37, 40))	('IDH1', 'Gene', (192, 196))	('IDH1R123H', 'Gene', (207, 216))	('AML', 'Disease', (37, 40))	('glioma', 'Disease', 'MESH:D005910', (29, 35))	('IDH2', 'Gene', '3418', (232, 236))	('thyroid carcinoma', 'Disease', (95, 112))
531800	31221981	Nonetheless, the molecular mechanisms through which D-2HG promotes tumorigenesis remain poorly understood.	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('promotes', 'PosReg', (58, 66))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('D-2HG', 'Var', (52, 57))	('tumor', 'Disease', (67, 72))
531801	31221981	Since D-2HG is a competitive inhibitor of alpha-KG-dependent dioxygenases, such as histone-, DNA- and RNA demethylases, D-2HG may induce dysregulation of histone, DNA, and RNA methylation in various cancer cell lines.	('D-2HG', 'Var', (120, 125))	('RNA methylation', 'MPA', (172, 187))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('dysregulation', 'MPA', (137, 150))	('histone', 'Protein', (154, 161))	('cancer', 'Disease', 'MESH:D009369', (199, 205))	('oxygen', 'Chemical', 'MESH:D010100', (63, 69))	('cancer', 'Disease', (199, 205))	('induce', 'Reg', (130, 136))	('DNA', 'MPA', (163, 166))	('alpha-KG', 'Chemical', 'MESH:D007656', (42, 50))
531804	31221981	Under normal conditions, the D-2HG level remains low because of the catalytic activity of endogenous D-2HG dehydrogenase (D2HGDH), which catalyzes the conversion of D-2HG to alpha-KG; however, mutant IDHs produce excess D-2HG, which accumulates in patients with glioma and AML.	('glioma', 'Disease', (262, 268))	('D-2HG dehydrogenase', 'Gene', '728294', (101, 120))	('AML', 'Disease', 'MESH:D015470', (273, 276))	('D2HGDH', 'Gene', '728294', (122, 128))	('IDH', 'Gene', (200, 203))	('excess', 'PosReg', (213, 219))	('mutant', 'Var', (193, 199))	('AML', 'Disease', (273, 276))	('D-2HG dehydrogenase', 'Gene', (101, 120))	('glioma', 'Disease', 'MESH:D005910', (262, 268))	('IDH', 'Gene', '3417', (200, 203))	('alpha-KG', 'Chemical', 'MESH:D007656', (174, 182))	('D-2HG', 'MPA', (220, 225))	('AML', 'Phenotype', 'HP:0004808', (273, 276))	('glioma', 'Phenotype', 'HP:0009733', (262, 268))	('patients', 'Species', '9606', (248, 256))	('D2HGDH', 'Gene', (122, 128))
531805	31221981	Similar to D-2HG (or R-2HG), excessive L-2HG (or S-2HG), an enantiomer of D-2HG, can also inhibit numerous alpha-KG-dependent enzymes.	('inhibit', 'NegReg', (90, 97))	('L-2HG', 'Var', (39, 44))	('alpha-KG', 'Chemical', 'MESH:D007656', (107, 115))	('alpha-KG-dependent enzymes', 'Enzyme', (107, 133))
531811	31221981	Similar to D-2HG, L-2HG inhibits the Jumonji family histone lysine demethylase KDM4C, resulting in aberrant accumulation of trimethylated histone 3 lysine 9 (H3K9me3).	('lysine', 'Chemical', 'MESH:D008239', (148, 154))	('inhibits', 'NegReg', (24, 32))	('accumulation', 'PosReg', (108, 120))	('KDM4C', 'Gene', (79, 84))	('trimethylated histone', 'Chemical', '-', (124, 145))	('trimethylated histone 3 lysine 9', 'MPA', (124, 156))	('KDM4C', 'Gene', '23081', (79, 84))	('lysine', 'Chemical', 'MESH:D008239', (60, 66))	('L-2HG', 'Var', (18, 23))
531816	31221981	Consistent with this idea, the NADH/NAD ratio increases when mitochondrial respiration is impaired; limited 2-HG oxidation in hematopoietic stem cells increases the levels of 2-HG, which is accompanied by inhibition of DNA and histone demethylation, leading to increased hypermethylation of both DNA and histones.	('DNA', 'Protein', (296, 299))	('increased', 'PosReg', (261, 270))	('DNA', 'Protein', (219, 222))	('increases', 'PosReg', (151, 160))	('NAD', 'Chemical', 'MESH:D009243', (31, 34))	('inhibition', 'NegReg', (205, 215))	('levels of 2-HG', 'MPA', (165, 179))	('oxidation', 'Var', (113, 122))	('histones', 'Protein', (304, 312))	('-HG', 'Chemical', '-', (176, 179))	('NADH', 'Chemical', 'MESH:D009243', (31, 35))	('NAD', 'Chemical', 'MESH:D009243', (36, 39))	('-HG', 'Chemical', '-', (109, 112))	('hypermethylation', 'MPA', (271, 287))	('histone', 'Protein', (227, 234))
531817	31221981	Homozygous germline loss-of-function mutations in D2HGDH or L-2HG dehydrogenase (L2HGDH) increase the D-2HG or L-2HG levels, respectively, in both urine and blood.	('D2HGDH', 'Gene', '728294', (50, 56))	('L2HGDH', 'Gene', (81, 87))	('L-2HG dehydrogenase', 'Gene', (60, 79))	('L2HGDH', 'Gene', '79944', (81, 87))	('L-2HG levels', 'MPA', (111, 123))	('loss-of-function', 'NegReg', (20, 36))	('D-2HG', 'MPA', (102, 107))	('mutations', 'Var', (37, 46))	('D2HGDH', 'Gene', (50, 56))	('increase', 'PosReg', (89, 97))	('L-2HG dehydrogenase', 'Gene', '79944', (60, 79))
531818	31221981	Systemic L-2HG elevations arising from inherited L2HGDH mutations have been associated with brain tumors.	('elevations', 'PosReg', (15, 25))	('mutations', 'Var', (56, 65))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('brain tumors', 'Disease', 'MESH:D001932', (92, 104))	('brain tumors', 'Phenotype', 'HP:0030692', (92, 104))	('brain tumors', 'Disease', (92, 104))	('associated', 'Reg', (76, 86))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('Systemic L-2HG', 'MPA', (0, 14))	('L2HGDH', 'Gene', (49, 55))	('L2HGDH', 'Gene', '79944', (49, 55))
531834	31221981	Furthermore, mutations in IDH1 and 2 in several cancers result in high D-2HG levels.	('cancers', 'Disease', (48, 55))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('cancers', 'Phenotype', 'HP:0002664', (48, 55))	('D-2HG levels', 'MPA', (71, 83))	('mutations', 'Var', (13, 22))	('high', 'PosReg', (66, 70))	('cancers', 'Disease', 'MESH:D009369', (48, 55))	('IDH1 and 2', 'Gene', '3417;3418', (26, 36))
531837	31221981	(iii) What is the molecular mechanism through which changes in histone methylation influence tumor progression?	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Disease', (93, 98))	('influence', 'Reg', (83, 92))	('changes', 'Var', (52, 59))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
531840	31221981	TCGA predicted JARID1C/KDM5C as a tumor suppressor, mutations in which drive cancer progression (Table 1).	('mutations', 'Var', (52, 61))	('tumor', 'Disease', (34, 39))	('KDM5C', 'Gene', (23, 28))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('KDM5C', 'Gene', '8242', (23, 28))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('drive', 'Reg', (71, 76))
531846	31221981	The ARID domain in JARID1B recognizes the GCACA/C consensus motif, whereas the PHD1 domain binds only unmethylated H3K4; thus, JARID1B persists after demethylation and is involved in repressing target genes.	('JARID1B', 'Gene', '10765', (19, 26))	('JARID1B', 'Gene', (19, 26))	('JARID1B', 'Gene', '10765', (127, 134))	('ARID', 'Disease', (4, 8))	('JARID1B', 'Gene', (127, 134))	('ARID', 'Disease', (20, 24))	('demethylation', 'Var', (150, 163))	('ARID', 'Disease', (128, 132))	('ARID', 'Disease', 'None', (20, 24))	('ARID', 'Disease', 'None', (4, 8))	('ARID', 'Disease', 'None', (128, 132))
531850	31221981	Mutations in JARID1C are associated with short stature, hyperreflexia, and autism.	('autism', 'Disease', (75, 81))	('associated', 'Reg', (25, 35))	('autism', 'Phenotype', 'HP:0000717', (75, 81))	('hyperreflexia', 'Phenotype', 'HP:0001347', (56, 69))	('Mutations', 'Var', (0, 9))	('hyperreflexia', 'Gene', '7974', (56, 69))	('autism', 'Disease', 'MESH:D001321', (75, 81))	('short stature', 'Phenotype', 'HP:0004322', (41, 54))	('short stature', 'Disease', 'MESH:D006130', (41, 54))	('JARID1C', 'Gene', (13, 20))	('hyperreflexia', 'Gene', (56, 69))	('short stature', 'Disease', (41, 54))
531851	31221981	Mutations in JARID1C have been identified in many cancers, such as clear cell renal cell carcinoma (ccRCC), pancreatic cancer, and human papillomavirus (HPV)-associated cancer (Table 1).	('cancer', 'Disease', (169, 175))	('cancer', 'Disease', (50, 56))	('cancers', 'Phenotype', 'HP:0002664', (50, 57))	('cancers', 'Disease', (50, 57))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('human papillomavirus', 'Disease', (131, 151))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (67, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('cancer', 'Disease', (119, 125))	('Mutations', 'Var', (0, 9))	('pancreatic cancer', 'Disease', 'MESH:D010190', (108, 125))	('human papillomavirus', 'Species', '10566', (131, 151))	('cancer', 'Disease', 'MESH:D009369', (169, 175))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('identified', 'Reg', (31, 41))	('cancers', 'Disease', 'MESH:D009369', (50, 57))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (67, 98))	('pancreatic cancer', 'Disease', (108, 125))	('HPV', 'Species', '10566', (153, 156))	('JARID1C', 'Gene', (13, 20))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('clear cell renal cell carcinoma', 'Disease', (67, 98))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (78, 98))	('ccRCC', 'Phenotype', 'HP:0006770', (100, 105))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (108, 125))
531855	31221981	In 786-O VHL-/- ccRCC cells, JARID1C knockdown significantly enhanced tumor growth in a xenograft mouse model, showing that JARID1C is a tumor suppressor and that its inactivating mutations in ccRCC promote tumors.	('knockdown', 'Var', (37, 46))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('tumors', 'Disease', (207, 213))	('ccRCC', 'Phenotype', 'HP:0006770', (193, 198))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('promote', 'PosReg', (199, 206))	('ccRCC', 'Gene', (193, 198))	('inactivating mutations', 'Var', (167, 189))	('tumors', 'Disease', 'MESH:D009369', (207, 213))	('VHL', 'Disease', (9, 12))	('ccRCC', 'Phenotype', 'HP:0006770', (16, 21))	('tumor', 'Disease', (137, 142))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('mouse', 'Species', '10090', (98, 103))	('tumor', 'Disease', (207, 212))	('enhanced', 'PosReg', (61, 69))	('tumor', 'Disease', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('JARID1C', 'Gene', (29, 36))	('VHL', 'Disease', 'MESH:D006623', (9, 12))	('tumors', 'Phenotype', 'HP:0002664', (207, 213))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
531856	31221981	Whole-exome sequencing of human pancreatic cancers identified truncating insertions and deletion mutations in JARID1C.	('truncating insertions', 'Var', (62, 83))	('JARID1C', 'Gene', (110, 117))	('deletion mutations', 'Var', (88, 106))	('pancreatic cancers', 'Disease', (32, 50))	('pancreatic cancers', 'Disease', 'MESH:D010190', (32, 50))	('cancers', 'Phenotype', 'HP:0002664', (43, 50))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (32, 49))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('pancreatic cancers', 'Phenotype', 'HP:0002894', (32, 50))	('human', 'Species', '9606', (26, 31))
531859	31221981	JARID1C knockdown increased the expression levels of the E6 and E7 oncogenes, suggesting that JARID1C can function as a tumor suppressor in HPV-associated cancers.	('increased', 'PosReg', (18, 27))	('JARID1C', 'Gene', (94, 101))	('knockdown', 'Var', (8, 17))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('cancers', 'Phenotype', 'HP:0002664', (155, 162))	('cancers', 'Disease', (155, 162))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('cancers', 'Disease', 'MESH:D009369', (155, 162))	('expression levels', 'MPA', (32, 49))	('JARID1C', 'Gene', (0, 7))	('tumor', 'Disease', (120, 125))	('HPV', 'Species', '10566', (140, 143))
531863	31221981	In ccRCC cells, JARID1C inactivation failed to reduce H3K4me3 at heterochromatic regions, preventing Suv38H1 H3K9 methyl transferase and HP1a from binding to heterochromatin.	('Suv38H1', 'Var', (101, 108))	('binding', 'Interaction', (147, 154))	('preventing', 'NegReg', (90, 100))	('inactivation', 'Var', (24, 36))	('ccRCC', 'Phenotype', 'HP:0006770', (3, 8))	('H3K4me3', 'Protein', (54, 61))	('H3K9 methyl transferase', 'Enzyme', (109, 132))	('HP1a', 'Gene', (137, 141))	('HP1a', 'Gene', '23468', (137, 141))
531877	31221981	JARID1D was considered a tumor suppressor because of its downregulation, mutation, or loss in prostate cancer and ccRCC.	('downregulation', 'NegReg', (57, 71))	('JARID1D', 'Gene', (0, 7))	('ccRCC', 'Disease', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('loss in prostate cancer', 'Disease', 'MESH:D011471', (86, 109))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('tumor', 'Disease', (25, 30))	('JARID1D', 'Gene', '8284', (0, 7))	('prostate cancer', 'Phenotype', 'HP:0012125', (94, 109))	('ccRCC', 'Phenotype', 'HP:0006770', (114, 119))	('loss in prostate cancer', 'Disease', (86, 109))	('mutation', 'Var', (73, 81))	('tumor', 'Disease', 'MESH:D009369', (25, 30))
531882	31221981	Unlike JARID1B, JARID1A knockdown altered H3K4 methylation, resulting in inhibition of proliferation and reduced drug resistance, which is suggestive of the oncogenic roles of JARID1A in breast cancer.	('altered', 'Reg', (34, 41))	('inhibition', 'NegReg', (73, 83))	('proliferation', 'CPA', (87, 100))	('JARID1A', 'Gene', '214899', (176, 183))	('reduced', 'NegReg', (105, 112))	('JARID1A', 'Gene', '214899', (16, 23))	('JARID1B', 'Gene', (7, 14))	('JARID1B', 'Gene', '10765', (7, 14))	('drug resistance', 'MPA', (113, 128))	('drug resistance', 'Phenotype', 'HP:0020174', (113, 128))	('breast cancer', 'Phenotype', 'HP:0003002', (187, 200))	('breast cancer', 'Disease', 'MESH:D001943', (187, 200))	('knockdown', 'Var', (24, 33))	('JARID1A', 'Gene', (176, 183))	('breast cancer', 'Disease', (187, 200))	('JARID1A', 'Gene', (16, 23))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('H3K4', 'Protein', (42, 46))	('methylation', 'MPA', (47, 58))
531883	31221981	(2009) reported that fusion of the C-terminal PHD domain of JARID1A/PHF23 to nucleoporin-98 generated potent oncoproteins in human leukemia.	('PHF23', 'Gene', (68, 73))	('JARID1A', 'Gene', (60, 67))	('nucleoporin-98', 'Gene', (77, 91))	('oncoproteins', 'MPA', (109, 121))	('human', 'Species', '9606', (125, 130))	('fusion', 'Var', (21, 27))	('PHF23', 'Gene', '79142', (68, 73))	('leukemia', 'Phenotype', 'HP:0001909', (131, 139))	('leukemia', 'Disease', 'MESH:D007938', (131, 139))	('leukemia', 'Disease', (131, 139))	('JARID1A', 'Gene', '214899', (60, 67))	('nucleoporin-98', 'Gene', '4928', (77, 91))
531885	31221981	showed that loss of JARID1A/RBP2 promotes senescence and inhibits proliferation in a histone demethylase activity- and Rb-dependent manner in mouse embryonic fibroblasts (MEFs).	('promotes', 'PosReg', (33, 41))	('MEFs', 'CellLine', 'CVCL:9115', (171, 175))	('Rb', 'Chemical', 'MESH:D012413', (119, 121))	('proliferation', 'CPA', (66, 79))	('mouse', 'Species', '10090', (142, 147))	('JARID1A', 'Gene', '214899', (20, 27))	('loss', 'Var', (12, 16))	('JARID1A', 'Gene', (20, 27))	('senescence', 'CPA', (42, 52))	('inhibits', 'NegReg', (57, 65))
531888	31221981	Similarly, JARID1A depletion inhibits proliferation, migration, invasion, and metastasis of lung cancer, suggesting oncogenic roles of JARID1A in lung tumorigenesis and progression.	('lung cancer', 'Phenotype', 'HP:0100526', (92, 103))	('depletion', 'Var', (19, 28))	('proliferation', 'CPA', (38, 51))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('JARID1A', 'Gene', (135, 142))	('invasion', 'CPA', (64, 72))	('metastasis of lung cancer', 'Disease', 'MESH:D009362', (78, 103))	('tumor', 'Disease', (151, 156))	('JARID1A', 'Gene', '214899', (11, 18))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('migration', 'CPA', (53, 62))	('metastasis of lung cancer', 'Disease', (78, 103))	('inhibits', 'NegReg', (29, 37))	('JARID1A', 'Gene', (11, 18))	('JARID1A', 'Gene', '214899', (135, 142))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
531893	31221981	JARID1B knockdown leads to an initial acceleration of tumor growth, followed by exhaustion.	('acceleration', 'PosReg', (38, 50))	('JARID1B', 'Gene', '10765', (0, 7))	('knockdown', 'Var', (8, 17))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('JARID1B', 'Gene', (0, 7))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumor', 'Disease', (54, 59))
531901	31221981	Two functional isoforms, ubiquitously transcribed tetratricopeptide repeats on the X chromosome (UTX)/KDM6A and JMJD3/KDM6B, have been identified as H3K27me3-, me2- and, me1-specific histone demethylases.	('KDM6A', 'Gene', (102, 107))	('me1', 'Gene', (170, 173))	('me1', 'Gene', '4199', (170, 173))	('me2', 'Gene', (160, 163))	('JMJD3', 'Gene', (112, 117))	('KDM6A', 'Gene', '7403', (102, 107))	('KDM6B', 'Gene', '23135', (118, 123))	('JMJD3', 'Gene', '23135', (112, 117))	('H3K27me3-', 'Var', (149, 158))	('KDM6B', 'Gene', (118, 123))	('me2', 'Gene', '4200', (160, 163))
531902	31221981	This escape from X-inactivation contributes to sex bias in many tumors, as a single mutation in UTX is sufficient for its loss of function in males but not in females.	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('sex bias in many tumors', 'Disease', 'MESH:D012735', (47, 70))	('sex bias in many tumors', 'Disease', (47, 70))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('contributes', 'Reg', (32, 43))	('UTX', 'Gene', (96, 99))	('mutation', 'Var', (84, 92))
531903	31221981	The UTX paralog, Y chromosome-linked UTY, is inactive due to a mutation in the JmjC domain.	('JmjC', 'Gene', (79, 83))	('UTY', 'Gene', '7404', (37, 40))	('mutation in', 'Var', (63, 74))	('UTY', 'Gene', (37, 40))
531906	31221981	UTX/KDM6A has been identified as a cancer driver gene via TCGA, as its loss or inactivation promotes several malignancies.	('KDM6A', 'Gene', (4, 9))	('promotes', 'PosReg', (92, 100))	('malignancies', 'Disease', (109, 121))	('inactivation', 'Var', (79, 91))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('KDM6A', 'Gene', '7403', (4, 9))	('loss', 'NegReg', (71, 75))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('malignancies', 'Disease', 'MESH:D009369', (109, 121))	('TCGA', 'Gene', (58, 62))	('cancer', 'Disease', (35, 41))
531913	31221981	Due to its H3K27me3, me2, and me1 demethylase activities, loss of UTX increases the H3K27me3 level at its target genes.	('UTX', 'Gene', (66, 69))	('loss', 'Var', (58, 62))	('me1', 'Gene', (30, 33))	('me1', 'Gene', '4199', (30, 33))	('me2', 'Gene', '4200', (21, 24))	('increases', 'PosReg', (70, 79))	('H3K27me3', 'Enzyme', (11, 19))	('H3K27me3 level', 'MPA', (84, 98))	('activities', 'MPA', (46, 56))	('me2', 'Gene', (21, 24))
531914	31221981	Several studies showed that loss of UTX represses a certain subset of genes by increasing the levels of the repressive H3K27me3 mark, ultimately promoting proliferation, clonogenicity, adhesion, and tumorigenicity in myeloid, bladder, and lung transformation.	('tumor', 'Disease', (199, 204))	('myeloid', 'Disease', (217, 224))	('loss', 'Var', (28, 32))	('bladder', 'CPA', (226, 233))	('H3K27me3', 'Protein', (119, 127))	('proliferation', 'CPA', (155, 168))	('promoting', 'PosReg', (145, 154))	('increasing', 'PosReg', (79, 89))	('UTX', 'Gene', (36, 39))	('lung transformation', 'CPA', (239, 258))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('clonogenicity', 'CPA', (170, 183))	('levels of', 'MPA', (94, 103))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('adhesion', 'CPA', (185, 193))
531915	31221981	Upon loss of the UTX demethylases, H3K27 methyl transferases, such as PRC2/EZH2, determine the levels of H3K27me3 on the UTX-EZH2 target genes.	('EZH2', 'Gene', (75, 79))	('H3K27me3', 'Var', (105, 113))	('EZH2', 'Gene', '2146', (125, 129))	('loss', 'NegReg', (5, 9))	('levels', 'MPA', (95, 101))	('EZH2', 'Gene', (125, 129))	('EZH2', 'Gene', '2146', (75, 79))
531916	31221981	Consistently, loss of UTX increases cellular sensitivity to EZH2 inhibition.	('EZH2', 'Gene', (60, 64))	('loss', 'Var', (14, 18))	('UTX', 'Protein', (22, 25))	('increases', 'PosReg', (26, 35))	('EZH2', 'Gene', '2146', (60, 64))
531918	31221981	In UTX/KDM6A-mutated urothelial bladder carcinoma, PRC2/EZH2 target genes, such as IGFBP3, are deregulated due to H3K27me3 enrichment.	('KDM6A', 'Gene', (7, 12))	('deregulated', 'PosReg', (95, 106))	('IGFBP3', 'Gene', (83, 89))	('urothelial bladder carcinoma', 'Disease', 'MESH:D001749', (21, 49))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (32, 49))	('KDM6A', 'Gene', '7403', (7, 12))	('EZH2', 'Gene', '2146', (56, 60))	('carcinoma', 'Phenotype', 'HP:0030731', (40, 49))	('H3K27me3 enrichment', 'Var', (114, 133))	('IGFBP3', 'Gene', '3486', (83, 89))	('EZH2', 'Gene', (56, 60))	('urothelial bladder carcinoma', 'Disease', (21, 49))
531921	31221981	EZH2 inhibition also restored the normal gene expression patterns and impaired the proliferation of tumor cells harboring mutations in an H3K4 methyltransferase, MLL3/KMT2C, or a tumor suppressor, BAP1, by rebalancing the H3K27me3 levels at MLL3/BAP1 target genes.	('tumor', 'Disease', (100, 105))	('tumor', 'Disease', 'MESH:D009369', (179, 184))	('BAP1', 'Gene', '8314', (246, 250))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('EZH2', 'Gene', '2146', (0, 4))	('EZH2', 'Gene', (0, 4))	('MLL3', 'Gene', '58508', (162, 166))	('KMT2C', 'Gene', '58508', (167, 172))	('KMT2C', 'Gene', (167, 172))	('BAP1', 'Gene', '8314', (197, 201))	('tumor', 'Phenotype', 'HP:0002664', (179, 184))	('BAP1', 'Gene', (246, 250))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('normal gene expression patterns', 'MPA', (34, 65))	('proliferation', 'CPA', (83, 96))	('restored', 'PosReg', (21, 29))	('MLL3', 'Gene', '58508', (241, 245))	('MLL3', 'Gene', (162, 166))	('H3K4 methyltransferase', 'Enzyme', (138, 160))	('impaired', 'NegReg', (70, 78))	('BAP1', 'Gene', (197, 201))	('H3K27me3 levels', 'MPA', (222, 237))	('rebalancing', 'Reg', (206, 217))	('mutations', 'Var', (122, 131))	('MLL3', 'Gene', (241, 245))	('tumor', 'Disease', (179, 184))
531922	31221981	In a range of human tumor types, a cancer-associated mutational hotspot was detected in the PHD domain of MLL3, which mediates association with BAP1.	('association', 'Interaction', (127, 138))	('human', 'Species', '9606', (14, 19))	('MLL3', 'Gene', (106, 110))	('BAP1', 'Gene', (144, 148))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('mutational', 'Var', (53, 63))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('MLL3', 'Gene', '58508', (106, 110))	('cancer', 'Disease', (35, 41))	('tumor', 'Disease', (20, 25))	('BAP1', 'Gene', '8314', (144, 148))
531923	31221981	Cancer cells that harbored mutations in the PHD domain of MLL3 or lacked BAP1 showed reduced recruitment of UTX/KDM6A to gene enhancers, with no reduction in the levels of the repressive H3K27me3 mark.	('MLL3', 'Gene', '58508', (58, 62))	('KDM6A', 'Gene', '7403', (112, 117))	('BAP1', 'Gene', '8314', (73, 77))	('recruitment', 'MPA', (93, 104))	('BAP1', 'Gene', (73, 77))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('MLL3', 'Gene', (58, 62))	('lacked', 'NegReg', (66, 72))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('mutations in', 'Var', (27, 39))	('reduced', 'NegReg', (85, 92))	('KDM6A', 'Gene', (112, 117))
531924	31221981	Thus, in cancer cells with MLL3 or BAP1 mutations, reduction of H3K27me3 via EZH2 inhibitors can restore the balance of H3K27me3 at enhancers where UTX is not properly recruited.	('H3K27me3', 'Protein', (64, 72))	('EZH2', 'Gene', (77, 81))	('cancer', 'Disease', (9, 15))	('reduction', 'NegReg', (51, 60))	('MLL3', 'Gene', '58508', (27, 31))	('EZH2', 'Gene', '2146', (77, 81))	('BAP1', 'Gene', '8314', (35, 39))	('MLL3', 'Gene', (27, 31))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('mutations', 'Var', (40, 49))	('BAP1', 'Gene', (35, 39))	('restore', 'PosReg', (97, 104))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('balance of H3K27me3', 'MPA', (109, 128))
531927	31221981	However, other studies showed that in certain types of cancer, an inactive UTX paralog is required for tumor development in males concomitant with loss of UTY and that the UTX-UTY double-knockout cells exhibited higher proliferation than the single-knockout cells, suggesting demethylase-independent tumor suppressor functions of UTX/KDM6A and UTY.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('UTY', 'Gene', '7404', (155, 158))	('tumor', 'Phenotype', 'HP:0002664', (300, 305))	('KDM6A', 'Gene', (334, 339))	('higher', 'PosReg', (212, 218))	('UTY', 'Gene', '7404', (344, 347))	('UTY', 'Gene', (155, 158))	('loss', 'Var', (147, 151))	('cancer', 'Disease', (55, 61))	('proliferation', 'CPA', (219, 232))	('tumor', 'Disease', (103, 108))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('UTY', 'Gene', '7404', (176, 179))	('UTY', 'Gene', (344, 347))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('tumor', 'Disease', (300, 305))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('tumor', 'Disease', 'MESH:D009369', (300, 305))	('KDM6A', 'Gene', '7403', (334, 339))	('UTY', 'Gene', (176, 179))
531928	31221981	Several studies showed that UTX is essential for the establishment of the active enhancer histone marks H3K4me1 and H3K27ac in a demethylase activity-independent manner via recruitment and coupling of an H3K4 methyltransferase complex (named COMPASS) and the histone acetyl transferase p300.	('p300', 'Gene', '2033', (286, 290))	('coupling', 'Interaction', (189, 197))	('enhancer', 'PosReg', (81, 89))	('p300', 'Gene', (286, 290))	('me1', 'Gene', '4199', (108, 111))	('me1', 'Gene', (108, 111))	('H3K27ac', 'Var', (116, 123))
531929	31221981	In embryonic stem cells, loss of UTX reduced the levels of H3K4me1/H3K27ac at enhancers and transcription.	('loss', 'Var', (25, 29))	('UTX', 'Protein', (33, 36))	('me1', 'Gene', '4199', (63, 66))	('reduced', 'NegReg', (37, 44))	('levels of', 'MPA', (49, 58))	('me1', 'Gene', (63, 66))
531932	31221981	Similarly, in many cancers and other diseases, enhancer-associated chromatin-modifying components, such as UTX and members of H3K4 methyltransferase complexes, are frequently mutated, leading to enhancer malfunction.	('cancers', 'Phenotype', 'HP:0002664', (19, 26))	('enhancer-associated', 'PosReg', (47, 66))	('cancers', 'Disease', (19, 26))	('cancers', 'Disease', 'MESH:D009369', (19, 26))	('enhancer malfunction', 'MPA', (195, 215))	('UTX', 'Disease', (107, 110))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('mutated', 'Var', (175, 182))
531933	31221981	In pancreatic cancer, loss of UTX causes aberrant activation of superenhancers that regulate oncogenes (such as Delta-Np63, MYC, and RUNX3) to drive an aggressive subtype of squamous-like pancreatic cancer.	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('Delta-Np63', 'Gene', (112, 122))	('pancreatic cancer', 'Disease', (3, 20))	('pancreatic cancer', 'Disease', 'MESH:D010190', (3, 20))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (188, 205))	('MYC', 'Gene', (124, 127))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('drive', 'PosReg', (143, 148))	('activation', 'PosReg', (50, 60))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (3, 20))	('UTX', 'Gene', (30, 33))	('RUNX3', 'Gene', (133, 138))	('RUNX3', 'Gene', '864', (133, 138))	('MYC', 'Gene', '4609', (124, 127))	('pancreatic cancer', 'Disease', (188, 205))	('loss', 'Var', (22, 26))	('pancreatic cancer', 'Disease', 'MESH:D010190', (188, 205))
531939	31221981	These findings suggest that loss of UTX contributes to drive tumor progression via repositioning of histone modification enzymes.	('loss', 'Var', (28, 32))	('histone modification enzymes', 'Enzyme', (100, 128))	('UTX', 'Gene', (36, 39))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('repositioning', 'Reg', (83, 96))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('drive', 'PosReg', (55, 60))	('tumor', 'Disease', (61, 66))
531946	31221981	Specific methylation of the K810 residue of Rb facilitates its interaction with CDK4 protein kinase.	('methylation', 'Var', (9, 20))	('CDK4', 'Gene', (80, 84))	('facilitates', 'PosReg', (47, 58))	('CDK4', 'Gene', '1019', (80, 84))	('K810', 'Var', (28, 32))	('Rb', 'Chemical', 'MESH:D012413', (44, 46))	('interaction', 'Interaction', (63, 74))	('K810', 'Chemical', '-', (28, 32))
531947	31221981	JMJD3 demethylates the K810 residue of Rb, which prevents CDK4 from phosphorylating the S807 and S811 residues of Rb in senescent cells.	('CDK4', 'Gene', '1019', (58, 62))	('K810', 'Chemical', '-', (23, 27))	('S807', 'Var', (88, 92))	('JMJD3', 'Gene', (0, 5))	('prevents', 'NegReg', (49, 57))	('S811 residues', 'Var', (97, 110))	('K810', 'Var', (23, 27))	('Rb', 'Chemical', 'MESH:D012413', (114, 116))	('phosphorylating', 'MPA', (68, 83))	('CDK4', 'Gene', (58, 62))	('JMJD3', 'Gene', '23135', (0, 5))	('Rb', 'Chemical', 'MESH:D012413', (39, 41))
531951	31221981	p53 increases the nuclear localization of JMJD3 via protein-protein interaction and recruits JMJD3 to its target genes, such as that encoding p21, where it demethylates the H3K27me3 repressive mark.	('p53', 'Gene', (0, 3))	('increases', 'PosReg', (4, 13))	('H3K27me3', 'Protein', (173, 181))	('p53', 'Gene', '7157', (0, 3))	('JMJD3', 'Gene', '23135', (93, 98))	('p21', 'Gene', '1026', (142, 145))	('JMJD3', 'Gene', '23135', (42, 47))	('nuclear localization', 'MPA', (18, 38))	('recruits', 'PosReg', (84, 92))	('p21', 'Gene', (142, 145))	('protein-protein', 'Protein', (52, 67))	('JMJD3', 'Gene', (42, 47))	('JMJD3', 'Gene', (93, 98))	('demethylates', 'Var', (156, 168))
531957	31221981	Loss of JMJD3 heterozygosity at chromosome 17p13.1 increased the aggressiveness of pancreatic ductal adenocarcinoma.	('increased', 'PosReg', (51, 60))	('JMJD3', 'Gene', (8, 13))	('JMJD3', 'Gene', '23135', (8, 13))	('aggressiveness of pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (65, 115))	('Loss', 'NegReg', (0, 4))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('heterozygosity', 'Var', (14, 28))	('aggressiveness of pancreatic ductal adenocarcinoma', 'Disease', (65, 115))	('aggressiveness', 'Phenotype', 'HP:0000718', (65, 79))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (83, 115))
531964	31221981	For example, the absence of JMJD3 is permissive for cell division under senescence stimuli in tumors that express senescence effectors such as p16, p53, and Rb, indicating that JMJD3 functions as a tumor suppressor.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('JMJD3', 'Gene', '23135', (28, 33))	('absence', 'Var', (17, 24))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('JMJD3', 'Gene', (28, 33))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('Rb', 'Chemical', 'MESH:D012413', (157, 159))	('JMJD3', 'Gene', '23135', (177, 182))	('tumors', 'Disease', (94, 100))	('JMJD3', 'Gene', (177, 182))	('p16', 'Gene', (143, 146))	('p53', 'Gene', '7157', (148, 151))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('tumor', 'Disease', (198, 203))	('p16', 'Gene', '1029', (143, 146))	('p53', 'Gene', (148, 151))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('tumor', 'Disease', (94, 99))
531969	31221981	Therefore, an increase in the robustness of the SASP due to JMJD3 reactivation might trigger both cellular senescence and immune responses.	('reactivation', 'Var', (66, 78))	('robustness', 'MPA', (30, 40))	('immune responses', 'CPA', (122, 138))	('trigger', 'Reg', (85, 92))	('SASP', 'Gene', (48, 52))	('SASP', 'Gene', '7295', (48, 52))	('cellular senescence', 'CPA', (98, 117))	('JMJD3', 'Gene', (60, 65))	('JMJD3', 'Gene', '23135', (60, 65))	('increase', 'PosReg', (14, 22))
531970	31221981	Conversely, JMJD3 reactivation might facilitate the recruitment of stem cells to tumors to replace old damaged cells, leading to tumor progression.	('tumors', 'Disease', (81, 87))	('leading to', 'Reg', (118, 128))	('tumors', 'Disease', 'MESH:D009369', (81, 87))	('JMJD3', 'Gene', (12, 17))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('JMJD3', 'Gene', '23135', (12, 17))	('facilitate', 'PosReg', (37, 47))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('recruitment', 'CPA', (52, 63))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Disease', (129, 134))	('reactivation', 'Var', (18, 30))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('tumor', 'Disease', (81, 86))
531977	31221981	A better understanding of the molecular mechanisms through which mutations in histone demethylases promote epigenetic plasticity to drive cancer progression will guide precision therapeutic strategies for the selection of histone demethylase and methyl-transferase inhibitors.	('drive', 'PosReg', (132, 137))	('cancer', 'Disease', (138, 144))	('promote', 'PosReg', (99, 106))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('epigenetic plasticity', 'MPA', (107, 128))	('cancer', 'Disease', 'MESH:D009369', (138, 144))	('mutations', 'Var', (65, 74))
531998	28515486	GSE40791 included 94 lung adenocarcinoma frozen tissues (53 derived from males, 41 derived from females) and 100 non-neoplastic lung samples (58 derived from males, 42 derived from females) (Supplementary Table S1).	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (21, 40))	('neoplastic lung', 'Phenotype', 'HP:0100526', (117, 132))	('men', 'Species', '9606', (197, 200))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (21, 40))	('lung adenocarcinoma', 'Disease', (21, 40))	('carcinoma', 'Phenotype', 'HP:0030731', (31, 40))	('GSE40791', 'Var', (0, 8))
532033	28515486	Unfortunately, TCF21 expression is commonly deregulated by promoter hypermethylation in different types of cancer.	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('deregulated', 'PosReg', (44, 55))	('expression', 'MPA', (21, 31))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('TCF21', 'Gene', (15, 20))	('promoter hypermethylation', 'Var', (59, 84))	('cancer', 'Disease', (107, 113))
532035	28515486	Study reported that TCF21 promoter methylation is correlated with decreased survival in patients with metastatic skin melanoma.	('melanoma', 'Phenotype', 'HP:0002861', (118, 126))	('TCF21', 'Gene', (20, 25))	('skin melanoma', 'Disease', (113, 126))	('survival', 'MPA', (76, 84))	('decreased', 'NegReg', (66, 75))	('patients', 'Species', '9606', (88, 96))	('methylation', 'Var', (35, 46))	('skin melanoma', 'Disease', 'MESH:D008545', (113, 126))
532037	28515486	For lung cancer, previous studies demonstrated that aberrant TCF21 promoter methylation existed in 9 of 10 lung cancer cell lines and the majority of lung cancer tissues (70-81%).	('TCF21', 'Gene', (61, 66))	('lung cancer', 'Phenotype', 'HP:0100526', (150, 161))	('lung cancer', 'Disease', (150, 161))	('lung cancer', 'Disease', 'MESH:D008175', (107, 118))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('lung cancer', 'Disease', (4, 15))	('lung cancer', 'Disease', 'MESH:D008175', (150, 161))	('lung cancer', 'Phenotype', 'HP:0100526', (4, 15))	('aberrant', 'Var', (52, 60))	('methylation', 'Var', (76, 87))	('lung cancer', 'Disease', (107, 118))	('promoter', 'MPA', (67, 75))	('lung cancer', 'Phenotype', 'HP:0100526', (107, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('lung cancer', 'Disease', 'MESH:D008175', (4, 15))
532043	28515486	We know that TCF21 is a crucial tumor suppressor, and TCF21 expression is commonly deregulated by aberrant promoter methylation in different types of cancer.	('expression', 'MPA', (60, 70))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('crucial tumor', 'Disease', 'MESH:D009369', (24, 37))	('crucial tumor', 'Disease', (24, 37))	('cancer', 'Disease', (150, 156))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('aberrant promoter methylation', 'Var', (98, 127))	('deregulated', 'PosReg', (83, 94))	('TCF21', 'Gene', (54, 59))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))
532138	24903567	Furthermore, infiltration by lymphocytes has been described in numerous human tumours, the presence of such cell often being associated with an improved prognosis  that these observations are in agreement with our study.	('tumours', 'Phenotype', 'HP:0002664', (78, 85))	('improved', 'PosReg', (144, 152))	('presence', 'Var', (91, 99))	('numerous human tumours', 'Disease', (63, 85))	('numerous human tumours', 'Disease', 'MESH:D009369', (63, 85))	('tumour', 'Phenotype', 'HP:0002664', (78, 84))
532152	33202377	Colon cancer-specific diagnostic and prognostic biomarkers based on genome-wide abnormal DNA methylation Abnormal DNA methylation is a major early contributor to colon cancer (COAD) development.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('men', 'Species', '9606', (189, 192))	('Colon cancer', 'Phenotype', 'HP:0003003', (0, 12))	('colon cancer', 'Disease', (162, 174))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('Colon cancer', 'Disease', (0, 12))	('abnormal', 'Var', (80, 88))	('Colon cancer', 'Disease', 'MESH:D015179', (0, 12))	('colon cancer', 'Phenotype', 'HP:0003003', (162, 174))	('colon cancer', 'Disease', 'MESH:D015179', (162, 174))
532163	33202377	Epigenetic modifications such as DNA methylation, genomic imprinting and RNA editing alter multiple signaling pathways during the development and progression of COAD.	('men', 'Species', '9606', (137, 140))	('RNA', 'Gene', (73, 76))	('alter', 'Reg', (85, 90))	('Epigenetic modifications', 'Var', (0, 24))
532170	33202377	reported that patients with greater methylation of a COAD biomarker group had a worse prognosis, although the difference was not dramatic in multivariate analysis.	('greater', 'PosReg', (28, 35))	('patients', 'Species', '9606', (14, 22))	('methylation', 'Var', (36, 47))
532186	33202377	When we analyzed the distance between these DMPs and promoter regions, we found that DMPs in or near promoter regions (i.e., in the 1st Exon, 5' UTR, TSS200 or TSS1500) were negatively associated with mRNA expression, whereas those outside promoter regions (i.e., in the Body or 3' UTR) were positively associated with gene expression.	('TSS200', 'Var', (150, 156))	('TSS1500', 'Var', (160, 167))	('DMPs', 'Chemical', 'MESH:D014494', (44, 48))	('DMPs', 'Chemical', 'MESH:D014494', (85, 89))	('negatively', 'NegReg', (174, 184))	('mRNA expression', 'MPA', (201, 216))
532189	33202377	Next, in order to construct a diagnostic model to distinguish COAD tumor tissues from normal intestinal epithelial tissues and the tumor tissues of nine other cancer types (BLCA, BRCA, CESC, glioblastoma [GBM], head and neck cancer [HNSC], liver cancer [LIHC], lung adenocarcinoma [LUAD], lung squamous cell carcinoma [LUSC] and endometrial cancer [UCEC]), we performed conditional screening and machine learning studies based on the genome-wide DMPs obtained from TCGA above (13716 Hyper-DMPs and 11403 Hypo-DMPs).	('BLCA', 'Phenotype', 'HP:0009725', (173, 177))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (261, 280))	('cancer', 'Disease', (225, 231))	('DMPs', 'Chemical', 'MESH:D014494', (489, 493))	('tumor', 'Disease', (131, 136))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (289, 317))	('lung squamous cell carcinoma', 'Disease', (289, 317))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (294, 317))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (261, 280))	('head and neck cancer', 'Phenotype', 'HP:0012288', (211, 231))	('tumor', 'Disease', (67, 72))	('neck cancer', 'Disease', 'MESH:D006258', (220, 231))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('cancer', 'Disease', (341, 347))	('carcinoma', 'Phenotype', 'HP:0030731', (271, 280))	('cancer', 'Disease', (159, 165))	('neck cancer', 'Disease', (220, 231))	('BRCA', 'Gene', '672', (179, 183))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('cancer', 'Disease', (246, 252))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('liver cancer', 'Disease', 'MESH:D006528', (240, 252))	('cancer', 'Phenotype', 'HP:0002664', (341, 347))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('carcinoma', 'Phenotype', 'HP:0030731', (308, 317))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))	('13716', 'Var', (477, 482))	('glioblastoma', 'Disease', 'MESH:D005909', (191, 203))	('DMPs', 'Chemical', 'MESH:D014494', (446, 450))	('endometrial cancer', 'Phenotype', 'HP:0012114', (329, 347))	('BRCA', 'Gene', (179, 183))	('DMPs', 'Chemical', 'MESH:D014494', (509, 513))	('cancer', 'Disease', 'MESH:D009369', (225, 231))	('liver cancer', 'Phenotype', 'HP:0002896', (240, 252))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('liver cancer', 'Disease', (240, 252))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('cancer', 'Disease', 'MESH:D009369', (341, 347))	('glioblastoma', 'Disease', (191, 203))	('endometrial cancer', 'Disease', (329, 347))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('COAD tumor', 'Disease', (62, 72))	('lung adenocarcinoma', 'Disease', (261, 280))	('cancer', 'Disease', 'MESH:D009369', (246, 252))	('glioblastoma', 'Phenotype', 'HP:0012174', (191, 203))	('endometrial cancer', 'Disease', 'MESH:D016889', (329, 347))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (289, 317))	('BRCA', 'Phenotype', 'HP:0003002', (179, 183))	('COAD tumor', 'Disease', 'MESH:D029424', (62, 72))
532194	33202377	As potential diagnostic biomarkers, nine Hyper-DMPs (cg26036626, cg03882585, cg08130988, cg16733654, cg12587766, cg08808128, cg13004587, cg05038216 and cg09746736) and one Hypo-DMP (cg26718707) were selected to construct a COAD-specific diagnostic model (Table 1).	('cg12587766', 'Var', (101, 111))	('cg16733654', 'Var', (89, 99))	('cg26718707', 'Chemical', '-', (182, 192))	('cg08808128', 'Chemical', '-', (113, 123))	('cg08130988', 'Chemical', '-', (77, 87))	('cg26036626', 'Chemical', '-', (53, 63))	('cg26036626', 'Var', (53, 63))	('cg16733654', 'Chemical', '-', (89, 99))	('cg12587766', 'Chemical', '-', (101, 111))	('cg08808128', 'Var', (113, 123))	('cg13004587', 'Var', (125, 135))	('cg08130988', 'Var', (77, 87))	('cg03882585', 'Chemical', '-', (65, 75))	('cg05038216', 'Var', (137, 147))	('Hypo-DMP', 'Chemical', '-', (172, 180))	('cg09746736', 'Var', (152, 162))	('cg13004587', 'Chemical', '-', (125, 135))	('cg03882585', 'Var', (65, 75))
532197	33202377	The COAD tumor samples were significantly differentiated from all the normal samples and the tumor samples from the nine other cancer types based on the nine Hyper-DMPs and one Hypo-DMP.	('Hypo-DMP', 'Chemical', '-', (177, 185))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('tumor', 'Disease', (93, 98))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('tumor', 'Disease', (9, 14))	('cancer', 'Disease', (127, 133))	('COAD tumor', 'Disease', (4, 14))	('Hyper-DMPs', 'Var', (158, 168))	('COAD tumor', 'Disease', 'MESH:D029424', (4, 14))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
532201	33202377	In addition, we used the five independent GEO COAD cohorts mentioned above (GSE42752, GSE53051, GSE77718, GSE48684 and GSE77954) as validation cohorts.	('GSE48684', 'Var', (106, 114))	('GSE42752', 'Var', (76, 84))	('GSE77954', 'Var', (119, 127))	('GSE53051', 'Var', (86, 94))	('GSE77718', 'Var', (96, 104))	('men', 'Species', '9606', (59, 62))
532203	33202377	The Hypo-DMP (cg26718707) corresponded to DIP2C, while the nine Hyper-DMPs corresponded to eight genes: FBLIM1 (cg26036626), SYNE1 (cg03882585), EFEMP1 (cg08130988), PTPRS (cg16733654), LIFR (cg12587766), CLIP4 (cg08808128 and cg05038216), SCGB3A1 (cg13004587) and SLC6A2 (cg09746736).	('cg03882585', 'Var', (132, 142))	('cg12587766', 'Chemical', '-', (192, 202))	('cg12587766', 'Var', (192, 202))	('cg08808128 and cg05038216', 'Var', (212, 237))	('cg03882585', 'Chemical', '-', (132, 142))	('cg09746736', 'Var', (273, 283))	('LIFR', 'Gene', '3977', (186, 190))	('LIFR', 'Gene', (186, 190))	('FBLIM1', 'Gene', '54751', (104, 110))	('SCGB3A1', 'Gene', '92304', (240, 247))	('PTPRS', 'Gene', (166, 171))	('EFEMP1', 'Gene', '2202', (145, 151))	('SYNE1', 'Gene', (125, 130))	('DIP2C', 'Gene', (42, 47))	('cg26036626', 'Var', (112, 122))	('cg16733654', 'Chemical', '-', (173, 183))	('FBLIM1', 'Gene', (104, 110))	('cg16733654', 'Var', (173, 183))	('cg08130988', 'Chemical', '-', (153, 163))	('SCGB3A1', 'Gene', (240, 247))	('PTPRS', 'Gene', '5802', (166, 171))	('CLIP4', 'Gene', '79745', (205, 210))	('SYNE1', 'Gene', '23345', (125, 130))	('SLC6A2', 'Gene', (265, 271))	('cg08130988', 'Var', (153, 163))	('CLIP4', 'Gene', (205, 210))	('cg26718707', 'Chemical', '-', (14, 24))	('cg05038216', 'Var', (227, 237))	('cg13004587', 'Var', (249, 259))	('cg26718707', 'Var', (14, 24))	('cg08808128', 'Chemical', '-', (212, 222))	('cg26036626', 'Chemical', '-', (112, 122))	('cg13004587', 'Chemical', '-', (249, 259))	('Hypo-DMP', 'Chemical', '-', (4, 12))	('DIP2C', 'Gene', '22982', (42, 47))	('SLC6A2', 'Gene', '6530', (265, 271))	('EFEMP1', 'Gene', (145, 151))
532220	33202377	Multivariate Cox stepwise regression analysis was applied to these 64 CpG sites, and six sites (cg00177496, cg01963906, cg05165940, cg12921795, cg19414598 and cg25783173) were included in our final hazard ratio model, which was constructed as a combined COAD prognostic model for OS prediction (Table 5).	('cg01963906', 'Var', (108, 118))	('Cox', 'Gene', (13, 16))	('cg25783173', 'Var', (159, 169))	('cg25783173', 'Chemical', '-', (159, 169))	('cg05165940', 'Var', (120, 130))	('cg00177496', 'Var', (96, 106))	('cg12921795', 'Var', (132, 142))	('cg01963906', 'Chemical', '-', (108, 118))	('Cox', 'Gene', '9377', (13, 16))	('cg19414598', 'Var', (144, 154))	('cg19414598', 'Chemical', '-', (144, 154))	('cg12921795', 'Chemical', '-', (132, 142))
532221	33202377	The six CpG sites from our COAD prognostic model were found to correspond to BDH1 (cg00177496), SYTL1 (cg01963906), SATB2 (cg05165940), WDR20 (cg12921795), DMC1 (cg19414598) and ZNF35 (cg25783173) (Figure 5A and Supplementary Table 4).	('ZNF35', 'Gene', '7584', (178, 183))	('DMC1', 'Gene', (156, 160))	('cg01963906', 'Var', (103, 113))	('men', 'Species', '9606', (218, 221))	('cg25783173', 'Var', (185, 195))	('WDR20', 'Gene', '91833', (136, 141))	('cg12921795', 'Var', (143, 153))	('SYTL1', 'Gene', (96, 101))	('cg19414598', 'Chemical', '-', (162, 172))	('cg05165940', 'Var', (123, 133))	('cg01963906', 'Chemical', '-', (103, 113))	('cg00177496', 'Var', (83, 93))	('cg19414598', 'Var', (162, 172))	('cg25783173', 'Chemical', '-', (185, 195))	('ZNF35', 'Gene', (178, 183))	('SYTL1', 'Gene', '84958', (96, 101))	('SATB2', 'Gene', (116, 121))	('cg12921795', 'Chemical', '-', (143, 153))	('DMC1', 'Gene', '11144', (156, 160))	('BDH1', 'Gene', '622', (77, 81))	('SATB2', 'Gene', '23314', (116, 121))	('WDR20', 'Gene', (136, 141))	('BDH1', 'Gene', (77, 81))
532223	33202377	The risk score formula for our COAD prognostic model was based on the regression coefficients and methylation levels of the six CpG sites, as follows: risk score = (38.52 x cg00177496 beta value) - (4.13 x cg01963906 beta value) + (2.574 x cg05165940 beta value) - (79.32 x cg12921795 beta value) + (2.31 x cg19414598 beta value) + (6.061 x cg25783173 beta value).	('cg05165940 beta', 'Var', (240, 255))	('cg12921795', 'Chemical', '-', (274, 284))	('cg19414598', 'Chemical', '-', (307, 317))	('cg25783173', 'Chemical', '-', (341, 351))	('cg01963906', 'Chemical', '-', (206, 216))	('cg00177496', 'Var', (173, 183))
532224	33202377	In the risk score formula, a positive coefficient for a CpG site (cg00177496, cg05165940, cg19414598 and cg25783173) indicates that hypermethylation of that site was associated with shorter OS in COAD patients.	('patients', 'Species', '9606', (201, 209))	('cg19414598', 'Var', (90, 100))	('cg19414598', 'Chemical', '-', (90, 100))	('hyper', 'Disease', 'MESH:D053306', (132, 137))	('cg00177496', 'Var', (66, 76))	('cg25783173', 'Var', (105, 115))	('hyper', 'Disease', (132, 137))	('cg05165940', 'Var', (78, 88))	('shorter OS', 'Disease', (182, 192))	('cg25783173', 'Chemical', '-', (105, 115))	('COAD', 'Disease', (196, 200))
532225	33202377	In contrast, a negative coefficient for a CpG site (cg01963906 and cg12921795) indicates that greater methylation of that site was associated with longer OS.	('methylation', 'MPA', (102, 113))	('associated', 'Reg', (131, 141))	('greater', 'PosReg', (94, 101))	('cg12921795', 'Var', (67, 77))	('longer OS', 'Disease', (147, 156))	('cg01963906', 'Chemical', '-', (52, 62))	('cg01963906', 'Var', (52, 62))	('cg12921795', 'Chemical', '-', (67, 77))
532227	33202377	Consistent with the results of the multivariate Cox stepwise regression analysis, the CpG sites with positive coefficients (cg00177496, cg05165940, cg19414598 and cg25783173) exhibited lower methylation levels in patients who survived long-term, while the CpG sites with negative coefficients (cg01963906 and cg12921795) exhibited higher methylation levels in patients who survived long-term.	('cg12921795', 'Var', (309, 319))	('lower', 'NegReg', (185, 190))	('cg25783173', 'Chemical', '-', (163, 173))	('cg01963906', 'Chemical', '-', (294, 304))	('cg19414598', 'Var', (148, 158))	('cg12921795', 'Chemical', '-', (309, 319))	('cg25783173', 'Var', (163, 173))	('cg05165940', 'Var', (136, 146))	('Cox', 'Gene', '9377', (48, 51))	('cg19414598', 'Chemical', '-', (148, 158))	('Cox', 'Gene', (48, 51))	('cg01963906', 'Var', (294, 304))	('cg00177496', 'Var', (124, 134))	('patients', 'Species', '9606', (360, 368))	('patients', 'Species', '9606', (213, 221))	('methylation levels', 'MPA', (338, 356))	('methylation levels', 'MPA', (191, 209))
532241	33202377	Previously identified markers of COAD prognosis have included hypermethylation of FAM134B, higher expression of MMP-11, abnormal methylation and expression of DIRAS1, upregulation of the long non-coding RNA BLACAT1 (a cell cycle regulator) and abnormal expression of 10 microRNAs (including hsa-mir-891a, hsa-mir-6854, etc.).	('hyper', 'Disease', 'MESH:D053306', (62, 67))	('MMP-11', 'Gene', '4320', (112, 118))	('DIRAS1', 'Gene', (159, 165))	('BLACAT1', 'Gene', (207, 214))	('expression', 'MPA', (145, 155))	('MMP-11', 'Gene', (112, 118))	('upregulation', 'PosReg', (167, 179))	('hsa-mir-891a', 'Gene', (291, 303))	('DIRAS1', 'Gene', '148252', (159, 165))	('hyper', 'Disease', (62, 67))	('hsa-mir-6854', 'Gene', '102465514', (305, 317))	('FAM134B', 'Gene', '54463', (82, 89))	('methylation', 'MPA', (129, 140))	('hsa-mir-6854', 'Gene', (305, 317))	('higher', 'PosReg', (91, 97))	('FAM134B', 'Gene', (82, 89))	('BLACAT1', 'Gene', '101669762', (207, 214))	('hsa-mir-891a', 'Gene', '100126341', (291, 303))	('expression', 'MPA', (253, 263))	('abnormal', 'Var', (120, 128))	('expression', 'MPA', (98, 108))
532264	33202377	Abnormal methylation of CpG islands is associated with the silencing of tumor suppressor genes.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('silencing', 'NegReg', (59, 68))	('tumor', 'Disease', (72, 77))	('associated', 'Reg', (39, 49))	('Abnormal', 'Var', (0, 8))	('methylation', 'MPA', (9, 20))	('CpG', 'Protein', (24, 27))	('tumor', 'Disease', 'MESH:D009369', (72, 77))
532291	33202377	Lastly, for machine learning in WEKA, we used BayesNet to construct the COAD-specific diagnostic model with the nine Hyper-DMPs and one Hypo-DMP in the training cohort from TCGA (including 200 COAD and 25 normal samples).	('Hypo-DMP', 'Chemical', '-', (136, 144))	('WEKA', 'Species', '9125', (32, 36))	('Hyper-DMPs', 'Var', (117, 127))	('COAD-specific', 'Disease', (72, 85))
532293	33202377	Thereafter, we imported the methylation values of the nine Hyper-DMPs and one Hypo-DMP from the validation cohort (TCGA validation set or GSE42752 or GSE53051 or GSE77718 or GSE48684 or GSE77954) to the Supplied test set option of the Classify panel.	('Hypo-DMP', 'Chemical', '-', (78, 86))	('GSE77718', 'Var', (162, 170))	('methylation', 'MPA', (28, 39))	('GSE42752', 'Var', (138, 146))	('GSE53051', 'Var', (150, 158))
532307	32604993	Lung cancer is the result of multistage carcinogenesis with gradually increasing genetic and epigenetic changes.	('genetic', 'Var', (81, 88))	('Lung cancer', 'Phenotype', 'HP:0100526', (0, 11))	('Lung cancer', 'Disease', (0, 11))	('epigenetic changes', 'Var', (93, 111))	('multistage carcinogenesis', 'Disease', 'MESH:D063646', (29, 54))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))	('Lung cancer', 'Disease', 'MESH:D008175', (0, 11))	('multistage carcinogenesis', 'Disease', (29, 54))
532321	32604993	Lung cancer does not result from the sudden transformation of bronchia epithelioma but from the final stage of multistage carcinogenesis, with gradually increasing genetic and epigenetic changes.	('genetic', 'Var', (164, 171))	('bronchia epithelioma', 'Disease', 'MESH:D002277', (62, 82))	('Lung cancer', 'Phenotype', 'HP:0100526', (0, 11))	('multistage carcinogenesis', 'Disease', 'MESH:D063646', (111, 136))	('Lung cancer', 'Disease', (0, 11))	('epigenetic changes', 'Var', (176, 194))	('Lung cancer', 'Disease', 'MESH:D008175', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))	('multistage carcinogenesis', 'Disease', (111, 136))	('bronchia epithelioma', 'Disease', (62, 82))
532325	32604993	Nowadays, mutations that are characteristic of lung cancer and which may enable diagnosis at the early stage of the disease are sought for.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('lung cancer', 'Disease', (47, 58))	('lung cancer', 'Phenotype', 'HP:0100526', (47, 58))	('lung cancer', 'Disease', 'MESH:D008175', (47, 58))	('mutations', 'Var', (10, 19))
532332	32604993	The molecular basis of lung cancer is the gradual accumulation of genetic and epigenetic changes in the cell nucleus.	('lung cancer', 'Disease', (23, 34))	('lung cancer', 'Phenotype', 'HP:0100526', (23, 34))	('epigenetic changes', 'Var', (78, 96))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('genetic', 'Var', (66, 73))	('lung cancer', 'Disease', 'MESH:D008175', (23, 34))
532337	32604993	Microsatellite alterations are extensions or deletions of small repeating DNA sequences and appear as microsatellite instability (MSI, i.e., allele shift) or loss of heterozygosity (LOH), which is the absence of a normally present allele.	('heterozygosity', 'MPA', (166, 180))	('alterations', 'Var', (15, 26))	('rat', 'Species', '10116', (19, 22))	('deletions', 'Var', (45, 54))	('Microsatellite alterations', 'Var', (0, 26))	('microsatellite instability', 'MPA', (102, 128))	('loss', 'NegReg', (158, 162))
532341	32604993	Mutations are an inherent feature of lung cancer development, and their detection has a significance in both the diagnostic and treatment stages of disease.	('lung cancer', 'Disease', (37, 48))	('lung cancer', 'Phenotype', 'HP:0100526', (37, 48))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('men', 'Species', '9606', (56, 59))	('Mutations', 'Var', (0, 9))	('lung cancer', 'Disease', 'MESH:D008175', (37, 48))	('men', 'Species', '9606', (133, 136))
532342	32604993	Mutations in cancerogenesis that confer growth advantage in the cancer cells are considered driver mutations.	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('growth', 'MPA', (40, 46))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('cancer', 'Disease', (13, 19))	('cancer', 'Disease', 'MESH:D009369', (13, 19))	('Mutations', 'Var', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
532347	32604993	Genomic alterations encompass mechanistic rearrangements of DNA, resulting in single nucleotide variants (SNVs) known as point mutations and small-scale deletions/insertions (indels) or copy number variants (CNVs), which reflect large-scale mutations such as amplifications, deletions, inversions, and translocations.	('deletions/insertions', 'Var', (153, 173))	('copy number', 'Var', (186, 197))	('rat', 'Species', '10116', (12, 15))	('men', 'Species', '9606', (51, 54))	('deletions', 'Disease', (275, 284))	('alterations', 'Var', (8, 19))	('single nucleotide variants', 'Var', (78, 104))	('DNA', 'Gene', (60, 63))
532366	32604993	Hence, genomic testing can help to identify genomic changes as potential biomarkers of lung cancer.	('lung cancer', 'Disease', 'MESH:D008175', (87, 98))	('lung cancer', 'Disease', (87, 98))	('genomic changes', 'Var', (44, 59))	('lung cancer', 'Phenotype', 'HP:0100526', (87, 98))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
532379	32604993	The identification of the cancer gene targets of each of somatic copy number alterations (SCNAs) is an important challenge.	('cancer', 'Disease', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('rat', 'Species', '10116', (81, 84))	('copy number alterations', 'Var', (65, 88))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))
532383	32604993	Past techniques that have been successfully used in the field of the cancer genome exploration are capillary electrophoresis-based "Sanger" sequencing, the array-based genome-wide analysis of amplifications and deletions, gene expression arrays, and retrovirus-mediated expression screening techniques.	('deletions', 'Var', (211, 220))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('rat', 'Species', '10116', (88, 91))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('cancer', 'Disease', (69, 75))
532386	32604993	In clinical practice, NGS may enable the detection of multiple targets or alteration types, such as mutations, gene copy changes, and rearrangements.	('rearrangements', 'Var', (134, 148))	('mutations', 'Var', (100, 109))	('rat', 'Species', '10116', (78, 81))	('men', 'Species', '9606', (143, 146))	('gene copy changes', 'Var', (111, 128))
532387	32604993	The molecular diagnostics of lung cancer, similarly to NGS applications purposes, is explored in two areas:for research purposes, to find novel druggable mutations, and in clinical practice to diagnose and select eligible patients for specific tyrosine kinase inhibitor (TKI) therapy.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('patients', 'Species', '9606', (222, 230))	('lung cancer', 'Disease', 'MESH:D008175', (29, 40))	('mutations', 'Var', (154, 163))	('lung cancer', 'Disease', (29, 40))	('lung cancer', 'Phenotype', 'HP:0100526', (29, 40))
532391	32604993	The sequencing of the lung cancer genome may identify unknown variants along with the known mutations.	('lung cancer', 'Disease', (22, 33))	('lung cancer', 'Phenotype', 'HP:0100526', (22, 33))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('variants', 'Var', (62, 70))	('lung cancer', 'Disease', 'MESH:D008175', (22, 33))
532393	32604993	The National Comprehensive Cancer Network Guidelines recommends testing a panel of genes for NSCLC, which consists of epidermal growth factor (EGFR) mutations, anapestic lymphoma kinase (ALK) rearrangements, and c-ros oncogene 1 (ROS1) rearrangements.	('rearrangements', 'Var', (192, 206))	('ROS1', 'Gene', (230, 234))	('men', 'Species', '9606', (201, 204))	('NSCLC', 'Disease', 'MESH:D002289', (93, 98))	('ALK', 'Gene', '238', (187, 190))	('Cancer', 'Phenotype', 'HP:0002664', (27, 33))	('ALK', 'Gene', (187, 190))	('c-ros oncogene 1', 'Gene', '6098', (212, 228))	('NSCLC', 'Disease', (93, 98))	('Cancer', 'Disease', (27, 33))	('NSCLC', 'Phenotype', 'HP:0030358', (93, 98))	('rearrangements', 'Var', (236, 250))	('EGFR', 'Gene', (143, 147))	('mutations', 'Var', (149, 158))	('anapestic lymphoma kinase', 'Gene', '238', (160, 185))	('epidermal growth factor', 'Gene', (118, 141))	('men', 'Species', '9606', (245, 248))	('epidermal growth factor', 'Gene', '1950', (118, 141))	('Cancer', 'Disease', 'MESH:D009369', (27, 33))	('anapestic lymphoma kinase', 'Gene', (160, 185))	('c-ros oncogene 1', 'Gene', (212, 228))	('EGFR', 'Gene', '1950', (143, 147))	('men', 'Species', '9606', (58, 61))	('lymphoma', 'Phenotype', 'HP:0002665', (170, 178))
532401	32604993	Epigenomics is currently a field of intense research and it fosters development in molecular cancer therapies.	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('Epigenomics', 'Var', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('men', 'Species', '9606', (75, 78))
532413	32604993	Among the tumor types analyzed, they found that NSCLC is one of the tumors with the highest rate of protein-altering mutations, with rates in adenocarcinomas and squamous cell carcinomas (SCCs) of 3.5 and 3.9 per megabase (Mb), respectively.	('NSCLC', 'Disease', (48, 53))	('tumors', 'Disease', 'MESH:D009369', (68, 74))	('carcinomas', 'Phenotype', 'HP:0030731', (176, 186))	('NSCLC', 'Phenotype', 'HP:0030358', (48, 53))	('tumor', 'Disease', (68, 73))	('SCCs', 'Phenotype', 'HP:0002860', (188, 192))	('tumor', 'Disease', (10, 15))	('rat', 'Species', '10116', (133, 136))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (162, 186))	('mutations', 'Var', (117, 126))	('SCC', 'Phenotype', 'HP:0002860', (188, 191))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('rat', 'Species', '10116', (92, 95))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (162, 186))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('tumors', 'Disease', (68, 74))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (162, 185))	('NSCLC', 'Disease', 'MESH:D002289', (48, 53))	('adenocarcinomas', 'Disease', 'MESH:D000230', (142, 157))	('adenocarcinomas', 'Disease', (142, 157))	('carcinomas', 'Phenotype', 'HP:0030731', (147, 157))	('squamous cell carcinomas', 'Disease', (162, 186))	('carcinoma', 'Phenotype', 'HP:0030731', (147, 156))	('carcinoma', 'Phenotype', 'HP:0030731', (176, 185))
532415	32604993	Studies that are concerned with mathematical modeling related to the clonal mutation burden in several cancer types showed that lung cancer reflects predominantly mutations accumulated at the early stages of tumorigenesis.	('mutations', 'Var', (163, 172))	('lung cancer', 'Disease', 'MESH:D008175', (128, 139))	('tumor', 'Disease', 'MESH:D009369', (208, 213))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('cancer', 'Disease', (133, 139))	('lung cancer', 'Disease', (128, 139))	('tumor', 'Disease', (208, 213))	('lung cancer', 'Phenotype', 'HP:0100526', (128, 139))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
532416	32604993	Lung tumors are characterized by extensive genomic aberrations, including aneusomy, the gains and losses of large chromosome regions, gene rearrangements, copy number gain, or amplifications.	('Lung tumors', 'Disease', 'MESH:D008175', (0, 11))	('men', 'Species', '9606', (148, 151))	('gains', 'PosReg', (88, 93))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('amplifications', 'Var', (176, 190))	('Lung tumors', 'Disease', (0, 11))	('Lung tumors', 'Phenotype', 'HP:0100526', (0, 11))	('copy number', 'Var', (155, 166))	('losses', 'NegReg', (98, 104))	('tumors', 'Phenotype', 'HP:0002664', (5, 11))	('rat', 'Species', '10116', (55, 58))	('gain', 'PosReg', (167, 171))	('aneusomy', 'Disease', (74, 82))
532420	32604993	The most frequently mutated proto-oncogenes in lung cancer are those from the MYC, RAS, and HER families.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('lung cancer', 'Disease', (47, 58))	('lung cancer', 'Phenotype', 'HP:0100526', (47, 58))	('lung cancer', 'Disease', 'MESH:D008175', (47, 58))	('mutated', 'Var', (20, 27))
532422	32604993	In lung cancer, the most frequent alterations among tumor suppressor genes are the mutations of TP53, RB, and p16.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('mutations', 'Var', (83, 92))	('TP53', 'Gene', (96, 100))	('tumor', 'Disease', (52, 57))	('lung cancer', 'Disease', (3, 14))	('lung cancer', 'Phenotype', 'HP:0100526', (3, 14))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('p16', 'Gene', (110, 113))	('lung cancer', 'Disease', 'MESH:D008175', (3, 14))	('rat', 'Species', '10116', (38, 41))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('frequent alterations', 'Reg', (25, 45))	('TP53', 'Gene', '7157', (96, 100))
532425	32604993	p53, KRAS (Kirsten rat sarcoma viral oncogene) mutations, microsatellite instability, and p16 methylation were found in 56%, 27%, 46%, and 38% of patients with NSCLC, respectively.	('p53', 'Gene', (0, 3))	('found', 'Reg', (111, 116))	('microsatellite', 'MPA', (58, 72))	('sarcoma', 'Disease', 'MESH:D012509', (23, 30))	('methylation', 'Var', (94, 105))	('KRAS', 'Gene', (5, 9))	('mutations', 'Var', (47, 56))	('rat', 'Species', '10116', (19, 22))	('NSCLC', 'Phenotype', 'HP:0030358', (160, 165))	('p16', 'Gene', (90, 93))	('sarcoma', 'Disease', (23, 30))	('NSCLC', 'Disease', (160, 165))	('sarcoma', 'Phenotype', 'HP:0100242', (23, 30))	('patients', 'Species', '9606', (146, 154))	('NSCLC', 'Disease', 'MESH:D002289', (160, 165))
532426	32604993	Their results also showed a higher frequency of p53 mutations in SCC than in adenocarcinoma, and a higher frequency of KRAS mutations in patients with the adenocarcinoma subtype.	('mutations', 'Var', (52, 61))	('p53', 'Gene', (48, 51))	('carcinoma', 'Phenotype', 'HP:0030731', (160, 169))	('adenocarcinoma', 'Disease', 'MESH:D000230', (77, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('patients', 'Species', '9606', (137, 145))	('SCC', 'Phenotype', 'HP:0002860', (65, 68))	('adenocarcinoma', 'Disease', (155, 169))	('SCC', 'Disease', (65, 68))	('KRAS', 'Gene', (119, 123))	('adenocarcinoma', 'Disease', 'MESH:D000230', (155, 169))	('adenocarcinoma', 'Disease', (77, 91))
532428	32604993	The first recognized mutations in NSCLC were identified in KRAS and TP53.	('NSCLC', 'Disease', (34, 39))	('NSCLC', 'Disease', 'MESH:D002289', (34, 39))	('NSCLC', 'Phenotype', 'HP:0030358', (34, 39))	('TP53', 'Gene', '7157', (68, 72))	('TP53', 'Gene', (68, 72))	('mutations', 'Var', (21, 30))
532429	32604993	Then, in 2004 mutations in the kinase domain of EGFR were described that changed the lung cancer treatment paradigm.	('lung cancer', 'Disease', (85, 96))	('changed', 'Reg', (73, 80))	('lung cancer', 'Phenotype', 'HP:0100526', (85, 96))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('EGFR', 'Gene', (48, 52))	('lung cancer', 'Disease', 'MESH:D008175', (85, 96))	('men', 'Species', '9606', (102, 105))	('mutations', 'Var', (14, 23))	('EGFR', 'Gene', '1950', (48, 52))
532430	32604993	Both KRAS and EGFR mutations are identified almost exclusively in lung adenocarcinomas, similarly to rearrangements involving ALK and ROS1, which were described in 2007.	('ALK', 'Gene', '238', (126, 129))	('EGFR', 'Gene', (14, 18))	('lung adenocarcinomas', 'Disease', (66, 86))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (66, 86))	('men', 'Species', '9606', (110, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('carcinomas', 'Phenotype', 'HP:0030731', (76, 86))	('KRAS', 'Gene', (5, 9))	('mutations', 'Var', (19, 28))	('ALK', 'Gene', (126, 129))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (66, 86))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (66, 85))	('EGFR', 'Gene', '1950', (14, 18))
532432	32604993	Activating EGFR mutations are found in about 15% of NSCLC, while ALK and ROS1 alterations are quite rare ( < 5% of lung cancers) but are frequent among light to never smokers.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('ALK', 'Gene', '238', (65, 68))	('Activating', 'PosReg', (0, 10))	('lung cancers', 'Phenotype', 'HP:0100526', (115, 127))	('NSCLC', 'Phenotype', 'HP:0030358', (52, 57))	('NSCLC', 'Disease', (52, 57))	('EGFR', 'Gene', (11, 15))	('mutations', 'Var', (16, 25))	('NSCLC', 'Disease', 'MESH:D002289', (52, 57))	('cancers', 'Phenotype', 'HP:0002664', (120, 127))	('lung cancers', 'Disease', (115, 127))	('rat', 'Species', '10116', (82, 85))	('ALK', 'Gene', (65, 68))	('lung cancers', 'Disease', 'MESH:D008175', (115, 127))	('EGFR', 'Gene', '1950', (11, 15))	('lung cancer', 'Phenotype', 'HP:0100526', (115, 126))
532440	32604993	Their results revealed differences in mutation frequency between adenocarcinoma and SCC, and as was expected, the characteristic activating mutations of adenocarcinoma such as KRAS, HRAS, NRAS, and EGFR were identified only in 3% of SCCs.	('SCC', 'Phenotype', 'HP:0002860', (233, 236))	('EGFR', 'Gene', (198, 202))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('NRAS', 'Gene', '4893', (188, 192))	('SCC', 'Phenotype', 'HP:0002860', (84, 87))	('NRAS', 'Gene', (188, 192))	('HRAS', 'Gene', (182, 186))	('EGFR', 'Gene', '1950', (198, 202))	('SCCs', 'Phenotype', 'HP:0002860', (233, 237))	('adenocarcinoma', 'Disease', (65, 79))	('HRAS', 'Gene', '3265', (182, 186))	('mutations', 'Var', (140, 149))	('carcinoma', 'Phenotype', 'HP:0030731', (158, 167))	('adenocarcinoma', 'Disease', (153, 167))	('adenocarcinoma', 'Disease', 'MESH:D000230', (65, 79))	('KRAS', 'Disease', (176, 180))	('adenocarcinoma', 'Disease', 'MESH:D000230', (153, 167))	('activating', 'PosReg', (129, 139))
532442	32604993	Current studies led to the identification of numerous recurrent changes in SCC, such as gene amplifications (CCND 1-3, CDK4, FGFR 1-3, MET, PDGFRA, PIK3CA, SOX2), gene fusions (FGFR3-TACC3), tumor suppressor mutations (PTEN, TP53), and point mutations (EPHA2, AKT1, DDR2), often in combination and some of them with available therapies (Table 2).	('point mutations', 'Var', (236, 251))	('FGFR 1-3', 'Gene', (125, 133))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('PIK3CA', 'Gene', (148, 154))	('SCC', 'Gene', (75, 78))	('PDGFRA', 'Gene', '5156', (140, 146))	('PTEN', 'Gene', (219, 223))	('PDGFRA', 'Gene', (140, 146))	('AKT1', 'Gene', '207', (260, 264))	('EPHA2', 'Gene', '1969', (253, 258))	('TP53', 'Gene', (225, 229))	('DDR2', 'Gene', '4921', (266, 270))	('PTEN', 'Gene', '5728', (219, 223))	('FGFR 1-3', 'Gene', '2260;2263;2261', (125, 133))	('AKT1', 'Gene', (260, 264))	('CDK4', 'Gene', (119, 123))	('CCND 1-3', 'Gene', (109, 117))	('TACC3', 'Gene', '10460', (183, 188))	('CCND 1-3', 'Gene', '595;894;896', (109, 117))	('tumor', 'Disease', (191, 196))	('TACC3', 'Gene', (183, 188))	('SCC', 'Phenotype', 'HP:0002860', (75, 78))	('PIK3CA', 'Gene', '5290', (148, 154))	('FGFR3', 'Gene', (177, 182))	('tumor', 'Disease', 'MESH:D009369', (191, 196))	('changes', 'Var', (64, 71))	('SOX2', 'Gene', (156, 160))	('DDR2', 'Gene', (266, 270))	('TP53', 'Gene', '7157', (225, 229))	('SOX2', 'Gene', '6657', (156, 160))	('CDK4', 'Gene', '1019', (119, 123))	('FGFR3', 'Gene', '2261', (177, 182))	('EPHA2', 'Gene', (253, 258))
532443	32604993	To sum up, in lung cancer the current National Comprehensive Cancer Network (NCCN), Domestic Lung Cancer Clinical Guidelines, and National Health and Family Planning Commission Diagnosis and Treatment Norms suggest that some driver gene variants, including the mutation of EGFR, KRAS, BRAF; the mutation or amplification of HER2 (human epidermal growth factor receptor 2), ALK, ROS1, and RET rearrangements; and the MET copy number amplification or variable shear variations in MET exon 14 are the essential parts of the "core gene list".	('Lung Cancer', 'Disease', (93, 104))	('HER2', 'Gene', (324, 328))	('Cancer', 'Disease', (61, 67))	('BRAF', 'Gene', '673', (285, 289))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('BRAF', 'Gene', (285, 289))	('variable shear variations', 'Var', (449, 474))	('EGFR', 'Gene', (273, 277))	('epidermal growth factor receptor 2', 'Gene', (336, 370))	('Cancer', 'Disease', 'MESH:D009369', (61, 67))	('Cancer', 'Phenotype', 'HP:0002664', (98, 104))	('lung cancer', 'Disease', (14, 25))	('MET exon 14', 'Gene', (478, 489))	('Lung Cancer', 'Disease', 'MESH:D008175', (93, 104))	('KRAS', 'Gene', (279, 283))	('Lung Cancer', 'Phenotype', 'HP:0100526', (93, 104))	('HER2', 'Gene', '2064', (324, 328))	('Cancer', 'Disease', (98, 104))	('EGFR', 'Gene', '1950', (273, 277))	('ALK', 'Gene', '238', (373, 376))	('lung cancer', 'Disease', 'MESH:D008175', (14, 25))	('men', 'Species', '9606', (196, 199))	('Cancer', 'Phenotype', 'HP:0002664', (61, 67))	('variants', 'Var', (237, 245))	('ALK', 'Gene', (373, 376))	('lung cancer', 'Phenotype', 'HP:0100526', (14, 25))	('human', 'Species', '9606', (330, 335))	('Cancer', 'Disease', 'MESH:D009369', (98, 104))	('MET copy number amplification', 'Var', (416, 445))	('men', 'Species', '9606', (401, 404))	('epidermal growth factor receptor 2', 'Gene', '2064', (336, 370))
532445	32604993	Another aspect of lung cancer molecular diagnosis is the analysis of microsatellite markers, potentially used to assess clonality.	('lung cancer', 'Disease', 'MESH:D008175', (18, 29))	('lung cancer', 'Phenotype', 'HP:0100526', (18, 29))	('microsatellite markers', 'Var', (69, 91))	('lung cancer', 'Disease', (18, 29))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))
532446	32604993	Miscrosatellite instability (MSI) is an effect of defective DNA mismatch repair (MMR) and has been implicated in tumorigenesis.	('tumor', 'Disease', (113, 118))	('Miscrosatellite instability', 'Disease', (0, 27))	('implicated', 'Reg', (99, 109))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('defective', 'Var', (50, 59))
532448	32604993	The most common mutations identified in HNPCC involve MLH1, MLH3, MSH2, MSH3, MSH6, PMS2, and POLE.	('MLH1', 'Gene', '4292', (54, 58))	('MLH3', 'Gene', (60, 64))	('MLH1', 'Gene', (54, 58))	('MSH3', 'Gene', '4437', (72, 76))	('mutations', 'Var', (16, 25))	('HNPCC', 'Disease', 'None', (40, 45))	('HNPCC', 'Phenotype', 'HP:0006716', (40, 45))	('MSH2', 'Gene', (66, 70))	('MSH6', 'Gene', (78, 82))	('PMS2', 'Gene', (84, 88))	('MSH6', 'Gene', '2956', (78, 82))	('HNPCC', 'Disease', (40, 45))	('MSH2', 'Gene', '4436', (66, 70))	('PMS2', 'Gene', '5395', (84, 88))	('MLH3', 'Gene', '27030', (60, 64))	('MSH3', 'Gene', (72, 76))
532451	32604993	The study focused on four markers detecting shifts or LOH:tetranucleotide repeat (D21S1245), recognized as being prone to microsatellite instability in various cancer types and dinucleotides D3S1234, D3S1300, and D3S4103 located in the introns of the FHIT (fragile histidine triad diadenosine triphosphatase) gene.	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('D3S1234', 'Var', (191, 198))	('cancer', 'Disease', (160, 166))	('tetranucleotide', 'Chemical', '-', (58, 73))	('FHIT', 'Gene', (251, 255))	('D21S1245', 'Var', (82, 90))	('FHIT', 'Gene', '2272', (251, 255))	('D3S1300', 'Var', (200, 207))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('D3S4103', 'Var', (213, 220))	('microsatellite', 'MPA', (122, 136))
532454	32604993	The FHIT gene encompasses the common fragile site FRA3B on chromosome 3 and shows a high rate of LOH in lung cancer, particularly in smokers.	('FRA3B', 'Gene', '2272', (50, 55))	('lung cancer', 'Disease', 'MESH:D008175', (104, 115))	('FRA3B', 'Gene', (50, 55))	('lung cancer', 'Disease', (104, 115))	('rat', 'Species', '10116', (89, 92))	('FHIT', 'Gene', (4, 8))	('lung cancer', 'Phenotype', 'HP:0100526', (104, 115))	('LOH', 'Var', (97, 100))	('FHIT', 'Gene', '2272', (4, 8))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))
532455	32604993	It was found that 56% (49 of 87) of NSCLC tumors showed microsatellite alterations (shift or LOH) in at least one locus.	('NSCLC tumors', 'Disease', 'MESH:D009369', (36, 48))	('NSCLC', 'Phenotype', 'HP:0030358', (36, 41))	('rat', 'Species', '10116', (75, 78))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('microsatellite alterations', 'Var', (56, 82))	('NSCLC tumors', 'Disease', (36, 48))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
532457	32604993	A total of 30 out of 49 (61%) patients with microsatellite alterations in tumor DNA also showed microsatellite changes in their plasma DNA.	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('microsatellite', 'MPA', (96, 110))	('patients', 'Species', '9606', (30, 38))	('tumor', 'Disease', (74, 79))	('rat', 'Species', '10116', (63, 66))	('changes', 'Reg', (111, 118))	('microsatellite alterations', 'Var', (44, 70))
532458	32604993	An enormous field of lung cancer molecular landscape is determined by epigenetic changes.	('lung cancer', 'Disease', (21, 32))	('lung cancer', 'Phenotype', 'HP:0100526', (21, 32))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('lung cancer', 'Disease', 'MESH:D008175', (21, 32))	('epigenetic', 'Var', (70, 80))
532460	32604993	These epigenetic disruptions may represent reliable biomarkers for lung cancer risk assessment, early diagnosis, prognosis stratification, molecular classification, and the prediction of treatment efficacy.	('epigenetic disruptions', 'Var', (6, 28))	('rat', 'Species', '10116', (125, 128))	('men', 'Species', '9606', (90, 93))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('lung cancer', 'Disease', 'MESH:D008175', (67, 78))	('men', 'Species', '9606', (192, 195))	('lung cancer', 'Disease', (67, 78))	('lung cancer', 'Phenotype', 'HP:0100526', (67, 78))
532461	32604993	Aberrant DNA methylation is catalyzed by three DNA methyltransferaze enzymes (DNMTs) and promotes carcinogenesis through the promoter methylation of tumor suppressor genes, leading to silencing their expression.	('carcinogenesis', 'Disease', 'MESH:D063646', (98, 112))	('silencing', 'NegReg', (184, 193))	('Aberrant', 'Var', (0, 8))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('carcinogenesis', 'Disease', (98, 112))	('promotes', 'PosReg', (89, 97))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('tumor', 'Disease', (149, 154))	('expression', 'MPA', (200, 210))
532465	32604993	In their study, CDKN2A methylation was evident in two sputum samples which had been collected from subjects almost three years prior to diagnosis.	('CDKN2A', 'Gene', (16, 22))	('CDKN2A', 'Gene', '1029', (16, 22))	('evident', 'Reg', (39, 46))	('methylation', 'Var', (23, 34))
532470	32604993	The hypermethylated genes in lung tumors such as APC, CKDN2A (encodes p16INK4A and p14arf), CHD13, RARB, and RASSF1A may be considered as tumor suppressors.	('lung tumors', 'Disease', (29, 40))	('tumor', 'Disease', (138, 143))	('p14arf', 'Gene', (83, 89))	('CKDN2A', 'Gene', (54, 60))	('hypermethylated', 'Var', (4, 19))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('tumor', 'Disease', (34, 39))	('APC', 'Disease', (49, 52))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('RARB', 'Gene', (99, 103))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('RARB', 'Gene', '5915', (99, 103))	('tumors', 'Phenotype', 'HP:0002664', (34, 40))	('lung tumors', 'Disease', 'MESH:D008175', (29, 40))	('p16INK4A', 'Gene', (70, 78))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('p16INK4A', 'Gene', '1029', (70, 78))	('RASSF1A', 'Gene', '11186', (109, 116))	('lung tumors', 'Phenotype', 'HP:0100526', (29, 40))	('APC', 'Disease', 'MESH:D011125', (49, 52))	('p14arf', 'Gene', '1029', (83, 89))	('RASSF1A', 'Gene', (109, 116))
532471	32604993	(2017) evaluated a panel of cancer-specific methylated genes in tumors and adjacent normal lung tissue from NSCLC patients.	('methylated', 'Var', (44, 54))	('NSCLC', 'Phenotype', 'HP:0030358', (108, 113))	('tumors', 'Disease', (64, 70))	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('NSCLC', 'Disease', (108, 113))	('NSCLC', 'Disease', 'MESH:D002289', (108, 113))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('patients', 'Species', '9606', (114, 122))	('cancer', 'Disease', (28, 34))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
532483	32604993	microRNAs are a class of small, single-stranded, non-coding RNAs that post-transcriptionally regulate the translation of target genes and influence a series of cellular functions, such as proliferation, differentiation, and apoptosis; therefore, an altered expression of miRNAs in different cancer types can affect the deregulation of cellular activities.	('deregulation', 'MPA', (319, 331))	('differentiation', 'CPA', (203, 218))	('cancer', 'Disease', (291, 297))	('cancer', 'Disease', 'MESH:D009369', (291, 297))	('cellular activities', 'CPA', (335, 354))	('altered', 'Var', (249, 256))	('apoptosis', 'CPA', (224, 233))	('affect', 'Reg', (308, 314))	('rat', 'Species', '10116', (195, 198))	('influence', 'Reg', (138, 147))	('cancer', 'Phenotype', 'HP:0002664', (291, 297))	('proliferation', 'CPA', (188, 201))
532484	32604993	microRNAs' resistance to endogenous and exogenous RNase activity, extreme temperatures, repeated freeze-thaw cycles, and pH changes enable their effective isolation in biological fluids and measurement using RT-qPCR.	('activity', 'MPA', (56, 64))	('RNase', 'Enzyme', (50, 55))	('men', 'Species', '9606', (197, 200))	('rat', 'Species', '10116', (79, 82))	('changes', 'Var', (124, 131))
532501	32604993	Out of the 15 selected microRNAs, 6 microRNAs (miR-155, miR-197, miR-182, miR-21, miR-128, and miR-183) were significantly elevated in the plasma of patients with lung cancer and subjected to further analysis.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('lung cancer', 'Disease', 'MESH:D008175', (163, 174))	('miR-197', 'Gene', (56, 63))	('patients', 'Species', '9606', (149, 157))	('miR-155', 'Gene', (47, 54))	('miR-183', 'Gene', '406959', (95, 102))	('miR-183', 'Gene', (95, 102))	('miR-182', 'Gene', '406958', (65, 72))	('elevated', 'PosReg', (123, 131))	('miR-197', 'Gene', '406974', (56, 63))	('miR-128', 'Var', (82, 89))	('miR-182', 'Gene', (65, 72))	('miR-21', 'Gene', '406991', (74, 80))	('lung cancer', 'Phenotype', 'HP:0100526', (163, 174))	('lung cancer', 'Disease', (163, 174))	('miR-155', 'Gene', '406947', (47, 54))	('miR-21', 'Gene', (74, 80))
532507	32604993	(2017) found that combined miR-9, miR-16, miR-205, and miR-486 can serve as potential NSCLC biomarkers with an 80% sensitivity and 95% specificity.	('miR-486', 'Gene', '619554', (55, 62))	('miR-16', 'Gene', '51573', (34, 40))	('NSCLC', 'Disease', (86, 91))	('NSCLC', 'Disease', 'MESH:D002289', (86, 91))	('miR-9', 'Var', (27, 32))	('miR-205', 'Gene', (42, 49))	('miR-486', 'Gene', (55, 62))	('NSCLC', 'Phenotype', 'HP:0030358', (86, 91))	('miR-205', 'Gene', '406988', (42, 49))	('miR-16', 'Gene', (34, 40))
532515	32604993	In a univariate analysis, five microRNAs:miR-26a-5p, miR-126-3p, miR-130b-3p, miR-205-5p, and miR-21-5p:were significantly associated with disease-free survival (DFS) in SCC patients, and four of these microRNAs (miR-26a-5p, miR-126-3p, miR-130b-3p, and miR-205-5p) were also associated with overall survival (OS).	('associated with', 'Reg', (123, 138))	('miR-130b-3p', 'Var', (237, 248))	('miR-21', 'Gene', (94, 100))	('miR-205', 'Gene', '406988', (78, 85))	('miR-26a-5p', 'Var', (41, 51))	('disease-free', 'Disease', (139, 151))	('miR-126-3p', 'Gene', '100302148', (53, 63))	('SCC', 'Disease', (170, 173))	('miR-26a-5p', 'Var', (213, 223))	('miR-205', 'Gene', (254, 261))	('associated', 'Reg', (276, 286))	('miR-126-3p', 'Gene', (225, 235))	('DFS', 'Disease', 'None', (162, 165))	('overall survival', 'MPA', (292, 308))	('miR-205', 'Gene', (78, 85))	('DFS', 'Disease', (162, 165))	('miR-126-3p', 'Gene', '100302148', (225, 235))	('miR-21', 'Gene', '406991', (94, 100))	('patients', 'Species', '9606', (174, 182))	('miR-130b-3p', 'Var', (65, 76))	('SCC', 'Phenotype', 'HP:0002860', (170, 173))	('miR-126-3p', 'Gene', (53, 63))	('miR-205', 'Gene', '406988', (254, 261))
532516	32604993	In adenocarcinoma patients, only miR-222-3p, miR-22-3p, and miR-93-5p were significantly associated with DFS, and miR-196-3p was associated with OS.	('miR-222-3p', 'Var', (33, 43))	('associated', 'Reg', (89, 99))	('associated', 'Reg', (129, 139))	('miR-22-3p', 'Gene', '407008', (45, 54))	('carcinoma', 'Phenotype', 'HP:0030731', (8, 17))	('DFS', 'Disease', 'None', (105, 108))	('adenocarcinoma', 'Disease', (3, 17))	('adenocarcinoma', 'Disease', 'MESH:D000230', (3, 17))	('miR-196-3p', 'Var', (114, 124))	('patients', 'Species', '9606', (18, 26))	('miR-93', 'Gene', '407051', (60, 66))	('miR-93', 'Gene', (60, 66))	('miR-22-3p', 'Gene', (45, 54))	('DFS', 'Disease', (105, 108))
532520	32604993	The researchers focused on angiogenic microRNAs, such as miR-18a, miR-19a, miR-20a, miR-92a, miR-126, miR-130a, miR-210, miR-296, and miR-378, that play an important role in tumorigenesis and angiogenesis.	('miR-20a', 'Gene', '406982', (75, 82))	('miR-378', 'Gene', (134, 141))	('miR-18a', 'Gene', '406953', (57, 64))	('angiogenesis', 'CPA', (192, 204))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('miR-19a', 'Gene', (66, 73))	('miR-378', 'Gene', '494327', (134, 141))	('miR-92a', 'Var', (84, 91))	('miR-19a', 'Gene', '406979', (66, 73))	('miR-126', 'Gene', '406913', (93, 100))	('miR-130a', 'Gene', '406919', (102, 110))	('miR-296', 'Gene', (121, 128))	('miR-210', 'Gene', '406992', (112, 119))	('miR-18a', 'Gene', (57, 64))	('miR-130a', 'Gene', (102, 110))	('tumor', 'Disease', (174, 179))	('miR-296', 'Gene', '407022', (121, 128))	('miR-210', 'Gene', (112, 119))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('miR-126', 'Gene', (93, 100))	('miR-20a', 'Gene', (75, 82))
532521	32604993	The comparison between microRNAs in the patients with NSCLC and the healthy controls showed that the plasma miR-18a and miR-126 expression levels were lower in the patients with NSCLC, whereas the expression levels of miR-19a, miR-20a, miR-92a, miR-130a, miR-210, miR-296, and miR-378 were higher in the patients with NSCLC.	('NSCLC', 'Phenotype', 'HP:0030358', (318, 323))	('miR-126', 'Gene', '406913', (120, 127))	('miR-18a', 'Gene', (108, 115))	('miR-92a', 'Var', (236, 243))	('miR-20a', 'Gene', (227, 234))	('miR-20a', 'Gene', '406982', (227, 234))	('NSCLC', 'Disease', 'MESH:D002289', (54, 59))	('miR-378', 'Gene', (277, 284))	('miR-18a', 'Gene', '406953', (108, 115))	('NSCLC', 'Disease', (54, 59))	('patients', 'Species', '9606', (164, 172))	('miR-19a', 'Gene', (218, 225))	('miR-210', 'Gene', '406992', (255, 262))	('miR-130a', 'Gene', '406919', (245, 253))	('miR-19a', 'Gene', '406979', (218, 225))	('patients', 'Species', '9606', (304, 312))	('NSCLC', 'Disease', 'MESH:D002289', (178, 183))	('miR-126', 'Gene', (120, 127))	('miR-378', 'Gene', '494327', (277, 284))	('higher', 'PosReg', (290, 296))	('NSCLC', 'Phenotype', 'HP:0030358', (54, 59))	('miR-296', 'Gene', (264, 271))	('miR-130a', 'Gene', (245, 253))	('miR-210', 'Gene', (255, 262))	('expression', 'MPA', (197, 207))	('miR-296', 'Gene', '407022', (264, 271))	('NSCLC', 'Disease', 'MESH:D002289', (318, 323))	('NSCLC', 'Disease', (178, 183))	('patients', 'Species', '9606', (40, 48))	('expression levels', 'MPA', (128, 145))	('lower', 'NegReg', (151, 156))	('NSCLC', 'Phenotype', 'HP:0030358', (178, 183))	('NSCLC', 'Disease', (318, 323))
532522	32604993	The low plasma expression levels of miR-18a, miR-20a, miR-92a, and miR-126 were correlated with a prolonged DFS, whereas high plasma miR-18a, miR-20a, miR-92a, miR-210, and miR-126 expression levels were correlated with a shorter OS.	('miR-92a', 'Var', (54, 61))	('miR-18a', 'Gene', (36, 43))	('expression levels', 'MPA', (15, 32))	('miR-126', 'Gene', '406913', (173, 180))	('DFS', 'Disease', 'None', (108, 111))	('miR-18a', 'Gene', '406953', (133, 140))	('DFS', 'Disease', (108, 111))	('miR-126', 'Gene', '406913', (67, 74))	('miR-18a', 'Gene', '406953', (36, 43))	('miR-210', 'Gene', '406992', (160, 167))	('miR-20a', 'Gene', (142, 149))	('miR-126', 'Gene', (173, 180))	('miR-20a', 'Gene', '406982', (142, 149))	('miR-210', 'Gene', (160, 167))	('miR-20a', 'Gene', (45, 52))	('miR-20a', 'Gene', '406982', (45, 52))	('low', 'NegReg', (4, 7))	('miR-126', 'Gene', (67, 74))	('miR-18a', 'Gene', (133, 140))
532536	32604993	The expressions of miR-27a-3p, miR-21, and miR-182 were significantly higher in the study group than in the healthy volunteers, whereas the miR-195 expression was significantly lower in the lung cancer group.	('lower', 'NegReg', (177, 182))	('miR-195', 'Gene', '406971', (140, 147))	('miR-27a-3p', 'Var', (19, 29))	('miR-182', 'Gene', (43, 50))	('expressions', 'MPA', (4, 15))	('miR-21', 'Gene', (31, 37))	('lung cancer', 'Disease', 'MESH:D008175', (190, 201))	('miR-21', 'Gene', '406991', (31, 37))	('higher', 'PosReg', (70, 76))	('miR-182', 'Gene', '406958', (43, 50))	('expression', 'MPA', (148, 158))	('lung cancer', 'Disease', (190, 201))	('lung cancer', 'Phenotype', 'HP:0100526', (190, 201))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('miR-195', 'Gene', (140, 147))
532540	32604993	Mutations of KRAS and TP53 were the earliest recognized mutations in NSCLC.	('NSCLC', 'Disease', (69, 74))	('NSCLC', 'Disease', 'MESH:D002289', (69, 74))	('Mutations', 'Var', (0, 9))	('TP53', 'Gene', '7157', (22, 26))	('KRAS', 'Gene', (13, 17))	('NSCLC', 'Phenotype', 'HP:0030358', (69, 74))	('TP53', 'Gene', (22, 26))
532541	32604993	In general, colon, pancreas, and lung carcinoma are associated with KRAS mutation, while somatic TP53 mutations occur in almost every type of cancer, with the highest rates in ovarian, esophageal, colorectal, head and neck, larynx, and lung cancers.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('lung carcinoma', 'Disease', 'MESH:D008175', (33, 47))	('TP53', 'Gene', '7157', (97, 101))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('lung cancers', 'Phenotype', 'HP:0100526', (236, 248))	('KRAS', 'Gene', (68, 72))	('rat', 'Species', '10116', (167, 170))	('colon', 'Disease', (12, 17))	('larynx', 'Disease', (224, 230))	('colon', 'Disease', 'MESH:D003110', (12, 17))	('cancer', 'Disease', 'MESH:D009369', (241, 247))	('mutation', 'Var', (73, 81))	('carcinoma', 'Phenotype', 'HP:0030731', (38, 47))	('pancreas', 'Disease', (19, 27))	('cancer', 'Disease', (142, 148))	('lung carcinoma', 'Disease', (33, 47))	('esophageal', 'Disease', (185, 195))	('associated', 'Reg', (52, 62))	('ovarian', 'Disease', (176, 183))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('colorectal', 'Disease', (197, 207))	('TP53', 'Gene', (97, 101))	('lung cancer', 'Phenotype', 'HP:0100526', (236, 247))	('lung cancers', 'Disease', 'MESH:D008175', (236, 248))	('cancer', 'Disease', (241, 247))	('cancers', 'Phenotype', 'HP:0002664', (241, 248))	('lung cancers', 'Disease', (236, 248))
532542	32604993	This shows that similar driver gene mutations may be found among different kind of tumors.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumors', 'Disease', (83, 89))	('mutations', 'Var', (36, 45))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('tumors', 'Disease', 'MESH:D009369', (83, 89))
532546	32604993	Recent studies have provided insights into resistance mutations against osimertinib:i.e., a third-generation EGFR inhibitor that is designed to target T790M:and crizotinib, which is the ALK inhibitor.	('ALK', 'Gene', (186, 189))	('EGFR', 'Gene', '1950', (109, 113))	('osimertinib', 'Chemical', '-', (72, 83))	('ALK', 'Gene', '238', (186, 189))	('rat', 'Species', '10116', (102, 105))	('crizotinib', 'Chemical', 'MESH:D000077547', (161, 171))	('T790M', 'Mutation', 'rs121434569', (151, 156))	('EGFR', 'Gene', (109, 113))	('T790M', 'Var', (151, 156))
532547	32604993	There are various resistance mechanisms to osimertinib, such as the resistant mutation at the cysteine residue at position 797 (C797) that abolishes the direct covalent binding of osimertinib or resistance via the activation of bypass pathways, such as MET amplification.	('osimertinib', 'Chemical', '-', (43, 54))	('abolishes', 'NegReg', (139, 148))	('C797', 'Var', (128, 132))	('cysteine', 'Chemical', 'MESH:D003545', (94, 102))	('bypass pathways', 'Pathway', (228, 243))	('osimertinib', 'Chemical', '-', (180, 191))	('resistance', 'MPA', (195, 205))	('direct covalent', 'MPA', (153, 168))	('osimertinib', 'Protein', (180, 191))
532548	32604993	(2017), the detection of an EGFR solvent front mutation (MAF of G796S/R) has been reported after treatment with osimertinib.	('MAF', 'Gene', '4094', (57, 60))	('G796S', 'Var', (64, 69))	('osimertinib', 'Chemical', '-', (112, 123))	('MAF', 'Gene', (57, 60))	('EGFR', 'Gene', (28, 32))	('men', 'Species', '9606', (102, 105))	('EGFR', 'Gene', '1950', (28, 32))	('G796S', 'SUBSTITUTION', 'None', (64, 69))
532550	32604993	(2016), not only the occurrence of the EGFR C797S mutation but also L792F/Y/H in three clinical subjects with acquired resistance to osimertinib treatment was observed.	('osimertinib', 'Chemical', '-', (133, 144))	('L792F', 'SUBSTITUTION', 'None', (68, 73))	('L792F', 'Var', (68, 73))	('C797S', 'Var', (44, 49))	('EGFR', 'Gene', '1950', (39, 43))	('C797S', 'Mutation', 'p.C797S', (44, 49))	('men', 'Species', '9606', (150, 153))	('EGFR', 'Gene', (39, 43))
532552	32604993	The study demonstrated secondary ALK mutations, a high ALK gene copy number, and the activation of EGFR signals expressed by a high EGFR polysomy and L858R in EGFR exon 21 after treatment with crizotinib.	('EGFR', 'Gene', '1950', (132, 136))	('EGFR', 'Gene', (99, 103))	('ALK', 'Gene', (33, 36))	('EGFR', 'Gene', '1950', (159, 163))	('crizotinib', 'Chemical', 'MESH:D000077547', (193, 203))	('ALK', 'Gene', '238', (55, 58))	('men', 'Species', '9606', (183, 186))	('rat', 'Species', '10116', (17, 20))	('EGFR', 'Gene', (132, 136))	('activation', 'PosReg', (85, 95))	('EGFR', 'Gene', (159, 163))	('mutations', 'Var', (37, 46))	('ALK', 'Gene', '238', (33, 36))	('EGFR', 'Gene', '1950', (99, 103))	('L858R', 'Mutation', 'p.L858R', (150, 155))	('ALK', 'Gene', (55, 58))	('L858R', 'Var', (150, 155))
532573	31966070	Immunohistochemistry revealed that TRIM59 was primarily located in the cytoplasm of tumor cells.	('tumor', 'Disease', (84, 89))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('TRIM59', 'Var', (35, 41))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))
532575	31966070	Furthermore, the TRIM59 expression level was associated with tumor differentiation (P=0.012), while no association was observed between TRIM59 expression and any other clinicopathological parameters.	('expression level', 'MPA', (24, 40))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('associated', 'Reg', (45, 55))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('TRIM59', 'Var', (17, 23))	('tumor', 'Disease', (61, 66))
532576	31966070	However, the average overall survival rate of patients with NSCLC in the high TRIM59 expression group was significantly lower than that in the low expression group (P=0.014), especially in patients with LUSC (P=0.016) and patients with poor differentiation (P=0.033).	('lower', 'NegReg', (120, 125))	('LUSC', 'Disease', (203, 207))	('LUSC', 'Disease', 'MESH:D002294', (203, 207))	('patients', 'Species', '9606', (46, 54))	('high TRIM59 expression', 'Var', (73, 95))	('patients', 'Species', '9606', (222, 230))	('patients', 'Species', '9606', (189, 197))	('NSCLC', 'Disease', (60, 65))	('overall survival', 'MPA', (21, 37))	('NSCLC', 'Disease', 'MESH:D002289', (60, 65))
532577	31966070	The multivariate analysis indicated that high TRIM59 expression is an independent prognostic factor in patients with NSCLC (P=0.018) and was associated with poor prognosis in patients with NSCLC.	('NSCLC', 'Disease', (117, 122))	('NSCLC', 'Disease', (189, 194))	('NSCLC', 'Disease', 'MESH:D002289', (189, 194))	('high', 'Var', (41, 45))	('NSCLC', 'Disease', 'MESH:D002289', (117, 122))	('TRIM59', 'Protein', (46, 52))	('patients', 'Species', '9606', (175, 183))	('expression', 'MPA', (53, 63))	('patients', 'Species', '9606', (103, 111))
532578	31966070	Therefore, TRIM59 may serve as a novel molecular biomarker to predict the prognosis of patients with NSCLC.	('NSCLC', 'Disease', 'MESH:D002289', (101, 106))	('TRIM59', 'Var', (11, 17))	('NSCLC', 'Disease', (101, 106))	('patients', 'Species', '9606', (87, 95))
532590	31966070	Lin et al reported that knockdown of TRIM59 inhibited tumor growth in prostate cancer.	('prostate cancer', 'Disease', 'MESH:D011471', (70, 85))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('prostate cancer', 'Phenotype', 'HP:0012125', (70, 85))	('inhibited', 'NegReg', (44, 53))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('prostate cancer', 'Disease', (70, 85))	('TRIM59', 'Gene', (37, 43))	('tumor', 'Disease', (54, 59))	('knockdown', 'Var', (24, 33))
532592	31966070	Additionally, TRIM59 induced epithelial-to-mesenchymal transition, and promoted migration and invasion of medulloblastoma cells through the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway.	('TRIM59', 'Var', (14, 20))	('induced', 'PosReg', (21, 28))	('medulloblastoma', 'Disease', 'MESH:D008527', (106, 121))	('promoted', 'PosReg', (71, 79))	('AKT', 'Gene', '207', (191, 194))	('migration', 'CPA', (80, 89))	('medulloblastoma', 'Phenotype', 'HP:0002885', (106, 121))	('AKT', 'Gene', (191, 194))	('epithelial-to-mesenchymal transition', 'CPA', (29, 65))	('medulloblastoma', 'Disease', (106, 121))
532603	31966070	The standard indirect immunoperoxidase procedures (Envision Plus; Dako; Agilent Technologies, Inc.) were adopted for immunohistochemistry to detect the expression of TRIM59 in NSCLC.	('NSCLC', 'Disease', 'MESH:D002289', (176, 181))	('NSCLC', 'Disease', (176, 181))	('TRIM59', 'Var', (166, 172))
532623	31966070	Among the 140 NSCLC tissue samples, the high-TRIM59 expression group comprised 83 samples, which was significantly higher than that found in normal tissues (59.3 vs. 10.0%; chi2 value, 9.201; P=0.0024; Fig.	('high-TRIM59 expression', 'Var', (40, 62))	('higher', 'PosReg', (115, 121))	('NSCLC', 'Disease', 'MESH:D002289', (14, 19))	('NSCLC', 'Disease', (14, 19))
532624	31966070	It was identified that TRIM59 was on average 1.32-fold more highly expressed in NSCLC tissue samples compared with paratumour samples (P<0.0001; Fig.	('more highly', 'PosReg', (55, 66))	('TRIM59', 'Var', (23, 29))	('NSCLC', 'Disease', 'MESH:D002289', (80, 85))	('NSCLC', 'Disease', (80, 85))
532625	31966070	Similarly, TRIM59 was on average 1.24-fold more highly expressed in LUAD (P<0.0001; Fig.	('LUAD', 'Disease', (68, 72))	('TRIM59', 'Var', (11, 17))	('LUAD', 'Disease', 'MESH:C538231', (68, 72))
532627	31966070	The 140 patients with NSCLC were classified into low and high TRIM59 expression groups and the clinicopathological characteristics of the patients were compared.	('high TRIM59', 'Var', (57, 68))	('NSCLC', 'Disease', (22, 27))	('NSCLC', 'Disease', 'MESH:D002289', (22, 27))	('patients', 'Species', '9606', (138, 146))	('patients', 'Species', '9606', (8, 16))
532629	31966070	However, no statistically significant associations were found between TRIM59 and tumor size (P=0.781), lymph node status (P=0.684), tumor stage (P=0.457) or any other clinicopathological characteristics.	('TRIM59', 'Var', (70, 76))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumor', 'Disease', (132, 137))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Disease', (81, 86))
532634	31966070	The results revealed that high expression of TRIM59 was significantly associated with worse OS time in patients with LUSC (P=0.016; Fig.	('LUSC', 'Disease', 'MESH:D002294', (117, 121))	('high expression', 'Var', (26, 41))	('worse OS time', 'CPA', (86, 99))	('TRIM59', 'Gene', (45, 51))	('LUSC', 'Disease', (117, 121))	('patients', 'Species', '9606', (103, 111))
532638	31966070	Additionally, Zhou et al reported that TRIM59 is upregulated in gastric cancer, and promotes the ubiquitination and degradation of p53 that affects tumor growth.	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('tumor', 'Disease', 'MESH:D009369', (148, 153))	('tumor', 'Disease', (148, 153))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('p53', 'Gene', (131, 134))	('TRIM59', 'Var', (39, 45))	('p53', 'Gene', '7157', (131, 134))	('gastric cancer', 'Disease', (64, 78))	('affects', 'Reg', (140, 147))	('upregulated', 'PosReg', (49, 60))	('gastric cancer', 'Disease', 'MESH:D013274', (64, 78))	('degradation', 'MPA', (116, 127))	('ubiquitination', 'MPA', (97, 111))	('promotes', 'PosReg', (84, 92))	('gastric cancer', 'Phenotype', 'HP:0012126', (64, 78))
532641	31966070	Dai et al reported that knockdown of TRIM66 inhibited malignant behavior and epithelial-mesenchymal transition in NSCLC cells.	('epithelial-mesenchymal transition', 'CPA', (77, 110))	('TRIM66', 'Gene', '9866', (37, 43))	('inhibited', 'NegReg', (44, 53))	('NSCLC', 'Disease', (114, 119))	('malignant behavior', 'CPA', (54, 72))	('NSCLC', 'Disease', 'MESH:D002289', (114, 119))	('TRIM66', 'Gene', (37, 43))	('knockdown', 'Var', (24, 33))
532646	31966070	Furthermore, it was found that TRIM59 facilitated the proliferation of colorectal cancer and promoted metastasis via the PI3K/AKT signaling pathway.	('colorectal cancer', 'Phenotype', 'HP:0003003', (71, 88))	('AKT', 'Gene', (126, 129))	('colorectal cancer', 'Disease', (71, 88))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('facilitated', 'PosReg', (38, 49))	('colorectal cancer', 'Disease', 'MESH:D015179', (71, 88))	('metastasis', 'CPA', (102, 112))	('proliferation', 'CPA', (54, 67))	('AKT', 'Gene', '207', (126, 129))	('promoted', 'PosReg', (93, 101))	('TRIM59', 'Var', (31, 37))
532659	31966070	Furthermore, it was identified that patients with high expression of TRIM59 had a worse prognosis than those with low TRIM59 expression, especially in patients with LUSC and patients with poor differentiation.	('LUSC', 'Disease', (165, 169))	('high expression', 'Var', (50, 65))	('patients', 'Species', '9606', (36, 44))	('TRIM59', 'Gene', (69, 75))	('patients', 'Species', '9606', (151, 159))	('patients', 'Species', '9606', (174, 182))	('LUSC', 'Disease', 'MESH:D002294', (165, 169))
532660	31966070	Consistent with the results of a study performed by Zhan et al, TRIM59 promoted the proliferation and migration of NSCLC cells by upregulating cell cycle-related proteins, which may affect the prognosis of the patients with NSCLC.	('upregulating', 'PosReg', (130, 142))	('promoted', 'PosReg', (71, 79))	('NSCLC', 'Disease', (115, 120))	('NSCLC', 'Disease', (224, 229))	('NSCLC', 'Disease', 'MESH:D002289', (115, 120))	('NSCLC', 'Disease', 'MESH:D002289', (224, 229))	('cell cycle-related proteins', 'Protein', (143, 170))	('TRIM59', 'Var', (64, 70))	('proliferation', 'CPA', (84, 97))	('patients', 'Species', '9606', (210, 218))	('migration', 'CPA', (102, 111))	('affect', 'Reg', (182, 188))
532661	31966070	Additionally, the multivariate analysis performed in the present study indicated that high TRIM59 expression is an independent prognostic factor for patients with NSCLC.	('patients', 'Species', '9606', (149, 157))	('NSCLC', 'Disease', (163, 168))	('NSCLC', 'Disease', 'MESH:D002289', (163, 168))	('TRIM59', 'Protein', (91, 97))	('high', 'Var', (86, 90))	('expression', 'MPA', (98, 108))
532663	31966070	In conclusion, the present study revealed that high TRIM59 expression was associated with worse prognosis in patients with NSCLC and that TRIM59 may serve as an important prognostic biomarker in patients with NSCLC.	('NSCLC', 'Disease', 'MESH:D002289', (209, 214))	('NSCLC', 'Disease', (123, 128))	('TRIM59', 'Gene', (52, 58))	('patients', 'Species', '9606', (109, 117))	('high', 'Var', (47, 51))	('NSCLC', 'Disease', 'MESH:D002289', (123, 128))	('expression', 'MPA', (59, 69))	('patients', 'Species', '9606', (195, 203))	('NSCLC', 'Disease', (209, 214))
532679	28615365	Rare germline mutations in TP53, RB1 and EGFR have been shown to confer inherited predisposition to lung cancer.	('TP53', 'Gene', '7157', (27, 31))	('TP53', 'Gene', (27, 31))	('EGFR', 'Gene', (41, 45))	('predisposition', 'Reg', (82, 96))	('germline mutations', 'Var', (5, 23))	('lung cancer', 'Phenotype', 'HP:0100526', (100, 111))	('RB1', 'Gene', (33, 36))	('lung cancer', 'Disease', (100, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('EGFR', 'Gene', '1956', (41, 45))	('lung cancer', 'Disease', 'MESH:D008175', (100, 111))	('RB1', 'Gene', '5925', (33, 36))
532696	28615365	In a second GWAS, a SNP within the CHRNA3 gene was strongly associated with smoking quantity and nicotine dependence.	('SNP', 'Var', (20, 23))	('nicotine', 'Chemical', 'MESH:D009538', (97, 105))	('smoking quantity', 'Disease', (76, 92))	('CHRNA3', 'Gene', '1136', (35, 41))	('nicotine dependence', 'Disease', (97, 116))	('CHRNA3', 'Gene', (35, 41))	('associated with', 'Reg', (60, 75))
532698	28615365	The results suggest that the variant on chromosome 15q25 confers risk of lung cancer through its effect on tobacco addiction.	('lung cancer', 'Disease', 'MESH:D008175', (73, 84))	('variant', 'Var', (29, 36))	('effect', 'Reg', (97, 103))	('risk', 'Reg', (65, 69))	('lung cancer', 'Disease', (73, 84))	('lung cancer', 'Phenotype', 'HP:0100526', (73, 84))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('tobacco', 'Species', '4097', (107, 114))	('tobacco addiction', 'Disease', (107, 124))
532700	28615365	Together, these three studies unequivocally support the 15q25 locus as harboring susceptibility variants for lung cancer or smoking behavior.	('lung cancer', 'Disease', (109, 120))	('lung cancer', 'Phenotype', 'HP:0100526', (109, 120))	('variants', 'Var', (96, 104))	('smoking behavior', 'Disease', (124, 140))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('lung cancer', 'Disease', 'MESH:D008175', (109, 120))
532712	28615365	However, DNA variants at 5p15 were associated with histological subtypes of lung cancer, with an increased frequency of the risk allele in cases with adenocarcinoma.	('variants', 'Var', (13, 21))	('lung cancer', 'Disease', 'MESH:D008175', (76, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (155, 164))	('adenocarcinoma', 'Disease', (150, 164))	('adenocarcinoma', 'Disease', 'MESH:D000230', (150, 164))	('associated', 'Reg', (35, 45))	('DNA', 'Var', (9, 12))	('lung cancer', 'Disease', (76, 87))	('lung cancer', 'Phenotype', 'HP:0100526', (76, 87))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))
532719	28615365	The top nine signals were followed-up and rare genetic variants were associated with squamous cell carcinoma in the BRCA2 gene on 13q13.1 and in CHEK2 on 22q12.1.	('variants', 'Var', (55, 63))	('CHEK2', 'Gene', (145, 150))	('CHEK2', 'Gene', '11200', (145, 150))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (85, 108))	('associated with', 'Reg', (69, 84))	('BRCA2', 'Gene', (116, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (85, 108))	('squamous cell carcinoma', 'Disease', (85, 108))	('BRCA2', 'Gene', '675', (116, 121))
532723	28615365	This GWAS highlighted the genetic heterogeneity across histological subtypes of lung cancer and reported novel loci for lung cancer per se (1p31.1, 6q27, 8p21.1, and 15q21.1) and adenocarcinoma (8p12, 10q24.3, 11q23.3, and 20q13.33).	('lung cancer', 'Disease', 'MESH:D008175', (80, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (184, 193))	('lung cancer', 'Disease', (120, 131))	('adenocarcinoma', 'Disease', (179, 193))	('p21', 'Gene', (155, 158))	('lung cancer', 'Phenotype', 'HP:0100526', (120, 131))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('p21', 'Gene', '644914', (155, 158))	('adenocarcinoma', 'Disease', 'MESH:D000230', (179, 193))	('8p12', 'Var', (195, 199))	('lung cancer', 'Disease', (80, 91))	('lung cancer', 'Phenotype', 'HP:0100526', (80, 91))	('lung cancer', 'Disease', 'MESH:D008175', (120, 131))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
532724	28615365	Previously reported lung cancer loci were more specifically associated with squamous cell carcinoma in this study including 6p21.33, 12p13.33, and 22q12.1.	('lung cancer', 'Disease', 'MESH:D008175', (20, 31))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (76, 99))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('squamous cell carcinoma', 'Disease', (76, 99))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (76, 99))	('12p13.33', 'Var', (133, 141))	('lung cancer', 'Disease', (20, 31))	('p21', 'Gene', (125, 128))	('lung cancer', 'Phenotype', 'HP:0100526', (20, 31))	('p21', 'Gene', '644914', (125, 128))	('associated', 'Reg', (60, 70))
532726	28615365	For example, the strongest lung cancer susceptibility variants on 15q25 have very low allele frequencies in Asian populations.	('15q25', 'Gene', (66, 71))	('lung cancer', 'Disease', (27, 38))	('lung cancer', 'Phenotype', 'HP:0100526', (27, 38))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('variants', 'Var', (54, 62))	('lung cancer', 'Disease', 'MESH:D008175', (27, 38))
532727	28615365	Similarly, variants on 6p21 found in Europeans are not polymorphic in Asians.	('p21', 'Gene', (24, 27))	('variants', 'Var', (11, 19))	('p21', 'Gene', '644914', (24, 27))
532729	28615365	In the same GWAS, but with an extended validation sample size, five new lung cancer loci were identified including 10p14, 5q32, 20q13.2, 5q31.1, and 1p36.32.	('20q13.2', 'Var', (128, 135))	('5q32', 'Var', (122, 126))	('10p14', 'Var', (115, 120))	('1p36.32', 'Var', (149, 156))	('lung cancer', 'Disease', (72, 83))	('lung cancer', 'Phenotype', 'HP:0100526', (72, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('lung cancer', 'Disease', 'MESH:D008175', (72, 83))
532735	28615365	The association with lung adenocarcinoma was also confirmed for 5p15, 3q28, and 6p21, but not for 13q12.12 and 22q12.2.	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (21, 40))	('3q28', 'Var', (70, 74))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (21, 40))	('5p15', 'Var', (64, 68))	('p21', 'Gene', (81, 84))	('lung adenocarcinoma', 'Disease', (21, 40))	('p21', 'Gene', '644914', (81, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (31, 40))
532748	28615365	SNPs on chromosome 12q13 in the ACVR1B and NR4A1 genes were associated with lung cancer, particularly in women and those who reported environmental tobacco smoke exposure.	('lung cancer', 'Disease', 'MESH:D008175', (76, 87))	('men', 'Species', '9606', (141, 144))	('men', 'Species', '9606', (107, 110))	('ACVR1B', 'Gene', '91', (32, 38))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('women', 'Species', '9606', (105, 110))	('lung cancer', 'Disease', (76, 87))	('SNPs', 'Var', (0, 4))	('lung cancer', 'Phenotype', 'HP:0100526', (76, 87))	('NR4A1', 'Gene', (43, 48))	('tobacco', 'Species', '4097', (148, 155))	('NR4A1', 'Gene', '3164', (43, 48))	('ACVR1B', 'Gene', (32, 38))	('associated with', 'Reg', (60, 75))
532749	28615365	Focused on DNA repair genes, a recent study revealed variants in GTF2H4 on 6p21 and in XRCC4 on 5q14.2 associated with lung cancer risk.	('lung cancer', 'Disease', (119, 130))	('associated', 'Reg', (103, 113))	('lung cancer', 'Phenotype', 'HP:0100526', (119, 130))	('p21', 'Gene', (76, 79))	('GTF2H4', 'Gene', '2968', (65, 71))	('XRCC4', 'Gene', (87, 92))	('lung cancer', 'Disease', 'MESH:D008175', (119, 130))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('XRCC4', 'Gene', '7518', (87, 92))	('GTF2H4', 'Gene', (65, 71))	('p21', 'Gene', '644914', (76, 79))	('variants', 'Var', (53, 61))
532755	28615365	By focusing on SNPs missed by traditional GWAS, this study identified 30 variants that showed evidence of association with lung cancer risk.	('association', 'Interaction', (106, 117))	('lung cancer', 'Disease', (123, 134))	('lung cancer', 'Phenotype', 'HP:0100526', (123, 134))	('variants', 'Var', (73, 81))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('lung cancer', 'Disease', 'MESH:D008175', (123, 134))
532767	28615365	The effects of genetic variants on lung cancer are likely to be amplified when multiple variants synergize together.	('lung cancer', 'Disease', 'MESH:D008175', (35, 46))	('lung cancer', 'Disease', (35, 46))	('lung cancer', 'Phenotype', 'HP:0100526', (35, 46))	('variants', 'Var', (23, 31))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))
532784	28615365	Accordingly, a number of studies have started to delineate the effects of genetic variants in specific subgroups of patients with lung cancer, which is important to reveal the true nature of genetic effects detected in GWAS and narrow the set of genetic variants and genes worthy of functional studies.	('variants', 'Var', (82, 90))	('lung cancer', 'Phenotype', 'HP:0100526', (130, 141))	('patients', 'Species', '9606', (116, 124))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('lung cancer', 'Disease', 'MESH:D008175', (130, 141))	('lung cancer', 'Disease', (130, 141))
532785	28615365	It is also important to know whether independent variants in the same loci are associated with lung cancer.	('lung cancer', 'Disease', (95, 106))	('associated', 'Reg', (79, 89))	('lung cancer', 'Phenotype', 'HP:0100526', (95, 106))	('variants', 'Var', (49, 57))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('lung cancer', 'Disease', 'MESH:D008175', (95, 106))
532808	28615365	This approach is also starting to reveal inherited variants associated with lung cancer survival and response to treatment.	('lung cancer', 'Disease', 'MESH:D008175', (76, 87))	('variants', 'Var', (51, 59))	('men', 'Species', '9606', (118, 121))	('lung cancer', 'Disease', (76, 87))	('lung cancer', 'Phenotype', 'HP:0100526', (76, 87))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('associated with', 'Reg', (60, 75))
532814	28615365	The identification of lung cancer-associated genetic variants associated with the expression of specific genes in a disease relevant tissue is an important step forward to understand the molecular mechanisms underpinning GWAS signals.	('lung cancer', 'Disease', (22, 33))	('lung cancer', 'Phenotype', 'HP:0100526', (22, 33))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('associated', 'Reg', (62, 72))	('lung cancer', 'Disease', 'MESH:D008175', (22, 33))	('variants', 'Var', (53, 61))
532822	28615365	GWAS variants of lung cancer may not exert their effects through gene regulation, but other molecular phenotypes such as protein expression, protein state, metabolite levels, and epigenetic marks.	('lung cancer', 'Disease', (17, 28))	('lung cancer', 'Phenotype', 'HP:0100526', (17, 28))	('epigenetic marks', 'Var', (179, 195))	('variants', 'Var', (5, 13))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('lung cancer', 'Disease', 'MESH:D008175', (17, 28))	('metabolite', 'MPA', (156, 166))
532828	28615365	To this effect, whole-exome sequencing in three members of a five-generation family affected by lung cancer has revealed a rare variants in PARK2 resulting in a loss-of-function of this tumor suppressor gene.	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('lung cancer', 'Disease', 'MESH:D008175', (96, 107))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('loss-of-function', 'NegReg', (161, 177))	('tumor', 'Disease', (186, 191))	('lung cancer', 'Disease', (96, 107))	('variants', 'Var', (128, 136))	('lung cancer', 'Phenotype', 'HP:0100526', (96, 107))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('PARK2', 'Gene', '5071', (140, 145))	('PARK2', 'Gene', (140, 145))
532829	28615365	Similarly, exome-sequencing of sporadic and familial cases of lung cancer identified rare deleterious mutations in GWAS-nominated loci located in the CDC147 and DBH genes.	('lung cancer', 'Phenotype', 'HP:0100526', (62, 73))	('lung cancer', 'Disease', (62, 73))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('mutations', 'Var', (102, 111))	('CDC147', 'Gene', (150, 156))	('lung cancer', 'Disease', 'MESH:D008175', (62, 73))	('DBH', 'Gene', (161, 164))
532830	28615365	Whole-genome sequencing in a family with very high aggregation of lung adenocarcinoma revealed a functional missense variant in the oncogene YAP1 associated with the risk of developing the disease.	('very high aggregation of lung adenocarcinoma', 'Disease', 'MESH:D000077192', (41, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('YAP1', 'Gene', (141, 145))	('YAP1', 'Gene', '10413', (141, 145))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (66, 85))	('missense variant', 'Var', (108, 124))	('very high aggregation of lung adenocarcinoma', 'Disease', (41, 85))	('associated', 'Reg', (146, 156))
532834	28615365	A genetic risk score built from seven telomere-length associated genetic variants was associated with lung cancer risk.	('lung cancer', 'Phenotype', 'HP:0100526', (102, 113))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('variants', 'Var', (73, 81))	('lung cancer', 'Disease', (102, 113))	('associated', 'Reg', (86, 96))	('lung cancer', 'Disease', 'MESH:D008175', (102, 113))
532841	28615365	Preliminary data provides some clues about inherited variants associated with lung cancer survival and response to treatment, but will require validation in larger-scale studies.	('lung cancer', 'Disease', (78, 89))	('lung cancer', 'Phenotype', 'HP:0100526', (78, 89))	('associated', 'Reg', (62, 72))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('lung cancer', 'Disease', 'MESH:D008175', (78, 89))	('variants', 'Var', (53, 61))	('men', 'Species', '9606', (120, 123))
532844	28615365	eQTL expression quantitative trait loci GWAS genome-wide association study LD linkage disequilibrium Mb megabase NSCLC non-small cell lung cancer SCLC small cell lung cancer SNP single nucleotide polymorphism TWAS transcriptome-wide association study	('single nucleotide polymorphism', 'Var', (178, 208))	('lung cancer', 'Phenotype', 'HP:0100526', (162, 173))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (123, 145))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('small cell lung cancer', 'Disease', 'MESH:D055752', (151, 173))	('small cell lung cancer', 'Disease', (151, 173))	('lung cancer', 'Phenotype', 'HP:0100526', (134, 145))	('SCLC', 'Gene', (146, 150))	('SCLC', 'Gene', '7864', (146, 150))	('megabase', 'Chemical', '-', (104, 112))	('small cell lung cancer', 'Disease', 'MESH:D055752', (123, 145))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (151, 173))	('NSCLC', 'Disease', 'MESH:D002289', (113, 118))	('small cell lung cancer', 'Disease', (123, 145))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('SCLC', 'Gene', '7864', (114, 118))	('SCLC', 'Gene', (114, 118))	('NSCLC', 'Disease', (113, 118))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (119, 145))
532845	28465643	PIK3CA gene mutations in Northwest Chinese esophageal squamous cell carcinoma To evaluate PIK3CA gene mutational status in Northwest Chinese esophageal squamous cell carcinoma (ESCC) patients, and examine the associations of PIK3CA gene mutations with clinicopathological characteristics and clinical outcome.	('esophageal squamous cell carcinoma', 'Disease', (43, 77))	('PIK3CA', 'Gene', (225, 231))	('associations', 'Interaction', (209, 221))	('PIK3CA', 'Gene', '5290', (225, 231))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (141, 175))	('carcinoma', 'Phenotype', 'HP:0030731', (166, 175))	('mutations', 'Var', (12, 21))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (152, 175))	('PIK3CA', 'Gene', (0, 6))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (54, 77))	('PIK3CA', 'Gene', (90, 96))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (43, 77))	('PIK3CA', 'Gene', '5290', (0, 6))	('carcinoma', 'Phenotype', 'HP:0030731', (68, 77))	('esophageal squamous cell carcinoma', 'Disease', (141, 175))	('PIK3CA', 'Gene', '5290', (90, 96))	('patients', 'Species', '9606', (183, 191))
532847	28465643	Pyrosequencing was applied to investigate mutations in exons 9 and 20 of PIK3CA gene in 210 Northwest Chinese ESCCs.	('PIK3CA', 'Gene', '5290', (73, 79))	('mutations', 'Var', (42, 51))	('PIK3CA', 'Gene', (73, 79))
532849	28465643	PIK3CA gene mutations in exon 9 were detected in 48 cases (22.9%) of a non-biased database of 210 curatively resected Northwest Chinese ESCCs.	('mutations', 'Var', (12, 21))	('PIK3CA', 'Gene', '5290', (0, 6))	('detected', 'Reg', (37, 45))	('PIK3CA', 'Gene', (0, 6))
532850	28465643	PIK3CA gene mutations were not associated with sex, tobacco use, alcohol use, tumor location, stage, or local recurrence.	('alcohol use', 'Phenotype', 'HP:0030955', (65, 76))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('mutations', 'Var', (12, 21))	('associated', 'Reg', (31, 41))	('PIK3CA', 'Gene', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('PIK3CA', 'Gene', '5290', (0, 6))	('tobacco', 'Species', '4097', (52, 59))	('alcohol', 'Chemical', 'MESH:D000438', (65, 72))	('tumor', 'Disease', (78, 83))
532851	28465643	When compared with wild-type PIK3CA gene cases, patients with PIK3CA gene mutations in exons 9 experienced significantly better disease-free survival and overall survival rates.	('PIK3CA', 'Gene', (62, 68))	('mutations in', 'Var', (74, 86))	('better', 'PosReg', (121, 127))	('disease-free survival', 'CPA', (128, 149))	('PIK3CA', 'Gene', '5290', (62, 68))	('PIK3CA', 'Gene', (29, 35))	('patients', 'Species', '9606', (48, 56))	('PIK3CA', 'Gene', '5290', (29, 35))	('overall survival rates', 'CPA', (154, 176))
532852	28465643	The results of this study suggest that PIK3CA gene mutations could act as a prognostic biomarker in Northwest Chinese ESCC patients.	('PIK3CA', 'Gene', (39, 45))	('mutations', 'Var', (51, 60))	('patients', 'Species', '9606', (123, 131))	('PIK3CA', 'Gene', '5290', (39, 45))
532853	28465643	Core tip: PIK3CA gene mutations have been associated with various prognoses in patients with different cancers.	('cancers', 'Disease', 'MESH:D009369', (103, 110))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('associated', 'Reg', (42, 52))	('PIK3CA', 'Gene', (10, 16))	('mutations', 'Var', (22, 31))	('patients', 'Species', '9606', (79, 87))	('PIK3CA', 'Gene', '5290', (10, 16))	('cancers', 'Phenotype', 'HP:0002664', (103, 110))	('cancers', 'Disease', (103, 110))
532854	28465643	However, no large-scale study has examined the prognostic impact of PIK3CA gene mutations in Northwest Chinese esophageal squamous cell carcinoma (ESCC).	('PIK3CA', 'Gene', (68, 74))	('mutations', 'Var', (80, 89))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (111, 145))	('PIK3CA', 'Gene', '5290', (68, 74))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (122, 145))	('esophageal squamous cell carcinoma', 'Disease', (111, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))
532856	28465643	It was found that PIK3CA gene mutations in Northwest Chinese ESCC are associated with favorable prognoses.	('PIK3CA', 'Gene', (18, 24))	('mutations', 'Var', (30, 39))	('PIK3CA', 'Gene', '5290', (18, 24))
532857	28465643	It has been suggested that PIK3CA gene mutational status can have a potential role as a prognostic biomarker for ESCC.	('mutational status', 'Var', (39, 56))	('ESCC', 'Disease', (113, 117))	('PIK3CA', 'Gene', '5290', (27, 33))	('PIK3CA', 'Gene', (27, 33))
532859	28465643	As one of the most commonly diagnosed cancers among men in China, the estimated number of new cases of esophageal cancer was 291238 in 2011, while the numbers of deaths was 218957 in the same year; by 2015, these numbers had increased to 477900 and 375000, respectively.	('477900', 'Var', (238, 244))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('esophageal cancer', 'Disease', (103, 120))	('men', 'Species', '9606', (52, 55))	('deaths', 'Disease', 'MESH:D003643', (162, 168))	('deaths', 'Disease', (162, 168))	('cancers', 'Phenotype', 'HP:0002664', (38, 45))	('esophageal cancer', 'Disease', 'MESH:D004938', (103, 120))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('291238', 'Var', (125, 131))	('cancers', 'Disease', 'MESH:D009369', (38, 45))	('cancers', 'Disease', (38, 45))
532864	28465643	The mutant PIK3CA gene stimulates the AKT pathway and promotes cell growth and invasion in various types of human cancer (Samuels, 2004 #620; Samuels, 2005 #638), including lung, breast, gastric, and colon.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('AKT', 'Gene', (38, 41))	('mutant', 'Var', (4, 10))	('stimulates', 'PosReg', (23, 33))	('breast', 'Disease', (179, 185))	('cancer', 'Disease', (114, 120))	('PIK3CA', 'Gene', (11, 17))	('AKT', 'Gene', '207', (38, 41))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('human', 'Species', '9606', (108, 113))	('PIK3CA', 'Gene', '5290', (11, 17))	('gastric', 'Disease', (187, 194))	('lung', 'Disease', (173, 177))	('invasion', 'CPA', (79, 87))	('colon', 'Disease', (200, 205))	('cell growth', 'CPA', (63, 74))	('promotes', 'PosReg', (54, 62))
532865	28465643	PIK3CA gene mutations have also been detected in Japanese and Korean ESCCs.	('mutations', 'Var', (12, 21))	('PIK3CA', 'Gene', '5290', (0, 6))	('PIK3CA', 'Gene', (0, 6))
532868	28465643	We therefore quantified PIK3CA gene mutations in 210 samples of curatively resected ESCCs using pyrosequencing, and examined the prognostic significance of PIK3CA gene mutations in Northwest Chinese ESCC patients.	('patients', 'Species', '9606', (204, 212))	('PIK3CA', 'Gene', (24, 30))	('PIK3CA', 'Gene', '5290', (156, 162))	('mutations', 'Var', (36, 45))	('PIK3CA', 'Gene', '5290', (24, 30))	('PIK3CA', 'Gene', (156, 162))
532877	28465643	Two sets of primers (Table 1) were used for the detection of any mutation points in exons 9 and 20 of the PIK3CA gene.	('PIK3CA', 'Gene', (106, 112))	('mutation points', 'Var', (65, 80))	('PIK3CA', 'Gene', '5290', (106, 112))
532882	28465643	The association between PIK3CA gene mutations and clinicopathological variables were performed using the chi2-test or Fisher's exact probability test.	('PIK3CA', 'Gene', (24, 30))	('mutations', 'Var', (36, 45))	('PIK3CA', 'Gene', '5290', (24, 30))
532884	28465643	In this study, PIK3CA gene mutations were only observed in exon 9 in 48 (22.9%) of 210 Northwest Chinese ESCC samples.	('mutations', 'Var', (27, 36))	('PIK3CA', 'Gene', '5290', (15, 21))	('PIK3CA', 'Gene', (15, 21))
532885	28465643	The most common mutation of PIK3CA exon 9 was the c.1634A>C (p.E545A) mutation, which was present in 35 tumors, followed by c.1633G>A (p.E545K) in 13 tumors.	('tumors', 'Disease', (150, 156))	('tumors', 'Disease', 'MESH:D009369', (150, 156))	('tumors', 'Phenotype', 'HP:0002664', (150, 156))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('c.1634A>C', 'Var', (50, 59))	('PIK3CA', 'Gene', (28, 34))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('c.1633G>A', 'Var', (124, 133))	('p.E545A', 'Mutation', 'rs121913274', (61, 68))	('tumors', 'Disease', (104, 110))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('c.1634A>C', 'Mutation', 'rs121913274', (50, 59))	('PIK3CA', 'Gene', '5290', (28, 34))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('c.1633G>A', 'Mutation', 'rs104886003', (124, 133))	('p.E545K', 'Mutation', 'rs104886003', (135, 142))
532886	28465643	We examined whether the influence of PIK3CA gene mutations on cancer-specific survival was modified by any of the evaluated clinical, pathologic, or epidemiologic variables of the ESCCs.	('PIK3CA', 'Gene', '5290', (37, 43))	('mutations', 'Var', (49, 58))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('modified', 'Reg', (91, 99))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('PIK3CA', 'Gene', (37, 43))
532887	28465643	As a result, we found that PIK3CA gene mutations were not significantly associated with any of the evaluated characteristics of ESCCs, namely sex (male vs female), tobacco use (yes vs no), alcohol use (yes vs no), tumor location (upper, middle vs lower thoracic), preoperative treatment (yes vs no), lymph node metastasis (yes vs no), or local recurrence (yes vs no) (all P > 0.01; Table 3).	('tumor', 'Disease', 'MESH:D009369', (214, 219))	('tobacco', 'Species', '4097', (164, 171))	('alcohol use', 'Phenotype', 'HP:0030955', (189, 200))	('associated', 'Reg', (72, 82))	('PIK3CA', 'Gene', (27, 33))	('mutations', 'Var', (39, 48))	('local recurrence', 'CPA', (338, 354))	('men', 'Species', '9606', (282, 285))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('tumor', 'Disease', (214, 219))	('PIK3CA', 'Gene', '5290', (27, 33))	('alcohol', 'Chemical', 'MESH:D000438', (189, 196))	('ESCCs', 'Disease', (128, 133))
532891	28465643	In the Kaplan-Meier analysis, patients with PIK3CA gene mutations experienced significantly longer disease-free survival (log rank P = 0.0094), cancer-specific survival (log rank P = 0.0059), and overall survival (log rank P = 0.0066) rates than those with the wild-type PIK3CA gene (Figure 1).	('PIK3CA', 'Gene', (44, 50))	('mutations', 'Var', (56, 65))	('disease-free survival', 'CPA', (99, 120))	('PIK3CA', 'Gene', (271, 277))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('PIK3CA', 'Gene', '5290', (44, 50))	('cancer', 'Disease', (144, 150))	('patients', 'Species', '9606', (30, 38))	('PIK3CA', 'Gene', '5290', (271, 277))	('overall survival', 'CPA', (196, 212))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('longer', 'PosReg', (92, 98))
532894	28465643	PIK3CA gene mutations and the subsequent activation of the PI3K/AKT pathway are considered to play a crucial role in cancer cell signaling pathways downstream of growth factors, cytokines, and other cellular stimuli in human neoplasm.	('human', 'Species', '9606', (219, 224))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('mutations', 'Var', (12, 21))	('neoplasm', 'Disease', (225, 233))	('AKT', 'Gene', '207', (64, 67))	('PIK3CA', 'Gene', (0, 6))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('PIK3CA', 'Gene', '5290', (0, 6))	('neoplasm', 'Disease', 'MESH:D009369', (225, 233))	('neoplasm', 'Phenotype', 'HP:0002664', (225, 233))	('activation', 'PosReg', (41, 51))	('cancer', 'Disease', (117, 123))	('AKT', 'Gene', (64, 67))
532895	28465643	We therefore conducted this study to examine the prognostic impact of PIK3CA gene mutations among 210 Northwest Chinese patients with curatively resected ESCC.	('PIK3CA', 'Gene', (70, 76))	('mutations', 'Var', (82, 91))	('PIK3CA', 'Gene', '5290', (70, 76))	('patients', 'Species', '9606', (120, 128))
532896	28465643	In this study, we identified PIK3CA gene mutations in 48 out of 210 (22.9%) Northwest Chinese patients with curatively resected ESCC, which is a rate similar to that previously observed in ESCC (21%), colorectal cancer (32%), and breast cancer (25%-40%), but slightly higher than that for gastric cancers (4.3%) and brain tumors (5%).	('breast cancer', 'Disease', 'MESH:D001943', (230, 243))	('brain tumors', 'Disease', (316, 328))	('breast cancer', 'Disease', (230, 243))	('gastric cancers', 'Disease', 'MESH:D013274', (289, 304))	('tumors', 'Phenotype', 'HP:0002664', (322, 328))	('gastric cancers', 'Phenotype', 'HP:0012126', (289, 304))	('gastric cancers', 'Disease', (289, 304))	('mutations', 'Var', (41, 50))	('patients', 'Species', '9606', (94, 102))	('colorectal cancer', 'Phenotype', 'HP:0003003', (201, 218))	('tumor', 'Phenotype', 'HP:0002664', (322, 327))	('ESCC', 'Disease', (128, 132))	('PIK3CA', 'Gene', '5290', (29, 35))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('brain tumors', 'Disease', 'MESH:D001932', (316, 328))	('brain tumors', 'Phenotype', 'HP:0030692', (316, 328))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))	('colorectal cancer', 'Disease', 'MESH:D015179', (201, 218))	('cancers', 'Phenotype', 'HP:0002664', (297, 304))	('breast cancer', 'Phenotype', 'HP:0003002', (230, 243))	('ESCC', 'Disease', (189, 193))	('cancer', 'Phenotype', 'HP:0002664', (297, 303))	('PIK3CA', 'Gene', (29, 35))	('colorectal cancer', 'Disease', (201, 218))
532899	28465643	When identifying PIK3CA gene mutations, other researchers typically use direct sequencing rather than the pyrosequencing used in the current study, which is a reliable high-throughput method that could be used as an alternative method for genotyping mutation studies.	('PIK3CA', 'Gene', (17, 23))	('mutations', 'Var', (29, 38))	('PIK3CA', 'Gene', '5290', (17, 23))
532901	28465643	Additionally, pyrosequencing has been shown to be more sensitive than regular sequencing in detecting EGFR and KRAS mutations in lung cancer patients.	('lung cancer', 'Disease', (129, 140))	('lung cancer', 'Phenotype', 'HP:0100526', (129, 140))	('KRAS', 'Gene', (111, 115))	('KRAS', 'Gene', '3845', (111, 115))	('mutations', 'Var', (116, 125))	('lung cancer', 'Disease', 'MESH:D008175', (129, 140))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('EGFR', 'Gene', '1956', (102, 106))	('EGFR', 'Gene', (102, 106))	('patients', 'Species', '9606', (141, 149))
532904	28465643	Previous studies examining the relationship between PIK3CA gene mutations and prognosis in human cancers have yielded variable results and showed that PIK3CA gene mutational status is not associated with ESCC patient survival, although it does denote a better prognosis in breast cancer and ovarian cancer.	('better', 'PosReg', (253, 259))	('mutational', 'Var', (163, 173))	('ovarian cancer', 'Disease', (291, 305))	('PIK3CA', 'Gene', (52, 58))	('human cancers', 'Disease', 'MESH:D009369', (91, 104))	('cancer', 'Phenotype', 'HP:0002664', (280, 286))	('ovarian cancer', 'Phenotype', 'HP:0100615', (291, 305))	('cancers', 'Phenotype', 'HP:0002664', (97, 104))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('PIK3CA', 'Gene', '5290', (151, 157))	('breast cancer', 'Phenotype', 'HP:0003002', (273, 286))	('PIK3CA', 'Gene', '5290', (52, 58))	('breast cancer', 'Disease', 'MESH:D001943', (273, 286))	('breast cancer', 'Disease', (273, 286))	('ovarian cancer', 'Disease', 'MESH:D010051', (291, 305))	('patient', 'Species', '9606', (209, 216))	('PIK3CA', 'Gene', (151, 157))	('cancer', 'Phenotype', 'HP:0002664', (299, 305))	('human cancers', 'Disease', (91, 104))
532906	28465643	We conducted this study to explore the prognostic impact of PIK3CA gene mutations among 210 Northwest Chinese patients with curatively resected ESCC.	('mutations', 'Var', (72, 81))	('PIK3CA', 'Gene', '5290', (60, 66))	('patients', 'Species', '9606', (110, 118))	('PIK3CA', 'Gene', (60, 66))
532907	28465643	It was revealed that PIK3CA gene mutations were associated with a favorable prognosis among patients with curatively resected ESCC, suggesting PIK3CA gene mutational status may be a prognostic biomarker for Northwest Chinese ESCC patients that can be used to identify the clinical outcome of patients with curatively resected ESCC, which is consistent with its roles in Japanese ESCC patients.	('PIK3CA', 'Gene', (143, 149))	('PIK3CA', 'Gene', (21, 27))	('ESCC', 'Disease', (326, 330))	('mutations', 'Var', (33, 42))	('patients', 'Species', '9606', (92, 100))	('patients', 'Species', '9606', (230, 238))	('patients', 'Species', '9606', (384, 392))	('PIK3CA', 'Gene', '5290', (143, 149))	('PIK3CA', 'Gene', '5290', (21, 27))	('patients', 'Species', '9606', (292, 300))
532908	28465643	Nonetheless, our findings regarding the correlation between PIK3CA mutations and favorable prognosis in esophageal cancer requires further confirmation by future independent studies using much larger non-biased cohorts of ESCCs.	('PIK3CA', 'Gene', (60, 66))	('PIK3CA', 'Gene', '5290', (60, 66))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('mutations', 'Var', (67, 76))	('esophageal cancer', 'Disease', (104, 121))	('esophageal cancer', 'Disease', 'MESH:D004938', (104, 121))
532909	28465643	In summary, this study suggests that PIK3CA gene mutations are associated with a favorable clinical outcome in operational resected ESCC, which supports the PIK3CA gene's role as a prognostic biomarker for ESCC.	('PIK3CA', 'Gene', '5290', (37, 43))	('mutations', 'Var', (49, 58))	('associated', 'Reg', (63, 73))	('PIK3CA', 'Gene', (157, 163))	('PIK3CA', 'Gene', '5290', (157, 163))	('PIK3CA', 'Gene', (37, 43))
532910	28465643	Our data correlates with that of previous studies suggesting that the acquisition of PIK3CA gene mutations may be an important molecular event in the etiology of a wide range of tumor types and highlights the potential broad applicability that the PIK3CA gene may have in the clinical outcome of human cancers.	('mutations', 'Var', (97, 106))	('human cancers', 'Disease', (296, 309))	('tumor', 'Disease', (178, 183))	('cancer', 'Phenotype', 'HP:0002664', (302, 308))	('PIK3CA', 'Gene', '5290', (85, 91))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('PIK3CA', 'Gene', (248, 254))	('cancers', 'Phenotype', 'HP:0002664', (302, 309))	('human cancers', 'Disease', 'MESH:D009369', (296, 309))	('PIK3CA', 'Gene', '5290', (248, 254))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('PIK3CA', 'Gene', (85, 91))
532911	28465643	Future studies are needed to confirm this association and clarify the exact molecular mechanisms by which PIK3CA gene mutations affects human cancer behavior.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('human', 'Species', '9606', (136, 141))	('PIK3CA', 'Gene', (106, 112))	('mutations', 'Var', (118, 127))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('PIK3CA', 'Gene', '5290', (106, 112))	('affects', 'Reg', (128, 135))	('cancer', 'Disease', (142, 148))
532915	28465643	High frequencies of somatic mutations conferring oncogenic potential have been found in the PIK3CA gene, which is associated with poor prognosis in patients with colorectal or lung cancer.	('patients', 'Species', '9606', (148, 156))	('PIK3CA', 'Gene', (92, 98))	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('PIK3CA', 'Gene', '5290', (92, 98))	('oncogenic potential', 'MPA', (49, 68))	('colorectal or lung cancer', 'Disease', (162, 187))	('associated', 'Reg', (114, 124))	('colorectal or lung cancer', 'Disease', 'MESH:D015179', (162, 187))	('mutations', 'Var', (28, 37))	('lung cancer', 'Phenotype', 'HP:0100526', (176, 187))
532916	28465643	In contrast, a relationship between PIK3CA gene mutations and favorable prognoses has been shown in breast cancer.	('PIK3CA', 'Gene', '5290', (36, 42))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('breast cancer', 'Disease', 'MESH:D001943', (100, 113))	('breast cancer', 'Phenotype', 'HP:0003002', (100, 113))	('breast cancer', 'Disease', (100, 113))	('PIK3CA', 'Gene', (36, 42))	('mutations', 'Var', (48, 57))
532918	28465643	The frequency of PIK3CA gene mutation in ESCC varied from 0% to 21%, which could likely introduce some bias in the statistical analyses of their clinical significance.	('mutation', 'Var', (29, 37))	('PIK3CA', 'Gene', (17, 23))	('PIK3CA', 'Gene', '5290', (17, 23))
532919	28465643	More than 80% of PIK3CA gene mutations detected were localized in exons 9 and 20 (helical and kinase domain), with three "hot-spot" mutations: E542K, E545K, and H1047R.	('E542K', 'Mutation', 'rs121913273', (143, 148))	('E545K', 'Mutation', 'rs104886003', (150, 155))	('H1047R', 'Mutation', 'rs121913279', (161, 167))	('E545K', 'Var', (150, 155))	('PIK3CA', 'Gene', (17, 23))	('PIK3CA', 'Gene', '5290', (17, 23))	('H1047R', 'Var', (161, 167))	('E542K', 'Var', (143, 148))
532920	28465643	A recent report correlated with previous studies suggesting that the acquisition of PIK3CA mutations may be an important molecular event in the etiology of ESCC, and that mutations are associated with their clinical outcome.	('PIK3CA', 'Gene', '5290', (84, 90))	('associated', 'Reg', (185, 195))	('mutations', 'Var', (91, 100))	('PIK3CA', 'Gene', (84, 90))	('mutations', 'Var', (171, 180))	('ESCC', 'Disease', (156, 160))
532921	28465643	This is, by far, one of the largest studies on the prognostic role of PIK3CA gene mutations in Northwest Chinese ESCC to date, and it shows that PIK3CA gene mutations in ESCC are associated with a favorable prognoses.	('PIK3CA', 'Gene', (70, 76))	('mutations', 'Var', (157, 166))	('PIK3CA', 'Gene', (145, 151))	('PIK3CA', 'Gene', '5290', (145, 151))	('PIK3CA', 'Gene', '5290', (70, 76))
532922	28465643	It has been suggested that PIK3CA gene mutational status can have a potential role as a prognostic biomarker for ESCC patients.	('ESCC', 'Disease', (113, 117))	('PIK3CA', 'Gene', (27, 33))	('mutational status', 'Var', (39, 56))	('PIK3CA', 'Gene', '5290', (27, 33))	('patients', 'Species', '9606', (118, 126))
532923	28465643	PIK3CA gene mutations are associated with a favorable clinical outcome in operational resected Northwest Chinese ESCC patients, thereby suggesting that the acquisition of PIK3CA gene mutations may be an important molecular event in the etiology of a wide range of tumor types and highlighting the potential broad applicability that PIK3CA gene may have in the clinical outcome of human cancers.	('tumor', 'Phenotype', 'HP:0002664', (264, 269))	('PIK3CA', 'Gene', (171, 177))	('cancers', 'Phenotype', 'HP:0002664', (386, 393))	('tumor', 'Disease', (264, 269))	('PIK3CA', 'Gene', (332, 338))	('mutations', 'Var', (12, 21))	('PIK3CA', 'Gene', '5290', (171, 177))	('human cancers', 'Disease', 'MESH:D009369', (380, 393))	('PIK3CA', 'Gene', '5290', (332, 338))	('PIK3CA', 'Gene', (0, 6))	('PIK3CA', 'Gene', '5290', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (386, 392))	('human cancers', 'Disease', (380, 393))	('tumor', 'Disease', 'MESH:D009369', (264, 269))	('patients', 'Species', '9606', (118, 126))
532926	28465643	The authors examined the associations of PIK3CA gene mutations with clinicopathological characteristics and clinical outcome in esophageal squamous cell carcinoma patients in Northwest China.	('associations', 'Interaction', (25, 37))	('patients', 'Species', '9606', (163, 171))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (139, 162))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (128, 162))	('carcinoma', 'Phenotype', 'HP:0030731', (153, 162))	('PIK3CA', 'Gene', (41, 47))	('mutations', 'Var', (53, 62))	('PIK3CA', 'Gene', '5290', (41, 47))	('esophageal squamous cell carcinoma', 'Disease', (128, 162))
532927	28465643	The study suggests that PIK3CA gene mutations are associated with a favorable clinical outcome in esophageal squamous cell cancer and that in the future the evaluation of PIK3CA gene mutations may be potentially applied as a prognostic marker.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('PIK3CA', 'Gene', (171, 177))	('PIK3CA', 'Gene', (24, 30))	('PIK3CA', 'Gene', '5290', (171, 177))	('esophageal squamous cell cancer', 'Disease', (98, 129))	('mutations', 'Var', (36, 45))	('PIK3CA', 'Gene', '5290', (24, 30))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (109, 129))	('associated', 'Reg', (50, 60))	('esophageal squamous cell cancer', 'Disease', 'MESH:D002294', (98, 129))
532959	28321397	Probes for the genes encoding CD44 (NM_001001392.1), NANOG (NM_024865.2), OCT4 (NM_002701.4), STAT3 (NM_139276.2), and the housekeeping genes glucuronidase beta (GUSB) (NM_000181.1), clathrin heavy chain (CLTC) (NM_4859.2), and hypoxanthine phosphoribosyltransferase 1 (NM_000194.1) were designed and manufactured by NanoString Technologies.	('NANOG', 'Gene', (53, 58))	('NM_024865.2', 'Var', (60, 71))	('NM_000194.1', 'Var', (270, 281))	('glucuronidase beta', 'Gene', (142, 160))	('glucuronidase beta', 'Gene', '2990', (142, 160))	('STAT3', 'Gene', (94, 99))	('hypoxanthine phosphoribosyltransferase 1', 'Gene', '3251', (228, 268))	('NM_002701.4', 'Var', (80, 91))	('GUSB', 'Gene', '2990', (162, 166))	('CLTC', 'Gene', '1213', (205, 209))	('NM_001001392.1', 'Var', (36, 50))	('STAT3', 'Gene', '6774', (94, 99))	('clathrin heavy chain', 'Gene', '1213', (183, 203))	('OCT4', 'Gene', '5460', (74, 78))	('NM_139276.2', 'Var', (101, 112))	('CLTC', 'Gene', (205, 209))	('CD44', 'Gene', '960', (30, 34))	('clathrin heavy chain', 'Gene', (183, 203))	('CD44', 'Gene', (30, 34))	('GUSB', 'Gene', (162, 166))	('OCT4', 'Gene', (74, 78))	('NANOG', 'Gene', '79923', (53, 58))	('hypoxanthine phosphoribosyltransferase 1', 'Gene', (228, 268))
532991	28321397	Overexpression of SOX2 in tumors has been correlated with increased tumor thickness and invasion, metastasis in esophageal cancer, drug resistance, and decreased survival in tumors such as breast cancer and lung adenocarcinoma.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (207, 226))	('drug resistance', 'Phenotype', 'HP:0020174', (131, 146))	('breast cancer', 'Phenotype', 'HP:0003002', (189, 202))	('decreased', 'NegReg', (152, 161))	('tumors', 'Phenotype', 'HP:0002664', (174, 180))	('Overexpression', 'Var', (0, 14))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('tumor', 'Disease', (68, 73))	('SOX2', 'Gene', '6657', (18, 22))	('tumors', 'Disease', (174, 180))	('SOX2', 'Gene', (18, 22))	('breast cancer', 'Disease', 'MESH:D001943', (189, 202))	('breast cancer', 'Disease', (189, 202))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Disease', (26, 31))	('esophageal cancer', 'Disease', 'MESH:D004938', (112, 129))	('increased', 'PosReg', (58, 67))	('invasion', 'CPA', (88, 96))	('tumors', 'Disease', 'MESH:D009369', (174, 180))	('drug resistance', 'CPA', (131, 146))	('lung adenocarcinoma', 'Disease', (207, 226))	('metastasis', 'CPA', (98, 108))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('esophageal cancer', 'Disease', (112, 129))	('survival', 'CPA', (162, 170))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('tumor', 'Disease', (174, 179))	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (207, 226))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('carcinoma', 'Phenotype', 'HP:0030731', (217, 226))	('tumors', 'Disease', (26, 32))
532998	28321397	examined 156 pancreatic cancer tissue samples and found that high nuclear expression of pSTAT3 was associated with higher tumor grade and shorter median survival, compared to those with low expression of pSTAT3.	('pancreatic cancer', 'Disease', (13, 30))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('pancreatic cancer', 'Disease', 'MESH:D010190', (13, 30))	('STAT3', 'Gene', '6774', (205, 210))	('high', 'Var', (61, 65))	('shorter', 'NegReg', (138, 145))	('median survival', 'CPA', (146, 161))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('STAT3', 'Gene', (205, 210))	('STAT3', 'Gene', '6774', (89, 94))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (13, 30))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('STAT3', 'Gene', (89, 94))	('tumor', 'Disease', (122, 127))
533012	33225619	Rare case of apatinib acquired resistance induced by point mutation of WRN p.V697F through activation of the PI3K/AKT apoptosis-inhibiting pathway Targeted therapy has become the main treatment for non-small cell lung cancer (NSCLC).	('AKT', 'Gene', '207', (114, 117))	('activation', 'PosReg', (91, 101))	('apatinib', 'Gene', (13, 21))	('induced', 'Reg', (42, 49))	('p.V697F', 'Mutation', 'p.V697F', (75, 82))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (202, 224))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (198, 224))	('NSCLC', 'Disease', 'MESH:D002289', (226, 231))	('point mutation', 'Var', (53, 67))	('apatinib', 'Chemical', 'MESH:C553458', (13, 21))	('NSCLC', 'Disease', (226, 231))	('lung cancer', 'Phenotype', 'HP:0100526', (213, 224))	('p.V697F', 'Var', (75, 82))	('non-small cell lung cancer', 'Disease', (198, 224))	('AKT', 'Gene', (114, 117))	('NSCLC', 'Phenotype', 'HP:0030358', (226, 231))	('men', 'Species', '9606', (189, 192))	('WRN', 'Gene', (71, 74))	('WRN', 'Gene', '7486', (71, 74))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (198, 224))	('acquired', 'Reg', (22, 30))
533023	33225619	A third gene mutation detection test showed that ALK and PTEN genetic mutations were obviously decreased; however, the patient was found to have developed WRN p.V697F (c.G2089T) point mutation, which was a new gene mutation.	('decreased', 'NegReg', (95, 104))	('WRN', 'Gene', (155, 158))	('ALK', 'Gene', '238', (49, 52))	('patient', 'Species', '9606', (119, 126))	('WRN', 'Gene', '7486', (155, 158))	('p.V697F (c.G2089T', 'Var', (159, 176))	('c.G2089T', 'Var', (168, 176))	('PTEN', 'Gene', (57, 61))	('p.V697F', 'Mutation', 'p.V697F', (159, 166))	('PTEN', 'Gene', '5728', (57, 61))	('c.G2089T', 'Mutation', 'c.2089G>T', (168, 176))	('ALK', 'Gene', (49, 52))
533024	33225619	We suspected that the WRN gene mutation had led to apatinib resistance.	('apatinib', 'Chemical', 'MESH:C553458', (51, 59))	('WRN', 'Gene', '7486', (22, 25))	('mutation', 'Var', (31, 39))	('WRN', 'Gene', (22, 25))	('led to', 'Reg', (44, 50))	('apatinib resistance', 'MPA', (51, 70))
533028	33225619	We believe that this report will be of interest to the readership because it expands the known repertoire of mutations that can occur in lung cancer after various treatments, particularly following treatment with apatinib.	('men', 'Species', '9606', (203, 206))	('lung cancer', 'Disease', (137, 148))	('lung cancer', 'Phenotype', 'HP:0100526', (137, 148))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('lung cancer', 'Disease', 'MESH:D008175', (137, 148))	('occur', 'Reg', (128, 133))	('mutations', 'Var', (109, 118))	('men', 'Species', '9606', (168, 171))	('apatinib', 'Chemical', 'MESH:C553458', (213, 221))
533041	33225619	CTCs can be obtained in the blood circulation system or the tumor genomic DNA fragment ctDNA, through high- throughput sequencing, point mutation, fusion gene, insertion and deletion, copy number variation, chromosome rearrangement and other genetic information of the whole tumorous genome.	('tumorous', 'Disease', (275, 283))	('chromosome rearrangement', 'Var', (207, 231))	('tumorous', 'Disease', 'MESH:D009369', (275, 283))	('tumor', 'Disease', 'MESH:D009369', (275, 280))	('tumor', 'Disease', (60, 65))	('tumor', 'Disease', (275, 280))	('men', 'Species', '9606', (227, 230))	('tumor', 'Phenotype', 'HP:0002664', (275, 280))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('deletion', 'Var', (174, 182))	('point mutation', 'Var', (131, 145))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('copy number variation', 'Var', (184, 205))	('fusion gene', 'Var', (147, 158))	('insertion', 'Var', (160, 169))	('men', 'Species', '9606', (82, 85))
533043	33225619	These rare gene mutations have a significant impact on the pathogenesis, resistance and progression of tumors.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('mutations', 'Var', (16, 25))	('tumors', 'Disease', 'MESH:D009369', (103, 109))	('tumors', 'Disease', (103, 109))	('resistance', 'CPA', (73, 83))	('impact', 'Reg', (45, 51))
533060	33225619	Therefore, it was reasonable to assume that the occurrence of the mutation in the WRN gene had led to apatinib resistance in this patient.	('patient', 'Species', '9606', (130, 137))	('WRN', 'Gene', (82, 85))	('WRN', 'Gene', '7486', (82, 85))	('mutation', 'Var', (66, 74))	('apatinib resistance', 'MPA', (102, 121))	('led to', 'Reg', (95, 101))	('apatinib', 'Chemical', 'MESH:C553458', (102, 110))
533062	33225619	The types of WRN p.V697F(c.G2089T) point mutation had obviously increased.	('p.V697F(c.G2089T', 'Var', (17, 33))	('p.V697F', 'Mutation', 'p.V697F', (17, 24))	('c.G2089T', 'Mutation', 'c.2089G>T', (25, 33))	('WRN', 'Gene', (13, 16))	('WRN', 'Gene', '7486', (13, 16))
533063	33225619	At the same time, a new ROS1 p.f339s point mutation had appeared, so it was reasonable to infer that under the pressure of apatinib, the mutation had produced a proliferation of new gene mutation subclones.	('apatinib', 'Chemical', 'MESH:C553458', (123, 131))	('ROS1', 'Gene', (24, 28))	('p.f339s', 'Var', (29, 36))	('ROS1', 'Gene', '6098', (24, 28))
533064	33225619	Hence there are many possibilities as to the appearance of the ROS1 mutation Table 1.	('mutation', 'Var', (68, 76))	('ROS1', 'Gene', (63, 67))	('ROS1', 'Gene', '6098', (63, 67))
533075	33225619	At present, the polynucleotide polymorphism of the WRN gene has been reported to be closely related to breast cancer in Chinese females, prostate cancer, esophageal cancer and non-Hodgkin's lymphoma.	('cancer', 'Disease', (146, 152))	("Hodgkin's lymphoma", 'Phenotype', 'HP:0012189', (180, 198))	('breast cancer', 'Disease', 'MESH:D001943', (103, 116))	('breast cancer', 'Disease', (103, 116))	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	("non-Hodgkin's lymphoma", 'Disease', (176, 198))	('prostate cancer', 'Disease', 'MESH:D011471', (137, 152))	('prostate cancer', 'Phenotype', 'HP:0012125', (137, 152))	('related', 'Reg', (92, 99))	('prostate cancer', 'Disease', (137, 152))	('WRN', 'Gene', (51, 54))	('WRN', 'Gene', '7486', (51, 54))	('cancer', 'Disease', (110, 116))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('lymphoma', 'Phenotype', 'HP:0002665', (190, 198))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('cancer', 'Disease', (165, 171))	('polynucleotide polymorphism', 'Var', (16, 43))	('polynucleotide', 'Chemical', 'MESH:D011119', (16, 30))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	("non-Hodgkin's lymphoma", 'Phenotype', 'HP:0012539', (176, 198))	('breast cancer', 'Phenotype', 'HP:0003002', (103, 116))	("non-Hodgkin's lymphoma", 'Disease', 'MESH:D008228', (176, 198))	('cancer', 'Disease', 'MESH:D009369', (110, 116))
533077	33225619	19 ,  20  In this study, we found that the apatinib resistant gene in a patient with multidrug-resistant, poorly differentiated squamous cell carcinoma is WRN p.V697F(c.G2089T) point mutation.	('WRN', 'Gene', (155, 158))	('WRN', 'Gene', '7486', (155, 158))	('c.G2089T', 'Var', (167, 175))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (128, 151))	('squamous cell carcinoma', 'Disease', (128, 151))	('c.G2089T', 'Mutation', 'c.2089G>T', (167, 175))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (128, 151))	('apatinib', 'Chemical', 'MESH:C553458', (43, 51))	('patient', 'Species', '9606', (72, 79))	('p.V697F', 'Mutation', 'p.V697F', (159, 166))	('carcinoma', 'Phenotype', 'HP:0030731', (142, 151))	('apatinib resistant', 'Gene', (43, 61))
533082	33225619	Meanwhile, the fusion mutation of MINPP1 & PAPSS2-PTEN causes the decrease in the protein phosphorylase and esterase in the PTEN gene,24  thus inducing the antagonistic inhibition of the PI3K/AKT signaling pathway and promoting the upregulation of PIP3, while the receptor of VEGFR2 blockades the downstream signaling pathway of PI3K, promotes the original activation pathway, thus upgrading TP53 and inducing tumor apoptosis.	('PTEN', 'Gene', (124, 128))	('MINPP1', 'Gene', '9562', (34, 40))	('tumor', 'Disease', 'MESH:D009369', (410, 415))	('the protein', 'MPA', (78, 89))	('AKT', 'Gene', '207', (192, 195))	('and', 'Reg', (397, 400))	('the', 'Gene', (120, 123))	('PTEN', 'Gene', '5728', (124, 128))	('tumor', 'Phenotype', 'HP:0002664', (410, 415))	('PTEN', 'Gene', (50, 54))	('TP53', 'Gene', (392, 396))	('MINPP1', 'Gene', (34, 40))	('original activation', 'Pathway', (348, 367))	('PAPSS2', 'Gene', '9060', (43, 49))	('antagonistic', 'NegReg', (156, 168))	('the', 'PosReg', (228, 231))	('PTEN', 'Gene', '5728', (50, 54))	('and', 'PosReg', (214, 217))	('the', 'NegReg', (62, 65))	('VEGFR2', 'Gene', (276, 282))	('thus', 'Reg', (138, 142))	('AKT', 'Gene', (192, 195))	('TP53', 'Gene', '7157', (392, 396))	('fusion mutation', 'Var', (15, 30))	('thus', 'PosReg', (377, 381))	('upgrading', 'MPA', (382, 391))	('tumor', 'Disease', (410, 415))	('VEGFR2', 'Gene', '3791', (276, 282))	('PAPSS2', 'Gene', (43, 49))
533084	33225619	Therefore we hypothesized that due to the suppressive effect of apatinib, the point mutation of WRN p.V697F(c.G2089T) might be responsible for inducing gene activation, thus the binding rate of RQC structural domain in WRN gene and TP53 increased, which again led to inactivation of TP53.	('TP53', 'Gene', (283, 287))	('increased', 'PosReg', (237, 246))	('WRN', 'Gene', (96, 99))	('WRN', 'Gene', (219, 222))	('gene', 'MPA', (152, 156))	('c.G2089T', 'Mutation', 'c.2089G>T', (108, 116))	('WRN', 'Gene', '7486', (96, 99))	('apatinib', 'Chemical', 'MESH:C553458', (64, 72))	('p.V697F(c.G2089T', 'Var', (100, 116))	('p.V697F', 'Mutation', 'p.V697F', (100, 107))	('c.G2089T', 'Var', (108, 116))	('TP53', 'Gene', '7157', (283, 287))	('activation', 'PosReg', (157, 167))	('TP53', 'Gene', '7157', (232, 236))	('TP53', 'Gene', (232, 236))	('inducing', 'PosReg', (143, 151))	('WRN', 'Gene', '7486', (219, 222))	('binding', 'Interaction', (178, 185))
533094	33329742	In the results, we identified serum miR-4687-3p that provided a high diagnostic accuracy of NSCLC (AUC = 0.679, 95%CI: 0.543-0.815) in the validation cohort.	('NSCLC', 'Phenotype', 'HP:0030358', (92, 97))	('miR-4687-3p', 'Chemical', '-', (36, 47))	('NSCLC', 'Disease', (92, 97))	('miR-4687-3p', 'Var', (36, 47))	('NSCLC', 'Disease', 'MESH:D002289', (92, 97))
533098	33329742	Meanwhile, overexpression of miR-4687-3p could promote the proliferation, invasion, and migration of the NSCLC cells compared with mimic NC.	('NSCLC', 'Disease', 'MESH:D002289', (105, 110))	('proliferation', 'CPA', (59, 72))	('miR-4687-3p', 'Var', (29, 40))	('invasion', 'CPA', (74, 82))	('NSCLC', 'Phenotype', 'HP:0030358', (105, 110))	('promote', 'PosReg', (47, 54))	('miR-4687-3p', 'Chemical', '-', (29, 40))	('migration', 'CPA', (88, 97))	('NSCLC', 'Disease', (105, 110))	('overexpression', 'PosReg', (11, 25))
533099	33329742	As a conclusion, our study first discovered that serum miR-4687-3p might have clinical potential as a non-invasive diagnostic biomarker for NSCLC and play an important role in the development of NSCLC.	('NSCLC', 'Disease', 'MESH:D002289', (195, 200))	('miR-4687-3p', 'Chemical', '-', (55, 66))	('NSCLC', 'Disease', 'MESH:D002289', (140, 145))	('NSCLC', 'Disease', (140, 145))	('NSCLC', 'Phenotype', 'HP:0030358', (195, 200))	('miR-4687-3p', 'Var', (55, 66))	('NSCLC', 'Phenotype', 'HP:0030358', (140, 145))	('NSCLC', 'Disease', (195, 200))	('serum miR-4687-3p', 'Var', (49, 66))
533144	33329742	In addition, miR-4687-3p provided a higher diagnostic accuracy of NSCLC than the other five miRNAs (AUC = 0.679, 95% CI: 0.543-0.815) (Figures 3C,D).	('miR-4687-3p', 'Var', (13, 24))	('higher', 'PosReg', (36, 42))	('NSCLC', 'Disease', (66, 71))	('NSCLC', 'Disease', 'MESH:D002289', (66, 71))	('miR-4687-3p', 'Chemical', '-', (13, 24))	('NSCLC', 'Phenotype', 'HP:0030358', (66, 71))
533145	33329742	The AUC of the combination of miR-4687-3p and miR-6087 using logistic regression model reached 0.780 (95%CI: 0.662-0.898) (Figure 3E).	('miR-6087', 'Gene', '102464835', (46, 54))	('miR-6087', 'Gene', (46, 54))	('miR-4687-3p', 'Var', (30, 41))	('miR-4687-3p', 'Chemical', '-', (30, 41))
533146	33329742	According to the TCGA database of NSCLC, the expression of the tissue miR-4687-3p was higher both in LUAD (Figure 4A) and LUSC (Figure 4B) than corresponding normal tissues (p < 0.05).	('NSCLC', 'Disease', (34, 39))	('NSCLC', 'Disease', 'MESH:D002289', (34, 39))	('miR-4687-3p', 'Var', (70, 81))	('LUAD', 'Phenotype', 'HP:0030078', (101, 105))	('NSCLC', 'Phenotype', 'HP:0030358', (34, 39))	('expression', 'MPA', (45, 55))	('higher', 'PosReg', (86, 92))	('miR-4687-3p', 'Chemical', '-', (70, 81))
533147	33329742	To explore the mechanism in the process of miR-4687-3p regulating NSCLC cell progression, we predicted the target genes of miR-4687-3p by using TargetScan, which provided 3,851 target genes.	('NSCLC', 'Disease', (66, 71))	('NSCLC', 'Disease', 'MESH:D002289', (66, 71))	('miR-4687-3p', 'Chemical', '-', (43, 54))	('miR-4687-3p', 'Chemical', '-', (123, 134))	('NSCLC', 'Phenotype', 'HP:0030358', (66, 71))	('miR-4687-3p', 'Var', (123, 134))
533152	33329742	The results showed that down-regulation of miR-4687-3p with inhibitor could markedly suppress the proliferation (Figure 7A), invasion (Figures 8A-C), and migration (Figures 9A-C) in CALU-3 cells compared to inhibitor NC, respectively.	('miR-4687-3p', 'Var', (43, 54))	('down-regulation', 'NegReg', (24, 39))	('miR-4687-3p', 'Chemical', '-', (43, 54))	('migration', 'CPA', (154, 163))	('suppress', 'NegReg', (85, 93))	('invasion', 'CPA', (125, 133))
533153	33329742	Overexpressed miR-4687-3p by using mimic could promote the proliferation (Figure 7B), invasion (Figures 8D-F), and migration (Figures 9D-F) of PC-9 cells, compared to the mimic NC, respectively.	('proliferation', 'CPA', (59, 72))	('migration', 'CPA', (115, 124))	('miR-4687-3p', 'Var', (14, 25))	('promote', 'PosReg', (47, 54))	('PC-9', 'CellLine', 'CVCL:B260', (143, 147))	('invasion', 'CPA', (86, 94))	('miR-4687-3p', 'Chemical', '-', (14, 25))
533154	33329742	In the study, serum miR-4687-3p was discovered up-regulated in NSCLC, compared to the healthy, and showed a remarkable differential diagnosis value for the first time.	('NSCLC', 'Disease', (63, 68))	('NSCLC', 'Disease', 'MESH:D002289', (63, 68))	('NSCLC', 'Phenotype', 'HP:0030358', (63, 68))	('serum miR-4687-3p', 'Var', (14, 31))	('up-regulated', 'PosReg', (47, 59))	('miR-4687-3p', 'Chemical', '-', (20, 31))
533166	33329742	By bioinformatics analysis, we revealed that miR-4687-3p owned 3,851 target genes, which significantly enriched the TGF-beta signaling pathway.	('TGF-beta', 'Gene', '7039', (116, 124))	('miR-4687-3p', 'Chemical', '-', (45, 56))	('miR-4687-3p', 'Var', (45, 56))	('TGF-beta', 'Gene', (116, 124))
533169	33329742	In the present study, the target genes enriched in the TGF-beta pathway implied that the miR-4687-3p might serve as a promoter affected the carcinogenesis of NSCLC.	('TGF-beta', 'Gene', (55, 63))	('miR-4687-3p', 'Var', (89, 100))	('affected', 'Reg', (127, 135))	('carcinogenesis of NSCLC', 'Disease', (140, 163))	('TGF-beta', 'Gene', '7039', (55, 63))	('NSCLC', 'Phenotype', 'HP:0030358', (158, 163))	('miR-4687-3p', 'Chemical', '-', (89, 100))	('carcinogenesis of NSCLC', 'Disease', 'MESH:D063646', (140, 163))
533170	33329742	Down-regulation miR-4687-3p could suppress the proliferation, invasion, and migration of NSCLC cells, while overexpression miR-4687-3p had the opposite effects.	('NSCLC', 'Disease', 'MESH:D002289', (89, 94))	('Down-regulation', 'Var', (0, 15))	('miR-4687-3p', 'Chemical', '-', (16, 27))	('NSCLC', 'Phenotype', 'HP:0030358', (89, 94))	('miR-4687-3p', 'Gene', (16, 27))	('invasion', 'CPA', (62, 70))	('miR-4687-3p', 'Chemical', '-', (123, 134))	('proliferation', 'CPA', (47, 60))	('suppress', 'NegReg', (34, 42))	('NSCLC', 'Disease', (89, 94))
533171	33329742	Importantly, data from the present study revealed that miR-4687-3p as a tumor promoter could promote tumor growth.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('miR-4687-3p', 'Chemical', '-', (55, 66))	('tumor', 'Disease', (72, 77))	('promote', 'PosReg', (93, 100))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('miR-4687-3p', 'Var', (55, 66))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('tumor', 'Disease', 'MESH:D009369', (101, 106))
533172	33329742	In conclusion, our results strongly suggested that serum miR-4687-3p overexpressed in NSCLC and miR-4687-3p could promote the growth and migration of NSCLC cells, which demonstrated that serum miR-4687-3p could be a novel and favorable biomarker for NSCLC.	('miR-4687-3p', 'Chemical', '-', (96, 107))	('NSCLC', 'Disease', 'MESH:D002289', (250, 255))	('NSCLC', 'Disease', 'MESH:D002289', (150, 155))	('NSCLC', 'Phenotype', 'HP:0030358', (250, 255))	('NSCLC', 'Disease', (86, 91))	('miR-4687-3p', 'Chemical', '-', (193, 204))	('miR-4687-3p', 'Chemical', '-', (57, 68))	('miR-4687-3p', 'Var', (96, 107))	('NSCLC', 'Disease', 'MESH:D002289', (86, 91))	('NSCLC', 'Phenotype', 'HP:0030358', (150, 155))	('NSCLC', 'Disease', (250, 255))	('NSCLC', 'Phenotype', 'HP:0030358', (86, 91))	('NSCLC', 'Disease', (150, 155))	('growth', 'CPA', (126, 132))	('promote', 'PosReg', (114, 121))
533175	33329742	We found that miR-4687-3p possesses the potency to promote NSCLC cells growth, migration, and invasion.	('invasion', 'CPA', (94, 102))	('migration', 'CPA', (79, 88))	('NSCLC', 'Disease', 'MESH:D002289', (59, 64))	('miR-4687-3p', 'Var', (14, 25))	('NSCLC', 'Phenotype', 'HP:0030358', (59, 64))	('miR-4687-3p', 'Chemical', '-', (14, 25))	('promote', 'PosReg', (51, 58))	('NSCLC', 'Disease', (59, 64))
533176	33329742	Our findings suggest that miR-4687-3p functions as a tumor promoter in NSCLC and holds promise as a prognostic biomarker and potential therapeutic target for NSCLC.	('NSCLC', 'Disease', (158, 163))	('NSCLC', 'Phenotype', 'HP:0030358', (71, 76))	('NSCLC', 'Disease', 'MESH:D002289', (158, 163))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('miR-4687-3p', 'Chemical', '-', (26, 37))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('NSCLC', 'Phenotype', 'HP:0030358', (158, 163))	('tumor', 'Disease', (53, 58))	('NSCLC', 'Disease', (71, 76))	('miR-4687-3p', 'Var', (26, 37))	('NSCLC', 'Disease', 'MESH:D002289', (71, 76))
533178	33329742	In this research, we evaluated the role of miR-4687-3p in NSCLC, but we did not identify the underlying molecular mechanisms.	('miR-4687-3p', 'Var', (43, 54))	('NSCLC', 'Disease', (58, 63))	('NSCLC', 'Disease', 'MESH:D002289', (58, 63))	('miR-4687-3p', 'Chemical', '-', (43, 54))	('NSCLC', 'Phenotype', 'HP:0030358', (58, 63))
533296	32442178	Dr Lambin has shares in the company Oncoradiomics SA and Convert pharmaceuticals SA and is co-inventor of two issued patents with royalties on radiomics (PCT/NL2014/050248, PCT/NL2014/050728) licensed to Oncoradiomics and one issue patent on mtDNA (PCT/EP2014/059089) licensed to ptTheragnostic/DNAmito, three non-patentable invention (softwares) licensed to  ptTheragnostic/DNAmito, Oncoradiomics and Health Innovation Ventures.	('N', 'Chemical', 'MESH:D009584', (245, 246))	('N', 'Chemical', 'MESH:D009584', (177, 178))	('PCT/NL2014/050728', 'Var', (173, 190))	('PCT/NL2014/050248', 'Var', (154, 171))	('N', 'Chemical', 'MESH:D009584', (158, 159))	('N', 'Chemical', 'MESH:D009584', (296, 297))	('N', 'Chemical', 'MESH:D009584', (376, 377))
533408	32226511	Importantly, high PSMD14 expression was associated with poor overall survival (OS) and disease-free survival (DFS) in LUAD patients.	('poor', 'NegReg', (56, 60))	('OS', 'Chemical', '-', (79, 81))	('high', 'Var', (13, 17))	('expression', 'MPA', (25, 35))	('PSMD14', 'Gene', (18, 24))	('patients', 'Species', '9606', (123, 131))	('PSMD14', 'Gene', '10213', (18, 24))	('disease-free survival', 'CPA', (87, 108))	('LUAD', 'Phenotype', 'HP:0030078', (118, 122))	('overall survival', 'CPA', (61, 77))
533409	32226511	Further, knockdown of PSMD14 significantly inhibited cell growth and caused G1 arrest and cellular senescence by increasing p21 stability in LUAD cells.	('arrest', 'Disease', 'MESH:D006323', (79, 85))	('knockdown', 'Var', (9, 18))	('caused', 'Reg', (69, 75))	('cell growth', 'CPA', (53, 64))	('inhibited', 'NegReg', (43, 52))	('increasing', 'PosReg', (113, 123))	('LUAD', 'Phenotype', 'HP:0030078', (141, 145))	('p21', 'Gene', (124, 127))	('arrest', 'Disease', (79, 85))	('p21', 'Gene', '644914', (124, 127))	('PSMD14', 'Gene', (22, 28))	('cellular senescence', 'CPA', (90, 109))	('PSMD14', 'Gene', '10213', (22, 28))
533410	32226511	PSMD14 knockdown also promoted cell apoptosis by increasing cleaved caspase-3 levels in H1299 cells.	('caspase-3', 'Gene', '836', (68, 77))	('PSMD14', 'Gene', (0, 6))	('PSMD14', 'Gene', '10213', (0, 6))	('promoted', 'PosReg', (22, 30))	('caspase-3', 'Gene', (68, 77))	('increasing', 'PosReg', (49, 59))	('cell apoptosis', 'CPA', (31, 45))	('knockdown', 'Var', (7, 16))
533429	32226511	High PSMD14 expression predicted a poor overall survival (OS) and disease-free survival (DFS) in lung adenocarcinoma (LUAD) patients.	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (97, 116))	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('OS', 'Chemical', '-', (58, 60))	('poor', 'NegReg', (35, 39))	('High', 'Var', (0, 4))	('lung adenocarcinoma', 'Disease', (97, 116))	('overall survival', 'CPA', (40, 56))	('disease-free survival', 'CPA', (66, 87))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (97, 116))	('LUAD', 'Phenotype', 'HP:0030078', (118, 122))	('PSMD14', 'Gene', (5, 11))	('PSMD14', 'Gene', '10213', (5, 11))	('patients', 'Species', '9606', (124, 132))
533439	32226511	To determine PSMD14 expression in NSCLC patients, we also analyzed and compared the data from Gene Expression Omnibus (GEO; https://www.ncbi.nlm.nih.gov/geoprofiles/17271077) under the following accession numbers: human adjacent normal lung (GSM47958 to GSM47976) and LUAD (GSM36757 to GSM36776).	('NSCLC', 'Disease', (34, 39))	('PSMD14', 'Gene', '10213', (13, 19))	('LUAD', 'Phenotype', 'HP:0030078', (268, 272))	('patients', 'Species', '9606', (40, 48))	('NSCLC', 'Disease', 'MESH:D002289', (34, 39))	('GSM36757 to GSM36776', 'Var', (274, 294))	('NSCLC', 'Phenotype', 'HP:0030358', (34, 39))	('human', 'Species', '9606', (214, 219))	('GSM47958', 'Var', (242, 250))	('GSM47976', 'Var', (254, 262))	('PSMD14', 'Gene', (13, 19))
533450	32226511	The tissues and cells were collected and homogenized in lysis buffer (P0013, Beyotime, Shanghai, China) containing protease inhibitor cocktail (P8340, Sigma, St Louis, Missouri, USA).	('SA', 'Chemical', 'MESH:C012546', (179, 181))	('P8340', 'Var', (144, 149))	('P0013', 'Var', (70, 75))
533453	32226511	The membranes were blocked in 5% nonfat milk for 1 h at room temperature (RT) and subsequently incubated overnight at 4 C with the following primary antibodies: PSMD14 (4197, Cell Signaling Technology, Danvers, MA, USA), p53 (sc-126, Santa Cruz Biotechnology, CA, USA), p21 (sc-53870, Santa Cruz), PUMA (sc-377015, Santa Cruz), caspase-3 (19677, Proteintech, Rosemont, IL, USA), cleaved caspase-3 (9661, Cell Signaling Technology, Danvers, MA, USA), and GAPDH (G9545, Sigma).	('caspase-3', 'Gene', '836', (328, 337))	('SA', 'Chemical', 'MESH:C012546', (374, 376))	('SA', 'Chemical', 'MESH:C012546', (216, 218))	('PSMD14', 'Gene', (161, 167))	('PSMD14', 'Gene', '10213', (161, 167))	('SA', 'Chemical', 'MESH:C012546', (265, 267))	('GAPDH', 'Gene', '2597', (454, 459))	('GAPDH', 'Gene', (454, 459))	('cleaved', 'Var', (379, 386))	('sc-377015', 'Var', (304, 313))	('p53', 'Gene', (221, 224))	('caspase-3', 'Gene', (387, 396))	('caspase-3', 'Gene', (328, 337))	('p53', 'Gene', '7157', (221, 224))	('SA', 'Chemical', 'MESH:C012546', (445, 447))	('p21', 'Gene', (270, 273))	('caspase-3', 'Gene', '836', (387, 396))	('p21', 'Gene', '644914', (270, 273))
533463	32226511	Immunohistochemical staining was observed using a Leica upright microscope (DM4000B, Leica Microsystems, Heidelberg, Germany).	('Leica Microsystems', 'Disease', '-', (85, 103))	('Leica Microsystems', 'Disease', (85, 103))	('DM4000B', 'Var', (76, 83))
533500	32226511	indicated that the knockdown of human deubiquitinase PSMD14 induces cell cycle arrest and senescence in human tumor cells.	('arrest', 'Disease', 'MESH:D006323', (79, 85))	('induces', 'Reg', (60, 67))	('senescence', 'CPA', (90, 100))	('knockdown', 'Var', (19, 28))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('arrest', 'Disease', (79, 85))	('human', 'Species', '9606', (104, 109))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (68, 85))	('PSMD14', 'Gene', (53, 59))	('PSMD14', 'Gene', '10213', (53, 59))	('human', 'Species', '9606', (32, 37))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
533506	32226511	To better understand the effect of PSMD14 knockdown on decreased cell viability, we examined cell cycle and apoptosis by PI staining followed by flow cytometry analysis.	('examined', 'Reg', (84, 92))	('PSMD14', 'Gene', (35, 41))	('PSMD14', 'Gene', '10213', (35, 41))	('cell viability', 'CPA', (65, 79))	('knockdown', 'Var', (42, 51))
533507	32226511	PSMD14 knockdown resulted in G1 phase arrest and decreased S phase in both H1299 and A549 cells.	('arrest', 'Disease', (38, 44))	('PSMD14', 'Gene', (0, 6))	('PSMD14', 'Gene', '10213', (0, 6))	('S phase', 'CPA', (59, 66))	('decreased', 'NegReg', (49, 58))	('knockdown', 'Var', (7, 16))	('arrest', 'Disease', 'MESH:D006323', (38, 44))
533508	32226511	Moreover, PSMD14 knockdown induced significant cell apoptosis (sub-G1 peak) in H1299 cells but not in A549 cells (Fig.	('knockdown', 'Var', (17, 26))	('PSMD14', 'Gene', (10, 16))	('PSMD14', 'Gene', '10213', (10, 16))	('cell apoptosis', 'CPA', (47, 61))
533510	32226511	We found cell morphology changed from spindle shape to an enlarged, flattened and irregular shape after PSMD14 was knocked down from H1299 and A549 cells.	('spindle shape', 'CPA', (38, 51))	('PSMD14', 'Gene', (104, 110))	('flattened', 'CPA', (68, 77))	('PSMD14', 'Gene', '10213', (104, 110))	('knocked down', 'Var', (115, 127))	('changed', 'Reg', (25, 32))	('cell morphology', 'CPA', (9, 24))
533511	32226511	SA-beta-Gal staining was conducted to evaluate cellular senescence after the PSMD14 knockdown.	('PSMD14', 'Gene', (77, 83))	('beta-Gal', 'Chemical', '-', (3, 11))	('knockdown', 'Var', (84, 93))	('PSMD14', 'Gene', '10213', (77, 83))
533513	32226511	These results indicated that knockdown of PSMD14 significantly enhanced cellular senescence.	('PSMD14', 'Gene', (42, 48))	('knockdown', 'Var', (29, 38))	('PSMD14', 'Gene', '10213', (42, 48))	('enhanced', 'PosReg', (63, 71))	('cellular senescence', 'CPA', (72, 91))
533514	32226511	Consistently, knockdown of PSMD14 expression significantly increased p21 levels in both cell lines and also increased cleaved caspase-3 levels in H1299 cells.	('caspase-3', 'Gene', '836', (126, 135))	('PSMD14', 'Gene', (27, 33))	('p21', 'Gene', (69, 72))	('increased', 'PosReg', (108, 117))	('p21', 'Gene', '644914', (69, 72))	('PSMD14', 'Gene', '10213', (27, 33))	('knockdown', 'Var', (14, 23))	('caspase-3', 'Gene', (126, 135))	('increased', 'PosReg', (59, 68))
533515	32226511	We also observed that p53 and PUMA levels were increased in A549 cells whereas caspase-3 expression remained unchanged following PSMD14 knockdown in both cell lines (Fig.	('expression', 'MPA', (89, 99))	('PSMD14', 'Gene', '10213', (129, 135))	('caspase-3', 'Gene', '836', (79, 88))	('p53', 'Gene', (22, 25))	('knockdown', 'Var', (136, 145))	('increased', 'PosReg', (47, 56))	('p53', 'Gene', '7157', (22, 25))	('caspase-3', 'Gene', (79, 88))	('PSMD14', 'Gene', (129, 135))
533516	32226511	To investigate whether the knockdown of PSMD14 affects protein stability, we examined the half-life of p53, p21, and PUMA after the cells were treated with CHX to block protein synthesis.	('knockdown', 'Var', (27, 36))	('CHX', 'Chemical', 'MESH:D003513', (156, 159))	('p53', 'Gene', (103, 106))	('p53', 'Gene', '7157', (103, 106))	('p21', 'Gene', (108, 111))	('p21', 'Gene', '644914', (108, 111))	('protein stability', 'MPA', (55, 72))	('PSMD14', 'Gene', (40, 46))	('PSMD14', 'Gene', '10213', (40, 46))
533518	32226511	Importantly, p53 and p21 protein stabilities were significantly increased after PSMD14 was knocked down in A549 cells (Fig.	('p21', 'Gene', (21, 24))	('p21', 'Gene', '644914', (21, 24))	('PSMD14', 'Gene', (80, 86))	('PSMD14', 'Gene', '10213', (80, 86))	('p53', 'Gene', (13, 16))	('increased', 'PosReg', (64, 73))	('knocked down', 'Var', (91, 103))	('p53', 'Gene', '7157', (13, 16))
533526	32226511	Consistently, high PSMD14 levels were closely related to larger tumor size, lymph node metastases, and advanced TNM stage, with a predicted poor OS and DFS in LUAD patients.	('metastases', 'Disease', (87, 97))	('tumor', 'Disease', (64, 69))	('related', 'Reg', (46, 53))	('OS', 'Chemical', '-', (145, 147))	('TNM', 'Gene', (112, 115))	('LUAD', 'Phenotype', 'HP:0030078', (159, 163))	('metastases', 'Disease', 'MESH:D009362', (87, 97))	('high', 'Var', (14, 18))	('patients', 'Species', '9606', (164, 172))	('poor', 'NegReg', (140, 144))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('PSMD14', 'Gene', (19, 25))	('PSMD14', 'Gene', '10213', (19, 25))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('TNM', 'Gene', '10178', (112, 115))
533529	32226511	We found that PSMD14 knockdown inhibited cell survival by inducing G1 phase cell cycle arrest and cellular senescence in both cell lines.	('inducing', 'NegReg', (58, 66))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (76, 93))	('arrest', 'Disease', 'MESH:D006323', (87, 93))	('cellular senescence', 'CPA', (98, 117))	('PSMD14', 'Gene', (14, 20))	('PSMD14', 'Gene', '10213', (14, 20))	('arrest', 'Disease', (87, 93))	('inhibited', 'NegReg', (31, 40))	('knockdown', 'Var', (21, 30))	('cell survival', 'CPA', (41, 54))
533530	32226511	These findings were consistent with the previous report by Ann Byrne et al., which indicated that knockdown of human deubiquitinase PSMD14 induced cell cycle arrest and senescence in human tumor cells.	('tumor', 'Disease', (189, 194))	('senescence', 'CPA', (169, 179))	('knockdown', 'Var', (98, 107))	('human', 'Species', '9606', (111, 116))	('PSMD14', 'Gene', (132, 138))	('PSMD14', 'Gene', '10213', (132, 138))	('human', 'Species', '9606', (183, 188))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (147, 164))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('arrest', 'Disease', 'MESH:D006323', (158, 164))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('arrest', 'Disease', (158, 164))
533533	32226511	These findings indicated that PSMD14 knockdown suppressed tumor growth by triggering different molecular pathways in the LUAD cells.	('PSMD14', 'Gene', '10213', (30, 36))	('tumor', 'Disease', (58, 63))	('triggering', 'Reg', (74, 84))	('molecular pathways', 'Pathway', (95, 113))	('suppressed', 'NegReg', (47, 57))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('LUAD', 'Phenotype', 'HP:0030078', (121, 125))	('knockdown', 'Var', (37, 46))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('PSMD14', 'Gene', (30, 36))
533536	32226511	We detected a significant increase in p53 levels, concomitantly with an increase in p21 and PUMA levels after PSMD14 depletion in p53 wild-type A549 cells.	('increase', 'PosReg', (72, 80))	('p53', 'Gene', (38, 41))	('p53', 'Gene', '7157', (38, 41))	('PUMA levels', 'MPA', (92, 103))	('PSMD14', 'Gene', (110, 116))	('PSMD14', 'Gene', '10213', (110, 116))	('depletion', 'Var', (117, 126))	('p53', 'Gene', (130, 133))	('p21', 'Gene', (84, 87))	('increase', 'PosReg', (26, 34))	('p21', 'Gene', '644914', (84, 87))	('p53', 'Gene', '7157', (130, 133))
533538	32226511	Supportively, we found that p21 was upregulated in both p53 null H1299 and p53 wild-type A549 cells after PSMD14 expression was ablated, suggesting that PSMD14 regulated cell cycle and senescence through a p53-independent pathway.	('p53', 'Gene', (206, 209))	('PSMD14', 'Gene', (106, 112))	('upregulated', 'PosReg', (36, 47))	('regulated', 'Reg', (160, 169))	('PSMD14', 'Gene', '10213', (106, 112))	('p53', 'Gene', '7157', (206, 209))	('p53', 'Gene', (56, 59))	('p21', 'Gene', (28, 31))	('p53', 'Gene', '7157', (56, 59))	('p21', 'Gene', '644914', (28, 31))	('p53', 'Gene', (75, 78))	('ablated', 'Var', (128, 135))	('PSMD14', 'Gene', (153, 159))	('senescence', 'CPA', (185, 195))	('p53', 'Gene', '7157', (75, 78))	('PSMD14', 'Gene', '10213', (153, 159))	('cell cycle', 'CPA', (170, 180))
533540	32226511	Proteasome disruption caused by PSMD14 depletion will lead to abnormal accumulation of these proteins.	('depletion', 'Var', (39, 48))	('lead to', 'Reg', (54, 61))	('PSMD14', 'Gene', (32, 38))	('PSMD14', 'Gene', '10213', (32, 38))	('accumulation of these proteins', 'MPA', (71, 101))	('Proteasome disruption', 'MPA', (0, 21))
533542	32226511	The high PSMD14 expression was associated with progressive disease and predicted poor OS and DFS in LUAD patients.	('patients', 'Species', '9606', (105, 113))	('LUAD', 'Phenotype', 'HP:0030078', (100, 104))	('OS', 'Chemical', '-', (86, 88))	('associated with', 'Reg', (31, 46))	('PSMD14', 'Gene', (9, 15))	('PSMD14', 'Gene', '10213', (9, 15))	('high', 'Var', (4, 8))	('DFS', 'Disease', (93, 96))	('progressive disease', 'Disease', (47, 66))	('poor OS', 'Disease', (81, 88))
533560	32210580	However, only a small portion of patients benefit from molecular targeted therapy or immunotherapy and do not develop therapeutic resistance.	('patients', 'Species', '9606', (33, 41))	('molecular targeted', 'Var', (55, 73))	('benefit', 'Reg', (42, 49))
533571	32210580	BMS582949, MK2206, SP600125 and AZD0530 were obtained from Selleck Chemicals LLC (Houston, TX, USA).	('SP600125', 'Chemical', 'MESH:C432165', (19, 27))	('AZD0530', 'Chemical', 'MESH:C515233', (32, 39))	('MK2206', 'Chemical', 'MESH:C548887', (11, 17))	('SP600125', 'Var', (19, 27))	('AZD0530', 'Var', (32, 39))	('BMS582949', 'Chemical', 'MESH:C552704', (0, 9))	('MK2206', 'Var', (11, 17))
533613	32210580	To identify the role of the 5-HT7 receptor in NSCLC progression, we used small interfering RNA to knockdown the gene expression of 5-HT7 receptor in two NSCLC cell lines: A549 and H1299.	('knockdown', 'Var', (98, 107))	('NSCLC', 'Disease', (46, 51))	('NSCLC', 'Disease', (153, 158))	('NSCLC', 'Disease', 'MESH:D002289', (46, 51))	('NSCLC', 'Disease', 'MESH:D002289', (153, 158))
533614	32210580	As shown, 5-HT7 receptor knockdown notably reduced the colony formation of the two NSCLC cell lines (Figure 3B) and decreased the rate of NSCLC cell proliferation (Figure 3C).	('rate', 'MPA', (130, 134))	('5-HT7 receptor', 'Protein', (10, 24))	('colony formation of the two', 'CPA', (55, 82))	('NSCLC', 'Disease', (138, 143))	('NSCLC', 'Disease', (83, 88))	('NSCLC', 'Disease', 'MESH:D002289', (138, 143))	('NSCLC', 'Disease', 'MESH:D002289', (83, 88))	('knockdown', 'Var', (25, 34))	('reduced', 'NegReg', (43, 50))	('decreased', 'NegReg', (116, 125))
533616	32210580	Knockdown of the 5-HT7 receptor caused decreased PCNA and survivin expression compared with that seen in NSCLC cells treated with the nontargeting negative control (Figure 4A, B, D, E).	('NSCLC', 'Disease', 'MESH:D002289', (105, 110))	('survivin', 'Protein', (58, 66))	('Knockdown', 'Var', (0, 9))	('PCNA', 'Gene', (49, 53))	('decreased', 'NegReg', (39, 48))	('NSCLC', 'Disease', (105, 110))	('PCNA', 'Gene', '5111', (49, 53))
533617	32210580	There was a significant downregulation of the expression of MMP9 (matrix metalloproteinase-9), a positive regulator of cancer cell metastasis, in 5-HT7 receptor knockdown A549 and H1299 cells (Figure 4A, B, D, E).	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('downregulation', 'NegReg', (24, 38))	('matrix metalloproteinase-9', 'Gene', (66, 92))	('cancer', 'Disease', (119, 125))	('knockdown', 'Var', (161, 170))	('MMP9', 'Gene', '4318', (60, 64))	('MMP9', 'Gene', (60, 64))	('expression', 'MPA', (46, 56))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('matrix metalloproteinase-9', 'Gene', '4318', (66, 92))
533618	32210580	We examined the mTOR, Akt, Src and MAPK family signaling pathways and discovered that the phosphorylation of Akt, Src and P38 was notably inhibited in A549 cells (Figure 4A and C) after transfection, but the phosphorylation of mTOR, JNK, and ERK was not inhibited.	('mTOR', 'Gene', (227, 231))	('ERK', 'Gene', (242, 245))	('Akt', 'Gene', (22, 25))	('inhibited', 'NegReg', (138, 147))	('Akt', 'Gene', (109, 112))	('P38', 'Gene', '5594', (122, 125))	('Akt', 'Gene', '207', (22, 25))	('mTOR', 'Gene', '2475', (227, 231))	('Akt', 'Gene', '207', (109, 112))	('P38', 'Gene', (122, 125))	('Src', 'Gene', (27, 30))	('Src', 'Gene', (114, 117))	('mTOR', 'Gene', (16, 20))	('JNK', 'Gene', (233, 236))	('transfection', 'Var', (186, 198))	('JNK', 'Gene', '5599', (233, 236))	('ERK', 'Gene', '5594', (242, 245))	('Src', 'Gene', '6714', (27, 30))	('mTOR', 'Gene', '2475', (16, 20))	('phosphorylation', 'MPA', (90, 105))	('Src', 'Gene', '6714', (114, 117))
533619	32210580	In H1299 cells, we detected that 5-HT7 receptor deficiency markedly suppressed the phosphorylation of JNK and Src (Figure 4D and F), but it did not suppress the phosphorylation of mTOR, Akt, ERK and P38.	('5-HT7 receptor', 'Protein', (33, 47))	('ERK', 'Gene', '5594', (191, 194))	('Akt', 'Gene', '207', (186, 189))	('mTOR', 'Gene', (180, 184))	('P38', 'Gene', (199, 202))	('ERK', 'Gene', (191, 194))	('mTOR', 'Gene', '2475', (180, 184))	('suppressed', 'NegReg', (68, 78))	('Akt', 'Gene', (186, 189))	('deficiency', 'Var', (48, 58))	('phosphorylation', 'MPA', (83, 98))	('JNK', 'Gene', (102, 105))	('Src', 'Gene', (110, 113))	('Src', 'Gene', '6714', (110, 113))	('JNK', 'Gene', '5599', (102, 105))	('P38', 'Gene', '5594', (199, 202))
533620	32210580	LP211, a selective agonist of the 5-HT7 receptor, was employed to activate 5-HT7 receptor downstream signaling in NSCLC cells.	('LP211', 'Var', (0, 5))	('LP211', 'Chemical', 'MESH:C573815', (0, 5))	('activate', 'PosReg', (66, 74))	('NSCLC', 'Disease', (114, 119))	('NSCLC', 'Disease', 'MESH:D002289', (114, 119))
533621	32210580	After a 2 h incubation with LP211, at concentrations that varied from 10 nM to 100 nM, A549 cells were harvested to detect the phosphorylation of Akt, Src and P38 signaling pathway proteins.	('P38', 'Gene', '5594', (159, 162))	('phosphorylation', 'MPA', (127, 142))	('Src', 'Gene', (151, 154))	('Src', 'Gene', '6714', (151, 154))	('Akt', 'Gene', (146, 149))	('P38', 'Gene', (159, 162))	('LP211', 'Var', (28, 33))	('LP211', 'Chemical', 'MESH:C573815', (28, 33))	('Akt', 'Gene', '207', (146, 149))
533623	32210580	Two NSCLC cell lines were cultured with different concentrations of LP211 until visible cell clusters formed (8 days).	('NSCLC', 'Disease', 'MESH:D002289', (4, 9))	('LP211', 'Var', (68, 73))	('LP211', 'Chemical', 'MESH:C573815', (68, 73))	('NSCLC', 'Disease', (4, 9))
533626	32210580	After treatment with or without 10 nM LP211, NSCLC cells were harvested at various times.	('NSCLC', 'Disease', 'MESH:D002289', (45, 50))	('NSCLC', 'Disease', (45, 50))	('LP211', 'Var', (38, 43))	('LP211', 'Chemical', 'MESH:C573815', (38, 43))
533630	32210580	Given these findings, A549 cells were incubated with 10 nM LP211 for 12 h before testing for migration and invasion, while H1299 cells were treated for 24 h. As expected, LP211 notably enhanced the migration and invasion capacities of the two NSCLC cell lines (Figure 5E and F).	('NSCLC', 'Disease', 'MESH:D002289', (243, 248))	('LP211', 'Var', (171, 176))	('invasion capacities', 'CPA', (212, 231))	('enhanced', 'PosReg', (185, 193))	('LP211', 'Chemical', 'MESH:C573815', (171, 176))	('LP211', 'Chemical', 'MESH:C573815', (59, 64))	('migration', 'CPA', (198, 207))	('NSCLC', 'Disease', (243, 248))
533631	32210580	Based on the previous results, NSCLC cells were pretreated with various inhibitors and then stimulated with 10 nM LP211, and the cell proteins were extracted.	('NSCLC', 'Disease', 'MESH:D002289', (31, 36))	('NSCLC', 'Disease', (31, 36))	('LP211', 'Var', (114, 119))	('LP211', 'Chemical', 'MESH:C573815', (114, 119))
533632	32210580	To explore the pathways involved in MMP9, PCNA and survivin expression, A549 cells and H1299 cells were incubated with 10 nM LP211 for 12 h and 24 h, respectively, following pretreatment with the corresponding inhibitors.	('MMP9', 'Gene', (36, 40))	('PCNA', 'Gene', (42, 46))	('MMP9', 'Gene', '4318', (36, 40))	('LP211', 'Var', (125, 130))	('LP211', 'Chemical', 'MESH:C573815', (125, 130))	('PCNA', 'Gene', '5111', (42, 46))
533633	32210580	We found that the P38 inhibitor BMS582949 (5 muM, 2 h) significantly reversed the effect of LP211 on MMP9 expression, and the Akt inhibitor MK2206 (5 muM, 1 h) suppressed the expression of survivin, in A549 cells (Figure 6A).	('MK2206', 'Chemical', 'MESH:C548887', (140, 146))	('expression', 'MPA', (175, 185))	('LP211', 'Var', (92, 97))	('LP211', 'Chemical', 'MESH:C573815', (92, 97))	('P38', 'Gene', (18, 21))	('MMP9', 'Gene', (101, 105))	('expression', 'MPA', (106, 116))	('Akt', 'Gene', '207', (126, 129))	('MMP9', 'Gene', '4318', (101, 105))	('survivin', 'Protein', (189, 197))	('BMS582949', 'Chemical', 'MESH:C552704', (32, 41))	('P38', 'Gene', '5594', (18, 21))	('Akt', 'Gene', (126, 129))	('suppressed', 'NegReg', (160, 170))
533634	32210580	We also validated that the Src inhibitor AZD0530 (8 muM, 3 h) could attenuate the effcts of LP211 on MMP9, PCNA and survivin in H1299 cells, and the JNK inhibitor SP600125 (40 muM, 1 h) partly reversed the effect of LP211 on survivin expression.	('effcts', 'MPA', (82, 88))	('attenuate', 'NegReg', (68, 77))	('AZD0530', 'Var', (41, 48))	('PCNA', 'Gene', '5111', (107, 111))	('LP211', 'Chemical', 'MESH:C573815', (92, 97))	('LP211', 'Chemical', 'MESH:C573815', (216, 221))	('LP211', 'Gene', (92, 97))	('MMP9', 'Gene', (101, 105))	('Src', 'Gene', (27, 30))	('Src', 'Gene', '6714', (27, 30))	('AZD0530', 'Chemical', 'MESH:C515233', (41, 48))	('MMP9', 'Gene', '4318', (101, 105))	('JNK', 'Gene', '5599', (149, 152))	('survivin', 'MPA', (116, 124))	('PCNA', 'Gene', (107, 111))	('JNK', 'Gene', (149, 152))	('SP600125', 'Chemical', 'MESH:C432165', (163, 171))
533635	32210580	LP211-induced migration (Figure 6C) and invasion (Figure 6D) were significantly suppressed by BMS582949 in A549 cells.	('migration', 'CPA', (14, 23))	('BMS582949', 'Chemical', 'MESH:C552704', (94, 103))	('invasion', 'CPA', (40, 48))	('BMS582949', 'Var', (94, 103))	('LP211', 'Chemical', 'MESH:C573815', (0, 5))	('LP211-induced', 'Gene', (0, 13))	('suppressed', 'NegReg', (80, 90))
533636	32210580	In H1299 cells, the enhanced migration (Figure 6C) and invasion (Figure 6D) were reversed by AZD0530.	('enhanced', 'PosReg', (20, 28))	('AZD0530', 'Chemical', 'MESH:C515233', (93, 100))	('AZD0530', 'Var', (93, 100))	('migration', 'CPA', (29, 38))	('invasion', 'CPA', (55, 63))
533653	32210580	After a 2 h incubation with LP211, changes in signaling activation appeared when the concentration of LP211 reached 100 nM in A549 cells.	('signaling activation', 'MPA', (46, 66))	('LP211', 'Var', (102, 107))	('LP211', 'Chemical', 'MESH:C573815', (102, 107))	('LP211', 'Var', (28, 33))	('LP211', 'Chemical', 'MESH:C573815', (28, 33))
533661	31807490	Detection of clinically relevant epidermal growth factor receptor pathway mutations in circulating cell-free tumor DNA using next generation sequencing in squamous cell carcinoma lung Limited repertoires of targets are available in the management of squamous cell carcinoma lung.	('squamous cell carcinoma lung', 'Disease', 'MESH:D002294', (250, 278))	('tumor', 'Disease', (109, 114))	('epidermal growth factor receptor', 'Gene', '1956', (33, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (264, 273))	('carcinoma', 'Phenotype', 'HP:0030731', (169, 178))	('mutations', 'Var', (74, 83))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (250, 273))	('squamous cell carcinoma lung', 'Disease', (155, 183))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (155, 178))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('squamous cell carcinoma lung', 'Disease', 'MESH:D002294', (155, 183))	('squamous cell carcinoma lung', 'Disease', (250, 278))	('epidermal growth factor receptor', 'Gene', (33, 65))
533662	31807490	In this study, we analyzed epidermal growth factor receptor (EGFR), RAS, BRAF mutations in lung cancer patients of squamous cell histology using next-generation sequencing (NGS) on the circulating cell-free DNA (cf-DNA).	('lung cancer', 'Phenotype', 'HP:0100526', (91, 102))	('RAS', 'Gene', (68, 71))	('BRAF', 'Gene', '673', (73, 77))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('epidermal growth factor receptor', 'Gene', (27, 59))	('EGFR', 'Gene', (61, 65))	('mutations', 'Var', (78, 87))	('lung cancer', 'Disease', 'MESH:D008175', (91, 102))	('epidermal growth factor receptor', 'Gene', '1956', (27, 59))	('patients', 'Species', '9606', (103, 111))	('BRAF', 'Gene', (73, 77))	('EGFR', 'Gene', '1956', (61, 65))	('lung cancer', 'Disease', (91, 102))
533664	31807490	Cf-DNA was extracted from peripheral blood and analyzed for EGFR, KRAS, NRAS, and BRAF mutations using NGS.	('NRAS', 'Gene', (72, 76))	('BRAF', 'Gene', '673', (82, 86))	('NRAS', 'Gene', '4893', (72, 76))	('Cf', 'Chemical', 'MESH:D002142', (0, 2))	('KRAS', 'Gene', '3845', (66, 70))	('BRAF', 'Gene', (82, 86))	('EGFR', 'Gene', '1956', (60, 64))	('EGFR', 'Gene', (60, 64))	('mutations', 'Var', (87, 96))	('KRAS', 'Gene', (66, 70))
533666	31807490	Eight clinically relevant mutations in the EGFR pathway were identified.	('mutations', 'Var', (26, 35))	('EGFR', 'Gene', '1956', (43, 47))	('EGFR', 'Gene', (43, 47))
533667	31807490	These include Exon 21 mutations in 4 patients, Exon 20 mutation in onepatient, complex mutations with coexisting Exon 21 and Exon18 in one patient and KRAS Exon 2 mutations in two patients.	('KRAS', 'Gene', '3845', (151, 155))	('mutations', 'Var', (163, 172))	('patient', 'Species', '9606', (37, 44))	('patients', 'Species', '9606', (37, 45))	('patient', 'Species', '9606', (70, 77))	('patient', 'Species', '9606', (139, 146))	('mutations', 'Var', (87, 96))	('Exon 21', 'Gene', (14, 21))	('patients', 'Species', '9606', (180, 188))	('mutations', 'Var', (22, 31))	('Exon', 'Var', (47, 51))	('patient', 'Species', '9606', (180, 187))	('KRAS', 'Gene', (151, 155))
533668	31807490	cf-DNA is a minimally invasive technique for detection of clinically relevant mutations in lung cancer patients.	('lung cancer', 'Phenotype', 'HP:0100526', (91, 102))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('mutations', 'Var', (78, 87))	('lung cancer', 'Disease', 'MESH:D008175', (91, 102))	('patients', 'Species', '9606', (103, 111))	('lung cancer', 'Disease', (91, 102))
533669	31807490	The use of novel advanced techniques such as NGS may help in detecting EGFR pathway mutations in patients with squamous cell carcinoma lung.	('carcinoma', 'Phenotype', 'HP:0030731', (125, 134))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (111, 134))	('mutations', 'Var', (84, 93))	('EGFR', 'Gene', '1956', (71, 75))	('patients', 'Species', '9606', (97, 105))	('squamous cell carcinoma lung', 'Disease', (111, 139))	('EGFR', 'Gene', (71, 75))	('squamous cell carcinoma lung', 'Disease', 'MESH:D002294', (111, 139))
533673	31807490	Recent studies identified molecular abnormalities such as SOX2 amplification, NFE2 L2 and KEAP1 mutations, PI3K pathway changes, fibroblast growth factor receptor 1 amplification, and discoidin domain receptor 2 mutations.	('SOX2', 'Gene', (58, 62))	('PI3K pathway', 'Pathway', (107, 119))	('molecular abnormalities', 'Disease', 'MESH:D030342', (26, 49))	('NFE2 L2', 'Gene', '4780', (78, 85))	('SOX2', 'Gene', '6657', (58, 62))	('fibroblast growth factor receptor 1', 'Gene', (129, 164))	('KEAP1', 'Gene', '9817', (90, 95))	('discoidin domain receptor 2', 'Gene', (184, 211))	('discoidin domain receptor 2', 'Gene', '4921', (184, 211))	('amplification', 'Var', (165, 178))	('NFE2 L2', 'Gene', (78, 85))	('mutations', 'Var', (212, 221))	('KEAP1', 'Gene', (90, 95))	('molecular abnormalities', 'Disease', (26, 49))	('fibroblast growth factor receptor 1', 'Gene', '2260', (129, 164))	('mutations', 'Var', (96, 105))
533674	31807490	Earlier studies suggest that abnormalities in the epidermal growth factor receptor (EGFR) pathway are uncommon in squamous cell carcinoma lung while recent evidence suggests that a subset of these patients harbor mutations in the EGFR pathway.	('EGFR', 'Gene', '1956', (230, 234))	('squamous cell carcinoma lung', 'Disease', 'MESH:D002294', (114, 142))	('EGFR', 'Gene', (230, 234))	('patients', 'Species', '9606', (197, 205))	('epidermal growth factor receptor', 'Gene', '1956', (50, 82))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (114, 137))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('EGFR', 'Gene', '1956', (84, 88))	('squamous cell carcinoma lung', 'Disease', (114, 142))	('epidermal growth factor receptor', 'Gene', (50, 82))	('EGFR', 'Gene', (84, 88))	('mutations', 'Var', (213, 222))
533675	31807490	In this study, we attempted to identify mutations in the EGFR pathway in circulating cell-free DNA (cf-DNA) using next-generation sequencing (NGS) among the patients with squamous cell carcinoma lung.	('squamous cell carcinoma lung', 'Disease', (171, 199))	('patients', 'Species', '9606', (157, 165))	('mutations', 'Var', (40, 49))	('EGFR', 'Gene', '1956', (57, 61))	('squamous cell carcinoma lung', 'Disease', 'MESH:D002294', (171, 199))	('carcinoma', 'Phenotype', 'HP:0030731', (185, 194))	('EGFR', 'Gene', (57, 61))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (171, 194))
533686	31807490	EGFR mutations analyzed include Exon 3; Exon 7; Exon 15; Exon 18: G719X; Exon 19: deletions; Exon 20: S768I, Insertions, T790M; Exon 21: L858R, L861Q, Exon 2, 3, 4 of KRAS and NRAS and also Exon 15: L597R/Q/S/V, V600E/K/L/R, K601E; Exon 11: G466V of BRAF.	('L861Q', 'Var', (144, 149))	('L858R', 'Var', (137, 142))	('Insertions', 'Var', (109, 119))	('L597R', 'Var', (199, 204))	('S768I', 'Var', (102, 107))	('V600E', 'Var', (212, 217))	('deletions', 'Var', (82, 91))	('NRAS', 'Gene', (176, 180))	('G466V', 'Var', (241, 246))	('K601E', 'Mutation', 'rs121913364', (225, 230))	('L861Q', 'Chemical', 'MESH:C106588', (144, 149))	('T790M', 'Mutation', 'rs121434569', (121, 126))	('KRAS', 'Gene', '3845', (167, 171))	('L597R', 'SUBSTITUTION', 'None', (199, 204))	('V600E', 'SUBSTITUTION', 'None', (212, 217))	('EGFR', 'Gene', (0, 4))	('G466V', 'Mutation', 'rs121913351', (241, 246))	('K601E', 'Var', (225, 230))	('L858R', 'Mutation', 'rs121434568', (137, 142))	('KRAS', 'Gene', (167, 171))	('EGFR', 'Gene', '1956', (0, 4))	('T790M', 'Var', (121, 126))	('S768I', 'SUBSTITUTION', 'None', (102, 107))	('BRAF', 'Gene', '673', (250, 254))	('NRAS', 'Gene', '4893', (176, 180))	('G719X', 'Mutation', 'p.G719X', (66, 71))	('BRAF', 'Gene', (250, 254))	('G719X', 'Var', (66, 71))
533688	31807490	Curated somatic database somatic variants from published literature, the Cancer Genome Atlas were used to identify reported mutation as per the AMP-ASCO-CAP guidelines.	('Cancer', 'Phenotype', 'HP:0002664', (73, 79))	('Cancer', 'Disease', 'MESH:D009369', (73, 79))	('mutation', 'Var', (124, 132))	('Cancer', 'Disease', (73, 79))	('AMP-ASCO', 'Chemical', 'MESH:D000249', (144, 152))
533692	31807490	Genomic analysis by NGS on the extracted cf-DNA revealed clinically relevant mutations in the EGFR pathway among 8 (50%) patients.	('EGFR', 'Gene', (94, 98))	('mutations', 'Var', (77, 86))	('patients', 'Species', '9606', (121, 129))	('EGFR', 'Gene', '1956', (94, 98))
533695	31807490	One patient had complex mutations with coexisting Exon 21 Leu858Arg and Exon18 Gly719Arg in the same sample.	('Leu858Arg', 'Var', (58, 67))	('Gly719Arg', 'Var', (79, 88))	('Gly719Arg', 'SUBSTITUTION', 'None', (79, 88))	('Leu858Arg', 'Chemical', 'MESH:C541942', (58, 67))	('patient', 'Species', '9606', (4, 11))
533696	31807490	Two patients had KRAS Exon2 Gly12Cys mutation.	('Gly12Cys', 'SUBSTITUTION', 'None', (28, 36))	('KRAS', 'Gene', (17, 21))	('patients', 'Species', '9606', (4, 12))	('KRAS', 'Gene', '3845', (17, 21))	('Gly12Cys', 'Var', (28, 36))
533697	31807490	Among the patients with Exon 21 mutation, two patients were treatment naive, and two patients were having progressive disease (one post gemcitabine/carboplatin-based chemotherapy and another post gemcitabine/carboplatin and docetaxel chemotherapy).	('gemcitabine', 'Chemical', 'MESH:C056507', (136, 147))	('progressive disease', 'Disease', (106, 125))	('patients', 'Species', '9606', (46, 54))	('gemcitabine', 'Chemical', 'MESH:C056507', (196, 207))	('Exon 21', 'Gene', (24, 31))	('docetaxel', 'Chemical', 'MESH:C067311', (224, 233))	('patients', 'Species', '9606', (85, 93))	('carboplatin', 'Chemical', 'MESH:D016190', (148, 159))	('patients', 'Species', '9606', (10, 18))	('mutation', 'Var', (32, 40))	('carboplatin', 'Chemical', 'MESH:D016190', (208, 219))
533699	31807490	Patient with Exon 20 T790M mutation had a hyper-progressive disease post-Nivolumab based regimen.	('hyper-progressive disease post-Nivolumab', 'Disease', 'MESH:D018450', (42, 82))	('hyper-progressive disease post-Nivolumab', 'Disease', (42, 82))	('T790M', 'Mutation', 'rs121434569', (21, 26))	('Patient', 'Species', '9606', (0, 7))	('T790M', 'Var', (21, 26))
533700	31807490	While one patient with KRAS mutation was treatment naive another had progressive disease post gemcitabine/carboplatin-based regimen [Table 2].	('carboplatin', 'Chemical', 'MESH:D016190', (106, 117))	('patient', 'Species', '9606', (10, 17))	('gemcitabine', 'Chemical', 'MESH:C056507', (94, 105))	('KRAS', 'Gene', (23, 27))	('mutation', 'Var', (28, 36))	('KRAS', 'Gene', '3845', (23, 27))
533703	31807490	Treatment Naive patients with EGFR Exon 21 mutations (n = 2) upfront received gemcitabine and carboplatin-based chemotherapy.	('EGFR', 'Gene', (30, 34))	('patients', 'Species', '9606', (16, 24))	('mutations', 'Var', (43, 52))	('carboplatin', 'Chemical', 'MESH:D016190', (94, 105))	('EGFR', 'Gene', '1956', (30, 34))	('gemcitabine', 'Chemical', 'MESH:C056507', (78, 89))
533712	31807490	In adenocarcinoma lung patients activating EGFR mutations account for 10%-15% in the Caucasian population and 40%-50% in the Asian population.	('adenocarcinoma lung', 'Disease', 'MESH:C538231', (3, 22))	('patients', 'Species', '9606', (23, 31))	('carcinoma', 'Phenotype', 'HP:0030731', (8, 17))	('EGFR', 'Gene', '1956', (43, 47))	('adenocarcinoma lung', 'Disease', (3, 22))	('activating', 'PosReg', (32, 42))	('EGFR', 'Gene', (43, 47))	('mutations', 'Var', (48, 57))
533713	31807490	The frequency of EGFR mutations in squamous cell carcinoma lung varies between 0% and 14.6%.	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('squamous cell carcinoma lung', 'Disease', (35, 63))	('mutations', 'Var', (22, 31))	('EGFR', 'Gene', '1956', (17, 21))	('squamous cell carcinoma lung', 'Disease', 'MESH:D002294', (35, 63))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (35, 58))	('EGFR', 'Gene', (17, 21))
533714	31807490	In the Indian population, the frequency of EGFR mutations in patients with adenocarcinoma lung ranges between 25%- and 40% while the frequency of EGFR mutations in squamous cell carcinoma lung in an earlier study was 4.5%.	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('squamous cell carcinoma lung', 'Disease', (164, 192))	('EGFR', 'Gene', '1956', (146, 150))	('patients', 'Species', '9606', (61, 69))	('EGFR', 'Gene', (146, 150))	('adenocarcinoma lung', 'Disease', (75, 94))	('EGFR', 'Gene', '1956', (43, 47))	('adenocarcinoma lung', 'Disease', 'MESH:C538231', (75, 94))	('squamous cell carcinoma lung', 'Disease', 'MESH:D002294', (164, 192))	('carcinoma', 'Phenotype', 'HP:0030731', (178, 187))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (164, 187))	('EGFR', 'Gene', (43, 47))	('mutations', 'Var', (48, 57))
533715	31807490	Most oncological societies favor EGFR mutational testing in squamous cell carcinoma lung in never smokers, small biopsy specimens, or mixed histology.	('squamous cell carcinoma lung', 'Disease', (60, 88))	('squamous cell carcinoma lung', 'Disease', 'MESH:D002294', (60, 88))	('EGFR', 'Gene', '1956', (33, 37))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (60, 83))	('mutational testing', 'Var', (38, 56))	('EGFR', 'Gene', (33, 37))
533716	31807490	The evidence regarding the responses to EGFR tyrosine kinase therapy in squamous cell carcinoma lung cancer patients harboring activating EGFR mutations is controversial.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (72, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('EGFR', 'Gene', '1956', (138, 142))	('activating', 'PosReg', (127, 137))	('squamous cell carcinoma lung cancer', 'Phenotype', 'HP:0030359', (72, 107))	('squamous cell carcinoma lung cancer', 'Disease', (72, 107))	('EGFR', 'Gene', (138, 142))	('EGFR', 'Gene', '1956', (40, 44))	('lung cancer', 'Phenotype', 'HP:0100526', (96, 107))	('EGFR', 'Gene', (40, 44))	('squamous cell carcinoma lung cancer', 'Disease', 'MESH:D018307', (72, 107))	('tyrosine', 'Chemical', 'None', (45, 53))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('patients', 'Species', '9606', (108, 116))	('mutations', 'Var', (143, 152))
533717	31807490	While some groups suggest a comparable median survival in EGFR mutation-positive adenocarcinoma and non-adenocarcinoma patients, others suggest a poor survival in EGFR positive squamous cell carcinoma lung patients when treated with EGFR tyrosine kinase inhibitors (TKI).	('EGFR', 'Gene', '1956', (233, 237))	('EGFR', 'Gene', '1956', (58, 62))	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('squamous cell carcinoma lung', 'Disease', 'MESH:D002294', (177, 205))	('EGFR', 'Gene', (233, 237))	('EGFR', 'Gene', (58, 62))	('patients', 'Species', '9606', (119, 127))	('EGFR', 'Gene', '1956', (163, 167))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (177, 200))	('carcinoma', 'Phenotype', 'HP:0030731', (191, 200))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('patients', 'Species', '9606', (206, 214))	('EGFR', 'Gene', (163, 167))	('mutation-positive', 'Var', (63, 80))	('adenocarcinoma and non-adenocarcinoma', 'Disease', 'MESH:D000230', (81, 118))	('squamous cell carcinoma lung', 'Disease', (177, 205))	('tyrosine', 'Chemical', 'None', (238, 246))
533721	31807490	KRAS mutations are relatively rare mutations in squamous cell histology than adenocarcinoma histology.	('adenocarcinoma', 'Disease', 'MESH:D000230', (77, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('mutations', 'Var', (5, 14))	('KRAS', 'Gene', (0, 4))	('squamous cell', 'Disease', (48, 61))	('adenocarcinoma', 'Disease', (77, 91))	('KRAS', 'Gene', '3845', (0, 4))
533722	31807490	Due to the rarity of these mutations in squamous cell carcinoma lung, currently, KRAS mutation analysis is not recommended.	('mutations', 'Var', (27, 36))	('squamous cell carcinoma lung', 'Disease', (40, 68))	('KRAS', 'Gene', '3845', (81, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (54, 63))	('squamous cell carcinoma lung', 'Disease', 'MESH:D002294', (40, 68))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (40, 63))	('KRAS', 'Gene', (81, 85))
533723	31807490	The prognostic and predictive implications of KRAS mutations in squamous cell carcinoma lung is controversial.	('squamous cell carcinoma lung', 'Disease', (64, 92))	('mutations', 'Var', (51, 60))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('KRAS', 'Gene', (46, 50))	('squamous cell carcinoma lung', 'Disease', 'MESH:D002294', (64, 92))	('KRAS', 'Gene', '3845', (46, 50))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (64, 87))
533724	31807490	In our study, we incorporated NGS for detecting clinically relevant mutations in the EGFR pathway in squamous cell carcinoma lung patients.	('EGFR', 'Gene', (85, 89))	('EGFR', 'Gene', '1956', (85, 89))	('squamous cell carcinoma lung', 'Disease', 'MESH:D002294', (101, 129))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (101, 124))	('patients', 'Species', '9606', (130, 138))	('mutations', 'Var', (68, 77))	('squamous cell carcinoma lung', 'Disease', (101, 129))
533726	31807490	The high frequency of activating mutations detected in squamous cell carcinoma lung noted in our study is the first as per our knowledge of the literature.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (55, 78))	('mutations', 'Var', (33, 42))	('squamous cell carcinoma lung', 'Disease', (55, 83))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))	('squamous cell carcinoma lung', 'Disease', 'MESH:D002294', (55, 83))
533728	31807490	The other reason might be that the earlier studies evaluated EGFR mutations using lesser sensitive techniques such as PCR.	('mutations', 'Var', (66, 75))	('EGFR', 'Gene', '1956', (61, 65))	('EGFR', 'Gene', (61, 65))
533730	31807490	A prospective study using advanced techniques such as NGS and with a larger sample size may help in detecting the true percentage of patients with squamous cell carcinoma lung carrying activating EGFR mutations.	('EGFR', 'Gene', (196, 200))	('mutations', 'Var', (201, 210))	('activating', 'PosReg', (185, 195))	('squamous cell carcinoma lung', 'Disease', (147, 175))	('patients', 'Species', '9606', (133, 141))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (147, 170))	('carcinoma', 'Phenotype', 'HP:0030731', (161, 170))	('EGFR', 'Gene', '1956', (196, 200))	('squamous cell carcinoma lung', 'Disease', 'MESH:D002294', (147, 175))
533731	31807490	Due to the limited treatment options in the management of squamous cell carcinoma lung detection of EGFR mutations may help further increase the treatment armamentarium.	('EGFR', 'Gene', '1956', (100, 104))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (58, 81))	('squamous cell carcinoma lung', 'Disease', (58, 86))	('EGFR', 'Gene', (100, 104))	('mutations', 'Var', (105, 114))	('squamous cell carcinoma lung', 'Disease', 'MESH:D002294', (58, 86))
533732	31807490	Cf-DNA is a minimally invasive technique for detection of clinically relevant mutations in lung cancer patients.	('lung cancer', 'Phenotype', 'HP:0100526', (91, 102))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('Cf', 'Chemical', 'MESH:D002142', (0, 2))	('mutations', 'Var', (78, 87))	('lung cancer', 'Disease', 'MESH:D008175', (91, 102))	('patients', 'Species', '9606', (103, 111))	('lung cancer', 'Disease', (91, 102))
533770	28120396	Low to moderate alcohol consumption was shown to be inversely associated with lung cancer risk when compared to non-drinkers with ORs of 0.80 (95%CI=0.70-0.90), 0.82 (95%CI=0.69-0.99) and 0.79 (95%CI=0.65-0.96) for the consumption of >0-4.9g per day, 5-9.9g per day, and 10-19.9g per day, respectively.	('lung cancer', 'Disease', (78, 89))	('lung cancer', 'Phenotype', 'HP:0100526', (78, 89))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('lung cancer', 'Disease', 'MESH:D008175', (78, 89))	('inversely', 'NegReg', (52, 61))	('alcohol', 'Chemical', 'MESH:D000438', (16, 23))	('Low', 'Var', (0, 3))
533771	28120396	Results from analyses stratified by histologic subtype showed inverse associations of low, moderate and heavier drinking with lung adenocarcinoma and squamous cell carcinoma.	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (126, 145))	('moderate', 'Var', (91, 99))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (126, 145))	('adenocarcinoma and squamous cell carcinoma', 'Disease', 'MESH:D002294', (131, 173))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (150, 173))	('inverse', 'NegReg', (62, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (164, 173))	('low', 'Var', (86, 89))	('lung adenocarcinoma', 'Disease', (126, 145))
533788	28120396	We also found alcohol consumption was associated with lower risk of both adenocarcinoma and squamous cell carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('adenocarcinoma and squamous cell carcinoma', 'Disease', 'MESH:D002294', (73, 115))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('lower', 'NegReg', (54, 59))	('alcohol', 'Chemical', 'MESH:D000438', (14, 21))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (92, 115))	('alcohol consumption', 'Var', (14, 33))
533791	28120396	The NIH-AARP Diet and Health Study, a prospective cohort study, reported lower risk among drinkers who consumed less than 12g (1 drink) of alcohol per day while Freudenheim et al., using a pooled analysis of cohort studies, found lower risk for women who drank less than 15g of alcohol per day.	('alcohol', 'Chemical', 'MESH:D000438', (139, 146))	('less', 'Var', (112, 116))	('women', 'Species', '9606', (245, 250))	('lower', 'NegReg', (73, 78))	('alcohol', 'Chemical', 'MESH:D000438', (278, 285))
533793	28120396	Among larger prospective cohort studies, one study found lung cancer risk increased with increased drinking in never smoking males but not females, while two other studies reported null results.	('drinking', 'Var', (99, 107))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('lung cancer', 'Disease', 'MESH:D008175', (57, 68))	('lung cancer', 'Disease', (57, 68))	('lung cancer', 'Phenotype', 'HP:0100526', (57, 68))
533818	28120396	Recent results from Mendelian randomization studies conflict with the commonly cited view that light to moderate alcohol consumption is causally linked to lower risk for ischaemic heart disease, with results from genetic analyses clearly indicating that genetic variation that predisposes to less drinking is associated with lower risk in both light/moderate and heavier drinkers.	('ischaemic heart disease', 'Disease', 'MESH:D003324', (170, 193))	('alcohol', 'Chemical', 'MESH:D000438', (113, 120))	('ischaemic heart disease', 'Disease', (170, 193))	('less drinking', 'Disease', (292, 305))	('genetic variation', 'Var', (254, 271))
533828	25880247	This study investigates the causes and underlying mechanisms of aberrant IGFBP-7 expression in unravelling head and neck squamous cell carcinoma (HNSCC).	('neck squamous cell carcinoma', 'Disease', (116, 144))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (107, 144))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (116, 144))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('IGFBP-7', 'Gene', (73, 80))	('aberrant', 'Var', (64, 72))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (121, 144))
533830	25880247	The epithelial-mesenchymal transition (EMT) marker genes and AKT/GSK3beta/beta-catenin signaling were further evaluated by Western blot for the understanding the role of aberrant IGFBP-7 expression and thereof putative mechanism.	('GSK3beta', 'Gene', '2932', (65, 73))	('IGFBP-7', 'Gene', (179, 186))	('AKT', 'Gene', '207', (61, 64))	('beta-catenin', 'Gene', (74, 86))	('aberrant', 'Var', (170, 178))	('AKT', 'Gene', (61, 64))	('GSK3beta', 'Gene', (65, 73))	('beta-catenin', 'Gene', '1499', (74, 86))
533832	25880247	Moreover, IGFBP-7 methylation status of 47 oral tongue tumors showed a positive correlation to invasive depth of the tumor, loco-regional recurrence, and cancer sequence.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tongue tumors', 'Disease', 'MESH:D014062', (48, 61))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Disease', (117, 122))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('cancer', 'Disease', (154, 160))	('tumor', 'Disease', (55, 60))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('tongue tumor', 'Phenotype', 'HP:0100648', (48, 60))	('methylation', 'Var', (18, 29))	('tongue tumors', 'Disease', (48, 61))	('IGFBP-7', 'Gene', (10, 17))	('tongue tumors', 'Phenotype', 'HP:0100648', (48, 61))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('loco-regional recurrence', 'CPA', (124, 148))	('tumor', 'Disease', 'MESH:D009369', (117, 122))	('correlation', 'Reg', (80, 91))
533841	25880247	In vitro studies have been demonstrated that IGFBP-7 can induce apoptosis in many cancer cells, e.g., breast and prostate cancer cells; and acts as a potential tumor suppressor against colorectal carcinogenesis.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('breast and prostate cancer', 'Disease', 'MESH:D011471', (102, 128))	('apoptosis', 'CPA', (64, 73))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('colorectal carcinogenesis', 'Disease', 'MESH:D063646', (185, 210))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('IGFBP-7', 'Var', (45, 52))	('colorectal carcinogenesis', 'Disease', (185, 210))	('induce', 'PosReg', (57, 63))	('tumor', 'Disease', (160, 165))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('prostate cancer', 'Phenotype', 'HP:0012125', (113, 128))
533842	25880247	Thereof, aberrant IGFBP-7 expression may contribute to the biological behavior of tumors and the outcomes of clinical.	('expression', 'MPA', (26, 36))	('tumors', 'Disease', (82, 88))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('biological behavior', 'CPA', (59, 78))	('clinical', 'Species', '191496', (109, 117))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('aberrant', 'Var', (9, 17))	('contribute', 'Reg', (41, 51))	('IGFBP-7', 'Gene', (18, 25))
533845	25880247	Aberrant DNA methylation in CpG islands of tumor suppressor genes is validated as a frequent molecular event in human carcinomas.	('Aberrant', 'Var', (0, 8))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('carcinomas', 'Phenotype', 'HP:0030731', (118, 128))	('carcinomas', 'Disease', (118, 128))	('carcinomas', 'Disease', 'MESH:D002277', (118, 128))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Disease', (43, 48))	('human', 'Species', '9606', (112, 117))
533846	25880247	Moreover, the hyper-methylation of cytosine in CpG islands is concomitant with the suppressed initiation of gene transcription and leads to carcinogenesis.	('carcinogenesis', 'Disease', 'MESH:D063646', (140, 154))	('initiation of gene transcription', 'MPA', (94, 126))	('carcinogenesis', 'Disease', (140, 154))	('cytosine', 'Chemical', 'MESH:D003596', (35, 43))	('leads to', 'Reg', (131, 139))	('hyper-methylation', 'Var', (14, 31))	('suppressed', 'NegReg', (83, 93))
533847	25880247	In one recent study, aberrant hyper-methylation of tumor suppressor genes was demonstrated to contribute the oral carcinogenesis.	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('aberrant hyper-methylation', 'Var', (21, 47))	('oral carcinogenesis', 'Disease', 'MESH:D063646', (109, 128))	('tumor', 'Disease', (51, 56))	('oral carcinogenesis', 'Disease', (109, 128))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('contribute', 'Reg', (94, 104))
533848	25880247	Additionally, the hyper-methylation of certain genes (CDKN2A, CDH13, FHIT, WWOX, CDH1, and RASSF1A) in various carcinomas such as lung cancer and HNSCC has been found to cause poor progression.	('lung cancer', 'Phenotype', 'HP:0100526', (130, 141))	('RASSF1A', 'Gene', '11186', (91, 98))	('CDH1', 'Gene', '999', (62, 66))	('CDKN2A', 'Gene', '1029', (54, 60))	('FHIT', 'Gene', (69, 73))	('RASSF1A', 'Gene', (91, 98))	('CDH13', 'Gene', '1012', (62, 67))	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('carcinomas', 'Phenotype', 'HP:0030731', (111, 121))	('CDH1', 'Gene', (62, 66))	('carcinomas', 'Disease', 'MESH:D002277', (111, 121))	('WWOX', 'Gene', '51741', (75, 79))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('FHIT', 'Gene', '2272', (69, 73))	('lung cancer', 'Disease', (130, 141))	('CDH13', 'Gene', (62, 67))	('CDH1', 'Gene', '999', (81, 85))	('HNSCC', 'Disease', (146, 151))	('CDKN2A', 'Gene', (54, 60))	('carcinomas', 'Disease', (111, 121))	('lung cancer', 'Disease', 'MESH:D008175', (130, 141))	('WWOX', 'Gene', (75, 79))	('CDH1', 'Gene', (81, 85))	('hyper-methylation', 'Var', (18, 35))
533897	25880247	We also found the phosphorylation of AKT was higher in A253-5 when compared to A253 cells (Figure 4A).	('AKT', 'Gene', '207', (37, 40))	('phosphorylation', 'MPA', (18, 33))	('A253-5', 'Var', (55, 61))	('AKT', 'Gene', (37, 40))	('higher', 'PosReg', (45, 51))
533901	25880247	Moreover, the inhibition of AKT/GSK3beta/beta-catenin signaling might be partially re-activated by transfection of siRNA against IGFBP-7.	('transfection', 'Var', (99, 111))	('beta-catenin', 'Gene', (41, 53))	('IGFBP-7', 'Gene', (129, 136))	('AKT', 'Gene', (28, 31))	('beta-catenin', 'Gene', '1499', (41, 53))	('GSK3beta', 'Gene', (32, 40))	('GSK3beta', 'Gene', '2932', (32, 40))	('AKT', 'Gene', '207', (28, 31))	('inhibition', 'NegReg', (14, 24))
533906	25880247	The data indicated the methylation status of IGFBP-7 was associated with invasive depth, loco-regional recurrence and cancer sequence (p = 0.03, 0.011 and 0.029, respectively).	('cancer', 'Disease', (118, 124))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('methylation status', 'Var', (23, 41))	('loco-regional recurrence', 'CPA', (89, 113))	('IGFBP-7', 'Gene', (45, 52))	('invasive depth', 'CPA', (73, 87))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('associated', 'Reg', (57, 67))
533907	25880247	The disease-free survival (DFS) in patients with methylated IGFBP-7 (1/2/4 year: 85%/ 58%/ 40%) was significantly poorer than those of patients with unmethylated IGFBP-7 (1/2/4 year: 100%/ 100%/ 80%) (p = 0.025) (Figure 5).	('IGFBP-7', 'Gene', (60, 67))	('patients', 'Species', '9606', (135, 143))	('disease-free survival', 'CPA', (4, 25))	('poorer', 'NegReg', (114, 120))	('methylated', 'Var', (49, 59))	('patients', 'Species', '9606', (35, 43))
533916	25880247	Aberrant hyper-methylation of tumor suppressor genes are well known to contribute to oral carcinogenesis.	('Aberrant hyper-methylation', 'Var', (0, 26))	('contribute', 'Reg', (71, 81))	('oral carcinogenesis', 'Disease', (85, 104))	('oral carcinogenesis', 'Disease', 'MESH:D063646', (85, 104))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('tumor', 'Disease', (30, 35))
533935	25880247	Aberrant hyper-methylation of IGFBP-7 in oral tongue tumors was significantly concomitant with tumor progression (invasive depth, loco-regional recurrence, and cancer consequence) and poor prognosis.	('concomitant with', 'Reg', (78, 94))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('cancer', 'Disease', (160, 166))	('tongue tumors', 'Disease', 'MESH:D014062', (46, 59))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tongue tumor', 'Phenotype', 'HP:0100648', (46, 58))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('invasive depth', 'CPA', (114, 128))	('tongue tumors', 'Phenotype', 'HP:0100648', (46, 59))	('IGFBP-7', 'Gene', (30, 37))	('Aberrant hyper-methylation', 'Var', (0, 26))	('tumor', 'Disease', (95, 100))	('cancer', 'Disease', 'MESH:D009369', (160, 166))	('loco-regional recurrence', 'CPA', (130, 154))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('tumor', 'Disease', (53, 58))	('tongue tumors', 'Disease', (46, 59))
533957	33688259	Similar findings were observed in the FFCD9901 study, where nCRT did not improve R0 resection rate or 3-year survival, but enhanced the postoperative mortality (11.1% vs 3.4%, P = 0.049) in patients with stage I or II EC compared with surgery alone.	('enhanced', 'PosReg', (123, 131))	('mortality', 'Disease', 'MESH:D003643', (150, 159))	('postoperative', 'MPA', (136, 149))	('patients', 'Species', '9606', (190, 198))	('mortality', 'Disease', (150, 159))	('nCRT', 'Var', (60, 64))
533958	33688259	For example, administration of 2 cycles of cisplatin with 5-FU, a previously most commonly used regimen, prior to surgery improved resection rate of R0 (60% vs 54%, P<0.0001) and 5-year survival rate (23% vs 17%, P = 0.03) compared with surgery alone in OEO2 study.	('resection rate', 'CPA', (131, 145))	('cisplatin', 'Var', (43, 52))	('5-year survival', 'CPA', (179, 194))	('5-FU', 'Chemical', 'MESH:D005472', (58, 62))	('cisplatin', 'Chemical', 'MESH:D002945', (43, 52))	('improved', 'PosReg', (122, 130))
533961	33688259	Furthermore, a recent study demonstrated that preoperative regimen of cisplatin, 5-FU and paclitaxel improved the pCR rate by 24.1%, R0 resection rate was 82.5%, and the perioperative mortality rate was only 1.9%.	('5-FU', 'Chemical', 'MESH:D005472', (81, 85))	('mortality', 'Disease', (184, 193))	('cisplatin', 'Chemical', 'MESH:D002945', (70, 79))	('paclitaxel', 'Chemical', 'MESH:D017239', (90, 100))	('pCR', 'Disease', (114, 117))	('improved', 'PosReg', (101, 109))	('R0 resection', 'CPA', (133, 145))	('mortality', 'Disease', 'MESH:D003643', (184, 193))	('cisplatin', 'Var', (70, 79))
534040	30109777	Icotinib has a modest therapeutic effect in patients with advanced lung SCC, especially for the population with EGFR mutations.	('EGFR', 'Gene', (112, 116))	('mutations', 'Var', (117, 126))	('patients', 'Species', '9606', (44, 52))	('SCC', 'Gene', (72, 75))	('SCC', 'Phenotype', 'HP:0002860', (72, 75))	('Icotinib', 'Chemical', 'MESH:C531470', (0, 8))	('EGFR', 'Gene', '1956', (112, 116))	('SCC', 'Gene', '6317', (72, 75))
534042	30109777	In recent decades, molecular targeted therapy has demonstrated clinical efficacy in cancer patients, such as epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) for advanced NSCLC patients with EGFR mutations.	('NSCLC', 'Phenotype', 'HP:0030358', (194, 199))	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('patients', 'Species', '9606', (91, 99))	('patients', 'Species', '9606', (200, 208))	('epidermal growth factor receptor', 'Gene', (109, 141))	('cancer', 'Disease', (84, 90))	('epidermal growth factor receptor', 'Gene', '1956', (109, 141))	('EGFR', 'Gene', '1956', (170, 174))	('NSCLC', 'Disease', (194, 199))	('EGFR', 'Gene', '1956', (214, 218))	('EGFR', 'Gene', (170, 174))	('NSCLC', 'Disease', 'MESH:D002289', (194, 199))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('EGFR', 'Gene', (214, 218))	('mutations', 'Var', (219, 228))
534043	30109777	EGFR-TKIs had been proven to offer prolonged progression-free survival (PFS) and better life quality than chemotherapy in advanced NSCLC patients with EGFR mutations in many clinical trials,3, 4, 5, 6, 7, 8, 9, 10 in which most of the patients were adenocarcinoma.	('adenocarcinoma', 'Disease', 'MESH:D000230', (249, 263))	('EGFR', 'Gene', (0, 4))	('EGFR', 'Gene', (151, 155))	('progression-free survival', 'CPA', (45, 70))	('mutations', 'Var', (156, 165))	('NSCLC', 'Disease', (131, 136))	('patients', 'Species', '9606', (235, 243))	('NSCLC', 'Phenotype', 'HP:0030358', (131, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (254, 263))	('patients', 'Species', '9606', (137, 145))	('NSCLC', 'Disease', 'MESH:D002289', (131, 136))	('EGFR', 'Gene', '1956', (0, 4))	('adenocarcinoma', 'Disease', (249, 263))	('EGFR', 'Gene', '1956', (151, 155))
534044	30109777	However, the efficacy of EGFR-TKIs in patients with lung SCC is limited, even in SCC patients with EGFR mutations.	('EGFR', 'Gene', (99, 103))	('SCC', 'Gene', '6317', (81, 84))	('mutations', 'Var', (104, 113))	('EGFR', 'Gene', (25, 29))	('SCC', 'Gene', '6317', (57, 60))	('SCC', 'Phenotype', 'HP:0002860', (57, 60))	('SCC', 'Phenotype', 'HP:0002860', (81, 84))	('patients', 'Species', '9606', (85, 93))	('patients', 'Species', '9606', (38, 46))	('SCC', 'Gene', (81, 84))	('EGFR', 'Gene', '1956', (99, 103))	('SCC', 'Gene', (57, 60))	('EGFR', 'Gene', '1956', (25, 29))
534045	30109777	EGFR mutation testing was an essential part of standard care for lung cancer.	('lung cancer', 'Disease', 'MESH:D008175', (65, 76))	('EGFR', 'Gene', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('lung cancer', 'Disease', (65, 76))	('lung cancer', 'Phenotype', 'HP:0100526', (65, 76))	('EGFR', 'Gene', '1956', (0, 4))	('mutation', 'Var', (5, 13))
534046	30109777	Several societies have issued guidelines and consensus statements regarding EGFR mutation testing in patients with lung SCC.	('patients', 'Species', '9606', (101, 109))	('SCC', 'Phenotype', 'HP:0002860', (120, 123))	('SCC', 'Gene', '6317', (120, 123))	('EGFR', 'Gene', '1956', (76, 80))	('mutation', 'Var', (81, 89))	('EGFR', 'Gene', (76, 80))	('SCC', 'Gene', (120, 123))
534047	30109777	According to the American Society of Clinical Oncology (ASCO), none of the patients with NSCLC should be excluded from having the EGFR genetic testing performed if the patient is being considered for first-line therapy with an EGFR-TKI and the decision is physician-driven.11 In Europe, the consensus of the European Society for Medical Oncology (ESMO) suggests that EGFR mutation testing should be performed in patients who are never/former light smokers and in patients with nonsquamous cell carcinoma.12 The consensus guideline from the College of American Pathologist (CAP), International Association for the Study of Lung Cancer (IASLC), and Association for Molecular Pathology (AMP) suggests EGFR mutation testing in lung ADC, in tumors where an ADC component cannot be excluded, and in cases, whose clinical criteria are unusual.13 The National Comprehensive Cancer Network (NCCN) guideline adopts the idea and suggests the consideration of EGFR mutation testing in lung SCC especially in never smokers, small biopsy specimens, or mixed histology.14 In summary, ASCO recommends EGFR mutation testing in all patients with SCC when EGFR-TKIs are considered, but ESMO/ACP/IASLC/AMP/NCCN suggests it only in some specific conditions.	('EGFR', 'Gene', '1956', (698, 702))	('SCC', 'Phenotype', 'HP:0002860', (978, 981))	('nonsquamous cell carcinoma', 'Disease', (477, 503))	('EGFR', 'Gene', (948, 952))	('patient', 'Species', '9606', (168, 175))	('EGFR', 'Gene', (227, 231))	('NSCLC', 'Phenotype', 'HP:0030358', (89, 94))	('nonsquamous cell carcinoma', 'Disease', 'MESH:C538614', (477, 503))	('Lung Cancer', 'Disease', (622, 633))	('carcinoma', 'Phenotype', 'HP:0030731', (494, 503))	('patients', 'Species', '9606', (412, 420))	('EGFR', 'Gene', (130, 134))	('EGFR', 'Gene', (367, 371))	('SCC', 'Phenotype', 'HP:0002860', (1128, 1131))	('EGFR', 'Gene', '1956', (1085, 1089))	('mutation', 'Var', (1090, 1098))	('Oncology', 'Phenotype', 'HP:0002664', (46, 54))	('SCC', 'Gene', '6317', (978, 981))	('patient', 'Species', '9606', (412, 419))	('tumor', 'Phenotype', 'HP:0002664', (736, 741))	('EGFR', 'Gene', (1137, 1141))	('Cancer', 'Phenotype', 'HP:0002664', (866, 872))	('tumors', 'Phenotype', 'HP:0002664', (736, 742))	('Cancer', 'Phenotype', 'HP:0002664', (627, 633))	('SCC', 'Gene', (978, 981))	('SCC', 'Gene', '6317', (1128, 1131))	('EGFR', 'Gene', '1956', (948, 952))	('Lung Cancer', 'Disease', 'MESH:D008175', (622, 633))	('patients', 'Species', '9606', (1114, 1122))	('EGFR', 'Gene', '1956', (227, 231))	('EGFR', 'Gene', (698, 702))	('patients', 'Species', '9606', (75, 83))	('Cancer', 'Disease', (866, 872))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (480, 503))	('EGFR', 'Gene', '1956', (367, 371))	('Lung Cancer', 'Phenotype', 'HP:0100526', (622, 633))	('SCC', 'Gene', (1128, 1131))	('tumors', 'Disease', (736, 742))	('EGFR', 'Gene', '1956', (130, 134))	('patients', 'Species', '9606', (463, 471))	('Oncology', 'Phenotype', 'HP:0002664', (337, 345))	('patient', 'Species', '9606', (75, 82))	('Cancer', 'Disease', (627, 633))	('NSCLC', 'Disease', 'MESH:D002289', (89, 94))	('EGFR', 'Gene', '1956', (1137, 1141))	('EGFR', 'Gene', (1085, 1089))	('Cancer', 'Disease', 'MESH:D009369', (627, 633))	('patient', 'Species', '9606', (463, 470))	('Cancer', 'Disease', 'MESH:D009369', (866, 872))	('tumors', 'Disease', 'MESH:D009369', (736, 742))	('NSCLC', 'Disease', (89, 94))	('patient', 'Species', '9606', (1114, 1121))
534056	30109777	Baseline clinical characteristics including age, gender, smoking history, tumor histology, clinical stage, Karnofsky performance status (KPS), EGFR mutation status, and treatment lines were collected.	('EGFR', 'Gene', (143, 147))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor', 'Disease', (74, 79))	('EGFR', 'Gene', '1956', (143, 147))	('mutation', 'Var', (148, 156))
534061	30109777	The propensity scores, which were calculated from the logistic regression models, included the following variables: age, gender, clinical stage, KPS, smoking history, EGFR mutation type, and treatment lines.	('mutation', 'Var', (172, 180))	('EGFR', 'Gene', '1956', (167, 171))	('EGFR', 'Gene', (167, 171))	('KPS', 'Disease', (145, 148))
534065	30109777	Mutations in the tyrosine kinase domain of EGFR were identified using the amplification refractory mutation system (ARMS).	('EGFR', 'Gene', '1956', (43, 47))	('EGFR', 'Gene', (43, 47))	('Mutations in', 'Var', (0, 12))
534076	30109777	The most common types of EGFR mutations were exon 19 deletion (36 patients) and exon 21 L858R (26 patients), and other mutation types were exon 18 (2 patients), exon 20 (1 patient), exon 20,21 (1 patient), exon21 L861Q (1 patient), exon 21 L858R+T790M (1 patient), and positive (11 patients).	('patient', 'Species', '9606', (98, 105))	('exon 19 deletion', 'Var', (45, 61))	('patient', 'Species', '9606', (255, 262))	('patients', 'Species', '9606', (150, 158))	('L861Q', 'Mutation', 'rs121913444', (213, 218))	('exon 20', 'Var', (161, 168))	('patient', 'Species', '9606', (150, 157))	('EGFR', 'Gene', (25, 29))	('L858R', 'Mutation', 'rs121434568', (240, 245))	('patients', 'Species', '9606', (282, 290))	('exon 21 L858R+T790M', 'Var', (232, 251))	('exon 18', 'Var', (139, 146))	('L858R', 'Mutation', 'rs121434568', (88, 93))	('patient', 'Species', '9606', (172, 179))	('patient', 'Species', '9606', (222, 229))	('patient', 'Species', '9606', (196, 203))	('patients', 'Species', '9606', (98, 106))	('exon21 L861Q', 'Var', (206, 218))	('EGFR', 'Gene', '1956', (25, 29))	('patients', 'Species', '9606', (66, 74))	('exon 21 L858R', 'Var', (80, 93))	('T790M', 'Mutation', 'rs121434569', (246, 251))	('patient', 'Species', '9606', (66, 73))	('patient', 'Species', '9606', (282, 289))	('L858R', 'Var', (88, 93))
534077	30109777	A total of 78 ADC patients with EGFR mutations were selected to compare with EGFR-mutated SCC patients.	('patients', 'Species', '9606', (94, 102))	('EGFR', 'Gene', '1956', (32, 36))	('SCC', 'Gene', (90, 93))	('SCC', 'Phenotype', 'HP:0002860', (90, 93))	('ADC', 'Disease', (14, 17))	('mutations', 'Var', (37, 46))	('EGFR', 'Gene', '1956', (77, 81))	('EGFR', 'Gene', (32, 36))	('patients', 'Species', '9606', (18, 26))	('SCC', 'Gene', '6317', (90, 93))	('EGFR', 'Gene', (77, 81))
534078	30109777	One SCC patient with EGFR mutations was not matched because of old age, poor performance status, and early clinical stage.	('SCC', 'Gene', (4, 7))	('EGFR', 'Gene', '1956', (21, 25))	('EGFR', 'Gene', (21, 25))	('SCC', 'Phenotype', 'HP:0002860', (4, 7))	('SCC', 'Gene', '6317', (4, 7))	('mutations', 'Var', (26, 35))	('patient', 'Species', '9606', (8, 15))
534079	30109777	The characteristics (age, gender, clinical stage, KPS, smoking history, EGFR mutation type, and treatment lines) of all patients were well balanced among groups and are summarized in Table 1.	('EGFR', 'Gene', '1956', (72, 76))	('mutation', 'Var', (77, 85))	('KPS', 'Disease', (50, 53))	('EGFR', 'Gene', (72, 76))	('patients', 'Species', '9606', (120, 128))
534088	30109777	EGFR mutation rate was low in lung SCC, and data of efficacy of EGFR-TKIs for patients with lung SCC are limited.	('EGFR', 'Gene', (0, 4))	('SCC', 'Gene', (35, 38))	('SCC', 'Phenotype', 'HP:0002860', (35, 38))	('patients', 'Species', '9606', (78, 86))	('SCC', 'Gene', (97, 100))	('SCC', 'Phenotype', 'HP:0002860', (97, 100))	('SCC', 'Gene', '6317', (35, 38))	('EGFR', 'Gene', '1956', (64, 68))	('EGFR', 'Gene', (64, 68))	('SCC', 'Gene', '6317', (97, 100))	('EGFR', 'Gene', '1956', (0, 4))	('mutation', 'Var', (5, 13))
534095	30109777	Better PFS and OS benefits were also seen in unselected lung SCC patients with a KPS >=80 compared with those with a KPS 60-80.	('SCC', 'Phenotype', 'HP:0002860', (61, 64))	('PFS', 'MPA', (7, 10))	('SCC', 'Gene', '6317', (61, 64))	('KPS >=80', 'Var', (81, 89))	('patients', 'Species', '9606', (65, 73))	('SCC', 'Gene', (61, 64))	('OS benefits', 'MPA', (15, 26))
534098	30109777	ADC patients with sensitizing EGFR mutations may survival about 30 months.	('EGFR', 'Gene', '1956', (30, 34))	('EGFR', 'Gene', (30, 34))	('patients', 'Species', '9606', (4, 12))	('mutations', 'Var', (35, 44))
534100	30109777	The OPTIMAL trial demonstrated that erlotinib was associated with a better PFS benefit for patients with EGFR mutations than standard chemotherapy,7 irrespective of histologic type, whereas there were only 10 nonadenocarcinoma patients enrolled in the erlotinib group.	('nonadenocarcinoma', 'Disease', (209, 226))	('patients', 'Species', '9606', (91, 99))	('mutations', 'Var', (110, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (217, 226))	('EGFR', 'Gene', '1956', (105, 109))	('erlotinib', 'Chemical', 'MESH:D000069347', (252, 261))	('erlotinib', 'Chemical', 'MESH:D000069347', (36, 45))	('nonadenocarcinoma', 'Disease', 'None', (209, 226))	('EGFR', 'Gene', (105, 109))	('patients', 'Species', '9606', (227, 235))	('PFS benefit', 'MPA', (75, 86))
534115	30109777	Icotinib should be considered as a potential treatment option for this patient population, and EGFR mutation test should be recommended in all patients with SCC.	('SCC', 'Gene', (157, 160))	('SCC', 'Phenotype', 'HP:0002860', (157, 160))	('patient', 'Species', '9606', (143, 150))	('SCC', 'Gene', '6317', (157, 160))	('patients', 'Species', '9606', (143, 151))	('mutation', 'Var', (100, 108))	('Icotinib', 'Chemical', 'MESH:C531470', (0, 8))	('EGFR', 'Gene', '1956', (95, 99))	('patient', 'Species', '9606', (71, 78))	('EGFR', 'Gene', (95, 99))
534121	28977894	Therefore, we investigated a new approach to lymph node (LN)-survival analysis by using pre-/post-NAC CT in pN0 esophageal cancer.	('NAC', 'Chemical', '-', (98, 101))	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('pN0 esophageal cancer', 'Phenotype', 'HP:0011459', (108, 129))	('pN0', 'Var', (108, 111))	('esophageal cancer', 'Disease', (112, 129))	('esophageal cancer', 'Disease', 'MESH:D004938', (112, 129))
534127	28977894	The size and number of lymph node on pre-/post-NAC CT were reliable and important prognostic factors in patients with pN0 esophageal cancer.	('esophageal cancer', 'Disease', (122, 139))	('esophageal cancer', 'Disease', 'MESH:D004938', (122, 139))	('pN0', 'Var', (118, 121))	('pN0 esophageal cancer', 'Phenotype', 'HP:0011459', (118, 139))	('patients', 'Species', '9606', (104, 112))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('NAC', 'Chemical', '-', (47, 50))
534132	28977894	Although the N classification is the most important prognostic factor in esophageal cancer because patients without lymph node involvement have a better prognosis than those with nodal involvement, we find that these patients presented different survival benefit after NAC downstaging occurrence in clinical follow-up.	('benefit', 'PosReg', (255, 262))	('NAC', 'Var', (269, 272))	('esophageal cancer', 'Disease', (73, 90))	('NAC', 'Chemical', '-', (269, 272))	('men', 'Species', '9606', (192, 195))	('survival', 'MPA', (246, 254))	('patients', 'Species', '9606', (99, 107))	('esophageal cancer', 'Disease', 'MESH:D004938', (73, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('nodal', 'Gene', (179, 184))	('patients', 'Species', '9606', (217, 225))	('downstaging', 'NegReg', (273, 284))	('nodal', 'Gene', '4838', (179, 184))	('men', 'Species', '9606', (134, 137))
534152	28977894	Multivariate survival analysis, including all statistically significant prognostic factors mentioned in univariate analysis (p value less than or equal to 0.05), was performed to determine the independent prognostic factors for pN0 esophageal squamous cell carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (257, 266))	('men', 'Species', '9606', (91, 94))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (232, 266))	('pN0', 'Var', (228, 231))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (243, 266))	('esophageal squamous cell carcinoma', 'Disease', (232, 266))
534158	28977894	Patients in pN0a group (n=50, median survival time not reached) survived longer (Figure 2).	('longer', 'PosReg', (73, 79))	('pN0a', 'Var', (12, 16))	('Patients', 'Species', '9606', (0, 8))
534172	28977894	On the other hand, some hazards of lymphadenopathy recurrence were involved in N0b group, which made their survival time similar to patients with pN1 staging.	('pN1', 'Gene', (146, 149))	('N0b', 'Var', (79, 82))	('lymphadenopathy', 'Disease', (35, 50))	('lymphadenopathy', 'Disease', 'MESH:D008206', (35, 50))	('lymphadenopathy', 'Phenotype', 'HP:0002716', (35, 50))	('pN1', 'Gene', '5270', (146, 149))	('patients', 'Species', '9606', (132, 140))
534174	28977894	We also compared the OS of pN0b patients with that of pN1 patients in the same study population (Figure 2).	('OS', 'Chemical', '-', (21, 23))	('pN1', 'Gene', '5270', (54, 57))	('patients', 'Species', '9606', (32, 40))	('pN0b', 'Var', (27, 31))	('pN1', 'Gene', (54, 57))	('patients', 'Species', '9606', (58, 66))
534211	28977894	In conclusion, the size and number of lymph node measured on pre-/post-NAC is a reliable and important prognostic factor in patients with pN0 esophageal squamous cell carcinoma.	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (142, 176))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (153, 176))	('pN0', 'Var', (138, 141))	('esophageal squamous cell carcinoma', 'Disease', (142, 176))	('carcinoma', 'Phenotype', 'HP:0030731', (167, 176))	('NAC', 'Chemical', '-', (71, 74))	('patients', 'Species', '9606', (124, 132))
534239	32114392	According to this, assessment of the expression of genes in different lung cancer patient cohorts showed that FGFR1 or FGFR4 expression alone showed no prognostic potential, and that only co-expression of FGFR1 and/or FGFR4 with N-cadherin inferred a poorer outcome.	('lung cancer', 'Disease', 'MESH:D008175', (70, 81))	('FGFR1', 'Gene', (205, 210))	('co-expression', 'Var', (188, 201))	('patient', 'Species', '9606', (82, 89))	('lung cancer', 'Disease', (70, 81))	('lung cancer', 'Phenotype', 'HP:0100526', (70, 81))	('FGFR4', 'Gene', (218, 223))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('FGFR1', 'Gene', (110, 115))	('FGFR4', 'Gene', (119, 124))
534240	32114392	Treatment of high-FGFR1 and/or FGFR4-expressing lung cancer cell lines and patient-derived xenografts with selective FGFR inhibitors showed high efficacy, but only in models with high FGFR1/4 and N-cadherin expression.	('lung cancer', 'Disease', 'MESH:D008175', (48, 59))	('inhibitors', 'Var', (122, 132))	('FGFR1/4', 'Gene', '2260;2264', (184, 191))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('FGFR', 'Gene', (117, 121))	('lung cancer', 'Disease', (48, 59))	('FGFR1/4', 'Gene', (184, 191))	('FGFR4-expressing', 'Gene', (31, 47))	('lung cancer', 'Phenotype', 'HP:0100526', (48, 59))	('patient', 'Species', '9606', (75, 82))
534248	32114392	NSCLC is characterised by numerous genomic aberrations underlying the disease, some of which are druggable oncogenic drivers such as ALK translocations and EGFR mutations, whose targeting has improved patient outcomes and changed clinical practices.	('NSCLC', 'Disease', 'MESH:D002289', (0, 5))	('EGFR', 'Gene', '1956', (156, 160))	('ALK', 'Gene', (133, 136))	('EGFR', 'Gene', (156, 160))	('mutations', 'Var', (161, 170))	('ALK', 'Gene', '238', (133, 136))	('patient', 'Species', '9606', (201, 208))	('NSCLC', 'Disease', (0, 5))
534251	32114392	In lung cancer, FGFR1 amplification is detected in approximately 20% of squamous cell carcinoma cases.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (72, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('lung cancer', 'Disease', (3, 14))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (72, 95))	('lung cancer', 'Phenotype', 'HP:0100526', (3, 14))	('squamous cell carcinoma', 'Disease', (72, 95))	('amplification', 'Var', (22, 35))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('detected', 'Reg', (39, 47))	('lung cancer', 'Disease', 'MESH:D008175', (3, 14))	('FGFR1', 'Gene', (16, 21))
534264	32114392	The following antibodies were used: FGFR1 (#9740, Cell signalling), FGFR4 (#8562, Cell signalling), pFGFR1 (06-1433, Millipore), pFGFR4 (MBS856043, MyBiosource), AKT (#9272, Cell signalling), pAKT (#9271, Cell signalling), p42/p44 (#9102, Cell signalling), p-p42/p44 (#9101, Cell signalling), STAT3 (#9139, Cell signalling), pSTAT3 (#9145, Cell signalling), alpha-tubulin (Sigma), EGFR (#4267, Cell signalling), pEGFR (#2234, Cell signalling), E-cadherin (#3195, Cell signalling) and N-cadherin (#3195, Cell signalling).	('AKT', 'Gene', '207', (162, 165))	('AKT', 'Gene', '207', (193, 196))	('STAT3', 'Gene', '6774', (326, 331))	('N-cadherin', 'Protein', (484, 494))	('p42', 'Gene', '23552', (223, 226))	('p44', 'Gene', (227, 230))	('p42', 'Gene', (259, 262))	('p44', 'Gene', '10561', (227, 230))	('alpha-tubulin (Sigma)', 'Gene', '10376', (358, 379))	('EGFR', 'Gene', (413, 417))	('STAT3', 'Gene', (293, 298))	('p42', 'Gene', '23552', (259, 262))	('EGFR', 'Gene', '1956', (381, 385))	('EGFR', 'Gene', (381, 385))	('STAT3', 'Gene', '6774', (293, 298))	('p44', 'Gene', (263, 266))	('AKT', 'Gene', (162, 165))	('AKT', 'Gene', (193, 196))	('alpha-tubulin (Sigma', 'Gene', (358, 378))	('p44', 'Gene', '10561', (263, 266))	('E-cadherin', 'Gene', (444, 454))	('EGFR', 'Gene', '1956', (413, 417))	('E-cadherin', 'Gene', '999', (444, 454))	('STAT3', 'Gene', (326, 331))	('p42', 'Gene', (223, 226))	('#2234', 'Var', (419, 424))
534275	32114392	Cells were then incubated with mouse anti-N-cadherin (#MA1-159, Thermo Fisher) and rabbit anti-FGFR1 (#9740, CST) or anti-FGFR4 (#8562, CST) antibodies at a 1:100 dilution in 1% BSA and 0.1% Triton X-100 in PBS for 3 h at room temperature.	('CST', 'Gene', '53897', (136, 139))	('PBS', 'Chemical', 'MESH:D007854', (207, 210))	('CST', 'Gene', (109, 112))	('CST', 'Gene', (136, 139))	('#MA1-159', 'Var', (54, 62))	('mouse', 'Species', '10090', (31, 36))	('#9740', 'Var', (102, 107))	('Triton X-100', 'Chemical', 'MESH:D017830', (191, 203))	('CST', 'Gene', '53897', (109, 112))	('#8562', 'Var', (129, 134))
534276	32114392	The cells were then labelled with Alexa Fluor  488 Goat Anti-Rabbit IgG (#R37116, Thermo Fisher) and Alexa Fluor  555 Donkey Anti-Mouse IgG secondary antibodies (#A-31570, Thermo Fisher) at a dilution of 1:250 for 1 h at room temperature.	('#R37116', 'Var', (73, 80))	('Alexa Fluor  555', 'Chemical', 'MESH:C000608607', (101, 117))	('Mouse', 'Species', '10090', (130, 135))	('#A-31570', 'Var', (162, 170))	('Alexa Fluor  488', 'Chemical', '-', (34, 50))
534285	32114392	Six models were used: TP43, TP60, TP91 (adenocarcinomas) and TP13, TP96 and TP114 (squamous cell carcinomas).	('carcinoma', 'Phenotype', 'HP:0030731', (45, 54))	('adenocarcinomas', 'Disease', (40, 55))	('TP43', 'Var', (22, 26))	('TP13', 'Var', (61, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (83, 106))	('carcinomas', 'Phenotype', 'HP:0030731', (45, 55))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (83, 107))	('TP60', 'Var', (28, 32))	('TP91', 'Var', (34, 38))	('carcinomas', 'Phenotype', 'HP:0030731', (97, 107))	('squamous cell carcinomas', 'Disease', (83, 107))	('adenocarcinomas', 'Disease', 'MESH:D000230', (40, 55))	('TP114', 'Var', (76, 81))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (83, 107))	('TP96', 'Var', (67, 71))
534288	32114392	When tumour volumes had reached 150 mm3, mice were randomised into 2 groups of 3-5 mice each for the control and AZD4547 treatment groups, with tumour sizes for the two groups being of similar mean and standard deviation.	('tumour', 'Disease', 'MESH:D009369', (5, 11))	('tumour', 'Phenotype', 'HP:0002664', (144, 150))	('tumour', 'Disease', 'MESH:D009369', (144, 150))	('mice', 'Species', '10090', (41, 45))	('tumour', 'Disease', (5, 11))	('mice', 'Species', '10090', (83, 87))	('AZD4547', 'Var', (113, 120))	('tumour', 'Disease', (144, 150))	('AZD4547', 'Chemical', 'MESH:C572463', (113, 120))	('tumour', 'Phenotype', 'HP:0002664', (5, 11))
534290	32114392	AZD4547 was administered by oral gavage 5 times per week at a concentration of 7.5 mg AZD4547/kg/day, in a 5-week-long treatment scheme unless the experiment had to be prematurely stopped due to excessive tumour growth.	('excessive tumour', 'Disease', (195, 211))	('AZD4547', 'Chemical', 'MESH:C572463', (0, 7))	('AZD4547', 'Chemical', 'MESH:C572463', (86, 93))	('AZD4547/kg/day', 'Var', (86, 100))	('excessive tumour', 'Disease', 'MESH:D009369', (195, 211))	('tumour', 'Phenotype', 'HP:0002664', (205, 211))
534296	32114392	Gene expression was analysed using TaqMan probes from Life Technologies: Hs00917379_m1 FAM (FGFR1), Hs01106908_m1 FAM (FGFR4), Hs01023894_m1 FAM (E-cadherin), Hs00983056_m1 FAM (N-cadherin), Hs99999905_m1 FAM (GAPDH), and Hs99999907_m1 FAM (B2M).	('Hs01023894_m1', 'Var', (127, 140))	('Hs99999905_m1', 'Var', (191, 204))	('Hs99999907_m1', 'Var', (222, 235))	('E-cadherin', 'Gene', (146, 156))	('E-cadherin', 'Gene', '999', (146, 156))	('Hs01106908_m1', 'Var', (100, 113))	('GAPDH', 'Gene', '2597', (210, 215))	('GAPDH', 'Gene', (210, 215))	('Hs00983056_m1', 'Var', (159, 172))	('Hs00917379_m1', 'Var', (73, 86))
534312	32114392	Further to the above, silencing of either FGFR in non-squamous A549 cells led to increased oncogenicity (Figs.	('oncogenicity', 'CPA', (91, 103))	('A549', 'CellLine', 'CVCL:0023', (63, 67))	('FGFR', 'Gene', (42, 46))	('silencing', 'Var', (22, 31))	('increased', 'PosReg', (81, 90))
534313	32114392	However, slightly increased activation of STAT3, AKT and p42/p44 signalling was observed after FGFR4 silencing in this cell line, while STAT3 signalling was upregulated, and a similar trend was observed for AKT and p42/p44 after FGFR1 silencing (Fig.	('p42', 'Gene', '23552', (57, 60))	('upregulated', 'PosReg', (157, 168))	('p44', 'Gene', (61, 64))	('STAT3', 'Gene', '6774', (136, 141))	('p44', 'Gene', '10561', (61, 64))	('p44', 'Gene', (219, 222))	('AKT', 'Gene', '207', (49, 52))	('AKT', 'Gene', '207', (207, 210))	('p44', 'Gene', '10561', (219, 222))	('silencing', 'Var', (101, 110))	('STAT3', 'Gene', (136, 141))	('FGFR4', 'Gene', (95, 100))	('STAT3', 'Gene', (42, 47))	('AKT', 'Gene', (49, 52))	('p42', 'Gene', (215, 218))	('p42', 'Gene', (57, 60))	('AKT', 'Gene', (207, 210))	('activation', 'PosReg', (28, 38))	('STAT3', 'Gene', '6774', (42, 47))	('p42', 'Gene', '23552', (215, 218))
534325	32114392	Consistently, when both FGFR1 and FGFR4 expression were taken into account (n = 89), patients with high FGFR1/4 and low N-cadherin expression had increased overall survival (Hazard Ratio of 1.89 [1.02-3.49], p = 0.039) compared to patients with elevated expression of both genes (Fig.	('FGFR1/4', 'Gene', '2260;2264', (104, 111))	('patients', 'Species', '9606', (231, 239))	('N-cadherin', 'Protein', (120, 130))	('increased', 'PosReg', (146, 155))	('overall survival', 'MPA', (156, 172))	('FGFR1/4', 'Gene', (104, 111))	('low', 'NegReg', (116, 119))	('high', 'Var', (99, 103))	('patients', 'Species', '9606', (85, 93))	('expression', 'MPA', (131, 141))
534329	32114392	This analysis unveiled a gene signature consisting of 55 upregulated genes (logFC>1, B>0) in tumours with high FGFR1/4 and N-cadherin expression (Fig.	('tumours', 'Disease', (93, 100))	('FGFR1/4', 'Gene', '2260;2264', (111, 118))	('high', 'Var', (106, 110))	('N-cadherin', 'Protein', (123, 133))	('tumour', 'Phenotype', 'HP:0002664', (93, 99))	('FGFR1/4', 'Gene', (111, 118))	('tumours', 'Phenotype', 'HP:0002664', (93, 100))	('tumours', 'Disease', 'MESH:D009369', (93, 100))	('upregulated', 'PosReg', (57, 68))
534332	32114392	Our results suggested that in high FGFR1/FGFR4-expressing tumours, FGFR inhibition would be effective only when N-cadherin is highly expressed.	('tumours', 'Phenotype', 'HP:0002664', (58, 65))	('tumour', 'Phenotype', 'HP:0002664', (58, 64))	('high', 'Var', (30, 34))	('FGFR1/FGFR4-expressing', 'Gene', (35, 57))	('tumours', 'Disease', 'MESH:D009369', (58, 65))	('tumours', 'Disease', (58, 65))
534333	32114392	To test this hypothesis, we assessed the effect of two selective FGFR inhibitors (BGJ398 and AZD4547) on a set of cell lines highly expressing these FGFRs, with variable endogenous (Fig.	('AZD4547', 'Var', (93, 100))	('BGJ398', 'Chemical', 'MESH:C568950', (82, 88))	('AZD4547', 'Chemical', 'MESH:C572463', (93, 100))	('BGJ398', 'Gene', (82, 88))
534337	32114392	Of note, among nine cell lines with FGFR1 amplification, three out of three with high N-cadherin and FGFR1 levels were among the most sensitive to dovitinib, while five out of six cell lines with low N-cadherin and/or FGFR1 expression levels showed limited dovitinib sensitivity (Supplementary Figure S5b).	('FGFR1', 'Gene', (218, 223))	('FGFR1', 'Gene', (36, 41))	('sensitive', 'MPA', (134, 143))	('dovitinib sensitivity', 'MPA', (257, 278))	('amplification', 'Var', (42, 55))	('dovitinib', 'Chemical', 'MESH:C500007', (147, 156))	('dovitinib', 'Chemical', 'MESH:C500007', (257, 266))
534339	32114392	Further to this, as an additional external validation of our results, we analysed data from GDSC and performed experiments analogous to those whose results are presented in Figure S5a, with sensitivity data for the FGFR inhibitors (FGFRis) AZD4547 and PD173074 (Figures S5c-d).	('AZD4547', 'Var', (240, 247))	('PD173074', 'Chemical', 'MESH:C115711', (252, 260))	('AZD4547', 'Chemical', 'MESH:C572463', (240, 247))	('PD173074', 'Var', (252, 260))
534340	32114392	We found trends in common with our results, with cell lines with high FGFR1/FGFR4 and CDH2 expression showing the highest sensitivity to either inhibitor.	('FGFR1/FGFR4', 'Gene', (70, 81))	('CDH2', 'Gene', '1000', (86, 90))	('sensitivity', 'MPA', (122, 133))	('high', 'Var', (65, 69))	('CDH2', 'Gene', (86, 90))
534341	32114392	Remarkably, in agreement with our results, in cell lines with high FGFR1 expression, those with high CDH2 expression showed a significantly higher sensitivity to AZD4547 (p = 0.004, Figure S5c).	('FGFR1', 'Gene', (67, 72))	('CDH2', 'Gene', '1000', (101, 105))	('higher', 'PosReg', (140, 146))	('sensitivity to AZD4547', 'MPA', (147, 169))	('AZD4547', 'Chemical', 'MESH:C572463', (162, 169))	('high', 'Var', (62, 66))	('CDH2', 'Gene', (101, 105))
534342	32114392	We selected several lung cancer PDX models with high FGFR1 expression and differential levels of N-cadherin: one adenocarcinoma and one squamous cell carcinoma PDX with high FGFR1 expression and low N-cadherin expression (TP60 and TP13, respectively), and one adenocarcinoma and one squamous cell carcinoma PDX with high expression of both genes (TP91 and TP114, respectively).	('lung cancer', 'Disease', 'MESH:D008175', (20, 31))	('adenocarcinoma', 'Disease', 'MESH:D000230', (113, 127))	('lung cancer', 'Phenotype', 'HP:0100526', (20, 31))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (136, 159))	('adenocarcinoma', 'Disease', (260, 274))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (283, 306))	('carcinoma', 'Phenotype', 'HP:0030731', (150, 159))	('FGFR1', 'Gene', (174, 179))	('TP91', 'Var', (347, 351))	('squamous cell carcinoma', 'Disease', (136, 159))	('TP60', 'Var', (222, 226))	('FGFR1', 'Gene', (53, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('expression', 'MPA', (180, 190))	('lung cancer', 'Disease', (20, 31))	('adenocarcinoma', 'Disease', 'MESH:D000230', (260, 274))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (283, 306))	('TP13', 'Var', (231, 235))	('adenocarcinoma', 'Disease', (113, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (297, 306))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (136, 159))	('squamous cell carcinoma', 'Disease', (283, 306))	('carcinoma', 'Phenotype', 'HP:0030731', (265, 274))
534346	32114392	This inhibitor had no effect on tumour growth in the PDX models with low N-cadherin expression (TP13 and TP60) (Fig.	('TP13', 'Var', (96, 100))	('tumour', 'Disease', (32, 38))	('low', 'NegReg', (69, 72))	('TP60', 'Var', (105, 109))	('expression', 'MPA', (84, 94))	('tumour', 'Phenotype', 'HP:0002664', (32, 38))	('N-cadherin', 'Protein', (73, 83))	('tumour', 'Disease', 'MESH:D009369', (32, 38))
534347	32114392	In contrast, in the models with higher N-cadherin expression (TP91 and TP114), AZD4547 treatment resulted in decreased tumour growth compared to the untreated tumours (tumour versus control volume (T/C)) of 14.4% and 25.5%, respectively).	('AZD4547', 'Var', (79, 86))	('higher', 'PosReg', (32, 38))	('N-cadherin', 'Protein', (39, 49))	('tumours', 'Disease', (159, 166))	('AZD4547', 'Chemical', 'MESH:C572463', (79, 86))	('decreased tumour', 'Disease', 'MESH:D009369', (109, 125))	('tumours', 'Phenotype', 'HP:0002664', (159, 166))	('tumours', 'Disease', 'MESH:D009369', (159, 166))	('decreased tumour', 'Disease', (109, 125))	('TP114', 'Var', (71, 76))	('tumour', 'Phenotype', 'HP:0002664', (168, 174))	('tumour', 'Disease', 'MESH:D009369', (168, 174))	('tumour', 'Phenotype', 'HP:0002664', (159, 165))	('tumour', 'Disease', 'MESH:D009369', (159, 165))	('tumour', 'Disease', (168, 174))	('tumour', 'Disease', (159, 165))	('tumour', 'Phenotype', 'HP:0002664', (119, 125))	('tumour', 'Disease', 'MESH:D009369', (119, 125))	('tumour', 'Disease', (119, 125))
534348	32114392	Indeed, AZD4547 treatment induced tumour shrinkage in these two models, and achieved 1/5 and 2/5 complete tumour regressions, respectively.	('tumour', 'Phenotype', 'HP:0002664', (106, 112))	('tumour', 'Disease', 'MESH:D009369', (106, 112))	('tumour', 'Disease', 'MESH:D009369', (34, 40))	('tumour regressions', 'Disease', (106, 124))	('AZD4547', 'Var', (8, 15))	('shrinkage', 'NegReg', (41, 50))	('tumour', 'Disease', (34, 40))	('tumour regressions', 'Disease', 'MESH:D009365', (106, 124))	('AZD4547', 'Chemical', 'MESH:C572463', (8, 15))	('tumour', 'Disease', (106, 112))	('tumour', 'Phenotype', 'HP:0002664', (34, 40))
534349	32114392	In the TP96 model, the observed effects were more pronounced, including a dramatically reduced tumour volume compared to the untreated group (T/C of 1.4%), a dramatic reduction in tumour volume from the initial volume, and 2/5 complete tumour regressions (Fig.	('tumour', 'Disease', 'MESH:D009369', (236, 242))	('tumour regressions', 'Disease', (236, 254))	('tumour', 'Disease', 'MESH:D009369', (95, 101))	('tumour', 'Disease', (236, 242))	('tumour', 'Phenotype', 'HP:0002664', (95, 101))	('reduced', 'NegReg', (87, 94))	('reduction', 'NegReg', (167, 176))	('TP96', 'Var', (7, 11))	('tumour', 'Disease', (95, 101))	('tumour regressions', 'Disease', 'MESH:D009365', (236, 254))	('tumour', 'Phenotype', 'HP:0002664', (180, 186))	('tumour', 'Disease', 'MESH:D009369', (180, 186))	('tumour', 'Phenotype', 'HP:0002664', (236, 242))	('tumour', 'Disease', (180, 186))
534353	32114392	FGFR1 aberrations, particularly amplification, have been associated with NSCLC, especially in squamous cell carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (94, 117))	('squamous cell carcinoma', 'Disease', (94, 117))	('amplification', 'Var', (32, 45))	('FGFR1', 'Gene', (0, 5))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (94, 117))	('NSCLC', 'Disease', (73, 78))	('NSCLC', 'Disease', 'MESH:D002289', (73, 78))	('associated', 'Reg', (57, 67))
534356	32114392	FGFR3 overexpression has also been reported to exert anti-oncogenic and pro-oncogenic effects, which were associated with epithelial-like and mesenchymal-like phenotypes, respectively, in pancreatic cell lines.	('associated', 'Reg', (106, 116))	('overexpression', 'Var', (6, 20))	('FGFR3', 'Gene', (0, 5))	('epithelial-like', 'CPA', (122, 137))	('mesenchymal-like', 'CPA', (142, 158))	('pancreatic', 'Disease', 'MESH:D010195', (188, 198))	('pancreatic', 'Disease', (188, 198))	('anti-oncogenic', 'CPA', (53, 67))	('pro-oncogenic effects', 'CPA', (72, 93))	('FGFR3', 'Gene', '2261', (0, 5))
534371	32114392	In addition, we found that FGF5 expression was upregulated in tumours with high FGFR1/4 and N-cadherin expression.	('N-cadherin', 'Protein', (92, 102))	('tumour', 'Phenotype', 'HP:0002664', (62, 68))	('upregulated', 'PosReg', (47, 58))	('expression', 'MPA', (103, 113))	('high', 'Var', (75, 79))	('FGFR1/4', 'Gene', '2260;2264', (80, 87))	('tumours', 'Phenotype', 'HP:0002664', (62, 69))	('FGFR1/4', 'Gene', (80, 87))	('FGF5', 'Gene', '2250', (27, 31))	('tumours', 'Disease', 'MESH:D009369', (62, 69))	('expression', 'MPA', (32, 42))	('FGF5', 'Gene', (27, 31))	('tumours', 'Disease', (62, 69))
534373	32114392	This result suggests a potential autocrine loop in lung cancer cells with high FGFR1 and N-cadherin (and thus, mesenchymal-like) co-expression.	('lung cancer', 'Disease', 'MESH:D008175', (51, 62))	('high', 'Var', (74, 78))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('N-cadherin', 'Protein', (89, 99))	('FGFR1', 'Gene', (79, 84))	('lung cancer', 'Disease', (51, 62))	('lung cancer', 'Phenotype', 'HP:0100526', (51, 62))
534376	32114392	We reported that FGFR inhibitors would only affect growth of those cell lines co-expressing FGFR1/4 and N-cadherin, and validated these results for FGFR1 in a publicly available panel of lung cancer cell lines treated with the FGFR1 inhibitor dovitinib.	('FGFR', 'Gene', (17, 21))	('lung cancer', 'Phenotype', 'HP:0100526', (187, 198))	('inhibitors', 'Var', (22, 32))	('lung cancer', 'Disease', 'MESH:D008175', (187, 198))	('dovitinib', 'Chemical', 'MESH:C500007', (243, 252))	('FGFR1/4', 'Gene', '2260;2264', (92, 99))	('affect', 'Reg', (44, 50))	('growth', 'MPA', (51, 57))	('lung cancer', 'Disease', (187, 198))	('FGFR1/4', 'Gene', (92, 99))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))
534379	32114392	Also, different potential indicators of FGFR inhibition sensitivity (MYC overexpression and certain gene expression signatures), or resistance (NRAS amplification, DUSP6 deletion, MET upregulation) have been identified.	('MET', 'MPA', (180, 183))	('DUSP6', 'Gene', '1848', (164, 169))	('upregulation', 'PosReg', (184, 196))	('DUSP6', 'Gene', (164, 169))	('FGFR', 'Gene', (40, 44))	('deletion', 'Var', (170, 178))
534380	32114392	Interestingly, within the PDX models tested, AZD4547 showed high efficacy in one of the models with the highest FGFR4 expression level (TP43) despite AZD4547 being highly active only to FGFR1-3.	('AZD4547', 'Var', (45, 52))	('AZD4547', 'Chemical', 'MESH:C572463', (45, 52))	('expression level', 'MPA', (118, 134))	('FGFR4', 'Gene', (112, 117))	('AZD4547', 'Chemical', 'MESH:C572463', (150, 157))
534383	32114392	It should also be noted that within the PDXs treated with a selective FGFR inhibitor, one KRAS-mutant lung adenocarcinoma PDX (TP91) showed high sensitivity, suggesting that FGFR1 inhibition may be an interesting therapeutic approach for selected KRAS-mutant tumours, which to date lack efficacious targeted therapies.	('inhibitor', 'Var', (75, 84))	('tumours', 'Phenotype', 'HP:0002664', (259, 266))	('tumours', 'Disease', 'MESH:D009369', (259, 266))	('KRAS', 'Gene', (90, 94))	('KRAS', 'Gene', '3845', (90, 94))	('tumours', 'Disease', (259, 266))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (102, 121))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (102, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('tumour', 'Phenotype', 'HP:0002664', (259, 265))	('FGFR', 'Gene', (70, 74))	('KRAS', 'Gene', (247, 251))	('lung adenocarcinoma', 'Disease', (102, 121))	('KRAS', 'Gene', '3845', (247, 251))
534386	32114392	Drs Quintanal-Villalonga, Molina-Pinelo, Carnero, Paz-Ares, and Ferrer jointly hold patent WO2019012174A1 and patent WO2019016422A1 (pending).	('WO2019012174A1', 'Var', (91, 105))	('Drs', 'Gene', (0, 3))	('Drs', 'Gene', '5411', (0, 3))
534447	29625050	Oncogenic Signaling Pathways in The Cancer Genome Atlas Genetic alterations in signaling pathways that control cell cycle progression, apoptosis, and cell growth are common hallmarks of cancer, but the extent, mechanisms, and co-occurrence of alterations in these pathways differ between individual tumors and tumor types.	('Cancer Genome Atlas', 'Disease', (36, 55))	('Cancer', 'Phenotype', 'HP:0002664', (36, 42))	('tumor', 'Phenotype', 'HP:0002664', (299, 304))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (36, 55))	('tumor', 'Disease', 'MESH:D009369', (310, 315))	('tumor', 'Disease', (299, 304))	('signaling pathways', 'Pathway', (79, 97))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('tumor', 'Phenotype', 'HP:0002664', (310, 315))	('tumors', 'Disease', (299, 305))	('tumors', 'Disease', 'MESH:D009369', (299, 305))	('tumor', 'Disease', (310, 315))	('alterations', 'Var', (64, 75))	('tumors', 'Phenotype', 'HP:0002664', (299, 305))	('cell', 'CPA', (111, 115))	('tumor', 'Disease', 'MESH:D009369', (299, 304))	('cancer', 'Disease', (186, 192))	('cancer', 'Disease', 'MESH:D009369', (186, 192))
534448	29625050	Using mutations, copy-number changes, mRNA expression, gene fusions and DNA methylation in 9,125 tumors profiled by The Cancer Genome Atlas (TCGA), we analyzed the mechanisms and patterns of somatic alterations in 10 canonical pathways: cell cycle, Hippo, Myc, Notch, NRF2, PI-3-Kinase/Akt, RTK-RAS, TGFbeta signaling, P53 and beta-catenin/WNT.	('Akt', 'Gene', (286, 289))	('NRF2', 'Gene', (268, 272))	('beta-catenin', 'Gene', (327, 339))	('P53', 'Gene', '7157', (319, 322))	('beta-catenin', 'Gene', '1499', (327, 339))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (120, 139))	('tumors', 'Disease', (97, 103))	('TGFbeta', 'Gene', (300, 307))	('Myc', 'Gene', '4609', (256, 259))	('Akt', 'Gene', '207', (286, 289))	('TGFbeta', 'Gene', '7040', (300, 307))	('Cancer', 'Phenotype', 'HP:0002664', (120, 126))	('Cancer Genome Atlas', 'Disease', (120, 139))	('tumors', 'Disease', 'MESH:D009369', (97, 103))	('mutations', 'Var', (6, 15))	('RTK-RAS', 'Pathway', (291, 298))	('cell cycle', 'Pathway', (237, 247))	('NRF2', 'Gene', '4780', (268, 272))	('Myc', 'Gene', (256, 259))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('P53', 'Gene', (319, 322))	('canonical pathways', 'Pathway', (217, 235))	('Notch', 'Gene', (261, 266))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('Hippo', 'Gene', (249, 254))	('Notch', 'Gene', '4853', (261, 266))
534452	29625050	An integrated analysis of genetic alterations in 10 signaling pathways in >9,000 tumors profiled by TCGA highlights significant representation of individual and co-occurring actionable alterations in these pathways, suggesting opportunities for targeted and combination therapies.	('000 tumors', 'Disease', 'MESH:D009369', (77, 87))	('genetic alterations', 'Var', (26, 45))	('TCGA', 'Gene', (100, 104))	('000 tumors', 'Disease', (77, 87))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumors', 'Phenotype', 'HP:0002664', (81, 87))	('alterations', 'Reg', (185, 196))
534453	29625050	Cancer is a disease in which cells have acquired the ability to divide and grow uncontrollably,, usually through genetic alterations in specific genes.	('Cancer', 'Disease', (0, 6))	('genetic alterations', 'Var', (113, 132))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))
534458	29625050	In these cases, many mutations, even when they occur in cancer genes, may have no functional effect.	('cancer', 'Disease', (56, 62))	('cancer', 'Disease', 'MESH:D009369', (56, 62))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('mutations', 'Var', (21, 30))
534460	29625050	Certain pathways, such as RTK-RAS signaling or the cell cycle pathway, are altered at high frequencies across many different tumor types, whereas other pathways are altered in more specific subsets of malignancies (e.g., alterations in the oxidative stress response pathway are strongly associated with squamous histologies).	('malignancies', 'Disease', (201, 213))	('altered', 'Reg', (165, 172))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('alterations', 'Var', (221, 232))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumor', 'Disease', (125, 130))	('oxidative stress', 'Phenotype', 'HP:0025464', (240, 256))	('altered', 'Reg', (75, 82))	('cell cycle pathway', 'Pathway', (51, 69))	('malignancies', 'Disease', 'MESH:D009369', (201, 213))	('RTK-RAS', 'MPA', (26, 33))	('associated', 'Reg', (287, 297))	('oxidative stress response pathway', 'Pathway', (240, 273))
534467	29625050	We evaluated 10 canonical signaling pathways with frequent genetic alterations, starting with key cancer genes explored in these pathways in previous TCGA publications, and focused on pathway members likely to be cancer drivers (functional contributors) or therapeutic targets.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('alterations', 'Var', (67, 78))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('cancer', 'Disease', 'MESH:D009369', (213, 219))	('cancer', 'Disease', (98, 104))	('canonical signaling pathways', 'Pathway', (16, 44))	('cancer', 'Disease', (213, 219))	('genetic alterations', 'Var', (59, 78))
534471	29625050	The selected genes in the ten pathways were then assessed for recurrent alterations within and across different tumor types as follows (Figure 1B): Alterations of pathway members were classified as activating events (usually specific recurrent missense mutations, i.e., hotspot mutations, amplifications or fusions involving oncogenes) or inactivating events (truncating mutations, specific recurrent missense or inframe mutations, deletions, as well as fusions and promoter hypermethylation of tumor suppressor genes).	('tumor', 'Disease', 'MESH:D009369', (495, 500))	('missense', 'Var', (401, 409))	('tumor', 'Phenotype', 'HP:0002664', (495, 500))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('promoter hypermethylation', 'Var', (466, 491))	('tumor', 'Disease', (495, 500))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('deletions', 'Var', (432, 441))	('truncating', 'Disease', (360, 370))	('missense mutations', 'Var', (244, 262))	('tumor', 'Disease', (112, 117))	('fusions', 'Var', (454, 461))
534473	29625050	In order to identify likely functional variants, we then used recurrence across tumor samples at the residue level (linear and 3D mutational hotspots,, see Methods) and prior knowledge about specific variants via the OncoKB knowledge base, which contains information about the oncogenic effects and treatment implications of variants in >400 cancer genes.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('cancer', 'Disease', 'MESH:D009369', (342, 348))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('cancer', 'Disease', (342, 348))	('tumor', 'Disease', (80, 85))	('cancer', 'Phenotype', 'HP:0002664', (342, 348))	('variants', 'Var', (325, 333))	('variants', 'Var', (39, 47))
534474	29625050	Epigenetic silencing through promoter DNA hypermethylation of tumor suppressor genes was evaluated using the RESET algorithm (see Methods).	('promoter DNA hypermethylation', 'Var', (29, 58))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('tumor', 'Disease', (62, 67))	('Epigenetic silencing', 'Var', (0, 20))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
534476	29625050	The resulting comprehensive dataset of different types of alterations across many tumor types form the basis of all subsequent analyses regarding pathways, patterns of co-occurrence and mutual exclusivity, as well as potential therapeutic implications.	('tumor', 'Disease', (82, 87))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('alterations', 'Var', (58, 69))
534479	29625050	Despite the fact that non-recurrent and not previously known alterations were filtered out as likely passenger events and were not included in the alteration frequencies, the microsatellite instability (MSI) and polymerase epsilon (POLE) mutant subtypes of gastrointestinal and uterine tumors, which had the highest mutation burden, also had the highest overall frequencies of pathway alterations.	('alterations', 'Reg', (385, 396))	('uterine tumors', 'Phenotype', 'HP:0010784', (278, 292))	('MSI', 'Disease', 'None', (203, 206))	('tumor', 'Phenotype', 'HP:0002664', (286, 291))	('gastrointestinal', 'Disease', 'MESH:D005767', (257, 273))	('tumors', 'Disease', (286, 292))	('tumors', 'Disease', 'MESH:D009369', (286, 292))	('MSI', 'Disease', (203, 206))	('tumors', 'Phenotype', 'HP:0002664', (286, 292))	('mutant', 'Var', (238, 244))	('gastrointestinal', 'Disease', (257, 273))	('microsatellite instability', 'MPA', (175, 201))
534480	29625050	This is possibly due to the frequent inactivating mutations introduced by the predominant mutation mechanisms in these tumor types  The RTK-RAS pathway was the signaling pathway with the highest median frequency of alterations (46% of samples) across all cancer types.	('tumor', 'Disease', (119, 124))	('cancer', 'Phenotype', 'HP:0002664', (255, 261))	('RTK-RAS pathway', 'Pathway', (136, 151))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('cancer', 'Disease', (255, 261))	('cancer', 'Disease', 'MESH:D009369', (255, 261))	('mutation', 'Var', (90, 98))
534487	29625050	Particularly interesting gene alterations across tumor types were observed in the RTK-RAS pathway.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumor', 'Disease', (49, 54))	('RTK-RAS pathway', 'Pathway', (82, 97))	('gene alterations', 'Var', (25, 41))
534489	29625050	KRAS alterations were most common in pancreatic carcinoma (PAAD, 72%), genomically stable colorectal cancer (69%), and lung adenocarcinoma (33%) (Figure 4B).	('KRAS', 'Gene', '3845', (0, 4))	('colorectal cancer', 'Disease', 'MESH:D015179', (90, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (48, 57))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (119, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('pancreatic carcinoma', 'Disease', (37, 57))	('colorectal cancer', 'Disease', (90, 107))	('colorectal cancer', 'Phenotype', 'HP:0003003', (90, 107))	('alterations', 'Var', (5, 16))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('lung adenocarcinoma', 'Disease', (119, 138))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (119, 138))	('pancreatic carcinoma', 'Disease', 'MESH:C562463', (37, 57))	('KRAS', 'Gene', (0, 4))	('common', 'Reg', (27, 33))
534490	29625050	BRAF alterations (predominantly known hotspot mutations) were found in melanoma and thyroid carcinoma, altered in 51% and 62% of samples, respectively.	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('melanoma', 'Phenotype', 'HP:0002861', (71, 79))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (84, 101))	('BRAF', 'Gene', '673', (0, 4))	('alterations', 'Var', (5, 16))	('melanoma and thyroid carcinoma', 'Disease', 'MESH:D008545', (71, 101))	('BRAF', 'Gene', (0, 4))
534491	29625050	EGFR alterations were predominantly found in glioblastoma (GBM, 50%), low grade glioma IDHwt (52%), HPV-negative head and neck cancer (HNSC HPV-, 13%), lung adenocarcinoma (13%), and esophagogastric squamous carcinoma (14%), while ERBB2 alterations were found most commonly in breast cancer and chromosomally unstable esophagogastric carcinoma (STES CIN 26% altered), as well as cervical carcinoma (CESC 23% altered).	('breast cancer', 'Phenotype', 'HP:0003002', (277, 290))	('carcinoma', 'Phenotype', 'HP:0030731', (208, 217))	('found', 'Reg', (36, 41))	('glioblastoma', 'Disease', (45, 57))	('alterations', 'Var', (5, 16))	('esophagogastric carcinoma', 'Phenotype', 'HP:0011459', (318, 343))	('ERBB2', 'Gene', '2064', (231, 236))	('cervical carcinoma', 'Disease', 'MESH:D002575', (379, 397))	('glioblastoma', 'Phenotype', 'HP:0012174', (45, 57))	('breast cancer', 'Disease', 'MESH:D001943', (277, 290))	('carcinoma', 'Phenotype', 'HP:0030731', (334, 343))	('breast cancer', 'Disease', (277, 290))	('IDH', 'Gene', (87, 90))	('chromosomally unstable esophagogastric carcinoma', 'Disease', 'MESH:D000789', (295, 343))	('CIN', 'Disease', 'MESH:D007674', (350, 353))	('carcinoma', 'Phenotype', 'HP:0030731', (388, 397))	('head and neck cancer', 'Phenotype', 'HP:0012288', (113, 133))	('chromosomally unstable esophagogastric carcinoma', 'Disease', (295, 343))	('glioma', 'Disease', (80, 86))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('EGFR', 'Gene', (0, 4))	('lung adenocarcinoma', 'Disease', (152, 171))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (199, 217))	('glioma', 'Disease', 'MESH:D005910', (80, 86))	('IDH', 'Gene', '3417', (87, 90))	('esophagogastric squamous carcinoma', 'Phenotype', 'HP:0011459', (183, 217))	('neck cancer', 'Disease', 'MESH:D006258', (122, 133))	('cancer', 'Phenotype', 'HP:0002664', (284, 290))	('neck cancer', 'Disease', (122, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (162, 171))	('alterations', 'Var', (237, 248))	('CIN', 'Disease', (350, 353))	('STES', 'Chemical', '-', (345, 349))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (152, 171))	('esophagogastric squamous carcinoma', 'Disease', (183, 217))	('esophagogastric squamous carcinoma', 'Disease', 'MESH:D002294', (183, 217))	('glioblastoma', 'Disease', 'MESH:D005909', (45, 57))	('glioma', 'Phenotype', 'HP:0009733', (80, 86))	('cervical carcinoma', 'Disease', (379, 397))	('EGFR', 'Gene', '1956', (0, 4))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (152, 171))	('ERBB2', 'Gene', (231, 236))
534492	29625050	While most of the alterations described here were previously reported as functional contributors, we identified relatively rare potentially oncogenic alterations in SOS1 (<1%).	('SOS1', 'Gene', (165, 169))	('alterations', 'Var', (150, 161))	('alterations', 'Var', (18, 29))	('SOS1', 'Gene', '6654', (165, 169))
534494	29625050	Specific germline mutations in this gene are involved in Noonan syndrome, and recurrent somatic mutations in SOS1 were recently identified in otherwise RAS-pathway driver-negative lung adenocarcinoma samples.	('Noonan syndrome', 'Disease', 'MESH:D009634', (57, 72))	('carcinoma', 'Phenotype', 'HP:0030731', (190, 199))	('SOS1', 'Gene', (109, 113))	('lung adenocarcinoma', 'Disease', (180, 199))	('involved', 'Reg', (45, 53))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (180, 199))	('SOS1', 'Gene', '6654', (109, 113))	('Noonan syndrome', 'Disease', (57, 72))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (180, 199))	('germline mutations', 'Var', (9, 27))
534495	29625050	We identified recurrent (hotspot) mutations (A90V/T, N233Y/S) and other known activating mutations (M269I/V, G434R, R552S/K/G/M, E846K) in SOS1 in a total of 1% of lung adenocarcinoma samples, 1% of uterine carcinomas, independent of subtype, and at lower frequencies in several other cancer types (Figure 4C).	('uterine carcinomas', 'Phenotype', 'HP:0010784', (199, 217))	('E846K', 'Var', (129, 134))	('uterine carcinoma', 'Phenotype', 'HP:0010784', (199, 216))	('R552S', 'SUBSTITUTION', 'None', (116, 121))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (164, 183))	('SOS1', 'Gene', (139, 143))	('G434R', 'Mutation', 'rs397517148', (109, 114))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (164, 183))	('M269I', 'SUBSTITUTION', 'None', (100, 105))	('carcinoma', 'Phenotype', 'HP:0030731', (207, 216))	('carcinomas', 'Phenotype', 'HP:0030731', (207, 217))	('carcinomas', 'Disease', 'MESH:D002277', (207, 217))	('G434R', 'Var', (109, 114))	('carcinoma', 'Phenotype', 'HP:0030731', (174, 183))	('cancer', 'Disease', (285, 291))	('M269I', 'Var', (100, 105))	('R552S', 'Var', (116, 121))	('N233Y', 'SUBSTITUTION', 'None', (53, 58))	('cancer', 'Phenotype', 'HP:0002664', (285, 291))	('N233Y', 'Var', (53, 58))	('A90V', 'Var', (45, 49))	('SOS1', 'Gene', '6654', (139, 143))	('E846K', 'Mutation', 'rs397517159', (129, 134))	('carcinomas', 'Disease', (207, 217))	('lung adenocarcinoma', 'Disease', (164, 183))	('cancer', 'Disease', 'MESH:D009369', (285, 291))	('A90V', 'SUBSTITUTION', 'None', (45, 49))
534497	29625050	A more detailed analysis of RAS pathway alterations is published separately, including a description of downstream transcriptional changes due to malfunctioning Ras signaling and results suggesting that multiple hits in the Ras pathway are capable of increasing overall Ras activity in RAS wildtype tumors.	('hits', 'Var', (212, 216))	('Ras', 'Gene', (224, 227))	('tumors', 'Disease', (299, 305))	('tumors', 'Disease', 'MESH:D009369', (299, 305))	('increasing', 'PosReg', (251, 261))	('tumors', 'Phenotype', 'HP:0002664', (299, 305))	('tumor', 'Phenotype', 'HP:0002664', (299, 304))	('Ras', 'Enzyme', (270, 273))
534499	29625050	Several pathways are featured in more detail as separate publications, including: 1) PI3K pathway: aberrations in the PI3K pathway were found predominantly as activating events in PIK3CA (less commonly in PIK3CB) and inactivating events in PTEN or PIK3R1 with PIK3CA and PTEN alterations being most commonly found in head and neck cancer, breast cancer, gastrointestinal and gynecological tumors; 2) TGFbeta pathway: The TGFbeta pathway had the highest alteration rate in pancreatic and gastrointestinal cancers, while renal and brain cancers, among others, had almost no alterations in this pathway; and 3) MYC pathway: MYC pathway alterations were most common in tumor types with amplification of chromosome 8, which contains MYC, such as breast cancer, ovarian cancer (OV), and others.	('TGFbeta', 'Gene', (421, 428))	('gastrointestinal', 'Disease', (354, 370))	('MYC', 'Gene', (608, 611))	('PIK3CA', 'Gene', (260, 266))	('tumor', 'Phenotype', 'HP:0002664', (389, 394))	('alterations', 'Reg', (633, 644))	('gastrointestinal', 'Disease', 'MESH:D005767', (354, 370))	('tumor', 'Disease', 'MESH:D009369', (665, 670))	('PIK3R1', 'Gene', '5295', (248, 254))	('TGFbeta', 'Gene', '7040', (421, 428))	('ovarian cancer', 'Disease', 'MESH:D010051', (756, 770))	('tumors', 'Disease', (389, 395))	('PIK3CB', 'Gene', (205, 211))	('pancreatic and gastrointestinal cancers', 'Disease', 'MESH:D010190', (472, 511))	('common', 'Reg', (655, 661))	('cancer', 'Phenotype', 'HP:0002664', (748, 754))	('MYC', 'Gene', '4609', (728, 731))	('MYC', 'Gene', (621, 624))	('PIK3CB', 'Gene', '5291', (205, 211))	('gastrointestinal', 'Disease', (487, 503))	('breast cancer', 'Phenotype', 'HP:0003002', (339, 352))	('renal and brain cancers', 'Disease', 'MESH:D007680', (519, 542))	('tumors', 'Disease', 'MESH:D009369', (389, 395))	('cancer', 'Phenotype', 'HP:0002664', (331, 337))	('tumor', 'Phenotype', 'HP:0002664', (665, 670))	('PIK3CA', 'Gene', '5290', (180, 186))	('MYC', 'Gene', '4609', (608, 611))	('gastrointestinal', 'Disease', 'MESH:D005767', (487, 503))	('PTEN', 'Gene', (240, 244))	('PTEN', 'Gene', (271, 275))	('ovarian cancer', 'Disease', (756, 770))	('breast cancer', 'Disease', 'MESH:D001943', (339, 352))	('ovarian cancer', 'Phenotype', 'HP:0100615', (756, 770))	('breast cancer', 'Phenotype', 'HP:0003002', (741, 754))	('breast cancer', 'Disease', (339, 352))	('PIK3CA', 'Gene', '5290', (260, 266))	('tumor', 'Disease', (389, 394))	('MYC', 'Gene', '4609', (621, 624))	('PIK3R1', 'Gene', (248, 254))	('cancer', 'Phenotype', 'HP:0002664', (346, 352))	('TGFbeta', 'Gene', (400, 407))	('PTEN', 'Gene', '5728', (240, 244))	('breast cancer', 'Disease', 'MESH:D001943', (741, 754))	('PTEN', 'Gene', '5728', (271, 275))	('tumor', 'Disease', 'MESH:D009369', (389, 394))	('breast cancer', 'Disease', (741, 754))	('cancers', 'Phenotype', 'HP:0002664', (504, 511))	('cancers', 'Phenotype', 'HP:0002664', (535, 542))	('MYC', 'Gene', (728, 731))	('TGFbeta', 'Gene', '7040', (400, 407))	('head and neck cancer', 'Phenotype', 'HP:0012288', (317, 337))	('amplification', 'Var', (682, 695))	('neck cancer', 'Disease', 'MESH:D006258', (326, 337))	('PIK3CA', 'Gene', (180, 186))	('neck cancer', 'Disease', (326, 337))	('tumors', 'Phenotype', 'HP:0002664', (389, 395))	('cancer', 'Phenotype', 'HP:0002664', (504, 510))	('cancer', 'Phenotype', 'HP:0002664', (535, 541))	('tumor', 'Disease', (665, 670))
534508	29625050	Indeed, numerous alterations affecting Rb-mediated cell cycle control were found co-occurring with TP53 mutations.	('TP53', 'Gene', '7157', (99, 103))	('Rb-mediated', 'MPA', (39, 50))	('mutations', 'Var', (104, 113))	('TP53', 'Gene', (99, 103))
534509	29625050	These included amplification of CCNE1, mutation of CDKN2A, RB1 loss, and amplification of CDK6 and E2F3 (Figure S4B).	('CDKN2A', 'Gene', '1029', (51, 57))	('RB1', 'Gene', (59, 62))	('CCNE1', 'Gene', (32, 37))	('CCNE1', 'Gene', '898', (32, 37))	('mutation', 'Var', (39, 47))	('amplification', 'Reg', (15, 28))	('loss', 'NegReg', (63, 67))	('CDK6', 'Gene', '1021', (90, 94))	('RB1', 'Gene', '5925', (59, 62))	('E2F3', 'Gene', '1871', (99, 103))	('E2F3', 'Gene', (99, 103))	('CDKN2A', 'Gene', (51, 57))	('CDK6', 'Gene', (90, 94))	('amplification', 'Var', (73, 86))
534510	29625050	Interestingly, TP53 mutations were found mutually exclusive with CDKN2A deletion, consistent with the latter invariably affecting both p16, regulating the cell cycle, and ARF, promoting p53-dependent apoptosis.	('CDKN2A', 'Gene', '1029', (65, 71))	('affecting', 'Reg', (120, 129))	('promoting', 'PosReg', (176, 185))	('regulating', 'Reg', (140, 150))	('p16', 'Gene', '1029', (135, 138))	('cell cycle', 'CPA', (155, 165))	('ARF', 'Disease', 'MESH:D058186', (171, 174))	('p53', 'Gene', (186, 189))	('TP53', 'Gene', (15, 19))	('p53', 'Gene', '7157', (186, 189))	('TP53', 'Gene', '7157', (15, 19))	('ARF', 'Disease', (171, 174))	('CDKN2A', 'Gene', (65, 71))	('p16', 'Gene', (135, 138))	('mutations', 'Var', (20, 29))	('deletion', 'Var', (72, 80))
534513	29625050	Overall, these results indicate that p53 signaling and cell cycle control are frequently co-altered across multiple tumor types, either through two independent events (e.g., mutations of TP53 and RB1), or through a single alteration that is able to affect both pathways (e.g., CDKN2A deletion).	('deletion', 'Var', (284, 292))	('CDKN2A', 'Gene', (277, 283))	('RB1', 'Gene', '5925', (196, 199))	('TP53', 'Gene', '7157', (187, 191))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('CDKN2A', 'Gene', '1029', (277, 283))	('cell cycle', 'CPA', (55, 65))	('TP53', 'Gene', (187, 191))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('affect', 'Reg', (249, 255))	('p53', 'Gene', (37, 40))	('p53', 'Gene', '7157', (37, 40))	('mutations', 'Var', (174, 183))	('tumor', 'Disease', (116, 121))	('RB1', 'Gene', (196, 199))	('co-altered', 'Reg', (89, 99))
534515	29625050	Here, gain of function mutations and amplifications of the NFE2L2 gene (encoding for NRF2) significantly co-occurred with PIK3CA amplification and tended to co-occur with PIK3CA mutations and PIK3CB amplification (Figure 6C).	('NRF2', 'Gene', (85, 89))	('PIK3CA', 'Gene', (122, 128))	('PIK3CA', 'Gene', (171, 177))	('PIK3CB', 'Gene', (192, 198))	('PIK3CB', 'Gene', '5291', (192, 198))	('PIK3CA', 'Gene', '5290', (171, 177))	('PIK3CA', 'Gene', '5290', (122, 128))	('NFE2L2', 'Gene', '4780', (59, 65))	('mutations', 'Var', (23, 32))	('gain of function', 'PosReg', (6, 22))	('NRF2', 'Gene', '4780', (85, 89))	('NFE2L2', 'Gene', (59, 65))
534516	29625050	Interestingly, even though NFE2L2 amplification was largely mutually exclusive with loss of STK11 (a.k.a.	('STK11', 'Gene', '6794', (92, 97))	('NFE2L2', 'Gene', '4780', (27, 33))	('NFE2L2', 'Gene', (27, 33))	('loss', 'Var', (84, 88))	('STK11', 'Gene', (92, 97))
534517	29625050	LKB1), the latter significantly co-occurred with loss of function mutations of KEAP1, a negative regulator of NFE2L2.	('NFE2L2', 'Gene', (110, 116))	('mutations', 'Var', (66, 75))	('KEAP1', 'Gene', (79, 84))	('LKB1', 'Gene', (0, 4))	('LKB1', 'Gene', '6794', (0, 4))	('loss of function', 'NegReg', (49, 65))	('NFE2L2', 'Gene', '4780', (110, 116))	('KEAP1', 'Gene', '9817', (79, 84))
534518	29625050	Co-occurring NRF2-PI3K pathway alterations were most frequent in lung tumors (both squamous cell and adenocarcinoma), esophageal carcinomas, head and neck squamous cell carcinoma and uterine carcinoma, independent of subtype (Figure 6D).	('carcinoma', 'Disease', (106, 115))	('carcinoma', 'Phenotype', 'HP:0030731', (169, 178))	('lung tumors', 'Disease', 'MESH:D008175', (65, 76))	('carcinoma', 'Disease', (169, 178))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('uterine carcinoma', 'Phenotype', 'HP:0010784', (183, 200))	('carcinomas', 'Phenotype', 'HP:0030731', (129, 139))	('neck squamous cell carcinoma', 'Disease', (150, 178))	('lung tumors', 'Phenotype', 'HP:0100526', (65, 76))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (150, 178))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('carcinoma', 'Disease', 'MESH:D002277', (129, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (191, 200))	('carcinoma', 'Disease', 'MESH:D002277', (106, 115))	('carcinoma', 'Disease', (191, 200))	('lung tumors', 'Disease', (65, 76))	('adenocarcinoma', 'Disease', (101, 115))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (155, 178))	('carcinoma', 'Disease', 'MESH:D002277', (169, 178))	('NRF2', 'Gene', '4780', (13, 17))	('esophageal carcinomas', 'Phenotype', 'HP:0011459', (118, 139))	('alterations', 'Var', (31, 42))	('esophageal carcinomas', 'Disease', 'MESH:D004938', (118, 139))	('adenocarcinoma', 'Disease', 'MESH:D000230', (101, 115))	('frequent', 'Reg', (53, 61))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('carcinoma', 'Disease', 'MESH:D002277', (191, 200))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('carcinoma', 'Disease', (129, 138))	('esophageal carcinomas', 'Disease', (118, 139))	('NRF2', 'Gene', (13, 17))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (141, 178))
534519	29625050	In these tumor types, alterations in NFE2L2 and KEAP1 were recurrent and almost perfectly mutually exclusive and they frequently co-occurred with PIK3CA activation or STK11 loss (Figure 6E).	('PIK3CA', 'Gene', '5290', (146, 152))	('STK11', 'Gene', (167, 172))	('co-occurred', 'Reg', (129, 140))	('NFE2L2', 'Gene', (37, 43))	('activation', 'PosReg', (153, 163))	('KEAP1', 'Gene', '9817', (48, 53))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('STK11', 'Gene', '6794', (167, 172))	('KEAP1', 'Gene', (48, 53))	('tumor', 'Disease', (9, 14))	('alterations', 'Var', (22, 33))	('loss', 'NegReg', (173, 177))	('PIK3CA', 'Gene', (146, 152))	('NFE2L2', 'Gene', '4780', (37, 43))
534524	29625050	In particular, alterations promoting EGFR activation (gain of function mutations, fusion, and amplification) were involved in the highest number of significant pairs.	('gain of function', 'PosReg', (54, 70))	('alterations', 'Var', (15, 26))	('EGFR', 'Gene', '1956', (37, 41))	('mutations', 'Var', (71, 80))	('activation', 'PosReg', (42, 52))	('EGFR', 'Gene', (37, 41))
534525	29625050	EGFR amplification was significantly mutually exclusive with activation of its paralog growth factor receptor Her2 (ERBB2, Figure 6H - Box 1) and with key drivers of the RAS pathway, including oncogenic mutations in BRAF and KRAS as well as loss of NF1 and RASA1 (Figure 6G).	('RASA1', 'Gene', (257, 262))	('amplification', 'Var', (5, 18))	('KRAS', 'Gene', '3845', (225, 229))	('Her2', 'Gene', (110, 114))	('RAS', 'Pathway', (170, 173))	('KRAS', 'Gene', (225, 229))	('EGFR', 'Gene', (0, 4))	('ERBB2', 'Gene', (116, 121))	('NF1', 'Gene', '4763', (249, 252))	('mutations', 'Var', (203, 212))	('RASA1', 'Gene', '5921', (257, 262))	('ERBB2', 'Gene', '2064', (116, 121))	('loss', 'Var', (241, 245))	('NF1', 'Gene', (249, 252))	('activation', 'PosReg', (61, 71))	('BRAF', 'Gene', '673', (216, 220))	('BRAF', 'Gene', (216, 220))	('EGFR', 'Gene', '1956', (0, 4))	('Her2', 'Gene', '2064', (110, 114))
534526	29625050	Since oncogenic EGFR can be synthetically lethal with mutated KRAS and can mediate resistance to BRAF inhibition in colon cancer and melanoma, these results suggest a similar antagonistic interaction with loss of NF1 or RASA1.	('KRAS', 'Gene', (62, 66))	('colon cancer', 'Disease', 'MESH:D015179', (116, 128))	('NF1', 'Gene', (213, 216))	('mutated', 'Var', (54, 61))	('EGFR', 'Gene', '1956', (16, 20))	('melanoma', 'Phenotype', 'HP:0002861', (133, 141))	('melanoma', 'Disease', (133, 141))	('colon cancer', 'Disease', (116, 128))	('BRAF', 'Gene', (97, 101))	('RASA1', 'Gene', '5921', (220, 225))	('mediate', 'Reg', (75, 82))	('EGFR', 'Gene', (16, 20))	('RASA1', 'Gene', (220, 225))	('KRAS', 'Gene', '3845', (62, 66))	('colon cancer', 'Phenotype', 'HP:0003003', (116, 128))	('NF1', 'Gene', '4763', (213, 216))	('melanoma', 'Disease', 'MESH:D008545', (133, 141))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('BRAF', 'Gene', '673', (97, 101))
534527	29625050	Overall, alterations of either of these genes were recurrent across multiple tumor types, although almost never in the same patient (Figure 6H - Box 2).	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('alterations', 'Var', (9, 20))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('patient', 'Species', '9606', (124, 131))	('tumor', 'Disease', (77, 82))
534528	29625050	On the other hand, in glioblastoma and IDH wild-type low grade glioma, EGFR amplifications were highly co-occurrent with either EGFR mutations or gene fusions (Figure 6H - Box 3) or with focal amplifications of chromosome 4q12, where both KIT and PDGFRA are located (Figure 6H - Box 4).	('PDGFRA', 'Gene', '5156', (247, 253))	('PDGFRA', 'Gene', (247, 253))	('glioblastoma', 'Disease', (22, 34))	('EGFR', 'Gene', '1956', (128, 132))	('EGFR', 'Gene', (128, 132))	('glioblastoma', 'Disease', 'MESH:D005909', (22, 34))	('gene fusions', 'Var', (146, 158))	('glioma', 'Disease', 'MESH:D005910', (63, 69))	('glioma', 'Phenotype', 'HP:0009733', (63, 69))	('amplifications', 'Var', (76, 90))	('EGFR', 'Gene', '1956', (71, 75))	('mutations', 'Var', (133, 142))	('glioblastoma', 'Phenotype', 'HP:0012174', (22, 34))	('IDH', 'Gene', (39, 42))	('co-occurrent', 'Reg', (103, 115))	('EGFR', 'Gene', (71, 75))	('IDH', 'Gene', '3417', (39, 42))	('glioma', 'Disease', (63, 69))
534529	29625050	It should be noted that the majority of EGFR and PDGFRA fusions were found coincident with amplifications in these genes, indicating that, potentially, in these cases the same structural variant was detected as both a copy number gain and a fusion.	('fusions', 'Var', (56, 63))	('copy number gain', 'Disease', (218, 234))	('PDGFRA', 'Gene', (49, 55))	('PDGFRA', 'Gene', '5156', (49, 55))	('copy number gain', 'Disease', 'MESH:D015430', (218, 234))	('EGFR', 'Gene', '1956', (40, 44))	('EGFR', 'Gene', (40, 44))
534530	29625050	Interestingly, co-amplification of EGFR and PDGFRA has been proposed to be an early event in glioblastoma development, where the two receptors heterodimerize under EGF stimulation and respond to EGFR-inhibitors.	('glioblastoma', 'Phenotype', 'HP:0012174', (93, 105))	('EGFR', 'Gene', (195, 199))	('co-amplification', 'Var', (15, 31))	('glioblastoma', 'Disease', 'MESH:D005909', (93, 105))	('EGFR', 'Gene', '1956', (35, 39))	('EGFR', 'Gene', (35, 39))	('glioblastoma', 'Disease', (93, 105))	('heterodimerize', 'MPA', (143, 157))	('respond', 'Reg', (184, 191))	('PDGFRA', 'Gene', '5156', (44, 50))	('EGFR', 'Gene', '1956', (195, 199))	('PDGFRA', 'Gene', (44, 50))
534532	29625050	A relatively small number of alterations in a subset of tumor types are currently biomarkers for standard care targeted therapies, and a larger number are potential biomarkers for investigational therapies, some with promising clinical results.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Disease', (56, 61))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('alterations', 'Var', (29, 40))
534534	29625050	Overall, 52% of tumors had at least one potentially actionable alteration in the ten signaling pathways, and 57% had at least one actionable alteration when including genes outside of these pathways, most notably BRCA1/2 and IDH1/2 (all numbers referenced below include these additional genes).	('BRCA1/2', 'Gene', '672;675', (213, 220))	('IDH1/2', 'Gene', (225, 231))	('tumors', 'Phenotype', 'HP:0002664', (16, 22))	('BRCA1/2', 'Gene', (213, 220))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('tumors', 'Disease', 'MESH:D009369', (16, 22))	('ten signaling pathways', 'Pathway', (81, 103))	('alteration', 'Var', (63, 73))	('tumors', 'Disease', (16, 22))	('IDH1/2', 'Gene', '3417;3418', (225, 231))
534535	29625050	Apart from the Her2-enriched breast cancer samples, most of which have a standard care targeted therapy, melanoma was the tumor type with the highest fraction of tumors with a Level 1 or 2A alteration (46%) (Figure 7A), mainly due to frequent BRAF mutations (Figure 7B), followed by esophagogastric cancers (ERBB2 amplifications).	('mutations', 'Var', (248, 257))	('tumor', 'Disease', (162, 167))	('Her2', 'Gene', '2064', (15, 19))	('tumors', 'Disease', 'MESH:D009369', (162, 168))	('tumor', 'Disease', (122, 127))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('breast cancer', 'Phenotype', 'HP:0003002', (29, 42))	('ERBB2', 'Gene', (308, 313))	('Her2', 'Gene', (15, 19))	('melanoma', 'Disease', 'MESH:D008545', (105, 113))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('breast cancer', 'Disease', 'MESH:D001943', (29, 42))	('esophagogastric cancers', 'Disease', (283, 306))	('breast cancer', 'Disease', (29, 42))	('esophagogastric cancers', 'Disease', 'MESH:C537006', (283, 306))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('ERBB2', 'Gene', '2064', (308, 313))	('BRAF', 'Gene', '673', (243, 247))	('BRAF', 'Gene', (243, 247))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumors', 'Phenotype', 'HP:0002664', (162, 168))	('cancers', 'Phenotype', 'HP:0002664', (299, 306))	('melanoma', 'Phenotype', 'HP:0002861', (105, 113))	('melanoma', 'Disease', (105, 113))	('cancer', 'Phenotype', 'HP:0002664', (299, 305))	('tumors', 'Disease', (162, 168))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))
534536	29625050	Luminal A breast cancer was the tumor type with the highest frequency of biomarkers with promising investigational data (Level 3A), driven by the high prevalence of PIK3CA, AKT1 and ERBB2 mutations.	('breast cancer', 'Disease', 'MESH:D001943', (10, 23))	('PIK3CA', 'Gene', (165, 171))	('breast cancer', 'Phenotype', 'HP:0003002', (10, 23))	('tumor', 'Disease', 'MESH:D009369', (32, 37))	('breast cancer', 'Disease', (10, 23))	('AKT1', 'Gene', (173, 177))	('ERBB2', 'Gene', '2064', (182, 187))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('ERBB2', 'Gene', (182, 187))	('AKT1', 'Gene', '207', (173, 177))	('PIK3CA', 'Gene', '5290', (165, 171))	('mutations', 'Var', (188, 197))	('tumor', 'Disease', (32, 37))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
534537	29625050	Several tumor types had frequent mutations that are biomarkers for drug sensitivity in other cancer types (Level 3B), including endometrial cancer, where PIK3CA mutations are common.	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('PIK3CA', 'Gene', (154, 160))	('drug sensitivity', 'Phenotype', 'HP:0020174', (67, 83))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('endometrial cancer', 'Disease', (128, 146))	('cancer', 'Disease', (140, 146))	('mutations', 'Var', (33, 42))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('PIK3CA', 'Gene', '5290', (154, 160))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('endometrial cancer', 'Phenotype', 'HP:0012114', (128, 146))	('tumor', 'Disease', (8, 13))	('endometrial cancer', 'Disease', 'MESH:D016889', (128, 146))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))
534545	29625050	By a similar consideration linking actionable alterations of targets to their inhibitors, a combination of HER2 and PI3K inhibitors might be beneficial across multiple tumor types, in particular Her2-enriched breast cancer (17%), uterine carcinosarcoma (UCS, 7%), chromosomally unstable endometrioid carcinoma (UCEC CN high, 7%), and cervical adenocarcinoma (7%) (Figure 7D).	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (230, 252))	('endometrioid carcinoma', 'Disease', 'MESH:D016889', (287, 309))	('HER2', 'Gene', (107, 111))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('cervical adenocarcinoma', 'Disease', 'MESH:D002575', (334, 357))	('Her2', 'Gene', '2064', (195, 199))	('carcinoma', 'Phenotype', 'HP:0030731', (300, 309))	('tumor', 'Disease', (168, 173))	('endometrioid carcinoma', 'Disease', (287, 309))	('carcinoma', 'Phenotype', 'HP:0030731', (348, 357))	('breast cancer', 'Phenotype', 'HP:0003002', (209, 222))	('Her2', 'Gene', (195, 199))	('cervical adenocarcinoma', 'Disease', (334, 357))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('carcinosarcoma', 'Disease', (238, 252))	('HER2', 'Gene', '2064', (107, 111))	('breast cancer', 'Disease', 'MESH:D001943', (209, 222))	('breast cancer', 'Disease', (209, 222))	('alterations', 'Var', (46, 57))	('carcinosarcoma', 'Disease', 'MESH:D002296', (238, 252))	('endometrioid carcinoma', 'Phenotype', 'HP:0012114', (287, 309))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
534547	29625050	While there are many steps from the observation of combinations of genetic alterations to valid combination therapies, this survey indicates the wide landscape of potential tumor-type specific novel therapeutic combinations that can be explored in experimental and clinical contexts.	('genetic alterations', 'Var', (67, 86))	('tumor-type', 'Disease', 'MESH:D009369', (173, 183))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumor-type', 'Disease', (173, 183))	('alterations', 'Var', (75, 86))
534553	29625050	They also underscore the potential for discovering previously uncharacterized alterations in pathway genes that occur at low frequencies and might otherwise remain statistically unnoticeable (see SOS1, Figure 4).	('SOS1', 'Gene', (196, 200))	('alterations', 'Var', (78, 89))	('SOS1', 'Gene', '6654', (196, 200))	('pathway genes', 'Gene', (93, 106))
534557	29625050	While the NRF2 pathway does not have therapies directly targeting any of the pathway members included in this study, alterations in NRF2 pathway members (NFE2L2 and KEAP1) are used as part of the inclusion criteria in the Phase 2 trial of a TORC1/2 inhibitor.	('alterations', 'Var', (117, 128))	('NFE2L2', 'Gene', '4780', (154, 160))	('NRF2', 'Gene', '4780', (132, 136))	('NRF2', 'Gene', (10, 14))	('KEAP1', 'Gene', (165, 170))	('NFE2L2', 'Gene', (154, 160))	('NRF2', 'Gene', (132, 136))	('TORC1/2', 'Gene', (241, 248))	('TORC1/2', 'Gene', '23373;200186', (241, 248))	('NRF2', 'Gene', '4780', (10, 14))	('KEAP1', 'Gene', '9817', (165, 170))
534558	29625050	Not all apparently functional mutations, however, represent therapeutic targets, as illustrated, e.g., by the unusually large number of mutations in the MSI-H and POLE-mutated tumor subtypes, of which only a small fraction plausibly dominate oncogenesis..	('MSI-H', 'Disease', (153, 158))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('tumor', 'Disease', (176, 181))	('MSI-H', 'Disease', 'MESH:D000848', (153, 158))	('mutations', 'Var', (136, 145))	('tumor', 'Disease', 'MESH:D009369', (176, 181))
534560	29625050	However, there is a growing corpus of promising preclinical data indicating such combinations can be effective, such as the combination of MDM2 and CDK4 inhibitors, and the combination of PI3K inhibitors and HER2 inhibitors in HER2-positive / PIK3CA mutant breast cancer patients, even when single gene-therapy approaches (e.g.	('PI3K', 'Var', (188, 192))	('MDM2', 'Gene', (139, 143))	('CDK4', 'Gene', '1019', (148, 152))	('HER2', 'Gene', '2064', (227, 231))	('PIK3CA', 'Gene', (243, 249))	('HER2', 'Gene', (208, 212))	('HER2', 'Gene', '2064', (208, 212))	('cancer', 'Phenotype', 'HP:0002664', (264, 270))	('breast cancer', 'Disease', 'MESH:D001943', (257, 270))	('PIK3CA', 'Gene', '5290', (243, 249))	('MDM2', 'Gene', '4193', (139, 143))	('breast cancer', 'Disease', (257, 270))	('patients', 'Species', '9606', (271, 279))	('breast cancer', 'Phenotype', 'HP:0003002', (257, 270))	('CDK4', 'Gene', (148, 152))	('HER2', 'Gene', (227, 231))
534575	29625050	The cancer hotspots algorithm that we used identifies recurrent alterations based on a cohort of 24,592 tumor samples.	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('tumor', 'Disease', (104, 109))	('alterations', 'Var', (64, 75))	('cancer', 'Disease', 'MESH:D009369', (4, 10))	('cancer', 'Disease', (4, 10))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
534577	29625050	For Genes within ROIs, copy number variants consistent with the role of the gene (amplification of OGs and deletions of TSGs) were retained.	('TSG', 'Gene', (120, 123))	('deletions', 'Var', (107, 116))	('TSG', 'Gene', '57045', (120, 123))	('ROIs', 'Gene', (17, 21))
534578	29625050	CDKN2A promoter methylation was assessed using Illumina Infinium HumanMethylation450 probe cg13601799 located within Exon 1a of CDKN2A (p16INK4a).	('CDKN2A', 'Gene', '1029', (128, 134))	('p16INK4a', 'Gene', (136, 144))	('cg13601799', 'Var', (91, 101))	('CDKN2A', 'Gene', (0, 6))	('p16INK4a', 'Gene', '1029', (136, 144))	('CDKN2A', 'Gene', (128, 134))	('CDKN2A', 'Gene', '1029', (0, 6))
534579	29625050	We described the selection of this probe for CDKN2A methylation calling in a prior report.	('CDKN2A', 'Gene', (45, 51))	('methylation', 'Var', (52, 63))	('CDKN2A', 'Gene', '1029', (45, 51))
534580	29625050	We required a Log2(foreground/background) log-ratio of 2 or greater for the U probe to ensure that the U signal was derived from tumor cells and not from contaminating normal cells in the case of a tumor with CDKN2A deletion.	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('CDKN2A', 'Gene', '1029', (209, 215))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('CDKN2A', 'Gene', (209, 215))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('deletion', 'Var', (216, 224))	('tumor', 'Disease', (198, 203))	('tumor', 'Disease', (129, 134))
534582	29625050	Out of these 627, 471 were called to have high level deletion for CDKN2A (-2 in GISTIC calls) and 120 had low level deletion for this gene (-1 in GISTIC calls), validating this approach.	('deletion', 'Var', (53, 61))	('CDKN2A', 'Gene', (66, 72))	('CDKN2A', 'Gene', '1029', (66, 72))
534583	29625050	Epigenetic DNA hypermethylation events at promoters of tumor suppressor genes that are associated with decreased gene expression were systematically identified using the RESET bioinformatic tool (Saghafinia, Mina, et al.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('Mina', 'Gene', (208, 212))	('Mina', 'Gene', '84864', (208, 212))	('gene expression', 'MPA', (113, 128))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Disease', (55, 60))	('Epigenetic', 'Var', (0, 10))
534595	29625050	For our pathway analyses, we included only the fusions that (a) involved at least one gene labeled as TSG in one of our pathway templates, or (b) involved at least one gene labeled as OG in one of our pathway templates and such that the fusion is labeled as oncogenic, likely oncogenic or predicted oncogenic in OncoKB.	('TSG', 'Gene', '57045', (102, 105))	('fusion', 'Var', (237, 243))	('TSG', 'Gene', (102, 105))
534597	29625050	We also included epigenetic silencing of CDKN2A based on DNA methylation analysis of the gene promoter and the epigenetic silencing of 15 additional genes uncovered by RESET.	('CDKN2A', 'Gene', '1029', (41, 47))	('epigenetic silencing', 'Var', (17, 37))	('CDKN2A', 'Gene', (41, 47))
534607	28900494	Results: Expression of LHX6 was found to be a favorable independent prognostic factor for overall survival (OS) of total lung adenocarcinoma patients (P=0.014) and patients with negative lymph nodes status (P=0.014) but not related the prognostic outcome of lung squamous cell carcinoma patients.	('lung adenocarcinoma', 'Disease', (121, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (258, 286))	('overall', 'MPA', (90, 97))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (121, 140))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (263, 286))	('patients', 'Species', '9606', (287, 295))	('carcinoma', 'Phenotype', 'HP:0030731', (277, 286))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (258, 286))	('Expression', 'Var', (9, 19))	('lung squamous cell carcinoma', 'Disease', (258, 286))	('Expression', 'Species', '29278', (9, 19))	('LHX6', 'Gene', (23, 27))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (121, 140))	('patients', 'Species', '9606', (164, 172))	('patients', 'Species', '9606', (141, 149))
534610	28900494	Furthermore, LHX6 suppressed the Wnt/beta-catenin pathway through transcriptionally silencing the expression of beta-catenin, and the promoter region (-1161 bp to +27 bp) was crucial for its inhibitory activity.	('Wnt/beta-catenin pathway', 'Pathway', (33, 57))	('silencing', 'NegReg', (84, 93))	('LHX6', 'Var', (13, 17))	('beta-catenin', 'Protein', (112, 124))	('suppressed', 'NegReg', (18, 28))	('expression', 'Species', '29278', (98, 108))	('expression', 'MPA', (98, 108))
534617	28900494	Recently, various genetic and epigenetic alterations have been shown to drive this process in lung cancer and even one gene may indicate adverse prognostic outcomes in lung adenocarcinoma and lung squamous cell carcinoma patients.	('lung adenocarcinoma and lung squamous cell carcinoma', 'Disease', 'MESH:D000077192', (168, 220))	('patients', 'Species', '9606', (221, 229))	('lung cancer', 'Disease', 'MESH:D008175', (94, 105))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (197, 220))	('carcinoma', 'Phenotype', 'HP:0030731', (211, 220))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (168, 187))	('lung cancer', 'Disease', (94, 105))	('drive', 'Reg', (72, 77))	('epigenetic alterations', 'Var', (30, 52))	('lung cancer', 'Phenotype', 'HP:0100526', (94, 105))	('carcinoma', 'Phenotype', 'HP:0030731', (178, 187))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (192, 220))
534620	28900494	Hypermethylation of LHX6 serves as a sensitive biomarker in early diagnosis of head and neck carcinomas and cervical cancer.	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('head and neck carcinomas and cervical cancer', 'Disease', 'MESH:D006258', (79, 123))	('Hypermethylation', 'Var', (0, 16))	('carcinomas', 'Phenotype', 'HP:0030731', (93, 103))	('head and neck carcinomas', 'Phenotype', 'HP:0012288', (79, 103))	('LHX6', 'Gene', (20, 24))
534621	28900494	We have previously reported that LHX6 is a novel tumor suppresser which is epigenetically silenced by DNA methylation in lung cancer, but whether it is related to the clinical progression has yet to be evaluated.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('lung cancer', 'Disease', 'MESH:D008175', (121, 132))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('LHX6', 'Gene', (33, 37))	('tumor', 'Disease', (49, 54))	('lung cancer', 'Disease', (121, 132))	('lung cancer', 'Phenotype', 'HP:0100526', (121, 132))	('DNA methylation', 'Var', (102, 117))
534651	28900494	After culturing for 24 h, the cells were transfected with LHX6-overexpression or Vector control and LHX6-miRNA or Control-miRNA, respectively.	('expression', 'Species', '29278', (67, 77))	('LHX6-miRNA', 'Var', (100, 110))	('LHX6-overexpression', 'Gene', (58, 77))
534661	28900494	The previously reported promoter region of full-length human beta-catenin (CTNNB1) promoter (Catenin-promoter-full: -2760/+27) and two overlapping regions, Catenin-promoter-1 (-2760/-1161) and Catenin-promoter-2 (-1952/+27), were amplified and cloned into a pGL3-basic vector (Promega, Madison, WI, USA).	('CTNNB1', 'Gene', (75, 81))	('pGL3', 'Gene', (258, 262))	('pGL3', 'Gene', '6391', (258, 262))	('human', 'Species', '9606', (55, 60))	('-2760/-1161', 'Var', (176, 187))	('-1952/+27', 'Var', (213, 222))
534682	28900494	A subgroup analysis based on histological types revealed that LHX6 was associated with overall survival (OS) of lung adenocarcinoma patients (n=720, HR=0.66, 95% CI =0.53-0.84, P<0.001) (Fig.	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (112, 131))	('overall survival', 'MPA', (87, 103))	('lung adenocarcinoma', 'Disease', (112, 131))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (112, 131))	('LHX6', 'Var', (62, 66))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('patients', 'Species', '9606', (132, 140))	('associated', 'Reg', (71, 81))
534687	28900494	Survival analysis using the Kaplan-Meier method and log rank test showed that high expression of LHX6 presented a longer survival time than that of low LHX6 expression in total lung adenocarcinoma patients and patients with negative lymph nodes (Fig.	('expression', 'Species', '29278', (157, 167))	('patients', 'Species', '9606', (197, 205))	('LHX6', 'Gene', (97, 101))	('high expression', 'Var', (78, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (187, 196))	('lung adenocarcinoma', 'Disease', (177, 196))	('expression', 'Species', '29278', (83, 93))	('survival time', 'CPA', (121, 134))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (177, 196))	('patients', 'Species', '9606', (210, 218))	('longer', 'PosReg', (114, 120))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (177, 196))
534696	28900494	Using a 4-days growth curve analysis, ectopic expression of LHX6 was found to significantly inhibit the proliferation of LTEP-a-2 and SPC-a-1 cells (Fig.	('proliferation', 'CPA', (104, 117))	('LHX6', 'Gene', (60, 64))	('inhibit', 'NegReg', (92, 99))	('ectopic expression', 'Var', (38, 56))	('expression', 'Species', '29278', (46, 56))	('SPC-a-1', 'CellLine', 'CVCL:6955', (134, 141))
534702	28900494	LHX6 expression was significantly reduced in the cells transfected with LHX6-miRNA as shown by WB (Fig.	('expression', 'MPA', (5, 15))	('reduced', 'NegReg', (34, 41))	('LHX6-miRNA', 'Var', (72, 82))	('LHX6', 'Gene', (0, 4))	('expression', 'Species', '29278', (5, 15))
534704	28900494	To determine the anti-tumorigenic and anti-metastasis role of LHX6 in vivo, LTEP-a-2-LHX6 stably and vector control cells were subcutaneously injected into nude mice.	('nude mice', 'Species', '10090', (156, 165))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('LTEP-a-2-LHX6', 'Var', (76, 89))	('tumor', 'Disease', (22, 27))
534706	28900494	The mean tumor weight was lower in nude mice injected with LHX6-overexpressing cells than in vector control mice (n=4, P=0.033) (Fig.	('nude mice', 'Species', '10090', (35, 44))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('mice', 'Species', '10090', (108, 112))	('tumor', 'Disease', (9, 14))	('mice', 'Species', '10090', (40, 44))	('LHX6-overexpressing cells', 'Var', (59, 84))	('lower', 'NegReg', (26, 31))
534711	28900494	A TOP/FOP flash reporter assay showed that LHX6 significantly inhibited the transcriptional activity of beta-catenin/T-cell factor (TCF) compared with the vector control transfectants in LTEP-a-2 and SPC-a-1 cell lines (Fig.	('LHX6', 'Var', (43, 47))	('TCF', 'Gene', '3172', (132, 135))	('SPC-a-1', 'CellLine', 'CVCL:6955', (200, 207))	('TCF', 'Gene', (132, 135))	('transcriptional activity', 'MPA', (76, 100))	('inhibited', 'NegReg', (62, 71))	('beta-catenin/T-cell factor', 'Gene', (104, 130))	('beta-catenin/T-cell factor', 'Gene', '3172', (104, 130))
534712	28900494	We subsequently analyzed the expression of the downstream genes of the Wnt/beta-catenin pathway and found that LHX6 decreased the mRNA and protein level of Cyclin D1, c-Myc and MMP7 (Fig.	('Cyclin D1', 'MPA', (156, 165))	('MMP7', 'MPA', (177, 181))	('c-Myc', 'MPA', (167, 172))	('expression', 'Species', '29278', (29, 39))	('LHX6', 'Var', (111, 115))	('decreased', 'NegReg', (116, 125))
534722	28900494	As a transcription factor, we first considered whether LHX6 could transcriptional silence the expression of beta-catenin.	('expression', 'Species', '29278', (94, 104))	('LHX6', 'Var', (55, 59))	('beta-catenin', 'Protein', (108, 120))	('expression', 'MPA', (94, 104))
534728	28900494	In addition, our data indicated that LHX6 inhibited the proliferation and metastasis of lung adenocarcinoma cells in vitro and in vivo.	('LHX6', 'Var', (37, 41))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (88, 107))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('proliferation', 'CPA', (56, 69))	('metastasis of lung adenocarcinoma', 'Disease', (74, 107))	('inhibited', 'NegReg', (42, 51))	('metastasis of lung adenocarcinoma', 'Disease', 'MESH:D009362', (74, 107))
534733	28900494	Furthermore, our clinical study suggested that LHX6 was an independent prognostic factor for lung adenocarcinoma patients and for patients with negative lymph node status.	('lung adenocarcinoma', 'Disease', (93, 112))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (93, 112))	('patients', 'Species', '9606', (113, 121))	('LHX6', 'Var', (47, 51))	('patients', 'Species', '9606', (130, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (93, 112))
534744	28900494	S5), and low expression of beta-catenin was found to predict a favorable OS in lung adenocarcinoma but an unfavorable OS in lung squamous carcinoma patients (Fig.	('patients', 'Species', '9606', (148, 156))	('low', 'Var', (9, 12))	('expression', 'Species', '29278', (13, 23))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('lung squamous carcinoma', 'Disease', (124, 147))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (79, 98))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (129, 147))	('beta-catenin', 'Protein', (27, 39))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (79, 98))	('lung squamous carcinoma', 'Disease', 'MESH:D002294', (124, 147))	('lung squamous carcinoma', 'Phenotype', 'HP:0030359', (124, 147))	('lung adenocarcinoma', 'Disease', (79, 98))
534751	28900494	Furthermore, we showed that LHX6 inhibits the Wnt/beta-catenin pathway by transcriptional silencing the expression of beta-catenin.	('Wnt/beta-catenin pathway', 'Pathway', (46, 70))	('silencing', 'NegReg', (90, 99))	('beta-catenin', 'Protein', (118, 130))	('expression', 'Species', '29278', (104, 114))	('expression', 'MPA', (104, 114))	('inhibits', 'NegReg', (33, 41))	('LHX6', 'Var', (28, 32))
534771	28118849	While most cancer-related bacteria are the dominant member of the microbiome, it is possible that rare members could cause driver mutations and/or that dominant members might be more abundant in tumors due to a favorable tumor microenvironment.	('tumors', 'Disease', (195, 201))	('tumors', 'Disease', 'MESH:D009369', (195, 201))	('tumor', 'Disease', (195, 200))	('tumors', 'Phenotype', 'HP:0002664', (195, 201))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('tumor', 'Phenotype', 'HP:0002664', (221, 226))	('tumor', 'Disease', (221, 226))	('mutations', 'Var', (130, 139))	('cause', 'Reg', (117, 122))	('cancer', 'Disease', 'MESH:D009369', (11, 17))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('cancer', 'Disease', (11, 17))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('tumor', 'Disease', 'MESH:D009369', (221, 226))
534800	28118849	Nine cancer types were examined (Table 1) and found to have differing abundances of putative bacterial read pairs ranging from 11% of patients with at least one sample containing bacterial read pairs in lung squamous cell carcinoma (LUSC) to 100% of patients having at least one sample with bacterial read pairs in STAD (Table 2).	('LUSC', 'Phenotype', 'HP:0030359', (233, 237))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (203, 231))	('cancer', 'Disease', 'MESH:D009369', (5, 11))	('bacterial read pairs', 'Var', (179, 199))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (203, 231))	('cancer', 'Disease', (5, 11))	('patients', 'Species', '9606', (250, 258))	('patients', 'Species', '9606', (134, 142))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (208, 231))	('carcinoma', 'Phenotype', 'HP:0030731', (222, 231))	('lung squamous cell carcinoma', 'Disease', (203, 231))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))
534804	28118849	All of the cancer types investigated had one or more samples containing read pairs present that were assigned to bacterial taxa (Table 2).	('read pairs', 'Var', (72, 82))	('cancer', 'Disease', (11, 17))	('cancer', 'Disease', 'MESH:D009369', (11, 17))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))
534872	28118849	For example, plates A056 and A084 appear distinct from plates A00Z, A034, A109, A10J, A115, and A12D (Additional file 5: Figure S4).	('A084', 'Var', (29, 33))	('A10J', 'Var', (80, 84))	('A109', 'Var', (74, 78))	('A10J', 'SUBSTITUTION', 'None', (80, 84))	('A12D', 'Mutation', 'p.A12D', (96, 100))	('A115', 'Var', (86, 90))	('A12D', 'Var', (96, 100))	('A034', 'Var', (68, 72))
534939	25234657	We used a high-sensitivity mass spectrometry-based mutation profiling platform to determine the EGFR mutation status, as well as other actionable alterations in a series of Asian TSCC.	('EGFR', 'Gene', (96, 100))	('SCC', 'Gene', (180, 183))	('SCC', 'Gene', '6317', (180, 183))	('mutation', 'Var', (101, 109))	('TSCC', 'Phenotype', 'HP:0030413', (179, 183))	('EGFR', 'Gene', '1956', (96, 100))
534941	25234657	Mutations were identified in 20/66(30.3%) of samples and involved TP53, STK11, MET, PIK3CA, BRAF and NRF2.	('NRF2', 'Gene', '4780', (101, 105))	('PIK3CA', 'Gene', '5290', (84, 90))	('BRAF', 'Gene', '673', (92, 96))	('TP53', 'Gene', '7157', (66, 70))	('TP53', 'Gene', (66, 70))	('BRAF', 'Gene', (92, 96))	('NRF2', 'Gene', (101, 105))	('MET', 'Gene', (79, 82))	('STK11', 'Gene', (72, 77))	('Mutations', 'Var', (0, 9))	('PIK3CA', 'Gene', (84, 90))	('STK11', 'Gene', '6794', (72, 77))
534942	25234657	No activating EGFR mutations or KRAS mutations were discovered in our series, where just over a third were never smokers.	('EGFR', 'Gene', '1956', (14, 18))	('EGFR', 'Gene', (14, 18))	('KRAS', 'Gene', (32, 36))	('activating', 'PosReg', (3, 13))	('mutations', 'Var', (19, 28))	('KRAS', 'Gene', '3845', (32, 36))
534944	25234657	BRAF and NRF2 mutations, which are novel in TSCC, were demonstrated in one sample each.	('SCC', 'Gene', (45, 48))	('NRF2', 'Gene', '4780', (9, 13))	('SCC', 'Gene', '6317', (45, 48))	('NRF2', 'Gene', (9, 13))	('BRAF', 'Gene', '673', (0, 4))	('TSCC', 'Phenotype', 'HP:0030413', (44, 48))	('BRAF', 'Gene', (0, 4))	('mutations', 'Var', (14, 23))
534945	25234657	Four of these tumors were propagated as immortalized cell lines and demonstrated the same mutations as the original tumor.	('mutations', 'Var', (90, 99))	('tumors', 'Disease', (14, 20))	('tumors', 'Phenotype', 'HP:0002664', (14, 20))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumors', 'Disease', 'MESH:D009369', (14, 20))	('original tumor', 'Disease', (107, 121))	('original tumor', 'Disease', 'MESH:D009369', (107, 121))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
534946	25234657	Using the Sequenom multiplexed LungCarta panel, we identified mutations in 6 genes, TP53, STK11, MET, PIK3CA, BRAF and NRF2, with the notable absence of EGFR and HER2 mutations in our series of Asian OSCC.	('PIK3CA', 'Gene', (102, 108))	('OS', 'Chemical', '-', (200, 202))	('mutations', 'Var', (167, 176))	('BRAF', 'Gene', '673', (110, 114))	('SCC', 'Gene', '6317', (201, 204))	('absence', 'NegReg', (142, 149))	('TP53', 'Gene', (84, 88))	('MET', 'Gene', (97, 100))	('BRAF', 'Gene', (110, 114))	('HER2', 'Gene', (162, 166))	('SCC', 'Gene', (201, 204))	('NRF2', 'Gene', '4780', (119, 123))	('STK11', 'Gene', (90, 95))	('EGFR', 'Gene', (153, 157))	('mutations', 'Var', (62, 71))	('TP53', 'Gene', '7157', (84, 88))	('PIK3CA', 'Gene', '5290', (102, 108))	('NRF2', 'Gene', (119, 123))	('STK11', 'Gene', '6794', (90, 95))	('HER2', 'Gene', '2064', (162, 166))	('EGFR', 'Gene', '1956', (153, 157))
534954	25234657	Specific activating EGFR mutations act as a predictive marker for tyrosine kinase inhibitors such as gefitinib and erlotinib in NSCLC, and have conferred significant improvement in overall survival.	('erlotinib', 'Chemical', 'MESH:D000069347', (115, 124))	('overall', 'MPA', (181, 188))	('mutations', 'Var', (25, 34))	('tyrosine kinase', 'Gene', '7294', (66, 81))	('EGFR', 'Gene', (20, 24))	('improvement', 'PosReg', (166, 177))	('NSCLC', 'Disease', (128, 133))	('gefitinib', 'Chemical', 'MESH:D000077156', (101, 110))	('activating', 'PosReg', (9, 19))	('NSCLC', 'Disease', 'MESH:D002289', (128, 133))	('tyrosine kinase', 'Gene', (66, 81))	('EGFR', 'Gene', '1956', (20, 24))
534956	25234657	Few studies have looked for EGFR mutations and other "actionable mutations" in OSCC, and most to date have been conducted in small heterogeneous HNSCC patient cohorts.	('SCC', 'Gene', '6317', (80, 83))	('SCC', 'Gene', (147, 150))	('EGFR', 'Gene', '1956', (28, 32))	('OS', 'Chemical', '-', (79, 81))	('EGFR', 'Gene', (28, 32))	('patient', 'Species', '9606', (151, 158))	('mutations', 'Var', (33, 42))	('SCC', 'Gene', '6317', (147, 150))	('SCC', 'Gene', (80, 83))
534957	25234657	Studies focused on oral or tongue squamous cell carcinoma show possible population differences in prevalence for EGFR mutation rates, suggesting ethnic differences may exist.	('tongue squamous cell carcinoma', 'Disease', (27, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (48, 57))	('EGFR', 'Gene', '1956', (113, 117))	('mutation', 'Var', (118, 126))	('EGFR', 'Gene', (113, 117))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (34, 57))	('tongue squamous cell carcinoma', 'Phenotype', 'HP:0030413', (27, 57))	('tongue squamous cell carcinoma', 'Disease', 'MESH:D002294', (27, 57))
534958	25234657	Similarly, large scale sequencing efforts in HNSCC by several collaborative groups have focused mainly in Caucasian populations, revealing common mutations in genes such as p53, p16, Notch, FAT1, H-Ras and Caspase8.	('mutations', 'Var', (146, 155))	('FAT1', 'Gene', '2195', (190, 194))	('p53', 'Gene', (173, 176))	('SCC', 'Gene', '6317', (47, 50))	('p16', 'Gene', (178, 181))	('FAT1', 'Gene', (190, 194))	('Caspase8', 'Gene', '841', (206, 214))	('p53', 'Gene', '7157', (173, 176))	('Notch', 'Gene', '4851', (183, 188))	('Caspase8', 'Gene', (206, 214))	('Notch', 'Gene', (183, 188))	('H-Ras', 'Gene', '3265', (196, 201))	('H-Ras', 'Gene', (196, 201))	('SCC', 'Gene', (47, 50))	('p16', 'Gene', '1029', (178, 181))
534961	25234657	Due to the potential similarities among aerodigestive tract cancers, we adopted the Sequenom LungCarta panel to comprehensively evaluate a set of 66 Asian tongue cancers for EGFR mutation status, as well as other commonly implicated "actionable" or "druggable" oncogenes and tumour suppressor genes and correlated these with clinic-pathologic and outcome data.	('EGFR', 'Gene', (174, 178))	('cancers', 'Disease', 'MESH:D009369', (162, 169))	('cancers', 'Phenotype', 'HP:0002664', (60, 67))	('cancers', 'Disease', (162, 169))	('cancers', 'Disease', (60, 67))	('tongue cancers', 'Disease', 'MESH:D014062', (155, 169))	('cancers', 'Disease', 'MESH:D009369', (60, 67))	('mutation', 'Var', (179, 187))	('tumour', 'Phenotype', 'HP:0002664', (275, 281))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('tongue cancers', 'Disease', (155, 169))	('tumour', 'Disease', 'MESH:D009369', (275, 281))	('tumour', 'Disease', (275, 281))	('cancers', 'Phenotype', 'HP:0002664', (162, 169))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('EGFR', 'Gene', '1956', (174, 178))
534983	25234657	There were thirteen unique alterations identified, with 16 tumors having a single variations and four tumors having two separate variations (Table 3).	('variations', 'Var', (82, 92))	('tumors', 'Disease', 'MESH:D009369', (102, 108))	('tumors', 'Disease', (102, 108))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('tumors', 'Disease', (59, 65))	('tumors', 'Disease', 'MESH:D009369', (59, 65))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
534985	25234657	Three PIK3CA mutations were "activating" (one with E542K and two with H1047N mutations).	('H1047N', 'Var', (70, 76))	('H1047N', 'Mutation', 'p.H1047N', (70, 76))	('PIK3CA', 'Gene', (6, 12))	('E542K', 'Mutation', 'rs121913273', (51, 56))	('PIK3CA', 'Gene', '5290', (6, 12))	('E542K', 'Var', (51, 56))
534987	25234657	In samples identified to have mutations, four (out of six attempted) have been successfully propagated in culture as cell lines: NPC7, TM24, TM44 and TM47 and profiling the cell lines confirmed that these harbored the same genetic alterations as the primary tumor they were derived from (Table 3).	('tumor', 'Disease', (258, 263))	('tumor', 'Disease', 'MESH:D009369', (258, 263))	('mutations', 'Var', (30, 39))	('tumor', 'Phenotype', 'HP:0002664', (258, 263))
534988	25234657	There was no significant association between smoking history and the presence of any mutation detected by the LungCarta panel (p = 0.967), or specific alterations in MET (p = 0.806), p53 (p = 0.520) and STK11 (p = 0.105) (Table 3).	('STK11', 'Gene', (203, 208))	('p53', 'Gene', (183, 186))	('p53', 'Gene', '7157', (183, 186))	('STK11', 'Gene', '6794', (203, 208))	('MET', 'Gene', (166, 169))	('alterations', 'Var', (151, 162))
534990	25234657	With regards to outcome analyses, there were no significant correlations between the presence of any mutation and overall survival (OS) or loco-regional recurrence-free survival (LRFS).	('presence', 'Var', (85, 93))	('overall survival', 'CPA', (114, 130))	('OS', 'Chemical', '-', (132, 134))	('loco-regional recurrence-free survival', 'CPA', (139, 177))
534993	25234657	Interestingly, however, the presence of the MET N375S variant was associated with poorer loco-regional recurrence rates compared to patients who did not harbor this mutation: median LRFS of 11 versus 90 months respectively (p = 0.008) (Figure 2a).	('poorer', 'NegReg', (82, 88))	('loco-regional recurrence rates', 'CPA', (89, 119))	('N375S', 'SUBSTITUTION', 'None', (48, 53))	('patients', 'Species', '9606', (132, 140))	('N375S', 'Var', (48, 53))
534996	25234657	In this study, we used a panel designed for lung cancer to identify mutations in oral tongue cancer.	('lung cancer', 'Phenotype', 'HP:0100526', (44, 55))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('lung cancer', 'Disease', 'MESH:D008175', (44, 55))	('oral tongue cancer', 'Disease', 'MESH:D014062', (81, 99))	('mutations', 'Var', (68, 77))	('oral tongue cancer', 'Disease', (81, 99))	('lung cancer', 'Disease', (44, 55))
534999	25234657	In contrast, other Asian cohorts, such as a large series from Korea, identified up to 14% of EGFR mutations in oral tongue SCC (n = 70), suggesting that population differences likely exist.	('EGFR', 'Gene', '1956', (93, 97))	('SCC', 'Gene', '6317', (123, 126))	('EGFR', 'Gene', (93, 97))	('mutations', 'Var', (98, 107))	('SCC', 'Gene', (123, 126))
535001	25234657	p53 mutations were the most common abnormality identified in 10.6% (7/66) of our patient cohort.	('p53', 'Gene', (0, 3))	('p53', 'Gene', '7157', (0, 3))	('mutations', 'Var', (4, 13))	('patient', 'Species', '9606', (81, 88))
535002	25234657	A recent study in Asian head and neck squamous cell carcinoma found that p53 mutations occurred in approximately 30% of HNSCC, in contrast to 60-80% in patients with risk factors such as smoking.	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (33, 61))	('occurred', 'Reg', (87, 95))	('SCC', 'Gene', (122, 125))	('carcinoma', 'Phenotype', 'HP:0030731', (52, 61))	('p53', 'Gene', (73, 76))	('p53', 'Gene', '7157', (73, 76))	('SCC', 'Gene', '6317', (122, 125))	('mutations', 'Var', (77, 86))	('neck squamous cell carcinoma', 'Disease', (33, 61))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (38, 61))	('patients', 'Species', '9606', (152, 160))
535003	25234657	We did not find any significant relationship between p53 mutations and outcome, although this is limited by the small sample size.	('mutations', 'Var', (57, 66))	('p53', 'Gene', (53, 56))	('p53', 'Gene', '7157', (53, 56))
535006	25234657	Consistent with its role in cancer development, we found that patients with the variant had a poorer outcome than their wild type counterparts, with median loco-regional recurrence-free survival of 11 months compared to 90 months in patients without wild type MET (p = 0.008).	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('variant', 'Var', (80, 87))	('loco-regional recurrence-free survival', 'CPA', (156, 194))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('patients', 'Species', '9606', (233, 241))	('cancer', 'Disease', (28, 34))	('patients', 'Species', '9606', (62, 70))
535011	25234657	First, the BRAF mutation (D594G) seen here in one patient has not been previously reported in TSCC, and indeed other BRAF mutations are also exceedingly rare in HNSCC (<2%).	('SCC', 'Gene', '6317', (95, 98))	('D594G', 'Var', (26, 31))	('TSCC', 'Phenotype', 'HP:0030413', (94, 98))	('SCC', 'Gene', (163, 166))	('BRAF', 'Gene', (117, 121))	('D594G', 'Mutation', 'rs121913338', (26, 31))	('SCC', 'Gene', '6317', (163, 166))	('BRAF', 'Gene', '673', (117, 121))	('SCC', 'Gene', (95, 98))	('patient', 'Species', '9606', (50, 57))	('BRAF', 'Gene', (11, 15))	('BRAF', 'Gene', '673', (11, 15))
535013	25234657	NRF2 mutation was also identified in this cohort consistent with the The Cancer Genome Atlas (TCGA) database where mutations in NFEL2 (which is the gene for NRF2) occur in 6% of HNSCC.	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (73, 92))	('NRF2', 'Gene', (0, 4))	('mutations', 'Var', (115, 124))	('SCC', 'Gene', '6317', (180, 183))	('SCC', 'Gene', (180, 183))	('occur', 'Reg', (163, 168))	('NRF2', 'Gene', '4780', (157, 161))	('NRF2', 'Gene', '4780', (0, 4))	('NFEL2', 'Gene', (128, 133))	('Cancer Genome Atlas', 'Disease', (73, 92))	('Cancer', 'Phenotype', 'HP:0002664', (73, 79))	('NRF2', 'Gene', (157, 161))
535017	25234657	It is however imperative to ensure high-tumor percentage in tissues examine to ensure that a lack of mutations reflects a true negative result rather than false negatives due to a high proportion of normal cells.	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('mutations', 'Var', (101, 110))
535023	25234657	In conclusion, we confirm that common activating EGFR mutations and KRAS mutations are not present in a large cohort of Asian tongue cancers.	('EGFR', 'Gene', '1956', (49, 53))	('tongue cancers', 'Disease', (126, 140))	('activating', 'PosReg', (38, 48))	('EGFR', 'Gene', (49, 53))	('mutations', 'Var', (54, 63))	('cancers', 'Phenotype', 'HP:0002664', (133, 140))	('KRAS', 'Gene', (68, 72))	('KRAS', 'Gene', '3845', (68, 72))	('tongue cancers', 'Disease', 'MESH:D014062', (126, 140))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
535028	33143142	Regulation of Canonical Oncogenic Signaling Pathways in Cancer via DNA Methylation Aberrant epigenetic modifications in oncogenic pathways can lead to the onset of different cancers.	('epigenetic modifications', 'Var', (92, 116))	('oncogenic pathways', 'Pathway', (120, 138))	('cancers', 'Phenotype', 'HP:0002664', (174, 181))	('lead to', 'Reg', (143, 150))	('Cancer', 'Phenotype', 'HP:0002664', (56, 62))	('cancers', 'Disease', (174, 181))	('Cancer', 'Disease', (56, 62))	('cancers', 'Disease', 'MESH:D009369', (174, 181))	('Cancer', 'Disease', 'MESH:D009369', (56, 62))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))
535033	33143142	Disruption of signaling pathways that plays a role in the normal development and cellular homeostasis may lead to the dysregulation of cellular signaling and bring about the onset of different diseases, including cancer.	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('cellular signaling', 'MPA', (135, 153))	('dysregulation', 'MPA', (118, 131))	('cancer', 'Disease', 'MESH:D009369', (213, 219))	('lead to', 'Reg', (106, 113))	('signaling pathways', 'Pathway', (14, 32))	('cancer', 'Disease', (213, 219))	('bring about', 'Reg', (158, 169))	('Disruption', 'Var', (0, 10))
535038	33143142	Combined with the Data Integration Analysis for Biomarker discovery (DIABLO) framework for machine learning and multi-omic analysis, we revisited the TCGA DNA methylation and RNA-Seq datasets for breast, colorectal, lung, and prostate cancer, and identified differentially methylated genes within the NRF2-KEAP1/PI3K oncogenic pathway, which regulates the expression of cytoprotective genes, that serve as potential therapeutic targets to treat different cancers.	('cancers', 'Phenotype', 'HP:0002664', (455, 462))	('DIABLO', 'Gene', (69, 75))	('meth', 'Disease', (159, 163))	('cancers', 'Disease', (455, 462))	('prostate cancer', 'Phenotype', 'HP:0012125', (226, 241))	('prostate cancer', 'Disease', (226, 241))	('cancer', 'Phenotype', 'HP:0002664', (455, 461))	('breast', 'Disease', (196, 202))	('colorectal', 'Disease', (204, 214))	('meth', 'Disease', 'None', (273, 277))	('cancers', 'Disease', 'MESH:D009369', (455, 462))	('NRF2', 'Gene', '4780', (301, 305))	('DIABLO', 'Gene', '56616', (69, 75))	('meth', 'Disease', (273, 277))	('differentially', 'Var', (258, 272))	('KEAP1', 'Gene', '9817', (306, 311))	('NRF2', 'Gene', (301, 305))	('meth', 'Disease', 'None', (159, 163))	('KEAP1', 'Gene', (306, 311))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))	('prostate cancer', 'Disease', 'MESH:D011471', (226, 241))
535047	33143142	However, some cancers may have relatively few genetic mutations, with their biology largely driven by other types of variations such as aberrant epigenetic modifications.	('cancers', 'Disease', (14, 21))	('aberrant epigenetic modifications', 'Var', (136, 169))	('cancers', 'Disease', 'MESH:D009369', (14, 21))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('cancers', 'Phenotype', 'HP:0002664', (14, 21))
535049	33143142	Aberrant DNA methylation has been associated with various diseases, including cancers.	('associated', 'Reg', (34, 44))	('Aberrant', 'Var', (0, 8))	('meth', 'Disease', 'None', (13, 17))	('cancers', 'Disease', 'MESH:D009369', (78, 85))	('DNA', 'Protein', (9, 12))	('cancers', 'Phenotype', 'HP:0002664', (78, 85))	('meth', 'Disease', (13, 17))	('cancers', 'Disease', (78, 85))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))
535051	33143142	Despite the varied and complex nature of modifications in the epigenetic landscape, many cancers display a high degree of similarity both across different tissues and within the tissues of origin.	('cancers', 'Phenotype', 'HP:0002664', (89, 96))	('cancers', 'Disease', 'MESH:D009369', (89, 96))	('cancers', 'Disease', (89, 96))	('modifications', 'Var', (41, 54))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
535052	33143142	Therefore, abnormal DNA methylation has been viewed as an attractive avenue for development of cancer diagnostics and therapeutics.	('DNA', 'Protein', (20, 23))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('abnormal', 'Var', (11, 19))	('cancer', 'Disease', (95, 101))	('meth', 'Disease', 'None', (24, 28))	('meth', 'Disease', (24, 28))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))
535053	33143142	Although thousands of studies have highlighted the value of using changes in DNA methylation as candidate biomarkers in the detection and treatment of various cancers, only a handful of these targets have been approved for clinical use (as summarized in Table 1).	('cancers', 'Disease', (159, 166))	('meth', 'Disease', 'None', (81, 85))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('changes', 'Var', (66, 73))	('meth', 'Disease', (81, 85))	('cancers', 'Phenotype', 'HP:0002664', (159, 166))	('DNA', 'Gene', (77, 80))	('cancers', 'Disease', 'MESH:D009369', (159, 166))
535055	33143142	However, few studies have investigated the effects of epigenetic changes (especially DNA methylation) on individual and complex signaling pathways across cancers at different anatomical sites.	('epigenetic changes', 'Var', (54, 72))	('cancers', 'Phenotype', 'HP:0002664', (154, 161))	('meth', 'Disease', 'None', (89, 93))	('cancers', 'Disease', 'MESH:D009369', (154, 161))	('cancers', 'Disease', (154, 161))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('meth', 'Disease', (89, 93))
535056	33143142	This ultimately has an effect on the downstream gene expression activation of different signaling pathways and can lead to various physiological or cellular responses (e.g., cell proliferation, differentiation, and metabolism), and any disruptions within these intra and/or extracellular communication chains can lead to the development of different diseases, including cancer.	('cell proliferation', 'CPA', (174, 192))	('disruptions', 'Var', (236, 247))	('physiological', 'CPA', (131, 144))	('cancer', 'Disease', 'MESH:D009369', (370, 376))	('cancer', 'Phenotype', 'HP:0002664', (370, 376))	('cancer', 'Disease', (370, 376))	('differentiation', 'CPA', (194, 209))	('activation', 'PosReg', (64, 74))	('effect', 'Reg', (23, 29))	('lead to', 'Reg', (313, 320))	('signaling pathways', 'Pathway', (88, 106))	('lead to', 'Reg', (115, 122))
535067	33143142	Using this methodology, we identified a number of CpG sites which are differentially methylated and discuss the potential of using these biomarkers as screening tools for disruptions in the NRF2-PI3K oncogenic signaling pathway, which acts as the major regulator of cytoprotective responses to both endogenous and exogenous stresses from reactive oxygen species (ROS), and serve as potential epigenetic biomodifiers in the diagnosis and treatment of the screened cancers.	('meth', 'Disease', (11, 15))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (338, 361))	('cancer', 'Phenotype', 'HP:0002664', (463, 469))	('NRF2', 'Gene', '4780', (190, 194))	('meth', 'Disease', 'None', (85, 89))	('cancers', 'Phenotype', 'HP:0002664', (463, 470))	('meth', 'Disease', (85, 89))	('disruptions', 'Var', (171, 182))	('NRF2', 'Gene', (190, 194))	('meth', 'Disease', 'None', (11, 15))	('cancers', 'Disease', (463, 470))	('cancers', 'Disease', 'MESH:D009369', (463, 470))	('ROS', 'Chemical', 'MESH:D017382', (363, 366))
535127	33143142	Given only two tissue-specific hypermethylation were detected in the using the MethylMine, pipeline (cg16171838 (ACVR1C), cg18061904 (ACVR1C)), they were excluded from the clustering analysis (Table S5).	('cg18061904', 'Var', (122, 132))	('cg16171838', 'Chemical', '-', (101, 111))	('ACVR1C', 'Gene', (134, 140))	('meth', 'Disease', (36, 40))	('cg16171838', 'Var', (101, 111))	('ACVR1C', 'Gene', (113, 119))	('ACVR1C', 'Gene', '130399', (134, 140))	('ACVR1C', 'Gene', '130399', (113, 119))	('MethylMine', 'Chemical', '-', (79, 89))	('meth', 'Disease', 'None', (36, 40))
535131	33143142	To determine the association of the differentially methylated genes and its effects on the regulation of associated signaling pathways, a multi-omic data integration approach was used (Section 3.4).	('differentially', 'Var', (36, 50))	('meth', 'Disease', 'None', (51, 55))	('meth', 'Disease', (51, 55))
535143	33143142	Although the plot suggested best performance can be achieved when ncomp = 3 (in both the overall and balanced error rate), only data from the first two components underwent further analysis given this appeared to provide a lower error rate (data not shown).	('lower error rate', 'Disease', 'MESH:D001919', (223, 239))	('ncomp = 3', 'Var', (66, 75))	('lower error rate', 'Disease', (223, 239))
535150	33143142	Although predominantly associated with neurological disorders (e.g., autism), dysregulation of AUTS2 has been implicated in both lung adenocarcinoma and prostate cancer.	('neurological disorders', 'Disease', 'MESH:D009422', (39, 61))	('dysregulation', 'Var', (78, 91))	('autism', 'Phenotype', 'HP:0000717', (69, 75))	('implicated', 'Reg', (110, 120))	('autism', 'Disease', 'MESH:D001321', (69, 75))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (129, 148))	('neurological disorders', 'Disease', (39, 61))	('carcinoma', 'Phenotype', 'HP:0030731', (139, 148))	('AUTS2', 'Gene', '26053', (95, 100))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('autism', 'Disease', (69, 75))	('lung adenocarcinoma and prostate cancer', 'Disease', 'MESH:D011471', (129, 168))	('prostate cancer', 'Phenotype', 'HP:0012125', (153, 168))	('AUTS2', 'Gene', (95, 100))	('associated', 'Reg', (23, 33))
535162	33143142	Aberrant DNA methylation is a widespread feature in cancer that can lead to the transcriptional regression of genes and alterations in different biological and molecular pathways that may play a role in the progression of oncogenesis.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('lead to', 'Reg', (68, 75))	('Aberrant', 'Var', (0, 8))	('transcriptional', 'MPA', (80, 95))	('meth', 'Disease', 'None', (13, 17))	('meth', 'Disease', (13, 17))	('DNA', 'Gene', (9, 12))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('regression', 'NegReg', (96, 106))	('alterations', 'Reg', (120, 131))
535163	33143142	Although many studies have described the effects of aberrant DNA methylation on the onset and progression of cancer, a survey of literature suggests there is still a limitation in studies that links abnormal methylation to the alterations of different signaling pathways that commonly occur in cancers across different anatomical sites.	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('cancer', 'Disease', 'MESH:D009369', (294, 300))	('meth', 'Disease', (208, 212))	('cancers', 'Disease', 'MESH:D009369', (294, 301))	('cancer', 'Disease', (109, 115))	('cancers', 'Phenotype', 'HP:0002664', (294, 301))	('cancer', 'Disease', (294, 300))	('cancers', 'Disease', (294, 301))	('aberrant', 'Var', (52, 60))	('meth', 'Disease', 'None', (65, 69))	('meth', 'Disease', 'None', (208, 212))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('cancer', 'Phenotype', 'HP:0002664', (294, 300))	('meth', 'Disease', (65, 69))
535164	33143142	In this study, we investigated the methylation profile of four canonical oncogenic signaling pathways by revisiting the TCGA dataset of the four most common cancers in the world, and explored the pathway-associated genes that may be epigenetically-driven among cancers across the different cancers, and could therefore be used as potential drug targets to correct the altered signaling pathways and the possibility of combination therapy to target multiple sites in patient care.	('patient', 'Species', '9606', (466, 473))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('cancers', 'Phenotype', 'HP:0002664', (261, 268))	('meth', 'Disease', (35, 39))	('cancers', 'Phenotype', 'HP:0002664', (290, 297))	('cancer', 'Phenotype', 'HP:0002664', (261, 267))	('meth', 'Disease', 'None', (35, 39))	('cancers', 'Disease', (290, 297))	('cancer', 'Phenotype', 'HP:0002664', (290, 296))	('cancers', 'Disease', 'MESH:D009369', (290, 297))	('cancers', 'Disease', 'MESH:D009369', (157, 164))	('cancers', 'Phenotype', 'HP:0002664', (157, 164))	('cancers across the different cancers', 'Disease', (261, 297))	('cancers across the different cancers', 'Disease', 'MESH:D009369', (261, 297))	('cancers', 'Disease', (157, 164))	('cancers', 'Disease', 'MESH:D009369', (261, 268))	('epigenetically-driven', 'Var', (233, 254))	('cancers', 'Disease', (261, 268))
535165	33143142	By filtering for CpG sites that corresponded to genes associated with each of the oncogenic signaling pathways described in this manuscript, we identified cohorts of CpG sites that are universally hypermethylated in the tumor samples of the four TCGA cancers screened and could serve as potential pan-cancer biomarkers.	('sites', 'Var', (170, 175))	('tumor', 'Phenotype', 'HP:0002664', (220, 225))	('CpG', 'Gene', (166, 169))	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('cancer', 'Disease', 'MESH:D009369', (301, 307))	('meth', 'Disease', 'None', (202, 206))	('tumor', 'Disease', (220, 225))	('cancer', 'Disease', (301, 307))	('cancers', 'Phenotype', 'HP:0002664', (251, 258))	('cancers', 'Disease', (251, 258))	('cancer', 'Disease', 'MESH:D009369', (251, 257))	('cancers', 'Disease', 'MESH:D009369', (251, 258))	('meth', 'Disease', (202, 206))	('cancer', 'Phenotype', 'HP:0002664', (301, 307))	('cancer', 'Disease', (251, 257))	('tumor', 'Disease', 'MESH:D009369', (220, 225))
535168	33143142	Previous studies have suggested that the inactivation of ARF (p14) through epigenetic silencing plays an important deregulating mechanism of the ARF-MDM2-p53 pathways, leading to a restriction of the tumor-suppressing activity of p53.	('deregulating', 'MPA', (115, 127))	('ARF', 'Disease', (57, 60))	('ARF', 'Disease', 'MESH:D058186', (145, 148))	('MDM2', 'Gene', '4193', (149, 153))	('p53', 'Gene', '7157', (230, 233))	('tumor', 'Disease', (200, 205))	('epigenetic silencing', 'Var', (75, 95))	('p53', 'Gene', (230, 233))	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('ARF', 'Disease', 'MESH:D058186', (57, 60))	('inactivation', 'Var', (41, 53))	('p14', 'Gene', '1029', (62, 65))	('p53', 'Gene', '7157', (154, 157))	('restriction', 'NegReg', (181, 192))	('ARF', 'Disease', (145, 148))	('p14', 'Gene', (62, 65))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('p53', 'Gene', (154, 157))	('MDM2', 'Gene', (149, 153))
535181	33143142	This epigenetic modification has been shown to regulate the expression of cervical cancer, renal cell carcinoma and glioblastoma.	('expression', 'MPA', (60, 70))	('epigenetic modification', 'Var', (5, 28))	('glioblastoma', 'Disease', (116, 128))	('regulate', 'Reg', (47, 55))	('glioblastoma', 'Disease', 'MESH:D005909', (116, 128))	('renal cell carcinoma', 'Disease', (91, 111))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (91, 111))	('glioblastoma', 'Phenotype', 'HP:0012174', (116, 128))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (91, 111))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('cancer', 'Disease', (83, 89))
535183	33143142	Furthermore, epigenetic reprograming of NRF2 can lead to its reactivation and subsequent induction of downstream target genes involved in cellular protection (Figure 2E), further suggesting the use of KEAP1 within the NRF2 pathway as a potential target for cancer treatment.	('induction', 'PosReg', (89, 98))	('NRF2', 'Gene', '4780', (40, 44))	('cancer', 'Phenotype', 'HP:0002664', (257, 263))	('KEAP1', 'Gene', (201, 206))	('NRF2', 'Gene', '4780', (218, 222))	('reactivation', 'MPA', (61, 73))	('KEAP1', 'Gene', '9817', (201, 206))	('NRF2', 'Gene', (40, 44))	('epigenetic reprograming', 'Var', (13, 36))	('cancer', 'Disease', 'MESH:D009369', (257, 263))	('NRF2', 'Gene', (218, 222))	('cancer', 'Disease', (257, 263))
535192	33143142	The RB pathway has been a focus in cancer therapy, as several components of this pathway, including p16Ink4a, cyclin D1 and RB, are frequently deleted or mutated during the progression of cancer.	('deleted', 'Var', (143, 150))	('cyclin D1', 'Gene', '595', (110, 119))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('RB', 'Gene', '5925', (4, 6))	('cyclin D1', 'Gene', (110, 119))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('RB', 'Gene', '5925', (124, 126))	('p16Ink4a', 'Gene', '1029', (100, 108))	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('RB', 'Phenotype', 'HP:0009919', (4, 6))	('cancer', 'Disease', (188, 194))	('p16Ink4a', 'Gene', (100, 108))	('RB', 'Phenotype', 'HP:0009919', (124, 126))	('mutated', 'Var', (154, 161))	('cancer', 'Disease', (35, 41))
535196	33143142	Specifically, glioma-CpG island methylator phenotype tumors are associated with hypermethylated promoters and IDH 1 mutations.	('associated', 'Reg', (64, 74))	('meth', 'Disease', (32, 36))	('meth', 'Disease', 'None', (85, 89))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('glioma-CpG', 'Disease', 'MESH:D005910', (14, 24))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('meth', 'Disease', (85, 89))	('IDH 1', 'Gene', '3417', (110, 115))	('mutations', 'Var', (116, 125))	('glioma', 'Phenotype', 'HP:0009733', (14, 20))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('glioma-CpG', 'Disease', (14, 24))	('meth', 'Disease', 'None', (32, 36))	('tumors', 'Disease', (53, 59))	('IDH 1', 'Gene', (110, 115))
535197	33143142	revealed a connection between the methylation at the MGMT (methylguanine DNA methyltransferase) promoter and a hypermutator phenotype secondary to mismatch repair deficiency occurring in glioma.	('meth', 'Disease', 'None', (77, 81))	('mismatch', 'Var', (147, 155))	('glioma', 'Disease', (187, 193))	('meth', 'Disease', 'None', (34, 38))	('methylguanine DNA methyltransferase', 'Gene', '4255', (59, 94))	('meth', 'Disease', 'None', (59, 63))	('meth', 'Disease', (77, 81))	('MGMT', 'Gene', (53, 57))	('meth', 'Disease', (34, 38))	('meth', 'Disease', (59, 63))	('connection', 'Reg', (11, 21))	('MGMT', 'Gene', '4255', (53, 57))	('glioma', 'Phenotype', 'HP:0009733', (187, 193))	('glioma', 'Disease', 'MESH:D005910', (187, 193))	('methylguanine DNA methyltransferase', 'Gene', (59, 94))
535223	33143142	As changes in DNA methylation may result in altered signaling pathways leading to the progression of cancer, here we demonstrated the potential of altering methylation-based targets within these pathways to change their phenotypic expressions, and ultimately switch the pathway back into a non-disease state.	('altering', 'Reg', (147, 155))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('result', 'Reg', (34, 40))	('meth', 'Disease', (156, 160))	('cancer', 'Disease', (101, 107))	('DNA', 'Gene', (14, 17))	('leading', 'Reg', (71, 78))	('changes', 'Var', (3, 10))	('altered', 'Reg', (44, 51))	('signaling pathways', 'Pathway', (52, 70))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('meth', 'Disease', 'None', (18, 22))	('change', 'Reg', (207, 213))	('switch', 'Reg', (259, 265))	('meth', 'Disease', 'None', (156, 160))	('phenotypic expressions', 'MPA', (220, 242))	('meth', 'Disease', (18, 22))
535288	31611978	Overexpression of PPIA was associated with poor relapse free survival of lung adenocarcinoma in datasets GSE32210 and GSE8894 using various primers, and poor OS in datasets GSE32210, GSE13213, jacob-00182-UM and GSE13213.	('PPIA', 'Gene', '5478', (18, 22))	('lung adenocarcinoma', 'Disease', (73, 92))	('PPIA', 'Gene', (18, 22))	('poor', 'NegReg', (43, 47))	('Overexpression', 'Var', (0, 14))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (73, 92))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (73, 92))	('relapse free survival', 'CPA', (48, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))
535290	31611978	In breast cancer, there was a certain level of contradiction, although the OS was revealed to be positively correlated with PPIA expression level (HR, 0.83) in dataset GSE9893, the other survival values of breast cancer were negatively correlated with PPIA expression, such as disease free survival in GSE4922-GPL96 (HR, 6.99 and 6.07 with different primers), relapse free survival in GSE1456-GPL96 (HR, 7.41 and 7.12 with different primers), distant metastasis free survival in GSE11121, GSE9195 and GSE2990, and disease specific survival in GSE3494-GPL96 and GSE1456-GPL96.	('GSE2990', 'Var', (501, 508))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('distant metastasis free survival', 'CPA', (443, 475))	('PPIA', 'Gene', (124, 128))	('breast cancer', 'Disease', 'MESH:D001943', (3, 16))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('disease specific survival', 'CPA', (514, 539))	('breast cancer', 'Disease', (3, 16))	('breast cancer', 'Disease', 'MESH:D001943', (206, 219))	('PPIA', 'Gene', '5478', (252, 256))	('breast cancer', 'Phenotype', 'HP:0003002', (3, 16))	('negatively', 'NegReg', (225, 235))	('breast cancer', 'Disease', (206, 219))	('breast cancer', 'Phenotype', 'HP:0003002', (206, 219))	('relapse free survival', 'CPA', (360, 381))	('PPIA', 'Gene', (252, 256))	('PPIA', 'Gene', '5478', (124, 128))	('GSE9195', 'Var', (489, 496))
535291	31611978	These results indicated that overexpression of PPIA was a risk factor for breast cancer progression and metastasis, and may be harnessed as a therapeutic target.	('breast cancer', 'Disease', (74, 87))	('breast cancer', 'Disease', 'MESH:D001943', (74, 87))	('metastasis', 'CPA', (104, 114))	('PPIA', 'Gene', '5478', (47, 51))	('overexpression', 'Var', (29, 43))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('PPIA', 'Gene', (47, 51))	('breast cancer', 'Phenotype', 'HP:0003002', (74, 87))
535301	31611978	The prognoses of tumor grade 1, 2, 3 and 4 in those with high PPIA expression levels were all poorer than the prognoses of respective tumor grades with low or median PPIA expression levels in LIHC.	('PPIA', 'Gene', '5478', (166, 170))	('tumor', 'Disease', (17, 22))	('PPIA', 'Gene', (62, 66))	('high', 'Var', (57, 61))	('PPIA', 'Gene', (166, 170))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('LIHC', 'Disease', (192, 196))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('PPIA', 'Gene', '5478', (62, 66))	('LIHC', 'Disease', 'MESH:D006528', (192, 196))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('tumor', 'Disease', (134, 139))
535302	31611978	The prognosis of low or median PPIA expression in every tumor grade was better than the prognosis of high PPIA expression in every tumor grade, as presented in Fig.	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('PPIA', 'Gene', (31, 35))	('tumor', 'Disease', (56, 61))	('PPIA', 'Gene', '5478', (106, 110))	('tumor', 'Disease', (131, 136))	('low', 'Var', (17, 20))	('PPIA', 'Gene', (106, 110))	('PPIA', 'Gene', '5478', (31, 35))	('expression', 'MPA', (36, 46))
535322	31611978	The OS of patients with high PPIA expression levels was significantly decreased compared with patients with low PPIA expression levels in the sorafenib-administered group.	('patients', 'Species', '9606', (94, 102))	('PPIA', 'Gene', '5478', (29, 33))	('sorafenib', 'Chemical', 'MESH:C471405', (142, 151))	('PPIA', 'Gene', '5478', (112, 116))	('decreased', 'NegReg', (70, 79))	('PPIA', 'Gene', (29, 33))	('high', 'Var', (24, 28))	('patients', 'Species', '9606', (10, 18))	('PPIA', 'Gene', (112, 116))
535323	31611978	This indicated that PPIA played a specific role in the progression of LIHC in the poorer OS subgroup of the sorafenib-administered group and that inhibition of PPIA expression or PPIA inhibitor ciclosporin A may be beneficial for sorafenib-administered patients.	('PPIA', 'Gene', '5478', (160, 164))	('PPIA', 'Gene', (20, 24))	('LIHC', 'Disease', (70, 74))	('LIHC', 'Disease', 'MESH:D006528', (70, 74))	('patients', 'Species', '9606', (253, 261))	('sorafenib', 'Chemical', 'MESH:C471405', (108, 117))	('PPIA', 'Gene', '5478', (20, 24))	('PPIA', 'Gene', (160, 164))	('PPIA', 'Gene', '5478', (179, 183))	('ciclosporin A', 'Chemical', 'MESH:D016572', (194, 207))	('inhibition', 'Var', (146, 156))	('PPIA', 'Gene', (179, 183))	('sorafenib', 'Chemical', 'MESH:C471405', (230, 239))
535332	31611978	Lu et al revealed that basolateral CD147 induced hepatocyte polarity loss by E-cadherin ubiquitination and degradation in the progression of hepatocellular carcinoma.	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (141, 165))	('loss', 'NegReg', (69, 73))	('hepatocellular carcinoma', 'Disease', (141, 165))	('hepatocyte polarity', 'MPA', (49, 68))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (141, 165))	('carcinoma', 'Phenotype', 'HP:0030731', (156, 165))	('degradation', 'MPA', (107, 118))	('E-cadherin', 'Gene', (77, 87))	('E-cadherin', 'Gene', '999', (77, 87))	('basolateral', 'Var', (23, 34))	('ubiquitination', 'MPA', (88, 102))	('CD147', 'Gene', (35, 40))
535344	31611978	CD4+ T cells expressing more CD147 migrated more readily to PPIA.	('migrated', 'CPA', (35, 43))	('CD147', 'Var', (29, 34))	('PPIA', 'Gene', '5478', (60, 64))	('CD4', 'Gene', '920', (0, 3))	('PPIA', 'Gene', (60, 64))	('CD4', 'Gene', (0, 3))
535355	29422544	In this study, we performed whole-exome sequencing and copy number profiling of 6 HPV (+) and 9 HPV (-) vulvar SCCs and found known mutations (TP53, CDKN2A and HRAS) and copy number alterations (CNAs) (7p and 8q gains and 2q loss) in HPV (-) SCCs.	('TP53', 'Gene', (143, 147))	('HPV', 'Species', '10566', (96, 99))	('CDKN2A', 'Gene', '1029', (149, 155))	('SCC', 'Phenotype', 'HP:0002860', (242, 245))	('HPV', 'Species', '10566', (234, 237))	('SCC', 'Phenotype', 'HP:0002860', (111, 114))	('7p', 'Var', (202, 204))	('loss', 'NegReg', (225, 229))	('HRAS', 'Gene', '3265', (160, 164))	('SCC', 'Gene', (111, 114))	('SCC', 'Gene', (242, 245))	('HRAS', 'Gene', (160, 164))	('HPV', 'Species', '10566', (82, 85))	('TP53', 'Gene', '7157', (143, 147))	('gains', 'PosReg', (212, 217))	('CDKN2A', 'Gene', (149, 155))	('SCC', 'Gene', '6317', (111, 114))	('SCC', 'Gene', '6317', (242, 245))
535356	29422544	In HPV (+), we found novel mutations in PIK3CA, BRCA2 and FBXW7 that had not been reported in vulvar SCCs.	('mutations', 'Var', (27, 36))	('PIK3CA', 'Gene', (40, 46))	('FBXW7', 'Gene', '55294', (58, 63))	('BRCA2', 'Gene', '675', (48, 53))	('PIK3CA', 'Gene', '5290', (40, 46))	('SCC', 'Gene', '6317', (101, 104))	('SCC', 'Gene', (101, 104))	('FBXW7', 'Gene', (58, 63))	('SCC', 'Phenotype', 'HP:0002860', (101, 104))	('BRCA2', 'Gene', (48, 53))	('HPV', 'Species', '10566', (3, 6))
535361	29422544	Our data provide useful information for both HPV (+) and HPV (-) vulvar SCCs and may aid in the development of clinical treatment strategies.	('SCC', 'Gene', '6317', (72, 75))	('HPV', 'Var', (57, 60))	('HPV', 'Species', '10566', (45, 48))	('SCC', 'Gene', (72, 75))	('SCC', 'Phenotype', 'HP:0002860', (72, 75))	('HPV', 'Species', '10566', (57, 60))
535366	29422544	Both HPV (+) and HPV (-) vulvar SCCs are preceded by vulvar intraepithelial neoplasia (VIN).	('vulvar intraepithelial neoplasia', 'Phenotype', 'HP:0032202', (53, 85))	('HPV', 'Gene', (17, 20))	('VIN', 'Phenotype', 'HP:0032202', (87, 90))	('HPV (+', 'Var', (5, 11))	('neoplasia', 'Phenotype', 'HP:0002664', (76, 85))	('intraepithelial neoplasia', 'Phenotype', 'HP:0032187', (60, 85))	('SCC', 'Gene', (32, 35))	('vulvar intraepithelial neoplasia', 'Disease', (53, 85))	('HPV', 'Species', '10566', (5, 8))	('vulvar intraepithelial neoplasia', 'Disease', 'MESH:D019048', (53, 85))	('SCC', 'Gene', '6317', (32, 35))	('SCC', 'Phenotype', 'HP:0002860', (32, 35))	('HPV', 'Species', '10566', (17, 20))
535372	29422544	Using a targeted sequencing approach for 14 genes, a recent study identified that most HPV-negative (-) vulvar SCCs (83%) contained one or more somatic mutations in TP53, CDKN2A, HRAS, KRAS, PIK3CA, PPP2R1A and PTEN, with TP53 being the most commonly mutated gene.	('TP53', 'Gene', (165, 169))	('mutations', 'Var', (152, 161))	('contained', 'Reg', (122, 131))	('PTEN', 'Gene', (211, 215))	('CDKN2A', 'Gene', '1029', (171, 177))	('HRAS', 'Gene', '3265', (179, 183))	('PIK3CA', 'Gene', '5290', (191, 197))	('HRAS', 'Gene', (179, 183))	('SCC', 'Phenotype', 'HP:0002860', (111, 114))	('TP53', 'Gene', '7157', (222, 226))	('TP53', 'Gene', '7157', (165, 169))	('KRAS', 'Gene', (185, 189))	('PPP2R1A', 'Gene', (199, 206))	('PIK3CA', 'Gene', (191, 197))	('SCC', 'Gene', '6317', (111, 114))	('HPV', 'Species', '10566', (87, 90))	('CDKN2A', 'Gene', (171, 177))	('SCC', 'Gene', (111, 114))	('TP53', 'Gene', (222, 226))
535373	29422544	In contrast, HPV-positive (+) vulvar SCCs harbored a TP53 mutation in 17% of cases but the remaining 83% were silent without any driver mutations.	('SCC', 'Gene', '6317', (37, 40))	('mutation', 'Var', (58, 66))	('harbored', 'Reg', (42, 50))	('TP53', 'Gene', '7157', (53, 57))	('SCC', 'Gene', (37, 40))	('SCC', 'Phenotype', 'HP:0002860', (37, 40))	('HPV', 'Species', '10566', (13, 16))	('TP53', 'Gene', (53, 57))
535376	29422544	Thus far, a number of studies have reported the mutational profiles of SCC in many organs (non-genital: head/neck, esophagus and skin; genital: uterine cervix and penis) using high-throughput genome profiling technologies.	('reported', 'Reg', (35, 43))	('SCC', 'Gene', (71, 74))	('uterine cervix', 'Phenotype', 'HP:0030160', (144, 158))	('mutational', 'Var', (48, 58))	('SCC', 'Phenotype', 'HP:0002860', (71, 74))	('SCC', 'Gene', '6317', (71, 74))
535388	29422544	Somatic mutations were detected by comparing tumor and matched normal sequencing data using MuTect and SomaticIndelDetector for point mutations and indels, respectively.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('tumor', 'Disease', (45, 50))	('point mutations', 'Var', (128, 143))	('tumor', 'Disease', 'MESH:D009369', (45, 50))
535389	29422544	PolyPhen-2 was used to predict the impact of an amino-acid substitution on protein function and structure.	('PolyPhen-2', 'Chemical', '-', (0, 10))	('amino-acid substitution', 'Var', (48, 71))	('protein', 'Protein', (75, 82))
535399	29422544	The base substitutions were mainly C>T or C>G and did not differ between HPV (+) and HPV (-) SCCs.	('HPV', 'Species', '10566', (73, 76))	('SCC', 'Gene', (93, 96))	('C>T', 'Var', (35, 38))	('SCC', 'Phenotype', 'HP:0002860', (93, 96))	('C>G', 'Var', (42, 45))	('SCC', 'Gene', '6317', (93, 96))	('HPV', 'Species', '10566', (85, 88))
535402	29422544	We identified a total of 56 cancer-related genes that contained not only known vulvar SCC mutations (TP53, CDKN2A, PIK3CA and HRAS) but also previously unknown vulvar SCC mutations, including APC, FBXW7, BRCA2, RB1 and FAT1 (Figure 2a).	('mutations', 'Var', (90, 99))	('HRAS', 'Gene', (126, 130))	('TP53', 'Gene', (101, 105))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('PIK3CA', 'Gene', (115, 121))	('FAT1', 'Gene', (219, 223))	('CDKN2A', 'Gene', '1029', (107, 113))	('SCC', 'Phenotype', 'HP:0002860', (167, 170))	('SCC', 'Phenotype', 'HP:0002860', (86, 89))	('RB1', 'Gene', (211, 214))	('BRCA2', 'Gene', (204, 209))	('FBXW7', 'Gene', (197, 202))	('SCC', 'Gene', '6317', (167, 170))	('TP53', 'Gene', '7157', (101, 105))	('SCC', 'Gene', '6317', (86, 89))	('FAT1', 'Gene', '2195', (219, 223))	('RB1', 'Gene', '5925', (211, 214))	('cancer', 'Disease', (28, 34))	('PIK3CA', 'Gene', '5290', (115, 121))	('SCC', 'Gene', (167, 170))	('FBXW7', 'Gene', '55294', (197, 202))	('SCC', 'Gene', (86, 89))	('APC', 'Disease', 'MESH:D011125', (192, 195))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('APC', 'Disease', (192, 195))	('BRCA2', 'Gene', '675', (204, 209))	('CDKN2A', 'Gene', (107, 113))	('HRAS', 'Gene', '3265', (126, 130))
535403	29422544	The putative driver mutations showed significantly higher mutation allele frequencies (mean MAFs; 0.19) than the other mutations (mean MAFs: 0.16, P=0.02).	('MAF', 'Gene', '4094', (92, 95))	('MAF', 'Gene', (92, 95))	('mutation allele frequencies', 'MPA', (58, 85))	('higher', 'PosReg', (51, 57))	('MAF', 'Gene', '4094', (135, 138))	('MAF', 'Gene', (135, 138))	('mutations', 'Var', (20, 29))
535404	29422544	The PolyPhen-2 analysis revealed that the majority of the putative driver mutations (34 of 56, 61%) were predicted to have damaging effects on protein function (Supplementary Table S3).	('PolyPhen-2', 'Chemical', '-', (4, 14))	('mutations', 'Var', (74, 83))	('protein function', 'MPA', (143, 159))
535406	29422544	The number of driver mutations in HPV (-) SCCs (average of 10.6 per tumor) was significantly higher than that of HPV (+) SCCs (average of 2.8 per tumor) (P=0.0002).	('higher', 'PosReg', (93, 99))	('tumor', 'Disease', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('HPV', 'Var', (34, 37))	('SCC', 'Gene', (42, 45))	('SCC', 'Phenotype', 'HP:0002860', (42, 45))	('tumor', 'Disease', (146, 151))	('SCC', 'Gene', (121, 124))	('SCC', 'Phenotype', 'HP:0002860', (121, 124))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('SCC', 'Gene', '6317', (42, 45))	('SCC', 'Gene', '6317', (121, 124))	('tumor', 'Disease', 'MESH:D009369', (146, 151))	('HPV', 'Species', '10566', (113, 116))	('HPV', 'Species', '10566', (34, 37))	('mutations', 'Var', (21, 30))
535407	29422544	However, 4 of 6 HPV (+) SCCs still harbored one of the known driver gene mutations (PIK3CA, BRCA2 and FBXW7) (Table 2).	('FBXW7', 'Gene', '55294', (102, 107))	('PIK3CA', 'Gene', '5290', (84, 90))	('SCC', 'Gene', (24, 27))	('SCC', 'Phenotype', 'HP:0002860', (24, 27))	('FBXW7', 'Gene', (102, 107))	('harbored', 'Reg', (35, 43))	('BRCA2', 'Gene', (92, 97))	('HPV', 'Species', '10566', (16, 19))	('SCC', 'Gene', '6317', (24, 27))	('PIK3CA', 'Gene', (84, 90))	('BRCA2', 'Gene', '675', (92, 97))	('mutations', 'Var', (73, 82))
535410	29422544	Of note, FAT1 harbored nonsilent mutations in 3 SCCs: VSCC15 with a nonsense mutation (p.W4175X), VSCC13 with 2 different nonsense mutations (p.S3268X and p.Q1455X) and VSCC9 with a missense mutation (p.D3749N).	('SCC', 'Gene', '6317', (99, 102))	('FAT1', 'Gene', '2195', (9, 13))	('p.D3749N', 'Mutation', 'rs772322719', (201, 209))	('p.Q1455X', 'Mutation', 'p.Q1455X', (155, 163))	('SCC', 'Gene', '6317', (170, 173))	('SCC', 'Gene', (99, 102))	('SCC', 'Phenotype', 'HP:0002860', (55, 58))	('p.S3268X', 'Mutation', 'p.S3268X', (142, 150))	('SCC', 'Phenotype', 'HP:0002860', (48, 51))	('SCC', 'Gene', (170, 173))	('FAT1', 'Gene', (9, 13))	('SCC', 'Gene', '6317', (55, 58))	('SCC', 'Gene', '6317', (48, 51))	('p.S3268X', 'Var', (142, 150))	('SCC', 'Phenotype', 'HP:0002860', (99, 102))	('p.W4175X', 'Var', (87, 95))	('SCC', 'Gene', (55, 58))	('SCC', 'Gene', (48, 51))	('p.D3749N', 'Var', (201, 209))	('SCC', 'Phenotype', 'HP:0002860', (170, 173))	('p.W4175X', 'Mutation', 'rs1477895983', (87, 95))	('p.Q1455X', 'Var', (155, 163))
535411	29422544	Three of six truncating mutations were identified in the FAT1 gene (p.W4175X, p.S3268X and p.Q1455X), which were located in known functional domains (cadherin domains and the intracytoplasmic domain) (Figure 2b).	('p.S3268X', 'Mutation', 'p.S3268X', (78, 86))	('p.Q1455X', 'Mutation', 'p.Q1455X', (91, 99))	('p.Q1455X', 'Var', (91, 99))	('p.W4175X', 'Mutation', 'rs1477895983', (68, 76))	('FAT1', 'Gene', '2195', (57, 61))	('p.S3268X', 'Var', (78, 86))	('FAT1', 'Gene', (57, 61))	('p.W4175X', 'Var', (68, 76))
535412	29422544	We analyzed signatures of the somatic mutations detected in the vulvar SCCs using the NMF algorithm (Figure 3a and b and Supplementary Figure S1) and found that C:G>T:A transitions, which are frequently observed in mutations with oxidative DNA damage, were predominant in the vulvar SCCs.	('SCC', 'Gene', '6317', (283, 286))	('SCC', 'Phenotype', 'HP:0002860', (283, 286))	('C:G>T:A', 'Var', (161, 168))	('SCC', 'Gene', (71, 74))	('SCC', 'Gene', (283, 286))	('SCC', 'Phenotype', 'HP:0002860', (71, 74))	('SCC', 'Gene', '6317', (71, 74))
535416	29422544	However, the C>T transition, in the context of TpCpG trinucleotides, was more abundant in HPV (-) SCCs (average contribution of 0.17 per tumor) than in HPV (+) SCCs (average contribution of 0.14 per tumor).	('tumor', 'Disease', (199, 204))	('C>T', 'Var', (13, 16))	('SCC', 'Phenotype', 'HP:0002860', (98, 101))	('tumor', 'Disease', (137, 142))	('HPV', 'Species', '10566', (90, 93))	('SCC', 'Gene', '6317', (98, 101))	('HPV', 'Species', '10566', (152, 155))	('HPV (-', 'Var', (90, 96))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('SCC', 'Gene', (160, 163))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('trinucleotides', 'Chemical', '-', (53, 67))	('SCC', 'Phenotype', 'HP:0002860', (160, 163))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('SCC', 'Gene', '6317', (160, 163))	('SCC', 'Gene', (98, 101))
535421	29422544	No significant difference in the number or length of CNAs was observed between HPV (+) and HPV (-) genomes (P=0.53 and 0.75, respectively) (Table 2).	('HPV', 'Species', '10566', (91, 94))	('HPV (+', 'Var', (79, 85))	('HPV', 'Species', '10566', (79, 82))	('HPV (-', 'Var', (91, 97))
535422	29422544	In the HPV (+) SCCs, we found 15 recurrently altered CNA regions, where a gain on 3q25.33-q29 was the most recurrent event (83%) (Table 3).	('altered', 'Reg', (45, 52))	('HPV', 'Species', '10566', (7, 10))	('SCC', 'Gene', (15, 18))	('gain', 'PosReg', (74, 78))	('SCC', 'Phenotype', 'HP:0002860', (15, 18))	('SCC', 'Gene', '6317', (15, 18))	('3q25.33-q29', 'Var', (82, 93))
535429	29422544	Importantly, 4 of 6 HPV (+) cases (VSCC1-4) showed copy gains at the PIK3CA locus (3q26.32).	('HPV', 'Species', '10566', (20, 23))	('HPV', 'Gene', (20, 23))	('SCC', 'Gene', (36, 39))	('copy gains', 'Var', (51, 61))	('SCC', 'Phenotype', 'HP:0002860', (36, 39))	('PIK3CA', 'Gene', (69, 75))	('PIK3CA', 'Gene', '5290', (69, 75))	('SCC', 'Gene', '6317', (36, 39))
535430	29422544	Two of them (VSCC1 and 4) harbored a hotspot missense mutation (p.E545K) (Figure 4c).	('p.E545K', 'Mutation', 'rs104886003', (64, 71))	('SCC', 'Gene', (14, 17))	('SCC', 'Phenotype', 'HP:0002860', (14, 17))	('SCC', 'Gene', '6317', (14, 17))	('p.E545K', 'Var', (64, 71))
535431	29422544	The MAF of the missense mutation at the PIK3CA copy gain locus was 49% and the mean MAF in the copy-number neutral region was 24% in VSCC4.	('MAF', 'Gene', '4094', (84, 87))	('PIK3CA', 'Gene', (40, 46))	('MAF', 'Gene', '4094', (4, 7))	('SCC', 'Phenotype', 'HP:0002860', (134, 137))	('SCC', 'Gene', '6317', (134, 137))	('PIK3CA', 'Gene', '5290', (40, 46))	('MAF', 'Gene', (4, 7))	('missense mutation', 'Var', (15, 32))	('SCC', 'Gene', (134, 137))	('MAF', 'Gene', (84, 87))
535432	29422544	Similarly, in VSCC1, the MAF of the mutation in the PIK3CA copy gain locus was 21% and the mean MAF in the copy-number neutral region was 17%.	('MAF', 'Gene', '4094', (25, 28))	('MAF', 'Gene', (25, 28))	('PIK3CA', 'Gene', (52, 58))	('MAF', 'Gene', (96, 99))	('MAF', 'Gene', '4094', (96, 99))	('SCC', 'Gene', (15, 18))	('PIK3CA', 'Gene', '5290', (52, 58))	('SCC', 'Phenotype', 'HP:0002860', (15, 18))	('SCC', 'Gene', '6317', (15, 18))	('mutation', 'Var', (36, 44))
535434	29422544	Next, we assessed the B-allele profiles of the 13 vulvar SCCs and identified 6 copy-neutral LOH events (2q33.1-q37.3, 3q11.2-q29, 7p22.3-p11.2, 7q22.1-q36.3, 9q22.2-q34.3 and 17p13.3-p11.2) in 4 (31%) cases (1 HPV (+) and 3 HPV (-)) where important cancer-related genes are located, including TP53, PIK3CA, NOTCH1, CASP8, EGFR, BRAF, FOXL2 and TP63 (Figure 5).	('TP63', 'Gene', (344, 348))	('cancer', 'Disease', (249, 255))	('PIK3CA', 'Gene', (299, 305))	('cancer', 'Phenotype', 'HP:0002664', (249, 255))	('HPV', 'Species', '10566', (210, 213))	('SCC', 'Phenotype', 'HP:0002860', (57, 60))	('TP63', 'Gene', '8626', (344, 348))	('TP53', 'Gene', '7157', (293, 297))	('2q33.1-q37.3', 'Var', (104, 116))	('NOTCH1', 'Gene', (307, 313))	('SCC', 'Gene', '6317', (57, 60))	('HPV', 'Species', '10566', (224, 227))	('CASP8', 'Gene', '841', (315, 320))	('cancer', 'Disease', 'MESH:D009369', (249, 255))	('FOXL2', 'Gene', '668', (334, 339))	('SCC', 'Gene', (57, 60))	('PIK3CA', 'Gene', '5290', (299, 305))	('FOXL2', 'Gene', (334, 339))	('CASP8', 'Gene', (315, 320))	('TP53', 'Gene', (293, 297))	('BRAF', 'Gene', (328, 332))	('EGFR', 'Gene', (322, 326))
535435	29422544	Two vulvar SCCs with HPV (+) had a recurrent region of kataegis (a focus of localized substitution hypermutations) at chromosome 16p12.3-q22.2 (chr16:19 566 736-72 137 834) (Figure 6).	('HPV', 'Species', '10566', (21, 24))	('SCC', 'Gene', (11, 14))	('SCC', 'Phenotype', 'HP:0002860', (11, 14))	('HPV', 'Var', (21, 24))	('SCC', 'Gene', '6317', (11, 14))
535436	29422544	Of note, the kataegis region in our study co-localized with the copy gain of the DHX38 gene, which is involved in RNA splicing.	('DHX38', 'Gene', '9785', (81, 86))	('copy gain', 'Var', (64, 73))	('DHX38', 'Gene', (81, 86))
535440	29422544	We found that the vulvar SCCs harbored not only known mutations in driver genes such as TP53, PIK3CA and HRAS but also novel mutations in cancer-related genes such as APC, FBXW7, BRCA2, RB1 and FAT1.	('BRCA2', 'Gene', '675', (179, 184))	('cancer', 'Disease', (138, 144))	('SCC', 'Phenotype', 'HP:0002860', (25, 28))	('APC', 'Disease', 'MESH:D011125', (167, 170))	('APC', 'Disease', (167, 170))	('FBXW7', 'Gene', '55294', (172, 177))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('TP53', 'Gene', '7157', (88, 92))	('mutations', 'Var', (54, 63))	('HRAS', 'Gene', '3265', (105, 109))	('FAT1', 'Gene', (194, 198))	('SCC', 'Gene', '6317', (25, 28))	('HRAS', 'Gene', (105, 109))	('cancer', 'Disease', 'MESH:D009369', (138, 144))	('PIK3CA', 'Gene', '5290', (94, 100))	('mutations', 'Var', (125, 134))	('SCC', 'Gene', (25, 28))	('RB1', 'Gene', (186, 189))	('FBXW7', 'Gene', (172, 177))	('BRCA2', 'Gene', (179, 184))	('TP53', 'Gene', (88, 92))	('FAT1', 'Gene', '2195', (194, 198))	('PIK3CA', 'Gene', (94, 100))	('RB1', 'Gene', '5925', (186, 189))
535442	29422544	For example, the TP53 mutation was known as a sole driver mutation in HPV (+) vulvar SCCs but other driver gene mutations (PIK3CA, BRCA2 and FBXW7) were detected in the HPV (+) SCCs in the present study.	('BRCA2', 'Gene', (131, 136))	('mutation', 'Var', (22, 30))	('SCC', 'Gene', '6317', (85, 88))	('SCC', 'Phenotype', 'HP:0002860', (85, 88))	('PIK3CA', 'Gene', (123, 129))	('HPV', 'Species', '10566', (70, 73))	('BRCA2', 'Gene', '675', (131, 136))	('SCC', 'Gene', (177, 180))	('PIK3CA', 'Gene', '5290', (123, 129))	('HPV', 'Species', '10566', (169, 172))	('FBXW7', 'Gene', '55294', (141, 146))	('SCC', 'Gene', '6317', (177, 180))	('SCC', 'Phenotype', 'HP:0002860', (177, 180))	('FBXW7', 'Gene', (141, 146))	('SCC', 'Gene', (85, 88))	('TP53', 'Gene', '7157', (17, 21))	('TP53', 'Gene', (17, 21))
535443	29422544	Most recurrent CNAs of HPV (+) SCCs in the present study were largely in agreement with those described in earlier studies, while those of HPV (-) were not, except for the gain on 8q.	('SCC', 'Gene', (31, 34))	('SCC', 'Phenotype', 'HP:0002860', (31, 34))	('SCC', 'Gene', '6317', (31, 34))	('HPV (+', 'Var', (23, 29))	('CNAs', 'Disease', (15, 19))	('HPV', 'Species', '10566', (139, 142))	('HPV', 'Species', '10566', (23, 26))
535444	29422544	Of note, the gain on 3q was the most recurrent CNA in the HPV (+) vulvar SCCs, while the gains on 7p and 8q and the loss on 2q were the most recurrent in HPV (-) cases.	('HPV', 'Disease', (58, 61))	('SCC', 'Gene', (73, 76))	('SCC', 'Phenotype', 'HP:0002860', (73, 76))	('SCC', 'Gene', '6317', (73, 76))	('gain', 'Var', (13, 17))	('HPV', 'Species', '10566', (154, 157))	('HPV', 'Species', '10566', (58, 61))
535448	29422544	The copy-neutral LOH may contribute to the development of tumors that are homozygous for preexisting mutations.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('tumors', 'Disease', (58, 64))	('tumors', 'Disease', 'MESH:D009369', (58, 64))	('contribute', 'Reg', (25, 35))	('copy-neutral LOH', 'Var', (4, 20))
535449	29422544	The copy-neutral LOH areas in the vulvar SCCs identified in this study harbored tumor suppressor genes (TP53 and CASP8) and an oncogene (PIK3CA).	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('SCC', 'Gene', (41, 44))	('PIK3CA', 'Gene', (137, 143))	('TP53', 'Gene', '7157', (104, 108))	('CASP8', 'Gene', '841', (113, 118))	('TP53', 'Gene', (104, 108))	('SCC', 'Phenotype', 'HP:0002860', (41, 44))	('CASP8', 'Gene', (113, 118))	('copy-neutral', 'Var', (4, 16))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('SCC', 'Gene', '6317', (41, 44))	('PIK3CA', 'Gene', '5290', (137, 143))	('tumor', 'Disease', (80, 85))
535450	29422544	We are the first to report this copy-neutral LOH in vulvar SCCs; however, its distribution as well as its biological and clinical significance in vulvar SCCs remains to be clarified.	('SCC', 'Gene', '6317', (153, 156))	('SCC', 'Gene', (59, 62))	('SCC', 'Phenotype', 'HP:0002860', (59, 62))	('SCC', 'Gene', '6317', (59, 62))	('copy-neutral', 'Var', (32, 44))	('SCC', 'Gene', (153, 156))	('SCC', 'Phenotype', 'HP:0002860', (153, 156))
535460	29422544	The most common mutation identified in this study was the TP53 mutation (5/15), consistent with previous studies.	('TP53', 'Gene', (58, 62))	('TP53', 'Gene', '7157', (58, 62))	('mutation', 'Var', (63, 71))
535461	29422544	The TP53 mutation in one case (VSCC8) was accompanied by a TP53 copy loss, which would result in the complete inactivation of TP53.	('mutation', 'Var', (9, 17))	('TP53', 'Gene', (59, 63))	('inactivation', 'NegReg', (110, 122))	('TP53', 'Gene', (126, 130))	('TP53', 'Gene', (4, 8))	('SCC', 'Gene', (32, 35))	('TP53', 'Gene', '7157', (4, 8))	('SCC', 'Phenotype', 'HP:0002860', (32, 35))	('SCC', 'Gene', '6317', (32, 35))	('TP53', 'Gene', '7157', (59, 63))	('TP53', 'Gene', '7157', (126, 130))	('copy loss', 'NegReg', (64, 73))
535463	29422544	Of them, 2 cases (VSCC1 and 4) harbored concurrent PIK3CA mutations, while the other 4 cases harbored only PIK3CA copy gains without any PIK3CA mutation.	('SCC', 'Gene', '6317', (19, 22))	('mutations', 'Var', (58, 67))	('PIK3CA', 'Gene', (137, 143))	('harbored', 'Reg', (31, 39))	('PIK3CA', 'Gene', '5290', (137, 143))	('PIK3CA', 'Gene', (51, 57))	('PIK3CA', 'Gene', (107, 113))	('SCC', 'Gene', (19, 22))	('PIK3CA', 'Gene', '5290', (107, 113))	('PIK3CA', 'Gene', '5290', (51, 57))	('SCC', 'Phenotype', 'HP:0002860', (19, 22))
535464	29422544	When combining the PIK3CA mutations with the copy gains, PIK3CA genetic alterations in vulvar SCCs reached 60%, suggesting that it may be the major genetic alteration in vulvar SCCs.	('PIK3CA', 'Gene', (19, 25))	('PIK3CA', 'Gene', '5290', (57, 63))	('PIK3CA', 'Gene', '5290', (19, 25))	('SCC', 'Gene', (94, 97))	('SCC', 'Gene', (177, 180))	('mutations', 'Var', (26, 35))	('SCC', 'Phenotype', 'HP:0002860', (94, 97))	('SCC', 'Gene', '6317', (94, 97))	('SCC', 'Phenotype', 'HP:0002860', (177, 180))	('SCC', 'Gene', '6317', (177, 180))	('PIK3CA', 'Gene', (57, 63))
535465	29422544	Further experimental validation of the concurrent PIK3CA alteration and its biological roles will be required.	('PIK3CA', 'Gene', (50, 56))	('alteration', 'Var', (57, 67))	('PIK3CA', 'Gene', '5290', (50, 56))
535466	29422544	Additionally, 3 HPV (-) SCCs harbored nonsense or missense mutations of the tumor suppressor gene FAT1, while the other 3 HPV (-) SCCs harbored FAT1 copy losses.	('SCC', 'Gene', (130, 133))	('HPV', 'Species', '10566', (122, 125))	('missense mutations', 'Var', (50, 68))	('SCC', 'Phenotype', 'HP:0002860', (130, 133))	('SCC', 'Gene', (24, 27))	('SCC', 'Phenotype', 'HP:0002860', (24, 27))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('SCC', 'Gene', '6317', (130, 133))	('FAT1', 'Gene', '2195', (98, 102))	('HPV', 'Species', '10566', (16, 19))	('SCC', 'Gene', '6317', (24, 27))	('FAT1', 'Gene', '2195', (144, 148))	('FAT1', 'Gene', (98, 102))	('harbored', 'Reg', (29, 37))	('FAT1', 'Gene', (144, 148))	('nonsense', 'Var', (38, 46))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
535467	29422544	All of these events occurred in HPV (-) SCCs, suggesting that an alteration in FAT1 would be an HPV (-) SCC-specific event, although the sample scale was not sufficient to conclude this hypothesis.	('HPV', 'Species', '10566', (96, 99))	('SCC', 'Gene', '6317', (40, 43))	('SCC', 'Gene', (104, 107))	('SCC', 'Phenotype', 'HP:0002860', (104, 107))	('HPV', 'Species', '10566', (32, 35))	('SCC', 'Phenotype', 'HP:0002860', (40, 43))	('alteration', 'Var', (65, 75))	('SCC', 'Gene', '6317', (104, 107))	('SCC', 'Gene', (40, 43))	('FAT1', 'Gene', '2195', (79, 83))	('FAT1', 'Gene', (79, 83))
535468	29422544	Recurrent somatic mutations of FAT1 have been reported in multiple human cancers, including head/neck SCC, cervical adenocarcinoma and glioblastoma; they reported truncating mutations (p.R146M, p.W543X and p.E314X) in the cadherin and cytoplasmic domains of the FAT1 gene, the same locations as those reported in our study.	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('glioblastoma', 'Phenotype', 'HP:0012174', (135, 147))	('FAT1', 'Gene', (31, 35))	('p.W543X', 'Var', (194, 201))	('FAT1', 'Gene', '2195', (262, 266))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('cancers', 'Disease', (73, 80))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('SCC', 'Gene', (102, 105))	('FAT1', 'Gene', '2195', (31, 35))	('SCC', 'Phenotype', 'HP:0002860', (102, 105))	('p.R146M', 'Var', (185, 192))	('p.E314X', 'Var', (206, 213))	('cancers', 'Disease', 'MESH:D009369', (73, 80))	('p.E314X', 'Mutation', 'p.E314X', (206, 213))	('FAT1', 'Gene', (262, 266))	('SCC', 'Gene', '6317', (102, 105))	('truncating', 'MPA', (163, 173))	('cervical adenocarcinoma and glioblastoma', 'Disease', 'MESH:D005909', (107, 147))	('p.R146M', 'Mutation', 'p.R146M', (185, 192))	('p.W543X', 'Mutation', 'p.W543X', (194, 201))	('human', 'Species', '9606', (67, 72))
535469	29422544	In addition, FAT1 inactivation by somatic mutations activates Wnt signaling and promotes tumorigenesis.	('inactivation', 'Var', (18, 30))	('Wnt signaling', 'Pathway', (62, 75))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('FAT1', 'Gene', '2195', (13, 17))	('FAT1', 'Gene', (13, 17))	('promotes', 'PosReg', (80, 88))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))	('activates', 'PosReg', (52, 61))
535470	29422544	HPV (-) head/neck SCCs harbor frequent FAT1 mutations with loss of functions, which are significantly associated with better overall survival in HPV (-) patients but not in HPV (+) patients.	('HPV', 'Species', '10566', (0, 3))	('patients', 'Species', '9606', (153, 161))	('SCC', 'Gene', (18, 21))	('FAT1', 'Gene', '2195', (39, 43))	('HPV', 'Species', '10566', (145, 148))	('HPV', 'Species', '10566', (173, 176))	('SCC', 'Phenotype', 'HP:0002860', (18, 21))	('FAT1', 'Gene', (39, 43))	('SCC', 'Gene', '6317', (18, 21))	('patients', 'Species', '9606', (181, 189))	('mutations', 'Var', (44, 53))	('better', 'PosReg', (118, 124))	('loss of functions', 'NegReg', (59, 76))
535471	29422544	Based on our data, the clinical significance of FAT1 inactivation in vulvar SCCs should be further examined in future studies.	('SCC', 'Gene', (76, 79))	('SCC', 'Phenotype', 'HP:0002860', (76, 79))	('SCC', 'Gene', '6317', (76, 79))	('FAT1', 'Gene', '2195', (48, 52))	('inactivation', 'Var', (53, 65))	('FAT1', 'Gene', (48, 52))
535476	29422544	The overlapping but different profiles of driver mutations and CNAs between HPV (+) and HPV (-) SCCs suggest that vulvar SCC development may require genetic alterations specific to either HPV-dependent or HPV-independent lesions in addition to common genetic alterations of HPV-dependent and HPV-independent SCCs.	('HPV', 'Species', '10566', (292, 295))	('SCC', 'Gene', '6317', (308, 311))	('mutations', 'Var', (49, 58))	('SCC', 'Gene', (96, 99))	('SCC', 'Phenotype', 'HP:0002860', (96, 99))	('HPV', 'Species', '10566', (76, 79))	('SCC', 'Gene', (121, 124))	('HPV', 'Species', '10566', (205, 208))	('SCC', 'Phenotype', 'HP:0002860', (121, 124))	('SCC', 'Gene', '6317', (96, 99))	('HPV', 'Species', '10566', (274, 277))	('HPV', 'Species', '10566', (88, 91))	('SCC', 'Gene', '6317', (121, 124))	('HPV', 'Species', '10566', (188, 191))	('SCC', 'Gene', (308, 311))	('SCC', 'Phenotype', 'HP:0002860', (308, 311))
535488	27596597	As further applications of TCGA to big data, SSNs were used to predict individual driver mutations for various types of cancer solely based on gene expressions without DNA sequence information, classify cancer phenotypes and identify cancer subtypes by network biomarkers for accurate diagnosis and prediction of diseases in individuals, which all agrees well with the experimental data.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('cancer', 'Disease', (203, 209))	('cancer', 'Disease', 'MESH:D009369', (234, 240))	('cancer', 'Disease', 'MESH:D009369', (203, 209))	('mutations', 'Var', (89, 98))	('cancer', 'Disease', (234, 240))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))
535494	27596597	The NSCLC (non-small cell lung cancer) cell line PC9 expressing the EGFR (epidermal growth factor receptor) exon 19 deletion mutation was purchased from ATCC (Manassas, VA, USA) and was grown in RPMI 1640 medium Supplementary with 10% fetal bovine serum.	('non-small cell lung cancer', 'Disease', (11, 37))	('deletion mutation', 'Var', (116, 133))	('PC9', 'Gene', '255738', (49, 52))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (15, 37))	('NSCLC', 'Disease', 'MESH:D002289', (4, 9))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('PC9', 'Gene', (49, 52))	('epidermal growth factor receptor', 'Gene', '1956', (74, 106))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (11, 37))	('bovine', 'Species', '9913', (241, 247))	('EGFR', 'Gene', '1956', (68, 72))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (11, 37))	('RPMI 1640 medium', 'Chemical', '-', (195, 211))	('EGFR', 'Gene', (68, 72))	('epidermal growth factor receptor', 'Gene', (74, 106))	('lung cancer', 'Phenotype', 'HP:0100526', (26, 37))	('NSCLC', 'Disease', (4, 9))
535543	27596597	From the above analysis, the abnormal interactions of TP53 with VEGFA, IGFBP3 and MUC1 are considered to be potential factors contributing to kidney cancer.	('IGFBP3', 'Gene', '3486', (71, 77))	('contributing', 'Reg', (126, 138))	('kidney cancer', 'Disease', 'MESH:D007680', (142, 155))	('interactions', 'Interaction', (38, 50))	('kidney cancer', 'Phenotype', 'HP:0009726', (142, 155))	('VEGFA', 'Gene', '7422', (64, 69))	('MUC1', 'Gene', (82, 86))	('MUC1', 'Gene', '4582', (82, 86))	('IGFBP3', 'Gene', (71, 77))	('TP53', 'Gene', '7157', (54, 58))	('kidney cancer', 'Disease', (142, 155))	('abnormal', 'Var', (29, 37))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('TP53', 'Gene', (54, 58))	('VEGFA', 'Gene', (64, 69))
535546	27596597	Thus, we called the relationship between TP53 and VEGFA +-UU (Negative Correlation Increases due to X Upregulation and Y Upregulation, TP53 as Y) for samples KIRC_2444, KIRC_3362 and KIRC_5457, and +-*N (Negative Correlation Increases due to X Upregulation and Y No change, TP53 as Y) for sample KIRC_4807.	('TP53', 'Gene', '7157', (41, 45))	('TP53', 'Gene', (41, 45))	('Upregulation', 'PosReg', (244, 256))	('VEGFA', 'Gene', '7422', (50, 55))	('+-*N', 'Var', (198, 202))	('TP53', 'Gene', '7157', (135, 139))	('Upregulation', 'PosReg', (121, 133))	('TP53', 'Gene', '7157', (274, 278))	('TP53', 'Gene', (135, 139))	('VEGFA', 'Gene', (50, 55))	('TP53', 'Gene', (274, 278))	('Upregulation', 'PosReg', (102, 114))
535572	27596597	Hence, the abnormal regulation between TP53 and CDC25C may disrupt the regulation of CDC25C by TP53, and render the cell cycle and cell division out of control.	('render', 'Reg', (105, 111))	('CDC25C', 'Gene', (85, 91))	('cell division', 'CPA', (131, 144))	('disrupt', 'NegReg', (59, 66))	('abnormal', 'Var', (11, 19))	('CDC25C', 'Gene', (48, 54))	('TP53', 'Gene', (95, 99))	('CDC25C', 'Gene', '995', (85, 91))	('regulation', 'MPA', (71, 81))	('TP53', 'Gene', '7157', (39, 43))	('CDC25C', 'Gene', '995', (48, 54))	('TP53', 'Gene', '7157', (95, 99))	('cell cycle', 'CPA', (116, 126))	('TP53', 'Gene', (39, 43))
535611	27596597	A mutation driver is a mutation that can confer growth advantage to the cell and be positively selected on cancer occurrence.	('mutation', 'Var', (2, 10))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('cancer', 'Disease', (107, 113))	('growth advantage', 'CPA', (48, 64))
535618	27596597	The result shows that there is an obviously higher mutation ratio for these functional driver genes than random genes in cancer samples of TCGA.	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('higher', 'PosReg', (44, 50))	('mutation', 'Var', (51, 59))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('cancer', 'Disease', (121, 127))
535619	27596597	This result implies that the functional driver genes tend toward mutation or dysfunction in cancer samples.	('dysfunction', 'MPA', (77, 88))	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('mutation', 'Var', (65, 73))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
535629	27596597	Our data show that knockdown of these genes did not impact cell growth in both PC9 and PC9-DR cells (Supplementary Figure S12).	('PC9', 'Gene', '255738', (79, 82))	('PC9', 'Gene', '255738', (87, 90))	('PC9', 'Gene', (79, 82))	('knockdown', 'Var', (19, 28))	('PC9', 'Gene', (87, 90))
535630	27596597	However, 73% of these genes (11 out of 15) were identified as important regulators of drug resistance since knockdown of any one of these 11 genes significantly conferred the PC9-DR cells with sensitivity to gefitinib (Figure 7B and C).	('knockdown', 'Var', (108, 117))	('drug resistance', 'Phenotype', 'HP:0020174', (86, 101))	('gefitinib', 'Chemical', 'MESH:D000077156', (208, 217))	('sensitivity to gefitinib', 'MPA', (193, 217))	('conferred', 'Reg', (161, 170))
535648	27596597	For example, TP53 has no differential expression in samples A0HO and A0DP in breast cancer (Figure 3A), i.e.	('breast cancer', 'Disease', (77, 90))	('TP53', 'Gene', (13, 17))	('breast cancer', 'Phenotype', 'HP:0003002', (77, 90))	('expression', 'MPA', (38, 48))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('A0DP', 'Var', (69, 73))	('A0HO', 'Var', (60, 64))	('TP53', 'Gene', '7157', (13, 17))	('breast cancer', 'Disease', 'MESH:D001943', (77, 90))
535674	32085461	Among the main mechanisms used by mitochondria for the malignant transformation of cells, first, there is the production of ROS, which favors the accumulation of potential oncogenic defects in DNA, and the activation of probable oncogenic signaling pathways.	('favors', 'PosReg', (135, 141))	('ROS', 'Chemical', 'MESH:D017382', (124, 127))	('oncogenic signaling pathways', 'Pathway', (229, 257))	('accumulation', 'PosReg', (146, 158))	('ROS', 'Gene', (124, 127))	('activation', 'PosReg', (206, 216))	('defects', 'Var', (182, 189))
535681	32085461	HIG2A has a role in the respiratory supercomplexes assembly, a function that has been evidenced in the C2C12 mouse cell line, where the knockdown of Higd2a (nomenclature of mice gene) impaired supercomplex formation by the release of CIV.	('supercomplex formation', 'MPA', (193, 215))	('impaired', 'NegReg', (184, 192))	('Higd2a', 'Gene', (149, 155))	('rat', 'Species', '10116', (29, 32))	('knockdown', 'Var', (136, 145))	('mice', 'Species', '10090', (173, 177))	('release', 'MPA', (223, 230))	('CIV', 'MPA', (234, 237))	('respiratory supercomplexes assembly', 'MPA', (24, 59))	('mouse', 'Species', '10090', (109, 114))
535682	32085461	Recently, we showed that the knockdown of HIGD2A (nomenclature of a human gene) decreases the activity of Complex I in the supercomplexes of HEK293 cells.	('human', 'Species', '9606', (68, 73))	('knockdown', 'Var', (29, 38))	('decreases', 'NegReg', (80, 89))	('activity', 'MPA', (94, 102))	('Complex I', 'Enzyme', (106, 115))	('HIGD2A', 'Gene', (42, 48))	('decreases the activity of Complex I', 'Phenotype', 'HP:0011923', (80, 115))
535687	32085461	These studies evidenced several probable binding sites for different transcription factors related to cell cycle control, including E2F-1, E2F-2, E2F-3a, E2F-4, and E2F-5.	('E2F-4', 'Gene', '1874', (154, 159))	('E2F-4', 'Gene', (154, 159))	('E2F-5', 'Gene', (165, 170))	('binding', 'Interaction', (41, 48))	('E2F-3a', 'Var', (146, 152))	('E2F-5', 'Gene', '1875', (165, 170))	('E2F-1, E2F-2', 'Gene', '1869;1870', (132, 144))
535695	32085461	Depletion of HIGD2A selectively impairs the viability of colon adenocarcinoma cells (DLD1), which are Ras mutant cells, suggesting a role of HIG2A in cell cycle regulation and a potential target in cancer therapy.	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('viability', 'CPA', (44, 53))	('mutant', 'Var', (106, 112))	('cancer', 'Disease', (198, 204))	('HIGD2A', 'Gene', (13, 19))	('colon adenocarcinoma', 'Disease', (57, 77))	('carcinoma', 'Phenotype', 'HP:0030731', (68, 77))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('Depletion', 'MPA', (0, 9))	('colon adenocarcinoma', 'Disease', 'MESH:D003110', (57, 77))	('impairs', 'NegReg', (32, 39))
535700	32085461	The microarray Illumina Human HT-12 V4.0 expression bead chips were used in the study; "Role of hypoxia in Diffuse Large B-cell Lymphoma: Metabolic repression and selective translation of HK2 facilitates development of DLBCL".	('facilitates', 'PosReg', (192, 203))	('B-cell Lymphoma', 'Disease', 'MESH:D016393', (121, 136))	('Lymphoma', 'Phenotype', 'HP:0002665', (128, 136))	('B-cell Lymphoma', 'Disease', (121, 136))	('Human', 'Species', '9606', (24, 29))	('selective translation', 'Var', (163, 184))	('HK2', 'Gene', (188, 191))	('HK2', 'Gene', '3099', (188, 191))	('hypoxia', 'Disease', (96, 103))	('hypoxia', 'Disease', 'MESH:D000860', (96, 103))	('DLBCL', 'Disease', (219, 224))	('development', 'CPA', (204, 215))	('B-cell Lymphoma', 'Phenotype', 'HP:0012191', (121, 136))
535730	32085461	The Catalogue of Somatic Mutations in Cancer (COSMIC) Cancer Gene Census (CGC) database indicates that the HIGD2A gene (COSG58129) has been reported as having mutations in 29 unique samples out of a total of 35183 samples; therefore, HIGD2A is not a known cancer-driving gene.	('Cancer', 'Phenotype', 'HP:0002664', (54, 60))	('Cancer', 'Disease', (54, 60))	('cancer', 'Disease', 'MESH:D009369', (256, 262))	('mutations', 'Var', (159, 168))	('cancer', 'Disease', (256, 262))	('Cancer', 'Disease', 'MESH:D009369', (54, 60))	('Cancer', 'Disease', (38, 44))	('Cancer', 'Phenotype', 'HP:0002664', (38, 44))	('Cancer', 'Disease', 'MESH:D009369', (38, 44))	('cancer', 'Phenotype', 'HP:0002664', (256, 262))	('HIGD2A', 'Gene', (107, 113))
535732	32085461	On the other hand, DNA methylation is a vital epigenetic mechanism that stabilizes gene expression and cellular states; their alteration has a role in tumor initiation and evolution.	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumor initiation', 'Disease', (151, 167))	('methylation', 'Var', (23, 34))	('alteration', 'Var', (126, 136))	('role', 'Reg', (143, 147))	('rat', 'Species', '10116', (130, 133))	('stabilizes gene expression', 'MPA', (72, 98))	('tumor initiation', 'Disease', 'MESH:D009369', (151, 167))	('cellular states', 'MPA', (103, 118))
535757	32085461	The effect of HIGD2A high expression level on DLBCL patient survival illustrates a downward trend of survival probability in patients (n = 11) with high expression in relation with patients (n = 36) with low expression, p = 0.85 (Figure 8).	('HIGD2A', 'Gene', (14, 20))	('survival', 'MPA', (101, 109))	('patient', 'Species', '9606', (181, 188))	('rat', 'Species', '10116', (75, 78))	('downward', 'NegReg', (83, 91))	('patients', 'Species', '9606', (181, 189))	('patient', 'Species', '9606', (52, 59))	('patient', 'Species', '9606', (125, 132))	('high expression', 'Var', (148, 163))	('patients', 'Species', '9606', (125, 133))
535805	32085461	Roscovitine is an inhibitor of CDK that suppresses the proliferation of mammalian cells lines, and roscovitine induced a significant increase in HIGD2A gene expression in the human embryonic kidney HEK293 cell line.	('human', 'Species', '9606', (175, 180))	('embryonic kidney', 'Disease', (181, 197))	('mammalian', 'Species', '9606', (72, 81))	('expression', 'MPA', (157, 167))	('rat', 'Species', '10116', (62, 65))	('suppresses', 'NegReg', (40, 50))	('roscovitine', 'Var', (99, 110))	('embryonic kidney', 'Disease', 'MESH:D007674', (181, 197))	('increase', 'PosReg', (133, 141))	('HIGD2A gene', 'Gene', (145, 156))	('Roscovitine', 'Chemical', 'MESH:D000077546', (0, 11))	('roscovitine', 'Chemical', 'MESH:D000077546', (99, 110))
535827	31360073	Collectively, this summary strongly suggests that targeting aberrant YAP/TAZ activation is a promising strategy for the suppression of squamous cell carcinoma.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (135, 158))	('YAP/TAZ', 'Protein', (69, 76))	('rat', 'Species', '10116', (105, 108))	('carcinoma', 'Phenotype', 'HP:0030731', (149, 158))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (135, 158))	('squamous cell carcinoma', 'Disease', (135, 158))	('aberrant', 'Var', (60, 68))
535836	31360073	On the contrary, aberrantly high activity of YAP/TAZ promotes cell overgrowth and tumor formation.	('promotes', 'PosReg', (53, 61))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('activity', 'MPA', (33, 41))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('cell overgrowth', 'CPA', (62, 77))	('YAP/TAZ', 'Gene', (45, 52))	('tumor', 'Disease', (82, 87))	('aberrantly high', 'Var', (17, 32))	('overgrowth', 'Phenotype', 'HP:0001548', (67, 77))
535842	31360073	Upon inactivation of the Hippo pathway, dephosphorylated YAP/TAZ translocates to the nucleus and binds to the transcription factor TEAD to induce expression of the genes involved in cell proliferation, anti-apoptosis, and epithelial-mesenchymal cell transformation (Figure 1).	('Hippo', 'Gene', '37247', (25, 30))	('anti-apoptosis', 'CPA', (202, 216))	('rat', 'Species', '10116', (194, 197))	('cell proliferation', 'CPA', (182, 200))	('binds', 'Interaction', (97, 102))	('Hippo', 'Gene', (25, 30))	('epithelial-mesenchymal cell transformation', 'CPA', (222, 264))	('induce', 'PosReg', (139, 145))	('inactivation', 'Var', (5, 17))	('expression', 'MPA', (146, 156))
535855	31360073	A previous study demonstrated that the WW domain specifically recognizes the PpxY (P is proline, x is any amino acid and y is tyrosine) motifs, thereby controlling the localization and activity of YAP/TAZ.	('activity', 'MPA', (185, 193))	('controlling', 'Reg', (152, 163))	('localization', 'MPA', (168, 180))	('proline', 'Chemical', 'MESH:D011392', (88, 95))	('PpxY', 'Var', (77, 81))	('tyrosine', 'Chemical', 'MESH:D014443', (126, 134))	('rat', 'Species', '10116', (24, 27))
535860	31360073	On the contrary, mutant YAP gene knockout mice showed marked epidermis shrinkage and delayed wound healing.	('YAP', 'Gene', (24, 27))	('mice', 'Species', '10090', (42, 46))	('wound healing', 'CPA', (93, 106))	('delayed wound healing', 'Phenotype', 'HP:0001058', (85, 106))	('epidermis shrinkage', 'CPA', (61, 80))	('mutant', 'Var', (17, 23))	('delayed', 'NegReg', (85, 92))
535883	31360073	For melanoma, recent papers described high expression of TAZ/YAP promoted its progression associated with stimulation of low-density lipoprotein receptor-related protein 1 (LRP1) and affects the postoperative survival of patients.	('patients', 'Species', '9606', (221, 229))	('low-density lipoprotein receptor-related protein 1', 'Gene', '4035', (121, 171))	('LRP1', 'Gene', '4035', (173, 177))	('progression', 'CPA', (78, 89))	('TAZ/YAP', 'Gene', (57, 64))	('stimulation', 'PosReg', (106, 117))	('high expression', 'Var', (38, 53))	('postoperative survival', 'CPA', (195, 217))	('promoted', 'PosReg', (65, 73))	('melanoma', 'Phenotype', 'HP:0002861', (4, 12))	('LRP1', 'Gene', (173, 177))	('melanoma', 'Disease', 'MESH:D008545', (4, 12))	('rat', 'Species', '10116', (202, 205))	('affects', 'Reg', (183, 190))	('melanoma', 'Disease', (4, 12))	('low-density lipoprotein receptor-related protein 1', 'Gene', (121, 171))
535909	31360073	An experiment by Wang et al showed that the level of nuclear YAP/TAZ in fibroblasts associated with perineural invasion was higher than those in the stroma of normal mucosa, suggesting that the transcription programs mediated by YAP/TAZ in the fibroblasts may contribute to perineural invasion in HNSCC.	('SCC', 'Gene', (299, 302))	('contribute', 'Reg', (260, 270))	('YAP/TAZ', 'Var', (229, 236))	('SCC', 'Phenotype', 'HP:0002860', (299, 302))	('SCC', 'Gene', '6317', (299, 302))	('perineural invasion', 'CPA', (274, 293))	('HNSCC', 'Phenotype', 'HP:0012288', (297, 302))
535910	31360073	Interestingly, a recent study reported that upregulation of a circular RNA, circPVT1 together with TP53 mutation resulted in increased proliferation of HNSCC cell lines through the formation of mut-p53/YAP/TEAD complex.	('TP53', 'Gene', (99, 103))	('SCC', 'Gene', '6317', (154, 157))	('increased', 'PosReg', (125, 134))	('HNSCC', 'Phenotype', 'HP:0012288', (152, 157))	('proliferation', 'CPA', (135, 148))	('upregulation', 'PosReg', (44, 56))	('p53', 'Gene', (198, 201))	('mutation', 'Var', (104, 112))	('p53', 'Gene', '7157', (198, 201))	('TP53', 'Gene', '7157', (99, 103))	('SCC', 'Gene', (154, 157))	('SCC', 'Phenotype', 'HP:0002860', (154, 157))	('rat', 'Species', '10116', (142, 145))
535913	31360073	Recent research showed the expression level of YAP was higher in OSCC tissues than that in adjacent normal tissues and YAP could drive the transcription of bcl-2 and c-myc genes subsequently leading to OSCC cell proliferation and resistance to apoptosis.	('drive', 'PosReg', (129, 134))	('resistance to apoptosis', 'CPA', (230, 253))	('SCC', 'Gene', (66, 69))	('SCC', 'Gene', (203, 206))	('SCC', 'Phenotype', 'HP:0002860', (66, 69))	('leading to', 'Reg', (191, 201))	('c-myc', 'Gene', '4609', (166, 171))	('bcl-2', 'Gene', '596', (156, 161))	('c-myc', 'Gene', (166, 171))	('YAP', 'Var', (119, 122))	('SCC', 'Gene', '6317', (66, 69))	('SCC', 'Gene', '6317', (203, 206))	('SCC', 'Phenotype', 'HP:0002860', (203, 206))	('transcription', 'MPA', (139, 152))	('rat', 'Species', '10116', (219, 222))	('expression level', 'MPA', (27, 43))	('bcl-2', 'Gene', (156, 161))
535925	31360073	It was reported that viral GPCR inhibited the Hippo pathway kinases Lats1/2 through Gq/11 and G12/13, which resulted in the activation of YAP/TAZ.	('activation', 'PosReg', (124, 134))	('Hippo', 'Gene', '37247', (46, 51))	('GPCR', 'Gene', '10663', (27, 31))	('inhibited', 'NegReg', (32, 41))	('GPCR', 'Gene', (27, 31))	('Hippo', 'Gene', (46, 51))	('YAP/TAZ', 'Disease', (138, 145))	('Lats1/2', 'Enzyme', (68, 75))	('G12/13', 'Var', (94, 100))
535937	26899259	Preclinical studies have shown that inhibition of the interaction between PD-1 and PD-L1 enhances the T-cell response and mediates antitumor activity.	('T-cell response', 'CPA', (102, 117))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('inhibition', 'Var', (36, 46))	('tumor', 'Disease', (135, 140))	('enhances', 'PosReg', (89, 97))	('PD-L1', 'Gene', (83, 88))	('interaction', 'Interaction', (54, 65))	('PD-1', 'Gene', (74, 78))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
535939	26899259	In this review, we highlight recent clinical trials using anti-PD-1 or anti-PD-L1 antibodies against several types of malignancies, including a trial conducted in our department, and describe the clinical perspectives and issues regarding the PD-1/PD-L1 blockade in cancer treatment.	('cancer', 'Disease', 'MESH:D009369', (266, 272))	('men', 'Species', '9606', (278, 281))	('PD-1/PD-L1 blockade', 'Disease', (243, 262))	('cancer', 'Disease', (266, 272))	('anti-PD-1', 'Var', (58, 67))	('men', 'Species', '9606', (173, 176))	('malignancies', 'Disease', 'MESH:D009369', (118, 130))	('PD-1/PD-L1 blockade', 'Disease', 'MESH:D010300', (243, 262))	('anti-PD-L1', 'Var', (71, 81))	('cancer', 'Phenotype', 'HP:0002664', (266, 272))	('malignancies', 'Disease', (118, 130))
535944	26899259	Several preclinical reports also showed that inhibition of the interaction between PD-1 and PD-L1 enhances the T-cell response and mediates antitumor activity.	('tumor', 'Disease', (144, 149))	('PD-L1', 'Gene', (92, 97))	('enhances', 'PosReg', (98, 106))	('interaction', 'Interaction', (63, 74))	('PD-1', 'Gene', (83, 87))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('inhibition', 'Var', (45, 55))	('T-cell response', 'CPA', (111, 126))
535959	26899259	The first phase III trial with nivolumab as a first-line therapy was conducted in 418 treatment-free patients with metastatic melanoma lacking a mutation in BRAF.	('patients', 'Species', '9606', (101, 109))	('nivolumab', 'Chemical', 'MESH:D000077594', (31, 40))	('BRAF', 'Gene', '673', (157, 161))	('men', 'Species', '9606', (91, 94))	('BRAF', 'Gene', (157, 161))	('melanoma', 'Disease', 'MESH:D008545', (126, 134))	('melanoma', 'Phenotype', 'HP:0002861', (126, 134))	('lacking', 'NegReg', (135, 142))	('melanoma', 'Disease', (126, 134))	('mutation', 'Var', (145, 153))
535966	26899259	ORR was threefold higher in the nivolumab group than in the chemotherapy group (32 % vs. 11 %).	('nivolumab', 'Chemical', 'MESH:D000077594', (32, 41))	('ORR', 'MPA', (0, 3))	('RR', 'Chemical', '-', (1, 3))	('nivolumab', 'Var', (32, 41))	('higher', 'PosReg', (18, 24))
535967	26899259	In another randomized phase III trial, 834 patients were with advanced melanoma were divided equally among three groups: pembrolizumab every 2 weeks, pembrolizumab every 3 weeks, or ipilimumab every 3 weeks.	('pembrolizumab', 'Chemical', 'MESH:C582435', (121, 134))	('advanced melanoma', 'Disease', 'MESH:D008545', (62, 79))	('advanced melanoma', 'Disease', (62, 79))	('patients', 'Species', '9606', (43, 51))	('melanoma', 'Phenotype', 'HP:0002861', (71, 79))	('pembrolizumab', 'Var', (150, 163))	('pembrolizumab', 'Chemical', 'MESH:C582435', (150, 163))	('ipilimumab', 'Chemical', 'MESH:D000074324', (182, 192))
535969	26899259	In 2014, the U.S. Food and Drug Administration (FDA) approved nivolumab and pembrolizumab for the treatment of advanced melanoma (both are limited to be approved for melanoma refractory to ipilimumab and with BRAF inhibitors, if the tumor harbors a BRAF mutation).	('advanced melanoma', 'Disease', (111, 128))	('melanoma', 'Phenotype', 'HP:0002861', (120, 128))	('melanoma', 'Disease', (120, 128))	('melanoma', 'Phenotype', 'HP:0002861', (166, 174))	('melanoma', 'Disease', (166, 174))	('tumor', 'Disease', (233, 238))	('nivolumab', 'Chemical', 'MESH:D000077594', (62, 71))	('tumor', 'Disease', 'MESH:D009369', (233, 238))	('men', 'Species', '9606', (103, 106))	('mutation', 'Var', (254, 262))	('melanoma', 'Disease', 'MESH:D008545', (120, 128))	('BRAF', 'Gene', '673', (249, 253))	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('BRAF', 'Gene', (249, 253))	('ipilimumab', 'Chemical', 'MESH:D000074324', (189, 199))	('melanoma', 'Disease', 'MESH:D008545', (166, 174))	('pembrolizumab', 'Chemical', 'MESH:C582435', (76, 89))	('advanced melanoma', 'Disease', 'MESH:D008545', (111, 128))	('BRAF', 'Gene', (209, 213))	('BRAF', 'Gene', '673', (209, 213))
535973	26899259	Other anti-PD-L1 antibodies, atezolizumab and durvalumab, in ongoing phase I trials have also exhibited clinical activities in patients with NSCLC.	('durvalumab', 'Chemical', 'MESH:C000613593', (46, 56))	('NSCLC', 'Disease', (141, 146))	('patients', 'Species', '9606', (127, 135))	('NSCLC', 'Disease', 'MESH:D002289', (141, 146))	('NSCLC', 'Phenotype', 'HP:0030358', (141, 146))	('atezolizumab', 'Chemical', 'MESH:C000594389', (29, 41))	('anti-PD-L1', 'Var', (6, 16))
535994	26899259	The RR values of these antibodies and the sample sizes of the respective studies are as follows: BMS-936559, 12 % (n = 17) and atezolizumab, 14 % (n = 56) in patients with RCC.	('atezolizumab', 'Chemical', 'MESH:C000594389', (127, 139))	('RR', 'Chemical', '-', (4, 6))	('patients', 'Species', '9606', (158, 166))	('RCC', 'Phenotype', 'HP:0005584', (172, 175))	('RCC', 'Disease', 'MESH:C538614', (172, 175))	('RCC', 'Disease', (172, 175))	('BMS-936559', 'Var', (97, 107))
536000	26899259	Later, the interim results became available from two other phase Ib clinical trials with anti-PD-1 antibody and anti-PD-L1 antibody (avelumab).	('anti-PD-1', 'Var', (89, 98))	('anti-PD-L1', 'Var', (112, 122))	('avelumab', 'Chemical', 'MESH:C000609138', (133, 141))
536010	26899259	In a phase II clinical trial of pembrolizumab in 50 patients with colon cancer, RR was higher in the mismatch repair-deficient group (n = 25) than in the mismatch repair-proficient group (n = 25), 62 % versus 0 % (see "Clinical perspectives and issues of PD-1 inhibitors" for details).	('mismatch repair-deficient', 'Var', (101, 126))	('colon cancer', 'Disease', (66, 78))	('RR', 'Chemical', '-', (80, 82))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('pembrolizumab', 'Chemical', 'MESH:C582435', (32, 45))	('colon cancer', 'Phenotype', 'HP:0003003', (66, 78))	('colon cancer', 'Disease', 'MESH:D015179', (66, 78))	('patients', 'Species', '9606', (52, 60))	('higher', 'PosReg', (87, 93))
536022	26899259	Clinical trials of combination treatments incorporating PD-1 inhibitors with conventional chemotherapies, molecular targeted drugs such as PARP inhibitors (olaparib and cediranib) for solid tumors, or multi-kinase inhibitor (sunitinib) for RCC, focal radiation therapy, and cancer immunomodulators are now underway.	('cancer', 'Phenotype', 'HP:0002664', (274, 280))	('inhibitors', 'Var', (61, 71))	('cancer', 'Disease', 'MESH:D009369', (274, 280))	('solid tumors', 'Disease', 'MESH:D009369', (184, 196))	('cediranib', 'Chemical', 'MESH:C500926', (169, 178))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('cancer', 'Disease', (274, 280))	('sunitinib', 'Chemical', 'MESH:D000077210', (225, 234))	('men', 'Species', '9606', (36, 39))	('PARP', 'Gene', '1302', (139, 143))	('olaparib', 'Chemical', 'MESH:C531550', (156, 164))	('PD-1', 'Gene', (56, 60))	('tumors', 'Phenotype', 'HP:0002664', (190, 196))	('solid tumors', 'Disease', (184, 196))	('PARP', 'Gene', (139, 143))	('RCC', 'Disease', 'MESH:C538614', (240, 243))	('RCC', 'Disease', (240, 243))	('RCC', 'Phenotype', 'HP:0005584', (240, 243))
536029	26899259	Since the first clinical trial of nivolumab in 2010, several reports of clinical trials of PD-1 inhibitors have shown that the therapeutic efficacy of PD-1 inhibitors is modestly correlated with PD-L1 expression in tumors.	('inhibitors', 'Var', (156, 166))	('tumors', 'Disease', 'MESH:D009369', (215, 221))	('PD-1', 'Gene', (151, 155))	('nivolumab', 'Chemical', 'MESH:D000077594', (34, 43))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('expression', 'MPA', (201, 211))	('PD-L1', 'Protein', (195, 200))	('tumors', 'Phenotype', 'HP:0002664', (215, 221))	('tumors', 'Disease', (215, 221))
536043	26899259	In addition, recent progress in genomic analysis using next-generation sequencing techniques has enabled comprehensive detection of mutations in cancer tissue.	('cancer', 'Disease', (145, 151))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('mutations', 'Var', (132, 141))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))
536044	26899259	According to The Cancer Genome Atlas, which covers 7042 tumor samples from 30 cancer types, the frequency of somatic gene mutations is highest in melanoma, followed by lung squamous cell carcinoma, lung adenocarcinoma, bladder cancer, stomach cancer, and esophageal adenocarcinoma.	('cancer', 'Phenotype', 'HP:0002664', (243, 249))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (255, 280))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('carcinoma', 'Phenotype', 'HP:0030731', (208, 217))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (227, 233))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (198, 217))	('esophageal adenocarcinoma', 'Disease', (255, 280))	('stomach cancer', 'Disease', (235, 249))	('carcinoma', 'Phenotype', 'HP:0030731', (271, 280))	('melanoma', 'Disease', 'MESH:D008545', (146, 154))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (173, 196))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (168, 196))	('lung squamous cell carcinoma', 'Disease', (168, 196))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (198, 217))	('cancer', 'Disease', 'MESH:D009369', (243, 249))	('Cancer', 'Phenotype', 'HP:0002664', (17, 23))	('Cancer', 'Disease', (17, 23))	('tumor', 'Disease', (56, 61))	('cancer', 'Disease', (78, 84))	('stomach cancer', 'Disease', 'MESH:D013274', (235, 249))	('bladder cancer', 'Disease', 'MESH:D001749', (219, 233))	('cancer', 'Disease', (227, 233))	('stomach cancer', 'Phenotype', 'HP:0012126', (235, 249))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('bladder cancer', 'Disease', (219, 233))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('highest', 'Reg', (135, 142))	('melanoma', 'Phenotype', 'HP:0002861', (146, 154))	('melanoma', 'Disease', (146, 154))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('bladder cancer', 'Phenotype', 'HP:0009725', (219, 233))	('carcinoma', 'Phenotype', 'HP:0030731', (187, 196))	('cancer', 'Disease', (243, 249))	('Cancer', 'Disease', 'MESH:D009369', (17, 23))	('lung adenocarcinoma', 'Disease', (198, 217))	('mutations', 'Var', (122, 131))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (255, 280))
536046	26899259	In other words, cancer types with numerous mutations necessarily also express numerous mutant cancer antigens, and immunosuppression mediated by the PD-1 pathway occurs in the presence of numerous T cells that specifically recognize those mutant antigens.	('cancer', 'Disease', 'MESH:D009369', (16, 22))	('cancer', 'Disease', (16, 22))	('mutant', 'Var', (87, 93))	('mutations', 'Var', (43, 52))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('mutant', 'Var', (239, 245))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
536047	26899259	This position supports the findings of fundamental research using a mouse model that demonstrated the existence of mutant cancer antigen-specific T cells, as well as reactivation of these cells by anti-PD-1 antibodies and anti-CTLA-4 antibodies (CTLA-4 is a receptor for the same immunosuppressive signals as PD-1).	('mouse', 'Species', '10090', (68, 73))	('anti-CTLA-4', 'Var', (222, 233))	('reactivation', 'MPA', (166, 178))	('mutant', 'Var', (115, 121))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('men', 'Species', '9606', (44, 47))	('anti-PD-1', 'Var', (197, 206))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))
536054	26899259	The results revealed that when numerous non-synonymous mutations were present, there were correlations between response to treatment, durable clinical benefit (i.e., partial response or stable disease for at least 6 months), and recurrence-free survival rate.	('non-synonymous mutations', 'Var', (40, 64))	('men', 'Species', '9606', (128, 131))	('partial', 'NegReg', (166, 173))
536058	26899259	In addition, in a phase I study in which the anti-PD-L1 antibody MPDL3280A was administered to 20 subjects, 1 CRC patient with deletion of a mismatch repair (MMR) gene exhibited a partial response.	('CRC', 'Disease', (110, 113))	('CRC', 'Phenotype', 'HP:0003003', (110, 113))	('CRC', 'Disease', 'MESH:D015179', (110, 113))	('deletion', 'Var', (127, 135))	('patient', 'Species', '9606', (114, 121))	('MMR', 'Gene', (158, 161))
536059	26899259	Therefore, the anti-PD-1 antibody pembrolizumab was administered to three cohorts, A, B, and C, respectively, comprising 25 CRC patients with MMR deletion, 25 CRC patients with normal MMR, and 21 patients with cancers other than CRC with MMR deletion.	('CRC', 'Disease', (124, 127))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('CRC', 'Phenotype', 'HP:0003003', (124, 127))	('patients', 'Species', '9606', (196, 204))	('CRC', 'Disease', 'MESH:D015179', (229, 232))	('CRC', 'Disease', 'MESH:D015179', (124, 127))	('cancers', 'Disease', 'MESH:D009369', (210, 217))	('CRC', 'Disease', (159, 162))	('patients', 'Species', '9606', (163, 171))	('CRC', 'Phenotype', 'HP:0003003', (159, 162))	('patients', 'Species', '9606', (128, 136))	('deletion', 'Var', (146, 154))	('CRC', 'Disease', (229, 232))	('CRC', 'Disease', 'MESH:D015179', (159, 162))	('cancers', 'Phenotype', 'HP:0002664', (210, 217))	('CRC', 'Phenotype', 'HP:0003003', (229, 232))	('pembrolizumab', 'Chemical', 'MESH:C582435', (34, 47))	('cancers', 'Disease', (210, 217))	('MMR', 'Gene', (142, 145))
536060	26899259	The therapeutic efficacy was very high in the CRC patients with MMR deletion, with a response rate of 62 % and a disease-control rate of 92 %.	('patients', 'Species', '9606', (50, 58))	('CRC', 'Disease', (46, 49))	('deletion', 'Var', (68, 76))	('MMR', 'Gene', (64, 67))	('CRC', 'Disease', 'MESH:D015179', (46, 49))	('CRC', 'Phenotype', 'HP:0003003', (46, 49))
536062	26899259	Furthermore, in the subjects with non-CRC cancers with MMR deletions, the response rate and disease-control rate were 60 % and 70 %, respectively, suggesting the possibility that MMR deletion is a predictive factor for the therapeutic efficacy of anti-PD-1 antibody, pembrolizumab.	('cancers', 'Disease', (42, 49))	('cancers', 'Disease', 'MESH:D009369', (42, 49))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('CRC', 'Phenotype', 'HP:0003003', (38, 41))	('deletions', 'Var', (59, 68))	('CRC', 'Disease', 'MESH:D015179', (38, 41))	('pembrolizumab', 'Chemical', 'MESH:C582435', (267, 280))	('cancers', 'Phenotype', 'HP:0002664', (42, 49))	('MMR', 'Gene', (179, 182))	('CRC', 'Disease', (38, 41))	('deletion', 'Var', (183, 191))	('MMR', 'Gene', (55, 58))
536063	26899259	In the manner already described, a search for biomarkers was recently carried out via comprehensive mutation analysis of the cancer genome using next-generation sequencing technology.	('cancer', 'Disease', (125, 131))	('mutation', 'Var', (100, 108))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))
536067	26899259	For example, it will be important to determine whether it is necessary to use combinations of biomarkers such as PD-L1+ tumor cells, PD-L1+ and PD-1+ tumor-infiltrating lymphocytes, frequencies of neo-antigens and tumor mutations, and the diversity of the T-cell repertoire.	('PD-L1+', 'Var', (133, 139))	('tumor', 'Disease', 'MESH:D009369', (214, 219))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('tumor', 'Disease', (214, 219))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('tumor', 'Disease', (150, 155))	('tumor', 'Disease', (120, 125))
536069	26899259	Common drug-related adverse events (AEs) of both anti-PD-1 and anti-PD-L1 antibodies include fatigue, rash, diarrhea, pruritus, decreased appetite, arthralgia, and nausea.	('rash', 'Disease', 'MESH:D005076', (102, 106))	('pruritus', 'Phenotype', 'HP:0000989', (118, 126))	('nausea', 'Disease', 'MESH:D009325', (164, 170))	('diarrhea', 'Disease', (108, 116))	('pruritus', 'Disease', 'MESH:D011537', (118, 126))	('pruritus', 'Disease', (118, 126))	('arthralgia', 'Phenotype', 'HP:0002829', (148, 158))	('arthralgia', 'Disease', 'MESH:D018771', (148, 158))	('AEs', 'Chemical', '-', (36, 39))	('antibodies', 'Var', (74, 84))	('fatigue', 'Disease', (93, 100))	('diarrhea', 'Disease', 'MESH:D003967', (108, 116))	('arthralgia', 'Disease', (148, 158))	('fatigue', 'Phenotype', 'HP:0012378', (93, 100))	('decreased', 'NegReg', (128, 137))	('nausea', 'Phenotype', 'HP:0002018', (164, 170))	('anti-PD-L1', 'Gene', (63, 73))	('anti-PD-1', 'Gene', (49, 58))	('rash', 'Phenotype', 'HP:0000988', (102, 106))	('fatigue', 'Disease', 'MESH:D005221', (93, 100))	('nausea', 'Disease', (164, 170))	('diarrhea', 'Phenotype', 'HP:0002014', (108, 116))	('decreased appetite', 'Phenotype', 'HP:0004396', (128, 146))	('rash', 'Disease', (102, 106))	('appetite', 'Disease', (138, 146))
536087	26899259	In addition, on the basis of reports of clinical findings obtained using PD-1 inhibitors, longstanding theories regarding cancer immune surveillance and cancer immunoediting, including the mechanism of cancer immune escape, have recently been confirmed by fundamental research on tumor immunology.	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('men', 'Species', '9606', (261, 264))	('cancer', 'Disease', (153, 159))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('inhibitors', 'Var', (78, 88))	('tumor', 'Disease', 'MESH:D009369', (280, 285))	('PD-1', 'Gene', (73, 77))	('cancer', 'Disease', 'MESH:D009369', (202, 208))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('tumor', 'Phenotype', 'HP:0002664', (280, 285))	('cancer', 'Disease', (202, 208))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('tumor', 'Disease', (280, 285))
536103	33287350	Our finding suggests a potential prognostic significance of PTEN loss and PIK3CA amplification in OSCC.	('PTEN loss', 'Disease', (60, 69))	('PIK3CA', 'Gene', '5290', (74, 80))	('OSCC', 'Disease', (98, 102))	('amplification', 'Var', (81, 94))	('PTEN loss', 'Disease', 'MESH:D006223', (60, 69))	('PIK3CA', 'Gene', (74, 80))
536121	33287350	After ligand binding (growth factors, cytokines, hormones), the receptor undergoes autophosphorylation which results in PI3K transposition into cell membrane by the receptor phosphotyrosine residues.	('results in', 'Reg', (109, 119))	('PI3K', 'Var', (120, 124))	('phosphotyrosine', 'Chemical', 'MESH:D019000', (174, 189))
536128	33287350	Gene activation in head and neck, lung, breast, colon, ovary, or cervix cancers may lead to neoplastic transformation, usually as a result of H1047R (exon 20), E542K, and E545K (exon 9) point mutations or gene amplifications.	('H1047R', 'Var', (142, 148))	('lung', 'Disease', (34, 38))	('neoplastic transformation', 'Disease', 'MESH:D002471', (92, 117))	('E542K', 'Var', (160, 165))	('activation', 'PosReg', (5, 15))	('H1047R', 'Mutation', 'rs121913279', (142, 148))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('cervix cancers', 'Disease', (65, 79))	('E545K', 'Mutation', 'rs104886003', (171, 176))	('lead to', 'Reg', (84, 91))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('cervix cancers', 'Phenotype', 'HP:0030079', (65, 79))	('E545K', 'Var', (171, 176))	('ovary', 'Disease', (55, 60))	('colon', 'Disease', (48, 53))	('ovary', 'Disease', 'MESH:D010051', (55, 60))	('neoplastic transformation', 'Disease', (92, 117))	('cervix cancers', 'Disease', 'MESH:D002583', (65, 79))	('breast', 'Disease', (40, 46))	('E542K', 'Mutation', 'rs121913273', (160, 165))
536129	33287350	As for the PTEN gene, its inactivation by deletions and missense point mutation frequently observed in prostate, breast, lung, endometrial and colorectal cancer is responsible for unstable cell proliferation.	('breast', 'Disease', (113, 119))	('PTEN', 'Gene', (11, 15))	('PTEN', 'Gene', '5728', (11, 15))	('endometrial', 'Disease', 'MESH:D014591', (127, 138))	('observed', 'Reg', (91, 99))	('colorectal cancer', 'Disease', (143, 160))	('lung', 'Disease', (121, 125))	('unstable cell proliferation', 'Phenotype', 'HP:0031377', (180, 207))	('missense point mutation', 'Var', (56, 79))	('deletions', 'Var', (42, 51))	('endometrial', 'Disease', (127, 138))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('colorectal cancer', 'Disease', 'MESH:D015179', (143, 160))	('inactivation', 'MPA', (26, 38))	('prostate', 'Disease', (103, 111))	('colorectal cancer', 'Phenotype', 'HP:0003003', (143, 160))
536130	33287350	Many studies of aberrations and mutations in PI3K in other tumors were described, but the literature documenting PIK3CA and PTEN genetic aberrations in OSCCs is limited.	('PTEN', 'Gene', (124, 128))	('PIK3CA', 'Gene', (113, 119))	('PTEN', 'Gene', '5728', (124, 128))	('PIK3CA', 'Gene', '5290', (113, 119))	('men', 'Species', '9606', (105, 108))	('tumors', 'Disease', (59, 65))	('tumors', 'Disease', 'MESH:D009369', (59, 65))	('mutations', 'Var', (32, 41))	('tumors', 'Phenotype', 'HP:0002664', (59, 65))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
536133	33287350	Survival rate was lower in patients with CDK1 positive expression when compared with CDK1 negative cases.	('positive expression', 'Var', (46, 65))	('lower', 'NegReg', (18, 23))	('CDK1', 'Gene', (85, 89))	('CDK1', 'Gene', '983', (85, 89))	('CDK1', 'Gene', '983', (41, 45))	('patients', 'Species', '9606', (27, 35))	('CDK1', 'Gene', (41, 45))	('Survival rate', 'CPA', (0, 13))
536136	33287350	PIK3CA point gene mutations were identified in 0% to 13.92% of patients, according to different studies, and PTEN deletion was found in 5% of cases.	('mutations', 'Var', (18, 27))	('PTEN', 'Gene', (109, 113))	('PIK3CA', 'Gene', (0, 6))	('PTEN', 'Gene', '5728', (109, 113))	('PIK3CA', 'Gene', '5290', (0, 6))	('patients', 'Species', '9606', (63, 71))	('deletion', 'Var', (114, 122))
536137	33287350	PIK3CA gene amplification has been described in 9% to 50% of OSCC patients.	('amplification', 'Var', (12, 25))	('PIK3CA', 'Gene', (0, 6))	('PIK3CA', 'Gene', '5290', (0, 6))	('OSCC', 'Disease', (61, 65))	('patients', 'Species', '9606', (66, 74))
536140	33287350	Up to date, some studies have shown that inhibitors of PI3K/AKT/PTEN pathway can support treatment in recurrent and metastatic oral or head and neck cancers.	('head and neck cancers', 'Phenotype', 'HP:0012288', (135, 156))	('recurrent', 'Disease', (102, 111))	('neck cancers', 'Disease', (144, 156))	('head and neck cancer', 'Disease', 'MESH:D006258', (135, 155))	('PTEN', 'Gene', '5728', (64, 68))	('men', 'Species', '9606', (94, 97))	('AKT', 'Gene', '207', (60, 63))	('neck cancers', 'Disease', 'MESH:D006258', (144, 156))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('inhibitors', 'Var', (41, 51))	('head and neck cancer', 'Phenotype', 'HP:0012288', (135, 155))	('PTEN', 'Gene', (64, 68))	('AKT', 'Gene', (60, 63))	('cancers', 'Phenotype', 'HP:0002664', (149, 156))
536184	33287350	It has been demonstrated that PIK3CA gene amplification was more common in tumors located in the lower gingiva compared to other locations (p = 0.040).	('PIK3CA', 'Gene', (30, 36))	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('common', 'Reg', (65, 71))	('PIK3CA', 'Gene', '5290', (30, 36))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('amplification', 'Var', (42, 55))	('tumors', 'Disease', (75, 81))	('tumors located in the lower gingiva', 'Phenotype', 'HP:0009094', (75, 110))
536188	33287350	In contrast, the presence of amplification and location of the tumor in the lower gingiva resulted in an almost six-fold increase in the risk of shortening the survival rate (HR = 5.783; 95% CI = 0.054-3.456; p = 0.037) (Table 3).	('tumor', 'Disease', (63, 68))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('amplification', 'Var', (29, 42))	('increase', 'PosReg', (121, 129))	('shortening', 'NegReg', (145, 155))	('tumor in the lower gingiva', 'Phenotype', 'HP:0009094', (63, 89))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('presence', 'Var', (17, 25))	('survival rate', 'CPA', (160, 173))
536237	33287350	In existing oral cancer studies, an increase in the frequency of PIK3CA gene amplification has been reported in 16.70% to 100% of patients.	('increase', 'PosReg', (36, 44))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('amplification', 'Var', (77, 90))	('PIK3CA', 'Gene', (65, 71))	('patients', 'Species', '9606', (130, 138))	('cancer', 'Disease', (17, 23))	('PIK3CA', 'Gene', '5290', (65, 71))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
536243	33287350	PIK3CA gene amplification was more common in tumors located in the lower gingiva compared to other locations.	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('common', 'Reg', (35, 41))	('tumors', 'Disease', (45, 51))	('tumors', 'Phenotype', 'HP:0002664', (45, 51))	('tumors located in the lower gingiva', 'Phenotype', 'HP:0009094', (45, 80))	('amplification', 'Var', (12, 25))	('PIK3CA', 'Gene', (0, 6))	('tumors', 'Disease', 'MESH:D009369', (45, 51))	('PIK3CA', 'Gene', '5290', (0, 6))
536245	33287350	Amplification was correlated with the stage of cancer (stage III/IV vs. I/II) and metastases to local lymph nodes.	('correlated', 'Reg', (18, 28))	('Amplification', 'Var', (0, 13))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('cancer', 'Disease', (47, 53))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('metastases', 'Disease', (82, 92))	('metastases', 'Disease', 'MESH:D009362', (82, 92))
536248	33287350	In the multivariate Cox proportional risk regression model, the copy number of the PIK3CA gene, the PIK3CA/CEP3 ratio, and clinical-pathological factors were not prognostic factors for survival.	('Cox', 'Gene', '1351', (20, 23))	('Cox', 'Gene', (20, 23))	('copy number', 'Var', (64, 75))	('PIK3CA', 'Gene', (100, 106))	('CEP3', 'Gene', '10602', (107, 111))	('CEP3', 'Gene', (107, 111))	('PIK3CA', 'Gene', (83, 89))	('PIK3CA', 'Gene', '5290', (83, 89))	('PIK3CA', 'Gene', '5290', (100, 106))
536249	33287350	In contrast, the presence of amplification and tumor location in the lower gingiva resulted in an almost six-fold increase in the risk of shortening overall survival.	('amplification', 'Var', (29, 42))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('shortening overall survival', 'MPA', (138, 165))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('presence', 'Var', (17, 25))	('tumor', 'Disease', (47, 52))
536251	33287350	Prognostic value of PIK3CA mutation has been observed for a number of tumors, particularly for breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('breast cancer', 'Disease', (95, 108))	('breast cancer', 'Phenotype', 'HP:0003002', (95, 108))	('PIK3CA', 'Gene', (20, 26))	('PIK3CA', 'Gene', '5290', (20, 26))	('tumors', 'Disease', (70, 76))	('mutation', 'Var', (27, 35))	('tumors', 'Disease', 'MESH:D009369', (70, 76))	('tumors', 'Phenotype', 'HP:0002664', (70, 76))	('breast cancer', 'Disease', 'MESH:D001943', (95, 108))
536252	33287350	For example, the identification of the PIK3CA gene mutation makes it possible to identify a special group of patients (PIK3CA-positive breast cancer) who receive the greatest benefit from molecular-targeted anti-PI3K therapy.	('PIK3CA', 'Gene', '5290', (39, 45))	('PIK3CA', 'Gene', (119, 125))	('patients', 'Species', '9606', (109, 117))	('PIK3CA', 'Gene', '5290', (119, 125))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('mutation', 'Var', (51, 59))	('breast cancer', 'Disease', 'MESH:D001943', (135, 148))	('breast cancer', 'Disease', (135, 148))	('PIK3CA', 'Gene', (39, 45))	('breast cancer', 'Phenotype', 'HP:0003002', (135, 148))
536255	33287350	On the other hand, PIK3CA protein expression was correlated with PIK3CA gene amplification in lung and colorectal cancer.	('correlated', 'Reg', (49, 59))	('PIK3CA', 'Gene', (19, 25))	('colorectal cancer', 'Disease', 'MESH:D015179', (103, 120))	('expression', 'MPA', (34, 44))	('PIK3CA', 'Gene', '5290', (19, 25))	('colorectal cancer', 'Phenotype', 'HP:0003003', (103, 120))	('lung', 'Disease', (94, 98))	('amplification', 'Var', (77, 90))	('PIK3CA', 'Gene', (65, 71))	('colorectal cancer', 'Disease', (103, 120))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('protein', 'Protein', (26, 33))	('PIK3CA', 'Gene', '5290', (65, 71))
536297	33287350	Our data suggest that the loss of PTEN protein may act as a prognostic factor for overall survival.	('PTEN', 'Gene', (34, 38))	('protein', 'Protein', (39, 46))	('loss', 'Var', (26, 30))	('overall survival', 'CPA', (82, 98))	('PTEN', 'Gene', '5728', (34, 38))
536298	33287350	The presence of amplification in tumors located in the lower gingiva resulted in an almost six-fold increase in the risk of shortening survival.	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('amplification', 'Var', (16, 29))	('shortening survival', 'MPA', (124, 143))	('tumors', 'Disease', 'MESH:D009369', (33, 39))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('tumors located in the lower gingiva', 'Phenotype', 'HP:0009094', (33, 68))	('tumors', 'Disease', (33, 39))
536312	32164050	We demonstrate that CARD9 is an independent prognostic factor in NSCLC patients and inhibits proliferation, migration, and invasion by suppressing MAPK/p38 pathway in NSCLC cells.	('NSCLC', 'Disease', 'MESH:D002289', (167, 172))	('MAPK/p38', 'Gene', '1432', (147, 155))	('NSCLC', 'Phenotype', 'HP:0030358', (167, 172))	('proliferation', 'CPA', (93, 106))	('invasion', 'CPA', (123, 131))	('patients', 'Species', '9606', (71, 79))	('NSCLC', 'Disease', 'MESH:D002289', (65, 70))	('MAPK/p38', 'Gene', (147, 155))	('CARD9', 'Var', (20, 25))	('NSCLC', 'Phenotype', 'HP:0030358', (65, 70))	('inhibits', 'NegReg', (84, 92))	('NSCLC', 'Disease', (167, 172))	('NSCLC', 'Disease', (65, 70))	('suppressing', 'NegReg', (135, 146))
536318	32164050	Recently, abnormal expression of CARD9 has been reported in various types of malignant diseases.	('CARD9', 'Gene', (33, 38))	('expression', 'MPA', (19, 29))	('malignant diseases', 'Disease', 'MESH:D009369', (77, 95))	('abnormal', 'Var', (10, 18))	('reported', 'Reg', (48, 56))	('malignant diseases', 'Disease', (77, 95))
536320	32164050	CARD9 can promote tumorigenesis of large intestines in the male APCmin mice, which mimics the genetic lesions associated with human familial adenomatous polyposis.	('mice', 'Species', '10090', (71, 75))	('human', 'Species', '9606', (126, 131))	('adenomatous polyposis', 'Phenotype', 'HP:0005227', (141, 162))	('tumor', 'Disease', (18, 23))	('CARD9', 'Var', (0, 5))	('familial adenomatous polyposis', 'Disease', (132, 162))	('promote', 'PosReg', (10, 17))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('familial adenomatous polyposis', 'Disease', 'MESH:D011125', (132, 162))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
536326	32164050	reported that CARD9 suppressed lung cancer development by inhibiting the expansion of myeloid-derived suppressor cells (MDSCs) and indoleamine 2,3-dioxygenase (IDO) production.	('lung cancer', 'Disease', 'MESH:D008175', (31, 42))	('IDO', 'Gene', (160, 163))	('indoleamine 2,3-dioxygenase', 'Gene', '3620', (131, 158))	('suppressed', 'NegReg', (20, 30))	('lung cancer', 'Disease', (31, 42))	('inhibiting', 'NegReg', (58, 68))	('lung cancer', 'Phenotype', 'HP:0100526', (31, 42))	('CARD9', 'Var', (14, 19))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('expansion', 'CPA', (73, 82))	('IDO', 'Gene', '3620', (160, 163))
536331	32164050	By generating CARD9-overexpressing and CARD9-knockdown NSCLC cell lines in vitro, we observed that CARD9 could promote cell apoptosis and inhibit cell cycle progression, invasion, migration via mitogen-activated protein kinases (MAPK)/p38 signaling pathway.	('p38', 'Gene', '1432', (235, 238))	('NSCLC', 'Disease', (55, 60))	('cell apoptosis', 'CPA', (119, 133))	('migration', 'CPA', (180, 189))	('CARD9', 'Var', (99, 104))	('cell cycle progression', 'CPA', (146, 168))	('NSCLC', 'Disease', 'MESH:D002289', (55, 60))	('p38', 'Gene', (235, 238))	('NSCLC', 'Phenotype', 'HP:0030358', (55, 60))	('inhibit', 'NegReg', (138, 145))	('invasion', 'CPA', (170, 178))	('promote', 'PosReg', (111, 118))
536379	32164050	Cell lysates from successfully transfected H1299 cells or PC9 cells were collected and immunoprecipitated with either 5 mug anti-CARD9 antibody (Santa Cruz Biotechnology, Santa Cruz, CA) or 1 mug anti-mouse IgG antibody (Beyotime) at 4C overnight.	('PC9', 'Gene', (58, 61))	('IgG antibody', 'Phenotype', 'HP:0003237', (207, 219))	('anti-CARD9', 'Var', (124, 134))	('mouse', 'Species', '10090', (201, 206))	('PC9', 'Gene', '255738', (58, 61))
536392	32164050	Based on TCGA datasets, the level of CARD9 in LUAD was negatively associated with TNM stage, tumor size, lymph node metastasis, and remote metastasis (Table 1).	('TNM', 'Gene', '10178', (82, 85))	('remote metastasis', 'CPA', (132, 149))	('CARD9', 'Var', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('negatively', 'NegReg', (55, 65))	('lymph node metastasis', 'CPA', (105, 126))	('TNM', 'Gene', (82, 85))	('tumor', 'Disease', (93, 98))	('LUAD', 'Phenotype', 'HP:0030078', (46, 50))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
536393	32164050	Consistent with this, patients with higher expression of CARD9 in LUAD had better OS than patients with lower expression of CARD9 (hazard ratio [HR], 0.710; p=0.023) (Fig.	('better', 'PosReg', (75, 81))	('CARD9', 'Var', (57, 62))	('LUAD', 'Phenotype', 'HP:0030078', (66, 70))	('patients', 'Species', '9606', (22, 30))	('patients', 'Species', '9606', (90, 98))
536399	32164050	Logistic regression analysis showed that the high expression of CARD9 was an independent protective factor for OS (odds ratio [OR], 0.127; p=0.022) and PFS (OR, 0.126; p=0.004), excluding confounding factors of age, sex, smocking status, and TNM stage.	('TNM', 'Gene', (242, 245))	('PFS', 'Disease', (152, 155))	('CARD9', 'Gene', (64, 69))	('TNM', 'Gene', '10178', (242, 245))	('high expression', 'Var', (45, 60))
536407	32164050	Since H1299 was relatively scarce in CARD9 production compared with THP-1 and PC9, H1299 shCARD9 was not generated.	('PC9', 'Gene', (78, 81))	('THP-1', 'Gene', '2736', (68, 73))	('THP-1', 'Gene', (68, 73))	('H1299', 'Var', (6, 11))	('CARD9 production', 'MPA', (37, 53))	('PC9', 'Gene', '255738', (78, 81))
536408	32164050	Wounding healing showed the migratory ability of H1299 and PC9 was inhibited by ectopic CARD9 (p=0.002 and p=0.007, respectively) (Fig.	('PC9', 'Gene', '255738', (59, 62))	('inhibited', 'NegReg', (67, 76))	('PC9', 'Gene', (59, 62))	('ectopic CARD9', 'Var', (80, 93))	('migratory ability', 'CPA', (28, 45))
536410	32164050	Meanwhile, in the matrigel invasion assays, CARD9 was found to block invasiveness capability of H1299 and PC9 (p=0.002 and p=0.010, respectively) (Fig.	('PC9', 'Gene', '255738', (106, 109))	('matrigel invasion assays', 'CPA', (18, 42))	('PC9', 'Gene', (106, 109))	('CARD9', 'Var', (44, 49))	('invasiveness capability', 'CPA', (69, 92))	('block', 'NegReg', (63, 68))
536414	32164050	Cell growth curve assays showed CARD9-overexpressing H1299 and PC9 had suppressed growth, and CARD9-knockdown PC9 had promoted growth (p < 0.001) (Fig.	('PC9', 'Gene', '255738', (63, 66))	('growth', 'CPA', (127, 133))	('H1299', 'Var', (53, 58))	('PC9', 'Gene', '255738', (110, 113))	('PC9', 'Gene', (63, 66))	('PC9', 'Gene', (110, 113))	('promoted', 'PosReg', (118, 126))	('growth', 'CPA', (82, 88))	('suppressed', 'NegReg', (71, 81))
536417	32164050	Ectopic expression of CARD9 in H1299 significantly induced G0/G1 arrest, exhibiting increased G0 to G1 phase cells (p=0.008) (Fig.	('G0 to G1 phase cells', 'CPA', (94, 114))	('CARD9', 'Gene', (22, 27))	('induced', 'PosReg', (51, 58))	('increased', 'PosReg', (84, 93))	('H1299', 'Var', (31, 36))	('G1 arrest', 'Disease', (62, 71))	('G1 arrest', 'Disease', 'MESH:D006323', (62, 71))
536419	32164050	On the other hand, knockdown of CARD9 in PC9 cells presented decreased population of G0 to G1-phase (p < 0.001) (Fig.	('PC9', 'Gene', (41, 44))	('CARD9', 'Gene', (32, 37))	('knockdown', 'Var', (19, 28))	('decreased', 'NegReg', (61, 70))	('PC9', 'Gene', '255738', (41, 44))
536421	32164050	In addition, by examining apoptosis by flow cytometry, we found that CARD9 could lead to more late apoptosis in H1299 and PC9 cells (p < 0.001 and p < 0.001, respectively) (Fig.	('PC9', 'Gene', (122, 125))	('late apoptosis', 'CPA', (94, 108))	('PC9', 'Gene', '255738', (122, 125))	('CARD9', 'Var', (69, 74))
536422	32164050	Taken together, CARD9 could impede NSCLC cell proliferation but enhance apoptosis in vitro.	('enhance', 'PosReg', (64, 71))	('NSCLC', 'Disease', (35, 40))	('CARD9', 'Var', (16, 21))	('NSCLC', 'Disease', 'MESH:D002289', (35, 40))	('apoptosis', 'CPA', (72, 81))	('impede', 'NegReg', (28, 34))	('NSCLC', 'Phenotype', 'HP:0030358', (35, 40))
536423	32164050	Previous studies had found that in anti-infection immunity, CARD9 recruited BCL10 and mucosa-associated lymphoid tissue 1 (MALT1) to form CBM (CARD9-BCL10-MALT1) complex, activating downstream such as nuclear factor kappaB (NF-kappaB) and MAPK signaling.	('activating', 'PosReg', (171, 181))	('infection', 'Disease', (40, 49))	('MALT1', 'Gene', (123, 128))	('infection', 'Disease', 'MESH:D007239', (40, 49))	('MALT1', 'Gene', '10892', (123, 128))	('NF-kappaB', 'Gene', '4790', (224, 233))	('MALT1', 'Gene', '10892', (155, 160))	('MALT1', 'Gene', (155, 160))	('CARD9', 'Var', (60, 65))	('nuclear factor kappaB', 'Pathway', (201, 222))	('NF-kappaB', 'Gene', (224, 233))	('MAPK signaling', 'Pathway', (239, 253))	('mucosa-associated lymphoid tissue 1', 'Gene', '10892', (86, 121))	('mucosa-associated lymphoid tissue 1', 'Gene', (86, 121))
536433	32164050	The cell growth curve assays showed a dramatical impeded growth in SB203580-treated PC9 shCARD9 cells (p < 0.001) (Fig.	('SB203580', 'Chemical', 'MESH:C093642', (67, 75))	('growth', 'MPA', (57, 63))	('PC9 shCARD9', 'Gene', (84, 95))	('SB203580-treated', 'Var', (67, 83))	('PC9 shCARD9', 'Gene', '255738;64170', (84, 95))	('impeded', 'NegReg', (49, 56))
536434	32164050	6B) while the growth of PC9 shControl cells was unaffected by SB203580 (Fig.	('SB203580', 'Var', (62, 70))	('PC9', 'Gene', (24, 27))	('PC9', 'Gene', '255738', (24, 27))	('SB203580', 'Chemical', 'MESH:C093642', (62, 70))
536437	32164050	Migration ability was also limited both in shControl and shCARD9 PC9 cells by SB203580 (p=0.021 and p=0.002, respectively) (Fig.	('SB203580', 'Chemical', 'MESH:C093642', (78, 86))	('SB203580', 'Var', (78, 86))	('limited', 'NegReg', (27, 34))	('PC9', 'Gene', (65, 68))	('PC9', 'Gene', '255738', (65, 68))	('Migration ability', 'CPA', (0, 17))
536439	32164050	Of note, late apoptosis in shControl PC9 cannot be induced but even be hindered by SB203580 (p=0.001) (Fig.	('hindered', 'NegReg', (71, 79))	('SB203580', 'Var', (83, 91))	('SB203580', 'Chemical', 'MESH:C093642', (83, 91))	('PC9', 'Gene', '255738', (37, 40))	('PC9', 'Gene', (37, 40))
536440	32164050	6F), though both late and early apoptosis of shCARD9 PC9 cells was indeed increased when intervened with SB203580 (p=0.046 and p=0.013, respectively) (Fig.	('SB203580', 'Var', (105, 113))	('increased', 'PosReg', (74, 83))	('PC9', 'Gene', (53, 56))	('PC9', 'Gene', '255738', (53, 56))	('SB203580', 'Chemical', 'MESH:C093642', (105, 113))
536442	32164050	6G) when p-p38 was blocked, but shControl PC9 group instead had slightly increased S-phase population with SB203580 treatment (p=0.020) (Fig.	('increased', 'PosReg', (73, 82))	('PC9', 'Gene', '255738', (42, 45))	('S-phase population', 'CPA', (83, 101))	('PC9', 'Gene', (42, 45))	('p38', 'Gene', '1432', (11, 14))	('SB203580', 'Var', (107, 115))	('SB203580', 'Chemical', 'MESH:C093642', (107, 115))	('p38', 'Gene', (11, 14))
536443	32164050	Studies have shown that abrogation of overactivated p38 signaling was able to reverse enhanced G1 to S transition and anti-apoptosis effect in CARD9-knockdown cells but not in normal PC9 cells.	('p38', 'Gene', (52, 55))	('PC9', 'Gene', '255738', (183, 186))	('G1 to S transition', 'CPA', (95, 113))	('enhanced', 'PosReg', (86, 94))	('PC9', 'Gene', (183, 186))	('abrogation', 'Var', (24, 34))	('p38', 'Gene', '1432', (52, 55))	('anti-apoptosis effect', 'CPA', (118, 139))
536445	32164050	Taken together, CARD9 impaired abilities of cell proliferation, migration, and invasion by suppressing MAPK/p38 signaling.	('suppressing', 'NegReg', (91, 102))	('CARD9', 'Var', (16, 21))	('MAPK/p38', 'Gene', '1432', (103, 111))	('impaired', 'NegReg', (22, 30))	('MAPK/p38', 'Gene', (103, 111))	('invasion', 'CPA', (79, 87))
536471	32164050	Recently, two new studies together explained CARD9 could also influence tumorigenesis via fungal-associated way.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Disease', (72, 77))	('fungal-associated way', 'CPA', (90, 111))	('CARD9', 'Var', (45, 50))	('influence', 'Reg', (62, 71))	('tumor', 'Disease', 'MESH:D009369', (72, 77))
536473	32164050	On the one hand, when infected by fungus, deficient CARD9 could cause a blocked activation of inflammation and production of IL-18, which was critical for epithelial restitution and T cells response.	('inflammation', 'Disease', 'MESH:D007249', (94, 106))	('infected', 'Disease', (22, 30))	('IL-18', 'Gene', (125, 130))	('inflammation', 'Disease', (94, 106))	('deficient', 'Var', (42, 51))	('CARD9', 'Gene', (52, 57))	('infected', 'Disease', 'MESH:D007239', (22, 30))	('IL-18', 'Gene', '3606', (125, 130))	('activation', 'PosReg', (80, 90))
536478	32164050	CARD9 in tumor cells also had effects on tumor development.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumor', 'Disease', 'MESH:D009369', (9, 14))	('tumor', 'Disease', (41, 46))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('CARD9', 'Var', (0, 5))	('tumor', 'Disease', (9, 14))	('effects', 'Reg', (30, 37))	('tumor', 'Disease', 'MESH:D009369', (41, 46))
536488	31137630	Our data suggests that CD40, BAFFR, RANK and LTbetaR play an important role in NSCLC and further supports the role of NF-kappaB alternative pathway in NSCLC.	('NF-kappaB', 'Gene', (118, 127))	('NSCLC', 'Disease', (151, 156))	('NSCLC', 'Disease', 'MESH:D002289', (79, 84))	('CD40', 'Var', (23, 27))	('NSCLC', 'Disease', 'MESH:D002289', (151, 156))	('NSCLC', 'Disease', (79, 84))	('LTbetaR', 'Gene', '4055', (45, 52))	('BAFFR', 'Gene', (29, 34))	('NF-kappaB', 'Gene', '4790', (118, 127))	('BAFFR', 'Gene', '115650', (29, 34))	('LTbetaR', 'Gene', (45, 52))
536495	31137630	Additionally, we have previously reported that genetic variations of NF-kappaB2 and BCL3 are related to lung cancer risk and OS.	('lung cancer', 'Disease', 'MESH:D008175', (104, 115))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('OS', 'Chemical', '-', (125, 127))	('NF-kappaB', 'Gene', '4790', (69, 78))	('BCL3', 'Gene', '602', (84, 88))	('lung cancer', 'Disease', (104, 115))	('genetic variations', 'Var', (47, 65))	('lung cancer', 'Phenotype', 'HP:0100526', (104, 115))	('BCL3', 'Gene', (84, 88))	('NF-kappaB', 'Gene', (69, 78))	('related', 'Reg', (93, 100))
536500	31137630	Moreover, signaling through LTbetaR has been correlated to formation of tertiary lymphoid organs, cytokine expression and cell proliferation, while it has also been associated with inflammation-related carcinogenesis.	('associated', 'Reg', (165, 175))	('LTbetaR', 'Gene', (28, 35))	('carcinogenesis', 'Disease', 'MESH:D063646', (202, 216))	('carcinogenesis', 'Disease', (202, 216))	('LTbetaR', 'Gene', '4055', (28, 35))	('correlated', 'Reg', (45, 55))	('signaling', 'Var', (10, 19))	('inflammation', 'Disease', 'MESH:D007249', (181, 193))	('inflammation', 'Disease', (181, 193))	('cytokine', 'MPA', (98, 106))	('cell proliferation', 'CPA', (122, 140))
536513	31137630	Kaplan Meier (KM)-plotter was used for OS analysis and Kaplan-Meier curves based on the publicly available data on the expression values of CD40, BAFFR, RANK and LTbetaR genes from stages I-III NSCLC patients (Affymetrix probe IDs: 215346_at, 1552892_at, 207037_at and 203005_at, respectively).	('LTbetaR', 'Gene', (162, 169))	('patients', 'Species', '9606', (200, 208))	('stages', 'Disease', (181, 187))	('207037_at', 'Var', (255, 264))	('NSCLC', 'Disease', (194, 199))	('OS', 'Chemical', '-', (39, 41))	('NSCLC', 'Disease', 'MESH:D002289', (194, 199))	('BAFFR', 'Gene', (146, 151))	('1552892_at', 'Var', (243, 253))	('BAFFR', 'Gene', '115650', (146, 151))	('LTbetaR', 'Gene', '4055', (162, 169))	('203005_at', 'Var', (269, 278))	('CD40', 'Gene', (140, 144))
536559	31137630	With regard to LTbetaR expression, patients with adenocarcinomas and high LTbetaR expression had poor clinical outcome after a five-year observation period (Figure 3k, p < 0.001).	('LTbetaR', 'Gene', '4055', (15, 22))	('carcinoma', 'Phenotype', 'HP:0030731', (54, 63))	('LTbetaR', 'Gene', '4055', (74, 81))	('LTbetaR', 'Gene', (15, 22))	('adenocarcinomas', 'Disease', 'MESH:D000230', (49, 64))	('adenocarcinomas', 'Disease', (49, 64))	('LTbetaR', 'Gene', (74, 81))	('carcinomas', 'Phenotype', 'HP:0030731', (54, 64))	('high', 'Var', (69, 73))	('patients', 'Species', '9606', (35, 43))
536567	31137630	CD40 expression in the cytoplasm or on the membrane was not significantly associated with five-year OS, although a trend was noted for a relation between high CD40 levels and improved five-year OS, compared to patients with lower expression rates (Figure 4h-i, p = 0.092 and p = 0.059, respectively).	('CD40', 'Gene', (0, 4))	('OS', 'Chemical', '-', (100, 102))	('high', 'Var', (154, 158))	('CD40 levels', 'MPA', (159, 170))	('OS', 'Chemical', '-', (194, 196))	('patients', 'Species', '9606', (210, 218))	('improved', 'PosReg', (175, 183))
536582	31137630	Findings on CD40 are consistent with the results published by Keidai et al., in which 51.9% of NSCLC tissue specimens and 78% of lung cancer cell lines (14 of 18) expressed CD40.	('lung cancer', 'Disease', (129, 140))	('NSCLC', 'Disease', 'MESH:D002289', (95, 100))	('lung cancer', 'Phenotype', 'HP:0100526', (129, 140))	('CD40', 'Var', (173, 177))	('lung cancer', 'Disease', 'MESH:D008175', (129, 140))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('NSCLC', 'Disease', (95, 100))
536604	31137630	have shown that human fibroblasts from various tissues express CD40, suggesting a role in immune response, while, recently in vitro studies have implicated CAFs in the enhancement of metastatic potential of lung cancer cells.	('metastatic potential', 'CPA', (183, 203))	('lung cancer', 'Disease', 'MESH:D008175', (207, 218))	('human', 'Species', '9606', (16, 21))	('role', 'Reg', (82, 86))	('CD40', 'Var', (63, 67))	('enhancement', 'PosReg', (168, 179))	('lung cancer', 'Disease', (207, 218))	('lung cancer', 'Phenotype', 'HP:0100526', (207, 218))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))
536616	31137630	In conclusion, this study shows that although mRNA expression levels of the immune system-related transmembrane receptors CD40, BAFFR, RANK and LTbetaR do not differ, protein levels of CD40 and BAFFR were lower in NSCLC while no change was observed in protein levels of RANK and LTbetaR.	('LTbetaR', 'Gene', (279, 286))	('BAFFR', 'Gene', '115650', (128, 133))	('LTbetaR', 'Gene', '4055', (144, 151))	('protein levels', 'MPA', (167, 181))	('NSCLC', 'Disease', 'MESH:D002289', (214, 219))	('NSCLC', 'Disease', (214, 219))	('LTbetaR', 'Gene', '4055', (279, 286))	('CD40', 'Var', (185, 189))	('lower', 'NegReg', (205, 210))	('CD40', 'Gene', (122, 126))	('LTbetaR', 'Gene', (144, 151))	('BAFFR', 'Gene', (194, 199))	('BAFFR', 'Gene', (128, 133))	('BAFFR', 'Gene', '115650', (194, 199))
536618	31137630	In addition, our data provide strong evidence that the expression of these receptors in tumor, immune or stroma cells have prognostic significance influencing the clinical outcome of operated NSCLC patients, while CD40 and BAFFR protein expression was correlated with development of distant metastases.	('NSCLC', 'Disease', (192, 197))	('influencing', 'Reg', (147, 158))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('CD40', 'Var', (214, 218))	('NSCLC', 'Disease', 'MESH:D002289', (192, 197))	('patients', 'Species', '9606', (198, 206))	('metastases', 'Disease', (291, 301))	('correlated', 'Reg', (252, 262))	('BAFFR', 'Gene', '115650', (223, 228))	('BAFFR', 'Gene', (223, 228))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('metastases', 'Disease', 'MESH:D009362', (291, 301))	('tumor', 'Disease', (88, 93))
536630	30657059	Initially, a driver-gene mutation unleashing abnormal proliferation represents the first strike in the pathway to cancer.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('mutation', 'Var', (25, 33))	('cancer', 'Disease', (114, 120))
536677	30657059	The active form of the integrin is achieved by Mn2+ ions binding to the ADMIDAS site and thereby inducing a conformational change.	('Mn2+', 'Chemical', '-', (47, 51))	('binding', 'Interaction', (57, 64))	('active', 'MPA', (4, 10))	('D', 'Chemical', 'MESH:D003903', (76, 77))	('inducing', 'Reg', (97, 105))	('D', 'Chemical', 'MESH:D003903', (73, 74))	('conformational change', 'MPA', (108, 129))	('Mn2+ ions', 'Var', (47, 56))
536705	30657059	In vitro targeting of ICAM1 reduced breast cancer cell invasion and metastasis.	('breast cancer', 'Phenotype', 'HP:0003002', (36, 49))	('ICAM1 reduced breast cancer', 'Disease', 'MESH:D001943', (22, 49))	('ICAM1 reduced breast cancer', 'Disease', (22, 49))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('targeting', 'Var', (9, 18))
536762	30657059	Dissimilar to its function in neural development, L1-CAM expression in cancer induces a motile and invasive tumor phenotype, promoting metastatic dissemination, aggressive tumor expansion and chemoresistance associated with a poor prognostic outcome.	('D', 'Chemical', 'MESH:D003903', (0, 1))	('aggressive tumor', 'Disease', 'MESH:D001523', (161, 177))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('induces', 'Reg', (78, 85))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('cancer', 'Disease', (71, 77))	('L1-CAM', 'Gene', (50, 56))	('promoting', 'PosReg', (125, 134))	('expression', 'Var', (57, 67))	('aggressive tumor', 'Disease', (161, 177))	('metastatic dissemination', 'CPA', (135, 159))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('chemoresistance', 'CPA', (192, 207))	('invasive tumor', 'Disease', 'MESH:D009369', (99, 113))	('invasive tumor', 'Disease', (99, 113))	('motile', 'CPA', (88, 94))
536766	30657059	On the one hand, motility is encouraged by the soluble L1-CAM ectodomain after cleavage, and on the other hand, by over expression of L1-CAM-promoting migration by enhancing L1-CAM-ss1 integrin interactions.	('motility', 'CPA', (17, 25))	('L1-CAM-promoting', 'Var', (134, 150))	('enhancing', 'PosReg', (164, 173))	('ss1', 'Gene', (181, 184))	('interactions', 'Interaction', (194, 206))	('encouraged', 'PosReg', (29, 39))	('ss1', 'Gene', '3123', (181, 184))	('over expression', 'PosReg', (115, 130))
536769	30657059	One may assume that by expressing L1-CAM, the tumor cell may gain the key to a lock on its metastatic journey, allowing substantial progress, even if it may not remain the only lock to be opened on its way.	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('metastatic journey', 'CPA', (91, 109))	('L1-CAM', 'Var', (34, 40))	('tumor', 'Disease', (46, 51))	('progress', 'MPA', (132, 140))	('gain', 'PosReg', (61, 65))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
536777	30657059	In addition, comparison of survival in L1-CAM-positive and -negative patients retrospectively revealed a significantly poorer outcome for positive L1-CAM patients; five-year overall survival was decreased by 20%.	('patients', 'Species', '9606', (154, 162))	('positive', 'Var', (138, 146))	('patients', 'Species', '9606', (69, 77))	('L1-CAM', 'Gene', (147, 153))	('decreased', 'NegReg', (195, 204))
536825	30657059	Orally active alphaVss3 integrin inhibitor MK-0429 reduced lung metastasis and melanoma burden in the mouse model.	('reduced', 'NegReg', (51, 58))	('MK-0429', 'Var', (43, 50))	('mouse', 'Species', '10090', (102, 107))	('MK-0429', 'Chemical', 'MESH:C478626', (43, 50))	('melanoma', 'Phenotype', 'HP:0002861', (79, 87))	('melanoma', 'Disease', (79, 87))	('lung metastasis', 'CPA', (59, 74))	('melanoma', 'Disease', 'MESH:D008545', (79, 87))
536840	30657059	An analysis revealed anti-metastatic effects of D-pinitol, a phytochemical, in human prostate cancer cells by reducing the cell surface expression of alphaVss3 integrin.	('alphaVss3 integrin', 'Protein', (150, 168))	('human', 'Species', '9606', (79, 84))	('anti-metastatic', 'CPA', (21, 36))	('D-pinitol', 'Var', (48, 57))	('prostate cancer', 'Disease', (85, 100))	('cell surface expression', 'MPA', (123, 146))	('reducing', 'NegReg', (110, 118))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('D-pinitol', 'Chemical', 'MESH:C021730', (48, 57))	('prostate cancer', 'Disease', 'MESH:D011471', (85, 100))	('prostate cancer', 'Phenotype', 'HP:0012125', (85, 100))
536844	30657059	However, other experimental investigations suggest that alphaVss3 does not play an important role in the adhesion of prostate cancer cells and its blockage causes no observable effect on the number of adhered cells, which could explain the failure in efficacy of alphaVss3-antagonists in phase I and II trials.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('prostate cancer', 'Disease', 'MESH:D011471', (117, 132))	('prostate cancer', 'Phenotype', 'HP:0012125', (117, 132))	('prostate cancer', 'Disease', (117, 132))	('blockage', 'Var', (147, 155))
536846	30657059	Similar to the results obtained in studies evaluating alphaVss3-antagonists, the inhibition of integrin alphaVss3 has had little therapeutic effect in several trials for solid tumors.	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('inhibition', 'Var', (81, 91))	('solid tumors', 'Disease', 'MESH:D009369', (170, 182))	('tumors', 'Phenotype', 'HP:0002664', (176, 182))	('solid tumors', 'Disease', (170, 182))
536851	30657059	A different alpha5ss1 integrin antagonist, integrin monoclonal antibody PF-04605412, demonstrated no anti-tumor activity too in a first-in-human clinical trial, leading to a discontinuation of its clinical development.	('PF-04605412', 'Var', (72, 83))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('ss1', 'Gene', (18, 21))	('human', 'Species', '9606', (139, 144))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('ss1', 'Gene', '3123', (18, 21))	('tumor', 'Disease', (106, 111))
536854	30657059	In a phase I trial of ATN-161 in patients with solid tumors, about 1/3 of the patients that administered ATN-161 displayed prolonged stable disease and different dose levels were well tolerated (see Table 3).	('patients', 'Species', '9606', (33, 41))	('solid tumors', 'Disease', (47, 59))	('ATN-161', 'Var', (105, 112))	('patients', 'Species', '9606', (78, 86))	('solid tumors', 'Disease', 'MESH:D009369', (47, 59))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))
536912	32922550	The disruption of CA4 may be associated with the perturbation of pH homeostasis in retina and correlated with retinitis pigmentosa.	('retinitis pigmentosa', 'Disease', (110, 130))	('correlated', 'Reg', (94, 104))	('pH homeostasis', 'MPA', (65, 79))	('retinitis pigmentosa', 'Phenotype', 'HP:0000510', (110, 130))	('perturbation', 'MPA', (49, 61))	('retinitis', 'Phenotype', 'HP:0032118', (110, 119))	('associated', 'Reg', (29, 39))	('retinitis pigmentosa', 'Disease', 'MESH:C538365', (110, 130))	('disruption', 'Var', (4, 14))	('CA4', 'Gene', (18, 21))	('CA4', 'Gene', '762', (18, 21))
536943	32922550	Formalin-fixed, paraffin-embedded KIRC tissues and human renal tissues were stained for anti-CA4 using ab236315 (Abcam, USA) at 1/3000 dilution in Fudan University Shanghai Cancer Center (FUSCC) cohort, and then independently evaluated by two experienced pathologists.	('Formalin', 'Chemical', 'MESH:D005557', (0, 8))	('Cancer', 'Disease', 'MESH:D009369', (173, 179))	('Cancer', 'Phenotype', 'HP:0002664', (173, 179))	('Cancer', 'Disease', (173, 179))	('human', 'Species', '9606', (51, 56))	('ab236315', 'Var', (103, 111))	('paraffin', 'Chemical', 'MESH:D010232', (16, 24))	('CA4', 'Gene', (93, 96))	('CA4', 'Gene', '762', (93, 96))
536962	32922550	Remarkably, CA4 amplification was obviously related to better PFS (KIRC: hazard ratio [HR] = 0.661, p < 0.001; LGG: HR = 0.552, p = 0.002; LUAD: HR = 0.922, p = 0.020; UVM: HR = 0.454, p = 0.001) and better OS (KIRC: HR = 0.847, p < 0.001; LGG: HR = 0.552, p < 0.001; LUAD: HR = 0.918, p = 0.007; UVM: HR = 0.454, p < 0.001) in all of these four cancers.	('CA4', 'Gene', (12, 15))	('CA4', 'Gene', '762', (12, 15))	('UVM', 'Phenotype', 'HP:0007716', (297, 300))	('LUAD', 'Phenotype', 'HP:0030078', (268, 272))	('PFS', 'MPA', (62, 65))	('amplification', 'Var', (16, 29))	('cancers', 'Disease', 'MESH:D009369', (346, 353))	('cancers', 'Phenotype', 'HP:0002664', (346, 353))	('LUAD', 'Phenotype', 'HP:0030078', (139, 143))	('cancers', 'Disease', (346, 353))	('better', 'PosReg', (55, 61))	('UVM', 'Phenotype', 'HP:0007716', (168, 171))	('cancer', 'Phenotype', 'HP:0002664', (346, 352))
536969	32922550	Notably, CA4 amplification obviously correlated with better PFS in KIRC, LGG and LUAD (KIRC: HR = 0.749, p = 0.003; LGG: HR = 0.585, p = 0.005; LUAD: HR = 0.927, p = 0.029) and better OS in KIRC, LGG and UVM (KIRC: HR = 0.900, p = 0.022; LGG: HR = 0.655, p = 0.029; UVM: HR = 0.689, p = 0.005).	('PFS', 'MPA', (60, 63))	('LUAD', 'Phenotype', 'HP:0030078', (81, 85))	('LUAD', 'Phenotype', 'HP:0030078', (144, 148))	('CA4', 'Gene', (9, 12))	('CA4', 'Gene', '762', (9, 12))	('UVM', 'Phenotype', 'HP:0007716', (266, 269))	('UVM', 'Phenotype', 'HP:0007716', (204, 207))	('amplification', 'Var', (13, 26))	('better', 'PosReg', (53, 59))
536993	32922550	Compared with low or no protein expression, high expression of CA2 is related to better survival outcomes, suggesting that CA2 can be a potential marker for this interstitial tumor diagnosis.	('survival', 'CPA', (88, 96))	('high', 'Var', (44, 48))	('tumor', 'Disease', (175, 180))	('CA2', 'Gene', (123, 126))	('CA2', 'Gene', '760', (123, 126))	('CA2', 'Gene', (63, 66))	('CA2', 'Gene', '760', (63, 66))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))
537030	33740988	The identification of antisense sequences, short interfering RNAs (siRNAs), microRNAs (miRNAs or miRs), anti-miRs, and mRNA-based platforms holds great promise in preclinical and early clinical evaluation against LC.	('miR', 'Gene', '220972', (109, 112))	('miR', 'Gene', (109, 112))	('short', 'MPA', (43, 48))	('antisense sequences', 'Var', (22, 41))	('miR', 'Gene', '220972', (87, 90))	('miR', 'Gene', (87, 90))	('miR', 'Gene', '220972', (97, 100))	('miR', 'Gene', (97, 100))
537041	33740988	Approximately 30% of LC patients harbor activating KRAS mutations, making it a potential drug target for LC therapy.	('activating', 'PosReg', (40, 50))	('mutations', 'Var', (56, 65))	('KRAS', 'Gene', (51, 55))	('patients', 'Species', '9606', (24, 32))
537042	33740988	However, mutant KRAS targeting drugs have been under development for many years and are only now being evaluated in clinical trials.	('mutant', 'Var', (9, 15))	('KRAS', 'Gene', (16, 20))	('men', 'Species', '9606', (60, 63))
537043	33740988	Similarly, treatment with tyrosine kinase inhibitors in the patients harboring EGFR mutations has been relatively ineffective in improving the overall survival (OS).	('EGFR', 'Gene', (79, 83))	('patients', 'Species', '9606', (60, 68))	('mutations', 'Var', (84, 93))	('men', 'Species', '9606', (16, 19))	('overall survival', 'MPA', (143, 159))
537045	33740988	The major reason for the failure of currently available therapeutic approaches is the development of drug resistance associated with gene mutations, cancer stem cells, overexpression of oncogenes, and deletion or inactivation of tumor suppressor genes.	('deletion', 'Var', (201, 209))	('cancer', 'Disease', (149, 155))	('drug resistance', 'MPA', (101, 116))	('tumor', 'Disease', 'MESH:D009369', (229, 234))	('men', 'Species', '9606', (93, 96))	('inactivation', 'Var', (213, 225))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('tumor', 'Disease', (229, 234))	('drug resistance', 'Phenotype', 'HP:0020174', (101, 116))	('overexpression', 'PosReg', (168, 182))	('cancer', 'Disease', 'MESH:D009369', (149, 155))	('mutations', 'Var', (138, 147))
537051	33740988	The current cancer treatment modalities, including surgery and chemotherapy, are far from ideal approaches, especially for the advanced stage tumors, as most of the tumors exhibit mutational diversity.	('exhibit', 'Reg', (172, 179))	('age', 'Gene', '5973', (138, 141))	('cancer', 'Disease', 'MESH:D009369', (12, 18))	('men', 'Species', '9606', (24, 27))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('cancer', 'Disease', (12, 18))	('tumors', 'Disease', (165, 171))	('mutational diversity', 'Var', (180, 200))	('tumors', 'Disease', 'MESH:D009369', (165, 171))	('tumors', 'Phenotype', 'HP:0002664', (165, 171))	('age', 'Gene', (138, 141))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('tumors', 'Disease', (142, 148))	('tumors', 'Disease', 'MESH:D009369', (142, 148))	('tumors', 'Phenotype', 'HP:0002664', (142, 148))
537059	33740988	The primary focus of oligonucleotide-based therapeutics includes gene silencing or activation and splice modulation that provides an extended range of potential targets beyond the conventionally accessible pharmacological strategies.	('splice modulation', 'Var', (98, 115))	('rat', 'Species', '10116', (224, 227))	('gene silencing', 'Var', (65, 79))	('oligonucleotide', 'Chemical', 'MESH:D009841', (21, 36))
537062	33740988	To achieve the desirable functions (such as gene silencing, splice modulation, transcript degradation, translational activation, or antigen synthesis), different oligonucleotide-based platforms, including antisense oligonucleotides, RNA-interference molecules, and mRNA transcripts, have been developed.	('oligonucleotide', 'Chemical', 'MESH:D009841', (215, 230))	('antisense', 'Var', (205, 214))	('oligonucleotides', 'Chemical', 'MESH:D009841', (215, 231))	('transcript degradation', 'MPA', (79, 101))	('oligonucleotide', 'Chemical', 'MESH:D009841', (162, 177))	('splice modulation', 'MPA', (60, 77))	('antigen synthesis', 'MPA', (132, 149))	('translational', 'MPA', (103, 116))
537079	33740988	The most common application of these ASOs is to manage the selective exclusion or inclusion of exon(s) through the modulation of alternative splicing (for example, exon skipping and inclusion), Fig.	('exon skipping', 'Var', (164, 177))	('age', 'Gene', '5973', (51, 54))	('alternative splicing', 'MPA', (129, 149))	('ASOs', 'Chemical', 'MESH:D016376', (37, 41))	('age', 'Gene', (51, 54))	('inclusion', 'Var', (182, 191))	('modulation', 'Reg', (115, 125))
537080	33740988	Interestingly, the ASOs steric block approach can be used for corrupting the target splice variant, where the exon skipping method hinders or downregulates the translation of the target transcript (Fig.	('translation', 'MPA', (160, 171))	('hinders', 'NegReg', (131, 138))	('ASOs', 'Chemical', 'MESH:D016376', (19, 23))	('exon skipping', 'Var', (110, 123))	('downregulates', 'NegReg', (142, 155))
537083	33740988	More recently, the combinatorial investigation of several approaches like ASOs, micro-/si- RNAs to increase the target RNA expression or protein translation has revolutionized the RNA-based therapeutic strategies for different diseases, including cancer.	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('rat', 'Species', '10116', (204, 207))	('protein translation', 'MPA', (137, 156))	('cancer', 'Disease', (247, 253))	('micro-/si-', 'Var', (80, 90))	('ASOs', 'Chemical', 'MESH:D016376', (74, 78))	('cancer', 'Disease', 'MESH:D009369', (247, 253))	('increase', 'PosReg', (99, 107))
537095	33740988	These approaches include siRNAs, small hairpin RNAs (shRNAs), microRNAs (miRNAs), long double-stranded RNAs processed through Dicer, and small specific sequences synthesized to meet the RNAi criterion.	('long double-stranded RNAs', 'Var', (82, 107))	('Dicer', 'Gene', '23405', (126, 131))	('miR', 'Gene', '220972', (73, 76))	('Dicer', 'Gene', (126, 131))	('miR', 'Gene', (73, 76))
537106	33740988	Few examples of atypical siRNAs include single-stranded RNAs, divalent siRNAs, self-delivering siRNAs, small internally segmented siRNAs, and Dicer substrate siRNAs.	('Dicer', 'Gene', '23405', (142, 147))	('Dicer', 'Gene', (142, 147))	('rat', 'Species', '10116', (153, 156))	('men', 'Species', '9606', (123, 126))	('single-stranded', 'Var', (40, 55))
537116	33740988	Recent studies showed that miRNAs regulate the methylation of CpG islands in the promoter region of different genes and, thus, directly regulate the transcriptional regulations through epigenetic modifications.	('transcriptional regulations', 'MPA', (149, 176))	('CpG islands', 'Protein', (62, 73))	('miR', 'Gene', '220972', (27, 30))	('epigenetic modifications', 'Var', (185, 209))	('miR', 'Gene', (27, 30))	('regulate', 'Reg', (136, 144))	('regulate', 'Reg', (34, 42))	('methylation', 'MPA', (47, 58))
537128	33740988	Similarly, RG-101 induced viral rebound, along with the substitutions in the binding regions of miR-122 (in the 5' UTR of the HCV genome) and developed resistance.	('viral rebound', 'MPA', (26, 39))	('substitutions', 'Var', (56, 69))	('developed', 'CPA', (142, 151))	('RG-101', 'Gene', (11, 17))	('HCV', 'Species', '11103', (126, 129))	('binding', 'Interaction', (77, 84))	('RG-101', 'Chemical', '-', (11, 17))	('induced', 'Reg', (18, 25))	('miR-122', 'Gene', '406906', (96, 103))	('miR-122', 'Gene', (96, 103))
537134	33740988	These oligonucleotides obstruct the regulatory interactions of miRNAs with target mRNA (Fig.	('obstruct', 'NegReg', (23, 31))	('miR', 'Gene', '220972', (63, 66))	('miR', 'Gene', (63, 66))	('oligonucleotides', 'Chemical', 'MESH:D009841', (6, 22))	('oligonucleotides', 'Var', (6, 22))	('regulatory interactions', 'MPA', (36, 59))
537143	33740988	On the other hand, mRNA is a molecule that overcomes these two major pitfalls (targeting and genome integration) and has emerged as a strong alternative to conventional gene therapy strategies.	('rat', 'Species', '10116', (105, 108))	('rat', 'Species', '10116', (184, 187))	('mRNA', 'Var', (19, 23))	('fall', 'Phenotype', 'HP:0002527', (72, 76))	('genome integration', 'CPA', (93, 111))
537147	33740988	showed that modification of mammalian RNA nucleosides (for example, 5-methylcytidine, N6-methyladenosine, 5-methyluracil, pseudouridine, and N7-methylguanosine) decreases the immunomodulatory signals and DCs exposed to these modified mRNAs reduced activation and cytokine production compared to DCs exposed to unmodified RNAs.	('5-methyluracil', 'Chemical', 'MESH:D013941', (106, 120))	('modified', 'Var', (225, 233))	('decreases', 'NegReg', (161, 170))	('reduced', 'NegReg', (240, 247))	('mammalian', 'Species', '9606', (28, 37))	('5-methylcytidine', 'Chemical', 'MESH:C016568', (68, 84))	('pseudouridine', 'Chemical', 'MESH:D011560', (122, 135))	('nucleosides', 'Chemical', 'MESH:D009705', (42, 53))	('activation', 'MPA', (248, 258))	('immunomodulatory signals', 'MPA', (175, 199))	('N7-methylguanosine', 'Var', (141, 159))	('N6-methyladenosine', 'Chemical', 'MESH:C010223', (86, 104))	('N6-methyladenosine', 'Var', (86, 104))	('cytokine production', 'MPA', (263, 282))	('modification', 'Var', (12, 24))	('N7-methylguanosine', 'Chemical', 'MESH:C016578', (141, 159))
537150	33740988	Thus, modifications in nucleosides overcome RNA-mediated activation of DCs.	('modifications', 'Var', (6, 19))	('nucleosides', 'Chemical', 'MESH:D009705', (23, 34))	('nucleosides', 'Protein', (23, 34))	('RNA-mediated activation', 'MPA', (44, 67))	('DCs', 'MPA', (71, 74))
537153	33740988	Each chemical modification plays a specific role like, m6A enhances mRNA turnover, regulates embryonic stem cell development, favors RNA decay, pre-mRNA splicing, adipogenesis, and prostate cancer bone metastasis.	('m6A', 'Var', (55, 58))	('adipogenesis', 'MPA', (163, 175))	('m6A', 'Chemical', '-', (55, 58))	('prostate cancer', 'Phenotype', 'HP:0012125', (181, 196))	('embryonic stem cell development', 'CPA', (93, 124))	('prostate cancer bone metastasis', 'Disease', 'MESH:D011471', (181, 212))	('RNA decay', 'MPA', (133, 142))	('favors', 'PosReg', (126, 132))	('regulates', 'Reg', (83, 92))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('enhances', 'PosReg', (59, 67))	('mRNA turnover', 'MPA', (68, 81))	('prostate cancer bone metastasis', 'Disease', (181, 212))	('pre-mRNA splicing', 'MPA', (144, 161))	('men', 'Species', '9606', (120, 123))
537154	33740988	Similarly, s2U regulates the structure of RNA, increases stability, and alters translational efficiency, while m5C induces codon rewiring and, in combination with other modifications, guides miRNA targeting.	('miR', 'Gene', (191, 194))	('s2U', 'Chemical', '-', (11, 14))	('m5C', 'Chemical', '-', (111, 114))	('stability', 'MPA', (57, 66))	('translational efficiency', 'MPA', (79, 103))	('m5C', 'Var', (111, 114))	('alters', 'Reg', (72, 78))	('RNA', 'Protein', (42, 45))	('codon rewiring', 'MPA', (123, 137))	('increases', 'PosReg', (47, 56))	('s2U', 'Var', (11, 14))	('induces', 'Reg', (115, 122))	('structure', 'MPA', (29, 38))	('regulates', 'Reg', (15, 24))	('miR', 'Gene', '220972', (191, 194))
537155	33740988	For translation, ribosomes scan mRNA transcripts at the 5' UTR within Kozak sequences to identify start codon, but the length of 5' UTR, presence of cis-elements, and m6A modulate ribosome scanning and finally regulate the translational efficiency.	('men', 'Species', '9606', (156, 159))	('translational efficiency', 'MPA', (223, 247))	('modulate', 'Reg', (171, 179))	('regulate', 'Reg', (210, 218))	('ribosome scanning', 'MPA', (180, 197))	('m6A', 'Var', (167, 170))	('m6A', 'Chemical', '-', (167, 170))
537156	33740988	Interestingly, some transcripts that retain m6A in their 5' UTR can be translated in a 5' cap-independent manner due to the direct binding of 5' UTR m6A with the eukaryotic initiation factor 3 (eIF3), which alone is enough to recruit the 43S ribosomal complex and initiate translation.	('m6A', 'Var', (149, 152))	('eIF3', 'Gene', '8661', (194, 198))	('m6A', 'Chemical', '-', (149, 152))	('m6A', 'Var', (44, 47))	('eIF3', 'Gene', (194, 198))	('binding', 'Interaction', (131, 138))	('m6A', 'Chemical', '-', (44, 47))	('eukaryotic initiation factor 3', 'Gene', '8661', (162, 192))	('eukaryotic initiation factor 3', 'Gene', (162, 192))
537157	33740988	Inhibition of N6-methylation in adenosine specifically decreases the translation of mRNA transcripts consisting 5'UTR m6A.	('mRNA transcripts consisting', 'MPA', (84, 111))	('translation', 'MPA', (69, 80))	('decreases', 'NegReg', (55, 64))	('adenosine', 'Chemical', 'MESH:D000241', (32, 41))	('m6A', 'Chemical', '-', (118, 121))	('Inhibition', 'Var', (0, 10))	('N6-methylation', 'Var', (14, 28))
537168	33740988	LINC000173.v1 upregulates the expression of VEGFA through miR-511-5p sponging and inhibition of LINC000173.v1 using ASOs resulted in decreased tumor growth and enhanced cisplatin sensitivity.	('LINC000173.v1', 'Var', (96, 109))	('decreased tumor', 'Disease', 'MESH:D002303', (133, 148))	('VEGFA', 'Gene', '7422', (44, 49))	('miR', 'Gene', '220972', (58, 61))	('miR', 'Gene', (58, 61))	('cisplatin', 'Chemical', 'MESH:D002945', (169, 178))	('VEGFA', 'Gene', (44, 49))	('ASOs', 'Chemical', 'MESH:D016376', (116, 120))	('cisplatin sensitivity', 'MPA', (169, 190))	('decreased tumor', 'Disease', (133, 148))	('enhanced', 'PosReg', (160, 168))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
537174	33740988	KRAS is a highly desirable target for cancer therapy; however, the development of pharmacological small molecules for mutant KRAS remains challenging, and most of the identified inhibitors are still in early-stage clinical trials.	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('KRAS', 'Gene', (125, 129))	('age', 'Gene', (210, 213))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('mutant', 'Var', (118, 124))	('men', 'Species', '9606', (74, 77))	('cancer', 'Disease', (38, 44))	('age', 'Gene', '5973', (210, 213))
537175	33740988	AZD4785 is a high-affinity KRAS mRNA-targeting therapeutic ASO that selectively decreases mutant KRAS mRNA as well as protein.	('ASO', 'Chemical', 'MESH:D016376', (59, 62))	('KRAS', 'Gene', (97, 101))	('mutant', 'Var', (90, 96))	('decreases', 'NegReg', (80, 89))	('AZD4785', 'Chemical', '-', (0, 7))
537176	33740988	AZD4785 downregulated the effector pathways and selectively decreased the proliferation of cells harboring mutant KRAS.	('decreased', 'NegReg', (60, 69))	('mutant', 'Var', (107, 113))	('AZD4785', 'Gene', (0, 7))	('rat', 'Species', '10116', (81, 84))	('KRAS', 'Gene', (114, 118))	('AZD4785', 'Chemical', '-', (0, 7))	('proliferation', 'CPA', (74, 87))	('effector pathways', 'Pathway', (26, 43))	('downregulated', 'NegReg', (8, 21))
537177	33740988	The systemic injection of AZD4785 to NSCLC mice xenografts and patient-derived xenografts harboring mutant KRAS inhibited KRAS expression and induced strong antitumor activity.	('mice', 'Species', '10090', (43, 47))	('KRAS', 'Gene', (107, 111))	('AZD4785', 'Chemical', '-', (26, 33))	('inhibited', 'NegReg', (112, 121))	('expression', 'MPA', (127, 137))	('mutant', 'Var', (100, 106))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('NSCLC', 'Disease', (37, 42))	('KRAS', 'Protein', (122, 126))	('patient', 'Species', '9606', (63, 70))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('NSCLC', 'Disease', 'MESH:D002289', (37, 42))	('tumor', 'Disease', (161, 166))
537178	33740988	This suggested that AZD4785 and other novel ASOs are innovative therapeutic approaches for treating KRAS- and other mutated oncogenes.	('AZD4785', 'Var', (20, 27))	('ASOs', 'Chemical', 'MESH:D016376', (44, 48))	('KRAS-', 'Disease', (100, 105))	('AZD4785', 'Chemical', '-', (20, 27))
537179	33740988	reported the construction of novel polyethylene glycol (PEG) ligated antisense therapeutic oligonucleotides that form a bottlebrush-like structure consisting of PEG side chains, DNA backbone, and overhangs of antisense oligonucleotides.	('bottlebrush', 'Disease', (120, 131))	('bottlebrush', 'Disease', 'None', (120, 131))	('oligonucleotides', 'Chemical', 'MESH:D009841', (91, 107))	('PEG', 'Var', (161, 164))	('polyethylene glycol', 'Chemical', 'MESH:D011092', (35, 54))	('PEG', 'Chemical', 'MESH:D011092', (56, 59))	('PEG', 'Chemical', 'MESH:D011092', (161, 164))	('oligonucleotides', 'Chemical', 'MESH:D009841', (219, 235))
537180	33740988	These formulations possess PEG at high density on the surface, which decreases the undesired interactions of ASOs with DNA and proteins (protecting from enzymatic degradation) and enhances the chances of antisense overhangs to hybridize with target mRNA, thereby reduce protein expression.	('enhances', 'PosReg', (180, 188))	('reduce', 'NegReg', (263, 269))	('antisense', 'Var', (204, 213))	('decreases', 'NegReg', (69, 78))	('hybridize', 'Interaction', (227, 236))	('ASOs', 'Chemical', 'MESH:D016376', (109, 113))	('interactions', 'Interaction', (93, 105))	('undesired', 'MPA', (83, 92))	('DNA', 'Protein', (119, 122))	('proteins', 'Protein', (127, 135))	('PEG', 'Chemical', 'MESH:D011092', (27, 30))	('protein expression', 'MPA', (270, 288))
537182	33740988	These modified ASOs had higher inhibition efficacies than conventional hairpins, and the antisense molecules decreased the proliferation of LC cell line expressing mutant KRAS (G12C) gene.	('decreased', 'NegReg', (109, 118))	('proliferation', 'CPA', (123, 136))	('mutant', 'Var', (164, 170))	('inhibition efficacies', 'MPA', (31, 52))	('ASOs', 'Chemical', 'MESH:D016376', (15, 19))	('G12C', 'Mutation', 'rs121913530', (177, 181))	('rat', 'Species', '10116', (130, 133))	('KRAS (G12C', 'Gene', (171, 181))
537187	33740988	ASOs targeting ARL4C (ASO-1316) showed decreased RAS-related substrate activity, inhibited cell proliferation and migration, and suppressed nuclear import of Yes-associated protein-1 (YAP-1) in lung cancer cell lines bearing KRAS and EGFR mutations.	('ASO-1316', 'Chemical', '-', (22, 30))	('suppressed', 'NegReg', (129, 139))	('EGFR', 'Gene', (234, 238))	('mutations', 'Var', (239, 248))	('lung cancer', 'Disease', 'MESH:D008175', (194, 205))	('YAP-1', 'Gene', '10413', (184, 189))	('lung cancer', 'Phenotype', 'HP:0100526', (194, 205))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('rat', 'Species', '10116', (103, 106))	('ARL4C', 'Gene', '10123', (15, 20))	('KRAS', 'Gene', (225, 229))	('ARL4C', 'Gene', (15, 20))	('decreased', 'NegReg', (39, 48))	('YAP-1', 'Gene', (184, 189))	('rat', 'Species', '10116', (117, 120))	('Yes-associated protein-1', 'Gene', (158, 182))	('inhibited', 'NegReg', (81, 90))	('nuclear import', 'MPA', (140, 154))	('ASOs', 'Chemical', 'MESH:D016376', (0, 4))	('rat', 'Species', '10116', (66, 69))	('lung cancer', 'Disease', (194, 205))	('RAS-related', 'Protein', (49, 60))	('Yes-associated protein-1', 'Gene', '10413', (158, 182))
537188	33740988	In addition, ASO-1316 reduced tumorigenicity of KRAS/EGFR mutated lung cancer cell lines in orthotopic mice models.	('KRAS/EGFR', 'Gene', (48, 57))	('ASO-1316', 'Chemical', '-', (13, 21))	('mice', 'Species', '10090', (103, 107))	('lung cancer', 'Disease', (66, 77))	('lung cancer', 'Phenotype', 'HP:0100526', (66, 77))	('tumor', 'Disease', 'MESH:D009369', (30, 35))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('mutated', 'Var', (58, 65))	('reduced', 'NegReg', (22, 29))	('tumor', 'Disease', (30, 35))	('lung cancer', 'Disease', 'MESH:D008175', (66, 77))
537191	33740988	ASOs-dA40/SPG targeting KRAS inhibited KRAS expression in Dectin-1 expressing LC cells and correspondingly decreased cell growth.	('KRAS', 'Var', (24, 28))	('inhibited', 'NegReg', (29, 38))	('expression', 'MPA', (44, 54))	('Dectin-1', 'Gene', (58, 66))	('decreased', 'NegReg', (107, 116))	('SPG', 'Chemical', 'MESH:C026818', (10, 13))	('Dectin-1', 'Gene', '64581', (58, 66))	('KRAS', 'Gene', (39, 43))	('cell growth', 'CPA', (117, 128))	('ASOs-dA40', 'Chemical', '-', (0, 9))
537199	33740988	Preclinical evaluations demonstrated that AZD9150 decreased the expression of STAT3 and exhibited prominent antitumor effects in several preclinical cancer models of lymphoma and LC.	('cancer', 'Disease', (149, 155))	('expression', 'MPA', (64, 74))	('cancer', 'Disease', 'MESH:D009369', (149, 155))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('STAT3', 'Gene', '6774', (78, 83))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('decreased', 'NegReg', (50, 59))	('STAT3', 'Gene', (78, 83))	('AZD9150', 'Chemical', 'MESH:C000610954', (42, 49))	('lymphoma', 'Disease', (166, 174))	('tumor', 'Disease', (112, 117))	('lymphoma', 'Disease', 'MESH:D008223', (166, 174))	('lymphoma', 'Phenotype', 'HP:0002665', (166, 174))	('AZD9150', 'Var', (42, 49))	('rat', 'Species', '10116', (31, 34))
537205	33740988	Further, CS3D inhibited cell proliferation, colonization and, increases apoptosis in vitro, and reduced tumor growth along with c-MYC expression in vivo.	('c-MYC', 'Gene', '4609', (128, 133))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('increases', 'PosReg', (62, 71))	('CS3D', 'Var', (9, 13))	('rat', 'Species', '10116', (36, 39))	('cell proliferation', 'CPA', (24, 42))	('c-MYC', 'Gene', (128, 133))	('tumor', 'Disease', (104, 109))	('inhibited', 'NegReg', (14, 23))	('apoptosis', 'CPA', (72, 81))	('colonization', 'CPA', (44, 56))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('reduced', 'NegReg', (96, 103))
537208	33740988	G3139 and RX-0201 are ASOs that target Bcl2 and Akt-1, respectively, but have exhibited limited efficacy in clinical trials due to inadequate delivery.	('RX-0201', 'Gene', (10, 17))	('Akt-1', 'Gene', (48, 53))	('G3139', 'Var', (0, 5))	('G3139', 'Chemical', 'MESH:C408162', (0, 5))	('ASOs', 'Chemical', 'MESH:D016376', (22, 26))	('inadequate delivery', 'Phenotype', 'HP:0001622', (131, 150))	('Bcl2', 'Protein', (39, 43))
537212	33740988	The T7-ASO-lipid nanoparticles decreased the expression of Bcl2 and Akt-1in LC cell lines, exhibited superior antitumor effects, and improved the overall survival (OS) in LC xenograft bearing mice.	('Bcl2', 'Gene', (59, 63))	('T7-ASO-lipid', 'Var', (4, 16))	('mice', 'Species', '10090', (192, 196))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('overall survival', 'CPA', (146, 162))	('superior', 'PosReg', (101, 109))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('lipid', 'Chemical', 'MESH:D008055', (11, 16))	('decreased', 'NegReg', (31, 40))	('tumor', 'Disease', (114, 119))	('expression', 'MPA', (45, 55))	('Akt-1in', 'Gene', (68, 75))	('improved', 'PosReg', (133, 141))	('ASO', 'Chemical', 'MESH:D016376', (7, 10))
537214	33740988	The G3139-GAP (with 2'-O-methyl nucleotides) was incorporated into DOTAP/egg PC/cholesterol/Tween 80 lipid nanoparticles, and anticancer efficacy was studied in A549 cells and xenograft mouse models.	('rat', 'Species', '10116', (56, 59))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('A549', 'CellLine', 'CVCL:0023', (161, 165))	('cancer', 'Disease', (130, 136))	('G3139-GAP', 'Var', (4, 13))	("2'-O-methyl nucleotides", 'Chemical', '-', (20, 43))	('mouse', 'Species', '10090', (186, 191))	('G3139', 'Chemical', 'MESH:C408162', (4, 9))	('lipid', 'Chemical', 'MESH:D008055', (101, 106))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('cholesterol', 'Chemical', 'MESH:D002784', (80, 91))	('Tween', 'Chemical', 'MESH:D011136', (92, 97))
537227	33740988	Instead of direct COX-2 inhibition, knockdown of delta-5-desaturase (D5D) offers a unique approach that limits the formation of arachidonic acid (a substrate for COX-2) and promotes the peroxidation of dihomo-gamma-linolenic acid leading the production of 8-hydroxyoctanoic acid (8-HOA).	('limits', 'NegReg', (104, 110))	('COX-2', 'Gene', '5743', (18, 23))	('arachidonic acid', 'Chemical', 'MESH:D016718', (128, 144))	('dihomo-gamma-linolenic acid', 'Chemical', 'MESH:D015126', (202, 229))	('COX-2', 'Gene', '5743', (162, 167))	('rat', 'Species', '10116', (153, 156))	('8-hydroxyoctanoic acid', 'MPA', (256, 278))	('delta-5-desaturase', 'Gene', '3992', (49, 67))	('formation of arachidonic acid', 'MPA', (115, 144))	('knockdown', 'Var', (36, 45))	('peroxidation', 'MPA', (186, 198))	('delta-5-desaturase', 'Gene', (49, 67))	('8-HOA', 'Chemical', 'MESH:C083377', (280, 285))	('8-hydroxyoctanoic acid', 'Chemical', 'MESH:C083377', (256, 278))	('COX-2', 'Gene', (18, 23))	('promotes', 'PosReg', (173, 181))	('COX-2', 'Gene', (162, 167))
537257	33740988	Low miRNA-195 and high Rap2C were associated with low OS in SCLC patients.	('Rap2C', 'Gene', (23, 28))	('miRNA-195', 'Gene', (4, 13))	('low OS', 'Disease', (50, 56))	('miRNA-195', 'Gene', '406971', (4, 13))	('SCLC', 'Gene', (60, 64))	('high', 'Var', (18, 22))	('patients', 'Species', '9606', (65, 73))	('SCLC', 'Gene', '7864', (60, 64))	('Low', 'NegReg', (0, 3))	('Rap2C', 'Gene', '57826', (23, 28))
537271	33740988	KRAS mutations are leading to the constitutive activation of the KRAS, which suggested the potential of mutant K-ras inhibition, may for NSCLC treatment.	('K-ras', 'Gene', (111, 116))	('NSCLC', 'Disease', (137, 142))	('K-ras', 'Gene', '3845', (111, 116))	('NSCLC', 'Disease', 'MESH:D002289', (137, 142))	('men', 'Species', '9606', (148, 151))	('activation', 'PosReg', (47, 57))	('mutations', 'Var', (5, 14))	('KRAS', 'Gene', (0, 4))	('KRAS', 'Gene', (65, 69))
537272	33740988	The approach combining siRNA and miRNA provides innovative therapeutic opportunities to combat oncogenic KRAS and other oncogenic mutations in LC simultaneously.	('miR', 'Gene', '220972', (33, 36))	('miR', 'Gene', (33, 36))	('mutations', 'Var', (130, 139))	('KRAS', 'Disease', (105, 109))
537273	33740988	The lipid-based polymeric nanoparticle containing the siRNA for knocking-down oncogenic KRAS and overexpressing miR-34a (p53-regulated tumor suppressor miRNA) has shown promising therapeutic effects in lung cancer.	('lipid', 'Chemical', 'MESH:D008055', (4, 9))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('p53', 'Gene', '7157', (121, 124))	('lung cancer', 'Phenotype', 'HP:0100526', (202, 213))	('overexpressing', 'PosReg', (97, 111))	('p53', 'Gene', (121, 124))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('miR', 'Gene', '220972', (152, 155))	('miR', 'Gene', '220972', (112, 115))	('lung cancer', 'Disease', (202, 213))	('tumor', 'Disease', (135, 140))	('knocking-down', 'Var', (64, 77))	('KRAS', 'Gene', (88, 92))	('miR-34a', 'Gene', (112, 119))	('polymer', 'Chemical', 'MESH:D011108', (16, 23))	('miR', 'Gene', (152, 155))	('tumor', 'Disease', 'MESH:D009369', (135, 140))	('miR', 'Gene', (112, 115))	('miR-34a', 'Gene', '407040', (112, 119))	('lung cancer', 'Disease', 'MESH:D008175', (202, 213))
537275	33740988	Furthermore, anti-mutant KRAS siRNA-loaded hybrid nanoparticles (AKSLHNs) have been shown to target the KRAS and inhibit the metastasis in a mouse model of lung cancer.	('metastasis in a mouse model', 'CPA', (125, 152))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('lung cancer', 'Disease', 'MESH:D008175', (156, 167))	('inhibit', 'NegReg', (113, 120))	('mouse', 'Species', '10090', (141, 146))	('anti-mutant', 'Var', (13, 24))	('KRAS', 'Protein', (104, 108))	('lung cancer', 'Disease', (156, 167))	('KRAS', 'Gene', (25, 29))	('lung cancer', 'Phenotype', 'HP:0100526', (156, 167))
537276	33740988	Similarly, most of the anti-EGFR therapies aim to target the EGFR mutations, and the status of the EGFR mutation determines the fate of such treatments.	('mutations', 'Var', (66, 75))	('EGFR', 'Gene', (61, 65))	('men', 'Species', '9606', (146, 149))
537277	33740988	In combination with TK inhibitors, siEGFR induced apoptosis and reduced NSCLC cell growth.	('NSCLC', 'Disease', (72, 77))	('NSCLC', 'Disease', 'MESH:D002289', (72, 77))	('siEGFR', 'Var', (35, 41))	('reduced', 'NegReg', (64, 71))	('apoptosis', 'CPA', (50, 59))
537278	33740988	Recently, silencing of EGFR-TKs by a siRNA pool and simultaneously delivering paclitaxel by using tumor-targeted nanostructured lipid carriers resulted in enhanced tissue distribution and anticancer effects compared with monotherapy or non-targeted therapy.	('EGFR-TKs', 'Gene', (23, 31))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tissue distribution', 'MPA', (164, 183))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('enhanced', 'PosReg', (155, 163))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('cancer', 'Disease', (192, 198))	('cancer', 'Disease', 'MESH:D009369', (192, 198))	('paclitaxel', 'Chemical', 'MESH:D017239', (78, 88))	('tumor', 'Disease', (98, 103))	('lipid', 'Chemical', 'MESH:D008055', (128, 133))	('silencing', 'Var', (10, 19))
537279	33740988	Studies have indicated that miRNAs contribute to the resistance of TK inhibitor in EGFR mutated NSCLC tumors.	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('EGFR', 'Gene', (83, 87))	('mutated', 'Var', (88, 95))	('miR', 'Gene', '220972', (28, 31))	('NSCLC tumors', 'Disease', 'MESH:D009369', (96, 108))	('miR', 'Gene', (28, 31))	('NSCLC tumors', 'Disease', (96, 108))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))
537280	33740988	Expression of miR-146b-5p was higher in the pleural discharge of treatment naive patients as compared to EGFR TK inhibitor-resistant patients.	('miR-146b-5p', 'Chemical', '-', (14, 25))	('Expression', 'MPA', (0, 10))	('higher', 'PosReg', (30, 36))	('patients', 'Species', '9606', (133, 141))	('men', 'Species', '9606', (70, 73))	('miR-146b-5p', 'Var', (14, 25))	('patients', 'Species', '9606', (81, 89))	('pleural discharge', 'Phenotype', 'HP:0002202', (44, 61))
537281	33740988	Overexpression of miR-146-5p in the resistant cells enhanced their sensitivity to EGFR TK inhibitors.	('enhanced', 'PosReg', (52, 60))	('miR-146-5p', 'Chemical', '-', (18, 28))	('sensitivity to EGFR TK inhibitors', 'MPA', (67, 100))	('miR-146-5p', 'Var', (18, 28))
537283	33740988	Mechanistically, miR-146b-5p targets interleukin 1 receptor-associated kinase 1 (IRAK1) by downregulating NF-kappaB and related cytokine production (IL-6 and IL-8).	('NF-kappaB', 'Gene', '4790', (106, 115))	('IL-6', 'Gene', (149, 153))	('miR-146b-5p', 'Var', (17, 28))	('NF-kappaB', 'Gene', (106, 115))	('IL-8', 'Gene', '3576', (158, 162))	('interleukin 1 receptor-associated kinase 1', 'Gene', '3654', (37, 79))	('interleukin 1 receptor-associated kinase 1', 'Gene', (37, 79))	('IL-6', 'Gene', '3569', (149, 153))	('cytokine production', 'MPA', (128, 147))	('downregulating', 'NegReg', (91, 105))	('IL-8', 'Gene', (158, 162))	('IRAK1', 'Gene', '3654', (81, 86))	('IRAK1', 'Gene', (81, 86))	('miR-146b-5p', 'Chemical', '-', (17, 28))
537284	33740988	Thus, miR-146b-5p has the potential to target IRAK1/NF-kappaB signaling, regulating EGFR TK inhibitor resistance, and may help combat resistance associated with TK inhibitors.	('EGFR TK inhibitor resistance', 'MPA', (84, 112))	('miR-146b-5p', 'Chemical', '-', (6, 17))	('target', 'Reg', (39, 45))	('IRAK1', 'Gene', (46, 51))	('IRAK1', 'Gene', '3654', (46, 51))	('miR-146b-5p', 'Var', (6, 17))	('resistance', 'MPA', (134, 144))	('NF-kappaB', 'Gene', '4790', (52, 61))	('NF-kappaB', 'Gene', (52, 61))	('regulating', 'Reg', (73, 83))
537287	33740988	Overexpression of miR-506-3p inhibited SHH signaling pathway and modulated epithelial to mesenchymal transition.	('inhibited', 'NegReg', (29, 38))	('epithelial to mesenchymal transition', 'CPA', (75, 111))	('SHH', 'Gene', '6469', (39, 42))	('miR-506-3p', 'Chemical', '-', (18, 28))	('miR-506-3p', 'Var', (18, 28))	('SHH', 'Gene', (39, 42))	('modulated', 'Reg', (65, 74))
537288	33740988	This study identified the SHH pathway as a novel therapeutic target of miR-506-3p in EGFR TK inhibitor-resistant EGFR mutated LC cell lines.	('miR-506-3p', 'Var', (71, 81))	('SHH', 'Gene', '6469', (26, 29))	('mutated', 'Var', (118, 125))	('SHH', 'Gene', (26, 29))	('miR-506-3p', 'Chemical', '-', (71, 81))
537291	33740988	FOXP4 is an important target for EGFR mutated LC and is involved in the regulation of pulmonary gene expression.	('mutated', 'Var', (38, 45))	('FOXP4', 'Gene', '116113', (0, 5))	('FOXP4', 'Gene', (0, 5))	('EGFR', 'Gene', (33, 37))
537293	33740988	miR-139-5p was shown to induce cisplatin sensitization of NSCLC cells.	('NSCLC', 'Disease', (58, 63))	('induce', 'PosReg', (24, 30))	('cisplatin', 'Chemical', 'MESH:D002945', (31, 40))	('NSCLC', 'Disease', 'MESH:D002289', (58, 63))	('cisplatin sensitization', 'MPA', (31, 54))	('miR-139-5p', 'Var', (0, 10))	('miR-139-5p', 'Chemical', '-', (0, 10))
537294	33740988	The expression of miR-139-5p was downregulated in NSCLC compared to adjacent normal tissue, and reduced expression was associated with cisplatin resistance.	('associated', 'Reg', (119, 129))	('cisplatin', 'MPA', (135, 144))	('expression', 'MPA', (4, 14))	('cisplatin', 'Chemical', 'MESH:D002945', (135, 144))	('expression', 'MPA', (104, 114))	('NSCLC', 'Disease', (50, 55))	('miR-139-5p', 'Chemical', '-', (18, 28))	('miR-139-5p', 'Var', (18, 28))	('NSCLC', 'Disease', 'MESH:D002289', (50, 55))	('downregulated', 'NegReg', (33, 46))	('reduced', 'NegReg', (96, 103))
537295	33740988	Overexpression of miR-139-5p resulted in enhanced sensitivity to cisplatin, inhibited cell proliferation, and induced apoptosis by modulating the Homeobox protein Hox B2 (HOXB2) and PI3K-AKT-caspase-3 axis.	('cisplatin', 'Chemical', 'MESH:D002945', (65, 74))	('HOXB2', 'Gene', (171, 176))	('enhanced', 'PosReg', (41, 49))	('caspase-3', 'Gene', '836', (191, 200))	('inhibited', 'NegReg', (76, 85))	('apoptosis', 'CPA', (118, 127))	('AKT', 'Gene', (187, 190))	('caspase-3', 'Gene', (191, 200))	('induced', 'Reg', (110, 117))	('HOXB2', 'Gene', '3212', (171, 176))	('Homeobox protein Hox B2', 'Gene', (146, 169))	('cell proliferation', 'CPA', (86, 104))	('sensitivity to cisplatin', 'MPA', (50, 74))	('miR-139-5p', 'Chemical', '-', (18, 28))	('AKT', 'Gene', '207', (187, 190))	('rat', 'Species', '10116', (98, 101))	('modulating', 'Reg', (131, 141))	('Homeobox protein Hox B2', 'Gene', '3212', (146, 169))	('miR-139-5p', 'Var', (18, 28))
537306	33740988	G3139, a Bcl-2 ASO, along with paclitaxel was well-tolerated in chemo-refractory SCLC patients.	('rat', 'Species', '10116', (55, 58))	('paclitaxel', 'Chemical', 'MESH:D017239', (31, 41))	('Bcl-2', 'Gene', (9, 14))	('Bcl-2', 'Gene', '596', (9, 14))	('G3139', 'Var', (0, 5))	('ASO', 'Chemical', 'MESH:D016376', (15, 18))	('G3139', 'Chemical', 'MESH:C408162', (0, 5))	('SCLC', 'Gene', '7864', (81, 85))	('SCLC', 'Gene', (81, 85))	('patients', 'Species', '9606', (86, 94))
537307	33740988	Further, G3139, in combination with carboplatin and etoposide showed promising results in SCLC patients.	('G3139', 'Var', (9, 14))	('G3139', 'Chemical', 'MESH:C408162', (9, 14))	('patients', 'Species', '9606', (95, 103))	('SCLC', 'Gene', '7864', (90, 94))	('SCLC', 'Gene', (90, 94))	('carboplatin', 'Chemical', 'MESH:D016190', (36, 47))	('etoposide', 'Chemical', 'MESH:D005047', (52, 61))
537320	33740988	The polyglutamate-derived brush polymer-based silencing of survivin using si-RNA (PPGS/si-survivin polyplex) combined with cisplatin exhibited synergistic cytotoxic effects on drug-resistant LC cells.	('cisplatin', 'Chemical', 'MESH:D002945', (123, 132))	('si-RNA', 'Var', (74, 80))	('survivin', 'Gene', (59, 67))	('silencing', 'NegReg', (46, 55))	('polyglutamate', 'Chemical', 'MESH:D011099', (4, 17))	('polymer', 'Chemical', 'MESH:D011108', (32, 39))	('drug-resistant', 'CPA', (176, 190))
537333	33740988	The exposure of cancer cell lines to exosomal miRNA-4315 induced apoptosis resistance to chemotherapy via inhibition of Bim (a pro-apoptotic protein) expression.	('expression', 'MPA', (150, 160))	('cancer', 'Disease', 'MESH:D009369', (16, 22))	('miRNA-4315', 'Chemical', '-', (46, 56))	('Bim', 'Gene', (120, 123))	('miRNA-4315', 'Var', (46, 56))	('cancer', 'Disease', (16, 22))	('Bim', 'Gene', '10018', (120, 123))	('apoptosis resistance to chemotherapy', 'CPA', (65, 101))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('inhibition', 'NegReg', (106, 116))	('induced', 'PosReg', (57, 64))
537348	33740988	BI1361849 increased antigen-specific immune responses in most patients, whereby antigen-specific antibody levels and functional T cells were increased by 80% and 40% of patients, respectively, supporting further clinical investigation.	('patients', 'Species', '9606', (169, 177))	('antigen-specific antibody levels', 'MPA', (80, 112))	('increased', 'PosReg', (141, 150))	('functional T cells', 'CPA', (117, 135))	('BI1361849', 'Chemical', '-', (0, 9))	('antigen-specific immune responses', 'MPA', (20, 53))	('BI1361849', 'Var', (0, 9))	('patients', 'Species', '9606', (62, 70))	('increased', 'PosReg', (10, 19))
537349	33740988	Similarly, another phase I/IIa study also demonstrated that CV9201 was well-tolerated and enhanced immune response in stage IIIB/IV NSCLC patients.	('CV9201', 'Var', (60, 66))	('rat', 'Species', '10116', (80, 83))	('age', 'Gene', (120, 123))	('immune response', 'CPA', (99, 114))	('NSCLC', 'Disease', (132, 137))	('enhanced', 'PosReg', (90, 98))	('age', 'Gene', '5973', (120, 123))	('NSCLC', 'Disease', 'MESH:D002289', (132, 137))	('rat', 'Species', '10116', (49, 52))	('patients', 'Species', '9606', (138, 146))
537360	33740988	Targeting is a major problem in cancer drug development, so such modifications also provide a window to further optimize the targeting of anticancer RNA drugs.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('modifications', 'Var', (65, 78))	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('men', 'Species', '9606', (51, 54))	('cancer', 'Disease', (32, 38))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('cancer', 'Disease', (142, 148))
537363	33740988	The field of RNA nucleoside modifications or epitranscriptomics is also under-investigated, including the identification of oligonucleotides that can target RNA modifications and the associated molecular pathways for the development of cancer therapies.	('molecular pathways', 'Pathway', (194, 212))	('cancer', 'Disease', 'MESH:D009369', (236, 242))	('nucleoside', 'Chemical', 'MESH:D009705', (17, 27))	('cancer', 'Disease', (236, 242))	('RNA', 'Gene', (157, 160))	('men', 'Species', '9606', (228, 231))	('oligonucleotides', 'Chemical', 'MESH:D009841', (124, 140))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('modifications', 'Var', (161, 174))
537421	32426701	Relative expression of the target gene was calculated as  NCtgene=(Ctgene-CtGAPDH); amplification fold = 2 Ct;  Ct >= 2 was considered positive, and  Ct < 2 negative.	('GAPDH', 'Gene', '2597', (76, 81))	('amplification fold = 2', 'Var', (84, 106))	('GAPDH', 'Gene', (76, 81))
537456	32426701	Deletion of JNK3 is associated with the occurrence and development of brain tumor.	('associated', 'Reg', (20, 30))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('JNK3', 'Gene', (12, 16))	('brain tumor', 'Disease', (70, 81))	('JNK3', 'Gene', '5602', (12, 16))	('brain tumor', 'Disease', 'MESH:D001932', (70, 81))	('brain tumor', 'Phenotype', 'HP:0030692', (70, 81))	('Deletion', 'Var', (0, 8))
537478	29115582	Myosin 1B (MYO1B) was directly regulated by miR-145-3p, and knockdown of MYO1B by siRNA inhibited cancer cell aggressiveness.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('MYO1B', 'Gene', '4430', (11, 16))	('inhibited', 'NegReg', (88, 97))	('MYO1B', 'Gene', (11, 16))	('cancer cell aggressiveness', 'Disease', 'MESH:C538614', (98, 124))	('Myosin 1B', 'Gene', (0, 9))	('miR-145', 'Gene', (44, 51))	('MYO1B', 'Gene', '4430', (73, 78))	('MYO1B', 'Gene', (73, 78))	('miR-145', 'Gene', '406937', (44, 51))	('aggressiveness', 'Phenotype', 'HP:0000718', (110, 124))	('knockdown', 'Var', (60, 69))	('cancer cell aggressiveness', 'Disease', (98, 124))	('Myosin 1B', 'Gene', '4430', (0, 9))
537480	29115582	Interestingly, high expression of MYO1B was associated with poor prognosis in patients with HNSCC by analysis of The Cancer Genome Atlas database (p=0.00452).	('high', 'Var', (15, 19))	('Cancer Genome Atlas', 'Disease', (117, 136))	('patients', 'Species', '9606', (78, 86))	('HNSCC', 'Disease', (92, 97))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (117, 136))	('HNSCC', 'Phenotype', 'HP:0012288', (92, 97))	('Cancer', 'Phenotype', 'HP:0002664', (117, 123))	('MYO1B', 'Gene', '4430', (34, 39))	('MYO1B', 'Gene', (34, 39))
537489	29115582	Thus, aberrant expression of miRNAs disrupts systematically regulated RNA networks in cancer cells.	('miR', 'Gene', (29, 32))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('miR', 'Gene', '22877', (29, 32))	('aberrant expression', 'Var', (6, 25))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('disrupts', 'NegReg', (36, 44))	('cancer', 'Disease', (86, 92))
537490	29115582	In fact, accumulating evidence has revealed that aberrant expression of miRNAs is deeply involved in the pathogenesis of human cancers.	('miR', 'Gene', '22877', (72, 75))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('involved', 'Reg', (89, 97))	('aberrant expression', 'Var', (49, 68))	('human', 'Species', '9606', (121, 126))	('cancers', 'Disease', 'MESH:D009369', (127, 134))	('cancers', 'Phenotype', 'HP:0002664', (127, 134))	('cancers', 'Disease', (127, 134))	('miR', 'Gene', (72, 75))
537506	29115582	The following RNA species were used in this study: mature miRNAs, Pre-miR miRNA Precursors (hsa-miR-145-3p, assay ID: PM 13036; hsa-miR-145-5p, assay ID: PM 11480), negative control miRNA (assay ID: AM 17111) (both from Applied Biosystems, Foster City, CA, USA), siRNA (Stealth Select RNAi siRNA; si-MYO1B P/N: HSS106714 and HSS106716; Invitrogen, Carlsbad, CA, USA).	('miR', 'Gene', '22877', (182, 185))	('miR', 'Gene', (70, 73))	('miR', 'Gene', (132, 135))	('MYO1B', 'Gene', '4430', (300, 305))	('miR-145', 'Gene', '406937', (132, 139))	('miR', 'Gene', (58, 61))	('miR', 'Gene', (74, 77))	('miR-145', 'Gene', (132, 139))	('miR', 'Gene', '22877', (70, 73))	('miR', 'Gene', '22877', (132, 135))	('miR', 'Gene', (96, 99))	('miR', 'Gene', '22877', (58, 61))	('miR-145', 'Gene', '406937', (96, 103))	('MYO1B', 'Gene', (300, 305))	('miR', 'Gene', (182, 185))	('miR', 'Gene', '22877', (74, 77))	('miR-145', 'Gene', (96, 103))	('miR', 'Gene', '22877', (96, 99))	('HSS106716', 'Var', (325, 334))
537524	29115582	Alternatively, we used sequences that were missing the miR-145-3p target sites (position 88-94 or position 1117-1123).	('miR-145', 'Gene', (55, 62))	('position 88-94', 'Var', (80, 94))	('miR-145', 'Gene', '406937', (55, 62))
537544	29115582	Similarly, after miR-145-5p transfection, miR-145-5p was detected by Ago2 immunoprecipitation (p<0.0001) (Fig.	('Ago2', 'Gene', '27161', (69, 73))	('miR-145', 'Gene', '406937', (42, 49))	('Ago2', 'Gene', (69, 73))	('-145-5p', 'Chemical', '-', (45, 52))	('-145-5p', 'Chemical', '-', (20, 27))	('transfection', 'Var', (28, 40))	('miR-145', 'Gene', (17, 24))	('miR-145', 'Gene', (42, 49))	('miR-145', 'Gene', '406937', (17, 24))
537558	29115582	Cotransfection with miR-145-3p and vectors significantly reduced luciferase activity in comparison with those in mock and miR-control transfectants in position 1117-1123 of the MYO1B 3'-UTR (Fig.	('activity', 'MPA', (76, 84))	('miR', 'Gene', '22877', (20, 23))	('miR', 'Gene', (122, 125))	('miR', 'Gene', (20, 23))	('MYO1B', 'Gene', '4430', (177, 182))	('MYO1B', 'Gene', (177, 182))	('vectors', 'Var', (35, 42))	('miR', 'Gene', '22877', (122, 125))	('miR-145', 'Gene', (20, 27))	('reduced', 'NegReg', (57, 64))	('luciferase', 'Enzyme', (65, 75))	('miR-145', 'Gene', '406937', (20, 27))
537561	29115582	Furthermore, we investigated effects of MYO1B knockdown on cell proliferation, migration, and invasion in HNSCC cell lines.	('knockdown', 'Var', (46, 55))	('investigated', 'Reg', (16, 28))	('MYO1B', 'Gene', '4430', (40, 45))	('MYO1B', 'Gene', (40, 45))	('HNSCC', 'Phenotype', 'HP:0012288', (106, 111))
537562	29115582	Cancer cell proliferation was significantly reduced in si-MYO1B transfectants in comparison with that in mock- or miR control-transfected cell lines (Fig.	('MYO1B', 'Gene', '4430', (58, 63))	('MYO1B', 'Gene', (58, 63))	('miR', 'Gene', '22877', (114, 117))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer cell proliferation', 'CPA', (0, 25))	('reduced', 'NegReg', (44, 51))	('miR', 'Gene', (114, 117))	('transfectants', 'Var', (64, 77))
537563	29115582	Additionally, migration activities were significantly suppressed in si-MYO1B transfectants in comparison with that in mock- or miR control-transfected cell lines (Fig.	('suppressed', 'NegReg', (54, 64))	('transfectants', 'Var', (77, 90))	('miR', 'Gene', (127, 130))	('MYO1B', 'Gene', '4430', (71, 76))	('MYO1B', 'Gene', (71, 76))	('migration activities', 'CPA', (14, 34))	('miR', 'Gene', '22877', (127, 130))
537564	29115582	Invasion activity was also significantly inhibited in si-MYO1B transfectants in comparison with that in mock- or miR control-transfected cell lines (Fig.	('miR', 'Gene', (113, 116))	('transfectants', 'Var', (63, 76))	('miR', 'Gene', '22877', (113, 116))	('MYO1B', 'Gene', '4430', (57, 62))	('MYO1B', 'Gene', (57, 62))	('inhibited', 'NegReg', (41, 50))	('Invasion activity', 'CPA', (0, 17))
537573	29115582	As a result, high expression of MYO1B was an independent predictive factor for survival [hazard ratio (HR), 1.68; 95% confidence interval (CI), 1.13-2.49; p=0.01] (Fig.	('survival', 'Disease', (79, 87))	('MYO1B', 'Gene', '4430', (32, 37))	('MYO1B', 'Gene', (32, 37))	('high expression', 'Var', (13, 28))
537578	29115582	Genes significantly downregulated by silencing of MYO1B are listed in Table III.	('MYO1B', 'Gene', '4430', (50, 55))	('downregulated', 'NegReg', (20, 33))	('MYO1B', 'Gene', (50, 55))	('silencing', 'Var', (37, 46))
537580	29115582	Accumulating evidence has shown that aberrant expression of miRNAs disrupts the well-ordered RNA networks in cancer cells and is involved in the pathogenesis of human cancers.	('human', 'Species', '9606', (161, 166))	('disrupts', 'NegReg', (67, 75))	('aberrant expression', 'Var', (37, 56))	('involved', 'Reg', (129, 137))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('miR', 'Gene', (60, 63))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('cancer', 'Disease', (167, 173))	('cancer', 'Disease', (109, 115))	('miR', 'Gene', '22877', (60, 63))	('cancers', 'Phenotype', 'HP:0002664', (167, 174))	('well-ordered RNA networks', 'CPA', (80, 105))	('cancers', 'Disease', (167, 174))	('cancers', 'Disease', 'MESH:D009369', (167, 174))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))
537589	29115582	Several studies have shown that downregulation of miR-145-5p is caused by hypermethylation of the promoter region of pre-miR-145 in prostate cancer.	('miR-145', 'Gene', (121, 128))	('prostate cancer', 'Disease', (132, 147))	('downregulation', 'NegReg', (32, 46))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('miR-145', 'Gene', (50, 57))	('miR-145', 'Gene', '406937', (121, 128))	('miR-145', 'Gene', '406937', (50, 57))	('prostate cancer', 'Disease', 'MESH:D011471', (132, 147))	('prostate cancer', 'Phenotype', 'HP:0012125', (132, 147))	('hypermethylation', 'Var', (74, 90))
537591	29115582	p53 mutations are found in >50% of patients with HNSCC.	('p53', 'Gene', (0, 3))	('p53', 'Gene', '7157', (0, 3))	('HNSCC', 'Phenotype', 'HP:0012288', (49, 54))	('HNSCC', 'Disease', (49, 54))	('patients', 'Species', '9606', (35, 43))	('found', 'Reg', (18, 23))	('mutations', 'Var', (4, 13))
537592	29115582	Thus, downregulation of miR-145-5p and miR-145-3p may be dependent on p53 inactivation in cancer cells.	('p53', 'Gene', (70, 73))	('p53', 'Gene', '7157', (70, 73))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('miR-145', 'Gene', (39, 46))	('miR-145', 'Gene', '406937', (39, 46))	('downregulation', 'NegReg', (6, 20))	('cancer', 'Disease', (90, 96))	('miR-145', 'Gene', '406937', (24, 31))	('miR-145', 'Gene', (24, 31))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('inactivation', 'Var', (74, 86))
537607	29115582	However, inhibition of cell proliferation was weak by knockdown of MYO1B in HNSCC cells.	('knockdown', 'Var', (54, 63))	('HNSCC', 'Phenotype', 'HP:0012288', (76, 81))	('MYO1B', 'Gene', '4430', (67, 72))	('MYO1B', 'Gene', (67, 72))	('cell proliferation', 'CPA', (23, 41))
537613	29115582	In cancer cells, MYO1B is highly expressed in PC-3 metastatic prostate cancer cells, and knockdown of MYO1B affects the cytoskeleton and cell migration.	('MYO1B', 'Gene', '4430', (17, 22))	('cytoskeleton', 'CPA', (120, 132))	('MYO1B', 'Gene', (17, 22))	('cell migration', 'CPA', (137, 151))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('prostate cancer', 'Phenotype', 'HP:0012125', (62, 77))	('cancer', 'Disease', (71, 77))	('PC-3', 'CellLine', 'CVCL:0035', (46, 50))	('cancer', 'Disease', 'MESH:D009369', (3, 9))	('cancer', 'Disease', (3, 9))	('prostate cancer', 'Disease', (62, 77))	('cancer', 'Phenotype', 'HP:0002664', (3, 9))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('knockdown', 'Var', (89, 98))	('MYO1B', 'Gene', '4430', (102, 107))	('MYO1B', 'Gene', (102, 107))	('affects', 'Reg', (108, 115))	('prostate cancer', 'Disease', 'MESH:D011471', (62, 77))
537614	29115582	Another study showed that knockdown of MYO1B significantly inhibits migratory and invasive abilities of HNSCC cells in vitro and in vivo.	('inhibits', 'NegReg', (59, 67))	('HNSCC', 'Phenotype', 'HP:0012288', (104, 109))	('MYO1B', 'Gene', '4430', (39, 44))	('MYO1B', 'Gene', (39, 44))	('knockdown', 'Var', (26, 35))
537620	29115582	Overexpression of ANXA10 has been reported in oral squamous cell carcinoma, and expression of ANXA10 promotes cancer cell proliferation through regulating mitogen-activated protein kinase signaling pathways.	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('ANXA10', 'Gene', '11199', (18, 24))	('oral squamous cell carcinoma', 'Disease', (46, 74))	('cancer', 'Disease', (110, 116))	('ANXA10', 'Gene', (18, 24))	('ANXA10', 'Gene', '11199', (94, 100))	('ANXA10', 'Gene', (94, 100))	('regulating', 'Reg', (144, 154))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (46, 74))	('promotes', 'PosReg', (101, 109))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (51, 74))	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('expression', 'Var', (80, 90))
537630	27564102	Treatment with irbesartan or AT1R-RNAi knockdown but not treatment with PD123319 significantly decreased the level of angiotensin II-induced ESCC cell proliferation.	('decreased', 'NegReg', (95, 104))	('irbesartan', 'Chemical', 'MESH:D000077405', (15, 25))	('men', 'Species', '9606', (62, 65))	('angiotensin II', 'Gene', (118, 132))	('knockdown', 'Var', (39, 48))	('AT1R-RNAi', 'Gene', (29, 38))	('men', 'Species', '9606', (5, 8))	('PD123319', 'Chemical', 'MESH:C073402', (72, 80))	('angiotensin II', 'Gene', '183', (118, 132))	('ESCC', 'Disease', (141, 145))
537631	27564102	Angiotensin II also caused mTOR activation in a dose-dependent manner, and everolimus or mTOR-RNAi knockdown significantly suppressed the level of angiotensin II-induced ESCC cell proliferation.	('angiotensin II', 'Gene', (147, 161))	('mTOR', 'MPA', (27, 31))	('activation', 'PosReg', (32, 42))	('suppressed', 'NegReg', (123, 133))	('everolimus', 'Chemical', 'MESH:D000068338', (75, 85))	('angiotensin II', 'Gene', '183', (147, 161))	('knockdown', 'Var', (99, 108))	('Angiotensin II', 'Gene', (0, 14))	('mTOR-RNAi', 'Gene', (89, 98))	('Angiotensin II', 'Gene', '183', (0, 14))	('ESCC', 'Disease', (170, 174))
537640	27564102	AT1R and AT2R have been detected in several types of cancers, and some have been reported to be associated with patients' prognosis.	('cancers', 'Phenotype', 'HP:0002664', (53, 60))	('detected', 'Reg', (24, 32))	('cancers', 'Disease', (53, 60))	('AT2R', 'Gene', (9, 13))	('cancers', 'Disease', 'MESH:D009369', (53, 60))	('associated', 'Reg', (96, 106))	('patients', 'Species', '9606', (112, 120))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('AT2R', 'Gene', '186', (9, 13))	('AT1R', 'Var', (0, 4))
537653	27564102	AT2R overexpression was significantly associated with high pathologic T classification (T3+4; P=0.016) and AT1R overexpression (P=0.001).	('AT1R', 'Var', (107, 111))	('high pathologic T classification', 'CPA', (54, 86))	('overexpression', 'PosReg', (5, 19))	('AT2R', 'Gene', (0, 4))	('AT2R', 'Gene', '186', (0, 4))
537657	27564102	The AT1R antagonists significantly decreased the level of angiotensin II-induced ESCC cell proliferation (P<0.05, Figure 3B), whereas the AT2R antagonist had no effect (P>0.05, Figure 3B).	('AT2R', 'Gene', (138, 142))	('AT1R', 'Gene', (4, 8))	('AT2R', 'Gene', '186', (138, 142))	('ESCC', 'Disease', (81, 85))	('antagonists', 'Var', (9, 20))	('decreased', 'NegReg', (35, 44))	('angiotensin II', 'Gene', '183', (58, 72))	('angiotensin II', 'Gene', (58, 72))
537664	27564102	The knockdown of endogenous AT1R in CE81T/VGH or CE48T/VGH cells led to a significant decrease of angiotensin II-induced ESCC cell proliferation, colony formation, and BrdU incorporation (P<0.05, Figure 3D and 3E and Supplementary Figure S1B and S1C).	('angiotensin II', 'Gene', '183', (98, 112))	('CE81T/VGH', 'Var', (36, 45))	('colony formation', 'CPA', (146, 162))	('CE48T/VGH', 'Var', (49, 58))	('men', 'Species', '9606', (223, 226))	('AT1R', 'Gene', (28, 32))	('angiotensin II', 'Gene', (98, 112))	('ESCC cell proliferation', 'CPA', (121, 144))	('BrdU', 'Chemical', 'MESH:D001973', (168, 172))	('decrease', 'NegReg', (86, 94))	('BrdU incorporation', 'CPA', (168, 186))
537665	27564102	Additionally, we also demonstrated that CE81T/VGH treated with irbesartan caused a dramatic reduction of angiotensin II-induced colony formation and BrdU incorporation (Figure 3F).	('BrdU incorporation', 'CPA', (149, 167))	('CE81T/VGH', 'Var', (40, 49))	('angiotensin II', 'Gene', '183', (105, 119))	('reduction', 'NegReg', (92, 101))	('angiotensin II', 'Gene', (105, 119))	('BrdU', 'Chemical', 'MESH:D001973', (149, 153))	('irbesartan', 'Chemical', 'MESH:D000077405', (63, 73))
537672	27564102	Additionally, Western blotting analyses also showed that angiotensin II stimulated p-mTOR expression in CE81T/VGH and CE48T/VGH cells in a dose-dependent manner (Figure 4A).	('angiotensin II', 'Gene', '183', (57, 71))	('stimulated', 'PosReg', (72, 82))	('CE48T/VGH', 'Var', (118, 127))	('angiotensin II', 'Gene', (57, 71))	('expression', 'MPA', (90, 100))	('CE81T/VGH', 'Var', (104, 113))	('p-mTOR', 'Protein', (83, 89))
537673	27564102	CE81T/VGH and CE48T/VGH cells were treated with everolimus (an mTOR inhibitor) prior to the angiotensin II treatment, and everolimus significantly decreased the level of angiotensin II-induced ESCC cell proliferation, colony formation, and BrdU incorporation (Figure 4B).	('men', 'Species', '9606', (112, 115))	('everolimus', 'Var', (122, 132))	('angiotensin II', 'Gene', (170, 184))	('decreased', 'NegReg', (147, 156))	('angiotensin II', 'Gene', (92, 106))	('colony formation', 'CPA', (218, 234))	('BrdU', 'Chemical', 'MESH:D001973', (240, 244))	('BrdU incorporation', 'CPA', (240, 258))	('everolimus', 'Chemical', 'MESH:D000068338', (48, 58))	('everolimus', 'Chemical', 'MESH:D000068338', (122, 132))	('CE48T/VGH', 'Var', (14, 23))	('angiotensin II', 'Gene', '183', (170, 184))	('ESCC cell proliferation', 'CPA', (193, 216))	('angiotensin II', 'Gene', '183', (92, 106))
537675	27564102	To further confirm the role of mTOR activation in angiotensin II-induced ESCC cell proliferation, siRNA was used to reduce endogenous mTOR expression in CE81T/VGH and CE48T/VGH cells.	('reduce', 'NegReg', (116, 122))	('angiotensin II', 'Gene', '183', (50, 64))	('angiotensin II', 'Gene', (50, 64))	('endogenous mTOR expression', 'MPA', (123, 149))	('CE48T/VGH', 'Var', (167, 176))	('CE81T/VGH', 'Var', (153, 162))
537676	27564102	The endogenous protein expression levels of mTOR in CE81T/VGH or CE48T/VGH cells transfected with siRNAs targeting mTOR were significantly reduced (Figure 4C and Supplementary Figure S2B).	('CE81T/VGH', 'Var', (52, 61))	('reduced', 'NegReg', (139, 146))	('siRNAs targeting', 'Var', (98, 114))	('endogenous protein expression levels', 'MPA', (4, 40))	('men', 'Species', '9606', (168, 171))
537677	27564102	The knockdown of endogenous mTOR in CE81T/VGH and CE48T/VGH cells led to a significant decrease in the angiotensin II-induced ESCC cell proliferative effect (P<0.05; Figure 4C and Supplementary Figure S2B).	('angiotensin II', 'Gene', (103, 117))	('CE81T/VGH', 'Var', (36, 45))	('CE48T/VGH', 'Var', (50, 59))	('men', 'Species', '9606', (186, 189))	('angiotensin II', 'Gene', '183', (103, 117))	('decrease', 'NegReg', (87, 95))	('ESCC cell proliferative effect', 'CPA', (126, 156))
537678	27564102	Additionally, the knockdown of endogenous AT1R in CE81T/VGH and CE48T/VGH cells also led to a decrease in the p-mTOR levels measured by Western blotting (Figure 4D and Supplementary Figure S2C).	('knockdown', 'Var', (18, 27))	('AT1R', 'Gene', (42, 46))	('p-mTOR levels', 'MPA', (110, 123))	('CE48T/VGH', 'Var', (64, 73))	('Western blotting', 'MPA', (136, 152))	('men', 'Species', '9606', (174, 177))	('CE81T/VGH', 'Var', (50, 59))	('decrease', 'NegReg', (94, 102))
537683	27564102	As shown in Figure 5A, angiotensin II significantly promoted CE81T/VGH xenograft tumor growth compared to a vehicle control group.	('CE81T/VGH', 'Var', (61, 70))	('angiotensin II', 'Gene', '183', (23, 37))	('angiotensin II', 'Gene', (23, 37))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('promoted', 'PosReg', (52, 60))	('tumor', 'Disease', (81, 86))
537732	27564102	For AT1R and AT2R, incubation without the primary antibody was used as a negative control, while normal adrenal gland was used as a positive control.	('AT2R', 'Gene', (13, 17))	('AT2R', 'Gene', '186', (13, 17))	('AT1R', 'Var', (4, 8))
537735	27564102	The AT1R or AT2R overexpression was defined as the presence of at least staining in  35% of tumor cells.	('AT1R', 'Var', (4, 8))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('AT2R', 'Gene', (12, 16))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('AT2R', 'Gene', '186', (12, 16))	('overexpression', 'PosReg', (17, 31))	('tumor', 'Disease', (92, 97))
537743	27564102	The CE81T/VGH and CE48T/VGH ESCC cell lines were obtained from the Bioresource Collection and Research Center (BCRC), and cultured in Dulbecco's Modified Eagle Medium (DMEM) supplemented with 10% fetal calf serum, 2 mmol/L glutamine, 100 U/mL penicillin, and 100 mug/mL streptomycin.	('DMEM', 'Chemical', '-', (168, 172))	('CE81T/VGH', 'Var', (4, 13))	('streptomycin', 'Chemical', 'MESH:D013307', (270, 282))	('calf', 'Species', '9913', (202, 206))	('penicillin', 'Chemical', 'MESH:D010406', (243, 253))	('men', 'Species', '9606', (180, 183))	("Dulbecco's Modified Eagle Medium", 'Chemical', '-', (134, 166))	('glutamine', 'Chemical', 'MESH:D005973', (223, 232))	('CE48T/VGH', 'Var', (18, 27))
537770	27564102	Dysplasia was defined as loss of polarity in the epithelial cells, nuclear pleomorphism and hyperchromasia, abnormal single cell keratinization (dyskeratosis), and increased or abnormal mitoses.	('polarity', 'MPA', (33, 41))	('dyskeratosis', 'Disease', (145, 157))	('hyperchromasia', 'Disease', (92, 106))	('hyperchromasia', 'Disease', 'None', (92, 106))	('dyskeratosis', 'Disease', 'MESH:D019871', (145, 157))	('nuclear pleomorphism', 'Var', (67, 87))	('loss', 'NegReg', (25, 29))	('Dysplasia', 'Disease', (0, 9))	('Dysplasia', 'Disease', 'MESH:D004476', (0, 9))
537779	24206917	Originally associated with hemotologic cancers, fusion genes have recently been discovered in a wide array of solid tumors, including sarcomas, carcinomas, and tumors of the central nervous system.	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))	('sarcomas', 'Disease', 'MESH:D012509', (134, 142))	('sarcoma', 'Phenotype', 'HP:0100242', (134, 141))	('tumors of the central nervous system', 'Disease', 'MESH:D016543', (160, 196))	('carcinomas', 'Phenotype', 'HP:0030731', (144, 154))	('sarcomas', 'Phenotype', 'HP:0100242', (134, 142))	('solid tumors', 'Disease', 'MESH:D009369', (110, 122))	('tumors of the central nervous system', 'Disease', (160, 196))	('carcinomas', 'Disease', 'MESH:D002277', (144, 154))	('sarcomas', 'Disease', (134, 142))	('hemotologic cancers', 'Disease', 'MESH:D009369', (27, 46))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('hemotologic cancers', 'Disease', (27, 46))	('cancers', 'Phenotype', 'HP:0002664', (39, 46))	('discovered', 'Reg', (80, 90))	('carcinomas', 'Disease', (144, 154))	('associated', 'Reg', (11, 21))	('fusion genes', 'Var', (48, 60))	('solid tumors', 'Disease', (110, 122))	('tumors of the central nervous system', 'Phenotype', 'HP:0100006', (160, 196))	('tumors', 'Phenotype', 'HP:0002664', (160, 166))
537780	24206917	Fusion genes are attractive as both therapeutic targets and diagnostic tools due to their inherent expression in tumor tissue alone.	('tumor', 'Disease', (113, 118))	('Fusion', 'Var', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('tumor', 'Disease', 'MESH:D009369', (113, 118))
537781	24206917	Therefore, the discovery and elucidation of fusion genes in various cancer types may provide more effective therapies in the future for cancer patients.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('patients', 'Species', '9606', (143, 151))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('cancer', 'Disease', (136, 142))	('cancer', 'Disease', (68, 74))	('fusion genes', 'Var', (44, 56))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
537782	24206917	Genomic instability, or the rearrangement of the genome inside of a cell, can result in cancer as well as other diseases.	('cancer', 'Disease', (88, 94))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('result in', 'Reg', (78, 87))	('rearrangement', 'Var', (28, 41))	('Genomic', 'MPA', (0, 7))	('men', 'Species', '9606', (37, 40))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))
537783	24206917	Genomic instability can describe gene mutations, translocations, copy number alterations, deletions, and inversions of pieces of DNA or even single nucleotides.	('translocations', 'Var', (49, 63))	('rat', 'Species', '10116', (81, 84))	('copy number alterations', 'Var', (65, 88))	('gene mutations', 'Var', (33, 47))	('inversions', 'Var', (105, 115))	('deletions', 'Var', (90, 99))
537786	24206917	Conversely, tumor suppressor genes also exist, and mutation or deletion of these genes can cause cancer.	('cause', 'Reg', (91, 96))	('cancer', 'Disease', (97, 103))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('mutation', 'Var', (51, 59))	('deletion', 'Var', (63, 71))	('tumor', 'Disease', (12, 17))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
537791	24206917	When mutated in a high-grade brain tumor, EGFR becomes constitutively activated.	('brain tumor', 'Disease', (29, 40))	('EGFR', 'Gene', '1956', (42, 46))	('brain tumor', 'Disease', 'MESH:D001932', (29, 40))	('tumor', 'Phenotype', 'HP:0002664', (35, 40))	('EGFR', 'Gene', (42, 46))	('brain tumor', 'Phenotype', 'HP:0030692', (29, 40))	('mutated', 'Var', (5, 12))
537792	24206917	Other genetic events, including gene translocations and deletions, can also occur and lead to cancer.	('gene translocations', 'Var', (32, 51))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('deletions', 'Var', (56, 65))	('lead to', 'Reg', (86, 93))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
537804	24206917	Since then, dozens of fusions have been identified in hematologic cancers, some of which have exhibited vast therapeutic benefit when targeted.	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('fusions', 'Var', (22, 29))	('hematologic cancers', 'Disease', 'MESH:D009369', (54, 73))	('hematologic cancers', 'Disease', (54, 73))	('cancers', 'Phenotype', 'HP:0002664', (66, 73))	('identified', 'Reg', (40, 50))
537807	24206917	For example, the promyelocytic leukemia (PML)-retinoic acid receptor alpha (RARA) fusion found in nearly 95% of acute promyelocytic leukemias occurs via reciprocal translocation of chromosomes 15 and 17, producing fusions that contain the oncogenic retinoic acid receptor alpha.	('leukemia', 'Phenotype', 'HP:0001909', (31, 39))	('retinoic acid receptor alpha', 'Gene', '5914', (249, 277))	('fusions', 'Var', (214, 221))	('promyelocytic leukemia', 'Phenotype', 'HP:0004836', (17, 39))	('RARA', 'Gene', (76, 80))	('promyelocytic leukemia', 'Disease', 'MESH:D015473', (118, 140))	('retinoic acid receptor alpha', 'Gene', (46, 74))	('promyelocytic leukemia', 'Disease', (17, 39))	('leukemia', 'Phenotype', 'HP:0001909', (132, 140))	('promyelocytic leukemias', 'Disease', (118, 141))	('promyelocytic leukemia', 'Phenotype', 'HP:0004836', (118, 140))	('retinoic acid receptor alpha', 'Gene', '5914', (46, 74))	('fusion', 'Var', (82, 88))	('leukemias', 'Phenotype', 'HP:0001909', (132, 141))	('retinoic acid receptor alpha', 'Gene', (249, 277))	('promyelocytic leukemia', 'Disease', 'MESH:D015473', (17, 39))	('promyelocytic leukemias', 'Disease', 'MESH:D015473', (118, 141))	('RARA', 'Gene', '5914', (76, 80))	('PML', 'Phenotype', 'HP:0004836', (41, 44))	('acute promyelocytic leukemias', 'Phenotype', 'HP:0004836', (112, 141))
537809	24206917	With the development of more sophisticated sequencing technologies came the discovery of fusion genes in solid tumors, including sarcoma, carcinoma, and tumors of the central nervous system (Figure 2).	('carcinoma', 'Disease', 'MESH:D002277', (138, 147))	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('fusion genes', 'Var', (89, 101))	('solid tumors', 'Disease', 'MESH:D009369', (105, 117))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('carcinoma', 'Disease', (138, 147))	('sarcoma', 'Disease', (129, 136))	('sarcoma', 'Disease', 'MESH:D012509', (129, 136))	('tumors of the central nervous system', 'Phenotype', 'HP:0100006', (153, 189))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('men', 'Species', '9606', (16, 19))	('tumors of the central nervous system', 'Disease', 'MESH:D016543', (153, 189))	('tumors', 'Phenotype', 'HP:0002664', (153, 159))	('tumors of the central nervous system', 'Disease', (153, 189))	('solid tumors', 'Disease', (105, 117))	('sarcoma', 'Phenotype', 'HP:0100242', (129, 136))
537818	24206917	The first detected fusion genes in sarcoma were found in a patient with Ewing sarcoma in 1983.	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (72, 85))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (72, 85))	('fusion', 'Var', (19, 25))	('sarcoma', 'Disease', (35, 42))	('sarcoma', 'Phenotype', 'HP:0100242', (35, 42))	('patient', 'Species', '9606', (59, 66))	('sarcoma', 'Disease', 'MESH:D012509', (78, 85))	('Ewing sarcoma', 'Disease', (72, 85))	('sarcoma', 'Disease', (78, 85))	('sarcoma', 'Phenotype', 'HP:0100242', (78, 85))	('sarcoma', 'Disease', 'MESH:D012509', (35, 42))
537823	24206917	Epidemiologic studies have illustrated that several cancers show a survival correlation with high IGF-1 (the ligand for IGF-1R) and low IGFBP-3 (a binding protein of IGF-1R).	('cancers', 'Disease', (52, 59))	('IGF-1R', 'Gene', (120, 126))	('rat', 'Species', '10116', (33, 36))	('IGF-1R', 'Gene', '3480', (120, 126))	('high IGF-1', 'Phenotype', 'HP:0030269', (93, 103))	('IGFBP-3', 'Gene', (136, 143))	('low IGFBP-3', 'Phenotype', 'HP:0031037', (132, 143))	('IGF-1', 'Gene', '3480', (98, 103))	('IGF-1', 'Gene', (98, 103))	('IGFBP-3', 'Gene', '3486', (136, 143))	('high', 'Var', (93, 97))	('cancers', 'Disease', 'MESH:D009369', (52, 59))	('IGF-1R', 'Gene', '3480', (166, 172))	('IGF-1R', 'Gene', (166, 172))	('IGF-1', 'Gene', '3480', (120, 125))	('IGF-1', 'Gene', (120, 125))	('low', 'NegReg', (132, 135))	('IGF-1', 'Gene', (166, 171))	('IGF-1', 'Gene', '3480', (166, 171))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('cancers', 'Phenotype', 'HP:0002664', (52, 59))
537828	24206917	Recent studies have identified another small subset of Ewing sarcoma patients who have fusions between the nuclear factor of activated T-cell transcription factor family with EWSR1.	('Ewing sarcoma', 'Disease', 'MESH:C563168', (55, 68))	('fusions', 'Var', (87, 94))	('EWSR1', 'Gene', '2130', (175, 180))	('sarcoma', 'Phenotype', 'HP:0100242', (61, 68))	('Ewing sarcoma', 'Disease', (55, 68))	('patients', 'Species', '9606', (69, 77))	('EWSR1', 'Gene', (175, 180))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (55, 68))
537831	24206917	As mentioned previously, Ewing sarcoma is characterized by exhibiting fusions between EWSR1 and the ETS family of transcription factors.	('EWSR1', 'Gene', (86, 91))	('sarcoma', 'Phenotype', 'HP:0100242', (31, 38))	('Ewing sarcoma', 'Disease', (25, 38))	('ETS', 'Chemical', '-', (100, 103))	('EWSR1', 'Gene', '2130', (86, 91))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (25, 38))	('fusions', 'Var', (70, 77))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (25, 38))	('men', 'Species', '9606', (3, 6))
537833	24206917	Specifically, fusions between the BCL-6 corepressor (BCOR) gene and cyclin B3 (CCNB3) gene were identified in 4% (24/594) of EWSR1-ETS-negative patients.	('ETS', 'Chemical', '-', (131, 134))	('cyclin B3', 'Gene', (68, 77))	('identified', 'Reg', (96, 106))	('EWSR1', 'Gene', (125, 130))	('BCL-6 corepressor', 'Gene', (34, 51))	('CCNB3', 'Gene', '85417', (79, 84))	('BCL-6 corepressor', 'Gene', '54880', (34, 51))	('BCOR', 'Gene', (53, 57))	('patients', 'Species', '9606', (144, 152))	('EWSR1', 'Gene', '2130', (125, 130))	('BCOR', 'Gene', '54880', (53, 57))	('cyclin B3', 'Gene', '85417', (68, 77))	('fusions', 'Var', (14, 21))	('CCNB3', 'Gene', (79, 84))
537834	24206917	The authors concluded that they discovered a new subset of "Ewing-like" tumors that are characterized by this BCOR-CCNB3 fusion but lack other known Ewing sarcoma fusions.	('BCOR', 'Gene', (110, 114))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('CCNB3', 'Gene', (115, 120))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (149, 162))	('BCOR', 'Gene', '54880', (110, 114))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (149, 162))	('Ewing-like" tumors', 'Disease', (60, 78))	('sarcoma', 'Phenotype', 'HP:0100242', (155, 162))	('fusion', 'Var', (121, 127))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('Ewing-like" tumors', 'Disease', 'MESH:C563168', (60, 78))	('CCNB3', 'Gene', '85417', (115, 120))	('Ewing sarcoma', 'Disease', (149, 162))	('Ewing-like" tumors', 'Phenotype', 'HP:0012254', (60, 78))
537841	24206917	The primary function of the SS18-SSX1 and SS18-SSX2 fusions is purportedly to regulate transcription, although no canonical DNA-binding domain exists in the fusion.	('SSX1', 'Gene', (33, 37))	('SSX2', 'Gene', '6757', (47, 51))	('regulate', 'Reg', (78, 86))	('SS18', 'Gene', '6760', (42, 46))	('transcription', 'MPA', (87, 100))	('SS18', 'Gene', '6760', (28, 32))	('SS18', 'Gene', (28, 32))	('SSX2', 'Gene', (47, 51))	('SSX1', 'Gene', '6756', (33, 37))	('fusions', 'Var', (52, 59))	('SS18', 'Gene', (42, 46))
537845	24206917	These sarcomas commonly harbor a translocation fusing EWSR1 on chromosome 22 to ATF1 on chromosome 12.	('sarcoma', 'Phenotype', 'HP:0100242', (6, 13))	('EWSR1', 'Gene', '2130', (54, 59))	('sarcomas', 'Disease', (6, 14))	('ATF1', 'Gene', (80, 84))	('ATF1', 'Gene', '466', (80, 84))	('EWSR1', 'Gene', (54, 59))	('translocation', 'Var', (33, 46))	('sarcomas', 'Disease', 'MESH:D012509', (6, 14))	('sarcomas', 'Phenotype', 'HP:0100242', (6, 14))
537855	24206917	Fusions containing another androgen-regulated promoter for the solute carrier family 45, member 3 (SLC45A3) gene have also been reported to be fused to the same three ETS family members and behave in a similar fashion to TMPRSS2, although this fusion occurs less commonly.	('Fusions', 'Var', (0, 7))	('TMPRSS2', 'Gene', '7113', (221, 228))	('ETS', 'Chemical', '-', (167, 170))	('solute carrier family 45, member 3', 'Gene', '85414', (63, 97))	('TMPRSS2', 'Gene', (221, 228))	('SLC45A3', 'Gene', '85414', (99, 106))	('SLC45A3', 'Gene', (99, 106))
537863	24206917	This fusion, originally characterized in congenital fibrosarcoma, was found to promote oncogenesis via activation of the Ras-MAPK and PI3K-AKT pathways.	('congenital fibrosarcoma', 'Disease', (41, 64))	('fusion', 'Var', (5, 11))	('congenital fibrosarcoma', 'Disease', 'MESH:D005354', (41, 64))	('AKT', 'Gene', '207', (139, 142))	('sarcoma', 'Phenotype', 'HP:0100242', (57, 64))	('MAPK', 'Gene', '5595;5594;5595', (125, 129))	('AKT', 'Gene', (139, 142))	('promote', 'PosReg', (79, 86))	('MAPK', 'Gene', (125, 129))	('activation', 'PosReg', (103, 113))	('oncogenesis', 'CPA', (87, 98))	('fibrosarcoma', 'Phenotype', 'HP:0100244', (52, 64))
537868	24206917	Bladder cancer is historically associated with activating mutations in the FGFR3 gene but has recently been shown to also harbor FGFR3-TACC3 fusion in about 10% of patients.	('FGFR3', 'Gene', (129, 134))	('mutations', 'Var', (58, 67))	('FGFR3', 'Gene', (75, 80))	('Bladder cancer', 'Disease', (0, 14))	('Bladder cancer', 'Phenotype', 'HP:0009725', (0, 14))	('TACC3', 'Gene', '10460', (135, 140))	('Bladder cancer', 'Disease', 'MESH:D001749', (0, 14))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('FGFR3', 'Gene', '2261', (129, 134))	('TACC3', 'Gene', (135, 140))	('FGFR3', 'Gene', '2261', (75, 80))	('patients', 'Species', '9606', (164, 172))	('activating', 'PosReg', (47, 57))
537895	24206917	The oncogenic function of the fusion is believed to be caused by overexpression of the ALK tyrosine kinase, which leads to constitutive activation of downstream signaling cascades, including Akt, MAPK, and signal transducer and activator of transcription 3 (STAT3).	('MAPK', 'Gene', '5595;5594;5595', (196, 200))	('Akt', 'Gene', '207', (191, 194))	('fusion', 'Var', (30, 36))	('MAPK', 'Gene', (196, 200))	('ALK', 'Gene', '238', (87, 90))	('Akt', 'Gene', (191, 194))	('activation', 'PosReg', (136, 146))	('STAT3', 'Gene', '6774', (258, 263))	('overexpression', 'PosReg', (65, 79))	('signal transducer and activator of transcription 3', 'Gene', '6774', (206, 256))	('ALK', 'Gene', (87, 90))	('STAT3', 'Gene', (258, 263))
537896	24206917	The ALK inhibitor PF02341066, known as crizontinib, is currently undergoing clinical trials and has demonstrated significant clinical efficacy thus far in patients with EML4-ALK-positive NSCLC.	('ALK', 'Gene', '238', (4, 7))	('EML4', 'Gene', '27436', (169, 173))	('NSCLC', 'Phenotype', 'HP:0030358', (187, 192))	('PF02341066', 'Chemical', 'MESH:D000077547', (18, 28))	('ALK', 'Gene', (174, 177))	('ALK', 'Gene', (4, 7))	('NSCLC', 'Disease', (187, 192))	('crizontinib', 'Chemical', '-', (39, 50))	('PF02341066', 'Var', (18, 28))	('NSCLC', 'Disease', 'MESH:D002289', (187, 192))	('patients', 'Species', '9606', (155, 163))	('EML4', 'Gene', (169, 173))	('ALK', 'Gene', '238', (174, 177))	('rat', 'Species', '10116', (107, 110))
537903	24206917	In 2009, a group discovered the MYB-nuclear factor 1 B-type (NFIB) fusion, which formed as a result of translocation between chromosomes 6 and 9, with on occurrence rate of 90%.	('rat', 'Species', '10116', (165, 168))	('MYB', 'Gene', '4602', (32, 35))	('translocation', 'Var', (103, 116))	('MYB', 'Gene', (32, 35))	('NFIB', 'Gene', (61, 65))	('NFIB', 'Gene', '4781', (61, 65))
537906	24206917	In fact, pleomorphic salivary gland adenomas have also been shown to harbor fusions of NFIB with high mobility group AT-Hook 2 (HMGA2).	('NFIB', 'Gene', (87, 91))	('high mobility group AT-Hook 2', 'Gene', (97, 126))	('HMGA2', 'Gene', (128, 133))	('pleomorphic salivary gland adenomas', 'Disease', 'MESH:C563250', (9, 44))	('high mobility group AT-Hook 2', 'Gene', '8091', (97, 126))	('NFIB', 'Gene', '4781', (87, 91))	('fusions', 'Var', (76, 83))	('pleomorphic salivary gland adenomas', 'Disease', (9, 44))	('HMGA2', 'Gene', '8091', (128, 133))
537907	24206917	The formation of the MYB-NFIB fusion resulted in the deletion of the 3' untranslated region of MYB.	('resulted in', 'Reg', (37, 48))	('deletion', 'Var', (53, 61))	('MYB', 'Gene', '4602', (95, 98))	('MYB', 'Gene', (95, 98))	('MYB', 'Gene', '4602', (21, 24))	('NFIB', 'Gene', (25, 29))	('MYB', 'Gene', (21, 24))	('NFIB', 'Gene', '4781', (25, 29))
537912	24206917	The mucoepidermoid carcinoma translocated 1 (MECT1)-Notch coactivator mastermind-like protein 2 (MAML2) fusion occurs in approximately 60% of patients with mucoepidermoid carcinoma and contains the MECT1 gene, also known as CREB-regulated transcription coactivator 1, fused to MAML2.	('MECT1', 'Gene', (198, 203))	('CREB-regulated transcription coactivator 1', 'Gene', '23373', (224, 266))	('CREB-regulated transcription coactivator 1', 'Gene', (224, 266))	('Notch', 'Gene', (52, 57))	('mucoepidermoid carcinoma', 'Disease', 'MESH:D018277', (156, 180))	('MAML2', 'Gene', '84441', (277, 282))	('mucoepidermoid carcinoma', 'Disease', 'MESH:D018277', (4, 28))	('MECT1', 'Gene', (45, 50))	('mucoepidermoid carcinoma translocated 1', 'Gene', '23373', (4, 43))	('mucoepidermoid carcinoma translocated 1', 'Gene', (4, 43))	('mastermind-like protein 2', 'Gene', '84441', (70, 95))	('Notch', 'Gene', '25496', (52, 57))	('MECT1', 'Gene', '23373', (198, 203))	('MAML2', 'Gene', (97, 102))	('fusion', 'Var', (104, 110))	('carcinoma', 'Phenotype', 'HP:0030731', (171, 180))	('carcinoma', 'Phenotype', 'HP:0030731', (19, 28))	('mastermind-like protein 2', 'Gene', (70, 95))	('MAML2', 'Gene', '84441', (97, 102))	('patients', 'Species', '9606', (142, 150))	('mucoepidermoid carcinoma', 'Disease', (156, 180))	('MAML2', 'Gene', (277, 282))	('MECT1', 'Gene', '23373', (45, 50))
537913	24206917	The fusion was found to induce Notch signaling and cause cellular transformation of RK3E epithelial cells.	('induce', 'Reg', (24, 30))	('Notch', 'Gene', '25496', (31, 36))	('cellular transformation', 'CPA', (57, 80))	('fusion', 'Var', (4, 10))	('Notch', 'Gene', (31, 36))	('cause', 'Reg', (51, 56))	('RK3', 'CellLine', 'CVCL:0503', (84, 87))
537914	24206917	Recent studies have shown that the presence of MAML2 rearrangements as measured by fluorescence in situ hybridization can be used as a mean to distinguish mucoepidermoid carcinoma from other oncocytic lesions.	('MAML2', 'Gene', (47, 52))	('mucoepidermoid carcinoma', 'Disease', 'MESH:D018277', (155, 179))	('men', 'Species', '9606', (62, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (170, 179))	('oncocytic lesions', 'Disease', (191, 208))	('mucoepidermoid carcinoma', 'Disease', (155, 179))	('rearrangements', 'Var', (53, 67))	('oncocytic lesions', 'Disease', 'MESH:C535584', (191, 208))	('MAML2', 'Gene', '84441', (47, 52))
537919	24206917	In 2000, the paired box gene 8 (PAX8)-peroxisome proliferator-activated receptor gamma (PPARG) fusion was identified in 60% of follicular thyroid cancer cases.	('thyroid cancer', 'Disease', (138, 152))	('paired box gene 8', 'Gene', '7849', (13, 30))	('thyroid cancer', 'Phenotype', 'HP:0002890', (138, 152))	('thyroid cancer', 'Disease', 'MESH:D013964', (138, 152))	('PPARG', 'Gene', (88, 93))	('peroxisome proliferator-activated receptor gamma', 'Gene', '5468', (38, 86))	('PAX8', 'Gene', '7849', (32, 36))	('peroxisome proliferator-activated receptor gamma', 'Gene', (38, 86))	('paired box gene 8', 'Gene', (13, 30))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('follicular thyroid cancer', 'Phenotype', 'HP:0006731', (127, 152))	('PAX8', 'Gene', (32, 36))	('fusion', 'Var', (95, 101))
537948	24206917	Genomic instability is a hallmark of cancer and can be described as gene mutation, amplification, translocation, deletion, and inversion events.	('hallmark of cancer', 'Disease', (25, 43))	('deletion', 'Var', (113, 121))	('hallmark of cancer', 'Disease', 'MESH:D009369', (25, 43))	('Genomic', 'MPA', (0, 7))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('translocation', 'Var', (98, 111))	('amplification', 'Var', (83, 96))
537949	24206917	The discovery of fusion genes in hematologic malignancies in the 1970s led to the development of potent therapeutics.	('fusion genes', 'Var', (17, 29))	('men', 'Species', '9606', (89, 92))	('hematologic malignancies', 'Disease', 'MESH:D019337', (33, 57))	('hematologic malignancies', 'Disease', (33, 57))
537963	32065978	Chronic UVR exposure leads to mutations in known tumor suppressor genes (TP53, NOTCH1, FAT1) and known oncogenes (HRAS, KRAS, NRAS).	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('KRAS', 'Gene', '3845', (120, 124))	('TP53', 'Gene', '7157', (73, 77))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('TP53', 'Gene', (73, 77))	('tumor', 'Disease', (49, 54))	('NRAS', 'Gene', '4893', (126, 130))	('HRAS', 'Gene', '3265', (114, 118))	('FAT1', 'Gene', '2195', (87, 91))	('mutations', 'Var', (30, 39))	('KRAS', 'Gene', (120, 124))	('HRAS', 'Gene', (114, 118))	('NRAS', 'Gene', (126, 130))	('NOTCH1', 'Gene', '4851', (79, 85))	('NOTCH1', 'Gene', (79, 85))	('FAT1', 'Gene', (87, 91))
537965	32065978	Genome sequencing of cSCC has revealed nearly universal inactivating or non-synonymous mutations in TP53.	('TP53', 'Gene', '7157', (100, 104))	('non-synonymous', 'MPA', (72, 86))	('inactivating', 'Var', (56, 68))	('TP53', 'Gene', (100, 104))	('cSCC', 'Phenotype', 'HP:0006739', (21, 25))
537968	32065978	In cell culture experiments, tacrolimus and mycophenolate were also shown to impair nucleotide excision repair pathways which are often used by keratinocytes to combat UVR-induced base substitution  Furthermore, increasing evidence suggests that the drugs given to modulate T cell immunity may have a carcinogenic effect by modulation of transcription factors.	('nucleotide', 'Enzyme', (84, 94))	('carcinogenic', 'Disease', 'MESH:D063646', (301, 313))	('tacrolimus', 'Chemical', 'MESH:D016559', (29, 39))	('carcinogenic', 'Disease', (301, 313))	('mycophenolate', 'Chemical', 'MESH:D009173', (44, 57))	('modulate', 'Var', (265, 273))	('impair', 'NegReg', (77, 83))	('modulation', 'Reg', (324, 334))
538009	32065978	PDT was found to be more effective at clearing field disease than topical chemotherapy and imiquimod in SOTRs.	('PDT', 'Var', (0, 3))	('imiquimod', 'Chemical', 'MESH:D000077271', (91, 100))	('clearing field disease', 'Disease', (38, 60))
538061	32065978	In a phase I study of an mTOR inhibitor combined with chemoradiation in head and neck cancer, 5mg day was associated with dose limiting mucositis in 1 of 6 patients, with grade 3 mucositis developing very early on during radiation.	('patients', 'Species', '9606', (156, 164))	('5mg day', 'Var', (94, 101))	('head and neck cancer', 'Disease', 'MESH:D006258', (72, 92))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('head and neck cancer', 'Phenotype', 'HP:0012288', (72, 92))	('mucositis', 'Disease', (136, 145))	('mucositis', 'Disease', (179, 188))	('mTOR', 'Gene', '2475', (25, 29))	('mucositis', 'Disease', 'MESH:D052016', (136, 145))	('mTOR', 'Gene', (25, 29))	('mucositis', 'Disease', 'MESH:D052016', (179, 188))
538099	31761621	Aberrant expression of embryonic mesendoderm factor MESP1 promotes tumorigenesis Mesoderm Posterior 1 (MESP1) belongs to the family of basic helix-loop-helix transcription factors.	('MESP1', 'Gene', '55897', (52, 57))	('Aberrant expression', 'Var', (0, 19))	('tumorigenesis', 'CPA', (67, 80))	('promotes', 'PosReg', (58, 66))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('MESP1', 'Gene', (52, 57))	('MESP1', 'Gene', (103, 108))	('MESP1', 'Gene', '55897', (103, 108))
538106	31761621	Ectopic MESP1 expression cooperates with loss of tumor suppressor ARF to transform murine fibroblasts.	('MESP1', 'Gene', (8, 13))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('loss of tumor', 'Disease', 'MESH:D009369', (41, 54))	('ARF', 'Disease', 'MESH:D058186', (66, 69))	('Ectopic', 'Var', (0, 7))	('ARF', 'Disease', (66, 69))	('loss of tumor', 'Disease', (41, 54))	('murine', 'Species', '10090', (83, 89))
538117	31761621	Co-expression of MESP1 and its target genes predicted poor prognosis in lung cancer patients.	('patients', 'Species', '9606', (84, 92))	('MESP1', 'Gene', (17, 22))	('lung cancer', 'Disease', (72, 83))	('Co-expression', 'Var', (0, 13))	('lung cancer', 'Phenotype', 'HP:0100526', (72, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('lung cancer', 'Disease', 'MESH:D008175', (72, 83))
538118	31761621	Implications of all the available evidence Our work provides the first evidence of aberrant expression, functional relevance and transcriptome-profiles of MESP1, which may serve as a promising biomarker and a therapeutic target in lung cancer.	('lung cancer', 'Disease', (231, 242))	('lung cancer', 'Phenotype', 'HP:0100526', (231, 242))	('aberrant', 'Var', (83, 91))	('lung cancer', 'Disease', 'MESH:D008175', (231, 242))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('MESP1', 'Gene', (155, 160))	('expression', 'MPA', (92, 102))
538126	31761621	The emerging theory of lineage addiction model proposes that altering the expression of these lineage-survival genes can give rise to precancerous cells with survival advantage and inbuilt framework to progress to full tumorigenicity.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('expression', 'MPA', (74, 84))	('survival advantage', 'CPA', (158, 176))	('give rise', 'Reg', (121, 130))	('altering', 'Var', (61, 69))	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('tumor', 'Disease', (219, 224))	('progress', 'PosReg', (202, 210))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('cancer', 'Disease', (137, 143))	('tumor', 'Disease', 'MESH:D009369', (219, 224))
538130	31761621	MESP1 null mouse embryos develop cardiac malformation, leading to embryonic lethality at E10.5.	('cardiac malformation', 'Disease', (33, 53))	('develop', 'PosReg', (25, 32))	('mouse', 'Species', '10090', (11, 16))	('MESP1', 'Gene', (0, 5))	('cardiac malformation', 'Phenotype', 'HP:0001627', (33, 53))	('embryonic lethality', 'Disease', 'MESH:D020964', (66, 85))	('cardiac malformation', 'Disease', 'MESH:D006331', (33, 53))	('embryonic lethality', 'Disease', (66, 85))	('E10.5', 'Var', (89, 94))
538132	31761621	Recently, MESP1 knockdown has been shown to attenuate vascular lineage differentiation of human induced pluripotent stem cells (iPSCs).	('attenuate', 'NegReg', (44, 53))	('MESP1', 'Gene', (10, 15))	('knockdown', 'Var', (16, 25))	('human', 'Species', '9606', (90, 95))	('vascular lineage differentiation', 'CPA', (54, 86))
538135	31761621	In this study, we report that MESP1 knockdown in NSCLC cells attenuated cell proliferation and survival.	('NSCLC', 'Disease', (49, 54))	('MESP1', 'Gene', (30, 35))	('NSCLC', 'Disease', 'MESH:D002289', (49, 54))	('knockdown', 'Var', (36, 45))	('cell proliferation', 'CPA', (72, 90))	('attenuated', 'NegReg', (61, 71))	('NSCLC', 'Phenotype', 'HP:0030358', (49, 54))
538140	31761621	For generating EK-mutant of mouse Mesp1 and human MESP1, site-directed mutagenesis kit from Millipore (KOD Xtreme Hot start DNA polymerase Cat # 71975) was used.	('human', 'Species', '9606', (44, 49))	('MESP1', 'Gene', (50, 55))	('EK-mutant', 'Var', (15, 24))	('mouse', 'Species', '10090', (28, 33))	('Hot start', 'Phenotype', 'HP:0031217', (114, 123))
538144	31761621	p19ARF null MEFs and p53 null MEFs were kind gifts from Dr. Martine F. Roussel and Dr. Charles J. Sherr (St. Jude Children's Research Hospital) and Dr. Michelle C. Barton (The University of Texas MD Anderson Cancer Center) respectively.	('Cancer', 'Disease', 'MESH:D009369', (208, 214))	('MEFs', 'CellLine', 'CVCL:9115', (12, 16))	('Children', 'Species', '9606', (114, 122))	('p19ARF', 'Var', (0, 6))	('MEFs', 'CellLine', 'CVCL:9115', (30, 34))	('p53 null', 'Var', (21, 29))	('Cancer', 'Disease', (208, 214))	('Cancer', 'Phenotype', 'HP:0002664', (208, 214))
538167	31761621	Antibodies used were: anti-MESP1 (ab173011 and ab230308); anti-FLAG (Cell Signaling, 8146S); anti-CDKN2A/p19ARF (ab80); anti-p14 ARF (Cell Signaling, 2407S); anti-V5 tag (MCA1360GA Biorad); anti-beta actin (AM1021b); anti-normal mouse IgG (Millipore-sigma 12-371); anti-p53 (sc-126 and sc-98).	('ARF', 'Disease', (108, 111))	('beta actin', 'Gene', (195, 205))	('AM1021b', 'Var', (207, 214))	('ARF', 'Disease', 'MESH:D058186', (129, 132))	('ARF', 'Disease', (129, 132))	('mouse', 'Species', '10090', (229, 234))	('beta actin', 'Gene', '11461', (195, 205))	('ARF', 'Disease', 'MESH:D058186', (108, 111))	('anti-p53', 'Var', (265, 273))
538179	31761621	For H358, tumors were harvested 15 days post-injection, while for A549, tumors were harvested 38 days post-injection.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('A549', 'CellLine', 'CVCL:0023', (66, 70))	('H358', 'CellLine', 'CVCL:1559', (4, 8))	('tumors', 'Disease', (10, 16))	('tumors', 'Disease', (72, 78))	('tumors', 'Disease', 'MESH:D009369', (10, 16))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('tumors', 'Phenotype', 'HP:0002664', (10, 16))	('H358', 'Var', (4, 8))
538189	31761621	Next, we validated the aberrant expression of MESP1 by qRT-PCR analysis of patient RNA samples of lung squamous cell carcinoma (n = 5), lung adenocarcinoma (n = 5) and normal lung tissue (n = 5) (Fig.	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (98, 126))	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (136, 155))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (103, 126))	('patient', 'Species', '9606', (75, 82))	('lung squamous cell carcinoma', 'Disease', (98, 126))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (136, 155))	('lung adenocarcinoma', 'Disease', (136, 155))	('MESP1', 'Gene', (46, 51))	('aberrant', 'Var', (23, 31))
538196	31761621	Intermediate and high MESP1 levels were associated with all stages of adenocarcinoma and squamous cell carcinoma (Supplementary Fig.	('high', 'Var', (17, 21))	('adenocarcinoma and squamous cell carcinoma', 'Disease', 'MESH:D002294', (70, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (89, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('associated', 'Reg', (40, 50))	('MESP1', 'Protein', (22, 27))	('men', 'Species', '9606', (120, 123))
538202	31761621	Colony formation assay indicated that MESP1 knockdown also significantly affects the growth ability of A549 and H358 cells as the number of colonies formed in knockdown cells were significantly lower (Fig.	('H358', 'CellLine', 'CVCL:1559', (112, 116))	('A549', 'CellLine', 'CVCL:0023', (103, 107))	('MESP1', 'Gene', (38, 43))	('knockdown', 'Var', (44, 53))	('affects', 'Reg', (73, 80))	('lower', 'NegReg', (194, 199))	('growth ability', 'CPA', (85, 99))
538203	31761621	Transient overexpression of wildtype MESP1, but not a mutant that negatively affects DNA binding (E91A/K92A, hereafter EK-mutant), induced proliferation and clonal growth of A549 cells (Fig.	('A549', 'CellLine', 'CVCL:0023', (174, 178))	('K92A', 'SUBSTITUTION', 'None', (103, 107))	('clonal growth', 'CPA', (157, 170))	('proliferation', 'CPA', (139, 152))	('E91A', 'SUBSTITUTION', 'None', (98, 102))	('induced', 'PosReg', (131, 138))	('K92A', 'Var', (103, 107))	('overexpression', 'PosReg', (10, 24))	('E91A', 'Var', (98, 102))	('MESP1', 'Gene', (37, 42))
538205	31761621	We next introduced FLAG-tagged wildtype or EK-mutant MESP1 gene into immortalized normal human bronchial epithelial cells (BEAS-2B).	('BEAS-2B', 'Chemical', '-', (123, 130))	('human', 'Species', '9606', (89, 94))	('EK-mutant', 'Var', (43, 52))	('MESP1', 'Gene', (53, 58))
538206	31761621	Unexpectedly, the cells stably expressing wildtype MESP1 grew slower than the cells expressing the control vector or EK-mutant (Supplementary Fig.	('wildtype', 'Var', (42, 50))	('slower', 'NegReg', (62, 68))	('grew', 'CPA', (57, 61))	('MESP1', 'Gene', (51, 56))	('men', 'Species', '9606', (134, 137))
538214	31761621	To test this hypothesis, we chose to overexpress MESP1 in cells that have genetic deletion of ARF (ARF-/-) followed by assessment of proliferation, transformation and transcriptome analyses (Figs.	('ARF', 'Disease', (94, 97))	('overexpress', 'PosReg', (37, 48))	('men', 'Species', '9606', (125, 128))	('ARF', 'Disease', 'MESH:D058186', (99, 102))	('deletion', 'Var', (82, 90))	('ARF', 'Disease', (99, 102))	('ARF', 'Disease', 'MESH:D058186', (94, 97))
538215	31761621	We introduced doxycycline-inducible V5-tagged wildtype (wt) or EK-mutant Mesp1 (E85A/K86A) in p19ARF-/- mouse embryonic fibroblasts (MEFs) (Fig.	('doxycycline', 'Chemical', 'MESH:D004318', (14, 25))	('MEFs', 'CellLine', 'CVCL:9115', (133, 137))	('mouse', 'Species', '10090', (104, 109))	('Mesp1', 'Gene', (73, 78))	('E85A', 'SUBSTITUTION', 'None', (80, 84))	('K86A', 'Var', (85, 89))	('K86A', 'SUBSTITUTION', 'None', (85, 89))	('E85A', 'Var', (80, 84))
538217	31761621	The growth rate of wt-Mesp1 ARF -/- MEFs was significantly higher than that of EK-mutant-Mesp1 or control ARF -/- MEFs (Fig.	('ARF', 'Disease', (28, 31))	('MEFs', 'CellLine', 'CVCL:9115', (114, 118))	('EK-mutant-Mesp1', 'Var', (79, 94))	('ARF', 'Disease', 'MESH:D058186', (106, 109))	('ARF', 'Disease', 'MESH:D058186', (28, 31))	('ARF', 'Disease', (106, 109))	('higher', 'PosReg', (59, 65))	('growth rate', 'MPA', (4, 15))	('MEFs', 'CellLine', 'CVCL:9115', (36, 40))
538218	31761621	Consistent with this, wt-Mesp1 ARF -/- MEFs generated significantly more colonies as compared to EK-mutant-Mesp1 or control ARF -/- MEFs (Fig.	('MEFs', 'CellLine', 'CVCL:9115', (39, 43))	('more', 'PosReg', (68, 72))	('EK-mutant-Mesp1', 'Var', (97, 112))	('colonies', 'CPA', (73, 81))	('MEFs', 'CellLine', 'CVCL:9115', (132, 136))	('ARF', 'Disease', 'MESH:D058186', (31, 34))	('ARF', 'Disease', 'MESH:D058186', (124, 127))	('ARF', 'Disease', (31, 34))	('ARF', 'Disease', (124, 127))
538219	31761621	As a measure of cellular transformation, we performed soft agar colony formation assay, and observed that wt-Mesp1 ARF -/- MEFs formed more colonies than control ARF -/- MEFs, whereas EK-mutant-Mesp1 ARF -/- MEFs failed to form any colonies on soft agar (Fig.	('colonies', 'CPA', (140, 148))	('agar', 'Chemical', 'MESH:D000362', (59, 63))	('MEFs', 'CellLine', 'CVCL:9115', (123, 127))	('ARF', 'Disease', (162, 165))	('ARF', 'Disease', (115, 118))	('ARF', 'Disease', (200, 203))	('ARF', 'Disease', 'MESH:D058186', (115, 118))	('EK-mutant-Mesp1', 'Var', (184, 199))	('MEFs', 'CellLine', 'CVCL:9115', (170, 174))	('ARF', 'Disease', 'MESH:D058186', (162, 165))	('agar', 'Chemical', 'MESH:D000362', (249, 253))	('MEFs', 'CellLine', 'CVCL:9115', (208, 212))	('ARF', 'Disease', 'MESH:D058186', (200, 203))
538220	31761621	On the other hand, Mesp1-overexpression did not induce survival, proliferation or transformation in MEFs null for p53, which still express ARF (Supplementary Fig.	('p53', 'Gene', (114, 117))	('ARF', 'Disease', 'MESH:D058186', (139, 142))	('ARF', 'Disease', (139, 142))	('MEFs', 'CellLine', 'CVCL:9115', (100, 104))	('null for', 'Var', (105, 113))	('men', 'Species', '9606', (150, 153))
538221	31761621	S3), suggesting that the loss of ARF but not p53 is essential for MESP1-mediated transformation.	('MESP1-mediated', 'CPA', (66, 80))	('ARF', 'Disease', 'MESH:D058186', (33, 36))	('ARF', 'Disease', (33, 36))	('loss', 'Var', (25, 29))
538222	31761621	These data suggest that MESP1 expression causes 'oncogenic stress' in the presence of ARF and when ARF is absent, MESP1 expression results in increased cell proliferation, survival and transformation.	('increased', 'PosReg', (142, 151))	('stress', 'Disease', 'MESH:D000079225', (59, 65))	('ARF', 'Disease', 'MESH:D058186', (99, 102))	('expression', 'Var', (30, 40))	('MESP1', 'Gene', (24, 29))	('stress', 'Disease', (59, 65))	('survival', 'CPA', (172, 180))	('ARF', 'Disease', (99, 102))	('ARF', 'Disease', 'MESH:D058186', (86, 89))	('ARF', 'Disease', (86, 89))	('MESP1', 'Gene', (114, 119))	('cell proliferation', 'CPA', (152, 170))	('transformation', 'CPA', (185, 199))
538224	31761621	In order to determine genome-wide downstream transcriptional targets of MESP1, we performed RNA-Seq in ARF-/- MEFs expressing wt- or EK-mutant Mesp1, and compared these datasets to gene expression profiles obtained in MESP1-depleted A549 cell lines (Fig.	('ARF', 'Disease', (103, 106))	('Mesp1', 'Gene', (143, 148))	('A549', 'CellLine', 'CVCL:0023', (233, 237))	('EK-mutant', 'Var', (133, 142))	('MEFs', 'CellLine', 'CVCL:9115', (110, 114))	('ARF', 'Disease', 'MESH:D058186', (103, 106))
538225	31761621	We first determined differentially expressed genes (DEGs) by comparing wt- vs. EK-mutant Mesp1 ARF-/- MEFs and obtained 1100 genes whose expression is dependent on wt- Mesp1 (Fig.	('ARF', 'Disease', 'MESH:D058186', (95, 98))	('MEFs', 'CellLine', 'CVCL:9115', (102, 106))	('ARF', 'Disease', (95, 98))	('EK-mutant', 'Var', (79, 88))	('Mesp1', 'Gene', (89, 94))
538233	31761621	To test if MESP1 directly regulates their expression, we first performed qRT-PCR to examine the relative levels of their mRNA transcripts in MESP1 knockdown A549 and H358 cancer cell lines.	('A549', 'CellLine', 'CVCL:0023', (157, 161))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('H358', 'CellLine', 'CVCL:1559', (166, 170))	('cancer', 'Disease', (171, 177))	('MESP1', 'Gene', (141, 146))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('knockdown', 'Var', (147, 156))
538244	31761621	To validate our in vitro findings and to evaluate the effect of MESP1 knockdown in tumor growth in vivo, xenograft assays were performed.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('knockdown', 'Var', (70, 79))	('tumor', 'Disease', (83, 88))	('MESP1', 'Gene', (64, 69))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
538264	31761621	For example, amplification of master melanocyte lineage regulator MITF in melanoma, amplification of normal lung development transcription factor TITF-1 in adenocarcinoma, pulmonary neuroendocrine (NE) cell development transcription factor ASCL1 in survival of NE-lung cancers and amplification of intestinal lineage development transcription factor CDX2 in colorectal cancer.	('colorectal cancer', 'Disease', 'MESH:D015179', (358, 375))	('NE-lung cancers', 'Disease', 'MESH:D008175', (261, 276))	('amplification', 'Var', (84, 97))	('TITF-1', 'Gene', (146, 152))	('amplification', 'Var', (13, 26))	('colorectal cancer', 'Disease', (358, 375))	('MITF', 'Gene', (66, 70))	('adenocarcinoma, pulmonary neuroendocrine', 'Disease', 'MESH:D000230', (156, 196))	('ASCL1', 'Gene', '429', (240, 245))	('melanoma', 'Disease', 'MESH:D008545', (74, 82))	('amplification', 'Var', (281, 294))	('lung cancer', 'Phenotype', 'HP:0100526', (264, 275))	('CDX2', 'Gene', '1045', (350, 354))	('cancers', 'Phenotype', 'HP:0002664', (269, 276))	('lung cancers', 'Phenotype', 'HP:0100526', (264, 276))	('men', 'Species', '9606', (120, 123))	('ASCL1', 'Gene', (240, 245))	('men', 'Species', '9606', (324, 327))	('cancer', 'Phenotype', 'HP:0002664', (269, 275))	('colorectal cancer', 'Phenotype', 'HP:0003003', (358, 375))	('CDX2', 'Gene', (350, 354))	('men', 'Species', '9606', (214, 217))	('TITF-1', 'Gene', '7080', (146, 152))	('NE-lung cancers', 'Disease', (261, 276))	('melanoma', 'Phenotype', 'HP:0002861', (74, 82))	('melanoma', 'Disease', (74, 82))	('cancer', 'Phenotype', 'HP:0002664', (369, 375))	('carcinoma', 'Phenotype', 'HP:0030731', (161, 170))	('MITF', 'Gene', '4286', (66, 70))
538270	31761621	We showed that MESP1 was able to transform mouse embryonic fibroblasts in p19ARF-null background but not p53-null background.	('transform', 'Reg', (33, 42))	('mouse', 'Species', '10090', (43, 48))	('p19ARF-null', 'Var', (74, 85))	('MESP1', 'Gene', (15, 20))
538272	31761621	In fact, many proteins require oncogenic cooperation to transform immortalized cells, such as between SOX2 and FGFR2 or FOXE1[7], between MITF and mutant BRAFV600E[6] and between TTF1/NKX2-1, NKX2-8 and PAX9 .	('mutant', 'Var', (147, 153))	('BRAFV600E', 'Gene', (154, 163))	('NKX2-1', 'Gene', '7080', (184, 190))	('NKX2-8', 'Gene', (192, 198))	('FOXE1[7', 'Gene', '2304;2301', (120, 127))	('PAX9', 'Gene', '5083', (203, 207))	('NKX2-1', 'Gene', (184, 190))	('TTF1', 'Gene', (179, 183))	('PAX9', 'Gene', (203, 207))	('NKX2-8', 'Gene', '26257;4824', (192, 198))	('FOXE1[7', 'Gene', (120, 127))	('FGFR2', 'Gene', (111, 116))	('MITF', 'Gene', '4286', (138, 142))	('SOX2', 'Gene', '6657', (102, 106))	('BRAFV600E', 'Mutation', 'rs113488022', (154, 163))	('SOX2', 'Gene', (102, 106))	('FGFR2', 'Gene', '2263', (111, 116))	('TTF1', 'Gene', '7270', (179, 183))	('MITF', 'Gene', (138, 142))
538274	31761621	To this end, we generated MEFs stably expressing wildtype or DNA-binding mutant Mesp1 in p19ARF-/- background and performed RNA-Seq to identify DEGs that are most likely dependent on DNA-binding ability of Mesp1.	('MEFs', 'CellLine', 'CVCL:9115', (26, 30))	('mutant', 'Var', (73, 79))	('DNA-binding', 'Reg', (61, 72))	('Mesp1', 'Gene', (80, 85))
538276	31761621	Comparative analyses of likely MESP1-targets (DEGs from wt vs. EK-mutant Mesp1 MEFs) and MESP1-dependent genes (DEGs from MESP1-depleted NSCLCs) resulted in a gene signature of 24 genes, as putative direct targets of MESP1 in lung cancer.	('NSCLCs', 'Disease', 'MESH:D002289', (137, 143))	('lung cancer', 'Disease', (226, 237))	('lung cancer', 'Phenotype', 'HP:0100526', (226, 237))	('Mesp1', 'Gene', (73, 78))	('NSCLC', 'Phenotype', 'HP:0030358', (137, 142))	('MEFs', 'CellLine', 'CVCL:9115', (79, 83))	('EK-mutant', 'Var', (63, 72))	('lung cancer', 'Disease', 'MESH:D008175', (226, 237))	('NSCLCs', 'Disease', (137, 143))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))
538278	31761621	Interestingly, our gene set enrichment analyses of the MESP1 targets revealed that majority of the genes have noted roles in cancer progression, especially EMT; such as, IGFBP4 promotes invasion and metastasis in renal cell carcinoma and glioblastoma by regulating key factors of EMT and tumor progression, CTGF expression is critical for migration and invasion of breast cancer and melanoma cells, loss of imprinting of MEST promotes invasiveness of breast cancer cells, FLT-4 with its ligand VEGF-C promotes metastasis and invasion of lung adenocarcinoma cells via its target contactin-1.	('cancer', 'Disease', 'MESH:D009369', (458, 464))	('melanoma', 'Phenotype', 'HP:0002861', (383, 391))	('lung adenocarcinoma', 'Disease', (537, 556))	('melanoma', 'Disease', (383, 391))	('CTGF', 'Gene', (307, 311))	('breast cancer', 'Disease', 'MESH:D001943', (451, 464))	('breast cancer', 'Disease', 'MESH:D001943', (365, 378))	('breast cancer', 'Disease', (365, 378))	('FLT-4', 'Gene', (472, 477))	('men', 'Species', '9606', (34, 37))	('carcinoma', 'Phenotype', 'HP:0030731', (547, 556))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (213, 233))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (537, 556))	('invasiveness of breast cancer', 'Disease', 'MESH:D001943', (435, 464))	('IGFBP4', 'Gene', '3487', (170, 176))	('MEST', 'Gene', (421, 425))	('cancer', 'Disease', (125, 131))	('glioblastoma', 'Disease', 'MESH:D005909', (238, 250))	('tumor', 'Disease', (288, 293))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (537, 556))	('cancer', 'Disease', (372, 378))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (213, 233))	('promotes', 'PosReg', (501, 509))	('cancer', 'Disease', (458, 464))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('invasion', 'CPA', (525, 533))	('contactin-1', 'Gene', (578, 589))	('melanoma', 'Disease', 'MESH:D008545', (383, 391))	('cancer', 'Phenotype', 'HP:0002664', (372, 378))	('tumor', 'Disease', 'MESH:D009369', (288, 293))	('FLT-4', 'Gene', '2324', (472, 477))	('MEST', 'Gene', '4232', (421, 425))	('VEGF-C', 'Gene', (494, 500))	('cancer', 'Phenotype', 'HP:0002664', (458, 464))	('glioblastoma', 'Disease', (238, 250))	('contactin-1', 'Gene', '1272', (578, 589))	('glioblastoma', 'Phenotype', 'HP:0012174', (238, 250))	('invasiveness of breast cancer', 'Disease', (435, 464))	('carcinoma', 'Phenotype', 'HP:0030731', (224, 233))	('VEGF-C', 'Gene', '7424', (494, 500))	('CTGF', 'Gene', '1490', (307, 311))	('loss', 'Var', (399, 403))	('metastasis', 'CPA', (510, 520))	('renal cell carcinoma', 'Disease', (213, 233))	('tumor', 'Phenotype', 'HP:0002664', (288, 293))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('breast cancer', 'Phenotype', 'HP:0003002', (451, 464))	('breast cancer', 'Phenotype', 'HP:0003002', (365, 378))	('cancer', 'Disease', 'MESH:D009369', (372, 378))	('IGFBP4', 'Gene', (170, 176))
538280	31761621	Moreover, the mechanisms that result in aberrant expression of MESP1 in lung cancer remain unknown.	('aberrant', 'Var', (40, 48))	('MESP1', 'Gene', (63, 68))	('lung cancer', 'Disease', (72, 83))	('lung cancer', 'Phenotype', 'HP:0100526', (72, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('lung cancer', 'Disease', 'MESH:D008175', (72, 83))
538303	30845357	In SCC, p53 mutation emerges as a dominant early genetic event with a mutational rate of 60-80% of cases and is associated with a more aggressive phenotype (Cancer Genome Atlas, 2015; Poeta et al., 2007).	('associated with', 'Reg', (112, 127))	('p53', 'Gene', (8, 11))	('SCC', 'Phenotype', 'HP:0002860', (3, 6))	('SCC', 'Gene', '6317', (3, 6))	('Cancer', 'Disease', (157, 163))	('p53', 'Gene', '7157', (8, 11))	('Cancer', 'Disease', 'MESH:D009369', (157, 163))	('Cancer', 'Phenotype', 'HP:0002664', (157, 163))	('mutation', 'Var', (12, 20))	('SCC', 'Gene', (3, 6))
538304	30845357	Several tumour-derived p53 mutations are gain-of-function mutations and act as driver oncogenes promoting metastatic dissemination and drug resistance (Alexandrova et al., 2017; Amelio et al., 2018; Kim and Lozano, 2018; Morrison et al., 2017; Muller and Vousden, 2014; Parrales et al., 2018; Vaughan et al., 2017).	('mutations', 'Var', (27, 36))	('tumour', 'Disease', (8, 14))	('promoting', 'PosReg', (96, 105))	('tumour', 'Phenotype', 'HP:0002664', (8, 14))	('gain-of-function', 'PosReg', (41, 57))	('drug resistance', 'CPA', (135, 150))	('p53', 'Gene', (23, 26))	('p53', 'Gene', '7157', (23, 26))	('drug resistance', 'Phenotype', 'HP:0020174', (135, 150))	('tumour', 'Disease', 'MESH:D009369', (8, 14))	('metastatic dissemination', 'CPA', (106, 130))
538305	30845357	In addition to gene mutation, others mechanisms may contribute to restraining p53 oncosuppressor activity in SCC, including overexpression/amplification of MDM2, infection with HPV E6 oncoprotein or transcriptional repression by EGF-R signalling (Kolev et al., 2008; Scheffner et al., 1990; Wu and Prives, 2018).	('transcriptional', 'MPA', (199, 214))	('SCC', 'Phenotype', 'HP:0002860', (109, 112))	('MDM2', 'Gene', (156, 160))	('SCC', 'Gene', '6317', (109, 112))	('p53', 'Gene', '7157', (78, 81))	('EGF-R', 'Gene', (229, 234))	('infection', 'Disease', (162, 171))	('mutation', 'Var', (20, 28))	('HPV', 'Species', '10566', (177, 180))	('overexpression/amplification', 'PosReg', (124, 152))	('p53', 'Gene', (78, 81))	('infection', 'Disease', 'MESH:D007239', (162, 171))	('SCC', 'Gene', (109, 112))	('restraining', 'NegReg', (66, 77))	('EGF-R', 'Gene', '1956', (229, 234))	('MDM2', 'Gene', '4193', (156, 160))
538308	30845357	The skin-specific genetic ablation of TP63 in a mouse model of chemical-induced skin carcinogenesis induces a rapid and dramatic tumour regression, demonstrating the exquisite dependence of SCC on high levels of p63 (Ramsey et al., 2013).	('tumour', 'Phenotype', 'HP:0002664', (129, 135))	('skin carcinogenesis', 'Disease', 'MESH:D063646', (80, 99))	('mouse', 'Species', '10090', (48, 53))	('tumour regression', 'Disease', (129, 146))	('genetic ablation', 'Var', (18, 34))	('ablation', 'Var', (26, 34))	('SCC', 'Gene', (190, 193))	('skin carcinogenesis', 'Disease', (80, 99))	('tumour regression', 'Disease', 'MESH:D009365', (129, 146))	('TP63', 'Gene', (38, 42))	('SCC', 'Phenotype', 'HP:0002860', (190, 193))	('SCC', 'Gene', '6317', (190, 193))
538311	30845357	The two main isoforms contain (TAp63) or lack (DeltaNp63), the N-terminal p53-homologous transactivation domain (Dotsch et al., 2010; Yang et al., 1998).	('lack', 'NegReg', (41, 45))	('p53', 'Gene', (74, 77))	('DeltaNp63', 'Chemical', '-', (47, 56))	('p53', 'Gene', '7157', (74, 77))	('TAp63', 'Var', (31, 36))
538312	30845357	The DeltaNp63alpha is the most abundant isoform expressed in the basal layer of stratified epithelia, where it maintains the proliferative potential and lineage specification of epithelial structures such as epidermis, lung, thymus and mammary gland (Candi et al., 2008; Mills et al., 1999; Shalom-Feuerstein et al., 2011; Soares and Zhou, 2018).	('lineage specification', 'CPA', (153, 174))	('maintains', 'PosReg', (111, 120))	('proliferative potential', 'CPA', (125, 148))	('DeltaNp63alpha', 'Var', (4, 18))	('DeltaNp63', 'Chemical', '-', (4, 13))
538313	30845357	The critical importance of p63 during epithelial morphogenesis has been demonstrated in diverse animal models and by the functional association of TP63 mutations with human diseases.	('TP63', 'Gene', (147, 151))	('association', 'Interaction', (132, 143))	('mutations', 'Var', (152, 161))	('human', 'Species', '9606', (167, 172))
538316	30845357	In humans, heterozygous mutations in TP63 cause several developmental disorders, which partially resemble the developmental defects observed in p63 null mice (Celli et al., 1999; Rinne et al., 2007).	('developmental disorders', 'Disease', (56, 79))	('developmental disorders', 'Disease', 'MESH:D002658', (56, 79))	('cause', 'Reg', (42, 47))	('TP63', 'Gene', (37, 41))	('humans', 'Species', '9606', (3, 9))	('mice', 'Species', '10090', (153, 157))	('heterozygous mutations', 'Var', (11, 33))
538317	30845357	Recent reports unveiled the key role of DeltaNp63 in controlling the epigenetic landscape of epithelial cells, as DeltaNp63 recruits epigenetic modulators and chromatin remodelling factors in order to directly regulate numerous target genes involved in cell proliferation, differentiation and adhesion (Fessing et al., 2011; Mardaryev et al., 2014, 2016).	('DeltaNp63', 'Chemical', '-', (40, 49))	('DeltaNp63', 'Var', (114, 123))	('regulate', 'Reg', (210, 218))	('DeltaNp63', 'Chemical', '-', (114, 123))
538323	30845357	DeltaNp63 is also able directly to induce the expression of the Notch ligand JAG2, likely favouring the initial step of skin differentiation (Candi et al., 2007).	('Notch', 'Gene', '4851;18128;4853;4854;4855', (64, 69))	('Notch', 'Gene', (64, 69))	('JAG2', 'Gene', (77, 81))	('skin differentiation', 'CPA', (120, 140))	('induce', 'PosReg', (35, 41))	('JAG2', 'Gene', '3714', (77, 81))	('DeltaNp63', 'Var', (0, 9))	('favouring', 'PosReg', (90, 99))	('expression', 'MPA', (46, 56))	('DeltaNp63', 'Chemical', '-', (0, 9))
538324	30845357	In the suprabasal layer, NOTCH1 counteracts DeltaNp63 activity in a negative feedback loop, directly or through the induction of the interferon regulatory factor 6 (IRF6), which may promote the proteasome-dependent degradation of DeltaNp63 (Moretti et al., 2010; Nguyen et al., 2006; Thomason et al., 2010).	('DeltaNp63', 'Gene', (230, 239))	('interferon regulatory factor 6', 'Gene', (133, 163))	('promote', 'PosReg', (182, 189))	('IRF6', 'Gene', (165, 169))	('IRF6', 'Gene', '3664', (165, 169))	('interferon regulatory factor 6', 'Gene', '3664', (133, 163))	('NOTCH1', 'Var', (25, 31))	('DeltaNp63', 'Chemical', '-', (230, 239))	('DeltaNp63', 'Chemical', '-', (44, 53))	('proteasome-dependent degradation', 'MPA', (194, 226))
538332	30845357	These data have been also confirmed in HNSCC cell lines, which express almost exclusively the DeltaNp63alpha isoform (Compagnone et al., 2017; Rocco et al., 2006).	('SCC', 'Gene', (41, 44))	('SCC', 'Phenotype', 'HP:0002860', (41, 44))	('DeltaNp63', 'Chemical', '-', (94, 103))	('SCC', 'Gene', '6317', (41, 44))	('DeltaNp63alpha', 'Var', (94, 108))
538333	30845357	Furthermore, some rare TP63 mutations reported in HNSCC samples are located in the TA domain, suggesting that DeltaNp63 isoform expression is positively selected during tumour evolution (Stransky et al., 2011).	('tumour', 'Disease', (169, 175))	('DeltaNp63', 'Chemical', '-', (110, 119))	('SCC', 'Gene', (52, 55))	('TP63', 'Gene', (23, 27))	('SCC', 'Phenotype', 'HP:0002860', (52, 55))	('tumour', 'Phenotype', 'HP:0002664', (169, 175))	('SCC', 'Gene', '6317', (52, 55))	('tumour', 'Disease', 'MESH:D009369', (169, 175))	('mutations', 'Var', (28, 37))
538334	30845357	Collectively, these data indicate that the major p63 isoform driving SCC tumourigenesis is DeltaNp63, likely the DeltaNp63alpha isoform (hereinafter referred as DeltaNp63).	('tumour', 'Disease', (73, 79))	('SCC', 'Gene', (69, 72))	('SCC', 'Phenotype', 'HP:0002860', (69, 72))	('SCC', 'Gene', '6317', (69, 72))	('tumour', 'Phenotype', 'HP:0002664', (73, 79))	('DeltaNp63', 'Var', (91, 100))	('tumour', 'Disease', 'MESH:D009369', (73, 79))	('DeltaNp63', 'Chemical', '-', (113, 122))	('DeltaNp63', 'Chemical', '-', (91, 100))	('DeltaNp63', 'Chemical', '-', (161, 170))
538337	30845357	Furthermore, in a model of chemical-induced skin carcinogenesis, DeltaNp63 expression accelerates the onset of papilloma occurrence, suggesting that DeltaNp63 favours the early steps of SCC development (Devos et al., 2017).	('skin carcinogenesis', 'Disease', (44, 63))	('SCC', 'Gene', '6317', (186, 189))	('papilloma', 'Disease', (111, 120))	('DeltaNp63', 'Gene', (65, 74))	('DeltaNp63', 'Var', (149, 158))	('DeltaNp63', 'Chemical', '-', (65, 74))	('papilloma', 'Disease', 'MESH:D010212', (111, 120))	('DeltaNp63', 'Chemical', '-', (149, 158))	('skin carcinogenesis', 'Disease', 'MESH:D063646', (44, 63))	('accelerates', 'PosReg', (86, 97))	('favours', 'PosReg', (159, 166))	('SCC', 'Gene', (186, 189))	('SCC', 'Phenotype', 'HP:0002860', (186, 189))	('papilloma', 'Phenotype', 'HP:0012740', (111, 120))
538338	30845357	In addition to gene amplification and/or overexpression, other genetic alterations foster DeltaNp63 oncogenic activity in SCC.	('oncogenic activity', 'CPA', (100, 118))	('SCC', 'Gene', (122, 125))	('SCC', 'Phenotype', 'HP:0002860', (122, 125))	('DeltaNp63', 'Chemical', '-', (90, 99))	('DeltaNp63', 'Gene', (90, 99))	('SCC', 'Gene', '6317', (122, 125))	('alterations', 'Var', (71, 82))	('foster', 'PosReg', (83, 89))
538341	30845357	NOTCH1 point mutations occur in 11-15% of HNSCC, in 8% of lung SCC and in more than 40% of cutaneous SCC (Agrawal et al., 2011, 2012; Pickering et al., 2013).	('SCC', 'Gene', '6317', (44, 47))	('SCC', 'Gene', (63, 66))	('SCC', 'Phenotype', 'HP:0002860', (63, 66))	('point mutations', 'Var', (7, 22))	('SCC', 'Gene', '6317', (63, 66))	('SCC', 'Gene', (101, 104))	('SCC', 'Phenotype', 'HP:0002860', (101, 104))	('SCC', 'Gene', (44, 47))	('NOTCH1', 'Gene', (0, 6))	('SCC', 'Gene', '6317', (101, 104))	('SCC', 'Phenotype', 'HP:0002860', (44, 47))
538342	30845357	Point mutations in the NOTCH2 gene have been also reported in 11% of HNSCC samples; these mutations are mutually exclusive and exhibit minimal overlap with amplification of the TP63 gene (Stransky et al., 2011).	('NOTCH2', 'Gene', (23, 29))	('TP63', 'Gene', (177, 181))	('NOTCH2', 'Gene', '4853', (23, 29))	('SCC', 'Gene', (71, 74))	('Point mutations', 'Var', (0, 15))	('SCC', 'Phenotype', 'HP:0002860', (71, 74))	('SCC', 'Gene', '6317', (71, 74))
538343	30845357	Importantly, NOTCH mutations are loss-of-function, missense or nonsense mutations, a strong indication of a tumour-suppressive function of Notch signalling in SCC.	('tumour', 'Disease', (108, 114))	('nonsense mutations', 'Var', (63, 81))	('SCC', 'Gene', (159, 162))	('missense', 'Var', (51, 59))	('Notch', 'Gene', '4851;18128;4853;4854;4855', (139, 144))	('SCC', 'Phenotype', 'HP:0002860', (159, 162))	('tumour', 'Phenotype', 'HP:0002664', (108, 114))	('SCC', 'Gene', '6317', (159, 162))	('Notch', 'Gene', (139, 144))	('NOTCH', 'Gene', (13, 18))	('tumour', 'Disease', 'MESH:D009369', (108, 114))	('loss-of-function', 'NegReg', (33, 49))
538344	30845357	This conclusion is also supported by in vivo evidence showing that Notch1 inactivation in the mouse epidermis promotes skin tumourigenesis (Nicolas et al., 2003; Proweller et al., 2006).	('tumour', 'Phenotype', 'HP:0002664', (124, 130))	('mouse', 'Species', '10090', (94, 99))	('promotes', 'PosReg', (110, 118))	('Notch1', 'Gene', (67, 73))	('Notch1', 'Gene', '18128', (67, 73))	('tumour', 'Disease', (124, 130))	('tumour', 'Disease', 'MESH:D009369', (124, 130))	('inactivation', 'Var', (74, 86))
538346	30845357	Furthermore, the high rate of TP53 mutation and the frequent amplification of EGF-R locus in SCC may cooperate to maintain the low expression of NOTCH1, thus favouring tumour proliferation (Kolev et al., 2008).	('EGF-R', 'Gene', '1956', (78, 83))	('TP53', 'Gene', (30, 34))	('tumour', 'Phenotype', 'HP:0002664', (168, 174))	('favouring', 'PosReg', (158, 167))	('tumour', 'Disease', 'MESH:D009369', (168, 174))	('SCC', 'Gene', (93, 96))	('low', 'NegReg', (127, 130))	('EGF-R', 'Gene', (78, 83))	('amplification', 'Var', (61, 74))	('expression', 'MPA', (131, 141))	('SCC', 'Phenotype', 'HP:0002860', (93, 96))	('mutation', 'Var', (35, 43))	('tumour', 'Disease', (168, 174))	('TP53', 'Gene', '7157', (30, 34))	('NOTCH1', 'Gene', (145, 151))	('SCC', 'Gene', '6317', (93, 96))
538351	30845357	Diverse genetic events such as promoter methylation and gene mutation impair IRF6 activity in SCC (Rotondo et al., 2016).	('SCC', 'Gene', (94, 97))	('IRF6', 'Gene', (77, 81))	('mutation', 'Var', (61, 69))	('impair', 'NegReg', (70, 76))	('IRF6', 'Gene', '3664', (77, 81))	('SCC', 'Phenotype', 'HP:0002860', (94, 97))	('SCC', 'Gene', '6317', (94, 97))	('activity', 'MPA', (82, 90))
538352	30845357	Mutations of the IRF6 gene have been reported in 7% of HNSCC patients and down-regulation of IRF6 has been correlated with tumour invasive and differentiation status of SCC (Stransky et al., 2011).	('SCC', 'Phenotype', 'HP:0002860', (57, 60))	('IRF6', 'Gene', '3664', (93, 97))	('SCC', 'Gene', '6317', (57, 60))	('tumour invasive', 'Disease', (123, 138))	('differentiation status', 'CPA', (143, 165))	('patients', 'Species', '9606', (61, 69))	('IRF6', 'Gene', (17, 21))	('SCC', 'Gene', (169, 172))	('down-regulation', 'NegReg', (74, 89))	('SCC', 'Phenotype', 'HP:0002860', (169, 172))	('Mutations', 'Var', (0, 9))	('IRF6', 'Gene', '3664', (17, 21))	('tumour', 'Phenotype', 'HP:0002664', (123, 129))	('SCC', 'Gene', '6317', (169, 172))	('SCC', 'Gene', (57, 60))	('IRF6', 'Gene', (93, 97))	('tumour invasive', 'Disease', 'MESH:D009361', (123, 138))
538353	30845357	Genomic amplification or overexpression of another squamous differentiation-related gene, SOX2, also contribute to enhance and activate DeltaNp63 oncogenic activity.	('Genomic amplification', 'Var', (0, 21))	('activate', 'PosReg', (127, 135))	('DeltaNp63', 'Chemical', '-', (136, 145))	('SOX2', 'Gene', '6657', (90, 94))	('oncogenic activity', 'CPA', (146, 164))	('SOX2', 'Gene', (90, 94))	('enhance', 'PosReg', (115, 122))	('overexpression', 'PosReg', (25, 39))	('DeltaNp63', 'Gene', (136, 145))
538356	30845357	Collectively, these data suggest that distinct genetic events, such as NOTCH mutations, TP63 genomic amplification/overexpression, TP53 mutation, IRF6 down-modulation and SOX2 amplification (see Fig.	('amplification/overexpression', 'PosReg', (101, 129))	('SOX2', 'Gene', '6657', (171, 175))	('IRF6', 'Gene', '3664', (146, 150))	('mutation', 'Var', (136, 144))	('TP63', 'Gene', (88, 92))	('TP53', 'Gene', '7157', (131, 135))	('TP53', 'Gene', (131, 135))	('SOX2', 'Gene', (171, 175))	('down-modulation', 'NegReg', (151, 166))	('IRF6', 'Gene', (146, 150))
538365	30845357	For instance, FBW7 is a tumour-suppressor gene frequently mutated in a variety of solid tumours, including SCC of different origins (Xiao et al., 2018).	('tumour', 'Disease', 'MESH:D009369', (88, 94))	('tumour', 'Phenotype', 'HP:0002664', (24, 30))	('tumour', 'Disease', (88, 94))	('tumours', 'Phenotype', 'HP:0002664', (88, 95))	('solid tumours', 'Disease', 'MESH:D009369', (82, 95))	('FBW7', 'Gene', (14, 18))	('SCC', 'Gene', (107, 110))	('tumour', 'Disease', 'MESH:D009369', (24, 30))	('SCC', 'Phenotype', 'HP:0002860', (107, 110))	('tumour', 'Disease', (24, 30))	('solid tumours', 'Disease', (82, 95))	('FBW7', 'Gene', '55294', (14, 18))	('tumour', 'Phenotype', 'HP:0002664', (88, 94))	('SCC', 'Gene', '6317', (107, 110))	('mutated', 'Var', (58, 65))
538368	30845357	In detail, a DeltaNp63 mutant refractory to APC/C activity increases keratinocyte proliferation, inhibits differentiation and has oncogenic activity in xenograft tumour transplantation assays.	('DeltaNp63', 'Chemical', '-', (13, 22))	('DeltaNp63', 'Gene', (13, 22))	('differentiation', 'CPA', (106, 121))	('tumour', 'Disease', (162, 168))	('APC', 'Disease', 'MESH:D011125', (44, 47))	('APC', 'Disease', (44, 47))	('inhibits', 'NegReg', (97, 105))	('keratinocyte proliferation', 'CPA', (69, 95))	('tumour', 'Phenotype', 'HP:0002664', (162, 168))	('oncogenic activity', 'CPA', (130, 148))	('tumour', 'Disease', 'MESH:D009369', (162, 168))	('mutant', 'Var', (23, 29))	('increases', 'PosReg', (59, 68))
538369	30845357	More importantly, high levels of STXBP4, a factor counteracting APC/C-mediated ubiquitination of DeltaNp63, significantly correlate with the accumulation of DeltaNp63 in skin and lung SCC (Rokudai et al., 2018).	('STXBP4', 'Gene', (33, 39))	('APC', 'Disease', 'MESH:D011125', (64, 67))	('DeltaNp63', 'Chemical', '-', (97, 106))	('APC', 'Disease', (64, 67))	('STXBP4', 'Gene', '252983', (33, 39))	('DeltaNp63', 'Gene', (97, 106))	('SCC', 'Gene', (184, 187))	('DeltaNp63', 'Var', (157, 166))	('DeltaNp63', 'Chemical', '-', (157, 166))	('SCC', 'Phenotype', 'HP:0002860', (184, 187))	('SCC', 'Gene', '6317', (184, 187))
538376	30845357	In HNSCC cells, it has been showed that DeltaNp63 is able to interact with p73, restraining the transcriptional activation of the pro-apoptotic gene PUMA.	('SCC', 'Gene', '6317', (5, 8))	('restraining', 'NegReg', (80, 91))	('transcriptional activation', 'MPA', (96, 122))	('PUMA', 'Gene', (149, 153))	('p73', 'Gene', '7161', (75, 78))	('DeltaNp63', 'Var', (40, 49))	('p73', 'Gene', (75, 78))	('SCC', 'Gene', (5, 8))	('DeltaNp63', 'Chemical', '-', (40, 49))	('SCC', 'Phenotype', 'HP:0002860', (5, 8))
538378	30845357	Although this mechanism may be relevant for the pro-survival effect exerted by DeltaNp63, other observations suggested alternative molecular mechanisms by which DeltaNp63 exerts its oncogenic function in SCC.	('DeltaNp63', 'Chemical', '-', (79, 88))	('oncogenic function', 'CPA', (182, 200))	('SCC', 'Gene', (204, 207))	('DeltaNp63', 'Var', (161, 170))	('SCC', 'Phenotype', 'HP:0002860', (204, 207))	('DeltaNp63', 'Chemical', '-', (161, 170))	('SCC', 'Gene', '6317', (204, 207))
538379	30845357	First, DeltaNp63 protein is able to transactivate specific target genes due to the presence of two transactivation domains, one located between the oligomerization domain and the SAM domain, and another at the first 26 amino acids (Dohn et al., 2001; Ghioni et al., 2002; Helton et al., 2006; Lena et al., 2015).	('protein', 'Protein', (17, 24))	('transactivate', 'MPA', (36, 49))	('transactivation', 'MPA', (99, 114))	('DeltaNp63', 'Var', (7, 16))	('DeltaNp63', 'Chemical', '-', (7, 16))
538381	30845357	Thirdly, most SCC exhibits both overexpression of DeltaNp63 and inactivating mutations in TP53, suggesting the existence of p53-independent oncogenic functions of DeltaNp63 (Neilsen et al., 2011; Nekulova et al., 2011).	('p53', 'Gene', (124, 127))	('DeltaNp63', 'Var', (163, 172))	('p53', 'Gene', '7157', (124, 127))	('SCC', 'Gene', (14, 17))	('DeltaNp63', 'Chemical', '-', (163, 172))	('TP53', 'Gene', '7157', (90, 94))	('SCC', 'Phenotype', 'HP:0002860', (14, 17))	('DeltaNp63', 'Chemical', '-', (50, 59))	('TP53', 'Gene', (90, 94))	('SCC', 'Gene', '6317', (14, 17))	('inactivating mutations', 'Var', (64, 86))
538382	30845357	Last but not least, in p53 wild-type lung SCC cells, depletion of p53 or p73 does not rescue the proliferation arrest caused by DeltaNp63 knockdown (Gallant-Behm et al., 2012).	('proliferation arrest', 'Disease', 'MESH:D006323', (97, 117))	('knockdown', 'Var', (138, 147))	('p53', 'Gene', '7157', (66, 69))	('p73', 'Gene', '7161', (73, 76))	('p73', 'Gene', (73, 76))	('SCC', 'Gene', (42, 45))	('SCC', 'Phenotype', 'HP:0002860', (42, 45))	('DeltaNp63', 'Chemical', '-', (128, 137))	('DeltaNp63', 'Gene', (128, 137))	('p53', 'Gene', (23, 26))	('p53', 'Gene', '7157', (23, 26))	('SCC', 'Gene', '6317', (42, 45))	('proliferation arrest', 'Disease', (97, 117))	('p53', 'Gene', (66, 69))
538383	30845357	Collectively, these observations clearly indicate that the activation or repression of diverse transcriptional target genes is a critical oncogenic outcome of DeltaNp63 activity in SCC, even though some transcriptional independent mechanisms have been described (Patturajan et al., 2002).	('activity', 'Var', (169, 177))	('SCC', 'Gene', (181, 184))	('DeltaNp63', 'Chemical', '-', (159, 168))	('SCC', 'Phenotype', 'HP:0002860', (181, 184))	('SCC', 'Gene', '6317', (181, 184))	('DeltaNp63', 'Gene', (159, 168))	('activation', 'PosReg', (59, 69))	('repression', 'NegReg', (73, 83))
538388	30845357	As we described before, DeltaNp63 is able to inhibit Notch signalling mainly by transcriptional repression of the HES1 gene, a downstream target of NOTCH1.	('DeltaNp63', 'Chemical', '-', (24, 33))	('HES1', 'Gene', (114, 118))	('transcriptional', 'MPA', (80, 95))	('HES1', 'Gene', '3280', (114, 118))	('repression', 'NegReg', (96, 106))	('Notch', 'Gene', '4851;18128;4853;4854;4855', (53, 58))	('Notch', 'Gene', (53, 58))	('inhibit', 'NegReg', (45, 52))	('DeltaNp63', 'Var', (24, 33))
538390	30845357	In diverse normal and SCC cells, DeltaNp63 may directly repress the transcription of NOTCH1 gene through a p53-responsive element.	('transcription', 'MPA', (68, 81))	('DeltaNp63', 'Var', (33, 42))	('p53', 'Gene', (107, 110))	('p53', 'Gene', '7157', (107, 110))	('repress', 'NegReg', (56, 63))	('DeltaNp63', 'Chemical', '-', (33, 42))	('SCC', 'Gene', (22, 25))	('NOTCH1 gene', 'Gene', (85, 96))	('SCC', 'Phenotype', 'HP:0002860', (22, 25))	('SCC', 'Gene', '6317', (22, 25))
538391	30845357	Interestingly, the ability of DeltaNp63 to affect NOTCH1 expression negatively has also been observed in the epidermis of DeltaNp63 knock-out mouse embryos (Romano et al., 2012), suggesting that the DeltaNp63/NOTCH1 pathway might be indicative of a regenerative state of tumour cells.	('expression', 'MPA', (57, 67))	('tumour', 'Phenotype', 'HP:0002664', (271, 277))	('NOTCH1', 'Gene', (50, 56))	('mouse', 'Species', '10090', (142, 147))	('affect', 'Reg', (43, 49))	('tumour', 'Disease', 'MESH:D009369', (271, 277))	('DeltaNp63', 'Var', (30, 39))	('tumour', 'Disease', (271, 277))	('DeltaNp63', 'Chemical', '-', (30, 39))	('DeltaNp63', 'Gene', (122, 131))	('DeltaNp63', 'Chemical', '-', (122, 131))	('DeltaNp63', 'Chemical', '-', (199, 208))
538392	30845357	The DeltaNp63-mediated repression of NOTCH1 has two major consequences: it inhibits the NOTCH1-mediated activation of terminal differentiation programme and sustains cell proliferation by suppressing the expression of the cyclin-dependent kinase (CDK) inhibitor p21WAF1/Cip1.	('terminal differentiation', 'CPA', (118, 142))	('DeltaNp63-mediated', 'Var', (4, 22))	('suppressing', 'NegReg', (188, 199))	('NOTCH1', 'Gene', (37, 43))	('Cip1', 'Gene', (270, 274))	('DeltaNp63', 'Chemical', '-', (4, 13))	('repression', 'NegReg', (23, 33))	('activation', 'MPA', (104, 114))	('cell proliferation', 'CPA', (166, 184))	('sustains', 'PosReg', (157, 165))	('expression', 'MPA', (204, 214))	('Cip1', 'Gene', '1026', (270, 274))	('NOTCH1-mediated', 'Gene', (88, 103))	('inhibits', 'NegReg', (75, 83))
538393	30845357	DeltaNp63 may also repress p21WAF1/Cip1 expression directly (Westfall et al., 2003) or through an NF-kappaB-dependent mechanism (Nguyen et al., 2006) .	('expression', 'MPA', (40, 50))	('Cip1', 'Gene', (35, 39))	('DeltaNp63', 'Var', (0, 9))	('repress', 'NegReg', (19, 26))	('Cip1', 'Gene', '1026', (35, 39))	('DeltaNp63', 'Chemical', '-', (0, 9))
538396	30845357	DeltaNp63 is able directly to repress KLF4 transcription and enhance ZNF750 expression to activate an early step of squamous differentiation (Cordani et al., 2011; Sen et al., 2012).	('enhance', 'PosReg', (61, 68))	('ZNF750', 'Gene', '79755', (69, 75))	('KLF4', 'Gene', (38, 42))	('squamous differentiation', 'CPA', (116, 140))	('KLF4', 'Gene', '9314', (38, 42))	('ZNF750', 'Gene', (69, 75))	('activate', 'PosReg', (90, 98))	('expression', 'MPA', (76, 86))	('DeltaNp63', 'Var', (0, 9))	('DeltaNp63', 'Chemical', '-', (0, 9))
538399	30845357	Genetic ablation of KLF4 in the oesophagus results in delayed differentiation and development of precancerous squamous cell dysplasia (Tetreault et al., 2010).	('KLF4', 'Gene', '9314', (20, 24))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('KLF4', 'Gene', (20, 24))	('squamous cell dysplasia', 'Phenotype', 'HP:0002860', (110, 133))	('Genetic ablation', 'Var', (0, 16))	('precancerous squamous cell dysplasia', 'Disease', (97, 133))	('precancerous squamous cell dysplasia', 'Disease', 'MESH:D011230', (97, 133))	('delayed', 'NegReg', (54, 61))
538401	30845357	Down-modulation of ZNF750 activity by gene mutation, deletion or under-expression has been observed in human SCC, and low ZNF750 expression is associated with poor survival (Hazawa et al., 2017; Zhang et al., 2018).	('poor', 'NegReg', (159, 163))	('low', 'NegReg', (118, 121))	('SCC', 'Gene', '6317', (109, 112))	('SCC', 'Phenotype', 'HP:0002860', (109, 112))	('expression', 'MPA', (129, 139))	('ZNF750', 'Gene', (122, 128))	('under-expression', 'Var', (65, 81))	('human', 'Species', '9606', (103, 108))	('deletion', 'Var', (53, 61))	('ZNF750', 'Gene', '79755', (19, 25))	('ZNF750', 'Gene', '79755', (122, 128))	('Down-modulation', 'NegReg', (0, 15))	('gene mutation', 'Var', (38, 51))	('SCC', 'Gene', (109, 112))	('activity', 'MPA', (26, 34))	('ZNF750', 'Gene', (19, 25))
538405	30845357	Notably, the expression of the majority of direct DeltaNp63 target genes is upregulated in response to DeltaNp63 silencing, indicating the dominant function of DeltaNp63 as transcriptional repressor in SCC.	('SCC', 'Gene', (202, 205))	('DeltaNp63', 'Chemical', '-', (103, 112))	('expression', 'MPA', (13, 23))	('SCC', 'Phenotype', 'HP:0002860', (202, 205))	('DeltaNp63', 'Gene', (103, 112))	('SCC', 'Gene', '6317', (202, 205))	('DeltaNp63', 'Chemical', '-', (160, 169))	('DeltaNp63', 'Chemical', '-', (50, 59))	('silencing', 'Var', (113, 122))	('upregulated', 'PosReg', (76, 87))
538409	30845357	As we will discuss later, HNSCC frequently displays amplification of ACTL6a, an epigenetic factor necessary for the DeltaNp63-mediated repression of WWC1.	('WWC1', 'Gene', (149, 153))	('SCC', 'Gene', (28, 31))	('ACTL6a', 'Gene', '86', (69, 75))	('SCC', 'Phenotype', 'HP:0002860', (28, 31))	('WWC1', 'Gene', '23286', (149, 153))	('SCC', 'Gene', '6317', (28, 31))	('DeltaNp63', 'Chemical', '-', (116, 125))	('amplification', 'Var', (52, 65))	('ACTL6a', 'Gene', (69, 75))
538418	30845357	Upon DeltaNp63 silencing, lung SCC cells undergo a block of proliferation which is dependent on the activation of the transforming growth factor beta (TGFbeta) signalling.	('SCC', 'Gene', (31, 34))	('SCC', 'Phenotype', 'HP:0002860', (31, 34))	('DeltaNp63', 'Chemical', '-', (5, 14))	('SCC', 'Gene', '6317', (31, 34))	('silencing', 'Var', (15, 24))	('transforming growth factor beta', 'Gene', '7040', (118, 149))	('TGFbeta', 'Gene', (151, 158))	('block', 'CPA', (51, 56))	('DeltaNp63', 'Gene', (5, 14))	('TGFbeta', 'Gene', '7040', (151, 158))	('transforming growth factor beta', 'Gene', (118, 149))	('lung', 'Disease', (26, 30))
538419	30845357	At molecular level, DeltaNp63 directly represses the transcription of TGFB2 and TGFBR2, thus restraining the activation of the TGFbeta signalling.	('activation', 'MPA', (109, 119))	('restraining', 'NegReg', (93, 104))	('TGFbeta', 'Gene', '7040', (127, 134))	('TGFbeta', 'Gene', (127, 134))	('TGFBR2', 'Gene', (80, 86))	('TGFB2', 'Gene', '7042', (70, 75))	('TGFB2', 'Gene', (70, 75))	('represses', 'NegReg', (39, 48))	('DeltaNp63', 'Var', (20, 29))	('TGFBR2', 'Gene', '7048', (80, 86))	('DeltaNp63', 'Chemical', '-', (20, 29))	('transcription', 'MPA', (53, 66))
538422	30845357	This is quite important, as the majority of SCC harbour mutations in the TP53 locus and TGFbeta signalling can exert tumour-prone or tumour-suppressive effects depending on cell context as well as on the p53 status (Ikushima and Miyazono, 2010; Karlsson et al., 2017).	('SCC', 'Gene', '6317', (44, 47))	('mutations', 'Var', (56, 65))	('TP53', 'Gene', '7157', (73, 77))	('tumour', 'Phenotype', 'HP:0002664', (133, 139))	('tumour', 'Disease', 'MESH:D009369', (133, 139))	('TGFbeta', 'Gene', (88, 95))	('tumour', 'Phenotype', 'HP:0002664', (117, 123))	('TP53', 'Gene', (73, 77))	('p53', 'Gene', (204, 207))	('p53', 'Gene', '7157', (204, 207))	('tumour', 'Disease', 'MESH:D009369', (117, 123))	('tumour', 'Disease', (133, 139))	('SCC', 'Gene', (44, 47))	('TGFbeta', 'Gene', '7040', (88, 95))	('tumour', 'Disease', (117, 123))	('SCC', 'Phenotype', 'HP:0002860', (44, 47))
538423	30845357	Interestingly, the dependence on RHOA to sustain cell cycle arrest upon DeltaNp63 depletion has not been observed in the immortalized keratinocyte cell line HaCaT, which harbours mutation of TP53 gene (Abraham et al., 2018).	('RHOA', 'Gene', '387', (33, 37))	('DeltaNp63', 'Chemical', '-', (72, 81))	('cell cycle', 'CPA', (49, 59))	('TP53', 'Gene', '7157', (191, 195))	('mutation', 'Var', (179, 187))	('TP53', 'Gene', (191, 195))	('HaCaT', 'CellLine', 'CVCL:0038', (157, 162))	('RHOA', 'Gene', (33, 37))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (49, 66))	('DeltaNp63', 'Var', (72, 81))
538424	30845357	Furthermore, in HNSCC cells, DeltaNp63 can enhance the pro-tumourigenic function of TGFbeta by repressing the expression of two microRNA (miRNA), miR-527 and miR-665, which target Smad4 and TGFbetaR2, respectively (Rodriguez Calleja et al., 2016).	('DeltaNp63', 'Var', (29, 38))	('Smad4', 'Gene', (180, 185))	('SCC', 'Phenotype', 'HP:0002860', (18, 21))	('miR-527', 'Gene', (146, 153))	('TGFbeta', 'Gene', (190, 197))	('DeltaNp63', 'Chemical', '-', (29, 38))	('miR-527', 'Gene', '574497', (146, 153))	('tumour', 'Phenotype', 'HP:0002664', (59, 65))	('TGFbeta', 'Gene', '7040', (190, 197))	('SCC', 'Gene', '6317', (18, 21))	('tumour', 'Disease', 'MESH:D009369', (59, 65))	('tumour', 'Disease', (59, 65))	('TGFbeta', 'Gene', (84, 91))	('SCC', 'Gene', (18, 21))	('miR-665', 'Gene', (158, 165))	('Smad4', 'Gene', '4089', (180, 185))	('TGFbeta', 'Gene', '7040', (84, 91))	('repressing', 'NegReg', (95, 105))	('miR-665', 'Gene', '100126315', (158, 165))	('expression', 'MPA', (110, 120))	('enhance', 'PosReg', (43, 50))
538425	30845357	Therefore, the effect of DeltaNp63 on TGFbeta signalling might be cell context-dependent and/or influenced by extrinsic factors, as we will discuss later.	('DeltaNp63', 'Chemical', '-', (25, 34))	('TGFbeta', 'Gene', '7040', (38, 45))	('TGFbeta', 'Gene', (38, 45))	('influenced', 'Reg', (96, 106))	('DeltaNp63', 'Var', (25, 34))
538438	30845357	Indeed, in H226 cells, DeltaNp63 represses the expression of its targets independently from HDAC action.	('DeltaNp63', 'Var', (23, 32))	('DeltaNp63', 'Chemical', '-', (23, 32))	('HDAC', 'Gene', (92, 96))	('represses', 'NegReg', (33, 42))	('HDAC', 'Gene', '9734', (92, 96))	('H226', 'CellLine', 'CVCL:J621', (11, 15))	('expression', 'MPA', (47, 57))
538443	30845357	In HNSCC, DeltaNp63 interacts with the SWI/SNF subunit ACTL6A, inducing the repression of WCC1 transcription, as we have described before.	('SCC', 'Gene', '6317', (5, 8))	('DeltaNp63', 'Chemical', '-', (10, 19))	('inducing', 'PosReg', (63, 71))	('repression', 'MPA', (76, 86))	('WCC1 transcription', 'Gene', (90, 108))	('ACTL6A', 'Gene', '86', (55, 61))	('SCC', 'Gene', (5, 8))	('DeltaNp63', 'Var', (10, 19))	('SCC', 'Phenotype', 'HP:0002860', (5, 8))	('ACTL6A', 'Gene', (55, 61))
538444	30845357	In contrast to what is observed in normal stratified epithelium, ACTL6A is frequently overexpressed in HNSCC and about 20% of HNSCC shows genomic co-amplification of ACTL6A and TP63 loci (Saladi et al., 2017).	('ACTL6A', 'Gene', (65, 71))	('ACTL6A', 'Gene', (166, 172))	('overexpressed', 'PosReg', (86, 99))	('TP63', 'Gene', (177, 181))	('SCC', 'Gene', (128, 131))	('ACTL6A', 'Gene', '86', (166, 172))	('ACTL6A', 'Gene', '86', (65, 71))	('SCC', 'Gene', '6317', (128, 131))	('SCC', 'Gene', (105, 108))	('SCC', 'Phenotype', 'HP:0002860', (128, 131))	('SCC', 'Phenotype', 'HP:0002860', (105, 108))	('co-amplification', 'Var', (146, 162))	('SCC', 'Gene', '6317', (105, 108))
538446	30845357	Conversely, in different types of cancer, genomic analysis identified several loss-of-function mutations in various SWI/SNF subunits, suggesting a tumour-suppressor role for this complex (Kadoch et al., 2013).	('SWI/SNF', 'Gene', (116, 123))	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('tumour', 'Phenotype', 'HP:0002664', (147, 153))	('tumour', 'Disease', 'MESH:D009369', (147, 153))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('cancer', 'Disease', (34, 40))	('mutations', 'Var', (95, 104))	('tumour', 'Disease', (147, 153))	('loss-of-function', 'NegReg', (78, 94))
538448	30845357	These molecular data together with the key importance of DeltaNp63-repressed pathways in mediating the mitogenic action of DeltaNp63 in SCC clearly indicate that DeltaNp63-mediated transcriptional repression is a crucial oncogenic outcome of DeltaNp63 in SCC as well as in other epithelial cancers (Regina et al., 2016a,2016b).	('SCC', 'Gene', (255, 258))	('SCC', 'Gene', (136, 139))	('epithelial cancers', 'Disease', (279, 297))	('DeltaNp63', 'Chemical', '-', (162, 171))	('SCC', 'Phenotype', 'HP:0002860', (136, 139))	('cancers', 'Phenotype', 'HP:0002664', (290, 297))	('DeltaNp63', 'Var', (242, 251))	('SCC', 'Phenotype', 'HP:0002860', (255, 258))	('SCC', 'Gene', '6317', (255, 258))	('SCC', 'Gene', '6317', (136, 139))	('DeltaNp63-mediated', 'Var', (162, 180))	('DeltaNp63', 'Chemical', '-', (242, 251))	('epithelial cancers', 'Disease', 'MESH:D000077216', (279, 297))	('DeltaNp63', 'Chemical', '-', (57, 66))	('cancer', 'Phenotype', 'HP:0002664', (290, 296))	('DeltaNp63', 'Chemical', '-', (123, 132))
538449	30845357	On the other hand, as described in the next paragraph, DeltaNp63 also exerts its oncogenic activity by enhancing the transcription of several pro-tumourigenic factors, and epigenetic modifications are likely to be involved in this oncogenic function.	('involved', 'Reg', (214, 222))	('DeltaNp63', 'Var', (55, 64))	('tumour', 'Disease', (146, 152))	('enhancing', 'PosReg', (103, 112))	('DeltaNp63', 'Chemical', '-', (55, 64))	('transcription', 'MPA', (117, 130))	('tumour', 'Phenotype', 'HP:0002664', (146, 152))	('oncogenic activity', 'CPA', (81, 99))	('epigenetic modifications', 'Var', (172, 196))	('tumour', 'Disease', 'MESH:D009369', (146, 152))
538450	30845357	Accordingly, a high mutation rate of the methyltransferase KMTD2, an DeltaNp63 interacting epigenetic factor involved in the transcriptional activation of epithelial target genes, has been observed in SCC (Lin-Shiao et al., 2018).	('DeltaNp63', 'Chemical', '-', (69, 78))	('SCC', 'Gene', (201, 204))	('mutation', 'Var', (20, 28))	('KMTD2', 'Gene', (59, 64))	('SCC', 'Phenotype', 'HP:0002860', (201, 204))	('SCC', 'Gene', '6317', (201, 204))	('observed', 'Reg', (189, 197))
538456	30845357	DeltaNp63 enhances the expression of integrin receptors (e.g.	('enhances', 'PosReg', (10, 18))	('integrin receptors', 'Protein', (37, 55))	('DeltaNp63', 'Var', (0, 9))	('DeltaNp63', 'Chemical', '-', (0, 9))	('expression', 'MPA', (23, 33))
538467	30845357	In detail, DeltaNp63 favours the activation of pro-mitogenic and pro-survival signals by EGF-R in an HA-dependent manner.	('DeltaNp63', 'Chemical', '-', (11, 20))	('activation', 'PosReg', (33, 43))	('EGF-R', 'Gene', '1956', (89, 94))	('HA', 'Chemical', 'MESH:D006820', (101, 103))	('EGF-R', 'Gene', (89, 94))	('DeltaNp63', 'Var', (11, 20))
538470	30845357	In HNSCC tumours, p63 expression is positively correlated with that of HAS3 and CD44, and the expression of three tumour-related CD44 variants is associated with HNSCC progression in clinical samples (Maula et al., 2003; Misra et al., 2011).	('SCC', 'Gene', '6317', (5, 8))	('CD44', 'Gene', '960', (129, 133))	('CD44', 'Gene', (129, 133))	('SCC', 'Gene', (5, 8))	('associated with', 'Reg', (146, 161))	('HAS3', 'Gene', '3038', (71, 75))	('tumour', 'Phenotype', 'HP:0002664', (114, 120))	('tumour', 'Phenotype', 'HP:0002664', (9, 15))	('HNSCC tumours', 'Disease', 'MESH:D000077195', (3, 16))	('tumour', 'Disease', 'MESH:D009369', (9, 15))	('CD44', 'Gene', '960', (80, 84))	('tumour', 'Disease', 'MESH:D009369', (114, 120))	('tumours', 'Phenotype', 'HP:0002664', (9, 16))	('CD44', 'Gene', (80, 84))	('tumour', 'Disease', (114, 120))	('tumour', 'Disease', (9, 15))	('SCC', 'Phenotype', 'HP:0002860', (164, 167))	('HNSCC tumours', 'Disease', (3, 16))	('SCC', 'Phenotype', 'HP:0002860', (5, 8))	('variants', 'Var', (134, 142))	('clinical samples', 'Species', '191496', (183, 199))	('SCC', 'Gene', '6317', (164, 167))	('HAS3', 'Gene', (71, 75))	('SCC', 'Gene', (164, 167))
538478	30845357	In diverse epithelial tumours,  Np63 directly activates the transcription of EGF-R, even though this mechanism seems to be tissue-specific (Danilov et al., 2011).	('tumours', 'Phenotype', 'HP:0002664', (22, 29))	('tumour', 'Phenotype', 'HP:0002664', (22, 28))	('EGF-R', 'Gene', '1956', (77, 82))	('epithelial tumours', 'Disease', 'MESH:D000077216', (11, 29))	('activates', 'PosReg', (46, 55))	('EGF-R', 'Gene', (77, 82))	('epithelial tumours', 'Disease', (11, 29))	('Np63', 'Var', (32, 36))	('transcription', 'MPA', (60, 73))
538479	30845357	Np63 is also able to induce the transcription of neuregulin (NRG1), a natural ligand of ErbB3 receptor (Forster et al., 2014).	('ErbB3', 'Gene', '2065', (88, 93))	('Np63', 'Var', (0, 4))	('NRG1', 'Gene', (61, 65))	('induce', 'PosReg', (21, 27))	('NRG1', 'Gene', '3084', (61, 65))	('transcription', 'MPA', (32, 45))	('ErbB3', 'Gene', (88, 93))
538483	30845357	Collectively, these data indicate that  Np63 exploits multiple oncogenic pathways to enhance EGF-R-mediated oncogenic signalling.	('EGF-R', 'Gene', '1956', (93, 98))	('EGF-R', 'Gene', (93, 98))	('Np63', 'Var', (40, 44))	('enhance', 'PosReg', (85, 92))
538487	30845357	By repressing IGFBP3 and concomitantly activating IRS1 expression,  Np63 is able to enhance circulating IGF-1 and increase its intracellular signalling, ultimately fostering the growth and survival of SCC cells.	('growth', 'CPA', (178, 184))	('intracellular signalling', 'MPA', (127, 151))	('increase', 'PosReg', (114, 122))	('fostering', 'PosReg', (164, 173))	('SCC', 'Gene', (201, 204))	('IGFBP3', 'Gene', (14, 20))	('survival', 'CPA', (189, 197))	('IRS1', 'Gene', '3667', (50, 54))	('IRS1', 'Gene', (50, 54))	('SCC', 'Phenotype', 'HP:0002860', (201, 204))	('SCC', 'Gene', '6317', (201, 204))	('activating', 'PosReg', (39, 49))	('IGFBP3', 'Gene', '3486', (14, 20))	('enhance', 'PosReg', (84, 91))	('IGF-1', 'Gene', '3479', (104, 109))	('Np63', 'Var', (68, 72))	('IGF-1', 'Gene', (104, 109))
538504	30845357	By recruiting neutrophils and macrophages, DeltaNp63 might also sustain tumour-associated angiogenesis.	('tumour', 'Phenotype', 'HP:0002664', (72, 78))	('DeltaNp63', 'Var', (43, 52))	('DeltaNp63', 'Chemical', '-', (43, 52))	('sustain', 'PosReg', (64, 71))	('tumour', 'Disease', 'MESH:D009369', (72, 78))	('tumour', 'Disease', (72, 78))
538505	30845357	In osteosarcoma cells, ectopic expression of DeltaNp63 induces VEGF secretion by activating STAT3/HIF-1alpha pathway in a cytokine-dependent manner (Bid et al., 2014).	('VEGF', 'Gene', (63, 67))	('DeltaNp63', 'Chemical', '-', (45, 54))	('HIF-1alpha', 'Gene', '3091', (98, 108))	('osteosarcoma', 'Disease', (3, 15))	('ectopic expression', 'Var', (23, 41))	('DeltaNp63', 'Gene', (45, 54))	('STAT3', 'Gene', '6774', (92, 97))	('VEGF', 'Gene', '7422', (63, 67))	('osteosarcoma', 'Phenotype', 'HP:0002669', (3, 15))	('induces', 'Reg', (55, 62))	('osteosarcoma', 'Disease', 'MESH:D012516', (3, 15))	('STAT3', 'Gene', (92, 97))	('HIF-1alpha', 'Gene', (98, 108))	('activating', 'PosReg', (81, 91))
538508	30845357	By doing this, DeltaNp63 stimulates the migration of lymphatic endothelial cells in a CCR6-dependent manner, which might explain the increased density of blood and lymphatic vessels observed in high DeltaNp63-expressing SCC.	('CCR6', 'Gene', '1235', (86, 90))	('SCC', 'Gene', (220, 223))	('SCC', 'Phenotype', 'HP:0002860', (220, 223))	('DeltaNp63', 'Var', (15, 24))	('stimulates', 'PosReg', (25, 35))	('SCC', 'Gene', '6317', (220, 223))	('DeltaNp63', 'Chemical', '-', (15, 24))	('migration of lymphatic endothelial cells', 'CPA', (40, 80))	('increased', 'PosReg', (133, 142))	('CCR6', 'Gene', (86, 90))	('DeltaNp63', 'Chemical', '-', (199, 208))
538518	30845357	DeltaNp63 deregulates the expression of several genes, such as POSTN, CDH2, L1CAM and WNT5A, which contributes to the anti-migratory ability exerted by p63 in SCC (Barbieri et al., 2006).	('anti-migratory ability', 'CPA', (118, 140))	('L1CAM', 'Gene', (76, 81))	('expression', 'MPA', (26, 36))	('POSTN', 'Gene', (63, 68))	('deregulates', 'Reg', (10, 21))	('CDH2', 'Gene', '1000', (70, 74))	('WNT5A', 'Gene', (86, 91))	('SCC', 'Gene', (159, 162))	('L1CAM', 'Gene', '3897', (76, 81))	('SCC', 'Phenotype', 'HP:0002860', (159, 162))	('POSTN', 'Gene', '10631', (63, 68))	('WNT5A', 'Gene', '7474', (86, 91))	('SCC', 'Gene', '6317', (159, 162))	('DeltaNp63', 'Var', (0, 9))	('CDH2', 'Gene', (70, 74))	('DeltaNp63', 'Chemical', '-', (0, 9))
538525	30845357	Ablation of DeltaNp63 or DUSP6/7 perturbs the TGFbeta-induced migration and invasion.	('DUSP6', 'Gene', (25, 30))	('TGFbeta', 'Gene', (46, 53))	('DUSP6', 'Gene', '1848', (25, 30))	('Ablation', 'Var', (0, 8))	('TGFbeta', 'Gene', '7040', (46, 53))	('DeltaNp63', 'Chemical', '-', (12, 21))	('DeltaNp63', 'Gene', (12, 21))	('perturbs', 'NegReg', (33, 41))
538528	30845357	Basal-like breast cancer cells that express DeltaNp63 rely on mammary fibroblasts to initiate ECM reorganization, permiting collective invasion (Dang et al., 2011, 2015).	('collective invasion', 'CPA', (124, 143))	('breast cancer', 'Disease', 'MESH:D001943', (11, 24))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('permiting', 'Reg', (114, 123))	('breast cancer', 'Disease', (11, 24))	('breast cancer', 'Phenotype', 'HP:0003002', (11, 24))	('DeltaNp63', 'Var', (44, 53))	('DeltaNp63', 'Chemical', '-', (44, 53))
538529	30845357	Similarly, luminal B type breast cancer cells expressing DeltaNp63 are limited to invading regions enriched in collagen I (Cheung et al., 2013).	('breast cancer', 'Disease', (26, 39))	('breast cancer', 'Phenotype', 'HP:0003002', (26, 39))	('DeltaNp63', 'Var', (57, 66))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('DeltaNp63', 'Chemical', '-', (57, 66))	('breast cancer', 'Disease', 'MESH:D001943', (26, 39))
538570	27689360	It was reported that TRIM24 could activate estrogen-dependent genes associated with cellular proliferation and tumor development in breast cancer, and was negatively correlated with survival of this disease.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('activate', 'PosReg', (34, 42))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('cellular proliferation', 'CPA', (84, 106))	('negatively', 'NegReg', (155, 165))	('TRIM24', 'Var', (21, 27))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('tumor', 'Disease', (111, 116))	('breast cancer', 'Disease', 'MESH:D001943', (132, 145))	('breast cancer', 'Disease', (132, 145))	('breast cancer', 'Phenotype', 'HP:0003002', (132, 145))	('estrogen-dependent genes', 'Gene', (43, 67))
538572	27689360	However, some other studies show that mice with deletion of TRIM24 are predisposed to spontaneous hepatocarcinogenesis with the increased oncogenic activity of RARalpha, demonstrating that TRIM24 gene functions as a tumor suppressor while RARalpha as an oncogene in the development and progression of liver cancer.	('tumor', 'Disease', (216, 221))	('liver cancer', 'Disease', (301, 313))	('hepatocarcinogenesis', 'Disease', (98, 118))	('mice', 'Species', '10090', (38, 42))	('cancer', 'Phenotype', 'HP:0002664', (307, 313))	('predisposed', 'Reg', (71, 82))	('TRIM24', 'Gene', (60, 66))	('tumor', 'Disease', 'MESH:D009369', (216, 221))	('hepatocarcinogenesis', 'Disease', 'MESH:D063646', (98, 118))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('deletion', 'Var', (48, 56))	('liver cancer', 'Phenotype', 'HP:0002896', (301, 313))	('liver cancer', 'Disease', 'MESH:D006528', (301, 313))
538593	27689360	The results demonstrate that 71.6% (78/109) of patients with low TRIM24 expression have lymph node metastasis (LNM) while only 28.4% (31/109) of patients with high expression have LNM (P=0.024, Table 1); 71.4% (70/98) of ones with low expression have pathological tumour-node-metastasis stage (pTNM stage) III while only 28.6% (28/98) of ones with high expression have pTNM stage III (P=0.046, Table 1), suggesting that TRIM24 may inhibit ESCC progression.	('patients', 'Species', '9606', (145, 153))	('TNM', 'Gene', '10178', (370, 373))	('tumour-node-metastasis', 'Disease', 'MESH:D009362', (264, 286))	('tumour-node-metastasis', 'Disease', (264, 286))	('inhibit', 'NegReg', (431, 438))	('low', 'NegReg', (61, 64))	('SCC', 'Gene', (440, 443))	('ES', 'Chemical', 'MESH:D004540', (439, 441))	('patients', 'Species', '9606', (47, 55))	('TNM', 'Gene', (370, 373))	('TNM', 'Gene', (295, 298))	('expression', 'MPA', (72, 82))	('tumour', 'Phenotype', 'HP:0002664', (264, 270))	('SCC', 'Gene', '6317', (440, 443))	('TRIM24', 'Var', (420, 426))	('TNM', 'Gene', '10178', (295, 298))	('TRIM24', 'Gene', (65, 71))
538594	27689360	Moreover, patients with low expression have more postoperative relapse and metastasis than those with high expression (72.4% [97/134] vs 27.6% [37/134], P=0.001, Table 1), implying that TRIM24 may suppress ESCC development and metastasis.	('postoperative', 'CPA', (49, 62))	('suppress', 'NegReg', (197, 205))	('metastasis', 'CPA', (75, 85))	('SCC', 'Gene', (207, 210))	('TRIM24', 'Var', (186, 192))	('ES', 'Chemical', 'MESH:D004540', (206, 208))	('patients', 'Species', '9606', (10, 18))	('SCC', 'Gene', '6317', (207, 210))
538596	27689360	As expected, Kaplan-Meier survival analysis shows that patients with high TRIM24 expression have significantly better overall survival (OS) and disease-free survival (DFS) than those with low expression (P<0.001, P<0.001, respectively; Fig.	('overall survival', 'CPA', (118, 134))	('disease-free survival', 'CPA', (144, 165))	('better', 'PosReg', (111, 117))	('TRIM24', 'Protein', (74, 80))	('high', 'Var', (69, 73))	('patients', 'Species', '9606', (55, 63))
538597	27689360	Survival analysis also display that 5-year OS and 5-year DFS of patients with high TRIM24 level are 64.4% and 57.2%, compared with 35.8% and 28.9% of those with low level, respectively, which hint that TRIM24 is a tumor suppressor in ESCC patients.	('TRIM24', 'Gene', (83, 89))	('high', 'Var', (78, 82))	('SCC', 'Gene', '6317', (235, 238))	('patients', 'Species', '9606', (64, 72))	('tumor', 'Disease', 'MESH:D009369', (214, 219))	('patients', 'Species', '9606', (239, 247))	('tumor', 'Phenotype', 'HP:0002664', (214, 219))	('ES', 'Chemical', 'MESH:D004540', (234, 236))	('tumor', 'Disease', (214, 219))	('hint', 'Gene', '3094', (192, 196))	('SCC', 'Gene', (235, 238))	('hint', 'Gene', (192, 196))
538602	27689360	As presented in Table 2, TRIM24 expression is identified as an independent survival predictor for OS (HR, 0.519; 95%CI, 0.341-0.788; P=0.002) and DFS (HR, 0.584; 95%CI, 0.397-0.861; P=0.007), and pTNM staging system is another independent prognostic factor.	('TNM', 'Gene', '10178', (197, 200))	('TNM', 'Gene', (197, 200))	('TRIM24 expression', 'Var', (25, 42))	('DFS', 'Disease', (146, 149))
538611	27689360	Since the above result shows that TRIM24 can provide additional prognostic information, we hypothesized that TRIM24 will improve the prediction of survival in ESCC patients when it is combined with pTNM staging system.	('TRIM24', 'Var', (109, 115))	('TNM', 'Gene', '10178', (199, 202))	('survival', 'Disease', (147, 155))	('TNM', 'Gene', (199, 202))	('SCC', 'Gene', (160, 163))	('patients', 'Species', '9606', (164, 172))	('improve', 'PosReg', (121, 128))	('ES', 'Chemical', 'MESH:D004540', (159, 161))	('SCC', 'Gene', '6317', (160, 163))
538620	27689360	These results suggest that TRIM24 can significantly improve postoperative prognostic prediction for ESCC patients in the combined risk model.	('patients', 'Species', '9606', (105, 113))	('TRIM24', 'Var', (27, 33))	('SCC', 'Gene', (101, 104))	('improve', 'PosReg', (52, 59))	('ES', 'Chemical', 'MESH:D004540', (100, 102))	('SCC', 'Gene', '6317', (101, 104))	('postoperative', 'MPA', (60, 73))
538621	27689360	In this study, our findings indicate that TRIM24 functions as a tumor suppressor in ESCC, which is conflicting with some reports on other cancers.	('ES', 'Chemical', 'MESH:D004540', (84, 86))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('tumor', 'Disease', (64, 69))	('SCC', 'Gene', '6317', (85, 88))	('TRIM24', 'Var', (42, 48))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('cancers', 'Phenotype', 'HP:0002664', (138, 145))	('SCC', 'Gene', (85, 88))	('cancers', 'Disease', (138, 145))	('cancers', 'Disease', 'MESH:D009369', (138, 145))
538622	27689360	However, in transgenic mice models, TRIM24 is demonstrated as a tumor suppressor and can suppress liver carcinogenesis via interacting with RARalpha.	('TRIM24', 'Var', (36, 42))	('tumor', 'Disease', (64, 69))	('transgenic mice', 'Species', '10090', (12, 27))	('liver carcinogenesis', 'Disease', 'MESH:D063646', (98, 118))	('interacting', 'Interaction', (123, 134))	('liver carcinogenesis', 'Disease', (98, 118))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('suppress', 'NegReg', (89, 97))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
538631	27689360	In the current study, immunohistochemical staining shows that TRIM24 protein is predominantly localized in the nuclei of ESCC cells and NECT cells, suggesting that it may be involved in the transcriptional process, which is in accordance with other reports.	('SCC', 'Gene', (122, 125))	('involved', 'Reg', (174, 182))	('SCC', 'Gene', '6317', (122, 125))	('TRIM24', 'Var', (62, 68))	('ES', 'Chemical', 'MESH:D004540', (121, 123))
538633	27689360	More important, our study shows that lower expression level of TRIM24 protein is associated with more lymph node metastasis, advanced pTNM stage and postoperative recurrence/metastasis, signifying that TRIM24 protein mainly functions as tumor suppressor in early development of ESCC and loss of TRIM24 protein may result in the progression of ESCC.	('TNM', 'Gene', (135, 138))	('tumor', 'Disease', (237, 242))	('SCC', 'Gene', (279, 282))	('ES', 'Chemical', 'MESH:D004540', (343, 345))	('result in', 'Reg', (314, 323))	('SCC', 'Gene', '6317', (344, 347))	('SCC', 'Gene', (344, 347))	('SCC', 'Gene', '6317', (279, 282))	('lymph node metastasis', 'CPA', (102, 123))	('ES', 'Chemical', 'MESH:D004540', (278, 280))	('expression level', 'MPA', (43, 59))	('TNM', 'Gene', '10178', (135, 138))	('loss', 'Var', (287, 291))	('lower', 'NegReg', (37, 42))	('tumor', 'Disease', 'MESH:D009369', (237, 242))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))
538634	27689360	Furthermore, survival analysis reveals that patients with decreased level of TRIM24 have a poor survival rate and that TRIM24 is an independent prognostic factor in ESCC.	('patients', 'Species', '9606', (44, 52))	('TRIM24', 'Var', (119, 125))	('survival rate', 'CPA', (96, 109))	('TRIM24', 'Gene', (77, 83))	('decreased', 'NegReg', (58, 67))	('SCC', 'Gene', (166, 169))	('ES', 'Chemical', 'MESH:D004540', (165, 167))	('poor', 'NegReg', (91, 95))	('SCC', 'Gene', '6317', (166, 169))
538638	27689360	An earlier study defined TRIM24 as an E3-ubiquitin ligase that could degrade p53 protein, and loss of TRIM24/bonus would result in increased p53 expression and p53-dependent apoptosis in Drosophila and p53-postive MCF7 human breast cancer cells.	('human', 'Species', '9606', (219, 224))	('increased', 'PosReg', (131, 140))	('p53-dependent apoptosis', 'CPA', (160, 183))	('TRIM24/bonus', 'Gene', (102, 114))	('MCF7', 'CellLine', 'CVCL:0031', (214, 218))	('loss', 'Var', (94, 98))	('Drosophila', 'Species', '7227', (187, 197))	('expression', 'MPA', (145, 155))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('degrade', 'NegReg', (69, 76))	('breast cancer', 'Disease', 'MESH:D001943', (225, 238))	('breast cancer', 'Phenotype', 'HP:0003002', (225, 238))	('breast cancer', 'Disease', (225, 238))	('p53', 'Protein', (141, 144))	('p53 protein', 'Protein', (77, 88))
538640	27689360	Importantly, in a mouse model with cre-mediated excision of exon 4 of TRIM24 (TRIM24dlE4/dlE4), Khetchoumian K et al found that deficiency of TRIM24 may lead to continuous hepatocytes proliferation, spontaneous hepatocarcino-genesis, and increased susceptibility to chemically induced HCC.	('TRIM24', 'Gene', (142, 148))	('hepatocarcino-genesis', 'Disease', 'MESH:D006938', (211, 232))	('mouse', 'Species', '10090', (18, 23))	('continuous', 'CPA', (161, 171))	('chemically induced HCC', 'Disease', (266, 288))	('deficiency', 'Var', (128, 138))	('lead to', 'Reg', (153, 160))	('hepatocarcino-genesis', 'Disease', (211, 232))
538643	27689360	Mechanically, TRIM24 inhibits RARalpha dependent transcription to negatively regulate IFN/ STAT signaling pathway in the hepatocarcinogenesis of mice.	('inhibits', 'NegReg', (21, 29))	('negatively regulate', 'NegReg', (66, 85))	('hepatocarcinogenesis', 'Disease', 'MESH:D063646', (121, 141))	('RARalpha', 'Protein', (30, 38))	('hepatocarcinogenesis', 'Disease', (121, 141))	('TRIM24', 'Var', (14, 20))	('mice', 'Species', '10090', (145, 149))	('IFN/ STAT signaling pathway', 'Pathway', (86, 113))
538686	27339696	Further, recurrent HBV integration at the KMT2B locus is present in three liver tumors, but absent in their matched adjacent normal samples, indicating that viral integration induced host driver genetic alterations are required on top of viral oncogene expression for initiation and progression of liver hepatocellular carcinoma.	('liver tumors', 'Disease', (74, 86))	('liver hepatocellular carcinoma', 'Disease', 'MESH:D006528', (298, 328))	('liver hepatocellular carcinoma', 'Disease', (298, 328))	('KMT2B', 'Gene', '9757', (42, 47))	('liver tumors', 'Phenotype', 'HP:0002896', (74, 86))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (319, 328))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('integration', 'Var', (23, 34))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (304, 328))	('KMT2B', 'Gene', (42, 47))	('liver tumors', 'Disease', 'MESH:D008113', (74, 86))	('HBV', 'Gene', (19, 22))
538687	27339696	Notably, viral integrations were found in many genes, including novel recurrent HPV integrations at PTPN13 in cervical cancer.	('cervical cancer', 'Disease', (110, 125))	('found', 'Reg', (33, 38))	('HPV', 'Species', '10566', (80, 83))	('PTPN13', 'Gene', '5783', (100, 106))	('HPV integrations', 'Var', (80, 96))	('PTPN13', 'Gene', (100, 106))	('cervical cancer', 'Disease', 'MESH:D002583', (110, 125))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
538688	27339696	Finally, we observed a set of HHV4 and HBV variants strongly associated with ethnic groups, likely due to viral sequence evolution under environmental influences.	('HBV', 'Gene', (39, 42))	('HHV4', 'Species', '10376', (30, 34))	('HHV4', 'Gene', (30, 34))	('variants', 'Var', (43, 51))	('associated', 'Reg', (61, 71))
538691	27339696	The Cancer Genome Atlas (TCGA) Pan-Cancer project has discovered numerous somatic mutations in key cancer genes.	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('cancer', 'Disease', (99, 105))	('mutations', 'Var', (82, 91))	('Cancer', 'Disease', (4, 10))	('Cancer', 'Disease', (35, 41))	('Cancer', 'Phenotype', 'HP:0002664', (4, 10))	('Cancer', 'Phenotype', 'HP:0002664', (35, 41))	('Cancer Genome Atlas', 'Disease', (4, 23))	('Cancer', 'Disease', 'MESH:D009369', (4, 10))	('Cancer', 'Disease', 'MESH:D009369', (35, 41))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (4, 23))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
538693	27339696	Also, mutational signatures related to endogenous and exogenous DNA damage have been found in different cancer types, such as the APOBEC-associated cytosine deaminase mutational signature and smoking-related cytosine-to-adenine signatures.	('cytosine', 'Chemical', 'MESH:D003596', (208, 216))	('adenine', 'Chemical', 'MESH:D000225', (220, 227))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('APOBEC-associated', 'Gene', (130, 147))	('mutational', 'Var', (167, 177))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('cytosine', 'Chemical', 'MESH:D003596', (148, 156))
538703	27339696	Three important issues are explicitly addressed in the present study: 1) differential viral expression and integration patterns between tumors and adjacent normal samples, 2) the discovery and implications of novel rare viral insertions and 3) differences among ethnicities that may point to environmental influences on viral sequence evolution.	('tumors', 'Disease', (136, 142))	('tumors', 'Disease', 'MESH:D009369', (136, 142))	('viral', 'MPA', (86, 91))	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('insertions', 'Var', (226, 236))	('integration', 'MPA', (107, 118))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('differences', 'Reg', (244, 255))
538723	27339696	However, we did observe some exceptional cases that were positive for two different viruses, for example, one STAD case having HHV4 and HHV5, one LIHC case having HBV and HPV16 (Fig.	('HHV5', 'Var', (136, 140))	('HPV16', 'Species', '333760', (171, 176))	('HHV4', 'Species', '10376', (127, 131))	('HHV5', 'Species', '10359', (136, 140))	('HHV4', 'Var', (127, 131))
538724	27339696	S3A) and one BLCA with having HPV6 and HPV11 (Fig.	('HPV11', 'Var', (39, 44))	('HPV6', 'Var', (30, 34))	('HPV11', 'Species', '10580', (39, 44))	('HPV', 'Species', '10566', (30, 33))	('HPV', 'Species', '10566', (39, 42))
538730	27339696	The clinical-pathological information shows that patient DD-A1EH with only HBV in adjacent normal has a family history of cancer, and sample DD-A11A with HBV in tumor has no family history of cancer, which may indicate different cancer etiologies, i.e., inherited mutations and HBV infection, respectively.	('DD-A1EH', 'Var', (57, 64))	('cancer', 'Disease', (229, 235))	('cancer', 'Disease', 'MESH:D009369', (229, 235))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('patient', 'Species', '9606', (49, 56))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('HBV infection', 'Disease', (278, 291))	('cancer', 'Disease', (192, 198))	('cancer', 'Disease', 'MESH:D009369', (192, 198))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('HBV infection', 'Disease', 'MESH:D006509', (278, 291))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('tumor', 'Disease', (161, 166))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))
538748	27339696	Importantly, in these six tumors, we found three samples with HBV virus integration in KMT2B (MLL4), suggesting the integration sites in this gene are important for the development of liver cancer, consistent with other studies.	('important', 'Reg', (151, 160))	('integration', 'Var', (72, 83))	('KMT2B', 'Gene', '9757', (87, 92))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumors', 'Phenotype', 'HP:0002664', (26, 32))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('liver cancer', 'Phenotype', 'HP:0002896', (184, 196))	('tumors', 'Disease', 'MESH:D009369', (26, 32))	('MLL4', 'Gene', (94, 98))	('liver cancer', 'Disease', 'MESH:D006528', (184, 196))	('MLL4', 'Gene', '9757', (94, 98))	('KMT2B', 'Gene', (87, 92))	('liver cancer', 'Disease', (184, 196))	('tumors', 'Disease', (26, 32))
538759	27339696	For instance, we found that EBER-1 is highly expressed in BR-8676.	('EBER-1', 'Gene', (28, 34))	('BR-8676', 'Var', (58, 65))	('BR', 'Chemical', 'MESH:D001966', (58, 60))
538763	27339696	Because disruption of apoptosis can lead to tumor initiation, progression, or metastasis, RNA2.7 can be regarded as a viral oncogene.	('disruption', 'Var', (8, 18))	('lead to', 'Reg', (36, 43))	('progression', 'CPA', (62, 73))	('tumor initiation', 'Disease', 'MESH:D009369', (44, 60))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('metastasis', 'CPA', (78, 88))	('apoptosis', 'Protein', (22, 31))	('tumor initiation', 'Disease', (44, 60))
538769	27339696	E6/E7 were involved in binding and degrading p53/Rb proteins and their expression suggests that HPV16 may also play a role in the tumorgenesis in these LGG samples.	('tumor', 'Disease', (130, 135))	('expression', 'MPA', (71, 81))	('E6/E7', 'Var', (0, 5))	('p53', 'Gene', (45, 48))	('play', 'Reg', (111, 115))	('p53', 'Gene', '7157', (45, 48))	('HPV16', 'Species', '333760', (96, 101))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('LGG', 'Disease', (152, 155))	('HPV16', 'Gene', (96, 101))	('binding', 'Interaction', (23, 30))	('degrading', 'NegReg', (35, 44))
538770	27339696	Discordant read pair analysis using Pindel (see Methods) revealed a battery of genes having recurrent HPV integrations in several cancers (Fig.	('cancers', 'Phenotype', 'HP:0002664', (130, 137))	('cancers', 'Disease', (130, 137))	('integrations', 'Var', (106, 118))	('cancers', 'Disease', 'MESH:D009369', (130, 137))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('HPV', 'Species', '10566', (102, 105))
538778	27339696	The second hotpot of recurrent virus integration is at the RAD51B locus in 8 CESC samples, which include 3 samples with HPV16, 2 samples with HPV39, one with HPV18 and one with HPV45; interestingly, two HNSC tumors also harbor HPV16 integration at RAD51B.	('RAD51B', 'Gene', (59, 65))	('RAD51B', 'Gene', '5890', (248, 254))	('RAD51B', 'Gene', '5890', (59, 65))	('HNSC tumors', 'Disease', (203, 214))	('RAD51B', 'Gene', (248, 254))	('HPV', 'Species', '10566', (227, 230))	('HPV16', 'Species', '333760', (120, 125))	('HPV', 'Species', '10566', (142, 145))	('tumor', 'Phenotype', 'HP:0002664', (208, 213))	('HPV', 'Species', '10566', (177, 180))	('HPV16 integration', 'Var', (227, 244))	('HPV16', 'Species', '333760', (227, 232))	('tumors', 'Phenotype', 'HP:0002664', (208, 214))	('HNSC tumors', 'Disease', 'MESH:D009369', (203, 214))	('HPV', 'Species', '10566', (158, 161))	('HPV', 'Species', '10566', (120, 123))
538779	27339696	Whole-genome sequencing analysis reveals that HPV integration amplifies the somatic copy number of this region.	('HPV', 'Species', '10566', (46, 49))	('integration', 'Var', (50, 61))	('amplifies', 'PosReg', (62, 71))	('HPV', 'Gene', (46, 49))
538784	27339696	Three samples (C5-A1M9, DS-A7WF, LP-A5U3) with viral integration at ERBB2 locus showed significantly increased expression across all exons (P-value < 0.05) (Fig.	('increased', 'PosReg', (101, 110))	('viral integration', 'Var', (47, 64))	('ERBB2', 'Gene', '2064', (68, 73))	('ERBB2', 'Gene', (68, 73))	('expression', 'MPA', (111, 121))
538792	27339696	4C, HPV18 integrates at intron 1 of PTPN13 in sample EK-A2PK, while HPV16 integrates at exons 2 and 14 for samples WL-A834 and VS-A8QC, respectively.	('HPV', 'Species', '10566', (4, 7))	('integrates', 'Reg', (10, 20))	('PTPN13', 'Gene', (36, 42))	('HPV16', 'Species', '333760', (68, 73))	('VS-A8QC', 'Var', (127, 134))	('HPV18', 'Gene', (4, 9))	('integrates', 'Reg', (74, 84))	('HPV16', 'Gene', (68, 73))	('HPV', 'Species', '10566', (68, 71))	('PTPN13', 'Gene', '5783', (36, 42))
538793	27339696	The distinct virus integration sites and the consistent increase of the expression of the integrated or nearby exons provide strong evidence of novel recurrent HPV integrations within PTPN13.	('increase', 'PosReg', (56, 64))	('integrations', 'Var', (164, 176))	('expression', 'MPA', (72, 82))	('PTPN13', 'Gene', '5783', (184, 190))	('HPV', 'Species', '10566', (160, 163))	('HPV', 'Gene', (160, 163))	('PTPN13', 'Gene', (184, 190))
538798	27339696	For example, TERT was recently implicated by somatic events or viral integration in hepatocarcinogensis.	('TERT', 'Gene', (13, 17))	('hepatocarcinogensis', 'Disease', (84, 103))	('TERT', 'Gene', '7015', (13, 17))	('hepatocarcinogensis', 'Disease', 'None', (84, 103))	('viral integration', 'Var', (63, 80))
538799	27339696	Figure 4D and Table S2 show that the integration sites on KMT2B are between exon 3 and exon 8 and integrations often lead to increased expression of exons following these sites; this holds true for TERT, as well (Fig.	('increased', 'PosReg', (125, 134))	('KMT2B', 'Gene', '9757', (58, 63))	('TERT', 'Gene', '7015', (198, 202))	('integrations', 'Var', (98, 110))	('KMT2B', 'Gene', (58, 63))	('TERT', 'Gene', (198, 202))	('expression of exons', 'MPA', (135, 154))
538803	27339696	The average number of variants for HHV4, HBV and HPV16 are 121, 52 and 22, respectively.	('HBV', 'Gene', (41, 44))	('HPV16', 'Gene', (49, 54))	('HHV4', 'Species', '10376', (35, 39))	('HHV4', 'Gene', (35, 39))	('variants', 'Var', (22, 30))	('HPV16', 'Species', '333760', (49, 54))
538805	27339696	Using RPHM >= 1000 and sites with coverage >10X, we selected 50 variant sites for HBV across 50 HBV-positive LIHC samples, 101 variants across 24 HHV4-positive STAD samples, 17 variants across 60 HPV16-postive HNSC samples and 22 variants across 142 HPV16-positive CESC samples.	('variants', 'Var', (127, 135))	('HBV', 'Gene', (82, 85))	('HPV16', 'Species', '333760', (250, 255))	('HHV4', 'Species', '10376', (146, 150))	('variant', 'Var', (64, 71))	('HPV16', 'Species', '333760', (196, 201))
538806	27339696	Figure 5A shows the unsupervised clustering results for HHV4 variants across HHV4-positive samples with Caucasian and Asian cohorts separated in distinct groups.	('HHV4', 'Species', '10376', (56, 60))	('HHV4', 'Gene', (56, 60))	('HHV4-positive', 'Gene', (77, 90))	('HHV4', 'Species', '10376', (77, 81))	('variants', 'Var', (61, 69))
538807	27339696	Three variants, C   T at sites 343 and 454 and G   A at site 633, result in amino acid substitutions, L418F and P455S in HBV polymerase protein and R160K in S protein, respectively.	('R160K', 'Mutation', 'rs1222267645', (148, 153))	('R160K', 'Var', (148, 153))	('P455S', 'Var', (112, 117))	('HBV', 'Gene', (121, 124))	('P455S', 'Mutation', 'p.P455S', (112, 117))	('L418F', 'Mutation', 'p.L418F', (102, 107))	('L418F', 'Var', (102, 107))
538808	27339696	Variants C   T at sites 505 and 586 and A   G at site 616 are missense mutations, which lead to the respective amino acid substitutions H472Y, R499W and I509 V in HBV polymerase.	('R499W', 'Var', (143, 148))	('I509 V', 'Mutation', 'p.I509V', (153, 159))	('R499W', 'Mutation', 'rs199530208', (143, 148))	('H472Y', 'Mutation', 'p.H472Y', (136, 141))	('H472Y', 'Var', (136, 141))	('I509 V', 'Var', (153, 159))	('HBV polymerase', 'Enzyme', (163, 177))
538809	27339696	Finally, the tumor and adjacent normal pairs have the same variants for the sites observed in Fig.	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('tumor', 'Disease', (13, 18))	('variants', 'Var', (59, 67))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
538810	27339696	5B, except for sample DD-A116, in which HBV found in the tumor has an additional variant (A   G) at site 1034, leading to an amino acid substitution Q648R in the HBV polymerase.	('Q648R', 'Var', (149, 154))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('Q648R', 'Mutation', 'rs1057519862', (149, 154))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('HBV polymerase', 'Enzyme', (162, 176))	('tumor', 'Disease', (57, 62))
538811	27339696	We also examined viral variation by cancer type by comparing HPV16 variants between CESC and HNSC samples.	('comparing', 'Reg', (51, 60))	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('HPV16', 'Gene', (61, 66))	('HPV16', 'Species', '333760', (61, 66))	('cancer', 'Disease', (36, 42))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('examined', 'Reg', (8, 16))	('variants', 'Var', (67, 75))
538813	27339696	Most HPV16 variants overlap between the two cancer types, which suggests they reflect population diversity rather than tissue origin.	('HPV16', 'Gene', (5, 10))	('HPV16', 'Species', '333760', (5, 10))	('variants', 'Var', (11, 19))	('overlap', 'Reg', (20, 27))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
538816	27339696	We did not observe any strong correlation between HPV16 variants and ethnic group.	('variants', 'Var', (56, 64))	('HPV16', 'Species', '333760', (50, 55))	('HPV16', 'Gene', (50, 55))
538819	27339696	HPV subtypes in BLCA are HPV45, HPV51, HPV56 and HPV6 and virus abundance in four samples is especially high (RPHM > 104).	('HPV45', 'Var', (25, 30))	('HPV', 'Species', '10566', (0, 3))	('HPV', 'Species', '10566', (25, 28))	('HPV', 'Species', '10566', (49, 52))	('HPV51', 'Var', (32, 37))	('HPV6', 'Var', (49, 53))	('HPV', 'Species', '10566', (32, 35))	('HPV', 'Species', '10566', (39, 42))	('HPV56', 'Var', (39, 44))
538829	27339696	For instance, recurrent HBV integrations in the KMT2B (MLL4) were observed in tumors, but none in adjacent normal samples.	('tumors', 'Disease', (78, 84))	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('KMT2B', 'Gene', '9757', (48, 53))	('HBV', 'Gene', (24, 27))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('MLL4', 'Gene', '9757', (55, 59))	('MLL4', 'Gene', (55, 59))	('integrations', 'Var', (28, 40))	('KMT2B', 'Gene', (48, 53))
538837	27339696	In addition, the analyses of virus variants in tumor samples reveal the association of virus variants and ethnicity groups for HBV in LIHC and HHV4 in STAD.	('HBV', 'Gene', (127, 130))	('HHV4', 'Gene', (143, 147))	('association', 'Interaction', (72, 83))	('variants', 'Var', (93, 101))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('LIHC', 'Disease', (134, 138))	('tumor', 'Disease', (47, 52))	('HHV4', 'Species', '10376', (143, 147))
538857	27339696	We used the contml tool from the PHYLIP toolkit (http://evolution.genetics.washington.edu/phylip.html) to construct phylogenetic trees based on variant allele fraction for HBV and HHV4.	('HHV4', 'Gene', (180, 184))	('HBV', 'Gene', (172, 175))	('HHV4', 'Species', '10376', (180, 184))	('variant', 'Var', (144, 151))
538887	32256809	The inclusion criteria were as follows: i) Age, 18-75 years; ii) histological type of small cell carcinoma, squamous cell carcinoma, adenocarcinoma and others; iii) KPS score >60 and iv) no neurological abnormalities.	('carcinoma', 'Phenotype', 'HP:0030731', (138, 147))	('carcinoma', 'Phenotype', 'HP:0030731', (97, 106))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (108, 131))	('small cell carcinoma', 'Disease', 'MESH:D018288', (86, 106))	('adenocarcinoma', 'Disease', (133, 147))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (108, 131))	('KPS score >60', 'Var', (165, 178))	('neurological abnormalities', 'Disease', (190, 216))	('squamous cell carcinoma', 'Disease', (108, 131))	('adenocarcinoma', 'Disease', 'MESH:D000230', (133, 147))	('small cell carcinoma', 'Phenotype', 'HP:0030357', (86, 106))	('neurological abnormalities', 'Disease', 'MESH:D009422', (190, 216))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('small cell carcinoma', 'Disease', (86, 106))	('neurological abnormalities', 'Phenotype', 'HP:0000707', (190, 216))
538979	31297902	Cells were added with 250 muL hybrid solution containing the probe (300 ng/mL) at 42 C overnight.	('muL', 'Gene', '4591', (26, 29))	('300 ng/mL', 'Var', (68, 77))	('muL', 'Gene', (26, 29))
538990	31297902	Next, protein was separated by electrophoresis and transferred onto a nitrocellulose membrane, which was blocked with 5% skim milk at 4 C overnight and incubated overnight with primary rabbit anti-human polyclonal antibodies to STC2 (1:500, ab63057); AKT (1:500, ab8805); p-AKT (1:500, ab38449); and PI3K (1:500, ab127617); p-PI3K (1:500, Y607; ab182651).	('1:500', 'Var', (332, 337))	('AKT', 'Gene', (251, 254))	('rabbit', 'Species', '9986', (185, 191))	('1:500', 'Var', (234, 239))	('si', 'Chemical', 'MESH:D012825', (43, 45))	('AKT', 'Gene', '207', (274, 277))	('1:500', 'Var', (279, 284))	('1:500', 'Var', (306, 311))	('AKT', 'Gene', '207', (251, 254))	('AKT', 'Gene', (274, 277))	('human', 'Species', '9606', (197, 202))
539019	31297902	While the results were reciprocal in HNSCC cells treated with si-HOTAIR when compared with blank and NC (P < 0.05) (Figure 2A-F).	('HNSCC', 'Disease', (37, 42))	('HNSCC', 'Phenotype', 'HP:0012288', (37, 42))	('HNSCC', 'Disease', 'MESH:C535575', (37, 42))	('si-HOTAIR', 'Var', (62, 71))	('si', 'Chemical', 'MESH:D012825', (62, 64))	('SCC', 'Phenotype', 'HP:0002860', (39, 42))
539031	31297902	An increased STC2 expression was observed, with reduced miR-206 expression in the miR-206 inhibitor group (P < 0.05).	('increased', 'PosReg', (3, 12))	('si', 'Chemical', 'MESH:D012825', (70, 72))	('miR-206', 'Gene', (82, 89))	('expression', 'MPA', (64, 74))	('reduced', 'NegReg', (48, 55))	('inhibitor', 'Var', (90, 99))	('expression', 'MPA', (18, 28))	('miR-206', 'Gene', (56, 63))	('STC2', 'Gene', (13, 17))	('si', 'Chemical', 'MESH:D012825', (24, 26))
539033	31297902	Overexpression of miR-206 or silencing STC2 inhibited PI3K/AKT signalling pathway activation.	('si', 'Chemical', 'MESH:D012825', (29, 31))	('si', 'Chemical', 'MESH:D012825', (10, 12))	('AKT', 'Gene', (59, 62))	('silencing', 'Var', (29, 38))	('inhibited', 'NegReg', (44, 53))	('activation', 'PosReg', (82, 92))	('AKT', 'Gene', '207', (59, 62))	('miR-206', 'Gene', (18, 25))	('STC2', 'Gene', (39, 43))	('si', 'Chemical', 'MESH:D012825', (63, 65))
539035	31297902	The results proved that in contrast to the blank and NC, miR-206 inhibitor increased number of migrating cells and invasive cells, while miR-206 mimic and si-STC2 exhibited opposite trends (P < 0.05).	('miR-206', 'Gene', (57, 64))	('inhibitor', 'Var', (65, 74))	('si', 'Chemical', 'MESH:D012825', (177, 179))	('si', 'Chemical', 'MESH:D012825', (119, 121))	('increased', 'PosReg', (75, 84))	('si', 'Chemical', 'MESH:D012825', (155, 157))
539036	31297902	Moreover, scratch test also verified that miR-206 inhibitor accelerated healing of scratches, while co-treatment of miR-206 inhibitor + si-STC2 revealed opposite trends.	('accelerated', 'PosReg', (60, 71))	('healing of scratches', 'CPA', (72, 92))	('si', 'Chemical', 'MESH:D012825', (136, 138))	('miR-206', 'Gene', (42, 49))	('inhibitor', 'Var', (50, 59))	('si', 'Chemical', 'MESH:D012825', (157, 159))
539037	31297902	Thus, effects of miR-206 inhibitor were reversed by si-STC2 (Figure 7E-F).	('si', 'Chemical', 'MESH:D012825', (52, 54))	('si-STC2', 'Var', (52, 59))	('miR-206', 'Gene', (17, 24))
539040	31297902	In HNSCC cells after miR-206 mimic or si-STC2 treatment, the G0/G1 phase cell cycle entry increased, S phase proportion decreased and apoptotic rate increased, while it was opposite in HNSCC cells after miR-206 inhibitor + si-STC2 treatment.	('decreased', 'NegReg', (120, 129))	('HNSCC', 'Phenotype', 'HP:0012288', (3, 8))	('HNSCC', 'Phenotype', 'HP:0012288', (185, 190))	('increased', 'PosReg', (90, 99))	('increased', 'PosReg', (149, 158))	('si', 'Chemical', 'MESH:D012825', (177, 179))	('apoptotic rate', 'CPA', (134, 148))	('SCC', 'Phenotype', 'HP:0002860', (187, 190))	('S phase proportion', 'CPA', (101, 119))	('HNSCC', 'Disease', 'MESH:C535575', (3, 8))	('HNSCC', 'Disease', 'MESH:C535575', (185, 190))	('si', 'Chemical', 'MESH:D012825', (38, 40))	('SCC', 'Phenotype', 'HP:0002860', (5, 8))	('HNSCC', 'Disease', (185, 190))	('G0/G1 phase cell cycle entry', 'CPA', (61, 89))	('si-STC2', 'Var', (38, 45))	('HNSCC', 'Disease', (3, 8))	('si', 'Chemical', 'MESH:D012825', (223, 225))
539048	31297902	When treated with HOTAIR + si-STC2, the invasion and proliferation of cells induced by HOTAIR were reversed by si-STC2 (Figure 8D-I).	('invasion', 'CPA', (40, 48))	('si-STC2', 'Var', (111, 118))	('si', 'Chemical', 'MESH:D012825', (111, 113))	('proliferation of cells', 'CPA', (53, 75))	('si', 'Chemical', 'MESH:D012825', (44, 46))	('si', 'Chemical', 'MESH:D012825', (27, 29))
539051	31297902	Mice treated with miR-206 mimic, si-STC2 or si-HOTAIR showed smaller tumour volume and lower weight (all P < 0.05) while mice following miR-206 inhibitor or HOTAIR treatment presented contrary trends.	('tumour', 'Disease', (69, 75))	('smaller', 'NegReg', (61, 68))	('si', 'Chemical', 'MESH:D012825', (33, 35))	('lower weight', 'Phenotype', 'HP:0004325', (87, 99))	('lower', 'NegReg', (87, 92))	('si-STC2', 'Var', (33, 40))	('si-HOTAIR', 'Var', (44, 53))	('tumour', 'Phenotype', 'HP:0002664', (69, 75))	('si', 'Chemical', 'MESH:D012825', (44, 46))	('weight', 'CPA', (93, 99))	('mice', 'Species', '10090', (121, 125))	('tumour', 'Disease', 'MESH:D009369', (69, 75))	('Mice', 'Species', '10090', (0, 4))
539052	31297902	These results showed that HOTAIR silencing or miR-206 overexpression inhibited tumour growth in vivo.	('HOTAIR', 'Var', (26, 32))	('si', 'Chemical', 'MESH:D012825', (33, 35))	('tumour growth', 'Disease', (79, 92))	('overexpression', 'PosReg', (54, 68))	('silencing', 'Var', (33, 42))	('tumour', 'Phenotype', 'HP:0002664', (79, 85))	('tumour growth', 'Disease', 'MESH:D006130', (79, 92))	('si', 'Chemical', 'MESH:D012825', (64, 66))	('inhibited', 'NegReg', (69, 78))	('miR-206', 'Gene', (46, 53))
539053	31297902	HNSCC is characterized by high recurrence, metastasis and unsatisfactory treatment results.21 There is evidence indicating that the dysregulation of lncRNAs functions crucially in the genesis and development of HNSCC.22 For instance, HOTAIR exerts a prognostic effect over biological functions of HNSCC.23 Notably, HOTAIR has been demonstrated to be correlated with cell apoptosis and proliferation in various human malignancies, including HNSCC.24 Thus, we investigated the role of HOTAIR in HNSCC, and findings revealed that silencing HOTAIR upregulate miR-206 to downregulate STC2, thus inhibiting HNSCC biological functions.	('miR-206', 'Gene', (555, 562))	('HOTAIR', 'Gene', (537, 543))	('HNSCC', 'Disease', (440, 445))	('si', 'Chemical', 'MESH:D012825', (50, 52))	('HNSCC', 'Disease', (493, 498))	('HNSCC', 'Phenotype', 'HP:0012288', (211, 216))	('HNSCC', 'Phenotype', 'HP:0012288', (297, 302))	('HNSCC', 'Disease', (0, 5))	('STC2', 'Gene', (579, 583))	('HNSCC', 'Disease', 'MESH:C535575', (601, 606))	('SCC', 'Phenotype', 'HP:0002860', (213, 216))	('HNSCC', 'Phenotype', 'HP:0012288', (440, 445))	('inhibiting', 'NegReg', (590, 600))	('HNSCC', 'Disease', 'MESH:C535575', (211, 216))	('HNSCC', 'Phenotype', 'HP:0012288', (493, 498))	('HNSCC', 'Disease', 'MESH:C535575', (297, 302))	('HNSCC', 'Phenotype', 'HP:0012288', (0, 5))	('upregulate', 'PosReg', (544, 554))	('HNSCC', 'Disease', 'MESH:C535575', (440, 445))	('downregulate', 'NegReg', (566, 578))	('HNSCC', 'Disease', 'MESH:C535575', (493, 498))	('SCC', 'Phenotype', 'HP:0002860', (299, 302))	('si', 'Chemical', 'MESH:D012825', (188, 190))	('HNSCC', 'Disease', 'MESH:C535575', (0, 5))	('silencing', 'Var', (527, 536))	('human', 'Species', '9606', (410, 415))	('HNSCC', 'Disease', (601, 606))	('SCC', 'Phenotype', 'HP:0002860', (442, 445))	('malignancies', 'Disease', 'MESH:D009369', (416, 428))	('SCC', 'Phenotype', 'HP:0002860', (495, 498))	('si', 'Chemical', 'MESH:D012825', (527, 529))	('HNSCC', 'Disease', (211, 216))	('malignancies', 'Disease', (416, 428))	('HNSCC', 'Disease', (297, 302))	('SCC', 'Phenotype', 'HP:0002860', (2, 5))	('si', 'Chemical', 'MESH:D012825', (377, 379))
539054	31297902	HOTAIR was highly expressed in HNSCC cells, and silenced HOTAIR consequently inhibited HNSCC cell proliferation, invasion and migration.	('HNSCC', 'Disease', 'MESH:C535575', (31, 36))	('HNSCC', 'Disease', 'MESH:C535575', (87, 92))	('HNSCC', 'Phenotype', 'HP:0012288', (87, 92))	('HNSCC', 'Disease', (31, 36))	('HOTAIR', 'Gene', (57, 63))	('inhibited', 'NegReg', (77, 86))	('HNSCC', 'Phenotype', 'HP:0012288', (31, 36))	('silenced', 'Var', (48, 56))	('SCC', 'Phenotype', 'HP:0002860', (89, 92))	('si', 'Chemical', 'MESH:D012825', (117, 119))	('si', 'Chemical', 'MESH:D012825', (48, 50))	('SCC', 'Phenotype', 'HP:0002860', (33, 36))	('HNSCC', 'Disease', (87, 92))
539057	31297902	miR-206 reduces biological functions of lung squamous cell carcinoma (SCC), thereby repressing cell proliferation, migration and invasion in lung SCC.30 Furthermore, previous research observed overexpressed miR-206 to inhibit cell proliferation and migration in colorectal cancer, highlighting the tumour-suppressive abilities of miR-206.31 Most importantly, consistent with our results, Liu et al observed miR-206 was downregulated in HNSCC, and overexpressed miR-206 could inhibit cell growth, migration and invasion in HNSCC.32 Notably, STC2 upregulation increased HNSCC cell proliferation, invasion and migration, tumour growth, and metastasis, revealing that STC2 could be a novel strategy for HNSCC treatment.33 Further, STC2 is a target of miR-206, and miR-206 could downregulate STC2 expression.	('si', 'Chemical', 'MESH:D012825', (90, 92))	('si', 'Chemical', 'MESH:D012825', (598, 600))	('HNSCC', 'Phenotype', 'HP:0012288', (568, 573))	('STC2', 'Gene', (787, 791))	('SCC', 'Disease', 'MESH:D002294', (146, 149))	('SCC', 'Disease', (701, 704))	('HNSCC', 'Disease', (699, 704))	('si', 'Chemical', 'MESH:D012825', (312, 314))	('miR-206', 'Var', (760, 767))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (40, 68))	('SCC', 'Disease', (146, 149))	('SCC', 'Phenotype', 'HP:0002860', (438, 441))	('SCC', 'Phenotype', 'HP:0002860', (524, 527))	('colorectal cancer', 'Disease', 'MESH:D015179', (262, 279))	('tumour', 'Phenotype', 'HP:0002664', (298, 304))	('HNSCC', 'Disease', 'MESH:C535575', (568, 573))	('tumour growth', 'Disease', (618, 631))	('tumour', 'Disease', 'MESH:D009369', (298, 304))	('HNSCC', 'Phenotype', 'HP:0012288', (699, 704))	('si', 'Chemical', 'MESH:D012825', (644, 646))	('SCC', 'Disease', 'MESH:D002294', (438, 441))	('colorectal cancer', 'Disease', (262, 279))	('tumour', 'Disease', (298, 304))	('SCC', 'Disease', 'MESH:D002294', (524, 527))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (45, 68))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (40, 68))	('lung squamous cell carcinoma', 'Disease', (40, 68))	('SCC', 'Disease', (438, 441))	('HNSCC', 'Disease', (522, 527))	('HNSCC', 'Disease', (436, 441))	('downregulate', 'NegReg', (774, 786))	('SCC', 'Phenotype', 'HP:0002860', (570, 573))	('SCC', 'Disease', (524, 527))	('lung SCC', 'Disease', 'MESH:D002294', (141, 149))	('SCC', 'Disease', 'MESH:D002294', (701, 704))	('HNSCC', 'Disease', 'MESH:C535575', (699, 704))	('si', 'Chemical', 'MESH:D012825', (514, 516))	('si', 'Chemical', 'MESH:D012825', (133, 135))	('SCC', 'Phenotype', 'HP:0002860', (70, 73))	('SCC', 'Disease', 'MESH:D002294', (570, 573))	('carcinoma', 'Phenotype', 'HP:0030731', (59, 68))	('lung SCC', 'Disease', (141, 149))	('si', 'Chemical', 'MESH:D012825', (798, 800))	('HNSCC', 'Phenotype', 'HP:0012288', (522, 527))	('HNSCC', 'Phenotype', 'HP:0012288', (436, 441))	('expression', 'MPA', (792, 802))	('si', 'Chemical', 'MESH:D012825', (362, 364))	('tumour', 'Disease', 'MESH:D009369', (618, 624))	('SCC', 'Disease', 'MESH:D002294', (70, 73))	('HNSCC', 'Disease', (568, 573))	('colorectal cancer', 'Phenotype', 'HP:0003003', (262, 279))	('tumour growth', 'Disease', 'MESH:D006130', (618, 631))	('tumour', 'Phenotype', 'HP:0002664', (618, 624))	('SCC', 'Disease', (570, 573))	('cancer', 'Phenotype', 'HP:0002664', (273, 279))	('tumour', 'Disease', (618, 624))	('SCC', 'Phenotype', 'HP:0002860', (146, 149))	('SCC', 'Disease', (70, 73))	('HNSCC', 'Disease', 'MESH:C535575', (522, 527))	('HNSCC', 'Disease', 'MESH:C535575', (436, 441))
539058	31297902	In consistency with our results, miR-206 inhibited tumour growth and metastasis in GC via targeting STC2.34 The impact of activated PI3K/AKT signalling pathway is significant in various fundamental biological activities.35 Likewise, the PI3K/AKT signalling pathway regulated cell biological functions in HNSCC.36 Furthermore, overexpressed miR-206 suppressed lung cancer cell migration and invasion via inhibition of the PI3K/AKT/mTOR signalling pathway.37  In conclusion, silencing HOTAIR could inhibit HNSCC biological functions via STC2 downregulation by competitively binding to miR-206.	('AKT', 'Gene', '207', (137, 140))	('HNSCC', 'Phenotype', 'HP:0012288', (304, 309))	('mTOR', 'Gene', (430, 434))	('HNSCC', 'Phenotype', 'HP:0012288', (504, 509))	('HNSCC', 'Disease', (504, 509))	('AKT', 'Gene', (426, 429))	('si', 'Chemical', 'MESH:D012825', (246, 248))	('lung cancer', 'Disease', 'MESH:D008175', (359, 370))	('tumour', 'Phenotype', 'HP:0002664', (51, 57))	('HNSCC', 'Disease', 'MESH:C535575', (304, 309))	('silencing', 'Var', (473, 482))	('AKT', 'Gene', (242, 245))	('tumour growth', 'Disease', 'MESH:D006130', (51, 64))	('HNSCC', 'Disease', 'MESH:C535575', (504, 509))	('si', 'Chemical', 'MESH:D012825', (467, 469))	('lung cancer', 'Phenotype', 'HP:0100526', (359, 370))	('mTOR', 'Gene', '2475', (430, 434))	('si', 'Chemical', 'MESH:D012825', (141, 143))	('GC', 'Disease', 'MESH:D013274', (83, 85))	('cancer', 'Phenotype', 'HP:0002664', (364, 370))	('inhibit', 'NegReg', (496, 503))	('si', 'Chemical', 'MESH:D012825', (435, 437))	('SCC', 'Phenotype', 'HP:0002860', (506, 509))	('AKT', 'Gene', '207', (426, 429))	('si', 'Chemical', 'MESH:D012825', (394, 396))	('si', 'Chemical', 'MESH:D012825', (6, 8))	('AKT', 'Gene', (137, 140))	('AKT', 'Gene', '207', (242, 245))	('binding', 'Interaction', (572, 579))	('si', 'Chemical', 'MESH:D012825', (76, 78))	('si', 'Chemical', 'MESH:D012825', (163, 165))	('GC', 'Phenotype', 'HP:0012126', (83, 85))	('tumour growth', 'Disease', (51, 64))	('SCC', 'Phenotype', 'HP:0002860', (306, 309))	('HNSCC', 'Disease', (304, 309))	('si', 'Chemical', 'MESH:D012825', (473, 475))	('downregulation', 'NegReg', (540, 554))	('STC2', 'Gene', (535, 539))	('lung cancer', 'Disease', (359, 370))
539065	30153850	The presence of CD3+, CD4+, CD8+, and forkhead box protein P3-positive (FOXP3+) TILs in tumor tissues obtained from 93 patients during surgery was examined using immunohistochemistry.	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('CD4', 'Gene', '920', (22, 25))	('FOXP3', 'Gene', (72, 77))	('patients', 'Species', '9606', (119, 127))	('CD3+', 'Var', (16, 20))	('CD8', 'Gene', (28, 31))	('CD4', 'Gene', (22, 25))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('FOXP3', 'Gene', '50943', (72, 77))	('forkhead box protein P3', 'Gene', '50943', (38, 61))	('CD8', 'Gene', '925', (28, 31))	('tumor', 'Disease', (88, 93))	('forkhead box protein P3', 'Gene', (38, 61))
539124	30153850	In univariate analysis, the 3-year OS of patients with ECE (46.2% vs. 94.4%, p = 0.000), N2/N3 disease (56.8% vs. 93.4%, p = 0.001), advanced-stage tumors (66.4% vs. 94.7%, p = 0.009), and a low CD8/FOXP3 ratio (63.8% vs. 87.3%, p = 0.001) (Fig.	('FOXP3', 'Gene', (199, 204))	('low', 'NegReg', (191, 194))	('tumor', 'Phenotype', 'HP:0002664', (148, 153))	('N2/N3 disease', 'Var', (89, 102))	('OS', 'Chemical', '-', (35, 37))	('FOXP3', 'Gene', '50943', (199, 204))	('CD8', 'Gene', (195, 198))	('ECE', 'Chemical', '-', (55, 58))	('patients', 'Species', '9606', (41, 49))	('advanced-stage tumors', 'Disease', (133, 154))	('advanced-stage tumors', 'Disease', 'MESH:D020178', (133, 154))	('CD8', 'Gene', '925', (195, 198))	('tumors', 'Phenotype', 'HP:0002664', (148, 154))	('ECE', 'Disease', (55, 58))
539125	30153850	In multivariate analysis, positive ECE (hazard ratio [HR] = 19.713, 95% CI = 2.594-149.833, p = 0.004) and N2/N3 (HR = 6.473, 95% CI = 1.465-28.609, p = 0.014) remained significant adverse prognostic factors for OS whereas a high CD8/FOXP3 ratio was a favorable prognostic factor for OS (HR = 0.015, 95% CI = 0.017-0.791, p = 0.028).	('N2/N3', 'Var', (107, 112))	('FOXP3', 'Gene', (234, 239))	('CD8', 'Gene', (230, 233))	('CD8', 'Gene', '925', (230, 233))	('ECE', 'Chemical', '-', (35, 38))	('FOXP3', 'Gene', '50943', (234, 239))	('OS', 'Chemical', '-', (284, 286))	('OS', 'Chemical', '-', (212, 214))
539126	30153850	In univariate analysis for LRFS, patients with moderate/poor differentiation (58.5% vs. 93.3%, p = 0.017), male sex (70.9% vs. 100%, p = 0.019), and close/positive margin (66.9% vs. 85.8%, p = 0.030) had significantly worse 3-year LRFS.	('LRFS', 'CPA', (231, 235))	('patients', 'Species', '9606', (33, 41))	('moderate/poor', 'Var', (47, 60))	('worse', 'NegReg', (218, 223))	('close/positive margin', 'Var', (149, 170))
539129	30153850	Patients with N2/N3 disease (65.2% vs. 81.7%, p = 0.098), moderate/poor differentiation (57.7% vs. 88.2%, p = 0.059), low CD8 (65.9% vs. 83.2%, p = 0.069), high FOXP3 (49.3% vs. 87.3%, p = 0.000) (Fig.	('low', 'Var', (118, 121))	('FOXP3', 'Gene', '50943', (161, 166))	('CD8', 'Gene', (122, 125))	('N2/N3 disease', 'Disease', (14, 27))	('CD8', 'Gene', '925', (122, 125))	('Patients', 'Species', '9606', (0, 8))	('FOXP3', 'Gene', (161, 166))	('high', 'Var', (156, 160))
539131	30153850	Multivariate analysis showed that in addition to the clinicopathological characteristics of ECE (HR = 5.268, 95% CI = 1.503-18.466, p = 0.022) and N2/N3 disease (HR = 16.335, 95% CI = 1.484-179.799, p = 0.024), patients with high FOXP3 still had worse RRFS (HR = 7.487, 95% CI = 1.786-31.395, p = 0.006).	('FOXP3', 'Gene', (230, 235))	('high', 'Var', (225, 229))	('ECE', 'Chemical', '-', (92, 95))	('patients', 'Species', '9606', (211, 219))	('RRFS', 'CPA', (252, 256))	('FOXP3', 'Gene', '50943', (230, 235))	('ECE', 'Disease', (92, 95))
539143	30153850	The other key findings of this study are that patients with a low CD8/FOXP3 ratio, high FOXP3 expression, and a low CD4/FOXP3 ratio had significantly less favorable OS, RRFS, and DMFS, respectively.	('patients', 'Species', '9606', (46, 54))	('CD8', 'Gene', (66, 69))	('FOXP3', 'Gene', '50943', (70, 75))	('CD4', 'Gene', '920', (116, 119))	('low', 'NegReg', (62, 65))	('FOXP3', 'Gene', (88, 93))	('CD4', 'Gene', (116, 119))	('FOXP3', 'Gene', (120, 125))	('CD8', 'Gene', '925', (66, 69))	('less', 'NegReg', (150, 154))	('DMFS', 'CPA', (179, 183))	('expression', 'MPA', (94, 104))	('high', 'Var', (83, 87))	('FOXP3', 'Gene', '50943', (88, 93))	('RRFS', 'CPA', (169, 173))	('OS', 'Chemical', '-', (165, 167))	('DMFS', 'Chemical', '-', (179, 183))	('FOXP3', 'Gene', (70, 75))	('FOXP3', 'Gene', '50943', (120, 125))
539146	30153850	By contrast, a high density of FOXP3 was associated with improved survival in tumors related to the lymphoid system, such as follicular lymphoma and classical Hodgkin lymphoma, or tumors exposed to a bacterial inflammatory environment, such as colorectal cancer.	('colorectal cancer', 'Phenotype', 'HP:0003003', (244, 261))	('follicular lymphoma', 'Disease', 'MESH:D008224', (125, 144))	('tumors', 'Phenotype', 'HP:0002664', (180, 186))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('improved', 'PosReg', (57, 65))	('FOXP3', 'Gene', '50943', (31, 36))	('Hodgkin lymphoma', 'Disease', 'MESH:D006689', (159, 175))	('Hodgkin lymphoma', 'Phenotype', 'HP:0012189', (159, 175))	('tumors', 'Phenotype', 'HP:0002664', (78, 84))	('cancer', 'Phenotype', 'HP:0002664', (255, 261))	('survival', 'MPA', (66, 74))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('lymphoma', 'Phenotype', 'HP:0002665', (167, 175))	('follicular lymphoma', 'Disease', (125, 144))	('lymphoma', 'Phenotype', 'HP:0002665', (136, 144))	('tumors', 'Disease', (180, 186))	('colorectal cancer', 'Disease', 'MESH:D015179', (244, 261))	('tumors', 'Disease', (78, 84))	('men', 'Species', '9606', (230, 233))	('high density', 'Var', (15, 27))	('colorectal cancer', 'Disease', (244, 261))	('tumors', 'Disease', 'MESH:D009369', (180, 186))	('tumors', 'Disease', 'MESH:D009369', (78, 84))	('FOXP3', 'Gene', (31, 36))	('Hodgkin lymphoma', 'Disease', (159, 175))
539151	30153850	This finding is in accordance with that of Weed et al., who demonstrated that nuclear FOXP3 TIL was associated with tumor recurrence within 3 years in a small cohort of patients with T1/T2 tongue SCC.	('SCC', 'Gene', (196, 199))	('patients', 'Species', '9606', (169, 177))	('FOXP3', 'Gene', (86, 91))	('nuclear', 'Var', (78, 85))	('SCC', 'Gene', '6317', (196, 199))	('associated with', 'Reg', (100, 115))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('FOXP3', 'Gene', '50943', (86, 91))	('tumor', 'Disease', (116, 121))
539156	30153850	High CD8 T-cell infiltration has been demonstrated to be associated with higher survival and locoregional control.	('CD8', 'Gene', (5, 8))	('CD8', 'Gene', '925', (5, 8))	('High', 'Var', (0, 4))	('locoregional control', 'CPA', (93, 113))	('survival', 'CPA', (80, 88))	('higher', 'PosReg', (73, 79))
539162	30153850	reported that patients with high immunohistochemical CD3 expression had significantly increased OS, progress-free survival (PFS), and DMFS compared with those without.	('increased', 'PosReg', (86, 95))	('DMFS', 'Chemical', '-', (134, 138))	('high', 'Var', (28, 32))	('progress-free survival', 'CPA', (100, 122))	('DMFS', 'CPA', (134, 138))	('patients', 'Species', '9606', (14, 22))	('CD3', 'Gene', (53, 56))	('OS', 'Chemical', '-', (96, 98))
539164	30153850	A study with a small cohort of patients with oral cavity squamous cell carcinoma showed that patients with high CD4 counts had decreased survival.	('decreased', 'NegReg', (127, 136))	('CD4', 'Gene', '920', (112, 115))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (57, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (57, 80))	('patients', 'Species', '9606', (31, 39))	('squamous cell carcinoma', 'Disease', (57, 80))	('survival', 'MPA', (137, 145))	('high', 'Var', (107, 111))	('patients', 'Species', '9606', (93, 101))	('CD4', 'Gene', (112, 115))
539171	28878238	APOBEC3A is an oral cancer prognostic biomarker in Taiwanese carriers of an APOBEC deletion polymorphism Oral squamous cell carcinoma is a prominent cancer worldwide, particularly in Taiwan.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('Oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (105, 133))	('cancer', 'Disease', (149, 155))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (110, 133))	('Oral squamous cell carcinoma', 'Disease', (105, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('APOBEC3A', 'Gene', '200315', (0, 8))	('cancer', 'Disease', 'MESH:D009369', (20, 26))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('APOBEC', 'Gene', (76, 82))	('cancer', 'Disease', (20, 26))	('deletion polymorphism', 'Var', (83, 104))	('APOBEC3A', 'Gene', (0, 8))	('cancer', 'Disease', 'MESH:D009369', (149, 155))
539172	28878238	By integrating omics analyses in 50 matched samples, we uncover in Taiwanese patients a predominant mutation signature associated with cytidine deaminase APOBEC, which correlates with the upregulation of APOBEC3A expression in the APOBEC3 gene cluster at 22q13.	('expression', 'Species', '29278', (213, 223))	('APOBEC', 'Gene', (154, 160))	('expression', 'MPA', (213, 223))	('cytidine deaminase', 'Gene', '978', (135, 153))	('APOBEC3A', 'Gene', (204, 212))	('APOBEC3', 'Gene', (231, 238))	('mutation', 'Var', (100, 108))	('patients', 'Species', '9606', (77, 85))	('upregulation', 'PosReg', (188, 200))	('cytidine deaminase', 'Gene', (135, 153))	('APOBEC3A', 'Gene', '200315', (204, 212))
539176	28878238	We thus report a frequent APOBEC mutational profile, which relates to a APOBEC3B-deletion germline polymorphism in Taiwanese oral squamous cell carcinoma that impacts expression of APOBEC3A, and is shown to be of clinical prognostic relevance.	('APOBEC', 'Gene', (26, 32))	('APOBEC3B', 'Gene', '9582', (72, 80))	('clinical', 'Species', '191496', (213, 221))	('APOBEC3A', 'Gene', '200315', (181, 189))	('mutational', 'Var', (33, 43))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (125, 153))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (130, 153))	('oral squamous cell carcinoma', 'Disease', (125, 153))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('expression', 'Species', '29278', (167, 177))	('APOBEC3B', 'Gene', (72, 80))	('expression', 'MPA', (167, 177))	('APOBEC3A', 'Gene', (181, 189))	('impacts', 'Reg', (159, 166))
539179	28878238	Here, the authors show that OSCC in Taiwanese show a frequent deletion polymorphism in the cytidine deaminases gene cluster APOBEC3 resulting in increased expression of A3A, which is shown to be of clinical prognostic relevance.	('APOBEC3', 'Gene', (124, 131))	('OS', 'Chemical', '-', (28, 30))	('cytidine deaminase', 'Gene', (91, 109))	('expression', 'Species', '29278', (155, 165))	('increased', 'PosReg', (145, 154))	('expression', 'MPA', (155, 165))	('A3A', 'Gene', '200315', (169, 172))	('clinical', 'Species', '191496', (198, 206))	('cytidine deaminase', 'Gene', '978', (91, 109))	('A3A', 'Gene', (169, 172))	('deletion polymorphism', 'Var', (62, 83))	('increased expression of A3A', 'Phenotype', 'HP:0032428', (145, 172))
539186	28878238	Genome-wide analyses of the head and neck cancer data reported by The Cancer Genome Atlas (TCGA) and an India-based research group revealed shared mutation spectrums, particularly in genes associated with cancer development (e.g., TP53, NOTCH1, FAT1, CASP8, and PIK3CA) and copy number variations (e.g., deletion of CDKN2A and amplification of FADD).	('CDKN2A', 'Gene', '1029', (316, 322))	('men', 'Species', '9606', (219, 222))	('cancer', 'Disease', 'MESH:D009369', (205, 211))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('TP53', 'Gene', '7157', (231, 235))	('NOTCH1', 'Gene', (237, 243))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (70, 89))	('FAT1', 'Gene', '2195', (245, 249))	('head and neck cancer', 'Phenotype', 'HP:0012288', (28, 48))	('neck cancer', 'Disease', 'MESH:D006258', (37, 48))	('NOTCH1', 'Gene', '4851', (237, 243))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('Cancer Genome Atlas', 'Disease', (70, 89))	('neck cancer', 'Disease', (37, 48))	('PIK3CA', 'Gene', '5290', (262, 268))	('FADD', 'Gene', '8772', (344, 348))	('amplification', 'Var', (327, 340))	('cancer', 'Disease', (205, 211))	('CASP8', 'Gene', '841', (251, 256))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('TP53', 'Gene', (231, 235))	('Cancer', 'Phenotype', 'HP:0002664', (70, 76))	('CDKN2A', 'Gene', (316, 322))	('deletion', 'Var', (304, 312))	('FAT1', 'Gene', (245, 249))	('CASP8', 'Gene', (251, 256))	('cancer', 'Disease', (42, 48))	('PIK3CA', 'Gene', (262, 268))	('FADD', 'Gene', (344, 348))
539190	28878238	A germline APOBEC3B (A3B) deletion polymorphism forms the fusion gene, APOBEC3A_B (A3A_B), which comprises the APOBEC3A (A3A) coding region and the APOBEC3B (A3B) 3'UTR.	('APOBEC3A', 'Gene', (111, 119))	('APOBEC3B', 'Gene', '9582', (148, 156))	('A3A', 'Gene', '200315', (121, 124))	('A3B', 'Gene', (158, 161))	('deletion polymorphism', 'Var', (26, 47))	('A3A', 'Gene', '200315', (83, 86))	('A3A', 'Gene', (83, 86))	('A3B', 'Gene', (21, 24))	('APOBEC3B', 'Gene', (11, 19))	('APOBEC3A', 'Gene', (71, 79))	('A3A', 'Gene', (121, 124))	('APOBEC3A', 'Gene', '200315', (111, 119))	('A3B', 'Gene', '9582', (158, 161))	('A3B', 'Gene', '9582', (21, 24))	('APOBEC3B', 'Gene', '9582', (11, 19))	('APOBEC3B', 'Gene', (148, 156))	('APOBEC3A', 'Gene', '200315', (71, 79))
539193	28878238	Both A3A and A3A_B were found to exhibit stronger cytidine deaminase activity than A3B in an in vitro study, and breast cancer patients harboring A3B deletions were found to have more APOBEC-dependent mutations than patients lacking an A3B deletion.	('breast cancer', 'Disease', 'MESH:D001943', (113, 126))	('breast cancer', 'Disease', (113, 126))	('stronger', 'PosReg', (41, 49))	('cytidine deaminase', 'Gene', '978', (50, 68))	('A3A', 'Gene', '200315', (13, 16))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('A3B', 'Gene', '9582', (236, 239))	('A3B', 'Gene', (83, 86))	('A3A', 'Gene', '200315', (5, 8))	('A3B', 'Gene', (146, 149))	('cytidine deaminase', 'Gene', (50, 68))	('patients', 'Species', '9606', (216, 224))	('A3A', 'Gene', (13, 16))	('deletions', 'Var', (150, 159))	('A3B', 'Gene', '9582', (83, 86))	('breast cancer', 'Phenotype', 'HP:0003002', (113, 126))	('A3B', 'Gene', '9582', (146, 149))	('more', 'PosReg', (179, 183))	('APOBEC-dependent', 'Gene', (184, 200))	('patients', 'Species', '9606', (127, 135))	('A3A', 'Gene', (5, 8))	('A3B', 'Gene', (236, 239))
539194	28878238	In this study, we extend our previous targeted sequencing effort in profiling OSCC mutations to a comprehensive and systems-based interrogation of mutational landscapes and their pathological consequences in Taiwanese OSCC patients (OSCC-Taiwan).	('mutations', 'Var', (83, 92))	('OS', 'Chemical', '-', (233, 235))	('Taiwanese OSCC patients', 'Disease', (208, 231))	('OSCC', 'Gene', (78, 82))	('OS', 'Chemical', '-', (218, 220))	('OS', 'Chemical', '-', (78, 80))	('patients', 'Species', '9606', (223, 231))
539203	28878238	A subset of the identified somatic mutations was validated in 49 tumor tissues using an IonAmpliSeq Comprehensive Cancer Panel (CCP; 409 cancer-related genes).	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('49 tumor', 'Disease', (62, 70))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('49 tumor', 'Disease', 'OMIM:617237', (62, 70))	('cancer', 'Disease', (137, 143))	('Cancer', 'Phenotype', 'HP:0002664', (114, 120))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))	('mutations', 'Var', (35, 44))
539206	28878238	In total, our exome sequencing analyses uncovered 24,051 somatic single-nucleotide variants (SNVs) and InDels (Supplementary Data 3 and Supplementary Fig.	('InDels', 'Var', (103, 109))	('men', 'Species', '9606', (117, 120))	('men', 'Species', '9606', (142, 145))	('single-nucleotide variants', 'Var', (65, 91))
539210	28878238	Interestingly, however, our analysis also identified somatic mutations in genes that turned out to be unique (CENPV) or locally prevalent (DHRS4, RASA1, and SETD8; mutated in >= 10% of the Taiwanese patients) (Fig.	('RASA1', 'Gene', (146, 151))	('SETD8', 'Gene', '387893', (157, 162))	('CENPV', 'Gene', (110, 115))	('mutations', 'Var', (61, 70))	('SETD8', 'Gene', (157, 162))	('DHRS4', 'Gene', (139, 144))	('CENPV', 'Gene', '201161', (110, 115))	('mutated', 'Var', (164, 171))	('patients', 'Species', '9606', (199, 207))	('DHRS4', 'Gene', '10901', (139, 144))	('RASA1', 'Gene', '5921', (146, 151))
539220	28878238	Previous pan-cancer analyses in 7042 cancers of various types defined distinct mutational signatures as being genetic hallmarks of different cancer types.	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('cancer', 'Disease', (37, 43))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('cancers', 'Phenotype', 'HP:0002664', (37, 44))	('cancers', 'Disease', (37, 44))	('cancer', 'Disease', (13, 19))	('cancer', 'Disease', 'MESH:D009369', (13, 19))	('cancers', 'Disease', 'MESH:D009369', (37, 44))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('mutational', 'Var', (79, 89))	('cancer', 'Disease', (141, 147))
539229	28878238	We further confirmed the significant upregulations of A3A and A3B (p < 0.0001) in a second cohort comprising 188 N/T paired OSCC samples (Supplementary Fig.	('men', 'Species', '9606', (144, 147))	('OS', 'Chemical', '-', (124, 126))	('upregulations', 'PosReg', (37, 50))	('A3B', 'Gene', (62, 65))	('188 N/T', 'Var', (109, 116))	('188 N/T', 'SUBSTITUTION', 'None', (109, 116))	('A3B', 'Gene', '9582', (62, 65))	('A3A', 'Gene', '200315', (54, 57))	('A3A', 'Gene', (54, 57))
539241	28878238	The accumulation of APOBEC-associated mutations requires inactivation of the DNA repair system (i.e., TP53 mutation), as reported in breast cancer.	('TP53', 'Gene', (102, 106))	('breast cancer', 'Disease', (133, 146))	('inactivation', 'NegReg', (57, 69))	('breast cancer', 'Phenotype', 'HP:0003002', (133, 146))	('DNA', 'Enzyme', (77, 80))	('APOBEC-associated', 'Gene', (20, 37))	('TP53', 'Gene', '7157', (102, 106))	('mutations', 'Var', (38, 47))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('breast cancer', 'Disease', 'MESH:D001943', (133, 146))
539242	28878238	Here, we discovered that the amounts of APOBEC-signature mutations were significantly correlated with the transcript abundance of A3A, but not A3B, in 27 OSCC patients with mutation of TP53 (p = 0.038 and 0.239, respectively; Supplementary Fig.	('A3A', 'Gene', '200315', (130, 133))	('TP53', 'Gene', (185, 189))	('transcript abundance', 'MPA', (106, 126))	('APOBEC-signature', 'Gene', (40, 56))	('A3A', 'Gene', (130, 133))	('men', 'Species', '9606', (232, 235))	('A3B', 'Gene', (143, 146))	('OSCC', 'Disease', (154, 158))	('OS', 'Chemical', '-', (154, 156))	('patients', 'Species', '9606', (159, 167))	('A3B', 'Gene', '9582', (143, 146))	('TP53', 'Gene', '7157', (185, 189))	('mutation', 'Var', (173, 181))
539246	28878238	However, three of them carried TP53 mutations and all four were E6 transcript-negative (Supplementary Table 5), suggesting that the mutation signatures were unrelated to HPV infection.	('HPV infection', 'Disease', 'MESH:D030361', (170, 183))	('TP53', 'Gene', '7157', (31, 35))	('men', 'Species', '9606', (94, 97))	('TP53', 'Gene', (31, 35))	('mutations', 'Var', (36, 45))	('carried', 'Reg', (23, 30))	('HPV infection', 'Disease', (170, 183))
539248	28878238	A previous report described a germline deletion polymorphism at the APOBEC3 locus that removes the coding region of A3B, leading to expression of a variant transcript in which the A3A coding sequence is fused to the 3'UTR of A3B  (termed A3A_B) (Fig.	('deletion polymorphism', 'Var', (39, 60))	('A3B', 'Gene', '9582', (116, 119))	('polymorphism', 'Var', (48, 60))	('coding region', 'MPA', (99, 112))	('A3B', 'Gene', (116, 119))	('A3A', 'Gene', '200315', (238, 241))	('A3B', 'Gene', '9582', (225, 228))	('removes', 'NegReg', (87, 94))	('A3A', 'Gene', '200315', (180, 183))	('APOBEC3', 'Gene', (68, 75))	('A3A', 'Gene', (238, 241))	('A3A', 'Gene', (180, 183))	('expression', 'Species', '29278', (132, 142))	('expression', 'MPA', (132, 142))	('leading to', 'Reg', (121, 131))	('A3B', 'Gene', (225, 228))
539251	28878238	Our RNA-Seq data further substantiated the presence of a variant transcript corresponding to this genomic polymorphism (Supplementary Data 8), and RT-PCR analysis with fusion-sensitive primers independently confirmed the expression of the deletion variant in A3B -/- and A3B +/- samples (Supplementary Fig.	('men', 'Species', '9606', (126, 129))	('A3B', 'Gene', (259, 262))	('deletion', 'Var', (239, 247))	('A3B', 'Gene', (271, 274))	('A3B', 'Gene', '9582', (259, 262))	('expression', 'Species', '29278', (221, 231))	('men', 'Species', '9606', (294, 297))	('A3B', 'Gene', '9582', (271, 274))
539282	28878238	Our results indicated that high A3A predicts better OS, DSS, and DFS, whereas A3B expression was not significantly correlated with treatment outcomes in our population.	('expression', 'Species', '29278', (82, 92))	('OS', 'Chemical', '-', (52, 54))	('DFS', 'CPA', (65, 68))	('A3B', 'Gene', (78, 81))	('better', 'PosReg', (45, 51))	('DFS', 'Chemical', 'MESH:C045207', (65, 68))	('high', 'Var', (27, 31))	('A3A', 'Gene', '200315', (32, 35))	('DSS', 'Chemical', '-', (56, 59))	('DSS', 'Disease', (56, 59))	('A3B', 'Gene', '9582', (78, 81))	('A3A', 'Gene', (32, 35))	('men', 'Species', '9606', (136, 139))
539287	28878238	This strategy enabled us to uncover several key novel attributes of OSCC, as follows: (1) This is the first report of APOBEC3B-deletion polymorphisms in a Taiwanese population, comprised mainly of Han-Chinese.	('OS', 'Chemical', '-', (68, 70))	('polymorphisms', 'Var', (136, 149))	('APOBEC3B', 'Gene', '9582', (118, 126))	('APOBEC3B', 'Gene', (118, 126))
539293	28878238	Given that APOBEC-induced mutations are now known to be prevalent in many cancers, it will be worthwhile to test this association in a larger cohort or in other cancer types in the future.	('prevalent', 'Reg', (56, 65))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancers', 'Disease', 'MESH:D009369', (74, 81))	('cancers', 'Phenotype', 'HP:0002664', (74, 81))	('APOBEC-induced', 'Gene', (11, 25))	('cancer', 'Disease', (74, 80))	('mutations', 'Var', (26, 35))	('cancers', 'Disease', (74, 81))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('cancer', 'Disease', (161, 167))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
539307	28878238	Collectively, our observations are consistent with the notion that, among patients carrying the APOBEC3B-deletion polymorphism, the 3'UTR of the variant A3A_B transcript may confer a new layer of regulation in OSCC that depends on both miRNAs and the disease context.	('OS', 'Chemical', '-', (210, 212))	('patients', 'Species', '9606', (74, 82))	('APOBEC3B', 'Gene', (96, 104))	('A3A', 'Gene', '200315', (153, 156))	('OSCC', 'Disease', (210, 214))	('APOBEC3B', 'Gene', '9582', (96, 104))	('variant', 'Var', (145, 152))	('regulation', 'MPA', (196, 206))	('A3A', 'Gene', (153, 156))
539315	28878238	Anti-cancer therapeutics may create an environment of ongoing DNA damage, thereby producing the single-stranded (ss) DNAs that act as substrates for the APOBEC enzymes.	('cancer', 'Disease', 'MESH:D009369', (5, 11))	('cancer', 'Disease', (5, 11))	('men', 'Species', '9606', (46, 49))	('single-stranded', 'Var', (96, 111))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))
539318	28878238	This may imply the impact of genetic variations on Taiwanese OSCC patients in comparison with patients from other regions, which has not been reported before.	('impact', 'Reg', (19, 25))	('genetic variations', 'Var', (29, 47))	('patients', 'Species', '9606', (94, 102))	('OS', 'Chemical', '-', (61, 63))	('Taiwanese OSCC', 'Disease', (51, 65))	('patients', 'Species', '9606', (66, 74))
539360	28878238	In total, 50 sets of tumor and matched normal samples were analyzed; from them, a total of 24,051 somatic mutations and 9883 reported germline single nucleotide variants (previously deposited in dbSNP) were identified.	('tumor', 'Disease', (21, 26))	('mutations', 'Var', (106, 115))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('single nucleotide variants', 'Var', (143, 169))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
539364	28878238	Supplementary Table 2 lists the q-values for the putative driver genes and percentage of patients having mutations in these genes in OSCC-Taiwan, OSCC-TCGA or OSCC-India.	('OS', 'Chemical', '-', (159, 161))	('OS', 'Chemical', '-', (146, 148))	('patients', 'Species', '9606', (89, 97))	('mutations', 'Var', (105, 114))	('OSCC-India', 'Gene', (159, 169))	('OSCC-Taiwan', 'Gene', (133, 144))	('OS', 'Chemical', '-', (133, 135))	('men', 'Species', '9606', (6, 9))
539365	28878238	The Ion Reporter software (variant caller V5.0.3.5; Life Technology) was used to perform variant calling and identify mutations across 49 matched tumor and normal samples.	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('mutations', 'Var', (118, 127))	('tumor', 'Disease', (146, 151))	('variant', 'Var', (89, 96))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
539384	28878238	To compare the mutational signatures across OSCC tumors, we extracted 172 TCGA-HNSC patients whose tumors were of the oral cavity according to an available supporting table, and used their data to generated a data subset consisting of 26,050 somatic SNV mutations (designated OSCC-TCGA).	('OSCC tumors', 'Disease', 'MESH:D009369', (44, 55))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))	('tumors', 'Disease', 'MESH:D009369', (99, 105))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('patients', 'Species', '9606', (84, 92))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('OS', 'Chemical', '-', (276, 278))	('tumors', 'Disease', (49, 55))	('tumors', 'Disease', 'MESH:D009369', (49, 55))	('OSCC tumors', 'Disease', (44, 55))	('OS', 'Chemical', '-', (44, 46))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('SNV', 'Gene', (250, 253))	('mutations', 'Var', (254, 263))	('tumors', 'Disease', (99, 105))
539417	28251187	More recently, high-risk serotypes of human papillomavirus (HPV) have emerged as the proximate cause of head and neck cancers, frequently involving the oropharynx, and altered demographic patterns as well as oncologic outcomes.	('altered', 'Reg', (168, 175))	('head and neck cancer', 'Phenotype', 'HP:0012288', (104, 124))	('cause', 'Reg', (95, 100))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('head and neck cancers', 'Disease', 'MESH:D006258', (104, 125))	('human papillomavirus', 'Species', '10566', (38, 58))	('HPV', 'Species', '10566', (60, 63))	('head and neck cancers', 'Phenotype', 'HP:0012288', (104, 125))	('serotypes', 'Var', (25, 34))	('cancers', 'Phenotype', 'HP:0002664', (118, 125))	('HPV', 'Gene', (60, 63))
539439	28251187	EGFR, CCND1 amplifications), while other findings were novel or unexpected in head and neck cancer (e.g.	('EGFR', 'Gene', (0, 4))	('head and neck cancer', 'Disease', 'MESH:D006258', (78, 98))	('CCND1', 'Gene', (6, 11))	('head and neck cancer', 'Phenotype', 'HP:0012288', (78, 98))	('amplifications', 'Var', (12, 26))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('EGFR', 'Gene', '1956', (0, 4))	('CCND1', 'Gene', '595', (6, 11))
539440	28251187	loss of function mutations in NOTCH1).	('NOTCH1', 'Gene', (30, 36))	('mutations', 'Var', (17, 26))	('loss of function', 'NegReg', (0, 16))	('NOTCH1', 'Gene', '4851', (30, 36))
539441	28251187	Importantly, the overall mutational burden in head and neck cancers is quite high, with an average of over 140 mutations per tumor.	('mutational', 'Var', (25, 35))	('head and neck cancers', 'Phenotype', 'HP:0012288', (46, 67))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('cancers', 'Phenotype', 'HP:0002664', (60, 67))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumor', 'Disease', (125, 130))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('head and neck cancer', 'Phenotype', 'HP:0012288', (46, 66))	('head and neck cancers', 'Disease', 'MESH:D006258', (46, 67))
539442	28251187	As a result, numerous targetable mutations are potentially present in each individual tumor.	('tumor', 'Disease', (86, 91))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('mutations', 'Var', (33, 42))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))
539447	28251187	This provides study subjects access to FDA-approved drugs used in other cancers if the mutational profile matches (e.g.	('mutational', 'Var', (87, 97))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('cancers', 'Phenotype', 'HP:0002664', (72, 79))	('cancers', 'Disease', (72, 79))	('cancers', 'Disease', 'MESH:D009369', (72, 79))
539448	28251187	patients with breast and head and neck cancer carrying the same ERBB2 amplification would both be treated with trastuzumab).	('head and neck cancer', 'Phenotype', 'HP:0012288', (25, 45))	('ERBB2', 'Gene', (64, 69))	('ERBB2', 'Gene', '2064', (64, 69))	('trastuzumab', 'Chemical', 'MESH:D000068878', (111, 122))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('breast and head and neck cancer', 'Disease', 'MESH:D006258', (14, 45))	('patients', 'Species', '9606', (0, 8))	('amplification', 'Var', (70, 83))
539449	28251187	Indeed, we and others have shown that up to 3% of HNSCC patients harbor ERBB2 amplifications suggesting that although rare, these agents may have an important role in personalized medicine trials.	('patients', 'Species', '9606', (56, 64))	('amplifications', 'Var', (78, 92))	('ERBB2', 'Gene', '2064', (72, 77))	('HNSCC', 'Disease', (50, 55))	('ERBB2', 'Gene', (72, 77))
539456	28251187	In addition, a plethora of trials incorporating checkpoint inhibitors into the first line treatment of recurrent/metastatic head and neck cancer (NCT02358031, NCT02658214), combining with anti-CTLA4 agents (NCT02551159) or radiation (NCT02609503, NCT02289209), and addition in the adjuvant setting (NCT02296684, NCT02641093) are ongoing and will be critical in defining their incorporation into current treatment algorithms.	('plethora', 'Phenotype', 'HP:0001050', (15, 23))	('NCT02296684', 'Var', (299, 310))	('NCT02358031', 'Var', (146, 157))	('head and neck cancer', 'Phenotype', 'HP:0012288', (124, 144))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('NCT02551159', 'Var', (207, 218))	('CTLA4', 'Gene', '1493', (193, 198))	('head and neck cancer', 'Disease', 'MESH:D006258', (124, 144))	('CTLA4', 'Gene', (193, 198))
539462	28251187	In contrast to this is the paradigm of ongoing personalized medicine trials (NCI-MATCH, TAPUR), where targeted therapies are proposed to be given only to those patients who carry mutations in the pathway of the potential agent.	('patients', 'Species', '9606', (160, 168))	('pathway', 'Pathway', (196, 203))	('mutations', 'Var', (179, 188))
539467	28251187	Another key consideration in interpreting sequencing results for personalized therapy application is how to stratify and select among the many identified mutations for targeted agents in genetically complex tumors (such as head and neck cancer with over 140 mutations per tumor).	('tumor', 'Phenotype', 'HP:0002664', (272, 277))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('tumor', 'Disease', (272, 277))	('head and neck cancer', 'Phenotype', 'HP:0012288', (223, 243))	('tumor', 'Disease', 'MESH:D009369', (207, 212))	('tumors', 'Phenotype', 'HP:0002664', (207, 213))	('mutations', 'Var', (154, 163))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('tumor', 'Disease', 'MESH:D009369', (272, 277))	('tumors', 'Disease', 'MESH:D009369', (207, 213))	('tumors', 'Disease', (207, 213))	('tumor', 'Disease', (207, 212))	('head and neck cancer', 'Disease', 'MESH:D006258', (223, 243))
539476	28251187	Do we sequence a T1N0 oral tongue cancer that is highly curable with surgery alone)?	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('oral tongue cancer', 'Disease', 'MESH:D014062', (22, 40))	('oral tongue cancer', 'Disease', (22, 40))	('T1N0', 'Var', (17, 21))
539486	28251187	Lung cancers have not shown a survival benefit with adjuvant targeted agents, although phase III studies in EGFR mutated patients are being planned.	('cancers', 'Phenotype', 'HP:0002664', (5, 12))	('EGFR', 'Gene', '1956', (108, 112))	('EGFR', 'Gene', (108, 112))	('Lung cancers', 'Disease', 'MESH:D008175', (0, 12))	('Lung cancers', 'Phenotype', 'HP:0100526', (0, 12))	('mutated', 'Var', (113, 120))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))	('Lung cancers', 'Disease', (0, 12))	('patients', 'Species', '9606', (121, 129))
539488	28251187	As recurrent and metastatic tumors proliferate, inherent genetic instability causes increased mutagenesis with the generation of potentially treatment-resistant subclones.	('tumors', 'Disease', 'MESH:D009369', (28, 34))	('tumors', 'Disease', (28, 34))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('mutagenesis', 'MPA', (94, 105))	('increased', 'PosReg', (84, 93))	('inherent genetic instability', 'Var', (48, 76))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
539489	28251187	Additionally, tumor subpopulations that survive initial chemotherapy and radiation may be selected for mutations that drive resistance to treatment.	('mutations', 'Var', (103, 112))	('tumor', 'Disease', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('tumor', 'Disease', 'MESH:D009369', (14, 19))
539509	28251187	For example, perhaps trastuzumab will work well for head and neck cancer patients with ERBB2 amplifications, but bevacizumab may not be effective for patients with VEGF aberrations.	('VEGF', 'Gene', (164, 168))	('VEGF', 'Gene', '7422', (164, 168))	('trastuzumab', 'Chemical', 'MESH:D000068878', (21, 32))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('patients', 'Species', '9606', (73, 81))	('bevacizumab', 'Chemical', 'MESH:D000068258', (113, 124))	('head and neck cancer', 'Phenotype', 'HP:0012288', (52, 72))	('amplifications', 'Var', (93, 107))	('patients', 'Species', '9606', (150, 158))	('ERBB2', 'Gene', (87, 92))	('ERBB2', 'Gene', '2064', (87, 92))	('head and neck cancer', 'Disease', 'MESH:D006258', (52, 72))
539522	26831400	Silencing IL-1beta with lentivirus-delivered shRNA significantly inhibited oral squamous cell carcinoma cell growth both in vivo and in vitro.	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('oral squamous cell carcinoma', 'Disease', (75, 103))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (80, 103))	('shRNA', 'Gene', (45, 50))	('IL-1beta', 'Gene', (10, 18))	('inhibited', 'NegReg', (65, 74))	('Silencing', 'Var', (0, 9))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (75, 103))
539541	26831400	To explore key node genes in the TME during oral carcinogenesis, epithelia and fibroblasts from the sequential stages of neoplasia, namely the normal, dysplasia and SCC stages (three rat epithelia/fibroblasts per sample, three samples per group), were collected for microarray analysis (GSE42780,GSE42780).	('rat', 'Species', '10116', (183, 186))	('epithelia', 'Disease', 'None', (187, 196))	('dysplasia', 'Disease', 'MESH:D004476', (151, 160))	('SCC', 'Gene', (165, 168))	('SCC', 'Phenotype', 'HP:0002860', (165, 168))	('GSE42780', 'Var', (296, 304))	('oral carcinogenesis', 'Disease', 'MESH:D063646', (44, 63))	('neoplasia', 'Phenotype', 'HP:0002664', (121, 130))	('epithelia', 'Disease', (187, 196))	('oral carcinogenesis', 'Disease', (44, 63))	('neoplasia', 'Disease', 'MESH:D009369', (121, 130))	('SCC', 'Gene', '6317', (165, 168))	('epithelia', 'Disease', 'None', (65, 74))	('epithelia', 'Disease', (65, 74))	('GSE42780', 'Var', (287, 295))	('neoplasia', 'Disease', (121, 130))	('dysplasia', 'Disease', (151, 160))
539557	26831400	IL-1beta expression in LV-shIL-1beta Cal27 cells was significantly decreased compared with that in control cells with LV-shNC (Fig.	('Cal27', 'CellLine', 'CVCL:1107', (37, 42))	('expression', 'MPA', (9, 19))	('IL-1beta', 'Gene', (0, 8))	('decreased', 'NegReg', (67, 76))	('LV-shIL-1beta', 'Var', (23, 36))
539558	26831400	After LV-shIL-1beta transfection, the growth of Cal27 cells after 48 h was inhibited compared with the growth of cells transfected with LV-shNC (P < 0.05) (Fig.	('LV-shIL-1beta', 'Var', (6, 19))	('transfection', 'Var', (20, 32))	('inhibited', 'NegReg', (75, 84))	('Cal27', 'CellLine', 'CVCL:1107', (48, 53))	('growth', 'CPA', (38, 44))
539562	26831400	Tumors from mice with LV- shIL-1beta were significantly smaller in volume and weight than those in mice with LV-shNC (P < 0.05) (Fig.	('mice', 'Species', '10090', (99, 103))	('volume', 'CPA', (67, 73))	('LV- shIL-1beta', 'Var', (22, 36))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('smaller', 'NegReg', (56, 63))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('mice', 'Species', '10090', (12, 16))
539571	26831400	A histological comparison between the 4NQO and IL-1Ra intervention groups showed that the mean scores of the anterior (2.40 +- 0.63 vs 1.75 +- 0.97) and middle (4.73 +- 2.71 vs 2.86 +- 1.43) thirds of the rat tongue were significantly lower in the IL-1Ra intervention group (P < 0.05) (Fig.	('lower', 'NegReg', (235, 240))	('IL-1Ra', 'Var', (248, 254))	('4NQO', 'Chemical', 'MESH:D015112', (38, 42))	('rat', 'Species', '10116', (205, 208))
539592	26831400	Our results demonstrated that IL-1beta knockdown significantly inhibited OSCC cell growth in vitro and in vivo and activated downstream genes, such as TGFbeta, that were also identified in the 4NQO rat model.	('knockdown', 'Var', (39, 48))	('IL-1beta', 'Gene', (30, 38))	('rat', 'Species', '10116', (19, 22))	('TGFbeta', 'Gene', '59086', (151, 158))	('rat', 'Species', '10116', (198, 201))	('SCC', 'Gene', (74, 77))	('TGFbeta', 'Gene', (151, 158))	('inhibited', 'NegReg', (63, 72))	('4NQO', 'Chemical', 'MESH:D015112', (193, 197))	('activated', 'PosReg', (115, 124))	('SCC', 'Phenotype', 'HP:0002860', (74, 77))	('SCC', 'Gene', '6317', (74, 77))
539642	26831400	For the tumorigenic assay, all 14 mice (7 mice/group) underwent subcutaneous injection of 100 mul (3.5 x 106) of viable cell suspension with LV-shIL-1beta or LV-shNC in the dorsal scapula region.	('mice', 'Species', '10090', (34, 38))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('mice', 'Species', '10090', (42, 46))	('scapula region', 'Phenotype', 'HP:0003691', (180, 194))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('tumor', 'Disease', (8, 13))	('LV-shIL-1beta', 'Var', (141, 154))	('LV-shNC', 'Var', (158, 165))
539656	26831400	Modulation of IL-1beta reprogrammes the tumor microenvironment to interrupt oral carcinogenesis.	('Modulation', 'Var', (0, 10))	('oral carcinogenesis', 'Disease', 'MESH:D063646', (76, 95))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('IL-1beta', 'Gene', (14, 22))	('oral carcinogenesis', 'Disease', (76, 95))
539657	26522444	Long Non Coding RNA MALAT1 Promotes Tumor Growth and Metastasis by inducing Epithelial-Mesenchymal Transition in Oral Squamous Cell Carcinoma The prognosis of advanced oral squamous cell carcinoma (OSCC) patients remains dismal, and a better understanding of the underlying mechanisms is critical for identifying effective targets with therapeutic potential to improve the survival of patients with OSCC.	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (168, 196))	('oral squamous cell carcinoma', 'Disease', (168, 196))	('patients', 'Species', '9606', (204, 212))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (173, 196))	('Metastasis', 'CPA', (53, 63))	('Tumor Growth', 'CPA', (36, 48))	('patients', 'Species', '9606', (385, 393))	('Carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('Epithelial-Mesenchymal Transition', 'CPA', (76, 109))	('MALAT1', 'Gene', (20, 26))	('Promotes', 'PosReg', (27, 35))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (118, 141))	('MALAT1', 'Gene', '378938', (20, 26))	('Long Non Coding', 'Var', (0, 15))	('Tumor', 'Phenotype', 'HP:0002664', (36, 41))	('carcinoma', 'Phenotype', 'HP:0030731', (187, 196))	('Oral Squamous Cell Carcinoma', 'Disease', 'MESH:D002294', (113, 141))	('inducing', 'Reg', (67, 75))	('Oral Squamous Cell Carcinoma', 'Disease', (113, 141))
539661	26522444	When knockdown by small interfering RNA (siRNA) in OSCC cell lines TSCCA and Tca8113, MALAT1 was shown to be required for maintaining epithelial-mesenchymal transition (EMT) mediated cell migration and invasion.	('MALAT1', 'Gene', '378938', (86, 92))	('small', 'Var', (18, 23))	('Tca8113', 'Chemical', '-', (77, 84))	('epithelial-mesenchymal transition', 'CPA', (134, 167))	('MALAT1', 'Gene', (86, 92))	('invasion', 'CPA', (202, 210))
539662	26522444	Western blot and immunofluorescence staining showed that MALAT1 knockdown significantly suppressed N-cadherin and Vimentin expression but induced E-cadherin expression in vitro.	('N-cadherin', 'Gene', (99, 109))	('E-cadherin', 'Gene', (146, 156))	('Vimentin', 'Gene', (114, 122))	('expression', 'MPA', (157, 167))	('E-cadherin', 'Gene', '999', (146, 156))	('N-cadherin', 'Gene', '1000', (99, 109))	('induced', 'PosReg', (138, 145))	('MALAT1', 'Gene', '378938', (57, 63))	('Vimentin', 'Gene', '7431', (114, 122))	('knockdown', 'Var', (64, 73))	('suppressed', 'NegReg', (88, 98))	('MALAT1', 'Gene', (57, 63))
539664	26522444	More importantly, targeting MALAT1 inhibited TSCCA cell-induced xenograft tumor growth in vivo.	('MALAT1', 'Gene', (28, 34))	('xenograft tumor', 'Disease', (64, 79))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('xenograft tumor', 'Disease', 'MESH:D009369', (64, 79))	('targeting', 'Var', (18, 27))	('inhibited', 'NegReg', (35, 44))	('MALAT1', 'Gene', '378938', (28, 34))
539676	26522444	Mechanistic investigations showed that MALAT1 was transcriptionally activated by c-Fos or Sp1 in renal cell carcinoma and lung cancer cells.	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('Sp1', 'Var', (90, 93))	('lung cancer', 'Disease', (122, 133))	('c-Fos', 'Gene', (81, 86))	('lung cancer', 'Phenotype', 'HP:0100526', (122, 133))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (97, 117))	('activated', 'PosReg', (68, 77))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (97, 117))	('MALAT1', 'Gene', '378938', (39, 45))	('transcriptionally', 'MPA', (50, 67))	('c-Fos', 'Gene', '2353', (81, 86))	('lung cancer', 'Disease', 'MESH:D008175', (122, 133))	('MALAT1', 'Gene', (39, 45))	('renal cell carcinoma', 'Disease', (97, 117))
539677	26522444	Another post-transcriptional regulation mechanism of MALAT1 by miR-101 and miR-217 exists in ESCC cells and this post-transcriptional silencing of MALAT1 could significantly suppress the proliferation of ESCC cells through the arrest of G2/M cell cycle.	('ESCC', 'Disease', (204, 208))	('miR', 'Gene', '220972', (75, 78))	('miR', 'Gene', (75, 78))	('MALAT1', 'Gene', (147, 153))	('miR-217', 'Gene', '406999', (75, 82))	('miR-217', 'Gene', (75, 82))	('MALAT1', 'Gene', '378938', (53, 59))	('miR', 'Gene', '220972', (63, 66))	('miR', 'Gene', (63, 66))	('proliferation', 'CPA', (187, 200))	('suppress', 'NegReg', (174, 182))	('G2/M cell cycle', 'CPA', (237, 252))	('post-transcriptional silencing', 'Var', (113, 143))	('MALAT1', 'Gene', (53, 59))	('MALAT1', 'Gene', '378938', (147, 153))
539690	26522444	In order to determine inhibition of MALAT1 might suppress OSCC cell invasion and migration in vitro, we transfected Tca8113 and Tscca OSCC cells with MALAT1 siRNA and a negative control oligonucleotide.	('inhibition', 'Var', (22, 32))	('OSCC cell invasion', 'CPA', (58, 76))	('Tca8113', 'Chemical', '-', (116, 123))	('MALAT1', 'Gene', '378938', (36, 42))	('oligonucleotide', 'Chemical', 'MESH:D009841', (186, 201))	('MALAT1', 'Gene', '378938', (150, 156))	('MALAT1', 'Gene', (36, 42))	('suppress', 'NegReg', (49, 57))	('MALAT1', 'Gene', (150, 156))
539691	26522444	At 24h, 48h and 72h after transfection, there was a significantly decrease of MALAT1 expression in both cell lines (P < 0.05, Fig.	('expression', 'MPA', (85, 95))	('transfection', 'Var', (26, 38))	('MALAT1', 'Gene', '378938', (78, 84))	('decrease', 'NegReg', (66, 74))	('MALAT1', 'Gene', (78, 84))
539692	26522444	As indicated by the wound-healing assay, MALAT1 knockdown inhibited Tca8113 and Tscca cell migration ability compared with negative control or scramble transfected cells (P < 0.05, Fig.	('MALAT1', 'Gene', '378938', (41, 47))	('Tscca cell migration ability', 'CPA', (80, 108))	('Tca8113', 'Chemical', '-', (68, 75))	('MALAT1', 'Gene', (41, 47))	('Tca8113', 'CPA', (68, 75))	('inhibited', 'NegReg', (58, 67))	('knockdown', 'Var', (48, 57))
539693	26522444	2g,h) revealed that in MALAT1 knockdown cells, invaded Tca8113 and Tscca cell numbers decreased significantly.	('invaded Tca8113', 'CPA', (47, 62))	('MALAT1', 'Gene', (23, 29))	('decreased', 'NegReg', (86, 95))	('knockdown', 'Var', (30, 39))	('Tca8113', 'Chemical', '-', (55, 62))	('MALAT1', 'Gene', '378938', (23, 29))	('Tscca cell numbers', 'CPA', (67, 85))
539702	26522444	In Tca8113 and Tscca cells, MALAT1 silencing induced E-cadherin by 2.65-6.65 folds (P < 0.05), and suppressed N-cadherin by 1.79-2.17 folds (P < 0.05) comparing to negative control and scramble cells (Fig.	('silencing', 'Var', (35, 44))	('MALAT1', 'Gene', (28, 34))	('suppressed', 'NegReg', (99, 109))	('E-cadherin', 'Gene', (53, 63))	('induced', 'PosReg', (45, 52))	('E-cadherin', 'Gene', '999', (53, 63))	('Tca8113', 'Chemical', '-', (3, 10))	('N-cadherin', 'Gene', (110, 120))	('N-cadherin', 'Gene', '1000', (110, 120))	('MALAT1', 'Gene', '378938', (28, 34))
539703	26522444	Similarly MALAT1 silencing suppressed Vimentin expression by 0.4-0.53 in both the two cell lines (P < 0.05, Fig.	('MALAT1', 'Gene', '378938', (10, 16))	('Vimentin', 'Gene', (38, 46))	('Vimentin', 'Gene', '7431', (38, 46))	('MALAT1', 'Gene', (10, 16))	('suppressed', 'NegReg', (27, 37))	('silencing', 'Var', (17, 26))
539708	26522444	Taken together, these data indicated that MALAT1 silencing could dramatically affect the EMT and rearrangement of cytoskeletal proteins in OSCC cells in vitro.	('silencing', 'Var', (49, 58))	('rearrangement', 'CPA', (97, 110))	('MALAT1', 'Gene', (42, 48))	('affect', 'Reg', (78, 84))	('MALAT1', 'Gene', '378938', (42, 48))
539710	26522444	We measured whether MALAT1 knockdown could affect beta-catenin transcriptional activity by the TOP flash reporter assay.	('MALAT1', 'Gene', (20, 26))	('knockdown', 'Var', (27, 36))	('affect', 'Reg', (43, 49))	('beta-catenin', 'Gene', (50, 62))	('MALAT1', 'Gene', '378938', (20, 26))	('beta-catenin', 'Gene', '1499', (50, 62))
539720	26522444	The transwell assay with matrigel revealed that in Hep-2 cells after transfection, invaded cell numbers increased significantly(P  < 0.05, Supplementary Figure 1c,d).	('increased', 'PosReg', (104, 113))	('invaded cell numbers', 'CPA', (83, 103))	('transfection', 'Var', (69, 81))	('Hep-2', 'CellLine', 'CVCL:1906', (51, 56))
539727	26522444	Recent integrated genomic analysis indicated that abnormal expression of lncRNAs contributes to human carcinogenesis, metastasis, stem cell differentiation, and resistance to chemotherapy or radiation.	('contributes', 'Reg', (81, 92))	('carcinogenesis', 'Disease', 'MESH:D063646', (102, 116))	('metastasis', 'CPA', (118, 128))	('human', 'Species', '9606', (96, 101))	('stem cell differentiation', 'CPA', (130, 155))	('carcinogenesis', 'Disease', (102, 116))	('expression', 'MPA', (59, 69))	('abnormal', 'Var', (50, 58))	('resistance to chemotherapy or radiation', 'CPA', (161, 200))	('lncRNAs', 'Gene', (73, 80))
539745	26522444	We proved that MALAT1 knockdown Tca8113 and Tscca cells displayed decreased migration and invasion in vitro.	('decreased', 'NegReg', (66, 75))	('knockdown', 'Var', (22, 31))	('MALAT1', 'Gene', '378938', (15, 21))	('Tca8113', 'Chemical', '-', (32, 39))	('MALAT1', 'Gene', (15, 21))
539755	26522444	Further investigation into the molecular mechanism underlying dysregulation of MALAT1 expression in OSCC cells will help to better understand tumor progression of OSCC, identify candidate biomarkers for OSCC prognosis, and guide the development of therapeutic targets for oral cancer.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('MALAT1', 'Gene', '378938', (79, 85))	('tumor', 'Disease', (142, 147))	('cancer', 'Phenotype', 'HP:0002664', (277, 283))	('oral cancer', 'Disease', 'MESH:D009062', (272, 283))	('MALAT1', 'Gene', (79, 85))	('dysregulation', 'Var', (62, 75))	('oral cancer', 'Disease', (272, 283))	('tumor', 'Disease', 'MESH:D009369', (142, 147))
539765	26522444	Double-stranded siRNAs (Sigma-Genosys, USA) were used to knockdown MALAT1 from cells at a final concentration of 20 mumol/L.	('MALAT1', 'Gene', '378938', (67, 73))	('MALAT1', 'Gene', (67, 73))	('knockdown', 'Var', (57, 66))
539786	26270652	High ABCG4 Expression Is Associated with Poor Prognosis in Non-Small-Cell Lung Cancer Patients Treated with Cisplatin-Based Chemotherapy ATP-binding cassette (ABC) transporters are associated with poor response to chemotherapy, and confer a poor prognosis in various malignancies.	('ABC', 'Gene', (159, 162))	('Expression', 'MPA', (11, 21))	('Non-Small-Cell Lung Cancer', 'Disease', 'MESH:D002289', (59, 85))	('ATP-binding cassette', 'Gene', (137, 157))	('Small-Cell Lung Cancer', 'Phenotype', 'HP:0030357', (63, 85))	('High', 'Var', (0, 4))	('Cisplatin', 'Chemical', 'MESH:D002945', (108, 117))	('ABC', 'Gene', '10058', (5, 8))	('ABCG4', 'Gene', (5, 10))	('ABCG4', 'Gene', '64137', (5, 10))	('ABC', 'Gene', (5, 8))	('Cancer', 'Phenotype', 'HP:0002664', (79, 85))	('Patients', 'Species', '9606', (86, 94))	('ATP-binding cassette', 'Gene', '10058', (137, 157))	('malignancies', 'Disease', 'MESH:D009369', (267, 279))	('Non-Small-Cell Lung Cancer', 'Phenotype', 'HP:0030358', (59, 85))	('malignancies', 'Disease', (267, 279))	('ABC', 'Gene', '10058', (159, 162))	('Lung Cancer', 'Phenotype', 'HP:0100526', (74, 85))	('Non-Small-Cell Lung Cancer', 'Disease', (59, 85))
539795	26270652	In conclusion, high ABCG4 expression was associated with a poor prognosis in patients with NSCLC treated with cisplatin-based chemotherapy.	('high', 'Var', (15, 19))	('expression', 'MPA', (26, 36))	('NSCLC', 'Disease', 'MESH:D002289', (91, 96))	('ABCG4', 'Gene', '64137', (20, 25))	('cisplatin', 'Chemical', 'MESH:D002945', (110, 119))	('ABCG4', 'Gene', (20, 25))	('patients', 'Species', '9606', (77, 85))	('NSCLC', 'Disease', (91, 96))
539864	26270652	However, high ABCG4 expression was significantly correlated with lung adenocarcinoma (53.0%) rather than lung squamous cell carcinoma (44.6%) (P<0.001), in poorly (55.2%) rather than well/moderately (42.5%) differentiated NSCLC (P = 0.008), and with increasing tumor node metastasis (TNM) stage II, III and IV (31.0% vs. 53.6% vs. 59.5%, respectively) (P<0.001) (Table 3).	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (110, 133))	('expression', 'MPA', (20, 30))	('ABCG4', 'Gene', '64137', (14, 19))	('tumor node metastasis', 'Disease', 'MESH:D009362', (261, 282))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (65, 84))	('tumor', 'Phenotype', 'HP:0002664', (261, 266))	('high', 'Var', (9, 13))	('lung squamous cell carcinoma', 'Disease', (105, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('NSCLC', 'Disease', (222, 227))	('ABCG4', 'Gene', (14, 19))	('tumor node metastasis', 'Disease', (261, 282))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (65, 84))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (105, 133))	('NSCLC', 'Disease', 'MESH:D002289', (222, 227))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (105, 133))	('lung adenocarcinoma', 'Disease', (65, 84))
539909	26270652	This study strongly suggests that high ABCG4 expression is associated with poor prognosis in patients with NSCLC treated with cisplatin-based chemotherapy, and patients with ABCG4-positive NSCLC may show resistance to cisplatin-based chemotherapy.	('NSCLC', 'Disease', (189, 194))	('patients', 'Species', '9606', (160, 168))	('ABCG4', 'Gene', '64137', (174, 179))	('NSCLC', 'Disease', (107, 112))	('ABCG4', 'Gene', (39, 44))	('NSCLC', 'Disease', 'MESH:D002289', (189, 194))	('NSCLC', 'Disease', 'MESH:D002289', (107, 112))	('ABCG4', 'Gene', (174, 179))	('high', 'Var', (34, 38))	('expression', 'MPA', (45, 55))	('ABCG4', 'Gene', '64137', (39, 44))	('cisplatin', 'Chemical', 'MESH:D002945', (218, 227))	('cisplatin', 'Chemical', 'MESH:D002945', (126, 135))	('patients', 'Species', '9606', (93, 101))
539910	26270652	Moreover, the present study is the first to indicate a potential role for ABCG4 expression as an independent predictive factor of poor prognosis in NSCLC patients treated with cisplatin-based combination chemotherapy.	('ABCG4', 'Gene', (74, 79))	('cisplatin', 'Chemical', 'MESH:D002945', (176, 185))	('NSCLC', 'Disease', (148, 153))	('patients', 'Species', '9606', (154, 162))	('NSCLC', 'Disease', 'MESH:D002289', (148, 153))	('ABCG4', 'Gene', '64137', (74, 79))	('expression', 'Var', (80, 90))
539918	33888994	A ZEB1-AS1 knockdown remarkably suppressed in vitro cancerous, biological processes of OSCC cell lines such as cell proliferation, invasion, migration, and epithelial-mesenchymal transition (EMT).	('cancerous', 'Disease', (52, 61))	('migration', 'CPA', (141, 150))	('invasion', 'CPA', (131, 139))	('ZEB1-AS1', 'Gene', '220930;6935;5729', (2, 10))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('cancerous', 'Disease', 'MESH:D009369', (52, 61))	('cell proliferation', 'CPA', (111, 129))	('epithelial-mesenchymal transition', 'CPA', (156, 189))	('biological processes of', 'CPA', (63, 86))	('ZEB1-AS1', 'Gene', (2, 10))	('knockdown', 'Var', (11, 20))	('suppressed', 'NegReg', (32, 42))
539919	33888994	The tumor growth was also inhibited by silencing ZEB1-AS1 in vivo, and a DLR assay confirmed the association between ZEB1-AS1 and miR-23a.	('tumor', 'Disease', (4, 9))	('inhibited', 'NegReg', (26, 35))	('ZEB1-AS1', 'Gene', (49, 57))	('ZEB1-AS1', 'Gene', (117, 125))	('miR-23a', 'Gene', '407010', (130, 137))	('miR-23a', 'Gene', (130, 137))	('association', 'Interaction', (97, 108))	('ZEB1-AS1', 'Gene', '220930;6935;5729', (49, 57))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('silencing', 'Var', (39, 48))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('ZEB1-AS1', 'Gene', '220930;6935;5729', (117, 125))
539928	33888994	Recently emerging evidence suggests that aberrant lncRNA expression levels occur frequently in human cancers, and these findings indicate that lncRNAs participate in tumor growth, angiogenesis, and metastasis.	('angiogenesis', 'CPA', (180, 192))	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('human', 'Species', '9606', (95, 100))	('cancers', 'Disease', 'MESH:D009369', (101, 108))	('cancers', 'Phenotype', 'HP:0002664', (101, 108))	('aberrant', 'Var', (41, 49))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('cancers', 'Disease', (101, 108))	('metastasis', 'CPA', (198, 208))	('tumor', 'Disease', (166, 171))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('participate', 'Reg', (151, 162))	('lncRNA expression levels', 'MPA', (50, 74))
539930	33888994	Ni et al reported that the progression of hepatocellular carcinoma (HCC) can be inhibited by lncRNA uc.134 by suppressing LATS1 ubiquitination, which is mediated by CUL4A.	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (42, 66))	('CUL4A', 'Gene', '8451', (165, 170))	('hepatocellular carcinoma', 'Disease', (42, 66))	('lncRNA', 'Var', (93, 99))	('LATS1', 'Gene', (122, 127))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (42, 66))	('carcinoma', 'Phenotype', 'HP:0030731', (57, 66))	('suppressing', 'NegReg', (110, 121))	('ubiquitination', 'MPA', (128, 142))	('LATS1', 'Gene', '9113', (122, 127))	('HCC', 'Phenotype', 'HP:0001402', (68, 71))	('CUL4A', 'Gene', (165, 170))
539937	33888994	Accumulating evidences indicate that miRNA-23a may be a critical regulator in carcinogenesis and aberrant miR-23a expression has been detected in many cancers.	('miRNA-23a', 'Gene', '407010', (37, 46))	('carcinogenesis', 'Disease', 'MESH:D063646', (78, 92))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('carcinogenesis', 'Disease', (78, 92))	('miR-23a', 'Gene', '407010', (106, 113))	('aberrant', 'Var', (97, 105))	('miR-23a', 'Gene', (106, 113))	('cancers', 'Disease', 'MESH:D009369', (151, 158))	('expression', 'MPA', (114, 124))	('cancers', 'Phenotype', 'HP:0002664', (151, 158))	('detected', 'Reg', (134, 142))	('miRNA-23a', 'Gene', (37, 46))	('cancers', 'Disease', (151, 158))
539943	33888994	Our results showed that OSCC cell proliferation, invasion, and migration in vitro can be suppressed by ZEB1-AS1 knockdown.	('suppressed', 'NegReg', (89, 99))	('ZEB1-AS1', 'Gene', (103, 111))	('knockdown', 'Var', (112, 121))	('invasion', 'CPA', (49, 57))	('OSCC cell proliferation', 'CPA', (24, 47))	('ZEB1-AS1', 'Gene', '220930;6935;5729', (103, 111))	('migration', 'CPA', (63, 72))
539944	33888994	We also demonstrated that OSCC tumor growth and EMT can be inhibited by silencing ZEB1-AS1 in vivo.	('OSCC tumor', 'Disease', 'MESH:D009369', (26, 36))	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('silencing', 'Var', (72, 81))	('EMT', 'CPA', (48, 51))	('ZEB1-AS1', 'Gene', '220930;6935;5729', (82, 90))	('inhibited', 'NegReg', (59, 68))	('OSCC tumor', 'Disease', (26, 36))	('ZEB1-AS1', 'Gene', (82, 90))
539993	33888994	Furthermore, the OS rates were lower in patients with high ZEB1-AS1 expression compared to those with low expression levels as shown by a Kaplan-Meier analysis (Figure 1I).	('ZEB1-AS1', 'Gene', (59, 67))	('high', 'Var', (54, 58))	('expression', 'MPA', (68, 78))	('patients', 'Species', '9606', (40, 48))	('OS rates', 'MPA', (17, 25))	('lower', 'NegReg', (31, 36))	('ZEB1-AS1', 'Gene', '220930;6935;5729', (59, 67))
540000	33888994	The expression of ZEB1-AS1 decreased in both SCC9 and CAL27 cells after sh-ZEB1-AS1 transfection, which was confirmed by qRT-PCRs (Figure 2B and C).	('sh-ZEB1-AS1', 'Gene', (72, 83))	('ZEB1-AS1', 'Gene', (18, 26))	('decreased', 'NegReg', (27, 36))	('sh-ZEB1-AS1', 'Gene', '220930;5729', (72, 83))	('expression', 'MPA', (4, 14))	('ZEB1-AS1', 'Gene', '220930;6935;5729', (75, 83))	('CAL27', 'CellLine', 'CVCL:1107', (54, 59))	('SCC9', 'CellLine', 'CVCL:1685', (45, 49))	('ZEB1-AS1', 'Gene', '220930;6935;5729', (18, 26))	('ZEB1-AS1', 'Gene', (75, 83))	('transfection', 'Var', (84, 96))
540001	33888994	Next, an EdU cell proliferation assay showed that the proliferative abilities of OSCC cells were suppressed by ZEB1-AS1 knockdowns (Figure 2D-G).	('ZEB1-AS1', 'Gene', (111, 119))	('knockdowns', 'Var', (120, 130))	('EdU', 'Chemical', '-', (9, 12))	('proliferative abilities of OSCC cells', 'CPA', (54, 91))	('ZEB1-AS1', 'Gene', '220930;6935;5729', (111, 119))	('suppressed', 'NegReg', (97, 107))
540002	33888994	We also found a reduced percentage of cells in the S phase and an increased percentage of cells in the G2M phase in SCC9 and CAL27 cells with a ZEB1-AS1 knockdown (Figure 2H-K).	('ZEB1-AS1', 'Gene', (144, 152))	('CAL27', 'CellLine', 'CVCL:1107', (125, 130))	('cells', 'CPA', (38, 43))	('knockdown', 'Var', (153, 162))	('SCC9', 'CellLine', 'CVCL:1685', (116, 120))	('cells', 'CPA', (90, 95))	('reduced', 'NegReg', (16, 23))	('S phase', 'CPA', (51, 58))	('ZEB1-AS1', 'Gene', '220930;6935;5729', (144, 152))
540007	33888994	The invasion ability of SCC9 and CAL27 cells was dramatically suppressed by a ZEB1-AS1 knockdown compared to negative controls (Figure 3I-L).	('ZEB1-AS1', 'Gene', '220930;6935;5729', (78, 86))	('CAL27', 'CellLine', 'CVCL:1107', (33, 38))	('suppressed', 'NegReg', (62, 72))	('SCC9', 'CellLine', 'CVCL:1685', (24, 28))	('ZEB1-AS1', 'Gene', (78, 86))	('knockdown', 'Var', (87, 96))
540009	33888994	There was a marked reduction in the expression levels of vimentin and N-cadherin in addition to upregulated expression of E-cadherin after silencing ZEB1-AS1 (Figure 3M and N).	('reduction', 'NegReg', (19, 28))	('N-cadherin', 'Gene', (70, 80))	('silencing', 'Var', (139, 148))	('E-cadherin', 'Gene', (122, 132))	('ZEB1-AS1', 'Gene', '220930;6935;5729', (149, 157))	('E-cadherin', 'Gene', '999', (122, 132))	('vimentin', 'Gene', '7431', (57, 65))	('upregulated', 'PosReg', (96, 107))	('ZEB1-AS1', 'Gene', (149, 157))	('vimentin', 'Gene', (57, 65))	('expression', 'MPA', (108, 118))	('N-cadherin', 'Gene', '1000', (70, 80))	('expression levels', 'MPA', (36, 53))
540020	33888994	ZEB1-AS1 knockdown significantly reduced the tumor volumes when compared to tumors in the NC groups (Figure 5A and D).	('ZEB1-AS1', 'Gene', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('knockdown', 'Var', (9, 18))	('tumor', 'Disease', (45, 50))	('tumor', 'Disease', (76, 81))	('ZEB1-AS1', 'Gene', '220930;6935;5729', (0, 8))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumors', 'Disease', (76, 82))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('reduced', 'NegReg', (33, 40))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
540024	33888994	Moreover, we confirmed reduced protein levels of N-cadherin and vimentin as well as increased E-cadherin expression in the ZEB1-AS1 knockdown groups (Figure 5H).	('E-cadherin', 'Gene', (94, 104))	('protein levels', 'MPA', (31, 45))	('E-cadherin', 'Gene', '999', (94, 104))	('knockdown', 'Var', (132, 141))	('ZEB1-AS1', 'Gene', '220930;6935;5729', (123, 131))	('vimentin', 'Gene', '7431', (64, 72))	('N-cadherin', 'Gene', (49, 59))	('vimentin', 'Gene', (64, 72))	('increased', 'PosReg', (84, 93))	('N-cadherin', 'Gene', '1000', (49, 59))	('ZEB1-AS1', 'Gene', (123, 131))	('reduced', 'NegReg', (23, 30))
540028	33888994	Moreover, the results of loss-of-function experiments demonstrated that the proliferation and EMT of OSCC cells could be suppressed by a ZEB1-AS1 knockdown in vitro.	('knockdown', 'Var', (146, 155))	('ZEB1-AS1', 'Gene', '220930;6935;5729', (137, 145))	('EMT of OSCC cells', 'CPA', (94, 111))	('proliferation', 'CPA', (76, 89))	('suppressed', 'NegReg', (121, 131))	('ZEB1-AS1', 'Gene', (137, 145))
540029	33888994	We also showed that tumor growth and metastasis can be suppressed by the knockdown of ZEB1-AS1 in vivo.	('ZEB1-AS1', 'Gene', (86, 94))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('suppressed', 'NegReg', (55, 65))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('ZEB1-AS1', 'Gene', '220930;6935;5729', (86, 94))	('tumor', 'Disease', (20, 25))	('knockdown', 'Var', (73, 82))
540037	33888994	Wang et al demonstrated that delivery of lncRNA-H19 increased AMPKalpha expression and subsequently reduced MMP9 activation, which suppressed tumor metastasis in gastric cancer.	('gastric cancer', 'Disease', 'MESH:D013274', (162, 176))	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('lncRNA-H19', 'Var', (41, 51))	('increased', 'PosReg', (52, 61))	('MMP9', 'Gene', (108, 112))	('reduced', 'NegReg', (100, 107))	('MMP9', 'Gene', '4318', (108, 112))	('gastric cancer', 'Phenotype', 'HP:0012126', (162, 176))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('tumor metastasis', 'Disease', 'MESH:D009362', (142, 158))	('tumor metastasis', 'Disease', (142, 158))	('AMPKalpha expression', 'MPA', (62, 82))	('suppressed', 'NegReg', (131, 141))	('gastric cancer', 'Disease', (162, 176))
540045	33888994	Confirm the aberrant ZEB1-AS1 expression in various oral cancer cell lines makes our results more convincing, and our results showed that all oral cancer cell lines used in the current study have a higher ZEB1-AS1 expression when compared with normal oral epithelial cell line HOK.	('ZEB1-AS1', 'Gene', (21, 29))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('cancer', 'Disease', (57, 63))	('ZEB1-AS1', 'Gene', '220930;6935;5729', (205, 213))	('ZEB1-AS1', 'Gene', (205, 213))	('ZEB1-AS1', 'Gene', '220930;6935;5729', (21, 29))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('aberrant', 'Var', (12, 20))	('cancer', 'Disease', (147, 153))	('expression', 'MPA', (214, 224))	('higher', 'PosReg', (198, 204))
540049	33888994	The results showed that considerable N-cadherin, vimentin downregulation as well as E-cadherin overexpression were caused by ZEB1-AS1 knockdowns both in vitro and in vivo.	('ZEB1-AS1', 'Gene', '220930;6935;5729', (125, 133))	('N-cadherin', 'Gene', '1000', (37, 47))	('E-cadherin', 'Gene', (84, 94))	('E-cadherin', 'Gene', '999', (84, 94))	('vimentin', 'Gene', (49, 57))	('knockdowns', 'Var', (134, 144))	('ZEB1-AS1', 'Gene', (125, 133))	('downregulation', 'NegReg', (58, 72))	('overexpression', 'PosReg', (95, 109))	('N-cadherin', 'Gene', (37, 47))	('vimentin', 'Gene', '7431', (49, 57))
540089	31030477	The most common types of HPVs associated with cervical cancer are HPV-16, -18, -33, -45, -31, -58, -52 and -35.	('associated', 'Reg', (30, 40))	('cervical cancer', 'Disease', 'MESH:D002583', (46, 61))	('cervical cancer', 'Disease', (46, 61))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('HPV-16', 'Var', (66, 72))	('HPV-16', 'Species', '333760', (66, 72))
540113	31030477	In research involving prostate cancer patients, those who had ADAM9 expression benefited more from targeted therapy (Josson et al., 2011).	('prostate cancer', 'Disease', (22, 37))	('targeted therapy', 'CPA', (99, 115))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('ADAM9', 'Gene', (62, 67))	('ADAM9', 'Gene', '8754', (62, 67))	('expression', 'Var', (68, 78))	('prostate cancer', 'Disease', 'MESH:D011471', (22, 37))	('benefited', 'PosReg', (79, 88))	('prostate cancer', 'Phenotype', 'HP:0012125', (22, 37))	('patients', 'Species', '9606', (38, 46))
540181	31889956	Genome-wide association studies and sequencing studies have identified many epigenetic alterations associated with the development of lung cancer.	('lung cancer', 'Disease', (134, 145))	('lung cancer', 'Phenotype', 'HP:0100526', (134, 145))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('lung cancer', 'Disease', 'MESH:D008175', (134, 145))	('epigenetic alterations', 'Var', (76, 98))	('associated', 'Reg', (99, 109))
540183	31889956	We summarize the major epigenetic modifications in lung cancer, focusing on DNA methylation and ncRNAs, their roles in tumorigenesis, and their effects on key signaling pathways.	('lung cancer', 'Disease', 'MESH:D008175', (51, 62))	('tumor', 'Disease', (119, 124))	('effects', 'Reg', (144, 151))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('lung cancer', 'Disease', (51, 62))	('lung cancer', 'Phenotype', 'HP:0100526', (51, 62))	('epigenetic', 'Var', (23, 33))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('methylation', 'Var', (80, 91))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))
540184	31889956	In addition, we describe the clinical application of epigenetic biomarkers in the early diagnosis, prognosis prediction, and oncotherapy of lung cancer.	('lung cancer', 'Disease', (140, 151))	('lung cancer', 'Phenotype', 'HP:0100526', (140, 151))	('epigenetic', 'Var', (53, 63))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('lung cancer', 'Disease', 'MESH:D008175', (140, 151))
540185	31889956	Understanding the epigenetic regulation mechanism of lung cancer can provide a new explanation for tumorigenesis and a new target for the precise treatment of lung cancer.	('tumor', 'Disease', (99, 104))	('epigenetic', 'Var', (18, 28))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('lung cancer', 'Disease', 'MESH:D008175', (159, 170))	('lung cancer', 'Disease', 'MESH:D008175', (53, 64))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('lung cancer', 'Disease', (159, 170))	('lung cancer', 'Phenotype', 'HP:0100526', (159, 170))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('lung cancer', 'Disease', (53, 64))	('lung cancer', 'Phenotype', 'HP:0100526', (53, 64))
540197	31889956	Molecular targeted therapy can significantly improve patient progression-free survival compared with standard chemotherapy.	('improve', 'PosReg', (45, 52))	('patient', 'Species', '9606', (53, 60))	('Molecular targeted therapy', 'Var', (0, 26))	('patient progression-free survival', 'CPA', (53, 86))
540203	31889956	The progression of cancer is a result of the accumulation of a combination of permanent genetic alterations, including point mutations, deletions, translocations, and/or amplifications, as well as dynamic epigenetic alterations, which are influenced by environmental factors.	('cancer', 'Disease', 'MESH:D009369', (19, 25))	('point mutations', 'Var', (119, 134))	('deletions', 'Var', (136, 145))	('cancer', 'Disease', (19, 25))	('epigenetic alterations', 'Var', (205, 227))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('amplifications', 'Var', (170, 184))	('translocations', 'Var', (147, 161))
540206	31889956	TP53 mutations are more commonly observed with advancing stage, suggesting a role during tumor progression.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('observed', 'Reg', (33, 41))	('mutations', 'Var', (5, 14))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
540207	31889956	In contrast, the frequency of KRAS mutations in LUAD seems constant across tumor grades, suggesting a role in tumor initiation or early tumorigenesis.	('tumor initiation', 'Disease', 'MESH:D009369', (110, 126))	('tumor', 'Disease', 'MESH:D009369', (110, 115))	('LUAD', 'Phenotype', 'HP:0030078', (48, 52))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('tumor initiation', 'Disease', (110, 126))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('KRAS', 'Gene', (30, 34))	('tumor', 'Disease', (136, 141))	('tumor', 'Disease', (75, 80))	('KRAS', 'Gene', '3845', (30, 34))	('mutations', 'Var', (35, 44))
540208	31889956	Mutations in these genes may affect gene expression, thereby promoting the development of lung cancer.	('lung cancer', 'Disease', 'MESH:D008175', (90, 101))	('gene expression', 'MPA', (36, 51))	('affect', 'Reg', (29, 35))	('lung cancer', 'Disease', (90, 101))	('lung cancer', 'Phenotype', 'HP:0100526', (90, 101))	('Mutations', 'Var', (0, 9))	('promoting', 'PosReg', (61, 70))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))
540209	31889956	In contrast to the somatic mutations found in lung cancer, a large number of genes are silenced or uncontrolled during lung carcinogenesis through epigenetic modifications.	('carcinogenesis', 'Disease', (124, 138))	('silenced', 'NegReg', (87, 95))	('epigenetic modifications', 'Var', (147, 171))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('lung cancer', 'Disease', 'MESH:D008175', (46, 57))	('carcinogenesis', 'Disease', 'MESH:D063646', (124, 138))	('lung cancer', 'Disease', (46, 57))	('lung cancer', 'Phenotype', 'HP:0100526', (46, 57))
540210	31889956	A large number of studies have shown that epigenetics plays an important role in the development of lung cancer.	('lung cancer', 'Phenotype', 'HP:0100526', (100, 111))	('epigenetics', 'Var', (42, 53))	('lung cancer', 'Disease', (100, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('lung cancer', 'Disease', 'MESH:D008175', (100, 111))
540212	31889956	Epigenetic alterations have become one of the cancer hallmarks, replacing the concept of malignant pathologies as solely genetic-based conditions.	('Epigenetic alterations', 'Var', (0, 22))	('cancer hallmarks', 'Disease', 'MESH:D009369', (46, 62))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('cancer hallmarks', 'Disease', (46, 62))
540218	31889956	Changes in these epigenetic factors result in the dysregulation of key oncogenes and tumor suppressor genes.	('tumor', 'Disease', (85, 90))	('dysregulation', 'MPA', (50, 63))	('oncogenes', 'Gene', (71, 80))	('result in', 'Reg', (36, 45))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('Changes', 'Var', (0, 7))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))
540219	31889956	Many of the epigenetic events in lung cancer affect cancer hallmarks, such as proliferation, invasion, metastasis, apoptosis, and cell cycle regulation.	('affect', 'Reg', (45, 51))	('lung cancer', 'Phenotype', 'HP:0100526', (33, 44))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('epigenetic events', 'Var', (12, 29))	('cancer hallmarks', 'Disease', (52, 68))	('cell cycle regulation', 'CPA', (130, 151))	('lung cancer', 'Disease', 'MESH:D008175', (33, 44))	('cancer hallmarks', 'Disease', 'MESH:D009369', (52, 68))	('invasion', 'CPA', (93, 101))	('apoptosis', 'CPA', (115, 124))	('metastasis', 'CPA', (103, 113))	('lung cancer', 'Disease', (33, 44))
540220	31889956	In addition to cancer hallmarks, several important signaling pathways are affected by epigenetic deregulation in lung cancer, such as the ERK family, the NF-kB signaling pathway, and the Hedgehog signaling pathway.	('Hedgehog signaling pathway', 'Pathway', (187, 213))	('affected', 'Reg', (74, 82))	('ERK', 'Gene', (138, 141))	('lung cancer', 'Disease', (113, 124))	('lung cancer', 'Phenotype', 'HP:0100526', (113, 124))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('cancer hallmarks', 'Disease', (15, 31))	('signaling pathways', 'Pathway', (51, 69))	('lung cancer', 'Disease', 'MESH:D008175', (113, 124))	('epigenetic deregulation', 'Var', (86, 109))	('ERK', 'Gene', '5594', (138, 141))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('NF-kB signaling pathway', 'Pathway', (154, 177))	('cancer hallmarks', 'Disease', 'MESH:D009369', (15, 31))
540221	31889956	Simultaneously, epigenetic events provide insight into the discovery of putative cancer biomarkers for early detection, disease monitoring, prognosis, risk assessment, and oncotherapy (Figure 2).	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('epigenetic events', 'Var', (16, 33))	('cancer', 'Disease', (81, 87))	('cancer', 'Disease', 'MESH:D009369', (81, 87))
540222	31889956	DNA methylation is an epigenetic event whose pattern is altered frequently in a wide variety of human cancers, including genome-wide hypomethylation and promoter-specific hypermethylation.	('hypomethylation', 'Var', (133, 148))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('promoter-specific hypermethylation', 'Disease', (153, 187))	('human', 'Species', '9606', (96, 101))	('altered', 'Reg', (56, 63))	('cancers', 'Disease', 'MESH:D009369', (102, 109))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))	('cancers', 'Disease', (102, 109))
540223	31889956	We summarized the genes for aberrant methylation in lung cancer (Table 1).	('lung cancer', 'Disease', 'MESH:D008175', (52, 63))	('lung cancer', 'Disease', (52, 63))	('lung cancer', 'Phenotype', 'HP:0100526', (52, 63))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('aberrant methylation', 'Var', (28, 48))
540226	31889956	Previous studies have shown that RASSF1A hypermethylation has early diagnostic and prognostic value in lung cancer.	('hypermethylation', 'Var', (41, 57))	('RASSF1A', 'Gene', '11186', (33, 40))	('lung cancer', 'Disease', 'MESH:D008175', (103, 114))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('lung cancer', 'Disease', (103, 114))	('lung cancer', 'Phenotype', 'HP:0100526', (103, 114))	('RASSF1A', 'Gene', (33, 40))
540230	31889956	This epigenetic alteration is associated with inferior survival, suggesting that MGMT promoter hypermethylation might be an important biomarker for biologically aggressive diseases in NSCLC.	('aggressive diseases', 'Disease', 'MESH:D001523', (161, 180))	('NSCLC', 'Phenotype', 'HP:0030358', (184, 189))	('aggressive diseases', 'Disease', (161, 180))	('NSCLC', 'Disease', (184, 189))	('epigenetic', 'Var', (5, 15))	('NSCLC', 'Disease', 'MESH:D002289', (184, 189))	('MGMT', 'Gene', '4255', (81, 85))	('MGMT', 'Gene', (81, 85))
540231	31889956	demonstrated that the incidence of MGMT methylation was significantly higher in neversmokers than in smokers and detected a higher frequency of mutations within the KRAS gene in neversmokers than previously reported.	('methylation', 'Var', (40, 51))	('KRAS', 'Gene', '3845', (165, 169))	('MGMT', 'Gene', (35, 39))	('MGMT', 'Gene', '4255', (35, 39))	('mutations', 'Var', (144, 153))	('KRAS', 'Gene', (165, 169))
540235	31889956	CDKN2A is frequently inactivated by homozygous deletion or promoter hypermethylation and rarely by point mutation in primary NSCLC.	('inactivated', 'NegReg', (21, 32))	('NSCLC', 'Disease', (125, 130))	('NSCLC', 'Disease', 'MESH:D002289', (125, 130))	('CDKN2A', 'Gene', (0, 6))	('promoter hypermethylation', 'Var', (59, 84))	('NSCLC', 'Phenotype', 'HP:0030358', (125, 130))	('CDKN2A', 'Gene', '1029', (0, 6))
540236	31889956	Previous studies have shown that the CDKN2A promoter region was methylated in lung cancer at frequencies between 20% and 70%.	('lung cancer', 'Disease', (78, 89))	('lung cancer', 'Phenotype', 'HP:0100526', (78, 89))	('CDKN2A', 'Gene', (37, 43))	('methylated', 'Var', (64, 74))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('CDKN2A', 'Gene', '1029', (37, 43))	('lung cancer', 'Disease', 'MESH:D008175', (78, 89))
540237	31889956	found that the detection of CDKN2A promoter methylation in exhaled breath condensate (EBC) was feasible and would be a useful biomarker for the diagnosis of NSCLC.	('methylation', 'Var', (44, 55))	('EBC', 'Chemical', '-', (86, 89))	('NSCLC', 'Phenotype', 'HP:0030358', (157, 162))	('CDKN2A', 'Gene', (28, 34))	('NSCLC', 'Disease', (157, 162))	('CDKN2A', 'Gene', '1029', (28, 34))	('NSCLC', 'Disease', 'MESH:D002289', (157, 162))
540240	31889956	DAPK promoter hypermethylation is correlated with the risk of NSCLC and is a potential biomarker for the prediction of poor prognosis in patients with NSCLC.	('NSCLC', 'Disease', (62, 67))	('NSCLC', 'Disease', (151, 156))	('DAPK', 'Gene', '1612', (0, 4))	('promoter hypermethylation', 'Var', (5, 30))	('NSCLC', 'Disease', 'MESH:D002289', (62, 67))	('NSCLC', 'Disease', 'MESH:D002289', (151, 156))	('patients', 'Species', '9606', (137, 145))	('DAPK', 'Gene', (0, 4))	('NSCLC', 'Phenotype', 'HP:0030358', (62, 67))	('NSCLC', 'Phenotype', 'HP:0030358', (151, 156))	('correlated', 'Reg', (34, 44))
540248	31889956	Many recent reports have identified aberrant lncRNA expression profiles associated or involved with different human malignant diseases.	('malignant diseases', 'Disease', 'MESH:D009369', (116, 134))	('associated', 'Reg', (72, 82))	('malignant diseases', 'Disease', (116, 134))	('human', 'Species', '9606', (110, 115))	('involved', 'Reg', (86, 94))	('lncRNA expression profiles', 'MPA', (45, 71))	('aberrant', 'Var', (36, 44))
540252	31889956	The high expression of HOTAIR is associated with metastasis and the poor prognosis of lung cancer.	('metastasis', 'CPA', (49, 59))	('lung cancer', 'Phenotype', 'HP:0100526', (86, 97))	('lung cancer', 'Disease', (86, 97))	('HOTAIR', 'Gene', (23, 29))	('high', 'Var', (4, 8))	('associated', 'Reg', (33, 43))	('HOTAIR', 'Gene', '100124700', (23, 29))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('lung cancer', 'Disease', 'MESH:D008175', (86, 97))
540257	31889956	showed that silencing HOTAIR decreased the drug resistance of NSCLC cells to crizotinib through the inhibition of autophagy by suppressing the phosphorylation of ULK1.	('ULK1', 'Gene', (162, 166))	('NSCLC', 'Disease', (62, 67))	('crizotinib', 'Chemical', 'MESH:D000077547', (77, 87))	('ULK1', 'Gene', '8408', (162, 166))	('phosphorylation', 'CPA', (143, 158))	('drug resistance', 'MPA', (43, 58))	('autophagy', 'CPA', (114, 123))	('suppressing', 'NegReg', (127, 138))	('HOTAIR', 'Gene', (22, 28))	('silencing', 'Var', (12, 21))	('NSCLC', 'Disease', 'MESH:D002289', (62, 67))	('HOTAIR', 'Gene', '100124700', (22, 28))	('decreased', 'NegReg', (29, 38))	('NSCLC', 'Phenotype', 'HP:0030358', (62, 67))	('drug resistance', 'Phenotype', 'HP:0020174', (43, 58))	('inhibition', 'NegReg', (100, 110))
540270	31889956	For instance, Hsa_circ_0007385 is significantly highly expressed in NSCLC.	('Hsa_circ_0007385', 'Var', (14, 30))	('NSCLC', 'Disease', 'MESH:D002289', (68, 73))	('NSCLC', 'Phenotype', 'HP:0030358', (68, 73))	('highly', 'PosReg', (48, 54))	('NSCLC', 'Disease', (68, 73))
540271	31889956	In-depth studies have found that hsa_circ_0007385 significantly inhibits proliferation, migration, and invasion of NSCLC cells by adsorbing miR-181 and significantly reduces the growth of gene knockout xenograft tumors.	('growth', 'CPA', (178, 184))	('adsorbing', 'Interaction', (130, 139))	('proliferation', 'CPA', (73, 86))	('tumors', 'Disease', (212, 218))	('tumors', 'Disease', 'MESH:D009369', (212, 218))	('NSCLC', 'Disease', (115, 120))	('tumors', 'Phenotype', 'HP:0002664', (212, 218))	('hsa_circ_0007385', 'Var', (33, 49))	('miR-181', 'Protein', (140, 147))	('migration', 'CPA', (88, 97))	('NSCLC', 'Disease', 'MESH:D002289', (115, 120))	('reduces', 'NegReg', (166, 173))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('inhibits', 'NegReg', (64, 72))	('invasion', 'CPA', (103, 111))	('NSCLC', 'Phenotype', 'HP:0030358', (115, 120))
540278	31889956	developed classifiers including four miRNAs (miR-23b, miR-221, miR-148b, and miR-423-3p) that can be showed as a signature for early detection of lung cancer, yielding a ROC curve area of 0.885.	('miR-221', 'Gene', '407006', (54, 61))	('miR-423-3p', 'Var', (77, 87))	('miR-23b', 'Gene', '407011', (45, 52))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('lung cancer', 'Disease', 'MESH:D008175', (146, 157))	('miR-148b', 'Gene', (63, 71))	('miR-221', 'Gene', (54, 61))	('miR-23b', 'Gene', (45, 52))	('lung cancer', 'Disease', (146, 157))	('lung cancer', 'Phenotype', 'HP:0100526', (146, 157))	('miR-148b', 'Gene', '442892', (63, 71))
540282	31889956	Hypoxic BMSC-derived exosomal miRNAs (miR-193a-3p, miR-210-3p, and miR-5100) promote the metastasis of lung cancer cells through STAT3-induced EMT.	('metastasis of lung cancer', 'Disease', (89, 114))	('EMT', 'Gene', (143, 146))	('promote', 'PosReg', (77, 84))	('EMT', 'Gene', '3702', (143, 146))	('STAT3', 'Gene', '6774', (129, 134))	('STAT3', 'Gene', (129, 134))	('miR-5100', 'Gene', (67, 75))	('miR-193a-3p', 'Var', (38, 49))	('miR-21', 'Gene', (51, 57))	('metastasis of lung cancer', 'Disease', 'MESH:D008175', (89, 114))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('lung cancer', 'Phenotype', 'HP:0100526', (103, 114))	('miR-5100', 'Gene', '100847014', (67, 75))	('miR-21', 'Gene', '406991', (51, 57))
540288	31889956	identified lncRNA-HAGLR as a positive prognostic marker for LUAD patients and found that HAGLR suppressed cell growth through the epigenetic silencing of E2F1.	('epigenetic silencing', 'Var', (130, 150))	('suppressed', 'NegReg', (95, 105))	('HAGLR', 'Gene', '401022', (89, 94))	('HAGLR', 'Gene', '401022', (18, 23))	('E2F1', 'Gene', '1869', (154, 158))	('cell growth', 'CPA', (106, 117))	('patients', 'Species', '9606', (65, 73))	('LUAD', 'Phenotype', 'HP:0030078', (60, 64))	('HAGLR', 'Gene', (89, 94))	('E2F1', 'Gene', (154, 158))	('HAGLR', 'Gene', (18, 23))
540296	31889956	Advances in epigenetics provide new perspectives for the treatment of lung cancer.	('lung cancer', 'Disease', 'MESH:D008175', (70, 81))	('lung cancer', 'Disease', (70, 81))	('lung cancer', 'Phenotype', 'HP:0100526', (70, 81))	('epigenetics', 'Var', (12, 23))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))
540303	31889956	A variety of known HDACi, including trichostatin A, SAHA, depsipeptide, and valproic acid, and some new HDACi, such as KD5170 and R306465, have been tested in lung cancer cell lines and transplantation models.	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('lung cancer', 'Disease', 'MESH:D008175', (159, 170))	('depsipeptide', 'Chemical', 'MESH:D047630', (58, 70))	('trichostatin A', 'Chemical', 'MESH:C012589', (36, 50))	('R306465', 'Var', (130, 137))	('lung cancer', 'Disease', (159, 170))	('lung cancer', 'Phenotype', 'HP:0100526', (159, 170))	('valproic acid', 'Chemical', 'MESH:D014635', (76, 89))	('KD5170', 'Var', (119, 125))	('tested', 'Reg', (149, 155))
540308	31889956	Epigenetic therapies (DNMTi, HDACi, and RNA-based therapeutics) may yield great opportunities in the treatment of NSCLC.	('Epigenetic', 'Var', (0, 10))	('NSCLC', 'Phenotype', 'HP:0030358', (114, 119))	('NSCLC', 'Disease', 'MESH:D002289', (114, 119))	('NSCLC', 'Disease', (114, 119))
540310	31889956	In addition, we described the clinical application of epigenetic biomarkers in the early diagnosis, prognosis prediction, and oncotherapy of lung cancer.	('epigenetic', 'Var', (54, 64))	('lung cancer', 'Disease', (141, 152))	('lung cancer', 'Phenotype', 'HP:0100526', (141, 152))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('lung cancer', 'Disease', 'MESH:D008175', (141, 152))
540317	31337951	Furthermore, LAMTOR5 expression was significantly correlated with the expression of p-AktSer473, p-S6Ser235/236, immune checkpoints (PD-L1, Galectin 9, VISTA and B7-H4) and macrophage markers (CD68 and CD163).	('Akt', 'Gene', (86, 89))	('p-S6Ser235/236', 'Var', (97, 111))	('correlated', 'Reg', (50, 60))	('Akt', 'Gene', '207', (86, 89))	('LAMTOR5', 'Gene', (13, 20))
540319	31337951	Consequently, we consider that high expression of LAMTOR5 might be a poor prognostic indicator and correlated with the immunosuppression of tumor microenvironment.	('LAMTOR5', 'Gene', (50, 57))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('correlated', 'Reg', (99, 109))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('high', 'Var', (31, 35))	('tumor', 'Disease', (140, 145))
540324	31337951	Abnormal expression of LAMTOR5 causes excessive centrosome production and multipolar mitotic spindles, resulting in chromosome segregation defects and genetic instability, which is actually indicative of emerging malignancy.	('genetic instability', 'Disease', 'MESH:D030342', (151, 170))	('resulting', 'Reg', (103, 112))	('Abnormal expression', 'Var', (0, 19))	('emerging malignancy', 'Disease', 'MESH:D009369', (204, 223))	('LAMTOR5', 'Gene', (23, 30))	('multipolar mitotic spindles', 'CPA', (74, 101))	('genetic instability', 'Disease', (151, 170))	('causes', 'Reg', (31, 37))	('chromosome segregation defects', 'CPA', (116, 146))	('centrosome', 'CPA', (48, 58))	('emerging malignancy', 'Disease', (204, 223))	('excessive', 'PosReg', (38, 47))
540338	31337951	Validate cohort using custom made human HNSCC tissue microarrays T12-412 TMA2, T15-411 and T17-790.	('human', 'Species', '9606', (34, 39))	('T12-412', 'Var', (65, 72))	('T17-790', 'Var', (91, 98))	('HNSCC', 'Phenotype', 'HP:0012288', (40, 45))	('T15-411', 'Var', (79, 86))
540344	31337951	The sections were incubated with monoclonal anti-human LAMTOR5 (1:800, Cell Signaling Technology), p-AktSer473 (1:50, Cell Signaling Technology), p-S6Ser235/236 (1:400, Cell Signaling Technology), programmed death ligand 1 (PD-L1) (1:100, Cell Signaling Technology), Galectin 9 (1:1000, Cell Signaling Technology), V-domain suppressor of T cell activation (VISTA) (1:400, Cell Signaling Technology), B7-homolog 4 (B7-H4) (1:800, Cell Signaling Technology), CD68 (1:50, Zymed) and CD163 (1:50, CWBiotech) or isotype-matched IgG controls at 4  C overnight.	('Akt', 'Gene', '207', (101, 104))	('programmed death ligand 1', 'Gene', '60533', (197, 222))	('B7-homolog 4', 'Gene', (400, 412))	('Akt', 'Gene', (101, 104))	('programmed death ligand 1', 'Gene', (197, 222))	('human', 'Species', '9606', (49, 54))	('B7-homolog 4', 'Gene', '242122', (400, 412))	('p-S6Ser235/236', 'Var', (146, 160))
540351	31337951	After confirming a Gaussian distribution of the sample, we used the two-tailed Pearson's statistics to analyze the correlation between expression of LAMTOR5 and p-AktSer473, p-S6Ser235/236, PD-L1, Galectin 9, VISTA, B7-H4, CD68 and CD163.	('Akt', 'Gene', '207', (163, 166))	('LAMTOR5', 'Gene', (149, 156))	('p-S6Ser235/236', 'Var', (174, 188))	('Akt', 'Gene', (163, 166))
540357	31337951	The results showed that high LAMTOR5 expression, together with pathological grade and tumor size, was significantly associated with poor survival of HNSCC patients (Table 1).	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Disease', (86, 91))	('HNSCC', 'Phenotype', 'HP:0012288', (149, 154))	('LAMTOR5', 'Gene', (29, 36))	('HNSCC', 'Disease', (149, 154))	('high', 'Var', (24, 28))	('patients', 'Species', '9606', (155, 163))	('expression', 'MPA', (37, 47))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('poor', 'NegReg', (132, 136))	('associated', 'Reg', (116, 126))
540363	31337951	We applied immunohistochemistry on human primary HNSCC tissue microarrays and found increased protein level of LAMTOR5, p-AktSer473, p-S6Ser235/236, PD-L1, Galectin 9, VISTA, B7-H4, CD68 and CD163 (Fig.	('PD-L1', 'Var', (149, 154))	('B7-H4', 'Var', (175, 180))	('HNSCC', 'Phenotype', 'HP:0012288', (49, 54))	('human', 'Species', '9606', (35, 40))	('p-S6Ser235/236', 'Var', (133, 147))	('protein level', 'MPA', (94, 107))	('Akt', 'Gene', '207', (122, 125))	('increased', 'PosReg', (84, 93))	('CD163', 'Var', (191, 196))	('Akt', 'Gene', (122, 125))
540364	31337951	Additionally, hierarchical clustering analysis also indicated that the expression levels of p-AktSer473, p-S6Ser235/236, PD-L1, LAMTOR5, B7-H4, VISTA, Galectin 9, CD68 and CD163 were closely related to each other (Fig.	('PD-L1', 'Gene', (121, 126))	('expression', 'MPA', (71, 81))	('p-S6Ser235/236', 'Var', (105, 119))	('Akt', 'Gene', (94, 97))	('Akt', 'Gene', '207', (94, 97))
540366	31337951	In addition, our previous work has indicated that mice with tissue-specific deletion of tumor suppressor gene Pten in epithelia would be more likely to develop HNSCC in a mouse model.	('deletion', 'Var', (76, 84))	('epithelia', 'Disease', 'None', (118, 127))	('epithelia', 'Disease', (118, 127))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('develop', 'PosReg', (152, 159))	('HNSCC', 'Disease', (160, 165))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('mice', 'Species', '10090', (50, 54))	('HNSCC', 'Phenotype', 'HP:0012288', (160, 165))	('Pten', 'Gene', (110, 114))	('mouse', 'Species', '10090', (171, 176))	('tumor', 'Disease', (88, 93))
540368	31337951	Indeed, there was an obvious increase of LAMTOR5, as well as F4/80 and VISTA, in the Pten cKO mice HNSCC compared with normal wild-type (WT) mice mucosa (Fig.	('Pten cKO', 'Var', (85, 93))	('HNSCC', 'Phenotype', 'HP:0012288', (99, 104))	('increase', 'PosReg', (29, 37))	('mice', 'Species', '10090', (141, 145))	('mice', 'Species', '10090', (94, 98))	('F4/80', 'Gene', '13733', (61, 66))	('LAMTOR5', 'CPA', (41, 48))	('F4/80', 'Gene', (61, 66))	('VISTA', 'CPA', (71, 76))
540373	31337951	Additionally, LAMTOR5 expression was notably correlated with the expression of p-AktSer473, p-S6Ser235/236, PD-L1, Galectin 9, VISTA, B7-H4, CD68 and CD163 in human primary HNSCC.	('PD-L1', 'Gene', (108, 113))	('Galectin 9', 'Gene', (115, 125))	('p-S6Ser235/236', 'Var', (92, 106))	('Akt', 'Gene', '207', (81, 84))	('CD68', 'Gene', (141, 145))	('B7-H4', 'Gene', (134, 139))	('CD163', 'Gene', (150, 155))	('VISTA', 'Gene', (127, 132))	('Akt', 'Gene', (81, 84))	('human', 'Species', '9606', (159, 164))	('HNSCC', 'Phenotype', 'HP:0012288', (173, 178))	('correlated', 'Reg', (45, 55))	('LAMTOR5', 'Gene', (14, 21))
540379	31337951	Herein we noticed that LAMTOR5 was positively correlated with p-AktSer473 and p-S6Ser235/236.	('p-S6Ser235/236', 'Var', (78, 92))	('Akt', 'Gene', '207', (64, 67))	('correlated', 'Reg', (46, 56))	('LAMTOR5', 'Gene', (23, 30))	('Akt', 'Gene', (64, 67))
540395	31337951	The correlation with p-AktSer473, p-S6Ser235/236, PD-L1, Galectin 9, VISTA, B7-H4, CD68 and CD163 presented us the probable connections between LAMTOR5 and PI3K/AKT/mTOR pathway, immune checkpoints and TAMs, suggesting the underlying mechanism of LAMTOR5 including immunosuppression and pro-angiogenesis.	('Akt', 'Gene', '207', (23, 26))	('p-S6Ser235/236', 'Var', (34, 48))	('Akt', 'Gene', (23, 26))	('AKT', 'Gene', '207', (161, 164))	('connections', 'Reg', (124, 135))	('mTOR', 'Gene', (165, 169))	('mTOR', 'Gene', '2475', (165, 169))	('AKT', 'Gene', (161, 164))
540398	30859062	A 71-year-old woman was diagnosed with squamous cell carcinoma with high programmed death-ligand 1 (PD-L1) expression and cT3N0M1a.	('cT3N0M1a', 'Var', (122, 130))	('PD-L1', 'Gene', '29126', (100, 105))	('programmed death-ligand 1', 'Gene', (73, 98))	('programmed death-ligand 1', 'Gene', '29126', (73, 98))	('expression', 'MPA', (107, 117))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (39, 62))	('woman', 'Species', '9606', (14, 19))	('squamous cell carcinoma', 'Disease', (39, 62))	('carcinoma', 'Phenotype', 'HP:0030731', (53, 62))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (39, 62))	('PD-L1', 'Gene', (100, 105))
540449	30859062	Patients with asthma with high eosinophil counts have a strong predisposition to allergies, low respiratory function, and a high frequency of exacerbation.	('eosinophil counts', 'Var', (31, 48))	('allergies', 'Disease', 'MESH:D004342', (81, 90))	('asthma', 'Disease', 'MESH:D001249', (14, 20))	('low', 'NegReg', (92, 95))	('allergies', 'Phenotype', 'HP:0012393', (81, 90))	('high eosinophil counts', 'Phenotype', 'HP:0001880', (26, 48))	('asthma', 'Disease', (14, 20))	('allergies', 'Disease', (81, 90))	('Patients', 'Species', '9606', (0, 8))	('asthma', 'Phenotype', 'HP:0002099', (14, 20))	('respiratory function', 'MPA', (96, 116))
540452	30859062	Lack of a fucose sugar moiety on the oligosaccharide core enhances the binding affinity of benralizumab to FcgammaRIIIalpha and augments ADCC, inducing apoptosis of target cells.	('inducing', 'PosReg', (143, 151))	('sugar', 'Chemical', 'MESH:D000073893', (17, 22))	('Lack', 'Var', (0, 4))	('FcgammaRIIIalpha', 'Gene', '2214', (107, 123))	('apoptosis', 'CPA', (152, 161))	('oligosaccharide', 'Chemical', 'MESH:D009844', (37, 52))	('binding affinity', 'Interaction', (71, 87))	('augments', 'NegReg', (128, 136))	('FcgammaRIIIalpha', 'Gene', (107, 123))	('benralizumab', 'Chemical', 'MESH:C571386', (91, 103))	('fucose', 'Chemical', 'MESH:D005643', (10, 16))	('ADCC', 'MPA', (137, 141))	('enhances', 'PosReg', (58, 66))
540473	27197191	Cross-cancer genome-wide analysis of lung, ovary, breast, prostate and colorectal cancer reveals novel pleiotropic associations Identifying genetic variants with pleiotropic associations can uncover common pathways influencing multiple cancers.	('colorectal cancer', 'Phenotype', 'HP:0003003', (71, 88))	('colorectal cancer', 'Disease', (71, 88))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('multiple cancers', 'Disease', (227, 243))	('ovary', 'Disease', 'MESH:D010051', (43, 48))	('cancers', 'Phenotype', 'HP:0002664', (236, 243))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('Cross-cancer', 'Disease', 'MESH:C537866', (0, 12))	('Cross-cancer', 'Disease', (0, 12))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('multiple cancers', 'Disease', 'MESH:D009369', (227, 243))	('variants', 'Var', (148, 156))	('colorectal cancer', 'Disease', 'MESH:D015179', (71, 88))	('uncover', 'Reg', (191, 198))	('breast', 'Disease', (50, 56))	('prostate', 'Disease', (58, 66))	('lung', 'Disease', (37, 41))	('ovary', 'Disease', (43, 48))
540476	27197191	We also identified a known breast cancer locus CASP8/ALS2CR12 associated with prostate cancer, a known cancer locus at CDKN2B-AS1 with different variants associated with lung adenocarcinoma and prostate cancer and confirmed the associations of a breast BRCA2 locus with lung and serous ovarian cancer.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('cancer', 'Disease', 'MESH:D009369', (203, 209))	('prostate cancer', 'Disease', 'MESH:D011471', (194, 209))	('cancer', 'Disease', (103, 109))	('prostate cancer', 'Phenotype', 'HP:0012125', (194, 209))	('CASP8', 'Gene', '841', (47, 52))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('BRCA2', 'Gene', (253, 258))	('prostate cancer', 'Disease', (194, 209))	('associated', 'Reg', (62, 72))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('cancer', 'Disease', (294, 300))	('variants', 'Var', (145, 153))	('ALS2CR12', 'Gene', '130540', (53, 61))	('lung and serous ovarian cancer', 'Disease', 'MESH:D010051', (270, 300))	('ALS2CR12', 'Gene', (53, 61))	('cancer', 'Phenotype', 'HP:0002664', (294, 300))	('cancer', 'Disease', (87, 93))	('CASP8', 'Gene', (47, 52))	('lung adenocarcinoma and prostate cancer', 'Disease', 'MESH:D011471', (170, 209))	('carcinoma', 'Phenotype', 'HP:0030731', (180, 189))	('CDKN2B-AS1', 'Gene', '100048912', (119, 129))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cancer', 'Disease', (203, 209))	('BRCA2', 'Gene', '675', (253, 258))	('breast cancer', 'Phenotype', 'HP:0003002', (27, 40))	('CDKN2B-AS1', 'Gene', (119, 129))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('associated', 'Reg', (154, 164))	('prostate cancer', 'Disease', 'MESH:D011471', (78, 93))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (170, 189))	('prostate cancer', 'Phenotype', 'HP:0012125', (78, 93))	('breast cancer', 'Disease', 'MESH:D001943', (27, 40))	('cancer', 'Disease', 'MESH:D009369', (294, 300))	('prostate cancer', 'Disease', (78, 93))	('ovarian cancer', 'Phenotype', 'HP:0100615', (286, 300))	('breast cancer', 'Disease', (27, 40))	('cancer', 'Disease', (34, 40))	('cancer', 'Disease', 'MESH:D009369', (87, 93))
540478	27197191	Genome wide association studies (GWAS) have identified hundreds of genetic variants that are associated with risk of specific cancers.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('cancers', 'Phenotype', 'HP:0002664', (126, 133))	('associated', 'Reg', (93, 103))	('cancers', 'Disease', (126, 133))	('cancers', 'Disease', 'MESH:D009369', (126, 133))	('variants', 'Var', (75, 83))
540480	27197191	One of the first identified pleiotropic loci is at 8q24, where genetic variants are associated with breast, prostate, colorectal and ovarian cancer risk, with some of the variants only associated with one cancer, while others are associated with multiple cancers.	('cancer', 'Disease', 'MESH:D009369', (205, 211))	('cancers', 'Phenotype', 'HP:0002664', (255, 262))	('multiple cancers', 'Disease', 'MESH:D009369', (246, 262))	('cancer', 'Disease', (255, 261))	('cancer', 'Phenotype', 'HP:0002664', (255, 261))	('ovarian cancer', 'Phenotype', 'HP:0100615', (133, 147))	('breast', 'Disease', (100, 106))	('associated', 'Reg', (84, 94))	('prostate', 'Disease', (108, 116))	('cancer', 'Disease', (141, 147))	('multiple cancers', 'Disease', (246, 262))	('cancer', 'Disease', (205, 211))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('cancer', 'Disease', 'MESH:D009369', (255, 261))	('variants', 'Var', (71, 79))	('colorectal and ovarian cancer', 'Disease', 'MESH:D015179', (118, 147))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('variants', 'Var', (171, 179))
540481	27197191	Similarly, genetic variants at the TERT-CLPTM1L region at 5p15.33 are associated with risk of lung, bladder, prostate, and other cancers.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('CLPTM1L', 'Gene', (40, 47))	('prostate', 'Disease', (109, 117))	('cancers', 'Disease', 'MESH:D009369', (129, 136))	('cancers', 'Phenotype', 'HP:0002664', (129, 136))	('lung', 'Disease', (94, 98))	('associated', 'Reg', (70, 80))	('cancers', 'Disease', (129, 136))	('genetic variants', 'Var', (11, 27))	('TERT', 'Gene', (35, 39))	('TERT', 'Gene', '7015', (35, 39))	('bladder', 'Disease', (100, 107))	('CLPTM1L', 'Gene', '81037', (40, 47))
540483	27197191	Furthermore, analyzing genomic data across multiple cancer sites might identify novel susceptibility loci, as variants that do not meet the stringent criteria for GWAS significance for any one cancer site, might show significant associations when multiple cancers are analyzed together.	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('multiple cancers', 'Disease', 'MESH:D009369', (247, 263))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('cancer', 'Phenotype', 'HP:0002664', (256, 262))	('cancer', 'Disease', 'MESH:D009369', (256, 262))	('cancers', 'Phenotype', 'HP:0002664', (256, 263))	('multiple cancer', 'Disease', (43, 58))	('cancer', 'Disease', (193, 199))	('cancer', 'Disease', (256, 262))	('variants', 'Var', (110, 118))	('multiple cancer', 'Disease', 'MESH:D009369', (43, 58))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('cancer', 'Disease', (52, 58))	('multiple cancers', 'Disease', (247, 263))	('multiple cancer', 'Disease', 'MESH:D009369', (247, 262))
540492	27197191	Logistic regression analysis using a log additive model was performed previously to test variant associations with cancer risk for the forty-five studies, providing per-allele odds ratios (ORs) adjusted for age, principal components and gender where applicable.	('cancer', 'Disease', (115, 121))	('cancer', 'Disease', 'MESH:D009369', (115, 121))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('variant', 'Var', (89, 96))
540495	27197191	The method generalizes the standard fixed effect meta-analysis by examining the association between a genetic variant and multiple subsets of cancers, allowing opposing direction of effects and null associations.	('cancers', 'Disease', 'MESH:D009369', (142, 149))	('cancers', 'Disease', (142, 149))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('cancers', 'Phenotype', 'HP:0002664', (142, 149))	('variant', 'Var', (110, 117))
540499	27197191	In order to find robust pleiotropic associations we first identified variants that showed evidence for pleiotropy and then sought to validate the individual variant cancer site associations in replication data sets.	('variants', 'Var', (69, 77))	('cancer', 'Disease', (165, 171))	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))
540500	27197191	We excluded variants where associations were obviously driven by a single cancer site.	('cancer', 'Disease', (74, 80))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('variants', 'Var', (12, 20))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
540501	27197191	We also selected variants associated with at least two cancers (including subtypes) at P < 5 x 10-3.	('cancers', 'Disease', 'MESH:D009369', (55, 62))	('variants', 'Var', (17, 25))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('cancers', 'Phenotype', 'HP:0002664', (55, 62))	('associated', 'Reg', (26, 36))	('cancers', 'Disease', (55, 62))
540502	27197191	Among variants selected, we further prioritized for validation those showing the strongest pleiotropic association in a region (based on subset or standard cross cancer meta-analysis), as well as those representing association peaks in site-specific analyses.	('cross cancer', 'Disease', 'MESH:C537866', (156, 168))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('variants', 'Var', (6, 14))	('cross cancer', 'Disease', (156, 168))
540504	27197191	For cross-ethnicity generalizability, we examined results for the selected variants in different race/ethnicities using data from Japan (lung), Nanjing (lung), Shanghai (breast), MEC, African American Breast Cancer GWAS Consortium (AABC), African Ancestry Prostate Cancer GWAS Consortium (AAPC), and San Francisco (breast for Latinas).	('Prostate Cancer GWAS', 'Disease', (256, 276))	('Breast Cancer GWAS', 'Disease', 'MESH:D001943', (201, 219))	('Breast Cancer GWAS', 'Disease', (201, 219))	('Breast Cancer', 'Phenotype', 'HP:0003002', (201, 214))	('AAPC', 'Disease', 'MESH:D011125', (289, 293))	('MEC', 'Gene', '56477', (179, 182))	('MEC', 'Gene', (179, 182))	('Prostate Cancer GWAS', 'Disease', 'MESH:D011471', (256, 276))	('Cancer', 'Phenotype', 'HP:0002664', (265, 271))	('Cancer', 'Phenotype', 'HP:0002664', (208, 214))	('variants', 'Var', (75, 83))	('Prostate Cancer', 'Phenotype', 'HP:0012125', (256, 271))	('AAPC', 'Disease', (289, 293))
540506	27197191	Enrichment is reflected in a leftward deflection of the Q-Q plot with decreasing P value categories of the conditioning cancer, indicating higher pleiotropy between cancer sites than expected by chance.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('leftward deflection', 'CPA', (29, 48))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('cancer', 'Disease', (165, 171))	('P value categories', 'Var', (81, 99))	('decreasing', 'NegReg', (70, 80))	('cancer', 'Disease', 'MESH:D009369', (165, 171))
540510	27197191	We also obtained TCGA eQTL data for 402 high-grade serous ovarian cases and 145 prostate tumor samples again investigating variants with validated associations and those in high LD (R2 > 0.7) with them.	('prostate tumor', 'Disease', (80, 94))	('prostate tumor', 'Disease', 'MESH:D011471', (80, 94))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('prostate tumor', 'Phenotype', 'HP:0100787', (80, 94))	('variants', 'Var', (123, 131))
540512	27197191	The software evaluates a variant's potential function in splicing regulation, TFBS prediction, miRNA binding site prediction and regulatory potential using in-house algorithms and tools developed elsewhere.	('TFBS', 'Gene', (78, 82))	('miRNA', 'MPA', (95, 100))	('algorithms', 'Disease', 'None', (165, 175))	('regulatory', 'MPA', (129, 139))	('splicing regulation', 'MPA', (57, 76))	('algorithms', 'Disease', (165, 175))	('variant', 'Var', (25, 32))
540513	27197191	After applying quality control filters 9,916,564 variants were analyzed for pleiotropic associations using 61,851 cases and 61,820 controls of European ancestry across five common cancer sites in the GAME-ON Network and GECCO (GAME-ON/GECCO) (Table 1).	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('cancer', 'Disease', (180, 186))	('variants', 'Var', (49, 57))
540515	27197191	One hundred and ninety variants in 33 regions (13 to 22 for each cancer site) were prioritized for follow-up for replication in Caucasian populations (55,789 cases and 330,490 controls) and generalizability (18,152 cancer cases and 21,410 controls) after the initial analysis (see Table 1 and Supplementary Table S1).	('cancer', 'Disease', (215, 221))	('cancer', 'Disease', 'MESH:D009369', (215, 221))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('variants', 'Var', (23, 31))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))
540517	27197191	Variants with replicated pleiotropic associations were not associated with cancer risk in other ethnic populations and therefore these data are not presented.	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('Variants', 'Var', (0, 8))	('cancer', 'Disease', (75, 81))	('cancer', 'Disease', 'MESH:D009369', (75, 81))
540518	27197191	Standard meta-analysis of GAME-ON/GECCO discovery data identified an association between rs1057941 located at 1q22 and overall risk of cancer (P = 1.74 x 10-7, Fig.	('rs1057941', 'Var', (89, 98))	('cancer', 'Disease', (135, 141))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('rs1057941', 'Mutation', 'rs1057941', (89, 98))	('cancer', 'Disease', 'MESH:D009369', (135, 141))
540519	27197191	Overall lung, lung squamous cell carcinoma (lung SqCC) and breast cancer were strongly associated with this variant in GAME-ON/GECCO data (Lung: OR = 1.08, 95% CI 1.05-1.12, P = 9.2 x 10-6; lung SqCC: OR = 1.10, 95% CI 1.04-1.16, P = 0.001; Breast: OR = 1.07, 95% CI 1.04-1.11, P = 6.08 x 10-5).	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (14, 42))	('breast cancer', 'Disease', 'MESH:D001943', (59, 72))	('carcinoma', 'Phenotype', 'HP:0030731', (33, 42))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('breast cancer', 'Disease', (59, 72))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (14, 42))	('associated', 'Reg', (87, 97))	('breast cancer', 'Phenotype', 'HP:0003002', (59, 72))	('lung', 'Disease', (190, 194))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (19, 42))	('lung', 'Disease', (8, 12))	('lung squamous cell carcinoma', 'Disease', (14, 42))	('variant', 'Var', (108, 115))
540522	27197191	The aggressive form of prostate cancer was also selected by ASSET as part of the subset of cancers associated with rs1057941.	('cancers', 'Disease', 'MESH:D009369', (91, 98))	('cancers', 'Phenotype', 'HP:0002664', (91, 98))	('rs1057941', 'Mutation', 'rs1057941', (115, 124))	('cancers', 'Disease', (91, 98))	('prostate cancer', 'Disease', (23, 38))	('rs1057941', 'Var', (115, 124))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('prostate cancer', 'Disease', 'MESH:D011471', (23, 38))	('prostate cancer', 'Phenotype', 'HP:0012125', (23, 38))
540524	27197191	Regional plots constructed from GAME-ON/GECCO results show a distinct peak in P values represented by rs1057941 in a 40kb region of LD at 1q22 that includes KRTCAP2, GBA, MTX1, MUC1, TRIM46, THBS3, ADAM15 and ASH1L for the cross-cancer analysis (Fig.	('rs1057941', 'Var', (102, 111))	('ADAM15', 'Gene', '8751', (198, 204))	('THBS3', 'Gene', (191, 196))	('ADAM15', 'Gene', (198, 204))	('cross-cancer', 'Disease', (223, 235))	('ASH1L', 'Gene', (209, 214))	('MTX1', 'Gene', '4580', (171, 175))	('KRTCAP2', 'Gene', (157, 164))	('GBA', 'Gene', (166, 169))	('TRIM46', 'Gene', (183, 189))	('TRIM46', 'Gene', '80128', (183, 189))	('ASH1L', 'Gene', '55870', (209, 214))	('GBA', 'Gene', '2629', (166, 169))	('THBS3', 'Gene', '7059', (191, 196))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('KRTCAP2', 'Gene', '200185', (157, 164))	('MUC1', 'Gene', (177, 181))	('MTX1', 'Gene', (171, 175))	('cross-cancer', 'Disease', 'MESH:C537866', (223, 235))	('MUC1', 'Gene', '4582', (177, 181))	('rs1057941', 'Mutation', 'rs1057941', (102, 111))
540525	27197191	2A), while for individual sites MUC1 variant rs4072037 was most significant for lung SqCC (P = 3.21 x 10-4) and the TRIM46 variant, rs3814316, for breast cancer (P = 3.06 x 10-6).	('breast cancer', 'Disease', 'MESH:D001943', (147, 160))	('rs3814316', 'Var', (132, 141))	('rs4072037', 'Var', (45, 54))	('rs3814316', 'Mutation', 'rs3814316', (132, 141))	('MUC1', 'Gene', (32, 36))	('rs4072037', 'Mutation', 'rs4072037', (45, 54))	('TRIM46', 'Gene', (116, 122))	('breast cancer', 'Disease', (147, 160))	('MUC1', 'Gene', '4582', (32, 36))	('breast cancer', 'Phenotype', 'HP:0003002', (147, 160))	('TRIM46', 'Gene', '80128', (116, 122))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('lung SqCC', 'Disease', (80, 89))
540526	27197191	These 3 variants are in high to complete LD with each other with pair-wise D' of 0.86 (rs1057941-rs3814316) or 1.00 (rs1057941-rs4072037, and rs3814316-rs4072037).	('rs1057941', 'Mutation', 'rs1057941', (87, 96))	('rs4072037', 'Mutation', 'rs4072037', (127, 136))	('rs1057941', 'Mutation', 'rs1057941', (117, 126))	('rs4072037', 'Mutation', 'rs4072037', (152, 161))	('rs1057941-rs4072037', 'Var', (117, 136))	('rs3814316-rs4072037', 'Var', (142, 161))	('rs1057941-rs3814316', 'Var', (87, 106))	('rs3814316', 'Mutation', 'rs3814316', (97, 106))	('rs3814316', 'Mutation', 'rs3814316', (142, 151))
540527	27197191	eQTL analyses indicated that rs4072037 acted as a normal lung tissue eQTL for two genes in this region, ADAM15 and THBS3, with two studies showing significant associations after adjustment for multiple comparisons and the third showing a nominally significant association consistent in direction with the other two (ADAM15: Laval P = 2.39 x 10-7, University of British Columbia P = 4.09 x 10-5, University of Groningen P = 0.08; THBS3: Laval P = 1.71 x 10-5, University of British Columbia P = 4.15 x 10-6, University of Groningen P = 0.004) (Fig 2B).	('ADAM15', 'Gene', (316, 322))	('THBS3', 'Gene', (115, 120))	('British Columbia P', 'Disease', 'OMIM:176500', (361, 379))	('ADAM15', 'Gene', (104, 110))	('British Columbia P', 'Disease', (473, 491))	('rs4072037', 'Var', (29, 38))	('THBS3', 'Gene', '7059', (429, 434))	('rs4072037', 'Mutation', 'rs4072037', (29, 38))	('British Columbia P', 'Disease', 'OMIM:176500', (473, 491))	('British Columbia P', 'Disease', (361, 379))	('ADAM15', 'Gene', '8751', (104, 110))	('THBS3', 'Gene', (429, 434))	('ADAM15', 'Gene', '8751', (316, 322))	('THBS3', 'Gene', '7059', (115, 120))
540529	27197191	The risk allele for rs4072037, A, was consistently associated with increased ADAM15 gene expression in all three studies.	('rs4072037', 'Var', (20, 29))	('rs4072037', 'Mutation', 'rs4072037', (20, 29))	('expression', 'MPA', (89, 99))	('ADAM15', 'Gene', '8751', (77, 83))	('increased', 'PosReg', (67, 76))	('ADAM15', 'Gene', (77, 83))
540530	27197191	In the UBC discovery set rs4072037 was the strongest eQTL among 33 variants.	('UBC', 'Gene', (7, 10))	('UBC', 'Gene', '7316', (7, 10))	('rs4072037', 'Var', (25, 34))	('rs4072037', 'Mutation', 'rs4072037', (25, 34))
540531	27197191	We identified a pleiotropic association between rs13016963 located in 2q33.1 and prostate (OR = 1.08, 95% CI 1.04-1.13, P = 3.05 x 10-5) and breast cancer (OR = 0.93, 95% CI 0.90-0.96, P = 5.75 x 10-5) (Fig.	('rs13016963', 'Var', (48, 58))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('breast cancer', 'Disease', 'MESH:D001943', (141, 154))	('prostate', 'Disease', (81, 89))	('rs13016963', 'Mutation', 'rs13016963', (48, 58))	('breast cancer', 'Disease', (141, 154))	('breast cancer', 'Phenotype', 'HP:0003002', (141, 154))
540534	27197191	The region was previously identified as harboring variants associated with breast cancer risk and the association found with breast cancer can be explained through LD (R2 = 0.74) with one of these (rs1830298, P value for breast cancer association = 1.02 x 10-7).	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('breast cancer', 'Disease', (75, 88))	('breast cancer', 'Phenotype', 'HP:0003002', (75, 88))	('rs1830298', 'Mutation', 'rs1830298', (198, 207))	('rs1830298', 'Var', (198, 207))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('associated', 'Reg', (59, 69))	('breast cancer', 'Disease', 'MESH:D001943', (125, 138))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('breast cancer', 'Disease', 'MESH:D001943', (221, 234))	('breast cancer', 'Disease', (125, 138))	('breast cancer', 'Disease', (221, 234))	('breast cancer', 'Phenotype', 'HP:0003002', (125, 138))	('breast cancer', 'Phenotype', 'HP:0003002', (221, 234))	('breast cancer', 'Disease', 'MESH:D001943', (75, 88))
540536	27197191	In Figure 3C, we show eQTL analysis results for rs1035142, which was in perfect LD with rs13016963 in the eQTL data set and was associated with BZW1 (P = 0.001, FDR = 0.04).	('BZW1', 'Gene', (144, 148))	('rs1035142', 'Mutation', 'rs1035142', (48, 57))	('rs13016963', 'Mutation', 'rs13016963', (88, 98))	('rs1035142', 'Var', (48, 57))	('associated', 'Reg', (128, 138))	('BZW1', 'Gene', '9689', (144, 148))	('rs13016963', 'Var', (88, 98))
540537	27197191	We do note that there were variants with more significant associations with BZW1 expression that fell outside of the LD range of R2>= 0.70 with rs13016963 (e.g., rs13113, P = 4.9 x 10-6, R2 = 0.62).	('BZW1', 'Gene', '9689', (76, 80))	('rs13113', 'Mutation', 'rs13113', (162, 169))	('associations', 'Interaction', (58, 70))	('rs13113', 'Var', (162, 169))	('rs13016963', 'Var', (144, 154))	('rs13016963', 'Mutation', 'rs13016963', (144, 154))	('BZW1', 'Gene', (76, 80))	('expression', 'MPA', (81, 91))
540541	27197191	In our analysis based on GAME-ON/GECCO discovery data, we observed suggestive evidence of association between the variant rs62560775 at CDKN2B-AS1 and lung adenocarcinoma (OR = 1.19, 95% CI =1.08-1.31, P = 2.77 x 10-4), as well as breast cancer (OR = 1.11, 95% CI 1.05-1.17, P = 5.30 x 10-4).	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (151, 170))	('rs62560775', 'Var', (122, 132))	('CDKN2B-AS1', 'Gene', '100048912', (136, 146))	('association', 'Interaction', (90, 101))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('CDKN2B-AS1', 'Gene', (136, 146))	('rs62560775', 'Mutation', 'rs62560775', (122, 132))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (151, 170))	('carcinoma', 'Phenotype', 'HP:0030731', (161, 170))	('breast cancer', 'Disease', 'MESH:D001943', (231, 244))	('breast cancer', 'Phenotype', 'HP:0003002', (231, 244))	('breast cancer', 'Disease', (231, 244))	('lung adenocarcinoma', 'Disease', (151, 170))
540543	27197191	The association of this variant with lung adenocarcinoma was the most significant in the region (Fig.	('association', 'Interaction', (4, 15))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (37, 56))	('carcinoma', 'Phenotype', 'HP:0030731', (47, 56))	('lung adenocarcinoma', 'Disease', (37, 56))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (37, 56))	('variant', 'Var', (24, 31))
540544	27197191	Another variant in the same region, rs1011970, was shown to be associated with prostate cancer (OR = 1.10, 95% CI = 1.05-1.15, P = 7.3 x 10-5).	('prostate cancer', 'Disease', 'MESH:D011471', (79, 94))	('rs1011970', 'Var', (36, 45))	('associated', 'Reg', (63, 73))	('prostate cancer', 'Phenotype', 'HP:0012125', (79, 94))	('rs1011970', 'Mutation', 'rs1011970', (36, 45))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('prostate cancer', 'Disease', (79, 94))
540545	27197191	This variant was found to be associated with breast cancer in a previous GWAS.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('breast cancer', 'Disease', 'MESH:D001943', (45, 58))	('variant', 'Var', (5, 12))	('breast cancer', 'Disease', (45, 58))	('breast cancer', 'Phenotype', 'HP:0003002', (45, 58))	('associated', 'Reg', (29, 39))
540547	27197191	The regional plots shows that this variant had the second most significant association with prostate cancer in the region.	('prostate cancer', 'Phenotype', 'HP:0012125', (92, 107))	('prostate cancer', 'Disease', (92, 107))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('prostate cancer', 'Disease', 'MESH:D011471', (92, 107))	('variant', 'Var', (35, 42))
540548	27197191	(The peak association for prostate cancer is represented by rs72652411, a variant not associated with any cancer other than prostate (Fig.	('prostate cancer', 'Disease', (26, 41))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('rs72652411', 'Var', (60, 70))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('rs72652411', 'Mutation', 'rs72652411', (60, 70))	('cancer', 'Disease', (106, 112))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('prostate cancer', 'Disease', 'MESH:D011471', (26, 41))	('cancer', 'Disease', (35, 41))	('prostate cancer', 'Phenotype', 'HP:0012125', (26, 41))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
540550	27197191	S3) is potentially functional and genome-wide significant associations between this variant and breast and lung cancer (driven by SqCC) were previously reported, with the latter study using a subset of the lung cancer data use here.	('lung cancer', 'Disease', 'MESH:D008175', (107, 118))	('variant', 'Var', (84, 91))	('lung cancer', 'Disease', (206, 217))	('breast and lung cancer', 'Disease', 'MESH:D001943', (96, 118))	('lung cancer', 'Phenotype', 'HP:0100526', (206, 217))	('lung cancer', 'Disease', (107, 118))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('lung cancer', 'Phenotype', 'HP:0100526', (107, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('lung cancer', 'Disease', 'MESH:D008175', (206, 217))
540551	27197191	More recently, a study focusing specifically on rs11571833 reported an association with serous ovarian cancer using the iCOGS data which formed our replication data set (P = 3 x 10-5).	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('serous ovarian cancer', 'Disease', (88, 109))	('rs11571833', 'Var', (48, 58))	('serous ovarian cancer', 'Disease', 'MESH:D010051', (88, 109))	('rs11571833', 'Mutation', 'rs11571833', (48, 58))	('ovarian cancer', 'Phenotype', 'HP:0100615', (95, 109))
540561	27197191	Further novel results include a locus at CASP8/ALS2CR12, known to be associated with breast cancer and melanoma, that was found to be associated with prostate cancer; while genetic variation at the 9p21.3 region, known to be associated with breast cancer and lung SqCC, appears to be associated with lung adenocarcinoma and prostate cancer.	('CASP8', 'Gene', '841', (41, 46))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (300, 319))	('ALS2CR12', 'Gene', '130540', (47, 55))	('melanoma', 'Phenotype', 'HP:0002861', (103, 111))	('melanoma', 'Disease', (103, 111))	('ALS2CR12', 'Gene', (47, 55))	('associated', 'Reg', (134, 144))	('lung adenocarcinoma and prostate cancer', 'Disease', 'MESH:D011471', (300, 339))	('carcinoma', 'Phenotype', 'HP:0030731', (310, 319))	('breast cancer', 'Phenotype', 'HP:0003002', (85, 98))	('cancer', 'Phenotype', 'HP:0002664', (248, 254))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('CASP8', 'Gene', (41, 46))	('prostate cancer', 'Disease', 'MESH:D011471', (150, 165))	('associated', 'Reg', (284, 294))	('prostate cancer', 'Phenotype', 'HP:0012125', (150, 165))	('cancer', 'Phenotype', 'HP:0002664', (333, 339))	('breast cancer', 'Disease', 'MESH:D001943', (85, 98))	('lung SqCC', 'Disease', (259, 268))	('breast cancer', 'Disease', (85, 98))	('prostate cancer', 'Disease', (150, 165))	('prostate cancer', 'Disease', 'MESH:D011471', (324, 339))	('genetic variation', 'Var', (173, 190))	('breast cancer', 'Phenotype', 'HP:0003002', (241, 254))	('prostate cancer', 'Phenotype', 'HP:0012125', (324, 339))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('prostate cancer', 'Disease', (324, 339))	('melanoma', 'Disease', 'MESH:D008545', (103, 111))	('breast cancer', 'Disease', 'MESH:D001943', (241, 254))	('breast cancer', 'Disease', (241, 254))	('associated', 'Reg', (225, 235))
540563	27197191	The locus at 1q22 represented by rs1057941, rs3814316 and rs4072037 lies in a region of LD that includes KRTCAP2, MTX1, TRIM46, MUC1, GBA, THBS3, ADAM15 and ASH1L.	('THBS3', 'Gene', '7059', (139, 144))	('rs4072037', 'Var', (58, 67))	('TRIM46', 'Gene', (120, 126))	('TRIM46', 'Gene', '80128', (120, 126))	('MTX1', 'Gene', (114, 118))	('KRTCAP2', 'Gene', '200185', (105, 112))	('GBA', 'Gene', (134, 137))	('rs3814316', 'Var', (44, 53))	('MTX1', 'Gene', '4580', (114, 118))	('GBA', 'Gene', '2629', (134, 137))	('rs4072037', 'Mutation', 'rs4072037', (58, 67))	('THBS3', 'Gene', (139, 144))	('ASH1L', 'Gene', (157, 162))	('rs1057941', 'Mutation', 'rs1057941', (33, 42))	('KRTCAP2', 'Gene', (105, 112))	('rs1057941', 'Var', (33, 42))	('MUC1', 'Gene', (128, 132))	('MUC1', 'Gene', '4582', (128, 132))	('ADAM15', 'Gene', '8751', (146, 152))	('ASH1L', 'Gene', '55870', (157, 162))	('ADAM15', 'Gene', (146, 152))	('rs3814316', 'Mutation', 'rs3814316', (44, 53))
540564	27197191	Of these variants, rs4072037 at MUC1 might be functional as it was shown to regulate alternative splicing of the second exon in MUC1 and modifies the gene's transcriptional activity.	('transcriptional activity', 'MPA', (157, 181))	('MUC1', 'Gene', (32, 36))	('MUC1', 'Gene', '4582', (32, 36))	('alternative splicing of the second exon', 'MPA', (85, 124))	('modifies', 'Reg', (137, 145))	('rs4072037', 'Var', (19, 28))	('rs4072037', 'Mutation', 'rs4072037', (19, 28))	('regulate', 'Reg', (76, 84))	('MUC1', 'Gene', (128, 132))	('MUC1', 'Gene', '4582', (128, 132))
540565	27197191	Aberrantly glycosylated MUC1 is overexpressed in most epithelial cancers and is known to have an oncogenic effect.	('epithelial cancers', 'Disease', 'MESH:D000077216', (54, 72))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('epithelial cancers', 'Disease', (54, 72))	('MUC1', 'Gene', (24, 28))	('Aberrantly glycosylated', 'Var', (0, 23))	('MUC1', 'Gene', '4582', (24, 28))	('cancers', 'Phenotype', 'HP:0002664', (65, 72))	('overexpressed', 'PosReg', (32, 45))
540568	27197191	Our lung eQTL investigation found no association with MUC1 expression but the risk allele, A, of rs4072037 was associated with increased expression of two other genes in the region (ADAM15 and THBS3).	('ADAM15', 'Gene', (182, 188))	('rs4072037', 'Var', (97, 106))	('expression', 'MPA', (137, 147))	('THBS3', 'Gene', '7059', (193, 198))	('rs4072037', 'Mutation', 'rs4072037', (97, 106))	('MUC1', 'Gene', (54, 58))	('MUC1', 'Gene', '4582', (54, 58))	('THBS3', 'Gene', (193, 198))	('ADAM15', 'Gene', '8751', (182, 188))	('increased', 'PosReg', (127, 136))
540569	27197191	This result suggests other mechanisms by which this variant could influence cancer risk.	('variant', 'Var', (52, 59))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('influence', 'Reg', (66, 75))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))
540572	27197191	A recent meta-analyses provided support for an association of this variant with gastric cancer in Asian populations, and a recent GWAS in the Icelandic population also suggested an association between this region and gastric cancer in European populations.	('gastric cancer', 'Disease', (80, 94))	('gastric cancer', 'Phenotype', 'HP:0012126', (217, 231))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('gastric cancer', 'Disease', 'MESH:D013274', (80, 94))	('variant', 'Var', (67, 74))	('gastric cancer', 'Phenotype', 'HP:0012126', (80, 94))	('gastric cancer', 'Disease', (217, 231))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('gastric cancer', 'Disease', 'MESH:D013274', (217, 231))	('association', 'Interaction', (47, 58))
540574	27197191	For 2q33.1, we found evidence for a pleiotropic effect for rs13016963 (at ALS2CR12) on breast and prostate cancer.	('prostate cancer', 'Phenotype', 'HP:0012125', (98, 113))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('breast and prostate cancer', 'Disease', 'MESH:D011471', (87, 113))	('ALS2CR12', 'Gene', '130540', (74, 82))	('rs13016963', 'Var', (59, 69))	('rs13016963', 'Mutation', 'rs13016963', (59, 69))	('ALS2CR12', 'Gene', (74, 82))
540575	27197191	This region is known to harbor breast cancer susceptibility loci: rs1045485, encoding the missense alteration D302H in CASP8 (adjacent to ALS2CR12), rs1830298 (mentioned above) at ALS2CR12 and rs1045494 at CASP8.	('breast cancer', 'Phenotype', 'HP:0003002', (31, 44))	('D302H', 'Var', (110, 115))	('rs1045494', 'Mutation', 'rs1045494', (193, 202))	('CASP8', 'Gene', '841', (119, 124))	('ALS2CR12', 'Gene', '130540', (180, 188))	('D302H', 'Mutation', 'rs1045485', (110, 115))	('breast cancer', 'Disease', 'MESH:D001943', (31, 44))	('breast cancer', 'Disease', (31, 44))	('ALS2CR12', 'Gene', (180, 188))	('CASP8', 'Gene', '841', (206, 211))	('rs1045485', 'Var', (66, 75))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('rs1830298', 'Mutation', 'rs1830298', (149, 158))	('ALS2CR12', 'Gene', '130540', (138, 146))	('rs1830298', 'Var', (149, 158))	('CASP8', 'Gene', (119, 124))	('ALS2CR12', 'Gene', (138, 146))	('CASP8', 'Gene', (206, 211))	('rs1045485', 'Mutation', 'rs1045485', (66, 75))	('rs1045494', 'Var', (193, 202))
540576	27197191	Of these three variants, rs1830298 was found to have the most significant association with breast cancer (P = 1.02 x 10-7) in our study, and was associated with prostate cancer risk (P = 5.2 x 10-4); whereas rs1045485 and rs1045494 were not.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('rs1830298', 'Mutation', 'rs1830298', (25, 34))	('breast cancer', 'Disease', (91, 104))	('rs1045494', 'Mutation', 'rs1045494', (222, 231))	('rs1830298', 'Var', (25, 34))	('breast cancer', 'Phenotype', 'HP:0003002', (91, 104))	('breast cancer', 'Disease', 'MESH:D001943', (91, 104))	('prostate cancer', 'Phenotype', 'HP:0012125', (161, 176))	('prostate cancer', 'Disease', 'MESH:D011471', (161, 176))	('associated', 'Reg', (145, 155))	('prostate cancer', 'Disease', (161, 176))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('association', 'Interaction', (74, 85))	('rs1045485', 'Mutation', 'rs1045485', (208, 217))
540577	27197191	For prostate cancer, rs13016963 represented the peak association, although we point out strong LD between rs13016963 and rs1830298 (R2 = 0.74).	('rs1830298', 'Var', (121, 130))	('prostate cancer', 'Disease', 'MESH:D011471', (4, 19))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('rs1830298', 'Mutation', 'rs1830298', (121, 130))	('prostate cancer', 'Phenotype', 'HP:0012125', (4, 19))	('rs13016963', 'Var', (106, 116))	('rs13016963', 'Var', (21, 31))	('rs13016963', 'Mutation', 'rs13016963', (21, 31))	('rs13016963', 'Mutation', 'rs13016963', (106, 116))	('prostate cancer', 'Disease', (4, 19))
540578	27197191	Interestingly, rs13016963 was also found to be associated with risk of melanoma in a previous GWAS in subjects of European descent indicating this variant may be associated with both prostate cancer and melanoma in Caucasian populations.	('rs13016963', 'Mutation', 'rs13016963', (15, 25))	('prostate cancer', 'Disease', (183, 198))	('melanoma', 'Phenotype', 'HP:0002861', (71, 79))	('rs13016963', 'Var', (15, 25))	('associated', 'Reg', (162, 172))	('melanoma', 'Disease', (71, 79))	('prostate cancer', 'Disease', 'MESH:D011471', (183, 198))	('melanoma', 'Disease', 'MESH:D008545', (71, 79))	('prostate cancer', 'Phenotype', 'HP:0012125', (183, 198))	('melanoma', 'Phenotype', 'HP:0002861', (203, 211))	('melanoma', 'Disease', (203, 211))	('associated', 'Reg', (47, 57))	('melanoma', 'Disease', 'MESH:D008545', (203, 211))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))
540580	27197191	Previous research has examined associations between other genetic variants in this region and prostate cancer risk.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('prostate cancer', 'Disease', 'MESH:D011471', (94, 109))	('prostate cancer', 'Phenotype', 'HP:0012125', (94, 109))	('variants', 'Var', (66, 74))	('prostate cancer', 'Disease', (94, 109))
540581	27197191	A possible association between the CASP8 histidine variant D302H and the more aggressive form of prostate cancer in European populations was reported.	('D302H', 'Var', (59, 64))	('prostate cancer', 'Disease', 'MESH:D011471', (97, 112))	('prostate cancer', 'Phenotype', 'HP:0012125', (97, 112))	('CASP8', 'Gene', (35, 40))	('CASP8', 'Gene', '841', (35, 40))	('histidine', 'Chemical', 'MESH:D006639', (41, 50))	('D302H', 'Mutation', 'rs1045485', (59, 64))	('prostate cancer', 'Disease', (97, 112))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
540582	27197191	This variant was however not associated with aggressive prostate cancer (P = 0.11) or overall prostate cancer (P = 0.14) in GAME-ON/GECCO.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('aggressive prostate cancer', 'Disease', 'MESH:D011471', (45, 71))	('prostate cancer', 'Disease', 'MESH:D011471', (94, 109))	('aggressive prostate cancer', 'Disease', (45, 71))	('prostate cancer', 'Disease', 'MESH:D011471', (56, 71))	('prostate cancer', 'Phenotype', 'HP:0012125', (94, 109))	('variant', 'Var', (5, 12))	('prostate cancer', 'Phenotype', 'HP:0012125', (56, 71))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('associated', 'Reg', (29, 39))	('prostate cancer', 'Disease', (94, 109))
540583	27197191	Our prostate eQTL analysis suggested that rs13016963 influences the expression of BZW1.	('BZW1', 'Gene', (82, 86))	('expression', 'MPA', (68, 78))	('rs13016963', 'Var', (42, 52))	('rs13016963', 'Mutation', 'rs13016963', (42, 52))	('BZW1', 'Gene', '9689', (82, 86))	('influences', 'Reg', (53, 63))
540587	27197191	We also found two potential functional variants in the region (rs700636 and rs1035142).	('rs700636', 'Var', (63, 71))	('rs700636', 'Mutation', 'rs700636', (63, 71))	('rs1035142', 'Mutation', 'rs1035142', (76, 85))	('rs1035142', 'Var', (76, 85))
540588	27197191	These variants are in strong LD with rs13016963 (R2>=0.93), and have associations with prostate cancer similar to rs13016963 in strength and are predicted to sit in miRNA binding sites.	('prostate cancer', 'Disease', (87, 102))	('rs13016963', 'Mutation', 'rs13016963', (37, 47))	('variants', 'Var', (6, 14))	('associations', 'Interaction', (69, 81))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('prostate cancer', 'Disease', 'MESH:D011471', (87, 102))	('prostate cancer', 'Phenotype', 'HP:0012125', (87, 102))	('rs13016963', 'Mutation', 'rs13016963', (114, 124))
540590	27197191	We observed a pleiotropic association of rs62560775 (located in the intronic region of CDKN2B-AS1) involving lung adenocarcinoma and breast cancer.	('breast cancer', 'Disease', (133, 146))	('breast cancer', 'Phenotype', 'HP:0003002', (133, 146))	('CDKN2B-AS1', 'Gene', (87, 97))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (109, 128))	('rs62560775', 'Mutation', 'rs62560775', (41, 51))	('rs62560775', 'Var', (41, 51))	('lung adenocarcinoma', 'Disease', (109, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (109, 128))	('CDKN2B-AS1', 'Gene', '100048912', (87, 97))	('breast cancer', 'Disease', 'MESH:D001943', (133, 146))
540591	27197191	The association with breast cancer might to be due to LD (R2 = 0.38) with a previously identified breast cancer susceptibility variant, rs1011970.	('breast cancer', 'Disease', 'MESH:D001943', (98, 111))	('breast cancer', 'Phenotype', 'HP:0003002', (98, 111))	('breast cancer', 'Disease', (98, 111))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('breast cancer', 'Disease', 'MESH:D001943', (21, 34))	('rs1011970', 'Var', (136, 145))	('breast cancer', 'Disease', (21, 34))	('breast cancer', 'Phenotype', 'HP:0003002', (21, 34))	('rs1011970', 'Mutation', 'rs1011970', (136, 145))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))
540592	27197191	Interestingly, we did replicate an association between rs1011970 and prostate cancer, suggesting this specific variant, or variants in LD with it contribute to risk for both breast and prostate cancer.	('contribute', 'Reg', (146, 156))	('rs1011970', 'Mutation', 'rs1011970', (55, 64))	('prostate cancer', 'Disease', 'MESH:D011471', (185, 200))	('prostate cancer', 'Disease', 'MESH:D011471', (69, 84))	('breast and prostate cancer', 'Disease', 'MESH:D011471', (174, 200))	('prostate cancer', 'Phenotype', 'HP:0012125', (185, 200))	('prostate cancer', 'Phenotype', 'HP:0012125', (69, 84))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('prostate cancer', 'Disease', (185, 200))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('risk', 'Reg', (160, 164))	('rs1011970', 'Var', (55, 64))	('prostate cancer', 'Disease', (69, 84))	('variants', 'Var', (123, 131))
540593	27197191	Timofeeva et al, found an association between this region and lung SqCC, represented by rs1333040, but this variant was not associated with adenocarcinoma in our data set (P = 0.62).	('rs1333040', 'Mutation', 'rs1333040', (88, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (145, 154))	('adenocarcinoma', 'Disease', (140, 154))	('rs1333040', 'Var', (88, 97))	('adenocarcinoma', 'Disease', 'MESH:D000230', (140, 154))	('lung SqCC', 'Disease', (62, 71))	('association', 'Interaction', (26, 37))
540595	27197191	LD between variants reported in these studies and either rs62560775 or rs1011970 range from R2 = 0.21 to R2 = 0.60, indicating that multiple variants in this region contribute to cancer risk.	('rs1011970', 'Var', (71, 80))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('rs1011970', 'Mutation', 'rs1011970', (71, 80))	('contribute', 'Reg', (165, 175))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('cancer', 'Disease', (179, 185))	('rs62560775', 'Mutation', 'rs62560775', (57, 67))	('rs62560775', 'Var', (57, 67))
540596	27197191	Despite that associations for different cancers were exerted from multiple variants, our results represent an important pleiotropic finding, as all variants are located in the same gene, CDKN2B-AS1.	('cancers', 'Phenotype', 'HP:0002664', (40, 47))	('cancers', 'Disease', 'MESH:D009369', (40, 47))	('CDKN2B-AS1', 'Gene', (187, 197))	('cancers', 'Disease', (40, 47))	('variants', 'Var', (148, 156))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('CDKN2B-AS1', 'Gene', '100048912', (187, 197))	('variants', 'Var', (75, 83))
540597	27197191	Modification of CDKN2B-AS1 activity could be the mechanism through which this locus influences cancer risk.	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('Modification', 'Var', (0, 12))	('CDKN2B-AS1', 'Gene', (16, 26))	('cancer', 'Disease', (95, 101))	('influences', 'Reg', (84, 94))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('activity', 'MPA', (27, 35))	('CDKN2B-AS1', 'Gene', '100048912', (16, 26))
540599	27197191	Although there is no known function for rs62660775 or rs1011970, a variant with which rs62660775 is in strong LD, rs3217986 (at R2 = 0.75), was identified to be located in a miRNA binding site and classified as likely to affect binding by Regulome.	('rs1011970', 'Var', (54, 63))	('rs62660775', 'Var', (86, 96))	('rs62660775', 'Mutation', 'rs62660775', (86, 96))	('rs1011970', 'Mutation', 'rs1011970', (54, 63))	('rs3217986', 'Var', (114, 123))	('affect', 'Reg', (221, 227))	('binding', 'Interaction', (228, 235))	('rs3217986', 'Mutation', 'rs3217986', (114, 123))	('rs62660775', 'Mutation', 'rs62660775', (40, 50))	('rs62660775', 'Var', (40, 50))
540601	27197191	Since our replication datasets sample sizes were often smaller than that of our discovery (GAME-ON/GECCO) set (depending on cancer site), we may have insufficient power to replicate true associations particularly for less common variants, underlining the importance of sample size for investigations of pleiotropy.	('cancer', 'Disease', (124, 130))	('insufficient', 'Disease', 'MESH:D000309', (150, 162))	('insufficient', 'Disease', (150, 162))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('variants', 'Var', (229, 237))	('cancer', 'Disease', 'MESH:D009369', (124, 130))
540602	27197191	In summary, using data from the GAME-ON initiative and GECCO, we have found four regions that show associations with multiple cancers, including a novel association between genetic variation at 1q22 and breast cancer and lung squamous cell carcinoma.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('breast cancer', 'Disease', 'MESH:D001943', (203, 216))	('multiple cancers', 'Disease', (117, 133))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('breast cancer', 'Disease', (203, 216))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (221, 249))	('breast cancer', 'Phenotype', 'HP:0003002', (203, 216))	('cancers', 'Phenotype', 'HP:0002664', (126, 133))	('associations', 'Interaction', (99, 111))	('1q22', 'Gene', (194, 198))	('multiple cancers', 'Disease', 'MESH:D009369', (117, 133))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (221, 249))	('carcinoma', 'Phenotype', 'HP:0030731', (240, 249))	('genetic variation at', 'Var', (173, 193))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (226, 249))	('lung squamous cell carcinoma', 'Disease', (221, 249))
540617	27527408	In addition, more adenocarcinoma patients possess genetic aberrations with available targeted therapy, such as EGFR mutations and ALK rearrangements.	('adenocarcinoma', 'Disease', 'MESH:D000230', (18, 32))	('patients', 'Species', '9606', (33, 41))	('EGFR', 'Gene', '1956', (111, 115))	('ALK', 'Gene', (130, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (23, 32))	('EGFR', 'Gene', (111, 115))	('mutations', 'Var', (116, 125))	('adenocarcinoma', 'Disease', (18, 32))	('ALK', 'Gene', '238', (130, 133))
540625	27527408	Subjective or erroneous evaluation of histopathology images may lead to poor therapeutic choice, which results in decreased survival and loss of quality of life in numerous patients.	('patients', 'Species', '9606', (173, 181))	('decreased', 'NegReg', (114, 123))	('loss', 'NegReg', (137, 141))	('survival', 'CPA', (124, 132))	('erroneous', 'Var', (14, 23))	('quality of life', 'CPA', (145, 160))
540737	25002953	Malignant neoplasms comprise a heterogeneous group of disorders in which aberrant or erratic cellular proliferation leads to profound derangements in organism well-being.	('men', 'Species', '9606', (141, 144))	('erratic cellular proliferation', 'CPA', (85, 115))	('aberrant', 'Var', (73, 81))	('Malignant neoplasms', 'Disease', 'MESH:D009369', (0, 19))	('neoplasms', 'Phenotype', 'HP:0002664', (10, 19))	('Malignant neoplasms', 'Disease', (0, 19))	('organism well-being', 'CPA', (150, 169))	('leads to', 'Reg', (116, 124))
540954	33923166	KLF5 Is Activated by Gene Amplification in Gastric Cancer and Is Essential for Gastric Cell Proliferation Gastric cancer is the third leading cause of cancer death worldwide.	('Gene Amplification', 'Var', (21, 39))	('KLF5', 'Gene', (0, 4))	('Gastric cancer', 'Disease', (106, 120))	('KLF5', 'Gene', '688', (0, 4))	('Gastric cancer', 'Disease', 'MESH:D013274', (106, 120))	('Activated', 'PosReg', (8, 17))	('Gastric Cancer', 'Disease', (43, 57))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('Gastric Cancer', 'Phenotype', 'HP:0012126', (43, 57))	('Gastric cancer', 'Phenotype', 'HP:0012126', (106, 120))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('Gastric Cancer', 'Disease', 'MESH:D013274', (43, 57))	('cancer death', 'Disease', (151, 163))	('Cancer', 'Phenotype', 'HP:0002664', (51, 57))	('cancer death', 'Disease', 'MESH:D009369', (151, 163))
540958	33923166	We found that KLF5 amplification mainly occurred in the chromosome instable tumors (CIN) and was significantly associated with TP53 mutation.	('mutation', 'Var', (132, 140))	('CIN', 'Disease', 'MESH:D007674', (84, 87))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('KLF5', 'MPA', (14, 18))	('associated', 'Reg', (111, 121))	('occurred', 'Reg', (40, 48))	('tumors', 'Disease', (76, 82))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('TP53', 'Gene', '7157', (127, 131))	('TP53', 'Gene', (127, 131))	('CIN', 'Disease', (84, 87))
540969	33923166	Drugs such as trastuzumab that targeting HER2 had been developed and showed good effects in selected gastric cancer patients with HER2 amplification.	('gastric cancer', 'Disease', (101, 115))	('amplification', 'Var', (135, 148))	('gastric cancer', 'Disease', 'MESH:D013274', (101, 115))	('patients', 'Species', '9606', (116, 124))	('trastuzumab', 'Chemical', 'MESH:D000068878', (14, 25))	('HER2', 'Gene', (41, 45))	('HER2', 'Gene', (130, 134))	('gastric cancer', 'Phenotype', 'HP:0012126', (101, 115))	('HER2', 'Gene', '2064', (130, 134))	('HER2', 'Gene', '2064', (41, 45))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))
540992	33923166	All four datasets are whole transcriptome profiling studies comparing Klf5 knockout versus wild-type mouse tissues.	('Klf5', 'Gene', (70, 74))	('knockout', 'Var', (75, 83))	('mouse', 'Species', '10090', (101, 106))
540999	33923166	Western blot was probed with antibodies against GAPDH (bsm-0978M, Bioss, Beijing, China) or KLF5 (ab24331, Abcam, Cambridge, UK).	('bsm-0978M', 'Var', (55, 64))	('GAPDH', 'Gene', '2597', (48, 53))	('GAPDH', 'Gene', (48, 53))
541003	33923166	Copy number variation (CNV) of KLF5 is prevalent in different tumor types, according to a previous study.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('Copy number variation', 'Var', (0, 21))	('KLF5', 'Gene', (31, 35))	('tumor', 'Disease', (62, 67))	('prevalent', 'Reg', (39, 48))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
541005	33923166	In pan-cancer of 33 tumor types, the KLF5 gene showed both amplifications and deletions in different tumor types.	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('KLF5 gene', 'Gene', (37, 46))	('cancer', 'Disease', (7, 13))	('cancer', 'Disease', 'MESH:D009369', (7, 13))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('tumor', 'Disease', (20, 25))	('deletions', 'Var', (78, 87))
541006	33923166	The rates of KLF5 variation ranged from 3.6% (acute myeloid leukemia, LAML) to 76.8% (uterine carcinosarcoma, UCS).	('acute myeloid leukemia', 'Disease', (46, 68))	('carcinosarcoma', 'Disease', 'MESH:D002296', (94, 108))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (46, 68))	('variation', 'Var', (18, 27))	('sarcoma', 'Phenotype', 'HP:0100242', (101, 108))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (86, 108))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (52, 68))	('carcinosarcoma', 'Disease', (94, 108))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (46, 68))	('leukemia', 'Phenotype', 'HP:0001909', (60, 68))
541008	33923166	Interestingly, both amplification and deletion of KLF5 could be found at a similar rate in some cancer types, such as uterine carcinosarcoma (UCS) and bladder cancer (BLCA).	('bladder cancer', 'Disease', (151, 165))	('cancer', 'Disease', (159, 165))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('carcinosarcoma', 'Disease', (126, 140))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('bladder cancer', 'Phenotype', 'HP:0009725', (151, 165))	('KLF5', 'Gene', (50, 54))	('sarcoma', 'Phenotype', 'HP:0100242', (133, 140))	('found', 'Reg', (64, 69))	('deletion', 'Var', (38, 46))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('amplification', 'Var', (20, 33))	('carcinosarcoma', 'Disease', 'MESH:D002296', (126, 140))	('bladder cancer', 'Disease', 'MESH:D001749', (151, 165))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('cancer', 'Disease', (96, 102))	('uterine carcinosarcoma', 'Phenotype', 'HP:0002891', (118, 140))
541011	33923166	In gastric cancer and a subset of bladder cancer, there were duplications of chromosome 13q as well as regional amplification of a region close to KLF5 (Figure 1B,C).	('gastric cancer', 'Phenotype', 'HP:0012126', (3, 17))	('duplications', 'Var', (61, 73))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('cancer', 'Phenotype', 'HP:0002664', (11, 17))	('bladder cancer', 'Phenotype', 'HP:0009725', (34, 48))	('bladder cancer', 'Disease', 'MESH:D001749', (34, 48))	('gastric cancer', 'Disease', (3, 17))	('bladder cancer', 'Disease', (34, 48))	('gastric cancer', 'Disease', 'MESH:D013274', (3, 17))
541012	33923166	In prostate cancer or another subset of bladder cancer, long segment deletion of chromosome 13q accounted for the loss of KLF5 (Figure 1B).	('bladder cancer', 'Phenotype', 'HP:0009725', (40, 54))	('prostate cancer', 'Phenotype', 'HP:0012125', (3, 18))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('loss', 'NegReg', (114, 118))	('bladder cancer', 'Disease', 'MESH:D001749', (40, 54))	('bladder cancer', 'Disease', (40, 54))	('prostate cancer', 'Disease', (3, 18))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('long segment deletion', 'Var', (56, 77))	('KLF5', 'Protein', (122, 126))	('prostate cancer', 'Disease', 'MESH:D011471', (3, 18))
541013	33923166	In gastrointestinal tumors with predominantly KLF5 amplification, including gastric cancer (STAD), colon cancer (COAD), and rectum cancer (READ), an increase in KLF5 transcripts could be observed (Figure 2, top 3).	('READ', 'Disease', (139, 143))	('gastrointestinal tumors', 'Disease', (3, 26))	('colon cancer', 'Disease', 'MESH:D015179', (99, 111))	('gastric cancer', 'Phenotype', 'HP:0012126', (76, 90))	('gastrointestinal tumors', 'Phenotype', 'HP:0007378', (3, 26))	('rectum cancer', 'Disease', 'MESH:D012004', (124, 137))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('KLF5 transcripts', 'MPA', (161, 177))	('increase', 'PosReg', (149, 157))	('colon cancer', 'Disease', (99, 111))	('READ', 'Disease', 'None', (139, 143))	('rectum cancer', 'Disease', (124, 137))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('gastric cancer', 'Disease', (76, 90))	('gastrointestinal tumors', 'Disease', 'MESH:D004067', (3, 26))	('COAD', 'Disease', 'MESH:D029424', (113, 117))	('KLF5 amplification', 'Var', (46, 64))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('rectum cancer', 'Phenotype', 'HP:0100743', (124, 137))	('gastric cancer', 'Disease', 'MESH:D013274', (76, 90))	('colon cancer', 'Phenotype', 'HP:0003003', (99, 111))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('COAD', 'Disease', (113, 117))
541014	33923166	For prostate cancer (PRAD), kidney chromophobe (KICH), and testicular germ cell tumors (TGCT), KLF5 deletion was predominant, and a decrease in KLF5 transcription could be observed (Figure 2, middle 3).	('prostate cancer', 'Disease', 'MESH:D011471', (4, 19))	('KLF5 transcription', 'MPA', (144, 162))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('prostate cancer', 'Phenotype', 'HP:0012125', (4, 19))	('kidney chromophobe', 'Disease', (28, 46))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('KICH', 'Disease', (48, 52))	('kidney chromophobe', 'Disease', 'MESH:D000238', (28, 46))	('prostate cancer', 'Disease', (4, 19))	('tumors', 'Disease', (80, 86))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('KICH', 'Disease', 'None', (48, 52))	('deletion', 'Var', (100, 108))	('germ cell tumors', 'Phenotype', 'HP:0100728', (70, 86))	('decrease', 'NegReg', (132, 140))	('KLF5', 'Gene', (95, 99))
541015	33923166	For other tumor types such as esophageal carcinoma (ESCA), bladder urothelial carcinoma (BLCA) and uterine corpus endometrial carcinoma (UCEC), which had comparable rates of KLF5 amplification and deletion, KLF5 expression changed in accordance to its copy number (Figure 2, bottom 3).	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (114, 135))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (30, 50))	('bladder urothelial carcinoma', 'Disease', (59, 87))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (30, 50))	('changed', 'Reg', (223, 230))	('deletion', 'Var', (197, 205))	('carcinoma', 'Phenotype', 'HP:0030731', (41, 50))	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('tumor', 'Disease', (10, 15))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('endometrial carcinoma', 'Disease', 'MESH:D016889', (114, 135))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('endometrial carcinoma', 'Disease', (114, 135))	('esophageal carcinoma', 'Disease', (30, 50))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (59, 87))
541024	33923166	This result suggested CNV of KLF5 was related to the overall chromosomal instability of gastric cancer.	('CNV', 'Var', (22, 25))	('gastric cancer', 'Disease', (88, 102))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('gastric cancer', 'Disease', 'MESH:D013274', (88, 102))	('KLF5', 'Gene', (29, 33))	('related', 'Reg', (38, 45))	('gastric cancer', 'Phenotype', 'HP:0012126', (88, 102))	('chromosomal instability', 'Phenotype', 'HP:0040012', (61, 84))
541026	33923166	As shown in Figure 4B, KLF5 CNV was significantly associated with TP53 mutation (chi-square test: p = 4.3 x 10-5).	('TP53', 'Gene', '7157', (66, 70))	('TP53', 'Gene', (66, 70))	('mutation', 'Var', (71, 79))	('KLF5', 'Var', (23, 27))	('associated', 'Reg', (50, 60))
541030	33923166	KLF5 high expression tumors were less represented in the diffused type of gastric cancer (odds ratio = 0.3, p = 4.0 x 10-5) and TP53 mutated samples (odds ratio = 0.56, p = 0.03) (Figure 5).	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('KLF5', 'Gene', (0, 4))	('less', 'NegReg', (33, 37))	('diffused', 'Disease', (57, 65))	('TP53', 'Gene', '7157', (128, 132))	('TP53', 'Gene', (128, 132))	('tumors', 'Disease', (21, 27))	('gastric cancer', 'Disease', (74, 88))	('high expression', 'PosReg', (5, 20))	('tumors', 'Disease', 'MESH:D009369', (21, 27))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('gastric cancer', 'Disease', 'MESH:D013274', (74, 88))	('mutated', 'Var', (133, 140))	('gastric cancer', 'Phenotype', 'HP:0012126', (74, 88))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
541031	33923166	In multivariate logistic regression analysis, the diffused type of Lauren classification, TP53 mutation, and the MSI subtype of molecular classification were independent predictors of KLF5 expression (Supplementary Table S3).	('KLF5 expression', 'MPA', (184, 199))	('TP53', 'Gene', '7157', (90, 94))	('TP53', 'Gene', (90, 94))	('mutation', 'Var', (95, 103))
541042	33923166	All five studies profiled whole transcriptome of Klf5 knockout transgenic mice.	('Klf5', 'Gene', (49, 53))	('transgenic mice', 'Species', '10090', (63, 78))	('knockout', 'Var', (54, 62))
541043	33923166	Of the 84 genes, Cdkn1c (cyclin-dependent kinase inhibitor 1C) was among the few genes that were upregulated after the knockout of Klf5 (Supplementary Table S5).	('Cdkn1c', 'Gene', '1028', (17, 23))	('cyclin-dependent kinase inhibitor 1C', 'Gene', (25, 61))	('cyclin-dependent kinase inhibitor 1C', 'Gene', '1028', (25, 61))	('knockout', 'Var', (119, 127))	('Cdkn1c', 'Gene', (17, 23))	('upregulated', 'PosReg', (97, 108))
541056	33923166	After the silencing of KLF5, GPRC5A expression was significantly downregulated (Figure 7B).	('downregulated', 'NegReg', (65, 78))	('KLF5', 'Gene', (23, 27))	('GPRC5A', 'Gene', (29, 35))	('expression', 'MPA', (36, 46))	('silencing', 'Var', (10, 19))	('GPRC5A', 'Gene', '9052', (29, 35))
541070	33923166	In addition, KLF5 was inactivated by the hemizygous deletion in prostate cancer, and re-expression of KLF5 inhibits cell growth in vitro.	('cell growth in vitro', 'CPA', (116, 136))	('prostate cancer', 'Disease', (64, 79))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('inhibits', 'NegReg', (107, 115))	('re-expression', 'Var', (85, 98))	('prostate cancer', 'Disease', 'MESH:D011471', (64, 79))	('KLF5', 'Gene', (102, 106))	('prostate cancer', 'Phenotype', 'HP:0012125', (64, 79))
541076	33923166	In most other tumor types, both KLF5 amplification and deletion were observed.	('tumor', 'Disease', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('deletion', 'Var', (55, 63))
541080	33923166	More importantly, in ApcMin/KRAS V12 double transgenic mice that had a great tendency to develop small intestine tumors, deleting one allele of Klf5 led to a 92% reduction in tumor burden.	('tumor', 'Disease', (113, 118))	('KRAS', 'Gene', (28, 32))	('tumor', 'Disease', (175, 180))	('reduction', 'NegReg', (162, 171))	('tumors', 'Disease', (113, 119))	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('transgenic mice', 'Species', '10090', (44, 59))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('deleting', 'Var', (121, 129))	('Klf5', 'Gene', (144, 148))	('KRAS', 'Gene', '16653', (28, 32))	('small intestine tumors', 'Phenotype', 'HP:0100833', (97, 119))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
541087	33923166	However, a later study revealed that the nuclear staining of KLF5 was associated with more advanced cancer and poorer survival.	('cancer', 'Disease', (100, 106))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('associated', 'Reg', (70, 80))	('poorer', 'NegReg', (111, 117))	('nuclear staining', 'Var', (41, 57))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('KLF5', 'Gene', (61, 65))
541098	33923166	In addition, we also observed decreased clone formation ability of gastric cancer cells when KLF5 was silenced.	('gastric cancer', 'Disease', (67, 81))	('KLF5', 'Gene', (93, 97))	('gastric cancer', 'Disease', 'MESH:D013274', (67, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('clone formation ability', 'CPA', (40, 63))	('gastric cancer', 'Phenotype', 'HP:0012126', (67, 81))	('silenced', 'Var', (102, 110))	('decreased', 'NegReg', (30, 39))
541105	33923166	In summary, this study revealed that KLF5 underwent amplification or deletion in different tumor types, which led to up- or downregulation of KLF5 mRNA expression accordingly.	('amplification', 'Var', (52, 65))	('KLF5', 'Gene', (142, 146))	('tumor', 'Disease', (91, 96))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('up-', 'PosReg', (117, 120))	('deletion', 'Var', (69, 77))	('KLF5', 'Gene', (37, 41))	('downregulation', 'NegReg', (124, 138))
541107	33923166	KLF5 amplification was significantly associated with genome-unstable tumors and TP53 mutation.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('TP53', 'Gene', '7157', (80, 84))	('tumors', 'Phenotype', 'HP:0002664', (69, 75))	('TP53', 'Gene', (80, 84))	('mutation', 'Var', (85, 93))	('tumors', 'Disease', (69, 75))	('tumors', 'Disease', 'MESH:D009369', (69, 75))	('associated', 'Reg', (37, 47))	('KLF5 amplification', 'Var', (0, 18))
541144	33550206	In addition, high LpPLA2 expression was associated with various tumors, such as prostate cancer and breast cancer, especially in metastatic and aggressive ones.	('LpPLA2', 'Gene', (18, 24))	('tumors', 'Disease', (64, 70))	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('high', 'Var', (13, 17))	('prostate cancer', 'Disease', 'MESH:D011471', (80, 95))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('metastatic', 'Disease', (129, 139))	('prostate cancer', 'Phenotype', 'HP:0012125', (80, 95))	('prostate cancer', 'Disease', (80, 95))	('breast cancer', 'Disease', 'MESH:D001943', (100, 113))	('breast cancer', 'Phenotype', 'HP:0003002', (100, 113))	('LpPLA2', 'Gene', '7941', (18, 24))	('breast cancer', 'Disease', (100, 113))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('associated', 'Reg', (40, 50))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
541192	33550206	Lp-PLA2 plays a causal relationship in the occurrence of colon cancer; therefore, the inhibition of Lp-PLA2 may be a promising method for the treatment of intestinal cancer.	('Lp-PLA2', 'Gene', '7941', (0, 7))	('Lp-PLA2', 'Gene', (0, 7))	('intestinal cancer', 'Disease', (155, 172))	('colon cancer', 'Phenotype', 'HP:0003003', (57, 69))	('Lp-PLA2', 'Gene', (100, 107))	('colon cancer', 'Disease', 'MESH:D015179', (57, 69))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('Lp-PLA2', 'Gene', '7941', (100, 107))	('inhibition', 'Var', (86, 96))	('colon cancer', 'Disease', (57, 69))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('intestinal cancer', 'Disease', 'MESH:D007414', (155, 172))
541224	33550206	Patients with high serum Lp-PLA2 were more likely to develop adenocarcinoma (C-index=0.777), while those with lower Lp-PLA2 had a high probability of developing squamous cell carcinoma (C-index=0.843).	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (161, 184))	('Lp-PLA2', 'Gene', (116, 123))	('carcinoma', 'Phenotype', 'HP:0030731', (66, 75))	('squamous cell carcinoma', 'Disease', (161, 184))	('Lp-PLA2', 'Gene', (25, 32))	('Lp-PLA2', 'Gene', '7941', (25, 32))	('adenocarcinoma', 'Disease', 'MESH:D000230', (61, 75))	('Patients', 'Species', '9606', (0, 8))	('develop', 'PosReg', (53, 60))	('carcinoma', 'Phenotype', 'HP:0030731', (175, 184))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (161, 184))	('high serum', 'Var', (14, 24))	('Lp-PLA2', 'Gene', '7941', (116, 123))	('adenocarcinoma', 'Disease', (61, 75))
541229	33550206	Second, Lp-PLA2 gene polymorphism was confirmed to be related to the disease, yet the genotypes were not detected in this study.	('disease', 'Disease', (69, 76))	('related', 'Reg', (54, 61))	('Lp-PLA2', 'Gene', (8, 15))	('Lp-PLA2', 'Gene', '7941', (8, 15))	('polymorphism', 'Var', (21, 33))
541264	32245251	Aberrant NF-kB regulation has been observed in many cancers.	('NF-kB regulation', 'Protein', (9, 25))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('cancers', 'Disease', (52, 59))	('Aberrant', 'Var', (0, 8))	('cancers', 'Phenotype', 'HP:0002664', (52, 59))	('observed', 'Reg', (35, 43))	('cancers', 'Disease', 'MESH:D009369', (52, 59))
541389	32102317	Positive-VM was strongly associated with poor OS (hazard ratio = 0.50; 95% confidence interval: 0.38-0.64), which remained consistent following the subgroup analysis of the studies.	('poor OS', 'Disease', (41, 48))	('OS', 'Chemical', '-', (46, 48))	('Positive-VM', 'Var', (0, 11))
541447	32102317	All the studies showed that positive-VM immunoreactivity is associated with a decreased probability of overall survival, so that patients with positive-VM were more likely to die compared with negative-VM patients.	('overall survival', 'CPA', (103, 119))	('patients', 'Species', '9606', (205, 213))	('positive-VM', 'Var', (143, 154))	('patients', 'Species', '9606', (129, 137))	('die', 'CPA', (175, 178))	('positive-VM', 'Var', (28, 39))	('decreased', 'NegReg', (78, 87))
541455	32102317	Indeed, our findings are in agreement with previous meta-analysis reports that have shown the association between VM positivity with decreased probability of patients' survival in different cancers.	('cancers', 'Phenotype', 'HP:0002664', (190, 197))	('cancers', 'Disease', (190, 197))	('positivity', 'Var', (117, 127))	('cancers', 'Disease', 'MESH:D009369', (190, 197))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('patients', 'Species', '9606', (158, 166))	('decreased', 'NegReg', (133, 142))
541458	32102317	In the same direction, another recent meta-analysis showed that positive VM was a reliable indicator of poor prognosis in digestive cancer patients.	('positive VM', 'Var', (64, 75))	('cancer', 'Disease', (132, 138))	('patients', 'Species', '9606', (139, 147))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('cancer', 'Disease', 'MESH:D009369', (132, 138))
541604	31391866	Over a decade after its initial funding, The Cancer Genome Atlas (TCGA) has generated vast amounts of data of 33 different kinds of primary tumor in different data types (including mRNA expression values, copy number variations, methylations and so on).	('methylations', 'Var', (229, 241))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('copy number variations', 'Var', (205, 227))	('Cancer', 'Phenotype', 'HP:0002664', (45, 51))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('CG', 'Chemical', '-', (67, 69))	('Cancer Genome Atlas', 'Disease', (45, 64))	('mRNA expression', 'MPA', (181, 196))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (45, 64))	('tumor', 'Disease', (140, 145))
541623	31391866	In addition, if the bigger variation for a gene is a negative one (median value in tumor samples is smaller than that in non-malignant samples), then the corresponding line is under the base line.	('tumor', 'Disease', (83, 88))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('variation', 'Var', (27, 36))
541636	31391866	To verify the performance of CG, we firstly applied the provided tools to a collection of TCGA GBM (Glioblastoma multiforme) samples due to the fact that those functional roles of a substantial number of copy number alterations have already been validated in preclinical models.	('Glioblastoma', 'Phenotype', 'HP:0012174', (100, 112))	('Glioblastoma multiforme', 'Disease', 'MESH:D005909', (100, 123))	('CG', 'Chemical', '-', (29, 31))	('TCGA GBM', 'Gene', (90, 98))	('copy number alterations', 'Var', (204, 227))	('CG', 'Chemical', '-', (91, 93))	('Glioblastoma multiforme', 'Disease', (100, 123))
541665	31391866	This work was generously supported by the National Natural Science Foundation of China [31331351] and the NCI Specialized Program in Research Excellence (SPORE) in Lung Cancer, P50CA70907, National Cancer Institute, USA.	('Cancer', 'Phenotype', 'HP:0002664', (169, 175))	('Lung Cancer', 'Disease', 'MESH:D008175', (164, 175))	('Lung Cancer', 'Disease', (164, 175))	('Lung Cancer', 'Phenotype', 'HP:0100526', (164, 175))	('P50CA70907', 'Var', (177, 187))	('Cancer', 'Phenotype', 'HP:0002664', (198, 204))
541674	29394946	Based on the in-house RT-qPCR, miR-198-5p expression was 4.3826 +- 1.7660 in LUSC tissues and 4.4522 +- 1.8263 in adjacent normal tissues (P = 0.885).	('5p', 'Chemical', '-', (39, 41))	('4.3826 +- 1.7660', 'Var', (57, 73))	('miR-198', 'Gene', (31, 38))	('LUSC', 'Phenotype', 'HP:0030359', (77, 81))	('miR-198', 'Gene', '406975', (31, 38))
541713	29394946	Using RT-qPCR, the expression of miR-198-5p in the LUSC tissues was (4.3826 +- 1.7660) compared with that in the non-tumor tissues (4.4522 +- 1.8263, P = 0.885) (Fig.	('LUSC', 'Phenotype', 'HP:0030359', (51, 55))	('miR-198', 'Gene', (33, 40))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('non-tumor', 'Disease', 'MESH:D009369', (113, 122))	('miR-198', 'Gene', '406975', (33, 40))	('non-tumor', 'Disease', (113, 122))	('4.3826', 'Var', (69, 75))	('5p', 'Chemical', '-', (41, 43))
541753	29394946	LUSC Lung squamous cell carcinoma GEO Gene Expression Omnibus FFPE Formalin-fixed, paraffin-embedded mRNA Messenger RNA miRNA Micro RNA TCGA The Cancer Genome Atlas AUC Area under the curve SROC Summarized receiver operating characteristic NSCLC Non-small cell lung cancer GO Gene Ontology KEGG Kyoto Encyclopedia of Genes and Genomes BP Biological processes CC Cellular components MF Molecular functions PPI Protein-protein interaction YF, GC, and YG participated in the design of this study.	('NSCLC', 'Disease', (240, 245))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (10, 33))	('paraffin', 'Chemical', 'MESH:D010232', (83, 91))	('squamous cell carcinoma', 'Disease', (10, 33))	('NSCLC', 'Disease', 'MESH:D002289', (240, 245))	('Non-small cell lung cancer', 'Disease', 'MESH:D002289', (246, 272))	('Non-small cell lung cancer', 'Phenotype', 'HP:0030358', (246, 272))	('lung cancer', 'Phenotype', 'HP:0100526', (261, 272))	('Non-small cell lung cancer', 'Disease', (246, 272))	('LUSC', 'Phenotype', 'HP:0030359', (0, 4))	('PPI', 'Var', (405, 408))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (250, 272))	('cancer', 'Phenotype', 'HP:0002664', (266, 272))	('Cancer', 'Phenotype', 'HP:0002664', (145, 151))	('NSCLC', 'Phenotype', 'HP:0030358', (240, 245))	('carcinoma', 'Phenotype', 'HP:0030731', (24, 33))	('Formalin', 'Chemical', 'MESH:D005557', (67, 75))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (10, 33))
541826	32878621	It is considered that the marked gain of histidine may enhance the total antioxidant and metal-binding capacity of the proteome of the cancer cell and thus potentially serve as a nonspecific compensatory mechanism to relieve consequences of the cancer-related aggravation of oxidative stress.	('cancer', 'Disease', (135, 141))	('cancer', 'Disease', 'MESH:D009369', (245, 251))	('cancer', 'Disease', (245, 251))	('enhance', 'PosReg', (55, 62))	('oxidative stress', 'Phenotype', 'HP:0025464', (275, 291))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('gain', 'PosReg', (33, 37))	('cancer', 'Phenotype', 'HP:0002664', (245, 251))	('histidine', 'Chemical', 'MESH:D006639', (41, 50))	('histidine', 'Var', (41, 50))	('cancer', 'Disease', 'MESH:D009369', (135, 141))	('metal', 'Chemical', 'MESH:D008670', (89, 94))
541847	32878621	This study was supported by National Natural Science Foundation of China (U1504814), Major projects of science and Technology Department in Henan Province (16110311200, 161100311300) and Anyang Science Foundation of Henan province (2016).	('men', 'Species', '9606', (132, 135))	('16110311200', 'Var', (156, 167))	('U1504814', 'Var', (74, 82))	('161100311300', 'Var', (169, 181))
541862	32382343	Recent evidence of the clinical efficacy of immunotherapeutic approaches, including chimeric antigen receptor, T-cell therapy, immune checkpoint blockade and vaccine therapy, for lung cancer suggests that immunotherapy will become the next major therapeutic advance for this disease.	('lung cancer', 'Disease', (179, 190))	('chimeric', 'Var', (84, 92))	('lung cancer', 'Phenotype', 'HP:0100526', (179, 190))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('lung cancer', 'Disease', 'MESH:D008175', (179, 190))
541869	32382343	Furthermore, MDSCs can contribute to patient resistance to immunotherapy.	('patient', 'Species', '9606', (37, 44))	('MDSCs', 'Var', (13, 18))	('contribute', 'Reg', (23, 33))	('patient resistance to immunotherapy', 'CPA', (37, 72))
541922	32382343	There was no significant association between CT antigens expression and MDSC infiltration, although CD33 was expressed more frequently in CT antigens patients with positive expression compared with patients with negative expression (Tables III and V).	('CD33', 'Gene', '945', (100, 104))	('CD33', 'Gene', (100, 104))	('patients', 'Species', '9606', (198, 206))	('patients', 'Species', '9606', (150, 158))	('positive expression', 'Var', (164, 183))
541944	32382343	However, the present study did demonstrate an association between high expression of MAGE-A4 or NY-ESO-1 and a poor prognosis in patients with NSCLC.	('NY-ESO-1', 'Gene', '246100', (96, 104))	('MAGE-A4', 'Gene', (85, 92))	('NSCLC', 'Disease', (143, 148))	('patients', 'Species', '9606', (129, 137))	('NSCLC', 'Disease', 'MESH:D002289', (143, 148))	('NSCLC', 'Phenotype', 'HP:0030358', (143, 148))	('high expression', 'Var', (66, 81))	('MAGE-A4', 'Gene', '4103', (85, 92))	('NY-ESO-1', 'Gene', (96, 104))
541948	32382343	The importance of MDSCs in cancer-related immunosuppression is evident by the inhibitory effect on T cell proliferation and function and the fact that removal of MDSCs can restore T cell effector function.	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('removal', 'Var', (151, 158))	('T cell proliferation', 'CPA', (99, 119))	('restore', 'PosReg', (172, 179))	('T cell effector function', 'CPA', (180, 204))	('cancer', 'Disease', (27, 33))	('MDSCs', 'Gene', (162, 167))	('cancer', 'Disease', 'MESH:D009369', (27, 33))
542002	31861130	In addition, several genetic alterations in tumor suppressor genes (APC, p53), proto-oncogenes (Myc), oncogenes (Ras), and genes controlling normal cellular processes (EIF3E, GSTM1) have been involved in oral carcinogenesis.	('EIF3E', 'Gene', (168, 173))	('APC', 'Disease', 'MESH:D011125', (68, 71))	('p53', 'Gene', (73, 76))	('APC', 'Disease', (68, 71))	('involved', 'Reg', (192, 200))	('Myc', 'Gene', '4609', (96, 99))	('Myc', 'Gene', (96, 99))	('p53', 'Gene', '7157', (73, 76))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('GSTM1', 'Gene', '2944', (175, 180))	('EIF3E', 'Gene', '3646', (168, 173))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('GSTM1', 'Gene', (175, 180))	('genetic alterations', 'Var', (21, 40))	('oral carcinogenesis', 'Disease', (204, 223))	('tumor', 'Disease', (44, 49))
542003	31861130	Evidence shows that epigenetic alterations, such as DNA methylation, histone modifications, and non-coding RNA modifications (miRNAs) are major regulatory mechanisms in the development and progression of oral cancer.	('histone', 'MPA', (69, 76))	('miR', 'Gene', '220972', (126, 129))	('miR', 'Gene', (126, 129))	('oral cancer', 'Disease', 'MESH:D009062', (204, 215))	('epigenetic', 'Var', (20, 30))	('oral cancer', 'Disease', (204, 215))	('DNA', 'MPA', (52, 55))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
542029	31861130	Dysregulated circulating miR-24 has been reported in other cancer locations, such as breast, colorectal, and lung cancers.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('cancers', 'Phenotype', 'HP:0002664', (114, 121))	('reported', 'Reg', (41, 49))	('colorectal', 'Disease', (93, 103))	('lung cancers', 'Disease', 'MESH:D008175', (109, 121))	('lung cancers', 'Phenotype', 'HP:0100526', (109, 121))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('miR', 'Gene', '220972', (25, 28))	('miR', 'Gene', (25, 28))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('Dysregulated', 'Var', (0, 12))	('lung cancers', 'Disease', (109, 121))	('colorectal', 'Disease', 'MESH:D015179', (93, 103))	('breast', 'Disease', (85, 91))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('cancer', 'Disease', (114, 120))
542130	31861130	MiR-320-3p and miR-517b-3p were expressed only in salivary extracellular vesicles from oral cancer patients while miR-412-3p and miR-512-3 were significantly increased in cancer patients as compared with healthy controls, presenting AUC values of 0.847 and 0.871, respectively.	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('miR', 'Gene', '220972', (114, 117))	('miR', 'Gene', '220972', (129, 132))	('patients', 'Species', '9606', (178, 186))	('miR', 'Gene', (114, 117))	('miR-412', 'Gene', '574433', (114, 121))	('miR', 'Gene', (129, 132))	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', (171, 177))	('patients', 'Species', '9606', (99, 107))	('MiR-320-3p', 'Var', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('miR', 'Gene', '220972', (15, 18))	('oral cancer', 'Disease', 'MESH:D009062', (87, 98))	('oral cancer', 'Disease', (87, 98))	('miR-412', 'Gene', (114, 121))	('increased', 'PosReg', (158, 167))	('miR', 'Gene', (15, 18))
542133	31861130	Recently, another study focusing on extracellular vesicles isolated from oral swirls developed an algorithm-based risk classification of five miRNAs (miR-24-3p, miR-21-5p, miR-99a-5p, let-7c-5p, and miR-100-5p) discriminating normal mucosa and oral cancer with an AUC of 0.867.	('oral cancer', 'Disease', 'MESH:D009062', (244, 255))	('miR', 'Gene', (172, 175))	('normal mucosa', 'Disease', (226, 239))	('miR-99a', 'Gene', (172, 179))	('oral cancer', 'Disease', (244, 255))	('cancer', 'Phenotype', 'HP:0002664', (249, 255))	('miR', 'Gene', '220972', (161, 164))	('24-3p', 'Chemical', 'MESH:D016655', (154, 159))	('miR', 'Gene', '220972', (150, 153))	('miR-99a', 'Gene', '407055', (172, 179))	('miR', 'Gene', (161, 164))	('miR', 'Gene', '220972', (199, 202))	('miR', 'Gene', '220972', (142, 145))	('miR-21-5p', 'Gene', (161, 170))	('miR-21-5p', 'Gene', '406997', (161, 170))	('miR', 'Gene', (150, 153))	('miR', 'Gene', '220972', (172, 175))	('let-7c-5p', 'Var', (184, 193))	('miR', 'Gene', (199, 202))	('miR', 'Gene', (142, 145))	('discriminating', 'Reg', (211, 225))
542145	31861130	High serum miR-483-5p expression was significantly associated with shorter overall survival, poorly differentiated tumors, late-stage and lymph node metastasis.	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('High', 'Var', (0, 4))	('late-stage', 'CPA', (123, 133))	('tumors', 'Disease', (115, 121))	('tumors', 'Disease', 'MESH:D009369', (115, 121))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('shorter', 'NegReg', (67, 74))	('overall survival', 'CPA', (75, 91))	('miR-483', 'Gene', '619552', (11, 18))	('lymph node metastasis', 'CPA', (138, 159))	('miR-483', 'Gene', (11, 18))
542169	31861130	Interestingly, it could also be possible to restore the expression of a tumor suppressor miRNA by inserting genes coding for miRNAs into viral constructs, such as adenovirus-associated vectors.	('restore', 'PosReg', (44, 51))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('miR', 'Gene', '220972', (89, 92))	('tumor', 'Disease', (72, 77))	('inserting', 'Var', (98, 107))	('miR', 'Gene', (89, 92))	('expression', 'MPA', (56, 66))	('miR', 'Gene', '220972', (125, 128))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('miR', 'Gene', (125, 128))
542176	31861130	This novel inhibitory-miRNA therapy is based on small molecule inhibitors of miRNAs that are known to be able to interact with RNA, inhibiting miRNA biogenesis or impeding miRNA-target interaction.	('miR', 'Gene', (77, 80))	('miR', 'Gene', '220972', (22, 25))	('interact', 'Interaction', (113, 121))	('miR', 'Gene', '220972', (143, 146))	('impeding', 'NegReg', (163, 171))	('miR', 'Gene', (143, 146))	('miR', 'Gene', '220972', (172, 175))	('miR', 'Gene', (172, 175))	('inhibitors', 'Var', (63, 73))	('inhibiting', 'NegReg', (132, 142))	('miR', 'Gene', (22, 25))	('miR', 'Gene', '220972', (77, 80))
542178	31861130	demonstrated that miR-184 inhibitor reduced the proliferation rate in three different tongue squamous cell carcinoma cell lines.	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('proliferation rate', 'CPA', (48, 66))	('miR-184', 'Gene', (18, 25))	('tongue squamous cell carcinoma', 'Disease', 'MESH:D002294', (86, 116))	('tongue squamous cell carcinoma', 'Disease', (86, 116))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (93, 116))	('miR-184', 'Gene', '406960', (18, 25))	('reduced', 'NegReg', (36, 43))	('inhibitor', 'Var', (26, 35))	('tongue squamous cell carcinoma', 'Phenotype', 'HP:0030413', (86, 116))
542179	31861130	observed that the blockage of miR-24 expression by anti-sense miR-24 locked nucleic acid yielded a decrease of endogenous miR-24 expression levels, inhibiting the growth of SAS oral cancer cell lines.	('blockage', 'NegReg', (18, 26))	('miR', 'Gene', '220972', (30, 33))	('miR', 'Gene', (30, 33))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('anti-sense', 'Var', (51, 61))	('miR', 'Gene', '220972', (62, 65))	('miR', 'Gene', (62, 65))	('miR', 'Gene', '220972', (122, 125))	('miR', 'Gene', (122, 125))	('decrease', 'NegReg', (99, 107))	('oral cancer', 'Disease', 'MESH:D009062', (177, 188))	('oral cancer', 'Disease', (177, 188))	('inhibiting', 'NegReg', (148, 158))
542180	31861130	Similarly, miR-146a locked nucleic acid decreased the proliferation rate of oral cancer cells in vitro.	('miR-146a locked nucleic acid', 'Var', (11, 39))	('oral cancer', 'Disease', 'MESH:D009062', (76, 87))	('oral cancer', 'Disease', (76, 87))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('proliferation rate of', 'CPA', (54, 75))	('decreased', 'NegReg', (40, 49))
542181	31861130	Interestingly, when miR-146a locked nucleic acid and scramble control locked nucleic acid were complexed with atelocollagen and injected into xenografic tumor mouse model, a significant decrease in tumoral growth was observed, which suggests that miR-146a locked nucleic acid represses the oncogenicity of oral cancer cells.	('miR-146a', 'Var', (247, 255))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('tumoral', 'Disease', (198, 205))	('miR-146a', 'Var', (20, 28))	('tumoral', 'Disease', 'MESH:D009369', (198, 205))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('mouse', 'Species', '10090', (159, 164))	('oral cancer', 'Disease', 'MESH:D009062', (306, 317))	('tumor', 'Disease', (153, 158))	('represses', 'NegReg', (276, 285))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('oral cancer', 'Disease', (306, 317))	('tumor', 'Disease', (198, 203))	('cancer', 'Phenotype', 'HP:0002664', (311, 317))	('decrease', 'NegReg', (186, 194))
542183	31861130	described circulating miR-187-5p as a potential oncogene in oral cancer and they found that miR-187-5p mimic increased exogenous miR-187-5p levels but did not alter miR-187-3p expression, demonstrating the high specificity of miR-187-5p mimic.	('oral cancer', 'Disease', 'MESH:D009062', (60, 71))	('miR-187', 'Gene', (129, 136))	('miR-187', 'Gene', '406963', (22, 29))	('miR-187', 'Gene', '406963', (129, 136))	('miR-187', 'Gene', '406963', (92, 99))	('miR-187', 'Gene', (92, 99))	('oral cancer', 'Disease', (60, 71))	('miR-187', 'Gene', '406963', (226, 233))	('miR-187', 'Gene', (226, 233))	('miR-187', 'Gene', (165, 172))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('miR-187', 'Gene', '406963', (165, 172))	('mimic', 'Var', (103, 108))	('increased', 'PosReg', (109, 118))	('miR-187', 'Gene', (22, 29))	('exogenous', 'MPA', (119, 128))
542217	31695781	NSCLC patients harboring genetic alterations in EGFR, ALK, ROS1 and BRAF can implement specific targeted therapies with superior efficacy and low toxicity.	('ALK', 'Gene', (54, 57))	('NSCLC', 'Disease', 'MESH:D002289', (0, 5))	('EGFR', 'Gene', '1956', (48, 52))	('BRAF', 'Gene', '673', (68, 72))	('ROS1', 'Gene', (59, 63))	('EGFR', 'Gene', (48, 52))	('BRAF', 'Gene', (68, 72))	('ROS1', 'Gene', '6098', (59, 63))	('NSCLC', 'Phenotype', 'HP:0030358', (0, 5))	('toxicity', 'Disease', 'MESH:D064420', (146, 154))	('toxicity', 'Disease', (146, 154))	('ALK', 'Gene', '238', (54, 57))	('patients', 'Species', '9606', (6, 14))	('NSCLC', 'Disease', (0, 5))	('genetic alterations', 'Var', (25, 44))
542222	31695781	Interestingly, Klotho has been shown to suppress a range of cancer types and its expression is usually downregulated in cancer due to hypermethylation in the promoter region.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('Klotho', 'Gene', '9365', (15, 21))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('suppress', 'NegReg', (40, 48))	('cancer', 'Disease', (60, 66))	('downregulated', 'NegReg', (103, 116))	('hypermethylation', 'Var', (134, 150))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('Klotho', 'Gene', (15, 21))	('expression', 'MPA', (81, 91))
542223	31695781	Overexpression of Klotho has been found to inhibit tumor growth in various animal models through inhibition of the TGFbeta1, WNT, FGF2, and IGF1 signaling pathways.	('FGF2', 'Gene', (130, 134))	('TGFbeta1', 'Gene', (115, 123))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('inhibition', 'NegReg', (97, 107))	('tumor', 'Disease', (51, 56))	('inhibit', 'NegReg', (43, 50))	('N', 'Chemical', 'MESH:D009584', (126, 127))	('FGF2', 'Gene', '2247', (130, 134))	('IGF1 signaling pathways', 'Pathway', (140, 163))	('Overexpression', 'Var', (0, 14))	('TGFbeta1', 'Gene', '7040', (115, 123))	('Klotho', 'Gene', '9365', (18, 24))	('Klotho', 'Gene', (18, 24))	('WNT', 'Pathway', (125, 128))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
542275	31695781	Through the comparative analysis between tumor and matched adjacent normal tissue, we identified large-scale amplification of SOX2 (26/37) and TP63 (24/37) and deletion of CDH1 (25/37) in tumor tissues.	('tumor', 'Disease', (188, 193))	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('CDH1', 'Gene', (172, 176))	('tumor', 'Disease', (41, 46))	('deletion', 'Var', (160, 168))	('CDH1', 'Gene', '999', (172, 176))	('TP63', 'Gene', (143, 147))	('TP63', 'Gene', '8626', (143, 147))	('tumor', 'Disease', 'MESH:D009369', (188, 193))	('tumor', 'Phenotype', 'HP:0002664', (188, 193))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('SOX2', 'Gene', '6657', (126, 130))	('SOX2', 'Gene', (126, 130))
542276	31695781	It was noted that KLB exhibited a deletion rate of 29.7% (11/37) in our cohort, indicating a relatively high frequency of DNA level changes (Figure 1F).	('changes', 'Reg', (132, 139))	('deletion', 'Var', (34, 42))	('DNA level', 'MPA', (122, 131))	('N', 'Chemical', 'MESH:D009584', (123, 124))
542309	31695781	H1581, HCC95, HCC15 and SK-MES-1 cells were scratched or re-seeded into the transwell plates after transfection with KLB-OE or KLB-EV respectively for 24 h. Compared with the control group, the migration (Figure 5A) and invasion (Figure 5B) were significantly reduced in the KLB-OE group.	('KLB-OE', 'Var', (275, 281))	('HCC15', 'CellLine', 'CVCL:2057', (14, 19))	('invasion', 'CPA', (220, 228))	('H1581', 'CellLine', 'CVCL:1479', (0, 5))	('migration', 'CPA', (194, 203))	('reduced', 'NegReg', (260, 267))	('HCC95', 'CellLine', 'CVCL:5137', (7, 12))	('SK-MES-1', 'CellLine', 'CVCL:0630', (24, 32))
542315	31695781	Downregulation of KLB in H520 exhibited a higher level of PCNA (Figure 6D).	('PCNA', 'Gene', '5111', (58, 62))	('Downregulation', 'NegReg', (0, 14))	('KLB', 'Gene', (18, 21))	('PCNA', 'Gene', (58, 62))	('H520', 'Var', (25, 29))	('H520', 'CellLine', 'CVCL:1566', (25, 29))
542316	31695781	Furthermore, we found that knockdown of KLB in A549 and SK-MES-1 cells could attenuate hydrogen peroxide-induced apoptosis by over 50% than the control group (Figure 6E).	('knockdown', 'Var', (27, 36))	('hydrogen peroxide', 'Chemical', 'MESH:D006861', (87, 104))	('SK-MES-1', 'CellLine', 'CVCL:0630', (56, 64))	('A549', 'CellLine', 'CVCL:0023', (47, 51))	('attenuate', 'NegReg', (77, 86))	('hydrogen peroxide-induced', 'MPA', (87, 112))	('KLB', 'Gene', (40, 43))
542320	31695781	The in vitro data prompted us to investigate the role of KLB in NSCLC in vivo, Using a subcutaneous model (Figure 7A), a marked reduction in tumor growth was observed in mice receiving KLB-OE lentivirus compared with those receiving the control lentivirus (Figure 7B).	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('NSCLC', 'Disease', 'MESH:D002289', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('reduction', 'NegReg', (128, 137))	('tumor', 'Disease', (141, 146))	('NSCLC', 'Phenotype', 'HP:0030358', (64, 69))	('mice', 'Species', '10090', (170, 174))	('KLB-OE lentivirus', 'Var', (185, 202))	('NSCLC', 'Disease', (64, 69))
542334	31695781	Proliferation of all four NSCLC cell lines was suppressed after betaKlotho addition at either 72 or 96 h depending on the cell line, while other two non-tumor cell lines, Beas-2b (bronchial epithelial cells) and HFL-1 (lung fibroblast cells) were barely affected even at the concentration of 400 ng/mL (Figure 8D).	('suppressed', 'NegReg', (47, 57))	('Beas-2', 'CellLine', 'CVCL:0168', (171, 177))	('betaKlotho', 'Var', (64, 74))	('non-tumor', 'Disease', (149, 158))	('NSCLC', 'Phenotype', 'HP:0030358', (26, 31))	('non-tumor', 'Disease', 'MESH:C580335', (149, 158))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('HFL-1', 'Gene', '3078', (212, 217))	('HFL-1', 'Gene', (212, 217))	('NSCLC', 'Disease', (26, 31))	('Proliferation', 'CPA', (0, 13))	('NSCLC', 'Disease', 'MESH:D002289', (26, 31))
542336	31695781	As expected, exogenous KLB decreased colony formation of NSCLC (Figure 8E).	('decreased', 'NegReg', (27, 36))	('NSCLC', 'Phenotype', 'HP:0030358', (57, 62))	('colony formation', 'CPA', (37, 53))	('NSCLC', 'Disease', (57, 62))	('exogenous', 'Var', (13, 22))	('NSCLC', 'Disease', 'MESH:D002289', (57, 62))
542340	31695781	Also, for H520 cells and HCC95 cells cultured with exogenous betaKlotho for 72 h, betaKlotho led to a significant increase in the percentage of cells in G0/G1 phase, as well as a significant decrease in the percentage of cells in S phase (Supplementary Figure 2B).	('cells in S phase', 'CPA', (221, 237))	('H520', 'CellLine', 'CVCL:1566', (10, 14))	('cells in G0/G1 phase', 'CPA', (144, 164))	('increase', 'PosReg', (114, 122))	('betaKlotho', 'Var', (82, 92))	('HCC95', 'CellLine', 'CVCL:5137', (25, 30))	('decrease', 'NegReg', (191, 199))
542347	31695781	KLB knockdown, however, even further promoted tumorigenic effect on NSCLC cells in vitro.	('tumor', 'Disease', 'MESH:D009369', (46, 51))	('NSCLC', 'Disease', 'MESH:D002289', (68, 73))	('promoted', 'PosReg', (37, 45))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('KLB', 'Gene', (0, 3))	('tumor', 'Disease', (46, 51))	('NSCLC', 'Phenotype', 'HP:0030358', (68, 73))	('knockdown', 'Var', (4, 13))	('NSCLC', 'Disease', (68, 73))
542352	31695781	We also found KLB copy number reduction and downregulation of expression by N stage in Oncomine database, and upregulation of KLB could inhibit the metastasis of cancer cells in vivo.	('upregulation', 'PosReg', (110, 122))	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('cancer', 'Disease', (162, 168))	('inhibit', 'NegReg', (136, 143))	('downregulation', 'NegReg', (44, 58))	('expression', 'MPA', (62, 72))	('KLB', 'Gene', (14, 17))	('reduction', 'NegReg', (30, 39))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('copy number', 'Var', (18, 29))	('N', 'Chemical', 'MESH:D009584', (76, 77))
542356	31695781	Third, exogenous betaKlotho or reintroduction of KLB inhibited NSCLC progression and it may achieve therapeutic potential for NSCLC.	('reintroduction', 'Var', (31, 45))	('NSCLC', 'Disease', (63, 68))	('NSCLC', 'Disease', 'MESH:D002289', (126, 131))	('inhibited', 'NegReg', (53, 62))	('NSCLC', 'Disease', 'MESH:D002289', (63, 68))	('achieve', 'PosReg', (92, 99))	('betaKlotho', 'Protein', (17, 27))	('KLB', 'Gene', (49, 52))	('NSCLC', 'Phenotype', 'HP:0030358', (126, 131))	('NSCLC', 'Phenotype', 'HP:0030358', (63, 68))	('exogenous', 'Var', (7, 16))	('NSCLC', 'Disease', (126, 131))
542363	31695781	A number of studies have also identified aberrant microRNA expression in cancer.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('aberrant', 'Var', (41, 49))	('microRNA expression', 'MPA', (50, 69))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('N', 'Chemical', 'MESH:D009584', (56, 57))
542364	31695781	Expressions of miR-34,miR-200, miR-126, miR-195, miR218, and several other microRNAs and lncRNAs were decreased in lung cancer, and these non-coding RNAs are very promising biomarkers in non-invasive screening methods.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('miR218', 'Var', (49, 55))	('miR-195', 'Gene', '406971', (40, 47))	('N', 'Chemical', 'MESH:D009584', (81, 82))	('miR-34', 'Gene', (15, 21))	('N', 'Chemical', 'MESH:D009584', (150, 151))	('miR-126', 'Gene', '406913', (31, 38))	('lung cancer', 'Disease', 'MESH:D008175', (115, 126))	('miR-126', 'Gene', (31, 38))	('miR-34', 'Gene', '407040', (15, 21))	('N', 'Chemical', 'MESH:D009584', (93, 94))	('miR-195', 'Gene', (40, 47))	('miR-200', 'Var', (22, 29))	('lung cancer', 'Disease', (115, 126))	('decreased', 'NegReg', (102, 111))	('lung cancer', 'Phenotype', 'HP:0100526', (115, 126))	('Expressions', 'MPA', (0, 11))
542389	31695781	In lung cancer, PPARgamma inhibits development of primary tumors and metastases in lung cancer, and activation of PPARgamma can promote apoptosis.	('inhibits', 'NegReg', (26, 34))	('lung cancer', 'Disease', 'MESH:D008175', (83, 94))	('lung cancer', 'Phenotype', 'HP:0100526', (3, 14))	('PPARgamma', 'Gene', '5468', (16, 25))	('metastases in lung cancer', 'Disease', (69, 94))	('lung cancer', 'Phenotype', 'HP:0100526', (83, 94))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('promote', 'PosReg', (128, 135))	('primary tumors', 'Disease', (50, 64))	('PPARgamma', 'Gene', (114, 123))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('lung cancer', 'Disease', (3, 14))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('PPARgamma', 'Gene', (16, 25))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('primary tumors', 'Disease', 'MESH:D001932', (50, 64))	('apoptosis', 'CPA', (136, 145))	('PPARgamma', 'Gene', '5468', (114, 123))	('activation', 'Var', (100, 110))	('lung cancer', 'Disease', 'MESH:D008175', (3, 14))	('metastases in lung cancer', 'Disease', 'MESH:D008175', (69, 94))
542467	31164623	Possible post-translational modifications (PTMs) were set at a maximum of 3 variable PTMs per peptide and included oxidation (at methionine residue (+15.995 Da)), acetylation (+42.011 Da), amidation (-0.984 Da), phosphorylation (at serine, threonine or tyrosine residue (+79.966 Da)), pyroglutamic acid (pyro-glu) formed from glutamic acid (-18.011 Da) and pyro-glu formed from glutamine (-17.027).	('+42.011 Da', 'Var', (176, 186))	('-17.027', 'Var', (389, 396))	('-0.984 Da', 'Var', (200, 209))	('glutamic acid', 'Chemical', 'MESH:D018698', (289, 302))	('pyro-glu', 'Chemical', 'MESH:D011761', (357, 365))	('glutamic acid', 'Chemical', 'MESH:D018698', (326, 339))	('pyro-glu', 'Chemical', 'MESH:D011761', (304, 312))	('glutamine', 'Chemical', 'MESH:D005973', (378, 387))	('+79.966 Da', 'Var', (271, 281))	('-18.011 Da', 'Var', (341, 351))
542498	31164623	An example is shown in Figure 6, where two m/z values (m/z 4961.6 and m/z 4934.9) are determined as characteristic peptides expressed in the lung tumor region, in both squamous and adenocarcinoma NSCLC tissues, with their corresponding 'area under the ROC curve (AUC)' scores, which represent the accuracy of the test; the closer to 1, the more perfect.	('lung tumor', 'Disease', (141, 151))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('carcinoma', 'Phenotype', 'HP:0030731', (186, 195))	('lung tumor', 'Phenotype', 'HP:0100526', (141, 151))	('peptides', 'Chemical', 'MESH:D010455', (115, 123))	('squamous and adenocarcinoma NSCLC tissues', 'Disease', 'MESH:D002294', (168, 209))	('NSCLC', 'Phenotype', 'HP:0030358', (196, 201))	('m/z 4934.9', 'Var', (70, 80))	('lung tumor', 'Disease', 'MESH:D008175', (141, 151))
542506	31164623	The fragmentation spectra were deconvoluted and de novo sequenced by using PEAKS software with possible variable PTMs of oxidation, phosphorylation, acetylation, amidation and pyro-glu formed from glutamic acid and from glutamine (with maximum 3 variable PTMs per peptide).	('phosphorylation', 'MPA', (132, 147))	('amidation', 'MPA', (162, 171))	('men', 'Species', '9606', (8, 11))	('pyro-glu', 'Chemical', 'MESH:D011761', (176, 184))	('glutamic acid', 'Chemical', 'MESH:D018698', (197, 210))	('pyro-glu', 'Var', (176, 184))	('glutamine', 'Chemical', 'MESH:D005973', (220, 229))	('acetylation', 'MPA', (149, 160))
542513	31164623	Overexpression of thymosin beta4 in the NSCLC region has been associated with carcinogenesis and tumor progression, where it is believed to activate cell migration and angiogenesis.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('activate', 'PosReg', (140, 148))	('carcinogenesis', 'Disease', 'MESH:D063646', (78, 92))	('thymosin beta4', 'Gene', '7114', (18, 32))	('associated', 'Reg', (62, 72))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('NSCLC', 'Phenotype', 'HP:0030358', (40, 45))	('carcinogenesis', 'Disease', (78, 92))	('thymosin beta4', 'Gene', (18, 32))	('tumor', 'Disease', (97, 102))	('cell migration', 'CPA', (149, 163))	('NSCLC', 'Disease', (40, 45))	('Overexpression', 'Var', (0, 14))	('angiogenesis', 'CPA', (168, 180))	('NSCLC', 'Disease', 'MESH:D002289', (40, 45))
542622	31200666	1), MMP11 expression differences yielded particularly high fold changes and high AUCs.	('MMP11', 'Gene', '4320', (4, 9))	('differences', 'Var', (21, 32))	('high AUCs', 'MPA', (76, 85))	('fold changes', 'MPA', (59, 71))	('MMP11', 'Gene', (4, 9))
542637	31200666	MMP-7 activation is directly associated with APC, and it is well established that APC mutations are frequently implicated as among the first mutations that occurs in the disease history of colon polyps as they progress to cancer.	('mutations', 'Var', (86, 95))	('cancer', 'Disease', 'MESH:D009369', (222, 228))	('APC', 'Disease', 'MESH:D011125', (82, 85))	('MMP-7', 'Gene', (0, 5))	('APC', 'Disease', (82, 85))	('cancer', 'Disease', (222, 228))	('colon polyps', 'Disease', (189, 201))	('MMP-7', 'Gene', '4316', (0, 5))	('APC', 'Disease', 'MESH:D011125', (45, 48))	('APC', 'Disease', (45, 48))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('colon polyps', 'Disease', 'MESH:D003111', (189, 201))
542638	31200666	APC mutations often lead to increased beta-catenin and thus overexpression of MMP-7.	('increased', 'PosReg', (28, 37))	('beta-catenin', 'Gene', (38, 50))	('MMP-7', 'Gene', (78, 83))	('MMP-7', 'Gene', '4316', (78, 83))	('APC', 'Disease', 'MESH:D011125', (0, 3))	('overexpression', 'PosReg', (60, 74))	('beta-catenin', 'Gene', '1499', (38, 50))	('APC', 'Disease', (0, 3))	('mutations', 'Var', (4, 13))
542656	31200666	It is likely that the dysregulation of one MMP alters the MMP ecosystem and means that MMPs are better predictors when analyzed in combination as opposed to individually.	('dysregulation', 'Var', (22, 35))	('MMP ecosystem', 'MPA', (58, 71))	('alters', 'Reg', (47, 53))	('MMPs', 'Gene', (87, 91))	('MMPs', 'Gene', '4312;4313;4314;4316;4317;4318;4319;4320;4321;4322;4323;4324;4325;4326;4327;64386;9313;118856;8510;10893;79148;64386;10893;79148;64386;10893;64066;79148', (87, 91))
542671	31200666	VHL mutation, whether inherited or sporadic is frequently implicated in the tumorigenesis of renal clear cell carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('renal clear cell carcinoma', 'Disease', 'MESH:C538614', (93, 119))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('renal clear cell carcinoma', 'Disease', (93, 119))	('mutation', 'Var', (4, 12))	('VHL', 'Gene', (0, 3))	('implicated', 'Reg', (58, 68))	('VHL', 'Gene', '7428', (0, 3))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
542672	31200666	With the loss of VHL, HIF is no longer properly degraded and free to induce the expression of proteins needed in hypoxic conditions.	('hypoxic conditions', 'Disease', (113, 131))	('hypoxic conditions', 'Disease', 'MESH:D009135', (113, 131))	('loss', 'Var', (9, 13))	('VHL', 'Gene', (17, 20))	('VHL', 'Gene', '7428', (17, 20))
542673	31200666	This leads to the upregulation of MMP14 in kidney clear cell carcinoma in patients with deletion of VHL.	('upregulation', 'PosReg', (18, 30))	('kidney clear cell carcinoma', 'Disease', 'MESH:C538614', (43, 70))	('deletion', 'Var', (88, 96))	('patients', 'Species', '9606', (74, 82))	('MMP14', 'Gene', '4323', (34, 39))	('kidney clear cell carcinoma', 'Disease', (43, 70))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('MMP14', 'Gene', (34, 39))	('VHL', 'Gene', (100, 103))	('VHL', 'Gene', '7428', (100, 103))
542686	29285837	New metformin derivative HL156A prevents oral cancer progression by inhibiting the insulin-like growth factor/AKT/mammalian target of rapamycin pathways Metformin is a biguanide widely prescribed as an antidiabetic drug for type 2 diabetes mellitus patients.	('Metformin', 'Chemical', 'MESH:D008687', (153, 162))	('AKT', 'Gene', (110, 113))	('metformin', 'Chemical', 'MESH:D008687', (4, 13))	('type 2 diabetes', 'Phenotype', 'HP:0005978', (224, 239))	('HL156A', 'Var', (25, 31))	('inhibiting', 'NegReg', (68, 78))	('diabetic', 'Disease', 'MESH:D003920', (206, 214))	('diabetic', 'Disease', (206, 214))	('mammalian target of rapamycin', 'Gene', '2475', (114, 143))	('insulin', 'Gene', (83, 90))	('AKT', 'Gene', '207', (110, 113))	('type 2 diabetes mellitus', 'Disease', (224, 248))	('biguanide', 'Chemical', 'MESH:D001645', (168, 177))	('diabetes mellitus', 'Phenotype', 'HP:0000819', (231, 248))	('oral cancer', 'Disease', 'MESH:D009062', (41, 52))	('type 2 diabetes mellitus', 'Disease', 'MESH:D003924', (224, 248))	('patients', 'Species', '9606', (249, 257))	('oral cancer', 'Disease', (41, 52))	('mammalian target of rapamycin', 'Gene', (114, 143))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('HL156A', 'CellLine', 'CVCL:2492', (25, 31))	('insulin', 'Gene', '3630', (83, 90))
542688	29285837	It was observed that HL156A significantly decreased FaDu and YD-10B cell viability and colony formation in a dose-dependent way.	('colony formation', 'CPA', (87, 103))	('HL156A', 'CellLine', 'CVCL:2492', (21, 27))	('HL156A', 'Var', (21, 27))	('decreased', 'NegReg', (42, 51))	('FaDu', 'Chemical', '-', (52, 56))	('YD-10B', 'Chemical', '-', (61, 67))
542689	29285837	HL156A also markedly reduced wound closure and migration of FaDu and YD-10B cells.	('reduced', 'NegReg', (21, 28))	('HL156A', 'Var', (0, 6))	('HL156A', 'CellLine', 'CVCL:2492', (0, 6))	('YD-10B', 'Chemical', '-', (69, 75))	('FaDu', 'Chemical', '-', (60, 64))	('wound closure', 'CPA', (29, 42))
542690	29285837	We observed that HL156A decreased mitochondrial membrane potential and induced reactive oxygen species (ROS) levels and apoptotic cells with caspase-3 and -9 activation.	('reactive oxygen species', 'Chemical', 'MESH:D017382', (79, 102))	('decreased', 'NegReg', (24, 33))	('apoptotic cells', 'CPA', (120, 135))	('induced', 'Reg', (71, 78))	('decreased mitochondrial membrane potential', 'Phenotype', 'HP:0040013', (24, 66))	('ROS', 'Chemical', 'MESH:D017382', (104, 107))	('caspase-3 and -9', 'Gene', '836;842', (141, 157))	('mitochondrial membrane potential', 'MPA', (34, 66))	('HL156A', 'Var', (17, 23))	('HL156A', 'CellLine', 'CVCL:2492', (17, 23))
542691	29285837	HL156A inhibited the expression and activation of insulin-like growth factor (IGF)-1 and its downstream proteins, AKT, mammalian target of rapamycin (mTOR), and ERK1/2.	('HL156A', 'Var', (0, 6))	('AKT', 'Gene', '207', (114, 117))	('HL156A', 'CellLine', 'CVCL:2492', (0, 6))	('ERK1/2', 'Gene', '5595;5594', (161, 167))	('mammalian target of rapamycin', 'Gene', (119, 148))	('mammalian target of rapamycin', 'Gene', '2475', (119, 148))	('activation', 'PosReg', (36, 46))	('AKT', 'Gene', (114, 117))	('expression', 'MPA', (21, 31))	('inhibited', 'NegReg', (7, 16))	('mTOR', 'Gene', '2475', (150, 154))	('insulin-like growth factor (IGF)-1', 'Gene', '3479', (50, 84))	('mTOR', 'Gene', (150, 154))	('ERK1/2', 'Gene', (161, 167))
542692	29285837	In addition, HL156A activated AMP-activated protein kinase/nuclear factor kappa B (AMPK-NF-kappaB) signaling of FaDu and YD-10B cells.	('HL156A', 'CellLine', 'CVCL:2492', (13, 19))	('YD-10B', 'Chemical', '-', (121, 127))	('nuclear factor kappa B', 'Gene', '4790', (59, 81))	('NF-kappaB', 'Gene', (88, 97))	('FaDu', 'Chemical', '-', (112, 116))	('NF-kappaB', 'Gene', '4790', (88, 97))	('AMPK', 'Gene', '5562', (83, 87))	('activated', 'PosReg', (20, 29))	('nuclear factor kappa B', 'Gene', (59, 81))	('AMPK', 'Gene', (83, 87))	('AMP-activated protein kinase', 'Gene', '5562', (30, 58))	('AMP-activated protein kinase', 'Gene', (30, 58))	('HL156A', 'Var', (13, 19))
542693	29285837	A xenograft mouse model further showed that HL156A suppressed AT84 mouse oral tumor growth, accompanied by down-regulated p-IGF-1, p-mTOR, proliferating cell nuclear antigen (PCNA) and promoted p-AMPK and TUNEL expression.	('TUNEL expression', 'MPA', (205, 221))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('oral tumor', 'Phenotype', 'HP:0100649', (73, 83))	('AMPK', 'Gene', '5562', (196, 200))	('HL156A', 'CellLine', 'CVCL:2492', (44, 50))	('p-IGF-1', 'Gene', (122, 129))	('proliferating cell nuclear antigen', 'Gene', '18538', (139, 173))	('down-regulated', 'NegReg', (107, 121))	('mouse', 'Species', '10090', (12, 17))	('mTOR', 'Gene', (133, 137))	('tumor', 'Disease', (78, 83))	('mouse', 'Species', '10090', (67, 72))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('suppressed', 'NegReg', (51, 61))	('proliferating cell nuclear antigen', 'Gene', (139, 173))	('AMPK', 'Gene', (196, 200))	('promoted', 'PosReg', (185, 193))	('mTOR', 'Gene', '2475', (133, 137))	('HL156A', 'Var', (44, 50))
542694	29285837	These results suggest the potential value of the new metformin derivative HL156A as a candidate for a therapeutic modality for the treatment of oral cancer.	('oral cancer', 'Disease', 'MESH:D009062', (144, 155))	('metformin', 'Chemical', 'MESH:D008687', (53, 62))	('oral cancer', 'Disease', (144, 155))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('HL156A', 'Var', (74, 80))	('HL156A', 'CellLine', 'CVCL:2492', (74, 80))
542700	29285837	It was reported that HL156A has protective effects against peritoneal and liver fibrosis.14, 15 It was also reported that HL156A inhibited LPS-induced inflammation of macrophages.	('inhibited', 'NegReg', (129, 138))	('HL156A', 'CellLine', 'CVCL:2492', (21, 27))	('liver fibrosis', 'Disease', (74, 88))	('HL156A', 'Var', (122, 128))	('liver fibrosis', 'Disease', 'MESH:D008103', (74, 88))	('HL156A', 'CellLine', 'CVCL:2492', (122, 128))	('inflammation', 'Disease', 'MESH:D007249', (151, 163))	('LPS', 'Chemical', 'MESH:D008070', (139, 142))	('inflammation', 'Disease', (151, 163))
542702	29285837	Our results suggest the potential abilities of the new metformin derivative HL156A as a candidate for a therapeutic modality for the treatment of oral cancer.	('metformin', 'Chemical', 'MESH:D008687', (55, 64))	('HL156A', 'CellLine', 'CVCL:2492', (76, 82))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('HL156A', 'Var', (76, 82))	('oral cancer', 'Disease', 'MESH:D009062', (146, 157))	('oral cancer', 'Disease', (146, 157))
542720	29285837	Antibodies against pCDK1 (sc101654), Cyclin B1 (sc245), caspase-3 (sc7148), caspase-9 (sc8355), caspase-7 (sc28295), PARP-1 (sc1561), SOD-1 (sc11407), NOS1 (sc5302), Nrf-2 (sc722), p70S6K (sc230), p-p70S6K (sc8416), p-mTOR (sc 101738), NF-kappaB (sc109), p-NF-kappaB (sc101752), MMP2 (sc13594), MMP9 (sc6840) were purchased from Santa Cruz Biotechnology (Santa Cruz, CA, USA).	('MMP9', 'Gene', '4318', (295, 299))	('Nrf-2', 'Gene', '4780', (166, 171))	('caspase-3', 'Gene', '836', (56, 65))	('p70S6K', 'Gene', (199, 205))	('NF-kappaB', 'Gene', '4790', (257, 266))	('NOS1', 'Gene', '4842', (151, 155))	('CDK1', 'Gene', (20, 24))	('caspase-7', 'Gene', (96, 105))	('mTOR', 'Gene', (218, 222))	('CDK1', 'Gene', '983', (20, 24))	('p70S6K', 'Gene', '6198', (181, 187))	('caspase-9', 'Gene', '842', (76, 85))	('PARP-1', 'Gene', (117, 123))	('caspase-3', 'Gene', (56, 65))	('NOS1', 'Gene', (151, 155))	('sc11407', 'Var', (141, 148))	('MMP2', 'Gene', (279, 283))	('mTOR', 'Gene', '2475', (218, 222))	('Nrf-2', 'Gene', (166, 171))	('caspase-9', 'Gene', (76, 85))	('NF-kappaB', 'Gene', (236, 245))	('p70S6K', 'Gene', (181, 187))	('sc101752', 'Var', (268, 276))	('p70S6K', 'Gene', '6198', (199, 205))	('MMP2', 'Gene', '4313', (279, 283))	('caspase-7', 'Gene', '840', (96, 105))	('SOD-1', 'Gene', '6647', (134, 139))	('Cyclin B1', 'Gene', (37, 46))	('NF-kappaB', 'Gene', '4790', (236, 245))	('SOD-1', 'Gene', (134, 139))	('PARP-1', 'Gene', '142', (117, 123))	('sc 101738', 'Var', (224, 233))	('Cyclin B1', 'Gene', '891', (37, 46))	('NF-kappaB', 'Gene', (257, 266))	('MMP9', 'Gene', (295, 299))
542721	29285837	The antibody against AMPK (2532S), p-AMPK (2535S), phosphorylated insulin-like growth factor-1 receptor (pIGF-1R) (3024S), AKT (9272S), pAKT (4060S), ERK1/2 (9102S), p-ERK1/2(9101S), and p-GSK-3alpha/beta (8566S) and the HRP-conjugated secondary antibody were purchased from Cell Signaling Technology (Beverly, MA, USA).	('AMPK', 'Gene', (37, 41))	('AKT', 'Gene', '207', (137, 140))	('GSK-3alpha', 'Gene', '2931', (189, 199))	('insulin-like growth factor-1 receptor', 'Gene', '3480', (66, 103))	('ERK1/2', 'Gene', (168, 174))	('ERK1/2', 'Gene', '5595;5594', (168, 174))	('8566S', 'Var', (206, 211))	('AMPK', 'Gene', '5562', (21, 25))	('2532S', 'Var', (27, 32))	('ERK1/2', 'Gene', (150, 156))	('AKT', 'Gene', (123, 126))	('9102S', 'Var', (158, 163))	('ERK1/2', 'Gene', '5595;5594', (150, 156))	('AMPK', 'Gene', '5562', (37, 41))	('2535S', 'Var', (43, 48))	('insulin-like growth factor-1 receptor', 'Gene', (66, 103))	('3024S', 'Var', (115, 120))	('4060S', 'Var', (142, 147))	('AKT', 'Gene', (137, 140))	('GSK-3alpha', 'Gene', (189, 199))	('9272S', 'Var', (128, 133))	('AKT', 'Gene', '207', (123, 126))	('AMPK', 'Gene', (21, 25))
542724	29285837	The supernatants were incubated with reaction buffer containing 2 mmol/L Ac-DEVD-AFC for caspase-3 and LEHD-AFC for caspase-9 (Abcam) in a caspase assay buffer at 37 C with 10 mmol/L DTT for 30 min.	('caspase-3', 'Gene', '836', (89, 98))	('caspase', 'Gene', (139, 146))	('Ac-DEVD', 'Chemical', '-', (73, 80))	('caspase', 'Gene', '842', (139, 146))	('caspase-9', 'Gene', '842', (116, 125))	('DTT', 'Chemical', 'MESH:D004229', (183, 186))	('caspase', 'Gene', (89, 96))	('caspase', 'Gene', '842', (89, 96))	('caspase', 'Gene', (116, 123))	('caspase-9', 'Gene', (116, 125))	('caspase', 'Gene', '842', (116, 123))	('caspase-3', 'Gene', (89, 98))	('LEHD-AFC', 'Var', (103, 111))
542736	29285837	Formalin-fixed paraffin-embedded tissues from AT84 xenografted tumors were used for immunohistochemical staining of p-IGF-1, p-mTOR, p-AMPK, and PCNA expression.	('AMPK', 'Gene', (135, 139))	('Formalin', 'Chemical', 'MESH:D005557', (0, 8))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('paraffin', 'Chemical', 'MESH:D010232', (15, 23))	('tumors', 'Disease', (63, 69))	('tumors', 'Disease', 'MESH:D009369', (63, 69))	('mTOR', 'Gene', (127, 131))	('mTOR', 'Gene', '2475', (127, 131))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('p-IGF-1', 'Var', (116, 123))	('AMPK', 'Gene', '5562', (135, 139))
542738	29285837	HL156A significantly decreased the growth of FaDu cells in a concentration-dependent way (Figure 1A).	('HL156A', 'Var', (0, 6))	('HL156A', 'CellLine', 'CVCL:2492', (0, 6))	('FaDu', 'Chemical', '-', (45, 49))	('decreased', 'NegReg', (21, 30))	('growth of FaDu cells', 'CPA', (35, 55))
542739	29285837	In FaDu cells, 40 mumol/L HL156A resulted in cell growth inhibition rates of 45% at 24 hours.	('HL156A', 'CellLine', 'CVCL:2492', (26, 32))	('cell growth', 'CPA', (45, 56))	('FaDu', 'Chemical', '-', (3, 7))	('HL156A', 'Var', (26, 32))
542740	29285837	Similarly, cell growth inhibition in YD-10B cells was also observed with HL156A treatment (Figure 1B).	('HL156A', 'Var', (73, 79))	('cell growth', 'CPA', (11, 22))	('HL156A', 'CellLine', 'CVCL:2492', (73, 79))	('YD-10B', 'Chemical', '-', (37, 43))
542743	29285837	At 40 mumol/L, HL156A markedly decreased the clonogenicity to approximately 25% and 13% compared to the control in both cell lines, respectively (Figure 1D).	('HL156A', 'CellLine', 'CVCL:2492', (15, 21))	('clonogenicity', 'CPA', (45, 58))	('decreased', 'NegReg', (31, 40))	('HL156A', 'Var', (15, 21))
542744	29285837	Thus, the results showed that HL156A inhibits the colony-forming ability of oral cancer cells.	('oral cancer', 'Disease', 'MESH:D009062', (76, 87))	('oral cancer', 'Disease', (76, 87))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('HL156A', 'Var', (30, 36))	('inhibits', 'NegReg', (37, 45))	('HL156A', 'CellLine', 'CVCL:2492', (30, 36))
542745	29285837	It was hypothesized that HL156A could induce alterations in cell cycle regulation.	('HL156A', 'Var', (25, 31))	('alterations', 'Reg', (45, 56))	('cell', 'MPA', (60, 64))	('HL156A', 'CellLine', 'CVCL:2492', (25, 31))
542747	29285837	As shown in Figure 2A, HL156A treatment caused a reduction in the G1 phase population and an increase in the G2/M population in both FaDu and YD-10B cells.	('G1 phase population', 'CPA', (66, 85))	('reduction', 'NegReg', (49, 58))	('increase', 'PosReg', (93, 101))	('YD-10B', 'Chemical', '-', (142, 148))	('HL156A', 'Var', (23, 29))	('HL156A', 'CellLine', 'CVCL:2492', (23, 29))	('FaDu', 'Chemical', '-', (133, 137))	('G2/M population', 'CPA', (109, 124))
542749	29285837	In FaDu and YD-10B cells, western blotting analysis showed that the levels of phospho-CDK1 and cyclin B were decreased by HL156A in a time-dependent way (Figure 2B).	('decreased', 'NegReg', (109, 118))	('FaDu', 'Chemical', '-', (3, 7))	('HL156A', 'Var', (122, 128))	('YD-10B', 'Chemical', '-', (12, 18))	('HL156A', 'CellLine', 'CVCL:2492', (122, 128))	('cyclin B', 'MPA', (95, 103))	('CDK1', 'Gene', (86, 90))	('CDK1', 'Gene', '983', (86, 90))
542751	29285837	To determine whether HL156A induces cell death in FaDu and YD-10B cells, we quantified apoptosis with flow cytometry using an Annexin v-FITC/PI double staining assay.	('HL156A', 'CellLine', 'CVCL:2492', (21, 27))	('Annexin v', 'Gene', (126, 135))	('HL156A', 'Var', (21, 27))	('YD-10B', 'Chemical', '-', (59, 65))	('Annexin v', 'Gene', '308', (126, 135))	('FaDu', 'Chemical', '-', (50, 54))
542752	29285837	As shown in Figure 3A, after 24 hours of HL156A treatment (40 or 60 mumol/L), there was a significant decrease in the number of living cells; 93.5% of the control cells were alive, whereas only 60.6% or 6.6% of the HL156A-treated FaDu cells were alive, respectively, whereas treatment with 40 mumol/L or 60 mumol/L HL156A stimulated a noteworthy increase in the proportion of apoptotic cells (32.9% with 40 mumol/L and 85.3% with 60 mumol/L) compared to the untreated control.	('FaDu', 'Chemical', '-', (230, 234))	('HL156A', 'CellLine', 'CVCL:2492', (41, 47))	('number of living cells', 'CPA', (118, 140))	('decrease', 'NegReg', (102, 110))	('apoptotic cells', 'CPA', (376, 391))	('increase', 'PosReg', (346, 354))	('HL156A', 'Var', (315, 321))	('HL156A', 'CellLine', 'CVCL:2492', (315, 321))	('HL156A', 'CellLine', 'CVCL:2492', (215, 221))
542754	29285837	Consistent with this observation, pro-caspase-3, -7, -9, and the inactive form poly (ADP-ribose) polymerase (PARP) were decreased in cells treated with HL156A compared with the control in a time-dependent way (Figure 3B).	('decreased', 'NegReg', (120, 129))	('pro-caspase-3', 'Gene', (34, 47))	('poly (ADP-ribose) polymerase', 'Gene', (79, 107))	('pro-caspase-3', 'Gene', '836', (34, 47))	('PARP', 'Gene', '142', (109, 113))	('poly (ADP-ribose) polymerase', 'Gene', '142', (79, 107))	('HL156A', 'Var', (152, 158))	('HL156A', 'CellLine', 'CVCL:2492', (152, 158))	('PARP', 'Gene', (109, 113))
542755	29285837	In addition, caspase-3 and caspase-9 activity was progressively induced by HL156A treatment in a time-dependent way (Figure 3C,D).	('caspase-3', 'Gene', '836', (13, 22))	('caspase-3', 'Gene', (13, 22))	('caspase-9', 'Gene', '842', (27, 36))	('HL156A', 'Var', (75, 81))	('activity', 'MPA', (37, 45))	('HL156A', 'CellLine', 'CVCL:2492', (75, 81))	('induced', 'PosReg', (64, 71))	('caspase-9', 'Gene', (27, 36))
542757	29285837	Interestingly, green fluorescence was increased in HL156A-treated cells, suggesting that HL156A led to a reduction in membrane potential (Figure 4A).	('HL156A', 'CellLine', 'CVCL:2492', (89, 95))	('HL156A', 'CellLine', 'CVCL:2492', (51, 57))	('membrane potential', 'MPA', (118, 136))	('reduction', 'NegReg', (105, 114))	('green fluorescence', 'MPA', (15, 33))	('HL156A', 'Var', (89, 95))	('increased', 'PosReg', (38, 47))
542759	29285837	Treatment with HL156A inhibited the level of SOD-1 in both cells in a time-dependent way (Figure 4B).	('SOD-1', 'Gene', '6647', (45, 50))	('inhibited', 'NegReg', (22, 31))	('SOD-1', 'Gene', (45, 50))	('HL156A', 'CellLine', 'CVCL:2492', (15, 21))	('HL156A', 'Var', (15, 21))
542760	29285837	However, the expression of Nrf-2 and its downstream target HO-1 was not changed during treatment with HL156A.	('HO-1', 'Gene', '3162', (59, 63))	('HL156A', 'CellLine', 'CVCL:2492', (102, 108))	('HL156A', 'Var', (102, 108))	('Nrf-2', 'Gene', (27, 32))	('HO-1', 'Gene', (59, 63))	('Nrf-2', 'Gene', '4780', (27, 32))
542761	29285837	It has been reported that mitochondrial malfunction leads to accumulation of ROS.18 Intracellular ROS production was assessed with fluorescence microscopy using the oxidation-sensitive dye DHE.	('ROS', 'Chemical', 'MESH:D017382', (98, 101))	('accumulation', 'PosReg', (61, 73))	('DHE', 'Chemical', 'MESH:C067883', (189, 192))	('ROS.18', 'Protein', (77, 83))	('malfunction', 'Var', (40, 51))	('mitochondrial malfunction', 'Phenotype', 'HP:0003287', (26, 51))	('ROS', 'Chemical', 'MESH:D017382', (77, 80))	('mitochondrial malfunction', 'Var', (26, 51))
542763	29285837	To examine the signaling mechanisms which might regulate apoptosis generation by HL156A, we focused attention on the insulin-like growth factor (IGF)/AKT/mTOR and AMPK pathways.	('AMPK', 'Gene', (163, 167))	('insulin', 'Gene', (117, 124))	('mTOR', 'Gene', (154, 158))	('AKT', 'Gene', '207', (150, 153))	('HL156A', 'Var', (81, 87))	('HL156A', 'CellLine', 'CVCL:2492', (81, 87))	('AKT', 'Gene', (150, 153))	('mTOR', 'Gene', '2475', (154, 158))	('AMPK', 'Gene', '5562', (163, 167))	('insulin', 'Gene', '3630', (117, 124))
542765	29285837	Phospho-IGF-1 levels decreased significantly after 12-h incubation in the presence of HL156A in FaDu and YD-10B cells (Figure 5A).	('FaDu', 'Chemical', '-', (96, 100))	('HL156A', 'Var', (86, 92))	('decreased', 'NegReg', (21, 30))	('HL156A', 'CellLine', 'CVCL:2492', (86, 92))	('Phospho-IGF-1 levels', 'MPA', (0, 20))	('YD-10B', 'Chemical', '-', (105, 111))
542766	29285837	We found that HL156A treatment inhibited AKT and ERK phosphorylation/activation and repressed phosphorylation of mTOR and p70S6K in a time-dependent way.	('p70S6K', 'Gene', (122, 128))	('p70S6K', 'Gene', '6198', (122, 128))	('HL156A', 'Var', (14, 20))	('HL156A', 'CellLine', 'CVCL:2492', (14, 20))	('mTOR', 'Gene', (113, 117))	('mTOR', 'Gene', '2475', (113, 117))	('AKT', 'Gene', '207', (41, 44))	('phosphorylation', 'MPA', (94, 109))	('phosphorylation/activation', 'PosReg', (53, 79))	('inhibited', 'NegReg', (31, 40))	('ERK', 'Gene', '5594', (49, 52))	('ERK', 'Gene', (49, 52))	('AKT', 'Gene', (41, 44))
542767	29285837	Our results indicate that HL156A could suppress activation and/or expression of IGF-I, leading to repression of phosphorylation of AKT and mTOR, which subsequently repressed phosphorylation of p70S6K.	('IGF-I', 'Gene', (80, 85))	('AKT', 'Gene', '207', (131, 134))	('phosphorylation', 'MPA', (112, 127))	('IGF-I', 'Gene', '3479', (80, 85))	('p70S6K', 'Gene', '6198', (193, 199))	('activation', 'MPA', (48, 58))	('mTOR', 'Gene', (139, 143))	('repression', 'NegReg', (98, 108))	('mTOR', 'Gene', '2475', (139, 143))	('AKT', 'Gene', (131, 134))	('expression', 'MPA', (66, 76))	('HL156A', 'CellLine', 'CVCL:2492', (26, 32))	('suppress', 'NegReg', (39, 47))	('HL156A', 'Var', (26, 32))	('p70S6K', 'Gene', (193, 199))
542768	29285837	HL156A also inhibits AKT/ERK1/2 signal transduction pathways that are important for cell proliferation as shown by a decrease in the expression of p-ERK1/2 (Thr202/Tyr204) after 6 hours of treatment (Figure 5A).	('HL156A', 'Var', (0, 6))	('expression', 'MPA', (133, 143))	('HL156A', 'CellLine', 'CVCL:2492', (0, 6))	('ERK1/2', 'Gene', '5595;5594', (25, 31))	('Thr202', 'Chemical', '-', (157, 163))	('ERK1/2', 'Gene', (149, 155))	('Tyr204', 'Chemical', '-', (164, 170))	('ERK1/2', 'Gene', '5595;5594', (149, 155))	('AKT', 'Gene', '207', (21, 24))	('inhibits', 'NegReg', (12, 20))	('decrease', 'NegReg', (117, 125))	('AKT', 'Gene', (21, 24))	('ERK1/2', 'Gene', (25, 31))
542769	29285837	Furthermore, western blot results showed that p-AMPK was increased in HL156A-treated FaDu and YD-10B cells whereas total AMPK remained unaltered (Figure 5B).	('FaDu', 'Chemical', '-', (85, 89))	('AMPK', 'Gene', (121, 125))	('AMPK', 'Gene', '5562', (121, 125))	('HL156A', 'CellLine', 'CVCL:2492', (70, 76))	('HL156A-treated', 'Var', (70, 84))	('YD-10B', 'Chemical', '-', (94, 100))	('increased', 'PosReg', (57, 66))	('AMPK', 'Gene', '5562', (48, 52))	('AMPK', 'Gene', (48, 52))
542771	29285837	HL156A decreased the expression of phospho NF-kappaB-p65 in FaDu and YD-10B cells in a time-dependent way.	('HL156A', 'Var', (0, 6))	('HL156A', 'CellLine', 'CVCL:2492', (0, 6))	('NF-kappaB', 'Gene', (43, 52))	('decreased', 'NegReg', (7, 16))	('YD-10B', 'Chemical', '-', (69, 75))	('expression', 'MPA', (21, 31))	('FaDu', 'Chemical', '-', (60, 64))	('NF-kappaB', 'Gene', '4790', (43, 52))
542774	29285837	Restoration of FaDu and YD-10B cells treated with 40 mumol/L HL156A slowly closed the scratch wound compared with the control cells at 24 hours or 36 hours after initiation of the scratch (Figure 6A).	('slowly', 'NegReg', (68, 74))	('FaDu', 'Chemical', '-', (15, 19))	('HL156A', 'Var', (61, 67))	('HL156A', 'CellLine', 'CVCL:2492', (61, 67))	('YD-10B', 'Chemical', '-', (24, 30))
542775	29285837	To confirm whether HL156A inhibits cell migration, we carried out in vitro Matrigel Transwell chamber assays.	('inhibits', 'NegReg', (26, 34))	('HL156A', 'Var', (19, 25))	('HL156A', 'CellLine', 'CVCL:2492', (19, 25))	('cell migration', 'CPA', (35, 49))
542776	29285837	When the FaDu and YD-10B cells were treated with HL156A, cell migration was significantly inhibited.	('HL156A', 'Var', (49, 55))	('HL156A', 'CellLine', 'CVCL:2492', (49, 55))	('YD-10B', 'Chemical', '-', (18, 24))	('FaDu', 'Chemical', '-', (9, 13))	('inhibited', 'NegReg', (90, 99))	('cell migration', 'CPA', (57, 71))
542777	29285837	HL156A, at a concentration of 40 mumol/L, decreased the migration of FaDu and YD-10B cells to 85% and 70% that of the control cells after 22 hours of treatment (Figure 6B).	('migration', 'CPA', (56, 65))	('HL156A', 'Var', (0, 6))	('HL156A', 'CellLine', 'CVCL:2492', (0, 6))	('decreased', 'NegReg', (42, 51))	('FaDu', 'Chemical', '-', (69, 73))	('YD-10B', 'Chemical', '-', (78, 84))
542778	29285837	Several studies have indicated that MMP signaling pathways play an important role in tumor invasion and migration.20, 21 To elucidate the mechanism by which HL156A inhibits migration in FaDu and YD-10B cells, we monitored the expression of MMP2 and MMP9.	('tumor', 'Disease', (85, 90))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('MMP', 'Gene', (36, 39))	('YD-10B', 'Chemical', '-', (195, 201))	('MMP', 'Gene', '4313;4318', (36, 39))	('HL156A', 'CellLine', 'CVCL:2492', (157, 163))	('MMP2', 'Gene', (240, 244))	('migration', 'CPA', (173, 182))	('FaDu', 'Chemical', '-', (186, 190))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('MMP', 'Gene', (249, 252))	('MMP', 'Gene', '4313;4318', (249, 252))	('inhibits', 'NegReg', (164, 172))	('MMP', 'Gene', (240, 243))	('MMP9', 'Gene', (249, 253))	('MMP', 'Gene', '4313;4318', (240, 243))	('MMP2', 'Gene', '4313', (240, 244))	('MMP9', 'Gene', '4318', (249, 253))	('HL156A', 'Var', (157, 163))
542779	29285837	Levels of MMP2 and MMP9 were reduced by HL156A treatment in a time-dependent way, with 50% inhibition in 40 mumol/L HL156A-treated FaDu and YD-10B cells (Figure 6C).	('MMP2', 'Gene', (10, 14))	('inhibition', 'NegReg', (91, 101))	('FaDu', 'Chemical', '-', (131, 135))	('reduced', 'NegReg', (29, 36))	('MMP9', 'Gene', '4318', (19, 23))	('MMP9', 'Gene', (19, 23))	('HL156A', 'CellLine', 'CVCL:2492', (116, 122))	('HL156A', 'Var', (40, 46))	('HL156A', 'CellLine', 'CVCL:2492', (40, 46))	('MMP2', 'Gene', '4313', (10, 14))	('YD-10B', 'Chemical', '-', (140, 146))
542780	29285837	In support of the identified in vitro antiproliferative effects of HL156A, a tumor xenograft model was used to examine alterations in the pathological characteristics in vivo.	('antiproliferative effects', 'MPA', (38, 63))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('HL156A', 'Var', (67, 73))	('HL156A', 'CellLine', 'CVCL:2492', (67, 73))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Disease', (77, 82))
542782	29285837	As shown in Figure 7, HL156A significantly inhibited tumor growth up to 82% relative to the control group at the end of the experiment (21 days).	('inhibited', 'NegReg', (43, 52))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('HL156A', 'Var', (22, 28))	('HL156A', 'CellLine', 'CVCL:2492', (22, 28))	('tumor', 'Disease', (53, 58))
542785	29285837	Tumor tissues treated with HL156A had larger areas of extensive cell changes showing nuclear pyknosis and cytoplasmic eosinophilia.	('HL156A', 'CellLine', 'CVCL:2492', (27, 33))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('HL156A', 'Var', (27, 33))	('nuclear pyknosis', 'CPA', (85, 101))	('eosinophilia', 'Disease', 'MESH:D004802', (118, 130))	('eosinophilia', 'Disease', (118, 130))	('eosinophilia', 'Phenotype', 'HP:0001880', (118, 130))
542786	29285837	In immunohistochemistry assay, tumors from the HL156A-treated group showed decreased levels of phosphorylated IGF-1 and mTOR compared to control.	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('levels of phosphorylated', 'MPA', (85, 109))	('IGF-1', 'Protein', (110, 115))	('tumors', 'Disease', (31, 37))	('tumors', 'Phenotype', 'HP:0002664', (31, 37))	('tumors', 'Disease', 'MESH:D009369', (31, 37))	('HL156A', 'CellLine', 'CVCL:2492', (47, 53))	('mTOR', 'Gene', (120, 124))	('mTOR', 'Gene', '2475', (120, 124))	('decreased levels of phosphorylated IGF', 'Phenotype', 'HP:0002850', (75, 113))	('HL156A-treated', 'Var', (47, 61))	('decreased', 'NegReg', (75, 84))
542787	29285837	Consistent with our western blot findings, HL156A increased the expression of p-AMPK compared with control (Figure 7C).	('AMPK', 'Gene', '5562', (80, 84))	('AMPK', 'Gene', (80, 84))	('expression', 'MPA', (64, 74))	('increased', 'PosReg', (50, 59))	('HL156A', 'Var', (43, 49))	('HL156A', 'CellLine', 'CVCL:2492', (43, 49))
542788	29285837	The antitumoral effects of HL156A in the in vivo study were also investigated by examining the expression of PCNA, a cell proliferation marker, and by TUNEL staining to assess the number of apoptotic cells using immunohistochemistry.	('HL156A', 'CellLine', 'CVCL:2492', (27, 33))	('PCNA', 'Gene', (109, 113))	('HL156A', 'Var', (27, 33))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('tumor', 'Disease', (8, 13))
542789	29285837	The number of PCNA-positive cells was significantly decreased in HL156A-treated tumor sections compared with tumors from control mice.	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumors', 'Disease', 'MESH:D009369', (109, 115))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('decreased', 'NegReg', (52, 61))	('HL156A-treated', 'Var', (65, 79))	('HL156A', 'CellLine', 'CVCL:2492', (65, 71))	('tumor', 'Disease', (80, 85))	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('mice', 'Species', '10090', (129, 133))	('tumors', 'Disease', (109, 115))	('tumor', 'Disease', (109, 114))
542793	29285837	We observed that tumor growth in HL156A- or metformin-treated mice was not dramatically inhibited during the experimental period but relatively smaller tumor volumes were observed compared to control (Figure S1).	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('tumor', 'Disease', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('smaller', 'NegReg', (144, 151))	('mice', 'Species', '10090', (62, 66))	('metformin', 'Chemical', 'MESH:D008687', (44, 53))	('tumor', 'Disease', (152, 157))	('HL156A', 'CellLine', 'CVCL:2492', (33, 39))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('HL156A-', 'Var', (33, 40))
542799	29285837	High concentrations of metformin (up to 10-15 mmol/L) have been shown to inhibit proliferation of various human cancer cell lines such as lung cancer cells (up to 15 mmol/L), endometrial cancer cells (up to 10 mmol/L), hepatocellular carcinoma cells (up to 10 mmol/L), and head and neck squamous carcinoma cells (5-20 mmol/L).26, 27, 28 HL156A exerted more potent inhibitory effects on the proliferation of glioblastoma cells than metformin.	('lung cancer', 'Disease', 'MESH:D008175', (138, 149))	('human', 'Species', '9606', (106, 111))	('endometrial cancer', 'Disease', 'MESH:D016889', (175, 193))	('cancer', 'Disease', (112, 118))	('head and neck squamous carcinoma', 'Phenotype', 'HP:0012288', (273, 305))	('lung cancer', 'Phenotype', 'HP:0100526', (138, 149))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('squamous carcinoma', 'Disease', (287, 305))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (219, 243))	('cancer', 'Disease', 'MESH:D009369', (187, 193))	('HL156A', 'CellLine', 'CVCL:2492', (337, 343))	('cancer', 'Disease', (143, 149))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('glioblastoma', 'Disease', 'MESH:D005909', (407, 419))	('inhibitory effects', 'NegReg', (364, 382))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('.26', 'Var', (325, 328))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (219, 243))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (287, 305))	('metformin', 'Chemical', 'MESH:D008687', (431, 440))	('lung cancer', 'Disease', (138, 149))	('carcinoma', 'Phenotype', 'HP:0030731', (234, 243))	('squamous carcinoma', 'Disease', 'MESH:D002294', (287, 305))	('endometrial cancer', 'Phenotype', 'HP:0012114', (175, 193))	('glioblastoma', 'Disease', (407, 419))	('hepatocellular carcinoma', 'Disease', (219, 243))	('cancer', 'Disease', (187, 193))	('metformin', 'Chemical', 'MESH:D008687', (23, 32))	('glioblastoma', 'Phenotype', 'HP:0012174', (407, 419))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('proliferation', 'CPA', (390, 403))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('endometrial cancer', 'Disease', (175, 193))	('carcinoma', 'Phenotype', 'HP:0030731', (296, 305))
542800	29285837	HL156A showed approximately 100-fold more potent effects compared to metformin.	('HL156A', 'CellLine', 'CVCL:2492', (0, 6))	('HL156A', 'Var', (0, 6))	('metformin', 'Chemical', 'MESH:D008687', (69, 78))	('effects', 'MPA', (49, 56))
542801	29285837	In a glioblastoma xenograft model, HL156A showed a comparable degree of inhibitory effect on in vivo tumor growth at the 30 mg/kg dose to that of metformin at 100 mg/kg.16, 29 We also found that HL156A inhibits cell growth at lower concentrations (<=40 mumol/L) than metformin in oral squamous carcinoma cells.	('glioblastoma', 'Disease', (5, 17))	('inhibits', 'NegReg', (202, 210))	('glioblastoma', 'Disease', 'MESH:D005909', (5, 17))	('metformin', 'Chemical', 'MESH:D008687', (267, 276))	('HL156A', 'CellLine', 'CVCL:2492', (35, 41))	('oral squamous carcinoma', 'Disease', (280, 303))	('tumor', 'Disease', (101, 106))	('cell growth', 'CPA', (211, 222))	('glioblastoma', 'Phenotype', 'HP:0012174', (5, 17))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('oral squamous carcinoma', 'Disease', 'MESH:D002294', (280, 303))	('carcinoma', 'Phenotype', 'HP:0030731', (294, 303))	('metformin', 'Chemical', 'MESH:D008687', (146, 155))	('HL156A', 'Var', (195, 201))	('HL156A', 'CellLine', 'CVCL:2492', (195, 201))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (285, 303))
542802	29285837	In our study, we found that the new metformin derivative HL156A significantly reduced growth of human oral squamous cell carcinoma FaDu and YD-10B cells.	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('metformin', 'Chemical', 'MESH:D008687', (36, 45))	('human', 'Species', '9606', (96, 101))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (107, 130))	('oral squamous cell carcinoma FaDu', 'Disease', 'MESH:D002294', (102, 135))	('HL156A', 'Var', (57, 63))	('HL156A', 'CellLine', 'CVCL:2492', (57, 63))	('reduced', 'NegReg', (78, 85))	('growth', 'MPA', (86, 92))	('YD-10B', 'Chemical', '-', (140, 146))	('oral squamous cell carcinoma FaDu', 'Disease', (102, 135))
542803	29285837	HL156A led to a reduction in colony formation in a dose-dependent way.	('HL156A', 'Var', (0, 6))	('HL156A', 'CellLine', 'CVCL:2492', (0, 6))	('reduction', 'NegReg', (16, 25))	('colony formation', 'CPA', (29, 45))
542805	29285837	The cell cycle was inhibited at the G2/M phase in the HL156A-treated cells that were analyzed.	('cell cycle', 'CPA', (4, 14))	('HL156A-treated', 'Var', (54, 68))	('HL156A', 'CellLine', 'CVCL:2492', (54, 60))	('inhibited', 'NegReg', (19, 28))
542806	29285837	Consistent with these results, HL156A treatment led to a remarkable decrease in cyclin B and cyclin-dependent kinase (CDK) 1 activity in FaDu and YD-10B cells.	('HL156A', 'Var', (31, 37))	('HL156A', 'CellLine', 'CVCL:2492', (31, 37))	('decrease', 'NegReg', (68, 76))	('activity', 'MPA', (125, 133))	('YD-10B', 'Chemical', '-', (146, 152))	('cyclin-dependent kinase (CDK) 1', 'Gene', '983', (93, 124))	('cyclin B', 'Enzyme', (80, 88))	('FaDu', 'Chemical', '-', (137, 141))
542807	29285837	In addition, expression of CDK4, CDK6, CDK2, cyclin A, and cyclin E protein was inhibited in HL156A-treated cells (data not shown).	('CDK6', 'Gene', '1021', (33, 37))	('CDK2', 'Gene', '1017', (39, 43))	('expression', 'MPA', (13, 23))	('HL156A', 'CellLine', 'CVCL:2492', (93, 99))	('cyclin A', 'Gene', (45, 53))	('CDK4', 'Gene', (27, 31))	('HL156A-treated', 'Var', (93, 107))	('cyclin E', 'MPA', (59, 67))	('cyclin A', 'Gene', '890', (45, 53))	('CDK4', 'Gene', '1019', (27, 31))	('CDK2', 'Gene', (39, 43))	('inhibited', 'NegReg', (80, 89))	('CDK6', 'Gene', (33, 37))
542809	29285837	Interestingly, we first found that HL156A-mediated apoptotic cell death was possibly associated with promotion of intracellular oxidative stress.	('promotion', 'PosReg', (101, 110))	('HL156A', 'CellLine', 'CVCL:2492', (35, 41))	('intracellular oxidative stress', 'MPA', (114, 144))	('oxidative stress', 'Phenotype', 'HP:0025464', (128, 144))	('apoptotic cell death', 'CPA', (51, 71))	('HL156A-mediated', 'Var', (35, 50))
542810	29285837	Consistent with previous reports regarding the relationship between the anticancer potency of metformin and the generation of ROS,30 our results showed that treatment with HL156A led to a reduction in mitochondrial membrane potential as well as an increase in ROS production in a time- and dose-dependent way.	('HL156A', 'Var', (172, 178))	('metformin', 'Chemical', 'MESH:D008687', (94, 103))	('HL156A', 'CellLine', 'CVCL:2492', (172, 178))	('increase', 'PosReg', (248, 256))	('ROS', 'Chemical', 'MESH:D017382', (260, 263))	('ROS', 'Chemical', 'MESH:D017382', (126, 129))	('mitochondrial membrane potential', 'MPA', (201, 233))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('increase in ROS production', 'Phenotype', 'HP:0025464', (248, 274))	('reduction', 'NegReg', (188, 197))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))	('ROS production', 'MPA', (260, 274))
542812	29285837	The imbalance between excessive ROS production and SOD-1 depletion may cause oxidative stress for oral cancer cells.	('depletion', 'NegReg', (57, 66))	('cause', 'Reg', (71, 76))	('oral cancer', 'Disease', 'MESH:D009062', (98, 109))	('SOD-1', 'Gene', '6647', (51, 56))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('oxidative stress', 'Phenotype', 'HP:0025464', (77, 93))	('oral cancer', 'Disease', (98, 109))	('SOD-1', 'Gene', (51, 56))	('oxidative stress', 'MPA', (77, 93))	('imbalance', 'Var', (4, 13))	('ROS', 'Chemical', 'MESH:D017382', (32, 35))	('excessive ROS production', 'Phenotype', 'HP:0025464', (22, 46))	('ROS production', 'MPA', (32, 46))	('imbalance', 'Phenotype', 'HP:0002172', (4, 13))
542813	29285837	This, combined with the reduction in membrane potential, resulted in the release of pro-apoptotic factors, such as cytochrome c, and the stimulation of caspases, which ultimately ends in apoptosis.17 Our study showed that HL156A gradually increased cell apoptosis, as evidenced by the increased activity of caspase-3, -7, -9, and poly (ADP-ribose) polymerase (PARP).	('cell apoptosis', 'CPA', (249, 263))	('caspases', 'Gene', '842', (152, 160))	('increased', 'PosReg', (285, 294))	('cytochrome c', 'Gene', (115, 127))	('PARP', 'Gene', (360, 364))	('cytochrome c', 'Gene', '54205', (115, 127))	('increased', 'PosReg', (239, 248))	('HL156A', 'Var', (222, 228))	('HL156A', 'CellLine', 'CVCL:2492', (222, 228))	('PARP', 'Gene', '142', (360, 364))	('activity', 'MPA', (295, 303))	('caspase-3, -7, -9, and poly (ADP-ribose) polymerase', 'Gene', '142;836;840;842', (307, 358))	('caspases', 'Gene', (152, 160))
542814	29285837	Another important point is that HL156A exerted more potent inhibitory effects on the migration of oral cancer cells than metformin.	('oral cancer', 'Disease', 'MESH:D009062', (98, 109))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('oral cancer', 'Disease', (98, 109))	('inhibitory effects', 'NegReg', (59, 77))	('HL156A', 'Var', (32, 38))	('HL156A', 'CellLine', 'CVCL:2492', (32, 38))	('metformin', 'Chemical', 'MESH:D008687', (121, 130))
542816	29285837	We also detected down-regulation of MMP-2 and MMP-9 protein levels in a time-dependent way following HL156A treatment.	('MMP-9', 'Gene', '4318', (46, 51))	('MMP-2', 'Gene', '4313', (36, 41))	('MMP-9', 'Gene', (46, 51))	('HL156A', 'Var', (101, 107))	('HL156A', 'CellLine', 'CVCL:2492', (101, 107))	('down-regulation', 'NegReg', (17, 32))	('MMP-2', 'Gene', (36, 41))
542817	29285837	A previous study showed that anticancer drugs markedly suppressed migration and invasion in malignant cancer cells and HUVEC, and the effect was partially MMP-dependent.20, 21, 31 Our results showed that HL156A is involved in the inhibition of FaDu and YD-10B cell migration through their ability to breakdown the extracellular matrix, especially MMP-2 and MMP-9.	('MMP-9', 'Gene', '4318', (357, 362))	('cancer', 'Disease', (33, 39))	('MMP-9', 'Gene', (357, 362))	('FaDu', 'Chemical', '-', (244, 248))	('HL156A', 'CellLine', 'CVCL:2492', (204, 210))	('MMP', 'Gene', (347, 350))	('MMP', 'Gene', (155, 158))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('MMP', 'Gene', '4313;4318', (155, 158))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('MMP', 'Gene', '4313;4318', (347, 350))	('YD-10B', 'Chemical', '-', (253, 259))	('breakdown', 'MPA', (300, 309))	('inhibition', 'NegReg', (230, 240))	('MMP-2', 'Gene', (347, 352))	('malignant cancer', 'Disease', 'MESH:D009369', (92, 108))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('cancer', 'Disease', (102, 108))	('HL156A', 'Var', (204, 210))	('FaDu', 'CPA', (244, 248))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('malignant cancer', 'Disease', (92, 108))	('MMP', 'Gene', (357, 360))	('MMP', 'Gene', '4313;4318', (357, 360))	('MMP-2', 'Gene', '4313', (347, 352))
542819	29285837	mTOR plays a major role in carcinogenesis, and activation of this pathway is associated with cancer progression.34 In the present study, HL156A was involved in mediating the antiproliferation effect through inhibiting the IGF/AKT/mTOR/p70S6K pathway in FaDu and YD-10B cells.	('YD-10B', 'Chemical', '-', (262, 268))	('HL156A', 'Var', (137, 143))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('p70S6K', 'Gene', '6198', (235, 241))	('antiproliferation', 'CPA', (174, 191))	('carcinogenesis', 'Disease', (27, 41))	('mTOR', 'Gene', (230, 234))	('mTOR', 'Gene', (0, 4))	('AKT', 'Gene', (226, 229))	('carcinogenesis', 'Disease', 'MESH:D063646', (27, 41))	('mTOR', 'Gene', '2475', (0, 4))	('mTOR', 'Gene', '2475', (230, 234))	('HL156A', 'CellLine', 'CVCL:2492', (137, 143))	('inhibiting', 'NegReg', (207, 217))	('cancer', 'Disease', (93, 99))	('p70S6K', 'Gene', (235, 241))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('AKT', 'Gene', '207', (226, 229))	('FaDu', 'Chemical', '-', (253, 257))
542820	29285837	In addition, HL156A blocked phosphorylation of the AKT substrate glycogen synthase kinase 3b and ERK1/2.	('HL156A', 'CellLine', 'CVCL:2492', (13, 19))	('AKT', 'Gene', (51, 54))	('ERK1/2', 'Gene', (97, 103))	('phosphorylation', 'MPA', (28, 43))	('ERK1/2', 'Gene', '5595;5594', (97, 103))	('blocked', 'NegReg', (20, 27))	('AKT', 'Gene', '207', (51, 54))	('HL156A', 'Var', (13, 19))
542822	29285837	Our results show that the effects of HL156A were partially induced by inhibiting these pathways, IGF/AKT/mTOR and/or AKT/ERK.	('ERK', 'Gene', '5594', (121, 124))	('AKT', 'Gene', '207', (117, 120))	('ERK', 'Gene', (121, 124))	('AKT', 'Gene', '207', (101, 104))	('AKT', 'Gene', (117, 120))	('AKT', 'Gene', (101, 104))	('HL156A', 'Var', (37, 43))	('mTOR', 'Gene', (105, 109))	('inhibiting', 'NegReg', (70, 80))	('mTOR', 'Gene', '2475', (105, 109))	('HL156A', 'CellLine', 'CVCL:2492', (37, 43))
542823	29285837	Herein, we also found that HL156A importantly induced activation of AMPK by phosphorylation together with suppression of NF-kappaB p65 in FaDu and YD-10B cells.	('HL156A', 'CellLine', 'CVCL:2492', (27, 33))	('NF-kappaB p65', 'Gene', (121, 134))	('AMPK', 'Gene', '5562', (68, 72))	('HL156A', 'Var', (27, 33))	('AMPK', 'Gene', (68, 72))	('NF-kappaB p65', 'Gene', '5970', (121, 134))	('FaDu', 'Chemical', '-', (138, 142))	('activation', 'PosReg', (54, 64))	('suppression', 'NegReg', (106, 117))	('YD-10B', 'Chemical', '-', (147, 153))
542824	29285837	A number of studies have shown indirect suppression of AMPK on NF-kappaB signaling by its downstream mediators, namely SIRT1, the Forkhead box O (FoxO) family, and peroxisome proliferator-activated receptor gamma co-activator 1alpha (PGC-1alpha).36 The HL156A-mediated decrease in NF-kappaB p65 phosphorylation may be accompanied by AMPK activation.	('NF-kappaB p65', 'Gene', '5970', (281, 294))	('NF-kappaB', 'Gene', '4790', (281, 290))	('SIRT1', 'Gene', '23411', (119, 124))	('peroxisome proliferator-activated receptor gamma co-activator 1alpha', 'Gene', '10891', (164, 232))	('NF-kappaB', 'Gene', '4790', (63, 72))	('NF-kappaB', 'Gene', (281, 290))	('HL156A', 'CellLine', 'CVCL:2492', (253, 259))	('HL156A-mediated', 'Var', (253, 268))	('AMPK', 'Gene', '5562', (333, 337))	('AMPK', 'Gene', '5562', (55, 59))	('AMPK', 'Gene', (333, 337))	('SIRT1', 'Gene', (119, 124))	('PGC-1alpha', 'Gene', (234, 244))	('NF-kappaB', 'Gene', (63, 72))	('PGC-1alpha', 'Gene', '10891', (234, 244))	('NF-kappaB p65', 'Gene', (281, 294))	('AMPK', 'Gene', (55, 59))	('decrease', 'NegReg', (269, 277))
542825	29285837	These results may suggest a role for HL156A in inhibiting the activation of NF-kappaB as well as in inhibition of the expression of proteins/cytokines that regulate inflammation.	('NF-kappaB', 'Gene', (76, 85))	('inhibiting', 'NegReg', (47, 57))	('activation', 'MPA', (62, 72))	('HL156A', 'Var', (37, 43))	('HL156A', 'CellLine', 'CVCL:2492', (37, 43))	('proteins/cytokines', 'Protein', (132, 150))	('NF-kappaB', 'Gene', '4790', (76, 85))	('inflammation', 'Disease', 'MESH:D007249', (165, 177))	('expression of', 'MPA', (118, 131))	('inflammation', 'Disease', (165, 177))	('inhibition', 'NegReg', (100, 110))
542827	29285837	A recent study showed that HL156A in combination with the chemotherapeutic agent temozolomide (TMZ) inhibited the invasive properties of glioblastoma and increased the survival rate in a xenograft mouse model.13 In our study, consistent with this, HL156A significantly reduced the growth of mouse oral squamous cell carcinoma AT84 xenograft tumors.	('temozolomide', 'Chemical', 'MESH:D000077204', (81, 93))	('HL156A', 'CellLine', 'CVCL:2492', (27, 33))	('carcinoma', 'Phenotype', 'HP:0030731', (316, 325))	('glioblastoma', 'Disease', (137, 149))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (302, 325))	('tumor', 'Phenotype', 'HP:0002664', (341, 346))	('reduced', 'NegReg', (269, 276))	('HL156A', 'Var', (248, 254))	('oral squamous cell carcinoma AT84 xenograft tumors', 'Disease', (297, 347))	('HL156A', 'CellLine', 'CVCL:2492', (248, 254))	('growth', 'MPA', (281, 287))	('oral squamous cell carcinoma AT84 xenograft tumors', 'Disease', 'MESH:D002294', (297, 347))	('glioblastoma', 'Disease', 'MESH:D005909', (137, 149))	('tumors', 'Phenotype', 'HP:0002664', (341, 347))	('TMZ', 'Chemical', 'MESH:D000077204', (95, 98))	('glioblastoma', 'Phenotype', 'HP:0012174', (137, 149))	('mouse', 'Species', '10090', (197, 202))	('mouse', 'Species', '10090', (291, 296))
542829	29285837	In contrast, p-AMPK expression was stronger in HL156A-treated tumor tissues.	('AMPK', 'Gene', '5562', (15, 19))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('AMPK', 'Gene', (15, 19))	('tumor', 'Disease', (62, 67))	('stronger', 'PosReg', (35, 43))	('HL156A', 'CellLine', 'CVCL:2492', (47, 53))	('HL156A-treated', 'Var', (47, 61))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
542830	29285837	Overall, our results showed that induction of apoptosis by HL156A may be associated with inhibition of cell proliferation through decreasing the mitochondrial membrane potential or IGF-1/AKT/mTOR signaling or inducing AMPK signaling in FaDu and YD-10B cells.	('AKT', 'Gene', '207', (187, 190))	('inducing', 'Reg', (209, 217))	('mitochondrial membrane potential', 'MPA', (145, 177))	('AMPK', 'Gene', (218, 222))	('AMPK', 'Gene', '5562', (218, 222))	('HL156A', 'CellLine', 'CVCL:2492', (59, 65))	('mTOR', 'Gene', (191, 195))	('HL156A', 'Var', (59, 65))	('mTOR', 'Gene', '2475', (191, 195))	('decreasing', 'NegReg', (130, 140))	('cell proliferation', 'CPA', (103, 121))	('AKT', 'Gene', (187, 190))	('inhibition', 'NegReg', (89, 99))	('YD-10B', 'Chemical', '-', (245, 251))	('FaDu', 'Chemical', '-', (236, 240))
542831	29285837	Collectively, the results of the present study suggest that HL156A may have the potential to arrest the progression of oral cancer through suppression of the IGF/AKT/mTOR pathway or MMP-2 and MMP-9 pathways.	('oral cancer', 'Disease', 'MESH:D009062', (119, 130))	('AKT', 'Gene', '207', (162, 165))	('MMP-9', 'Gene', (192, 197))	('arrest', 'Disease', 'MESH:D006323', (93, 99))	('mTOR', 'Gene', (166, 170))	('oral cancer', 'Disease', (119, 130))	('mTOR', 'Gene', '2475', (166, 170))	('MMP-2', 'Gene', (182, 187))	('AKT', 'Gene', (162, 165))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('suppression', 'NegReg', (139, 150))	('arrest', 'Disease', (93, 99))	('HL156A', 'Var', (60, 66))	('HL156A', 'CellLine', 'CVCL:2492', (60, 66))	('MMP-2', 'Gene', '4313', (182, 187))	('MMP-9', 'Gene', '4318', (192, 197))
542833	29285837	In conclusion, the results clarify the beneficial effect of HL156A in reducing oral cancer development.	('oral cancer', 'Disease', 'MESH:D009062', (79, 90))	('oral cancer', 'Disease', (79, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('reducing', 'NegReg', (70, 78))	('HL156A', 'Var', (60, 66))	('HL156A', 'CellLine', 'CVCL:2492', (60, 66))
542834	26790612	Exome sequencing reveals recurrent REV3L mutations in cisplatin-resistant squamous cell carcinoma of head and neck Dacomitinib, an irreversible pan-HER inhibitor, had shown modest clinical activity in squamous cell carcinoma of head and neck (SCCHN) patients.	('mutations', 'Var', (41, 50))	('Dacomitinib', 'Chemical', 'MESH:C525726', (115, 126))	('carcinoma of head and neck', 'Phenotype', 'HP:0012288', (215, 241))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (201, 224))	('patients', 'Species', '9606', (250, 258))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (74, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('REV3L', 'Gene', (35, 40))	('cisplatin', 'Chemical', 'MESH:D002945', (54, 63))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (201, 224))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (74, 97))	('squamous cell carcinoma', 'Disease', (201, 224))	('carcinoma', 'Phenotype', 'HP:0030731', (215, 224))	('REV3L', 'Gene', '5980', (35, 40))	('squamous cell carcinoma', 'Disease', (74, 97))	('carcinoma of head and neck', 'Phenotype', 'HP:0012288', (88, 114))
542836	26790612	To characterize the genetic landscape of cisplatin-treated SCCHN genomes and identify potential predictive biomarkers for dacomitinib sensitivity, we performed whole exome sequencing on 18 cisplatin-resistant metastatic SCCHN tumors and their matched germline DNA.	('tumors', 'Phenotype', 'HP:0002664', (226, 232))	('SCCHN tumors', 'Disease', 'MESH:D009369', (220, 232))	('cisplatin', 'Chemical', 'MESH:D002945', (41, 50))	('dacomitinib', 'Chemical', 'MESH:C525726', (122, 133))	('SCCHN tumors', 'Disease', (220, 232))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))	('cisplatin-resistant', 'Var', (189, 208))	('cisplatin', 'Chemical', 'MESH:D002945', (189, 198))
542838	26790612	Cisplatin-treated SCCHN genomes uniquely exhibited a novel mutational signature characterized by C:G to A:T transversions at CCR sequence contexts that may have arisen due to error-prone translesional synthesis.	('exhibited', 'Reg', (41, 50))	('Cisplatin', 'Chemical', 'MESH:D002945', (0, 9))	('C:G to', 'Var', (97, 103))
542841	26790612	Our data suggest that the 'platinum' mutational signature and inactivation of REV3L may inform treatment options in patients of recurrent SCCHN.	('REV3L', 'Gene', '5980', (78, 83))	('inform', 'Reg', (88, 94))	('patients', 'Species', '9606', (116, 124))	('inactivation', 'Var', (62, 74))	('mutational', 'Var', (37, 47))	('REV3L', 'Gene', (78, 83))	('platinum', 'Chemical', 'MESH:D010984', (27, 35))
542848	26790612	Therefore, there is a pressing need to identify molecular predictors to evaluate the efficacy of EGFR inhibitors in order to maximize the clinical benefit of EGFR inhibitors.	('EGFR', 'Gene', (158, 162))	('EGFR', 'Gene', '1956', (97, 101))	('inhibitors', 'Var', (102, 112))	('EGFR', 'Gene', (97, 101))	('EGFR', 'Gene', '1956', (158, 162))
542849	26790612	Cancer genome sequencing has revealed that specific mutagens or mutagenic processes produce characteristic patterns of somatic mutations, called mutation signatures, in the cancer genome.	('cancer', 'Disease', 'MESH:D009369', (173, 179))	('cancer', 'Disease', (173, 179))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('mutations', 'Var', (127, 136))
542851	26790612	DNA damage and the resulting mutations, if not repaired by DNA repair mechanisms, accumulate during cisplatin-based chemotherapy and may have impact on tumor biology and drug resistance.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('cisplatin', 'Chemical', 'MESH:D002945', (100, 109))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('mutations', 'Var', (29, 38))	('tumor', 'Disease', (152, 157))	('have impact', 'Reg', (137, 148))	('drug resistance', 'CPA', (170, 185))	('drug resistance', 'Phenotype', 'HP:0020174', (170, 185))	('accumulate', 'PosReg', (82, 92))
542865	26790612	The majority (76.1%) of the predicted SNVs are found in less than 20% of all the tumor sequencing reads, including most (91.9%) of the cisplatin-associated C > A transversions (Fig.	('C > A transversions', 'Var', (156, 175))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('cisplatin', 'Chemical', 'MESH:D002945', (135, 144))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Disease', (81, 86))
542867	26790612	This signature is characterized by the prominence of C > A mutations mainly occurring on CpCpA and CpCpG trinucleotide contexts.	('C > A', 'Gene', (53, 58))	('mutations', 'Var', (59, 68))	('trinucleotide', 'Chemical', '-', (105, 118))
542870	26790612	In addition, the substantial C >A mutation on CpC dinucleotides, especially those preceding purines, suggested the preferential misincorporation of adenine opposite the 5'G of the Pt-GpG adducts.	('purines', 'Chemical', 'MESH:D011687', (92, 99))	('C >A mutation', 'Var', (29, 42))	('misincorporation', 'MPA', (128, 144))	('adenine', 'Chemical', 'MESH:D000225', (148, 155))
542872	26790612	We therefore, proposed that the major substitution associated with cisplatin are TpGpG > TpTpG and CpGpG > CpTpG and this sequence preference may arise from activated error-prone translesion DNA replication activity on the DNA binding sites of cisplatin.	('CpGpG >', 'Var', (99, 106))	('TpGpG > TpTpG', 'Var', (81, 94))	('cisplatin', 'Chemical', 'MESH:D002945', (244, 253))	('cisplatin', 'Chemical', 'MESH:D002945', (67, 76))
542878	26790612	Applying the same procedure on the dacomitinib-sensitive patients (n = 7; Supplemetary Table S6) and dacomitinib-resistant patients (n = 11; Supplementary Figure S7) identified another two genes (REV3L and EPYC) to be frequently mutated in dacomitinib-sensitive patient but not in the overall cohort.	('patient', 'Species', '9606', (123, 130))	('REV3L', 'Gene', (196, 201))	('patient', 'Species', '9606', (57, 64))	('patients', 'Species', '9606', (57, 65))	('patients', 'Species', '9606', (123, 131))	('REV3L', 'Gene', '5980', (196, 201))	('dacomitinib', 'Chemical', 'MESH:C525726', (240, 251))	('mutated', 'Var', (229, 236))	('EPYC', 'Gene', '1833', (206, 210))	('dacomitinib', 'Chemical', 'MESH:C525726', (35, 46))	('patient', 'Species', '9606', (262, 269))	('dacomitinib', 'Chemical', 'MESH:C525726', (101, 112))	('EPYC', 'Gene', (206, 210))
542881	26790612	For the 26 somatic variants, only REV3L showed significant enrichment to dacomitinib-sensitive tumors (P = 0.04; Fisher's exact test; Fig.	('tumors', 'Disease', 'MESH:D009369', (95, 101))	('REV3L', 'Gene', (34, 39))	('dacomitinib-sensitive', 'MPA', (73, 94))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('REV3L', 'Gene', '5980', (34, 39))	('dacomitinib', 'Chemical', 'MESH:C525726', (73, 84))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('tumors', 'Disease', (95, 101))	('variants', 'Var', (19, 27))
542882	26790612	Most of identified REV3L mutations are apparently loss-of-functional events (one missense mutation and two frameshifting indels; Fig.	('REV3L', 'Gene', '5980', (19, 24))	('mutations', 'Var', (25, 34))	('frameshifting indels', 'Var', (107, 127))	('loss-of-functional', 'NegReg', (50, 68))	('REV3L', 'Gene', (19, 24))
542884	26790612	All three REV3L variants were not present in dbSNP135, 1000Genomes or the NIH-NHLBI6500 exome databases, indicating that these mutations may be pathogenic.	('REV3L', 'Gene', (10, 15))	('REV3L', 'Gene', '5980', (10, 15))	('dbSNP135', 'Chemical', '-', (45, 53))	('pathogenic', 'Reg', (144, 154))	('mutations', 'Var', (127, 136))	('variants', 'Var', (16, 24))
542886	26790612	We observed significant enrichment of mutations in REV3L (Fisher exact test, P = 0.02) and KRAS (Fisher exact test, P = 0.01) in our dataset compared to TCGA (Fig.	('REV3L', 'Gene', (51, 56))	('mutations', 'Var', (38, 47))	('REV3L', 'Gene', '5980', (51, 56))	('KRAS', 'Gene', (91, 95))	('KRAS', 'Gene', '3845', (91, 95))
542887	26790612	Notably, two cisplatin-resistant patients harboured the hotspot G12D KRAS mutation, an alteration that is rarely observed in treatment-naive SCCHN.	('KRAS', 'Gene', (69, 73))	('KRAS', 'Gene', '3845', (69, 73))	('patients', 'Species', '9606', (33, 41))	('G12D', 'Var', (64, 68))	('G12D', 'Mutation', 'rs121913529', (64, 68))	('cisplatin', 'Chemical', 'MESH:D002945', (13, 22))
542888	26790612	Consistent with this, we observed an additional REV3L frameshift indel in one dacomitinib-sensitive tumor (T15) at a very low frequency (<5%).	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('dacomitinib', 'Chemical', 'MESH:C525726', (78, 89))	('REV3L', 'Gene', (48, 53))	('tumor', 'Disease', (100, 105))	('REV3L', 'Gene', '5980', (48, 53))	('frameshift indel', 'Var', (54, 70))	('tumor', 'Disease', 'MESH:D009369', (100, 105))
542889	26790612	Strongly supporting our hypothesis, all three REV3L mutations were confirmed in cisplatin-treated samples but not in cisplatin-naive samples using bi-directional Sanger sequencing (Supplementary Figure S2).	('mutations', 'Var', (52, 61))	('cisplatin', 'Chemical', 'MESH:D002945', (117, 126))	('cisplatin', 'Chemical', 'MESH:D002945', (80, 89))	('REV3L', 'Gene', (46, 51))	('REV3L', 'Gene', '5980', (46, 51))	('confirmed', 'Reg', (67, 76))
542890	26790612	The final REV3L mutations were predicted at below Sanger's detection level and we are unable to confirm this mutation.	('REV3L', 'Gene', (10, 15))	('REV3L', 'Gene', '5980', (10, 15))	('mutations', 'Var', (16, 25))
542891	26790612	Inactivation of REV3L induces accumulation of persistent DNA damages containing unrepairable DNA double strand breaks (DSBs) in cancer cells, leading to suppression of tumor cell growth and induction of cellular senescence.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('accumulation', 'PosReg', (30, 42))	('tumor', 'Disease', (168, 173))	('suppression', 'NegReg', (153, 164))	('induction', 'Reg', (190, 199))	('REV3L', 'Gene', '5980', (16, 21))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('cellular senescence', 'CPA', (203, 222))	('REV3L', 'Gene', (16, 21))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('Inactivation', 'Var', (0, 12))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))	('cancer', 'Disease', (128, 134))
542892	26790612	EGFR inhibitors induce cell cycle arrest and cellular senescence in tumor cells sustaining DNA DSBs by suppressing DNA repair capacity.	('tumor', 'Disease', (68, 73))	('arrest', 'Disease', (34, 40))	('EGFR', 'Gene', (0, 4))	('inhibitors', 'Var', (5, 15))	('cellular senescence', 'CPA', (45, 64))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('DNA repair capacity', 'MPA', (115, 134))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('EGFR', 'Gene', '1956', (0, 4))	('arrest', 'Disease', 'MESH:D006323', (34, 40))	('suppressing', 'NegReg', (103, 114))
542893	26790612	Therefore, we hypothesize that there is a favourable antitumor interaction between REV3L inactivation and dacomitinib via accumulation of unrepairable DNA DSBs.	('accumulation', 'PosReg', (122, 134))	('inactivation', 'Var', (89, 101))	('REV3L', 'Gene', (83, 88))	('dacomitinib', 'Chemical', 'MESH:C525726', (106, 117))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('REV3L', 'Gene', '5980', (83, 88))	('tumor', 'Disease', (57, 62))
542897	26790612	Next, we evaluated whether REV3L depletion may enhance sensitivity to dacomitinib in FADU and MSKQLL2 cells.	('sensitivity to dacomitinib', 'MPA', (55, 81))	('enhance', 'PosReg', (47, 54))	('depletion', 'Var', (33, 42))	('REV3L', 'Gene', (27, 32))	('dacomitinib', 'Chemical', 'MESH:C525726', (70, 81))	('REV3L', 'Gene', '5980', (27, 32))	('MSKQLL2', 'CellLine', 'CVCL:6991', (94, 101))
542901	26790612	In contrast, synergistic antitumor effects were not observed by the combined treatment of siREV3L with paclitaxel or cisplatin, suggesting that loss of REV3L function may contribute to selective sensitization of tumor cells to dacomitinib (Supplementary Figure S5).	('loss', 'Var', (144, 148))	('REV3L', 'Gene', '5980', (92, 97))	('paclitaxel', 'Chemical', 'MESH:D017239', (103, 113))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('cisplatin', 'Chemical', 'MESH:D002945', (117, 126))	('contribute', 'Reg', (171, 181))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('dacomitinib', 'Chemical', 'MESH:C525726', (227, 238))	('REV3L', 'Gene', (152, 157))	('tumor', 'Disease', 'MESH:D009369', (212, 217))	('REV3L', 'Gene', '5980', (152, 157))	('tumor', 'Disease', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('REV3L', 'Gene', (92, 97))	('sensitization', 'MPA', (195, 208))	('tumor', 'Disease', (212, 217))
542902	26790612	Together, these data suggest that REV3L inactivation enhance response to dacomitinib by inducing cell cycle arrest and cellular senescence.	('response to dacomitinib', 'MPA', (61, 84))	('REV3L', 'Gene', (34, 39))	('cellular senescence', 'CPA', (119, 138))	('arrest', 'Disease', 'MESH:D006323', (108, 114))	('inducing', 'PosReg', (88, 96))	('REV3L', 'Gene', '5980', (34, 39))	('dacomitinib', 'Chemical', 'MESH:C525726', (73, 84))	('arrest', 'Disease', (108, 114))	('enhance', 'PosReg', (53, 60))	('inactivation', 'Var', (40, 52))
542904	26790612	EGFR inhibitors have been reported to attenuate HR repair of DNA DSBs, resulting in persistent DNA damage.	('EGFR', 'Gene', (0, 4))	('attenuate', 'NegReg', (38, 47))	('DNA damage', 'MPA', (95, 105))	('inhibitors', 'Var', (5, 15))	('HR repair', 'CPA', (48, 57))	('DNA DSBs', 'Disease', (61, 69))	('EGFR', 'Gene', '1956', (0, 4))
542915	26790612	Extensive exome-wide studies in SCCHN have been reported, uncovering recurrent somatic mutations in TP53 (47-72%), NOTCH1 (14-19%), CDKN2A (9-22%), PIK3CA (6-21%), FBXW7 (5%), HRAS (4-8%) and CASP8 (8%).	('CDKN2A', 'Gene', (132, 138))	('NOTCH1', 'Gene', (115, 121))	('PIK3CA', 'Gene', '5290', (148, 154))	('TP53', 'Gene', '7157', (100, 104))	('CDKN2A', 'Gene', '1029', (132, 138))	('FBXW7', 'Gene', '55294', (164, 169))	('HRAS', 'Gene', '3265', (176, 180))	('TP53', 'Gene', (100, 104))	('CASP8', 'Gene', (192, 197))	('CASP8', 'Gene', '841', (192, 197))	('FBXW7', 'Gene', (164, 169))	('HRAS', 'Gene', (176, 180))	('PIK3CA', 'Gene', (148, 154))	('NOTCH1', 'Gene', '4851', (115, 121))	('mutations', 'Var', (87, 96))
542920	26790612	First, the 'platinum' signature is prominently observed in cisplatin-resistant genomes, but not in treatment-naive SCCHN genomes.	('cisplatin', 'Chemical', 'MESH:D002945', (59, 68))	('cisplatin-resistant', 'Var', (59, 78))	("'platinum", 'MPA', (11, 20))	('platinum', 'Chemical', 'MESH:D010984', (12, 20))
542924	26790612	Our study also suggests that REV3L may be a novel driver gene in SCCHN, the mutations of which are selected during cisplatin treatment and these mutations confer sensitivity to dacomitinib treatment.	('SCCHN', 'Disease', (65, 70))	('mutations', 'Var', (76, 85))	('cisplatin', 'Chemical', 'MESH:D002945', (115, 124))	('mutations', 'Var', (145, 154))	('REV3L', 'Gene', (29, 34))	('dacomitinib', 'Chemical', 'MESH:C525726', (177, 188))	('REV3L', 'Gene', '5980', (29, 34))
542927	26790612	Second, we independently confirmed all three REV3L mutations using Sanger sequencing in cisplatin-treated tumor samples but not in the cisplatin-naive samples from the same patients.	('mutations', 'Var', (51, 60))	('patients', 'Species', '9606', (173, 181))	('REV3L', 'Gene', (45, 50))	('cisplatin', 'Chemical', 'MESH:D002945', (88, 97))	('cisplatin', 'Chemical', 'MESH:D002945', (135, 144))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('REV3L', 'Gene', '5980', (45, 50))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Disease', (106, 111))
542928	26790612	This suggests that REV3L mutations or clonal selection is a consequence of cisplatin treatment.	('REV3L', 'Gene', '5980', (19, 24))	('cisplatin', 'Chemical', 'MESH:D002945', (75, 84))	('mutations', 'Var', (25, 34))	('REV3L', 'Gene', (19, 24))
542929	26790612	Third, we observed a significant increase in sensitivity to dacomitinib in two dacomitinib-resistant cell lines upon REV3L silencing.	('dacomitinib', 'Chemical', 'MESH:C525726', (60, 71))	('sensitivity', 'MPA', (45, 56))	('REV3L', 'Gene', (117, 122))	('increase', 'PosReg', (33, 41))	('dacomitinib', 'Chemical', 'MESH:C525726', (79, 90))	('REV3L', 'Gene', '5980', (117, 122))	('silencing', 'Var', (123, 132))
542930	26790612	Thus, REV3L mutational status may be a promising predictive biomarker for dacomitinib in SCCHN.	('SCCHN', 'Disease', (89, 94))	('dacomitinib', 'Chemical', 'MESH:C525726', (74, 85))	('REV3L', 'Gene', '5980', (6, 11))	('mutational', 'Var', (12, 22))	('REV3L', 'Gene', (6, 11))
542933	26790612	Therefore, somatic inactivation of REV3L may result in the accumulation of unrepairable DNA DSBs, which makes tumor cells vulnerable to dacomitinib-mediated inhibition of HR repair.	('dacomitinib', 'Chemical', 'MESH:C525726', (136, 147))	('accumulation', 'PosReg', (59, 71))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('REV3L', 'Gene', (35, 40))	('REV3L', 'Gene', '5980', (35, 40))	('inactivation', 'Var', (19, 31))	('result in', 'Reg', (45, 54))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
542934	26790612	Indeed, our functional assays indicate that REV3L knockdown significantly increased the DNA DSBs, suggesting the loss of TLS.	('TLS', 'Gene', (121, 124))	('REV3L', 'Gene', '5980', (44, 49))	('DNA DSBs', 'Disease', (88, 96))	('knockdown', 'Var', (50, 59))	('TLS', 'Gene', '2521', (121, 124))	('loss', 'NegReg', (113, 117))	('increased', 'PosReg', (74, 83))	('REV3L', 'Gene', (44, 49))
542943	26790612	We suggest a potential utility of this signature and provide a proof of principle that sequencing of previously treated tumor samples may uncover treatment-induced driver mutations as well as provide additional molecular targets for cancer therapy.	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('cancer', 'Disease', 'MESH:D009369', (233, 239))	('cancer', 'Disease', (233, 239))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('mutations', 'Var', (171, 180))	('tumor', 'Disease', (120, 125))
542949	26790612	In this study, we define mutations as somatic base substitutions (point mutations) and indels that are present in the tumor genome but absent in the matched normal genomes.	('indels', 'Var', (87, 93))	('mutations', 'Var', (25, 34))	('tumor', 'Disease', 'MESH:D009369', (118, 123))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('tumor', 'Disease', (118, 123))
542955	26790612	the six mutation categories of base substitutions (C >A, C >G, C >T, T >A, T >C, and T >G) were further classified into 96 trinucleotides taking into consideration of 5' and 3' nucleotides immediate to the mutated base.	('T >G', 'Var', (85, 89))	('T >C', 'Var', (75, 79))	('T >A', 'Var', (69, 73))	('trinucleotides', 'Chemical', '-', (123, 137))	('C >G', 'Var', (57, 61))	('C >A', 'Var', (51, 55))	('C >T', 'Var', (63, 67))
542975	26790612	Exome sequencing reveals recurrent REV3L mutations in cisplatin-resistant squamous cell carcinoma of head and neck.	('mutations', 'Var', (41, 50))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (74, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('cisplatin', 'Chemical', 'MESH:D002945', (54, 63))	('REV3L', 'Gene', (35, 40))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (74, 97))	('REV3L', 'Gene', '5980', (35, 40))	('squamous cell carcinoma', 'Disease', (74, 97))	('carcinoma of head and neck', 'Phenotype', 'HP:0012288', (88, 114))
542978	25406731	However, the distribution in tissue and role of CYP2C8, 2C9, 2J2 and sEH in human breast carcinogenesis remains uncertain.	('breast carcinogenesis', 'Disease', (82, 103))	('sEH', 'Gene', (69, 72))	('breast carcinogenesis', 'Disease', 'MESH:D063646', (82, 103))	('2C9', 'Gene', (56, 59))	('CYP2C8', 'Var', (48, 54))	('human', 'Species', '9606', (76, 81))	('2J2', 'Gene', (61, 64))	('sEH', 'Gene', '2053', (69, 72))
542980	25406731	The level of 14,15-EET/14,15-DHET in BC patients was detected by ELISA; the expression and distribution of CYP2C8, 2C9, 2J2 and sEH was determined by quantitative RT-PCR and immunohistochemical staining; and cell proliferation and migration was analyzed by MTT and transwell assays, respectively.	('sEH', 'Gene', '2053', (128, 131))	('patients', 'Species', '9606', (40, 48))	('14,15-EET', 'Chemical', 'MESH:C046782', (13, 22))	('sEH', 'Gene', (128, 131))	('MTT', 'Chemical', 'MESH:C070243', (257, 260))	('2C9', 'Gene', (115, 118))	('CYP2C8', 'Var', (107, 113))	('14,15-DHET', 'Chemical', 'MESH:C107016', (23, 33))	('BC', 'Phenotype', 'HP:0003002', (37, 39))
542983	25406731	Furthermore, CYP2C8 and 2C9 protein levels positively correlated with Ki67 status, and CYP2J2 levels positively correlated with histological grade and tumor size.	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('CYP2J2', 'Gene', '1573', (87, 93))	('correlated', 'Reg', (112, 122))	('tumor', 'Disease', (151, 156))	('CYP2C8 and 2C9', 'Gene', '1558;1559', (13, 27))	('correlated', 'Reg', (54, 64))	('CYP2J2', 'Gene', (87, 93))	('Ki67', 'Chemical', '-', (70, 74))	('Ki67 status', 'Var', (70, 81))	('tumor', 'Disease', 'MESH:D009369', (151, 156))	('histological grade', 'CPA', (128, 146))
542985	25406731	In MDA-MB-231 cells, siRNA knockdown of CYP2C8, 2C9 or 2J2 reduced cell proliferation, by 24.5%, 29.13%, or 22.7% and decreased cell migration by 49.1%, 44.9%, and 50.9%, respectively.	('2J2', 'Gene', (55, 58))	('reduced', 'NegReg', (59, 66))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (3, 13))	('CYP2C8', 'Var', (40, 46))	('2C9', 'Gene', (48, 51))	('cell migration', 'CPA', (128, 142))	('decreased', 'NegReg', (118, 127))	('cell proliferation', 'CPA', (67, 85))
542986	25406731	Similarly, with adenovirus overexpression of sEH, both cell proliferation and migration rates were reduced by 31.4% and 45.8%, respectively.	('sEH', 'Gene', (45, 48))	('sEH', 'Gene', '2053', (45, 48))	('adenovirus', 'Var', (16, 26))	('cell proliferation', 'CPA', (55, 73))	('migration rates', 'CPA', (78, 93))	('overexpression', 'PosReg', (27, 41))	('reduced', 'NegReg', (99, 106))
542994	25406731	In humans, CYP2C8, 2C9 and 2J2 subfamily members participate in the synthesis of EETs, which are then quickly metabolized by soluble epoxide hydrolase (sEH) into their respective diols in most tissues.	('sEH', 'Gene', '2053', (152, 155))	('EETs', 'Chemical', '-', (81, 85))	('sEH', 'Gene', (152, 155))	('humans', 'Species', '9606', (3, 9))	('CYP2C8', 'Var', (11, 17))	('2C9', 'Gene', (19, 22))	('soluble epoxide hydrolase', 'Gene', (125, 150))	('soluble epoxide hydrolase', 'Gene', '2053', (125, 150))	('2J2', 'Gene', (27, 30))	('participate', 'Reg', (49, 60))
542995	25406731	Thus, the balance of CYP2C8, 2C9, and 2J2, as well as sEH expression is responsible for sustaining EET concentration.	('sEH', 'Gene', '2053', (54, 57))	('sustaining', 'PosReg', (88, 98))	('EET concentration', 'MPA', (99, 116))	('CYP2C8', 'Var', (21, 27))	('sEH', 'Gene', (54, 57))
542996	25406731	CYP2C8, 2C9, 2J2 and sEH expression has been detected in several tumor tissues and cells, which supports a role for EETs in cancer.	('cancer', 'Disease', (124, 130))	('sEH', 'Gene', (21, 24))	('EETs', 'Chemical', '-', (116, 120))	('tumor', 'Disease', (65, 70))	('2C9', 'Gene', (8, 11))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('CYP2C8', 'Var', (0, 6))	('sEH', 'Gene', '2053', (21, 24))	('2J2', 'Gene', (13, 16))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('cancer', 'Disease', 'MESH:D009369', (124, 130))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
543004	25406731	Although many studies have focused on EET synthesis and metabolic enzymes in several cancers, the characteristics and roles of EET isoforms such as CYP2C8, 2C9, and 2J2, and sEH in BC remains poorly understood.	('cancers', 'Disease', 'MESH:D009369', (85, 92))	('cancers', 'Phenotype', 'HP:0002664', (85, 92))	('sEH', 'Gene', '2053', (174, 177))	('cancers', 'Disease', (85, 92))	('BC', 'Phenotype', 'HP:0003002', (181, 183))	('CYP2C8', 'Var', (148, 154))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('sEH', 'Gene', (174, 177))
543006	25406731	We conducted a retrospective investigation of the level of EET and expression and distribution of CYP2C8, 2C9, and 2J2 and sEH in human BC tissue and adjacent noncancerous tissue.	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('2C9', 'Gene', (106, 109))	('cancer', 'Disease', (162, 168))	('BC', 'Phenotype', 'HP:0003002', (136, 138))	('sEH', 'Gene', '2053', (123, 126))	('2J2', 'Gene', (115, 118))	('CYP2C8', 'Var', (98, 104))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('sEH', 'Gene', (123, 126))	('human', 'Species', '9606', (130, 135))
543027	25406731	After culture for 24 hr at 50% to 60% density, cells were transfected with 40 mumol/L siRNA pools for CYP2C8, 2C9 or 2J2 by the Jet PEI method (Polyplus, San Marcos, CA) or infected with adenovirus sEH (Ad-sEH), a recombinant Ad expressing human-EPXH2.	('sEH', 'Gene', (206, 209))	('human', 'Species', '9606', (240, 245))	('CYP2C8', 'Var', (102, 108))	('sEH', 'Gene', '2053', (198, 201))	('sEH', 'Gene', '2053', (206, 209))	('sEH', 'Gene', (198, 201))
543029	25406731	Primers for CYP2C8, 2C9, 2J2, sEH and beta-actin were as we described previously.	('CYP2C8', 'Var', (12, 18))	('2C9', 'Var', (20, 23))	('sEH', 'Gene', '2053', (30, 33))	('beta-actin', 'Gene', '728378', (38, 48))	('beta-actin', 'Gene', (38, 48))	('sEH', 'Gene', (30, 33))
543038	25406731	The Mann-Whitney two-sample test was used to assess differences in 14,15-EET levels and mRNA expression of CYP2C8, 2C9, and 2J2, as well as sEH in BC and adjacent noncancerous tissue.	('sEH', 'Gene', (140, 143))	('cancer', 'Disease', (166, 172))	('14,15-EET', 'Chemical', 'MESH:C046782', (67, 76))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('mRNA expression', 'MPA', (88, 103))	('BC', 'Phenotype', 'HP:0003002', (147, 149))	('sEH', 'Gene', '2053', (140, 143))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('CYP2C8', 'Var', (107, 113))
543039	25406731	Spearman correlation was used to analyze the correlation of clinicopathological variables and CYP2C8, 2C9, and 2J2, as well as sEH protein expression.	('2J2', 'Gene', (111, 114))	('sEH', 'Gene', '2053', (127, 130))	('CYP2C8', 'Var', (94, 100))	('2C9', 'Gene', (102, 105))	('sEH', 'Gene', (127, 130))
543040	25406731	EETs and their synthetic and metabolic enzymes (CYP2C8, 2C9, 2J2 and sEH) promote angiogenesis, inflammation, and carcinogenesis.	('carcinogenesis', 'Disease', (114, 128))	('sEH', 'Gene', (69, 72))	('promote', 'PosReg', (74, 81))	('2C9', 'Gene', (56, 59))	('angiogenesis', 'CPA', (82, 94))	('EETs', 'Chemical', '-', (0, 4))	('CYP2C8', 'Var', (48, 54))	('sEH', 'Gene', '2053', (69, 72))	('inflammation', 'Disease', 'MESH:D007249', (96, 108))	('2J2', 'Gene', (61, 64))	('carcinogenesis', 'Disease', 'MESH:D063646', (114, 128))	('inflammation', 'Disease', (96, 108))
543051	25406731	To further investigate the functional role of CYP2C8, 2C9, and 2J2 and sEH in BC cells, we transfected CYP2C8, 2C9 and 2J2 siRNA into MDA-MB-231 cells.	('MDA-MB-231', 'CellLine', 'CVCL:0062', (134, 144))	('sEH', 'Gene', '2053', (71, 74))	('BC', 'Phenotype', 'HP:0003002', (78, 80))	('2C9', 'Var', (111, 114))	('CYP2C8', 'Var', (103, 109))	('sEH', 'Gene', (71, 74))
543056	25406731	Indeed, previous in vivo and in vitro studies, including ours, have shown that CYP2C8, 2C9, and 2JC promote cancer cell proliferation, migration, angiogenesis, survival and invasion in several types of cancer such as hepatocellular carcinoma, esophageal carcinoma, and malignant hematologic disease.	('survival', 'CPA', (160, 168))	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('invasion', 'CPA', (173, 181))	('hematologic disease', 'Phenotype', 'HP:0001871', (279, 298))	('hepatocellular carcinoma', 'Disease', (217, 241))	('migration', 'CPA', (135, 144))	('malignant hematologic disease', 'Disease', (269, 298))	('carcinoma', 'Phenotype', 'HP:0030731', (232, 241))	('CYP2C8', 'Var', (79, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (254, 263))	('cancer', 'Disease', 'MESH:D009369', (108, 114))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (243, 263))	('cancer', 'Disease', 'MESH:D009369', (202, 208))	('esophageal carcinoma', 'Disease', (243, 263))	('malignant hematologic disease', 'Disease', 'MESH:D019337', (269, 298))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (217, 241))	('promote', 'PosReg', (100, 107))	('cancer', 'Disease', (108, 114))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (243, 263))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (217, 241))	('2C9', 'Var', (87, 90))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('2JC', 'Var', (96, 99))	('cancer', 'Disease', (202, 208))	('angiogenesis', 'CPA', (146, 158))
543057	25406731	In the present study, we find a high level of 14,15-EET with increasing CYP2C8, 2C9 and 2J2 expression, and decreasing sEH mRNA and protein expression in BC as compared with adjacent noncancerous tissue.	('cancer', 'Disease', 'MESH:D009369', (186, 192))	('increasing', 'PosReg', (61, 71))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('BC', 'Phenotype', 'HP:0003002', (154, 156))	('expression', 'MPA', (92, 102))	('2J2', 'Gene', (88, 91))	('sEH', 'Gene', '2053', (119, 122))	('2C9', 'Gene', (80, 83))	('sEH', 'Gene', (119, 122))	('decreasing', 'NegReg', (108, 118))	('CYP2C8', 'Var', (72, 78))	('cancer', 'Disease', (186, 192))	('14,15-EET', 'Chemical', 'MESH:C046782', (46, 55))
543058	25406731	We further show that knockdown of CYP2C8, 2C9 and 2J2 or overexpression of sEH inhibits the proliferation and migration of BC cells.	('inhibits', 'NegReg', (79, 87))	('2C9', 'Gene', (42, 45))	('sEH', 'Gene', '2053', (75, 78))	('BC', 'Phenotype', 'HP:0003002', (123, 125))	('CYP2C8', 'Var', (34, 40))	('2J2', 'Gene', (50, 53))	('sEH', 'Gene', (75, 78))
543060	25406731	However, recent studies have detected a sustained high level of EETs by upregulated CYP2C8, 2C9 and 2J2, or downregulated sEH in various cancers such as renal, lung, basal cell, bladder, ovarian, colon, and prostate cell carcinomas.	('colon', 'Disease', (196, 201))	('cancers', 'Phenotype', 'HP:0002664', (137, 144))	('renal', 'Disease', (153, 158))	('lung', 'Disease', (160, 164))	('cancers', 'Disease', (137, 144))	('ovarian', 'Disease', (187, 194))	('2C9', 'Gene', (92, 95))	('sEH', 'Gene', (122, 125))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('CYP2C8', 'Var', (84, 90))	('carcinoma', 'Phenotype', 'HP:0030731', (221, 230))	('bladder', 'Disease', (178, 185))	('prostate cell carcinomas', 'Disease', 'MESH:D011472', (207, 231))	('basal cell', 'Disease', (166, 176))	('prostate cell carcinomas', 'Disease', (207, 231))	('2J2', 'Gene', (100, 103))	('cancers', 'Disease', 'MESH:D009369', (137, 144))	('upregulated', 'PosReg', (72, 83))	('carcinomas', 'Phenotype', 'HP:0030731', (221, 231))	('sEH', 'Gene', '2053', (122, 125))	('EETs', 'Chemical', '-', (64, 68))	('downregulated', 'NegReg', (108, 121))	('EETs', 'MPA', (64, 68))
543069	25406731	The elevated CYP2C8, 2C9, and 2J2 expression observed here may represent aggressiveness of BC cells and might predict worse cell behavior in BC patients.	('BC', 'Phenotype', 'HP:0003002', (91, 93))	('aggressiveness', 'Phenotype', 'HP:0000718', (73, 87))	('expression', 'MPA', (34, 44))	('predict', 'Reg', (110, 117))	('2C9', 'MPA', (21, 24))	('CYP2C8', 'Var', (13, 19))	('aggressiveness', 'Disease', 'MESH:D001523', (73, 87))	('2J2', 'Gene', (30, 33))	('patients', 'Species', '9606', (144, 152))	('BC', 'Phenotype', 'HP:0003002', (141, 143))	('elevated', 'PosReg', (4, 12))	('aggressiveness', 'Disease', (73, 87))
543071	25406731	In vitro and in vivo studies also indicate that EETs may promote cancer progression by directly inducing cancer cell proliferation, survival, migration, and invasion, by changing the tumor microenvironment (inducing angiogenesis) and/or inducing immunosuppression in an autocrine and/or paracrine manner.	('inducing', 'Reg', (96, 104))	('migration', 'CPA', (142, 151))	('cancer', 'Disease', (105, 111))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('angiogenesis', 'CPA', (216, 228))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('cancer', 'Disease', (65, 71))	('changing', 'Reg', (170, 178))	('promote', 'PosReg', (57, 64))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('EETs', 'Var', (48, 52))	('survival', 'CPA', (132, 140))	('immunosuppression', 'CPA', (246, 263))	('inducing', 'Reg', (237, 245))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('tumor', 'Disease', (183, 188))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('invasion', 'CPA', (157, 165))	('EETs', 'Chemical', '-', (48, 52))
543078	25406731	This result is further supported by our in vitro findings showing that knockdown of CYP2C8, 2C9 or 2J2 and overexpression of sEH inhibits the proliferation and slows the migration of BC cells.	('CYP2C8', 'Var', (84, 90))	('sEH', 'Gene', '2053', (125, 128))	('migration', 'CPA', (170, 179))	('proliferation', 'CPA', (142, 155))	('sEH', 'Gene', (125, 128))	('2J2', 'Gene', (99, 102))	('slows', 'NegReg', (160, 165))	('inhibits', 'NegReg', (129, 137))	('2C9', 'Gene', (92, 95))	('BC', 'Phenotype', 'HP:0003002', (183, 185))
543079	25406731	Although the expression and role of CYP2C8, 2C9, and 2J2, and sEH have been reported in several tumors, their regulation is largely unknown.	('CYP2C8', 'Var', (36, 42))	('sEH', 'Gene', (62, 65))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumors', 'Disease', (96, 102))	('reported', 'Reg', (76, 84))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('2J2', 'Gene', (53, 56))	('sEH', 'Gene', '2053', (62, 65))	('tumors', 'Disease', 'MESH:D009369', (96, 102))	('2C9', 'Gene', (44, 47))
543080	25406731	Evidence from our previous study showed that hypermethylation of the sEH promoter in HepG2 cells suppresses its transcription by an SP-1-dependent mechanism.	('suppresses', 'NegReg', (97, 107))	('hypermethylation', 'Var', (45, 61))	('sEH', 'Gene', (69, 72))	('HepG2', 'CellLine', 'CVCL:0027', (85, 90))	('sEH', 'Gene', '2053', (69, 72))	('transcription', 'MPA', (112, 125))
543083	25406731	Multiple pathways, including EGFR/PI3K/Akt, EGFR/mitogen-activated protein kinase, tumor necrosis factor-alpha and pro-metastatic matrix metalloproteinases are also involved in the mechanism by which EETs induce cancer cell proliferation and survival.	('EETs', 'Var', (200, 204))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('Akt', 'Gene', '207', (39, 42))	('tumor necrosis factor-alpha', 'Gene', (83, 110))	('tumor necrosis factor-alpha', 'Gene', '7124', (83, 110))	('EGFR', 'Gene', '1956', (29, 33))	('cancer', 'Disease', (212, 218))	('EGFR', 'Gene', (29, 33))	('Akt', 'Gene', (39, 42))	('cancer', 'Disease', 'MESH:D009369', (212, 218))	('EGFR', 'Gene', (44, 48))	('EGFR', 'Gene', '1956', (44, 48))	('induce', 'PosReg', (205, 211))	('survival', 'CPA', (242, 250))	('EETs', 'Chemical', '-', (200, 204))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))
543085	25406731	In conclusion, increased EET levels in BC might be due to upregulation of CYP2C8, 2C9, and 2J2 and downregulation of sEH, and knockdown of CYP2C8, 2C9, and 2J2 and overexpression of sEH could partially attenuate the proliferation and migration of BC cells.	('EET levels', 'MPA', (25, 35))	('downregulation', 'NegReg', (99, 113))	('CYP2C8', 'Var', (74, 80))	('attenuate', 'NegReg', (202, 211))	('sEH', 'Gene', (117, 120))	('upregulation', 'PosReg', (58, 70))	('increased', 'PosReg', (15, 24))	('2J2', 'Gene', (91, 94))	('BC', 'Phenotype', 'HP:0003002', (247, 249))	('sEH', 'Gene', '2053', (182, 185))	('knockdown', 'Var', (126, 135))	('CYP2C8', 'Var', (139, 145))	('2C9', 'Gene', (82, 85))	('sEH', 'Gene', (182, 185))	('BC', 'Phenotype', 'HP:0003002', (39, 41))	('sEH', 'Gene', '2053', (117, 120))
543106	33542657	The inclusion criteria that were used to identify eligible patients included: age between 18 and 79 years, primary tumor location of the liver (ICD-O-3 site code C22), only one primary site or more primaries, pathologically confirmed squamous cell carcinoma (8070/3, 8071/3, 8072/3, 8073/3, and 8076/3), stages I-IV tumors according to the American Joint Committee on Cancer (AJCC) staging system, 7th version.	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (234, 257))	('tumors', 'Phenotype', 'HP:0002664', (316, 322))	('tumor', 'Disease', (115, 120))	('Cancer', 'Phenotype', 'HP:0002664', (368, 374))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('squamous cell carcinoma', 'Disease', (234, 257))	('tumor', 'Phenotype', 'HP:0002664', (316, 321))	('tumors', 'Disease', (316, 322))	('patients', 'Species', '9606', (59, 67))	('Cancer', 'Disease', (368, 374))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('tumor location of the liver', 'Phenotype', 'HP:0002896', (115, 142))	('8070/3', 'Var', (259, 265))	('tumors', 'Disease', 'MESH:D009369', (316, 322))	('Cancer', 'Disease', 'MESH:D009369', (368, 374))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (234, 257))	('tumor', 'Disease', (316, 321))	('carcinoma', 'Phenotype', 'HP:0030731', (248, 257))	('tumor', 'Disease', 'MESH:D009369', (316, 321))
543203	31749831	Genomic Profiling of Driver Gene Mutations in Chinese Patients With Non-Small Cell Lung Cancer Worldwide, especially in China, lung cancer accounts to a major cause of mortality related to cancer.	('Small Cell Lung Cancer', 'Phenotype', 'HP:0030357', (72, 94))	('Cancer', 'Phenotype', 'HP:0002664', (88, 94))	('cancer', 'Disease', (132, 138))	('Mutations', 'Var', (33, 42))	('lung cancer', 'Disease', (127, 138))	('lung cancer', 'Phenotype', 'HP:0100526', (127, 138))	('Patients', 'Species', '9606', (54, 62))	('Non-Small Cell Lung Cancer', 'Disease', (68, 94))	('Lung Cancer', 'Phenotype', 'HP:0100526', (83, 94))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('Non-Small Cell Lung Cancer', 'Disease', 'MESH:D002289', (68, 94))	('lung cancer', 'Disease', 'MESH:D008175', (127, 138))	('Non-Small Cell Lung Cancer', 'Phenotype', 'HP:0030358', (68, 94))	('cancer', 'Disease', 'MESH:D009369', (189, 195))	('cancer', 'Disease', 'MESH:D009369', (132, 138))	('cancer', 'Disease', (189, 195))
543204	31749831	Treatment decisions mainly depend on oncogenic driver mutations, which offer novel therapeutic targets for anticancer therapy.	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('mutations', 'Var', (54, 63))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))
543205	31749831	Hence, this is an extensive study of these mutations in Non-small-cell lung cancer (NSCLC) Chinese patients.	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (60, 82))	('NSCLC', 'Phenotype', 'HP:0030358', (84, 89))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('NSCLC', 'Disease', (84, 89))	('patients', 'Species', '9606', (99, 107))	('mutations', 'Var', (43, 52))	('Non-small-cell lung cancer', 'Disease', (56, 82))	('Non-small-cell lung cancer', 'Disease', 'MESH:D002289', (56, 82))	('Non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (56, 82))	('NSCLC', 'Disease', 'MESH:D002289', (84, 89))	('lung cancer', 'Phenotype', 'HP:0100526', (71, 82))
543207	31749831	Further, four promising candidates for druggable mutations of epidermal growth factor receptor (EGFR) were revealed that open up avenues to develop and design personal therapeutic approaches for patients harboring mutations.	('mutations', 'Var', (49, 58))	('epidermal growth factor receptor', 'Gene', (62, 94))	('EGFR', 'Gene', (96, 100))	('epidermal growth factor receptor', 'Gene', '1956', (62, 94))	('patients', 'Species', '9606', (195, 203))
543212	31749831	Treatment strategies for NSCLC have been revolutionized since the identification of epidermal growth factor receptor (EGFR) activating mutations which predict response to EGFR tyrosine kinase inhibitors (TKIs) in 2004.	('epidermal growth factor receptor', 'Gene', '1956', (84, 116))	('NSCLC', 'Disease', (25, 30))	('mutations', 'Var', (135, 144))	('NSCLC', 'Disease', 'MESH:D002289', (25, 30))	('NSCLC', 'Phenotype', 'HP:0030358', (25, 30))	('EGFR', 'Gene', (118, 122))	('epidermal growth factor receptor', 'Gene', (84, 116))	('tyrosine', 'Chemical', 'None', (176, 184))
543214	31749831	Guidelines from clinical practice offer recommendations of an analysis of mutations in EGFR before the start of therapy of advanced NSCLC.	('NSCLC', 'Phenotype', 'HP:0030358', (132, 137))	('mutations', 'Var', (74, 83))	('EGFR', 'Gene', (87, 91))	('NSCLC', 'Disease', (132, 137))	('clinical', 'Species', '191496', (16, 24))	('NSCLC', 'Disease', 'MESH:D002289', (132, 137))
543215	31749831	To date, at least nine important driver mutations causing NSCLC have been described and several markers are already used for best treatment strategy selection.	('mutations', 'Var', (40, 49))	('NSCLC', 'Phenotype', 'HP:0030358', (58, 63))	('NSCLC', 'Disease', (58, 63))	('NSCLC', 'Disease', 'MESH:D002289', (58, 63))
543216	31749831	In this context, the pervasiveness and occurrence of these mutations are different across populations such as that of East Asians and the white with more mutations in EGFR and lesser mutations in Kirsten Rat Sarcoma Viral Proto-Oncogene (KRAS).	('Sarcoma', 'Phenotype', 'HP:0100242', (208, 215))	('Rat Sarcoma', 'CellLine', 'CVCL:0492', (204, 215))	('EGFR', 'Gene', (167, 171))	('mutations', 'Var', (154, 163))
543217	31749831	With very little data in this regard from mainland China, a study that describes the pattern of driver mutations will facilitate personal medicine for NSCLC and on the design of clinical trials.	('mutations', 'Var', (103, 112))	('NSCLC', 'Disease', (151, 156))	('NSCLC', 'Disease', 'MESH:D002289', (151, 156))	('clinical', 'Species', '191496', (178, 186))	('NSCLC', 'Phenotype', 'HP:0030358', (151, 156))
543218	31749831	The identification of these mutations has been facilitated by the use of three-dimensional (3D) protein structures to analyze interactions between proteins found more in mutations associated with cancer as used by and.	('cancer', 'Phenotype', 'HP:0002664', (196, 202))	('interactions', 'Interaction', (126, 138))	('mutations', 'Var', (170, 179))	('cancer', 'Disease', 'MESH:D009369', (196, 202))	('cancer', 'Disease', (196, 202))	('mutations', 'Var', (28, 37))
543220	31749831	The current work reports an inclusive set of driver mutations in a large set of probable NSCLC patients of Chinese origin.	('mutations', 'Var', (52, 61))	('NSCLC', 'Disease', 'MESH:D002289', (89, 94))	('patients', 'Species', '9606', (95, 103))	('NSCLC', 'Phenotype', 'HP:0030358', (89, 94))	('NSCLC', 'Disease', (89, 94))
543221	31749831	Several rarely reported mutations, including EGFR mutations (V742I, I789M, N842H) related with erlotinib, gefitinib, lapatinib, and EGFR mutation (S811C) related with afatinib were discovered.	('EGFR', 'Gene', (45, 49))	('V742I', 'Mutation', 'rs587778250', (61, 66))	('afatinib', 'Chemical', 'MESH:C522924', (167, 175))	('I789M', 'Mutation', 'p.I789M', (68, 73))	('lapatinib', 'Chemical', 'MESH:C490728', (117, 126))	('related', 'Reg', (82, 89))	('I789M', 'Var', (68, 73))	('N842H', 'SUBSTITUTION', 'None', (75, 80))	('S811C', 'Var', (147, 152))	('S811C', 'Chemical', 'MESH:C523047', (147, 152))	('N842H', 'Var', (75, 80))	('gefitinib', 'Chemical', 'MESH:C419708', (106, 115))	('erlotinib', 'Chemical', 'MESH:C400278', (95, 104))	('V742I', 'Var', (61, 66))
543225	31749831	Lung Cancer Ten Genes Panel (Geneis Co.Ltd) was used to test mutations in the EGFR kinase domain, KRAS, NRAS, PIK3CA, HER2 kinase, BRAF, as well as fusions of ALK, ROS1, RET along with Mesenchymal Epithelial Transition Proto-Oncogene (MET) amplifications.	('Cancer', 'Phenotype', 'HP:0002664', (5, 11))	('HER2', 'Gene', (118, 122))	('ROS1', 'Gene', '6098', (164, 168))	('NRAS', 'Gene', (104, 108))	('Lung Cancer', 'Phenotype', 'HP:0100526', (0, 11))	('fusions', 'Var', (148, 155))	('RET', 'Gene', (170, 173))	('KRAS', 'Gene', (98, 102))	('PIK3CA', 'Gene', '5290', (110, 116))	('ALK', 'Gene', '238', (159, 162))	('ROS1', 'Gene', (164, 168))	('mutations', 'Var', (61, 70))	('HER2', 'Gene', '2064', (118, 122))	('ALK', 'Gene', (159, 162))	('BRAF', 'Gene', '673', (131, 135))	('BRAF', 'Gene', (131, 135))	('NRAS', 'Gene', '4893', (104, 108))	('RET', 'Gene', '5979', (170, 173))	('PIK3CA', 'Gene', (110, 116))
543230	31749831	Droplet digital PCR was used to validate these potential driver gene mutations in our clinical cases.	('Droplet digital', 'Disease', 'MESH:D058066', (0, 15))	('mutations', 'Var', (69, 78))	('clinical', 'Species', '191496', (86, 94))	('Droplet digital', 'Disease', (0, 15))
543231	31749831	The distribution is as followed: mutations in EGFR kinase: 55.9%, KRAS: 11.7%, NRAS: 0.7%, PIK3CA: 2.9%, HER2 (the analysis involved insertions in exon 20): 2.1%, BRAF: 1.6%.	('PIK3CA', 'Gene', (91, 97))	('BRAF', 'Gene', (163, 167))	('BRAF', 'Gene', '673', (163, 167))	('HER2', 'Gene', (105, 109))	('NRAS', 'Gene', '4893', (79, 83))	('EGFR kinase', 'Gene', (46, 57))	('HER2', 'Gene', '2064', (105, 109))	('PIK3CA', 'Gene', '5290', (91, 97))	('mutations', 'Var', (33, 42))	('NRAS', 'Gene', (79, 83))
543233	31749831	As shown in Figure 1, 55.9% patients showed EGFR mutations, while the highest frequency of L858R was observed in 28.1% of the patients, followed by exon 19 deletion (20.6%).	('mutations', 'Var', (49, 58))	('L858R', 'Mutation', 'rs121434568', (91, 96))	('patients', 'Species', '9606', (126, 134))	('EGFR', 'Gene', (44, 48))	('patients', 'Species', '9606', (28, 36))
543234	31749831	KRAS mutations were detected in 11.7% patients, with most of these were located in codon 12 (9.4%).	('KRAS', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))	('patients', 'Species', '9606', (38, 46))
543238	31749831	However, EGFR and ALK mutations, KRAS and BRAF mutations, KRAS and ALK mutations, and BRAF and ALK mutations were mutually exclusive in our study (Figure 2).	('KRAS', 'Gene', (58, 62))	('KRAS', 'Disease', (33, 37))	('BRAF', 'Gene', '673', (42, 46))	('ALK', 'Gene', '238', (18, 21))	('ALK', 'Gene', (95, 98))	('ALK', 'Gene', '238', (67, 70))	('mutations', 'Var', (47, 56))	('BRAF', 'Gene', '673', (86, 90))	('mutations', 'Var', (71, 80))	('EGFR', 'Gene', (9, 13))	('ALK', 'Gene', '238', (95, 98))	('ALK', 'Gene', (18, 21))	('mutations', 'Var', (22, 31))	('BRAF', 'Gene', (42, 46))	('BRAF', 'Gene', (86, 90))	('ALK', 'Gene', (67, 70))
543242	31749831	And it was the same for the most common mutations exon 19 deletions and exon 21 L858R.	('L858R', 'Var', (80, 85))	('L858R', 'Mutation', 'rs121434568', (80, 85))	('exon 19 deletions', 'Var', (50, 67))
543243	31749831	Another notable difference was that 33.5-34.2% of non-Asian patients had a KRAS mutation and this was significantly higher than the rate of 8.5-11.7% found for East Asians.	('patients', 'Species', '9606', (60, 68))	('KRAS', 'Gene', (75, 79))	('mutation', 'Var', (80, 88))
543249	31749831	Sequencing of 1,760 blood samples (from July 2016 to October 2018) of patients revealed the following distribution: Mutations in EGFR: 32.6% patients, KRAS: 11.2% patients, NRAS: 1.0% patients, PIK3CA mutations: 2.9%, HER2 kinase domain mutations: 0.9%, BRAF: 2.9% patients while MET amplifications were 0.7% (Table 3).	('patients', 'Species', '9606', (70, 78))	('mutations', 'Var', (201, 210))	('patients', 'Species', '9606', (163, 171))	('patients', 'Species', '9606', (184, 192))	('HER2', 'Gene', (218, 222))	('NRAS', 'Gene', (173, 177))	('HER2', 'Gene', '2064', (218, 222))	('Mutations', 'Var', (116, 125))	('NRAS', 'Gene', '4893', (173, 177))	('BRAF', 'Gene', '673', (254, 258))	('PIK3CA', 'Gene', (194, 200))	('patients', 'Species', '9606', (265, 273))	('BRAF', 'Gene', (254, 258))	('EGFR', 'Gene', (129, 133))	('patients', 'Species', '9606', (141, 149))	('PIK3CA', 'Gene', '5290', (194, 200))
543250	31749831	It is noteworthy that the frequency of drug sensitive mutations, such as EGFR exon 19del and L858R, was reduced when compared with tissues (10.8% in blood and 20.6% in tissues for Exon 19del; 13.1% in blood and 28.1% in tissues for L858R).	('19del', 'Mutation', 'c.19del', (83, 88))	('reduced', 'NegReg', (104, 111))	('L858R', 'Mutation', 'rs121434568', (232, 237))	('exon 19del', 'Var', (78, 88))	('EGFR', 'Gene', (73, 77))	('L858R', 'Var', (93, 98))	('L858R', 'Mutation', 'rs121434568', (93, 98))	('19del', 'Mutation', 'c.19del', (185, 190))	('Exon 19del', 'Var', (180, 190))
543251	31749831	However, the frequency of drug resistant mutations, such as EGFR T790M, was increased when compared with tissues (5.1% in blood and 2.1% in tissues).	('T790M', 'Mutation', 'rs121434569', (65, 70))	('EGFR', 'Gene', (60, 64))	('T790M', 'Var', (65, 70))
543253	31749831	In 134 lung squamous cell carcinoma tissue samples, there were 7 (5.2%) EGFR mutations, 6 (4.5%) KRAS mutations, 12 (9.0%) PIK3CA mutations, 1 (0.7%) BRAF mutations and 1 (0.7%) MET amplifications.	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (7, 35))	('KRAS', 'Gene', (97, 101))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (12, 35))	('PIK3CA', 'Gene', (123, 129))	('lung squamous cell carcinoma', 'Disease', (7, 35))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (7, 35))	('PIK3CA', 'Gene', '5290', (123, 129))	('BRAF', 'Gene', (150, 154))	('EGFR', 'Gene', (72, 76))	('BRAF', 'Gene', '673', (150, 154))	('mutations', 'Var', (102, 111))	('mutations', 'Var', (77, 86))	('carcinoma', 'Phenotype', 'HP:0030731', (26, 35))
543254	31749831	In 96 lung squamous cell carcinoma blood samples, there were 8 (8.3%) EGFR mutations, 7 (7.3%) KRAS mutations, 6 (6.3%) PIK3CA mutations and 1 (1.0%) BRAF mutations.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (11, 34))	('PIK3CA', 'Gene', (120, 126))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (6, 34))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (6, 34))	('lung squamous cell carcinoma', 'Disease', (6, 34))	('BRAF', 'Gene', (150, 154))	('BRAF', 'Gene', '673', (150, 154))	('PIK3CA', 'Gene', '5290', (120, 126))	('EGFR', 'Gene', (70, 74))	('KRAS', 'Gene', (95, 99))	('mutations', 'Var', (75, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (25, 34))
543256	31749831	It is noteworthy that the rate of mutation of PIK3CA in these samples is relatively higher when compared with lung adenocarcinoma.	('PIK3CA', 'Gene', '5290', (46, 52))	('lung adenocarcinoma', 'Disease', (110, 129))	('higher', 'Reg', (84, 90))	('mutation', 'Var', (34, 42))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (110, 129))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (110, 129))	('PIK3CA', 'Gene', (46, 52))
543257	31749831	We first collected the 3,243 tumors data of lung adenocarcinoma patients in China and several rarely reported mutations, including EGFR mutations (V742I, I789M, N842H) related with erlotinib, gefitinib, lapatinib, and EGFR mutations (S811C) related with afatinib were discovered (Table 5, Figure 3) by filtered in 800 potential druggable mutations of Hotspot3D.	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('EGFR', 'Gene', (131, 135))	('N842H', 'Var', (161, 166))	('gefitinib', 'Chemical', 'MESH:C419708', (192, 201))	('carcinoma', 'Phenotype', 'HP:0030731', (54, 63))	('I789M', 'Mutation', 'p.I789M', (154, 159))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('afatinib', 'Chemical', 'MESH:C522924', (254, 262))	('N842H', 'SUBSTITUTION', 'None', (161, 166))	('tumors data of lung adenocarcinoma', 'Disease', 'MESH:C538231', (29, 63))	('lapatinib', 'Chemical', 'MESH:C490728', (203, 212))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (44, 63))	('V742I', 'Var', (147, 152))	('I789M', 'Var', (154, 159))	('S811C', 'Chemical', 'MESH:C523047', (234, 239))	('V742I', 'Mutation', 'rs587778250', (147, 152))	('erlotinib', 'Chemical', 'MESH:C400278', (181, 190))	('patients', 'Species', '9606', (64, 72))	('tumors data of lung adenocarcinoma', 'Disease', (29, 63))
543258	31749831	Droplet digital PCR was used to validate these EGFR variants in our clinical cases.	('Droplet digital', 'Disease', 'MESH:D058066', (0, 15))	('variants', 'Var', (52, 60))	('Droplet digital', 'Disease', (0, 15))	('clinical', 'Species', '191496', (68, 76))	('EGFR', 'Gene', (47, 51))
543259	31749831	Identification of oncogenic driver mutations in NSCLC has greatly promoted clinical use and development of targeted drugs.	('NSCLC', 'Disease', (48, 53))	('NSCLC', 'Disease', 'MESH:D002289', (48, 53))	('clinical', 'Species', '191496', (75, 83))	('NSCLC', 'Phenotype', 'HP:0030358', (48, 53))	('promoted', 'PosReg', (66, 74))	('mutations', 'Var', (35, 44))
543263	31749831	Comparison of driver gene mutations of lung adenocarcinoma with other races showed that the mutational frequencies were similar between mainland China (this study), Hong Kong, and Japan populations.	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (39, 58))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (39, 58))	('mutations', 'Var', (26, 35))	('lung adenocarcinoma', 'Disease', (39, 58))
543265	31749831	However, the EGFR mutation frequencies in East Asian lung adenocarcinoma were higher than previously reported in USA/Europe patients, whereas the overall frequency of KRAS mutations was much lower than in the West instead.	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (53, 72))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (53, 72))	('lung adenocarcinoma', 'Disease', (53, 72))	('higher', 'PosReg', (78, 84))	('mutation', 'Var', (18, 26))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))	('EGFR', 'Gene', (13, 17))	('patients', 'Species', '9606', (124, 132))
543268	31749831	Subjects carried BRAF mutations with percent of 1.6%, and most of them were a V600E mutation.	('BRAF', 'Gene', '673', (17, 21))	('V600E', 'Mutation', 'rs113488022', (78, 83))	('BRAF', 'Gene', (17, 21))	('mutations', 'Var', (22, 31))	('V600E', 'Var', (78, 83))
543271	31749831	In addition, EGFR and ALK mutations, KRAS and ALK mutations, and BRAF and ALK mutations were mutually exclusive in our study.	('ALK', 'Gene', (74, 77))	('ALK', 'Gene', '238', (46, 49))	('KRAS', 'Gene', (37, 41))	('mutations', 'Var', (26, 35))	('ALK', 'Gene', '238', (22, 25))	('BRAF', 'Gene', '673', (65, 69))	('ALK', 'Gene', '238', (74, 77))	('BRAF', 'Gene', (65, 69))	('ALK', 'Gene', (46, 49))	('EGFR', 'Gene', (13, 17))	('ALK', 'Gene', (22, 25))
543272	31749831	We also found three cases of simultaneous mutations of EGFR along with BRAF, which was first found in Li 'study.	('EGFR', 'Gene', (55, 59))	('mutations', 'Var', (42, 51))	('BRAF', 'Gene', (71, 75))	('BRAF', 'Gene', '673', (71, 75))
543273	31749831	Interestingly, a triple mutation EGFR L858R+EGFR T790M+KRAS G12D was identified in our study, which was rarely reported at present.	('T790M+KRAS G12D', 'Var', (49, 64))	('L858R', 'Mutation', 'rs121434568', (38, 43))	('G12D', 'Mutation', 'rs121913529', (60, 64))	('EGFR', 'Gene', (33, 37))	('T790M', 'Mutation', 'rs121434569', (49, 54))
543275	31749831	1,760 lung adenocarcinoma patient blood samples were tested for analyzing mutations in EGFR, KRAS, NRAS, PIK3CA, HER2, BRAF and MET in cfDNA.	('PIK3CA', 'Gene', (105, 111))	('patient', 'Species', '9606', (26, 33))	('KRAS', 'Gene', (93, 97))	('BRAF', 'Gene', '673', (119, 123))	('HER2', 'Gene', (113, 117))	('mutations', 'Var', (74, 83))	('EGFR', 'Gene', (87, 91))	('PIK3CA', 'Gene', '5290', (105, 111))	('carcinoma', 'Phenotype', 'HP:0030731', (16, 25))	('BRAF', 'Gene', (119, 123))	('HER2', 'Gene', '2064', (113, 117))	('MET', 'Gene', (128, 131))	('NRAS', 'Gene', (99, 103))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (6, 25))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (6, 25))	('NRAS', 'Gene', '4893', (99, 103))	('lung adenocarcinoma', 'Disease', (6, 25))
543276	31749831	The distribution of drug sensitive mutations, such as EGFR exon19del as well as, L858R, was decreased in comparison with these mutation in tissues, while the frequency of drug resistant mutations, such as EGFR T790M, was increased.	('exon19del', 'Var', (59, 68))	('T790M', 'Var', (210, 215))	('EGFR', 'Var', (205, 209))	('L858R', 'Mutation', 'rs121434568', (81, 86))	('19del', 'Mutation', 'c.19del', (63, 68))	('decreased', 'NegReg', (92, 101))	('EGFR', 'Gene', (54, 58))	('distribution', 'MPA', (4, 16))	('T790M', 'Mutation', 'rs121434569', (210, 215))	('L858R', 'Var', (81, 86))
543279	31749831	It can be seen from the mutation frequency of EGFR T790M (2.1%), which was close to the de novo T790M frequency reported in the literature.	('T790M', 'Var', (51, 56))	('EGFR', 'Gene', (46, 50))	('T790M', 'Mutation', 'rs121434569', (96, 101))	('T790M', 'Mutation', 'rs121434569', (51, 56))
543286	31749831	Here, we screened 230 Chinese patient samples of lung SCC and reported the rarity of two most ubiquitous mutations in KRAS and EGFR seen in lung adenocarcinoma, while PIK3CA mutations were relatively high when compared with lung adenocarcinoma.	('lung adenocarcinoma', 'Disease', (224, 243))	('patient', 'Species', '9606', (30, 37))	('PIK3CA', 'Gene', '5290', (167, 173))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (140, 159))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (140, 159))	('KRAS', 'Gene', (118, 122))	('lung SCC', 'Disease', 'MESH:D002294', (49, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (150, 159))	('SCC', 'Phenotype', 'HP:0002860', (54, 57))	('lung adenocarcinoma', 'Disease', (140, 159))	('mutations', 'Var', (105, 114))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (224, 243))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (224, 243))	('carcinoma', 'Phenotype', 'HP:0030731', (234, 243))	('lung SCC', 'Disease', (49, 57))	('PIK3CA', 'Gene', (167, 173))	('EGFR', 'Gene', (127, 131))
543287	31749831	Most of the mutations are unknown in lung SCCs and it needs further research.	('lung SCC', 'Disease', 'MESH:D002294', (37, 45))	('lung SCC', 'Disease', (37, 45))	('SCC', 'Phenotype', 'HP:0002860', (42, 45))	('mutations', 'Var', (12, 21))
543288	31749831	Besides this, we made a profound analysis of the 3,243 tumors data of lung adenocarcinoma patients in China, then three EGFR mutations (V742I, I789M, N842H) related with erlotinib, gefitinib, lapatinib, and one EGFR mutation (S811C) related with afatinib were discovered by filtered in Hotspot3D results.	('lapatinib', 'Chemical', 'MESH:C490728', (192, 201))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('erlotinib', 'Chemical', 'MESH:C400278', (170, 179))	('I789M', 'Var', (143, 148))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (70, 89))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('EGFR', 'Gene', (120, 124))	('gefitinib', 'Chemical', 'MESH:C419708', (181, 190))	('tumors data of lung adenocarcinoma', 'Disease', 'MESH:C538231', (55, 89))	('afatinib', 'Chemical', 'MESH:C522924', (246, 254))	('S811C', 'Chemical', 'MESH:C523047', (226, 231))	('N842H', 'Var', (150, 155))	('patients', 'Species', '9606', (90, 98))	('V742I', 'Var', (136, 141))	('tumors data of lung adenocarcinoma', 'Disease', (55, 89))	('V742I', 'Mutation', 'rs587778250', (136, 141))	('I789M', 'Mutation', 'p.I789M', (143, 148))	('N842H', 'SUBSTITUTION', 'None', (150, 155))
543289	31749831	Next, we will continue to validate the function of the four EGFR rare druggable mutations by the following methods: (i) to predict of drug interaction based on protein structures; (ii) to perform biological validation in cultured cells; (iii) to establish the feasibility evaluation of clinical significance of these mutations by follow-up patients had these four EGFR rare mutations.	('mutations', 'Var', (80, 89))	('clinical', 'Species', '191496', (286, 294))	('drug interaction', 'Phenotype', 'HP:0020172', (134, 150))	('patients', 'Species', '9606', (340, 348))	('EGFR', 'Gene', (60, 64))
543290	31749831	Interestingly, we found that these EGFR rare variants always coexist with some common activating mutations in clinical samples.	('variants', 'Var', (45, 53))	('clinical samples', 'Species', '191496', (110, 126))	('EGFR', 'Gene', (35, 39))
543294	31749831	There was an identification of four rare mutations in EGFR in these patients, such results can raise new possibilities for designing personalized treatments for patients carrying these mutations.	('mutations', 'Var', (41, 50))	('patients', 'Species', '9606', (68, 76))	('EGFR', 'Gene', (54, 58))	('patients', 'Species', '9606', (161, 169))
543295	31749831	Genomic profiling of driver gene mutations of a sizeable Chinese patient set with NSCLC was performed.	('NSCLC', 'Phenotype', 'HP:0030358', (82, 87))	('mutations', 'Var', (33, 42))	('patient', 'Species', '9606', (65, 72))	('NSCLC', 'Disease', (82, 87))	('NSCLC', 'Disease', 'MESH:D002289', (82, 87))
543296	31749831	Four promising candidates for druggable mutations of EGFR were revealed, which opens up new avenues in the development of therapies that target individual patients carrying such genetic alterations.	('EGFR', 'Gene', (53, 57))	('mutations', 'Var', (40, 49))	('patients', 'Species', '9606', (155, 163))
543302	31383898	Interestingly, patients with lung adenocarcinoma accumulating iron in the TME show higher numbers of M1-like pro-inflammatory TAMs and a survival advantage compared to iron-negative patients.	('patients', 'Species', '9606', (15, 23))	('TAMs', 'Chemical', '-', (126, 130))	('iron', 'Chemical', 'MESH:D007501', (62, 66))	('iron', 'Chemical', 'MESH:D007501', (168, 172))	('lung adenocarcinoma', 'Disease', (29, 48))	('M1-like pro-inflammatory TAMs', 'MPA', (101, 130))	('accumulating', 'Var', (49, 61))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (29, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (39, 48))	('patients', 'Species', '9606', (182, 190))	('higher', 'PosReg', (83, 89))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (29, 48))	('survival advantage', 'CPA', (137, 155))
543379	31383898	These iron-positive macrophages (iTAMs) are hallmarked by low expression of the iron exporter ferroportin and positivity for CD86, CD163, and HMOX1 as well as a pro-inflammatory phenotype with the ability to kill tumor cells.	('tumor', 'Disease', (213, 218))	('iron', 'Chemical', 'MESH:D007501', (6, 10))	('TAMs', 'Chemical', '-', (34, 38))	('HMOX1', 'Gene', '3162', (142, 147))	('expression', 'MPA', (62, 72))	('CD163', 'Gene', '9332', (131, 136))	('low', 'NegReg', (58, 61))	('iron', 'Chemical', 'MESH:D007501', (80, 84))	('positivity', 'Var', (110, 120))	('tumor', 'Disease', 'MESH:D009369', (213, 218))	('CD86', 'Gene', '942', (125, 129))	('CD86', 'Gene', (125, 129))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('CD163', 'Gene', (131, 136))	('HMOX1', 'Gene', (142, 147))
543449	31172135	However, there are examples whereby cells either maintain or reactivate pluripotency factors to preserve the increased potential for the healing of wounds or tissue homeostasis.	('reactivate', 'Var', (61, 71))	('pluripotency', 'Disease', (72, 84))	('pluripotency', 'Disease', 'None', (72, 84))	('healing of wounds', 'CPA', (137, 154))
543451	31172135	In this review, we will summarize the somatic repression of pluripotency factors, their role in tissue homeostasis and wound repair, and the human diseases that are associated with pluripotency factor misregulation with an emphasis on their role in the etiology of multiple cancers.	('multiple cancers', 'Disease', (265, 281))	('pluripotency', 'Disease', 'None', (181, 193))	('cancers', 'Phenotype', 'HP:0002664', (274, 281))	('multiple cancers', 'Disease', 'MESH:D009369', (265, 281))	('pluripotency', 'Disease', (60, 72))	('misregulation', 'Var', (201, 214))	('human', 'Species', '9606', (141, 146))	('pluripotency', 'Disease', 'None', (60, 72))	('cancer', 'Phenotype', 'HP:0002664', (274, 280))	('pluripotency', 'Disease', (181, 193))
543464	31172135	It was found that let-7 miRNAs suppress self-renewal in ES cells and their downregulation was able to de-differentiate somatic cells to iPS cells.	('downregulation', 'NegReg', (75, 89))	('iPS', 'Chemical', '-', (136, 139))	('de-differentiate', 'NegReg', (102, 118))	('let-7', 'Gene', (18, 23))	('miRNAs', 'Var', (24, 30))	('suppress', 'NegReg', (31, 39))	('self-renewal', 'CPA', (40, 52))
543468	31172135	Due to the importance of the core pluripotency factors in the establishment of ES and iPS cells, it is no surprise that mutations in these factors can cause developmental diseases.	('iPS', 'Chemical', '-', (86, 89))	('pluripotency', 'Disease', 'None', (34, 46))	('developmental diseases', 'Disease', (157, 179))	('developmental diseases', 'Disease', 'MESH:D001848', (157, 179))	('cause', 'Reg', (151, 156))	('mutations', 'Var', (120, 129))	('pluripotency', 'Disease', (34, 46))
543469	31172135	As Sox2 remains expressed past the blastocyst stage and into organogenesis, mutations in the gene can cause a multitude of developmental defects (Table 1).	('Sox2', 'Gene', (3, 7))	('developmental defects', 'Disease', (123, 144))	('developmental defects', 'Disease', 'MESH:D003147', (123, 144))	('mutations', 'Var', (76, 85))	('cause', 'Reg', (102, 107))	('blastocyst', 'Disease', (35, 45))	('blastocyst', 'Disease', 'MESH:D020964', (35, 45))
543470	31172135	In the past two decades, scientists have attributed many developmental problems to misregulation of these core factors, predominantly SOX2.	('developmental problems', 'Phenotype', 'HP:0001263', (57, 79))	('SOX2', 'Gene', '6657', (134, 138))	('misregulation', 'Var', (83, 96))	('SOX2', 'Gene', (134, 138))
543474	31172135	However, mutations in Sox2 do cause defects in postnatal mouse development in the telencephalon, particularly in the hippocampus dentate gyrus through misregulation of sonic hedgehog signaling.	('misregulation', 'Var', (151, 164))	('defects', 'NegReg', (36, 43))	('mutations', 'Var', (9, 18))	('sonic hedgehog signaling', 'MPA', (168, 192))	('telencephalon', 'Disease', (82, 95))	('telencephalon', 'Disease', 'None', (82, 95))	('Sox2', 'Gene', (22, 26))	('mouse', 'Species', '10090', (57, 62))
543476	31172135	It is no surprise that mutations in Sox2 have been known to affect the formation of the hypothalamus-pituitary system, by causing hypoplasia of the anterior pituitary and gonadotrophin deficiency, resulting in fertility deficiencies.	('hypoplasia of the anterior pituitary and gonadotrophin deficiency', 'Phenotype', 'HP:0010627', (130, 195))	('causing', 'Reg', (122, 129))	('deficiency', 'Disease', 'MESH:D007153', (185, 195))	('gonadotrophin deficiency', 'Phenotype', 'HP:0008213', (171, 195))	('hypothalamus-pituitary system', 'Disease', (88, 117))	('hypothalamus-pituitary system', 'Disease', 'MESH:D007029', (88, 117))	('mutations', 'Var', (23, 32))	('hypoplasia of the anterior pituitary', 'Disease', 'MESH:D010900', (130, 166))	('fertility deficiencies', 'Disease', 'MESH:D007246', (210, 232))	('Sox2', 'Gene', (36, 40))	('affect', 'Reg', (60, 66))	('fertility deficiencies', 'Disease', (210, 232))	('fertility deficiencies', 'Phenotype', 'HP:0000144', (210, 232))	('resulting in', 'Reg', (197, 209))	('hypoplasia of the anterior pituitary', 'Disease', (130, 166))	('deficiency', 'Disease', (185, 195))	('formation of the hypothalamus', 'Phenotype', 'HP:0025058', (71, 100))
543477	31172135	Mutations in Sox2 have also been shown to affect eye development, causing anophthalmia or microthalmia.	('affect', 'Reg', (42, 48))	('causing', 'Reg', (66, 73))	('eye development', 'CPA', (49, 64))	('Mutations', 'Var', (0, 9))	('anophthalmia or microthalmia', 'Disease', 'MESH:D000853', (74, 102))	('Sox2', 'Gene', (13, 17))	('anophthalmia or microthalmia', 'Disease', (74, 102))	('anophthalmia', 'Phenotype', 'HP:0000528', (74, 86))
543479	31172135	Sox2 mutations can result in these defects occurring together: coloboma, heart malformation, atresia of the choanae, retarded growth and development, and genital and ear abnormalities or (CHARGE) syndrome as a result.	('retarded growth', 'Disease', 'MESH:D006130', (117, 132))	('Sox2', 'Gene', (0, 4))	('coloboma', 'Disease', (63, 71))	('retarded growth', 'Disease', (117, 132))	('heart malformation', 'Disease', 'MESH:D006330', (73, 91))	('result', 'Reg', (19, 25))	('heart malformation', 'Phenotype', 'HP:0001627', (73, 91))	('retarded growth', 'Phenotype', 'HP:0001510', (117, 132))	('atresia', 'Disease', (93, 100))	('mutations', 'Var', (5, 14))	('heart malformation', 'Disease', (73, 91))	('atresia', 'Disease', 'MESH:D018633', (93, 100))	('ear abnormalities or (CHARGE) syndrome', 'Disease', 'MESH:D058747', (166, 204))	('retarded growth and development', 'Phenotype', 'HP:0001263', (117, 148))	('coloboma', 'Phenotype', 'HP:0000589', (63, 71))
543480	31172135	If Sox2 is mutated, this can sometimes result in anophthalmia,-esophageal-genital syndrome (AEG) where the formation of the esophagus and trachea is abnormal and these structures fail to separate.	('Sox2', 'Gene', (3, 7))	('AEG', 'Disease', 'MESH:C565948', (92, 95))	('result in', 'Reg', (39, 48))	('AEG', 'Disease', (92, 95))	('anophthalmia,-esophageal-genital syndrome', 'Disease', 'MESH:C565948', (49, 90))	('anophthalmia', 'Phenotype', 'HP:0000528', (49, 61))	('genital syndrome', 'Phenotype', 'HP:0000078', (74, 90))	('mutated', 'Var', (11, 18))
543481	31172135	Sox2 mutations have also been implicated in chronic kidney disease.	('Sox2', 'Gene', (0, 4))	('kidney disease', 'Disease', 'MESH:D007674', (52, 66))	('mutations', 'Var', (5, 14))	('kidney disease', 'Phenotype', 'HP:0000112', (52, 66))	('implicated', 'Reg', (30, 40))	('chronic kidney disease', 'Phenotype', 'HP:0012622', (44, 66))	('kidney disease', 'Disease', (52, 66))
543483	31172135	Oct4 is necessary for the switch from the pluripotent stem cells to the germ cells, thus problems with this mechanism can lead to infertility.	('lead to', 'Reg', (122, 129))	('infertility', 'Phenotype', 'HP:0000789', (130, 141))	('infertility', 'Disease', 'MESH:D007247', (130, 141))	('infertility', 'Disease', (130, 141))	('problems', 'Var', (89, 97))
543484	31172135	Although mutations in Oct4 itself do not cause any developmental diseases directly, the misregulation of many of Oct4's binding partners is associated with diseases.	('developmental diseases', 'Disease', (51, 73))	('diseases', 'Disease', (156, 164))	('associated', 'Reg', (140, 150))	('binding', 'Interaction', (120, 127))	('mutations', 'Var', (9, 18))	('misregulation', 'Var', (88, 101))	('developmental diseases', 'Disease', 'MESH:D001848', (51, 73))	('Oct4', 'Gene', (113, 117))	('Oct4', 'Gene', (22, 26))
543488	31172135	In a chemically-induced model of mouse squamous cell carcinoma, Sox2 enriched cells were the tumor propagating cells, and conditional deletion of Sox2 decreased tumor formation and led to regression in existing tumors.	('tumors', 'Disease', 'MESH:D009369', (211, 217))	('conditional deletion', 'Var', (122, 142))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (39, 62))	('tumor', 'Disease', (211, 216))	('tumor', 'Disease', (161, 166))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (39, 62))	('tumors', 'Phenotype', 'HP:0002664', (211, 217))	('Sox2', 'Gene', (146, 150))	('decreased', 'NegReg', (151, 160))	('carcinoma', 'Phenotype', 'HP:0030731', (53, 62))	('squamous cell carcinoma', 'Disease', (39, 62))	('regression', 'NegReg', (188, 198))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('tumors', 'Disease', (211, 217))	('tumor', 'Disease', (93, 98))	('mouse', 'Species', '10090', (33, 38))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
543489	31172135	Sox2 expression was required for tumorigenicity of mouse osteosarcoma and knockout of Sox2 decreases the cancer stem cell-like phenotype seen in Sox2+ osteosarcoma cells.	('sarcoma', 'Phenotype', 'HP:0100242', (62, 69))	('osteosarcoma', 'Disease', (151, 163))	('knockout', 'Var', (74, 82))	('osteosarcoma', 'Disease', 'MESH:D012516', (57, 69))	('osteosarcoma', 'Phenotype', 'HP:0002669', (151, 163))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('osteosarcoma', 'Disease', 'MESH:D012516', (151, 163))	('Sox2', 'Gene', (86, 90))	('mouse', 'Species', '10090', (51, 56))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('decreases the cancer', 'Disease', 'MESH:D009369', (91, 111))	('sarcoma', 'Phenotype', 'HP:0100242', (156, 163))	('decreases the cancer', 'Disease', (91, 111))	('tumor', 'Disease', (33, 38))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('osteosarcoma', 'Phenotype', 'HP:0002669', (57, 69))	('osteosarcoma', 'Disease', (57, 69))
543490	31172135	In both human and mouse bladder cancer, Sox2 is overexpressed in pre-neoplastic and neoplastic tumors, where the knockout of Sox2 decreased tumor invasiveness.	('neoplastic tumors', 'Disease', 'MESH:D009369', (84, 101))	('mouse', 'Species', '10090', (18, 23))	('bladder cancer', 'Phenotype', 'HP:0009725', (24, 38))	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('knockout', 'Var', (113, 121))	('Sox2', 'Gene', (125, 129))	('neoplastic tumors', 'Disease', (84, 101))	('bladder cancer', 'Disease', 'MESH:D001749', (24, 38))	('decreased tumor invasiveness', 'Disease', (130, 158))	('bladder cancer', 'Disease', (24, 38))	('decreased tumor invasiveness', 'Disease', 'MESH:D009369', (130, 158))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('human', 'Species', '9606', (8, 13))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))
543491	31172135	Given that Sox2 is a pluripotency gene, it is unsurprising that expression of Sox2 in human glioblastoma multiforme (GBM) cells was able to direct differentiation in to a stem-like state capable of tumor propagation.	('pluripotency', 'Disease', 'None', (21, 33))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('glioblastoma multiforme', 'Disease', (92, 115))	('glioblastoma', 'Phenotype', 'HP:0012174', (92, 104))	('tumor', 'Disease', (198, 203))	('human', 'Species', '9606', (86, 91))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('glioblastoma multiforme', 'Disease', 'MESH:D005909', (92, 115))	('expression', 'Var', (64, 74))	('Sox2', 'Gene', (78, 82))	('differentiation in', 'CPA', (147, 165))	('pluripotency', 'Disease', (21, 33))
543495	31172135	In a larger patient set, Sox2 expression was found to be prognostic of poor overall and disease-free survival.	('overall', 'CPA', (76, 83))	('Sox2', 'Gene', (25, 29))	('disease-free survival', 'CPA', (88, 109))	('poor', 'NegReg', (71, 75))	('expression', 'Var', (30, 40))	('patient', 'Species', '9606', (12, 19))
543500	31172135	In addition to the studies linking Sox2 expression to cancer phenotypes, a number of studies have shown an association between expression of Sox2 and clinical outcome.	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('Sox2', 'Gene', (141, 145))	('cancer', 'Disease', (54, 60))	('association', 'Interaction', (107, 118))	('expression', 'Var', (127, 137))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
543504	31172135	A large study of patients with gastric cancer who had undergone surgical resection of the tumor found that Sox2 positivity was correlated with invasion depth, lymph node metastasis or invasion, and that the prognosis of patients with Sox2 positive cancers was significantly worse than the prognosis of patients who had Sox2 negative cancers.	('patients', 'Species', '9606', (220, 228))	('worse', 'Reg', (274, 279))	('cancers', 'Phenotype', 'HP:0002664', (248, 255))	('gastric cancer', 'Disease', (31, 45))	('positive', 'Var', (239, 247))	('cancers', 'Disease', (248, 255))	('cancers', 'Phenotype', 'HP:0002664', (333, 340))	('tumor', 'Disease', (90, 95))	('cancer', 'Phenotype', 'HP:0002664', (248, 254))	('cancers', 'Disease', (333, 340))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('lymph node metastasis', 'Disease', 'MESH:D009362', (159, 180))	('gastric cancer', 'Disease', 'MESH:D013274', (31, 45))	('cancer', 'Phenotype', 'HP:0002664', (333, 339))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('Sox2', 'Gene', (234, 238))	('invasion', 'CPA', (184, 192))	('Sox2', 'Gene', (107, 111))	('lymph node metastasis', 'Disease', (159, 180))	('patients', 'Species', '9606', (17, 25))	('invasion depth', 'CPA', (143, 157))	('correlated', 'Reg', (127, 137))	('cancers', 'Disease', 'MESH:D009369', (248, 255))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('gastric cancer', 'Phenotype', 'HP:0012126', (31, 45))	('cancers', 'Disease', 'MESH:D009369', (333, 340))	('patients', 'Species', '9606', (302, 310))
543509	31172135	A 2014 study by Justilien et al found an overexpression of SOX2 by way of amplification of chromosome 3q26 in five human lung cancer cell lines.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('lung cancer', 'Disease', 'MESH:D008175', (121, 132))	('amplification', 'Var', (74, 87))	('lung cancer', 'Disease', (121, 132))	('human', 'Species', '9606', (115, 120))	('lung cancer', 'Phenotype', 'HP:0100526', (121, 132))	('overexpression', 'PosReg', (41, 55))	('SOX2', 'Gene', '6657', (59, 63))	('SOX2', 'Gene', (59, 63))
543513	31172135	Chromosomal amplification of SOX2 has also been implicated in small cell lung cancer (SCLC).	('SCLC', 'Disease', (86, 90))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (62, 84))	('SCLC', 'Disease', 'MESH:D018288', (86, 90))	('small cell lung cancer', 'Disease', (62, 84))	('Chromosomal amplification', 'Var', (0, 25))	('SOX2', 'Gene', (29, 33))	('SOX2', 'Gene', '6657', (29, 33))	('SCLC', 'Phenotype', 'HP:0030357', (86, 90))	('lung cancer', 'Phenotype', 'HP:0100526', (73, 84))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('implicated', 'Reg', (48, 58))	('small cell lung cancer', 'Disease', 'MESH:D055752', (62, 84))
543514	31172135	The means of Sox2 upregulation may be varied and tissue-specific, however, as Sox2 can be directly repressed by RB1, loss of Rb1 function is often a driver mutation for many tumors associated with Sox2 upregulation .	('RB1', 'Gene', '5925', (112, 115))	('tumors', 'Disease', (174, 180))	('tumors', 'Disease', 'MESH:D009369', (174, 180))	('loss', 'Var', (117, 121))	('Rb1', 'Gene', (125, 128))	('RB1', 'Gene', (112, 115))	('Rb1', 'Gene', '5925', (125, 128))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('tumors', 'Phenotype', 'HP:0002664', (174, 180))
543516	31172135	In contrast to small cell lung cancer, lung squamous cell carcinomas are not strongly associated with Rb1 mutation, yet Sox2 is clearly associated with their growth and maintenance.	('associated', 'Reg', (136, 146))	('Rb1', 'Gene', '5925', (102, 105))	('lung squamous cell carcinomas', 'Disease', 'MESH:D002294', (39, 68))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (44, 68))	('small cell lung cancer', 'Disease', 'MESH:D055752', (15, 37))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (15, 37))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('carcinomas', 'Phenotype', 'HP:0030731', (58, 68))	('mutation', 'Var', (106, 114))	('lung squamous cell carcinomas', 'Disease', (39, 68))	('small cell lung cancer', 'Disease', (15, 37))	('Rb1', 'Gene', (102, 105))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (44, 67))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))	('lung cancer', 'Phenotype', 'HP:0100526', (26, 37))
543519	31172135	In cervical cancer with upregulations of epidermal growth factor (EGF) receptor, knockdown of the EGF/PI3K pathway reduced expression of Sox2, suggesting that this pathway may play a role in the upregulation of Sox2 in cervical cancer.	('expression', 'MPA', (123, 133))	('EGF', 'Gene', (98, 101))	('Sox2', 'Protein', (137, 141))	('reduced', 'NegReg', (115, 122))	('cervical cancer', 'Disease', 'MESH:D002583', (3, 18))	('cervical cancer', 'Disease', (219, 234))	('cervical cancer', 'Disease', 'MESH:D002583', (219, 234))	('EGF', 'Gene', (66, 69))	('cervical cancer', 'Disease', (3, 18))	('upregulations', 'PosReg', (24, 37))	('knockdown', 'Var', (81, 90))	('EGF', 'Gene', '1950', (98, 101))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('epidermal growth factor (EGF) receptor', 'Gene', '1956', (41, 79))	('EGF', 'Gene', '1950', (66, 69))
543520	31172135	Also in this study, it was found that expression of miR-181a-2-3p and let-7i-5p was able to downregulate Sox2 expression, alluding to a dual role of miRNA and EGF receptor in mediating Sox2 levels.	('miR-181a-2', 'Gene', (52, 62))	('downregulate', 'NegReg', (92, 104))	('miR-181a-2', 'Gene', '406954', (52, 62))	('EGF', 'Gene', (159, 162))	('Sox2', 'Gene', (105, 109))	('expression', 'MPA', (110, 120))	('let-7i-5p', 'Var', (70, 79))	('EGF', 'Gene', '1950', (159, 162))
543526	31172135	A study in tongue squamous cell carcinoma also found Sox2-dependent overactivation of the Wnt/beta-Catenin pathway, which was associated with epithelial-to-mesenchymal transition (EMT).	('tongue squamous cell carcinoma', 'Disease', 'MESH:D002294', (11, 41))	('tongue squamous cell carcinoma', 'Disease', (11, 41))	('beta-Catenin', 'Gene', (94, 106))	('beta-Catenin', 'Gene', '1499', (94, 106))	('Sox2-dependent', 'Var', (53, 67))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (18, 41))	('overactivation', 'PosReg', (68, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (32, 41))	('epithelial-to-mesenchymal transition', 'Disease', (142, 178))	('tongue squamous cell carcinoma', 'Phenotype', 'HP:0030413', (11, 41))
543529	31172135	AFF4 levels changed in parallel with Sox2, and knockout of AFF4 led to decreased proliferation, migration, and invasion of cells, as well as decreased aldehyde dehydrogenase activity, important for tumor initiation.	('migration', 'CPA', (96, 105))	('invasion of cells', 'CPA', (111, 128))	('tumor', 'Disease', 'MESH:D009369', (198, 203))	('AFF4', 'Gene', '27125', (59, 63))	('knockout', 'Var', (47, 55))	('AFF4', 'Gene', (0, 4))	('AFF4', 'Gene', (59, 63))	('decreased', 'NegReg', (141, 150))	('aldehyde dehydrogenase activity', 'MPA', (151, 182))	('AFF4', 'Gene', '27125', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('tumor', 'Disease', (198, 203))	('proliferation', 'CPA', (81, 94))	('decreased', 'NegReg', (71, 80))
543531	31172135	In GBM cells, Sox2 expression downregulates the tumor suppressors BEX1 and BEX2, however this effect is likely indirect as there are no SOX2 binding domains in either BEX protein.	('BEX', 'Gene', '27018', (75, 78))	('Sox2', 'Gene', (14, 18))	('BEX1', 'Gene', (66, 70))	('BEX', 'Gene', (66, 69))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('tumor', 'Disease', (48, 53))	('BEX2', 'Gene', '84707', (75, 79))	('expression', 'Var', (19, 29))	('downregulates', 'NegReg', (30, 43))	('BEX', 'Gene', '27018', (167, 170))	('BEX1', 'Gene', '55859', (66, 70))	('BEX', 'Gene', '27018', (66, 69))	('BEX', 'Gene', (75, 78))	('SOX2', 'Gene', '6657', (136, 140))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('BEX2', 'Gene', (75, 79))	('SOX2', 'Gene', (136, 140))	('BEX', 'Gene', (167, 170))
543532	31172135	Sequencing of GBM cells, showed that that miR-145, miR-143, miR-253-5p, and miR-462 expression levels were responsive to Sox2 levels.	('miR-462', 'Var', (76, 83))	('miR-145', 'Gene', '406937', (42, 49))	('miR-143', 'Gene', '406935', (51, 58))	('expression levels', 'MPA', (84, 101))	('miR-253-5p', 'Var', (60, 70))	('miR-145', 'Gene', (42, 49))	('miR-143', 'Gene', (51, 58))
543540	31172135	In somatic tissues of adult mice, expression of Oct4 was sufficient to drive epithelial growths, which are dependent on Oct4 for proliferation.	('drive', 'PosReg', (71, 76))	('mice', 'Species', '10090', (28, 32))	('Oct4', 'Gene', (48, 52))	('expression', 'Var', (34, 44))	('epithelial growths', 'CPA', (77, 95))
543542	31172135	In non-small cell lung cancer with an activating epidermal growth factor receptor (EGFR) mutation, Oct4 was also associated with treatment resistance and expression of CD133.	('EGFR', 'Gene', '1956', (83, 87))	('associated with', 'Reg', (113, 128))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (3, 29))	('activating', 'PosReg', (38, 48))	('epidermal growth factor receptor', 'Gene', (49, 81))	('treatment resistance', 'CPA', (129, 149))	('mutation', 'Var', (89, 97))	('EGFR', 'Gene', (83, 87))	('lung cancer', 'Phenotype', 'HP:0100526', (18, 29))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (3, 29))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (7, 29))	('epidermal growth factor receptor', 'Gene', '1956', (49, 81))	('CD133', 'Gene', (168, 173))	('non-small cell lung cancer', 'Disease', (3, 29))	('expression', 'MPA', (154, 164))
543550	31172135	In a separate study of human non-small cell lung cancer, Oct4 expression was associated with poor differentiation, and poor prognosis in patients who underwent surgical resection Oct4 was also overexpressed in ovarian cancer samples and was correlated with histological grade.	('lung cancer', 'Phenotype', 'HP:0100526', (44, 55))	('Oct4', 'Gene', (179, 183))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (29, 55))	('ovarian cancer', 'Disease', 'MESH:D010051', (210, 224))	('correlated', 'Reg', (241, 251))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (33, 55))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('overexpressed', 'PosReg', (193, 206))	('human', 'Species', '9606', (23, 28))	('Oct4', 'Gene', (57, 61))	('ovarian cancer', 'Disease', (210, 224))	('associated', 'Reg', (77, 87))	('poor differentiation', 'CPA', (93, 113))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (29, 55))	('patients', 'Species', '9606', (137, 145))	('ovarian cancer', 'Phenotype', 'HP:0100615', (210, 224))	('non-small cell lung cancer', 'Disease', (29, 55))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('expression', 'Var', (62, 72))
543554	31172135	Oct4-mediated expression of FSH, leading to apoptotic inhibition also increased the expansion of ovarian stem-like cancer cells and upregulated the expression of other cancer-relevant genes like Notch, Sox2, and Nanog.	('apoptotic inhibition', 'MPA', (44, 64))	('expression', 'Var', (14, 24))	('cancer', 'Disease', (115, 121))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('expression', 'MPA', (148, 158))	('increased', 'PosReg', (70, 79))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('expansion', 'CPA', (84, 93))	('cancer', 'Disease', (168, 174))	('FSH', 'Gene', (28, 31))	('upregulated', 'PosReg', (132, 143))	('cancer', 'Disease', 'MESH:D009369', (115, 121))
543559	31172135	NEAT1 or MALAT1 overexpression led to cancer cell proliferation, migration, and invasion, and knocking down NEAT1 or MALAT1 decreased cancer cell growth and motility.	('MALAT1', 'Gene', '378938', (9, 15))	('NEAT1', 'Gene', (0, 5))	('MALAT1', 'Gene', (117, 123))	('cancer', 'Disease', (134, 140))	('NEAT1', 'Gene', '283131', (108, 113))	('cancer', 'Disease', (38, 44))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('MALAT1', 'Gene', '378938', (117, 123))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('knocking down', 'Var', (94, 107))	('invasion', 'CPA', (80, 88))	('migration', 'CPA', (65, 74))	('overexpression', 'PosReg', (16, 30))	('NEAT1', 'Gene', '283131', (0, 5))	('cancer', 'Disease', 'MESH:D009369', (134, 140))	('decreased', 'NegReg', (124, 133))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('MALAT1', 'Gene', (9, 15))	('NEAT1', 'Gene', (108, 113))
543560	31172135	These lncRNAs were so important to cancer progression that co-expression of both, along with Oct4 was predictive of poor prognosis in lung cancer patients.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('lung cancer', 'Disease', (134, 145))	('lung cancer', 'Phenotype', 'HP:0100526', (134, 145))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('co-expression', 'Var', (59, 72))	('lung cancer', 'Disease', 'MESH:D008175', (134, 145))	('cancer', 'Disease', 'MESH:D009369', (35, 41))	('patients', 'Species', '9606', (146, 154))	('cancer', 'Disease', (35, 41))	('cancer', 'Disease', (139, 145))
543573	31172135	In a mouse model of mammary cancer, Nanog signaling accelerated tumor growth and caused tumors to be highly metastatic.	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('tumor', 'Disease', (64, 69))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('caused', 'Reg', (81, 87))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('mouse', 'Species', '10090', (5, 10))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('tumors', 'Disease', (88, 94))	('cancer', 'Disease', (28, 34))	('tumor', 'Disease', (88, 93))	('accelerated', 'PosReg', (52, 63))	('Nanog signaling', 'Var', (36, 51))
543578	31172135	In hepatocellular carcinoma, expression of Nanog was correlated with a worse clinical outcome.	('carcinoma', 'Phenotype', 'HP:0030731', (18, 27))	('hepatocellular carcinoma', 'Disease', (3, 27))	('expression', 'Var', (29, 39))	('correlated', 'Reg', (53, 63))	('Nanog', 'Gene', (43, 48))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (3, 27))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (3, 27))
543589	31172135	Nevertheless, it is possible that the effect of Nanog is tumor or tissue specific and warrants further research.	('tumor', 'Disease', (57, 62))	('Nanog', 'Var', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('tumor', 'Disease', 'MESH:D009369', (57, 62))
543590	31172135	Nanog may exert its tumorigenic effects via a variety of downstream targets.	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('Nanog', 'Var', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('tumor', 'Disease', (20, 25))
543593	31172135	In this model, Nanog was found to be associated with the expression of a number of tumor-relevant genes, including EMT markers and PDGFRa, which can also drive tumorigenesis, angiogenesis, and metastasis, corroborating Nanog's effect in breast cancer.	('expression', 'MPA', (57, 67))	('Nanog', 'Var', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('drive', 'PosReg', (154, 159))	('PDGFRa', 'Gene', (131, 137))	('tumor', 'Disease', (83, 88))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('breast cancer', 'Disease', 'MESH:D001943', (237, 250))	('metastasis', 'CPA', (193, 203))	('breast cancer', 'Disease', (237, 250))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('angiogenesis', 'CPA', (175, 187))	('breast cancer', 'Phenotype', 'HP:0003002', (237, 250))	('tumor', 'Disease', (160, 165))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('PDGFRa', 'Gene', '5156', (131, 137))
543595	31172135	Nanog expression levels decreased when IGF1R was knocked out, indicating the presence of some sort of feedback loop along this signaling axis.	('Nanog expression levels', 'MPA', (0, 23))	('IGF1R', 'Gene', (39, 44))	('knocked out', 'Var', (49, 60))	('decreased', 'NegReg', (24, 33))	('IGF1R', 'Gene', '3480', (39, 44))
543597	31172135	Interestingly, in human colorectal carcinoma, NANOG knockdown decreased expression of SOX2 and OCT4, indicating that the probable feedback loop between these three factors is relevant in cancer as well.	('cancer', 'Disease', 'MESH:D009369', (187, 193))	('carcinoma', 'Phenotype', 'HP:0030731', (35, 44))	('SOX2', 'Gene', '6657', (86, 90))	('decreased', 'NegReg', (62, 71))	('cancer', 'Disease', (187, 193))	('SOX2', 'Gene', (86, 90))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (24, 44))	('human', 'Species', '9606', (18, 23))	('expression', 'MPA', (72, 82))	('NANOG', 'Gene', '79923', (46, 51))	('OCT4', 'Gene', '5460', (95, 99))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('OCT4', 'Gene', (95, 99))	('colorectal carcinoma', 'Disease', (24, 44))	('knockdown', 'Var', (52, 61))	('NANOG', 'Gene', (46, 51))
543601	31172135	Cells given DHT had higher tumorigenesis, proliferation, migration, and colony and sphere formation, all phenotypes observed in NANOG-high cancers.	('NANOG', 'Gene', (128, 133))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('DHT', 'Var', (12, 15))	('proliferation', 'CPA', (42, 55))	('tumor', 'Disease', (27, 32))	('cancers', 'Disease', 'MESH:D009369', (139, 146))	('cancers', 'Phenotype', 'HP:0002664', (139, 146))	('higher', 'PosReg', (20, 26))	('cancers', 'Disease', (139, 146))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('migration', 'CPA', (57, 66))	('DHT', 'Chemical', '-', (12, 15))	('NANOG', 'Gene', '79923', (128, 133))	('tumor', 'Disease', 'MESH:D009369', (27, 32))
543618	30538558	In the genomic alterations analysis, two hotspot mutations (S2021C/F and E314K/V) were identified in Pfam protein domains.	('S2021C', 'Var', (60, 66))	('E314K', 'Var', (73, 78))	('S2021C', 'SUBSTITUTION', 'None', (60, 66))	('E314K', 'SUBSTITUTION', 'None', (73, 78))
543623	30538558	The high incidence of lung cancer is due to tobacco smoking, indoor air pollution, outdoor pollution, genetic alterations, and other factors.	('lung cancer', 'Disease', (22, 33))	('lung cancer', 'Phenotype', 'HP:0100526', (22, 33))	('tobacco', 'Species', '4097', (44, 51))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('due', 'Reg', (37, 40))	('lung cancer', 'Disease', 'MESH:D008175', (22, 33))	('genetic alterations', 'Var', (102, 121))
543624	30538558	The genetic alterations associated with lung cancer include epidermal growth factor receptor (EGFR) mutations, anaplastic lymphoma kinase (ALK) fusion or rearrangement, and other aberrations.	('mutations', 'Var', (100, 109))	('ALK', 'Gene', (139, 142))	('rearrangement', 'Var', (154, 167))	('EGFR', 'Gene', '1956', (94, 98))	('men', 'Species', '9606', (163, 166))	('fusion', 'Var', (144, 150))	('epidermal growth factor receptor', 'Gene', '1956', (60, 92))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('anaplastic lymphoma kinase', 'Gene', '238', (111, 137))	('lung cancer', 'Disease', 'MESH:D008175', (40, 51))	('EGFR', 'Gene', (94, 98))	('lymphoma', 'Phenotype', 'HP:0002665', (122, 130))	('epidermal growth factor receptor', 'Gene', (60, 92))	('ALK', 'Gene', '238', (139, 142))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (111, 130))	('anaplastic lymphoma kinase', 'Gene', (111, 137))	('lung cancer', 'Disease', (40, 51))	('lung cancer', 'Phenotype', 'HP:0100526', (40, 51))
543645	30538558	In the present study, alteration frequencies of hub genes were performed based on Mutation and DNA copy-number alterations in four selected lung cancer subtypes (Pan-Lung Cancer-TCGA, Nat Genet 2016; Lung Adenocarcinoma-TCGA, Provisional; Lung Squamous Cell Carcinoma-TCGA, Provisional; Small-Cell Lung Cancer, U Cologne, Nature 2015).	('carcinoma', 'Phenotype', 'HP:0030731', (210, 219))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('Lung Squamous Cell Carcinoma', 'Phenotype', 'HP:0030359', (239, 267))	('Adenocarcinoma', 'Disease', (205, 219))	('Lung Adenocarcinoma', 'Phenotype', 'HP:0030078', (200, 219))	('Lung Squamous Cell Carcinoma', 'Disease', (239, 267))	('hub', 'Gene', (48, 51))	('lung cancer', 'Disease', (140, 151))	('Lung Cancer', 'Phenotype', 'HP:0100526', (166, 177))	('Carcinoma', 'Phenotype', 'HP:0030731', (258, 267))	('Small-Cell Lung Cancer', 'Disease', 'MESH:D055752', (287, 309))	('hub', 'Gene', '1993', (48, 51))	('DNA', 'Gene', (95, 98))	('Cancer', 'Phenotype', 'HP:0002664', (303, 309))	('Mutation', 'Var', (82, 90))	('Small-Cell Lung Cancer', 'Disease', (287, 309))	('lung cancer', 'Disease', 'MESH:D008175', (140, 151))	('Lung Cancer', 'Phenotype', 'HP:0100526', (298, 309))	('Adenocarcinoma', 'Disease', 'MESH:D000230', (205, 219))	('lung cancer', 'Phenotype', 'HP:0100526', (140, 151))	('Cancer', 'Phenotype', 'HP:0002664', (171, 177))	('Lung Squamous Cell Carcinoma', 'Disease', 'MESH:D002294', (239, 267))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (244, 267))	('alterations', 'Var', (111, 122))	('Small-Cell Lung Cancer', 'Phenotype', 'HP:0030357', (287, 309))
543664	30538558	Further, the graphical summary of mutations showed that there were 113 CENPF nonsynonymous mutations in lung cancer samples, and 3 of them were S2021C/F in the CENPF domain (Figure 8B).	('CENPF', 'Gene', (160, 165))	('CENPF', 'Gene', (71, 76))	('lung cancer', 'Disease', 'MESH:D008175', (104, 115))	('S2021C', 'Var', (144, 150))	('S2021C', 'SUBSTITUTION', 'None', (144, 150))	('CENPF', 'Gene', '1063', (71, 76))	('CENPF', 'Gene', '1063', (160, 165))	('lung cancer', 'Disease', (104, 115))	('lung cancer', 'Phenotype', 'HP:0100526', (104, 115))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))
543665	30538558	There were six CENPU nonsynonymous mutations in lung cancer samples, two of them being E314K/V in the CENPU domain (Figure 8C).	('nonsynonymous mutations', 'Var', (21, 44))	('CENPU', 'Gene', (102, 107))	('lung cancer', 'Disease', 'MESH:D008175', (48, 59))	('CENPU', 'Gene', '79682', (15, 20))	('CENPU', 'Gene', '79682', (102, 107))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('lung cancer', 'Disease', (48, 59))	('E314K', 'Var', (87, 92))	('E314K', 'SUBSTITUTION', 'None', (87, 92))	('lung cancer', 'Phenotype', 'HP:0100526', (48, 59))	('CENPU', 'Gene', (15, 20))
543667	30538558	The results showed that high AUARB mRNA expression (HR =1.84 [1.62-2.1], log-rank P<1x10-16) was associated with worse overall survival for lung cancer patients, as were KIF2C (HR =1.78 [1.57-2.03], log-rank P<1x10-16), BUB1B (HR =1.71 [1.5-1.94], log-rank P=2.2x10-16), HMMR (HR =1.44 [1.27-1.64], log-rank P=1.5x10-08), CENPF (HR =1.57 [1.38-1.78], log-rank P=3.4x10-12), and CENPU (HR =1.86 [1.58-2.21], log-rank P=1.5x10-13) (Figure 9).	('lung cancer', 'Disease', (140, 151))	('AUARB', 'Gene', (29, 34))	('CENPU', 'Gene', (378, 383))	('BUB1B', 'Gene', '701', (220, 225))	('CENPF', 'Gene', '1063', (322, 327))	('HMMR', 'Gene', '3161', (271, 275))	('BUB1B', 'Gene', (220, 225))	('lung cancer', 'Phenotype', 'HP:0100526', (140, 151))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('HMMR', 'Gene', (271, 275))	('KIF2C', 'Gene', (170, 175))	('lung cancer', 'Disease', 'MESH:D008175', (140, 151))	('high', 'Var', (24, 28))	('patients', 'Species', '9606', (152, 160))	('CENPU', 'Gene', '79682', (378, 383))	('CENPF', 'Gene', (322, 327))	('KIF2C', 'Gene', '11004', (170, 175))	('worse', 'NegReg', (113, 118))
543674	30538558	We found hub genes mutation frequencies were the highest in LAC.	('mutation', 'Var', (19, 27))	('hub', 'Gene', (9, 12))	('highest', 'Reg', (49, 56))	('LAC', 'Phenotype', 'HP:0030078', (60, 63))	('hub', 'Gene', '1993', (9, 12))
543676	30538558	Two hotspot mutations (S2021C/F and E314K/V) were identified in Pfam protein domains, illustrating that these may be potential targets for lung cancer.	('lung cancer', 'Disease', (139, 150))	('S2021C', 'Var', (23, 29))	('S2021C', 'SUBSTITUTION', 'None', (23, 29))	('E314K', 'Var', (36, 41))	('E314K', 'SUBSTITUTION', 'None', (36, 41))	('lung cancer', 'Disease', 'MESH:D008175', (139, 150))	('lung cancer', 'Phenotype', 'HP:0100526', (139, 150))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
543681	30538558	Overexpression of an inactive form of Aurora B results in multinucleation and polyploidy, and tetraploidy has been shown to increase the frequency of chromosomal alterations and promote tumorigenesis of p53-deficient cells.	('increase', 'PosReg', (124, 132))	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('multinucleation', 'CPA', (58, 73))	('tetraploidy', 'Var', (94, 105))	('polyploidy', 'Disease', 'MESH:D011123', (78, 88))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('promote', 'PosReg', (178, 185))	('chromosomal alterations', 'CPA', (150, 173))	('Aurora B', 'Gene', (38, 46))	('results in', 'Reg', (47, 57))	('tumor', 'Disease', (186, 191))	('Aurora B', 'Gene', '9212', (38, 46))	('increase the frequency of chromosomal alterations', 'Phenotype', 'HP:0040012', (124, 173))	('p53', 'Gene', '7157', (203, 206))	('polyploidy', 'Disease', (78, 88))	('p53', 'Gene', (203, 206))
543690	30538558	The abnormal expression of KIF2C is associated with abnormal mitosis, chromosomal aberrations, and malignant transformation.	('abnormal mitosis', 'Disease', (52, 68))	('abnormal', 'Var', (4, 12))	('KIF2C', 'Gene', (27, 32))	('abnormal mitosis', 'Disease', 'MESH:D000014', (52, 68))	('KIF2C', 'Gene', '11004', (27, 32))	('chromosomal aberrations', 'Phenotype', 'HP:0040012', (70, 93))	('malignant transformation', 'CPA', (99, 123))	('associated', 'Reg', (36, 46))	('chromosomal aberrations', 'CPA', (70, 93))
543691	30538558	Therefore, the deregulation of KIF2C expression can contribute to cancer development and progression.	('progression', 'CPA', (89, 100))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('KIF2C', 'Gene', (31, 36))	('men', 'Species', '9606', (80, 83))	('KIF2C', 'Gene', '11004', (31, 36))	('deregulation', 'Var', (15, 27))	('contribute', 'Reg', (52, 62))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('expression', 'MPA', (37, 47))	('cancer', 'Disease', (66, 72))
543702	30538558	Aberrant expression or mutations of BUB1B can cause aneuploidy.	('Aberrant expression', 'Var', (0, 19))	('aneuploidy', 'Disease', (52, 62))	('mutations', 'Var', (23, 32))	('aneuploidy', 'Disease', 'MESH:D000782', (52, 62))	('cause', 'Reg', (46, 51))	('BUB1B', 'Gene', (36, 41))	('BUB1B', 'Gene', '701', (36, 41))
543707	30538558	Cell cycle dysregulation underlies the aberrant cell proliferation that characterizes cancer, and the loss of cell cycle checkpoint control promotes genetic instability.	('aberrant cell proliferation', 'Phenotype', 'HP:0031377', (39, 66))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('cell proliferation', 'CPA', (48, 66))	('Cell cycle dysregulation', 'Phenotype', 'HP:0011018', (0, 24))	('Cell cycle', 'CPA', (0, 10))	('genetic', 'MPA', (149, 156))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('loss', 'Var', (102, 106))	('cancer', 'Disease', (86, 92))
543719	30538558	Andriani et al reported that lung cancers with both FHIT and p53 inactivation displayed high levels of CENPF expression.	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('lung cancers', 'Disease', 'MESH:D008175', (29, 41))	('expression', 'MPA', (109, 119))	('inactivation', 'Var', (65, 77))	('lung cancers', 'Phenotype', 'HP:0100526', (29, 41))	('CENPF', 'Gene', (103, 108))	('CENPF', 'Gene', '1063', (103, 108))	('p53', 'Gene', '7157', (61, 64))	('cancers', 'Phenotype', 'HP:0002664', (34, 41))	('FHIT', 'Gene', (52, 56))	('lung cancers', 'Disease', (29, 41))	('p53', 'Gene', (61, 64))	('lung cancer', 'Phenotype', 'HP:0100526', (29, 40))	('FHIT', 'Gene', '2272', (52, 56))
543729	30538558	These observations suggested that CENPU abnormalities may contribute to the risk of developing lung cancer.	('lung cancer', 'Disease', (95, 106))	('lung cancer', 'Phenotype', 'HP:0100526', (95, 106))	('CENPU', 'Gene', (34, 39))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('contribute', 'Reg', (58, 68))	('lung cancer', 'Disease', 'MESH:D008175', (95, 106))	('CENPU', 'Gene', '79682', (34, 39))	('abnormalities', 'Var', (40, 53))
543738	24871328	The overarching goal is to elucidate the landscape of DNA and RNA aberrations within and across tumor lineages and integrate the information with clinical characteristics, including patient outcome.	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('clinical', 'Species', '191496', (146, 154))	('tumor', 'Disease', (96, 101))	('patient', 'Species', '9606', (182, 189))	('RNA', 'Gene', (62, 65))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('DNA', 'Gene', (54, 57))	('aberrations', 'Var', (66, 77))
543762	24871328	Besides diversity in methodology, a number of cancer specific hypotheses, including post-translational regulation of HER2 expression, cytoplasmic HER2 localization, intratumoral heterogeneity of HER2 amplification or polysomy 17 have been suggested.	('HER2', 'Gene', (117, 121))	('amplification', 'Var', (200, 213))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('polysomy 17', 'Var', (217, 228))	('HER2', 'Gene', '2064', (146, 150))	('HER2', 'Gene', '2064', (117, 121))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('cancer', 'Disease', (46, 52))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('tumor', 'Disease', (170, 175))	('HER2', 'Gene', (195, 199))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('HER2', 'Gene', '2064', (195, 199))	('HER2', 'Gene', (146, 150))
543764	24871328	With the advent of TDM1 toxin conjugate therapy (trastuzumab emtansine), the higher frequency of elevated HER2 protein levels in BLCA, LUAD, endometrial, and colorectal cancers supports the (pre)clinical exploration of TDM1, which binds HER2 to deliver a potent cell-cycle toxin (a mechanism of activity independent from trastuzumab, a drug with limited activity in endometrial cancer in previous studies) in these tumor lineages.	('colorectal cancer', 'Phenotype', 'HP:0003003', (158, 175))	('endometrial cancer', 'Disease', 'MESH:D016889', (366, 384))	('colorectal cancers', 'Disease', (158, 176))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('TDM1', 'Var', (219, 223))	('tumor', 'Disease', (415, 420))	('HER2', 'Gene', (106, 110))	('tumor', 'Disease', 'MESH:D009369', (415, 420))	('trastuzumab', 'Chemical', 'MESH:D000068878', (321, 332))	('elevated', 'PosReg', (97, 105))	('colorectal cancers', 'Disease', 'MESH:D015179', (158, 176))	('HER2', 'Gene', '2064', (237, 241))	('tumor', 'Phenotype', 'HP:0002664', (415, 420))	('clinical', 'Species', '191496', (195, 203))	('endometrial cancer', 'Phenotype', 'HP:0012114', (366, 384))	('cancer', 'Phenotype', 'HP:0002664', (378, 384))	('trastuzumab', 'Chemical', 'MESH:D000068878', (49, 60))	('HER2', 'Gene', '2064', (106, 110))	('endometrial cancer', 'Disease', (366, 384))	('HER2', 'Gene', (237, 241))	('cancers', 'Phenotype', 'HP:0002664', (169, 176))
543767	24871328	Associations of specific mutations and copy number changes with the clusters were primarily based on known associations of mutations and copy number changes with tumor lineage.	('mutations', 'Var', (25, 34))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('Associations', 'Interaction', (0, 12))	('tumor', 'Disease', (162, 167))	('copy number', 'Var', (39, 50))	('tumor', 'Disease', 'MESH:D009369', (162, 167))
543768	24871328	Cluster_E includes 70% of basal-like breast cancers, the majority of HER2 positive breast cancers (87%) and the largest group of bladder cancers (35%), including many with amplified HER2 (Fig.	('breast cancers', 'Disease', (37, 51))	('amplified', 'Var', (172, 181))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('breast cancers', 'Disease', 'MESH:D001943', (83, 97))	('breast cancers', 'Disease', (83, 97))	('cancers', 'Phenotype', 'HP:0002664', (137, 144))	('breast cancers', 'Phenotype', 'HP:0003002', (37, 51))	('bladder cancers', 'Phenotype', 'HP:0009725', (129, 144))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('bladder cancer', 'Phenotype', 'HP:0009725', (129, 143))	('breast cancer', 'Phenotype', 'HP:0003002', (37, 50))	('breast cancers', 'Phenotype', 'HP:0003002', (83, 97))	('breast cancer', 'Phenotype', 'HP:0003002', (83, 96))	('HER2', 'Gene', '2064', (69, 73))	('HER2', 'Gene', '2064', (182, 186))	('bladder cancers', 'Disease', 'MESH:D001749', (129, 144))	('bladder cancers', 'Disease', (129, 144))	('cancers', 'Phenotype', 'HP:0002664', (44, 51))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('HER2', 'Gene', (69, 73))	('HER2', 'Gene', (182, 186))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('breast cancers', 'Disease', 'MESH:D001943', (37, 51))
543769	24871328	Cluster_E is defined by TP53 mutations, elevated HER2, cyclinB1 and Rab25 protein levels and low ER and PR levels (Supplementary Table 2).	('cyclinB1', 'Gene', (55, 63))	('cyclinB1', 'Gene', '891', (55, 63))	('TP53', 'Gene', (24, 28))	('elevated', 'PosReg', (40, 48))	('mutations', 'Var', (29, 38))	('HER2', 'Gene', '2064', (49, 53))	('Rab25', 'Gene', '57111', (68, 73))	('HER2', 'Gene', (49, 53))	('low', 'NegReg', (93, 96))	('Rab25', 'Gene', (68, 73))	('TP53', 'Gene', '7157', (24, 28))
543773	24871328	Membership in cluster_F is associated with TP53 mutations and elevated total and phosphorylated EGFR (EGFRp1068 and EGFRp1173), phosphorylated SRC (SRCpY527) and low ER and PR levels.	('EGFR', 'Protein', (96, 100))	('EGFRp1173', 'Var', (116, 125))	('TP53', 'Gene', '7157', (43, 47))	('TP53', 'Gene', (43, 47))	('elevated', 'PosReg', (62, 70))	('mutations', 'Var', (48, 57))	('low', 'NegReg', (162, 165))
543774	24871328	Although TP53 mutations are usually associated with copy number changes and a limited number of recurrent mutations in cancer genes, cluster_F is unexpectedly enriched in recurrent cancer gene mutations (Supplementary Table 6).	('cancer', 'Phenotype', 'HP:0002664', (181, 187))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('TP53', 'Gene', '7157', (9, 13))	('cancer', 'Disease', (119, 125))	('mutations', 'Var', (193, 202))	('TP53', 'Gene', (9, 13))	('cancer', 'Disease', 'MESH:D009369', (181, 187))	('cancer', 'Disease', (181, 187))	('associated', 'Reg', (36, 46))	('mutations', 'Var', (14, 23))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
543775	24871328	3), tumors with TP53 mutations show significantly higher rates of co-mutations in the top-25 driver mutations (Methods, P<0.0001, t-test, n=162).	('higher', 'PosReg', (50, 56))	('tumors', 'Disease', (4, 10))	('co-mutations', 'MPA', (66, 78))	('tumors', 'Disease', 'MESH:D009369', (4, 10))	('tumors', 'Phenotype', 'HP:0002664', (4, 10))	('TP53', 'Gene', '7157', (16, 20))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('TP53', 'Gene', (16, 20))	('mutations', 'Var', (21, 30))
543782	24871328	2d) may be due to the absence of VHL mutations (Fisher's exact test (FE), P = 0.008, n=454), which has been associated with a worse outcome in kidney cancer.	('absence', 'NegReg', (22, 29))	('kidney cancer', 'Disease', (143, 156))	('VHL', 'Gene', (33, 36))	('mutations', 'Var', (37, 46))	('VHL', 'Gene', '7428', (33, 36))	('kidney cancer', 'Disease', 'MESH:D007680', (143, 156))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('kidney cancer', 'Phenotype', 'HP:0009726', (143, 156))
543783	24871328	Bladder cancers in cluster_B show worse survival compared to all other BLCA, which may be due to associations with TP53 mutation (FE, P<0.001) and cMYC amplification (FE, P = 0.042) (n=127) (Fig.	('cMYC', 'Gene', (147, 151))	('cancers', 'Phenotype', 'HP:0002664', (8, 15))	('Bladder cancers', 'Phenotype', 'HP:0009725', (0, 15))	('worse', 'NegReg', (34, 39))	('Bladder cancer', 'Phenotype', 'HP:0009725', (0, 14))	('cMYC', 'Gene', '4609', (147, 151))	('TP53', 'Gene', '7157', (115, 119))	('mutation', 'Var', (120, 128))	('associations', 'Interaction', (97, 109))	('survival', 'MPA', (40, 48))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('TP53', 'Gene', (115, 119))	('Bladder cancers', 'Disease', (0, 15))	('Bladder cancers', 'Disease', 'MESH:D001749', (0, 15))
543789	24871328	Cluster_I was primarily driven by phosphoPEA15, YB1, EEF2 and ETS1 proteins (Supplementary Table 9), which were markedly elevated in a subset of colorectal tumors (18%).	('EEF2', 'Gene', (53, 57))	('colorectal tumors', 'Disease', 'MESH:D015179', (145, 162))	('ETS1', 'Gene', '2113', (62, 66))	('ETS1', 'Gene', (62, 66))	('YB1', 'Gene', (48, 51))	('phosphoPEA15', 'Var', (34, 46))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('colorectal tumors', 'Disease', (145, 162))	('YB1', 'Gene', '4904', (48, 51))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('EEF2', 'Gene', '1938', (53, 57))	('elevated', 'PosReg', (121, 129))
543794	24871328	Tumors in cluster_IIb were enriched in EGFR mutations, contained few PTEN mutations, and had elevated RTK pathway and suppressed mTOR pathway signatures.	('RTK pathway', 'Pathway', (102, 113))	('PTEN', 'Gene', '5728', (69, 73))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('suppressed', 'NegReg', (118, 128))	('mTOR', 'Gene', '2475', (129, 133))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('mTOR', 'Gene', (129, 133))	('mutations', 'Var', (44, 53))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('EGFR', 'Gene', (39, 43))	('elevated', 'PosReg', (93, 101))	('PTEN', 'Gene', (69, 73))
543800	24871328	Cluster_III also had high beta-catenin levels, suggesting activation of the canonical Wnt-signaling pathway.	('beta-catenin', 'Gene', '1499', (26, 38))	('Cluster_III', 'Var', (0, 11))	('canonical Wnt-signaling pathway', 'Pathway', (76, 107))	('high', 'PosReg', (21, 25))	('beta-catenin', 'Gene', (26, 38))	('activation', 'PosReg', (58, 68))
543801	24871328	Cluster_IV also had high beta-catenin, as well as activated AKT, MAPK and mTOR pathways, but suppressed DNA damage, apoptosis, EMT and cell cycle pathways.	('MAPK', 'Pathway', (65, 69))	('EMT', 'Gene', (127, 130))	('activated', 'PosReg', (50, 59))	('EMT', 'Gene', '3702', (127, 130))	('apoptosis', 'CPA', (116, 125))	('beta-catenin', 'Gene', '1499', (25, 37))	('high', 'PosReg', (20, 24))	('AKT', 'Gene', '207', (60, 63))	('mTOR', 'Gene', (74, 78))	('mTOR', 'Gene', '2475', (74, 78))	('Cluster_IV', 'Var', (0, 10))	('suppressed', 'NegReg', (93, 103))	('DNA', 'MPA', (104, 107))	('beta-catenin', 'Gene', (25, 37))	('AKT', 'Gene', (60, 63))	('cell cycle pathways', 'CPA', (135, 154))
543807	24871328	COAD in cluster_V had better outcome compared to COAD located in other clusters (Fig.	('COAD', 'Disease', (0, 4))	('cluster_V', 'Var', (8, 17))	('COAD', 'Disease', (49, 53))	('COAD', 'Disease', 'MESH:D029424', (0, 4))	('COAD', 'Disease', 'MESH:D029424', (49, 53))
543808	24871328	3g) (n=334), which may, in part, be due to depletion of mutations in TP53 (6% vs. 15%, Fisher's Exact (FE) P = 0.05), APC (14% vs. 25%, FE P = 0.044) and KRAS (5% vs. 16%, FE P = 0.013), consistent with previous literature showing these are associated with a worse outcome.	('KRAS', 'Gene', '3845', (154, 158))	('mutations', 'Var', (56, 65))	('TP53', 'Gene', '7157', (69, 73))	('TP53', 'Gene', (69, 73))	('depletion', 'MPA', (43, 52))	('APC', 'Disease', 'MESH:D011125', (118, 121))	('APC', 'Disease', (118, 121))	('KRAS', 'Gene', (154, 158))
543809	24871328	The poor outcome for KIRC in cluster_VII may be partly due to enrichment of TP53 mutations (6% vs. 0.8%, FE P = 0.005, n=454) (Fig.	('TP53', 'Gene', '7157', (76, 80))	('TP53', 'Gene', (76, 80))	('mutations', 'Var', (81, 90))
543813	24871328	In general in the RBN analysis, pathway scores were associated with tumor lineage (Fig.	('tumor', 'Disease', (68, 73))	('associated', 'Reg', (52, 62))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('pathway scores', 'Var', (32, 46))
543844	24871328	PhosphoSRC (SRCpY416) and the transferrin receptor (TFRC) showed an association in three diseases suggesting particular importance for outcome.	('TFRC', 'Gene', '7037', (52, 56))	('association', 'Interaction', (68, 79))	('transferrin receptor', 'Gene', '7037', (30, 50))	('PhosphoSRC (SRCpY416', 'Var', (0, 20))	('TFRC', 'Gene', (52, 56))	('transferrin receptor', 'Gene', (30, 50))	('three diseases', 'Disease', (83, 97))
543850	24871328	Other expected links were seen in only a subset of tumors such as pAKT with pPRAS40 and pTSC2 (tuberinPT1462), consistent with differential wiring of signaling pathways in different cancers.	('AKT', 'Gene', '207', (67, 70))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('TSC', 'Gene', (89, 92))	('TSC', 'Gene', '7248', (89, 92))	('AKT', 'Gene', (67, 70))	('pPRAS40', 'Var', (76, 83))	('cancers', 'Phenotype', 'HP:0002664', (182, 189))	('tumors', 'Disease', (51, 57))	('tumors', 'Disease', 'MESH:D009369', (51, 57))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('cancers', 'Disease', (182, 189))	('cancers', 'Disease', 'MESH:D009369', (182, 189))
543876	24871328	This mainly concerns EGFRpY1068 (but not EGFRpY1173), which cross-reacts with overexpressed HER2pY1248.	('EGFRpY1068', 'Var', (21, 31))	('HER2', 'Gene', '2064', (92, 96))	('HER2', 'Gene', (92, 96))
543892	24871328	We therefore compared samples in which HER2 was amplified vs. not amplified, aiming to find a threshold that might be reasonable to test.	('HER2', 'Gene', '2064', (39, 43))	('amplified', 'Var', (48, 57))	('HER2', 'Gene', (39, 43))
543900	24871328	Significantly mutated genes (present in more than 5% of tumors in the dataset, resulting in 16 genes) are included as are the two most frequently observed amplifications.	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('mutated', 'Var', (14, 21))	('tumors', 'Disease', (56, 62))	('tumors', 'Phenotype', 'HP:0002664', (56, 62))	('tumors', 'Disease', 'MESH:D009369', (56, 62))
543929	24244370	An Integrated Inspection of the Somatic Mutations in a Lung Squamous Cell Carcinoma Using Next-Generation Sequencing Squamous cell carcinoma (SCC) of the lung kills over 350,000 people annually worldwide, and is the main lung cancer histotype with no targeted treatments.	('people', 'Species', '9606', (178, 184))	('Carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('Squamous cell carcinoma', 'Disease', 'MESH:D002294', (117, 140))	('Squamous Cell Carcinoma', 'Disease', 'MESH:D002294', (60, 83))	('lung cancer', 'Disease', 'MESH:D008175', (221, 232))	('Lung Squamous Cell Carcinoma', 'Phenotype', 'HP:0030359', (55, 83))	('SCC', 'Gene', (142, 145))	('Mutations', 'Var', (40, 49))	('Squamous cell carcinoma', 'Phenotype', 'HP:0002860', (117, 140))	('Squamous Cell Carcinoma', 'Disease', (60, 83))	('SCC', 'Gene', '6317', (142, 145))	('Squamous cell carcinoma', 'Disease', (117, 140))	('lung cancer', 'Phenotype', 'HP:0100526', (221, 232))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (60, 83))	('lung cancer', 'Disease', (221, 232))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
543933	24244370	Our results show that LUDLU-1 lacks the mutational signature that has been previously associated with tobacco exposure in other lung cancer subtypes, and suggests that DNA-repair efficiency is adversely affected; LUDLU-1 contains somatic mutations in TP53 and BRCA2, allelic imbalance in the expression of two cancer-associated BRCA1 germline polymorphisms and reduced transcription of a potentially endogenous PARP2 inhibitor.	('TP53', 'Gene', (251, 255))	('tobacco', 'Species', '4097', (102, 109))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('reduced', 'NegReg', (361, 368))	('BRCA1', 'Gene', '672', (328, 333))	('BRCA1', 'Gene', (328, 333))	('cancer', 'Disease', (310, 316))	('lung cancer', 'Disease', 'MESH:D008175', (128, 139))	('mutations', 'Var', (238, 247))	('cancer', 'Phenotype', 'HP:0002664', (310, 316))	('lung cancer', 'Phenotype', 'HP:0100526', (128, 139))	('TP53', 'Gene', '7157', (251, 255))	('expression', 'MPA', (292, 302))	('BRCA2', 'Gene', (260, 265))	('cancer', 'Disease', (133, 139))	('transcription', 'MPA', (369, 382))	('cancer', 'Disease', 'MESH:D009369', (310, 316))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('imbalance', 'Phenotype', 'HP:0002172', (275, 284))	('PARP2', 'Gene', '10038', (411, 416))	('PARP2', 'Gene', (411, 416))	('lung cancer', 'Disease', (128, 139))	('BRCA2', 'Gene', '675', (260, 265))
543946	24244370	We have previously catalogued the transcriptional consequences of somatic structural variants in this cell line but here we focus on point mutations, aiming to see whether the mutational signature would give insight into disease etiology or carcinogenic mechanism, as it has for other cancer subtypes.	('variants', 'Var', (85, 93))	('cancer', 'Phenotype', 'HP:0002664', (285, 291))	('carcinogenic', 'Disease', 'MESH:D063646', (241, 253))	('give', 'Reg', (203, 207))	('cancer', 'Disease', (285, 291))	('carcinogenic', 'Disease', (241, 253))	('cancer', 'Disease', 'MESH:D009369', (285, 291))
543951	24244370	All sequencing data have been submitted to the NCBI sequencing read archive (SRA: http://www.ncbi.nlm.nih.gov/sra) under accession numbers ERP001465 (LUDLU-1 and LIMM-NBE1 RNA sequencing) and ERP001771 (LUDLU-1 and AGLCL DNA sequencing).	('SRA', 'Gene', '10011', (77, 80))	('SRA', 'Gene', (77, 80))	('sra', 'Gene', '10011', (110, 113))	('sra', 'Gene', (110, 113))	('ERP001771', 'Var', (192, 201))	('ERP001465', 'Var', (139, 148))
543952	24244370	the tumour sample and matched normal) are compared, to identify somatic variants, using a tool called calldiff that is included in their proprietary cgatools 1.5.0, build 31, software suite.	('tumour', 'Phenotype', 'HP:0002664', (4, 10))	('tumour', 'Disease', 'MESH:D009369', (4, 10))	('tumour', 'Disease', (4, 10))	('variants', 'Var', (72, 80))
543967	24244370	This somatic mutation causes Arg248Trp; this is highly likely to inactivate the tumour-supressor function of p53, a protein involved in DNA repair, by removing the ability of Arg248 to directly contact the DNA response element via the minor groove.	('tumour', 'Disease', (80, 86))	('contact', 'Interaction', (194, 201))	('Arg248', 'Chemical', '-', (29, 35))	('ability', 'MPA', (164, 171))	('tumour', 'Phenotype', 'HP:0002664', (80, 86))	('p53', 'Gene', (109, 112))	('Arg248', 'Var', (175, 181))	('removing', 'NegReg', (151, 159))	('p53', 'Gene', '7157', (109, 112))	('tumour', 'Disease', 'MESH:D009369', (80, 86))	('Arg248Trp', 'SUBSTITUTION', 'None', (29, 38))	('Arg248Trp', 'Var', (29, 38))	('inactivate', 'NegReg', (65, 75))	('Arg248', 'Chemical', '-', (175, 181))
543968	24244370	This specific p53 variant has been shown to be a gain-of-function mutation that promotes tumorigenesis.	('p53', 'Gene', '7157', (14, 17))	('p53', 'Gene', (14, 17))	('tumorigenesis', 'CPA', (89, 102))	('promotes', 'PosReg', (80, 88))	('variant', 'Var', (18, 25))
543969	24244370	Included in the list of genes affected by structural variants is BRCA2, a tumour suppressor gene encoding a protein that repairs double-stranded (ds)DNA breaks by homologous recombination.	('BRCA2', 'Gene', '675', (65, 70))	('tumour', 'Disease', 'MESH:D009369', (74, 80))	('tumour', 'Disease', (74, 80))	('BRCA2', 'Gene', (65, 70))	('tumour', 'Phenotype', 'HP:0002664', (74, 80))	('variants', 'Var', (53, 61))
543972	24244370	This signature consists of an excess of G.T mutations, where G.T denotes a GC base pair being mutated to a TA base pair, and has been observed in both SCLC (34% prevalence) and lung adenocarcinoma (46% prevalence) whole genome sequencing data.	('carcinoma', 'Phenotype', 'HP:0030731', (187, 196))	('lung adenocarcinoma', 'Disease', (177, 196))	('G.T', 'Gene', (40, 43))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (177, 196))	('SCLC', 'Disease', (151, 155))	('mutations', 'Var', (44, 53))	('SCLC', 'Disease', 'MESH:D018288', (151, 155))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (177, 196))
543976	24244370	Tobacco carcinogens cause CpG.T transversions more frequently at methylated CpG dinucelotide resulting in an expected increase in somatic CpG.T mutations outside of CpG islands, where 65% of CpGs are methylated compared to 15% within islands, in smokers.	('transversions', 'Var', (32, 45))	('increase', 'PosReg', (118, 126))	('CpG.T', 'Gene', (26, 31))	('methylated', 'Var', (65, 75))	('Tobacco', 'Species', '4097', (0, 7))	('dinucelotide', 'Chemical', '-', (80, 92))	('mutations', 'Var', (144, 153))	('CpG.T', 'Gene', (138, 143))
543983	24244370	Expression of PARP2 itself shows only modest differences between our samples (62 RPKM in LUDLU-1 and 98 in the normal) but antisense transcripts can regulate their mRNA counterparts post-transcriptionally, most often, though not exclusively, resulting in decreased protein levels.	('regulate', 'Reg', (149, 157))	('protein levels', 'MPA', (265, 279))	('antisense transcripts', 'Var', (123, 144))	('mRNA counterparts', 'MPA', (164, 181))	('decreased', 'NegReg', (255, 264))	('PARP2', 'Gene', '10038', (14, 19))	('PARP2', 'Gene', (14, 19))
543985	24244370	AI is commonly observed in cancer as a result of genomic alterations such as copy number changes and loss of heterozygosity.	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('copy number changes', 'Var', (77, 96))	('loss of heterozygosity', 'Var', (101, 123))	('cancer', 'Disease', (27, 33))	('cancer', 'Disease', 'MESH:D009369', (27, 33))
543988	24244370	In total, 143 of the variants with AI are non-synonymous, with one being somatic and three being germline but located within cancer genes, as summarised in Table 3.	('variants', 'Var', (21, 29))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('cancer', 'Disease', (125, 131))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))
543989	24244370	We note that two non-synonymous, germline BRCA1 variants in LUDLU-1 have imbalanced expression in favour of the mutant allele.	('BRCA1', 'Gene', '672', (42, 47))	('imbalance', 'Phenotype', 'HP:0002172', (73, 82))	('imbalanced expression', 'MPA', (73, 94))	('BRCA1', 'Gene', (42, 47))	('variants', 'Var', (48, 56))	('LUDLU-1', 'Gene', (60, 67))
543990	24244370	In both cases the mutant allele is a genetic modifier of breast cancer risk, indicating that the resulting protein is altered in a manner that, whilst not able to cause disease in isolation, creates a predisposition.	('breast cancer', 'Disease', (57, 70))	('breast cancer', 'Phenotype', 'HP:0003002', (57, 70))	('mutant', 'Var', (18, 24))	('altered', 'Reg', (118, 125))	('protein', 'Protein', (107, 114))	('breast cancer', 'Disease', 'MESH:D001943', (57, 70))	('creates', 'Reg', (191, 198))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
543992	24244370	Transcription-coupled repair (TCR) in a SCLC was recently investigated by ascertaining the expression levels of genes harbouring somatic mutations using microarrays, and annotating expressed variants as being on the transcribed or non-transcribed strand, according to Ensembl gene annotations.	('SCLC', 'Disease', 'MESH:D018288', (40, 44))	('variants', 'Var', (191, 199))	('SCLC', 'Disease', (40, 44))
543993	24244370	1A shows that, in accordance with previous findings, we observed more purine mutations on the non-transcribed than the transcribed strand; we found, however, the reverse to be true for G>A transitions.	('G>A', 'Var', (185, 188))	('purine mutations', 'MPA', (70, 86))	('purine', 'Chemical', 'MESH:C030985', (70, 76))
544005	24244370	G>T transversions as the predominating somatic mutation with altered proportions inside and outside of CpG islands) is not a consequence of exposure to tobacco carcinogens in lung cancers.	('carcinogens in lung cancers', 'Disease', 'MESH:D008175', (160, 187))	('cancers', 'Phenotype', 'HP:0002664', (180, 187))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('transversions', 'Var', (4, 17))	('lung cancer', 'Phenotype', 'HP:0100526', (175, 186))	('lung cancers', 'Phenotype', 'HP:0100526', (175, 187))	('carcinogens in lung cancers', 'Disease', (160, 187))	('tobacco', 'Species', '4097', (152, 159))	('G>T transversions', 'Var', (0, 17))
544013	24244370	Knocking out Trp53, the ortholog in mice, does not directly cause cancer but increases the likelihood of spontaneous tumour formation owing to defective DNA repair or apoptosis.	('DNA', 'MPA', (153, 156))	('apoptosis', 'CPA', (167, 176))	('Trp53', 'Gene', '22059', (13, 18))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('tumour', 'Phenotype', 'HP:0002664', (117, 123))	('tumour', 'Disease', 'MESH:D009369', (117, 123))	('defective', 'NegReg', (143, 152))	('increases', 'PosReg', (77, 86))	('mice', 'Species', '10090', (36, 40))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('tumour', 'Disease', (117, 123))	('Trp53', 'Gene', (13, 18))	('Knocking out', 'Var', (0, 12))	('cancer', 'Disease', (66, 72))
544014	24244370	A somatic deletion in LUDLU-1 is suspected to deactivate one copy of BRCA2.	('BRCA2', 'Gene', '675', (69, 74))	('LUDLU-1', 'Gene', (22, 29))	('deactivate', 'NegReg', (46, 56))	('deletion', 'Var', (10, 18))	('BRCA2', 'Gene', (69, 74))
544016	24244370	Similarly, allelic imbalance in favour of mutant BRCA1 containing 2 germline variants associated with cancer risk could contribute to a DNA-repair deficient phenotype.	('mutant', 'Var', (42, 48))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('BRCA1', 'Gene', '672', (49, 54))	('imbalance', 'Phenotype', 'HP:0002172', (19, 28))	('allelic', 'Var', (11, 18))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('BRCA1', 'Gene', (49, 54))
544030	24244370	The value of whole genome sequencing has been questioned when exon sequencing, possible with much larger sample numbers, can deliver tumour markers and drug targets.	('tumour', 'Disease', (133, 139))	('tumour', 'Phenotype', 'HP:0002664', (133, 139))	('exon sequencing', 'Var', (62, 77))	('tumour', 'Disease', 'MESH:D009369', (133, 139))
544031	24244370	However, our in-depth cross-platform analysis of a single sample has allowed us to speculate on underlying mechanisms of tumourigenesis and predict that hyper-mutation was caused by DNA-repair deficiencies.	('tumour', 'Phenotype', 'HP:0002664', (121, 127))	('hyper-mutation', 'Disease', (153, 167))	('deficiencies', 'Var', (193, 205))	('tumour', 'Disease', 'MESH:D009369', (121, 127))	('tumour', 'Disease', (121, 127))	('caused by', 'Reg', (172, 181))
544066	33613758	According to histologic type, histologic codes were classified as follows: (1) SQCC: 8052, 8070-8075, 8083, 8084, 8123, (2) AD: 8244, 8245, 8250-8255, 8260, 8290, 8310, 8323, 8333, 8480, 8481, 8490, 8507, 8550, 8570, 8571, 8574, and 8576.	('AD', 'Disease', (124, 126))	('AD', 'Disease', 'MESH:D000544', (124, 126))	('8570', 'Var', (211, 215))	('8310', 'Var', (163, 167))	('8323', 'Var', (169, 173))	('8290', 'Var', (157, 161))	('8481', 'Var', (187, 191))	('8260', 'Var', (151, 155))	('8550', 'Var', (205, 209))	('8490', 'Var', (193, 197))	('SQCC', 'Phenotype', 'HP:0002860', (79, 83))	('8574', 'Var', (223, 227))	('8250-8255', 'Var', (140, 149))	('8480', 'Var', (181, 185))	('8571', 'Var', (217, 221))	('8576', 'Var', (233, 237))	('8333', 'Var', (175, 179))
544077	33613758	The HR (95%CI, P) of the SG group were 0.689 (0.519-0.914, P=0.01), 0.896 (0.752-1.067, P=0.217) comparing with the WR group in patients with SQCC and AD, respectively.	('0.896', 'Var', (68, 73))	('SQCC', 'Disease', (142, 146))	('SQCC', 'Phenotype', 'HP:0002860', (142, 146))	('AD', 'Disease', 'MESH:D000544', (151, 153))	('AD', 'Disease', (151, 153))	('patients', 'Species', '9606', (128, 136))
544146	30572031	Short answer: Focal positivity for TTF1 is considered a positive reaction indicating pulmonary adenocarcinoma in the proper clinical context, whereas for p40 the cut-off rate should be positivity in more than 50% of tumor nuclei.	('tumor', 'Disease', (216, 221))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('pulmonary adenocarcinoma', 'Disease', 'MESH:D000230', (85, 109))	('p40', 'Gene', '8626', (154, 157))	('Focal positivity', 'Var', (14, 30))	('pulmonary adenocarcinoma', 'Phenotype', 'HP:0030078', (85, 109))	('tumor', 'Disease', 'MESH:D009369', (216, 221))	('TTF1', 'Gene', (35, 39))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('p40', 'Gene', (154, 157))	('pulmonary adenocarcinoma', 'Disease', (85, 109))
544149	30572031	Regarding TTF1 immunoreactivity, focal positivity is considered a positive reaction (Figure 2), indicative of adenocarcinoma in the proper clinical context.	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('focal positivity', 'Var', (33, 49))	('TTF1', 'Gene', (10, 14))	('adenocarcinoma', 'Disease', (110, 124))	('adenocarcinoma', 'Disease', 'MESH:D000230', (110, 124))
544152	30572031	The cut-off value for p40 should be positivity in more than 50% of tumor nuclei.	('p40', 'Gene', '8626', (22, 25))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('p40', 'Gene', (22, 25))	('tumor', 'Disease', (67, 72))	('positivity', 'Var', (36, 46))
544161	30572031	Another challenging situation is the recurrence of EGFR mutated adenocarcinomas following targeted therapy that results in a pure squamous cell carcinoma that may be p40 positive and TTF1 negative while retaining the original EGFR mutation, sometime with an additional T790M mutation.	('negative', 'NegReg', (188, 196))	('EGFR', 'Gene', (51, 55))	('mutated', 'Var', (56, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('squamous cell carcinoma', 'Disease', (130, 153))	('T790M', 'Var', (269, 274))	('results in', 'Reg', (112, 122))	('p40', 'Gene', (166, 169))	('EGFR', 'Gene', (226, 230))	('EGFR', 'Gene', '1956', (226, 230))	('carcinoma', 'Phenotype', 'HP:0030731', (69, 78))	('EGFR', 'Gene', '1956', (51, 55))	('p40', 'Gene', '8626', (166, 169))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (130, 153))	('adenocarcinomas', 'Disease', 'MESH:D000230', (64, 79))	('adenocarcinomas', 'Disease', (64, 79))	('carcinomas', 'Phenotype', 'HP:0030731', (69, 79))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (130, 153))	('T790M', 'Mutation', 'rs121434569', (269, 274))
544163	30572031	A number of different TTF1 clones are commercially available including rabbit and goat polyclonal antibodies, mouse monoclonal antibodies including 8G7G3/1, SPT24, BGX-397A, SMP150 and 5S143 clones, and rabbit monoclonal antibodies including SP141, EP15844, C12-I and G21-G clones.	('rabbit', 'Species', '9986', (71, 77))	('rabbit', 'Species', '9986', (203, 209))	('EP15844', 'Var', (249, 256))	('TTF1', 'Gene', (22, 26))
544167	30572031	However, when referring to TTF1 staining in lung squamous cell carcinoma, the specificity for adenocarcinoma is higher in 8G7G3/1 than SPT24 (Figure 3).	('specificity', 'MPA', (78, 89))	('higher', 'PosReg', (112, 118))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (49, 72))	('lung squamous cell carcinoma', 'Disease', (44, 72))	('8G7G3/1', 'Var', (122, 129))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (44, 72))	('adenocarcinoma', 'Disease', (94, 108))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))	('adenocarcinoma', 'Disease', 'MESH:D000230', (94, 108))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (44, 72))
544168	30572031	It is noted that a certain percentage of squamous cell carcinoma are labelled with TTF1, particularly when applying a signal amplification system; the frequency of positivity in squamous cell carcinoma is higher with SPT24.	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (178, 201))	('squamous cell carcinoma', 'Disease', (41, 64))	('squamous cell carcinoma', 'Disease', (178, 201))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (41, 64))	('carcinoma', 'Phenotype', 'HP:0030731', (55, 64))	('SPT24', 'Var', (217, 222))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (178, 201))	('carcinoma', 'Phenotype', 'HP:0030731', (192, 201))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (41, 64))
544189	30572031	For these reasons, molecular testing is still recommended in the 2015 WHO classification in case of a CK5/6 (-), CK7 (+), TTF1 (-) p40 (-) and mucicarmine (-) NSCC.	('p40', 'Gene', '8626', (131, 134))	('TTF1', 'Gene', (122, 126))	('NSCC', 'Disease', 'MESH:D002289', (159, 163))	('mucicarmine', 'Var', (143, 154))	('NSCC', 'Phenotype', 'HP:0030358', (159, 163))	('mucicarmine', 'Chemical', 'MESH:C029618', (143, 154))	('CK7', 'Gene', (113, 116))	('CK5/6', 'Gene', '3852', (102, 107))	('p40', 'Gene', (131, 134))	('NSCC', 'Disease', (159, 163))	('CK5/6', 'Gene', (102, 107))	('CK7', 'Gene', '3855', (113, 116))
544192	30572031	TTF1 negativity correlates with invasive mucinous adenocarcinoma and solid adenocarcinoma with mucin (Figure 5), with only 10% to 15% of mucinous adenocarcinoma being TTF1 positive.	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('TTF1', 'Gene', (0, 4))	('mucin', 'Gene', (95, 100))	('mucinous adenocarcinoma', 'Disease', (137, 160))	('mucin', 'Gene', '100508689', (41, 46))	('carcinoma', 'Phenotype', 'HP:0030731', (55, 64))	('mucinous adenocarcinoma', 'Disease', 'MESH:D002288', (137, 160))	('invasive mucinous adenocarcinoma and solid adenocarcinoma', 'Disease', 'MESH:D002288', (32, 89))	('mucin', 'Gene', (137, 142))	('negativity', 'Var', (5, 15))	('carcinoma', 'Phenotype', 'HP:0030731', (151, 160))	('mucinous adenocarcinoma', 'Disease', (41, 64))	('mucinous adenocarcinoma', 'Disease', 'MESH:D002288', (41, 64))	('mucin', 'Gene', (41, 46))	('mucin', 'Gene', '100508689', (95, 100))	('mucin', 'Gene', '100508689', (137, 142))
544247	30572031	Recently, an excellent performance of GATA3 has been reported in this distinction, and 100% sensitivity for sarcomatoid/desmoplastic malignant mesothelioma in particular suggested that lack of GATA3 expression could be used to exclude the diagnosis of sarcomatoid mesothelioma.	('GATA3', 'Gene', '2625', (38, 43))	('sarcomatoid/desmoplastic malignant mesothelioma', 'Disease', (108, 155))	('GATA3', 'Gene', (193, 198))	('sarcoma', 'Phenotype', 'HP:0100242', (108, 115))	('malignant mesothelioma', 'Phenotype', 'HP:0100001', (133, 155))	('sarcomatoid mesothelioma', 'Disease', 'MESH:D008654', (252, 276))	('lack', 'Var', (185, 189))	('GATA3', 'Gene', '2625', (193, 198))	('sarcoma', 'Phenotype', 'HP:0100242', (252, 259))	('sarcomatoid/desmoplastic malignant mesothelioma', 'Disease', 'MESH:C562839', (108, 155))	('GATA3', 'Gene', (38, 43))	('sarcomatoid mesothelioma', 'Disease', (252, 276))
544253	30572031	Molecular testing may support the diagnosis of sarcomatoid carcinoma by identifying alterations typical of non-small cell carcinoma, such as EGFR, KRAS or MET exon 14 splice site mutations, of which the latter are associated with sarcomatoid histology.	('sarcomatoid', 'Disease', (230, 241))	('sarcomatoid carcinoma', 'Disease', (47, 68))	('MET exon 14 splice site mutations', 'Var', (155, 188))	('non-small cell carcinoma', 'Disease', 'MESH:D002289', (107, 131))	('sarcomatoid', 'Disease', (47, 58))	('small cell carcinoma', 'Phenotype', 'HP:0030357', (111, 131))	('associated', 'Reg', (214, 224))	('KRAS', 'Gene', (147, 151))	('sarcomatoid carcinoma', 'Disease', 'MESH:D002292', (47, 68))	('sarcoma', 'Phenotype', 'HP:0100242', (230, 237))	('EGFR', 'Gene', '1956', (141, 145))	('sarcomatoid', 'Disease', 'MESH:D002292', (230, 241))	('sarcoma', 'Phenotype', 'HP:0100242', (47, 54))	('sarcomatoid carcinoma', 'Phenotype', 'HP:0100242', (47, 68))	('sarcomatoid', 'Disease', 'MESH:D002292', (47, 58))	('non-small cell carcinoma', 'Phenotype', 'HP:0030358', (107, 131))	('non-small cell carcinoma', 'Disease', (107, 131))	('carcinoma', 'Phenotype', 'HP:0030731', (59, 68))	('sarcomatoid histology', 'Phenotype', 'HP:0100242', (230, 251))	('EGFR', 'Gene', (141, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('KRAS', 'Gene', '3845', (147, 151))
544302	30572031	Further, nonspecific labeling with polyclonal Napsin-A in mucinous adenocarcinomas appears to have peculiar supranuclear localization opposed to the pan-cytoplasmic granular staining present with monoclonal Napsin-A, possibly due to cross-reaction with pan-mucin antigen by the polyclonal antibody (Figure 14).	('polyclonal', 'Var', (35, 45))	('mucin', 'Gene', '100508689', (58, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('carcinomas', 'Phenotype', 'HP:0030731', (72, 82))	('mucin', 'Gene', '100508689', (257, 262))	('supranuclear', 'MPA', (108, 120))	('mucinous adenocarcinomas', 'Disease', 'MESH:D002288', (58, 82))	('mucin', 'Gene', (58, 63))	('Napsin-A', 'Gene', (207, 215))	('mucin', 'Gene', (257, 262))	('Napsin-A', 'Gene', '9476', (46, 54))	('Napsin-A', 'Gene', '9476', (207, 215))	('Napsin-A', 'Gene', (46, 54))	('mucinous adenocarcinomas', 'Disease', (58, 82))
544352	30572031	As aberrant TTF1 expression in schwannoma was recently reported, we do not still recognize all of them.	('aberrant', 'Var', (3, 11))	('schwannoma', 'Disease', (31, 41))	('schwannoma', 'Disease', 'MESH:D009442', (31, 41))	('TTF1', 'Gene', (12, 16))	('schwannoma', 'Phenotype', 'HP:0100008', (31, 41))
544357	29920955	The associations between EGFR expression, EGFR gene copy numbers, and clinical efficacy were detected by immunohistochemistry and fluorescence in situ hybridization (FISH).	('EGFR', 'Gene', '1956', (42, 46))	('EGFR', 'Gene', (25, 29))	('EGFR', 'Gene', (42, 46))	('EGFR', 'Gene', '1956', (25, 29))	('clinical efficacy', 'CPA', (70, 87))	('copy numbers', 'Var', (52, 64))
544401	29920955	Sensory neuropathy were observed in 15 patients administered paclitaxel or cisplatin, and an elevated serum creatinine level was observed in one patient administered cisplatin.	('patient', 'Species', '9606', (39, 46))	('patients', 'Species', '9606', (39, 47))	('Sensory neuropathy', 'Disease', (0, 18))	('cisplatin', 'Chemical', 'MESH:D002945', (166, 175))	('Sensory neuropathy', 'Disease', 'MESH:D000699', (0, 18))	('elevated serum creatinine', 'Phenotype', 'HP:0003259', (93, 118))	('paclitaxel', 'Chemical', 'MESH:D017239', (61, 71))	('patient', 'Species', '9606', (145, 152))	('creatinine', 'Chemical', 'MESH:D003404', (108, 118))	('serum creatinine level', 'MPA', (102, 124))	('neuropathy', 'Phenotype', 'HP:0009830', (8, 18))	('Sensory neuropathy', 'Phenotype', 'HP:0000763', (0, 18))	('cisplatin', 'Chemical', 'MESH:D002945', (75, 84))	('observed', 'Reg', (24, 32))	('paclitaxel', 'Var', (61, 71))
544418	29920955	Most patients (85%) were smokers; therefore, it was difficult to analyze the effect of EGFR mutation and smoking history on nimotuzumab efficacy.	('EGFR', 'Gene', '1956', (87, 91))	('mutation', 'Var', (92, 100))	('patients', 'Species', '9606', (5, 13))	('EGFR', 'Gene', (87, 91))	('nimotuzumab', 'Chemical', 'MESH:C501466', (124, 135))
544443	33434272	network edge score) to score the edges of PGIN by integrating the co-mutation score across cancer type-specific data and the personalized co-expression score of each individual patient.	('co-mutation', 'Var', (66, 77))	('PGIN', 'Disease', (42, 46))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('PGIN', 'Chemical', '-', (42, 46))	('patient', 'Species', '9606', (177, 184))
544575	33434272	The results of CPGD on different subtypes of cancer patients with single sample network construction methods were shown in Figure 6, from which we can see that the discovery rate of paired-SSN and CSN is higher than that of SPCC and LIONESS methods, and the discovery rate of paired-SSN and CSN is almost equal.	('discovery', 'MPA', (164, 173))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('paired-SSN', 'Var', (182, 192))	('PCC', 'Gene', '1421', (225, 228))	('higher', 'PosReg', (204, 210))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('cancer', 'Disease', (45, 51))	('patients', 'Species', '9606', (52, 60))	('PCC', 'Gene', (225, 228))
544581	33434272	From Supplementary Figure S9, we can see that the discovery rate of PDGs predicted with CPGD is significantly higher than mean discovery rate of those genes chose with random selection, which is consistent on two benchmark cancer datasets.	('CPGD', 'Var', (88, 92))	('cancer', 'Disease', (223, 229))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('discovery', 'MPA', (50, 59))	('PDG', 'Gene', '26227', (68, 71))	('cancer', 'Disease', 'MESH:D009369', (223, 229))	('PDG', 'Gene', (68, 71))	('higher', 'PosReg', (110, 116))
544584	33434272	We also compared weight-NCUA method with another MMS-based critical nodes selection method (called MMS_critical), which identified the critical nodes such that removing such a node will require more nodes to control the network and is also a candidate method for predicting PDGs in PGIN.	('PDG', 'Gene', '26227', (274, 277))	('PGIN', 'Chemical', '-', (282, 286))	('PDG', 'Gene', (274, 277))	('removing', 'Var', (160, 168))
544636	33434272	The score of co-mutation edge indices the co-mutation probability of two mutated genes in individual tumors to promote tumorigenesis and anticancer drug responses.	('tumor', 'Disease', (119, 124))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('tumors', 'Disease', 'MESH:D009369', (101, 107))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('co-mutation', 'Var', (42, 53))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('tumors', 'Disease', (101, 107))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('cancer', 'Disease', (141, 147))	('promote', 'PosReg', (111, 118))
544657	32473645	Overexpression of LINC00173.v1 promoted, while silencing LINC00173.v1 inhibited the proliferation and migration of vascular endothelial cells and the tumorigenesis of SQC cells in vitro and in vivo.	('LINC00173', 'Gene', '100287569', (18, 27))	('LINC00173', 'Gene', (57, 66))	('LINC00173', 'Gene', '100287569', (57, 66))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('LINC00173', 'Gene', (18, 27))	('silencing', 'Var', (47, 56))	('proliferation', 'CPA', (84, 97))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('inhibited', 'NegReg', (70, 79))	('tumor', 'Disease', (150, 155))
544673	32473645	The disruption of VEGF autocrine activity in lung cancer cells has been reported to be a preventive regimen for tumor formation.	('lung cancer', 'Disease', 'MESH:D008175', (45, 56))	('VEGF', 'Protein', (18, 22))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('lung cancer', 'Disease', (45, 56))	('lung cancer', 'Phenotype', 'HP:0100526', (45, 56))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('disruption', 'Var', (4, 14))	('tumor', 'Disease', (112, 117))
544676	32473645	Furthermore, the function of lncRNAs as competing endogenous RNAs (ceRNAs) has received great attention as a "miRNA sponge" to disrupt miRNA-mediated degradation of target mRNAs, and dysregulation of miRNAs has been extensively demonstrated to contribute to tumorigenesis, progression and metastasis in numerous cancer types, including lung cancer.	('tumor', 'Phenotype', 'HP:0002664', (258, 263))	('metastasis', 'CPA', (289, 299))	('lung cancer', 'Phenotype', 'HP:0100526', (336, 347))	('progression', 'CPA', (273, 284))	('tumor', 'Disease', (258, 263))	('cancer', 'Phenotype', 'HP:0002664', (341, 347))	('cancer', 'Phenotype', 'HP:0002664', (312, 318))	('lung cancer', 'Disease', (336, 347))	('cancer', 'Disease', 'MESH:D009369', (312, 318))	('cancer', 'Disease', (312, 318))	('lung cancer', 'Disease', 'MESH:D008175', (336, 347))	('miRNA-mediated degradation', 'MPA', (135, 161))	('cancer', 'Disease', 'MESH:D009369', (341, 347))	('tumor', 'Disease', 'MESH:D009369', (258, 263))	('cancer', 'Disease', (341, 347))	('contribute', 'Reg', (244, 254))	('disrupt', 'NegReg', (127, 134))	('dysregulation', 'Var', (183, 196))
544679	32473645	Gain and loss of function assays demonstrated that upregulating LINC00173.v1 promoted, while silencing LINC00173.v1 attenuated the proliferation and migration of vascular endothelial cells and tumorigenesis of SQC cells in vitro and in vivo; these effects were dependent on miR-511-5p/VEGFA axis.	('silencing', 'Var', (93, 102))	('miR-511-5p', 'Chemical', '-', (274, 284))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('proliferation', 'CPA', (131, 144))	('LINC00173', 'Gene', (64, 73))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('LINC00173', 'Gene', (103, 112))	('LINC00173', 'Gene', '100287569', (64, 73))	('tumor', 'Disease', (193, 198))	('attenuated', 'NegReg', (116, 126))	('LINC00173', 'Gene', '100287569', (103, 112))
544690	32473645	A549 and HFL1 were grown in F12K Medium (Gibco, USA), and Calu-1 was grown in McCoy's 5a Medium (Gibco, USA).	('A549', 'CellLine', 'CVCL:0023', (0, 4))	('HFL1', 'Gene', '3078', (9, 13))	("McCoy's 5a Medium", 'Chemical', 'MESH:C113109', (78, 95))	('HFL1', 'Gene', (9, 13))	('F12K', 'SUBSTITUTION', 'None', (28, 32))	('F12K', 'Var', (28, 32))
544705	32473645	Tumor cell proportion was scored as follows: 0 (no positive tumor cells); 1 (< 10% positive tumor cells); 2 (10-35% positive tumor cells); 3 (35-70% positive tumor cells) and 4 (> 70% positive tumor cells).	('10-35', 'Var', (109, 114))	('tumor', 'Disease', (158, 163))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Disease', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('tumor', 'Disease', (92, 97))	('35-70', 'Var', (142, 147))	('tumor', 'Disease', (193, 198))	('tumor', 'Disease', (60, 65))
544732	32473645	Mice were injected intraperitoneally with low- and high- dose of LINC00173.v1 antisense LNA  GapmeRs (5 mg/kg, ASO-LD; 25 mg/kg, ASO-HD; Exiqon, Denmark) or negative control (PBS) weekly for 4 weeks.	('antisense', 'Var', (78, 87))	('ASO', 'Chemical', 'MESH:D016376', (111, 114))	('PBS', 'Chemical', 'MESH:D007854', (175, 178))	('LINC00173', 'Gene', (65, 74))	('HD', 'Disease', 'MESH:D006816', (133, 135))	('ASO', 'Chemical', 'MESH:D016376', (129, 132))	('Mice', 'Species', '10090', (0, 4))	('LINC00173', 'Gene', '100287569', (65, 74))
544757	32473645	Although there was no correlation between the expression levels of LINC00173.v1 and clinicopathological characteristics (Supplemental Table 7 and Supplemental Table 8), Kaplan-Meier survival analysis showed that SQC patients with high expression of LINC00173.v1 had poorer progression-free (PFS) and overall survival (OS), as well as local relapse-free survival (LRFS) and distant metastasis-free survival (DMFS) in SQC patients compared with low expression of LINC00173.v1 (Fig.	('LINC00173', 'Gene', (67, 76))	('LINC00173', 'Gene', '100287569', (461, 470))	('progression-free', 'CPA', (273, 289))	('patients', 'Species', '9606', (420, 428))	('local relapse-free survival', 'CPA', (334, 361))	('LINC00173', 'Gene', '100287569', (249, 258))	('overall survival', 'CPA', (300, 316))	('LINC00173', 'Gene', '100287569', (67, 76))	('high', 'Var', (230, 234))	('distant metastasis-free survival', 'CPA', (373, 405))	('patients', 'Species', '9606', (216, 224))	('LINC00173', 'Gene', (461, 470))	('poorer', 'NegReg', (266, 272))	('LINC00173', 'Gene', (249, 258))
544768	32473645	Tube formation assay and transwell assay revealed that overexpression of LINC00173.v1 not only promoted mesh formation by human umbilical vein endothelial cells (HUVECs), but also enhanced the migration ability of HUVECs, while silencing LINC00173.v1 yielded the opposite results (Fig.	('LINC00173', 'Gene', '100287569', (73, 82))	('human', 'Species', '9606', (122, 127))	('promoted', 'PosReg', (95, 103))	('silencing', 'Var', (228, 237))	('HUVEC', 'CellLine', 'CVCL:2959', (162, 167))	('LINC00173', 'Gene', '100287569', (238, 247))	('mesh formation', 'CPA', (104, 118))	('LINC00173', 'Gene', (73, 82))	('enhanced', 'PosReg', (180, 188))	('HUVEC', 'CellLine', 'CVCL:2959', (214, 219))	('LINC00173', 'Gene', (238, 247))	('migration ability', 'CPA', (193, 210))
544770	32473645	Overexpression of LINC00173.v1 increased, while silencing LINC00173.v1 shortened the length of the 2nd and 3rd vessels of lung cancer cells cultured on CAM (Fig.	('silencing', 'Var', (48, 57))	('LINC00173', 'Gene', '100287569', (18, 27))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('lung cancer', 'Disease', (122, 133))	('lung cancer', 'Phenotype', 'HP:0100526', (122, 133))	('LINC00173', 'Gene', (18, 27))	('LINC00173', 'Gene', (58, 67))	('lung cancer', 'Disease', 'MESH:D008175', (122, 133))	('shortened', 'NegReg', (71, 80))	('LINC00173', 'Gene', '100287569', (58, 67))
544774	32473645	Taken together, these findings revealed that silencing LINC00173.v1 inhibits the proliferation and migration of vascular endothelial cells by influencing the expression of VEGFA.	('silencing', 'Var', (45, 54))	('LINC00173', 'Gene', '100287569', (55, 64))	('expression', 'MPA', (158, 168))	('influencing', 'Reg', (142, 153))	('inhibits', 'NegReg', (68, 76))	('LINC00173', 'Gene', (55, 64))	('VEGFA', 'Protein', (172, 177))
544779	32473645	Importantly, upregulating LINC00173.v1 enhanced, while silencing LINC00173.v1 reduced lymphatic or blood vessel density (CD31+ LBV) in tumor tissues (Fig.	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('LINC00173', 'Gene', (26, 35))	('silencing', 'Var', (55, 64))	('tumor', 'Disease', (135, 140))	('LINC00173', 'Gene', (65, 74))	('lymphatic or blood vessel density', 'CPA', (86, 119))	('LINC00173', 'Gene', '100287569', (26, 35))	('reduced', 'NegReg', (78, 85))	('LINC00173', 'Gene', '100287569', (65, 74))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
544789	32473645	Collectively, our findings demonstrated that silencing LINC00173.v1 inhibits the tumorigenesis of lung cancer cells in vivo.	('silencing', 'Var', (45, 54))	('LINC00173', 'Gene', '100287569', (55, 64))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('lung cancer', 'Disease', (98, 109))	('lung cancer', 'Phenotype', 'HP:0100526', (98, 109))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('lung cancer', 'Disease', 'MESH:D008175', (98, 109))	('LINC00173', 'Gene', (55, 64))	('inhibits', 'NegReg', (68, 76))	('tumor', 'Disease', (81, 86))
544792	32473645	Then, we further analyzed the correlation of LINC00173.v1 with all reported miRNAs in the lung cancer dataset from TCGA, and found that the expression levels of six miRNAs, including miR-126-5p, miR-126-3p, miR-145-3p, miR-511-5p, miR-143-3p and miR-100-5p, were negatively correlated with LINC00173.v1, and were downregulated in SQC tissues compared with those in ANT (Fig.	('lung cancer', 'Disease', 'MESH:D008175', (90, 101))	('miR-100-5p', 'Var', (246, 256))	('miR-145', 'Gene', (207, 214))	('miR-126-3p', 'Gene', (195, 205))	('miR-126', 'Gene', (195, 202))	('lung cancer', 'Phenotype', 'HP:0100526', (90, 101))	('miR-143-3p', 'Var', (231, 241))	('LINC00173', 'Gene', '100287569', (45, 54))	('miR-126-3p', 'Gene', '100302148', (195, 205))	('negatively', 'NegReg', (263, 273))	('LINC00173', 'Gene', '100287569', (290, 299))	('LINC00173', 'Gene', (45, 54))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('miR-126', 'Gene', (183, 190))	('LINC00173', 'Gene', (290, 299))	('miR-126', 'Gene', '406913', (195, 202))	('miR-511-5p', 'Var', (219, 229))	('lung cancer', 'Disease', (90, 101))	('expression', 'MPA', (140, 150))	('miR-145', 'Gene', '406937', (207, 214))	('downregulated', 'NegReg', (313, 326))	('miR-126', 'Gene', '406913', (183, 190))	('miR-511-5p', 'Chemical', '-', (219, 229))
544795	32473645	RNA immunoprecipitation (RIP) assays demonstrated a direct association of miR-511-5p with the transcripts of LINC00173.v1 (Supplemental Figure 5b).	('association', 'Interaction', (59, 70))	('transcripts', 'MPA', (94, 105))	('miR-511-5p', 'Var', (74, 84))	('LINC00173', 'Gene', (109, 118))	('miR-511-5p', 'Chemical', '-', (74, 84))	('LINC00173', 'Gene', '100287569', (109, 118))
544796	32473645	Furthermore, a luciferase assay showed that upregulating miR-511-5p inhibited, while silencing miR-511-5p enhanced the luciferase reporter activity of LINC00173.v1, but not of the mutant LINC00173.v1 (Fig.	('LINC00173', 'Gene', '100287569', (151, 160))	('LINC00173', 'Gene', (187, 196))	('enhanced', 'PosReg', (106, 114))	('miR-511-5p', 'Var', (57, 67))	('miR-511-5p', 'Chemical', '-', (95, 105))	('miR-511-5p', 'Chemical', '-', (57, 67))	('miR-511-5p', 'Var', (95, 105))	('LINC00173', 'Gene', '100287569', (187, 196))	('inhibited', 'NegReg', (68, 77))	('luciferase', 'Enzyme', (119, 129))	('LINC00173', 'Gene', (151, 160))	('upregulating', 'PosReg', (44, 56))	('silencing miR-511-5p', 'Var', (85, 105))
544798	32473645	Therefore, these findings indicated that LINC00173.v1 promotes the proliferation and migration of vascular endothelial cells by sponging miR-511-5p as a ceRNA.	('LINC00173', 'Gene', '100287569', (41, 50))	('sponging', 'Var', (128, 136))	('miR-511-5p', 'Var', (137, 147))	('proliferation', 'CPA', (67, 80))	('LINC00173', 'Gene', (41, 50))	('miR-511-5p', 'Chemical', '-', (137, 147))	('migration', 'CPA', (85, 94))	('promotes', 'PosReg', (54, 62))
544799	32473645	By analyzing miRanda algorithms, we found that VEGFA may be a potential target of miR-511-5p (Supplemental Figure 5c), which has been further demonstrated by the aforementioned real-time qPCR analysis (Fig.	('miR-511-5p', 'Chemical', '-', (82, 92))	('miRanda algorithms', 'Disease', 'MESH:C537402', (13, 31))	('miR-511-5p', 'Var', (82, 92))	('miRanda algorithms', 'Disease', (13, 31))
544800	32473645	RT-qPCR analysis further revealed that upregulating miR-511-5p reduced, while silencing miR-511-5p increased the mRNA expression levels of VEGFA (Supplemental Figure 5d).	('miR-511-5p', 'Var', (88, 98))	('miR-511-5p', 'Chemical', '-', (88, 98))	('reduced', 'NegReg', (63, 70))	('mRNA expression levels of VEGFA', 'MPA', (113, 144))	('silencing miR-511-5p', 'Var', (78, 98))	('increased', 'PosReg', (99, 108))	('miR-511-5p', 'Var', (52, 62))	('miR-511-5p', 'Chemical', '-', (52, 62))	('upregulating', 'PosReg', (39, 51))
544801	32473645	The RIP assay further revealed a direct association of miR-511-5p with the VEGFA transcript (Supplemental Figure 5e), demonstrating the direct repressive effect of miR-511-5p on VEGFA.	('miR-511-5p', 'Chemical', '-', (55, 65))	('VEGFA transcript', 'Gene', (75, 91))	('miR-511-5p', 'Var', (55, 65))	('miR-511-5p', 'Chemical', '-', (164, 174))
544802	32473645	A luciferase assay showed that upregulating miR-511-5p attenuated, while silencing miR-511-5p elevated the reporter activity of the 3'UTR of VEGFA (Supplemental Figure 5f).	('elevated', 'PosReg', (94, 102))	('miR-511-5p', 'Var', (44, 54))	('silencing miR-511-5p', 'Var', (73, 93))	('attenuated', 'NegReg', (55, 65))	('miR-511-5p', 'Chemical', '-', (44, 54))	('upregulating', 'PosReg', (31, 43))	('miR-511-5p', 'Var', (83, 93))	('reporter activity', 'MPA', (107, 124))	('miR-511-5p', 'Chemical', '-', (83, 93))
544808	32473645	On the other hand, as a ceRNA for miR-511-5p, LINC00173.v1 has been demonstrated to promote the proliferation and migration of vascular endothelial cells by sponging miR-511-5p in vitro (Fig.	('miR-511-5p', 'Var', (166, 176))	('miR-511-5p', 'Chemical', '-', (166, 176))	('promote', 'PosReg', (84, 91))	('LINC00173', 'Gene', '100287569', (46, 55))	('proliferation', 'CPA', (96, 109))	('migration', 'CPA', (114, 123))	('miR-511-5p', 'Chemical', '-', (34, 44))	('sponging', 'Var', (157, 165))	('LINC00173', 'Gene', (46, 55))
544819	32473645	This finding supported the notion that DeltaNp63alpha may be responsible for the specific overexpression of LINC00173.v1 in SQC tissues.	('LINC00173', 'Gene', (108, 117))	('LINC00173', 'Gene', '100287569', (108, 117))	('overexpression', 'PosReg', (90, 104))	('DeltaNp63alpha', 'Var', (39, 53))
544821	32473645	Real-time PCR analysis further demonstrated that upregulating DeltaNp63alpha elevated, while silencing DeltaNp63alpha reduced LINC00173.v1 expression (Fig.	('DeltaNp63alpha', 'Gene', (62, 76))	('silencing', 'Var', (93, 102))	('upregulating', 'PosReg', (49, 61))	('reduced', 'NegReg', (118, 125))	('LINC00173', 'Gene', (126, 135))	('LINC00173', 'Gene', '100287569', (126, 135))
544823	32473645	A ChIP assay showed that DeltaNp63alpha had high affinity for the P2 and P4 binding sites in the promoter region of LINC00173.v1 in lung cancer cells (Fig.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('LINC00173', 'Gene', (116, 125))	('lung cancer', 'Disease', 'MESH:D008175', (132, 143))	('LINC00173', 'Gene', '100287569', (116, 125))	('lung cancer', 'Disease', (132, 143))	('P4 binding', 'Protein', (73, 83))	('lung cancer', 'Phenotype', 'HP:0100526', (132, 143))	('DeltaNp63alpha', 'Var', (25, 39))
544825	32473645	However, the luciferase activity of the LINC00173.v1 promoter was decreased by mutation of either P2 or P4, but was not significantly influenced by DeltaNp63alpha when both P2 and P4 binding sites were mutated (Fig.	('activity', 'MPA', (24, 32))	('LINC00173', 'Gene', (40, 49))	('decreased', 'NegReg', (66, 75))	('luciferase', 'Enzyme', (13, 23))	('mutation', 'Var', (79, 87))	('LINC00173', 'Gene', '100287569', (40, 49))
544829	32473645	Here, we reported that overexpression of LINC00173.v1 caused by DeltaNp63alpha at the transcriptional level was observed in SQC tissues, and was significantly correlated with early relapse and distant metastasis in SQC patients.	('early relapse', 'CPA', (175, 188))	('overexpression', 'PosReg', (23, 37))	('LINC00173', 'Gene', '100287569', (41, 50))	('distant metastasis', 'CPA', (193, 211))	('correlated with', 'Reg', (159, 174))	('LINC00173', 'Gene', (41, 50))	('DeltaNp63alpha', 'Var', (64, 78))	('patients', 'Species', '9606', (219, 227))
544834	32473645	Similarly, dysregulation of cytoplasmic lncRNAs has been extensively implicated in recurrence and metastasis in lung cancer.	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('lung cancer', 'Disease', (112, 123))	('lung cancer', 'Phenotype', 'HP:0100526', (112, 123))	('metastasis', 'CPA', (98, 108))	('lung cancer', 'Disease', 'MESH:D008175', (112, 123))	('dysregulation', 'Var', (11, 24))	('implicated', 'Reg', (69, 79))
544837	32473645	Importantly, the stimulatory effects of LINC00173.v1 overexpression on the proliferation and migration of vascular endothelial cells in vitro and the tumorigenesis of lung cancer cells in vivo were differentially abrogated by recombinant VEGF monoclonal antibody bevacizumab, agomir-511-5p and mutant LINC00173.v1.	('LINC00173', 'Gene', (301, 310))	('LINC00173', 'Gene', (40, 49))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('lung cancer', 'Disease', (167, 178))	('overexpression', 'PosReg', (53, 67))	('migration', 'CPA', (93, 102))	('lung cancer', 'Phenotype', 'HP:0100526', (167, 178))	('LINC00173', 'Gene', '100287569', (301, 310))	('bevacizumab', 'Chemical', 'MESH:D000068258', (263, 274))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('LINC00173', 'Gene', '100287569', (40, 49))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('mutant', 'Var', (294, 300))	('lung cancer', 'Disease', 'MESH:D008175', (167, 178))	('proliferation', 'CPA', (75, 88))	('tumor', 'Disease', (150, 155))	('abrogated', 'NegReg', (213, 222))
544839	32473645	Recent studies have demonstrated that aberrant expression of lncRNAs plays an important role in the proliferation and migration of vascular endothelial cells in lung cancer.	('aberrant expression', 'Var', (38, 57))	('proliferation', 'CPA', (100, 113))	('lung cancer', 'Disease', (161, 172))	('lung cancer', 'Phenotype', 'HP:0100526', (161, 172))	('migration', 'CPA', (118, 127))	('lncRNAs', 'Gene', (61, 68))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('lung cancer', 'Disease', 'MESH:D008175', (161, 172))
544841	32473645	lncRNA LOC100132354 has been demonstrated to promote the proliferation and migration of vascular endothelial cells by upregulating VEGFA/VEGFR2 expression in lung adenocarcinoma, which further contributed to the tumorigenesis of lung adenocarcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (239, 248))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (158, 177))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (229, 248))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('carcinoma', 'Phenotype', 'HP:0030731', (168, 177))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (229, 248))	('VEGFR2', 'Gene', (137, 143))	('migration of vascular endothelial cells', 'CPA', (75, 114))	('expression', 'MPA', (144, 154))	('VEGFR2', 'Gene', '3791', (137, 143))	('LOC100132354', 'Var', (7, 19))	('contributed', 'Reg', (193, 204))	('promote', 'PosReg', (45, 52))	('upregulating', 'PosReg', (118, 130))	('lung adenocarcinoma', 'Disease', (158, 177))	('tumor', 'Disease', (212, 217))	('tumor', 'Disease', 'MESH:D009369', (212, 217))	('lung adenocarcinoma', 'Disease', (229, 248))	('proliferation', 'CPA', (57, 70))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (158, 177))
544851	32473645	Importantly, our results further revealed that silencing LINC00173.v1 not only inhibited the tumorigenesis of lung cancer cells, but also reinforced the chemotherapeutic sensitivity of lung cancer cells to cisplatin in vivo when an antisense oligonucleotide (ASO) targeting LINC00173.v1 was administered.	('lung cancer', 'Disease', (110, 121))	('ASO', 'Chemical', 'MESH:D016376', (259, 262))	('silencing', 'Var', (47, 56))	('lung cancer', 'Disease', 'MESH:D008175', (185, 196))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('reinforced', 'PosReg', (138, 148))	('lung cancer', 'Phenotype', 'HP:0100526', (185, 196))	('LINC00173', 'Gene', '100287569', (274, 283))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('lung cancer', 'Disease', 'MESH:D008175', (110, 121))	('cisplatin', 'Chemical', 'MESH:D002945', (206, 215))	('LINC00173', 'Gene', (274, 283))	('LINC00173', 'Gene', '100287569', (57, 66))	('lung cancer', 'Phenotype', 'HP:0100526', (110, 121))	('inhibited', 'NegReg', (79, 88))	('LINC00173', 'Gene', (57, 66))	('tumor', 'Disease', (93, 98))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('lung cancer', 'Disease', (185, 196))	('oligonucleotide', 'Chemical', 'MESH:D009841', (242, 257))	('chemotherapeutic sensitivity', 'CPA', (153, 181))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
544853	32473645	Importantly, our results demonstrated that inhibition of LINC00173.v1 with antisense oligonucleotides not only reduced the tumor growth of SQC cells in vivo, but also dramatically enhanced the therapeutic sensitivity of SQC cells to cisplatin in vivo, suggesting the potential therapeutic efficacy of LINC00173.v1 as a chemotherapeutic sensitizer in SQC.	('LINC00173', 'Gene', (301, 310))	('inhibition', 'Var', (43, 53))	('LINC00173', 'Gene', (57, 66))	('tumor', 'Disease', (123, 128))	('LINC00173', 'Gene', '100287569', (301, 310))	('LINC00173', 'Gene', '100287569', (57, 66))	('reduced', 'NegReg', (111, 118))	('oligonucleotides', 'Chemical', 'MESH:D009841', (85, 101))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('therapeutic sensitivity', 'MPA', (193, 216))	('enhanced', 'PosReg', (180, 188))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('cisplatin', 'Chemical', 'MESH:D002945', (233, 242))
544875	30825353	In conclusion, poor prognosis in EAC overexpressing SCCA1 is due to reduced tumor chemosensitivity as well as intratumoral immunity impairment, likely induced by this molecule.	('immunity impairment', 'Phenotype', 'HP:0002721', (123, 142))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('SCCA1', 'Gene', (52, 57))	('overexpressing', 'Var', (37, 51))	('tumor', 'Disease', (76, 81))	('tumor', 'Disease', (115, 120))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('SCCA1', 'Gene', '6317', (52, 57))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('reduced', 'NegReg', (68, 75))	('tumoral', 'Disease', (115, 122))	('tumoral', 'Disease', 'MESH:D009369', (115, 122))
544901	30825353	The primary Abs, murine IgG1, specific for the CD80, CD4, CD8, programmed death ligand-1 (PD-L1), PD-L2, and CD107 (Table S1) were added and incubated for 30 minutes at room temperature.	('CD80', 'Gene', (47, 51))	('CD8', 'Gene', (58, 61))	('CD8', 'Gene', (47, 50))	('PD-L1', 'Gene', '29126', (90, 95))	('PD-L2', 'Gene', (98, 103))	('CD8', 'Gene', '925', (47, 50))	('CD80', 'Gene', '941', (47, 51))	('PD-L2', 'Gene', '80380', (98, 103))	('CD8', 'Gene', '925', (58, 61))	('murine', 'Species', '10090', (17, 23))	('CD4', 'Gene', (53, 56))	('CD4', 'Gene', '920', (53, 56))	('CD107', 'Var', (109, 114))	('PD-L1', 'Gene', (90, 95))
544939	30825353	Tumor SCCA1 was higher in patients receiving docetaxel (P = .003) (Figure 3A), whereas SCCA1-IgM and free SCCA1 levels in serum were not significantly different in patients receiving docetaxel (Table S3).	('docetaxel', 'Var', (45, 54))	('higher', 'PosReg', (16, 22))	('SCCA1', 'Gene', (87, 92))	('docetaxel', 'Chemical', 'MESH:D000077143', (45, 54))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('SCCA1', 'Gene', '6317', (106, 111))	('SCCA1', 'Gene', '6317', (6, 11))	('docetaxel', 'Chemical', 'MESH:D000077143', (183, 192))	('patients', 'Species', '9606', (26, 34))	('SCCA1', 'Gene', '6317', (87, 92))	('SCCA1', 'Gene', (106, 111))	('patients', 'Species', '9606', (164, 172))	('SCCA1', 'Gene', (6, 11))
544967	30825353	We observed that OE33 cells, overexpressing SCCA1, were more resistant to cell death than the control OE19 cells after treatment with epirubicin, docetaxel, and cisplatin, whereas cell viability was not affected by treatment with and 5-FU.	('cell death', 'CPA', (74, 84))	('overexpressing', 'Var', (29, 43))	('docetaxel', 'Chemical', 'MESH:D000077143', (146, 155))	('SCCA1', 'Gene', '6317', (44, 49))	('5-FU', 'Chemical', 'MESH:D005472', (234, 238))	('resistant', 'CPA', (61, 70))	('SCCA1', 'Gene', (44, 49))	('epirubicin', 'Chemical', 'MESH:D015251', (134, 144))	('cisplatin', 'Chemical', 'MESH:D002945', (161, 170))
544968	30825353	Moreover, OE19 cells transfected to overexpress SCCA1 were more resistant to docetaxel treatment than OE33 expressing SCCA1 levels approximately 200 times less.	('SCCA1', 'Gene', (118, 123))	('SCCA1', 'Gene', '6317', (48, 53))	('resistant to docetaxel treatment', 'MPA', (64, 96))	('docetaxel', 'Chemical', 'MESH:D000077143', (77, 86))	('overexpress', 'Var', (36, 47))	('SCCA1', 'Gene', (48, 53))	('SCCA1', 'Gene', '6317', (118, 123))
544971	30825353	Thus, a reduced chemosensitivity in patients with high levels of SCCA1 could explain, at least in part, the poor prognosis of these patients.	('patients', 'Species', '9606', (36, 44))	('reduced', 'NegReg', (8, 15))	('SCCA1', 'Gene', '6317', (65, 70))	('high levels', 'Var', (50, 61))	('patients', 'Species', '9606', (132, 140))	('SCCA1', 'Gene', (65, 70))	('chemosensitivity', 'MPA', (16, 32))
544976	30825353	All these data indicate the presence of a direct or an indirect effect of high levels of SCCA1 expression on the immune surveillance mechanisms, resulting in intratumoral immunity impairment that might concur with the worse prognosis of patients with high SCCA1 expression.	('immunity impairment', 'Phenotype', 'HP:0002721', (171, 190))	('tumoral', 'Disease', 'MESH:D009369', (163, 170))	('SCCA1', 'Gene', '6317', (89, 94))	('SCCA1', 'Gene', '6317', (256, 261))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('SCCA1', 'Gene', (256, 261))	('tumoral', 'Disease', (163, 170))	('high levels', 'Var', (74, 85))	('SCCA1', 'Gene', (89, 94))	('patients', 'Species', '9606', (237, 245))
544987	30423811	NVP-BEZ235 Attenuated Cell Proliferation and Migration in the Squamous Cell Carcinoma of Oral Cavities and p70S6K Inhibition Mimics its Effect NVP-BEZ235 or BEZ235 is a dual inhibitor of adenosine triphosphate (ATP)-competitive phosphoinositide 3-kinase (PI3K)/mammalian-target-of-rapamycin (mTOR) and is promising for cancer treatment.	('Squamous Cell Carcinoma of Oral Cavities', 'Phenotype', 'HP:0030413', (62, 102))	('BEZ235', 'Var', (157, 163))	('mTOR', 'Gene', '2475', (292, 296))	('cancer', 'Disease', (319, 325))	('mammalian-target-of-rapamycin', 'Gene', '2475', (261, 290))	('p70S6K', 'Gene', '6198', (107, 113))	('adenosine triphosphate', 'Chemical', 'MESH:D000255', (187, 209))	('cancer', 'Phenotype', 'HP:0002664', (319, 325))	('ATP', 'Chemical', 'MESH:D000255', (211, 214))	('Cell Proliferation', 'CPA', (22, 40))	('Squamous Cell Carcinoma of Oral Cavities', 'Disease', 'MESH:D002294', (62, 102))	('Squamous Cell Carcinoma of Oral Cavities', 'Disease', (62, 102))	('Carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('mammalian-target-of-rapamycin', 'Gene', (261, 290))	('NVP-BEZ235', 'Var', (143, 153))	('NVP-BEZ235', 'Var', (0, 10))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (62, 85))	('BEZ235', 'Chemical', 'MESH:C531198', (157, 163))	('cancer', 'Disease', 'MESH:D009369', (319, 325))	('p70S6K', 'Gene', (107, 113))	('mTOR', 'Gene', (292, 296))	('Attenuated', 'NegReg', (11, 21))	('BEZ235', 'Chemical', 'MESH:C531198', (4, 10))	('BEZ235', 'Chemical', 'MESH:C531198', (147, 153))	('men', 'Species', '9606', (331, 334))
544992	30423811	In NVP-BEZ235-treated SCC-4 and SCC-25 cells, the phosphorylation of 70-kDa ribosomal S6 kinase (p70S6K), but not mTOR, decreased within 24 h. NVP-BEZ235 inhibited OSCC-cell proliferation, migration, and invasion possibly by directly deregulating the phosphorylation of p70S6K.	('S6 kinase', 'Gene', '6198', (86, 95))	('invasion', 'CPA', (204, 212))	('S6 kinase', 'Gene', (86, 95))	('SCC', 'Gene', (165, 168))	('p70S6K', 'Gene', (97, 103))	('migration', 'CPA', (189, 198))	('p70S6K', 'Gene', (270, 276))	('BEZ235', 'Chemical', 'MESH:C531198', (7, 13))	('inhibited', 'NegReg', (154, 163))	('SCC-4', 'Gene', (22, 27))	('mTOR', 'Gene', (114, 118))	('SCC', 'Gene', '6317', (32, 35))	('NVP-BEZ235', 'Var', (143, 153))	('phosphorylation', 'MPA', (251, 266))	('mTOR', 'Gene', '2475', (114, 118))	('SCC', 'Gene', (32, 35))	('SCC', 'Gene', '6317', (22, 25))	('p70S6K', 'Gene', '6198', (97, 103))	('SCC-4', 'Gene', '23383', (22, 27))	('p70S6K', 'Gene', '6198', (270, 276))	('deregulating', 'NegReg', (234, 246))	('BEZ235', 'Chemical', 'MESH:C531198', (147, 153))	('SCC', 'Gene', (22, 25))	('SCC', 'Gene', '6317', (165, 168))	('SCC-25', 'CellLine', 'CVCL:1682', (32, 38))
545012	30423811	NVP-BEZ235 has exhibited antitumor effects on lung cancer, human glioma cells, breast cancer, melanoma, pancreatic cancer, sarcoma, nasopharyngeal cancer, and hepatoma.	('nasopharyngeal cancer', 'Disease', 'MESH:D009303', (132, 153))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('breast cancer', 'Disease', 'MESH:D001943', (79, 92))	('melanoma', 'Disease', 'MESH:D008545', (94, 102))	('pancreatic cancer', 'Disease', (104, 121))	('breast cancer', 'Disease', (79, 92))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('lung cancer', 'Disease', (46, 57))	('hepatoma', 'Disease', 'MESH:D006528', (159, 167))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('sarcoma', 'Disease', 'MESH:D012509', (123, 130))	('nasopharyngeal cancer', 'Phenotype', 'HP:0100630', (132, 153))	('sarcoma', 'Disease', (123, 130))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (104, 121))	('glioma', 'Disease', (65, 71))	('NVP-BEZ235', 'Var', (0, 10))	('melanoma', 'Phenotype', 'HP:0002861', (94, 102))	('melanoma', 'Disease', (94, 102))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('glioma', 'Disease', 'MESH:D005910', (65, 71))	('lung cancer', 'Disease', 'MESH:D008175', (46, 57))	('lung cancer', 'Phenotype', 'HP:0100526', (46, 57))	('hepatoma', 'Disease', (159, 167))	('human', 'Species', '9606', (59, 64))	('sarcoma', 'Phenotype', 'HP:0100242', (123, 130))	('nasopharyngeal cancer', 'Disease', (132, 153))	('BEZ235', 'Chemical', 'MESH:C531198', (4, 10))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('glioma', 'Phenotype', 'HP:0009733', (65, 71))	('pancreatic cancer', 'Disease', 'MESH:D010190', (104, 121))	('breast cancer', 'Phenotype', 'HP:0003002', (79, 92))	('tumor', 'Disease', (29, 34))
545019	30423811	Activation of p70S6K occurs via phosphorylation at serine-411 (Ser411), threonine-421 (Thr421), and Ser424 by endogenous mitogens such as epidermal growth factor, thrombin, and lysophosphatidic acid.	('Ser424', 'Var', (100, 106))	('thrombin', 'Gene', (163, 171))	('threonine', 'Chemical', 'MESH:D013912', (72, 81))	('Ser411', 'Chemical', '-', (63, 69))	('Ser424', 'Chemical', '-', (100, 106))	('serine', 'Chemical', 'MESH:D012694', (51, 57))	('thrombin', 'Gene', '2147', (163, 171))	('lysophosphatidic acid', 'Chemical', 'MESH:C032881', (177, 198))	('threonine-421', 'MPA', (72, 85))	('p70S6K', 'Gene', (14, 20))	('phosphorylation', 'MPA', (32, 47))	('p70S6K', 'Gene', '6198', (14, 20))	('Thr421', 'Chemical', '-', (87, 93))
545021	30423811	In the present study, we investigated the effect of NVP-BEZ235 on PI3K/AKT/mTOR signaling in OSCC cells in vitro.	('NVP-BEZ235', 'Var', (52, 62))	('AKT', 'Gene', '207', (71, 74))	('SCC', 'Gene', (94, 97))	('BEZ235', 'Chemical', 'MESH:C531198', (56, 62))	('SCC', 'Gene', '6317', (94, 97))	('AKT', 'Gene', (71, 74))	('mTOR', 'Gene', '2475', (75, 79))	('mTOR', 'Gene', (75, 79))
545022	30423811	We first discovered that NVP-BEZ235 inhibited proliferation and attenuated cell migration in a subset of SCC-4 and SCC-25 cells and thus enhanced reduction of p70S6K expression.	('enhanced', 'PosReg', (137, 145))	('inhibited', 'NegReg', (36, 45))	('SCC-4', 'Gene', '23383', (105, 110))	('SCC-4', 'Gene', (105, 110))	('proliferation', 'CPA', (46, 59))	('SCC-25', 'CellLine', 'CVCL:1682', (115, 121))	('cell migration', 'CPA', (75, 89))	('p70S6K', 'Gene', (159, 165))	('BEZ235', 'Chemical', 'MESH:C531198', (29, 35))	('p70S6K', 'Gene', '6198', (159, 165))	('reduction', 'NegReg', (146, 155))	('attenuated', 'NegReg', (64, 74))	('NVP-BEZ235', 'Var', (25, 35))
545027	30423811	After 72 h of treatment, NVP-BEZ235 had significantly inhibited the growth of SCC-4 (Figure 2A) and SCC-25 (Figure 2C) when it was used at concentrations of 7.5 nM and greater.	('inhibited', 'NegReg', (54, 63))	('SCC-4', 'Gene', '23383', (78, 83))	('SCC-25', 'CellLine', 'CVCL:1682', (100, 106))	('SCC-25', 'Gene', (100, 106))	('SCC-4', 'Gene', (78, 83))	('men', 'Species', '9606', (19, 22))	('BEZ235', 'Chemical', 'MESH:C531198', (29, 35))	('growth', 'CPA', (68, 74))	('NVP-BEZ235', 'Var', (25, 35))
545030	30423811	Weaker migratory ability was observed in SCC-4 and SCC-25 cells that had been treated with NVP-BEZ235 through the detection of the wound-healing assay (Figure 3A).	('SCC-4', 'Gene', (41, 46))	('BEZ235', 'Chemical', 'MESH:C531198', (95, 101))	('SCC-25', 'CellLine', 'CVCL:1682', (51, 57))	('migratory ability', 'CPA', (7, 24))	('NVP-BEZ235', 'Var', (91, 101))	('SCC-4', 'Gene', '23383', (41, 46))	('Weaker', 'NegReg', (0, 6))
545031	30423811	In SCC-4 cells, migration was significantly slower in the cells that had been treated with NVP-BEZ235 for 4 to 24 h than in untreated cells.	('BEZ235', 'Chemical', 'MESH:C531198', (95, 101))	('slower', 'NegReg', (44, 50))	('migration', 'CPA', (16, 25))	('SCC-4', 'Gene', '23383', (3, 8))	('NVP-BEZ235', 'Var', (91, 101))	('SCC-4', 'Gene', (3, 8))
545034	30423811	After incubation for 24 h in transwell chambers, the number of cells that had migrated or invaded was markedly decreased in NVP-BEZ235-treated SCC-4 (p < 0.01) and SCC-25 (p < 0.01) cells.	('SCC-25', 'CellLine', 'CVCL:1682', (164, 170))	('NVP-BEZ235-treated', 'Var', (124, 142))	('decreased', 'NegReg', (111, 120))	('invaded', 'CPA', (90, 97))	('BEZ235', 'Chemical', 'MESH:C531198', (128, 134))	('SCC-4', 'Gene', '23383', (143, 148))	('SCC-4', 'Gene', (143, 148))
545037	30423811	As displayed in Figure 4A, the expression of phospho-p70S6K was completely abolished in SCC-4 (2 days) and SCC-25 (18 h) after PF-4708671 treatment.	('p70S6K', 'Gene', '6198', (53, 59))	('SCC-4', 'Gene', '23383', (88, 93))	('PF-4708671', 'Chemical', 'MESH:C552719', (127, 137))	('SCC-4', 'Gene', (88, 93))	('SCC-25', 'CellLine', 'CVCL:1682', (107, 113))	('PF-4708671', 'Var', (127, 137))	('expression', 'MPA', (31, 41))	('men', 'Species', '9606', (143, 146))	('p70S6K', 'Gene', (53, 59))	('abolished', 'NegReg', (75, 84))
545038	30423811	The expression of phosphor-mTOR was also downregulated by PF-4708671 treatment.	('downregulated', 'NegReg', (41, 54))	('expression', 'MPA', (4, 14))	('PF-4708671', 'Chemical', 'MESH:C552719', (58, 68))	('PF-4708671', 'Var', (58, 68))	('men', 'Species', '9606', (74, 77))	('mTOR', 'Gene', (27, 31))	('mTOR', 'Gene', '2475', (27, 31))
545040	30423811	After 72 h of PF-4708671 treatment, the growth of SCC-4 and SCC-25 cells was significantly inhibited (Figure 4B).	('SCC-25', 'CellLine', 'CVCL:1682', (60, 66))	('SCC-4', 'Gene', '23383', (50, 55))	('inhibited', 'NegReg', (91, 100))	('SCC-4', 'Gene', (50, 55))	('PF-4708671', 'Chemical', 'MESH:C552719', (14, 24))	('growth', 'CPA', (40, 46))	('men', 'Species', '9606', (30, 33))	('PF-4708671', 'Var', (14, 24))
545041	30423811	SCC-4 cells were more sensitive to PF-4708671 than SCC-25 cells were.	('SCC-25', 'CellLine', 'CVCL:1682', (51, 57))	('SCC-4', 'Gene', '23383', (0, 5))	('PF-4708671', 'Chemical', 'MESH:C552719', (35, 45))	('SCC-4', 'Gene', (0, 5))	('PF-4708671', 'Var', (35, 45))
545042	30423811	The migratory and invasion abilities of SCC-4 and SCC-25 cells were also weakened by the phospho-p70S6K inhibitor (PF-4708671).	('p70S6K', 'Gene', '6198', (97, 103))	('SCC-4', 'Gene', '23383', (40, 45))	('weakened', 'NegReg', (73, 81))	('SCC-4', 'Gene', (40, 45))	('SCC-25', 'CellLine', 'CVCL:1682', (50, 56))	('PF-4708671', 'Chemical', 'MESH:C552719', (115, 125))	('PF-4708671', 'Var', (115, 125))	('p70S6K', 'Gene', (97, 103))
545043	30423811	In SCC-4 cells, migration was significantly slower in cells treated with PF-4708671 for 4 to 36 h than in untreated cells.	('PF-4708671', 'Var', (73, 83))	('slower', 'NegReg', (44, 50))	('PF-4708671', 'Chemical', 'MESH:C552719', (73, 83))	('migration', 'CPA', (16, 25))	('SCC-4', 'Gene', '23383', (3, 8))	('SCC-4', 'Gene', (3, 8))
545044	30423811	In SCC-25 cells, migration was significantly slower at 24 and 36 h after PF-4708671 treatment (Figure 5A).	('migration', 'CPA', (17, 26))	('PF-4708671', 'Var', (73, 83))	('SCC-25', 'CellLine', 'CVCL:1682', (3, 9))	('slower', 'NegReg', (45, 51))	('men', 'Species', '9606', (89, 92))	('PF-4708671', 'Chemical', 'MESH:C552719', (73, 83))
545045	30423811	After incubating for 24 h in transwell chambers, the number of migrated and invaded cells was markedly decreased in PF-4708671-treated SCC-4 (p < 0.05) and SCC-25 (p < 0.05) cells (Figure 5B).	('PF-4708671-treated', 'Var', (116, 134))	('SCC-4', 'Gene', (135, 140))	('PF-4708671', 'Chemical', 'MESH:C552719', (116, 126))	('decreased', 'NegReg', (103, 112))	('SCC-25', 'CellLine', 'CVCL:1682', (156, 162))	('SCC-4', 'Gene', '23383', (135, 140))
545049	30423811	Currently, NVP-BEZ235 is in phase I/II clinical trials and was demonstrated to control solid tumors in a preclinical mouse model.	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('solid tumors', 'Disease', 'MESH:D009369', (87, 99))	('mouse', 'Species', '10090', (117, 122))	('solid tumors', 'Disease', (87, 99))	('tumors', 'Phenotype', 'HP:0002664', (93, 99))	('control', 'PosReg', (79, 86))	('BEZ235', 'Chemical', 'MESH:C531198', (15, 21))	('NVP-BEZ235', 'Var', (11, 21))
545052	30423811	Our in vitro results demonstrated that NVP-BEZ235 significantly reduced SCC-4 and SCC-25 proliferation.	('SCC-25', 'CellLine', 'CVCL:1682', (82, 88))	('SCC-4', 'Gene', (72, 77))	('SCC-25 proliferation', 'CPA', (82, 102))	('NVP-BEZ235', 'Var', (39, 49))	('reduced', 'NegReg', (64, 71))	('SCC-4', 'Gene', '23383', (72, 77))	('BEZ235', 'Chemical', 'MESH:C531198', (43, 49))
545053	30423811	They also revealed that NVP-BEZ235 suppressed phospho-mTOR and phospho-p70S6K levels.	('p70S6K', 'Gene', (71, 77))	('p70S6K', 'Gene', '6198', (71, 77))	('BEZ235', 'Chemical', 'MESH:C531198', (28, 34))	('mTOR', 'Gene', '2475', (54, 58))	('suppressed', 'NegReg', (35, 45))	('mTOR', 'Gene', (54, 58))	('NVP-BEZ235', 'Var', (24, 34))
545056	30423811	The effect of NVP-BEZ235 on the apoptosis of OSCC cells may be associated with the phosphorylation of S6K.	('NVP-BEZ235', 'Var', (14, 24))	('apoptosis', 'CPA', (32, 41))	('S6K', 'Gene', '6198', (102, 105))	('associated', 'Reg', (63, 73))	('phosphorylation', 'MPA', (83, 98))	('BEZ235', 'Chemical', 'MESH:C531198', (18, 24))	('SCC', 'Gene', (46, 49))	('S6K', 'Gene', (102, 105))	('SCC', 'Gene', '6317', (46, 49))
545057	30423811	The antitumor effects of NVP-BEZ235 result not only from inhibiting the Akt survival pathway but also from promoting cell apoptosis.	('inhibiting', 'NegReg', (57, 67))	('Akt', 'Gene', (72, 75))	('promoting', 'PosReg', (107, 116))	('tumor', 'Disease', 'MESH:D009369', (8, 13))	('tumor', 'Phenotype', 'HP:0002664', (8, 13))	('cell apoptosis', 'CPA', (117, 131))	('tumor', 'Disease', (8, 13))	('BEZ235', 'Chemical', 'MESH:C531198', (29, 35))	('Akt', 'Gene', '207', (72, 75))	('NVP-BEZ235', 'Var', (25, 35))
545059	30423811	NVP-BEZ235 completely reduces phosphor-p70S6K activation and can inhibit phospho-mTOR activation.	('p70S6K', 'Gene', '6198', (39, 45))	('NVP-BEZ235', 'Var', (0, 10))	('BEZ235', 'Chemical', 'MESH:C531198', (4, 10))	('reduces', 'NegReg', (22, 29))	('mTOR', 'Gene', (81, 85))	('inhibit', 'NegReg', (65, 72))	('mTOR', 'Gene', '2475', (81, 85))	('p70S6K', 'Gene', (39, 45))
545062	30423811	The rate of distant metastasis or regional lymph node metastasis of OSCC is possibly reduced by NVP-BEZ235.	('NVP-BEZ235', 'Var', (96, 106))	('distant metastasis', 'CPA', (12, 30))	('SCC', 'Gene', (69, 72))	('BEZ235', 'Chemical', 'MESH:C531198', (100, 106))	('SCC', 'Gene', '6317', (69, 72))	('regional lymph node metastasis', 'CPA', (34, 64))	('reduced', 'NegReg', (85, 92))
545066	30423811	The fatigue, diarrhea, nausea, and mucositis that has been reported with NVP-BEZ235 has limited the doses in which it is commonly prescribed, and it is unsurprising that combined PI3K and mTOR blockades resulted in frequent adverse effects.	('BEZ235', 'Chemical', 'MESH:C531198', (77, 83))	('diarrhea', 'Disease', 'MESH:D003967', (13, 21))	('nausea', 'Disease', (23, 29))	('nausea', 'Disease', 'MESH:D009325', (23, 29))	('mucositis', 'Disease', (35, 44))	('diarrhea', 'Disease', (13, 21))	('PI3K', 'Var', (179, 183))	('fatigue', 'Disease', (4, 11))	('nausea', 'Phenotype', 'HP:0002018', (23, 29))	('fatigue', 'Phenotype', 'HP:0012378', (4, 11))	('mucositis', 'Disease', 'MESH:D052016', (35, 44))	('NVP-BEZ235', 'Gene', (73, 83))	('mTOR', 'Gene', (188, 192))	('mTOR', 'Gene', '2475', (188, 192))	('fatigue', 'Disease', 'MESH:D005221', (4, 11))	('limited', 'NegReg', (88, 95))	('diarrhea', 'Phenotype', 'HP:0002014', (13, 21))
545071	30423811	Indeed, the phospho-p70S6K inhibitor (PF-4708671) could suppress not only phospho-p70S6K but also phospho-mTOR, which is a result superior even to that obtained with NVP-BEZ235 (Figure 4).	('suppress', 'NegReg', (56, 64))	('p70S6K', 'Gene', (20, 26))	('p70S6K', 'Gene', '6198', (82, 88))	('p70S6K', 'Gene', (82, 88))	('PF-4708671', 'Chemical', 'MESH:C552719', (38, 48))	('PF-4708671', 'Var', (38, 48))	('p70S6K', 'Gene', '6198', (20, 26))	('mTOR', 'Gene', (106, 110))	('mTOR', 'Gene', '2475', (106, 110))	('BEZ235', 'Chemical', 'MESH:C531198', (170, 176))
545073	30423811	Even p70S6K is the downstream of PI3K/AKT/mTOR pathway, inhibition of phospho-p70S6K could still reduce the phosphorylation of mTOR.	('mTOR', 'Gene', '2475', (42, 46))	('p70S6K', 'Gene', (5, 11))	('mTOR', 'Gene', '2475', (127, 131))	('AKT', 'Gene', (38, 41))	('mTOR', 'Gene', (42, 46))	('p70S6K', 'Gene', '6198', (5, 11))	('p70S6K', 'Gene', '6198', (78, 84))	('p70S6K', 'Gene', (78, 84))	('inhibition', 'Var', (56, 66))	('phosphorylation', 'MPA', (108, 123))	('mTOR', 'Gene', (127, 131))	('AKT', 'Gene', '207', (38, 41))	('reduce', 'NegReg', (97, 103))
545080	30423811	The PCR reaction mixture contained 25 ng of cDNA; 0.5 muL of mTOR gene-expression assay (Hs00234508_m1, Applied Biosystems, Foster City, CA, USA) or beta-actin (ACTB) gene-expression assay (Hs01060665_g1, Applied Biosystems, Foster City, CA, USA); and 5 muL of 2x TaqMan Universal PCR Master Mix (Applied Biosystems, Foster City, CA, USA).	('beta-actin', 'Gene', (149, 159))	('Hs01060665_g1', 'Var', (190, 203))	('Mix', 'Gene', '83881', (292, 295))	('Hs00234508_m1', 'Var', (89, 102))	('ACTB', 'Gene', (161, 165))	('mTOR', 'Gene', (61, 65))	('ACTB', 'Gene', '60', (161, 165))	('mTOR', 'Gene', '2475', (61, 65))	('beta-actin', 'Gene', '728378', (149, 159))	('Mix', 'Gene', (292, 295))
545092	30423811	The primary antibodies and antibodies against phosphorylated epitopes used in this study were mTOR, phospho-mTOR (Ser2448), p70S6K, and phospho-p70S6K (all purchased from Cell Signaling Technologies, Danvers, MA, USA).	('Ser2448', 'Chemical', '-', (114, 121))	('mTOR', 'Gene', (108, 112))	('mTOR', 'Gene', '2475', (108, 112))	('p70S6K', 'Gene', (144, 150))	('mTOR', 'Gene', (94, 98))	('mTOR', 'Gene', '2475', (94, 98))	('p70S6K', 'Gene', '6198', (144, 150))	('Ser2448', 'Var', (114, 121))	('p70S6K', 'Gene', (124, 130))	('p70S6K', 'Gene', '6198', (124, 130))
545109	26507825	Overall, we identify associations of potential clinical relevance among genes/micro RNAs/proteins using our statistical analysis from 25 cancer types and 18 clinical parameters that include clinical stage or smoking history.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('cancer', 'Disease', (137, 143))	('genes/micro RNAs/proteins', 'Var', (72, 97))	('associations', 'Interaction', (21, 33))
545124	26507825	For example, for colorectal cancer, the elastic-net analysis identified hyper-methylation of MLH1 and mutations of TGFBR2 as top predictors for a tumor with microsatellite instability (MSI):these are well-known examples of MSI-related events.	('colorectal cancer', 'Phenotype', 'HP:0003003', (17, 34))	('MSI', 'Disease', 'None', (185, 188))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('TGFBR2', 'Gene', (115, 121))	('colorectal cancer', 'Disease', (17, 34))	('tumor', 'Disease', (146, 151))	('MSI', 'Disease', 'None', (223, 226))	('MSI', 'Disease', (185, 188))	('mutations', 'Var', (102, 111))	('microsatellite instability', 'MPA', (157, 183))	('MSI', 'Disease', (223, 226))	('tumor', 'Disease', 'MESH:D009369', (146, 151))	('MLH1', 'Gene', (93, 97))	('MLH1', 'Gene', '4292', (93, 97))	('colorectal cancer', 'Disease', 'MESH:D015179', (17, 34))	('hyper-methylation', 'Var', (72, 89))	('TGFBR2', 'Gene', '7048', (115, 121))
545125	26507825	Subsequently, we identified genetic aberrations in cancer genes indicative of clinical stage in colorectal cancer, considering multiple genomic features and clinical data.	('genetic aberrations', 'Var', (28, 47))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('colorectal cancer', 'Phenotype', 'HP:0003003', (96, 113))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('colorectal cancer', 'Disease', (96, 113))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('cancer', 'Disease', (107, 113))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('colorectal cancer', 'Disease', 'MESH:D015179', (96, 113))
545149	26507825	In addition, we included genes with significant mutations (MutSig; 852), focal amplifications (CN-AmpPeak; 502), and focal deletions (CN-DelPeak; 2,105) that were reported by Broad Firehose from TCGA data for all 25 cancers (Additional file 3: Table S3).	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('cancers', 'Phenotype', 'HP:0002664', (216, 223))	('cancers', 'Disease', (216, 223))	('cancers', 'Disease', 'MESH:D009369', (216, 223))	('mutations', 'Var', (48, 57))
545152	26507825	Of note, in gene-oriented analysis, all of the samples had methylation values that were determined with two platforms, Infinium HumanMethylation27 (HM27) and/or Infinium HumanMethylation450 (HM450).	('HM27', 'CellLine', 'CVCL:8807', (148, 152))	('methylation', 'MPA', (59, 70))	('HumanMethylation27', 'Var', (128, 146))
545156	26507825	For example, there are four molecular subtypes in breast cancer: triple positive, Her2 positive, ER positive, and triple negative.	('Her2', 'Gene', (82, 86))	('positive', 'Reg', (87, 95))	('breast cancer', 'Disease', 'MESH:D001943', (50, 63))	('Her2', 'Gene', '2064', (82, 86))	('ER positive', 'Var', (97, 108))	('triple positive', 'Var', (65, 80))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('breast cancer', 'Disease', (50, 63))	('breast cancer', 'Phenotype', 'HP:0003002', (50, 63))
545157	26507825	Thus, using these four designated subtypes, we complete the following multiple binary comparisons: triple negative subtype versus others, Her2 positive versus others, ER positive versus others, and triple positive versus others.	('ER positive', 'Var', (167, 178))	('Her2', 'Gene', '2064', (138, 142))	('triple positive', 'Var', (198, 213))	('Her2', 'Gene', (138, 142))	('triple negative', 'Disease', (99, 114))
545165	26507825	We conducted a Fisher's exact test using a 2 x 2 contingency table with four numbers: (1) number of samples with amplified HEATR3 in stage I and II, (2) number of samples without amplified HEATR3 in stage I and II, (3) number of samples with amplified HEATR3 in stage III and IV, and (4) number of samples without amplified HEATR3 in stage III and IV.	('HEATR3', 'Gene', (123, 129))	('HEATR3', 'Gene', '55027', (123, 129))	('HEATR3', 'Gene', (189, 195))	('HEATR3', 'Gene', '55027', (189, 195))	('HEATR3', 'Gene', '55027', (324, 330))	('HEATR3', 'Gene', (324, 330))	('HEATR3', 'Gene', '55027', (252, 258))	('amplified', 'Var', (113, 122))	('HEATR3', 'Gene', (252, 258))
545177	26507825	In this search, users can also see the frequency of mutations and copy number changes on TP53 across all cancer types located in separate tabs labeled "Frequency-Mutation" and "Frequency-Copy Number."	('mutations', 'Var', (52, 61))	('TP53', 'Gene', '7157', (89, 93))	('TP53', 'Gene', (89, 93))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('copy number changes', 'Var', (66, 85))
545178	26507825	Sort functions for each column allows users to visualize that TP53 is most frequently mutated, amplified, or deleted in OV, HNSC, and KICH respectively.	('KICH', 'Disease', (134, 138))	('TP53', 'Gene', '7157', (62, 66))	('mutated', 'Var', (86, 93))	('TP53', 'Gene', (62, 66))	('KICH', 'Disease', 'None', (134, 138))	('deleted', 'Var', (109, 116))
545184	26507825	Once a clinical parameter is selected from the drop-down menu, a high-level summary page provides a visualization of the number of clinically relevant genes, miRs, or proteins across all cancer types (Fig.	('miRs', 'Var', (158, 162))	('cancer', 'Disease', 'MESH:D009369', (187, 193))	('cancer', 'Disease', (187, 193))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('proteins', 'Protein', (167, 175))
545191	26507825	For example, a user can determine the difference in PIK3CA mutation frequency in stomach cancer between patients with EBV infections and patients without EBV infections.	('EBV infections', 'Disease', (154, 168))	('EBV infections', 'Disease', 'MESH:D020031', (154, 168))	('PIK3CA', 'Gene', (52, 58))	('patients', 'Species', '9606', (137, 145))	('patients', 'Species', '9606', (104, 112))	('stomach cancer', 'Disease', 'MESH:D013274', (81, 95))	('mutation', 'Var', (59, 67))	('PIK3CA', 'Gene', '5290', (52, 58))	('stomach cancer', 'Phenotype', 'HP:0012126', (81, 95))	('EBV infections', 'Disease', (118, 132))	('stomach cancer', 'Disease', (81, 95))	('EBV infections', 'Disease', 'MESH:D020031', (118, 132))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
545194	26507825	As indicated by the search results, 16.4 % of the EBV-negative samples have mutations on PIK3CA while 83.3 % of EBV-positive samples harbor the same mutation (Fig.	('mutations', 'Var', (76, 85))	('PIK3CA', 'Gene', (89, 95))	('PIK3CA', 'Gene', '5290', (89, 95))	('EBV', 'Species', '10376', (50, 53))	('EBV', 'Species', '10376', (112, 115))
545195	26507825	For example, if a user wishes to know how many samples have TP53 CNVs overlapping with TP53 mutations in colorectal cancer, a user selects TP53 with copy number for the first target and TP53 with mutation for the second target (Fig.	('TP53', 'Gene', '7157', (87, 91))	('colorectal cancer', 'Disease', 'MESH:D015179', (105, 122))	('TP53', 'Gene', (87, 91))	('TP53', 'Gene', '7157', (186, 190))	('TP53', 'Gene', '7157', (139, 143))	('mutations', 'Var', (92, 101))	('TP53', 'Gene', '7157', (60, 64))	('colorectal cancer', 'Phenotype', 'HP:0003003', (105, 122))	('TP53', 'Gene', (186, 190))	('TP53', 'Gene', (139, 143))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('TP53', 'Gene', (60, 64))	('colorectal cancer', 'Disease', (105, 122))
545196	26507825	Once submitted, the query result page provides a graph showing the distribution of CNV of TP53 between samples with TP53 mutations and samples without TP53 mutations (Fig.	('TP53', 'Gene', (116, 120))	('mutations', 'Var', (121, 130))	('TP53', 'Gene', (151, 155))	('TP53', 'Gene', '7157', (90, 94))	('TP53', 'Gene', (90, 94))	('TP53', 'Gene', '7157', (116, 120))	('TP53', 'Gene', '7157', (151, 155))
545197	26507825	7c; example of TP53), the results page will show expression levels by mutation status of the selected candidate gene/miR/protein (Fig.	('expression levels', 'MPA', (49, 66))	('TP53', 'Gene', '7157', (15, 19))	('TP53', 'Gene', (15, 19))	('mutation', 'Var', (70, 78))
545204	25931286	High frequency targetable EGFR mutations in sinonasal squamous cell carcinomas arising from inverted sinonasal papilloma Inverted sinonasal papilloma (ISP) is a locally aggressive neoplasm associated with sinonasal squamous cell carcinoma (SNSCC) in 10-25% of cases.	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (54, 78))	('sinonasal papilloma', 'Disease', (101, 120))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (215, 238))	('sinonasal papilloma', 'Disease', (130, 149))	('neoplasm', 'Phenotype', 'HP:0002664', (180, 188))	('papilloma', 'Disease', (140, 149))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (54, 78))	('papilloma', 'Disease', 'MESH:D010212', (140, 149))	('sinonasal squamous cell carcinoma', 'Phenotype', 'HP:0012182', (205, 238))	('carcinoma', 'Phenotype', 'HP:0030731', (229, 238))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (54, 77))	('aggressive neoplasm', 'Disease', (169, 188))	('papilloma', 'Phenotype', 'HP:0012740', (140, 149))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (215, 238))	('squamous cell carcinomas', 'Disease', (54, 78))	('SNSCC', 'Phenotype', 'HP:0012182', (240, 245))	('EGFR', 'Gene', (26, 30))	('mutations', 'Var', (31, 40))	('sinonasal squamous cell carcinoma', 'Phenotype', 'HP:0012182', (44, 77))	('sinonasal papilloma', 'Disease', 'MESH:D010212', (101, 120))	('aggressive neoplasm', 'Disease', 'MESH:D001523', (169, 188))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (54, 77))	('sinonasal papilloma', 'Disease', 'MESH:D010212', (130, 149))	('squamous cell carcinoma', 'Disease', (215, 238))	('papilloma', 'Disease', (111, 120))	('papilloma', 'Disease', 'MESH:D010212', (111, 120))	('carcinoma', 'Phenotype', 'HP:0030731', (68, 77))	('EGFR', 'Gene', '1956', (26, 30))	('papilloma', 'Phenotype', 'HP:0012740', (111, 120))	('carcinomas', 'Phenotype', 'HP:0030731', (68, 78))
545206	25931286	EGFR mutations were not identified in exophytic or oncocytic papillomas or non-ISP-associated SNSCC suggesting that the ISP/SNSCC spectrum is biologically distinct among sinonasal squamous tumors.	('sinonasal', 'Disease', (170, 179))	('EGFR', 'Gene', (0, 4))	('oncocytic papillomas', 'Disease', 'MESH:C535584', (51, 71))	('SNSCC', 'Phenotype', 'HP:0012182', (124, 129))	('papilloma', 'Phenotype', 'HP:0012740', (61, 70))	('SNSCC', 'Phenotype', 'HP:0012182', (94, 99))	('squamous tumors', 'Disease', (180, 195))	('mutations', 'Var', (5, 14))	('tumors', 'Phenotype', 'HP:0002664', (189, 195))	('squamous tumors', 'Disease', 'MESH:D002294', (180, 195))	('oncocytic papillomas', 'Disease', (51, 71))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('papillomas', 'Phenotype', 'HP:0012740', (61, 71))
545207	25931286	Patients with ISP harboring EGFR mutations also exhibited an increased progression-free survival compared to those with wild-type EGFR.	('EGFR', 'Gene', (28, 32))	('mutations', 'Var', (33, 42))	('Patients', 'Species', '9606', (0, 8))	('increased', 'PosReg', (61, 70))	('progression-free survival', 'CPA', (71, 96))
545208	25931286	Finally, treatment of ISP-associated carcinoma cells with irreversible EGFR inhibitors resulted in inactivation of EGFR signaling and growth inhibition.	('EGFR signaling', 'MPA', (115, 129))	('carcinoma', 'Disease', 'MESH:D002277', (37, 46))	('growth inhibition', 'CPA', (134, 151))	('carcinoma', 'Phenotype', 'HP:0030731', (37, 46))	('inhibitors', 'Var', (76, 86))	('carcinoma', 'Disease', (37, 46))	('inactivation', 'NegReg', (99, 111))	('EGFR', 'Gene', (71, 75))
545209	25931286	These findings implicate a prominent role for activating EGFR mutations in the pathogenesis of ISP and associated SNSCC and rationalize consideration of irreversible EGFR inhibitors in the therapy of these tumors.	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('mutations', 'Var', (62, 71))	('tumors', 'Phenotype', 'HP:0002664', (206, 212))	('SNSCC', 'Phenotype', 'HP:0012182', (114, 119))	('tumors', 'Disease', (206, 212))	('tumors', 'Disease', 'MESH:D009369', (206, 212))	('ISP', 'Disease', (95, 98))	('SNSCC', 'Disease', (114, 119))	('activating', 'PosReg', (46, 56))	('implicate', 'Reg', (15, 24))	('EGFR', 'Gene', (57, 61))
545220	25931286	Sanger sequencing demonstrated an EGFR N771_H773dup mutation in UM-SCC-112 cells as well in FFPE resection material from which this cell line was derived.	('N771_H773dup', 'Var', (39, 51))	('H773dup', 'Mutation', 'p.773dupH', (44, 51))	('EGFR', 'Gene', (34, 38))
545221	25931286	An EGFR S768_D770dup mutation was identified in SCCNC4 cells.	('D770dup', 'Mutation', 'p.770dupD', (13, 20))	('S768_D770dup', 'Var', (8, 20))	('EGFR', 'Gene', (3, 7))	('SCCNC4', 'CellLine', 'CVCL:X158', (48, 54))
545222	25931286	HCC 827 cells were obtained from the American Type Culture Collection and an EGFR E746_A750del mutation was confirmed by Sanger sequencing.	('A750del', 'Mutation', 'c.750delA', (87, 94))	('E746_A750del', 'Var', (82, 94))	('EGFR', 'Gene', (77, 81))
545229	25931286	Western blotting analyses were performed by the standard protocol using assorted primary antibodies: anti-pEGFR (pY1082, clone D7A5, Cell Signaling Technology), anti-EGFR (polyclonal, Cell Signaling Technology), anti-p-MEK 1/2 (pS217/221, polyclonal, Cell Signaling Technology), anti-MEK 1/2 (polyclonal, Cell Signaling Technology), anti-pAKT (pS473, clone 587F11), and anti-AKT (polyclonal, Cell Signaling Technology).	('MEK 1/2', 'Gene', '26395;26396', (219, 226))	('MEK 1/2', 'Gene', (284, 291))	('anti-EGFR', 'Var', (161, 170))	('MEK 1/2', 'Gene', '26395;26396', (284, 291))	('MEK 1/2', 'Gene', (219, 226))
545230	25931286	Clinical variables, including age at diagnosis, gender, smoking history, AJCC tumor (T) stage, margin status at primary resection, recurrence, progression to carcinoma, and/or death due to disease, were evaluated for potential association with EGFR mutation status.	('mutation', 'Var', (249, 257))	('carcinoma', 'Disease', (158, 167))	('EGFR', 'Gene', (244, 248))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('carcinoma', 'Disease', 'MESH:D002277', (158, 167))	('death', 'Disease', 'MESH:D003643', (176, 181))	('death', 'Disease', (176, 181))	('tumor', 'Disease', (78, 83))	('carcinoma', 'Phenotype', 'HP:0030731', (158, 167))
545234	25931286	EGFR mutations are extremely rare in squamous cell carcinomas of the head and neck as a whole as well as in sinonasal adenocarcinoma.	('carcinomas of the head and neck', 'Phenotype', 'HP:0012288', (51, 82))	('EGFR', 'Gene', (0, 4))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (37, 61))	('carcinomas', 'Phenotype', 'HP:0030731', (51, 61))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (37, 60))	('mutations', 'Var', (5, 14))	('carcinoma', 'Phenotype', 'HP:0030731', (51, 60))	('squamous cell carcinomas', 'Disease', (37, 61))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (37, 61))	('sinonasal adenocarcinoma', 'Disease', 'MESH:C535701', (108, 132))	('sinonasal adenocarcinoma', 'Disease', (108, 132))
545235	25931286	Sequencing a total of 50 ISP and 22 ISP-associated SNSCC demonstrated EGFR mutations in 88% and 77% of tumors, respectively (Fig.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('SNSCC', 'Phenotype', 'HP:0012182', (51, 56))	('tumors', 'Phenotype', 'HP:0002664', (103, 109))	('tumors', 'Disease', 'MESH:D009369', (103, 109))	('tumors', 'Disease', (103, 109))	('EGFR', 'Gene', (70, 74))	('mutations', 'Var', (75, 84))
545237	25931286	This is in contrast to lung adenocarcinoma in which EGFR exon 19 deletions predominate and exon 20 insertions account for 4-9%.	('EGFR', 'Gene', (52, 56))	('exon 19 deletions', 'Var', (57, 74))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (23, 42))	('carcinoma', 'Phenotype', 'HP:0030731', (33, 42))	('lung adenocarcinoma', 'Disease', (23, 42))	('deletions', 'Var', (65, 74))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (23, 42))
545238	25931286	These mutations affect the loop following the C-helix region of the kinase domain and have been shown to result in constitutive activation of EGFR in lung adenocarcinoma.	('activation', 'PosReg', (128, 138))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (150, 169))	('carcinoma', 'Phenotype', 'HP:0030731', (160, 169))	('EGFR', 'Gene', (142, 146))	('affect', 'Reg', (16, 22))	('lung adenocarcinoma', 'Disease', (150, 169))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (150, 169))	('mutations', 'Var', (6, 15))
545246	25931286	To determine the specificity of EGFR mutations among squamous sinonasal lesions, we evaluated a total of 20 non-ISP-associated SNSCCs, 10 exophytic sinonasal papillomas (ESP) and 5 oncocytic sinonasal papillomas (OSP) using Sanger sequencing of EGFR exons 18-21 (Fig.	('SNSCC', 'Phenotype', 'HP:0012182', (127, 132))	('papillomas', 'Phenotype', 'HP:0012740', (158, 168))	('papillomas', 'Phenotype', 'HP:0012740', (201, 211))	('non-ISP-associated SNSCCs', 'Disease', (108, 133))	('mutations', 'Var', (37, 46))	('papilloma', 'Phenotype', 'HP:0012740', (158, 167))	('sinonasal papillomas', 'Disease', (148, 168))	('sinonasal papillomas', 'Disease', 'MESH:D010212', (148, 168))	('EGFR', 'Gene', (245, 249))	('sinonasal papillomas', 'Disease', 'MESH:D010212', (191, 211))	('papilloma', 'Phenotype', 'HP:0012740', (201, 210))	('oncocytic sinonasal papillomas', 'Disease', 'MESH:C535584', (181, 211))	('oncocytic sinonasal papillomas', 'Disease', (181, 211))	('SNSCCs', 'Disease', (127, 133))
545250	25931286	This finding implicates EGFR mutation status as a potential prognostic marker which may be useful in predicted which ISP patients will progress to SNSCC.	('mutation', 'Var', (29, 37))	('SNSCC', 'Phenotype', 'HP:0012182', (147, 152))	('SNSCC', 'Disease', (147, 152))	('EGFR', 'Gene', (24, 28))	('implicates', 'Reg', (13, 23))	('progress', 'PosReg', (135, 143))	('patients', 'Species', '9606', (121, 129))
545251	25931286	Several small molecule inhibitors targeting EGFR are FDA-approved or in clinical trials for the treatment of neoplasms with activating EGFR mutations - principally EGFR mutated lung cancer.	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('EGFR', 'Gene', (164, 168))	('mutated', 'Var', (169, 176))	('lung cancer', 'Disease', 'MESH:D008175', (177, 188))	('mutations -', 'Var', (140, 151))	('neoplasms', 'Phenotype', 'HP:0002664', (109, 118))	('activating', 'PosReg', (124, 134))	('EGFR', 'Gene', (135, 139))	('lung cancer', 'Disease', (177, 188))	('neoplasm', 'Phenotype', 'HP:0002664', (109, 117))	('neoplasms', 'Disease', 'MESH:D009369', (109, 118))	('neoplasms', 'Disease', (109, 118))	('lung cancer', 'Phenotype', 'HP:0100526', (177, 188))
545252	25931286	In contrast to lung cancers with EGFR exon 19 deletions, those with exon 20 insertions are generally resistant to the currently available reversible EGFR inhibitors gefitinib and erlotinib.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('lung cancers', 'Disease', 'MESH:D008175', (15, 27))	('resistant', 'MPA', (101, 110))	('lung cancers', 'Phenotype', 'HP:0100526', (15, 27))	('insertions', 'Var', (76, 86))	('erlotinib', 'Chemical', 'MESH:D000069347', (179, 188))	('cancers', 'Phenotype', 'HP:0002664', (20, 27))	('lung cancers', 'Disease', (15, 27))	('gefitinib', 'Chemical', 'MESH:D000077156', (165, 174))	('lung cancer', 'Phenotype', 'HP:0100526', (15, 26))
545253	25931286	However, several studies have shown more robust in vitro sensitivity of exon 20 mutated lung cancer to irreversible EGFR inhibitors and the therapeutic potential of irreversible inhibitors is currently being investigated in clinical trials.	('lung cancer', 'Disease', (88, 99))	('lung cancer', 'Phenotype', 'HP:0100526', (88, 99))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('lung cancer', 'Disease', 'MESH:D008175', (88, 99))	('mutated', 'Var', (80, 87))	('sensitivity', 'MPA', (57, 68))	('exon 20', 'Gene', (72, 79))
545254	25931286	In order evaluate the functional significance of EGFR mutations in ISP/SNSCC and to assess the potential utility of therapeutic agents targeting these mutations, we obtained two cell lines derived from ISP-associated SNSCC - SCCNC4 and UM-SCC-112.	('SCCNC4', 'CellLine', 'CVCL:X158', (225, 231))	('EGFR', 'Gene', (49, 53))	('mutations', 'Var', (54, 63))	('SNSCC', 'Phenotype', 'HP:0012182', (71, 76))	('SNSCC', 'Phenotype', 'HP:0012182', (217, 222))
545255	25931286	EGFR mutations were found in both cells lines (EGFR S768_D770dup and N771_H773dup, respectively).	('H773dup', 'Mutation', 'p.773dupH', (74, 81))	('N771_H773dup', 'Var', (69, 81))	('S768_D770dup', 'Var', (52, 64))	('D770dup', 'Mutation', 'p.770dupD', (57, 64))
545256	25931286	These cell lines were compared with UM-SCC-33 (a non-ISP-associated SNSCC cell line found to be EGFR wild-type) and HCC 827 (an inhibitor-sensitive lung cancer cell line with an EGFR exon 19 deletion: E746_A750del).	('lung cancer', 'Disease', 'MESH:D008175', (148, 159))	('A750del', 'Mutation', 'c.750delA', (206, 213))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('lung cancer', 'Disease', (148, 159))	('lung cancer', 'Phenotype', 'HP:0100526', (148, 159))	('SNSCC', 'Phenotype', 'HP:0012182', (68, 73))	('E746_A750del', 'Var', (201, 213))
545260	25931286	By comparison, the lung cancer cell line with an EGFR exon 19 deletion (HCC 827) was sensitive to both classes of inhibitors (IC50 <= 169 nM), and EGFR wild-type, non-ISP-associated SNSCC (UM-SCC-33) was resistant to all inhibitors (IC50 > 10,000 nM).	('SNSCC', 'Phenotype', 'HP:0012182', (182, 187))	('lung cancer', 'Phenotype', 'HP:0100526', (19, 30))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('EGFR', 'Gene', (49, 53))	('lung cancer', 'Disease', 'MESH:D008175', (19, 30))	('deletion', 'Var', (62, 70))	('lung cancer', 'Disease', (19, 30))
545298	31618839	Notably, within both the favorable prognosis group Cluster 2 and the unfavorable prognosis group Cluster 4, TMB/TGF- score positive cases showed significantly longer OS intervals than the TMB/TGF- score negative counterparts (Table 3).	('positive', 'Var', (123, 131))	('TMB/TGF- score', 'Gene', (108, 122))	('TMB', 'Chemical', 'MESH:D014289', (188, 191))	('TMB', 'Chemical', 'MESH:D014289', (108, 111))	('OS intervals', 'MPA', (166, 178))	('longer', 'PosReg', (159, 165))
545336	30704450	A novel method of using the log2 ratio of the tumor mutation frequency to the paired normal mutation frequency is computed for each patient and missense mutation.	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('missense', 'Var', (144, 152))	('tumor', 'Disease', (46, 51))	('patient', 'Species', '9606', (132, 139))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
545357	30704450	TMF profiles incorporate the tumor data on the number of reads supporting the mutation vs. the reference genome.	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('mutation', 'Var', (78, 86))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumor', 'Disease', (29, 34))	('TMF', 'Chemical', '-', (0, 3))
545369	30704450	While association of SDHA copy number variation to prognosis was found in lung squamous cell carcinoma, we have found no literature exploring the connection of SDHA to lung adenocarcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('SDHA to lung adenocarcinoma', 'Disease', (160, 187))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (79, 102))	('SDHA', 'Gene', (21, 25))	('lung squamous cell carcinoma', 'Disease', (74, 102))	('SDHA', 'Gene', '6389', (160, 164))	('copy number variation', 'Var', (26, 47))	('association', 'Interaction', (6, 17))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (168, 187))	('SDHA to lung adenocarcinoma', 'Disease', 'MESH:D000077192', (160, 187))	('carcinoma', 'Phenotype', 'HP:0030731', (178, 187))	('SDHA', 'Gene', (160, 164))	('SDHA', 'Gene', '6389', (21, 25))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (74, 102))
545371	30704450	PFKM has mutations associated with survival outcomes in lung squamous cell carcinoma.	('associated', 'Reg', (19, 29))	('mutations', 'Var', (9, 18))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (61, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('PFKM', 'Gene', (0, 4))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (56, 84))	('lung squamous cell carcinoma', 'Disease', (56, 84))
545374	30704450	Finally, it has been found that certain MMP8 mutations are correlated with risk of developing lung cancer.	('mutations', 'Var', (45, 54))	('lung cancer', 'Disease', 'MESH:D008175', (94, 105))	('MMP8', 'Gene', '4317', (40, 44))	('lung cancer', 'Disease', (94, 105))	('lung cancer', 'Phenotype', 'HP:0100526', (94, 105))	('MMP8', 'Gene', (40, 44))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('correlated', 'Reg', (59, 69))
545385	30704450	Unlike the LUAD signature where all genes were positively associated with increased risk, mutations in seven of the genes are associated with reduced risk (USP50, UBTD1, ZNF83, FBX038, C11orf53, IQCH, and CHI3L1) and are denoted in green in Figs.	('UBTD1', 'Gene', '80019', (163, 168))	('ZNF83', 'Gene', (170, 175))	('mutations', 'Var', (90, 99))	('FBX038', 'Gene', (177, 183))	('CHI3L1', 'Gene', '1116', (205, 211))	('reduced', 'NegReg', (142, 149))	('LUAD', 'Phenotype', 'HP:0030078', (11, 15))	('IQCH', 'Gene', (195, 199))	('C11orf53', 'Gene', '341032', (185, 193))	('UBTD1', 'Gene', (163, 168))	('C11orf53', 'Gene', (185, 193))	('ZNF83', 'Gene', '55769', (170, 175))	('USP50', 'Gene', '373509', (156, 161))	('IQCH', 'Gene', '64799', (195, 199))	('USP50', 'Gene', (156, 161))	('CHI3L1', 'Gene', (205, 211))
545388	30704450	Copy number variation of RERG is correlated with CRC risk.	('correlated', 'Reg', (33, 43))	('Copy number variation', 'Var', (0, 21))	('RERG', 'Gene', '85004', (25, 29))	('CRC risk', 'Disease', (49, 57))	('RERG', 'Gene', (25, 29))
545393	30704450	PDHB diminishes the oncogenic effects of miR-146b-5p on the growth and invasion of CRC.	('PDHB', 'Gene', (0, 4))	('PDHB', 'Gene', '5162', (0, 4))	('miR-146b-5p', 'Var', (41, 52))	('oncogenic effects', 'CPA', (20, 37))	('diminishes', 'NegReg', (5, 15))
545396	30704450	Lastly, alterations of CDH24 contribute to tumorigenesis, as CDH24 is important to the maintenance of cell adhesion.	('contribute', 'Reg', (29, 39))	('CDH24', 'Gene', '64403', (61, 66))	('CDH24', 'Gene', (23, 28))	('alterations', 'Var', (8, 19))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('CDH24', 'Gene', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Disease', (43, 48))	('CDH24', 'Gene', '64403', (23, 28))
545413	30704450	We demonstrated the robustness of MFR profiles and its potential to be a powerful prognostic tool in cancer, unlike other alternative types of somatic mutation profiles, TMF, BM, and NetNorM, that did not achieve statistically significant risk stratification in validation datasets.	('MFR', 'Gene', (34, 37))	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('cancer', 'Disease', (101, 107))	('TMF', 'Chemical', '-', (170, 173))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('profiles', 'Var', (38, 46))
545419	30704450	For patient i, the MAF files contain the number of reads supporting the reference allele for mutation j, TRCij and NRCij for tumor and normal samples, respectively.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('MAF', 'Gene', (19, 22))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('patient', 'Species', '9606', (4, 11))	('tumor', 'Disease', (125, 130))	('NRCij', 'Gene', (115, 120))	('mutation', 'Var', (93, 101))	('MAF', 'Gene', '4094', (19, 22))
545438	28422739	The combined analysis showed that the methylation status of the four genes had a sensitivity of 70.3% and a specificity of 73.9% in the prediction of NSCLC risk for study cohort.	('NSCLC', 'Disease', 'MESH:D002289', (150, 155))	('NSCLC', 'Disease', (150, 155))	('NSCLC', 'Phenotype', 'HP:0030358', (150, 155))	('methylation status', 'Var', (38, 56))
545440	28422739	In addition, SFRP1 and SFRP2 hypermethylation events were specific to male patients.	('SFRP1', 'Gene', (13, 18))	('patients', 'Species', '9606', (75, 83))	('hypermethylation', 'Var', (29, 45))	('SFRP2', 'Gene', '6423', (23, 28))	('SFRP2', 'Gene', (23, 28))	('SFRP1', 'Gene', '6422', (13, 18))
545442	28422739	Moreover, GEO database analysis showed that 5'-Aza-deoxycytidine was able to upregulate gene expression in several lung cancer cell lines.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('upregulate', 'PosReg', (77, 87))	('gene expression', 'MPA', (88, 103))	('lung cancer', 'Disease', 'MESH:D008175', (115, 126))	("5'-Aza-deoxycytidine", 'Chemical', 'MESH:D000077209', (44, 64))	("5'-Aza-deoxycytidine", 'Var', (44, 64))	('lung cancer', 'Disease', (115, 126))	('lung cancer', 'Phenotype', 'HP:0100526', (115, 126))
545450	28422739	Aberrant DNA methylation of CpG islands may lead to the transcriptional silencing of tumor suppressor genes.	('tumor', 'Disease', (85, 90))	('lead to', 'Reg', (44, 51))	('Aberrant DNA methylation', 'Var', (0, 24))	('transcriptional', 'MPA', (56, 71))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('silencing', 'NegReg', (72, 81))
545455	28422739	SFRP2 and WIF1 promoter methylation was previously suggested to play important roles in Wnt signaling in lung cancer.	('WIF1', 'Gene', (10, 14))	('lung cancer', 'Phenotype', 'HP:0100526', (105, 116))	('SFRP2', 'Gene', '6423', (0, 5))	('SFRP2', 'Gene', (0, 5))	('WIF1', 'Gene', '11197', (10, 14))	('play', 'Reg', (64, 68))	('roles', 'Reg', (79, 84))	('methylation', 'Var', (24, 35))	('lung cancer', 'Disease', 'MESH:D008175', (105, 116))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('lung cancer', 'Disease', (105, 116))
545465	28422739	Therefore, the percentages of hypermethylation for SFRP1, SFRP2, WIF1 and PRKCB were 25.2% (28/111), 7.2% (8/111), 9.0% (10/111) and 21.6% (24/111) with corresponding PMR cut-off values of 13.694, 360.400, 127.500 and 27.494.	('WIF1', 'Gene', (65, 69))	('WIF1', 'Gene', '11197', (65, 69))	('SFRP2', 'Gene', '6423', (58, 63))	('SFRP1', 'Gene', '6422', (51, 56))	('SFRP2', 'Gene', (58, 63))	('PRKCB', 'Gene', (74, 79))	('hypermethylation', 'MPA', (30, 46))	('SFRP1', 'Gene', (51, 56))	('360.400', 'Var', (197, 204))	('PRKCB', 'Gene', '5579', (74, 79))
545467	28422739	As shown in Table 1, no association was identified between PRKCB or WIF1 methylation and gender, age, histological type, clinical stage, tumor location, differentiation and smoking behavior.	('PRKCB', 'Gene', (59, 64))	('tumor', 'Disease', (137, 142))	('PRKCB', 'Gene', '5579', (59, 64))	('methylation', 'Var', (73, 84))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('WIF1', 'Gene', (68, 72))	('WIF1', 'Gene', '11197', (68, 72))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
545473	28422739	Although WIF1 methylation lacked in good predictive capability, a combined analysis of the four markers improved test accuracy with a sensitivity of 70.3% and a specificity of 73.9% with AUC of 0.747 (95% CI: 0.683-0.811).	('improved', 'PosReg', (104, 112))	('test accuracy', 'MPA', (113, 126))	('WIF1', 'Gene', (9, 13))	('methylation', 'Var', (14, 25))	('WIF1', 'Gene', '11197', (9, 13))
545475	28422739	As shown in Figure 2D, a higher diagnostic value of the epigenetic panel among NSCLC patients has been found and the combination AUC of four genes was 0.932 (95% CI: 0.914-0.950).	('NSCLC', 'Disease', 'MESH:D002289', (79, 84))	('patients', 'Species', '9606', (85, 93))	('NSCLC', 'Phenotype', 'HP:0030358', (79, 84))	('epigenetic panel', 'Var', (56, 72))	('NSCLC', 'Disease', (79, 84))
545478	28422739	SFRP1 methylation was shown as a moderate factor of OS in the univariate analysis (P = 0.055), three factors were included in subsequent multivariate analysis.	('SFRP1', 'Gene', '6422', (0, 5))	('methylation', 'Var', (6, 17))	('SFRP1', 'Gene', (0, 5))
545479	28422739	A further Cox regression analysis showed there was no association of SFRP1 methylation with the OS of NSCLC patients (HR = 1.001, 95% CI = 0.996-1.007).	('NSCLC', 'Disease', 'MESH:D002289', (102, 107))	('methylation', 'Var', (75, 86))	('SFRP1', 'Gene', '6422', (69, 74))	('Cox', 'Gene', (10, 13))	('NSCLC', 'Phenotype', 'HP:0030358', (102, 107))	('SFRP1', 'Gene', (69, 74))	('patients', 'Species', '9606', (108, 116))	('NSCLC', 'Disease', (102, 107))	('association', 'Interaction', (54, 65))	('Cox', 'Gene', '9377', (10, 13))
545482	28422739	It was intriguing that positive correlations were found between two CpG sites of PRKCB (cg24250393 and cg08406370) and gene expression (Spearman r = 0.152, P < 0.001, Figure 3E; Spearman r = 0.116, P = 0.001, Figure 3F, respectively), suggesting that there might be a complex epigenetic regulation in PRKCB gene expression.	('PRKCB', 'Gene', '5579', (301, 306))	('PRKCB', 'Gene', '5579', (81, 86))	('cg24250393', 'Var', (88, 98))	('cg08406370', 'Var', (103, 113))	('PRKCB', 'Gene', (81, 86))	('PRKCB', 'Gene', (301, 306))
545485	28422739	We observed that the expression levels of SFRP1, SFRP2 and PRKCB gene in A549 were significantly elevated after demethylation (P = 0.017, P = 0.043, P = 0.008, respectively; Figure 4).	('elevated', 'PosReg', (97, 105))	('PRKCB', 'Gene', (59, 64))	('SFRP1', 'Gene', '6422', (42, 47))	('A549', 'CellLine', 'CVCL:0023', (73, 77))	('expression levels', 'MPA', (21, 38))	('demethylation', 'Var', (112, 125))	('SFRP1', 'Gene', (42, 47))	('PRKCB', 'Gene', '5579', (59, 64))	('SFRP2', 'Gene', '6423', (49, 54))	('SFRP2', 'Gene', (49, 54))
545486	28422739	Similar demethylation induced upregulation of SFRP2 and WIF1 expression was found in H1993 (P = 0.027) and H2073 (P = 0.017).	('H1993', 'CellLine', 'CVCL:1512', (85, 90))	('H1993', 'Var', (85, 90))	('WIF1', 'Gene', (56, 60))	('H2073', 'Var', (107, 112))	('WIF1', 'Gene', '11197', (56, 60))	('SFRP2', 'Gene', '6423', (46, 51))	('upregulation', 'PosReg', (30, 42))	('SFRP2', 'Gene', (46, 51))	('expression', 'MPA', (61, 71))
545488	28422739	However, no significant promoter activity could be found for the recombinant plasmids of SFRP1 (+464 bp to +863 bp), SFRP2 (+261 bp to +660 bp) and WIF1 (-511 bp to 111 bp).	('+464', 'Var', (96, 100))	('SFRP1', 'Gene', (89, 94))	('SFRP2', 'Gene', '6423', (117, 122))	('WIF1', 'Gene', (148, 152))	('SFRP2', 'Gene', (117, 122))	('WIF1', 'Gene', '11197', (148, 152))	('+261 bp', 'Var', (124, 131))	('SFRP1', 'Gene', '6422', (89, 94))
545491	28422739	Dysregulation of Wnt signaling pathway is often implicated in cancer initiation.	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('Dysregulation', 'Var', (0, 13))	('Wnt signaling pathway', 'Pathway', (17, 38))	('cancer initiation', 'Disease', 'MESH:D009369', (62, 79))	('implicated', 'Reg', (48, 58))	('cancer initiation', 'Disease', (62, 79))
545492	28422739	Aberrant epigenetic regulation of Wnt pathway genes has been identified to be a common signature in adenocarcinoma.	('Aberrant epigenetic', 'Var', (0, 19))	('Wnt pathway genes', 'Gene', (34, 51))	('adenocarcinoma', 'Disease', (100, 114))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('adenocarcinoma', 'Disease', 'MESH:D000230', (100, 114))
545493	28422739	Wnt antagonist or inhibitors are known as tumor suppressors, implying that hypermethylation-induced silencing of these tumor suppressor genes may participate in the pathogenesis or progression of human malignancies.	('tumor', 'Disease', (119, 124))	('silencing', 'NegReg', (100, 109))	('participate', 'Reg', (146, 157))	('tumor', 'Disease', (42, 47))	('malignancies', 'Disease', 'MESH:D009369', (202, 214))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('human', 'Species', '9606', (196, 201))	('malignancies', 'Disease', (202, 214))	('tumor', 'Disease', 'MESH:D009369', (119, 124))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('hypermethylation-induced', 'Var', (75, 99))
545496	28422739	The translational value of the epigenetic panel we have found may allow the early detection of lung cancer and represent an increased probability of cure for patients.	('lung cancer', 'Disease', (95, 106))	('lung cancer', 'Phenotype', 'HP:0100526', (95, 106))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('lung cancer', 'Disease', 'MESH:D008175', (95, 106))	('patients', 'Species', '9606', (158, 166))	('epigenetic', 'Var', (31, 41))
545499	28422739	Aberrant DNA methylation has been suggested as the early event during lung carcinogenesis.	('lung carcinogenesis', 'Disease', 'MESH:D063646', (70, 89))	('lung carcinogenesis', 'Disease', (70, 89))	('Aberrant', 'Var', (0, 8))	('DNA', 'Protein', (9, 12))
545500	28422739	Downregulation of Wnt inhibitors (e.g., by hypermethylation) is common in NSCLC tumor cell lines and resected samples.	('NSCLC', 'Phenotype', 'HP:0030358', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('Downregulation', 'NegReg', (0, 14))	('NSCLC tumor', 'Disease', 'MESH:D009369', (74, 85))	('NSCLC tumor', 'Disease', (74, 85))	('hypermethylation', 'Var', (43, 59))
545507	28422739	DNA methylation emerged as a promising biomarker for early detection, which was independent of the genomic composition of the primary tumor.	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('tumor', 'Disease', (134, 139))	('methylation', 'Var', (4, 15))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))
545514	28422739	Although mRNA expression could be one of the distinct types of cancer biomarkers, it is advisable to establish a methylation-based diagnostic system for cancers since DNA methylation frequently regulates gene expression and occurs in the early stage of tumorigenesis.	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('cancers', 'Disease', 'MESH:D009369', (153, 160))	('cancers', 'Disease', (153, 160))	('cancer', 'Disease', (153, 159))	('tumor', 'Disease', 'MESH:D009369', (253, 258))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('methylation', 'Var', (171, 182))	('tumor', 'Phenotype', 'HP:0002664', (253, 258))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('tumor', 'Disease', (253, 258))	('cancer', 'Disease', 'MESH:D009369', (63, 69))	('gene expression', 'MPA', (204, 219))	('cancers', 'Phenotype', 'HP:0002664', (153, 160))	('cancer', 'Disease', (63, 69))	('regulates', 'Reg', (194, 203))
545515	28422739	Previous studies has reported the diagnostic values of SFRP1 methylation in cutaneous squamous cell carcinoma and esophageal squamous cell carcinoma recurrence.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (125, 148))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (86, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('methylation', 'Var', (61, 72))	('SFRP1', 'Gene', '6422', (55, 60))	('cutaneous squamous cell carcinoma', 'Disease', (76, 109))	('carcinoma', 'Phenotype', 'HP:0030731', (139, 148))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (114, 148))	('cutaneous squamous cell carcinoma', 'Phenotype', 'HP:0006739', (76, 109))	('SFRP1', 'Gene', (55, 60))	('cutaneous squamous cell carcinoma', 'Disease', 'MESH:D002294', (76, 109))	('esophageal squamous cell carcinoma', 'Disease', (114, 148))
545516	28422739	SFRP2 hypermethylation has also been shown in several cancers including acute myeloblastic leukemia, mesothelioma, bladder cancer, liver cancer, as well as lung cancer.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('cancers', 'Disease', 'MESH:D009369', (54, 61))	('shown', 'Reg', (37, 42))	('acute myeloblastic leukemia', 'Phenotype', 'HP:0004808', (72, 99))	('liver cancer', 'Disease', 'MESH:D006528', (131, 143))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('liver cancer', 'Phenotype', 'HP:0002896', (131, 143))	('leukemia', 'Phenotype', 'HP:0001909', (91, 99))	('lung cancer', 'Disease', (156, 167))	('liver cancer', 'Disease', (131, 143))	('myeloblastic leukemia', 'Disease', (78, 99))	('SFRP2', 'Gene', '6423', (0, 5))	('hypermethylation', 'Var', (6, 22))	('cancers', 'Phenotype', 'HP:0002664', (54, 61))	('cancers', 'Disease', (54, 61))	('myeloblastic leukemia', 'Disease', 'MESH:D015470', (78, 99))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('bladder cancer', 'Disease', 'MESH:D001749', (115, 129))	('bladder cancer', 'Disease', (115, 129))	('SFRP2', 'Gene', (0, 5))	('lung cancer', 'Disease', 'MESH:D008175', (156, 167))	('mesothelioma', 'Disease', (101, 113))	('bladder cancer', 'Phenotype', 'HP:0009725', (115, 129))	('myeloblastic leukemia', 'Phenotype', 'HP:0012324', (78, 99))	('lung cancer', 'Phenotype', 'HP:0100526', (156, 167))	('mesothelioma', 'Disease', 'MESH:D008654', (101, 113))
545518	28422739	Interestingly, our results revealed a more frequent SFRP1 and SFRP2 methylation in male NSCLC patients.	('SFRP1', 'Gene', '6422', (52, 57))	('patients', 'Species', '9606', (94, 102))	('NSCLC', 'Phenotype', 'HP:0030358', (88, 93))	('methylation', 'Var', (68, 79))	('SFRP2', 'Gene', '6423', (62, 67))	('SFRP2', 'Gene', (62, 67))	('SFRP1', 'Gene', (52, 57))	('more', 'PosReg', (38, 42))	('NSCLC', 'Disease', (88, 93))	('NSCLC', 'Disease', 'MESH:D002289', (88, 93))
545525	28422739	Clinical studies of WIF1 methylation or downregulation were particularly common in lung cancer; however, it had a weak diagnostic role in the current study.	('WIF1', 'Gene', (20, 24))	('lung cancer', 'Disease', 'MESH:D008175', (83, 94))	('WIF1', 'Gene', '11197', (20, 24))	('downregulation', 'NegReg', (40, 54))	('common', 'Reg', (73, 79))	('lung cancer', 'Disease', (83, 94))	('methylation', 'Var', (25, 36))	('lung cancer', 'Phenotype', 'HP:0100526', (83, 94))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))
545536	28422739	With analyzing TCGA data, we have found significant correlations for SFRP1_cg15839448, SFRP2_cg05774801, WIF1_cg21383810 methylation and their host gene expression, although the correlation coefficients were weak.	('SFRP1', 'Gene', '6422', (69, 74))	('SFRP2', 'Gene', '6423', (87, 92))	('SFRP2', 'Gene', (87, 92))	('SFRP1', 'Gene', (69, 74))	('WIF1', 'Gene', (105, 109))	('methylation', 'Var', (121, 132))	('WIF1', 'Gene', '11197', (105, 109))	('CG', 'Chemical', 'MESH:C028505', (16, 18))	('correlations', 'Interaction', (52, 64))
545537	28422739	Notably, results from GEO dataset gave a support that gene expression could be restored in some lung cancer cells after demethylation, to some extent, suggesting a potential effect of DNA methylation on gene silencing.	('lung cancer', 'Disease', 'MESH:D008175', (96, 107))	('gene expression', 'MPA', (54, 69))	('restored', 'PosReg', (79, 87))	('lung cancer', 'Disease', (96, 107))	('demethylation', 'Var', (120, 133))	('lung cancer', 'Phenotype', 'HP:0100526', (96, 107))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))
545540	28422739	Cancer cells suffer a global reduction of activation markers H3K4me3 and H4K16ac and a gain in the repressive markers H3K27me3, H3K9me3 and H4K20me3, which is closely related with transcriptional regulation.	('gain', 'PosReg', (87, 91))	('H3K4me3', 'Var', (61, 68))	('H4K16ac', 'Var', (73, 80))	('repressive', 'MPA', (99, 109))	('reduction', 'NegReg', (29, 38))	('H4K20me3', 'Var', (140, 148))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('activation', 'PosReg', (42, 52))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('H3K27me3', 'Var', (118, 126))	('H3K9me3', 'Var', (128, 135))
545541	28422739	In esophageal squamous cell carcinoma, DNA methylation and histone acetylation has been found to synergize silencing SFRP1 gene expression.	('SFRP1', 'Gene', '6422', (117, 122))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (14, 37))	('carcinoma', 'Phenotype', 'HP:0030731', (28, 37))	('esophageal squamous cell carcinoma', 'Disease', (3, 37))	('SFRP1', 'Gene', (117, 122))	('DNA methylation', 'Var', (39, 54))	('expression', 'MPA', (128, 138))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (3, 37))	('silencing', 'NegReg', (107, 116))
545542	28422739	Likewise, an aberrant gain of the repressive mark H3K27me3 could decrease the expression of SFRP1 gene in addition to DNA hypermethylation in prostate cancer cell line.	('SFRP1', 'Gene', (92, 97))	('expression', 'MPA', (78, 88))	('H3K27me3', 'Var', (50, 58))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('prostate cancer', 'Disease', 'MESH:D011471', (142, 157))	('prostate cancer', 'Phenotype', 'HP:0012125', (142, 157))	('SFRP1', 'Gene', '6422', (92, 97))	('decrease', 'NegReg', (65, 73))	('prostate cancer', 'Disease', (142, 157))	('gain', 'PosReg', (22, 26))
545550	28422739	In summary, our study identified that a methylation panel of Wnt signal pathway genes (SFRP1, SFRP2, WIF1 and PRKCB) might be used as diagnostic biomarkers of NSCLC risk.	('methylation', 'Var', (40, 51))	('SFRP1', 'Gene', '6422', (87, 92))	('NSCLC', 'Disease', (159, 164))	('WIF1', 'Gene', (101, 105))	('SFRP1', 'Gene', (87, 92))	('SFRP2', 'Gene', '6423', (94, 99))	('NSCLC', 'Disease', 'MESH:D002289', (159, 164))	('PRKCB', 'Gene', (110, 115))	('WIF1', 'Gene', '11197', (101, 105))	('SFRP2', 'Gene', (94, 99))	('PRKCB', 'Gene', '5579', (110, 115))	('NSCLC', 'Phenotype', 'HP:0030358', (159, 164))
545572	28422739	The fragments of SFRP1 promoter (+464 bp to +863bp), SFRP2 promoter (+261 bp to +660 bp), WIF1 promoter (-511 bp to -111 bp), and PRKCB promoter (-580 bp to -180 bp) were chemically synthesized.	('SFRP1', 'Gene', '6422', (17, 22))	('SFRP2', 'Gene', (53, 58))	('PRKCB', 'Gene', '5579', (130, 135))	('+261', 'Var', (69, 73))	('WIF1', 'Gene', (90, 94))	('SFRP1', 'Gene', (17, 22))	('WIF1', 'Gene', '11197', (90, 94))	('SFRP2', 'Gene', '6423', (53, 58))	('+464 bp', 'Var', (33, 40))	('PRKCB', 'Gene', (130, 135))
545575	28422739	ROC curves were constructed and the AUCs were calculated to determine the diagnostic role of four genes methylation for NSCLC.	('NSCLC', 'Phenotype', 'HP:0030358', (120, 125))	('NSCLC', 'Disease', 'MESH:D002289', (120, 125))	('methylation', 'Var', (104, 115))	('NSCLC', 'Disease', (120, 125))
545647	27642215	A factor which may promote tumor genesis is represented by the mutations in tumor suppressor gene.	('mutations', 'Var', (63, 72))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('promote', 'PosReg', (19, 26))	('tumor', 'Disease', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
545648	27642215	APC gene is such an example; mutations occurring in this gene conduct to the synthesis of a short nonfunctional APC protein.	('conduct to', 'Reg', (62, 72))	('APC', 'Gene', (112, 115))	('APC', 'Gene', (0, 3))	('mutations', 'Var', (29, 38))	('APC', 'Gene', '324', (112, 115))	('APC', 'Gene', '324', (0, 3))
545655	27642215	The development of cSCC is influenced by many other modifications induced by UV radiation such as the presence of melanocortin-1 receptor (associated with fair skin and red hair) which represents a risk factor for developing cSCC as well as melanoma, increased telomerase activity which may protect cSCC from apoptosis, and mutations of NOTCH genes, which are tumor suppressor genes identified in 75% of patients diagnosed with cSCC.	('melanoma', 'Phenotype', 'HP:0002861', (241, 249))	('melanoma', 'Disease', (241, 249))	('patients', 'Species', '9606', (404, 412))	('SCC', 'Gene', (300, 303))	('SCC', 'Gene', '6317', (20, 23))	('SCC', 'Gene', '6317', (226, 229))	('melanocortin-1 receptor', 'Gene', (114, 137))	('melanocortin-1 receptor', 'Gene', '4157', (114, 137))	('increased', 'PosReg', (251, 260))	('SCC', 'Gene', (20, 23))	('tumor', 'Disease', (360, 365))	('SCC', 'Gene', (226, 229))	('fair skin', 'Phenotype', 'HP:0007513', (155, 164))	('SCC', 'Phenotype', 'HP:0002860', (429, 432))	('NOTCH genes', 'Gene', (337, 348))	('tumor', 'Disease', 'MESH:D009369', (360, 365))	('melanoma', 'Disease', 'MESH:D008545', (241, 249))	('mutations', 'Var', (324, 333))	('SCC', 'Gene', '6317', (429, 432))	('SCC', 'Phenotype', 'HP:0002860', (300, 303))	('telomerase', 'Protein', (261, 271))	('tumor', 'Phenotype', 'HP:0002664', (360, 365))	('SCC', 'Gene', (429, 432))	('SCC', 'Phenotype', 'HP:0002860', (20, 23))	('SCC', 'Phenotype', 'HP:0002860', (226, 229))	('red hair', 'Phenotype', 'HP:0002297', (169, 177))	('SCC', 'Gene', '6317', (300, 303))	('influenced', 'Reg', (27, 37))
545661	27642215	These alterations may further influence apoptosis, proliferation, inflammation, and differentiation which may result in SCC development.	('alterations', 'Var', (6, 17))	('inflammation', 'Disease', (66, 78))	('apoptosis', 'CPA', (40, 49))	('SCC', 'Phenotype', 'HP:0002860', (120, 123))	('SCC', 'Gene', '6317', (120, 123))	('influence', 'Reg', (30, 39))	('proliferation', 'CPA', (51, 64))	('differentiation', 'CPA', (84, 99))	('inflammation', 'Disease', 'MESH:D007249', (66, 78))	('SCC', 'Gene', (120, 123))	('result in', 'Reg', (110, 119))
545663	27642215	The same results were obtained for mTOR (Ser2448), 4EBP1 (Ser65), 70S6K1 (Thr421), p70S6K1 (Thr421/Ser424), and S6 (Ser6).	('Thr421', 'Chemical', '-', (92, 98))	('Ser65', 'Chemical', '-', (58, 63))	('p70S6K1 (Thr421/Ser424', 'Var', (83, 105))	('Thr421', 'Chemical', '-', (74, 80))	('mTOR', 'Gene', (35, 39))	('4EBP1', 'Gene', (51, 56))	('mTOR', 'Gene', '2475', (35, 39))	('Thr421/Ser424', 'Var', (92, 105))	('Ser2448', 'Var', (41, 48))	('Ser6', 'Chemical', '-', (58, 62))	('Ser6', 'Chemical', '-', (116, 120))	('Ser424', 'Chemical', '-', (99, 105))	('Ser2448', 'Chemical', '-', (41, 48))	('4EBP1', 'Gene', '1978', (51, 56))
545674	27642215	It was discovered that SCC in mice is determined by Pam212, a keratinocyte cell population which does not have the ability of metastasizing, although cells that drift from Pam212 (LY lines) were found in lymph nodes metastases.	('mice', 'Species', '10090', (30, 34))	('SCC', 'Gene', '6317', (23, 26))	('lymph nodes metastases', 'Disease', (204, 226))	('lymph nodes metastases', 'Disease', 'MESH:D009362', (204, 226))	('Pam212', 'Chemical', '-', (172, 178))	('SCC', 'Gene', (23, 26))	('SCC', 'Phenotype', 'HP:0002860', (23, 26))	('Pam212', 'Var', (172, 178))	('Pam212', 'Chemical', '-', (52, 58))
545692	27642215	New treatment strategies that target CD133 would be useful for patients with high expression of this protein, who are at risk of developing cSCC with poor prognosis.	('expression', 'MPA', (82, 92))	('high', 'Var', (77, 81))	('SCC', 'Gene', (141, 144))	('CD133', 'Gene', (37, 42))	('CD133', 'Gene', '8842', (37, 42))	('SCC', 'Phenotype', 'HP:0002860', (141, 144))	('SCC', 'Gene', '6317', (141, 144))	('patients', 'Species', '9606', (63, 71))
545695	27642215	The mechanism explaining why EGFR has high expression in HNSCC is not completely elucidated, although several hypotheses including mutations in the receptor, high ligand levels, and increased mRNA transcription have been proposed (see Figure 2).	('mutations', 'Var', (131, 140))	('increased', 'PosReg', (182, 191))	('SCC', 'Gene', (59, 62))	('high ligand levels', 'MPA', (158, 176))	('SCC', 'Phenotype', 'HP:0002860', (59, 62))	('SCC', 'Gene', '6317', (59, 62))	('mRNA transcription', 'MPA', (192, 210))	('EGFR', 'Gene', '1956', (29, 33))	('EGFR', 'Gene', (29, 33))
545707	27642215	In oral squamous cell carcinoma, measuring mitochondrial DNA (mtDNA) may be useful for postoperative monitoring considering the fact that an important number of patients with head and neck SCC (HNSCC) that had histological negative margins had mtDNA mutations.	('SCC', 'Gene', (196, 199))	('SCC', 'Gene', (189, 192))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (3, 31))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (8, 31))	('SCC', 'Phenotype', 'HP:0002860', (196, 199))	('SCC', 'Gene', '6317', (196, 199))	('SCC', 'Phenotype', 'HP:0002860', (189, 192))	('SCC', 'Gene', '6317', (189, 192))	('carcinoma', 'Phenotype', 'HP:0030731', (22, 31))	('patients', 'Species', '9606', (161, 169))	('oral squamous cell carcinoma', 'Disease', (3, 31))	('mutations', 'Var', (250, 259))	('mtDNA', 'Gene', (244, 249))
545709	27642215	analyzed postoperative blood samples from 61 patients, and of those 16 had high mtDNA mutations which were correlated either with a local recurrence or with distant metastasis within the next 9 months after surgical treatment.	('mutations', 'Var', (86, 95))	('mtDNA', 'Gene', (80, 85))	('patients', 'Species', '9606', (45, 53))	('distant metastasis', 'CPA', (157, 175))
545710	27642215	It is really important to note that mutations in mtDNA are identified only in tumoral tissue, and depending on the intensity it can be used as a prognostic predictor for patients with oSCC.	('patients', 'Species', '9606', (170, 178))	('mtDNA', 'Gene', (49, 54))	('SCC', 'Gene', (185, 188))	('SCC', 'Phenotype', 'HP:0002860', (185, 188))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('mutations', 'Var', (36, 45))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('SCC', 'Gene', '6317', (185, 188))	('tumor', 'Disease', (78, 83))
545713	27642215	Viral infection is a very important risk factor; HPV DNA incorporates itself in the human genome and induces an important expression of viral genes E6 and E7 which inactivates tumor suppressor genes.	('expression', 'MPA', (122, 132))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('Viral infection', 'Disease', (0, 15))	('tumor', 'Disease', (176, 181))	('inactivates', 'NegReg', (164, 175))	('human', 'Species', '9606', (84, 89))	('Viral infection', 'Disease', 'MESH:D001102', (0, 15))	('HPV DNA', 'Var', (49, 56))	('induces', 'Reg', (101, 108))	('tumor', 'Disease', 'MESH:D009369', (176, 181))
545720	27642215	Studies showed that defective expression of plectin induces genomic instability which creates favourable circumstances for cancer development and progression.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('plectin', 'Gene', '5339', (44, 51))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('cancer', 'Disease', (123, 129))	('induces', 'Reg', (52, 59))	('plectin', 'Gene', (44, 51))	('defective expression', 'Var', (20, 40))	('genomic', 'MPA', (60, 67))
545750	26104160	Initially described by Ambros and colleagues in the model organism Caenorhabditis elegans, miRNAs have been shown to modulate a broad range of molecular processes involved in tissue homeostasis and, ultimately, in the pathogenesis of human diseases, including cancer.	('modulate', 'Reg', (117, 125))	('human', 'Species', '9606', (234, 239))	('cancer', 'Disease', 'MESH:D009369', (260, 266))	('miRNAs', 'Var', (91, 97))	('Caenorhabditis elegans', 'Species', '6239', (67, 89))	('cancer', 'Disease', (260, 266))	('cancer', 'Phenotype', 'HP:0002664', (260, 266))
545767	26104160	The reasoning behind dividing samples in these two groups was to minimize biological variation within the groups and, possibly, to be able to select stronger markers linked to the metastatic phenotype due to their earlier presence in the tumor progression (i.e., in T1/T2N+ samples) or maybe a protective role due to their presence in non-metastatic larger tumors.	('tumor', 'Disease', (357, 362))	('tumor', 'Disease', 'MESH:D009369', (238, 243))	('tumors', 'Disease', (357, 363))	('tumors', 'Disease', 'MESH:D009369', (357, 363))	('tumors', 'Phenotype', 'HP:0002664', (357, 363))	('tumor', 'Phenotype', 'HP:0002664', (238, 243))	('T1/T2N+', 'Var', (266, 273))	('tumor', 'Disease', (238, 243))	('tumor', 'Disease', 'MESH:D009369', (357, 362))	('tumor', 'Phenotype', 'HP:0002664', (357, 362))
545775	26104160	In squamous cell carcinomas, increased expression of miR-21 was observed in human tumors characterized by p53 mutations and distant metastasis, and the augmented expression of miR-21, mediated by active mTOR and Stat3 signaling, conferred increased invasive properties to mouse keratinocytes in vitro and in vivo.	('p53', 'Gene', '7157', (106, 109))	('tumors', 'Disease', (82, 88))	('augmented', 'PosReg', (152, 161))	('increased', 'PosReg', (29, 38))	('carcinoma', 'Phenotype', 'HP:0030731', (17, 26))	('miR-21', 'Gene', (53, 59))	('p53', 'Gene', (106, 109))	('miR-21', 'Gene', '406991', (176, 182))	('mTOR', 'Gene', '2475', (203, 207))	('carcinomas', 'Phenotype', 'HP:0030731', (17, 27))	('tumors', 'Disease', 'MESH:D009369', (82, 88))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (3, 27))	('Stat3', 'Gene', (212, 217))	('expression', 'MPA', (39, 49))	('mutations', 'Var', (110, 119))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (3, 27))	('invasive properties to mouse keratinocytes', 'CPA', (249, 291))	('miR-21', 'Gene', (176, 182))	('Stat3', 'Gene', '6774', (212, 217))	('increased', 'PosReg', (239, 248))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (3, 26))	('mouse', 'Species', '10090', (272, 277))	('men', 'Species', '9606', (155, 158))	('tumors', 'Phenotype', 'HP:0002664', (82, 88))	('miR-21', 'Gene', '406991', (53, 59))	('squamous cell carcinomas', 'Disease', (3, 27))	('human', 'Species', '9606', (76, 81))	('expression', 'MPA', (162, 172))	('mTOR', 'Gene', (203, 207))
545803	26104160	We show that despite homogeneity in their global expression, small RNAs other than miRNAs are expressed and should exert a regulatory function associated with the cancer phenotype.	('associated', 'Reg', (143, 153))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('small', 'Var', (61, 66))	('regulatory function', 'MPA', (123, 142))	('cancer', 'Disease', (163, 169))	('cancer', 'Disease', 'MESH:D009369', (163, 169))	('RNAs', 'Protein', (67, 71))
545811	26104160	We corroborate results on two metastasis inhibitors studied in other cancer types, miR-31 and miR-130b, and on two metastasis enhancers, miR-181 and miR-296, in the context of OSCC.	('miR-296', 'Gene', '407022', (149, 156))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('miR-181', 'Var', (137, 144))	('miR-31', 'Gene', (83, 89))	('miR-130b', 'Gene', '406920', (94, 102))	('miR-296', 'Gene', (149, 156))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('miR-130b', 'Gene', (94, 102))	('miR-31', 'Gene', '407035', (83, 89))	('cancer', 'Disease', (69, 75))
545827	26104160	MiRNAs evaluated in plasma were those identified as differentially expressed between N+ and N0 tumors following small RNA sequencing in this study but which had been previously detected in plasma by a large scale study: miR-20b (Exiqon 204755), miR-30a (Exiqon 205695), miR-31 (Exiqon 204236), miR-106a (Exiqon 204563), miR-130b (Exiqon 204317), miR-139 (Exiqon 205874), miR-296 (Exiqon 204436), miR-301 (Exiqon 204687), miR-335 (Exiqon 204151), miR-551b (Exiqon 204067).	('miR-30a', 'Gene', (245, 252))	('miR-551b', 'Gene', (446, 454))	('miR-106a', 'Gene', '406899', (294, 302))	('miR-139', 'Gene', '406931', (346, 353))	('Exiqon 205874', 'Var', (355, 368))	('miR-296', 'Gene', '407022', (371, 378))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('Exiqon 204236', 'Var', (278, 291))	('miR-31', 'Gene', (270, 276))	('miR-335', 'Gene', '442904', (421, 428))	('miR-301', 'Gene', '407027', (396, 403))	('miR-20b', 'Gene', (220, 227))	('miR-139', 'Gene', (346, 353))	('miR-130b', 'Gene', '406920', (320, 328))	('miR-130b', 'Gene', (320, 328))	('N0 tumors', 'Disease', 'MESH:D009369', (92, 101))	('Exiqon 204151', 'Var', (430, 443))	('miR-551b', 'Gene', '693136', (446, 454))	('miR-301', 'Gene', (396, 403))	('Exiqon', 'Var', (254, 260))	('Exiqon 204687', 'Var', (405, 418))	('miR-106a', 'Gene', (294, 302))	('miR-31', 'Gene', '407035', (270, 276))	('miR-335', 'Gene', (421, 428))	('miR-30a', 'Gene', '407029', (245, 252))	('miR-20b', 'Gene', '574032', (220, 227))	('N0 tumors', 'Disease', (92, 101))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('miR-296', 'Gene', (371, 378))
545836	32064261	Although COME of gene mutations in pan-cancer have been well explored, little is known about the COME of DNA methylation in pan-cancer.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('cancer', 'Disease', (39, 45))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('mutations', 'Var', (22, 31))	('cancer', 'Disease', (128, 134))
545842	32064261	Taken together, we identified millions of COME events of DNA methylation in pan-cancer and detected functional epigenetic COME events that could separate tumor patients into different subtypes, which may benefit the diagnosis and prognosis of pan-cancer.	('patients', 'Species', '9606', (160, 168))	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('DNA methylation', 'Var', (57, 72))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancer', 'Disease', (247, 253))	('cancer', 'Disease', 'MESH:D009369', (247, 253))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('benefit', 'PosReg', (204, 211))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('cancer', 'Disease', (80, 86))	('tumor', 'Disease', (154, 159))
545843	32064261	An increasing number of studies have indicated that aberrant DNAm plays an important role in diverse diseases, especially cancers.	('cancers', 'Disease', 'MESH:D009369', (122, 129))	('cancers', 'Phenotype', 'HP:0002664', (122, 129))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('cancers', 'Disease', (122, 129))	('aberrant DNAm', 'Var', (52, 65))
545844	32064261	For example, the hypermethylation of CpG island in promoter region of tumor suppressor genes have been observed in pediatric acute myeloid leukemia, bladder and adult brain tumors as well as hepatocellular carcinoma, which may lead to proliferative advantages and aggressive phenotypes during tumorigenesis.	('bladder', 'Disease', (149, 156))	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('tumor', 'Disease', 'MESH:D009369', (293, 298))	('hepatocellular carcinoma', 'Disease', (191, 215))	('tumors', 'Phenotype', 'HP:0002664', (173, 179))	('acute myeloid leukemia', 'Disease', (125, 147))	('observed', 'Reg', (103, 111))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('brain tumors', 'Phenotype', 'HP:0030692', (167, 179))	('tumor', 'Phenotype', 'HP:0002664', (293, 298))	('brain tumors', 'Disease', 'MESH:D001932', (167, 179))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('hypermethylation', 'Var', (17, 33))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (125, 147))	('carcinoma', 'Phenotype', 'HP:0030731', (206, 215))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (191, 215))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (125, 147))	('brain tumors', 'Disease', (167, 179))	('bladder', 'Disease', 'MESH:D001745', (149, 156))	('leukemia', 'Phenotype', 'HP:0001909', (139, 147))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (131, 147))	('proliferative', 'CPA', (235, 248))	('tumor', 'Disease', (70, 75))	('tumor', 'Disease', (173, 178))	('tumor', 'Disease', (293, 298))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (191, 215))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
545848	32064261	Co-methylation has been reported as a new indicator for discovering functional associations between gene pairs in breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('breast cancer', 'Disease', 'MESH:D001943', (114, 127))	('breast cancer', 'Phenotype', 'HP:0003002', (114, 127))	('breast cancer', 'Disease', (114, 127))	('Co-methylation', 'Var', (0, 14))
545854	32064261	Our results suggest that the COME events of DNA methylation could play important roles in tumorigenesis and may benefit the prognosis of different cancers.	('prognosis', 'CPA', (124, 133))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('cancers', 'Disease', 'MESH:D009369', (147, 154))	('cancers', 'Phenotype', 'HP:0002664', (147, 154))	('cancers', 'Disease', (147, 154))	('DNA', 'Gene', (44, 47))	('methylation', 'Var', (48, 59))	('benefit', 'PosReg', (112, 119))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('play', 'Reg', (66, 70))
545875	32064261	Moreover, aberrant methylation of hub gene AGR2 was reported to be associated with ovarian cancer, while MT3 was a putative tumor suppressor gene in pediatric acute myeloid leukemia.	('hub', 'Gene', '1993', (34, 37))	('tumor', 'Disease', (124, 129))	('aberrant methylation', 'Var', (10, 30))	('ovarian cancer', 'Disease', (83, 97))	('tumor', 'Disease', 'MESH:D009369', (124, 129))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (159, 181))	('ovarian cancer', 'Phenotype', 'HP:0100615', (83, 97))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (165, 181))	('MT3', 'Gene', '4504', (105, 108))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (159, 181))	('leukemia', 'Phenotype', 'HP:0001909', (173, 181))	('AGR2', 'Gene', (43, 47))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('MT3', 'Gene', (105, 108))	('associated', 'Reg', (67, 77))	('AGR2', 'Gene', '10551', (43, 47))	('ovarian cancer', 'Disease', 'MESH:D010051', (83, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('hub', 'Gene', (34, 37))	('acute myeloid leukemia', 'Disease', (159, 181))
545881	32064261	Aberrant DNA methylation of some of those top 10 genes with the highest degree has been reported to be associated with neoplasms, such as HHIPL1, GABRB2, FOXF1 and RSPO4 (: Figure 2E).	('GABRB2', 'Gene', (146, 152))	('neoplasms', 'Disease', 'MESH:D009369', (119, 128))	('Aberrant', 'Var', (0, 8))	('associated', 'Reg', (103, 113))	('RSPO4', 'Gene', '343637', (164, 169))	('neoplasms', 'Phenotype', 'HP:0002664', (119, 128))	('FOXF1', 'Gene', (154, 159))	('GABRB2', 'Gene', '2561', (146, 152))	('FOXF1', 'Gene', '2294', (154, 159))	('HHIPL1', 'Gene', (138, 144))	('HHIPL1', 'Gene', '84439', (138, 144))	('neoplasm', 'Phenotype', 'HP:0002664', (119, 127))	('RSPO4', 'Gene', (164, 169))	('neoplasms', 'Disease', (119, 128))
545884	32064261	To further explore the associations between aberrant DNA methylation of zinc fingers gene family and neoplasms, we found that those genes were significantly enriched in regulation of transcription, DNA binding transcription factor activity, RNA polymerase II regulatory region sequence-specific DNA binding, Neuroactive ligand-receptor interaction, and so on (Supplementary Table S3).	('neoplasms', 'Phenotype', 'HP:0002664', (101, 110))	('regulation', 'MPA', (169, 179))	('neoplasms', 'Disease', 'MESH:D009369', (101, 110))	('binding', 'Interaction', (299, 306))	('neoplasms', 'Disease', (101, 110))	('neoplasm', 'Phenotype', 'HP:0002664', (101, 109))	('transcription', 'MPA', (183, 196))	('aberrant', 'Var', (44, 52))	('interaction', 'Interaction', (336, 347))
545901	32064261	As for neoplasm histologic grade (Figures 5G,H), cluster 3 of kidney renal clear cell carcinoma (KIRC) is enriched in grade G3 and G4, and poorer prognosis was observed in this cluster (Figure 4).	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('neoplasm', 'Disease', (7, 15))	('grade G3', 'Var', (118, 126))	('neoplasm', 'Phenotype', 'HP:0002664', (7, 15))	('kidney renal clear cell carcinoma', 'Disease', (62, 95))	('neoplasm', 'Disease', 'MESH:D009369', (7, 15))	('kidney renal clear cell carcinoma', 'Disease', 'MESH:D002292', (62, 95))	('KIRC', 'Disease', (97, 101))	('KIRC', 'Disease', 'MESH:D002292', (97, 101))
545911	32064261	Hypermethylation of the CpG sites on GRM6 (glutamate metabotropic receptor 6) was reported to be a hallmark of CIMP in clear cell renal cell carcinomas.	('clear cell renal cell carcinomas', 'Phenotype', 'HP:0006770', (119, 151))	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('glutamate metabotropic receptor 6', 'Gene', '2916', (43, 76))	('clear cell renal cell carcinomas', 'Disease', (119, 151))	('Hypermethylation', 'Var', (0, 16))	('clear cell renal cell carcinomas', 'Disease', 'MESH:D002292', (119, 151))	('carcinomas', 'Phenotype', 'HP:0030731', (141, 151))	('renal cell carcinomas', 'Phenotype', 'HP:0005584', (130, 151))	('GRM6', 'Gene', '2916', (37, 41))	('glutamate metabotropic receptor 6', 'Gene', (43, 76))	('GRM6', 'Gene', (37, 41))
545912	32064261	In contrast, cluster C7 was associated with the poorest prognosis and co-methylation of GRB7-SLC45A4 was enriched in this group (p-value <0.001, hypergeometric test).	('poorest', 'NegReg', (48, 55))	('co-methylation', 'Var', (70, 84))	('cluster C7', 'Disease', (13, 23))	('SLC45A4', 'Gene', (93, 100))	('GRB7', 'Gene', '2886', (88, 92))	('GRB7', 'Gene', (88, 92))	('cluster C7', 'Disease', 'MESH:C566443', (13, 23))	('SLC45A4', 'Gene', '57210', (93, 100))
545915	32064261	The result shows that patients with co-methylation of CRMP1-GRM6 have better outcomes (p-value <0.0001, log-rank test, Figure 6C), whereas patients with co-methylation of GRB7-SLC45A4 exhibit significantly poorer prognosis (p-value <0.0001, log-rank test, Figure 6D).	('GRM6', 'Gene', (60, 64))	('patients', 'Species', '9606', (139, 147))	('outcomes', 'MPA', (77, 85))	('SLC45A4', 'Gene', (176, 183))	('patients', 'Species', '9606', (22, 30))	('CRMP1', 'Gene', '1400', (54, 59))	('better', 'PosReg', (70, 76))	('GRM6', 'Gene', '2916', (60, 64))	('co-methylation', 'Var', (36, 50))	('CRMP1', 'Gene', (54, 59))	('GRB7', 'Gene', '2886', (171, 175))	('SLC45A4', 'Gene', '57210', (176, 183))	('GRB7', 'Gene', (171, 175))
545918	32064261	Although several studies have reported the epigenetic silencing of the zinc finger gene family, we are the first to identify functional epigenetic modules of the zinc finger gene family in six cancer types by integrating gene expression and DNA methylation data in the context of COME networks.	('cancer', 'Disease', (193, 199))	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('epigenetic', 'Var', (43, 53))
545919	32064261	Methylation was reported to be the main mechanism for downregulation of tumor cell growth suppressor ZNF677 in non-small cell lung cancers (NSCLCs) and the methylation of ZNF677 could be used in the prognosis of NSCLCs.	('cancers', 'Phenotype', 'HP:0002664', (131, 138))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('non-small cell lung cancers', 'Disease', (111, 138))	('NSCLCs', 'Disease', 'MESH:D002289', (140, 146))	('ZNF677', 'Gene', (171, 177))	('NSCLCs', 'Disease', 'MESH:D002289', (212, 218))	('non-small cell lung cancers', 'Phenotype', 'HP:0030358', (111, 138))	('ZNF677', 'Gene', '342926', (101, 107))	('ZNF677', 'Gene', (101, 107))	('downregulation', 'NegReg', (54, 68))	('Methylation', 'Var', (0, 11))	('small cell lung cancers', 'Phenotype', 'HP:0030357', (115, 138))	('tumor', 'Disease', (72, 77))	('non-small cell lung cancers', 'Disease', 'MESH:D002289', (111, 138))	('NSCLCs', 'Disease', (140, 146))	('NSCLCs', 'Disease', (212, 218))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('lung cancers', 'Phenotype', 'HP:0100526', (126, 138))	('ZNF677', 'Gene', '342926', (171, 177))
546077	31918173	In a hallmark review by Hanahan and Weinberg, it is suggested that there are six essential fundamental processes involved in the maintenance of any malignancy, including the resistance of cell death, continued proliferation, evasion of growth suppressors, enabling replicative immortality, inducing angiogenesis and activating invasion and metastasis.	('mortality', 'Disease', (279, 288))	('angiogenesis', 'CPA', (299, 311))	('malignancy', 'Disease', (148, 158))	('activating', 'PosReg', (316, 326))	('malignancy', 'Disease', 'MESH:D009369', (148, 158))	('inducing', 'PosReg', (290, 298))	('mortality', 'Disease', 'MESH:D003643', (279, 288))	('evasion', 'Var', (225, 232))	('enabling', 'PosReg', (256, 264))
546084	31918173	For instance, loss of function of p16 and p53 is associated with proliferation and evasion of growth suppressors, dysregulation of the Notch and WNT pathways may assist in enabling replicative immortality and avoiding cell differentiation, and the AKT pathway plays key roles in invasion and metastasis.	('evasion', 'MPA', (83, 90))	('p53', 'Gene', '7157', (42, 45))	('mortality', 'Disease', (195, 204))	('AKT', 'Gene', '207', (248, 251))	('metastasis', 'CPA', (292, 302))	('p53', 'Gene', (42, 45))	('Notch', 'Gene', '31293', (135, 140))	('enabling', 'PosReg', (172, 180))	('assist', 'Reg', (162, 168))	('p16', 'Gene', (34, 37))	('WNT pathways', 'Pathway', (145, 157))	('invasion', 'CPA', (279, 287))	('p16', 'Gene', '1029', (34, 37))	('dysregulation', 'Var', (114, 127))	('mortality', 'Disease', 'MESH:D003643', (195, 204))	('avoiding cell differentiation', 'CPA', (209, 238))	('Notch', 'Gene', (135, 140))	('proliferation', 'CPA', (65, 78))	('AKT', 'Gene', (248, 251))	('loss of function', 'NegReg', (14, 30))	('growth', 'Protein', (94, 100))
546091	31918173	Thus, disruption of p16 activity results in a loss of cell senescence, subsequently leading to dysplasia.	('activity', 'MPA', (24, 32))	('leading to', 'Reg', (84, 94))	('loss', 'NegReg', (46, 50))	('dysplasia', 'Disease', 'MESH:C536170', (95, 104))	('p16', 'Gene', (20, 23))	('cell senescence', 'CPA', (54, 69))	('dysplasia', 'Disease', (95, 104))	('disruption', 'Var', (6, 16))	('p16', 'Gene', '1029', (20, 23))
546092	31918173	Similar to other types of H&N malignancies, OCSCC is often negative for p16.	('for', 'Var', (68, 71))	('p16', 'Gene', '1029', (72, 75))	('malignancies', 'Disease', (30, 42))	('OCSCC', 'Chemical', '-', (44, 49))	('p16', 'Gene', (72, 75))	('malignancies', 'Disease', 'MESH:D009369', (30, 42))
546093	31918173	Moreover, OCSCC patients with p16 inactivation have significantly lower survival than patients with normal or amplified levels of p16.	('p16', 'Gene', (30, 33))	('OCSCC', 'Disease', (10, 15))	('survival', 'MPA', (72, 80))	('inactivation', 'Var', (34, 46))	('p16', 'Gene', (130, 133))	('patients', 'Species', '9606', (16, 24))	('lower', 'NegReg', (66, 71))	('p16', 'Gene', '1029', (30, 33))	('p16', 'Gene', '1029', (130, 133))	('OCSCC', 'Chemical', '-', (10, 15))	('patients', 'Species', '9606', (86, 94))
546097	31918173	Moreover, several studies showed that CCND1 amplification and cyclin D1 expression were associated with decreased survival and poor prognosis in OCSCC patients.	('cyclin D1', 'Gene', (62, 71))	('survival', 'MPA', (114, 122))	('OCSCC', 'Chemical', '-', (145, 150))	('CCND1', 'Gene', '595', (38, 43))	('OCSCC', 'Disease', (145, 150))	('decreased', 'NegReg', (104, 113))	('amplification', 'Var', (44, 57))	('expression', 'MPA', (72, 82))	('patients', 'Species', '9606', (151, 159))	('CCND1', 'Gene', (38, 43))	('cyclin D1', 'Gene', '595', (62, 71))
546098	31918173	Inhibition of Cyclin D1 suppresses activation of the cyclin dependent kinases CDK4 and CDK6, which drive cell cycle progression by preventing the phosphorylation and inactivation of pRb.	('phosphorylation', 'MPA', (146, 161))	('preventing', 'NegReg', (131, 141))	('CDK4', 'Gene', (78, 82))	('inactivation', 'MPA', (166, 178))	('CDK6', 'Gene', '1021', (87, 91))	('CDK4', 'Gene', '1019', (78, 82))	('Cyclin D1', 'Gene', (14, 23))	('Cyclin D1', 'Gene', '595', (14, 23))	('Inhibition', 'Var', (0, 10))	('suppresses', 'NegReg', (24, 34))	('CDK6', 'Gene', (87, 91))	('pRb', 'Gene', '5925', (182, 185))	('pRb', 'Gene', (182, 185))
546100	31918173	Dysregulation of pRb occurs early in oral epithelial dysplasia and is associated with higher likelihood of transformation to malignant carcinoma.	('malignant carcinoma', 'Disease', (125, 144))	('oral epithelial dysplasia', 'Disease', (37, 62))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('Dysregulation', 'Var', (0, 13))	('malignant carcinoma', 'Disease', 'MESH:D009369', (125, 144))	('pRb', 'Gene', (17, 20))	('pRb', 'Gene', '5925', (17, 20))	('oral epithelial dysplasia', 'Disease', 'MESH:D017573', (37, 62))
546101	31918173	Inactivation of the p53 protein, which is encoded by the gene TP53 (located on chromosome 17p12), plays a prominent role in the pathogenesis of various solid malignancies including head and neck cancers.	('p53', 'Gene', (20, 23))	('p53', 'Gene', '7157', (20, 23))	('TP53', 'Gene', '7157', (62, 66))	('head and neck cancer', 'Phenotype', 'HP:0012288', (181, 201))	('malignancies', 'Disease', 'MESH:D009369', (158, 170))	('TP53', 'Gene', (62, 66))	('head and neck cancer', 'Disease', 'MESH:D006258', (181, 201))	('malignancies', 'Disease', (158, 170))	('head and neck cancers', 'Phenotype', 'HP:0012288', (181, 202))	('cancers', 'Phenotype', 'HP:0002664', (195, 202))	('neck cancers', 'Disease', (190, 202))	('neck cancers', 'Disease', 'MESH:D006258', (190, 202))	('Inactivation', 'Var', (0, 12))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
546103	31918173	Mutations in exon 4 or intron 6 of the TP53 are commonly detected in the majority (84%) of H&N cancers, including OCSCC, p53 is a useful prognosticator of OCSCC.	('OCSCC', 'Chemical', '-', (155, 160))	('OCSCC', 'Chemical', '-', (114, 119))	('including', 'Disease', (104, 113))	('p53', 'Gene', (121, 124))	('p53', 'Gene', '7157', (121, 124))	('cancers', 'Phenotype', 'HP:0002664', (95, 102))	('N cancers', 'Disease', (93, 102))	('N cancers', 'Disease', 'MESH:D009369', (93, 102))	('detected', 'Reg', (57, 65))	('Mutations in', 'Var', (0, 12))	('TP53', 'Gene', '7157', (39, 43))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('TP53', 'Gene', (39, 43))
546113	31918173	On the other hand, inactivating mutations in NOTCH1 are present in 11-19% of HNSCC tumors, suggesting that NOTCH1 may act as a tumor suppressor in HNSCC, in contrast with its proto-oncogenic role in other cancers.	('cancers', 'Disease', 'MESH:D009369', (205, 212))	('tumor', 'Disease', (83, 88))	('HNSCC tumors', 'Disease', (77, 89))	('inactivating mutations', 'Var', (19, 41))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('NOTCH1', 'Gene', (45, 51))	('NOTCH1', 'Gene', (107, 113))	('cancers', 'Phenotype', 'HP:0002664', (205, 212))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('cancers', 'Disease', (205, 212))	('tumors', 'Phenotype', 'HP:0002664', (83, 89))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('NOTCH1', 'Gene', '4851', (45, 51))	('NOTCH1', 'Gene', '4851', (107, 113))	('tumor', 'Disease', (127, 132))	('HNSCC tumors', 'Disease', 'MESH:D000077195', (77, 89))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('HNSCC', 'Disease', (147, 152))
546115	31918173	Pickering and colleagues found that 9% of patients with OCSCC harbor inactivating mutations in NOTCH1 and that OCSCC proliferation in vitro was inhibited by functional NOTCH1 signaling.	('OCSCC', 'Chemical', '-', (111, 116))	('OCSCC', 'Chemical', '-', (56, 61))	('OCSCC', 'Disease', (56, 61))	('inactivating mutations', 'Var', (69, 91))	('NOTCH1', 'Gene', '4851', (95, 101))	('NOTCH1', 'Gene', (95, 101))	('inhibited', 'NegReg', (144, 153))	('NOTCH1', 'Gene', '4851', (168, 174))	('NOTCH1', 'Gene', (168, 174))	('patients', 'Species', '9606', (42, 50))
546117	31918173	Higher rates of NOTCH1 mutation (43%) were found in Chinese patients with OSC, whereas NOTCH1 mutations were uncommon in Singaporean patients with oral tongue squamous cell carcinoma, suggesting that NOTCH1 inactivation may have complex genetic interactions in the pathogenesis of OCSCC.	('NOTCH1', 'Gene', '4851', (16, 22))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (159, 182))	('oral tongue squamous cell carcinoma', 'Disease', 'MESH:D002294', (147, 182))	('mutation', 'Var', (23, 31))	('NOTCH1', 'Gene', (16, 22))	('patients', 'Species', '9606', (60, 68))	('patients', 'Species', '9606', (133, 141))	('carcinoma', 'Phenotype', 'HP:0030731', (173, 182))	('tongue squamous cell carcinoma', 'Phenotype', 'HP:0030413', (152, 182))	('OSC', 'Disease', (74, 77))	('oral tongue squamous cell carcinoma', 'Disease', (147, 182))	('OCSCC', 'Chemical', '-', (281, 286))	('OCSCC', 'Disease', (281, 286))	('NOTCH1', 'Gene', '4851', (200, 206))	('NOTCH1', 'Gene', (200, 206))	('NOTCH1', 'Gene', '4851', (87, 93))	('NOTCH1', 'Gene', (87, 93))
546120	31918173	In these studies, NOTCH1 expression was correlated with T-stage and clinical stage, and depletion of Notch1 caused decreased cell proliferation.	('depletion', 'Var', (88, 97))	('NOTCH1', 'Gene', (18, 24))	('expression', 'MPA', (25, 35))	('decreased', 'NegReg', (115, 124))	('cell proliferation', 'CPA', (125, 143))	('correlated', 'Reg', (40, 50))	('Notch1', 'Gene', (101, 107))	('Notch1', 'Gene', '4851', (101, 107))	('NOTCH1', 'Gene', '4851', (18, 24))
546122	31918173	Thus, tumorigenesis may arise from multiple forms of dysregulation of the Notch signaling pathway, suggesting that its careful regulation is essential for proper cell function.	('dysregulation', 'Var', (53, 66))	('Notch', 'Gene', '31293', (74, 79))	('arise from', 'Reg', (24, 34))	('tumor', 'Disease', 'MESH:D009369', (6, 11))	('Notch', 'Gene', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (6, 11))	('tumor', 'Disease', (6, 11))
546125	31918173	Mutations in CTNNB1, which encodes beta-catenin, are rare in HNSCC; however, inactivating mutations in NOTCH1 and FAT1 signaling prevent their inhibition of CTNNB1 expression.	('beta-catenin', 'Gene', (35, 47))	('CTNNB1', 'Gene', '1499', (13, 19))	('FAT1', 'Gene', '2195', (114, 118))	('prevent', 'NegReg', (129, 136))	('inhibition', 'MPA', (143, 153))	('FAT1', 'Gene', (114, 118))	('expression', 'MPA', (164, 174))	('CTNNB1', 'Gene', (157, 163))	('CTNNB1', 'Gene', (13, 19))	('beta-catenin', 'Gene', '1499', (35, 47))	('Mutations', 'Var', (0, 9))	('NOTCH1', 'Gene', '4851', (103, 109))	('NOTCH1', 'Gene', (103, 109))	('inactivating mutations', 'Var', (77, 99))	('CTNNB1', 'Gene', '1499', (157, 163))
546128	31918173	High expression of EGFR is associated with tumor aggressiveness and poor survival of patients with OCSCC, including specifically oral tongue cancers.	('High', 'Var', (0, 4))	('poor', 'NegReg', (68, 72))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (43, 63))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('associated', 'Reg', (27, 37))	('EGFR', 'Gene', '1956', (19, 23))	('patients', 'Species', '9606', (85, 93))	('oral tongue cancers', 'Disease', (129, 148))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('oral tongue cancers', 'Disease', 'MESH:D014062', (129, 148))	('EGFR', 'Gene', (19, 23))	('cancers', 'Phenotype', 'HP:0002664', (141, 148))	('OCSCC', 'Chemical', '-', (99, 104))	('tumor aggressiveness', 'Disease', (43, 63))	('OCSCC', 'Disease', (99, 104))	('aggressiveness', 'Phenotype', 'HP:0000718', (49, 63))
546148	31918173	Processes such as methylation or demethylation of the gene promoter regions play a crucial role in gene silencing or gene expression, respectively.The silencing of tumor suppressor genes due to methylation is one of the hallmarks of carcinogenesis.	('tumor', 'Disease', (164, 169))	('methylation', 'Var', (194, 205))	('carcinogenesis', 'Disease', 'MESH:D063646', (233, 247))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('carcinogenesis', 'Disease', (233, 247))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('silencing', 'NegReg', (151, 160))
546152	31918173	In tobacco users, 28-58% of precancerous oral tissues demonstrated genome-wide DNA methylation, with levels of methylation increasing throughout the progression to oral cancers.	('oral cancers', 'Disease', (164, 176))	('DNA methylation', 'Var', (79, 94))	('cancer', 'Disease', (169, 175))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('tobacco', 'Species', '4097', (3, 10))	('increasing', 'PosReg', (123, 133))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('oral cancers', 'Disease', 'MESH:D009369', (164, 176))	('cancer', 'Disease', (31, 37))	('cancer', 'Disease', 'MESH:D009369', (169, 175))	('cancers', 'Phenotype', 'HP:0002664', (169, 176))
546155	31918173	miR-200ab-429, miR-200c-141, miR-205, miR-137) or hypomethylation (i.e.	('miR-200c-141', 'Var', (15, 27))	('miR-205', 'Gene', (29, 36))	('miR-137', 'Gene', (38, 45))	('miR-205', 'Gene', '406988', (29, 36))	('miR-137', 'Gene', '406928', (38, 45))	('miR-200ab-429', 'Var', (0, 13))	('hypomethylation', 'Var', (50, 65))
546158	31918173	The prominence of epigenetic alterations in OCSCC suggests that treatments targeting methyltransferases may prove to be effective.	('epigenetic alterations', 'Var', (18, 40))	('OCSCC', 'Chemical', '-', (44, 49))	('OCSCC', 'Gene', (44, 49))
546163	31918173	Further research on epigenetic alterations in circulating tumor DNA in patients with OCSCC and other HNSCCs may allow early and non-invasive diagnosis of the disease using plasma samples.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('HNSCCs', 'Disease', 'MESH:D000077195', (101, 107))	('patients', 'Species', '9606', (71, 79))	('HNSCCs', 'Disease', (101, 107))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('epigenetic alterations', 'Var', (20, 42))	('OCSCC', 'Chemical', '-', (85, 90))	('OCSCC', 'Disease', (85, 90))
546172	31918173	EMT is also prominently driven by the expression of transforming growth factor beta (TGF-beta), which activates cell spreading and separation of cell borders.	('TGF-beta', 'Gene', (85, 93))	('separation of cell borders', 'CPA', (131, 157))	('TGF-beta', 'Gene', '7039', (85, 93))	('cell spreading', 'CPA', (112, 126))	('expression', 'Var', (38, 48))	('activates', 'PosReg', (102, 111))	('transforming growth factor beta', 'Gene', (52, 83))	('transforming growth factor beta', 'Gene', '7124', (52, 83))
546185	31918173	Phosphorylation of beta-catenin leads to its dissociation from a complex with E-cadherin, resulting in loss of cell adhesion and subsequent tumor cell invasion, while translocation of beta-catenin to the nucleus allows it to act as an oncogenic transcription factor.	('tumor', 'Phenotype', 'HP:0002664', (140, 145))	('Phosphorylation', 'Var', (0, 15))	('E-cadherin', 'Gene', (78, 88))	('cell adhesion', 'CPA', (111, 124))	('beta-catenin', 'Gene', (184, 196))	('tumor', 'Disease', 'MESH:D009369', (140, 145))	('beta-catenin', 'Gene', (19, 31))	('beta-catenin', 'Gene', '1499', (184, 196))	('E-cadherin', 'Gene', '999', (78, 88))	('beta-catenin', 'Gene', '1499', (19, 31))	('dissociation', 'MPA', (45, 57))	('loss', 'NegReg', (103, 107))	('tumor', 'Disease', (140, 145))
546187	31918173	Both EGFR gene copy number and elevated protein levels are associated with tumor stage, depth of invasion, lymph node metastasis, bone invasion, and perineural invasion.	('lymph node metastasis', 'CPA', (107, 128))	('perineural invasion', 'CPA', (149, 168))	('depth of invasion', 'CPA', (88, 105))	('copy number', 'Var', (15, 26))	('bone invasion', 'CPA', (130, 143))	('EGFR', 'Gene', '1956', (5, 9))	('associated', 'Reg', (59, 69))	('protein levels', 'MPA', (40, 54))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('elevated', 'PosReg', (31, 39))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('EGFR', 'Gene', (5, 9))	('tumor', 'Disease', (75, 80))
546194	31918173	Among the most promising immunotherapies are inhibitors of PD-1 and PD-L1, which cause a durable anti-tumor response and disease stabilization.	('PD-1', 'Gene', (59, 63))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('PD-L1', 'Gene', (68, 73))	('inhibitors', 'Var', (45, 55))	('disease stabilization', 'CPA', (121, 142))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('PD-L1', 'Gene', '29126', (68, 73))
546199	31918173	As the majority of cancers continue to progress on PD-1 and PD-L1 inhibitors, the identification of predictive biomarkers is essential for improved treatment.	('cancers', 'Phenotype', 'HP:0002664', (19, 26))	('PD-1', 'Gene', (51, 55))	('cancers', 'Disease', (19, 26))	('PD-L1', 'Gene', (60, 65))	('cancers', 'Disease', 'MESH:D009369', (19, 26))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('inhibitors', 'Var', (66, 76))	('PD-L1', 'Gene', '29126', (60, 65))	('progress', 'PosReg', (39, 47))
546207	31918173	Cancers with greater mutational burden demonstrate increased response to immunotherapy with PD-1 inhibitors, perhaps due to augmented formation of tumor-specific antigens (neoantigens), which may provide targets recognized by the immune system.	('PD-1', 'Gene', (92, 96))	('tumor', 'Disease', (147, 152))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('formation', 'MPA', (134, 143))	('Cancers', 'Disease', (0, 7))	('increased', 'PosReg', (51, 60))	('response', 'CPA', (61, 69))	('Cancers', 'Phenotype', 'HP:0002664', (0, 7))	('augmented', 'PosReg', (124, 133))	('Cancers', 'Disease', 'MESH:D009369', (0, 7))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('mutational burden', 'Var', (21, 38))	('inhibitors', 'Var', (97, 107))
546216	32803172	The T cell differentiation landscape is shaped by tumour mutations in lung cancer Tumour mutational burden (TMB) predicts immunotherapy outcome in non-small cell lung cancer (NSCLC), consistent with immune recognition of tumour neoantigens.	('tumour', 'Disease', (221, 227))	('lung cancer', 'Disease', 'MESH:D008175', (162, 173))	('TMB', 'Chemical', '-', (108, 111))	('lung cancer', 'Disease', (70, 81))	('NSCLC', 'Phenotype', 'HP:0030358', (175, 180))	('mutations', 'Var', (57, 66))	('lung cancer', 'Phenotype', 'HP:0100526', (162, 173))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('non-small cell lung cancer', 'Disease', (147, 173))	('tumour', 'Phenotype', 'HP:0002664', (50, 56))	('lung cancer', 'Disease', 'MESH:D008175', (70, 81))	('tumour', 'Disease', 'MESH:D009369', (50, 56))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (147, 173))	('tumour', 'Disease', (50, 56))	('predicts', 'Reg', (113, 121))	('lung cancer', 'Phenotype', 'HP:0100526', (70, 81))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (151, 173))	('NSCLC', 'Disease', 'MESH:D002289', (175, 180))	('Tumour', 'Phenotype', 'HP:0002664', (82, 88))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (147, 173))	('tumour', 'Phenotype', 'HP:0002664', (221, 227))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('NSCLC', 'Disease', (175, 180))	('tumour', 'Disease', 'MESH:D009369', (221, 227))
546239	32803172	We found an abundance of PD1hi CD4 (Figure 1C) and CD8 (Figure 1D) T cells, consistent with the phenotype of chronically stimulated, tumour reactive and dysfunctional T cells in NSCLC.	('dysfunctional T', 'Disease', (153, 168))	('NSCLC', 'Disease', (178, 183))	('tumour', 'Phenotype', 'HP:0002664', (133, 139))	('tumour', 'Disease', 'MESH:D009369', (133, 139))	('NSCLC', 'Disease', 'MESH:D002289', (178, 183))	('CD8', 'Gene', (51, 54))	('tumour', 'Disease', (133, 139))	('CD8', 'Gene', '925', (51, 54))	('NSCLC', 'Phenotype', 'HP:0030358', (178, 183))	('PD1hi CD4', 'Var', (25, 34))	('dysfunctional T', 'Disease', 'MESH:D009461', (153, 168))
546240	32803172	PD1hi CD8 T cells were divided into two main subsets distinguished by differential expression of CD57, a characteristic marker of extensive replication and terminal effector function in circulating T cells (Figures 1B, D).	('CD8', 'Gene', (6, 9))	('CD8', 'Gene', '925', (6, 9))	('CD57', 'Gene', (97, 101))	('PD1hi', 'Var', (0, 5))	('CD57', 'Gene', '27087', (97, 101))
546265	32803172	Neither the burden of insertion-deletion mutations, nor tumour region subclonal diversity measured by the Shannon index (see Methods), correlated with the abundance of these subsets (Extended Data Fig.	('tumour', 'Phenotype', 'HP:0002664', (56, 62))	('tumour', 'Disease', (56, 62))	('insertion-deletion mutations', 'Var', (22, 50))	('tumour', 'Disease', 'MESH:D009369', (56, 62))
546309	32803172	In general, TCF7 expression was higher amongst CD4 vs. CD8 T cells, both by scRNAseq and flow cytometry (Figure 4D, Extended Data Fig.	('CD4', 'Var', (47, 50))	('higher', 'PosReg', (32, 38))	('expression', 'MPA', (17, 27))	('TCF7', 'Gene', (12, 16))	('CD8', 'Gene', (55, 58))	('CD8', 'Gene', '925', (55, 58))
546345	32803172	Whilst attention has focused on CD8 progenitor populations, we show that intra-tumoural differentiation skewing is most striking amongst CD4 cells, where the majority of TCF7-expressing T cells reside, including within the PD1/TOX co-expressing Tdys subset that is phenotypically and transcriptionally similar to neoantigen-multimer reactive CD8 T cells.	('CD4', 'Var', (137, 140))	('CD8', 'Gene', '925', (32, 35))	('Tdys', 'Chemical', '-', (245, 249))	('CD8', 'Gene', (342, 345))	('TCF7-expressing', 'Gene', (170, 185))	('CD8', 'Gene', '925', (342, 345))	('tumour', 'Phenotype', 'HP:0002664', (79, 85))	('tumour', 'Disease', 'MESH:D009369', (79, 85))	('CD8', 'Gene', (32, 35))	('TOX', 'Gene', '9760', (227, 230))	('TOX', 'Gene', (227, 230))	('tumour', 'Disease', (79, 85))
546358	32803172	Recent studies suggest mutational burden is positively associated with outcomes amongst immunotherapy-treated patients.	('mutational burden', 'Var', (23, 40))	('associated', 'Reg', (55, 65))	('patients', 'Species', '9606', (110, 118))
546359	32803172	Opposing effects of TMB may occur if mutations generate antigenic targets for tumour recognition and control by early differentiated T cells that are driven to dysfunctional states by chronic target exposure or deprived of niche within the tumour microenvironment as later differentiated cells accumulate.	('tumour', 'Disease', 'MESH:D009369', (78, 84))	('TMB', 'Chemical', '-', (20, 23))	('tumour', 'Phenotype', 'HP:0002664', (240, 246))	('tumour', 'Disease', (78, 84))	('tumour', 'Disease', 'MESH:D009369', (240, 246))	('mutations', 'Var', (37, 46))	('tumour', 'Disease', (240, 246))	('tumour', 'Phenotype', 'HP:0002664', (78, 84))
546389	32803172	For survival and linear regression analyses, z-score scaled non-silent mutations per Mb were used as published (https://gdc.cancer.gov/about-data/publications/panimmune) and found to give very similar results to mutational burden estimated from the MC3 project data.	('cancer', 'Disease', (124, 130))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('mutations', 'Var', (71, 80))	('non-silent', 'Var', (60, 70))	('cancer', 'Disease', 'MESH:D009369', (124, 130))
546403	32803172	Neoantigen-specific CD8 T cells were identified using high throughput MHC multimer screening of candidate mutant peptides generated from patient-specific neoantigens of predicted <500nM affinity for cognate HLA as previously described.	('CD8', 'Gene', (20, 23))	('CD8', 'Gene', '925', (20, 23))	('mutant', 'Var', (106, 112))	('patient', 'Species', '9606', (137, 144))
546405	32803172	In patient L011 with lung adenocarcinoma, TILs were found to recognize the HLA-B*3501 restricted, MTFR2D326Y-derived mutated sequence FAFQEYDSF (netMHC binding score: 22), but not the wild type sequence FAFQEDDSF (netMHC binding score: 10).	('MTFR2', 'Gene', (98, 103))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (21, 40))	('TIL', 'Gene', '7096', (42, 45))	('MTFR2', 'Gene', '113115', (98, 103))	('FAFQEYDSF', 'Var', (134, 143))	('patient', 'Species', '9606', (3, 10))	('netMHC', 'Chemical', '-', (145, 151))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (21, 40))	('TIL', 'Gene', (42, 45))	('HLA-B', 'Gene', (75, 80))	('netMHC', 'Chemical', '-', (214, 220))	('HLA-B', 'Gene', '3106', (75, 80))	('lung adenocarcinoma', 'Disease', (21, 40))	('carcinoma', 'Phenotype', 'HP:0030731', (31, 40))
546407	32803172	Finally, in patient L012, TILs were found to recognize the HLA-B*0702 restricted, MYADMR30W-derived mutated sequence SPMIVGSPW (netMHC binding score: 15) as well as the wild type sequence SPMIVGSPR (netMHC binding score: 1329).	('HLA-B', 'Gene', '3106', (59, 64))	('TIL', 'Gene', (26, 29))	('netMHC', 'Chemical', '-', (199, 205))	('TIL', 'Gene', '7096', (26, 29))	('SPMIVGSPW', 'Var', (117, 126))	('netMHC', 'Chemical', '-', (128, 134))	('patient', 'Species', '9606', (12, 19))	('HLA-B', 'Gene', (59, 64))
546411	32803172	Neoantigen-specific CD8 T cells were tracked with peptide-MHC multimers conjugated with either streptavidin PE, APC, BV650 or PE-Cy-7 (all from Biolegend) and gated as double (L011, L021) or single (L012) positive cells among live, single CD8 T cells.	('CD8', 'Gene', (239, 242))	('L021', 'Var', (182, 186))	('CD8', 'Gene', '925', (239, 242))	('APC', 'Disease', 'MESH:D011125', (112, 115))	('APC', 'Disease', (112, 115))	('CD8', 'Gene', (20, 23))	('CD8', 'Gene', '925', (20, 23))
546412	32803172	We have previously identified neoantigen multimer reactive CD8 T cells targeted against a clonal neoantigen (arising from the mutated MTFR2 gene) in NSCLC tumour regions derived from patient L011.	('NSCLC tumour', 'Disease', 'MESH:D009369', (149, 161))	('mutated', 'Var', (126, 133))	('NSCLC', 'Phenotype', 'HP:0030358', (149, 154))	('tumour', 'Phenotype', 'HP:0002664', (155, 161))	('CD8', 'Gene', (59, 62))	('MTFR2', 'Gene', '113115', (134, 139))	('CD8', 'Gene', '925', (59, 62))	('NSCLC tumour', 'Disease', (149, 161))	('patient', 'Species', '9606', (183, 190))	('MTFR2', 'Gene', (134, 139))
546448	32803172	3F, from the following publications; GSE11057, GSE26928, GSE3982.	('GSE3982', 'Chemical', '-', (57, 64))	('GSE3982', 'Var', (57, 64))	('GSE26928', 'Var', (47, 55))	('GSE11057', 'Var', (37, 45))
546451	32803172	Early, CD8 dysfunctional vs. Naive-like and multimer reactive vs. multimer negative cells.	('dysfunctional', 'Var', (11, 24))	('CD8', 'Gene', (7, 10))	('CD8', 'Gene', '925', (7, 10))
546459	32803172	have previously published RNA sequencing data on genes differentially expressed by mouse Tcf7/Lef1 knockout vs. wildtype CD8 thymocytes.	('Lef1', 'Gene', (94, 98))	('mouse T', 'CellLine', 'CVCL:0594', (83, 90))	('knockout', 'Var', (99, 107))	('CD8', 'Gene', '925', (121, 124))	('Lef1', 'Gene', '16842', (94, 98))	('CD8', 'Gene', (121, 124))	('Tcf7', 'Gene', (89, 93))	('Tcf7', 'Gene', '21414', (89, 93))
546466	31949395	Aberrant DNA methylation is a common event in metastatic lung cancer.	('Aberrant', 'Var', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('lung cancer', 'Disease', 'MESH:D008175', (57, 68))	('DNA', 'Protein', (9, 12))	('methyl', 'Chemical', 'MESH:C031105', (13, 19))	('lung cancer', 'Disease', (57, 68))	('lung cancer', 'Phenotype', 'HP:0100526', (57, 68))
546467	31949395	We aimed to identify new epigenetic regulation of metastasis-associated genes and characterize their effects on lung cancer progression.	('epigenetic regulation', 'Var', (25, 46))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('lung cancer', 'Disease', (112, 123))	('lung cancer', 'Phenotype', 'HP:0100526', (112, 123))	('metastasis-associated genes', 'Gene', (50, 77))	('effects', 'Reg', (101, 108))	('lung cancer', 'Disease', 'MESH:D008175', (112, 123))
546481	31949395	Our results suggest that stomatin may be a target for epigenetic regulation and can be used to prevent metastatic diseases.	('metastatic diseases', 'Disease', (103, 122))	('epigenetic regulation', 'Var', (54, 75))	('stomatin', 'Gene', '2040', (25, 33))	('stomatin', 'Gene', (25, 33))
546486	31949395	Hypermethylation of gene promoter drives secondary recruitment of histone-modifying enzymes to modulate the proximate chromatin environment in lung cancer.	('lung cancer', 'Disease', (143, 154))	('Hypermethylation', 'Var', (0, 16))	('lung cancer', 'Phenotype', 'HP:0100526', (143, 154))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('methyl', 'Chemical', 'MESH:C031105', (5, 11))	('lung cancer', 'Disease', 'MESH:D008175', (143, 154))
546488	31949395	Aberrant methylation of multiple gene promoters is a common phenomenon in the key step of metastasis, epithelial-to-mesenchymal transition (EMT).	('methyl', 'Chemical', 'MESH:C031105', (9, 15))	('epithelial-to-mesenchymal transition', 'CPA', (102, 138))	('Aberrant methylation', 'Var', (0, 20))
546492	31949395	Besides regulating the methylation state of certain genes, EMT-TFs such as TWIST1/2 and ZEB2 have also been modulated by DNA methylation.	('TWIST1/2', 'Gene', (75, 83))	('ZEB2', 'Gene', (88, 92))	('TWIST1/2', 'Gene', '7291;117581', (75, 83))	('methyl', 'Chemical', 'MESH:C031105', (125, 131))	('DNA methylation', 'Var', (121, 136))	('methyl', 'Chemical', 'MESH:C031105', (23, 29))	('regulating', 'Reg', (8, 18))	('methylation state', 'MPA', (23, 40))	('ZEB2', 'Gene', '9839', (88, 92))	('modulated', 'Reg', (108, 117))
546511	31949395	GSE27716, based on the Affymetrix GPL570 platform (HG-U133_Plus_2, Affymetrix Human Genome U133 Plus 2.0 Array), included 17 noninvasive bronchioloalveolar carcinomas (BAC) and 23 adenocarcinomas with mixed (AC-mixed) subtype invasive LUAD.	('bronchioloalveolar carcinomas', 'Disease', 'MESH:D002282', (137, 166))	('carcinoma', 'Phenotype', 'HP:0030731', (156, 165))	('invasive LUAD', 'Disease', 'MESH:D009361', (226, 239))	('GSE27716', 'Var', (0, 8))	('invasive LUAD', 'Disease', (226, 239))	('bronchioloalveolar carcinomas', 'Disease', (137, 166))	('adenocarcinomas', 'Disease', 'MESH:D000230', (180, 195))	('carcinomas', 'Phenotype', 'HP:0030731', (156, 166))	('LUAD', 'Phenotype', 'HP:0030078', (235, 239))	('adenocarcinomas', 'Disease', (180, 195))	('carcinoma', 'Phenotype', 'HP:0030731', (185, 194))	('Human', 'Species', '9606', (78, 83))	('carcinomas', 'Phenotype', 'HP:0030731', (185, 195))
546512	31949395	GSE49644, based on the Affymetrix GPL570 platform (HG-U133_Plus_2, Affymetrix Human Genome U133 Plus 2.0 Array), simulated EMT by culturing A549 and NCI-H358 cells in the presence of TGFbeta for three weeks.	('A549', 'CellLine', 'CVCL:0023', (140, 144))	('TGFbeta', 'Gene', '7040', (183, 190))	('EMT', 'CPA', (123, 126))	('TGFbeta', 'Gene', (183, 190))	('NCI-H358', 'CellLine', 'CVCL:1559', (149, 157))	('Human', 'Species', '9606', (78, 83))	('GSE49644', 'Var', (0, 8))
546524	31949395	Cycloheximide (#508739) and actinomycin D (#114666) were purchased from Sigma-Aldrich (St. Louis, USA).	('#114666', 'Var', (43, 50))	('actinomycin D', 'Chemical', 'MESH:D003609', (28, 41))	('#508739', 'Var', (15, 22))	('Cycloheximide (#508739)', 'Chemical', 'MESH:D003513', (0, 23))
546533	31949395	After 60 d, metastatic nodules in the lungs of the A549-NC group and A549-STOM group were observed.	('A549', 'CellLine', 'CVCL:0023', (69, 73))	('metastatic nodules in the lungs', 'CPA', (12, 43))	('A549', 'CellLine', 'CVCL:0023', (51, 55))	('A549-NC', 'Var', (51, 58))
546536	31949395	Cells were stained with stomatin (abcam, #ab169524), E-cadherin (Cell Signaling Technology, #14472S), Vimentin (Santa Cruz Biotechnology, #sc-6260) and secondary Alexa Flour 488 (#A11001) or 594 (#A11012) (Life Technologies, Thermo Fisher Scientific, Waltham, USA).	('Vimentin', 'Gene', '7431', (102, 110))	('#A11012', 'Var', (196, 203))	('stomatin', 'Gene', (24, 32))	('stomatin', 'Gene', '2040', (24, 32))	('E-cadherin', 'Gene', (53, 63))	('E-cadherin', 'Gene', '999', (53, 63))	('#A11001', 'Var', (179, 186))	('Vimentin', 'Gene', (102, 110))
546565	31949395	Then we knocked down (named H1299-sistom and A549-sistom) and overexpressed stomatin in H1299 and A549 cell lines.	('A549', 'CellLine', 'CVCL:0023', (98, 102))	('overexpressed', 'PosReg', (62, 75))	('stomatin', 'Gene', (76, 84))	('A549', 'CellLine', 'CVCL:0023', (45, 49))	('stomatin', 'Gene', '2040', (76, 84))	('H1299', 'CellLine', 'CVCL:0060', (88, 93))	('knocked down', 'Var', (8, 20))	('H1299', 'CellLine', 'CVCL:0060', (28, 33))
546571	31949395	Phalloidin staining revealed the membrane-associated actin filaments and homogeneous cytoplasmic actin in A549-sinc and H1299-sinc cells, whereas A549-sistom and H1299-sistom cells exhibited reorganization of the actin cytoskeleton with actin polymerization and formation of stress fibers (Figure 3E), indicating increased cellular motility.	('H1299', 'CellLine', 'CVCL:0060', (162, 167))	('increased', 'PosReg', (313, 322))	('H1299-sistom', 'Var', (162, 174))	('A549', 'CellLine', 'CVCL:0023', (146, 150))	('H1299', 'CellLine', 'CVCL:0060', (120, 125))	('stress fibers', 'CPA', (275, 288))	('Phalloidin', 'Chemical', 'MESH:D010590', (0, 10))	('actin polymerization', 'CPA', (237, 257))	('reorganization', 'PosReg', (191, 205))	('cellular motility', 'CPA', (323, 340))	('A549-sistom', 'Var', (146, 157))	('A549', 'CellLine', 'CVCL:0023', (106, 110))
546577	31949395	We injected A549-NC and A549-STOM cells (3x106 cells/mouse) into the tail vein of BALB/c nu/nu mice for 60 days, and visual and HE evaluation of lung metastases showed fewer and smaller foci in A549-STOM group (Figure 4, P=0.0265).	('A549', 'CellLine', 'CVCL:0023', (24, 28))	('mice', 'Species', '10090', (95, 99))	('smaller', 'NegReg', (178, 185))	('A549', 'CellLine', 'CVCL:0023', (12, 16))	('metastases', 'Disease', (150, 160))	('A549', 'CellLine', 'CVCL:0023', (194, 198))	('mouse', 'Species', '10090', (53, 58))	('metastases', 'Disease', 'MESH:D009362', (150, 160))	('A549-STOM', 'Var', (194, 203))
546590	31949395	Microarray analysis of HBE vs. HBE-5Aza indicated the upregulation of stomatin in response to 5-Aza, indicating the potential contribution of DNA methylation to stomatin expression.	('stomatin', 'Gene', (70, 78))	('HBE-5Aza', 'CellLine', 'CVCL:0287', (31, 39))	('methyl', 'Chemical', 'MESH:C031105', (146, 152))	('5-Aza', 'Var', (94, 99))	('upregulation', 'PosReg', (54, 66))	('stomatin', 'Gene', '2040', (70, 78))	('5-Aza', 'Chemical', 'MESH:D001372', (94, 99))	('stomatin', 'Gene', (161, 169))	('stomatin', 'Gene', '2040', (161, 169))
546595	31949395	In addition, A549 cells treated with 5-Aza exhibited a further decrease in stomatin promoter methylation (P<0.01) (Figure 6E).	('methyl', 'Chemical', 'MESH:C031105', (93, 99))	('decrease', 'NegReg', (63, 71))	('5-Aza', 'Chemical', 'MESH:D001372', (37, 42))	('5-Aza', 'Var', (37, 42))	('stomatin', 'Gene', (75, 83))	('A549', 'CellLine', 'CVCL:0023', (13, 17))	('stomatin', 'Gene', '2040', (75, 83))
546596	31949395	Our data suggest that the expression of stomatin is inversely correlated to the degree of its DNA methylation, suggesting that TGFbeta1 might silence stomatin expression through epigenetic mechanisms.	('TGFbeta1', 'Gene', '7040', (127, 135))	('stomatin', 'Gene', (40, 48))	('expression', 'MPA', (159, 169))	('TGFbeta1', 'Gene', (127, 135))	('stomatin', 'Gene', '2040', (40, 48))	('stomatin', 'Gene', (150, 158))	('epigenetic', 'Var', (178, 188))	('silence', 'NegReg', (142, 149))	('methyl', 'Chemical', 'MESH:C031105', (98, 104))	('stomatin', 'Gene', '2040', (150, 158))
546602	31949395	As expected, E-cadherin regulated by DNA methylation was dramatically increased in response to 5-Aza, and 5-Aza restored TGFbeta1-induced suppression of E-cadherin in A549 cells (Supplementary Figure S2C).	('E-cadherin', 'Gene', (153, 163))	('E-cadherin', 'Gene', '999', (153, 163))	('increased', 'PosReg', (70, 79))	('5-Aza', 'Chemical', 'MESH:D001372', (106, 111))	('suppression', 'NegReg', (138, 149))	('S2C', 'Chemical', 'MESH:D013455', (200, 203))	('E-cadherin', 'Gene', (13, 23))	('E-cadherin', 'Gene', '999', (13, 23))	('TGFbeta1', 'Gene', '7040', (121, 129))	('5-Aza', 'Var', (106, 111))	('TGFbeta1', 'Gene', (121, 129))	('methyl', 'Chemical', 'MESH:C031105', (41, 47))	('A549', 'CellLine', 'CVCL:0023', (167, 171))	('5-Aza', 'Chemical', 'MESH:D001372', (95, 100))
546613	31949395	A subset of epigenetically regulated genes is associated with EMT processes in NSCLC, and many genes that distinguish "epithelial-like" cells from "mesenchymal-like" cells are downregulated by DNA methylation during the EMT process.	('NSCLC', 'Disease', 'MESH:D002289', (79, 84))	('DNA methylation', 'Var', (193, 208))	('NSCLC', 'Phenotype', 'HP:0030358', (79, 84))	('methyl', 'Chemical', 'MESH:C031105', (197, 203))	('downregulated', 'NegReg', (176, 189))	('associated', 'Reg', (46, 56))	('NSCLC', 'Disease', (79, 84))
546629	31949395	These results not only support the aforementioned concept that aberrant DNA methylation not only affects the activity of the TGFbeta pathway but also highlights the modulation of stomatin expression through DNA hypomethylation during TGFbeta1-induced EMT.	('stomatin', 'Gene', '2040', (179, 187))	('TGFbeta', 'Gene', '7040', (234, 241))	('methyl', 'Chemical', 'MESH:C031105', (76, 82))	('expression', 'MPA', (188, 198))	('aberrant', 'Var', (63, 71))	('TGFbeta', 'Gene', '7040', (125, 132))	('methyl', 'Chemical', 'MESH:C031105', (215, 221))	('TGFbeta1', 'Gene', '7040', (234, 242))	('TGFbeta', 'Gene', (234, 241))	('activity', 'MPA', (109, 117))	('TGFbeta1', 'Gene', (234, 242))	('modulation', 'Reg', (165, 175))	('stomatin', 'Gene', (179, 187))	('affects', 'Reg', (97, 104))	('TGFbeta', 'Gene', (125, 132))
546682	30089500	There are ten cancer types that have a TP53 mutation rate greater than 50% in total (Fig.	('cancer', 'Disease', (14, 20))	('mutation', 'Var', (44, 52))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('TP53', 'Gene', '7157', (39, 43))	('cancer', 'Disease', 'MESH:D009369', (14, 20))	('TP53', 'Gene', (39, 43))
546683	30089500	Moreover, we can find a summary of the variant classification of TP53 mutations in cancers, e.g., in pancreatic adenocarcinoma (PAAD), 64 and 12% of TP53 mutations being missense and frame-shift insertion, respectively (Fig.	('cancers', 'Disease', 'MESH:D009369', (83, 90))	('cancers', 'Phenotype', 'HP:0002664', (83, 90))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (101, 126))	('mutations', 'Var', (70, 79))	('TP53', 'Gene', '7157', (65, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (117, 126))	('TP53', 'Gene', (65, 69))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('TP53', 'Gene', '7157', (149, 153))	('mutations', 'Var', (154, 163))	('missense', 'Var', (170, 178))	('TP53', 'Gene', (149, 153))	('pancreatic adenocarcinoma', 'Disease', 'MESH:D010190', (101, 126))	('pancreatic adenocarcinoma', 'Disease', (101, 126))	('PAAD', 'Phenotype', 'HP:0006725', (128, 132))	('frame-shift insertion', 'Var', (183, 204))	('cancers', 'Disease', (83, 90))
546684	30089500	Importantly, we can find the associations of TP53 mutations with survival prognosis in cancers.	('cancers', 'Disease', (87, 94))	('TP53', 'Gene', (45, 49))	('mutations', 'Var', (50, 59))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cancers', 'Phenotype', 'HP:0002664', (87, 94))	('associations', 'Interaction', (29, 41))	('cancers', 'Disease', 'MESH:D009369', (87, 94))	('survival prognosis', 'CPA', (65, 83))	('TP53', 'Gene', '7157', (45, 49))
546685	30089500	For example, TP53 mutations are associated with worse survival (overall and disease free survival) prognosis in PAAD (Fig.	('TP53', 'Gene', (13, 17))	('PAAD', 'Phenotype', 'HP:0006725', (112, 116))	('PAAD', 'Disease', (112, 116))	('TP53', 'Gene', '7157', (13, 17))	('mutations', 'Var', (18, 27))
546687	30089500	In fact, previous studies have shown that PLK1 interacted with TP53, and that p53 dysfunction caused enhanced expression of PLK1 in cancers.	('PLK1', 'Gene', (124, 128))	('cancers', 'Disease', (132, 139))	('cancers', 'Disease', 'MESH:D009369', (132, 139))	('TP53', 'Gene', '7157', (63, 67))	('PLK1', 'Gene', '5347', (42, 46))	('TP53', 'Gene', (63, 67))	('PLK1', 'Gene', '5347', (124, 128))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('p53', 'Gene', (78, 81))	('expression', 'MPA', (110, 120))	('enhanced', 'PosReg', (101, 109))	('p53', 'Gene', '7157', (78, 81))	('cancers', 'Phenotype', 'HP:0002664', (132, 139))	('PLK1', 'Gene', (42, 46))	('dysfunction', 'Var', (82, 93))
546712	30089500	In addition, TCOA shows that mir-1269, mir-10b, mir-224, and mir-183 are overexpressed in LIHC with more than 4-fold expression increase compared to normal tissue, while mir-1258, mir-675, mir-490, mir-424, mir-483, mir-1247, mir-199b, mir-199a-2, mir-139, mir-199a-1, mir-3607, and mir-451 are underexpressed in LIHC with more than 4-fold expression decrease compared to normal tissue (Fig.	('mir-183', 'Gene', '406959', (61, 68))	('mir-10b', 'Gene', '406903', (39, 46))	('mir-483', 'Gene', '619552', (207, 214))	('mir-675', 'Gene', '100033819', (180, 187))	('mir-199b', 'Gene', (226, 234))	('mir-451', 'Gene', '574411', (283, 290))	('TCOA', 'Chemical', '-', (13, 17))	('mir-139', 'Gene', '406931', (248, 255))	('mir-139', 'Gene', (248, 255))	('mir-199a-2', 'Gene', (236, 246))	('mir-10b', 'Gene', (39, 46))	('mir-451', 'Gene', (283, 290))	('mir-199a-2', 'Gene', '406977', (236, 246))	('mir-1269', 'Var', (29, 37))	('expression', 'MPA', (117, 127))	('mir-224', 'Gene', '407009', (48, 55))	('mir-483', 'Gene', (207, 214))	('mir-199b', 'Gene', '406978', (226, 234))	('mir-424', 'Gene', '494336', (198, 205))	('mir-424', 'Gene', (198, 205))	('decrease', 'NegReg', (351, 359))	('mir-183', 'Gene', (61, 68))	('mir-199a-1', 'Gene', (257, 267))	('increase', 'PosReg', (128, 136))	('mir-490', 'Gene', '574443', (189, 196))	('expression', 'MPA', (340, 350))	('mir-675', 'Gene', (180, 187))	('mir-490', 'Gene', (189, 196))	('mir-199a-1', 'Gene', '406976', (257, 267))	('mir-224', 'Gene', (48, 55))
546733	30089500	Kaplan-Meier survival curves were used to show the survival (OS or DFS) differences between gene-mutated cancer patients and gene-wildtype cancer patients, and between gene, miRNA or protein higher-expression-level patients and lower-expression-level patients.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('patients', 'Species', '9606', (215, 223))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('protein', 'Protein', (183, 190))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('patients', 'Species', '9606', (112, 120))	('gene-mutated', 'Var', (92, 104))	('higher-expression-level', 'PosReg', (191, 214))	('OS', 'Chemical', '-', (61, 63))	('miRNA', 'Protein', (174, 179))	('patients', 'Species', '9606', (251, 259))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('patients', 'Species', '9606', (146, 154))	('cancer', 'Disease', (139, 145))
546780	28884120	Positivity of neuroendocrine markers including chromogranin A, synaptophysin, and CD56 was suggestive of small cell carcinoma.	('CD56', 'Gene', (82, 86))	('chromogranin A', 'Gene', '1113', (47, 61))	('small cell carcinoma', 'Disease', (105, 125))	('small cell carcinoma', 'Disease', 'MESH:D018288', (105, 125))	('synaptophysin', 'Gene', (63, 76))	('chromogranin A', 'Gene', (47, 61))	('Positivity', 'Var', (0, 10))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('CD56', 'Gene', '4684', (82, 86))	('synaptophysin', 'Gene', '6855', (63, 76))	('small cell carcinoma', 'Phenotype', 'HP:0030357', (105, 125))
546829	28095872	The sections were incubated overnight at 4  C with the following primary antibodies: CD1alpha (1:100, DAKO), CD3 (1:100, DAKO), CD5 (1:200, DAKO), CD20 (1:100, DAKO), CD99 (1:200, DAKO), CK (Pan) (1:200, DAKO), CK19 (1:200, DAKO), CK20 (1:100, DAKO), Ki-67 (1:200, DAKO), p63 (1:100, DAKO) and TdT (1:100, DAKO).	('1:100', 'Var', (114, 119))	('p63', 'Gene', (272, 275))	('CD20', 'Gene', (147, 151))	('CD1alpha', 'Gene', (85, 93))	('CK20', 'Gene', (231, 235))	('p63', 'Gene', '8626', (272, 275))	('TdT', 'Gene', (294, 297))	('1:200', 'Var', (197, 202))	('CD99', 'Gene', (167, 171))	('CD20', 'Gene', '54474', (147, 151))	('CK19', 'Gene', (211, 215))	('1:100', 'Var', (277, 282))	('1:200', 'Var', (258, 263))	('1:100', 'Var', (95, 100))	('CK20', 'Gene', '54474', (231, 235))	('1:100', 'Var', (237, 242))	('CK19', 'Gene', '3880', (211, 215))	('1:100', 'Var', (299, 304))	('CD99', 'Gene', '4267', (167, 171))	('CD5', 'Gene', (128, 131))	('1:200, DAKO', 'Var', (217, 228))	('CD1alpha', 'Gene', '909', (85, 93))	('CD3', 'Gene', (109, 112))	('TdT', 'Gene', '1791', (294, 297))	('CD5', 'Gene', '921', (128, 131))
546905	31828882	NRF2 is aberrantly activated in cancer cells due to various causes, including somatic mutations in the KEAP1 and NRF2 (NFE2L2) genes, and confers growth and survival advantages on cancer cells.	('mutations', 'Var', (86, 95))	('KEAP1', 'Gene', '9817', (103, 108))	('NRF2', 'Gene', (0, 4))	('NFE2L2', 'Gene', '4780', (119, 125))	('activated', 'PosReg', (19, 28))	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('cancer', 'Disease', (32, 38))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('KEAP1', 'Gene', (103, 108))	('NFE2L2', 'Gene', (119, 125))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('cancer', 'Disease', (180, 186))
546906	31828882	Multiple lines of evidence suggest that aberrantly activated NRF2 in cancer cells drives their malignant progression and that the cancer cells consequently develop "NRF2 addiction.	('aberrantly activated', 'Var', (40, 60))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('cancer', 'Disease', (130, 136))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('malignant progression', 'CPA', (95, 116))	('develop', 'PosReg', (156, 163))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('NRF2', 'Gene', (61, 65))	('cancer', 'Disease', (69, 75))
546928	31828882	To characterize a mutation profile leading to an elevated activity of the NRF2 signaling pathway in NSCLC, we conducted exome analysis of 88 NSCLC cell lines (Tables S2-S4).	('activity', 'MPA', (58, 66))	('NSCLC', 'Disease', (100, 105))	('S2-S4', 'Chemical', 'MESH:D013455', (166, 171))	('NSCLC', 'Disease', (141, 146))	('NSCLC', 'Disease', 'MESH:D002289', (100, 105))	('NRF2 signaling pathway', 'Pathway', (74, 96))	('NSCLC', 'Disease', 'MESH:D002289', (141, 146))	('mutation', 'Var', (18, 26))	('elevated', 'PosReg', (49, 57))	('NSCLC', 'Phenotype', 'HP:0030358', (141, 146))	('NSCLC', 'Phenotype', 'HP:0030358', (100, 105))
546933	31828882	Many of the 30 NSCLC cell lines with high NRF2 activity possess non-synonymous mutations in either KEAP1, NRF2 (NFE2L2) or CUL3 (Figure 1B).	('NSCLC', 'Disease', 'MESH:D002289', (15, 20))	('KEAP1', 'Gene', (99, 104))	('NFE2L2', 'Gene', (112, 118))	('CUL3', 'Gene', '8452', (123, 127))	('NSCLC', 'Phenotype', 'HP:0030358', (15, 20))	('CUL3', 'Gene', (123, 127))	('NRF2', 'Gene', (42, 46))	('NSCLC', 'Disease', (15, 20))	('activity', 'MPA', (47, 55))	('KEAP1', 'Gene', '9817', (99, 104))	('NFE2L2', 'Gene', '4780', (112, 118))	('NRF2', 'Gene', (106, 110))	('mutations', 'Var', (79, 88))
546934	31828882	These mutations were expected to disrupt the CUL3-KEAP1-mediated ubiquitination of NRF2, resulting in the persistent stabilization of NRF2.	('KEAP1', 'Gene', (50, 55))	('NRF2', 'Protein', (134, 138))	('CUL3', 'Gene', '8452', (45, 49))	('CUL3', 'Gene', (45, 49))	('ubiquitination', 'MPA', (65, 79))	('NRF2', 'Protein', (83, 87))	('KEAP1', 'Gene', '9817', (50, 55))	('stabilization', 'MPA', (117, 130))	('disrupt', 'NegReg', (33, 40))	('mutations', 'Var', (6, 15))
546935	31828882	Non-synonymous NRF2 mutations were detected most frequently in squamous cell carcinoma, as previous study reported.12 Non-synonymous mutations found in a few cell lines with low NRF2 activity were interpreted as functionally silent mutations.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (63, 86))	('silent', 'NegReg', (225, 231))	('squamous cell carcinoma', 'Disease', (63, 86))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (63, 86))	('N', 'Chemical', 'MESH:D009584', (0, 1))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('N', 'Chemical', 'MESH:D009584', (15, 16))	('mutations', 'Var', (133, 142))	('N', 'Chemical', 'MESH:D009584', (178, 179))	('N', 'Chemical', 'MESH:D009584', (118, 119))
546937	31828882	To further characterize the genetic alterations of the 9 cell lines, we first examined the KEAP1, NRF2 (NFE2L2) and CUL3 loci in more detail by collecting single nucleotide polymorphisms (SNP) in these loci that were detected in only NRF2-high NSCLC cell lines (Figure 2A).	('NSCLC', 'Disease', (244, 249))	('KEAP1', 'Gene', (91, 96))	('NSCLC', 'Disease', 'MESH:D002289', (244, 249))	('N', 'Chemical', 'MESH:D009584', (98, 99))	('CUL3', 'Gene', '8452', (116, 120))	('single nucleotide polymorphisms', 'Var', (155, 186))	('CUL3', 'Gene', (116, 120))	('N', 'Chemical', 'MESH:D009584', (234, 235))	('NFE2L2', 'Gene', '4780', (104, 110))	('N', 'Chemical', 'MESH:D009584', (244, 245))	('KEAP1', 'Gene', '9817', (91, 96))	('N', 'Chemical', 'MESH:D009584', (189, 190))	('NSCLC', 'Phenotype', 'HP:0030358', (244, 249))	('NFE2L2', 'Gene', (104, 110))	('N', 'Chemical', 'MESH:D009584', (104, 105))
546942	31828882	As for 1 of the 9 NRF2-high NSCLC cell lines, RERF-LC-MS, a homozygous 3-bp deletion in the BTB domain of KEAP1 (p.G119_M120>V, COSM2812645) has been registered in the Catalogue of Somatic Mutations in Cancer (COSMIC) database.	('NSCLC', 'Disease', (28, 33))	('KEAP1', 'Gene', (106, 111))	('NSCLC', 'Disease', 'MESH:D002289', (28, 33))	('KEAP1', 'Gene', '9817', (106, 111))	('Cancer', 'Phenotype', 'HP:0002664', (202, 208))	('deletion in', 'Var', (76, 87))	('NSCLC', 'Phenotype', 'HP:0030358', (28, 33))	('p.G119_M120>V', 'Var', (113, 126))	('p.G119_M120>V', 'Mutation', 'p.G119V', (113, 126))
546946	31828882	In the 9 NSCLC cell lines without non-synonymous mutations in the KEAP1, NRF2 and CUL3 genes, TP53 (6 cell lines; shown in parentheses), ALK (6 cell lines), ROS1 (6 cell lines), and EGFR (5 cell lines) were also frequently mutated.	('mutated', 'Var', (223, 230))	('EGFR', 'Gene', '1956', (182, 186))	('CUL3', 'Gene', '8452', (82, 86))	('EGFR', 'Gene', (182, 186))	('KEAP1', 'Gene', '9817', (66, 71))	('ROS1', 'Gene', '6098', (157, 161))	('ROS1', 'Gene', (157, 161))	('CUL3', 'Gene', (82, 86))	('NRF2', 'Gene', (73, 77))	('NSCLC', 'Disease', (9, 14))	('ALK', 'Gene', (137, 140))	('TP53', 'Gene', (94, 98))	('NSCLC', 'Disease', 'MESH:D002289', (9, 14))	('TP53', 'Gene', '7157', (94, 98))	('KEAP1', 'Gene', (66, 71))	('ALK', 'Gene', '238', (137, 140))	('NSCLC', 'Phenotype', 'HP:0030358', (9, 14))
546948	31828882	A previous study demonstrated that oncogenic mutations in KRAS and BRAF upregulate the transcription of NRF2.13 These mutations were detected in approximately one-third of 88 cell lines irrespective of the NRF2 activation status, suggesting that KRAS and BRAF mutations do not explain the elevated NRF2 pathway activity in the absence of mutations in the KEAP1, NRF2 and CUL3 genes.	('elevated', 'PosReg', (289, 297))	('KRAS', 'Gene', (58, 62))	('mutations', 'Var', (45, 54))	('BRAF', 'Gene', '673', (67, 71))	('KRAS', 'Gene', '3845', (58, 62))	('NRF2', 'Gene', (362, 366))	('BRAF', 'Gene', (67, 71))	('KEAP1', 'Gene', '9817', (355, 360))	('CUL3', 'Gene', '8452', (371, 375))	('BRAF', 'Gene', '673', (255, 259))	('KRAS', 'Gene', (246, 250))	('CUL3', 'Gene', (371, 375))	('BRAF', 'Gene', (255, 259))	('KEAP1', 'Gene', (355, 360))	('NRF2 pathway', 'Pathway', (298, 310))	('mutations', 'Var', (260, 269))	('activity', 'MPA', (311, 319))	('KRAS', 'Gene', '3845', (246, 250))
546949	31828882	Other mechanisms, such as the accumulation of the p62/SQSTM1 protein,14, 15, 16 fumarate17, 18 and iASPP19 and exon skipping of NRF2,20 might be present as causes for NRF2 pathway activation.	('activation', 'PosReg', (180, 190))	('accumulation', 'PosReg', (30, 42))	('exon skipping', 'Var', (111, 124))	('SQSTM1', 'Gene', (54, 60))	('iASPP', 'Gene', (99, 104))	('iASPP', 'Gene', '10848', (99, 104))	('SQSTM1', 'Gene', '8878', (54, 60))	('p62', 'Gene', '8878', (50, 53))	('fumarate', 'Chemical', 'MESH:D005650', (80, 88))	('NRF2 pathway', 'Pathway', (167, 179))	('p62', 'Gene', (50, 53))
546963	31828882	l-Cysteinylglycine disulfide, which is an oxidized form of a dipeptide derived from the breakdown of glutathione, was higher in NRF2-high cells than NRF2-low cells (Figure 5B; panel xi), reflecting the enhanced glutathione synthesis in NRF2-high cells.	('higher', 'PosReg', (118, 124))	('NRF2-high', 'Var', (128, 137))	('l-Cysteinylglycine disulfide', 'Chemical', 'MESH:C028505', (0, 28))	('enhanced', 'PosReg', (202, 210))	('glutathione', 'Chemical', 'MESH:D005978', (101, 112))	('glutathione', 'Chemical', 'MESH:D005978', (211, 222))	('dipeptide', 'Chemical', 'MESH:D004151', (61, 70))	('l-Cysteinylglycine disulfide', 'MPA', (0, 28))
546976	31828882	In contrast, whole transcriptome segregated the 18 cell lines better in terms of KEAP1 mutation status than activation status of NRF2 pathway (Figure 7, panel iv).	('KEAP1', 'Gene', (81, 86))	('mutation', 'Var', (87, 95))	('KEAP1', 'Gene', '9817', (81, 86))
546981	31828882	Non-synonymous somatic mutations of the KEAP1, NRF2 and CUL3 genes are frequently observed in cancers that occur in the lungs, bladder, head and neck, and are recognized as major causes of the persistent activation of NRF2, especially in NSCLC.21, 22 This study suggests the presence of alternative mechanisms that induce the activation of the NRF2 pathway in NSCLC cell lines.	('cancers', 'Disease', 'MESH:D009369', (94, 101))	('NSCLC', 'Disease', (238, 243))	('CUL3', 'Gene', '8452', (56, 60))	('N', 'Chemical', 'MESH:D009584', (218, 219))	('NSCLC', 'Phenotype', 'HP:0030358', (238, 243))	('N', 'Chemical', 'MESH:D009584', (360, 361))	('mutations', 'Var', (23, 32))	('KEAP1', 'Gene', '9817', (40, 45))	('cancers', 'Phenotype', 'HP:0002664', (94, 101))	('N', 'Chemical', 'MESH:D009584', (344, 345))	('cancers', 'Disease', (94, 101))	('KEAP1', 'Gene', (40, 45))	('NSCLC', 'Disease', 'MESH:D002289', (360, 365))	('N', 'Chemical', 'MESH:D009584', (0, 1))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('N', 'Chemical', 'MESH:D009584', (238, 239))	('CUL3', 'Gene', (56, 60))	('NSCLC', 'Disease', (360, 365))	('N', 'Chemical', 'MESH:D009584', (47, 48))	('NRF2 pathway', 'Pathway', (344, 356))	('observed', 'Reg', (82, 90))	('NSCLC', 'Phenotype', 'HP:0030358', (360, 365))	('NSCLC', 'Disease', 'MESH:D002289', (238, 243))	('NRF2', 'Gene', (47, 51))
546982	31828882	Mutations in the regulatory regions might be one of the causes for altered expression levels of the KEAP1, NRF2 and CUL3 genes, resulting in increased NRF2 activity.	('KEAP1', 'Gene', '9817', (100, 105))	('CUL3', 'Gene', '8452', (116, 120))	('increased', 'PosReg', (141, 150))	('NRF2', 'Enzyme', (151, 155))	('activity', 'MPA', (156, 164))	('CUL3', 'Gene', (116, 120))	('NRF2', 'Gene', (107, 111))	('Mutations', 'Var', (0, 9))	('KEAP1', 'Gene', (100, 105))	('expression levels', 'MPA', (75, 92))
546990	31828882	This study described genetic, transcriptomic and metabolomic signatures of multiple NSCLC cell lines and extracted common features of those with high NRF2 activity.	('NRF2', 'Gene', (150, 154))	('activity', 'MPA', (155, 163))	('NSCLC', 'Phenotype', 'HP:0030358', (84, 89))	('NSCLC', 'Disease', (84, 89))	('NSCLC', 'Disease', 'MESH:D002289', (84, 89))	('high', 'Var', (145, 149))
546993	31464517	Polymorphisms in Long Noncoding RNA-Prostate Cancer-Associated Transcript 1 Are Associated with Lung Cancer Susceptibility in a Northeastern Chinese Population Long noncoding RNAs (lncRNAs) are a new class of potential biomarkers and therapeutic targets for cancer.	('Lung Cancer Susceptibility', 'Disease', (96, 122))	('cancer', 'Phenotype', 'HP:0002664', (258, 264))	('nt', 'Chemical', 'MESH:D009711', (213, 215))	('Prostate Cancer', 'Phenotype', 'HP:0012125', (36, 51))	('Prostate Cancer-Associated Transcript 1', 'Gene', (36, 75))	('Polymorphisms', 'Var', (0, 13))	('Associated', 'Reg', (80, 90))	('Cancer', 'Phenotype', 'HP:0002664', (45, 51))	('cancer', 'Disease', 'MESH:D009369', (258, 264))	('Prostate Cancer-Associated Transcript 1', 'Gene', '100750225', (36, 75))	('cancer', 'Disease', (258, 264))	('Lung Cancer', 'Phenotype', 'HP:0100526', (96, 107))	('Cancer', 'Phenotype', 'HP:0002664', (101, 107))
546994	31464517	In this study, we chose four single nucleotide polymorphisms (SNPs) in lncRNA-PCAT1 (rs1026411 G>A, rs12543663 A>C, rs710886 T>C, and rs16901904 T>C) to investigate the association between genetic variant in lncRNA-PCAT1 and susceptibility to lung cancer.	('rs1026411', 'Mutation', 'rs1026411', (85, 94))	('rs12543663', 'Mutation', 'rs12543663', (100, 110))	('lung cancer', 'Disease', (243, 254))	('PCAT1', 'Gene', '100750225', (78, 83))	('PCAT1', 'Gene', '100750225', (215, 220))	('lung cancer', 'Phenotype', 'HP:0100526', (243, 254))	('rs16901904 T>C', 'Var', (134, 148))	('nt', 'Chemical', 'MESH:D009711', (202, 204))	('cancer', 'Phenotype', 'HP:0002664', (248, 254))	('PCAT1', 'Gene', (78, 83))	('PCAT1', 'Gene', (215, 220))	('rs1026411 G>A', 'Var', (85, 98))	('rs12543663 A>C', 'Var', (100, 114))	('lung cancer', 'Disease', 'MESH:D008175', (243, 254))	('rs16901904', 'Mutation', 'rs16901904', (134, 144))	('rs710886 T>C', 'Var', (116, 128))	('rs710886', 'Mutation', 'rs710886', (116, 124))
546999	31464517	However, polymorphisms in rs1026411 and rs710886 were observed to have significant associations with susceptibility to non-small cell lung cancer (AG vs. GG: odds ratio [OR]a = 0.701, p* = 0.020 and AA+AG vs. GG: ORa = 0.711 [superscript "a" refers to OR adjusted by age, gender, and smoking], p* = 0.017 [asterisks "*" refers to p adjusted by age, gender, and smoking] for rs1026411; CT vs. TT: ORa = 0.723, p* = 0.047 and CC+CT vs. TT: ORa = 0.729, p* = 0.038 for rs710886).	('rs710886', 'Var', (40, 48))	('lung cancer', 'Phenotype', 'HP:0100526', (134, 145))	('rs1026411', 'Mutation', 'rs1026411', (374, 383))	('associations', 'Interaction', (83, 95))	('rs1026411', 'Var', (26, 35))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (119, 145))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('rs1026411', 'Var', (374, 383))	('non-small cell lung cancer', 'Disease', (119, 145))	('nt', 'Chemical', 'MESH:D009711', (80, 82))	('rs710886', 'Mutation', 'rs710886', (40, 48))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (123, 145))	('polymorphisms', 'Var', (9, 22))	('rs710886', 'Mutation', 'rs710886', (466, 474))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (119, 145))	('rs1026411', 'Mutation', 'rs1026411', (26, 35))
547000	31464517	Besides, the rs1026411 polymorphism had a similar association with lung adenocarcinoma risk (AG vs. GG: ORa = 0.663, p* = 0.019 and AA+AG vs. GG: ORa = 0.685, p* = 0.020).	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (67, 86))	('rs1026411', 'Mutation', 'rs1026411', (13, 22))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (67, 86))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('lung adenocarcinoma', 'Disease', (67, 86))	('rs1026411', 'Var', (13, 22))
547001	31464517	Polymorphisms in rs710886 and rs16901904 were observed to be associated with lung squamous cell carcinoma risk (CC+CT vs. TT: ORa = 0.638, p* = 0.040 for rs710886; CC vs. TT: ORa = 2.582, p* = 0.033 and CC vs. TT+CT: ORa = 2.381, p* = 0.048 for rs16901904).	('rs16901904', 'Var', (30, 40))	('rs710886', 'Mutation', 'rs710886', (154, 162))	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (82, 105))	('rs16901904', 'Mutation', 'rs16901904', (245, 255))	('rs710886', 'Var', (17, 25))	('rs710886', 'Var', (154, 162))	('rs710886', 'Mutation', 'rs710886', (17, 25))	('rs16901904', 'Var', (245, 255))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (77, 105))	('rs16901904', 'Mutation', 'rs16901904', (30, 40))	('associated', 'Reg', (61, 71))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (77, 105))	('lung squamous cell carcinoma', 'Disease', (77, 105))
547003	31464517	Our results suggested that polymorphisms in lncRNA-PCAT1 might be associated with lung cancer susceptibility in a northeastern Chinese population.	('lung cancer', 'Phenotype', 'HP:0100526', (82, 93))	('PCAT1', 'Gene', (51, 56))	('lung cancer', 'Disease', (82, 93))	('associated', 'Reg', (66, 76))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('lung cancer', 'Disease', 'MESH:D008175', (82, 93))	('polymorphisms', 'Var', (27, 40))	('PCAT1', 'Gene', '100750225', (51, 56))
547011	31464517	Previous studies have indicated that lncRNAs are widely correlated to multiple cancers, the mutation and abnormal expression of which are closely associated with tumorigenesis, metastasis, and tumor stage (Kornfeld and Bruning,; Vitiello et al.,; Bartonicek et al.,).	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('mutation', 'Var', (92, 100))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('multiple cancers', 'Disease', (70, 86))	('tumor', 'Disease', (162, 167))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('metastasis', 'CPA', (177, 187))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('multiple cancers', 'Disease', 'MESH:D009369', (70, 86))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('associated', 'Reg', (146, 156))	('tumor', 'Disease', (193, 198))	('expression', 'MPA', (114, 124))	('tumor', 'Disease', 'MESH:D009369', (162, 167))	('correlated', 'Reg', (56, 66))
547013	31464517	There is substantial evidence to support the association between SNPs in ncRNA and cancer risk.	('ncRNA', 'Disease', (73, 78))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('SNPs', 'Var', (65, 69))	('nt', 'Chemical', 'MESH:D009711', (15, 17))	('cancer', 'Disease', (83, 89))
547017	31464517	In addition, some researchers have conducted some studies to explore associations between genetic variation in lncRNA-PCAT1 and cancer susceptibility in the past few years.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('PCAT1', 'Gene', '100750225', (118, 123))	('associations', 'Interaction', (69, 81))	('genetic variation', 'Var', (90, 107))	('PCAT1', 'Gene', (118, 123))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('cancer', 'Disease', (128, 134))
547018	31464517	In the study from Yuan et al., they selected four tagging SNPs (tagSNPs) and found that rs1902432 was a new susceptibility locus for prostate cancer in a Chinese population.	('prostate cancer', 'Phenotype', 'HP:0012125', (133, 148))	('prostate cancer', 'Disease', (133, 148))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('rs1902432', 'Mutation', 'rs1902432', (88, 97))	('susceptibility', 'Reg', (108, 122))	('rs1902432', 'Var', (88, 97))	('prostate cancer', 'Disease', 'MESH:D011471', (133, 148))
547019	31464517	A study in blabber cancer patients showed that rs710886 was an expression quantitative trait locos (eQTL) for lncRNA-PCAT1 and may be a potential biomarker for the risk of bladder cancer (Lin et al.,).	('nt', 'Chemical', 'MESH:D009711', (140, 142))	('PCAT1', 'Gene', (117, 122))	('blabber cancer', 'Disease', 'MESH:D009369', (11, 25))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('bladder cancer', 'Phenotype', 'HP:0009725', (172, 186))	('rs710886', 'Var', (47, 55))	('rs710886', 'Mutation', 'rs710886', (47, 55))	('patients', 'Species', '9606', (26, 34))	('nt', 'Chemical', 'MESH:D009711', (31, 33))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('bladder cancer', 'Disease', 'MESH:D001749', (172, 186))	('PCAT1', 'Gene', '100750225', (117, 122))	('bladder cancer', 'Disease', (172, 186))	('blabber cancer', 'Disease', (11, 25))	('nt', 'Chemical', 'MESH:D009711', (77, 79))
547020	31464517	There were also researchers who explored the association between polymorphisms on lncRNA-PCAT1 and gastric cancer risk.	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('polymorphisms', 'Var', (65, 78))	('gastric cancer', 'Disease', (99, 113))	('PCAT1', 'Gene', '100750225', (89, 94))	('gastric cancer', 'Disease', 'MESH:D013274', (99, 113))	('gastric cancer', 'Phenotype', 'HP:0012126', (99, 113))	('PCAT1', 'Gene', (89, 94))
547021	31464517	They selected rs1026411 and rs12543663 in lncRNA-PCAT1 and their results suggested that genetic variants in the two loci had no significant association with gastric cancer risk (He et al.,).	('gastric cancer', 'Phenotype', 'HP:0012126', (157, 171))	('association', 'Interaction', (140, 151))	('rs1026411', 'Mutation', 'rs1026411', (14, 23))	('variants', 'Var', (96, 104))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('rs12543663', 'Var', (28, 38))	('PCAT1', 'Gene', (49, 54))	('nt', 'Chemical', 'MESH:D009711', (137, 139))	('gastric cancer', 'Disease', (157, 171))	('rs1026411', 'Var', (14, 23))	('nt', 'Chemical', 'MESH:D009711', (101, 103))	('gastric cancer', 'Disease', 'MESH:D013274', (157, 171))	('PCAT1', 'Gene', '100750225', (49, 54))	('rs12543663', 'Mutation', 'rs12543663', (28, 38))
547022	31464517	Our previous GWAS results suggested a significant association between rs1026411 and rs12543663 polymorphisms and lung cancer risk; however, the result was based on a smaller sample size.	('lung cancer', 'Disease', (113, 124))	('lung cancer', 'Phenotype', 'HP:0100526', (113, 124))	('nt', 'Chemical', 'MESH:D009711', (47, 49))	('rs12543663', 'Mutation', 'rs12543663', (84, 94))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('rs1026411', 'Mutation', 'rs1026411', (70, 79))	('rs12543663', 'Var', (84, 94))	('lung cancer', 'Disease', 'MESH:D008175', (113, 124))	('rs1026411', 'Var', (70, 79))
547023	31464517	Previous studies had indicated that rs710886 and rs16901904 were tagSNPs of lncRNA-PCAT1 and rs710886 may be an eQTL for lncRNA-PCAT1.	('rs16901904', 'Mutation', 'rs16901904', (49, 59))	('PCAT1', 'Gene', (83, 88))	('PCAT1', 'Gene', '100750225', (128, 133))	('rs16901904', 'Var', (49, 59))	('rs710886', 'Mutation', 'rs710886', (93, 101))	('PCAT1', 'Gene', (128, 133))	('rs710886', 'Mutation', 'rs710886', (36, 44))	('rs710886', 'Var', (93, 101))	('PCAT1', 'Gene', '100750225', (83, 88))	('rs710886', 'Var', (36, 44))
547024	31464517	In this study, we took into account sample size and previous studies about genetic variants in lncRNA-PCAT1 and cancer risk and chose four SNPs in lncRNA-PCAT1 (rs1026411, rs12543663, rs710886, and rs16901904) to investigate the association between genetic variants in lncRNA-PCAT1 and susceptibility to lung cancer.	('cancer', 'Disease', (112, 118))	('PCAT1', 'Gene', '100750225', (102, 107))	('lung cancer', 'Disease', 'MESH:D008175', (304, 315))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('lung cancer', 'Phenotype', 'HP:0100526', (304, 315))	('rs16901904', 'Mutation', 'rs16901904', (198, 208))	('rs1026411', 'Var', (161, 170))	('rs710886', 'Mutation', 'rs710886', (184, 192))	('PCAT1', 'Gene', (154, 159))	('nt', 'Chemical', 'MESH:D009711', (33, 35))	('cancer', 'Disease', (309, 315))	('rs1026411', 'Mutation', 'rs1026411', (161, 170))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('cancer', 'Phenotype', 'HP:0002664', (309, 315))	('PCAT1', 'Gene', '100750225', (154, 159))	('rs16901904', 'Var', (198, 208))	('nt', 'Chemical', 'MESH:D009711', (88, 90))	('rs710886', 'Var', (184, 192))	('lung cancer', 'Disease', (304, 315))	('rs12543663', 'Mutation', 'rs12543663', (172, 182))	('PCAT1', 'Gene', (276, 281))	('rs12543663', 'Var', (172, 182))	('nt', 'Chemical', 'MESH:D009711', (24, 26))	('nt', 'Chemical', 'MESH:D009711', (262, 264))	('cancer', 'Disease', 'MESH:D009369', (309, 315))	('PCAT1', 'Gene', (102, 107))	('PCAT1', 'Gene', '100750225', (276, 281))
547051	31464517	The genotype frequency distributions of these SNPs in control group were in agreement with HWE (chi2 = 0.185, p = 0.667 for rs1026411; chi2 = 0.187, p = 0.665 for rs12543663; chi2 = 0.202, p = 0.653 for rs710886; and chi2 = 0.237, p = 0.627 for rs16901904).	('rs710886', 'Mutation', 'rs710886', (203, 211))	('rs12543663', 'Mutation', 'rs12543663', (163, 173))	('rs16901904', 'Mutation', 'rs16901904', (245, 255))	('nt', 'Chemical', 'MESH:D009711', (56, 58))	('rs710886', 'Var', (203, 211))	('nt', 'Chemical', 'MESH:D009711', (83, 85))	('rs16901904', 'Var', (245, 255))	('men', 'Species', '9606', (81, 84))	('rs1026411', 'Mutation', 'rs1026411', (124, 133))	('rs12543663', 'Var', (163, 173))	('rs1026411', 'Var', (124, 133))
547052	31464517	The associations of polymorphisms in lncRNA-PCAT1 with susceptibility to lung cancer and non-small cell lung cancer are shown in Table 2.	('lung cancer', 'Disease', 'MESH:D008175', (73, 84))	('lung cancer', 'Disease', 'MESH:D008175', (104, 115))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (93, 115))	('PCAT1', 'Gene', '100750225', (44, 49))	('polymorphisms', 'Var', (20, 33))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (89, 115))	('lung cancer', 'Phenotype', 'HP:0100526', (104, 115))	('non-small cell lung cancer', 'Disease', (89, 115))	('lung cancer', 'Disease', (73, 84))	('PCAT1', 'Gene', (44, 49))	('lung cancer', 'Phenotype', 'HP:0100526', (73, 84))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('associations', 'Interaction', (4, 16))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (89, 115))
547054	31464517	However, we found that genetic variants in rs1026411 and rs710886 had significant associations with susceptibility to non-small cell lung cancer (AG vs. GG: ORa = 0.701, 95% CI = 0.520-0.946, p* = 0.020 and AA+AG vs. GG: ORa = 0.711, 95% CI = 0.538-0.940, p* = 0.017 for rs1026411; CT vs. TT: ORa = 0.723, 95% CI = 0.525-0.995, p* = 0.047 and CC+CT vs. TT: ORa = 0.729, 95% CI = 0.541-0.982, p* = 0.038 for rs710886).	('rs710886', 'Var', (407, 415))	('rs710886', 'Var', (57, 65))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (118, 144))	('variants', 'Var', (31, 39))	('rs1026411', 'Var', (43, 52))	('lung cancer', 'Phenotype', 'HP:0100526', (133, 144))	('non-small cell lung cancer', 'Disease', (118, 144))	('rs1026411', 'Mutation', 'rs1026411', (271, 280))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('nt', 'Chemical', 'MESH:D009711', (79, 81))	('rs710886', 'Mutation', 'rs710886', (407, 415))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (122, 144))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (118, 144))	('rs1026411', 'Var', (271, 280))	('associations', 'Interaction', (82, 94))	('rs1026411', 'Mutation', 'rs1026411', (43, 52))	('nt', 'Chemical', 'MESH:D009711', (36, 38))	('rs710886', 'Mutation', 'rs710886', (57, 65))
547055	31464517	In addition, we failed to find a significant association between polymorphisms in rs12543663 and rs16901904 and the risk of lung cancer and non-small cell lung cancer.	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (140, 166))	('lung cancer', 'Disease', 'MESH:D008175', (124, 135))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('rs12543663', 'Var', (82, 92))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (140, 166))	('nt', 'Chemical', 'MESH:D009711', (42, 44))	('non-small cell lung cancer', 'Disease', (140, 166))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (144, 166))	('rs16901904', 'Mutation', 'rs16901904', (97, 107))	('lung cancer', 'Phenotype', 'HP:0100526', (155, 166))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('lung cancer', 'Disease', (124, 135))	('rs12543663', 'Mutation', 'rs12543663', (82, 92))	('lung cancer', 'Phenotype', 'HP:0100526', (124, 135))	('rs16901904', 'Var', (97, 107))	('lung cancer', 'Disease', 'MESH:D008175', (155, 166))
547056	31464517	Table 3 described the results of associations between polymorphisms in lncRNA-PCAT1 and susceptibility to the subtypes of lung cancer, including lung adenocarcinoma and squamous cell carcinoma.	('polymorphisms', 'Var', (54, 67))	('carcinoma', 'Phenotype', 'HP:0030731', (155, 164))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('lung adenocarcinoma', 'Disease', (145, 164))	('lung cancer', 'Disease', (122, 133))	('PCAT1', 'Gene', '100750225', (78, 83))	('lung cancer', 'Phenotype', 'HP:0100526', (122, 133))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (169, 192))	('carcinoma', 'Phenotype', 'HP:0030731', (183, 192))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (169, 192))	('squamous cell carcinoma', 'Disease', (169, 192))	('PCAT1', 'Gene', (78, 83))	('associations', 'Interaction', (33, 45))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (145, 164))	('lung cancer', 'Disease', 'MESH:D008175', (122, 133))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (145, 164))	('susceptibility', 'Reg', (88, 102))
547057	31464517	We found that polymorphisms in rs1026411 had a significant association with lung adenocarcinoma risk (AG vs. GG: ORa = 0.663, 95% CI = 0.470-0.936, p* = 0.019 and AA+AG vs. GG: ORa = 0.685, 95% CI = 0.497-0.943, p* = 0.020).	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('lung adenocarcinoma', 'Disease', (76, 95))	('association', 'Interaction', (59, 70))	('rs1026411', 'Mutation', 'rs1026411', (31, 40))	('nt', 'Chemical', 'MESH:D009711', (56, 58))	('polymorphisms', 'Var', (14, 27))	('rs1026411', 'Var', (31, 40))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (76, 95))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (76, 95))
547058	31464517	In squamous cell carcinoma, CC or CT genotype of rs710886 had a significantly decreased risk compared with TT genotype carrier (ORa = 0.638, 95% CI = 0.416-0.980, p* = 0.040).	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (3, 26))	('rs710886', 'Mutation', 'rs710886', (49, 57))	('rs710886', 'Var', (49, 57))	('nt', 'Chemical', 'MESH:D009711', (73, 75))	('carcinoma', 'Phenotype', 'HP:0030731', (17, 26))	('decreased', 'NegReg', (78, 87))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (3, 26))	('squamous cell carcinoma', 'Disease', (3, 26))
547059	31464517	Besides, polymorphisms in rs16901904 also showed significant results in this subgroup.	('rs16901904', 'Mutation', 'rs16901904', (26, 36))	('results', 'Reg', (61, 68))	('rs16901904', 'Var', (26, 36))	('nt', 'Chemical', 'MESH:D009711', (58, 60))
547060	31464517	In comparison with the TT genotype carrier, the risk of squamous cell carcinoma significantly increased in the CC genotype (ORa = 2.582, 95% CI = 1.078-6.186, p* = 0.033); meanwhile, the recessive model of rs16901904 also presented significant results (ORa = 2.381, 95% CI = 1.009-5.620, p* = 0.048).	('nt', 'Chemical', 'MESH:D009711', (89, 91))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (56, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('squamous cell carcinoma', 'Disease', (56, 79))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (56, 79))	('nt', 'Chemical', 'MESH:D009711', (241, 243))	('nt', 'Chemical', 'MESH:D009711', (227, 229))	('rs16901904', 'Var', (206, 216))	('rs16901904', 'Mutation', 'rs16901904', (206, 216))
547074	31464517	Another study showed that lncRNA-PCAT1 contributes to prostate cancer risk by regulating FSCN1 via miR-145-5p (Xu et al.,).	('contributes', 'Reg', (39, 50))	('FSCN1', 'Gene', (89, 94))	('PCAT1', 'Gene', '100750225', (33, 38))	('FSCN1', 'Gene', '6624', (89, 94))	('prostate cancer', 'Disease', (54, 69))	('regulating', 'Reg', (78, 88))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('nt', 'Chemical', 'MESH:D009711', (41, 43))	('miR-145-5p', 'Var', (99, 109))	('PCAT1', 'Gene', (33, 38))	('prostate cancer', 'Disease', 'MESH:D011471', (54, 69))	('prostate cancer', 'Phenotype', 'HP:0012125', (54, 69))
547078	31464517	showed that rs1902432 polymorphisms in lncRNA-PCAT1 had a significant association with prostate cancer risk in the additive model, co-dominant model, and recessive model.	('prostate cancer', 'Disease', (87, 102))	('association', 'Reg', (70, 81))	('nt', 'Chemical', 'MESH:D009711', (140, 142))	('PCAT1', 'Gene', (46, 51))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('prostate cancer', 'Disease', 'MESH:D011471', (87, 102))	('rs1902432', 'Mutation', 'rs1902432', (12, 21))	('prostate cancer', 'Phenotype', 'HP:0012125', (87, 102))	('PCAT1', 'Gene', '100750225', (46, 51))	('nt', 'Chemical', 'MESH:D009711', (67, 69))	('rs1902432 polymorphisms', 'Var', (12, 35))
547081	31464517	Through this research, we found that polymorphisms in lncRNA-PCAT1 had a significant association with lung cancer risk.	('polymorphisms', 'Var', (37, 50))	('nt', 'Chemical', 'MESH:D009711', (82, 84))	('lung cancer', 'Phenotype', 'HP:0100526', (102, 113))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('PCAT1', 'Gene', '100750225', (61, 66))	('lung cancer', 'Disease', (102, 113))	('association', 'Reg', (85, 96))	('lung cancer', 'Disease', 'MESH:D008175', (102, 113))	('PCAT1', 'Gene', (61, 66))
547082	31464517	Rs1902432 was in high linkage disequilibrium (r2 = 0.99) with rs1026411, based on HaploReg v4.1 (Ward and Kellis,).	('v4.1', 'Gene', (91, 95))	('Rs1902432', 'Var', (0, 9))	('Rs1902432', 'Mutation', 'Rs1902432', (0, 9))	('rs1026411', 'Mutation', 'rs1026411', (62, 71))	('rs1026411', 'Var', (62, 71))	('v4.1', 'Gene', '28783', (91, 95))
547083	31464517	In our study, genetic variants in rs1026411 may be protective factors in non-small cell lung cancer, which is different from rs1902432 in prostate cancer.	('non-small cell lung cancer', 'Disease', (73, 99))	('rs1026411', 'Mutation', 'rs1026411', (34, 43))	('rs1902432', 'Mutation', 'rs1902432', (125, 134))	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('nt', 'Chemical', 'MESH:D009711', (117, 119))	('prostate cancer', 'Disease', 'MESH:D011471', (138, 153))	('prostate cancer', 'Phenotype', 'HP:0012125', (138, 153))	('nt', 'Chemical', 'MESH:D009711', (27, 29))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('rs1026411', 'Var', (34, 43))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (77, 99))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (73, 99))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (73, 99))	('prostate cancer', 'Disease', (138, 153))	('lung cancer', 'Phenotype', 'HP:0100526', (88, 99))
547085	31464517	The analysis results of HaploReg database (Ward and Kellis,) also showed that rs710886 is an eQTL for PCAT1 and is located at a region that overlaps with enhancer histone marks in two tissues.	('rs710886', 'Mutation', 'rs710886', (78, 86))	('PCAT1', 'Gene', '100750225', (102, 107))	('PCAT1', 'Gene', (102, 107))	('rs710886', 'Var', (78, 86))
547086	31464517	Our results indicated that rs710886 polymorphisms were significantly associated with reduced risk of non-small cell lung cancer.	('nt', 'Chemical', 'MESH:D009711', (64, 66))	('rs710886', 'Mutation', 'rs710886', (27, 35))	('non-small cell lung cancer', 'Disease', (101, 127))	('lung cancer', 'Phenotype', 'HP:0100526', (116, 127))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (105, 127))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (101, 127))	('rs710886', 'Var', (27, 35))	('reduced', 'NegReg', (85, 92))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (101, 127))
547089	31464517	Although rs16901904 polymorphisms had no statistically significant association with the risk of lung cancer, non-small cell lung cancer, and lung adenocarcinoma, we find that rs16901904 polymorphisms were associated with the risk of lung squamous cell carcinoma.	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (233, 261))	('rs16901904', 'Mutation', 'rs16901904', (9, 19))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (238, 261))	('lung squamous cell carcinoma', 'Disease', (233, 261))	('rs16901904', 'Mutation', 'rs16901904', (175, 185))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (141, 160))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (109, 135))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('lung cancer', 'Disease', 'MESH:D008175', (96, 107))	('lung cancer', 'Phenotype', 'HP:0100526', (96, 107))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (113, 135))	('associated', 'Reg', (205, 215))	('carcinoma', 'Phenotype', 'HP:0030731', (151, 160))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (109, 135))	('carcinoma', 'Phenotype', 'HP:0030731', (252, 261))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (141, 160))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (233, 261))	('rs16901904', 'Var', (175, 185))	('lung adenocarcinoma', 'Disease', (141, 160))	('lung cancer', 'Disease', 'MESH:D008175', (124, 135))	('nt', 'Chemical', 'MESH:D009711', (64, 66))	('lung cancer', 'Disease', (96, 107))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('non-small cell lung cancer', 'Disease', (109, 135))	('lung cancer', 'Phenotype', 'HP:0100526', (124, 135))
547093	31464517	Genetic variants in lncRNA-PCAT1 may be associated with lung cancer susceptibility in a northeastern Chinese population.	('PCAT1', 'Gene', (27, 32))	('lung cancer', 'Phenotype', 'HP:0100526', (56, 67))	('Ge', 'Chemical', 'MESH:D005857', (0, 2))	('lung cancer', 'Disease', 'MESH:D008175', (56, 67))	('nt', 'Chemical', 'MESH:D009711', (13, 15))	('PCAT1', 'Gene', '100750225', (27, 32))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('associated', 'Reg', (40, 50))	('lung cancer', 'Disease', (56, 67))	('Genetic variants', 'Var', (0, 16))
547098	31211495	Survival analysis and functional annotation of long non-coding RNAs in lung adenocarcinoma Long non-coding RNAs (lncRNAs) are a subclass of non-protein coding transcripts that are involved in several regulatory processes and are considered as potential biomarkers for almost all cancer types.	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (71, 90))	('lung adenocarcinoma', 'Disease', (71, 90))	('cancer', 'Phenotype', 'HP:0002664', (279, 285))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (71, 90))	('involved', 'Reg', (180, 188))	('Long non-coding', 'Var', (91, 106))	('cancer', 'Disease', 'MESH:D009369', (279, 285))	('cancer', 'Disease', (279, 285))
547167	31211495	Specific lipids play important roles in endoplasmic reticulum stress, intracellular oncogenic signalling and the relation between cancer cells and cells of the tumour microenvironment.72 Also, it has been shown that the aberrant lipid metabolism promotes prostate cancer73 and blocking of the lipid catabolism decreases prostate tumour growth.72 In addition, GO:0006414 (translational elongation) is the hub GO-BP term in Module A and is common among CADM3-AS1, LINC00467 and SNHG6.	('men', 'Species', '9606', (179, 182))	('cancer', 'Disease', (264, 270))	('tumour', 'Phenotype', 'HP:0002664', (329, 335))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('CADM3-AS1', 'Gene', (451, 460))	('tumour', 'Disease', 'MESH:D009369', (329, 335))	('SNHG6', 'Gene', '641638', (476, 481))	('cancer', 'Phenotype', 'HP:0002664', (264, 270))	('tumour', 'Disease', (329, 335))	('aberrant lipid metabolism', 'Phenotype', 'HP:0003119', (220, 245))	('catabolism decreases prostate tumour growth', 'Disease', 'MESH:D011471', (299, 342))	('lipid', 'Chemical', 'MESH:D008055', (9, 14))	('LINC00467', 'Gene', '84791', (462, 471))	('GO:0006414', 'Var', (359, 369))	('catabolism decreases prostate tumour growth', 'Disease', (299, 342))	('prostate tumour', 'Phenotype', 'HP:0100787', (320, 335))	('lipids', 'Chemical', 'MESH:D008055', (9, 15))	('LINC00467', 'Gene', (462, 471))	('CADM3-AS1', 'Gene', '100131825;57863;5729', (451, 460))	('SNHG6', 'Gene', (476, 481))	('lipid', 'Chemical', 'MESH:D008055', (229, 234))	('tumour', 'Phenotype', 'HP:0002664', (160, 166))	('decreases prostate', 'Phenotype', 'HP:0008687', (310, 328))	('cancer', 'Disease', 'MESH:D009369', (264, 270))	('tumour', 'Disease', 'MESH:D009369', (160, 166))	('tumour', 'Disease', (160, 166))	('cancer', 'Disease', (130, 136))	('lipid', 'Chemical', 'MESH:D008055', (293, 298))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))
547169	31211495	Also, their overexpression predicts poor prognosis in lung cancer.74 The LAProLncRs in Module B of the lncRNA-GO-BP network are associated with well-known cancer-related biological processes and signalling pathways and GO:0051058 (negative regulation of small GTPase mediated signal transduction) was identified as the hub GO-BP term in this module.	('lung cancer', 'Disease', (54, 65))	('lung cancer', 'Phenotype', 'HP:0100526', (54, 65))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('lung cancer', 'Disease', 'MESH:D008175', (54, 65))	('GO:0051058', 'Var', (219, 229))	('associated', 'Reg', (128, 138))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))	('cancer', 'Disease', (155, 161))	('cancer', 'Disease', 'MESH:D009369', (155, 161))
547172	31211495	Also, the pathway enrichment analysis demonstrated that the LAProLncRs in Module B might synergistically function in the neuroactive ligand-receptor interaction pathway.	('men', 'Species', '9606', (24, 27))	('neuroactive ligand-receptor interaction pathway', 'Pathway', (121, 168))	('function', 'Reg', (105, 113))	('Module B', 'Gene', (74, 82))	('LAProLncRs', 'Var', (60, 70))
547224	30400986	The FoundationACT assay has a sensitivity of >= 99.3% and a positive predictive value (PPV) of 100% for base substitutions at allele frequency (AF) > 0.4%, a sensitivity of >= 98.5%, and a PPV of > 100% for insertion/deletions and a sensitivity of > 99% and a PPV of 98.0% for rearrangements at AF > 1.0%.	('insertion/deletions', 'Var', (207, 226))	('AF', 'Disease', 'MESH:D001281', (144, 146))	('base substitutions', 'Var', (104, 122))	('AF', 'Disease', 'MESH:D001281', (295, 297))
547234	30400986	A total of 215 GAs were detected in 81 patients, with an average of 2.7 GAs per sample (range 1-11), including 154 (72%) base substitutions, 34 (16%) insertions/deletions, 14 (7%) amplifications, and 13 (6%) rearrangements/fusions (Table 3).	('patients', 'Species', '9606', (39, 47))	('rearrangements/fusions', 'Var', (208, 230))	('amplifications', 'Var', (180, 194))	('insertions/deletions', 'Var', (150, 170))	('base substitutions', 'Var', (121, 139))
547237	30400986	Similar to a recent report, there were more concordance GAs in base substitutions in TP53 (93%), KRAS (88%), EGFR (77%), and PIK3CA (50%) genes (Fig.	('base substitutions', 'Var', (63, 81))	('TP53', 'Gene', (85, 89))	('KRAS', 'Gene', (97, 101))	('KRAS', 'Gene', '3845', (97, 101))	('PIK3CA', 'Gene', (125, 131))	('EGFR', 'Gene', '1956', (109, 113))	('PIK3CA', 'Gene', '5290', (125, 131))	('TP53', 'Gene', '7157', (85, 89))	('EGFR', 'Gene', (109, 113))
547248	30400986	MSAF was significantly higher in GA >= 1 versus GA = 0 cohorts in the fresh blood specimens (Fig.	('GA >= 1', 'Var', (33, 40))	('higher', 'PosReg', (23, 29))	('AF', 'Disease', 'MESH:D001281', (2, 4))
547262	30400986	In addition to our primary findings, FoundationACT also detected resistant mutations in two patients, one each with advanced NSCLC and breast cancer, which were not present on the tissue-based FoundationOne assay.	('NSCLC', 'Disease', (125, 130))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('patients', 'Species', '9606', (92, 100))	('NSCLC', 'Disease', 'MESH:D002289', (125, 130))	('mutations', 'Var', (75, 84))	('breast cancer', 'Disease', 'MESH:D001943', (135, 148))	('breast cancer', 'Disease', (135, 148))	('breast cancer', 'Phenotype', 'HP:0003002', (135, 148))
547277	29973584	Large-scale tumor sequencing has revolutionized the identification of somatic driver alterations but has had limited impact on the identification of cancer predisposition genes (CPGs).	('cancer', 'Disease', (149, 155))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('alterations', 'Var', (85, 96))	('tumor', 'Disease', (12, 17))	('cancer', 'Disease', 'MESH:D009369', (149, 155))
547279	29973584	Applied to ~10,000 tumor exomes the approach identifies known and putative CPGs - including the chromatin modifier NSD1 - that contribute to cancer through a combination of rare germline variants and somatic loss-of-heterozygosity (LOH).	('000 tumor', 'Disease', 'MESH:D009369', (15, 24))	('germline variants', 'Var', (178, 195))	('NSD1', 'Gene', '64324', (115, 119))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('loss-of-heterozygosity', 'NegReg', (208, 230))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('000 tumor', 'Disease', (15, 24))	('contribute', 'Reg', (127, 137))	('NSD1', 'Gene', (115, 119))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('cancer', 'Disease', (141, 147))
547281	29973584	Inherited germline variants and somatic mutations contribute to cancer.	('contribute', 'Reg', (50, 60))	('germline variants', 'Var', (10, 27))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
547282	29973584	Here, the authors present the statistical method ALFRED that tests the two-hit hypothesis of tumorigenesis and apply it to ~10,000 tumor exomes to identify rare germline variants that affect putative cancer predisposition genes, contributing substantially to cancer risk.	('cancer', 'Disease', 'MESH:D009369', (259, 265))	('tumor', 'Disease', 'MESH:D009369', (93, 98))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('tumor', 'Disease', (93, 98))	('variants', 'Var', (170, 178))	('tumor', 'Disease', (131, 136))	('cancer', 'Phenotype', 'HP:0002664', (259, 265))	('000 tumor', 'Disease', 'MESH:D009369', (127, 136))	('contributing', 'Reg', (229, 241))	('cancer', 'Disease', 'MESH:D009369', (200, 206))	('000 tumor', 'Disease', (127, 136))	('cancer', 'Disease', (200, 206))	('cancer', 'Disease', (259, 265))
547284	29973584	However, it was Alfred Knudson's 'two-hit' hypothesis that initiated the identification of cancer predisposition genes (CPGs) in which deleterious germline variants have been associated with increased risks of cancer.	('associated', 'Reg', (175, 185))	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('variants', 'Var', (156, 164))	('cancer', 'Disease', 'MESH:D009369', (210, 216))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('cancer', 'Disease', (210, 216))
547285	29973584	Through a statistical analysis of retinoblastoma cases, Knudson proposed that 'two hits' to the DNA were necessary to cause cancer and that in children with the inherited form of the disease the first hit is inherited variation in one allele of the gene with the 'second hit' being a somatically acquired inactivation of the second allele.	('retinoblastoma', 'Gene', (34, 48))	('retinoblastoma', 'Gene', '5925', (34, 48))	('cancer', 'Disease', (124, 130))	('retinoblastoma', 'Phenotype', 'HP:0009919', (34, 48))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('children', 'Species', '9606', (143, 151))	('variation', 'Var', (218, 227))	('cancer', 'Disease', 'MESH:D009369', (124, 130))
547286	29973584	This model was confirmed by the identification of biallelic inactivation of the RB1 gene in retinoblastoma and indeed most known high-penetrance inherited cancer predisposition variants are loss-of-function mutations in recessively acting tumor suppressor (TS) genes.	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('TS', 'Gene', '7248', (257, 259))	('RB1', 'Gene', (80, 83))	('retinoblastoma', 'Gene', (92, 106))	('tumor suppressor', 'Gene', (239, 255))	('tumor', 'Phenotype', 'HP:0002664', (239, 244))	('retinoblastoma', 'Phenotype', 'HP:0009919', (92, 106))	('biallelic inactivation', 'Var', (50, 72))	('variants', 'Var', (177, 185))	('tumor suppressor', 'Gene', '7248', (239, 255))	('RB1', 'Gene', '5925', (80, 83))	('loss-of-function', 'NegReg', (190, 206))	('cancer', 'Disease', (155, 161))	('cancer', 'Disease', 'MESH:D009369', (155, 161))	('retinoblastoma', 'Gene', '5925', (92, 106))
547287	29973584	Tumor sequencing has led to the systematic identification of somatically acquired cancer driver alterations.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('alterations', 'Var', (96, 107))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))
547288	29973584	As for other genetic diseases, an important reason for this is the low statistical power to detect associations between rare genetic variants and disease risk in genome-wide analyses, even in large population studies.	('variants', 'Var', (133, 141))	('genetic diseases', 'Disease', 'MESH:D030342', (13, 29))	('genetic diseases', 'Disease', (13, 29))
547292	29973584	To predict loss of heterozygosity (LOH) in each tumor from exome sequencing data, ALFRED uses all germline variants in coding and noncoding regions within each gene with sufficient sequencing coverage (expanding the analyzed region to 100 kb for genes shorter than this size) and then tests for allelic imbalance (AI), a change in variant allele frequencies (VAFs) in the tumor compared to in the matched non-tumor sample from each patient, Supplementary Fig.	('tumor', 'Disease', 'MESH:D009369', (372, 377))	('tumor', 'Disease', (409, 414))	('tumor', 'Disease', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (372, 377))	('patient', 'Species', '9606', (432, 439))	('variants', 'Var', (107, 115))	('tumor', 'Disease', (372, 377))	('tests', 'Reg', (285, 290))	('tumor', 'Disease', 'MESH:D009369', (409, 414))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (409, 414))	('change', 'Reg', (321, 327))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('imbalance', 'Phenotype', 'HP:0002172', (303, 312))
547293	29973584	ALFRED classifies germline variants (identified from non-tumor DNA; mainly from blood) as potentially damaging if they have a minor allele frequency (MAF) <0.1% in the Exome Aggregation Consortium (ExAC) database and result in a premature stop codon, frameshift, splice site inactivation, or missense change predicted as deleterious by the MetaLR consensus algorithm.	('splice site', 'MPA', (263, 274))	('premature stop codon', 'MPA', (229, 249))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('missense change', 'Var', (292, 307))	('tumor', 'Disease', (57, 62))	('frameshift', 'MPA', (251, 261))
547295	29973584	The first test is for an excess of RDGVs in a gene in tumor samples with putative LOH of the gene, compared to the frequency of RDGVs in the samples without LOH in that gene.	('LOH', 'Var', (82, 85))	('RDGVs', 'Var', (35, 40))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumor', 'Disease', (54, 59))
547303	29973584	At a false discovery rate (FDR) = 0.2, 13 genes were individually enriched for RDGVs in tumors with AI and exhibited AI in favor of the variant allele (henceforth referred to as 'ALFRED genes') (Supplementary Data 3).	('tumors', 'Disease', 'MESH:D009369', (88, 94))	('variant', 'Var', (136, 143))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumors', 'Disease', (88, 94))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))
547310	29973584	Five genes were enriched for rare PTVs in tumors with AI and exhibited AI in favor of the variant alleles, of which three genes (BRCA1/2 and ATM) overlap with our initial ALFRED design (RDGVs based model), while TNFSF13B (excess of rare PTVs in AI samples over samples without AI samples = 0.37%, PTV-ALFRED P = 1.85 x 10-3) and ACACB (excess = 0.41%, PTV-ALFRED P = 3.02 x 10-3) are newly detected (Supplementary Fig.	('tumors', 'Disease', (42, 48))	('tumors', 'Disease', 'MESH:D009369', (42, 48))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('ACACB', 'Gene', '32', (329, 334))	('TNFSF13B', 'Gene', (212, 220))	('TNFSF13B', 'Gene', '10673', (212, 220))	('BRCA', 'Phenotype', 'HP:0003002', (129, 133))	('ACACB', 'Gene', (329, 334))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('BRCA1/2 and ATM', 'Gene', '472;672;675', (129, 144))	('variant', 'Var', (90, 97))
547314	29973584	We next tested whether cancer genes identified by recurrent somatic alterations but not previously reported to harbor inherited risk variants also showed evidence of carrying recessive RDGVs that predispose to cancer via a two-hit mechanism.	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('cancer', 'Disease', (23, 29))	('cancer', 'Disease', 'MESH:D009369', (23, 29))	('cancer', 'Disease', 'MESH:D009369', (210, 216))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('variants', 'Var', (133, 141))	('cancer', 'Disease', (210, 216))
547315	29973584	Somatic cancer genes known to act via gain-of-function alterations (oncogenes; OGs) showed no significant enrichment for RDGVs in samples with AI (Fig.	('cancer', 'Disease', (8, 14))	('alterations', 'Var', (55, 66))	('gain-of-function', 'PosReg', (38, 54))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('cancer', 'Disease', 'MESH:D009369', (8, 14))
547328	29973584	2d and Supplementary Data 5) also had an enrichment of RDGVs in a matched cancer type compared to in controls (P < 0.05, Fig.	('cancer', 'Disease', (74, 80))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('RDGVs', 'Var', (55, 60))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
547334	29973584	If RDGVs in a gene contribute similar risk to many cancer types then they would not show enrichment in this test.	('RDGVs', 'Var', (3, 8))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))
547336	29973584	We performed two analyses: the first using all samples and the second restricted to tumor samples with AI in the gene of interest.	('tumor', 'Disease', (84, 89))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('AI in', 'Var', (103, 108))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))
547339	29973584	For example, RDGVs in BRCA1 and BRCA2 were, as expected, significantly enriched in OV and BRCA compared to in all the other cancer samples (BRCA1, excess of RDGVs in BRCA compared to non-breast cancer = 2.1%, 95% CI: 1.1-3.1%, excess in OV = 6.7%, 5.1-8.2%; BRCA2, excess in BRCA = 1.3%, 0.49-2.1%; excess in OV = 3.9%, 2.7-5.1%).	('BRCA2', 'Gene', '675', (258, 263))	('BRCA1', 'Gene', (140, 145))	('BRCA', 'Gene', (166, 170))	('non-breast cancer', 'Disease', 'MESH:D001943', (183, 200))	('OV', 'Phenotype', 'HP:0025318', (237, 239))	('BRCA', 'Gene', '672', (22, 26))	('cancer', 'Disease', 'MESH:D009369', (124, 130))	('cancer', 'Disease', 'MESH:D009369', (194, 200))	('BRCA', 'Gene', '672', (140, 144))	('OV', 'Phenotype', 'HP:0025318', (309, 311))	('BRCA', 'Gene', '672', (258, 262))	('BRCA', 'Gene', (275, 279))	('BRCA', 'Phenotype', 'HP:0003002', (90, 94))	('BRCA2', 'Gene', (32, 37))	('BRCA', 'Phenotype', 'HP:0003002', (32, 36))	('RDGVs', 'Var', (157, 162))	('non-breast cancer', 'Disease', (183, 200))	('BRCA', 'Gene', (22, 26))	('breast cancer', 'Phenotype', 'HP:0003002', (187, 200))	('BRCA', 'Phenotype', 'HP:0003002', (166, 170))	('BRCA', 'Gene', (140, 144))	('BRCA', 'Gene', (258, 262))	('BRCA', 'Gene', '672', (90, 94))	('BRCA', 'Gene', '672', (32, 36))	('BRCA2', 'Gene', '675', (32, 37))	('BRCA2', 'Gene', (258, 263))	('RDGVs', 'Var', (13, 18))	('OV', 'Phenotype', 'HP:0025318', (83, 85))	('cancer', 'Disease', (124, 130))	('cancer', 'Disease', (194, 200))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('BRCA', 'Gene', '672', (166, 170))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('BRCA1', 'Gene', '672', (22, 27))	('BRCA', 'Gene', (90, 94))	('BRCA', 'Gene', (32, 36))	('BRCA', 'Phenotype', 'HP:0003002', (22, 26))	('BRCA', 'Phenotype', 'HP:0003002', (140, 144))	('BRCA1', 'Gene', '672', (140, 145))	('BRCA1', 'Gene', (22, 27))	('BRCA', 'Gene', '672', (275, 279))
547342	29973584	Next, we estimated the total contribution of RDGVs in the ALFRED genes to cancer risk by quantifying the excess frequency of ALFRED gene RDGVs in cancer patients over that in the general population.	('RDGVs', 'Var', (137, 142))	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('ALFRED', 'Gene', (58, 64))	('patients', 'Species', '9606', (153, 161))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Disease', (74, 80))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
547346	29973584	Strikingly, 21.7% of OV patients carried RDGVs in ALFRED genes, which is an excess of 14.6% over controls (95% CI: 11.6-17.1%).	('OV', 'Phenotype', 'HP:0025318', (21, 23))	('ALFRED genes', 'Gene', (50, 62))	('RDGVs', 'Var', (41, 46))	('patients', 'Species', '9606', (24, 32))
547347	29973584	Other cancer types with a substantial contribution of RDGVs in ALFRED genes include BRCA (7.0% by excess of cases versus controls, adjusted to random expectation; 95% CI: 4.7-9.1%) and UCEC (3.8% excess, 95% CI: 1.1-6.2%).	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('BRCA', 'Gene', (84, 88))	('BRCA', 'Phenotype', 'HP:0003002', (84, 88))	('BRCA', 'Gene', '672', (84, 88))	('cancer', 'Disease', 'MESH:D009369', (6, 12))	('RDGVs', 'Var', (54, 59))	('UCEC', 'Disease', (185, 189))	('cancer', 'Disease', (6, 12))	('ALFRED genes', 'Gene', (63, 75))
547350	29973584	The excess of RDGVs in these three CPGs in cases versus controls suggests that RDGVs in these three genes are implicated in a median of 1.2% of cancer cases across the 17 cancer types (range: 0.24-11.4%).	('RDGVs', 'Var', (79, 84))	('implicated in', 'Reg', (110, 123))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('cancer', 'Disease', (171, 177))	('cancer', 'Disease', (144, 150))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
547352	29973584	In OV, for example, the excess of cancer cases that carry RDGVs in any ALFRED gene after excluding known CPGs is 4.0% (95% CI: 1.6-5.0%).	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('ALFRED gene', 'Gene', (71, 82))	('RDGVs', 'Var', (58, 63))	('cancer', 'Disease', 'MESH:D009369', (34, 40))	('cancer', 'Disease', (34, 40))	('OV', 'Phenotype', 'HP:0025318', (3, 5))
547357	29973584	To estimate the total proportion of cancer cases attributable to rare germline risk variants for each cancer type, we combined the ALFRED genes with the previously reported CPGs (for any cancer type).	('cancer', 'Disease', 'MESH:D009369', (187, 193))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('cancer', 'Disease', (187, 193))	('cancer', 'Disease', (36, 42))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('variants', 'Var', (84, 92))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))
547358	29973584	In total, RDGVs in these 56 genes explain a median of 5.4% of cancer cases across the 17 cancer types (excess frequency of cases with a RDGV over frequency of controls, adjusted to a random expectation; range 2.3-15.2%).	('RDGVs', 'Var', (10, 15))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('cancer', 'Disease', (89, 95))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
547359	29973584	For instance, a total of 15.2% (95% CI: 12.1-17.7%) of OV and 9.3% of BRCA cases (95% CI: 6.2-12.4%) can be explained by RDGVs in the 56 genes (Supplementary Fig.	('OV', 'Phenotype', 'HP:0025318', (55, 57))	('BRCA', 'Phenotype', 'HP:0003002', (70, 74))	('RDGVs', 'Var', (121, 126))	('BRCA', 'Gene', '672', (70, 74))	('BRCA', 'Gene', (70, 74))
547363	29973584	Our results suggest that multiple somatic cancer drivers and putative new genes also harbor germline genetic variants that predispose to cancer in the general population.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (137, 143))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('cancer', 'Disease', (137, 143))	('variants', 'Var', (109, 117))	('predispose', 'Reg', (123, 133))
547364	29973584	For example, the histone H3 lysine 36 methyltransferase NSD1 was the second most significantly enriched gene in our case-control analysis with an excess of RDGVs in cases compared with controls = 0.72% (P < 1.14 x 10-3, 95% CI: 0.27-1.2%).	('NSD1', 'Gene', (56, 60))	('RDGVs', 'Var', (156, 161))	('NSD1', 'Gene', '64324', (56, 60))	('lysine', 'Chemical', 'MESH:D008239', (28, 34))
547365	29973584	This suggests that RDGVs in NSD1 are causally implicated in ~0.72% of cancers, a similar magnitude of effect as we observe for the well-known cancer predisposition genes BRCA1 (0.64%) and ATM (0.68%).	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('implicated', 'Reg', (46, 56))	('NSD1', 'Gene', (28, 32))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('BRCA', 'Phenotype', 'HP:0003002', (170, 174))	('BRCA1', 'Gene', '672', (170, 175))	('ATM', 'Gene', (188, 191))	('RDGVs', 'Var', (19, 24))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('cancers', 'Disease', (70, 77))	('cancers', 'Disease', 'MESH:D009369', (70, 77))	('cancers', 'Phenotype', 'HP:0002664', (70, 77))	('BRCA1', 'Gene', (170, 175))	('cancer', 'Disease', (70, 76))	('ATM', 'Gene', '472', (188, 191))	('NSD1', 'Gene', '64324', (28, 32))	('cancer', 'Disease', (142, 148))
547367	29973584	Here we have presented evidence that NSD1 also carries germline cancer predisposition variants.	('NSD1', 'Gene', '64324', (37, 41))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('variants', 'Var', (86, 94))	('NSD1', 'Gene', (37, 41))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
547369	29973584	However, the variants in NSD1 enriched in cancer patients are distinct from the variants that cause Sotos syndrome (Supplementary Fig.	('variants', 'Var', (13, 21))	('NSD1', 'Gene', (25, 29))	('Sotos syndrome', 'Disease', (100, 114))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('NSD1', 'Gene', '64324', (25, 29))	('Sotos syndrome', 'Disease', 'MESH:D058495', (100, 114))	('patients', 'Species', '9606', (49, 57))
547371	29973584	Considered as a set, RDGVs in the ALFRED genes can explain a substantial proportion of the cancer cases analyzed by the TCGA project: a median of 2.3% across the 17 individual cancer types with sufficient sample sizes.	('RDGVs', 'Var', (21, 26))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('ALFRED genes', 'Gene', (34, 46))	('cancer', 'Disease', (176, 182))	('cancer', 'Disease', 'MESH:D009369', (176, 182))
547372	29973584	However, in several cancers the contribution is substantially higher, with 14.6% of OV, 7.0% of BRCA, and 3.8% of UCEC cases attributable to RDGVs in these genes.	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('BRCA', 'Phenotype', 'HP:0003002', (96, 100))	('BRCA', 'Gene', '672', (96, 100))	('UCEC', 'Disease', (114, 118))	('BRCA', 'Gene', (96, 100))	('RDGVs', 'Var', (141, 146))	('OV', 'Phenotype', 'HP:0025318', (84, 86))	('cancers', 'Phenotype', 'HP:0002664', (20, 27))	('cancers', 'Disease', (20, 27))	('cancers', 'Disease', 'MESH:D009369', (20, 27))
547373	29973584	Including additional known CPGs further increases the estimate of the proportion of cases attributable to RDGVs: a median of 5.4% across the 17 individual cancer types, with 15.2% of OV, 9.3% of BRCA, and 6.0% of UCEC cases attributable to RDGVs in ALFRED genes, respectively.	('OV', 'Phenotype', 'HP:0025318', (183, 185))	('RDGVs', 'Var', (240, 245))	('BRCA', 'Phenotype', 'HP:0003002', (195, 199))	('BRCA', 'Gene', (195, 199))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('ALFRED genes', 'Gene', (249, 261))	('esp', 'Gene', '148713', (264, 267))	('UCEC', 'Disease', (213, 217))	('esp', 'Gene', (264, 267))	('cancer', 'Disease', (155, 161))	('cancer', 'Disease', 'MESH:D009369', (155, 161))	('BRCA', 'Gene', '672', (195, 199))
547386	29973584	(http://exac.broadinstitute.org/), the TCGA cancer samples had a median 4574 nonsynonymous, stop gain and stop loss, splice SNVs and coding indels in the filtered regions, as annotated by the Annovar tool version 2014-11-12 (ref.	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('splice SNVs', 'Var', (117, 128))	('nonsynonymous', 'MPA', (77, 90))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('TCGA', 'Gene', (39, 43))	('coding indels', 'Var', (133, 146))
547389	29973584	We called the germline variants (single-nucleotide and short indels) on the normal and the tumor samples independently using Illumina IVC.	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumor', 'Disease', (91, 96))	('single-nucleotide', 'Var', (33, 50))
547390	29973584	Of the data Annovar reports, we used (i) the consequences of the mutations: synonymous, missense, truncating, splice site, frameshift indel, and in-frame indel, using the RefSeq gene annotations; (ii) the estimated effect of missense mutations via the MetaLR predictor, which combines nine deleteriousness scores including PolyPhen-2, SIFT and others.	('missense mutations', 'Var', (225, 243))	('SIFT', 'Disease', (335, 339))	('SIFT', 'Disease', 'None', (335, 339))
547391	29973584	This filtering was performed on the full ExAC, which includes germline variants of TCGA samples in addition to other non-cancer cohorts.	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('germline variants', 'Var', (62, 79))	('non-cancer', 'Disease', (117, 127))	('non-cancer', 'Disease', 'MESH:D009369', (117, 127))	('TCGA', 'Gene', (83, 87))
547393	29973584	Before performing a statistical test to call LOH, we applied an effect size threshold, requiring that the tumor VAF of a germline variant must be either higher than 0.7 or lower than 0.3.	('variant', 'Var', (130, 137))	('lower', 'NegReg', (172, 177))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Disease', (106, 111))
547395	29973584	Each variant in a gene (and possibly surrounding regions) that meets the effect size threshold was further tested individually using a two-tailed Fisher's test that compares the read counts supporting the variant and the reference alleles in the tumor, versus the read counts supporting the variant and the reference alleles in the normal (noncancerous) tissue.	('cancer', 'Phenotype', 'HP:0002664', (343, 349))	('variant', 'Var', (205, 212))	('tumor', 'Disease', 'MESH:D009369', (246, 251))	('cancer', 'Disease', (343, 349))	('cancer', 'Disease', 'MESH:D009369', (343, 349))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('tumor', 'Disease', (246, 251))
547398	29973584	Additionally, we removed the RDGVs that were recurrent at the same position in more than 1% of our samples (TCGA or control samples), thereby excluding four variants (17-46608203-A-G, 20-5548206-TC-T, 21-34924148-A-G and X-2833605-C-T).	('20-5548206-TC-T', 'Var', (184, 199))	('X-2833605-C-T', 'Var', (221, 234))	('20-5548206-TC-T', 'CellLine', 'CVCL:2300', (184, 199))	('excluding', 'NegReg', (142, 151))	('17-46608203-A-G', 'Var', (167, 182))	('21-34924148-A-G', 'Var', (201, 216))
547399	29973584	We first tested for an excess of RDGVs in samples with putative LOH compared to in samples without putative LOH of all possible genes (N = 14,143), collapsing together all SNVs/indels in each gene in each sample and using the exomes of all 30 cancer types (Supplementary Fig.	('cancer', 'Phenotype', 'HP:0002664', (243, 249))	('cancer', 'Disease', 'MESH:D009369', (243, 249))	('cancer', 'Disease', (243, 249))	('SNVs/indels', 'Var', (172, 183))
547400	29973584	Finally, 2983 genes were defined as ALFRED tested genes, which carried at least five RDGVs (of which at least one with >=10% increased VAF of RDGVs in tumor compared to matched normal sample; 6692 genes were excluded that were carrying less than five RDGVs and, additionally, 329 genes were excluded if they carried no RDGV with >=10% increased VAF), with an above-average (10.0%) frequency of putative LOH in the gene in the pan-cancer data (8809 genes were excluded that were lower than 10.0% frequency of putative LOH; 4672 genes were carrying less than five RDGVs and lower putative LOH frequencies than average frequency of putative LOH; Supplementary Fig, 6a).	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('cancer', 'Phenotype', 'HP:0002664', (430, 436))	('tumor', 'Disease', (151, 156))	('4672 genes', 'Var', (522, 532))	('cancer', 'Disease', 'MESH:D009369', (430, 436))	('cancer', 'Disease', (430, 436))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
547406	29973584	Genes with dominant gain-of-function variants would not be significant in ALFRED analysis (e.g., no excess of RDGVs in AI samples compared to no-AI samples), but would be significant in the case-control analysis, meaning the variants are enriched in cancer patients in comparison to the general population.	('cancer', 'Disease', 'MESH:D009369', (250, 256))	('cancer', 'Disease', (250, 256))	('gain-of-function', 'PosReg', (20, 36))	('patients', 'Species', '9606', (257, 265))	('cancer', 'Phenotype', 'HP:0002664', (250, 256))	('variants', 'Var', (37, 45))
547436	29973584	To empirically estimate the effects of the 10% cutoff, we examined the samples containing rare truncating (nonsense or frameshift indel) variants of six genes that were previously associated with inherited ovarian carcinoma(BRCA1, BRCA2, MSH6, PALB2, RAD51, and TP53) in the TCGA ovarian cancer data (N = 51 in our data set); these were the putative true positive LOH events.	('BRCA2', 'Gene', (231, 236))	('MSH6', 'Gene', (238, 242))	('PALB2', 'Gene', (244, 249))	('MSH6', 'Gene', '2956', (238, 242))	('cancer', 'Phenotype', 'HP:0002664', (288, 294))	('variants', 'Var', (137, 145))	('BRCA', 'Phenotype', 'HP:0003002', (224, 228))	('TP53', 'Gene', '7157', (262, 266))	('ovarian cancer', 'Disease', 'MESH:D010051', (280, 294))	('carcinoma', 'Phenotype', 'HP:0030731', (214, 223))	('BRCA', 'Phenotype', 'HP:0003002', (231, 235))	('BRCA2', 'Gene', '675', (231, 236))	('PALB2', 'Gene', '79728', (244, 249))	('inherited ovarian carcinoma', 'Disease', (196, 223))	('BRCA1', 'Gene', '672', (224, 229))	('ovarian cancer', 'Disease', (280, 294))	('BRCA1', 'Gene', (224, 229))	('inherited ovarian carcinoma', 'Disease', 'MESH:D010051', (196, 223))	('ovarian cancer', 'Phenotype', 'HP:0100615', (280, 294))	('RAD51', 'Gene', (251, 256))	('RAD51', 'Gene', '5888', (251, 256))	('TP53', 'Gene', (262, 266))	('associated with', 'Reg', (180, 195))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (206, 223))
547479	29850009	did not find any correlation between CD20+ B cells infiltration and prognosis in ovarian epithelial tumors.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('ovarian epithelial tumors', 'Disease', (81, 106))	('CD20+', 'Var', (37, 42))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('ovarian epithelial tumors', 'Disease', 'MESH:D000077216', (81, 106))	('ovarian epithelial tumors', 'Phenotype', 'HP:0025318', (81, 106))
547480	29850009	indicated that higher number of CD20+ B cells in early stage of hypopharynx squamous cell carcinoma was associated with improved locoregional control.	('improved', 'PosReg', (120, 128))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (76, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (90, 99))	('hypopharynx squamous cell carcinoma', 'Disease', (64, 99))	('hypopharynx squamous cell carcinoma', 'Disease', 'MESH:D002294', (64, 99))	('locoregional control', 'CPA', (129, 149))	('CD20+ B cells', 'Var', (32, 45))	('hypopharynx squamous cell carcinoma', 'Phenotype', 'HP:0012182', (64, 99))	('early stage of hypopharynx', 'Phenotype', 'HP:3000053', (49, 75))
547518	28288180	All antibodies used in this study were commercially purchased: choromogranin A (IS50230, dilution 1:1000, Dako, Glostrup, Denmark), synaptophysin (PA0299 Bond Ready-To-Use Primary antibody, Leica Biosysytems, Nussloch, Germany) and CD56 (CD56-1B6-R-7 Bond Ready-To-Use Primary antibody, Leica Biosysytems, Nussloch, Germany), Ki67 (M7240, dilution 1:100, Dako, Glostrup, Denmark), c-kit (A4502, dilution 1:100, Dako, Glostrup, Denmark), p53 (N1581, dilution 1:10, Dako, Glostrup, Denmark), p63 (413751, dilution 1:5, Nichirei, Tokyo, Japan), CK5/6 (M7237, dilution 1:250, Dako, Glostrup, Denmark) and CK20 (413491, dilution 1:1000, Nichirei, Tokyo, Japan).	('p53', 'Gene', '7157', (437, 440))	('synaptophysin', 'Gene', '6855', (132, 145))	('CD56', 'Gene', '4684', (238, 242))	('CK5/6', 'Gene', (542, 547))	('c-kit', 'Gene', '3815', (381, 386))	('p53', 'Gene', (437, 440))	('p63', 'Gene', (490, 493))	('CK20', 'Gene', (601, 605))	('p63', 'Gene', '8626', (490, 493))	('413751', 'Var', (495, 501))	('N1581', 'Var', (442, 447))	('CK20', 'Gene', '54474', (601, 605))	('synaptophysin', 'Gene', (132, 145))	('M7237', 'Var', (549, 554))	('CD56', 'Gene', (232, 236))	('CK5/6', 'Gene', '3852', (542, 547))	('c-kit', 'Gene', (381, 386))	('CD56', 'Gene', '4684', (232, 236))	('CD56', 'Gene', (238, 242))
547556	28288180	Heterozygosity is also frequently observed in neuroendocrine NEC of the esophagus as a pathologic feature and co-existence of squamous cell carcinoma and/or adenocarcinoma are also often observed.	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (126, 149))	('squamous cell carcinoma', 'Disease', (126, 149))	('Heterozygosity', 'Var', (0, 14))	('adenocarcinoma', 'Disease', (157, 171))	('NEC', 'Phenotype', 'HP:0100634', (61, 64))	('neuroendocrine NEC of the esophagus', 'Disease', (46, 81))	('adenocarcinoma', 'Disease', 'MESH:D000230', (157, 171))	('observed', 'Reg', (34, 42))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (126, 149))	('carcinoma', 'Phenotype', 'HP:0030731', (162, 171))
547562	28288180	Similar to squamous cell carcinoma of the esophagus in which the abnormality of p53 plays an important role in carcinogenesis, the abnormality of p53 might play some role in the carcinogenesis or progression for NEC of the esophagus.	('role', 'Reg', (166, 170))	('p53', 'Gene', (146, 149))	('NEC', 'Phenotype', 'HP:0100634', (212, 215))	('carcinoma', 'Phenotype', 'HP:0030731', (25, 34))	('squamous cell carcinoma of the esophagus', 'Disease', 'MESH:D002294', (11, 51))	('carcinoma of the esophagus', 'Phenotype', 'HP:0011459', (25, 51))	('p53', 'Gene', '7157', (80, 83))	('carcinogenesis', 'Disease', (178, 192))	('NEC of the esophagus', 'Disease', (212, 232))	('play', 'Reg', (156, 160))	('p53', 'Gene', (80, 83))	('carcinogenesis', 'Disease', 'MESH:D063646', (178, 192))	('abnormality', 'Var', (131, 142))	('carcinogenesis', 'Disease', (111, 125))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (11, 34))	('squamous cell carcinoma of the esophagus', 'Disease', (11, 51))	('p53', 'Gene', '7157', (146, 149))	('abnormality', 'Var', (65, 76))	('carcinogenesis', 'Disease', 'MESH:D063646', (111, 125))
547563	28288180	In pulmonary neuroendocrine tumors, protein abnormality, loss of heterozygosity and gene mutation were observed and the incidence of these abnormalities progressively increased with increasing severity of tumor type.	('neuroendocrine tumors', 'Phenotype', 'HP:0100634', (13, 34))	('tumor', 'Disease', (28, 33))	('gene mutation', 'Var', (84, 97))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('tumors', 'Phenotype', 'HP:0002664', (28, 34))	('pulmonary neuroendocrine tumors', 'Disease', 'MESH:D018358', (3, 34))	('pulmonary neuroendocrine tumors', 'Disease', (3, 34))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('protein', 'Protein', (36, 43))	('tumor', 'Disease', (205, 210))	('tumor', 'Disease', 'MESH:D009369', (28, 33))	('loss of', 'NegReg', (57, 64))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))
547565	28288180	Huang reported a low frequency of CK20 positivity in NEC of the esophagus.	('CK20', 'Gene', (34, 38))	('CK20', 'Gene', '54474', (34, 38))	('NEC', 'Phenotype', 'HP:0100634', (53, 56))	('NEC of the esophagus', 'Disease', (53, 73))	('positivity', 'Var', (39, 49))
547567	28288180	There has been reported that p53 abnormality was also rare events in Merkel cell carcinoma of the skin.	('p53', 'Gene', (29, 32))	('Merkel cell carcinoma of the skin', 'Phenotype', 'HP:0030447', (69, 102))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('Merkel cell carcinoma of the skin', 'Disease', 'MESH:D015266', (69, 102))	('p53', 'Gene', '7157', (29, 32))	('Merkel cell carcinoma of the skin', 'Disease', (69, 102))	('abnormality', 'Var', (33, 44))
547569	28288180	There were no significant differences of prognosis according to the immunohistochemical status of p53 and/or c-kit, or others (CK20 and Ki67).	('c-kit', 'Gene', (109, 114))	('Ki67', 'Var', (136, 140))	('p53', 'Gene', (98, 101))	('p53', 'Gene', '7157', (98, 101))	('CK20', 'Gene', (127, 131))	('CK20', 'Gene', '54474', (127, 131))	('c-kit', 'Gene', '3815', (109, 114))
547592	27571908	Although it has been revealed that mutations of several oncogenes, including Kirsten rat sarcoma viral oncogene homolog, anaplastic lymphoma kinase and epidermal growth factor receptor, or genome amplification contribute to the promotion and advanced stages of SCC, further investigations to identify novel targets and elucidate molecular mechanisms are required.	('lymphoma', 'Phenotype', 'HP:0002665', (132, 140))	('SCC', 'Gene', (261, 264))	('sarcoma viral', 'Disease', (89, 102))	('SCC', 'Phenotype', 'HP:0002860', (261, 264))	('anaplastic lymphoma', 'Disease', 'MESH:D017728', (121, 140))	('rat', 'Species', '10116', (85, 88))	('promotion', 'PosReg', (228, 237))	('epidermal growth factor receptor', 'Gene', '24329', (152, 184))	('SCC', 'Gene', '6317', (261, 264))	('contribute', 'Reg', (210, 220))	('epidermal growth factor receptor', 'Gene', (152, 184))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (121, 140))	('sarcoma', 'Phenotype', 'HP:0100242', (89, 96))	('advanced stages', 'CPA', (242, 257))	('sarcoma viral', 'Disease', 'MESH:D001102', (89, 102))	('anaplastic lymphoma', 'Disease', (121, 140))	('mutations', 'Var', (35, 44))
547595	27571908	The dysregulation of miRNAs has been demonstrated in several types of tumor, including lung cancer, breast cancer and colon cancer, promoting tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('colon cancer', 'Disease', (118, 130))	('dysregulation', 'Var', (4, 17))	('miR', 'Gene', (21, 24))	('lung cancer', 'Disease', (87, 98))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('promoting', 'PosReg', (132, 141))	('breast cancer', 'Phenotype', 'HP:0003002', (100, 113))	('colon cancer', 'Phenotype', 'HP:0003003', (118, 130))	('lung cancer', 'Disease', 'MESH:D008175', (87, 98))	('tumor', 'Disease', (142, 147))	('rat', 'Species', '10116', (44, 47))	('breast cancer', 'Disease', 'MESH:D001943', (100, 113))	('lung cancer', 'Phenotype', 'HP:0100526', (87, 98))	('breast cancer', 'Disease', (100, 113))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('colon cancer', 'Disease', 'MESH:D015179', (118, 130))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('tumor', 'Disease', (70, 75))	('miR', 'Gene', '220972', (21, 24))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
547598	27571908	The deregulation of GRN has been found in several types of tumor, including breast cancer, prostate cancer, chronic lymphocytic leukemia and hepatocellular carcinoma.	('tumor', 'Disease', (59, 64))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (141, 165))	('prostate cancer', 'Disease', (91, 106))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('GRN', 'Gene', (20, 23))	('hepatocellular carcinoma', 'Disease', (141, 165))	('found', 'Reg', (33, 38))	('GRN', 'Gene', '2896', (20, 23))	('breast cancer', 'Phenotype', 'HP:0003002', (76, 89))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('deregulation', 'Var', (4, 16))	('carcinoma', 'Phenotype', 'HP:0030731', (156, 165))	('chronic lymphocytic leukemia', 'Disease', 'MESH:D015451', (108, 136))	('chronic lymphocytic leukemia', 'Disease', (108, 136))	('breast cancer', 'Disease', (76, 89))	('breast cancer', 'Disease', 'MESH:D001943', (76, 89))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (141, 165))	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (108, 136))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('leukemia', 'Phenotype', 'HP:0001909', (128, 136))	('prostate cancer', 'Disease', 'MESH:D011471', (91, 106))	('prostate cancer', 'Phenotype', 'HP:0012125', (91, 106))
547604	27571908	In addition, GRN was identified as a potential target of miR-588, which was upregulated in SCC tissues, and the abnormal expression of GRN was involved in the tumor-suppressive functions mediated by miR-588.	('tumor', 'Phenotype', 'HP:0002664', (159, 164))	('GRN', 'Gene', (13, 16))	('involved', 'Reg', (143, 151))	('miR-588', 'Gene', '693173', (57, 64))	('expression', 'MPA', (121, 131))	('miR-588', 'Gene', (57, 64))	('GRN', 'Gene', '2896', (13, 16))	('GRN', 'Gene', (135, 138))	('tumor', 'Disease', (159, 164))	('miR-588', 'Gene', (199, 206))	('SCC', 'Gene', (91, 94))	('miR-588', 'Gene', '693173', (199, 206))	('upregulated', 'PosReg', (76, 87))	('tumor', 'Disease', 'MESH:D009369', (159, 164))	('GRN', 'Gene', '2896', (135, 138))	('SCC', 'Phenotype', 'HP:0002860', (91, 94))	('abnormal', 'Var', (112, 120))	('SCC', 'Gene', '6317', (91, 94))
547657	27571908	The results were confirmed the hypothesis that the knockdown of miR-588 increases SCC cell migration and invasion (Fig.	('invasion', 'CPA', (105, 113))	('rat', 'Species', '10116', (94, 97))	('SCC', 'Phenotype', 'HP:0002860', (82, 85))	('SCC', 'Gene', '6317', (82, 85))	('increases', 'PosReg', (72, 81))	('miR-588', 'Gene', (64, 71))	('miR-588', 'Gene', '693173', (64, 71))	('SCC', 'Gene', (82, 85))	('knockdown', 'Var', (51, 60))
547664	27571908	The present study subsequently used an antagonist of miR-588 and found that suppressing miR-588 significantly enhanced the expression of GRN in SCC cell lines (Fig.	('miR-588', 'Gene', '693173', (53, 60))	('miR-588', 'Gene', (53, 60))	('expression', 'MPA', (123, 133))	('miR-588', 'Gene', (88, 95))	('GRN', 'Gene', '2896', (137, 140))	('SCC', 'Gene', (144, 147))	('SCC', 'Phenotype', 'HP:0002860', (144, 147))	('miR-588', 'Gene', '693173', (88, 95))	('suppressing', 'Var', (76, 87))	('enhanced', 'PosReg', (110, 118))	('SCC', 'Gene', '6317', (144, 147))	('GRN', 'Gene', (137, 140))
547710	27571908	Therefore, the present study assessed the expression of VEGF when siRNA was used to knockdown GRN in SCC cells.	('VEGF', 'Gene', (56, 60))	('knockdown', 'Var', (84, 93))	('GRN', 'Gene', (94, 97))	('SCC', 'Gene', (101, 104))	('SCC', 'Phenotype', 'HP:0002860', (101, 104))	('VEGF', 'Gene', '7422', (56, 60))	('GRN', 'Gene', '2896', (94, 97))	('SCC', 'Gene', '6317', (101, 104))
547712	27571908	It it also well documented that the expression of GRN has been associated with drug resistance in NSCLC.	('NSCLC', 'Disease', (98, 103))	('NSCLC', 'Phenotype', 'HP:0030358', (98, 103))	('expression', 'Var', (36, 46))	('drug resistance', 'Phenotype', 'HP:0020174', (79, 94))	('associated with', 'Reg', (63, 78))	('GRN', 'Gene', (50, 53))	('drug resistance', 'MPA', (79, 94))	('NSCLC', 'Disease', 'MESH:D002289', (98, 103))	('GRN', 'Gene', '2896', (50, 53))
547764	32391047	In terms of prognosis, LUAD patients with a high mRNAsi showed significantly worse outcomes than those with a low mRNAsi for both OS and PFS (Figures 1G,I).	('high', 'Var', (44, 48))	('mRNAsi', 'Disease', (49, 55))	('mRNAsi', 'Disease', (114, 120))	('mRNAsi', 'Disease', 'None', (49, 55))	('mRNAsi', 'Disease', 'None', (114, 120))	('low mRNAsi', 'Disease', (110, 120))	('patients', 'Species', '9606', (28, 36))	('LUAD', 'Phenotype', 'HP:0030078', (23, 27))	('low mRNAsi', 'Disease', 'MESH:D009800', (110, 120))
547779	32391047	However, for different AJCC grades, only RAD54L, RAD51, and KIFC1 were significantly expressed with regard to different grades (Figure 5G).	('RAD54L', 'Var', (41, 47))	('RAD51', 'Gene', (49, 54))	('KIFC1', 'Gene', (60, 65))	('RAD51', 'Gene', '5888', (49, 54))	('KIFC1', 'Gene', '3833', (60, 65))
547781	32391047	As the expression of these genes increased, the amount of TIICs decreased, while RAD54L was positively correlated with CD4 + T cells.	('CD4', 'Gene', '920', (119, 122))	('correlated', 'Interaction', (103, 113))	('decreased', 'NegReg', (64, 73))	('expression', 'MPA', (7, 17))	('increased', 'PosReg', (33, 42))	('CD4', 'Gene', (119, 122))	('RAD54L', 'Var', (81, 87))	('amount', 'MPA', (48, 54))
547782	32391047	The risk score is (0.411* expression level of CHEK1) + (-0.367* expression level of KIFC1) + (0.326* expression level of RAD54L).	('expression', 'MPA', (26, 36))	('KIFC1', 'Gene', (84, 89))	('KIFC1', 'Gene', '3833', (84, 89))	('expression level', 'MPA', (101, 117))	('expression level', 'MPA', (64, 80))	('CHEK1', 'Gene', (46, 51))	('0.411*', 'Var', (19, 25))
547798	32391047	The overexpression of CHEK1 contributes to the development of resistance to MTAs, while the knockout of CHEK1 contributes to the enhancement of MTAs and inhibition of the growth of NSCLC cells.	('NSCLC', 'Disease', 'MESH:D002289', (181, 186))	('CHEK1', 'Gene', (22, 27))	('inhibition', 'NegReg', (153, 163))	('growth', 'MPA', (171, 177))	('knockout', 'Var', (92, 100))	('resistance to MTAs', 'MPA', (62, 80))	('NSCLC', 'Phenotype', 'HP:0030358', (181, 186))	('enhancement', 'PosReg', (129, 140))	('men', 'Species', '9606', (54, 57))	('MTAs', 'MPA', (144, 148))	('CHEK1', 'Gene', (104, 109))	('NSCLC', 'Disease', (181, 186))	('men', 'Species', '9606', (136, 139))
547801	32391047	Another study showed that the abnormal expression of other genes, such as cancer testis antigen (CTA), can also promote RAD51 filament formation and simultaneously enhance the sensitivity to DNA damaging agents.	('enhance', 'PosReg', (164, 171))	('abnormal', 'Var', (30, 38))	('RAD51', 'Gene', '5888', (120, 125))	('cancer testis', 'Phenotype', 'HP:0010788', (74, 87))	('promote', 'PosReg', (112, 119))	('cancer testis', 'Disease', 'MESH:D013736', (74, 87))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))	('sensitivity to DNA damaging agents', 'MPA', (176, 210))	('RAD51', 'Gene', (120, 125))	('men', 'Species', '9606', (130, 133))	('cancer testis', 'Disease', (74, 87))
547804	32391047	Some studies have suggested that mutations in the KIF gene family are involved in the formation of many cancers.	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('mutations', 'Var', (33, 42))	('involved', 'Reg', (70, 78))	('KIF gene', 'Gene', (50, 58))	('cancers', 'Phenotype', 'HP:0002664', (104, 111))	('cancers', 'Disease', (104, 111))	('cancers', 'Disease', 'MESH:D009369', (104, 111))
547809	32391047	Using RT-qPCR and Western blot detection of NSCLC and adjacent normal lung tissue samples, found that KIFC1 is highly expressed in NSCLC tissues and that silencing KIFC1 inhibits NSCLC cell proliferation.	('NSCLC', 'Disease', 'MESH:D002289', (44, 49))	('NSCLC', 'Disease', 'MESH:D002289', (179, 184))	('NSCLC', 'Disease', (131, 136))	('NSCLC', 'Phenotype', 'HP:0030358', (131, 136))	('KIFC1', 'Gene', (102, 107))	('NSCLC', 'Phenotype', 'HP:0030358', (44, 49))	('NSCLC', 'Disease', 'MESH:D002289', (131, 136))	('KIFC1', 'Gene', '3833', (102, 107))	('KIFC1', 'Gene', '3833', (164, 169))	('inhibits', 'NegReg', (170, 178))	('KIFC1', 'Gene', (164, 169))	('NSCLC', 'Phenotype', 'HP:0030358', (179, 184))	('NSCLC', 'Disease', (44, 49))	('silencing', 'Var', (154, 163))	('NSCLC', 'Disease', (179, 184))
547810	32391047	Using flow cytometry to examine the cell cycle, we found that silencing KIFC1 could arrest the cell cycle in G2/M phase, suggesting that KIFC1 can be used as a biomarker for lung cancer diagnosis and treatment.	('silencing', 'Var', (62, 71))	('lung cancer', 'Disease', (174, 185))	('lung cancer', 'Phenotype', 'HP:0100526', (174, 185))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('arrest', 'Disease', 'MESH:D006323', (84, 90))	('KIFC1', 'Gene', (137, 142))	('men', 'Species', '9606', (205, 208))	('arrest', 'Disease', (84, 90))	('cell cycle in G2/M phase', 'CPA', (95, 119))	('lung cancer', 'Disease', 'MESH:D008175', (174, 185))	('KIFC1', 'Gene', '3833', (137, 142))	('KIFC1', 'Gene', (72, 77))	('KIFC1', 'Gene', '3833', (72, 77))
547812	32391047	found that FEN1 plays a key role in the rapid proliferation of NSCLC cells and confirmed in a mouse model that treatment with an FEN1 inhibitor enhanced the sensitivity of NSCLC cells to DNA damaging agents and that combined therapy with cisplatin could significantly inhibit the progression of cancer cells.	('NSCLC', 'Disease', (63, 68))	('inhibitor', 'Var', (134, 143))	('sensitivity', 'MPA', (157, 168))	('men', 'Species', '9606', (116, 119))	('cancer', 'Disease', 'MESH:D009369', (295, 301))	('NSCLC', 'Disease', 'MESH:D002289', (63, 68))	('NSCLC', 'Disease', (172, 177))	('enhanced', 'PosReg', (144, 152))	('cancer', 'Disease', (295, 301))	('NSCLC', 'Disease', 'MESH:D002289', (172, 177))	('cisplatin', 'Chemical', 'MESH:D002945', (238, 247))	('mouse', 'Species', '10090', (94, 99))	('NSCLC', 'Phenotype', 'HP:0030358', (63, 68))	('NSCLC', 'Phenotype', 'HP:0030358', (172, 177))	('cancer', 'Phenotype', 'HP:0002664', (295, 301))	('FEN1', 'Gene', (129, 133))	('inhibit', 'NegReg', (268, 275))
547815	32391047	Therefore, inhibitors targeting FEN1 may be a promising anticancer strategy.	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('cancer', 'Disease', (60, 66))	('inhibitors', 'Var', (11, 21))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('FEN1', 'Gene', (32, 36))
547832	28878044	The main histological subtypes of NSCLC are adenocarcinoma and squamous cell carcinoma, with the presence of specific DNA mutations allowing further molecular stratification.	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('NSCLC', 'Disease', (34, 39))	('adenocarcinoma', 'Disease', (44, 58))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (63, 86))	('squamous cell carcinoma', 'Disease', (63, 86))	('NSCLC', 'Disease', 'MESH:D002289', (34, 39))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (63, 86))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('DNA', 'Gene', (118, 121))	('adenocarcinoma', 'Disease', 'MESH:D000230', (44, 58))	('mutations', 'Var', (122, 131))
547888	28878044	This seminal study demonstrated a significant reduction in lung cancer specific (20%) and all-cause (6.7%) mortality in the LDCT arm.	('reduction in lung cancer', 'Disease', 'MESH:D008175', (46, 70))	('lung cancer', 'Phenotype', 'HP:0100526', (59, 70))	('reduction in lung cancer', 'Disease', (46, 70))	('LDCT', 'Var', (124, 128))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
547928	28878044	Alteration in miRNA expression has been implicated in the pathogenesis of most cancers.	('cancers', 'Disease', (79, 86))	('miRNA expression', 'Protein', (14, 30))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('Alteration', 'Var', (0, 10))	('implicated', 'Reg', (40, 50))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('cancers', 'Disease', 'MESH:D009369', (79, 86))
547966	28878044	used a panel of six antibodies (antibodies to APEX1, NOLC1, PXN, Bac clone R580E16 and MT-RNR2) on serum obtained from lung cancer patients prior to diagnosis and at diagnosis, as well as controls.	('patients', 'Species', '9606', (131, 139))	('MT-RNR2', 'Gene', (87, 94))	('APEX1', 'Gene', (46, 51))	('lung cancer', 'Disease', (119, 130))	('Bac', 'Var', (65, 68))	('NOLC1', 'Gene', (53, 58))	('PXN', 'Gene', (60, 63))	('MT-RNR2', 'Gene', '4550', (87, 94))	('PXN', 'Gene', '5829', (60, 63))	('lung cancer', 'Phenotype', 'HP:0100526', (119, 130))	('NOLC1', 'Gene', '9221', (53, 58))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('lung cancer', 'Disease', 'MESH:D008175', (119, 130))	('APEX1', 'Gene', '328', (46, 51))
547971	28878044	The utility of ctDNA in lung cancer was demonstrated in a study of NSCLC, where common mutations were identified to create a library for detecting mutations associated with NSCLC.	('mutations', 'Var', (147, 156))	('associated', 'Reg', (157, 167))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('NSCLC', 'Disease', (173, 178))	('lung cancer', 'Disease', (24, 35))	('NSCLC', 'Disease', 'MESH:D002289', (67, 72))	('lung cancer', 'Phenotype', 'HP:0100526', (24, 35))	('NSCLC', 'Disease', (67, 72))	('NSCLC', 'Disease', 'MESH:D002289', (173, 178))	('lung cancer', 'Disease', 'MESH:D008175', (24, 35))
547976	28878044	Mutations in TP53 and KRAS were detectable on average 20 months and 14 months prior to cancer diagnosis, respectively, but only in 4.6% of patients for TP53 and 1.5% for KRAS.	('cancer', 'Disease', (87, 93))	('TP53', 'Gene', (13, 17))	('patients', 'Species', '9606', (139, 147))	('KRAS', 'Gene', (170, 174))	('TP53', 'Gene', '7157', (152, 156))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('Mutations', 'Var', (0, 9))	('detectable', 'Reg', (32, 42))	('KRAS', 'Gene', (22, 26))	('TP53', 'Gene', (152, 156))	('KRAS', 'Gene', '3845', (170, 174))	('KRAS', 'Gene', '3845', (22, 26))	('TP53', 'Gene', '7157', (13, 17))	('cancer', 'Disease', 'MESH:D009369', (87, 93))
547977	28878044	Furthermore, 3% and 0.9% controls that did not develop cancer in over 5 years of follow up were also positive for TP53 and KRAS mutations.	('mutations', 'Var', (128, 137))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('TP53', 'Gene', '7157', (114, 118))	('positive', 'Reg', (101, 109))	('KRAS', 'Gene', (123, 127))	('TP53', 'Gene', (114, 118))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('KRAS', 'Gene', '3845', (123, 127))	('cancer', 'Disease', (55, 61))
547978	28878044	In working towards developing an assay for early detection, one study evaluated mutations in TP53 in early and late stage SCLC, comparing these with controls to get an idea of the specificity of this approach.	('mutations', 'Var', (80, 89))	('TP53', 'Gene', '7157', (93, 97))	('TP53', 'Gene', (93, 97))	('SCLC', 'Gene', '7864', (122, 126))	('SCLC', 'Gene', (122, 126))
547979	28878044	TP53 mutations were identified in 35% early stage and 54% late stage tumours, but these could also be identified in 11% matched controls.	('tumours', 'Disease', (69, 76))	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))	('tumour', 'Phenotype', 'HP:0002664', (69, 75))	('tumours', 'Phenotype', 'HP:0002664', (69, 76))	('tumours', 'Disease', 'MESH:D009369', (69, 76))
547987	28878044	Furthermore, there is growing evidence for extensive genetic mosaicism in healthy tissue, including the presence of mutations in genes that have a known role in cancer.	('genes', 'Gene', (129, 134))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('presence', 'Reg', (104, 112))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('mutations', 'Var', (116, 125))	('cancer', 'Disease', (161, 167))
547988	28878044	While the sensitivity of candidate gene analysis using droplet digital PCR based approaches is higher, a broader panel of genetic mutations could be more informative on tumour presence as the sensitivity of next-generation sequencing increases.	('tumour', 'Disease', 'MESH:D009369', (169, 175))	('mutations', 'Var', (130, 139))	('tumour', 'Phenotype', 'HP:0002664', (169, 175))	('tumour', 'Disease', (169, 175))
548023	28878044	Interestingly, one retrospective study comparing sputum samples taken prior to histological diagnosis of lung adenocarcinoma found that KRAS mutations could be detected in the sputum of 5 out of 11 patients with KRAS positive tumours between 1 month and 4 years prior to clinical diagnosis.	('KRAS', 'Gene', '3845', (212, 216))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (105, 124))	('mutations', 'Var', (141, 150))	('patients', 'Species', '9606', (198, 206))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('tumours', 'Phenotype', 'HP:0002664', (226, 233))	('tumour', 'Phenotype', 'HP:0002664', (226, 232))	('lung adenocarcinoma', 'Disease', (105, 124))	('detected', 'Reg', (160, 168))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (105, 124))	('KRAS', 'Gene', (136, 140))	('tumours', 'Disease', 'MESH:D009369', (226, 233))	('KRAS', 'Gene', (212, 216))	('tumours', 'Disease', (226, 233))	('KRAS', 'Gene', '3845', (136, 140))
548024	28878044	A prospective study in a LDCT cohort tested sputum for KRAS and p53 mutations, in addition to p16INK4A, RASSF1A and NORE1A hypermethylation in 820 heavy smokers.	('KRAS', 'Gene', (55, 59))	('p16INK4A', 'Gene', (94, 102))	('NORE1A', 'Gene', (116, 122))	('RASSF1A', 'Gene', (104, 111))	('NORE1A', 'Gene', '83593', (116, 122))	('p16INK4A', 'Gene', '1029', (94, 102))	('KRAS', 'Gene', '3845', (55, 59))	('RASSF1A', 'Gene', '11186', (104, 111))	('mutations', 'Var', (68, 77))	('p53', 'Gene', (64, 67))	('p53', 'Gene', '7157', (64, 67))
548025	28878044	At least one mutation or hypermethylation was present in 56 patients, of which only 1 developed lung cancer after 3 years of follow up.	('lung cancer', 'Disease', 'MESH:D008175', (96, 107))	('hypermethylation', 'Var', (25, 41))	('patients', 'Species', '9606', (60, 68))	('lung cancer', 'Disease', (96, 107))	('lung cancer', 'Phenotype', 'HP:0100526', (96, 107))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))
548060	28878044	This approach has therefore been successful in the TRACERx study, where specific DNA mutations identified in resected tumours were monitored through ctDNA after surgery, but in the context of early detection, where details of the tumour are unknown, it is altogether more difficult.	('tumours', 'Disease', 'MESH:D009369', (118, 125))	('tumour', 'Disease', (118, 124))	('tumours', 'Disease', (118, 125))	('tumour', 'Phenotype', 'HP:0002664', (230, 236))	('tumours', 'Phenotype', 'HP:0002664', (118, 125))	('tumour', 'Disease', 'MESH:D009369', (118, 124))	('mutations', 'Var', (85, 94))	('tumour', 'Disease', 'MESH:D009369', (230, 236))	('tumour', 'Phenotype', 'HP:0002664', (118, 124))	('tumour', 'Disease', (230, 236))	('DNA', 'Gene', (81, 84))
548082	28176852	Given that the forced expression of wild-type but not mutant podoplanin lacking platelet-aggregating ability led to the acquisition of metastatic ability of non-metastatic Chinese hamster ovary (CHO) cells and enhanced the rate of tumour arrest in the lung, the platelet aggregation-inducing activity of podoplanin was suggested to be directly linked to its ability to facilitate metastasis formation.	('tumour arrest', 'Disease', 'MESH:D006323', (231, 244))	('metastatic ability', 'CPA', (135, 153))	('metastasis formation', 'CPA', (380, 400))	('platelet aggregation', 'Disease', 'MESH:D001791', (262, 282))	('Chinese hamster', 'Species', '10029', (172, 187))	('enhanced', 'PosReg', (210, 218))	('platelet aggregation', 'Disease', (262, 282))	('podoplanin', 'Gene', (61, 71))	('CHO', 'CellLine', 'CVCL:0213', (195, 198))	('platelet aggregation', 'Phenotype', 'HP:0003540', (262, 282))	('acquisition', 'PosReg', (120, 131))	('tumour arrest', 'Disease', (231, 244))	('expression', 'Species', '29278', (22, 32))	('mutant', 'Var', (54, 60))	('tumour', 'Phenotype', 'HP:0002664', (231, 237))
548103	28176852	S3, several soluble factors were at higher concentrations in the supernatants of UM-UC-5- and H226-platelet reactants than in the supernatants of A549-platelet reactants that were not aggregated.	('higher', 'PosReg', (36, 42))	('A549', 'CellLine', 'CVCL:0023', (146, 150))	('H226-platelet', 'Var', (94, 107))	('UM-UC-5', 'CellLine', 'CVCL:2750', (81, 88))	('H226', 'CellLine', 'CVCL:J621', (94, 98))
548111	28176852	As TGF-beta signalling occurs through the formation of heterotetrameric receptor complexes of type I and type II TGF-beta receptors (TGFbetaR1 and TGFbetaR2) by ligand binding, we treated UM-UC-5 cells with either a pan-TGF-beta-neutralizing mAb (1D11) or TGF-beta receptor inhibitors (LY2157299, targets both TGFbetaR1 and TGFbetaR2; SB431542, targets TGFbetaR1) and observed that morphological changes and EMT induced by supernatants of UM-UC-5 cell-platelet reactants were abolished (Fig.	('LY2157299', 'Chemical', 'MESH:C557799', (286, 295))	('SB431542', 'Chemical', 'MESH:C459179', (335, 343))	('LY2157299', 'Var', (286, 295))	('UM-UC-5', 'CellLine', 'CVCL:2750', (188, 195))	('abolished', 'NegReg', (476, 485))	('UM-UC-5', 'CellLine', 'CVCL:2750', (439, 446))	('EMT', 'CPA', (408, 411))	('morphological changes', 'CPA', (382, 403))
548119	28176852	Consistent with suppression of platelet aggregation induction by those cells, the levels of TGF-beta1 in the supernatants of UM-UC-5/shPDPN_23- and UM-UC-5/shPDPN_26-platelet reactants were below the limit of detection by enzyme-linked immunosorbent assay (ELISA; Fig.	('platelet aggregation', 'Disease', (31, 51))	('platelet aggregation', 'Disease', 'MESH:D001791', (31, 51))	('platelet aggregation', 'Phenotype', 'HP:0003540', (31, 51))	('UM-UC-5', 'CellLine', 'CVCL:2750', (125, 132))	('UM-UC-5', 'CellLine', 'CVCL:2750', (148, 155))	('TGF-beta1', 'Gene', (92, 101))	('UM-UC-5/shPDPN_23-', 'Var', (125, 143))	('levels', 'MPA', (82, 88))
548120	28176852	In a mouse metastasis model, haematogenous metastasis to the lung was suppressed by podoplanin knockdown in UM-UC-5 cells that were inoculated to the mice (Supplementary Fig.	('haematogenous metastasis to the lung', 'CPA', (29, 65))	('mice', 'Species', '10090', (150, 154))	('podoplanin', 'Gene', (84, 94))	('UM-UC-5', 'CellLine', 'CVCL:2750', (108, 115))	('suppressed', 'NegReg', (70, 80))	('knockdown', 'Var', (95, 104))	('mouse', 'Species', '10090', (5, 10))
548123	28176852	inoculation of UM-UC-5 cells via the tail vein were decreased by a single dose of 1D11 mAb 1 hr prior to the inoculation (Fig.	('UM-UC-5', 'CellLine', 'CVCL:2750', (15, 22))	('decreased', 'NegReg', (52, 61))	('1D11 mAb', 'Var', (82, 90))
548133	28176852	In contrast, administration of 1D11 mAb significantly reduced the number of UM-UC-5 cells in lungs at 48 h after cell inoculation (P = 0.0173 by Mann-Whitney U test) (Fig.	('1D11 mAb', 'Var', (31, 39))	('reduced', 'NegReg', (54, 61))	('UM-UC-5', 'CellLine', 'CVCL:2750', (76, 83))
548139	28176852	Furthermore, the observed EMT-like morphology was suppressed by pretreatment with 1D11 mAb or LY2157299 (Supplementary Fig.	('suppressed', 'NegReg', (50, 60))	('1D11 mAb', 'Var', (82, 90))	('LY2157299', 'Chemical', 'MESH:C557799', (94, 103))	('EMT-like morphology', 'CPA', (26, 45))	('LY2157299', 'Var', (94, 103))
548143	28176852	We fo6und that TGF-beta knockdown in UM-UC-5 cells did not affect the level of TGF-beta released on platelet aggregation and that platelets seemed to contain much more TGF-beta than UM-UC-5 cells when they were compared at the ratio used in the platelet aggregation assay.	('platelet aggregation', 'Disease', (100, 120))	('platelet aggregation', 'Disease', 'MESH:D001791', (100, 120))	('UM-UC-5', 'CellLine', 'CVCL:2750', (182, 189))	('platelet aggregation', 'Phenotype', 'HP:0003540', (100, 120))	('TGF-beta', 'Gene', (15, 23))	('platelet aggregation', 'Disease', (245, 265))	('platelet aggregation', 'Disease', 'MESH:D001791', (245, 265))	('platelet aggregation', 'Phenotype', 'HP:0003540', (245, 265))	('knockdown', 'Var', (24, 33))	('UM-UC-5', 'CellLine', 'CVCL:2750', (37, 44))
548149	28176852	In addition, podoplanin is rarely expressed in breast cancer; thus, platelet activation by podoplanin-expressing tumours might be qualitatively different from that induced by podoplanin-negative tumours.	('podoplanin-expressing', 'Var', (91, 112))	('tumour', 'Phenotype', 'HP:0002664', (113, 119))	('breast cancer', 'Disease', (47, 60))	('tumours', 'Phenotype', 'HP:0002664', (113, 120))	('breast cancer', 'Phenotype', 'HP:0003002', (47, 60))	('tumour', 'Phenotype', 'HP:0002664', (195, 201))	('tumours', 'Disease', 'MESH:D009369', (113, 120))	('tumours', 'Phenotype', 'HP:0002664', (195, 202))	('tumours', 'Disease', (113, 120))	('tumours', 'Disease', 'MESH:D009369', (195, 202))	('platelet activation', 'MPA', (68, 87))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('tumours', 'Disease', (195, 202))	('breast cancer', 'Disease', 'MESH:D001943', (47, 60))
548160	28176852	4f) of UM-UC-5 cells were altered by podoplanin knockdown.	('altered', 'Reg', (26, 33))	('UM-UC-5', 'CellLine', 'CVCL:2750', (7, 14))	('podoplanin', 'Gene', (37, 47))	('knockdown', 'Var', (48, 57))
548173	28176852	In the current study, we showed that administration of an anti- TGF-beta 1D11 mAb decreased the number of both lung-trapped UM-UC-5 cells and lung metastatic foci in an experimental metastasis model (Fig.	('lung metastatic foci', 'CPA', (142, 162))	('lung-trapped UM-UC-5 cells', 'CPA', (111, 137))	('UM-UC-5', 'CellLine', 'CVCL:2750', (124, 131))	('anti-', 'Var', (58, 63))	('TGF-beta 1D11', 'Gene', (64, 77))	('decreased', 'NegReg', (82, 91))
548174	28176852	These inhibitory effects of 1D11 mAb were likely mediated by the inhibition of EMT of UM-UC-5 cells in peripheral blood and their subsequent extravasation.	('inhibition', 'NegReg', (65, 75))	('EMT', 'CPA', (79, 82))	('UM-UC-5', 'CellLine', 'CVCL:2750', (86, 93))	('1D11 mAb', 'Var', (28, 36))	('extravasation', 'MPA', (141, 154))
548175	28176852	As TGF-beta was also shown to suppress the antitumor function of natural killer cells by downregulating NKG2D immunoreceptor, administration of 1D11 mAb might restore antitumor immunity mounted by the host.	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('tumor', 'Disease', 'MESH:D009369', (47, 52))	('NKG2D', 'Protein', (104, 109))	('1D11', 'Var', (144, 148))	('restore', 'PosReg', (159, 166))	('tumor', 'Phenotype', 'HP:0002664', (47, 52))	('suppress', 'NegReg', (30, 38))	('tumor', 'Disease', (171, 176))	('downregulating', 'NegReg', (89, 103))	('tumor', 'Disease', (47, 52))	('TGF-beta', 'Gene', (3, 11))
548176	28176852	In addition, podoplanin knockdown resulted in suppression of pulmonary metastasis of UM-UC-5 cells, implicating both TGF-beta and podoplanin as potential therapeutic targets for development of antimetastatic therapeutics.	('suppression', 'NegReg', (46, 57))	('podoplanin', 'Gene', (13, 23))	('UM-UC-5', 'CellLine', 'CVCL:2750', (85, 92))	('knockdown', 'Var', (24, 33))	('pulmonary metastasis of UM-UC-5', 'CPA', (61, 92))
548177	28176852	5, administration of 1D11 mAb 1 h prior to tumour cell inoculation significantly reduced the number of lung metastatic foci.	('tumour', 'Disease', (43, 49))	('1D11', 'Var', (21, 25))	('reduced', 'NegReg', (81, 88))	('tumour', 'Phenotype', 'HP:0002664', (43, 49))	('tumour', 'Disease', 'MESH:D009369', (43, 49))
548216	28176852	Additionally, in some experiments, 1D11 mAb was administrated two more times after tumour cell inoculation for a total of three times.	('1D11', 'Var', (35, 39))	('tumour', 'Disease', (83, 89))	('tumour', 'Disease', 'MESH:D009369', (83, 89))	('tumour', 'Phenotype', 'HP:0002664', (83, 89))
548331	33086649	identified a new cancer subtype that was associated with a poor patient outcome, using gene expression, methylation, point mutation and copy number changes.	('patient', 'Species', '9606', (64, 71))	('point mutation', 'Var', (117, 131))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('copy number changes', 'Var', (136, 155))	('cancer', 'Disease', (17, 23))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
548359	33086649	Most of the studies have shown a positive correlation between NKX2-1 over-expression and survival, which is consistent with our findings (Figure 6).	('NKX2-1', 'Gene', (62, 68))	('survival', 'CPA', (89, 97))	('NKX2-1', 'Gene', '7080', (62, 68))	('over-expression', 'Var', (69, 84))
548360	33086649	NKX2-1 expression is generally thought to be associated with a good prognosis, although some studies have reported the opposite.	('NKX2-1', 'Gene', '7080', (0, 6))	('expression', 'Var', (7, 17))	('NKX2-1', 'Gene', (0, 6))
548511	32046192	Growing evidence indicates that mutations and/or deregulations that affect snoRNAs, as well as host genes, play a significant role in oncogenesis.	('snoRNA', 'Gene', '6079', (75, 81))	('deregulations', 'Var', (49, 62))	('oncogenesis', 'CPA', (134, 145))	('snoRNA', 'Gene', (75, 81))	('mutations', 'Var', (32, 41))
548512	32046192	Among the possible factors underlying snoRNA/host gene expression deregulation is copy number alteration (CNA).	('snoRNA', 'Gene', '6079', (38, 44))	('snoRNA', 'Gene', (38, 44))	('copy number', 'Var', (82, 93))
548532	32046192	Genetic instability is a common feature in many cancer types; genetic alterations involving protein-coding genes (among which are snoRNA host genes) are, in most cases, very well characterized.	('snoRNA', 'Gene', '6079', (130, 136))	('snoRNA', 'Gene', (130, 136))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('genetic alterations', 'Var', (62, 81))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('protein-coding', 'Protein', (92, 106))
548534	32046192	Growing evidence indicates that mutations and/or deregulation affecting snoRNAs may play a significant role in oncogenesis, even though the mechanism by which snoRNA deregulation ultimately contributes to cancer onset remains, in most cases, unknown.	('role', 'Reg', (103, 107))	('cancer', 'Disease', 'MESH:D009369', (205, 211))	('play', 'Reg', (84, 88))	('deregulation', 'Var', (49, 61))	('cancer', 'Disease', (205, 211))	('deregulation', 'Var', (166, 178))	('snoRNA', 'Gene', '6079', (159, 165))	('snoRNA', 'Gene', '6079', (72, 78))	('mutations', 'Var', (32, 41))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('oncogenesis', 'CPA', (111, 122))	('snoRNA', 'Gene', (72, 78))	('contributes', 'Reg', (190, 201))	('snoRNA', 'Gene', (159, 165))
548535	32046192	Deregulation of specific snoRNAs has been proposed to help in generating a cancer-prone setting by affecting different cancer-related cellular processes, like those controlling cellular growth, death, invasion and angiogenesis.	('death', 'Disease', (194, 199))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('Deregulation', 'Var', (0, 12))	('angiogenesis', 'CPA', (214, 226))	('affecting', 'Reg', (99, 108))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('cancer', 'Disease', (75, 81))	('cancer', 'Disease', (119, 125))	('snoRNA', 'Gene', (25, 31))	('snoRNA', 'Gene', '6079', (25, 31))	('death', 'Disease', 'MESH:D003643', (194, 199))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('invasion', 'CPA', (201, 209))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
548545	32046192	We calculated the overall percentage of samples with copy number alterations co-occurring in host genes and snoRNA that belonged to 295 pairs extracted from the snoDB database .	('copy number alterations', 'Var', (53, 76))	('snoRNA', 'Gene', (108, 114))	('snoRNA', 'Gene', '6079', (108, 114))
548553	32046192	For 39% of the couples no CNA was detected in any of the tumor types queried (Table S1), suggesting that CNAs in each of these genes might confer a disadvantage in cell growth; for 10% of the couples CNA was detected to some extent throughout all of the different tumor types, while for the remaining 51% CNA was found in some tumors and not in others (Figure 1a).	('tumor', 'Phenotype', 'HP:0002664', (264, 269))	('tumors', 'Disease', 'MESH:D009369', (327, 333))	('tumor', 'Phenotype', 'HP:0002664', (327, 332))	('tumors', 'Phenotype', 'HP:0002664', (327, 333))	('tumor', 'Disease', (264, 269))	('CNAs', 'Var', (105, 109))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('tumor', 'Disease', (327, 332))	('disadvantage', 'NegReg', (148, 160))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('cell growth', 'CPA', (164, 175))	('tumors', 'Disease', (327, 333))	('tumor', 'Disease', (57, 62))	('tumor', 'Disease', 'MESH:D009369', (264, 269))	('tumor', 'Disease', 'MESH:D009369', (327, 332))
548557	32046192	Indeed, when analyzing the CNA data for the snoRNA/host gene couples separately for each tumor type, it is clear that a co-occurrence of an amplification or deletion is not always the most frequent event.	('snoRNA', 'Gene', (44, 50))	('snoRNA', 'Gene', '6079', (44, 50))	('deletion', 'Var', (157, 165))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
548558	32046192	Indeed, there are cases where an amplification or deletion of the snoRNA does not co-occur with the same event in the host gene, and vice-versa (Figure 2a).	('snoRNA', 'Gene', (66, 72))	('deletion', 'Var', (50, 58))	('snoRNA', 'Gene', '6079', (66, 72))
548559	32046192	Co-occurrence of CNA happened for about half of the mutant couples in the majority of the tumors, with striking exceptions for KIRCs (where co-occurrence happens 3 times more frequently) and BRCAs (where in more than half of the couples, alterations are not co-occurring).	('mutant', 'Var', (52, 58))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('KIRC', 'Disease', (127, 131))	('BRCA', 'Gene', (191, 195))	('tumors', 'Disease', (90, 96))	('tumors', 'Disease', 'MESH:D009369', (90, 96))	('BRCA', 'Gene', '672', (191, 195))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('KIRC', 'Disease', 'MESH:C538614', (127, 131))
548565	32046192	Within each tumor type, the number of amplifications or deletions in the snoRNA only group, and in the co-occurrence group was summed.	('amplifications', 'Var', (38, 52))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('snoRNA', 'Gene', (73, 79))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('deletions', 'Var', (56, 65))	('tumor', 'Disease', (12, 17))	('snoRNA', 'Gene', '6079', (73, 79))
548573	32046192	Other couples recurring in multiple cancer types are SNORA15/CCT6A, altered in 5-12% of cases of HNSC, KIRC, SKCM, and UCEC; SNORA14B/TOMM20, altered in close to 20% of COADs and, to a lower extent, in OV, UCEC, and GMB; SNORD72/RPL37, altered in over 10% of SKCM and, to a lower extent (4-8%) in HNSC, KIRC, and UCEC; SNORA56 and SNORA36A/DKC1, mutated in 0.5-5% of HNSC, KIRC, BRCA, and UCEC patients; and SNORA70G/RAP1B, altered in 4-5% of patients in HNSC, KIRC, and UCEC.	('KIRC', 'Disease', 'MESH:C538614', (103, 107))	('SNORA36A', 'Gene', (331, 339))	('SNORA15', 'Gene', '677803', (53, 60))	('KIRC', 'Disease', 'MESH:C538614', (461, 465))	('BRCA', 'Gene', '672', (379, 383))	('multiple cancer', 'Disease', (27, 42))	('SNORD72', 'Gene', '619564', (221, 228))	('COAD', 'Disease', (169, 173))	('patients', 'Species', '9606', (443, 451))	('RAP1B', 'Gene', (417, 422))	('SNORA70G', 'Gene', (408, 416))	('SNORA36A', 'Gene', '677817', (331, 339))	('RAP1B', 'Gene', '5908', (417, 422))	('SNORA14B', 'Gene', (125, 133))	('SNORA15', 'Gene', (53, 60))	('SKCM', 'Disease', (109, 113))	('CCT6A', 'Gene', (61, 66))	('DKC1', 'Gene', (340, 344))	('BRCA', 'Gene', (379, 383))	('KIRC', 'Disease', (303, 307))	('SNORA70G', 'Gene', '100379132', (408, 416))	('patients', 'Species', '9606', (394, 402))	('SNORA56', 'Gene', '677835', (319, 326))	('mutated', 'Var', (346, 353))	('CCT6A', 'Gene', '908', (61, 66))	('SNORA56', 'Gene', (319, 326))	('DKC1', 'Gene', '1736', (340, 344))	('KIRC', 'Disease', (373, 377))	('COAD', 'Disease', 'MESH:D015179', (169, 173))	('SKCM', 'Disease', (259, 263))	('TOMM20', 'Gene', (134, 140))	('KIRC', 'Disease', (103, 107))	('KIRC', 'Disease', (461, 465))	('RPL37', 'Gene', '6167', (229, 234))	('SNORD72', 'Gene', (221, 228))	('multiple cancer', 'Disease', 'MESH:D009369', (27, 42))	('SKCM', 'Disease', 'MESH:C562393', (109, 113))	('TOMM20', 'Gene', '9804', (134, 140))	('RPL37', 'Gene', (229, 234))	('KIRC', 'Disease', 'MESH:C538614', (303, 307))	('SNORA14B', 'Gene', '677802', (125, 133))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('KIRC', 'Disease', 'MESH:C538614', (373, 377))	('SKCM', 'Disease', 'MESH:C562393', (259, 263))
548578	32046192	This may indicate that, in this specific pathology, alterations in snoRNAs and host genes may be related to a generalized genomic instability, and may therefore play a role as passenger mutations.	('snoRNA', 'Gene', '6079', (67, 73))	('snoRNA', 'Gene', (67, 73))	('related', 'Reg', (97, 104))	('alterations', 'Var', (52, 63))	('play', 'Reg', (161, 165))
548580	32046192	We reasoned that copy number alterations likely impacts upon the differential expression of snoRNAs and host genes.	('impacts', 'Reg', (48, 55))	('expression', 'MPA', (78, 88))	('copy number alterations', 'Var', (17, 40))	('snoRNA', 'Gene', (92, 98))	('snoRNA', 'Gene', '6079', (92, 98))
548591	32046192	Furthermore, it is worthwhile to note that less than half of the over-expressed targets are present in the shortlist of the couples undergoing CNA, suggesting that, in many cases, large amplifications and deletions of snoRNAs and of their host genes do not directly impact upon their expression.	('deletions', 'Var', (205, 214))	('snoRNA', 'Gene', (218, 224))	('expression', 'MPA', (284, 294))	('snoRNA', 'Gene', '6079', (218, 224))
548592	32046192	Somatic DNA copy number alterations (CNA) are nearly ubiquitous in cancer and alter a greater portion of the cancer genome than any other type of somatic genetic alteration, playing important roles in oncogenesis and cancer therapy.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('alter', 'Reg', (78, 83))	('cancer', 'Disease', (67, 73))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('cancer', 'Disease', (109, 115))	('cancer', 'Disease', (217, 223))	('copy number alterations', 'Var', (12, 35))	('cancer', 'Disease', 'MESH:D009369', (217, 223))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))
548605	32046192	This event was found more frequently in the sense of CNA of the host gene as opposed to the snoRNA, but in some cases also in the converse direction.	('snoRNA', 'Gene', (92, 98))	('snoRNA', 'Gene', '6079', (92, 98))	('CNA', 'Var', (53, 56))
548612	32046192	Even though further studies are necessary to shed light on this matter, a role for EIF4A2 in lung cancer and in other cancer types has been previously proposed, indicating that these mutations might have a driver, rather than passenger, role in tumorigenesis.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('cancer', 'Disease', (118, 124))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('mutations', 'Var', (183, 192))	('lung cancer', 'Disease', 'MESH:D008175', (93, 104))	('tumor', 'Disease', 'MESH:D009369', (245, 250))	('lung cancer', 'Phenotype', 'HP:0100526', (93, 104))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('tumor', 'Phenotype', 'HP:0002664', (245, 250))	('cancer', 'Disease', (98, 104))	('EIF4A2', 'Gene', (83, 89))	('tumor', 'Disease', (245, 250))	('lung cancer', 'Disease', (93, 104))	('EIF4A2', 'Gene', '1974', (83, 89))
548625	32046192	However, with the exception of the few selected cases discussed above, for most of the observed alterations precise mechanistic insights regarding their role in tumorigenesis are currently lacking.	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('alterations', 'Var', (96, 107))	('tumor', 'Disease', (161, 166))	('tumor', 'Disease', 'MESH:D009369', (161, 166))
548628	32046192	To understand how alterations of snoRNA genes can contribute to cancer, new studies implementing adequate technical approaches on tumor material of human origin are required to allow for the characterization of the biological significance of mutation and/or alteration of the expression of snoRNAs and their host genes.	('snoRNA', 'Gene', (33, 39))	('snoRNA', 'Gene', '6079', (33, 39))	('alterations', 'Var', (18, 29))	('contribute', 'Reg', (50, 60))	('snoRNA', 'Gene', (290, 296))	('snoRNA', 'Gene', '6079', (290, 296))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('human', 'Species', '9606', (148, 153))	('alteration', 'Var', (258, 268))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('tumor', 'Disease', (130, 135))	('mutation', 'Var', (242, 250))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
548639	30558663	Furthermore, the cytotoxicity of chimeric antigen receptor T cells against various cancer cells was further augmented by invariant natural killer T cells.	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('cytotoxicity', 'Disease', (17, 29))	('chimeric', 'Var', (33, 41))	('augmented', 'PosReg', (108, 117))	('cancer', 'Disease', 'MESH:D009369', (83, 89))	('cytotoxicity', 'Disease', 'MESH:D064420', (17, 29))	('cancer', 'Disease', (83, 89))
548686	30558663	After 72 h of incubation, the cells were collected and stained with anti-mouse IgG, anti-Valpha24, anti-CD8 and 7AAD.	('IgG', 'Protein', (79, 82))	('CD8', 'Gene', (104, 107))	('mouse', 'Species', '10090', (73, 78))	('7AAD', 'Chemical', 'MESH:C025942', (112, 116))	('anti-Valpha24', 'Var', (84, 97))	('CD8', 'Gene', '925', (104, 107))
548745	29206174	A Looking-Glass of Non-Coding RNAs in Oral Cancer Oral cancer is a multifactorial pathology and is characterized by the lack of efficient treatment and accurate diagnostic tools.	('Oral Cancer', 'Disease', 'MESH:D009062', (38, 49))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('Oral Cancer', 'Disease', (38, 49))	('Oral cancer', 'Disease', (50, 61))	('Cancer Oral cancer', 'Phenotype', 'HP:0100649', (43, 61))	('Non-Coding RNAs', 'Var', (19, 34))	('Oral cancer', 'Disease', 'MESH:D009062', (50, 61))	('men', 'Species', '9606', (143, 146))	('Cancer', 'Phenotype', 'HP:0002664', (43, 49))
548756	29206174	Cancer, including OSCC, is regarded as a multifactorial disease, thought to be the result of various genetic modifications that induce the activation of oncogenes and silencing of tumor suppressor genes.	('tumor', 'Disease', 'MESH:D009369', (180, 185))	('tumor', 'Phenotype', 'HP:0002664', (180, 185))	('activation', 'PosReg', (139, 149))	('tumor', 'Disease', (180, 185))	('oncogenes', 'Protein', (153, 162))	('Cancer', 'Disease', (0, 6))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('silencing', 'Var', (167, 176))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('OSCC', 'Disease', (18, 22))
548757	29206174	Nevertheless, there is increased evidence that deregulated epigenetic mechanisms in association with genetic alterations play a compelling role in the development and progression of human cancers.	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('human', 'Species', '9606', (182, 187))	('cancers', 'Phenotype', 'HP:0002664', (188, 195))	('deregulated epigenetic', 'Var', (47, 69))	('cancers', 'Disease', (188, 195))	('cancers', 'Disease', 'MESH:D009369', (188, 195))	('men', 'Species', '9606', (158, 161))	('epigenetic', 'Var', (59, 69))
548776	29206174	If the sequence complementarity between the miRNA and its target mRNA is faultless, it will lead to endonucleolytic cleavage and mRNA degradation via the RISC complex.	('miR', 'Gene', '220972', (44, 47))	('miR', 'Gene', (44, 47))	('faultless', 'Var', (73, 82))	('sequence complementarity', 'Var', (7, 31))	('lead to', 'Reg', (92, 99))	('endonucleolytic cleavage', 'MPA', (100, 124))	('men', 'Species', '9606', (22, 25))	('mRNA degradation', 'MPA', (129, 145))
548790	29206174	Since they are involved in basically all biological processes, aberrant miRNA expression can trigger the initiation of numerous diseases, including cancer.	('cancer', 'Disease', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('aberrant', 'Var', (63, 71))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('trigger', 'Reg', (93, 100))	('miR', 'Gene', '220972', (72, 75))	('initiation of numerous diseases', 'Disease', (105, 136))	('miR', 'Gene', (72, 75))	('initiation of numerous diseases', 'Disease', 'MESH:D007319', (105, 136))
548816	29206174	At the same time, a negative correlation was observed between miR-125b and p53 expression level, and between TP53 mutation status and miR-125b.	('miR', 'Gene', '220972', (134, 137))	('miR', 'Gene', '220972', (62, 65))	('mutation status', 'Var', (114, 129))	('negative', 'NegReg', (20, 28))	('miR', 'Gene', (62, 65))	('miR', 'Gene', (134, 137))	('TP53', 'Gene', '7157', (109, 113))	('p53', 'Gene', (75, 78))	('p53', 'Gene', '7157', (75, 78))	('TP53', 'Gene', (109, 113))
548826	29206174	In TSCC cell lines, miR-138 deregulation was also correlated to increased proliferation.	('TSCC', 'Phenotype', 'HP:0030413', (3, 7))	('deregulation', 'Var', (28, 40))	('miR', 'Gene', '220972', (20, 23))	('miR', 'Gene', (20, 23))	('proliferation', 'CPA', (74, 87))	('increased', 'PosReg', (64, 73))
548840	29206174	A recent paper shows that Puma (p53 upregulated modulator of apoptosis) is a direct target of miR-222, and that the downregulation of miR-222 reduces cell growth and induces apoptosis in oral cancer, probably by the direct upregulation of Puma expression.	('downregulation', 'Var', (116, 130))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('miR-222', 'Gene', (134, 141))	('apoptosis', 'CPA', (174, 183))	('reduces', 'NegReg', (142, 149))	('p53', 'Gene', (32, 35))	('p53', 'Gene', '7157', (32, 35))	('miR-222', 'Gene', '407007', (94, 101))	('cell growth', 'CPA', (150, 161))	('induces', 'Reg', (166, 173))	('oral cancer', 'Disease', 'MESH:D009062', (187, 198))	('oral cancer', 'Disease', (187, 198))	('miR-222', 'Gene', (94, 101))	('miR-222', 'Gene', '407007', (134, 141))
548842	29206174	There is evidence that inhibition of Stat3 produces suppression of miR-21, resulting in the upregulation of Pten, Pdcd4, and Timp-3 and, cell growth suppression.	('Timp-3', 'Gene', (125, 131))	('Timp-3', 'Gene', '7078', (125, 131))	('miR-21', 'Gene', '406991', (67, 73))	('inhibition', 'Var', (23, 33))	('Stat3', 'Gene', (37, 42))	('Pdcd4', 'Gene', (114, 119))	('suppression', 'NegReg', (52, 63))	('Stat3', 'Gene', '6774', (37, 42))	('cell growth suppression', 'CPA', (137, 160))	('upregulation', 'PosReg', (92, 104))	('Pdcd4', 'Gene', '27250', (114, 119))	('miR-21', 'Gene', (67, 73))	('Pten', 'Gene', '5728', (108, 112))	('Pten', 'Gene', (108, 112))
548849	29206174	Transfection with these two miRNAs in OSCC cells was shown to reduce cell growth, partly via caspase-mediated apoptosis.	('reduce', 'NegReg', (62, 68))	('Transfection', 'Var', (0, 12))	('miR', 'Gene', '220972', (28, 31))	('miR', 'Gene', (28, 31))	('caspase-mediated apoptosis', 'CPA', (93, 119))	('cell growth', 'CPA', (69, 80))
548850	29206174	Furthermore, the mTOR component Rictor is a target of miR-218 and, probably, the overexpression of Rictor through silencing of miR-218 leads to the activation of the Tor-Akt pathway, ultimately contributing to oral carcinogenesis.	('contributing to', 'Reg', (194, 209))	('miR-21', 'Gene', (127, 133))	('Rictor', 'Gene', (32, 38))	('activation', 'PosReg', (148, 158))	('Rictor', 'Gene', '253260', (99, 105))	('mTOR', 'Gene', (17, 21))	('Tor', 'Gene', (166, 169))	('miR-21', 'Gene', (54, 60))	('oral carcinogenesis', 'Disease', (210, 229))	('mTOR', 'Gene', '2475', (17, 21))	('Tor', 'Gene', '6097', (166, 169))	('Rictor', 'Gene', '253260', (32, 38))	('Rictor', 'Gene', (99, 105))	('overexpression', 'PosReg', (81, 95))	('Akt', 'Gene', (170, 173))	('miR-21', 'Gene', '406991', (127, 133))	('Akt', 'Gene', '207', (170, 173))	('silencing', 'Var', (114, 123))	('miR-21', 'Gene', '406991', (54, 60))	('oral carcinogenesis', 'Disease', 'MESH:D063646', (210, 229))
548853	29206174	Silencing of miR-126 also correlates with oral carcinogenesis through the activation of angiogenesis and lymphangiogenesis in oral tumors.	('miR-126', 'Gene', '406913', (13, 20))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('lymphangiogenesis', 'CPA', (105, 122))	('miR-126', 'Gene', (13, 20))	('angiogenesis', 'CPA', (88, 100))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('oral tumors', 'Phenotype', 'HP:0100649', (126, 137))	('activation', 'PosReg', (74, 84))	('oral carcinogenesis', 'Disease', 'MESH:D063646', (42, 61))	('oral carcinogenesis', 'Disease', (42, 61))	('oral tumors', 'Disease', 'MESH:D020820', (126, 137))	('Silencing', 'Var', (0, 9))	('oral tumors', 'Disease', (126, 137))
548861	29206174	MiR-21 is also involved in promoting migration and invasion in OSCC by targeting and downregulating Pdcd4 expression, correlated with poor overall survival rates.	('MiR-21', 'Gene', (0, 6))	('downregulating', 'NegReg', (85, 99))	('targeting', 'Var', (71, 80))	('promoting', 'PosReg', (27, 36))	('expression', 'MPA', (106, 116))	('Pdcd4', 'Gene', (100, 105))	('Pdcd4', 'Gene', '27250', (100, 105))	('migration', 'CPA', (37, 46))	('MiR-21', 'Gene', '406991', (0, 6))	('invasion', 'CPA', (51, 59))	('OSCC', 'Disease', (63, 67))
548870	29206174	Oncogenic miR-146a is correlated with tumorigenesis and metastasis in OSCC.	('metastasis', 'CPA', (56, 66))	('tumor', 'Disease', (38, 43))	('OSCC', 'Disease', (70, 74))	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('miR-146a', 'Gene', (10, 18))	('correlated', 'Reg', (22, 32))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('Oncogenic', 'Var', (0, 9))	('miR-146a', 'Gene', '406938', (10, 18))
548877	29206174	Tumor suppressor miR-491-5p exerts its role in repressing OSCC metastasis by targeting Git1, which leads to the perturbation of FAK/paxilin and ERK1/2 signaling along with MMP2/9 expression and activity.	('paxilin', 'Chemical', '-', (132, 139))	('MMP2/9', 'Gene', '4313;4318', (172, 178))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('ERK1/2', 'Gene', (144, 150))	('repressing OSCC', 'Disease', (47, 62))	('targeting', 'Var', (77, 86))	('perturbation', 'NegReg', (112, 124))	('ERK1/2', 'Gene', '5595;5594', (144, 150))	('miR-491', 'Gene', '574444', (17, 24))	('Git1', 'Gene', (87, 91))	('MMP2/9', 'Gene', (172, 178))	('miR-491', 'Gene', (17, 24))	('FAK', 'Gene', '5747', (128, 131))	('5p', 'Chemical', '-', (25, 27))	('Git1', 'Gene', '28964', (87, 91))	('FAK', 'Gene', (128, 131))	('OSCC', 'Disease', (58, 62))
548881	29206174	Of these, 5 were correlated with patient survival rates, namely piR-35953, piR-36984, piR-39592, piR-36715 and piR-30506.	('patient', 'Species', '9606', (33, 40))	('piR-36715', 'Var', (97, 106))	('piR-35953', 'Var', (64, 73))	('piR-36984', 'Var', (75, 84))	('piR-39592', 'Var', (86, 95))	('piR-30506', 'Var', (111, 120))
548883	29206174	Recently, a panel of 13 piRNAs was identified in OSCC related to smoking, from which NONHSAT123636 and NONHSAT113708 are directly correlated with tumor stage, along with NONHSAT067200, which predicts the patient survival rate.	('patient', 'Species', '9606', (204, 211))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('related', 'Reg', (54, 61))	('NONHSAT123636', 'Var', (85, 98))	('tumor', 'Disease', (146, 151))	('NONHSAT113708', 'Var', (103, 116))	('correlated', 'Reg', (130, 140))	('OSCC', 'Disease', (49, 53))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
548896	29206174	The expression of Meg-3 is significantly affected by the degree of DNA methylation, with important role in patient prognostic.	('DNA', 'Var', (67, 70))	('expression', 'MPA', (4, 14))	('affected', 'Reg', (41, 49))	('Meg-3', 'Gene', (18, 23))	('patient', 'Species', '9606', (107, 114))	('Meg-3', 'Gene', '55384', (18, 23))
548906	29206174	In the case of Hotair, certain genetic alterations (rs920778, uc003opf.1, and rs11752942) were related with head and neck cancer susceptibility.	('Hotair', 'Gene', (15, 21))	('rs11752942', 'Var', (78, 88))	('rs920778', 'Mutation', 'rs920778', (52, 60))	('related', 'Reg', (95, 102))	('head and neck cancer', 'Phenotype', 'HP:0012288', (108, 128))	('rs11752942', 'Mutation', 'rs11752942', (78, 88))	('rs920778', 'Var', (52, 60))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('head and neck cancer', 'Disease', 'MESH:D006258', (108, 128))	('Hotair', 'Gene', '100124700', (15, 21))
548916	29206174	The loss of this RNA expression causes cell growth and proliferation in human cancers, thus supporting the claim that Meg3 is a tumor suppressor lncRNA.	('ncRNA', 'Gene', '220202', (146, 151))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('human', 'Species', '9606', (72, 77))	('cancers', 'Disease', 'MESH:D009369', (78, 85))	('cancers', 'Phenotype', 'HP:0002664', (78, 85))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('cancers', 'Disease', (78, 85))	('RNA', 'Gene', (17, 20))	('cell growth', 'CPA', (39, 50))	('ncRNA', 'Gene', (146, 151))	('tumor', 'Disease', (128, 133))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('Meg3', 'Gene', '55384', (118, 122))	('Meg3', 'Gene', (118, 122))	('causes', 'Reg', (32, 38))	('loss', 'Var', (4, 8))
548929	29206174	CircRNA-100290 is upregulated in oral cancer tissue and it induces cancer progression by sponging the miR-29 family members.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('oral cancer', 'Disease', (33, 44))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('miR', 'Gene', '220972', (102, 105))	('cancer', 'Disease', (67, 73))	('miR', 'Gene', (102, 105))	('induces', 'Reg', (59, 66))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('cancer', 'Disease', (38, 44))	('upregulated', 'PosReg', (18, 29))	('oral cancer', 'Disease', 'MESH:D009062', (33, 44))	('CircRNA-100290', 'Var', (0, 14))
548939	29206174	Exosomes cargo in oral cancer was related to viral contamination, and thought to affect the microenvironment.	('men', 'Species', '9606', (104, 107))	('oral cancer', 'Disease', 'MESH:D009062', (18, 29))	('affect', 'Reg', (81, 87))	('oral cancer', 'Disease', (18, 29))	('related', 'Reg', (34, 41))	('Exosomes', 'Var', (0, 8))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))
548951	29206174	The various miRNAs, each with its own palette of targeted genes, acts on various signaling pathways that sustain oral cancer hallmarks, such as apoptosis evasion, sustained proliferation, autonomous growth, angiogenesis, invasion and metastasis, which is why microRNAs are commonly regarded as the best candidates for developing new cancer therapies.	('signaling pathways', 'Pathway', (81, 99))	('cancer', 'Disease', (118, 124))	('angiogenesis', 'CPA', (207, 219))	('metastasis', 'CPA', (234, 244))	('oral cancer hallmarks', 'Disease', (113, 134))	('sustained proliferation', 'CPA', (163, 186))	('invasion', 'CPA', (221, 229))	('cancer', 'Disease', 'MESH:D009369', (333, 339))	('oral cancer hallmarks', 'Disease', 'MESH:D009062', (113, 134))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('apoptosis', 'CPA', (144, 153))	('cancer', 'Disease', (333, 339))	('genes', 'Var', (58, 63))	('cancer', 'Phenotype', 'HP:0002664', (333, 339))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('miR', 'Gene', '220972', (12, 15))	('autonomous growth', 'CPA', (188, 205))	('miR', 'Gene', (12, 15))
548965	28686671	Thus far, the majority of ctDNA studies have focused on detection of tumor-specific point mutations after cancer diagnosis for the purpose of post-treatment surveillance.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('point mutations', 'Var', (84, 99))	('tumor', 'Disease', (69, 74))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('cancer', 'Disease', (106, 112))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
548977	28686671	A series of studies have demonstrated the ability to detect tumor derived genetic aberrations in circulating free DNA (cfDNA).	('genetic aberrations', 'Var', (74, 93))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Disease', (60, 65))	('tumor', 'Disease', 'MESH:D009369', (60, 65))
548982	28686671	Copy number variations (CNVs), like point mutations, are common and causal for a large proportion of cancer types.	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('causal', 'Reg', (68, 74))	('cancer', 'Disease', (101, 107))	('Copy number variations', 'Var', (0, 22))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('point mutations', 'Disease', (36, 51))
548998	28686671	Cancer CNVs, especially amplifications, often exceed a single copy gained or lost.	('lost', 'NegReg', (77, 81))	('amplifications', 'Var', (24, 38))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))
549019	28686671	The random forest was also readily capable of detecting the presence of cancer as expected: TPR of 0.854 and PPV of 0.997 at 100 Mb ctDNA CNV resolution and TPR of 0.895 and PPV of 0.995 at 5 Mb resolution (Fig 4B).	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('TPR', 'Var', (92, 95))	('cancer', 'Disease', (72, 78))
549028	28686671	Most cancer types demonstrate a PPV of >80% at even coarse grain resolution (100Mb) outpacing the PPV of diagnostic tests currently used in clinical practice.	('100Mb', 'Var', (77, 82))	('cancer', 'Disease', (5, 11))	('cancer', 'Disease', 'MESH:D009369', (5, 11))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))
549046	28686671	However, the unbiased nature of ctDNA sequencing can create challenges for clinical follow-up given that individual cancer mutations, especially point mutations, are not quite as cancer type specific as serum tumor markers.	('tumor', 'Disease', (209, 214))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('point mutations', 'Var', (145, 160))	('tumor', 'Disease', 'MESH:D009369', (209, 214))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cancer', 'Disease', (179, 185))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))	('mutations', 'Var', (123, 132))
549047	28686671	Since there is a large degree of overlap in the recurrent point mutations that drive common cancer types, point mutations tend to be the least useful molecular determinant of tissue of origin.	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('cancer', 'Disease', (92, 98))	('point mutations', 'Var', (58, 73))	('cancer', 'Disease', 'MESH:D009369', (92, 98))
549080	33129231	PR-619 could inhibit ESCC cell growth and induce G2/M cell cycle arrest by downregulating cyclin B1 and upregulating p21.	('arrest', 'Disease', 'MESH:D006323', (65, 71))	('PR-619', 'Var', (0, 6))	('induce', 'PosReg', (42, 48))	('p21', 'Gene', (117, 120))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (54, 71))	('cyclin B1', 'Gene', '891', (90, 99))	('upregulating', 'PosReg', (104, 116))	('ESCC', 'Disease', (21, 25))	('arrest', 'Disease', (65, 71))	('cyclin B1', 'Gene', (90, 99))	('p21', 'Gene', '644914', (117, 120))	('downregulating', 'NegReg', (75, 89))	('inhibit', 'NegReg', (13, 20))	('PR-619', 'Chemical', 'MESH:C570894', (0, 6))
549081	33129231	Meanwhile, PR-619 led to the accumulation of ubiquitylated proteins, induced ER stress and triggered apoptosis by the ATF4-Noxa axis.	('PR-619', 'Var', (11, 17))	('ATF4', 'Gene', (118, 122))	('Noxa', 'Gene', '5366', (123, 127))	('Noxa', 'Gene', (123, 127))	('accumulation', 'PosReg', (29, 41))	('ER stress', 'MPA', (77, 86))	('ATF4', 'Gene', '468', (118, 122))	('ubiquitylated proteins', 'MPA', (45, 67))	('apoptosis', 'CPA', (101, 110))	('induced', 'Reg', (69, 76))	('triggered', 'Reg', (91, 100))	('PR-619', 'Chemical', 'MESH:C570894', (11, 17))
549083	33129231	Ubiquitin E1 inhibitor, PYR-41, could reduce the accumulation of ubi-proteins and alleviate ER stress, G2/M cell cycle arrest, apoptosis and autophagy in PR-619-treated ESCC cells.	('arrest', 'Disease', (119, 125))	('alleviate', 'NegReg', (82, 91))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (108, 125))	('autophagy', 'CPA', (141, 150))	('ER stress', 'MPA', (92, 101))	('apoptosis', 'CPA', (127, 136))	('PYR-41', 'Var', (24, 30))	('reduce', 'NegReg', (38, 44))	('PYR-41', 'Chemical', 'MESH:C523934', (24, 30))	('arrest', 'Disease', 'MESH:D006323', (119, 125))	('PR-619', 'Chemical', 'MESH:C570894', (154, 160))	('accumulation of ubi-proteins', 'MPA', (49, 77))
549084	33129231	Furthermore, blocking autophagy by chloroquine or bafilomycin A1 enhanced the cell growth inhibition effect and apoptosis induced by PR-619.	('apoptosis', 'CPA', (112, 121))	('bafilomycin A1', 'Chemical', 'MESH:C040929', (50, 64))	('cell growth inhibition effect', 'CPA', (78, 107))	('enhanced', 'PosReg', (65, 73))	('chloroquine', 'Chemical', 'MESH:D002738', (35, 46))	('PR-619', 'Chemical', 'MESH:C570894', (133, 139))	('blocking', 'NegReg', (13, 21))	('autophagy', 'CPA', (22, 31))	('PR-619', 'Var', (133, 139))
549086	33129231	PR-619 could inhibit oesophageal squamous cell carcinoma cell growth and induce G2/M cell cycle arrest by downregulating the expression of cyclin B1 and upregulating the protein level of p21.	('PR-619', 'Var', (0, 6))	('arrest', 'Disease', 'MESH:D006323', (96, 102))	('carcinoma', 'Phenotype', 'HP:0030731', (47, 56))	('cyclin B1', 'Gene', '891', (139, 148))	('cyclin B1', 'Gene', (139, 148))	('inhibit', 'NegReg', (13, 20))	('induce', 'PosReg', (73, 79))	('upregulating', 'PosReg', (153, 165))	('PR-619', 'Chemical', 'MESH:C570894', (0, 6))	('downregulating', 'NegReg', (106, 120))	('protein level', 'MPA', (170, 183))	('p21', 'Gene', (187, 190))	('expression', 'MPA', (125, 135))	('p21', 'Gene', '644914', (187, 190))	('oesophageal squamous cell carcinoma', 'Disease', (21, 56))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (33, 56))	('arrest', 'Disease', (96, 102))	('oesophageal squamous cell carcinoma', 'Disease', 'MESH:D002294', (21, 56))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (85, 102))
549097	33129231	Inactivation of DUBs by inhibitors showed promising antitumour activity in multiple tumours.	('antitumour activity', 'CPA', (52, 71))	('tumours', 'Disease', 'MESH:D009369', (84, 91))	('tumours', 'Disease', (84, 91))	('DUBs', 'Gene', (16, 20))	('tumours', 'Phenotype', 'HP:0002664', (84, 91))	('Inactivation', 'Var', (0, 12))
549098	33129231	P5091 significantly inhibited cell growth of ovarian cancer, 19  oesophageal cancer 15  and colorectal cancer 20  in vitro and in vivo.	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('ovarian cancer', 'Phenotype', 'HP:0100615', (45, 59))	('colorectal cancer', 'Disease', 'MESH:D015179', (92, 109))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('inhibited', 'NegReg', (20, 29))	('P5091', 'Var', (0, 5))	('oesophageal cancer', 'Disease', (65, 83))	('cell growth', 'CPA', (30, 41))	('oesophageal cancer', 'Disease', 'MESH:D009369', (65, 83))	('ovarian cancer', 'Disease', 'MESH:D010051', (45, 59))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('colorectal cancer', 'Phenotype', 'HP:0003003', (92, 109))	('ovarian cancer', 'Disease', (45, 59))	('colorectal cancer', 'Disease', (92, 109))
549099	33129231	Meanwhile, P5091 induced apoptosis in multiple myeloma cells resistant to conventional and Bortezomib therapies.	('multiple myeloma', 'Disease', 'MESH:D009101', (38, 54))	('Bortezomib', 'Chemical', 'MESH:D000069286', (91, 101))	('multiple myeloma', 'Disease', (38, 54))	('apoptosis', 'CPA', (25, 34))	('P5091', 'Var', (11, 16))	('multiple myeloma', 'Phenotype', 'HP:0006775', (38, 54))
549101	33129231	21  And then, b-AP15 was identified as an anti-cancer deubiquitinase inhibitor in many cancers.	('cancer', 'Disease', (87, 93))	('cancers', 'Disease', (87, 94))	('b-AP15', 'Var', (14, 20))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('cancer', 'Disease', (47, 53))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cancers', 'Phenotype', 'HP:0002664', (87, 94))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('cancers', 'Disease', 'MESH:D009369', (87, 94))
549109	33129231	33  More recently, Kuo et al reported that PR-619 could effectively induce dose- and time-dependent cytotoxicity and ER stress-related apoptosis in metastatic bladder urothelial carcinoma (UC) and potentiate cisplatin-induced cytotoxicity in UC.	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (159, 187))	('induce', 'PosReg', (68, 74))	('bladder urothelial carcinoma', 'Disease', (159, 187))	('PR-619', 'Chemical', 'MESH:C570894', (43, 49))	('cytotoxicity', 'Disease', (226, 238))	('cisplatin', 'Chemical', 'MESH:D002945', (208, 217))	('PR-619', 'Var', (43, 49))	('cytotoxicity', 'Disease', (100, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (178, 187))	('cytotoxicity', 'Disease', 'MESH:D064420', (226, 238))	('potentiate', 'PosReg', (197, 207))	('cytotoxicity', 'Disease', 'MESH:D064420', (100, 112))
549115	33129231	Ubiquitin E1 inhibitor, PYR-41, could reduce the accumulation of ubiquitinated proteins and alleviate ER stress, G2/M cell cycle arrest, apoptosis and autophagy.	('arrest', 'Disease', (129, 135))	('alleviate', 'NegReg', (92, 101))	('apoptosis', 'CPA', (137, 146))	('autophagy', 'CPA', (151, 160))	('accumulation of ubiquitinated proteins', 'MPA', (49, 87))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (118, 135))	('ER stress', 'MPA', (102, 111))	('PYR-41', 'Var', (24, 30))	('reduce', 'NegReg', (38, 44))	('arrest', 'Disease', 'MESH:D006323', (129, 135))	('PYR-41', 'Chemical', 'MESH:C523934', (24, 30))
549133	33129231	Cell lysates were prepared for Western blotting analysis, with antibodies against p21, p-WEE1 (Ser642), WEE1, Cyclin B1, p-Histone H3 (Ser10), Cdc25c, ATF4, BiP, p-ACC(Ser79), ACC, LC3, p-eIF2alpha (Ser51), eIF2alpha, FOXO3a, cleaved CASP9, cleaved CASP3, cleaved PARP, PARP, Bax, Bak, Bcl-xl, Mcl-1, XIAP, CIAP1, CIAP2 (Cell Signaling Technology, Inc, Boston, MA), Noxa (Millipore, Billerica, MA), c-Myc and Ub (Santa Cruz Biotechnology, Santa Cruz, CA), HIF-1alpha and AMPKalpha (Abgent, Shanghai, China), p-AMPKalpha (Thr172), Histone H3, Capase3 and Capase9 (Beyotime, China).	('p21', 'Gene', '644914', (82, 85))	('Noxa', 'Gene', (366, 370))	('AMPKalpha', 'Chemical', '-', (510, 519))	('CASP3', 'Gene', '836', (249, 254))	('eIF2alpha', 'Gene', (207, 216))	('c-Myc', 'Gene', (399, 404))	('WEE1', 'Gene', '7465', (89, 93))	('CASP9', 'Gene', (234, 239))	('HIF-1alpha', 'Gene', '3091', (456, 466))	('p-ACC', 'Chemical', '-', (162, 167))	('Capase9', 'Gene', (554, 561))	('eIF2alpha', 'Gene', '83939', (207, 216))	('AMPKalpha', 'Chemical', '-', (471, 480))	('c-Myc', 'Gene', '4609', (399, 404))	('CIAP2', 'Gene', (314, 319))	('LC3', 'Gene', (181, 184))	('PARP', 'Gene', '1302', (264, 268))	('CASP9', 'Gene', '842', (234, 239))	('BiP', 'Gene', (157, 160))	('PARP', 'Gene', '1302', (270, 274))	('BiP', 'Gene', '2662', (157, 160))	('XIAP', 'Gene', '331', (301, 305))	('p21', 'Gene', (82, 85))	('Bak', 'Gene', '578', (281, 284))	('WEE1', 'Gene', (104, 108))	('Ser10', 'Chemical', '-', (135, 140))	('eIF2alpha', 'Gene', (188, 197))	('HIF-1alpha', 'Gene', (456, 466))	('Bax', 'Gene', (276, 279))	('CIAP1', 'Gene', '329', (307, 312))	('eIF2alpha', 'Gene', '83939', (188, 197))	('CIAP2', 'Gene', '330', (314, 319))	('ATF4', 'Gene', (151, 155))	('Bax', 'Gene', '581', (276, 279))	('Cyclin B1', 'Gene', (110, 119))	('PARP', 'Gene', (264, 268))	('Cdc25c', 'Gene', (143, 149))	('PARP', 'Gene', (270, 274))	('WEE1', 'Gene', (89, 93))	('ATF4', 'Gene', '468', (151, 155))	('FOXO3a', 'Gene', (218, 224))	('Cyclin B1', 'Gene', '891', (110, 119))	('Noxa', 'Gene', '5366', (366, 370))	('CIAP1', 'Gene', (307, 312))	('p-AMPKalpha', 'Chemical', '-', (508, 519))	('LC3', 'Gene', '84557', (181, 184))	('Bcl-xl', 'Gene', '598', (286, 292))	('Thr172', 'Chemical', '-', (521, 527))	('p-AMPKalpha', 'Var', (508, 519))	('Bak', 'Gene', (281, 284))	('XIAP', 'Gene', (301, 305))	('WEE1', 'Gene', '7465', (104, 108))	('Cdc25c', 'Gene', '995', (143, 149))	('CASP3', 'Gene', (249, 254))	('Bcl-xl', 'Gene', (286, 292))	('FOXO3a', 'Gene', '2309', (218, 224))
549150	33129231	Results showed that PR-619 inhibited the growth of ESCC cells Kyse30, Kyse450, EC1 and EC109, as evidenced by dose-dependent inhibition of cell proliferation (Figure 1A) and colony formation (Figure 1B).	('PR-619', 'Var', (20, 26))	('EC1', 'Gene', '4819', (79, 82))	('EC1', 'Gene', (79, 82))	('colony formation', 'CPA', (174, 190))	('EC1', 'Gene', '4819', (87, 90))	('EC1', 'Gene', (87, 90))	('Kyse30', 'Var', (62, 68))	('cell proliferation', 'CPA', (139, 157))	('inhibited', 'NegReg', (27, 36))	('growth', 'MPA', (41, 47))	('PR-619', 'Chemical', 'MESH:C570894', (20, 26))	('Kyse450', 'Var', (70, 77))	('inhibition', 'NegReg', (125, 135))
549153	33129231	Results showed that PR-619 induced the phosphorylation of Wee1 (inhibitor of G2-M phase transition 38 ,  39 ), increased the protein level of p21 and decreased the expression of cyclin B1 and p-Histone H3, a hallmark of M-phase cells 39 ,  40  (Figure 1D), while PR-619 treatment has no obvious effect on the expression of Cdc25c (an essential regulator of G2/M transition 41 ,  42 ) and the total protein level of Wee1 and Histone H3 (Figure 1D).	('Cdc25c', 'Gene', (323, 329))	('PR-619', 'Chemical', 'MESH:C570894', (263, 269))	('PR-619', 'Var', (20, 26))	('Wee1', 'Gene', (415, 419))	('p-Histone', 'MPA', (192, 201))	('Wee1', 'Gene', (58, 62))	('Cdc25c', 'Gene', '995', (323, 329))	('p21', 'Gene', (142, 145))	('protein level', 'MPA', (125, 138))	('p21', 'Gene', '644914', (142, 145))	('cyclin B1', 'Gene', '891', (178, 187))	('decreased', 'NegReg', (150, 159))	('cyclin B1', 'Gene', (178, 187))	('phosphorylation', 'MPA', (39, 54))	('Wee1', 'Gene', '7465', (415, 419))	('Wee1', 'Gene', '7465', (58, 62))	('PR-619', 'Chemical', 'MESH:C570894', (20, 26))	('increased', 'PosReg', (111, 120))	('expression', 'MPA', (164, 174))
549157	33129231	Besides, PR-619 effectively induced the cleavage of CASP9, CASP3 and PARP (Figure 2D).	('CASP3', 'Gene', '836', (59, 64))	('CASP9', 'Gene', (52, 57))	('CASP3', 'Gene', (59, 64))	('PR-619', 'Var', (9, 15))	('PARP', 'Gene', '1302', (69, 73))	('PR-619', 'Chemical', 'MESH:C570894', (9, 15))	('CASP9', 'Gene', '842', (52, 57))	('PARP', 'Gene', (69, 73))	('induced', 'Reg', (28, 35))	('cleavage', 'MPA', (40, 48))
549158	33129231	These results suggested that PR-619 triggered apoptosis in ESCC cells.	('apoptosis', 'CPA', (46, 55))	('PR-619', 'Var', (29, 35))	('PR-619', 'Chemical', 'MESH:C570894', (29, 35))
549167	33129231	Furthermore, knockdown of ATF4 rescued PR-619-induced apoptosis (Figure 3D), downregulated the expression of Noxa and led to a lower level of c-PARP (Figure 3E).	('apoptosis', 'CPA', (54, 63))	('downregulated', 'NegReg', (77, 90))	('PARP', 'Gene', '1302', (144, 148))	('ATF4', 'Gene', '468', (26, 30))	('Noxa', 'Gene', (109, 113))	('Noxa', 'Gene', '5366', (109, 113))	('ATF4', 'Gene', (26, 30))	('PARP', 'Gene', (144, 148))	('lower', 'NegReg', (127, 132))	('PR-619', 'Chemical', 'MESH:C570894', (39, 45))	('knockdown', 'Var', (13, 22))	('PR-619-induced', 'Var', (39, 53))	('expression', 'MPA', (95, 105))
549170	33129231	These results indicated that PR-619 triggered ER stress and induced ATF4-Noxa-mediated apoptosis in ESCC cells.	('ER stress', 'MPA', (46, 55))	('PR-619', 'Chemical', 'MESH:C570894', (29, 35))	('induced', 'Reg', (60, 67))	('PR-619', 'Var', (29, 35))	('ATF4', 'Gene', (68, 72))	('Noxa', 'Gene', '5366', (73, 77))	('ATF4', 'Gene', '468', (68, 72))	('Noxa', 'Gene', (73, 77))
549174	33129231	Furthermore, we found that the inhibition of autophagy with either CQ or BafA1 significantly enhanced PR-619-induced inhibition of cell viability (Figure 4E) and PR-619-induced apoptosis (Figure 4F).	('inhibition', 'NegReg', (31, 41))	('autophagy', 'CPA', (45, 54))	('PR-619-induced', 'Var', (102, 116))	('BafA1', 'Gene', (73, 78))	('PR-619', 'Chemical', 'MESH:C570894', (162, 168))	('cell viability', 'CPA', (131, 145))	('enhanced PR', 'Phenotype', 'HP:0008151', (93, 104))	('BafA1', 'Chemical', 'MESH:C040929', (73, 78))	('CQ', 'Chemical', 'MESH:D002738', (67, 69))	('enhanced', 'PosReg', (93, 101))	('inhibition', 'NegReg', (117, 127))	('PR-619', 'Chemical', 'MESH:C570894', (102, 108))
549175	33129231	Co-treatment with CQ or BafA1 resulted in an increased level of cleaved PARP and caspase3 than treatment with PR-619 alone (Figure 4G) in both Kyse30 and Kyse450 cells.	('BafA1', 'Var', (24, 29))	('PR-619', 'Chemical', 'MESH:C570894', (110, 116))	('increased', 'PosReg', (45, 54))	('BafA1', 'Chemical', 'MESH:C040929', (24, 29))	('CQ', 'Chemical', 'MESH:D002738', (18, 20))	('PARP', 'Gene', '1302', (72, 76))	('PARP', 'Gene', (72, 76))	('caspase3', 'Gene', (81, 89))	('caspase3', 'Gene', '836', (81, 89))
549176	33129231	These results revealed that PR-619 activated pro-survival autophagy, and blockage of the autophagic response significantly enhanced the cell growth inhibition efficacy of PR-619 on ESCC cells.	('enhanced', 'PosReg', (123, 131))	('pro-survival autophagy', 'CPA', (45, 67))	('autophagic response', 'CPA', (89, 108))	('cell growth inhibition efficacy', 'CPA', (136, 167))	('PR-619', 'Chemical', 'MESH:C570894', (171, 177))	('ESCC', 'Disease', (181, 185))	('PR-619', 'Var', (171, 177))	('PR-619', 'Chemical', 'MESH:C570894', (28, 34))	('activated', 'PosReg', (35, 44))	('blockage', 'NegReg', (73, 81))
549179	33129231	45 ,  46 ,  47  Therefore, we next investigate whether PR-619 induced autophagy through the activation of Ca2+-CaMKKbeta-AMPK signalling cascade.	('AMPK', 'Gene', (121, 125))	('Ca2+', 'Chemical', 'MESH:D000069285', (106, 110))	('induced', 'PosReg', (62, 69))	('autophagy', 'CPA', (70, 79))	('PR-619', 'Var', (55, 61))	('CaMKKbeta', 'Gene', (111, 120))	('PR-619', 'Chemical', 'MESH:C570894', (55, 61))	('AMPK', 'Gene', '5563', (121, 125))	('CaMKKbeta', 'Gene', '84254', (111, 120))
549181	33129231	The fluorescence intensity of the Ca2+ dye and the number of Fluo-3+ cells also gradually increased in response to PR-619 (Figure 5B-C).	('PR-619', 'Chemical', 'MESH:C570894', (115, 121))	('increased', 'PosReg', (90, 99))	('Ca2+', 'Chemical', 'MESH:D000069285', (34, 38))	('PR-619', 'Var', (115, 121))	('fluorescence intensity of the Ca2+ dye', 'MPA', (4, 42))
549182	33129231	Meanwhile, PR-619 treatment significantly upregulated the protein level of p-AMPKalpha and p-ACC, a substrate of AMPK (Figure 5D).	('PR-619', 'Var', (11, 17))	('AMPK', 'Gene', (113, 117))	('p-ACC', 'Chemical', '-', (91, 96))	('AMPK', 'Gene', (77, 81))	('AMPK', 'Gene', '5563', (113, 117))	('p-ACC', 'MPA', (91, 96))	('upregulated', 'PosReg', (42, 53))	('p-AMPKalpha', 'Chemical', '-', (75, 86))	('AMPK', 'Gene', '5563', (77, 81))	('PR-619', 'Chemical', 'MESH:C570894', (11, 17))
549187	33129231	Meanwhile, AMPK inhibition significantly enhanced PR-619-induced cell growth inhibition (Figure 6B-C) and cell apoptosis (Figure 6D-E).	('enhanced', 'PosReg', (41, 49))	('cell apoptosis', 'CPA', (106, 120))	('PR-619', 'Chemical', 'MESH:C570894', (50, 56))	('enhanced PR', 'Phenotype', 'HP:0008151', (41, 52))	('PR-619-induced', 'Gene', (50, 64))	('AMPK', 'Gene', '5563', (11, 15))	('cell growth inhibition', 'CPA', (65, 87))	('AMPK', 'Gene', (11, 15))	('inhibition', 'Var', (16, 26))
549189	33129231	AMPK inhibition enhanced PR-619-induced cytotoxicity, probably through blocking autophagy and facilitating cell apoptosis.	('cytotoxicity', 'Disease', (40, 52))	('enhanced PR', 'Phenotype', 'HP:0008151', (16, 27))	('AMPK', 'Gene', '5563', (0, 4))	('inhibition', 'Var', (5, 15))	('PR-619-induced', 'Gene', (25, 39))	('autophagy', 'CPA', (80, 89))	('cytotoxicity', 'Disease', 'MESH:D064420', (40, 52))	('AMPK', 'Gene', (0, 4))	('blocking', 'NegReg', (71, 79))	('cell apoptosis', 'CPA', (107, 121))	('PR-619', 'Chemical', 'MESH:C570894', (25, 31))	('enhanced', 'PosReg', (16, 24))
549192	33129231	Results showed that PYR-41 treatment decreased apoptosis (Figure 7A), G2/M cell cycle arrest (Figure 7B) and autophagy (Figure 7C) in PR-619-treated cells.	('arrest', 'Disease', 'MESH:D006323', (86, 92))	('apoptosis', 'CPA', (47, 56))	('arrest', 'Disease', (86, 92))	('PYR-41', 'Var', (20, 26))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (75, 92))	('PR-619', 'Chemical', 'MESH:C570894', (134, 140))	('PYR-41', 'Chemical', 'MESH:C523934', (20, 26))	('autophagy', 'CPA', (109, 118))	('decreased', 'NegReg', (37, 46))
549193	33129231	PYR-41 effectively diminished the accumulation of conjugated ubiquitin and inhibited ER stress that induced by PR-619 (Figure 7D).	('PR-619', 'Chemical', 'MESH:C570894', (111, 117))	('diminished', 'NegReg', (19, 29))	('conjugated ubiquitin', 'MPA', (50, 70))	('inhibited', 'NegReg', (75, 84))	('ER stress', 'MPA', (85, 94))	('accumulation', 'MPA', (34, 46))	('PYR-41', 'Var', (0, 6))	('PYR-41', 'Chemical', 'MESH:C523934', (0, 6))
549194	33129231	Following the above results (Figures 1D, 3E and 5E), PYR-41 downregulated the expression of ATF4-Noxa and the cleavage of PARP; rescued the expression of Cyclin B1 and downregulated the protein level of p21; and decreased the expression of phosphorylated AMPKalpha and LC3II (Figure 7D) in PR-619-treated cells.	('Cyclin B1', 'Gene', (154, 163))	('ATF4', 'Gene', (92, 96))	('expression', 'MPA', (226, 236))	('LC3', 'Gene', (269, 272))	('ATF4', 'Gene', '468', (92, 96))	('Cyclin B1', 'Gene', '891', (154, 163))	('PARP', 'Gene', '1302', (122, 126))	('downregulated', 'NegReg', (168, 181))	('decreased', 'NegReg', (212, 221))	('LC3', 'Gene', '84557', (269, 272))	('PARP', 'Gene', (122, 126))	('AMPKalpha', 'Chemical', '-', (255, 264))	('PYR-41', 'Chemical', 'MESH:C523934', (53, 59))	('protein level', 'MPA', (186, 199))	('cleavage', 'MPA', (110, 118))	('Noxa', 'Gene', '5366', (97, 101))	('downregulated', 'NegReg', (60, 73))	('rescued', 'PosReg', (128, 135))	('PYR-41', 'Var', (53, 59))	('p21', 'Gene', (203, 206))	('expression', 'MPA', (78, 88))	('expression', 'MPA', (140, 150))	('p21', 'Gene', '644914', (203, 206))	('PR-619', 'Chemical', 'MESH:C570894', (290, 296))	('Noxa', 'Gene', (97, 101))
549196	33129231	In previous studies, we demonstrated that inactivation of USP7 or USP14 with specific inhibitor led to the effective suppression of ESCC cell growth in vitro and in murine model.	('suppression', 'NegReg', (117, 128))	('USP14', 'Gene', (66, 71))	('inactivation', 'Var', (42, 54))	('USP7', 'Gene', (58, 62))	('murine', 'Species', '10090', (165, 171))	('ESCC', 'Disease', (132, 136))
549197	33129231	13 ,  15  However, it is unknown whether broad-range DUB inhibitor PR-619 could also significantly inhibit ESCC cell growth via disrupting the dynamic balance of ubiquitin conjugation.	('inhibit', 'NegReg', (99, 106))	('PR-619', 'Var', (67, 73))	('PR-619', 'Chemical', 'MESH:C570894', (67, 73))	('disrupting', 'NegReg', (128, 138))	('ESCC', 'Disease', (107, 111))	('dynamic balance of ubiquitin conjugation', 'MPA', (143, 183))
549203	33129231	49 ,  50  Knocking-down of USP14 arrested cell cycle at G2/M phase.	('arrest', 'Disease', 'MESH:D006323', (33, 39))	('cell cycle at G2/M phase', 'CPA', (42, 66))	('Knocking-down', 'Var', (10, 23))	('arrest', 'Disease', (33, 39))	('USP14', 'Gene', (27, 32))
549205	33129231	However, Ling et al reported that knockdown of USP22 by siRNA induced cells G0/G1 cell cycle arrest via the c-Myc/cyclin D2 pathway in HepG2 cells.	('USP22', 'Gene', '23326', (47, 52))	('c-Myc', 'Gene', '4609', (108, 113))	('arrest', 'Disease', 'MESH:D006323', (93, 99))	('c-Myc', 'Gene', (108, 113))	('Ling', 'Species', '163112', (9, 13))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (82, 99))	('arrest', 'Disease', (93, 99))	('knockdown', 'Var', (34, 43))	('USP22', 'Gene', (47, 52))	('HepG2', 'CellLine', 'CVCL:0027', (135, 140))
549206	33129231	51  Most recently, Kuo et al revealed that PR-619 treatment induced G0/G1 cell cycle arrest in bladder urothelial carcinoma cells with decreased p-Histone H3 (Ser10) and increased p21 and phospho-CDK2 (Tyr15).	('Ser10', 'Chemical', '-', (159, 164))	('Tyr15', 'Chemical', '-', (202, 207))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('PR-619', 'Chemical', 'MESH:C570894', (43, 49))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (74, 91))	('increased', 'PosReg', (170, 179))	('p21', 'Gene', (180, 183))	('bladder urothelial carcinoma', 'Disease', 'MESH:D001749', (95, 123))	('p-Histone', 'MPA', (145, 154))	('CDK2', 'Gene', '1017', (196, 200))	('PR-619', 'Var', (43, 49))	('p21', 'Gene', '644914', (180, 183))	('bladder urothelial carcinoma', 'Disease', (95, 123))	('decreased', 'NegReg', (135, 144))	('arrest', 'Disease', 'MESH:D006323', (85, 91))	('arrest', 'Disease', (85, 91))	('CDK2', 'Gene', (196, 200))
549209	33129231	Besides, ubiquitin E1 inhibitor PYR-41 rescued the expression of Cyclin B1, downregulated p21 and reduced the accumulation of G2/M phase cells in PR-619-treated ESCC cells, which implied that PR-619 triggered G2/M cell cycle arrest in ESCC by regulating the expression of cyclin B1 and p21.	('rescued', 'PosReg', (39, 46))	('PR-619', 'Chemical', 'MESH:C570894', (146, 152))	('Cyclin B1', 'Gene', (65, 74))	('arrest', 'Disease', 'MESH:D006323', (225, 231))	('expression', 'MPA', (51, 61))	('accumulation', 'MPA', (110, 122))	('reduced', 'NegReg', (98, 105))	('PR-619', 'Chemical', 'MESH:C570894', (192, 198))	('Cyclin B1', 'Gene', '891', (65, 74))	('PYR-41', 'Chemical', 'MESH:C523934', (32, 38))	('p21', 'Gene', (286, 289))	('p21', 'Gene', '644914', (286, 289))	('G2/M phase cells', 'CPA', (126, 142))	('PYR-41', 'Var', (32, 38))	('cyclin B1', 'Gene', (272, 281))	('cyclin B1', 'Gene', '891', (272, 281))	('G2/M', 'CPA', (209, 213))	('regulating', 'Reg', (243, 253))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (214, 231))	('arrest', 'Disease', (225, 231))	('p21', 'Gene', (90, 93))	('p21', 'Gene', '644914', (90, 93))	('downregulated', 'NegReg', (76, 89))
549212	33129231	35 ,  54  In the present study, we found that PR-619 treatment led to the accumulation of poly-ubiquitinated proteins and triggered ER stress in ESCC cells, as evidenced by the increased expression of Bip, p-eIF2alpha and ATF4.	('Bip', 'Gene', (201, 204))	('Bip', 'Gene', '2662', (201, 204))	('ER stress', 'MPA', (132, 141))	('PR-619', 'Chemical', 'MESH:C570894', (46, 52))	('ATF4', 'Gene', (222, 226))	('increased', 'PosReg', (177, 186))	('PR-619', 'Var', (46, 52))	('eIF2alpha', 'Gene', (208, 217))	('ATF4', 'Gene', '468', (222, 226))	('expression', 'MPA', (187, 197))	('accumulation', 'PosReg', (74, 86))	('eIF2alpha', 'Gene', '83939', (208, 217))	('triggered', 'Reg', (122, 131))
549215	33129231	Furthermore, ubiquitin E1 inhibitor PYR-41 could alleviate the accumulation of conjugated ubiquitin, inhibit ER stress, decrease the expression of ATF4-Noxa and cleaved PARP in PR-619-treated cells.	('expression', 'MPA', (133, 143))	('PYR-41', 'Var', (36, 42))	('inhibit', 'NegReg', (101, 108))	('PR-619', 'Chemical', 'MESH:C570894', (177, 183))	('decrease', 'NegReg', (120, 128))	('ATF4', 'Gene', (147, 151))	('ER stress', 'MPA', (109, 118))	('PYR-41', 'Chemical', 'MESH:C523934', (36, 42))	('cleaved', 'MPA', (161, 168))	('PARP', 'Gene', '1302', (169, 173))	('Noxa', 'Gene', '5366', (152, 156))	('PARP', 'Gene', (169, 173))	('alleviate', 'NegReg', (49, 58))	('accumulation of conjugated ubiquitin', 'MPA', (63, 99))	('ATF4', 'Gene', '468', (147, 151))	('Noxa', 'Gene', (152, 156))
549224	33129231	PYR-41 could reduce the accumulation of ubiquitinated proteins, alleviate ER stress and decrease autophagy in PR-619-treated cells.	('decrease', 'NegReg', (88, 96))	('accumulation of ubiquitinated proteins', 'MPA', (24, 62))	('PR-619', 'Chemical', 'MESH:C570894', (110, 116))	('ER stress', 'MPA', (74, 83))	('alleviate', 'NegReg', (64, 73))	('reduce', 'NegReg', (13, 19))	('autophagy', 'CPA', (97, 106))	('PYR-41', 'Var', (0, 6))	('PYR-41', 'Chemical', 'MESH:C523934', (0, 6))
549225	33129231	Besides, the treatment of STO-609, a CaMKKbeta inhibitor, led to the inactivation of AMPKalpha induced by PR-619, decreased the expression of p-AMPKalpha and accompanied by reduced LC3-II.	('AMPKalpha', 'Chemical', '-', (144, 153))	('LC3', 'Gene', '84557', (181, 184))	('inactivation', 'NegReg', (69, 81))	('AMPKalpha', 'Chemical', '-', (85, 94))	('LC3', 'Gene', (181, 184))	('reduced', 'NegReg', (173, 180))	('CaMKKbeta', 'Gene', '84254', (37, 46))	('STO-609', 'Chemical', 'MESH:C458525', (26, 33))	('p-AMPKalpha', 'Chemical', '-', (142, 153))	('PR-619', 'Chemical', 'MESH:C570894', (106, 112))	('decreased', 'NegReg', (114, 123))	('AMPKalpha', 'Protein', (85, 94))	('expression', 'MPA', (128, 138))	('CaMKKbeta', 'Gene', (37, 46))	('p-AMPKalpha', 'MPA', (142, 153))	('PR-619', 'Var', (106, 112))
549228	33129231	Collectively, this study revealed the detailed mechanism of PR-619 in ESCC cells (Figure 8).	('ESCC', 'Disease', (70, 74))	('PR-619', 'Chemical', 'MESH:C570894', (60, 66))	('PR-619', 'Var', (60, 66))
549231	33129231	Besides, PR-619 could activate autophagy through Ca2+-CaMKKbeta-AMPK signalling.	('CaMKKbeta', 'Gene', '84254', (54, 63))	('autophagy', 'CPA', (31, 40))	('PR-619', 'Var', (9, 15))	('AMPK', 'Gene', (64, 68))	('PR-619', 'Chemical', 'MESH:C570894', (9, 15))	('Ca2+', 'Chemical', 'MESH:D000069285', (49, 53))	('CaMKKbeta', 'Gene', (54, 63))	('activate', 'PosReg', (22, 30))	('AMPK', 'Gene', '5563', (64, 68))
549234	32341351	Using genomic sequencing of 612 ESCC patients, we analyzed the associations of ZNF750 mutations with clinicopathologic features and its prognostic value.	('mutations', 'Var', (86, 95))	('ESCC', 'Disease', (32, 36))	('associations', 'Interaction', (63, 75))	('patients', 'Species', '9606', (37, 45))	('ZNF750', 'Gene', (79, 85))
549235	32341351	The results showed ZNF750 mutations/deletions are significantly associated with malignant progression and poor prognosis of ESCC patients.	('associated', 'Reg', (64, 74))	('mutations/deletions', 'Var', (26, 45))	('patients', 'Species', '9606', (129, 137))	('ESCC', 'Disease', (124, 128))	('ZNF750', 'Gene', (19, 25))	('malignant progression', 'CPA', (80, 101))
549236	32341351	Decreased ZNF750 in ESCC cells induces enhanced angiogenesis of human umbilical vein endothelial cells (HUVECs) and human arterial endothelial cells (HAECs), and the effect may be indirectly mediated by FOXC2.	('Decreased', 'Var', (0, 9))	('human', 'Species', '9606', (64, 69))	('ZNF750', 'Gene', (10, 16))	('HUVEC', 'CellLine', 'CVCL:2959', (104, 109))	('enhanced', 'PosReg', (39, 47))	('angiogenesis', 'CPA', (48, 60))	('human', 'Species', '9606', (116, 121))
549238	32341351	Our study reveals a novel mechanism of ZNF750, highlights a significance of ZNF750 as a metastatic and prognostic biomarker, and offers potential therapeutic targets for ESCC patients harboring ZNF750 mutations.	('mutations', 'Var', (201, 210))	('ZNF750', 'Gene', (76, 82))	('patients', 'Species', '9606', (175, 183))	('ZNF750', 'Gene', (194, 200))	('ESCC', 'Disease', (170, 174))
549240	32341351	Recent studies have profiled ESCC genomic alterations and have identified significantly mutated genes (SMGs) including TP53, ZNF750, NOTCH1, FAT1, NFE2L2, copy number amplifications occurring in SOX2, TERT, FGFR1, MDM1, and common deletions of RB1 etc.	('FAT1', 'Gene', (141, 145))	('ZNF750', 'Gene', (125, 131))	('TP53', 'Gene', '7157', (119, 123))	('FGFR1', 'Gene', (207, 212))	('RB1', 'Gene', (244, 247))	('NFE2L2', 'Gene', '4780', (147, 153))	('NOTCH1', 'Gene', (133, 139))	('TERT', 'Gene', (201, 205))	('MDM1', 'Gene', (214, 218))	('FAT1', 'Gene', '2195', (141, 145))	('copy number amplifications', 'Var', (155, 181))	('deletions', 'Var', (231, 240))	('TERT', 'Gene', '7015', (201, 205))	('RB1', 'Gene', '5925', (244, 247))	('NOTCH1', 'Gene', '4851', (133, 139))	('NFE2L2', 'Gene', (147, 153))	('MDM1', 'Gene', '56890', (214, 218))	('TP53', 'Gene', (119, 123))	('FGFR1', 'Gene', '2260', (207, 212))	('SOX2', 'Gene', '6657', (195, 199))	('SOX2', 'Gene', (195, 199))
549244	32341351	ZNF750 also suppressed migration of SCC cells by directly inhibiting transactivation of LAMC2.	('migration of SCC cells', 'CPA', (23, 45))	('transactivation', 'MPA', (69, 84))	('inhibiting', 'NegReg', (58, 68))	('LAMC2', 'Gene', (88, 93))	('LAMC2', 'Gene', '3918', (88, 93))	('suppressed', 'NegReg', (12, 22))	('ZNF750', 'Var', (0, 6))
549245	32341351	Recent attempts to decipher the significance of ZNF750 for tumorigenesis in ESCC have revealed that ZNF750 might act as a tumor suppressor gene.	('ZNF750', 'Var', (100, 106))	('tumor', 'Disease', (59, 64))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('ESCC', 'Disease', (76, 80))	('tumor', 'Disease', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
549247	32341351	In this study, we reveal the associations ZNF750 mutations and/or deletions with clinical variables using genomic sequencing data of 612 pairs of ESCC tumor and normal samples from China and explore the molecular mechanism through which ZNF750 plays a critical role in driving the formation of metastatic ESCC.	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('ZNF750', 'Gene', (42, 48))	('mutations', 'Var', (49, 58))	('tumor', 'Disease', (151, 156))	('associations', 'Interaction', (29, 41))	('deletions', 'Var', (66, 75))	('metastatic ESCC', 'Disease', (294, 309))	('tumor', 'Disease', 'MESH:D009369', (151, 156))
549249	32341351	Our findings reveal an underlying mechanism by which loss-function of ZNF750 contributes to ESCC progression, provide a potential metastatic and prognostic biomarker and several therapeutic targets for ESCC patients harboring ZNF750 mutations and/or deletions.	('patients', 'Species', '9606', (207, 215))	('deletions', 'Var', (250, 259))	('ZNF750', 'Gene', (226, 232))	('ESCC', 'Disease', (92, 96))	('ZNF750', 'Gene', (70, 76))	('loss-function', 'NegReg', (53, 66))	('ESCC', 'Disease', (202, 206))	('mutations', 'Var', (233, 242))
549254	32341351	Together with our previous 104 ESCC patients recruited from the Taihang Mountain of North-Central China, we analyzed the associations of ZNF750 mutations with patients' clinical features in a cohort of 612 ESCC patients in this study.	('patients', 'Species', '9606', (211, 219))	('patients', 'Species', '9606', (36, 44))	('ZNF750', 'Gene', (137, 143))	('mutations', 'Var', (144, 153))	('patients', 'Species', '9606', (159, 167))
549257	32341351	We also imputed deviation in the allele frequency of heterozygous single-nucleotide variation to predict the tumor purity and ploidy for each sample with a median of 51.18%.	('tumor', 'Disease', 'MESH:D009369', (109, 114))	('single-nucleotide variation', 'Var', (66, 93))	('tumor', 'Disease', (109, 114))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))
549259	32341351	For each paired sample, somatic single-nucleotide variants (SNVs) and small insertions and deletions (indels) were detected by MuTect2 (http://archive.broadinstitute.org/cancer/cga/mutect).	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('single-nucleotide variants', 'Var', (32, 58))	('cga', 'Gene', '1113', (177, 180))	('cancer', 'Disease', (170, 176))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('cga', 'Gene', (177, 180))
549264	32341351	Immortalized esophageal epithelial cell SHEE and ESCC cell lines KYSE140, KYSE150, KYSE180, KYSE410, KYSE510, KYSE450, Colo680N, ECA109 were stored at Shanxi key laboratory of carcinogenesis and translational research on esophageal cancer, Shanxi Medical University.	('cancer', 'Disease', 'MESH:D009369', (232, 238))	('KYSE180', 'Var', (83, 90))	('cancer', 'Disease', (232, 238))	('KYSE410', 'Var', (92, 99))	('KYSE150', 'CellLine', 'CVCL:1348', (74, 81))	('KYSE150', 'Var', (74, 81))	('carcinogenesis', 'Disease', 'MESH:D063646', (176, 190))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('KYSE180', 'CellLine', 'CVCL:1349', (83, 90))	('carcinogenesis', 'Disease', (176, 190))	('KYSE510', 'Var', (101, 108))	('HE', 'Chemical', '-', (41, 43))	('KYSE450', 'CellLine', 'CVCL:1353', (110, 117))
549291	32341351	Approximately 1 x 107 cells transfected with pcDNA3.1-HA ZNF750-wt were cross-linked in 1% formaldehyde at 37  C for 10 min, and then 1.25 M glycine was added to quench the excess formaldehyde at room temperature for 5 min.	('pcDNA3.1-HA', 'Var', (45, 56))	('formaldehyde', 'Chemical', 'MESH:D005557', (91, 103))	('glycine', 'Chemical', 'MESH:D005998', (141, 148))	('formaldehyde', 'Chemical', 'MESH:D005557', (180, 192))	('ZNF750-wt', 'Gene', (57, 66))
549297	32341351	RIP was performed to assess the interaction between DANCR and miR-4707-3p using a Magna RIP kit (Millipore, USA) according to the manufacturer's instruction.	('RIP', 'Gene', '3267', (0, 3))	('RIP', 'Gene', (88, 91))	('RIP', 'Gene', (0, 3))	('RIP', 'Gene', '3267', (88, 91))	('miR-4707-3p', 'Var', (62, 73))	('interaction', 'Interaction', (32, 43))
549308	32341351	Moreover, we observed recurrent mutations in noncoding regions of ZNF750, being mutated in 48 out of 508 (9.5%) tumors that have WGS data available.	('tumors', 'Disease', (112, 118))	('ZNF750', 'Gene', (66, 72))	('tumors', 'Phenotype', 'HP:0002664', (112, 118))	('mutations', 'Var', (32, 41))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('tumors', 'Disease', 'MESH:D009369', (112, 118))
549312	32341351	Although most features were not statistically significant, this analysis identified the following statistically significant patterns: (i) ZNF750 mutations (n = 48 tumors) were significantly associated with late pathological stage (P = 0.000078), (ii) patients harboring ZNF750 mutations exhibited more lymph node metastasis (P = 0.00011) and more distant metastasis (P = 0.001) compared with patients harboring no mutations in ZNF750 (Table 1), and (iii) patients in subgroup of "ZNF750-wt" showed significantly better survival as compared to patients in subgroup of "mutated" (Kaplan-Meier analysis, P = 0.026; Cox regression, P = 0.029, hazard ratio (HR): 1.541, 95% confidence interval (CI): 1.044-2.261) (Fig.	('patients', 'Species', '9606', (455, 463))	('lymph node metastasis', 'CPA', (302, 323))	('mutations', 'Var', (145, 154))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('better', 'PosReg', (512, 518))	('mutations', 'Var', (277, 286))	('tumors', 'Disease', (163, 169))	('tumors', 'Disease', 'MESH:D009369', (163, 169))	('ZNF750', 'Gene', (138, 144))	('associated', 'Reg', (190, 200))	('patients', 'Species', '9606', (251, 259))	('patients', 'Species', '9606', (392, 400))	('patients', 'Species', '9606', (543, 551))	('tumors', 'Phenotype', 'HP:0002664', (163, 169))	('distant metastasis', 'CPA', (347, 365))	('ZNF750', 'Gene', (270, 276))
549313	32341351	Strikingly, analysis of copy number alterations in 508 pairs of WGS revealed that ZNF750 copy number loss (n = 71) was statistically associated with more lymph node metastasis (P = 0.046) compared with patients harboring no deletions in ZNF750.	('ZNF750', 'Gene', (82, 88))	('loss', 'NegReg', (101, 105))	('copy number', 'Var', (89, 100))	('patients', 'Species', '9606', (202, 210))	('lymph node metastasis', 'CPA', (154, 175))	('more', 'PosReg', (149, 153))
549314	32341351	Subsequently, Kaplan-Meier's analysis revealed that patients with ZNF750 copy number loss developed more-frequent recurrence and had poorer survival (P = 0.048, Fig.	('poorer', 'NegReg', (133, 139))	('recurrence', 'MPA', (114, 124))	('ZNF750', 'Gene', (66, 72))	('survival', 'MPA', (140, 148))	('patients', 'Species', '9606', (52, 60))	('copy number loss', 'Var', (73, 89))
549316	32341351	Together, these findings suggest that there are clear associations between ZNF750 mutations/deletions and clinical characteristics of Chinese ESCC patients, supporting the clinical potential of ZNF750 mutations/deletions with its ability to estimate the metastasis and survival of patients with ESCC.	('mutations/deletions', 'Var', (201, 220))	('patients', 'Species', '9606', (281, 289))	('mutations/deletions', 'Var', (82, 101))	('associations', 'Interaction', (54, 66))	('patients', 'Species', '9606', (147, 155))	('ZNF750', 'Gene', (194, 200))	('ZNF750', 'Gene', (75, 81))
549321	32341351	We found that the proliferation rates of HUVEC were not significantly increased when treated with conditioned medium from KYSE140 cells with ZNF750 knockdown.	('HUVEC', 'CellLine', 'CVCL:2959', (41, 46))	('knockdown', 'Var', (148, 157))	('ZNF750', 'Gene', (141, 147))
549334	32341351	Importantly, knockdown FOXC2 in ZNF750 knockdown KYSE140 cells decreased the ability of migration, invasion and tube formation in HUVEC cells treated with conditioned medium (CM) from ZNF750 knockdown KYSE140 cells and KYSE450 cells, respectively (Fig.	('decreased', 'NegReg', (63, 72))	('KYSE450', 'CellLine', 'CVCL:1353', (219, 226))	('tube formation', 'CPA', (112, 126))	('FOXC2', 'Gene', (23, 28))	('knockdown', 'Var', (13, 22))	('HUVEC', 'CellLine', 'CVCL:2959', (130, 135))
549336	32341351	We then detected the effect of ZNF750 and FOXC2 on Ang-2 and VEGFs, and found ZNF750 knockdown induced up-regulation of Ang-2 and VEGFs in ESCC cells whereas downregulated FOXC2 reversed the phenomenon (Fig.	('Ang-2', 'Gene', (120, 125))	('up-regulation', 'PosReg', (103, 116))	('FOXC2', 'Gene', (172, 177))	('Ang-2', 'Gene', (51, 56))	('Ang-2', 'Gene', '285', (51, 56))	('knockdown', 'Var', (85, 94))	('VEGFs', 'MPA', (130, 135))	('Ang-2', 'Gene', '285', (120, 125))	('ZNF750', 'Gene', (78, 84))
549337	32341351	Thus, FOXC2 may act as a mediator of tumor angiogenesis induced by ZNF750 knockdown in ESCC.	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('FOXC2', 'Gene', (6, 11))	('knockdown', 'Var', (74, 83))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('ESCC', 'Disease', (87, 91))	('ZNF750', 'Gene', (67, 73))
549345	32341351	4h), indicating that miR-4707-3p probably binds to the predicted MRE region of DANCR, thus downregulates DANCR expression (Fig.	('miR-4707-3p', 'Var', (21, 32))	('downregulates', 'NegReg', (91, 104))	('DANCR', 'Protein', (105, 110))	('4h', 'Chemical', '-', (0, 2))
549346	32341351	Moreover, RNA-Binding Protein Immunoprecipitation Assay (RIP) experiment using antibody against Ago2 in KYSE150 cell extracts showed that DANCR and miR-4707-3p were preferentially enriched in Ago2-containing miRNPs relative to the control IgG immunoprecipitates (Fig.	('preferentially', 'PosReg', (165, 179))	('Ago2', 'Gene', (96, 100))	('RIP', 'Gene', (57, 60))	('RNA-Binding Protein Immunoprecipitation Assay', 'Gene', (10, 55))	('KYSE150', 'CellLine', 'CVCL:1348', (104, 111))	('RNA-Binding Protein Immunoprecipitation Assay', 'Gene', '3267', (10, 55))	('Ago2', 'Gene', '27161', (192, 196))	('RIP', 'Gene', '3267', (57, 60))	('miR-4707-3p', 'Var', (148, 159))	('Ago2', 'Gene', '27161', (96, 100))	('Ago2', 'Gene', (192, 196))
549347	32341351	4j), indicating that DANCR, likely through interacting with miR-4707-3p, was present in Ago2-containing miRNPs.	('interacting', 'Interaction', (43, 54))	('Ago2', 'Gene', '27161', (88, 92))	('miR-4707-3p', 'Var', (60, 71))	('Ago2', 'Gene', (88, 92))
549348	32341351	Silence of miR-4707-3p led to an increase of FOXC2 mRNA and protein level in KYSE-150 cells whereas augmentation of miR-4707-3p caused a decrease of FOXC2 in Eca109 cells (Fig.	('decrease', 'NegReg', (137, 145))	('FOXC2', 'Gene', (45, 50))	('increase', 'PosReg', (33, 41))	('KYSE-150', 'CellLine', 'CVCL:1348', (77, 85))	('miR-4707-3p', 'Var', (116, 127))	('miR-4707-3p', 'Var', (11, 22))	('Silence', 'Var', (0, 7))
549350	32341351	Given that the DANCR/miR-4707-3p/FOXC2 axis in ESCC, we hypothesize ZNF750 may directly downregulate DANCR expression, strengthened the interaction of miR-4707-3p with FOXC2-3'UTR in a ceRNA manner, leading to degradation of FOXC2 mRNA, thus playing tumor suppressive role in ESCC.	('degradation', 'MPA', (210, 221))	('downregulate', 'NegReg', (88, 100))	('ESCC', 'Disease', (47, 51))	('tumor', 'Disease', 'MESH:D009369', (250, 255))	('FOXC2', 'Gene', (225, 230))	('tumor', 'Phenotype', 'HP:0002664', (250, 255))	('DANCR', 'Protein', (101, 106))	('miR-4707-3p', 'Var', (151, 162))	('strengthened', 'PosReg', (119, 131))	('interaction', 'Interaction', (136, 147))	('ZNF750', 'Var', (68, 74))	('tumor', 'Disease', (250, 255))	('ESCC', 'Disease', (276, 280))
549351	32341351	To further validate this hypothesis, western blot and qPCR were used to detect the expression of DANCR, miR-4707-3p, FOXC2 in ZNF750 knockdown or overexpression cells and xenograft mouse samples.	('DANCR', 'Gene', (97, 102))	('FOXC2', 'Gene', (117, 122))	('mouse', 'Species', '10090', (181, 186))	('miR-4707-3p', 'Var', (104, 115))
549359	32341351	Consistent with our paired ESCC samples, we found the negatively correlation of ZNF750 mRNA with FOXC2 mRNA in 92 ESCC cases (r = -0.2151, P = 0.0395), 513 cases of head and neck squamous cell carcinoma (r = -0.2211, P < 0.0001), 493 cases of squamous cell carcinoma of lung (r = -0.1327, P = 0.0031), and 300 cases of cervical squamous cell carcinoma (r = -0.1518, P = 0.0085), suggesting a possibility of ZNF750 deregulates FOXC2 expression in human squamous cell carcinoma (Fig.	('human', 'Species', '9606', (446, 451))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (179, 202))	('expression', 'MPA', (432, 442))	('carcinoma', 'Phenotype', 'HP:0030731', (193, 202))	('carcinoma', 'Phenotype', 'HP:0030731', (342, 351))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (452, 475))	('cervical squamous cell carcinoma', 'Disease', (319, 351))	('neck squamous cell carcinoma', 'Disease', (174, 202))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (328, 351))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (174, 202))	('squamous cell carcinoma of lung', 'Disease', (243, 274))	('cervical squamous cell carcinoma', 'Disease', 'MESH:D002294', (319, 351))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (452, 475))	('carcinoma of lung', 'Phenotype', 'HP:0100526', (257, 274))	('FOXC2', 'Gene', (426, 431))	('deregulates', 'NegReg', (414, 425))	('carcinoma', 'Phenotype', 'HP:0030731', (466, 475))	('squamous cell carcinoma', 'Disease', (452, 475))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (243, 266))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (179, 202))	('squamous cell carcinoma of lung', 'Disease', 'MESH:D002294', (243, 274))	('ZNF750', 'Var', (407, 413))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (328, 351))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (243, 266))	('carcinoma', 'Phenotype', 'HP:0030731', (257, 266))
549360	32341351	6c-e).These datas indicate a possibility of ZNF750 deregulates FOXC2 expression in human squamous cell carcinoma.	('deregulates', 'NegReg', (51, 62))	('FOXC2', 'Gene', (63, 68))	('human', 'Species', '9606', (83, 88))	('expression', 'MPA', (69, 79))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (89, 112))	('ZNF750', 'Var', (44, 50))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (89, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('squamous cell carcinoma', 'Disease', (89, 112))
549362	32341351	In this study, we profiled mutation and copy number alterations of ZNF750 and uncovered its potential prognostic value for ESCC patients in an enlarged ESCC cohort.	('ESCC', 'Disease', (123, 127))	('mutation', 'Var', (27, 35))	('enlarged ESCC', 'Phenotype', 'HP:0003565', (143, 156))	('ZNF750', 'Gene', (67, 73))	('patients', 'Species', '9606', (128, 136))	('copy number alterations', 'Var', (40, 63))
549366	32341351	Together with several lines of functional evidences, ZNF750 may work in a loss-of-function manner and its dysregulation may be crucial for tumor formation and progression in ESCC.	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('dysregulation', 'Var', (106, 119))	('ESCC', 'Disease', (174, 178))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumor', 'Disease', (139, 144))	('ZNF750', 'Gene', (53, 59))	('loss-of-function', 'NegReg', (74, 90))
549370	32341351	In this study, we found that loss-function of ZNF750 significant promoted tumor angiogenesis, which indicates anti-angiogenesis might be an efficient method in the inhibition of the growth and metastasis of ESCC with ZNF750 mutation or deletion.	('ESCC', 'Disease', (207, 211))	('growth', 'CPA', (182, 188))	('ZNF750', 'Gene', (217, 223))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('loss-function', 'NegReg', (29, 42))	('deletion', 'Var', (236, 244))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('mutation', 'Var', (224, 232))	('promoted', 'PosReg', (65, 73))	('tumor', 'Disease', (74, 79))	('ZNF750', 'Gene', (46, 52))
549372	32341351	In agreement with previous reports on various types of human cancers, DANCR may also act as an oncogene in ESCC progression, supporting that DANCR may offer a potential therapeutic target for those ESCC patients harboring mutations of ZNF750.	('ESCC', 'Disease', (198, 202))	('human', 'Species', '9606', (55, 60))	('cancers', 'Disease', 'MESH:D009369', (61, 68))	('cancers', 'Phenotype', 'HP:0002664', (61, 68))	('cancers', 'Disease', (61, 68))	('patients', 'Species', '9606', (203, 211))	('mutations', 'Var', (222, 231))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('ZNF750', 'Gene', (235, 241))	('ESCC', 'Disease', (107, 111))
549374	32341351	MiR-4707-3p was previously rarely reported in human cancers.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('cancers', 'Disease', (52, 59))	('MiR-4707-3p', 'Var', (0, 11))	('human', 'Species', '9606', (46, 51))	('cancers', 'Phenotype', 'HP:0002664', (52, 59))	('MiR-4707-3p', 'Chemical', '-', (0, 11))	('cancers', 'Disease', 'MESH:D009369', (52, 59))
549375	32341351	Functionally, knockdown of miR-4707-3p promoted tumor angiogenesis probably by releasing the oncogenic role of FOXC2.	('promoted', 'PosReg', (39, 47))	('tumor', 'Disease', (48, 53))	('releasing', 'PosReg', (79, 88))	('FOXC2', 'Gene', (111, 116))	('miR-4707-3p', 'Var', (27, 38))	('knockdown', 'Var', (14, 23))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
549378	32341351	Hence, besides the DANCR, our study provides evidence to support additional potential therapeutic target, FOXC2, for those ESCC patients with ZNF750 mutations.	('patients', 'Species', '9606', (128, 136))	('ZNF750', 'Gene', (142, 148))	('mutations', 'Var', (149, 158))	('ESCC', 'Disease', (123, 127))
549399	32322580	Therefore, even though all Rho family GTPases play a role in cancer malignancy, this review will focus on new strategies to target Rac and Cdc42 activation via blocking the exchange of GDP to GTP.	('exchange', 'Var', (173, 181))	('GTP', 'Chemical', 'MESH:D006160', (192, 195))	('Cdc42', 'Gene', '998', (139, 144))	('cancer malignancy', 'Disease', 'MESH:D009369', (61, 78))	('GDP', 'Chemical', 'MESH:D006153', (185, 188))	('Rac', 'Protein', (131, 134))	('cancer malignancy', 'Disease', (61, 78))	('blocking', 'NegReg', (160, 168))	('GTP', 'Chemical', 'MESH:D006160', (38, 41))	('Cdc42', 'Gene', (139, 144))	('GDP', 'Protein', (185, 188))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))
549403	32322580	However, elucidation of the molecular basis for Rho GTPase activation by GEFs using crystal structure analysis coupled to functional mutant analysis of specific residues in Rac and Cdc42 that interact with different GEFs have enabled a deeper understanding of Rho GTPase/GEF molecular interactions.	('GEF', 'Gene', (216, 219))	('GEF', 'Gene', (73, 76))	('Rac', 'Gene', (173, 176))	('GEF', 'Gene', '9181', (271, 274))	('interactions', 'Interaction', (285, 297))	('GEF', 'Gene', '9181', (216, 219))	('Cdc42', 'Gene', '998', (181, 186))	('GTP', 'Chemical', 'MESH:D006160', (264, 267))	('GEF', 'Gene', '9181', (73, 76))	('GTP', 'Chemical', 'MESH:D006160', (52, 55))	('mutant', 'Var', (133, 139))	('Cdc42', 'Gene', (181, 186))	('GEF', 'Gene', (271, 274))
549417	32322580	However, GEFs themselves can become oncogenic by mutation or dysregulated expression (Table 1).	('expression', 'MPA', (74, 84))	('GEF', 'Gene', (9, 12))	('GEF', 'Gene', '9181', (9, 12))	('mutation', 'Var', (49, 57))	('dysregulated', 'Var', (61, 73))
549426	32322580	Several studies have identified TIAM1 as an oncogene due to its overexpression or mutation in epithelial cancers with poor prognosis, such as non-small cell lung cancer (NSCLC), stomach, endometrial, colorectal, pancreatic, and cervical cancer (Table 1).	('colorectal', 'Disease', (200, 210))	('cancers', 'Phenotype', 'HP:0002664', (105, 112))	('cancer', 'Disease', (162, 168))	('cancer', 'Disease', (105, 111))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('stomach', 'Disease', (178, 185))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (142, 168))	('pancreatic', 'Disease', (212, 222))	('TIAM1', 'Gene', (32, 37))	('mutation', 'Var', (82, 90))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (146, 168))	('NSCLC', 'Disease', 'MESH:D002289', (170, 175))	('epithelial cancers', 'Disease', 'MESH:D009369', (94, 112))	('cancer', 'Disease', (237, 243))	('colorectal', 'Disease', 'MESH:D015179', (200, 210))	('non-small cell lung cancer', 'Disease', (142, 168))	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('TIAM1', 'Gene', '7074', (32, 37))	('epithelial cancers', 'Disease', (94, 112))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('NSCLC', 'Disease', (170, 175))	('lung cancer', 'Phenotype', 'HP:0100526', (157, 168))	('endometrial', 'Disease', (187, 198))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (142, 168))	('overexpression', 'PosReg', (64, 78))	('pancreatic', 'Disease', 'MESH:D010195', (212, 222))	('cancer', 'Disease', 'MESH:D009369', (237, 243))
549429	32322580	In addition to overexpression, Tiam1 was shown to be mutated in neuroblastoma where certain point mutations were associated with a better outcome in patients with neuroblastoma, and thus, implicated with dysregulation in Tiam1 signaling.	('neuroblastoma', 'Disease', 'MESH:D009447', (163, 176))	('patients', 'Species', '9606', (149, 157))	('neuroblastoma', 'Disease', 'MESH:D009447', (64, 77))	('neuroblastoma', 'Disease', (163, 176))	('neuroblastoma', 'Disease', (64, 77))	('Tiam1', 'Gene', (31, 36))	('mutations', 'Var', (98, 107))	('neuroblastoma', 'Phenotype', 'HP:0003006', (163, 176))	('neuroblastoma', 'Phenotype', 'HP:0003006', (64, 77))	('better', 'PosReg', (131, 137))
549431	32322580	Therefore, blocking the Tiam1/Rac1 interaction has the potential to reduce metastasis from multiple cancer types.	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('interaction', 'Interaction', (35, 46))	('Rac1', 'Gene', '5879', (30, 34))	('reduce', 'NegReg', (68, 74))	('metastasis', 'CPA', (75, 85))	('blocking', 'Var', (11, 19))	('Rac1', 'Gene', (30, 34))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))
549433	32322580	Structure-based mutagenesis of specific residues in the beta2 and beta3 strands in the switch 1 (residues 30-48) and Switch II (residues 59-75) regions of Rac1 identified Trp56 as a residue that is critical for GEF binding to Rac.	('beta3', 'Gene', '28883', (66, 71))	('Trp56', 'Chemical', '-', (171, 176))	('beta3', 'Gene', (66, 71))	('GEF', 'Gene', '9181', (211, 214))	('GEF', 'Gene', (211, 214))	('Trp56', 'Var', (171, 176))	('mutagenesis', 'Var', (16, 27))	('beta2', 'Gene', (56, 61))	('Rac1', 'Gene', '5879', (155, 159))	('beta2', 'Gene', '27239', (56, 61))	('Rac1', 'Gene', (155, 159))
549434	32322580	Based on this premise, the small molecule NSC23766 was identified through a structure-based virtual screen as an inhibitor of the Tiam1 and Trio GEF interactions with Rac1.	('NSC23766', 'Var', (42, 50))	('GEF', 'Gene', (145, 148))	('Rac1', 'Gene', '5879', (167, 171))	('Trio', 'Gene', '7204', (140, 144))	('Rac1', 'Gene', (167, 171))	('GEF', 'Gene', '9181', (145, 148))	('Tiam1', 'Gene', (130, 135))	('NSC23766', 'Chemical', 'MESH:C487513', (42, 50))	('Trio', 'Gene', (140, 144))	('interactions', 'Interaction', (149, 161))
549435	32322580	Even though its high IC50 (~50 muM) limits its therapeutic use, NSC23766 reduces invasion and growth of multiple cancer types, including prostate, breast, gastric, leukemia, lymphoma, and glioblastoma.	('glioblastoma', 'Disease', (188, 200))	('glioblastoma', 'Phenotype', 'HP:0012174', (188, 200))	('cancer', 'Disease', (113, 119))	('NSC23766', 'Var', (64, 72))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('reduces', 'NegReg', (73, 80))	('lymphoma', 'Phenotype', 'HP:0002665', (174, 182))	('breast', 'Disease', (147, 153))	('invasion', 'CPA', (81, 89))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('growth', 'CPA', (94, 100))	('leukemia', 'Phenotype', 'HP:0001909', (164, 172))	('NSC23766', 'Chemical', 'MESH:C487513', (64, 72))	('lymphoma', 'Disease', (174, 182))	('glioblastoma', 'Disease', 'MESH:D005909', (188, 200))	('prostate', 'Disease', (137, 145))	('gastric', 'Disease', (155, 162))	('leukemia', 'Disease', (164, 172))	('leukemia', 'Disease', 'MESH:D007938', (164, 172))	('lymphoma', 'Disease', 'MESH:D008223', (174, 182))
549437	32322580	Nonetheless, although the use of NSC23766 may look promising in some instances, the high effective concentrations (muM range) and the reported off-target effects in platelets, on alfa-1-adrenergic receptors and CXCR4 chemokine receptors, limits its therapeutic use.	('CXCR4', 'Gene', '7852', (211, 216))	('alfa-1-adrenergic', 'MPA', (179, 196))	('limits', 'NegReg', (238, 244))	('CXCR4', 'Gene', (211, 216))	('NSC23766', 'Var', (33, 41))	('NSC23766', 'Chemical', 'MESH:C487513', (33, 41))
549439	32322580	Compounds ZINC08010136 (IC50, 12.2 muM) and ZINC07949036 (IC50, 24.1 muM), and ZINC69391 (IC50 of 61 muM) are some of the molecules identified by this group as Rac1/Tiam1 inhibitors.	('ZINC08010136', 'Var', (10, 22))	('Rac1', 'Gene', (160, 164))	('ZINC69391', 'Chemical', 'MESH:C000595961', (79, 88))	('ZINC07949036', 'Var', (44, 56))	('ZINC69391', 'Var', (79, 88))	('ZINC07949036', 'Chemical', '-', (44, 56))	('ZINC08010136', 'Chemical', '-', (10, 22))	('Rac1', 'Gene', '5879', (160, 164))
549440	32322580	In the case of ZINC69391, this molecule was able to inhibit cell cycle progression, cell proliferation, migration, and lung metastasis in highly invasive breast cancer models.	('invasive breast cancer', 'Disease', 'MESH:D001943', (145, 167))	('inhibit', 'NegReg', (52, 59))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('migration', 'CPA', (104, 113))	('breast cancer', 'Phenotype', 'HP:0003002', (154, 167))	('invasive breast cancer', 'Disease', (145, 167))	('ZINC69391', 'Chemical', 'MESH:C000595961', (15, 24))	('lung metastasis', 'CPA', (119, 134))	('cell proliferation', 'CPA', (84, 102))	('cell cycle progression', 'CPA', (60, 82))	('ZINC69391', 'Var', (15, 24))
549441	32322580	Using the structure of ZINC69391 as a template, a more potent Rac inhibitor, named 1A-116, was produced, but this molecule has a different mechanism of action that does not involve Tiam-1.	('ZINC69391', 'Var', (23, 32))	('Tiam-1', 'Gene', (181, 187))	('Rac', 'Enzyme', (62, 65))	('ZINC69391', 'Chemical', 'MESH:C000595961', (23, 32))	('Tiam-1', 'Gene', '7074', (181, 187))	('1A-116', 'Chemical', '-', (83, 89))
549452	32322580	Phosphorylation of Trio at tyrosine 2681 (Y2681) leads to the activation of Rac1 and promotes colorectal cancer invasion.	('Trio', 'Gene', '7204', (19, 23))	('Rac1', 'Gene', (76, 80))	('Trio', 'Gene', (19, 23))	('colorectal cancer', 'Disease', 'MESH:D015179', (94, 111))	('Y2681', 'Var', (42, 47))	('promotes', 'PosReg', (85, 93))	('colorectal cancer', 'Phenotype', 'HP:0003003', (94, 111))	('Rac1', 'Gene', '5879', (76, 80))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('colorectal cancer', 'Disease', (94, 111))	('activation', 'PosReg', (62, 72))	('tyrosine', 'Chemical', 'MESH:D014443', (27, 35))
549456	32322580	Studies have shown Trio overexpression and (or) mutations in esophageal squamous cell carcinoma, NSCLC, stomach cancer, endometrial cancer, colorectal cancer, and glioblastoma (Table 1).	('stomach cancer', 'Disease', 'MESH:D013274', (104, 118))	('Trio', 'Gene', '7204', (19, 23))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (72, 95))	('endometrial cancer', 'Disease', 'MESH:D016889', (120, 138))	('stomach cancer', 'Phenotype', 'HP:0012126', (104, 118))	('glioblastoma', 'Disease', (163, 175))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (61, 95))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('glioblastoma', 'Phenotype', 'HP:0012174', (163, 175))	('mutations', 'Var', (48, 57))	('colorectal cancer', 'Phenotype', 'HP:0003003', (140, 157))	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('Trio', 'Gene', (19, 23))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('stomach cancer', 'Disease', (104, 118))	('overexpression', 'PosReg', (24, 38))	('NSCLC', 'Disease', 'MESH:D002289', (97, 102))	('colorectal cancer', 'Disease', 'MESH:D015179', (140, 157))	('endometrial cancer', 'Phenotype', 'HP:0012114', (120, 138))	('esophageal squamous cell carcinoma', 'Disease', (61, 95))	('colorectal cancer', 'Disease', (140, 157))	('NSCLC', 'Disease', (97, 102))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('endometrial cancer', 'Disease', (120, 138))	('glioblastoma', 'Disease', 'MESH:D005909', (163, 175))
549457	32322580	In glioblastoma, patients with a low survival rate had higher expression of Trio, Ect2 and Vav3, as well as high Rac1 expression.	('Trio', 'Gene', (76, 80))	('Vav3', 'Gene', (91, 95))	('Rac1', 'Gene', (113, 117))	('Vav3', 'Gene', '10451', (91, 95))	('Rac1', 'Gene', '5879', (113, 117))	('glioblastoma', 'Phenotype', 'HP:0012174', (3, 15))	('expression', 'MPA', (62, 72))	('glioblastoma', 'Disease', (3, 15))	('glioblastoma', 'Disease', 'MESH:D005909', (3, 15))	('patients', 'Species', '9606', (17, 25))	('higher', 'PosReg', (55, 61))	('high', 'Var', (108, 112))	('Trio', 'Gene', '7204', (76, 80))	('Ect2', 'Gene', '1894', (82, 86))	('Ect2', 'Gene', (82, 86))
549458	32322580	The compounds NSC23766 and CPYPP also inhibit Trio and have been tested in a variety of cancer models.	('CPYPP', 'Gene', (27, 32))	('NSC23766', 'Var', (14, 22))	('cancer', 'Disease', (88, 94))	('Trio', 'Gene', (46, 50))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('NSC23766', 'Chemical', 'MESH:C487513', (14, 22))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('inhibit', 'NegReg', (38, 45))	('tested', 'Reg', (65, 71))	('Trio', 'Gene', '7204', (46, 50))
549465	32322580	Vav1 knockdown reduced tumor growth in nude mice from NSCLC cells expressing oncogenic K-Ras.	('knockdown', 'Var', (5, 14))	('nude mice', 'Species', '10090', (39, 48))	('tumor', 'Disease', 'MESH:D009369', (23, 28))	('Vav1', 'Gene', (0, 4))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('reduced', 'NegReg', (15, 22))	('K-Ras', 'Gene', (87, 92))	('NSCLC', 'Disease', (54, 59))	('tumor', 'Disease', (23, 28))	('K-Ras', 'Gene', '16653', (87, 92))	('NSCLC', 'Disease', 'MESH:D002289', (54, 59))
549467	32322580	Moreover, demethylation of VAV1 in the promoter region was shown to increase Vav1 expression in pancreatic cancer, and targeting Vav1 inhibited pancreatic cancer metastasis.	('pancreatic cancer', 'Disease', (96, 113))	('expression', 'MPA', (82, 92))	('Vav1', 'Gene', (77, 81))	('VAV1', 'Gene', (27, 31))	('pancreatic cancer', 'Disease', 'MESH:D010190', (96, 113))	('pancreatic cancer', 'Disease', 'MESH:D010190', (144, 161))	('inhibited', 'NegReg', (134, 143))	('Vav1', 'Gene', (129, 133))	('targeting', 'Var', (119, 128))	('pancreatic cancer metastasis', 'Disease', 'MESH:D010190', (144, 172))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (144, 161))	('demethylation', 'Var', (10, 23))	('increase', 'PosReg', (68, 76))	('VAV1', 'Gene', '7409', (27, 31))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (96, 113))	('pancreatic cancer metastasis', 'Disease', (144, 172))
549470	32322580	Vav1 is expressed in a majority of breast tumors; however, Vav1 may induce apoptosis in certain breast cancer cell lines, in a p53 dependent manner.	('induce', 'Reg', (68, 74))	('breast tumors', 'Disease', (35, 48))	('Vav1', 'Var', (59, 63))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('apoptosis', 'CPA', (75, 84))	('breast cancer', 'Disease', 'MESH:D001943', (96, 109))	('breast tumors', 'Disease', 'MESH:D001943', (35, 48))	('breast cancer', 'Disease', (96, 109))	('breast tumors', 'Phenotype', 'HP:0100013', (35, 48))	('breast cancer', 'Phenotype', 'HP:0003002', (96, 109))	('p53', 'Gene', '7157', (127, 130))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('p53', 'Gene', (127, 130))
549471	32322580	This effect may explain the observation that in early invasive breast cancer, high nuclear expression of Vav1 was correlated with a lower incidence of disease relapse.	('Vav1', 'Gene', (105, 109))	('high', 'Var', (78, 82))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('invasive breast cancer', 'Disease', 'MESH:D001943', (54, 76))	('breast cancer', 'Phenotype', 'HP:0003002', (63, 76))	('invasive breast cancer', 'Disease', (54, 76))
549472	32322580	The E59K and D51E oncogenic Vav1 point mutations identified from human lung adenocarcinoma resulted in truncation and overexpression of Vav1 with increased catalytic GEF activity for Rac1 activation.	('human', 'Species', '9606', (65, 70))	('overexpression', 'PosReg', (118, 132))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (71, 90))	('E59K', 'Mutation', 'p.E59K', (4, 8))	('Vav1', 'Gene', (136, 140))	('increased', 'PosReg', (146, 155))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (71, 90))	('lung adenocarcinoma', 'Disease', (71, 90))	('GEF', 'Gene', (166, 169))	('Vav1', 'Gene', (28, 32))	('truncation', 'MPA', (103, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('D51E', 'Var', (13, 17))	('E59K', 'Var', (4, 8))	('GEF', 'Gene', '9181', (166, 169))	('Rac1', 'Gene', (183, 187))	('Rac1', 'Gene', '5879', (183, 187))	('D51E', 'Mutation', 'p.D51E', (13, 17))
549473	32322580	D797N, another Vav1 mutation, described from NIH-3T3 fibroblasts, also demonstrated enhanced activation of Rac1 and upregulated the downstream effector c-Jun, thereby confirming transformation properties to Vav1.	('c-Jun', 'Gene', (152, 157))	('upregulated', 'PosReg', (116, 127))	('D797N', 'Var', (0, 5))	('NIH-3T3', 'CellLine', 'CVCL:0594', (45, 52))	('D797N', 'Mutation', 'rs950938415', (0, 5))	('c-Jun', 'Gene', '3725', (152, 157))	('Rac1', 'Gene', '5879', (107, 111))	('enhanced activation', 'PosReg', (84, 103))	('Rac1', 'Gene', (107, 111))	('Vav1', 'Gene', (15, 19))
549489	32322580	However, Vav3 expression was higher in ER negative tissue, and high levels of nuclear Vav3 was associated with poorer endocrine therapy response.	('higher', 'PosReg', (29, 35))	('high levels', 'Var', (63, 74))	('Vav3', 'Gene', '10451', (86, 90))	('Vav3', 'Gene', (86, 90))	('expression', 'MPA', (14, 24))	('Vav3', 'Gene', (9, 13))	('Vav3', 'Gene', '10451', (9, 13))
549499	32322580	These residues have been shown to interact tightly with Glu201 and Gln331 in the DH domain of Vav.	('Gln331', 'Var', (67, 73))	('Glu201', 'Var', (56, 62))	('Vav', 'Gene', '7409', (94, 97))	('Glu201', 'Chemical', '-', (56, 62))	('Gln331', 'Chemical', '-', (67, 73))	('Vav', 'Gene', (94, 97))	('interact', 'Interaction', (34, 42))
549509	32322580	In a recent study, azathioprine also blocked Vav1 signaling in pancreatic tumor cells, inhibiting cell migration, and decreasing metastasis in mouse models.	('decreasing', 'NegReg', (118, 128))	('mouse', 'Species', '10090', (143, 148))	('pancreatic tumor', 'Disease', 'MESH:D010190', (63, 79))	('blocked', 'NegReg', (37, 44))	('cell migration', 'CPA', (98, 112))	('azathioprine', 'Chemical', 'MESH:D001379', (19, 31))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('pancreatic tumor', 'Phenotype', 'HP:0002894', (63, 79))	('metastasis', 'CPA', (129, 139))	('azathioprine', 'Var', (19, 31))	('inhibiting', 'NegReg', (87, 97))	('Vav1 signaling', 'MPA', (45, 59))	('pancreatic tumor', 'Disease', (63, 79))
549514	32322580	Thus, phosphorylation patterns in both P-Rex1 and 2 regulate Rac1 activation and has potential for designing novel targeted therapies.	('phosphorylation patterns', 'Var', (6, 30))	('Rac1', 'Gene', '5879', (61, 65))	('P-Rex1 and 2', 'Gene', '57580;80243', (39, 51))	('activation', 'MPA', (66, 76))	('Rac1', 'Gene', (61, 65))	('regulate', 'Reg', (52, 60))
549515	32322580	Both P-Rex1 and P-Rex2, possess oncogenic activities, and are expressed and mutated in multiple cancer types (Table 1).	('P-Rex2', 'Gene', (16, 22))	('oncogenic activities', 'CPA', (32, 52))	('P-Rex1', 'Var', (5, 11))	('P-Rex2', 'Gene', '80243', (16, 22))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('cancer', 'Disease', 'MESH:D009369', (96, 102))	('cancer', 'Disease', (96, 102))
549518	32322580	Furthermore, demethylation in the PREX promoter has been associated with breast cancer mortality.	('cancer mortality', 'Disease', (80, 96))	('cancer mortality', 'Disease', 'MESH:D003643', (80, 96))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('breast cancer', 'Disease', 'MESH:D001943', (73, 86))	('PREX', 'Protein', (34, 38))	('breast cancer', 'Disease', (73, 86))	('demethylation', 'Var', (13, 26))	('associated with', 'Reg', (57, 72))	('breast cancer', 'Phenotype', 'HP:0003002', (73, 86))
549522	32322580	P-Rex2 mutations are also reported from metastatic melanoma, which results in a truncated protein, losing its ability to bind to PTEN and increasing its GEF activity.	('bind', 'Interaction', (121, 125))	('results in', 'Reg', (67, 77))	('losing', 'NegReg', (99, 105))	('PTEN', 'Gene', (129, 133))	('GEF', 'Gene', (153, 156))	('P-Rex2', 'Gene', (0, 6))	('PTEN', 'Gene', '5728', (129, 133))	('P-Rex2', 'Gene', '80243', (0, 6))	('truncated', 'MPA', (80, 89))	('melanoma', 'Disease', 'MESH:D008545', (51, 59))	('ability', 'MPA', (110, 117))	('melanoma', 'Phenotype', 'HP:0002861', (51, 59))	('melanoma', 'Disease', (51, 59))	('increasing', 'PosReg', (138, 148))	('GEF', 'Gene', '9181', (153, 156))	('mutations', 'Var', (7, 16))
549523	32322580	Therefore, inhibiting P-Rex may block breast cancer metastasis, and the compound 1A-116, an analog of the previously discussed ZINC69391, was shown to inhibit the interaction of the GEF P-Rex1 with Rac1 with an IC50 = 4 muM.	('Rac1', 'Gene', '5879', (198, 202))	('inhibiting', 'Var', (11, 21))	('GEF', 'Gene', '9181', (182, 185))	('block breast cancer metastasis', 'Disease', (32, 62))	('Rac1', 'Gene', (198, 202))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('interaction', 'Interaction', (163, 174))	('block breast cancer metastasis', 'Disease', 'MESH:D001943', (32, 62))	('1A-116', 'Chemical', '-', (81, 87))	('breast cancer', 'Phenotype', 'HP:0003002', (38, 51))	('inhibit', 'NegReg', (151, 158))	('ZINC69391', 'Chemical', 'MESH:C000595961', (127, 136))	('GEF', 'Gene', (182, 185))
549525	32322580	Also, IA-116 reduced cell proliferation and invasion in other cancer types, such as leukemia and glioma.	('glioma', 'Disease', (97, 103))	('invasion', 'CPA', (44, 52))	('cell proliferation', 'CPA', (21, 39))	('leukemia', 'Disease', (84, 92))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('leukemia', 'Phenotype', 'HP:0001909', (84, 92))	('IA-116', 'Var', (6, 12))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('glioma', 'Disease', 'MESH:D005910', (97, 103))	('glioma', 'Phenotype', 'HP:0009733', (97, 103))	('reduced', 'NegReg', (13, 20))	('leukemia', 'Disease', 'MESH:D007938', (84, 92))
549537	32322580	Moreover, in a HER2+ breast cancer mouse model, DOCK1 promoted invasion to the lungs, where the lung metastases overexpressed DOCK1 compared to primary tumors.	('promoted', 'PosReg', (54, 62))	('lung metastases', 'Disease', 'MESH:D009362', (96, 111))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('tumors', 'Disease', 'MESH:D009369', (152, 158))	('breast cancer', 'Disease', 'MESH:D001943', (21, 34))	('DOCK1', 'Gene', (48, 53))	('invasion to the lungs', 'CPA', (63, 84))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('breast cancer', 'Disease', (21, 34))	('mouse', 'Species', '10090', (35, 40))	('breast cancer', 'Phenotype', 'HP:0003002', (21, 34))	('DOCK1', 'Var', (126, 131))	('tumors', 'Disease', (152, 158))	('tumors', 'Phenotype', 'HP:0002664', (152, 158))	('lung metastases', 'Disease', (96, 111))
549538	32322580	DOCK1 expression and mutations have been reported from a number of cancers (Table 1).	('DOCK1', 'Gene', (0, 5))	('reported', 'Reg', (41, 49))	('cancers', 'Phenotype', 'HP:0002664', (67, 74))	('cancers', 'Disease', (67, 74))	('cancers', 'Disease', 'MESH:D009369', (67, 74))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('mutations', 'Var', (21, 30))
549540	32322580	This compound also targeted DOCK1 in melanoma cells with the oncogenic Rac1 P29S mutation.	('Rac1', 'Gene', '5879', (71, 75))	('Rac1', 'Gene', (71, 75))	('melanoma', 'Phenotype', 'HP:0002861', (37, 45))	('P29S', 'Var', (76, 80))	('melanoma', 'Disease', (37, 45))	('P29S', 'Mutation', 'rs1057519874', (76, 80))	('melanoma', 'Disease', 'MESH:D008545', (37, 45))	('DOCK1', 'Protein', (28, 33))	('targeted', 'Reg', (19, 27))
549541	32322580	Hence, DOCK1 inhibition could be an approach for the treatment of cancers associated with the Rac1 P29S oncogenic mutation.	('P29S', 'Mutation', 'rs1057519874', (99, 103))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('cancers', 'Phenotype', 'HP:0002664', (66, 73))	('cancers', 'Disease', (66, 73))	('Rac1', 'Gene', '5879', (94, 98))	('cancers', 'Disease', 'MESH:D009369', (66, 73))	('P29S', 'Var', (99, 103))	('Rac1', 'Gene', (94, 98))
549550	32322580	Inhibitory activity of these peptides to DOCK2 was in the nanomolar range, and conjugation with PB1-F2 increased cellular uptake of these peptides.	('DOCK2', 'Gene', (41, 46))	('increased', 'PosReg', (103, 112))	('conjugation', 'Var', (79, 90))	('DOCK2', 'Gene', '1794', (41, 46))	('Inhibitory activity', 'MPA', (0, 19))	('cellular uptake', 'CPA', (113, 128))
549554	32322580	DOCK5 has also being implicated in acute myeloid leukemia (, 30668141), and recently, an oncogenic variant of DOCK5 was described from head and neck squamous cell carcinoma.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (149, 172))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (135, 172))	('DOCK5', 'Gene', '80005', (0, 5))	('neck squamous cell carcinoma', 'Disease', (144, 172))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (35, 57))	('leukemia', 'Phenotype', 'HP:0001909', (49, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (163, 172))	('variant', 'Var', (99, 106))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (144, 172))	('DOCK5', 'Gene', (0, 5))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (41, 57))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (35, 57))	('implicated', 'Reg', (21, 31))	('DOCK5', 'Gene', '80005', (110, 115))	('acute myeloid leukemia', 'Disease', (35, 57))	('DOCK5', 'Gene', (110, 115))
549564	32322580	AZA197 also reduced tumor growth and extended survival in a mouse model of colon cancer.	('colon cancer', 'Phenotype', 'HP:0003003', (75, 87))	('extended', 'PosReg', (37, 45))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('reduced', 'NegReg', (12, 19))	('colon cancer', 'Disease', 'MESH:D015179', (75, 87))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('colon cancer', 'Disease', (75, 87))	('AZA197', 'Var', (0, 6))	('AZA197', 'Chemical', 'MESH:C000589260', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('survival', 'CPA', (46, 54))	('mouse', 'Species', '10090', (60, 65))	('tumor', 'Disease', (20, 25))
549566	32322580	Nonetheless, AZA197 showed toxicity in concentrations higher than 20 muM in NIH3T3 fibroblasts and colon cancer cells, and may not prove to be pharmacologically useful.	('colon cancer', 'Phenotype', 'HP:0003003', (99, 111))	('toxicity', 'Disease', 'MESH:D064420', (27, 35))	('toxicity', 'Disease', (27, 35))	('colon cancer', 'Disease', 'MESH:D015179', (99, 111))	('NIH3T3', 'CellLine', 'CVCL:0594', (76, 82))	('AZA197', 'Chemical', 'MESH:C000589260', (13, 19))	('colon cancer', 'Disease', (99, 111))	('AZA197', 'Var', (13, 19))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))
549567	32322580	Another molecule that inhibits Cdc42 activation through Dbs is Compound 19, an alpha-helix mimetic that targets the K774, L777, and Q770 residues of Dbs that mediate the interaction between Dbs and Cdc42.	('K774', 'Var', (116, 120))	('Cdc42', 'Gene', '998', (198, 203))	('Q770', 'Var', (132, 136))	('Dbs', 'Gene', (149, 152))	('Dbs', 'Gene', '23263', (149, 152))	('Dbs', 'Gene', '23263', (56, 59))	('Dbs', 'Gene', (56, 59))	('Cdc42', 'Gene', (31, 36))	('L777', 'Var', (122, 126))	('Dbs', 'Gene', '23263', (190, 193))	('Dbs', 'Gene', (190, 193))	('Cdc42', 'Gene', (198, 203))	('interaction', 'Interaction', (170, 181))	('Cdc42', 'Gene', '998', (31, 36))	('inhibits', 'NegReg', (22, 30))
549572	32322580	Even though low expression of ITSN1 was recently correlated with higher grade in breast and lung cancer, A role for ITSN in neuroblastoma has been shown by a study where knockdown of ITSN decreased orthotopic neuroblastoma growth in mice.	('neuroblastoma', 'Phenotype', 'HP:0003006', (209, 222))	('neuroblastoma', 'Disease', (124, 137))	('decreased', 'NegReg', (188, 197))	('lung cancer', 'Phenotype', 'HP:0100526', (92, 103))	('knockdown', 'Var', (170, 179))	('mice', 'Species', '10090', (233, 237))	('neuroblastoma growth', 'Disease', (209, 229))	('neuroblastoma', 'Phenotype', 'HP:0003006', (124, 137))	('ITSN1', 'Gene', (30, 35))	('neuroblastoma', 'Disease', 'MESH:D009447', (209, 222))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('ITSN1', 'Gene', '16443', (30, 35))	('neuroblastoma', 'Disease', (209, 222))	('neuroblastoma', 'Disease', 'MESH:D009447', (124, 137))	('neuroblastoma growth', 'Disease', 'MESH:D009447', (209, 229))	('expression', 'MPA', (16, 26))	('breast and lung cancer', 'Disease', 'MESH:D001943', (81, 103))
549574	32322580	The compound Pirl1 was developed to target the Phe56 residue in Cdc42, which has been demonstrated to be crucial for GEF binding.	('GEF', 'Gene', (117, 120))	('Phe56 residue', 'Var', (47, 60))	('Cdc42', 'Gene', '998', (64, 69))	('GEF', 'Gene', '9181', (117, 120))	('Phe56', 'Chemical', '-', (47, 52))	('Cdc42', 'Gene', (64, 69))
549580	32322580	With an IC50 of 0.098 nM, ZCL367 demonstrated beneficial effects in lung and prostate cancer cells by inhibiting migration, proliferation, and cell cycle progression.	('ZCL367', 'Chemical', '-', (26, 32))	('cell cycle progression', 'CPA', (143, 165))	('inhibiting', 'NegReg', (102, 112))	('prostate cancer', 'Disease', (77, 92))	('proliferation', 'CPA', (124, 137))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('beneficial', 'PosReg', (46, 56))	('prostate cancer', 'Phenotype', 'HP:0012125', (77, 92))	('ZCL367', 'Var', (26, 32))	('prostate cancer', 'Disease', 'MESH:D011471', (77, 92))	('migration', 'CPA', (113, 122))	('lung', 'Disease', (68, 72))
549583	32322580	Hence, ZCL367's efficacy and low IC50 makes it a promising anti metastatic cancer therapeutic for further development.	('ZCL367', 'Var', (7, 13))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('cancer', 'Disease', (75, 81))	('ZCL367', 'Chemical', '-', (7, 13))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))
549596	32322580	Notably, a number of HER2 therapy resistance signaling pathways are regulated by Rac signaling and targeting Rac has been shown to block breast cancer metastasis.	('breast cancer', 'Phenotype', 'HP:0003002', (137, 150))	('block breast cancer metastasis', 'Disease', 'MESH:D001943', (131, 161))	('block breast cancer metastasis', 'Disease', (131, 161))	('targeting', 'Var', (99, 108))	('HER2 therapy resistance signaling pathways', 'Pathway', (21, 63))	('Rac', 'Gene', (109, 112))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
549600	32322580	Similar to trastuzumab, lapatinib resistance circumvents its kinase inhibitory function by acquiring point mutations in HER2 and EGFR, as well as via elevated downstream signaling.	('kinase inhibitory function', 'MPA', (61, 87))	('lapatinib', 'Chemical', 'MESH:D000077341', (24, 33))	('downstream signaling', 'MPA', (159, 179))	('trastuzumab', 'Chemical', 'MESH:D000068878', (11, 22))	('EGFR', 'Gene', '1956', (129, 133))	('elevated', 'PosReg', (150, 158))	('HER2', 'Protein', (120, 124))	('EGFR', 'Gene', (129, 133))	('circumvents', 'NegReg', (45, 56))	('point mutations', 'Var', (101, 116))
549602	32322580	In addition, Rac1 inhibition has been shown to overcome gefitinib (EGFR-targeted therapeutic) resistance in NSCLC.	('gefitinib', 'MPA', (56, 65))	('gefitinib', 'Chemical', 'MESH:D000077156', (56, 65))	('Rac1', 'Gene', (13, 17))	('Rac1', 'Gene', '5879', (13, 17))	('NSCLC', 'Disease', (108, 113))	('NSCLC', 'Disease', 'MESH:D002289', (108, 113))	('EGFR', 'Gene', '1956', (67, 71))	('inhibition', 'Var', (18, 28))	('EGFR', 'Gene', (67, 71))
549609	32322580	Therefore, as has been shown by us using mammosphere assays, Rac/Cdc42 inhibition can reduce stem cell-like growth in breast cancer.	('inhibition', 'Var', (71, 81))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('Cdc42', 'Gene', '998', (65, 70))	('breast cancer', 'Disease', 'MESH:D001943', (118, 131))	('reduce', 'NegReg', (86, 92))	('breast cancer', 'Disease', (118, 131))	('stem cell-like growth', 'CPA', (93, 114))	('breast cancer', 'Phenotype', 'HP:0003002', (118, 131))	('Cdc42', 'Gene', (65, 70))
549611	32322580	Given the central role of Rac and Cdc42 in immune cell function, Rac/Cdc42 inhibitors also have potential for targeting immune cell migration and inflammation, including infiltration of perivascular macrophages, increased vascular permeability, and lymphatic penetration.	('Cdc42', 'Gene', (69, 74))	('lymphatic penetration', 'CPA', (249, 270))	('inflammation', 'Disease', 'MESH:D007249', (146, 158))	('inhibitors', 'Var', (75, 85))	('infiltration', 'CPA', (170, 182))	('inflammation', 'Disease', (146, 158))	('immune cell migration', 'CPA', (120, 141))	('vascular permeability', 'CPA', (222, 243))	('Cdc42', 'Gene', '998', (34, 39))	('Cdc42', 'Gene', '998', (69, 74))	('targeting', 'Reg', (110, 119))	('increased', 'PosReg', (212, 221))	('Cdc42', 'Gene', (34, 39))
549612	32322580	Indeed, we have shown that Rac inhibition decreases macrophage and neutrophil penetration of the TMEM.	('decreases', 'NegReg', (42, 51))	('Rac', 'Protein', (27, 30))	('inhibition', 'Var', (31, 41))	('TMEM', 'Chemical', '-', (97, 101))
549613	32322580	Therefore, an additional benefit of Rac/Cdc42 inhibition is the reduction in bone marrow-derived cells that promote the metastatic dissemination of cancer cells in the TMEM.	('cancer', 'Disease', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('TMEM', 'Chemical', '-', (168, 172))	('inhibition', 'Var', (46, 56))	('Cdc42', 'Gene', '998', (40, 45))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('promote', 'PosReg', (108, 115))	('Cdc42', 'Gene', (40, 45))
549618	32322580	NSC23766 has also been shown to overcome resistance to fludarabine in chronic lymphocytic leukemia where Tiam1/Rac1 is upregulated.	('NSC23766', 'Var', (0, 8))	('fludarabine', 'Chemical', 'MESH:C024352', (55, 66))	('chronic lymphocytic leukemia', 'Phenotype', 'HP:0005550', (70, 98))	('chronic lymphocytic leukemia', 'Disease', 'MESH:D015451', (70, 98))	('NSC23766', 'Chemical', 'MESH:C487513', (0, 8))	('overcome', 'PosReg', (32, 40))	('chronic lymphocytic leukemia', 'Disease', (70, 98))	('leukemia', 'Phenotype', 'HP:0001909', (90, 98))	('Rac1', 'Gene', '5879', (111, 115))	('resistance to fludarabine', 'MPA', (41, 66))	('Rac1', 'Gene', (111, 115))
549619	32322580	Also, Rac1 inhibition with NSC23766 increases the cytotoxic effect of Adriamycin, in the treatment of mantle cell lymphoma, an aggressive B-cell lymphoma.	('mantle cell lymphoma', 'Disease', (102, 122))	('cell lymphoma', 'Phenotype', 'HP:0012191', (140, 153))	('aggressive B-cell lymphoma', 'Disease', 'MESH:D016393', (127, 153))	('mantle cell lymphoma', 'Disease', 'MESH:D020522', (102, 122))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (138, 153))	('NSC23766', 'Chemical', 'MESH:C487513', (27, 35))	('aggressive B-cell lymphoma', 'Disease', (127, 153))	('Rac1', 'Gene', '5879', (6, 10))	('Adriamycin', 'Chemical', 'MESH:D004317', (70, 80))	('lymphoma', 'Phenotype', 'HP:0002665', (114, 122))	('lymphoma', 'Phenotype', 'HP:0002665', (145, 153))	('Rac1', 'Gene', (6, 10))	('increases', 'PosReg', (36, 45))	('inhibition', 'NegReg', (11, 21))	('cytotoxic effect', 'CPA', (50, 66))	('cell lymphoma', 'Phenotype', 'HP:0012191', (109, 122))	('NSC23766', 'Var', (27, 35))
549628	32322580	Overall, this review provides ample evidence for the utility of Rac/Cdc42 inhibitors both individually, and in combination with current targeted and cytotoxic therapeutics to overcome therapy resistance and augment established cancer therapies to specifically block metastasis.	('Cdc42', 'Gene', (68, 73))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('inhibitors', 'Var', (74, 84))	('Cdc42', 'Gene', '998', (68, 73))	('metastasis', 'CPA', (266, 276))	('cancer', 'Disease', (227, 233))	('cancer', 'Disease', 'MESH:D009369', (227, 233))	('block', 'NegReg', (260, 265))
549630	32322580	In conclusion, the plethora of compelling data discussed in this review realizes the promise of Rac/Cdc42 inhibitors as viable therapeutics for metastatic cancer, and we look forward to their routine use in standard cancer care.	('Cdc42', 'Gene', (100, 105))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('plethora', 'Phenotype', 'HP:0001050', (19, 27))	('Cdc42', 'Gene', '998', (100, 105))	('inhibitors', 'Var', (106, 116))	('cancer', 'Disease', (216, 222))	('cancer', 'Disease', 'MESH:D009369', (216, 222))	('cancer', 'Disease', (155, 161))	('cancer', 'Disease', 'MESH:D009369', (155, 161))
549638	28860350	Particularly, we identified a novel mutational signature similar to Catalogue Of Somatic Mutations In Cancer (COSMIC)signature 16, which has prognostic value in OSCC.	('Cancer', 'Phenotype', 'HP:0002664', (102, 108))	('Mutations', 'Var', (89, 98))	('SCC', 'Gene', (162, 165))	('SCC', 'Phenotype', 'HP:0002860', (162, 165))	('SCC', 'Gene', '6317', (162, 165))
549639	28860350	Two newly discovered SMGs, CUL3 and ZFP36L2, were validated as important tumour-suppressors specific to the OSCC subtype.	('SCC', 'Phenotype', 'HP:0002860', (109, 112))	('SCC', 'Gene', '6317', (109, 112))	('tumour', 'Disease', (73, 79))	('ZFP36L2', 'Var', (36, 43))	('SMG', 'Gene', (21, 24))	('tumour', 'Phenotype', 'HP:0002664', (73, 79))	('tumour', 'Disease', 'MESH:D009369', (73, 79))	('SCC', 'Gene', (109, 112))	('SMG', 'Gene', '23034', (21, 24))
549640	28860350	CUL3 was homozygously deleted specifically in OSCC and other squamous cell cancers (SCCs).	('SCC', 'Gene', '6317', (84, 87))	('SCC', 'Phenotype', 'HP:0002860', (47, 50))	('SCC', 'Gene', '6317', (47, 50))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (61, 81))	('cancers', 'Phenotype', 'HP:0002664', (75, 82))	('SCC', 'Phenotype', 'HP:0002860', (84, 87))	('CUL3', 'Gene', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('squamous cell cancers', 'Disease', (61, 82))	('SCC', 'Gene', (84, 87))	('squamous cell cancers', 'Phenotype', 'HP:0002860', (61, 82))	('deleted', 'Var', (22, 29))	('SCCs', 'Phenotype', 'HP:0002860', (84, 88))	('SCC', 'Gene', (47, 50))	('squamous cell cancers', 'Disease', 'MESH:D002294', (61, 82))
549641	28860350	Notably, ZFP36L2 is associated with super-enhancer in healthy oesophageal mucosa; DNA hypermethylation in its super-enhancer reduced active histone markers in squamous cancer cells, suggesting an epigenetic inactivation of a super-enhancer-associated SCC suppressor.	('squamous cancer', 'Disease', 'MESH:D002294', (159, 174))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('squamous cancer', 'Disease', (159, 174))	('SCC', 'Phenotype', 'HP:0002860', (251, 254))	('epigenetic inactivation', 'Var', (196, 219))	('SCC', 'Gene', '6317', (251, 254))	('reduced', 'NegReg', (125, 132))	('active histone markers', 'MPA', (133, 155))	('squamous cancer', 'Phenotype', 'HP:0002860', (159, 174))	('SCC', 'Gene', (251, 254))
549649	28860350	SCC-specific hypermethylation of the super-enhancer of ZFP36L2 silences this tumour suppressor.	('SCC', 'Gene', (0, 3))	('SCC', 'Phenotype', 'HP:0002860', (0, 3))	('tumour', 'Disease', 'MESH:D009369', (77, 83))	('silences', 'NegReg', (63, 71))	('hypermethylation', 'Var', (13, 29))	('tumour', 'Disease', (77, 83))	('SCC', 'Gene', '6317', (0, 3))	('ZFP36L2', 'Gene', (55, 62))	('tumour', 'Phenotype', 'HP:0002664', (77, 83))
549652	28860350	Several gene mutations and mutational signatures are correlated with the overall survival of patients with oesophageal cancer, which might serve potential prognostic biomarkers.	('correlated', 'Reg', (53, 63))	('oesophageal cancer', 'Disease', 'MESH:D009369', (107, 125))	('oesophageal cancer', 'Disease', (107, 125))	('mutations', 'Var', (13, 22))	('patients', 'Species', '9606', (93, 101))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
549660	28860350	We, therefore, reasoned that combining samples across data sets and performing an SMG re-analysis will allow us to identify additional driver genes, by increasing the statistical power to distinguish infrequent driver mutations from passengers.	('SMG', 'Gene', (82, 85))	('SMG', 'Gene', '23034', (82, 85))	('mutations', 'Var', (218, 227))	('increasing', 'PosReg', (152, 162))
549670	28860350	With q value=0.1 as a cut-off, 19 and 17 genes were significantly mutated in OSCC and OAC, respectively (figure 1A).	('mutated', 'Var', (66, 73))	('SCC', 'Gene', '6317', (78, 81))	('OAC', 'Disease', (86, 89))	('OAC', 'Chemical', '-', (86, 89))	('SCC', 'Gene', (78, 81))	('SCC', 'Phenotype', 'HP:0002860', (78, 81))
549677	28860350	Importantly, the large number of samples empowered us to identify many novel SMGs which were mutated at moderate or low frequencies, including ATF5, PTCH1, CUL3, ZFP36L2 in OSCC and EPHA2, PCDH18, C6orf114, CHRNB1, PGCP in OAC.	('PCDH18', 'Gene', (189, 195))	('CUL3', 'Gene', (156, 160))	('SMG', 'Gene', (77, 80))	('PTCH1', 'Gene', '5727', (149, 154))	('EPHA2', 'Gene', (182, 187))	('PGCP', 'Gene', '10404', (215, 219))	('SCC', 'Phenotype', 'HP:0002860', (174, 177))	('PTCH1', 'Gene', (149, 154))	('C6orf114', 'Gene', '54438', (197, 205))	('OAC', 'Chemical', '-', (223, 226))	('ZFP36L2', 'Var', (162, 169))	('EPHA2', 'Gene', '1969', (182, 187))	('SCC', 'Gene', '6317', (174, 177))	('SMG', 'Gene', '23034', (77, 80))	('ATF5', 'Gene', '22809', (143, 147))	('C6orf114', 'Gene', (197, 205))	('CHRNB1', 'Gene', '1140', (207, 213))	('ATF5', 'Gene', (143, 147))	('SCC', 'Gene', (174, 177))	('PCDH18', 'Gene', '54510', (189, 195))	('PGCP', 'Gene', (215, 219))	('CHRNB1', 'Gene', (207, 213))
549678	28860350	Some of these, like ATF5 and ZFP36L2, had mutations that occurred at low frequency but were associated with very strong features of driver mutations, leading to significant q values.	('q values', 'MPA', (173, 181))	('mutations', 'Var', (42, 51))	('ATF5', 'Gene', (20, 24))	('ATF5', 'Gene', '22809', (20, 24))
549681	28860350	We next determined the clonal status of these SMGs by assessing their cancer cell fractions through integrative analysis of tumour cellularity (online supplementary table 2), variant allele frequency as well as variant copy number, as described previously.	('SMG', 'Gene', (46, 49))	('SMG', 'Gene', '23034', (46, 49))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('tumour', 'Phenotype', 'HP:0002664', (124, 130))	('variant', 'Var', (175, 182))	('tumour', 'Disease', 'MESH:D009369', (124, 130))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('tumour', 'Disease', (124, 130))
549686	28860350	This result demonstrates that mutations within these SMGs in the non-corresponding subtype (eg, MLL2 mutations in OAC, or DOCK2 mutations in OSCC) arise late during tumorigenesis and may reflect random passenger events rather than drivers.	('mutations', 'Var', (101, 110))	('DOCK2', 'Gene', '1794', (122, 127))	('mutations', 'Var', (128, 137))	('SCC', 'Gene', (142, 145))	('SMG', 'Gene', (53, 56))	('MLL2', 'Gene', '9757', (96, 100))	('SMG', 'Gene', '23034', (53, 56))	('SCC', 'Phenotype', 'HP:0002860', (142, 145))	('mutations', 'Var', (30, 39))	('DOCK2', 'Gene', (122, 127))	('SCC', 'Gene', '6317', (142, 145))	('OAC', 'Chemical', '-', (114, 117))	('MLL2', 'Gene', (96, 100))
549687	28860350	Not surprisingly, SMGs generally had significantly more clonal mutations compared with non-SMGs in both malignancies, in line with the findings in most cancer types reported by us and others (figure 1E).	('SMG', 'Gene', '23034', (18, 21))	('cancer', 'Disease', (152, 158))	('SMG', 'Gene', (91, 94))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('clonal mutations', 'Var', (56, 72))	('malignancies', 'Disease', 'MESH:D009369', (104, 116))	('more', 'PosReg', (51, 55))	('SMG', 'Gene', '23034', (91, 94))	('malignancies', 'Disease', (104, 116))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('SMG', 'Gene', (18, 21))
549690	28860350	OAC cases dominated by signature 17 were found to have more mutations in DOCK2 and PCDH18 (online supplementary table 3).	('PCDH18', 'Gene', (83, 89))	('PCDH18', 'Gene', '54510', (83, 89))	('DOCK2', 'Gene', (73, 78))	('OAC', 'Disease', (0, 3))	('DOCK2', 'Gene', '1794', (73, 78))	('OAC', 'Chemical', '-', (0, 3))	('mutations', 'Var', (60, 69))
549692	28860350	Notably, APOBEC signature-positive OSCC samples had significantly more mutations targeting driver genes including ZNF750, PIK3CA, MLL2, MLL3 and RB1 (online supplementary table 3), with some of these associations having been reported previously.	('RB1', 'Gene', (145, 148))	('PIK3CA', 'Gene', (122, 128))	('ZNF750', 'Gene', '79755', (114, 120))	('MLL3', 'Gene', (136, 140))	('MLL2', 'Gene', '9757', (130, 134))	('APOBEC signature-positive', 'Gene', (9, 34))	('PIK3CA', 'Gene', '5290', (122, 128))	('RB1', 'Gene', '5925', (145, 148))	('MLL2', 'Gene', (130, 134))	('ZNF750', 'Gene', (114, 120))	('SCC', 'Gene', (36, 39))	('mutations', 'Var', (71, 80))	('more', 'PosReg', (66, 70))	('SCC', 'Phenotype', 'HP:0002860', (36, 39))	('SCC', 'Gene', '6317', (36, 39))	('MLL3', 'Gene', '58508', (136, 140))
549694	28860350	Importantly, the large sample size enabled the discovery of novel mutational signatures which have not been established in these cancers.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('cancers', 'Phenotype', 'HP:0002664', (129, 136))	('cancers', 'Disease', 'MESH:D009369', (129, 136))	('cancers', 'Disease', (129, 136))	('mutational', 'Var', (66, 76))
549698	28860350	Signature 4 features frequent C > A mutations resembling a mutational profile induced in vitro by exposing cells to benzo[a]pyrene (a tobacco carcinogen).	('benzo[a]pyrene', 'Chemical', 'MESH:D001564', (116, 130))	('tobacco', 'Species', '4097', (134, 141))	('mutations', 'Var', (36, 45))	('C > A', 'Gene', (30, 35))
549701	28860350	In addition, we found a novel signature, signature-A, which exhibited both C > A transversion and C > T transitions (with a sharp increase in frequency in GCN context) in both OSCC and OAC cohorts.	('C > A transversion', 'Var', (75, 93))	('C > T', 'Var', (98, 103))	('SCC', 'Gene', (177, 180))	('GCN', 'Chemical', '-', (155, 158))	('SCC', 'Phenotype', 'HP:0002860', (177, 180))	('OAC', 'Chemical', '-', (185, 188))	('SCC', 'Gene', '6317', (177, 180))
549703	28860350	Supporting this hypothesis, enriched C > T mutations in the GCN context are also a feature of the established signature 15, which is associated with defective DNA mismatch repair in STAD and small cell lung cancers.	('GCN', 'Chemical', '-', (60, 63))	('small cell lung cancers', 'Disease', (191, 214))	('cancers', 'Phenotype', 'HP:0002664', (207, 214))	('DNA mismatch repair', 'MPA', (159, 178))	('STAD', 'Disease', (182, 186))	('C > T mutations', 'Var', (37, 52))	('lung cancers', 'Phenotype', 'HP:0100526', (202, 214))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('defective', 'Var', (149, 158))	('small cell lung cancers', 'Disease', 'MESH:D055752', (191, 214))	('small cell lung cancers', 'Phenotype', 'HP:0030357', (191, 214))
549707	28860350	We found that mutations of several driver genes (all SMGs except for BRCA1, which was tested because it has been associated with treatment response and survival in oesophageal cancer) were associated with patients' outcome in univariate log-rank analysis, including EP300, AJUBA and BRCA1 in OSCC, and FBXW7 and PTEN in OAC (figure 3A, online supplementary figure 6).	('AJUBA', 'Gene', '84962', (273, 278))	('patients', 'Species', '9606', (205, 213))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('AJUBA', 'Gene', (273, 278))	('FBXW7', 'Gene', (302, 307))	('EP300', 'Gene', '2033', (266, 271))	('SMG', 'Gene', (53, 56))	('PTEN', 'Gene', (312, 316))	('SCC', 'Phenotype', 'HP:0002860', (293, 296))	('mutations', 'Var', (14, 23))	('EP300', 'Gene', (266, 271))	('oesophageal cancer', 'Disease', (164, 182))	('FBXW7', 'Gene', '55294', (302, 307))	('BRCA1', 'Gene', (283, 288))	('associated', 'Reg', (189, 199))	('SCC', 'Gene', '6317', (293, 296))	('PTEN', 'Gene', '5728', (312, 316))	('BRCA1', 'Gene', '672', (69, 74))	('SCC', 'Gene', (293, 296))	('oesophageal cancer', 'Disease', 'MESH:D009369', (164, 182))	('BRCA1', 'Gene', (69, 74))	('SMG', 'Gene', '23034', (53, 56))	('BRCA1', 'Gene', '672', (283, 288))	('OAC', 'Chemical', '-', (320, 323))	('associated', 'Reg', (113, 123))
549709	28860350	When controlling for all covariates in a Cox regression model, KDM6A, EP300 and AJUBA mutations were either significant or borderline significant for OSCC, while FBXW7 remained significant for OAC (figure 3B).	('mutations', 'Var', (86, 95))	('KDM6A', 'Gene', (63, 68))	('OAC', 'Chemical', '-', (193, 196))	('Cox', 'Gene', '1351', (41, 44))	('SCC', 'Phenotype', 'HP:0002860', (151, 154))	('AJUBA', 'Gene', (80, 85))	('SCC', 'Gene', '6317', (151, 154))	('Cox', 'Gene', (41, 44))	('EP300', 'Gene', (70, 75))	('EP300', 'Gene', '2033', (70, 75))	('FBXW7', 'Gene', '55294', (162, 167))	('KDM6A', 'Gene', '7403', (63, 68))	('FBXW7', 'Gene', (162, 167))	('AJUBA', 'Gene', '84962', (80, 85))	('SCC', 'Gene', (151, 154))
549715	28860350	We noted that depletion of either CUL3 or ZFP36L2 (but not ATF5 or PTCH1) consistently enhanced the proliferation of OSCC cells (online supplementary figure 7).	('PTCH1', 'Gene', (67, 72))	('ATF5', 'Gene', (59, 63))	('proliferation', 'CPA', (100, 113))	('SCC', 'Gene', (118, 121))	('PTCH1', 'Gene', '5727', (67, 72))	('enhanced', 'PosReg', (87, 95))	('ATF5', 'Gene', '22809', (59, 63))	('ZFP36L2', 'Var', (42, 49))	('SCC', 'Gene', '6317', (118, 121))	('SCC', 'Phenotype', 'HP:0002860', (118, 121))	('depletion', 'MPA', (14, 23))
549717	28860350	Consistent with the cell proliferation results, silencing of either CUL3 or ZFP36L2 promoted foci formation of different OSCC cells.	('silencing', 'Var', (48, 57))	('SCC', 'Gene', (122, 125))	('CUL3', 'Gene', (68, 72))	('ZFP36L2', 'Gene', (76, 83))	('promoted', 'PosReg', (84, 92))	('SCC', 'Phenotype', 'HP:0002860', (122, 125))	('SCC', 'Gene', '6317', (122, 125))
549719	28860350	Further, ectopic expression of either CUL3 or ZFP36L2 significantly repressed xenograft growth in mice, with ZFP36L2 showing a stronger inhibitory effect (figure 4F).	('ZFP36L2', 'Gene', (46, 53))	('ZFP36L2', 'Var', (109, 116))	('xenograft growth in mice', 'CPA', (78, 102))	('repressed', 'NegReg', (68, 77))	('mice', 'Species', '10090', (98, 102))
549723	28860350	Oxidative stress contributes to the pathogenesis of many malignancies, and mutations in both KEAP1 and NFE2L2 are driver events in a variety of carcinomas, including OSCC but not OAC.	('carcinomas', 'Disease', (144, 154))	('events', 'Reg', (121, 127))	('carcinomas', 'Disease', 'MESH:D002277', (144, 154))	('KEAP1', 'Gene', '9817', (93, 98))	('malignancies', 'Disease', 'MESH:D009369', (57, 69))	('SCC', 'Gene', '6317', (167, 170))	('SCC', 'Phenotype', 'HP:0002860', (167, 170))	('malignancies', 'Disease', (57, 69))	('OAC', 'Disease', (179, 182))	('NFE2L2', 'Gene', '4780', (103, 109))	('Oxidative stress', 'Phenotype', 'HP:0025464', (0, 16))	('KEAP1', 'Gene', (93, 98))	('mutations', 'Var', (75, 84))	('NFE2L2', 'Gene', (103, 109))	('OAC', 'Chemical', '-', (179, 182))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('SCC', 'Gene', (167, 170))	('carcinomas', 'Phenotype', 'HP:0030731', (144, 154))
549725	28860350	In our analysis, both CUL3 and NFE2L2 were significantly mutated in OSCC samples but not in OAC; and as expected, mutations in the CUL3/KEAP1/NFE2L2 pathway were mutually exclusive (online supplementary figure 10A).	('KEAP1', 'Gene', (136, 141))	('CUL3', 'Gene', (22, 26))	('mutations', 'Var', (114, 123))	('SCC', 'Gene', (69, 72))	('SCC', 'Phenotype', 'HP:0002860', (69, 72))	('NFE2L2', 'Gene', '4780', (31, 37))	('OAC', 'Chemical', '-', (92, 95))	('NFE2L2', 'Gene', '4780', (142, 148))	('SCC', 'Gene', '6317', (69, 72))	('NFE2L2', 'Gene', (31, 37))	('mutated', 'Var', (57, 64))	('KEAP1', 'Gene', '9817', (136, 141))	('NFE2L2', 'Gene', (142, 148))
549726	28860350	Notably, interrogation of TCGA copy number data sets revealed focal homozygous deletions in the CUL3 locus in OSCC (figure 5A).	('deletions', 'Var', (79, 88))	('SCC', 'Gene', (111, 114))	('CUL3', 'Gene', (96, 100))	('SCC', 'Phenotype', 'HP:0002860', (111, 114))	('SCC', 'Gene', '6317', (111, 114))
549727	28860350	Examination for both CUL3 genomic mutations and deletions across all TCGA-profiled tumours found that these genetic lesions were highly enriched in SCCs, including LUSC, HNSC, CESC and BLCA, relative to other cancer types (figure 5A,B).	('tumours', 'Disease', (83, 90))	('CESC', 'Disease', (176, 180))	('LUSC', 'Disease', (164, 168))	('cancer', 'Disease', 'MESH:D009369', (209, 215))	('enriched', 'Reg', (136, 144))	('HNSC', 'Disease', (170, 174))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))	('SCCs', 'Phenotype', 'HP:0002860', (148, 152))	('SCC', 'Gene', (148, 151))	('BLCA', 'Disease', (185, 189))	('cancer', 'Disease', (209, 215))	('deletions', 'Var', (48, 57))	('tumours', 'Phenotype', 'HP:0002664', (83, 90))	('SCC', 'Phenotype', 'HP:0002860', (148, 151))	('tumour', 'Phenotype', 'HP:0002664', (83, 89))	('SCC', 'Gene', '6317', (148, 151))	('TCGA-profiled', 'Gene', (69, 82))	('tumours', 'Disease', 'MESH:D009369', (83, 90))
549728	28860350	The genomic deletions led to decreased transcript abundance across all types of SCCs (figure 5C), strongly suggesting CUL3 as tumour suppressor in squamous cell malignancies, and supporting our earlier functional results.	('transcript abundance', 'MPA', (39, 59))	('deletions', 'Var', (12, 21))	('SCC', 'Gene', '6317', (80, 83))	('SCC', 'Phenotype', 'HP:0002860', (80, 83))	('CUL3', 'Gene', (118, 122))	('tumour', 'Phenotype', 'HP:0002664', (126, 132))	('tumour', 'Disease', 'MESH:D009369', (126, 132))	('tumour', 'Disease', (126, 132))	('decreased', 'NegReg', (29, 38))	('SCC', 'Gene', (80, 83))	('SCCs', 'Phenotype', 'HP:0002860', (80, 84))	('squamous cell malignancies', 'Phenotype', 'HP:0002860', (147, 173))	('squamous cell malignancies', 'Disease', (147, 173))	('squamous cell malignancies', 'Disease', 'MESH:D002294', (147, 173))
549730	28860350	As expected, NRF2 pathway was prominently controlled by CUL3, as both NRF2 protein itself and its canonical target genes (ABCC3, PRDX1) were upregulated on depletion of CUL3 (figure 5D,E, online supplementary figure 10B).	('ABCC3', 'Gene', '8714', (122, 127))	('ABCC3', 'Gene', (122, 127))	('PRDX1', 'Gene', '5052', (129, 134))	('NRF2', 'Gene', '4780', (70, 74))	('NRF2', 'Gene', (70, 74))	('NRF2', 'Gene', '4780', (13, 17))	('upregulated', 'PosReg', (141, 152))	('protein', 'Protein', (75, 82))	('NRF2', 'Gene', (13, 17))	('PRDX1', 'Gene', (129, 134))	('depletion', 'Var', (156, 165))	('CUL3', 'Gene', (169, 173))
549731	28860350	Moreover, CUL3 inactivation by either mutation or deletion was significantly associated with increased NRF2 protein expression in patients with TCGA HNSC(figure 5F).	('deletion', 'Var', (50, 58))	('NRF2', 'Gene', (103, 107))	('increased', 'PosReg', (93, 102))	('protein', 'Protein', (108, 115))	('patients', 'Species', '9606', (130, 138))	('CUL3', 'Gene', (10, 14))	('mutation', 'Var', (38, 46))	('inactivation', 'NegReg', (15, 27))	('NRF2', 'Gene', '4780', (103, 107))
549733	28860350	Notably, CUL3 knockdown increased beta-catenin protein level, with concordant changes of Wnt-beta-catenin downstream factors, such as c-Myc, Cyclin D1 and p27 (figure 5D).	('Wnt', 'Gene', '35975', (89, 92))	('CUL3', 'Gene', (9, 13))	('Cyclin D1', 'Gene', (141, 150))	('beta-catenin', 'Gene', (93, 105))	('Myc', 'Gene', '4609', (136, 139))	('Myc', 'Gene', (136, 139))	('beta-catenin', 'Gene', '1499', (34, 46))	('changes', 'Reg', (78, 85))	('Wnt', 'Gene', (89, 92))	('p27', 'Gene', '3429', (155, 158))	('beta-catenin', 'Gene', (34, 46))	('p27', 'Gene', (155, 158))	('beta-catenin', 'Gene', '1499', (93, 105))	('knockdown', 'Var', (14, 23))	('Cyclin D1', 'Gene', '595', (141, 150))	('increased', 'PosReg', (24, 33))
549734	28860350	Further supporting this regulation, CUL3 mutation or deletion were significantly associated with the upregulation of beta-catenin protein in both OSCC and HNSC cohorts (figure 5F).	('CUL3', 'Gene', (36, 40))	('beta-catenin', 'Gene', (117, 129))	('SCC', 'Gene', (147, 150))	('SCC', 'Phenotype', 'HP:0002860', (147, 150))	('upregulation', 'PosReg', (101, 113))	('deletion', 'Var', (53, 61))	('SCC', 'Gene', '6317', (147, 150))	('beta-catenin', 'Gene', '1499', (117, 129))	('mutation', 'Var', (41, 49))
549742	28860350	For example, ZFP36L2 inhibited T cell leukaemia in mice, but it enhanced the malignancy of pancreatic adenocarcinoma cells.	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('mice', 'Species', '10090', (51, 55))	('malignancy of pancreatic adenocarcinoma', 'Disease', 'MESH:D010190', (77, 116))	('pancreatic adenocarcinoma', 'Phenotype', 'HP:0006725', (91, 116))	('malignancy of pancreatic adenocarcinoma', 'Disease', (77, 116))	('ZFP36L2', 'Var', (13, 20))	('inhibited', 'NegReg', (21, 30))	('T cell leukaemia', 'Disease', 'MESH:D015458', (31, 47))	('malignancy of pancreatic', 'Phenotype', 'HP:0002894', (77, 101))	('T cell leukaemia', 'Disease', (31, 47))	('enhanced', 'PosReg', (64, 72))
549744	28860350	Considering the low incidence of ZFP36L2 mutations in OSCC (~2%), we explored alternative genomic aberrations.	('mutations', 'Var', (41, 50))	('ZFP36L2', 'Gene', (33, 40))	('SCC', 'Gene', (55, 58))	('SCC', 'Phenotype', 'HP:0002860', (55, 58))	('SCC', 'Gene', '6317', (55, 58))
549750	28860350	Importantly, all but one of the 13 CpGs uniquely hypermethylated in OSCC were inversely correlated with ZFP36L2 expression, indicative of epigenetic silencing (figure 6F,G).	('SCC', 'Gene', (69, 72))	('SCC', 'Phenotype', 'HP:0002860', (69, 72))	('correlated', 'Interaction', (88, 98))	('SCC', 'Gene', '6317', (69, 72))	('ZFP36L2', 'Gene', (104, 111))	('hypermethylated', 'Var', (49, 64))	('expression', 'MPA', (112, 122))
549756	28860350	Importantly, H3K27ac modification was markedly diminished in OSCC cells in the same region that both gained DNA methylation (figure 6H, between red dotted lines) and correlated with ZFP36L2 silencing (figure 6F,G).	('silencing', 'NegReg', (190, 199))	('SCC', 'Phenotype', 'HP:0002860', (62, 65))	('diminished', 'NegReg', (47, 57))	('SCC', 'Gene', '6317', (62, 65))	('gained', 'PosReg', (101, 107))	('DNA methylation', 'MPA', (108, 123))	('ZFP36L2', 'MPA', (182, 189))	('H3K27ac', 'Var', (13, 20))	('SCC', 'Gene', (62, 65))
549759	28860350	In LUSC, we confirmed that the ZFP36L2 super-enhancer region had a hypermethylation pattern similar to OSCC in two out of four tumour cases, but was unmethylated in two normal lung epithelium samples (online supplementary figure 11).	('hypermethylation', 'MPA', (67, 83))	('SCC', 'Gene', '6317', (104, 107))	('tumour', 'Phenotype', 'HP:0002664', (127, 133))	('tumour', 'Disease', 'MESH:D009369', (127, 133))	('SCC', 'Gene', (104, 107))	('SCC', 'Phenotype', 'HP:0002860', (104, 107))	('ZFP36L2', 'Var', (31, 38))	('tumour', 'Disease', (127, 133))
549762	28860350	Both the pattern of super-enhancer hypermethylation and its correlation to ZFP36L2 silencing were strikingly similar across all types of SCCs, but not STAD (figure 6C-G and figure 7A).	('hypermethylation', 'Var', (35, 51))	('ZFP36L2', 'Gene', (75, 82))	('SCC', 'Phenotype', 'HP:0002860', (137, 140))	('silencing', 'MPA', (83, 92))	('SCC', 'Gene', '6317', (137, 140))	('SCCs', 'Phenotype', 'HP:0002860', (137, 141))	('SCC', 'Gene', (137, 140))
549764	28860350	Given that increased DNA methylation can prevent the regulation of some transcription factors on targeted DNA elements, these data together indicate that hypermethylation may decrease the binding of transcription factor(s) to ZFP36L2 super-enhancer and maintain its silencing in SCC.	('binding', 'Interaction', (188, 195))	('SCC', 'Gene', (279, 282))	('decrease', 'NegReg', (175, 183))	('SCC', 'Phenotype', 'HP:0002860', (279, 282))	('prevent', 'NegReg', (41, 48))	('regulation', 'MPA', (53, 63))	('SCC', 'Gene', '6317', (279, 282))	('silencing', 'MPA', (266, 275))	('hypermethylation', 'Var', (154, 170))
549767	28860350	A number of subtype-specific genetic aberrations have been established as driver events, such as the OSCC-specific amplification of SOX2 and TP63 and mutations of NOTCH1 and ZNF750, and the OAC-specific deletion of SMAD4 and mutations of KRAS and ARID1A.	('ZNF750', 'Gene', (174, 180))	('SMAD4', 'Gene', (215, 220))	('ARID1A', 'Gene', (247, 253))	('mutations', 'Var', (150, 159))	('SMAD4', 'Gene', '4089', (215, 220))	('NOTCH1', 'Gene', (163, 169))	('SCC', 'Phenotype', 'HP:0002860', (102, 105))	('TP63', 'Gene', (141, 145))	('ARID1A', 'Gene', '8289', (247, 253))	('OAC', 'Chemical', '-', (190, 193))	('KRAS', 'Gene', '3845', (238, 242))	('deletion', 'Var', (203, 211))	('NOTCH1', 'Gene', '4851', (163, 169))	('TP63', 'Gene', '8626', (141, 145))	('SCC', 'Gene', '6317', (102, 105))	('SOX2', 'Gene', (132, 136))	('mutations', 'Var', (225, 234))	('SOX2', 'Gene', '6657', (132, 136))	('KRAS', 'Gene', (238, 242))	('ZNF750', 'Gene', '79755', (174, 180))	('SCC', 'Gene', (102, 105))
549770	28860350	The present data show that these two subtypes are molecularly distinct and reveal several new distinguishing molecular features including (1) novel SMGs and differences in clonal composition; (2) subtype-specific mutational signatures and a signature-based prognostic biomarker; and (3) subtype-specific inactivation of a novel tumour suppressor, ZFP36L2, by both genetic and epigenetic mechanisms.	('SMG', 'Gene', (148, 151))	('tumour', 'Phenotype', 'HP:0002664', (328, 334))	('SMG', 'Gene', '23034', (148, 151))	('tumour', 'Disease', 'MESH:D009369', (328, 334))	('tumour', 'Disease', (328, 334))	('mutational', 'Var', (213, 223))	('inactivation', 'NegReg', (304, 316))	('ZFP36L2', 'Gene', (347, 354))
549772	28860350	However, one should keep in mind that even a subtle increase of the rate of sequencing artefacts and/or SNPs in mutation calling may make true SMGs harder to be distinguished from the background, leading to false-negative results.	('SNPs', 'Var', (104, 108))	('SMG', 'Gene', '23034', (143, 146))	('SMG', 'Gene', (143, 146))
549776	28860350	Two out of four OSCC-specific SMGs (CUL3 and ZFP36L2) displayed strong antiproliferation function in OSCC but not in OAC cells.	('SCC', 'Phenotype', 'HP:0002860', (102, 105))	('SCC', 'Gene', '6317', (102, 105))	('SCC', 'Phenotype', 'HP:0002860', (17, 20))	('SCC', 'Gene', '6317', (17, 20))	('SMG', 'Gene', (30, 33))	('SMG', 'Gene', '23034', (30, 33))	('ZFP36L2', 'Var', (45, 52))	('OAC', 'Chemical', '-', (117, 120))	('SCC', 'Gene', (102, 105))	('antiproliferation', 'MPA', (71, 88))	('SCC', 'Gene', (17, 20))
549780	29399148	Mutant-allele fraction heterogeneity is associated with non-small cell lung cancer patient survival Genetic intratumor heterogeneity is associated with tumor occurrence, development and overall outcome.	('associated', 'Reg', (136, 146))	('tumor', 'Disease', (113, 118))	('non-small cell lung cancer', 'Disease', (56, 82))	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (56, 82))	('tumor', 'Disease', (152, 157))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (60, 82))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (56, 82))	('patient', 'Species', '9606', (83, 90))	('Mutant-allele', 'Var', (0, 13))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('lung cancer', 'Phenotype', 'HP:0100526', (71, 82))
549795	29399148	Recently, a study has proposed a new method, mutant-allele tumor heterogeneity (MATH), that has been successfully applied in head and neck squamous cell carcinoma (HNSC) populations to differentiate patient prognosis.	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (125, 162))	('neck squamous cell carcinoma', 'Disease', (134, 162))	('mutant-allele', 'Var', (45, 58))	('tumor', 'Disease', (59, 64))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (139, 162))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (134, 162))	('carcinoma', 'Phenotype', 'HP:0030731', (153, 162))	('patient', 'Species', '9606', (199, 206))	('HNSC', 'Phenotype', 'HP:0012288', (164, 168))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
549802	29399148	To identify genomic loci that had tumor-specific mutations based on tumor-normal pairs, the number of mutant reads and reference allele reads at each mutant locus was obtained from whole exome sequencing data of tumor and adjacent normal tissues.	('tumor', 'Disease', (68, 73))	('tumor', 'Disease', (34, 39))	('mutations', 'Var', (49, 58))	('tumor', 'Disease', 'MESH:D009369', (212, 217))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('tumor', 'Disease', (212, 217))
549803	29399148	MAF, also called variant allele frequency (VAF), was calculated as: As reported previously, MAF was influenced by presence of sub-clonal mutations and copy number alterations, which are higher when a locus is mutated earlier in a clonal evolution or undergoes allele-specific amplification.	('VAF', 'Chemical', '-', (43, 46))	('influenced', 'Reg', (100, 110))	('copy number alterations', 'Var', (151, 174))
549804	29399148	The patients usually had a number of mutant loci, leading to different MAF values (most of them were hundreds) within each patient.	('patient', 'Species', '9606', (123, 130))	('patient', 'Species', '9606', (4, 11))	('mutant', 'Var', (37, 43))	('patients', 'Species', '9606', (4, 12))	('MAF values', 'MPA', (71, 81))
549818	29399148	In this study, based on the theory that high genetic heterogeneity is associated with worse overall survival, we propose an information entropy-based score, EMAF, to evaluate the uncertainty of individual genome-wide mutational distribution patterns of tumor DNA, also described as MAF heterogeneity.	('tumor', 'Disease', 'MESH:D009369', (253, 258))	('tumor', 'Phenotype', 'HP:0002664', (253, 258))	('associated', 'Reg', (70, 80))	('tumor', 'Disease', (253, 258))	('high genetic heterogeneity', 'Var', (40, 66))
549821	29399148	Our hypothesis is that high EMAF indicates an early start and a high percentage of sub-clonal mutations, which make the tumor more aggressive as well as representing a more disordered regulation mechanism.	('disordered', 'Disease', 'MESH:D030342', (173, 183))	('aggressive', 'CPA', (131, 141))	('disordered', 'Disease', (173, 183))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('sub-clonal mutations', 'Var', (83, 103))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('tumor', 'Disease', (120, 125))
549832	29399148	NSCLC is so complicated that could be affected by somatic mutation explored in this study as well as some other factors such as performance status, chemotherapy after surgery or relapse, which might cause bias.	('NSCLC', 'Disease', 'MESH:D002289', (0, 5))	('NSCLC', 'Phenotype', 'HP:0030358', (0, 5))	('affected', 'Reg', (38, 46))	('somatic mutation', 'Var', (50, 66))	('NSCLC', 'Disease', (0, 5))
549947	33795635	Aberration in PI3K-AKT pathway has involved in the tumorigenesis in many types of cancer.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor', 'Disease', (51, 56))	('involved', 'Reg', (35, 43))	('AKT', 'Gene', '207', (19, 22))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('tumor', 'Disease', 'MESH:D009369', (51, 56))	('AKT', 'Gene', (19, 22))	('Aberration', 'Var', (0, 10))
549948	33795635	Inhibition of CDK4/6 pathway has demonstrated favorable effects in patients with dysregulated CDK4/6 activity.	('CDK4/6', 'Gene', (14, 20))	('patients', 'Species', '9606', (67, 75))	('activity', 'MPA', (101, 109))	('CDK4/6', 'Gene', '1019;1021', (94, 100))	('Inhibition', 'Var', (0, 10))	('CDK4/6', 'Gene', '1019;1021', (14, 20))	('dysregulated', 'Var', (81, 93))	('CDK4/6', 'Gene', (94, 100))
549951	33795635	The sub-studies evaluated the newly developed drugs based on the following mutations: (1) taselisib for PIK3CA mutations, (2) palbociclib for CDK gene alteration, (3) AZD4547 for FGFR gene alteration, (4) rilotumumab against MET plus erlotinib targeting EGFR, (5) talazoparib targeting PARP and telisotuzumab vedotin against MET.	('palbociclib', 'Chemical', 'MESH:C500026', (126, 137))	('telisotuzumab', 'Chemical', '-', (295, 308))	('PIK3CA', 'Gene', '5290', (104, 110))	('MET', 'Gene', (325, 328))	('AZD4547', 'Chemical', 'MESH:C572463', (167, 174))	('mutations', 'Var', (111, 120))	('taselisib', 'Chemical', 'MESH:C582924', (90, 99))	('rilotumumab', 'Chemical', 'MESH:C524459', (205, 216))	('MET', 'Gene', '79811', (225, 228))	('vedotin', 'Chemical', '-', (309, 316))	('EGFR', 'Gene', (254, 258))	('FGFR', 'Gene', (179, 183))	('PARP', 'Gene', '1302', (286, 290))	('PIK3CA', 'Gene', (104, 110))	('MET', 'Gene', '79811', (325, 328))	('talazoparib', 'Chemical', 'MESH:C586365', (264, 275))	('PARP', 'Gene', (286, 290))	('mutations', 'Var', (75, 84))	('erlotinib', 'Chemical', 'MESH:D000069347', (234, 243))	('EGFR', 'Gene', '1956', (254, 258))	('MET', 'Gene', (225, 228))
549953	33795635	In Lung-MAP trial, if patients were found to harbor PIK3CA mutation, they would be assigned to S1400B sub-study.	('patients', 'Species', '9606', (22, 30))	('PIK3CA', 'Gene', (52, 58))	('mutation', 'Var', (59, 67))	('S1400B', 'SUBSTITUTION', 'None', (95, 101))	('PIK3CA', 'Gene', '5290', (52, 58))	('S1400B', 'Var', (95, 101))
549955	33795635	For patients harboring mutations in CCND1, CCND2, CCND3, and CDK4, they would be allocated into sub-study S1400C, subjecting to palbociclib (investigational) vs docetaxel (standard of care).	('CCND3', 'Gene', '896', (50, 55))	('CCND2', 'Gene', (43, 48))	('palbociclib', 'Chemical', 'MESH:C500026', (128, 139))	('CCND1', 'Gene', (36, 41))	('CDK4', 'Gene', (61, 65))	('CCND1', 'Gene', '595', (36, 41))	('S1400C', 'Mutation', 'p.S1400C', (106, 112))	('mutations', 'Var', (23, 32))	('CCND3', 'Gene', (50, 55))	('CDK4', 'Gene', '1019', (61, 65))	('patients', 'Species', '9606', (4, 12))	('CCND2', 'Gene', '894', (43, 48))	('docetaxel', 'Chemical', 'MESH:D000077143', (161, 170))
549956	33795635	The S1400D sub-study evaluating AZD4547 (investigational) vs docetaxel (standard of care) had minimal activity but bearable safety in LUSC patients with predominant FGFR1/FGFR3-amplification.	('patients', 'Species', '9606', (139, 147))	('FGFR3', 'Gene', (171, 176))	('AZD4547', 'Var', (32, 39))	('FGFR1', 'Gene', (165, 170))	('FGFR1', 'Gene', '2260', (165, 170))	('AZD4547', 'Chemical', 'MESH:C572463', (32, 39))	('docetaxel', 'Chemical', 'MESH:D000077143', (61, 70))	('S1400D', 'Mutation', 'p.S1400D', (4, 10))	('FGFR3', 'Gene', '2261', (171, 176))	('LUSC', 'Disease', (134, 138))
549972	28759038	Recently, understudied repetitive DNA regions called microsatellites have been identified as genetic risk markers for a number of diseases including various cancers (breast, ovarian and brain).	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('microsatellites', 'Var', (53, 68))	('cancers', 'Disease', 'MESH:D009369', (157, 164))	('cancers', 'Phenotype', 'HP:0002664', (157, 164))	('breast, ovarian', 'Disease', 'MESH:D010051', (166, 181))	('cancers', 'Disease', (157, 164))
549974	28759038	Comparing whole-exome germline sequencing data from 488 TCGA lung cancer samples to germline exome data from 390 control samples from the 1000 genomes project, we identified 119 potentially informative microsatellite loci.	('lung cancer', 'Disease', (61, 72))	('lung cancer', 'Phenotype', 'HP:0100526', (61, 72))	('microsatellite loci', 'Var', (202, 221))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('lung cancer', 'Disease', 'MESH:D008175', (61, 72))
549987	28759038	However, an abundance of neurological disorders have been linked to length specific variations in repetitive DNA microsatellites (MST).	('neurological disorders', 'Disease', 'MESH:D009422', (25, 47))	('linked', 'Reg', (58, 64))	('variations', 'Var', (84, 94))	('neurological disorders', 'Disease', (25, 47))
549988	28759038	Recent studies have shown that microsatellites contribute to the genetic complexity of various cancers.	('contribute', 'Reg', (47, 57))	('cancers', 'Phenotype', 'HP:0002664', (95, 102))	('microsatellites', 'Var', (31, 46))	('cancers', 'Disease', (95, 102))	('cancers', 'Disease', 'MESH:D009369', (95, 102))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))
549989	28759038	Based on these previous findings it is hypothesized that microsatellites may play a role in the genetics of lung cancer.	('lung cancer', 'Disease', 'MESH:D008175', (108, 119))	('play', 'Reg', (77, 81))	('microsatellites', 'Var', (57, 72))	('role', 'Reg', (84, 88))	('lung cancer', 'Disease', (108, 119))	('lung cancer', 'Phenotype', 'HP:0100526', (108, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
549990	28759038	Our previous work in computationally discovering clinically informative MST loci from publically available data sets (The Cancer Genome Atlas of affected individuals, the 1000 Genomes Project of healthy 'normal' individuals) have yielded disease specific germline MST loci variations for breast cancer, ovarian cancer, glioblastoma and lower-grade glioma and that these germline variants were rarely altered in matching tumors.	('tumor', 'Phenotype', 'HP:0002664', (420, 425))	('Cancer', 'Phenotype', 'HP:0002664', (122, 128))	('Cancer Genome Atlas', 'Disease', (122, 141))	('glioma', 'Phenotype', 'HP:0009733', (348, 354))	('tumors', 'Disease', (420, 426))	('cancer', 'Phenotype', 'HP:0002664', (295, 301))	('cancer', 'Phenotype', 'HP:0002664', (311, 317))	('tumors', 'Disease', 'MESH:D009369', (420, 426))	('ovarian cancer', 'Disease', 'MESH:D010051', (303, 317))	('breast cancer', 'Phenotype', 'HP:0003002', (288, 301))	('glioblastoma', 'Disease', 'MESH:D005909', (319, 331))	('breast cancer', 'Disease', 'MESH:D001943', (288, 301))	('ovarian cancer', 'Disease', (303, 317))	('breast cancer', 'Disease', (288, 301))	('glioma', 'Disease', (348, 354))	('glioblastoma', 'Disease', (319, 331))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (122, 141))	('glioma', 'Disease', 'MESH:D005910', (348, 354))	('ovarian cancer', 'Phenotype', 'HP:0100615', (303, 317))	('MST', 'Gene', (264, 267))	('tumors', 'Phenotype', 'HP:0002664', (420, 426))	('glioblastoma', 'Phenotype', 'HP:0012174', (319, 331))	('variations', 'Var', (273, 283))
549991	28759038	We have also shown somatic MST variability and the presence of minor alleles can act as indicative disease markers for colorectal and liver cancer.	('liver cancer', 'Phenotype', 'HP:0002896', (134, 146))	('minor', 'Var', (63, 68))	('colorectal and liver cancer', 'Disease', 'MESH:D015179', (119, 146))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('presence', 'Var', (51, 59))
549992	28759038	The goal of this research was to discover and further evaluate a set of microsatellite markers for lung cancer risk via comparison of patient germline and normal control germline exome sequences.	('lung cancer', 'Disease', (99, 110))	('microsatellite', 'Var', (72, 86))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('lung cancer', 'Disease', 'MESH:D008175', (99, 110))	('patient', 'Species', '9606', (134, 141))	('lung cancer', 'Phenotype', 'HP:0100526', (99, 110))
550022	28759038	On average 37% of the lung cancer samples in these 5 studies contained mutations in at least one of the 13 genes (Supplementary Table 10).	('lung cancer', 'Disease', (22, 33))	('contained', 'Reg', (61, 70))	('lung cancer', 'Phenotype', 'HP:0100526', (22, 33))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('lung cancer', 'Disease', 'MESH:D008175', (22, 33))	('mutations', 'Var', (71, 80))
550023	28759038	An LUSC study with 177 lung cancer samples had ~50% of the samples with mutations in at least one out of the 13 genes (Supplementary Table 10).	('mutations', 'Var', (72, 81))	('lung cancer', 'Disease', (23, 34))	('lung cancer', 'Phenotype', 'HP:0100526', (23, 34))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('lung cancer', 'Disease', 'MESH:D008175', (23, 34))	('LUSC', 'Phenotype', 'HP:0030359', (3, 7))
550026	28759038	When all 13 genes were examined for possible drug-ability, using DrugDB, REL and ARID1B were found to be clinically actionable.	('ARID1B', 'Gene', (81, 87))	('DrugDB', 'Var', (65, 71))	('ARID1B', 'Gene', '57492', (81, 87))
550043	28759038	Mutations in REL was found to co-occur with mutations in 4 other signature genes (PPP1R21, CCDC88A, ATG3 and PRPF18) and similarly ARID1B was found to co-occur with 2 signature genes (IMPG1 and FUBP3; Supplementary Table 11).	('PRPF18', 'Gene', (109, 115))	('CCDC88A', 'Gene', '55704', (91, 98))	('PRPF18', 'Gene', '8559', (109, 115))	('ATG3', 'Gene', (100, 104))	('IMPG1', 'Gene', '3617', (184, 189))	('FUBP3', 'Gene', '8939', (194, 199))	('FUBP3', 'Gene', (194, 199))	('ARID1B', 'Gene', (131, 137))	('IMPG1', 'Gene', (184, 189))	('PPP1R21', 'Gene', '129285', (82, 89))	('Mutations', 'Var', (0, 9))	('mutations', 'Var', (44, 53))	('ATG3', 'Gene', '64422', (100, 104))	('ARID1B', 'Gene', '57492', (131, 137))	('CCDC88A', 'Gene', (91, 98))	('REL', 'Gene', (13, 16))	('PPP1R21', 'Gene', (82, 89))
550053	28759038	It can be deduced that alterations in REL could predispose a smoker to increased risk of cancer compared to a non-smoker.	('REL', 'Gene', (38, 41))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('cancer', 'Disease', (89, 95))	('alterations', 'Var', (23, 34))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('predispose', 'Reg', (48, 58))
550054	28759038	Overexpression of REL has been associated to many lymphoid cancers such as primary mediastinal B-cell lymphoma, classical Hodgkin's lymphoma, and solid tumors such as breast cancer, pancreatic cancer and head and neck cancer but not lung cancer.	('pancreatic cancer', 'Disease', 'MESH:D010190', (182, 199))	('breast cancer', 'Disease', (167, 180))	('lymphoma', 'Disease', (102, 110))	('lymphoma', 'Disease', 'MESH:D008223', (102, 110))	('lung cancer', 'Phenotype', 'HP:0100526', (233, 244))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('Overexpression', 'Var', (0, 14))	('lymphoma', 'Disease', (132, 140))	('lymphoma', 'Disease', 'MESH:D008223', (132, 140))	('head and neck cancer', 'Phenotype', 'HP:0012288', (204, 224))	('pancreatic cancer', 'Disease', (182, 199))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('associated', 'Reg', (31, 41))	('lymphoid cancers', 'Disease', (50, 66))	("Hodgkin's lymphoma", 'Phenotype', 'HP:0012189', (122, 140))	('solid tumors', 'Disease', (146, 158))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	("Hodgkin's lymphoma", 'Disease', 'MESH:D006689', (122, 140))	('head and neck cancer', 'Disease', 'MESH:D006258', (204, 224))	('lymphoma', 'Phenotype', 'HP:0002665', (102, 110))	('lung cancer', 'Disease', (233, 244))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (182, 199))	('lymphoma', 'Phenotype', 'HP:0002665', (132, 140))	('lymphoid cancers', 'Disease', 'MESH:D009369', (50, 66))	('solid tumors', 'Disease', 'MESH:D009369', (146, 158))	('breast cancer', 'Phenotype', 'HP:0003002', (167, 180))	("Hodgkin's lymphoma", 'Disease', (122, 140))	('REL', 'Gene', (18, 21))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('cancers', 'Phenotype', 'HP:0002664', (59, 66))	('lung cancer', 'Disease', 'MESH:D008175', (233, 244))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (95, 110))	('tumors', 'Phenotype', 'HP:0002664', (152, 158))	('breast cancer', 'Disease', 'MESH:D001943', (167, 180))
550056	28759038	It can be inferred that intronic mutations located in between two exons in close proximity of each other can affect protein structure in the REL homology domain that can influence downstream effects of the NFB pathway and consequently predispose individuals to cancer.	('protein structure in the REL homology domain', 'MPA', (116, 160))	('cancer', 'Phenotype', 'HP:0002664', (261, 267))	('intronic mutations', 'Var', (24, 42))	('NFB pathway', 'Pathway', (206, 217))	('affect', 'Reg', (109, 115))	('cancer', 'Disease', (261, 267))	('cancer', 'Disease', 'MESH:D009369', (261, 267))	('predispose', 'Reg', (235, 245))	('influence', 'Reg', (170, 179))
550059	28759038	Dysfunctions in the two significantly enriched pathways can possibly encourage lung carcinogenesis through chromatin remodeling, inflammation and tumor microenvironment restructuring.	('Dysfunctions', 'Var', (0, 12))	('encourage', 'PosReg', (69, 78))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('lung carcinogenesis', 'Disease', (79, 98))	('tumor', 'Disease', (146, 151))	('inflammation', 'Disease', 'MESH:D007249', (129, 141))	('inflammation', 'Disease', (129, 141))	('lung carcinogenesis', 'Disease', 'MESH:D063646', (79, 98))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
550079	26436532	Systematic analysis of somatic mutations impacting gene expression in 12 tumour types We present a novel hierarchical Bayes statistical model, xseq, to systematically quantify the impact of somatic mutations on expression profiles.	('tumour', 'Disease', (73, 79))	('mutations', 'Var', (31, 40))	('impacting', 'Reg', (41, 50))	('tumour', 'Phenotype', 'HP:0002664', (73, 79))	('tumour', 'Disease', 'MESH:D009369', (73, 79))
550080	26436532	We then use xseq to analyse thousands of tumour data sets available through The Cancer Genome Atlas, to systematically quantify somatic mutations impacting expression profiles.	('tumour', 'Phenotype', 'HP:0002664', (41, 47))	('tumour', 'Disease', 'MESH:D009369', (41, 47))	('Cancer Genome Atlas', 'Disease', (80, 99))	('expression profiles', 'MPA', (156, 175))	('mutations', 'Var', (136, 145))	('Cancer', 'Phenotype', 'HP:0002664', (80, 86))	('impacting', 'Reg', (146, 155))	('tumour', 'Disease', (41, 47))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (80, 99))
550081	26436532	We identify 30 novel cis-effect tumour suppressor gene candidates, enriched in loss-of-function mutations and biallelic inactivation.	('tumour', 'Disease', (32, 38))	('loss-of-function', 'NegReg', (79, 95))	('biallelic inactivation', 'Var', (110, 132))	('tumour', 'Phenotype', 'HP:0002664', (32, 38))	('mutations', 'Var', (96, 105))	('tumour', 'Disease', 'MESH:D009369', (32, 38))
550082	26436532	We reveal two important novel characteristics of mutation impact on expression: (1) patients harbouring known driver mutations exhibit different downstream gene expression consequences; (2) expression patterns for some mutations are stable across tumour types.	('mutations', 'Var', (117, 126))	('tumour', 'Phenotype', 'HP:0002664', (247, 253))	('patients', 'Species', '9606', (84, 92))	('tumour type', 'Disease', 'MESH:D009369', (247, 258))	('tumour type', 'Disease', (247, 258))	('mutations', 'Var', (219, 228))
550083	26436532	These results have critical implications for identification and interpretation of mutations with consequent impact on transcription in cancer.	('cancer', 'Disease', (135, 141))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('mutations', 'Var', (82, 91))	('transcription', 'MPA', (118, 131))	('cancer', 'Disease', 'MESH:D009369', (135, 141))	('impact', 'Reg', (108, 114))
550084	26436532	Assessing functional impact of mutations in cancer on gene expression can improve our understanding of cancer biology and may identify potential therapeutic targets.	('mutations', 'Var', (31, 40))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('improve', 'PosReg', (74, 81))	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
550086	26436532	describe a novel statistical model named xseq for a systematic survey of how mutations impact transcriptome landscapes across 12 different tumour types.	('tumour type', 'Disease', (139, 150))	('tumour type', 'Disease', 'MESH:D009369', (139, 150))	('tumour', 'Phenotype', 'HP:0002664', (139, 145))	('mutations', 'Var', (77, 86))	('transcriptome landscapes', 'MPA', (94, 118))	('impact', 'Reg', (87, 93))
550087	26436532	Human cancers acquire malignant properties following a stepwise accumulation of somatic genomic alterations and subsequent evolutionary selection on resultant phenotypic changes.	('Human', 'Species', '9606', (0, 5))	('alterations', 'Var', (96, 107))	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('malignant properties', 'CPA', (22, 42))	('cancers', 'Disease', 'MESH:D009369', (6, 13))	('cancers', 'Phenotype', 'HP:0002664', (6, 13))	('cancers', 'Disease', (6, 13))
550089	26436532	We have assessed the impact of mutations on gene expression as a means of quantifying potential phenotypic effects, and for novel cancer gene discovery.	('cancer', 'Disease', (130, 136))	('mutations', 'Var', (31, 40))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))
550090	26436532	This concept is motivated by biological hypotheses predicting that some functional mutations will exhibit a 'transcriptional shadow', resulting from a mechanistic impact on the gene expression profile of a tumour.	('mutations', 'Var', (83, 92))	('tumour', 'Phenotype', 'HP:0002664', (206, 212))	('gene expression profile', 'MPA', (177, 200))	('tumour', 'Disease', 'MESH:D009369', (206, 212))	('tumour', 'Disease', (206, 212))	('impact', 'Reg', (163, 169))
550091	26436532	For example, loss-of-function mutations (nonsense mutations, frame-shifting indels, splice site mutations or homozygous copy number deletions) occurring in tumour suppressor genes such as TP53 can cause loss of expression due to nonsense-mediated messenger RNA (mRNA) decay or gene dosage effects.	('tumour', 'Disease', 'MESH:D009369', (156, 162))	('loss-of-function', 'NegReg', (13, 29))	('tumour', 'Disease', (156, 162))	('tumour', 'Phenotype', 'HP:0002664', (156, 162))	('mutations', 'Var', (30, 39))	('frame-shifting', 'Var', (61, 75))	('TP53', 'Gene', '7157', (188, 192))	('TP53', 'Gene', (188, 192))	('mutations', 'Var', (96, 105))	('expression', 'MPA', (211, 221))	('loss', 'NegReg', (203, 207))
550092	26436532	beta-Catenin (CTNNB1) mutations, which drive constitutive activation of Wnt signalling in several cancer types, are a potent example of mutational impact on gene expression.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('CTNNB1', 'Gene', '1499', (14, 20))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('Wnt signalling', 'MPA', (72, 86))	('beta-Catenin', 'Gene', (0, 12))	('beta-Catenin', 'Gene', '1499', (0, 12))	('cancer', 'Disease', (98, 104))	('mutations', 'Var', (22, 31))	('CTNNB1', 'Gene', (14, 20))	('activation', 'PosReg', (58, 68))
550093	26436532	Large-scale data sets generated by international consortia provide opportunities to define the landscape of mutations impacting gene expression in thousands of tumours across the major cancer types.	('tumours across the major cancer', 'Disease', (160, 191))	('mutations', 'Var', (108, 117))	('tumours across the major cancer', 'Disease', 'MESH:D009369', (160, 191))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('gene expression', 'MPA', (128, 143))	('tumour', 'Phenotype', 'HP:0002664', (160, 166))	('impacting', 'Reg', (118, 127))	('tumours', 'Phenotype', 'HP:0002664', (160, 167))
550094	26436532	The Cancer Genome Atlas (TCGA) projects have generated genomic and transcriptomic data from multiple cancer types, providing a systematic characterization of somatic mutations, copy number alterations, oncogenic processes, mutated sub-networks or pathways, and genomic signature-defined tumour subtypes.	('cancer', 'Disease', 'MESH:D009369', (101, 107))	('mutated', 'Var', (223, 230))	('mutations', 'Var', (166, 175))	('tumour', 'Disease', (287, 293))	('cancer', 'Disease', (101, 107))	('Cancer', 'Phenotype', 'HP:0002664', (4, 10))	('sub-networks', 'Pathway', (231, 243))	('copy number alterations', 'Var', (177, 200))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('Cancer Genome Atlas', 'Disease', (4, 23))	('tumour', 'Phenotype', 'HP:0002664', (287, 293))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (4, 23))	('tumour', 'Disease', 'MESH:D009369', (287, 293))
550095	26436532	MOCA detects differently expressed genes in the presence of mutations in a gene, and tests the significance of the correlation (between mutation and gene differential expression).	('mutations', 'Var', (60, 69))	('detects', 'Reg', (5, 12))	('MOCA', 'Gene', '1795', (0, 4))	('MOCA', 'Gene', (0, 4))
550099	26436532	We identify 30 novel cis-effect tumour suppressor gene candidates, enriched in loss-of-function mutations and frequent biallelic inactivations.	('tumour', 'Disease', (32, 38))	('loss-of-function', 'NegReg', (79, 95))	('tumour', 'Phenotype', 'HP:0002664', (32, 38))	('mutations', 'Var', (96, 105))	('tumour', 'Disease', 'MESH:D009369', (32, 38))
550102	26436532	On the basis of the trans-analysis, we find two important characteristics of mutations impacting gene expression that could not be revealed with other methods: (1) a stratification of patients harbouring known driver mutations, but that exhibit different downstream gene expression consequences; (2) identification of mutations driving expression patterns that are stable across tumour types, thereby nominating important molecular targets for therapeutic intervention, transcending anatomic sites of origin.	('patients', 'Species', '9606', (184, 192))	('impacting', 'Reg', (87, 96))	('mutations', 'Var', (318, 327))	('tumour', 'Phenotype', 'HP:0002664', (379, 385))	('mutations', 'Var', (77, 86))	('tumour type', 'Disease', (379, 390))	('gene expression', 'MPA', (97, 112))	('tumour type', 'Disease', 'MESH:D009369', (379, 390))
550108	26436532	The output of xseq consists of: (a) the probability that a recurrently mutated gene g influences gene expression across the population of patients (denoted by P(Dg=1), Supplementary Table 2); and (b) the probability that an individual mutation in gene g in an individual patient m influences expression within that patient (denoted by P(Fg,m=1)).	('mutation', 'Var', (235, 243))	('patient', 'Species', '9606', (315, 322))	('influences', 'Reg', (86, 96))	('patient', 'Species', '9606', (271, 278))	('expression', 'MPA', (292, 302))	('patient', 'Species', '9606', (138, 145))	('m influences', 'Reg', (279, 291))	('gene expression', 'MPA', (97, 112))	('patients', 'Species', '9606', (138, 146))
550110	26436532	Gg,m,n {downregulation, neutral, upregulation} denotes the status of the nth gene connected to gene g in patient m. The central assumption is that a mutation in gene g of patient m impacting gene expression (denoted by Fg,m=1) more frequently co-associates with non-neutral states in its connected genes, compared with the mutations that do not impact expression.	('gene expression', 'MPA', (191, 206))	('patient', 'Species', '9606', (105, 112))	('patient', 'Species', '9606', (171, 178))	('impacting', 'Reg', (181, 190))	('mutation', 'Var', (149, 157))
550111	26436532	To represent a recurrent pattern of expression impact across multiple patients, we consider information across all patients with a mutation in gene g. This allows for borrowing of statistical strength across multiple gene expression patterns co-associating with mutations to generalize whether a mutated gene is impacting expression across the population (denoted by Dg=1).	('mutated', 'Var', (296, 303))	('patients', 'Species', '9606', (115, 123))	('patients', 'Species', '9606', (70, 78))	('impacting', 'Reg', (312, 321))	('expression', 'MPA', (322, 332))	('mutation', 'Var', (131, 139))
550112	26436532	The learning problem is to estimate the conditional probabilities of a variable given its parents, for example, thetaF=1 D=1:the probability of a mutation impacting expression in a specific patient given that this gene's mutations impact expression across patients (Fig.	('mutations', 'Var', (221, 230))	('impact', 'Reg', (231, 237))	('expression', 'MPA', (165, 175))	('patients', 'Species', '9606', (256, 264))	('impacting', 'Reg', (155, 164))	('expression', 'MPA', (238, 248))	('mutation', 'Var', (146, 154))	('patient', 'Species', '9606', (256, 263))	('patient', 'Species', '9606', (190, 197))
550114	26436532	The classifiers were motivated by the pattern of distributed loss-of-function mutations across a gene for tumour suppressors (for example, TP53) and hotspot mutations at one or relatively few loci for oncogenes (for example, KRAS).	('tumour', 'Phenotype', 'HP:0002664', (106, 112))	('tumour', 'Disease', 'MESH:D009369', (106, 112))	('KRAS', 'Gene', (225, 229))	('TP53', 'Gene', '7157', (139, 143))	('mutations', 'Var', (78, 87))	('KRAS', 'Gene', '3845', (225, 229))	('tumour', 'Disease', (106, 112))	('TP53', 'Gene', (139, 143))	('loss-of-function', 'NegReg', (61, 77))
550120	26436532	To examine how the model would translate to independently generated data, we used the METABRIC data to validate the predicted copy number alterations from TCGA in breast cancer.	('TCGA', 'Gene', (155, 159))	('copy number alterations', 'Var', (126, 149))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('breast cancer', 'Disease', 'MESH:D001943', (163, 176))	('breast cancer', 'Phenotype', 'HP:0003002', (163, 176))	('breast cancer', 'Disease', (163, 176))
550128	26436532	We next characterized the tumour suppressor properties of the 65 xseq cis-effect predictions for consistency with known patterns of enrichment for loss-of-function mutations (Methods).	('tumour', 'Disease', 'MESH:D009369', (26, 32))	('tumour', 'Disease', (26, 32))	('loss-of-function', 'NegReg', (147, 163))	('tumour', 'Phenotype', 'HP:0002664', (26, 32))	('mutations', 'Var', (164, 173))
550138	26436532	Of the 30 novel predictions, 18 genes accumulated enriched loss-of-function mutations (P(TSG)>=0.2, P value<0.001), 10 genes encode transcription factors (P value<0.05), 21 genes (P value<0.001) encode human phosphoproteins, three genes reside on the X chromosome (P value<0.1).	('mutations', 'Var', (76, 85))	('human', 'Species', '9606', (202, 207))	('loss-of-function', 'NegReg', (59, 75))	('TSG', 'Gene', (89, 92))	('TSG', 'Gene', '57045', (89, 92))
550142	26436532	We next estimated the proportion of known tumour suppressor genes harbouring cis-effect loss-of-function mutations.	('tumour', 'Phenotype', 'HP:0002664', (42, 48))	('tumour', 'Disease', 'MESH:D009369', (42, 48))	('mutations', 'Var', (105, 114))	('tumour', 'Disease', (42, 48))	('loss-of-function', 'NegReg', (88, 104))
550144	26436532	We found that 23/131 genes (significant enrichment of cis-effect genes, P value<0.001) were predicted to exhibit cis-expression effects indicating that loss-of-function mutations in ~17.6% of tumour suppressor genes yield concomitant changes in mRNA expression levels.	('mRNA expression levels', 'MPA', (245, 267))	('tumour', 'Phenotype', 'HP:0002664', (192, 198))	('mutations', 'Var', (169, 178))	('tumour', 'Disease', 'MESH:D009369', (192, 198))	('tumour', 'Disease', (192, 198))	('loss-of-function', 'NegReg', (152, 168))	('changes', 'Reg', (234, 241))
550145	26436532	Application of xseq to predict mutations impacting expression in trans resulted in a total of 150 genes across the 12 cancer types (P(D)>=0.8; Supplementary Table 7; Supplementary Fig.	('cancer', 'Disease', (118, 124))	('mutations', 'Var', (31, 40))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('impacting', 'Reg', (41, 50))	('expression', 'MPA', (51, 61))	('cancer', 'Disease', 'MESH:D009369', (118, 124))
550153	26436532	The gene which harboured the largest number of high-probability mutations was KPNA2 in breast cancer (Supplementary Fig.	('KPNA2', 'Gene', (78, 83))	('breast cancer', 'Disease', 'MESH:D001943', (87, 100))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('KPNA2', 'Gene', '3838', (78, 83))	('breast cancer', 'Disease', (87, 100))	('mutations', 'Var', (64, 73))	('breast cancer', 'Phenotype', 'HP:0003002', (87, 100))
550154	26436532	To examine other sources of evidence of functional effects, we analysed high-probability missense mutations across all the tumour types, and computed the enrichment of phosphorylation-related SNVs (pSNVs).	('tumour type', 'Disease', (123, 134))	('missense mutations', 'Var', (89, 107))	('tumour type', 'Disease', 'MESH:D009369', (123, 134))	('phosphorylation-related', 'MPA', (168, 191))	('tumour', 'Phenotype', 'HP:0002664', (123, 129))
550157	26436532	The Pan-Cancer data set included 241,700 (236,367 unique) missense mutations.	('missense mutations', 'Var', (58, 76))	('Cancer', 'Disease', 'MESH:D009369', (8, 14))	('Cancer', 'Phenotype', 'HP:0002664', (8, 14))	('Cancer', 'Disease', (8, 14))
550159	26436532	We asked whether these mutations across tumour types correlated with the dysregulation of the same set of genes.	('tumour type', 'Disease', 'MESH:D009369', (40, 51))	('tumour type', 'Disease', (40, 51))	('correlated', 'Reg', (53, 63))	('mutations', 'Var', (23, 32))	('tumour', 'Phenotype', 'HP:0002664', (40, 46))	('dysregulation', 'MPA', (73, 86))
550160	26436532	We focused on those genes whose mutations were predicted to influence gene expression in multiple tumour types.	('multiple tumour', 'Disease', (89, 104))	('tumour', 'Phenotype', 'HP:0002664', (98, 104))	('tumour type', 'Disease', (98, 109))	('tumour type', 'Disease', 'MESH:D009369', (98, 109))	('influence', 'Reg', (60, 69))	('mutations', 'Var', (32, 41))	('multiple tumour', 'Disease', 'MESH:D009369', (89, 104))
550161	26436532	For each gene connected to the mutated gene g in a tumour type, we counted how many times this gene was dysregulated (P(G='upregulation')>=0.5 or P(G='downregulation')>=0.5) in the presence of high-probability mutations (P(F)>=0.5).	('mutations', 'Var', (210, 219))	('dysregulated', 'PosReg', (104, 116))	('tumour', 'Phenotype', 'HP:0002664', (51, 57))	('tumour type', 'Disease', 'MESH:D009369', (51, 62))	("G='upregulation", 'PosReg', (120, 135))	('tumour type', 'Disease', (51, 62))
550163	26436532	Mutations in RB1 correlated with the same group of gene dysregulations across several tumour types.	('RB1', 'Gene', '5925', (13, 16))	('gene dysregulations', 'MPA', (51, 70))	('tumour', 'Phenotype', 'HP:0002664', (86, 92))	('Mutations', 'Var', (0, 9))	('tumour type', 'Disease', (86, 97))	('tumour type', 'Disease', 'MESH:D009369', (86, 97))	('RB1', 'Gene', (13, 16))	('correlated', 'Reg', (17, 27))
550164	26436532	In particular, we observed that RB1 mutations correlated with E2F family gene upregulations (for example, E2F1; Supplementary Data 7; Supplementary Fig.	('upregulations', 'PosReg', (78, 91))	('RB1', 'Gene', (32, 35))	('mutations', 'Var', (36, 45))	('E2F1', 'Gene', '1869', (106, 110))	('E2F1', 'Gene', (106, 110))	('E2F family gene', 'Gene', (62, 77))	('RB1', 'Gene', '5925', (32, 35))
550167	26436532	To confirm these correlations, for each gene connected to RB1 in the original full influence graph (Methods), in each tumour type, we compared the expression of this gene in the patients with RB1 mutations to the patients without RB1 mutations using the Limma package.	('tumour type', 'Disease', 'MESH:D009369', (118, 129))	('RB1', 'Gene', '5925', (58, 61))	('RB1', 'Gene', '5925', (192, 195))	('RB1', 'Gene', '5925', (230, 233))	('patients', 'Species', '9606', (178, 186))	('mutations', 'Var', (196, 205))	('tumour', 'Phenotype', 'HP:0002664', (118, 124))	('patients', 'Species', '9606', (213, 221))	('tumour type', 'Disease', (118, 129))	('RB1', 'Gene', (58, 61))	('RB1', 'Gene', (192, 195))	('RB1', 'Gene', (230, 233))	('compared', 'Reg', (134, 142))
550171	26436532	In addition, aberrations (mutations and amplifications) in the transcription factor NFE2L2 in six different tumour types (BLCA, head and neck squamous cell carcinoma, kidney renal clear cell carcinoma, lung adenocarcinoma, LUSC and UCEC) exhibited trans-effects on gene expression (P(D)>=0.8).	('trans-effects', 'Reg', (248, 261))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (137, 165))	('tumour', 'Phenotype', 'HP:0002664', (108, 114))	('kidney renal clear cell carcinoma', 'Disease', 'MESH:C538614', (167, 200))	('lung adenocarcinoma', 'Disease', (202, 221))	('NFE2L2', 'Gene', (84, 90))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (142, 165))	('carcinoma', 'Phenotype', 'HP:0030731', (191, 200))	('carcinoma', 'Phenotype', 'HP:0030731', (212, 221))	('aberrations', 'Var', (13, 24))	('kidney renal clear cell carcinoma', 'Disease', (167, 200))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (202, 221))	('carcinoma', 'Phenotype', 'HP:0030731', (156, 165))	('gene expression', 'MPA', (265, 280))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (202, 221))	('tumour type', 'Disease', 'MESH:D009369', (108, 119))	('NFE2L2', 'Gene', '4780', (84, 90))	('tumour type', 'Disease', (108, 119))	('neck squamous cell carcinoma', 'Disease', (137, 165))
550173	26436532	26) were significantly upregulated in five and four tumour types, respectively, in the presence of NFE2L2 aberrations (FDR<0.1; Supplementary Data 7).	('upregulated', 'PosReg', (23, 34))	('NFE2L2', 'Gene', (99, 105))	('tumour', 'Phenotype', 'HP:0002664', (52, 58))	('tumour type', 'Disease', 'MESH:D009369', (52, 63))	('tumour type', 'Disease', (52, 63))	('aberrations', 'Var', (106, 117))	('NFE2L2', 'Gene', '4780', (99, 105))
550176	26436532	28 show the correlation between NFE2L2 aberrations and its direct regulator and binding partner, KEAP1 expression upregulation.	('upregulation', 'PosReg', (114, 126))	('NFE2L2', 'Gene', (32, 38))	('KEAP1', 'Gene', '9817', (97, 102))	('KEAP1', 'Gene', (97, 102))	('aberrations', 'Var', (39, 50))	('NFE2L2', 'Gene', '4780', (32, 38))
550177	26436532	We investigated whether xseq probabilities P(F) could stratify patients harbouring mutations in the same cancer driver gene.	('mutations', 'Var', (83, 92))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('patients', 'Species', '9606', (63, 71))
550178	26436532	in each tumour type for the presence of bimodal xseq P(F) distributions over patients harbouring mutations in the genes of interest (Supplementary Methods).	('mutations', 'Var', (97, 106))	('tumour', 'Phenotype', 'HP:0002664', (8, 14))	('patients', 'Species', '9606', (77, 85))	('tumour type', 'Disease', (8, 19))	('tumour type', 'Disease', 'MESH:D009369', (8, 19))
550180	26436532	This was particularly evident for CTNNB1 mutations in UCEC (Fig.	('mutations', 'Var', (41, 50))	('UCEC', 'Disease', (54, 58))	('CTNNB1', 'Gene', (34, 40))	('CTNNB1', 'Gene', '1499', (34, 40))
550181	26436532	6a); 53/72 patients harboured high-probability CTNNB1 mutations (P(F)>=0.5), with all 53 patients harbouring CTNNB1 hotspot mutations (mutations hitting codons between 31 and 45).	('CTNNB1', 'Gene', (47, 53))	('CTNNB1', 'Gene', (109, 115))	('mutations', 'Var', (54, 63))	('mutations', 'Var', (135, 144))	('CTNNB1', 'Gene', '1499', (47, 53))	('CTNNB1', 'Gene', '1499', (109, 115))	('patients', 'Species', '9606', (89, 97))	('patients', 'Species', '9606', (11, 19))
550182	26436532	By contrast, only 9/19 patients without high xseq probability CTNNB1 mutations harboured hotspot mutations (Fig.	('mutations', 'Var', (97, 106))	('mutations', 'Var', (69, 78))	('patients', 'Species', '9606', (23, 31))	('CTNNB1', 'Gene', (62, 68))	('CTNNB1', 'Gene', '1499', (62, 68))
550183	26436532	In addition, 9/19 patients harboured POLE mutations, or were annotated as 'ultramutated' (tumours with more mutations than Q3+IQR x 4.5, where Q3 is the third quartile of mutation counts across a corresponding tumour type, and IQR is the interquartile range, as defined in syn1729383), suggesting that the CTNNB1 mutations were inconsequential passenger mutations (Supplementary Fig.	('CTNNB1', 'Gene', '1499', (306, 312))	('mutations', 'Var', (108, 117))	('tumour', 'Phenotype', 'HP:0002664', (90, 96))	('tumour', 'Phenotype', 'HP:0002664', (210, 216))	('tumours', 'Phenotype', 'HP:0002664', (90, 97))	('tumour type', 'Disease', (210, 221))	('CTNNB1', 'Gene', (306, 312))	('mutations', 'Var', (313, 322))	('patients', 'Species', '9606', (18, 26))	('tumour type', 'Disease', 'MESH:D009369', (210, 221))	('tumours', 'Disease', 'MESH:D009369', (90, 97))	('tumours', 'Disease', (90, 97))
550186	26436532	Similar results for RB1 mutations in UCEC are shown in Fig.	('UCEC', 'Disease', (37, 41))	('mutations', 'Var', (24, 33))	('RB1', 'Gene', (20, 23))	('RB1', 'Gene', '5925', (20, 23))
550187	26436532	All 11 loss-of-function mutations (in eight patients) were predicted to have high probabilities (P(F)>=0.5); however, only 2/13 patients that did not harbour loss-of-function mutations were predicted to accumulate high-probability mutations (P(F)>=0.5, Fig.	('patients', 'Species', '9606', (44, 52))	('mutations', 'Var', (231, 240))	('loss-of-function', 'NegReg', (7, 23))	('mutations', 'Var', (24, 33))	('patients', 'Species', '9606', (128, 136))
550189	26436532	As such, patients' tumours with these 'inert' mutations do not exhibit expected pathway dysregulation.	('patients', 'Species', '9606', (9, 17))	('tumours', 'Phenotype', 'HP:0002664', (19, 26))	('mutations', 'Var', (46, 55))	('tumours', 'Disease', 'MESH:D009369', (19, 26))	('tumours', 'Disease', (19, 26))	('tumour', 'Phenotype', 'HP:0002664', (19, 25))
550191	26436532	TP53 mutations in UCEC also showed bimodal distributions (Supplementary Fig.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))
550192	26436532	TP53 frequently accumulates both loss-of-function mutations and missense mutations.	('TP53', 'Gene', '7157', (0, 4))	('missense mutations', 'Var', (64, 82))	('TP53', 'Gene', (0, 4))	('mutations', 'Var', (50, 59))	('loss-of-function', 'NegReg', (33, 49))
550193	26436532	However, patients with P(F)>=0.5 were more likely to harbour copy number hemizygous deletions (36 patients harboured co-occurring hemizygous deletions, compared with eight patients with P(F)<0.5; only nine patients lacked copy number alterations in the group with P(F)>=0.5 compared with 12 in the group with P(F)<0.5, P value<0.005.)	('P(F)>=0.5', 'Var', (23, 32))	('patients', 'Species', '9606', (9, 17))	('copy number', 'Var', (61, 72))	('patients', 'Species', '9606', (98, 106))	('patients', 'Species', '9606', (206, 214))	('patients', 'Species', '9606', (172, 180))
550194	26436532	We developed a probabilistic model, xseq to quantitatively assess the association of mutations with dysregulated gene expression in 12 tumour types.	('tumour type', 'Disease', 'MESH:D009369', (135, 146))	('association', 'Interaction', (70, 81))	('tumour', 'Phenotype', 'HP:0002664', (135, 141))	('mutations', 'Var', (85, 94))	('tumour type', 'Disease', (135, 146))
550197	26436532	These genes showed the hallmarks of tumour suppressor genes including a distribution of loss-of-function mutations, and biallelic inactivation through loss-of-function mutations and heterozygous deletions.	('tumour', 'Disease', 'MESH:D009369', (36, 42))	('tumour', 'Disease', (36, 42))	('loss-of-function', 'NegReg', (151, 167))	('mutations', 'Var', (105, 114))	('tumour', 'Phenotype', 'HP:0002664', (36, 42))	('loss-of-function', 'NegReg', (88, 104))	('mutations', 'Var', (168, 177))
550198	26436532	In addition, we assessed the landscape of mutations impacting gene expression in trans across the 12 tumour types.	('tumour type', 'Disease', (101, 112))	('gene expression', 'MPA', (62, 77))	('impacting', 'Reg', (52, 61))	('tumour', 'Phenotype', 'HP:0002664', (101, 107))	('mutations', 'Var', (42, 51))	('tumour type', 'Disease', 'MESH:D009369', (101, 112))
550200	26436532	Recent synthesis of mutation rates and discovery 'saturation' in genome-wide sequencing studies has indicated that current standard of study design has under-sampled important mutations, and that for some 50 tumour types, sequencing of >2,000 cases are needed to reach comprehensive sampling.	('mutations', 'Var', (176, 185))	('tumour type', 'Disease', 'MESH:D009369', (208, 219))	('under-sampled', 'NegReg', (152, 165))	('tumour type', 'Disease', (208, 219))	('tumour', 'Phenotype', 'HP:0002664', (208, 214))
550203	26436532	In our analysis, constitutive activation of Wnt signalling genes due to CTNNB1 mutation segregates almost exclusively with known hotspot mutations.	('activation', 'PosReg', (30, 40))	('Wnt signalling genes', 'Gene', (44, 64))	('CTNNB1', 'Gene', (72, 78))	('mutation', 'Var', (79, 87))	('CTNNB1', 'Gene', '1499', (72, 78))
550204	26436532	However, several cases exhibited mutation in CTNNB1 without evidence of Wnt activation, resulting in low xseq probabilities.	('CTNNB1', 'Gene', '1499', (45, 51))	('mutation', 'Var', (33, 41))	('CTNNB1', 'Gene', (45, 51))	('exhibited', 'Reg', (23, 32))	('low xseq probabilities', 'MPA', (101, 123))
550208	26436532	Despite distinct histologies and cell contexts of source tumours, RB1 loss-of-function mutations and NFE2L2 mutations/amplifications exhibited similar expression patterns.	('NFE2L2', 'Gene', (101, 107))	('tumours', 'Phenotype', 'HP:0002664', (57, 64))	('RB1', 'Gene', '5925', (66, 69))	('mutations/amplifications', 'Var', (108, 132))	('tumours', 'Disease', 'MESH:D009369', (57, 64))	('tumours', 'Disease', (57, 64))	('loss-of-function', 'NegReg', (70, 86))	('tumour', 'Phenotype', 'HP:0002664', (57, 63))	('NFE2L2', 'Gene', '4780', (101, 107))	('mutations', 'Var', (87, 96))	('RB1', 'Gene', (66, 69))
550210	26436532	Accordingly, we observed that RB1 mutations correlated with E2F family gene upregulation across tumour types.	('upregulation', 'PosReg', (76, 88))	('E2F family gene', 'Gene', (60, 75))	('tumour', 'Phenotype', 'HP:0002664', (96, 102))	('tumour type', 'Disease', (96, 107))	('RB1', 'Gene', (30, 33))	('tumour type', 'Disease', 'MESH:D009369', (96, 107))	('mutations', 'Var', (34, 43))	('RB1', 'Gene', '5925', (30, 33))
550212	26436532	We observed NFE2L2 mutations correlated with upregulation of KEAP1, as well as of oxidative stress genes (for example, GCLM, GCLC, TXNRD1, GPX2 and NQO1).	('KEAP1', 'Gene', (61, 66))	('NQO1', 'Gene', '1728', (148, 152))	('NFE2L2', 'Gene', (12, 18))	('GPX2', 'Gene', '2877', (139, 143))	('oxidative stress', 'Phenotype', 'HP:0025464', (82, 98))	('GCLM', 'Gene', (119, 123))	('TXNRD1', 'Gene', (131, 137))	('GPX2', 'Gene', (139, 143))	('mutations', 'Var', (19, 28))	('TXNRD1', 'Gene', '7296', (131, 137))	('GCLM', 'Gene', '2730', (119, 123))	('KEAP1', 'Gene', '9817', (61, 66))	('upregulation', 'PosReg', (45, 57))	('NQO1', 'Gene', (148, 152))	('NFE2L2', 'Gene', '4780', (12, 18))	('GCLC', 'Gene', (125, 129))	('GCLC', 'Gene', '2729', (125, 129))
550213	26436532	While therapeutic responses to targeted inhibitors administered against the same mutation can have variable effects due to intrinsic gene expression context (for example, BRAF inhibition in melanoma and colorectal cancer), the mutations we outlined (such as RB1 and NFE2L2 mutations) exhibit stable profiles and represent important targets for future development of broadly applicable therapeutics.	('RB1', 'Gene', (258, 261))	('NFE2L2', 'Gene', (266, 272))	('melanoma', 'Disease', (190, 198))	('melanoma', 'Phenotype', 'HP:0002861', (190, 198))	('colorectal cancer', 'Phenotype', 'HP:0003003', (203, 220))	('RB1', 'Gene', '5925', (258, 261))	('melanoma', 'Disease', 'MESH:D008545', (190, 198))	('BRAF', 'Gene', '673', (171, 175))	('mutations', 'Var', (273, 282))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('colorectal cancer', 'Disease', (203, 220))	('BRAF', 'Gene', (171, 175))	('colorectal cancer', 'Disease', 'MESH:D015179', (203, 220))	('NFE2L2', 'Gene', '4780', (266, 272))
550214	26436532	An intriguing evolutionary implication arises from these mutations: phenotypic impact is selected for in multiple heterogeneous tumour microenvironments, indicating independent convergence of phenotype transcending cell context.	('tumour', 'Phenotype', 'HP:0002664', (128, 134))	('tumour', 'Disease', (128, 134))	('mutations', 'Var', (57, 66))	('tumour', 'Disease', 'MESH:D009369', (128, 134))
550216	26436532	Although genes are rarely mutated multiple times within a single patient, some large tumour suppressor genes (such as ARID1A) accumulate multiple mutations, as a result of their long coding sequences.	('mutations', 'Var', (146, 155))	('tumour', 'Disease', 'MESH:D009369', (85, 91))	('tumour', 'Disease', (85, 91))	('patient', 'Species', '9606', (65, 72))	('ARID1A', 'Gene', '8289', (118, 124))	('accumulate', 'PosReg', (126, 136))	('ARID1A', 'Gene', (118, 124))	('tumour', 'Phenotype', 'HP:0002664', (85, 91))
550217	26436532	Similarly, in glioblastoma and lung cancers, EGFR is frequently mutated multiple times in single patients, often due to the emergence of clonal populations following the administration of EGFR inhibitors.	('EGFR', 'Gene', (45, 49))	('cancers', 'Phenotype', 'HP:0002664', (36, 43))	('EGFR', 'Gene', '1956', (188, 192))	('lung cancers', 'Phenotype', 'HP:0100526', (31, 43))	('glioblastoma and lung cancers', 'Disease', 'MESH:D005909', (14, 43))	('mutated', 'Var', (64, 71))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('glioblastoma', 'Phenotype', 'HP:0012174', (14, 26))	('EGFR', 'Gene', (188, 192))	('EGFR', 'Gene', '1956', (45, 49))	('patients', 'Species', '9606', (97, 105))
550219	26436532	Direct, model-based integration of mutations and co-acquired gene expression measurements from tumour samples enhances interpretation capacity of discovered mutations leading to optimal selectivity of targets for functional studies and development of novel therapeutics.	('tumour', 'Disease', 'MESH:D009369', (95, 101))	('interpretation', 'MPA', (119, 133))	('tumour', 'Disease', (95, 101))	('mutations', 'Var', (157, 166))	('enhances', 'PosReg', (110, 118))	('tumour', 'Phenotype', 'HP:0002664', (95, 101))
550220	26436532	The xseq model specifies how the expression Y of a group of genes in a patient is influenced by the somatic mutation status of a gene g in the patient (Fig.	('patient', 'Species', '9606', (143, 150))	('influenced', 'Reg', (82, 92))	('expression', 'MPA', (33, 43))	('mutation', 'Var', (108, 116))	('patient', 'Species', '9606', (71, 78))
550223	26436532	In our experiments, to systematically analyse all the data sets, for the nth gene connected to gene g, we estimate the upregulation probability by , where m is the mth patients harbouring gene g mutations, M is the total number of patients harbouring gene g mutations and ym,n is the expression of the nth gene connected to g in patient m.  means downregulation, neutral and upregulation of the nth gene connected to g in patient m, respectively.	('mutations', 'Var', (258, 267))	('patient', 'Species', '9606', (329, 336))	('patients', 'Species', '9606', (231, 239))	('patient', 'Species', '9606', (422, 429))	('upregulation', 'PosReg', (375, 387))	('nth gene', 'Gene', (395, 403))	('patient', 'Species', '9606', (168, 175))	('downregulation', 'NegReg', (347, 361))	('mutations', 'Var', (195, 204))	('patients', 'Species', '9606', (168, 176))	('patient', 'Species', '9606', (231, 238))
550228	26436532	We can see that some patients without RUNX1 mutations still showed similar expression pattern to those with RUNX1 mutations.	('RUNX1', 'Gene', '861', (38, 43))	('RUNX1', 'Gene', (108, 113))	('mutations', 'Var', (114, 123))	('RUNX1', 'Gene', '861', (108, 113))	('patients', 'Species', '9606', (21, 29))	('mutations', 'Var', (44, 53))	('RUNX1', 'Gene', (38, 43))	('expression', 'MPA', (75, 85))
550230	26436532	Phenocopying may be a common event in cancer because of DNA methylation and other epigenetic alterations, and it may suggest novel treatment opportunities.	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('DNA methylation', 'Var', (56, 71))	('alterations', 'Var', (93, 104))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('cancer', 'Disease', (38, 44))
550236	26436532	In a recent review, a '20/20 rule' is used to identify driver genes: for oncogenes, at least 20% of all the mutations are required to be hotspot missense mutations or in-frame indels; for tumour suppressor genes, at least 20% of all the mutations are required to be loss-of-function mutations.	('tumour', 'Phenotype', 'HP:0002664', (188, 194))	('mutations', 'Var', (108, 117))	('tumour', 'Disease', 'MESH:D009369', (188, 194))	('in-frame indels', 'Var', (167, 182))	('tumour', 'Disease', (188, 194))	('loss-of-function', 'NegReg', (266, 282))	('missense mutations', 'Var', (145, 163))	('mutations', 'Var', (237, 246))
550238	26436532	Similarly, when predicting tumour suppressor genes, we first count the number of loss-of-function mutations ng,loss in gene g, and Ng.	('loss', 'NegReg', (111, 115))	('loss-of-function', 'NegReg', (81, 97))	('mutations ng', 'Var', (98, 110))	('tumour', 'Phenotype', 'HP:0002664', (27, 33))	('tumour', 'Disease', 'MESH:D009369', (27, 33))	('tumour', 'Disease', (27, 33))
550244	26436532	Some mutated genes are not expressed in cancer cells, and therefore the mutations in these genes are less likely to be pathogenic.	('mutations', 'Var', (72, 81))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('cancer', 'Disease', (40, 46))
550248	26436532	Here we use the 90th percentile instead of median considering the gene dosage effects of copy number deletions on expression in cancer.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('copy number deletions', 'Var', (89, 110))	('cancer', 'Disease', (128, 134))
550256	26436532	Before analysing the trans-effects of somatic mutations, we first remove the cis-effects of copy number alterations on expression; copy number alterations are common in cancer and the majority have cis-effects on expression.	('cancer', 'Disease', (169, 175))	('expression', 'MPA', (213, 223))	('copy number alterations', 'Var', (131, 154))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('cancer', 'Disease', 'MESH:D009369', (169, 175))
550262	24277457	Common and complex Notch1 mutations in Chinese oral squamous cell carcinoma To determine Notch1 mutation status in oral squamous cell carcinoma (OSCC) from Chinese population and its potential clinical implications.	('oral squamous cell carcinoma', 'Disease', (115, 143))	('Notch1', 'Gene', (89, 95))	('Notch1', 'Gene', '4851', (89, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (66, 75))	('oral squamous cell carcinoma', 'Disease', (47, 75))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (120, 143))	('mutations', 'Var', (26, 35))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (115, 143))	('Notch1', 'Gene', (19, 25))	('Notch1', 'Gene', '4851', (19, 25))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (47, 75))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (52, 75))
550263	24277457	Surgically resected OSCC tissues from 51 Chinese patients and 13 head and neck cancer (HNSCC) cell lines were sequenced for mutations in the entire coding regions of Notch1 and TP53 using a next-generation sequencing platform.	('HNSCC', 'Phenotype', 'HP:0012288', (87, 92))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('head and neck cancer', 'Phenotype', 'HP:0012288', (65, 85))	('neck cancer', 'Disease', 'MESH:D006258', (74, 85))	('neck cancer', 'Disease', (74, 85))	('Notch1', 'Gene', (166, 172))	('TP53', 'Gene', '7157', (177, 181))	('patients', 'Species', '9606', (49, 57))	('Notch1', 'Gene', '4851', (166, 172))	('TP53', 'Gene', (177, 181))	('mutations in', 'Var', (124, 136))
550265	24277457	Six mutations in Notch1 and 11 mutations in TP53 coding regions were detected in 4 (31%) and 10 (77%) of the 13 HNSCC cell lines, respectively.	('Notch1', 'Gene', (17, 23))	('detected', 'Reg', (69, 77))	('Notch1', 'Gene', '4851', (17, 23))	('TP53', 'Gene', '7157', (44, 48))	('HNSCC', 'Phenotype', 'HP:0012288', (112, 117))	('mutations', 'Var', (4, 13))	('TP53', 'Gene', (44, 48))
550266	24277457	Forty-two somatic Notch1 mutations, including 7 nonsense mutations and 11 mutations within the domain commonly harboring potential activating mutations in ALL, were detected in 22 (43%) of the 51 Chinese OSCC tumors.	('mutations', 'Var', (25, 34))	('tumors', 'Phenotype', 'HP:0002664', (209, 215))	('Notch1', 'Gene', (18, 24))	('OSCC tumors', 'Disease', (204, 215))	('Notch1', 'Gene', '4851', (18, 24))	('ALL', 'Phenotype', 'HP:0006721', (155, 158))	('OSCC tumors', 'Disease', 'MESH:D009369', (204, 215))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))
550267	24277457	In comparison, 25 somatic TP53 mutations were observed in 21 (41%) of the 51 tumors.	('tumors', 'Disease', (77, 83))	('tumors', 'Disease', 'MESH:D009369', (77, 83))	('TP53', 'Gene', (26, 30))	('mutations', 'Var', (31, 40))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('TP53', 'Gene', '7157', (26, 30))
550268	24277457	Patients whose tumors carried Notch1 mutation had a significantly shorter overall and disease-free survivals (P=.004 and P=.001, respectively, by log-rank test) compared to those whose tumors carried no Notch1 mutation.	('Notch1', 'Gene', (203, 209))	('Notch1', 'Gene', '4851', (30, 36))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('mutation', 'Var', (37, 45))	('shorter', 'NegReg', (66, 73))	('Notch1', 'Gene', '4851', (203, 209))	('tumors', 'Disease', (185, 191))	('tumors', 'Phenotype', 'HP:0002664', (185, 191))	('tumors', 'Disease', 'MESH:D009369', (15, 21))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('disease-free survivals', 'CPA', (86, 108))	('Patients', 'Species', '9606', (0, 8))	('tumors', 'Disease', 'MESH:D009369', (185, 191))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('Notch1', 'Gene', (30, 36))	('tumors', 'Disease', (15, 21))
550269	24277457	Multivariate analysis showed that both Notch1 mutation and lymph node metastasis are independent prognostic factors in the patient population (P=.001).	('patient', 'Species', '9606', (123, 130))	('mutation', 'Var', (46, 54))	('Notch1', 'Gene', '4851', (39, 45))	('Notch1', 'Gene', (39, 45))
550270	24277457	All 15 patients with both Notch1 mutation and nodal metastasis recurred or metastasized within 2 years after surgery.	('mutation', 'Var', (33, 41))	('metastasized', 'CPA', (75, 87))	('Notch1', 'Gene', (26, 32))	('patients', 'Species', '9606', (7, 15))	('Notch1', 'Gene', '4851', (26, 32))
550271	24277457	Notch1 mutation is common in Chinese OSCC and associates with clinical outcomes.	('Notch1', 'Gene', (0, 6))	('associates with', 'Reg', (46, 61))	('Notch1', 'Gene', '4851', (0, 6))	('mutation', 'Var', (7, 15))
550277	24277457	Two research teams recently performed whole-exome sequencing of HNSCC and revealed an unexpectedly high rates of somatic Notch1 mutations (11-15%) in the Caucasian populations.	('mutations', 'Var', (128, 137))	('HNSCC', 'Phenotype', 'HP:0012288', (64, 69))	('Notch1', 'Gene', (121, 127))	('Notch1', 'Gene', '4851', (121, 127))
550278	24277457	Because the mutations reported in these studies are either leading to potential protein inactivation or located at domains impacting ligand binding, Notch1 is considered as a tumor suppressor in HNSCC.	('tumor', 'Disease', (175, 180))	('mutations', 'Var', (12, 21))	('Notch1', 'Gene', (149, 155))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('protein', 'Protein', (80, 87))	('Notch1', 'Gene', '4851', (149, 155))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('HNSCC', 'Phenotype', 'HP:0012288', (195, 200))	('impacting', 'NegReg', (123, 132))	('inactivation', 'NegReg', (88, 100))	('ligand binding', 'Interaction', (133, 147))	('HNSCC', 'Disease', (195, 200))
550305	24277457	Four (66%) of the 6 nucleotide substitutions in Notch1 gene were located at EGF repeat domain (amino acids 20 to 1426) including a nonsense mutation, C931x, at the Abruptex region (amino acids 907 to 1143).	('Notch1', 'Gene', (48, 54))	('EGF', 'Gene', '1950', (76, 79))	('Notch1', 'Gene', '4851', (48, 54))	('EGF', 'Gene', (76, 79))	('C931x', 'Mutation', 'p.C931fsX', (150, 155))	('C931x', 'Var', (150, 155))
550308	24277457	The remaining 42 (27%) were non-synonymous somatic mutations in 22 (43%) of the tumors.	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('non-synonymous somatic mutations', 'Var', (28, 60))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('tumors', 'Disease', (80, 86))
550309	24277457	The locations of the non-synonymous mutations in Notch1 functional domains were shown in Figure 1A and Table 2.	('Notch1', 'Gene', (49, 55))	('Notch1', 'Gene', '4851', (49, 55))	('non-synonymous mutations', 'Var', (21, 45))
550310	24277457	Epidermal growth factor (EGF) repeats domain (excluding Abruptex region) was one of the most common regions with mutations (12 or 29%), which resembled previously reported Notch1 mutations in HNSCC (Fig.	('Notch1', 'Gene', (172, 178))	('HNSCC', 'Phenotype', 'HP:0012288', (192, 197))	('Epidermal growth factor', 'Gene', (0, 23))	('Notch1', 'Gene', '4851', (172, 178))	('mutations', 'Var', (113, 122))	('EGF', 'Gene', (25, 28))	('mutations', 'Var', (179, 188))	('EGF', 'Gene', '1950', (25, 28))	('Epidermal growth factor', 'Gene', '1950', (0, 23))
550311	24277457	1B) whereas 12 (29%) of the mutations from 8 (36%) of the 22 tumors locate at Notch1 HD domain (Table 2) where most of the activating mutations were reported in hematologic malignancies (Fig.	('tumors', 'Disease', (61, 67))	('tumors', 'Disease', 'MESH:D009369', (61, 67))	('Notch1', 'Gene', '4851', (78, 84))	('activating', 'PosReg', (123, 133))	('hematologic malignancies', 'Disease', (161, 185))	('HD', 'Disease', 'MESH:D006816', (85, 87))	('hematologic malignancies', 'Disease', 'MESH:D019337', (161, 185))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('mutations', 'Var', (134, 143))	('tumors', 'Phenotype', 'HP:0002664', (61, 67))	('Notch1', 'Gene', (78, 84))	('mutations', 'Var', (28, 37))
550312	24277457	Abruptex region, which was also located at the EGF repeat domain, contains the most mutations (13 or 31%).	('mutations', 'Var', (84, 93))	('EGF', 'Gene', (47, 50))	('EGF', 'Gene', '1950', (47, 50))
550313	24277457	There were several mutation "hot spots", including 7 mutations at codon 1641 (P>L/S) in 5 (10%) of the 51 tumors, 3 mutations at codon 1713 (N>S) in 3 tumors, 3 mutations at codon 1133 (C>Y) in 3 tumors, and 2 mutations at codons 1107 and 1474 both resulted in a stop codon.	('mutations at codon 1641', 'Var', (53, 76))	('resulted in', 'Reg', (249, 260))	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('tumors', 'Phenotype', 'HP:0002664', (196, 202))	('tumor', 'Phenotype', 'HP:0002664', (151, 156))	('tumors', 'Disease', (106, 112))	('tumors', 'Disease', (151, 157))	('tumors', 'Disease', (196, 202))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('tumors', 'Disease', 'MESH:D009369', (151, 157))	('tumors', 'Disease', 'MESH:D009369', (196, 202))	('tumors', 'Phenotype', 'HP:0002664', (151, 157))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (196, 201))
550314	24277457	Corresponding normal tissues were not available for 5 tumors, including the tumor (SCC9) carried 10 nucleotide variations.	('tumors', 'Disease', 'MESH:D009369', (54, 60))	('nucleotide variations', 'Var', (100, 121))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor', 'Disease', (76, 81))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('tumor', 'Disease', (54, 59))	('tumors', 'Phenotype', 'HP:0002664', (54, 60))	('tumors', 'Disease', (54, 60))
550315	24277457	For TP53, a total of 67 nucleotide substitutions were identified including 41 (61%) SNPs (15 INDEL SNPs in the non-coding areas and 26 at codon 72 leading to P>R substitution).	('TP53', 'Gene', '7157', (4, 8))	('P>R substitution', 'Var', (158, 174))	('TP53', 'Gene', (4, 8))
550316	24277457	There were 26 somatic mutations including 25 non-synonymous mutations from 21 (41%) of the tumors and 1 synonymous mutation.	('tumors', 'Disease', (91, 97))	('tumors', 'Disease', 'MESH:D009369', (91, 97))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('non-synonymous mutations', 'Var', (45, 69))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))
550317	24277457	No significant association was observed between Notch1 mutation status and any of the clinical/pathological parameters except a marginal significant difference between TP53 mutation and older age (Table 3).	('Notch1', 'Gene', (48, 54))	('TP53', 'Gene', '7157', (168, 172))	('TP53', 'Gene', (168, 172))	('Notch1', 'Gene', '4851', (48, 54))	('mutation', 'Var', (55, 63))
550318	24277457	There was also no association between Notch1 and TP53 mutations in these tumors (Table 3).	('tumors', 'Disease', 'MESH:D009369', (73, 79))	('Notch1', 'Gene', (38, 44))	('Notch1', 'Gene', '4851', (38, 44))	('TP53', 'Gene', (49, 53))	('TP53', 'Gene', '7157', (49, 53))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('mutations', 'Var', (54, 63))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('tumors', 'Disease', (73, 79))
550320	24277457	In univariate analysis, Notch1 mutation and lymph node metastasis were found to associate with the disease-free survival (DFS) of the patient population (P=.002 and P<.001, respectively; Table 4).	('associate', 'Reg', (80, 89))	('Notch1', 'Gene', '4851', (24, 30))	('mutation', 'Var', (31, 39))	('lymph node metastasis', 'CPA', (44, 65))	('disease-free', 'Disease', (99, 111))	('patient', 'Species', '9606', (134, 141))	('Notch1', 'Gene', (24, 30))
550321	24277457	Patients whose tumors carried Notch1 mutation had significantly shorter overall survival (OS) and DFS than those whose tumors carried no Notch1 mutation (Fig.	('tumors', 'Phenotype', 'HP:0002664', (119, 125))	('Notch1', 'Gene', '4851', (30, 36))	('tumors', 'Phenotype', 'HP:0002664', (15, 21))	('Notch1', 'Gene', '4851', (137, 143))	('mutation', 'Var', (37, 45))	('tumors', 'Disease', (119, 125))	('overall survival', 'MPA', (72, 88))	('tumors', 'Disease', 'MESH:D009369', (119, 125))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumors', 'Disease', 'MESH:D009369', (15, 21))	('tumor', 'Phenotype', 'HP:0002664', (119, 124))	('Patients', 'Species', '9606', (0, 8))	('DFS', 'CPA', (98, 101))	('Notch1', 'Gene', (30, 36))	('Notch1', 'Gene', (137, 143))	('tumors', 'Disease', (15, 21))	('shorter', 'NegReg', (64, 71))
550323	24277457	Both Notch1 mutation and lymph node metastasis were independently associated with DFS (P<.001 for both factors; Table 3).	('lymph node metastasis', 'CPA', (25, 46))	('Notch1', 'Gene', '4851', (5, 11))	('DFS', 'Disease', (82, 85))	('associated', 'Reg', (66, 76))	('Notch1', 'Gene', (5, 11))	('mutation', 'Var', (12, 20))
550324	24277457	Patients who had lymph node metastasis with tumors carried Notch1 mutation showed worst OS and DFS whereas those who had no lymph node metastasis and no Notch1 mutation in the tumors showed the best survivals (Fig.	('tumors', 'Disease', (44, 50))	('tumors', 'Disease', 'MESH:D009369', (44, 50))	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('Notch1', 'Gene', (59, 65))	('tumors', 'Disease', (176, 182))	('Notch1', 'Gene', '4851', (59, 65))	('Patients', 'Species', '9606', (0, 8))	('tumors', 'Disease', 'MESH:D009369', (176, 182))	('tumors', 'Phenotype', 'HP:0002664', (176, 182))	('Notch1', 'Gene', (153, 159))	('DFS', 'CPA', (95, 98))	('mutation', 'Var', (66, 74))	('Notch1', 'Gene', '4851', (153, 159))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))
550325	24277457	All 15 (100%) patients with lymph node metastasis and Notch1 mutation in the tumors had tumor relapse or metastasis after curative treatment and 14 (93%) of the patients died during the follow-up compared to only 2 (15%) of the 13 patients with no lymph node metastasis and no Notch1 mutation did so (Fig.	('tumors', 'Disease', (77, 83))	('tumors', 'Disease', 'MESH:D009369', (77, 83))	('Notch1', 'Gene', '4851', (277, 283))	('tumors', 'Phenotype', 'HP:0002664', (77, 83))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('patients', 'Species', '9606', (231, 239))	('mutation', 'Var', (61, 69))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('patients', 'Species', '9606', (161, 169))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor', 'Disease', (88, 93))	('Notch1', 'Gene', (54, 60))	('Notch1', 'Gene', (277, 283))	('patients', 'Species', '9606', (14, 22))	('tumor', 'Disease', (77, 82))	('Notch1', 'Gene', '4851', (54, 60))
550328	24277457	It has been well-documented that the mutation rates of epidermal growth factor receptor (EGFR) are highly variable in non-small cell lung cancer (NSCLC) among different ethnic populations.	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (118, 144))	('EGFR', 'Gene', (89, 93))	('mutation', 'Var', (37, 45))	('lung cancer', 'Phenotype', 'HP:0100526', (133, 144))	('epidermal growth factor receptor', 'Gene', (55, 87))	('non-small cell lung cancer', 'Disease', (118, 144))	('NSCLC', 'Disease', (146, 151))	('NSCLC', 'Phenotype', 'HP:0030358', (146, 151))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('NSCLC', 'Disease', 'MESH:D002289', (146, 151))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (122, 144))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (118, 144))	('epidermal growth factor receptor', 'Gene', '1956', (55, 87))	('EGFR', 'Gene', '1956', (89, 93))
550329	24277457	In Asians, 30-60% NSCLC tumors carry EGFR mutation compared to only 10-15% in Caucasian population, which is clinically important because tumors with EGFR mutations are particularly sensitive to EGFR tyrosine kinase inhibitors.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('EGFR', 'Gene', (195, 199))	('tumors', 'Disease', (24, 30))	('tumors', 'Disease', 'MESH:D009369', (138, 144))	('EGFR', 'Gene', '1956', (150, 154))	('NSCLC tumors', 'Disease', (18, 30))	('tumors', 'Disease', 'MESH:D009369', (24, 30))	('EGFR', 'Gene', '1956', (37, 41))	('mutation', 'Var', (42, 50))	('sensitive', 'MPA', (182, 191))	('EGFR', 'Gene', '1956', (195, 199))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('NSCLC tumors', 'Disease', 'MESH:D009369', (18, 30))	('EGFR', 'Gene', (150, 154))	('tumors', 'Phenotype', 'HP:0002664', (24, 30))	('tumors', 'Disease', (138, 144))	('NSCLC', 'Phenotype', 'HP:0030358', (18, 23))	('EGFR', 'Gene', (37, 41))
550332	24277457	Since exposure to tobacco and alcohol was associated with a high frequency of TP53 mutations in HNSCC, it will be interesting to determine its potential impact on Notch1 mutations.	('mutations', 'Var', (83, 92))	('HNSCC', 'Phenotype', 'HP:0012288', (96, 101))	('alcohol', 'Chemical', 'MESH:D000438', (30, 37))	('Notch1', 'Gene', (163, 169))	('Notch1', 'Gene', '4851', (163, 169))	('tobacco', 'Species', '4097', (18, 25))	('TP53', 'Gene', '7157', (78, 82))	('TP53', 'Gene', (78, 82))	('HNSCC', 'Gene', (96, 101))
550335	24277457	However, we cannot rule out the possibility that the high CG content in human Notch1 coding regions (64%) may impact the probability to detect certain mutations when different sequencing methods are used.	('Notch1', 'Gene', '4851', (78, 84))	('CG', 'Chemical', 'MESH:C028505', (58, 60))	('CG content', 'Var', (58, 68))	('impact', 'Reg', (110, 116))	('human', 'Species', '9606', (72, 77))	('Notch1', 'Gene', (78, 84))	('mutations', 'Var', (151, 160))
550336	24277457	We noted there were more C>T transitions in Notch1 (40%) than in TP53 (28%).	('Notch1', 'Gene', '4851', (44, 50))	('C>T', 'Var', (25, 28))	('TP53', 'Gene', '7157', (65, 69))	('TP53', 'Gene', (65, 69))	('Notch1', 'Gene', (44, 50))
550337	24277457	Since C>T transition was associated with tobacco and alcohol consumption and mainly located in CpG islands, the higher incidence of C>T transition in Notch1 might be a result of the exposure to these risk factors and the high GC contents in Notch1 (65% in coding region).	('alcohol', 'Chemical', 'MESH:D000438', (53, 60))	('Notch1', 'Gene', '4851', (150, 156))	('Notch1', 'Gene', (241, 247))	('associated', 'Reg', (25, 35))	('Notch1', 'Gene', '4851', (241, 247))	('C>T transition', 'Var', (132, 146))	('C>T', 'Disease', (6, 9))	('tobacco', 'Species', '4097', (41, 48))	('Notch1', 'Gene', (150, 156))
550338	24277457	One of these tumors (SCC9) exhibited 10 nucleotide variations including a nonsense mutation (Q1733x) which is probably a somatic event.	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('tumors', 'Disease', (13, 19))	('Q1733x', 'Var', (93, 99))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
550340	24277457	Another key finding in our study is the spectrum of the Notch1 mutations.	('mutations', 'Var', (63, 72))	('Notch1', 'Gene', (56, 62))	('Notch1', 'Gene', '4851', (56, 62))
550341	24277457	One of the common domains with mutations is the epidermal growth factor (EGF) repeats (12 or 29%), which is consistent with previous reports for HNSCC although all but one (E424K) of the mutations at different codons (Tables S4).	('epidermal growth factor', 'Gene', (48, 71))	('mutations', 'Var', (31, 40))	('EGF', 'Gene', '1950', (73, 76))	('HNSCC', 'Phenotype', 'HP:0012288', (145, 150))	('epidermal growth factor', 'Gene', '1950', (48, 71))	('E424K', 'Var', (173, 178))	('E424K', 'Mutation', 'rs1341448592', (173, 178))	('EGF', 'Gene', (73, 76))
550342	24277457	Another common domain with mutations is HD (12 or 29%) including 2 "hotspots" (P1641S in 4 tumors and N1713S in 3 tumors) (Table S5).	('mutations', 'Var', (27, 36))	('tumors', 'Disease', (91, 97))	('P1641S', 'Mutation', 'rs535702482', (79, 85))	('tumors', 'Disease', 'MESH:D009369', (91, 97))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('HD', 'Disease', 'MESH:D006816', (40, 42))	('N1713S', 'Mutation', 'rs200053816', (102, 108))	('N1713S', 'Var', (102, 108))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumors', 'Disease', (114, 120))	('tumors', 'Disease', 'MESH:D009369', (114, 120))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('P1641S', 'Var', (79, 85))
550343	24277457	HD is one of the two regions where mutations are commonly observed in leukemia patients, including P1641S, with a predicted ligand-independent gain-of-function phenotype.	('gain-of-function', 'PosReg', (143, 159))	('P1641S', 'Var', (99, 105))	('P1641S', 'Mutation', 'rs535702482', (99, 105))	('leukemia', 'Disease', (70, 78))	('patients', 'Species', '9606', (79, 87))	('leukemia', 'Disease', 'MESH:D007938', (70, 78))	('leukemia', 'Phenotype', 'HP:0001909', (70, 78))	('HD', 'Disease', 'MESH:D006816', (0, 2))
550344	24277457	Abruptex domain contains the most mutations (13 or 31%) including 3 nonsense mutations and a hotspot mutation (C1133Y in 3 tumors) (Table S5).	('tumors', 'Phenotype', 'HP:0002664', (123, 129))	('tumors', 'Disease', (123, 129))	('tumors', 'Disease', 'MESH:D009369', (123, 129))	('C1133Y', 'Var', (111, 117))	('C1133Y', 'Mutation', 'rs1371638608', (111, 117))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))
550345	24277457	Because Abruptex domain plays a role in suppressing cis-inhibition of Notch1 signaling, mutations in this region are thought as gain-of-function mutations.	('Notch1', 'Gene', (70, 76))	('mutations', 'Var', (88, 97))	('Notch1', 'Gene', '4851', (70, 76))	('cis-inhibition', 'MPA', (52, 66))	('suppressing', 'NegReg', (40, 51))
550346	24277457	Our results, therefore, suggest a more complex Notch1 mutation spectrum, including the existence of mutations within the domain commonly harboring potential activating mutations in acute lymphoblastic leukemia, in OSCC of the Chinese population than their Caucasian counterparts.	('mutations', 'Var', (100, 109))	('Notch1', 'Gene', '4851', (47, 53))	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (181, 209))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (187, 209))	('activating', 'PosReg', (157, 167))	('acute lymphoblastic leukemia', 'Disease', (181, 209))	('leukemia', 'Phenotype', 'HP:0001909', (201, 209))	('acute lymphoblastic leukemia', 'Disease', 'MESH:D054198', (181, 209))	('Notch1', 'Gene', (47, 53))
550347	24277457	In solid tumors, activating Notch1 mutations have been reported, mostly in NSCLC.	('Notch1', 'Gene', (28, 34))	('NSCLC', 'Phenotype', 'HP:0030358', (75, 80))	('Notch1', 'Gene', '4851', (28, 34))	('activating', 'PosReg', (17, 27))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('solid tumors', 'Disease', (3, 15))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('NSCLC', 'Disease', (75, 80))	('NSCLC', 'Disease', 'MESH:D002289', (75, 80))	('solid tumors', 'Disease', 'MESH:D009369', (3, 15))	('mutations', 'Var', (35, 44))
550348	24277457	It, however, should be noted that most of the "activating" mutations were insufficient to induce malignancies in the experimental model systems.	('insufficient', 'Disease', (74, 86))	('induce', 'Reg', (90, 96))	('malignancies', 'Disease', 'MESH:D009369', (97, 109))	('mutations', 'Var', (59, 68))	('insufficient', 'Disease', 'MESH:D000309', (74, 86))	('malignancies', 'Disease', (97, 109))
550350	24277457	Importantly, our study is the first to reveal a relationship between Notch1 mutation status and clinical outcomes in patients with OSCC.	('OSCC', 'Disease', (131, 135))	('Notch1', 'Gene', (69, 75))	('Notch1', 'Gene', '4851', (69, 75))	('patients', 'Species', '9606', (117, 125))	('mutation status', 'Var', (76, 91))
550351	24277457	Our results indicate that Notch1 mutation is a poor prognostic factor for both OS and DFS in the Chinese OSCC patients.	('mutation', 'Var', (33, 41))	('DFS', 'Disease', (86, 89))	('Notch1', 'Gene', (26, 32))	('patients', 'Species', '9606', (110, 118))	('Notch1', 'Gene', '4851', (26, 32))
550354	24277457	We recognize the complexity of Notch1 mutations identified in our study and acknowledge several limitations which will require further investigations.	('Notch1', 'Gene', (31, 37))	('mutations', 'Var', (38, 47))	('Notch1', 'Gene', '4851', (31, 37))
550355	24277457	This factor may also impact the analyses with the TP53 mutation status.	('mutation', 'Var', (55, 63))	('TP53', 'Gene', (50, 54))	('TP53', 'Gene', '7157', (50, 54))	('impact', 'Reg', (21, 27))
550359	24277457	Recently, high frequencies of potentially loss of function mutations in Notch1 were observed in head and neck squamous cell carcinoma (HNSCC) of Caucasian populations.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (110, 133))	('Notch1', 'Gene', (72, 78))	('carcinoma', 'Phenotype', 'HP:0030731', (124, 133))	('HNSCC', 'Phenotype', 'HP:0012288', (135, 140))	('Notch1', 'Gene', '4851', (72, 78))	('loss of function', 'NegReg', (42, 58))	('mutations', 'Var', (59, 68))	('neck squamous cell carcinoma', 'Disease', (105, 133))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (105, 133))
550362	24277457	In this study, we reported a high frequency (43%) of Notch1 mutation, including mutations within the domain commonly harboring activating mutations in acute lymphoblastic leukemia (ALL), in oral squamous cell carcinoma (OSCC) of Chinese patients, which is significantly higher than the frequencies (<20%) reported in Caucasian populations.	('oral squamous cell carcinoma', 'Disease', (190, 218))	('mutation', 'Var', (60, 68))	('leukemia', 'Phenotype', 'HP:0001909', (171, 179))	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (151, 179))	('acute lymphoblastic leukemia', 'Disease', (151, 179))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (157, 179))	('ALL', 'Phenotype', 'HP:0006721', (181, 184))	('acute lymphoblastic leukemia', 'Disease', 'MESH:D054198', (151, 179))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (195, 218))	('Notch1', 'Gene', (53, 59))	('carcinoma', 'Phenotype', 'HP:0030731', (209, 218))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (190, 218))	('patients', 'Species', '9606', (237, 245))	('Notch1', 'Gene', '4851', (53, 59))
550363	24277457	We further observed a significant association between Notch1 mutation and shorter survival times in OSCC patients.	('shorter', 'NegReg', (74, 81))	('patients', 'Species', '9606', (105, 113))	('mutation', 'Var', (61, 69))	('Notch1', 'Gene', (54, 60))	('OSCC', 'Disease', (100, 104))	('Notch1', 'Gene', '4851', (54, 60))
550364	24277457	The results suggest an important role of Notch1 mutations in oral tumorigenesis and potential implications of these mutations as biomarkers and interventional targets.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('Notch1', 'Gene', (41, 47))	('tumor', 'Disease', (66, 71))	('Notch1', 'Gene', '4851', (41, 47))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('mutations', 'Var', (48, 57))
550366	32931455	A total of 1,206 differentially expressed genes (DEGs) in early NSCLC were identified compared to normal lung tissue samples in GSE33532 and GSE29013.	('NSCLC', 'Disease', 'MESH:D002289', (64, 69))	('differentially expressed genes', 'MPA', (17, 47))	('NSCLC', 'Phenotype', 'HP:0030358', (64, 69))	('GSE33532', 'Var', (128, 136))	('NSCLC', 'Disease', (64, 69))
550398	32931455	Moreover, the high hub GSVA index was associated with a better prognosis in LUSC, which contrasted with that of LUAD.	('LUSC', 'Phenotype', 'HP:0030359', (76, 80))	('hub', 'Gene', (19, 22))	('LUSC', 'Disease', (76, 80))	('GSVA', 'Chemical', '-', (23, 27))	('high', 'Var', (14, 18))	('LUAD', 'Phenotype', 'HP:0030078', (112, 116))	('hub', 'Gene', '1993', (19, 22))
550411	32931455	Unsurprisingly, previous studies have found that some of these genes were associated with NSCLCs.	('NSCLCs', 'Disease', (90, 96))	('associated', 'Reg', (74, 84))	('genes', 'Var', (63, 68))	('NSCLCs', 'Disease', 'MESH:D002289', (90, 96))	('NSCLC', 'Phenotype', 'HP:0030358', (90, 95))
550414	32931455	A high expression of RRM2 is a poor prognostic factor for LUAD and is a biomarker for the LUAD potential prediction of metastasis and prognosis, though it may be favorable for LUSC, according to the corresponding obtained results.	('RRM2', 'Gene', '6241', (21, 25))	('RRM2', 'Gene', (21, 25))	('LUAD', 'Phenotype', 'HP:0030078', (58, 62))	('LUSC', 'Phenotype', 'HP:0030359', (176, 180))	('LUAD', 'Disease', (58, 62))	('high', 'Var', (2, 6))	('expression', 'MPA', (7, 17))	('LUAD', 'Phenotype', 'HP:0030078', (90, 94))
550421	32931455	In the present study, two NSCLC gene expression profile datasets were downloaded from the Gene Expression Omnibus (GEO, https://www.ncbi.nlm.nih.gov/geo/) database, GSE33532 and GSE29013.	('GSE29013', 'Var', (178, 186))	('NSCLC', 'Phenotype', 'HP:0030358', (26, 31))	('GSE33532', 'Var', (165, 173))	('NSCLC', 'Disease', (26, 31))	('NSCLC', 'Disease', 'MESH:D002289', (26, 31))
550422	32931455	The data set of GSE33532 includes 80 early NSCLC tissue samples (40 adenocarcinomas, 16 squamous cell carcinomas, and 24 NSCLCs of mixed type) and 20 normal lung tissue samples.	('NSCLCs', 'Disease', (121, 127))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (88, 111))	('squamous cell carcinomas', 'Disease', (88, 112))	('adenocarcinomas', 'Disease', 'MESH:D000230', (68, 83))	('adenocarcinomas', 'Disease', (68, 83))	('NSCLCs', 'Disease', 'MESH:D002289', (121, 127))	('carcinomas', 'Phenotype', 'HP:0030731', (73, 83))	('carcinoma', 'Phenotype', 'HP:0030731', (102, 111))	('NSCLC', 'Disease', 'MESH:D002289', (43, 48))	('NSCLC', 'Disease', 'MESH:D002289', (121, 126))	('NSCLC', 'Disease', (43, 48))	('carcinomas', 'Phenotype', 'HP:0030731', (102, 112))	('GSE33532', 'Var', (16, 24))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (88, 112))	('NSCLC', 'Disease', (121, 126))	('NSCLC', 'Phenotype', 'HP:0030358', (43, 48))	('NSCLC', 'Phenotype', 'HP:0030358', (121, 126))	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (88, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
550436	31778288	We found that high expression of ITGA11 was associated with lower recurrence-free survival in all NSCLC patients (P = 0.043) and in stage I NSCLC patients (P = 0.049).	('NSCLC', 'Disease', 'MESH:D002289', (140, 145))	('ITGA11', 'Gene', (33, 39))	('NSCLC', 'Phenotype', 'HP:0030358', (98, 103))	('NSCLC', 'Phenotype', 'HP:0030358', (140, 145))	('ITGA11', 'Gene', '22801', (33, 39))	('high expression', 'Var', (14, 29))	('NSCLC', 'Disease', (98, 103))	('patients', 'Species', '9606', (146, 154))	('recurrence-free survival', 'CPA', (66, 90))	('patients', 'Species', '9606', (104, 112))	('NSCLC', 'Disease', 'MESH:D002289', (98, 103))	('NSCLC', 'Disease', (140, 145))	('lower', 'NegReg', (60, 65))
550438	31778288	Overexpression of ITGA11 in lung cancer cell lines had little effect on cell proliferation but resulted in increased migration and invasion capacity.	('ITGA11', 'Gene', (18, 24))	('lung cancer', 'Disease', 'MESH:D008175', (28, 39))	('increased', 'PosReg', (107, 116))	('ITGA11', 'Gene', '22801', (18, 24))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('invasion capacity', 'CPA', (131, 148))	('lung cancer', 'Disease', (28, 39))	('Overexpression', 'Var', (0, 14))	('lung cancer', 'Phenotype', 'HP:0100526', (28, 39))
550449	31778288	The aim of the present study was to determine whether and how aberrant ITGA11 expression in lung cancer leads to worse outcomes.	('lung cancer', 'Disease', (92, 103))	('lung cancer', 'Phenotype', 'HP:0100526', (92, 103))	('ITGA11', 'Gene', (71, 77))	('aberrant', 'Var', (62, 70))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('lung cancer', 'Disease', 'MESH:D008175', (92, 103))	('ITGA11', 'Gene', '22801', (71, 77))
550484	31778288	A total of 28 patients (35%) had EGFR gene mutations, 16 patients (20%) had wild-type EGFR and 36 patients (45%) had unknown EGFR mutation status.	('EGFR', 'Gene', '1956', (86, 90))	('EGFR', 'Gene', '1956', (125, 129))	('patients', 'Species', '9606', (57, 65))	('patients', 'Species', '9606', (98, 106))	('EGFR', 'Gene', '1956', (33, 37))	('EGFR', 'Gene', (86, 90))	('mutations', 'Var', (43, 52))	('EGFR', 'Gene', (125, 129))	('EGFR', 'Gene', (33, 37))	('patients', 'Species', '9606', (14, 22))
550487	31778288	In addition, expression of ITGA11 was not related to EGFR mutation status (P = 0.563).	('ITGA11', 'Gene', '22801', (27, 33))	('mutation', 'Var', (58, 66))	('EGFR', 'Gene', '1956', (53, 57))	('EGFR', 'Gene', (53, 57))	('ITGA11', 'Gene', (27, 33))
550490	31778288	Kaplan-Meier analysis showed that high expression of ITGA11 was associated with lower recurrence-free survival (P = 0.043, Figure 2A).	('high expression', 'Var', (34, 49))	('ITGA11', 'Gene', (53, 59))	('ITGA11', 'Gene', '22801', (53, 59))	('lower', 'NegReg', (80, 85))	('recurrence-free survival', 'CPA', (86, 110))
550492	31778288	In stage I patients, high expression of ITGA11 was also associated with lower recurrence-free survival (P = 0.049, Figure 2B).	('recurrence-free survival', 'CPA', (78, 102))	('ITGA11', 'Gene', (40, 46))	('lower', 'NegReg', (72, 77))	('high expression', 'Var', (21, 36))	('patients', 'Species', '9606', (11, 19))	('ITGA11', 'Gene', '22801', (40, 46))
550496	31778288	Kaplan-Meier analysis showed that high expression of ITGA11 was associated with lower overall survival (P = 0.011, Figure 2C).	('high expression', 'Var', (34, 49))	('ITGA11', 'Gene', (53, 59))	('ITGA11', 'Gene', '22801', (53, 59))	('lower', 'NegReg', (80, 85))	('overall survival', 'MPA', (86, 102))
550498	31778288	In stage I patients from the TCGA database, high expression of ITGA11 was also associated with lower overall survival (P = 0.035, Figure 2D).	('lower', 'NegReg', (95, 100))	('overall survival', 'MPA', (101, 117))	('high expression', 'Var', (44, 59))	('ITGA11', 'Gene', '22801', (63, 69))	('patients', 'Species', '9606', (11, 19))	('ITGA11', 'Gene', (63, 69))
550504	31778288	In H23 and H441 cells that overexpressed ITGA11, the cell number was similar to controls regardless of collagen coating.	('overexpressed', 'Var', (27, 40))	('ITGA11', 'Gene', '22801', (41, 47))	('H441', 'CellLine', 'CVCL:1561', (11, 15))	('H23', 'CellLine', 'CVCL:1547', (3, 6))	('ITGA11', 'Gene', (41, 47))
550510	31778288	Our study demonstrated that high expression of ITGA11 was associated with advanced stage and lower recurrence-free survival in patients with NSCLC.	('associated', 'Reg', (58, 68))	('recurrence-free survival', 'CPA', (99, 123))	('ITGA11', 'Gene', (47, 53))	('NSCLC', 'Disease', (141, 146))	('patients', 'Species', '9606', (127, 135))	('lower', 'NegReg', (93, 98))	('NSCLC', 'Disease', 'MESH:D002289', (141, 146))	('high expression', 'Var', (28, 43))	('advanced stage', 'CPA', (74, 88))	('ITGA11', 'Gene', '22801', (47, 53))	('NSCLC', 'Phenotype', 'HP:0030358', (141, 146))
550516	31778288	Poor prognosis was also shown in patients with stage I lung cancer with high expression of ITGA11.	('stage I lung cancer', 'Disease', (47, 66))	('patients', 'Species', '9606', (33, 41))	('stage I lung cancer', 'Disease', 'MESH:D008175', (47, 66))	('ITGA11', 'Gene', (91, 97))	('lung cancer', 'Phenotype', 'HP:0100526', (55, 66))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))	('high', 'Var', (72, 76))	('ITGA11', 'Gene', '22801', (91, 97))
550517	31778288	Integrin alpha11 affects cell spreading, motility and collagen remodeling in mesenchymal cells.15, 28 The lack of ITGA11 chain in fibroblasts was reported to reduce cell attachment and cell spread on collagen I, which was consistent with our results of larger size in ITGA11-overexpressed cells.	('ITGA11', 'Gene', (114, 120))	('lack', 'Var', (106, 110))	('reduce', 'NegReg', (158, 164))	('cell spread on collagen I', 'CPA', (185, 210))	('ITGA11', 'Gene', '22801', (268, 274))	('Integrin alpha11', 'Gene', '22801', (0, 16))	('ITGA11', 'Gene', '22801', (114, 120))	('Integrin alpha11', 'Gene', (0, 16))	('cell attachment', 'CPA', (165, 180))	('ITGA11', 'Gene', (268, 274))
550524	31778288	In conclusion, high expression of ITGA11 in NSCLC was associated with higher stage and postoperative recurrence.	('high', 'Var', (15, 19))	('ITGA11', 'Gene', '22801', (34, 40))	('NSCLC', 'Disease', 'MESH:D002289', (44, 49))	('NSCLC', 'Phenotype', 'HP:0030358', (44, 49))	('ITGA11', 'Gene', (34, 40))	('postoperative recurrence', 'CPA', (87, 111))	('NSCLC', 'Disease', (44, 49))	('associated', 'Reg', (54, 64))	('higher stage', 'CPA', (70, 82))
550566	31612060	Mutational and copy number variations (CNVs) analyses of the BEX family members in LUAD samples were performed using cBioPortal for Cancer Genomics  as described previously.	('copy number variations', 'Var', (15, 37))	('LUAD', 'Phenotype', 'HP:0030078', (83, 87))	('LUAD', 'Disease', (83, 87))	('LUAD', 'Disease', 'MESH:C538231', (83, 87))	('BEX', 'Gene', '27018', (61, 64))	('Cancer', 'Phenotype', 'HP:0002664', (132, 138))	('BEX', 'Gene', (61, 64))
550602	31612060	The total alteration frequency of gene mutations, amplifications and deletions in patients with LUAD was <2% (Fig.	('LUAD', 'Phenotype', 'HP:0030078', (96, 100))	('LUAD', 'Disease', (96, 100))	('LUAD', 'Disease', 'MESH:C538231', (96, 100))	('patients', 'Species', '9606', (82, 90))	('deletions', 'Var', (69, 78))	('amplifications', 'Var', (50, 64))
550612	31612060	The abnormal expression of the BEX family has been implicated in various types of cancer, such as breast cancer and oral squamous cell carcinoma.	('breast cancer', 'Disease', 'MESH:D001943', (98, 111))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (116, 144))	('breast cancer', 'Phenotype', 'HP:0003002', (98, 111))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('BEX', 'Gene', (31, 34))	('breast cancer', 'Disease', (98, 111))	('abnormal', 'Var', (4, 12))	('expression', 'MPA', (13, 23))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('cancer', 'Disease', (82, 88))	('oral squamous cell carcinoma', 'Disease', (116, 144))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('BEX', 'Gene', '27018', (31, 34))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('implicated', 'Reg', (51, 61))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (121, 144))
550615	31612060	As the total alteration frequency of gene mutations, amplifications and deletions was <2%, the expression levels of the BEX family were likely not associated with mutations or CNVs.	('BEX', 'Gene', '27018', (120, 123))	('mutations', 'Var', (42, 51))	('BEX', 'Gene', (120, 123))	('deletions', 'Var', (72, 81))
550702	24959746	Our hypothesis was that CAR modulation by its ligands could alter the anti-tumor efficacy of paclitaxel, an antineoplastic agent commonly used for lung cancer chemotherapy in humans.	('modulation', 'Var', (28, 38))	('alter', 'Reg', (60, 65))	('lung cancer', 'Disease', (147, 158))	('paclitaxel', 'Chemical', 'MESH:D017239', (93, 103))	('lung cancer', 'Phenotype', 'HP:0100526', (147, 158))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('humans', 'Species', '9606', (175, 181))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('tumor', 'Disease', (75, 80))	('lung cancer', 'Disease', 'MESH:D008175', (147, 158))
550707	24959746	These results indicate that specific modulation of CAR by the agonist TCPOBOP improves the anti-tumor efficacy of paclitaxel in E9 cancer cells.	('cancer', 'Disease', (131, 137))	('TCPOBOP', 'Chemical', 'MESH:C028474', (70, 77))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('improves', 'PosReg', (78, 86))	('paclitaxel', 'Chemical', 'MESH:D017239', (114, 124))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('tumor', 'Disease', (96, 101))	('E9', 'CellLine', 'CVCL:5V04', (128, 130))	('TCPOBOP', 'Gene', (70, 77))	('modulation', 'Var', (37, 47))	('tumor', 'Disease', 'MESH:D009369', (96, 101))	('cancer', 'Disease', 'MESH:D009369', (131, 137))
550733	24959746	In the adenocarcinoma study, from 230 samples, 17.8% of the cases (41/230) presented genetic alterations of hCAR, including Copy Number Alterations (CNA), mutations or altered gene expression (Fig.	('altered', 'Reg', (168, 175))	('hCAR', 'Gene', '9970', (108, 112))	('mutations', 'Var', (155, 164))	('Copy', 'Disease', (124, 128))	('adenocarcinoma', 'Disease', (7, 21))	('hCAR', 'Gene', (108, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (12, 21))	('adenocarcinoma', 'Disease', 'MESH:D000230', (7, 21))
550746	24959746	Here we demonstrate that specific CAR modulation by agonists, but not by inverse-agonists, increased the anti-tumor efficacy of paclitaxel in both murine and human lung cancer cells.	('modulation', 'Var', (38, 48))	('lung cancer', 'Disease', (164, 175))	('human', 'Species', '9606', (158, 163))	('lung cancer', 'Phenotype', 'HP:0100526', (164, 175))	('paclitaxel', 'Chemical', 'MESH:D017239', (128, 138))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('tumor', 'Disease', (110, 115))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('increased', 'PosReg', (91, 100))	('lung cancer', 'Disease', 'MESH:D008175', (164, 175))	('murine', 'Species', '10090', (147, 153))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
550770	24959746	CAR expression analysis in mouse cancer cells treated with CAR ligands alone, paclitaxel alone, or a combination of both, revealed that Paclitaxel increased the gene expression of CAR independent of its association with TCPOBOP or androstenol.	('Paclitaxel', 'Var', (136, 146))	('cancer', 'Disease', (33, 39))	('increased', 'PosReg', (147, 156))	('Paclitaxel', 'Chemical', 'MESH:D017239', (136, 146))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('mouse', 'Species', '10090', (27, 32))	('gene expression', 'MPA', (161, 176))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('androstenol', 'Chemical', 'MESH:D000737', (231, 242))	('paclitaxel', 'Chemical', 'MESH:D017239', (78, 88))	('CAR', 'Gene', (180, 183))	('TCPOBOP', 'Chemical', 'MESH:C028474', (220, 227))
550771	24959746	Accordingly Agreeing with this result, in silico docking analysis of TCPOBOP, Androstenol and Paclitaxel into CAR protein structure demonstrated that Paclitaxel fits into the ligand-binding pocket of mCAR receptor, which could increase CAR expression by positive feedback.	('increase', 'PosReg', (227, 235))	('Paclitaxel', 'Var', (150, 160))	('TCPOBOP', 'Chemical', 'MESH:C028474', (69, 76))	('mCAR', 'Gene', '13052', (200, 204))	('Androstenol', 'Chemical', 'MESH:D000737', (78, 89))	('CAR expression', 'MPA', (236, 250))	('fits', 'Disease', (161, 165))	('Paclitaxel', 'Chemical', 'MESH:D017239', (94, 104))	('mCAR', 'Gene', (200, 204))	('fits', 'Disease', 'MESH:D012640', (161, 165))	('Paclitaxel', 'Chemical', 'MESH:D017239', (150, 160))
550780	24959746	However, when we analyzed TCGA data from the two studies of NSCLC, only a small proportion of cases presented with MGMT DNA methylation (data not shown).	('MGMT DNA methylation', 'Var', (115, 135))	('NSCLC', 'Disease', (60, 65))	('NSCLC', 'Phenotype', 'HP:0030358', (60, 65))	('NSCLC', 'Disease', 'MESH:D002289', (60, 65))
550783	24959746	These authors demonstrated that OS and disease-free survival of the high WT1 expression group were longer compared to those of the lower expression group.	('longer', 'PosReg', (99, 105))	('high WT1 expression', 'Var', (68, 87))	('OS', 'Chemical', '-', (32, 34))	('disease-free survival', 'CPA', (39, 60))
550784	24959746	Finally, they concluded that low WT1 expression predicted poor prognosis in patients with NSCLC.	('patients', 'Species', '9606', (76, 84))	('low', 'Var', (29, 32))	('NSCLC', 'Disease', (90, 95))	('WT1 expression', 'Protein', (33, 47))	('NSCLC', 'Disease', 'MESH:D002289', (90, 95))	('NSCLC', 'Phenotype', 'HP:0030358', (90, 95))
550851	31450902	M DI Domenico et al also found that N-Cadherin expression were characterized by a malignant phenotype associated with a worse clinical outcome, reduced overall survival and a major tendency for loco-regional invasion and metastasis.	('reduced', 'NegReg', (144, 151))	('N-Cadherin', 'Gene', '1000', (36, 46))	('loco-regional invasion', 'CPA', (194, 216))	('expression', 'Var', (47, 57))	('metastasis', 'CPA', (221, 231))	('overall survival', 'CPA', (152, 168))	('N-Cadherin', 'Gene', (36, 46))
550867	31450902	Whereas the 5-year survival rate of patients with N-cadherin-positive tumours was significantly lower than that of patients with N-cadherin-negative tumours.	('tumours', 'Disease', 'MESH:D009369', (149, 156))	('patients', 'Species', '9606', (115, 123))	('patients', 'Species', '9606', (36, 44))	('tumours', 'Disease', (149, 156))	('lower', 'NegReg', (96, 101))	('tumour', 'Phenotype', 'HP:0002664', (70, 76))	('tumour', 'Phenotype', 'HP:0002664', (149, 155))	('tumours', 'Phenotype', 'HP:0002664', (70, 77))	('tumours', 'Disease', 'MESH:D009369', (70, 77))	('N-cadherin-positive', 'Var', (50, 69))	('tumours', 'Phenotype', 'HP:0002664', (149, 156))	('tumours', 'Disease', (70, 77))
550877	28633632	The roles of miR-455-3p in activation of the Wnt/beta-catenin and transforming growth factor-beta (TGF-beta)/Smad pathways were determined by luciferase and RNA immunoprecipitation assays.	('beta-catenin', 'Gene', (49, 61))	('transforming growth factor-beta', 'Gene', (66, 97))	('beta-catenin', 'Gene', '1499', (49, 61))	('miR-455-3p', 'Chemical', '-', (13, 23))	('transforming growth factor-beta', 'Gene', '7040', (66, 97))	('TGF-beta', 'Gene', '7040', (99, 107))	('miR-455-3p', 'Var', (13, 23))	('activation', 'PosReg', (27, 37))	('TGF-beta', 'Gene', (99, 107))
550878	28633632	We found that miR-455-3p played essential roles in ESCC chemoresistance and tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('ESCC', 'Disease', (51, 55))	('miR-455-3p', 'Chemical', '-', (14, 24))	('miR-455-3p', 'Var', (14, 24))	('tumor', 'Disease', 'MESH:D009369', (76, 81))
550879	28633632	Treatment with a miR-455-3p antagomir dramatically chemosensitized ESCC cells and reduced the subpopulations of CD90+ and CD271+ T-ICs via deactivation of multiple stemness-associated pathways, including Wnt/beta-catenin and TGF-beta signaling.	('CD90', 'Gene', (112, 116))	('ESCC', 'Disease', (67, 71))	('TGF-beta', 'Gene', '7040', (225, 233))	('chemosensitized', 'Reg', (51, 66))	('deactivation', 'NegReg', (139, 151))	('TGF-beta', 'Gene', (225, 233))	('stemness-associated pathways', 'Pathway', (164, 192))	('CD90', 'Gene', '7070', (112, 116))	('beta-catenin', 'Gene', (208, 220))	('miR-455-3p', 'Chemical', '-', (17, 27))	('miR-455-3p', 'Var', (17, 27))	('beta-catenin', 'Gene', '1499', (208, 220))	('reduced', 'NegReg', (82, 89))	('CD271+', 'Var', (122, 128))
550880	28633632	Importantly, miR-455-3p exhibited aberrant upregulation in various human cancer types, and was significantly associated with decreased overall survival of cancer patients.	('cancer', 'Disease', (73, 79))	('patients', 'Species', '9606', (162, 170))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('decreased', 'NegReg', (125, 134))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('overall survival', 'CPA', (135, 151))	('miR-455-3p', 'Chemical', '-', (13, 23))	('miR-455-3p', 'Var', (13, 23))	('upregulation', 'PosReg', (43, 55))	('human', 'Species', '9606', (67, 72))	('cancer', 'Disease', (155, 161))	('cancer', 'Disease', 'MESH:D009369', (155, 161))
550881	28633632	Our results demonstrate that miR-455-3p functions as an oncomiR in ESCC progression and may provide a potential therapeutic target to achieve better clinical outcomes in cancer patients.	('miR-455-3p', 'Chemical', '-', (29, 39))	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('ESCC', 'Disease', (67, 71))	('miR-455-3p', 'Var', (29, 39))	('cancer', 'Disease', (170, 176))	('patients', 'Species', '9606', (177, 185))	('clinical', 'Species', '191496', (149, 157))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))
550888	28633632	found that CD133+ HCC cells display a preferential capacity for self-renewal and in vivo tumor initiation.	('self-renewal', 'CPA', (64, 76))	('HCC', 'Phenotype', 'HP:0001402', (18, 21))	('tumor initiation', 'Disease', (89, 105))	('preferential', 'PosReg', (38, 50))	('CD133+', 'Var', (11, 17))	('HCC', 'Gene', (18, 21))	('tumor initiation', 'Disease', 'MESH:D009369', (89, 105))	('HCC', 'Gene', '619501', (18, 21))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))
550890	28633632	The identification and characterization of T-ICs has revealed that multiple intracellular signaling pathways, activated by heritable genetic and epigenetic alterations and the tumor microenvironment, are involved in the induction and maintenance of T-IC-like traits and are constitutively overactivated in T-ICs.	('epigenetic alterations', 'Var', (145, 167))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('tumor', 'Disease', (176, 181))	('intracellular', 'Pathway', (76, 89))	('T-IC-like', 'Disease', (249, 258))	('tumor', 'Disease', 'MESH:D009369', (176, 181))
550897	28633632	Herein, we report that treatment with antagomir-455-3p chemosensitized esophageal squamous cell carcinoma (ESCC) cells and reduced the CD90+ and CD271+ T-IC subpopulations via the inhibition of multiple stemness-associated pathways, including Wnt/beta-catenin and TGF-beta signaling.	('TGF-beta', 'Gene', '7040', (264, 272))	('carcinoma', 'Phenotype', 'HP:0030731', (96, 105))	('TGF-beta', 'Gene', (264, 272))	('beta-catenin', 'Gene', '1499', (247, 259))	('esophageal squamous cell carcinoma', 'Disease', (71, 105))	('antagomir-455-3p', 'Var', (38, 54))	('CD90', 'Gene', '7070', (135, 139))	('reduced', 'NegReg', (123, 130))	('CD271+', 'Var', (145, 151))	('CD90', 'Gene', (135, 139))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (71, 105))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (82, 105))	('beta-catenin', 'Gene', (247, 259))	('inhibition', 'NegReg', (180, 190))	('stemness-associated pathways', 'Pathway', (203, 231))
550923	28633632	Furthermore, in vivo limiting dilution assay showed EC-CR cells exhibited an increased capacity to form tumors compared with EC-UT cells.	('EC-UT', 'CellLine', 'CVCL:X006', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('EC-CR', 'Var', (52, 57))	('tumors', 'Phenotype', 'HP:0002664', (104, 110))	('EC-CR', 'Chemical', '-', (52, 57))	('tumors', 'Disease', (104, 110))	('tumors', 'Disease', 'MESH:D009369', (104, 110))	('increased', 'PosReg', (77, 86))
550925	28633632	Consistently, in an in vitro tumorsphere formation assay, EC-CR cells formed significantly larger and more numerous tumorspheres than EC-UT cells (Fig.	('tumors', 'Disease', (116, 122))	('tumors', 'Disease', 'MESH:D009369', (116, 122))	('numerous tumorspheres', 'Disease', 'None', (107, 128))	('EC-CR', 'Var', (58, 63))	('EC-CR', 'Chemical', '-', (58, 63))	('more', 'PosReg', (102, 106))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('EC-UT', 'CellLine', 'CVCL:X006', (134, 139))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('numerous tumorspheres', 'Disease', (107, 128))	('tumors', 'Disease', 'MESH:D009369', (29, 35))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumors', 'Disease', (29, 35))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))
550926	28633632	The proportions of CD90+ and CD271+ cells, previously identified as T-IC subpopulations in ESCC, and side-population (SP) cells increased among EC-CR cells compared with EC-UT cells (Fig.	('EC-UT', 'CellLine', 'CVCL:X006', (170, 175))	('EC-CR', 'Chemical', '-', (144, 149))	('ESCC', 'Disease', (91, 95))	('CD271+ cells', 'Var', (29, 41))	('SP', 'Chemical', '-', (118, 120))	('increased', 'PosReg', (128, 137))	('CD90', 'Gene', '7070', (19, 23))	('CD90', 'Gene', (19, 23))	('EC-CR', 'Var', (144, 149))
550931	28633632	Strikingly, gene set enrichment analysis (GSEA) of The Cancer Genome Atlas (TCGA) datasets revealed that ESCC exhibiting high miR-455-3p expression was enriched in resistance gene sets for chemotherapeutic drugs such as CDDP, DOC, doxorubicin, gefitinib, dasatinib, cyclophosphamide, and vincristine, whereas ESCC exhibiting low miR-455-3p expression was enriched in chemotherapy sensitive gene sets (Fig.	('miR-455-3p expression', 'Var', (126, 147))	('CDDP', 'Chemical', 'MESH:D002945', (220, 224))	('GSEA', 'Chemical', '-', (42, 46))	('miR-455-3p', 'Chemical', '-', (329, 339))	('miR-455-3p', 'Chemical', '-', (126, 136))	('DOC', 'Chemical', 'MESH:D000077143', (226, 229))	('Cancer Genome Atlas', 'Disease', (55, 74))	('Cancer', 'Phenotype', 'HP:0002664', (55, 61))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (55, 74))
550932	28633632	2b and Additional file 2: Figure S1A), suggesting that miR-455-3p contributes to ESCC chemoresistance.	('miR-455-3p', 'Var', (55, 65))	('contributes', 'Reg', (66, 77))	('ESCC', 'Disease', (81, 85))	('miR-455-3p', 'Chemical', '-', (55, 65))
550933	28633632	As predicted, overexpressing miR-455-3p conferred resistance to CDDP and DOC in EC-UT and Kyse30 cells, but silencing miR-455-3p enhanced the sensitivity of EC-CR and Eca109 cells to chemotherapeutic agents (Additional file 2: Figure S1B).	('miR-455-3p', 'Chemical', '-', (118, 128))	('enhanced', 'PosReg', (129, 137))	('EC-UT', 'CellLine', 'CVCL:X006', (80, 85))	('miR-455-3p', 'Chemical', '-', (29, 39))	('silencing', 'Var', (108, 117))	('CDDP', 'MPA', (64, 68))	('miR-455-3p', 'Gene', (118, 128))	('resistance', 'MPA', (50, 60))	('sensitivity', 'MPA', (142, 153))	('DOC', 'Chemical', 'MESH:D000077143', (73, 76))	('CDDP', 'Chemical', 'MESH:D002945', (64, 68))	('EC-CR', 'Chemical', '-', (157, 162))
550935	28633632	Collectively, these results suggest that miR-455-3p plays an important role in ESCC chemoresistance.	('miR-455-3p', 'Var', (41, 51))	('ESCC', 'Disease', (79, 83))	('miR-455-3p', 'Chemical', '-', (41, 51))
550936	28633632	Consistent with the GSEA of TCGA datasets, through which miR-455-3p expression was found to be significantly associated with stemness signatures, miR-455-3p-transduced cells formed larger and more numerous tumorspheres containing higher proportions of CD90+/CD271+ and SP cells than control cells (Fig.	('miR-455-3p', 'Chemical', '-', (146, 156))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('miR-455-3p-transduced', 'Var', (146, 167))	('miR-455-3p', 'Chemical', '-', (57, 67))	('SP', 'Chemical', '-', (269, 271))	('tumors', 'Phenotype', 'HP:0002664', (206, 212))	('more', 'PosReg', (192, 196))	('numerous tumorspheres', 'Disease', 'None', (197, 218))	('CD90', 'Gene', '7070', (252, 256))	('CD90', 'Gene', (252, 256))	('numerous tumorspheres', 'Disease', (197, 218))	('larger', 'PosReg', (181, 187))	('GSEA', 'Chemical', '-', (20, 24))
550937	28633632	Importantly, limiting dilution and serial transplantation assays revealed a significantly higher tumor incidence and greater tumor-forming capacity in miR-455-3p-transduced ESCC cells than in control cells (Fig.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('ESCC', 'Disease', (173, 177))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('greater', 'PosReg', (117, 124))	('tumor', 'Disease', (97, 102))	('tumor', 'Disease', (125, 130))	('miR-455-3p', 'Chemical', '-', (151, 161))	('miR-455-3p-transduced', 'Var', (151, 172))	('higher', 'PosReg', (90, 96))
550938	28633632	2f), indicating that miR-455-3p contributes to the tumor-forming and self-renewal capabilities of ESCC cells.	('self-renewal capabilities', 'CPA', (69, 94))	('contributes', 'PosReg', (32, 43))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor', 'Disease', (51, 56))	('ESCC', 'Disease', (98, 102))	('miR-455-3p', 'Chemical', '-', (21, 31))	('miR-455-3p', 'Var', (21, 31))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
550941	28633632	Similarly, silencing of miR-455-3p drastically enhanced the inhibitory effect of CDDP on tumor growth in Eca109 cells and increased the apoptotic rate in Eca109 tumors (Additional file 3: Figure S2A and B).	('silencing', 'Var', (11, 20))	('enhanced', 'PosReg', (47, 55))	('tumors', 'Disease', (161, 167))	('tumors', 'Phenotype', 'HP:0002664', (161, 167))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('inhibitory effect', 'MPA', (60, 77))	('miR-455-3p', 'Chemical', '-', (24, 34))	('tumors', 'Disease', 'MESH:D009369', (161, 167))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('miR-455-3p', 'Var', (24, 34))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('CDDP', 'Gene', (81, 85))	('CDDP', 'Chemical', 'MESH:D002945', (81, 85))	('increased', 'PosReg', (122, 131))	('apoptotic rate', 'CPA', (136, 150))	('tumor', 'Disease', (161, 166))	('tumor', 'Disease', (89, 94))
550942	28633632	These results demonstrate that silencing miR-455-3p causes the chemosensitization of ESCC cells.	('silencing', 'Var', (31, 40))	('miR-455-3p', 'Protein', (41, 51))	('miR-455-3p', 'Chemical', '-', (41, 51))	('ESCC', 'Disease', (85, 89))	('causes', 'Reg', (52, 58))	('chemosensitization', 'CPA', (63, 81))
550943	28633632	Consistent with the enhancement of T-IC-like traits in ESCC cells by miR-455-3p, the antagomir-455-3p significantly repressed the tumor-initiating and self-renewal abilities of ESCC cells in vivo, and exerted an inhibitory effect on the tumorsphere-forming abilities of EC-CR and Eca109 cells in vitro (Fig.	('EC-CR', 'Chemical', '-', (270, 275))	('antagomir-455-3p', 'Var', (85, 101))	('tumor', 'Disease', (237, 242))	('tumors', 'Disease', (237, 243))	('tumors', 'Disease', 'MESH:D009369', (237, 243))	('tumors', 'Phenotype', 'HP:0002664', (237, 243))	('tumor', 'Disease', 'MESH:D009369', (130, 135))	('tumor', 'Phenotype', 'HP:0002664', (130, 135))	('repressed', 'NegReg', (116, 125))	('miR-455-3p', 'Chemical', '-', (69, 79))	('tumor', 'Disease', 'MESH:D009369', (237, 242))	('miR-455-3p', 'Var', (69, 79))	('tumor', 'Disease', (130, 135))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))
550944	28633632	3b and c and Additional file 3: Figure S2C), providing further evidence that miR-455-3p contributes to the T-IC-like traits of ESCC cells.	('T-IC-like traits', 'CPA', (107, 123))	('miR-455-3p', 'Chemical', '-', (77, 87))	('miR-455-3p', 'Var', (77, 87))
550945	28633632	Concordantly, silencing miR-455-3p in EC-CR and Eca109 cells significantly decreased the proportion of CD90+/CD271+ and SP cells and reduced the expression of stemness-associated factors (Fig.	('CD90', 'Gene', '7070', (103, 107))	('EC-CR', 'Chemical', '-', (38, 43))	('stemness-associated factors', 'CPA', (159, 186))	('CD90', 'Gene', (103, 107))	('SP cells', 'CPA', (120, 128))	('miR-455-3p', 'Chemical', '-', (24, 34))	('silencing miR-455-3p', 'Var', (14, 34))	('expression', 'MPA', (145, 155))	('miR-455-3p', 'Var', (24, 34))	('SP', 'Chemical', '-', (120, 122))	('reduced', 'NegReg', (133, 140))	('decreased', 'NegReg', (75, 84))
550946	28633632	Consistent with TCGA analysis, the results of which showed that miR-455-3p was markedly upregulated in ESCC and correlated with shorter overall and disease-free survival in patients with ESCC (Fig.	('ESCC', 'Disease', (187, 191))	('upregulated', 'PosReg', (88, 99))	('patients', 'Species', '9606', (173, 181))	('overall', 'CPA', (136, 143))	('miR-455-3p', 'Chemical', '-', (64, 74))	('shorter', 'NegReg', (128, 135))	('miR-455-3p', 'Var', (64, 74))	('disease-free survival', 'CPA', (148, 169))	('ESCC', 'Disease', (103, 107))
550948	28633632	Importantly, patients with higher miR-455-3p expression experienced shorter overall and disease-free survival, whereas patients with lower miR-455-3p expression experienced longer overall and disease-free survival (P < 0.05; Fig.	('disease-free survival', 'CPA', (88, 109))	('longer', 'PosReg', (173, 179))	('miR-455-3p expression', 'Var', (34, 55))	('patients', 'Species', '9606', (13, 21))	('miR-455-3p', 'Chemical', '-', (34, 44))	('patients', 'Species', '9606', (119, 127))	('miR-455-3p', 'Chemical', '-', (139, 149))	('shorter', 'NegReg', (68, 75))
550950	28633632	Thus, both TCGA analysis and these results suggest a potential link between miR-455-3p overexpression and ESCC progression.	('miR-455-3p', 'Chemical', '-', (76, 86))	('ESCC', 'Disease', (106, 110))	('miR-455-3p', 'Var', (76, 86))
550952	28633632	4c and d and Additional file 4: Figure S3C, both in vitro and in vivo chemoresistance experiments indicated that PDEC2 cells with higher miR-455-3p expression exhibited greater resistance to chemotherapeutic drugs than PDEC1 cells with lower miR-455-3p expression.	('miR-455-3p', 'Chemical', '-', (242, 252))	('higher', 'PosReg', (130, 136))	('PDEC1', 'CellLine', 'CVCL:B526', (219, 224))	('miR-455-3p', 'Chemical', '-', (137, 147))	('greater', 'PosReg', (169, 176))	('resistance to chemotherapeutic drugs', 'MPA', (177, 213))	('PDEC2', 'CellLine', 'CVCL:1901', (113, 118))	('miR-455-3p', 'Var', (137, 147))	('PDEC2', 'Gene', (113, 118))
550953	28633632	Importantly, silencing miR-455-3p dramatically enhanced the sensitivity of PDEC2 cells to chemotherapeutic drugs, and reduced the percentages of CD90+/CD271+ and SP cells and tumorsphere-forming capability of PDEC2 cells (Fig.	('tumors', 'Disease', (175, 181))	('SP cells', 'CPA', (162, 170))	('tumors', 'Disease', 'MESH:D009369', (175, 181))	('tumors', 'Phenotype', 'HP:0002664', (175, 181))	('enhanced', 'PosReg', (47, 55))	('miR-455-3p', 'Chemical', '-', (23, 33))	('PDEC2', 'CellLine', 'CVCL:1901', (75, 80))	('CD90', 'Gene', '7070', (145, 149))	('reduced', 'NegReg', (118, 125))	('sensitivity', 'MPA', (60, 71))	('CD90', 'Gene', (145, 149))	('PDEC2', 'CellLine', 'CVCL:1901', (209, 214))	('SP', 'Chemical', '-', (162, 164))	('miR-455-3p', 'Gene', (23, 33))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('silencing', 'Var', (13, 22))
550954	28633632	Together, these results support the contribution of miR-455-3p to the chemoresistance and tumorigenesis of ESCC.	('chemoresistance', 'CPA', (70, 85))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('miR-455-3p', 'Chemical', '-', (52, 62))	('miR-455-3p', 'Var', (52, 62))	('ESCC', 'Disease', (107, 111))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
550955	28633632	Consistent with the GSEA findings that miR-455-3p levels were significantly correlated with gene signatures regulated by the Wnt/beta-catenin and TGF-beta/Smad pathways (Fig.	('miR-455-3p', 'Var', (39, 49))	('TGF-beta', 'Gene', '7040', (146, 154))	('beta-catenin', 'Gene', '1499', (129, 141))	('TGF-beta', 'Gene', (146, 154))	('miR-455-3p', 'Chemical', '-', (39, 49))	('beta-catenin', 'Gene', (129, 141))	('GSEA', 'Chemical', '-', (20, 24))	('gene signatures', 'MPA', (92, 107))	('correlated', 'Reg', (76, 86))
550956	28633632	5a and Additional file 5: Figure S4A), overexpression of miR-455-3p significantly enhanced, but silencing of miR-455-3p reduced, luciferase reporter activities and levels of expression of nuclear beta-catenin, phosphorylated (p)-Smad2, and downstream genes in their respective pathways (Fig.	('enhanced', 'PosReg', (82, 90))	('beta-catenin', 'Gene', '1499', (196, 208))	('Smad2', 'Gene', (229, 234))	('luciferase reporter', 'Enzyme', (129, 148))	('expression', 'MPA', (174, 184))	('miR-455-3p', 'Chemical', '-', (57, 67))	('activities', 'MPA', (149, 159))	('miR-455-3p', 'Chemical', '-', (109, 119))	('miR-455-3p', 'Var', (57, 67))	('miR-455-3p', 'Gene', (109, 119))	('levels', 'MPA', (164, 170))	('silencing', 'NegReg', (96, 105))	('reduced', 'NegReg', (120, 127))	('Smad2', 'Gene', '4087', (229, 234))	('beta-catenin', 'Gene', (196, 208))
550957	28633632	5b and c and Additional file 5: Figure S4B), suggesting that miR-455-3p contributes to activation of the Wnt/beta-catenin and TGF-beta/Smad pathways in ESCC.	('TGF-beta', 'Gene', (126, 134))	('activation', 'PosReg', (87, 97))	('miR-455-3p', 'Chemical', '-', (61, 71))	('miR-455-3p', 'Var', (61, 71))	('beta-catenin', 'Gene', (109, 121))	('TGF-beta', 'Gene', '7040', (126, 134))	('beta-catenin', 'Gene', '1499', (109, 121))	('ESCC', 'Disease', (152, 156))
550960	28633632	Analysis using publicly available algorithms (Target Scan, miRWalk, and miRanda) showed that a number of negative regulators, including DKK3, GSK3beta, TCF7L1, IGFBP4, AMER1, CSNK1A1, TLE3, TLE4, TCF3, NKD2, SOX1, and SOST (Wnt/beta-catenin pathway) and Smurf2, NEDD4L, FKBP1A, BAMBI, PAK2, SKI, and PPM1A (TGF-beta/Smad pathway), were potential targets of miR-455-3p (Fig.	('BAMBI', 'Gene', (278, 283))	('DKK3', 'Gene', '27122', (136, 140))	('AMER1', 'Gene', (168, 173))	('NEDD4L', 'Gene', (262, 268))	('Smurf2', 'Gene', (254, 260))	('TGF-beta', 'Gene', (307, 315))	('NEDD4L', 'Gene', '23327', (262, 268))	('GSK3beta', 'Gene', '2932', (142, 150))	('miR-455-3p', 'Var', (357, 367))	('BAMBI', 'Gene', '25805', (278, 283))	('SKI', 'Gene', '6497', (291, 294))	('PAK2', 'Gene', (285, 289))	('SOST', 'Gene', (218, 222))	('CSNK1A1', 'Gene', (175, 182))	('CSNK1A1', 'Gene', '1452', (175, 182))	('IGFBP4', 'Gene', (160, 166))	('PAK2', 'Gene', '5062', (285, 289))	('AMER1', 'Gene', '139285', (168, 173))	('SOX1', 'Gene', '6656', (208, 212))	('TCF7L1', 'Gene', (152, 158))	('TLE3', 'Gene', (184, 188))	('NKD2', 'Gene', (202, 206))	('SOST', 'Gene', '50964', (218, 222))	('GSK3beta', 'Gene', (142, 150))	('PPM1A', 'Gene', '5494', (300, 305))	('TLE4', 'Gene', (190, 194))	('NKD2', 'Gene', '85409', (202, 206))	('FKBP1A', 'Gene', (270, 276))	('Smurf2', 'Gene', '64750', (254, 260))	('TLE4', 'Gene', '7091', (190, 194))	('FKBP1A', 'Gene', '2280', (270, 276))	('SKI', 'Gene', (291, 294))	('beta-catenin', 'Gene', (228, 240))	('IGFBP4', 'Gene', '3487', (160, 166))	('beta-catenin', 'Gene', '1499', (228, 240))	('PPM1A', 'Gene', (300, 305))	('TGF-beta', 'Gene', '7040', (307, 315))	('DKK3', 'Gene', (136, 140))	('TCF3', 'Gene', (196, 200))	('TLE3', 'Gene', '7090', (184, 188))	('miR-455-3p', 'Chemical', '-', (357, 367))	('TCF3', 'Gene', '6929', (196, 200))	('SOX1', 'Gene', (208, 212))	('TCF7L1', 'Gene', '83439', (152, 158))
550961	28633632	RIP assays revealed a higher degree of association of miR-455-3p with DKK3, GSK3beta, Smurf2, and PPM1A in both EC-CR and Eca109 cells (Fig.	('GSK3beta', 'Gene', (76, 84))	('miR-455-3p', 'Chemical', '-', (54, 64))	('PPM1A', 'Gene', (98, 103))	('miR-455-3p', 'Var', (54, 64))	('GSK3beta', 'Gene', '2932', (76, 84))	('DKK3', 'Gene', '27122', (70, 74))	('Smurf2', 'Gene', (86, 92))	('DKK3', 'Gene', (70, 74))	('PPM1A', 'Gene', '5494', (98, 103))	('Smurf2', 'Gene', '64750', (86, 92))	('EC-CR', 'Chemical', '-', (112, 117))	('association', 'Interaction', (39, 50))
550963	28633632	These results suggest that miR-455-3p activates the Wnt/beta-catenin and TGF-beta/Smad pathways by directly binding to the 3' UTRs of a number of negative regulators.	('TGF-beta', 'Gene', '7040', (73, 81))	('TGF-beta', 'Gene', (73, 81))	('beta-catenin', 'Gene', (56, 68))	('binding', 'Interaction', (108, 115))	('beta-catenin', 'Gene', '1499', (56, 68))	('miR-455-3p', 'Var', (27, 37))	('miR-455-3p', 'Chemical', '-', (27, 37))	('activates', 'PosReg', (38, 47))
550964	28633632	Analysis of TCGA datasets indicated that miR-455-3p was also markedly upregulated in other human cancers, including gastric, lung, bladder, breast, cervical, kidney, and uterine cancers (Fig.	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('gastric', 'Disease', (116, 123))	('uterine cancers', 'Phenotype', 'HP:0010784', (170, 185))	('breast', 'Disease', (140, 146))	('cancers', 'Phenotype', 'HP:0002664', (97, 104))	('kidney', 'Disease', (158, 164))	('cancers', 'Disease', (97, 104))	('cancers', 'Disease', 'MESH:D009369', (178, 185))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('bladder', 'Disease', (131, 138))	('miR-455-3p', 'Chemical', '-', (41, 51))	('lung', 'Disease', (125, 129))	('cancers', 'Disease', 'MESH:D009369', (97, 104))	('cancers', 'Phenotype', 'HP:0002664', (178, 185))	('cancers', 'Disease', (178, 185))	('cervical', 'Disease', (148, 156))	('miR-455-3p', 'Var', (41, 51))	('upregulated', 'PosReg', (70, 81))	('human', 'Species', '9606', (91, 96))
550965	28633632	6a), suggesting that miR-455-3p may also function as an oncomiR in other human cancers.	('cancers', 'Disease', (79, 86))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('miR-455-3p', 'Chemical', '-', (21, 31))	('human', 'Species', '9606', (73, 78))	('miR-455-3p', 'Var', (21, 31))	('cancers', 'Phenotype', 'HP:0002664', (79, 86))	('cancers', 'Disease', 'MESH:D009369', (79, 86))
550966	28633632	Importantly, higher miR-455-3p expression was associated with shorter overall survival and significantly correlated with gene signatures regulated by the Wnt/beta-catenin and TGF-beta/Smad pathways in gastric, kidney, and lung cancers (Fig.	('miR-455-3p', 'Chemical', '-', (20, 30))	('gastric', 'Disease', (201, 208))	('gene signatures', 'MPA', (121, 136))	('higher', 'PosReg', (13, 19))	('correlated', 'Reg', (105, 115))	('miR-455-3p', 'Var', (20, 30))	('TGF-beta', 'Gene', '7040', (175, 183))	('beta-catenin', 'Gene', (158, 170))	('overall survival', 'MPA', (70, 86))	('beta-catenin', 'Gene', '1499', (158, 170))	('lung cancers', 'Disease', 'MESH:D008175', (222, 234))	('expression', 'MPA', (31, 41))	('lung cancers', 'Disease', (222, 234))	('TGF-beta', 'Gene', (175, 183))	('shorter', 'NegReg', (62, 69))	('lung cancer', 'Phenotype', 'HP:0100526', (222, 233))	('cancer', 'Phenotype', 'HP:0002664', (227, 233))	('lung cancers', 'Phenotype', 'HP:0100526', (222, 234))	('kidney', 'Disease', (210, 216))	('cancers', 'Phenotype', 'HP:0002664', (227, 234))
550967	28633632	Furthermore, RIP assays indicated that miR-455-3p was associated with different negative regulators of the Wnt/beta-catenin and TGF-beta/Smad pathways in gastric and kidney cancer cells (Fig.	('TGF-beta', 'Gene', '7040', (128, 136))	('miR-455-3p', 'Var', (39, 49))	('TGF-beta', 'Gene', (128, 136))	('beta-catenin', 'Gene', (111, 123))	('gastric and kidney cancer', 'Disease', 'MESH:D013274', (154, 179))	('kidney cancer', 'Phenotype', 'HP:0009726', (166, 179))	('cancer', 'Phenotype', 'HP:0002664', (173, 179))	('beta-catenin', 'Gene', '1499', (111, 123))	('miR-455-3p', 'Chemical', '-', (39, 49))	('negative regulators', 'MPA', (80, 99))
550968	28633632	Moreover, silencing miR-455-3p in gastric and bladder cancer cells dramatically decreased the transcriptional activities of the Wnt/beta-catenin and TGF-beta/Smad pathways and CDDP resistance (Fig.	('CDDP resistance', 'CPA', (176, 191))	('TGF-beta', 'Gene', '7040', (149, 157))	('miR-455-3p', 'Chemical', '-', (20, 30))	('beta-catenin', 'Gene', (132, 144))	('silencing miR-455-3p', 'Var', (10, 30))	('bladder cancer', 'Disease', (46, 60))	('TGF-beta', 'Gene', (149, 157))	('miR-455-3p', 'Var', (20, 30))	('decreased', 'NegReg', (80, 89))	('CDDP', 'Chemical', 'MESH:D002945', (176, 180))	('beta-catenin', 'Gene', '1499', (132, 144))	('bladder cancer', 'Disease', 'MESH:D001749', (46, 60))	('bladder cancer', 'Phenotype', 'HP:0009725', (46, 60))	('transcriptional activities', 'MPA', (94, 120))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
550969	28633632	Altogether, these results imply that aberrant miR-455-3p expression activates T-IC-associated signaling pathways, leading to cancer progression, chemotherapy failure, and poor clinical outcomes (Fig.	('leading to', 'Reg', (114, 124))	('miR-455-3p', 'Chemical', '-', (46, 56))	('T-IC-associated signaling pathways', 'Pathway', (78, 112))	('miR-455-3p', 'Var', (46, 56))	('clinical', 'Species', '191496', (176, 184))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('activates', 'PosReg', (68, 77))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('chemotherapy failure', 'CPA', (145, 165))	('aberrant miR-455-3p', 'Var', (37, 56))
550970	28633632	It is generally acknowledged that an association exists between T-ICs and poor prognosis, tumor recurrence, and chemoradiotherapy failure in multiple human cancers.	('human', 'Species', '9606', (150, 155))	('cancers', 'Phenotype', 'HP:0002664', (156, 163))	('T-ICs', 'Var', (64, 69))	('cancers', 'Disease', (156, 163))	('cancers', 'Disease', 'MESH:D009369', (156, 163))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
550973	28633632	Furthermore, we demonstrated that miR-455-3p plays essential roles in ESCC chemoresistance and tumorigenesis, and that treatment with a miR-455-3p antagomir chemosensitizes ESCC cells and reduces ESCC T-ICs subpopulations.	('ESCC', 'Disease', (173, 177))	('miR-455-3p', 'Chemical', '-', (136, 146))	('miR-455-3p', 'Chemical', '-', (34, 44))	('ESCC', 'Disease', (196, 200))	('miR-455-3p', 'Var', (136, 146))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('chemosensitizes', 'CPA', (157, 172))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('ESCC chemoresistance', 'CPA', (70, 90))	('tumor', 'Disease', (95, 100))	('reduces', 'NegReg', (188, 195))
550974	28633632	Our results suggest that the chemoresistant ESCC cells examined in our study possess T-IC-like traits, and that miR-455-3p represents a potential therapeutic target to achieve better clinical outcomes in cancer patients.	('cancer', 'Disease', (204, 210))	('cancer', 'Disease', 'MESH:D009369', (204, 210))	('patients', 'Species', '9606', (211, 219))	('miR-455-3p', 'Chemical', '-', (112, 122))	('clinical', 'Species', '191496', (183, 191))	('miR-455-3p', 'Var', (112, 122))	('cancer', 'Phenotype', 'HP:0002664', (204, 210))	('T-IC-like', 'CPA', (85, 94))
550975	28633632	We found that the proportions of both CD90+ and CD271+ cells, previously identified as ESCC T-ICs, were increased among chemoresistant ESCC cells, suggesting the existence of multiple T-IC subpopulations within ESCC tumors.	('CD271+', 'Var', (48, 54))	('increased', 'PosReg', (104, 113))	('tumors', 'Disease', (216, 222))	('tumors', 'Disease', 'MESH:D009369', (216, 222))	('tumors', 'Phenotype', 'HP:0002664', (216, 222))	('tumor', 'Phenotype', 'HP:0002664', (216, 221))	('CD90', 'Gene', '7070', (38, 42))	('CD90', 'Gene', (38, 42))
550977	28633632	The same phenomenon was also observed in liver (CD24+ and CD133+) and colon (CD44+ and CD26+) cancers.	('cancers', 'Disease', 'MESH:D009369', (94, 101))	('CD44', 'Gene', '960', (77, 81))	('CD24', 'Gene', '100133941', (48, 52))	('cancers', 'Phenotype', 'HP:0002664', (94, 101))	('CD44', 'Gene', (77, 81))	('CD133+', 'Var', (58, 64))	('colon', 'Disease', (70, 75))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('CD26', 'Gene', '1803', (87, 91))	('liver', 'Disease', (41, 46))	('CD26', 'Gene', (87, 91))	('CD24', 'Gene', (48, 52))	('cancers', 'Disease', (94, 101))
550979	28633632	We found that miR-455-3p overexpression significantly increased, but miR-455-3p inhibition reduced, the subpopulations of CD90+ and CD271+ T-ICs, suggesting that miR-455-3p functions in the interconversion between ESCC cells and ESCC T-IC subpopulations.	('increased', 'PosReg', (54, 63))	('reduced', 'NegReg', (91, 98))	('CD271+', 'Var', (132, 138))	('CD90', 'Gene', '7070', (122, 126))	('miR-455-3p', 'Chemical', '-', (14, 24))	('miR-455-3p', 'Chemical', '-', (162, 172))	('miR-455-3p', 'Chemical', '-', (69, 79))	('CD90', 'Gene', (122, 126))
550983	28633632	We found that silencing of miR-455-3p simultaneously deactivated multiple T-IC-associated pathways, resulting in functional inhibition of ESCC chemoresistance and tumor recurrence, suggesting that miR-455-3p may be a suitable therapeutic target for the treatment of ESCC.	('miR-455-3p', 'Gene', (27, 37))	('silencing', 'Var', (14, 23))	('inhibition', 'NegReg', (124, 134))	('miR-455-3p', 'Chemical', '-', (197, 207))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('deactivated', 'NegReg', (53, 64))	('tumor', 'Disease', (163, 168))	('miR-455-3p', 'Chemical', '-', (27, 37))	('ESCC', 'Disease', (138, 142))	('T-IC-associated pathways', 'Pathway', (74, 98))
550985	28633632	Consistent with our finding that miR-455-3p is upregulated in ESCC and multiple distinct cancer types, miR-455-3p is also overexpressed in glioma, oral squamous cell cancer, and triple-negative breast cancer, where it contributes to cancer chemoresistance, proliferation, and invasion/migration.	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('cancer', 'Disease', (201, 207))	('upregulated', 'PosReg', (47, 58))	('glioma', 'Disease', (139, 145))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (152, 172))	('glioma', 'Disease', 'MESH:D005910', (139, 145))	('cancer', 'Disease', (89, 95))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('overexpressed', 'PosReg', (122, 135))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('contributes', 'Reg', (218, 229))	('cancer', 'Disease', 'MESH:D009369', (233, 239))	('glioma', 'Phenotype', 'HP:0009733', (139, 145))	('miR-455-3p', 'Chemical', '-', (33, 43))	('breast cancer', 'Phenotype', 'HP:0003002', (194, 207))	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('cancer', 'Disease', (166, 172))	('oral squamous cell cancer', 'Disease', 'MESH:D002294', (147, 172))	('oral squamous cell cancer', 'Disease', (147, 172))	('cancer', 'Disease', 'MESH:D009369', (89, 95))	('miR-455-3p', 'Gene', (33, 43))	('miR-455-3p', 'Chemical', '-', (103, 113))	('breast cancer', 'Disease', 'MESH:D001943', (194, 207))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('breast cancer', 'Disease', (194, 207))	('proliferation', 'CPA', (257, 270))	('cancer', 'Disease', (233, 239))	('miR-455-3p', 'Var', (103, 113))	('ESCC', 'Disease', (62, 66))	('invasion/migration', 'CPA', (276, 294))
550986	28633632	However, miR-455-3p is reportedly downregulated in prostate and colon cancer, and upregulation of miR-455-3p can inhibit the cancer proliferation.	('miR-455-3p', 'Chemical', '-', (98, 108))	('downregulated', 'NegReg', (34, 47))	('colon cancer', 'Disease', 'MESH:D015179', (64, 76))	('colon cancer', 'Phenotype', 'HP:0003003', (64, 76))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('miR-455-3p', 'Gene', (9, 19))	('miR-455-3p', 'Var', (98, 108))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('inhibit', 'NegReg', (113, 120))	('colon cancer', 'Disease', (64, 76))	('upregulation', 'PosReg', (82, 94))	('cancer', 'Disease', (125, 131))	('prostate', 'Disease', (51, 59))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('miR-455-3p', 'Chemical', '-', (9, 19))
550987	28633632	These studies imply that miR-455-3p can act as either an oncomiR or a tumor-suppressive miRNA depending on the tumor type.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumor', 'Disease', (70, 75))	('tumor', 'Disease', (111, 116))	('miR-455-3p', 'Chemical', '-', (25, 35))	('miR-455-3p', 'Var', (25, 35))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
550989	28633632	Furthermore, we demonstrated that aberrantly expressed miR-455-3p in ESCC cells simultaneously activates Wnt/beta-catenin and TGF-beta/Smad signaling through concurrent suppression of multiple negative regulators of these pathways.	('TGF-beta', 'Gene', (126, 134))	('negative regulators', 'Pathway', (193, 212))	('suppression', 'NegReg', (169, 180))	('beta-catenin', 'Gene', (109, 121))	('activates', 'PosReg', (95, 104))	('TGF-beta', 'Gene', '7040', (126, 134))	('miR-455-3p', 'Chemical', '-', (55, 65))	('miR-455-3p', 'Var', (55, 65))	('beta-catenin', 'Gene', '1499', (109, 121))
550991	28633632	In this study, we identified miR-455-3p as essential for ESCC chemoresistance both in vivo and in vitro.	('chemoresistance', 'CPA', (62, 77))	('miR-455-3p', 'Chemical', '-', (29, 39))	('ESCC', 'Disease', (57, 61))	('miR-455-3p', 'Var', (29, 39))
550992	28633632	We found that miR-455-3p levels are significantly correlated with poorer disease-free survival and overall survival in patients with primary ESCC.	('patients', 'Species', '9606', (119, 127))	('poorer', 'NegReg', (66, 72))	('disease-free survival', 'CPA', (73, 94))	('miR-455-3p levels', 'Var', (14, 31))	('overall survival', 'CPA', (99, 115))	('primary ESCC', 'Disease', (133, 145))	('miR-455-3p', 'Chemical', '-', (14, 24))
550993	28633632	Inhibition of miR-455-3p chemosensitizes ESCC cells and reduces the subpopulations of CD90+ and CD271+ T-ICs via the suppression of multiple T-IC-associated pathways, including the Wnt/beta-catenin and TGF-beta pathways.	('suppression', 'NegReg', (117, 128))	('TGF-beta', 'Gene', (202, 210))	('miR-455-3p', 'Gene', (14, 24))	('CD90', 'Gene', '7070', (86, 90))	('beta-catenin', 'Gene', '1499', (185, 197))	('CD271+', 'Var', (96, 102))	('CD90', 'Gene', (86, 90))	('ESCC', 'Disease', (41, 45))	('reduces', 'NegReg', (56, 63))	('T-IC-associated pathways', 'Pathway', (141, 165))	('subpopulations', 'MPA', (68, 82))	('miR-455-3p', 'Chemical', '-', (14, 24))	('TGF-beta', 'Gene', '7040', (202, 210))	('beta-catenin', 'Gene', (185, 197))
550994	28633632	Importantly, miR-455-3p is aberrantly upregulated in numerous cancers and significantly associated with the decreased overall survival of cancer patients.	('patients', 'Species', '9606', (145, 153))	('cancer', 'Disease', (138, 144))	('numerous cancers', 'Disease', 'MESH:D009369', (53, 69))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('upregulated', 'PosReg', (38, 49))	('miR-455-3p', 'Chemical', '-', (13, 23))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('overall', 'MPA', (118, 125))	('numerous cancers', 'Disease', (53, 69))	('miR-455-3p', 'Var', (13, 23))	('cancer', 'Disease', (62, 68))	('decreased', 'NegReg', (108, 117))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('cancers', 'Phenotype', 'HP:0002664', (62, 69))	('cancer', 'Disease', 'MESH:D009369', (138, 144))
551065	33330121	The presence of H. pylori is mainly responsible for gastric inflammation and ulceration and significantly increases the risk of gastric cancer.	('gastric cancer', 'Disease', (128, 142))	('responsible', 'Reg', (36, 47))	('ulceration', 'Disease', (77, 87))	('gastric cancer', 'Disease', 'MESH:D013274', (128, 142))	('gastric inflammation', 'Disease', 'MESH:D013272', (52, 72))	('gastric cancer', 'Phenotype', 'HP:0012126', (128, 142))	('gastric inflammation', 'Disease', (52, 72))	('gastric inflammation', 'Phenotype', 'HP:0005263', (52, 72))	('increases', 'PosReg', (106, 115))	('presence', 'Var', (4, 12))	('H. pylori', 'Gene', (16, 25))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('H. pylori', 'Species', '210', (16, 25))
551073	33330121	Individuals who underwent an eradication of H. pylori demonstrated a lower incidence of gastric cancer than those who did not receive eradicative therapy.	('H. pylori', 'Species', '210', (44, 53))	('gastric cancer', 'Disease', (88, 102))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('gastric cancer', 'Disease', 'MESH:D013274', (88, 102))	('lower', 'NegReg', (69, 74))	('gastric cancer', 'Phenotype', 'HP:0012126', (88, 102))	('eradication', 'Var', (29, 40))	('H. pylori', 'Gene', (44, 53))
551084	33330121	reported that the presence of Fusobacterium nucleatum DNA was 415 times greater in tumor tissues than adjacent normal tissues, which might be associated with colorectal cancer.	('colorectal cancer', 'Phenotype', 'HP:0003003', (158, 175))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('Fusobacterium', 'Var', (30, 43))	('greater', 'PosReg', (72, 79))	('tumor', 'Disease', (83, 88))	('colorectal cancer', 'Disease', (158, 175))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('associated', 'Reg', (142, 152))	('Fusobacterium nucleatum', 'Species', '851', (30, 53))	('colorectal cancer', 'Disease', 'MESH:D015179', (158, 175))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
551094	33330121	The Apc min/+mice (the mice model with adenomatous polyposis coli (APC) gene mutation) gavaged with feces from colorectal cancer patients had more intestinal tumors compared with healthy controls or the mice gavaged with phosphate-buffered saline.	('tumors', 'Phenotype', 'HP:0002664', (158, 164))	('mice', 'Species', '10090', (13, 17))	('mutation', 'Var', (77, 85))	('adenomatous polyposis coli', 'Phenotype', 'HP:0005227', (39, 65))	('phosphate-buffered saline', 'Chemical', '-', (221, 246))	('Apc', 'Gene', (4, 7))	('Apc', 'Gene', '11789', (4, 7))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('colorectal cancer', 'Disease', 'MESH:D015179', (111, 128))	('mice', 'Species', '10090', (203, 207))	('intestinal tumors', 'Disease', (147, 164))	('adenomatous polyposis coli', 'Gene', (39, 65))	('more', 'PosReg', (142, 146))	('colorectal cancer', 'Disease', (111, 128))	('patients', 'Species', '9606', (129, 137))	('adenomatous polyposis', 'Phenotype', 'HP:0005227', (39, 60))	('adenomatous polyposis coli', 'Gene', '11789', (39, 65))	('colorectal cancer', 'Phenotype', 'HP:0003003', (111, 128))	('intestinal tumors', 'Disease', 'MESH:D007414', (147, 164))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('mice', 'Species', '10090', (23, 27))
551104	33330121	The Chlamydia trachomatis were reported to be a possible co-factor for cervical cancer development.	('cervical cancer', 'Disease', (71, 86))	('cervical cancer', 'Disease', 'MESH:D002583', (71, 86))	('men', 'Species', '9606', (94, 97))	('Chlamydia trachomatis', 'Var', (4, 25))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('Chlamydia trachomatis', 'Species', '813', (4, 25))
551108	33330121	The infections of Atopobium vaginae, Dialister invisus, Finegoldia magna, Gardnerella vaginalis, Prevotella buccalis, and P. timonensis were significantly associated with the high risk of high-grade squamous intraepithelial neoplasia and cervical cancer.	('cervical cancer', 'Disease', (238, 253))	('neoplasia', 'Phenotype', 'HP:0002664', (224, 233))	('infections', 'Disease', (4, 14))	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('squamous intraepithelial neoplasia', 'Disease', 'MESH:D000081483', (199, 233))	('Dialister invisus', 'Species', '218538', (37, 54))	('intraepithelial neoplasia', 'Phenotype', 'HP:0032187', (208, 233))	('associated', 'Reg', (155, 165))	('Finegoldia magna', 'Species', '1260', (56, 72))	('Prevotella buccalis', 'Species', '28127', (97, 116))	('P. timonensis', 'Var', (122, 135))	('Gardnerella vaginalis', 'Species', '2702', (74, 95))	('squamous intraepithelial neoplasia', 'Disease', (199, 233))	('infections', 'Disease', 'MESH:D007239', (4, 14))	('Atopobium vaginae', 'Species', '82135', (18, 35))	('cervical cancer', 'Disease', 'MESH:D002583', (238, 253))	('P. timonensis', 'Species', '225915', (122, 135))
551120	33330121	Particularly, the relative abundance of Anoxynatronum sibiricum might be associated with the stage of tumor.	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('associated', 'Reg', (73, 83))	('Anoxynatronum', 'Var', (40, 53))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('Anoxynatronum sibiricum', 'Species', '210623', (40, 63))
551134	33330121	The genomic integration of human herpesviruses -6a at the telomeric region could be a contributing factor to ovarian cancer.	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('ovarian cancer', 'Disease', 'MESH:D010051', (109, 123))	('genomic integration', 'Var', (4, 23))	('human', 'Species', '9606', (27, 32))	('contributing factor', 'Reg', (86, 105))	('ovarian cancer', 'Disease', (109, 123))	('ovarian cancer', 'Phenotype', 'HP:0100615', (109, 123))
551170	33330121	Microbes might affect the immune status to promote the development and progression of several cancers, as described in a number of studies.	('cancers', 'Disease', 'MESH:D009369', (94, 101))	('men', 'Species', '9606', (62, 65))	('promote', 'PosReg', (43, 50))	('Microbes', 'Var', (0, 8))	('affect', 'Reg', (15, 21))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('development', 'CPA', (55, 66))	('cancers', 'Phenotype', 'HP:0002664', (94, 101))	('progression', 'CPA', (71, 82))	('cancers', 'Disease', (94, 101))	('immune status', 'CPA', (26, 39))
551182	33330121	In MSI-high colorectal cancer, the abundant neoantigens due to a large number of transcoding mutations could lead to a strong immune response to the tumor.	('colorectal cancer', 'Disease', (12, 29))	('lead to', 'Reg', (109, 116))	('transcoding', 'Gene', (81, 92))	('mutations', 'Var', (93, 102))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('colorectal cancer', 'Disease', 'MESH:D015179', (12, 29))	('neoantigens', 'MPA', (44, 55))	('tumor', 'Disease', (149, 154))	('colorectal cancer', 'Phenotype', 'HP:0003003', (12, 29))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))
551190	33330121	Chronic mucosal formation of IL17A produced by Th 17 cells might alter signaling pathways in colon epithelial cells or induce changes or mutations in DNA structure that facilitated the transformation of colon epithelial cells contributing to carcinogenesis.	('Chronic mucosal', 'Disease', (0, 15))	('carcinogenesis', 'Disease', (242, 256))	('IL17A', 'Gene', (29, 34))	('mutations', 'Var', (137, 146))	('Chronic mucosal', 'Disease', 'MESH:D052016', (0, 15))	('alter', 'Reg', (65, 70))	('changes', 'Reg', (126, 133))	('DNA structure', 'Gene', (150, 163))	('IL17A', 'Gene', '3605', (29, 34))	('carcinogenesis', 'Disease', 'MESH:D063646', (242, 256))	('signaling pathways', 'Pathway', (71, 89))	('transformation', 'CPA', (185, 199))	('facilitated', 'PosReg', (169, 180))
551209	33330121	Genetic changes, mainly those associated with DNA damage and repair, are known to be linked to cancer.	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('Genetic changes', 'Var', (0, 15))	('cancer', 'Disease', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('linked', 'Reg', (85, 91))
551222	33330121	The deficiency in homologous recombination repair was shown to induce genomic instability and a hyper-dependence on alternative DNA repair mechanisms and to enhance the sensitivity of double-strand break-inducing agents.	('enhance', 'PosReg', (157, 164))	('genomic instability', 'CPA', (70, 89))	('alternative DNA repair mechanisms', 'MPA', (116, 149))	('induce', 'Reg', (63, 69))	('deficiency', 'Var', (4, 14))	('sensitivity', 'MPA', (169, 180))	('homologous recombination repair', 'Protein', (18, 49))	('hyper-dependence', 'Disease', (96, 112))	('hyper-dependence', 'Disease', 'MESH:D000437', (96, 112))
551262	33330121	Although the pathogenic mechanisms of microbes in cancer can be divided into the four main areas of modulating inflammation, immunity, DNA damage, and metabolism, microbes can induce the incidence of cancer through multiple pathogenic mechanisms.	('microbes', 'Var', (163, 171))	('cancer', 'Disease', (50, 56))	('inflammation', 'Disease', (111, 123))	('inflammation', 'Disease', 'MESH:D007249', (111, 123))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('induce', 'Reg', (176, 182))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (200, 206))	('cancer', 'Disease', (200, 206))
551269	33330121	In prostate cancer, Mycoplasma hyorhinis might induce tumorigenesis not only indirectly through a partial chronic inflammatory response, but also directly through bacterial protein products, such as p37, that exert oncogenic effects.	('Mycoplasma hyorhinis', 'Var', (20, 40))	('p37', 'Gene', '3184', (199, 202))	('prostate cancer', 'Phenotype', 'HP:0012125', (3, 18))	('induce', 'PosReg', (47, 53))	('p37', 'Gene', (199, 202))	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('prostate cancer', 'Disease', (3, 18))	('cancer', 'Phenotype', 'HP:0002664', (12, 18))	('Mycoplasma hyorhinis', 'Species', '2100', (20, 40))	('tumor', 'Disease', (54, 59))	('prostate cancer', 'Disease', 'MESH:D011471', (3, 18))
551270	33330121	In lung cancer, microbes might lead to malignancy through microbial dysbiosis, genotoxicity and virulence effects, inflammation, immune responses, and metabolism.	('inflammation', 'Disease', 'MESH:D007249', (115, 127))	('virulence effects', 'MPA', (96, 113))	('microbial', 'MPA', (58, 67))	('metabolism', 'CPA', (151, 161))	('dysbiosis', 'Disease', (68, 77))	('lung cancer', 'Disease', (3, 14))	('dysbiosis', 'Disease', 'MESH:D064806', (68, 77))	('inflammation', 'Disease', (115, 127))	('microbes', 'Var', (16, 24))	('lung cancer', 'Phenotype', 'HP:0100526', (3, 14))	('lead to', 'Reg', (31, 38))	('malignancy', 'Disease', 'MESH:D009369', (39, 49))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('malignancy', 'Disease', (39, 49))	('lung cancer', 'Disease', 'MESH:D008175', (3, 14))	('immune responses', 'CPA', (129, 145))
551277	33330121	After the cocolonization with pks+ E. coli and Bacteroides fragilis, the DNA damage was obviously enhanced in the mice colon epithelial cells.	('enhanced', 'PosReg', (98, 106))	('DNA damage', 'MPA', (73, 83))	('Bacteroides fragilis', 'Species', '817', (47, 67))	('pks+ E. coli', 'Var', (30, 42))	('mice', 'Species', '10090', (114, 118))	('E. coli', 'Species', '562', (35, 42))
551308	33330121	Bacteria have so far remained as the most studied microbes worldwide, and bacteria might affect the incidence and development of cancer through four major special pathogenic mechanisms, including modulating inflammation, immunity, DNA damage, and metabolism.	('inflammation', 'Disease', 'MESH:D007249', (207, 219))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('men', 'Species', '9606', (121, 124))	('modulating', 'Reg', (196, 206))	('inflammation', 'Disease', (207, 219))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('immunity', 'CPA', (221, 229))	('bacteria', 'Var', (74, 82))	('affect', 'Reg', (89, 95))	('incidence', 'CPA', (100, 109))	('development', 'CPA', (114, 125))	('metabolism', 'CPA', (247, 257))
551323	31935820	Moreover, we are the first researchers to demonstrate that celecoxib can affect proline metabolism, causing an increase in pro-apoptotic factors (PRODH/POX, PPARgamma), reducing the expression of HIF-1alpha and activating apoptosis.	('increase', 'PosReg', (111, 119))	('apoptosis', 'CPA', (222, 231))	('celecoxib', 'Chemical', 'MESH:D000068579', (59, 68))	('PPARgamma', 'Gene', '5468', (157, 166))	('reducing', 'NegReg', (169, 177))	('pro-apoptotic', 'MPA', (123, 136))	('HIF-1alpha', 'Gene', (196, 206))	('proline metabolism', 'MPA', (80, 98))	('POX', 'Gene', (152, 155))	('PRODH', 'Gene', (146, 151))	('expression', 'MPA', (182, 192))	('PPARgamma', 'Gene', (157, 166))	('PRODH', 'Gene', '5625', (146, 151))	('celecoxib', 'Var', (59, 68))	('activating', 'PosReg', (211, 221))	('affect', 'Reg', (73, 79))	('HIF-1alpha', 'Gene', '3091', (196, 206))	('proline', 'Chemical', 'MESH:D011392', (80, 87))	('POX', 'Gene', '5625', (152, 155))
551337	31935820	Studies have also demonstrated a relationship between proline oxidase and cyclooxygenase II activity (COX-2), where the high expression of PRODH/POX inhibited COX-2 expression.	('proline oxidase', 'Gene', (54, 69))	('PRODH', 'Gene', (139, 144))	('COX-2', 'Gene', (159, 164))	('COX-2', 'Gene', '5743', (159, 164))	('expression', 'MPA', (165, 175))	('POX', 'Gene', (145, 148))	('high expression', 'Var', (120, 135))	('oxygen', 'Chemical', 'MESH:D010100', (79, 85))	('POX', 'Gene', '5625', (145, 148))	('cyclooxygenase II', 'Enzyme', (74, 91))	('proline oxidase', 'Gene', '5625', (54, 69))	('PRODH', 'Gene', '5625', (139, 144))	('COX-2', 'Gene', (102, 107))	('COX-2', 'Gene', '5743', (102, 107))	('activity', 'MPA', (92, 100))	('inhibited', 'NegReg', (149, 158))
551412	31935820	Having considered the effects described above, we assumed that celecoxib as a PRODH/POX activator can promote apoptosis through this pathway (both intrinsic and extrinsic).	('apoptosis', 'CPA', (110, 119))	('PRODH', 'Gene', (78, 83))	('celecoxib', 'Chemical', 'MESH:D000068579', (63, 72))	('promote', 'PosReg', (102, 109))	('celecoxib', 'Var', (63, 72))	('POX', 'Gene', (84, 87))	('PRODH', 'Gene', '5625', (78, 83))	('POX', 'Gene', '5625', (84, 87))
551428	31935820	To the best of our knowledge, this is the first study demonstrating apoptosis activation by celecoxib via the PRODH/POX pathway in cancer cells.	('PRODH', 'Gene', (110, 115))	('cancer', 'Disease', (131, 137))	('celecoxib', 'Var', (92, 101))	('POX', 'Gene', (116, 119))	('POX', 'Gene', '5625', (116, 119))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('apoptosis', 'CPA', (68, 77))	('PRODH', 'Gene', '5625', (110, 115))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('celecoxib', 'Chemical', 'MESH:D000068579', (92, 101))
551458	31935820	We are the first researchers to demonstrate that celecoxib affects proline metabolism, causes the induction of apoptosis through increased expression of pro-apoptotic factors (PRODH/POX and PPARgamma) and reduction of HIF-1alpha, which indicates the potential of this drug to inhibit tumour growth, tumour invasion and angiogenesis.	('tumour', 'Disease', 'MESH:D009369', (284, 290))	('HIF-1alpha', 'Gene', '3091', (218, 228))	('POX', 'Gene', '5625', (182, 185))	('PPARgamma', 'Gene', '5468', (190, 199))	('reduction', 'NegReg', (205, 214))	('tumour', 'Phenotype', 'HP:0002664', (299, 305))	('tumour', 'Disease', (284, 290))	('tumour', 'Disease', 'MESH:D009369', (299, 305))	('tumour invasion', 'Disease', 'MESH:D009361', (299, 314))	('proline', 'Chemical', 'MESH:D011392', (67, 74))	('celecoxib', 'Var', (49, 58))	('tumour', 'Disease', (299, 305))	('apoptosis', 'CPA', (111, 120))	('inhibit', 'NegReg', (276, 283))	('increased', 'PosReg', (129, 138))	('HIF-1alpha', 'Gene', (218, 228))	('affects', 'Reg', (59, 66))	('angiogenesis', 'CPA', (319, 331))	('PPARgamma', 'Gene', (190, 199))	('POX', 'Gene', (182, 185))	('celecoxib', 'Chemical', 'MESH:D000068579', (49, 58))	('PRODH', 'Gene', (176, 181))	('PRODH', 'Gene', '5625', (176, 181))	('proline metabolism', 'MPA', (67, 85))	('expression', 'MPA', (139, 149))	('tumour invasion', 'Disease', (299, 314))	('tumour', 'Phenotype', 'HP:0002664', (284, 290))
551514	31396482	The combined risk ratio of these studies was 1.42 (95%CI = 1.25-1.62), representing a statistically significant correlation between high total TAM number and high T stage (p < 0.00001).	('high', 'Var', (132, 136))	('TAM', 'Gene', (143, 146))	('high', 'Disease', (158, 162))	('TAM', 'Gene', '8205', (143, 146))
551515	31396482	The average rate of advanced T stage was 52.6% in those samples with high CD68 density, and 37.6% in samples with low CD68 density.	('advanced T stage', 'CPA', (20, 36))	('CD68', 'Gene', (118, 122))	('CD68', 'Gene', (74, 78))	('CD68', 'Gene', '968', (74, 78))	('CD68', 'Gene', '968', (118, 122))	('high', 'Var', (69, 73))
551522	31396482	Cumulatively, high density of CD68+ TAMs was correlated with a risk ratio of 1.42 (95%CI = 1.23-1.65, p < 0.00001).	('high density', 'Var', (14, 26))	('CD68', 'Gene', (30, 34))	('CD68', 'Gene', '968', (30, 34))	('TAMs', 'Chemical', '-', (36, 40))
551525	31396482	The average rate of nodal positivity was 55% in samples with high CD163 density, and 34% in samples with low CD163 density.	('CD163', 'Gene', '9332', (109, 114))	('CD163', 'Gene', (109, 114))	('high', 'Var', (61, 65))	('CD163', 'Gene', '9332', (66, 71))	('nodal', 'Gene', (20, 25))	('CD163', 'Gene', (66, 71))	('nodal', 'Gene', '4838', (20, 25))
551528	31396482	The average rate of vascular invasion was 39.1% in samples with high CD68 density, and 18.9% in samples with low CD68 density.	('CD68', 'Gene', (69, 73))	('high', 'Var', (64, 68))	('CD68', 'Gene', '968', (69, 73))	('CD68', 'Gene', (113, 117))	('CD68', 'Gene', '968', (113, 117))	('vascular invasion', 'CPA', (20, 37))
551530	31396482	The average rate of vascular invasion was 51.9% in samples with high CD163 density, and 21.7% in samples with low CD163 density.	('high', 'Var', (64, 68))	('vascular invasion', 'CPA', (20, 37))	('CD163', 'Gene', '9332', (69, 74))	('CD163', 'Gene', '9332', (114, 119))	('CD163', 'Gene', (69, 74))	('CD163', 'Gene', (114, 119))
551533	31396482	The average rate of lymphatic invasion was 57.5% in those samples with high CD68 density, and 38.1% in samples with low CD68 density.	('high', 'Var', (71, 75))	('CD68', 'Gene', (76, 80))	('CD68', 'Gene', '968', (76, 80))	('CD68', 'Gene', (120, 124))	('lymphatic invasion', 'CPA', (20, 38))	('CD68', 'Gene', '968', (120, 124))
551535	31396482	The average rate of lymphatic invasion was 60.0% in samples with high CD163 density, and 36.1% in samples with low CD163 density.	('CD163', 'Gene', '9332', (70, 75))	('CD163', 'Gene', '9332', (115, 120))	('high', 'Var', (65, 69))	('CD163', 'Gene', (70, 75))	('lymphatic invasion', 'CPA', (20, 38))	('CD163', 'Gene', (115, 120))
551538	31396482	The average rate of poor differentiation was 50.6% in samples with high CD68 density, and 35.9% in samples with low CD68 density.	('high', 'Var', (67, 71))	('CD68', 'Gene', (72, 76))	('CD68', 'Gene', '968', (72, 76))	('CD68', 'Gene', '968', (116, 120))	('CD68', 'Gene', (116, 120))	('poor differentiation', 'CPA', (20, 40))
551540	31396482	The average rate of poor differentiation was 55.2% in those samples with high CD163 density, and 45.1% in samples with low CD163 density.	('CD163', 'Gene', (78, 83))	('CD163', 'Gene', '9332', (123, 128))	('CD163', 'Gene', (123, 128))	('high', 'Var', (73, 77))	('CD163', 'Gene', '9332', (78, 83))	('poor differentiation', 'CPA', (20, 40))
551545	31396482	The analysis shows that an increase in total TAMs, particularly the M2-like subtype, was associated with a significant increase in risk for high T stage and nodal positivity.	('TAMs', 'Chemical', '-', (45, 49))	('high T stage', 'Disease', (140, 152))	('nodal', 'Gene', (157, 162))	('M2-like', 'Var', (68, 75))	('nodal', 'Gene', '4838', (157, 162))	('increase', 'PosReg', (27, 35))
551567	31396482	Humanized anti-CD40 antibodies have been shown to re-educate M2-like TAMs to become M1-like, and induce tumor regression and improve survival in pancreatic cancer mouse models and surgically incurable patients.	('pancreatic cancer', 'Phenotype', 'HP:0002894', (145, 162))	('survival', 'CPA', (133, 141))	('patients', 'Species', '9606', (201, 209))	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('TAMs', 'Chemical', '-', (69, 73))	('pancreatic cancer', 'Disease', (145, 162))	('CD40', 'Gene', '21939', (15, 19))	('antibodies', 'Var', (20, 30))	('tumor', 'Disease', (104, 109))	('pancreatic cancer', 'Disease', 'MESH:D010190', (145, 162))	('CD40', 'Gene', (15, 19))	('cancer', 'Phenotype', 'HP:0002664', (156, 162))	('induce', 'PosReg', (97, 103))	('mouse', 'Species', '10090', (163, 168))	('improve', 'PosReg', (125, 132))	('tumor', 'Disease', 'MESH:D009369', (104, 109))
551568	31396482	Inhibitors of the colony-stimulating factor 1 and its associated receptor (CSF1/CSF1R), which serve to generate monocyte progenitors and differentiate TAMs, have demonstrated benefit in skewing TAM population from protumoral to anti-tumoral predominance.	('TAM', 'Gene', (151, 154))	('CSF1', 'Gene', (80, 84))	('TAM', 'Gene', '8205', (194, 197))	('colony-stimulating factor 1 and its associated receptor', 'Gene', '1435', (18, 73))	('tumor', 'Phenotype', 'HP:0002664', (217, 222))	('TAMs', 'Chemical', '-', (151, 155))	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('CSF1', 'Gene', '1435', (75, 79))	('tumoral', 'Disease', (233, 240))	('Inhibitors', 'Var', (0, 10))	('tumoral', 'Disease', (217, 224))	('CSF1', 'Gene', (75, 79))	('tumoral', 'Disease', 'MESH:D009369', (233, 240))	('tumoral', 'Disease', 'MESH:D009369', (217, 224))	('TAM', 'Gene', '8205', (151, 154))	('TAM', 'Gene', (194, 197))	('skewing', 'CPA', (186, 193))	('CSF1', 'Gene', '1435', (80, 84))
551569	31396482	Blockade of CSF1R in pancreatic ductal adenocarcinoma mouse models was shown to increase the activity of anti-tumor T cells, as well as improve response to PD-L1 checkpoint immunotherapy.	('improve', 'PosReg', (136, 143))	('activity', 'MPA', (93, 101))	('increase', 'PosReg', (80, 88))	('PD-L1', 'Gene', (156, 161))	('CSF1R', 'Gene', (12, 17))	('Blockade', 'Var', (0, 8))	('tumor', 'Disease', (110, 115))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('response', 'MPA', (144, 152))	('PD-L1', 'Gene', '60533', (156, 161))	('pancreatic ductal adenocarcinoma', 'Disease', (21, 53))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (21, 53))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (21, 53))	('carcinoma', 'Phenotype', 'HP:0030731', (44, 53))	('mouse', 'Species', '10090', (54, 59))	('tumor', 'Disease', 'MESH:D009369', (110, 115))
551604	29720147	Up-regulated expression of CRBP-1 is associated with poor prognosis in TSCC, so it might potentially serve as an additional prognostic marker, and the inhibition of CRBP-1 might provide new therapeutic approaches for TSCC.	('TSCC', 'Phenotype', 'HP:0030413', (217, 221))	('TSCC', 'Disease', (217, 221))	('CRBP-1', 'Gene', '5947', (165, 171))	('expression', 'MPA', (13, 23))	('CRBP-1', 'Gene', '5947', (27, 33))	('Up-regulated', 'PosReg', (0, 12))	('CRBP-1', 'Gene', (165, 171))	('CRBP-1', 'Gene', (27, 33))	('inhibition', 'Var', (151, 161))	('TSCC', 'Phenotype', 'HP:0030413', (71, 75))	('TSCC', 'Disease', (71, 75))
551611	29720147	The biological effects of retinol are primarily mediated by all trans-retinoic acid receptors (RARs) and 9-cis retinoic acid receptors (RXRs).	('retinol', 'Chemical', 'MESH:D014801', (26, 33))	('mediated', 'Reg', (48, 56))	('9-cis', 'Var', (105, 110))
551648	29720147	The obtained proteins were then transferred to a polyvinylidene difluoride membrane that was incubated with a CRBP-1 primary antibody (1:1000, Abcam, U.S.A.) or beta-actin (1:1000, Abcam, U.S.A.) and with 5% skim milk.	('polyvinylidene difluoride', 'Chemical', 'MESH:C024865', (49, 74))	('CRBP-1', 'Gene', '5947', (110, 116))	('1:1000', 'Var', (135, 141))	('beta-actin', 'Gene', '728378', (161, 171))	('beta-actin', 'Gene', (161, 171))	('CRBP-1', 'Gene', (110, 116))
551667	29720147	High expression of CRBP-1 was correlated with a shorter overall survival time (P = 0.008) as shown in Fig.	('High', 'Var', (0, 4))	('CRBP-1', 'Gene', (19, 25))	('overall survival time', 'CPA', (56, 77))	('shorter', 'NegReg', (48, 55))	('CRBP-1', 'Gene', '5947', (19, 25))
551681	29720147	Aberrant CRBP-1 expression has been found closely connected with different tumors and affected patient's prognosis.	('tumors', 'Disease', 'MESH:D009369', (75, 81))	('patient', 'Species', '9606', (95, 102))	('Aberrant', 'Var', (0, 8))	('CRBP-1', 'Gene', '5947', (9, 15))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('tumors', 'Disease', (75, 81))	('expression', 'MPA', (16, 26))	('CRBP-1', 'Gene', (9, 15))	('connected', 'Reg', (50, 59))
551685	29720147	Some reserchers also found that aberrant CRBP-1 expression related to the differentiation status of breast carcinoma, endometrial carcinoma and larynx carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('CRBP-1', 'Gene', '5947', (41, 47))	('expression', 'MPA', (48, 58))	('breast carcinoma', 'Disease', (100, 116))	('endometrial carcinoma and larynx carcinoma', 'Disease', 'MESH:D016889', (118, 160))	('CRBP-1', 'Gene', (41, 47))	('breast carcinoma', 'Disease', 'MESH:D001943', (100, 116))	('larynx carcinoma', 'Phenotype', 'HP:0012118', (144, 160))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('aberrant', 'Var', (32, 40))	('breast carcinoma', 'Phenotype', 'HP:0003002', (100, 116))	('endometrial carcinoma', 'Phenotype', 'HP:0012114', (118, 139))	('related', 'Reg', (59, 66))	('carcinoma', 'Phenotype', 'HP:0030731', (151, 160))
551705	29720147	To find out the answer, MTT and transwell assay were conducted in CAL-27 and SCC-25 cell lines with CRBP-1 knocked down.	('CRBP-1', 'Gene', '5947', (100, 106))	('MTT', 'Chemical', 'MESH:C070243', (24, 27))	('CRBP-1', 'Gene', (100, 106))	('knocked down', 'Var', (107, 119))	('SCC-25', 'CellLine', 'CVCL:1682', (77, 83))
551710	29720147	In addition, in vitro studies revealed that knocking down CRBP-1 inhibit the proliferation and invasion of CAL-27 and SCC-25 cell lines.	('CRBP-1', 'Gene', '5947', (58, 64))	('SCC-25', 'CellLine', 'CVCL:1682', (118, 124))	('CRBP-1', 'Gene', (58, 64))	('inhibit', 'NegReg', (65, 72))	('knocking down', 'Var', (44, 57))	('proliferation', 'CPA', (77, 90))
551714	29720147	Knockdown of CRBP-1 weaken the proliferation and invasion ability of TSCC cells.	('CRBP-1', 'Gene', '5947', (13, 19))	('Knockdown', 'Var', (0, 9))	('proliferation', 'CPA', (31, 44))	('TSCC', 'Phenotype', 'HP:0030413', (69, 73))	('CRBP-1', 'Gene', (13, 19))	('invasion ability', 'CPA', (49, 65))	('weaken', 'NegReg', (20, 26))
551720	28734226	Inhibition of pRB Pathway Differentially Modulates Apoptosis in Esophageal Cancer Cells Esophageal cancer is the sixth most common cause of cancer-related death worldwide.	('Cancer', 'Phenotype', 'HP:0002664', (75, 81))	('Apoptosis', 'CPA', (51, 60))	('Esophageal Cancer', 'Disease', (64, 81))	('Esophageal Cancer', 'Disease', 'MESH:D004938', (64, 81))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('Esophageal cancer', 'Disease', (88, 105))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('cancer', 'Disease', (99, 105))	('Inhibition', 'Var', (0, 10))	('Modulates', 'Reg', (41, 50))	('Esophageal cancer', 'Disease', 'MESH:D004938', (88, 105))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('pRB Pathway', 'Pathway', (14, 25))
551722	28734226	Alterations in the signaling pathway of the tumor suppressor gene Rb-1, which encodes a phosphoprotein (pRB) that negatively regulates the G1/S transition of the cell cycle, are present in 70% of all tumors, but its role in esophageal cancer is still unclear.	('Rb-1', 'Gene', '5925', (66, 70))	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('esophageal cancer', 'Disease', (224, 241))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('Alterations', 'Var', (0, 11))	('negatively', 'NegReg', (114, 124))	('esophageal cancer', 'Disease', 'MESH:D004938', (224, 241))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('tumor', 'Disease', (200, 205))	('tumors', 'Phenotype', 'HP:0002664', (200, 206))	('tumors', 'Disease', (200, 206))	('tumors', 'Disease', 'MESH:D009369', (200, 206))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('G1/S', 'CPA', (139, 143))	('cancer', 'Phenotype', 'HP:0002664', (235, 241))	('tumor', 'Disease', (44, 49))	('Rb-1', 'Gene', (66, 70))
551725	28734226	We investigated the status of phosphorylation of pRB along esophageal tumorigenesis stages, as well as whether hyperphosphorylation of pRB could suppress apoptosis induced by cisplatin, 5-FU, or TNF-alpha in esophageal cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('suppress', 'NegReg', (145, 153))	('esophageal tumor', 'Disease', 'MESH:D004938', (59, 75))	('apoptosis', 'CPA', (154, 163))	('esophageal cancer', 'Disease', (208, 225))	('esophageal tumor', 'Disease', (59, 75))	('5-FU', 'Chemical', 'MESH:D005472', (186, 190))	('hyperphosphorylation', 'Var', (111, 131))	('cisplatin', 'Chemical', 'MESH:D002945', (175, 184))	('esophageal tumor', 'Phenotype', 'HP:0100751', (59, 75))	('pRB', 'Gene', (135, 138))	('esophageal cancer', 'Disease', 'MESH:D004938', (208, 225))
551727	28734226	When RB-1 was knocked down or CDK inhibitors reduced the levels of phosphorylated pRB, opposite apoptotic effects were observed, depending on the combination of drugs tested: whereas TNF-alpha- and cisplatin-induced apoptosis increased, 5-FU-induced apoptosis decreased.	('levels of phosphorylated', 'MPA', (57, 81))	('decreased', 'NegReg', (260, 269))	('reduced', 'NegReg', (45, 52))	('RB-1', 'Gene', '5925', (5, 9))	('apoptosis', 'CPA', (216, 225))	('knocked down', 'Var', (14, 26))	('5-FU', 'Chemical', 'MESH:D005472', (237, 241))	('cisplatin', 'Chemical', 'MESH:D002945', (198, 207))	('RB-1', 'Gene', (5, 9))
551740	28734226	Mutations in Rb-1 occur in childhood retina tumor, in 90% of small cell lung cancers (SCLC), and in 70% of bladder cancers.	('small cell lung cancers', 'Phenotype', 'HP:0030357', (61, 84))	('cancers', 'Phenotype', 'HP:0002664', (115, 122))	('cancers', 'Disease', 'MESH:D009369', (77, 84))	('cancers', 'Disease', (115, 122))	('occur', 'Reg', (18, 23))	('bladder cancers', 'Phenotype', 'HP:0009725', (107, 122))	('Rb-1', 'Gene', '5925', (13, 17))	('tumor', 'Disease', (44, 49))	('tumor', 'Disease', 'MESH:D009369', (44, 49))	('retina tumor', 'Phenotype', 'HP:0009919', (37, 49))	('Mutations', 'Var', (0, 9))	('lung cancer', 'Phenotype', 'HP:0100526', (72, 83))	('cancers', 'Disease', 'MESH:D009369', (115, 122))	('cancers', 'Phenotype', 'HP:0002664', (77, 84))	('cancers', 'Disease', (77, 84))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('lung cancers', 'Phenotype', 'HP:0100526', (72, 84))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (61, 83))	('Rb-1', 'Gene', (13, 17))
551744	28734226	This finding suggests that, in esophageal adenocarcinoma, as in colon cancers and glioblastomas, the pRB pathway may be altered by pRB hyperphosphorylation, rather than by the loss of Rb-1.	('colon cancers', 'Phenotype', 'HP:0003003', (64, 77))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (31, 56))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (31, 56))	('altered', 'Reg', (120, 127))	('glioblastomas', 'Phenotype', 'HP:0012174', (82, 95))	('colon cancer', 'Phenotype', 'HP:0003003', (64, 76))	('glioblastoma', 'Disease', 'MESH:D005909', (82, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (47, 56))	('pRB', 'Protein', (131, 134))	('cancers', 'Phenotype', 'HP:0002664', (70, 77))	('cancers', 'Disease', (70, 77))	('esophageal adenocarcinoma', 'Disease', (31, 56))	('Rb-1', 'Gene', (184, 188))	('glioblastoma', 'Disease', (82, 94))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('glioblastoma', 'Phenotype', 'HP:0012174', (82, 94))	('Rb-1', 'Gene', '5925', (184, 188))	('cancers', 'Disease', 'MESH:D009369', (70, 77))	('pRB pathway', 'Pathway', (101, 112))	('hyperphosphorylation', 'Var', (135, 155))
551746	28734226	Additionally, Sarbia and colleagues showed that loss of pRb expression is not a common event in esophageal adenocarcinoma.	('pRb', 'Gene', (56, 59))	('loss', 'Var', (48, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('esophageal adenocarcinoma', 'Disease', 'MESH:D004938', (96, 121))	('esophageal adenocarcinoma', 'Disease', (96, 121))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (96, 121))
551751	28734226	Our results suggest that combining CDK inhibitors and currently used chemotherapeutic agents can block proliferation and increase cancer cell death and is a promising strategy to treat esophagus cancer.	('inhibitors', 'Var', (39, 49))	('esophagus cancer', 'Disease', 'MESH:D004938', (185, 201))	('proliferation', 'CPA', (103, 116))	('increase cancer cell death', 'Disease', (121, 147))	('block', 'NegReg', (97, 102))	('CDK', 'Protein', (35, 38))	('increase cancer cell death', 'Disease', 'MESH:D003643', (121, 147))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('esophagus cancer', 'Disease', (185, 201))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))
551763	28734226	Cells were kept under 5% CO2 at 37  C. The cell lines were genetically tested by STR-PCR (the investigated loci were D2S1338, D19S433, CSF1PO, TPOX, TH01, vWA, d16S539, d7s820, d13s317, D5S818, FGA, D3S1358, D18S51, D8S1179, D21S11, and amelogenia) to confirm origin and rule out cross-contamination.	('D5S818', 'Var', (186, 192))	('D8S1179', 'Var', (216, 223))	('D2S1338', 'Var', (117, 124))	('FGA', 'Gene', (194, 197))	('D18S51', 'Var', (208, 214))	('d13s317', 'Var', (177, 184))	('d7s820', 'Var', (169, 175))	('CO2', 'Chemical', '-', (25, 28))	('D19S433', 'Var', (126, 133))	('D21S11', 'Var', (225, 231))	('D3S1358', 'Var', (199, 206))	('d16S539', 'Var', (160, 167))	('FGA', 'Gene', '2243', (194, 197))
551785	28734226	In the TE-13 squamous cell carcinoma cell line, pRB inhibition, either through silencing, Ros, or Flavo treatment, also increased TNF/CHX-induced cell death (P < .001 for pRB silencing or Ros pretreatment and P < .001 for Flavo pretreatment; Figure 2D).	('Ros', 'Chemical', 'MESH:D000077546', (90, 93))	('squamous cell carcinoma', 'Disease', (13, 36))	('Flavo', 'Chemical', 'MESH:C077990', (222, 227))	('TNF', 'Gene', '7124', (130, 133))	('Flavo', 'Chemical', 'MESH:C077990', (98, 103))	('pRB', 'Gene', (171, 174))	('carcinoma', 'Phenotype', 'HP:0030731', (27, 36))	('Ros', 'Chemical', 'MESH:D000077546', (188, 191))	('pRB', 'Gene', (48, 51))	('CHX', 'Chemical', 'MESH:D003513', (134, 137))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (13, 36))	('silencing', 'Var', (175, 184))	('increased', 'PosReg', (120, 129))	('TNF', 'Gene', (130, 133))	('silencing', 'Var', (79, 88))	('inhibition', 'NegReg', (52, 62))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (13, 36))
551787	28734226	Because protein synthesis inhibitors are too toxic for use in cancer therapy, we also tested whether CDK inhibitors or pRB silencing could enhance TNF-alpha-induced cell death without cycloheximide.	('pRB', 'Gene', (119, 122))	('inhibitors', 'Var', (105, 115))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('cycloheximide', 'Chemical', 'MESH:D003513', (184, 197))	('cell death', 'CPA', (165, 175))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('tested', 'Reg', (86, 92))	('silencing', 'Var', (123, 132))	('CDK', 'Protein', (101, 104))	('enhance', 'PosReg', (139, 146))
551788	28734226	CDK inhibitors did increase the TNF-alpha-induced activated caspase 3/7 levels, but the effectiveness of each inhibitor depended on the cell line.	('caspase 3', 'Gene', '836', (60, 69))	('increase', 'PosReg', (19, 27))	('CDK', 'Gene', (0, 3))	('inhibitors', 'Var', (4, 14))	('caspase 3', 'Gene', (60, 69))
551791	28734226	In TE-13 cells, Flavo, Ros, or pRB knockdown induced a small but significant increase in the percentage of caspase-positive cells after TNF-alpha treatment.	('knockdown', 'Var', (35, 44))	('Flavo', 'Chemical', 'MESH:C077990', (16, 21))	('pRB', 'Gene', (31, 34))	('Ros', 'Chemical', 'MESH:D000077546', (23, 26))	('increase', 'PosReg', (77, 85))
551792	28734226	The highest increase to 15% of caspase-positive cells (a two-fold increase of the TNF-alpha -induced cell death) was obtained with Flavo + TNF-alpha.	('Flavo + TNF-alpha', 'Var', (131, 148))	('increase', 'PosReg', (12, 20))	('caspase-positive cells', 'CPA', (31, 53))	('Flavo', 'Chemical', 'MESH:C077990', (131, 136))
551795	28734226	In OE-21 cells (Figure 3B), the percentage of 5-FU-induced caspase-positive cells dropped from 19% to 10% after Ros pretreatment (P < .001), to 8% after pRB silencing (P < .001), whereas Flavo treatment had no effect on 5-FU-induced cell death.	('dropped', 'NegReg', (82, 89))	('5-FU', 'Chemical', 'MESH:D005472', (220, 224))	('Flavo', 'Chemical', 'MESH:C077990', (187, 192))	('Ros', 'Chemical', 'MESH:D000077546', (112, 115))	('OE', 'Chemical', 'MESH:C108709', (3, 5))	('silencing', 'Var', (157, 166))	('Ros', 'Gene', (112, 115))	('5-FU', 'Chemical', 'MESH:D005472', (46, 50))	('pRB', 'Gene', (153, 156))
551796	28734226	In TE-13 cells, 5-FU-induced cell death declined from 22% to 13% after pRB silencing (P < .001), and to 14% after Ros pretreatment (P < .001), with Flavo having no significant effect.	('5-FU', 'Chemical', 'MESH:D005472', (16, 20))	('cell death', 'CPA', (29, 39))	('declined', 'NegReg', (40, 48))	('silencing', 'Var', (75, 84))	('Flavo', 'Chemical', 'MESH:C077990', (148, 153))	('pRB', 'Gene', (71, 74))	('Ros', 'Chemical', 'MESH:D000077546', (114, 117))
551799	28734226	In OE-21 and TE-13 cells, all forms of pRB inhibition (pRB silencing, Ros or Flavo treatment) resulted in increased CIS-induced caspase activity (Figure 4B and C).	('Ros', 'Chemical', 'MESH:D000077546', (70, 73))	('Flavo', 'Chemical', 'MESH:C077990', (77, 82))	('CIS-induced', 'MPA', (116, 127))	('inhibition', 'NegReg', (43, 53))	('OE', 'Chemical', 'MESH:C108709', (3, 5))	('increased', 'PosReg', (106, 115))	('silencing', 'Var', (59, 68))	('pRB', 'Gene', (39, 42))
551800	28734226	Table 1 summarizes the effect of different combinations of pRB inactivation methods and chemotherapeutic agents on human esophageal cancer cell death.	('esophageal cancer', 'Disease', (121, 138))	('inactivation', 'Var', (63, 75))	('pRB', 'Gene', (59, 62))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('human', 'Species', '9606', (115, 120))	('esophageal cancer', 'Disease', 'MESH:D004938', (121, 138))
551809	28734226	We also showed that, in general, down-regulation of pRB phosphorylation by CDK inhibitors, or silencing of pRB with siRNA, sensitizes both adenocarcinoma and squamous cell carcinoma esophageal cell lines to the chemotherapeutic agent cisplatin and to the cytokine TNF-alpha.	('cisplatin', 'Chemical', 'MESH:D002945', (234, 243))	('adenocarcinoma and squamous cell carcinoma esophageal', 'Disease', 'MESH:D000077277', (139, 192))	('silencing', 'Var', (94, 103))	('down-regulation', 'NegReg', (33, 48))	('pRB', 'Protein', (52, 55))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (158, 181))	('pRB', 'Gene', (107, 110))	('sensitizes', 'Reg', (123, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('phosphorylation', 'MPA', (56, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (172, 181))
551810	28734226	However, inhibition of pRB phosphorylation increased the resistance of esophageal cancer cell lines to 5-FU, an anticancer drug used worldwide, regardless of whether the cell death was detected by caspase 3/7 activity (Figure 2, Figure 3, Figure 4) or pyknotic nuclei (data not shown).	('esophageal cancer', 'Disease', 'MESH:D004938', (71, 88))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('cancer', 'Disease', (116, 122))	('resistance', 'MPA', (57, 67))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('5-FU', 'Chemical', 'MESH:D005472', (103, 107))	('caspase 3', 'Gene', (197, 206))	('caspase 3', 'Gene', '836', (197, 206))	('increased', 'PosReg', (43, 52))	('esophageal cancer', 'Disease', (71, 88))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('pRB', 'Protein', (23, 26))	('inhibition', 'Var', (9, 19))
551815	28734226	Thus, it may be the case that, in the esophageal cell lines analyzed in our study, autophagy works as a death mechanism induced by 5-FU, which would explain the increased cell resistance observed when pRB function was modulated.	('5-FU', 'Chemical', 'MESH:D005472', (131, 135))	('autophagy', 'CPA', (83, 92))	('5-FU', 'Var', (131, 135))
551817	28734226	Accordingly, the phosphorylation resistant form of RB1 causes contrasting effects in response to different apoptotic stimuli.	('phosphorylation', 'Var', (17, 32))	('RB1', 'Gene', (51, 54))	('response to different apoptotic stimuli', 'MPA', (85, 124))	('RB1', 'Gene', '5925', (51, 54))
551822	28734226	These results suggest that pRB phosphorylation protects some esophageal cancer cells against TNF-alpha-induced cell death and, more importantly, that this combination may have the potential to increase the survival of esophageal cancer patients.	('esophageal cancer', 'Disease', (61, 78))	('pRB', 'Protein', (27, 30))	('esophageal cancer', 'Disease', 'MESH:D004938', (61, 78))	('increase', 'PosReg', (193, 201))	('survival', 'CPA', (206, 214))	('patients', 'Species', '9606', (236, 244))	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('esophageal cancer', 'Disease', (218, 235))	('phosphorylation', 'Var', (31, 46))	('esophageal cancer', 'Disease', 'MESH:D004938', (218, 235))
551832	28734226	Our findings indicate that modulation of the pRB pathway and/or the use of CDK inhibitors should be considered for optimal and, possibly, tailored treatment of esophageal cancer.	('modulation', 'Var', (27, 37))	('pRB pathway', 'Pathway', (45, 56))	('esophageal cancer', 'Disease', (160, 177))	('esophageal cancer', 'Disease', 'MESH:D004938', (160, 177))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))
551840	27941992	The overall survival and disease-free survival of patients with high levels of KIF20A expression were significantly poorer than those with low KIF20A expression.	('KIF20A', 'Gene', (79, 85))	('overall survival', 'CPA', (4, 20))	('patients', 'Species', '9606', (50, 58))	('disease-free survival', 'CPA', (25, 46))	('poorer', 'NegReg', (116, 122))	('high levels', 'Var', (64, 75))
551842	27941992	KIF20A aberrant expression is a novel independent unfavorable prognostic factor and may present a potential therapeutic target for cervical cancer.	('aberrant expression', 'Var', (7, 26))	('cervical cancer', 'Disease', 'MESH:D002583', (131, 146))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('cervical cancer', 'Disease', (131, 146))	('KIF20A', 'Gene', (0, 6))
551924	27941992	Kaplan-Meier analysis demonstrated that KIF20A-positive patients exhibited significantly reduced OS (log-rank, P < 0.001) and DFS (log-rank, P = 0.007) times than KIF20A-negative patients (Fig 3B and 3C).	('patients', 'Species', '9606', (56, 64))	('KIF20A-positive', 'Var', (40, 55))	('DFS', 'MPA', (126, 129))	('patients', 'Species', '9606', (179, 187))	('reduced', 'NegReg', (89, 96))
551935	27941992	As the proliferation and migration of pancreatic ductal adenocarcinoma cells were significantly reduced by silencing KIF20A, KIF20A has been suggested as a novel anti-cancer drug target.	('KIF20A', 'Gene', (117, 123))	('silencing', 'Var', (107, 116))	('migration', 'CPA', (25, 34))	('cancer', 'Disease', 'MESH:D009369', (167, 173))	('proliferation', 'CPA', (7, 20))	('cancer', 'Disease', (167, 173))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (38, 70))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))	('pancreatic ductal adenocarcinoma', 'Disease', (38, 70))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (38, 70))	('reduced', 'NegReg', (96, 103))
551937	27941992	Moreover, KIF20A peptides were shown to cause expansion of HLA-A2-restricted cytotoxic T cells in HLA-A2 transgenic mice without causing autoimmunity, and those T cells successfully exhibited cytotoxic responses to cancer cells expressing KIF20A.	('expansion', 'PosReg', (46, 55))	('KIF20A', 'Gene', (10, 16))	('cancer', 'Disease', (215, 221))	('cancer', 'Disease', 'MESH:D009369', (215, 221))	('autoimmunity', 'Phenotype', 'HP:0002960', (137, 149))	('peptides', 'Var', (17, 25))	('cytotoxic responses', 'CPA', (192, 211))	('transgenic mice', 'Species', '10090', (105, 120))	('autoimmunity', 'Disease', (137, 149))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('autoimmunity', 'Disease', 'MESH:D001327', (137, 149))	('exhibited', 'Reg', (182, 191))
551943	27941992	Furthermore, knockdown of KIF20A strongly impeded proliferation and induced apoptosis of both tamoxifen-sensitive and tamoxifen-resistant breast cancer cells.	('tamoxifen', 'Chemical', 'MESH:D013629', (118, 127))	('induced', 'Reg', (68, 75))	('proliferation', 'CPA', (50, 63))	('KIF20A', 'Gene', (26, 32))	('breast cancer', 'Disease', 'MESH:D001943', (138, 151))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('breast cancer', 'Phenotype', 'HP:0003002', (138, 151))	('breast cancer', 'Disease', (138, 151))	('tamoxifen', 'Chemical', 'MESH:D013629', (94, 103))	('impeded', 'NegReg', (42, 49))	('apoptosis', 'CPA', (76, 85))	('knockdown', 'Var', (13, 22))
551944	27941992	Another study showed that KIF20A/Mklp2 inhibition interferes with in vitro angiogenesis in the absence of mitosis.	('inhibition', 'Var', (39, 49))	('absence of mitosis', 'Disease', 'MESH:D004832', (95, 113))	('Mklp2', 'Gene', (33, 38))	('absence of mitosis', 'Disease', (95, 113))	('interferes', 'NegReg', (50, 60))	('Mklp2', 'Gene', '10112', (33, 38))
551945	27941992	Dysregulation of Mad2 (mitotic arrest deficient 2) was also shown to cause cytokinesis failure by misregulating KIF20A and the chromosome passenger complex, and so contributes to chromosome instability and tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('chromosome instability', 'CPA', (179, 201))	('Mad2', 'Gene', '4085', (17, 21))	('Dysregulation', 'Var', (0, 13))	('misregulating', 'Var', (98, 111))	('tumor', 'Disease', (206, 211))	('Mad2', 'Gene', (17, 21))	('KIF20A', 'Gene', (112, 118))	('chromosome instability', 'Phenotype', 'HP:0040012', (179, 201))	('mitotic arrest deficient 2', 'Gene', (23, 49))	('mitotic arrest deficient 2', 'Gene', '4085', (23, 49))	('cytokinesis failure', 'MPA', (75, 94))	('contributes to', 'Reg', (164, 178))	('tumor', 'Disease', 'MESH:D009369', (206, 211))
551946	27941992	Finally, inhibition of KIF20A specifically induced potent p53-independent apoptosis at non-DNA damaging concentrations in Ewing sarcoma cell lines.	('Ewing sarcoma', 'Disease', (122, 135))	('sarcoma', 'Phenotype', 'HP:0100242', (128, 135))	('Ewing sarcoma', 'Disease', 'MESH:C563168', (122, 135))	('Ewing sarcoma', 'Phenotype', 'HP:0012254', (122, 135))	('KIF20A', 'Gene', (23, 29))	('p53', 'Gene', (58, 61))	('inhibition', 'Var', (9, 19))	('p53', 'Gene', '7157', (58, 61))
551947	27941992	Therefore, KIF20A has a diverse range of functions that may together contribute to the increased tumorigenesis observed in patients with cervical SCC with high KIF20A expression.	('increased', 'PosReg', (87, 96))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('SCC', 'Gene', (146, 149))	('patients', 'Species', '9606', (123, 131))	('KIF20A', 'Gene', (160, 166))	('tumor', 'Disease', (97, 102))	('SCC', 'Phenotype', 'HP:0002860', (146, 149))	('SCC', 'Gene', '6317', (146, 149))	('high', 'Var', (155, 159))	('expression', 'MPA', (167, 177))
551954	27941992	Previous studies have elucidated that aberrant serum SCC-Ag can precede the clinical diagnosis of relapse in 46-92% of cases.	('SCC', 'Gene', '6317', (53, 56))	('aberrant', 'Var', (38, 46))	('SCC', 'Gene', (53, 56))	('relapse', 'Disease', (98, 105))	('SCC', 'Phenotype', 'HP:0002860', (53, 56))
551963	27941992	Our findings proved that KIF20A was an independent prognostic factor associated with poorer survival outcomes in cervical SCC patients.	('poorer', 'NegReg', (85, 91))	('SCC', 'Gene', (122, 125))	('SCC', 'Phenotype', 'HP:0002860', (122, 125))	('SCC', 'Gene', '6317', (122, 125))	('KIF20A', 'Var', (25, 31))	('patients', 'Species', '9606', (126, 134))
551968	27941992	These E6/E7 oncoproteins have been shown to upregulate A3B (a major mutagenic protein) expression in HPV-induced tumorigenesis.	('tumor', 'Disease', (113, 118))	('E6/E7', 'Var', (6, 11))	('upregulate', 'PosReg', (44, 54))	('expression', 'MPA', (87, 97))	('A3B', 'Gene', (55, 58))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('HPV', 'Species', '10566', (101, 104))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))
551970	27941992	In this study, aberrant KIF20A protein expression was observed in HPV-positive cervical cancer samples (31.9%), whereas HPV-negative specimens expressed low levels of KIF20A (16.6%).	('HPV', 'Species', '10566', (66, 69))	('protein', 'Protein', (31, 38))	('observed', 'Reg', (54, 62))	('HPV-positive cervical cancer', 'Disease', 'MESH:D030361', (66, 94))	('HPV-positive cervical cancer', 'Disease', (66, 94))	('aberrant', 'Var', (15, 23))	('KIF20A', 'Gene', (24, 30))	('expression', 'MPA', (39, 49))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('HPV', 'Species', '10566', (120, 123))
551972	27941992	Our results suggest that KIF20A might make the cervix more prone to HPV infection, which provides insight into the HPV-induced carcinogenesis process.	('carcinogenesis', 'Disease', 'MESH:D063646', (127, 141))	('HPV infection', 'Disease', (68, 81))	('prone', 'PosReg', (59, 64))	('carcinogenesis', 'Disease', (127, 141))	('KIF20A', 'Var', (25, 31))	('HPV', 'Species', '10566', (115, 118))	('HPV', 'Species', '10566', (68, 71))	('HPV infection', 'Disease', 'MESH:D030361', (68, 81))
551974	27941992	PLNM has also been shown to be an independent prognostic parameter in cervical cancer.	('PLNM', 'Var', (0, 4))	('cervical cancer', 'Disease', (70, 85))	('cervical cancer', 'Disease', 'MESH:D002583', (70, 85))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))
551990	32403254	Moreover, proteins containing linear ubiquitin-specific binding domains, such as NF-kappaB-essential modulator (NEMO), optineurin, A20-binding inhibitors of NF-kappaB (ABINs), and A20, modulate the functions of LUBAC, and the dysregulation of the LUBAC-mediated linear ubiquitination pathway induces cancer and inflammatory, autoimmune, and neurodegenerative diseases.	('NF-kappaB-essential modulator', 'Gene', (81, 110))	('neurodegenerative diseases', 'Phenotype', 'HP:0002180', (341, 367))	('dysregulation', 'Var', (226, 239))	('induces', 'Reg', (292, 299))	('NEMO', 'Gene', '8517', (112, 116))	('autoimmune', 'CPA', (325, 335))	('LUBAC', 'Chemical', '-', (247, 252))	('optineurin', 'Gene', (119, 129))	('neurodegenerative diseases', 'Disease', 'MESH:D019636', (341, 367))	('A20', 'Gene', (180, 183))	('ABINs', 'Chemical', '-', (168, 173))	('ubiquitin', 'Gene', (269, 278))	('optineurin', 'Gene', '10133', (119, 129))	('ubiquitin', 'Gene', (37, 46))	('modulate', 'Reg', (185, 193))	('cancer', 'Disease', (300, 306))	('NEMO', 'Gene', (112, 116))	('A20', 'Gene', (131, 134))	('neurodegenerative diseases', 'Disease', (341, 367))	('cancer', 'Phenotype', 'HP:0002664', (300, 306))	('functions', 'MPA', (198, 207))	('A20', 'Gene', '7128', (180, 183))	('LUBAC', 'Chemical', '-', (211, 216))	('ubiquitin', 'Gene', '38456', (269, 278))	('NF-kappaB-essential modulator', 'Gene', '8517', (81, 110))	('ubiquitin', 'Gene', '38456', (37, 46))	('cancer', 'Disease', 'MESH:D009369', (300, 306))	('A20', 'Gene', '7128', (131, 134))	('inflammatory', 'CPA', (311, 323))
552002	32403254	The conjugation of monoubiquitin and multiple-monoubiquitins to substrates is principally involved in membrane trafficking and endocytosis.	('monoubiquitin', 'Chemical', '-', (19, 32))	('membrane trafficking', 'MPA', (102, 122))	('monoubiquitin', 'Protein', (19, 32))	('conjugation', 'MPA', (4, 15))	('endocytosis', 'MPA', (127, 138))	('involved', 'Reg', (90, 98))	('monoubiquitin', 'Chemical', '-', (46, 59))	('multiple-monoubiquitins', 'Var', (37, 60))
552003	32403254	The isopeptide bond-linked ubiquitination is mediated via seven internal Lys residues (K6, K11, K27, K29, K33, K48, and K63).	('ubiquitin', 'Gene', (27, 36))	('K33', 'Var', (106, 109))	('Lys', 'Chemical', 'MESH:D008239', (73, 76))	('ubiquitin', 'Gene', '38456', (27, 36))	('K11', 'Var', (91, 94))	('K6', 'Var', (87, 89))	('K63', 'Var', (120, 123))	('mediated', 'Reg', (45, 53))	('K27', 'Gene', '342574', (96, 99))	('K48', 'Var', (111, 114))	('K27', 'Gene', (96, 99))	('K29', 'Var', (101, 104))	('K63', 'Chemical', '-', (120, 123))
552004	32403254	Among them, the K48-linked polyubiquitin chain, which is the most common, serves as a typical proteasomal degradation signal, and the K63-linked polyubiquitin chain, the second most predominant linkage, is involved in non-proteasomal functions, such as signal transduction and DNA repair.	('ubiquitin', 'Gene', (31, 40))	('K48-linked', 'Var', (16, 26))	('ubiquitin', 'Gene', '38456', (31, 40))	('ubiquitin', 'Gene', (149, 158))	('ubiquitin', 'Gene', '38456', (149, 158))	('K63-linked', 'Var', (134, 144))	('proteasomal degradation signal', 'MPA', (94, 124))	('K63', 'Chemical', '-', (134, 137))
552019	32403254	During the course of linear ubiquitination, the RING1 domain in HOIP binds a ubiquitin-charged E2.	('ubiquitin', 'Gene', (28, 37))	('ubiquitin', 'Gene', '38456', (28, 37))	('HOIP', 'Gene', (64, 68))	('binds', 'Interaction', (69, 74))	('ubiquitin', 'Gene', (77, 86))	('ubiquitin', 'Gene', '38456', (77, 86))	('HOIP', 'Gene', '55072', (64, 68))	('RING1 domain', 'Var', (48, 60))
552020	32403254	Subsequently, the donor ubiquitin is transiently transferred to the active Cys885 in the RING2 domain of HOIP via a thioester-linkage.	('HOIP', 'Gene', (105, 109))	('Cys885', 'Chemical', '-', (75, 81))	('HOIP', 'Gene', '55072', (105, 109))	('ubiquitin', 'Gene', (24, 33))	('Cys885', 'Var', (75, 81))	('RING2', 'Gene', '7923', (89, 94))	('RING2', 'Gene', (89, 94))	('ubiquitin', 'Gene', '38456', (24, 33))
552022	32403254	In contrast to HOIP, the RBR domain in HOIL-1L uniquely catalyzes the oxyester-bond monoubiquitination of Ser/Thr residues through the active Cys458.	('HOIL-1L', 'Gene', (39, 46))	('HOIP', 'Gene', (15, 19))	('Ser', 'Chemical', 'MESH:D012694', (106, 109))	('HOIL-1L', 'Gene', '24105', (39, 46))	('catalyzes', 'Reg', (56, 65))	('Cys458', 'Var', (142, 148))	('Cys458', 'Chemical', '-', (142, 148))	('oxyester-bond monoubiquitination', 'MPA', (70, 102))	('Thr', 'Chemical', 'MESH:D013912', (110, 113))	('HOIP', 'Gene', '55072', (15, 19))	('Ser/Thr residues', 'MPA', (106, 122))	('monoubiquitin', 'Chemical', '-', (84, 97))
552037	32403254	Interestingly, the conjugation of two linearly linked molecules of ubiquitin (linear diubiquitin) to NEMO sufficiently induces IKK activation.	('activation', 'PosReg', (131, 141))	('ubiquitin', 'Gene', (87, 96))	('induces', 'Reg', (119, 126))	('ubiquitin', 'Gene', '38456', (87, 96))	('IKK', 'Protein', (127, 130))	('ubiquitin', 'Gene', (67, 76))	('ubiquitin', 'Gene', '38456', (67, 76))	('NEMO', 'Gene', '8517', (101, 105))	('NEMO', 'Gene', (101, 105))	('conjugation', 'Var', (19, 30))
552040	32403254	Upon TNF-alpha stimulation, mammalian Ste20-like kinase (MST1, also called STK4) is recruited to TNFR in a TRAF2-dependent manner and phosphorylates Ser1066 in the LDD domain of HOIP, which attenuates the E3 activity of LUBAC.	('Ser1066', 'Chemical', '-', (149, 156))	('TNFR', 'Gene', '7132', (97, 101))	('STK4', 'Gene', '6789', (75, 79))	('recruited', 'PosReg', (84, 93))	('Ste20-like kinase', 'Gene', (38, 55))	('TNFR', 'Gene', (97, 101))	('STK4', 'Gene', (75, 79))	('MST1', 'Gene', (57, 61))	('mammalian', 'Species', '9606', (28, 37))	('HOIP', 'Gene', '55072', (178, 182))	('Ste20-like kinase', 'Gene', '9748', (38, 55))	('E3 activity', 'MPA', (205, 216))	('LUBAC', 'Chemical', '-', (220, 225))	('attenuates', 'NegReg', (190, 200))	('TRAF2', 'Gene', (107, 112))	('Ser1066', 'Var', (149, 156))	('TRAF2', 'Gene', '7186', (107, 112))	('HOIP', 'Gene', (178, 182))	('MST1', 'Gene', '4485', (57, 61))	('phosphorylates', 'Var', (134, 148))
552044	32403254	Importantly, the K63/M1-hybrid ubiquitin chain can become conjugated to interleukin 1 receptor-associated kinase 1 (IRAK1) and IRAK4.	('ubiquitin', 'Gene', (31, 40))	('IRAK4', 'Gene', (127, 132))	('interleukin 1 receptor-associated kinase 1', 'Gene', '3654', (72, 114))	('interleukin 1 receptor-associated kinase 1', 'Gene', (72, 114))	('ubiquitin', 'Gene', '38456', (31, 40))	('K63/M1-hybrid', 'Var', (17, 30))	('IRAK4', 'Gene', '51135', (127, 132))	('IRAK1', 'Gene', '3654', (116, 121))	('IRAK1', 'Gene', (116, 121))	('K63', 'Chemical', '-', (17, 20))	('conjugated', 'Interaction', (58, 68))
552051	32403254	In the course of the TCR pathway, HOIL-1L is cleaved at Arg165-Gly166 by MALT1, a paracaspase.	('TCR', 'Pathway', (21, 24))	('Arg165-Gly166', 'Var', (56, 69))	('HOIL-1L', 'Gene', (34, 41))	('MALT1', 'Gene', (73, 78))	('MALT1', 'Gene', '10892', (73, 78))	('Gly166', 'Chemical', '-', (63, 69))	('HOIL-1L', 'Gene', '24105', (34, 41))	('Arg165', 'Chemical', '-', (56, 62))
552057	32403254	Similarly, the XIAP-mediated K63-linked ubiquitination of RIP2 recruits LUBAC to activate the NOD2-mediated NF-kappaB activation pathway, which plays an important role in the bacterial peptidoglycan-mediated innate immune response.	('activate', 'PosReg', (81, 89))	('NOD2', 'Gene', '64127', (94, 98))	('K63-linked', 'Var', (29, 39))	('RIP2', 'Gene', '8767', (58, 62))	('XIAP', 'Gene', (15, 19))	('LUBAC', 'Chemical', '-', (72, 77))	('K63', 'Chemical', '-', (29, 32))	('NOD2', 'Gene', (94, 98))	('XIAP', 'Gene', '331', (15, 19))	('ubiquitin', 'Gene', (40, 49))	('RIP2', 'Gene', (58, 62))	('ubiquitin', 'Gene', '38456', (40, 49))
552068	32403254	However, the genetic deletions of caspase 8 and Rip3k in mice (Sharpincpd/cpdm/Casp8+/-/Rip3k-/-) completely alleviated the phenotype.	('mice', 'Species', '10090', (57, 61))	('Sharpin', 'Gene', (63, 70))	('Casp8', 'Gene', (79, 84))	('Rip3', 'Gene', (88, 92))	('Rip3', 'Gene', '56532', (48, 52))	('caspase', 'Protein', (34, 41))	('deletions', 'Var', (21, 30))	('cpdm', 'Gene', '106025', (74, 78))	('Casp8', 'Gene', '12370', (79, 84))	('cpdm', 'Gene', (74, 78))	('Rip3', 'Gene', '56532', (88, 92))	('alleviated', 'NegReg', (109, 119))	('Rip3', 'Gene', (48, 52))	('Sharpin', 'Gene', '106025', (63, 70))
552069	32403254	Recently, Sharma and coworkers showed that the genetic ablation of MyD88 in Sharpin-deficient cpdm mice (Sharpincpd/cpdm/Myd88-/-) completely and partially rescued the skin lesions and systemic inflammation, respectively.	('cpdm', 'Gene', '106025', (94, 98))	('Sharpin', 'Gene', (76, 83))	('Myd88', 'Gene', (121, 126))	('Sharpin', 'Gene', (105, 112))	('cpdm', 'Gene', '106025', (116, 120))	('rescued', 'PosReg', (156, 163))	('genetic ablation', 'Var', (47, 63))	('Sharpin', 'Gene', '106025', (76, 83))	('inflammation', 'Disease', 'MESH:D007249', (194, 206))	('Sharpin', 'Gene', '106025', (105, 112))	('MyD88', 'Gene', (67, 72))	('Myd88', 'Gene', '17874', (121, 126))	('mice', 'Species', '10090', (99, 103))	('inflammation', 'Disease', (194, 206))	('cpdm', 'Gene', (94, 98))	('cpdm', 'Gene', (116, 120))	('ablation', 'Var', (55, 63))	('skin lesions', 'Disease', 'MESH:D012871', (168, 180))	('skin lesions', 'Disease', (168, 180))
552075	32403254	STAT1 is linearly ubiquitinated at the K511 and K652 residues by LUBAC, which inhibits binding to the type I IFN receptor, IFNAR2, and the linear ubiquitination of STAT1 is removed by OTULIN.	('STAT1', 'Gene', '6772', (0, 5))	('ubiquitin', 'Gene', (146, 155))	('ubiquitin', 'Gene', (18, 27))	('ubiquitin', 'Gene', '38456', (18, 27))	('STAT1', 'Gene', '6772', (164, 169))	('ubiquitin', 'Gene', '38456', (146, 155))	('type', 'Protein', (102, 106))	('binding', 'Interaction', (87, 94))	('K511', 'Var', (39, 43))	('LUBAC', 'Chemical', '-', (65, 70))	('IFNAR2', 'Gene', '3455', (123, 129))	('IFNAR2', 'Gene', (123, 129))	('inhibits', 'NegReg', (78, 86))	('K652', 'Var', (48, 52))	('STAT1', 'Gene', (164, 169))	('STAT1', 'Gene', (0, 5))
552093	32403254	Interestingly, OTULIN binds to the N-terminal PUB domain of HOIP through the PUB domain-interacting motif (PIM), and the phosphorylation of Tyr56 in the PIM of OTULIN abrogated the HOIP binding.	('HOIP', 'Gene', (60, 64))	('Tyr56', 'Chemical', '-', (140, 145))	('HOIP', 'Gene', '55072', (181, 185))	('HOIP', 'Gene', (181, 185))	('phosphorylation', 'MPA', (121, 136))	('Tyr56', 'Var', (140, 145))	('abrogated', 'NegReg', (167, 176))	('binding', 'Interaction', (186, 193))	('HOIP', 'Gene', '55072', (60, 64))
552094	32403254	In humans, genetic mutations in OTULIN cause multiple symptoms, such as recurrent fevers, autoantibodies, diarrhea, panniculitis, and arthritis, which are collectively referred to as OTULIN-related autoinflammatory syndrome (ORAS).	('panniculitis', 'Disease', (116, 128))	('OTULIN-related autoinflammatory syndrome', 'Disease', 'OMIM:617099', (183, 223))	('recurrent fevers', 'Disease', (72, 88))	('panniculitis', 'Disease', 'MESH:D015434', (116, 128))	('ORAS', 'Disease', 'OMIM:617099', (225, 229))	('recurrent fevers', 'Phenotype', 'HP:0001954', (72, 88))	('cause', 'Reg', (39, 44))	('diarrhea', 'Phenotype', 'HP:0002014', (106, 114))	('fevers', 'Phenotype', 'HP:0001945', (82, 88))	('genetic mutations', 'Var', (11, 28))	('arthritis', 'Disease', 'MESH:D001168', (134, 143))	('diarrhea', 'Disease', (106, 114))	('arthritis', 'Disease', (134, 143))	('panniculitis', 'Phenotype', 'HP:0012490', (116, 128))	('humans', 'Species', '9606', (3, 9))	('autoinflammatory syndrome', 'Phenotype', 'HP:0002960', (198, 223))	('OTULIN', 'Gene', (32, 38))	('diarrhea', 'Disease', 'MESH:D003967', (106, 114))	('ORAS', 'Disease', (225, 229))	('autoantibodies', 'Disease', (90, 104))	('OTULIN-related autoinflammatory syndrome', 'Disease', (183, 223))	('arthritis', 'Phenotype', 'HP:0001369', (134, 143))
552095	32403254	These mutations deregulate the LUBAC-mediated linear ubiquitination signal, and the OTULIN-deficiency causes cell-type-specific LUBAC degradation.	('deregulate', 'Reg', (16, 26))	('causes', 'Reg', (102, 108))	('OTULIN-deficiency', 'Disease', 'OMIM:617099', (84, 101))	('LUBAC', 'Chemical', '-', (31, 36))	('ubiquitin', 'Gene', (53, 62))	('ubiquitin', 'Gene', '38456', (53, 62))	('cell-type-specific LUBAC degradation', 'MPA', (109, 145))	('OTULIN-deficiency', 'Disease', (84, 101))	('mutations', 'Var', (6, 15))	('LUBAC', 'Chemical', '-', (128, 133))
552108	32403254	Furthermore, we revealed the structural bases of the CYLD USP domain recognition of either K63 or linear diubiquitin, and the interaction of a potential CYLD inhibitor, subquinocin.	('K63', 'Var', (91, 94))	('CYLD', 'Gene', '1540', (153, 157))	('CYLD', 'Gene', (53, 57))	('interaction', 'Interaction', (126, 137))	('ubiquitin', 'Gene', (107, 116))	('CYLD', 'Gene', '1540', (53, 57))	('ubiquitin', 'Gene', '38456', (107, 116))	('K63', 'Chemical', '-', (91, 94))	('CYLD', 'Gene', (153, 157))	('subquinocin', 'Chemical', '-', (169, 180))
552111	32403254	Recently, a familial variant of CYLD with the M719V missense mutation was identified in the induction of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), with enhanced K63-deubiquitinating activity and NF-kappaB suppression.	('ubiquitin', 'Gene', '38456', (196, 205))	('dementia', 'Phenotype', 'HP:0000726', (120, 128))	('M719V missense mutation', 'Var', (46, 69))	('frontotemporal dementia', 'Phenotype', 'HP:0002145', (105, 128))	('ALS', 'Phenotype', 'HP:0007354', (170, 173))	('CYLD', 'Gene', (32, 36))	('FTD', 'Disease', 'MESH:C563003', (130, 133))	('amyotrophic lateral sclerosis', 'Phenotype', 'HP:0007354', (139, 168))	('dementia', 'Disease', (120, 128))	('K63', 'Chemical', '-', (190, 193))	('dementia', 'Disease', 'MESH:D003704', (120, 128))	('NF-kappaB', 'Protein', (224, 233))	('ubiquitin', 'Gene', (196, 205))	('CYLD', 'Gene', '1540', (32, 36))	('FTD', 'Phenotype', 'HP:0002145', (130, 133))	('FTD', 'Disease', (130, 133))	('enhanced', 'PosReg', (181, 189))	('amyotrophic lateral sclerosis', 'Disease', 'MESH:D000690', (139, 168))	('amyotrophic lateral sclerosis', 'Disease', (139, 168))	('suppression', 'NegReg', (234, 245))	('M719V', 'Mutation', 'p.M719V', (46, 51))
552112	32403254	Moreover, this M719V variant of CYLD impairs autophagosome maturation and increases the cytosolic localization of TDP-43.	('M719V', 'Mutation', 'p.M719V', (15, 20))	('TDP-43', 'Gene', (114, 120))	('impairs', 'NegReg', (37, 44))	('TDP-43', 'Gene', '23435', (114, 120))	('increases', 'PosReg', (74, 83))	('CYLD', 'Gene', (32, 36))	('M719V', 'Var', (15, 20))	('autophagosome maturation', 'CPA', (45, 69))	('cytosolic localization', 'MPA', (88, 110))	('CYLD', 'Gene', '1540', (32, 36))
552119	32403254	Although the K63-linked and linear diubiquitins adopt similar conformations, the NEMO UBAN domain shows approximately 100-fold higher affinity to the linear ubiquitin chain than the K63-chain.	('NEMO', 'Gene', (81, 85))	('UBA', 'Chemical', '-', (86, 89))	('ubiquitin', 'Gene', '38456', (37, 46))	('NEMO', 'Gene', '8517', (81, 85))	('ubiquitin', 'Gene', (37, 46))	('K63', 'Chemical', '-', (13, 16))	('ubiquitin', 'Gene', '38456', (157, 166))	('linear', 'Protein', (150, 156))	('affinity', 'Interaction', (134, 142))	('ubiquitin', 'Gene', (157, 166))	('higher', 'PosReg', (127, 133))	('K63-linked', 'Var', (13, 23))	('K63', 'Chemical', '-', (182, 185))
552122	32403254	Missense mutations in the NEMO-UBAN domain in humans cause X-linked anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID).	('cause', 'Reg', (53, 58))	('NEMO', 'Gene', (26, 30))	('UBA', 'Chemical', '-', (31, 34))	('NEMO', 'Gene', '8517', (26, 30))	('anhidrotic ectodermal dysplasia', 'Phenotype', 'HP:0007476', (68, 99))	('humans', 'Species', '9606', (46, 52))	('ectodermal dysplasia', 'Phenotype', 'HP:0000968', (79, 99))	('X-linked anhidrotic ectodermal dysplasia', 'Disease', (59, 99))	('immunodeficiency', 'Phenotype', 'HP:0002721', (105, 121))	('X-linked anhidrotic ectodermal dysplasia', 'Disease', 'MESH:D053358', (59, 99))	('immunodeficiency', 'Disease', 'MESH:D007153', (105, 121))	('immunodeficiency', 'Disease', (105, 121))	('Missense mutations', 'Var', (0, 18))
552126	32403254	In 2010, reports demonstrated that genetic mutations in OPTN are associated with ALS, and include an E478G missense mutation in the UBAN domain of human OPTN.	('OPTN', 'Gene', '10133', (153, 157))	('OPTN', 'Gene', '10133', (56, 60))	('human', 'Species', '9606', (147, 152))	('E478G missense', 'Var', (101, 115))	('UBA', 'Chemical', '-', (132, 135))	('E478G', 'Mutation', 'rs267606929', (101, 106))	('associated', 'Reg', (65, 75))	('ALS', 'Phenotype', 'HP:0007354', (81, 84))	('OPTN', 'Gene', (56, 60))	('OPTN', 'Gene', (153, 157))	('ALS', 'Disease', (81, 84))
552127	32403254	We analyzed the effects of the POAG- and ALS-associated mutants of OPTN on the LUBAC- and TNF-alpha-mediated NF-kappaB activation in HEK293T cells, and showed that the ALS-associated OPTN mutants lost their ability to suppress NF-kappaB activation, mainly due to the dysfunction in the UBAN domain of OPTN.	('OPTN', 'Gene', '10133', (67, 71))	('OPTN', 'Gene', (301, 305))	('OPTN', 'Gene', (67, 71))	('lost', 'NegReg', (196, 200))	('activation', 'MPA', (237, 247))	('OPTN', 'Gene', '10133', (301, 305))	('HEK293T', 'CellLine', 'CVCL:0063', (133, 140))	('suppress', 'NegReg', (218, 226))	('NF-kappaB', 'Pathway', (227, 236))	('UBA', 'Chemical', '-', (286, 289))	('LUBAC', 'Chemical', '-', (79, 84))	('OPTN', 'Gene', (183, 187))	('UBA', 'Chemical', '-', (80, 83))	('OPTN', 'Gene', '10133', (183, 187))	('mutants', 'Var', (188, 195))	('ALS', 'Phenotype', 'HP:0007354', (168, 171))	('ALS', 'Phenotype', 'HP:0007354', (41, 44))
552129	32403254	Thus, linear ubiquitin binding by OPTN regulates NF-kappaB activation and apoptosis, and consequently suppresses ALS.	('regulates', 'Reg', (39, 48))	('apoptosis', 'CPA', (74, 83))	('ALS', 'MPA', (113, 116))	('NF-kappaB', 'Protein', (49, 58))	('OPTN', 'Gene', (34, 38))	('activation', 'MPA', (59, 69))	('suppresses', 'NegReg', (102, 112))	('OPTN', 'Gene', '10133', (34, 38))	('linear', 'Var', (6, 12))	('ALS', 'Phenotype', 'HP:0007354', (113, 116))	('binding', 'Interaction', (23, 30))	('ubiquitin', 'Gene', (13, 22))	('ubiquitin', 'Gene', '38456', (13, 22))
552135	32403254	Moreover, dysfunctions and polymorphisms of A20 are correlated with various disorders, such as B cell lymphoma, systemic lupus erythematosus (SLE), inflammatory bowel disease, rheumatoid arthritis, and psoriasis.	('correlated', 'Reg', (52, 62))	('inflammatory bowel disease', 'Phenotype', 'HP:0002037', (148, 174))	('inflammatory bowel disease', 'Disease', 'MESH:D015212', (148, 174))	('dysfunctions', 'Var', (10, 22))	('polymorphisms', 'Var', (27, 40))	('inflammatory bowel disease', 'Disease', (148, 174))	('systemic lupus erythematosus', 'Disease', (112, 140))	('psoriasis', 'Disease', 'MESH:D011565', (202, 211))	('psoriasis', 'Disease', (202, 211))	('B cell lymphoma', 'Disease', 'MESH:D016393', (95, 110))	('rheumatoid arthritis', 'Phenotype', 'HP:0001370', (176, 196))	('A20', 'Gene', (44, 47))	('arthritis', 'Phenotype', 'HP:0001369', (187, 196))	('systemic lupus erythematosus', 'Phenotype', 'HP:0002725', (112, 140))	('B cell lymphoma', 'Phenotype', 'HP:0012191', (95, 110))	('SLE', 'Disease', 'MESH:D008180', (142, 145))	('SLE', 'Disease', (142, 145))	('lymphoma', 'Phenotype', 'HP:0002665', (102, 110))	('rheumatoid arthritis', 'Disease', (176, 196))	('SLE', 'Phenotype', 'HP:0002725', (142, 145))	('systemic lupus erythematosus', 'Disease', 'MESH:D008180', (112, 140))	('A20', 'Gene', '7128', (44, 47))	('B cell lymphoma', 'Disease', (95, 110))	('rheumatoid arthritis', 'Disease', 'MESH:D001172', (176, 196))	('psoriasis', 'Phenotype', 'HP:0003765', (202, 211))
552136	32403254	A20 reportedly removes the K63-linked ubiquitin chain from RIP1 by the DUB activity through the OTU domain, and conjugates K48-linked ubiquitin to RIP1 by the E3 activity in the ZF4 domain, leading to the proteasomal degradation of RIP1.	('removes', 'NegReg', (15, 22))	('K63', 'Chemical', '-', (27, 30))	('A20', 'Gene', '7128', (0, 3))	('RIP1', 'Gene', (232, 236))	('K48-linked', 'Var', (123, 133))	('proteasomal degradation', 'MPA', (205, 228))	('ubiquitin', 'Gene', '38456', (38, 47))	('ubiquitin', 'Gene', '38456', (134, 143))	('ubiquitin', 'Gene', (134, 143))	('ZF4', 'Chemical', '-', (178, 181))	('RIP1', 'Gene', (147, 151))	('A20', 'Gene', (0, 3))	('RIP1', 'Gene', (59, 63))	('RIP1', 'Gene', '8737', (232, 236))	('RIP1', 'Gene', '8737', (147, 151))	('ubiquitin', 'Gene', (38, 47))	('RIP1', 'Gene', '8737', (59, 63))
552138	32403254	Indeed, although A20 hydrolyzes K48- and K63-linked ubiquitin chains, it does not cleave a linear ubiquitin chain.	('K63-linked', 'Var', (41, 51))	('K63', 'Chemical', '-', (41, 44))	('ubiquitin', 'Gene', (52, 61))	('K48-', 'Var', (32, 36))	('ubiquitin', 'Gene', '38456', (52, 61))	('A20', 'Gene', '7128', (17, 20))	('ubiquitin', 'Gene', (98, 107))	('ubiquitin', 'Gene', '38456', (98, 107))	('A20', 'Gene', (17, 20))
552140	32403254	We solved the crystal structure of human A20 ZF7 with linear ubiquitin, and found that the B cell lymphoma-inducible missense mutations within ZF7 caused the lack of linear ubiquitin-binding.	('lack', 'NegReg', (158, 162))	('B cell lymphoma', 'Disease', 'MESH:D016393', (91, 106))	('B cell lymphoma', 'Disease', (91, 106))	('B cell lymphoma', 'Phenotype', 'HP:0012191', (91, 106))	('human', 'Species', '9606', (35, 40))	('A20', 'Gene', '7128', (41, 44))	('lymphoma', 'Phenotype', 'HP:0002665', (98, 106))	('ubiquitin', 'Gene', (173, 182))	('ZF7', 'Gene', (143, 146))	('missense mutations', 'Var', (117, 135))	('ubiquitin', 'Gene', (61, 70))	('ubiquitin', 'Gene', '38456', (173, 182))	('A20', 'Gene', (41, 44))	('ubiquitin', 'Gene', '38456', (61, 70))
552142	32403254	Recent studies using knock-in mice revealed that those carrying mutations in ZF7 spontaneously developed arthritis, although mice with mutations of the OTU or ZF4 domain showed no overt inflammatory phenotype.	('mice', 'Species', '10090', (30, 34))	('developed', 'Reg', (95, 104))	('ZF4', 'Chemical', '-', (159, 162))	('ZF7', 'Gene', (77, 80))	('arthritis', 'Disease', (105, 114))	('mice', 'Species', '10090', (125, 129))	('mutations', 'Var', (64, 73))	('arthritis', 'Phenotype', 'HP:0001369', (105, 114))	('arthritis', 'Disease', 'MESH:D001168', (105, 114))
552146	32403254	The Hoip or Hoil-1l knockout mice are embryonic lethal, while the spontaneous deficiency of Sharpin reportedly induces severe dermatitis, indicating that the LUBAC activity is crucial for development and homeostasis.	('Hoil-1l', 'Gene', '24105', (12, 19))	('deficiency', 'Var', (78, 88))	('Hoip', 'Gene', (4, 8))	('Hoip', 'Gene', '268749', (4, 8))	('LUBAC', 'Chemical', '-', (158, 163))	('mice', 'Species', '10090', (29, 33))	('Hoil-1l', 'Gene', (12, 19))	('Sharpin', 'Gene', (92, 99))	('Sharpin', 'Gene', '106025', (92, 99))	('induces', 'Reg', (111, 118))	('dermatitis', 'Disease', 'MESH:D003872', (126, 136))	('dermatitis', 'Disease', (126, 136))	('dermatitis', 'Phenotype', 'HP:0011123', (126, 136))
552147	32403254	In humans, inherited HOIL-1L mutations reportedly induce polyglucosan body myopathy with or without immunodeficiency and autoinflammation (Table 1).	('polyglucosan body myopathy', 'Disease', (57, 83))	('immunodeficiency', 'Disease', 'MESH:D007153', (100, 116))	('myopathy', 'Phenotype', 'HP:0003198', (75, 83))	('inflammation', 'Disease', 'MESH:D007249', (125, 137))	('inflammation', 'Disease', (125, 137))	('immunodeficiency', 'Disease', (100, 116))	('HOIL-1L', 'Gene', (21, 28))	('mutations', 'Var', (29, 38))	('HOIL-1L', 'Gene', '24105', (21, 28))	('humans', 'Species', '9606', (3, 9))	('polyglucosan body myopathy', 'Disease', 'MESH:C564878', (57, 83))	('induce', 'Reg', (50, 56))	('immunodeficiency', 'Phenotype', 'HP:0002721', (100, 116))
552148	32403254	Moreover, the L72P missense mutation in the PUB domain of HOIP in a patient with multiorgan autoinflammation, immunodeficiency, amylopectinosis, and systemic lymphangiectasia, and another case of HOIP deficiency with early-onset immunodeficiency and autoinflammation, but not amylopectinosis and lymphangiectasia, were recently identified.	('HOIP', 'Gene', '55072', (196, 200))	('immunodeficiency', 'Phenotype', 'HP:0002721', (110, 126))	('inflammation', 'Disease', (254, 266))	('immunodeficiency', 'Phenotype', 'HP:0002721', (229, 245))	('lymphangiectasia', 'Phenotype', 'HP:0031842', (158, 174))	('systemic lymphangiectasia', 'Disease', (149, 174))	('lymphangiectasia', 'Disease', (296, 312))	('HOIP', 'Gene', (196, 200))	('HOIP deficiency', 'Disease', 'MESH:D007153', (196, 211))	('lymphangiectasia', 'Disease', 'MESH:D008201', (296, 312))	('L72P', 'Mutation', 'rs794729666', (14, 18))	('inflammation', 'Disease', 'MESH:D007249', (96, 108))	('L72P missense', 'Var', (14, 27))	('systemic lymphangiectasia', 'Disease', 'MESH:D008201', (149, 174))	('HOIP', 'Gene', '55072', (58, 62))	('immunodeficiency', 'Disease', (110, 126))	('immunodeficiency', 'Disease', (229, 245))	('lymphangiectasia', 'Disease', (158, 174))	('lymphangiectasia', 'Phenotype', 'HP:0031842', (296, 312))	('inflammation', 'Disease', 'MESH:D007249', (254, 266))	('inflammation', 'Disease', (96, 108))	('HOIP deficiency', 'Disease', (196, 211))	('immunodeficiency', 'Disease', 'MESH:D007153', (110, 126))	('patient', 'Species', '9606', (68, 75))	('lymphangiectasia', 'Disease', 'MESH:D008201', (158, 174))	('HOIP', 'Gene', (58, 62))	('immunodeficiency', 'Disease', 'MESH:D007153', (229, 245))
552149	32403254	These HOIP mutations affect the expression of type I IFN regulated genes.	('mutations', 'Var', (11, 20))	('HOIP', 'Gene', '55072', (6, 10))	('HOIP', 'Gene', (6, 10))	('expression', 'MPA', (32, 42))	('affect', 'Reg', (21, 27))	('type I IFN regulated genes', 'Gene', (46, 72))
552152	32403254	Patients with ABC-DLBCL usually have a worse prognosis than those with GCB-DLBCL, and oncogenic mutations in NF-kappaB signaling proteins, such as in the CD79B, CARMA1, MYD88, and A20 genes, are associated with ABC-DLBCL.	('associated', 'Reg', (195, 205))	('ABC-DLBCL', 'Disease', (211, 220))	('CARMA1', 'Gene', (161, 167))	('A20', 'Gene', (180, 183))	('CD79B', 'Gene', '974', (154, 159))	('CD79B', 'Gene', (154, 159))	('CARMA1', 'Gene', '84433', (161, 167))	('MYD88', 'Gene', '4615', (169, 174))	('MYD88', 'Gene', (169, 174))	('Patients', 'Species', '9606', (0, 8))	('NF-kappaB', 'Protein', (109, 118))	('A20', 'Gene', '7128', (180, 183))	('mutations', 'Var', (96, 105))
552153	32403254	Staudt's group identified single nucleotide polymorphisms (SNPs) in human HOIP that cause the Q622L and Q584H substitutions, which are significantly associated with ABC-DLBCL.	('Q584H', 'Var', (104, 109))	('HOIP', 'Gene', (74, 78))	('human', 'Species', '9606', (68, 73))	('Q622L', 'Var', (94, 99))	('Q584H', 'Mutation', 'rs184184005', (104, 109))	('Q622L', 'Mutation', 'rs149481717', (94, 99))	('ABC-DLBCL', 'Disease', (165, 174))	('HOIP', 'Gene', '55072', (74, 78))	('associated', 'Reg', (149, 159))	('cause', 'Reg', (84, 89))
552154	32403254	Unexpectedly, these replacements, located in the UBA domain of HOIP, enhance the interactions with HOIL-1L and HOIP, resulting in the increased NF-kappaB activity.	('activity', 'MPA', (154, 162))	('replacements', 'Var', (20, 32))	('HOIL-1L', 'Gene', (99, 106))	('HOIL-1L', 'Gene', '24105', (99, 106))	('HOIP', 'Gene', '55072', (63, 67))	('UBA', 'Chemical', '-', (49, 52))	('enhance', 'PosReg', (69, 76))	('HOIP', 'Gene', (63, 67))	('HOIP', 'Gene', '55072', (111, 115))	('HOIP', 'Gene', (111, 115))	('NF-kappaB', 'Protein', (144, 153))	('increased', 'PosReg', (134, 143))	('interactions', 'Interaction', (81, 93))
552156	32403254	Indeed, the silencing of HOIP also reportedly reduces the viability of ABC-DLBCL cells.	('HOIP', 'Gene', '55072', (25, 29))	('viability', 'CPA', (58, 67))	('HOIP', 'Gene', (25, 29))	('silencing', 'Var', (12, 21))	('reduces', 'NegReg', (46, 53))
552168	32403254	Although most ALS cases are sporadic, around 10% are familial, and mutations in approximately 20 genes encoding proteins involved in protein/RNA aggregation (SOD1, TDP-43, hnRNPA1/2, and FUS), neuroinflammation (TBK1), the ubiquitin-proteasome pathway (UBQLN2), and autophagy (C9orf72, OPTN, SQSTM1/p62, and VCP) have been identified.	('ubiquitin', 'Gene', (223, 232))	('FUS', 'Gene', '2521', (187, 190))	('ALS', 'Disease', (14, 17))	('hnRNPA1/2', 'Gene', (172, 181))	('inflammation', 'Disease', (198, 210))	('SQSTM1', 'Gene', (292, 298))	('protein/RNA', 'MPA', (133, 144))	('SOD1', 'Gene', (158, 162))	('SOD1', 'Gene', '6647', (158, 162))	('p62', 'Gene', '8878', (299, 302))	('VCP', 'Gene', (308, 311))	('p62', 'Gene', (299, 302))	('TDP-43', 'Gene', '23435', (164, 170))	('TBK1', 'Gene', '29110', (212, 216))	('OPTN', 'Gene', '10133', (286, 290))	('UBQLN2', 'Gene', (253, 259))	('SQSTM1', 'Gene', '8878', (292, 298))	('ubiquitin', 'Gene', '38456', (223, 232))	('TBK1', 'Gene', (212, 216))	('VCP', 'Gene', '7415', (308, 311))	('C9orf72', 'Gene', '203228', (277, 284))	('autophagy', 'CPA', (266, 275))	('C9orf72', 'Gene', (277, 284))	('UBQLN2', 'Gene', '29978', (253, 259))	('hnRNPA1/2', 'Gene', '3178;3181', (172, 181))	('FUS', 'Gene', (187, 190))	('ALS', 'Phenotype', 'HP:0007354', (14, 17))	('inflammation', 'Disease', 'MESH:D007249', (198, 210))	('mutations', 'Var', (67, 76))	('OPTN', 'Gene', (286, 290))	('TDP-43', 'Gene', (164, 170))
552169	32403254	Although OPTN reportedly functions as an autophagy receptor, we determined that the ALS-associated OPTN mutations, E478G and Q398X, abrogated the inhibitory effects of OPTN on LUBAC-mediated NF-kappaB activation, and accelerated TNF-induced cell death in HEK293T and HeLa cells.	('OPTN', 'Gene', '10133', (99, 103))	('OPTN', 'Gene', '10133', (9, 13))	('death', 'Disease', (246, 251))	('inhibitory effects', 'MPA', (146, 164))	('OPTN', 'Gene', '10133', (168, 172))	('LUBAC-mediated', 'MPA', (176, 190))	('OPTN', 'Gene', (99, 103))	('abrogated', 'NegReg', (132, 141))	('E478G', 'Mutation', 'rs267606929', (115, 120))	('accelerated', 'PosReg', (217, 228))	('activation', 'MPA', (201, 211))	('Q398X', 'Var', (125, 130))	('OPTN', 'Gene', (9, 13))	('death', 'Disease', 'MESH:D003643', (246, 251))	('HeLa', 'CellLine', 'CVCL:0030', (267, 271))	('E478G', 'Var', (115, 120))	('OPTN', 'Gene', (168, 172))	('LUBAC', 'Chemical', '-', (176, 181))	('ALS', 'Phenotype', 'HP:0007354', (84, 87))	('HEK293T', 'CellLine', 'CVCL:0063', (255, 262))	('Q398X', 'Mutation', 'rs267606928', (125, 130))
552170	32403254	Importantly, the intracytoplasmic inclusions in neurons from patients with the heterozygous E478G and homozygous Q398X mutations reacted with an anti-linear ubiquitin antibody, and they were co-localized with TDP-43 and phosphorylated p65, which is an activated form of NF-kappaB.	('reacted', 'Reg', (129, 136))	('p65', 'Gene', (235, 238))	('Q398X', 'Var', (113, 118))	('patients', 'Species', '9606', (61, 69))	('Q398X', 'Mutation', 'rs267606928', (113, 118))	('p65', 'Gene', '5970', (235, 238))	('TDP-43', 'Gene', '23435', (209, 215))	('TDP-43', 'Gene', (209, 215))	('ubiquitin', 'Gene', (157, 166))	('E478G', 'Var', (92, 97))	('E478G', 'Mutation', 'rs267606929', (92, 97))	('ubiquitin', 'Gene', '38456', (157, 166))
552174	32403254	Similarly, we showed that K63-linked ubiquitin was predominantly detected in intermediate and thick bundles, and linear- and K63-linked ubiquitin immunoreactants were not always co-localized.	('K63', 'Chemical', '-', (125, 128))	('ubiquitin', 'Gene', (37, 46))	('K63', 'Chemical', '-', (26, 29))	('ubiquitin', 'Gene', '38456', (37, 46))	('K63-linked', 'Var', (26, 36))	('ubiquitin', 'Gene', '38456', (136, 145))	('ubiquitin', 'Gene', (136, 145))
552184	32403254	Therefore, LUBAC inhibitors will facilitate investigations of its enzymatic mechanisms and the cellular bases for immune responses, and serve as potential therapeutics for various LUBAC-related disorders.	('LUBAC', 'Chemical', '-', (180, 185))	('LUBAC', 'Chemical', '-', (11, 16))	('inhibitors', 'Var', (17, 27))	('LUBAC', 'Gene', (11, 16))
552185	32403254	As described above, stapled peptides targeting the HOIP-HOIL-1L interface suppressed the viability of ABC-DLBCL cells.	('viability', 'CPA', (89, 98))	('suppressed', 'NegReg', (74, 84))	('HOIP', 'Gene', '55072', (51, 55))	('HOIP', 'Gene', (51, 55))	('HOIL-1L', 'Gene', (56, 63))	('peptides', 'Var', (28, 36))	('HOIL-1L', 'Gene', '24105', (56, 63))
552191	32403254	Importantly, they showed that compound was covalently attached to the catalytic Cys885 of HOIP via Michael addition, by accommodation in a hydrophobic pocket formed by Tyr878, Leu880, and Phe888, and stabilization by hydrogen bonds with the main-chain CO and NH groups of His889 and the Ogamma atom of Ser899.	('Phe888', 'Var', (188, 194))	('Tyr878', 'Var', (168, 174))	('Leu880', 'Chemical', '-', (176, 182))	('Cys885', 'Chemical', '-', (80, 86))	('Leu880', 'Var', (176, 182))	('Ser899', 'Chemical', '-', (302, 308))	('His889', 'Chemical', '-', (272, 278))	('Phe888', 'Chemical', '-', (188, 194))	('Tyr878', 'Chemical', '-', (168, 174))	('hydrogen', 'Chemical', 'MESH:D006859', (217, 225))	('HOIP', 'Gene', (90, 94))	('HOIP', 'Gene', '55072', (90, 94))
552193	32403254	These sequence variations of RING2 may be beneficial for the HOIP specificity of compound.	('HOIP', 'Gene', (61, 65))	('RING2', 'Gene', '7923', (29, 34))	('variations', 'Var', (15, 25))	('RING2', 'Gene', (29, 34))	('beneficial', 'Reg', (42, 52))	('HOIP', 'Gene', '55072', (61, 65))
552199	32403254	We recently determined that HOIPINs are conjugated to the active site Cys885 in the RING2 domain of HOIP through Michael addition, and interrupt the RING-HECT-hybrid reaction in HOIP.	('RING-HECT-hybrid reaction', 'MPA', (149, 174))	('Cys885', 'Var', (70, 76))	('HOIP', 'Gene', '55072', (100, 104))	('HOIP', 'Gene', '55072', (28, 32))	('HOIP', 'Gene', '55072', (178, 182))	('Cys885', 'Chemical', '-', (70, 76))	('RING2', 'Gene', '7923', (84, 89))	('HOIP', 'Gene', (100, 104))	('HOIP', 'Gene', (178, 182))	('RING2', 'Gene', (84, 89))	('HOIP', 'Gene', (28, 32))	('HOIPINs', 'Chemical', '-', (28, 35))	('interrupt', 'NegReg', (135, 144))
552200	32403254	The benzoate, 2,6-difluorophenyl, and 1H-pyrazol-4-yl moieties of HOIPIN-8 interact with Arg935 and Asp936, which are located in the LDD domain of human HOIP (Figure 5).	('HOIPIN-8', 'Chemical', '-', (66, 74))	('1H-pyrazol-4-yl', 'Chemical', '-', (38, 53))	('interact', 'Reg', (75, 83))	('human', 'Species', '9606', (147, 152))	('benzoate', 'Chemical', 'MESH:D001565', (4, 12))	('Asp936', 'Chemical', '-', (100, 106))	('HOIP', 'Gene', '55072', (66, 70))	('Asp936', 'Var', (100, 106))	('2,6-difluorophenyl', 'Chemical', '-', (14, 32))	('HOIP', 'Gene', (66, 70))	('HOIP', 'Gene', '55072', (153, 157))	('Arg935', 'Var', (89, 95))	('HOIP', 'Gene', (153, 157))	('Arg935', 'Chemical', '-', (89, 95))
552201	32403254	Arg935 and Asp936 in the LDD domain reportedly interact with Glu16 and Thr14 in the acceptor ubiquitin, and the Ala mutations of these residues abrogated the linear ubiquitination activity.	('Arg935', 'Var', (0, 6))	('Glu16', 'Chemical', '-', (61, 66))	('ubiquitin', 'Gene', (93, 102))	('Arg935', 'Chemical', '-', (0, 6))	('Asp936', 'Chemical', '-', (11, 17))	('ubiquitin', 'Gene', '38456', (93, 102))	('interact', 'Reg', (47, 55))	('mutations', 'Var', (116, 125))	('Asp936', 'Var', (11, 17))	('Thr14', 'Chemical', '-', (71, 76))	('Ala', 'Chemical', 'MESH:D000409', (112, 115))	('abrogated', 'NegReg', (144, 153))	('ubiquitin', 'Gene', (165, 174))	('ubiquitin', 'Gene', '38456', (165, 174))
552203	32403254	In addition, the 1-methyl-1H-pyrazol-4-yl moiety of HOIPIN-8 interacts with His887, Phe905, and Leu922 of HOIP (Figure 5).	('HOIPIN-8', 'Chemical', '-', (52, 60))	('HOIP', 'Gene', (106, 110))	('His887', 'Chemical', '-', (76, 82))	('Leu922', 'Chemical', '-', (96, 102))	('Leu922', 'Var', (96, 102))	('Phe905', 'Chemical', '-', (84, 90))	('interacts', 'Reg', (61, 70))	('HOIP', 'Gene', '55072', (52, 56))	('1-methyl-1H-pyrazol-4-yl', 'Chemical', '-', (17, 41))	('HOIP', 'Gene', (52, 56))	('His887', 'Var', (76, 82))	('Phe905', 'Var', (84, 90))	('HOIP', 'Gene', '55072', (106, 110))
552210	32403254	To date, dysfunctions in skin barrier production, IL-23/IL17-mediated lymphocyte signaling, and the NF-kappaB pathway are reportedly involved in the pathogenesis of psoriasis.	('IL-23', 'Gene', (50, 55))	('involved', 'Reg', (133, 141))	('psoriasis', 'Phenotype', 'HP:0003765', (165, 174))	('IL-23', 'Gene', '51561', (50, 55))	('skin barrier production', 'MPA', (25, 48))	('IL17', 'Gene', (56, 60))	('psoriasis', 'Disease', 'MESH:D011565', (165, 174))	('IL17', 'Gene', '3605', (56, 60))	('psoriasis', 'Disease', (165, 174))	('NF-kappaB pathway', 'Pathway', (100, 117))	('dysfunctions', 'Var', (9, 21))
552215	32403254	Therefore, the impaired LUBAC activity and the aberrant functions in linear ubiquitin decoders are associated with autoinflammatory and neurodegenerative diseases, and cancers.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('impaired', 'NegReg', (15, 23))	('neurodegenerative diseases', 'Disease', 'MESH:D019636', (136, 162))	('ubiquitin', 'Gene', (76, 85))	('cancers', 'Disease', 'MESH:D009369', (168, 175))	('aberrant functions', 'Var', (47, 65))	('ubiquitin', 'Gene', '38456', (76, 85))	('LUBAC', 'Chemical', '-', (24, 29))	('cancers', 'Phenotype', 'HP:0002664', (168, 175))	('cancers', 'Disease', (168, 175))	('neurodegenerative diseases', 'Disease', (136, 162))	('LUBAC', 'Protein', (24, 29))	('neurodegenerative diseases', 'Phenotype', 'HP:0002180', (136, 162))	('autoinflammatory', 'Disease', (115, 131))	('associated', 'Reg', (99, 109))
552218	32403254	Concomitant with aging, maturation, and liquid-liquid phase separation (LLPS), LUBAC-mediated linear ubiquitin and/or K63-linked ubiquitin chains will be conjugated to NCI.	('LLPS', 'Disease', (72, 76))	('LLPS', 'Disease', 'None', (72, 76))	('ubiquitin', 'Gene', (101, 110))	('ubiquitin', 'Gene', '38456', (101, 110))	('K63', 'Chemical', '-', (118, 121))	('LUBAC', 'Chemical', '-', (79, 84))	('ubiquitin', 'Gene', (129, 138))	('K63-linked', 'Var', (118, 128))	('ubiquitin', 'Gene', '38456', (129, 138))
552219	32403254	We speculated that it may further generate complex-types of ubiquitin chains, such as K48/linear-branched chains, in the thick bundles.	('ubiquitin', 'Gene', '38456', (60, 69))	('K48/linear-branched', 'Var', (86, 105))	('ubiquitin', 'Gene', (60, 69))
552228	32343702	In this study, we showed that the expression levels of miR-652-5p in tumour tissues and serum samples of oesophageal squamous cell carcinoma (OSCC) patients were lower compared to non-tumorous tissues and serum samples from healthy subjects, respectively.	('tumour', 'Disease', (69, 75))	('patients', 'Species', '9606', (148, 156))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (117, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('oesophageal squamous cell carcinoma', 'Disease', 'MESH:D002294', (105, 140))	('tumorous', 'Disease', 'MESH:D009369', (184, 192))	('tumorous', 'Disease', (184, 192))	('lower', 'NegReg', (162, 167))	('tumour', 'Phenotype', 'HP:0002664', (69, 75))	('miR-652-5p', 'Chemical', '-', (55, 65))	('tumour', 'Disease', 'MESH:D009369', (69, 75))	('oesophageal squamous cell carcinoma', 'Disease', (105, 140))	('miR-652-5p', 'Var', (55, 65))	('expression levels', 'MPA', (34, 51))
552229	32343702	Decreased expression of miR-652-5p was correlated with TNM stages, lymph node metastasis, and short overall survival (OS).	('TNM', 'Gene', '10178', (55, 58))	('Decreased', 'NegReg', (0, 9))	('miR-652-5p', 'Chemical', '-', (24, 34))	('lymph node metastasis', 'CPA', (67, 88))	('expression', 'MPA', (10, 20))	('miR-652-5p', 'Var', (24, 34))	('TNM', 'Gene', (55, 58))
552230	32343702	More frequent CpG sites hypermethylation in the upstream of miR-652-5p was found in OSCC tissues compared to adjacent normal tissues.	('hypermethylation', 'Var', (24, 40))	('miR-652-5p', 'Chemical', '-', (60, 70))	('miR-652-5p', 'Gene', (60, 70))	('OSCC', 'Disease', (84, 88))
552231	32343702	Subsequently, miR-652-5p downregulation promoted the proliferation and metastasis of OSCC, and regulated cell cycle both in cells and in vivo.	('metastasis of OSCC', 'CPA', (71, 89))	('promoted', 'PosReg', (40, 48))	('regulated', 'Reg', (95, 104))	('miR-652-5p', 'Chemical', '-', (14, 24))	('proliferation', 'CPA', (53, 66))	('miR-652-5p', 'Var', (14, 24))	('downregulation', 'NegReg', (25, 39))	('cell cycle', 'CPA', (105, 115))
552232	32343702	The dual-luciferase reporter assay confirmed that poly (ADP-ribose) glycohydrolase (PARG) and vascular endothelial growth factor A (VEGFA) were the direct targets of miR-652-5p.	('miR-652-5p', 'Var', (166, 176))	('vascular endothelial growth factor A', 'Gene', '7422', (94, 130))	('vascular endothelial growth factor A', 'Gene', (94, 130))	('miR-652-5p', 'Chemical', '-', (166, 176))	('poly (ADP-ribose) glycohydrolase', 'Gene', '8505', (50, 82))
552233	32343702	Moreover, the delivery of miR-652-5p agomir suppressed tumour growth and metastasis, and inhibited the protein expressions of PARG and VEGFA in nude mice.	('suppressed', 'NegReg', (44, 54))	('VEGFA', 'Protein', (135, 140))	('PARG', 'Protein', (126, 130))	('metastasis', 'CPA', (73, 83))	('inhibited', 'NegReg', (89, 98))	('protein expressions', 'MPA', (103, 122))	('tumour', 'Phenotype', 'HP:0002664', (55, 61))	('tumour growth', 'Disease', (55, 68))	('nude mice', 'Species', '10090', (144, 153))	('tumour growth', 'Disease', 'MESH:D006130', (55, 68))	('miR-652-5p agomir', 'Var', (26, 43))	('miR-652-5p', 'Chemical', '-', (26, 36))
552234	32343702	This study confirmed that miR-652-5p underexpression was a result of the hypermethylated promotor, which regulated OSCC development by targeting PARG and VEGF.	('VEGF', 'Gene', '7422', (154, 158))	('miR-652-5p', 'Var', (26, 36))	('regulated', 'Reg', (105, 114))	('OSCC development', 'CPA', (115, 131))	('VEGF', 'Gene', (154, 158))	('miR-652-5p', 'Chemical', '-', (26, 36))
552251	32343702	Recent findings revealed that miR-652-5p might be a promising prognostic biomarker in patients with locally advanced oesophageal adenocarcinoma.	('miR-652-5p', 'Chemical', '-', (30, 40))	('adenocarcinoma', 'Disease', (129, 143))	('miR-652-5p', 'Var', (30, 40))	('adenocarcinoma', 'Disease', 'MESH:D000230', (129, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('patients', 'Species', '9606', (86, 94))
552252	32343702	However, the regulatory impact of miR-652-5p in OSCC remains to be elucidated.	('miR-652-5p', 'Chemical', '-', (34, 44))	('OSCC', 'Disease', (48, 52))	('miR-652-5p', 'Var', (34, 44))
552253	32343702	In the current study, we assessed the expression level of miR-652-5p and its prognostic significance in OSCC.	('OSCC', 'Disease', (104, 108))	('miR-652-5p', 'Chemical', '-', (58, 68))	('miR-652-5p', 'Var', (58, 68))
552258	32343702	The miR-652-5p signal was confined to scattered in the positive images of tumour tissues (Fig 1A and 1B).	('tumour', 'Disease', 'MESH:D009369', (74, 80))	('miR-652-5p', 'Chemical', '-', (4, 14))	('tumour', 'Disease', (74, 80))	('miR-652-5p', 'Var', (4, 14))	('tumour', 'Phenotype', 'HP:0002664', (74, 80))
552259	32343702	The expression of miR-652-5p was significantly decreased in tumour tissue samples, especially the ones from OSCC stages III and IV, as compared to the controls (Fig 1C and 1D).	('tumour', 'Disease', 'MESH:D009369', (60, 66))	('tumour', 'Disease', (60, 66))	('expression', 'MPA', (4, 14))	('miR-652-5p', 'Chemical', '-', (18, 28))	('miR-652-5p', 'Var', (18, 28))	('tumour', 'Phenotype', 'HP:0002664', (60, 66))	('decreased', 'NegReg', (47, 56))
552260	32343702	The downregulation of miR-652-5p was associated with OSCC stages and lymph node metastasis (Table 1).	('miR-652-5p', 'Var', (22, 32))	('OSCC stages', 'Disease', (53, 64))	('downregulation', 'NegReg', (4, 18))	('miR-652-5p', 'Chemical', '-', (22, 32))	('lymph node metastasis', 'CPA', (69, 90))
552261	32343702	Also, the overall survival (OS) of patients was significantly shorter in the ones with low miR-652-5p expression (Fig 2A).	('overall survival', 'CPA', (10, 26))	('shorter', 'NegReg', (62, 69))	('miR-652-5p expression', 'Var', (91, 112))	('patients', 'Species', '9606', (35, 43))	('low', 'NegReg', (87, 90))	('miR-652-5p', 'Chemical', '-', (91, 101))
552262	32343702	The mRNA level of miR-652-5p in OSCC tissues, particularly the ones from patients at advanced stages or with lymph node metastasis, was remarkably lower than that in normal samples (Fig 2B), (Fig 2C and 2D, Table 1).	('mRNA level', 'MPA', (4, 14))	('lower', 'NegReg', (147, 152))	('OSCC', 'Disease', (32, 36))	('miR-652-5p', 'Chemical', '-', (18, 28))	('miR-652-5p', 'Var', (18, 28))	('patients', 'Species', '9606', (73, 81))
552263	32343702	The underexpression of miR-652-5p was associated with the poor prognosis of OSCC patients (Fig 2E).	('OSCC', 'Disease', (76, 80))	('miR-652-5p', 'Chemical', '-', (23, 33))	('miR-652-5p', 'Var', (23, 33))	('patients', 'Species', '9606', (81, 89))
552264	32343702	Data also showed that miR-652-5p was an independent prognostic factor for the OS of OSCC patients (S1 Table).	('patients', 'Species', '9606', (89, 97))	('OS of OSCC patients', 'Disease', (78, 97))	('miR-652-5p', 'Chemical', '-', (22, 32))	('miR-652-5p', 'Var', (22, 32))
552265	32343702	The serum expression of miR-652-5p in OSCC patients was significantly lower in comparison to the controls (Fig 2F, S2 Table).	('patients', 'Species', '9606', (43, 51))	('miR-652-5p', 'Chemical', '-', (24, 34))	('miR-652-5p', 'Var', (24, 34))	('serum expression', 'MPA', (4, 20))	('lower', 'NegReg', (70, 75))	('OSCC', 'Disease', (38, 42))
552266	32343702	The serum level of miR-652-5p was negatively correlated with the lymph node metastasis and advanced stages of OSCC (Fig 2G and 2H, S2 Table).	('miR-652-5p', 'Chemical', '-', (19, 29))	('miR-652-5p', 'Var', (19, 29))	('serum level', 'MPA', (4, 15))	('negatively', 'NegReg', (34, 44))	('lymph node metastasis', 'CPA', (65, 86))	('OSCC', 'Disease', (110, 114))
552267	32343702	The receiver operating characteristic (ROC) curve showed that the area under the curve (AUC) for plasma miR-652-5p was 0.919, indicating the diagnosis potential of serum miR-652-5p for OSCC (Fig 2I).	('miR-652-5p', 'Var', (170, 180))	('serum miR-652-5p', 'Var', (164, 180))	('miR-652-5p', 'Chemical', '-', (104, 114))	('miR-652-5p', 'Chemical', '-', (170, 180))	('OSCC', 'Disease', (185, 189))
552275	32343702	By using hierarchical clustering analysis, we observed that the density of methylated CpG dinucleotides was increased in OSCC samples compared to paired normal tissues (Fig 4B).	('methylated', 'Var', (75, 85))	('OSCC', 'Disease', (121, 125))	('density', 'MPA', (64, 71))	('increased', 'PosReg', (108, 117))	('CpG dinucleotides', 'Chemical', 'MESH:C015772', (86, 103))	('CpG', 'Gene', (86, 89))
552278	32343702	The methylation of miR-652-5p in EC109 (41.94% vs. 17.70%) and KYSE150 (51.19% vs. 23.02%) cells were predominantly inactivated at the presence of 5-aza-CdR (Fig 4D).	('miR-652-5p', 'Chemical', '-', (19, 29))	('methylation', 'MPA', (4, 15))	('KYSE150', 'CellLine', 'CVCL:1348', (63, 70))	('5-aza-CdR', 'Var', (147, 156))	('inactivated', 'NegReg', (116, 127))
552279	32343702	Correspondingly, the high expression of miR-652-5p was negatively correlated with the methylation level in these 5-aza-CdR-treated cells (Fig 4E).	('expression', 'MPA', (26, 36))	('miR-652-5p', 'Var', (40, 50))	('negatively', 'NegReg', (55, 65))	('methylation level', 'MPA', (86, 103))	('miR-652-5p', 'Chemical', '-', (40, 50))
552280	32343702	These findings implied that miR-652-5p downregulation in OSCC was correlated with promoter hypermethylation, while the demethylation of the promoter gene induced the upregulation of miR-652-5p.	('miR-652-5p', 'MPA', (182, 192))	('promoter hypermethylation', 'MPA', (82, 107))	('upregulation', 'PosReg', (166, 178))	('miR-652-5p', 'Chemical', '-', (28, 38))	('miR-652-5p', 'Chemical', '-', (182, 192))	('demethylation', 'Var', (119, 132))	('OSCC', 'Disease', (57, 61))	('miR-652-5p', 'Gene', (28, 38))	('downregulation', 'NegReg', (39, 53))
552281	32343702	Among the tested OSCC cells, EC109 and KYSE150 showed the lowest miR-652-5p expression (Fig 5A) and were used for the overexpression study.	('KYSE150', 'Var', (39, 46))	('miR-652-5p', 'Chemical', '-', (65, 75))	('lowest', 'NegReg', (58, 64))	('KYSE150', 'CellLine', 'CVCL:1348', (39, 46))	('miR-652-5p expression', 'MPA', (65, 86))
552284	32343702	Upregulated exogenous expression of miR-652-5p efficiently impeded the growth, colony formation, and migration/invasion of OSCC cells (Fig 5C-5H).	('miR-652-5p', 'Chemical', '-', (36, 46))	('migration/invasion', 'CPA', (101, 119))	('miR-652-5p', 'Var', (36, 46))	('growth', 'CPA', (71, 77))	('impeded', 'NegReg', (59, 66))	('colony formation', 'CPA', (79, 95))	('exogenous', 'MPA', (12, 21))	('Upregulated', 'PosReg', (0, 11))
552286	32343702	Data showed an increased number of cells in G0/G1 phase upon upregulation of miR-652-5p in both EC109 and KYSE150 cell lines (Fig 5I and 5J), suggesting that miR-652-5p overexpression led to G1 phase arrest in OSCC cells.	('arrest', 'Disease', 'MESH:D006323', (200, 206))	('miR-652-5p', 'Chemical', '-', (158, 168))	('KYSE150', 'CellLine', 'CVCL:1348', (106, 113))	('miR-652-5p', 'Gene', (77, 87))	('miR-652-5p', 'Var', (158, 168))	('upregulation', 'PosReg', (61, 73))	('arrest', 'Disease', (200, 206))	('miR-652-5p', 'Chemical', '-', (77, 87))	('overexpression', 'PosReg', (169, 183))
552289	32343702	We also found that miR-652-5p downexpression decreased G1 phase cells but increased the number of cells at G2/M phase (S1H and S1I Fig).	('miR-652-5p', 'Chemical', '-', (19, 29))	('miR-652-5p downexpression', 'Var', (19, 44))	('decreased', 'NegReg', (45, 54))	('increased', 'PosReg', (74, 83))	('G1 phase cells', 'CPA', (55, 69))
552290	32343702	Therefore, miR-652-5p downregulation could promote the proliferation of OSCC cells.	('downregulation', 'NegReg', (22, 36))	('promote', 'PosReg', (43, 50))	('miR-652-5p', 'Chemical', '-', (11, 21))	('proliferation of OSCC cells', 'CPA', (55, 82))	('miR-652-5p', 'Var', (11, 21))
552291	32343702	To further investigate the mechanisms by which miR-652-5p mediates the progression of OSCC, we searched for the potential downstream genes of miR-652-5p on bioinformatics databases (i.e.	('miR-652-5p', 'Chemical', '-', (47, 57))	('miR-652-5p', 'Chemical', '-', (142, 152))	('miR-652-5p', 'Var', (142, 152))	('OSCC', 'Disease', (86, 90))
552293	32343702	Poly (ADP-ribose) glycohydrolase (PARG) and vascular endothelial growth factor A (VEGFA), two key proteins associated with cell cycling, proliferation, invasion, and metastasis, appeared to be the potential targets of miR-652-5p (Fig 6B).	('Poly (ADP-ribose) glycohydrolase', 'Gene', '8505', (0, 32))	('miR-652-5p', 'Var', (218, 228))	('vascular endothelial growth factor A', 'Gene', '7422', (44, 80))	('vascular endothelial growth factor A', 'Gene', (44, 80))	('miR-652-5p', 'Chemical', '-', (218, 228))
552295	32343702	On the contrary, the downregulation of miR-652-5p by inhibitor promoted the expressions of PARG and VEGFA at both translational and transcriptional levels (Fig 6E and 6F).	('miR-652-5p', 'Var', (39, 49))	('miR-652-5p', 'Chemical', '-', (39, 49))	('downregulation', 'NegReg', (21, 35))	('expressions', 'MPA', (76, 87))	('promoted', 'PosReg', (63, 71))	('PARG', 'Gene', (91, 95))	('VEGFA', 'Protein', (100, 105))
552298	32343702	The inhibition of miR-652-5p on PARG- or VEGFA-3'UTR was sequence-specific as mutant PARG or VEGFA did not decrease the luciferase activities in miR-652-5p mimic-transfected cells.	('luciferase', 'Enzyme', (120, 130))	('activities', 'MPA', (131, 141))	('miR-652-5p', 'Chemical', '-', (18, 28))	('miR-652-5p', 'Chemical', '-', (145, 155))	('PARG', 'Gene', (85, 89))	('mutant', 'Var', (78, 84))
552299	32343702	The above results implied that miR-652-5p directly targeted PARG and VEGFA.	('targeted', 'Reg', (51, 59))	('miR-652-5p', 'Var', (31, 41))	('PARG', 'CPA', (60, 64))	('miR-652-5p', 'Chemical', '-', (31, 41))
552300	32343702	Next, we performed a rescue experiment to ascertain that miR-652-5p targeted on PARG and VEGFA.	('targeted', 'Reg', (68, 76))	('miR-652-5p', 'Chemical', '-', (57, 67))	('miR-652-5p', 'Var', (57, 67))
552301	32343702	The endogenous expressions of PARG and VEGFA in EC109 and KYSE150 cells were inhibited by miR-652-5p mimic but recovered by the delivery of PARG- or VEGFA- overexpression constructs (S2A and S2B Fig).	('endogenous expressions', 'MPA', (4, 26))	('KYSE150', 'CellLine', 'CVCL:1348', (58, 65))	('PARG', 'Protein', (30, 34))	('inhibited', 'NegReg', (77, 86))	('VEGFA', 'Protein', (39, 44))	('miR-652-5p', 'Chemical', '-', (90, 100))	('miR-652-5p mimic', 'Var', (90, 106))
552303	32343702	KYSE510 cells were transfected with vectors to knockdown miR-652-5p or control vectors (Fig 7A).	('KYSE510', 'CellLine', 'CVCL:1354', (0, 7))	('knockdown miR-652-5p', 'Var', (47, 67))	('miR-652-5p', 'Chemical', '-', (57, 67))	('miR-652-5p', 'Var', (57, 67))
552307	32343702	A significantly increased growth rate was shown in mice inoculated with miR-652-5p-deficient cells compared to the controls(Fig 7B).	('mice', 'Species', '10090', (51, 55))	('growth', 'MPA', (26, 32))	('miR-652-5p', 'Chemical', '-', (72, 82))	('miR-652-5p-deficient cells', 'Var', (72, 98))	('increased', 'PosReg', (16, 25))
552309	32343702	The tumours in miR-652-5p-downregulated group were larger compared to the control animals (Fig 7C and 7D).	('larger', 'PosReg', (51, 57))	('tumour', 'Phenotype', 'HP:0002664', (4, 10))	('miR-652-5p-downregulated', 'Var', (15, 39))	('tumours', 'Phenotype', 'HP:0002664', (4, 11))	('tumours', 'Disease', 'MESH:D009369', (4, 11))	('miR-652-5p', 'Chemical', '-', (15, 25))	('tumours', 'Disease', (4, 11))
552313	32343702	Seven days later, miR-652-5p agomir or control agomir was injected into the subcutaneous tumour of mice every five days for thirty-five days.	('mice', 'Species', '10090', (99, 103))	('tumour', 'Phenotype', 'HP:0002664', (89, 95))	('miR-652-5p agomir', 'Var', (18, 35))	('tumour', 'Disease', 'MESH:D009369', (89, 95))	('tumour', 'Disease', (89, 95))	('subcutaneous tumour', 'Phenotype', 'HP:0001482', (76, 95))	('miR-652-5p', 'Chemical', '-', (18, 28))
552315	32343702	These findings indicated that miR-652-5p overexpression successfully compromised the tumourigenicity of KYSE510 cells in a mouse model.	('miR-652-5p', 'Chemical', '-', (30, 40))	('tumour', 'Disease', 'MESH:D009369', (85, 91))	('mouse', 'Species', '10090', (123, 128))	('tumour', 'Disease', (85, 91))	('compromised', 'NegReg', (69, 80))	('tumour', 'Phenotype', 'HP:0002664', (85, 91))	('KYSE510', 'CellLine', 'CVCL:1354', (104, 111))	('miR-652-5p overexpression', 'Var', (30, 55))
552317	32343702	Decreased Ki-67 expression was observed in the tumour sections from miR-652-5p agomir-treated group (Fig 7J).	('tumour', 'Disease', 'MESH:D009369', (47, 53))	('miR-652-5p', 'Chemical', '-', (68, 78))	('Decreased', 'NegReg', (0, 9))	('miR-652-5p', 'Var', (68, 78))	('tumour', 'Disease', (47, 53))	('Ki-67', 'Chemical', '-', (10, 15))	('expression', 'MPA', (16, 26))	('tumour', 'Phenotype', 'HP:0002664', (47, 53))	('Ki-67', 'Protein', (10, 15))
552325	32343702	The downregulated miR-652-5p level was also significantly associated with lymph node metastasis and more advanced stages of OSCC.	('downregulated', 'NegReg', (4, 17))	('miR-652-5p', 'Chemical', '-', (18, 28))	('lymph node metastasis', 'CPA', (74, 95))	('miR-652-5p level', 'Var', (18, 34))
552332	32343702	These results indicated a great potential of miR-652-5p as a non-invasive diagnostic biomarker in OSCC with high specificity and sensitivity.	('miR-652-5p', 'Var', (45, 55))	('OSCC', 'Disease', (98, 102))	('miR-652-5p', 'Chemical', '-', (45, 55))
552336	32343702	Therefore, exosomal miR-652-5p is likely to be a promising non-invasive biomarker and a targetable factor for OSCC diagnosis.	('miR-652-5p', 'Chemical', '-', (20, 30))	('OSCC', 'Disease', (110, 114))	('exosomal miR-652-5p', 'Var', (11, 30))
552337	32343702	Additionally, we showed that the lower expression of miR-652-5p was correlated with poor OS in OSCC patients.	('miR-652-5p', 'Var', (53, 63))	('miR-652-5p', 'Chemical', '-', (53, 63))	('patients', 'Species', '9606', (100, 108))	('OSCC', 'Disease', (95, 99))	('expression', 'MPA', (39, 49))	('poor OS', 'Disease', (84, 91))	('lower', 'NegReg', (33, 38))
552340	32343702	The current study is the first to demonstrate the prognostic and diagnostic potential of miR-652-5p in OSCC.	('OSCC', 'Disease', (103, 107))	('miR-652-5p', 'Chemical', '-', (89, 99))	('miR-652-5p', 'Var', (89, 99))
552341	32343702	DNA hypermethylation-mediated inactivation of miRNAsis a key mechanism of tumorigenesis by silencing tumour suppressor genes.	('miR', 'Gene', (46, 49))	('tumorigenesis', 'CPA', (74, 87))	('inactivation', 'Var', (30, 42))	('tumour', 'Disease', (101, 107))	('miR', 'Gene', '220972', (46, 49))	('silencing', 'NegReg', (91, 100))	('tumour', 'Phenotype', 'HP:0002664', (101, 107))	('tumour', 'Disease', 'MESH:D009369', (101, 107))
552342	32343702	We hypothesized that the downregulation of miR-652-5p was epigenetically silenced by DNA hypermethylation.	('downregulation', 'NegReg', (25, 39))	('miR-652-5p', 'Var', (43, 53))	('miR-652-5p', 'Chemical', '-', (43, 53))
552343	32343702	The hypermethylation of CpG sites in miR-652-5p was found in OSCC clinical samples.	('found', 'Reg', (52, 57))	('miR-652-5p', 'Gene', (37, 47))	('OSCC', 'Disease', (61, 65))	('miR-652-5p', 'Chemical', '-', (37, 47))	('hypermethylation', 'Var', (4, 20))
552344	32343702	Further analysis verified that 5-aza-CdR-stimulated hypermethylation dramatically augmented miR-652-5p expression in OSCC cells.	('miR-652-5p expression', 'MPA', (92, 113))	('augmented', 'PosReg', (82, 91))	('miR-652-5p', 'Chemical', '-', (92, 102))	('hypermethylation', 'Var', (52, 68))
552345	32343702	The above data support the notion that DNA hypermethylation led to reduced miR-652-5p expression during the development of OSCC.	('miR-652-5p', 'Gene', (75, 85))	('hypermethylation', 'Var', (43, 59))	('reduced', 'NegReg', (67, 74))	('miR-652-5p', 'Chemical', '-', (75, 85))
552349	32343702	Consistent with these findings, we found that miR-652-5p overexpression suppressed the proliferation, migration/invasion, and colony formation of OSCC cells.	('miR-652-5p', 'Var', (46, 56))	('proliferation', 'CPA', (87, 100))	('migration/invasion', 'CPA', (102, 120))	('suppressed', 'NegReg', (72, 82))	('miR-652-5p', 'Chemical', '-', (46, 56))	('colony formation of OSCC cells', 'CPA', (126, 156))
552350	32343702	The upregulation of miR-652-5p resulted in significant S phage reduction and G0/G1 arrest in OSCC cells.	('S phage', 'CPA', (55, 62))	('arrest', 'Disease', 'MESH:D006323', (83, 89))	('miR-652-5p', 'Chemical', '-', (20, 30))	('arrest', 'Disease', (83, 89))	('miR-652-5p', 'Var', (20, 30))	('reduction', 'NegReg', (63, 72))	('upregulation', 'PosReg', (4, 16))
552351	32343702	More importantly, miR-652-5p expression in the tissue samples of metastatic OSCC patients was lower in contrast to non-cancerous or non-progressive OSCC tissues.	('cancerous', 'Disease', 'MESH:D009369', (119, 128))	('patients', 'Species', '9606', (81, 89))	('miR-652-5p', 'Chemical', '-', (18, 28))	('lower', 'NegReg', (94, 99))	('cancerous', 'Disease', (119, 128))	('miR-652-5p', 'Var', (18, 28))	('metastatic OSCC', 'Disease', (65, 80))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
552358	32343702	Consistently, our results suggest that miR-652-5p functions as an OSCC suppressor and may be used to develop new treatment methods for OSCC patients.	('miR-652-5p', 'Var', (39, 49))	('OSCC', 'Disease', (135, 139))	('patients', 'Species', '9606', (140, 148))	('miR-652-5p', 'Chemical', '-', (39, 49))	('OSCC', 'Disease', (66, 70))
552360	32343702	To further explore the tumour-suppressive role of miR-652-5p in OSCC, we searched for its potential targets.	('tumour', 'Phenotype', 'HP:0002664', (23, 29))	('miR-652-5p', 'Chemical', '-', (50, 60))	('tumour', 'Disease', 'MESH:D009369', (23, 29))	('miR-652-5p', 'Var', (50, 60))	('OSCC', 'Disease', (64, 68))	('tumour', 'Disease', (23, 29))
552361	32343702	The bioinformatics analysis indicated that miR-652-5p bound to the 3'UTR of PARG and VEGFA to inhibit their expressions.	('miR-652-5p', 'Var', (43, 53))	('expressions', 'MPA', (108, 119))	('miR-652-5p', 'Chemical', '-', (43, 53))	('bound', 'Interaction', (54, 59))	('inhibit', 'NegReg', (94, 101))
552364	32343702	The silencing of PARG inhibited the growth of human colon cancer cells and reduced liver metastases in a murine colon carcinoma model.	('colon cancer', 'Disease', (52, 64))	('inhibited', 'NegReg', (22, 31))	('colon carcinoma', 'Disease', (112, 127))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('murine', 'Species', '10090', (105, 111))	('liver metastases', 'Disease', (83, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('reduced', 'NegReg', (75, 82))	('human', 'Species', '9606', (46, 51))	('liver metastases', 'Disease', 'MESH:D009362', (83, 99))	('colon carcinoma', 'Disease', 'MESH:D003110', (112, 127))	('colon cancer', 'Phenotype', 'HP:0003003', (52, 64))	('colon cancer', 'Disease', 'MESH:D015179', (52, 64))	('silencing', 'Var', (4, 13))	('PARG', 'Gene', (17, 21))
552368	32343702	Our study suggest that miR-652-5p may inhibit the growth and metastasis of OSCC via targeting PARG and VEGFA.	('miR-652-5p', 'Chemical', '-', (23, 33))	('miR-652-5p', 'Var', (23, 33))	('OSCC', 'Disease', (75, 79))	('PARG', 'Protein', (94, 98))	('inhibit', 'NegReg', (38, 45))	('VEGFA', 'Protein', (103, 108))
552369	32343702	Further investigations are needed to determine whether other potential factors are involved in miR-652-5p-mediated OSCC progression.	('miR-652-5p-mediated', 'Var', (95, 114))	('miR-652-5p', 'Chemical', '-', (95, 105))	('OSCC', 'Disease', (115, 119))
552371	32343702	Studies on the regulatory effects of soluble factors and/or exosomal contents on miR-652-5p in OSCC tumour microenvironment will be of great importance in the future.	('miR-652-5p', 'Chemical', '-', (81, 91))	('OSCC tumour', 'Disease', (95, 106))	('OSCC tumour', 'Disease', 'MESH:D009369', (95, 106))	('miR-652-5p', 'Var', (81, 91))	('tumour', 'Phenotype', 'HP:0002664', (100, 106))
552389	32343702	RNA, DNA, and proteins were isolated and analysed to determine the methylation status of miR-652-5p and the expressions of miR-652-5p and its target genes.	('miR-652-5p', 'Chemical', '-', (89, 99))	('miR-652-5p', 'Chemical', '-', (123, 133))	('miR-652-5p', 'Var', (123, 133))	('expressions', 'MPA', (108, 119))	('miR-652-5p', 'Gene', (89, 99))
552392	32343702	qRT-PCR was performed to assess the expressions of miR-652-5p, total RNAs, PARG and VEGF for the reverse transcription reactions using a Step One Plus real-time system (AB Applied Biosystems, Carlsbad, USA).	('VEGF', 'Gene', (84, 88))	('miR-652-5p', 'Var', (51, 61))	('miR-652-5p', 'Chemical', '-', (51, 61))	('VEGF', 'Gene', '7422', (84, 88))
552394	32343702	OSCC cells were co-transfected with miR-652-5p mimics (or control miR) and PARG- and VEGFA-3'UTR (or PARG- and VEGFA-mut).	('miR-652-5p', 'Chemical', '-', (36, 46))	('miR', 'Gene', (66, 69))	('PARG-', 'Var', (75, 80))	('miR', 'Gene', '220972', (66, 69))	('miR', 'Gene', '220972', (36, 39))	('miR', 'Gene', (36, 39))
552397	32343702	OSCC cells (1 x103 cells/well) were cultivated in six-well plates and transfected with miR-652-5p mimic (or control mimic) and miR-652-5p inhibitor (or control inhibitor).	('miR-652-5p', 'Chemical', '-', (87, 97))	('miR-652-5p mimic', 'Var', (87, 103))	('miR-652-5p inhibitor', 'Var', (127, 147))	('miR-652-5p', 'Chemical', '-', (127, 137))
552405	32343702	Recombinant lentiviral vectors containing the overexpression sequence of miR-652-5p and irrelevant sequence (negative control) were ordered from XIEBHC Biotechnology (Beijing, China).	('overexpression', 'PosReg', (46, 60))	('miR-652-5p', 'Chemical', '-', (73, 83))	('miR-652-5p', 'Var', (73, 83))
552412	32343702	The potential tumorigenic and metastatic effects of miR-652-5p on OSCC were investigated in the mouse models of subcutaneous and metastasis.	('miR-652-5p', 'Chemical', '-', (52, 62))	('miR-652-5p', 'Var', (52, 62))	('OSCC', 'Disease', (66, 70))	('mouse', 'Species', '10090', (96, 101))
552426	32343702	Wilcoxon's test was used to compare the expression of miR-652-5p between OSCC and normal oesophageal tissues.	('OSCC', 'Disease', (73, 77))	('miR-652-5p', 'Chemical', '-', (54, 64))	('miR-652-5p', 'Var', (54, 64))
552430	32343702	Reviewer #1: Overview The manuscript is about a research on miR-652-5p in esophageal cancer, particularly ESCC.	('miR-652-5p', 'Var', (60, 70))	('cancer', 'Disease', 'MESH:D009369', (85, 91))	('ESCC', 'Disease', (106, 110))	('cancer', 'Disease', (85, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('miR-652-5p', 'Chemical', '-', (60, 70))
552431	32343702	With human ESCC tissues, the authors found miR-652-5p is downregulated in a number of ESCC tissues.	('miR-652-5p', 'Var', (43, 53))	('downregulated', 'NegReg', (57, 70))	('miR-652-5p', 'Chemical', '-', (43, 53))	('human', 'Species', '9606', (5, 10))	('ESCC', 'Disease', (86, 90))
552432	32343702	Importantly, the downregulation of miR-652-5p is correlated with the prognosis of ESCC patients.	('ESCC', 'Disease', (82, 86))	('patients', 'Species', '9606', (87, 95))	('downregulation', 'NegReg', (17, 31))	('miR-652-5p', 'Chemical', '-', (35, 45))	('miR-652-5p', 'Var', (35, 45))
552433	32343702	The down regulation of miR-652-5p in the blood samples of ESCC indicated miR-652-5p is a potential blood biomarker for the prognosis of ESCC.	('down regulation', 'NegReg', (4, 19))	('miR-652-5p', 'Chemical', '-', (23, 33))	('ESCC', 'Disease', (136, 140))	('miR-652-5p', 'Gene', (23, 33))	('miR-652-5p', 'Chemical', '-', (73, 83))	('miR-652-5p', 'Var', (73, 83))
552435	32343702	The authors also provided adequate molecular mechanistic work to elucidate the molecular pathways that are altered in miR-652-5p downregulated ESCC, and epigenetic evidences for its downregulation.	('miR-652-5p', 'Var', (118, 128))	('downregulated', 'NegReg', (129, 142))	('ESCC', 'Disease', (143, 147))	('miR-652-5p', 'Chemical', '-', (118, 128))
552436	32343702	have studied the biological functions, clinical significance and therapeutic implications of miR-652-5p in ESCC.	('miR-652-5p', 'Var', (93, 103))	('ESCC', 'Disease', (107, 111))	('miR-652-5p', 'Chemical', '-', (93, 103))
552437	32343702	They found that down-regulated expression of miR-652-5p by hypermethylation of its promoter may contribute to the progression of ESCC.	('hypermethylation', 'Var', (59, 75))	('ESCC', 'Disease', (129, 133))	('miR-652-5p', 'Chemical', '-', (45, 55))	('expression', 'MPA', (31, 41))	('miR-652-5p', 'Var', (45, 55))	('down-regulated', 'NegReg', (16, 30))
552451	29997523	Pooled results showed that high level of HMGA2 was significantly correlated with poor OS (HR = 1.88, 95% confidence interval (CI) = 1.68-2.11, P < 0.001) and poor DFS (HR = 2.49, 95% CI = 1.44-4.28, P = 0.001) in cancer patients.	('poor', 'Disease', (158, 162))	('high level', 'Var', (27, 37))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('cancer', 'Disease', 'MESH:D009369', (213, 219))	('patients', 'Species', '9606', (220, 228))	('HMGA2', 'Gene', '8091', (41, 46))	('cancer', 'Disease', (213, 219))	('HMGA2', 'Gene', (41, 46))	('poor OS', 'Disease', (81, 88))
552452	29997523	However, subgroup analyses revealed that the high expressed HMGA2 was associated with poor OS in head and neck cancer, gastric cancer and colorectal cancer, but not esophageal cancer and ovarian cancer.	('ovarian cancer', 'Disease', 'MESH:D010051', (187, 201))	('esophageal cancer', 'Disease', (165, 182))	('HMGA2', 'Gene', '8091', (60, 65))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('gastric cancer', 'Disease', (119, 133))	('colorectal cancer', 'Phenotype', 'HP:0003003', (138, 155))	('ovarian cancer', 'Disease', (187, 201))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('gastric cancer', 'Disease', 'MESH:D013274', (119, 133))	('high expressed', 'Var', (45, 59))	('ovarian cancer', 'Phenotype', 'HP:0100615', (187, 201))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('HMGA2', 'Gene', (60, 65))	('head and neck cancer', 'Phenotype', 'HP:0012288', (97, 117))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('gastric cancer', 'Phenotype', 'HP:0012126', (119, 133))	('colorectal cancer', 'Disease', 'MESH:D015179', (138, 155))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('esophageal cancer', 'Disease', 'MESH:D004938', (165, 182))	('poor OS', 'Disease', (86, 93))	('colorectal cancer', 'Disease', (138, 155))	('head and neck cancer', 'Disease', 'MESH:D006258', (97, 117))
552487	29997523	Pooled results also demonstrated that high HMGA2 expression was associated with shorter DFS in cancer patients (HR = 2.49, 95% CI = 1.44-4.28) (Figure 3).	('DFS', 'MPA', (88, 91))	('HMGA2', 'Gene', '8091', (43, 48))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('patients', 'Species', '9606', (102, 110))	('cancer', 'Disease', (95, 101))	('expression', 'MPA', (49, 59))	('high', 'Var', (38, 42))	('HMGA2', 'Gene', (43, 48))	('shorter', 'NegReg', (80, 87))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))
552491	29997523	Results show that high expression level of HMGA2 was associated with poor OS in gastric cancer (HR = 1.94, 95% CI = 1.42-2.65, P < 0.001), head and neck cancer (HR = 1.77, 95% CI = 1.37-2.29, P < 0.001), colorectal cancer (HR = 2.13, 95% CI = 1.48-3.05, P < 0.001) and other cancers (HR = 2, 95% CI = 1.68-2.40, P < 0.001), but not esophageal cancer (HR = 1.15, 95% CI = 0.55-2.37, P = 0.712) and ovarian cancer (HR = 1.07, 95% CI = 0.55-2.37, P = 0.712).	('gastric cancer', 'Disease', (80, 94))	('HMGA2', 'Gene', '8091', (43, 48))	('poor OS', 'Disease', (69, 76))	('colorectal cancer', 'Phenotype', 'HP:0003003', (204, 221))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('cancers', 'Disease', 'MESH:D009369', (275, 282))	('cancer', 'Phenotype', 'HP:0002664', (343, 349))	('high expression level', 'Var', (18, 39))	('gastric cancer', 'Disease', 'MESH:D013274', (80, 94))	('head and neck cancer', 'Phenotype', 'HP:0012288', (139, 159))	('ovarian cancer', 'Disease', 'MESH:D010051', (397, 411))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))	('colorectal cancer', 'Disease', 'MESH:D015179', (204, 221))	('HMGA2', 'Gene', (43, 48))	('gastric cancer', 'Phenotype', 'HP:0012126', (80, 94))	('cancers', 'Phenotype', 'HP:0002664', (275, 282))	('colorectal cancer', 'Disease', (204, 221))	('cancers', 'Disease', (275, 282))	('head and neck cancer', 'Disease', 'MESH:D006258', (139, 159))	('ovarian cancer', 'Disease', (397, 411))	('esophageal cancer', 'Disease', 'MESH:D004938', (332, 349))	('cancer', 'Phenotype', 'HP:0002664', (275, 281))	('ovarian cancer', 'Phenotype', 'HP:0100615', (397, 411))	('esophageal cancer', 'Disease', (332, 349))
552492	29997523	As a result, we found that high level of HMGA2 was related with poor OS in 13 types of cancers.	('cancers', 'Disease', (87, 94))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cancers', 'Phenotype', 'HP:0002664', (87, 94))	('HMGA2', 'Gene', (41, 46))	('HMGA2', 'Gene', '8091', (41, 46))	('related', 'Reg', (51, 58))	('cancers', 'Disease', 'MESH:D009369', (87, 94))	('high level', 'Var', (27, 37))	('poor OS', 'Disease', (64, 71))
552498	29997523	Results showed that there was no publication bias existed in studies on HMGA2 overexpression in association with OS (P = 0.597.	('overexpression', 'Var', (78, 92))	('HMGA2', 'Gene', '8091', (72, 77))	('HMGA2', 'Gene', (72, 77))
552504	29997523	Significant association between high expressed HMGA2 and poor overall survival in patients was found in 14 types of cancers.	('HMGA2', 'Gene', '8091', (47, 52))	('high expressed', 'Var', (32, 46))	('poor', 'NegReg', (57, 61))	('patients', 'Species', '9606', (82, 90))	('HMGA2', 'Gene', (47, 52))	('cancers', 'Disease', 'MESH:D009369', (116, 123))	('cancers', 'Phenotype', 'HP:0002664', (116, 123))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cancers', 'Disease', (116, 123))	('overall survival', 'MPA', (62, 78))
552506	29997523	Considering the TCGA datasets and our meta-analysis, we identified correlation between high HMGA2 expression and head and neck cancer, pancreatic ductal adenocarcinoma, ccRCC, hepatocellular carcinoma, esophageal adenocarcinoma and ovarian carcinoma, except breast cancer and gastric cancer.	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (135, 167))	('esophageal adenocarcinoma and ovarian carcinoma', 'Disease', 'MESH:D010051', (202, 249))	('cancer', 'Phenotype', 'HP:0002664', (265, 271))	('hepatocellular carcinoma', 'Disease', (176, 200))	('high', 'Var', (87, 91))	('ccRCC', 'Phenotype', 'HP:0006770', (169, 174))	('gastric cancer', 'Disease', (276, 290))	('HMGA2', 'Gene', (92, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (191, 200))	('carcinoma', 'Phenotype', 'HP:0030731', (240, 249))	('breast cancer', 'Phenotype', 'HP:0003002', (258, 271))	('carcinoma', 'Phenotype', 'HP:0030731', (158, 167))	('esophageal adenocarcinoma', 'Phenotype', 'HP:0011459', (202, 227))	('head and neck cancer', 'Phenotype', 'HP:0012288', (113, 133))	('correlation', 'Interaction', (67, 78))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('breast cancer', 'Disease', 'MESH:D001943', (258, 271))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (135, 167))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (176, 200))	('gastric cancer', 'Disease', 'MESH:D013274', (276, 290))	('breast cancer', 'Disease', (258, 271))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (232, 249))	('cancer', 'Phenotype', 'HP:0002664', (284, 290))	('HMGA2', 'Gene', '8091', (92, 97))	('pancreatic ductal adenocarcinoma', 'Disease', (135, 167))	('carcinoma', 'Phenotype', 'HP:0030731', (218, 227))	('head and neck cancer', 'Disease', 'MESH:D006258', (113, 133))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (176, 200))	('gastric cancer', 'Phenotype', 'HP:0012126', (276, 290))	('ccRCC', 'Disease', (169, 174))	('expression', 'MPA', (98, 108))
552514	29997523	The meta-analysis results suggested that high expression of HMGA2 was associated with shorter OS and DFS in patients with cancers.	('patients', 'Species', '9606', (108, 116))	('HMGA2', 'Gene', '8091', (60, 65))	('shorter', 'NegReg', (86, 93))	('high expression', 'Var', (41, 56))	('HMGA2', 'Gene', (60, 65))	('DFS', 'CPA', (101, 104))	('cancers', 'Disease', 'MESH:D009369', (122, 129))	('cancers', 'Phenotype', 'HP:0002664', (122, 129))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('cancers', 'Disease', (122, 129))
552518	29997523	Patients with high expressed HMGA2 in ccRCC, head and neck cancer, hepatocellular carcinoma and pancreatic ductal adenocarcinoma showed a significant shorter OS than patients with a low level of HMGA2 expression.	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (67, 91))	('head and neck cancer', 'Phenotype', 'HP:0012288', (45, 65))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (96, 128))	('HMGA2', 'Gene', (29, 34))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (67, 91))	('Patients', 'Species', '9606', (0, 8))	('HMGA2', 'Gene', (195, 200))	('ccRCC', 'Disease', (38, 43))	('pancreatic ductal adenocarcinoma', 'Disease', (96, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('head and neck cancer', 'Disease', 'MESH:D006258', (45, 65))	('high expressed', 'Var', (14, 28))	('hepatocellular carcinoma', 'Disease', (67, 91))	('ccRCC', 'Phenotype', 'HP:0006770', (38, 43))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (96, 128))	('shorter', 'NegReg', (150, 157))	('HMGA2', 'Gene', '8091', (29, 34))	('HMGA2', 'Gene', '8091', (195, 200))	('carcinoma', 'Phenotype', 'HP:0030731', (82, 91))	('patients', 'Species', '9606', (166, 174))
552527	29997523	A study conducted by suggested silencing HMGA2 expression in ovarian cancer cells could have a therapeutic effect on ovarian cancer.	('ovarian cancer', 'Disease', 'MESH:D010051', (61, 75))	('silencing', 'Var', (31, 40))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('ovarian cancer', 'Phenotype', 'HP:0100615', (117, 131))	('ovarian cancer', 'Disease', 'MESH:D010051', (117, 131))	('ovarian cancer', 'Disease', (61, 75))	('HMGA2', 'Gene', '8091', (41, 46))	('ovarian cancer', 'Disease', (117, 131))	('HMGA2', 'Gene', (41, 46))	('ovarian cancer', 'Phenotype', 'HP:0100615', (61, 75))
552627	28607605	Therefore, this finding approves that Notch2 signaling plays an important role in mutation of lung adenocarcinoma, especially in never-smoking female at east Asia.	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('mutation', 'Var', (82, 90))	('lung adenocarcinoma', 'Disease', (94, 113))	('Notch2', 'Gene', (38, 44))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (94, 113))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (94, 113))	('Notch2', 'Gene', '4853', (38, 44))
552643	28607605	Our study suggested that lung adenocarcinoma patients with both high expressions of Notch1 and Notch3 had poor DFS by Kaplan-Meier survival curve.	('Notch3', 'Gene', '4854', (95, 101))	('carcinoma', 'Phenotype', 'HP:0030731', (35, 44))	('Notch3', 'Gene', (95, 101))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (25, 44))	('Notch1', 'Gene', (84, 90))	('high expressions', 'Var', (64, 80))	('patients', 'Species', '9606', (45, 53))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (25, 44))	('Notch1', 'Gene', '4851', (84, 90))	('lung adenocarcinoma', 'Disease', (25, 44))
552653	28607605	EGFR mutation status was not analysis at our study, but the mutation rate was relative higher in east Asia.	('mutation', 'Var', (60, 68))	('higher', 'Reg', (87, 93))	('EGFR', 'Gene', (0, 4))	('east Asia', 'Disease', (97, 106))	('EGFR', 'Gene', '1956', (0, 4))
552658	26754874	The chromosome 3q26 OncCassette: a multigenic driver of human cancer Recurrent copy number variations (CNVs) are genetic alterations commonly observed in human tumors.	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('human', 'Species', '9606', (154, 159))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('human', 'Species', '9606', (56, 61))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('copy number variations', 'Var', (79, 101))	('tumors', 'Disease', (160, 166))	('tumors', 'Disease', 'MESH:D009369', (160, 166))
552659	26754874	One of the most frequent CNVs in human tumors involves copy number gains (CNGs) at chromosome 3q26, which is estimated to occur in >20% of human tumors.	('tumors', 'Disease', (39, 45))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('CNG', 'Chemical', '-', (74, 77))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('copy number gains', 'Var', (55, 72))	('tumors', 'Disease', (145, 151))	('tumors', 'Phenotype', 'HP:0002664', (145, 151))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('human', 'Species', '9606', (33, 38))	('human', 'Species', '9606', (139, 144))	('tumors', 'Disease', 'MESH:D009369', (145, 151))	('tumors', 'Disease', 'MESH:D009369', (39, 45))
552660	26754874	The high prevalence and frequent occurrence of 3q26 CNG suggest that it drives the biology of tumors harboring this genetic alteration.	('3q26 CNG', 'Var', (47, 55))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('tumors', 'Disease', (94, 100))	('CNG', 'Chemical', '-', (52, 55))
552665	26754874	Integration of available genetic, genomic, biochemical and functional data demonstrates that SOX2, ECT2, PRKCI and PIK3CA are cooperating oncogenes that function within an integrated cell signaling network that drives a highly aggressive, stem-like phenotype in LSCC tumors harboring 3q26 amplification.	('drives', 'PosReg', (211, 217))	('SCC', 'Gene', '6317', (263, 266))	('SOX2', 'Gene', (93, 97))	('SOX2', 'Gene', '6657', (93, 97))	('PRKCI', 'Gene', '5584', (105, 110))	('PRKCI', 'Gene', (105, 110))	('tumor', 'Phenotype', 'HP:0002664', (267, 272))	('3q26 amplification', 'Var', (284, 302))	('tumors', 'Phenotype', 'HP:0002664', (267, 273))	('PIK3CA', 'Gene', (115, 121))	('SCC', 'Gene', (263, 266))	('tumors', 'Disease', (267, 273))	('PIK3CA', 'Gene', '5290', (115, 121))	('tumors', 'Disease', 'MESH:D009369', (267, 273))
552667	26754874	Genomic analysis indicates that the 3q26 OncCassette also operates in other major tumor types that exhibit frequent 3q26 CNGs, including head and neck squamous cell carcinoma (HNSCC), ovarian serous cancer and cervical cancer.	('neck squamous cell carcinoma (HNSCC), ovarian serous cancer', 'Disease', 'MESH:D000077195', (146, 205))	('ovarian serous cancer', 'Phenotype', 'HP:0012887', (184, 205))	('cancer', 'Phenotype', 'HP:0002664', (199, 205))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('3q26 CNGs', 'Var', (116, 125))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (137, 174))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('cervical cancer', 'Disease', 'MESH:D002583', (210, 225))	('CNG', 'Chemical', '-', (121, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (165, 174))	('cervical cancer', 'Disease', (210, 225))	('tumor', 'Disease', (82, 87))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (151, 174))
552669	26754874	Cancer is a disease of progressive genetic alterations that conspire to drive a cellular phenotype characterized by uncontrolled growth, aggressive invasive behavior, enhanced survival, evasion of immune surveillance, and resistance to therapeutic interventions.	('enhanced', 'PosReg', (167, 175))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))	('alterations', 'Var', (43, 54))	('aggressive invasive behavior', 'Phenotype', 'HP:0000718', (137, 165))	('survival', 'CPA', (176, 184))
552671	26754874	In M-type tumors, somatic mutations that either activate oncogenes or inactivate tumor suppressor genes are the predominant genetic alterations.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('M-type tumors', 'Disease', 'MESH:C566367', (3, 16))	('tumor', 'Disease', (10, 15))	('activate', 'PosReg', (48, 56))	('tumors', 'Phenotype', 'HP:0002664', (10, 16))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('oncogenes', 'Protein', (57, 66))	('mutations', 'Var', (26, 35))	('M-type tumors', 'Disease', (3, 16))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('inactivate', 'NegReg', (70, 80))	('tumor', 'Disease', (81, 86))
552672	26754874	In contrast, in C-type tumors recurrent gene copy number variations (CNVs) are the predominant genetic alterations.	('C-type tumors', 'Disease', 'MESH:D019698', (16, 29))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('C-type tumors', 'Disease', (16, 29))	('gene copy number variations', 'Var', (40, 67))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))
552673	26754874	Many of the key oncogenic driver mutations occurring in M-type tumors have been identified, molecularly characterized, functionally validated, and in some cases therapeutically targeted; prominent examples include EGFR, BRAF and PI3KCA mutations that are key drivers of oncogenic phenotypes.	('M-type tumors', 'Disease', (56, 69))	('M-type tumors', 'Disease', 'MESH:C566367', (56, 69))	('PI3', 'Gene', (229, 232))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('EGFR', 'Gene', '1956', (214, 218))	('BRAF', 'Gene', '673', (220, 224))	('mutations', 'Var', (236, 245))	('EGFR', 'Gene', (214, 218))	('BRAF', 'Gene', (220, 224))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('PI3', 'Gene', '5266', (229, 232))
552674	26754874	Likewise, prevalent recurring inactivating mutations in tumor suppressor genes, including those in TP53, CDKN2A (p16), PTEN and APC, have been well-documented and molecularly characterized.	('p16', 'Gene', (113, 116))	('TP53', 'Gene', (99, 103))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('CDKN2A', 'Gene', (105, 111))	('tumor', 'Disease', (56, 61))	('CDKN2A', 'Gene', '1029', (105, 111))	('APC', 'Disease', 'MESH:D011125', (128, 131))	('p16', 'Gene', '1029', (113, 116))	('PTEN', 'Gene', (119, 123))	('PTEN', 'Gene', '5728', (119, 123))	('TP53', 'Gene', '7157', (99, 103))	('APC', 'Disease', (128, 131))	('inactivating mutations', 'Var', (30, 52))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
552676	26754874	Comparative Genomic Hybridization (CGH) studies and more recent global genomic initiatives, such as The Cancer Genome Atlas (TCGA) project, have revealed that C-type tumors exhibit frequent and recurrent CNVs, both CNGs, or deletions, often encompassing large chromosomal regions (including, in some cases, entire chromosomal arms).	('C-type tumors', 'Disease', 'MESH:D019698', (159, 172))	('CNG', 'Chemical', '-', (215, 218))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('C-type tumors', 'Disease', (159, 172))	('CNGs', 'Disease', (215, 219))	('deletions', 'Var', (224, 233))	('CNVs', 'Var', (204, 208))	('Cancer', 'Disease', (104, 110))	('Cancer', 'Disease', 'MESH:D009369', (104, 110))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))	('Cancer', 'Phenotype', 'HP:0002664', (104, 110))
552678	26754874	Recurrent CNVs involving loss of specific chromosomal regions are in some cases associated with loss of specific tumor suppressor genes; the most prevalent CNV in human tumors involves loss of chromosome 9p21 containing the prominent tumor suppressor target CDKN2A (reviewed in).	('tumor', 'Disease', (113, 118))	('tumor', 'Disease', (234, 239))	('loss', 'Var', (185, 189))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('tumors', 'Disease', 'MESH:D009369', (169, 175))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('human', 'Species', '9606', (163, 168))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumors', 'Phenotype', 'HP:0002664', (169, 175))	('tumor', 'Disease', (169, 174))	('CDKN2A', 'Gene', (258, 264))	('tumor', 'Disease', 'MESH:D009369', (234, 239))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('tumors', 'Disease', (169, 175))	('CDKN2A', 'Gene', '1029', (258, 264))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))
552679	26754874	However, for many recurrent CNVs involving chromosome loss, the relevant tumor suppressor(s) remain to be conclusively identified and functionally validated.	('tumor', 'Disease', (73, 78))	('chromosome loss', 'Var', (43, 58))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Disease', 'MESH:D009369', (73, 78))
552682	26754874	Examples of CNGs driving oncogene activation through increased expression include amplification of CMYC at chromosome 8q24, cyclin D1 (CCND1) at chromosome 11q23, and EGFR at chromosome 7p11.	('CNG', 'Chemical', '-', (12, 15))	('cyclin D1', 'Gene', '595', (124, 133))	('CCND1', 'Gene', (135, 140))	('cyclin D1', 'Gene', (124, 133))	('CMYC', 'Gene', '4609', (99, 103))	('amplification', 'Var', (82, 95))	('expression', 'MPA', (63, 73))	('CMYC', 'Gene', (99, 103))	('CCND1', 'Gene', '595', (135, 140))	('increased', 'PosReg', (53, 62))	('activation', 'PosReg', (34, 44))	('EGFR', 'Gene', '1956', (167, 171))	('oncogene', 'Gene', (25, 33))	('EGFR', 'Gene', (167, 171))
552683	26754874	However, unlike the situation involving specific oncogenic somatic mutations, in which a distinct mutation specifically defines the molecular target of the genetic alteration, the relevant target(s) of many recurrent cancer-associated CNGs are not readily apparent in the context of tumor biology.	('CNG', 'Chemical', '-', (235, 238))	('tumor', 'Disease', 'MESH:D009369', (283, 288))	('mutation', 'Var', (98, 106))	('tumor', 'Phenotype', 'HP:0002664', (283, 288))	('cancer', 'Disease', (217, 223))	('cancer', 'Disease', 'MESH:D009369', (217, 223))	('tumor', 'Disease', (283, 288))	('cancer', 'Phenotype', 'HP:0002664', (217, 223))
552684	26754874	Herein, we describe the genomic, genetic and functional characterization of the most common CNG event in human tumors, 3q26 amplification.	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('CNG', 'Chemical', '-', (92, 95))	('tumors', 'Disease', 'MESH:D009369', (111, 117))	('tumors', 'Disease', (111, 117))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('3q26 amplification', 'Var', (119, 137))	('human', 'Species', '9606', (105, 110))
552688	26754874	A GISTIC score of +1 or +2 was considered to indicate the presence of significant CNG in that gene.	('TIC', 'Disease', (5, 8))	('TIC', 'Disease', 'None', (5, 8))	('CNG', 'Chemical', '-', (82, 85))	('CNG', 'Var', (82, 85))	('TIC', 'Phenotype', 'HP:0100033', (5, 8))
552695	26754874	Tumors were segregated into two groups; those exhibiting CNG at the locus for the gene being interrogated and those exhibiting no CNG at that locus.	('CNG', 'Chemical', '-', (57, 60))	('CNG', 'Var', (57, 60))	('CNG', 'Chemical', '-', (130, 133))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))
552697	26754874	35 of the 50 genes were found to exhibit expression that was significantly higher in tumors harboring CNG at that gene than in those not exhibiting CNG.	('tumors', 'Disease', 'MESH:D009369', (85, 91))	('expression', 'MPA', (41, 51))	('higher', 'PosReg', (75, 81))	('CNG', 'Chemical', '-', (102, 105))	('CNG', 'Var', (102, 105))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))	('CNG', 'Chemical', '-', (148, 151))	('tumors', 'Disease', (85, 91))
552701	26754874	Independent CGH analyses revealed prevalent 3q26 CNVs in cervical (77-90%), esophageal (50-69%), HNSCC (50-91%), LSCC (77-85%), ovarian serous (36-51%) and endometrial serous cancers (50%).	('cervical', 'Disease', (57, 65))	('3q26', 'Gene', (44, 48))	('SCC', 'Gene', '6317', (99, 102))	('endometrial serous cancers', 'Disease', (156, 182))	('SCC', 'Gene', (114, 117))	('esophageal', 'Disease', (76, 86))	('endometrial serous cancers', 'Disease', 'MESH:D016889', (156, 182))	('SCC', 'Gene', '6317', (114, 117))	('ovarian serous', 'Disease', 'MESH:D010051', (128, 142))	('cancers', 'Phenotype', 'HP:0002664', (175, 182))	('ovarian serous', 'Disease', (128, 142))	('SCC', 'Gene', (99, 102))	('CNVs', 'Var', (49, 53))	('cancer', 'Phenotype', 'HP:0002664', (175, 181))
552702	26754874	3q26 CNGs were also observed in 76% of small cell lung cancers (SCLC), though the estimate of prevalence in SCLC must be considered tentative given the extremely small sample size of these studies.	('small cell lung cancers', 'Phenotype', 'HP:0030357', (39, 62))	('3q26', 'Var', (0, 4))	('small cell lung cancers', 'Disease', (39, 62))	('lung cancers', 'Phenotype', 'HP:0100526', (50, 62))	('CNG', 'Chemical', '-', (5, 8))	('SCLC', 'Disease', (64, 68))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('SCLC', 'Disease', 'MESH:D018288', (64, 68))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (39, 61))	('small cell lung cancers', 'Disease', 'MESH:D055752', (39, 62))	('observed', 'Reg', (20, 28))	('cancers', 'Phenotype', 'HP:0002664', (55, 62))	('lung cancer', 'Phenotype', 'HP:0100526', (50, 61))	('SCLC', 'Disease', (108, 112))	('SCLC', 'Disease', 'MESH:D018288', (108, 112))
552706	26754874	Analysis revealed extremely prevalent chromosome 3q26 CNGs in LSCC (85%), esophageal (85%), ovarian serous (85%), cervical (78%), HNSCC (75%) and bladder (60%) cancers.	('cancers', 'Disease', 'MESH:D009369', (160, 167))	('CNG', 'Chemical', '-', (54, 57))	('bladder', 'Disease', (146, 153))	('chromosome', 'Var', (38, 48))	('SCC', 'Gene', (63, 66))	('cancers', 'Disease', (160, 167))	('cancers', 'Phenotype', 'HP:0002664', (160, 167))	('SCC', 'Gene', (132, 135))	('cervical', 'Disease', (114, 122))	('CNGs', 'Var', (54, 58))	('SCC', 'Gene', '6317', (63, 66))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('ovarian serous', 'Disease', (92, 106))	('prevalent', 'Reg', (28, 37))	('ovarian serous', 'Disease', 'MESH:D010051', (92, 106))	('SCC', 'Gene', '6317', (132, 135))	('esophageal', 'Disease', (74, 84))
552707	26754874	3q26 CNGs were of intermediate prevalence (20-35%) in stomach, lung adenocarcinoma, breast, uterine and liver cancers, and of lower, but significant, prevalence (10-18%) in prostate, pancreatic, sarcoma, glioblastoma, kidney and colorectal cancers (Figure 1).	('glioblastoma', 'Disease', 'MESH:D005909', (204, 216))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (63, 82))	('CNG', 'Chemical', '-', (5, 8))	('breast', 'Disease', (84, 90))	('cancers', 'Phenotype', 'HP:0002664', (240, 247))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (63, 82))	('glioblastoma', 'Disease', (204, 216))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('glioblastoma', 'Phenotype', 'HP:0012174', (204, 216))	('kidney and colorectal cancers', 'Disease', 'MESH:D015179', (218, 247))	('uterine', 'Disease', (92, 99))	('liver cancers', 'Disease', 'MESH:D006528', (104, 117))	('sarcoma', 'Disease', 'MESH:D012509', (195, 202))	('cancers', 'Phenotype', 'HP:0002664', (110, 117))	('pancreatic', 'Disease', 'MESH:D010195', (183, 193))	('sarcoma', 'Disease', (195, 202))	('3q26', 'Var', (0, 4))	('prostate', 'Disease', (173, 181))	('liver cancers', 'Phenotype', 'HP:0002896', (104, 117))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('lung adenocarcinoma', 'Disease', (63, 82))	('sarcoma', 'Phenotype', 'HP:0100242', (195, 202))	('pancreatic', 'Disease', (183, 193))	('stomach', 'Disease', (54, 61))	('liver cancers', 'Disease', (104, 117))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
552708	26754874	Our analysis confirms earlier CGH studies demonstrating very high frequency 3q26 CNGs in many tumors types (i.e.	('CNG', 'Chemical', '-', (81, 84))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumors', 'Disease', 'MESH:D009369', (94, 100))	('tumors', 'Disease', (94, 100))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('3q26 CNGs', 'Var', (76, 85))
552712	26754874	Several lines of experimental evidence indicate that 3q26 CNG is an oncogenic driver in affected tumors.	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('CNG', 'Chemical', '-', (58, 61))	('tumors', 'Disease', (97, 103))	('tumors', 'Phenotype', 'HP:0002664', (97, 103))	('3q26 CNG', 'Var', (53, 61))	('tumors', 'Disease', 'MESH:D009369', (97, 103))
552713	26754874	First, 3q26 CNGs are observed in precancerous lesions, demonstrating that this is an early event in tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Disease', (100, 105))	('precancerous lesions', 'Disease', 'MESH:D011230', (33, 53))	('precancerous lesions', 'Disease', (33, 53))	('3q26 CNGs', 'Var', (7, 16))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('CNG', 'Chemical', '-', (12, 15))
552715	26754874	Both the CIS and the subsequent LSCC lesion harbored specific 3q26 CNG, indicating occurrence of this event prior to progression to malignant LSCC.	('SCC', 'Gene', (143, 146))	('SCC', 'Gene', '6317', (33, 36))	('3q26 CNG', 'Var', (62, 70))	('SCC', 'Gene', '6317', (143, 146))	('SCC', 'Gene', (33, 36))	('CNG', 'Chemical', '-', (67, 70))
552716	26754874	Similarly, 3q26 CNGs were found to be present in both early stage pre-invasive lung squamous cell lesions and in invasive LSCCs, albeit at a higher frequency in the more advanced lesions.	('CNG', 'Chemical', '-', (16, 19))	('lung squamous cell lesions', 'Disease', (79, 105))	('3q26', 'Var', (11, 15))	('SCC', 'Gene', '6317', (123, 126))	('squamous cell lesions', 'Phenotype', 'HP:0002860', (84, 105))	('lung squamous cell lesions', 'Disease', 'MESH:D002294', (79, 105))	('SCC', 'Gene', (123, 126))
552718	26754874	Since 3q26 CNGs are detected in pre-invasive lesions that progress to LSCC, 3q26 CNG, and/or increased expression of 3q26 target genes, has been proposed as a biomarker of early pre-cancerous lesions with a high potential for progression to invasive LSCC.	('cancerous lesions', 'Disease', 'MESH:D009062', (182, 199))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('CNG', 'Chemical', '-', (81, 84))	('cancerous lesions', 'Disease', (182, 199))	('SCC', 'Gene', '6317', (251, 254))	('increased', 'PosReg', (93, 102))	('expression', 'MPA', (103, 113))	('3q26 CNG', 'Var', (76, 84))	('SCC', 'Gene', '6317', (71, 74))	('CNG', 'Chemical', '-', (11, 14))	('SCC', 'Gene', (71, 74))	('SCC', 'Gene', (251, 254))
552719	26754874	Similar findings of 3q26 CNGs in early malignant or preneoplastic lesions have been observed in cervical cancer and HNSCC.	('preneoplastic lesions', 'CPA', (52, 73))	('neoplastic lesions', 'Phenotype', 'HP:0002664', (55, 73))	('SCC', 'Gene', (118, 121))	('CNG', 'Chemical', '-', (25, 28))	('3q26 CNGs', 'Var', (20, 29))	('cervical cancer', 'Disease', 'MESH:D002583', (96, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('SCC', 'Gene', '6317', (118, 121))	('cervical cancer', 'Disease', (96, 111))
552720	26754874	CGH analysis of normal cervical epithelium, dysplasias (subcategorized as mild, moderate and severe), and stage I invasive carcinomas, revealed that 3q26 CNGs are the most consistent chromosomal aberration occurring in dysplastic cells that progress to invasive cervical carcinoma.	('3q26 CNGs', 'Var', (149, 158))	('dysplastic', 'Disease', 'MESH:D004416', (219, 229))	('carcinomas', 'Disease', (123, 133))	('CNG', 'Chemical', '-', (154, 157))	('dysplastic', 'Disease', (219, 229))	('invasive cervical carcinoma', 'Disease', 'MESH:D002575', (253, 280))	('invasive cervical carcinoma', 'Disease', (253, 280))	('dysplasias', 'Disease', (44, 54))	('chromosomal aberration', 'Phenotype', 'HP:0040012', (183, 205))	('progress', 'PosReg', (241, 249))	('dysplasias', 'Disease', 'MESH:D004476', (44, 54))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))	('carcinomas', 'Phenotype', 'HP:0030731', (123, 133))	('carcinomas', 'Disease', 'MESH:D002277', (123, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (271, 280))
552721	26754874	Likewise, a study of HNSCC found 3q26 CNGs in 3% of normal mucosa, 25% of premalignant tissue, and 56% of invasive HNSCCs, while a second report found frequent 3q CNGs in low grade HNSCCs.	('3q26 CNGs', 'Var', (33, 42))	('SCC', 'Gene', '6317', (23, 26))	('SCC', 'Gene', (117, 120))	('SCC', 'Gene', (183, 186))	('invasive HNSCCs', 'Disease', 'MESH:D000077195', (106, 121))	('SCC', 'Gene', '6317', (183, 186))	('CNG', 'Chemical', '-', (38, 41))	('SCC', 'Gene', '6317', (117, 120))	('SCC', 'Gene', (23, 26))	('CNG', 'Chemical', '-', (163, 166))	('invasive HNSCCs', 'Disease', (106, 121))
552724	26754874	In primary HNSCC tumors, 3q26 CNG is associated with significantly higher rates of tumor recurrence and cancer-related death, and with shorter disease-specific survival when compared to tumors not harboring 3q26 CNG.	('tumor', 'Disease', (83, 88))	('tumors', 'Disease', (17, 23))	('tumor', 'Disease', (186, 191))	('cancer', 'Disease', (104, 110))	('tumor', 'Disease', 'MESH:D009369', (83, 88))	('HNSCC tumors', 'Disease', 'MESH:D000077195', (11, 23))	('3q26 CNG', 'Var', (25, 33))	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('tumors', 'Phenotype', 'HP:0002664', (186, 192))	('HNSCC tumors', 'Disease', (11, 23))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('higher', 'PosReg', (67, 73))	('tumor', 'Disease', (17, 22))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('tumors', 'Disease', (186, 192))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('disease-specific survival', 'CPA', (143, 168))	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('CNG', 'Chemical', '-', (30, 33))	('CNG', 'Chemical', '-', (212, 215))	('tumors', 'Disease', 'MESH:D009369', (186, 192))	('shorter', 'NegReg', (135, 142))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))
552725	26754874	Consistent with this observation, 3q26 CNG is more frequently observed in high grade ovarian serous tumors when compared to low grade tumors, suggesting an association with disease progression and acquisition of an aggressive phenotype in ovarian cancer.	('tumors', 'Phenotype', 'HP:0002664', (134, 140))	('ovarian serous tumors', 'Disease', 'MESH:D010051', (85, 106))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('3q26 CNG', 'Var', (34, 42))	('tumors', 'Disease', (134, 140))	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('association', 'Interaction', (156, 167))	('ovarian serous tumors', 'Disease', (85, 106))	('observed', 'Reg', (62, 70))	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumors', 'Disease', 'MESH:D009369', (134, 140))	('ovarian cancer', 'Disease', 'MESH:D010051', (239, 253))	('ovarian serous tumors', 'Phenotype', 'HP:0012887', (85, 106))	('tumors', 'Disease', (100, 106))	('CNG', 'Chemical', '-', (39, 42))	('ovarian cancer', 'Disease', (239, 253))	('tumors', 'Disease', 'MESH:D009369', (100, 106))	('ovarian cancer', 'Phenotype', 'HP:0100615', (239, 253))
552726	26754874	Similarly, 3q26 CNGs were found at significantly higher frequencies in metastatic esophageal squamous cell carcinomas when compared to those tumors that did not metastasize.	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('esophageal squamous cell carcinomas', 'Disease', (82, 117))	('CNG', 'Chemical', '-', (16, 19))	('esophageal squamous cell carcinomas', 'Disease', 'MESH:D000077277', (82, 117))	('carcinomas', 'Phenotype', 'HP:0030731', (107, 117))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (93, 116))	('tumors', 'Disease', (141, 147))	('tumors', 'Disease', 'MESH:D009369', (141, 147))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('higher frequencies', 'PosReg', (49, 67))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (93, 117))	('3q26 CNGs', 'Var', (11, 20))
552727	26754874	These findings support a role for 3q26 CNG in tumor aggressiveness, progression and/or clinical outcome in essentially all of the major tumor types that frequently harbor this alteration.	('3q26 CNG', 'Var', (34, 42))	('tumor aggressiveness', 'Disease', 'MESH:D001523', (46, 66))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('CNG', 'Chemical', '-', (39, 42))	('tumor', 'Disease', (46, 51))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('tumor aggressiveness', 'Disease', (46, 66))	('aggressiveness', 'Phenotype', 'HP:0000718', (52, 66))	('tumor', 'Disease', (136, 141))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
552728	26754874	The third line of evidence that 3q26 CNG is an oncogenic driver comes from a genetic analysis of strain-specific differences in susceptibility to tobacco smoke carcinogen-induced LSCC in the mouse.	('CNG', 'Chemical', '-', (37, 40))	('SCC', 'Gene', (180, 183))	('3q26', 'Var', (32, 36))	('mouse', 'Species', '10090', (191, 196))	('SCC', 'Gene', '6317', (180, 183))	('tobacco', 'Species', '4097', (146, 153))
552740	26754874	We further reasoned that the most critical target genes within this group would exhibit expression that is driven by 3q26 CNG in human tumors.	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('3q26 CNG', 'Var', (117, 125))	('CNG', 'Chemical', '-', (122, 125))	('tumors', 'Disease', (135, 141))	('tumors', 'Disease', 'MESH:D009369', (135, 141))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))	('human', 'Species', '9606', (129, 134))	('expression', 'MPA', (88, 98))
552746	26754874	The genomic analysis above indicates that 3q26 CNG drives tumorigenesis by coordinately overexpressing a set of core genes that functionally interact within a signaling network.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('3q26 CNG', 'Var', (42, 50))	('CNG', 'Chemical', '-', (47, 50))	('overexpressing', 'PosReg', (88, 102))	('drives', 'PosReg', (51, 57))	('tumor', 'Disease', 'MESH:D009369', (58, 63))
552754	26754874	Likewise, ectopic expression of SOX2 in HNSCC cells promotes "stemness" while SOX2 knockdown (KD) in HNSCC TICs reduces self-renewal, chemoresistance and tumorigenicity, demonstrating a functional role for SOX2 in 3q26 amplified cancers.	('cancers', 'Disease', 'MESH:D009369', (229, 236))	('knockdown', 'Var', (83, 92))	('tumor', 'Disease', (154, 159))	('TIC', 'Disease', (107, 110))	('SOX2', 'Gene', '6657', (32, 36))	('SOX2', 'Gene', (32, 36))	('tumor', 'Disease', 'MESH:D009369', (154, 159))	('promotes', 'PosReg', (52, 60))	('KD', 'Disease', 'MESH:C537017', (94, 96))	('SCC', 'Gene', '6317', (42, 45))	('TICs', 'Phenotype', 'HP:0100033', (107, 111))	('ectopic expression', 'Var', (10, 28))	('SOX2', 'Gene', (206, 210))	('reduces', 'NegReg', (112, 119))	('SOX2', 'Gene', '6657', (206, 210))	('cancers', 'Phenotype', 'HP:0002664', (229, 236))	('SCC', 'Gene', (42, 45))	('cancers', 'Disease', (229, 236))	('TIC', 'Phenotype', 'HP:0100033', (107, 110))	('SOX2', 'Gene', '6657', (78, 82))	('SCC', 'Gene', '6317', (103, 106))	('SOX2', 'Gene', (78, 82))	('tumor', 'Phenotype', 'HP:0002664', (154, 159))	('cancer', 'Phenotype', 'HP:0002664', (229, 235))	('self-renewal', 'CPA', (120, 132))	('SCC', 'Gene', (103, 106))	('chemoresistance', 'CPA', (134, 149))	('TIC', 'Disease', 'None', (107, 110))
552757	26754874	Gene amplification drives SOX2 expression in lung, esophageal and other squamous cell cancers.	('lung', 'Disease', (45, 49))	('squamous cell cancers', 'Disease', (72, 93))	('squamous cell cancers', 'Phenotype', 'HP:0002860', (72, 93))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('drives', 'Reg', (19, 25))	('esophageal', 'Disease', (51, 61))	('Gene amplification', 'Var', (0, 18))	('expression', 'MPA', (31, 41))	('squamous cell cancers', 'Disease', 'MESH:D002294', (72, 93))	('cancers', 'Phenotype', 'HP:0002664', (86, 93))	('SOX2', 'Gene', '6657', (26, 30))	('SOX2', 'Gene', (26, 30))
552758	26754874	ShRNA-mediated knockdown of SOX2 expression and candidate neighboring genes in 3q26 amplified and non-amplified cancer cell lines revealed that inhibition of SOX2 expression had the largest differential anti-proliferative effect on 3q26 amplified SCC cell lines.	('SOX2', 'Gene', '6657', (28, 32))	('SCC', 'Gene', (247, 250))	('SOX2', 'Gene', (28, 32))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('inhibition', 'Var', (144, 154))	('SCC', 'Gene', '6317', (247, 250))	('anti-proliferative effect', 'CPA', (203, 228))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('SOX2', 'Gene', (158, 162))	('SOX2', 'Gene', '6657', (158, 162))
552773	26754874	These findings are consistent with the prevalence of chromosome 3q26 CNGs in LSCCs and the relatively rare occurrence of 3q26 CNGs in LADCs.	('SCC', 'Gene', '6317', (78, 81))	('chromosome 3q26 CNGs', 'Var', (53, 73))	('CNG', 'Chemical', '-', (126, 129))	('CNG', 'Chemical', '-', (69, 72))	('SCC', 'Gene', (78, 81))
552775	26754874	In addition to LSCC, ovarian tumors also show tumor-specific amplification at 3q26.	('ovarian tumors', 'Disease', 'MESH:D010051', (21, 35))	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumor', 'Disease', (46, 51))	('SCC', 'Gene', (16, 19))	('amplification', 'Var', (61, 74))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('tumor', 'Disease', (29, 34))	('SCC', 'Gene', '6317', (16, 19))	('ovarian tumors', 'Disease', (21, 35))	('ovarian tumors', 'Phenotype', 'HP:0100615', (21, 35))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
552776	26754874	Ect2 is overexpressed in ovarian tumors harboring ECT2 amplification compared to whole normal ovary indicating that tumor-specific ECT2 amplification also drives Ect2 expression in ovarian tumors.	('amplification', 'Var', (55, 68))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('ovarian tumors', 'Phenotype', 'HP:0100615', (181, 195))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('expression', 'MPA', (167, 177))	('tumors', 'Phenotype', 'HP:0002664', (189, 195))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('tumor', 'Disease', (33, 38))	('ovarian tumors', 'Disease', (25, 39))	('ovarian tumors', 'Disease', 'MESH:D010051', (25, 39))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('Ect2', 'Gene', (162, 166))	('overexpressed', 'PosReg', (8, 21))	('tumors', 'Phenotype', 'HP:0002664', (33, 39))	('ovarian tumors', 'Disease', (181, 195))	('ovarian tumors', 'Disease', 'MESH:D010051', (181, 195))	('tumor', 'Disease', (189, 194))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('tumor', 'Disease', (116, 121))	('ovarian tumors', 'Phenotype', 'HP:0100615', (25, 39))
552777	26754874	Thus, a major mechanism driving Ect2 expression is tumor-specific amplification of ECT2 as part of the 3q26 amplicon.	('amplification', 'Var', (66, 79))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumor', 'Disease', (51, 56))	('ECT2', 'Gene', (83, 87))	('Ect2', 'Gene', (32, 36))	('tumor', 'Disease', 'MESH:D009369', (51, 56))
552780	26754874	PIK3CA is frequently targeted for oncogenic activation either by somatic mutation or CNG as part of the 3q26 amplicon.	('CNG', 'Chemical', '-', (85, 88))	('PIK3CA', 'Gene', '5290', (0, 6))	('CNG', 'Var', (85, 88))	('PIK3CA', 'Gene', (0, 6))
552781	26754874	PIK3CA is frequently mutated in breast, endometrial, colorectal, urinary tract and ovarian cancers (reviewed in).	('cancers', 'Phenotype', 'HP:0002664', (91, 98))	('urinary tract and ovarian cancers', 'Disease', 'MESH:D014571', (65, 98))	('colorectal', 'Disease', (53, 63))	('ovarian cancer', 'Phenotype', 'HP:0100615', (83, 97))	('endometrial', 'Disease', (40, 51))	('PIK3CA', 'Gene', (0, 6))	('ovarian cancers', 'Phenotype', 'HP:0100615', (83, 98))	('PIK3CA', 'Gene', '5290', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('breast', 'Disease', (32, 38))	('mutated', 'Var', (21, 28))	('colorectal', 'Disease', 'MESH:D015179', (53, 63))
552782	26754874	These "hot spot" mutations, H1047R, E545K and E542K, are non-synonymous missense mutations that confer constitutive kinase activity.	('E545K', 'Var', (36, 41))	('E542K', 'Var', (46, 51))	('H1047R', 'Mutation', 'rs121913279', (28, 34))	('constitutive kinase activity', 'MPA', (103, 131))	('E542K', 'Mutation', 'rs121913273', (46, 51))	('H1047R', 'Var', (28, 34))	('E545K', 'Mutation', 'rs104886003', (36, 41))
552783	26754874	Amplification of PIK3CA has been found in primary ovarian tumors and ovarian cancer cell lines, primary cervical tumors and cervical cancer cell lines, HNSCC primary tumors and LSCC.	('SCC', 'Gene', '6317', (154, 157))	('primary ovarian tumors', 'Disease', (42, 64))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('SCC', 'Gene', '6317', (178, 181))	('PIK3CA', 'Gene', '5290', (17, 23))	('primary ovarian tumors', 'Disease', 'MESH:D010051', (42, 64))	('SCC', 'Gene', (154, 157))	('tumors', 'Phenotype', 'HP:0002664', (166, 172))	('primary cervical tumors', 'Disease', 'MESH:D002583', (96, 119))	('HNSCC primary tumors', 'Disease', (152, 172))	('SCC', 'Gene', (178, 181))	('ovarian cancer', 'Disease', (69, 83))	('found', 'Reg', (33, 38))	('ovarian cancer', 'Phenotype', 'HP:0100615', (69, 83))	('cervical cancer', 'Disease', (124, 139))	('cervical cancer', 'Disease', 'MESH:D002583', (124, 139))	('HNSCC primary tumors', 'Disease', 'MESH:D000077195', (152, 172))	('tumors', 'Phenotype', 'HP:0002664', (58, 64))	('PIK3CA', 'Gene', (17, 23))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('cervical tumors', 'Phenotype', 'HP:0030159', (104, 119))	('Amplification', 'Var', (0, 13))	('primary cervical tumors', 'Disease', (96, 119))	('ovarian tumors', 'Phenotype', 'HP:0100615', (50, 64))	('ovarian cancer', 'Disease', 'MESH:D010051', (69, 83))
552786	26754874	CNGs in PIK3CA have been shown to correlate with its mRNA expression in HNSCC cell primary tumors.	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('CNGs', 'Var', (0, 4))	('primary tumors', 'Disease', (83, 97))	('primary tumors', 'Disease', 'MESH:D009369', (83, 97))	('CNG', 'Chemical', '-', (0, 3))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('SCC', 'Gene', (74, 77))	('PIK3CA', 'Gene', (8, 14))	('mRNA expression', 'MPA', (53, 68))	('SCC', 'Gene', '6317', (74, 77))	('PIK3CA', 'Gene', '5290', (8, 14))
552787	26754874	CNGs in PIK3CA are prevalent in thyroid cancer, particularly follicular thyroid carcinoma (FTC) and anaplastic thyroid carcinoma (ATC) sub-types which exhibit 24% and 42% CNG, respectively.	('CNGs', 'Var', (0, 4))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (72, 89))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (111, 128))	('CNG', 'Chemical', '-', (171, 174))	('thyroid cancer', 'Phenotype', 'HP:0002890', (32, 46))	('follicular thyroid carcinoma', 'Disease', (61, 89))	('PIK3CA', 'Gene', '5290', (8, 14))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('anaplastic thyroid carcinoma', 'Disease', 'MESH:D065646', (100, 128))	('anaplastic thyroid carcinoma', 'Phenotype', 'HP:0011779', (100, 128))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('thyroid cancer', 'Disease', (32, 46))	('CNG', 'Chemical', '-', (0, 3))	('PIK3CA', 'Gene', (8, 14))	('follicular thyroid carcinoma', 'Phenotype', 'HP:0006731', (61, 89))	('prevalent', 'Reg', (19, 28))	('follicular thyroid carcinoma', 'Disease', 'MESH:D018263', (61, 89))	('thyroid cancer', 'Disease', 'MESH:D013964', (32, 46))	('anaplastic thyroid carcinoma', 'Disease', (100, 128))
552788	26754874	Several studies have shown that PIK3CA amplification is associated with overexpression of p110alpha in thyroid tumors.	('PIK3CA', 'Gene', '5290', (32, 38))	('p110alpha', 'Gene', (90, 99))	('p110alpha', 'Gene', '5290', (90, 99))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('amplification', 'Var', (39, 52))	('thyroid tumors', 'Disease', (103, 117))	('thyroid tumors', 'Disease', 'MESH:D013959', (103, 117))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('associated', 'Reg', (56, 66))	('overexpression', 'MPA', (72, 86))	('PIK3CA', 'Gene', (32, 38))
552789	26754874	Endometrial tumors with 3q amplification overexpress PIK3CA when compared with unamplified tumors.	('tumors', 'Disease', (91, 97))	('tumors', 'Disease', 'MESH:D009369', (91, 97))	('tumors', 'Phenotype', 'HP:0002664', (91, 97))	('Endometrial tumors', 'Disease', 'MESH:D016889', (0, 18))	('PIK3CA', 'Gene', '5290', (53, 59))	('3q amplification', 'Var', (24, 40))	('overexpress', 'PosReg', (41, 52))	('PIK3CA', 'Gene', (53, 59))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('tumors', 'Disease', (12, 18))	('tumors', 'Phenotype', 'HP:0002664', (12, 18))	('Endometrial tumors', 'Disease', (0, 18))	('tumors', 'Disease', 'MESH:D009369', (12, 18))
552790	26754874	In a separate study, 9 of 15 (60.0%) gastric cancer cell lines and 17 of 55 (30.9%) primary gastric carcinomas harbored PIK3CA amplification, whereas no normal and benign tumor tissues showed abnormal amplification.	('PIK3CA', 'Gene', (120, 126))	('gastric carcinomas', 'Disease', 'MESH:D013274', (92, 110))	('gastric carcinomas', 'Disease', (92, 110))	('gastric cancer', 'Disease', (37, 51))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('gastric cancer', 'Disease', 'MESH:D013274', (37, 51))	('carcinomas', 'Phenotype', 'HP:0030731', (100, 110))	('tumor', 'Disease', 'MESH:D009369', (171, 176))	('PIK3CA', 'Gene', '5290', (120, 126))	('gastric cancer', 'Phenotype', 'HP:0012126', (37, 51))	('tumor', 'Phenotype', 'HP:0002664', (171, 176))	('tumor', 'Disease', (171, 176))	('amplification', 'Var', (127, 140))
552791	26754874	In addition, amplification of PIK3CA in gastric tumor cell lines was strongly associated with increased transcript level.	('PIK3CA', 'Gene', (30, 36))	('transcript level', 'MPA', (104, 120))	('increased', 'PosReg', (94, 103))	('PIK3CA', 'Gene', '5290', (30, 36))	('gastric tumor', 'Disease', (40, 53))	('amplification', 'Var', (13, 26))	('gastric tumor', 'Disease', 'MESH:D013274', (40, 53))	('gastric tumor', 'Phenotype', 'HP:0006753', (40, 53))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
552797	26754874	PKCiota expression is predictive of poor outcome in patients with bile duct, lung, ovarian, pancreatic and prostate cancers.	('PKCiota expression', 'Var', (0, 18))	('pancreatic', 'Disease', 'MESH:D010195', (92, 102))	('ovarian', 'Disease', (83, 90))	('ovarian', 'Disease', 'MESH:D010051', (83, 90))	('pancreatic', 'Disease', (92, 102))	('cancers', 'Disease', 'MESH:D009369', (116, 123))	('cancers', 'Phenotype', 'HP:0002664', (116, 123))	('bile duct', 'Disease', (66, 75))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cancers', 'Disease', (116, 123))	('lung', 'Disease', (77, 81))	('prostate cancers', 'Phenotype', 'HP:0012125', (107, 123))	('patients', 'Species', '9606', (52, 60))
552802	26754874	PRKCI is frequently amplified in NSCLC, and amplification drives PKCiota expression in NSCLC primary tumors and established cell lines.	('NSCLC', 'Disease', (87, 92))	('NSCLC', 'Disease', 'MESH:D002289', (87, 92))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('amplification', 'Var', (44, 57))	('PRKCI', 'Gene', (0, 5))	('expression', 'MPA', (73, 83))	('PRKCI', 'Gene', '5584', (0, 5))	('NSCLC', 'Disease', (33, 38))	('NSCLC primary tumors', 'Disease', (87, 107))	('tumors', 'Phenotype', 'HP:0002664', (101, 107))	('NSCLC', 'Disease', 'MESH:D002289', (33, 38))	('NSCLC primary tumors', 'Disease', 'MESH:D009369', (87, 107))	('PKCiota', 'Gene', (65, 72))
552803	26754874	Disruption of PKCiota signaling blocks transformed growth of NSCLC cell lines with PRKCI amplification, demonstrating that PKCiota is a critical target of 3q26 amplification in NSCLC.	('NSCLC', 'Disease', (177, 182))	('NSCLC', 'Disease', (61, 66))	('amplification', 'Var', (89, 102))	('PRKCI', 'Gene', '5584', (83, 88))	('NSCLC', 'Disease', 'MESH:D002289', (177, 182))	('NSCLC', 'Disease', 'MESH:D002289', (61, 66))	('PRKCI', 'Gene', (83, 88))	('Disruption', 'Var', (0, 10))
552804	26754874	PRKCI amplification is associated with lymph node metastases in ESCC, and PKCiota promotes metastasis of ESCC cell lines.	('promotes', 'PosReg', (82, 90))	('SCC', 'Gene', (65, 68))	('SCC', 'Gene', '6317', (106, 109))	('metastases', 'Disease', (50, 60))	('PRKCI', 'Gene', (0, 5))	('metastasis', 'CPA', (91, 101))	('SCC', 'Gene', '6317', (65, 68))	('PRKCI', 'Gene', '5584', (0, 5))	('amplification', 'Var', (6, 19))	('metastases', 'Disease', 'MESH:D009362', (50, 60))	('associated', 'Reg', (23, 33))	('SCC', 'Gene', (106, 109))
552806	26754874	PRKCI is frequently amplified and overexpressed in ovarian serous cancer and PRKCI amplification predicts poor patient survival.	('ovarian serous cancer', 'Disease', 'MESH:D010051', (51, 72))	('PRKCI', 'Gene', '5584', (77, 82))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('poor', 'NegReg', (106, 110))	('PRKCI', 'Gene', (77, 82))	('ovarian serous cancer', 'Disease', (51, 72))	('PRKCI', 'Gene', (0, 5))	('PRKCI', 'Gene', '5584', (0, 5))	('patient', 'Species', '9606', (111, 118))	('ovarian serous cancer', 'Phenotype', 'HP:0012887', (51, 72))	('amplification', 'Var', (83, 96))	('overexpressed', 'PosReg', (34, 47))
552809	26754874	As described above, each of the four 3q26 nodal genes, SOX2, ECT2, PIK3CA and PRKCI, have individually been shown to function in the establishment and maintenance of the transformed phenotype of 3q26 driven tumors.	('PIK3CA', 'Gene', '5290', (67, 73))	('SOX2', 'Gene', (55, 59))	('ECT2', 'Gene', (61, 65))	('SOX2', 'Gene', '6657', (55, 59))	('PRKCI', 'Gene', '5584', (78, 83))	('3q26', 'Var', (195, 199))	('function', 'Reg', (117, 125))	('PRKCI', 'Gene', (78, 83))	('tumors', 'Phenotype', 'HP:0002664', (207, 213))	('tumor', 'Phenotype', 'HP:0002664', (207, 212))	('tumors', 'Disease', 'MESH:D009369', (207, 213))	('tumors', 'Disease', (207, 213))	('PIK3CA', 'Gene', (67, 73))
552810	26754874	It is also quite evident that these genes operate in a tumor environment in which they are coordinately amplified and overexpressed in tumors harboring 3q26 CNGs, demonstrating that these genes are genetically integrated with the oncogenic behavior of these tumors.	('tumor', 'Phenotype', 'HP:0002664', (258, 263))	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('tumors', 'Disease', (258, 264))	('tumors', 'Phenotype', 'HP:0002664', (258, 264))	('tumor', 'Disease', (258, 263))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('CNG', 'Chemical', '-', (157, 160))	('tumor', 'Disease', (135, 140))	('tumors', 'Disease', 'MESH:D009369', (258, 264))	('tumor', 'Disease', (55, 60))	('tumors', 'Disease', (135, 141))	('tumors', 'Disease', 'MESH:D009369', (135, 141))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))	('tumor', 'Disease', 'MESH:D009369', (258, 263))	('3q26 CNGs', 'Var', (152, 161))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
552814	26754874	SKIL/SNO, which resides at 3q26, was found to be consistently over-expressed in ESCC cell lines and primary tumors that exhibit 3q26 amplification, suggesting that this gene is a potential target of 3q26 amplification.	('SCC', 'Gene', '6317', (81, 84))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('SNO', 'Gene', (5, 8))	('over-expressed', 'PosReg', (62, 76))	('primary tumors', 'Disease', (100, 114))	('amplification', 'Var', (133, 146))	('SKIL', 'Gene', (0, 4))	('primary tumors', 'Disease', 'MESH:D009369', (100, 114))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('3q26', 'Gene', (128, 132))	('SCC', 'Gene', (81, 84))	('SKIL', 'Gene', '6498', (0, 4))	('SNO', 'Gene', '22904', (5, 8))
552820	26754874	Like PKCiota and Par6, RNAi-mediated knockdown of Ect2 in NSCLC cells inhibits Rac1 activation and transformation.	('NSCLC', 'Disease', (58, 63))	('NSCLC', 'Disease', 'MESH:D002289', (58, 63))	('knockdown', 'Var', (37, 46))	('inhibits', 'NegReg', (70, 78))	('Par6', 'Gene', (17, 21))	('Rac1', 'Gene', '5879', (79, 83))	('Ect2', 'Gene', (50, 54))	('Par6', 'Gene', '50855', (17, 21))	('Rac1', 'Gene', (79, 83))
552832	26754874	This study led us to hypothesize that the oncogenic function of PKCiota is to establish and maintain a TIC phenotype in LSCC tumors harboring 3q26 CNG as well.	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('3q26 CNG', 'Var', (142, 150))	('tumors', 'Disease', 'MESH:D009369', (125, 131))	('SCC', 'Gene', (121, 124))	('tumors', 'Disease', (125, 131))	('CNG', 'Chemical', '-', (147, 150))	('TIC', 'Phenotype', 'HP:0100033', (103, 106))	('tumors', 'Phenotype', 'HP:0002664', (125, 131))	('SCC', 'Gene', '6317', (121, 124))	('TIC', 'Disease', 'None', (103, 106))	('TIC', 'Disease', (103, 106))
552841	26754874	The realization that 3q26 CNG drives oncogenesis through coordinated overexpression of biochemically and functionally linked genes presents both challenges and opportunities for therapeutic intervention.	('drives', 'PosReg', (30, 36))	('overexpression', 'PosReg', (69, 83))	('oncogenesis', 'CPA', (37, 48))	('3q26 CNG', 'Var', (21, 29))	('CNG', 'Chemical', '-', (26, 29))
552851	26754874	Our initial clinical experience with these agents has demonstrated proof of principle for PKCiota inhibition using ATM or ANF as a viable therapeutic approach in both LSCC and ovarian serous cancer, tumor types exhibiting frequent 3q26 CNGs.	('SCC', 'Gene', (168, 171))	('tumor', 'Disease', (199, 204))	('CNG', 'Chemical', '-', (236, 239))	('3q26 CNGs', 'Var', (231, 240))	('ovarian serous cancer', 'Phenotype', 'HP:0012887', (176, 197))	('ovarian serous cancer', 'Disease', 'MESH:D010051', (176, 197))	('SCC', 'Gene', '6317', (168, 171))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('ovarian serous cancer', 'Disease', (176, 197))	('ANF', 'Chemical', 'MESH:D001310', (122, 125))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('PKCiota', 'Enzyme', (90, 97))
552859	26754874	Further functional characterization of the 3q26 OncCassette holds considerable promise of revealing further opportunities for development of novel combined therapeutic intervention strategies that target unique vulnerabilities of 3q26 CNG driven tumors.	('3q26', 'Var', (230, 234))	('tumors', 'Phenotype', 'HP:0002664', (246, 252))	('CNG', 'Chemical', '-', (235, 238))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('tumors', 'Disease', (246, 252))	('tumors', 'Disease', 'MESH:D009369', (246, 252))
552862	32894652	Copy number alterations are correlated with aberrant CBX3 expression in LUAD .	('expression', 'MPA', (58, 68))	('LUAD', 'Phenotype', 'HP:0030078', (72, 76))	('CBX3', 'Gene', (53, 57))	('Copy number alterations', 'Var', (0, 23))	('LUAD', 'Disease', (72, 76))	('aberrant', 'Var', (44, 52))	('CBX3', 'Gene', '11335', (53, 57))	('correlated', 'Reg', (28, 38))
552871	32894652	Aberrant expression of CBX3 in LUAD is correlated with DNA copy number alteration.	('Aberrant', 'Var', (0, 8))	('correlated', 'Reg', (39, 49))	('LUAD', 'Phenotype', 'HP:0030078', (31, 35))	('CBX3', 'Gene', (23, 27))	('expression', 'MPA', (9, 19))	('CBX3', 'Gene', '11335', (23, 27))
552885	32894652	In hepatocellular carcinoma, abnormal mRNA expressions of CBX1-3, CBX6 and CBX8 were independent prognostic predictors for shorter overall survival (OS), and the mutation rate of CBX family members was up to 51%, which was also observed to be negatively associated with OS and DFS [10].	('carcinoma', 'Phenotype', 'HP:0030731', (18, 27))	('CBX8', 'Gene', '57332', (75, 79))	('DFS [10]', 'Disease', (277, 285))	('CBX', 'Gene', '10951', (66, 69))	('CBX', 'Gene', '10951', (58, 61))	('CBX', 'Gene', '10951', (179, 182))	('mutation', 'Var', (162, 170))	('CBX1-3', 'Gene', '10951;84733;11335', (58, 64))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (3, 27))	('CBX1-3', 'Gene', (58, 64))	('CBX', 'Gene', (75, 78))	('shorter', 'NegReg', (123, 130))	('CBX8', 'Gene', (75, 79))	('CBX', 'Gene', (58, 61))	('CBX', 'Gene', (179, 182))	('CBX', 'Gene', (66, 69))	('abnormal mRNA expressions', 'Var', (29, 54))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (3, 27))	('hepatocellular carcinoma', 'Disease', (3, 27))	('overall survival', 'MPA', (131, 147))	('CBX6', 'Gene', '23466', (66, 70))	('CBX', 'Gene', '10951', (75, 78))	('CBX6', 'Gene', (66, 70))
552946	32894652	Studies have shown that stage-specific epigenetic changes can serve as powerful and reliable tools for early diagnosis and prognosis monitoring, as well as effective therapeutic targets for patients with lung cancer [15].	('epigenetic changes', 'Var', (39, 57))	('lung cancer', 'Disease', 'MESH:D008175', (204, 215))	('patients', 'Species', '9606', (190, 198))	('lung cancer', 'Disease', (204, 215))	('lung cancer', 'Phenotype', 'HP:0100526', (204, 215))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
552974	32894652	Among all of the mechanisms, genetic and epigenetic alterations, including CNA, DNA methylation and somatic mutations, commonly cause aberrant gene expression accompanied by anomalous cancer cell behavior.	('CNA', 'Disease', (75, 78))	('methylation', 'Var', (84, 95))	('mutations', 'Var', (108, 117))	('aberrant gene expression', 'MPA', (134, 158))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('anomalous cancer', 'Disease', 'MESH:D009369', (174, 190))	('epigenetic alterations', 'Var', (41, 63))	('cause', 'Reg', (128, 133))	('anomalous cancer', 'Disease', (174, 190))
552976	32894652	The results displayed that aberrant expression of CBX3 may be related with CNA, rather than DNA methylation.	('CNA', 'Disease', (75, 78))	('aberrant', 'Var', (27, 35))	('CBX3', 'Gene', (50, 54))	('related', 'Reg', (62, 69))	('CBX3', 'Gene', '11335', (50, 54))	('expression', 'MPA', (36, 46))
553028	28469313	The rate of diagnosis of thoracic disease is improved by appling EBUS-TBNA applied, while patients get little hurt during the diagnosis.	('improved', 'PosReg', (45, 53))	('diagnosis', 'MPA', (12, 21))	('appling', 'Var', (57, 64))	('thoracic disease', 'Disease', (25, 41))	('thoracic disease', 'Disease', 'MESH:D013896', (25, 41))	('patients', 'Species', '9606', (90, 98))	('EBUS-TBNA', 'Gene', (65, 74))
553052	27899982	Survival analysis indicated that the prognosis of patients with a high SOX2 expression was significantly better than those with a low SOX2 expression.	('better', 'PosReg', (105, 111))	('patients', 'Species', '9606', (50, 58))	('expression', 'MPA', (76, 86))	('SOX2', 'Gene', (71, 75))	('high', 'Var', (66, 70))	('SOX2', 'Gene', '6657', (71, 75))	('SOX2', 'Gene', '6657', (134, 138))	('SOX2', 'Gene', (134, 138))
553061	27899982	The abnormal expression of SOX2 is associated with the occurrence and development of many malignant carcinomas, such as esophageal, breast, gastric and colon carcinoma.	('malignant carcinomas', 'Disease', 'MESH:D009369', (90, 110))	('esophageal', 'Disease', (120, 130))	('gastric', 'Disease', (140, 147))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('carcinomas', 'Phenotype', 'HP:0030731', (100, 110))	('abnormal', 'Var', (4, 12))	('malignant carcinomas', 'Disease', (90, 110))	('expression', 'MPA', (13, 23))	('esophageal', 'Disease', 'MESH:D004941', (120, 130))	('associated with', 'Reg', (35, 50))	('breast', 'Disease', (132, 138))	('colon carcinoma', 'Disease', (152, 167))	('carcinoma', 'Phenotype', 'HP:0030731', (158, 167))	('colon carcinoma', 'Disease', 'MESH:D015179', (152, 167))	('SOX2', 'Gene', (27, 31))	('SOX2', 'Gene', '6657', (27, 31))
553073	27899982	The SOX2 antibody was purchased from Bethyl Laboratories, Inc. (A301-741A; Montgomery, TX, USA).	('SOX2', 'Gene', (4, 8))	('A301-741A;', 'Var', (64, 74))	('SOX2', 'Gene', '6657', (4, 8))
553081	27899982	The expression of SOX2 in NSCLC tissues showed 29 cases (22.8%) of negative (-) expression, 53 cases (41.7%) of positive (+) expression, 28 cases (22.8%) of positive (++) expression, and 16 cases (12.6%) of positive (+++) expression.	('SOX2', 'Gene', '6657', (18, 22))	('positive', 'PosReg', (112, 120))	('SOX2', 'Gene', (18, 22))	('NSCLC', 'Phenotype', 'HP:0030358', (26, 31))	('expression', 'MPA', (125, 135))	('negative', 'NegReg', (67, 75))	('NSCLC', 'Disease', (26, 31))	('positive (++', 'Var', (157, 169))	('NSCLC', 'Disease', 'MESH:D002289', (26, 31))
553083	27899982	Positive (++) and (+++) was considered a high SOX2 expression, and negative (-) and positive (+) were considered a low SOX2 expression.	('+++', 'Var', (19, 22))	('SOX2', 'Gene', '6657', (46, 50))	('SOX2', 'Gene', (46, 50))	('SOX2', 'Gene', (119, 123))	('SOX2', 'Gene', '6657', (119, 123))	('Positive (++', 'Var', (0, 12))
553092	27899982	The prognosis of patients with a high SOX2 expression was significantly better than those with a low SOX2 expression (Fig 2).	('SOX2', 'Gene', (38, 42))	('high', 'Var', (33, 37))	('SOX2', 'Gene', '6657', (101, 105))	('SOX2', 'Gene', (101, 105))	('better', 'PosReg', (72, 78))	('patients', 'Species', '9606', (17, 25))	('SOX2', 'Gene', '6657', (38, 42))
553116	25198510	Prognostic Value Analysis of Mutational and Clinicopathological Factors in Non-Small Cell Lung Cancer Targeting activating oncogenic driver mutations in lung adenocarcinoma has led to prolonged survival in patients harboring these specific genetic alterations.	('Cancer', 'Phenotype', 'HP:0002664', (95, 101))	('carcinoma', 'Phenotype', 'HP:0030731', (163, 172))	('lung adenocarcinoma', 'Disease', (153, 172))	('Non-Small Cell Lung Cancer', 'Disease', 'MESH:D002289', (75, 101))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (153, 172))	('Non-Small Cell Lung Cancer', 'Phenotype', 'HP:0030358', (75, 101))	('patients', 'Species', '9606', (206, 214))	('Small Cell Lung Cancer', 'Phenotype', 'HP:0030357', (79, 101))	('mutations', 'Var', (140, 149))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (153, 172))	('Lung Cancer', 'Phenotype', 'HP:0100526', (90, 101))	('Non-Small Cell Lung Cancer', 'Disease', (75, 101))	('activating', 'PosReg', (112, 122))
553120	25198510	EGFR, KRAS, HER2, BRAF mutation and ALK fusion were mutated in 25.2%, 6.5%, 1.9%, 0.9% and 3.7% of lung adenocarcinomas.	('KRAS', 'Gene', '3845', (6, 10))	('EGFR', 'Gene', (0, 4))	('mutated', 'Var', (52, 59))	('HER2', 'Gene', (12, 16))	('ALK', 'Gene', '238', (36, 39))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (99, 118))	('HER2', 'Gene', '2064', (12, 16))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('lung adenocarcinomas', 'Disease', (99, 119))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (99, 119))	('BRAF', 'Gene', '673', (18, 22))	('EGFR', 'Gene', '1956', (0, 4))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (99, 119))	('carcinomas', 'Phenotype', 'HP:0030731', (109, 119))	('BRAF', 'Gene', (18, 22))	('KRAS', 'Gene', (6, 10))	('ALK', 'Gene', (36, 39))
553122	25198510	Lung adenocarcinoma with EGFR and KRAS mutations showed no significant difference in Disease-free Survival (DFS) and Overall Survival (OS).	('KRAS', 'Gene', '3845', (34, 38))	('EGFR', 'Gene', (25, 29))	('Disease-free', 'Disease', (85, 97))	('mutations', 'Var', (39, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (10, 19))	('Lung adenocarcinoma', 'Phenotype', 'HP:0030078', (0, 19))	('Lung adenocarcinoma', 'Disease', (0, 19))	('Lung adenocarcinoma', 'Disease', 'MESH:D000077192', (0, 19))	('KRAS', 'Gene', (34, 38))	('EGFR', 'Gene', '1956', (25, 29))
553123	25198510	Cox Multi-variate analysis revealed that only N stage and HER2 mutation were independent predictors of worse overall survival (HR = 1.653, 95% CI 1.219-2.241, P = 0.001; HR = 12.344, 95% CI 2.615-58.275, P = 0.002).	('worse', 'NegReg', (103, 108))	('mutation', 'Var', (63, 71))	('overall survival', 'MPA', (109, 125))	('HER2', 'Gene', (58, 62))	('HER2', 'Gene', '2064', (58, 62))
553125	25198510	These results indicate that dividing lung adenocarcinoma into molecular subtypes according to oncogenic driver mutations doesn't predict survival difference of the disease.	('mutations', 'Var', (111, 120))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (37, 56))	('carcinoma', 'Phenotype', 'HP:0030731', (47, 56))	('lung adenocarcinoma', 'Disease', (37, 56))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (37, 56))
553131	25198510	Uncovering of activating mutations in tyrosine kinase domain of EGFR has led to developing and wide use of gefetinib and erlotinib, which has proven to be effective in the treatment for part of EGFR mutated lung adenocarcinomas.	('mutated', 'Var', (199, 206))	('erlotinib', 'Chemical', 'MESH:D000069347', (121, 130))	('mutations', 'Var', (25, 34))	('lung adenocarcinomas', 'Disease', (207, 227))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (207, 226))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (207, 227))	('carcinomas', 'Phenotype', 'HP:0030731', (217, 227))	('men', 'Species', '9606', (177, 180))	('activating', 'PosReg', (14, 24))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (207, 227))	('EGFR', 'Gene', '1956', (194, 198))	('EGFR', 'Gene', (194, 198))	('EGFR', 'Gene', '1956', (64, 68))	('EGFR', 'Gene', (64, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (217, 226))	('gefetinib', 'Chemical', '-', (107, 116))
553132	25198510	According to specific oncogenic driver mutations, lung adenocarcinoma is divided to molecular subtypes such as EGFR, KRAS, ALK, HER2, BRAF and so on.	('KRAS', 'Gene', (117, 121))	('HER2', 'Gene', (128, 132))	('ALK', 'Gene', (123, 126))	('HER2', 'Gene', '2064', (128, 132))	('EGFR', 'Gene', '1956', (111, 115))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (50, 69))	('BRAF', 'Gene', '673', (134, 138))	('KRAS', 'Gene', '3845', (117, 121))	('mutations', 'Var', (39, 48))	('lung adenocarcinoma', 'Disease', (50, 69))	('EGFR', 'Gene', (111, 115))	('BRAF', 'Gene', (134, 138))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (50, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (60, 69))	('ALK', 'Gene', '238', (123, 126))
553135	25198510	Frequent mutation, amplification or loss of FGFR1, PTEN, PIK3CA, NFE2L2, NRF have been identified in comprehensive genomic study in lung squamous cell carcinoma.	('PIK3CA', 'Gene', '5290', (57, 63))	('loss', 'NegReg', (36, 40))	('PTEN', 'Gene', (51, 55))	('amplification', 'Var', (19, 32))	('FGFR1', 'Gene', '2260', (44, 49))	('NRF', 'Gene', (73, 76))	('PTEN', 'Gene', '5728', (51, 55))	('mutation', 'Var', (9, 17))	('carcinoma', 'Phenotype', 'HP:0030731', (151, 160))	('PIK3CA', 'Gene', (57, 63))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (132, 160))	('identified', 'Reg', (87, 97))	('NFE2L2', 'Gene', '4780', (65, 71))	('FGFR1', 'Gene', (44, 49))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (137, 160))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (132, 160))	('lung squamous cell carcinoma', 'Disease', (132, 160))	('NFE2L2', 'Gene', (65, 71))	('NRF', 'Gene', '55922', (73, 76))
553137	25198510	Recently, human cancer genome sequencing studies have revealed somatic mutaitons in the core promoter of human telomerase reverse transcriptase (hTERT).	('hTERT', 'Gene', '7015', (145, 150))	('cancer', 'Disease', 'MESH:D009369', (16, 22))	('human', 'Species', '9606', (10, 15))	('telomerase reverse transcriptase', 'Gene', (111, 143))	('cancer', 'Disease', (16, 22))	('hTERT', 'Gene', (145, 150))	('telomerase reverse transcriptase', 'Gene', '7015', (111, 143))	('mutaitons', 'Var', (71, 80))	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('human', 'Species', '9606', (105, 110))
553138	25198510	Either C228T or C250T of hTERT promoter mutations elevated transcriptional activity of hTERT gene in the luciferase reporter assays.	('C228T', 'Var', (7, 12))	('hTERT', 'Gene', '7015', (25, 30))	('elevated', 'PosReg', (50, 58))	('transcriptional activity', 'MPA', (59, 83))	('hTERT', 'Gene', (25, 30))	('hTERT', 'Gene', (87, 92))	('C228T', 'Mutation', 'rs774905136', (7, 12))	('C250T', 'Mutation', 'rs372811772', (16, 21))	('hTERT', 'Gene', '7015', (87, 92))	('C250T', 'Var', (16, 21))
553139	25198510	The tumor types with frequent hTERT promoter mutations included Melanoma (71%), Glioma (51%), Myxoid liposarcoma (79%), Urothelial carcinoma of bladder (66%).	('tumor', 'Disease', (4, 9))	('Myxoid liposarcoma', 'Disease', 'MESH:D018208', (94, 112))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('Melanoma', 'Disease', (64, 72))	('liposarcoma', 'Phenotype', 'HP:0012034', (101, 112))	('Myxoid liposarcoma', 'Phenotype', 'HP:0012268', (94, 112))	('hTERT', 'Gene', '7015', (30, 35))	('Melanoma', 'Phenotype', 'HP:0002861', (64, 72))	('Glioma', 'Disease', 'MESH:D005910', (80, 86))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('Urothelial carcinoma of bladder', 'Phenotype', 'HP:0006740', (120, 151))	('Glioma', 'Phenotype', 'HP:0009733', (80, 86))	('hTERT', 'Gene', (30, 35))	('Myxoid liposarcoma', 'Disease', (94, 112))	('mutations', 'Var', (45, 54))	('Urothelial carcinoma of bladder', 'Disease', (120, 151))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('Urothelial carcinoma of bladder', 'Disease', 'MESH:D001749', (120, 151))	('Glioma', 'Disease', (80, 86))	('Melanoma', 'Disease', 'MESH:D008545', (64, 72))
553140	25198510	Evidences in above studies suggested that hTERT promoter mutations potentially act as a driver gene in melanoma.	('melanoma', 'Disease', 'MESH:D008545', (103, 111))	('hTERT', 'Gene', (42, 47))	('mutations', 'Var', (57, 66))	('melanoma', 'Phenotype', 'HP:0002861', (103, 111))	('hTERT', 'Gene', '7015', (42, 47))	('melanoma', 'Disease', (103, 111))
553142	25198510	It's necessary to show the prevalence of hTERT promoter mutation in NSCLC samples as lung cancer shares driver mutated genes with melanoma, such as BRAF and NRAS .	('hTERT', 'Gene', '7015', (41, 46))	('lung cancer', 'Disease', (85, 96))	('NSCLC', 'Disease', 'MESH:D002289', (68, 73))	('lung cancer', 'Phenotype', 'HP:0100526', (85, 96))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('lung cancer', 'Disease', 'MESH:D008175', (85, 96))	('hTERT', 'Gene', (41, 46))	('NRAS', 'Gene', (157, 161))	('BRAF', 'Gene', (148, 152))	('NRAS', 'Gene', '4893', (157, 161))	('melanoma', 'Disease', 'MESH:D008545', (130, 138))	('NSCLC', 'Phenotype', 'HP:0030358', (68, 73))	('melanoma', 'Phenotype', 'HP:0002861', (130, 138))	('melanoma', 'Disease', (130, 138))	('BRAF', 'Gene', '673', (148, 152))	('mutation', 'Var', (56, 64))	('NSCLC', 'Disease', (68, 73))
553155	25198510	Among these, 17 were deletions in exon 19 and 6 were L858R missense changes.	('L858R missense', 'Var', (53, 67))	('L858R', 'Mutation', 'rs121434568', (53, 58))	('deletions', 'Var', (21, 30))
553156	25198510	Other alterations included 1 exon 20 insertion, exon 20 D807N and T790A mutations, 1 exom 18 R705K mutation.	('T790A', 'Mutation', 'c.790T>A', (66, 71))	('D807N', 'Mutation', 'rs1169312254', (56, 61))	('D807N', 'Var', (56, 61))	('R705K', 'Var', (93, 98))	('R705K', 'Mutation', 'p.R705K', (93, 98))	('T790A mutations', 'Var', (66, 81))
553157	25198510	Six samples (5.6%) had a KRAS mutation, including five G12V mutations and an I36M missense mutation.	('G12V', 'Mutation', 'rs121913529', (55, 59))	('I36M', 'Mutation', 'rs727503109', (77, 81))	('I36M missense', 'Var', (77, 90))	('G12V mutations', 'Var', (55, 69))	('KRAS', 'Gene', (25, 29))	('KRAS', 'Gene', '3845', (25, 29))
553158	25198510	Two samples harbored HER2 exon 20 mutation, including a 776 to 779 YVMA insertion and a S789P mutation.	('S789P', 'Var', (88, 93))	('S789P', 'Mutation', 'p.S789P', (88, 93))	('HER2', 'Gene', '2064', (21, 25))	('HER2', 'Gene', (21, 25))	('776 to 779 YVMA', 'Var', (56, 71))
553161	25198510	Because mutations of EGFR, KRAS, HER2, BRAF, as well as ALK fusions have been well established to be existed in lung adenocarcinoma, these mutation and fusion genes that 'drives' lung adenocarcinoma were not screened in lung squamous cell carcinoma.	("'drives'", 'PosReg', (170, 178))	('KRAS', 'Gene', '3845', (27, 31))	('carcinoma', 'Phenotype', 'HP:0030731', (239, 248))	('HER2', 'Gene', '2064', (33, 37))	('KRAS', 'Gene', (27, 31))	('lung adenocarcinoma', 'Disease', (179, 198))	('EGFR', 'Gene', '1956', (21, 25))	('BRAF', 'Gene', '673', (39, 43))	('BRAF', 'Gene', (39, 43))	('mutations', 'Var', (8, 17))	('lung adenocarcinoma', 'Disease', (112, 131))	('carcinoma', 'Phenotype', 'HP:0030731', (189, 198))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (179, 198))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (220, 248))	('HER2', 'Gene', (33, 37))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (179, 198))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (112, 131))	('EGFR', 'Gene', (21, 25))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (112, 131))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (225, 248))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (220, 248))	('lung squamous cell carcinoma', 'Disease', (220, 248))	('ALK', 'Gene', '238', (56, 59))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('ALK', 'Gene', (56, 59))
553162	25198510	Neither C228T nor C250T mutations was validated in the 174 NSCLC samples after reverse sequencing.	('NSCLC', 'Disease', 'MESH:D002289', (59, 64))	('C250T', 'Var', (18, 23))	('NSCLC', 'Phenotype', 'HP:0030358', (59, 64))	('C228T', 'Var', (8, 13))	('C250T', 'Mutation', 'rs372811772', (18, 23))	('C228T', 'Mutation', 'rs774905136', (8, 13))	('NSCLC', 'Disease', (59, 64))
553166	25198510	Cox multivariate forward stepwise analysis (adjusting for age, gender, smoking history, clinical stage, histologic subtypes and mutational status) revealed that only lymphnode stage (N stage) and HER2 mutation was independent predictors of poorer overall survival (HR 1.653, 95% CI 1.219-2.241; P = 0.001; HR 12.344, 95% CI 2.615-58.275; P = 0.002).	('poorer', 'NegReg', (240, 246))	('HER2', 'Gene', (196, 200))	('lymphnode stage', 'Disease', (166, 181))	('overall survival', 'MPA', (247, 263))	('clinical', 'Species', '191496', (88, 96))	('HER2', 'Gene', '2064', (196, 200))	('mutation', 'Var', (201, 209))
553168	25198510	Identification of oncogenic driver mutations in lung adenocarcinoma has greatly promoted clinical use and development of targeted drugs.	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (48, 67))	('promoted', 'PosReg', (80, 88))	('lung adenocarcinoma', 'Disease', (48, 67))	('men', 'Species', '9606', (113, 116))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (48, 67))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))	('clinical', 'Species', '191496', (89, 97))	('mutations', 'Var', (35, 44))
553171	25198510	The EGFR mutation, KRAS mutation and EGFR/KRAS wild type groups showed no significant difference in both relapse-free survival and overall survival in the present study.	('mutation', 'Var', (9, 17))	('KRAS', 'Gene', (42, 46))	('KRAS', 'Gene', '3845', (42, 46))	('EGFR', 'Gene', (4, 8))	('KRAS', 'Gene', (19, 23))	('EGFR', 'Gene', '1956', (37, 41))	('KRAS', 'Gene', '3845', (19, 23))	('EGFR', 'Gene', (37, 41))	('EGFR', 'Gene', '1956', (4, 8))
553173	25198510	Our results suggest that specific driver mutation of EGFR or KRAS gene doesn't predict survival advantage or disadvantage when these patients didn't receive specific target therapies.	('patients', 'Species', '9606', (133, 141))	('survival advantage', 'CPA', (87, 105))	('mutation', 'Var', (41, 49))	('KRAS', 'Gene', (61, 65))	('EGFR', 'Gene', '1956', (53, 57))	('EGFR', 'Gene', (53, 57))	('KRAS', 'Gene', '3845', (61, 65))
553174	25198510	In the multivariate analysis, HER2 mutation was identified as independent predictor of unfavorable prognosis.	('HER2', 'Gene', '2064', (30, 34))	('HER2', 'Gene', (30, 34))	('mutation', 'Var', (35, 43))
553175	25198510	Because only two samples harbored HER2 mutation, further study with larger number of samples are needed to confirm this result.	('HER2', 'Gene', '2064', (34, 38))	('mutation', 'Var', (39, 47))	('HER2', 'Gene', (34, 38))
553178	25198510	Several studies have identified frequent hTERT 5' promoter mutations in melanoma, gliomas, as well as from relatively low rates of self renewal tissues like liposarcomas, hepatocellular carcinomas, urothelial carcinomas, squamous cell carcinomas of the tongue and medulloblastomas.	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (221, 245))	('hTERT', 'Gene', '7015', (41, 46))	('hepatocellular carcinomas', 'Disease', (171, 196))	('liposarcomas', 'Phenotype', 'HP:0012034', (157, 169))	('liposarcoma', 'Phenotype', 'HP:0012034', (157, 168))	('squamous cell carcinomas of the tongue', 'Disease', 'MESH:D002294', (221, 259))	('melanoma', 'Phenotype', 'HP:0002861', (72, 80))	('melanoma', 'Disease', (72, 80))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (221, 244))	('hTERT', 'Gene', (41, 46))	('liposarcomas', 'Disease', (157, 169))	('gliomas', 'Disease', (82, 89))	('medulloblastomas', 'Disease', (264, 280))	('carcinoma', 'Phenotype', 'HP:0030731', (209, 218))	('urothelial carcinomas', 'Disease', (198, 219))	('urothelial carcinomas', 'Disease', 'MESH:D014526', (198, 219))	('carcinoma', 'Phenotype', 'HP:0030731', (235, 244))	('gliomas', 'Disease', 'MESH:D005910', (82, 89))	('mutations', 'Var', (59, 68))	('hepatocellular carcinomas', 'Disease', 'MESH:D006528', (171, 196))	('melanoma', 'Disease', 'MESH:D008545', (72, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (186, 195))	('carcinomas', 'Phenotype', 'HP:0030731', (186, 196))	('liposarcomas', 'Disease', 'MESH:D008080', (157, 169))	('medulloblastomas', 'Disease', 'MESH:D008527', (264, 280))	('gliomas', 'Phenotype', 'HP:0009733', (82, 89))	('carcinomas', 'Phenotype', 'HP:0030731', (235, 245))	('hepatocellular carcinomas', 'Phenotype', 'HP:0001402', (171, 196))	('carcinomas', 'Phenotype', 'HP:0030731', (209, 219))	('squamous cell carcinomas of the tongue', 'Phenotype', 'HP:0030413', (221, 259))	('squamous cell carcinomas of the tongue', 'Disease', (221, 259))
553183	25198510	In conclusion, our work illustrated the mutation spectrum of EGFR, KRAS, HER2, BRAF and ALK in lung adenocarcinoma, as well as confirmed that hTERT 5' promoter region mutation rarely occurred in NSCLC samples.	('HER2', 'Gene', '2064', (73, 77))	('hTERT', 'Gene', '7015', (142, 147))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (95, 114))	('BRAF', 'Gene', '673', (79, 83))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('KRAS', 'Gene', '3845', (67, 71))	('BRAF', 'Gene', (79, 83))	('NSCLC', 'Disease', 'MESH:D002289', (195, 200))	('hTERT', 'Gene', (142, 147))	('KRAS', 'Gene', (67, 71))	('HER2', 'Gene', (73, 77))	('EGFR', 'Gene', '1956', (61, 65))	('NSCLC', 'Disease', (195, 200))	('mutation', 'Var', (40, 48))	('NSCLC', 'Phenotype', 'HP:0030358', (195, 200))	('lung adenocarcinoma', 'Disease', (95, 114))	('ALK', 'Gene', '238', (88, 91))	('ALK', 'Gene', (88, 91))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (95, 114))	('EGFR', 'Gene', (61, 65))
553188	24672554	Very heavy drinkers had increased risk of P < 0.0001 OR, 6.0 (95% CI: 1.957-18.398) and those who smoked cigarettes and drank alcohol had poorly differentiated tumors G3, P < 0.001, OR 11.652 (95% CI 2.305-58.895), and G4, P=0.52 OR 7.286 (95% CI 0.726-73.075).	('tumors', 'Phenotype', 'HP:0002664', (160, 166))	('P <', 'Var', (42, 45))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('tumors', 'Disease', (160, 166))	('tumors', 'Disease', 'MESH:D009369', (160, 166))
553208	24672554	Many molecular epidemiologic studies have shown that alcohol intake and cigarette smoking cause mutation of p53 and p16 genes as well as overexpression of cyclin D1.	('cyclin D1', 'Gene', (155, 164))	('p53', 'Gene', (108, 111))	('p53', 'Gene', '7157', (108, 111))	('p16', 'Gene', (116, 119))	('mutation', 'Var', (96, 104))	('overexpression', 'PosReg', (137, 151))	('p16', 'Gene', '1029', (116, 119))	('cyclin D1', 'Gene', '595', (155, 164))
553209	24672554	P53 gene mutation and cyclin D1 over expression among others predispose to less differentiated squamous cell carcinoma in the head and neck region.	('mutation', 'Var', (9, 17))	('cyclin', 'Gene', (22, 28))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (95, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('P53', 'Gene', (0, 3))	('P53', 'Gene', '7157', (0, 3))	('predispose', 'Reg', (61, 71))	('over expression', 'PosReg', (32, 47))
553228	32086382	This work considered the neoantigen-class I MHC binding affinity and only retained the top neoantigens resulting from missense mutations with the highest binding affinity within each tumor clone.	('tumor', 'Disease', 'MESH:D009369', (183, 188))	('tumor', 'Phenotype', 'HP:0002664', (183, 188))	('MHC', 'Gene', (44, 47))	('binding', 'Interaction', (48, 55))	('MHC', 'Gene', '3107', (44, 47))	('tumor', 'Disease', (183, 188))	('missense mutations', 'Var', (118, 136))
553234	32086382	Subclonal mutations are unique to different clones, and if a subclonal mutation is in a clone with a larger clonal fraction, the neoantigens associated with this mutation are likely to have a stronger effect on the survival of the tumor cells than subclonal mutations associated with minor clones.	('tumor', 'Disease', 'MESH:D009369', (231, 236))	('stronger', 'PosReg', (192, 200))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('effect', 'Reg', (201, 207))	('tumor', 'Disease', (231, 236))	('neoantigens', 'MPA', (129, 140))	('mutation', 'Var', (162, 170))
553235	32086382	Besides, each somatic mutation could generate a different number of neoantigens of different peptide lengths (8 to 11 amino acids for class I MHC-binding peptides, 15 amino acids for class II-binding peptides), with different registers (a sliding window of protein segments around the mutated position) and presented by different HLA alleles (class I and class II).	('MHC', 'Gene', (142, 145))	('mutation', 'Var', (22, 30))	('MHC', 'Gene', '3107', (142, 145))	('generate', 'Reg', (37, 45))	('neoantigens', 'MPA', (68, 79))
553236	32086382	We hypothesize that a favorable distribution of neoantigens and tumor mutations occurs when immunogenic neoantigens are concentrated on truncal mutations (Fig.	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('truncal', 'Var', (136, 143))	('tumor', 'Disease', (64, 69))	('tumor', 'Disease', 'MESH:D009369', (64, 69))
553237	32086382	When the mutations with higher VAFs are also the mutations that generate more neoantigens (favorable distribution), the product value will be larger (a higher CSiN score).	('VAFs', 'Disease', (31, 35))	('larger', 'PosReg', (142, 148))	('mutations', 'Var', (9, 18))	('VAFs', 'Disease', 'None', (31, 35))	('neoantigens', 'MPA', (78, 89))	('product', 'MPA', (120, 127))
553272	32086382	In this cohort, CSiN scores of patients with DCB are higher than CSiN scores of patients with NCB with marginal significance (Fig.	('higher', 'PosReg', (53, 59))	('patients', 'Species', '9606', (80, 88))	('DCB', 'Var', (45, 48))	('DCB', 'Chemical', 'MESH:D015101', (45, 48))	('CSiN scores', 'MPA', (16, 27))	('patients', 'Species', '9606', (31, 39))
553284	32086382	We observed patients with higher CSiN scores had a non-significant trend of better survival than patients with low CSiN scores in the high T cell infiltration subset of patients (Fig.	('patients', 'Species', '9606', (12, 20))	('patients', 'Species', '9606', (169, 177))	('scores', 'Var', (38, 44))	('better', 'PosReg', (76, 82))	('patients', 'Species', '9606', (97, 105))
553287	32086382	Our implementations of the CSiN, neoantigen load, and neoantigen fitness indices have considered both MHC class I and class II neoantigens, and also neoantigens generated from insertions/deletions and stop-loss mutations.	('MHC', 'Gene', '3107', (102, 105))	('MHC', 'Gene', (102, 105))	('stop-loss mutations', 'Var', (201, 220))	('insertions/deletions', 'Var', (176, 196))
553289	32086382	made a qualitative observation that CTLA-4-resistant tumors could be enriched for subclonal mutations, which may enhance total neoantigen burden but not elicit an effective antitumor response due to the subclonal nature of these neoantigens.	('CTLA-4', 'Gene', '1493', (36, 42))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('mutations', 'Var', (92, 101))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('CTLA-4', 'Gene', (36, 42))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('tumor', 'Disease', (53, 58))	('total neoantigen burden', 'MPA', (121, 144))	('tumor', 'Disease', (177, 182))	('tumors', 'Disease', (53, 59))	('enhance', 'PosReg', (113, 120))
553298	32086382	While RCCs have low neoantigen/mutation loads, Turajlic et al discovered that RCCs have the highest number of insertion/deletion mutations on a pan-cancer basis, which tend to encode high quality neoantigens.	('cancer', 'Disease', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('insertion/deletion mutations', 'Var', (110, 138))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('RCC', 'Disease', (78, 81))	('RCC', 'Phenotype', 'HP:0005584', (78, 81))	('RCC', 'Disease', 'MESH:C538614', (78, 81))	('RCC', 'Phenotype', 'HP:0005584', (6, 9))	('RCC', 'Disease', 'MESH:C538614', (6, 9))	('RCC', 'Disease', (6, 9))
553314	32086382	The name CSiN was selected because the pairing of tumor mutations and neoantigens and its effect on the overall score bear analogy to the Cauchy-Schwarz inequality, which describes the upper bound of the product sum of two vectors of real numbers and the condition for the equality to be achieved.	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('mutations', 'Var', (56, 65))	('tumor', 'Disease', (50, 55))	('tumor', 'Disease', 'MESH:D009369', (50, 55))
553317	32086382	All SNPs and Indels were combined and only kept if there were at least 7 total (wild type and variant) reads in the normal sample and at least 3 variant reads in the tumor sample.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('variant', 'Var', (94, 101))	('tumor', 'Disease', (166, 171))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))
553369	32286381	The immune cell infiltration was mainly mediated by chemokine/receptor expression networks and cancer genetic alterations in tumor tissue via a systematic analysis of multiple cancers.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('cancers', 'Phenotype', 'HP:0002664', (176, 183))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('cancer', 'Disease', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('tumor', 'Disease', (125, 130))	('multiple cancers', 'Disease', (167, 183))	('immune cell infiltration', 'CPA', (4, 28))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('cancer', 'Disease', (176, 182))	('genetic alterations', 'Var', (102, 121))	('multiple cancers', 'Disease', 'MESH:D009369', (167, 183))
553376	32286381	It was verified that STC1 could accelerate tumor growth and reduce disease-free survival in mice.	('STC1', 'Var', (21, 25))	('reduce', 'NegReg', (60, 66))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Disease', (43, 48))	('accelerate', 'PosReg', (32, 42))	('disease-free survival', 'CPA', (67, 88))
553377	32286381	Methylation of the SFTPA2 promoter represents a potential biomarker for lung cancer diagnosis.	('Methylation', 'Var', (0, 11))	('SFTPA2', 'Gene', (19, 25))	('lung cancer', 'Disease', (72, 83))	('lung cancer', 'Phenotype', 'HP:0100526', (72, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('lung cancer', 'Disease', 'MESH:D008175', (72, 83))
553379	32286381	Mutations in many of these genes have previously been implicated in cancer risk, viral host-response, or epithelial immunity.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('implicated', 'Reg', (54, 64))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('Mutations', 'Var', (0, 9))	('cancer', 'Disease', (68, 74))	('viral host-response', 'CPA', (81, 100))	('epithelial immunity', 'CPA', (105, 124))
553384	32286381	The methylation of DKK1 may be considered a prognostic marker in oral cancer.	('DKK1', 'Gene', (19, 23))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('methylation', 'Var', (4, 15))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))
553385	32286381	DKK1 knockdown increased cellular migration and invasiveness in oral cancer cells.	('cellular migration', 'CPA', (25, 43))	('cancer', 'Disease', 'MESH:D009369', (69, 75))	('knockdown', 'Var', (5, 14))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('DKK1', 'Gene', (0, 4))	('increased', 'PosReg', (15, 24))	('invasiveness in', 'CPA', (48, 63))	('cancer', 'Disease', (69, 75))
553390	32286381	SH2D1A is also a SH2 domain-containing protein, which mutations caused the X-linked lymphoproliferative syndrome (XLP) and was associated with B-cell lymphomas.	('lymphomas', 'Phenotype', 'HP:0002665', (150, 159))	('associated', 'Reg', (127, 137))	('XLP', 'Disease', 'MESH:D008232', (114, 117))	('SH2D1A', 'Gene', (0, 6))	('mutations', 'Var', (54, 63))	('XLP', 'Disease', (114, 117))	('X-linked lymphoproliferative syndrome', 'Disease', 'MESH:D008232', (75, 112))	('B-cell lymphomas', 'Disease', 'MESH:D016393', (143, 159))	('lymphoproliferative syndrome', 'Phenotype', 'HP:0005523', (84, 112))	('B-cell lymphomas', 'Phenotype', 'HP:0012191', (143, 159))	('X-linked lymphoproliferative syndrome', 'Disease', (75, 112))	('B-cell lymphomas', 'Disease', (143, 159))	('caused', 'Reg', (64, 70))
553486	30967777	Apigenin Combined With Gefitinib Blocks Autophagy Flux and Induces Apoptotic Cell Death Through Inhibition of HIF-1alpha, c-Myc, p-EGFR, and Glucose Metabolism in EGFR L858R+T790M-Mutated H1975 Cells Cancer cells are characterized by abnormally increased glucose uptake and active bio-energy and biosynthesis to support the proliferation, metastasis, and drug resistant survival.	('Blocks', 'NegReg', (33, 39))	('Autophagy Flux', 'CPA', (40, 54))	('HIF-1alpha', 'Gene', (110, 120))	('EGFR', 'Gene', (131, 135))	('EGFR', 'Gene', (163, 167))	('c-Myc', 'Gene', '4609', (122, 127))	('Cancer', 'Phenotype', 'HP:0002664', (200, 206))	('H1975', 'CellLine', 'CVCL:1511', (188, 193))	('glucose uptake', 'CPA', (255, 269))	('Cancer', 'Disease', (200, 206))	('biosynthesis', 'CPA', (296, 308))	('metastasis', 'CPA', (339, 349))	('Gefitinib', 'Chemical', 'MESH:D000077156', (23, 32))	('increased glucose', 'Phenotype', 'HP:0003074', (245, 262))	('EGFR', 'Gene', '1956', (163, 167))	('Glucose Metabolism', 'Disease', (141, 159))	('EGFR', 'Gene', '1956', (131, 135))	('L858R', 'Mutation', 'rs121434568', (168, 173))	('HIF-1alpha', 'Gene', '3091', (110, 120))	('glucose', 'Chemical', 'MESH:D005947', (255, 262))	('Cancer', 'Disease', 'MESH:D009369', (200, 206))	('Apoptotic Cell Death', 'CPA', (67, 87))	('Inhibition', 'NegReg', (96, 106))	('increased', 'PosReg', (245, 254))	('T790M', 'Mutation', 'rs121434569', (174, 179))	('Glucose Metabolism', 'Disease', 'MESH:D044882', (141, 159))	('c-Myc', 'Gene', (122, 127))	('L858R+T790M-Mutated', 'Var', (168, 187))
553487	30967777	We examined the therapeutic value of the combination of apigenin (a natural small-molecule inhibitor of Glut1 belonging to the flavonoid family) and gefitinib on epidermal growth factor receptor (EGFR)-resistant mutant non-small cell lung cancer, to notably damage glucose utilization and thus suppress cell growth and malignant behavior.	('damage', 'NegReg', (258, 264))	('epidermal growth factor receptor', 'Gene', '1956', (162, 194))	('glucose utilization', 'MPA', (265, 284))	('mutant', 'Var', (212, 218))	('cell lung cancer', 'Disease', 'MESH:D008175', (229, 245))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (219, 245))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))	('lung cancer', 'Phenotype', 'HP:0100526', (234, 245))	('suppress', 'NegReg', (294, 302))	('malignant behavior', 'CPA', (319, 337))	('gefitinib', 'Chemical', 'MESH:D000077156', (149, 158))	('epidermal growth factor receptor', 'Gene', (162, 194))	('apigenin', 'Chemical', 'MESH:D047310', (56, 64))	('flavonoid', 'Chemical', 'MESH:D005419', (127, 136))	('cell lung cancer', 'Disease', (229, 245))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (223, 245))	('glucose', 'Chemical', 'MESH:D005947', (265, 272))	('cell growth', 'CPA', (303, 314))
553488	30967777	Here, we demonstrate that apigenin combined with gefitinib inhibits multiple oncogenic drivers such as c-Myc, HIF-1alpha, and EGFR, reduces Gluts and MCT1 protein expression, and inactivates the 5' adenosine monophosphate-activated protein kinase (AMPK) signaling, which regulates glucose uptake and maintains energy metabolism, leading to impaired energy utilization in EGFR L858R-T790M-mutated H1975 lung cancer cells.	('adenosine monophosphate-activated protein kinase', 'Gene', '5563', (198, 246))	('HIF-1alpha', 'Gene', (110, 120))	('gefitinib', 'Chemical', 'MESH:D000077156', (49, 58))	('AMPK', 'Gene', '5563', (248, 252))	('MCT1', 'Gene', '6566', (150, 154))	('energy utilization', 'MPA', (349, 367))	('cancer', 'Phenotype', 'HP:0002664', (407, 413))	('L858R', 'Mutation', 'rs121434568', (376, 381))	('L858R-T790M-mutated', 'Var', (376, 395))	('apigenin', 'Chemical', 'MESH:D047310', (26, 34))	('lung cancer', 'Disease', (402, 413))	('glucose uptake', 'MPA', (281, 295))	('c-Myc', 'Gene', (103, 108))	('inactivates', 'NegReg', (179, 190))	('T790M', 'Mutation', 'rs121434569', (382, 387))	('c-Myc', 'Gene', '4609', (103, 108))	('AMPK', 'Gene', (248, 252))	('energy metabolism', 'MPA', (310, 327))	('inhibits', 'NegReg', (59, 67))	('regulates', 'Reg', (271, 280))	('glucose', 'Chemical', 'MESH:D005947', (281, 288))	('adenosine monophosphate-activated protein kinase', 'Gene', (198, 246))	('lung cancer', 'Disease', 'MESH:D008175', (402, 413))	('MCT1', 'Gene', (150, 154))	('EGFR', 'Gene', (126, 130))	('H1975', 'CellLine', 'CVCL:1511', (396, 401))	('lung cancer', 'Phenotype', 'HP:0100526', (402, 413))	('Gluts', 'Protein', (140, 145))	('reduces', 'NegReg', (132, 139))	('oncogenic', 'CPA', (77, 86))	('impaired', 'NegReg', (340, 348))
553489	30967777	H1975 cells exhibit dysregulated metabolism and apoptotic cell death following treatment with apigenin + gefitinib.	('dysregulated metabolism', 'MPA', (20, 43))	('H1975', 'Var', (0, 5))	('apigenin', 'Chemical', 'MESH:D047310', (94, 102))	('gefitinib', 'Chemical', 'MESH:D000077156', (105, 114))	('apoptotic cell death', 'CPA', (48, 68))	('H1975', 'CellLine', 'CVCL:1511', (0, 5))
553494	30967777	The mutation rate of epidermal growth factor receptor (EGFR) in mainland China population has reached 50.2%, and the activating mutation rate is 48.0%.	('epidermal growth factor receptor', 'Gene', '1956', (21, 53))	('epidermal growth factor receptor', 'Gene', (21, 53))	('EGFR', 'Gene', (55, 59))	('mutation', 'Var', (4, 12))
553495	30967777	In all EGFR mutations of NSCLC patients, deletion of EGFR exon 19 and mutation of EGFR L858R exon 21 account for 85-90%.	('EGFR', 'Gene', (82, 86))	('EGFR', 'Gene', (7, 11))	('NSCLC', 'Disease', (25, 30))	('mutations', 'Var', (12, 21))	('NSCLC', 'Disease', 'MESH:D002289', (25, 30))	('deletion', 'Var', (41, 49))	('L858R', 'Mutation', 'rs121434568', (87, 92))	('patients', 'Species', '9606', (31, 39))	('EGFR', 'Gene', (53, 57))	('mutation', 'Var', (70, 78))	('NSCLC', 'Phenotype', 'HP:0030358', (25, 30))
553497	30967777	However, acquired resistance to these EGFR-TKIs frequently develops after 9-13 months exposure, and mutation of EGFR T790M accounts for 60% of this acquired resistance associated with progressive disease after first response to TKIs.	('EGFR', 'Gene', (112, 116))	('acquired', 'MPA', (9, 17))	('associated with', 'Reg', (168, 183))	('mutation', 'Var', (100, 108))	('T790M', 'Mutation', 'rs121434569', (117, 122))	('progressive disease', 'Disease', (184, 203))
553501	30967777	EGFR-TKIs such as gefitinib inhibit glucose uptake in vitro and models of EGFR mutant NSCLC in vivo.	('NSCLC', 'Disease', (86, 91))	('mutant', 'Var', (79, 85))	('gefitinib', 'Chemical', 'MESH:D000077156', (18, 27))	('NSCLC', 'Disease', 'MESH:D002289', (86, 91))	('glucose', 'Chemical', 'MESH:D005947', (36, 43))	('NSCLC', 'Phenotype', 'HP:0030358', (86, 91))	('glucose uptake', 'CPA', (36, 50))	('EGFR', 'Gene', (74, 78))	('inhibit', 'NegReg', (28, 35))
553502	30967777	However, earlier studies found that TKIs such as erlotinib do not sufficiently reduce the nuclear HIF-1alpha and c-Myc protein levels in PC-9 (EGFR exon 19 deletion) xenograft mouse model when used alone, but a combination of erlotinib + cisplatin produced significant nuclear HIF-1alpha and c-Myc downregulation and tumor size inhibition.	('tumor', 'Phenotype', 'HP:0002664', (317, 322))	('erlotinib', 'Chemical', 'MESH:D000069347', (49, 58))	('tumor', 'Disease', 'MESH:D009369', (317, 322))	('tumor', 'Disease', (317, 322))	('downregulation', 'NegReg', (298, 312))	('c-Myc', 'Gene', (292, 297))	('mouse', 'Species', '10090', (176, 181))	('PC-9', 'Gene', '100102', (137, 141))	('cisplatin', 'Chemical', 'MESH:D002945', (238, 247))	('nuclear HIF-1alpha', 'MPA', (269, 287))	('erlotinib', 'Chemical', 'MESH:D000069347', (226, 235))	('c-Myc', 'Gene', '4609', (113, 118))	('PC-9', 'Gene', (137, 141))	('c-Myc', 'Gene', (113, 118))	('c-Myc', 'Gene', '4609', (292, 297))	('deletion', 'Var', (156, 164))
553511	30967777	Whether targeting both c-Myc and HIF-1alpha to regulate glucose utilization changes the dynamics of the apoptotic mechanism in EGFR mutant intrinsic TKIs resistance in NSCLC is unknown.	('glucose', 'Chemical', 'MESH:D005947', (56, 63))	('mutant', 'Var', (132, 138))	('NSCLC', 'Disease', 'MESH:D002289', (168, 173))	('c-Myc', 'Gene', '4609', (23, 28))	('NSCLC', 'Phenotype', 'HP:0030358', (168, 173))	('c-Myc', 'Gene', (23, 28))	('EGFR', 'Gene', (127, 131))	('NSCLC', 'Disease', (168, 173))
553513	30967777	In this study, we emphasized the necessity and effectiveness of combined use in resistant cancer treatment and, for the first time, revealed that apigenin + gefitinib combination inhibits AMPK signaling pathway and oncogenic drivers c-Myc, HIF-1alpha, and EGFR and damages the glucose uptake and utilization on EGFR mutant-resistant NSCLC cells.	('c-Myc', 'Gene', (233, 238))	('NSCLC', 'Disease', 'MESH:D002289', (333, 338))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('mutant-resistant', 'Var', (316, 332))	('glucose', 'Chemical', 'MESH:D005947', (277, 284))	('EGFR', 'Protein', (256, 260))	('NSCLC', 'Disease', (333, 338))	('apigenin', 'Var', (146, 154))	('gefitinib', 'Chemical', 'MESH:D000077156', (157, 166))	('c-Myc', 'Gene', '4609', (233, 238))	('utilization', 'MPA', (296, 307))	('NSCLC', 'Phenotype', 'HP:0030358', (333, 338))	('glucose uptake', 'CPA', (277, 291))	('cancer', 'Disease', 'MESH:D009369', (90, 96))	('damages', 'NegReg', (265, 272))	('HIF-1alpha', 'Protein', (240, 250))	('AMPK', 'Gene', '5563', (188, 192))	('inhibits', 'NegReg', (179, 187))	('oncogenic', 'CPA', (215, 224))	('AMPK', 'Gene', (188, 192))	('apigenin', 'Chemical', 'MESH:D047310', (146, 154))	('cancer', 'Disease', (90, 96))
553549	30967777	EGFR-TKI insensitive cell line NCI-H1975 contains mutations of L858R,  E746-A750, and T790M at exon 20.	('L858R', 'Var', (63, 68))	('L858R', 'Mutation', 'rs121434568', (63, 68))	('T790M', 'Mutation', 'rs121434569', (86, 91))	('NCI-H1975', 'CellLine', 'CVCL:1511', (31, 40))	('E746-A750', 'Var', (71, 80))	('T790M', 'Var', (86, 91))
553559	30967777	We similarly used the human high metastatic lung squamous cancer cell line 95-D, which is an EGFR mutant wild type, to determine the effect of increasing doses of apigenin and gefitinib alone or in combination.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('gefitinib', 'Chemical', 'MESH:D000077156', (176, 185))	('lung squamous cancer', 'Disease', (44, 64))	('apigenin', 'Chemical', 'MESH:D047310', (163, 171))	('squamous cancer', 'Phenotype', 'HP:0002860', (49, 64))	('lung squamous cancer', 'Disease', 'MESH:D008175', (44, 64))	('human', 'Species', '9606', (22, 27))	('lung squamous cancer', 'Phenotype', 'HP:0030359', (44, 64))	('mutant', 'Var', (98, 104))
553562	30967777	These findings show that apigenin combined with gefitinib selectively induces a beneficial response in EGFR L858R-T790M mutant H1975 cells.	('T790M', 'Mutation', 'rs121434569', (114, 119))	('beneficial response', 'PosReg', (80, 99))	('L858R-T790M', 'Var', (108, 119))	('gefitinib', 'Chemical', 'MESH:D000077156', (48, 57))	('H1975', 'Gene', (127, 132))	('EGFR', 'Gene', (103, 107))	('apigenin', 'Chemical', 'MESH:D047310', (25, 33))	('L858R', 'Mutation', 'rs121434568', (108, 113))	('H1975', 'CellLine', 'CVCL:1511', (127, 132))
553574	30967777	As shown (Figures 3A, B), the majority of H1975 cells were spindle shaped and had pseudopodia.	('H1975', 'Var', (42, 47))	('spindle shaped', 'CPA', (59, 73))	('pseudopodia', 'CPA', (82, 93))	('H1975', 'CellLine', 'CVCL:1511', (42, 47))
553576	30967777	Similarly, gefitinib changed the cell morphology to oval shape and cell detachment, while Hoechst33342 staining showed high nuclear DNA condensation.	('oval shape', 'CPA', (52, 62))	('cell detachment', 'CPA', (67, 82))	('gefitinib', 'Chemical', 'MESH:D000077156', (11, 20))	('Hoechst33342', 'Chemical', 'MESH:C017807', (90, 102))	('gefitinib', 'Var', (11, 20))	('changed', 'Reg', (21, 28))
553598	30967777	Furthermore, autophagy flux was blocked after treatment of H1975 cells with gefitinib and the combination as illustrated by the band alteration from LC3-I to LC3-II, suggesting increased expression of lipidated LC3 and p62 (Figure 5A).	('LC3', 'Gene', (158, 161))	('blocked', 'NegReg', (32, 39))	('p62', 'Gene', '23636', (219, 222))	('LC3', 'Gene', '84557', (149, 152))	('LC3', 'Gene', (149, 152))	('p62', 'Gene', (219, 222))	('increased', 'PosReg', (177, 186))	('autophagy flux', 'CPA', (13, 27))	('LC3', 'Gene', '84557', (211, 214))	('gefitinib', 'Chemical', 'MESH:D000077156', (76, 85))	('lipidated', 'Var', (201, 210))	('LC3', 'Gene', (211, 214))	('increased expression of lipidated LC3', 'Phenotype', 'HP:0003141', (177, 214))	('expression', 'MPA', (187, 197))	('H1975', 'CellLine', 'CVCL:1511', (59, 64))	('LC3', 'Gene', '84557', (158, 161))
553604	30967777	Taken together, these results indicate that treatment with apigenin + gefitinib combination inhibits the AMPK pathway and autophagy flux, leading to enhanced H1975 apoptotic cell death.	('H1975', 'CellLine', 'CVCL:1511', (158, 163))	('AMPK', 'Gene', (105, 109))	('apigenin', 'Chemical', 'MESH:D047310', (59, 67))	('autophagy flux', 'CPA', (122, 136))	('gefitinib', 'Chemical', 'MESH:D000077156', (70, 79))	('enhanced', 'PosReg', (149, 157))	('inhibits', 'NegReg', (92, 100))	('AMPK', 'Gene', '5563', (105, 109))	('H1975', 'Var', (158, 163))
553606	30967777	Therefore, c-Myc expression was decreased by using 10058-F4 treatment and that specifically prevents the c-Myc-Max interaction and inhibits transactivation of c-Myc target gene expression.	('c-Myc', 'Gene', (11, 16))	('c-Myc', 'Gene', '4609', (159, 164))	('prevents', 'NegReg', (92, 100))	('10058-F4 treatment', 'Var', (51, 69))	('c-Myc', 'Gene', (159, 164))	('c-Myc', 'Gene', '4609', (105, 110))	('10058-F4', 'Chemical', '-', (51, 59))	('inhibits', 'NegReg', (131, 139))	('transactivation', 'MPA', (140, 155))	('decreased', 'NegReg', (32, 41))	('c-Myc', 'Gene', (105, 110))	('c-Myc', 'Gene', '4609', (11, 16))
553607	30967777	We found that 1005-F4 changed the morphology of H1975 to a more spindle-shaped and decreased p-EGFR, HIF-1alpha, and c-Myc expression but upregulated Glut1 protein expression (Figures 6A, B).	('H1975', 'Var', (48, 53))	('H1975', 'CellLine', 'CVCL:1511', (48, 53))	('decreased', 'NegReg', (83, 92))	('more', 'PosReg', (59, 63))	('p-EGFR', 'MPA', (93, 99))	('1005-F4', 'Var', (14, 21))	('c-Myc', 'Gene', (117, 122))	('Glut1 protein', 'Protein', (150, 163))	('spindle-shaped', 'CPA', (64, 78))	('upregulated', 'PosReg', (138, 149))	('c-Myc', 'Gene', '4609', (117, 122))
553611	30967777	The results revealed that KC7F2 led to a spindle-shaped morphology accompanied with a significant inhibition of HIF-1alpha expression and an increase in c-Myc expression.	('expression', 'MPA', (123, 133))	('increase', 'PosReg', (141, 149))	('c-Myc', 'Gene', '4609', (153, 158))	('inhibition', 'NegReg', (98, 108))	('HIF-1alpha', 'Protein', (112, 122))	('spindle-shaped morphology', 'CPA', (41, 66))	('expression', 'MPA', (159, 169))	('c-Myc', 'Gene', (153, 158))	('KC7F2', 'Var', (26, 31))
553621	30967777	In the current study, as shown in Figure 8, we show that a combination of apigenin + gefitinib in EGFR-mutated, TKI-resistant NSCLC will induce metabolic stress and energetic disturbance in H1975 cells, which lead to apoptotic cell death.	('induce', 'Reg', (137, 143))	('apigenin', 'Var', (74, 82))	('NSCLC', 'Disease', 'MESH:D002289', (126, 131))	('gefitinib', 'Chemical', 'MESH:D000077156', (85, 94))	('lead to', 'Reg', (209, 216))	('H1975', 'CellLine', 'CVCL:1511', (190, 195))	('energetic disturbance', 'CPA', (165, 186))	('NSCLC', 'Phenotype', 'HP:0030358', (126, 131))	('apoptotic cell death', 'CPA', (217, 237))	('combination', 'Interaction', (59, 70))	('apigenin', 'Chemical', 'MESH:D047310', (74, 82))	('metabolic', 'MPA', (144, 153))	('NSCLC', 'Disease', (126, 131))
553627	30967777	Clinical data indicate that high BIM expression decreases the risk of mortality and progression in EGFR-mutant NSCLC patient.	('NSCLC', 'Disease', (111, 116))	('BIM', 'Gene', '10018', (33, 36))	('decreases', 'NegReg', (48, 57))	('EGFR-mutant', 'Var', (99, 110))	('NSCLC', 'Disease', 'MESH:D002289', (111, 116))	('BIM', 'Gene', (33, 36))	('patient', 'Species', '9606', (117, 124))	('EGFR-mutant', 'Gene', (99, 110))	('NSCLC', 'Phenotype', 'HP:0030358', (111, 116))
553629	30967777	Next, we investigated the mechanism of apoptosis in each treatment group of H1975 cells and found that combination therapy induced apoptosis by activating caspase-3, inactivating PARP-1, increasing BIM, and reducing Bcl-2 expression (Figure 3E).	('PARP-1', 'Gene', (179, 185))	('caspase-3', 'Gene', (155, 164))	('increasing', 'PosReg', (187, 197))	('PARP-1', 'Gene', '142', (179, 185))	('inactivating', 'Var', (166, 178))	('activating', 'PosReg', (144, 154))	('H1975', 'CellLine', 'CVCL:1511', (76, 81))	('BIM', 'Gene', '10018', (198, 201))	('caspase-3', 'Gene', '836', (155, 164))	('BIM', 'Gene', (198, 201))	('reducing', 'NegReg', (207, 215))	('Bcl-2', 'Gene', (216, 221))	('Bcl-2', 'Gene', '596', (216, 221))
553630	30967777	We found that the compound combination caused significant energetic stress by reducing intracellular ATP production (Figure 4B), glucose uptake (Figure 4D), and Gluts protein expression (Figure 4E).	('reducing', 'NegReg', (78, 86))	('combination', 'Var', (27, 38))	('energetic stress', 'MPA', (58, 74))	('Gluts protein', 'Protein', (161, 174))	('glucose uptake', 'MPA', (129, 143))	('intracellular ATP production', 'MPA', (87, 115))	('glucose', 'Chemical', 'MESH:D005947', (129, 136))	('ATP', 'Chemical', 'MESH:D000255', (101, 104))
553635	30967777	The Myc/Max interaction inhibitor 10058-F4 (30 mg/kg) did not have a significant inhibitory effect on the human prostate cancer xenograft model in vivo.	('human', 'Species', '9606', (106, 111))	('prostate cancer', 'Phenotype', 'HP:0012125', (112, 127))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('Myc', 'Gene', '4609', (4, 7))	('10058-F4', 'Chemical', '-', (34, 42))	('prostate cancer', 'Disease', (112, 127))	('Myc', 'Gene', (4, 7))	('10058-F4', 'Var', (34, 42))	('prostate cancer', 'Disease', 'MESH:D011471', (112, 127))
553636	30967777	Here, inhibition of HIF-1alpha resulted in increased c-Myc but no effect on p-EGFR and Glut1 expression in H1975 cells (Figure 6H).	('H1975', 'CellLine', 'CVCL:1511', (107, 112))	('c-Myc', 'Gene', '4609', (53, 58))	('HIF-1alpha', 'Protein', (20, 30))	('inhibition', 'Var', (6, 16))	('increased', 'PosReg', (43, 52))	('c-Myc', 'Gene', (53, 58))	('Glut1', 'Protein', (87, 92))
553640	30967777	In addition, autophagy was essential to the elementary growth and survival of H1975 cells (Figure 5B), and H1975 cells experienced autophagy flux as CQ induced LC3-II expression (Figure 5H).	('H1975', 'Var', (107, 112))	('H1975', 'CellLine', 'CVCL:1511', (107, 112))	('CQ', 'Chemical', 'MESH:D002738', (149, 151))	('H1975', 'CellLine', 'CVCL:1511', (78, 83))	('LC3', 'Gene', '84557', (160, 163))	('autophagy flux', 'CPA', (131, 145))	('LC3', 'Gene', (160, 163))
553643	30967777	Based on a large number of preclinical evidence, there are many clinical trials recently present the safety and efficiency of hydroxychloroquine (HCQ), a less toxic drug than CQ, combined with TKIs or anti-angiogenesis or chemotherapy in NSCLC (NCT00977470, NCT00809237, NCT00933803, and NCT01649947).	('NCT00977470', 'Var', (245, 256))	('HCQ', 'Chemical', 'MESH:D006886', (146, 149))	('NSCLC', 'Phenotype', 'HP:0030358', (238, 243))	('hydroxychloroquine', 'Chemical', 'MESH:D006886', (126, 144))	('CQ', 'Chemical', 'MESH:D002738', (147, 149))	('NCT01649947', 'Var', (288, 299))	('NSCLC', 'Disease', (238, 243))	('NCT00809237', 'Var', (258, 269))	('NCT00933803', 'Var', (271, 282))	('NSCLC', 'Disease', 'MESH:D002289', (238, 243))	('CQ', 'Chemical', 'MESH:D002738', (175, 177))
553649	30217221	PTEN encodes a 403-amino acid peptide, which is composed of a phosphatidylinositol-4,5-bisphosphate-binding domain (PBD) (residues 1-13), a catalytic phosphatase domain (PD) (residues 14-185), a C2 membrane binding domain (C2D)(residues 186-350), and a C-terminal tail (residues 351-403).	('PD', 'Disease', 'MESH:D010300', (170, 172))	('amino acid peptide', 'Chemical', '-', (19, 37))	('residues 186-350', 'Var', (228, 244))	('phosphatidylinositol-4,5-bisphosphate', 'Chemical', 'MESH:D019269', (62, 99))	('PTEN', 'Gene', (0, 4))
553651	30217221	The C2 domain includes two tyrosine phosphorylation sites (Y240 and Y315).	('Y240', 'Var', (59, 63))	('Y315', 'Var', (68, 72))	('tyrosine', 'Chemical', 'MESH:D014443', (27, 35))
553653	30217221	There are two PDZ-binding domains and six phosphorylation sites in the C-terminal tail, including threonine 366 (Thr366), serine 370 (Ser370), Ser380, Thr382, Thr383 and Ser385 (Fig.	('Ser380', 'Var', (143, 149))	('Ser385', 'Chemical', '-', (170, 176))	('Ser380', 'Chemical', '-', (143, 149))	('Thr382', 'Var', (151, 157))	('Ser385', 'Var', (170, 176))	('Thr382', 'Chemical', '-', (151, 157))	('Thr383', 'Chemical', '-', (159, 165))	('Thr383', 'Var', (159, 165))	('PD', 'Disease', 'MESH:D010300', (14, 16))	('Thr366', 'Chemical', '-', (113, 119))	('Thr366', 'Var', (113, 119))	('threonine', 'Chemical', 'MESH:D013912', (98, 107))	('Ser370', 'Var', (134, 140))	('Ser370', 'Chemical', '-', (134, 140))	('serine', 'Chemical', 'MESH:D012694', (122, 128))
553656	30217221	PTEN also dephosphorylates Src homology 2-containing protein (Shc) directly, and inhibits the activation of Shc/Raf/ERK1/2 (extracellular signal-regulated kinase) signaling cascade.	('inhibits', 'NegReg', (81, 89))	('ERK1/2', 'Gene', '5595;5594', (116, 122))	('Raf', 'Gene', '22882', (112, 115))	('Shc', 'Gene', '6464', (108, 111))	('Src homology 2-containing protein', 'Gene', '6464', (27, 60))	('Raf', 'Gene', (112, 115))	('Src homology 2-containing protein', 'Gene', (27, 60))	('Shc', 'Gene', (62, 65))	('ERK1/2', 'Gene', (116, 122))	('Shc', 'Gene', (108, 111))	('PTEN', 'Var', (0, 4))	('Shc', 'Gene', '6464', (62, 65))
553657	30217221	Through controlling these pathways, PTEN ultimately represses cell survival, proliferation, metastasis and so on (Fig.	('represses', 'NegReg', (52, 61))	('cell survival', 'CPA', (62, 75))	('rat', 'Species', '10116', (84, 87))	('metastasis', 'CPA', (92, 102))	('PTEN', 'Var', (36, 40))
553658	30217221	PTEN expression alteration is crucial to the pathogenesis of cancer and other diseases.	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('cancer', 'Disease', (61, 67))	('rat', 'Species', '10116', (20, 23))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('PTEN', 'Gene', (0, 4))	('alteration', 'Var', (16, 26))
553659	30217221	Low level of PTEN caused by homozygous deletions, frameshift, nonsense mutations or hypermethylation of the gene or destability of the protein occurs frequently in various human cancers and PTEN depletion in mice leads to a substantial rise in tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (244, 249))	('nonsense mutations', 'Var', (62, 80))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('depletion', 'NegReg', (195, 204))	('tumor', 'Disease', (244, 249))	('cancers', 'Disease', 'MESH:D009369', (178, 185))	('human', 'Species', '9606', (172, 177))	('frameshift', 'Var', (50, 60))	('cancers', 'Phenotype', 'HP:0002664', (178, 185))	('cancers', 'Disease', (178, 185))	('hypermethylation', 'Var', (84, 100))	('rise', 'PosReg', (236, 240))	('tumor', 'Disease', 'MESH:D009369', (244, 249))	('mice', 'Species', '10090', (208, 212))
553660	30217221	PTEN mutations were reported as a cause of obesity and autism spectrum disorders.	('obesity', 'Phenotype', 'HP:0001513', (43, 50))	('autism', 'Phenotype', 'HP:0000717', (55, 61))	('mutations', 'Var', (5, 14))	('cause', 'Reg', (34, 39))	('obesity and autism spectrum disorders', 'Disease', 'MESH:D009765', (43, 80))	('PTEN', 'Gene', (0, 4))	('autism spectrum disorders', 'Phenotype', 'HP:0000729', (55, 80))
553665	30217221	Inhibition of PTEN rescued synaptic function and cognition in cellular and animal models of Alzheimer's disease, whereas PTEN transgenic mice displayed synaptic depression.	('PTEN', 'Gene', (14, 18))	("Alzheimer's disease", 'Disease', (92, 111))	('rescued', 'PosReg', (19, 26))	("Alzheimer's disease", 'Phenotype', 'HP:0002511', (92, 111))	('depression', 'Disease', (161, 171))	('depression', 'Phenotype', 'HP:0000716', (161, 171))	('cognition', 'CPA', (49, 58))	('synaptic function', 'MPA', (27, 44))	('Inhibition', 'Var', (0, 10))	('transgenic mice', 'Species', '10090', (126, 141))	("Alzheimer's disease", 'Disease', 'MESH:D000544', (92, 111))	('depression', 'Disease', 'MESH:D000275', (161, 171))
553680	30217221	Inhibition of miR-21 reversed EMT by increasing PTEN protein level in head and neck squamous cell carcinoma (HNSCC), resulting in the suppression of cell proliferation and motility.	('increasing', 'PosReg', (37, 47))	('miR-21', 'Gene', '406991', (14, 20))	('carcinoma', 'Phenotype', 'HP:0030731', (98, 107))	('miR-21', 'Gene', (14, 20))	('neck squamous cell carcinoma', 'Disease', (79, 107))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (79, 107))	('suppression', 'NegReg', (134, 145))	('Inhibition', 'Var', (0, 10))	('cell proliferation', 'CPA', (149, 167))	('rat', 'Species', '10116', (161, 164))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (84, 107))	('PTEN protein level', 'MPA', (48, 66))
553689	30217221	The relative activity of the luciferase harboring PTEN 3'UTR was promoted in A549 cells but repressed in 293 T cells by miR-130.	('luciferase', 'Enzyme', (29, 39))	('293 T', 'CellLine', 'CVCL:0063', (105, 110))	('miR', 'Gene', '220972', (120, 123))	('miR', 'Gene', (120, 123))	("PTEN 3'UTR", 'Var', (50, 60))	('promoted', 'PosReg', (65, 73))	('activity', 'MPA', (13, 21))	('A549', 'CellLine', 'CVCL:0023', (77, 81))
553702	30217221	Overexpression of DNMT1 led to PTEN downregulation due to the CpG island methylation in promoter, which promoted tumorigenesis of breast cancer, ovarian cancer and acute myeloid leukemia (AML).	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('ovarian cancer', 'Disease', 'MESH:D010051', (145, 159))	('DNMT1', 'Gene', '1786', (18, 23))	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('acute myeloid leukemia', 'Disease', (164, 186))	('leukemia', 'Phenotype', 'HP:0001909', (178, 186))	('tumor', 'Disease', (113, 118))	('ovarian cancer', 'Disease', (145, 159))	('downregulation', 'NegReg', (36, 50))	('breast cancer', 'Phenotype', 'HP:0003002', (130, 143))	('AML', 'Disease', 'MESH:D015470', (188, 191))	('ovarian cancer', 'Phenotype', 'HP:0100615', (145, 159))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('DNMT1', 'Gene', (18, 23))	('AML', 'Phenotype', 'HP:0004808', (188, 191))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (170, 186))	('AML', 'Disease', (188, 191))	('breast cancer', 'Disease', 'MESH:D001943', (130, 143))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (164, 186))	('breast cancer', 'Disease', (130, 143))	('PTEN', 'MPA', (31, 35))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (164, 186))	('methylation', 'Var', (73, 84))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('promoted', 'PosReg', (104, 112))
553705	30217221	Curcumin treatment suppressed liver fibrosis by inducing miR-29b expression in HSCs, which led to the low expression of DNMT3b and PTEN hypomethylation (Fig.	('inducing', 'PosReg', (48, 56))	('Curcumin', 'Chemical', 'MESH:D003474', (0, 8))	('DNMT3b', 'Gene', (120, 126))	('suppressed', 'NegReg', (19, 29))	('miR-29b', 'Gene', (57, 64))	('expression', 'MPA', (106, 116))	('liver fibrosis', 'Disease', (30, 44))	('low', 'NegReg', (102, 105))	('PTEN', 'MPA', (131, 135))	('expression', 'MPA', (65, 75))	('liver fibrosis', 'Disease', 'MESH:D008103', (30, 44))	('HSC', 'Gene', (79, 82))	('HSC', 'Gene', '2523', (79, 82))	('DNMT3b', 'Gene', '1789', (120, 126))	('miR-29b', 'Gene', '407024', (57, 64))	('liver fibrosis', 'Phenotype', 'HP:0001395', (30, 44))	('hypomethylation', 'Var', (136, 151))
553708	30217221	Overexpression of miR-101 or silencing of DNMT3A induced the hypomethylation of PTEN promoter which was verified by a methylation specific PCR assay.	('PTEN', 'Gene', (80, 84))	('silencing', 'Var', (29, 38))	('DNMT3A', 'Gene', (42, 48))	('DNMT3A', 'Gene', '1788', (42, 48))	('miR', 'Gene', '220972', (18, 21))	('miR', 'Gene', (18, 21))	('hypomethylation', 'MPA', (61, 76))
553721	30217221	Homeobox (HOX) transcript antisense RNA (HOTAIR) is encoded within the HoxC gene cluster on chromosome 12, which silences the expression of HoxD genes and numerous tumor and metastasis suppressors by interacting with chromatin-remodeling enzymes.	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('HoxC', 'Gene', '3220', (71, 75))	('expression', 'MPA', (126, 136))	('antisense', 'Var', (26, 35))	('numerous tumor', 'Disease', (155, 169))	('HoxC', 'Gene', (71, 75))	('interacting', 'Interaction', (200, 211))	('HoxD genes', 'Gene', (140, 150))	('numerous tumor', 'Disease', 'MESH:D009369', (155, 169))	('silences', 'NegReg', (113, 121))
553741	30217221	lncRNA GAS5 competes with PTEN to bind miR-21, and depletion or overexpression of lncRNA GAS5 could increase or decrease miR-21 expression, resulting in the downregulation or upregulation of PTEN level in these tumor cells.	('GAS5', 'Gene', '60674', (89, 93))	('tumor', 'Disease', (211, 216))	('upregulation', 'PosReg', (175, 187))	('increase', 'PosReg', (100, 108))	('miR-21', 'Gene', '406991', (121, 127))	('GAS5', 'Gene', '60674', (7, 11))	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('downregulation', 'NegReg', (157, 171))	('GAS5', 'Gene', (89, 93))	('expression', 'MPA', (128, 138))	('depletion', 'Var', (51, 60))	('miR-21', 'Gene', '406991', (39, 45))	('miR-21', 'Gene', (121, 127))	('PTEN level', 'MPA', (191, 201))	('GAS5', 'Gene', (7, 11))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('decrease', 'NegReg', (112, 120))	('overexpression', 'PosReg', (64, 78))	('miR-21', 'Gene', (39, 45))
553749	30217221	MiR-494 expression was upregulated with XIST knockdown, whereas was downregulated with XIST overexpression.	('XIST', 'Gene', '7503', (87, 91))	('upregulated', 'PosReg', (23, 34))	('XIST', 'Gene', (40, 44))	('downregulated', 'NegReg', (68, 81))	('XIST', 'Gene', '7503', (40, 44))	('MiR-494', 'Gene', '574452', (0, 7))	('MiR-494', 'Gene', (0, 7))	('XIST', 'Gene', (87, 91))	('expression', 'MPA', (8, 18))	('knockdown', 'Var', (45, 54))
553771	30217221	HOTAIR knockdown suppressed HSC proliferation and activation in vitro and in vivo, increasing PTEN level, with the loss of DNA methylation mediated by miR-29b.	('loss', 'NegReg', (115, 119))	('PTEN level', 'MPA', (94, 104))	('DNA methylation', 'MPA', (123, 138))	('activation', 'CPA', (50, 60))	('suppressed', 'NegReg', (17, 27))	('rat', 'Species', '10116', (39, 42))	('HSC', 'Gene', (28, 31))	('miR-29b', 'Gene', (151, 158))	('knockdown', 'Var', (7, 16))	('HSC', 'Gene', '2523', (28, 31))	('increasing', 'PosReg', (83, 93))	('miR-29b', 'Gene', '407024', (151, 158))
553773	30217221	Collectively, HOTAIR might contribute to PTEN promoter methylation via sponging miR-29b.	('miR-29b', 'Gene', '407024', (80, 87))	('PTEN', 'Protein', (41, 45))	('contribute', 'Reg', (27, 37))	('sponging', 'Var', (71, 79))	('miR-29b', 'Gene', (80, 87))
553776	30217221	PTENP1 asRNA alpha knockdown induces cell cycle arrest and sensitizes cells to doxorubicin, suggesting the biological function for the PTENP1 asRNAs.	('sensitizes', 'Reg', (59, 69))	('induces', 'Reg', (29, 36))	('PTENP1', 'Gene', '11191', (135, 141))	('knockdown', 'Var', (19, 28))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (37, 54))	('doxorubicin', 'Chemical', 'MESH:D004317', (79, 90))	('cell cycle arrest', 'CPA', (37, 54))	('PTENP1', 'Gene', (0, 6))	('PTENP1', 'Gene', '11191', (0, 6))	('PTENP1', 'Gene', (135, 141))
553804	29457794	In another study, human population variation was studied by integrating protein structures with the human erythrocyte metabolic network to understand the adverse effects of drugs on genetic variants and identify new pathways related to drug perturbation.	('variants', 'Var', (190, 198))	('human', 'Species', '9606', (18, 23))	('human', 'Species', '9606', (100, 105))	('genetic variants', 'Var', (182, 198))
553818	29457794	Within the subset of SNPs that map to the representative domain of ARSA (SCOP: d1e2sp_), the mutation P428L (P426L in PDB 1e2s; dbSNP rs28940893) is associated with Metachromatic Leukodystrophy Disease (MLD).	('P426L', 'Mutation', 'rs28940893', (109, 114))	('P428L', 'Mutation', 'rs28940893', (102, 107))	('Metachromatic Leukodystrophy Disease', 'Disease', (165, 201))	('ARSA', 'Gene', (67, 71))	('Metachromatic Leukodystrophy Disease', 'Phenotype', 'HP:0006926', (165, 201))	('ARSA', 'Gene', '410', (67, 71))	('associated with', 'Reg', (149, 164))	('Metachromatic Leukodystrophy Disease', 'Disease', 'MESH:D007966', (165, 201))	('MLD', 'Disease', 'MESH:D007966', (203, 206))	('MLD', 'Disease', (203, 206))	('Leukodystrophy', 'Phenotype', 'HP:0002415', (179, 193))	('rs28940893', 'Mutation', 'rs28940893', (134, 144))	('P428L', 'Var', (102, 107))
553819	29457794	This mutation influences the biological assembly of ARSA, in which the native homo-octamer state (Figure 4(a)) is disfavored relative to the dimeric state (Figure 4(b)).	('biological assembly', 'MPA', (29, 48))	('influences', 'Reg', (14, 24))	('ARSA', 'Gene', (52, 56))	('ARSA', 'Gene', '410', (52, 56))	('mutation', 'Var', (5, 13))
553822	29457794	We studied 889 somatic cancer mutations from 88 genes (which were previously analyzed) from whole-exome sequence data from 178 tumour-normal pairs of lung squamous cell carcinoma.	('lung squamous cell carcinoma', 'Disease', (150, 178))	('carcinoma', 'Phenotype', 'HP:0030731', (169, 178))	('tumour', 'Phenotype', 'HP:0002664', (127, 133))	('tumour', 'Disease', 'MESH:D009369', (127, 133))	('cancer', 'Disease', (23, 29))	('cancer', 'Disease', 'MESH:D009369', (23, 29))	('mutations', 'Var', (30, 39))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (150, 178))	('tumour', 'Disease', (127, 133))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (155, 178))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (150, 178))
553825	29457794	For example, we find that selecting the top 25% of the data recovers 82 and 88 percent based on co-occurrence aids in identifying known oncogenic mutations and GOF mutations, respectively (compared to 1.6 and 2.9 percent when selected at random; Figure 5(c); for a sensitivity analysis, see Supplementary Note 5).	('aid', 'Gene', '57379', (110, 113))	('mutations', 'Var', (164, 173))	('aid', 'Gene', (110, 113))	('mutations', 'Var', (146, 155))
553826	29457794	These findings suggest that cancer mutations cluster in functionally-relevant parts of protein domains and that this property could guide the discovery of novel biomarkers and drug targets.	('cancer', 'Disease', (28, 34))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('mutations', 'Var', (35, 44))
553831	29457794	Yet, a 3D hotspot analysis of the mutations in this gene suggested that this gene may be important in cancer (Figure 5 (e)).	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('mutations', 'Var', (34, 43))
553832	29457794	This finding was recently validated, confirming that inhibition of ACAT1 suppresses GBM growth by blocking SREBP-1-mediated lipogenesis.	('inhibition', 'Var', (53, 63))	('SREBP-1', 'Gene', '6720', (107, 114))	('SREBP-1', 'Gene', (107, 114))	('ACAT1', 'Gene', (67, 72))	('ACAT1', 'Gene', '38', (67, 72))	('blocking', 'NegReg', (98, 106))	('GBM growth', 'CPA', (84, 94))	('suppresses', 'NegReg', (73, 83))
553843	29457794	Integrated frameworks like Recon3D enable understanding of how mutations or binding events lead to downstream responses and could aid in the identification of novel targets when coupled to structural bioinformatics, molecular dynamics simulations, and kinetic modeling.	('aid', 'Gene', (130, 133))	('lead to', 'Reg', (91, 98))	('mutations', 'Var', (63, 72))	('aid', 'Gene', '57379', (130, 133))
553860	29457794	Functional annotations of the missense mutations were also annotated using SIFT (http://sift.jcvi.org/).	('missense mutations', 'Var', (30, 48))	('SIFT', 'Disease', 'None', (75, 79))	('SIFT', 'Disease', (75, 79))
553861	29457794	All annotated gene-drug pairs contain information such as dosing guidelines, drug label annotations and each pair is generally specified in more than 1 type of annotation (dosing guideline, drug label, clinical annotation, variant annotation, VIP, or pathway).	('VIP', 'Gene', '7432', (243, 246))	('variant', 'Var', (223, 230))	('VIP', 'Gene', (243, 246))
553864	29457794	For this study, we used high level (processed) data from a subset of pre-analyzed mutations from 178 tumour-normal pairs of lung squamous cell carcinoma.	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (124, 152))	('tumour', 'Disease', (101, 107))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (129, 152))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (124, 152))	('lung squamous cell carcinoma', 'Disease', (124, 152))	('mutations', 'Var', (82, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (143, 152))	('tumour', 'Phenotype', 'HP:0002664', (101, 107))	('tumour', 'Disease', 'MESH:D009369', (101, 107))
553865	29457794	Within this set of genes, we found that 889 somatic cancer mutations map to residues that have been successfully resolved in the crystallographic structures of proteins.	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('mutations', 'Var', (59, 68))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('map', 'Reg', (69, 72))
553866	29457794	We used the list of 86 genes to query the cBioportal web-based dataset and downloaded various information including: somatic cancer mutations, cancer study sample IDs, amino acid mutations, annotations (coming from various sources, such as http://oncokb.org/ and https://www.mycancergenome.org/), type of mutation, copy number changes, overlapping mutations in COSMIC, the predicted functional impact score (from Mutation Assessor), variant allele frequency in the tumor sample, and total number of nonsynonymous mutations in the sample.	('functional impact score', 'MPA', (383, 406))	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('mutations', 'Var', (348, 357))	('cancer', 'Disease', (277, 283))	('tumor', 'Disease', 'MESH:D009369', (465, 470))	('cancer', 'Disease', 'MESH:D009369', (277, 283))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('tumor', 'Phenotype', 'HP:0002664', (465, 470))	('copy number changes', 'Var', (315, 334))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('tumor', 'Disease', (465, 470))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('cancer', 'Phenotype', 'HP:0002664', (277, 283))
553888	28500316	So far, many genetic association studies have revealed numerous variants underlying smoking-attributable cancers.	('cancers', 'Phenotype', 'HP:0002664', (105, 112))	('cancers', 'Disease', (105, 112))	('cancers', 'Disease', 'MESH:D009369', (105, 112))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('variants', 'Var', (64, 72))
553889	28500316	One of the most robust findings in genome-wide association studies is that variants in the CHRNA5/A3/B4 cluster on chromosome 15q24-25.1 show a significant association with both nicotine dependence and lung cancer.	('association', 'Reg', (156, 167))	('lung cancer', 'Phenotype', 'HP:0100526', (202, 213))	('CHRNA5/A3/B4', 'Gene', (91, 103))	('dependence and lung cancer', 'Disease', 'MESH:D008175', (187, 213))	('nicotine', 'Chemical', 'MESH:D009538', (178, 186))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('variants', 'Var', (75, 83))
553892	28500316	Furthermore, multiple lines of evidence from candidate gene-specific methylation (GSM) studies have indicated that aberrant DNAm in the promoter region of susceptibility genes for cigarette smoking confer a risk of cancer.	('aberrant DNAm', 'Var', (115, 128))	('cancer', 'Disease', (215, 221))	('cancer', 'Disease', 'MESH:D009369', (215, 221))	('DNAm', 'Var', (124, 128))	('cancer', 'Phenotype', 'HP:0002664', (215, 221))
553894	28500316	The primary objective of this study was to test this hypothesis by determining whether these methylated genes in smokers are indeed enriched in well-documented biological pathways implicated in the etiology of cancer.	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('methylated genes', 'Var', (93, 109))	('cancer', 'Disease', (210, 216))	('cancer', 'Disease', 'MESH:D009369', (210, 216))
553902	28500316	Interestingly, various crucial cancer-related genes, such as AHRR, CYP1A1, TNF, SMARCA4, CDK6, RARA, RXRB, CDKN1A, RARG, and NFE2L2, were enriched in the "aryl hydrocarbon receptor signaling pathway" (Supplementary Table S5), through which abnormal epigenetic programming may trigger smoking-attributable cancer (Fig.	('aryl hydrocarbon receptor', 'Gene', '11622', (155, 180))	('trigger', 'Reg', (276, 283))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('abnormal epigenetic programming', 'Var', (240, 271))	('cancer', 'Disease', (305, 311))	('CYP1A1', 'Gene', (67, 73))	('cancer', 'Disease', 'MESH:D009369', (305, 311))	('CDK6', 'Gene', (89, 93))	('TNF', 'Gene', (75, 78))	('AHR', 'Gene', '11622', (61, 64))	('SMARCA4', 'Gene', (80, 87))	('aryl hydrocarbon receptor', 'Gene', (155, 180))	('CDKN1A', 'Gene', (107, 113))	('AHR', 'Gene', (61, 64))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('cancer', 'Disease', (31, 37))	('cancer', 'Phenotype', 'HP:0002664', (305, 311))	('SMARCA4', 'Gene', '6597', (80, 87))
553909	28500316	After examining the correlation between methylation loci and RNA expression in lung adenocarcinoma (LUAD) and lung squamous-cell carcinoma (LUSC) samples, we found that large portions of the methylation loci were significantly positively or negatively correlated with RNA expression in both LUAD (Fig.	('negatively', 'NegReg', (241, 251))	('RNA', 'Gene', (268, 271))	('LUAD', 'Phenotype', 'HP:0030078', (100, 104))	('expression', 'MPA', (272, 282))	('LUAD', 'Phenotype', 'HP:0030078', (291, 295))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('correlated', 'Reg', (252, 262))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (79, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('lung adenocarcinoma (LUAD) and lung squamous-cell carcinoma', 'Disease', 'MESH:D000077192', (79, 138))	('methylation', 'Var', (191, 202))	('positively', 'PosReg', (227, 237))
553910	28500316	5a,b, and Supplementary Figure S4a,b) and LUSC (Table 4 and Supplementary Figures S5a,b and S6a,b), and the cg11314684 probe in the gene body of AKT3, the cg02385153 probe in the gene body of AHRR, and the cg24538512 probe in the gene body of NFATC1 were significantly positively correlated with RNA expression in both LUAD (Table 4 and Supplementary Figure S4c,d) and LUSC (Table 4 and Supplementary Figure S5c,d).	('cg24538512', 'Var', (206, 216))	('NFATC1', 'Gene', (243, 249))	('LUAD', 'Phenotype', 'HP:0030078', (319, 323))	('AKT3', 'Gene', (145, 149))	('correlated', 'Reg', (280, 290))	('AHR', 'Gene', '11622', (192, 195))	('cg11314684', 'Var', (108, 118))	('AHR', 'Gene', (192, 195))	('RNA expression', 'MPA', (296, 310))	('cg02385153', 'Var', (155, 165))
553911	28500316	On the other hand, we found that most of the methylation loci that correlated with RNA expression were significantly differentially expressed in the control tissues vs. cancer in both LUAD and LUSC samples (Supplementary Table S12 and Supplementary Figures S7 and S8).	('cancer', 'Disease', (169, 175))	('LUAD', 'Phenotype', 'HP:0030078', (184, 188))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('differentially', 'Reg', (117, 131))	('methylation', 'Var', (45, 56))	('cancer', 'Disease', 'MESH:D009369', (169, 175))	('RNA', 'Gene', (83, 86))
553919	28500316	Knockdown of AHRR is correlated with greater tumor cell invasiveness in many tissues, including those of the lung, colon, ovary, and breast.	('ovary', 'Disease', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))	('Knockdown', 'Var', (0, 9))	('tumor', 'Disease', (45, 50))	('AHR', 'Gene', '11622', (13, 16))	('AHR', 'Gene', (13, 16))	('colon', 'Disease', (115, 120))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('greater', 'PosReg', (37, 44))
553920	28500316	Epigenetic association studies have provided consistent evidence that F2RL3 methylation predisposes to implicatation in lung or colon cancer.	('lung or colon cancer', 'Disease', (120, 140))	('predisposes', 'Reg', (88, 99))	('lung or colon cancer', 'Disease', 'MESH:D008175', (120, 140))	('methylation', 'Var', (76, 87))	('F2RL3', 'Gene', (70, 75))	('colon cancer', 'Phenotype', 'HP:0003003', (128, 140))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
553921	28500316	demonstrated that smoking-induced hypomethylation in AHRR and F2RL3 contributes to the risk of lung cancer, providing evidence of specific altered methylation that can mediate the effect of smoking on cancer pathogenesis.	('methylation', 'MPA', (147, 158))	('lung cancer', 'Disease', (95, 106))	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('lung cancer', 'Phenotype', 'HP:0100526', (95, 106))	('cancer', 'Disease', (201, 207))	('AHR', 'Gene', '11622', (53, 56))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('AHR', 'Gene', (53, 56))	('altered', 'Reg', (139, 146))	('lung cancer', 'Disease', 'MESH:D008175', (95, 106))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('F2RL3', 'Gene', (62, 67))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('hypomethylation', 'Var', (34, 49))
553924	28500316	By performing an enrichment analysis for smoking-related phenotypes in the NHGRI-EBI GWAS Catalog, these authors found that these smoking-related methylated genes were significantly overrepresented in all types of cancer (P = 8.0 x 10-15), lung adenocarcinoma (P = 1.5 x 10-3), and colorectal cancer (P = 1.4 x 10-3), which is in line with our findings.	('cancer', 'Disease', (293, 299))	('cancer', 'Disease', 'MESH:D009369', (293, 299))	('overrepresented', 'PosReg', (182, 197))	('colorectal cancer', 'Disease', 'MESH:D015179', (282, 299))	('lung adenocarcinoma', 'Disease', (240, 259))	('cancer', 'Disease', (214, 220))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (240, 259))	('colorectal cancer', 'Phenotype', 'HP:0003003', (282, 299))	('carcinoma', 'Phenotype', 'HP:0030731', (250, 259))	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('colorectal cancer', 'Disease', (282, 299))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (240, 259))	('cancer', 'Phenotype', 'HP:0002664', (293, 299))	('methylated', 'Var', (146, 156))	('cancer', 'Disease', 'MESH:D009369', (214, 220))
553927	28500316	Our findings thus suggest that abnormalities in the pathway of "RAR activation" confer susceptibility to cancer.	('abnormalities', 'Var', (31, 44))	('cancer', 'Disease', (105, 111))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('susceptibility', 'Reg', (87, 101))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))
553928	28500316	reported that the "RAR activation" pathway is affected by differential methylation in cancers.	('methylation', 'Var', (71, 82))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('cancers', 'Phenotype', 'HP:0002664', (86, 93))	('cancers', 'Disease', (86, 93))	('cancers', 'Disease', 'MESH:D009369', (86, 93))	('affected', 'Reg', (46, 54))
553933	28500316	Together, abnormal smoking-related DNAm in the aryl hydrocarbon receptor signaling pathway may induce more DNA adduct formation that leads to miscoding of the sequence of DNA (see Fig.	('leads to', 'Reg', (133, 141))	('aryl hydrocarbon receptor', 'Gene', (47, 72))	('DNA adduct formation', 'MPA', (107, 127))	('abnormal', 'Var', (10, 18))	('aryl hydrocarbon receptor', 'Gene', '11622', (47, 72))	('more', 'PosReg', (102, 106))	('miscoding', 'MPA', (142, 151))	('induce', 'Reg', (95, 101))	('DNAm', 'Var', (35, 39))
553942	28500316	Aberrant methylation of NOTCH1 may thus lead to a greater risk of smoking-induced cancer.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('lead to', 'Reg', (40, 47))	('NOTCH1', 'Gene', (24, 30))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('Aberrant methylation', 'Var', (0, 20))
553945	28500316	Both DNA mutation and methylation influence the expression of SMARCA4 in cancers such as Burkitt lymphoma, ovarian carcinoma, and lung cancer.	('lung cancer', 'Phenotype', 'HP:0100526', (130, 141))	('ovarian carcinoma', 'Disease', (107, 124))	('Burkitt lymphoma', 'Disease', (89, 105))	('ovarian carcinoma', 'Phenotype', 'HP:0025318', (107, 124))	('cancers', 'Phenotype', 'HP:0002664', (73, 80))	('Burkitt lymphoma', 'Disease', 'MESH:D002051', (89, 105))	('methylation', 'Var', (22, 33))	('lymphoma', 'Phenotype', 'HP:0002665', (97, 105))	('cancers', 'Disease', (73, 80))	('SMARCA4', 'Gene', (62, 69))	('expression', 'MPA', (48, 58))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('lung cancer', 'Disease', (130, 141))	('Burkitt lymphoma', 'Phenotype', 'HP:0030080', (89, 105))	('cancers', 'Disease', 'MESH:D009369', (73, 80))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('SMARCA4', 'Gene', '6597', (62, 69))	('lung cancer', 'Disease', 'MESH:D008175', (130, 141))	('influence', 'Reg', (34, 43))	('ovarian carcinoma', 'Disease', 'MESH:D010051', (107, 124))
553946	28500316	Consistently, two methylation loci (cg18040892 and cg23963476) were significantly inversely correlated with RNA expression of SMARCA4 in LUSC samples.	('cg23963476', 'Var', (51, 61))	('SMARCA4', 'Gene', (126, 133))	('SMARCA4', 'Gene', '6597', (126, 133))	('inversely', 'NegReg', (82, 91))	('correlated', 'Reg', (92, 102))	('cg18040892', 'Var', (36, 46))	('RNA expression', 'MPA', (108, 122))
553947	28500316	The extent of methylation of the cg23963476 probe, which is hypomethylated in smokers, was significantly lower in LUSC tissues than in control tissues, suggesting that smoking-associated hypomethylation of SMARCA4 elicits the development of lung cancer.	('lower', 'NegReg', (105, 110))	('methylation', 'MPA', (14, 25))	('lung cancer', 'Disease', (241, 252))	('SMARCA4', 'Gene', (206, 213))	('SMARCA4', 'Gene', '6597', (206, 213))	('lung cancer', 'Phenotype', 'HP:0100526', (241, 252))	('hypomethylation', 'Var', (187, 202))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))	('cg23963476', 'Gene', (33, 43))	('elicits', 'Reg', (214, 221))	('lung cancer', 'Disease', 'MESH:D008175', (241, 252))
553948	28500316	DUSP4, which belongs to dual-specificity phosphatase (DUSPs) family, regulating the activity and location of MAPKs, is a negative regulator of extracellular-regulated kinase activity and is upregulated in EGFR-mutant lung cancer cell lines compared with K-ras-mutant cells.	('lung cancer', 'Disease', 'MESH:D008175', (217, 228))	('lung cancer', 'Disease', (217, 228))	('EGFR-mutant', 'Var', (205, 216))	('lung cancer', 'Phenotype', 'HP:0100526', (217, 228))	('extracellular-regulated kinase activity', 'MPA', (143, 182))	('EGFR-mutant', 'Gene', (205, 216))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('DUSP4', 'Gene', (0, 5))	('upregulated', 'PosReg', (190, 201))
553951	28500316	In the present study, we found that two smoking-associated methylation probes (cg07151117 and cg24379915) that are correlated with RNA expression of DUSP4 were significantly hypomethylated in both LUAD and LUSC cancer tissues compared with the control samples.	('cancer', 'Disease', 'MESH:D009369', (211, 217))	('cg24379915', 'Var', (94, 104))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('DUSP4', 'Gene', (149, 154))	('cancer', 'Disease', (211, 217))	('cg07151117', 'Var', (79, 89))	('hypomethylated', 'Var', (174, 188))	('LUAD', 'Phenotype', 'HP:0030078', (197, 201))	('LUAD', 'Disease', (197, 201))
553952	28500316	These results indicate that hypomethylated DUSP4 is involved in smoking-induced lung cancer.	('lung cancer', 'Disease', 'MESH:D008175', (80, 91))	('DUSP4', 'Protein', (43, 48))	('lung cancer', 'Disease', (80, 91))	('involved', 'Reg', (52, 60))	('lung cancer', 'Phenotype', 'HP:0100526', (80, 91))	('hypomethylated', 'Var', (28, 42))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
553959	28500316	More studies are warranted to reveal the specific function of aberrant methylation of particular genes in response to smoking in the development of cancer.	('cancer', 'Disease', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('aberrant methylation', 'Var', (62, 82))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))
554049	32316322	Non-Coding RNAs in Lung Tumor Initiation and Progression Lung cancer is one of the deadliest forms of cancer affecting society today.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('Tumor', 'Phenotype', 'HP:0002664', (24, 29))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('Lung cancer', 'Disease', 'MESH:D008175', (57, 68))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('cancer', 'Disease', (62, 68))	('Lung Tumor', 'Disease', (19, 29))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('Non-Coding RNAs', 'Var', (0, 15))	('Lung cancer', 'Phenotype', 'HP:0100526', (57, 68))	('Lung cancer', 'Disease', (57, 68))	('Lung Tumor', 'Phenotype', 'HP:0100526', (19, 29))
554050	32316322	Non-coding RNAs, such as microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), through the transcriptional, post-transcriptional, and epigenetic changes they impose, have been found to be dysregulated to affect lung cancer tumorigenesis and metastasis.	('metastasis', 'CPA', (269, 279))	('tumor', 'Disease', (251, 256))	('lung cancer', 'Disease', (239, 250))	('lung cancer', 'Phenotype', 'HP:0100526', (239, 250))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('affect', 'Reg', (232, 238))	('lung cancer', 'Disease', 'MESH:D008175', (239, 250))	('epigenetic changes', 'Var', (162, 180))	('tumor', 'Disease', 'MESH:D009369', (251, 256))	('tumor', 'Phenotype', 'HP:0002664', (251, 256))
554052	32316322	For initiation, these hallmarks include tumor initiating cells, immortalization, activation of oncogenes and inactivation of tumor suppressors.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('activation', 'PosReg', (81, 91))	('tumor', 'Disease', (125, 130))	('immortalization', 'CPA', (64, 79))	('oncogenes', 'Protein', (95, 104))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', (40, 45))	('inactivation', 'Var', (109, 121))
554054	32316322	The targeting of these hallmarks with non-coding RNAs can affect vital metabolic and cell signaling pathways, which as a result can potentially have a role in cancerous and pathological processes.	('cancerous', 'Disease', (159, 168))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('role', 'Reg', (151, 155))	('have', 'Reg', (144, 148))	('cancerous', 'Disease', 'MESH:D009369', (159, 168))	('non-coding RNAs', 'Var', (38, 53))	('affect', 'Reg', (58, 64))
554063	32316322	This is shown by the observance that adenocarcinoma is commonly caused by liver kinase B1 (STK11) mutations, epidermal growth factor receptor (EGFR) kinase domain mutations, tyrosine-protein kinase MET (MET) amplification, Kirsten rat sarcoma viral (KRAS) mutations, and anaplastic lymphoma kinase (ALK) mutations.	('tyrosine-protein kinase MET', 'Gene', (174, 201))	('rat', 'Species', '10116', (231, 234))	('mutations', 'Var', (256, 265))	('epidermal growth factor receptor', 'Gene', (109, 141))	('STK11', 'Gene', (91, 96))	('adenocarcinoma', 'Disease', (37, 51))	('sarcoma', 'Disease', 'MESH:D012509', (235, 242))	('sarcoma', 'Disease', (235, 242))	('anaplastic lymphoma kinase', 'Disease', (271, 297))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (271, 290))	('caused', 'Reg', (64, 70))	('MET', 'Gene', (198, 201))	('EGFR', 'Gene', (143, 147))	('MET', 'Gene', '4233', (198, 201))	('adenocarcinoma', 'Disease', 'MESH:D000230', (37, 51))	('tyrosine-protein kinase MET', 'Gene', '24553', (174, 201))	('sarcoma', 'Phenotype', 'HP:0100242', (235, 242))	('MET', 'Gene', (203, 206))	('MET', 'Gene', '4233', (203, 206))	('mutations', 'Var', (98, 107))	('mutations', 'Var', (304, 313))	('STK11', 'Gene', '314621', (91, 96))	('lymphoma', 'Phenotype', 'HP:0002665', (282, 290))	('epidermal growth factor receptor', 'Gene', '24329', (109, 141))	('carcinoma', 'Phenotype', 'HP:0030731', (42, 51))
554064	32316322	Alternatively, squamous-cell carcinoma is commonly caused by EGFR amplification, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) amplification and MET amplification.	('PIK3CA', 'Gene', '5290', (153, 159))	('amplification', 'Var', (66, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (29, 38))	('squamous-cell carcinoma', 'Phenotype', 'HP:0002860', (15, 38))	('squamous-cell carcinoma', 'Disease', (15, 38))	('caused', 'Reg', (51, 57))	('MET', 'Gene', '4233', (179, 182))	('MET', 'Gene', (179, 182))	('phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha', 'Gene', '5290', (81, 151))	('squamous-cell carcinoma', 'Disease', 'MESH:D002294', (15, 38))	('amplification', 'Var', (161, 174))	('PIK3CA', 'Gene', (153, 159))	('EGFR', 'Gene', (61, 65))
554065	32316322	In addition, SCLC is commonly caused by MET mutations and PIK3CA amplification.	('MET', 'Gene', (40, 43))	('PIK3CA', 'Gene', (58, 64))	('PIK3CA', 'Gene', '5290', (58, 64))	('SCLC', 'Phenotype', 'HP:0030357', (13, 17))	('SCLC', 'Gene', '7864', (13, 17))	('amplification', 'Var', (65, 78))	('caused', 'Reg', (30, 36))	('MET', 'Gene', '4233', (40, 43))	('SCLC', 'Gene', (13, 17))
554066	32316322	Yet, other abnormalities such as tumor protein p53 (TP53) mutations are highly found throughout all the aforementioned types of lung cancers.	('lung cancers', 'Phenotype', 'HP:0100526', (128, 140))	('mutations', 'Var', (58, 67))	('TP53', 'Gene', '7157', (52, 56))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('cancers', 'Phenotype', 'HP:0002664', (133, 140))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('TP53', 'Gene', (52, 56))	('lung cancers', 'Disease', (128, 140))	('lung cancer', 'Phenotype', 'HP:0100526', (128, 139))	('tumor', 'Disease', (33, 38))	('found', 'Reg', (79, 84))	('lung cancers', 'Disease', 'MESH:D008175', (128, 140))	('p53', 'Gene', (47, 50))	('p53', 'Gene', '7157', (47, 50))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
554071	32316322	These inhibitors selectively modify the mutant cysteine residue in GDP-bound KRAS G12C and inhibit GTP-loading and downstream KRAS-dependent signaling.	('modify', 'Reg', (29, 35))	('GTP', 'Chemical', 'MESH:D006160', (99, 102))	('cysteine residue', 'MPA', (47, 63))	('GDP', 'Chemical', 'MESH:D006153', (67, 70))	('inhibit', 'NegReg', (91, 98))	('KRAS', 'Gene', (77, 81))	('GTP-loading', 'MPA', (99, 110))	('cysteine', 'Chemical', 'MESH:D003545', (47, 55))	('mutant', 'Var', (40, 46))	('KRAS-dependent signaling', 'MPA', (126, 150))	('G12C', 'Chemical', '-', (82, 86))
554073	32316322	Thus, genetic mutations/signaling pathways-based targeted therapies for lung cancer will demonstrate promise of success in the future.	('genetic mutations/signaling', 'Var', (6, 33))	('lung cancer', 'Disease', (72, 83))	('lung cancer', 'Phenotype', 'HP:0100526', (72, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('rat', 'Species', '10116', (96, 99))	('lung cancer', 'Disease', 'MESH:D008175', (72, 83))
554080	32316322	Furthermore, signaling pathways that act as either oncogenes or tumor suppressors in lung cancer, such as notch, wingless-related integration site and hedgehog have been found to be abnormally expressed in TICs, indicating TICs expression of these signaling pathways can lead to tumorigenesis in lung cancer.	('lung cancer', 'Disease', 'MESH:D008175', (296, 307))	('tumor', 'Phenotype', 'HP:0002664', (279, 284))	('expression', 'Var', (228, 238))	('TIC', 'Phenotype', 'HP:0100033', (206, 209))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('TICs', 'Disease', (206, 210))	('TIC', 'Phenotype', 'HP:0100033', (223, 226))	('TICs', 'Disease', (223, 227))	('lung cancer', 'Phenotype', 'HP:0100526', (296, 307))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('lung cancer', 'Disease', (85, 96))	('rat', 'Species', '10116', (135, 138))	('notch', 'Gene', '4851;4854', (106, 111))	('TICs', 'Disease', 'MESH:D020323', (223, 227))	('TICs', 'Disease', 'MESH:D020323', (206, 210))	('cancer', 'Phenotype', 'HP:0002664', (301, 307))	('tumor', 'Disease', (279, 284))	('lung cancer', 'Disease', (296, 307))	('lung cancer', 'Disease', 'MESH:D008175', (85, 96))	('lead to', 'Reg', (271, 278))	('tumor', 'Disease', 'MESH:D009369', (279, 284))	('tumor', 'Disease', (64, 69))	('lung cancer', 'Phenotype', 'HP:0100526', (85, 96))	('TICs', 'Phenotype', 'HP:0100033', (223, 227))	('TICs', 'Phenotype', 'HP:0100033', (206, 210))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('notch', 'Gene', (106, 111))
554088	32316322	Historically, it was believed that the upregulation/activation of the gene telomerase reverse transcriptase (hTERT) solely leads to immortalization, but recent research suggests that immortalization is a two-step process in which hTERT promoter mutations and further subsequent upregulation of telomerase occurs.	('hTERT', 'Gene', (230, 235))	('upregulation', 'PosReg', (278, 290))	('telomerase reverse transcriptase', 'Gene', (75, 107))	('hTERT', 'Gene', '7015', (230, 235))	('telomerase', 'Enzyme', (294, 304))	('hTERT', 'Gene', '7015', (109, 114))	('promoter mutations', 'Var', (236, 254))	('telomerase reverse transcriptase', 'Gene', '7015', (75, 107))	('hTERT', 'Gene', (109, 114))
554091	32316322	After cells become immortalized, genetic mutations of oncogenes and the inactivation of tumor suppressors are the next critical step in lung tumor initiation for both NSCLC and SCLC.	('tumor', 'Disease', 'MESH:D009369', (141, 146))	('lung tumor initiation', 'Disease', 'MESH:D008175', (136, 157))	('SCLC', 'Gene', '7864', (168, 172))	('SCLC', 'Gene', (168, 172))	('NSCLC', 'Phenotype', 'HP:0030358', (167, 172))	('lung tumor', 'Phenotype', 'HP:0100526', (136, 146))	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('tumor', 'Disease', (88, 93))	('oncogenes', 'Gene', (54, 63))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('genetic mutations', 'Var', (33, 50))	('lung tumor initiation', 'Disease', (136, 157))	('SCLC', 'Phenotype', 'HP:0030357', (177, 181))	('NSCLC', 'Disease', 'MESH:D002289', (167, 172))	('SCLC', 'Phenotype', 'HP:0030357', (168, 172))	('tumor', 'Disease', (141, 146))	('SCLC', 'Gene', '7864', (177, 181))	('SCLC', 'Gene', (177, 181))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('NSCLC', 'Disease', (167, 172))
554092	32316322	The alteration of certain oncogenes and the inactivation of certain tumor suppressor cells tends to be more prevalent depending on the type and subtype of lung cancer.	('alteration', 'Reg', (4, 14))	('tumor', 'Disease', (68, 73))	('rat', 'Species', '10116', (8, 11))	('prevalent', 'Reg', (108, 117))	('lung cancer', 'Disease', (155, 166))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('lung cancer', 'Phenotype', 'HP:0100526', (155, 166))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('oncogenes', 'Protein', (26, 35))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('inactivation', 'Var', (44, 56))	('lung cancer', 'Disease', 'MESH:D008175', (155, 166))
554093	32316322	For instance, adenocarcinoma is generally induced in part to alterations in KRAS, ALK, ROS proto-oncogene 1 (ROS1), Ret proto-oncogene (RET), neurotrophic receptor kinase 1 and neuregulin.	('ROS1', 'Gene', '6098', (109, 113))	('RET', 'Gene', '5979', (136, 139))	('Ret', 'Gene', (116, 119))	('ROS proto-oncogene 1', 'Gene', '6098', (87, 107))	('ROS proto-oncogene 1', 'Gene', (87, 107))	('ALK', 'Gene', (82, 85))	('Ret', 'Gene', '5979', (116, 119))	('KRAS', 'Gene', (76, 80))	('rat', 'Species', '10116', (65, 68))	('carcinoma', 'Phenotype', 'HP:0030731', (19, 28))	('RET', 'Gene', (136, 139))	('alterations', 'Var', (61, 72))	('adenocarcinoma', 'Disease', (14, 28))	('induced', 'Reg', (42, 49))	('ROS1', 'Gene', (109, 113))	('adenocarcinoma', 'Disease', 'MESH:D000230', (14, 28))
554094	32316322	Furthermore, squamous cell carcinoma is commonly a byproduct of mutations in TP53, cyclin dependent kinase inhibitor 2A (CDKN2A), SOX2, and akt serine/thereonine kinase (AKT).	('CDKN2A', 'Gene', '1029', (121, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (27, 36))	('squamous cell carcinoma', 'Disease', (13, 36))	('serine', 'Chemical', 'MESH:D012694', (144, 150))	('cyclin dependent kinase inhibitor 2A', 'Gene', '1029', (83, 119))	('AKT', 'Gene', '207', (170, 173))	('SOX2', 'Gene', (130, 134))	('cyclin dependent kinase inhibitor 2A', 'Gene', (83, 119))	('akt serine/thereonine kinase', 'Pathway', (140, 168))	('AKT', 'Gene', (170, 173))	('mutations', 'Var', (64, 73))	('SOX2', 'Gene', '6657', (130, 134))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (13, 36))	('TP53', 'Gene', '7157', (77, 81))	('CDKN2A', 'Gene', (121, 127))	('TP53', 'Gene', (77, 81))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (13, 36))
554095	32316322	In SCLC, mutations of rb transcriptional corepressor 1 (RB1) and TP53 are a more common occurrence compared to NSCLC.	('SCLC', 'Gene', '7864', (3, 7))	('SCLC', 'Phenotype', 'HP:0030357', (3, 7))	('SCLC', 'Gene', (3, 7))	('TP53', 'Gene', '7157', (65, 69))	('TP53', 'Gene', (65, 69))	('rb transcriptional corepressor 1', 'Gene', '5925', (22, 54))	('NSCLC', 'Disease', (111, 116))	('RB1', 'Gene', (56, 59))	('mutations', 'Var', (9, 18))	('NSCLC', 'Disease', 'MESH:D002289', (111, 116))	('rb transcriptional corepressor 1', 'Gene', (22, 54))	('RB1', 'Gene', '5925', (56, 59))	('common', 'Reg', (81, 87))	('SCLC', 'Gene', (112, 116))	('NSCLC', 'Phenotype', 'HP:0030358', (111, 116))	('SCLC', 'Gene', '7864', (112, 116))	('SCLC', 'Phenotype', 'HP:0030357', (112, 116))
554096	32316322	TP53 is a well-known tumor suppressor, whose alteration leads to uncontrolled cellular growth.	('TP53', 'Gene', '7157', (0, 4))	('uncontrolled', 'MPA', (65, 77))	('TP53', 'Gene', (0, 4))	('tumor', 'Disease', (21, 26))	('leads to', 'Reg', (56, 64))	('alteration', 'Var', (45, 55))	('tumor', 'Disease', 'MESH:D009369', (21, 26))	('rat', 'Species', '10116', (49, 52))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
554098	32316322	Overall, lung tumor initiation involves immortalization followed by transformation mediated by activation of oncogenes and inactivation of tumor suppressors.	('inactivation', 'Var', (123, 135))	('tumor', 'Disease', 'MESH:D009369', (139, 144))	('tumor', 'Disease', (14, 19))	('lung tumor initiation', 'Disease', (9, 30))	('lung tumor initiation', 'Disease', 'MESH:D008175', (9, 30))	('activation', 'PosReg', (95, 105))	('lung tumor', 'Phenotype', 'HP:0100526', (9, 19))	('tumor', 'Disease', (139, 144))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('oncogenes', 'Protein', (109, 118))	('tumor', 'Disease', 'MESH:D009369', (14, 19))	('immortalization', 'CPA', (40, 55))	('tumor', 'Phenotype', 'HP:0002664', (14, 19))
554106	32316322	After a cell becomes immortalized and has become transformed through the activation of oncogenes and inactivation of tumor suppressor genes, research suggest the first step in metastasis begins with tumor cells invading the stroma of its primary tumor site.	('tumor', 'Disease', (199, 204))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumor', 'Disease', (117, 122))	('tumor', 'Disease', 'MESH:D009369', (246, 251))	('tumor', 'Phenotype', 'HP:0002664', (246, 251))	('tumor', 'Disease', 'MESH:D009369', (199, 204))	('inactivation', 'Var', (101, 113))	('tumor', 'Phenotype', 'HP:0002664', (199, 204))	('tumor', 'Disease', (246, 251))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
554111	32316322	For instance, upregulated expressions of Notch 1 in hypoxic lung adenocarcinoma cells activate insulin-like growth factor 1 receptor (IGF1R) via binding to the IGF1R promoter directly leading to activation of Akt1, which allows the tumor cells to survive under hypoxic parameters.	('Akt1', 'Gene', (209, 213))	('expressions', 'Var', (26, 37))	('activate', 'PosReg', (86, 94))	('insulin-like growth factor 1 receptor', 'Gene', '3480', (95, 132))	('upregulated', 'PosReg', (14, 25))	('Notch 1', 'Gene', (41, 48))	('binding', 'Interaction', (145, 152))	('Akt1', 'Gene', '207', (209, 213))	('IGF1R', 'Gene', '3480', (160, 165))	('hypoxic lung adenocarcinoma', 'Disease', 'MESH:D000077192', (52, 79))	('IGF1R', 'Gene', '3480', (134, 139))	('tumor', 'Disease', (232, 237))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (60, 79))	('IGF1R', 'Gene', (160, 165))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('IGF1R', 'Gene', (134, 139))	('tumor', 'Disease', 'MESH:D009369', (232, 237))	('hypoxic lung adenocarcinoma', 'Disease', (52, 79))	('insulin-like growth factor 1 receptor', 'Gene', (95, 132))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('Notch 1', 'Gene', '4851', (41, 48))	('activation', 'PosReg', (195, 205))
554119	32316322	Cells resistant to EGFR TKIs may undergo T790M substitution and C797S mutation.	('undergo', 'Reg', (33, 40))	('C797S', 'Mutation', 'rs1057519861', (64, 69))	('T790M substitution', 'Var', (41, 59))	('C797S', 'Var', (64, 69))	('T790M', 'Mutation', 'rs121434569', (41, 46))
554121	32316322	Since both of these mutations work hand in hand, previous and recent research suggests co-targeting both EGFR and c-MET in lung cancer.	('c-MET', 'Gene', (114, 119))	('lung cancer', 'Disease', (123, 134))	('lung cancer', 'Phenotype', 'HP:0100526', (123, 134))	('EGFR', 'Protein', (105, 109))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('lung cancer', 'Disease', 'MESH:D008175', (123, 134))	('c-MET', 'Gene', '4233', (114, 119))	('mutations', 'Var', (20, 29))
554122	32316322	Another common mutation is through the Echinoderm microtubule-associated protein-like 4 (EML4) and ALK mutations, but resistance prevailed due to mutations in C1156Y and L1196M within EML4-ALK.	('C1156Y', 'Var', (159, 165))	('ALK', 'Gene', (99, 102))	('EML4', 'Gene', (89, 93))	('C1156Y', 'Mutation', 'rs1057519859', (159, 165))	('Echinoderm microtubule-associated protein-like 4', 'Gene', '27436', (39, 87))	('EML4', 'Gene', '27436', (89, 93))	('EML4', 'Gene', (184, 188))	('Echinoderm microtubule-associated protein-like 4', 'Gene', (39, 87))	('L1196M', 'Mutation', 'rs1057519784', (170, 176))	('L1196M', 'Var', (170, 176))	('EML4', 'Gene', '27436', (184, 188))
554123	32316322	KRAS in NSCLC include G12C (most common), G12D, G13D and G12V.	('G12D', 'Mutation', 'rs121913529', (42, 46))	('NSCLC', 'Phenotype', 'HP:0030358', (8, 13))	('G13D', 'Mutation', 'rs112445441', (48, 52))	('G12V', 'Var', (57, 61))	('G12C', 'Chemical', '-', (22, 26))	('SCLC', 'Phenotype', 'HP:0030357', (9, 13))	('G12V', 'Mutation', 'rs121913529', (57, 61))	('NSCLC', 'Disease', (8, 13))	('G12C', 'Var', (22, 26))	('G12D', 'Var', (42, 46))	('NSCLC', 'Disease', 'MESH:D002289', (8, 13))	('G13D', 'Var', (48, 52))
554124	32316322	Currently resistance against AMG510 is due in part to the fact that G12C inhibitor only binds to the inactive state of G12C.	('binds', 'Interaction', (88, 93))	('G12C', 'Var', (68, 72))	('AMG510', 'Chemical', '-', (29, 35))	('G12C', 'Chemical', '-', (68, 72))	('G12C', 'Chemical', '-', (119, 123))
554125	32316322	After G12C inhibitor is introduced into a culture they induce lower overall KRAS activity, but after a brief period KRAS activity resumes due to the production of new G12C that is in an active state, making G12C inhibitor obsolete, as they are not able to bind to their targets and inhibit them.	('G12C', 'Chemical', '-', (6, 10))	('G12C', 'Chemical', '-', (207, 211))	('KRAS', 'CPA', (76, 80))	('G12C', 'Var', (167, 171))	('G12C', 'Chemical', '-', (167, 171))	('inhibit', 'NegReg', (282, 289))
554135	32316322	Dysregulation of certain non-coding RNAs in lung TICs control tumor initiation and progression.	('tumor initiation', 'Disease', 'MESH:D009369', (62, 78))	('lung TICs', 'Phenotype', 'HP:0100035', (44, 53))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('Dysregulation', 'Var', (0, 13))	('TIC', 'Phenotype', 'HP:0100033', (49, 52))	('tumor initiation', 'Disease', (62, 78))	('lung TICs', 'Disease', (44, 53))	('lung TICs', 'Disease', 'MESH:D013981', (44, 53))	('TICs', 'Phenotype', 'HP:0100033', (49, 53))	('progression', 'CPA', (83, 94))
554142	32316322	Knocking down HOTAIR inhibits features of TICs including frequencies of side population cells and spheroid forming cells.	('inhibits', 'NegReg', (21, 29))	('Knocking down', 'Var', (0, 13))	('HOTAIR', 'Gene', '100124700', (14, 20))	('spheroid forming cells', 'CPA', (98, 120))	('TIC', 'Phenotype', 'HP:0100033', (42, 45))	('TICs', 'Disease', (42, 46))	('TICs', 'Disease', 'MESH:D020323', (42, 46))	('TICs', 'Phenotype', 'HP:0100033', (42, 46))	('HOTAIR', 'Gene', (14, 20))
554145	32316322	Activation of Simian virus 40 small T antigen (SV40 ST) and TERT in human bronchial epithelial cells induces an upregulation of miR-27a leading to enhanced immortalization.	('Simian virus 40', 'Species', '1891767', (14, 29))	('enhanced', 'PosReg', (147, 155))	('miR-27a', 'Gene', (128, 135))	('human', 'Species', '9606', (68, 73))	('TERT', 'Gene', '7015', (60, 64))	('immortalization', 'CPA', (156, 171))	('upregulation', 'PosReg', (112, 124))	('miR-27a', 'Gene', '407018', (128, 135))	('SV40', 'Var', (47, 51))	('TERT', 'Gene', (60, 64))
554149	32316322	Similarly, other tumor suppressive miRNAs including miR-486-5p, miR-613, miR-340, and miR-34b-3p upregulate expression of CDK4 in NSCLC.	('NSCLC', 'Disease', 'MESH:D002289', (130, 135))	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('tumor', 'Disease', (17, 22))	('miR-486-5p', 'Var', (52, 62))	('upregulate', 'PosReg', (97, 107))	('miR-340', 'Gene', (73, 80))	('miR-34b', 'Gene', '407041', (86, 93))	('miR-340', 'Gene', '442908', (73, 80))	('NSCLC', 'Phenotype', 'HP:0030358', (130, 135))	('SCLC', 'Phenotype', 'HP:0030357', (131, 135))	('miR-34b', 'Gene', (86, 93))	('CDK4', 'Gene', '1019', (122, 126))	('CDK4', 'Gene', (122, 126))	('expression', 'MPA', (108, 118))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('NSCLC', 'Disease', (130, 135))	('miR-613', 'Gene', '693198', (64, 71))	('miR-613', 'Gene', (64, 71))
554151	32316322	The ability of non-coding RNAs to interact with oncogenes is a valuable hallmark in lung tumor initiation and progression.	('lung tumor initiation', 'Disease', (84, 105))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('non-coding', 'Var', (15, 25))	('lung tumor', 'Phenotype', 'HP:0100526', (84, 94))	('lung tumor initiation', 'Disease', 'MESH:D008175', (84, 105))	('RNAs', 'Gene', (26, 30))	('interact', 'Interaction', (34, 42))
554152	32316322	The first miRNA discovered was let-7 family including let-7a, let-7b, let-7c, let-7d, let-7e, let-7f, let-7g, let-7i, miR-98, and miR-202.	('let-7e', 'Gene', '406887', (86, 92))	('let-7i', 'Gene', (110, 116))	('miR-98', 'Gene', (118, 124))	('let-7c', 'Gene', (70, 76))	('let-7c', 'Gene', '406885', (70, 76))	('let-7e', 'Gene', (86, 92))	('let-7g', 'Gene', (102, 108))	('let-7d', 'Gene', (78, 84))	('let-7b', 'Gene', '406884', (62, 68))	('let-7i', 'Gene', '406891', (110, 116))	('let-7a', 'Var', (54, 60))	('let-7b', 'Gene', (62, 68))	('let-7f', 'Var', (94, 100))	('let-7d', 'Gene', '406886', (78, 84))	('let-7g', 'Gene', '406890', (102, 108))	('miR-202', 'Gene', (130, 137))	('miR-202', 'Gene', '574448', (130, 137))	('miR-98', 'Gene', '407054', (118, 124))
554159	32316322	Another key relationship between non-coding RNAs and lung cancer is how miRNAs can be used as diagnostic markers.	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('lung cancer', 'Disease', 'MESH:D008175', (53, 64))	('non-coding RNAs', 'Var', (33, 48))	('lung cancer', 'Disease', (53, 64))	('lung cancer', 'Phenotype', 'HP:0100526', (53, 64))
554165	32316322	Although most ADAR editing occurs in non-coding regions in lung cancer, few studies have shown the crosstalk between ADAR and non-coding RNAs.	('lung cancer', 'Disease', 'MESH:D008175', (59, 70))	('ADAR', 'Gene', '103', (117, 121))	('editing', 'Var', (19, 26))	('ADAR', 'Gene', (14, 18))	('lung cancer', 'Disease', (59, 70))	('lung cancer', 'Phenotype', 'HP:0100526', (59, 70))	('ADAR', 'Gene', (117, 121))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('ADAR', 'Gene', '103', (14, 18))
554166	32316322	have demonstrated that ADAR1 gene amplification in NSCLC promotes tumor growth via enhanced A-to-I editing of RNA transcripts including miR-381.	('A-to-I editing', 'MPA', (92, 106))	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('rat', 'Species', '10116', (12, 15))	('SCLC', 'Phenotype', 'HP:0030357', (52, 56))	('enhanced', 'PosReg', (83, 91))	('miR-381', 'Gene', (136, 143))	('NSCLC promotes tumor', 'Disease', 'MESH:D009369', (51, 71))	('ADAR1', 'Gene', (23, 28))	('amplification', 'Var', (34, 47))	('NSCLC promotes tumor', 'Disease', (51, 71))	('miR-381', 'Gene', '494330', (136, 143))	('NSCLC', 'Phenotype', 'HP:0030358', (51, 56))	('ADAR1', 'Gene', '103', (23, 28))
554167	32316322	It is consistent to previous finding that reduced miR-381 expression promotes tumor cells proliferation and resistance to platinum-based chemotherapy via upregulating inhibitor of DNA binding 1 (ID1) levels directly in NSCLC.	('rat', 'Species', '10116', (97, 100))	('SCLC', 'Phenotype', 'HP:0030357', (220, 224))	('miR-381', 'Gene', (50, 57))	('expression', 'MPA', (58, 68))	('promotes', 'PosReg', (69, 77))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('platinum', 'Chemical', 'MESH:D010984', (122, 130))	('inhibitor of DNA binding 1', 'Gene', (167, 193))	('upregulating', 'PosReg', (154, 166))	('NSCLC', 'Disease', 'MESH:D002289', (219, 224))	('inhibitor of DNA binding 1', 'Gene', '3397', (167, 193))	('miR-381', 'Gene', '494330', (50, 57))	('NSCLC', 'Disease', (219, 224))	('ID1', 'Gene', (195, 198))	('reduced', 'Var', (42, 49))	('NSCLC', 'Phenotype', 'HP:0030358', (219, 224))	('tumor', 'Disease', (78, 83))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('resistance', 'CPA', (108, 118))	('ID1', 'Gene', '3397', (195, 198))
554172	32316322	Recently, N6-methyladenine (m6A) modifications affecting internal modification of mRNAs have been gaining more attention due to their ability to affect cancer.	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('internal modification', 'MPA', (57, 78))	('affect', 'Reg', (145, 151))	('m6A', 'Chemical', '-', (28, 31))	('N6-methyladenine', 'Chemical', 'MESH:C005955', (10, 26))	('modifications', 'Var', (33, 46))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))
554174	32316322	It has been identified that m6A modifications regulate miRNA biogenesis, and vice versa.	('regulate', 'Reg', (46, 54))	('m6A', 'Gene', (28, 31))	('m6A', 'Chemical', '-', (28, 31))	('miRNA biogenesis', 'MPA', (55, 71))	('modifications', 'Var', (32, 45))
554181	32316322	With a better understanding of the interactions between RNA modification and their effect on non-coding RNAs, they could serve as potential targets to inhibit lung tumor initiation and progression.	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('modification', 'Var', (60, 72))	('lung tumor initiation', 'Disease', (159, 180))	('interactions', 'Interaction', (35, 47))	('lung tumor', 'Phenotype', 'HP:0100526', (159, 169))	('lung tumor initiation', 'Disease', 'MESH:D008175', (159, 180))	('inhibit', 'NegReg', (151, 158))	('RNA', 'Protein', (56, 59))
554188	32316322	It suggests that non-coding RNAs play important roles in lung tumor cell proliferation.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('rat', 'Species', '10116', (80, 83))	('lung tumor', 'Disease', 'MESH:D008175', (57, 67))	('lung tumor', 'Disease', (57, 67))	('non-coding RNAs', 'Var', (17, 32))	('lung tumor', 'Phenotype', 'HP:0100526', (57, 67))
554194	32316322	Further study showed that PTEN inactivation led to nuclear translocation of beta-catenin and Snail/Slug in lung cancer cells.	('Slug', 'Gene', '6591', (99, 103))	('beta-catenin', 'Gene', '1499', (76, 88))	('nuclear translocation', 'MPA', (51, 72))	('inactivation', 'Var', (31, 43))	('Slug', 'Gene', (99, 103))	('beta-catenin', 'Gene', (76, 88))	('lung cancer', 'Disease', 'MESH:D008175', (107, 118))	('Snail', 'Gene', (93, 98))	('Snail', 'Gene', '6615', (93, 98))	('PTEN', 'Gene', (26, 30))	('lung cancer', 'Disease', (107, 118))	('lung cancer', 'Phenotype', 'HP:0100526', (107, 118))	('PTEN', 'Gene', '5728', (26, 30))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))
554198	32316322	miR-574-5p is an oncogenic miRNA in SCLC as its promotion leads to repression of protein tyrosine phosphatase receptor type U (PTPRU), which in turn increases tyrosine phosphorylation of beta-catenin.	('protein tyrosine phosphatase receptor type U', 'Gene', (81, 125))	('repression', 'NegReg', (67, 77))	('promotion', 'PosReg', (48, 57))	('tyrosine', 'Chemical', 'MESH:D014443', (159, 167))	('beta-catenin', 'Gene', (187, 199))	('tyrosine phosphorylation', 'MPA', (159, 183))	('SCLC', 'Gene', '7864', (36, 40))	('increases', 'PosReg', (149, 158))	('SCLC', 'Gene', (36, 40))	('miR-574-5p', 'Var', (0, 10))	('beta-catenin', 'Gene', '1499', (187, 199))	('SCLC', 'Phenotype', 'HP:0030357', (36, 40))	('PTPRU', 'Gene', (127, 132))	('protein tyrosine phosphatase receptor type U', 'Gene', '10076', (81, 125))	('PTPRU', 'Gene', '10076', (127, 132))	('tyrosine', 'Chemical', 'MESH:D014443', (89, 97))
554205	32316322	As shown, EMT, tumor cell proliferation, and invasion are key hallmarks involved in lung cancer metastasis that can be promoted by non-coding RNAs.	('lung cancer', 'Disease', (84, 95))	('non-coding RNAs', 'Var', (131, 146))	('lung cancer', 'Phenotype', 'HP:0100526', (84, 95))	('EMT', 'CPA', (10, 13))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('promoted', 'PosReg', (119, 127))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('rat', 'Species', '10116', (33, 36))	('tumor', 'Disease', (15, 20))	('lung cancer', 'Disease', 'MESH:D008175', (84, 95))	('invasion', 'CPA', (45, 53))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
554235	32316322	Recently, it was reported that upregulated miR-147b in EGFR mutant lung adenocarcinoma cells mediates drug tolerance to EGFR TKI osimertinib via repression of Von Hippel-Lindau (VHL) and succinate dehydrogenase (SDH).	('lung adenocarcinoma', 'Disease', (67, 86))	('VHL', 'Gene', (178, 181))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (67, 86))	('osimertinib', 'Chemical', 'MESH:C000596361', (129, 140))	('drug tolerance', 'MPA', (102, 116))	('succinate dehydrogenase', 'Gene', '6390', (187, 210))	('SDH', 'Gene', '6390', (212, 215))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (67, 86))	('mediates', 'Reg', (93, 101))	('EGFR', 'Gene', (55, 59))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('Von Hippel-Lindau', 'Gene', '7428', (159, 176))	('VHL', 'Gene', '7428', (178, 181))	('Von Hippel-Lindau', 'Gene', (159, 176))	('SDH', 'Gene', (212, 215))	('miR-147b', 'Gene', '100126311', (43, 51))	('upregulated', 'PosReg', (31, 42))	('miR-147b', 'Gene', (43, 51))	('succinate dehydrogenase', 'Gene', (187, 210))	('mutant', 'Var', (60, 66))
554243	32316322	As a result, non-coding RNAs affecting the cell signaling pathways also have a role in regulation of different cell metabolism cycles including glycolysis, pentose phosphate pathway (PPP), tricarboxylic acid cycle (TCA), and lipid synthesis.	('cell signaling pathways', 'Pathway', (43, 66))	('lipid synthesis', 'MPA', (225, 240))	('regulation', 'MPA', (87, 97))	('pentose phosphate', 'Chemical', 'MESH:D010428', (156, 173))	('lipid', 'Chemical', 'MESH:D008055', (225, 230))	('non-coding RNAs', 'Var', (13, 28))	('glycolysis', 'MPA', (144, 154))	('cell metabolism cycles', 'MPA', (111, 133))	('tricarboxylic acid', 'Chemical', 'MESH:D014233', (189, 207))	('affecting', 'Reg', (29, 38))	('tricarboxylic acid cycle', 'MPA', (189, 213))	('pentose phosphate pathway', 'MPA', (156, 181))
554244	32316322	Targeting of the enzymes within these metabolic cycles by non-coding RNAs has been reported, which could suggest alteration of cellular processes by controlling non-coding RNA regulation.	('non-coding RNAs', 'Var', (58, 73))	('rat', 'Species', '10116', (117, 120))	('alteration', 'Reg', (113, 123))
554269	32316322	looked at how glycolysis was enhanced due to increased glucose uptake and lactate production in order to keep the EGFR mutant NSCLC nourished.	('glucose', 'Chemical', 'MESH:D005947', (55, 62))	('NSCLC', 'Disease', 'MESH:D002289', (126, 131))	('increased', 'PosReg', (45, 54))	('glycolysis', 'MPA', (14, 24))	('lactate', 'Chemical', 'MESH:D019344', (74, 81))	('NSCLC', 'Disease', (126, 131))	('NSCLC', 'Phenotype', 'HP:0030358', (126, 131))	('lactate production', 'MPA', (74, 92))	('EGFR', 'Gene', (114, 118))	('SCLC', 'Phenotype', 'HP:0030357', (127, 131))	('mutant', 'Var', (119, 125))	('enhanced', 'PosReg', (29, 37))	('increased glucose', 'Phenotype', 'HP:0003074', (45, 62))	('glucose uptake', 'MPA', (55, 69))
554271	32316322	By altering metabolism, cancer cells are able to manage themselves and pursue oncogenic processes, so by targeting of specific receptors or enzymes by non-coding RNAs could inhibit these processes and force cancer cells to find alternative resources or simply die.	('cancer', 'Disease', 'MESH:D009369', (207, 213))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('non-coding', 'Var', (151, 161))	('cancer', 'Disease', (207, 213))	('altering', 'Reg', (3, 11))	('RNAs', 'Gene', (162, 166))	('metabolism', 'MPA', (12, 22))	('cancer', 'Disease', (24, 30))	('cancer', 'Disease', 'MESH:D009369', (24, 30))	('cancer', 'Phenotype', 'HP:0002664', (207, 213))	('force', 'Reg', (201, 206))	('inhibit', 'NegReg', (173, 180))
554272	32316322	The MET signaling pathway can be altered through overexpression of MET and/or its ligand the hepatocyte growth factor, and genetic variation of the MET gene, both common in oncogenic processes.	('MET', 'Gene', (4, 7))	('MET', 'Gene', '4233', (4, 7))	('altered', 'Reg', (33, 40))	('MET', 'Gene', '4233', (67, 70))	('MET', 'Gene', '4233', (148, 151))	('overexpression', 'PosReg', (49, 63))	('MET', 'Gene', (67, 70))	('MET', 'Gene', (148, 151))	('genetic variation', 'Var', (123, 140))
554276	32316322	Others have found that targeting of c-MET with miR-19a and miR-409-3p could inhibit downstream signaling of the Akt signaling pathway as well.	('miR-19a', 'Gene', (47, 54))	('c-MET', 'Gene', '4233', (36, 41))	('inhibit', 'NegReg', (76, 83))	('downstream', 'MPA', (84, 94))	('miR-19a', 'Gene', '406979', (47, 54))	('Akt', 'Gene', '207', (112, 115))	('c-MET', 'Gene', (36, 41))	('Akt', 'Gene', (112, 115))	('miR-409-3p', 'Var', (59, 69))
554277	32316322	Due to crosstalk between KRAS/MET and EGFR/MET, dual targeting of these signaling pathways via non-coding RNAs could potentially predict drug sensitivity, biomarker potential, and prognostic value.	('MET', 'Gene', '4233', (30, 33))	('MET', 'Gene', (43, 46))	('crosstalk', 'Reg', (7, 16))	('MET', 'Gene', '4233', (43, 46))	('drug sensitivity', 'Phenotype', 'HP:0020174', (137, 153))	('non-coding', 'Var', (95, 105))	('predict', 'Reg', (129, 136))	('RNAs', 'Gene', (106, 110))	('MET', 'Gene', (30, 33))
554282	32316322	As for the role of miRNA, it was found that the overexpression of miR-296-3p reduced the level of phosphorylation in this pathway without reducing mRNA expression by targeting apurinic/apyrimidinic endodeoxyribonuclease 1 (APEX1), therefore possibly inhibiting the pathway's progression particularly in NSCLC.	('NSCLC', 'Phenotype', 'HP:0030358', (303, 308))	('inhibiting', 'NegReg', (250, 260))	('miR-296-3p', 'Var', (66, 76))	('NSCLC', 'Disease', (303, 308))	('apurinic/apyrimidinic endodeoxyribonuclease 1', 'Gene', (176, 221))	('APEX1', 'Gene', '328', (223, 228))	('NSCLC', 'Disease', 'MESH:D002289', (303, 308))	('SCLC', 'Phenotype', 'HP:0030357', (304, 308))	('miR-296-3p', 'Chemical', '-', (66, 76))	('level of phosphorylation', 'MPA', (89, 113))	('apurinic/apyrimidinic endodeoxyribonuclease 1', 'Gene', '328', (176, 221))	('targeting', 'Reg', (166, 175))	('APEX1', 'Gene', (223, 228))
554283	32316322	Additionally, miR-296-3p has been reported to have lower levels of expression in comparison to normal lung epithelial cells, and it played a role in inhibiting NSCLC cell proliferation as well as cisplatin sensitivity by targeting C-X3-C motif chemokine receptor 1(CX3CR1) which is upstream of PI3K signaling.	('SCLC', 'Phenotype', 'HP:0030357', (161, 165))	('NSCLC', 'Disease', (160, 165))	('cisplatin', 'Chemical', 'MESH:D002945', (196, 205))	('miR-296-3p', 'Var', (14, 24))	('CX3CR1', 'Gene', '1524', (265, 271))	('cisplatin sensitivity', 'MPA', (196, 217))	('NSCLC', 'Disease', 'MESH:D002289', (160, 165))	('NSCLC', 'Phenotype', 'HP:0030358', (160, 165))	('miR-296-3p', 'Chemical', '-', (14, 24))	('lower', 'NegReg', (51, 56))	('CX3CR1', 'Gene', (265, 271))	('inhibiting', 'NegReg', (149, 159))	('C-X3-C motif chemokine receptor 1', 'Gene', (231, 264))	('C-X3-C motif chemokine receptor 1', 'Gene', '1524', (231, 264))	('rat', 'Species', '10116', (178, 181))	('targeting', 'Reg', (221, 230))	('levels of expression', 'MPA', (57, 77))
554284	32316322	miR-142-3p was found to have an association between the PI3K/Akt/mTOR pathway and high mobility group box 1 (HMBG1) induced autophagy, a process of cellular degradation that if in a high presence can demonstrate conflicting results such as promoting tumor survival versus preventing tumorigenesis.	('rat', 'Species', '10116', (207, 210))	('tumor', 'Disease', 'MESH:D009369', (283, 288))	('association', 'Interaction', (32, 43))	('tumor', 'Disease', (250, 255))	('mTOR', 'Gene', (65, 69))	('tumor', 'Phenotype', 'HP:0002664', (283, 288))	('tumor', 'Disease', 'MESH:D009369', (250, 255))	('Akt', 'Gene', (61, 64))	('preventing', 'NegReg', (272, 282))	('promoting', 'PosReg', (240, 249))	('HMBG1', 'Gene', (109, 114))	('mTOR', 'Gene', '2475', (65, 69))	('autophagy', 'CPA', (124, 133))	('high mobility group box 1', 'Gene', (82, 107))	('high mobility group box 1', 'Gene', '3146', (82, 107))	('Akt', 'Gene', '207', (61, 64))	('tumor', 'Phenotype', 'HP:0002664', (250, 255))	('miR-142-3p', 'Chemical', '-', (0, 10))	('tumor', 'Disease', (283, 288))	('miR-142-3p', 'Var', (0, 10))
554285	32316322	In this case, NSCLC autophagy was inhibited via the overexpression of miR-142-3p.	('miR-142-3p', 'Chemical', '-', (70, 80))	('NSCLC', 'Disease', (14, 19))	('NSCLC', 'Disease', 'MESH:D002289', (14, 19))	('inhibited', 'NegReg', (34, 43))	('SCLC', 'Phenotype', 'HP:0030357', (15, 19))	('NSCLC', 'Phenotype', 'HP:0030358', (14, 19))	('overexpression', 'PosReg', (52, 66))	('miR-142-3p', 'Var', (70, 80))
554287	32316322	PTEN is a protein found to terminate hyperactive signaling of PI3K, and the loss of its function has been noted in various human cancers.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('hyperactive', 'Disease', 'MESH:D006948', (37, 48))	('human', 'Species', '9606', (123, 128))	('cancers', 'Disease', 'MESH:D009369', (129, 136))	('PI3K', 'Var', (62, 66))	('cancers', 'Phenotype', 'HP:0002664', (129, 136))	('cancers', 'Disease', (129, 136))	('terminate', 'NegReg', (27, 36))	('PTEN', 'Gene', (0, 4))	('PTEN', 'Gene', '5728', (0, 4))	('hyperactive', 'Disease', (37, 48))
554291	32316322	found that there was a link between the PI3K/Akt/mTOR pathway and aerobic glycolysis as well as maintenance of glucose transporter 1 (GLUT1) through optimal membrane localization specifically in EGFR mutated lung adenocarcinoma cells.	('glucose transporter 1', 'Gene', '6513', (111, 132))	('mTOR', 'Gene', (49, 53))	('Akt', 'Gene', (45, 48))	('GLUT1', 'Gene', (134, 139))	('EGFR', 'Gene', (195, 199))	('mTOR', 'Gene', '2475', (49, 53))	('GLUT1', 'Gene', '6513', (134, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (218, 227))	('mutated', 'Var', (200, 207))	('lung adenocarcinoma', 'Disease', (208, 227))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (208, 227))	('Akt', 'Gene', '207', (45, 48))	('aerobic glycolysis', 'MPA', (66, 84))	('glucose transporter 1', 'Gene', (111, 132))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (208, 227))
554295	32316322	Targeting GLUTs by non-coding RNAs could potentially have a role in decreasing tumorigenesis.	('tumor', 'Disease', (79, 84))	('non-coding RNAs', 'Var', (19, 34))	('decreasing', 'NegReg', (68, 78))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
554298	32316322	HIF-1alpha can also modulate lncRNA HOTAIR to promote lung tumorigenesis in hypoxic conditions and miR-210-3p to prevent HIF-1alpha degradation via suppression of SDHD enzymatic activity.	('HIF-1alpha', 'Gene', (121, 131))	('promote', 'PosReg', (46, 53))	('SDHD', 'Gene', (163, 167))	('SDHD', 'Gene', '6392', (163, 167))	('prevent', 'NegReg', (113, 120))	('lung tumor', 'Phenotype', 'HP:0100526', (54, 64))	('degradation', 'MPA', (132, 143))	('HOTAIR', 'Gene', (36, 42))	('lung tumor', 'Disease', (54, 64))	('suppression', 'NegReg', (148, 159))	('HIF-1alpha', 'Gene', '3091', (0, 10))	('lung tumor', 'Disease', 'MESH:D008175', (54, 64))	('HIF-1alpha', 'Gene', '3091', (121, 131))	('HOTAIR', 'Gene', '100124700', (36, 42))	('miR-210-3p', 'Var', (99, 109))	('miR-210-', 'Chemical', '-', (99, 107))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('HIF-1alpha', 'Gene', (0, 10))
554303	32316322	The crosstalk between the two pathways perhaps demonstrates how multiple pathways become involved in tumorigenesis and proliferation, and by targeting one can reduce activation of the other.	('involved', 'Reg', (89, 97))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', (101, 106))	('rat', 'Species', '10116', (54, 57))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('rat', 'Species', '10116', (126, 129))	('targeting', 'Var', (141, 150))	('proliferation', 'CPA', (119, 132))
554306	32316322	Homogenous KRAS G12D mutant, a common mutation causing dysregulation of the MAPK pathway, has been reported to favor glucose fueled TCA cycling due to glucose metabolic reprogramming and reactive oxygen species (ROS) management, leading to increased malignancy.	('increased', 'PosReg', (240, 249))	('glucose', 'Chemical', 'MESH:D005947', (117, 124))	('favor', 'PosReg', (111, 116))	('ROS', 'Chemical', 'MESH:D017382', (212, 215))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (187, 210))	('MAPK', 'Gene', (76, 80))	('KRAS G12D mutant', 'Var', (11, 27))	('glucose fueled TCA cycling', 'MPA', (117, 143))	('G12D', 'Mutation', 'rs121913529', (16, 20))	('malignancy', 'Disease', 'MESH:D009369', (250, 260))	('malignancy', 'Disease', (250, 260))	('glucose', 'Chemical', 'MESH:D005947', (151, 158))
554308	32316322	Non-coding RNAs such as miR-21 and miR-30c have shown upregulation with KRAS G12D overexpression, which as a result enhance regulation of Ras downstream pathways.	('Ras downstream pathways', 'Pathway', (138, 161))	('miR-21', 'Gene', (24, 30))	('regulation', 'MPA', (124, 134))	('enhance', 'PosReg', (116, 123))	('upregulation', 'PosReg', (54, 66))	('miR-30c', 'Gene', (35, 42))	('G12D', 'Mutation', 'rs121913529', (77, 81))	('miR-21', 'Gene', '406991', (24, 30))	('miR-30c', 'Gene', '407031', (35, 42))	('KRAS G12D', 'Var', (72, 81))
554313	32316322	Through this pathway, mutation at and surrounding the beta-catenin site is most common in cancers, but in regard to lung cancer, its distinguishing factor is based on alterations to various Wnt proteins including Wnt-1-5a, frizzled class receptor 8 (FZD8), and the gene beta-catenin.	('cancers', 'Disease', (90, 97))	('mutation', 'Var', (22, 30))	('lung cancer', 'Disease', (116, 127))	('lung cancer', 'Phenotype', 'HP:0100526', (116, 127))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('beta-catenin', 'Gene', (270, 282))	('Wnt-1-5a, frizzled class receptor 8', 'Gene', '8325', (213, 248))	('beta-catenin', 'Gene', (54, 66))	('alterations', 'Reg', (167, 178))	('rat', 'Species', '10116', (171, 174))	('FZD8', 'Gene', '8325', (250, 254))	('lung cancer', 'Disease', 'MESH:D008175', (116, 127))	('FZD8', 'Gene', (250, 254))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('beta-catenin', 'Gene', '1499', (270, 282))	('beta-catenin', 'Gene', '1499', (54, 66))	('cancers', 'Disease', 'MESH:D009369', (90, 97))
554316	32316322	Other lncRNAs that work as a suppressor include MEG3, interaction with p53 to downregulate beta-catenin, and AK126698, negative regulation of FZD8.	('negative regulation', 'NegReg', (119, 138))	('AK126698', 'Var', (109, 117))	('FZD8', 'Gene', '8325', (142, 146))	('FZD8', 'Gene', (142, 146))	('MEG3', 'Gene', '55384', (48, 52))	('downregulate', 'NegReg', (78, 90))	('beta-catenin', 'Gene', (91, 103))	('p53', 'Gene', (71, 74))	('p53', 'Gene', '7157', (71, 74))	('interaction', 'Interaction', (54, 65))	('beta-catenin', 'Gene', '1499', (91, 103))	('MEG3', 'Gene', (48, 52))
554320	32316322	It has been reported that Wnt/beta-catenin can be regulated through the inactivation of the DVL2-NRX complex formation by elevating ROS (Ca2+ mediated), which can additionally cause accumulation of nuclear beta-catenin in human neural progenitor cells.	('beta-catenin', 'Gene', '1499', (30, 42))	('accumulation', 'PosReg', (182, 194))	('beta-catenin', 'Gene', '1499', (206, 218))	('DVL2', 'Gene', '1856', (92, 96))	('DVL2', 'Gene', (92, 96))	('Ca2+', 'Chemical', 'MESH:D000069285', (137, 141))	('inactivation', 'Var', (72, 84))	('ROS', 'Chemical', 'MESH:D017382', (132, 135))	('elevating', 'PosReg', (122, 131))	('human', 'Species', '9606', (222, 227))	('beta-catenin', 'Gene', (30, 42))	('beta-catenin', 'Gene', (206, 218))
554321	32316322	Accumulation of beta-catenin through glucose has also been reported to enhance the signaling pathway and as a result increase the risk of cancer development.	('Accumulation', 'Var', (0, 12))	('signaling pathway', 'Pathway', (83, 100))	('increase', 'PosReg', (117, 125))	('cancer', 'Disease', (138, 144))	('beta-catenin', 'Gene', (16, 28))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('glucose', 'Chemical', 'MESH:D005947', (37, 44))	('beta-catenin', 'Gene', '1499', (16, 28))	('enhance', 'PosReg', (71, 78))	('cancer', 'Disease', 'MESH:D009369', (138, 144))
554332	32316322	In contrast, miR-125a-5p has been found to be a tumor suppressor and was downregulated in NSCLC.	('tumor', 'Disease', (48, 53))	('miR-125a-5p', 'Var', (13, 24))	('NSCLC', 'Disease', (90, 95))	('NSCLC', 'Disease', 'MESH:D002289', (90, 95))	('miR-125a-5p', 'Chemical', '-', (13, 24))	('downregulated', 'NegReg', (73, 86))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('SCLC', 'Phenotype', 'HP:0030357', (91, 95))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('NSCLC', 'Phenotype', 'HP:0030358', (90, 95))
554362	32316322	reported that organoid cultures can maintain cancer-related gene mutations, both apoptotic and proliferating.	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('rat', 'Species', '10116', (102, 105))	('cancer', 'Disease', 'MESH:D009369', (45, 51))	('cancer', 'Disease', (45, 51))	('mutations', 'Var', (65, 74))
554392	31480608	In normal human fibroblasts the same concentrations of G3B31N conjugate were less effective in inhibition of proliferation and induction of apoptosis, as measured by caspase 3/7 activity in a manner depending on increase of PGE2 production by either COX-1/COX-2.	('human', 'Species', '9606', (10, 15))	('PGE2', 'Chemical', 'MESH:D015232', (224, 228))	('PGE2', 'MPA', (224, 228))	('inhibition', 'NegReg', (95, 105))	('caspase 3', 'Gene', (166, 175))	('apoptosis', 'CPA', (140, 149))	('caspase 3', 'Gene', '836', (166, 175))	('COX-2', 'Gene', (256, 261))	('G3B31N', 'Var', (55, 61))	('COX-1', 'Gene', (250, 255))	('increase', 'PosReg', (212, 220))	('COX-2', 'Gene', '5743', (256, 261))	('proliferation', 'CPA', (109, 122))	('COX-1', 'Gene', '5742', (250, 255))
554409	31480608	Symptoms of nephro- and hepatotoxicity of COX-2 inhibitors observed after prolonged treatment particularly in diabetic and kidney disease-suffering patients limits its application.	('COX-2', 'Gene', '5743', (42, 47))	('patients', 'Species', '9606', (148, 156))	('hepatotoxicity', 'Disease', 'MESH:D056486', (24, 38))	('kidney disease', 'Phenotype', 'HP:0000112', (123, 137))	('diabetic and kidney disease', 'Disease', 'MESH:D003928', (110, 137))	('inhibitors', 'Var', (48, 58))	('COX-2', 'Gene', (42, 47))	('hepatotoxicity', 'Disease', (24, 38))
554425	31480608	PAMAM G3 vehicle substituted with one amide-linked biotin (G3B) was synthesized according to optimized protocols followed by covalent binding of N to obtain two conjugates containing average 18 and 31 residues of N (G3B18N and G3B31N).	('G3B18N', 'Var', (216, 222))	('G3B31N', 'Var', (227, 233))	('biotin', 'Chemical', 'MESH:D001710', (51, 57))	('PAMAM', 'Chemical', 'MESH:C522249', (0, 5))	('amide', 'Chemical', 'MESH:D000577', (38, 43))
554463	31480608	Based upon integral intensity of 1H resonances in the spectra of nimesulide containing conjugates the average number of 18 and 31 moieties of N, and an average of biotin was present in G3B18N and G3B31N, respectively, as determined by 1H NMR.	('G3B31N', 'Var', (196, 202))	('biotin', 'Chemical', 'MESH:D001710', (163, 169))	('G3B18N', 'Var', (185, 191))	('nimesulide', 'Chemical', 'MESH:C012655', (65, 75))
554485	31480608	It has to be pointed out, that at 10 muM G3B18N concentration was nearly three times more toxic for cancer (20% viability) than fibroblasts (55% viability).	('G3B18N', 'Var', (41, 47))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('muM', 'Gene', '56925', (37, 40))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('muM', 'Gene', (37, 40))
554487	31480608	Calculated selectivity index (ratio of IC50 of cancer to IC50 of normal cells) revealed that dendrimer conjugates, particularly G3BN18, were more selective against cancer cells than N alone, with a selectivity index equal to 0.41 (Table 1).	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('cancer', 'Disease', (47, 53))	('G3BN18', 'Var', (128, 134))	('cancer', 'Disease', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))
554492	31480608	Estimated IC50 for SCC-15 cells were about 6.0 muM and 1.6 muM and for BJ cells 14.5 muM and 2.0 muM (G3B18N and G3B31N, respectively).	('muM', 'Gene', (85, 88))	('G3B31N', 'Var', (113, 119))	('muM', 'Gene', '56925', (59, 62))	('muM', 'Gene', (47, 50))	('muM', 'Gene', '56925', (97, 100))	('muM', 'Gene', (59, 62))	('muM', 'Gene', (97, 100))	('muM', 'Gene', '56925', (85, 88))	('muM', 'Gene', '56925', (47, 50))
554495	31480608	Thus, the biotinylation and substitution of PAMAM G3 with 18 or 31 residues of N changed its cytotoxicity profile and selectivity.	('cytotoxicity', 'Disease', 'MESH:D064420', (93, 105))	('biotin', 'Chemical', 'MESH:D001710', (10, 16))	('changed', 'Reg', (81, 88))	('PAMAM', 'Chemical', 'MESH:C522249', (44, 49))	('cytotoxicity', 'Disease', (93, 105))	('selectivity', 'MPA', (118, 129))	('substitution', 'Var', (28, 40))
554496	31480608	This resulted in a higher cytotoxicity of G3B18N against SCC-15 cells as compared to normal fibroblasts, with SI equal to 0.41 (Table 1).	('cytotoxicity', 'Disease', (26, 38))	('higher', 'PosReg', (19, 25))	('G3B18N', 'Var', (42, 48))	('cytotoxicity', 'Disease', 'MESH:D064420', (26, 38))
554499	31480608	In proliferation assay the G3B18N exerted high selectivity against cancer cells.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('G3B18N', 'Var', (27, 33))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('cancer', 'Disease', (67, 73))
554510	31480608	Inhibition of apoptosis is the canonical marker of cancer and has been a target for the development of anticancer strategies.	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('apoptosis', 'CPA', (14, 23))	('Inhibition', 'Var', (0, 10))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('cancer', 'Disease', (107, 113))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))
554528	31480608	As was mentioned in the Introduction, high expression of COX-2 protein is a marker of a majority of malignances.	('high', 'Var', (38, 42))	('malignances', 'Disease', (100, 111))	('COX-2', 'Gene', (57, 62))	('COX-2', 'Gene', '5743', (57, 62))
554530	31480608	No effect of G3BN18 treatment on COX-2 protein level was observed in SCC-15 cells at all tested concentrations, whereas G3BN31 significantly induced enzyme expression at 5-10 muM concentrations to about twice the control level (Figure 6).	('muM', 'Gene', '56925', (175, 178))	('muM', 'Gene', (175, 178))	('COX-2', 'Gene', (33, 38))	('G3BN31', 'Var', (120, 126))	('COX-2', 'Gene', '5743', (33, 38))	('induced', 'Reg', (141, 148))	('enzyme expression', 'MPA', (149, 166))
554531	31480608	In fibroblasts, G3BN18 exerted limited effect on COX-2 expression with an increase of up to 170% of control at 2.5 muM concentration and without/small effect (120%) at 5-10 muM concentration.	('COX-2', 'Gene', (49, 54))	('COX-2', 'Gene', '5743', (49, 54))	('muM', 'Gene', '56925', (173, 176))	('increase', 'PosReg', (74, 82))	('expression', 'MPA', (55, 65))	('muM', 'Gene', '56925', (115, 118))	('G3BN18', 'Var', (16, 22))	('muM', 'Gene', (173, 176))	('muM', 'Gene', (115, 118))
554532	31480608	More remarkable changes were observed after G3BN31 treatment that induced of COX-2 protein expression, up to three- and five-fold of control level at 2.5-10 muM concentration (Figure 6).	('expression', 'MPA', (91, 101))	('muM', 'Gene', (157, 160))	('G3BN31', 'Var', (44, 50))	('protein', 'Protein', (83, 90))	('COX-2', 'Gene', (77, 82))	('COX-2', 'Gene', '5743', (77, 82))	('muM', 'Gene', '56925', (157, 160))
554540	31480608	In fibroblasts, both G3BN18 and G3BN31 significantly decreased PGE2 production at 1.25 microM concentration, which confirmed the inhibitory action of dendrimer-bound nimesulide on COX-2 activity.	('COX-2', 'Gene', (180, 185))	('G3BN18', 'Var', (21, 27))	('PGE2', 'Chemical', 'MESH:D015232', (63, 67))	('COX-2', 'Gene', '5743', (180, 185))	('PGE2 production', 'MPA', (63, 78))	('nimesulide', 'Chemical', 'MESH:C012655', (166, 176))	('decreased', 'NegReg', (53, 62))	('G3BN31', 'Var', (32, 38))
554544	31480608	However, increased PGE2 production was observed at higher concentrations:at 5 microM with G3BN31 and at 10 microM with both conjugates.	('G3BN31', 'Var', (90, 96))	('PGE2 production', 'MPA', (19, 34))	('increased', 'PosReg', (9, 18))	('PGE2', 'Chemical', 'MESH:D015232', (19, 23))
554548	31480608	COX-2-selective inhibitor NS398 dramatically reduced PGE2 secretion in oral carcinoma-derived cell lines at 10 and 20 muM concentrations, but growth inhibition was not observed after 72 h treatment.	('NS398', 'Var', (26, 31))	('reduced', 'NegReg', (45, 52))	('oral carcinoma', 'Disease', (71, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('muM', 'Gene', '56925', (118, 121))	('PGE2 secretion', 'MPA', (53, 67))	('oral carcinoma', 'Disease', 'MESH:D009062', (71, 85))	('COX-2', 'Gene', (0, 5))	('COX-2', 'Gene', '5743', (0, 5))	('muM', 'Gene', (118, 121))	('PGE2', 'Chemical', 'MESH:D015232', (53, 57))
554554	31480608	Particularly interesting are observations that various selective COX-2 inhibitors decrease the proliferation rate and induce apoptosis in a manner not related to the COX-2/PGE2 axis.	('COX-2', 'Gene', (166, 171))	('inhibitors', 'Var', (71, 81))	('COX-2', 'Gene', '5743', (65, 70))	('COX-2', 'Gene', (65, 70))	('decrease', 'NegReg', (82, 90))	('COX-2', 'Gene', '5743', (166, 171))	('PGE2', 'Chemical', 'MESH:D015232', (172, 176))	('induce', 'Reg', (118, 124))	('apoptosis', 'CPA', (125, 134))	('proliferation rate', 'CPA', (95, 113))
554555	31480608	The phenomenon observed in SCC-15 cells that, despite the inhibitory action of G3B18N and particularly G3B31N conjugates on proliferation rate at low concentrations (1.25-5 muM), only a small increase of caspase 3/7 activity and no increase of PGE2 production was seen, is in agreement with other data, showing that much lower concentrations of N affects the death of cancer cells than that required for COX-2 inhibition.	('cancer', 'Disease', (368, 374))	('COX-2', 'Gene', (404, 409))	('PGE2', 'Chemical', 'MESH:D015232', (244, 248))	('proliferation', 'CPA', (124, 137))	('caspase 3', 'Gene', (204, 213))	('cancer', 'Phenotype', 'HP:0002664', (368, 374))	('G3B18N', 'Var', (79, 85))	('COX-2', 'Gene', '5743', (404, 409))	('muM', 'Gene', '56925', (173, 176))	('caspase 3', 'Gene', '836', (204, 213))	('G3B31N', 'Var', (103, 109))	('muM', 'Gene', (173, 176))	('cancer', 'Disease', 'MESH:D009369', (368, 374))	('activity', 'MPA', (216, 224))
554558	31480608	However, the G3B31N, with higher amount of nimesulide, exerted a much lower inhibitory effect up to a 2.5 microM concentration and was without effect at 5-10 microM.	('lower', 'NegReg', (70, 75))	('inhibitory effect', 'MPA', (76, 93))	('G3B31N', 'Var', (13, 19))	('nimesulide', 'Chemical', 'MESH:C012655', (43, 53))
554563	31480608	Substitution of biotinylated PAMAM G3 dendrimers with 18 (G3B18N) or 31 (G3B31N) nimesulide residues remarkably increased activity of this drug compared to its native form.	('PAMAM', 'Chemical', 'MESH:C522249', (29, 34))	('increased', 'PosReg', (112, 121))	('nimesulide', 'Chemical', 'MESH:C012655', (81, 91))	('biotin', 'Chemical', 'MESH:D001710', (16, 22))	('G3B31N', 'Var', (73, 79))	('activity', 'MPA', (122, 130))
554564	31480608	IC50 estimated for G3B18N was 6.0 muM and 14.5 muM in SCC-15 and BJ cells, respectively, with SI = 0.41 as compared to IC50 equal to 430 muM and 590 muM for nimesulide alone.	('muM', 'Gene', '56925', (34, 37))	('muM', 'Gene', '56925', (137, 140))	('nimesulide', 'Chemical', 'MESH:C012655', (157, 167))	('muM', 'Gene', (137, 140))	('muM', 'Gene', '56925', (149, 152))	('muM', 'Gene', (47, 50))	('muM', 'Gene', (34, 37))	('muM', 'Gene', (149, 152))	('G3B18N', 'Var', (19, 25))	('muM', 'Gene', '56925', (47, 50))
554566	31480608	In normal human fibroblasts (BJ), the same concentrations of G3B31N conjugate was less effective in inhibition of proliferation and increased apoptosis as measured by caspase 3/7 activity in a manner depending on the increase of PGE2 production by either COX-1/COX-2.	('G3B31N', 'Var', (61, 67))	('COX-2', 'Gene', (261, 266))	('COX-2', 'Gene', '5743', (261, 266))	('human', 'Species', '9606', (10, 15))	('COX-1', 'Gene', (255, 260))	('COX-1', 'Gene', '5742', (255, 260))	('increased', 'PosReg', (132, 141))	('caspase 3', 'Gene', (167, 176))	('caspase 3', 'Gene', '836', (167, 176))	('apoptosis', 'CPA', (142, 151))	('PGE2', 'Chemical', 'MESH:D015232', (229, 233))
554571	28389380	To meet these challenges, we developed an algorithm, eTumorType, to identify cancer types based on copy number variations (CNVs) of the cancer founding clone.	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('cancer', 'Disease', (136, 142))	('copy number variations', 'Var', (99, 121))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('Tumor', 'Phenotype', 'HP:0002664', (54, 59))
554654	28389380	These results indicate that predicting cancer types using founding clone CNVs of cancer hallmark-associated genes performs stably across different sample populations, and therefore contributes to robustness.	('CNVs', 'Var', (73, 77))	('cancer', 'Disease', (39, 45))	('cancer', 'Disease', 'MESH:D009369', (39, 45))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('cancer', 'Disease', (81, 87))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))
554683	28389380	However, eTumorType is capable of discriminating cancer types, which is beyond the current studies on CTC or cfDNA data, as the majority of these studies only focused on finding features (e.g., CNV, mutation, microRNA, methylation, and gene expression) associated with specific cancer types.	('methylation', 'MPA', (219, 230))	('cancer', 'Phenotype', 'HP:0002664', (278, 284))	('Tumor', 'Phenotype', 'HP:0002664', (10, 15))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('CNV', 'Gene', (194, 197))	('mutation', 'Var', (199, 207))	('gene', 'MPA', (236, 240))	('cancer', 'Disease', 'MESH:D009369', (278, 284))	('microRNA', 'MPA', (209, 217))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('cancer', 'Disease', (278, 284))	('cancer', 'Disease', (49, 55))
554708	28389380	The cancer hallmarks considered in eTumorType allow capturing the genomic variations which are most likely to be associated with cancer development and progression, thereby contributing to robustness.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('cancer', 'Phenotype', 'HP:0002664', (4, 10))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (4, 10))	('Tumor', 'Phenotype', 'HP:0002664', (36, 41))	('cancer', 'Disease', (4, 10))	('variations', 'Var', (74, 84))
554741	26951089	In our institution, patients with HNSCC who underwent neck dissection with pathologic findings of close or positive resection margin, ECS, multiple regional lymph node metastasis, or pT4, with or without primary tumor resection were treated with postoperative radiation therapy.	('tumor', 'Disease', 'MESH:D009369', (212, 217))	('pT4', 'Var', (183, 186))	('patients', 'Species', '9606', (20, 28))	('tumor', 'Phenotype', 'HP:0002664', (212, 217))	('ECS', 'Disease', (134, 137))	('HNSCC', 'Phenotype', 'HP:0012288', (34, 39))	('tumor', 'Disease', (212, 217))	('HNSCC', 'Disease', (34, 39))
554748	26951089	Agents used for NAC was either the combination of CDDP and 5FU or CDDP, 5FU, and docetaxel.	('CDDP', 'Var', (50, 54))	('CDDP', 'Chemical', '-', (66, 70))	('5FU', 'Chemical', 'MESH:D005472', (72, 75))	('CDDP', 'Chemical', '-', (50, 54))	('CDDP', 'Var', (66, 70))	('NAC', 'Chemical', '-', (16, 19))	('5FU', 'Chemical', 'MESH:D005472', (59, 62))	('docetaxel', 'Chemical', 'MESH:D000077143', (81, 90))
554854	26634452	Lung cancer was coded by ICD-9-CM 162 or ICD 10 C34.0, C34.1, C34.2, C34.3, C34.8, and C34.9.	('ICD', 'Gene', (41, 44))	('ICD', 'Gene', '79158', (41, 44))	('ICD', 'Gene', (25, 28))	('ICD', 'Gene', '79158', (25, 28))	('Lung cancer', 'Phenotype', 'HP:0100526', (0, 11))	('C34.3', 'Var', (69, 74))	('C34.2', 'Var', (62, 67))	('C34.9', 'Var', (87, 92))	('Lung cancer', 'Disease', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))	('C34.8', 'Var', (76, 81))	('Lung cancer', 'Disease', 'MESH:D008175', (0, 11))	('C34.1', 'Var', (55, 60))
554949	33658076	Indeed, dual PDE inhibition and A2AR activation via compound combinations exhibited synergy (according to isobologram analysis) in cAMP elevation, and was observed to inhibit proliferation in other cancer cell types such as multiple myeloma and diffuse large B-cell lymphoma.	('PDE', 'Gene', (13, 16))	('multiple myeloma', 'Disease', (224, 240))	('inhibit', 'NegReg', (167, 174))	('B-cell lymphoma', 'Disease', 'MESH:D016393', (259, 274))	('A2AR', 'Gene', (32, 36))	('combinations', 'Var', (61, 73))	('cancer', 'Disease', (198, 204))	('cAMP elevation', 'MPA', (131, 145))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('proliferation', 'CPA', (175, 188))	('B-cell lymphoma', 'Phenotype', 'HP:0012191', (259, 274))	('multiple myeloma', 'Phenotype', 'HP:0006775', (224, 240))	('B-cell lymphoma', 'Disease', (259, 274))	('A2AR', 'Gene', '135', (32, 36))	('PDE', 'Gene', '501', (13, 16))	('multiple myeloma', 'Disease', 'MESH:D009101', (224, 240))	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('lymphoma', 'Phenotype', 'HP:0002665', (266, 274))	('activation', 'PosReg', (37, 47))	('inhibition', 'NegReg', (17, 27))	('cAMP', 'Chemical', 'MESH:D000242', (131, 135))
554959	33658076	For this reason, the structure-based computational approach was focused on the more challenging goal, which involved identifying whether known PDE10A inhibitors are A2AR agonists.	('A2AR', 'Gene', '135', (165, 169))	('PDE10A', 'Gene', '10846', (143, 149))	('A2AR', 'Gene', (165, 169))	('inhibitors', 'Var', (150, 160))	('PDE10A', 'Gene', (143, 149))
554961	33658076	It is postulated that the motion of the residue Val84 in Transmembrane Helix 3, upon A2AR ligand binding, might discriminate between agonist and antagonist activity, which has not previously been studied by any MD approaches.	('Val84', 'Chemical', '-', (48, 53))	('A2AR', 'Gene', '135', (85, 89))	('A2AR', 'Gene', (85, 89))	('Val84', 'Var', (48, 53))	('discriminate', 'Reg', (112, 124))
554970	33658076	Importantly, for future reference, no significant activity of the A2AR selective agonist CGS21680 at PDE10A was detected.	('CGS21680', 'Var', (89, 97))	('CGS21680', 'Chemical', 'MESH:C061282', (89, 97))	('A2AR', 'Gene', '135', (66, 70))	('PDE10A', 'Gene', (101, 107))	('A2AR', 'Gene', (66, 70))	('PDE10A', 'Gene', '10846', (101, 107))
554973	33658076	Importantly, this analysis highlighted that the interaction of Tyr683, a residue belonging to a 'selectivity pocket' of PDE10A, through a hydrogen bond with the thioether of the compounds could explain their PDE10A subtype selectivity.	('PDE10A', 'Gene', '10846', (120, 126))	('hydrogen bond', 'MPA', (138, 151))	('PDE10A', 'Gene', (208, 214))	('Tyr683', 'Var', (63, 69))	('interaction', 'Interaction', (48, 59))	('hydrogen', 'Chemical', 'MESH:D006859', (138, 146))	('thioether', 'Chemical', 'MESH:D013440', (161, 170))	('PDE10A', 'Gene', '10846', (208, 214))	('PDE10A', 'Gene', (120, 126))	('Tyr683', 'Chemical', '-', (63, 69))
554975	33658076	In this structure a relatively large displacement of the Val84 residue was observed (when referenced to its average distance to Leu249, a residue that is comparatively static in position relative to the structure as a whole (Additional file 1: Table S1).	('Leu249', 'Var', (128, 134))	('Leu249', 'Chemical', '-', (128, 134))	('Val84', 'Var', (57, 62))	('Val84', 'Chemical', '-', (57, 62))
554977	33658076	The selection of the structure to be used as the docking model for the A2AR was based on the Val84-Leu249 inter-residue distances found for the active/inactive forms of the A2AR protein crystal structures reported in the protein data bank (PDB).	('Val84', 'Chemical', '-', (93, 98))	('Val84-Leu249', 'Var', (93, 105))	('Leu249', 'Chemical', '-', (99, 105))	('A2AR', 'Gene', '135', (173, 177))	('A2AR', 'Gene', '135', (71, 75))	('A2AR', 'Gene', (173, 177))	('A2AR', 'Gene', (71, 75))
554981	33658076	This is in agreement with a previous study by Rodriguez et al., where the A2AR crystal structure (PDB ID: 2YDO) displayed the highest enrichment factor value (EF1 %) for docked agonists over the other active crystal structures of the A2AR.	('A2AR', 'Gene', (74, 78))	('A2AR', 'Gene', '135', (234, 238))	('A2AR', 'Gene', (234, 238))	('A2AR', 'Gene', '135', (74, 78))	('docked', 'Var', (170, 176))
554989	33658076	This residue is located in the core region of the receptor and part of a sub-pocket formed by Leu85, Met177, Trp246 and Leu249.	('Trp246', 'Var', (109, 115))	('Met177', 'Chemical', '-', (101, 107))	('Leu85', 'Chemical', '-', (94, 99))	('Leu249', 'Var', (120, 126))	('Trp246', 'Chemical', '-', (109, 115))	('Leu249', 'Chemical', '-', (120, 126))	('Leu85', 'Var', (94, 99))	('Met177', 'Var', (101, 107))
554991	33658076	Hence, the selectivity of A2AR agonists could be attributed to the conformational preferences of the His250 amino acid residue that contributes to shaping the orthosteric site to favor their selectivity.	('A2AR', 'Gene', '135', (26, 30))	('orthosteric site', 'MPA', (159, 175))	('His250', 'Var', (101, 107))	('A2AR', 'Gene', (26, 30))	('selectivity', 'MPA', (191, 202))	('His250', 'Chemical', '-', (101, 107))
554992	33658076	Indeed, the interaction with this residue is only observed for the selective A2AR co-crystallized agonists, CGS21680 (PDB ID: 4UHR) and UK432097 (PDB ID: 3QAK) but not for the non-selective co-crystallized agonists NECA (PDB ID: 2YDV) and adenosine (PDB ID: 2YDO).	('A2AR', 'Gene', (77, 81))	('CGS21680', 'Var', (108, 116))	('adenosine', 'Chemical', 'MESH:D000241', (239, 248))	('NECA', 'Chemical', 'MESH:D019830', (215, 219))	('CGS21680', 'Chemical', 'MESH:C061282', (108, 116))	('UK432097', 'Var', (136, 144))	('A2AR', 'Gene', '135', (77, 81))	('UK432097', 'Chemical', 'MESH:C557757', (136, 144))
554993	33658076	These results appear to confirm that interactions with His250 serve to improve binding to the lipophilic sub-pocket which suggests this is a driver for A2AR sub-type selectivity.	('interactions', 'Var', (37, 49))	('lipophilic sub-pocket', 'MPA', (94, 115))	('binding', 'Interaction', (79, 86))	('His250', 'Chemical', '-', (55, 61))	('A2AR', 'Gene', '135', (152, 156))	('A2AR', 'Gene', (152, 156))	('His250', 'Var', (55, 61))	('improve', 'PosReg', (71, 78))
554994	33658076	Compound 1 hydrogen bonds via the nitrogen of the quinazoline ring with Asn253, and via the imidazo ring with Glu169.	('hydrogen bonds', 'Interaction', (11, 25))	('quinazoline', 'Chemical', 'MESH:D011799', (50, 61))	('nitrogen', 'Chemical', 'MESH:D009584', (34, 42))	('hydrogen', 'Chemical', 'MESH:D006859', (11, 19))	('Asn253', 'Chemical', '-', (72, 78))	('Asn253', 'Var', (72, 78))	('Glu169', 'Chemical', '-', (110, 116))
554998	33658076	The compounds were not predicted to display all the interactions exhibited by the agonist co-crystallized ligands, in particular the Thr88 and Ser277 interactions, which are also characteristic of the ZM241385 antagonist.	('ZM241385', 'Chemical', 'MESH:C097270', (201, 209))	('Thr88', 'Chemical', '-', (133, 138))	('interactions', 'Interaction', (52, 64))	('Ser277', 'Chemical', '-', (143, 149))	('Ser277', 'Var', (143, 149))
554999	33658076	However, it has been reported in the literature that mutating these residues has a stronger influence on agonist activity than upon the antagonist activity of the A2AR ligands, but not on the binding to the A2AR.	('influence', 'Reg', (92, 101))	('antagonist activity', 'MPA', (136, 155))	('mutating', 'Var', (53, 61))	('A2AR', 'Gene', '135', (207, 211))	('A2AR', 'Gene', '135', (163, 167))	('A2AR', 'Gene', (207, 211))	('A2AR', 'Gene', (163, 167))	('agonist activity', 'MPA', (105, 121))
555000	33658076	As for the co-crystallized A2AR antagonists (PDB ID: 5IU4 3UZA, 5K2A, 4EIY, 3EML, 5NM2, 5JTB, 5UVI, and 5UIG), these only show interactions with Phe168, Asn253, and Glu169 residues.	('JTB', 'Gene', (89, 92))	('interactions', 'Interaction', (127, 139))	('A2AR', 'Gene', '135', (27, 31))	('A2AR', 'Gene', (27, 31))	('Phe168', 'Var', (145, 151))	('Phe168', 'Chemical', '-', (145, 151))	('Glu169', 'Chemical', '-', (165, 171))	('Asn253', 'Chemical', '-', (153, 159))	('JTB', 'Gene', '10899', (89, 92))
555003	33658076	This suggested an investigation (using molecular dynamics) into whether the His250 movement would differ between selective versus non-selective A2AR agonist binding (discussed in the supporting information) and also to investigate whether the motion of Val84 would vary upon agonist and antagonist binding.	('binding', 'Interaction', (298, 305))	('A2AR', 'Gene', '135', (144, 148))	('His250', 'Chemical', '-', (76, 82))	('A2AR', 'Gene', (144, 148))	('Val84', 'Chemical', '-', (253, 258))	('His250', 'Var', (76, 82))	('differ', 'Reg', (98, 104))
555004	33658076	The analysis of the active and inactive forms of the available A2AR crystal structures is in accordance with reports in the literature, which mention that Val84 in TM3 has to move by approximately 2 A upon agonist binding to avoid a steric clash between the ligand and the receptor.	('steric clash', 'MPA', (233, 245))	('Val84', 'Chemical', '-', (155, 160))	('A2AR', 'Gene', '135', (63, 67))	('A2AR', 'Gene', (63, 67))	('Val84', 'Var', (155, 160))	('TM3', 'Gene', '7170', (164, 167))	('TM3', 'Gene', (164, 167))
555005	33658076	MD simulations (100 ns) were performed for the co-crystallized structures (PDB IDs: 5IU4 and 2YDO), which exhibited the largest differences observed in the distance between the alpha-carbons of Val84 in TM3, and Leu249, a relatively fixed residue in TM6 (12.96 A and 14.53 A, see methods for details).	('TM6', 'Chemical', '-', (250, 253))	('PDB IDs', 'Disease', (75, 82))	('Val84', 'Chemical', '-', (194, 199))	('Leu249', 'Var', (212, 218))	('Leu249', 'Chemical', '-', (212, 218))	('Val84', 'Var', (194, 199))	('TM3', 'Gene', (203, 206))	('alpha-carbons', 'Chemical', '-', (177, 190))	('PDB IDs', 'Disease', 'MESH:C535742', (75, 82))	('TM3', 'Gene', '7170', (203, 206))
555006	33658076	The same MD analysis was carried out for the apo structure of the A2AR (PDB ID: 5IU4), the docked triazoloquinazolines 1, 4 and 5 with the highest predicted affinities, compound 6 (with lowest predicted affinity), CHEMBL3799351 (a potent antagonist), and CGS21680 (the selective and potent A2AR agonist).	('A2AR', 'Gene', (290, 294))	('CGS21680', 'Var', (255, 263))	('CGS21680', 'Chemical', 'MESH:C061282', (255, 263))	('quinazoline', 'Chemical', 'MESH:D011799', (106, 117))	('A2AR', 'Gene', '135', (66, 70))	('affinities', 'MPA', (157, 167))	('A2AR', 'Gene', (66, 70))	('CHEMBL3799351', 'Var', (214, 227))	('A2AR', 'Gene', '135', (290, 294))	('CHEMBL3799351', 'Chemical', '-', (214, 227))
555008	33658076	For the subsequent 50 ns the agonist bound structures showed an increase of the Calpha distances between Val84 and Leu249, with an increased distance equivalent to the active protein crystal structure (PDB ID: 2YDO).	('Leu249', 'Chemical', '-', (115, 121))	('Val84', 'Gene', (105, 110))	('increase', 'PosReg', (64, 72))	('Calpha distances', 'MPA', (80, 96))	('Val84', 'Chemical', '-', (105, 110))	('Leu249', 'Var', (115, 121))
555009	33658076	To gain further insights from the change in the Calpha distances between Val84 and Leu249 for the agonist bound structures (which are the systems of interest in this study), longer simulations of 500 ns were carried for compounds 1, 5, and CGS21680, in addition to the active and inactive cocrystal structures (PDB IDs: 2YDO and 5IU4).	('Leu249', 'Chemical', '-', (83, 89))	('CGS21680', 'Var', (240, 248))	('PDB IDs', 'Disease', 'MESH:C535742', (311, 318))	('Val84', 'Chemical', '-', (73, 78))	('CGS21680', 'Chemical', 'MESH:C061282', (240, 248))	('PDB IDs', 'Disease', (311, 318))	('Leu249', 'Var', (83, 89))
555010	33658076	Over the first 50 ns the structures were annealing, and for the rest of the simulation (the last 450 ns) compounds 1, 5 and CGS21680 increased their Calpha distances between Val84 and approaching the distance observed for the active protein crystal structure (PDB ID: 2YDO), as shown in Fig.	('CGS21680', 'Var', (124, 132))	('Val84', 'Chemical', '-', (174, 179))	('CGS21680', 'Chemical', 'MESH:C061282', (124, 132))	('increased', 'PosReg', (133, 142))	('Calpha distances', 'MPA', (149, 165))	('Val84', 'Protein', (174, 179))
555011	33658076	3b, c. Hence, the increase in the distance between Val84 and Leu249 residues observed upon A2AR agonist binding appears to serve as a useful conformational descriptor for receptor activation by A2AR ligands.	('increase', 'PosReg', (18, 26))	('A2AR', 'Gene', (194, 198))	('A2AR', 'Gene', '135', (91, 95))	('Leu249 residues', 'Var', (61, 76))	('distance', 'MPA', (34, 42))	('A2AR', 'Gene', (91, 95))	('Val84', 'Chemical', '-', (51, 56))	('Val84', 'Var', (51, 56))	('binding', 'Interaction', (104, 111))	('Leu249', 'Chemical', '-', (61, 67))	('A2AR', 'Gene', '135', (194, 198))
555016	33658076	Using HEK293 cells we determined the disassociation constant (KD) of CA200645 at the Nluc-A2AR to be 65 nM (Fig.	('CA200645', 'Var', (69, 77))	('HEK293', 'CellLine', 'CVCL:0045', (6, 12))	('A2AR', 'Gene', '135', (90, 94))	('CA200645', 'Chemical', '-', (69, 77))	('A2AR', 'Gene', (90, 94))
555017	33658076	We next extended our studies to use a classical competition binding assay  where non-fluorescent ligands compete for binding at the Nluc-A2AR with CA200645.	('A2AR', 'Gene', '135', (137, 141))	('A2AR', 'Gene', (137, 141))	('binding', 'Interaction', (117, 124))	('CA200645', 'Chemical', '-', (147, 155))	('CA200645', 'Var', (147, 155))
555018	33658076	Using this approach, we determined the pKi for NECA as 6.36 +- 0.09 and CGS21680 as 6.39 +- 0.04 while isoprenaline (a non-selective agonist of beta-adrenoceptors) failed to displace CA200645 (Fig.	('CA200645', 'Var', (183, 191))	('CGS21680', 'Var', (72, 80))	('isoprenaline', 'Chemical', 'MESH:D007545', (103, 115))	('NECA', 'Chemical', 'MESH:D019830', (47, 51))	('CGS21680', 'Chemical', 'MESH:C061282', (72, 80))	('CA200645', 'Chemical', '-', (183, 191))
555020	33658076	Identification of AR subtype selectivity of triazoloquinazolines was performed using previously characterised yeast strains expressing human A1R, A2AR or A2BR.	('quinazoline', 'Chemical', 'MESH:D011799', (52, 63))	('A2BR', 'Var', (154, 158))	('A2AR', 'Gene', '135', (146, 150))	('human', 'Species', '9606', (135, 140))	('A2AR', 'Gene', (146, 150))	('A1R', 'Var', (141, 144))	('A2BR', 'Chemical', '-', (154, 158))	('yeast', 'Species', '4932', (110, 115))
555026	33658076	Antagonism with ZM241385 displayed non-classical antagonism, which is presumed to be due to the dual effects upon endogenous PDE10A (Additional file 1: Figure S5).	('non-classical antagonism', 'MPA', (35, 59))	('PDE10A', 'Gene', (125, 131))	('PDE10A', 'Gene', '10846', (125, 131))	('ZM241385', 'Chemical', 'MESH:C097270', (16, 24))	('ZM241385', 'Var', (16, 24))
555027	33658076	For compound 6, treatment with ZM241385 solely reduced Emax and basal levels, with no effect on the response range (Fig.	('Emax', 'MPA', (55, 59))	('ZM241385', 'Var', (31, 39))	('ZM241385', 'Chemical', 'MESH:C097270', (31, 39))	('basal levels', 'MPA', (64, 76))	('reduced', 'NegReg', (47, 54))
555028	33658076	ZM241385 has been suggested to be an inverse agonist at the A2AR potentially explaining these effects.	('A2AR', 'Gene', (60, 64))	('ZM241385', 'Var', (0, 8))	('A2AR', 'Gene', '135', (60, 64))	('ZM241385', 'Chemical', 'MESH:C097270', (0, 8))
555033	33658076	However, sole activation of the A2AR, via CGS21680 stimulation, had no anti-proliferative effects upon either cell type (Additional file 1: Figure S6, Table S3).	('activation', 'PosReg', (14, 24))	('CGS21680', 'Var', (42, 50))	('anti-proliferative effects', 'CPA', (71, 97))	('CGS21680', 'Chemical', 'MESH:C061282', (42, 50))	('A2AR', 'Gene', '135', (32, 36))	('A2AR', 'Gene', (32, 36))
555040	33658076	LK-2 cells express the A1R, A2BR and very low levels of PDE10A, but lacked expression of the A2AR (Fig.	('A1R', 'Var', (23, 26))	('PDE10A', 'Gene', (56, 62))	('A2BR', 'Var', (28, 32))	('PDE10A', 'Gene', '10846', (56, 62))	('A2AR', 'Gene', '135', (93, 97))	('A2AR', 'Gene', (93, 97))	('A2BR', 'Chemical', '-', (28, 32))
555054	33658076	In contrast, compound 6 displays no anti-proliferative activity in any cell type tested whilst CGS21680 is only anti-proliferative in H1563 cells (Fig.	('CGS21680', 'Chemical', 'MESH:C061282', (95, 103))	('H1563', 'CellLine', 'CVCL:1475', (134, 139))	('anti-proliferative activity', 'MPA', (36, 63))	('CGS21680', 'Var', (95, 103))
555064	33658076	It is suggested that the observed A2AR sub-type selectivity for 1-3 is attributed to their predicted interactions with the His250 residue, which is an interaction present only in the selective co-crystallized A2AR agonists, such as CGS21680 and UK432097.	('CGS21680', 'Chemical', 'MESH:C061282', (232, 240))	('His250', 'Chemical', '-', (123, 129))	('A2AR', 'Gene', '135', (209, 213))	('A2AR', 'Gene', '135', (34, 38))	('A2AR', 'Gene', (209, 213))	('A2AR', 'Gene', (34, 38))	('UK432097', 'Var', (245, 253))	('His250', 'Var', (123, 129))	('UK432097', 'Chemical', 'MESH:C557757', (245, 253))	('interactions', 'Interaction', (101, 113))	('CGS21680', 'Var', (232, 240))
555067	33658076	Moreover, MD analysis highlighted the motion of Val84 in TM3 as an essential requirement for A2AR activation.	('Val84', 'Chemical', '-', (48, 53))	('Val84', 'Var', (48, 53))	('A2AR', 'Gene', '135', (93, 97))	('TM3', 'Gene', '7170', (57, 60))	('A2AR', 'Gene', (93, 97))	('TM3', 'Gene', (57, 60))
555069	33658076	Compound 1 (as a selective A2AR agonist and a PDE10A inhibitor) exhibited increased potency for both cAMP accumulation and anti-proliferative actions, which increased in tandem with the combined target expression (A2AR and PDE10A) across the NSCLC cell lines, from LK-2-H520-H1792-H1563.	('cAMP accumulation', 'MPA', (101, 118))	('cAMP', 'Chemical', 'MESH:D000242', (101, 105))	('A2AR', 'Gene', (214, 218))	('PDE10A', 'Gene', (223, 229))	('potency', 'MPA', (84, 91))	('LK-2-H520-H1792-H1563', 'Var', (265, 286))	('A2AR', 'Gene', '135', (214, 218))	('A2AR', 'Gene', '135', (27, 31))	('A2AR', 'Gene', (27, 31))	('PDE10A', 'Gene', '10846', (223, 229))	('increased', 'PosReg', (74, 83))	('LK-2-H520-H1792-H1563', 'CellLine', 'CVCL:1495', (265, 286))	('PDE10A', 'Gene', (46, 52))	('NSCLC', 'Disease', (242, 247))	('increased', 'PosReg', (157, 166))	('NSCLC', 'Disease', 'MESH:D002289', (242, 247))	('anti-proliferative actions', 'CPA', (123, 149))	('PDE10A', 'Gene', '10846', (46, 52))
555073	33658076	From the ZINC database, eleven purchasable triazoloquinazolines that were experimentally determined as PDE10A inhibitors were identified using a search for the triazoloquinazoline substructure with the following criteria: Uniprot ID: Q9Y233 and IC50 < 10 microM.	('PDE10A', 'Gene', (103, 109))	('PDE10A', 'Gene', '10846', (103, 109))	('quinazoline', 'Chemical', 'MESH:D011799', (168, 179))	('Q9Y233', 'Var', (234, 240))	('quinazoline', 'Chemical', 'MESH:D011799', (51, 62))
555076	33658076	All the active forms of the A2AR protein crystal structure with the following PDB IDs (4UG2, 4UHR, 3QAK, 2YDO, and 2YDV) and the inactive forms with the following PDB IDs (5IU4, 3UZA, 5K2A, 4EIY, 3EML, 5NM2, 5JTB, 5UVI, and 5UIG) were downloaded into MOE.	('JTB', 'Gene', (209, 212))	('PDB IDs', 'Disease', (163, 170))	('5IU4', 'Var', (172, 176))	('PDB IDs', 'Disease', 'MESH:C535742', (78, 85))	('A2AR', 'Gene', '135', (28, 32))	('PDB IDs', 'Disease', (78, 85))	('A2AR', 'Gene', (28, 32))	('PDB IDs', 'Disease', 'MESH:C535742', (163, 170))	('JTB', 'Gene', '10899', (209, 212))
555077	33658076	It has been reported in the literature that Val84 in TM3, which is located in the orthosteric site, has to shift its position upon agonist binding owing to a steric clash with the ligand, which may contribute to the 2 A shift observed in H3.	('TM3', 'Gene', '7170', (53, 56))	('TM3', 'Gene', (53, 56))	('shift', 'Reg', (107, 112))	('Val84', 'Chemical', '-', (44, 49))	('Val84', 'Var', (44, 49))
555079	33658076	The 'fixed' amino acid residue selected was Leu249 in TM6.	('TM6', 'Chemical', '-', (54, 57))	('Leu249', 'Var', (44, 50))	('Leu249', 'Chemical', '-', (44, 50))	('TM6', 'Gene', (54, 57))
555082	33658076	For each PDB ID of the active and inactive forms of the A2AR crystal structures, the distance between the alpha-carbons of Val84 in TM3 and Leu249 in TM6 was measured in MOE using the measure > distances option.	('Val84', 'Chemical', '-', (123, 128))	('TM3', 'Gene', (132, 135))	('alpha-carbons', 'Chemical', '-', (106, 119))	('TM6', 'Chemical', '-', (150, 153))	('TM3', 'Gene', '7170', (132, 135))	('Leu249', 'Var', (140, 146))	('Leu249', 'Chemical', '-', (140, 146))	('A2AR', 'Gene', '135', (56, 60))	('A2AR', 'Gene', (56, 60))	('Val84', 'Gene', (123, 128))
555086	33658076	Given that Val84 displayed the highest displacement from the Leu249 residue in the protein crystal structure with the PDB ID: 2YDO, it was selected as the best candidate for shortlisting candidates of A2AR agonists.	('Val84', 'Chemical', '-', (11, 16))	('Val84', 'Var', (11, 16))	('Leu249', 'Var', (61, 67))	('Leu249', 'Chemical', '-', (61, 67))	('A2AR', 'Gene', '135', (201, 205))	('A2AR', 'Gene', (201, 205))	('displacement', 'MPA', (39, 51))
555102	33658076	Additionally compounds 1, 4 and 5 (with the highest predicted affinities and the most potent agonists identified), compound 6 (which did not exhibit any agonist activity), CHEMBL3799351 (an antagonist with an IC50 = 4.35 nM and confidence score equal to 9) and CGS21680 (the selective and potent A2AR agonist) and adenosine (a non-selective adenosine receptor agonist), were docked into the inactive form of the A2AR protein crystal structure (PDB ID: 5IU4) for MD simulation and analysis.	('adenosine', 'Chemical', 'MESH:D000241', (341, 350))	('CGS21680', 'Var', (261, 269))	('CHEMBL3799351', 'Var', (172, 185))	('A2AR', 'Gene', '135', (412, 416))	('A2AR', 'Gene', '135', (296, 300))	('adenosine', 'Chemical', 'MESH:D000241', (314, 323))	('A2AR', 'Gene', (412, 416))	('CHEMBL3799351', 'Chemical', '-', (172, 185))	('A2AR', 'Gene', (296, 300))	('CGS21680', 'Chemical', 'MESH:C061282', (261, 269))
555104	33658076	Based on a structural analysis of the available A2AR crystal structures, the distance between the alpha-carbons of Val84 in TM3 and Leu249 in TM6 was selected for investigation as a conformational descriptor for receptor activation.	('alpha-carbons', 'Chemical', '-', (98, 111))	('Leu249', 'Var', (132, 138))	('Leu249', 'Chemical', '-', (132, 138))	('TM3', 'Gene', '7170', (124, 127))	('TM3', 'Gene', (124, 127))	('Val84', 'Chemical', '-', (115, 120))	('A2AR', 'Gene', '135', (48, 52))	('A2AR', 'Gene', (48, 52))	('TM6', 'Chemical', '-', (142, 145))	('Val84', 'Gene', (115, 120))
555105	33658076	The two A2AR co-crystallized structures (PDB IDs: 5IU4 and 2YDO), which exhibited the largest difference in alpha-carbon distances between Val84 in TM3 and Leu249 in TM6 (12.96 A versus 14.53 A respectively), were selected for molecular dynamics simulation.	('Leu249', 'Var', (156, 162))	('TM3', 'Gene', '7170', (148, 151))	('Leu249', 'Chemical', '-', (156, 162))	('TM3', 'Gene', (148, 151))	('Val84', 'Chemical', '-', (139, 144))	('PDB IDs', 'Disease', 'MESH:C535742', (41, 48))	('Val84', 'Var', (139, 144))	('carbon', 'Chemical', 'MESH:D002244', (114, 120))	('A2AR', 'Gene', '135', (8, 12))	('PDB IDs', 'Disease', (41, 48))	('A2AR', 'Gene', (8, 12))	('TM6', 'Chemical', '-', (166, 169))
555107	33658076	Likewise, CHEMBL3799351, CGS21680 and adenosine were docked into the orthosteric site of the inactive form of the A2AR protein crystal (PDB ID: 5IU4) to obtain simulations of control compounds.	('CGS21680', 'Var', (25, 33))	('CHEMBL3799351', 'Chemical', '-', (10, 23))	('CGS21680', 'Chemical', 'MESH:C061282', (25, 33))	('A2AR', 'Gene', '135', (114, 118))	('adenosine', 'Chemical', 'MESH:D000241', (38, 47))	('A2AR', 'Gene', (114, 118))
555110	33658076	Then plots were obtained for the RMSD values of His250 in TM6, and the alpha-carbons distances between Val84 in TM3 and Leu249 in TM6 for the simulated systems over 100 ns using the seaborn library.	('Val84', 'Chemical', '-', (103, 108))	('TM6', 'Chemical', '-', (130, 133))	('TM6', 'Chemical', '-', (58, 61))	('His250', 'Chemical', '-', (48, 54))	('Leu249', 'Var', (120, 126))	('Leu249', 'Chemical', '-', (120, 126))	('His250', 'Var', (48, 54))	('TM3', 'Gene', '7170', (112, 115))	('TM3', 'Gene', (112, 115))	('alpha-carbons', 'Chemical', '-', (71, 84))	('Val84', 'Gene', (103, 108))
555121	33658076	Afterwards, each well was tested for the ability of CGS21680 to elevate cAMP, performing further culturing with appropriately responding clones as described.	('CGS21680', 'Chemical', 'MESH:C061282', (52, 60))	('cAMP', 'MPA', (72, 76))	('CGS21680', 'Var', (52, 60))	('cAMP', 'Chemical', 'MESH:D000242', (72, 76))
555125	33658076	Yeast cells expressing either the A1R, A2AR, or A2BR were treated with either NECA, CGS21680 or compounds 1-6, in order to measure the activity of each, as previously described.	('A2BR', 'Chemical', '-', (48, 52))	('CGS21680', 'Chemical', 'MESH:C061282', (84, 92))	('A2AR', 'Gene', (39, 43))	('A2BR', 'Var', (48, 52))	('Yeast', 'Species', '4932', (0, 5))	('activity', 'MPA', (135, 143))	('NECA', 'Chemical', 'MESH:D019830', (78, 82))	('A2AR', 'Gene', '135', (39, 43))
555154	31592232	The results of the western blotting (WB) of Human Umbilical Vein Endothelial Cells (HUVECs) after coculture with lung adenocarcinoma H1975 cells, H1975 cell-supernatants and H1975-derived EVs showed that YAP derived from H1975 cells can enter HUVECs via EVs.	('Human', 'Species', '9606', (44, 49))	('H1975', 'Var', (221, 226))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (113, 132))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (113, 132))	('lung adenocarcinoma', 'Disease', (113, 132))	('carcinoma', 'Phenotype', 'HP:0030731', (123, 132))
555231	30453543	Recently, we showed that the T-box transcription factor BRACHYURY could be a strong regulator of EMT and the CSC phenotype, which were effectively suppressed by a BRACHYURY knockdown in an adenoid cystic carcinoma cell line.	('BRACHYURY', 'Gene', '6899', (56, 65))	('BRACHYURY', 'Gene', (56, 65))	('BRACHYURY', 'Gene', '6899', (163, 172))	('BRACHYURY', 'Gene', (163, 172))	('adenoid cystic carcinoma', 'Disease', 'MESH:D003528', (189, 213))	('CSC phenotype', 'CPA', (109, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (204, 213))	('knockdown', 'Var', (173, 182))	('EMT', 'CPA', (97, 100))	('suppressed', 'NegReg', (147, 157))	('adenoid cystic carcinoma', 'Disease', (189, 213))
555254	30453543	In our previous study, we demonstrated that a CSC-like cell line (adenoid cystic carcinoma), ACCS-M GFP undergoes EMT, and that small hairpin RNA (shRNA) silencing of BRACHYURY downregulates EMT (and stem cell markers) in that cell line and leads to a loss of CSC-like and EMT characteristics of this cell line.	('downregulates', 'NegReg', (177, 190))	('adenoid cystic carcinoma', 'Disease', 'MESH:D003528', (66, 90))	('BRACHYURY', 'Gene', '6899', (167, 176))	('BRACHYURY', 'Gene', (167, 176))	('EMT', 'CPA', (191, 194))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('loss', 'NegReg', (252, 256))	('adenoid cystic carcinoma', 'Disease', (66, 90))	('silencing', 'Var', (154, 163))
555255	30453543	Tumourigenesis and metastasis of ACCS-M GFP in vivo were inhibited completely by BRACHYURY knockdown and partially by knockdown of SOX2, the conventional CSC regulator gene.	('knockdown', 'Var', (118, 127))	('inhibited', 'NegReg', (57, 66))	('SOX2', 'Gene', (131, 135))	('knockdown', 'Var', (91, 100))	('metastasis', 'CPA', (19, 29))	('BRACHYURY', 'Gene', '6899', (81, 90))	('BRACHYURY', 'Gene', (81, 90))	('Tumourigenesis', 'CPA', (0, 14))
555258	30453543	In this regard, BRACHYURY silencing could effectively control cancer stemness and offer a new concept for the development of cancer treatments.	('control', 'PosReg', (54, 61))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('BRACHYURY', 'Gene', '6899', (16, 25))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('BRACHYURY', 'Gene', (16, 25))	('cancer stemness', 'Disease', 'MESH:D009369', (62, 77))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('silencing', 'Var', (26, 35))	('cancer', 'Disease', (125, 131))	('cancer', 'Disease', 'MESH:D009369', (125, 131))	('cancer stemness', 'Disease', (62, 77))
555261	30453543	We also showed that BRACHYURY knockdown completely inhibits CSC and EMT phenotypes of the ACCS-M GFP cells.	('CSC', 'CPA', (60, 63))	('inhibits', 'NegReg', (51, 59))	('EMT phenotypes', 'CPA', (68, 82))	('BRACHYURY', 'Gene', '6899', (20, 29))	('knockdown', 'Var', (30, 39))	('BRACHYURY', 'Gene', (20, 29))
555267	30453543	In contrast, the BRACHYURY knockdown on ACCS-M GFP cells remarkably inhibited sphere formation in both the primary (P = 0.0001, ANOVA) and the secondary assay (P = 0.0001, ANOVA), with respect to both the diameter and the number of spheres (Figure 1).	('knockdown', 'Var', (27, 36))	('sphere formation', 'CPA', (78, 94))	('inhibited', 'NegReg', (68, 77))	('BRACHYURY', 'Gene', '6899', (17, 26))	('BRACHYURY', 'Gene', (17, 26))
555275	30453543	In contrast, mRNA levels of all markers decreased significantly in the BRACHYURY knockdown cells (ACCS-M shBra) compared to parental ACCS-M GFP cells.	('BRACHYURY', 'Gene', '6899', (71, 80))	('mRNA levels of all markers', 'MPA', (13, 39))	('BRACHYURY', 'Gene', (71, 80))	('knockdown', 'Var', (81, 90))	('decreased', 'NegReg', (40, 49))
555281	30453543	In contrast, co-expression of BRACHYURY and SOX2 enhanced sphere formation in both the primary and the secondary sphere assays, with respect to both the diameter and the number of spheres, in ACCS and TF cells.	('enhanced', 'PosReg', (49, 57))	('co-expression', 'Var', (13, 26))	('BRACHYURY', 'Gene', '6899', (30, 39))	('secondary sphere assays', 'CPA', (103, 126))	('BRACHYURY', 'Gene', (30, 39))	('SOX2', 'Gene', (44, 48))	('sphere formation', 'CPA', (58, 74))
555288	30453543	The above results suggested that co-expression of BRACHYURY and SOX2 induces the CSC phenotype.	('co-expression', 'Var', (33, 46))	('BRACHYURY', 'Gene', '6899', (50, 59))	('BRACHYURY', 'Gene', (50, 59))	('induces', 'Reg', (69, 76))	('CSC', 'Disease', (81, 84))	('SOX2', 'Gene', (64, 68))
555306	30453543	We recently showed that CSC phenotypes, including EMT, could be blocked by knocking down the transcriptional factor BRACHYURY in vitro and in vivo.	('CSC', 'Disease', (24, 27))	('BRACHYURY', 'Gene', '6899', (116, 125))	('BRACHYURY', 'Gene', (116, 125))	('EMT', 'CPA', (50, 53))	('knocking down', 'Var', (75, 88))
555307	30453543	We also showed downregulation of EMT-related genes, stem cell markers, and loss of tumourigenic and metastatic potential in vivo as a result of knockdown of BRACHYURY in a CSC-like cell line, ACCS-M GFP.	('downregulation', 'NegReg', (15, 29))	('EMT-related genes', 'Gene', (33, 50))	('BRACHYURY', 'Gene', '6899', (157, 166))	('tumour', 'Phenotype', 'HP:0002664', (83, 89))	('BRACHYURY', 'Gene', (157, 166))	('loss of tumourigenic', 'Disease', (75, 95))	('knockdown', 'Var', (144, 153))	('loss of tumourigenic', 'Disease', 'MESH:D015431', (75, 95))	('stem cell', 'CPA', (52, 61))
555309	30453543	also reported that a BRACHYURY knockdown via siRNA resulted in downregulation of expression of CD44, CD166, CD133, ALDH1, and NANOG in colon cancer, and they concluded that BRACHYURY participates in establishment of CSC characteristics by inducing NANOG expression.	('ALDH1', 'Gene', (115, 120))	('CD166', 'Gene', '214', (101, 106))	('colon cancer', 'Disease', (135, 147))	('BRACHYURY', 'Gene', (173, 182))	('BRACHYURY', 'Gene', (21, 30))	('downregulation', 'NegReg', (63, 77))	('expression', 'MPA', (81, 91))	('NANOG', 'Gene', '79923', (248, 253))	('inducing', 'PosReg', (239, 247))	('NANOG', 'Gene', (248, 253))	('colon cancer', 'Phenotype', 'HP:0003003', (135, 147))	('CD166', 'Gene', (101, 106))	('CD44', 'Gene', '960', (95, 99))	('BRACHYURY', 'Gene', '6899', (173, 182))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('CD44', 'Gene', (95, 99))	('ALDH1', 'Gene', '216', (115, 120))	('BRACHYURY', 'Gene', '6899', (21, 30))	('colon cancer', 'Disease', 'MESH:D015179', (135, 147))	('NANOG', 'Gene', '79923', (126, 131))	('NANOG', 'Gene', (126, 131))	('CD133', 'Gene', (108, 113))	('CD133', 'Gene', '8842', (108, 113))	('knockdown', 'Var', (31, 40))
555326	30453543	reported that silencing of the SOX2 gene reduces the tumourigenic potential of a lung cancer cell line (A549 cells) with downregulation of C-MYC, WNT1, WNT2, and NOTCH1 in mice; these authors uncovered 246 additional target cancer genes of SOX2.	('A549', 'CellLine', 'CVCL:0023', (104, 108))	('tumour', 'Disease', (53, 59))	('C-MYC', 'Gene', '4609', (139, 144))	('lung cancer', 'Disease', 'MESH:D008175', (81, 92))	('cancer', 'Disease', (224, 230))	('C-MYC', 'Gene', (139, 144))	('silencing', 'Var', (14, 23))	('lung cancer', 'Phenotype', 'HP:0100526', (81, 92))	('reduces', 'NegReg', (41, 48))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('mice', 'Species', '10090', (172, 176))	('NOTCH1', 'Gene', '18128', (162, 168))	('cancer', 'Disease', (86, 92))	('WNT2', 'Gene', '22413', (152, 156))	('WNT2', 'Gene', (152, 156))	('WNT1', 'Gene', '22408', (146, 150))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('downregulation', 'NegReg', (121, 135))	('cancer', 'Disease', 'MESH:D009369', (224, 230))	('lung cancer', 'Disease', (81, 92))	('SOX2', 'Gene', (31, 35))	('NOTCH1', 'Gene', (162, 168))	('WNT1', 'Gene', (146, 150))	('tumour', 'Phenotype', 'HP:0002664', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('tumour', 'Disease', 'MESH:D009369', (53, 59))
555336	30453543	In other words, the closer to the centre of the network (SOX2 and BRACHYURY) a target factor is, the greater the impact of its inactivation on EMT and cancer stemness.	('BRACHYURY', 'Gene', (66, 75))	('inactivation', 'Var', (127, 139))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('cancer stemness', 'Disease', 'MESH:D009369', (151, 166))	('cancer stemness', 'Disease', (151, 166))	('BRACHYURY', 'Gene', '6899', (66, 75))
555338	30453543	In this study, we showed that co-expression of BRACHYURY and SOX2 promotes both EMT and self-renewal phenotypes in ACCS-GFP cells; phenotypes that resemble ACCS-M GFP, the CSC-like cell line from in vivo selection.	('self-renewal phenotypes', 'CPA', (88, 111))	('co-expression', 'Var', (30, 43))	('BRACHYURY', 'Gene', '6899', (47, 56))	('BRACHYURY', 'Gene', (47, 56))	('EMT', 'CPA', (80, 83))	('promotes', 'PosReg', (66, 74))	('SOX2', 'Gene', (61, 65))
555346	30453543	Because it has been described in our previous study, tumourigenesis and metastasis of ACCSM cell were prevented completely by silencing of BRACHYURY and partially by silencing of SOX2 in vivo.	('prevented', 'NegReg', (102, 111))	('tumour', 'Phenotype', 'HP:0002664', (53, 59))	('BRACHYURY', 'Gene', '6899', (139, 148))	('BRACHYURY', 'Gene', (139, 148))	('metastasis of', 'CPA', (72, 85))	('tumour', 'Disease', (53, 59))	('silencing', 'Var', (166, 175))	('tumour', 'Disease', 'MESH:D009369', (53, 59))	('silencing', 'Var', (126, 135))
555359	30453543	ACCS-Bra and TF-Bra cells were generated via transfection of the pCMV6-Brachyury vector into ACCS-GFP and TF-GFP cells, respectively.	('transfection', 'Var', (45, 57))	('Brachyury', 'Gene', '6899', (71, 80))	('Brachyury', 'Gene', (71, 80))
555389	26407999	A549 and SK-MES-1 CM and secreted-proteins significantly enhanced endothelial surface E-selectin levels after 30 min and 4 h and tumour cell adhesion after 30 min, 4 and 24 h. Both coincided with significant glycocalyx degradation; A549 and SK-MES-1 CM removing 55 +- 12 % and 58 +- 18.7 % of WGA-FITC binding, respectively.	('tumour', 'Phenotype', 'HP:0002664', (129, 135))	('A549', 'Var', (232, 236))	('SK-MES-1 CM', 'Var', (241, 252))	('A549', 'CellLine', 'CVCL:0023', (0, 4))	('enhanced endothelial surface E-selectin levels', 'Phenotype', 'HP:0032240', (57, 103))	('removing', 'NegReg', (253, 261))	('tumour', 'Disease', 'MESH:D009369', (129, 135))	('FITC', 'Chemical', 'MESH:D016650', (297, 301))	('tumour', 'Disease', (129, 135))	('SK-MES', 'Chemical', '-', (241, 247))	('SK-MES', 'Chemical', '-', (9, 15))	('A549', 'CellLine', 'CVCL:0023', (232, 236))	('WGA-FITC', 'Protein', (293, 301))
555400	26407999	Several studies have shown that altered E-selectin expression on activated endothelial cells greatly influences metastasis formation and subsequent colonization, and increased circulating E-selectin levels have been associated with metastasis of both breast and colon carcinoma cells to the liver.	('increased circulating E-selectin levels', 'Phenotype', 'HP:0032240', (166, 205))	('metastasis formation', 'CPA', (112, 132))	('circulating E-selectin levels', 'MPA', (176, 205))	('associated with', 'Reg', (216, 231))	('increased', 'PosReg', (166, 175))	('metastasis', 'CPA', (232, 242))	('altered', 'Var', (32, 39))	('breast and colon carcinoma', 'Disease', 'MESH:D015179', (251, 277))	('colonization', 'CPA', (148, 160))	('influences', 'Reg', (101, 111))	('E-selectin', 'Protein', (40, 50))	('carcinoma', 'Phenotype', 'HP:0030731', (268, 277))
555409	26407999	Importantly, we identify E-selectin as the key adhesion molecule involved in the initial tethering of the lung tumour cells and for the first time demonstrate that loss of integrity of the cerebral endothelial glycocalyx enhances exposure of E-selectin and tumour cell adhesion.	('loss', 'Var', (164, 168))	('enhances', 'PosReg', (221, 229))	('tumour', 'Phenotype', 'HP:0002664', (257, 263))	('tumour', 'Phenotype', 'HP:0002664', (111, 117))	('rat', 'Species', '10116', (154, 157))	('lung tumour', 'Phenotype', 'HP:0100526', (106, 117))	('tumour', 'Disease', 'MESH:D009369', (257, 263))	('exposure', 'MPA', (230, 238))	('tumour', 'Disease', 'MESH:D009369', (111, 117))	('tumour', 'Disease', (257, 263))	('E-selectin', 'Protein', (242, 252))	('tumour', 'Disease', (111, 117))	('lung tumour', 'Disease', (106, 117))	('lung tumour', 'Disease', 'MESH:D008175', (106, 117))
555412	26407999	Cells were cultured and grown to confluence in rat tail collagen type I coated tissue culture flasks at 37  C under 5 % CO2 atmosphere using Endothelial Cell Basal MV2 Medium (C-22221, PromoCell, Germany) supplemented with MV2 supplement pack (C-39221, PromoCell, Germany).	('rat tail', 'Phenotype', 'HP:0002825', (47, 55))	('MV2', 'Chemical', '-', (164, 167))	('rat', 'Species', '10116', (47, 50))	('C-39221', 'Var', (244, 251))	('CO2', 'Chemical', '-', (120, 123))	('MV2', 'Chemical', '-', (223, 226))	('C-22221', 'Var', (176, 183))
555413	26407999	Human NSCLC cell lines, A549 and SK-MES-1, were purchased from the European Collection of Cell Cultures (ECACC; Salisbury, UK) and cultured in Dulbecco's Modified Eagle Medium (DMEM, Lonza, Slough, UK) supplemented with L-glutamine (2 mM), gentamicin (50 mug/ml) and 10 % (v/v) FBS (Sigma Aldrich, Gillingham, UK).	("Dulbecco's Modified Eagle Medium", 'Chemical', '-', (143, 175))	('Human', 'Species', '9606', (0, 5))	('FBS', 'Disease', (278, 281))	('NSCLC', 'Disease', 'MESH:D002289', (6, 11))	('A549', 'CellLine', 'CVCL:0023', (24, 28))	('gentamicin', 'Chemical', 'MESH:D005839', (240, 250))	('L-glutamine', 'Chemical', 'MESH:D005973', (220, 231))	('NSCLC', 'Phenotype', 'HP:0030358', (6, 11))	('FBS', 'Disease', 'MESH:D005198', (278, 281))	('DMEM', 'Chemical', '-', (177, 181))	('SK-MES', 'Chemical', '-', (33, 39))	('NSCLC', 'Disease', (6, 11))	('50', 'Var', (252, 254))
555448	26407999	Cerebral ECs exposed to both A549 and SK-MES-1 CM also demonstrated enhanced levels of surface E-selectin at 4 h (272 +- 96.1 % and 177 +- 70.4 % respectively).	('enhanced', 'PosReg', (68, 76))	('SK-MES', 'Chemical', '-', (38, 44))	('levels', 'MPA', (77, 83))	('A549', 'CellLine', 'CVCL:0023', (29, 33))	('rat', 'Species', '10116', (62, 65))	('A549', 'Var', (29, 33))	('SK-MES-1 CM', 'Var', (38, 49))
555450	26407999	Furthermore, at 30 min A549 CM also appeared to significantly enhance the exposure of P-selectin on the surface of hCMEC/D3 cells (128 +- 30.6 % v control 100 %) (p <= 0.037, n = 3).	('P-selectin', 'Gene', '6403', (86, 96))	('exposure', 'MPA', (74, 82))	('enhance', 'PosReg', (62, 69))	('P-selectin', 'Gene', (86, 96))	('A549 CM', 'Var', (23, 30))	('A549', 'CellLine', 'CVCL:0023', (23, 27))
555455	26407999	3a & c) Interestingly, a reduced, but still significant, increase in tumour cell adhesion was also observed after only 30 min of A549 and SK-MES-1 CM treatment; 137 +- 17.3 % and 170 +- 85.4 %, respectively.	('tumour', 'Disease', (69, 75))	('tumour', 'Phenotype', 'HP:0002664', (69, 75))	('tumour', 'Disease', 'MESH:D009369', (69, 75))	('and SK-MES-1', 'Var', (134, 146))	('SK-MES', 'Chemical', '-', (138, 144))	('A549', 'CellLine', 'CVCL:0023', (129, 133))
555473	26407999	An even greater reduction in glycocalyx staining was observed after 24 h to 45 +- 10.9 % and 42 +- 17.1 % after exposure to A549 and SK-MES-1 CM, respectively vs control (100 %).	('SK-MES', 'Chemical', '-', (133, 139))	('A549', 'CellLine', 'CVCL:0023', (124, 128))	('reduction', 'NegReg', (16, 25))	('glycocalyx staining', 'MPA', (29, 48))	('A549', 'Var', (124, 128))	('SK-MES-1 CM', 'Var', (133, 144))
555479	26407999	After 30 min, significantly increased levels of HA were detected in the SK-MES-1 CM treated endothelial supernate (56.94 +- 23.6 ng/ml vs control, 0.74 +- 0.04 ng/ml) and raised syndecan-1 levels (1.15 +- 1.09 ng/ml vs control [not detected]) were observed in the A549 CM exposed endothelial supernates (Fig.	('increased', 'PosReg', (28, 37))	('syndecan-1', 'Gene', (178, 188))	('HA', 'Chemical', 'MESH:D006820', (48, 50))	('A549', 'CellLine', 'CVCL:0023', (264, 268))	('SK-MES-1', 'Var', (72, 80))	('SK-MES', 'Chemical', '-', (72, 78))	('syndecan-1', 'Gene', '6382', (178, 188))
555492	26407999	For instance, in NSCLC a positive correlation has been identified between high TNF-alpha expression and favourable prognosis.	('NSCLC', 'Disease', (17, 22))	('expression', 'MPA', (89, 99))	('high', 'Var', (74, 78))	('NSCLC', 'Disease', 'MESH:D002289', (17, 22))	('TNF-alpha', 'Gene', (79, 88))	('NSCLC', 'Phenotype', 'HP:0030358', (17, 22))	('TNF-alpha', 'Gene', '7124', (79, 88))
555527	26407999	Our data suggest that combining inhibitors capable of interrupting the contacts between E-selectin and its ligand along with preservation of glycocalyx integrity may represent a novel treatment modality for reducing brain metastasis in primary lung tumour patients.	('tumour', 'Phenotype', 'HP:0002664', (249, 255))	('interrupting', 'NegReg', (54, 66))	('brain metastasis', 'CPA', (216, 232))	('inhibitors', 'Var', (32, 42))	('primary lung tumour', 'Disease', 'MESH:D008175', (236, 255))	('patients', 'Species', '9606', (256, 264))	('reducing', 'NegReg', (207, 215))	('E-selectin', 'Protein', (88, 98))	('primary lung tumour', 'Disease', (236, 255))	('contacts', 'Interaction', (71, 79))	('lung tumour', 'Phenotype', 'HP:0100526', (244, 255))
555534	32328202	The hypo-methylations of EMP3 and SERPINE1 were contributing to the high expressions of EMP3 and SERPINE1 in old LGG patients.	('EMP3', 'Gene', (25, 29))	('SERPINE1', 'Gene', '5054', (97, 105))	('SERPINE1', 'Gene', (97, 105))	('EMP3', 'Gene', '2014', (25, 29))	('high', 'PosReg', (68, 72))	('expressions', 'MPA', (73, 84))	('EMP3', 'Gene', (88, 92))	('hypo-methylations', 'Var', (4, 21))	('patients', 'Species', '9606', (117, 125))	('LGG', 'Disease', (113, 116))	('SERPINE1', 'Gene', '5054', (34, 42))	('SERPINE1', 'Gene', (34, 42))	('EMP3', 'Gene', '2014', (88, 92))
555536	32328202	Moreover, high expressions of IGFBP2, EMP3, TIMP1 and SERPINE1 were associated with the worse prognosis of LGG patients.	('EMP3', 'Gene', (38, 42))	('associated', 'Reg', (68, 78))	('TIMP1', 'Gene', (44, 49))	('LGG', 'Disease', (107, 110))	('EMP3', 'Gene', '2014', (38, 42))	('IGFBP2', 'Gene', '3485', (30, 36))	('SERPINE1', 'Gene', '5054', (54, 62))	('SERPINE1', 'Gene', (54, 62))	('IGFBP2', 'Gene', (30, 36))	('TIMP1', 'Gene', '7076', (44, 49))	('high expressions', 'Var', (10, 26))	('patients', 'Species', '9606', (111, 119))
555537	32328202	Furthermore, we demonstrated that EMP3 and SERPINE1 were connected with each other and the combination of EMP3 and SERPINE1 had better prognostic effects in glioma patients.	('EMP3', 'Gene', '2014', (106, 110))	('EMP3', 'Gene', (34, 38))	('glioma', 'Disease', 'MESH:D005910', (157, 163))	('EMP3', 'Gene', '2014', (34, 38))	('SERPINE1', 'Gene', '5054', (115, 123))	('glioma', 'Phenotype', 'HP:0009733', (157, 163))	('SERPINE1', 'Gene', (43, 51))	('SERPINE1', 'Gene', (115, 123))	('patients', 'Species', '9606', (164, 172))	('better', 'PosReg', (128, 134))	('glioma', 'Disease', (157, 163))	('SERPINE1', 'Gene', '5054', (43, 51))	('combination', 'Var', (91, 102))	('EMP3', 'Gene', (106, 110))
555560	32328202	At last, we demonstrate the prognostic effects of combination of EMP3 and SERPINE1 genes in glioma patients.	('EMP3', 'Gene', (65, 69))	('glioma', 'Disease', (92, 98))	('patients', 'Species', '9606', (99, 107))	('EMP3', 'Gene', '2014', (65, 69))	('SERPINE1', 'Gene', '5054', (74, 82))	('SERPINE1', 'Gene', (74, 82))	('combination', 'Var', (50, 61))	('glioma', 'Disease', 'MESH:D005910', (92, 98))	('glioma', 'Phenotype', 'HP:0009733', (92, 98))
555564	32328202	The gene expression series matrix of normal and cancerous brain tissues was downloaded from the Gene Expression Omnibus (GEO) website (www.ncbi.nlm.nih.gov/geo), and included the GEO datasets GSE4920, GSE16011 and GSE50161.	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('cancerous', 'Disease', 'MESH:D009369', (48, 57))	('GSE50161', 'Var', (214, 222))	('GSE16011', 'Var', (201, 209))	('cancerous brain', 'Phenotype', 'HP:0030692', (48, 63))	('GSE4920', 'Var', (192, 199))	('cancerous', 'Disease', (48, 57))
555619	32328202	Similarly, age related gene SERPINE1 was hypo-methylated in old LGG patients, compared with young LGG patients (P=5.35e-05) (Figure 4B).	('SERPINE1', 'Gene', '5054', (28, 36))	('SERPINE1', 'Gene', (28, 36))	('patients', 'Species', '9606', (102, 110))	('patients', 'Species', '9606', (68, 76))	('hypo-methylated', 'Var', (41, 56))	('LGG', 'Disease', (64, 67))
555629	32328202	For example, high IGFBP2, EMP3, TIMP1 and SERPINE1 expressions were all positively associated with the overall survival of LGG patients, while, high SFRP2, IRX1, KLRC3 and LUZP2 expressions were all negatively associated with the overall survival of LGG patients (Table 2).	('IGFBP2', 'Gene', '3485', (18, 24))	('IRX1', 'Gene', '79192', (156, 160))	('TIMP1', 'Gene', (32, 37))	('LUZP2', 'Gene', '338645', (172, 177))	('SFRP2', 'Gene', (149, 154))	('positively', 'PosReg', (72, 82))	('SERPINE1', 'Gene', (42, 50))	('IGFBP2', 'Gene', (18, 24))	('high', 'Var', (13, 17))	('TIMP1', 'Gene', '7076', (32, 37))	('KLRC3', 'Gene', '3823', (162, 167))	('EMP3', 'Gene', (26, 30))	('KLRC3', 'Gene', (162, 167))	('SERPINE1', 'Gene', '5054', (42, 50))	('LGG', 'Disease', (250, 253))	('LGG', 'Disease', (123, 126))	('IRX1', 'Gene', (156, 160))	('EMP3', 'Gene', '2014', (26, 30))	('LUZP2', 'Gene', (172, 177))	('patients', 'Species', '9606', (127, 135))	('associated', 'Reg', (83, 93))	('SFRP2', 'Gene', '6423', (149, 154))	('patients', 'Species', '9606', (254, 262))
555640	32328202	We found that patients with both high EMP3 and SERPINE1 expressions were particular with lowest overall survival in glioma patients (Figure 7B).	('EMP3', 'Gene', (38, 42))	('high', 'Var', (33, 37))	('glioma', 'Disease', 'MESH:D005910', (116, 122))	('lowest', 'NegReg', (89, 95))	('glioma', 'Disease', (116, 122))	('patients', 'Species', '9606', (123, 131))	('EMP3', 'Gene', '2014', (38, 42))	('overall survival', 'MPA', (96, 112))	('patients', 'Species', '9606', (14, 22))	('SERPINE1', 'Gene', '5054', (47, 55))	('SERPINE1', 'Gene', (47, 55))	('glioma', 'Phenotype', 'HP:0009733', (116, 122))
555641	32328202	Patients with the low expression of EMP3 or SERPINE1 had better clinical outcomes (Figure 7B).	('EMP3', 'Gene', (36, 40))	('Patients', 'Species', '9606', (0, 8))	('SERPINE1', 'Gene', '5054', (44, 52))	('SERPINE1', 'Gene', (44, 52))	('low expression', 'Var', (18, 32))	('EMP3', 'Gene', '2014', (36, 40))
555650	32328202	Moreover, EMP3 and SERPINE1 were highly correlated with each other (Figure 8D) and the combination of EMP3 and SERPINE1 genes had better survival prediction in Chinese patients with LGG (Figure 8E).	('EMP3', 'Gene', (10, 14))	('better', 'PosReg', (130, 136))	('survival', 'CPA', (137, 145))	('EMP3', 'Gene', '2014', (102, 106))	('SERPINE1', 'Gene', '5054', (111, 119))	('SERPINE1', 'Gene', (111, 119))	('EMP3', 'Gene', '2014', (10, 14))	('combination', 'Var', (87, 98))	('SERPINE1', 'Gene', '5054', (19, 27))	('SERPINE1', 'Gene', (19, 27))	('patients', 'Species', '9606', (168, 176))	('EMP3', 'Gene', (102, 106))	('LGG', 'Disease', (182, 185))
555669	32328202	Furthermore, high expressions of IGFBP2, EMP3, TIMP1 and SERPINE1 are associated with low overall survival of LGG patients (Figure 6).	('EMP3', 'Gene', (41, 45))	('patients', 'Species', '9606', (114, 122))	('high', 'Var', (13, 17))	('IGFBP2', 'Gene', '3485', (33, 39))	('TIMP1', 'Gene', (47, 52))	('LGG', 'Disease', (110, 113))	('EMP3', 'Gene', '2014', (41, 45))	('IGFBP2', 'Gene', (33, 39))	('SERPINE1', 'Gene', '5054', (57, 65))	('TIMP1', 'Gene', '7076', (47, 52))	('low', 'NegReg', (86, 89))	('SERPINE1', 'Gene', (57, 65))	('overall survival', 'MPA', (90, 106))
555670	32328202	Interestingly, EMP3 and SERPINE1 are connected with each other and the combination of EMP3 and SERPINE1 genes have better prognostic effects in glioma patients (Figure 7B and 7C).	('glioma', 'Disease', 'MESH:D005910', (144, 150))	('glioma', 'Phenotype', 'HP:0009733', (144, 150))	('SERPINE1', 'Gene', '5054', (24, 32))	('SERPINE1', 'Gene', (24, 32))	('patients', 'Species', '9606', (151, 159))	('EMP3', 'Gene', (86, 90))	('SERPINE1', 'Gene', (95, 103))	('SERPINE1', 'Gene', '5054', (95, 103))	('EMP3', 'Gene', (15, 19))	('glioma', 'Disease', (144, 150))	('better', 'PosReg', (115, 121))	('EMP3', 'Gene', '2014', (86, 90))	('combination', 'Var', (71, 82))	('EMP3', 'Gene', '2014', (15, 19))
555673	32328202	Although the expression of IGFBP2 is controlled by epigenetic DNA methylation in glioma patients, we find no significant different methylation intensity of IGFBP2 and TIMP1 genes between old and young LGG patients (Figure 4B).	('epigenetic', 'Var', (51, 61))	('glioma', 'Phenotype', 'HP:0009733', (81, 87))	('IGFBP2', 'Gene', (27, 33))	('patients', 'Species', '9606', (205, 213))	('IGFBP2', 'Gene', '3485', (156, 162))	('IGFBP2', 'Gene', (156, 162))	('patients', 'Species', '9606', (88, 96))	('TIMP1', 'Gene', (167, 172))	('glioma', 'Disease', (81, 87))	('LGG', 'Disease', (201, 204))	('TIMP1', 'Gene', '7076', (167, 172))	('IGFBP2', 'Gene', '3485', (27, 33))	('controlled', 'Reg', (37, 47))	('glioma', 'Disease', 'MESH:D005910', (81, 87))
555761	32726984	However, this miRNA was found with significantly deregulated levels in cancer; miR-16 overexpression was associated with osteoclast differentiation and bone metastasis, and variable, aberrant miR-6 levels were associated with breast cancer in patients with and without lymph node metastasis.	('cancer', 'Phenotype', 'HP:0002664', (233, 239))	('miR-16', 'Gene', (79, 85))	('osteoclast differentiation', 'CPA', (121, 147))	('aberrant', 'Var', (183, 191))	('miR', 'Gene', (14, 17))	('miR', 'Gene', '220972', (192, 195))	('patients', 'Species', '9606', (243, 251))	('cancer', 'Disease', (71, 77))	('breast cancer', 'Phenotype', 'HP:0003002', (226, 239))	('cancer', 'Disease', 'MESH:D009369', (233, 239))	('miR-16', 'Gene', '51573', (79, 85))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('bone metastasis', 'CPA', (152, 167))	('breast cancer', 'Disease', 'MESH:D001943', (226, 239))	('breast cancer', 'Disease', (226, 239))	('miR', 'Gene', (192, 195))	('miR', 'Gene', '220972', (79, 82))	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('associated', 'Reg', (210, 220))	('cancer', 'Disease', (233, 239))	('miR', 'Gene', (79, 82))	('miR', 'Gene', '220972', (14, 17))	('associated', 'Reg', (105, 115))	('overexpression', 'PosReg', (86, 100))
555768	32726984	Targeting specific mutations of KRAS is now possible, as is targeting the proteins downstream of KRAS, such as Rho.	('KRAS', 'Gene', (97, 101))	('KRAS', 'Gene', (32, 36))	('KRAS', 'Gene', '3845', (97, 101))	('mutations', 'Var', (19, 28))	('KRAS', 'Gene', '3845', (32, 36))	('Rho', 'Disease', (111, 114))
555814	32726984	We then assembled an interaction network between deregulated miRNAs and their target genes, including transcription factors and tyrosine kinases participating in these interactions.	('miR', 'Gene', (61, 64))	('interaction', 'Interaction', (21, 32))	('deregulated', 'Var', (49, 60))	('miR', 'Gene', '220972', (61, 64))
555826	32399122	Spectrum of ALDH1 mRNA in smokers and non-smokers with adenocarcinoma or squamous cell lung carcinoma Lung cancer is the leading cause of cancer-related death worldwide.	('cancer', 'Disease', (138, 144))	('ALDH1', 'Gene', (12, 17))	('squamous cell lung carcinoma', 'Disease', 'MESH:D002294', (73, 101))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('adenocarcinoma', 'Disease', (55, 69))	('Lung cancer', 'Disease', 'MESH:D008175', (102, 113))	('death', 'Disease', 'MESH:D003643', (153, 158))	('cancer', 'Disease', 'MESH:D009369', (138, 144))	('adenocarcinoma', 'Disease', 'MESH:D000230', (55, 69))	('Lung cancer', 'Phenotype', 'HP:0100526', (102, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('Lung cancer', 'Disease', (102, 113))	('squamous cell lung carcinoma', 'Phenotype', 'HP:0030359', (73, 101))	('ALDH1', 'Gene', '216', (12, 17))	('cancer', 'Disease', (107, 113))	('mRNA', 'Var', (18, 22))	('cause', 'Reg', (129, 134))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (60, 69))	('squamous cell lung carcinoma', 'Disease', (73, 101))	('death', 'Disease', (153, 158))
555845	32399122	Kaplan-Meier analysis revealed that high ALDH1A1 mRNA was correlated with a benign survival rate of non-smokers with LUAD (p = 0.047, Figure 1).	('ALDH1A1', 'Gene', (41, 48))	('LUAD', 'Phenotype', 'HP:0030078', (117, 121))	('ALDH1A1', 'Gene', '216', (41, 48))	('benign survival rate', 'CPA', (76, 96))	('mRNA', 'MPA', (49, 53))	('high', 'Var', (36, 40))
555851	32399122	found that ALDH1A1 mRNA in NSCLC is associated with better prognosis.	('ALDH1A1', 'Gene', (11, 18))	('NSCLC', 'Disease', (27, 32))	('mRNA', 'Var', (19, 23))	('NSCLC', 'Disease', 'MESH:D002289', (27, 32))	('ALDH1A1', 'Gene', '216', (11, 18))	('NSCLC', 'Phenotype', 'HP:0030358', (27, 32))
555852	32399122	In this study, we found that high ALDH1A1 mRNA was correlated with a benign survival rate of non-smokers with LUAD using the KM plotter.	('high', 'Var', (29, 33))	('ALDH1A1', 'Gene', (34, 41))	('LUAD', 'Phenotype', 'HP:0030078', (110, 114))	('ALDH1A1', 'Gene', '216', (34, 41))	('mRNA', 'MPA', (42, 46))
555853	32399122	In most cancers, high expression of the ALDH1A1 protein was associated with a poor prognosis, such as breast cancer, colorectal carcinoma, and gastric cancer.	('breast cancer', 'Phenotype', 'HP:0003002', (102, 115))	('ALDH1A1', 'Gene', (40, 47))	('gastric cancer', 'Disease', (143, 157))	('breast cancer', 'Disease', 'MESH:D001943', (102, 115))	('cancers', 'Phenotype', 'HP:0002664', (8, 15))	('breast cancer', 'Disease', (102, 115))	('colorectal carcinoma', 'Disease', (117, 137))	('cancers', 'Disease', (8, 15))	('protein', 'Protein', (48, 55))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (117, 137))	('carcinoma', 'Phenotype', 'HP:0030731', (128, 137))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('gastric cancer', 'Disease', 'MESH:D013274', (143, 157))	('ALDH1A1', 'Gene', '216', (40, 47))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('expression', 'MPA', (22, 32))	('associated', 'Reg', (60, 70))	('cancers', 'Disease', 'MESH:D009369', (8, 15))	('gastric cancer', 'Phenotype', 'HP:0012126', (143, 157))	('high', 'Var', (17, 21))
555867	31979114	Plasma treatment generates reactive oxygen and nitrogen species, including O, O3, OH, H2O2, HO2, NO, ONOOH amongst many others.	('reactive oxygen and nitrogen species', 'Chemical', '-', (27, 63))	('ONOOH', 'Chemical', '-', (101, 106))	('H2O2', 'Chemical', 'MESH:D006861', (86, 90))	('H2O2', 'Var', (86, 90))	('HO2', 'Gene', (92, 95))	('HO2', 'Gene', '3163', (92, 95))	('O3', 'Chemical', 'MESH:D010126', (78, 80))
555907	31979114	By means of computer simulations, the permeation of ROS and RNS across native and oxidized phospholipid bilayers has been investigated and these analyses revealed that the assessed RNS (i.e., NO, NO2, N2O4) and O3 can permeate more easily through both native and oxidized phospholipid bilayers compared to hydrophilic ROS (i.e., OH, HO2, H2O2), indicating their potential importance in plasma medicine.	('ROS', 'Chemical', 'MESH:D017382', (318, 321))	('H2O2', 'Chemical', 'MESH:D006861', (338, 342))	('RNS', 'Chemical', 'MESH:D011886', (181, 184))	('N2O4', 'Chemical', '-', (201, 205))	('HO2', 'Gene', (333, 336))	('ROS', 'Chemical', 'MESH:D017382', (52, 55))	('phospholipid', 'Chemical', 'MESH:D010743', (272, 284))	('O3', 'Chemical', 'MESH:D010126', (211, 213))	('N2O4', 'Var', (201, 205))	('permeate', 'MPA', (218, 226))	('NO2', 'Chemical', 'MESH:D009585', (196, 199))	('RNS', 'Chemical', 'MESH:D011886', (60, 63))	('HO2', 'Gene', '3163', (333, 336))	('phospholipid', 'Chemical', 'MESH:D010743', (91, 103))
555908	31979114	Nitric oxide (NO) regulates posttranslational modifications, S-nitrosation, as well as genome-wide epigenetic modifications that can have both tumor-promoting and tumor-suppressing effects.	('epigenetic modifications', 'Var', (99, 123))	('tumor', 'Disease', (143, 148))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('S-nitrosation', 'MPA', (61, 74))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('Nitric oxide', 'Chemical', 'MESH:D009569', (0, 12))	('tumor', 'Disease', (163, 168))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('posttranslational modifications', 'MPA', (28, 59))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))
555944	31979114	Such lesion include oxidative damage, DNA single strand and DNA double strand breaks (DSB), as well as DNA crosslinks and crosslinks between DNA and proteins.	('oxidative damage', 'MPA', (20, 36))	('single strand', 'Var', (42, 55))	('DSB', 'Chemical', '-', (86, 89))	('proteins', 'Protein', (149, 157))	('double strand breaks', 'CPA', (64, 84))	('crosslinks', 'Var', (122, 132))	('crosslinks', 'Var', (107, 117))
555945	31979114	Furthermore, free radicals can cause modifications of purine and pyrimidine rings, strand cleavage and chromosomal abnormalities.	('strand cleavage', 'CPA', (83, 98))	('purine', 'Chemical', 'MESH:C030985', (54, 60))	('chromosomal abnormalities', 'Disease', (103, 128))	('free radicals', 'Var', (13, 26))	('pyrimidine', 'Chemical', 'MESH:C030986', (65, 75))	('chromosomal abnormalities', 'Disease', 'MESH:D002869', (103, 128))	('cause', 'Reg', (31, 36))	('free radicals', 'Chemical', 'MESH:D005609', (13, 26))	('modifications', 'MPA', (37, 50))
555953	31979114	A multiphase cell cycle arrest associated with DSB and a subsequent apoptosis induction was also observed in glioblastoma and colorectal carcinoma cells.	('DSB', 'Chemical', '-', (47, 50))	('glioblastoma', 'Disease', (109, 121))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (126, 146))	('glioblastoma', 'Disease', 'MESH:D005909', (109, 121))	('apoptosis', 'CPA', (68, 77))	('glioblastoma', 'Phenotype', 'HP:0012174', (109, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('DSB', 'Var', (47, 50))	('colorectal carcinoma', 'Disease', (126, 146))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (13, 30))
555960	31979114	Despite these findings, DSB may not be a direct effect of CAP mediated low-ROS on DNA but rather a consequence of CAP induced apoptosis.	('CAP', 'Chemical', '-', (114, 117))	('DSB', 'Chemical', '-', (24, 27))	('DSB', 'Disease', (24, 27))	('CAP', 'Chemical', '-', (58, 61))	('ROS', 'Chemical', 'MESH:D017382', (75, 78))	('low-ROS', 'Var', (71, 78))
555974	31979114	Modulating ROS levels or targeting antioxidants for cancer treatment is not a new concept.	('Modulating', 'Var', (0, 10))	('ROS levels', 'MPA', (11, 21))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('ROS', 'Chemical', 'MESH:D017382', (11, 14))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))
556072	30911684	Since the sequencing of the first genomic DNA from a leukemia patient, various studies have identified somatic and germline variants in key cancer genes.	('leukemia', 'Disease', (53, 61))	('patient', 'Species', '9606', (62, 69))	('variants', 'Var', (124, 132))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('leukemia', 'Phenotype', 'HP:0001909', (53, 61))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('leukemia', 'Disease', 'MESH:D007938', (53, 61))
556073	30911684	Although large-scale sequencing projects such as The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC) continue to catalog variants across cancer types, only a minority of patients harbor tumors with genomic aberrations associated with sensitivity to targeted therapy.	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('Cancer Genome Atlas', 'Disease', (53, 72))	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('Cancer', 'Disease', 'MESH:D009369', (53, 59))	('Cancer', 'Phenotype', 'HP:0002664', (53, 59))	('variants', 'Var', (154, 162))	('cancer', 'Disease', (170, 176))	('tumors', 'Disease', (219, 225))	('Cancer', 'Disease', (102, 108))	('tumors', 'Disease', 'MESH:D009369', (219, 225))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (53, 72))	('tumors', 'Phenotype', 'HP:0002664', (219, 225))	('Cancer', 'Disease', 'MESH:D009369', (102, 108))	('Cancer', 'Phenotype', 'HP:0002664', (102, 108))	('patients', 'Species', '9606', (203, 211))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('Cancer', 'Disease', (53, 59))
556075	30911684	PD-L1 and PD-L2 on tumor cells or antigen-presenting cells suppress T-cell immune response by binding to PD-1 on T-cells.	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('binding', 'Interaction', (94, 101))	('PD-L2', 'Var', (10, 15))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('PD-L1', 'Var', (0, 5))	('T-cell immune response', 'CPA', (68, 90))	('tumor', 'Disease', (19, 24))	('suppress', 'NegReg', (59, 67))	('PD-1', 'Gene', (105, 109))
556076	30911684	To escape attack by immune cells, tumor cells overexpress PD-L1 by gene amplification, utilization of an ectopic promoter, and disruption of 3' untranslated regions (3' UTRs), in addition to PTEN loss-of function and EGFR mutations.	('EGFR', 'Gene', '1956', (217, 221))	('EGFR', 'Gene', (217, 221))	('tumor', 'Disease', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))	('PTEN', 'Gene', (191, 195))	('PTEN', 'Gene', '5728', (191, 195))	('disruption', 'Var', (127, 137))	('mutations', 'Var', (222, 231))	('PD-L1', 'Gene', (58, 63))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('loss-of function', 'NegReg', (196, 212))	('overexpress', 'PosReg', (46, 57))
556077	30911684	Other studies indicate that EGFR mutations are not associated with an increased PD-L1 expression and a better clinical response of PD-L1 immune checkpoint inhibitors.	('PD-L1', 'Gene', (80, 85))	('EGFR', 'Gene', '1956', (28, 32))	('EGFR', 'Gene', (28, 32))	('mutations', 'Var', (33, 42))	('expression', 'MPA', (86, 96))	('increased PD', 'Phenotype', 'HP:0008151', (70, 82))
556079	30911684	Anti-PD-1 and anti-PD-L1 immune checkpoint blockades show favorable clinical outcome for treating patients with high PD-1 and PD-L1 expression.	('PD-1', 'Gene', (117, 121))	('PD-L1', 'Gene', (126, 131))	('high', 'Var', (112, 116))	('patients', 'Species', '9606', (98, 106))
556086	30911684	Here, using TCGA RNA-Seq data for six virus-associated tumors, we systematically study the associations between virus-positivity and the tumor microenvironment, as measured by expression of PD-L1, PD-L2, PD-1, CD80, CD86, CTLA-4, Tim-3, LAG3, and 4-1BB and the prevalence of infiltrating immune cells across multiple types of human cancers.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('CD86', 'Gene', '942', (216, 220))	('CD86', 'Gene', (216, 220))	('CD80', 'Gene', (210, 214))	('4-1BB', 'Gene', (247, 252))	('PD-L2', 'Gene', (197, 202))	('cancers', 'Disease', 'MESH:D009369', (332, 339))	('tumors', 'Phenotype', 'HP:0002664', (55, 61))	('LAG3', 'Gene', (237, 241))	('4-1BB', 'Gene', '3604', (247, 252))	('human', 'Species', '9606', (326, 331))	('Tim-3', 'Gene', '84868', (230, 235))	('PD-L1', 'Var', (190, 195))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumors', 'Disease', (55, 61))	('CTLA-4', 'Gene', '1493', (222, 228))	('tumor', 'Disease', (137, 142))	('cancers', 'Phenotype', 'HP:0002664', (332, 339))	('CTLA-4', 'Gene', (222, 228))	('cancers', 'Disease', (332, 339))	('tumors', 'Disease', 'MESH:D009369', (55, 61))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('cancer', 'Phenotype', 'HP:0002664', (332, 338))	('tumor', 'Disease', (55, 60))	('associations', 'Interaction', (91, 103))	('CD80', 'Gene', '941', (210, 214))	('LAG3', 'Gene', '3902', (237, 241))	('Tim-3', 'Gene', (230, 235))	('PD-1', 'Gene', (204, 208))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))
556089	30911684	In addition, we found HPV integrations at PD-L1 and PD-L2 are associated with high expression of these genes.	('associated', 'Reg', (62, 72))	('integrations', 'Var', (26, 38))	('HPV', 'Species', '10566', (22, 25))	('high expression', 'MPA', (78, 93))	('PD-L1', 'Gene', (42, 47))	('PD-L2', 'Gene', (52, 57))
556098	30911684	Of these, we identified three tumors with HPV integrations at PD-L1 or PD-L2 by using discordant read pair analysis (Methods, Fig.	('integrations', 'Var', (46, 58))	('tumors', 'Disease', (30, 36))	('tumors', 'Phenotype', 'HP:0002664', (30, 36))	('HPV', 'Species', '10566', (42, 45))	('tumors', 'Disease', 'MESH:D009369', (30, 36))	('tumor', 'Phenotype', 'HP:0002664', (30, 35))
556103	30911684	Although different integration patterns and anatomic sites were observed in the three tumors, HPV integrations at PD-L1 or PD-L2 were all accompanied by higher expression levels of these genes compared with those in virus-negative tumors (Fig.	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumors', 'Disease', 'MESH:D009369', (231, 237))	('PD-L1', 'Gene', (114, 119))	('higher', 'PosReg', (153, 159))	('tumors', 'Phenotype', 'HP:0002664', (231, 237))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('HPV', 'Species', '10566', (94, 97))	('integrations', 'Var', (98, 110))	('tumors', 'Disease', (86, 92))	('tumors', 'Disease', 'MESH:D009369', (86, 92))	('tumors', 'Phenotype', 'HP:0002664', (86, 92))	('expression levels', 'MPA', (160, 177))	('PD-L2', 'Gene', (123, 128))	('tumors', 'Disease', (231, 237))
556107	30911684	This result indicates that high PD-L1 or PD-L2 expression induced by HPV integration is a phenomenon that is selectively associated with HPV in HNSC tumors, with PD-L1 or PD-L2 integrations occurring in 4.2% of HNSC HPV-positive tumors.	('HNSC', 'Phenotype', 'HP:0012288', (211, 215))	('integration', 'Var', (73, 84))	('HPV', 'Species', '10566', (69, 72))	('tumor', 'Phenotype', 'HP:0002664', (229, 234))	('tumors', 'Phenotype', 'HP:0002664', (149, 155))	('HNSC HPV-positive tumors', 'Disease', 'MESH:D030361', (211, 235))	('tumors', 'Phenotype', 'HP:0002664', (229, 235))	('PD-L1', 'Gene', (32, 37))	('HPV', 'Gene', (69, 72))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('expression', 'MPA', (47, 57))	('HNSC HPV-positive tumors', 'Disease', (211, 235))	('HPV', 'Species', '10566', (137, 140))	('HPV', 'Species', '10566', (216, 219))	('HNSC', 'Phenotype', 'HP:0012288', (144, 148))	('PD-L2', 'Gene', (41, 46))	('associated', 'Reg', (121, 131))	('HNSC tumors', 'Disease', 'MESH:D009369', (144, 155))	('HNSC tumors', 'Disease', (144, 155))
556115	30911684	In HNSC, we found that three tumors with HPV integrations had high expression of PD-L1 or PD-L2, i.e., TCGA-CV-5443 and TCGA-T2-A6X0 with 11.8 and 9.2 for PD-L1 and TCGA-HL-7533 with 10 for PD-L2 (RSEM in log2 scale).	('HPV', 'Species', '10566', (41, 44))	('PD-L1', 'Gene', (81, 86))	('TCGA-HL-7533', 'CellLine', 'CVCL:2492', (165, 177))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumors', 'Phenotype', 'HP:0002664', (29, 35))	('integrations', 'Var', (45, 57))	('TCGA-CV-5443', 'Var', (103, 115))	('tumors', 'Disease', 'MESH:D009369', (29, 35))	('expression', 'MPA', (67, 77))	('tumors', 'Disease', (29, 35))	('HNSC', 'Phenotype', 'HP:0012288', (3, 7))	('PD-L2', 'Gene', (90, 95))
556118	30911684	However, we found a higher level of PD-L1, PD-L2, CD80, CD86, Tim-3, LAG3, and 4-1BB in EBV-positive STAD and cytomegalovirus-positive colon and rectum adenocarcinoma than in virus-negative tumor samples (Fig.	('PD-L2', 'Var', (43, 48))	('PD-L1', 'MPA', (36, 41))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('Tim-3', 'Gene', (62, 67))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('4-1BB', 'Gene', (79, 84))	('EBV', 'Species', '10376', (88, 91))	('colon and rectum adenocarcinoma', 'Disease', 'MESH:D012004', (135, 166))	('Tim-3', 'Gene', '84868', (62, 67))	('tumor', 'Disease', (190, 195))	('carcinoma', 'Phenotype', 'HP:0030731', (157, 166))	('LAG3', 'Gene', (69, 73))	('CD80', 'Gene', (50, 54))	('LAG3', 'Gene', '3902', (69, 73))	('CD86', 'Gene', '942', (56, 60))	('CD86', 'Gene', (56, 60))	('4-1BB', 'Gene', '3604', (79, 84))	('CD80', 'Gene', '941', (50, 54))
556132	30911684	3, we separated samples into four different groups based on supervised clustering results, i.e., Virus-/T-celllow, HPV+/T-celllow, Virus-/T-cellhigh, and HPV+/T-cellhigh.	('HPV+/T-celllow', 'Disease', (115, 129))	('HPV', 'Species', '10566', (115, 118))	('HPV+/T-cellhigh', 'Var', (154, 169))	('Virus-/T-celllow', 'Disease', (97, 113))	('HPV', 'Species', '10566', (154, 157))	('Virus-/T-cellhigh', 'Disease', (131, 148))
556147	30911684	For instance, an ICOS signature was identified in EBV-positive STAD (Supplementary Table 2) as well as HPV-positive HNSC; The expression of ICOS increases about two-fold in EBV-positive STAD and HPV-positive HNSC compared to virus-negative samples.	('HPV', 'Species', '10566', (195, 198))	('EBV-positive', 'Var', (173, 185))	('expression', 'MPA', (126, 136))	('HNSC', 'Phenotype', 'HP:0012288', (208, 212))	('HPV', 'Species', '10566', (103, 106))	('EBV', 'Species', '10376', (173, 176))	('ICOS', 'Gene', (17, 21))	('ICOS', 'Gene', (140, 144))	('EBV', 'Species', '10376', (50, 53))	('HNSC', 'Phenotype', 'HP:0012288', (116, 120))	('increases', 'PosReg', (145, 154))	('ICOS', 'Gene', '29851', (17, 21))	('ICOS', 'Gene', '29851', (140, 144))
556170	30911684	We found that immune response is associated with a positive prognosis in patients with HPV-positive HNSC, but not in those with virus-negative HNSC (Fig.	('HNSC', 'Disease', (100, 104))	('HPV-positive', 'Var', (87, 99))	('HPV', 'Species', '10566', (87, 90))	('HNSC', 'Phenotype', 'HP:0012288', (143, 147))	('HNSC', 'Phenotype', 'HP:0012288', (100, 104))	('immune response', 'CPA', (14, 29))	('patients', 'Species', '9606', (73, 81))
556174	30911684	The HPV-positive cohort contained no variants in either TP53 or CDKN2A and only one in FAT1; in the HPV-negative cohort, these genes were frequently mutated.	('HPV', 'Species', '10566', (4, 7))	('HPV', 'Species', '10566', (100, 103))	('TP53', 'Gene', '7157', (56, 60))	('CDKN2A', 'Gene', (64, 70))	('CDKN2A', 'Gene', '1029', (64, 70))	('TP53', 'Gene', (56, 60))	('variants', 'Var', (37, 45))	('FAT1', 'Gene', '2195', (87, 91))	('FAT1', 'Gene', (87, 91))
556183	30911684	We also found samples with HPV integrations in other immune-related genes (NR4A2, TBC1D1, BTNL9, DTX1, FOXP1, INPP4B, PDE4D, and STAT4) have an increased expression of these genes.	('PDE4D', 'Gene', (118, 123))	('HPV', 'Species', '10566', (27, 30))	('BTNL9', 'Gene', (90, 95))	('FOXP1', 'Gene', '27086', (103, 108))	('DTX1', 'Gene', (97, 101))	('NR4A2', 'Gene', '4929', (75, 80))	('STAT4', 'Gene', (129, 134))	('integrations', 'Var', (31, 43))	('PDE4D', 'Gene', '5144', (118, 123))	('INPP4B', 'Gene', (110, 116))	('BTNL9', 'Gene', '153579', (90, 95))	('TBC1D1', 'Gene', (82, 88))	('NR4A2', 'Gene', (75, 80))	('FOXP1', 'Gene', (103, 108))	('increased', 'PosReg', (144, 153))	('expression', 'MPA', (154, 164))
556184	30911684	Previous studies show that high expression of NR4A2, BTNL9, FOXP1, or PDE4D can antagonize immune response or is associated with tumor progression.	('FOXP1', 'Gene', '27086', (60, 65))	('immune response', 'CPA', (91, 106))	('associated with', 'Reg', (113, 128))	('antagonize', 'NegReg', (80, 90))	('BTNL9', 'Gene', (53, 58))	('FOXP1', 'Gene', (60, 65))	('PDE4D', 'Gene', '5144', (70, 75))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('NR4A2', 'Gene', (46, 51))	('PDE4D', 'Gene', (70, 75))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('high expression', 'Var', (27, 42))	('tumor', 'Disease', (129, 134))	('BTNL9', 'Gene', '153579', (53, 58))	('NR4A2', 'Gene', '4929', (46, 51))
556199	30911684	One explanation is that HBV promotes cancer in a different way than EBV/HPV, which are directly oncogenic, HBV promotes cancer by making the liver cirrhotic/inflamed chronically.	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('liver cirrhotic', 'Disease', 'MESH:D008103', (141, 156))	('cancer', 'Disease', (37, 43))	('cancer', 'Disease', (120, 126))	('cancer', 'Disease', 'MESH:D009369', (120, 126))	('liver cirrhotic', 'Disease', (141, 156))	('HBV', 'Var', (107, 110))	('EBV', 'Species', '10376', (68, 71))	('HPV', 'Species', '10566', (72, 75))	('HBV', 'Species', '10407', (24, 27))	('promotes', 'PosReg', (111, 119))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('HBV', 'Species', '10407', (107, 110))
556213	30911684	In addition, though the current work does not identify clear mechanisms by which virus infection affects PD-L1 and PD-L2 expression, it nonetheless suggests that viruses may aid tumors in evading the PD-1 immune checkpoint pathway across multiple cancer types.	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('PD-1 immune checkpoint pathway', 'Pathway', (200, 230))	('tumors', 'Disease', (178, 184))	('tumors', 'Disease', 'MESH:D009369', (178, 184))	('tumors', 'Phenotype', 'HP:0002664', (178, 184))	('virus infection', 'Disease', (81, 96))	('aid', 'PosReg', (174, 177))	('cancer', 'Disease', (247, 253))	('viruses', 'Var', (162, 169))	('evading', 'CPA', (188, 195))	('cancer', 'Disease', 'MESH:D009369', (247, 253))	('virus infection', 'Disease', 'MESH:D015658', (81, 96))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))
556231	30813343	Aberrant KIF2A expression promoted the malignant transformation of this disease.	('Aberrant', 'Var', (0, 8))	('KIF2A', 'Gene', '3796', (9, 14))	('promoted', 'PosReg', (26, 34))	('expression', 'MPA', (15, 25))	('malignant transformation', 'CPA', (39, 63))	('KIF2A', 'Gene', (9, 14))
556238	30813343	Many mutations accumulate in LUSQ cells owing to the influence of heavy smoking over many years.	('LUSQ', 'Phenotype', 'HP:0030359', (29, 33))	('accumulate', 'Reg', (15, 25))	('mutations', 'Var', (5, 14))	('LUSQ', 'Chemical', '-', (29, 33))
556247	30813343	Thus, aberrantly expressed miRNAs can disrupt normal cell function, thereby supporting cancer pathogenesis.	('cancer', 'Disease', (87, 93))	('disrupt', 'NegReg', (38, 45))	('miR', 'Gene', '220972', (27, 30))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('miR', 'Gene', (27, 30))	('aberrantly expressed', 'Var', (6, 26))	('normal cell function', 'CPA', (46, 66))	('cancer', 'Disease', 'MESH:D009369', (87, 93))
556248	30813343	Many studies have shown that aberrantly expressed miRNAs are involved in the pathogenesis of many diseases, including cancer.	('miR', 'Gene', '220972', (50, 53))	('cancer', 'Disease', (118, 124))	('miR', 'Gene', (50, 53))	('aberrantly expressed', 'Var', (29, 49))	('involved', 'Reg', (61, 69))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('cancer', 'Disease', 'MESH:D009369', (118, 124))
556271	30813343	Moreover, restoration of miR-451a expression promoted cleaved poly (ADP-ribose) polymerase (PARP) expression (Figure 3).	('PARP', 'Gene', (92, 96))	('miR-451a', 'Gene', '574411', (25, 33))	('miR-451a', 'Gene', (25, 33))	('restoration', 'Var', (10, 21))	('PARP', 'Gene', '142', (92, 96))	('promoted', 'PosReg', (45, 53))	('poly (ADP-ribose) polymerase', 'Gene', '142', (62, 90))	('poly (ADP-ribose) polymerase', 'Gene', (62, 90))
556281	30813343	Among these candidate genes, high expression of KIF2A was significantly associated with LUSQ pathogenesis (5-year OS: p = 0.043 and 5-year DFS: p = 0.028; Figure 5).	('high', 'Var', (29, 33))	('LUSQ', 'Chemical', '-', (88, 92))	('LUSQ', 'Phenotype', 'HP:0030359', (88, 92))	('LUSQ pathogenesis', 'Disease', (88, 105))	('associated', 'Reg', (72, 82))	('KIF2A', 'Gene', (48, 53))	('KIF2A', 'Gene', '3796', (48, 53))
556282	30813343	Furthermore, among patients with adjusting clinical stage and age distribution, patients with high expression of KIF2A also showed significantly poor prognosis compared with patients with low expression of KIF2A (5-year OS: p = 0.029; Figure S5A).	('poor', 'NegReg', (145, 149))	('patients', 'Species', '9606', (80, 88))	('patients', 'Species', '9606', (19, 27))	('KIF2A', 'Gene', (113, 118))	('patients', 'Species', '9606', (174, 182))	('clinical', 'Species', '191496', (43, 51))	('KIF2A', 'Gene', '3796', (113, 118))	('KIF2A', 'Gene', (206, 211))	('high expression', 'Var', (94, 109))	('KIF2A', 'Gene', '3796', (206, 211))
556283	30813343	Moreover, among LUSQ patients with early clinical stage (stage I and II), high expression of KIF2A was significantly associated not only with prognosis but also with cancer recurrence (Figure S5B).	('LUSQ', 'Phenotype', 'HP:0030359', (16, 20))	('cancer', 'Disease', (166, 172))	('cancer', 'Disease', 'MESH:D009369', (166, 172))	('associated', 'Reg', (117, 127))	('high', 'Var', (74, 78))	('LUSQ', 'Chemical', '-', (16, 20))	('patients', 'Species', '9606', (21, 29))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('KIF2A', 'Gene', (93, 98))	('KIF2A', 'Gene', '3796', (93, 98))	('clinical', 'Species', '191496', (41, 49))
556285	30813343	In addition, TCGA database analyses showed that high expression of KIF2A was associated with poor prognosis in patients with renal papillary cell carcinoma and hepatocellular carcinoma (Figure S3).	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('KIF2A', 'Gene', (67, 72))	('KIF2A', 'Gene', '3796', (67, 72))	('renal papillary cell carcinoma and hepatocellular carcinoma', 'Disease', 'MESH:C538614', (125, 184))	('renal papillary cell carcinoma', 'Phenotype', 'HP:0006766', (125, 155))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (160, 184))	('high expression', 'Var', (48, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (175, 184))	('patients', 'Species', '9606', (111, 119))
556287	30813343	Levels of KIF2A mRNA and protein were significantly suppressed by miR-451a transfection into EBC-1 and SK-MES-1 cells compared with those in mock- or control-transfected cells (Figure 6A,B).	('Levels', 'MPA', (0, 6))	('SK-MES-1', 'CellLine', 'CVCL:0630', (103, 111))	('transfection', 'Var', (75, 87))	('miR-451a', 'Gene', '574411', (66, 74))	('miR-451a', 'Gene', (66, 74))	('suppressed', 'NegReg', (52, 62))	('KIF2A', 'Gene', (10, 15))	('KIF2A', 'Gene', '3796', (10, 15))
556301	30813343	Cancer cell proliferation was significantly suppressed by si-KIF2A transfection in comparison with those in mock- or control-transfected LUSQ cells (Figure 10A,D).	('suppressed', 'NegReg', (44, 54))	('transfection', 'Var', (67, 79))	('LUSQ', 'Chemical', '-', (137, 141))	('LUSQ', 'Phenotype', 'HP:0030359', (137, 141))	('KIF2A', 'Gene', (61, 66))	('KIF2A', 'Gene', '3796', (61, 66))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))
556302	30813343	Moreover, the apoptotic cell numbers were increased in si-KIF2A transfected cells compared with those in mock- or control-transfected cells (Figure 10B,C,E,F).	('increased', 'PosReg', (42, 51))	('KIF2A', 'Gene', (58, 63))	('KIF2A', 'Gene', '3796', (58, 63))	('apoptotic cell numbers', 'CPA', (14, 36))	('transfected', 'Var', (64, 75))
556304	30813343	Further analyses showed that cancer cell motility, including migration and invasive abilities, was markedly inhibited by knockdown of KIF2A via si-KIF2A transfection compared with those in mock- or control-transfected LUSQ cells (Figure 12A,B).	('knockdown', 'Var', (121, 130))	('cancer', 'Disease', (29, 35))	('LUSQ', 'Chemical', '-', (218, 222))	('invasive abilities', 'CPA', (75, 93))	('KIF2A', 'Gene', (134, 139))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))	('migration', 'CPA', (61, 70))	('KIF2A', 'Gene', '3796', (134, 139))	('KIF2A', 'Gene', (147, 152))	('KIF2A', 'Gene', '3796', (147, 152))	('cancer', 'Disease', 'MESH:D009369', (29, 35))	('transfection', 'Var', (153, 165))	('inhibited', 'NegReg', (108, 117))	('LUSQ', 'Phenotype', 'HP:0030359', (218, 222))
556313	30813343	Furthermore, CORO1C is coordinately regulated by miR-1 and miR-133a, and aberrant expression of CORO1C enhances the migration and invasive abilities of LUSQ cells.	('miR-1', 'Gene', (49, 54))	('miR-1', 'Gene', '79187', (59, 64))	('invasive abilities of LUSQ cells', 'CPA', (130, 162))	('CORO1C', 'Gene', (13, 19))	('LUSQ', 'Chemical', '-', (152, 156))	('CORO1C', 'Gene', '23603', (13, 19))	('aberrant expression', 'Var', (73, 92))	('miR-1', 'Gene', '79187', (49, 54))	('LUSQ', 'Phenotype', 'HP:0030359', (152, 156))	('CORO1C', 'Gene', (96, 102))	('miR-1', 'Gene', (59, 64))	('enhances', 'PosReg', (103, 111))	('CORO1C', 'Gene', '23603', (96, 102))
556320	30813343	Downregulation of miR-451a has been reported in other types of cancers and its ectopic expression inhibits cancer cell aggressiveness, including that in gastric cancer, glioblastoma, nasopharyngeal cancer, renal cell carcinoma, and prostate cancer.	('gastric cancer', 'Disease', 'MESH:D013274', (153, 167))	('Downregulation', 'NegReg', (0, 14))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('cancer cell aggressiveness', 'Disease', (107, 133))	('prostate cancer', 'Disease', 'MESH:D011471', (232, 247))	('prostate cancer', 'Phenotype', 'HP:0012125', (232, 247))	('nasopharyngeal cancer', 'Phenotype', 'HP:0100630', (183, 204))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (206, 226))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('prostate cancer', 'Disease', (232, 247))	('miR-451a', 'Gene', (18, 26))	('gastric cancer', 'Phenotype', 'HP:0012126', (153, 167))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('cancers', 'Phenotype', 'HP:0002664', (63, 70))	('cancers', 'Disease', (63, 70))	('glioblastoma', 'Disease', 'MESH:D005909', (169, 181))	('nasopharyngeal cancer', 'Disease', (183, 204))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('aggressiveness', 'Phenotype', 'HP:0000718', (119, 133))	('ectopic expression', 'Var', (79, 97))	('cancer cell aggressiveness', 'Disease', 'MESH:C538614', (107, 133))	('inhibits', 'NegReg', (98, 106))	('renal cell carcinoma', 'Disease', (206, 226))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (206, 226))	('glioblastoma', 'Disease', (169, 181))	('gastric cancer', 'Disease', (153, 167))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('nasopharyngeal cancer', 'Disease', 'MESH:D009303', (183, 204))	('glioblastoma', 'Phenotype', 'HP:0012174', (169, 181))	('miR-451a', 'Gene', '574411', (18, 26))	('carcinoma', 'Phenotype', 'HP:0030731', (217, 226))	('cancers', 'Disease', 'MESH:D009369', (63, 70))
556325	30813343	Elucidation of molecular mechanisms of aberrantly expressed miRNAs in cancer cells is an important issue for cancer research.	('miR', 'Gene', '220972', (60, 63))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('miR', 'Gene', (60, 63))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('cancer', 'Disease', (109, 115))	('aberrantly expressed', 'Var', (39, 59))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))
556337	30813343	Our current data confirmed that aberrant expression of KIF2A enhanced cancer cell aggressiveness in LUSQ cells.	('KIF2A', 'Gene', '3796', (55, 60))	('enhanced', 'PosReg', (61, 69))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('cancer cell aggressiveness', 'Disease', (70, 96))	('LUSQ', 'Chemical', '-', (100, 104))	('LUSQ', 'Phenotype', 'HP:0030359', (100, 104))	('aggressiveness', 'Phenotype', 'HP:0000718', (82, 96))	('cancer cell aggressiveness', 'Disease', 'MESH:C538614', (70, 96))	('KIF2A', 'Gene', (55, 60))	('aberrant expression', 'Var', (32, 51))
556339	30813343	Recently, several reports have shown that aberrantly expressed KIF2A is detected in several cancers, including breast, oral, colorectal, and ovarian cancers, and its expression contributes to cancer cell malignancies.	('cancer cell malignancies', 'Disease', (192, 216))	('contributes', 'Reg', (177, 188))	('ovarian cancers', 'Disease', (141, 156))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('ovarian cancers', 'Disease', 'MESH:D010051', (141, 156))	('cancers', 'Disease', 'MESH:D009369', (92, 99))	('KIF2A', 'Gene', (63, 68))	('aberrantly expressed', 'Var', (42, 62))	('cancers', 'Phenotype', 'HP:0002664', (149, 156))	('colorectal', 'Disease', (125, 135))	('cancers', 'Disease', (149, 156))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('ovarian cancers', 'Phenotype', 'HP:0100615', (141, 156))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('expression', 'MPA', (166, 176))	('cancers', 'Phenotype', 'HP:0002664', (92, 99))	('breast', 'Disease', (111, 117))	('detected', 'Reg', (72, 80))	('oral', 'Disease', (119, 123))	('cancer cell malignancies', 'Disease', 'MESH:D009369', (192, 216))	('cancers', 'Disease', (92, 99))	('KIF2A', 'Gene', '3796', (63, 68))	('colorectal', 'Disease', 'MESH:D015179', (125, 135))	('cancers', 'Disease', 'MESH:D009369', (149, 156))
556342	30813343	In lung cancers (LUSQ and LUAD), aberrantly expressed KIF2A may serve as a valuable prognosis marker and candidate for therapeutic targeting.	('cancers', 'Phenotype', 'HP:0002664', (8, 15))	('LUSQ', 'Phenotype', 'HP:0030359', (17, 21))	('lung cancers', 'Disease', (3, 15))	('LUSQ', 'Chemical', '-', (17, 21))	('lung cancer', 'Phenotype', 'HP:0100526', (3, 14))	('KIF2A', 'Gene', (54, 59))	('KIF2A', 'Gene', '3796', (54, 59))	('aberrantly expressed', 'Var', (33, 53))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('lung cancers', 'Disease', 'MESH:D008175', (3, 15))	('lung cancers', 'Phenotype', 'HP:0100526', (3, 15))
556345	30813343	Among the genes involved in these pathways, a previous study showed that overexpression of MCM2 is associated with OS in patients with LUSQ and that its aberrant expression participates in the development and progression of LUSQ.	('LUSQ', 'Chemical', '-', (135, 139))	('LUSQ', 'Disease', (135, 139))	('participates', 'Reg', (173, 185))	('MCM2', 'Gene', '4171', (91, 95))	('LUSQ', 'Phenotype', 'HP:0030359', (224, 228))	('MCM2', 'Gene', (91, 95))	('LUSQ', 'Chemical', '-', (224, 228))	('LUSQ', 'Phenotype', 'HP:0030359', (135, 139))	('aberrant', 'Var', (153, 161))	('overexpression', 'PosReg', (73, 87))	('associated', 'Reg', (99, 109))	('patients', 'Species', '9606', (121, 129))
556347	30813343	Aberrant expression of these oncogenic genes contributes to the development, metastasis, and drug resistance of LUSQ.	('Aberrant expression', 'Var', (0, 19))	('LUSQ', 'Phenotype', 'HP:0030359', (112, 116))	('development', 'CPA', (64, 75))	('LUSQ', 'Chemical', '-', (112, 116))	('drug resistance', 'CPA', (93, 108))	('contributes', 'Reg', (45, 56))	('drug resistance', 'Phenotype', 'HP:0020174', (93, 108))	('metastasis', 'CPA', (77, 87))
556378	30813343	Our approach, to identify aberrantly expressed miRNAs and their downstream cancer-related genes, is a groundbreaking strategy to uncover the novel molecular mechanisms mediating the pathogenesis of LUSQ.	('LUSQ', 'Chemical', '-', (198, 202))	('aberrantly expressed', 'Var', (26, 46))	('cancer', 'Disease', 'MESH:D009369', (75, 81))	('LUSQ', 'Disease', (198, 202))	('miR', 'Gene', '220972', (47, 50))	('miR', 'Gene', (47, 50))	('cancer', 'Disease', (75, 81))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('LUSQ', 'Phenotype', 'HP:0030359', (198, 202))
556392	30029671	Collectively, our results identify beta-catenin/CBP interaction as a novel target for anti-HNSCC therapy and provide evidence that derivatives of ICG-001 with enhanced inhibitory activity may serve as an effective strategy to interfere with aggressive features of HNSCC.	('derivatives', 'Var', (131, 142))	('ICG-001', 'Chemical', 'MESH:C492448', (146, 153))	('enhanced', 'PosReg', (159, 167))	('SCC', 'Gene', (93, 96))	('interfere', 'NegReg', (226, 235))	('ICG-001', 'Gene', (146, 153))	('SCC', 'Gene', (266, 269))	('SCC', 'Gene', '6317', (266, 269))	('SCC', 'Gene', '6317', (93, 96))	('inhibitory activity', 'MPA', (168, 187))
556394	30029671	In contrast, persistent activation of beta-catenin signaling due to somatic inactivating mutations in the upstream regulatory components of the Wnt pathway, or as a result of activating mutations in the beta-catenin gene, CTNNB1, can contribute to the development of many cancers.	('CTNNB1', 'Gene', (222, 228))	('Wnt', 'Gene', '114487', (144, 147))	('activating', 'PosReg', (175, 185))	('cancer', 'Phenotype', 'HP:0002664', (272, 278))	('mutations', 'Var', (186, 195))	('inactivating mutations', 'Var', (76, 98))	('cancers', 'Phenotype', 'HP:0002664', (272, 279))	('beta-catenin signaling', 'MPA', (38, 60))	('contribute', 'Reg', (234, 244))	('CTNNB1', 'Gene', '1499', (222, 228))	('Wnt', 'Gene', (144, 147))	('activation', 'PosReg', (24, 34))	('cancers', 'Disease', (272, 279))	('cancers', 'Disease', 'MESH:D009369', (272, 279))
556395	30029671	In head and neck cancer, which presents primarily as head and neck squamous cell carcinoma (HNSCC), mutations in CTNNB1 are relatively infrequent.	('mutations', 'Var', (100, 109))	('CTNNB1', 'Gene', (113, 119))	('neck squamous cell carcinoma', 'Disease', (62, 90))	('neck cancer', 'Disease', 'MESH:D006258', (12, 23))	('SCC', 'Gene', (94, 97))	('neck cancer', 'Disease', (12, 23))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (62, 90))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (67, 90))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (53, 90))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('SCC', 'Gene', '6317', (94, 97))	('CTNNB1', 'Gene', '1499', (113, 119))	('head and neck cancer', 'Phenotype', 'HP:0012288', (3, 23))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
556396	30029671	Instead, beta-catenin activity is induced by the more common mutations in negative regulators of Wnt/beta-catenin signaling, specifically in NOTCH1, FAT1, and AJUBA, where the inappropriate stabilization of beta-catenin has been correlated with de-differentiation and poor prognosis.	('FAT1', 'Gene', '2195', (149, 153))	('de-differentiation', 'CPA', (245, 263))	('Wnt', 'Gene', '114487', (97, 100))	('AJUBA', 'Gene', (159, 164))	('beta-catenin activity', 'MPA', (9, 30))	('FAT1', 'Gene', (149, 153))	('mutations', 'Var', (61, 70))	('NOTCH1', 'Gene', '4851', (141, 147))	('AJUBA', 'Gene', '84962', (159, 164))	('induced', 'Reg', (34, 41))	('NOTCH1', 'Gene', (141, 147))	('Wnt', 'Gene', (97, 100))	('stabilization', 'MPA', (190, 203))
556401	30029671	Recently, CSCs with increased beta-catenin transcriptional activity were identified in HNSCC, suggesting that targeting beta-catenin has the potential to inhibit and eliminate treatment-resistant CSCs, thereby intercepting this malignancy.	('increased', 'PosReg', (20, 29))	('eliminate', 'NegReg', (166, 175))	('SCC', 'Gene', '6317', (89, 92))	('inhibit', 'NegReg', (154, 161))	('malignancy', 'Disease', 'MESH:D009369', (228, 238))	('treatment-resistant CSCs', 'Disease', (176, 200))	('beta-catenin', 'Protein', (120, 132))	('targeting', 'Var', (110, 119))	('malignancy', 'Disease', (228, 238))	('SCC', 'Gene', (89, 92))
556460	30029671	For characterization of cells from immunocompetent SCC mouse model by multicolor flow cytometry staining, cells were first incubated with Zombie Aqua Live-dead dye (Biolegend) in PBS for 20 min, washed, pre-blocked with mouse antiCD16/32 FcBlock (Biolegend), and stained with the cocktail of conjugated fluorescent anti-mouse antibodies: CD29 eFluor 450, CD166 PE and CD133 PerCP-e710 (eBioscience), CD44 BV786, EpCAM FITC, E-Cadherin PE-Cy7, CD24 Alexa Fluor 647, and CD45 APC-750 (BioLegend) for 30 min.	('CD44 BV786', 'Var', (400, 410))	('E-Cadherin', 'Gene', '12550', (424, 434))	('SCC', 'Gene', (51, 54))	('mouse', 'Species', '10090', (220, 225))	('CD24', 'Var', (443, 447))	('CD45', 'Gene', (469, 473))	('CD45', 'Gene', '19264', (469, 473))	('mouse', 'Species', '10090', (55, 60))	('mouse', 'Species', '10090', (320, 325))	('APC', 'Disease', 'MESH:D011125', (474, 477))	('SCC', 'Gene', '6317', (51, 54))	('CD29', 'Var', (338, 342))	('CD166', 'Var', (355, 360))	('APC', 'Disease', (474, 477))	('E-Cadherin', 'Gene', (424, 434))
556505	30029671	Immunoblot analyses of protein products of genes impacted by ICG-001 in CAL27 and HSC-3 revealed reduction in the steady-state levels of survivin, the BIRC5 gene protein product, and products of genes associated with stem cell-like-phenotypes, HELLS and KRT14 (Additional file 1: Figures S4 and S5).	('reduction', 'NegReg', (97, 106))	('CAL27', 'CellLine', 'CVCL:1107', (72, 77))	('HSC-3', 'Gene', (82, 87))	('HELLS', 'Gene', (244, 249))	('HELLS', 'Gene', '3070', (244, 249))	('ICG-001', 'Chemical', 'MESH:C492448', (61, 68))	('KRT14', 'Gene', '3861', (254, 259))	('survivin', 'MPA', (137, 145))	('BIRC5', 'Gene', '332', (151, 156))	('ICG-001', 'Var', (61, 68))	('HSC-3', 'Gene', '150353', (82, 87))	('BIRC5', 'Gene', (151, 156))	('KRT14', 'Gene', (254, 259))
556517	30029671	In addition, levels of survivin were reduced in response to ICG-001 in FaDu cells.	('ICG-001', 'Chemical', 'MESH:C492448', (60, 67))	('levels of', 'MPA', (13, 22))	('ICG-001', 'Var', (60, 67))	('survivin', 'Protein', (23, 31))	('reduced', 'NegReg', (37, 44))
556519	30029671	To assess whether transcriptional effects of ICG-001 treatment correlated with that induced by beta-catenin knockdown in OSCC in vitro, we first generated a gene list ranked by differential expression of beta-catenin siRNA knockdown (KD) versus control in HSC-3 cells (Additional file 3).	('SCC', 'Gene', (122, 125))	('OS', 'Chemical', '-', (121, 123))	('HSC-3', 'Gene', (256, 261))	('ICG-001', 'Gene', (45, 52))	('SCC', 'Gene', '6317', (122, 125))	('knockdown', 'Var', (223, 232))	('HSC-3', 'Gene', '150353', (256, 261))	('ICG-001', 'Chemical', 'MESH:C492448', (45, 52))
556528	30029671	Further, starting at 13 days post-inoculation, we observed a significant reduction in tumor volume (P < 0.005, two-tailed t test) following treatment with ICG-001, relative to vehicle treated-control mice (Fig.	('ICG-001', 'Var', (155, 162))	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('tumor', 'Disease', (86, 91))	('mice', 'Species', '10090', (200, 204))	('ICG-001', 'Chemical', 'MESH:C492448', (155, 162))	('tumor', 'Disease', 'MESH:D009369', (86, 91))	('reduction', 'NegReg', (73, 82))
556532	30029671	Immunofluorescence analyses of these tumors showed that the ICG-001-treated tumors phenocopied ICG-001-treated OSCC cell lines in vitro and displayed robust E-cadherin and beta-catenin junctional localization with an almost complete loss of a mesenchymal protein vimentin, further indicating that ICG-001 promoted an epithelial phenotype (Fig.	('ICG-001', 'Chemical', 'MESH:C492448', (95, 102))	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('ICG-001', 'Var', (297, 304))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('tumors', 'Disease', (37, 43))	('loss', 'NegReg', (233, 237))	('ICG-001', 'Chemical', 'MESH:C492448', (297, 304))	('SCC', 'Gene', '6317', (112, 115))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('ICG-001', 'Chemical', 'MESH:C492448', (60, 67))	('OS', 'Chemical', '-', (111, 113))	('tumors', 'Disease', (76, 82))	('E-cadherin', 'Protein', (157, 167))	('epithelial phenotype', 'CPA', (317, 337))	('tumors', 'Disease', 'MESH:D009369', (37, 43))	('SCC', 'Gene', (112, 115))	('promoted', 'PosReg', (305, 313))	('tumors', 'Disease', 'MESH:D009369', (76, 82))
556537	30029671	We next searched for subpopulations of cells with immature cell surface markers from TC-1-derived tumors by flow cytometry using a panel of primitive epithelial cell surface markers that included CD44, CD29, CD24, CD166, and CD133.	('tumors', 'Disease', (98, 104))	('CD44', 'Var', (196, 200))	('tumors', 'Phenotype', 'HP:0002664', (98, 104))	('CD29', 'Var', (202, 206))	('CD133', 'Gene', (225, 230))	('tumors', 'Disease', 'MESH:D009369', (98, 104))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('CD24', 'Var', (208, 212))	('TC-1', 'CellLine', 'CVCL:1F93', (85, 89))	('CD166', 'Var', (214, 219))	('TC-1-derived', 'Gene', (85, 97))
556541	30029671	Thus, ICG-001 inhibited aggressive phenotypes of TC-1 cells in a manner similar to its effects on OSCC cells and tumors.	('SCC', 'Gene', '6317', (99, 102))	('tumors', 'Disease', (113, 119))	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('TC-1', 'CellLine', 'CVCL:1F93', (49, 53))	('aggressive phenotypes', 'CPA', (24, 45))	('inhibited', 'NegReg', (14, 23))	('ICG-001', 'Chemical', 'MESH:C492448', (6, 13))	('OS', 'Chemical', '-', (98, 100))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('SCC', 'Gene', (99, 102))	('ICG-001', 'Var', (6, 13))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
556553	30029671	To determine the role of beta-catenin on aggressive behavior of OSCC cell subpopulations, we used fluorescence-activated cell sorting (FACS) to isolate CD44+CD24lowCD29+ and CD44+CD24highCD29+ cells from RFP-expressing HSC-3 cells (Fig.	('SCC', 'Gene', (65, 68))	('CD44+CD24lowCD29+', 'Var', (152, 169))	('HSC-3', 'Gene', '150353', (219, 224))	('CD44+CD24highCD29+', 'Var', (174, 192))	('SCC', 'Gene', '6317', (65, 68))	('HSC-3', 'Gene', (219, 224))	('RFP', 'Gene', (204, 207))	('OS', 'Chemical', '-', (64, 66))	('aggressive behavior', 'Phenotype', 'HP:0000718', (41, 60))	('RFP', 'Gene', '5987', (204, 207))
556554	30029671	After sorting, CD44+CD24lowCD29+, CD44+CD24highCD29+, and unsorted HSC-3 cells were cultured for 12 h and then treated with either vehicle control (DMSO) or 10 muM ICG-001 for 24 h. Remarkably, untreated CD44+CD24highCD29+ cells showed rapid growth and metastasis within the first 2 h following injection.	('muM', 'Gene', (160, 163))	('HSC-3', 'Gene', (67, 72))	('metastasis', 'CPA', (253, 263))	('HSC-3', 'Gene', '150353', (67, 72))	('muM', 'Gene', '56925', (160, 163))	('ICG-001', 'Chemical', 'MESH:C492448', (164, 171))	('DMSO', 'Chemical', 'MESH:D004121', (148, 152))	('CD44+CD24highCD29+', 'Var', (204, 222))
556556	30029671	After 24 h, the CD44+CD24highCD29+ cells exhibited more extensive metastases compared to both the unsorted (P = 0.001, two-tailed t test) and CD44+CD24lowCD29+ groups (P = 0.0001, two-tailed t test).	('metastases', 'Disease', (66, 76))	('CD44+CD24highCD29+', 'Var', (16, 34))	('metastases', 'Disease', 'MESH:D009362', (66, 76))
556557	30029671	Notably, ICG-001 treatment significantly reduced metastasis of CD44+CD24highCD29+ (P < 0.0001, two-tailed t test) and unsorted cells (P < 0.0001, two-tailed t test; Fig.	('reduced', 'NegReg', (41, 48))	('metastasis', 'CPA', (49, 59))	('ICG-001', 'Chemical', 'MESH:C492448', (9, 16))	('CD44+CD24highCD29+', 'Var', (63, 81))
556576	30029671	Here, we applied computational approaches to interrogate gene expression signatures in response to the disruption of beta-catenin-CBP interaction with a small molecule antagonist, ICG-001, in OSCC cell lines and to align them with patho-clinical features of human OSCC tumors.	('SCC', 'Gene', (265, 268))	('ICG-001', 'Chemical', 'MESH:C492448', (180, 187))	('human', 'Species', '9606', (258, 263))	('OSCC tumors', 'Disease', (264, 275))	('OS', 'Chemical', '-', (264, 266))	('tumor', 'Phenotype', 'HP:0002664', (269, 274))	('tumors', 'Phenotype', 'HP:0002664', (269, 275))	('SCC', 'Gene', '6317', (265, 268))	('beta-catenin-CBP', 'Protein', (117, 133))	('SCC', 'Gene', (193, 196))	('disruption', 'Var', (103, 113))	('OSCC tumors', 'Disease', 'MESH:D009369', (264, 275))	('OS', 'Chemical', '-', (192, 194))	('interaction', 'Interaction', (134, 145))	('SCC', 'Gene', '6317', (193, 196))
556578	30029671	Our studies highlight the significance of beta-catenin/CBP signaling in the pathobiology of OSCC and suggest that inhibition of beta-catenin-CBP activity with ICG-001 promotes epithelial differentiation program.	('epithelial differentiation program', 'CPA', (176, 210))	('ICG-001', 'Chemical', 'MESH:C492448', (159, 166))	('promotes', 'PosReg', (167, 175))	('activity', 'MPA', (145, 153))	('SCC', 'Gene', (93, 96))	('ICG-001', 'Gene', (159, 166))	('beta-catenin-CBP', 'Protein', (128, 144))	('OS', 'Chemical', '-', (92, 94))	('SCC', 'Gene', '6317', (93, 96))	('inhibition', 'Var', (114, 124))
556580	30029671	Our work provides new evidence for the feasibility of using inhibitors of beta-catenin/CBP activity for the treatment of head and neck cancer patients.	('neck cancer', 'Disease', 'MESH:D006258', (130, 141))	('inhibitors', 'Var', (60, 70))	('head and neck cancer', 'Phenotype', 'HP:0012288', (121, 141))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('neck cancer', 'Disease', (130, 141))	('patients', 'Species', '9606', (142, 150))	('beta-catenin/CBP', 'Protein', (74, 90))
556595	30029671	Another novel finding from this study is that disruption of the beta-catenin-CBP interaction with ICG-001 in OSCC cell lines destabilizes CBP without greatly affecting E-cadherin or beta-catenin transcript or protein levels.	('disruption', 'Var', (46, 56))	('destabilizes', 'NegReg', (125, 137))	('beta-catenin transcript', 'MPA', (182, 205))	('SCC', 'Gene', (110, 113))	('ICG-001', 'Chemical', 'MESH:C492448', (98, 105))	('beta-catenin-CBP', 'Protein', (64, 80))	('OS', 'Chemical', '-', (109, 111))	('SCC', 'Gene', '6317', (110, 113))	('interaction', 'Interaction', (81, 92))	('CBP', 'MPA', (138, 141))
556603	30029671	GSEA of the YAP/TAZ-associated signature revealed a significant positive correlation between ICG-001 treatment and YAP/TAZ knockdown in HSC-3 cells (Additional file 1: Figure S8b; FDR q < 0.001), suggesting potential convergence between YAP/TAZ and CBP and/or beta-catenin in OSCC.	('SCC', 'Gene', (277, 280))	('YAP', 'Gene', '10413', (115, 118))	('YAP', 'Gene', (237, 240))	('ICG-001', 'Gene', (93, 100))	('TAZ', 'Gene', '6901', (241, 244))	('HSC-3', 'Gene', (136, 141))	('YAP', 'Gene', (12, 15))	('TAZ', 'Gene', (241, 244))	('YAP', 'Gene', '10413', (237, 240))	('knockdown', 'Var', (123, 132))	('GSEA', 'Chemical', '-', (0, 4))	('ICG-001', 'Chemical', 'MESH:C492448', (93, 100))	('OS', 'Chemical', '-', (276, 278))	('YAP', 'Gene', (115, 118))	('TAZ', 'Gene', '6901', (16, 19))	('TAZ', 'Gene', (16, 19))	('TAZ', 'Gene', '6901', (119, 122))	('YAP', 'Gene', '10413', (12, 15))	('TAZ', 'Gene', (119, 122))	('SCC', 'Gene', '6317', (277, 280))	('HSC-3', 'Gene', '150353', (136, 141))
556608	30029671	Furthermore, in CRC cell lines, ICG-001 inhibited the expression of the BIRC5 gene product, survivin, coincident with upregulation of caspase 3 activity.	('BIRC5', 'Gene', (72, 77))	('expression', 'MPA', (54, 64))	('ICG-001', 'Chemical', 'MESH:C492448', (32, 39))	('inhibited', 'NegReg', (40, 49))	('upregulation', 'PosReg', (118, 130))	('ICG-001', 'Var', (32, 39))	('caspase 3', 'Gene', (134, 143))	('BIRC5', 'Gene', '332', (72, 77))	('activity', 'MPA', (144, 152))	('caspase 3', 'Gene', '836', (134, 143))	('survivin', 'Gene', (92, 100))
556628	29599409	Many of the identified copy number aberrations and somatic mutations in the primary tumor were typical of HPV(-) HNSCC, but none pointed to obvious therapeutic choices.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('HPV', 'Disease', (106, 109))	('tumor', 'Disease', (84, 89))	('copy number aberrations', 'Var', (23, 46))
556641	29599409	In HPV-negative HNSCC, mutation in the tumor suppressor gene TP53 is by far the most common event, detected in 74% of the TCGA HNSCC patient cohort, and is associated with poor clinical outcome.	('mutation', 'Var', (23, 31))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('patient', 'Species', '9606', (133, 140))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('associated', 'Reg', (156, 166))	('tumor', 'Disease', (39, 44))	('TP53', 'Gene', '7157', (61, 65))	('TP53', 'Gene', (61, 65))
556646	29599409	We identified not only strategies to capitalize on the tumor's TP53 mutant status via synthetic lethality with G2/M checkpoint regulators such as WEE1 and CHK1, but also vulnerabilities associated with mitotic spindle function, developmental and growth factor pathways, protein degradation machinery, and apoptosis.	('CHK1', 'Gene', '1111', (155, 159))	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('TP53', 'Gene', '7157', (63, 67))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('TP53', 'Gene', (63, 67))	('tumor', 'Disease', (55, 60))	('CHK1', 'Gene', (155, 159))	('mutant', 'Var', (68, 74))
556675	29599409	Mutation in TP53 was further confirmed by capillary electrophoresis-based sequencing method using Applied Biosystems (ABI) 3730xl DNA Analyzers (Thermo Fisher Scientific) with primer sets as previously described.	('TP53', 'Gene', '7157', (12, 16))	('TP53', 'Gene', (12, 16))	('Mutation', 'Var', (0, 8))
556682	29599409	Mutated genes in FHCRC-SCC-1 that were also mutated in TCGA at 1% or higher frequency are shown in black.	('Mutated', 'Var', (0, 7))	('SCC-1', 'Gene', '5885', (23, 28))	('SCC-1', 'Gene', (23, 28))	('mutated', 'Var', (44, 51))
556683	29599409	To identify frequently over-expressed genes in the TCGA HNSCC patient cohort, we used the tumor (syn1571420) and normal (syn1571422) RNA-seq transcript profiles and after filtering non-detected transcripts calculated the average transcript levels for each gene.	('syn1571422', 'Var', (121, 131))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('patient', 'Species', '9606', (62, 69))	('tumor', 'Disease', (90, 95))	('syn1571420', 'Var', (97, 107))	('over-expressed', 'PosReg', (23, 37))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
556685	29599409	Similarly, we identify frequently amplified genes in TCGA using tumor (syn1571428) and normal (syn1571430) genome-wide SNP6 array (CNV) profiles.	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('syn1571430', 'Var', (95, 105))	('tumor', 'Disease', (64, 69))	('TCGA', 'Gene', (53, 57))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('syn1571428', 'Var', (71, 81))
556688	29599409	Briefly, optimal transfection conditions were established by comparing cell viability after knockdown of KIF11 with Hs_KIF11_6 siRNA (QIAGEN Inc, Cat #SI02653693), which causes cell arrest in mitosis, to non-targeting control siRNA (NTC) and reagent-only mock controls.	('causes', 'Reg', (170, 176))	('KIF11', 'Gene', (119, 124))	('KIF11', 'Gene', '3832', (105, 110))	('knockdown', 'Var', (92, 101))	('cell arrest', 'CPA', (177, 188))	('KIF11', 'Gene', '3832', (119, 124))	('mitosis', 'Disease', (192, 199))	('mitosis', 'Disease', 'None', (192, 199))	('KIF11', 'Gene', (105, 110))
556707	29599409	Immunostaining showed high levels of nuclear p53 and sequencing identified a TP53 mutation P278S (Figure 1B-C).	('TP53', 'Gene', '7157', (77, 81))	('TP53', 'Gene', (77, 81))	('P278S', 'Mutation', 'rs17849781', (91, 96))	('P278S', 'Var', (91, 96))
556708	29599409	The original tumor was intrinsically cisplatin resistant and gain of function p53 mutations are associated with chemoresistance, so we examined the effect of cisplatin on p53 activity.	('gain of function', 'PosReg', (61, 77))	('original tumor', 'Disease', (4, 18))	('chemoresistance', 'CPA', (112, 127))	('mutations', 'Var', (82, 91))	('p53', 'Gene', (78, 81))	('cisplatin', 'Chemical', 'MESH:D002945', (37, 46))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('original tumor', 'Disease', 'MESH:D009369', (4, 18))	('cisplatin', 'Chemical', 'MESH:D002945', (158, 167))
556712	29599409	CGH analysis detected copy number changes, several of which are also commonly observed in HNSCC, such as amplification in 3p12.1 - p11.2, 11p13 - p12, 11q12.3 - q13.4, and 20q11.21 - q12, and deletion in 9p21.3 and 18q11.2 - q23.	('p12', 'Gene', '56655', (146, 149))	('HNSCC', 'Disease', (90, 95))	('p11', 'Gene', '6281', (131, 134))	('amplification', 'Var', (105, 118))	('p21', 'Gene', '1026', (205, 208))	('p12', 'Gene', '56655', (123, 126))	('deletion', 'Var', (192, 200))	('p12', 'Gene', (146, 149))	('p21', 'Gene', (205, 208))	('p11', 'Gene', (131, 134))	('p12', 'Gene', (123, 126))
556714	29599409	Multi-gene panel tests are increasingly used to identify aberrations in common cancer genes that may be actionable for precision oncology (i.e.	('oncology', 'Phenotype', 'HP:0002664', (129, 137))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('aberrations', 'Var', (57, 68))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))
556718	29599409	FHCRC-SCC-1 harbors a TP53 mutation, consistent with the high prevalence of TP53 mutation in HPV-negative HNSCC.	('SCC-1', 'Gene', (6, 11))	('TP53', 'Gene', '7157', (76, 80))	('SCC-1', 'Gene', '5885', (6, 11))	('mutation', 'Var', (27, 35))	('TP53', 'Gene', (76, 80))	('TP53', 'Gene', '7157', (22, 26))	('TP53', 'Gene', (22, 26))
556719	29599409	Amplification of 11q13 in FHCRC-SCC-1 is also frequently observed in solid tumors including one quarter of HNSCC cases.	('HNSCC', 'Disease', (107, 112))	('SCC-1', 'Gene', '5885', (32, 37))	('solid tumors', 'Disease', 'MESH:D009369', (69, 81))	('observed', 'Reg', (57, 65))	('Amplification of', 'Var', (0, 16))	('solid tumors', 'Disease', (69, 81))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('SCC-1', 'Gene', (32, 37))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))
556721	29599409	Other alterations in FHCRC-SCC-1 that are frequently observed in HNSCC include deletion of the tumor suppressors CDKN2A and CDKN2B, amplification of oncogenes PIK3CA and MYC, and mutation in the receptor tyrosine kinase (RTK) ephrin receptor EPHA3.	('SCC-1', 'Gene', (27, 32))	('mutation', 'Var', (179, 187))	('MYC', 'Gene', (170, 173))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('PIK3CA', 'Gene', '5290', (159, 165))	('deletion', 'Var', (79, 87))	('amplification', 'Var', (132, 145))	('CDKN2A', 'Gene', (113, 119))	('EPHA3', 'Gene', (242, 247))	('CDKN2B', 'Gene', (124, 130))	('MYC', 'Gene', '4609', (170, 173))	('observed', 'Reg', (53, 61))	('EPHA3', 'Gene', '2042', (242, 247))	('CDKN2A', 'Gene', '1029', (113, 119))	('PIK3CA', 'Gene', (159, 165))	('tumor', 'Disease', (95, 100))	('CDKN2B', 'Gene', '1030', (124, 130))	('SCC-1', 'Gene', '5885', (27, 32))	('tumor', 'Disease', 'MESH:D009369', (95, 100))
556723	29599409	Mutations in this gene were recently shown in advanced and recurrent HNSCC tumors and conferred sensitivity to the kinase inhibitor dasatinib.	('conferred', 'Reg', (86, 95))	('shown', 'Reg', (37, 42))	('Mutations', 'Var', (0, 9))	('sensitivity to the', 'MPA', (96, 114))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('HNSCC tumors', 'Disease', (69, 81))	('tumors', 'Phenotype', 'HP:0002664', (75, 81))	('dasatinib', 'Chemical', 'MESH:D000069439', (132, 141))	('HNSCC tumors', 'Disease', 'MESH:D000077195', (69, 81))
556724	29599409	However, the DDR2 mutation in FHCRC-SCC-1 was in the 3'UTR making it less likely to be functional.	('SCC-1', 'Gene', '5885', (36, 41))	('DDR2', 'Gene', '4921', (13, 17))	('DDR2', 'Gene', (13, 17))	('mutation', 'Var', (18, 26))	('SCC-1', 'Gene', (36, 41))
556725	29599409	The frequent alteration of these eighteen genes in HNSCC is suggestive of a functional role in FHCRC-SCC-1 pathogenesis, but beyond well-studied genes such as TP53, CDKN2A or MYC, this evidence is not definitive and insufficient to guide treatment.	('MYC', 'Gene', (175, 178))	('insufficient', 'Disease', (216, 228))	('insufficient', 'Disease', 'MESH:D000309', (216, 228))	('alteration', 'Var', (13, 23))	('MYC', 'Gene', '4609', (175, 178))	('TP53', 'Gene', '7157', (159, 163))	('SCC-1', 'Gene', (101, 106))	('TP53', 'Gene', (159, 163))	('CDKN2A', 'Gene', (165, 171))	('CDKN2A', 'Gene', '1029', (165, 171))	('SCC-1', 'Gene', '5885', (101, 106))
556728	29599409	Given deletion of CDKN2A and amplification of CCND1, one could hypothesize an overactive CDK4/6 pathway and sensitivity to CDK4 inhibitors such as palbociclib.	('CDK4/6', 'Gene', '1019;1021', (89, 95))	('CDKN2A', 'Gene', '1029', (18, 24))	('CCND1', 'Gene', (46, 51))	('amplification', 'Var', (29, 42))	('CCND1', 'Gene', '595', (46, 51))	('CDK4', 'Gene', (123, 127))	('deletion', 'Var', (6, 14))	('CDK4/6', 'Gene', (89, 95))	('CDK4', 'Gene', (89, 93))	('CDK4', 'Gene', '1019', (123, 127))	('overactive', 'PosReg', (78, 88))	('CDKN2A', 'Gene', (18, 24))	('CDK4', 'Gene', '1019', (89, 93))
556729	29599409	Alternatively, mutations in FGF genes might confer sensitivity to FGF/FGFR/RTK inhibitors and mutations in other RTKs such as EPHA3 and DDR2 might predict sensitivity to dasatinib.	('EPHA3', 'Gene', '2042', (126, 131))	('sensitivity to', 'MPA', (155, 169))	('EPHA3', 'Gene', (126, 131))	('FGF genes', 'Gene', (28, 37))	('mutations', 'Var', (15, 24))	('DDR2', 'Gene', '4921', (136, 140))	('sensitivity', 'MPA', (51, 62))	('DDR2', 'Gene', (136, 140))	('dasatinib', 'Chemical', 'MESH:D000069439', (170, 179))	('predict', 'Reg', (147, 154))
556731	29599409	Here, we focused only on genes whose knock-down caused growth inhibition, which we will refer to as "candidate target genes" (CTGs).	('knock-down', 'Var', (37, 47))	('growth', 'MPA', (55, 61))	('CTGs', 'Chemical', '-', (126, 130))
556733	29599409	We next sought to identify actionable targets among somatically mutated genes by testing whether siRNA-mediated knockdown impacted viability of FHCRC-SCC-1 derived cell cultures.	('SCC-1', 'Gene', (150, 155))	('viability', 'MPA', (131, 140))	('impacted', 'Reg', (122, 130))	('SCC-1', 'Gene', '5885', (150, 155))	('testing', 'Reg', (81, 88))	('knockdown', 'Var', (112, 121))
556735	29599409	Interestingly, four of the nine genes that were both mutated and CTGs, TP53, DNAH5, EPHA3, and FAT2, are also mutated in the TCGA HNSCC dataset at a frequency of 3% or higher (Table 1).	('TP53', 'Gene', '7157', (71, 75))	('EPHA3', 'Gene', (84, 89))	('CTGs', 'Chemical', '-', (65, 69))	('mutated', 'Var', (110, 117))	('FAT2', 'Gene', '2196', (95, 99))	('FAT2', 'Gene', (95, 99))	('EPHA3', 'Gene', '2042', (84, 89))	('DNAH5', 'Gene', (77, 82))	('TP53', 'Gene', (71, 75))	('DNAH5', 'Gene', '1767', (77, 82))
556736	29599409	siRNA to EPHA2, related to EPHA3, also reduced viability of FHCRC-SCC-1 cells and EPHA2 is mutated in HNSCC at ~4% frequency and FAT1, related to FAT2, is mutated at ~23% frequency.	('EPHA2', 'Gene', (82, 87))	('EPHA3', 'Gene', '2042', (27, 32))	('FAT1', 'Gene', '2195', (129, 133))	('SCC-1', 'Gene', (66, 71))	('mutated', 'Var', (91, 98))	('EPHA3', 'Gene', (27, 32))	('FAT2', 'Gene', '2196', (146, 150))	('FAT1', 'Gene', (129, 133))	('SCC-1', 'Gene', '5885', (66, 71))	('reduced', 'NegReg', (39, 46))	('FAT2', 'Gene', (146, 150))	('viability', 'CPA', (47, 56))
556737	29599409	This combination of mutational and functional evidence suggests that, in addition to TP53, mutations in DNAH5, EPHA3/EPHA2, and FAT2/FAT1 could have a driver role in FHCRC-SCC-1 and possibly other head and neck cancers with these mutations.	('EPHA3', 'Gene', '2042', (111, 116))	('TP53', 'Gene', (85, 89))	('DNAH5', 'Gene', (104, 109))	('FAT1', 'Gene', '2195', (133, 137))	('head and neck cancer', 'Disease', 'MESH:D006258', (197, 217))	('EPHA3', 'Gene', (111, 116))	('FAT2', 'Gene', '2196', (128, 132))	('SCC-1', 'Gene', '5885', (172, 177))	('FAT2', 'Gene', (128, 132))	('TP53', 'Gene', '7157', (85, 89))	('cancers', 'Phenotype', 'HP:0002664', (211, 218))	('head and neck cancers', 'Phenotype', 'HP:0012288', (197, 218))	('neck cancers', 'Disease', (206, 218))	('neck cancers', 'Disease', 'MESH:D006258', (206, 218))	('SCC-1', 'Gene', (172, 177))	('DNAH5', 'Gene', '1767', (104, 109))	('mutations', 'Var', (91, 100))	('FAT1', 'Gene', (133, 137))	('head and neck cancer', 'Phenotype', 'HP:0012288', (197, 217))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))
556738	29599409	Similarly, intersection of the genes included in the siRNA library with genes amplified or highly expressed in FHCRC-SCC-1 revealed that knockdown of only ~5.3% (20/379) of copy number amplified genes and ~7.6% (18/238) of highly expressed genes led to a reduction in viability (Figure 2C, middle and right panels).	('SCC-1', 'Gene', (117, 122))	('viability', 'CPA', (268, 277))	('SCC-1', 'Gene', '5885', (117, 122))	('knockdown', 'Var', (137, 146))	('reduction', 'NegReg', (255, 264))
556740	29599409	siRNA-mediated knockdown of 121 out of 174 of the retested genes (70%) significantly reduced viability of FHCRC-SCC-1 cells (p<0.05, Figure 3A), and the remaining 53 trended in the same direction indicating a high level of reproducibility of results from the primary screen.	('knockdown', 'Var', (15, 24))	('viability', 'CPA', (93, 102))	('reduced', 'NegReg', (85, 92))	('SCC-1', 'Gene', (112, 117))	('SCC-1', 'Gene', '5885', (112, 117))
556746	29599409	TP53 was both mutated (P278S) and identified as a CTG in FHCRC-SCC-1 (Figure 3A), consistent with a gain of function and pro-survival activity for this mutation as previously shown in lung cancer.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('SCC-1', 'Gene', (63, 68))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('lung cancer', 'Disease', 'MESH:D008175', (184, 195))	('P278S', 'Var', (23, 28))	('SCC-1', 'Gene', '5885', (63, 68))	('gain of function', 'PosReg', (100, 116))	('lung cancer', 'Disease', (184, 195))	('lung cancer', 'Phenotype', 'HP:0100526', (184, 195))	('P278S', 'Mutation', 'rs17849781', (23, 28))
556757	29599409	FHCRC-SCC-1 tumor cells were 15 times more sensitive to the WEE1 inhibitor AZD1775 (IC50 = 0.13 microM vs. 1.9 microM, Figure 5B) relative to NOK cells.	('SCC-1', 'Gene', (6, 11))	('AZD1775', 'Chemical', 'MESH:C549567', (75, 82))	('sensitive', 'MPA', (43, 52))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('SCC-1', 'Gene', '5885', (6, 11))	('WEE1', 'Gene', (60, 64))	('AZD1775', 'Var', (75, 82))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('tumor', 'Disease', (12, 17))
556762	29599409	Similarly, despite FHCRC-SCC-1 harboring a CDKN2A deletion which includes p16INK4A, cells' response to CDK4 inhibitor palbociclib, did not show preferential activity toward FHCRC-SCC-1 relative to NOK cells (Supp.	('CDK4', 'Gene', '1019', (103, 107))	('SCC-1', 'Gene', (179, 184))	('p16INK4A', 'Gene', (74, 82))	('deletion', 'Var', (50, 58))	('CDKN2A', 'Gene', (43, 49))	('SCC-1', 'Gene', '5885', (179, 184))	('SCC-1', 'Gene', (25, 30))	('CDKN2A', 'Gene', '1029', (43, 49))	('SCC-1', 'Gene', '5885', (25, 30))	('p16INK4A', 'Gene', '1029', (74, 82))	('CDK4', 'Gene', (103, 107))
556764	29599409	Consonant with the lack of effect of these targeted agents, siRNAs to either FGFR1 or CDK4 did not reduce viability of FHCRC-SCC-1 cells (Supp.	('CDK4', 'Gene', (86, 90))	('FGFR1', 'Gene', (77, 82))	('CDK4', 'Gene', '1019', (86, 90))	('reduce', 'NegReg', (99, 105))	('FGFR1', 'Gene', '2260', (77, 82))	('SCC-1', 'Gene', (125, 130))	('viability', 'MPA', (106, 115))	('SCC-1', 'Gene', '5885', (125, 130))	('siRNAs', 'Var', (60, 66))
556765	29599409	This lack of response to palbociclib is also observed in metastatic breast cancers harboring CDKN2A genetic alterations.	('CDKN2A', 'Gene', (93, 99))	('genetic alterations', 'Var', (100, 119))	('breast cancers', 'Disease', 'MESH:D001943', (68, 82))	('CDKN2A', 'Gene', '1029', (93, 99))	('breast cancers', 'Disease', (68, 82))	('cancers', 'Phenotype', 'HP:0002664', (75, 82))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('breast cancers', 'Phenotype', 'HP:0003002', (68, 82))
556766	29599409	The drug library contained five mTOR inhibitors, rapamycin, PI-103, PP121, GSK1059615, and BEZ235.	('BEZ235', 'Chemical', 'MESH:C531198', (91, 97))	('PI-103', 'Chemical', 'MESH:C522973', (60, 66))	('rapamycin', 'Chemical', 'MESH:D020123', (49, 58))	('PI-103', 'Var', (60, 66))	('PP121', 'Var', (68, 73))	('PP121', 'Chemical', '-', (68, 73))	('GSK1059615', 'Chemical', '-', (75, 85))	('GSK1059615', 'Var', (75, 85))
556771	29599409	This trial tests the WEE1 inhibitor AZD1775 alone followed by a combination with cisplatin/docetaxel given to previously untreated advanced HNSCC patients (NCT02508246).	('AZD1775', 'Var', (36, 43))	('AZD1775', 'Chemical', 'MESH:C549567', (36, 43))	('cisplatin', 'Chemical', 'MESH:D002945', (81, 90))	('docetaxel', 'Chemical', 'MESH:D000077143', (91, 100))	('patients', 'Species', '9606', (146, 154))	('advanced HNSCC', 'Disease', (131, 145))
556780	29599409	Of note, this patient's tumor carried a mutation in PIK3CA (E545K) and a recent phase I study of apitolisib reported a partial response in two patients whose tumors carried the same PIK3CA mutation.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('tumors', 'Phenotype', 'HP:0002664', (158, 164))	('PIK3CA', 'Gene', (52, 58))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('tumors', 'Disease', (158, 164))	('patient', 'Species', '9606', (143, 150))	('PIK3CA', 'Gene', '5290', (182, 188))	('E545K', 'Mutation', 'rs104886003', (60, 65))	('tumors', 'Disease', 'MESH:D009369', (158, 164))	('tumor', 'Disease', (24, 29))	('patient', 'Species', '9606', (14, 21))	('PIK3CA', 'Gene', '5290', (52, 58))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('tumor', 'Disease', (158, 163))	('E545K', 'Var', (60, 65))	('PIK3CA', 'Gene', (182, 188))	('patients', 'Species', '9606', (143, 151))	('apitolisib', 'Chemical', '-', (97, 107))	('tumor', 'Disease', 'MESH:D009369', (158, 163))
556781	29599409	Finally, as seen in our FHCRC-SCC1 primary culture, despite FHCRC-SCC-7A having a mutation in CDKN2A (R58X), this was not associated with sensitivity to any of the CDK2/4/6 inhibitors tested.	('CDK2/4/6', 'Gene', (164, 172))	('CDK2/4/6', 'Gene', '1017;1019;1021', (164, 172))	('CDKN2A', 'Gene', '1029', (94, 100))	('SCC1', 'Gene', '5885', (30, 34))	('R58X', 'Mutation', 'rs121913387', (102, 106))	('R58X', 'Var', (102, 106))	('SCC1', 'Gene', (30, 34))	('CDKN2A', 'Gene', (94, 100))
556785	29599409	To illustrate this approach on the subtype of head and neck cancers with the greatest unmet need, we studied a patient with HPV-negative p53 mutant oral cavity HNSCC who died of disease in less than one year despite the most aggressive treatments with surgery and cisplatin chemoradiation.	('head and neck cancer', 'Disease', 'MESH:D006258', (46, 66))	('head and neck cancers', 'Phenotype', 'HP:0012288', (46, 67))	('cancers', 'Phenotype', 'HP:0002664', (60, 67))	('neck cancers', 'Disease', (55, 67))	('mutant', 'Var', (141, 147))	('cisplatin', 'Chemical', 'MESH:D002945', (264, 273))	('oral cavity HNSCC', 'Disease', (148, 165))	('neck cancers', 'Disease', 'MESH:D006258', (55, 67))	('head and neck cancer', 'Phenotype', 'HP:0012288', (46, 66))	('patient', 'Species', '9606', (111, 118))	('p53', 'Gene', (137, 140))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
556786	29599409	Comprehensive genomic analysis of this patient's tumor revealed a heterogeneous mutational profile that is typical for HPV-negative HNSCC, with mutations or deletions in tumor suppressor genes such as TP53 and CDKN2A, amplification of oncogenes such as MYC and CCND1 and over 200 additional somatic variants and many copy number aberrations overall pointing to defects in cell cycle regulation, cell adhesion/polarity, and growth factor signaling (Supp.	('cell adhesion/polarity', 'CPA', (395, 417))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('MYC', 'Gene', '4609', (253, 256))	('tumor', 'Disease', (170, 175))	('cell cycle regulation', 'CPA', (372, 393))	('CDKN2A', 'Gene', (210, 216))	('mutations', 'Var', (144, 153))	('tumor', 'Disease', 'MESH:D009369', (170, 175))	('TP53', 'Gene', (201, 205))	('growth factor signaling', 'MPA', (423, 446))	('CDKN2A', 'Gene', '1029', (210, 216))	('patient', 'Species', '9606', (39, 46))	('CCND1', 'Gene', '595', (261, 266))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('tumor', 'Disease', (49, 54))	('MYC', 'Gene', (253, 256))	('CCND1', 'Gene', (261, 266))	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('deletions', 'Var', (157, 166))	('defects', 'NegReg', (361, 368))	('TP53', 'Gene', '7157', (201, 205))	('variants', 'Var', (299, 307))
556799	29599409	TP53 mutations result in loss of the G1 checkpoint leading to an increased reliance on the G2 checkpoint to maintain genome stability.	('increased', 'PosReg', (65, 74))	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('mutations', 'Var', (5, 14))	('loss', 'NegReg', (25, 29))	('G1 checkpoint', 'MPA', (37, 50))	('reliance', 'MPA', (75, 83))
556800	29599409	Thus, WEE1 and CHK1 inhibitors have been developed with the hopes that they would be selectively lethal against p53 mutant cancer cells, particularly in combination with genotoxic therapy.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('genotoxic', 'Chemical', '-', (170, 179))	('CHK1', 'Gene', '1111', (15, 19))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('cancer', 'Disease', (123, 129))	('p53', 'Gene', (112, 115))	('mutant', 'Var', (116, 122))	('CHK1', 'Gene', (15, 19))
556801	29599409	We and others have shown that inhibiting WEE1 in p53 mutant cells leads to mitotic cell death and treatment with AZD1775 either alone or in combination with cisplatin blocked growth of p53 mutant HNSCC xenografts in mice.	('inhibiting', 'NegReg', (30, 40))	('p53', 'Gene', (185, 188))	('p53', 'Gene', (49, 52))	('mice', 'Species', '10090', (216, 220))	('mutant', 'Var', (189, 195))	('cisplatin', 'Chemical', 'MESH:D002945', (157, 166))	('mutant', 'Var', (53, 59))	('mitotic cell death', 'CPA', (75, 93))	('WEE1', 'Gene', (41, 45))	('AZD1775', 'Chemical', 'MESH:C549567', (113, 120))
556803	29599409	The relative sensitivity to AZD1775 of tumor cells cultured from two of these patients was concordant with the patient response or non-response in-vivo.	('patient', 'Species', '9606', (78, 85))	('AZD1775', 'Var', (28, 35))	('tumor', 'Disease', 'MESH:D009369', (39, 44))	('AZD1775', 'Chemical', 'MESH:C549567', (28, 35))	('patients', 'Species', '9606', (78, 86))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('patient', 'Species', '9606', (111, 118))	('tumor', 'Disease', (39, 44))
556804	29599409	Both tumors had TP53 mutations, while the non-responder had an HRAS mutation, potentially linked to the lack of response to targeted agents.	('tumors', 'Disease', (5, 11))	('HRAS', 'Gene', '3265', (63, 67))	('tumors', 'Disease', 'MESH:D009369', (5, 11))	('HRAS', 'Gene', (63, 67))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('TP53', 'Gene', '7157', (16, 20))	('tumors', 'Phenotype', 'HP:0002664', (5, 11))	('TP53', 'Gene', (16, 20))	('mutations', 'Var', (21, 30))
556805	29599409	Antitumor activity of AZD1775 as a single agent has been shown in a recent phase I trial with confirmed partial responses seen in two patients carrying BRCA mutations, one of which was a head and neck cancer patient.	('tumor', 'Disease', (4, 9))	('patient', 'Species', '9606', (208, 215))	('patient', 'Species', '9606', (134, 141))	('BRCA', 'Gene', (152, 156))	('patients', 'Species', '9606', (134, 142))	('BRCA', 'Gene', '672', (152, 156))	('mutations', 'Var', (157, 166))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('head and neck cancer', 'Phenotype', 'HP:0012288', (187, 207))	('AZD1775', 'Gene', (22, 29))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('AZD1775', 'Chemical', 'MESH:C549567', (22, 29))	('head and neck cancer', 'Disease', 'MESH:D006258', (187, 207))
556807	29599409	Our functional analysis also implicates mutant p53 as a driver of this patient's aggressive tumor and non-responsiveness to cisplatin.	('aggressive tumor', 'Disease', 'MESH:D001523', (81, 97))	('cisplatin', 'Chemical', 'MESH:D002945', (124, 133))	('aggressive tumor', 'Disease', (81, 97))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('mutant', 'Var', (40, 46))	('p53', 'Gene', (47, 50))	('patient', 'Species', '9606', (71, 78))
556808	29599409	Gain of function mutations in p53 can protect cells from deregulated MYC and chemotherapy induced apoptosis.	('MYC', 'Gene', (69, 72))	('p53', 'Gene', (30, 33))	('MYC', 'Gene', '4609', (69, 72))	('mutations', 'Var', (17, 26))	('Gain of function', 'PosReg', (0, 16))
556811	29599409	In addition, gain of function mutations in p53 lead to abrogation of the G2/M checkpoint after DNA damage, centrosome amplification, and aberrant mitosis, which could explain the strong dependence of FHCRC-SCC-1 cells on disruption of spindle function and G2/M regulation.	('SCC-1', 'Gene', (206, 211))	('abrogation', 'NegReg', (55, 65))	('gain of function', 'PosReg', (13, 29))	('G2/M checkpoint', 'Pathway', (73, 88))	('aberrant mitosis', 'Disease', (137, 153))	('aberrant mitosis', 'Disease', 'MESH:D002869', (137, 153))	('SCC-1', 'Gene', '5885', (206, 211))	('mutations', 'Var', (30, 39))	('p53', 'Gene', (43, 46))
556812	29599409	In summary, targeting both the G2/M vulnerability of p53 mutant cells, as well as inhibiting antiapoptotic proteins such as MCL-1, may provide a valuable drug combination approach for head and neck cancer with dual alterations of MYC and TP53.	('head and neck cancer', 'Disease', 'MESH:D006258', (184, 204))	('MYC', 'Gene', (230, 233))	('inhibiting', 'NegReg', (82, 92))	('MCL-1', 'Gene', '4170', (124, 129))	('antiapoptotic proteins', 'MPA', (93, 115))	('MCL-1', 'Gene', (124, 129))	('TP53', 'Gene', '7157', (238, 242))	('mutant', 'Var', (57, 63))	('p53', 'Gene', (53, 56))	('MYC', 'Gene', '4609', (230, 233))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('head and neck cancer', 'Phenotype', 'HP:0012288', (184, 204))	('TP53', 'Gene', (238, 242))
556814	29599409	Both EPHA2 and EPHA3 were identified as vulnerabilities by siRNA profiling in both FHCRC-SCC-1 and HNSCC cell lines.	('SCC-1', 'Gene', (89, 94))	('SCC-1', 'Gene', '5885', (89, 94))	('EPHA3', 'Gene', '2042', (15, 20))	('EPHA3', 'Gene', (15, 20))	('EPHA2', 'Var', (5, 10))
556818	29599409	Functional profiling also helped clarify that DDR2 mutation was not likely a driver mutation as knockdown did not decrease viability.	('DDR2', 'Gene', (46, 50))	('mutation', 'Var', (51, 59))	('DDR2', 'Gene', '4921', (46, 50))
556819	29599409	Finally, the dependency of p53 mutant HNSCC cells on WEE1 and CHK1 reinforces the therapeutic potential of targeting G2/M checkpoint regulators as a therapeutic option for these aggressive cancers.	('aggressive cancers', 'Disease', (178, 196))	('mutant', 'Var', (31, 37))	('aggressive cancers', 'Disease', 'MESH:D009369', (178, 196))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('CHK1', 'Gene', (62, 66))	('p53', 'Gene', (27, 30))	('cancers', 'Phenotype', 'HP:0002664', (189, 196))	('CHK1', 'Gene', '1111', (62, 66))
556830	24523874	Although BRF2 overexpression and high MVD indicated poor 5-year overall survival (p = 0.004 and p = 0.019, respectively), multivariate analysis demonstrated that only BRF2 overexpression was an independent prognostic factor for unfavorable overall survival (P = 0.021).	('BRF2', 'Gene', (9, 13))	('overexpression', 'Var', (14, 28))	('BRF2', 'Gene', '55290', (167, 171))	('BRF2', 'Gene', (167, 171))	('overall survival', 'MPA', (64, 80))	('BRF2', 'Gene', '55290', (9, 13))	('poor', 'NegReg', (52, 56))
556879	24523874	2); Furthermore, multivariate analysis identified BRF2 overexpression (P = 0.036) and MVD (P = 0.034) as independent prognostic factors for progression-free survival.	('overexpression', 'PosReg', (55, 69))	('BRF2', 'Gene', (50, 54))	('BRF2', 'Gene', '55290', (50, 54))	('MVD', 'Var', (86, 89))
556880	24523874	However, only BRF2 overexpression retained its significance as an independent prognostic factor for overall as well as progression-free survival (P = 0.021, Table 3 and Table 4).	('BRF2', 'Gene', (14, 18))	('BRF2', 'Gene', '55290', (14, 18))	('overexpression', 'Var', (19, 33))
556882	24523874	For patients without BRF2 overexpression, we detected a highly significant inferior overall survival (OS) and Disease-free survival (PFS), respectively, in patients with high MVD compared with patients with low MVD (P = 0.003 for OS and P = 0.001 for PFS, Table 5).	('patients', 'Species', '9606', (156, 164))	('patients', 'Species', '9606', (193, 201))	('BRF2', 'Gene', '55290', (21, 25))	('high MVD', 'Var', (170, 178))	('inferior', 'NegReg', (75, 83))	('overall survival', 'CPA', (84, 100))	('BRF2', 'Gene', (21, 25))	('patients', 'Species', '9606', (4, 12))	('Disease-free survival', 'CPA', (110, 131))
556886	24523874	Univariate analysis demonstrated that the overall 5-year survival rate of patients with BRF2 protein high expression was significantly lower than that of the remaining patients among squamous cell carcinoma, and we also found such a trend in adenocarcinoma, despite the statistical analysis does not make sense; (P = 0.007 and P = 0.130, respectly; Fig.	('adenocarcinoma', 'Disease', 'MESH:D000230', (242, 256))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (183, 206))	('BRF2', 'Gene', (88, 92))	('protein', 'Protein', (93, 100))	('patients', 'Species', '9606', (74, 82))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (183, 206))	('carcinoma', 'Phenotype', 'HP:0030731', (197, 206))	('squamous cell carcinoma', 'Disease', (183, 206))	('lower', 'NegReg', (135, 140))	('patients', 'Species', '9606', (168, 176))	('adenocarcinoma', 'Disease', (242, 256))	('carcinoma', 'Phenotype', 'HP:0030731', (247, 256))	('BRF2', 'Gene', '55290', (88, 92))	('high expression', 'Var', (101, 116))
556891	24523874	However, high MVD was significantly associated with T status in NSCLC, but not associated with age, gender, smoking, histology and differentiation.	('NSCLC', 'Disease', 'MESH:D002289', (64, 69))	('NSCLC', 'Phenotype', 'HP:0030358', (64, 69))	('T status', 'Disease', (52, 60))	('associated', 'Reg', (36, 46))	('NSCLC', 'Disease', (64, 69))	('high', 'Var', (9, 13))
556899	24523874	However, in multivariate analysis, only BRF2 expression could independently and significantly predict overall 5-year survival, despite the finding that high MVD was significantly associated with tumor recurrence.	('tumor', 'Disease', (195, 200))	('predict', 'Reg', (94, 101))	('associated with', 'Reg', (179, 194))	('BRF2', 'Gene', (40, 44))	('tumor', 'Disease', 'MESH:D009369', (195, 200))	('high', 'Var', (152, 156))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('BRF2', 'Gene', '55290', (40, 44))	('MVD', 'MPA', (157, 160))
556903	33680380	Role of EGFR gene polymorphisms in oral squamous cell carcinoma patients of Southeast Iran: A case-control study The decisive etiology of oral squamous cell carcinoma (OSCC) is still ambiguous, but we recognize the contribution of genetic aberration and environmental agents due to OSCC initiation.	('patients', 'Species', '9606', (64, 72))	('carcinoma', 'Phenotype', 'HP:0030731', (54, 63))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (35, 63))	('EGFR', 'Gene', '1956', (8, 12))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (138, 166))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (40, 63))	('carcinoma', 'Phenotype', 'HP:0030731', (157, 166))	('polymorphisms', 'Var', (18, 31))	('oral squamous cell carcinoma', 'Disease', (35, 63))	('EGFR', 'Gene', (8, 12))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (143, 166))	('oral squamous cell carcinoma', 'Disease', (138, 166))
556904	33680380	In the current study, we elucidate the potential impact of EGFR gene polymorphisms on the risk of OSCC in Southeast Iran.	('polymorphisms', 'Var', (69, 82))	('OSCC', 'Disease', (98, 102))	('EGFR', 'Gene', '1956', (59, 63))	('EGFR', 'Gene', (59, 63))
556906	33680380	Three polymorphisms of the EGFR gene (rs2227983, rs2293347 and rs2227984) were genotype by Tetra-ARMS PCR.	('EGFR', 'Gene', '1956', (27, 31))	('rs2227984', 'Var', (63, 72))	('EGFR', 'Gene', (27, 31))	('rs2227984', 'Mutation', 'rs2227984', (63, 72))	('Thr', 'Chemical', 'MESH:D013912', (0, 3))	('rs2227983', 'Var', (38, 47))	('rs2293347', 'Mutation', 'rs2293347', (49, 58))	('rs2227983', 'Mutation', 'rs2227983', (38, 47))	('rs2293347', 'Var', (49, 58))
556908	33680380	In rs2227984 and rs2293347, no statistical differences showed in the distribution of genotypes between the case and control group.	('rs2293347', 'Var', (17, 26))	('rs2227984', 'Mutation', 'rs2227984', (3, 12))	('rs2227984', 'Var', (3, 12))	('rs2293347', 'Mutation', 'rs2293347', (17, 26))
556909	33680380	The present investigation indicated that rs2227983 polymorphism might contribute to OSCC susceptibility in Iran's southeast population.	('rs2227983', 'Var', (41, 50))	('contribute', 'Reg', (70, 80))	('rs2227983', 'Mutation', 'rs2227983', (41, 50))	('OSCC', 'Disease', (84, 88))
556927	33680380	indicated that nuclear EGFR variation, EGFR phosphorylation and TGF-alpha level can be as predictive factors in patients with head and neck squamous cell carcinoma treated by EGFR inhibitor drugs.	('phosphorylation', 'MPA', (44, 59))	('EGFR', 'Gene', (175, 179))	('TGF-alpha', 'Gene', '7039', (64, 73))	('variation', 'Var', (28, 37))	('patients', 'Species', '9606', (112, 120))	('TGF-alpha', 'Gene', (64, 73))	('EGFR', 'Gene', '1956', (23, 27))	('neck squamous cell carcinoma', 'Disease', (135, 163))	('EGFR', 'Gene', '1956', (39, 43))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (140, 163))	('EGFR', 'Gene', (39, 43))	('carcinoma', 'Phenotype', 'HP:0030731', (154, 163))	('EGFR', 'Gene', (23, 27))	('EGFR', 'Gene', '1956', (175, 179))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (126, 163))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (135, 163))
556929	33680380	Furthermore, their study suggested that EGFR polymorphisms can be beneficial in EGFR-targeted antibody therapies.	('beneficial', 'PosReg', (66, 76))	('EGFR', 'Gene', '1956', (80, 84))	('EGFR', 'Gene', (80, 84))	('polymorphisms', 'Var', (45, 58))	('EGFR', 'Gene', '1956', (40, 44))	('EGFR', 'Gene', (40, 44))
556931	33680380	Molecular epidemiologic studies in 2006 showed that EGFR gene variations might be related to alteration in cellular biological activities.	('cellular biological activities', 'CPA', (107, 137))	('alteration', 'Reg', (93, 103))	('EGFR', 'Gene', '1956', (52, 56))	('EGFR', 'Gene', (52, 56))	('variations', 'Var', (62, 72))	('related', 'Reg', (82, 89))
556932	33680380	Nevertheless, the impact of functional and actual frequency EGFR genotypes of Sistan-Baluchestan province OSCC patient population has not been reported yet, here we probably study the correlation between single nucleotide polymorphisms (rs2227983, rs2227984 and rs2293347) of EGFR polymorphisms and OSCC susceptibility to elucidate the precise role in the sample Iranian population.	('rs2227984', 'Var', (248, 257))	('rs2227984', 'Mutation', 'rs2227984', (248, 257))	('rs2293347', 'Mutation', 'rs2293347', (262, 271))	('rs2293347', 'Var', (262, 271))	('EGFR', 'Gene', '1956', (276, 280))	('EGFR', 'Gene', (276, 280))	('EGFR', 'Gene', '1956', (60, 64))	('rs2227983', 'Var', (237, 246))	('patient', 'Species', '9606', (111, 118))	('rs2227983', 'Mutation', 'rs2227983', (237, 246))	('EGFR', 'Gene', (60, 64))	('OSCC', 'Disease', (299, 303))
556936	33680380	The EGFR single nucleotide polymorphisms rs2227983(R497K), rs2227984 (T584T) and rs2293347 (D994D) were genotyped using tetra-ARMS PCR techniques.	('rs2227984', 'Var', (59, 68))	('rs2293347', 'Mutation', 'rs2293347', (81, 90))	('D994D', 'Mutation', 'rs2293347', (92, 97))	('rs2227984', 'Mutation', 'rs2227984', (59, 68))	('EGFR', 'Gene', (4, 8))	('rs2293347', 'Var', (81, 90))	('R497K', 'Mutation', 'rs2227983', (51, 56))	('rs2227983', 'Var', (41, 50))	('rs2227983', 'Mutation', 'rs2227983', (41, 50))	('EGFR', 'Gene', '1956', (4, 8))
556938	33680380	PCR was done with temperature profile as follows: initial denaturation step (95  C for 5 min), followed by 30 cycles of denaturation (95 C for 1 min), annealing (69 C for 1 min for rs2227984, 62 C for rs2293347 and rs2227983) and extension step (72 C for 1 min), and final extension (72 C for 5 min).	('rs2227984', 'Mutation', 'rs2227984', (181, 190))	('rs2227983', 'Var', (215, 224))	('rs2227983', 'Mutation', 'rs2227983', (215, 224))	('rs2293347', 'Mutation', 'rs2293347', (201, 210))	('rs2293347', 'Var', (201, 210))	('rs2227984', 'Var', (181, 190))
556940	33680380	The odds ratios (ORs) and 95% confidence intervals (CIs) for overall OSCC were estimated, seeking the probable correlation between EGFR polymorphisms and OSCC susceptibility.	('EGFR', 'Gene', '1956', (131, 135))	('polymorphisms', 'Var', (136, 149))	('EGFR', 'Gene', (131, 135))	('OSCC', 'Disease', (154, 158))
556942	33680380	As shown in table 2, in rs2227983, the frequency of heterozygous AG (P=0.02, OR=2.3) and AG+AA genotype (P=0.03, OR=2.2) were significantly higher in cases than the control group.	('rs2227983', 'Var', (24, 33))	('higher', 'PosReg', (140, 146))	('rs2227983', 'Mutation', 'rs2227983', (24, 33))
556943	33680380	In rs2293347 and rs2227984, no statistical difference was shown in the distribution of genotypes and alleles.	('rs2293347', 'Var', (3, 12))	('rs2293347', 'Mutation', 'rs2293347', (3, 12))	('rs2227984', 'Mutation', 'rs2227984', (17, 26))	('rs2227984', 'Var', (17, 26))
556950	33680380	The majority of patients with head and neck squamous cell carcinoma treated with a cetuximab-based therapy have been shown, EGFR variation could be a useful biomarker for less skin toxicity and poor prognosis.	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (39, 67))	('cetuximab', 'Chemical', 'MESH:D000068818', (83, 92))	('EGFR', 'Gene', '1956', (124, 128))	('skin toxicity', 'Disease', (176, 189))	('skin toxicity', 'Disease', 'MESH:D012871', (176, 189))	('patients', 'Species', '9606', (16, 24))	('EGFR', 'Gene', (124, 128))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (44, 67))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (30, 67))	('variation', 'Var', (129, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))	('neck squamous cell carcinoma', 'Disease', (39, 67))
556951	33680380	In the current study, we evaluated the potential impact of three genotypes of the EGFR gene; rs2227983, rs2227984, and rs2293347 in OSCC patients of the southeast of Iran.	('EGFR', 'Gene', (82, 86))	('OSCC', 'Disease', (132, 136))	('rs2227983', 'Mutation', 'rs2227983', (93, 102))	('rs2293347', 'Mutation', 'rs2293347', (119, 128))	('rs2293347', 'Var', (119, 128))	('rs2227984', 'Var', (104, 113))	('patients', 'Species', '9606', (137, 145))	('rs2227984', 'Mutation', 'rs2227984', (104, 113))	('EGFR', 'Gene', '1956', (82, 86))	('rs2227983', 'Var', (93, 102))
556953	33680380	The results showed that the heterozygous AG variation was common in patients than the control individuals.	('common', 'Reg', (58, 64))	('heterozygous', 'Var', (28, 40))	('patients', 'Species', '9606', (68, 76))
556954	33680380	Also, results indicated that the presence of A allele at rs2227983 polymorphic site (AG + AA) of the EGFR gene is related to OSCC susceptibility and this genotype is in association with OSCC predisposition.	('association', 'Reg', (169, 180))	('OSCC', 'Disease', (186, 190))	('rs2227983', 'Var', (57, 66))	('EGFR', 'Gene', '1956', (101, 105))	('EGFR', 'Gene', (101, 105))	('rs2227983', 'Mutation', 'rs2227983', (57, 66))	('related', 'Reg', (114, 121))	('OSCC', 'Disease', (125, 129))
556956	33680380	reported that the variant A has more reduced tyrosine kinase activity than G allele and it can lead to reductions in ligand binding, growth stimulation and induction of proto-oncogenes MYC, FOS and JUN.	('FOS', 'Gene', '2353', (190, 193))	('ligand binding', 'Interaction', (117, 131))	('growth stimulation', 'CPA', (133, 151))	('MYC', 'Gene', (185, 188))	('tyrosine kinase', 'Gene', '7294', (45, 60))	('reductions', 'NegReg', (103, 113))	('FOS', 'Gene', (190, 193))	('JUN', 'Gene', (198, 201))	('MYC', 'Gene', '4609', (185, 188))	('tyrosine kinase', 'Gene', (45, 60))	('reduced', 'NegReg', (37, 44))	('induction', 'MPA', (156, 165))	('variant', 'Var', (18, 25))
556957	33680380	Some evidence demonstrated that the R497K-Lys genotype has not been involved in cancer predisposition and displayed the correlation with the improved clinical outcome in several tumors.	('tumors', 'Disease', (178, 184))	('tumors', 'Disease', 'MESH:D009369', (178, 184))	('tumors', 'Phenotype', 'HP:0002664', (178, 184))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('improved', 'PosReg', (141, 149))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('R497K-Lys', 'Var', (36, 45))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('Lys', 'Chemical', 'MESH:D008239', (42, 45))	('cancer', 'Disease', (80, 86))	('R497K', 'Mutation', 'rs2227983', (36, 41))
556961	33680380	in 2012 showed that the rs2227983 variation could be a promising prognostic factor for EGFR chemotherapy patients with advanced cancer of the head and neck.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('EGFR', 'Gene', '1956', (87, 91))	('patients', 'Species', '9606', (105, 113))	('EGFR', 'Gene', (87, 91))	('rs2227983', 'Var', (24, 33))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('rs2227983', 'Mutation', 'rs2227983', (24, 33))	('cancer', 'Disease', (128, 134))
556962	33680380	in 2014 indicated that EGFR R521K G>A (rs2227983) genotypes could be critical predictor markers in patients with advanced primary pharyngolaryngeal squamous cell carcinoma treated with cancer drugs concurrently.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (148, 171))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('pharyngolaryngeal squamous cell carcinoma', 'Phenotype', 'HP:0012182', (130, 171))	('squamous cell carcinoma', 'Disease', (148, 171))	('rs2227983', 'Mutation', 'rs2227983', (39, 48))	('R521K', 'Var', (28, 33))	('patients', 'Species', '9606', (99, 107))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (148, 171))	('EGFR', 'Gene', '1956', (23, 27))	('R521K', 'SUBSTITUTION', 'None', (28, 33))	('cancer', 'Disease', 'MESH:D009369', (185, 191))	('EGFR', 'Gene', (23, 27))	('cancer', 'Disease', (185, 191))	('carcinoma', 'Phenotype', 'HP:0030731', (162, 171))
556963	33680380	- In rs2293347, with an A G substitution leading to an aspartate (ASP) change in codon 994 to the same amino acid in the coding region of exon 25.	('rs2293347', 'Var', (5, 14))	('ASP', 'Gene', (66, 69))	('ASP', 'Gene', '259266', (66, 69))	('rs2293347', 'Mutation', 'rs2293347', (5, 14))	('aspartate', 'Chemical', 'MESH:D001224', (55, 64))
556965	33680380	in 2009 reported that EGFR variation in rs2293347 (D994D) was related to the clinical outcome of Gefitinib treatment in advanced non-small-cell lung cancer (NSCLC) patients, the response rate of GG genotype patients was almost double with that of other genotypes (71.2% versus 37.5%,).	('NSCLC', 'Disease', 'MESH:D002289', (157, 162))	('rs2293347', 'Mutation', 'rs2293347', (40, 49))	('patients', 'Species', '9606', (207, 215))	('rs2293347', 'Var', (40, 49))	('lung cancer', 'Phenotype', 'HP:0100526', (144, 155))	('variation', 'Var', (27, 36))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('related', 'Reg', (62, 69))	('Gefitinib', 'Chemical', 'MESH:D000077156', (97, 106))	('EGFR', 'Gene', '1956', (22, 26))	('NSCLC', 'Disease', (157, 162))	('patients', 'Species', '9606', (164, 172))	('D994D', 'Mutation', 'rs2293347', (51, 56))	('non-small-cell lung cancer', 'Disease', (129, 155))	('EGFR', 'Gene', (22, 26))	('non-small-cell lung cancer', 'Disease', 'MESH:D002289', (129, 155))
556967	33680380	in 2013 study 7 EGFR gene exons in gastric cancer of the Chinese population and could not find any relation between rs2227984 and rs2293347 gastric cancer risk.	('gastric cancer', 'Phenotype', 'HP:0012126', (140, 154))	('rs2227984', 'Mutation', 'rs2227984', (116, 125))	('rs2293347', 'Var', (130, 139))	('gastric cancer', 'Phenotype', 'HP:0012126', (35, 49))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('gastric cancer', 'Disease', (140, 154))	('EGFR', 'Gene', '1956', (16, 20))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('gastric cancer', 'Disease', 'MESH:D013274', (140, 154))	('rs2293347', 'Mutation', 'rs2293347', (130, 139))	('gastric cancer', 'Disease', (35, 49))	('EGFR', 'Gene', (16, 20))	('gastric cancer', 'Disease', 'MESH:D013274', (35, 49))
556968	33680380	Some evidence reported that different EGFR SNPs, such as rs2293347 and rs2227983, were involved in tumor biological behavior, including tumor metastasis, progression, and could be affected tumorigenesis.	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('EGFR', 'Gene', '1956', (38, 42))	('tumor', 'Disease', (99, 104))	('rs2293347', 'Var', (57, 66))	('involved', 'Reg', (87, 95))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('tumor', 'Disease', (136, 141))	('affected', 'Reg', (180, 188))	('tumor metastasis', 'Disease', 'MESH:D009362', (136, 152))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('rs2227983', 'Mutation', 'rs2227983', (71, 80))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumor', 'Disease', (189, 194))	('progression', 'CPA', (154, 165))	('rs2227983', 'Var', (71, 80))	('EGFR', 'Gene', (38, 42))	('tumor metastasis', 'Disease', (136, 152))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('rs2293347', 'Mutation', 'rs2293347', (57, 66))
556970	33680380	In a study, results showed that EGFR polymorphism at exon 25 sites probably are associated with NSCLC progression.	('NSCLC', 'Disease', (96, 101))	('NSCLC', 'Disease', 'MESH:D002289', (96, 101))	('EGFR', 'Gene', '1956', (32, 36))	('associated', 'Reg', (80, 90))	('EGFR', 'Gene', (32, 36))	('polymorphism', 'Var', (37, 49))
556971	33680380	The meta-analysis and systematic meta-analysis revealed that the EGFR R521K variation is not related to cancer risk, regarding various anticancer therapies may require further studies.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('EGFR', 'Gene', '1956', (65, 69))	('R521K', 'Mutation', 'rs2227983', (70, 75))	('EGFR', 'Gene', (65, 69))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('R521K', 'Var', (70, 75))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('cancer', 'Disease', (139, 145))
556975	33680380	In conclusion this study indicated that the EGFR G>A (rs2227983) polymorphism was the promising predictor factor in OSCC patients in the southeast population of Iran.	('rs2227983', 'Var', (54, 63))	('rs2227983', 'Mutation', 'rs2227983', (54, 63))	('OSCC', 'Disease', (116, 120))	('predictor', 'Reg', (96, 105))	('G>A (rs2227983', 'Var', (49, 63))	('EGFR', 'Gene', '1956', (44, 48))	('EGFR', 'Gene', (44, 48))	('patients', 'Species', '9606', (121, 129))
556976	33680380	However, our data can not yet definitely emphasize the role of EGFR gene variations.	('EGFR', 'Gene', '1956', (63, 67))	('EGFR', 'Gene', (63, 67))	('variations', 'Var', (73, 83))
557021	28732212	Molecular signature: In case of prostate adenocarcinoma, 246 primary prostate tumor samples were divided into seven subtypes defined by ERG (ETS transcription factor), ETV1/4 (ETS variant 1/4) and FLI1 (Fli-1 proto-oncogene, ETS transcription factor) gene fusions and SPOP (speckle type BTB/POZ protein), FOXA1 (forkhead box A1) and IDH1 (isocitrate dehydrogenase (NADP(+)) 1, cytosolic) mutations.	('ERG', 'Gene', '2078', (136, 139))	('SPOP', 'Gene', (268, 272))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('ETV1/4', 'Gene', '2115;2118', (168, 174))	('Fli-1 proto-oncogene', 'Gene', '2313', (203, 223))	('ETS variant 1/4', 'Gene', (176, 191))	('carcinoma', 'Phenotype', 'HP:0030731', (46, 55))	('ETS variant 1/4', 'Gene', '2115;2118', (176, 191))	('ETV1/4', 'Gene', (168, 174))	('prostate adenocarcinoma', 'Disease', (32, 55))	('IDH1', 'Gene', (333, 337))	('mutations', 'Var', (388, 397))	('Fli-1 proto-oncogene', 'Gene', (203, 223))	('FLI1', 'Gene', (197, 201))	('forkhead box A1', 'Gene', (312, 327))	('forkhead box A1', 'Gene', '3169', (312, 327))	('FOXA1', 'Gene', '3169', (305, 310))	('FLI1', 'Gene', '2313', (197, 201))	('FOXA1', 'Gene', (305, 310))	('prostate adenocarcinoma', 'Disease', 'MESH:D011471', (32, 55))	('IDH1', 'Gene', '3417', (333, 337))	('prostate tumor', 'Disease', (69, 83))	('ERG', 'Gene', (136, 139))	('prostate tumor', 'Disease', 'MESH:D011471', (69, 83))	('prostate tumor', 'Phenotype', 'HP:0100787', (69, 83))
557072	28732212	The KM plot depicting the effect of high and low/medium CDKN1A expression on overall survival of African American, Caucasian, and Asian patients shows a cumulative significance of 0.039.	('low/medium', 'Var', (45, 55))	('patients', 'Species', '9606', (136, 144))	('CDKN1A', 'Gene', (56, 62))	('high', 'Var', (36, 40))	('CDKN1A', 'Gene', '1026', (56, 62))
557074	28732212	On careful observation of the KM plots, one can observe that high expression of CDKN1A significantly (P = .023) correlates with overall survival in Caucasian HNSC patients.	('patients', 'Species', '9606', (163, 171))	('high', 'Var', (61, 65))	('overall survival', 'CPA', (128, 144))	('correlates with', 'Reg', (112, 127))	('CDKN1A', 'Gene', (80, 86))	('CDKN1A', 'Gene', '1026', (80, 86))
557095	28418919	In nude mice xenografts, overexpressing ZNF452 also promoted tumor proliferation and metastasis.	('ZNF452', 'Gene', '114821', (40, 46))	('overexpressing', 'Var', (25, 39))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('ZNF452', 'Gene', (40, 46))	('metastasis', 'CPA', (85, 95))	('nude mice', 'Species', '10090', (3, 12))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('promoted', 'PosReg', (52, 60))	('tumor', 'Disease', (61, 66))
557115	28418919	Kaplan-Meier analysis result showed that the overall survival of patients with positive ZNF452 expression (42.73 +-2.87 months) was significantly shorter than those with negative ZNF452 expression (62.67 +-1.91 months, P<0.001, Figure 1H).	('ZNF452', 'Gene', (179, 185))	('positive', 'Var', (79, 87))	('expression', 'Var', (95, 105))	('ZNF452', 'Gene', (88, 94))	('ZNF452', 'Gene', '114821', (179, 185))	('shorter', 'NegReg', (146, 153))	('patients', 'Species', '9606', (65, 73))	('ZNF452', 'Gene', '114821', (88, 94))
557128	28418919	The protein levels of CyclinD1 and CyclinE1, as well as p-Rb, were upregulated after ZNF452 overexpression, and they were correspondingly decreased by ZNF452 knock-down (Figure 3D).	('ZNF452', 'Gene', (151, 157))	('protein levels', 'MPA', (4, 18))	('CyclinE1', 'Gene', '898', (35, 43))	('knock-down', 'Var', (158, 168))	('CyclinE1', 'Gene', (35, 43))	('p-Rb', 'Gene', (56, 60))	('CyclinD1', 'Gene', (22, 30))	('decreased', 'NegReg', (138, 147))	('ZNF452', 'Gene', '114821', (85, 91))	('ZNF452', 'Gene', '114821', (151, 157))	('p-Rb', 'Gene', '5925', (56, 60))	('overexpression', 'Var', (92, 106))	('ZNF452', 'Gene', (85, 91))	('CyclinD1', 'Gene', '595', (22, 30))	('upregulated', 'PosReg', (67, 78))
557130	28418919	Tumor migration (Figure 4A) and invasion (Figure 4B) were also enhanced by transfecting ZNF452 plasmid in A549 cells or depressed by transfecting ZNF452 siRNA in H1299 cells.	('ZNF452', 'Gene', '114821', (88, 94))	('H1299', 'CellLine', 'CVCL:0060', (162, 167))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('depressed', 'Disease', (120, 129))	('enhanced', 'PosReg', (63, 71))	('ZNF452', 'Gene', (146, 152))	('ZNF452', 'Gene', (88, 94))	('depressed', 'Disease', 'MESH:D000275', (120, 129))	('A549', 'CellLine', 'CVCL:0023', (106, 110))	('transfecting', 'Var', (75, 87))	('Tumor migration', 'CPA', (0, 15))	('ZNF452', 'Gene', '114821', (146, 152))	('invasion', 'CPA', (32, 40))
557136	28418919	The Ki-67 expression was higher in ZNF452 overexpressing group than the control (Figure 5C).	('ZNF452', 'Gene', (35, 41))	('expression', 'MPA', (10, 20))	('Ki-67', 'Protein', (4, 9))	('overexpressing', 'Var', (42, 56))	('higher', 'PosReg', (25, 31))	('ZNF452', 'Gene', '114821', (35, 41))
557201	28418919	The A549 and H1299 cells were transfected with pCMV6 or pCMV6- ZNF452 plasmids, negative control or ZNF452-siRNA for 48 hours.	('A549', 'CellLine', 'CVCL:0023', (4, 8))	('ZNF452', 'Gene', (63, 69))	('ZNF452', 'Gene', (100, 106))	('pCMV6', 'Var', (47, 52))	('ZNF452', 'Gene', '114821', (63, 69))	('ZNF452', 'Gene', '114821', (100, 106))	('H1299', 'CellLine', 'CVCL:0060', (13, 18))	('pCMV6-', 'Var', (56, 62))
557216	27729640	Association of Vascular Endothelial Growth Factor (VEGF) Gene Polymorphisms with the Risk and Prognosis of Cutaneous Squamous Cell Carcinoma Cutaneous squamous cell carcinoma (cSCC) is the second most common type of non-melanoma skin cancer (NMSC) globally.	('cancer', 'Phenotype', 'HP:0002664', (234, 240))	('Cutaneous Squamous Cell Carcinoma', 'Phenotype', 'HP:0006739', (107, 140))	('VEGF', 'Gene', '7422', (51, 55))	('Cutaneous squamous cell carcinoma', 'Disease', (141, 174))	('Association', 'Interaction', (0, 11))	('cSCC', 'Phenotype', 'HP:0006739', (176, 180))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (151, 174))	('VEGF', 'Gene', (51, 55))	('Vascular Endothelial Growth Factor', 'Gene', (15, 49))	('Cutaneous squamous cell carcinoma', 'Disease', 'MESH:D002294', (141, 174))	('melanoma', 'Phenotype', 'HP:0002861', (220, 228))	('Carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('carcinoma', 'Phenotype', 'HP:0030731', (165, 174))	('Cutaneous Squamous Cell Carcinoma', 'Disease', 'MESH:D002294', (107, 140))	('non-melanoma skin cancer', 'Disease', 'MESH:D012878', (216, 240))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (117, 140))	('Polymorphisms', 'Var', (62, 75))	('Cutaneous Squamous Cell Carcinoma', 'Disease', (107, 140))	('Cutaneous squamous cell carcinoma', 'Phenotype', 'HP:0006739', (141, 174))	('non-melanoma skin cancer', 'Disease', (216, 240))	('Vascular Endothelial Growth Factor', 'Gene', '7422', (15, 49))	('skin cancer', 'Phenotype', 'HP:0008069', (229, 240))
557217	27729640	The aims of this study were to further systematically clarify the potential association of rs833061 (-460 C>T) and rs1570360 (-1154 G>A), two SNPs of VEGF, with the risk of cSCC and the prognostic impacts on cSCC patients.	('rs833061', 'Mutation', 'rs833061', (91, 99))	('rs833061 (-460 C>T', 'Var', (91, 109))	('cSCC', 'Phenotype', 'HP:0006739', (208, 212))	('VEGF', 'Gene', '7422', (150, 154))	('cSCC', 'Phenotype', 'HP:0006739', (173, 177))	('cSCC', 'Disease', (208, 212))	('-1154 G>A', 'Mutation', 'rs1570360', (126, 135))	('cSCC', 'Disease', (173, 177))	('rs1570360 (-1154 G>A', 'Var', (115, 135))	('-460 C>T', 'Mutation', 'rs833061', (101, 109))	('patients', 'Species', '9606', (213, 221))	('VEGF', 'Gene', (150, 154))	('rs1570360', 'Mutation', 'rs1570360', (115, 124))
557221	27729640	Distributions of allele frequencies and genotype of -460 C>T in the case and control group were statistically different; the TT + CT genotype was significantly correlated with a decrease risk of cSCC (OR=0.36, 95% CI=0.21-0.63, P<0.001).	('CT', 'Chemical', 'MESH:D002251', (130, 132))	('decrease', 'NegReg', (178, 186))	('cSCC', 'Phenotype', 'HP:0006739', (195, 199))	('-460 C>T', 'Mutation', 'rs833061', (52, 60))	('TT + CT', 'Var', (125, 132))	('cSCC', 'Disease', (195, 199))
557224	27729640	For VEGF-1154 G>A, the AA genotype was significantly correlated with the reduced overall survival in cSCC patients, with the mean survival time of 23.88 months (P=0.009).	('cSCC', 'Disease', (101, 105))	('reduced', 'NegReg', (73, 80))	('patients', 'Species', '9606', (106, 114))	('VEGF-1154 G>A', 'Var', (4, 17))	('overall survival', 'MPA', (81, 97))	('cSCC', 'Phenotype', 'HP:0006739', (101, 105))
557240	27729640	Single-nucleotide polymorphisms (SNPs) of VEGF that can be found in the promoter or other regulatory regions may regulate VEGF expression or activity.	('VEGF', 'Gene', '7422', (122, 126))	('regulate', 'Reg', (113, 121))	('expression', 'MPA', (127, 137))	('activity', 'MPA', (141, 149))	('Single-nucleotide polymorphisms', 'Var', (0, 31))	('VEGF', 'Gene', '7422', (42, 46))	('VEGF', 'Gene', (122, 126))	('VEGF', 'Gene', (42, 46))
557241	27729640	The involvement of VEGF polymorphisms in cancer progression has been demonstrated in several types of tumors.	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('tumors', 'Disease', (102, 108))	('tumors', 'Disease', 'MESH:D009369', (102, 108))	('tumors', 'Phenotype', 'HP:0002664', (102, 108))	('VEGF', 'Gene', (19, 23))	('polymorphisms', 'Var', (24, 37))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('VEGF', 'Gene', '7422', (19, 23))	('involvement', 'Reg', (4, 15))	('men', 'Species', '9606', (11, 14))
557242	27729640	VEGF polymorphisms have previously been described in solid carcinomas, containing lung cancer, non-Hodgkin's lymphoma, cervical cancer, colorectal cancer, esophageal squamous cell carcinoma (ESCC), and oral squamous cell carcinoma (OSCC).	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('carcinomas', 'Phenotype', 'HP:0030731', (59, 69))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (207, 230))	("non-Hodgkin's lymphoma", 'Phenotype', 'HP:0012539', (95, 117))	('colorectal cancer', 'Disease', 'MESH:D015179', (136, 153))	('lung cancer', 'Disease', 'MESH:D008175', (82, 93))	('cancer', 'Disease', (128, 134))	('lung cancer', 'Phenotype', 'HP:0100526', (82, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (221, 230))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (155, 189))	('colorectal cancer', 'Disease', (136, 153))	("non-Hodgkin's lymphoma", 'Disease', 'MESH:D008228', (95, 117))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (166, 189))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	("Hodgkin's lymphoma", 'Phenotype', 'HP:0012189', (99, 117))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('solid carcinomas', 'Disease', (53, 69))	('cancer', 'Disease', (87, 93))	("non-Hodgkin's lymphoma", 'Disease', (95, 117))	('lymphoma', 'Phenotype', 'HP:0002665', (109, 117))	('carcinoma', 'Phenotype', 'HP:0030731', (180, 189))	('VEGF', 'Gene', '7422', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('carcinoma', 'Phenotype', 'HP:0030731', (59, 68))	('VEGF', 'Gene', (0, 4))	('polymorphisms', 'Var', (5, 18))	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('colorectal cancer', 'Phenotype', 'HP:0003003', (136, 153))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (202, 230))	('lung cancer', 'Disease', (82, 93))	('oral squamous cell carcinoma', 'Disease', (202, 230))	('esophageal squamous cell carcinoma', 'Disease', (155, 189))	('solid carcinomas', 'Disease', 'MESH:D018250', (53, 69))	('cancer', 'Disease', (147, 153))	('described', 'Reg', (40, 49))	('cancer', 'Disease', 'MESH:D009369', (87, 93))
557245	27729640	The -1154460C>T SNP (rs833061) and -1154G>A SNP (rs1570360) are located at the promoter region and may regulate promoter activity.	('rs1570360', 'Mutation', 'rs1570360', (49, 58))	('rs1570360', 'Var', (49, 58))	('promoter activity', 'MPA', (112, 129))	('rs833061', 'Var', (21, 29))	('rs833061', 'Mutation', 'rs833061', (21, 29))	('-1154G>A', 'Mutation', 'rs1570360', (35, 43))	('-1154460C>T', 'Mutation', 'c.-1154460C>T', (4, 15))	('regulate', 'Reg', (103, 111))
557246	27729640	However, the effect of VEGF gene -460C>T SNP (rs833061) and -1154G>A SNP (rs1570360) on cSCC risk and prognosis remains unclear.	('cSCC', 'Phenotype', 'HP:0006739', (88, 92))	('rs1570360', 'Mutation', 'rs1570360', (74, 83))	('VEGF', 'Gene', (23, 27))	('rs1570360', 'Var', (74, 83))	('cSCC', 'Disease', (88, 92))	('-460C>T', 'Mutation', 'rs833061', (33, 40))	('rs833061', 'Var', (46, 54))	('rs833061', 'Mutation', 'rs833061', (46, 54))	('-1154G>A', 'Mutation', 'rs1570360', (60, 68))	('VEGF', 'Gene', '7422', (23, 27))
557247	27729640	In the current study, the -460C>T SNP (rs833061) and -1154G>A SNP (rs1570360) within the VEGF gene were detected in cSCC patients; a regular follow-up was conducted for all the patients.	('rs833061', 'Var', (39, 47))	('detected', 'Reg', (104, 112))	('rs833061', 'Mutation', 'rs833061', (39, 47))	('VEGF', 'Gene', '7422', (89, 93))	('rs1570360', 'Mutation', 'rs1570360', (67, 76))	('patients', 'Species', '9606', (177, 185))	('cSCC', 'Phenotype', 'HP:0006739', (116, 120))	('rs1570360', 'Var', (67, 76))	('-460C>T', 'Mutation', 'rs833061', (26, 33))	('cSCC', 'Disease', (116, 120))	('VEGF', 'Gene', (89, 93))	('-1154G>A', 'Mutation', 'rs1570360', (53, 61))	('patients', 'Species', '9606', (121, 129))
557274	27729640	The genotype distribution of VEGF-460C>T and VEGF-1154 G>A showed no significant correlation with age, sex, or lymph node metastasis (all P>0.05) (Table 2).	('VEGF-1154', 'Gene', (45, 54))	('lymph node metastasis', 'Disease', (111, 132))	('VEGF-460C>T', 'Var', (29, 40))	('lymph node metastasis', 'Disease', 'MESH:D009362', (111, 132))
557283	27729640	For VEGF-460C>T SNP, the mean survival time of cSCC patients with CC, CT, and TT genotype were 28.92, 53.54, and 58.75 months, respectively.	('cSCC', 'Phenotype', 'HP:0006739', (47, 51))	('VEGF-460C>T SNP', 'Var', (4, 19))	('CT', 'Chemical', 'MESH:D002251', (70, 72))	('cSCC', 'Disease', (47, 51))	('patients', 'Species', '9606', (52, 60))
557285	27729640	For VEGF-1154 G>A SNP, the mean survival time of cSCC patients with GG, GA, and AA genotypes were 41.19, 36.41, and 23.88 months, respectively; compared to the GG and GA genotypes, the AA genotype had a significant correlation with decreased overall survival time (P=0.009, Figure 4).	('cSCC', 'Disease', (49, 53))	('overall survival', 'MPA', (242, 258))	('patients', 'Species', '9606', (54, 62))	('GA', 'Chemical', 'MESH:D005708', (72, 74))	('VEGF-1154 G>A', 'Var', (4, 17))	('cSCC', 'Phenotype', 'HP:0006739', (49, 53))	('GA', 'Chemical', 'MESH:D005708', (167, 169))	('decreased', 'NegReg', (232, 241))
557295	27729640	Therefore, we can reason that there was a much lower cSCC risk for individuals with the CT heterozygote genotype in their VEGF-460 C>T region, indicating that the VEGF-460 C>T polymorphism could act as a candidate genetic biomarker in cSCC patients.	('lower', 'NegReg', (47, 52))	('CT', 'Chemical', 'MESH:D002251', (88, 90))	('cSCC', 'Phenotype', 'HP:0006739', (235, 239))	('cSCC', 'Phenotype', 'HP:0006739', (53, 57))	('patients', 'Species', '9606', (240, 248))	('cSCC', 'Disease', (53, 57))	('VEGF-460', 'Gene', (122, 130))	('VEGF-460', 'Var', (163, 171))
557297	27729640	However, there were several studies concerning VEGF-460 C>T polymorphism in other cancers.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('cancers', 'Phenotype', 'HP:0002664', (82, 89))	('cancers', 'Disease', (82, 89))	('VEGF-460', 'Gene', (47, 55))	('cancers', 'Disease', 'MESH:D009369', (82, 89))	('C>T polymorphism', 'Var', (56, 72))
557305	27729640	The results demonstrate that the TT genotype of -460 C>T is a protective factor in comparison to genotypes of CT and CC, positively affecting the survival time of cSCC patients (P<0.001).	('of -460 C>T', 'Var', (45, 56))	('cSCC', 'Disease', (163, 167))	('-460 C>T', 'Mutation', 'rs833061', (48, 56))	('CT', 'Chemical', 'MESH:D002251', (110, 112))	('patients', 'Species', '9606', (168, 176))	('survival time', 'CPA', (146, 159))	('affecting', 'Reg', (132, 141))	('cSCC', 'Phenotype', 'HP:0006739', (163, 167))
557309	27729640	Other studies revealed the -1154 GG genotype to be an adverse survival factor in colorectal cancer, but it was associated with a higher overall survival of the 1154 A allele in advanced breast cancer.	('colorectal cancer', 'Disease', (81, 98))	('-1154 GG', 'Var', (27, 35))	('1154 A', 'Var', (160, 166))	('higher', 'PosReg', (129, 135))	('breast cancer', 'Disease', 'MESH:D001943', (186, 199))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('colorectal cancer', 'Disease', 'MESH:D015179', (81, 98))	('breast cancer', 'Disease', (186, 199))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('breast cancer', 'Phenotype', 'HP:0003002', (186, 199))	('colorectal cancer', 'Phenotype', 'HP:0003003', (81, 98))
557316	27356570	The DEGs in the lung squamous cell carcinoma group were enriched in the following three pathways: Hsa04110, Cell cycle; hsa03030, DNA replication; and hsa03430, mismatch repair.	('hsa03030', 'Var', (120, 128))	('lung squamous cell carcinoma', 'Disease', (16, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (35, 44))	('mismatch repair', 'CPA', (161, 176))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (16, 44))	('hsa03430', 'Var', (151, 159))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (16, 44))	('DNA replication', 'CPA', (130, 145))	('Hsa04110', 'Var', (98, 106))	('Cell cycle', 'CPA', (108, 118))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (21, 44))
557365	27356570	DVL3 has also been identified as a candidate driver for genomic amplification of chromosome 3q26-29 in lung squamous cell carcinoma of the lung.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (108, 131))	('genomic amplification', 'Var', (56, 77))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (103, 131))	('lung squamous cell carcinoma of the lung', 'Disease', 'MESH:D055752', (103, 143))	('DVL3', 'Gene', (0, 4))	('lung squamous cell carcinoma of the lung', 'Disease', (103, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('carcinoma of the lung', 'Phenotype', 'HP:0100526', (122, 143))	('DVL3', 'Gene', '1857', (0, 4))
557366	27356570	Knocking down of DVL3 protein can lead to cell growth inhibition Therefore, DVL3 may be considered a reliable biomarker to distinguish between these two types of lung cancer.	('Knocking down', 'Var', (0, 13))	('DVL3', 'Gene', '1857', (76, 80))	('lung cancer', 'Disease', 'MESH:D008175', (162, 173))	('DVL3', 'Gene', (17, 21))	('cell growth inhibition', 'CPA', (42, 64))	('lung cancer', 'Disease', (162, 173))	('protein', 'Protein', (22, 29))	('lung cancer', 'Phenotype', 'HP:0100526', (162, 173))	('DVL3', 'Gene', (76, 80))	('DVL3', 'Gene', '1857', (17, 21))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))
557374	27356570	Sequist et al reported that a potent inhibitor of HSP90, IPI-504, exerts clinical activity in patients with NSCLC, particularly among patients with anaplastic lymphoma kinase gene rearrangements.	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (148, 167))	('patients', 'Species', '9606', (94, 102))	('HSP90', 'Gene', '3320', (50, 55))	('anaplastic lymphoma', 'Disease', (148, 167))	('patients', 'Species', '9606', (134, 142))	('NSCLC', 'Disease', (108, 113))	('rearrangements', 'Var', (180, 194))	('anaplastic lymphoma', 'Disease', 'MESH:D017728', (148, 167))	('NSCLC', 'Disease', 'MESH:D002289', (108, 113))	('lymphoma', 'Phenotype', 'HP:0002665', (159, 167))	('IPI-504', 'Chemical', 'MESH:C112765', (57, 64))	('HSP90', 'Gene', (50, 55))
557376	27356570	CDK2 is a member of the cyclin-dependent kinases, and inhibition of CDK2 has been reported to induce anaphase catastrophe and lead to apoptosis in NSCLC.	('NSCLC', 'Disease', (147, 152))	('inhibition', 'Var', (54, 64))	('anaphase catastrophe', 'CPA', (101, 121))	('NSCLC', 'Disease', 'MESH:D002289', (147, 152))	('CDK2', 'Gene', '1017', (68, 72))	('CDK2', 'Gene', (0, 4))	('apoptosis', 'CPA', (134, 143))	('lead to', 'Reg', (126, 133))	('CDK2', 'Gene', '1017', (0, 4))	('induce', 'PosReg', (94, 100))	('CDK2', 'Gene', (68, 72))
557378	27356570	Furthermore, Abrams et al evaluated the activity of the indolinone kinase inhibitor SU11248 against the receptor tyrosine kinase KIT in SCLC; the results suggested that SU11248 may have clinical potential for the treatment of SCLC via direct KIT-mediated antitumor activity.	('SU11248', 'Var', (169, 176))	('tumor', 'Disease', 'MESH:D009369', (259, 264))	('tumor', 'Phenotype', 'HP:0002664', (259, 264))	('SU11248', 'Chemical', 'MESH:D000077210', (169, 176))	('SCLC', 'Gene', '7864', (226, 230))	('tumor', 'Disease', (259, 264))	('SCLC', 'Gene', '7864', (136, 140))	('SCLC', 'Gene', (136, 140))	('SU11248', 'Chemical', 'MESH:D000077210', (84, 91))	('SCLC', 'Gene', (226, 230))
557494	32356485	Downregulation of MMP11 enhanced bladder cancer cell migration and invasion in BC cells, indicating it might be a good prognostic marker for the survival of patients with bladder cancer.	('MMP11', 'Gene', (18, 23))	('bladder cancer', 'Disease', 'MESH:D001749', (33, 47))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('bladder cancer', 'Phenotype', 'HP:0009725', (171, 185))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('invasion', 'CPA', (67, 75))	('bladder cancer', 'Disease', (33, 47))	('MMP11', 'Gene', '4320', (18, 23))	('bladder cancer', 'Disease', 'MESH:D001749', (171, 185))	('Downregulation', 'Var', (0, 14))	('bladder cancer', 'Disease', (171, 185))	('patients', 'Species', '9606', (157, 165))	('enhanced', 'PosReg', (24, 32))	('bladder cancer', 'Phenotype', 'HP:0009725', (33, 47))
557524	32356485	The expression of miR-139-3p in ESCA/ESCC was significantly upregulated in GSE114110, GSE112264, and GSE113486, whereas no statistical significance was observed in the GSE112840 data set (Figure 3D).	('GSE112264', 'Var', (86, 95))	('GSE', 'Chemical', '-', (86, 89))	('miR-139-3p', 'Gene', (18, 28))	('upregulated', 'PosReg', (60, 71))	('GSE', 'Chemical', '-', (101, 104))	('expression', 'MPA', (4, 14))	('GSE113486', 'Var', (101, 110))	('GSE114110', 'Var', (75, 84))	('GSE', 'Chemical', '-', (75, 78))	('ESCA', 'Phenotype', 'HP:0011459', (32, 36))	('GSE', 'Chemical', '-', (168, 171))	('miR-139-3p', 'Gene', '406931', (18, 28))
557571	31905960	PIK3CA Gene Mutations in Solid Malignancies: Association with Clinicopathological Parameters and Prognosis Phosphoinositide kinases (PIKs) are a group of lipid kinases that are important upstream activators of various significant signaling pathways.	('Solid Malignancies', 'Disease', (25, 43))	('PIK3CA', 'Gene', '5290', (0, 6))	('Mutations', 'Var', (12, 21))	('PIK3CA', 'Gene', (0, 6))
557572	31905960	Hyperactivation of the PI3K/AKT/mTOR pathways:either via mutations or genomic amplification:confers key oncogenic activity, essential for the development and progression of several solid tumors.	('oncogenic', 'CPA', (104, 113))	('mTOR', 'Gene', '2475', (32, 36))	('tumor', 'Phenotype', 'HP:0002664', (187, 192))	('solid tumors', 'Disease', (181, 193))	('mTOR', 'Gene', (32, 36))	('mutations', 'Var', (57, 66))	('solid tumors', 'Disease', 'MESH:D009369', (181, 193))	('tumors', 'Phenotype', 'HP:0002664', (187, 193))
557573	31905960	Alterations in the PIK3CA gene are associated with poor prognosis of solid malignancies.	('PIK3CA', 'Gene', (19, 25))	('Alterations', 'Var', (0, 11))	('associated', 'Reg', (35, 45))	('solid malignancies', 'Disease', (69, 87))	('solid malignancies', 'Disease', 'MESH:D018250', (69, 87))
557574	31905960	Although the literature reports contradictory prognostic values of PIK3CA in aggressive cancers, most of the available data highlight the important role of PIK3CA mutation in mediating tumorigenesis via increased signaling of the PI3K/AKT/mTOR survival pathway.	('tumor', 'Disease', (185, 190))	('cancers', 'Phenotype', 'HP:0002664', (88, 95))	('signaling', 'MPA', (213, 222))	('mTOR', 'Gene', (239, 243))	('mTOR', 'Gene', '2475', (239, 243))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('aggressive cancers', 'Disease', 'MESH:D009369', (77, 95))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('aggressive cancers', 'Disease', (77, 95))	('mutation', 'Var', (163, 171))	('PIK3CA', 'Gene', (156, 162))	('increased', 'PosReg', (203, 212))
557576	31905960	This article reviews the role of PIK3CA mutations and inhibitors of PI3K/AKT/mTOR pathways in major cancer types and examines its association with clinicopathological parameters and prognosis.	('cancer', 'Phenotype', 'HP:0002664', (100, 106))	('mTOR', 'Gene', '2475', (77, 81))	('mutations', 'Var', (40, 49))	('mTOR', 'Gene', (77, 81))	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('PIK3CA', 'Gene', (33, 39))	('association', 'Interaction', (130, 141))
557579	31905960	PI3K is activated by a growth factor bound receptor tyrosine kinase (RTK), and once activated, it phosphorylates other signaling molecules, in a substrate specific manner, resulting in downstream conduction of chemical signals.	('PI3K', 'Var', (0, 4))	('receptor tyrosine kinase', 'Gene', '5979', (43, 67))	('resulting in', 'Reg', (172, 184))	('conduction of chemical signals', 'MPA', (196, 226))	('RTK', 'Gene', '5979', (69, 72))	('receptor tyrosine kinase', 'Gene', (43, 67))	('RTK', 'Gene', (69, 72))
557583	31905960	The present review discusses the association of mutations in the PIK3CA p110a catalytic subunit of PI3K due to the increasing reports of the altered protein product of this gene being involved in several human cancer types.	('cancer', 'Phenotype', 'HP:0002664', (210, 216))	('involved', 'Reg', (184, 192))	('PI3K', 'Gene', (99, 103))	('p110a', 'Gene', '5290', (72, 77))	('PIK3CA', 'Gene', (65, 71))	('p110a', 'Gene', (72, 77))	('cancer', 'Disease', 'MESH:D009369', (210, 216))	('human', 'Species', '9606', (204, 209))	('cancer', 'Disease', (210, 216))	('mutations', 'Var', (48, 57))
557584	31905960	Gene insertions, deletions, and somatic missense mutations in this gene have been reported in many human cancer types, like colon, breast, brain, liver, stomach, and lung cancers.	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('cancer', 'Disease', (105, 111))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('colon', 'Disease', (124, 129))	('reported', 'Reg', (82, 90))	('missense mutations', 'Var', (40, 58))	('stomach', 'Disease', (153, 160))	('breast', 'Disease', (131, 137))	('liver', 'Disease', (146, 151))	('lung cancers', 'Disease', 'MESH:D008175', (166, 178))	('deletions', 'Var', (17, 26))	('lung cancers', 'Disease', (166, 178))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('cancer', 'Disease', (171, 177))	('lung cancer', 'Phenotype', 'HP:0100526', (166, 177))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('lung cancers', 'Phenotype', 'HP:0100526', (166, 178))	('brain', 'Disease', (139, 144))	('cancers', 'Phenotype', 'HP:0002664', (171, 178))	('human', 'Species', '9606', (99, 104))
557585	31905960	were the first to show the association of PI3Ks, especially its subunit p110alpha, with cancer.	('p110alpha', 'Gene', (72, 81))	('cancer', 'Disease', (88, 94))	('p110alpha', 'Gene', '5290', (72, 81))	('cancer', 'Disease', 'MESH:D009369', (88, 94))	('association', 'Interaction', (27, 38))	('PI3Ks', 'Var', (42, 47))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))
557589	31905960	In these tumors, the PTEN mutation results in the constitutive activation of the PI3K pathway.	('mutation', 'Var', (26, 34))	('tumor', 'Phenotype', 'HP:0002664', (9, 14))	('PTEN', 'Gene', (21, 25))	('tumors', 'Phenotype', 'HP:0002664', (9, 15))	('PI3K pathway', 'Pathway', (81, 93))	('tumors', 'Disease', (9, 15))	('PTEN', 'Gene', '5728', (21, 25))	('tumors', 'Disease', 'MESH:D009369', (9, 15))	('activation', 'PosReg', (63, 73))
557591	31905960	Mutations in the regulatory subunit of PI3K (p85) have been reported in ovarian and colon cancers.	('colon cancer', 'Phenotype', 'HP:0003003', (84, 96))	('ovarian', 'Disease', 'MESH:D010049', (72, 79))	('p85', 'Gene', '5295', (45, 48))	('ovarian', 'Disease', (72, 79))	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('colon cancers', 'Disease', (84, 97))	('p85', 'Gene', (45, 48))	('colon cancers', 'Phenotype', 'HP:0003003', (84, 97))	('Mutations', 'Var', (0, 9))	('cancers', 'Phenotype', 'HP:0002664', (90, 97))	('colon cancers', 'Disease', 'MESH:D015179', (84, 97))	('reported', 'Reg', (60, 68))
557592	31905960	A recent study demonstrated 13% mutational frequency of PIK3CA in solid tumors.	('solid tumors', 'Disease', 'MESH:D009369', (66, 78))	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('PIK3CA', 'Gene', (56, 62))	('solid tumors', 'Disease', (66, 78))	('mutational', 'Var', (32, 42))
557594	31905960	The present review article discussed the role of PIK3CA mutations in various types of solid malignancies in terms of prevalence, potential correlation with clinicopathological parameters, and role in PI3K-targeted inhibition.	('PIK3CA', 'Gene', (49, 55))	('mutations', 'Var', (56, 65))	('solid malignancies', 'Disease', 'MESH:D018250', (86, 104))	('solid malignancies', 'Disease', (86, 104))
557595	31905960	Missense mutations in PIK3CA are commonly found in several types of breast cancers.	('breast cancers', 'Disease', 'MESH:D001943', (68, 82))	('cancers', 'Phenotype', 'HP:0002664', (75, 82))	('breast cancers', 'Disease', (68, 82))	('breast cancer', 'Phenotype', 'HP:0003002', (68, 81))	('found', 'Reg', (42, 47))	('breast cancers', 'Phenotype', 'HP:0003002', (68, 82))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('PIK3CA', 'Gene', (22, 28))	('Missense mutations', 'Var', (0, 18))
557596	31905960	The PIK3CA mutations in breast cancer were initially reported by Samuels et al..	('mutations', 'Var', (11, 20))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('breast cancer', 'Disease', 'MESH:D001943', (24, 37))	('breast cancer', 'Phenotype', 'HP:0003002', (24, 37))	('PIK3CA', 'Gene', (4, 10))	('breast cancer', 'Disease', (24, 37))
557597	31905960	In their study, only one out of 12 patients had mutation in PIK3CA.	('mutation', 'Var', (48, 56))	('PIK3CA', 'Gene', (60, 66))	('patients', 'Species', '9606', (35, 43))
557600	31905960	It is now believed that mutations of PIK3CA are found in 20-30% of all human breast cancers.	('breast cancers', 'Disease', 'MESH:D001943', (77, 91))	('breast cancers', 'Disease', (77, 91))	('human', 'Species', '9606', (71, 76))	('breast cancer', 'Phenotype', 'HP:0003002', (77, 90))	('cancers', 'Phenotype', 'HP:0002664', (84, 91))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('found', 'Reg', (48, 53))	('breast cancers', 'Phenotype', 'HP:0003002', (77, 91))	('mutations', 'Var', (24, 33))	('PIK3CA', 'Gene', (37, 43))
557601	31905960	Several studies have evaluated the correlation of PIK3CA mutations with clinicopathological parameters such as estrogen receptor (ER)/progesterone receptor (PR) positivity, the presence of lymph node metastases, and response to therapy in breast cancers (Table 1).	('breast cancer', 'Phenotype', 'HP:0003002', (239, 252))	('breast cancers', 'Disease', 'MESH:D001943', (239, 253))	('cancers', 'Phenotype', 'HP:0002664', (246, 253))	('breast cancers', 'Disease', (239, 253))	('ER', 'Gene', '2099', (130, 132))	('metastases', 'Disease', (200, 210))	('metastases', 'Disease', 'MESH:D009362', (200, 210))	('mutations', 'Var', (57, 66))	('estrogen receptor', 'Gene', (111, 128))	('progesterone receptor', 'Gene', '5241', (134, 155))	('cancer', 'Phenotype', 'HP:0002664', (246, 252))	('estrogen receptor', 'Gene', '2099', (111, 128))	('breast cancers', 'Phenotype', 'HP:0003002', (239, 253))	('progesterone receptor', 'Gene', (134, 155))	('PIK3CA', 'Gene', (50, 56))
557602	31905960	were the first to report a definite clinicopathological correlate of PIK3CA mutations in breast cancer.	('mutations', 'Var', (76, 85))	('breast cancer', 'Disease', 'MESH:D001943', (89, 102))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('breast cancer', 'Disease', (89, 102))	('breast cancer', 'Phenotype', 'HP:0003002', (89, 102))	('PIK3CA', 'Gene', (69, 75))
557603	31905960	They reported that PIK3CA mutations were frequently seen in tumors with normally expressed PTEN, ER, PR, and ERBB2 genes, as well as in tumors with nodal involvement.	('tumors', 'Disease', (136, 142))	('PIK3CA', 'Gene', (19, 25))	('tumors', 'Disease', 'MESH:D009369', (136, 142))	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('ERBB2', 'Gene', '2064', (109, 114))	('seen', 'Reg', (52, 56))	('ERBB2', 'Gene', (109, 114))	('tumors', 'Disease', 'MESH:D009369', (60, 66))	('mutations', 'Var', (26, 35))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('ER', 'Gene', '2099', (97, 99))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('PTEN', 'Gene', (91, 95))	('PTEN', 'Gene', '5728', (91, 95))	('ER', 'Gene', '2099', (109, 111))	('tumors', 'Disease', (60, 66))
557604	31905960	Studies demonstrated that mutations in PIK3CA were more common in hormone receptor-positive and HER2-positive breast cancers.	('common', 'Reg', (56, 62))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('hormone receptor', 'Gene', (66, 82))	('breast cancers', 'Phenotype', 'HP:0003002', (110, 124))	('hormone receptor', 'Gene', '3164', (66, 82))	('mutations', 'Var', (26, 35))	('breast cancers', 'Disease', 'MESH:D001943', (110, 124))	('breast cancers', 'Disease', (110, 124))	('HER2', 'Gene', (96, 100))	('HER2', 'Gene', '2064', (96, 100))	('cancers', 'Phenotype', 'HP:0002664', (117, 124))	('PIK3CA', 'Gene', (39, 45))	('breast cancer', 'Phenotype', 'HP:0003002', (110, 123))
557605	31905960	In a recent study by Wu et al., it was shown that PIK3CA mutations were positively associated with ER-positive, PR-positive, and low Ki67 labeling index, and negatively correlated with the triple-negative breast cancer subtype.	('breast cancer', 'Phenotype', 'HP:0003002', (205, 218))	('mutations', 'Var', (57, 66))	('associated', 'Reg', (83, 93))	('breast cancer', 'Disease', 'MESH:D001943', (205, 218))	('ER', 'Gene', '2099', (99, 101))	('PIK3CA', 'Gene', (50, 56))	('breast cancer', 'Disease', (205, 218))	('negatively', 'NegReg', (158, 168))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))
557606	31905960	PIK3CA mutations were not associated with age at diagnosis, tumor stage, lymph node status, tumor size, or HER2 status.	('HER2', 'Gene', '2064', (107, 111))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('PIK3CA', 'Gene', (0, 6))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Disease', (92, 97))	('tumor', 'Disease', (60, 65))	('HER2', 'Gene', (107, 111))	('mutations', 'Var', (7, 16))
557607	31905960	demonstrated that PIK3CA mutation significantly reduced disease-free survival (DFS) compared to wild-type (WT) PIK3CA in patients with ER-positive tumors.	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('tumors', 'Disease', (147, 153))	('tumors', 'Phenotype', 'HP:0002664', (147, 153))	('reduced', 'NegReg', (48, 55))	('mutation', 'Var', (25, 33))	('ER', 'Gene', '2099', (135, 137))	('tumors', 'Disease', 'MESH:D009369', (147, 153))	('PIK3CA', 'Gene', (18, 24))	('disease-free survival', 'CPA', (56, 77))	('patients', 'Species', '9606', (121, 129))
557608	31905960	Subsequent studies reported that PIK3CA mutations were highly associated with the morphology, race, ER status, PR status, and HER2 status in breast cancer.	('ER', 'Gene', '2099', (100, 102))	('associated', 'Reg', (62, 72))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('breast cancer', 'Disease', 'MESH:D001943', (141, 154))	('mutations', 'Var', (40, 49))	('breast cancer', 'Disease', (141, 154))	('HER2', 'Gene', (126, 130))	('HER2', 'Gene', '2064', (126, 130))	('breast cancer', 'Phenotype', 'HP:0003002', (141, 154))	('PIK3CA', 'Gene', (33, 39))	('ER', 'Gene', '2099', (127, 129))
557609	31905960	Recently, co-mutation of TP53 and PIK3CA was found to be associated with poor survival in residual disease after neoadjuvant chemotherapy in breast cancer.	('PIK3CA', 'Gene', (34, 40))	('TP53', 'Gene', (25, 29))	('co-mutation', 'Var', (10, 21))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('TP53', 'Gene', '7157', (25, 29))	('breast cancer', 'Disease', 'MESH:D001943', (141, 154))	('breast cancer', 'Disease', (141, 154))	('breast cancer', 'Phenotype', 'HP:0003002', (141, 154))	('poor', 'NegReg', (73, 77))	('residual disease', 'Disease', (90, 106))	('associated', 'Reg', (57, 67))
557610	31905960	In addition, studies have reported exon 9 mutations are independently associated with early recurrence and death, whereas exon 20 PIK3CA mutations are associated with optimal prognosis.	('PIK3CA', 'Gene', (130, 136))	('exon 9 mutations', 'Var', (35, 51))	('associated', 'Reg', (70, 80))	('death', 'Disease', 'MESH:D003643', (107, 112))	('early recurrence', 'CPA', (86, 102))	('death', 'Disease', (107, 112))	('mutations', 'Var', (42, 51))
557612	31905960	Another important clinicopathological correlate of PIK3CA mutation is that they are more frequently found in lobular breast cancers as compared to ductal breast cancers.	('breast cancers', 'Phenotype', 'HP:0003002', (154, 168))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('breast cancers', 'Disease', 'MESH:D001943', (154, 168))	('breast cancers', 'Phenotype', 'HP:0003002', (117, 131))	('breast cancers', 'Disease', (154, 168))	('breast cancers', 'Disease', 'MESH:D001943', (117, 131))	('breast cancer', 'Phenotype', 'HP:0003002', (154, 167))	('breast cancers', 'Disease', (117, 131))	('cancer', 'Phenotype', 'HP:0002664', (124, 130))	('mutation', 'Var', (58, 66))	('PIK3CA', 'Gene', (51, 57))	('cancers', 'Phenotype', 'HP:0002664', (161, 168))	('breast cancer', 'Phenotype', 'HP:0003002', (117, 130))	('cancers', 'Phenotype', 'HP:0002664', (124, 131))	('found', 'Reg', (100, 105))
557613	31905960	reported that this observation was specific for patients with exon 9 mutations.	('exon 9 mutations', 'Var', (62, 78))	('mutations', 'Var', (69, 78))	('patients', 'Species', '9606', (48, 56))
557614	31905960	PIK3CA mutations have also been correlated with response to therapy in breast cancer.	('breast cancer', 'Disease', (71, 84))	('breast cancer', 'Phenotype', 'HP:0003002', (71, 84))	('correlated', 'Reg', (32, 42))	('PIK3CA', 'Gene', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('breast cancer', 'Disease', 'MESH:D001943', (71, 84))	('mutations', 'Var', (7, 16))
557615	31905960	reported that mutations in PIK3CA make breast cancers resistant to antibody-based therapeutic trastuzumab.	('breast cancer', 'Phenotype', 'HP:0003002', (39, 52))	('cancers', 'Phenotype', 'HP:0002664', (46, 53))	('PIK3CA', 'Gene', (27, 33))	('resistant', 'MPA', (54, 63))	('trastuzumab', 'Chemical', 'MESH:D000068878', (94, 105))	('breast cancers', 'Phenotype', 'HP:0003002', (39, 53))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('breast cancers', 'Disease', 'MESH:D001943', (39, 53))	('breast cancers', 'Disease', (39, 53))	('mutations', 'Var', (14, 23))
557616	31905960	have suggested that over activation of PIK3CA due to oncogenic mutations rendered breast cancer cells refractive to the anti-HER2 agent Lapatinib.	('mutations', 'Var', (63, 72))	('breast cancer', 'Disease', (82, 95))	('HER2', 'Gene', (125, 129))	('breast cancer', 'Phenotype', 'HP:0003002', (82, 95))	('HER2', 'Gene', '2064', (125, 129))	('breast cancer', 'Disease', 'MESH:D001943', (82, 95))	('Lapatinib', 'Chemical', 'MESH:D000077341', (136, 145))	('PIK3CA', 'Gene', (39, 45))	('over activation', 'PosReg', (20, 35))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
557617	31905960	found no association between PIK3CA mutations and a response to anthracyline and paclitaxel-based chemotherapy.	('PIK3CA', 'Gene', (29, 35))	('paclitaxel', 'Chemical', 'MESH:D017239', (81, 91))	('anthracyline', 'Chemical', '-', (64, 76))	('mutations', 'Var', (36, 45))
557619	31905960	Mutations in the PIK3CA have been reported to be associated with resistance to several antitumor agents such as paclitaxel, tamoxifen, and trastuzumab.	('PIK3CA', 'Gene', (17, 23))	('associated', 'Reg', (49, 59))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('Mutations', 'Var', (0, 9))	('paclitaxel', 'Chemical', 'MESH:D017239', (112, 122))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('trastuzumab', 'Chemical', 'MESH:D000068878', (139, 150))	('tumor', 'Disease', (91, 96))	('tamoxifen', 'Chemical', 'MESH:D013629', (124, 133))	('resistance', 'MPA', (65, 75))
557620	31905960	It has been shown that PI3K and ER pathways have a synergistic effect on tumor progression.	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Disease', (73, 78))	('ER', 'Gene', '2099', (32, 34))	('PI3K', 'Var', (23, 27))
557621	31905960	Recently, it was shown that Everolimus treatment along with chemotherapy suppressed PIK3CA, ESR1, and GATA3 gene mutation.	('mutation', 'Var', (113, 121))	('Everolimus', 'Chemical', 'MESH:D000068338', (28, 38))	('ESR1', 'Gene', '2099', (92, 96))	('GATA3', 'Gene', (102, 107))	('PIK3CA', 'Gene', (84, 90))	('suppressed', 'NegReg', (73, 83))	('ESR1', 'Gene', (92, 96))	('GATA3', 'Gene', '2625', (102, 107))
557623	31905960	A recent study reported PIK3CA mutation frequency of 14% in Belgian colorectal cancer patients.	('PIK3CA', 'Gene', (24, 30))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('Belgian colorectal cancer', 'Disease', (60, 85))	('Belgian colorectal cancer', 'Disease', 'MESH:D015179', (60, 85))	('mutation', 'Var', (31, 39))	('colorectal cancer', 'Phenotype', 'HP:0003003', (68, 85))	('patients', 'Species', '9606', (86, 94))
557625	31905960	Another study also supported this finding but showed no correlation of PIK3CA gene mutations with clinical parameters such as gender, age, cancer stage, or differentiation.	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('mutations', 'Var', (83, 92))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('PIK3CA', 'Gene', (71, 77))	('cancer', 'Disease', (139, 145))
557626	31905960	PIK3CA mutations were reported to be more prevalent in the "protruded-type" of colon cancer as compared to the "flat-type" colon cancers.	('flat-type" colon cancers', 'Disease', (112, 136))	('prevalent', 'Reg', (42, 51))	('colon cancer', 'Disease', (79, 91))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('flat-type" colon cancers', 'Disease', 'MESH:D015179', (112, 136))	('colon cancer', 'Phenotype', 'HP:0003003', (123, 135))	('cancers', 'Phenotype', 'HP:0002664', (129, 136))	('colon cancer', 'Phenotype', 'HP:0003003', (79, 91))	('PIK3CA', 'Gene', (0, 6))	('colon cancer', 'Disease', 'MESH:D015179', (123, 135))	('colon cancer', 'Disease', 'MESH:D015179', (79, 91))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))	('colon cancers', 'Phenotype', 'HP:0003003', (123, 136))	('mutations', 'Var', (7, 16))
557627	31905960	Family history or inherited predisposition did not have any effect on the frequency of PIK3CA gene mutations in colorectal cancer.	('colorectal cancer', 'Disease', (112, 129))	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('colorectal cancer', 'Disease', 'MESH:D015179', (112, 129))	('mutations', 'Var', (99, 108))	('colorectal cancer', 'Phenotype', 'HP:0003003', (112, 129))	('PIK3CA', 'Gene', (87, 93))
557629	31905960	The mutational frequency of PIK3CA in colon cancers shows gender bias with more frequency in the females as compared to the males.	('colon cancers', 'Phenotype', 'HP:0003003', (38, 51))	('cancers', 'Phenotype', 'HP:0002664', (44, 51))	('colon cancers', 'Disease', 'MESH:D015179', (38, 51))	('PIK3CA', 'Gene', (28, 34))	('colon cancer', 'Phenotype', 'HP:0003003', (38, 50))	('colon cancers', 'Disease', (38, 51))	('mutational', 'Var', (4, 14))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
557630	31905960	However, a recent study did not find any significant difference between male and female colon cancer patients with respect to frequency of PIK3CA mutations.	('patients', 'Species', '9606', (101, 109))	('colon cancer', 'Phenotype', 'HP:0003003', (88, 100))	('mutations', 'Var', (146, 155))	('colon cancer', 'Disease', 'MESH:D015179', (88, 100))	('colon cancer', 'Disease', (88, 100))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('PIK3CA', 'Gene', (139, 145))
557631	31905960	All the cases with PIK3CA mutations in poorly differentiated clusters had nodal metastases, high pathological TNM stage, and lymphatic invasion.	('PIK3CA', 'Gene', (19, 25))	('lymphatic invasion', 'CPA', (125, 143))	('metastases', 'Disease', (80, 90))	('metastases', 'Disease', 'MESH:D009362', (80, 90))	('TNM', 'Gene', '10178', (110, 113))	('mutations', 'Var', (26, 35))	('TNM', 'Gene', (110, 113))
557632	31905960	A recent study highlighted that PIK3CA mutation is associated with decreased risk of peritoneal metastases in metastatic colorectal cancer.	('mutation', 'Var', (39, 47))	('metastases', 'Disease', 'MESH:D009362', (96, 106))	('colorectal cancer', 'Phenotype', 'HP:0003003', (121, 138))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('colorectal cancer', 'Disease', (121, 138))	('decreased', 'NegReg', (67, 76))	('colorectal cancer', 'Disease', 'MESH:D015179', (121, 138))	('metastases', 'Disease', (96, 106))	('PIK3CA', 'Gene', (32, 38))
557634	31905960	Similarly, PIK3CA amplifications were associated with the occurrence of diffuse-type and poorly differentiated gastric cancers and peritoneal recurrence as compared to those without PIK3CA amplifications.	('gastric cancers', 'Disease', (111, 126))	('gastric cancers', 'Phenotype', 'HP:0012126', (111, 126))	('peritoneal recurrence', 'Disease', (131, 152))	('associated with', 'Reg', (38, 53))	('cancers', 'Phenotype', 'HP:0002664', (119, 126))	('PIK3CA', 'Gene', (11, 17))	('diffuse-type', 'Disease', (72, 84))	('amplifications', 'Var', (18, 32))	('poorly', 'Disease', (89, 95))	('gastric cancers', 'Disease', 'MESH:D013274', (111, 126))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
557635	31905960	It was also demonstrated that PIK3CA mutations conferred resistance to colon cancer cells against anti-EGFR antibodies.	('PIK3CA', 'Gene', (30, 36))	('EGFR', 'Gene', '1956', (103, 107))	('colon cancer', 'Phenotype', 'HP:0003003', (71, 83))	('colon cancer', 'Disease', 'MESH:D015179', (71, 83))	('EGFR', 'Gene', (103, 107))	('resistance', 'MPA', (57, 67))	('mutations', 'Var', (37, 46))	('colon cancer', 'Disease', (71, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))
557637	31905960	Furthermore, another study even reported PIK3CA mutation to be associated with good prognosis in patients with microsatellite stability (MSS) stage I-III colon cancer with a significantly increased five-year relapse-free interval in patients with PIK3CA-mutated MSS tumors vs. those with PIK3CA WT MSS tumors.	('PIK3CA-mutated', 'Var', (247, 261))	('tumor', 'Phenotype', 'HP:0002664', (302, 307))	('tumor', 'Phenotype', 'HP:0002664', (266, 271))	('tumors', 'Phenotype', 'HP:0002664', (302, 308))	('PIK3CA', 'Gene', (41, 47))	('colon cancer', 'Phenotype', 'HP:0003003', (154, 166))	('tumors', 'Disease', (302, 308))	('mutation', 'Var', (48, 56))	('patients', 'Species', '9606', (97, 105))	('tumors', 'Disease', 'MESH:D009369', (302, 308))	('colon cancer', 'Disease', 'MESH:D015179', (154, 166))	('patients', 'Species', '9606', (233, 241))	('tumors', 'Phenotype', 'HP:0002664', (266, 272))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('colon cancer', 'Disease', (154, 166))	('tumors', 'Disease', 'MESH:D009369', (266, 272))	('increased', 'PosReg', (188, 197))	('tumors', 'Disease', (266, 272))
557638	31905960	Interestingly, recent clinical trials have strongly highlighted that low-dose aspirin (100 mg/day) can act as therapy in colorectal cancer patients positive for PIK3CA mutations and who have undergone surgical resection in terms of reducing the risk of recurrence.	('patients', 'Species', '9606', (139, 147))	('aspirin', 'Chemical', 'MESH:D001241', (78, 85))	('colorectal cancer', 'Phenotype', 'HP:0003003', (121, 138))	('PIK3CA', 'Gene', (161, 167))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('positive', 'Reg', (148, 156))	('colorectal cancer', 'Disease', (121, 138))	('colorectal cancer', 'Disease', 'MESH:D015179', (121, 138))	('mutations', 'Var', (168, 177))
557639	31905960	PIK3CA gene amplifications have been reported in lung cancer.	('lung cancer', 'Disease', 'MESH:D008175', (49, 60))	('PIK3CA', 'Gene', (0, 6))	('lung cancer', 'Disease', (49, 60))	('lung cancer', 'Phenotype', 'HP:0100526', (49, 60))	('amplifications', 'Var', (12, 26))	('reported', 'Reg', (37, 45))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
557640	31905960	The frequency of PIK3CA gene mutation in lung cancer varies significantly.	('mutation', 'Var', (29, 37))	('PIK3CA', 'Gene', (17, 23))	('lung cancer', 'Disease', (41, 52))	('lung cancer', 'Phenotype', 'HP:0100526', (41, 52))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('lung cancer', 'Disease', 'MESH:D008175', (41, 52))
557641	31905960	reported a low frequency of PIK3CA mutations (4%) in lung cancer, with higher frequency seen in squamous cell carcinoma (7%) as compared to adenocarcinoma (2%).	('squamous cell carcinoma', 'Disease', (96, 119))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (96, 119))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('carcinoma', 'Phenotype', 'HP:0030731', (145, 154))	('carcinoma', 'Phenotype', 'HP:0030731', (110, 119))	('adenocarcinoma', 'Disease', (140, 154))	('PIK3CA', 'Gene', (28, 34))	('lung cancer', 'Disease', 'MESH:D008175', (53, 64))	('adenocarcinoma', 'Disease', 'MESH:D000230', (140, 154))	('lung cancer', 'Disease', (53, 64))	('lung cancer', 'Phenotype', 'HP:0100526', (53, 64))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (96, 119))	('mutations', 'Var', (35, 44))
557643	31905960	Kawano et al., for the first time, reported the amplification of mutant PIK3CA alleles in cancer cells.	('cancer', 'Phenotype', 'HP:0002664', (90, 96))	('mutant', 'Var', (65, 71))	('PIK3CA', 'Gene', (72, 78))	('amplification', 'MPA', (48, 61))	('cancer', 'Disease', (90, 96))	('cancer', 'Disease', 'MESH:D009369', (90, 96))
557644	31905960	PI3K pathway alterations have been identified in over 50% of lung squamous cell carcinoma cases.	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('lung squamous cell carcinoma', 'Disease', (61, 89))	('identified', 'Reg', (35, 45))	('PI3K pathway', 'Pathway', (0, 12))	('alterations', 'Var', (13, 24))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (66, 89))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (61, 89))
557645	31905960	However, a recent study in young lung adenocarcinoma patients demonstrated the absence of PIK3CA gene mutations.	('patients', 'Species', '9606', (53, 61))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (33, 52))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (33, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (43, 52))	('PIK3CA', 'Gene', (90, 96))	('absence', 'NegReg', (79, 86))	('mutations', 'Var', (102, 111))	('lung adenocarcinoma', 'Disease', (33, 52))
557647	31905960	The frequency of PIK3CA gene mutations was higher in metastatic lung adenocarcinoma than in primary tumors.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('primary tumors', 'Disease', 'MESH:D001932', (92, 106))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (64, 83))	('PIK3CA gene', 'Gene', (17, 28))	('higher', 'Reg', (43, 49))	('mutations', 'Var', (29, 38))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (64, 83))	('tumors', 'Phenotype', 'HP:0002664', (100, 106))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('lung adenocarcinoma', 'Disease', (64, 83))	('primary tumors', 'Disease', (92, 106))
557648	31905960	PIK3CA mutation was significantly associated with higher risk of lung failure in patients undergoing lung stereotactic body radiation therapy.	('associated', 'Reg', (34, 44))	('lung failure', 'Disease', 'MESH:D008171', (65, 77))	('patients', 'Species', '9606', (81, 89))	('PIK3CA', 'Gene', (0, 6))	('lung failure', 'Disease', (65, 77))	('mutation', 'Var', (7, 15))	('stereotactic body', 'Phenotype', 'HP:0000733', (106, 123))
557649	31905960	PIK3CA mutations were reported to be associated with invasive growth, vacuolar signs, and margin lobulation on chest CT. PIK3CA gene mutations were shown to be associated with metastases, poor prognosis, and shorter PFS times.	('PFS times', 'CPA', (216, 225))	('metastases', 'Disease', 'MESH:D009362', (176, 186))	('PIK3CA', 'Gene', (121, 127))	('vacuolar signs', 'Phenotype', 'HP:0001922', (70, 84))	('mutations', 'Var', (133, 142))	('poor prognosis', 'CPA', (188, 202))	('metastases', 'Disease', (176, 186))	('associated', 'Reg', (160, 170))
557650	31905960	Contradictory findings are reported in the literature regarding the role of PIK3CA gene mutations in thyroid cancers.	('cancers', 'Phenotype', 'HP:0002664', (109, 116))	('thyroid cancer', 'Phenotype', 'HP:0002890', (101, 115))	('mutations', 'Var', (88, 97))	('PIK3CA', 'Gene', (76, 82))	('thyroid cancers', 'Disease', (101, 116))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('thyroid cancers', 'Disease', 'MESH:D013964', (101, 116))
557652	31905960	However, these studies indicate that PIK3CA mutations are prevalent in aplastic thyroid cancer and follicular thyroid cancer as compared to papillary carcinoma of the thyroid.	('thyroid cancer', 'Phenotype', 'HP:0002890', (110, 124))	('papillary carcinoma of the thyroid', 'Disease', 'MESH:C536915', (140, 174))	('thyroid cancer', 'Phenotype', 'HP:0002890', (80, 94))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (150, 159))	('follicular thyroid cancer', 'Disease', (99, 124))	('mutations', 'Var', (44, 53))	('aplastic thyroid cancer', 'Disease', 'MESH:D013964', (71, 94))	('follicular thyroid cancer', 'Disease', 'MESH:C572845', (99, 124))	('cancer', 'Phenotype', 'HP:0002664', (88, 94))	('follicular thyroid cancer', 'Phenotype', 'HP:0006731', (99, 124))	('aplastic thyroid cancer', 'Disease', (71, 94))	('papillary carcinoma of the thyroid', 'Disease', (140, 174))	('PIK3CA', 'Gene', (37, 43))	('prevalent', 'Reg', (58, 67))
557653	31905960	In an initial study, PIK3CA mutations were identified in the highest proportion in the anaplastic thyroid carcinomas (16%), followed by follicular thyroid carcinomas (8%), and papillary thyroid carcinomas (2%).	('anaplastic thyroid carcinomas', 'Phenotype', 'HP:0011779', (87, 116))	('PIK3CA', 'Gene', (21, 27))	('follicular thyroid carcinomas', 'Disease', 'MESH:C572845', (136, 165))	('carcinomas', 'Phenotype', 'HP:0030731', (106, 116))	('thyroid carcinomas', 'Disease', 'MESH:D013964', (186, 204))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (147, 164))	('thyroid carcinomas', 'Disease', 'MESH:D013964', (98, 116))	('papillary thyroid carcinomas', 'Disease', 'MESH:C536915', (176, 204))	('follicular thyroid carcinomas', 'Phenotype', 'HP:0006731', (136, 165))	('papillary thyroid carcinomas', 'Disease', (176, 204))	('papillary thyroid carcinomas', 'Phenotype', 'HP:0002895', (176, 204))	('follicular thyroid carcinomas', 'Disease', (136, 165))	('thyroid carcinomas', 'Disease', (98, 116))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (186, 203))	('thyroid carcinomas', 'Disease', 'MESH:D013964', (147, 165))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (98, 115))	('thyroid carcinomas', 'Phenotype', 'HP:0002890', (186, 204))	('mutations', 'Var', (28, 37))	('carcinoma', 'Phenotype', 'HP:0030731', (155, 164))	('carcinoma', 'Phenotype', 'HP:0030731', (194, 203))	('thyroid carcinomas', 'Phenotype', 'HP:0002890', (98, 116))	('carcinomas', 'Phenotype', 'HP:0030731', (155, 165))	('carcinomas', 'Phenotype', 'HP:0030731', (194, 204))	('papillary thyroid carcinoma', 'Phenotype', 'HP:0002895', (176, 203))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('thyroid carcinomas', 'Phenotype', 'HP:0002890', (147, 165))
557654	31905960	Subsequent studies have shown varying prevalence of mutation in different subtypes of thyroid cancer, but PIK3CA mutations were the most commonly found in anaplastic cancers and the least observed in papillary.	('thyroid cancer', 'Phenotype', 'HP:0002890', (86, 100))	('cancers', 'Disease', (166, 173))	('thyroid cancer', 'Disease', (86, 100))	('cancers', 'Disease', 'MESH:D009369', (166, 173))	('PIK3CA', 'Gene', (106, 112))	('thyroid cancer', 'Disease', 'MESH:D013964', (86, 100))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('mutations', 'Var', (113, 122))	('cancers', 'Phenotype', 'HP:0002664', (166, 173))	('cancer', 'Phenotype', 'HP:0002664', (166, 172))	('found', 'Reg', (146, 151))
557655	31905960	reported the frequency of PIK3CA mutations to be 13% in follicular thyroid carcinomas and 1% in papillary thyroid carcinomas.	('thyroid carcinomas', 'Phenotype', 'HP:0002890', (67, 85))	('follicular thyroid carcinomas', 'Disease', 'MESH:C572845', (56, 85))	('thyroid carcinomas', 'Phenotype', 'HP:0002890', (106, 124))	('papillary thyroid carcinoma', 'Phenotype', 'HP:0002895', (96, 123))	('carcinoma', 'Phenotype', 'HP:0030731', (114, 123))	('carcinomas', 'Phenotype', 'HP:0030731', (114, 124))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (67, 84))	('mutations', 'Var', (33, 42))	('follicular thyroid carcinomas', 'Phenotype', 'HP:0006731', (56, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (75, 84))	('carcinomas', 'Phenotype', 'HP:0030731', (75, 85))	('papillary thyroid carcinomas', 'Disease', 'MESH:C536915', (96, 124))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (106, 123))	('follicular thyroid carcinomas', 'Disease', (56, 85))	('papillary thyroid carcinomas', 'Phenotype', 'HP:0002895', (96, 124))	('papillary thyroid carcinomas', 'Disease', (96, 124))	('PIK3CA', 'Gene', (26, 32))
557656	31905960	reported a 2% frequency of PIK3CA mutations in papillary thyroid carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (65, 74))	('papillary thyroid carcinoma', 'Disease', 'MESH:C536915', (47, 74))	('papillary thyroid carcinoma', 'Disease', (47, 74))	('PIK3CA', 'Gene', (27, 33))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (57, 74))	('papillary thyroid carcinoma', 'Phenotype', 'HP:0002895', (47, 74))	('mutations', 'Var', (34, 43))
557657	31905960	reported a 14% frequency of PIK3CA mutations in anaplastic thyroid cancer.	('PIK3CA', 'Gene', (28, 34))	('anaplastic thyroid cancer', 'Phenotype', 'HP:0011779', (48, 73))	('thyroid cancer', 'Phenotype', 'HP:0002890', (59, 73))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('aplastic thyroid cancer', 'Disease', 'MESH:D013964', (50, 73))	('aplastic thyroid cancer', 'Disease', (50, 73))	('mutations', 'Var', (35, 44))
557658	31905960	This distribution of PIK3CA mutations among thyroid cancer subtypes may raise the valid possibility of it playing a role towards more aggressive cancer development, mirroring the different natural history of anaplastic (most aggressive) vs. papillary thyroid cancer (least aggressive).	('cancer', 'Disease', (145, 151))	('cancer', 'Disease', 'MESH:D009369', (259, 265))	('PIK3CA', 'Gene', (21, 27))	('playing', 'Reg', (106, 113))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('anaplastic', 'Disease', (208, 218))	('papillary thyroid cancer', 'Phenotype', 'HP:0002895', (241, 265))	('thyroid cancer', 'Disease', (44, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('thyroid cancer', 'Disease', 'MESH:D013964', (251, 265))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('thyroid cancer', 'Phenotype', 'HP:0002890', (251, 265))	('cancer', 'Disease', (259, 265))	('thyroid cancer', 'Disease', 'MESH:D013964', (44, 58))	('cancer', 'Phenotype', 'HP:0002664', (259, 265))	('thyroid cancer', 'Phenotype', 'HP:0002890', (44, 58))	('cancer', 'Disease', (52, 58))	('mutations', 'Var', (28, 37))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('papillary thyroid cancer', 'Disease', (241, 265))	('papillary thyroid cancer', 'Disease', 'MESH:C536915', (241, 265))
557662	31905960	reported a protective effect of SNP rs17849071 of PIK3CA gene in follicular thyroid cancer.	('thyroid cancer', 'Phenotype', 'HP:0002890', (76, 90))	('follicular thyroid cancer', 'Disease', 'MESH:C572845', (65, 90))	('rs17849071', 'DBSNP_MENTION', 'None', (36, 46))	('rs17849071', 'Var', (36, 46))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('follicular thyroid cancer', 'Disease', (65, 90))	('PIK3CA', 'Gene', (50, 56))	('follicular thyroid cancer', 'Phenotype', 'HP:0006731', (65, 90))
557663	31905960	BRAF and PIK3CA mutations cooperatively promoted anaplastic thyroid cancer.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('aplastic thyroid cancer', 'Disease', 'MESH:D013964', (51, 74))	('promoted', 'PosReg', (40, 48))	('anaplastic thyroid cancer', 'Phenotype', 'HP:0011779', (49, 74))	('aplastic thyroid cancer', 'Disease', (51, 74))	('mutations', 'Var', (16, 25))	('BRAF', 'Gene', '673', (0, 4))	('thyroid cancer', 'Phenotype', 'HP:0002890', (60, 74))	('PIK3CA', 'Gene', (9, 15))	('BRAF', 'Gene', (0, 4))
557664	31905960	Additionally, in cooperation with KRAS mutations, PIK3CA mutations were reported to be associated with metastasis in thyroid cancer.	('KRAS', 'Gene', '3845', (34, 38))	('thyroid cancer', 'Phenotype', 'HP:0002890', (117, 131))	('thyroid cancer', 'Disease', 'MESH:D013964', (117, 131))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('mutations', 'Var', (57, 66))	('associated with', 'Reg', (87, 102))	('PIK3CA', 'Gene', (50, 56))	('KRAS', 'Gene', (34, 38))	('thyroid cancer', 'Disease', (117, 131))	('metastasis', 'CPA', (103, 113))
557665	31905960	Studies conducted to elucidate the role of PIK3CA mutations in the clinicopathological parameters and prognosis point that these mutations have minimal association with the prognosis of thyroid cancers.	('cancers', 'Phenotype', 'HP:0002664', (194, 201))	('mutations', 'Var', (50, 59))	('thyroid cancer', 'Phenotype', 'HP:0002890', (186, 200))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('thyroid cancers', 'Disease', (186, 201))	('minimal', 'NegReg', (144, 151))	('thyroid cancers', 'Disease', 'MESH:D013964', (186, 201))	('PIK3CA', 'Gene', (43, 49))
557666	31905960	However, the presence of PIK3CA mutation, along with other activating mutations, resulted in increased rates of mortality and aggressive metastasis.	('aggressive metastasis', 'Disease', (126, 147))	('increased', 'PosReg', (93, 102))	('PIK3CA', 'Gene', (25, 31))	('mortality', 'CPA', (112, 121))	('presence', 'Var', (13, 21))	('mutation', 'Var', (32, 40))	('aggressive metastasis', 'Disease', 'MESH:D009362', (126, 147))
557667	31905960	PIK3CA gene mutations are frequently observed in head and neck carcinoma.	('mutations', 'Var', (12, 21))	('observed', 'Reg', (37, 45))	('PIK3CA', 'Gene', (0, 6))	('neck carcinoma', 'Disease', (58, 72))	('neck carcinoma', 'Disease', 'MESH:D006258', (58, 72))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))
557668	31905960	An initial study reported PIK3CA mutational frequency of 11% in squamous cell carcinoma in pharyngeal cancer samples.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('mutational', 'Var', (33, 43))	('pharyngeal cancer', 'Phenotype', 'HP:0100638', (91, 108))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (64, 87))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (64, 87))	('PIK3CA', 'Gene', (26, 32))	('squamous cell carcinoma', 'Disease', (64, 87))
557669	31905960	The same group further reported a higher frequency (21%) of PIK3CA mutation in tumors of mixed origin.	('mutation', 'Var', (67, 75))	('PIK3CA', 'Gene', (60, 66))	('tumors', 'Disease', 'MESH:D009369', (79, 85))	('tumors', 'Disease', (79, 85))	('tumors', 'Phenotype', 'HP:0002664', (79, 85))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))
557672	31905960	HNSCC patients were reported to harbor PIK3CA mutations at even higher frequency, with a mutational frequency of 31%.	('patients', 'Species', '9606', (6, 14))	('PIK3CA', 'Gene', (39, 45))	('mutations', 'Var', (46, 55))
557673	31905960	In salivary duct carcinoma (SDC), the mutation frequency of PIK3CA was shown to be 28%.	('SDC', 'Disease', 'MESH:D012465', (28, 31))	('PIK3CA', 'Gene', (60, 66))	('salivary duct carcinoma', 'Disease', 'MESH:D012465', (3, 26))	('mutation', 'Var', (38, 46))	('SDC', 'Disease', (28, 31))	('salivary duct carcinoma', 'Disease', (3, 26))	('carcinoma', 'Phenotype', 'HP:0030731', (17, 26))
557674	31905960	Novel mutations in PIK3CA were recently reported as candidate driver events in human papillomavirus (HPV)-positive OSCCs.	('PIK3CA', 'Gene', (19, 25))	('human papillomavirus', 'Disease', (79, 99))	('papilloma', 'Phenotype', 'HP:0012740', (85, 94))	('human papillomavirus', 'Species', '10566', (79, 99))	('HPV', 'Species', '10566', (101, 104))	('mutations', 'Var', (6, 15))
557677	31905960	While one study revealed no association between PIK3CA and responsiveness to PI3K-targeted drugs, another group reported PIK3CA mutations to be associated with potential benefit from matched targeted therapy in parathyroid carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (223, 232))	('mutations', 'Var', (128, 137))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (215, 232))	('parathyroid carcinoma', 'Disease', 'MESH:D010282', (211, 232))	('PIK3CA', 'Gene', (121, 127))	('benefit', 'PosReg', (170, 177))	('parathyroid carcinoma', 'Disease', (211, 232))	('parathyroid carcinoma', 'Phenotype', 'HP:0006780', (211, 232))
557678	31905960	In a recent study evaluating the effect of nonsteroidal anti-inflammatory drugs (NSAID) on survival in head and neck cancer, patients with PIK3CA mutations or amplification showed prolonged disease-specific survival and overall survival with NSAID use as compared with non-NSAID users.	('amplification', 'Var', (159, 172))	('mutations', 'Var', (146, 155))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('head and neck cancer', 'Phenotype', 'HP:0012288', (103, 123))	('PIK3CA', 'Gene', (139, 145))	('prolonged', 'PosReg', (180, 189))	('disease-specific survival', 'CPA', (190, 215))	('head and neck cancer', 'Disease', 'MESH:D006258', (103, 123))	('overall survival', 'CPA', (220, 236))	('patients', 'Species', '9606', (125, 133))
557679	31905960	Mutations in PIK3CA gene were associated with improved outcomes among metastatic HPV-positive oropharyngeal cancer, with similar results reported in HPV-negative oropharyngeal cancer.	('pharyngeal cancer', 'Phenotype', 'HP:0100638', (97, 114))	('PIK3CA', 'Gene', (13, 19))	('HPV', 'Species', '10566', (149, 152))	('HPV-positive', 'Disease', (81, 93))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('improved', 'PosReg', (46, 54))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('Mutations', 'Var', (0, 9))	('outcomes', 'MPA', (55, 63))	('HPV', 'Species', '10566', (81, 84))	('pharyngeal cancer', 'Phenotype', 'HP:0100638', (165, 182))	('cancer', 'Disease', (176, 182))	('cancer', 'Disease', 'MESH:D009369', (176, 182))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
557681	31905960	Initial reports of PIK3CA gene mutations in esophageal cancers demonstrated that these mutations were present in 12% of squamous cell carcinomas and 6% of adenocarcinomas of the esophagus.	('squamous cell carcinomas', 'Disease', 'MESH:D002294', (120, 144))	('PIK3CA', 'Gene', (19, 25))	('esophageal cancers', 'Disease', (44, 62))	('mutations', 'Var', (31, 40))	('carcinoma', 'Phenotype', 'HP:0030731', (160, 169))	('squamous cell carcinomas', 'Disease', (120, 144))	('esophageal cancers', 'Disease', 'MESH:D004938', (44, 62))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (120, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (134, 143))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (120, 144))	('adenocarcinomas of the esophagus', 'Disease', (155, 187))	('carcinomas', 'Phenotype', 'HP:0030731', (160, 170))	('cancers', 'Phenotype', 'HP:0002664', (55, 62))	('carcinomas', 'Phenotype', 'HP:0030731', (134, 144))	('adenocarcinomas of the esophagus', 'Disease', 'MESH:C562730', (155, 187))	('present', 'Reg', (102, 109))
557682	31905960	showed no involvement of PIK3CA mutations in esophageal squamous cell carcinoma.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (56, 79))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('PIK3CA', 'Gene', (25, 31))	('mutations', 'Var', (32, 41))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:C562729', (45, 79))	('esophageal squamous cell carcinoma', 'Disease', (45, 79))
557683	31905960	Recently, PIK3CA mutations were identified in 21.7% of chagasic megaesophagus associated with esophageal squamous cell carcinoma cases.	('associated', 'Reg', (78, 88))	('PIK3CA', 'Gene', (10, 16))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (105, 128))	('esophageal squamous cell carcinoma', 'Disease', (94, 128))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:C562729', (94, 128))	('identified', 'Reg', (32, 42))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('mutations', 'Var', (17, 26))	('chagasic megaesophagus', 'Disease', (55, 77))
557686	31905960	A meta-analysis showed that PIK3CA mutation has no significant effects on overall survival and disease-free survival in esophageal squamous cell carcinoma.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (131, 154))	('carcinoma', 'Phenotype', 'HP:0030731', (145, 154))	('PIK3CA', 'Gene', (28, 34))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:C562729', (120, 154))	('esophageal squamous cell carcinoma', 'Disease', (120, 154))	('mutation', 'Var', (35, 43))
557687	31905960	However, patients with PIK3CA gene mutations in exon 9 have better disease-free survival and overall survival rates.	('better', 'PosReg', (60, 66))	('patients', 'Species', '9606', (9, 17))	('PIK3CA gene', 'Gene', (23, 34))	('overall survival rates', 'CPA', (93, 115))	('mutations in', 'Var', (35, 47))	('disease-free survival', 'CPA', (67, 88))
557688	31905960	showed that PIK3CA gene mutations are independent favorable prognostic marker in esophageal cancer patients in terms of survival.	('esophageal cancer', 'Disease', 'MESH:D004938', (81, 98))	('patients', 'Species', '9606', (99, 107))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('mutations', 'Var', (24, 33))	('esophageal cancer', 'Disease', (81, 98))	('PIK3CA', 'Gene', (12, 18))
557689	31905960	The PI3K/AKT/mTOR pathway is altered in approximately 20% cases, by mutations in PIK3CA gene.	('PIK3CA', 'Gene', (81, 87))	('mTOR', 'Gene', (13, 17))	('altered', 'Reg', (29, 36))	('mTOR', 'Gene', '2475', (13, 17))	('mutations', 'Var', (68, 77))
557690	31905960	Next generation sequencing revealed the presence of PIK3CA gene mutations in RCC but not in the clear cell subtype (cc-RCC), which is the major and most deadly RCC.	('RCC', 'Disease', 'MESH:D002292', (160, 163))	('RCC', 'Disease', (160, 163))	('RCC', 'Disease', (77, 80))	('PIK3CA', 'Gene', (52, 58))	('RCC', 'Disease', 'MESH:D002292', (77, 80))	('RCC', 'Disease', 'MESH:D002292', (119, 122))	('RCC', 'Disease', (119, 122))	('mutations', 'Var', (64, 73))
557692	31905960	PIK3CA mutations have also been reported in nephroblastomatosis or Wilms tumor.	('Wilms tumor', 'Disease', (67, 78))	('Wilms tumor', 'Disease', 'MESH:D009396', (67, 78))	('nephroblastomatosis', 'Disease', (44, 63))	('Wilms tumor', 'Phenotype', 'HP:0002667', (67, 78))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('PIK3CA', 'Gene', (0, 6))	('nephroblastomatosis', 'Disease', 'MESH:C536399', (44, 63))	('reported', 'Reg', (32, 40))	('nephroblastomatosis', 'Phenotype', 'HP:0008643', (44, 63))	('mutations', 'Var', (7, 16))
557693	31905960	PIK3CA mutations have been reported in urothelial papilloma cases.	('reported', 'Reg', (27, 35))	('papilloma', 'Phenotype', 'HP:0012740', (50, 59))	('urothelial papilloma', 'Disease', (39, 59))	('PIK3CA', 'Gene', (0, 6))	('urothelial papilloma', 'Disease', 'MESH:D010212', (39, 59))	('mutations', 'Var', (7, 16))
557694	31905960	PIK3CA gene amplification has been observed in recurrent ovarian cancer and yolk sac tumors.	('ovarian cancer', 'Disease', 'MESH:D010051', (57, 71))	('ovarian cancer', 'Phenotype', 'HP:0100615', (57, 71))	('ovarian cancer', 'Disease', (57, 71))	('amplification', 'Var', (12, 25))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('PIK3CA', 'Gene', (0, 6))	('recurrent ovarian cancer', 'Phenotype', 'HP:0008209', (47, 71))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('observed', 'Reg', (35, 43))	('yolk sac tumors', 'Disease', (76, 91))	('yolk sac tumors', 'Disease', 'MESH:D018240', (76, 91))	('tumors', 'Phenotype', 'HP:0002664', (85, 91))
557695	31905960	In addition, PIK3CA mutation was identified in 38% endometrial cancer samples.	('PIK3CA', 'Gene', (13, 19))	('endometrial cancer', 'Disease', (51, 69))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('mutation', 'Var', (20, 28))	('endometrial cancer', 'Phenotype', 'HP:0012114', (51, 69))	('identified', 'Reg', (33, 43))	('endometrial cancer', 'Disease', 'MESH:D016889', (51, 69))
557696	31905960	Amplification of PIK3CA has been associated with pathogenesis of cervical cancer.	('Amplification', 'Var', (0, 13))	('PIK3CA', 'Gene', (17, 23))	('associated', 'Reg', (33, 43))	('cervical cancer', 'Disease', (65, 80))	('cervical cancer', 'Disease', 'MESH:D002583', (65, 80))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
557697	31905960	reported PIK3CA mutations in 14% invasive cervical carcinomas, while Cui et al.	('invasive cervical carcinomas', 'Disease', (33, 61))	('invasive cervical carcinomas', 'Disease', 'MESH:D002583', (33, 61))	('carcinomas', 'Phenotype', 'HP:0030731', (51, 61))	('mutations', 'Var', (16, 25))	('PIK3CA', 'Gene', (9, 15))	('carcinoma', 'Phenotype', 'HP:0030731', (51, 60))
557698	31905960	reported these mutations in 8.15% of invasive cervical carcinomas.	('carcinomas', 'Phenotype', 'HP:0030731', (55, 65))	('invasive cervical carcinomas', 'Disease', (37, 65))	('invasive cervical carcinomas', 'Disease', 'MESH:D002583', (37, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (55, 64))	('mutations', 'Var', (15, 24))
557699	31905960	PIK3CA gene mutation has also been identified in small cell carcinoma of cervix.	('small cell carcinoma', 'Disease', (49, 69))	('small cell carcinoma', 'Disease', 'MESH:D018288', (49, 69))	('identified', 'Reg', (35, 45))	('carcinoma of cervix', 'Phenotype', 'HP:0030079', (60, 79))	('PIK3CA', 'Gene', (0, 6))	('small cell carcinoma', 'Phenotype', 'HP:0030357', (49, 69))	('carcinoma', 'Phenotype', 'HP:0030731', (60, 69))	('mutation', 'Var', (12, 20))
557700	31905960	A recent study in cervical cancer showed that PIK3CA mutation status did not have any significant association with clinicopathological characteristics but highlighted an association with poor overall survival.	('poor', 'NegReg', (187, 191))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('mutation status', 'Var', (53, 68))	('overall survival', 'MPA', (192, 208))	('cervical cancer', 'Disease', (18, 33))	('cervical cancer', 'Disease', 'MESH:D002583', (18, 33))	('PIK3CA', 'Gene', (46, 52))
557702	31905960	PIK3CA mutations were observed in 10% of bladder cancer patients and are associated with cisplatin resistance and a migratory phenotype in cervical cancer cells.	('patients', 'Species', '9606', (56, 64))	('cervical cancer', 'Disease', 'MESH:D002583', (139, 154))	('cisplatin resistance', 'MPA', (89, 109))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('cervical cancer', 'Disease', (139, 154))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('migratory', 'CPA', (116, 125))	('PIK3CA', 'Gene', (0, 6))	('associated', 'Reg', (73, 83))	('bladder cancer', 'Phenotype', 'HP:0009725', (41, 55))	('cisplatin', 'Chemical', 'MESH:D002945', (89, 98))	('bladder cancer', 'Disease', 'MESH:D001749', (41, 55))	('bladder cancer', 'Disease', (41, 55))	('mutations', 'Var', (7, 16))
557705	31905960	Hyperactivation of PI3K signaling is a hallmark of cancer, and activating mutations in this pathway are common in solid malignancies.	('solid malignancies', 'Disease', (114, 132))	('activating', 'PosReg', (63, 73))	('Hyperactivation', 'Var', (0, 15))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('hallmark of cancer', 'Disease', (39, 57))	('PI3K signaling', 'Pathway', (19, 33))	('hallmark of cancer', 'Disease', 'MESH:D009369', (39, 57))	('solid malignancies', 'Disease', 'MESH:D018250', (114, 132))
557706	31905960	Preclinical tests have demonstrated that cancer cell lines derived from solid cancers became sensitive to hormone therapy, chemotherapy, or other targeted therapies when they are treated with PI3K or mTOR inhibitors.	('PI3K', 'Var', (192, 196))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('mTOR', 'Gene', (200, 204))	('mTOR', 'Gene', '2475', (200, 204))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('sensitive', 'Reg', (93, 102))	('cancers', 'Disease', 'MESH:D009369', (78, 85))	('cancers', 'Phenotype', 'HP:0002664', (78, 85))	('cancers', 'Disease', (78, 85))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (41, 47))
557707	31905960	The PI3K/AKT/mTOR pathway inhibitors were found to be effective in improving progression-free survival in patients with PI3K pathway mutations.	('PI3K', 'Gene', (120, 124))	('improving', 'PosReg', (67, 76))	('mutations', 'Var', (133, 142))	('mTOR', 'Gene', (13, 17))	('patients', 'Species', '9606', (106, 114))	('mTOR', 'Gene', '2475', (13, 17))	('progression-free survival', 'CPA', (77, 102))
557712	31905960	Although PI3K mutations were thought to be associated with oncogenesis, it was only in the year 2004, its contributory role in cancer has been established unequivocally.	('PI3K mutations', 'Var', (9, 23))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('cancer', 'Disease', (127, 133))
557715	31905960	Literature search reveals that a number of studies have established the role of phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) mutations in oncogenesis.	('oncogenesis', 'CPA', (174, 185))	('PIK3CA', 'Gene', (153, 159))	('mutations', 'Var', (161, 170))	('phosphatidylinositol-4,5-bisphosphate', 'Chemical', 'MESH:D019269', (80, 117))
557716	31905960	The Cancer Genome Atlas has concluded mutations of PIK3CA as one of the most common genetic events associated with at least 12 different types of solid cancers.	('cancers', 'Disease', (152, 159))	('cancers', 'Disease', 'MESH:D009369', (152, 159))	('PIK3CA', 'Gene', (51, 57))	('Cancer', 'Phenotype', 'HP:0002664', (4, 10))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('cancers', 'Phenotype', 'HP:0002664', (152, 159))	('mutations', 'Var', (38, 47))	('associated', 'Reg', (99, 109))
557717	31905960	Commonly-identified cancers of solid tumors associated with PI3K3CA are breast cancer (>30% of total cases), bladder cancer (>20% of total cases), colorectal cancer (>17% of total cancer), and squamous cell cancer of head neck region (>15% of total cases).	('PI3K3CA', 'Var', (60, 67))	('cancer', 'Disease', 'MESH:D009369', (20, 26))	('breast cancer', 'Disease', 'MESH:D001943', (72, 85))	('breast cancer', 'Disease', (72, 85))	('tumors', 'Phenotype', 'HP:0002664', (37, 43))	('solid tumors', 'Disease', 'MESH:D009369', (31, 43))	('colorectal cancer', 'Phenotype', 'HP:0003003', (147, 164))	('cancer', 'Disease', (207, 213))	('squamous cell cancer of head neck', 'Disease', (193, 226))	('cancer', 'Disease', (158, 164))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('cancer', 'Disease', (117, 123))	('cancer', 'Disease', (79, 85))	('cancers', 'Disease', 'MESH:D009369', (20, 27))	('cancer', 'Disease', (180, 186))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('squamous cell cancer of head neck', 'Disease', 'MESH:C535575', (193, 226))	('bladder cancer', 'Disease', 'MESH:D001749', (109, 123))	('bladder cancer', 'Disease', (109, 123))	('colorectal cancer', 'Disease', 'MESH:D015179', (147, 164))	('cancer', 'Disease', (20, 26))	('bladder cancer', 'Phenotype', 'HP:0009725', (109, 123))	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('cancer', 'Disease', 'MESH:D009369', (207, 213))	('colorectal cancer', 'Disease', (147, 164))	('breast cancer', 'Phenotype', 'HP:0003002', (72, 85))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('solid tumors', 'Disease', (31, 43))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (193, 213))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('cancers', 'Phenotype', 'HP:0002664', (20, 27))	('cancer', 'Disease', 'MESH:D009369', (180, 186))	('cancers', 'Disease', (20, 27))	('cancer', 'Disease', 'MESH:D009369', (79, 85))
557719	31905960	From January 2013 to December 2014, 19,784 tumor samples (of more than 40 different types of cancer) sent by thousands of doctors across 60 countries were tested at a single commercial laboratory for molecular profiling to identify genetic and proteomic aberrations in the PI3K pathway.	('aberrations', 'Var', (254, 265))	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('PI3K pathway', 'Pathway', (273, 285))	('tumor', 'Disease', (43, 48))
557720	31905960	They found around 38% of the patients had one or more mutations in the PI3K pathway proteins; the most common aberration (30%) was loss of PTEN (phosphatase and tensin homologue) followed by mutations in PIK3CA (13%).	('patients', 'Species', '9606', (29, 37))	('phosphatase and tensin homologue', 'Gene', '5728', (145, 177))	('mutations', 'Var', (54, 63))	('mutations', 'Var', (191, 200))	('PI3K pathway proteins', 'Pathway', (71, 92))	('PTEN', 'Gene', (139, 143))	('loss', 'NegReg', (131, 135))	('PTEN', 'Gene', '5728', (139, 143))	('PIK3CA', 'Gene', (204, 210))
557721	31905960	PIK3CA mutation was associated most commonly with endometrial (37%), breast (31%), cervical (29%), and anal cancers (27%).	('associated', 'Reg', (20, 30))	('cancers', 'Phenotype', 'HP:0002664', (108, 115))	('cervical', 'Disease', (83, 91))	('endometrial', 'Disease', (50, 61))	('breast', 'Disease', (69, 75))	('PIK3CA', 'Gene', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('mutation', 'Var', (7, 15))	('cancers', 'Disease', 'MESH:D009369', (108, 115))	('cancers', 'Disease', (108, 115))
557725	31905960	Most commonly associated cancer varieties with PIK3CA mutation were endometrial cancer (uterine corpus) (52%) and breast carcinoma (33.6%).	('carcinoma', 'Phenotype', 'HP:0030731', (121, 130))	('mutation', 'Var', (54, 62))	('PIK3CA', 'Gene', (47, 53))	('breast carcinoma', 'Phenotype', 'HP:0003002', (114, 130))	('endometrial cancer', 'Phenotype', 'HP:0012114', (68, 86))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))	('endometrial cancer', 'Disease', 'MESH:D016889', (68, 86))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('cancer', 'Disease', 'MESH:D009369', (25, 31))	('breast carcinoma', 'Disease', 'MESH:D001943', (114, 130))	('breast carcinoma', 'Disease', (114, 130))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('cancer', 'Disease', (25, 31))	('endometrial cancer', 'Disease', (68, 86))	('cancer', 'Disease', (80, 86))
557726	31905960	Discovery of PIK3CA mutations in majority of cancers has led to new targets for treatment of those cancers.	('PIK3CA', 'Gene', (13, 19))	('cancer', 'Phenotype', 'HP:0002664', (45, 51))	('cancers', 'Disease', 'MESH:D009369', (99, 106))	('cancers', 'Phenotype', 'HP:0002664', (99, 106))	('cancers', 'Disease', (99, 106))	('cancers', 'Disease', 'MESH:D009369', (45, 52))	('cancers', 'Phenotype', 'HP:0002664', (45, 52))	('cancers', 'Disease', (45, 52))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('mutations', 'Var', (20, 29))
557728	31905960	All these studies indicate that PI3K pathway inhibitors in solid malignancies improved progression-free survival in cancer types with PI3K mutations.	('mutations', 'Var', (139, 148))	('solid malignancies', 'Disease', (59, 77))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('progression-free survival', 'CPA', (87, 112))	('PI3K', 'Gene', (134, 138))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('solid malignancies', 'Disease', 'MESH:D018250', (59, 77))	('improved', 'PosReg', (78, 86))
557730	31905960	PIK3CA gene mutations are clinically important in most solid malignancies.	('mutations', 'Var', (12, 21))	('solid malignancies', 'Disease', (55, 73))	('PIK3CA', 'Gene', (0, 6))	('important', 'Reg', (37, 46))	('solid malignancies', 'Disease', 'MESH:D018250', (55, 73))
557731	31905960	In addition, these mutations have implications in the effectiveness of the treatment and prognosis of cancers.	('implications', 'Reg', (34, 46))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('mutations', 'Var', (19, 28))	('cancers', 'Disease', 'MESH:D009369', (102, 109))	('cancers', 'Phenotype', 'HP:0002664', (102, 109))	('cancers', 'Disease', (102, 109))
557732	31905960	However, contradictory reports exist in the literature regarding the effect of PIK3CA gene mutations on the prognosis of different cancers.	('cancers', 'Disease', 'MESH:D009369', (131, 138))	('cancers', 'Phenotype', 'HP:0002664', (131, 138))	('cancers', 'Disease', (131, 138))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('PIK3CA', 'Gene', (79, 85))	('mutations', 'Var', (91, 100))
557734	31905960	However, larger prospective studies should be conducted to further elucidate the role of PIK3CA mutations in solid malignancies.	('PIK3CA', 'Gene', (89, 95))	('solid malignancies', 'Disease', 'MESH:D018250', (109, 127))	('solid malignancies', 'Disease', (109, 127))	('mutations', 'Var', (96, 105))
557744	31025831	PD-L1 positivity was significantly more prevalent in cases with genetic alterations than in cases without genetic alterations.	('rat', 'Species', '10116', (76, 79))	('rat', 'Species', '10116', (118, 121))	('positivity', 'Var', (6, 16))	('prevalent', 'Reg', (40, 49))	('PD-L1', 'Gene', (0, 5))	('genetic alterations', 'Var', (64, 83))	('PD-L1', 'Gene', '29126', (0, 5))
557745	31025831	Furthermore, both PD-L1 positivity and high PD-L1 expression (>=50%) had statistically significant associations with Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations.	('rat', 'Species', '10116', (125, 128))	('sarcoma', 'Disease', 'MESH:D012509', (129, 136))	('mutations', 'Var', (167, 176))	('PD-L1', 'Gene', (44, 49))	('PD-L1', 'Gene', '29126', (44, 49))	('sarcoma', 'Disease', (129, 136))	('associations', 'Interaction', (99, 111))	('PD-L1', 'Gene', (18, 23))	('sarcoma', 'Phenotype', 'HP:0100242', (129, 136))	('expression', 'MPA', (50, 60))	('PD-L1', 'Gene', '29126', (18, 23))
557748	31025831	The association of PD-L1 expression with KRAS mutations may have clinical relevance in selecting patients with NSCLC for immunotherapy.	('PD-L1', 'Gene', (19, 24))	('mutations', 'Var', (46, 55))	('association', 'Interaction', (4, 15))	('NSCLC', 'Disease', (111, 116))	('PD-L1', 'Gene', '29126', (19, 24))	('NSCLC', 'Disease', 'MESH:D002289', (111, 116))	('KRAS', 'Gene', (41, 45))	('patients', 'Species', '9606', (97, 105))
557756	31025831	Some studies have observed that high PD-L1 expression is associated with smoking, an advanced stage, squamous morphology, and molecular alterations, including epidermal growth factor receptor (EGFR), Kirsten rat sarcoma viral oncogene homolog (KRAS), and anaplastic lymphoma kinase (ALK) oncogenic mutations, whereas other studies have shown conflicting results.	('sarcoma', 'Phenotype', 'HP:0100242', (212, 219))	('high', 'Var', (32, 36))	('lymphoma', 'Phenotype', 'HP:0002665', (266, 274))	('PD-L1', 'Gene', (37, 42))	('rat', 'Species', '10116', (208, 211))	('epidermal growth factor receptor', 'Gene', (159, 191))	('squamous', 'Disease', (101, 109))	('PD-L1', 'Gene', '29126', (37, 42))	('smoking', 'Disease', (73, 80))	('anaplastic lymphoma kinase', 'Gene', '266802', (255, 281))	('epidermal growth factor receptor', 'Gene', '24329', (159, 191))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (255, 274))	('sarcoma', 'Disease', 'MESH:D012509', (212, 219))	('rat', 'Species', '10116', (140, 143))	('anaplastic lymphoma kinase', 'Gene', (255, 281))	('expression', 'MPA', (43, 53))	('sarcoma', 'Disease', (212, 219))	('associated', 'Reg', (57, 67))
557775	31025831	An analysis of the neoplasm-associated variants included the use of hg19, Torrent Suite Software, and the GenomOncology platform.	('neoplasm', 'Disease', (19, 27))	('neoplasm', 'Disease', 'MESH:D009369', (19, 27))	('neoplasm', 'Phenotype', 'HP:0002664', (19, 27))	('hg19', 'Gene', (68, 72))	('variants', 'Var', (39, 47))
557776	31025831	The lung carcinoma panel (22 genes) detected mutations in the following genes: AKT1, ALK, BRAF, CTNNB1, DDR2, EGFR, ERBB2, ERBB4, FBXW7, FGFR1, FGFR2, FGFR3, KRAS, MAP2K1, MET (excluding exon-skipping mutations), NOTCH1, NRAS, PIK3CA, PTEN, SMAD4, STK11, and TP53.	('BRAF', 'Gene', (90, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (9, 18))	('SMAD4', 'Gene', '4089', (241, 246))	('ALK', 'Gene', (85, 88))	('NRAS', 'Gene', '4893', (221, 225))	('PIK3CA', 'Gene', (227, 233))	('FGFR1', 'Gene', (137, 142))	('AKT1', 'Gene', (79, 83))	('PTEN', 'Gene', (235, 239))	('FGFR3', 'Gene', (151, 156))	('NOTCH1', 'Gene', (213, 219))	('TP53', 'Gene', (259, 263))	('DDR2', 'Gene', (104, 108))	('FBXW7', 'Gene', '55294', (130, 135))	('CTNNB1', 'Gene', '1499', (96, 102))	('FGFR3', 'Gene', '2261', (151, 156))	('STK11', 'Gene', (248, 253))	('NOTCH1', 'Gene', '4851', (213, 219))	('MAP2K1', 'Gene', '5604', (164, 170))	('PTEN', 'Gene', '5728', (235, 239))	('MAP2K1', 'Gene', (164, 170))	('lung carcinoma', 'Disease', (4, 18))	('FGFR2', 'Gene', (144, 149))	('NRAS', 'Gene', (221, 225))	('BRAF', 'Gene', '673', (90, 94))	('EGFR', 'Gene', (110, 114))	('ERBB2', 'Gene', (116, 121))	('MET', 'Gene', (172, 175))	('TP53', 'Gene', '7157', (259, 263))	('CTNNB1', 'Gene', (96, 102))	('STK11', 'Gene', '6794', (248, 253))	('FGFR1', 'Gene', '2260', (137, 142))	('SMAD4', 'Gene', (241, 246))	('PIK3CA', 'Gene', '5290', (227, 233))	('FGFR2', 'Gene', '2263', (144, 149))	('mutations', 'Var', (45, 54))	('ERBB4', 'Gene', '2066', (123, 128))	('ERBB2', 'Gene', '2064', (116, 121))	('AKT1', 'Gene', '207', (79, 83))	('FBXW7', 'Gene', (130, 135))	('ERBB4', 'Gene', (123, 128))	('DDR2', 'Gene', '4921', (104, 108))	('KRAS', 'Gene', (158, 162))	('lung carcinoma', 'Disease', 'MESH:D008175', (4, 18))
557777	31025831	The solid tumor mutation panel (48 genes) detected cancer-associated mutations in ABL1, AKT1, ALK, APC, ATM, BRAF, CDH1, CDKN2A, CSF1R, CTNNB1, EGFR, ERBB2, ERBB4, EZH2, FBXW7, FGFR1, FGFR2, FGFR3, GNA11, GNAS, GNAQ, HNF1A, HRAS, IDH1, IDH2, JAK2, JAK3, KDR, KIT, KRAS, MET, MLH1, NOTCH1, NPM1, NRAS, PDGFRA, PIK3CA, PTPN11, PTEN, RB1, RET, SMAD4, SMARCB1, SMO, SRC, STK11, TP53, and VHL.	('SMO', 'Gene', (357, 360))	('FGFR3', 'Gene', (191, 196))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('ABL1', 'Gene', '25', (82, 86))	('IDH1', 'Gene', (230, 234))	('GNAS', 'Gene', '2778', (205, 209))	('RET', 'Gene', (336, 339))	('CDH1', 'Gene', '999', (115, 119))	('CTNNB1', 'Gene', (136, 142))	('NOTCH1', 'Gene', (281, 287))	('FGFR1', 'Gene', '2260', (177, 182))	('JAK2', 'Gene', '3717', (242, 246))	('TP53', 'Gene', (374, 378))	('PDGFRA', 'Gene', '5156', (301, 307))	('PDGFRA', 'Gene', (301, 307))	('NRAS', 'Gene', '4893', (295, 299))	('ABL1', 'Gene', (82, 86))	('MLH1', 'Gene', (275, 279))	('CTNNB1', 'Gene', '1499', (136, 142))	('FBXW7', 'Gene', '55294', (170, 175))	('GNAS', 'Gene', (205, 209))	('PTEN', 'Gene', '5728', (325, 329))	('TP53', 'Gene', '7157', (374, 378))	('BRAF', 'Gene', (109, 113))	('GNAQ', 'Gene', (211, 215))	('BRAF', 'Gene', '673', (109, 113))	('MLH1', 'Gene', '4292', (275, 279))	('IDH2', 'Gene', (236, 240))	('FGFR2', 'Gene', (184, 189))	('IDH2', 'Gene', '3418', (236, 240))	('PIK3CA', 'Gene', '5290', (309, 315))	('IDH1', 'Gene', '3417', (230, 234))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('SRC', 'Gene', '6714', (362, 365))	('mutations', 'Var', (69, 78))	('HRAS', 'Gene', (224, 228))	('STK11', 'Gene', (367, 372))	('FBXW7', 'Gene', (170, 175))	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('EZH2', 'Gene', '2146', (164, 168))	('ATM', 'Gene', '472', (104, 107))	('SMARCB1', 'Gene', (348, 355))	('PIK3CA', 'Gene', (309, 315))	('PTEN', 'Gene', (325, 329))	('cancer', 'Disease', (51, 57))	('JAK3', 'Gene', (248, 252))	('FGFR1', 'Gene', (177, 182))	('JAK2', 'Gene', (242, 246))	('GNA11', 'Gene', (198, 203))	('KDR', 'Gene', '3791', (254, 257))	('ATM', 'Gene', (104, 107))	('CSF1R', 'Gene', '1436', (129, 134))	('ERBB4', 'Gene', '2066', (157, 162))	('JAK3', 'Gene', '3718', (248, 252))	('VHL', 'Gene', (384, 387))	('ERBB2', 'Gene', (150, 155))	('PTPN11', 'Gene', '5781', (317, 323))	('NRAS', 'Gene', (295, 299))	('HRAS', 'Gene', '3265', (224, 228))	('APC', 'Disease', (99, 102))	('GNA11', 'Gene', '2767', (198, 203))	('FGFR2', 'Gene', '2263', (184, 189))	('VHL', 'Gene', '7428', (384, 387))	('SMO', 'Gene', '6608', (357, 360))	('NPM1', 'Gene', (289, 293))	('SMARCB1', 'Gene', '6598', (348, 355))	('KDR', 'Gene', (254, 257))	('EZH2', 'Gene', (164, 168))	('SMAD4', 'Gene', (341, 346))	('GNAQ', 'Gene', '2776', (211, 215))	('FGFR3', 'Gene', '2261', (191, 196))	('PTPN11', 'Gene', (317, 323))	('CDKN2A', 'Gene', (121, 127))	('NPM1', 'Gene', '4869', (289, 293))	('tumor', 'Disease', (10, 15))	('ERBB4', 'Gene', (157, 162))	('CSF1R', 'Gene', (129, 134))	('HNF1A', 'Gene', '6927', (217, 222))	('SMAD4', 'Gene', '4089', (341, 346))	('RB1', 'Gene', (331, 334))	('HNF1A', 'Gene', (217, 222))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('APC', 'Disease', 'MESH:D011125', (99, 102))	('CDKN2A', 'Gene', '1029', (121, 127))	('ERBB2', 'Gene', '2064', (150, 155))	('CDH1', 'Gene', (115, 119))	('RB1', 'Gene', '5925', (331, 334))	('AKT1', 'Gene', '207', (88, 92))	('SRC', 'Gene', (362, 365))	('NOTCH1', 'Gene', '4851', (281, 287))	('STK11', 'Gene', '6794', (367, 372))	('AKT1', 'Gene', (88, 92))	('RET', 'Gene', '5979', (336, 339))
557800	31025831	One hundred ninety cases underwent molecular analysis, and 74 showed mutations/rearrangements, including 6 in EGFR exon 19, 1 in EGFR exon 21, 56 in KRAS, 4 in MET, 6 in ALK, and 1 in RET (Table 1).	('mutations/rearrangements', 'Var', (69, 93))	('RET', 'Gene', (184, 187))	('RET', 'Gene', '5979', (184, 187))	('EGFR', 'Gene', (110, 114))
557801	31025831	The cytologic group showed more cases with advanced stages, but the histologic group showed more squamous cell carcinoma cases and more cases with KRAS mutations (Table 1).	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (97, 120))	('KRAS mutations', 'Var', (147, 161))	('squamous cell carcinoma', 'Disease', (97, 120))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (97, 120))
557805	31025831	First, we examined the association of PD-L1 positivity (>=1%) with clinicopathologic features and molecular alterations.	('rat', 'Species', '10116', (112, 115))	('positivity', 'Var', (44, 54))	('PD-L1', 'Gene', (38, 43))	('PD-L1', 'Gene', '29126', (38, 43))
557806	31025831	As shown in Table 2, PD-L1 positivity was significantly associated with any molecular alteration and KRAS mutations but was not associated with other specific molecular mutations (eg, EGFR and ALK), histologic types, smoking, stage, age, or sex.	('molecular alteration', 'CPA', (76, 96))	('positivity', 'Var', (27, 37))	('KRAS', 'Gene', (101, 105))	('associated', 'Reg', (56, 66))	('PD-L1', 'Gene', (21, 26))	('mutations', 'Var', (106, 115))	('PD-L1', 'Gene', '29126', (21, 26))	('rat', 'Species', '10116', (90, 93))
557808	31025831	As shown in Table 3 (PD-L1 with >=50% expression vs PD-L1 with 1%-49% expression) and Table 4 (PD-L1 with >=50% expression vs PD-L1 with <50% expression), high PD-L1 expression was significantly associated with KRAS mutations but was not associated with other molecular mutations, histologic types, smoking, stage, age, or sex.	('associated', 'Reg', (195, 205))	('PD-L1', 'Gene', '29126', (52, 57))	('KRAS mutations', 'Disease', (211, 225))	('PD-L1', 'Gene', (160, 165))	('expression', 'MPA', (166, 176))	('PD-L1', 'Gene', (52, 57))	('PD-L1', 'Gene', (95, 100))	('PD-L1', 'Gene', (126, 131))	('PD-L1', 'Gene', (21, 26))	('PD-L1', 'Gene', '29126', (160, 165))	('PD-L1', 'Gene', '29126', (126, 131))	('high', 'Var', (155, 159))	('PD-L1', 'Gene', '29126', (95, 100))	('PD-L1', 'Gene', '29126', (21, 26))
557811	31025831	PD-L1 expression levels showed a significant difference only between groups with KRAS mutations and without KRAS mutations (78% vs 40%).	('PD-L1', 'Gene', (0, 5))	('PD-L1', 'Gene', '29126', (0, 5))	('KRAS mutations', 'Var', (81, 95))	('expression levels', 'MPA', (6, 23))
557829	31025831	Some studies have documented an association between PD-L1 expression and molecular alterations, including EGFR mutations, KRAS mutations, and ALK translocations, whereas other studies have failed to find such correlations.	('mutations', 'Var', (111, 120))	('ALK', 'Disease', (142, 145))	('PD-L1', 'Gene', '29126', (52, 57))	('KRAS mutations', 'Disease', (122, 136))	('PD-L1', 'Gene', (52, 57))	('association', 'Interaction', (32, 43))	('rat', 'Species', '10116', (87, 90))	('EGFR', 'Gene', (106, 110))
557830	31025831	Our study did demonstrate a significant correlation of PD-L1 expression (PD-L1 positivity, high PD-L1 expression, and expression levels) with KRAS mutations but not with any other mutations.	('mutations', 'Var', (147, 156))	('PD-L1', 'Gene', '29126', (96, 101))	('PD-L1', 'Gene', '29126', (55, 60))	('PD-L1', 'Gene', '29126', (73, 78))	('correlation', 'Interaction', (40, 51))	('expression levels', 'MPA', (118, 135))	('rat', 'Species', '10116', (21, 24))	('PD-L1', 'Gene', (96, 101))	('PD-L1', 'Gene', (55, 60))	('KRAS', 'Disease', (142, 146))	('PD-L1', 'Gene', (73, 78))
557831	31025831	One study investigated the underlining mechanism regulating PD-L1 expression in NSCLCs with KRAS mutations and found that mitogen-activated protein kinase signaling along with signal transducer and activator of transcription 3 was crucial for PD-L1 expression.	('mutations', 'Var', (97, 106))	('mitogen-activated protein kinase signaling', 'MPA', (122, 164))	('PD-L1', 'Gene', (60, 65))	('NSCLC', 'Disease', (80, 85))	('KRAS', 'Gene', (92, 96))	('PD-L1', 'Gene', (243, 248))	('NSCLC', 'Disease', 'MESH:D002289', (80, 85))	('PD-L1', 'Gene', '29126', (60, 65))	('PD-L1', 'Gene', '29126', (243, 248))	('signal transducer and activator of transcription 3', 'Gene', '6774', (176, 226))
557832	31025831	There was no significant difference in PD-L1 expression between all surgical specimens (with or without molecular testing) and all cytologic specimens (with or without molecular testing), but the PD-L1-positive rate was significantly higher in surgical specimens with molecular testing than in cytologic specimens with molecular testing; this suggests an association between PD-L1 expression and KRAS mutations.	('PD-L1', 'Gene', (375, 380))	('PD-L1', 'Gene', (39, 44))	('PD-L1', 'Gene', '29126', (196, 201))	('PD-L1', 'Gene', '29126', (375, 380))	('rat', 'Species', '10116', (211, 214))	('molecular testing', 'Var', (268, 285))	('PD-L1', 'Gene', '29126', (39, 44))	('mutations', 'Var', (401, 410))	('association', 'Interaction', (355, 366))	('higher', 'PosReg', (234, 240))	('PD-L1', 'Gene', (196, 201))	('KRAS', 'Disease', (396, 400))
557836	31025831	The US Food and Drug Administration has approved immunomodulatory therapies as second-line agents for patients with advanced NSCLC and as first-line therapy for patients with NSCLC with a high level of PD-L1 expression (>=50%) and an absence of EGFR mutations or ALK rearrangements.	('NSCLC', 'Disease', 'MESH:D002289', (175, 180))	('PD-L1', 'Gene', '29126', (202, 207))	('NSCLC', 'Disease', (125, 130))	('patients', 'Species', '9606', (102, 110))	('rat', 'Species', '10116', (29, 32))	('NSCLC', 'Disease', 'MESH:D002289', (125, 130))	('absence', 'NegReg', (234, 241))	('patients', 'Species', '9606', (161, 169))	('mutations', 'Var', (250, 259))	('EGFR', 'Gene', (245, 249))	('PD-L1', 'Gene', (202, 207))	('NSCLC', 'Disease', (175, 180))
557837	31025831	The finding of an association of PD-L1 expression and KRAS mutations suggests that PD-L1 testing should be performed for patients with KRAS-mutated NSCLC because immunotherapy is the only potentially personalized therapy in these patients.	('PD-L1', 'Gene', '29126', (83, 88))	('PD-L1', 'Gene', (33, 38))	('NSCLC', 'Disease', (148, 153))	('PD-L1', 'Gene', '29126', (33, 38))	('association', 'Interaction', (18, 29))	('patients', 'Species', '9606', (230, 238))	('KRAS', 'Gene', (54, 58))	('NSCLC', 'Disease', 'MESH:D002289', (148, 153))	('PD-L1', 'Gene', (83, 88))	('mutations', 'Var', (59, 68))	('patients', 'Species', '9606', (121, 129))
557843	31025831	Second, some groups such as those with EGFR or ALK alterations had a small number of cases, and this limited the statistical analysis power in these groups.	('EGFR', 'Gene', (39, 43))	('alterations', 'Var', (51, 62))	('ALK', 'Gene', (47, 50))	('rat', 'Species', '10116', (55, 58))
557844	31025831	Similarly, lower EGFR or ALK alteration rates in the current study cohort in comparison with the general population might be caused by this selective bias because patients with EGFR or ALK alterations usually received EGFR- or ALK-targeted therapy instead of immunotherapy.	('patients', 'Species', '9606', (163, 171))	('rat', 'Species', '10116', (193, 196))	('rat', 'Species', '10116', (40, 43))	('lower', 'NegReg', (11, 16))	('rat', 'Species', '10116', (33, 36))	('ALK', 'Gene', (185, 188))	('EGFR', 'Gene', (177, 181))	('alterations', 'Var', (189, 200))
557846	31025831	The association between PD-L1 expression and KRAS mutations may have clinical relevance in selecting patients with NSCLC for immunotherapy.	('patients', 'Species', '9606', (101, 109))	('mutations', 'Var', (50, 59))	('NSCLC', 'Disease', (115, 120))	('NSCLC', 'Disease', 'MESH:D002289', (115, 120))	('PD-L1', 'Gene', (24, 29))	('KRAS', 'Gene', (45, 49))	('PD-L1', 'Gene', '29126', (24, 29))
557860	29033581	Although several tyrosine kinase inhibitors targeting the epidermal growth factor receptor (EGFR) mutation and anaplastic lymphoma kinase rearrangement have contributed to the increased survival of patients with NSCLC, platinum-based combination chemotherapy is the standard of care for advanced diseases, especially in patients who do not harbor these genetic abnormalities.	('NSCLC', 'Disease', 'MESH:D002289', (212, 217))	('epidermal growth factor receptor', 'Gene', (58, 90))	('lymphoma', 'Disease', (122, 130))	('mutation', 'Var', (98, 106))	('increased', 'PosReg', (176, 185))	('patients', 'Species', '9606', (198, 206))	('genetic abnormalities', 'Disease', 'MESH:D030342', (353, 374))	('lymphoma', 'Disease', 'MESH:D008223', (122, 130))	('NSCLC', 'Phenotype', 'HP:0030358', (212, 217))	('lymphoma', 'Phenotype', 'HP:0002665', (122, 130))	('epidermal growth factor receptor', 'Gene', '1956', (58, 90))	('genetic abnormalities', 'Disease', (353, 374))	('EGFR', 'Gene', '1956', (92, 96))	('EGFR', 'Gene', (92, 96))	('platinum', 'Chemical', 'MESH:D010984', (219, 227))	('NSCLC', 'Disease', (212, 217))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (111, 130))	('patients', 'Species', '9606', (320, 328))
557861	29033581	Although several potential predictive biomarkers such as the KRAS mutation and the excision repair of cross-complementation group 1 in the context of platinum-based chemotherapy have been extensively investigated, the clinical utility of those biomarkers was found to be unacceptable.	('platinum', 'Chemical', 'MESH:D010984', (150, 158))	('KRAS', 'Gene', (61, 65))	('mutation', 'Var', (66, 74))	('KRAS', 'Gene', '3845', (61, 65))
557883	29033581	The cutoff H-score for discriminating between low and high NANOG expression was defined as the point with the lowest p-value on the log-rank test for all possible H-scores.	('NANOG', 'Gene', '79923', (59, 64))	('low', 'Var', (46, 49))	('NANOG', 'Gene', (59, 64))
557890	29033581	EGFR mutational status was analyzed in 20 adenocarcinomas; eight patients (40%) were mutated while 12 patients (60%) were wild-type.	('adenocarcinomas', 'Disease', 'MESH:D000230', (42, 57))	('EGFR', 'Gene', (0, 4))	('patients', 'Species', '9606', (102, 110))	('adenocarcinomas', 'Disease', (42, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (47, 56))	('mutated', 'Var', (85, 92))	('patients', 'Species', '9606', (65, 73))	('EGFR', 'Gene', '1956', (0, 4))
557912	29033581	Multivariate analysis showed that old age (HR =1.18, 95% CI: 1.06-2.14), poor performance status (HR =2.42, 95% CI: 1.47-3.99), advanced stage (HR =1.84, 95% CI: 1.16-3.10), and high NANOG levels (HR =3.00, 95% CI: 1.98-4.54) were significantly associated with shorter OS.	('NANOG', 'Gene', '79923', (183, 188))	('shorter OS', 'Disease', (261, 271))	('NANOG', 'Gene', (183, 188))	('high', 'Var', (178, 182))
557923	29033581	In multivariate analysis, poor performance (HR =1.62, 95% CI: 1.11-2.27) and high NANOG levels (HR =3.64, 95% CI: 2.20-8.14) were significantly associated with shorter OS.	('NANOG', 'Gene', '79923', (82, 87))	('NANOG', 'Gene', (82, 87))	('high', 'Var', (77, 81))	('shorter OS', 'Disease', (160, 170))	('poor', 'NegReg', (26, 30))
557972	31750240	We recently reported that a splicing switch from KHK-C to KHK-A occurs in hepatocellular carcinoma (HCC), leading to fructose metabolism reduction, and KHK-A phosphorylates and activates phosphoribosyl pyrophosphate synthetase 1 (PRPS1), resulting in increased de novo nucleic acid synthesis for HCC development.	('fructose metabolism reduction', 'Disease', 'MESH:D015318', (117, 146))	('HCC', 'Disease', 'MESH:D006528', (296, 299))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('increased', 'PosReg', (251, 260))	('HCC', 'Disease', (100, 103))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (74, 98))	('KHK-A', 'Gene', (58, 63))	('HCC', 'Phenotype', 'HP:0001402', (100, 103))	('KHK-A', 'Var', (152, 157))	('de novo nucleic acid synthesis', 'MPA', (261, 291))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (74, 98))	('HCC', 'Disease', (296, 299))	('HCC', 'Phenotype', 'HP:0001402', (296, 299))	('fructose metabolism reduction', 'Disease', (117, 146))	('activates', 'PosReg', (177, 186))	('PRPS1', 'Gene', (230, 235))	('phosphoribosyl pyrophosphate', 'Chemical', 'MESH:D010754', (187, 215))	('HCC', 'Disease', 'MESH:D006528', (100, 103))	('hepatocellular carcinoma', 'Disease', (74, 98))	('fructose metabolism reduction', 'Phenotype', 'HP:0011033', (117, 146))
557973	31750240	Under oxidative stress, KHK-A dissociates from PRPS1 and phosphorylates p62 to activate Nrf2, and activated Nrf2 induces gene expression to counteract oxidative stress and promote HCC development in mice.	('HCC', 'Disease', 'MESH:D006528', (180, 183))	('Nrf2', 'Gene', (88, 92))	('induces', 'Reg', (113, 120))	('mice', 'Species', '10090', (199, 203))	('HCC', 'Phenotype', 'HP:0001402', (180, 183))	('oxidative stress', 'Phenotype', 'HP:0025464', (151, 167))	('activate', 'PosReg', (79, 87))	('oxidative stress', 'Phenotype', 'HP:0025464', (6, 22))	('promote', 'PosReg', (172, 179))	('gene expression', 'MPA', (121, 136))	('Nrf2', 'Gene', (108, 112))	('activated', 'Var', (98, 107))	('HCC', 'Disease', (180, 183))
557974	31750240	Notably, high KHK-A expression predicted a poor prognosis for HCC patients.	('expression', 'MPA', (20, 30))	('HCC', 'Disease', (62, 65))	('HCC', 'Disease', 'MESH:D006528', (62, 65))	('KHK-A', 'Protein', (14, 19))	('HCC', 'Phenotype', 'HP:0001402', (62, 65))	('patients', 'Species', '9606', (66, 74))	('high', 'Var', (9, 13))
557975	31750240	Thus, KHK-A reprograms HCC cell metabolism and other cellular activities by reducing fructose metabolism and increasing de novo nucleic acid synthesis and the antioxidative stress response by the protein kinase activity of KHK-A.	('fructose metabolism', 'Disease', 'MESH:D015318', (85, 104))	('HCC', 'Disease', 'MESH:D006528', (23, 26))	('increasing', 'PosReg', (109, 119))	('antioxidative stress', 'Phenotype', 'HP:0025464', (159, 179))	('reducing fructose metabolism', 'Phenotype', 'HP:0011033', (76, 104))	('HCC', 'Disease', (23, 26))	('protein', 'Enzyme', (196, 203))	('HCC', 'Phenotype', 'HP:0001402', (23, 26))	('oxidative stress', 'Phenotype', 'HP:0025464', (163, 179))	('de novo nucleic acid synthesis', 'MPA', (120, 150))	('reducing', 'NegReg', (76, 84))	('fructose metabolism', 'Disease', (85, 104))	('KHK-A', 'Var', (6, 11))	('antioxidative stress response', 'MPA', (159, 188))	('KHK-A', 'Gene', (223, 228))
557983	31750240	However, whether ACSS2 pS659 expression is a biomarker for the clinical features and prognosis of cancer is unknown.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('ACSS2', 'Gene', (17, 22))	('pS659', 'Var', (23, 28))	('cancer', 'Disease', (98, 104))	('ACSS2', 'Gene', '55902', (17, 22))
557984	31750240	In this study, we examined the expression of KHK-A and ACSS2 pS659 in human NSCLC specimens and the relationship between their abundance and clinical relevance in a large cohort of surgically resected NSCLCs.	('ACSS2', 'Gene', '55902', (55, 60))	('NSCLC', 'Phenotype', 'HP:0030358', (201, 206))	('NSCLC', 'Disease', (76, 81))	('NSCLCs', 'Disease', (201, 207))	('human', 'Species', '9606', (70, 75))	('NSCLC', 'Disease', (201, 206))	('NSCLC', 'Disease', 'MESH:D002289', (76, 81))	('pS659', 'Var', (61, 66))	('NSCLCs', 'Disease', 'MESH:D002289', (201, 207))	('NSCLC', 'Disease', 'MESH:D002289', (201, 206))	('ACSS2', 'Gene', (55, 60))	('NSCLC', 'Phenotype', 'HP:0030358', (76, 81))	('KHK-A', 'Gene', (45, 50))
557985	31750240	We found that both KHK-A and ACSS2 pS659 are independent prognostic factors for NSCLC patients after surgery, and the combination of KHK-A and ACSS2 pS659 can be used as a prognostic indicator for all stages of NSCLC.	('ACSS2', 'Gene', (29, 34))	('NSCLC', 'Phenotype', 'HP:0030358', (80, 85))	('ACSS2', 'Gene', '55902', (29, 34))	('NSCLC', 'Phenotype', 'HP:0030358', (211, 216))	('NSCLC', 'Disease', (80, 85))	('KHK-A', 'Var', (133, 138))	('NSCLC', 'Disease', (211, 216))	('ACSS2', 'Gene', (143, 148))	('NSCLC', 'Disease', 'MESH:D002289', (80, 85))	('ACSS2', 'Gene', '55902', (143, 148))	('NSCLC', 'Disease', 'MESH:D002289', (211, 216))	('patients', 'Species', '9606', (86, 94))
558007	31750240	In addition, high ACSS2 pS659 expression was associated with older age (P = 0.015) and advanced TNM stage (P = 0.048).	('pS659', 'Var', (24, 29))	('TNM', 'Gene', '10178', (96, 99))	('high', 'Var', (13, 17))	('TNM', 'Gene', (96, 99))	('ACSS2', 'Gene', (18, 23))	('ACSS2', 'Gene', '55902', (18, 23))
558009	31750240	In addition, high ACSS2 pS659 expression levels were also correlated with a poor 5-years OS rate (Figure 2B; high vs. low: 24.2 vs. 62.1%, P < 0.001).	('poor', 'NegReg', (76, 80))	('pS659', 'Var', (24, 29))	('high', 'Var', (13, 17))	('5-years OS rate', 'CPA', (81, 96))	('ACSS2', 'Gene', (18, 23))	('ACSS2', 'Gene', '55902', (18, 23))	('expression levels', 'MPA', (30, 47))
558011	31750240	We observed that OS was significantly different among the four subgroups (Figure 2C, P < 0.001) and that high expression of both KHK-A and ACSS2 pS659 appeared to have the worst prognosis with the lowest survival rates (5-years OS: 21.1%).	('ACSS2', 'Gene', '55902', (139, 144))	('lowest', 'NegReg', (197, 203))	('ACSS2', 'Gene', (139, 144))	('survival rates', 'CPA', (204, 218))	('pS659', 'Var', (145, 150))	('KHK-A', 'Gene', (129, 134))	('high expression', 'Var', (105, 120))
558012	31750240	In contrast, patients with low tumor expression of both KHK-A and ACSS2 pS659 had the best prognosis with the highest OS rate (5-years OS: 69.1%).	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('ACSS2', 'Gene', (66, 71))	('pS659', 'Var', (72, 77))	('low tumor', 'Disease', (27, 36))	('patients', 'Species', '9606', (13, 21))	('ACSS2', 'Gene', '55902', (66, 71))	('low tumor', 'Disease', 'MESH:D009800', (27, 36))	('KHK-A', 'Gene', (56, 61))
558016	31750240	Table 4 shows that the combination of KHK-A and ACSS2 pS659 was an independent predictor of OS (HR = 2.803, 95% CI = 1.920-4.094 for II vs.	('ACSS2', 'Gene', '55902', (48, 53))	('ACSS2', 'Gene', (48, 53))	('KHK-A', 'Gene', (38, 43))	('combination', 'Var', (23, 34))
558019	31750240	These results indicate that the combined expression of KHK-A and ACSS2 pS659 is inversely correlated with OS in all stages of NSCLC.	('KHK-A', 'Gene', (55, 60))	('NSCLC', 'Disease', 'MESH:D002289', (126, 131))	('correlated', 'Reg', (90, 100))	('expression', 'MPA', (41, 51))	('NSCLC', 'Phenotype', 'HP:0030358', (126, 131))	('ACSS2', 'Gene', (65, 70))	('ACSS2', 'Gene', '55902', (65, 70))	('pS659', 'Var', (71, 76))	('NSCLC', 'Disease', (126, 131))
558024	31750240	Of note, we showed that high expression levels of KHK-A and ACSS2 pS659 were correlated with reduced OS in NSCLC.	('NSCLC', 'Disease', (107, 112))	('pS659', 'Var', (66, 71))	('NSCLC', 'Disease', 'MESH:D002289', (107, 112))	('reduced', 'NegReg', (93, 100))	('ACSS2', 'Gene', '55902', (60, 65))	('ACSS2', 'Gene', (60, 65))	('KHK-A', 'Gene', (50, 55))	('expression levels', 'MPA', (29, 46))	('NSCLC', 'Phenotype', 'HP:0030358', (107, 112))
558031	31750240	High ACSS2 expression predicted a poor prognosis in patients with renal cell carcinoma and bladder cancer, whereas low ACSS2 expression predicted a poor prognosis in gastric cancer and hepatocellular carcinoma.	('gastric cancer', 'Disease', (166, 180))	('hepatocellular carcinoma', 'Disease', (185, 209))	('carcinoma', 'Phenotype', 'HP:0030731', (200, 209))	('ACSS2', 'Gene', (119, 124))	('renal cell carcinoma', 'Disease', 'MESH:D002292', (66, 86))	('ACSS2', 'Gene', (5, 10))	('gastric cancer', 'Disease', 'MESH:D013274', (166, 180))	('High', 'Var', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('patients', 'Species', '9606', (52, 60))	('renal cell carcinoma', 'Disease', (66, 86))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (185, 209))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (66, 86))	('ACSS2', 'Gene', '55902', (119, 124))	('gastric cancer', 'Phenotype', 'HP:0012126', (166, 180))	('carcinoma', 'Phenotype', 'HP:0030731', (77, 86))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (185, 209))	('bladder cancer', 'Disease', 'MESH:D001749', (91, 105))	('ACSS2', 'Gene', '55902', (5, 10))	('bladder cancer', 'Disease', (91, 105))	('bladder cancer', 'Phenotype', 'HP:0009725', (91, 105))	('low', 'NegReg', (115, 118))
558032	31750240	Our previous study showed that the phosphorylation of ACSS2 at S659 rather than its expression level is critical for GBM cells to counteract energy stress.	('ACSS2', 'Gene', '55902', (54, 59))	('phosphorylation', 'MPA', (35, 50))	('ACSS2', 'Gene', (54, 59))	('at S659', 'Var', (60, 67))
558033	31750240	S659-phosphorylated ACSS2 translocates to the nucleus, leading to the binding to downstream genes and acetyl-CoA production, which induces histone acetylation and gene expression for glioma development.	('acetyl', 'Chemical', 'MESH:C011632', (102, 108))	('acetyl', 'Chemical', 'MESH:C011632', (147, 153))	('glioma', 'Disease', (183, 189))	('binding', 'Interaction', (70, 77))	('histone acetylation', 'MPA', (139, 158))	('acetyl-CoA', 'MPA', (102, 112))	('S659-phosphorylated', 'Var', (0, 19))	('acetyl-CoA', 'Chemical', 'MESH:D000105', (102, 112))	('ACSS2', 'Gene', '55902', (20, 25))	('ACSS2', 'Gene', (20, 25))	('induces', 'PosReg', (131, 138))	('glioma', 'Disease', 'MESH:D005910', (183, 189))	('glioma', 'Phenotype', 'HP:0009733', (183, 189))	('gene expression', 'MPA', (163, 178))
558035	31750240	We showed here that the combination of KHK-A and ACSS2 pS659 was an independent prognostic biomarker for NSCLC and was inversely related with OS in all stages of NSCLC.	('NSCLC', 'Disease', 'MESH:D002289', (105, 110))	('ACSS2', 'Gene', '55902', (49, 54))	('NSCLC', 'Phenotype', 'HP:0030358', (105, 110))	('NSCLC', 'Disease', (162, 167))	('KHK-A', 'Gene', (39, 44))	('related', 'Reg', (129, 136))	('combination', 'Var', (24, 35))	('NSCLC', 'Disease', 'MESH:D002289', (162, 167))	('NSCLC', 'Disease', (105, 110))	('ACSS2', 'Gene', (49, 54))	('NSCLC', 'Phenotype', 'HP:0030358', (162, 167))
558058	29037201	The dysregulation of lncRNAs plays pivotal roles in many kinds of diseases, particularly in cancer.	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('dysregulation', 'Var', (4, 17))	('roles', 'Reg', (43, 48))	('lncRNAs', 'Protein', (21, 28))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))
558100	27994498	The current study explored the effect of survivin gene polymorphisms and EGFR mutations in non-small-cell lung carcinoma (NSCLC) patients.	('NSCLC', 'Disease', 'MESH:D002289', (122, 127))	('carcinoma', 'Phenotype', 'HP:0030731', (111, 120))	('EGFR', 'Gene', '1956', (73, 77))	('small-cell lung carcinoma', 'Phenotype', 'HP:0030357', (95, 120))	('patients', 'Species', '9606', (129, 137))	('EGFR', 'Gene', (73, 77))	('lung carcinoma', 'Disease', 'MESH:D008175', (106, 120))	('mutations', 'Var', (78, 87))	('NSCLC', 'Phenotype', 'HP:0030358', (122, 127))	('lung carcinoma', 'Disease', (106, 120))	('non-small-cell lung carcinoma', 'Phenotype', 'HP:0030358', (91, 120))	('NSCLC', 'Disease', (122, 127))	('survivin', 'Protein', (41, 49))
558101	27994498	A total of 360 participants, including 291 adenocarcinoma lung cancer and 69 squamous cell carcinoma lung cancer patients, were selected for the analysis of three survivin genetic variants (survivin -31, +9194, and +9809) by using real-time PCR genotyping.	('adenocarcinoma lung cancer', 'Disease', (43, 69))	('squamous cell carcinoma lung cancer', 'Disease', (77, 112))	('participants', 'Species', '9606', (15, 27))	('squamous cell carcinoma lung cancer', 'Disease', 'MESH:D002294', (77, 112))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))	('adenocarcinoma lung cancer', 'Disease', 'MESH:D008175', (43, 69))	('patients', 'Species', '9606', (113, 121))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (77, 100))	('carcinoma', 'Phenotype', 'HP:0030731', (48, 57))	('lung cancer', 'Phenotype', 'HP:0100526', (58, 69))	('adenocarcinoma lung cancer', 'Phenotype', 'HP:0030078', (43, 69))	('survivin', 'Gene', (163, 171))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('lung cancer', 'Phenotype', 'HP:0100526', (101, 112))	('squamous cell carcinoma lung cancer', 'Phenotype', 'HP:0030359', (77, 112))	('survivin -31', 'Var', (190, 202))
558102	27994498	The results indicated that GC+CC genotypes of survivin -31 were significant association with EGFR mutation in lung adenocarcinoma patients (adjusted odds ratio=3.498, 95% CI = 1.171-10.448; p<0.01).	('survivin -31', 'Gene', (46, 58))	('association', 'Reg', (76, 87))	('EGFR', 'Gene', '1956', (93, 97))	('mutation', 'Var', (98, 106))	('lung adenocarcinoma', 'Disease', (110, 129))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (110, 129))	('GC+CC', 'Var', (27, 32))	('EGFR', 'Gene', (93, 97))	('patients', 'Species', '9606', (130, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (110, 129))
558103	27994498	Moreover, The GC+CC genotypes of survivin -31 were associated with EGFR L858R mutation but not in exon 19 in-frame deletions.	('survivin -31', 'Gene', (33, 45))	('GC+CC', 'Var', (14, 19))	('associated', 'Reg', (51, 61))	('L858R mutation', 'Var', (72, 86))	('L858R', 'Mutation', 'rs121434568', (72, 77))	('EGFR', 'Gene', '1956', (67, 71))	('EGFR', 'Gene', (67, 71))
558104	27994498	Furthermore, among patients in exon 19 in-frame deletions, those who have at least one polymorphic G allele of survivin -31 have an increased incidence to develop late-stage when compared with those patients homozygous for C/C (OR, 4.800; 95% CI, 1.305-17.658).	('survivin', 'Gene', (111, 119))	('patients', 'Species', '9606', (199, 207))	('patients', 'Species', '9606', (19, 27))	('in-frame deletions', 'Var', (39, 57))
558105	27994498	In conclusion, our results showed that survivin genetic variants were related to EGFR mutation in lung adenocarcinoma patients and might contribute to pathological development to NSCLC.	('carcinoma', 'Phenotype', 'HP:0030731', (108, 117))	('NSCLC', 'Disease', 'MESH:D002289', (179, 184))	('related', 'Reg', (70, 77))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (98, 117))	('contribute to', 'Reg', (137, 150))	('variants', 'Var', (56, 64))	('NSCLC', 'Phenotype', 'HP:0030358', (179, 184))	('survivin', 'Protein', (39, 47))	('mutation', 'Var', (86, 94))	('lung adenocarcinoma', 'Disease', (98, 117))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (98, 117))	('patients', 'Species', '9606', (118, 126))	('EGFR', 'Gene', '1956', (81, 85))	('NSCLC', 'Disease', (179, 184))	('EGFR', 'Gene', (81, 85))
558108	27994498	The effect of EGFR tyrosine kinase inhibitors (EGFR-TKI) has been linked to EGFR mutations in cancer cells, most of which are exon 19 deletions followed by exon 21 L858R mutations.	('EGFR', 'Gene', '1956', (14, 18))	('L858R', 'Var', (164, 169))	('EGFR', 'Gene', (14, 18))	('EGFR', 'Gene', '1956', (76, 80))	('L858R', 'Mutation', 'rs121434568', (164, 169))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('EGFR', 'Gene', (76, 80))	('cancer', 'Disease', (94, 100))	('mutations', 'Var', (81, 90))	('EGFR', 'Gene', '1956', (47, 51))	('EGFR', 'Gene', (47, 51))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
558109	27994498	Current studies on EGFR mutations have shown a higher tendency of EGFR mutations in adenocarcinoma, such as in female cancer patients with no smoking history.	('adenocarcinoma', 'Disease', 'MESH:D000230', (84, 98))	('cancer', 'Disease', (118, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('EGFR', 'Gene', '1956', (66, 70))	('EGFR', 'Gene', (66, 70))	('EGFR', 'Gene', '1956', (19, 23))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('mutations', 'Var', (71, 80))	('EGFR', 'Gene', (19, 23))	('adenocarcinoma', 'Disease', (84, 98))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('patients', 'Species', '9606', (125, 133))
558110	27994498	Regarding racial differences in EGFR mutations, EGFR mutations have been observed in approximately 12%-15% of Caucasian patients with lung adenocarcinoma, but the rate can be as high as 60% in Asian populations.	('EGFR', 'Gene', '1956', (48, 52))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (134, 153))	('EGFR', 'Gene', '1956', (32, 36))	('EGFR', 'Gene', (48, 52))	('mutations', 'Var', (53, 62))	('lung adenocarcinoma', 'Disease', (134, 153))	('mutations', 'Var', (37, 46))	('patients', 'Species', '9606', (120, 128))	('EGFR', 'Gene', (32, 36))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (134, 153))
558112	27994498	Nevertheless, even in patients with EGFR mutations, the treatment efficacy of these drugs is only approximately 60%-70%.	('mutations', 'Var', (41, 50))	('EGFR', 'Gene', (36, 40))	('patients', 'Species', '9606', (22, 30))	('EGFR', 'Gene', '1956', (36, 40))
558120	27994498	In fact, the SNP of survivin influences the severity and prognosis of many types of cancer including stomach, colorectal, and lung cancer.	('colorectal', 'Disease', (110, 120))	('survivin', 'Protein', (20, 28))	('cancer', 'Disease', (131, 137))	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('lung cancer', 'Disease', 'MESH:D008175', (126, 137))	('cancer', 'Disease', (84, 90))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('stomach', 'Disease', (101, 108))	('lung cancer', 'Disease', (126, 137))	('lung cancer', 'Phenotype', 'HP:0100526', (126, 137))	('influences', 'Reg', (29, 39))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('SNP', 'Var', (13, 16))
558121	27994498	Although the SNP of survivin -31 G/C and other SNPs that can affect survivin expression, the association between the SNP of survivin and EGFR mutations in NSCLC still needs to be verified.	('EGFR', 'Gene', (137, 141))	('mutations', 'Var', (142, 151))	('expression', 'MPA', (77, 87))	('survivin', 'Gene', (124, 132))	('NSCLC', 'Disease', (155, 160))	('-31 G/C', 'Var', (29, 36))	('affect', 'Reg', (61, 67))	('NSCLC', 'Disease', 'MESH:D002289', (155, 160))	('survivin', 'Protein', (68, 76))	('EGFR', 'Gene', '1956', (137, 141))	('NSCLC', 'Phenotype', 'HP:0030358', (155, 160))	('-31 G/C', 'SUBSTITUTION', 'None', (29, 36))
558122	27994498	Moreover, the high EGFR mutation rate, including L858R in exon 21 or in-frame deletion in exon 19, was found in Taiwan populations.	('in-frame deletion', 'Var', (69, 86))	('EGFR', 'Gene', '1956', (19, 23))	('L858R', 'Var', (49, 54))	('EGFR', 'Gene', (19, 23))	('L858R', 'Mutation', 'rs121434568', (49, 54))
558123	27994498	Therefore, the present study examined the association between survivin SNP and EGFR mutations and explored the association between survivin SNP and the clinicopathological characteristics in NSCLC.	('EGFR', 'Gene', '1956', (79, 83))	('survivin', 'Gene', (62, 70))	('EGFR', 'Gene', (79, 83))	('NSCLC', 'Phenotype', 'HP:0030358', (191, 196))	('association', 'Interaction', (42, 53))	('mutations', 'Var', (84, 93))	('NSCLC', 'Disease', (191, 196))	('NSCLC', 'Disease', 'MESH:D002289', (191, 196))	('examined', 'Reg', (29, 37))
558128	27994498	Allelic discrimination of survivin -31, +9194, and +9809 gene polymorphism was assessed with the ABI StepOne  Real-Time PCR System (Applied Biosystems, Foster City, CA, USA) and analyzed using SDS vers.	('survivin', 'Gene', (26, 34))	('SDS', 'Chemical', 'MESH:D012967', (193, 196))	('+9809', 'Var', (51, 56))	('+9194', 'Var', (40, 45))
278794	27994498	The odds ratio and 95% CIs of the association between the genotype frequencies and EGFR mutation risk and the clinical pathological characteristics were estimated using multiple logistic regression models after controlling for other covariates.	('EGFR', 'Gene', '1956', (83, 87))	('mutation', 'Var', (88, 96))	('EGFR', 'Gene', (83, 87))
558135	27994498	The distribution frequency of survivin -31, +9194 and +9809 genotypes in the lung adenocarcinoma and squamous cell carcinoma are shown in Table 2.	('survivin', 'Gene', (30, 38))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (77, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (115, 124))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (101, 124))	('lung adenocarcinoma', 'Disease', (77, 96))	('+9194', 'Var', (44, 49))	('+9809', 'Var', (54, 59))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (77, 96))	('adenocarcinoma and squamous cell carcinoma', 'Disease', 'MESH:D002294', (82, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))
558136	27994498	The alleles with the highest distribution frequency for -31, +9194 and +9809 of survivin in recruited patients with NSCLC were heterozygous C/G, homozygous A/A, and heterozygous T/C, respectively.	('NSCLC', 'Disease', 'MESH:D002289', (116, 121))	('C/G', 'Var', (140, 143))	('patients', 'Species', '9606', (102, 110))	('+9194', 'Var', (61, 66))	('NSCLC', 'Phenotype', 'HP:0030358', (116, 121))	('+9809', 'Var', (71, 76))	('survivin', 'Gene', (80, 88))	('NSCLC', 'Disease', (116, 121))
558137	27994498	After adjusting variables, there was no significant difference between the lung adenocarcinoma and squamous cell carcinoma with polymorphisms of the survivin -31, +9194 and +9809 genotypes when compared with wild-type individuals.	('survivin -31', 'Gene', (149, 161))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (75, 94))	('+9194', 'Var', (163, 168))	('+9809', 'Var', (173, 178))	('lung adenocarcinoma', 'Disease', (75, 94))	('adenocarcinoma and squamous cell carcinoma', 'Disease', 'MESH:D002294', (80, 122))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (99, 122))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (75, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (113, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('polymorphisms', 'Var', (128, 141))
558138	27994498	We further investigated the associations between EGFR mutations and patient's characteristics.	('EGFR', 'Gene', '1956', (49, 53))	('patient', 'Species', '9606', (68, 75))	('investigated', 'Reg', (11, 23))	('EGFR', 'Gene', (49, 53))	('mutations', 'Var', (54, 63))
558139	27994498	As shown in Table 3, both substitution mutation (L858R) and Exon 19 in-frame deletion mutations were shown higher percentage in female patients (male vs. female = 19.2% vs. 80.8% and 44.9% vs. 55.1%, respectively) and in never-smoker patients (never-smokers vs. ever-smokers = 88.5% vs.11.5% and 73.5% vs. 26.5%, respectively).	('substitution mutation (L858R', 'Var', (26, 54))	('patients', 'Species', '9606', (135, 143))	('L858R', 'Var', (49, 54))	('patients', 'Species', '9606', (234, 242))	('L858R', 'Mutation', 'rs121434568', (49, 54))
558140	27994498	The data of distribution were shown significantly different between control (wild-type) and EGFR mutations in gender (p<0.05) and cigarette smoking status (p<0.05).	('EGFR', 'Gene', (92, 96))	('mutations', 'Var', (97, 106))	('different', 'Reg', (50, 59))	('EGFR', 'Gene', '1956', (92, 96))
558141	27994498	These results indicated that EGFR mutations were associated with gender and cigarette smoking status.	('EGFR', 'Gene', '1956', (29, 33))	('associated', 'Reg', (49, 59))	('EGFR', 'Gene', (29, 33))	('mutations', 'Var', (34, 43))
558142	27994498	To clarify the association between the polymorphism of survivin gene and EGFR mutation, the distribution frequency of survivin (-31, +9194 and +9809) gene genotypes and EGFR mutation type in lung adenocarcinoma patients were estimated.	('EGFR', 'Gene', '1956', (73, 77))	('patients', 'Species', '9606', (211, 219))	('carcinoma', 'Phenotype', 'HP:0030731', (201, 210))	('EGFR', 'Gene', (73, 77))	('lung adenocarcinoma', 'Disease', (191, 210))	('EGFR', 'Gene', '1956', (169, 173))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (191, 210))	('EGFR', 'Gene', (169, 173))	('-31', 'Var', (128, 131))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (191, 210))
558143	27994498	As the results shown in Table 4, GC and GC+CC genotypes of survivin -31 were shown significantly association with EGFR mutation in lung adenocarcinoma patients (AOR = 3.622, 95% CI = 1.158-11.325 and AOR = 3.498, 95% CI = 1.171-10.448, respectively).	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('mutation', 'Var', (119, 127))	('lung adenocarcinoma', 'Disease', (131, 150))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (131, 150))	('patients', 'Species', '9606', (151, 159))	('EGFR', 'Gene', '1956', (114, 118))	('association', 'Interaction', (97, 108))	('EGFR', 'Gene', (114, 118))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (131, 150))
558144	27994498	Moreover, the results of Table 5 were shown that GC+CC genotypes of survivin -31 were shown slightly association with L858R mutation in lung adenocarcinoma patients (AOR = 0.5187, 95% CI = 0.935-2.242).	('patients', 'Species', '9606', (156, 164))	('carcinoma', 'Phenotype', 'HP:0030731', (146, 155))	('survivin -31', 'Gene', (68, 80))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (136, 155))	('GC+CC', 'Var', (49, 54))	('association', 'Interaction', (101, 112))	('lung adenocarcinoma', 'Disease', (136, 155))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (136, 155))	('L858R', 'Var', (118, 123))	('L858R', 'Mutation', 'rs121434568', (118, 123))
558145	27994498	These results indicated the polymorphism of survivin -31 genes were associated with EGFR mutation in adenocarcinoma patients.	('survivin -31', 'Gene', (44, 56))	('polymorphism', 'Var', (28, 40))	('associated', 'Reg', (68, 78))	('adenocarcinoma', 'Disease', 'MESH:D000230', (101, 115))	('patients', 'Species', '9606', (116, 124))	('mutation', 'Var', (89, 97))	('EGFR', 'Gene', '1956', (84, 88))	('carcinoma', 'Phenotype', 'HP:0030731', (106, 115))	('EGFR', 'Gene', (84, 88))	('adenocarcinoma', 'Disease', (101, 115))
558146	27994498	Associations between survivin SNPs and clinicopathological characteristics of lung cancer To revealed the association between polymorphisms of survivin gene and different clinical stage of lung cancer in different EGFR mutation of patients.	('lung cancer', 'Disease', (78, 89))	('lung cancer', 'Phenotype', 'HP:0100526', (78, 89))	('Associations', 'Interaction', (0, 12))	('association', 'Interaction', (106, 117))	('patients', 'Species', '9606', (231, 239))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('polymorphisms', 'Var', (126, 139))	('survivin gene', 'Gene', (143, 156))	('EGFR', 'Gene', '1956', (214, 218))	('lung cancer', 'Phenotype', 'HP:0100526', (189, 200))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('lung cancer', 'Disease', 'MESH:D008175', (78, 89))	('lung cancer', 'Disease', (189, 200))	('EGFR', 'Gene', (214, 218))	('lung cancer', 'Disease', 'MESH:D008175', (189, 200))
558147	27994498	As shown in Table 6, CG+GG genotype of survivin -31 was shown significantly association with clinical advanced stage in lung adenocarcinoma patients with exon 19 mutations (OR = 4.800, 95% CI = 1.305-17.658; p=0.014).	('association', 'Reg', (76, 87))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (120, 139))	('survivin -31', 'Gene', (39, 51))	('mutations', 'Var', (162, 171))	('CG', 'Chemical', 'MESH:C028505', (21, 23))	('exon 19 mutations', 'Var', (154, 171))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (120, 139))	('patients', 'Species', '9606', (140, 148))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('CG+GG', 'Var', (21, 26))	('lung adenocarcinoma', 'Disease', (120, 139))
558148	27994498	These findings indicated that the polymorphisms of survivin -31 may associated with clinical advanced stage of lung cancer.	('associated with', 'Reg', (68, 83))	('lung cancer', 'Disease', 'MESH:D008175', (111, 122))	('polymorphisms', 'Var', (34, 47))	('survivin -31', 'Gene', (51, 63))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('lung cancer', 'Disease', (111, 122))	('lung cancer', 'Phenotype', 'HP:0100526', (111, 122))
558150	27994498	However, few studies have investigated how SNP is related to EGFR mutations or prognosis in lung cancer.	('mutations', 'Var', (66, 75))	('lung cancer', 'Disease', (92, 103))	('lung cancer', 'Phenotype', 'HP:0100526', (92, 103))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('lung cancer', 'Disease', 'MESH:D008175', (92, 103))	('EGFR', 'Gene', '1956', (61, 65))	('EGFR', 'Gene', (61, 65))
558151	27994498	The present study revealed that survivin -31 polymorphism may be associated with EGFR mutations, particularly L858R mutations.	('mutations', 'Var', (86, 95))	('polymorphism', 'Var', (45, 57))	('L858R mutations', 'Var', (110, 125))	('associated', 'Reg', (65, 75))	('L858R', 'Mutation', 'rs121434568', (110, 115))	('survivin -31', 'Protein', (32, 44))	('EGFR', 'Gene', '1956', (81, 85))	('EGFR', 'Gene', (81, 85))
558152	27994498	Furthermore, in patients with exon 19 mutations, survivin -31 polymorphisms have an increased incidence to develop late-stage.	('exon 19 mutations', 'Var', (30, 47))	('patients', 'Species', '9606', (16, 24))	('polymorphisms', 'Var', (62, 75))	('survivin -31', 'Gene', (49, 61))	('mutations', 'Var', (38, 47))
558153	27994498	To our best knowledge, the present study is the first reports to show a link between survivin SNP and EGFR mutations in patients with lung cancer.	('lung cancer', 'Disease', (134, 145))	('lung cancer', 'Phenotype', 'HP:0100526', (134, 145))	('mutations', 'Var', (107, 116))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('EGFR', 'Gene', (102, 106))	('lung cancer', 'Disease', 'MESH:D008175', (134, 145))	('patients', 'Species', '9606', (120, 128))	('EGFR', 'Gene', '1956', (102, 106))	('link', 'Reg', (72, 76))	('survivin', 'Protein', (85, 93))
558156	27994498	The present study also identified an association between survivin -31 polymorphism and the EGFR mutation statues, suggesting that EGFR mutations may impair the effect of TKIs; that is, patients with survivin -31G/G genotypes may have higher survivin protein expression.	('EGFR', 'Gene', (91, 95))	('effect', 'MPA', (160, 166))	('mutations', 'Var', (135, 144))	('survivin protein', 'Protein', (241, 257))	('survivin -31G/G', 'Var', (199, 214))	('impair', 'NegReg', (149, 155))	('patients', 'Species', '9606', (185, 193))	('higher', 'PosReg', (234, 240))	('EGFR', 'Gene', '1956', (130, 134))	('EGFR', 'Gene', (130, 134))	('EGFR', 'Gene', '1956', (91, 95))
558157	27994498	The results were consistent with previous reports that an association between SNP of survivin and lung cancer as well as higher transcriptional activity in the C/C genotype, the latter of which may elevate survivin protein expression.	('survivin', 'Gene', (85, 93))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('lung cancer', 'Disease', (98, 109))	('survivin protein', 'Protein', (206, 222))	('lung cancer', 'Phenotype', 'HP:0100526', (98, 109))	('lung cancer', 'Disease', 'MESH:D008175', (98, 109))	('SNP', 'Var', (78, 81))	('higher', 'PosReg', (121, 127))	('elevate', 'PosReg', (198, 205))
558158	27994498	In addition to linking the SNP of survivin -31C/G to the incidence of lung cancer, previous studies have also revealed some clinical manifestations related to survivin -31 C/G polymorphism.	('lung cancer', 'Disease', 'MESH:D008175', (70, 81))	('-31 C/G', 'Mutation', 'rs1405874622', (168, 175))	('lung cancer', 'Disease', (70, 81))	('lung cancer', 'Phenotype', 'HP:0100526', (70, 81))	('-31C/G', 'SUBSTITUTION', 'None', (43, 49))	('survivin -31', 'Gene', (159, 171))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('-31C/G', 'Var', (43, 49))
558162	27994498	The present study showed that survivin -31C/C was stage-related in patients with EGFR exon 19 mutations.	('patients', 'Species', '9606', (67, 75))	('mutations', 'Var', (94, 103))	('survivin -31C/C', 'Protein', (30, 45))	('exon 19 mutations', 'Var', (86, 103))	('EGFR', 'Gene', '1956', (81, 85))	('EGFR', 'Gene', (81, 85))
558163	27994498	However, this relation was not observed in the EGFR wild type or in lung cancer patients with L858R mutations.	('lung cancer', 'Disease', (68, 79))	('patients', 'Species', '9606', (80, 88))	('lung cancer', 'Phenotype', 'HP:0100526', (68, 79))	('L858R mutations', 'Var', (94, 109))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('lung cancer', 'Disease', 'MESH:D008175', (68, 79))	('EGFR', 'Gene', '1956', (47, 51))	('L858R', 'Mutation', 'rs121434568', (94, 99))	('EGFR', 'Gene', (47, 51))
558164	27994498	A possible explanation is that the effect of survivin differs according to the type of EGFR mutation.	('survivin', 'Protein', (45, 53))	('mutation', 'Var', (92, 100))	('EGFR', 'Gene', '1956', (87, 91))	('EGFR', 'Gene', (87, 91))
558166	27994498	Another possibility is that EGFR L858R and exon 19 mutations exists different oncogenic ability.	('L858R', 'Mutation', 'rs121434568', (33, 38))	('EGFR', 'Gene', '1956', (28, 32))	('oncogenic ability', 'CPA', (78, 95))	('EGFR', 'Gene', (28, 32))	('exon 19', 'Var', (43, 50))	('L858R', 'Var', (33, 38))
558167	27994498	Although the previous study showed exon 19 to have a higher oncogenic ability compared with that of L858R, the role of survivin in these two distinct mutation processes requires further examination.	('exon', 'Var', (35, 39))	('higher', 'PosReg', (53, 59))	('oncogenic ability', 'CPA', (60, 77))	('L858R', 'Mutation', 'rs121434568', (100, 105))
558168	27994498	In conclusion, our results showed that survivin genetic variants are related to EGFR mutation in lung adenocarcinoma patients and might contribute to pathological development to NSCLC.	('carcinoma', 'Phenotype', 'HP:0030731', (107, 116))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (97, 116))	('NSCLC', 'Disease', (178, 183))	('NSCLC', 'Disease', 'MESH:D002289', (178, 183))	('lung adenocarcinoma', 'Disease', (97, 116))	('EGFR', 'Gene', '1956', (80, 84))	('mutation', 'Var', (85, 93))	('EGFR', 'Gene', (80, 84))	('variants', 'Var', (56, 64))	('contribute to', 'Reg', (136, 149))	('survivin', 'Protein', (39, 47))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (97, 116))	('NSCLC', 'Phenotype', 'HP:0030358', (178, 183))	('patients', 'Species', '9606', (117, 125))	('related', 'Reg', (69, 76))
558169	27994498	The findings provide a hint for the genesis of EGFR mutations.	('mutations', 'Var', (52, 61))	('EGFR', 'Gene', '1956', (47, 51))	('EGFR', 'Gene', (47, 51))
558176	27562343	These data provide statistical evidence that inactivation of cell fate-specifying transcription factors in cancer is an important step in carcinogenesis and that it occurs predominantly through a mechanism associated with promoter hypermethylation.	('inactivation', 'NegReg', (45, 57))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('promoter hypermethylation', 'Var', (222, 247))	('carcinogenesis', 'Disease', 'MESH:D063646', (138, 152))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('cancer', 'Disease', (107, 113))	('carcinogenesis', 'Disease', (138, 152))
558177	27562343	Biological evidence for this model has recently come from studies showing how genetic mutations in epigenetic regulators such as isocitrate dehydrogenases can result in the inactivation of key transcription factors, promoting cancer.	('result in', 'Reg', (159, 168))	('inactivation', 'MPA', (173, 185))	('genetic mutations', 'Var', (78, 95))	('isocitrate dehydrogenases', 'Gene', (129, 154))	('cancer', 'Disease', (226, 232))	('key', 'Protein', (189, 192))	('cancer', 'Disease', 'MESH:D009369', (226, 232))	('promoting', 'PosReg', (216, 225))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
558181	27562343	Moreover, inactivation of key transcription factors has been associated with other epigenetic alterations such as histone remodelling, raising further questions as to the role of the observed DNA hypermethylation in cancer.	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('inactivation', 'Var', (10, 22))	('histone', 'MPA', (114, 121))	('cancer', 'Disease', (216, 222))	('cancer', 'Disease', 'MESH:D009369', (216, 222))	('associated', 'Reg', (61, 71))
558182	27562343	For instance, epigenetic silencing of HNF4A (a key liver-specifying TF) in liver cancer has been linked to loss of promoter H3K4me3 without changes in promoter methylation.	('HNF4A', 'Gene', (38, 43))	('liver cancer', 'Disease', (75, 87))	('loss', 'NegReg', (107, 111))	('epigenetic silencing', 'Var', (14, 34))	('promoter H3K4me3', 'Protein', (115, 131))	('liver cancer', 'Phenotype', 'HP:0002896', (75, 87))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('HNF4A', 'Gene', '3172', (38, 43))	('liver cancer', 'Disease', 'MESH:D006528', (75, 87))
558183	27562343	Given the large-scale availability of mutational, copy number variation (CNV) and DNA methylation data in primary cancer material, no study has yet systematically explored which mechanism, i.e.	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('copy number variation', 'Var', (50, 71))	('cancer', 'Disease', (114, 120))
558184	27562343	mutation, CNV loss, or promoter hypermethylation, is predominantly associated with in-cis silencing of transcription factors in cancer.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('CNV loss', 'Disease', 'MESH:D015431', (10, 18))	('CNV loss', 'Disease', (10, 18))	('in-cis', 'MPA', (83, 89))	('mutation', 'Var', (0, 8))	('promoter hypermethylation', 'Var', (23, 48))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('cancer', 'Disease', (128, 134))
558191	27562343	This resulted in an expression data set of 17,967 uniquely annotated Entrez gene IDs and 239 samples, including 107 hESC lines, 52 induced pluripotent stem cells and 32 somatic differentiated tissue samples, with the rest of the samples representing human cell lines.	('Entrez gene', 'Gene', (69, 80))	('human', 'Species', '9606', (250, 255))	('IDs', 'Var', (81, 84))
558193	27562343	However, the stomach samples were not considered further because the top principal component of variation in the corresponding stomach adenocarcinoma (STAD) TCGA data set correlated with an unknown confounding factor, most likely representing cellular heterogeneity.	('variation', 'Var', (96, 105))	('stomach adenocarcinoma', 'Disease', 'MESH:D013274', (127, 149))	('correlated', 'Reg', (171, 181))	('carcinoma', 'Phenotype', 'HP:0030731', (140, 149))	('stomach adenocarcinoma', 'Disease', (127, 149))
558212	27562343	We hypothesized that TFs which are important for differentiation of a tissue type, and which are, therefore, expressed in that tissue type, may be under selection pressure to undergo silencing in the corresponding cancer type.	('cancer', 'Phenotype', 'HP:0002664', (214, 220))	('silencing', 'Var', (183, 192))	('cancer', 'Disease', (214, 220))	('cancer', 'Disease', 'MESH:D009369', (214, 220))
558217	27562343	As a concrete example, FOXA1 (HNF4A) is a transcription factor important for the specification of the intestine and stomach as well as liver and silencing of HNF4A leads to liver cancer.	('liver cancer', 'Disease', (173, 185))	('HNF4A', 'Gene', (158, 163))	('FOXA1', 'Gene', '3169', (23, 28))	('leads to', 'Reg', (164, 172))	('silencing', 'Var', (145, 154))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('HNF4A', 'Gene', '3172', (30, 35))	('FOXA1', 'Gene', (23, 28))	('liver cancer', 'Disease', 'MESH:D006528', (173, 185))	('liver cancer', 'Phenotype', 'HP:0002896', (173, 185))	('HNF4A', 'Gene', '3172', (158, 163))	('HNF4A', 'Gene', (30, 35))
558224	27562343	In the case of colon cancer, silenced TFs included well known intestinal differentiation factors such as CDX1, CDX2 and NEUROD1.	('colon cancer', 'Phenotype', 'HP:0003003', (15, 27))	('NEUROD1', 'Gene', '4760', (120, 127))	('colon cancer', 'Disease', 'MESH:D015179', (15, 27))	('CDX1', 'Gene', '1044', (105, 109))	('CDX2', 'Gene', '1045', (111, 115))	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('NEUROD1', 'Gene', (120, 127))	('colon cancer', 'Disease', (15, 27))	('CDX1', 'Gene', (105, 109))	('silenced', 'Var', (29, 37))	('included', 'Reg', (42, 50))	('CDX2', 'Gene', (111, 115))
558230	27562343	In order to assess the statistical and biological significance of these observations, we next compared the degree of molecular alteration of the silenced TFs with that of all genes underexpressed in the given cancer type, as well as to a randomly chosen set of genes, a procedure which adjusts for the differential sensitivity of the different molecular assays.	('cancer', 'Disease', 'MESH:D009369', (209, 215))	('silenced', 'Var', (145, 153))	('cancer', 'Disease', (209, 215))	('TFs', 'Gene', (154, 157))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
558231	27562343	Likewise, the average frequency of inactivating mutations of these TFs across cancers was generally not higher compared with underexpressed genes or randomly selected genes (Fig.	('inactivating mutations', 'Var', (35, 57))	('cancers', 'Phenotype', 'HP:0002664', (78, 85))	('cancers', 'Disease', 'MESH:D009369', (78, 85))	('cancers', 'Disease', (78, 85))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))
558232	27562343	In general, for each cancer type there were more TFs and tumours with significant positive differential methylation statistics than the corresponding expected number had the genes been drawn from the set of all cancer underexpressed genes (Additional file 1: Figure S12).	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('cancer', 'Disease', 'MESH:D009369', (211, 217))	('tumours', 'Phenotype', 'HP:0002664', (57, 64))	('cancer', 'Phenotype', 'HP:0002664', (211, 217))	('cancer', 'Disease', (211, 217))	('tumours', 'Disease', 'MESH:D009369', (57, 64))	('tumours', 'Disease', (57, 64))	('methylation', 'Var', (104, 115))	('cancer', 'Disease', (21, 27))	('cancer', 'Disease', 'MESH:D009369', (21, 27))	('tumour', 'Phenotype', 'HP:0002664', (57, 63))
558234	27562343	Using a meta-analysis over all cancer types, it was only for the case of promoter hypermethylation that we observed a significantly higher level of alteration at the silenced TFs compared with all underexpressed genes (Table 1; P < 10-8 for promoter hypermethylation, P = 0.98 for CNV loss and P = 0.47 for mutation, combined Fisher test).	('promoter hypermethylation', 'Var', (73, 98))	('higher', 'PosReg', (132, 138))	('alteration', 'MPA', (148, 158))	('cancer', 'Disease', (31, 37))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('CNV loss', 'Disease', (281, 289))	('mutation', 'Var', (307, 315))	('CNV loss', 'Disease', 'MESH:D015431', (281, 289))	('TFs', 'Gene', (175, 178))
558235	27562343	We note that if we compared all underexpressed genes in a given cancer type to a randomly selected set of genes, then all molecular categories were significant, consistent with the view that all molecular events, be it promoter hypermethylation, CNV loss or inactivating mutation, are associated with underexpression in cancer (Additional file 1: Figure S14).	('inactivating mutation', 'Var', (258, 279))	('underexpression', 'MPA', (301, 316))	('cancer', 'Disease', (64, 70))	('cancer', 'Disease', 'MESH:D009369', (64, 70))	('cancer', 'Phenotype', 'HP:0002664', (320, 326))	('cancer', 'Disease', 'MESH:D009369', (320, 326))	('CNV loss', 'Disease', (246, 254))	('CNV loss', 'Disease', 'MESH:D015431', (246, 254))	('promoter hypermethylation', 'Var', (219, 244))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('cancer', 'Disease', (320, 326))
558236	27562343	4 and Table 1 suggest that promoter hypermethylation is the more likely mechanism associated with in-cis TF silencing in cancer.	('silencing', 'NegReg', (108, 117))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('cancer', 'Disease', (121, 127))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('promoter hypermethylation', 'Var', (27, 52))
558239	27562343	For each TF and across all tumours exhibiting underexpression of this TF, we then counted the fraction of tumours exhibiting genomic loss of the TF, as well as the fraction of tumours exhibiting hypermethylation of the TF's promoter ("Methods").	('tumours', 'Disease', 'MESH:D009369', (176, 183))	('tumours', 'Disease', (176, 183))	('tumour', 'Phenotype', 'HP:0002664', (106, 112))	('tumours', 'Phenotype', 'HP:0002664', (106, 113))	('tumour', 'Phenotype', 'HP:0002664', (27, 33))	('tumour', 'Phenotype', 'HP:0002664', (176, 182))	('tumours', 'Phenotype', 'HP:0002664', (27, 34))	('loss', 'NegReg', (133, 137))	('tumours', 'Disease', 'MESH:D009369', (106, 113))	('tumours', 'Disease', (106, 113))	('tumours', 'Phenotype', 'HP:0002664', (176, 183))	('tumours', 'Disease', 'MESH:D009369', (27, 34))	('tumours', 'Disease', (27, 34))	('hypermethylation', 'Var', (195, 211))
558240	27562343	In general, this revealed that promoter hypermethylation events could account for a higher fraction of cancers exhibiting underexpression of the corresponding TF compared with genomic loss (Fig.	('cancers', 'Disease', 'MESH:D009369', (103, 110))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('cancers', 'Disease', (103, 110))	('cancers', 'Phenotype', 'HP:0002664', (103, 110))	('promoter hypermethylation', 'Var', (31, 56))
558246	27562343	Indeed, broadly speaking, there were three types of silenced TFs in each cancer type (Fig.	('TFs', 'Gene', (61, 64))	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('silenced', 'Var', (52, 60))
558255	27562343	Next, we asked if the mechanism associated with silenced TFs is similar between cancer types.	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('silenced', 'Var', (48, 56))	('cancer', 'Disease', 'MESH:D009369', (80, 86))	('TFs', 'Gene', (57, 60))	('cancer', 'Disease', (80, 86))
558261	27562343	Although impairment of differentiation is a well known cancer hallmark, only a few concrete examples of TF inactivation have been shown to block differentiation and predispose to epithelial cancer.	('predispose', 'Reg', (165, 175))	('differentiation', 'CPA', (145, 160))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('epithelial cancer', 'Disease', 'MESH:D000077216', (179, 196))	('inactivation', 'Var', (107, 119))	('cancer', 'Phenotype', 'HP:0002664', (190, 196))	('block', 'NegReg', (139, 144))	('epithelial cancer', 'Phenotype', 'HP:0031492', (179, 196))	('cancer hallmark', 'Disease', (55, 70))	('epithelial cancer', 'Disease', (179, 196))	('cancer hallmark', 'Disease', 'MESH:D009369', (55, 70))
558266	27562343	Indeed, whereas CNV loss and inactivation mutations are known to affect tumour suppressors, the frequencies of these events across tumours of a given cancer type are generally quite low, making it difficult to identify novel cancer driver genes.	('tumours', 'Disease', (131, 138))	('cancer', 'Disease', (225, 231))	('tumour', 'Phenotype', 'HP:0002664', (131, 137))	('tumour', 'Disease', 'MESH:D009369', (131, 137))	('cancer', 'Phenotype', 'HP:0002664', (225, 231))	('CNV loss', 'Disease', (16, 24))	('tumours', 'Phenotype', 'HP:0002664', (131, 138))	('tumours', 'Disease', 'MESH:D009369', (131, 138))	('tumour', 'Disease', (131, 137))	('low', 'NegReg', (182, 185))	('cancer', 'Disease', (150, 156))	('CNV loss', 'Disease', 'MESH:D015431', (16, 24))	('cancer', 'Phenotype', 'HP:0002664', (150, 156))	('cancer', 'Disease', 'MESH:D009369', (225, 231))	('inactivation mutations', 'Var', (29, 51))	('tumour', 'Phenotype', 'HP:0002664', (72, 78))	('tumour', 'Disease', 'MESH:D009369', (72, 78))	('tumour', 'Disease', (72, 78))	('affect', 'Reg', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (150, 156))	('mutations', 'Var', (42, 51))
558271	27562343	Also, the important role of DNAm alterations at super-enhancers and associated DNAm and mRNA expression changes at linked gene promoters in cancer has recently been noted.	('DNAm', 'MPA', (79, 83))	('mRNA expression', 'MPA', (88, 103))	('DNAm', 'MPA', (28, 32))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('alterations', 'Var', (33, 44))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))
558272	27562343	Thus, our data can't distinguish between a causative model, in which promoter hypermethylation causes the observed underexpression of the TFs, from an effects model, in which the observed hypermethylation and silencing is the consequence of an upstream TF inactivation event, be this a CNV loss, inactivating mutation, promoter methylation or increased methylation at an enhancer.	('promoter', 'MPA', (319, 327))	('methylation', 'MPA', (353, 364))	('silencing', 'MPA', (209, 218))	('underexpression', 'MPA', (115, 130))	('CNV loss', 'Disease', 'MESH:D015431', (286, 294))	('hypermethylation', 'MPA', (188, 204))	('CNV loss', 'Disease', (286, 294))	('inactivating mutation', 'Var', (296, 317))	('increased', 'PosReg', (343, 352))	('inactivation', 'NegReg', (256, 268))
558275	27562343	Moreover, it has recently been noted that bivalently marked miRNA promoters are also frequently hypermethylated in cancer, with many of these also exhibiting underexpression.	('cancer', 'Disease', (115, 121))	('bivalently marked', 'Var', (42, 59))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('miRNA', 'Protein', (60, 65))	('hypermethylated', 'Var', (96, 111))	('cancer', 'Disease', 'MESH:D009369', (115, 121))
558279	27562343	This normal-adjacent tissue may already contain age-associated epigenetic field defects, which may reduce the sensitivity to detect silencing events in cancer.	('cancer', 'Disease', (152, 158))	('silencing events', 'MPA', (132, 148))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('reduce', 'NegReg', (99, 105))	('sensitivity', 'MPA', (110, 121))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('epigenetic field defects', 'Var', (63, 87))
558286	27562343	For instance, as remarked earlier, HNF4A is a TF which is needed for liver specification, silencing of it leading to liver cancer, yet it is also expressed in other tissue types such as kidney and stomach.	('HNF4A', 'Gene', '3172', (35, 40))	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('liver cancer', 'Phenotype', 'HP:0002896', (117, 129))	('silencing', 'Var', (90, 99))	('liver cancer', 'Disease', 'MESH:D006528', (117, 129))	('HNF4A', 'Gene', (35, 40))	('liver cancer', 'Disease', (117, 129))	('leading to', 'Reg', (106, 116))
558293	27562343	This suggests that putative differentiation blocks arising as a result of their inactivation are strongly selected for during carcinogenesis.	('carcinogenesis', 'Disease', 'MESH:D063646', (126, 140))	('inactivation', 'Var', (80, 92))	('carcinogenesis', 'Disease', (126, 140))
558294	27562343	Importantly, our data suggest that the silencing of these TFs in cancer is predominantly associated with promoter hypermethylation.	('associated', 'Reg', (89, 99))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('silencing', 'Var', (39, 48))	('promoter', 'MPA', (105, 113))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('TFs', 'Gene', (58, 61))
558296	27197178	Burden of non-synonymous mutations among TCGA cancers and candidate immune checkpoint inhibitor responses Immune checkpoint inhibitor treatment represents a promising approach towards treating cancer and has been shown to be effective in a subset of melanoma, non-small cell lung cancer (NSCLC) and kidney cancers.	('cancers', 'Phenotype', 'HP:0002664', (306, 313))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('cancers', 'Disease', 'MESH:D009369', (46, 53))	('cancers', 'Disease', (306, 313))	('cancer', 'Disease', (193, 199))	('cancer', 'Disease', (280, 286))	('NSCLC', 'Phenotype', 'HP:0030358', (288, 293))	('kidney cancers', 'Phenotype', 'HP:0009726', (299, 313))	('cancer', 'Phenotype', 'HP:0002664', (193, 199))	('cancer', 'Phenotype', 'HP:0002664', (280, 286))	('cancer', 'Disease', 'MESH:D009369', (306, 312))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (264, 286))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (260, 286))	('melanoma', 'Disease', 'MESH:D008545', (250, 258))	('cancer', 'Disease', 'MESH:D009369', (193, 199))	('cancer', 'Disease', 'MESH:D009369', (280, 286))	('cancers', 'Phenotype', 'HP:0002664', (46, 53))	('cancers', 'Disease', 'MESH:D009369', (306, 313))	('cancer', 'Disease', (46, 52))	('cancers', 'Disease', (46, 53))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (260, 286))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('cancer', 'Disease', (306, 312))	('NSCLC', 'Disease', 'MESH:D002289', (288, 293))	('non-synonymous mutations', 'Var', (10, 34))	('cancer', 'Phenotype', 'HP:0002664', (306, 312))	('lung cancer', 'Phenotype', 'HP:0100526', (275, 286))	('kidney cancers', 'Disease', (299, 313))	('melanoma', 'Phenotype', 'HP:0002861', (250, 258))	('non-small cell lung cancer', 'Disease', (260, 286))	('melanoma', 'Disease', (250, 258))	('kidney cancers', 'Disease', 'MESH:D007680', (299, 313))	('TCGA', 'Gene', (41, 45))	('NSCLC', 'Disease', (288, 293))
558297	27197178	Recent studies have suggested that the number of non-synonymous mutations (NsM) can be used to select melanoma and NSCLC patients most likely to benefit from checkpoint inhibitor treatment.	('non-synonymous mutations', 'Var', (49, 73))	('NSCLC', 'Disease', (115, 120))	('melanoma', 'Phenotype', 'HP:0002861', (102, 110))	('melanoma', 'Disease', (102, 110))	('NSCLC', 'Disease', 'MESH:D002289', (115, 120))	('melanoma', 'Disease', 'MESH:D008545', (102, 110))	('patients', 'Species', '9606', (121, 129))	('NSCLC', 'Phenotype', 'HP:0030358', (115, 120))
558304	27197178	Recently, a new generation of immune therapeutics based on immune checkpoint inhibition, including anti-CTLA-4, anti-PD-1 and anti-PD1-L1, has emerged as a promising development in the treatment of select cancers.	('anti-CTLA-4', 'Var', (99, 110))	('cancers', 'Disease', 'MESH:D009369', (205, 212))	('cancers', 'Disease', (205, 212))	('PD1', 'Gene', (131, 134))	('PD1', 'Gene', '5133', (131, 134))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('anti-PD-1', 'Var', (112, 121))	('cancers', 'Phenotype', 'HP:0002664', (205, 212))
558307	27197178	Previously a series of studies have examined somatic alterations to identify possible predictive signatures; these have included studies of gene expression signature associated with immune infiltration, neoantigen load, NRAS mutation status and neoantigen-derived tetrapeptide signature.	('NRAS', 'Gene', '4893', (220, 224))	('NRAS', 'Gene', (220, 224))	('mutation status', 'Var', (225, 240))
558308	27197178	Of these, the neoantigen load is most promising, particularly for treatment of melanoma and NSCLC.	('NSCLC', 'Phenotype', 'HP:0030358', (92, 97))	('neoantigen load', 'Var', (14, 29))	('NSCLC', 'Disease', (92, 97))	('melanoma', 'Phenotype', 'HP:0002861', (79, 87))	('melanoma', 'Disease', (79, 87))	('NSCLC', 'Disease', 'MESH:D002289', (92, 97))	('melanoma', 'Disease', 'MESH:D008545', (79, 87))
558309	27197178	Non-synonymous somatic mutations can generate neoantigens, which, in turn, can be recognized by the immune system, triggering an anticancer immune response.	('Non-synonymous', 'Var', (0, 14))	('neoantigens', 'MPA', (46, 57))	('generate', 'Reg', (37, 45))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('cancer', 'Disease', (133, 139))	('triggering', 'Reg', (115, 125))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
558310	27197178	It has been observed that a higher number of non-synonymous mutations correlates with a response to checkpoint inhibitors in melanoma and NSCLC.	('melanoma', 'Phenotype', 'HP:0002861', (125, 133))	('melanoma', 'Disease', (125, 133))	('NSCLC', 'Disease', (138, 143))	('melanoma', 'Disease', 'MESH:D008545', (125, 133))	('non-synonymous mutations', 'Var', (45, 69))	('NSCLC', 'Disease', 'MESH:D002289', (138, 143))	('response to', 'MPA', (88, 99))	('NSCLC', 'Phenotype', 'HP:0030358', (138, 143))
558311	27197178	Here, we conducted an analysis of the non-synonymous mutation load across the 7,757 tumor samples drawn from 26 distinct cancers in The Cancer Genome Atlas (TCGA), to infer possible cancers that might be prioritized for subsequent study of immune checkpoint inhibitors.	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('cancers', 'Disease', (121, 128))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('cancers', 'Disease', 'MESH:D009369', (121, 128))	('Cancer Genome Atlas', 'Disease', (136, 155))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (136, 155))	('Cancer', 'Phenotype', 'HP:0002664', (136, 142))	('cancers', 'Phenotype', 'HP:0002664', (182, 189))	('tumor', 'Disease', (84, 89))	('non-synonymous mutation load', 'Var', (38, 66))	('cancers', 'Disease', (182, 189))	('cancers', 'Disease', 'MESH:D009369', (182, 189))	('cancers', 'Phenotype', 'HP:0002664', (121, 128))
558315	27197178	A literature search was performed in the PubMed database (http://www.ncbi.nlm.nih.gov/pubmed, October 20, 2015) using combinations of the search terms: cancer, response, mutation, checkpoint inhibitor, CTLA4 and PD1.	('PD1', 'Gene', (212, 215))	('cancer', 'Disease', (152, 158))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('CTLA4', 'Gene', '1493', (202, 207))	('CTLA4', 'Gene', (202, 207))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('PD1', 'Gene', '5133', (212, 215))	('mutation', 'Var', (170, 178))
558341	27197178	In a comparison of the three published studies, using an ROC assessment for NsM against the checkpoint response rate, we observed similar cutoffs when comparing tumor types, but interestingly, the NSCLC study treated with anti-PD-1 had better AUC, which suggests perhaps better accuracy for NsM to predict immunotherapy response.	('NSCLC', 'Phenotype', 'HP:0030358', (197, 202))	('tumor', 'Disease', 'MESH:D009369', (161, 166))	('AUC', 'MPA', (243, 246))	('NSCLC', 'Disease', (197, 202))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('NSCLC', 'Disease', 'MESH:D002289', (197, 202))	('better', 'PosReg', (236, 242))	('tumor', 'Disease', (161, 166))	('anti-PD-1', 'Var', (222, 231))
558345	27197178	For anti-CTLA-4, plus dacarbazine, the range of 1 year survival is between 41.2 to 53.7% for melanoma patients, which is lower than our analysis predicts, however, anti-CTLA-4 appears to be less efficacious than anti-PD-1.	('melanoma', 'Phenotype', 'HP:0002861', (93, 101))	('melanoma', 'Disease', (93, 101))	('anti-CTLA-4', 'Var', (164, 175))	('melanoma', 'Disease', 'MESH:D008545', (93, 101))	('dacarbazine', 'Chemical', 'MESH:D003606', (22, 33))	('patients', 'Species', '9606', (102, 110))
558352	27197178	Alternatively, anti-CTLA-4 is active for adjuvant therapy in melanoma stage III patients which suggests that activity is not restricted to stage IV patients.	('anti-CTLA-4', 'Var', (15, 26))	('patients', 'Species', '9606', (148, 156))	('patients', 'Species', '9606', (80, 88))	('stage III', 'Disease', (70, 79))	('melanoma', 'Phenotype', 'HP:0002861', (61, 69))	('melanoma', 'Disease', (61, 69))	('melanoma', 'Disease', 'MESH:D008545', (61, 69))
558358	27197178	To the best of our knowledge, there are no published phase III clinical trials from colorectal cancer, however, some studies suggest that the subset of colorectal cancers with mismatch repair-deficient would have better immune checkpoint inhibition response.	('colorectal cancer', 'Disease', (84, 101))	('immune checkpoint inhibition response', 'MPA', (220, 257))	('mismatch repair-deficient', 'Var', (176, 201))	('colorectal cancer', 'Disease', 'MESH:D015179', (152, 169))	('better', 'PosReg', (213, 219))	('colorectal cancer', 'Disease', 'MESH:D015179', (84, 101))	('colorectal cancer', 'Phenotype', 'HP:0003003', (152, 169))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('colorectal cancer', 'Phenotype', 'HP:0003003', (84, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('colorectal cancers', 'Disease', 'MESH:D015179', (152, 170))	('cancers', 'Phenotype', 'HP:0002664', (163, 170))	('colorectal cancers', 'Disease', (152, 170))
558371	31696517	Consistent with the effect of risk alleles on gene expression levels, IREB2 knockdown and AQP3 overproduction promote endogenous DNA damage.	('knockdown', 'Var', (76, 85))	('endogenous DNA damage', 'MPA', (118, 139))	('overproduction', 'Var', (95, 109))	('IREB2', 'Gene', (70, 75))	('promote', 'PosReg', (110, 117))	('AQP3', 'Gene', '360', (90, 94))	('AQP3', 'Gene', (90, 94))
558384	31696517	The GWAS was performed using logistic regression to evaluate the association of genetic variants with overall lung cancer and the predominant histological subtypes including adenocarcinoma (n = 11,273), squamous cell carcinoma (n = 7,426) and small cell lung cancer (SCLC; n = 2,664).	('adenocarcinoma', 'Disease', (174, 188))	('SCLC', 'Disease', (267, 271))	('lung cancer', 'Disease', (110, 121))	('SCLC', 'Phenotype', 'HP:0030357', (267, 271))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (243, 265))	('adenocarcinoma', 'Disease', 'MESH:D000230', (174, 188))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (203, 226))	('variants', 'Var', (88, 96))	('lung cancer', 'Disease', 'MESH:D008175', (254, 265))	('lung cancer', 'Disease', 'MESH:D008175', (110, 121))	('SCLC', 'Disease', 'MESH:D018288', (267, 271))	('lung cancer', 'Phenotype', 'HP:0100526', (254, 265))	('lung cancer', 'Phenotype', 'HP:0100526', (110, 121))	('cancer', 'Phenotype', 'HP:0002664', (259, 265))	('small cell lung cancer', 'Disease', 'MESH:D055752', (243, 265))	('carcinoma', 'Phenotype', 'HP:0030731', (179, 188))	('small cell lung cancer', 'Disease', (243, 265))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (203, 226))	('association', 'Interaction', (65, 76))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (217, 226))	('squamous cell carcinoma', 'Disease', (203, 226))
558447	31696517	In contrast, the strongest lung eQTL variants for MTAP, N4BP2L2 and MTMR3 have weak GWAS p values (Supporting Information Fig.	('N4BP2L2', 'Gene', '10443', (56, 63))	('N4BP2L2', 'Gene', (56, 63))	('MTMR3', 'Gene', '8897', (68, 73))	('MTAP', 'Gene', (50, 54))	('MTMR3', 'Gene', (68, 73))	('MTAP', 'Gene', '4507', (50, 54))	('variants', 'Var', (37, 45))
558456	31696517	We hypothesized that some of the TWAS-nominated genes might promote cancer by increasing endogenous DNA damage, and subsequently lead to genome instability.	('promote', 'PosReg', (60, 67))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('lead to', 'Reg', (129, 136))	('increasing', 'PosReg', (78, 88))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('genes', 'Var', (48, 53))	('endogenous DNA damage', 'MPA', (89, 110))	('cancer', 'Disease', (68, 74))	('genome instability', 'MPA', (137, 155))
558459	31696517	We discovered that knockdown of IREB2 increased endogenous DNA damage in human lung fibroblasts (Fig.	('endogenous DNA damage', 'MPA', (48, 69))	('knockdown', 'Var', (19, 28))	('human', 'Species', '9606', (73, 78))	('IREB2', 'Gene', (32, 37))	('increased', 'PosReg', (38, 47))
558467	31696517	As with other complex diseases, the GWAS risk variants for lung cancer are mostly located in noncoding regions and are thus believed to mediate their effects by influencing gene expression of nearby genes.	('lung cancer', 'Disease', 'MESH:D008175', (59, 70))	('influencing', 'Reg', (161, 172))	('lung cancer', 'Disease', (59, 70))	('lung cancer', 'Phenotype', 'HP:0100526', (59, 70))	('variants', 'Var', (46, 54))	('gene expression', 'MPA', (173, 188))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
558474	31696517	In the current study, we further demonstrated that AQP3 overproduction promotes endogenous DNA damage in human lung fibroblasts.	('human', 'Species', '9606', (105, 110))	('promotes', 'PosReg', (71, 79))	('endogenous DNA damage', 'MPA', (80, 101))	('AQP3', 'Gene', '360', (51, 55))	('AQP3', 'Gene', (51, 55))	('overproduction', 'Var', (56, 70))
558479	31696517	Mutations in this gene have been associated with cardiomyopathy.	('cardiomyopathy', 'Phenotype', 'HP:0001638', (49, 63))	('cardiomyopathy', 'Disease', 'MESH:D009202', (49, 63))	('cardiomyopathy', 'Disease', (49, 63))	('Mutations', 'Var', (0, 9))	('associated', 'Reg', (33, 43))
558481	31696517	SNP rs114020893 located in lncRNA NEXN-AS1 was associated with lung cancer and with a similar association between adenocarcinoma and squamous cell carcinoma subgroups.	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (133, 156))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('lung cancer', 'Disease', 'MESH:D008175', (63, 74))	('adenocarcinoma', 'Disease', 'MESH:D000230', (114, 128))	('rs114020893', 'Mutation', 'rs114020893', (4, 15))	('NEXN-AS1', 'Gene', '374987', (34, 42))	('NEXN-AS1', 'Gene', (34, 42))	('SNP rs114020893', 'Var', (0, 15))	('lung cancer', 'Disease', (63, 74))	('lung cancer', 'Phenotype', 'HP:0100526', (63, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('adenocarcinoma', 'Disease', (114, 128))	('associated', 'Reg', (47, 57))	('carcinoma', 'Phenotype', 'HP:0030731', (147, 156))	('squamous cell carcinoma', 'Disease', (133, 156))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (133, 156))
558482	31696517	In silico analysis then predicted that rs114020893 could change the folding structure of NEXN-AS1.	('rs114020893', 'Mutation', 'rs114020893', (39, 50))	('folding structure', 'MPA', (68, 85))	('NEXN-AS1', 'Gene', '374987', (89, 97))	('NEXN-AS1', 'Gene', (89, 97))	('rs114020893', 'Var', (39, 50))	('change', 'Reg', (57, 63))
558488	31696517	15q25 is the locus most strongly associated with lung cancer, but also a leading susceptibility locus for smoking behavior and other traits related to lung disease such as chronic obstructive pulmonary disease (COPD).	('COPD', 'Disease', (211, 215))	('lung disease', 'Disease', 'MESH:D008171', (151, 163))	('lung disease', 'Phenotype', 'HP:0002088', (151, 163))	('15q25', 'Var', (0, 5))	('lung cancer', 'Disease', 'MESH:D008175', (49, 60))	('chronic obstructive pulmonary disease', 'Phenotype', 'HP:0006510', (172, 209))	('chronic obstructive pulmonary disease', 'Disease', 'MESH:D029424', (172, 209))	('chronic obstructive pulmonary disease', 'Disease', (172, 209))	('lung cancer', 'Disease', (49, 60))	('associated', 'Reg', (33, 43))	('lung cancer', 'Phenotype', 'HP:0100526', (49, 60))	('lung disease', 'Disease', (151, 163))	('COPD', 'Phenotype', 'HP:0006510', (211, 215))	('COPD', 'Disease', 'MESH:D029424', (211, 215))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('obstructive pulmonary disease', 'Phenotype', 'HP:0006536', (180, 209))
558489	31696517	COPD and lung cancer-associated variants in 15q25 are known expression and methylation QTL (eQTL and meQTL) for multiple genes and tissues.	('COPD', 'Phenotype', 'HP:0006510', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (14, 20))	('lung cancer', 'Disease', 'MESH:D008175', (9, 20))	('COPD', 'Disease', (0, 4))	('COPD', 'Disease', 'MESH:D029424', (0, 4))	('variants', 'Var', (32, 40))	('15q25', 'Gene', (44, 49))	('lung cancer', 'Disease', (9, 20))	('lung cancer', 'Phenotype', 'HP:0100526', (9, 20))
558495	31696517	Silencing of IREB2 in these cells has been shown to modulate the expression of iron metabolism-related genes (transferrin receptor and ferritin) and injection of wild-type IREB2 in mice was shown to stimulate growth of tumor xenografts.	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('mice', 'Species', '10090', (181, 185))	('IREB2', 'Gene', (13, 18))	('tumor', 'Disease', (219, 224))	('transferrin receptor', 'Gene', (110, 130))	('ferritin', 'Gene', (135, 143))	('iron', 'Chemical', 'MESH:D007501', (79, 83))	('stimulate', 'PosReg', (199, 208))	('expression', 'MPA', (65, 75))	('tumor', 'Disease', 'MESH:D009369', (219, 224))	('Silencing', 'Var', (0, 9))	('transferrin receptor', 'Gene', '22042', (110, 130))	('modulate', 'Reg', (52, 60))
558497	31696517	In the current study, knockdown of IREB2 was shown to increase endogenous DNA damage in human lung fibroblasts, supporting a potential cancer-promoting role in the lung by elevated DNA damage and genomic instability.	('endogenous DNA damage', 'MPA', (63, 84))	('genomic instability', 'CPA', (196, 215))	('cancer', 'Disease', (135, 141))	('IREB2', 'Gene', (35, 40))	('increase', 'PosReg', (54, 62))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('knockdown', 'Var', (22, 31))	('human', 'Species', '9606', (88, 93))	('DNA damage', 'MPA', (181, 191))	('elevated', 'PosReg', (172, 180))	('cancer', 'Disease', 'MESH:D009369', (135, 141))
558499	31696517	Variation in these genes have been strongly associated with smoking behavior and other aspects of addiction, thus indirectly affecting lung cancer risk through modulation of smoking behavior.	('associated', 'Reg', (44, 54))	('lung cancer', 'Phenotype', 'HP:0100526', (135, 146))	('lung cancer', 'Disease', 'MESH:D008175', (135, 146))	('affecting', 'Reg', (125, 134))	('Variation', 'Var', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('lung cancer', 'Disease', (135, 146))	('smoking behavior', 'Disease', (60, 76))
558500	31696517	Similarly, other forms of genetic variation may be modulating function at this locus, for example, one most associated SNP at this locus encodes a missense change in CHRNA5 (rs16969968).	('rs16969968', 'Mutation', 'rs16969968', (174, 184))	('CHRNA5', 'Gene', (166, 172))	('rs16969968', 'Var', (174, 184))	('missense change', 'Var', (147, 162))	('CHRNA5', 'Gene', '1138', (166, 172))
558509	31696517	This leaves out a large proportion of genes including known and potential cancer genes, particularly variants that influence gene product function through other ways.	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('cancer', 'Disease', (74, 80))	('variants', 'Var', (101, 109))	('influence', 'Reg', (115, 124))	('gene product function', 'MPA', (125, 146))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
558520	31861233	Silencing CD47 significantly suppressed cell viability and orosphere formation, accompanied by a downregulated expression of CD133, SRY-Box transcription factor 2 (SOX2), octamer-binding transcription factor 4 (OCT4), and c-Myc.	('CD133', 'Gene', (125, 130))	('CD47', 'Gene', (10, 14))	('octamer-binding transcription factor 4', 'Gene', '5460', (171, 209))	('orosphere formation', 'CPA', (59, 78))	('CD133', 'Gene', '8842', (125, 130))	('octamer-binding transcription factor 4', 'Gene', (171, 209))	('cell viability', 'CPA', (40, 54))	('expression', 'MPA', (111, 121))	('downregulated', 'NegReg', (97, 110))	('c-Myc', 'Gene', '4609', (222, 227))	('c-Myc', 'Gene', (222, 227))	('Silencing', 'Var', (0, 9))	('suppressed', 'NegReg', (29, 39))
558522	31861233	Silencing CD47, in combination with radiation, could provide an alternative and improved therapeutic efficacy for OSCC patients.	('OSCC', 'Disease', (114, 118))	('CD47', 'Gene', (10, 14))	('patients', 'Species', '9606', (119, 127))	('therapeutic efficacy', 'CPA', (89, 109))	('improved', 'PosReg', (80, 88))	('Silencing', 'Var', (0, 9))
558529	31861233	Previously, we demonstrated that the direct targeting of CSCs or so-called tumor-initiating cells (TICs) in OSCC by gene loss of function or therapeutic targeting inhibited the malignant and metastatic traits of OSCC cells, eliminated their CSCs-like properties, including enhanced clonogenicity, orosphere formation, and self-renewal, as well as improved their sensitivity to chemo- and/or radiation therapy, thus, highlighting the therapeutic significance of preferentially targeting the CSCs pool as an efficacious anti-OSCC strategy for mitigating the menace of radioresistance, cancer recurrence, and metastasis, while improving survival rates in patients with OSCC.	('gene', 'Var', (116, 120))	('cancer', 'Phenotype', 'HP:0002664', (583, 589))	('TICs', 'Disease', 'MESH:D020323', (99, 103))	('mitigating', 'NegReg', (541, 551))	('radioresistance', 'CPA', (566, 581))	('improving', 'PosReg', (624, 633))	('CSCs-like properties', 'CPA', (241, 261))	('inhibited', 'NegReg', (163, 172))	('orosphere formation', 'CPA', (297, 316))	('tumor', 'Disease', (75, 80))	('self-renewal', 'CPA', (322, 334))	('tumor', 'Disease', 'MESH:D009369', (75, 80))	('cancer', 'Disease', 'MESH:D009369', (583, 589))	('loss of function', 'NegReg', (121, 137))	('TICs', 'Phenotype', 'HP:0100033', (99, 103))	('improved', 'PosReg', (347, 355))	('patients', 'Species', '9606', (652, 660))	('tumor', 'Phenotype', 'HP:0002664', (75, 80))	('eliminated', 'NegReg', (224, 234))	('TICs', 'Disease', (99, 103))	('metastasis', 'CPA', (606, 616))	('clonogenicity', 'CPA', (282, 295))	('cancer', 'Disease', (583, 589))	('sensitivity', 'MPA', (362, 373))	('enhanced', 'PosReg', (273, 281))
558572	31861233	We also demonstrated using downloaded and reanalyzed malignant OSCC data from the TCGA HNSCC cohort that high CD47 expression conferred a significant survival disadvantage in OSCC patients with high CD47 expression, compared to those with low CD47 expression (p = 0.0391; Figure 1D).	('high', 'Var', (105, 109))	('high', 'Var', (194, 198))	('HNSCC', 'Phenotype', 'HP:0012288', (87, 92))	('survival', 'CPA', (150, 158))	('CD47', 'Gene', (110, 114))	('disadvantage', 'NegReg', (159, 171))	('CD47', 'Gene', (199, 203))	('OSCC', 'Disease', (175, 179))	('expression', 'MPA', (204, 214))	('patients', 'Species', '9606', (180, 188))
558590	31861233	In corroboratory assays, we also observed that the loss of CD47 in SAS (upper panel) and TW2.6 (lower panel) cells led to the loss of the characteristic OSCC spindle-shaped/fibroblastoid mesenchymal morphology, acquisition of round/oval epithelial and loose cell-to-cell contact (Figure 4D).	('SAS', 'Gene', (67, 70))	('loss', 'Var', (51, 55))	('CD47', 'Gene', (59, 63))	('acquisition', 'PosReg', (211, 222))	('loose cell-to-cell contact', 'CPA', (252, 278))	('loss', 'NegReg', (126, 130))	('SAS', 'Gene', '6302', (67, 70))
558594	31861233	Results of our analyses further validated earlier demonstrated direct and inverse correlation of CD47 with VIM and CDH1, respectively, with the significance of correlation r-value = 0.081 p-value = 0.23 T-value = 1.198 for CD47 versus VIM, and r-value = -0.061 p-value = 0.37 T-value = -0.898 for CD47 versus CDH1, with both sharing same degrees of freedom = 218 (Figure 5C,D).	('VIM', 'Gene', (107, 110))	('CDH1', 'Gene', (309, 313))	('VIM', 'Gene', '7431', (235, 238))	('CDH1', 'Gene', '999', (309, 313))	('inverse', 'NegReg', (74, 81))	('CDH1', 'Gene', (115, 119))	('VIM', 'Gene', (235, 238))	('r-value', 'Var', (172, 179))	('VIM', 'Gene', '7431', (107, 110))	('CDH1', 'Gene', '999', (115, 119))
558595	31861233	Understanding the critical role of radiotherapy as a vital treatment modality in OSCC that facilitates oral tumor size reduction and oral function preservation, we next examined the effect of altered CD47 expression on the viability and/or proliferation of the OSCC cell lines, SAS and TW2.6, using the radiotherapy-based cell viability assay.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('tumor', 'Disease', (108, 113))	('CD47', 'Gene', (200, 204))	('OSCC', 'Disease', (81, 85))	('SAS', 'Gene', '6302', (278, 281))	('oral tumor', 'Phenotype', 'HP:0100649', (103, 113))	('SAS', 'Gene', (278, 281))	('examined', 'Reg', (169, 177))	('altered', 'Var', (192, 199))
558604	31861233	These results demonstrated that molecular attenuation of shCD47 as a therapeutic strategy abrogated the CSCs-related radio-resistance of OSCC cells.	('CSCs-related', 'Disease', (104, 116))	('shCD', 'Gene', (57, 61))	('abrogated', 'NegReg', (90, 99))	('molecular attenuation', 'Var', (32, 53))	('shCD', 'Gene', '399694', (57, 61))
558610	31861233	Consistent with our data showing that high CD47 expression conferred ~20% survival disadvantage and positively correlated with disease stage progression, they also suggested that CD47 might serve as a reliable predictive biomarker for oral pre-cancer and cancer progression, thus hinting on its probable role as an important molecular target for designing novel anticancer therapeutics for OSCC patients.	('survival', 'CPA', (74, 82))	('cancer', 'Phenotype', 'HP:0002664', (366, 372))	('cancer', 'Phenotype', 'HP:0002664', (255, 261))	('correlated', 'Reg', (111, 121))	('OSCC', 'Disease', (390, 394))	('cancer', 'Disease', 'MESH:D009369', (366, 372))	('cancer', 'Phenotype', 'HP:0002664', (244, 250))	('expression', 'MPA', (48, 58))	('disadvantage', 'NegReg', (83, 95))	('high', 'Var', (38, 42))	('cancer', 'Disease', (366, 372))	('patients', 'Species', '9606', (395, 403))	('cancer', 'Disease', (255, 261))	('cancer', 'Disease', 'MESH:D009369', (255, 261))	('CD47', 'Var', (179, 183))	('CD47', 'Gene', (43, 47))	('cancer', 'Disease', (244, 250))	('cancer', 'Disease', 'MESH:D009369', (244, 250))
558620	31861233	Similarly, enhanced phagocytosis of CD47-rich CD133+ ovarian TICs, which are relatively resistant to current anticancer treatment, is triggered by treatment with anti-CD47 mAb or CD47 knockdown.	('CD47', 'Gene', (179, 183))	('phagocytosis', 'CPA', (20, 32))	('knockdown', 'Var', (184, 193))	('TICs', 'Phenotype', 'HP:0100033', (61, 65))	('CD133', 'Gene', (46, 51))	('ovarian TICs', 'Disease', (53, 65))	('CD133', 'Gene', '8842', (46, 51))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('cancer', 'Disease', (113, 119))	('enhanced', 'PosReg', (11, 19))	('ovarian TICs', 'Disease', 'MESH:D010049', (53, 65))	('anti-CD47 mAb', 'Var', (162, 175))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
558625	31861233	Thus, interestingly, having shown the existence of a positive correlation of CD47 expression with CSC, EMT, and metastatic phenotypes, as well as an inverse correlation with OSCC patients' overall survival, cell death; we finally demonstrated that the suppression of CD47 expression enhanced the sensitivity of OSCC-SCs to radiation therapy, as evidenced by the remarkable synergistic effect of concurrent CD47 knockdown and radiotherapy on cell viability, migration, invasiveness, clonogenic, and orospheric survival (Figure 6).	('migration', 'CPA', (457, 466))	('invasiveness', 'CPA', (468, 480))	('orospheric survival', 'CPA', (498, 517))	('sensitivity', 'MPA', (296, 307))	('suppression', 'NegReg', (252, 263))	('clonogenic', 'CPA', (482, 492))	('CD47', 'Gene', (406, 410))	('knockdown', 'Var', (411, 420))	('patients', 'Species', '9606', (179, 187))	('CD47', 'Gene', (267, 271))	('cell viability', 'CPA', (441, 455))	('enhanced', 'PosReg', (283, 291))
558637	31861233	The CD47 knockdown of shCD47 also suppressed orosphere formation, reduced colony formation, and enhanced radiosensitivity in OSCC by dysregulation of our proposed CD47-CSCs-EMT signaling loop.	('reduced', 'NegReg', (66, 73))	('knockdown', 'Var', (9, 18))	('shCD', 'Gene', (22, 26))	('enhanced', 'PosReg', (96, 104))	('enhanced radiosensitivity', 'Phenotype', 'HP:0010997', (96, 121))	('suppressed', 'NegReg', (34, 44))	('orosphere formation', 'CPA', (45, 64))	('colony formation', 'CPA', (74, 90))	('radiosensitivity', 'MPA', (105, 121))	('shCD', 'Gene', '399694', (22, 26))
558720	30001987	In the expansion cohort, prespecified exploratory objectives were measurement of expression of p-VEGF receptors, p-PDGF receptors, p-c-kit and p-EGFR by immunohistochemistry on pretreatment and post-cycle 1 tumour tissue.	('tumour', 'Disease', (207, 213))	('VEGF', 'Gene', (97, 101))	('EGFR', 'Gene', '1956', (145, 149))	('p-PDGF receptors', 'Gene', (113, 129))	('EGFR', 'Gene', (145, 149))	('tumour', 'Phenotype', 'HP:0002664', (207, 213))	('VEGF', 'Gene', '7422', (97, 101))	('p-c-kit', 'Var', (131, 138))	('tumour', 'Disease', 'MESH:D009369', (207, 213))
558824	30001987	Cetuximab:an EGFR inhibitor-improved overall survival in first-line recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) when added to palliative chemotherapy, but had a modest clinical benefit.	('HNSCC', 'Phenotype', 'HP:0012288', (131, 136))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (92, 129))	('inhibitor-improved', 'PosReg', (18, 36))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('overall survival', 'MPA', (37, 53))	('neck squamous cell carcinoma', 'Disease', (101, 129))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (101, 129))	('Cetuximab', 'Chemical', 'MESH:D000068818', (0, 9))	('inhibitor-improved', 'Var', (18, 36))	('EGFR', 'Gene', '1956', (13, 17))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (106, 129))	('EGFR', 'Gene', (13, 17))
558832	31429720	Distinct signatures of lung cancer types: aberrant mucin O-glycosylation and compromised immune response Genomic initiatives such as The Cancer Genome Atlas (TCGA) contain data from -omics profiling of thousands of tumor samples, which may be used to decipher cancer signaling, and related alterations.	('cancer', 'Disease', 'MESH:D009369', (260, 266))	('Cancer Genome Atlas', 'Disease', (137, 156))	('aberrant', 'Var', (42, 50))	('tumor', 'Phenotype', 'HP:0002664', (215, 220))	('mucin', 'Gene', (51, 56))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('lung cancer', 'Disease', (23, 34))	('mucin', 'Gene', '100508689', (51, 56))	('Cancer', 'Phenotype', 'HP:0002664', (137, 143))	('cancer', 'Disease', (260, 266))	('compromised immune response', 'Phenotype', 'HP:0002721', (77, 104))	('lung cancer', 'Disease', 'MESH:D008175', (23, 34))	('tumor', 'Disease', (215, 220))	('cancer', 'Disease', (28, 34))	('cancer', 'Phenotype', 'HP:0002664', (260, 266))	('lung cancer', 'Phenotype', 'HP:0100526', (23, 34))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('tumor', 'Disease', 'MESH:D009369', (215, 220))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (137, 156))
558850	31429720	This pioneering study established the prognostic impact of changes in gene-expression for NSCLC patients.	('NSCLC', 'Disease', 'MESH:D002289', (90, 95))	('NSCLC', 'Disease', (90, 95))	('patients', 'Species', '9606', (96, 104))	('changes', 'Var', (59, 66))
558944	31429720	Future studies on naive tumor samples or LUSC and LUAD cellular models, where the IL6 gene can be modulated by overexpression or silencing, could shed light on its role within the two lung cancer types.	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('IL6', 'Gene', '3569', (82, 85))	('IL6', 'Gene', (82, 85))	('tumor', 'Disease', (24, 29))	('cancer', 'Phenotype', 'HP:0002664', (189, 195))	('lung cancer', 'Disease', 'MESH:D008175', (184, 195))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('silencing', 'Var', (129, 138))	('lung cancer', 'Disease', (184, 195))	('lung cancer', 'Phenotype', 'HP:0100526', (184, 195))
558961	31429720	Therefore, the risk associated with high gene expression of ITGA6, FABP5 (in LUAD) or ICA1 (in LUSC) is low, resulting in a better prognosis for these patients.	('FABP5', 'Gene', '2171', (67, 72))	('high gene expression', 'Var', (36, 56))	('ITGA6', 'Gene', '3655', (60, 65))	('ITGA6', 'Gene', (60, 65))	('patients', 'Species', '9606', (151, 159))	('FABP5', 'Gene', (67, 72))	('ICA1', 'Gene', (86, 90))	('ICA1', 'Gene', '3382', (86, 90))
558977	31429720	CSTA deregulation has been associated with different cancer types, and specifically breast cancer.	('breast cancer', 'Phenotype', 'HP:0003002', (84, 97))	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('associated', 'Reg', (27, 37))	('CSTA', 'Gene', '1475', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('CSTA', 'Gene', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('deregulation', 'Var', (5, 17))	('breast cancer', 'Disease', 'MESH:D001943', (84, 97))	('breast cancer', 'Disease', (84, 97))
558981	31429720	Of note, its levels can be regulated by the miR-34b-3p microRNA in bladder cancer.	('bladder cancer', 'Disease', 'MESH:D001749', (67, 81))	('bladder cancer', 'Disease', (67, 81))	('bladder cancer', 'Phenotype', 'HP:0009725', (67, 81))	('levels', 'MPA', (13, 19))	('miR-34b-3p microRNA', 'Var', (44, 63))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('regulated', 'Reg', (27, 36))
559011	31429720	When dysregulated, these proteins promote cancer progression and metastasis.	('metastasis', 'CPA', (65, 75))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('dysregulated', 'Var', (5, 17))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('promote', 'PosReg', (34, 41))
559020	31429720	Moreover, MUC5B silencing was shown to reduce chemo-resistance of breast tumor cells, suggesting this as an interesting target also for LUAD, where we found MUC5B as one of the up-regulated genes.	('reduce', 'NegReg', (39, 45))	('breast tumor', 'Disease', 'MESH:D001943', (66, 78))	('MUC5B', 'Gene', '727897', (157, 162))	('MUC5B', 'Gene', (157, 162))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('breast tumor', 'Disease', (66, 78))	('MUC5B', 'Gene', '727897', (10, 15))	('MUC5B', 'Gene', (10, 15))	('silencing', 'Var', (16, 25))	('breast tumor', 'Phenotype', 'HP:0100013', (66, 78))
559030	31429720	The activation of these pathways relies on the dysregulation or mutations of usual suspects in cancer such as p53, cMYC, and the beta-catenin/WNT.	('p53', 'Gene', (110, 113))	('dysregulation', 'Var', (47, 60))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('p53', 'Gene', '7157', (110, 113))	('cancer', 'Disease', (95, 101))	('cMYC', 'Gene', (115, 119))	('beta-catenin', 'Gene', (129, 141))	('mutations', 'Var', (64, 73))	('cMYC', 'Gene', '4609', (115, 119))	('beta-catenin', 'Gene', '1499', (129, 141))
559042	32911849	In mammals, both iRhoms are involved in maturation and trafficking of the ubiquitous transmembrane protease a disintegrin and metalloprotease (ADAM) 17, which through cleaving many biologically active molecules has a critical role in tumor necrosis factor alpha (TNFalpha), epidermal growth factor receptor (EGFR), interleukin-6 (IL-6) and Notch signaling.	('interleukin-6', 'Gene', (315, 328))	('tumor necrosis factor alpha', 'Gene', '21926', (234, 261))	('iRhom', 'Gene', '2768944', (17, 22))	('a disintegrin and metalloprotease (ADAM) 17', 'Gene', '11491', (108, 151))	('cleaving', 'Var', (167, 175))	('epidermal growth factor receptor', 'Gene', '13649', (274, 306))	('iRhom', 'Gene', (17, 22))	('TNFalpha', 'Gene', (263, 271))	('Notch signaling', 'MPA', (340, 355))	('tumor', 'Phenotype', 'HP:0002664', (234, 239))	('epidermal growth factor receptor', 'Gene', (274, 306))	('interleukin-6', 'Gene', '16193', (315, 328))	('tumor necrosis factor alpha', 'Gene', (234, 261))
559063	32911849	At the cell surface, alteration in the intramolecular disulfide bridge status of ADAM17 by disulfide isomerases, or in response to changes in the local redox environment such as during inflammatory events, induces a conformational change regulating ADAM17 activity as well.	('conformational change', 'MPA', (216, 237))	('induces', 'Reg', (206, 213))	('disulfide', 'Chemical', 'MESH:D004220', (54, 63))	('ADAM17', 'Gene', (81, 87))	('ADAM17', 'Enzyme', (249, 255))	('alteration', 'Var', (21, 31))	('disulfide', 'Chemical', 'MESH:D004220', (91, 100))	('intramolecular disulfide bridge status', 'MPA', (39, 77))	('activity', 'MPA', (256, 264))	('changes', 'Reg', (131, 138))
559067	32911849	This interaction was shown to be specific to ADAM17 and not its closest relative ADAM10.	('ADAM17', 'Var', (45, 51))	('ADAM10', 'Gene', '11487', (81, 87))	('ADAM10', 'Gene', (81, 87))
559069	32911849	The iRhom2 loss of function sincere (sin) mutation provided more nuanced insights into the complete mechanism of iRhom-ADAM17 regulation.	('iRhom', 'Gene', '2768944', (4, 9))	('iRhom', 'Gene', '2768944', (113, 118))	('mutation', 'Var', (42, 50))	('loss of function', 'NegReg', (11, 27))	('iRhom', 'Gene', (4, 9))	('iRhom', 'Gene', (113, 118))
559070	32911849	iRhom2 gain of function mutations in its N-terminal cytoplasmic tail, identified in the inherited Tylosis with oesophageal cancer (TOC) syndrome, result in increased EGFR ligand shedding and subsequent activation of EGFR signaling (Box 1).	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('inherited Tylosis', 'Disease', 'MESH:D015776', (88, 105))	('EGFR', 'Protein', (166, 170))	('gain of function', 'PosReg', (7, 23))	('EGFR signaling', 'Pathway', (216, 230))	('oesophageal cancer (TOC) syndrome', 'Disease', 'MESH:C536164', (111, 144))	('iRhom2', 'Gene', (0, 6))	('increased', 'PosReg', (156, 165))	('activation', 'PosReg', (202, 212))	('inherited Tylosis', 'Disease', (88, 105))	('mutations', 'Var', (24, 33))	('shedding', 'MPA', (178, 186))
559071	32911849	The same TOC gain of function mutations were also found to enhance shedding of TNFRs.	('enhance', 'PosReg', (59, 66))	('gain of function', 'PosReg', (13, 29))	('shedding', 'MPA', (67, 75))	('mutations', 'Var', (30, 39))	('TNFR', 'Gene', '21937', (79, 83))	('TNFR', 'Gene', (79, 83))
559072	32911849	Consistently, two studies employing the same mouse curly bare (cub) iRhom2 mutation which deletes most of the cytoplasmic domain showed alterations in EGFR signaling.	('iRhom2', 'Gene', (68, 74))	('mutation', 'Var', (75, 83))	('mouse', 'Species', '10090', (45, 50))	('alterations', 'Reg', (136, 147))	('EGFR signaling', 'MPA', (151, 165))
559083	32911849	iRhom2 deficient mice appear healthy, viable, and show no gross phenotype, while ADAM17 deficient mice exhibit severe symptoms after birth.	('mice', 'Species', '10090', (17, 21))	('iRhom2', 'Gene', (0, 6))	('deficient', 'Var', (7, 16))	('ADAM17', 'Gene', (81, 87))	('mice', 'Species', '10090', (98, 102))
559099	32911849	iRhom2 null mice and those with the sin mutation, that inhibits iRhom2's ability to efficiently traffic ADAM17 from the ER to the Golgi, have reduced soluble TNFalpha (Table 1).	('iRhom2', 'Gene', (64, 70))	('mutation', 'Var', (40, 48))	('reduced', 'NegReg', (142, 149))	('inhibits', 'NegReg', (55, 63))	('soluble TNFalpha', 'MPA', (150, 166))	('ability', 'MPA', (73, 80))	('mice', 'Species', '10090', (12, 16))
559116	32911849	In addition to the open eye phenotype, EGFR deficient mice exhibit developmental defects in several organs including skin, lung and gastrointestinal tract.	('developmental defects', 'Disease', 'MESH:D000014', (67, 88))	('deficient', 'Var', (44, 53))	('EGFR', 'Gene', (39, 43))	('open eye', 'Disease', (19, 27))	('mice', 'Species', '10090', (54, 58))	('developmental defects', 'Disease', (67, 88))	('open eye', 'Disease', 'MESH:D005597', (19, 27))
559118	32911849	Increased EGFR signaling in epithelial cancers occurs by a number of mechanisms, including over-expression of EGFR or its ligands, defective ligand processing, activating mutations in EGFR, or excessive EGFR transactivation.	('ligand', 'Protein', (141, 147))	('EGFR', 'Protein', (203, 207))	('cancers', 'Phenotype', 'HP:0002664', (39, 46))	('EGFR', 'Gene', (110, 114))	('transactivation', 'MPA', (208, 223))	('epithelial cancers', 'Disease', 'MESH:D009369', (28, 46))	('defective', 'NegReg', (131, 140))	('EGFR', 'Gene', (184, 188))	('Increased', 'PosReg', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('mutations', 'Var', (171, 180))	('over-expression', 'PosReg', (91, 106))	('activating', 'PosReg', (160, 170))	('EGFR signaling', 'MPA', (10, 24))	('epithelial cancers', 'Disease', (28, 46))
559120	32911849	Autosomal-dominant inherited TOC familial cancer syndrome patients were then found to have an activating mutation in iRhom2 that increased EGFR ligand shedding, firmly putting iRhom2 in the midst of EGFR related cancers as well as epithelial homeostasis (Box 1).	('Autosomal-dominant inherited TOC familial cancer syndrome', 'Disease', 'MESH:D009386', (0, 57))	('mutation', 'Var', (105, 113))	('EGFR ligand shedding', 'MPA', (139, 159))	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('iRhom2', 'Gene', (117, 123))	('increased', 'PosReg', (129, 138))	('cancers', 'Phenotype', 'HP:0002664', (212, 219))	('cancers', 'Disease', 'MESH:D009369', (212, 219))	('patients', 'Species', '9606', (58, 66))	('cancers', 'Disease', (212, 219))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))
559122	32911849	In mouse models of the syndrome it was shown that deletion of the EGFR ligand AR or ADAM17 were able to restore normal skin phenotype and that the defect was skin specific.	('normal skin phenotype', 'MPA', (112, 133))	('deletion', 'Var', (50, 58))	('mouse', 'Species', '10090', (3, 8))	('EGFR', 'Gene', (66, 70))	('ADAM17', 'Gene', (84, 90))	('AR', 'Gene', '11839', (78, 80))	('restore', 'PosReg', (104, 111))
559131	32911849	In a mouse model of lupus nephritis, lack of iRhom2 resulted in protection from progressive renal injury via these pathways.	('progressive renal injury', 'Phenotype', 'HP:0012622', (80, 104))	('lupus nephritis', 'Disease', 'MESH:D008181', (20, 35))	('protection', 'NegReg', (64, 74))	('lack', 'Var', (37, 41))	('lupus nephritis', 'Disease', (20, 35))	('renal injury', 'Disease', (92, 104))	('nephritis', 'Phenotype', 'HP:0000123', (26, 35))	('iRhom2', 'Gene', (45, 51))	('mouse', 'Species', '10090', (5, 10))	('renal injury', 'Disease', 'MESH:D007674', (92, 104))
559140	32911849	The second paper relates to the spontaneous iRhom2 uncovered (Uncv) mouse mutation which displays a hairless phenotype in the BALB/c background.	('mouse', 'Species', '10090', (68, 73))	('mutation', 'Var', (74, 82))	('Uncv', 'Gene', '109602', (62, 66))	('iRhom2 uncovered', 'Gene', (44, 60))	('Uncv', 'Gene', (62, 66))
559149	32911849	The authors also found that absence of iRhom2 resulted in reduced MAVS levels.	('MAVS', 'Gene', (66, 70))	('MAVS', 'Gene', '228607', (66, 70))	('iRhom2', 'Gene', (39, 45))	('reduced', 'NegReg', (58, 65))	('absence', 'Var', (28, 35))
559154	32911849	iRhom2 deficient mice were thus more susceptible to lethal herpes simplex Virus 1 (HSV-1) infections than their wild type counterparts.	('herpes simplex', 'Phenotype', 'HP:0012302', (59, 73))	('mice', 'Species', '10090', (17, 21))	('iRhom2', 'Gene', (0, 6))	('susceptible', 'Reg', (37, 48))	('deficient', 'Var', (7, 16))	('herpes simplex Virus 1', 'Species', '10298', (59, 81))	('(HSV-1) infections', 'Disease', 'MESH:C536395', (82, 100))	('lethal herpes simplex', 'Phenotype', 'HP:0012302', (52, 73))
559159	32911849	As K16 mutations also present with palmar and plantar hyperkeratosis, the authors investigated iRhom2 gain of function mutations in TOC and their relation to K16 expression.	('plantar hyperkeratosis', 'Disease', 'MESH:D016523', (46, 68))	('hyperkeratosis', 'Phenotype', 'HP:0000962', (54, 68))	('plantar hyperkeratosis', 'Phenotype', 'HP:0007556', (46, 68))	('gain of function', 'PosReg', (102, 118))	('palmar and plantar hyperkeratosis', 'Phenotype', 'HP:0000972', (35, 68))	('plantar hyperkeratosis', 'Disease', (46, 68))	('K16', 'Gene', (3, 6))	('mutations', 'Var', (119, 128))	('mutations', 'Var', (7, 16))
559165	32911849	Using family pedigrees and DNA samples from 3 US, UK and German families, single amino acid substitutions in exon 6 of RHBDF2 were identified as the underlying cause of the syndrome.	('cause', 'Reg', (160, 165))	('RHBDF2', 'Gene', (119, 125))	('single amino acid substitutions in', 'Var', (74, 108))	('syndrome', 'Disease', (173, 181))	('RHBDF2', 'Gene', '217344', (119, 125))
559166	32911849	This was further confirmed independently in a Finnish family and an African family showing again a single amino acid substitution between the two identified before and all within the highly conserved region of the N-terminal cytoplasmic tail of iRhom2: a p.Ile186Thr mutation in the US and UK families, a p.Asp188Asn mutation in the Finnish family, a p.Asp188Tyr in the African family and a p.Pro189Leu mutation in the German family.	('p.Asp188Tyr', 'Var', (351, 362))	('p.Asp188Asn', 'Mutation', 'rs387907130', (305, 316))	('p.Asp188Asn', 'Var', (305, 316))	('p.Pro189Leu', 'Mutation', 'rs387907130', (391, 402))	('p.Asp188Tyr', 'Mutation', 'p.D188Y', (351, 362))	('p.Ile186Thr', 'Mutation', 'rs387907129', (255, 266))	('p.Ile186Thr', 'Var', (255, 266))
559167	32911849	The underlying mechanism was related to the mutations activating iRhom2 which leads to increased ADAM17 maturation and activity in epidermal keratinocytes from TOC patients, which in turn increases shedding of TNFalpha, AR, TGFalpha and HB-EGF and enhances EGFR phosphorylation.	('activating', 'PosReg', (54, 64))	('increases', 'PosReg', (188, 197))	('increased', 'PosReg', (87, 96))	('EGFR', 'Protein', (257, 261))	('TNFalpha', 'Protein', (210, 218))	('iRhom2', 'Gene', (65, 71))	('shedding', 'MPA', (198, 206))	('AR', 'Gene', '11839', (220, 222))	('mutations', 'Var', (44, 53))	('ADAM17', 'Protein', (97, 103))	('TGFalpha', 'Protein', (224, 232))	('activity', 'MPA', (119, 127))	('HB-EGF', 'Protein', (237, 243))	('patients', 'Species', '9606', (164, 172))	('enhances', 'PosReg', (248, 256))
559175	32911849	Notably, severe phenotypes observed in ADAM17 deficient mice are not observed in mice deficient for iRhom2 alone, which might suggest little side effects for a therapy targeting iRhom2 specifically.	('ADAM17', 'Gene', (39, 45))	('mice', 'Species', '10090', (56, 60))	('mice', 'Species', '10090', (81, 85))	('deficient', 'Var', (46, 55))
559193	28819306	Overexpression of EDIL3 can contribute to carcinogenesis by reducing apoptosis in cancer cells and promoting cancer vascularization.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('cancer', 'Disease', (109, 115))	('carcinogenesis', 'Disease', 'MESH:D063646', (42, 56))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('carcinogenesis', 'Disease', (42, 56))	('Overexpression', 'Var', (0, 14))	('apoptosis', 'CPA', (69, 78))	('EDIL3', 'Gene', (18, 23))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('promoting', 'PosReg', (99, 108))	('reducing', 'NegReg', (60, 68))
559248	28819306	Vimentin expression was higher in the EDIL3-positive group than in the EDIL3-negative group (p < 0.001, Table 2).	('Vimentin', 'Gene', '7431', (0, 8))	('higher', 'PosReg', (24, 30))	('EDIL3-positive', 'Var', (38, 52))	('expression', 'MPA', (9, 19))	('Vimentin', 'Gene', (0, 8))
559250	28819306	The mean microvessel density in tumors positive for EDIL3 was significantly (p = 0.008) higher than that in tumors negative for EDIL3 in all cases (Fig.	('higher', 'PosReg', (88, 94))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('EDIL3', 'Var', (52, 57))	('microvessel density', 'CPA', (9, 28))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumors', 'Disease', (108, 114))	('tumors', 'Disease', 'MESH:D009369', (108, 114))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('tumors', 'Disease', (32, 38))	('tumors', 'Disease', 'MESH:D009369', (32, 38))
559260	28819306	Patients with EDIL3 expression were more likely to have the mucinous adenocarcinoma subtype (17.6% vs. 2.3%) and less likely to have the solid adenocarcinoma subtype (11.8% vs. 22.1%) than were EDIL3-negative patients (P = 0.004; Table 4).	('solid adenocarcinoma subtype', 'Disease', 'MESH:D000230', (137, 165))	('mucinous adenocarcinoma subtype', 'Disease', (60, 91))	('EDIL3 expression', 'Var', (14, 30))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('Patients', 'Species', '9606', (0, 8))	('patients', 'Species', '9606', (209, 217))	('solid adenocarcinoma subtype', 'Disease', (137, 165))	('mucinous adenocarcinoma subtype', 'Disease', 'MESH:D002288', (60, 91))	('carcinoma', 'Phenotype', 'HP:0030731', (148, 157))
559264	28819306	Thirdly, this study revealed that EDIL3 expression is significantly associated with tumor angiogenesis, characterized by microvessel density in lung adenocarcinoma tissue.	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('associated', 'Reg', (68, 78))	('microvessel density', 'CPA', (121, 140))	('expression', 'Var', (40, 50))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (144, 163))	('tumor', 'Disease', (84, 89))	('EDIL3', 'Gene', (34, 39))	('carcinoma', 'Phenotype', 'HP:0030731', (154, 163))	('lung adenocarcinoma', 'Disease', (144, 163))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (144, 163))
559266	28819306	These results suggest that EDIL3 expression may promote tumor progression through enhancing EMT and tumor angiogenesis in lung adenocarcinoma.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('expression', 'Var', (33, 43))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('tumor', 'Disease', (100, 105))	('tumor', 'Disease', (56, 61))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (122, 141))	('enhancing', 'PosReg', (82, 91))	('EDIL3', 'Gene', (27, 32))	('promote', 'PosReg', (48, 55))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('lung adenocarcinoma', 'Disease', (122, 141))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (122, 141))
559269	28819306	Furthermore, murine Lewis lung carcinoma cells engineered to express EDIL3 have a 2- to 4-fold increase in capillary density and an accelerated growth rate.	('rat', 'Species', '10116', (138, 141))	('accelerated', 'PosReg', (132, 143))	('capillary density', 'CPA', (107, 124))	('Lewis lung carcinoma', 'Disease', (20, 40))	('Lewis lung carcinoma', 'Disease', 'MESH:D018827', (20, 40))	('express', 'Var', (61, 68))	('increase', 'PosReg', (95, 103))	('murine', 'Species', '10090', (13, 19))	('rat', 'Species', '10116', (151, 154))	('EDIL3', 'Gene', (69, 74))	('carcinoma', 'Phenotype', 'HP:0030731', (31, 40))	('growth rate', 'CPA', (144, 155))
559274	28819306	Overexpression of angiopoietin 2 can promote EMT-induced angiogenesis in oral squamous cell carcinoma.	('angiopoietin 2', 'Gene', (18, 32))	('EMT-induced angiogenesis', 'CPA', (45, 69))	('promote', 'PosReg', (37, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (73, 101))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (78, 101))	('Overexpression', 'Var', (0, 14))	('oral squamous cell carcinoma', 'Disease', (73, 101))	('angiopoietin 2', 'Gene', '285', (18, 32))
559287	28819306	In this study, groups that expressed EDIL3 were more likely to have the mucinous adenocarcinoma subtype than were EDIL3-negative groups.	('mucinous adenocarcinoma subtype', 'Disease', 'MESH:D002288', (72, 103))	('mucinous adenocarcinoma subtype', 'Disease', (72, 103))	('EDIL3', 'Var', (37, 42))	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))
559288	28819306	Mucinous adenocarcinoma is strongly correlated with KRAS (Kirsten rat sarcoma viral oncogene homolog) mutations.	('sarcoma', 'Disease', (70, 77))	('KRAS', 'Gene', (52, 56))	('sarcoma', 'Phenotype', 'HP:0100242', (70, 77))	('correlated', 'Reg', (36, 46))	('mutations', 'Var', (102, 111))	('Mucinous adenocarcinoma', 'Disease', (0, 23))	('sarcoma', 'Disease', 'MESH:D012509', (70, 77))	('rat', 'Species', '10116', (66, 69))	('Mucinous adenocarcinoma', 'Disease', 'MESH:D002288', (0, 23))	('carcinoma', 'Phenotype', 'HP:0030731', (14, 23))
559289	28819306	reported that KRAS-G12C mutants overexpress EMT genes in surgically resected lung adenocarcinoma.	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (77, 96))	('mutants', 'Var', (24, 31))	('lung adenocarcinoma', 'Disease', (77, 96))	('EMT genes', 'Gene', (44, 53))	('G12C', 'Mutation', 'rs121913530', (19, 23))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (77, 96))	('overexpress', 'PosReg', (32, 43))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))
559293	28819306	Downregulation of EDIL3 with small interfering RNA gene therapy has been shown to suppress the growth of colon tumors by inhibiting angiogenesis and cell proliferation in a mouse model.	('growth', 'MPA', (95, 101))	('colon tumors', 'Disease', (105, 117))	('colon tumors', 'Phenotype', 'HP:0100273', (105, 117))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('Downregulation', 'NegReg', (0, 14))	('tumors', 'Phenotype', 'HP:0002664', (111, 117))	('colon tumors', 'Disease', 'MESH:D015179', (105, 117))	('mouse', 'Species', '10090', (173, 178))	('inhibiting', 'NegReg', (121, 131))	('rat', 'Species', '10116', (161, 164))	('suppress', 'NegReg', (82, 90))	('cell proliferation', 'CPA', (149, 167))	('EDIL3', 'Gene', (18, 23))	('small interfering RNA', 'Var', (29, 50))	('angiogenesis', 'CPA', (132, 144))
559296	28819306	It has been reported that knockdown of EDIL3 by shRNA-containing plasmids promotes anoikis and inhibits anchorage-independent tumor growth in a pancreatic ductal adenocarcinoma cell line.	('promotes', 'PosReg', (74, 82))	('EDIL3', 'Gene', (39, 44))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('anoikis', 'CPA', (83, 90))	('carcinoma', 'Phenotype', 'HP:0030731', (167, 176))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('knockdown', 'Var', (26, 35))	('pancreatic ductal adenocarcinoma', 'Disease', (144, 176))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (144, 176))	('inhibits', 'NegReg', (95, 103))	('tumor', 'Disease', (126, 131))
559314	29688867	Aberrant activation of oncogenes and tumor-related signaling pathways can induce the metabolic reprogramming of prostate or breast cancer cells, producing specific metabolic fingerprints.	('activation', 'PosReg', (9, 19))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('Aberrant', 'Var', (0, 8))	('prostate', 'Disease', (112, 120))	('metabolic reprogramming', 'CPA', (85, 108))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('breast cancer', 'Disease', 'MESH:D001943', (124, 137))	('oncogenes', 'Protein', (23, 32))	('breast cancer', 'Phenotype', 'HP:0003002', (124, 137))	('tumor', 'Disease', (37, 42))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('breast cancer', 'Disease', (124, 137))	('induce', 'Reg', (74, 80))
559315	29688867	Furthermore, the inactivation of tumor suppressor genes is an important factor underlying tumor metabolic changes.	('inactivation', 'Var', (17, 29))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumor', 'Disease', (33, 38))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
559319	29688867	Metabolic changes can induce radioresistance as well, and the alterations in the glycolytic metabolism were shown to contribute to radioresistance development.	('glycolytic metabolism', 'MPA', (81, 102))	('rat', 'Species', '10116', (66, 69))	('radioresistance development', 'CPA', (131, 158))	('Metabolic changes', 'Var', (0, 17))	('induce', 'Reg', (22, 28))	('contribute', 'Reg', (117, 127))	('alterations', 'Var', (62, 73))	('radioresistance', 'CPA', (29, 44))
559327	29688867	The IR induces oxidative stress in cancers cells, and free OH radicals are considered the IR-induced common mediators of DNA damage, including single-strand breaks (SSB) and double-strand breaks (DSB), which disturb the DNA structure, triggering cell death.	('cell', 'CPA', (246, 250))	('double-strand breaks', 'Var', (174, 194))	('SSB', 'Chemical', '-', (165, 168))	('free OH radicals', 'Chemical', '-', (54, 70))	('triggering', 'Reg', (235, 245))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('oxidative stress', 'MPA', (15, 31))	('single-strand breaks', 'Var', (143, 163))	('cancers', 'Disease', 'MESH:D009369', (35, 42))	('cancers', 'Phenotype', 'HP:0002664', (35, 42))	('cancers', 'Disease', (35, 42))	('oxidative stress', 'Phenotype', 'HP:0025464', (15, 31))
559328	29688867	Combined, these effects lead to the DNA damage, chromosomal instability, mutation and apoptosis in cancer cells, ultimately killing them (Fig.	('chromosomal instability', 'Phenotype', 'HP:0040012', (48, 71))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('cancer', 'Disease', (99, 105))	('chromosomal instability', 'CPA', (48, 71))	('lead to', 'Reg', (24, 31))	('apoptosis', 'CPA', (86, 95))	('mutation', 'Var', (73, 81))	('killing', 'NegReg', (124, 131))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('DNA', 'MPA', (36, 39))
559333	29688867	PI3K signaling pathway regulates the steady-state homologous recombination levels, promoting DNA damage repair, and the PI3K inhibitor PI-103 can significantly enhance radiation-induced death.	('promoting', 'PosReg', (83, 92))	('PI3', 'Gene', '5266', (0, 3))	('PI3', 'Gene', '5266', (120, 123))	('PI-103', 'Var', (135, 141))	('PI-103', 'Chemical', 'MESH:C522973', (135, 141))	('PI3', 'Gene', (120, 123))	('DNA damage repair', 'MPA', (93, 110))	('enhance', 'PosReg', (160, 167))	('radiation-induced death', 'CPA', (168, 191))	('homologous recombination levels', 'MPA', (50, 81))	('PI3', 'Gene', (0, 3))
559339	29688867	For example, the cell adhesion molecule vitronectin (VTN) is an important oncogene, and the dysregulation of its expression promotes the migration and invasion of nasopharyngeal carcinoma (NPC) as well as resistance of the NPC cells to radiotherapy.	('NPC', 'Phenotype', 'HP:0100630', (189, 192))	('dysregulation', 'Var', (92, 105))	('NPC', 'Gene', (223, 226))	('nasopharyngeal carcinoma', 'Phenotype', 'HP:0100630', (163, 187))	('promotes', 'PosReg', (124, 132))	('NPC', 'Gene', (189, 192))	('expression', 'MPA', (113, 123))	('VTN', 'Gene', (53, 56))	('NPC', 'Gene', '4864', (223, 226))	('VTN', 'Gene', '7448', (53, 56))	('vitronectin', 'Gene', (40, 51))	('NPC', 'Gene', '4864', (189, 192))	('nasopharyngeal carcinoma', 'Disease', (163, 187))	('invasion', 'CPA', (151, 159))	('migration', 'CPA', (137, 146))	('rat', 'Species', '10116', (140, 143))	('resistance', 'CPA', (205, 215))	('vitronectin', 'Gene', '7448', (40, 51))	('NPC', 'Phenotype', 'HP:0100630', (223, 226))	('nasopharyngeal carcinoma', 'Disease', 'MESH:D000077274', (163, 187))	('carcinoma', 'Phenotype', 'HP:0030731', (178, 187))
559340	29688867	Additionally, many miRNAs, e.g., miR-29c and miR-22, have tumor-suppressor roles, and the alteration in their expression in lung and breast cancer cells represents an important cause of radioresistance.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('breast cancer', 'Disease', (133, 146))	('rat', 'Species', '10116', (94, 97))	('miR-22', 'Gene', '407004', (45, 51))	('breast cancer', 'Phenotype', 'HP:0003002', (133, 146))	('miR-29c', 'Gene', (33, 40))	('miR-22', 'Gene', (45, 51))	('miR-29c', 'Gene', '407026', (33, 40))	('breast cancer', 'Disease', 'MESH:D001943', (133, 146))	('expression', 'MPA', (110, 120))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('alteration', 'Var', (90, 100))
559344	29688867	Its dysfunctions may promote the development of systemic autoimmune diseases, such as lupus, while in cancer, it may promote or inhibit the survival and proliferation of cancer cells in the TME.	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('inhibit', 'NegReg', (128, 135))	('autoimmune diseases', 'Phenotype', 'HP:0002960', (57, 76))	('lupus', 'Disease', (86, 91))	('cancer', 'Disease', (170, 176))	('rat', 'Species', '10116', (160, 163))	('survival', 'CPA', (140, 148))	('systemic autoimmune diseases', 'Disease', 'MESH:D020274', (48, 76))	('dysfunctions', 'Var', (4, 16))	('promote', 'PosReg', (21, 28))	('systemic autoimmune diseases', 'Disease', (48, 76))	('cancer', 'Disease', (102, 108))	('cancer', 'Disease', 'MESH:D009369', (102, 108))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('promote', 'PosReg', (117, 124))	('lupus', 'Disease', 'MESH:D008180', (86, 91))
559374	29688867	The inhibition of mitochondrial respiration by mitochondrial respiratory modulators (e.g., di-nitro phenol) leads to a considerable increase in the glycolytic index.	('increase', 'PosReg', (132, 140))	('di-nitro phenol', 'Chemical', 'MESH:D004140', (91, 106))	('rat', 'Species', '10116', (66, 69))	('mitochondrial respiration', 'MPA', (18, 43))	('rat', 'Species', '10116', (37, 40))	('di-nitro phenol', 'Var', (91, 106))	('glycolytic index', 'MPA', (148, 164))	('inhibition', 'NegReg', (4, 14))
559383	29688867	Additionally, WZB117, a small molecule, acts as a specific inhibitor of GLUT1, overcoming the resistance of cancer cells to radiation.	('overcoming', 'PosReg', (79, 89))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('WZB117', 'Chemical', 'MESH:C576807', (14, 20))	('WZB117', 'Var', (14, 20))	('cancer', 'Disease', (108, 114))	('cancer', 'Disease', 'MESH:D009369', (108, 114))
559385	29688867	Furthermore, the antisense oligonucleotide chain (AS-ODNs) of GLUT1 can also induce the radiosensitivity of laryngeal carcinoma cells (Fig.	('laryngeal carcinoma', 'Phenotype', 'HP:0012118', (108, 127))	('induce', 'PosReg', (77, 83))	('antisense oligonucleotide chain', 'Var', (17, 48))	('oligonucleotide', 'Chemical', 'MESH:D009841', (27, 42))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('GLUT1', 'Gene', (62, 67))	('radiosensitivity', 'CPA', (88, 104))	('laryngeal carcinoma', 'Disease', (108, 127))	('laryngeal carcinoma', 'Disease', 'MESH:D007827', (108, 127))
559388	29688867	Alterations in glucose metabolism after radiotherapy can lead to the accumulation of large amounts of lactic acid, which is one of the unique malignant tumor phenotypes.	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('glucose metabolism', 'Disease', (15, 33))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('Alterations', 'Var', (0, 11))	('lead to', 'Reg', (57, 64))	('tumor', 'Disease', (152, 157))	('lactic acid', 'Chemical', 'MESH:D019344', (102, 113))	('glucose metabolism', 'Disease', 'MESH:D044882', (15, 33))	('lactic acid', 'MPA', (102, 113))	('accumulation of', 'MPA', (69, 84))	('rat', 'Species', '10116', (4, 7))
559405	29688867	Acting as a tumor suppressor, the expression of miR-34 was shown to negatively correlate with radioresistance development and to induce the sensitivity of the hepatocellular carcinoma cells to radiotherapy by inhibiting the expression of LDHA (Fig.	('miR-34', 'Gene', '407040', (48, 54))	('sensitivity', 'MPA', (140, 151))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (159, 183))	('induce', 'PosReg', (129, 135))	('hepatocellular carcinoma', 'Disease', (159, 183))	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (159, 183))	('inhibiting', 'NegReg', (209, 219))	('radioresistance development', 'CPA', (94, 121))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('expression', 'Var', (34, 44))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('LDHA', 'Gene', (238, 242))	('expression', 'MPA', (224, 234))	('miR-34', 'Gene', (48, 54))	('tumor', 'Disease', (12, 17))	('carcinoma', 'Phenotype', 'HP:0030731', (174, 183))	('negatively', 'NegReg', (68, 78))	('LDHA', 'Gene', '3939', (238, 242))
559445	29688867	The mechanisms underlying the development of radioresistance may include the following: An increasing number of studies have shown that, by targeting HIF1 activity, tumor antioxidant capacity can be reduced, as it affects the TME and promotes the sensitivity of solid tumors to radiotherapy.	('HIF1', 'Gene', '3091', (150, 154))	('tumor', 'Disease', (165, 170))	('activity', 'MPA', (155, 163))	('tumor', 'Phenotype', 'HP:0002664', (268, 273))	('affects', 'Reg', (214, 221))	('promotes', 'PosReg', (234, 242))	('targeting', 'Var', (140, 149))	('tumor', 'Disease', (268, 273))	('tumors', 'Phenotype', 'HP:0002664', (268, 274))	('tumor', 'Disease', 'MESH:D009369', (165, 170))	('solid tumors', 'Disease', (262, 274))	('HIF1', 'Gene', (150, 154))	('tumor', 'Phenotype', 'HP:0002664', (165, 170))	('TME', 'MPA', (226, 229))	('solid tumors', 'Disease', 'MESH:D009369', (262, 274))	('tumor', 'Disease', 'MESH:D009369', (268, 273))	('reduced', 'NegReg', (199, 206))
559446	29688867	By combining HIF1 targeting and radiotherapy, improved therapeutic effects can be achieved.	('targeting', 'Var', (18, 27))	('HIF1', 'Gene', '3091', (13, 17))	('HIF1', 'Gene', (13, 17))	('therapeutic effects', 'CPA', (55, 74))
559448	29688867	Additionally, HIF1alpha inhibition leads to the downregulation of stem cell markers and a decrease in radioresistance of cervical cancer cells.	('stem cell markers', 'CPA', (66, 83))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('cancer', 'Disease', (130, 136))	('HIF1alpha', 'Gene', (14, 23))	('inhibition', 'Var', (24, 34))	('downregulation', 'NegReg', (48, 62))	('HIF1alpha', 'Gene', '3091', (14, 23))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('decrease', 'NegReg', (90, 98))
559449	29688867	Various HIF1 inhibitors function through different signaling pathways, thereby enhancing the efficacy of radiotherapy.	('function', 'Reg', (24, 32))	('efficacy of radiotherapy', 'CPA', (93, 117))	('HIF1', 'Gene', (8, 12))	('inhibitors', 'Var', (13, 23))	('enhancing', 'PosReg', (79, 88))	('signaling pathways', 'Pathway', (51, 69))	('HIF1', 'Gene', '3091', (8, 12))
559451	29688867	KNK437 can abrogate hypoxia-induced anti-radiation effects by targeting both AKT and HIF1alpha.	('KNK437', 'Var', (0, 6))	('HIF1alpha', 'Gene', (85, 94))	('AKT', 'Pathway', (77, 80))	('HIF1alpha', 'Gene', '3091', (85, 94))	('targeting', 'Reg', (62, 71))	('hypoxia', 'Disease', (20, 27))	('hypoxia', 'Disease', 'MESH:D000860', (20, 27))	('abrogate', 'NegReg', (11, 19))
559456	29688867	NVP-BEZ235, an inhibitor of PI3K/mTOR signaling pathway, can inhibit the activation of HIF1alpha/VEGF signaling pathway in endometrial cancer and suppress radioresistance development.	('activation', 'PosReg', (73, 83))	('NVP-BEZ235', 'Var', (0, 10))	('endometrial cancer', 'Disease', 'MESH:D016889', (123, 141))	('VEGF', 'Gene', (97, 101))	('suppress', 'NegReg', (146, 154))	('radioresistance development', 'CPA', (155, 182))	('BEZ235', 'Chemical', 'MESH:C531198', (4, 10))	('mTOR', 'Gene', '2475', (33, 37))	('endometrial cancer', 'Phenotype', 'HP:0012114', (123, 141))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('HIF1alpha', 'Gene', (87, 96))	('inhibit', 'NegReg', (61, 68))	('mTOR', 'Gene', (33, 37))	('PI3', 'Gene', '5266', (28, 31))	('HIF1alpha', 'Gene', '3091', (87, 96))	('VEGF', 'Gene', '7422', (97, 101))	('endometrial cancer', 'Disease', (123, 141))	('PI3', 'Gene', (28, 31))
559457	29688867	As STAT3 inhibitors, NSC74859 and Stattic can improve the radiosensitivity of esophageal cancer through the inhibition of hypoxia and radiation-induced STAT3 activation, as well as the expression of HIF1alpha and VEGF.	('STAT3', 'Gene', (3, 8))	('NSC74859', 'Var', (21, 29))	('STAT3', 'Gene', '6774', (152, 157))	('inhibition', 'NegReg', (108, 118))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))	('STAT3', 'Gene', (152, 157))	('HIF1alpha', 'Gene', (199, 208))	('radiosensitivity', 'CPA', (58, 74))	('hypoxia', 'Disease', (122, 129))	('hypoxia', 'Disease', 'MESH:D000860', (122, 129))	('VEGF', 'Gene', '7422', (213, 217))	('improve', 'PosReg', (46, 53))	('HIF1alpha', 'Gene', '3091', (199, 208))	('STAT3', 'Gene', '6774', (3, 8))	('esophageal cancer', 'Disease', (78, 95))	('esophageal cancer', 'Disease', 'MESH:D004938', (78, 95))	('VEGF', 'Gene', (213, 217))
559469	29688867	The M2 isoform (PKM2) is a key regulator of glycolysis, expressed only in cancer cells, and targeting this molecule can inhibit cell viability, induce G2/M arrest, and promote apoptosis.	('induce', 'PosReg', (144, 150))	('G2/M arrest', 'CPA', (151, 162))	('targeting', 'Var', (92, 101))	('PKM2', 'Gene', (16, 20))	('PKM2', 'Gene', '5315', (16, 20))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('promote', 'PosReg', (168, 175))	('cancer', 'Disease', (74, 80))	('cell viability', 'CPA', (128, 142))	('inhibit', 'NegReg', (120, 127))	('apoptosis', 'CPA', (176, 185))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
559480	29688867	The combination of 2-DG and histone deacetylase transferase inhibitors can induce apoptosis in glioblastoma cells, while 2-DG can also significantly inhibit the expression of HK2 and induce apoptosis (Fig.	('inhibit', 'NegReg', (149, 156))	('2-DG', 'Chemical', 'MESH:D003847', (19, 23))	('glioblastoma', 'Disease', (95, 107))	('glioblastoma', 'Disease', 'MESH:D005909', (95, 107))	('apoptosis', 'CPA', (82, 91))	('expression', 'MPA', (161, 171))	('glioblastoma', 'Phenotype', 'HP:0012174', (95, 107))	('2-DG', 'Chemical', 'MESH:D003847', (121, 125))	('HK2', 'Gene', (175, 178))	('HK2', 'Gene', '3099', (175, 178))	('2-DG', 'Var', (121, 125))	('induce', 'PosReg', (183, 189))	('apoptosis', 'CPA', (190, 199))
559505	29688867	This suggests that radiotherapy can lead to the considerable alterations in the mitochondrial protein expression, and therefore induce radioresistance.	('mitochondrial protein expression', 'MPA', (80, 112))	('rat', 'Species', '10116', (65, 68))	('radiotherapy', 'Var', (19, 31))	('alterations', 'Reg', (61, 72))	('induce', 'Reg', (128, 134))	('radioresistance', 'CPA', (135, 150))
559508	29688867	After silencing ATAD3A, the expression of ATM, histone H2AX, and H3 was shown to decrease, inhibiting the DNA damage repair and ultimately promoting tumor cell radiosensitivity.	('inhibiting', 'NegReg', (91, 101))	('ATM', 'Gene', '472', (42, 45))	('decrease', 'NegReg', (81, 89))	('DNA damage repair', 'MPA', (106, 123))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('cell radiosensitivity', 'Phenotype', 'HP:0010997', (155, 176))	('expression', 'MPA', (28, 38))	('ATAD3A', 'Gene', '55210', (16, 22))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('promoting', 'PosReg', (139, 148))	('tumor', 'Disease', (149, 154))	('ATM', 'Gene', (42, 45))	('ATAD3A', 'Gene', (16, 22))	('silencing', 'Var', (6, 15))	('histone H2AX', 'Protein', (47, 59))
559511	29688867	Mutations in the SIRT3 Thr150Ala/Ser159Ala lead to a decrease in MnSOD activity and the production of mitochondrial ATP, increasing sensitivity to radiotherapy.	('Thr150Ala', 'SUBSTITUTION', 'None', (23, 32))	('production of mitochondrial ATP', 'MPA', (88, 119))	('MnSOD', 'Gene', (65, 70))	('SIRT3', 'Gene', '23410', (17, 22))	('SIRT3', 'Gene', (17, 22))	('decrease', 'NegReg', (53, 61))	('ATP', 'Chemical', 'MESH:D000255', (116, 119))	('Ser159Ala', 'Chemical', '-', (33, 42))	('sensitivity', 'MPA', (132, 143))	('Thr150Ala', 'Var', (23, 32))	('Mutations', 'Var', (0, 9))	('increasing', 'PosReg', (121, 131))	('MnSOD', 'Gene', '6648', (65, 70))
559516	29688867	Mitochondrial MKP1 confers radioresistance to HER2 overexpressing breast cancer cells, and by co-suppressing the expression of MKP1 and HER2, breast cancer cell apoptosis can be induced, while inhibiting radioresistance (Fig.	('MKP1', 'Gene', (14, 18))	('breast cancer', 'Disease', 'MESH:D001943', (142, 155))	('breast cancer', 'Disease', (142, 155))	('HER2', 'Gene', '2064', (136, 140))	('expression', 'MPA', (113, 123))	('HER2', 'Gene', '2064', (46, 50))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('MKP1', 'Gene', '1843', (127, 131))	('radioresistance', 'CPA', (204, 219))	('inhibiting', 'NegReg', (193, 203))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('HER2', 'Gene', (136, 140))	('MKP1', 'Gene', (127, 131))	('breast cancer', 'Phenotype', 'HP:0003002', (66, 79))	('MKP1', 'Gene', '1843', (14, 18))	('induced', 'PosReg', (178, 185))	('HER2', 'Gene', (46, 50))	('co-suppressing', 'Var', (94, 108))	('radioresistance', 'CPA', (27, 42))	('breast cancer', 'Disease', 'MESH:D001943', (66, 79))	('breast cancer', 'Phenotype', 'HP:0003002', (142, 155))	('breast cancer', 'Disease', (66, 79))
559522	29688867	MEK-specific inhibitor PD98059 was shown to prevent the observed effects of MEK/ERK on MMP and the development of radioresistance.	('prevent', 'NegReg', (44, 51))	('ERK', 'Gene', '5594', (80, 83))	('MMP', 'Disease', (87, 90))	('MEK', 'Gene', (0, 3))	('PD98059', 'Chemical', 'MESH:C093973', (23, 30))	('ERK', 'Gene', (80, 83))	('MEK', 'Gene', '5609', (0, 3))	('MEK', 'Gene', (76, 79))	('MEK', 'Gene', '5609', (76, 79))	('PD98059', 'Var', (23, 30))
559529	29688867	3), suggesting that the mtKATP pathway is a key regulator of radiosensitivity in gliomas, and the blockers and inhibitors of mtKATP channel and MAPK/ERK kinase, respectively, may represent novel therapeutics of the treatment of gliomas.	('mtKATP', 'Gene', (125, 131))	('glioma', 'Phenotype', 'HP:0009733', (81, 87))	('ERK', 'Gene', (149, 152))	('gliomas', 'Disease', 'MESH:D005910', (228, 235))	('ATP', 'Chemical', 'MESH:D000255', (27, 30))	('gliomas', 'Disease', (228, 235))	('gliomas', 'Phenotype', 'HP:0009733', (228, 235))	('glioma', 'Phenotype', 'HP:0009733', (228, 234))	('gliomas', 'Disease', 'MESH:D005910', (81, 88))	('ATP', 'Chemical', 'MESH:D000255', (128, 131))	('gliomas', 'Disease', (81, 88))	('gliomas', 'Phenotype', 'HP:0009733', (81, 88))	('inhibitors', 'Var', (111, 121))	('ERK', 'Gene', '5594', (149, 152))	('blockers', 'Var', (98, 106))
559531	29688867	An increasing number of studies demonstrated that radioresistance development can be associated with tumor metabolism, as the radiotherapy may induce alterations in many molecules and signaling pathways involved in the tumor cell metabolism, and metabolic changes may affect the efficacy of radiotherapy.	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('affect', 'Reg', (268, 274))	('tumor', 'Disease', (219, 224))	('rat', 'Species', '10116', (154, 157))	('tumor', 'Disease', (101, 106))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('rat', 'Species', '10116', (39, 42))	('radioresistance development', 'CPA', (50, 77))	('alterations', 'Reg', (150, 161))	('radiotherapy', 'Var', (126, 138))	('tumor', 'Disease', 'MESH:D009369', (219, 224))	('efficacy of radiotherapy', 'CPA', (279, 303))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('metabolic changes', 'CPA', (246, 263))
559608	27499599	Obstruction of both ureters results in uremia and is a leading cause of death.	('uremia', 'Disease', 'MESH:D014511', (39, 45))	('uremia', 'Disease', (39, 45))	('Obstruction', 'Var', (0, 11))	('death', 'Disease', 'MESH:D003643', (72, 77))	('death', 'Disease', (72, 77))	('results in', 'Reg', (28, 38))
559647	32667739	Osimertinib for compound EGFR exon 19 deletion/T790M mutated lung squamous cell carcinoma The role of the epidermal growth factor receptor (EGFR) mutation status testing in lung squamous cell carcinoma (SqCC) remains controversial.	('lung squamous cell carcinoma', 'Disease', (61, 89))	('EGFR', 'Gene', (140, 144))	('mutated', 'Var', (53, 60))	('carcinoma', 'Phenotype', 'HP:0030731', (192, 201))	('carcinoma', 'Phenotype', 'HP:0030731', (80, 89))	('EGFR', 'Gene', (25, 29))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (173, 201))	('EGFR', 'Gene', '1956', (140, 144))	('deletion/T790M mutated', 'Var', (38, 60))	('Osimertinib', 'Chemical', 'MESH:C000596361', (0, 11))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (173, 201))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (61, 89))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (178, 201))	('EGFR', 'Gene', '1956', (25, 29))	('lung squamous cell carcinoma', 'Disease', (173, 201))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (66, 89))	('epidermal growth factor receptor', 'Gene', (106, 138))	('T790M', 'Mutation', 'rs121434569', (47, 52))	('epidermal growth factor receptor', 'Gene', '1956', (106, 138))	('SqCC', 'Phenotype', 'HP:0002860', (203, 207))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (61, 89))
559648	32667739	Evidence of the effectiveness of osimertinib in SqCC with EGFR T790M mutation is limited.	('EGFR', 'Gene', '1956', (58, 62))	('EGFR', 'Gene', (58, 62))	('SqCC', 'Phenotype', 'HP:0002860', (48, 52))	('osimertinib', 'Chemical', 'MESH:C000596361', (33, 44))	('T790M', 'Mutation', 'rs121434569', (63, 68))	('T790M', 'Var', (63, 68))	('SqCC', 'Disease', (48, 52))
559649	32667739	Here, we describe a hitherto unreported case of a stage III SqCC patient with compound mutation of EGFR exon 19 deletion (19Del) and T790M mutation.	('EGFR', 'Gene', (99, 103))	('T790M', 'Mutation', 'rs121434569', (133, 138))	('SqCC', 'Disease', (60, 64))	('T790M mutation', 'Var', (133, 147))	('patient', 'Species', '9606', (65, 72))	('EGFR', 'Gene', '1956', (99, 103))	('SqCC', 'Phenotype', 'HP:0002860', (60, 64))
559651	32667739	We suggest that EGFR mutation testing should be performed in Asian patients who have not been definitively diagnosed with SqCC due to small lung biopsy samples.	('patients', 'Species', '9606', (67, 75))	('SqCC', 'Phenotype', 'HP:0002860', (122, 126))	('mutation', 'Var', (21, 29))	('EGFR', 'Gene', '1956', (16, 20))	('small lung', 'Phenotype', 'HP:0002089', (134, 144))	('EGFR', 'Gene', (16, 20))
559652	32667739	Osimertinib has shown good efficacy in SqCC harboring a "primary" resistance mechanism (EGFR T790M).	('SqCC', 'Phenotype', 'HP:0002860', (39, 43))	('SqCC', 'Disease', (39, 43))	('Osimertinib', 'Chemical', 'MESH:C000596361', (0, 11))	('EGFR', 'Gene', '1956', (88, 92))	('T790M', 'Mutation', 'rs121434569', (93, 98))	('T790M', 'Var', (93, 98))	('EGFR', 'Gene', (88, 92))
559653	32667739	An unreported case of stage III squamous cell carcinoma with synchronous occurrence of EGFR exon 19 deletion (19Del) and T790M mutation.	('T790M', 'Var', (121, 126))	('EGFR', 'Gene', '1956', (87, 91))	('III squamous cell carcinoma', 'Disease', (28, 55))	('carcinoma', 'Phenotype', 'HP:0030731', (46, 55))	('III squamous cell carcinoma', 'Disease', 'MESH:D002294', (28, 55))	('EGFR', 'Gene', (87, 91))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (32, 55))	('T790M', 'Mutation', 'rs121434569', (121, 126))
559655	32667739	EGFR mutation testing should be performed in Asian patients who are not definitively diagnosed with SqCC due to small lung biopsy samples.	('EGFR', 'Gene', (0, 4))	('SqCC', 'Phenotype', 'HP:0002860', (100, 104))	('small lung', 'Phenotype', 'HP:0002089', (112, 122))	('patients', 'Species', '9606', (51, 59))	('SqCC', 'Disease', (100, 104))	('EGFR', 'Gene', '1956', (0, 4))	('mutation', 'Var', (5, 13))
559657	32667739	EGFR mutations have become an important therapeutic target for the treatment of nonsquamous NSCLC.	('EGFR', 'Gene', (0, 4))	('NSCLC', 'Phenotype', 'HP:0030358', (92, 97))	('mutations', 'Var', (5, 14))	('NSCLC', 'Disease', (92, 97))	('EGFR', 'Gene', '1956', (0, 4))	('NSCLC', 'Disease', 'MESH:D002289', (92, 97))
559658	32667739	EGFR exon 19 deletion (19Del) and exon 21 Leu858Arg point mutation (L858R), which are associated with favorable outcomes in patients treated with EGFR-tyrosine kinase inhibitors (TKIs), account for 90% of all EGFR mutations.	('EGFR', 'Gene', (0, 4))	('EGFR', 'Gene', (209, 213))	('EGFR', 'Gene', '1956', (146, 150))	('Leu858Arg', 'Mutation', 'rs121434568', (42, 51))	('EGFR', 'Gene', '1956', (209, 213))	('L858R', 'Mutation', 'rs121434568', (68, 73))	('mutations', 'Var', (214, 223))	('EGFR', 'Gene', (146, 150))	('Leu858Arg', 'Var', (42, 51))	('EGFR', 'Gene', '1956', (0, 4))	('patients', 'Species', '9606', (124, 132))
559659	32667739	EGFR exon 20 Thr790Met point mutation (T790M) was present in approximately 50% to 60% of acquired resistance to EGFR-TKI.3 EGFR T790M mutation can also be detected in a small proportion of tumors before treatment with EGFR-TKIs.4 Third generation TKIs, such as osimertinib, have demonstrated efficacy in patients who develop resistance to first or second generation EGFR-TKIs due to T790M mutation.5   EGFR mutation rate is 40% to 50% in lung adenocarcinoma (ADC) cases in east Asian populations.6 However, in Asian SqCC patients, incidence of EGFR mutation is relatively low, varying from 2% to 13%.7, 8, 9, 10 The role of EGFR mutation status testing and EGFR-TKIs in SqCC remains controversial.	('EGFR', 'Gene', (123, 127))	('EGFR', 'Gene', (624, 628))	('EGFR', 'Gene', (402, 406))	('Thr790Met', 'SUBSTITUTION', 'None', (13, 22))	('EGFR', 'Gene', (544, 548))	('EGFR', 'Gene', (218, 222))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('lung adenocarcinoma', 'Disease', (438, 457))	('patients', 'Species', '9606', (521, 529))	('tumors', 'Phenotype', 'HP:0002664', (189, 195))	('EGFR', 'Gene', '1956', (657, 661))	('SqCC', 'Phenotype', 'HP:0002860', (516, 520))	('EGFR', 'Gene', '1956', (123, 127))	('T790M', 'Mutation', 'rs121434569', (383, 388))	('EGFR', 'Gene', (112, 116))	('EGFR', 'Gene', (366, 370))	('EGFR', 'Gene', '1956', (624, 628))	('EGFR', 'Gene', (0, 4))	('EGFR', 'Gene', '1956', (402, 406))	('patients', 'Species', '9606', (304, 312))	('EGFR', 'Gene', '1956', (544, 548))	('tumors', 'Disease', (189, 195))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (438, 457))	('EGFR', 'Gene', '1956', (218, 222))	('Thr790Met', 'Var', (13, 22))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (438, 457))	('osimertinib', 'Chemical', 'MESH:C000596361', (261, 272))	('T790M', 'Mutation', 'rs121434569', (39, 44))	('T790M', 'Mutation', 'rs121434569', (128, 133))	('carcinoma', 'Phenotype', 'HP:0030731', (448, 457))	('SqCC', 'Phenotype', 'HP:0002860', (670, 674))	('tumors', 'Disease', 'MESH:D009369', (189, 195))	('EGFR', 'Gene', '1956', (112, 116))	('EGFR', 'Gene', '1956', (366, 370))	('EGFR', 'Gene', '1956', (0, 4))	('EGFR', 'Gene', (657, 661))
559660	32667739	Some oncology groups recommend EGFR mutation testing in all SqCC patients when clinical features indicate a higher probability of an oncogenic driver (ASCO, ACP/IASLC/AMP),11 while others recommend it only for patients with SqCC who have never smoked or who have mixed subtypes (ESMO and NCCN).12  Here, we report a case of locally advanced SqCC harboring EGFR exon 19Del/T790M mutation with a pathological complete tumor response after osimertinib treatment.	('SqCC', 'Phenotype', 'HP:0002860', (224, 228))	('EGFR', 'Gene', '1956', (356, 360))	('EGFR', 'Gene', '1956', (31, 35))	('tumor', 'Disease', (416, 421))	('SqCC', 'Phenotype', 'HP:0002860', (341, 345))	('patients', 'Species', '9606', (210, 218))	('tumor', 'Disease', 'MESH:D009369', (416, 421))	('osimertinib', 'Chemical', 'MESH:C000596361', (437, 448))	('patients', 'Species', '9606', (65, 73))	('T790M', 'Mutation', 'rs121434569', (372, 377))	('exon 19Del/T790M', 'Var', (361, 377))	('tumor', 'Phenotype', 'HP:0002664', (416, 421))	('SqCC', 'Phenotype', 'HP:0002860', (60, 64))	('SqCC', 'Disease', (341, 345))	('EGFR', 'Gene', (356, 360))	('EGFR', 'Gene', (31, 35))	('mixed subtypes', 'Species', '384619', (263, 277))	('AMP', 'Chemical', 'MESH:D000249', (167, 170))	('oncology', 'Phenotype', 'HP:0002664', (5, 13))
559666	32667739	Amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) revealed compound occurrence of EGFR exon 19Del and T790M mutation (Fig 2g).	('EGFR', 'Gene', (110, 114))	('T790M', 'Var', (130, 135))	('T790M', 'Mutation', 'rs121434569', (130, 135))	('EGFR', 'Gene', '1956', (110, 114))
559669	32667739	He had normal lung function, no comorbidities, and his clinical stage was cT3N2M0 IIIB (AJCC eighth version).	('AJCC eighth version', 'Disease', (88, 107))	('AJCC eighth version', 'Disease', 'MESH:D061285', (88, 107))	('cT3N2M0 IIIB', 'Var', (74, 86))
559670	32667739	According to NCCN guidelines, the third-generation EGFR inhibitor osimertinib is the preferred first-line therapy option for patients with metastatic NSCLC with sensitizing EGFR mutations.	('NSCLC', 'Disease', 'MESH:D002289', (150, 155))	('EGFR', 'Gene', (51, 55))	('NSCLC', 'Phenotype', 'HP:0030358', (150, 155))	('EGFR', 'Gene', '1956', (173, 177))	('mutations', 'Var', (178, 187))	('EGFR', 'Gene', (173, 177))	('NSCLC', 'Disease', (150, 155))	('osimertinib', 'Chemical', 'MESH:C000596361', (66, 77))	('EGFR', 'Gene', '1956', (51, 55))	('patients', 'Species', '9606', (125, 133))
559678	32667739	Here we describe a hitherto unreported case of a stage III SqCC in a patient with synchronous occurrence of EGFR exon 19Del and T790M mutation treated with osimertinib.	('T790M', 'Mutation', 'rs121434569', (128, 133))	('EGFR', 'Gene', '1956', (108, 112))	('stage III SqCC', 'Disease', (49, 63))	('EGFR', 'Gene', (108, 112))	('SqCC', 'Phenotype', 'HP:0002860', (59, 63))	('osimertinib', 'Chemical', 'MESH:C000596361', (156, 167))	('SqCC', 'Disease', (59, 63))	('patient', 'Species', '9606', (69, 76))	('T790M mutation', 'Var', (128, 142))
559679	32667739	To date, only a few cases of squamous cell transformation from LADC treated with EGFR-TKIs with concomitant T790M have been reported.13, 14, 15 There are no reports on the use of osimertinib in SqCC with primary EGFR exon 19Del and T790M compound mutation.	('T790M', 'Mutation', 'rs121434569', (108, 113))	('T790M', 'Mutation', 'rs121434569', (232, 237))	('T790M', 'Var', (232, 237))	('EGFR', 'Gene', '1956', (212, 216))	('EGFR', 'Gene', (81, 85))	('SqCC', 'Phenotype', 'HP:0002860', (194, 198))	('osimertinib', 'Chemical', 'MESH:C000596361', (179, 190))	('EGFR', 'Gene', '1956', (81, 85))	('EGFR', 'Gene', (212, 216))
559682	32667739	Ho and colleagues studied 148 small lung biopsy cases with pathological diagnosis of SqCC or NSCLC favor SqCC, and found an EGFR mutation rate of 5.2% (7/135) in SqCC and 46.2% (6/13) in NSCLC favor SqCC.	('NSCLC', 'Phenotype', 'HP:0030358', (187, 192))	('SqCC', 'Phenotype', 'HP:0002860', (105, 109))	('NSCLC', 'Disease', (93, 98))	('EGFR', 'Gene', '1956', (124, 128))	('mutation', 'Var', (129, 137))	('SqCC', 'Phenotype', 'HP:0002860', (85, 89))	('SqCC', 'Phenotype', 'HP:0002860', (199, 203))	('NSCLC', 'Disease', 'MESH:D002289', (93, 98))	('SqCC', 'Phenotype', 'HP:0002860', (162, 166))	('EGFR', 'Gene', (124, 128))	('NSCLC', 'Disease', (187, 192))	('small lung', 'Phenotype', 'HP:0002089', (30, 40))	('NSCLC', 'Disease', 'MESH:D002289', (187, 192))	('NSCLC', 'Phenotype', 'HP:0030358', (93, 98))	('SqCC', 'Disease', (162, 166))
559690	32667739	According to the FLAURA trial, osimertinib showed efficacy superior to that of standard EGFR-TKIs in the first-line treatment of EGFR mutation-positive advanced NSCLC, with a similar safety profile and lower rates of serious adverse events.22 However, evidence of the effectiveness of osimertinib in SqCC with EGFR T790M mutation is limited.	('osimertinib', 'Chemical', 'MESH:C000596361', (31, 42))	('NSCLC', 'Disease', 'MESH:D002289', (161, 166))	('osimertinib', 'Chemical', 'MESH:C000596361', (285, 296))	('T790M mutation', 'Var', (315, 329))	('EGFR', 'Gene', '1956', (310, 314))	('NSCLC', 'Phenotype', 'HP:0030358', (161, 166))	('T790M', 'Mutation', 'rs121434569', (315, 320))	('EGFR', 'Gene', '1956', (129, 133))	('SqCC', 'Phenotype', 'HP:0002860', (300, 304))	('EGFR', 'Gene', '1956', (88, 92))	('EGFR', 'Gene', (310, 314))	('EGFR', 'Gene', (129, 133))	('NSCLC', 'Disease', (161, 166))	('SqCC', 'Disease', (300, 304))	('FLAURA', 'Chemical', '-', (17, 23))	('EGFR', 'Gene', (88, 92))
559691	32667739	reported a case of SqCC with secondary T790M mutation receiving osimertinib, and PFS was less than 10 months.	('T790M', 'Mutation', 'rs121434569', (39, 44))	('SqCC', 'Disease', (19, 23))	('osimertinib', 'Chemical', 'MESH:C000596361', (64, 75))	('secondary T790M mutation', 'Var', (29, 53))	('SqCC', 'Phenotype', 'HP:0002860', (19, 23))
559693	32667739	More cases are needed to clarify the efficacy of osimertinib in SqCC with EGFR T790M mutation.	('SqCC', 'Phenotype', 'HP:0002860', (64, 68))	('osimertinib', 'Chemical', 'MESH:C000596361', (49, 60))	('SqCC', 'Disease', (64, 68))	('T790M', 'Mutation', 'rs121434569', (79, 84))	('EGFR', 'Gene', '1956', (74, 78))	('T790M', 'Var', (79, 84))	('EGFR', 'Gene', (74, 78))
559696	32667739	More clinical trials are needed to provide convincing evidence for customized therapy for SqCC patients with EGFR mutations.	('SqCC', 'Disease', (90, 94))	('patients', 'Species', '9606', (95, 103))	('mutations', 'Var', (114, 123))	('EGFR', 'Gene', '1956', (109, 113))	('SqCC', 'Phenotype', 'HP:0002860', (90, 94))	('EGFR', 'Gene', (109, 113))
559697	32667739	As far as we are aware, this is the first reported EGFR Exon 19Del/T790M mutation SqCC case with pathologic complete response to osimertinib, which serves as direct evidence of the effectiveness of osimertinib in SqCC.	('SqCC', 'Gene', (82, 86))	('SqCC', 'Phenotype', 'HP:0002860', (82, 86))	('EGFR', 'Gene', (51, 55))	('T790M', 'Mutation', 'rs121434569', (67, 72))	('SqCC', 'Phenotype', 'HP:0002860', (213, 217))	('osimertinib', 'Chemical', 'MESH:C000596361', (198, 209))	('osimertinib', 'Chemical', 'MESH:C000596361', (129, 140))	('EGFR', 'Gene', '1956', (51, 55))	('Exon 19Del/T790M mutation', 'Var', (56, 81))
559699	32667739	Further clinical data in patients with SqCC harboring a "primary" resistance mechanism (T790M) to TKIs may be helpful in order to optimize the best treatment for these patients.	('SqCC', 'Phenotype', 'HP:0002860', (39, 43))	('T790M', 'Mutation', 'rs121434569', (88, 93))	('T790M', 'Var', (88, 93))	('TKIs', 'Gene', (98, 102))	('patients', 'Species', '9606', (25, 33))	('patients', 'Species', '9606', (168, 176))
559714	30997737	Such tumors are further subdivided on basis of various other parameters such as mucin staining, various markers analyzed by molecular data and immunohisto/cytochemistry.9, 10 Various new marker genetic alterations are recommended now in the panel of molecular testing to classify NSCLC including mutations in epidermal growth factor receptor (EGFR), B-Raf proto-oncogene (BRAF), and the expression of programmed death ligand 1 (PD-L1) in small biopsy samples and cytologic specimens 11, 12, 13, 14 (Figure 1).	('tumors', 'Disease', (5, 11))	('tumors', 'Disease', 'MESH:D009369', (5, 11))	('PD-L1', 'Gene', (428, 433))	('epidermal growth factor receptor', 'Gene', (309, 341))	('programmed death ligand 1', 'Gene', (401, 426))	('programmed death ligand 1', 'Gene', '29126', (401, 426))	('epidermal growth factor receptor', 'Gene', '1956', (309, 341))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('B-Raf proto-oncogene', 'Gene', '673', (350, 370))	('B-Raf proto-oncogene', 'Gene', (350, 370))	('EGFR', 'Gene', (343, 347))	('NSCLC', 'Disease', (280, 285))	('tumors', 'Phenotype', 'HP:0002664', (5, 11))	('BRAF', 'Gene', (372, 376))	('mutations', 'Var', (296, 305))	('NSCLC', 'Disease', 'MESH:D002289', (280, 285))
559717	30997737	Epidermal growth factor receptor gene is a tyrosine kinase belonging to ErbB family and along with its ligand has shown various abnormalities in NSCLC including protein overexpression, gene amplification, and mutations leading to its progression.15, 16 The anomalous activities of EGFR along with helping in tumor growth and development also regulate various cellular activities like apoptosis and angiogenesis.	('development', 'CPA', (325, 336))	('ErbB', 'Gene', '1956', (72, 76))	('regulate', 'Reg', (342, 350))	('NSCLC', 'Disease', (145, 150))	('tyrosine kinase', 'Gene', (43, 58))	('EGFR', 'Gene', (281, 285))	('Epidermal growth factor receptor', 'Gene', (0, 32))	('tumor', 'Disease', 'MESH:D009369', (308, 313))	('NSCLC', 'Disease', 'MESH:D002289', (145, 150))	('apoptosis', 'CPA', (384, 393))	('tumor', 'Phenotype', 'HP:0002664', (308, 313))	('Epidermal growth factor receptor', 'Gene', '1956', (0, 32))	('anomalous', 'Var', (257, 266))	('tumor', 'Disease', (308, 313))	('angiogenesis', 'CPA', (398, 410))	('tyrosine kinase', 'Gene', '7294', (43, 58))	('ErbB', 'Gene', (72, 76))	('cellular activities', 'CPA', (359, 378))
559718	30997737	Several groups have identified somatic mutations in EGFR in patients with lung carcinoma with increased frequency in patients who are nonsmokers, female patients, and patients from East Asian parts.17 Nearly 90% of these mutations are present in first four exons (18-21) of tyrosine kinase domain of the EGFR gene, which are either an in-frame deletion in exon 19 or a missense mutation in exon 21.18, 19, 20, 21, 22 Other tyrosine kinases involved in resistance mechanism include insulin-like growth factor 1 receptor, KRAS mutations, and the epithelial-to-mesenchymal transition.23  Human epidermal growth factor receptor 2 (HER2), also known as NEU, EGFR2, or ERBB2, is another member of EGFR family.23, 24, 25, 26, 27 Mutations in HER2 have been identified in LUAD patients28 however, the frequency of such mutations is less than 5%.	('lung carcinoma', 'Disease', 'MESH:D008175', (74, 88))	('patients', 'Species', '9606', (769, 777))	('NEU', 'Gene', '2064', (648, 651))	('patients', 'Species', '9606', (117, 125))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('tyrosine kinase', 'Gene', (274, 289))	('patients', 'Species', '9606', (60, 68))	('HER2', 'Gene', '2064', (627, 631))	('tyrosine kinase', 'Gene', '7294', (274, 289))	('NEU', 'Gene', (648, 651))	('insulin-like growth factor 1 receptor', 'Gene', (481, 518))	('Mutations', 'Var', (722, 731))	('HER2', 'Gene', '2064', (735, 739))	('Human epidermal growth factor receptor 2', 'Gene', (585, 625))	('lung carcinoma', 'Disease', (74, 88))	('ERBB2', 'Gene', (663, 668))	('tyrosine kinase', 'Gene', (423, 438))	('patients', 'Species', '9606', (153, 161))	('HER2', 'Gene', (627, 631))	('insulin-like growth factor 1 receptor', 'Gene', '3480', (481, 518))	('patients', 'Species', '9606', (167, 175))	('tyrosine kinase', 'Gene', '7294', (423, 438))	('ERBB2', 'Gene', '2064', (663, 668))	('Human epidermal growth factor receptor 2', 'Gene', '2064', (585, 625))	('HER2', 'Gene', (735, 739))
559719	30997737	All the HER2 mutations were found in exon 20 and were in frame insertion mutations.	('mutations', 'Var', (13, 22))	('HER2', 'Gene', '2064', (8, 12))	('HER2', 'Gene', (8, 12))
559723	30997737	It has been found that about 15%-30% of LUAD has mutations in KRAS, a member of RAS family and is the reason for resistance to EGFR inhibitors (tyrosine kinase inhibitors and cetuximab) and chemotherapy.29 Most of these mutations are transversion mutations which effect exon 12 in 90% of patients and rest in exon 13.	('patients', 'Species', '9606', (288, 296))	('tyrosine kinase', 'Gene', (144, 159))	('effect', 'Reg', (263, 269))	('cetuximab', 'Chemical', 'MESH:D000068818', (175, 184))	('tyrosine kinase', 'Gene', '7294', (144, 159))	('mutations', 'Var', (220, 229))
559729	30997737	Inhibitors have been designed for this pathway under various categories which include Pan-PI3K inhibitors binding to the catalytic p110 subunits of class IA PI3Ks, PI3Kalpha, PI3Kbeta, PI3Kdelta, and PI3Kgamma.	('PI3Kalpha', 'Gene', '5290', (164, 173))	('PI3Kalpha', 'Gene', (164, 173))	('PI3Kdelta', 'Gene', '5293', (185, 194))	('PI3Kbeta', 'Gene', (175, 183))	('binding', 'Interaction', (106, 113))	('PI3Ks', 'Var', (157, 162))	('p110', 'Gene', '100616443', (131, 135))	('p110', 'Gene', (131, 135))	('PI3Kgamma', 'Gene', '5294', (200, 209))	('PI3Kgamma', 'Gene', (200, 209))	('PI3Kbeta', 'Gene', '5291', (175, 183))	('PI3Kdelta', 'Gene', (185, 194))
559759	30997737	Tumor genotyping for identification of genetic alterations has helped in deciding the targeted therapy individualized for the patients.84, 85, 86 Usually mutations observed in tumors occur in the genes encoding proteins of signaling pathways which are involved in cellular proliferation and survival.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('proteins', 'Protein', (211, 219))	('tumors', 'Disease', (176, 182))	('tumors', 'Disease', 'MESH:D009369', (176, 182))	('occur', 'Reg', (183, 188))	('tumors', 'Phenotype', 'HP:0002664', (176, 182))	('patients', 'Species', '9606', (126, 134))	('mutations', 'Var', (154, 163))
559760	30997737	These mutations help in formation and maintenance of tumors.	('help', 'Reg', (16, 20))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('mutations', 'Var', (6, 15))	('tumors', 'Disease', (53, 59))
559773	30997737	It was observed that a marginal increase in the median overall survival of 11.3 months was seen with cetuximab when compared to 10.1 months with chemotherapy alone.	('cetuximab', 'Var', (101, 110))	('cetuximab', 'Chemical', 'MESH:D000068818', (101, 110))	('overall', 'MPA', (55, 62))	('increase', 'PosReg', (32, 40))
559781	30997737	Patients with activating EGFR mutations (L858R and Del19) have shown good response with these inhibitors.	('EGFR', 'Gene', (25, 29))	('Del19', 'Var', (51, 56))	('L858R', 'Var', (41, 46))	('activating', 'PosReg', (14, 24))	('Patients', 'Species', '9606', (0, 8))	('L858R', 'Mutation', 'rs121434568', (41, 46))
559782	30997737	The major drawback with these inhibitors was development of tumor resistance mainly due to EGFR T790M resistance mutation after a period of time.	('EGFR', 'Gene', (91, 95))	('due', 'Reg', (84, 87))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('T790M', 'Mutation', 'rs121434569', (96, 101))	('tumor', 'Disease', (60, 65))	('T790M', 'Var', (96, 101))
559790	30997737	This finding led to development of many drugs which target T790M.	('led to', 'Reg', (13, 19))	('T790M', 'Var', (59, 64))	('T790M', 'Mutation', 'rs121434569', (59, 64))
559793	30997737	The first inhibitor to receive FDA and EMA approval in November 2015 and February 2016, respectively, for NSCLC patients showing T790M was osimertinib (AZD9291) (Table 1).	('T790M', 'Mutation', 'rs121434569', (129, 134))	('NSCLC', 'Disease', 'MESH:D002289', (106, 111))	('T790M', 'Var', (129, 134))	('patients', 'Species', '9606', (112, 120))	('osimertinib', 'Chemical', 'MESH:C000603933', (139, 150))	('NSCLC', 'Disease', (106, 111))	('AZD9291', 'Chemical', 'MESH:C000596361', (152, 159))
559795	30997737	This molecule is a mono-anilino-pyrimidine compound binding covalently and has shown promising activity against various EGFR mutations like L858R, L858R/T790M, exon 19 deletion, and exon 19 deletion/T790MCross DAE102 (Table 1).	('L858R', 'Var', (140, 145))	('T790M', 'Mutation', 'rs121434569', (153, 158))	('exon 19 deletion/T790MCross', 'Var', (182, 209))	('mono-anilino-pyrimidine', 'Chemical', '-', (19, 42))	('L858R', 'Mutation', 'rs121434568', (140, 145))	('L858R', 'Mutation', 'rs121434568', (147, 152))	('binding', 'Interaction', (52, 59))	('T790M', 'Mutation', 'rs121434569', (199, 204))	('activity', 'MPA', (95, 103))	('DAE102', 'Chemical', '-', (210, 216))	('L858R/T790M', 'Var', (147, 158))	('exon 19 deletion', 'Var', (160, 176))	('deletion', 'Var', (168, 176))	('EGFR', 'Gene', (120, 124))
559797	30997737	It binds covalently with receptor and leading to irreversible enzymatic inhibition of activating EGFR mutations and T790M mutation; however, it does not affect/bind with wild-type EGFR.	('enzymatic inhibition', 'MPA', (62, 82))	('binds', 'Interaction', (3, 8))	('T790M mutation', 'Var', (116, 130))	('T790M', 'Mutation', 'rs121434569', (116, 121))	('activating', 'PosReg', (86, 96))	('EGFR', 'Gene', (97, 101))	('mutations', 'Var', (102, 111))
559801	30997737	In phase II trial, 76 patients of NSCLC who were confirmed for T790M were treated with 800 mg daily dose and the overall response rate was found to be 61%.	('NSCLC', 'Disease', (34, 39))	('NSCLC', 'Disease', 'MESH:D002289', (34, 39))	('patients', 'Species', '9606', (22, 30))	('T790M', 'Mutation', 'rs121434569', (63, 68))	('T790M', 'Var', (63, 68))
559805	30997737	This drug is also undergoing phase II trial in combination with nivolumab, an anti-PD-1 monoclonal antibody in EGFR mutant/T790M+ NSCLC patients who have progressed on first-line EGFR TKI (NCT02323126) (Table 1).	('NSCLC', 'Disease', 'MESH:D002289', (130, 135))	('nivolumab', 'Chemical', 'MESH:D000077594', (64, 73))	('T790M', 'Mutation', 'rs121434569', (123, 128))	('EGFR', 'Gene', (111, 115))	('patients', 'Species', '9606', (136, 144))	('mutant/T790M+', 'Var', (116, 129))	('NSCLC', 'Disease', (130, 135))
559807	30997737	Mutations in KRAS gene are the most common molecular abnormalities in human malignancies.	('malignancies', 'Disease', (76, 88))	('molecular abnormalities', 'Disease', 'MESH:C567116', (43, 66))	('human', 'Species', '9606', (70, 75))	('Mutations', 'Var', (0, 9))	('malignancies', 'Disease', 'MESH:D009369', (76, 88))	('KRAS', 'Gene', (13, 17))	('molecular abnormalities', 'Disease', (43, 66))
559809	30997737	The development of FTI as monotherapy was banned after two inhibitors namely R1155777 and salirasib, which is a farnesylcysteine mimetic, 108 were inactive in a KRAS-mutated NSCLC cohort.109  Various molecules, SML-8-73-1(targets the guanine nucleotide binding pocket of the KRAS product of the G12C mutation)110 and ARS-853(binds to KRAS/G12C),111 have shown encouraging preclinical data.	('R1155777', 'Chemical', '-', (77, 85))	('G12C', 'Mutation', 'rs121913530', (339, 343))	('NSCLC', 'Disease', 'MESH:D002289', (174, 179))	('SML-8-73-1', 'Var', (211, 221))	('farnesylcysteine', 'Chemical', 'MESH:C057785', (112, 128))	('guanine nucleotide', 'Chemical', 'MESH:D006150', (234, 252))	('salirasib', 'Chemical', 'MESH:C093323', (90, 99))	('FTI', 'Chemical', '-', (19, 22))	('G12C', 'Mutation', 'rs121913530', (295, 299))	('NSCLC', 'Disease', (174, 179))
559810	30997737	Selumetinib which is a selective allosteric inhibitor of MEK1/MEK2 showed good preclinical activity in KRAS-mutated cancers.112 The combination of selumentinib and docetaxel when compared with docetaxel monotherapy showed better overall response ratio in a phase 2 trial; however, no change was observed in overall survival with increased chances of side effects which include febrile neutropenia (14%) for the combination versus 0% for docetaxel.113 Trametinib which is also a MEK inhibitor has received regulatory approval for v-Raf murine sarcoma viral oncogene homolog B (BRAF) mutated advanced melanoma.	('v-Raf murine sarcoma viral oncogene homolog B', 'Gene', '673', (529, 574))	('MEK1', 'Gene', (57, 61))	('docetaxel', 'Chemical', 'MESH:D000077143', (193, 202))	('febrile neutropenia', 'Disease', (377, 396))	('melanoma', 'Disease', 'MESH:D008545', (599, 607))	('MEK2', 'Gene', (62, 66))	('cancers', 'Disease', 'MESH:D009369', (116, 123))	('MEK2', 'Gene', '26396', (62, 66))	('docetaxel', 'Chemical', 'MESH:D000077143', (437, 446))	('mutated', 'Var', (582, 589))	('BRAF', 'Gene', (576, 580))	('neutropenia', 'Phenotype', 'HP:0001875', (385, 396))	('MEK1', 'Gene', '26395', (57, 61))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('docetaxel', 'Chemical', 'MESH:D000077143', (164, 173))	('febrile neutropenia', 'Disease', 'MESH:D009503', (377, 396))	('v-Raf murine sarcoma viral oncogene homolog B', 'Gene', (529, 574))	('melanoma', 'Phenotype', 'HP:0002861', (599, 607))	('melanoma', 'Disease', (599, 607))	('cancers', 'Phenotype', 'HP:0002664', (116, 123))	('cancers', 'Disease', (116, 123))	('sarcoma', 'Phenotype', 'HP:0100242', (542, 549))
559811	30997737	It has been observed that mutations in PI3K catalytic subunit coexist with KRAS mutations and PI3K/AKT signaling increases in KRAS mutated cells.	('mutations', 'Var', (80, 89))	('PI3K', 'Gene', (39, 43))	('AKT', 'Gene', '207', (99, 102))	('mutations', 'Var', (26, 35))	('KRAS', 'Gene', (75, 79))	('AKT', 'Gene', (99, 102))	('increases', 'PosReg', (113, 122))
559812	30997737	Based on this hypothesis, pretreated patients having various KRAS mutated tumors were taken for a phase I trial and were given AKT inhibitor in combination with selumetinib.	('mutated', 'Var', (66, 73))	('patients', 'Species', '9606', (37, 45))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumors', 'Disease', (74, 80))	('AKT', 'Gene', '207', (127, 130))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('KRAS', 'Gene', (61, 65))	('selumetinib', 'Chemical', 'MESH:C517975', (161, 172))	('AKT', 'Gene', (127, 130))	('tumors', 'Disease', 'MESH:D009369', (74, 80))
559814	30997737	Cyclin-dependent kinases 4 and 6 are important for KRAS-driven oncogenesis and thus can be a putative target in NSCLC.115 Abemaciclib, a CDK4/6 inhibitor, showed promising data in patients with KRAS mutation.	('CDK4/6', 'Gene', '1019;1021', (137, 143))	('KRAS', 'Disease', (194, 198))	('Cyclin', 'Gene', '5111', (0, 6))	('mutation', 'Var', (199, 207))	('patients', 'Species', '9606', (180, 188))	('CDK4/6', 'Gene', (137, 143))	('NSCLC', 'Disease', (112, 117))	('Cyclin', 'Gene', (0, 6))	('NSCLC', 'Disease', 'MESH:D002289', (112, 117))
559819	30997737	Strategies used to inhibit MET/HGFR pathway include antagonists of HGFR as well as monoclonal antibodies against HGFR and MET.	('HGFR', 'Gene', (113, 117))	('HGFR', 'Gene', (67, 71))	('inhibit', 'NegReg', (19, 26))	('antagonists', 'Var', (52, 63))	('HGFR', 'Gene', '4233', (31, 35))	('HGFR', 'Gene', (31, 35))	('HGFR', 'Gene', '4233', (113, 117))	('HGFR', 'Gene', '4233', (67, 71))
559851	30997737	A higher expression of PD-L1 has been observed in many malignant cell population and studies have shown that blocking it with anti-PDL-1 antibody restores T-cell function thereby leading to tumor suppression.	('blocking', 'Var', (109, 117))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('PD-L1', 'Gene', (23, 28))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('T-cell function', 'MPA', (155, 170))	('tumor', 'Disease', (190, 195))	('expression', 'MPA', (9, 19))	('PDL-1', 'Gene', '29126', (131, 136))	('restores', 'PosReg', (146, 154))	('PDL-1', 'Gene', (131, 136))
559869	30997737	Vaccine with this protein CIMAVax was developed in Cuba which included recombinant human epidermal growth factor, P64K Neisseria meningitides carrier protein, and immunoadjuvant Montanide ISA 51.	('Montanide', 'Chemical', '-', (178, 187))	('P64K', 'Var', (114, 118))	('Neisseria meningitides carrier', 'Phenotype', 'HP:0005381', (119, 149))	('P64K', 'Mutation', 'p.P64K', (114, 118))	('Neisseria meningitides', 'Disease', 'MESH:D008581', (119, 141))	('human', 'Species', '9606', (83, 88))	('Neisseria meningitides', 'Disease', (119, 141))
559993	28868193	Another study found that expression of KIP20A was linked to poorer survival among patients and may contribute to progression of early-stage (I and II) cervical squamous cancer.	('poorer', 'NegReg', (60, 66))	('KIP20A', 'Gene', (39, 45))	('contribute', 'Reg', (99, 109))	('patients', 'Species', '9606', (82, 90))	('squamous cancer', 'Phenotype', 'HP:0002860', (160, 175))	('survival', 'MPA', (67, 75))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('squamous cancer', 'Disease', 'MESH:D002294', (160, 175))	('squamous cancer', 'Disease', (160, 175))	('expression', 'Var', (25, 35))
559994	28868193	Additionally, signaling activation of the protein kinase mTOR, which is involved in protein synthesis, has been noted in both HPV-negative and HPV-positive cervical cancer tissues and cell lines; mTOR inhibitors have also shown to effectively decrease the activity of mTOR along with remarkably decreasing tumor burden.	('HPV', 'Species', '10566', (143, 146))	('inhibitors', 'Var', (201, 211))	('decrease', 'NegReg', (243, 251))	('tumor', 'Disease', 'MESH:D009369', (306, 311))	('decreasing', 'NegReg', (295, 305))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))	('tumor', 'Phenotype', 'HP:0002664', (306, 311))	('HPV-positive cervical cancer', 'Disease', 'MESH:D030361', (143, 171))	('mTOR', 'Enzyme', (268, 272))	('HPV-positive cervical cancer', 'Disease', (143, 171))	('tumor', 'Disease', (306, 311))	('activity', 'MPA', (256, 264))	('HPV', 'Species', '10566', (126, 129))
560013	27396756	Using rhabdomyosarcoma cells as an experimental model, we found that expression of constitutively active mTOR (E2419K) conferred resistance to CPX inhibition of cell proliferation, suggesting that CPX inhibition of mTORC1 contributed to its anticancer effect.	('CPX', 'Chemical', 'MESH:D000077768', (143, 146))	('cancer', 'Disease', 'MESH:D009369', (245, 251))	('mTORC1', 'Gene', (215, 221))	('E2419K', 'Mutation', 'rs587777900', (111, 117))	('cell proliferation', 'CPA', (161, 179))	('mTOR', 'Gene', (215, 219))	('cancer', 'Disease', (245, 251))	('mTOR', 'Gene', '2475', (215, 219))	('mTOR', 'Gene', (105, 109))	('resistance', 'MPA', (129, 139))	('mTOR', 'Gene', '2475', (105, 109))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (6, 22))	('E2419K', 'Var', (111, 117))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (6, 22))	('cancer', 'Phenotype', 'HP:0002664', (245, 251))	('rhabdomyosarcoma', 'Disease', (6, 22))	('CPX', 'Chemical', 'MESH:D000077768', (197, 200))	('mTORC1', 'Gene', '382056', (215, 221))
560017	27396756	This is supported by the findings that CPX activated AMPK; inhibition of AMPK with Compound C or ectopic expression of dominant negative AMPKalpha partially prevented CPX from inhibiting mTORC1; silencing TSC2 attenuated CPX inhibition of mTORC1; and CPX also increased AMPK-mediated phosphorylation of raptor (S792).	('attenuated', 'NegReg', (210, 220))	('mTORC1', 'Gene', (187, 193))	('AMPK', 'Gene', (53, 57))	('AMPK', 'Gene', '5563', (73, 77))	('TSC2', 'Gene', (205, 209))	('mTORC1', 'Gene', '382056', (187, 193))	('AMPK', 'Gene', '5563', (270, 274))	('AMPKalpha', 'Chemical', '-', (137, 146))	('increased', 'PosReg', (260, 269))	('AMPK', 'Gene', (137, 141))	('inhibiting', 'NegReg', (176, 186))	('AMPK', 'Gene', (73, 77))	('silencing', 'Var', (195, 204))	('CPX', 'Chemical', 'MESH:D000077768', (167, 170))	('AMPK', 'Gene', (270, 274))	('mTORC1', 'Gene', (239, 245))	('CPX', 'Chemical', 'MESH:D000077768', (221, 224))	('AMPK', 'Gene', '5563', (53, 57))	('raptor', 'Protein', (303, 309))	('mTORC1', 'Gene', '382056', (239, 245))	('CPX', 'Chemical', 'MESH:D000077768', (39, 42))	('CPX', 'Chemical', 'MESH:D000077768', (251, 254))	('TSC2', 'Gene', '7249', (205, 209))	('AMPK', 'Gene', '5563', (137, 141))
560022	27396756	In the yeast Saccharomyces cerevisiae, CPX may also exert its effect by disrupting DNA repair, cell division signals and structures (mitotic spindles) as well as some elements of intracellular transport.	('CPX', 'Chemical', 'MESH:D000077768', (39, 42))	('CPX', 'Var', (39, 42))	('yeast', 'Species', '4932', (7, 12))	('intracellular transport', 'MPA', (179, 202))	('disrupting', 'NegReg', (72, 82))	('DNA repair', 'MPA', (83, 93))	('Saccharomyces cerevisiae', 'Species', '4932', (13, 37))
560026	27396756	It has been shown that CPX induces cell death in murine and human myeloma and lymphoma cells by inhibiting the iron-containing enzyme ribonucleotide reductase, and Wnt/beta-catenin pathway.	('murine', 'Species', '10090', (49, 55))	('beta-catenin', 'Gene', '1499', (168, 180))	('iron', 'Chemical', 'MESH:D007501', (111, 115))	('lymphoma', 'Phenotype', 'HP:0002665', (78, 86))	('CPX', 'Var', (23, 26))	('iron-containing enzyme ribonucleotide reductase', 'MPA', (111, 158))	('inhibiting', 'NegReg', (96, 106))	('myeloma and lymphoma', 'Disease', 'MESH:D009101', (66, 86))	('cell death', 'CPA', (35, 45))	('human', 'Species', '9606', (60, 65))	('CPX', 'Chemical', 'MESH:D000077768', (23, 26))	('beta-catenin', 'Gene', (168, 180))
560030	27396756	Of interest, a recent study has reported that CPX enhances parthenolide-induced cell death in leukemic cells, by inhibiting the phosphorylation of ribosomal p70 S6 kinase 1 (S6K1) on T389, implying inhibition of the mammalian target of rapamycin (mTOR) complex 1 (mTORC1).	('enhances', 'PosReg', (50, 58))	('CPX', 'Var', (46, 49))	('inhibition', 'NegReg', (198, 208))	('S6K1', 'Gene', '6198', (174, 178))	('mTOR', 'Gene', (247, 251))	('phosphorylation', 'MPA', (128, 143))	('mTOR', 'Gene', (264, 268))	('parthenolide-induced cell death', 'CPA', (59, 90))	('mTOR', 'Gene', '2475', (247, 251))	('mTORC1', 'Gene', (264, 270))	('leukemic cells', 'Disease', 'MESH:D007938', (94, 108))	('mTOR', 'Gene', '2475', (264, 268))	('inhibiting', 'NegReg', (113, 123))	('mammalian target of rapamycin', 'Gene', '2475', (216, 245))	('mTORC1', 'Gene', '382056', (264, 270))	('leukemic cells', 'Disease', (94, 108))	('CPX', 'Chemical', 'MESH:D000077768', (46, 49))	('parthenolide', 'Chemical', 'MESH:C002669', (59, 71))	('S6K1', 'Gene', (174, 178))	('mammalian target of rapamycin', 'Gene', (216, 245))
560037	27396756	Dysregulation of mTOR signaling is associated with human diseases including cancer.	('Dysregulation', 'Var', (0, 13))	('associated', 'Reg', (35, 45))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('human', 'Species', '9606', (51, 56))	('mTOR', 'Gene', (17, 21))	('mTOR', 'Gene', '2475', (17, 21))	('cancer', 'Disease', (76, 82))	('cancer', 'Disease', 'MESH:D009369', (76, 82))
560040	27396756	However, only modest efficacy has been achieved in many other solid tumors when treated with rapalogs alone, probably due to the fact that rapalogs inhibit S6K1, which results in a feedback activation of insulin receptor substrate 1 (IRS1)-Akt pathway.	('insulin receptor substrate 1', 'Gene', '3667', (204, 232))	('activation', 'PosReg', (190, 200))	('Akt', 'Gene', (240, 243))	('IRS1', 'Gene', (234, 238))	('inhibit', 'NegReg', (148, 155))	('tumors', 'Phenotype', 'HP:0002664', (68, 74))	('insulin receptor substrate 1', 'Gene', (204, 232))	('rapalogs', 'Var', (139, 147))	('Akt', 'Gene', '207', (240, 243))	('S6K1', 'Gene', (156, 160))	('solid tumors', 'Disease', (62, 74))	('S6K1', 'Gene', '6198', (156, 160))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('IRS1', 'Gene', '3667', (234, 238))	('solid tumors', 'Disease', 'MESH:D009369', (62, 74))
560050	27396756	Activated AMPK also phosphorylates tuberous sclerosis complex 2 (TSC2) at T1227 and S1345, promoting the formation and activation of TSC1/2 complex, which catalyzes the conversion of Rheb-GTP to Rheb-GDP and thus inhibits mTORC1 activity.	('activation', 'MPA', (119, 129))	('AMPK', 'Gene', '5563', (10, 14))	('TSC1/2', 'Gene', (133, 139))	('GDP', 'Chemical', 'MESH:D006153', (200, 203))	('Rheb', 'Gene', (183, 187))	('inhibits', 'NegReg', (213, 221))	('tuberous sclerosis', 'Disease', 'MESH:D014402', (35, 53))	('AMPK', 'Gene', (10, 14))	('Rheb', 'Gene', '6009', (195, 199))	('promoting', 'PosReg', (91, 100))	('S1345', 'Var', (84, 89))	('TSC2', 'Gene', '7249', (65, 69))	('tuberous sclerosis', 'Disease', (35, 53))	('mTORC1', 'Gene', (222, 228))	('T1227', 'Var', (74, 79))	('mTORC1', 'Gene', '382056', (222, 228))	('Rheb', 'Gene', '6009', (183, 187))	('TSC2', 'Gene', (65, 69))	('TSC1/2', 'Gene', '7248;7249', (133, 139))	('Rheb', 'Gene', (195, 199))
560051	27396756	In addition, activated AMPK can phosphorylate raptor (S792), resulting in inhibition of mTORC1 as well.	('AMPK', 'Gene', '5563', (23, 27))	('mTORC1', 'Gene', (88, 94))	('AMPK', 'Gene', (23, 27))	('inhibition', 'NegReg', (74, 84))	('mTORC1', 'Gene', '382056', (88, 94))	('S792', 'Var', (54, 58))
560054	27396756	Using rhabdomyosarcoma cells (Rh30 and RD) as an experimental model, we demonstrated that CPX inhibited RMS tumor cell growth in vitro and in vivo by inhibiting mTORC1 signaling.	('inhibiting', 'NegReg', (150, 160))	('Rh30', 'Gene', (30, 34))	('inhibited', 'NegReg', (94, 103))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('mTORC1', 'Gene', '382056', (161, 167))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (6, 22))	('RMS tumor', 'Disease', 'MESH:D009369', (104, 113))	('Rh30', 'Gene', '6007', (30, 34))	('RMS tumor', 'Disease', (104, 113))	('CPX', 'Chemical', 'MESH:D000077768', (90, 93))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (6, 22))	('mTORC1', 'Gene', (161, 167))	('rhabdomyosarcoma', 'Disease', (6, 22))	('CPX', 'Var', (90, 93))
560110	27396756	As mTOR lies downstream of IGFR, and dysregualtion of IGFR-mTOR pathway occurs frequently in a variety of tumors, including rhabdomyosarcoma, we also investigated whether CPX inhibits IGF-I-activated mTORC1 signaling.	('IGF-I', 'Gene', (184, 189))	('CPX', 'Chemical', 'MESH:D000077768', (171, 174))	('tumors', 'Disease', (106, 112))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (124, 140))	('IGF-I', 'Gene', '3479', (184, 189))	('mTOR', 'Gene', '2475', (59, 63))	('mTOR', 'Gene', (3, 7))	('mTORC1', 'Gene', (200, 206))	('IGFR', 'Gene', '3480', (54, 58))	('mTOR', 'Gene', (200, 204))	('tumors', 'Disease', 'MESH:D009369', (106, 112))	('mTORC1', 'Gene', '382056', (200, 206))	('IGFR', 'Gene', (54, 58))	('mTOR', 'Gene', '2475', (3, 7))	('IGFR', 'Gene', '3480', (27, 31))	('mTOR', 'Gene', '2475', (200, 204))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('rhabdomyosarcoma', 'Disease', (124, 140))	('IGFR', 'Gene', (27, 31))	('tumors', 'Phenotype', 'HP:0002664', (106, 112))	('dysregualtion', 'Var', (37, 50))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (124, 140))	('mTOR', 'Gene', (59, 63))
560112	27396756	As predicted, treatment with IGF-I (10 ng/ml) for 1 h stimulated mTORC1-mediated phosphorylation of S6K1 (T389) and 4E-BP1 (S65 and T70) in serum-starved Rh30 cells (Fig.	('4E-BP1', 'Gene', '1978', (116, 122))	('IGF-I', 'Gene', (29, 34))	('Rh30', 'Gene', (154, 158))	('stimulated', 'PosReg', (54, 64))	('S6K1', 'Gene', (100, 104))	('T70', 'Var', (132, 135))	('T389', 'Var', (106, 110))	('Rh30', 'Gene', '6007', (154, 158))	('4E-BP1', 'Gene', (116, 122))	('IGF-I', 'Gene', '3479', (29, 34))	('S6K1', 'Gene', '6198', (100, 104))	('mTORC1', 'Gene', '382056', (65, 71))	('S65', 'Var', (124, 127))	('mTORC1', 'Gene', (65, 71))
560115	27396756	mTORC2 phosphorylates Akt on S473.	('Akt', 'Gene', (22, 25))	('S473', 'Var', (29, 33))	('mTORC2', 'Gene', (0, 6))	('mTORC2', 'Gene', '74343', (0, 6))	('Akt', 'Gene', '207', (22, 25))
560116	27396756	As CPX has been found to activate the phosphorylation of Akt (S473) in leukemia cells, we also examined whether this is the case in the solid tumor cells.	('tumor', 'Phenotype', 'HP:0002664', (142, 147))	('S473', 'Var', (62, 66))	('activate', 'PosReg', (25, 33))	('leukemia', 'Disease', (71, 79))	('leukemia', 'Phenotype', 'HP:0001909', (71, 79))	('phosphorylation', 'MPA', (38, 53))	('Akt', 'Gene', '207', (57, 60))	('CPX', 'Chemical', 'MESH:D000077768', (3, 6))	('tumor', 'Disease', (142, 147))	('Akt', 'Gene', (57, 60))	('tumor', 'Disease', 'MESH:D009369', (142, 147))	('leukemia', 'Disease', 'MESH:D007938', (71, 79))
560118	27396756	Unexpectedly, treatment with CPX induced the phosphoryaltion of Akt (S473) in Rh30 and PCI-13 cells (Fig.	('S473', 'Var', (69, 73))	('Rh30', 'Gene', '6007', (78, 82))	('Akt', 'Gene', '207', (64, 67))	('Akt', 'Gene', (64, 67))	('phosphoryaltion', 'MPA', (45, 60))	('Rh30', 'Gene', (78, 82))	('CPX', 'Chemical', 'MESH:D000077768', (29, 32))
560126	27396756	Given the critical role of mTOR in cell proliferation, next, we determined whether inhibition of mTORC1 signaling contributes to CPX inhibition of cell proliferation.	('CPX', 'MPA', (129, 132))	('mTORC1', 'Gene', (97, 103))	('mTOR', 'Gene', '2475', (97, 101))	('mTOR', 'Gene', (97, 101))	('cell proliferation', 'CPA', (147, 165))	('inhibition', 'NegReg', (133, 143))	('mTORC1', 'Gene', '382056', (97, 103))	('inhibition', 'Var', (83, 93))	('mTOR', 'Gene', (27, 31))	('CPX', 'Chemical', 'MESH:D000077768', (129, 132))	('mTOR', 'Gene', '2475', (27, 31))
560127	27396756	For this, rhabdomyosarcoma RD and Rh30 cells were used as an experimental model, and transfected with the empty vector pcDNA3 and pcDNA3-mTOR (E2419K).	('Rh30', 'Gene', (34, 38))	('E2419K', 'Mutation', 'rs587777900', (143, 149))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (10, 26))	('E2419K', 'Var', (143, 149))	('mTOR', 'Gene', (137, 141))	('mTOR', 'Gene', '2475', (137, 141))	('rhabdomyosarcoma', 'Disease', (10, 26))	('Rh30', 'Gene', '6007', (34, 38))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (10, 26))
560131	27396756	In line with this, expression of constitutively active mTOR also significantly enhanced the cell proliferation, compared with the vector control (Fig.	('mTOR', 'Gene', (55, 59))	('mTOR', 'Gene', '2475', (55, 59))	('expression', 'Var', (19, 29))	('enhanced', 'PosReg', (79, 87))	('cell proliferation', 'CPA', (92, 110))
560132	27396756	Of interest, expression of the constitutively active mTOR rendered a significant resistance to CPX inhibition of cell proliferation (Fig.	('resistance to CPX inhibition', 'MPA', (81, 109))	('expression', 'Var', (13, 23))	('mTOR', 'Gene', (53, 57))	('mTOR', 'Gene', '2475', (53, 57))	('CPX', 'Chemical', 'MESH:D000077768', (95, 98))
560138	27396756	Of note, at the end of the experiment, the average weight of the tumors was reduced by 21.7% and 50.8% in the animals treated with 20 and 60 mg/kg of CPX, respectively, compared with the vehicle control (Fig.	('CPX', 'Chemical', 'MESH:D000077768', (150, 153))	('CPX', 'Var', (150, 153))	('tumors', 'Disease', (65, 71))	('reduced', 'NegReg', (76, 83))	('tumors', 'Disease', 'MESH:D009369', (65, 71))	('tumors', 'Phenotype', 'HP:0002664', (65, 71))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
560141	27396756	The results indicate that CPX inhibits the xenografted tumor growth by inhibiting cell proliferation and inducing apoptosis of RD cells in the tumors.	('inhibiting', 'NegReg', (71, 81))	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('tumor', 'Disease', (143, 148))	('CPX', 'Chemical', 'MESH:D000077768', (26, 29))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('cell proliferation', 'CPA', (82, 100))	('CPX', 'Var', (26, 29))	('tumors', 'Disease', (143, 149))	('tumors', 'Disease', 'MESH:D009369', (143, 149))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Disease', (55, 60))	('inducing', 'Reg', (105, 113))	('tumor', 'Disease', 'MESH:D009369', (143, 148))	('apoptosis', 'CPA', (114, 123))	('inhibits', 'NegReg', (30, 38))
560147	27396756	5A (I, II), CPX altered neither the total cellular protein level nor the phosphorylation level of IGFR, PI3K or PTEN.	('IGFR', 'Gene', '3480', (98, 102))	('PI3K', 'Var', (104, 108))	('phosphorylation level', 'MPA', (73, 94))	('PTEN', 'Gene', (112, 116))	('CPX', 'Chemical', 'MESH:D000077768', (12, 15))	('PTEN', 'Gene', '5728', (112, 116))	('IGFR', 'Gene', (98, 102))
560161	27396756	To confirm the above finding, Rh30 cells were infected with recombinant adenovirus expressing a c-myc-tagged dominant negative (DN) AMPKalpha (Ad-AMPKalpha-DN), or GFP (Ad-GFP, control) for 24 h, followed by exposure to CPX (0-20 microM) for 24 h. We found that infection with Ad-AMPKalpha-DN resulted in high expression of myc-tagged AMPKalpha-DN (Fig.	('AMPKalpha', 'Chemical', '-', (146, 155))	('Ad-AMPKalpha-DN', 'Chemical', '-', (143, 158))	('c-myc', 'Gene', (96, 101))	('Rh30', 'Gene', '6007', (30, 34))	('AMPKalpha', 'Chemical', '-', (132, 141))	('AMPKalpha', 'Chemical', '-', (280, 289))	('myc-tagged', 'Protein', (324, 334))	('Ad-AMPKalpha-DN', 'Var', (277, 292))	('Ad-', 'Chemical', '-', (169, 172))	('Ad-AMPKalpha-DN', 'Chemical', '-', (277, 292))	('expression', 'MPA', (310, 320))	('AMPKalpha', 'Chemical', '-', (335, 344))	('AMPKalpha-DN', 'Chemical', '-', (146, 158))	('c-myc', 'Gene', '4609', (96, 101))	('AMPKalpha-DN', 'Chemical', '-', (280, 292))	('AMPKalpha-DN', 'Chemical', '-', (335, 347))	('Ad-', 'Chemical', '-', (143, 146))	('Rh30', 'Gene', (30, 34))	('CPX', 'Chemical', 'MESH:D000077768', (220, 223))	('Ad-', 'Chemical', '-', (277, 280))
560164	27396756	Of interest, the cells infected with Ad-AMPKalpha-DN, but not Ad-GFP, were highly resistant to the inhibitory effect of CPX on mTORC1 signaling (Fig.	('Ad-AMPKalpha-DN', 'Chemical', '-', (37, 52))	('mTORC1', 'Gene', (127, 133))	('mTORC1', 'Gene', '382056', (127, 133))	('CPX', 'Chemical', 'MESH:D000077768', (120, 123))	('Ad-', 'Chemical', '-', (37, 40))	('Ad-AMPKalpha-DN', 'Var', (37, 52))	('Ad-', 'Chemical', '-', (62, 65))
560173	27396756	6A (I, II), lentiviral shRNA to TSC2 downregulated the expression of TSC2 by approximately 70% in Rh30 cells, compared with lentiviral shRNA to GFP (control).	('Rh30', 'Gene', (98, 102))	('downregulated', 'NegReg', (37, 50))	('lentiviral shRNA', 'Var', (12, 28))	('TSC2', 'Gene', '7249', (69, 73))	('TSC2', 'Gene', (69, 73))	('Rh30', 'Gene', '6007', (98, 102))	('expression', 'MPA', (55, 65))	('TSC2', 'Gene', '7249', (32, 36))	('TSC2', 'Gene', (32, 36))
560185	27396756	Of interest, a recent study has reported that CPX enhances parthenolide-induced cell death in acute myeloid leukemia cells, by inhibiting the phosphorylation of S6K1 (T389), implying inhibition of mTORC1.	('acute myeloid leukemia', 'Disease', (94, 116))	('enhances', 'PosReg', (50, 58))	('CPX', 'Var', (46, 49))	('S6K1', 'Gene', (161, 165))	('T389', 'Var', (167, 171))	('parthenolide', 'Chemical', 'MESH:C002669', (59, 71))	('S6K1', 'Gene', '6198', (161, 165))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (94, 116))	('mTORC1', 'Gene', (197, 203))	('leukemia', 'Phenotype', 'HP:0001909', (108, 116))	('inhibiting', 'NegReg', (127, 137))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (94, 116))	('parthenolide-induced', 'MPA', (59, 79))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (100, 116))	('phosphorylation', 'MPA', (142, 157))	('CPX', 'Chemical', 'MESH:D000077768', (46, 49))	('mTORC1', 'Gene', '382056', (197, 203))
560190	27396756	In this study, using rhabdomyosarcoma cells as an experimental model, we found that ectopic expression of constitutively active mTOR (E2419K) conferred a significant resistance to CPX inhibition of proliferation in RD and Rh30 cells (Fig.	('resistance to CPX inhibition', 'MPA', (166, 194))	('mTOR', 'Gene', (128, 132))	('mTOR', 'Gene', '2475', (128, 132))	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (21, 37))	('E2419K', 'Var', (134, 140))	('Rh30', 'Gene', '6007', (222, 226))	('CPX', 'Chemical', 'MESH:D000077768', (180, 183))	('proliferation', 'CPA', (198, 211))	('rhabdomyosarcoma', 'Disease', (21, 37))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (21, 37))	('Rh30', 'Gene', (222, 226))	('E2419K', 'Mutation', 'rs587777900', (134, 140))
560200	27396756	INK128, AZD8055 and OSI-027) do, which compete with ATP and bind to the catalytic site of mTOR, inhibiting both mTORC1 and mTORC2.	('mTOR', 'Gene', (90, 94))	('mTORC1', 'Gene', (112, 118))	('mTOR', 'Gene', '2475', (90, 94))	('mTORC2', 'Gene', (123, 129))	('mTORC1', 'Gene', '382056', (112, 118))	('inhibiting', 'NegReg', (96, 106))	('mTOR', 'Gene', '2475', (123, 127))	('AZD8055', 'Var', (8, 15))	('mTOR', 'Gene', '2475', (112, 116))	('mTOR', 'Gene', (112, 116))	('ATP', 'Chemical', 'MESH:D000255', (52, 55))	('mTOR', 'Gene', (123, 127))	('AZD8055', 'Chemical', 'MESH:C546624', (8, 15))	('mTORC2', 'Gene', '74343', (123, 129))	('INK128', 'Chemical', 'MESH:C572449', (0, 6))	('OSI-027', 'Chemical', 'MESH:C568605', (20, 27))
560203	27396756	This is evidenced by the findings that 1) CPX did not alter the level of either the cellular protein or the phosphorylation of IGFR, PI3K or PTEN (Fig.	('IGFR', 'Gene', '3480', (127, 131))	('PTEN', 'Gene', (141, 145))	('PTEN', 'Gene', '5728', (141, 145))	('CPX', 'Chemical', 'MESH:D000077768', (42, 45))	('phosphorylation', 'MPA', (108, 123))	('level of', 'MPA', (64, 72))	('IGFR', 'Gene', (127, 131))	('PI3K', 'Var', (133, 137))
560218	27396756	Since CPX can activate the phosphorylation of Akt (S473) in leukemia cells, here we also investigated whether this is the case in solid tumor cells.	('Akt', 'Gene', '207', (46, 49))	('leukemia', 'Phenotype', 'HP:0001909', (60, 68))	('CPX', 'Chemical', 'MESH:D000077768', (6, 9))	('activate', 'PosReg', (14, 22))	('Akt', 'Gene', (46, 49))	('phosphorylation', 'MPA', (27, 42))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('tumor', 'Disease', (136, 141))	('leukemia', 'Disease', (60, 68))	('S473', 'Var', (51, 55))	('leukemia', 'Disease', 'MESH:D007938', (60, 68))
560220	27396756	Consistent with the finding in leukemia cells, the phosphorylation of Akt (S473) was indeed induced by 24 h-treatment with CPX in rhabdomyosarcoma (Rh30) and head and neck cancer (PCI-13) cells (Fig.	('rhabdomyosarcoma', 'Phenotype', 'HP:0002859', (130, 146))	('head and neck cancer', 'Phenotype', 'HP:0012288', (158, 178))	('CPX', 'Chemical', 'MESH:D000077768', (123, 126))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('leukemia', 'Disease', (31, 39))	('leukemia', 'Phenotype', 'HP:0001909', (31, 39))	('Akt', 'Gene', (70, 73))	('induced', 'Reg', (92, 99))	('leukemia', 'Disease', 'MESH:D007938', (31, 39))	('Rh30', 'Gene', (148, 152))	('rhabdomyosarcoma', 'Disease', (130, 146))	('head and neck cancer', 'Disease', 'MESH:D006258', (158, 178))	('phosphorylation', 'MPA', (51, 66))	('S473', 'Var', (75, 79))	('rhabdomyosarcoma', 'Disease', 'MESH:D012208', (130, 146))	('Akt', 'Gene', '207', (70, 73))	('Rh30', 'Gene', '6007', (148, 152))
560221	27396756	In contrast, the phosphorylation of Akt (S473) was inhibited by 24 h-treatment with CPX in breast (MDA-MB-231) and lung cancer (A427) cells (Fig.	('S473', 'Var', (41, 45))	('cancer', 'Phenotype', 'HP:0002664', (120, 126))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (99, 109))	('CPX', 'Chemical', 'MESH:D000077768', (84, 87))	('phosphorylation', 'MPA', (17, 32))	('Akt', 'Gene', (36, 39))	('lung cancer', 'Disease', 'MESH:D008175', (115, 126))	('inhibited', 'NegReg', (51, 60))	('lung cancer', 'Disease', (115, 126))	('Akt', 'Gene', '207', (36, 39))	('lung cancer', 'Phenotype', 'HP:0100526', (115, 126))
560226	27396756	In summary, here, for the first time, we show that CPX inhibits mTORC1 signaling in tumor cells in vitro and in vivo, but may inhibit or activate mTORC2-mediated phosphorylation of Akt in a cell line dependent manner.	('mTORC2', 'Gene', (146, 152))	('mTORC1', 'Gene', '382056', (64, 70))	('tumor', 'Disease', 'MESH:D009369', (84, 89))	('mTORC2', 'Gene', '74343', (146, 152))	('CPX', 'Chemical', 'MESH:D000077768', (51, 54))	('inhibits', 'NegReg', (55, 63))	('mTORC1', 'Gene', (64, 70))	('tumor', 'Phenotype', 'HP:0002664', (84, 89))	('tumor', 'Disease', (84, 89))	('inhibit', 'NegReg', (126, 133))	('Akt', 'Gene', '207', (181, 184))	('Akt', 'Gene', (181, 184))	('CPX', 'Var', (51, 54))	('activate', 'PosReg', (137, 145))
560273	31996171	On ROC analysis (Table 2), the respective sensitivities and specificities for ESCC detection were 50 and 97.81% for PET/CT scan and 100 and 81.75% for NBI endoscopy; the area under the curve (AUC) values were 0.739 [95% confidence interval (CI), 0.660-0.808; p = 0.004] for PET/CT scan and 0.909 (95% CI, 0.850-0.950; p < 0.001) for NBI endoscopy (Fig.	('ESCC', 'Disease', 'MESH:C562729', (78, 82))	('PET/CT scan', 'Var', (274, 285))	('ESCC', 'Disease', (78, 82))
560278	31996171	Among the variables, including age, sex, high-risk HNC location, and advanced stage of HNC, only high-risk HNC location was predictive of the risk for development of SPC of the esophagus, with an odds ratio (OR) of 4.7 (95% CI, 1.26-17.55; p = 0.025).	('HNC', 'Phenotype', 'HP:0012288', (87, 90))	('HNC', 'Phenotype', 'HP:0012288', (107, 110))	('high-risk', 'Var', (97, 106))	('SPC of the esophagus', 'Disease', (166, 186))	('HNC', 'Phenotype', 'HP:0012288', (51, 54))	('men', 'Species', '9606', (158, 161))
560440	31775885	Association between polymorphism in CDKN2B-AS1 gene and its interaction with smoking on the risk of lung cancer in a Chinese population Long non-coding RNAs became the hot spots in the carcinogenesis of various tumors.	('polymorphism', 'Var', (20, 32))	('CDKN2B-AS1', 'Gene', '100048912', (36, 46))	('carcinogenesis of various tumors', 'Disease', (185, 217))	('carcinogenesis of various tumors', 'Disease', 'MESH:D063646', (185, 217))	('lung cancer', 'Phenotype', 'HP:0100526', (100, 111))	('CDKN2B-AS1', 'Gene', (36, 46))	('lung cancer', 'Disease', (100, 111))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('Association', 'Interaction', (0, 11))	('tumors', 'Phenotype', 'HP:0002664', (211, 217))	('lung cancer', 'Disease', 'MESH:D008175', (100, 111))
560441	31775885	This case-control study evaluated the association between the rs2151280 in lncRNA CDKN2B-AS1 and lung cancer risk.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('CDKN2B-AS1', 'Gene', '100048912', (82, 92))	('lung cancer', 'Disease', 'MESH:D008175', (97, 108))	('rs2151280', 'Mutation', 'rs2151280', (62, 71))	('CDKN2B-AS1', 'Gene', (82, 92))	('lung cancer', 'Disease', (97, 108))	('lung cancer', 'Phenotype', 'HP:0100526', (97, 108))	('rs2151280', 'Var', (62, 71))
560443	31775885	Odds ratios and their 95% confidence intervals were calculated by unconditional logistic regression analysis to evaluate the association between the rs2151280 and lung cancer risk.	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('lung cancer', 'Disease', 'MESH:D008175', (163, 174))	('rs2151280', 'Var', (149, 158))	('association', 'Interaction', (125, 136))	('lung cancer', 'Phenotype', 'HP:0100526', (163, 174))	('lung cancer', 'Disease', (163, 174))	('rs2151280', 'Mutation', 'rs2151280', (149, 158))
560444	31775885	Compared with individuals carrying TT genotype, individuals carrying CC genotype of rs2151280 had a decreased risk of lung cancer (OR = 0.640, 95%CI = 0.421-0.972, P = 0.036).	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('lung cancer', 'Disease', 'MESH:D008175', (118, 129))	('rs2151280', 'Var', (84, 93))	('decreased', 'NegReg', (100, 109))	('lung cancer', 'Disease', (118, 129))	('lung cancer', 'Phenotype', 'HP:0100526', (118, 129))	('rs2151280', 'Mutation', 'rs2151280', (84, 93))
560445	31775885	In the recessive model, rs2151280 CC genotype was observed to reduce the risk of lung cancer (OR = 0.684).	('lung cancer', 'Disease', (81, 92))	('lung cancer', 'Phenotype', 'HP:0100526', (81, 92))	('rs2151280 CC', 'Var', (24, 36))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('reduce', 'NegReg', (62, 68))	('rs2151280', 'Mutation', 'rs2151280', (24, 33))	('lung cancer', 'Disease', 'MESH:D008175', (81, 92))
560447	31775885	The rs2151280 was significantly associated with lung adenocarcinoma risk (CCvsTT: OR = 0.567, 95%CI = 0.333-0.965, P = 0.037; CCvsTC+TT: OR = 0.543, 95%CI 0.330-0.893, P = 0.016, respectively).	('rs2151280', 'Mutation', 'rs2151280', (4, 13))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (48, 67))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (48, 67))	('associated', 'Reg', (32, 42))	('rs2151280', 'Var', (4, 13))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))	('lung adenocarcinoma', 'Disease', (48, 67))
560448	31775885	However, there was no significant association between rs2151280 and lung squamous cell carcinoma risk in five models.	('rs2151280', 'Mutation', 'rs2151280', (54, 63))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (73, 96))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (68, 96))	('lung squamous cell carcinoma', 'Disease', (68, 96))	('rs2151280', 'Var', (54, 63))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (68, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (87, 96))
560449	31775885	The quantitative analysis suggested that there were no significant interactions of rs2151280 with smoking exposure to lung cancer susceptibility.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('lung cancer', 'Disease', 'MESH:D008175', (118, 129))	('rs2151280', 'Mutation', 'rs2151280', (83, 92))	('lung cancer', 'Disease', (118, 129))	('lung cancer', 'Phenotype', 'HP:0100526', (118, 129))	('rs2151280', 'Var', (83, 92))
560450	31775885	This hospital-based case-control study suggested that CDKN2B-AS1 rs2151280 T>C was associated with the risk of lung cancer.	('CDKN2B-AS1', 'Gene', '100048912', (54, 64))	('rs2151280 T>C', 'Var', (65, 78))	('lung cancer', 'Disease', 'MESH:D008175', (111, 122))	('associated', 'Reg', (83, 93))	('rs2151280', 'Mutation', 'rs2151280', (65, 74))	('CDKN2B-AS1', 'Gene', (54, 64))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('lung cancer', 'Disease', (111, 122))	('lung cancer', 'Phenotype', 'HP:0100526', (111, 122))
560461	31775885	With the in-depth study of high-throughput technologies, many genome-wide association studies (GWASs) had found the correlation between long non-coding RNAs (lncRNAs) and multiple cancers.	('correlation', 'Interaction', (116, 127))	('cancers', 'Phenotype', 'HP:0002664', (180, 187))	('cancers', 'Disease', 'MESH:D009369', (180, 187))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('cancers', 'Disease', (180, 187))	('long non-coding RNAs', 'Var', (136, 156))
560464	31775885	GWAS had shown that SNPs in this region (9p21) were associated with many diseases, including cancers.	('cancers', 'Disease', (93, 100))	('cancers', 'Phenotype', 'HP:0002664', (93, 100))	('associated', 'Reg', (52, 62))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('SNPs', 'Var', (20, 24))	('cancers', 'Disease', 'MESH:D009369', (93, 100))	('diseases', 'Disease', (73, 81))
560472	31775885	The result also found that 9p21.3 variants in the region of CDKN2B-AS1 were associated with squamous cell lung cancer.	('variants', 'Var', (34, 42))	('CDKN2B-AS1', 'Gene', '100048912', (60, 70))	('squamous cell lung cancer', 'Phenotype', 'HP:0030359', (92, 117))	('lung cancer', 'Phenotype', 'HP:0100526', (106, 117))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('associated with', 'Reg', (76, 91))	('squamous cell lung cancer', 'Disease', 'MESH:D018307', (92, 117))	('CDKN2B-AS1', 'Gene', (60, 70))	('squamous cell lung cancer', 'Disease', (92, 117))
560474	31775885	rs2151280 was located within the lncRNA CDKN2B-AS1 at 9p21.3.	('rs2151280', 'Var', (0, 9))	('CDKN2B-AS1', 'Gene', '100048912', (40, 50))	('rs2151280', 'Mutation', 'rs2151280', (0, 9))	('CDKN2B-AS1', 'Gene', (40, 50))
560475	31775885	Because rs2151280 might affect the expression of CDKN2B-AS1, and CDKN2B-AS1 expression might affect the susceptibility of lung cancer, we suspected that rs2151280 might affect the susceptibility of lung cancer.	('expression', 'MPA', (35, 45))	('lung cancer', 'Disease', 'MESH:D008175', (122, 133))	('lung cancer', 'Disease', (198, 209))	('rs2151280', 'Mutation', 'rs2151280', (8, 17))	('lung cancer', 'Phenotype', 'HP:0100526', (122, 133))	('affect', 'Reg', (93, 99))	('CDKN2B-AS1', 'Gene', '100048912', (65, 75))	('CDKN2B-AS1', 'Gene', '100048912', (49, 59))	('CDKN2B-AS1', 'Gene', (65, 75))	('rs2151280', 'Var', (153, 162))	('CDKN2B-AS1', 'Gene', (49, 59))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('affect', 'Reg', (169, 175))	('lung cancer', 'Disease', 'MESH:D008175', (198, 209))	('affect', 'Reg', (24, 30))	('cancer', 'Phenotype', 'HP:0002664', (203, 209))	('lung cancer', 'Phenotype', 'HP:0100526', (198, 209))	('lung cancer', 'Disease', (122, 133))	('rs2151280', 'Var', (8, 17))	('expression', 'MPA', (76, 86))	('rs2151280', 'Mutation', 'rs2151280', (153, 162))
560476	31775885	Emerging evidence demonstrated that rs2151280 was related to various kinds of malignant tumors, which indirectly confirmed the importance of rs2151280 in cancer susceptibility.	('rs2151280', 'Var', (141, 150))	('malignant tumors', 'Disease', (78, 94))	('related', 'Reg', (50, 57))	('rs2151280', 'Mutation', 'rs2151280', (36, 45))	('malignant tumors', 'Disease', 'MESH:D009369', (78, 94))	('cancer', 'Disease', (154, 160))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('rs2151280', 'Var', (36, 45))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumors', 'Phenotype', 'HP:0002664', (88, 94))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('rs2151280', 'Mutation', 'rs2151280', (141, 150))
560477	31775885	rs2151280 was initially discovered by a GWAS research on the correlation between rs2151280 and the risk of basal cell carcinoma, and the results showed that rs2151280 was related to the risk of basal cell carcinoma (BCC).	('rs2151280', 'Mutation', 'rs2151280', (157, 166))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (107, 127))	('basal cell carcinoma', 'Disease', 'MESH:D002280', (107, 127))	('basal cell carcinoma', 'Disease', (107, 127))	('related', 'Reg', (171, 178))	('rs2151280', 'Var', (157, 166))	('rs2151280', 'Mutation', 'rs2151280', (0, 9))	('rs2151280', 'Mutation', 'rs2151280', (81, 90))	('BCC', 'Disease', (216, 219))	('rs2151280', 'Var', (81, 90))	('basal cell carcinoma', 'Disease', 'MESH:D002280', (194, 214))	('basal cell carcinoma', 'Disease', (194, 214))	('carcinoma', 'Phenotype', 'HP:0030731', (205, 214))	('carcinoma', 'Phenotype', 'HP:0030731', (118, 127))	('basal cell carcinoma', 'Phenotype', 'HP:0002671', (194, 214))	('BCC', 'Phenotype', 'HP:0002671', (216, 219))	('BCC', 'Disease', 'MESH:D002280', (216, 219))
560478	31775885	The high expression of CDKN2B-AS1 and the low expression of p14ARF were associated with rs2151280 TT variant in peripheral blood mononuclear cells (PBMCs).	('p14ARF', 'Gene', (60, 66))	('rs2151280', 'Mutation', 'rs2151280', (88, 97))	('CDKN2B-AS1', 'Gene', '100048912', (23, 33))	('rs2151280 TT', 'Var', (88, 100))	('high', 'PosReg', (4, 8))	('expression', 'MPA', (9, 19))	('p14ARF', 'Gene', '1029', (60, 66))	('CDKN2B-AS1', 'Gene', (23, 33))	('low', 'NegReg', (42, 45))	('expression', 'MPA', (46, 56))
560479	31775885	Molecular epidemiological studies had shown that rs2151280 was associated with various cancer risks (BCC and plexiform neurofibromas (PNF)).	('cancer', 'Disease', (87, 93))	('rs2151280', 'Var', (49, 58))	('BCC', 'Disease', (101, 104))	('BCC', 'Phenotype', 'HP:0002671', (101, 104))	('BCC', 'Disease', 'MESH:D002280', (101, 104))	('associated', 'Reg', (63, 73))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('neurofibromas', 'Disease', (119, 132))	('neurofibromas', 'Phenotype', 'HP:0001067', (119, 132))	('plexiform neurofibromas', 'Phenotype', 'HP:0009732', (109, 132))	('neurofibromas', 'Disease', 'MESH:D009455', (119, 132))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('rs2151280', 'Mutation', 'rs2151280', (49, 58))
560480	31775885	The association between CDKN2B-AS1 rs2151280 and esophageal squamous cell carcinoma (ESCC) was not found in the study.	('rs2151280', 'Var', (35, 44))	('CDKN2B-AS1', 'Gene', '100048912', (24, 34))	('carcinoma', 'Phenotype', 'HP:0030731', (74, 83))	('ESCC', 'Disease', (85, 89))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (60, 83))	('esophageal squamous cell carcinoma', 'Disease', (49, 83))	('rs2151280', 'Mutation', 'rs2151280', (35, 44))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:C562729', (49, 83))	('ESCC', 'Disease', 'MESH:C562729', (85, 89))	('CDKN2B-AS1', 'Gene', (24, 34))
560481	31775885	The relationship between CDKN2B-AS1 rs2151280 and the risk of lung cancer was still unclear in the world.	('CDKN2B-AS1', 'Gene', (25, 35))	('rs2151280', 'Mutation', 'rs2151280', (36, 45))	('lung cancer', 'Phenotype', 'HP:0100526', (62, 73))	('CDKN2B-AS1', 'Gene', '100048912', (25, 35))	('lung cancer', 'Disease', (62, 73))	('rs2151280', 'Var', (36, 45))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('lung cancer', 'Disease', 'MESH:D008175', (62, 73))
560482	31775885	Because the association between CDKN2B-AS1 rs2151280 and lung cancer was undefined, our research had some innovation in investigating the association between CDKN2B-AS1 rs2151280 and lung cancer risk.	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('rs2151280', 'Var', (169, 178))	('rs2151280', 'Mutation', 'rs2151280', (43, 52))	('lung cancer', 'Disease', 'MESH:D008175', (183, 194))	('CDKN2B-AS1', 'Gene', '100048912', (32, 42))	('CDKN2B-AS1', 'Gene', '100048912', (158, 168))	('rs2151280', 'Var', (43, 52))	('lung cancer', 'Disease', 'MESH:D008175', (57, 68))	('CDKN2B-AS1', 'Gene', (32, 42))	('CDKN2B-AS1', 'Gene', (158, 168))	('lung cancer', 'Disease', (183, 194))	('lung cancer', 'Phenotype', 'HP:0100526', (183, 194))	('rs2151280', 'Mutation', 'rs2151280', (169, 178))	('lung cancer', 'Disease', (57, 68))	('lung cancer', 'Phenotype', 'HP:0100526', (57, 68))
560484	31775885	And we also evaluated the interaction of rs2151280 with smoking status on the risk of lung cancer in the case-control study.	('lung cancer', 'Phenotype', 'HP:0100526', (86, 97))	('lung cancer', 'Disease', (86, 97))	('rs2151280', 'Mutation', 'rs2151280', (41, 50))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('rs2151280', 'Var', (41, 50))	('lung cancer', 'Disease', 'MESH:D008175', (86, 97))
560485	31775885	As far as we know, this was the first time to evaluate the effect of rs2151280 in lncRNA CDKN2B-AS1 on lung cancer risk.	('lung cancer', 'Disease', 'MESH:D008175', (103, 114))	('CDKN2B-AS1', 'Gene', '100048912', (89, 99))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('lung cancer', 'Disease', (103, 114))	('lung cancer', 'Phenotype', 'HP:0100526', (103, 114))	('rs2151280', 'Mutation', 'rs2151280', (69, 78))	('CDKN2B-AS1', 'Gene', (89, 99))	('rs2151280', 'Var', (69, 78))
560495	31775885	The goodness-of-fit chi2 test was used to examine the Hardy-Weinberg equilibrium (HWE) of rs2151280.	('Hardy-Weinberg equilibrium', 'Disease', (54, 80))	('rs2151280', 'Mutation', 'rs2151280', (90, 99))	('rs2151280', 'Var', (90, 99))
560496	31775885	We calculated the odds ratios (ORs) with their 95% confidence intervals (CIs) by unconditional logistic regression to evaluate the relationship between rs2151280 and lung cancer risk.	('rs2151280', 'Var', (152, 161))	('lung cancer', 'Disease', 'MESH:D008175', (166, 177))	('rs2151280', 'Mutation', 'rs2151280', (152, 161))	('lung cancer', 'Disease', (166, 177))	('lung cancer', 'Phenotype', 'HP:0100526', (166, 177))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))
560497	31775885	The interaction of smoking status and rs2151280 on risk of lung cancer was evaluated by logistic regression on additive model and multiplicative model.	('lung cancer', 'Disease', 'MESH:D008175', (59, 70))	('lung cancer', 'Disease', (59, 70))	('rs2151280', 'Mutation', 'rs2151280', (38, 47))	('lung cancer', 'Phenotype', 'HP:0100526', (59, 70))	('rs2151280', 'Var', (38, 47))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
560502	31775885	The observed genotype frequencies for rs2151280 were in agreement with Hardy-Weinberg equilibrium.	('rs2151280', 'Var', (38, 47))	('rs2151280', 'Mutation', 'rs2151280', (38, 47))	('Hardy-Weinberg', 'Disease', (71, 85))	('men', 'Species', '9606', (61, 64))
560504	31775885	The association between rs2151280 and lung cancer risk was shown in Table 2.	('lung cancer', 'Disease', (38, 49))	('lung cancer', 'Phenotype', 'HP:0100526', (38, 49))	('rs2151280', 'Mutation', 'rs2151280', (24, 33))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))	('lung cancer', 'Disease', 'MESH:D008175', (38, 49))	('rs2151280', 'Var', (24, 33))
560505	31775885	Compared with individuals carrying TT genotype, individuals with CC genotype of rs2151280 had a lower lung cancer risk (OR = 0.654, 95% CI = 0.443-0.965, P = 0.033).	('rs2151280', 'Var', (80, 89))	('lung cancer', 'Phenotype', 'HP:0100526', (102, 113))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('lower', 'NegReg', (96, 101))	('lung cancer', 'Disease', (102, 113))	('lung cancer', 'Disease', 'MESH:D008175', (102, 113))	('rs2151280', 'Mutation', 'rs2151280', (80, 89))
560506	31775885	In the recessive model, individuals carrying variant homozygote CC genotypes were associated with a significantly lower risk of lung cancer compared with individuals carrying heterozygote TC and TT genotype (adjusted OR = 0.648, 95%CI = 0.439-0.957, P = 0.029).	('lung cancer', 'Disease', 'MESH:D008175', (128, 139))	('lung cancer', 'Disease', (128, 139))	('lung cancer', 'Phenotype', 'HP:0100526', (128, 139))	('lower', 'NegReg', (114, 119))	('variant', 'Var', (45, 52))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
560507	31775885	In allele comparison, the C allele was associated with a lower risk of non-small-cell lung cancer (OR = 0.674, 95%CI = 0.560-0.812, P < 0.001) in Table 2.	('lung cancer', 'Phenotype', 'HP:0100526', (86, 97))	('C allele', 'Var', (26, 34))	('lung cancer', 'Disease', (86, 97))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (75, 97))	('lung cancer', 'Disease', 'MESH:D008175', (86, 97))	('lower', 'NegReg', (57, 62))
560508	31775885	The associations of rs2151280 with lung adenocarcinoma (AD) and lung squamous cell carcinoma (SQ) were shown in Table 3.	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (64, 92))	('lung adenocarcinoma', 'Disease', (35, 54))	('SQ', 'Phenotype', 'HP:0002860', (94, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (45, 54))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (69, 92))	('lung squamous cell carcinoma', 'Disease', (64, 92))	('rs2151280', 'Mutation', 'rs2151280', (20, 29))	('AD', 'Disease', (56, 58))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (35, 54))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (64, 92))	('AD', 'Disease', 'MESH:D000230', (56, 58))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (35, 54))	('rs2151280', 'Var', (20, 29))	('carcinoma', 'Phenotype', 'HP:0030731', (83, 92))	('associations', 'Interaction', (4, 16))
560513	31775885	We performed the stratification analyses to further estimate the association between rs2151280 and risk of lung cancer.	('rs2151280', 'Mutation', 'rs2151280', (85, 94))	('lung cancer', 'Disease', 'MESH:D008175', (107, 118))	('association', 'Interaction', (65, 76))	('rs2151280', 'Var', (85, 94))	('lung cancer', 'Disease', (107, 118))	('lung cancer', 'Phenotype', 'HP:0100526', (107, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))
560514	31775885	In the subgroup analysis by gender, there was a significant correlation between rs2151280 and lung cancer risk in female (Table 4).	('rs2151280', 'Var', (80, 89))	('lung cancer', 'Disease', 'MESH:D008175', (94, 105))	('lung cancer', 'Disease', (94, 105))	('lung cancer', 'Phenotype', 'HP:0100526', (94, 105))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('rs2151280', 'Mutation', 'rs2151280', (80, 89))
560516	31775885	Compared with TT genotype and TC genotype, variant CC genotype was associated with lower risk of lung cancer and NSCLC (adjusted OR were 0.538 and 0.572, 95% CI were 0.326-0.888, and 0.335-0.975, P were 0.015 and 0.040, respectively).	('NSCLC', 'Disease', (113, 118))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('lung cancer', 'Disease', 'MESH:D008175', (97, 108))	('variant CC', 'Var', (43, 53))	('NSCLC', 'Phenotype', 'HP:0030358', (113, 118))	('lower', 'NegReg', (83, 88))	('lung cancer', 'Disease', (97, 108))	('lung cancer', 'Phenotype', 'HP:0100526', (97, 108))	('NSCLC', 'Disease', 'MESH:D002289', (113, 118))
560517	31775885	However, in the subgroup of age, we failed to find any statistically significant associations between rs2151280 and the risk of lung cancer and NSCLC (Table 5).	('NSCLC', 'Disease', (144, 149))	('lung cancer', 'Disease', 'MESH:D008175', (128, 139))	('NSCLC', 'Disease', 'MESH:D002289', (144, 149))	('rs2151280', 'Mutation', 'rs2151280', (102, 111))	('rs2151280', 'Var', (102, 111))	('lung cancer', 'Disease', (128, 139))	('NSCLC', 'Phenotype', 'HP:0030358', (144, 149))	('lung cancer', 'Phenotype', 'HP:0100526', (128, 139))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
560518	31775885	In the subgroup of smoking, we found the significant association among rs2151280 with the risk of lung cancer and NSCLC in the individuals who had never exposed to smoking (Table 6).	('NSCLC', 'Phenotype', 'HP:0030358', (114, 119))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('lung cancer', 'Disease', (98, 109))	('rs2151280', 'Mutation', 'rs2151280', (71, 80))	('lung cancer', 'Phenotype', 'HP:0100526', (98, 109))	('rs2151280', 'Var', (71, 80))	('NSCLC', 'Disease', (114, 119))	('NSCLC', 'Disease', 'MESH:D002289', (114, 119))	('lung cancer', 'Disease', 'MESH:D008175', (98, 109))
560519	31775885	Carriers of the rs2151280 CC genotype had a lower lung cancer risk than carriers with TT genotype (adjusted OR = 0.518, 95%CI = 0.316-0.851, P = 0.009).	('lung cancer', 'Disease', (50, 61))	('lower', 'NegReg', (44, 49))	('rs2151280', 'Mutation', 'rs2151280', (16, 25))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('lung cancer', 'Disease', 'MESH:D008175', (50, 61))	('rs2151280 CC', 'Var', (16, 28))	('lung cancer', 'Phenotype', 'HP:0100526', (50, 61))
560520	31775885	Individuals carrying variant homozygote CC genotype had decreased risk of lung cancer by 0.561-fold (adjusted OR = 0.561, 95%CI = 0.354-0.891, P = 0.014) compared individuals carrying with heterozygote TC and TT genotype.	('lung cancer', 'Disease', (74, 85))	('lung cancer', 'Phenotype', 'HP:0100526', (74, 85))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('decreased', 'NegReg', (56, 65))	('lung cancer', 'Disease', 'MESH:D008175', (74, 85))	('variant', 'Var', (21, 28))
560521	31775885	CDKN2B-AS1 rs2151280 was significantly associated with the risk of NSCLC (CC vs TT: OR = 0.572, 95%CI = 0.334-0.980, P = 0.042; CCvsTC+TT: OR = 0.587, 95%CI = 0.356-0.968, P = 0.037, respectively).	('CDKN2B-AS1', 'Gene', (0, 10))	('NSCLC', 'Phenotype', 'HP:0030358', (67, 72))	('CDKN2B-AS1', 'Gene', '100048912', (0, 10))	('NSCLC', 'Disease', (67, 72))	('rs2151280', 'Mutation', 'rs2151280', (11, 20))	('NSCLC', 'Disease', 'MESH:D002289', (67, 72))	('rs2151280', 'Var', (11, 20))
560522	31775885	Tables 7, 8, 9 had shown the interaction between rs2151280 and smoking exposure on the susceptibility of lung cancer, NSCLC, AD, and SQ on additive interaction.	('lung cancer', 'Phenotype', 'HP:0100526', (105, 116))	('rs2151280', 'Var', (49, 58))	('NSCLC', 'Phenotype', 'HP:0030358', (118, 123))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('lung cancer', 'Disease', 'MESH:D008175', (105, 116))	('rs2151280', 'Mutation', 'rs2151280', (49, 58))	('NSCLC', 'Disease', (118, 123))	('SQ', 'Phenotype', 'HP:0002860', (133, 135))	('interaction', 'Interaction', (29, 40))	('NSCLC', 'Disease', 'MESH:D002289', (118, 123))	('AD', 'Disease', 'MESH:D000230', (125, 127))	('AD', 'Disease', (125, 127))	('lung cancer', 'Disease', (105, 116))
560526	31775885	Due to the P value was more than 0.05, the results of multiplicative interaction indicated that there were no association between rs2151280 risk genotypes with smoking exposure and lung cancer risk.	('rs2151280', 'Mutation', 'rs2151280', (130, 139))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('lung cancer', 'Disease', (181, 192))	('rs2151280', 'Var', (130, 139))	('lung cancer', 'Phenotype', 'HP:0100526', (181, 192))	('lung cancer', 'Disease', 'MESH:D008175', (181, 192))
560540	31775885	In this study, we demonstrated that the rs2151280 in lncRNA CDKN2B-AS1 was significantly associated with lung cancer.	('lung cancer', 'Phenotype', 'HP:0100526', (105, 116))	('associated', 'Reg', (89, 99))	('CDKN2B-AS1', 'Gene', '100048912', (60, 70))	('rs2151280', 'Mutation', 'rs2151280', (40, 49))	('rs2151280', 'Var', (40, 49))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('lung cancer', 'Disease', 'MESH:D008175', (105, 116))	('CDKN2B-AS1', 'Gene', (60, 70))	('lung cancer', 'Disease', (105, 116))
560542	31775885	This study was the first time to suggest that rs2151280 might be an important risk factor in lung cancer.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('rs2151280', 'Var', (46, 55))	('lung cancer', 'Disease', 'MESH:D008175', (93, 104))	('lung cancer', 'Disease', (93, 104))	('lung cancer', 'Phenotype', 'HP:0100526', (93, 104))	('rs2151280', 'Mutation', 'rs2151280', (46, 55))
560543	31775885	Specifically, the results of our study suggested that rs2151280 CC genotype could be a protecting factor in lung cancer compared with TT genotype, especially among adenocarcinoma patients.	('rs2151280', 'Mutation', 'rs2151280', (54, 63))	('lung cancer', 'Disease', 'MESH:D008175', (108, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (169, 178))	('adenocarcinoma', 'Disease', (164, 178))	('adenocarcinoma', 'Disease', 'MESH:D000230', (164, 178))	('lung cancer', 'Disease', (108, 119))	('lung cancer', 'Phenotype', 'HP:0100526', (108, 119))	('patients', 'Species', '9606', (179, 187))	('rs2151280 CC', 'Var', (54, 66))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
560545	31775885	The C allele had reduced the risk of NSCLC.	('NSCLC', 'Phenotype', 'HP:0030358', (37, 42))	('C allele', 'Var', (4, 12))	('NSCLC', 'Disease', (37, 42))	('NSCLC', 'Disease', 'MESH:D002289', (37, 42))	('reduced', 'NegReg', (17, 24))
560551	31775885	Therefore, in this case-control study, we investigated the interaction between smoking status exposure and the rs2151280 C/T on lung cancer risk.	('lung cancer', 'Disease', 'MESH:D008175', (128, 139))	('investigated', 'Reg', (42, 54))	('lung cancer', 'Disease', (128, 139))	('rs2151280 C/T', 'Var', (111, 124))	('lung cancer', 'Phenotype', 'HP:0100526', (128, 139))	('rs2151280', 'Mutation', 'rs2151280', (111, 120))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))
560552	31775885	The crossover analysis suggested that the interaction between rs2151280 and smoking exposure on the susceptibility of lung cancer, NSCLC, AD, and SQ were existed in Chinese population.	('AD', 'Disease', (138, 140))	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('SQ', 'Phenotype', 'HP:0002860', (146, 148))	('lung cancer', 'Disease', 'MESH:D008175', (118, 129))	('NSCLC', 'Disease', (131, 136))	('NSCLC', 'Disease', 'MESH:D002289', (131, 136))	('rs2151280', 'Mutation', 'rs2151280', (62, 71))	('lung cancer', 'Disease', (118, 129))	('lung cancer', 'Phenotype', 'HP:0100526', (118, 129))	('NSCLC', 'Phenotype', 'HP:0030358', (131, 136))	('AD', 'Disease', 'MESH:D000230', (138, 140))	('rs2151280', 'Var', (62, 71))
560555	31775885	Therefore, the relationship between the rs2151280 in lncRNA CDKN2B-AS1 and lung cancer risk need to be validated by further large size studies.	('lung cancer', 'Disease', (75, 86))	('lung cancer', 'Phenotype', 'HP:0100526', (75, 86))	('CDKN2B-AS1', 'Gene', '100048912', (60, 70))	('rs2151280', 'Mutation', 'rs2151280', (40, 49))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('rs2151280', 'Var', (40, 49))	('lung cancer', 'Disease', 'MESH:D008175', (75, 86))	('CDKN2B-AS1', 'Gene', (60, 70))
560556	31775885	Our findings provided new insights into the roles of rs2151280 in lung cancer risk in northern Chinese Han population.	('rs2151280', 'Mutation', 'rs2151280', (53, 62))	('rs2151280', 'Var', (53, 62))	('lung cancer', 'Disease', (66, 77))	('lung cancer', 'Phenotype', 'HP:0100526', (66, 77))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('lung cancer', 'Disease', 'MESH:D008175', (66, 77))
560560	25793373	The 12p13.33/RAD52 Locus and Genetic Susceptibility to Squamous Cell Cancers of Upper Aerodigestive Tract Genetic variants located within the 12p13.33/RAD52 locus have been associated with lung squamous cell carcinoma (LUSC).	('RAD52', 'Gene', (151, 156))	('LUSC', 'Phenotype', 'HP:0030359', (219, 223))	('Squamous Cell Cancers', 'Phenotype', 'HP:0002860', (55, 76))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (189, 217))	('RAD52', 'Gene', '5893', (13, 18))	('carcinoma', 'Phenotype', 'HP:0030731', (208, 217))	('Squamous Cell Cancers', 'Disease', (55, 76))	('Squamous Cell Cancers', 'Disease', 'MESH:D002294', (55, 76))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (189, 217))	('RAD52', 'Gene', '5893', (151, 156))	('variants', 'Var', (114, 122))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (194, 217))	('lung squamous cell carcinoma', 'Disease', (189, 217))	('associated with', 'Reg', (173, 188))	('Cancers', 'Phenotype', 'HP:0002664', (69, 76))	('Cancer', 'Phenotype', 'HP:0002664', (69, 75))	('RAD52', 'Gene', (13, 18))
560561	25793373	Here, within 5,947 UADT cancers and 7,789 controls from 9 different studies, we found rs10849605, a common intronic variant in RAD52, to be also associated with upper aerodigestive tract (UADT) squamous cell carcinoma cases (OR = 1.09, 95% CI: 1.04-1.15, p = 6x10-4).	('upper aerodigestive tract', 'Disease', (161, 186))	('rs10849605', 'Var', (86, 96))	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('RAD52', 'Gene', '5893', (127, 132))	('carcinoma', 'Phenotype', 'HP:0030731', (208, 217))	('UADT cancers', 'Disease', 'MESH:D006258', (19, 31))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (194, 217))	('cancers', 'Phenotype', 'HP:0002664', (24, 31))	('associated with', 'Reg', (145, 160))	('squamous cell carcinoma', 'Disease', (194, 217))	('UADT cancers', 'Disease', (19, 31))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (194, 217))	('RAD52', 'Gene', (127, 132))	('rs10849605', 'Mutation', 'rs10849605', (86, 96))
560562	25793373	We additionally identified rs10849605 as a RAD52 cis-eQTL inUADT(p = 1x10-3) and LUSC (p = 9x10-4) tumours, with the UADT/LUSC risk allele correlated with increased RAD52 expression levels.	('UADT/LUSC', 'Disease', (117, 126))	('RAD52', 'Gene', '5893', (165, 170))	('tumours', 'Phenotype', 'HP:0002664', (99, 106))	('increased', 'PosReg', (155, 164))	('tumours', 'Disease', 'MESH:D009369', (99, 106))	('tumours', 'Disease', (99, 106))	('RAD52', 'Gene', (43, 48))	('LUSC', 'Phenotype', 'HP:0030359', (122, 126))	('LUSC', 'Phenotype', 'HP:0030359', (81, 85))	('expression levels', 'MPA', (171, 188))	('rs10849605', 'Var', (27, 37))	('RAD52', 'Gene', (165, 170))	('rs10849605', 'Mutation', 'rs10849605', (27, 37))	('RAD52', 'Gene', '5893', (43, 48))
560569	25793373	Genome wide association studies (GWAS) have implicated the rs10849605 genetic variant at 12p13.33, the locus that encompasses RAD52 in the human genome, to be associated with a modest, but statistically significant, increased risk of lung cancer.	('rs10849605', 'Mutation', 'rs10849605', (59, 69))	('rs10849605', 'Var', (59, 69))	('lung cancer', 'Disease', (234, 245))	('lung cancer', 'Phenotype', 'HP:0100526', (234, 245))	('human', 'Species', '9606', (139, 144))	('RAD52', 'Gene', (126, 131))	('RAD52', 'Gene', '5893', (126, 131))	('cancer', 'Phenotype', 'HP:0002664', (239, 245))	('lung cancer', 'Disease', 'MESH:D008175', (234, 245))
560575	25793373	The rs10849605 was genotyped using Illumina bead arrays or TaqMan genotyping (C__1244798_10, Applied Biosystems, Carlsbad, CA) at IARC as described elsewhere.	('rs10849605', 'Mutation', 'rs10849605', (4, 14))	('C__1244798_10', 'Var', (78, 91))	('rs10849605', 'Var', (4, 14))
560577	25793373	Somatic point mutations were exonic functional variants defined as either truncating, impacting splicing or missense variants predicted as deleterious by SIFT/POLYPHEN2.	('SIFT', 'Disease', 'None', (154, 158))	('truncating', 'MPA', (74, 84))	('missense', 'Var', (108, 116))	('splicing', 'MPA', (96, 104))	('impacting', 'Reg', (86, 95))	('SIFT', 'Disease', (154, 158))
560581	25793373	rs10849605 is located inside the 5' region of RAD52 and was not covered by exome sequencing.	('rs10849605', 'Mutation', 'rs10849605', (0, 10))	('RAD52', 'Gene', (46, 51))	('RAD52', 'Gene', '5893', (46, 51))	('rs10849605', 'Var', (0, 10))
560582	25793373	The association between the variants and UADT cancer risk was estimated by odds ratio (ORs) and 95% confidence intervals (CIs) per allele under the log-additive model and genotype derived from multivariate unconditional logistic regression, with sex and study specific country of origin included in the model as covariates (S1 Table).	('association', 'Interaction', (4, 15))	('variants', 'Var', (28, 36))	('UADT cancer', 'Disease', 'MESH:D006258', (41, 52))	('UADT cancer', 'Disease', (41, 52))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))
560583	25793373	The association between rs10849605 germline genotype and RAD52 tumor expression levels (eQTL) was tested on 263 HNSC, 223 LUSC and 125 LUAD using a linear model.	('tumor', 'Disease', (63, 68))	('HNSC', 'Phenotype', 'HP:0012288', (112, 116))	('RAD52', 'Gene', (57, 62))	('tested', 'Reg', (98, 104))	('LUAD', 'Phenotype', 'HP:0030078', (135, 139))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('LUSC', 'Phenotype', 'HP:0030359', (122, 126))	('rs10849605', 'Mutation', 'rs10849605', (24, 34))	('RAD52', 'Gene', '5893', (57, 62))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('rs10849605', 'Var', (24, 34))
560585	25793373	Therefore we tested the eQTL effect of rs10849605 on RAD52 tumor expression using both adjusted and non-adjusted linear models as described in Table B in S1 File.	('tumor', 'Disease', (59, 64))	('rs10849605', 'Var', (39, 49))	('RAD52', 'Gene', (53, 58))	('rs10849605', 'Mutation', 'rs10849605', (39, 49))	('tested', 'Reg', (13, 19))	('RAD52', 'Gene', '5893', (53, 58))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
560587	25793373	We genotyped rs10849605 in 5,947 UADT cancer cases and 7,789 control individuals from 9 studies.	('UADT cancer', 'Disease', 'MESH:D006258', (33, 44))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('UADT cancer', 'Disease', (33, 44))	('rs10849605', 'Var', (13, 23))	('rs10849605', 'Mutation', 'rs10849605', (13, 23))
560589	25793373	As observed in squamous cell carcinoma of the lung, the C allele was associated with a modest increase in UADT cancer risk (Fig.	('squamous cell carcinoma of the lung', 'Disease', (15, 50))	('carcinoma', 'Phenotype', 'HP:0030731', (29, 38))	('UADT cancer', 'Disease', 'MESH:D006258', (106, 117))	('squamous cell carcinoma of the lung', 'Disease', 'MESH:D002294', (15, 50))	('squamous cell carcinoma of the lung', 'Phenotype', 'HP:0030359', (15, 50))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('UADT cancer', 'Disease', (106, 117))	('carcinoma of the lung', 'Phenotype', 'HP:0100526', (29, 50))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (15, 38))	('C allele', 'Var', (56, 64))
560592	25793373	There was little evidence to suggest this variant altered consumption patterns of tobacco and alcohol (p = 0.53 and p = 0.40, respectively, pack/years and ethanol/day taken as a continuous variable).	('ethanol', 'Chemical', 'MESH:D000431', (155, 162))	('consumption', 'MPA', (58, 69))	('tobacco', 'Species', '4097', (82, 89))	('altered', 'Reg', (50, 57))	('alcohol', 'Chemical', 'MESH:D000438', (94, 101))	('variant', 'Var', (42, 49))
560593	25793373	We next undertook in-silico analysis of the rs10849605 variant and the RAD52/12p13.33 locus in the head and neck and lung cancers genomically characterised by the Cancer Genome Atlas (TCGA).	('lung cancers', 'Disease', (117, 129))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('rs10849605', 'Var', (44, 54))	('RAD52', 'Gene', (71, 76))	('lung cancer', 'Phenotype', 'HP:0100526', (117, 128))	('rs10849605', 'Mutation', 'rs10849605', (44, 54))	('lung cancers', 'Disease', 'MESH:D008175', (117, 129))	('cancers', 'Phenotype', 'HP:0002664', (122, 129))	('lung cancers', 'Phenotype', 'HP:0100526', (117, 129))	('Cancer Genome Atlas', 'Disease', (163, 182))	('RAD52', 'Gene', '5893', (71, 76))	('Cancer', 'Phenotype', 'HP:0002664', (163, 169))	('Cancer Genome Atlas', 'Disease', 'MESH:D009369', (163, 182))
560594	25793373	rs10849605 is located near the putative promoter 5' to the RAD52 gene, therefore we hypothesized that this, or a correlated proxy variant, might influence RAD52 gene expression.	('rs10849605', 'Mutation', 'rs10849605', (0, 10))	('RAD52', 'Gene', (155, 160))	('RAD52', 'Gene', '5893', (59, 64))	('RAD52', 'Gene', '5893', (155, 160))	('RAD52', 'Gene', (59, 64))	('expression', 'MPA', (166, 176))	('rs10849605', 'Var', (0, 10))	('influence', 'Reg', (145, 154))
560595	25793373	We performed an expression quantitative trait locus (eQTL) analysis between rs10849605 and RAD52 expression levels in HNSC (n = 263), using data where both RNAseq of the tumors and genotyping had been carried out by TCGA within the same individuals.	('rs10849605', 'Mutation', 'rs10849605', (76, 86))	('tumors', 'Disease', (170, 176))	('HNSC', 'Phenotype', 'HP:0012288', (118, 122))	('tumor', 'Phenotype', 'HP:0002664', (170, 175))	('RAD52', 'Gene', (91, 96))	('tumors', 'Phenotype', 'HP:0002664', (170, 176))	('RAD52', 'Gene', '5893', (91, 96))	('tumors', 'Disease', 'MESH:D009369', (170, 176))	('rs10849605', 'Var', (76, 86))
560596	25793373	rs10849605 was significantly associated with RAD52 gene expression levels in HNSC (Fig.	('rs10849605', 'Mutation', 'rs10849605', (0, 10))	('RAD52', 'Gene', (45, 50))	('HNSC', 'Phenotype', 'HP:0012288', (77, 81))	('RAD52', 'Gene', '5893', (45, 50))	('associated', 'Reg', (29, 39))	('HNSC', 'Disease', (77, 81))	('rs10849605', 'Var', (0, 10))
560597	25793373	2, n = 263, p = 9x10-4), suggesting that rs10849605 is a cis-eQTL locus for RAD52.	('RAD52', 'Gene', (76, 81))	('RAD52', 'Gene', '5893', (76, 81))	('rs10849605', 'Var', (41, 51))	('rs10849605', 'Mutation', 'rs10849605', (41, 51))
560598	25793373	The C allele of rs10849605, associated with risk of HNSC, was correlated with increased RAD52 expression levels (Fig.	('HNSC', 'Disease', (52, 56))	('rs10849605', 'Mutation', 'rs10849605', (16, 26))	('rs10849605', 'Var', (16, 26))	('expression levels', 'MPA', (94, 111))	('RAD52', 'Gene', (88, 93))	('increased', 'PosReg', (78, 87))	('RAD52', 'Gene', '5893', (88, 93))	('HNSC', 'Phenotype', 'HP:0012288', (52, 56))
560601	25793373	While statistically significant, the eQTL for rs10849605 accounted for only a small proportion of the variance (approximately 4%) in RAD52 expression in HNSC and LUSC tumours, an observation in line with the relatively modest genetic risk observed with this variant.	('LUSC', 'Phenotype', 'HP:0030359', (162, 166))	('HNSC', 'Phenotype', 'HP:0012288', (153, 157))	('HNSC and LUSC tumours', 'Disease', 'MESH:D009369', (153, 174))	('rs10849605', 'Mutation', 'rs10849605', (46, 56))	('tumours', 'Phenotype', 'HP:0002664', (167, 174))	('rs10849605', 'Var', (46, 56))	('RAD52', 'Gene', (133, 138))	('expression', 'MPA', (139, 149))	('RAD52', 'Gene', '5893', (133, 138))
560602	25793373	Within somatic mutations recalled from paired normal-tumor exome sequencing samples of 305 HNSC and 243 LUSC, RAD52 was rarely mutated somatically (point mutations and insertions deletions), with only 2 HNSC (0.60% of tumors) and one LUSC (0.40% of tumors) patients harbouring a somatic missense variant, and no somatic insertion or deletion observed.	('LUSC', 'Phenotype', 'HP:0030359', (104, 108))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Disease', (249, 254))	('HNSC', 'Phenotype', 'HP:0012288', (203, 207))	('tumor', 'Disease', (218, 223))	('tumors', 'Disease', (249, 255))	('missense variant', 'Var', (287, 303))	('tumors', 'Disease', 'MESH:D009369', (249, 255))	('tumor', 'Disease', 'MESH:D009369', (249, 254))	('tumor', 'Disease', 'MESH:D009369', (218, 223))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('HNSC', 'Phenotype', 'HP:0012288', (91, 95))	('patients', 'Species', '9606', (257, 265))	('tumors', 'Phenotype', 'HP:0002664', (218, 224))	('RAD52', 'Gene', (110, 115))	('tumor', 'Phenotype', 'HP:0002664', (249, 254))	('tumor', 'Phenotype', 'HP:0002664', (218, 223))	('tumors', 'Phenotype', 'HP:0002664', (249, 255))	('tumors', 'Disease', (218, 224))	('LUSC', 'Phenotype', 'HP:0030359', (234, 238))	('RAD52', 'Gene', '5893', (110, 115))	('tumor', 'Disease', (53, 58))	('tumors', 'Disease', 'MESH:D009369', (218, 224))
560603	25793373	By contrast, we analysed the TCGA somatic copy number variation (CNV) data of 374 HNSC, 464 LUSC and 476 LUAD tumors and found that the 12p13.33 locus was a frequent region of copy number gain in HNSC (7.2% of cases) and LUSC (11.2% of cases).	('TCGA', 'Gene', (29, 33))	('LUSC', 'Phenotype', 'HP:0030359', (221, 225))	('LUAD tumors', 'Disease', 'MESH:D009369', (105, 116))	('tumor', 'Phenotype', 'HP:0002664', (110, 115))	('LUAD tumors', 'Disease', (105, 116))	('HNSC', 'Phenotype', 'HP:0012288', (82, 86))	('HNSC', 'Phenotype', 'HP:0012288', (196, 200))	('tumors', 'Phenotype', 'HP:0002664', (110, 116))	('LUSC', 'Phenotype', 'HP:0030359', (92, 96))	('12p13.33', 'Var', (136, 144))	('LUAD', 'Phenotype', 'HP:0030078', (105, 109))	('gain', 'PosReg', (188, 192))	('copy number', 'Var', (176, 187))
560604	25793373	Copy number gain of 12p13.33 was observed in a lower proportion of LUAD tumors (3.9% of cases) (Fig.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('LUAD tumors', 'Disease', 'MESH:D009369', (67, 78))	('Copy number gain', 'Var', (0, 16))	('LUAD tumors', 'Disease', (67, 78))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('LUAD', 'Phenotype', 'HP:0030078', (67, 71))
560607	25793373	However, rs10849605 appeared to influence only RAD52 expression levels (Table D in S1 File).	('rs10849605', 'Var', (9, 19))	('influence', 'Reg', (32, 41))	('rs10849605', 'Mutation', 'rs10849605', (9, 19))	('RAD52', 'Gene', (47, 52))	('expression levels', 'MPA', (53, 70))	('RAD52', 'Gene', '5893', (47, 52))
560608	25793373	Our study has identified rs10849605 to be associated with UADT cancer (p = 6x10-4).	('associated', 'Reg', (42, 52))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('UADT cancer', 'Disease', 'MESH:D006258', (58, 69))	('UADT cancer', 'Disease', (58, 69))	('rs10849605', 'Mutation', 'rs10849605', (25, 35))	('rs10849605', 'Var', (25, 35))
560610	25793373	Nevertheless, our findings are consistent with the observation that rs10849605 (or variants correlated with it) have also been associated with lung cancer, and particularly lung squamous cell carcinomas.	('associated', 'Reg', (127, 137))	('lung cancer', 'Disease', (143, 154))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (178, 202))	('lung cancer', 'Phenotype', 'HP:0100526', (143, 154))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('lung squamous cell carcinomas', 'Disease', (173, 202))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (173, 201))	('lung cancer', 'Disease', 'MESH:D008175', (143, 154))	('rs10849605', 'Mutation', 'rs10849605', (68, 78))	('rs10849605', 'Var', (68, 78))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (178, 201))	('lung squamous cell carcinomas', 'Disease', 'MESH:D002294', (173, 202))	('carcinoma', 'Phenotype', 'HP:0030731', (192, 201))	('carcinomas', 'Phenotype', 'HP:0030731', (192, 202))
560611	25793373	As found in lung cancer, the allele C of the susceptibility variant rs10849605 was associated with a modest increased risk of UADT.	('lung cancer', 'Disease', 'MESH:D008175', (12, 23))	('UADT', 'Disease', (126, 130))	('lung cancer', 'Disease', (12, 23))	('rs10849605', 'Mutation', 'rs10849605', (68, 78))	('lung cancer', 'Phenotype', 'HP:0100526', (12, 23))	('rs10849605', 'Var', (68, 78))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
560612	25793373	rs10849605 is located at chromosome 12p13.33, a locus that contains the RAD52 gene.	('rs10849605', 'Mutation', 'rs10849605', (0, 10))	('rs10849605', 'Var', (0, 10))	('RAD52', 'Gene', (72, 77))	('RAD52', 'Gene', '5893', (72, 77))
560615	25793373	12p13.33 was a region of significant somatic copy number gain in HNSC and LUSC, suggesting that somatic amplification of 12p13.33 is an important molecular event in a subset of tumors.	('tumors', 'Phenotype', 'HP:0002664', (177, 183))	('tumors', 'Disease', 'MESH:D009369', (177, 183))	('LUSC', 'Phenotype', 'HP:0030359', (74, 78))	('copy number', 'Var', (45, 56))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('tumors', 'Disease', (177, 183))	('gain', 'PosReg', (57, 61))	('HNSC', 'Phenotype', 'HP:0012288', (65, 69))
560617	25793373	Importantly, rs10849605 was an eQTL in HNSC and LUSC for RAD52 only, suggesting RAD52 as the most probable candidate driver gene for both the genetic susceptibility and tumorigenesis at this locus.	('LUSC', 'Phenotype', 'HP:0030359', (48, 52))	('tumor', 'Disease', 'MESH:D009369', (169, 174))	('RAD52', 'Gene', (80, 85))	('HNSC', 'Phenotype', 'HP:0012288', (39, 43))	('tumor', 'Phenotype', 'HP:0002664', (169, 174))	('RAD52', 'Gene', (57, 62))	('rs10849605', 'Var', (13, 23))	('RAD52', 'Gene', '5893', (80, 85))	('tumor', 'Disease', (169, 174))	('rs10849605', 'Mutation', 'rs10849605', (13, 23))	('RAD52', 'Gene', '5893', (57, 62))
560618	25793373	As an eQTL, the rs10849605 UADT and LUSC risk associated allele (allele C) was correlated with increased RAD52 expression levels.	('LUSC risk', 'Disease', (36, 45))	('LUSC', 'Phenotype', 'HP:0030359', (36, 40))	('rs10849605', 'Mutation', 'rs10849605', (16, 26))	('rs10849605', 'Var', (16, 26))	('RAD52', 'Gene', (105, 110))	('expression levels', 'MPA', (111, 128))	('RAD52', 'Gene', '5893', (105, 110))	('increased', 'PosReg', (95, 104))
560623	25793373	Targeted inhibition of RAD52 in BRCA2 deficient cells results in genomic instability and cell growth inhibition, leading to the suggestion of RAD52 as a potential therapeutic target using synthetic lethality approaches.	('inhibition', 'NegReg', (9, 19))	('RAD52', 'Gene', (142, 147))	('cell growth inhibition', 'CPA', (89, 111))	('genomic instability', 'CPA', (65, 84))	('BRCA2', 'Gene', (32, 37))	('RAD52', 'Gene', (23, 28))	('RAD52', 'Gene', '5893', (142, 147))	('deficient', 'Var', (38, 47))	('BRCA2', 'Gene', '675', (32, 37))	('RAD52', 'Gene', '5893', (23, 28))
560624	25793373	Our results linking RAD52 higher gene expression to UADT and LUSC, along with our recent observation that a rare truncating BRCA2 genetic variant, rs11571833 (K3326X) is associated with a 2.5 fold risk of squamous cell carcinomas of the lung and UADT, suggests that such targeted therapy approaches may be worth investigating in UADT and LUSC tumors.	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (205, 229))	('RAD52', 'Gene', '5893', (20, 25))	('K3326X', 'Mutation', 'rs11571833', (159, 165))	('BRCA2', 'Gene', '675', (124, 129))	('associated', 'Reg', (170, 180))	('LUSC tumors', 'Disease', 'MESH:D009369', (338, 349))	('rs11571833 (K3326X', 'Var', (147, 165))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (205, 228))	('LUSC tumors', 'Disease', (338, 349))	('LUSC', 'Phenotype', 'HP:0030359', (338, 342))	('LUSC', 'Phenotype', 'HP:0030359', (61, 65))	('squamous cell carcinomas of the lung', 'Disease', (205, 241))	('rs11571833', 'Mutation', 'rs11571833', (147, 157))	('RAD52', 'Gene', (20, 25))	('carcinoma', 'Phenotype', 'HP:0030731', (219, 228))	('carcinomas', 'Phenotype', 'HP:0030731', (219, 229))	('tumors', 'Phenotype', 'HP:0002664', (343, 349))	('BRCA2', 'Gene', (124, 129))	('tumor', 'Phenotype', 'HP:0002664', (343, 348))	('squamous cell carcinomas of the lung', 'Disease', 'MESH:D002294', (205, 241))
560630	33469301	Kaplan-Meier analysis revealed that high ACTL6A expression was significantly associated with poor overall survival (OS) (P = 0.008, HR= 2.562, 95% CI: 1.241-5.289), and decision curve analysis (DCA) demonstrated that ACTL6A could increase the clinical prognostic efficiency of the original clinical prediction model.	('DCA', 'Chemical', '-', (194, 197))	('expression', 'MPA', (48, 58))	('ACTL6A', 'Gene', (41, 47))	('poor', 'NegReg', (93, 97))	('increase', 'PosReg', (230, 238))	('overall', 'MPA', (98, 105))	('high', 'Var', (36, 40))
560631	33469301	ACTL6A knockdown resulted in G1 phase arrest, with downregulation of cyclin D1, CDK2 and S6K1/pS6 pathway proteins and upregulation of p21 and p27, while overexpression of ACTL6A facilitated the entry of more cells into S phase with upregulated cyclin D1, CDK2 and S6K1/pS6 pathway proteins and downregulated p21 and p27.	('p27', 'Gene', '3429', (143, 146))	('arrest', 'Disease', (38, 44))	('pS6', 'Gene', (94, 97))	('p27', 'Gene', (143, 146))	('S phase', 'CPA', (220, 227))	('upregulation', 'PosReg', (119, 131))	('p27', 'Gene', '3429', (317, 320))	('p27', 'Gene', (317, 320))	('facilitated', 'PosReg', (179, 190))	('pS6', 'Gene', '338413', (270, 273))	('downregulated', 'NegReg', (295, 308))	('p21', 'Gene', (309, 312))	('cyclin D1', 'Gene', (245, 254))	('CDK2', 'Gene', '1017', (256, 260))	('upregulated', 'PosReg', (233, 244))	('pS6', 'Gene', '338413', (94, 97))	('p21', 'Gene', (135, 138))	('ACTL6A', 'Gene', (0, 6))	('CDK2', 'Gene', (256, 260))	('arrest', 'Disease', 'MESH:D006323', (38, 44))	('cyclin D1', 'Gene', (69, 78))	('CDK2', 'Gene', '1017', (80, 84))	('cyclin D1', 'Gene', '595', (245, 254))	('CDK2', 'Gene', (80, 84))	('cyclin D1', 'Gene', '595', (69, 78))	('downregulation', 'NegReg', (51, 65))	('p21', 'Gene', '1026', (309, 312))	('p21', 'Gene', '1026', (135, 138))	('pS6', 'Gene', (270, 273))	('knockdown', 'Var', (7, 16))
560633	33469301	ACTL6A expression may affect the proliferation and DNA synthesis of ESCC cells by facilitating ESCC cell cycle redistribution via the S6K1/pS6 pathway.	('pS6', 'Gene', '338413', (139, 142))	('DNA synthesis', 'MPA', (51, 64))	('SCC', 'Phenotype', 'HP:0002860', (96, 99))	('SCC', 'Phenotype', 'HP:0002860', (69, 72))	('ESCC', 'Disease', (95, 99))	('proliferation', 'CPA', (33, 46))	('affect', 'Reg', (22, 28))	('pS6', 'Gene', (139, 142))	('facilitating', 'Reg', (82, 94))	('expression', 'Var', (7, 17))	('ACTL6A', 'Gene', (0, 6))
560640	33469301	In general, the SWI/SNF complex acts as a tumor suppressor; however, protein subunits of this complex are frequently mutated or lost in tumors, creating circumstances that are permissive for cancer development.	('tumors', 'Disease', (136, 142))	('tumors', 'Disease', 'MESH:D009369', (136, 142))	('cancer', 'Disease', (191, 197))	('tumor', 'Disease', (42, 47))	('mutated', 'Var', (117, 124))	('cancer', 'Disease', 'MESH:D009369', (191, 197))	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('lost', 'NegReg', (128, 132))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('cancer', 'Phenotype', 'HP:0002664', (191, 197))	('tumor', 'Disease', (136, 141))
560642	33469301	Deficiency of Brg1 was previously shown to induce cell cycle arrest through an RB-dependent mechanism, and Brg1 is preferentially recruited by p53 to a subset of p53-dependent promoters, including the p21 promoter, in melanoma.	('arrest', 'Disease', (61, 67))	('Brg1', 'Gene', '6597', (107, 111))	('p53', 'Gene', '7157', (143, 146))	('p53', 'Gene', (162, 165))	('p21', 'Gene', '1026', (201, 204))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (50, 67))	('p21', 'Gene', (201, 204))	('melanoma', 'Phenotype', 'HP:0002861', (218, 226))	('melanoma', 'Disease', (218, 226))	('p53', 'Gene', '7157', (162, 165))	('arrest', 'Disease', 'MESH:D006323', (61, 67))	('melanoma', 'Disease', 'MESH:D008545', (218, 226))	('Brg1', 'Gene', (14, 18))	('Brg1', 'Gene', '6597', (14, 18))	('p53', 'Gene', (143, 146))	('Brg1', 'Gene', (107, 111))	('preferentially recruited', 'PosReg', (115, 139))	('Deficiency', 'Var', (0, 10))
560645	33469301	ACTL6A expression leads to cell cycle arrest in head and neck squamous cell carcinoma (HNSCC) and epidermal squamous cell carcinoma (SCC) by interacting with the p21 promoter directly.	('arrest', 'Disease', (38, 44))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (62, 85))	('neck squamous cell carcinoma', 'Disease', (57, 85))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (27, 44))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (57, 85))	('p21', 'Gene', '1026', (162, 165))	('epidermal squamous cell carcinoma', 'Disease', (98, 131))	('ACTL6A', 'Gene', (0, 6))	('interacting', 'Interaction', (141, 152))	('arrest', 'Disease', 'MESH:D006323', (38, 44))	('SCC', 'Phenotype', 'HP:0002860', (133, 136))	('HNSCC', 'Phenotype', 'HP:0012288', (87, 92))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (108, 131))	('epidermal squamous cell carcinoma', 'Disease', 'MESH:D002294', (98, 131))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (48, 85))	('carcinoma', 'Phenotype', 'HP:0030731', (76, 85))	('p21', 'Gene', (162, 165))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('expression', 'Var', (7, 17))	('SCC', 'Phenotype', 'HP:0002860', (89, 92))
560650	33469301	S6K1 always phosphorylates S6 protein at Ser235, Ser236, Ser240, Ser244, and Ser247.	('Ser244', 'Var', (65, 71))	('Ser247', 'Var', (77, 83))	('Ser236', 'Var', (49, 55))	('Ser235', 'Chemical', '-', (41, 47))	('Ser236', 'Chemical', '-', (49, 55))	('Ser240', 'Chemical', '-', (57, 63))	('S6 protein', 'Protein', (27, 37))	('Ser235', 'Var', (41, 47))	('Ser240', 'Var', (57, 63))	('Ser244', 'Chemical', '-', (65, 71))	('Ser247', 'Chemical', '-', (77, 83))
560675	33469301	Primary antibodies used in the whole experiment are listed below: ACTL6A (NB100-61628) from Novus Biologicals (USA); p21 (#2946), CDK2 (#18048), S6 (#2217) and pS6 (#5364) from Cell Signaling Technology (USA); S6K1 (sc-8418) from Santa Cruz; GAPDH (10494-1-AP), cyclinD1 (26939-1-AP) and p27 (25614-1-AP) from Proteintech (Wuhan, China).	('CDK2', 'Gene', (130, 134))	('pS6', 'Gene', '338413', (160, 163))	('cyclinD1', 'Gene', (262, 270))	('p21', 'Gene', '1026', (117, 120))	('cyclinD1', 'Gene', '595', (262, 270))	('CDK2', 'Gene', '1017', (130, 134))	('p21', 'Gene', (117, 120))	('26939-1-AP', 'Var', (272, 282))	('GAPDH', 'Gene', '2597', (242, 247))	('pS6', 'Gene', (160, 163))	('GAPDH', 'Gene', (242, 247))	('p27', 'Gene', (288, 291))	('#18048', 'Var', (136, 142))	('p27', 'Gene', '3429', (288, 291))
560698	33469301	The OS prognosis of the group with positive ACTL6A expression in both ESCC tissues and corresponding noncancerous tissues was the worst among all four groups (P=0.009, Figure 1H).	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('positive', 'Var', (35, 43))	('ACTL6A', 'Gene', (44, 50))	('expression', 'MPA', (51, 61))	('SCC', 'Phenotype', 'HP:0002860', (71, 74))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))
560699	33469301	In addition, univariate and multivariate Cox regression analysis showed that positive ACTL6A expression was a significant and independent prognostic marker of the OS of ESCC patients (Table 2).	('ACTL6A', 'Gene', (86, 92))	('positive', 'Var', (77, 85))	('patients', 'Species', '9606', (174, 182))	('expression', 'MPA', (93, 103))	('SCC', 'Phenotype', 'HP:0002860', (170, 173))	('ESCC patients', 'Disease', (169, 182))
560703	33469301	To analyze the proliferation stimulation effect of ACTL6A on ESCC, we used seven ESCC cell lines: TE7, KYSE510, KYSE150, KYSE450, EC1, EC9706 and EC109.	('KYSE150', 'CellLine', 'CVCL:1348', (112, 119))	('SCC', 'Phenotype', 'HP:0002860', (82, 85))	('EC9706', 'Var', (135, 141))	('EC1', 'Gene', '4819', (130, 133))	('EC1', 'Gene', (130, 133))	('SCC', 'Phenotype', 'HP:0002860', (62, 65))	('EC1', 'Gene', (146, 149))	('KYSE450', 'Var', (121, 128))	('KYSE510', 'Var', (103, 110))	('EC9706', 'CellLine', 'CVCL:E307', (135, 141))	('TE7', 'CellLine', 'CVCL:9972', (98, 101))	('KYSE150', 'Var', (112, 119))	('EC1', 'Gene', '4819', (146, 149))
560712	33469301	These results demonstrated that the proportion of cells in G1 phase significantly increased in EC1 cells transduced with Lv-shACTL6A compared with mock-transduced EC1 cells, while the proportion of cells in S phase significantly increased in TE7 cells transduced with Lv-ACTL6A compared with TE7 cells transduced with empty vector (Figure 3A).	('TE7', 'CellLine', 'CVCL:9972', (242, 245))	('G1 phase', 'CPA', (59, 67))	('increased', 'PosReg', (229, 238))	('EC1', 'Gene', '4819', (163, 166))	('EC1', 'Gene', (163, 166))	('Lv-shACTL6A', 'Var', (121, 132))	('increased', 'PosReg', (82, 91))	('TE7', 'CellLine', 'CVCL:9972', (292, 295))	('EC1', 'Gene', '4819', (95, 98))	('EC1', 'Gene', (95, 98))
560717	33469301	ACTL6A expression resulted in upregulated S6K1 and pS6, while ACTL6A knockdown downregulated these proteins; the expression level of S6 remained the same, indicating that ACTL6A regulates the S6K1/pS6 pathway by affecting pS6 phosphorylation in TE7 and EC1 cells (Figure 3C).	('ACTL6A', 'Var', (171, 177))	('pS6', 'Gene', (51, 54))	('affecting', 'Reg', (212, 221))	('pS6', 'Gene', '338413', (222, 225))	('upregulated', 'PosReg', (30, 41))	('phosphorylation', 'MPA', (226, 241))	('regulates', 'Reg', (178, 187))	('downregulated', 'NegReg', (79, 92))	('TE7', 'CellLine', 'CVCL:9972', (245, 248))	('pS6', 'Gene', '338413', (51, 54))	('EC1', 'Gene', '4819', (253, 256))	('pS6', 'Gene', (222, 225))	('pS6', 'Gene', (197, 200))	('S6K1', 'MPA', (42, 46))	('ACTL6A', 'Gene', (0, 6))	('EC1', 'Gene', (253, 256))	('pS6', 'Gene', '338413', (197, 200))
560718	33469301	To validate the effect of ACTL6A on ESCC cells in vivo, we subcutaneously injected TE7 cells transduced with Lv-ACTL6A or Lv-CON and EC1 cells transduced with Lv-shACTL6A-1 or Lv-shCON into the flank region of 5-week-old nude mice to establish a mouse xenograft model.	('EC1', 'Gene', (133, 136))	('EC1', 'Gene', '4819', (133, 136))	('SCC', 'Phenotype', 'HP:0002860', (37, 40))	('mouse', 'Species', '10090', (246, 251))	('Lv-ACTL6A', 'Var', (109, 118))	('nude mice', 'Species', '10090', (221, 230))	('TE7', 'CellLine', 'CVCL:9972', (83, 86))
560721	33469301	Immunohistochemical analysis also showed that Ki67, S6K1 and pS6 expression was significantly higher in xenograft mouse model tissues with ACTL6A overexpression than in control tissues and was markedly lower in xenograft mouse model tissues with suppressed ACTL6A than in mock-transduced vector tissues, which indicated that the expression of ACTL6A played a vital role in the proliferation of ESCC cells in vivo (Figure 4E).	('Ki67', 'Gene', (46, 50))	('pS6', 'Gene', '338413', (61, 64))	('ACTL6A overexpression', 'Var', (139, 160))	('SCC', 'Phenotype', 'HP:0002860', (395, 398))	('lower', 'NegReg', (202, 207))	('mouse', 'Species', '10090', (221, 226))	('S6K1', 'Gene', (52, 56))	('overexpression', 'Var', (146, 160))	('expression', 'MPA', (65, 75))	('mouse', 'Species', '10090', (114, 119))	('Ki67', 'Gene', '17345', (46, 50))	('pS6', 'Gene', (61, 64))	('higher', 'PosReg', (94, 100))
560723	33469301	In this research, we demonstrated that patients with positive ACTL6A expression had obviously shortened OS compared with those with negative ACTL6A expression.	('patients', 'Species', '9606', (39, 47))	('expression', 'Var', (69, 79))	('shortened', 'NegReg', (94, 103))	('ACTL6A', 'Gene', (62, 68))	('positive', 'Var', (53, 61))
560728	33469301	Our subsequent mechanistic research demonstrated the tumor promoting effects of ACTL6A upregulation and the antitumor effects of ACTL6A knockdown in ESCC cells in vitro and in vivo.	('ESCC', 'Disease', (149, 153))	('tumor', 'Disease', 'MESH:D009369', (53, 58))	('tumor', 'Disease', 'MESH:D009369', (112, 117))	('knockdown', 'Var', (136, 145))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumor', 'Phenotype', 'HP:0002664', (112, 117))	('ACTL6A', 'Gene', (129, 135))	('tumor', 'Disease', (53, 58))	('tumor', 'Disease', (112, 117))	('SCC', 'Phenotype', 'HP:0002860', (150, 153))	('ACTL6A', 'Gene', (80, 86))	('upregulation', 'PosReg', (87, 99))
560729	33469301	Our flow cytometry results showed that ACTL6A knockdown led to G1 phase arrest, whereas ACTL6A upregulation caused cells to accumulate in S phase in ESCC cells upon PI labeling.	('arrest', 'Disease', 'MESH:D006323', (72, 78))	('knockdown', 'Var', (46, 55))	('ACTL6A', 'Gene', (88, 94))	('arrest', 'Disease', (72, 78))	('ACTL6A', 'Gene', (39, 45))	('accumulate', 'PosReg', (124, 134))	('S phase', 'CPA', (138, 145))	('upregulation', 'PosReg', (95, 107))	('SCC', 'Phenotype', 'HP:0002860', (150, 153))
560731	33469301	These results are in line with the discovery for laryngeal squamous cell carcinoma cells that ACTL6A cooperates with p63 to inhibit p21, a cell-cycle-regulatory gene, and epidermal growth factor (EGF) family ligand NRG1, and the loss of endogenous ACTL6A results in the accumulation of cells in G1/G07.	('ACTL6A', 'Gene', (248, 254))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (59, 82))	('NRG1', 'Gene', (215, 219))	('ACTL6A', 'Gene', (94, 100))	('squamous cell carcinoma', 'Disease', (59, 82))	('p21', 'Gene', '1026', (132, 135))	('NRG1', 'Gene', '3084', (215, 219))	('cells in G1/G07', 'CPA', (286, 301))	('p63', 'Gene', (117, 120))	('p21', 'Gene', (132, 135))	('loss', 'Var', (229, 233))	('accumulation', 'PosReg', (270, 282))	('inhibit', 'NegReg', (124, 131))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (59, 82))	('p63', 'Gene', '8626', (117, 120))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))
560736	33469301	Ji et al revealed that ACTL6A overexpression promotes cellular proliferation in vitro and in vivo possibly through the direct interaction and stabilization of the transcriptional regulator YAP/TAZ.	('interaction', 'Interaction', (126, 137))	('YAP', 'Gene', (189, 192))	('ACTL6A', 'Gene', (23, 29))	('cellular proliferation', 'CPA', (54, 76))	('promotes', 'PosReg', (45, 53))	('YAP', 'Gene', '55249', (189, 192))	('TAZ', 'Gene', '6901', (193, 196))	('overexpression', 'Var', (30, 44))	('TAZ', 'Gene', (193, 196))
560739	33469301	Our results showed that knockdown of ACTL6A led to suppression of cell cycle progression by inhibiting the expression of cyclin D1 and CDK2, while changes in the expression of S6K1 and pS6 had the same tendency.	('cyclin D1', 'Gene', (121, 130))	('CDK2', 'Gene', '1017', (135, 139))	('cyclin D1', 'Gene', '595', (121, 130))	('pS6', 'Gene', (185, 188))	('ACTL6A', 'Gene', (37, 43))	('suppression', 'NegReg', (51, 62))	('cell cycle progression', 'CPA', (66, 88))	('expression', 'MPA', (107, 117))	('pS6', 'Gene', '338413', (185, 188))	('CDK2', 'Gene', (135, 139))	('knockdown', 'Var', (24, 33))	('inhibiting', 'NegReg', (92, 102))
560741	33469301	Thus, it is reasonable to speculate that deletion of ACTL6A leads to suppression of the S6K1/pS6 pathway, resulting in a delay in entry into S phase in ESCC.	('entry into S phase in ESCC', 'MPA', (130, 156))	('suppression', 'NegReg', (69, 80))	('ACTL6A', 'Gene', (53, 59))	('pS6', 'Gene', (93, 96))	('deletion', 'Var', (41, 49))	('delay', 'NegReg', (121, 126))	('pS6', 'Gene', '338413', (93, 96))	('SCC', 'Phenotype', 'HP:0002860', (153, 156))
560743	33469301	In addition, liver-specific S6 knockout in mice led to severe cell cycle arrest, indicating the critical role of S6 in cell cycle progression.	('mice', 'Species', '10090', (43, 47))	('arrest', 'Disease', 'MESH:D006323', (73, 79))	('arrest', 'Disease', (73, 79))	('knockout', 'Var', (31, 39))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (62, 79))
560744	33469301	In conclusion, the present study indicates that a clinical model including the ACTL6A expression level may predict patient outcome more efficiently than a model that does not include ACTL6A expression, and mechanistic studies demonstrated that ACTL6A may function to promote oncogenesis and growth in vitro and in vivo via phosphorylation of S6.	('promote', 'PosReg', (267, 274))	('oncogenesis', 'CPA', (275, 286))	('growth', 'CPA', (291, 297))	('ACTL6A', 'Var', (244, 250))	('patient', 'Species', '9606', (115, 122))	('phosphorylation', 'Var', (323, 338))
560747	29193723	We found TRAF6 was overexpressed in human SCCHN tissues, and high TRAF6 expression was associated with lymphatic metastasis and resulted in poor prognosis in patients with SCCHN.	('TRAF6', 'Gene', (66, 71))	('lymphatic metastasis', 'CPA', (103, 123))	('high', 'Var', (61, 65))	('SCCHN', 'Disease', (172, 177))	('expression', 'MPA', (72, 82))	('associated with', 'Reg', (87, 102))	('patients', 'Species', '9606', (158, 166))	('human', 'Species', '9606', (36, 41))
560748	29193723	Moreover, the expression of Vimentin, Slug and N-cadherin was down-regulated and that of E-cadherin was elevated after TRAF6 knockdown but decreased by transforming growth factor beta 1 (TGF-beta1) and CAL27 similar to mesenchymal cells formed after TGF-beta1 induction.	('CAL27', 'CellLine', 'CVCL:1107', (202, 207))	('knockdown', 'Var', (125, 134))	('Slug', 'Protein', (38, 42))	('TGF-beta1', 'Gene', '7040', (187, 196))	('TGF-beta1', 'Gene', '7040', (250, 259))	('transforming growth factor beta 1', 'Gene', (152, 185))	('Vimentin', 'Protein', (28, 36))	('down-regulated', 'NegReg', (62, 76))	('elevated', 'PosReg', (104, 112))	('E-cadherin', 'Gene', (89, 99))	('E-cadherin', 'Gene', '999', (89, 99))	('N-cadherin', 'Gene', (47, 57))	('N-cadherin', 'Gene', '1000', (47, 57))	('expression', 'MPA', (14, 24))	('decreased', 'NegReg', (139, 148))	('TGF-beta1', 'Gene', (187, 196))	('TRAF6', 'Gene', (119, 124))	('TGF-beta1', 'Gene', (250, 259))	('transforming growth factor beta 1', 'Gene', '7040', (152, 185))
560749	29193723	Flow cytometry showed TRAF6 knockdown reduced ALDH1-positive cancer stem cells.	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('reduced', 'NegReg', (38, 45))	('cancer', 'Disease', (61, 67))	('TRAF6', 'Gene', (22, 27))	('ALDH1-positive', 'Protein', (46, 60))	('knockdown', 'Var', (28, 37))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))
560761	29193723	TRAF6 is unique because it can activate multiple signalling pathways, such as NF-kappaB signalling 19, 20, 21.	('NF-kappaB', 'Gene', '4790', (78, 87))	('TRAF6', 'Var', (0, 5))	('activate', 'PosReg', (31, 39))	('NF-kappaB', 'Gene', (78, 87))
560764	29193723	TRAF6 knockdown can significantly decrease invasion and metastasis abilities in melanomas and lung cancer 23, 27.	('melanomas', 'Phenotype', 'HP:0002861', (80, 89))	('metastasis abilities in melanomas and lung cancer', 'Disease', 'MESH:D009362', (56, 105))	('decrease', 'NegReg', (34, 42))	('knockdown', 'Var', (6, 15))	('lung cancer', 'Phenotype', 'HP:0100526', (94, 105))	('TRAF6', 'Gene', (0, 5))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
560765	29193723	Recent studies have shown that high TRAF6 expression is associated with a poor prognosis in glioma and colon cancer 28, 29.	('glioma', 'Disease', 'MESH:D005910', (92, 98))	('colon cancer', 'Disease', (103, 115))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('expression', 'MPA', (42, 52))	('glioma', 'Phenotype', 'HP:0009733', (92, 98))	('glioma', 'Disease', (92, 98))	('TRAF6', 'Gene', (36, 41))	('colon cancer', 'Phenotype', 'HP:0003003', (103, 115))	('colon cancer', 'Disease', 'MESH:D015179', (103, 115))	('high', 'Var', (31, 35))
560769	29193723	In addition, increased TRAF6 expression is closely associated with lymph node metastasis in patients with SCCHN, and log-rank analysis showed that high TRAF6 expression in the overall survival of patients with SCCHN represents poor prognosis.	('expression', 'MPA', (158, 168))	('TRAF6', 'Gene', (152, 157))	('TRAF6', 'Gene', (23, 28))	('lymph node metastasis', 'CPA', (67, 88))	('patients', 'Species', '9606', (196, 204))	('high', 'Var', (147, 151))	('associated', 'Reg', (51, 61))	('patients', 'Species', '9606', (92, 100))	('expression', 'MPA', (29, 39))	('increased', 'PosReg', (13, 22))
560807	29193723	In addition, previous studies reported that patients with high TRAF6 expression have a worse survival rate in glioma and colon cancers 28, 29.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('glioma', 'Disease', (110, 116))	('patients', 'Species', '9606', (44, 52))	('colon cancers', 'Phenotype', 'HP:0003003', (121, 134))	('worse', 'NegReg', (87, 92))	('colon cancers', 'Disease', 'MESH:D015179', (121, 134))	('colon cancer', 'Phenotype', 'HP:0003003', (121, 133))	('glioma', 'Phenotype', 'HP:0009733', (110, 116))	('cancers', 'Phenotype', 'HP:0002664', (127, 134))	('glioma', 'Disease', 'MESH:D005910', (110, 116))	('high', 'Var', (58, 62))	('TRAF6', 'Gene', (63, 68))	('colon cancers', 'Disease', (121, 134))
560808	29193723	As expected, log-rank analysis showed that the overall survival rate of patients with high TRAF6 expression levels presented poor prognosis (P = 0.017, Fig.	('patients', 'Species', '9606', (72, 80))	('expression', 'MPA', (97, 107))	('TRAF6', 'Gene', (91, 96))	('high', 'Var', (86, 90))
560812	29193723	Interestingly, EMT-related proteins N-cadherin, Vimentin and Slug were significantly reduced after transfecting with TRAF6 siRNA (Figs 2B and S2E).	('EMT-related', 'CPA', (15, 26))	('TRAF6', 'Gene', (117, 122))	('N-cadherin', 'Gene', '1000', (36, 46))	('Vimentin', 'Protein', (48, 56))	('Slug', 'CPA', (61, 65))	('transfecting', 'Var', (99, 111))	('reduced', 'NegReg', (85, 92))	('N-cadherin', 'Gene', (36, 46))
560819	29193723	Overall, TRAF6 knockdown effectively reduces the invasion ability and the EMT process in human SCCHN cells in vitro.	('human', 'Species', '9606', (89, 94))	('knockdown', 'Var', (15, 24))	('TRAF6', 'Gene', (9, 14))	('invasion ability', 'CPA', (49, 65))	('EMT process in human', 'CPA', (74, 94))	('reduces', 'NegReg', (37, 44))
560823	29193723	Furthermore, TRAF6 is unique because it can activate multiple signalling pathways including NF-kappaB signalling 19, 20, 21.	('NF-kappaB', 'Gene', '4790', (92, 101))	('activate', 'PosReg', (44, 52))	('NF-kappaB', 'Gene', (92, 101))	('TRAF6', 'Var', (13, 18))
560847	29193723	Additionally, some studies have shown that high TRAF6 expression represented a poor prognosis in glioma and colon cancers 28, 29.	('TRAF6', 'Gene', (48, 53))	('expression', 'MPA', (54, 64))	('cancers', 'Phenotype', 'HP:0002664', (114, 121))	('high', 'Var', (43, 47))	('colon cancers', 'Disease', (108, 121))	('glioma', 'Disease', (97, 103))	('colon cancers', 'Phenotype', 'HP:0003003', (108, 121))	('colon cancers', 'Disease', 'MESH:D015179', (108, 121))	('colon cancer', 'Phenotype', 'HP:0003003', (108, 120))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('glioma', 'Disease', 'MESH:D005910', (97, 103))	('glioma', 'Phenotype', 'HP:0009733', (97, 103))
560848	29193723	The overall survival rate of patients with high TRAF6 expression represents a poor prognosis, which was consistent with the researches mentioned above.	('TRAF6', 'Gene', (48, 53))	('patients', 'Species', '9606', (29, 37))	('high', 'Var', (43, 47))
560855	29193723	Moreover, our results showed that TRAF6 participated in the NF-kappaB activation, which indicated that TRAF6 may play a key role in the CSC regulation through NF-kappaB signalling in human SCCHN cells.	('NF-kappaB', 'Gene', '4790', (60, 69))	('TRAF6', 'Var', (103, 108))	('NF-kappaB', 'Gene', (60, 69))	('human', 'Species', '9606', (183, 188))	('NF-kappaB', 'Gene', '4790', (159, 168))	('activation', 'PosReg', (70, 80))	('NF-kappaB', 'Gene', (159, 168))
560860	29193723	Interestingly, EMT-related proteins N-cadherin, Vimentin and Slug were significantly reduced after transfecting with TRAF6 siRNA, and the expression of E-cadherin was elevated.	('EMT-related', 'CPA', (15, 26))	('TRAF6', 'Gene', (117, 122))	('E-cadherin', 'Gene', (152, 162))	('N-cadherin', 'Gene', '1000', (36, 46))	('Vimentin', 'Protein', (48, 56))	('E-cadherin', 'Gene', '999', (152, 162))	('elevated', 'PosReg', (167, 175))	('Slug', 'CPA', (61, 65))	('expression', 'MPA', (138, 148))	('reduced', 'NegReg', (85, 92))	('transfecting', 'Var', (99, 111))	('N-cadherin', 'Gene', (36, 46))
560870	29193723	Therefore, inhibition of TRAF6 may be an effective approach to eliminate CSCs, reversing the EMT phenotype and consequently eradicating cancer cells to improve the prognosis of patients with head and neck cancer.	('cancer', 'Disease', 'MESH:D009369', (205, 211))	('TRAF6', 'Gene', (25, 30))	('neck cancer', 'Disease', (200, 211))	('cancer', 'Disease', (205, 211))	('EMT phenotype', 'CPA', (93, 106))	('patients', 'Species', '9606', (177, 185))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('head and neck cancer', 'Phenotype', 'HP:0012288', (191, 211))	('reversing', 'Reg', (79, 88))	('cancer', 'Disease', (136, 142))	('inhibition', 'Var', (11, 21))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('neck cancer', 'Disease', 'MESH:D006258', (200, 211))	('improve', 'PosReg', (152, 159))	('CSCs', 'Disease', (73, 77))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
560879	27822069	Furthermore, patients with high stromal SPARC reactivity in biopsy specimens such as transbronchial lung biopsy or surgical specimens tended to respond better to nab-paclitaxel.	('SPARC', 'Gene', '6678', (40, 45))	('respond', 'MPA', (144, 151))	('nab', 'Chemical', '-', (162, 165))	('SPARC', 'Gene', (40, 45))	('patients', 'Species', '9606', (13, 21))	('paclitaxel', 'Chemical', 'MESH:D017239', (166, 176))	('high', 'Var', (27, 31))	('better', 'PosReg', (152, 158))
560893	27822069	Expression of SPARC is correlated with prognosis in breast cancer cases, and high SPARC stromal reactivity is correlated with improved survival in pancreatic cancer cases.	('pancreatic cancer', 'Disease', 'MESH:D010190', (147, 164))	('SPARC', 'Gene', (82, 87))	('improved', 'PosReg', (126, 134))	('SPARC', 'Gene', '6678', (14, 19))	('high', 'Var', (77, 81))	('breast cancer', 'Disease', 'MESH:D001943', (52, 65))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('breast cancer', 'Disease', (52, 65))	('correlated', 'Reg', (23, 33))	('SPARC', 'Gene', (14, 19))	('breast cancer', 'Phenotype', 'HP:0003002', (52, 65))	('pancreatic cancer', 'Phenotype', 'HP:0002894', (147, 164))	('SPARC', 'Gene', '6678', (82, 87))	('pancreatic cancer', 'Disease', (147, 164))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
560916	27822069	Immunostaining positivity was significantly higher in patients with Brinkman index (BI) >=400 (80/98, 82%) compared to those with BI <400 (65/102, 64%; P=0.01).	('Immunostaining positivity', 'MPA', (0, 25))	('Brinkman', 'Disease', (68, 76))	('higher', 'PosReg', (44, 50))	('patients', 'Species', '9606', (54, 62))	('>=400', 'Var', (88, 93))
560918	27822069	Differences according to gender, pathological stage, EGFR mutation status, and lymphatic invasion were not statistically significant.	('EGFR', 'Gene', (53, 57))	('EGFR', 'Gene', '1956', (53, 57))	('mutation', 'Var', (58, 66))
560921	27822069	Among the patients in stage I, those with positive staining for stromal SPARC had significantly shorter survival than negative staining (log-rank P=0.05, Figure 2).	('survival', 'MPA', (104, 112))	('shorter', 'NegReg', (96, 103))	('SPARC', 'Gene', '6678', (72, 77))	('positive staining', 'Var', (42, 59))	('SPARC', 'Gene', (72, 77))	('patients', 'Species', '9606', (10, 18))
560948	27822069	A high level of caveolin-1, a major component of caveolae, in tumor stroma was reported to be associated with improved response to nab-paclitaxel in conjunction with carboplatin and improved survival in NSCLC patients.	('NSCLC', 'Disease', (203, 208))	('nab', 'Chemical', '-', (131, 134))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('paclitaxel', 'Chemical', 'MESH:D017239', (135, 145))	('NSCLC', 'Disease', 'MESH:D002289', (203, 208))	('improved', 'PosReg', (182, 190))	('improved', 'PosReg', (110, 118))	('response', 'MPA', (119, 127))	('survival', 'MPA', (191, 199))	('high', 'Var', (2, 6))	('tumor stroma', 'Disease', 'MESH:D009369', (62, 74))	('caveolin-1', 'Gene', (16, 26))	('patients', 'Species', '9606', (209, 217))	('tumor stroma', 'Disease', (62, 74))	('NSCLC', 'Phenotype', 'HP:0030358', (203, 208))	('caveolin-1', 'Gene', '857', (16, 26))	('carboplatin', 'Chemical', 'MESH:D016190', (166, 177))
560955	26760963	GPR171 expression enhances proliferation and metastasis of lung cancer cells G protein-coupled receptors (GPCRs) are among the most significant therapeutic targets and some of them promote the growth and metastasis of cancer.	('metastasis of lung cancer', 'Disease', (45, 70))	('metastasis of cancer', 'Disease', (204, 224))	('proliferation', 'CPA', (27, 40))	('GPCR', 'Gene', (106, 110))	('metastasis of cancer', 'Disease', 'MESH:D009362', (204, 224))	('lung cancer', 'Phenotype', 'HP:0100526', (59, 70))	('metastasis of lung cancer', 'Disease', 'MESH:D009362', (45, 70))	('promote', 'PosReg', (181, 188))	('GPCR', 'Gene', '442206', (106, 110))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('GPR171', 'Gene', (0, 6))	('expression', 'Var', (7, 17))	('enhances', 'PosReg', (18, 26))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))	('GPR171', 'Gene', '29909', (0, 6))
560956	26760963	Here, we show that an increase in the levels of GPR171 is crucial for lung cancer tumor progression in vitro and in vivo.	('GPR171', 'Var', (48, 54))	('increase', 'PosReg', (22, 30))	('lung cancer', 'Phenotype', 'HP:0100526', (70, 81))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('lung cancer tumor', 'Disease', (70, 87))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('lung cancer tumor', 'Disease', 'MESH:D008175', (70, 87))
560957	26760963	Immunostaining of clinical samples indicated that GPR171 was overexpressed in 46.8% of lung carcinoma tissues.	('GPR171', 'Var', (50, 56))	('clinical samples', 'Species', '191496', (18, 34))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('lung carcinoma', 'Disease', 'MESH:D008175', (87, 101))	('lung carcinoma', 'Disease', (87, 101))	('overexpressed', 'PosReg', (61, 74))
560960	26760963	Notably, inhibition of GPR171 synergistically enhanced the tumoricidal activity of an epidermal growth factor receptor (EGFR) inhibitor in lung cancer cells.	('lung cancer', 'Disease', (139, 150))	('tumor', 'Disease', (59, 64))	('epidermal growth factor receptor', 'Gene', (86, 118))	('lung cancer', 'Disease', 'MESH:D008175', (139, 150))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('GPR171', 'Gene', (23, 29))	('enhanced', 'PosReg', (46, 54))	('EGFR', 'Gene', '1956', (120, 124))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('epidermal growth factor receptor', 'Gene', '1956', (86, 118))	('lung cancer', 'Phenotype', 'HP:0100526', (139, 150))	('inhibition', 'Var', (9, 19))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('EGFR', 'Gene', (120, 124))
560970	26760963	The disappointing response to EGFR inhibitors among Caucasians is likely related to mutations in the EGFR.	('EGFR', 'Gene', (30, 34))	('EGFR', 'Gene', '1956', (101, 105))	('EGFR', 'Gene', (101, 105))	('mutations', 'Var', (84, 93))	('EGFR', 'Gene', '1956', (30, 34))
560980	26760963	For example, ERBB2 (HER2), a well-known proto-oncogene, is overexpressed owing to gene amplification in 25-30% of invasive ductal breast carcinomas.	('gene amplification', 'Var', (82, 100))	('carcinomas', 'Phenotype', 'HP:0030731', (137, 147))	('invasive ductal breast carcinomas', 'Disease', (114, 147))	('overexpressed', 'PosReg', (59, 72))	('invasive ductal breast carcinomas', 'Disease', 'MESH:D018270', (114, 147))	('ERBB2', 'Gene', '2064', (13, 18))	('breast carcinomas', 'Phenotype', 'HP:0003002', (130, 147))	('ERBB2', 'Gene', (13, 18))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('HER2', 'Gene', (20, 24))	('HER2', 'Gene', '2064', (20, 24))
560992	26760963	The immunohistochemisty analysis showed that GPR171 was expressed in various lung cancer tissues, but was rarely detected in normal bronchial epithelium (Table 1).	('lung cancer', 'Phenotype', 'HP:0100526', (77, 88))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('GPR171', 'Var', (45, 51))	('lung cancer', 'Disease', 'MESH:D008175', (77, 88))	('lung cancer', 'Disease', (77, 88))
561003	26760963	To determine if GPR171 has a role in cellular proliferation, we examined the growth rates of an NSCLC cancer cell line, Calu-6 (lung anaplastic carcinoma), expressing one of two different small hairpin RNAs (shRNAs) against GPR171 or control shRNA.	('Calu-6', 'CellLine', 'CVCL:0236', (120, 126))	('NSCLC cancer', 'Disease', 'MESH:D009369', (96, 108))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('lung anaplastic carcinoma', 'Disease', (128, 153))	('SCLC', 'Phenotype', 'HP:0030357', (97, 101))	('GPR171', 'Var', (224, 230))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('NSCLC', 'Phenotype', 'HP:0030358', (96, 101))	('NSCLC cancer', 'Disease', (96, 108))	('lung anaplastic carcinoma', 'Disease', 'MESH:D002277', (128, 153))
561004	26760963	GPR171 silencing with shRNA #1 or #2 significantly suppressed cell proliferation, reducing the growth of Calu-6 cells to 32.7% (p = 8.4x10-4) and 16.7% (p = 2.2x10-4) of that in control shRNA cells, respectively, 4 days after infection (Figure 2A).	('infection', 'Disease', 'MESH:D007239', (226, 235))	('reducing', 'NegReg', (82, 90))	('growth', 'MPA', (95, 101))	('cell proliferation', 'CPA', (62, 80))	('suppressed', 'NegReg', (51, 61))	('Calu-6', 'CellLine', 'CVCL:0236', (105, 111))	('GPR171', 'Gene', (0, 6))	('silencing', 'Var', (7, 16))	('infection', 'Disease', (226, 235))
561006	26760963	Consistent with Calu-6 cell results, A549 cells expressing GPR171 siRNA #1 or #2 grew ~30% (p = 6.3x10-3) and ~65% (p = 3.3x10-3) less than cells expressing control siRNA 3 days after transfection (Figure 2B).	('GPR171 siRNA #1', 'Var', (59, 74))	('less', 'NegReg', (130, 134))	('Calu-6', 'CellLine', 'CVCL:0236', (16, 22))	('grew', 'CPA', (81, 85))	('A549', 'CellLine', 'CVCL:0023', (37, 41))
561007	26760963	As expected, overexpression of GPR171 in WI-38 and IMR-90 normal lung fibroblast cell lines enhanced cell proliferation, increasing growth by 47.1% (p = 0.014) and 35.2% (p = 6.4x10-3), respectively, compared with that of cells expressing control siRNA (Figure 2C).	('GPR171', 'Var', (31, 37))	('overexpression', 'PosReg', (13, 27))	('IMR-90', 'CellLine', 'CVCL:0347', (51, 57))	('increasing', 'PosReg', (121, 131))	('growth', 'MPA', (132, 138))	('cell proliferation', 'CPA', (101, 119))	('enhanced', 'PosReg', (92, 100))
561011	26760963	Treatment with the anti-GPR171 antibody attenuated the proliferation of Calu-6 cells (Figure 3A), reducing cell viability to 28.2% (p = 7.2x10-4) of that in cells treated with control IgG after 4 days of treatment.	('reducing', 'NegReg', (98, 106))	('proliferation', 'CPA', (55, 68))	('Calu-6', 'CellLine', 'CVCL:0236', (72, 78))	('cell viability', 'CPA', (107, 121))	('IgG', 'Gene', '16059', (184, 187))	('IgG', 'Gene', (184, 187))	('attenuated', 'NegReg', (40, 50))	('anti-GPR171', 'Var', (19, 30))
561014	26760963	As expected, anti-GPR171 antibody treatment resulted in significant inhibition of Calu-6 xenograft tumors (p=0.026; Figure 3B and 3C).	('anti-GPR171', 'Var', (13, 24))	('Calu-6', 'CellLine', 'CVCL:0236', (82, 88))	('xenograft tumors', 'Disease', (89, 105))	('inhibition', 'NegReg', (68, 78))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('xenograft tumors', 'Disease', 'MESH:D009369', (89, 105))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))
561015	26760963	The inhibition of cancer cell proliferation observed after knocking down GPR171 with shRNA or siRNA, or inhibiting it with a blocking antibody suggests that GPR171 is a promising anti-cancer target in lung cancer.	('cancer', 'Disease', (184, 190))	('GPR171', 'Gene', (73, 79))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('lung cancer', 'Disease', (201, 212))	('knocking', 'Var', (59, 67))	('lung cancer', 'Disease', 'MESH:D008175', (201, 212))	('cancer', 'Phenotype', 'HP:0002664', (184, 190))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('cancer', 'Disease', 'MESH:D009369', (206, 212))	('lung cancer', 'Phenotype', 'HP:0100526', (201, 212))	('cancer', 'Disease', (206, 212))	('cancer', 'Disease', 'MESH:D009369', (184, 190))	('inhibition', 'NegReg', (4, 14))	('cancer', 'Disease', (18, 24))	('cancer', 'Disease', 'MESH:D009369', (18, 24))
561016	26760963	To our knowledge, this is the first demonstration that GPR171 plays a tumor-promoting role by inducing cancer cell proliferation.	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('inducing', 'PosReg', (94, 102))	('tumor', 'Disease', (70, 75))	('GPR171', 'Var', (55, 61))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
561021	26760963	Indeed, we found that siRNA-mediated depletion of GPR171 in A549 cells caused approximately an 81% decrease in invasion (p = 2.0x10-6) and an 87% reduction in migration (p = 1.0x10-7) (Figure 4A).	('depletion', 'Var', (37, 46))	('migration', 'CPA', (159, 168))	('GPR171', 'Gene', (50, 56))	('decrease', 'NegReg', (99, 107))	('invasion', 'CPA', (111, 119))	('A549', 'CellLine', 'CVCL:0023', (60, 64))	('reduction', 'NegReg', (146, 155))
561022	26760963	Similarly, we found that invasion and migration were reduced by 35.7% (p = 2.6x10-6) and 44.7% (p = 4.1x10-6), respectively, in GPR171-ablated Calu-6 cells compared with control cells (Figure 4B).	('reduced', 'NegReg', (53, 60))	('Calu-6', 'CellLine', 'CVCL:0236', (143, 149))	('GPR171-ablated', 'Var', (128, 142))	('invasion', 'CPA', (25, 33))
561025	26760963	EGFR has the most frequent mutation rate (10-30%), compared with ALK (5%) and BRAF (2%) in NSCLC.	('NSCLC', 'Disease', 'MESH:D002289', (91, 96))	('ALK', 'Gene', '238', (65, 68))	('BRAF', 'Gene', '673', (78, 82))	('EGFR', 'Gene', (0, 4))	('NSCLC', 'Phenotype', 'HP:0030358', (91, 96))	('BRAF', 'Gene', (78, 82))	('mutation', 'Var', (27, 35))	('ALK', 'Gene', (65, 68))	('SCLC', 'Phenotype', 'HP:0030357', (92, 96))	('NSCLC', 'Disease', (91, 96))	('EGFR', 'Gene', '1956', (0, 4))
561032	26760963	To test the efficacy of combined treatment with inhibitors of GPR171 and EGFR, we treated Calu-6 cells with an anti-GPR171 antibody in the presence or absence of AG1478, an EGFR-specific small molecule inhibitor.	('EGFR', 'Gene', '1956', (73, 77))	('Calu-6', 'CellLine', 'CVCL:0236', (90, 96))	('EGFR', 'Gene', (73, 77))	('EGFR', 'Gene', '1956', (173, 177))	('anti-GPR171', 'Var', (111, 122))	('AG1478', 'Chemical', 'MESH:C101044', (162, 168))	('EGFR', 'Gene', (173, 177))
561033	26760963	Treatment of cells with the anti-GPR171 antibody or AG1478 alone reduced cell viability by 23.0% (p = 0.019) and 27.3% (p = 9.3x10-3), respectively (Figure 5B).	('AG1478', 'Gene', (52, 58))	('reduced', 'NegReg', (65, 72))	('AG1478', 'Chemical', 'MESH:C101044', (52, 58))	('cell viability', 'CPA', (73, 87))	('anti-GPR171', 'Var', (28, 39))
561034	26760963	Combined treatment anti-GPR171 antibody and AG1478 led to a 66.3% reduction in cell viability (p = 1.5x10-3), indicating a synergistic effect.	('AG1478', 'Chemical', 'MESH:C101044', (44, 50))	('cell viability', 'CPA', (79, 93))	('AG1478', 'Var', (44, 50))	('antibody', 'Var', (31, 39))	('anti-GPR171 antibody', 'Var', (19, 39))	('reduction', 'NegReg', (66, 75))
561035	26760963	Collectively, these findings indicate that combined inhibition of GPR171 and EGFR may be a promising strategy for lung cancer treatment, reflecting the fact that GPR171 induces tumorigenesis in an EGFR-independent manner.	('tumor', 'Disease', (177, 182))	('lung cancer', 'Disease', 'MESH:D008175', (114, 125))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('lung cancer', 'Disease', (114, 125))	('EGFR', 'Gene', '1956', (197, 201))	('EGFR', 'Gene', '1956', (77, 81))	('induces', 'Reg', (169, 176))	('lung cancer', 'Phenotype', 'HP:0100526', (114, 125))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('GPR171', 'Var', (162, 168))	('EGFR', 'Gene', (77, 81))	('EGFR', 'Gene', (197, 201))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
561039	26760963	To date, inhibition of EGFR has been the most widely used targeted therapy in lung cancer.	('lung cancer', 'Disease', (78, 89))	('lung cancer', 'Phenotype', 'HP:0100526', (78, 89))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('EGFR', 'Gene', '1956', (23, 27))	('lung cancer', 'Disease', 'MESH:D008175', (78, 89))	('EGFR', 'Gene', (23, 27))	('inhibition', 'Var', (9, 19))
561040	26760963	Our findings indicate that inhibition of GPR171 may be an important strategy for alternative or combinatorial therapy with EGFR inhibitors such as gefitinib, erlotinib, and cetuximab.	('EGFR', 'Gene', (123, 127))	('gefitinib', 'Chemical', 'MESH:D000077156', (147, 156))	('cetuximab', 'Chemical', 'MESH:D000068818', (173, 182))	('inhibition', 'Var', (27, 37))	('erlotinib', 'Chemical', 'MESH:D000069347', (158, 167))	('EGFR', 'Gene', '1956', (123, 127))	('GPR171', 'Gene', (41, 47))
561042	26760963	Depletion of GPR171 causes an increase in food intake, providing a provocative link to the lung cancer-protective effect of being overweight suggested by meta-analyses.	('lung cancer', 'Phenotype', 'HP:0100526', (91, 102))	('overweight', 'Phenotype', 'HP:0025502', (130, 140))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('Depletion', 'Var', (0, 9))	('lung cancer', 'Disease', 'MESH:D008175', (91, 102))	('food intake', 'MPA', (42, 53))	('GPR171', 'Gene', (13, 19))	('increase', 'PosReg', (30, 38))	('lung cancer', 'Disease', (91, 102))
561043	26760963	In our experiments, the body weights of anti-GPR171 antibody-treated BALB/c nude mice were not significantly altered from those of control IgG-treated mice within a month (Supplementary Figure 3).	('mice', 'Species', '10090', (81, 85))	('mice', 'Species', '10090', (151, 155))	('IgG', 'Gene', '16059', (139, 142))	('anti-GPR171', 'Var', (40, 51))	('IgG', 'Gene', (139, 142))	('nude mice', 'Species', '10090', (76, 85))
561044	26760963	Considering that 7-12 weeks are required for significant body weight changes after GPR171 shRNA virus infection, we cannot exclude the possibility of a link between GPR171 and body weight.	('GPR171', 'Var', (83, 89))	('infection', 'Disease', 'MESH:D007239', (102, 111))	('infection', 'Disease', (102, 111))
561048	26760963	Therefore, the presence of BigLEN might be a key to the tumorigenesis of lung cancer, and activation of GPR171, as well as the level of GPR171, might contribute to tumorigenesis.	('BigLEN', 'Gene', '27344', (27, 33))	('lung cancer', 'Disease', 'MESH:D008175', (73, 84))	('tumor', 'Disease', (164, 169))	('activation', 'PosReg', (90, 100))	('BigLEN', 'Gene', (27, 33))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('tumor', 'Disease', (56, 61))	('presence', 'Var', (15, 23))	('contribute', 'Reg', (150, 160))	('lung cancer', 'Disease', (73, 84))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('lung cancer', 'Phenotype', 'HP:0100526', (73, 84))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('GPR171', 'Gene', (104, 110))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
561049	26760963	Further studies are needed to verify the mechanism by which GPR171 promotes proliferation and metastasis in lung cancer and to apply it for the development of a new anticancer drug.	('metastasis in lung cancer', 'Disease', (94, 119))	('promotes', 'PosReg', (67, 75))	('GPR171', 'Var', (60, 66))	('cancer', 'Disease', (169, 175))	('cancer', 'Disease', 'MESH:D009369', (113, 119))	('metastasis in lung cancer', 'Disease', 'MESH:D009362', (94, 119))	('proliferation', 'CPA', (76, 89))	('cancer', 'Disease', (113, 119))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('lung cancer', 'Phenotype', 'HP:0100526', (108, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('cancer', 'Disease', 'MESH:D009369', (169, 175))
561152	24591771	Preclinical studies have shown that patients with low tumor tissue RRM1 expression had greater median length of disease progression and median survival time than did patients with high tumor tissue RRM1 expression.	('RRM1', 'Gene', (67, 71))	('high tumor', 'Disease', (180, 190))	('survival time', 'CPA', (143, 156))	('low tumor', 'Disease', 'MESH:D009800', (50, 59))	('greater', 'PosReg', (87, 94))	('high tumor', 'Disease', 'MESH:D009369', (180, 190))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('low tumor', 'Disease', (50, 59))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))	('expression', 'Var', (72, 82))
561154	24591771	Some studies demonstrated that NSCLC patients with high BRCA1 mRNA expression had low efficacy with cisplatin therapy but high efficacy with the antimicrotubule drugs docetaxel and vinorelbine, which suggested that BRCA1 may be an important prognostic indicator and predictive factor for chemotherapy success in NSCLC patients.	('mRNA', 'MPA', (62, 66))	('NSCLC', 'Disease', (31, 36))	('BRCA1', 'Gene', (56, 61))	('high', 'Var', (51, 55))	('docetaxel', 'Chemical', 'MESH:D000077143', (167, 176))	('vinorelbine', 'Chemical', 'MESH:D000077235', (181, 192))
561157	24591771	Liver, kidney, and bone marrow function met the following requirements: blood transaminase <2 times normal, WBC >4.0 x 109/L, platelets >100 x 109/L, and serum creatinine <1.5 times normal.	('>100', 'Var', (136, 140))	('kidney', 'CPA', (7, 13))	('blood transaminase', 'MPA', (72, 90))	('serum creatinine', 'MPA', (154, 170))	('creatinine', 'Chemical', 'MESH:D003404', (160, 170))
561165	24591771	cDNA samples were stored at -20 C. Primers were designed based on the GeneBank sequence of RRM1 (AF107045), ERCC1 (AF001925), BRCA1 (U14680), and the housekeeping gene beta-actin (AY582799).	('U14680', 'Var', (133, 139))	('RRM1', 'Gene', (91, 95))	('BRCA1', 'Gene', (126, 131))	('AF107045', 'Var', (97, 105))	('beta-actin', 'Gene', '728378', (168, 178))	('ERCC1', 'Gene', (108, 113))	('beta-actin', 'Gene', (168, 178))	('AF001925', 'Var', (115, 123))
561238	30050313	Blockade of this pathway markedly attenuated CEP55-mediated proliferation, migration, invasion and epithelial-mesenchymal transition of ESCC cells.	('epithelial-mesenchymal transition of', 'CPA', (99, 135))	('Blockade', 'Var', (0, 8))	('CEP55', 'Gene', '55165', (45, 50))	('migration', 'CPA', (75, 84))	('CEP55', 'Gene', (45, 50))	('invasion', 'CPA', (86, 94))	('attenuated', 'NegReg', (34, 44))
561251	30050313	However, the prognostic value of CEP55 in patients with pN0 ESCC and its biological function in ESCC cells remain unclear.	('pN0', 'Var', (56, 59))	('patients', 'Species', '9606', (42, 50))	('CEP55', 'Gene', '55165', (33, 38))	('CEP55', 'Gene', (33, 38))
561263	30050313	Five established human ESCC cell lines (Eca109, KYSE150, KYSE450, EC9706 and TE-1) and one normal human esophageal epithelial cell line (HET-1A) were purchased from the Cell Bank of the Shanghai Institute in China.	('KYSE150', 'Var', (48, 55))	('KYSE450', 'Var', (57, 64))	('human', 'Species', '9606', (17, 22))	('EC9706', 'CellLine', 'CVCL:E307', (66, 72))	('EC', 'Phenotype', 'HP:0011459', (66, 68))	('human', 'Species', '9606', (98, 103))
561302	30050313	Thus, Eca109 and KYSE450 cells were used to knock down CEP55 with shRNA.	('knock down', 'Var', (44, 54))	('CEP55', 'Gene', '55165', (55, 60))	('CEP55', 'Gene', (55, 60))
561307	30050313	Clonogenic assays showed that CEP55 knockdown abrogated the colony-formation ability of Eca109 and KYSE450 cells (P<0.001; Figure 3Ba and Bb).	('CEP55', 'Gene', '55165', (30, 35))	('colony-formation ability', 'CPA', (60, 84))	('CEP55', 'Gene', (30, 35))	('abrogated', 'NegReg', (46, 55))	('knockdown', 'Var', (36, 45))
561314	30050313	In addition, the invasive ability was altered with the changed expression of CEP55 in ESCC cells (P<0.01; Figure 4Ba-d).	('altered', 'Reg', (38, 45))	('CEP55', 'Gene', '55165', (77, 82))	('changed', 'Reg', (55, 62))	('CEP55', 'Gene', (77, 82))	('invasive ability', 'CPA', (17, 33))	('expression', 'Var', (63, 73))
561322	30050313	Administration of LY294002 (20 microM), wortmannin (5 microM) and MK2206 (1 microM) markedly decreased the proliferation of ESCC cells.	('wortmannin', 'Chemical', 'MESH:D000077191', (40, 50))	('proliferation', 'CPA', (107, 120))	('LY294002', 'Var', (18, 26))	('MK2206', 'Chemical', 'MESH:C548887', (66, 72))	('decreased', 'NegReg', (93, 102))	('MK2206', 'Var', (66, 72))	('LY294002', 'Chemical', 'MESH:C085911', (18, 26))	('ESCC', 'Disease', (124, 128))
561350	30050313	Thus, CEP55 knockdown decreased the expression of pAktS473 and pAktT308 and CEP55 overexpression increased the activation of AktS473 and AktT308.	('Akt', 'Gene', (51, 54))	('increased', 'PosReg', (97, 106))	('Akt', 'Gene', (125, 128))	('CEP55', 'Gene', '55165', (6, 11))	('knockdown', 'Var', (12, 21))	('CEP55', 'Gene', (6, 11))	('Akt', 'Gene', '207', (64, 67))	('Akt', 'Gene', '207', (137, 140))	('Akt', 'Gene', '207', (51, 54))	('Akt', 'Gene', (64, 67))	('Akt', 'Gene', (137, 140))	('Akt', 'Gene', '207', (125, 128))	('CEP55', 'Gene', '55165', (76, 81))	('CEP55', 'Gene', (76, 81))	('expression', 'MPA', (36, 46))	('decreased', 'NegReg', (22, 31))
561352	30050313	Next, LY294002, wortmannin and MK2206 were used to block the PI3K/Akt pathway.	('Akt', 'Gene', (66, 69))	('LY294002', 'Var', (6, 14))	('wortmannin', 'Chemical', 'MESH:D000077191', (16, 26))	('MK2206', 'Chemical', 'MESH:C548887', (31, 37))	('LY294002', 'Chemical', 'MESH:C085911', (6, 14))	('Akt', 'Gene', '207', (66, 69))	('MK2206', 'Var', (31, 37))
561378	28881601	The aberrant lncRNA expression profile has been reported to correlate to the development and survival in patients with different kinds of cancers, including LUSC, which reveals the potential of lncRNAs as prognostic cancer biomarkers.	('cancer', 'Disease', (138, 144))	('patients', 'Species', '9606', (105, 113))	('cancer', 'Phenotype', 'HP:0002664', (216, 222))	('aberrant', 'Var', (4, 12))	('correlate', 'Reg', (60, 69))	('cancers', 'Phenotype', 'HP:0002664', (138, 145))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('lncRNA expression profile', 'MPA', (13, 38))	('cancer', 'Disease', (216, 222))	('cancer', 'Disease', 'MESH:D009369', (216, 222))	('LUSC', 'Disease', (157, 161))	('cancers', 'Disease', (138, 145))	('cancer', 'Disease', 'MESH:D009369', (138, 144))	('cancers', 'Disease', 'MESH:D009369', (138, 145))
561397	28881601	However, only the expression of one key lncRNA, ZNF503-AS1, could be achieved in four datasets (GSE19188, GSE30219, GSE33479, GSE74706) provided ZNF503-AS1 expression data both in LUSC tissues and non-cancerous tissues, which showed the significantly lower level of ZNF503-AS1 in LUSC cases (Supplementary Table 1).	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('ZNF503-AS1', 'Gene', (145, 155))	('ZNF503-AS1', 'Gene', '253264', (48, 58))	('cancer', 'Disease', (201, 207))	('GSE74706', 'Var', (126, 134))	('lower', 'NegReg', (251, 256))	('ZNF503-AS1', 'Gene', '253264', (145, 155))	('ZNF503-AS1', 'Gene', (266, 276))	('LUSC', 'Disease', (280, 284))	('GSE30219', 'Var', (106, 114))	('GSE33479', 'Var', (116, 124))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('ZNF503-AS1', 'Gene', (48, 58))	('ZNF503-AS1', 'Gene', '253264', (266, 276))	('GSE19188', 'Var', (96, 104))
561406	28881601	Since the genetic alteration includes gene amplification, mRNA upregulation, mRNA downregulation and all types of mutations, the clinical value of these genetic alterations of lncRNAs are somehow too generalized for clinical setting.	('gene amplification', 'Var', (38, 56))	('mutations', 'Var', (114, 123))	('downregulation', 'NegReg', (82, 96))	('mRNA', 'MPA', (77, 81))	('clinical', 'Species', '191496', (129, 137))	('clinical', 'Species', '191496', (216, 224))	('upregulation', 'PosReg', (63, 75))	('mRNA', 'MPA', (58, 62))
561409	28881601	also reported that 12 in 133 aberrant miRNAs were related to OS of TCGA LUSC cohort.	('related', 'Reg', (50, 57))	('aberrant miRNAs', 'Var', (29, 44))	('OS', 'Chemical', '-', (61, 63))
561412	28881601	Furthermore, a 6-lncRNA signature expression pattern (RP11-111M22.3, TOPORS-AS1, RP11-383C5.4, AC078883.3, AC007566.10 and AC011526.1) was observed to be notably related to the OS of LUSC.	('AC078883.3', 'Var', (95, 105))	('RP11', 'Gene', '26121', (81, 85))	('OS', 'Chemical', '-', (177, 179))	('OS of LUSC', 'Disease', (177, 187))	('RP11', 'Gene', (54, 58))	('RP11', 'Gene', '26121', (54, 58))	('RP11', 'Gene', (81, 85))	('TOPORS-AS1', 'Gene', (69, 79))	('TOPORS-AS1', 'Gene', '100129250', (69, 79))	('related', 'Reg', (162, 169))
561415	28881601	carried out an array-based transcriptional analysis of lncRNAs in 603 cases of NSCLC by repurposing microarray probes from three Gene Expression Omnibus (GEO) database (GSE37745, GSE31210 and GSE50081).	('NSCLC', 'Disease', 'MESH:D002289', (79, 84))	('GSE37745', 'Var', (169, 177))	('GSE50081', 'Var', (192, 200))	('GSE31210', 'Var', (179, 187))	('NSCLC', 'Disease', (79, 84))
561416	28881601	They found that an expression pattern of eight lncRNAs was closely related to OS of NSCLC patients, including RP11-21L23.2, CTD-2358C21.4, RP11-94L15.2, GPR158-AS1, KCNK15-AS1, AC104134.2, RP11-701P16.5 and RP11-379F4.4.	('CTD', 'Gene', '1283', (124, 127))	('RP11', 'Gene', '26121', (207, 211))	('NSCLC', 'Disease', 'MESH:D002289', (84, 89))	('AS1', 'Gene', (172, 175))	('related', 'Reg', (67, 74))	('AC104134.2', 'Var', (177, 187))	('RP11', 'Gene', (139, 143))	('AS1', 'Gene', '5729', (160, 163))	('RP11', 'Gene', '26121', (110, 114))	('NSCLC', 'Disease', (84, 89))	('RP11', 'Gene', (207, 211))	('GPR158', 'Gene', '57512', (153, 159))	('RP11', 'Gene', '26121', (189, 193))	('CTD', 'Gene', (124, 127))	('OS', 'Chemical', '-', (78, 80))	('AS1', 'Gene', '5729', (172, 175))	('patients', 'Species', '9606', (90, 98))	('RP11', 'Gene', (110, 114))	('KCNK15', 'Gene', (165, 171))	('GPR158', 'Gene', (153, 159))	('AS1', 'Gene', (160, 163))	('RP11', 'Gene', '26121', (139, 143))	('RP11', 'Gene', (189, 193))	('KCNK15', 'Gene', '60598', (165, 171))
561419	28881601	A risk score model was built up on the basis of the expression data of eight lncRNAs (AK021595, BC030759, AK000053, AK124307, BC020384, AK022024, CR615992 and AF085995) in the training dataset (GSE30219).	('AK000053', 'Var', (106, 114))	('AK124307', 'Var', (116, 124))	('BC030759', 'Var', (96, 104))	('CR', 'Chemical', 'MESH:D002857', (146, 148))	('AF085995', 'Var', (159, 167))	('CR615992', 'Var', (146, 154))	('BC020384', 'Var', (126, 134))	('AK022024', 'Var', (136, 144))	('AK021595', 'Var', (86, 94))
561420	28881601	They further validated the association between these lncRNAs and survival of lung cancer patients in another three independent testing sets (GSE31210, GSE37745 and GSE19188).	('lung cancer', 'Phenotype', 'HP:0100526', (77, 88))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('lung cancer', 'Disease', 'MESH:D008175', (77, 88))	('patients', 'Species', '9606', (89, 97))	('GSE37745', 'Var', (151, 159))	('lung cancer', 'Disease', (77, 88))	('GSE19188', 'Var', (164, 172))	('GSE31210', 'Var', (141, 149))
561449	33976158	Furthermore, together with our study, analysis of two public datasets involving more than 1500 NSCLC patients showed that RFC4 gene amplification, and high RFC4 and NICD1 levels were tightly correlated with NSCLC metastasis, progression and poor patient prognosis.	('patient', 'Species', '9606', (246, 253))	('patients', 'Species', '9606', (101, 109))	('NSCLC', 'Disease', 'MESH:D002289', (95, 100))	('NSCLC', 'Phenotype', 'HP:0030358', (207, 212))	('amplification', 'Var', (132, 145))	('RFC4 gene', 'Gene', (122, 131))	('NSCLC', 'Phenotype', 'HP:0030358', (95, 100))	('NSCLC metastasis', 'Disease', 'MESH:D009362', (207, 223))	('NSCLC', 'Disease', (207, 212))	('patient', 'Species', '9606', (101, 108))	('NSCLC metastasis', 'Disease', (207, 223))	('correlated with', 'Reg', (191, 206))	('NSCLC', 'Disease', (95, 100))	('NSCLC', 'Disease', 'MESH:D002289', (207, 212))
561466	33976158	Canonical Notch signaling is initiated by interactions between specific ligands, such as JAG family members on signal-sending cells and their receptors, such as Notch family members on signal-receiving cells; proteolysis of Notch at the extracellular juxtamembrane site by ADAM10 and then cleavage at the transmembrane domain of Notch by gamma-secretase, then leads to the release of the intracellular domain of the Notch protein (NICD).	('ADAM10', 'Gene', '102', (273, 279))	('cleavage', 'Var', (289, 297))	('leads to', 'Reg', (360, 368))	('ADAM10', 'Gene', (273, 279))
561467	33976158	NICD translocates into the nucleus and binds to the DNA-binding transcription factor RBP-Jkappa, resulting in conversion of RBP-Jkappa from a transcriptional repressor to a transcriptional activator, leading to consequent transcription of key downstream targets such as HES1, HES5, and HEY1, which are transcriptional repressors important for suppressing the transcription of differentiation-promoting genes.	('transcription', 'MPA', (222, 235))	('HES1', 'Gene', (270, 274))	('HES5', 'Gene', '388585', (276, 280))	('RBP-Jkappa', 'Gene', '3516', (124, 134))	('HEY1', 'Gene', (286, 290))	('HES5', 'Gene', (276, 280))	('HEY1', 'Gene', '23462', (286, 290))	('RBP-Jkappa', 'Gene', (124, 134))	('transcription', 'MPA', (359, 372))	('conversion', 'Var', (110, 120))	('HES1', 'Gene', '3280', (270, 274))	('RBP-Jkappa', 'Gene', '3516', (85, 95))	('RBP-Jkappa', 'Gene', (85, 95))
561469	33976158	For example, CDK8 can be recruited to the NICD-RBP-Jkappa complex to phosphorylate NICD, and the E3 ligase FBXW7 subsequently recognizes the phosphorylated NICD to cause its ubiquitin-dependent degradation in the nucleus.	('ubiquitin-dependent degradation in the nucleus', 'MPA', (174, 220))	('FBXW7', 'Gene', '55294', (107, 112))	('cause', 'Reg', (164, 169))	('phosphorylated', 'Var', (141, 155))	('CDK8', 'Gene', (13, 17))	('RBP-Jkappa', 'Gene', '3516', (47, 57))	('FBXW7', 'Gene', (107, 112))	('RBP-Jkappa', 'Gene', (47, 57))	('CDK8', 'Gene', '1024', (13, 17))
561471	33976158	In this context, mutations in the heterodimer and PEST domains of Notch1, which confer ligand-independent cleavage of Notch1 and resistance to CDK8/FBXW7-mediated phosphorylation and degradation of NICD1, have been frequently identified in patients with acute T cell lymphoblastic leukemia (T-ALL).	('identified', 'Reg', (226, 236))	('acute T cell lymphoblastic leukemia', 'Disease', 'MESH:D054218', (254, 289))	('Notch1', 'Gene', (66, 72))	('acute T cell lymphoblastic leukemia', 'Disease', (254, 289))	('FBXW7', 'Gene', (148, 153))	('leukemia', 'Phenotype', 'HP:0001909', (281, 289))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (267, 289))	('Notch1', 'Gene', '4851', (66, 72))	('acute T cell lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (254, 289))	('FBXW7', 'Gene', '55294', (148, 153))	('Notch1', 'Gene', (118, 124))	('patients', 'Species', '9606', (240, 248))	('CDK8', 'Gene', (143, 147))	('Notch1', 'Gene', '4851', (118, 124))	('CDK8', 'Gene', '1024', (143, 147))	('mutations', 'Var', (17, 26))	('T cell lymphoblastic leukemia', 'Phenotype', 'HP:0006727', (260, 289))	('P', 'Chemical', 'MESH:D010758', (50, 51))
561472	33976158	In addition, inactivating mutations in FBXW7, which lead to NICD1 stabilization and overactivated Notch signaling, are present in colorectal, gastric, pancreatic, endometrial, and blood cancers.	('endometrial', 'Disease', (163, 174))	('inactivating mutations', 'Var', (13, 35))	('FBXW7', 'Gene', (39, 44))	('overactivated', 'PosReg', (84, 97))	('blood cancers', 'Disease', 'MESH:D007022', (180, 193))	('cancers', 'Phenotype', 'HP:0002664', (186, 193))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('gastric', 'Disease', (142, 149))	('colorectal', 'Disease', (130, 140))	('blood cancers', 'Disease', (180, 193))	('Notch signaling', 'MPA', (98, 113))	('NICD1 stabilization', 'MPA', (60, 79))	('blood cancers', 'Phenotype', 'HP:0001909', (180, 193))	('pancreatic', 'Disease', 'MESH:D010195', (151, 161))	('FBXW7', 'Gene', '55294', (39, 44))	('pancreatic', 'Disease', (151, 161))
561480	33976158	The overexpression of NICD1 consistently conferred potent metastatic and stemness properties to NSCLC cells, as NICD1-overexpressing cells exhibited prominent systemic metastasis and lung metastases when they were injected intracardially and intravenously, respectively, and were able to form tumors when as few as 5 x 103 cells were subcutaneously inoculated (Fig.	('metastatic', 'CPA', (58, 68))	('NICD1-overexpressing', 'PosReg', (112, 132))	('tumors', 'Phenotype', 'HP:0002664', (293, 299))	('NSCLC', 'Disease', (96, 101))	('lung metastases', 'Disease', (183, 198))	('lung metastases', 'Disease', 'MESH:D009362', (183, 198))	('tumor', 'Phenotype', 'HP:0002664', (293, 298))	('NSCLC', 'Disease', 'MESH:D002289', (96, 101))	('systemic metastasis', 'CPA', (159, 178))	('tumors', 'Disease', 'MESH:D009369', (293, 299))	('stemness properties', 'CPA', (73, 92))	('NICD1-overexpressing', 'Var', (112, 132))	('tumors', 'Disease', (293, 299))	('NSCLC', 'Phenotype', 'HP:0030358', (96, 101))
561482	33976158	1i and Supplementary Data 1), silencing RFC4, one subunit of the replication factor C (RFC) complex, consisting of RFC1, RFC2, RFC3, RFC4, and RFC5, which function in DNA replication and repair as polymerase accessory proteins, not only significantly reversed NICD1-enhanced tumor cell proliferation and survival but also markedly reversed the effects of NICD1 on promoting the abilities to invade and to form tumor spheres, and on increasing the proportion of side-population (SP) cells and the expression of invasion- and stemness-promoting genes (Fig.	('tumor', 'Disease', 'MESH:D009369', (410, 415))	('tumor', 'Disease', (275, 280))	('tumor', 'Disease', 'MESH:D009369', (275, 280))	('RFC2', 'Gene', '5982', (121, 125))	('invasion-', 'CPA', (510, 519))	('RFC5', 'Gene', '5985', (143, 147))	('RFC2', 'Gene', (121, 125))	('tumor', 'Phenotype', 'HP:0002664', (410, 415))	('SP', 'Chemical', '-', (478, 480))	('silencing', 'Var', (30, 39))	('tumor', 'Phenotype', 'HP:0002664', (275, 280))	('increasing', 'PosReg', (432, 442))	('RFC1', 'Gene', '5981', (115, 119))	('RFC5', 'Gene', (143, 147))	('RFC3', 'Gene', '5983', (127, 131))	('survival', 'CPA', (304, 312))	('RFC1', 'Gene', (115, 119))	('abilities', 'CPA', (378, 387))	('tumor', 'Disease', (410, 415))	('RFC4', 'Gene', (40, 44))	('NICD1-enhanced', 'PosReg', (260, 274))	('RFC3', 'Gene', (127, 131))	('promoting', 'PosReg', (364, 373))	('expression', 'MPA', (496, 506))
561483	33976158	Moreover, silencing RFC4 significantly compromised the invasive and self-renewal abilities of NICD1-overexpressing NSCLC cells, even when cell proliferation was inhibited by mitomycin C (a DNA synthesis inhibitor) treatment or cell death was induced by cisplatin treatment (Supplementary Fig.	('NSCLC', 'Phenotype', 'HP:0030358', (115, 120))	('compromised', 'NegReg', (39, 50))	('death', 'Disease', 'MESH:D003643', (232, 237))	('death', 'Disease', (232, 237))	('mitomycin C', 'Chemical', 'MESH:D016685', (174, 185))	('RFC4', 'Gene', (20, 24))	('NSCLC', 'Disease', (115, 120))	('NSCLC', 'Disease', 'MESH:D002289', (115, 120))	('cisplatin', 'Chemical', 'MESH:D002945', (253, 262))	('silencing', 'Var', (10, 19))
561488	33976158	In parallel, silencing RBP-Jkappa significantly inhibited RFC4 expression and reversed NICD1-induced upregulation of RFC4 expression, and inhibiting Notch1 activation similarly reversed the RBP-Jkappa-induced increase in RFC4 levels (Fig.	('expression', 'MPA', (122, 132))	('upregulation', 'PosReg', (101, 113))	('RBP-Jkappa', 'Gene', '3516', (190, 200))	('Notch1', 'Gene', (149, 155))	('RFC4', 'Gene', (117, 121))	('RBP-Jkappa', 'Gene', (190, 200))	('expression', 'MPA', (63, 73))	('RFC4', 'Gene', (58, 62))	('inhibiting', 'NegReg', (138, 148))	('inhibited', 'NegReg', (48, 57))	('Notch1', 'Gene', '4851', (149, 155))	('RBP-Jkappa', 'Gene', '3516', (23, 33))	('RBP-Jkappa', 'Gene', (23, 33))	('silencing', 'Var', (13, 22))	('RFC4 levels', 'MPA', (221, 232))
561492	33976158	Additionally, when distinct, serial 500 bp DNA fragments containing the putative RBP-Jkappa binding site with wild type or mutated sequences were separately cloned upstream of a luciferase reporter gene, only the luciferase activity of the reporter with wild-type sequences was significantly increased by NICD1 overexpression and inhibited by RBP-Jkappa knockdown; silencing RBP-Jkappa also markedly abrogated the above transcription-enhancing effect of NICD1 overexpression (Fig.	('RBP-Jkappa', 'Gene', (343, 353))	('RBP-Jkappa', 'Gene', '3516', (375, 385))	('abrogated', 'NegReg', (400, 409))	('silencing', 'Var', (365, 374))	('RBP-Jkappa', 'Gene', (375, 385))	('RBP-Jkappa', 'Gene', '3516', (343, 353))	('RBP-Jkappa', 'Gene', '3516', (81, 91))	('RBP-Jkappa', 'Gene', (81, 91))	('transcription-enhancing', 'MPA', (420, 443))
561500	33976158	In parallel, as few as 5 x 103 RFC4-overexpressing cells developed subcutaneous tumors, whereas more than 5 x 104 vector-control cells and 5 x 105 RFC4-silenced cells were required for tumor formation (Fig.	('tumor', 'Disease', (185, 190))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('RFC4-overexpressing', 'Var', (31, 50))	('subcutaneous tumors', 'Phenotype', 'HP:0001482', (67, 86))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('tumor', 'Disease', (80, 85))	('tumor', 'Disease', 'MESH:D009369', (185, 190))	('tumors', 'Disease', (80, 86))	('developed', 'PosReg', (57, 66))	('tumors', 'Disease', 'MESH:D009369', (80, 86))	('tumor', 'Phenotype', 'HP:0002664', (185, 190))
561502	33976158	Consistently, silencing RFC4 significantly suppressed the ability of highly metastatic murine lung cancer cells to form lung metastases when injected intravenously or to develop subcutaneous tumors when injected with various cell numbers ranging from 5 x 103 to 5 x 105 in C57BL/6N mice (Fig.	('silencing', 'Var', (14, 23))	('murine', 'Species', '10090', (87, 93))	('lung metastases', 'Disease', 'MESH:D009362', (120, 135))	('lung cancer', 'Disease', 'MESH:D008175', (94, 105))	('tumors', 'Phenotype', 'HP:0002664', (191, 197))	('RFC4', 'Gene', (24, 28))	('tumors', 'Disease', 'MESH:D009369', (191, 197))	('mice', 'Species', '10090', (282, 286))	('subcutaneous tumors', 'Phenotype', 'HP:0001482', (178, 197))	('lung cancer', 'Disease', (94, 105))	('tumor', 'Phenotype', 'HP:0002664', (191, 196))	('lung cancer', 'Phenotype', 'HP:0100526', (94, 105))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('tumors', 'Disease', (191, 197))	('develop', 'Reg', (170, 177))	('lung metastases', 'Disease', (120, 135))	('suppressed', 'NegReg', (43, 53))
561504	33976158	Notably, consistent with the role of RFC4 in DNA replication and repair, overexpression of RFC4 was significantly promoted, whereas knockdown of RFC4 markedly suppressed NSCLC cell proliferation, cell cycle progression, and resistance to cisplatin-induced cell apoptosis (Supplementary Fig.	('cell cycle progression', 'CPA', (196, 218))	('NSCLC', 'Phenotype', 'HP:0030358', (170, 175))	('RFC4', 'Gene', (91, 95))	('knockdown', 'Var', (132, 141))	('resistance to cisplatin-induced cell apoptosis', 'CPA', (224, 270))	('cisplatin', 'Chemical', 'MESH:D002945', (238, 247))	('NSCLC', 'Disease', (170, 175))	('RFC4', 'Gene', (145, 149))	('suppressed', 'NegReg', (159, 169))	('promoted', 'PosReg', (114, 122))	('NSCLC', 'Disease', 'MESH:D002289', (170, 175))	('overexpression', 'PosReg', (73, 87))
561507	33976158	5a), and silencing RFC2 or RFC5 or silencing the essential DNA replication accessory gene PCNA reversed the promoting effects of RFC4 on NSCLC cell proliferation but failed to interfere with RFC4-induced Notch1 signaling activation or RFC4-potentiated tumor invasion and stemness in vitro or tumor metastasis and tumorigenicity in vivo (Supplementary Fig.	('NSCLC', 'Disease', (137, 142))	('RFC2', 'Gene', '5982', (19, 23))	('tumor', 'Disease', (313, 318))	('tumor', 'Disease', 'MESH:D009369', (252, 257))	('RFC2', 'Gene', (19, 23))	('NSCLC', 'Phenotype', 'HP:0030358', (137, 142))	('tumor metastasis', 'Disease', (292, 308))	('PCNA', 'Gene', (90, 94))	('tumor', 'Disease', 'MESH:D009369', (313, 318))	('RFC5', 'Gene', (27, 31))	('tumor', 'Phenotype', 'HP:0002664', (292, 297))	('RFC4-potentiated', 'PosReg', (235, 251))	('tumor', 'Phenotype', 'HP:0002664', (252, 257))	('tumor', 'Phenotype', 'HP:0002664', (313, 318))	('PCNA', 'Gene', '5111', (90, 94))	('Notch1', 'Gene', (204, 210))	('Notch1', 'Gene', '4851', (204, 210))	('silencing', 'Var', (35, 44))	('silencing', 'Var', (9, 18))	('tumor', 'Disease', (292, 297))	('NSCLC', 'Disease', 'MESH:D002289', (137, 142))	('RFC5', 'Gene', '5985', (27, 31))	('tumor metastasis', 'Disease', 'MESH:D009362', (292, 308))	('tumor', 'Disease', (252, 257))	('tumor', 'Disease', 'MESH:D009369', (292, 297))
561510	33976158	Interestingly, RFC4 overexpression largely increased, whereas silencing RFC4 decreased NICD1 protein levels without affecting the mRNA levels of Notch1 or the quantities of full-length Notch1 proteins both in various NSCLC cell lines and primary NSCLC cells (Fig.	('silencing', 'Var', (62, 71))	('NSCLC', 'Disease', (217, 222))	('NSCLC', 'Phenotype', 'HP:0030358', (246, 251))	('NSCLC', 'Disease', 'MESH:D002289', (217, 222))	('Notch1', 'Gene', (185, 191))	('Notch1', 'Gene', '4851', (185, 191))	('Notch1', 'Gene', (145, 151))	('Notch1', 'Gene', '4851', (145, 151))	('NSCLC', 'Disease', (246, 251))	('RFC4', 'Gene', (72, 76))	('NSCLC', 'Phenotype', 'HP:0030358', (217, 222))	('increased', 'PosReg', (43, 52))	('NSCLC', 'Disease', 'MESH:D002289', (246, 251))	('NICD1 protein levels', 'MPA', (87, 107))	('decreased', 'NegReg', (77, 86))
561511	33976158	Indeed, silencing RFC4 caused a remarkable increase in K48-linked polyubiquitination of NICD1, and thus overexpressing RFC4 markedly prolonged, whereas silencing RFC4 greatly shortened the half-lives of NICD1 proteins in both various NSCLC cell lines and primary NSCLC cells (Fig.	('NSCLC', 'Disease', (234, 239))	('shortened', 'NegReg', (175, 184))	('NSCLC', 'Phenotype', 'HP:0030358', (263, 268))	('half-lives', 'MPA', (189, 199))	('NSCLC', 'Disease', 'MESH:D002289', (234, 239))	('silencing', 'Var', (8, 17))	('RFC4', 'Gene', (18, 22))	('NSCLC', 'Disease', (263, 268))	('K48-linked polyubiquitination', 'MPA', (55, 84))	('increase', 'PosReg', (43, 51))	('NSCLC', 'Phenotype', 'HP:0030358', (234, 239))	('NSCLC', 'Disease', 'MESH:D002289', (263, 268))	('prolonged', 'PosReg', (133, 142))
561512	33976158	Consequently, overexpressing RFC4 significantly promoted, whereas silencing RFC4 inhibited, the transcriptional activity of the Notch signaling and thus the expression of several canonical downstream genes in various NSCLC cells (Fig.	('NSCLC', 'Disease', (217, 222))	('Notch signaling', 'MPA', (128, 143))	('transcriptional activity', 'MPA', (96, 120))	('expression', 'MPA', (157, 167))	('silencing', 'Var', (66, 75))	('NSCLC', 'Disease', 'MESH:D002289', (217, 222))	('inhibited', 'NegReg', (81, 90))	('RFC4', 'Gene', (76, 80))	('RFC4', 'Gene', (29, 33))	('NSCLC', 'Phenotype', 'HP:0030358', (217, 222))	('promoted', 'PosReg', (48, 56))
561513	33976158	Similarly, silencing RFC4 reversed the activation of the Notch signaling pre-induced by NICD1 or JAG1 in NSCLC cells, and the Notch signaling in NSCLC cells pre-silenced with RFC4 became insensitive to stimulation of JAG1 overexpression in HUVECs (Supplementary Fig.	('silencing', 'Var', (11, 20))	('NSCLC', 'Disease', 'MESH:D002289', (105, 110))	('HUVEC', 'CellLine', 'CVCL:2959', (240, 245))	('RFC4', 'Gene', (21, 25))	('Notch signaling', 'MPA', (57, 72))	('activation', 'PosReg', (39, 49))	('NSCLC', 'Phenotype', 'HP:0030358', (105, 110))	('NSCLC', 'Disease', (145, 150))	('JAG1', 'Gene', (217, 221))	('JAG1', 'Gene', '182', (97, 101))	('NSCLC', 'Disease', 'MESH:D002289', (145, 150))	('JAG1', 'Gene', (97, 101))	('NSCLC', 'Disease', (105, 110))	('NSCLC', 'Phenotype', 'HP:0030358', (145, 150))	('JAG1', 'Gene', '182', (217, 221))
561514	33976158	Additionally, although RFC4 knockdown does not globally interfere with NICD-dependent transcription, silencing RFC4 reversed NICD1-induced expression of a set of Notch1 signaling downstream genes to various degrees (Supplementary Fig.	('silencing', 'Var', (101, 110))	('RFC4', 'Gene', (111, 115))	('Notch1', 'Gene', (162, 168))	('Notch1', 'Gene', '4851', (162, 168))	('expression', 'MPA', (139, 149))
561524	33976158	First, the SPR kinetic analysis showed that the binding affinity between RFC4 and NICD1 was approximately five folds higher than that between CDK8 and NICD1 (Fig.	('RFC4', 'Var', (73, 77))	('CDK8', 'Gene', (142, 146))	('NICD1', 'Gene', (82, 87))	('SP', 'Chemical', '-', (11, 13))	('CDK8', 'Gene', '1024', (142, 146))	('higher', 'PosReg', (117, 123))	('binding affinity', 'Interaction', (48, 64))
561526	33976158	Third, while silencing RFC4 mildly enhanced the interaction between NICD1 and CDK8, silencing CDK8 significantly enhanced the interaction between NICD1 and RFC4; in parallel, overexpressing RFC4 significantly abrogated the binding of NICD1 to CDK8, whereas CDK8 overexpression mildly impaired the binding of NICD1 to RFC4 (Fig.	('CDK8', 'Gene', '1024', (257, 261))	('interaction', 'Interaction', (126, 137))	('CDK8', 'Gene', (94, 98))	('RFC4', 'Var', (190, 194))	('binding', 'Interaction', (223, 230))	('silencing', 'Var', (84, 93))	('CDK8', 'Gene', (78, 82))	('interaction', 'Interaction', (48, 59))	('CDK8', 'Gene', (243, 247))	('CDK8', 'Gene', '1024', (94, 98))	('overexpressing', 'Var', (175, 189))	('abrogated', 'NegReg', (209, 218))	('binding', 'Interaction', (297, 304))	('CDK8', 'Gene', '1024', (78, 82))	('CDK8', 'Gene', '1024', (243, 247))	('enhanced', 'PosReg', (113, 121))	('CDK8', 'Gene', (257, 261))
561529	33976158	As a result, RFC4 overexpression significantly decreased, whereas silencing RFC4 increased total serine and threonine phosphorylation of nuclear NICD1 proteins, and silencing CDK8 reversed the corresponding effects of silencing RFC4 on serine and threonine phosphorylation levels and total protein levels of nuclear NICD1, as well as on the transcriptional activity of Notch signaling (Fig.	('threonine', 'Chemical', 'MESH:D013912', (247, 256))	('silencing', 'Var', (66, 75))	('threonine', 'Chemical', 'MESH:D013912', (108, 117))	('serine', 'Chemical', 'MESH:D012694', (236, 242))	('Notch signaling', 'MPA', (369, 384))	('silencing', 'Var', (218, 227))	('transcriptional activity', 'MPA', (341, 365))	('RFC4', 'Gene', (76, 80))	('RFC4', 'Gene', (228, 232))	('serine', 'Chemical', 'MESH:D012694', (97, 103))	('increased', 'PosReg', (81, 90))	('CDK8', 'Gene', (175, 179))	('silencing', 'Var', (165, 174))	('CDK8', 'Gene', '1024', (175, 179))	('decreased', 'NegReg', (47, 56))
561532	33976158	Based on these data, we hypothesize that the binding of RFC4 to the PEST domain of NICD1 might repel other NICD1-interactive proteins, including various NICD1 kinases, resulting in abrogation of NICD1 phosphorylation at multiple serine or threonine amino acids, such as S2514, S2517, T2512, and T2542, in the PEST domain.	('S2514', 'Var', (270, 275))	('binding', 'Interaction', (45, 52))	('P', 'Chemical', 'MESH:D010758', (68, 69))	('S2517', 'Var', (277, 282))	('P', 'Chemical', 'MESH:D010758', (309, 310))	('threonine amino acids', 'Chemical', '-', (239, 260))	('NICD1-interactive', 'Protein', (107, 124))	('NICD1', 'Gene', (83, 88))	('RFC4', 'Gene', (56, 60))	('T2542', 'Var', (295, 300))	('NICD1 phosphorylation', 'MPA', (195, 216))	('serine', 'Chemical', 'MESH:D012694', (229, 235))	('T2512', 'Var', (284, 289))	('abrogation', 'NegReg', (181, 191))	('repel', 'NegReg', (95, 100))
561534	33976158	In parallel, silencing RFC4 failed to cause K48-linked polyubiquitination of NICD1 when FBXW7 or CDK8 was pre-silenced or depleted (Fig.	('K48-linked polyubiquitination', 'MPA', (44, 73))	('NICD1', 'Gene', (77, 82))	('FBXW7', 'Gene', (88, 93))	('CDK8', 'Gene', (97, 101))	('CDK8', 'Gene', '1024', (97, 101))	('FBXW7', 'Gene', '55294', (88, 93))	('RFC4', 'Gene', (23, 27))	('silencing', 'Var', (13, 22))
561537	33976158	Moreover, silencing RFC4 caused little, if any, alteration in the prominent inducing effect of stabilized NICD1 on the self-renewal and invasive abilities and SP increase of NSCLC cells (Supplementary Fig.	('self-renewal', 'CPA', (119, 131))	('NSCLC', 'Disease', 'MESH:D002289', (174, 179))	('invasive abilities', 'CPA', (136, 154))	('inducing', 'PosReg', (76, 84))	('RFC4', 'Gene', (20, 24))	('NICD1', 'Gene', (106, 111))	('SP', 'Chemical', '-', (159, 161))	('NSCLC', 'Phenotype', 'HP:0030358', (174, 179))	('SP increase', 'CPA', (159, 170))	('silencing', 'Var', (10, 19))	('NSCLC', 'Disease', (174, 179))
561538	33976158	Additionally, while NSCLC cells expressing stabilized mutant NICD1 developed excessive lung metastases when they were injected intravenously and were able to form detectable tumors even when 5 x 103 cells were subcutaneously inoculated, silencing RFC4 could not compromise the potent metastatic and tumorigenic abilities of these NICD1-mutant NSCLC cells (Fig.	('lung metastases', 'Disease', (87, 102))	('NSCLC', 'Phenotype', 'HP:0030358', (343, 348))	('tumor', 'Phenotype', 'HP:0002664', (174, 179))	('tumor', 'Phenotype', 'HP:0002664', (299, 304))	('silencing', 'Var', (237, 246))	('NSCLC', 'Disease', 'MESH:D002289', (20, 25))	('tumors', 'Disease', (174, 180))	('NSCLC', 'Disease', (20, 25))	('NICD1', 'Gene', (61, 66))	('tumors', 'Disease', 'MESH:D009369', (174, 180))	('NSCLC', 'Phenotype', 'HP:0030358', (20, 25))	('mutant', 'Var', (54, 60))	('RFC4', 'Gene', (247, 251))	('tumor', 'Disease', (174, 179))	('NSCLC', 'Disease', 'MESH:D002289', (343, 348))	('tumor', 'Disease', (299, 304))	('lung metastases', 'Disease', 'MESH:D009362', (87, 102))	('tumor', 'Disease', 'MESH:D009369', (174, 179))	('tumor', 'Disease', 'MESH:D009369', (299, 304))	('NSCLC', 'Disease', (343, 348))	('tumors', 'Phenotype', 'HP:0002664', (174, 180))
561539	33976158	Consistently, subcutaneous tumors formed by NICD1-mutant NSCLC cells presented significantly increased levels of RFC4, CCND1, and PCNA and a decreased proportion of TUNNEL-positive tumor cells as compared to those formed by vector-control cells, whereas subcutaneous tumors formed by RFC4-silenced NICD1-mutant NSCLC cells presented remarkable reductions in RFC4 protein levels and only marginally altered levels of NICD1, CCND1, or PCNA expression or apoptotic tumor cell proportion (Fig.	('CCND1', 'Gene', '595', (423, 428))	('PCNA', 'Gene', (130, 134))	('tumor', 'Disease', 'MESH:D009369', (267, 272))	('increased', 'PosReg', (93, 102))	('NSCLC', 'Phenotype', 'HP:0030358', (57, 62))	('tumors', 'Disease', 'MESH:D009369', (27, 33))	('NSCLC', 'Phenotype', 'HP:0030358', (311, 316))	('subcutaneous tumors', 'Phenotype', 'HP:0001482', (254, 273))	('CCND1', 'Gene', (423, 428))	('tumors', 'Phenotype', 'HP:0002664', (267, 273))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('PCNA', 'Gene', '5111', (433, 437))	('tumor', 'Disease', (27, 32))	('tumor', 'Phenotype', 'HP:0002664', (267, 272))	('PCNA', 'Gene', '5111', (130, 134))	('tumor', 'Disease', (462, 467))	('subcutaneous tumors', 'Phenotype', 'HP:0001482', (14, 33))	('tumor', 'Disease', 'MESH:D009369', (27, 32))	('tumors', 'Disease', (267, 273))	('CCND1', 'Gene', '595', (119, 124))	('reductions', 'NegReg', (344, 354))	('tumor', 'Disease', 'MESH:D009369', (462, 467))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('CCND1', 'Gene', (119, 124))	('tumors', 'Disease', 'MESH:D009369', (267, 273))	('NSCLC', 'Disease', 'MESH:D002289', (57, 62))	('NSCLC', 'Disease', 'MESH:D002289', (311, 316))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('tumor', 'Disease', (181, 186))	('tumors', 'Disease', (27, 33))	('tumor', 'Phenotype', 'HP:0002664', (462, 467))	('RFC4 protein levels', 'MPA', (358, 377))	('PCNA', 'Gene', (433, 437))	('tumor', 'Disease', (267, 272))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('NSCLC', 'Disease', (57, 62))	('NSCLC', 'Disease', (311, 316))	('NICD1-mutant', 'Var', (44, 56))
561542	33976158	8e-g), suggesting that RFC4 promotes NSCLC metastasis and stemness properties in a Notch1 signaling-dependent manner, whereas NSCLC cells harboring high levels of RFC4 and NICD1, which constitute a positive feedback loop, are insensitive to gamma-secretase inhibitor treatment.	('NSCLC', 'Disease', 'MESH:D002289', (126, 131))	('NSCLC', 'Phenotype', 'HP:0030358', (37, 42))	('NSCLC metastasis', 'Disease', (37, 53))	('NSCLC metastasis', 'Disease', 'MESH:D009362', (37, 53))	('Notch1', 'Gene', (83, 89))	('stemness properties', 'CPA', (58, 77))	('Notch1', 'Gene', '4851', (83, 89))	('promotes', 'PosReg', (28, 36))	('NSCLC', 'Disease', (37, 42))	('NSCLC', 'Phenotype', 'HP:0030358', (126, 131))	('RFC4', 'Var', (23, 27))	('NSCLC', 'Disease', 'MESH:D002289', (37, 42))	('NSCLC', 'Disease', (126, 131))
561546	33976158	Furthermore, patients with high RFC4 expression showed shorter overall and LN metastasis-free survival than those with low RFC4 expression and notably, patients with high levels of both RFC4 and nuclear NICD1 had significantly shorter LN metastasis-free survival times than those with high RFC4 or nuclear NICD1 alone (Fig.	('nuclear NICD1', 'Var', (195, 208))	('high RFC4 expression', 'Var', (27, 47))	('LN metastasis-free survival', 'CPA', (75, 102))	('patients', 'Species', '9606', (13, 21))	('RFC4', 'Var', (186, 190))	('shorter', 'NegReg', (227, 234))	('shorter', 'NegReg', (55, 62))	('LN metastasis-free survival times', 'CPA', (235, 268))	('patients', 'Species', '9606', (152, 160))
561547	33976158	Additionally, analyses of the online kmplot database (http://kmplot.com/analysis/) consisting of 1432 NSCLC patients and the MSKCC datasets consisting of 177 NSCLC patients showed that high RFC4 levels correlated with shorter overall survival time and progression-free as well as LN metastasis-free survival time (Supplementary Fig.	('RFC4', 'Protein', (190, 194))	('progression-free', 'CPA', (252, 268))	('NSCLC', 'Disease', (158, 163))	('NSCLC', 'Disease', 'MESH:D002289', (102, 107))	('high RFC4 levels', 'Phenotype', 'HP:0032300', (185, 201))	('NSCLC', 'Disease', 'MESH:D002289', (158, 163))	('LN metastasis-free survival time', 'CPA', (280, 312))	('NSCLC', 'Phenotype', 'HP:0030358', (102, 107))	('overall survival time', 'CPA', (226, 247))	('high', 'Var', (185, 189))	('NSCLC', 'Phenotype', 'HP:0030358', (158, 163))	('patients', 'Species', '9606', (108, 116))	('patients', 'Species', '9606', (164, 172))	('NSCLC', 'Disease', (102, 107))	('shorter', 'NegReg', (218, 225))
561549	33976158	Consistent with previous reports showing amplification of chromosome region 3q27, where the RFC4 gene is located in various types of cancers, including lung cancer, we found that 2.3% of 516 patients with LUAD and 40.3% of 501 patients with LUSC in the TCGA lung cancer datasets had RFC4 amplification in their lung tumors and that RFC4 mRNA levels were increased approximately 2.93- and 9.42-fold on average in LUAD and LUSC, respectively (Fig.	('lung cancer', 'Disease', 'MESH:D008175', (258, 269))	('tumors', 'Phenotype', 'HP:0002664', (316, 322))	('lung tumors', 'Phenotype', 'HP:0100526', (311, 322))	('cancers', 'Disease', 'MESH:D009369', (133, 140))	('lung cancer', 'Phenotype', 'HP:0100526', (258, 269))	('cancer', 'Phenotype', 'HP:0002664', (263, 269))	('lung tumor', 'Phenotype', 'HP:0100526', (311, 321))	('RFC4 mRNA levels', 'MPA', (332, 348))	('tumor', 'Phenotype', 'HP:0002664', (316, 321))	('amplification', 'Var', (288, 301))	('lung tumors', 'Disease', (311, 322))	('lung cancer', 'Disease', 'MESH:D008175', (152, 163))	('increased', 'PosReg', (354, 363))	('LUAD', 'Phenotype', 'HP:0030078', (205, 209))	('lung cancer', 'Phenotype', 'HP:0100526', (152, 163))	('patients', 'Species', '9606', (227, 235))	('RFC4', 'Gene', (283, 287))	('LUAD', 'Phenotype', 'HP:0030078', (412, 416))	('cancers', 'Phenotype', 'HP:0002664', (133, 140))	('lung cancer', 'Disease', (258, 269))	('cancers', 'Disease', (133, 140))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('patients', 'Species', '9606', (191, 199))	('LUAD', 'Disease', (412, 416))	('LUSC', 'Disease', (421, 425))	('lung tumors', 'Disease', 'MESH:D008175', (311, 322))	('lung cancer', 'Disease', (152, 163))
561550	33976158	Moreover, the increase in genomic DNA levels of the RFC4 gene was validated in 6 out of 10 pairs of NSCLC tissues as compared to the adjacent normal lung tissue, and RFC4 mRNA expression indeed correlated with its DNA level (Fig.	('correlated', 'Reg', (194, 204))	('DNA level', 'MPA', (214, 223))	('RFC4', 'Gene', (52, 56))	('RFC4', 'Var', (166, 170))	('NSCLC', 'Disease', (100, 105))	('NSCLC', 'Disease', 'MESH:D002289', (100, 105))	('NSCLC', 'Phenotype', 'HP:0030358', (100, 105))	('increase', 'PosReg', (14, 22))
561551	33976158	Importantly, high copy numbers of RFC4 DNA were mainly found in the primary tumors of NSCLC patients with local or distant metastasis (Fig.	('found', 'Reg', (55, 60))	('NSCLC', 'Disease', (86, 91))	('high copy numbers', 'Var', (13, 30))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('patients', 'Species', '9606', (92, 100))	('NSCLC', 'Disease', 'MESH:D002289', (86, 91))	('tumors', 'Disease', (76, 82))	('tumors', 'Disease', 'MESH:D009369', (76, 82))	('tumors', 'Phenotype', 'HP:0002664', (76, 82))	('RFC4 DNA', 'Gene', (34, 42))	('NSCLC', 'Phenotype', 'HP:0030358', (86, 91))
561552	33976158	Furthermore, NSCLC patients with RFC4 amplification or high RFC4 DNA copy numbers in their lung tumors showed shorter overall or metastasis-free survival than those without RFC4 amplification or with low RFC4 DNA copy numbers (Fig.	('NSCLC', 'Disease', (13, 18))	('overall', 'CPA', (118, 125))	('RFC4 amplification', 'Var', (33, 51))	('patients', 'Species', '9606', (19, 27))	('lung tumors', 'Disease', (91, 102))	('NSCLC', 'Disease', 'MESH:D002289', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (96, 101))	('tumors', 'Phenotype', 'HP:0002664', (96, 102))	('shorter', 'NegReg', (110, 117))	('lung tumors', 'Phenotype', 'HP:0100526', (91, 102))	('RFC4 DNA', 'Gene', (60, 68))	('NSCLC', 'Phenotype', 'HP:0030358', (13, 18))	('lung tumors', 'Disease', 'MESH:D008175', (91, 102))	('high', 'Var', (55, 59))	('lung tumor', 'Phenotype', 'HP:0100526', (91, 101))	('metastasis-free survival', 'CPA', (129, 153))
561555	33976158	In contrast to many other cancer types, the commonly found genetic alterations in genes such as Notch1, JAG1, and FBXW7 central to NICD1 synthesis and Notch signaling are rarely present in NSCLC tumors.	('JAG1', 'Gene', '182', (104, 108))	('tumors', 'Phenotype', 'HP:0002664', (195, 201))	('NSCLC tumors', 'Disease', (189, 201))	('cancer', 'Disease', (26, 32))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('Notch1', 'Gene', (96, 102))	('Notch1', 'Gene', '4851', (96, 102))	('JAG1', 'Gene', (104, 108))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('FBXW7', 'Gene', '55294', (114, 119))	('NSCLC', 'Phenotype', 'HP:0030358', (189, 194))	('NSCLC tumors', 'Disease', 'MESH:D009369', (189, 201))	('FBXW7', 'Gene', (114, 119))	('tumor', 'Phenotype', 'HP:0002664', (195, 200))	('genetic alterations', 'Var', (59, 78))
561560	33976158	In this context, as a DNA replication factor, RFC4 in the NICD1/RBP-Jkappa complex might help to convert the responsive elements of the target genes from repressive to transcriptionally active for RBP-Jkappa activation.	('convert', 'Reg', (97, 104))	('RFC4', 'Var', (46, 50))	('repressive', 'MPA', (154, 164))	('RBP-Jkappa', 'Gene', '3516', (197, 207))	('RBP-Jkappa', 'Gene', (197, 207))	('RBP-Jkappa', 'Gene', '3516', (64, 74))	('RBP-Jkappa', 'Gene', (64, 74))	('responsive elements', 'MPA', (109, 128))
561563	33976158	In this context, we propose that a positive feedback loop initiated by RFC4 gene amplification causes amplified and sustained overactivation of Notch signaling and facilitates transcriptional activation of a set of metastasis- and cancer stemness-promoting genes in NSCLC.	('cancer stemness', 'Disease', 'MESH:D009369', (231, 246))	('facilitates', 'PosReg', (164, 175))	('NSCLC', 'Disease', 'MESH:D002289', (266, 271))	('overactivation', 'PosReg', (126, 140))	('cancer stemness', 'Disease', (231, 246))	('NSCLC', 'Phenotype', 'HP:0030358', (266, 271))	('Notch signaling', 'MPA', (144, 159))	('amplification', 'Var', (81, 94))	('cancer', 'Phenotype', 'HP:0002664', (231, 237))	('NSCLC', 'Disease', (266, 271))	('RFC4', 'Gene', (71, 75))	('transcriptional activation', 'MPA', (176, 202))
561569	33976158	Additionally, it has been suggested that Notch pathway mutations are not the most suitable biomarkers for predicting NSCLC response to gamma-secretase inhibitors.	('NSCLC', 'Disease', (117, 122))	('Notch pathway', 'Gene', (41, 54))	('mutations', 'Var', (55, 64))	('NSCLC', 'Disease', 'MESH:D002289', (117, 122))	('NSCLC', 'Phenotype', 'HP:0030358', (117, 122))
561572	33976158	Additionally, in many types of squamous cancers, such as squamous cell carcinoma of the head and neck, skin, oral cavity, and esophagus, 10-20% of tumor cases harbor inactivating mutations in the Notch1 gene, and many studies suggest the tumor-suppressive roles of Notch1 in these squamous cancers.	('squamous cancers', 'Disease', (281, 297))	('Notch1', 'Gene', (265, 271))	('tumor', 'Phenotype', 'HP:0002664', (238, 243))	('Notch1', 'Gene', '4851', (265, 271))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (57, 80))	('tumor', 'Disease', (147, 152))	('cancers', 'Phenotype', 'HP:0002664', (40, 47))	('squamous cancers', 'Disease', 'MESH:D002294', (281, 297))	('squamous cancers', 'Disease', (31, 47))	('carcinoma', 'Phenotype', 'HP:0030731', (71, 80))	('tumor', 'Disease', 'MESH:D009369', (147, 152))	('squamous cell carcinoma', 'Disease', (57, 80))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('esophagus', 'Disease', (126, 135))	('inactivating mutations', 'Var', (166, 188))	('squamous cancers', 'Disease', 'MESH:D002294', (31, 47))	('tumor', 'Disease', (238, 243))	('tumor', 'Phenotype', 'HP:0002664', (147, 152))	('Notch1', 'Gene', (196, 202))	('tumor', 'Disease', 'MESH:D009369', (238, 243))	('Notch1', 'Gene', '4851', (196, 202))	('cancers', 'Phenotype', 'HP:0002664', (290, 297))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (57, 80))	('cancer', 'Phenotype', 'HP:0002664', (290, 296))
561573	33976158	In LUSC, approximately 5% of patient samples harbor inactivating mutations in the Notch1 gene.	('inactivating mutations', 'Var', (52, 74))	('Notch1', 'Gene', '4851', (82, 88))	('Notch1', 'Gene', (82, 88))	('patient', 'Species', '9606', (29, 36))
561579	33976158	Additionally, we found that high levels of RFC4, as well as RFC4 gene amplification, were more frequently found in primary NSCLC tumors from patients bearing LN metastasis and correlate with short overall survival and metastasis-free and progression-free survival time, indicating potentially promising diagnostic and prognostic values of RFC4, especially for metastatic NSCLC patients.	('NSCLC', 'Disease', (371, 376))	('NSCLC', 'Disease', (123, 128))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('NSCLC', 'Disease', 'MESH:D002289', (123, 128))	('NSCLC', 'Disease', 'MESH:D002289', (371, 376))	('patients', 'Species', '9606', (141, 149))	('NSCLC tumors', 'Disease', 'MESH:D009369', (123, 135))	('found', 'Reg', (106, 111))	('patients', 'Species', '9606', (377, 385))	('NSCLC', 'Phenotype', 'HP:0030358', (371, 376))	('NSCLC', 'Phenotype', 'HP:0030358', (123, 128))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('NSCLC tumors', 'Disease', (123, 135))	('RFC4', 'Gene', (60, 64))	('amplification', 'Var', (70, 83))
561580	33976158	Notably, other cancer types, such as esophageal and ovarian cancers, in which aberrantly activated Notch1 signaling plays important roles, also have distinct high proportions of RFC4 gene amplification, and high RFC4 levels significantly correlates with poor prognosis of patients with these cancers, indicating that the oncogenic effects of RFC4 are not limited to NSCLC.	('Notch1', 'Gene', '4851', (99, 105))	('cancer', 'Disease', 'MESH:D009369', (15, 21))	('NSCLC', 'Phenotype', 'HP:0030358', (366, 371))	('aberrantly', 'Var', (78, 88))	('gene amplification', 'Var', (183, 201))	('ovarian cancers', 'Phenotype', 'HP:0100615', (52, 67))	('NSCLC', 'Disease', (366, 371))	('RFC4', 'MPA', (212, 216))	('cancer', 'Disease', 'MESH:D009369', (60, 66))	('cancers', 'Disease', 'MESH:D009369', (60, 67))	('esophageal and ovarian cancers', 'Disease', 'MESH:D004941', (37, 67))	('cancers', 'Phenotype', 'HP:0002664', (292, 299))	('cancer', 'Disease', (292, 298))	('cancers', 'Disease', (292, 299))	('cancer', 'Phenotype', 'HP:0002664', (292, 298))	('cancer', 'Disease', (15, 21))	('activated', 'PosReg', (89, 98))	('patients', 'Species', '9606', (272, 280))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('NSCLC', 'Disease', 'MESH:D002289', (366, 371))	('cancers', 'Phenotype', 'HP:0002664', (60, 67))	('cancers', 'Disease', (60, 67))	('RFC4', 'Gene', (178, 182))	('high RFC4 levels', 'Phenotype', 'HP:0032300', (207, 223))	('cancer', 'Disease', (60, 66))	('cancer', 'Disease', 'MESH:D009369', (292, 298))	('cancers', 'Disease', 'MESH:D009369', (292, 299))	('Notch1', 'Gene', (99, 105))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
561587	33976158	The open reading frames of RFC4, NICD1, and NICD1 mutant resistant to CDK8/FBXW7-mediated degradation were generated by PCR amplification and subcloned into the pSin-EF2 lentiviral vectors (Addgene) with different antibiotic resistance genes and various deletion mutants of HA-tagged NICD1 and FLAG-tagged RFC4 or NICD1, as well as HA-tagged ubiquitin, were subcloned into a pcDNA 3.1 vector.	('RFC4', 'Gene', (27, 31))	('NICD1', 'Gene', (44, 49))	('FBXW7', 'Gene', (75, 80))	('P', 'Chemical', 'MESH:D010758', (120, 121))	('CDK8', 'Gene', (70, 74))	('CDK8', 'Gene', '1024', (70, 74))	('RFC4', 'Gene', (306, 310))	('mutant', 'Var', (50, 56))	('NICD1', 'Gene', (314, 319))	('deletion', 'Var', (254, 262))	('FBXW7', 'Gene', '55294', (75, 80))
561591	33976158	Stable cell lines were generated via retroviral or lentiviral infection and selected with appropriate antibiotics for 10-14 days.	('lentiviral', 'Var', (51, 61))	('infection', 'Disease', (62, 71))	('infection', 'Disease', 'MESH:D007239', (62, 71))
561632	33976158	To assess the self-renewal abilities of NSCLC cells in the tumorigenicity model, indicated cells of various dosages (5 x 105, 5 x 104 and 5 x 103) were subcutaneously inoculated.	('tumor', 'Disease', (59, 64))	('5 x 105', 'Var', (117, 124))	('NSCLC', 'Phenotype', 'HP:0030358', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('NSCLC', 'Disease', (40, 45))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))	('NSCLC', 'Disease', 'MESH:D002289', (40, 45))
561636	33976158	IHC assays using anti-NICD1, anti-RFC4, or anti-HES1 were separately conducted on paraffin-embedded specimens of NSCLC patients.	('HES1', 'Gene', '3280', (48, 52))	('patients', 'Species', '9606', (119, 127))	('NSCLC', 'Phenotype', 'HP:0030358', (113, 118))	('anti-NICD1', 'Var', (17, 27))	('paraffin', 'Chemical', 'MESH:D010232', (82, 90))	('HES1', 'Gene', (48, 52))	('NSCLC', 'Disease', (113, 118))	('anti-RFC4', 'Var', (29, 38))	('NSCLC', 'Disease', 'MESH:D002289', (113, 118))
561706	32579974	CD274 (PD-L1), and PDCD1LG2 (PD-L2) were exclusively expressed in migrating DCs, suggesting DCs in the draining lymph node may limit anti-PD-1 therapy response, possibly explaining the observation of novel T cell clone infiltration into tumors after anti-PD-1 therapy.	('CD274', 'Gene', '29126', (0, 5))	('PDCD1LG2', 'Gene', (19, 27))	('PD-L2', 'Gene', (29, 34))	('PD-L2', 'Gene', '80380', (29, 34))	('tumors', 'Disease', (237, 243))	('tumors', 'Disease', 'MESH:D009369', (237, 243))	('PD-1', 'Gene', (255, 259))	('tumors', 'Phenotype', 'HP:0002664', (237, 243))	('limit', 'NegReg', (127, 132))	('PD-1', 'Gene', '5133', (255, 259))	('PD-1', 'Gene', (138, 142))	('CD274', 'Gene', (0, 5))	('PD-1', 'Gene', '5133', (138, 142))	('DCs', 'Var', (92, 95))	('PDCD1LG2', 'Gene', '80380', (19, 27))	('PD-L1', 'Gene', (7, 12))	('tumor', 'Phenotype', 'HP:0002664', (237, 242))	('PD-L1', 'Gene', '29126', (7, 12))
561749	32579974	Tumors with copy number variation (CNV) loss of a gene represent a "natural" genetic loss-of-function experiment, and, as expected, CNV loss was generally associated with lower expression (Figure S6E; STAR Methods).	('copy number variation', 'Var', (12, 33))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('loss-of-function', 'NegReg', (85, 101))	('loss', 'NegReg', (40, 44))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('STAR', 'Gene', '6770', (201, 205))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('expression', 'Species', '29278', (177, 187))	('loss', 'NegReg', (136, 140))	('STAR', 'Gene', (201, 205))	('expression', 'MPA', (177, 187))	('lower', 'NegReg', (171, 176))
561775	32579974	Tumors from TCGA with high TSK gene expression were associated with worse overall survival across six epithelial cancers (Figure S7H), consistent with this subpopulation's role in malignant behavior.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('worse', 'NegReg', (68, 73))	('high', 'Var', (22, 26))	('cancers', 'Disease', 'MESH:D009369', (113, 120))	('cancers', 'Phenotype', 'HP:0002664', (113, 120))	('overall survival', 'MPA', (74, 90))	('cancers', 'Disease', (113, 120))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('TSK', 'Gene', (27, 30))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('expression', 'Species', '29278', (36, 46))	('S7', 'Gene', '6264', (129, 131))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))
561784	32579974	The identification of TSK-enriched genes implicated in EMT as well as intercellular communication with CAFs and endothelial cells raises the possibility that TSK cells induce the fibroblast and endothelial states shown to contribute to tumor progression, immunosuppression, and heterogeneity.	('CAF', 'Gene', '8850', (103, 106))	('contribute', 'Reg', (222, 232))	('TSK-enriched', 'Gene', (22, 34))	('induce', 'PosReg', (168, 174))	('tumor', 'Disease', 'MESH:D009369', (236, 241))	('tumor', 'Phenotype', 'HP:0002664', (236, 241))	('TSK', 'Var', (158, 161))	('CAF', 'Gene', (103, 106))	('tumor', 'Disease', (236, 241))
561788	32579974	Patients with a high expression of the TSK markers ITGB1 and PLAU exhibited significantly lower progression-free survival after treatment with PD-1 checkpoint inhibitors.	('high expression', 'Var', (16, 31))	('ITGB1', 'Gene', '3688', (51, 56))	('PD-1', 'Gene', (143, 147))	('PLAU', 'Gene', (61, 65))	('PD-1', 'Gene', '5133', (143, 147))	('expression', 'Species', '29278', (21, 31))	('progression-free survival', 'CPA', (96, 121))	('TSK', 'Gene', (39, 42))	('lower', 'NegReg', (90, 95))	('ITGB1', 'Gene', (51, 56))	('Patients', 'Species', '9606', (0, 8))
561800	32579974	SCID Hairless Outbred (SHO, Crl:SHO-PrkdcscidHrhr, Charles River) mice and NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (Jackson Laboratory) were all female and 8-9 weeks in age at the time of injection for xenograft tumor experiments.	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('mice', 'Species', '10090', (66, 70))	('SCID Hairless', 'Disease', 'MESH:D053632', (0, 13))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumor', 'Disease', (205, 210))	('Crl', 'Gene', '133396', (28, 31))	('SCID Hairless', 'Disease', (0, 13))	('Crl', 'Gene', (28, 31))	('Il2rgtm1Wjl/SzJ', 'Var', (92, 107))
561840	32579974	The TSO sequence (AAGCAGTGGTATCAACGCAGAGTACATGGG) was used as a non-internal 5' adaptor with a minimum overlap of 5, meaning that partial matches (up to 5 base pairs) or intact TSO sequences were removed from the 5' end of read 2.	('mum', 'Gene', '56925', (99, 102))	('mum', 'Gene', (99, 102))	('partial matches', 'Var', (130, 145))
561928	32579974	The resulting aligned reads were processed using GATK 4.1.0.0 and Mutect2 variant calling for tumor-normal matched pairs, mostly following parameters from the GATK 4 documentation (https://gatk.broadinstitute.org).	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('Mutect2', 'Gene', (66, 73))	('variant', 'Var', (74, 81))	('tumor', 'Disease', (94, 99))
561965	32579974	To determine the average proportion of samples of each tumor type exhibiting copy number variation of every gene, we first downloaded the Gistic2 gene-level thresholded copy number tables from the UCSC Xena database (https://xenabrowser.net/datapages/).	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('copy number variation', 'Var', (77, 98))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('tumor', 'Disease', (55, 60))
562003	28877065	In the sinonasal tract, HPV positivity is largely associated with the non-keratinizing squamous cell carcinoma phenotype, but Bishop, et al.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (87, 110))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('HPV', 'Species', '10566', (24, 27))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (87, 110))	('positivity', 'Var', (28, 38))	('squamous cell carcinoma', 'Disease', (87, 110))	('associated', 'Reg', (50, 60))
562062	28877065	The basal/myoepithelial cell marker p40 (or p63) was positive in 48 of 49 cases (98%).	('myoepithelial', 'Disease', (10, 23))	('myoepithelial', 'Disease', 'MESH:D009208', (10, 23))	('p40', 'Var', (36, 39))
562066	28877065	PCR-based HPV typing, performed on 14 cases, revealed HPV type 33 (n=9), type 35 (n=3), type 56 (n=1), and HPV type unknown (n=1).	('type 35', 'Var', (73, 80))	('HPV', 'Species', '10566', (10, 13))	('HPV type 33', 'Var', (54, 65))	('HPV type unknown', 'Disease', 'MESH:D030361', (107, 123))	('HPV', 'Species', '10566', (107, 110))	('HPV type unknown', 'Disease', (107, 123))	('HPV', 'Species', '10566', (54, 57))	('type 56', 'Var', (88, 95))
562069	28877065	Because of the morphologic resemblance that many of the HMSCs shared with adenoid cystic carcinoma, a subset of the tumors was evaluated for rearrangements of MYB (n=15), MYBL1 (n=6), and NFIB (n=6).	('tumors', 'Disease', (116, 122))	('tumors', 'Disease', 'MESH:D009369', (116, 122))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('MYB', 'Gene', (159, 162))	('adenoid cystic carcinoma', 'Disease', (74, 98))	('MYBL1', 'Gene', (171, 176))	('rearrangements', 'Var', (141, 155))	('NFIB', 'Gene', (188, 192))	('MYBL1', 'Gene', '4603', (171, 176))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('MYB', 'Gene', '4602', (171, 174))	('NFIB', 'Gene', '4781', (188, 192))	('adenoid cystic carcinoma', 'Disease', 'MESH:D003528', (74, 98))	('men', 'Species', '9606', (150, 153))	('tumors', 'Phenotype', 'HP:0002664', (116, 122))	('MYB', 'Gene', (171, 174))	('MYB', 'Gene', '4602', (159, 162))
562108	28877065	Finally, while HPV type 16 is by far the most common HPV type in oropharyngeal squamous cell carcinoma, the uncommon HPV type 33 is most common in HMSC (seen in two-thirds of cases), with only one case harboring HPV16.	('carcinoma', 'Phenotype', 'HP:0030731', (93, 102))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (79, 102))	('squamous cell carcinoma', 'Disease', (79, 102))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (79, 102))	('HPV', 'Species', '10566', (117, 120))	('HPV16', 'Species', '333760', (212, 217))	('HPV', 'Species', '10566', (15, 18))	('oropharyngeal squamous cell carcinoma', 'Phenotype', 'HP:0012182', (65, 102))	('HMSC', 'Disease', (147, 151))	('HPV', 'Species', '10566', (53, 56))	('HPV type 33', 'Var', (117, 128))	('common', 'Reg', (137, 143))	('HPV', 'Species', '10566', (212, 215))
562117	25303977	Significantly mutated genes were identified with MutSig or complementary methods developed to specifically identify candidate tumor suppressors based upon their inactivating mutation bias.	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('inactivating mutation bias', 'Var', (161, 187))	('tumor', 'Disease', (126, 131))
562120	25303977	KMT2C mutations were associated with poor outcome and increased bone invasion.	('bone invasion', 'CPA', (64, 77))	('KMT2C', 'Gene', '58508', (0, 5))	('KMT2C', 'Gene', (0, 5))	('increased', 'PosReg', (54, 63))	('mutations', 'Var', (6, 15))
562133	25303977	Specific mutations in cSCC have been identified in TP53, NOTCH receptors, and RAS.	('cSCC', 'Gene', (22, 26))	('TP53', 'Gene', (51, 55))	('cSCC', 'Phenotype', 'HP:0006739', (22, 26))	('mutations', 'Var', (9, 18))	('NOTCH', 'Gene', (57, 62))	('RAS', 'Disease', (78, 81))	('NOTCH', 'Gene', '4851;18128;4853;18129', (57, 62))	('identified', 'Reg', (37, 47))	('TP53', 'Gene', '7157', (51, 55))
562137	25303977	We hypothesized that the analysis of genomic data from a larger cohort of patients with clinically aggressive cSCC disease would permit more definitive characterization of the mutations that contribute to overall disease progression in this subset of disease with poorer prognosis.	('cSCC disease', 'Disease', (110, 122))	('patients', 'Species', '9606', (74, 82))	('mutations', 'Var', (176, 185))	('cSCC', 'Phenotype', 'HP:0006739', (110, 114))
562155	25303977	Instead, the vast majority of mutations appear to be caused by exposure to UV light, as is expected for skin tumors.	('skin tumors', 'Disease', (104, 115))	('skin tumors', 'Disease', 'MESH:D012878', (104, 115))	('mutations', 'Var', (30, 39))	('caused', 'Reg', (53, 59))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('skin tumors', 'Phenotype', 'HP:0008069', (104, 115))
562161	25303977	This mutation signature is more similar to that of HPV negative head and neck squamous cell carcinoma (HNSCC), with a C>T frequency around 40% (Figure 2B).	('HNSCC', 'Phenotype', 'HP:0012288', (103, 108))	('carcinoma', 'Phenotype', 'HP:0030731', (92, 101))	('neck squamous cell carcinoma', 'Disease', (73, 101))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (64, 101))	('C>T', 'Var', (118, 121))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (78, 101))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (73, 101))
562167	25303977	TP53, CDKN2A, NOTCH2, NOTCH1, and AJUBA were identified as significant by all four methods, whereas SNX25, EIF2D, and PARD3 were significant by the three alternative methods but not by MutSig.	('EIF2D', 'Gene', '1939', (107, 112))	('TP53', 'Gene', '7157', (0, 4))	('SNX25', 'Gene', (100, 105))	('TP53', 'Gene', (0, 4))	('AJUBA', 'Gene', '84962', (34, 39))	('NOTCH2', 'Var', (14, 20))	('PARD3', 'Gene', (118, 123))	('PARD3', 'Gene', '56288', (118, 123))	('CDKN2A', 'Gene', (6, 12))	('EIF2D', 'Gene', (107, 112))	('SNX25', 'Gene', '83891', (100, 105))	('AJUBA', 'Gene', (34, 39))	('CDKN2A', 'Gene', '1029', (6, 12))
562171	25303977	The presence of moderately frequent mutations in eight common genes suggests that the biology of cSCC may be similar to that of HNSCC, In both cSCC and HNSCC, NOTCH1 alterations appear to be inactivating (Figure 4) because the missense mutations cluster in the EGF-like repeats responsible for ligand binding, and the truncating mutations are distributed throughout the gene but not clustered in the C-terminal PEST domain, in contrast to what is found for T-cell Acute Lymphoblastic Leukemia.	('Acute Lymphoblastic Leukemia', 'Phenotype', 'HP:0006721', (464, 492))	('T-cell Acute Lymphoblastic Leukemia', 'Disease', 'MESH:D054218', (457, 492))	('T-cell Acute Lymphoblastic Leukemia', 'Phenotype', 'HP:0006727', (457, 492))	('Lymphoblastic Leukemia', 'Phenotype', 'HP:0005526', (470, 492))	('alterations', 'Var', (166, 177))	('HNSCC', 'Phenotype', 'HP:0012288', (152, 157))	('cSCC', 'Phenotype', 'HP:0006739', (143, 147))	('HNSCC', 'Phenotype', 'HP:0012288', (128, 133))	('mutations', 'Var', (36, 45))	('Leukemia', 'Phenotype', 'HP:0001909', (484, 492))	('T-cell Acute Lymphoblastic Leukemia', 'Disease', (457, 492))	('missense mutations', 'Var', (227, 245))	('cSCC', 'Phenotype', 'HP:0006739', (97, 101))	('binding', 'Interaction', (301, 308))	('NOTCH1', 'Gene', (159, 165))
562173	25303977	NOTCH2 mutations are not statistically significant in HNSCC by MutSig, but do have a high inactivating mutation ratio in this cancer as well (Figure 4).	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('NOTCH2', 'Gene', (0, 6))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('HNSCC', 'Disease', (54, 59))	('HNSCC', 'Phenotype', 'HP:0012288', (54, 59))	('inactivating mutation', 'MPA', (90, 111))	('mutations', 'Var', (7, 16))
562175	25303977	Mutations in the oxidative stress gene NFE2L2 were first described in LUSC (15% of cases) and later found in HNSCC (7%).	('NFE2L2', 'Gene', (39, 45))	('LUSC', 'Phenotype', 'HP:0030359', (70, 74))	('oxidative stress', 'Phenotype', 'HP:0025464', (17, 33))	('Mutations', 'Var', (0, 9))	('NFE2L2', 'Gene', '4780', (39, 45))	('HNSCC', 'Phenotype', 'HP:0012288', (109, 114))
562177	25303977	PIK3CA is also significantly mutated in LUSC (16%) and HNSCC (19%), but was mutated only five times in four cSCC patients (10%) and was not statistically significant (Table 1).	('HNSCC', 'Phenotype', 'HP:0012288', (55, 60))	('HNSCC', 'Disease', (55, 60))	('patients', 'Species', '9606', (113, 121))	('LUSC', 'Phenotype', 'HP:0030359', (40, 44))	('PIK3CA', 'Gene', (0, 6))	('mutated', 'Var', (29, 36))	('LUSC', 'Disease', (40, 44))	('PIK3CA', 'Gene', '5290', (0, 6))	('cSCC', 'Phenotype', 'HP:0006739', (108, 112))
562178	25303977	Melanoma is characterized by frequent hotspot mutations in BRAF and NRAS.	('Melanoma', 'Disease', 'MESH:D008545', (0, 8))	('Melanoma', 'Phenotype', 'HP:0002861', (0, 8))	('mutations', 'Var', (46, 55))	('Melanoma', 'Disease', (0, 8))	('NRAS', 'Gene', (68, 72))	('BRAF', 'Gene', '673', (59, 63))	('BRAF', 'Gene', (59, 63))	('NRAS', 'Gene', '4893', (68, 72))
562180	25303977	However, hotspot mutations in RAC1 and STK19 have been reported in melanoma and were found in our cohort.	('STK19', 'Gene', (39, 44))	('reported', 'Reg', (55, 63))	('melanoma', 'Phenotype', 'HP:0002861', (67, 75))	('melanoma', 'Disease', (67, 75))	('RAC1', 'Gene', '5879', (30, 34))	('melanoma', 'Disease', 'MESH:D008545', (67, 75))	('STK19', 'Gene', '8859', (39, 44))	('RAC1', 'Gene', (30, 34))	('mutations', 'Var', (17, 26))
562181	25303977	We observed 1 P29S mutation in RAC1, and 5 mutations around D89 in STK19.	('P29S', 'Var', (14, 18))	('STK19', 'Gene', (67, 72))	('P29S', 'Mutation', 'rs1057519874', (14, 18))	('RAC1', 'Gene', (31, 35))	('RAC1', 'Gene', '5879', (31, 35))	('STK19', 'Gene', '8859', (67, 72))
562182	25303977	These included 3 D89N, 1 E88K, and 1 P90S mutations (Supplemental Table S5).	('D89N', 'Mutation', 'rs267600971', (17, 21))	('E88K', 'Var', (25, 29))	('D89N', 'Var', (17, 21))	('P90S', 'Var', (37, 41))	('E88K', 'Mutation', 'p.E88K', (25, 29))	('P90S', 'Mutation', 'rs1060501203', (37, 41))
562184	25303977	PARD3 and RASA1 were mutated in 31% and 13% of cSCC patients (Table 1), with 33% and 66% of their mutations predicted to truncate or eliminate the proteins (Figure 3), respectively.	('PARD3', 'Gene', (0, 5))	('cSCC', 'Phenotype', 'HP:0006739', (47, 51))	('PARD3', 'Gene', '56288', (0, 5))	('eliminate', 'NegReg', (133, 142))	('mutations', 'Var', (98, 107))	('truncate', 'NegReg', (121, 129))	('cSCC', 'Disease', (47, 51))	('RASA1', 'Gene', '5921', (10, 15))	('mutated', 'Var', (21, 28))	('proteins', 'Protein', (147, 155))	('patients', 'Species', '9606', (52, 60))	('RASA1', 'Gene', (10, 15))
562189	25303977	RIPK4 was mutated in 28% of the tumors with a UV signature, with all mutations clustering in either exon 2 or exon 8 which encode the kinase and ankyrin repeat domains, respectively.	('mutated', 'Var', (10, 17))	('mutations', 'Var', (69, 78))	('RIPK4', 'Gene', (0, 5))	('tumors', 'Phenotype', 'HP:0002664', (32, 38))	('tumor', 'Phenotype', 'HP:0002664', (32, 37))	('tumors', 'Disease', (32, 38))	('tumors', 'Disease', 'MESH:D009369', (32, 38))
562192	25303977	To begin addressing the importance of genetic alterations in cSCC, the top candidate genes along with the total number of mutations per patient were analyzed for clinicopathological associations.	('cSCC', 'Gene', (61, 65))	('genetic', 'Var', (38, 45))	('patient', 'Species', '9606', (136, 143))	('cSCC', 'Phenotype', 'HP:0006739', (61, 65))
562196	25303977	Tumors classified as acantholytic had a median number of mutations (3589) that was roughly 1.5 times greater than tumors with no specific histologic subtype (2295) and more than triple the median number of mutations (1033) in tumors with sarcomatoid or adenosquamous histology.	('adenosquamous histology', 'Disease', (253, 276))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumors', 'Phenotype', 'HP:0002664', (226, 232))	('sarcomatoid', 'Disease', (238, 249))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('tumors', 'Disease', (226, 232))	('tumors', 'Disease', 'MESH:D009369', (226, 232))	('Tumors', 'Disease', (0, 6))	('mutations', 'Var', (57, 66))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('tumors', 'Disease', (114, 120))	('tumors', 'Disease', 'MESH:D009369', (114, 120))	('tumors', 'Phenotype', 'HP:0002664', (114, 120))	('sarcomatoid', 'Disease', 'MESH:C538614', (238, 249))	('tumor', 'Phenotype', 'HP:0002664', (226, 231))
562197	25303977	Tumors with AJUBA mutations were positively correlated with depth of invasion (p = 0.02), and on average invaded with a depth (16.0 +- 6.4 mm) almost twice that of tumors lacking the mutation (8.4 +- 5.6 mm).	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('tumors', 'Disease', (164, 170))	('tumors', 'Disease', 'MESH:D009369', (164, 170))	('tumors', 'Phenotype', 'HP:0002664', (164, 170))	('Tumors', 'Disease', (0, 6))	('AJUBA', 'Gene', (12, 17))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('depth of invasion', 'CPA', (60, 77))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('AJUBA', 'Gene', '84962', (12, 17))	('mutations', 'Var', (18, 27))
562198	25303977	Approximately 70% of patients with NOTCH2 mutations had PNI present compared to just 33% of patients with no NOTCH2 mutation.	('NOTCH2', 'Gene', (35, 41))	('patients', 'Species', '9606', (92, 100))	('patients', 'Species', '9606', (21, 29))	('PNI', 'Disease', (56, 59))	('mutations', 'Var', (42, 51))
562199	25303977	Interestingly, NOTCH2 mutations were also associated with primary tumor site (p=0.04), as the presence of NOTCH2 mutation was more common in cSCCs arising in the scalp or periorbital regions compared to the ear (Figure 5A).	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('mutation', 'Var', (113, 121))	('cSCCs', 'Disease', (141, 146))	('cSCC', 'Phenotype', 'HP:0006739', (141, 145))	('primary tumor', 'Disease', (58, 71))	('common', 'Reg', (131, 137))	('presence', 'Var', (94, 102))	('primary tumor', 'Disease', 'MESH:D009369', (58, 71))	('scalp', 'Disease', 'MESH:C538225', (162, 167))	('scalp', 'Disease', (162, 167))	('NOTCH2', 'Gene', (106, 112))
562200	25303977	The increased tendency for tumors with NOTCH2 mutations to have PNI may be independent from tumor site, as there was no significant association between tumor site and PNI (p=0.19).	('tumor', 'Disease', 'MESH:D009369', (152, 157))	('tumor', 'Phenotype', 'HP:0002664', (27, 32))	('mutations', 'Var', (46, 55))	('PNI', 'Disease', (64, 67))	('tumor', 'Phenotype', 'HP:0002664', (152, 157))	('tumor', 'Disease', (27, 32))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumors', 'Disease', (27, 33))	('tumor', 'Disease', (152, 157))	('tumors', 'Disease', 'MESH:D009369', (27, 33))	('tumors', 'Phenotype', 'HP:0002664', (27, 33))	('NOTCH2', 'Gene', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Disease', (92, 97))	('tumor', 'Disease', 'MESH:D009369', (27, 32))
562201	25303977	There was a highly significant positive association between bone invasion and KMT2C mutations (p=0.008).	('KMT2C', 'Gene', '58508', (78, 83))	('KMT2C', 'Gene', (78, 83))	('mutations', 'Var', (84, 93))	('positive', 'PosReg', (31, 39))	('bone invasion', 'CPA', (60, 73))
562203	25303977	Consistent with the positive association between KMT2C and bone invasion, patients with KMT2C mutation had significantly shorter recurrent free survival times (p=0.003) with a median recurrent survival of 21.6 months compared to 167.5 months for patients with wild type KMT2C (Figure 5B).	('recurrent free survival', 'MPA', (129, 152))	('KMT2C', 'Gene', (49, 54))	('KMT2C', 'Gene', '58508', (49, 54))	('KMT2C', 'Gene', '58508', (88, 93))	('KMT2C', 'Gene', (88, 93))	('patients', 'Species', '9606', (246, 254))	('patients', 'Species', '9606', (74, 82))	('KMT2C', 'Gene', '58508', (270, 275))	('KMT2C', 'Gene', (270, 275))	('shorter', 'NegReg', (121, 128))	('mutation', 'Var', (94, 102))
562204	25303977	The hazard ratio for recurrence or death for patients with KMT2C mutation was 5.16 (1.55 to 17.18, 95% CI) compared to those whose tumors were wild type.	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('mutation', 'Var', (65, 73))	('patients', 'Species', '9606', (45, 53))	('tumors', 'Disease', 'MESH:D009369', (131, 137))	('tumors', 'Disease', (131, 137))	('KMT2C', 'Gene', (59, 64))	('death', 'Disease', (35, 40))	('death', 'Disease', 'MESH:D003643', (35, 40))	('KMT2C', 'Gene', '58508', (59, 64))
562205	25303977	Similarly, patients with tumors harboring KMT2C mutation had trends towards shorter time to disease recurrence (p=0.07), and shorter overall survival (p=0.09).	('patients', 'Species', '9606', (11, 19))	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('tumors', 'Disease', (25, 31))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('time to disease recurrence', 'CPA', (84, 110))	('tumors', 'Disease', 'MESH:D009369', (25, 31))	('mutation', 'Var', (48, 56))	('shorter', 'NegReg', (125, 132))	('overall survival', 'MPA', (133, 149))	('KMT2C', 'Gene', (42, 47))	('shorter', 'NegReg', (76, 83))	('KMT2C', 'Gene', '58508', (42, 47))
562206	25303977	Poor prognosis of patients with KMT2C mutation appeared to be independent from bone invasion, as patients with bone invasion did not have shortened recurrent free survival times (p=0.98).	('KMT2C', 'Gene', (32, 37))	('KMT2C', 'Gene', '58508', (32, 37))	('mutation', 'Var', (38, 46))	('patients', 'Species', '9606', (18, 26))	('patients', 'Species', '9606', (97, 105))
562210	25303977	Interestingly, another group has recently characterized the genomic landscape of BCC, and also observed frequent mutations in NOTCH1, NOTCH2, and TP53.	('TP53', 'Gene', '7157', (146, 150))	('BCC', 'Phenotype', 'HP:0002671', (81, 84))	('NOTCH1', 'Gene', (126, 132))	('TP53', 'Gene', (146, 150))	('mutations', 'Var', (113, 122))	('NOTCH2', 'Gene', (134, 140))
562212	25303977	PTCH1 mutations occurred in 75% of BCC tumors and 70% of the alterations were inactivating.	('BCC tumors', 'Disease', 'MESH:D009369', (35, 45))	('PTCH1', 'Gene', (0, 5))	('tumor', 'Phenotype', 'HP:0002664', (39, 44))	('occurred', 'Reg', (16, 24))	('PTCH1', 'Gene', '5727', (0, 5))	('BCC tumors', 'Disease', (35, 45))	('BCC', 'Phenotype', 'HP:0002671', (35, 38))	('tumors', 'Phenotype', 'HP:0002664', (39, 45))	('mutations', 'Var', (6, 15))
562213	25303977	In our cSCC cohort, PTCH1 mutations occurred in just 17% of patients and only 2 mutations were inactivating, suggesting that PTCH1 is not a driver in aggressive cSCC.	('PTCH1', 'Gene', '5727', (125, 130))	('cSCC', 'Phenotype', 'HP:0006739', (7, 11))	('PTCH1', 'Gene', (20, 25))	('patients', 'Species', '9606', (60, 68))	('cSCC', 'Phenotype', 'HP:0006739', (161, 165))	('mutations', 'Var', (26, 35))	('PTCH1', 'Gene', (125, 130))	('PTCH1', 'Gene', '5727', (20, 25))
562220	25303977	A similar role is likely in cSCC, since conditional knockout of NOTCH1 in mouse skin predisposes animals to skin tumors.	('skin tumors', 'Phenotype', 'HP:0008069', (108, 119))	('skin tumors', 'Disease', (108, 119))	('cSCC', 'Disease', (28, 32))	('conditional knockout', 'Var', (40, 60))	('NOTCH1', 'Gene', (64, 70))	('predisposes', 'Reg', (85, 96))	('cSCC', 'Phenotype', 'HP:0006739', (28, 32))	('skin tumors', 'Disease', 'MESH:D012878', (108, 119))	('mouse', 'Species', '10090', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
562221	25303977	A role for NOTCH2 in cancers is less clear because mice with conditional knockout of NOTCH2 are not predisposed to tumors.	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('mice', 'Species', '10090', (51, 55))	('tumors', 'Disease', (115, 121))	('conditional knockout', 'Var', (61, 81))	('tumors', 'Disease', 'MESH:D009369', (115, 121))	('cancers', 'Disease', 'MESH:D009369', (21, 28))	('cancers', 'Phenotype', 'HP:0002664', (21, 28))	('cancers', 'Disease', (21, 28))	('tumors', 'Phenotype', 'HP:0002664', (115, 121))	('NOTCH2', 'Gene', (85, 91))
562225	25303977	NOTCH1 and NOTCH2 may both be a barrier to carcinogenesis in some systems (human), while NOTCH1 may be the primary barrier for other systems (mouse).	('NOTCH2', 'Var', (11, 17))	('carcinogenesis', 'CPA', (43, 57))	('mouse', 'Species', '10090', (142, 147))	('NOTCH1', 'Var', (0, 6))	('human', 'Species', '9606', (75, 80))
562226	25303977	Inactivating mutations in this gene are associated with a severe autosomal recessive lethal disease in humans known as Popliteal Pterygium Syndrome (also Bartsocas-Papas syndrome) that affects the face, limbs, and genitalia.	('Popliteal Pterygium Syndrome', 'Disease', (119, 147))	('Papas syndrome', 'Disease', 'MESH:C536253', (164, 178))	('Papas syndrome', 'Disease', (164, 178))	('autosomal recessive lethal disease', 'Disease', 'MESH:D030342', (65, 99))	('Inactivating mutations', 'Var', (0, 22))	('Popliteal Pterygium', 'Phenotype', 'HP:0009756', (119, 138))	('genitalia', 'Disease', (214, 223))	('Pterygium', 'Phenotype', 'HP:0001059', (129, 138))	('autosomal recessive lethal disease', 'Disease', (65, 99))	('humans', 'Species', '9606', (103, 109))	('genitalia', 'Disease', 'MESH:D012734', (214, 223))	('associated', 'Reg', (40, 50))
562227	25303977	Knockout of RIPK4 in mice produces a similar neonatal lethal syndrome accompanied by defective epidermal differentiation, including keratinocyte hyperplasia with expanded spinous and granular layers.	('hyperplasia', 'Disease', (145, 156))	('mice', 'Species', '10090', (21, 25))	('RIPK4', 'Gene', (12, 17))	('defective', 'NegReg', (85, 94))	('hyperplasia', 'Disease', 'MESH:D006965', (145, 156))	('Knockout', 'Var', (0, 8))	('epidermal differentiation', 'CPA', (95, 120))	('neonatal', 'Disease', (45, 53))
562228	25303977	The clustering of RIPK4 mutations within the kinase and ankyrin repeat domains, strongly suggests the mutations were non-random and support a hypothesis that RIPK4 is a putative tumor suppressor for aggressive cSCC.	('tumor', 'Disease', (178, 183))	('aggressive cSCC', 'Disease', (199, 214))	('cSCC', 'Phenotype', 'HP:0006739', (210, 214))	('tumor', 'Disease', 'MESH:D009369', (178, 183))	('mutations', 'Var', (24, 33))	('RIPK4', 'Gene', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))
562233	25303977	RAS GTPase family members with confirmed tumor suppressor function include NF1, DAB2IP, and RASAL2, which are frequently inactivated in tumors through genomic loss, mutation, or epigenetic silencing.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumors', 'Disease', (136, 142))	('epigenetic silencing', 'Var', (178, 198))	('tumors', 'Disease', 'MESH:D009369', (136, 142))	('tumors', 'Phenotype', 'HP:0002664', (136, 142))	('RASAL2', 'Gene', '9462', (92, 98))	('genomic loss', 'Var', (151, 163))	('tumor', 'Disease', (41, 46))	('NF1', 'Gene', (75, 78))	('DAB2IP', 'Gene', '153090', (80, 86))	('mutation', 'Var', (165, 173))	('NF1', 'Gene', '4763', (75, 78))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('RASAL2', 'Gene', (92, 98))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('DAB2IP', 'Gene', (80, 86))	('tumor', 'Disease', (136, 141))
562234	25303977	Inactivation of these genes has been proposed to explain activation of the RAS pathway in tumors that do not harboring specific RAS mutations.	('RAS pathway', 'Pathway', (75, 86))	('activation', 'PosReg', (57, 67))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumors', 'Disease', (90, 96))	('tumors', 'Disease', 'MESH:D009369', (90, 96))	('tumors', 'Phenotype', 'HP:0002664', (90, 96))	('Inactivation', 'Var', (0, 12))
562235	25303977	The role of RASA1 in cancer has not been clearly defined, despite the fact that it is frequently inactivated by mutation in many other tumor types.	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('mutation', 'Var', (112, 120))	('RASA1', 'Gene', '5921', (12, 17))	('tumor', 'Disease', (135, 140))	('RASA1', 'Gene', (12, 17))	('inactivated', 'NegReg', (97, 108))	('cancer', 'Disease', (21, 27))	('cancer', 'Disease', 'MESH:D009369', (21, 27))	('tumor', 'Disease', 'MESH:D009369', (135, 140))
562242	25303977	In our cohort of aggressive cSCC, we found frequent inactivating mutations in KMT2C, which encodes a component of a histone methylation complex involved in transcriptional regulation.	('inactivating mutations', 'Var', (52, 74))	('KMT2C', 'Gene', '58508', (78, 83))	('KMT2C', 'Gene', (78, 83))	('cSCC', 'Phenotype', 'HP:0006739', (28, 32))
562243	25303977	Inactivating KMT2C mutations have been reported for a number of tumors, including cancers of the stomach, bladder, and breast.	('cancers of the stomach', 'Phenotype', 'HP:0006753', (82, 104))	('breast', 'Disease', (119, 125))	('tumors', 'Disease', (64, 70))	('tumors', 'Disease', 'MESH:D009369', (64, 70))	('tumors', 'Phenotype', 'HP:0002664', (64, 70))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('bladder', 'Disease', (106, 113))	('cancers', 'Phenotype', 'HP:0002664', (82, 89))	('mutations', 'Var', (19, 28))	('cancers', 'Disease', (82, 89))	('Inactivating', 'Var', (0, 12))	('cancers', 'Disease', 'MESH:D009369', (82, 89))	('KMT2C', 'Gene', '58508', (13, 18))	('KMT2C', 'Gene', (13, 18))	('reported', 'Reg', (39, 47))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))
562244	25303977	In the TCGA stomach cancer dataset there is a trend towards reduced overall survival in patients with KMT2C mutation compared to patients who are wild type (median 13 vs 59 months).	('cancer', 'Phenotype', 'HP:0002664', (20, 26))	('patients', 'Species', '9606', (129, 137))	('patients', 'Species', '9606', (88, 96))	('stomach cancer', 'Disease', 'MESH:D013274', (12, 26))	('KMT2C', 'Gene', (102, 107))	('mutation', 'Var', (108, 116))	('KMT2C', 'Gene', '58508', (102, 107))	('stomach cancer', 'Phenotype', 'HP:0012126', (12, 26))	('overall survival', 'MPA', (68, 84))	('reduced', 'NegReg', (60, 67))	('stomach cancer', 'Disease', (12, 26))
562245	25303977	In our aggressive cSCC cohort, patients with KMT2C mutations had significantly shorter recurrent free survival, shorter time to recurrence, and were more likely to have bone invasion.	('mutations', 'Var', (51, 60))	('shorter', 'NegReg', (79, 86))	('recurrent free survival', 'CPA', (87, 110))	('patients', 'Species', '9606', (31, 39))	('cSCC', 'Phenotype', 'HP:0006739', (18, 22))	('KMT2C', 'Gene', '58508', (45, 50))	('shorter', 'NegReg', (112, 119))	('KMT2C', 'Gene', (45, 50))	('bone invasion', 'CPA', (169, 182))
562251	25303977	KMT2C mutations are associated with poor outcome and could represent a new biomarker for aggressive disease.	('aggressive disease', 'Disease', 'MESH:D001523', (89, 107))	('KMT2C', 'Gene', '58508', (0, 5))	('KMT2C', 'Gene', (0, 5))	('aggressive disease', 'Disease', (89, 107))	('mutations', 'Var', (6, 15))
562252	25303977	Mutations in HRAS and STK19 are candidate oncogenic events, but are not yet targetable.	('HRAS', 'Gene', (13, 17))	('STK19', 'Gene', (22, 27))	('Mutations', 'Var', (0, 9))	('HRAS', 'Gene', '3265', (13, 17))	('STK19', 'Gene', '8859', (22, 27))
562253	24565984	Down regulation of RhoC by microRNA-138 results in de-activation of FAK, Src and Erk1/2 signaling pathway in head and neck squamous cell carcinoma RhoC a pro-metastatic oncogene is constitutively active in many head and neck squamous cell carcinomas.	('neck squamous cell carcinomas', 'Disease', (220, 249))	('Erk1/2', 'Gene', (81, 87))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (211, 248))	('carcinoma', 'Phenotype', 'HP:0030731', (239, 248))	('FAK', 'Gene', (68, 71))	('neck squamous cell carcinomas', 'Disease', 'MESH:D000077195', (220, 249))	('Down regulation', 'NegReg', (0, 15))	('Src', 'Gene', '6714', (73, 76))	('microRNA-138', 'Var', (27, 39))	('FAK', 'Gene', '5747', (68, 71))	('neck squamous cell carcinoma', 'Disease', (118, 146))	('Erk1/2', 'Gene', '5595;5594', (81, 87))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (118, 146))	('carcinomas', 'Phenotype', 'HP:0030731', (239, 249))	('de-activation', 'NegReg', (51, 64))	('RhoC', 'Gene', '389', (147, 151))	('RhoC', 'Gene', (147, 151))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (225, 249))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (220, 248))	('RhoC', 'Gene', (19, 23))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (123, 146))	('RhoC', 'Gene', '389', (19, 23))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (109, 146))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (225, 248))	('head and neck squamous cell carcinomas', 'Phenotype', 'HP:0012288', (211, 249))	('carcinoma', 'Phenotype', 'HP:0030731', (137, 146))	('Src', 'Gene', (73, 76))	('many head', 'Phenotype', 'HP:0000256', (206, 215))
562259	24565984	Moreover, this study for the first time shows that down regulation of FAK, Src and Erk1/2 by miR-138 overexpression is due to inhibition of RhoC in HNSCC.	('Src', 'Gene', (75, 78))	('Src', 'Gene', '6714', (75, 78))	('FAK', 'Gene', '5747', (70, 73))	('down regulation', 'NegReg', (51, 66))	('HNSCC', 'Phenotype', 'HP:0012288', (148, 153))	('Erk1/2', 'Gene', (83, 89))	('inhibition', 'NegReg', (126, 136))	('miR-138', 'Gene', (93, 100))	('overexpression', 'Var', (101, 115))	('RhoC', 'Protein', (140, 144))	('FAK', 'Gene', (70, 73))
562280	24565984	compared expression patterns of miRNAs between the parental MDA-MB-231 human breast cancer line and its variants that are highly metastatic to the bone or lungs and identified eight miRNAs that are down regulated.	('breast cancer', 'Disease', (77, 90))	('breast cancer', 'Phenotype', 'HP:0003002', (77, 90))	('variants', 'Var', (104, 112))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('breast cancer', 'Disease', 'MESH:D001943', (77, 90))	('MDA-MB-231', 'CellLine', 'CVCL:0062', (60, 70))	('human', 'Species', '9606', (71, 76))
562282	24565984	In a previous study we reported the role of miR-107, a tumor suppressor microRNA which inhibits the expression of PKCepsilon in head and neck cancer.	('tumor', 'Disease', 'MESH:D009369', (55, 60))	('tumor', 'Phenotype', 'HP:0002664', (55, 60))	('PKCepsilon', 'Gene', (114, 124))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('inhibits', 'NegReg', (87, 95))	('tumor', 'Disease', (55, 60))	('miR-107', 'Var', (44, 51))	('expression', 'MPA', (100, 110))	('PKCepsilon', 'Gene', '5581', (114, 124))	('head and neck cancer', 'Phenotype', 'HP:0012288', (128, 148))	('head and neck cancer', 'Disease', 'MESH:D006258', (128, 148))
562284	24565984	on head and neck cancer cell lines reported the role of miR-34a as a tumor suppressor and that dysregulation of this miR promotes angiogenesis in their mouse model.	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('dysregulation', 'Var', (95, 108))	('tumor', 'Disease', (69, 74))	('miR-34a', 'Gene', (56, 63))	('angiogenesis', 'CPA', (130, 142))	('miR-34a', 'Gene', '723848', (56, 63))	('mouse', 'Species', '10090', (152, 157))	('head and neck cancer', 'Disease', 'MESH:D006258', (3, 23))	('promotes', 'PosReg', (121, 129))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('head and neck cancer', 'Phenotype', 'HP:0012288', (3, 23))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
562290	24565984	We observed a significant down regulation of P-FAKY397, P-SrcY416, and P-Erk1/2 in miR-138 over expressing HNSCC cell lines, suggesting miR-138 activity affects downstream signaling molecules of RhoC that are involved in cancer cell growth, invasion, progression and metastasis.	('cancer', 'Disease', 'MESH:D009369', (221, 227))	('HNSCC', 'Phenotype', 'HP:0012288', (107, 112))	('miR-138', 'Var', (136, 143))	('cancer', 'Disease', (221, 227))	('SrcY416', 'Chemical', '-', (58, 65))	('P-FAKY397', 'Var', (45, 54))	('P-SrcY416', 'Var', (56, 65))	('miR-138', 'Gene', (83, 90))	('cancer', 'Phenotype', 'HP:0002664', (221, 227))	('down regulation', 'NegReg', (26, 41))	('FAKY397', 'Chemical', '-', (47, 54))	('affects', 'Reg', (153, 160))
562292	24565984	University of Michigan squamous cell carcinoma cell lines (UM-SCC)-1 and -47 are derived from the patients with T2N0 of floor of the mouth and T3N1 of the tongue respectively.	('T3N1', 'Var', (143, 147))	('carcinoma', 'Phenotype', 'HP:0030731', (37, 46))	('UM-SCC', 'CellLine', 'CVCL:7707', (59, 65))	('patients', 'Species', '9606', (98, 106))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (23, 46))	('T2N0', 'Var', (112, 116))	('squamous cell carcinoma', 'Disease', (23, 46))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (23, 46))
562297	24565984	Overexpression of miR-138 and miR-control (whose sequence does not match with the 3'UTR of any known mRNA) in UM-SCC-1 and -47 were achieved transiently using lipofectAMINE2000 in absence of antibiotic free DMEM supplemented with 10% FBS.	('SCC-1 and -47', 'Gene', '5795', (113, 126))	('FBS', 'Disease', 'MESH:D005198', (234, 237))	('DMEM', 'Chemical', '-', (207, 211))	('FBS', 'Disease', (234, 237))	('miR-138', 'Var', (18, 25))	('UM-SCC-1', 'CellLine', 'CVCL:7707', (110, 118))
562302	24565984	Then the membranes were incubated overnight with polyclonal RhoC, P-FAKY397, P-srcY416, and P-ERK1/2 primary antibodies or with Tubulin (as a loading control).	('P-srcY416', 'Var', (77, 86))	('ERK1/2', 'Gene', '5595', (94, 100))	('P-FAKY397', 'Var', (66, 75))	('ERK1/2', 'Gene', (94, 100))	('FAKY397', 'Chemical', '-', (68, 75))
562316	24565984	The inverse correlation observed in the expression of RhoC and miR-138 strongly supports and confirms previous findings that miR-138 is a tumor suppressor that down regulates RhoC expression.	('tumor', 'Disease', (138, 143))	('down regulates', 'NegReg', (160, 174))	('expression', 'MPA', (180, 190))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('miR-138', 'Var', (125, 132))	('RhoC', 'Protein', (175, 179))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))
562317	24565984	Our data is also in accordance with the findings reported earlier that showed the binding of miR-138 at 3'UTR of RhoC mRNA could impair its function in tongue squamous cell carcinoma.	('impair', 'NegReg', (129, 135))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (159, 182))	('tongue squamous cell carcinoma', 'Disease', 'MESH:D002294', (152, 182))	('function', 'MPA', (140, 148))	('carcinoma', 'Phenotype', 'HP:0030731', (173, 182))	('tongue squamous cell carcinoma', 'Disease', (152, 182))	('miR-138', 'Var', (93, 100))	('binding', 'Interaction', (82, 89))
562336	24565984	Phosphorylation of FAKY397 was decreased by 80% and 60% in UM-SCC-1 and -47 respectively.	('FAKY397', 'Var', (19, 26))	('decreased', 'NegReg', (31, 40))	('SCC-1 and -47', 'Gene', '5795', (62, 75))	('Phosphorylation', 'MPA', (0, 15))	('FAKY397', 'Chemical', '-', (19, 26))	('UM-SCC-1', 'CellLine', 'CVCL:7707', (59, 67))
562337	24565984	A similar decrease in phosphorylation of SrcY416 and Erk1/2 was also observed in UM-SCC-1 and -47 respectively upon miR-138 over expression in HNSCC cell lines (Fig.	('miR-138', 'Gene', (116, 123))	('UM-SCC-1', 'CellLine', 'CVCL:7707', (81, 89))	('SrcY416', 'Var', (41, 48))	('decrease', 'NegReg', (10, 18))	('SrcY416', 'Chemical', '-', (41, 48))	('over expression', 'PosReg', (124, 139))	('SCC-1 and -47', 'Gene', '5795', (84, 97))	('HNSCC', 'Phenotype', 'HP:0012288', (143, 148))	('phosphorylation', 'MPA', (22, 37))	('Erk1/2', 'Gene', (53, 59))
562351	24565984	We can conclude from these findings that miR-138 is a tumor suppressor microRNA that plays a significant role in regulation of RhoC expression.	('tumor', 'Disease', 'MESH:D009369', (54, 59))	('regulation', 'MPA', (113, 123))	('tumor', 'Phenotype', 'HP:0002664', (54, 59))	('miR-138', 'Var', (41, 48))	('RhoC', 'Protein', (127, 131))	('tumor', 'Disease', (54, 59))
562352	24565984	These results suggest miR-138 is an important tumor suppressor that is needed to keep low expression levels of RhoC in the cells.	('miR-138', 'Var', (22, 29))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('RhoC', 'Protein', (111, 115))	('expression levels', 'MPA', (90, 107))	('tumor', 'Disease', (46, 51))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
562356	24565984	This signifies a robust role for miR-138 which not only involves lowering the expression of RhoC, but also in disrupting various cancer phenotypes in HNSCC cell lines (Figs.	('miR-138', 'Var', (33, 40))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('expression', 'MPA', (78, 88))	('cancer', 'Disease', (129, 135))	('RhoC', 'Protein', (92, 96))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('lowering', 'NegReg', (65, 73))	('HNSCC', 'Phenotype', 'HP:0012288', (150, 155))	('disrupting', 'NegReg', (110, 120))
562370	24565984	Our results show the down regulation of both Src and Erk1/2 upon RhoC inactivation, signifying the role of RhoC in promoting the activation of cancer cell survival proteins in HNSCC.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('RhoC', 'Gene', (65, 69))	('promoting', 'PosReg', (115, 124))	('HNSCC', 'Phenotype', 'HP:0012288', (176, 181))	('inactivation', 'Var', (70, 82))	('Src', 'Gene', (45, 48))	('activation', 'PosReg', (129, 139))	('Src', 'Gene', '6714', (45, 48))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('down regulation', 'NegReg', (21, 36))	('Erk1/2', 'Gene', (53, 59))
562371	24565984	A schema describing how miR-138 attenuates the activation of various onco-proteins is given in Fig.	('activation', 'MPA', (47, 57))	('schema', 'Disease', (2, 8))	('miR-138', 'Var', (24, 31))	('attenuates', 'NegReg', (32, 42))	('schema', 'Disease', 'None', (2, 8))
562373	24565984	The first could be loss of heterozygosity (LOH), a form of allelic imbalance that can result in the complete loss of an allele or from an increase in copy number of one allele relative to the other, and is an important mechanism by which there is loss of expression of tumor suppressor genes.	('copy', 'MPA', (150, 154))	('increase', 'PosReg', (138, 146))	('tumor', 'Disease', 'MESH:D009369', (269, 274))	('tumor', 'Phenotype', 'HP:0002664', (269, 274))	('loss', 'NegReg', (109, 113))	('tumor', 'Disease', (269, 274))	('imbalance', 'Phenotype', 'HP:0002172', (67, 76))	('loss', 'Var', (19, 23))
562374	24565984	Recent studies using SNP array technology show that in addition to solid tumors, hematologic malignancies also have a high frequency of LOH due to genomic deletions or gains.	('solid tumors', 'Disease', (67, 79))	('hematologic malignancies', 'Disease', 'MESH:D019337', (81, 105))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('hematologic malignancies', 'Disease', (81, 105))	('LOH', 'Disease', (136, 139))	('genomic deletions', 'Var', (147, 164))	('solid tumors', 'Disease', 'MESH:D009369', (67, 79))	('tumors', 'Phenotype', 'HP:0002664', (73, 79))	('gains', 'PosReg', (168, 173))
562375	24565984	In this biological phenomenon, a region of the genome where a tumor suppressor gene is located is transcriptionally repressed due to methylation of cytosine residues.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('methylation', 'Var', (133, 144))	('tumor', 'Disease', (62, 67))	('cytosine', 'Chemical', 'MESH:D003596', (148, 156))	('cytosine', 'Protein', (148, 156))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
562378	24565984	In addition to this, over expressing miR-138 attenuates FAKY397, SrcY416, and Erk1/2 activation.	('activation', 'MPA', (85, 95))	('miR-138', 'Gene', (37, 44))	('FAKY397', 'Chemical', '-', (56, 63))	('Erk1/2', 'Enzyme', (78, 84))	('attenuates', 'NegReg', (45, 55))	('SrcY416', 'Chemical', '-', (65, 72))	('SrcY416', 'MPA', (65, 72))	('FAKY397', 'Var', (56, 63))
562389	32190537	discovered that high RAD51 expression was directly associated with increased chemo- and radio-resistance, along with dismal outcomes and prognoses in breast cancer patients.	('RAD51', 'Gene', (21, 26))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('breast cancer', 'Disease', 'MESH:D001943', (150, 163))	('breast cancer', 'Phenotype', 'HP:0003002', (150, 163))	('high', 'Var', (16, 20))	('breast cancer', 'Disease', (150, 163))	('expression', 'MPA', (27, 37))	('associated', 'Reg', (51, 61))	('increased', 'PosReg', (67, 76))
562391	32190537	Furthermore, the results from a recent meta-analysis revealed that high RAD51 expression could increase the risk of patients developing head and neck tumors.	('tumors', 'Disease', (150, 156))	('tumors', 'Disease', 'MESH:D009369', (150, 156))	('tumors', 'Phenotype', 'HP:0002664', (150, 156))	('high', 'Var', (67, 71))	('neck tumors', 'Disease', (145, 156))	('RAD51', 'Gene', (72, 77))	('head and neck tumors', 'Phenotype', 'HP:0012288', (136, 156))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('neck tumors', 'Disease', 'MESH:D006258', (145, 156))
562416	32190537	The homozygous gene RAD51 GG was found to be most often in breast cancer patients, while RAD51 G172T has the most clinical significance in cervical cancer.	('RAD51 GG', 'Var', (20, 28))	('RAD51 G172T', 'Var', (89, 100))	('cervical cancer', 'Disease', (139, 154))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('breast cancer', 'Disease', (59, 72))	('G172T', 'Var', (95, 100))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('breast cancer', 'Phenotype', 'HP:0003002', (59, 72))	('G172T', 'Mutation', 'rs1801321', (95, 100))
562417	32190537	used T0070907 (T007), one kind of peroxisome proliferator-activated receptor gamma (PPARgamma), to weaken the expression of RAD51 in cervical cancer and disturb the mitosis of tumor cells.	('disturb the mitosis of tumor', 'Disease', 'MESH:D009369', (153, 181))	('cervical', 'Disease', (133, 141))	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('weaken', 'NegReg', (99, 105))	('RAD51', 'Protein', (124, 129))	('PPARgamma', 'Gene', (84, 93))	('PPARgamma', 'Gene', '5468', (84, 93))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('T0070907', 'Var', (5, 13))	('peroxisome proliferator-activated receptor gamma', 'Gene', (34, 82))	('disturb the mitosis of tumor', 'Disease', (153, 181))	('expression', 'MPA', (110, 120))	('peroxisome proliferator-activated receptor gamma', 'Gene', '5468', (34, 82))
562421	32190537	High expression of RAD51 in breast cancer was previously shown to increase the risk of brain metastases and micrometastases.	('increase', 'PosReg', (66, 74))	('High expression', 'Var', (0, 15))	('micrometastases', 'CPA', (108, 123))	('brain metastases', 'Disease', 'MESH:D009362', (87, 103))	('brain metastases', 'Disease', (87, 103))	('cancer', 'Phenotype', 'HP:0002664', (35, 41))	('breast cancer', 'Phenotype', 'HP:0003002', (28, 41))	('RAD51', 'Gene', (19, 24))
562425	31535064	The 5-year OS was 81.7% for LNR <=0.233 and 47.1% for LNR >0.233, and the 5-year OS was 79.6% for LODDS <=-0.1 and 51.8% for LODDS >-0.1, respectively.	('LODDS', 'Chemical', '-', (98, 103))	('LODDS', 'Chemical', '-', (125, 130))	('LNR >0.233', 'Var', (54, 64))	('LNR', 'Var', (28, 31))
562440	31535064	Patients with synchronous or metachronous malignancies, recurrent tumors, unresectable disease/macroscopic incomplete resection, follow-up period <3 years, pN3 disease, the number of dissected lymph nodes <6, and distant metastases were excluded from the study.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('pN3', 'Var', (156, 159))	('malignancies', 'Disease', 'MESH:D009369', (42, 54))	('metastases', 'Disease', (221, 231))	('tumors', 'Disease', (66, 72))	('tumors', 'Disease', 'MESH:D009369', (66, 72))	('tumors', 'Phenotype', 'HP:0002664', (66, 72))	('synchronous', 'Disease', 'MESH:D009378', (14, 25))	('Patients', 'Species', '9606', (0, 8))	('malignancies', 'Disease', (42, 54))	('synchronous', 'Disease', (14, 25))	('metastases', 'Disease', 'MESH:D009362', (221, 231))
562461	31535064	The 5-year OS was 79.6% for LODDS <=-0.1 and 51.8% for LODDS >-0.1 of log odds ratio, respectively (P < .0001); the 5-year DFS was 79.3% for LODDS <=-0.1 and 51.6% for LODDS >-0.1 of log odds ratio, respectively (P < .0001).	('LODDS', 'Chemical', '-', (55, 60))	('LODDS <=-0.1', 'Var', (141, 153))	('LODDS >-0.1', 'Var', (168, 179))	('LODDS', 'Chemical', '-', (141, 146))	('LODDS', 'Chemical', '-', (168, 173))	('LODDS', 'Chemical', '-', (28, 33))
562484	31535064	Based on our data, the results indicated that the high LNR (P = .041) was close to recurrence; in particular, the results showed that the patients with a high LNR had a 2-fold higher risk (26.1%, 12/46) of recurrence than patients with a low LNR (13.7%, 25/183).	('patients', 'Species', '9606', (222, 230))	('recurrence', 'CPA', (206, 216))	('low LNR', 'Phenotype', 'HP:0012213', (238, 245))	('patients', 'Species', '9606', (138, 146))	('high LNR', 'Var', (154, 162))
562501	32987632	We investigated this specific effect by confirming the ability of Schlafen 12 to reduce cell proliferation of lung adenocarcinoma cells in vitro but not that of lung squamous cell carcinoma.	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (161, 189))	('lung adenocarcinoma', 'Disease', (110, 129))	('reduce', 'NegReg', (81, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (180, 189))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (110, 129))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (166, 189))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (161, 189))	('lung squamous cell carcinoma', 'Disease', (161, 189))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (110, 129))	('carcinoma', 'Phenotype', 'HP:0030731', (120, 129))	('Schlafen 12', 'Chemical', '-', (66, 77))	('cell proliferation', 'CPA', (88, 106))	('Schlafen', 'Var', (66, 74))
562506	32987632	We investigated survival differences in high versus low SLFN12-expressing tumors in two databases.	('high', 'Var', (40, 44))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('SLFN12', 'Gene', (56, 62))	('tumors', 'Disease', (74, 80))	('SLFN12', 'Gene', '55106', (56, 62))	('tumors', 'Phenotype', 'HP:0002664', (74, 80))	('tumors', 'Disease', 'MESH:D009369', (74, 80))
562513	32987632	SLFN12 overexpression reduced c-myc protein in LUAD cell lines but not in LUSC, by inhibiting c-myc translation.	('c-myc', 'Gene', (30, 35))	('overexpression', 'Var', (7, 21))	('SLFN12', 'Gene', '55106', (0, 6))	('SLFN12', 'Gene', (0, 6))	('c-myc', 'Gene', '4609', (94, 99))	('LUSC', 'Phenotype', 'HP:0030359', (74, 78))	('inhibiting', 'NegReg', (83, 93))	('c-myc', 'Gene', (94, 99))	('reduced', 'NegReg', (22, 29))	('LUAD', 'Phenotype', 'HP:0030078', (47, 51))	('c-myc', 'Gene', '4609', (30, 35))
562525	32987632	SLFN5 expression has been reported to be prognostically favorable in lung cancers, but it activates epithelial to mesenchymal transition in vitro.	('SLFN5', 'Gene', (0, 5))	('activates', 'PosReg', (90, 99))	('lung cancers', 'Disease', (69, 81))	('SLFN5', 'Gene', '162394', (0, 5))	('lung cancers', 'Disease', 'MESH:D008175', (69, 81))	('cancers', 'Phenotype', 'HP:0002664', (74, 81))	('lung cancer', 'Phenotype', 'HP:0100526', (69, 80))	('epithelial to mesenchymal transition', 'CPA', (100, 136))	('lung cancers', 'Phenotype', 'HP:0100526', (69, 81))	('expression', 'Var', (6, 16))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
562526	32987632	High SLFN11 expression is also associated with a favorable outcome in lung cancers, perhaps at least in part because it sensitizes lung cancer to specific cytotoxic drugs such as DNA alkylating agents and PARP inhibitors.	('lung cancer', 'Disease', 'MESH:D008175', (70, 81))	('High', 'Var', (0, 4))	('PARP', 'Gene', '142', (205, 209))	('cancers', 'Phenotype', 'HP:0002664', (75, 82))	('lung cancers', 'Disease', (70, 82))	('lung cancers', 'Phenotype', 'HP:0100526', (70, 82))	('lung cancer', 'Disease', 'MESH:D008175', (131, 142))	('lung cancers', 'Disease', 'MESH:D008175', (70, 82))	('lung cancer', 'Phenotype', 'HP:0100526', (70, 81))	('SLFN11', 'Gene', (5, 11))	('sensitizes', 'Reg', (120, 130))	('cancer', 'Phenotype', 'HP:0002664', (75, 81))	('PARP', 'Gene', (205, 209))	('lung cancer', 'Disease', (131, 142))	('SLFN11', 'Gene', '91607', (5, 11))	('lung cancer', 'Phenotype', 'HP:0100526', (131, 142))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))
562532	32987632	Our analysis demonstrated that high versus low SLFN12 expression is able to classify the lung adenocarcinoma, but not squamous cell carcinoma patients into good versus poor survival.	('low', 'NegReg', (43, 46))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (89, 108))	('carcinoma', 'Phenotype', 'HP:0030731', (132, 141))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (118, 141))	('squamous cell carcinoma', 'Disease', (118, 141))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (118, 141))	('carcinoma', 'Phenotype', 'HP:0030731', (99, 108))	('lung adenocarcinoma', 'Disease', (89, 108))	('high', 'Var', (31, 35))	('patients', 'Species', '9606', (142, 150))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (89, 108))	('SLFN12', 'Gene', '55106', (47, 53))	('SLFN12', 'Gene', (47, 53))
562539	32987632	The median survival for patients with adenocarcinoma who expressed high levels of SLFN12 was 117.3 months versus 73.3 months in patients with low SLFN12 expression (Figure 1A).	('high', 'Var', (67, 71))	('SLFN12', 'Gene', '55106', (82, 88))	('SLFN12', 'Gene', (82, 88))	('adenocarcinoma', 'Disease', (38, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (43, 52))	('adenocarcinoma', 'Disease', 'MESH:D000230', (38, 52))	('SLFN12', 'Gene', '55106', (146, 152))	('patients', 'Species', '9606', (24, 32))	('patients', 'Species', '9606', (128, 136))	('SLFN12', 'Gene', (146, 152))
562550	32987632	Moreover, time-course analysis of mRNA levels at 48 and 72 hours after AdSLFN12 transfection demonstrated a similar trend in mRNA levels of the differentiation markers as seen previously (Figure S3).	('mRNA levels', 'MPA', (125, 136))	('SLFN12', 'Gene', '55106', (73, 79))	('SLFN12', 'Gene', (73, 79))	('mRNA levels', 'MPA', (34, 45))	('transfection', 'Var', (80, 92))
562555	32987632	In H1975 cells, cell number was reduced at 72 hours after AdSLFN12 transfection compared with cells infected with AdCMV control (2.96-fold +- 0.30 vs. 3.89-fold +- 0.41, n = 10, p < 0.01, Figure 3C).	('H1975', 'Var', (3, 8))	('AdCMV', 'Chemical', '-', (114, 119))	('SLFN12', 'Gene', '55106', (60, 66))	('transfection', 'Var', (67, 79))	('SLFN12', 'Gene', (60, 66))	('H1975', 'CellLine', 'CVCL:1511', (3, 8))	('infected', 'Disease', 'MESH:D007239', (100, 108))	('reduced', 'NegReg', (32, 39))	('infected', 'Disease', (100, 108))	('cell number', 'CPA', (16, 27))
562587	32987632	Indeed, analysis of c-myc protein translation using L-AHA metabolic labeling and Click-iT chemistry demonstrated that SLFN12 overexpression through AdSLFN12 transfection of H23 cells significantly reduced c-myc translation by 55% compared with control cells transfected with the empty vector control AdCMV (Figure 6F,G).	('L-AHA metabolic labeling', 'Disease', 'MESH:D008659', (52, 76))	('SLFN12', 'Gene', '55106', (150, 156))	('c-myc', 'Gene', '4609', (20, 25))	('c-myc', 'Gene', (20, 25))	('SLFN12', 'Gene', (150, 156))	('L-AHA metabolic labeling', 'Disease', (52, 76))	('transfection', 'Var', (157, 169))	('reduced', 'NegReg', (197, 204))	('SLFN12', 'Gene', '55106', (118, 124))	('SLFN12', 'Gene', (118, 124))	('c-myc', 'Gene', '4609', (205, 210))	('overexpression', 'PosReg', (125, 139))	('c-myc', 'Gene', (205, 210))	('AdCMV', 'Chemical', '-', (300, 305))
562613	32987632	As we knew that SLFN12 alters cell differentiation, we initially sought an explanation for the apparent protective implications of high SLFN12 expression in lung adenocarcinoma by examining the expression of several important differentiation markers.	('SLFN12', 'Gene', '55106', (136, 142))	('SLFN12', 'Gene', (136, 142))	('expression', 'MPA', (143, 153))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (157, 176))	('carcinoma', 'Phenotype', 'HP:0030731', (167, 176))	('cell differentiation', 'CPA', (30, 50))	('SLFN12', 'Gene', (16, 22))	('lung adenocarcinoma', 'Disease', (157, 176))	('SLFN12', 'Gene', '55106', (16, 22))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (157, 176))	('high', 'Var', (131, 135))
562626	32987632	Although c-myc knockdown reported to induce apoptosis in lung cancer cells, it still needs to be determined if SLFN12 induces apoptosis through c-myc pathway or another independent pathway.	('knockdown', 'Var', (15, 24))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('lung cancer', 'Phenotype', 'HP:0100526', (57, 68))	('c-myc', 'Gene', (144, 149))	('apoptosis', 'CPA', (126, 135))	('SLFN12', 'Gene', '55106', (111, 117))	('c-myc', 'Gene', '4609', (9, 14))	('lung cancer', 'Disease', 'MESH:D008175', (57, 68))	('c-myc', 'Gene', (9, 14))	('SLFN12', 'Gene', (111, 117))	('induces', 'Reg', (118, 125))	('lung cancer', 'Disease', (57, 68))	('c-myc', 'Gene', '4609', (144, 149))
562639	32987632	This suggests that alterations in c-myc are one of the axes through which SLFN12 exerts its action, while other downstream targets of SLFN12 await future exploration.	('SLFN12', 'Gene', (134, 140))	('SLFN12', 'Gene', '55106', (74, 80))	('c-myc', 'Gene', '4609', (34, 39))	('SLFN12', 'Gene', (74, 80))	('SLFN12', 'Gene', '55106', (134, 140))	('c-myc', 'Gene', (34, 39))	('alterations', 'Var', (19, 30))
562647	32987632	Thus, it is possible that overexpressing SLFN12 might have an effect, while there is simply not enough basal SLFN12 to have much of an effect on c-myc without or with further reduction by the shRNA.	('SLFN12', 'Gene', (109, 115))	('effect', 'Reg', (135, 141))	('overexpressing', 'Var', (26, 40))	('SLFN12', 'Gene', (41, 47))	('c-myc', 'Gene', '4609', (145, 150))	('SLFN12', 'Gene', '55106', (41, 47))	('c-myc', 'Gene', (145, 150))	('SLFN12', 'Gene', '55106', (109, 115))
562706	32987632	On the next day, the cells were transfected with either AdSLFN12 or AdCMV as a control and incubated for 60 hours at 37  C with 5% CO2.	('AdCMV', 'Var', (68, 73))	('SLFN12', 'Gene', '55106', (58, 64))	('SLFN12', 'Gene', (58, 64))	('AdCMV', 'Chemical', '-', (68, 73))	('CO2', 'Chemical', 'MESH:D002245', (131, 134))
562715	32987632	On the following day, cells were infected with AdSLFN12 or AdCMV.	('infected', 'Disease', (33, 41))	('AdCMV', 'Var', (59, 64))	('SLFN12', 'Gene', '55106', (49, 55))	('SLFN12', 'Gene', (49, 55))	('AdCMV', 'Chemical', '-', (59, 64))	('infected', 'Disease', 'MESH:D007239', (33, 41))
562723	32987632	The cells were then infected with AdSLFN12 or AdCMV.	('infected', 'Disease', 'MESH:D007239', (20, 28))	('infected', 'Disease', (20, 28))	('AdCMV', 'Var', (46, 51))	('SLFN12', 'Gene', '55106', (36, 42))	('AdCMV', 'Chemical', '-', (46, 51))	('SLFN12', 'Gene', (36, 42))
562736	31831009	The authors also conducted the Receiver Operating Characteristic (ROC) curve analysis of several selected circRNAs and revealed high diagnostic potential of hsa_circ_0077837 and hsa_circ_0001821 in discriminating NSCLC from normal tissues.	('hsa_circ_0001821', 'Var', (178, 194))	('NSCLC', 'Disease', 'MESH:D002289', (213, 218))	('NSCLC', 'Phenotype', 'HP:0030358', (213, 218))	('hsa_circ_0077837', 'Var', (157, 173))	('NSCLC', 'Disease', (213, 218))
562737	31831009	Authors' results also highlighted the potential application of hsa_circ_0001073 and hsa_circ_0001495 for diagnostic in the histopathological subtyping of NSCLC.	('NSCLC', 'Phenotype', 'HP:0030358', (154, 159))	('NSCLC', 'Disease', 'MESH:D002289', (154, 159))	('hsa_circ_0001495', 'Var', (84, 100))	('NSCLC', 'Disease', (154, 159))
562740	31523055	Aberrations in Notch-Hedgehog signalling reveal cancer stem cells harbouring conserved oncogenic properties associated with hypoxia and immunoevasion Cancer stem cells (CSCs) have innate abilities to resist even the harshest of therapies.	('hypoxia', 'Disease', 'MESH:D000860', (124, 131))	('Notch', 'Gene', '31293', (15, 20))	('Cancer', 'Disease', 'MESH:D009369', (150, 156))	('Cancer', 'Disease', (150, 156))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('Cancer', 'Phenotype', 'HP:0002664', (150, 156))	('Aberrations', 'Var', (0, 11))	('cancer', 'Disease', (48, 54))	('cancer', 'Disease', 'MESH:D009369', (48, 54))	('hypoxia', 'Disease', (124, 131))	('Notch', 'Gene', (15, 20))
562754	31523055	Concentrating on Notch and Hedgehog signalling pathways, we seek to attain a comprehensive understanding of how somatic copy number alterations and expression profiles of pathway genes along with their downstream targets could influence tumour progression and prognosis.	('tumour', 'Phenotype', 'HP:0002664', (237, 243))	('Notch', 'Gene', (17, 22))	('tumour', 'Disease', 'MESH:D009369', (237, 243))	('prognosis', 'CPA', (260, 269))	('tumour', 'Disease', (237, 243))	('Notch', 'Gene', '31293', (17, 22))	('influence', 'Reg', (227, 236))	('copy number alterations', 'Var', (120, 143))
562760	31523055	Hedgehog signalling promotes the expression of Jagged2 (a Notch ligand) and in ovarian cancer mice models, inhibition of Jagged1 would sensitise tumours to docetaxel treatment by affecting GLI2 function.	('Jagged1', 'Gene', (121, 128))	('Jagged2', 'Gene', '16450', (47, 54))	('tumours', 'Phenotype', 'HP:0002664', (145, 152))	('mice', 'Species', '10090', (94, 98))	('expression', 'MPA', (33, 43))	('Notch', 'Gene', (58, 63))	('affecting', 'Reg', (179, 188))	('ovarian cancer', 'Disease', 'MESH:D010051', (79, 93))	('tumour', 'Phenotype', 'HP:0002664', (145, 151))	('sensitise tumours', 'Disease', (135, 152))	('docetaxel', 'Chemical', 'MESH:D000077143', (156, 165))	('sensitise tumours', 'Disease', 'MESH:D009369', (135, 152))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('ovarian cancer', 'Disease', (79, 93))	('ovarian cancer', 'Phenotype', 'HP:0100615', (79, 93))	('GLI2 function', 'MPA', (189, 202))	('Jagged2', 'Gene', (47, 54))	('Notch', 'Gene', '31293', (58, 63))	('inhibition', 'Var', (107, 117))	('Jagged1', 'Gene', '16449', (121, 128))
562784	31523055	Lung squamous cell carcinoma (LUSC) had the highest fraction of samples harbouring amplified Hedgehog genes, while endometrial cancer (UCEC) had the fewest somatic gains (Fig.	('amplified', 'Var', (83, 92))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('endometrial cancer', 'Disease', (115, 133))	('Lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (0, 28))	('carcinoma', 'Phenotype', 'HP:0030731', (19, 28))	('Hedgehog genes', 'Gene', (93, 107))	('endometrial cancer', 'Phenotype', 'HP:0012114', (115, 133))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (5, 28))	('endometrial cancer', 'Disease', 'MESH:D016889', (115, 133))	('Lung squamous cell carcinoma', 'Disease', (0, 28))
562833	31523055	CD105, CD29, CD44, CD73, CD90 and NESTIN were positively correlated with 13-gene scores in renal cancers (Fig.	('cancers', 'Phenotype', 'HP:0002664', (97, 104))	('NESTIN', 'Gene', '10763', (34, 40))	('CD44', 'Var', (13, 17))	('correlated', 'Reg', (57, 67))	('CD29', 'Var', (7, 11))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('CD105', 'Var', (0, 5))	('CD90', 'Var', (25, 29))	('CD7', 'Gene', (19, 22))	('renal cancers', 'Disease', 'MESH:D007680', (91, 104))	('renal cancers', 'Disease', (91, 104))	('renal cancer', 'Phenotype', 'HP:0009726', (91, 103))	('CD7', 'Gene', '924', (19, 22))	('NESTIN', 'Gene', (34, 40))
562834	31523055	S4); an observation which is consistent with these genes being markers of renal CSCs.	('renal CSCs', 'Disease', (74, 84))	('genes', 'Var', (51, 56))	('renal CSCs', 'Disease', 'MESH:D007674', (74, 84))
562842	31523055	To determine whether these associations harboured prognostic information, patients were categorised by their 13-gene scores and expression profiles of individual TFs into four categories: (1) high 13-gene score and high TF expression, (2) high 13-gene score and low TF expression, (3) low 13-gene score and high TF expression and (4) low 13-gene score and low TF expression (Fig.	('high 13-gene score', 'Var', (192, 210))	('expression', 'MPA', (315, 325))	('TF', 'Gene', '2152', (266, 268))	('high', 'Var', (239, 243))	('TF', 'Gene', '2152', (360, 362))	('patients', 'Species', '9606', (74, 82))	('low', 'NegReg', (356, 359))	('TF', 'Gene', '2152', (312, 314))	('TF', 'Gene', '2152', (220, 222))	('low', 'NegReg', (262, 265))	('low', 'NegReg', (285, 288))	('TF', 'Gene', '2152', (162, 164))
562848	31523055	Glioma stem cells have increased ability to stimulate angiogenesis through VEGF upregulation and inhibition of HIFs could reduce CSC survival, self-renewal and proliferation.	('inhibition', 'Var', (97, 107))	('VEGF', 'Gene', '7422', (75, 79))	('angiogenesis', 'CPA', (54, 66))	('reduce', 'NegReg', (122, 128))	('upregulation', 'PosReg', (80, 92))	('self-renewal', 'CPA', (143, 155))	('stimulate', 'PosReg', (44, 53))	('Glioma', 'Phenotype', 'HP:0009733', (0, 6))	('proliferation', 'CPA', (160, 173))	('Glioma', 'Disease', 'MESH:D005910', (0, 6))	('VEGF', 'Gene', (75, 79))	('HIFs', 'Gene', (111, 115))	('Glioma', 'Disease', (0, 6))	('CSC survival', 'CPA', (129, 141))
562867	31523055	Aberrations in the Notch-Hedgehog signalling axis are frequently implicated in malignant progression.	('Notch', 'Gene', '31293', (19, 24))	('malignant progression', 'CPA', (79, 100))	('Aberrations', 'Var', (0, 11))	('implicated', 'Reg', (65, 75))	('Notch', 'Gene', (19, 24))
562871	31523055	In clear cell renal cell carcinoma, inhibition of Notch signalling reduced anchorage-independent growth and mice treated with Notch inhibitors had impaired growth of transplanted cancer cells.	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (3, 34))	('anchorage-independent growth', 'CPA', (75, 103))	('Notch', 'Gene', (126, 131))	('inhibition', 'Var', (36, 46))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (14, 34))	('Notch', 'Gene', '31293', (50, 55))	('carcinoma', 'Phenotype', 'HP:0030731', (25, 34))	('Notch', 'Gene', '31293', (126, 131))	('mice', 'Species', '10090', (108, 112))	('reduced', 'NegReg', (67, 74))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (3, 34))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('impaired', 'NegReg', (147, 155))	('cancer', 'Disease', (179, 185))	('clear cell renal cell carcinoma', 'Disease', (3, 34))	('Notch', 'Gene', (50, 55))
562886	31523055	Inhibition of EZH2 in renal cancer cell lines led to increased apoptosis.	('renal cancer', 'Phenotype', 'HP:0009726', (22, 34))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('renal cancer', 'Disease', 'MESH:D007680', (22, 34))	('EZH2', 'Gene', (14, 18))	('EZH2', 'Gene', '2146', (14, 18))	('increased', 'PosReg', (53, 62))	('apoptosis', 'CPA', (63, 72))	('Inhibition', 'Var', (0, 10))	('renal cancer', 'Disease', (22, 34))
562971	31035945	Interestingly, AUC values for CA 125 were the lowest (0.7340 and 0.6309, respectively) among all tested parameters.	('lowest', 'NegReg', (46, 52))	('CA 125', 'Gene', '94025', (30, 36))	('AUC values', 'MPA', (15, 25))	('CA 125', 'Gene', (30, 36))	('0.6309', 'Var', (65, 71))
563030	28878842	Cells treated with EPZ-5687 displayed no appreciable change in H3K27me3.	('H3K27me3', 'Protein', (63, 71))	('EPZ-5687', 'Var', (19, 27))	('EPZ-5687', 'Chemical', '-', (19, 27))
563031	28878842	Cells treated with DZNeP showed the most dramatic expressional changes, with decreased EGFR in HPV-positive cell lines and an overall increase in proliferation markers in HPV-negative cell lines.	('HPV', 'Species', '10566', (171, 174))	('proliferation markers', 'CPA', (146, 167))	('EGFR', 'Gene', '1956', (87, 91))	('DZNeP', 'Chemical', '-', (19, 24))	('DZNeP', 'Var', (19, 24))	('EGFR', 'Gene', (87, 91))	('HPV', 'Species', '10566', (95, 98))	('increase', 'PosReg', (134, 142))	('decreased', 'NegReg', (77, 86))
563035	28878842	Our findings suggest that EZH2 inhibitors are a viable therapeutic option for the role of epigenetic effect, potentially sensitizing tumors to current chemotherapies or limiting cell differentiation.	('EZH2', 'Gene', '2146', (26, 30))	('tumors', 'Phenotype', 'HP:0002664', (133, 139))	('epigenetic effect', 'Var', (90, 107))	('EZH2', 'Gene', (26, 30))	('tumors', 'Disease', (133, 139))	('tumors', 'Disease', 'MESH:D009369', (133, 139))	('tumor', 'Phenotype', 'HP:0002664', (133, 138))	('limiting', 'NegReg', (169, 177))	('sensitizing', 'Reg', (121, 132))	('inhibitors', 'Var', (31, 41))	('cell differentiation', 'CPA', (178, 198))
563043	28878842	Histone methylation, an epigenetic modification, has come increasingly to the forefront of cancer research, with evidence of dysregulation of various histone modifications such as trimethylation at lysine 20 of histone H4 and trimethylation at lysine 27 of histone H3 (H3K27me3) to be integral in the development and maintenance, metastasis, and resistance to chemo- and radiotherapies of various cancers.	('lysine', 'Chemical', 'MESH:D008239', (244, 250))	('dysregulation', 'MPA', (125, 138))	('cancers', 'Disease', (397, 404))	('cancer', 'Disease', (397, 403))	('histone H4', 'Gene', '8294', (211, 221))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('trimethylation at lysine', 'Var', (226, 250))	('lysine', 'Chemical', 'MESH:D008239', (198, 204))	('cancers', 'Phenotype', 'HP:0002664', (397, 404))	('cancer', 'Phenotype', 'HP:0002664', (397, 403))	('trimethylation at lysine', 'Var', (180, 204))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('histone H4', 'Gene', (211, 221))	('cancer', 'Disease', 'MESH:D009369', (397, 403))	('cancers', 'Disease', 'MESH:D009369', (397, 404))
563045	28878842	Overexpression of EZH2 has frequently been associated with increased tumor aggression and poor clinical outcomes, as well as a potential role in the formation of cancer stem cells.	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('cancer', 'Disease', (162, 168))	('aggression', 'Phenotype', 'HP:0000718', (75, 85))	('EZH2', 'Gene', '2146', (18, 22))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('EZH2', 'Gene', (18, 22))	('Overexpression', 'Var', (0, 14))	('associated', 'Reg', (43, 53))	('tumor aggression', 'Disease', (69, 85))	('increased', 'PosReg', (59, 68))	('tumor aggression', 'Disease', 'MESH:D001523', (69, 85))
563048	28878842	p16(INK4A), a clinical surrogate marker for HPV positivity, further supported EZH2's role in HPV-mediated tumorigenesis as a global trend of H3K27me3 elevation is present within the HPV-positive patient epigenome.	('H3K27me3', 'Var', (141, 149))	('HPV', 'Species', '10566', (182, 185))	('elevation', 'PosReg', (150, 159))	('p16', 'Gene', (0, 3))	('patient', 'Species', '9606', (195, 202))	('HPV', 'Species', '10566', (93, 96))	('tumor', 'Disease', 'MESH:D009369', (106, 111))	('HPV', 'Species', '10566', (44, 47))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('p16', 'Gene', '1029', (0, 3))	('EZH2', 'Gene', '2146', (78, 82))	('EZH2', 'Gene', (78, 82))	('tumor', 'Disease', (106, 111))
563064	28878842	Membranes were washed extensively in PBST and incubated separately in 1:5000 HRP-conjugated anti-rabbit secondary antibody (Cat#: 170-5046 BIO-RAD) and 1:5000 HRP-conjugated anti-mouse secondary antibody (Cat#: 170-5047 BIO-RAD) for 1 h at room temperature in PBST + 5% milk.	('mouse', 'Species', '10090', (179, 184))	('RAD', 'Gene', (143, 146))	('rabbit', 'Species', '9986', (97, 103))	('RAD', 'Gene', (224, 227))	('PBS', 'Chemical', '-', (37, 40))	('PBS', 'Chemical', '-', (260, 263))	('RAD', 'Gene', '6236', (143, 146))	('Cat#: 170-5047', 'Var', (205, 219))	('RAD', 'Gene', '6236', (224, 227))
563074	28878842	A 1:100 dilution of anti-H3K27me2 primary antibody (ab194690 Abcam) in PBST + 5% milk solution was used to identify H3K27me2 expression following treatment (Additional file 2: Figure S12), followed by an incubation in 1:2000 HRP-conjugated anti-rabbit secondary antibody (Cat#: 170-6515 BIO-RAD) in PBST + 5% milk.	('RAD', 'Gene', (291, 294))	('PBS', 'Chemical', '-', (71, 74))	('rabbit', 'Species', '9986', (245, 251))	('RAD', 'Gene', '6236', (291, 294))	('H3K27me2', 'Var', (116, 124))	('PBS', 'Chemical', '-', (299, 302))
563085	28878842	GAPDH primers/probe (unique assay ID: dHsaCPE5031596/dHsaCPE5031597 BIO-RAD) were utilized as a secondary internal reference and compared to EEF2 values against a probe with known trends, EGFR (See Additional file 3: Figure S10).	('EGFR', 'Gene', '1956', (188, 192))	('RAD', 'Gene', (72, 75))	('EEF2', 'Gene', '1938', (141, 145))	('dHsaCPE5031596/dHsaCPE5031597', 'Var', (38, 67))	('EEF2', 'Gene', (141, 145))	('EGFR', 'Gene', (188, 192))	('GAPDH', 'Gene', '2597', (0, 5))	('RAD', 'Gene', '6236', (72, 75))	('GAPDH', 'Gene', (0, 5))
563090	28878842	Analysis of the Western blots show DZNeP-treated cell lines have a reduction of H3K27me3 only present in HPV-negative cell line SCC-1, while HPV-negative SCC-9 and HPV-positive cell lines (SCC-47 and SCC-104) appear to have H3K27me3 levels comparable to untreated or DMSO only-treated cells.	('H3K27me3', 'MPA', (224, 232))	('DZNeP', 'Chemical', '-', (35, 40))	('DZNeP-treated', 'Var', (35, 48))	('HPV', 'Species', '10566', (141, 144))	('DMSO', 'Chemical', 'MESH:D004121', (267, 271))	('reduction', 'NegReg', (67, 76))	('SCC-9', 'CellLine', 'CVCL:1685', (154, 159))	('HPV', 'Species', '10566', (105, 108))	('SCC-47', 'CellLine', 'CVCL:7759', (189, 195))	('HPV', 'Species', '10566', (164, 167))	('H3K27me3', 'Protein', (80, 88))
563093	28878842	To compare the baseline protein levels of EZH2 and H3K27me3 in individual cell lines, Western blot analysis was performed utilizing either an anti-EZH2 or anti-H3K27me3 antibody (Fig.	('anti-H3K27me3', 'Var', (155, 168))	('EZH2', 'Gene', '2146', (147, 151))	('EZH2', 'Gene', (147, 151))	('EZH2', 'Gene', '2146', (42, 46))	('EZH2', 'Gene', (42, 46))
563098	28878842	SCC-1 and SCC-47 show the highest levels of H3K27me3 relative to the other cell lines; however, HPV-positive SCC-47 displays low EZH2 expression and HPV-negative SCC-1 displays high EZH2 expression.	('HPV', 'Species', '10566', (96, 99))	('SCC-47', 'CellLine', 'CVCL:7759', (109, 115))	('expression', 'MPA', (134, 144))	('HPV', 'Species', '10566', (149, 152))	('EZH2', 'Gene', (182, 186))	('EZH2', 'Gene', '2146', (182, 186))	('SCC-47', 'Gene', (109, 115))	('SCC-47', 'CellLine', 'CVCL:7759', (10, 16))	('EZH2', 'Gene', '2146', (129, 133))	('HPV-positive', 'Var', (96, 108))	('low', 'NegReg', (125, 128))	('EZH2', 'Gene', (129, 133))
563105	28878842	Again, EPZ-5687 had no appreciable reduction in H3K27me3, with levels remaining comparable to DMSO or untreated cells.	('EPZ-5687', 'Var', (7, 15))	('EPZ-5687', 'Chemical', '-', (7, 15))	('H3K27me3', 'Protein', (48, 56))	('DMSO', 'Chemical', 'MESH:D004121', (94, 98))	('reduction', 'NegReg', (35, 44))
563115	28878842	Treatment with DZNeP displayed the greatest variability and overall amount of expressional changes within the cell lines relative to GSK-343 and EPZ-5687.	('DZNeP', 'Chemical', '-', (15, 20))	('DZNeP', 'Var', (15, 20))	('GSK-343', 'Chemical', 'MESH:C586265', (133, 140))	('expressional', 'MPA', (78, 90))	('EPZ-5687', 'Chemical', '-', (145, 153))
563153	28878842	Leukemia and prostate models have demonstrated DZNeP's anti-proliferative and anti-metastatic properties, respectively, and reduced tumor-mitigated angiogenesis in a glioblastoma xenograft model.	('glioblastoma', 'Phenotype', 'HP:0012174', (166, 178))	('Leukemia', 'Disease', 'MESH:D007938', (0, 8))	('reduced', 'NegReg', (124, 131))	('tumor', 'Disease', 'MESH:D009369', (132, 137))	('DZNeP', 'Var', (47, 52))	('anti-metastatic properties', 'CPA', (78, 104))	('tumor', 'Phenotype', 'HP:0002664', (132, 137))	('Leukemia', 'Disease', (0, 8))	('DZNeP', 'Chemical', '-', (47, 52))	('tumor', 'Disease', (132, 137))	('Leukemia', 'Phenotype', 'HP:0001909', (0, 8))	('anti-proliferative', 'CPA', (55, 73))	('glioblastoma', 'Disease', (166, 178))	('glioblastoma', 'Disease', 'MESH:D005909', (166, 178))
563166	28878842	EPZ-5687 showed very little efficacy in both the ability to demethylate H3K27me3 or lead to desired expressional changes of observed genes within an OPSCC model.	('demethylate', 'Var', (60, 71))	('lead to', 'Reg', (84, 91))	('SCC', 'Gene', '6317', (151, 154))	('EPZ-5687', 'Chemical', '-', (0, 8))	('OPSCC', 'Phenotype', 'HP:0012182', (149, 154))	('H3K27me3', 'Protein', (72, 80))	('expressional changes', 'MPA', (100, 120))	('SCC', 'Gene', (151, 154))
563167	28878842	These results were unexpected given EPZ-5687 is also an S-adenosyl-L-methionine (SAM)-competitive inhibitor of EZH2 and has shown > 500-fold selectivity to EZH2 over other human protein methylases in lymphoma models.	('lymphoma', 'Disease', 'MESH:D008223', (200, 208))	('lymphoma', 'Phenotype', 'HP:0002665', (200, 208))	('S-adenosyl-L-methionine', 'Chemical', 'MESH:D012436', (56, 79))	('EPZ-5687', 'Var', (36, 44))	('human', 'Species', '9606', (172, 177))	('EZH2', 'Gene', '2146', (111, 115))	('EZH2', 'Gene', '2146', (156, 160))	('EZH2', 'Gene', (111, 115))	('EZH2', 'Gene', (156, 160))	('lymphoma', 'Disease', (200, 208))	('EPZ-5687', 'Chemical', '-', (36, 44))	('SAM', 'Chemical', 'MESH:D012436', (81, 84))
563168	28878842	The possibility of this discrimination could be due to EPZ-5687's > 5-fold affinity to the A677G mutant over EZH2 wildtype, but H3K27me3 inhibition was still present in both variants.	('A677G', 'Var', (91, 96))	('EPZ-5687', 'Chemical', '-', (55, 63))	('A677G', 'Mutation', 'rs1057519833', (91, 96))	('EZH2', 'Gene', '2146', (109, 113))	('EZH2', 'Gene', (109, 113))
563172	28878842	Theoretically, varying methylation at promotor regions may limit the epigenetic effects of EZH2 inhibitors, instead only reactivating genes not silenced by DNA methylation.	('EZH2', 'Gene', (91, 95))	('EZH2', 'Gene', '2146', (91, 95))	('epigenetic effects', 'MPA', (69, 87))	('reactivating', 'PosReg', (121, 133))	('methylation', 'Var', (23, 34))	('limit', 'NegReg', (59, 64))	('inhibitors', 'Var', (96, 106))	('varying methylation', 'Var', (15, 34))
563174	28878842	Therefore, desired epigenetic effects of EZH2 inhibitors may be further enhanced by combination with Dnmt inhibitors such as 5-azacytidine.	('inhibitors', 'Var', (46, 56))	('Dnmt', 'Gene', '1786', (101, 105))	('EZH2', 'Gene', (41, 45))	('EZH2', 'Gene', '2146', (41, 45))	('combination', 'Interaction', (84, 95))	('epigenetic effects', 'MPA', (19, 37))	('enhanced', 'PosReg', (72, 80))	('5-azacytidine', 'Chemical', 'MESH:D001374', (125, 138))	('Dnmt', 'Gene', (101, 105))
563175	28878842	5-Azacytidine, for example, has been shown to cause neutropenia.	('cause', 'Reg', (46, 51))	('neutropenia', 'Disease', (52, 63))	('5-Azacytidine', 'Var', (0, 13))	('neutropenia', 'Disease', 'MESH:D009503', (52, 63))	('neutropenia', 'Phenotype', 'HP:0001875', (52, 63))	('5-Azacytidine', 'Chemical', 'MESH:D001374', (0, 13))
563178	28878842	ChIP-sequence analyses performed on colon, breast, and leukemia cancer cell lines by Sato and colleagues has already shown evidence for the synergistic effects of Dnmt inhibitors with histone methyltransferase inhibitors while maintaining their selectivity toward various oncogenes.	('Dnmt', 'Gene', (163, 167))	('histone methyltransferase', 'Gene', '56979', (184, 209))	('Dnmt', 'Gene', '1786', (163, 167))	('leukemia cancer', 'Disease', 'MESH:D009369', (55, 70))	('leukemia cancer', 'Disease', (55, 70))	('leukemia', 'Phenotype', 'HP:0001909', (55, 63))	('histone methyltransferase', 'Gene', (184, 209))	('inhibitors', 'Var', (168, 178))	('cancer', 'Phenotype', 'HP:0002664', (64, 70))
563184	28878842	suggests DMSO impacting a cell's epigenetic profile.	('DMSO', 'Var', (9, 13))	('epigenetic profile', 'MPA', (33, 51))	('DMSO', 'Chemical', 'MESH:D004121', (9, 13))	('impacting', 'Reg', (14, 23))
563186	28878842	Contrasting results were seen in a study performed by Kita et al., showing DMSO reducing stemness in association with decreased DNMT3A and DNMT3L expression.	('DMSO', 'Var', (75, 79))	('DNMT3A', 'Gene', (128, 134))	('DMSO', 'Chemical', 'MESH:D004121', (75, 79))	('stemness', 'Disease', 'MESH:D020295', (89, 97))	('stemness', 'Disease', (89, 97))	('DNMT3L', 'Gene', (139, 145))	('decreased', 'NegReg', (118, 127))	('reducing', 'NegReg', (80, 88))	('expression', 'MPA', (146, 156))	('DNMT3A', 'Gene', '1788', (128, 134))	('DNMT3L', 'Gene', '29947', (139, 145))
563192	28878842	In HNSCC cell culture models, the targeting of EZH2 and its related pathways appears to have anti-tumorigenic effects which may be dependent on oncogenic HPV status.	('SCC', 'Gene', '6317', (5, 8))	('HNSCC', 'Phenotype', 'HP:0012288', (3, 8))	('EZH2', 'Gene', (47, 51))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('targeting', 'Var', (34, 43))	('SCC', 'Gene', (5, 8))	('tumor', 'Disease', (98, 103))	('HPV', 'Species', '10566', (154, 157))	('EZH2', 'Gene', '2146', (47, 51))
563227	28423526	Similar, high density of M2 macrophages in tumor islet also were correlated with lymph node metastasis of ESCCs (P < 0.05).	('high density', 'Var', (9, 21))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('ESCCs', 'Disease', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('lymph node metastasis', 'CPA', (81, 102))	('correlated with', 'Reg', (65, 80))	('tumor', 'Disease', (43, 48))
563235	28423526	We compared three categories of MMP9 positive staining combinations (1+, 2+/3+, and 1+/2+/3+) to MMP9 negative (0) staining (Table 4).	('1+/2+/3+', 'Var', (84, 92))	('MMP9', 'Gene', '4318', (97, 101))	('MMP9', 'Gene', (97, 101))	('MMP9', 'Gene', '4318', (32, 36))	('MMP9', 'Gene', (32, 36))
563240	28423526	Cases with high MMP9 expression showed strong invasion (T3-T4 vs T1-T2 = 63.1% vs 40.0%; P < 0.05) and metastasis (pN+ vs pN- =73.5% vs 37.7%; P = 0.001), and were clearly present in advanced ESCC stages (III-IV vs I-II = 78.9% vs 40.3%; P < 0.001) (Table 5).	('ESCC', 'Disease', (192, 196))	('high', 'Var', (11, 15))	('MMP9', 'Gene', '4318', (16, 20))	('MMP9', 'Gene', (16, 20))	('metastasis', 'CPA', (103, 113))	('invasion', 'CPA', (46, 54))
563249	28423526	Moreover, after Multivariate Cox proportional hazard analysis, we found high-density of M2 macrophages in tumor stroma could serve as an independent prognostic factor for the patients of Kazakh ESCCs (HR = 5.464, P < 0.05, Table 6).	('tumor stroma', 'Disease', 'MESH:D009369', (106, 118))	('tumor stroma', 'Disease', (106, 118))	('patients', 'Species', '9606', (175, 183))	('tumor', 'Phenotype', 'HP:0002664', (106, 111))	('high-density', 'Var', (72, 84))
563258	28423526	He and Clear's studies also showed that a high-density of macrophages was associated with worse prognosis in oral cancer and Follicular lymphoma.	('Follicular lymphoma', 'Disease', 'MESH:D008224', (125, 144))	('oral cancer', 'Disease', (109, 120))	('Follicular lymphoma', 'Disease', (125, 144))	('lymphoma', 'Phenotype', 'HP:0002665', (136, 144))	('high-density', 'Var', (42, 54))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('oral cancer', 'Disease', 'MESH:D009062', (109, 120))
563263	28423526	We found the mean value of MVD in tumor was significantly higher compared to corresponding CAN tissues, similar to classify of M2 macrophages density, high MVD in tumor was significantly associated with more malignant phenotypes including lymph node metastasis and clinical stage progression.	('tumor', 'Disease', (34, 39))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('high', 'Var', (151, 155))	('lymph node metastasis', 'CPA', (239, 260))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('MVD', 'MPA', (156, 159))	('clinical stage progression', 'CPA', (265, 291))	('more', 'PosReg', (203, 207))	('malignant phenotypes', 'CPA', (208, 228))	('tumor', 'Disease', (163, 168))	('associated with', 'Reg', (187, 202))	('tumor', 'Disease', 'MESH:D009369', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (34, 39))
563269	28423526	Furthermore, high expression of MMP9 was significantly associated with invasion depth, lymph node metastasis and later clinical stage of Kazakh ESCCs.	('high', 'Var', (13, 17))	('associated', 'Reg', (55, 65))	('invasion depth', 'CPA', (71, 85))	('MMP9', 'Gene', '4318', (32, 36))	('MMP9', 'Gene', (32, 36))	('lymph node metastasis', 'CPA', (87, 108))
563275	28423526	Moreover, the results were also similar to some tumor vitro studies, genetic ablation of MMP9 in tumor recipients, resulting in decreased MVD in developing tumors and even preventing the angiogenic switch during cancer progression, provided original evidence for the functional involvement of host MMP9 in tumor angiogenesis.	('MMP9', 'Gene', '4318', (89, 93))	('MMP9', 'Gene', (89, 93))	('angiogenic switch', 'MPA', (187, 204))	('ablation', 'Var', (77, 85))	('tumor', 'Disease', (306, 311))	('cancer', 'Disease', 'MESH:D009369', (212, 218))	('tumor', 'Disease', (156, 161))	('preventing', 'NegReg', (172, 182))	('tumor', 'Disease', 'MESH:D009369', (306, 311))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('tumor', 'Disease', (97, 102))	('decreased', 'NegReg', (128, 137))	('tumors', 'Phenotype', 'HP:0002664', (156, 162))	('MMP9', 'Gene', '4318', (298, 302))	('MMP9', 'Gene', (298, 302))	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('tumor', 'Disease', (48, 53))	('men', 'Species', '9606', (285, 288))	('tumor', 'Phenotype', 'HP:0002664', (306, 311))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('cancer', 'Disease', (212, 218))	('tumor', 'Disease', 'MESH:D009369', (48, 53))	('tumors', 'Disease', (156, 162))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('tumors', 'Disease', 'MESH:D009369', (156, 162))	('tumor', 'Phenotype', 'HP:0002664', (48, 53))
563276	28423526	Specific ablation of MMP9 positive TAMs with zoledronic acid resulted in reduced tumor angiogenesis, leading to a conclusion that TAMs deliver angiogenesis-inducing MMP9 are implicated in invasion-promoting processes such as flicking of the angiogenic switch.	('TAMs', 'Chemical', '-', (130, 134))	('MMP9', 'Gene', '4318', (165, 169))	('MMP9', 'Gene', '4318', (21, 25))	('ablation', 'Var', (9, 17))	('zoledronic acid', 'Chemical', 'MESH:D000077211', (45, 60))	('reduced', 'NegReg', (73, 80))	('tumor', 'Disease', 'MESH:D009369', (81, 86))	('TAMs', 'Chemical', '-', (35, 39))	('tumor', 'Phenotype', 'HP:0002664', (81, 86))	('MMP9', 'Gene', (165, 169))	('tumor', 'Disease', (81, 86))	('MMP9', 'Gene', (21, 25))
563334	31131124	Enlargement of all extraocular muscles sparing the musculotendinous junctions and involving the left and right orbits symmetrically is typically associated with Graves disease.	('Enlargement', 'Var', (0, 11))	('Graves disease', 'Phenotype', 'HP:0100647', (161, 175))	('associated', 'Reg', (145, 155))	('Graves disease', 'Disease', (161, 175))	('Graves disease', 'Disease', 'MESH:D006111', (161, 175))
563338	26553224	It remains unclear how variations in p-STAT3 expression influence clinical outcomes in esophageal squamous cell carcinoma (ESCC).	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (87, 121))	('STAT3', 'Gene', '6774', (39, 44))	('esophageal squamous cell carcinoma', 'Disease', (87, 121))	('STAT3', 'Gene', (39, 44))	('carcinoma', 'Phenotype', 'HP:0030731', (112, 121))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (98, 121))	('influence', 'Reg', (56, 65))	('variations', 'Var', (23, 33))
563390	26553224	The median overall survival time on this study of 8.9 months in patients with positive expression of pSTAT3 and 9.9 months in p-STAT3 negative group is comparable to the results in phase II and III studies testing platinoid-based combinations.	('STAT3', 'Gene', '6774', (128, 133))	('patients', 'Species', '9606', (64, 72))	('STAT3', 'Gene', (128, 133))	('STAT3', 'Gene', '6774', (102, 107))	('positive expression', 'Var', (78, 97))	('STAT3', 'Gene', (102, 107))
563401	26553224	More importantly, high expression of STAT3 was found to have a highly significant relationship with advanced tumor stage (P = 0.047) and poor prognosis (P = 0.023).	('advanced tumor', 'Disease', 'MESH:D020178', (100, 114))	('STAT3', 'Gene', '6774', (37, 42))	('STAT3', 'Gene', (37, 42))	('high', 'Var', (18, 22))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('advanced tumor', 'Disease', (100, 114))
563403	26553224	Similarly, in our study, we determined that high expression of STAT3 significantly correlated with poor prognosis.	('correlated', 'Reg', (83, 93))	('high', 'Var', (44, 48))	('STAT3', 'Gene', (63, 68))	('STAT3', 'Gene', '6774', (63, 68))
563423	33292100	The resulting uracil-induced mutations contribute to genomic variation, which may result in neutral, beneficial or harmful consequences for the cancer.	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('genomic variation', 'MPA', (53, 70))	('uracil', 'Chemical', 'MESH:D014498', (14, 20))	('mutations', 'Var', (29, 38))	('cancer', 'Disease', (144, 150))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
563428	33292100	It has long been known that cancer has a basis in somatic mutations that alter a diversity of cellular functions resulting in sustained proliferative signalling, evasion of growth suppressors and genome instability.	('mutations', 'Var', (58, 67))	('evasion', 'MPA', (162, 169))	('cancer', 'Phenotype', 'HP:0002664', (28, 34))	('growth', 'CPA', (173, 179))	('sustained proliferative signalling', 'MPA', (126, 160))	('genome instability', 'CPA', (196, 214))	('cancer', 'Disease', 'MESH:D009369', (28, 34))	('cancer', 'Disease', (28, 34))	('alter', 'Reg', (73, 78))
563432	33292100	and Roberts et al.. Then, in 2013, the extensive resources generated by The Cancer Genome Atlas (TCGA) revealed APOBEC mutagenesis in multiple cancer types.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('Cancer', 'Phenotype', 'HP:0002664', (76, 82))	('Cancer', 'Disease', 'MESH:D009369', (76, 82))	('Cancer', 'Disease', (76, 82))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('mutagenesis', 'Var', (119, 130))	('APOBEC', 'Gene', (112, 118))
563433	33292100	There are seven APOBEC3 (A3) enzymes in humans (A3A-H, excluding E) that are capable of inducing DNA mutations through the deamination of cytosine to form promutagenic uracil on single-stranded (ss) DNA.	('uracil', 'Chemical', 'MESH:D014498', (168, 174))	('mutations', 'Var', (101, 110))	('APOBEC3', 'Gene', '140564', (16, 23))	('APOBEC3', 'Gene', (16, 23))	('A3A', 'Gene', '200315', (48, 51))	('A3', 'Chemical', '-', (25, 27))	('A3A', 'Gene', (48, 51))	('A3', 'Chemical', '-', (48, 50))	('humans', 'Species', '9606', (40, 46))	('DNA', 'Gene', (97, 100))	('cytosine', 'Chemical', 'MESH:D003596', (138, 146))	('inducing', 'Reg', (88, 96))	('deamination', 'MPA', (123, 134))
563452	33292100	However, A3-mediated deamination of cytosines to uracils can also lead to C-to-T mutations directly through DNA replication using uracil as a template or other mutations by translesion synthesis (TLS) polymerases that insert incorrect bases opposite abasic sites after uracil removal.	('C-to-T', 'Gene', (74, 80))	('mutations', 'Var', (160, 169))	('uracil', 'Chemical', 'MESH:D014498', (49, 55))	('A3-mediated', 'Var', (9, 20))	('uracils', 'Chemical', 'MESH:D014498', (49, 56))	('uracil', 'Chemical', 'MESH:D014498', (269, 275))	('lead to', 'Reg', (66, 73))	('mutations', 'Var', (81, 90))	('uracil', 'Chemical', 'MESH:D014498', (130, 136))	('cytosines', 'Chemical', 'MESH:D003596', (36, 45))	('DNA', 'Disease', (108, 111))	('A3', 'Chemical', '-', (9, 11))
563453	33292100	According to yeast experiments, the observed C-to-G transversions that are linked to A3 deamination activity may be caused by TLS bypass over an abasic site by REV1 and DNA polymerase zeta after uracil base removal by UNG2.	('uracil', 'Chemical', 'MESH:D014498', (195, 201))	('UNG', 'Gene', (218, 221))	('A3', 'Chemical', '-', (85, 87))	('REV1', 'Gene', (160, 164))	('C-to-G', 'Var', (45, 51))	('yeast', 'Species', '4932', (13, 18))	('caused by', 'Reg', (116, 125))	('transversions', 'Var', (52, 65))	('REV1', 'Gene', '854527', (160, 164))	('UNG', 'Gene', '7374', (218, 221))	('bypass over', 'PosReg', (130, 141))	('TLS', 'Gene', (126, 129))	('men', 'Species', '9606', (25, 28))
563462	33292100	A3G was the first A3 enzyme demonstrated to have restriction activity against HIV infection through G-to-A mutations in the sense DNA strand creating non-infectious virions when uracils in the anti-sense DNA were used as a template in DNA synthesis.	('HIV infection', 'Disease', 'MESH:D015658', (78, 91))	('uracils', 'Chemical', 'MESH:D014498', (178, 185))	('mutations', 'Var', (107, 116))	('DNA', 'Gene', (130, 133))	('A3', 'Chemical', '-', (0, 2))	('HIV infection', 'Disease', (78, 91))	('A3G', 'Gene', (0, 3))	('A3', 'Chemical', '-', (18, 20))	('non-infectious virions', 'MPA', (150, 172))	('A3G', 'Gene', '60489', (0, 3))
563469	33292100	Otherwise, A3B would suppress viral replication through deamination of cytosines.	('viral replication', 'CPA', (30, 47))	('A3B', 'Var', (11, 14))	('deamination of cytosines', 'MPA', (56, 80))	('cytosines', 'Chemical', 'MESH:D003596', (71, 80))	('suppress', 'NegReg', (21, 29))
563478	33292100	In general, these mutations occur randomly across the genome during our lifetime and sometimes the 'wrong combination' of somatic mutations can transform a normal cell into a tumoural cell.	('tumour', 'Phenotype', 'HP:0002664', (175, 181))	('mutations', 'Var', (130, 139))	('transform', 'Reg', (144, 153))	('tumoural', 'Disease', 'MESH:D009369', (175, 183))	('tumoural', 'Disease', (175, 183))
563479	33292100	Four members of A3 enzymes contain two zinc-coordinating domains (A3B, A3D, A3F and A3G) and three members contain one zinc-coordinating domain (A3A, A3C and A3H) with the consensus sequence His-X-Glu-X23-28-Pro-Cys-X2-4-Cys (figure 1a).	('A3', 'Chemical', '-', (158, 160))	('A3G', 'Gene', (84, 87))	('A3A', 'Gene', (145, 148))	('A3H', 'Gene', (158, 161))	('A3', 'Chemical', '-', (84, 86))	('A3H', 'Gene', '164668', (158, 161))	('A3', 'Chemical', '-', (76, 78))	('Glu', 'Chemical', 'MESH:D018698', (197, 200))	('A3', 'Chemical', '-', (150, 152))	('A3A', 'Gene', '200315', (145, 148))	('A3', 'Chemical', '-', (66, 68))	('zinc-coordinating', 'MPA', (39, 56))	('A3', 'Chemical', '-', (145, 147))	('His', 'Chemical', 'MESH:D006639', (191, 194))	('A3C', 'Mutation', 'c.3A>C', (150, 153))	('A3G', 'Gene', '60489', (84, 87))	('His-X-Glu-X23-28-Pro-Cys-X2-4-Cys', 'Var', (191, 224))	('A3', 'Chemical', '-', (71, 73))	('A3', 'Chemical', '-', (16, 18))
563482	33292100	The APOBEC enzymes induce mutations in a sequence-specific manner and the majority of A3 family members preferentially deaminate the central cytidine in 5'HTCW trinucleotide motifs (where H = A, C or T and W = A or T; the deaminated based is underlined) within ssDNA substrate, except A3G (5'CCCA) that deaminates cytidines in a different sequence motif.	('cytidines', 'Chemical', 'MESH:D003562', (314, 323))	('A3G', 'Gene', (285, 288))	('APOBEC', 'Gene', (4, 10))	('mutations', 'Var', (26, 35))	('A3', 'Chemical', '-', (86, 88))	('cytidine', 'Chemical', 'MESH:D003562', (141, 149))	('cytidine', 'Chemical', 'MESH:D003562', (314, 322))	('trinucleotide', 'Chemical', '-', (160, 173))	('A3', 'Chemical', '-', (285, 287))	('A3G', 'Gene', '60489', (285, 288))
563484	33292100	A3D, A3G and A3F all bind cellular RNA and form a ribonucleoprotein high molecular weight molecule that is catalytically inactive in vitro unless treated with RNaseA.	('A3D', 'Var', (0, 3))	('A3', 'Chemical', '-', (13, 15))	('A3', 'Chemical', '-', (0, 2))	('A3G', 'Gene', (5, 8))	('A3G', 'Gene', '60489', (5, 8))	('RNA', 'Protein', (35, 38))	('bind', 'Interaction', (21, 25))	('A3F', 'Var', (13, 16))	('A3', 'Chemical', '-', (5, 7))
563493	33292100	The deoxycytidine deaminase activity of A3A, A3B and A3H Hap I, as leading candidates, has been implicated in cancer and tumour evolution by providing the cells with a diverse pool of mutations.	('cancer', 'Disease', (110, 116))	('A3H', 'Gene', '164668', (53, 56))	('cytidine deaminase', 'Gene', '978', (9, 27))	('tumour', 'Phenotype', 'HP:0002664', (121, 127))	('cytidine deaminase', 'Gene', (9, 27))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('A3H', 'Gene', (53, 56))	('tumour', 'Disease', 'MESH:D009369', (121, 127))	('A3B', 'Var', (45, 48))	('tumour', 'Disease', (121, 127))	('A3A', 'Gene', '200315', (40, 43))	('A3A', 'Gene', (40, 43))	('implicated', 'Reg', (96, 106))	('cancer', 'Disease', 'MESH:D009369', (110, 116))
563506	33292100	The processivity of several members of the AID/APOBEC family members on ssDNA has been reported and the results have implications for the finding that mutations associated with AID or A3s are often clustered.	('AID', 'Gene', (177, 180))	('A3s', 'Chemical', '-', (184, 187))	('AID', 'Gene', '57379', (177, 180))	('AID', 'Gene', '57379', (43, 46))	('AID', 'Gene', (43, 46))	('A3s', 'Gene', (184, 187))	('mutations', 'Var', (151, 160))
563510	33292100	The ability to cycle between ssDNA substrates was important to not only quickly access the transiently ssDNA being replicated but also ssDNA bound by RPA, suggesting that the ability to compete for ssDNA rather than processivity was most important for A3s to induce 'off-target' deaminations.	('A3s', 'Chemical', '-', (252, 255))	('RPA', 'Gene', '6117', (150, 153))	('A3s', 'Var', (252, 255))	('deaminations', 'MPA', (279, 291))	('RPA', 'Gene', (150, 153))	("'off-target'", 'PosReg', (266, 278))
563514	33292100	These results demonstrate that during replication stress where larger amounts of ssDNA accumulate, the protective RPA barrier is less effective against A3A, A3B and A3H Hap I.	('A3H', 'Gene', (165, 168))	('less', 'NegReg', (129, 133))	('RPA', 'Gene', (114, 117))	('A3H', 'Gene', '164668', (165, 168))	('A3B', 'Var', (157, 160))	('A3A', 'Gene', '200315', (152, 155))	('A3A', 'Gene', (152, 155))	('RPA', 'Gene', '6117', (114, 117))
563518	33292100	For A3A, there was an association of mutations in a yeast system with the non-transcribed strand, but the majority of mutations correlated with the lagging strand of replication.	('correlated', 'Reg', (128, 138))	('A3A', 'Gene', '200315', (4, 7))	('A3A', 'Gene', (4, 7))	('mutations', 'Var', (118, 127))	('lagging strand of replication', 'MPA', (148, 177))	('mutations', 'Var', (37, 46))	('non-transcribed strand', 'MPA', (74, 96))	('association', 'Interaction', (22, 33))	('yeast', 'Species', '4932', (52, 57))
563519	33292100	No cellular studies examining A3H Hap I in this regard are available, but a study using a bioinformatics approach has suggested that A3H Hap I could act early in lung cancer mutations and possibly contribute to the APOBEC signature in A3B-null BRCA.	('BRCA', 'Gene', '672', (244, 248))	('contribute', 'Reg', (197, 207))	('A3H', 'Gene', '164668', (133, 136))	('A3H', 'Gene', '164668', (30, 33))	('lung cancer', 'Disease', 'MESH:D008175', (162, 173))	('BRCA', 'Gene', (244, 248))	('A3H', 'Gene', (30, 33))	('lung cancer', 'Disease', (162, 173))	('lung cancer', 'Phenotype', 'HP:0100526', (162, 173))	('A3H', 'Gene', (133, 136))	('mutations', 'Var', (174, 183))	('cancer', 'Phenotype', 'HP:0002664', (167, 173))
563525	33292100	Genomic instability is one of the hallmarks of cancer that cause both aberrant chromosomal architecture and mutational changes at the single nucleotide level.	('mutational', 'Var', (108, 118))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('Genomic', 'Disease', (0, 7))	('cancer', 'Disease', (47, 53))	('cause', 'Reg', (59, 64))	('aberrant', 'Var', (70, 78))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))
563528	33292100	In addition to other endogenous mutational factors, now it is well known that some members of the A3 enzymes are an endogenous source of somatic mutations found in approximately 15% of sequenced human tumours such as, BRCA, bladder, cervix, lung (adenocarcinoma and squamous cell carcinoma), head and neck, myeloma, renal cell carcinoma, stomach and thyroid.	('carcinoma', 'Phenotype', 'HP:0030731', (327, 336))	('stomach', 'Disease', (338, 345))	('mutations', 'Var', (145, 154))	('tumours', 'Disease', (201, 208))	('tumours', 'Phenotype', 'HP:0002664', (201, 208))	('cervix', 'Disease', (233, 239))	('myeloma', 'Disease', (307, 314))	('tumours', 'Disease', 'MESH:D009369', (201, 208))	('thyroid', 'Disease', (350, 357))	('renal cell carcinoma', 'Disease', 'MESH:C538614', (316, 336))	('adenocarcinoma and squamous cell carcinoma', 'Disease', 'MESH:D002294', (247, 289))	('tumour', 'Phenotype', 'HP:0002664', (201, 207))	('BRCA', 'Gene', '672', (218, 222))	('carcinoma', 'Phenotype', 'HP:0030731', (252, 261))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (266, 289))	('renal cell carcinoma', 'Disease', (316, 336))	('bladder', 'Disease', (224, 231))	('BRCA', 'Gene', (218, 222))	('A3', 'Chemical', '-', (98, 100))	('human', 'Species', '9606', (195, 200))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (316, 336))	('carcinoma', 'Phenotype', 'HP:0030731', (280, 289))	('myeloma', 'Disease', 'MESH:D009101', (307, 314))
563530	33292100	The APOBEC family of cytidine deaminases generates particular genome-wide mutational signatures and a signature of localized hypermutation called 'kataegis' or 'mutation clusters'.	('cytidine deaminase', 'Gene', (21, 39))	('mutational', 'Var', (74, 84))	('APOBEC family', 'Gene', (4, 17))	('cytidine deaminase', 'Gene', '978', (21, 39))
563531	33292100	Two signatures characterized by C-to-T and/or C-to-G mutations at TpCpX trinucleotides were identified (the underlined base is the mutated base and X can be any base) in several cancer types and are among the most common mutational signatures found in human cancer.	('cancer', 'Phenotype', 'HP:0002664', (258, 264))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('C-to-G mutations', 'Var', (46, 62))	('trinucleotides', 'Chemical', '-', (72, 86))	('C-to-T', 'Var', (32, 38))	('cancer', 'Disease', 'MESH:D009369', (258, 264))	('cancer', 'Disease', (178, 184))	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('TpCpX', 'Gene', (66, 71))	('cancer', 'Disease', (258, 264))	('human', 'Species', '9606', (252, 257))
563532	33292100	Signature 2 is composed predominantly of C-to-T transitions with fewer C-to-G transversions and Signature 13 is dominated by C-to-G transversions at a TpCpX sequence context and due to error-prone repair of APOBEC-induced uracils.	('uracils', 'Chemical', 'MESH:D014498', (222, 229))	('transversions', 'Var', (132, 145))	('APOBEC-induced', 'Gene', (207, 221))	('C-to-G transversions', 'Var', (125, 145))
563541	33292100	The 'off-target' mutations in the host genome produced by members of the A3 family, that are the basis of its relationship to cancer, has been associated with cancer development, progression, metastasis and drug resistance.	('cancer', 'Disease', (159, 165))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	("'off-target'", 'PosReg', (4, 16))	('associated', 'Reg', (143, 153))	('men', 'Species', '9606', (173, 176))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('cancer', 'Disease', (126, 132))	('progression', 'CPA', (179, 190))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('drug resistance', 'CPA', (207, 222))	('A3', 'Chemical', '-', (73, 75))	('drug resistance', 'Phenotype', 'HP:0020174', (207, 222))	('metastasis', 'CPA', (192, 202))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('mutations', 'Var', (17, 26))
563542	33292100	Most cancer cells and tumours show overexpression (20- to 60-fold) of A3B, A3A or A3H Hap I mRNA.	('tumours', 'Phenotype', 'HP:0002664', (22, 29))	('tumour', 'Phenotype', 'HP:0002664', (22, 28))	('cancer', 'Disease', 'MESH:D009369', (5, 11))	('tumours', 'Disease', 'MESH:D009369', (22, 29))	('A3H', 'Gene', '164668', (82, 85))	('cancer', 'Disease', (5, 11))	('tumours', 'Disease', (22, 29))	('A3H', 'Gene', (82, 85))	('A3A', 'Gene', '200315', (75, 78))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))	('overexpression', 'PosReg', (35, 49))	('A3B', 'Var', (70, 73))	('A3A', 'Gene', (75, 78))
563545	33292100	Mutations captured in cancer genomes could have been generated by APOBEC deaminases over the lifetime of a cell lineage, whereas mRNA captures expression at the single time point of sample acquisition and not necessarily at the time of active mutagenesis.	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('cancer', 'Disease', (22, 28))	('APOBEC', 'Gene', (66, 72))	('Mutations', 'Var', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))
563550	33292100	Mutations are thought to be the key drivers of recurrence, metastasis and therapeutic resistance of cancer.	('cancer', 'Disease', (100, 106))	('cancer', 'Disease', 'MESH:D009369', (100, 106))	('Mutations', 'Var', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (100, 106))
563551	33292100	The studies on the molecular origins of mutations in BRCA have implicated several mechanisms, including both spontaneous and enzyme catalysed deamination of DNA cytidine.	('cytidine', 'Chemical', 'MESH:D003562', (161, 169))	('BRCA', 'Gene', '672', (53, 57))	('mutations', 'Var', (40, 49))	('BRCA', 'Gene', (53, 57))	('deamination of DNA cytidine', 'MPA', (142, 169))
563556	33292100	In particular, A3A and A3B have been considered the main mutagenic enzymes that generate APOBEC-signature mutations in breast and other tumour types because overexpression of these enzymes triggers DNA damage responses and inflicts chromosomal mutations in hallmark trinucleotide contexts.	('chromosomal', 'Gene', (232, 243))	('tumour', 'Disease', 'MESH:D009369', (136, 142))	('tumour', 'Disease', (136, 142))	('trinucleotide', 'Chemical', '-', (266, 279))	('overexpression', 'PosReg', (157, 171))	('inflicts', 'Reg', (223, 231))	('mutations', 'Var', (106, 115))	('A3A', 'Gene', '200315', (15, 18))	('triggers', 'Reg', (189, 197))	('APOBEC-signature', 'Gene', (89, 105))	('A3A', 'Gene', (15, 18))	('DNA damage responses', 'MPA', (198, 218))	('tumour', 'Phenotype', 'HP:0002664', (136, 142))
563558	33292100	The analysis of the APOBEC-signature mutation load in cancer exons showed that it is statistically correlated with A3A and A3B transcript abundance.	('mutation load', 'Var', (37, 50))	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('cancer', 'Disease', (54, 60))	('A3A', 'Gene', (115, 118))	('A3A', 'Gene', '200315', (115, 118))	('correlated', 'Reg', (99, 109))	('A3B transcript abundance', 'MPA', (123, 147))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('APOBEC-signature', 'Gene', (20, 36))
563562	33292100	Multiple lines of evidence suggested that A3B, the only constitutively nuclear ssDNA deaminase, was the primary source of the mutations found in BRCA.	('BRCA', 'Gene', (145, 149))	('BRCA', 'Gene', '672', (145, 149))	('mutations', 'Var', (126, 135))
563564	33292100	The analysis of cell line and tumour datasets showing that A3B gene expression is upregulated in malignant versus normal tissues and epithelial cell lines have shown correlations between A3B expression and the presence of certain somatic mutations, particularly in TP53 and phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) (figure 3).	('correlations', 'Reg', (166, 178))	('expression', 'MPA', (68, 78))	('tumour', 'Disease', 'MESH:D009369', (30, 36))	('TP53', 'Gene', '7157', (265, 269))	('mutations', 'Var', (238, 247))	('PIK3CA', 'Gene', (347, 353))	('A3B', 'Gene', (187, 190))	('upregulated', 'PosReg', (82, 93))	('tumour', 'Disease', (30, 36))	('tumour', 'Phenotype', 'HP:0002664', (30, 36))	('TP53', 'Gene', (265, 269))	('PIK3CA', 'Gene', '5290', (347, 353))	('phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha', 'Gene', '5290', (274, 345))	('expression', 'MPA', (191, 201))	('A3B gene', 'Gene', (59, 67))
563571	33292100	They proposed that A3B expression is unlikely to account for APOBEC-mediated mutagenesis in breast tumours but might contribute to cancer development based on the possible mitogenic effect of A3B, a deamination-independent effect.	('cancer', 'Disease', (131, 137))	('men', 'Species', '9606', (145, 148))	('tumours', 'Phenotype', 'HP:0002664', (99, 106))	('mitogenic effect', 'CPA', (172, 188))	('breast tumours', 'Disease', 'MESH:D001943', (92, 106))	('cancer', 'Phenotype', 'HP:0002664', (131, 137))	('A3B', 'Var', (192, 195))	('contribute', 'Reg', (117, 127))	('cancer', 'Disease', 'MESH:D009369', (131, 137))	('breast tumours', 'Disease', (92, 106))	('tumour', 'Phenotype', 'HP:0002664', (99, 105))	('breast tumour', 'Phenotype', 'HP:0100013', (92, 105))
563577	33292100	p53 controls the A3B expression and since ER- tumours are enriched for inactivating p53 mutations, this could contribute to elevated levels of A3B expression in this type of tumour that is significantly higher compared with ER+ breast tumours.	('tumours', 'Phenotype', 'HP:0002664', (235, 242))	('breast tumours', 'Disease', 'MESH:D001943', (228, 242))	('expression', 'MPA', (147, 157))	('tumours', 'Disease', 'MESH:D009369', (235, 242))	('tumour', 'Disease', (46, 52))	('mutations', 'Var', (88, 97))	('A3B', 'Protein', (17, 20))	('ER', 'Gene', '2069', (224, 226))	('tumour', 'Phenotype', 'HP:0002664', (235, 241))	('p53', 'Gene', '7157', (0, 3))	('tumour', 'Disease', 'MESH:D009369', (235, 241))	('tumour', 'Disease', (235, 241))	('higher', 'PosReg', (203, 209))	('A3B', 'Protein', (143, 146))	('levels', 'MPA', (133, 139))	('breast tumours', 'Disease', (228, 242))	('p53', 'Gene', (0, 3))	('tumours', 'Disease', (46, 53))	('p53', 'Gene', '7157', (84, 87))	('tumours', 'Phenotype', 'HP:0002664', (46, 53))	('tumour', 'Phenotype', 'HP:0002664', (174, 180))	('tumours', 'Disease', 'MESH:D009369', (46, 53))	('tumour', 'Disease', 'MESH:D009369', (174, 180))	('expression', 'MPA', (21, 31))	('tumour', 'Disease', (174, 180))	('tumours', 'Disease', (235, 242))	('p53', 'Gene', (84, 87))	('ER', 'Gene', '2069', (42, 44))	('breast tumour', 'Phenotype', 'HP:0100013', (228, 241))	('tumour', 'Phenotype', 'HP:0002664', (46, 52))	('elevated', 'PosReg', (124, 132))	('tumour', 'Disease', 'MESH:D009369', (46, 52))
563585	33292100	The induction of A3B was found to be stronger in cell lines harbouring mutant TP53 than in those with wild-type TP53 (figure 3).	('stronger', 'PosReg', (37, 45))	('A3B', 'Protein', (17, 20))	('induction', 'MPA', (4, 13))	('mutant', 'Var', (71, 77))	('TP53', 'Gene', '7157', (78, 82))	('TP53', 'Gene', '7157', (112, 116))	('TP53', 'Gene', (78, 82))	('TP53', 'Gene', (112, 116))
563587	33292100	The role of DNA replication stress in mediating genomic instability could link the high level of somatic copy number aberrations and single nucleotide diversity caused by A3 activity that are both observed in human epidermal growth factor receptor 2 (HER2)+ tumours.	('tumours', 'Disease', (258, 265))	('human', 'Species', '9606', (209, 214))	('epidermal growth factor receptor 2', 'Gene', '2064', (215, 249))	('A3', 'Chemical', '-', (171, 173))	('tumour', 'Phenotype', 'HP:0002664', (258, 264))	('tumours', 'Phenotype', 'HP:0002664', (258, 265))	('HER2', 'Gene', (251, 255))	('tumours', 'Disease', 'MESH:D009369', (258, 265))	('epidermal growth factor receptor 2', 'Gene', (215, 249))	('HER2', 'Gene', '2064', (251, 255))	('single nucleotide diversity', 'Var', (133, 160))
563590	33292100	The oncogenic signalling, cytotoxic drugs and genetic modulators of replication stress are all able to modulate A3 activity, although it has not been explored if there is a mechanistic connection between the underlying causes of chromosomal copy number aberrations and the generation of A3 mutagenesis in HER2+ BRCA.	('modulate', 'Reg', (103, 111))	('A3', 'Chemical', '-', (112, 114))	('BRCA', 'Gene', (311, 315))	('chromosomal', 'Var', (229, 240))	('activity', 'MPA', (115, 123))	('HER2', 'Gene', (305, 309))	('mutagenesis', 'Var', (290, 301))	('HER2', 'Gene', '2064', (305, 309))	('A3', 'Chemical', '-', (287, 289))	('BRCA', 'Gene', '672', (311, 315))
563592	33292100	Despite all aforementioned findings, the importance of A3B in cancer has been questioned with the observation that APOBEC-signature mutations are still clearly evident in A3B-null breast tumours (figure 3).	('breast tumours', 'Disease', 'MESH:D001943', (180, 194))	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('APOBEC-signature', 'Gene', (115, 131))	('mutations', 'Var', (132, 141))	('breast tumour', 'Phenotype', 'HP:0100013', (180, 193))	('tumour', 'Phenotype', 'HP:0002664', (187, 193))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('A3B-null', 'Gene', (171, 179))	('breast tumours', 'Disease', (180, 194))	('tumours', 'Phenotype', 'HP:0002664', (187, 194))	('men', 'Species', '9606', (17, 20))
563593	33292100	A 29.5 kb deletion that removes the entire A3B coding sequence and fuses the 3' untranslated regions (UTR) of A3A and A3B forms a hybrid gene that is predicted to produce a transcript which is predominantly constituted of A3A sequence but replaces the A3A 3'UTR with the A3B 3' UTR and encodes a protein that has an identical amino acid sequence to A3A.	('A3A', 'Gene', (349, 352))	('produce', 'Reg', (163, 170))	('A3A', 'Gene', (222, 225))	('A3B', 'Gene', (43, 46))	('A3A', 'Gene', '200315', (110, 113))	('removes', 'NegReg', (24, 31))	('A3A', 'Gene', (110, 113))	('A3A', 'Gene', '200315', (252, 255))	('deletion', 'Var', (10, 18))	('replaces', 'NegReg', (239, 247))	('A3A', 'Gene', '200315', (222, 225))	('A3A', 'Gene', (252, 255))	('A3A', 'Gene', '200315', (349, 352))
563594	33292100	Some studies showed that the A3B deletion increases the risk of BRCA and increases tumour mutational burden.	('A3B', 'Gene', (29, 32))	('increases', 'PosReg', (42, 51))	('increases tumour', 'Disease', (73, 89))	('deletion', 'Var', (33, 41))	('BRCA', 'Gene', '672', (64, 68))	('tumour', 'Phenotype', 'HP:0002664', (83, 89))	('increases tumour', 'Disease', 'MESH:D009369', (73, 89))	('BRCA', 'Gene', (64, 68))
563595	33292100	A genome-wide association study in the Chinese population demonstrated the A3B deletion is associated with BRCA (odds ratio (OR) 1.3 one-copy, 1.8 two-copy deletion, p = 2.0 x 10-24), which was replicated in a European population (OR 1.2 one-copy, 2.3 two-copy deletion, p = 0.005).	('odds ratio (OR) 1.3', 'Gene', (113, 132))	('A3B', 'Gene', (75, 78))	('BRCA', 'Gene', '672', (107, 111))	('BRCA', 'Gene', (107, 111))	('deletion', 'Var', (79, 87))	('odds ratio (OR) 1.3', 'Gene', '128360', (113, 132))	('associated', 'Reg', (91, 101))
563596	33292100	However, including familial BRCA for the first time, a later study showed a lack of association of the A3B deletion with BRCA risk, which was independently validated in three European cohorts (in total: 2972 cases and 3682 controls).	('association', 'Interaction', (84, 95))	('BRCA', 'Gene', '672', (28, 32))	('BRCA', 'Gene', '672', (121, 125))	('BRCA', 'Gene', (28, 32))	('BRCA', 'Gene', (121, 125))	('A3B', 'Gene', (103, 106))	('deletion', 'Var', (107, 115))
563597	33292100	This study provided direct evidence for the generation of the transcriptionally active hybrid gene A3A/A3B from the allele with the A3B deletion and confirmed the suggested structure of A3A/A3B transcript, which enabled A3A, A3B and A3A/A3B expression levels to be distinguished.	('A3A', 'Gene', '200315', (233, 236))	('A3A', 'Gene', '200315', (220, 223))	('A3A', 'Gene', (99, 102))	('A3A', 'Gene', (233, 236))	('A3A', 'Gene', (220, 223))	('deletion', 'Var', (136, 144))	('A3A', 'Gene', '200315', (186, 189))	('A3A', 'Gene', '200315', (99, 102))	('A3B', 'Gene', (132, 135))	('A3A', 'Gene', (186, 189))
563598	33292100	The knowledge of the exact structure of the hybrid transcript is vital for the design of comprehensive tests for analysis of the influence of the A3B deletion genotype on the expression of A3B, A3A and the A3A/A3B hybrid gene.	('A3A', 'Gene', '200315', (206, 209))	('A3A', 'Gene', (206, 209))	('deletion', 'Var', (150, 158))	('A3A', 'Gene', (194, 197))	('A3A', 'Gene', '200315', (194, 197))	('A3B', 'Gene', (146, 149))
563599	33292100	A recent study showed that the germline A3B deletion influenced the APOBEC mutational signature, neoantigen loads and relative immune cell compositions in BRCA.	('APOBEC', 'Gene', (68, 74))	('BRCA', 'Gene', '672', (155, 159))	('influenced', 'Reg', (53, 63))	('deletion', 'Var', (44, 52))	('BRCA', 'Gene', (155, 159))	('mutational signature', 'MPA', (75, 95))	('neoantigen loads', 'MPA', (97, 113))
563601	33292100	As the homozygous carriers of the A3B deletion allele are predicted not to make any A3B protein, other APOBEC enzymes must contribute to APOBEC-signature mutations during tumour development.	('men', 'Species', '9606', (185, 188))	('tumour', 'Phenotype', 'HP:0002664', (171, 177))	('tumour', 'Disease', 'MESH:D009369', (171, 177))	('tumour', 'Disease', (171, 177))	('A3B', 'Gene', (34, 37))	('deletion', 'Var', (38, 46))
563602	33292100	In this regard, one study of APOBEC-induced mutations from A3B deleted BRCA tumours revealed that the only tumours displaying the APOBEC mutation signature also contained the nuclear A3H Hap I, providing correlative evidence that this protein may be the additional source of mutagenesis (figure 3).	('tumours', 'Phenotype', 'HP:0002664', (107, 114))	('APOBEC', 'Gene', (130, 136))	('tumours', 'Disease', 'MESH:D009369', (107, 114))	('tumours', 'Disease', 'MESH:D009369', (76, 83))	('tumours', 'Disease', (107, 114))	('mutation', 'Var', (137, 145))	('A3H', 'Gene', (183, 186))	('tumours', 'Disease', (76, 83))	('tumour', 'Phenotype', 'HP:0002664', (76, 82))	('tumour', 'Phenotype', 'HP:0002664', (107, 113))	('BRCA tumours', 'Disease', 'MESH:D009369', (71, 83))	('BRCA tumours', 'Disease', (71, 83))	('A3B', 'Gene', (59, 62))	('mutations', 'Var', (44, 53))	('A3H', 'Gene', '164668', (183, 186))	('tumours', 'Phenotype', 'HP:0002664', (76, 83))
563606	33292100	Another study found the A3A mutational footprints in tumours, but no corresponding A3A expression and suggested that A3A is upregulated early, but later inactivated, perhaps due to being the most active deaminase that could cause cell death through its activity over time.	('A3A', 'Gene', '200315', (24, 27))	('tumours', 'Disease', 'MESH:D009369', (53, 60))	('tumours', 'Disease', (53, 60))	('A3A', 'Gene', '200315', (83, 86))	('A3A', 'Gene', '200315', (117, 120))	('A3A', 'Gene', (24, 27))	('A3A', 'Gene', (83, 86))	('A3A', 'Gene', (117, 120))	('tumour', 'Phenotype', 'HP:0002664', (53, 59))	('upregulated', 'PosReg', (124, 135))	('mutational', 'Var', (28, 38))	('tumours', 'Phenotype', 'HP:0002664', (53, 60))
563607	33292100	In addition, A3A and A3B can be differentiated by their different preferred tetranucleotide motifs, 5'YTCA and 5'RTCA (Y = T or C and R = G or A), respectively, when inducing mutations in a yeast model system.	('A3A', 'Gene', '200315', (13, 16))	('A3A', 'Gene', (13, 16))	('mutations', 'Var', (175, 184))	('inducing', 'Reg', (166, 174))	('TCA', 'Chemical', 'MESH:D014238', (103, 106))	('TCA', 'Chemical', 'MESH:D014238', (114, 117))	('yeast', 'Species', '4932', (190, 195))
563608	33292100	However, over-representation of mutations in the 5'YTCA motif predominates in a variety of cancers as well as among mutations actively acquired in BRCA cell lines, suggesting A3A may likewise contribute to cancer mutagenesis.	('A3A', 'Gene', '200315', (175, 178))	('A3A', 'Gene', (175, 178))	('BRCA', 'Gene', (147, 151))	('cancers', 'Disease', 'MESH:D009369', (91, 98))	('cancers', 'Phenotype', 'HP:0002664', (91, 98))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('cancers', 'Disease', (91, 98))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('over-representation', 'PosReg', (9, 28))	('contribute', 'Reg', (192, 202))	('mutations', 'Var', (32, 41))	('TCA', 'Chemical', 'MESH:D014238', (52, 55))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('cancer', 'Disease', (206, 212))	('cancer', 'Disease', 'MESH:D009369', (206, 212))	('BRCA', 'Gene', '672', (147, 151))
563609	33292100	A3A was often reported to have undetectable expression in BRCA lines, but more recently, some evidence indicates that A3A may be a major cause of APOBEC-induced mutation in BRCA and account for the majority of cytidine deaminase activity in extracts from multiple BRCA cell lines, despite higher A3B expression.	('A3A', 'Gene', '200315', (0, 3))	('cytidine deaminase', 'Gene', '978', (210, 228))	('BRCA', 'Gene', '672', (264, 268))	('BRCA', 'Gene', '672', (58, 62))	('mutation', 'Var', (161, 169))	('BRCA', 'Gene', (58, 62))	('A3A', 'Gene', (0, 3))	('BRCA', 'Gene', (264, 268))	('cytidine deaminase', 'Gene', (210, 228))	('cause', 'Reg', (137, 142))	('expression', 'MPA', (300, 310))	('A3A', 'Gene', '200315', (118, 121))	('BRCA', 'Gene', '672', (173, 177))	('A3A', 'Gene', (118, 121))	('APOBEC-induced', 'Gene', (146, 160))	('A3B', 'Protein', (296, 299))	('BRCA', 'Gene', (173, 177))	('higher', 'PosReg', (289, 295))
563611	33292100	By contrast, a median 13.1-fold higher A3A mRNA expression level was observed in the APOBEC-mutated BRCA lines compared to non-APOBEC-mutated lines and the overall abundance of APOBEC-induced mutations linearly correlated with A3A expression.	('BRCA', 'Gene', '672', (100, 104))	('higher', 'PosReg', (32, 38))	('BRCA', 'Gene', (100, 104))	('A3A', 'Gene', '200315', (227, 230))	('A3A', 'Gene', (227, 230))	('APOBEC-mutated', 'Gene', (85, 99))	('mutations', 'Var', (192, 201))	('A3A', 'Gene', '200315', (39, 42))	('expression', 'MPA', (231, 241))	('APOBEC-induced', 'Gene', (177, 191))	('A3A', 'Gene', (39, 42))
563613	33292100	A3A is more active biochemically than the next most potent somatic mutators A3B and A3H Hap I and RNA binding is known to inhibit the activity of A3B and partially inhibit the activity of A3H, but not A3A, suggesting that A3A may be a better candidate than A3H Hap I in causing the APOBEC mutation signature in A3B null BRCA.	('A3A', 'Gene', '200315', (0, 3))	('activity', 'MPA', (176, 184))	('A3A', 'Gene', (201, 204))	('mutation', 'Var', (289, 297))	('A3A', 'Gene', '200315', (222, 225))	('inhibit', 'NegReg', (164, 171))	('activity', 'MPA', (134, 142))	('A3H', 'Gene', (188, 191))	('A3B', 'Gene', (311, 314))	('A3H', 'Gene', '164668', (188, 191))	('BRCA', 'Gene', '672', (320, 324))	('A3A', 'Gene', (0, 3))	('A3A', 'Gene', '200315', (201, 204))	('A3H', 'Gene', (84, 87))	('A3H', 'Gene', (257, 260))	('A3H', 'Gene', '164668', (84, 87))	('A3A', 'Gene', (222, 225))	('APOBEC', 'Gene', (282, 288))	('A3H', 'Gene', '164668', (257, 260))	('BRCA', 'Gene', (320, 324))	('inhibit', 'NegReg', (122, 129))
563616	33292100	In addition to mutagenesis linked to deamination of ssDNA, A3A as well as A3B have been reported to be involved in RNA editing.	('ssDNA', 'Gene', (52, 57))	('RNA editing', 'MPA', (115, 126))	('A3A', 'Gene', '200315', (59, 62))	('A3A', 'Gene', (59, 62))	('involved', 'Reg', (103, 111))	('mutagenesis', 'Var', (15, 26))
563620	33292100	developed a strategy using hotspot APOBEC-signature mutations in RNA stem-loops identified from A3A-positive tumours and droplet digital PCR to quantify the ongoing activity of A3A in tumours.	('mutations', 'Var', (52, 61))	('tumours', 'Phenotype', 'HP:0002664', (109, 116))	('A3A', 'Gene', '200315', (96, 99))	('tumours', 'Disease', 'MESH:D009369', (109, 116))	('tumours', 'Disease', 'MESH:D009369', (184, 191))	('tumours', 'Disease', (184, 191))	('tumour', 'Phenotype', 'HP:0002664', (184, 190))	('A3A', 'Gene', (96, 99))	('tumours', 'Disease', (109, 116))	('A3A', 'Gene', '200315', (177, 180))	('RNA', 'Gene', (65, 68))	('A3A', 'Gene', (177, 180))	('tumours', 'Phenotype', 'HP:0002664', (184, 191))	('APOBEC-signature', 'Gene', (35, 51))	('tumour', 'Phenotype', 'HP:0002664', (109, 115))
563621	33292100	They found that A3A expression and A3A-mediated DNA mutagenesis in tumours, but not those of A3B, correlate with APOBEC-signature mutations in RNA stem-loops.	('A3A', 'Gene', '200315', (35, 38))	('tumours', 'Disease', 'MESH:D009369', (67, 74))	('tumours', 'Disease', (67, 74))	('mutagenesis', 'Var', (52, 63))	('A3A', 'Gene', (35, 38))	('APOBEC-signature', 'Gene', (113, 129))	('mutations', 'Var', (130, 139))	('A3A', 'Gene', '200315', (16, 19))	('A3A', 'Gene', (16, 19))	('tumour', 'Phenotype', 'HP:0002664', (67, 73))	('tumours', 'Phenotype', 'HP:0002664', (67, 74))
563625	33292100	In line with this RNA-editing activity of the A3 enzymes, a recent bioinformatic study identified that A3-mediated RNA editing occurs in breast tumours and is positively associated with elevated immune activity and improved survival (figure 3).	('immune activity', 'CPA', (195, 210))	('tumour', 'Phenotype', 'HP:0002664', (144, 150))	('breast tumours', 'Disease', (137, 151))	('survival', 'CPA', (224, 232))	('A3', 'Chemical', '-', (103, 105))	('tumours', 'Phenotype', 'HP:0002664', (144, 151))	('improved', 'PosReg', (215, 223))	('breast tumours', 'Disease', 'MESH:D001943', (137, 151))	('breast tumour', 'Phenotype', 'HP:0100013', (137, 150))	('A3', 'Chemical', '-', (46, 48))	('A3-mediated RNA editing', 'Var', (103, 126))	('elevated', 'PosReg', (186, 194))
563628	33292100	While they could detect C-to-U RNA-editing events in the tumours, the cellular origin of such events remains unclear.	('tumours', 'Phenotype', 'HP:0002664', (57, 64))	('tumours', 'Disease', 'MESH:D009369', (57, 64))	('tumours', 'Disease', (57, 64))	('C-to-U RNA-editing', 'Var', (24, 42))	('tumour', 'Phenotype', 'HP:0002664', (57, 63))
563630	33292100	Further investigations implementing methods such as single-cell sequencing and isolation of sub-populations of cells from tumours are needed to definitively know if the editing occurs in cancerous epithelial or immune cells of breast tumours.	('cancerous epithelial', 'Disease', (187, 207))	('men', 'Species', '9606', (28, 31))	('breast tumour', 'Phenotype', 'HP:0100013', (227, 240))	('tumours', 'Phenotype', 'HP:0002664', (122, 129))	('cancerous epithelial', 'Disease', 'MESH:D009369', (187, 207))	('tumour', 'Phenotype', 'HP:0002664', (234, 240))	('tumours', 'Phenotype', 'HP:0002664', (234, 241))	('breast tumours', 'Disease', (227, 241))	('tumours', 'Disease', 'MESH:D009369', (122, 129))	('cancer', 'Phenotype', 'HP:0002664', (187, 193))	('editing', 'Var', (169, 176))	('breast tumours', 'Disease', 'MESH:D001943', (227, 241))	('tumours', 'Disease', 'MESH:D009369', (234, 241))	('tumours', 'Disease', (122, 129))	('tumours', 'Disease', (234, 241))	('tumour', 'Phenotype', 'HP:0002664', (122, 128))
563631	33292100	The biological consequences of the editing events on cancer development, progression and immune response also remain unknown.	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('men', 'Species', '9606', (67, 70))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('editing', 'Var', (35, 42))
563633	33292100	Also, it is important to elucidate which of the enzymes A3A, A3B and A3H Hap I are involved earlier in promoting cell transformation or later in promoting BRCA progression.	('A3H', 'Gene', (69, 72))	('promoting', 'PosReg', (103, 112))	('BRCA', 'Gene', '672', (155, 159))	('promoting', 'PosReg', (145, 154))	('A3B', 'Var', (61, 64))	('BRCA', 'Gene', (155, 159))	('A3A', 'Gene', '200315', (56, 59))	('A3H', 'Gene', '164668', (69, 72))	('A3A', 'Gene', (56, 59))	('cell transformation', 'CPA', (113, 132))
563639	33292100	In addition to smoking, one major cause of the heavy mutation load of NSCLC, the expression of APOBEC family members, especially A3B, was reported as a key source of mutations specifically in two subtypes of NSCLC: adenocarcinoma and squamous cell carcinoma.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (234, 257))	('SCLC', 'Phenotype', 'HP:0030357', (209, 213))	('mutations', 'Var', (166, 175))	('NSCLC', 'Disease', (70, 75))	('NSCLC', 'Disease', 'MESH:D002289', (70, 75))	('adenocarcinoma and squamous cell carcinoma', 'Disease', 'MESH:D002294', (215, 257))	('NSCLC', 'Disease', (208, 213))	('carcinoma', 'Phenotype', 'HP:0030731', (220, 229))	('SCLC', 'Phenotype', 'HP:0030357', (71, 75))	('NSCLC', 'Disease', 'MESH:D002289', (208, 213))	('carcinoma', 'Phenotype', 'HP:0030731', (248, 257))
563643	33292100	According to this endogenous mutational process driving subclonal expansions, mutations within an A3B context were found in driver genes such as PTPRD, PIK3CA, EP300, TGFBR1 and AKAP9 (figure 4).	('PIK3CA', 'Gene', '5290', (152, 158))	('AKAP9', 'Gene', (178, 183))	('TGFBR1', 'Gene', '7046', (167, 173))	('mutations', 'Var', (78, 87))	('TGFBR1', 'Gene', (167, 173))	('PTPRD', 'Gene', '5789', (145, 150))	('AKAP9', 'Gene', '10142', (178, 183))	('PTPRD', 'Gene', (145, 150))	('PIK3CA', 'Gene', (152, 158))	('EP300', 'Gene', (160, 165))	('EP300', 'Gene', '2033', (160, 165))
563644	33292100	Also, there was evidence for spatial heterogeneity in APOBEC activity; in one adeno squamous tumour, the APOBEC signature was found enriched in the adenocarcinoma branch, harbouring driver mutations in PTPRD and TGFBR1 within an APOBEC context, but not the squamous carcinoma branch.	('squamous carcinoma branch', 'Disease', (257, 282))	('PTPRD', 'Gene', '5789', (202, 207))	('adenocarcinoma branch', 'Disease', 'MESH:D000230', (148, 169))	('carcinoma', 'Phenotype', 'HP:0030731', (153, 162))	('carcinoma', 'Phenotype', 'HP:0030731', (266, 275))	('squamous carcinoma branch', 'Disease', 'MESH:D002294', (257, 282))	('PTPRD', 'Gene', (202, 207))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (257, 275))	('squamous tumour', 'Disease', (84, 99))	('adenocarcinoma branch', 'Disease', (148, 169))	('TGFBR1', 'Gene', (212, 218))	('squamous tumour', 'Phenotype', 'HP:0002860', (84, 99))	('tumour', 'Phenotype', 'HP:0002664', (93, 99))	('TGFBR1', 'Gene', '7046', (212, 218))	('mutations', 'Var', (189, 198))	('squamous tumour', 'Disease', 'MESH:D002294', (84, 99))
563646	33292100	Most of these subclonal mutations were found in the PIK3CA helical domain (E545 K) that have been previously linked to APOBEC-mediated mutagenesis in cervical and head/neck tumours.	('head/neck tumours', 'Disease', 'MESH:D006258', (163, 180))	('cervical', 'Disease', (150, 158))	('E545 K', 'Mutation', 'rs104886003', (75, 81))	('head/neck tumours', 'Disease', (163, 180))	('PIK3CA', 'Gene', '5290', (52, 58))	('PIK3CA', 'Gene', (52, 58))	('tumour', 'Phenotype', 'HP:0002664', (173, 179))	('E545 K', 'Var', (75, 81))	('tumours', 'Phenotype', 'HP:0002664', (173, 180))	('linked', 'Reg', (109, 115))
563647	33292100	The importance of APOBEC later in tumour evolution is highlighted by the observation that this mutational process in lung adenocarcinoma and squamous carcinoma was found to be the major source of subclonal cancer gene mutations (figure 4) relative to clonal driver gene mutations, suggesting APOBEC is a mutagenic source, fuelling cancer heterogeneity and subclonal diversification.	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (117, 136))	('cancer', 'Disease', (331, 337))	('cancer', 'Disease', 'MESH:D009369', (331, 337))	('cancer', 'Phenotype', 'HP:0002664', (206, 212))	('mutations', 'Var', (218, 227))	('squamous carcinoma', 'Disease', 'MESH:D002294', (141, 159))	('tumour', 'Disease', 'MESH:D009369', (34, 40))	('squamous carcinoma', 'Disease', (141, 159))	('tumour', 'Disease', (34, 40))	('carcinoma', 'Phenotype', 'HP:0030731', (150, 159))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (141, 159))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (117, 136))	('cancer', 'Phenotype', 'HP:0002664', (331, 337))	('cancer', 'Disease', (206, 212))	('cancer', 'Disease', 'MESH:D009369', (206, 212))	('carcinoma', 'Phenotype', 'HP:0030731', (127, 136))	('lung adenocarcinoma', 'Disease', (117, 136))	('tumour', 'Phenotype', 'HP:0002664', (34, 40))
563648	33292100	In addition to A3B, a bioinformatics approach significantly associated the cytidine deaminase A3H Hap I with clonal APOBEC-signature mutations in lung adenocarcinoma (figure 4).	('A3H', 'Gene', (94, 97))	('carcinoma', 'Phenotype', 'HP:0030731', (156, 165))	('lung adenocarcinoma', 'Disease', (146, 165))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (146, 165))	('cytidine deaminase', 'Gene', '978', (75, 93))	('mutations', 'Var', (133, 142))	('APOBEC-signature', 'Gene', (116, 132))	('A3H', 'Gene', '164668', (94, 97))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (146, 165))	('cytidine deaminase', 'Gene', (75, 93))
563649	33292100	Later, a computational study supported this idea and identified the association of SNP rs139298, that is correlated with lung cancer and creates a K121E mutation in A3H Hap I.	('K121E', 'Mutation', 'rs139298', (147, 152))	('A3H', 'Gene', (165, 168))	('lung cancer', 'Disease', 'MESH:D008175', (121, 132))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('K121E', 'Var', (147, 152))	('SNP', 'Gene', (83, 86))	('rs139298', 'Mutation', 'rs139298', (87, 95))	('correlated', 'Reg', (105, 115))	('A3H', 'Gene', '164668', (165, 168))	('lung cancer', 'Disease', (121, 132))	('lung cancer', 'Phenotype', 'HP:0100526', (121, 132))
563652	33292100	However, the K121E mutation was shown to destabilize A3H Hap I in cells and supported the conclusion that the loss of A3H Hap I activity through the K121E variant may benefit the cancer and be detrimental to the host, suggesting that A3H Hap I deamination activity can induce tumour cell death or immune recognition.	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('tumour cell death', 'Disease', 'MESH:D003643', (276, 293))	('K121E', 'Var', (149, 154))	('K121E', 'Var', (13, 18))	('K121E', 'Mutation', 'rs139298', (149, 154))	('A3H', 'Gene', (118, 121))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('K121E', 'Mutation', 'rs139298', (13, 18))	('A3H', 'Gene', '164668', (118, 121))	('benefit', 'PosReg', (167, 174))	('immune recognition', 'CPA', (297, 315))	('A3H', 'Gene', (53, 56))	('destabilize', 'NegReg', (41, 52))	('men', 'Species', '9606', (198, 201))	('tumour cell death', 'Disease', (276, 293))	('A3H', 'Gene', (234, 237))	('A3H', 'Gene', '164668', (53, 56))	('A3H', 'Gene', '164668', (234, 237))	('tumour', 'Phenotype', 'HP:0002664', (276, 282))	('cancer', 'Disease', (179, 185))
563653	33292100	These data emphasize that it is important to use additional genetic or clinical data for determining the beneficial or detrimental effects of A3-induced mutations.	('A3-induced', 'Gene', (142, 152))	('mutations', 'Var', (153, 162))	('A3', 'Chemical', '-', (142, 144))	('men', 'Species', '9606', (124, 127))
563656	33292100	When genomic sequences from lung adenocarcinomas were stratified by A3B and FHIT expression, those with high A3B and FHIT loss showed significantly higher A3 signature mutation loads than high A3B expressers with normal FHIT levels.	('FHIT', 'Gene', (220, 224))	('FHIT', 'Gene', (117, 121))	('FHIT loss', 'Disease', (117, 126))	('A3', 'Chemical', '-', (109, 111))	('FHIT loss', 'Disease', 'MESH:D014786', (117, 126))	('high A3B', 'Var', (104, 112))	('A3', 'Chemical', '-', (155, 157))	('FHIT', 'Gene', '2272', (220, 224))	('carcinoma', 'Phenotype', 'HP:0030731', (38, 47))	('FHIT', 'Gene', (76, 80))	('carcinomas', 'Phenotype', 'HP:0030731', (38, 48))	('higher', 'PosReg', (148, 154))	('FHIT', 'Gene', '2272', (117, 121))	('A3', 'Chemical', '-', (68, 70))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (28, 48))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (28, 47))	('A3', 'Chemical', '-', (193, 195))	('FHIT', 'Gene', '2272', (76, 80))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (28, 48))	('lung adenocarcinomas', 'Disease', (28, 48))
563659	33292100	Also, evidence of preferential benefit from therapeutic approaches has emerged in patients with tumours with the highest mutational load.	('mutational load', 'Var', (121, 136))	('patients', 'Species', '9606', (82, 90))	('tumours', 'Phenotype', 'HP:0002664', (96, 103))	('tumour', 'Phenotype', 'HP:0002664', (96, 102))	('tumours', 'Disease', 'MESH:D009369', (96, 103))	('tumours', 'Disease', (96, 103))
563660	33292100	This suggests that the evolutionary trade-off for increased fitness brought about by an increased mutation rate is the risk of tumour neo-antigenic presentation and immune control (figure 4).	('tumour', 'Phenotype', 'HP:0002664', (127, 133))	('fitness', 'Disease', (60, 67))	('increased', 'PosReg', (50, 59))	('fitness', 'Disease', 'MESH:D012640', (60, 67))	('tumour', 'Disease', 'MESH:D009369', (127, 133))	('tumour', 'Disease', (127, 133))	('mutation rate', 'Var', (98, 111))
563666	33292100	It was demonstrated in advanced NSCLC, in patients treated with an antibody targeting PD-1, response rates of 17-21% with some responses being remarkably durable.	('antibody', 'Var', (67, 75))	('NSCLC', 'Disease', (32, 37))	('PD-1', 'Gene', (86, 90))	('SCLC', 'Phenotype', 'HP:0030357', (33, 37))	('NSCLC', 'Disease', 'MESH:D002289', (32, 37))	('patients', 'Species', '9606', (42, 50))
563674	33292100	This study implicates A3B and APOBEC mutational signatures as novel predictive biomarkers for checkpoint blockade immunotherapy response in NSCLC and suggests immunotherapy as a novel treatment option for A3B overexpressing NSCLC.	('A3B', 'Gene', (22, 25))	('APOBEC', 'Gene', (30, 36))	('men', 'Species', '9606', (189, 192))	('NSCLC', 'Disease', 'MESH:D002289', (140, 145))	('NSCLC', 'Disease', (224, 229))	('SCLC', 'Phenotype', 'HP:0030357', (141, 145))	('mutational', 'Var', (37, 47))	('NSCLC', 'Disease', 'MESH:D002289', (224, 229))	('overexpressing', 'PosReg', (209, 223))	('SCLC', 'Phenotype', 'HP:0030357', (225, 229))	('NSCLC', 'Disease', (140, 145))
563681	33292100	About 80% of bladder tumours in the TCGA have an APOBEC mutation signature that is also frequently found in BRCA, lung, head and neck, and cervical cancers.	('cancers', 'Phenotype', 'HP:0002664', (148, 155))	('tumour', 'Phenotype', 'HP:0002664', (21, 27))	('BRCA', 'Gene', (108, 112))	('BRCA', 'Gene', '672', (108, 112))	('tumours', 'Phenotype', 'HP:0002664', (21, 28))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('found', 'Reg', (99, 104))	('APOBEC', 'Gene', (49, 55))	('lung', 'Disease', (114, 118))	('bladder tumours', 'Disease', (13, 28))	('mutation', 'Var', (56, 64))	('cervical cancers', 'Disease', (139, 155))	('bladder tumours', 'Disease', 'MESH:D001749', (13, 28))	('cervical cancers', 'Disease', 'MESH:D002583', (139, 155))
563684	33292100	Both A3A and A3B were induced in all cell lines by bleomycin, but the effect was more robust for A3B.	('A3B', 'Gene', (13, 16))	('bleomycin', 'Var', (51, 60))	('bleomycin', 'Chemical', 'MESH:D001761', (51, 60))	('A3A', 'Gene', '200315', (5, 8))	('A3A', 'Gene', (5, 8))
563687	33292100	The analysis of TCGA BLCA patient datasets revealed that a single nucleotide polymorphism, rs1014971, but not the germline A3A/A3B deletion, was associated with BLCA risk, increased A3B expression and enrichment with APOBEC-signature mutations in bladder tumours (figure 5).	('A3A', 'Gene', (123, 126))	('APOBEC-signature', 'Gene', (217, 233))	('patient', 'Species', '9606', (26, 33))	('rs1014971', 'Mutation', 'rs1014971', (91, 100))	('increased', 'PosReg', (172, 181))	('bladder tumours', 'Disease', 'MESH:D001749', (247, 262))	('tumour', 'Phenotype', 'HP:0002664', (255, 261))	('rs1014971', 'Var', (91, 100))	('tumours', 'Phenotype', 'HP:0002664', (255, 262))	('men', 'Species', '9606', (207, 210))	('BLCA', 'Disease', (161, 165))	('increased A3B expression', 'Phenotype', 'HP:0032430', (172, 196))	('A3B', 'Protein', (182, 185))	('expression', 'MPA', (186, 196))	('bladder tumours', 'Disease', (247, 262))	('mutations', 'Var', (234, 243))	('A3A', 'Gene', '200315', (123, 126))
563688	33292100	Also, this group demonstrated that TCGA BLCA patients with increased APOBEC mutagenesis had significantly improved survival, and that the tumours from patients homozygous for the rs17000526-A allele were enriched for TP53 and PIK3CA mutations (figure 5).	('improved', 'PosReg', (106, 114))	('TP53', 'Gene', '7157', (217, 221))	('PIK3CA', 'Gene', (226, 232))	('TP53', 'Gene', (217, 221))	('mutagenesis', 'Var', (76, 87))	('rs17000526-A', 'Var', (179, 191))	('patients', 'Species', '9606', (151, 159))	('tumour', 'Phenotype', 'HP:0002664', (138, 144))	('tumours', 'Phenotype', 'HP:0002664', (138, 145))	('patients', 'Species', '9606', (45, 53))	('rs17000526', 'Mutation', 'rs17000526', (179, 189))	('APOBEC', 'Gene', (69, 75))	('PIK3CA', 'Gene', '5290', (226, 232))	('survival', 'CPA', (115, 123))	('increased', 'PosReg', (59, 68))	('tumours', 'Disease', 'MESH:D009369', (138, 145))	('tumours', 'Disease', (138, 145))
563690	33292100	When evaluating the effects of all A3 isoforms on survival, the effect of A3B expression was comparable to that of rs17000526 and similar in treated and untreated patients, while the effect of A3A expression was much stronger in treated compared to untreated patients suggesting that mutagenesis caused by A3B may represent a genetically regulated mechanism contributing to cancer initiation, while mutagenesis caused by A3A may represent events occurring in tumours and influenced by the tumour-specific environment, including treatment.	('tumour', 'Disease', 'MESH:D009369', (459, 465))	('tumour', 'Disease', (459, 465))	('men', 'Species', '9606', (512, 515))	('tumour', 'Disease', 'MESH:D009369', (489, 495))	('A3A', 'Gene', (193, 196))	('cancer initiation', 'Disease', 'MESH:D009369', (374, 391))	('cancer', 'Phenotype', 'HP:0002664', (374, 380))	('patients', 'Species', '9606', (259, 267))	('men', 'Species', '9606', (533, 536))	('contributing', 'Reg', (358, 370))	('A3', 'Chemical', '-', (306, 308))	('A3A', 'Gene', (421, 424))	('A3B', 'Var', (306, 309))	('patients', 'Species', '9606', (163, 171))	('tumours', 'Disease', (459, 466))	('A3', 'Chemical', '-', (35, 37))	('A3A', 'Gene', '200315', (193, 196))	('A3', 'Chemical', '-', (193, 195))	('tumours', 'Phenotype', 'HP:0002664', (459, 466))	('A3', 'Chemical', '-', (74, 76))	('tumours', 'Disease', 'MESH:D009369', (459, 466))	('rs17000526', 'Mutation', 'rs17000526', (115, 125))	('tumour', 'Phenotype', 'HP:0002664', (489, 495))	('A3A', 'Gene', '200315', (421, 424))	('cancer initiation', 'Disease', (374, 391))	('A3', 'Chemical', '-', (421, 423))	('tumour', 'Phenotype', 'HP:0002664', (459, 465))	('tumour', 'Disease', (489, 495))
563691	33292100	Increased mutation loads, especially in DNA repair genes, were also associated with a response to neoadjuvant cisplatin-based treatment of MIBC (figure 5).	('DNA repair genes', 'Gene', (40, 56))	('MIBC', 'Chemical', '-', (139, 143))	('associated with', 'Reg', (68, 83))	('cisplatin', 'Chemical', 'MESH:D002945', (110, 119))	('men', 'Species', '9606', (131, 134))	('mutation loads', 'Var', (10, 24))	('response', 'MPA', (86, 94))
563694	33292100	They confirmed that MIBCs show high overall mutation rates similar to those of melanoma and NSCLC, and these high rates are principally associated with mutation signatures from APOBEC enzymes.	('associated', 'Reg', (136, 146))	('mutation', 'Var', (44, 52))	('SCLC', 'Phenotype', 'HP:0030357', (93, 97))	('MIBC', 'Chemical', '-', (20, 24))	('NSCLC', 'Disease', (92, 97))	('melanoma', 'Phenotype', 'HP:0002861', (79, 87))	('melanoma', 'Disease', (79, 87))	('NSCLC', 'Disease', 'MESH:D002289', (92, 97))	('melanoma', 'Disease', 'MESH:D008545', (79, 87))
563695	33292100	Most BLCA mutations are clonal, suggesting that APOBEC's mutagenic activity occurs early in BLCA development.	('mutations', 'Var', (10, 19))	('APOBEC', 'Gene', (48, 54))	('BLCA', 'Gene', (5, 9))	('men', 'Species', '9606', (104, 107))
563696	33292100	For instance, mutations in specific cancer genes as TP53 and ARID1A show a tendency to be clonal, but focusing on subclonal mutations in known cancer driver genes, in APOBEC-associated BLCA more than 45% of subclonal mutations in driver genes occurred in an APOBEC context.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('ARID1A', 'Gene', (61, 67))	('cancer', 'Disease', 'MESH:D009369', (36, 42))	('TP53', 'Gene', '7157', (52, 56))	('cancer', 'Disease', (36, 42))	('occurred', 'Reg', (243, 251))	('TP53', 'Gene', (52, 56))	('cancer', 'Disease', (143, 149))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))	('ARID1A', 'Gene', '8289', (61, 67))	('mutations', 'Var', (14, 23))
563702	33292100	Recently, several groups investigated the APOBEC mutational signature in the TCGA, Beijing Genomics Institute and Cancer Cell Line Encyclopedia BLCA datasets and its relationship with specific mutations, molecular subtype, gene expression and survival.	('Cancer', 'Disease', 'MESH:D009369', (114, 120))	('mutational', 'Var', (49, 59))	('APOBEC', 'Gene', (42, 48))	('Cancer', 'Disease', (114, 120))	('Cancer', 'Phenotype', 'HP:0002664', (114, 120))
563704	33292100	They hypothesized that tumours with high levels of APOBEC-mediated mutagenesis would be enriched for mutations in DNA damage response genes and express genes related to activation of the immune system at higher levels, while tumours with low levels of APOBEC-mediated mutagenesis may have enrichments for oncogenes.	('tumour', 'Phenotype', 'HP:0002664', (23, 29))	('mutations', 'Var', (101, 110))	('tumours', 'Disease', 'MESH:D009369', (225, 232))	('tumours', 'Phenotype', 'HP:0002664', (23, 30))	('tumours', 'Disease', (225, 232))	('tumours', 'Disease', 'MESH:D009369', (23, 30))	('tumours', 'Disease', (23, 30))	('DNA damage response genes', 'Gene', (114, 139))	('men', 'Species', '9606', (295, 298))	('tumour', 'Phenotype', 'HP:0002664', (225, 231))	('tumours', 'Phenotype', 'HP:0002664', (225, 232))
563707	33292100	Tumours enriched for APOBEC mutagenesis had better survival and were more likely to have mutations in both DNA damage repair and chromatin-modifying genes such as TP53, PIK3CA (primarily at E542 K and E545 K), ATR, BRCA2, MLL, MLL3 and ARID1A (figure 5).	('ATR', 'Gene', '545', (210, 213))	('Tumour', 'Phenotype', 'HP:0002664', (0, 6))	('DNA damage repair', 'Gene', (107, 124))	('E545 K', 'Mutation', 'rs104886003', (201, 207))	('better', 'PosReg', (44, 50))	('MLL3', 'Gene', '58508', (227, 231))	('BRCA2', 'Gene', (215, 220))	('TP53', 'Gene', (163, 167))	('mutations', 'Reg', (89, 98))	('PIK3CA', 'Gene', (169, 175))	('E542 K', 'Var', (190, 196))	('MLL', 'Gene', '4297', (222, 225))	('MLL', 'Gene', (222, 225))	('mutagenesis', 'Var', (28, 39))	('survival', 'CPA', (51, 59))	('ATR', 'Gene', (210, 213))	('MLL3', 'Gene', (227, 231))	('BRCA2', 'Gene', '675', (215, 220))	('ARID1A', 'Gene', (236, 242))	('TP53', 'Gene', '7157', (163, 167))	('APOBEC', 'Gene', (21, 27))	('E545 K', 'Var', (201, 207))	('MLL', 'Gene', (227, 230))	('MLL', 'Gene', '4297', (227, 230))	('E542 K', 'Mutation', 'rs200491706', (190, 196))	('ARID1A', 'Gene', '8289', (236, 242))	('Tumours', 'Phenotype', 'HP:0002664', (0, 7))	('PIK3CA', 'Gene', '5290', (169, 175))
563708	33292100	Bladder tumours not enriched for APOBEC mutagenesis were more likely to have mutations in FGFR3 and the RAS family of oncogenes (KRAS/HRAS/NRAS), which are mutually exclusive, and these patients had poor overall survival.	('HRAS', 'Gene', (134, 138))	('NRAS', 'Gene', (139, 143))	('tumours', 'Disease', (8, 15))	('FGFR3', 'Gene', '2261', (90, 95))	('NRAS', 'Gene', '4893', (139, 143))	('KRAS', 'Gene', (129, 133))	('tumour', 'Phenotype', 'HP:0002664', (8, 14))	('mutations', 'Var', (77, 86))	('KRAS', 'Gene', '3845', (129, 133))	('FGFR3', 'Gene', (90, 95))	('tumours', 'Phenotype', 'HP:0002664', (8, 15))	('HRAS', 'Gene', '3265', (134, 138))	('patients', 'Species', '9606', (186, 194))	('tumours', 'Disease', 'MESH:D009369', (8, 15))
563712	33292100	It has been suggested that hypermutation could enhance the effectiveness of immune stimulation therapy to treat cancer, by means of the generation of tumour-specific neoantigens that might trigger targeted destruction by the immune system.	('enhance', 'PosReg', (47, 54))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('tumour', 'Disease', 'MESH:D009369', (150, 156))	('tumour', 'Disease', (150, 156))	('effectiveness', 'MPA', (59, 72))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('hypermutation', 'Var', (27, 40))	('tumour', 'Phenotype', 'HP:0002664', (150, 156))
563713	33292100	BLCA often has high levels of enrichment for APOBEC mutagenesis and A3A-like signatures.	('A3A', 'Gene', (68, 71))	('mutagenesis', 'Var', (52, 63))	('men', 'Species', '9606', (36, 39))	('APOBEC', 'Protein', (45, 51))	('A3A', 'Gene', '200315', (68, 71))
563714	33292100	The clinical observations in BLCA patients treated with available immune therapies raise the intriguing possibility that hypermutation in BLCA (mainly by A3A) could contribute substantially to the success of immune therapies.	('A3A', 'Gene', (154, 157))	('hypermutation', 'Var', (121, 134))	('patients', 'Species', '9606', (34, 42))	('A3A', 'Gene', '200315', (154, 157))
563717	33292100	At least 14 HPV types are carcinogenic, and these 'high-risk' (HR) types, among which HPV16 and HPV18 are the most studied, cause human cancers in the mucosal epithelia of several sites, including the cervix, vulva, vagina, penis, anus, and head and neck, especially those from the oropharynx that includes the tonsils and tongue base.	('HPV', 'Species', '10566', (96, 99))	('HPV', 'Species', '10566', (86, 89))	('carcinogenic', 'Disease', 'MESH:D063646', (26, 38))	('cancers', 'Phenotype', 'HP:0002664', (136, 143))	('carcinogenic', 'Disease', (26, 38))	('types', 'Var', (67, 72))	('HPV1', 'Species', '12080', (96, 100))	('cancers', 'Disease', (136, 143))	('cancers', 'Disease', 'MESH:D009369', (136, 143))	('HPV1', 'Species', '12080', (86, 90))	('HPV', 'Species', '10566', (12, 15))	('HPV18', 'Var', (96, 101))	('HPV16', 'Species', '333760', (86, 91))	('cause', 'Reg', (124, 129))	('HPV16', 'Var', (86, 91))	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('human', 'Species', '9606', (130, 135))
563723	33292100	The strong enrichment of the APOBEC signature in cervical cancer exomes and the previous evidence for A3 editing of HPV genomes in plantar warts and pre-cancerous cervical lesions suggest that the presence of HPV in cells might somehow induce or potentiate A3 activity, damaging the host genome and resulting in the observed enrichment of these mutational signatures in HPV-associated cancers.	('cancerous cervical lesions', 'Phenotype', 'HP:0030159', (153, 179))	('cancer', 'Phenotype', 'HP:0002664', (58, 64))	('cancer', 'Disease', (153, 159))	('cancer', 'Phenotype', 'HP:0002664', (385, 391))	('mutational signatures', 'MPA', (345, 366))	('damaging', 'Reg', (270, 278))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('HPV', 'Species', '10566', (209, 212))	('men', 'Species', '9606', (17, 20))	('HPV', 'Species', '10566', (116, 119))	('HPV', 'Species', '10566', (370, 373))	('A3', 'Chemical', '-', (102, 104))	('presence', 'Var', (197, 205))	('cancer', 'Disease', 'MESH:D009369', (58, 64))	('cancer', 'Disease', 'MESH:D009369', (385, 391))	('cancers', 'Disease', 'MESH:D009369', (385, 392))	('potentiate', 'PosReg', (246, 256))	('cancer', 'Disease', 'MESH:D009369', (153, 159))	('HPV', 'Gene', (209, 212))	('cancerous cervical lesions', 'Disease', 'MESH:D002583', (153, 179))	('A3', 'Chemical', '-', (257, 259))	('cancerous cervical lesions', 'Disease', (153, 179))	('activity', 'MPA', (260, 268))	('induce', 'PosReg', (236, 242))	('warts', 'Phenotype', 'HP:0200043', (139, 144))	('cancer', 'Disease', (385, 391))	('men', 'Species', '9606', (331, 334))	('cancers', 'Phenotype', 'HP:0002664', (385, 392))	('cancer', 'Disease', (58, 64))	('cancers', 'Disease', (385, 392))
563725	33292100	Several studies indicate that NF-kappaB pathway activation, p53 inactivation by HPV oncoprotein E6 activation, or loss-of-function mutations in the TP53 gene and replication stress activation are responsible for transcriptional activation of APOBEC, in particular, A3B (figure 6).	('mutations', 'Var', (131, 140))	('inactivation', 'NegReg', (64, 76))	('activation', 'PosReg', (228, 238))	('NF-kappaB', 'Gene', '4790', (30, 39))	('TP53', 'Gene', '7157', (148, 152))	('TP53', 'Gene', (148, 152))	('HPV', 'Species', '10566', (80, 83))	('p53', 'Gene', (60, 63))	('NF-kappaB', 'Gene', (30, 39))	('loss-of-function', 'NegReg', (114, 130))	('activation', 'PosReg', (48, 58))	('transcriptional', 'MPA', (212, 227))	('APOBEC', 'Gene', (242, 248))	('p53', 'Gene', '7157', (60, 63))
563727	33292100	The loss of p53 activity through mutations (e.g.	('mutations', 'Var', (33, 42))	('p53', 'Gene', '7157', (12, 15))	('p53', 'Gene', (12, 15))	('activity', 'MPA', (16, 24))	('loss', 'NegReg', (4, 8))
563728	33292100	in BRCA) or HPV-16 E6/E7-mediated downregulation, causes A3B upregulation.	('BRCA', 'Gene', (3, 7))	('BRCA', 'Gene', '672', (3, 7))	('HPV-16', 'Species', '333760', (12, 18))	('downregulation', 'NegReg', (34, 48))	('upregulation', 'PosReg', (61, 73))	('A3B', 'Protein', (57, 60))	('HPV-16', 'Gene', (12, 18))	('E6/E7-mediated', 'Var', (19, 33))
563729	33292100	Thus, inactivation of p53 by viral protein E6 activation or loss of function of p53 mutations can activate A3B function, increase genome instability and promote tumour initiation.	('tumour initiation', 'Disease', (161, 178))	('tumour initiation', 'Disease', 'MESH:D009369', (161, 178))	('loss of function', 'NegReg', (60, 76))	('increase', 'PosReg', (121, 129))	('activation', 'PosReg', (46, 56))	('p53', 'Gene', (80, 83))	('p53', 'Gene', (22, 25))	('A3B', 'Protein', (107, 110))	('tumour', 'Phenotype', 'HP:0002664', (161, 167))	('function', 'MPA', (111, 119))	('mutations', 'Var', (84, 93))	('p53', 'Gene', '7157', (80, 83))	('p53', 'Gene', '7157', (22, 25))	('promote', 'PosReg', (153, 160))	('genome instability', 'MPA', (130, 148))	('activate', 'PosReg', (98, 106))
563735	33292100	Translation of LINE1 results in neoantigen expression, so transcription of repetitive elements would put HR-HPV-infected cells at risk of extinction through adaptive immune responses.	('HR-HPV-infected', 'Disease', (105, 120))	('neoantigen expression', 'MPA', (32, 53))	('HR-HPV-infected', 'Disease', 'MESH:D030361', (105, 120))	('LINE1', 'Gene', (15, 20))	('men', 'Species', '9606', (89, 92))	('results in', 'Reg', (21, 31))	('Translation', 'Var', (0, 11))
563739	33292100	A3s target the ssDNA in R-loops and can thereby also activate the DNA damage response, which benefits virus replication (figure 6).	('benefits', 'PosReg', (93, 101))	('R-loops', 'Protein', (24, 31))	('DNA', 'CPA', (66, 69))	('virus replication', 'MPA', (102, 119))	('A3s', 'Chemical', '-', (0, 3))	('A3s', 'Var', (0, 3))	('activate', 'PosReg', (53, 61))
563741	33292100	HPV16 or HPV18 induces A3B expression in cultured cells of BRCA and HNSCC, and the virus-encoded protein E6 directly binds the A3B promoter and triggers transcription.	('BRCA', 'Gene', '672', (59, 63))	('induces', 'Reg', (15, 22))	('HPV1', 'Species', '12080', (0, 4))	('BRCA', 'Gene', (59, 63))	('binds', 'Interaction', (117, 122))	('HPV16', 'Species', '333760', (0, 5))	('A3B', 'Protein', (23, 26))	('HPV16', 'Var', (0, 5))	('triggers', 'Reg', (144, 152))	('HPV1', 'Species', '12080', (9, 13))	('transcription', 'MPA', (153, 166))	('HPV18', 'Gene', (9, 14))
563743	33292100	E6-mediated p53 degradation, therefore, not only de-represses A3B transcription via the DREAM complex, but also results in increased levels of TEAD expression, further activating the A3B promoter (figure 6).	('increased', 'PosReg', (123, 132))	('activating', 'PosReg', (168, 178))	('TEAD expression', 'MPA', (143, 158))	('DREAM', 'Gene', '30818', (88, 93))	('p53', 'Gene', (12, 15))	('A3B', 'Gene', (62, 65))	('transcription', 'MPA', (66, 79))	('p53', 'Gene', '7157', (12, 15))	('degradation', 'Var', (16, 27))	('levels', 'MPA', (133, 139))	('de-represses', 'NegReg', (49, 61))	('DREAM', 'Gene', (88, 93))
563746	33292100	The distribution of PIK3CA-activating mutations is different in head and neck cancers, with exclusively helical domain C-to-T transitions observed in HPV-positive tumours and a combination of helical domain and kinase domain mutations in HPV-negative tumours.	('observed', 'Reg', (138, 146))	('HPV-positive tumours', 'Disease', (150, 170))	('HPV-negative tumours', 'Disease', 'MESH:D030361', (238, 258))	('head and neck cancers', 'Phenotype', 'HP:0012288', (64, 85))	('tumour', 'Phenotype', 'HP:0002664', (251, 257))	('helical domain', 'MPA', (104, 118))	('PIK3CA', 'Gene', (20, 26))	('HPV-negative tumours', 'Disease', (238, 258))	('tumours', 'Phenotype', 'HP:0002664', (163, 170))	('tumours', 'Phenotype', 'HP:0002664', (251, 258))	('PIK3CA', 'Gene', '5290', (20, 26))	('cancers', 'Phenotype', 'HP:0002664', (78, 85))	('tumour', 'Phenotype', 'HP:0002664', (163, 169))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('mutations', 'Var', (38, 47))	('HPV-positive tumours', 'Disease', 'MESH:D030361', (150, 170))	('head and neck cancers', 'Disease', 'MESH:D006258', (64, 85))
563747	33292100	The HPV-positive tumours have 5'-TGA-to-TAA transitions (complementary strand 5'-TCA-to-TTA) that convert both helical domain Glu542 and Glu545 to Lys, whereas HPV-negative tumours often have a 5'-CAT-to-CGT transition mutation resulting in a kinase domain His1047 to Arg substitution.	('His1047 to Arg', 'Mutation', 'p.H1047R', (257, 271))	('TTA', 'Chemical', 'MESH:C062078', (88, 91))	('tumours', 'Phenotype', 'HP:0002664', (17, 24))	('HPV-positive tumours', 'Disease', (4, 24))	('convert', 'Reg', (98, 105))	('TCA', 'Chemical', 'MESH:D014238', (81, 84))	('men', 'Species', '9606', (63, 66))	('tumour', 'Phenotype', 'HP:0002664', (17, 23))	('HPV-positive tumours', 'Disease', 'MESH:D030361', (4, 24))	('kinase', 'MPA', (243, 249))	('HPV-negative tumours', 'Disease', (160, 180))	('CGT', 'Gene', '7368', (204, 207))	('tumours', 'Phenotype', 'HP:0002664', (173, 180))	('Glu542 and Glu545 to Lys', 'Mutation', 'p.E,E542,545K', (126, 150))	('Glu545 to Lys', 'SUBSTITUTION', 'None', (137, 150))	('CGT', 'Gene', (204, 207))	('helical domain Glu542', 'MPA', (111, 132))	('Glu545 to Lys', 'Var', (137, 150))	('HPV-negative tumours', 'Disease', 'MESH:D030361', (160, 180))	('tumour', 'Phenotype', 'HP:0002664', (173, 179))
563748	33292100	Similar helical domain biases have also been reported for PIK3CA mutations in other APOBEC-signature tumour types, implying as the common denominator the APOBEC mutagenesis and not viral infection.	('viral infection', 'Disease', 'MESH:D001102', (181, 196))	('APOBEC-signature', 'Disease', (84, 100))	('tumour', 'Disease', (101, 107))	('PIK3CA', 'Gene', (58, 64))	('viral infection', 'Disease', (181, 196))	('PIK3CA', 'Gene', '5290', (58, 64))	('tumour', 'Disease', 'MESH:D009369', (101, 107))	('tumour', 'Phenotype', 'HP:0002664', (101, 107))	('helical domain biases', 'MPA', (8, 29))	('mutations', 'Var', (65, 74))
563750	33292100	The distinctive pattern of APOBEC-signature mutations in exon 9 of the PIK3CA proto-oncogene in HPV-positive HNSCC and in other cancer types displaying the APOBEC mutational signature implicates APOBEC activity in the generation of oncogenic driver events, findings that were confirmed by analysis of TCGA HPV-positive HNSCC cohorts.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('HPV', 'Species', '10566', (96, 99))	('APOBEC-signature', 'Gene', (27, 43))	('PIK3CA', 'Gene', '5290', (71, 77))	('HPV', 'Species', '10566', (306, 309))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('mutations', 'Var', (44, 53))	('implicates', 'Reg', (184, 194))	('PIK3CA', 'Gene', (71, 77))	('cancer', 'Disease', (128, 134))
563755	33292100	It could be that when the mutations are occurring during development of these tumours, they are correlated with the expression of the A3 responsible, but that this relationship is lost following subsequent downregulation, possibly because of the role of A3s as transient hypermutators.	('correlated', 'Reg', (96, 106))	('A3', 'Chemical', '-', (134, 136))	('expression', 'MPA', (116, 126))	('tumours', 'Phenotype', 'HP:0002664', (78, 85))	('A3', 'Chemical', '-', (254, 256))	('tumours', 'Disease', 'MESH:D009369', (78, 85))	('tumours', 'Disease', (78, 85))	('downregulation', 'NegReg', (206, 220))	('mutations', 'Var', (26, 35))	('men', 'Species', '9606', (64, 67))	('lost', 'NegReg', (180, 184))	('tumour', 'Phenotype', 'HP:0002664', (78, 84))	('A3s', 'Chemical', '-', (254, 257))
563756	33292100	The preponderance of A3-induced mutations in HPV-driven cervical cancer, together with the observation that A3-induced mutations are enriched in the HPV-associated subset of HNSCC, suggest a possible off-target response to the virus.	('A3-induced', 'Gene', (21, 31))	('HPV', 'Species', '10566', (45, 48))	('HPV', 'Species', '10566', (149, 152))	('A3', 'Chemical', '-', (21, 23))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('A3', 'Chemical', '-', (108, 110))	('mutations', 'Var', (32, 41))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))
563759	33292100	Also, A3A expression is associated with HPV16 genome integration and hypermutations in oropharyngeal cancers.	('cancers', 'Disease', 'MESH:D009369', (101, 108))	('A3A', 'Gene', '200315', (6, 9))	('associated', 'Reg', (24, 34))	('HPV16', 'Species', '333760', (40, 45))	('cancers', 'Phenotype', 'HP:0002664', (101, 108))	('cancers', 'Disease', (101, 108))	('HPV16', 'Gene', (40, 45))	('A3A', 'Gene', (6, 9))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('hypermutations', 'Var', (69, 83))
563762	33292100	The cervical epithelium is an oestrogen-responsive tissue; indeed, HPV E6/E7-driven cervical cancer development in transgenic mice can be promoted by oestradiol infusion over several months.	('cancer', 'Disease', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (93, 99))	('transgenic mice', 'Species', '10090', (115, 130))	('men', 'Species', '9606', (107, 110))	('E6/E7-driven', 'Var', (71, 83))	('oestradiol', 'Chemical', 'MESH:D004958', (150, 160))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('HPV', 'Species', '10566', (67, 70))	('HPV', 'Gene', (67, 70))	('promoted', 'PosReg', (138, 146))
563763	33292100	Considering these factors, it is a possibility that A3B could also fuel cervical carcinogenesis via this non-mutagenic but nonetheless deaminase-dependent transcriptional activity.	('carcinogenesis', 'Disease', 'MESH:D063646', (81, 95))	('carcinogenesis', 'Disease', (81, 95))	('A3B', 'Var', (52, 55))	('fuel', 'PosReg', (67, 71))	('deaminase-dependent transcriptional activity', 'MPA', (135, 179))
563765	33292100	first reported the evidence for APOBEC editing of HPV in human cells and noted that HPV1a DNA co-transfected with A3A, A3C and A3H but not A3B displayed evidence of cytidine deamination, and while low-risk HPV genomes isolated from warts display evidence of A3 editing, several tested low-risk E6 variants did not upregulate A3B in cultured keratinocytes.	('cytidine deamination', 'MPA', (165, 185))	('A3', 'Chemical', '-', (119, 121))	('A3', 'Chemical', '-', (127, 129))	('warts', 'Phenotype', 'HP:0200043', (232, 237))	('A3A', 'Gene', (114, 117))	('HPV', 'Species', '10566', (84, 87))	('variants', 'Var', (297, 305))	('A3H', 'Gene', (127, 130))	('human', 'Species', '9606', (57, 62))	('A3H', 'Gene', '164668', (127, 130))	('A3', 'Chemical', '-', (139, 141))	('HPV', 'Species', '10566', (50, 53))	('HPV1', 'Species', '12080', (84, 88))	('cytidine', 'Chemical', 'MESH:D003562', (165, 173))	('A3A', 'Gene', '200315', (114, 117))	('A3', 'Chemical', '-', (258, 260))	('A3', 'Chemical', '-', (114, 116))	('HPV', 'Species', '10566', (206, 209))	('A3C', 'Mutation', 'c.3A>C', (119, 122))	('A3', 'Chemical', '-', (325, 327))
563767	33292100	The first hypothesis considered the possibility that the A3 response to HPV infection (mediated by A3A and/or A3C, A3H) is entirely separate from any role in host mutagenesis (mediated by A3B) during cancer development.	('A3H', 'Gene', '164668', (115, 118))	('A3', 'Chemical', '-', (188, 190))	('A3A', 'Gene', (99, 102))	('A3', 'Chemical', '-', (99, 101))	('men', 'Species', '9606', (214, 217))	('HPV infection', 'Disease', 'MESH:D030361', (72, 85))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('A3C', 'Var', (110, 113))	('A3H', 'Gene', (115, 118))	('A3', 'Chemical', '-', (110, 112))	('HPV infection', 'Disease', (72, 85))	('cancer', 'Disease', 'MESH:D009369', (200, 206))	('A3A', 'Gene', '200315', (99, 102))	('A3', 'Chemical', '-', (115, 117))	('A3', 'Chemical', '-', (57, 59))	('cancer', 'Disease', (200, 206))	('A3C', 'Mutation', 'c.3A>C', (110, 113))
563771	33292100	Although further investigations will be necessary, these observations suggest A3A, rather than A3B, may be the major source of somatic mutations to the host genome in HPV-associated cancer.	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('mutations', 'Var', (135, 144))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('cancer', 'Disease', (182, 188))	('A3A', 'Gene', '200315', (78, 81))	('HPV', 'Species', '10566', (167, 170))	('A3A', 'Gene', (78, 81))
563776	33292100	This study showed that IFN-beta treatment upregulated A3A expression in cervical keratinocytes, and that knockdown of A3A expression reduced IFN-beta-induced hypermutation of the viral E2 gene (figure 6).	('IFN-beta', 'Gene', '3438', (23, 31))	('IFN-beta', 'Gene', (23, 31))	('expression', 'MPA', (58, 68))	('knockdown', 'Var', (105, 114))	('A3A', 'Gene', '200315', (118, 121))	('men', 'Species', '9606', (37, 40))	('A3A', 'Gene', (118, 121))	('upregulated', 'PosReg', (42, 53))	('IFN-beta', 'Gene', '3438', (141, 149))	('A3A', 'Gene', '200315', (54, 57))	('A3A', 'Gene', (54, 57))	('IFN-beta', 'Gene', (141, 149))	('reduced', 'NegReg', (133, 140))
563779	33292100	HPV restriction by A3A is deaminase-dependent, as a catalytically inactive mutant A3A was unable to restrict HPV infection.	('A3A', 'Gene', (82, 85))	('HPV', 'Species', '10566', (0, 3))	('HPV infection', 'Disease', (109, 122))	('mutant', 'Var', (75, 81))	('HPV infection', 'Disease', 'MESH:D030361', (109, 122))	('HPV', 'Species', '10566', (109, 112))	('A3A', 'Gene', '200315', (19, 22))	('A3A', 'Gene', (19, 22))	('A3A', 'Gene', '200315', (82, 85))
563788	33292100	The results obtained suggest that A3s activate BER in HNSCC, mediate repair of cisplatin ICLs and thereby, sensitize cells to cisplatin which likely contributes to the improved patient responses observed in HPV-infected patients.	('repair', 'MPA', (69, 75))	('ICLs', 'Disease', 'None', (89, 93))	('cisplatin', 'Chemical', 'MESH:D002945', (79, 88))	('mediate', 'Reg', (61, 68))	('HPV-infected', 'Disease', 'MESH:D030361', (207, 219))	('HPV-infected', 'Disease', (207, 219))	('HNSCC', 'Protein', (54, 59))	('cisplatin', 'Chemical', 'MESH:D002945', (126, 135))	('patient', 'Species', '9606', (177, 184))	('activate', 'PosReg', (38, 46))	('patient', 'Species', '9606', (220, 227))	('patients', 'Species', '9606', (220, 228))	('ER', 'Gene', '2069', (48, 50))	('A3s', 'Chemical', '-', (34, 37))	('ICLs', 'Disease', (89, 93))	('A3s', 'Var', (34, 37))	('sensitize', 'Reg', (107, 116))
563789	33292100	Contrary to the idea that A3-mediated somatic mutations may drive HPV-positive cancer progression, recent cancer immunology studies have shown that high levels of somatic mutations favour anti-tumour immune responses that also coincide with better prognosis after immunotherapies.	('HPV', 'Species', '10566', (66, 69))	('tumour', 'Disease', (193, 199))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('cancer', 'Disease', (106, 112))	('tumour', 'Phenotype', 'HP:0002664', (193, 199))	('A3', 'Chemical', '-', (26, 28))	('mutations', 'Var', (171, 180))	('favour', 'PosReg', (181, 187))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('tumour', 'Disease', 'MESH:D009369', (193, 199))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
563790	33292100	Tumour neoantigens are recognized as emerging targets for personalized cancer immunotherapies, implying that cancers with a high level of A3 mutation signatures may be beneficial for immunotherapies that induce robust anti-tumour T-cell responses specific to neoantigens generated by A3-mediated mutations.	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('tumour', 'Phenotype', 'HP:0002664', (223, 229))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('cancers', 'Disease', 'MESH:D009369', (109, 116))	('cancer', 'Disease', (71, 77))	('cancers', 'Phenotype', 'HP:0002664', (109, 116))	('Tumour', 'Phenotype', 'HP:0002664', (0, 6))	('cancers', 'Disease', (109, 116))	('cancer', 'Disease', (109, 115))	('tumour', 'Disease', 'MESH:D009369', (223, 229))	('tumour', 'Disease', (223, 229))	('A3', 'Chemical', '-', (138, 140))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('mutation', 'Var', (141, 149))	('mutations', 'Var', (296, 305))	('A3', 'Chemical', '-', (284, 286))
563793	33292100	In this regard, A3-mediated mutations could be used beneficially to identify T-cell epitopes and treat HPV-positive cancer patients.	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('HPV', 'Species', '10566', (103, 106))	('patients', 'Species', '9606', (123, 131))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('mutations', 'Var', (28, 37))	('A3', 'Chemical', '-', (16, 18))
563795	33292100	Thus, it would be interesting to investigate if A3 mutation loads in patients correlate to better outcome following current immunotherapies targeting immune checkpoint blockades, e.g.	('mutation loads', 'Var', (51, 65))	('better', 'PosReg', (91, 97))	('patients', 'Species', '9606', (69, 77))	('A3', 'Chemical', '-', (48, 50))
563798	33292100	This analysis revealed that cervical infections with a greater burden of somatic HPV16 A3-induced mutations are more likely to be benign or subsequently clear (figure 6), suggesting they may reduce persistence, and thus progression, within the host.	('infections', 'Disease', 'MESH:D007239', (37, 47))	('persistence', 'MPA', (198, 209))	('HPV16', 'Species', '333760', (81, 86))	('infections', 'Disease', (37, 47))	('mutations', 'Var', (98, 107))	('HPV16 A3-induced', 'Gene', (81, 97))	('A3', 'Chemical', '-', (87, 89))	('reduce', 'NegReg', (191, 197))
563804	33292100	The leading candidates for inducing mutations in cancer are A3B, A3A and A3H Hap I.	('inducing', 'Reg', (27, 35))	('A3H', 'Gene', (73, 76))	('cancer', 'Phenotype', 'HP:0002664', (49, 55))	('A3A', 'Gene', '200315', (65, 68))	('A3A', 'Gene', (65, 68))	('mutations', 'Var', (36, 45))	('cancer', 'Disease', 'MESH:D009369', (49, 55))	('A3H', 'Gene', '164668', (73, 76))	('cancer', 'Disease', (49, 55))
563806	33292100	A3B, for example, could provide a mutation rate that is in some cases beneficial favouring immune responses following immunotherapy with a positive outcome for the cancer patients, but in other cases, it is related with poor clinical outcomes.	('beneficial', 'PosReg', (70, 80))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('mutation', 'Var', (34, 42))	('patients', 'Species', '9606', (171, 179))	('cancer', 'Disease', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('immune responses', 'CPA', (91, 107))
563812	33292100	Undoubtedly, knowledge of A3 mutagenesis in cancer may yield significant diagnostic and prognostic value and could open the doors towards new therapeutic opportunities.	('cancer', 'Disease', (44, 50))	('cancer', 'Disease', 'MESH:D009369', (44, 50))	('mutagenesis', 'Var', (29, 40))	('A3', 'Chemical', '-', (26, 28))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))
563817	33292100	(ii) How and when can we avoid the off-target A3-induced mutations that results in poor clinical outcomes, and (iii) why does A3 overexpression sometimes have a clinical benefit for cancer patients?	('A3', 'Chemical', '-', (126, 128))	('cancer', 'Phenotype', 'HP:0002664', (182, 188))	('overexpression', 'PosReg', (129, 143))	('cancer', 'Disease', 'MESH:D009369', (182, 188))	('mutations', 'Var', (57, 66))	('A3-induced', 'Gene', (46, 56))	('cancer', 'Disease', (182, 188))	('patients', 'Species', '9606', (189, 197))	('A3', 'Chemical', '-', (46, 48))
563872	30984238	The subgroup with the poorest prognosis (blue) significantly corresponded to LOC84931, PRAME, DBN1, SCAND3, and TUBB3 over-expression.	('PRAME', 'Gene', '23532', (87, 92))	('DBN1', 'Gene', (94, 98))	('DBN1', 'Gene', '1627', (94, 98))	('SCAND3', 'Gene', '114821', (100, 106))	('SCAND3', 'Gene', (100, 106))	('PRAME', 'Gene', (87, 92))	('LOC84931', 'Var', (77, 85))	('over-expression', 'PosReg', (118, 133))	('TUBB3', 'Gene', (112, 117))	('TUBB3', 'Gene', '10381', (112, 117))
563874	30984238	Second, we performed survival analysis on each single feature using the kmeans as a general clustering method, and found that more than 1/3 relevant features showed good partition ability with a Log-rank test p-value< 0.05 including five genes (LOC84931, DBN1, SCAND3, TUBB3, ICOS), six CpG sites (cg11796219, cg08749305, cg07258916, cg05869617, cg01762070, cg15966877), and six miRNAs (hsa-miR-767, hsa-miR-3200, hsa-miR-483, hsa-miR-9-2, hsa-miR-584, hsa-miR-342).	('SCAND3', 'Gene', '114821', (261, 267))	('cg08749305', 'Var', (310, 320))	('TUBB3', 'Gene', (269, 274))	('cg15966877', 'Var', (358, 368))	('hsa-miR-342', 'Gene', (453, 464))	('hsa-miR-483', 'Gene', '619552', (414, 425))	('TUBB3', 'Gene', '10381', (269, 274))	('hsa-miR-342', 'Gene', '442909', (453, 464))	('cg11796219', 'Var', (298, 308))	('miR-3200', 'Gene', (404, 412))	('cg01762070', 'Var', (346, 356))	('ICOS', 'Gene', '29851', (276, 280))	('cg05869617', 'Var', (334, 344))	('SCAND3', 'Gene', (261, 267))	('hsa-miR-9-2', 'Gene', '407047', (427, 438))	('cg07258916', 'Var', (322, 332))	('ICOS', 'Gene', (276, 280))	('hsa-miR-767', 'Gene', '768215', (387, 398))	('DBN1', 'Gene', '1627', (255, 259))	('hsa-miR-584', 'Gene', (440, 451))	('hsa-miR-767', 'Gene', (387, 398))	('hsa-miR-584', 'Gene', '693169', (440, 451))	('DBN1', 'Gene', (255, 259))	('hsa-miR-483', 'Gene', (414, 425))	('hsa-miR-9-2', 'Gene', (427, 438))	('miR-3200', 'Gene', '100422912', (404, 412))
563880	30984238	The most significant features, included cg22831949, falls in PTPRN2, which was found to inhibit apoptosis and promote cancer formation in breast cancer (Sorokin et al.,); cg07258916 corresponding to PLXNA4 which belongs to the plexin family, and was previously indicated to inhibit tumor cell migration (Balakrishnan et al.,); cg11796219 matched with C3orf21, while C3orf21 ablation was proved to promote cell proliferation, inhibite apoptosis and accelerate cell migration in lung cancer.	('cancer', 'Disease', (145, 151))	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('cancer', 'Disease', 'MESH:D009369', (482, 488))	('tumor', 'Disease', (282, 287))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('inhibit', 'NegReg', (88, 95))	('C3orf21', 'Gene', '152002', (366, 373))	('promote', 'PosReg', (397, 404))	('tumor', 'Disease', 'MESH:D009369', (282, 287))	('lung cancer', 'Disease', 'MESH:D008175', (477, 488))	('cell proliferation', 'CPA', (405, 423))	('apoptosis', 'CPA', (434, 443))	('cg22831949', 'Var', (40, 50))	('C3orf21', 'Gene', '152002', (351, 358))	('C3orf21', 'Gene', (366, 373))	('lung cancer', 'Phenotype', 'HP:0100526', (477, 488))	('PTPRN2', 'Gene', (61, 67))	('breast cancer', 'Phenotype', 'HP:0003002', (138, 151))	('PLXNA4', 'Gene', (199, 205))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('cancer', 'Disease', (118, 124))	('C3orf21', 'Gene', (351, 358))	('tumor', 'Phenotype', 'HP:0002664', (282, 287))	('cancer', 'Disease', (482, 488))	('inhibit', 'NegReg', (274, 281))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('breast cancer', 'Disease', 'MESH:D001943', (138, 151))	('breast cancer', 'Disease', (138, 151))	('accelerate', 'PosReg', (448, 458))	('cg07258916', 'Var', (171, 181))	('PTPRN2', 'Gene', '5799', (61, 67))	('cancer', 'Phenotype', 'HP:0002664', (482, 488))	('inhibite', 'NegReg', (425, 433))	('PLXNA4', 'Gene', '91584', (199, 205))	('cg11796219', 'Var', (327, 337))	('lung cancer', 'Disease', (477, 488))	('falls', 'Phenotype', 'HP:0002527', (52, 57))	('cell migration', 'CPA', (459, 473))
563921	33956788	It was found that NCUA performs better than other methods on control efficiency for attractor (8,484, 8.484, 27) and attractor (-8,484, -8.484, 27).	('NCUA', 'Chemical', '-', (18, 22))	('-8,484', 'Var', (128, 134))	('control', 'MPA', (61, 68))
563935	33956788	On the other hand, to evaluate the efficiency of sample-specific network drivers recognition for personalized drug target discovery, the number of sample-specific network drivers/genes targeted by drug combinations were calculated, and anti-cancer drug combinations were ranked for each patient based on the combinational drug target network (S2 File).	('patient', 'Species', '9606', (287, 294))	('combinations', 'Var', (202, 214))	('cancer', 'Phenotype', 'HP:0002664', (241, 247))	('cancer', 'Disease', (241, 247))	('cancer', 'Disease', 'MESH:D009369', (241, 247))
564030	33956788	Then, delete node w and add a new node vepsilonVT-Mt which can cover the edges connected by node w in the bipartite graph G(VT, V , E1).	('delete', 'Var', (6, 12))	('VT', 'Disease', 'MESH:D017180', (124, 126))	('vepsilonVT', 'Disease', 'None', (39, 49))	('VT', 'Disease', 'MESH:D017180', (47, 49))	('vepsilonVT', 'Disease', (39, 49))
564041	31792655	Moreover, we developed a MALAT1 silencing model in human laryngeal tumor cells by transfecting MALAT1 small interfering RNA into human laryngeal carcinoma cell line Hep-2 and pharyngeal carcinoma cell line FaDu with Lipofectamine 2000 system.	('MALAT1', 'Gene', (95, 101))	('small interfering RNA', 'Var', (102, 123))	('carcinoma', 'Disease', 'MESH:D002277', (186, 195))	('carcinoma', 'Disease', 'MESH:D002277', (145, 154))	('carcinoma', 'Phenotype', 'HP:0030731', (145, 154))	('laryngeal carcinoma', 'Phenotype', 'HP:0012118', (135, 154))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('Hep-2', 'CellLine', 'CVCL:1906', (165, 170))	('carcinoma', 'Phenotype', 'HP:0030731', (186, 195))	('silencing', 'NegReg', (32, 41))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('human', 'Species', '9606', (51, 56))	('carcinoma', 'Disease', (186, 195))	('carcinoma', 'Disease', (145, 154))	('human', 'Species', '9606', (129, 134))	('tumor', 'Disease', (67, 72))
564042	31792655	Cell cycle analysis, Cell Counting Kit-8 assay, Transwell assay, quantitative reverse transcription PCR, and wound-healing assays were performed to evaluate the impact of MALAT1 depletion on laryngeal or hypopharyngeal cancer cell's growth, proliferation, apoptosis, invasion and migration.	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('invasion', 'CPA', (267, 275))	('migration', 'CPA', (280, 289))	('hypopharyngeal cancer', 'Disease', (204, 225))	('apoptosis', 'CPA', (256, 265))	('pharyngeal cancer', 'Phenotype', 'HP:0100638', (208, 225))	('depletion', 'Var', (178, 187))	('hypopharyngeal cancer', 'Disease', 'MESH:D007012', (204, 225))	('growth', 'CPA', (233, 239))
564068	31792655	For the intronic MALAT1 knockdown, a pool of ten siRNAs (sense 5'-3': CCCUCUAAAUAAGGAAUATT, antisense 3'-5': UUAUUCCUUAUUUAGAGGGTT, labeled with 5'FAM) targeting intronic regions in MALTA1 were transfected into cells, and RNA isolated as above.	('MALTA1', 'Gene', (182, 188))	('knockdown', 'Var', (24, 33))	("5'FAM", 'Chemical', 'MESH:C031179', (145, 150))	('MALAT1', 'Gene', (17, 23))
564085	31792655	In addition, flow cytometric analysis showed that MALAT1 depletion resulted in cell cycle arrested at G1/G2 phase in both Hep-2 and FaDu cell lines (Fig.	('MALAT1', 'Gene', (50, 56))	('Hep-2', 'CellLine', 'CVCL:1906', (122, 127))	('cell cycle arrested at G1/G2 phase', 'CPA', (79, 113))	('depletion', 'Var', (57, 66))
564086	31792655	Moreover, for Hep-2 cell lines, much less cells entered into S phase after si-MALAT1 interference.	('S phase', 'CPA', (61, 68))	('si-MALAT1 interference', 'Var', (75, 97))	('entered', 'Reg', (48, 55))	('Hep-2', 'CellLine', 'CVCL:1906', (14, 19))
564087	31792655	Moreover, MALAT1 depletion also induced apoptosis in Hep-2 and FaDu cell lines (Fig.	('Hep-2', 'CellLine', 'CVCL:1906', (53, 58))	('apoptosis', 'CPA', (40, 49))	('MALAT1', 'Gene', (10, 16))	('depletion', 'Var', (17, 26))	('induced', 'Reg', (32, 39))
564090	31792655	The result showed that silencing the expression of MALAT1 impeded invasion and migration both in Hep-2 and FaDu cell lines (Fig.	('Hep-2', 'CellLine', 'CVCL:1906', (97, 102))	('impeded', 'NegReg', (58, 65))	('MALAT1', 'Gene', (51, 57))	('silencing', 'Var', (23, 32))
564110	31792655	Nevertheless, in the study by Kim et al., the authors showed that targeted inactivation of MALAT1 in a mouse model of breast cancer promoted lung metastasis, without altering the expression of its adjacent genes as previous researches did.	('mouse', 'Species', '10090', (103, 108))	('breast cancer', 'Phenotype', 'HP:0003002', (118, 131))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('breast cancer', 'Disease', (118, 131))	('breast cancer', 'Disease', 'MESH:D001943', (118, 131))	('targeted inactivation', 'Var', (66, 87))	('promoted', 'PosReg', (132, 140))	('lung metastasis', 'Disease', (141, 156))	('MALAT1', 'Gene', (91, 97))	('lung metastasis', 'Disease', 'MESH:D009362', (141, 156))
564114	31792655	Our results demonstrated that down-regulating MALAT1 can induce increased laryngeal cancer cell apoptosis and inhibition of cell proliferation.	('inhibition', 'NegReg', (110, 120))	('laryngeal cancer', 'Disease', 'MESH:D007822', (74, 90))	('laryngeal cancer', 'Disease', (74, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('down-regulating', 'Var', (30, 45))	('laryngeal cancer', 'Phenotype', 'HP:0012118', (74, 90))	('cell proliferation', 'CPA', (124, 142))	('increased', 'PosReg', (64, 73))	('MALAT1', 'Gene', (46, 52))
564121	31792655	In our study when depleting MALAT1 in laryngeal cancer cell lines, the invasion and migration of both laryngeal cancer cell lines Hep-2 and hypopharyngeal cancer cell FaDu were inhibited.	('inhibited', 'NegReg', (177, 186))	('laryngeal cancer', 'Phenotype', 'HP:0012118', (38, 54))	('MALAT1', 'Gene', (28, 34))	('Hep-2', 'CellLine', 'CVCL:1906', (130, 135))	('cancer', 'Phenotype', 'HP:0002664', (48, 54))	('cancer', 'Phenotype', 'HP:0002664', (155, 161))	('depleting', 'Var', (18, 27))	('migration', 'CPA', (84, 93))	('laryngeal cancer', 'Disease', 'MESH:D007822', (102, 118))	('hypopharyngeal cancer', 'Disease', 'MESH:D007012', (140, 161))	('laryngeal cancer', 'Disease', 'MESH:D007822', (38, 54))	('pharyngeal cancer', 'Phenotype', 'HP:0100638', (144, 161))	('laryngeal cancer', 'Disease', (102, 118))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('laryngeal cancer', 'Phenotype', 'HP:0012118', (102, 118))	('hypopharyngeal cancer', 'Disease', (140, 161))	('laryngeal cancer', 'Disease', (38, 54))
564122	31792655	Nonetheless, in a wound-healing assay, we noticed that silencing MALAT1 did not lead to significant diversity for Hep-2 cell lines.	('Hep-2', 'CellLine', 'CVCL:1906', (114, 119))	('silencing', 'Var', (55, 64))	('MALAT1', 'Gene', (65, 71))
564143	31516613	Deregulated expression of TOXs has been reported in a variety of cancer types, including lung cancer.	('Deregulated', 'Var', (0, 11))	('TOX', 'Gene', '9760', (26, 29))	('lung cancer', 'Disease', (89, 100))	('TOX', 'Gene', (26, 29))	('lung cancer', 'Phenotype', 'HP:0100526', (89, 100))	('lung cancer', 'Disease', 'MESH:D008175', (89, 100))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('cancer', 'Phenotype', 'HP:0002664', (94, 100))	('expression', 'MPA', (12, 22))	('reported', 'Reg', (40, 48))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('cancer', 'Disease', (94, 100))	('cancer', 'Disease', 'MESH:D009369', (94, 100))
564146	31516613	It was revealed that TOX expression profiles differed between lung cancer and normal tissues, and high expression of TOX mRNAs generally predicted improved survival outcomes.	('survival outcomes', 'CPA', (156, 173))	('lung cancer', 'Phenotype', 'HP:0100526', (62, 73))	('high', 'Var', (98, 102))	('TOX', 'Gene', '9760', (21, 24))	('TOX', 'Gene', (21, 24))	('lung cancer', 'Disease', (62, 73))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('TOX', 'Gene', '9760', (117, 120))	('TOX', 'Gene', (117, 120))	('lung cancer', 'Disease', 'MESH:D008175', (62, 73))	('improved', 'PosReg', (147, 155))
564157	31516613	Increasing evidence has demonstrated that TOX gene family members are aberrantly expressed or mutated in various human diseases, particularly in malignancies, such as breast cancer.	('malignancies', 'Disease', (145, 157))	('mutated', 'Var', (94, 101))	('breast cancer', 'Disease', (167, 180))	('breast cancer', 'Phenotype', 'HP:0003002', (167, 180))	('human', 'Species', '9606', (113, 118))	('malignancies', 'Disease', 'MESH:D009369', (145, 157))	('TOX', 'Gene', '9760', (42, 45))	('TOX', 'Gene', (42, 45))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('breast cancer', 'Disease', 'MESH:D001943', (167, 180))
564160	31516613	A previous study by Tessema et al demonstrated that TOX1 is hypermethylated in breast cancer tissues but not in adjacent normal tissues, indicating that TOX1 may be a novel tumor biomarker.	('TOX1', 'Gene', (52, 56))	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('TOX1', 'Gene', '9760', (153, 157))	('breast cancer', 'Disease', 'MESH:D001943', (79, 92))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('hypermethylated', 'Var', (60, 75))	('breast cancer', 'Disease', (79, 92))	('breast cancer', 'Phenotype', 'HP:0003002', (79, 92))	('tumor', 'Disease', (173, 178))	('TOX1', 'Gene', (153, 157))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('Tessema', 'Disease', (20, 27))	('Tessema', 'Disease', 'None', (20, 27))	('TOX1', 'Gene', '9760', (52, 56))
564162	31516613	Zhang et al reported that TOX3 rs3803662 is associated with a significantly favorable prognosis in patients with diffuse-type gastric cancer.	('rs3803662', 'Var', (31, 40))	('TOX3', 'Gene', (26, 30))	('gastric cancer', 'Disease', (126, 140))	('gastric cancer', 'Disease', 'MESH:D013274', (126, 140))	('patients', 'Species', '9606', (99, 107))	('rs3803662', 'Mutation', 'rs3803662', (31, 40))	('gastric cancer', 'Phenotype', 'HP:0012126', (126, 140))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))
564197	31516613	The results revealed that high TOX3 mRNA expression was significantly associated with improved FP in a subgroup of patients who had never smoked (HR=0.370; P=7.500x10-5; Table I).	('patients', 'Species', '9606', (115, 123))	('improved', 'PosReg', (86, 94))	('high', 'Var', (26, 30))	('TOX3', 'Protein', (31, 35))
564198	31516613	By contrast, high mRNA TOX4 expression was significantly associated with improved FP both in patients with smoking (HR=0.730; P=0.012) and without smoking history (HR=0.560; P=0.018) (Table I).	('high', 'Var', (13, 17))	('TOX4', 'Gene', (23, 27))	('expression', 'MPA', (28, 38))	('improved', 'PosReg', (73, 81))	('TOX4', 'Gene', '9878', (23, 27))	('mRNA', 'MPA', (18, 22))	('patients', 'Species', '9606', (93, 101))
564199	31516613	Notably, the present data also demonstrated that high levels of TOX3 mRNA were significantly associated with increased OS in patients who had received chemotherapy (HR=0.580; P=8.200x10-3; Table II), indicating a potential role of TOX3 in the chemosensitivity of lung cancer.	('lung cancer', 'Disease', (263, 274))	('lung cancer', 'Phenotype', 'HP:0100526', (263, 274))	('TOX3', 'Var', (64, 68))	('cancer', 'Phenotype', 'HP:0002664', (268, 274))	('high', 'Var', (49, 53))	('lung cancer', 'Disease', 'MESH:D008175', (263, 274))	('patients', 'Species', '9606', (125, 133))
564210	31516613	Recently, deregulated expression of TOX family members has been reported in a wide range of human cancer types.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('TOX', 'Gene', '9760', (36, 39))	('TOX', 'Gene', (36, 39))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('cancer', 'Disease', (98, 104))	('deregulated', 'Var', (10, 21))	('reported', 'Reg', (64, 72))	('human', 'Species', '9606', (92, 97))	('expression', 'MPA', (22, 32))
564216	31516613	In a genome-wide comparison of DNA methylation between normal and tumor cells performed in a previous study, it was indicated that TOX1 was silenced through CpG hypermethylation in lung cancer, which provides a possible mechanism for the development of lung cancer.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('lung cancer', 'Phenotype', 'HP:0100526', (253, 264))	('hypermethylation', 'Var', (161, 177))	('cancer', 'Phenotype', 'HP:0002664', (258, 264))	('TOX1', 'Gene', '9760', (131, 135))	('lung cancer', 'Disease', (253, 264))	('tumor', 'Disease', (66, 71))	('cancer', 'Phenotype', 'HP:0002664', (186, 192))	('TOX1', 'Gene', (131, 135))	('lung cancer', 'Disease', (181, 192))	('lung cancer', 'Phenotype', 'HP:0100526', (181, 192))	('lung cancer', 'Disease', 'MESH:D008175', (253, 264))	('CpG hypermethylation', 'Var', (157, 177))	('silenced', 'NegReg', (140, 148))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('lung cancer', 'Disease', 'MESH:D008175', (181, 192))
564220	31516613	Further survival analysis with Kaplan-Meier plotter revealed that high levels of TOX3 mRNA were significantly associated with increased FP and OS in patients with lung adenocarcinoma.	('patients', 'Species', '9606', (149, 157))	('lung adenocarcinoma', 'Disease', (163, 182))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (163, 182))	('carcinoma', 'Phenotype', 'HP:0030731', (173, 182))	('TOX3', 'Gene', (81, 85))	('high', 'Var', (66, 70))	('increased', 'PosReg', (126, 135))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (163, 182))
564222	31516613	This hypothesis was supported by Riaz et al, who indicated that TOX3 may act as a tumor-suppressor gene, as the risk allele rs3803662 was significantly associated with low TOX3 expression in breast cancer.	('breast cancer', 'Disease', 'MESH:D001943', (191, 204))	('low', 'NegReg', (168, 171))	('Riaz', 'Gene', '23598', (33, 37))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('rs3803662', 'Var', (124, 133))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('tumor', 'Disease', (82, 87))	('TOX3', 'Protein', (172, 176))	('rs3803662', 'Mutation', 'rs3803662', (124, 133))	('Riaz', 'Gene', (33, 37))	('expression', 'MPA', (177, 187))	('breast cancer', 'Disease', (191, 204))	('breast cancer', 'Phenotype', 'HP:0003002', (191, 204))
564223	31516613	Additionally, TOX3 knockdown increased cell proliferation in breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('breast cancer', 'Disease', (61, 74))	('breast cancer', 'Phenotype', 'HP:0003002', (61, 74))	('knockdown', 'Var', (19, 28))	('increased', 'PosReg', (29, 38))	('TOX3', 'Gene', (14, 18))	('cell proliferation', 'CPA', (39, 57))	('breast cancer', 'Disease', 'MESH:D001943', (61, 74))
564224	31516613	In addition, the TOX3 rs3803662 CT/TT genotype was associated with improved survival in patients with diffuse-type gastric cancer, acting as an independent prognostic marker.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('gastric cancer', 'Disease', 'MESH:D013274', (115, 129))	('rs3803662', 'Mutation', 'rs3803662', (22, 31))	('survival', 'MPA', (76, 84))	('patients', 'Species', '9606', (88, 96))	('gastric cancer', 'Phenotype', 'HP:0012126', (115, 129))	('TOX3', 'Gene', (17, 21))	('rs3803662', 'Var', (22, 31))	('improved', 'PosReg', (67, 75))	('gastric cancer', 'Disease', (115, 129))
564225	31516613	Notably, to the best of our knowledge, the present study is the first to report that high TOX3 transcription levels predict improved survival in patients with lung cancer who have received chemotherapy.	('patients', 'Species', '9606', (145, 153))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('lung cancer', 'Disease', 'MESH:D008175', (159, 170))	('improved', 'PosReg', (124, 132))	('high', 'Var', (85, 89))	('survival', 'MPA', (133, 141))	('lung cancer', 'Disease', (159, 170))	('lung cancer', 'Phenotype', 'HP:0100526', (159, 170))
564239	31516613	It has been demonstrated in previous studies that in vivo HAVCR2 blockade with other checkpoint inhibitors enhances antitumor immunity and suppresses tumor growth in a number of preclinical tumor models, which strongly indicate a potential role in tumor progression.	('enhances', 'PosReg', (107, 115))	('tumor', 'Disease', (248, 253))	('suppresses', 'NegReg', (139, 149))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('tumor', 'Disease', 'MESH:D009369', (150, 155))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('HAVCR2', 'Gene', (58, 64))	('tumor', 'Disease', (190, 195))	('blockade', 'Var', (65, 73))	('tumor', 'Phenotype', 'HP:0002664', (150, 155))	('tumor', 'Disease', 'MESH:D009369', (248, 253))	('tumor', 'Phenotype', 'HP:0002664', (248, 253))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('tumor', 'Disease', (150, 155))	('tumor', 'Disease', (120, 125))
564243	31516613	In summary, ectopic TOX expression is common in lung cancer.	('lung cancer', 'Disease', 'MESH:D008175', (48, 59))	('TOX', 'Gene', '9760', (20, 23))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('TOX', 'Gene', (20, 23))	('lung cancer', 'Disease', (48, 59))	('lung cancer', 'Phenotype', 'HP:0100526', (48, 59))	('ectopic', 'Var', (12, 19))	('common', 'Reg', (38, 44))
564281	30366393	In parallel with the bone marrow lactic acid concentration, the progression of allodynia and thermal hyperalgesia was significantly suppressed by MCT4 knockdown in SAS cells seven days after the cancer cell injection (Figure 5B).	('knockdown', 'Var', (151, 160))	('thermal hyperalgesia', 'Disease', (93, 113))	('lactic acid', 'Chemical', 'MESH:D019344', (33, 44))	('hyperalgesia', 'Phenotype', 'HP:0031005', (101, 113))	('cancer', 'Disease', (195, 201))	('allodynia', 'Disease', (79, 88))	('cancer', 'Disease', 'MESH:D009369', (195, 201))	('allodynia', 'Phenotype', 'HP:0012533', (79, 88))	('thermal hyperalgesia', 'Disease', 'MESH:D006930', (93, 113))	('MCT4', 'Gene', (146, 150))	('allodynia', 'Disease', 'MESH:D006930', (79, 88))	('cancer', 'Phenotype', 'HP:0002664', (195, 201))	('suppressed', 'NegReg', (132, 142))
564287	30366393	These results demonstrated that MCT4 knockdown decreased pERK1/2 and TRPV1 upregulation in DRGs by SAS injection into the tibia, as shown by the immunofluorescence staining (Figure 6B).	('MCT4', 'Gene', (32, 36))	('TRPV1', 'Gene', '193034', (69, 74))	('knockdown', 'Var', (37, 46))	('upregulation', 'PosReg', (75, 87))	('ERK1/2', 'Gene', '26417;26413', (58, 64))	('TRPV1', 'Gene', (69, 74))	('ERK1/2', 'Gene', (58, 64))	('decreased', 'NegReg', (47, 56))
564303	30366393	These data support our hypothesis that lactic acid also provides nutrition and induces sensory neuron axis sprouting.	('lactic acid', 'Var', (39, 50))	('lactic acid', 'Chemical', 'MESH:D019344', (39, 50))	('induces', 'Reg', (79, 86))	('sensory neuron axis sprouting', 'CPA', (87, 116))	('sensory neuron axis sprouting', 'Phenotype', 'HP:0025551', (87, 116))	('nutrition', 'MPA', (65, 74))
564307	30366393	However, MCT4 knockdown decreased HNSCC-BP in mice.	('decreased', 'NegReg', (24, 33))	('MCT4', 'Gene', (9, 13))	('HNSCC-BP', 'MPA', (34, 42))	('mice', 'Species', '10090', (46, 50))	('knockdown', 'Var', (14, 23))	('HNSCC', 'Phenotype', 'HP:0012288', (34, 39))
564313	30366393	Wakabayashi showed that the disruption of the TRPV1 gene attenuated cancer-induced bone pain.	('bone pain', 'Disease', 'MESH:D010146', (83, 92))	('cancer', 'Phenotype', 'HP:0002664', (68, 74))	('TRPV1', 'Gene', '193034', (46, 51))	('bone pain', 'Disease', (83, 92))	('disruption', 'Var', (28, 38))	('pain', 'Phenotype', 'HP:0012531', (88, 92))	('cancer', 'Disease', 'MESH:D009369', (68, 74))	('bone pain', 'Phenotype', 'HP:0002653', (83, 92))	('cancer', 'Disease', (68, 74))	('attenuated', 'NegReg', (57, 67))	('TRPV1', 'Gene', (46, 51))
564324	30366393	The human oral squamous cell carcinoma cell lines SAS (#JCRB0260), HSC-2 (#JCRB0622), HSC-3 (#JCRB0623), HSC-4 (#JCRB0624), OSC-19 (#JCRB0198), and MCF-7(#JCRB0134) were obtained from the Human Science Resources Bank (Osaka, Japan).	('Human', 'Species', '9606', (188, 193))	('human', 'Species', '9606', (4, 9))	('carcinoma', 'Phenotype', 'HP:0030731', (29, 38))	('HSC-3', 'Gene', '150353', (86, 91))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (10, 38))	('#JCRB0624', 'Var', (112, 121))	('OSC-19', 'Disease', (124, 130))	('OSC-19', 'Disease', 'MESH:C567026', (124, 130))	('MCF-7', 'CellLine', 'CVCL:0031', (148, 153))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (15, 38))	('#JCRB0623', 'Var', (93, 102))	('oral squamous cell carcinoma', 'Disease', (10, 38))	('#JCRB0622', 'Var', (74, 83))	('HSC-3', 'Gene', (86, 91))	('#JCRB0260', 'Var', (55, 64))
564411	29434933	Positive p16INK4A expression was significantly higher in the group exhibiting positive expression of PD-L1 compared with the group exhibiting negative expression of PD-L1 (38.2 vs. 12.5%; P<0.01; Table II).	('p16INK4A', 'Gene', '1029', (9, 17))	('higher', 'PosReg', (47, 53))	('PD-L1', 'Gene', '29126', (101, 106))	('positive expression', 'Var', (78, 97))	('PD-L1', 'Gene', (165, 170))	('expression', 'MPA', (18, 28))	('p16INK4A', 'Gene', (9, 17))	('PD-L1', 'Gene', '29126', (165, 170))	('PD-L1', 'Gene', (101, 106))
564412	29434933	Furthermore, the mean age of patients exhibiting positive PD-L1 expression was significantly higher than those exhibiting negative PD-L1 expression (62.5+-10.4 vs. 57.0+-11.7; P<0.01; Table II).	('higher', 'PosReg', (93, 99))	('PD-L1', 'Gene', '29126', (58, 63))	('patients', 'Species', '9606', (29, 37))	('PD-L1', 'Gene', '29126', (131, 136))	('positive', 'Var', (49, 57))	('expression', 'Var', (64, 74))	('PD-L1', 'Gene', (58, 63))	('PD-L1', 'Gene', (131, 136))
564439	29434933	The association between PD-L1 expression and patient outcomes is controversial; it has been demonstrated in lung cancer that PD-L1 expression is correlated with an improved outcome, however, this has not been the case in the other study.	('expression', 'Var', (131, 141))	('lung cancer', 'Disease', 'MESH:D008175', (108, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('improved', 'PosReg', (164, 172))	('PD-L1', 'Gene', '29126', (125, 130))	('lung cancer', 'Disease', (108, 119))	('patient', 'Species', '9606', (45, 52))	('PD-L1', 'Gene', (24, 29))	('lung cancer', 'Phenotype', 'HP:0100526', (108, 119))	('PD-L1', 'Gene', (125, 130))	('PD-L1', 'Gene', '29126', (24, 29))
564474	26934957	At 28 days post-orthotopic transplantation, we found that DDR2 knockdown reduced the number of disseminated metastases and tumor weights in the gastric walls (Fig.	('metastases', 'Disease', (108, 118))	('tumor', 'Disease', (123, 128))	('reduced', 'NegReg', (73, 80))	('metastases', 'Disease', 'MESH:D009362', (108, 118))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('knockdown', 'Var', (63, 72))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('DDR2', 'Gene', (58, 62))
564486	26934957	Recently, it was reported that DDR2 stabilized SNAIL1 to reduce E-cadherin protein levels and promoted the EMT in breast cancer cells.	('DDR2', 'Var', (31, 35))	('reduce', 'NegReg', (57, 63))	('SNAIL1', 'Gene', (47, 53))	('SNAIL1', 'Gene', '6615', (47, 53))	('EMT', 'CPA', (107, 110))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('E-cadherin', 'Gene', (64, 74))	('E-cadherin', 'Gene', '999', (64, 74))	('breast cancer', 'Disease', 'MESH:D001943', (114, 127))	('breast cancer', 'Phenotype', 'HP:0003002', (114, 127))	('promoted', 'PosReg', (94, 102))	('breast cancer', 'Disease', (114, 127))
564487	26934957	Recent data revealed that DDR2 mutations in lung squamous cell carcinoma could be therapeutically targeted by dasatinib.	('mutations', 'Var', (31, 40))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (49, 72))	('lung squamous cell carcinoma', 'Disease', (44, 72))	('DDR2', 'Gene', (26, 30))	('dasatinib', 'Chemical', 'MESH:D000069439', (110, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (63, 72))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (44, 72))
564488	26934957	In GC, DDR2 mutations exist at a rate of 3.7% (8/219; The Cancer Genome Atlas data), which is similar to that observed in lung squamous cell carcinoma.	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('GC', 'Phenotype', 'HP:0012126', (3, 5))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (122, 150))	('mutations', 'Var', (12, 21))	('lung squamous cell carcinoma', 'Disease', (122, 150))	('Cancer', 'Phenotype', 'HP:0002664', (58, 64))	('Cancer', 'Disease', (58, 64))	('Cancer', 'Disease', 'MESH:D009369', (58, 64))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (127, 150))	('DDR2', 'Gene', (7, 11))
564498	26934957	In conclusion, we established a peritoneal dissemination-associated gene-expression signature in GC and revealed that inhibiting DDR2 by dasatinib suppressed peritoneal dissemination.	('peritoneal dissemination-associated', 'Disease', (32, 67))	('dasatinib', 'Chemical', 'MESH:D000069439', (137, 146))	('suppressed', 'NegReg', (147, 157))	('DDR2', 'Gene', (129, 133))	('inhibiting', 'Var', (118, 128))	('GC', 'Phenotype', 'HP:0012126', (97, 99))	('peritoneal dissemination', 'CPA', (158, 182))
564499	26934957	The human scirrhous GC cell lines HSC-44PE, HSC-39, HSC-58, 44As3, 39As8Luc, 58As1Luc, and 58As9 were described previously.	('human', 'Species', '9606', (4, 9))	('44As3', 'Var', (60, 65))	('39As8Luc', 'Var', (67, 75))	('GC', 'Phenotype', 'HP:0012126', (20, 22))
564528	26934957	To assess the influence of DDR2 on GC dissemination, 1 x 106 cancer cells (58As9Luc control, DDR2 sh#1, or DDR2 sh#2 cells) were transplanted into the gastric wall of each mouse.	('DDR2', 'Var', (93, 97))	('cancer', 'Disease', 'MESH:D009369', (61, 67))	('GC', 'Phenotype', 'HP:0012126', (35, 37))	('mouse', 'Species', '10090', (172, 177))	('cancer', 'Disease', (61, 67))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))
564538	29755650	We compared the effects of the proteasome inhibitors bortezomib, ixazomib and carfilzomib and the ubiquitin E1 enzyme inhibitor MLN7243/TAK-243 on cell viability and cell death in normal keratinocytes and cutaneous squamous cell carcinoma (cSCC) cell lines.	('cutaneous squamous cell carcinoma', 'Disease', (205, 238))	('carcinoma', 'Phenotype', 'HP:0030731', (229, 238))	('carfilzomib', 'Chemical', 'MESH:C524865', (78, 89))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (215, 238))	('cSCC', 'Phenotype', 'HP:0006739', (240, 244))	('MLN7243/TAK-243', 'Var', (128, 143))	('cutaneous squamous cell carcinoma', 'Phenotype', 'HP:0006739', (205, 238))	('MLN7243', 'Chemical', 'MESH:C000622638', (128, 135))	('cutaneous squamous cell carcinoma', 'Disease', 'MESH:D002294', (205, 238))	('bortezomib', 'Chemical', 'MESH:D000069286', (53, 63))	('ixazomib', 'Chemical', 'MESH:C548400', (65, 73))
564541	29755650	Low expression of the ubiquitin E1 UBA1/UBE1 participates in conferring susceptibility to MLN7243 by increasing sensitivity to MLN7243-mediated attenuation of ubiquitination.	('increasing', 'PosReg', (101, 111))	('UBA1', 'Gene', '7317', (35, 39))	('UBE1', 'Gene', (40, 44))	('susceptibility', 'MPA', (72, 86))	('MLN7243', 'Chemical', 'MESH:C000622638', (127, 134))	('expression', 'MPA', (4, 14))	('sensitivity to MLN7243-mediated attenuation', 'MPA', (112, 155))	('UBA1', 'Gene', (35, 39))	('ubiquitination', 'MPA', (159, 173))	('MLN7243', 'Chemical', 'MESH:C000622638', (90, 97))	('UBE1', 'Gene', '7317', (40, 44))	('Low', 'NegReg', (0, 3))	('MLN7243', 'Var', (90, 97))
564571	29755650	MLN7243/TAK-243 is a recently developed high-affinity inhibitor with selectivity for ubiquitin E1s over other UBL protein E1s.	('MLN7243/TAK-243', 'Var', (0, 15))	('MLN7243', 'Chemical', 'MESH:C000622638', (0, 7))	('ubiquitin E1s', 'Protein', (85, 98))
564573	29755650	MLN7243 is the first ubiquitin E1 inhibitor to enter a clinical trial for cancer therapy (NCT02045095).	('clinical', 'Species', '191496', (55, 63))	('cancer', 'Disease', 'MESH:D009369', (74, 80))	('MLN7243', 'Chemical', 'MESH:C000622638', (0, 7))	('cancer', 'Disease', (74, 80))	('MLN7243', 'Var', (0, 7))	('cancer', 'Phenotype', 'HP:0002664', (74, 80))
564574	29755650	It has been observed that in mice systemically treated with MLN7243 plasma levels decline rapidly but the inhibitor has a long half-life in tumours.	('tumour', 'Phenotype', 'HP:0002664', (140, 146))	('MLN7243', 'Chemical', 'MESH:C000622638', (60, 67))	('MLN7243', 'Var', (60, 67))	('plasma levels', 'MPA', (68, 81))	('tumours', 'Phenotype', 'HP:0002664', (140, 147))	('tumours', 'Disease', 'MESH:D009369', (140, 147))	('tumours', 'Disease', (140, 147))	('decline', 'NegReg', (82, 89))	('mice', 'Species', '10090', (29, 33))
564584	29755650	In addition, we confirmed that MLN7243 can reduce the cellular level of ubiquitin conjugates (Figure 3D).	('cellular level of ubiquitin conjugates', 'MPA', (54, 92))	('reduce', 'NegReg', (43, 49))	('MLN7243', 'Var', (31, 38))	('MLN7243', 'Chemical', 'MESH:C000622638', (31, 38))
564586	29755650	MLN7243 decreased UBA1 and UBA6 thioesters and thioesters of the UBA6 specific E2 UBE2Z/USE1 (Supplementary Figure 1 and Figure 7).	('USE1', 'Gene', (88, 92))	('UBA6', 'Gene', '55236', (65, 69))	('UBA1', 'Gene', (18, 22))	('MLN7243', 'Chemical', 'MESH:C000622638', (0, 7))	('UBA6', 'Gene', (27, 31))	('thioesters', 'Chemical', '-', (32, 42))	('UBA6', 'Gene', (65, 69))	('UBA6 specific E2 UBE2Z', 'Gene', (65, 87))	('MLN7243', 'Var', (0, 7))	('thioesters', 'Chemical', '-', (47, 57))	('thioesters', 'MPA', (47, 57))	('decreased', 'NegReg', (8, 17))	('UBA1', 'Gene', '7317', (18, 22))	('UBA6 specific E2 UBE2Z', 'Gene', '55236', (65, 87))	('UBA6', 'Gene', '55236', (27, 31))	('USE1', 'Gene', '55850', (88, 92))
564587	29755650	This confirms that both UBA1 and UBA6 are inhibited by MLN7243.	('UBA6', 'Gene', (33, 37))	('UBA1', 'Gene', (24, 28))	('UBA6', 'Gene', '55236', (33, 37))	('MLN7243', 'Chemical', 'MESH:C000622638', (55, 62))	('inhibited', 'NegReg', (42, 51))	('UBA1', 'Gene', '7317', (24, 28))	('MLN7243', 'Var', (55, 62))
564603	29755650	The ubiquitin E1 inhibitor MLN7243 selectively killed a subset of cSCC lines (Figure 3).	('MLN7243', 'Chemical', 'MESH:C000622638', (27, 34))	('cSCC', 'Phenotype', 'HP:0006739', (66, 70))	('killed', 'NegReg', (47, 53))	('MLN7243', 'Var', (27, 34))	('cSCC lines', 'CPA', (66, 76))
564606	29755650	There were striking differences between responses to this inhibitor and bortezomib: MLN7243-sensitive SCCRDEBMet and SCCIC1Met cells were the most resistant to bortezomib (Figure 1 and 3).	('resistant', 'MPA', (147, 156))	('MLN7243', 'Chemical', 'MESH:C000622638', (84, 91))	('bortezomib', 'Chemical', 'MESH:D000069286', (72, 82))	('MLN7243-sensitive', 'Var', (84, 101))	('bortezomib', 'Chemical', 'MESH:D000069286', (160, 170))
564618	29755650	There was a general increase in cSCC cells compared to normal keratinocytes of free monomeric ubiquitin, proteasome subunits and Ser51 phosphorylated eiF2alpha (Supplementary Figure 4).	('Ser51', 'Var', (129, 134))	('eiF2alpha', 'Gene', '83939', (150, 159))	('Ser51', 'Chemical', '-', (129, 134))	('eiF2alpha', 'Gene', (150, 159))	('free monomeric ubiquitin', 'MPA', (79, 103))	('cSCC', 'Phenotype', 'HP:0006739', (32, 36))	('increase', 'PosReg', (20, 28))
564624	29755650	Proteasome inhibition reduces the level of mono-ubiquitinated histone H2A/H2B due to depletion of the pool of free ubiquitin.	('H2B', 'Gene', '8349', (74, 77))	('inhibition', 'Var', (11, 21))	('reduces', 'NegReg', (22, 29))	('depletion of the pool of free ubiquitin', 'MPA', (85, 124))	('H2B', 'Gene', (74, 77))	('level of mono-ubiquitinated', 'MPA', (34, 61))
564639	29755650	c-MYC expression was increased in all cSCC cell lines with elevated NOXA and knockdown of c-MYC reduced basal NOXA expression (Figure 5B and 5C).	('increased', 'PosReg', (21, 30))	('NOXA', 'Gene', (110, 114))	('c-MYC', 'Gene', (90, 95))	('expression', 'MPA', (6, 16))	('c-MYC', 'Gene', '4609', (0, 5))	('NOXA', 'Gene', '5366', (110, 114))	('knockdown', 'Var', (77, 86))	('cSCC', 'Phenotype', 'HP:0006739', (38, 42))	('NOXA', 'Gene', '5366', (68, 72))	('elevated', 'PosReg', (59, 67))	('NOXA', 'Gene', (68, 72))	('c-MYC', 'Gene', (0, 5))	('c-MYC', 'Gene', '4609', (90, 95))	('reduced', 'NegReg', (96, 103))
564649	29755650	To identify determinants of sensitivity to MLN7243 the protein expression of the ubiquitin E1 UBA1 was compared in the panel of cells used in this study (Figure 7A).	('MLN7243', 'Chemical', 'MESH:C000622638', (43, 50))	('MLN7243', 'Var', (43, 50))	('UBA1', 'Gene', (94, 98))	('UBA1', 'Gene', '7317', (94, 98))
564653	29755650	In cSCC cells there was an inverse association between MLN7243 sensitivity and UBA1 expression.	('UBA1', 'Gene', (79, 83))	('MLN7243', 'Chemical', 'MESH:C000622638', (55, 62))	('inverse', 'NegReg', (27, 34))	('cSCC', 'Phenotype', 'HP:0006739', (3, 7))	('expression', 'MPA', (84, 94))	('UBA1', 'Gene', '7317', (79, 83))	('MLN7243 sensitivity', 'Var', (55, 74))
564655	29755650	SCCRDEBMet cells had the lowest levels of both UBA1 isoforms and death in these cells was the most sensitive to a pulse of MLN7243 (Figure 3).	('UBA1', 'Gene', (47, 51))	('MLN7243', 'Chemical', 'MESH:C000622638', (123, 130))	('UBA1', 'Gene', '7317', (47, 51))	('MLN7243', 'Var', (123, 130))	('lowest', 'NegReg', (25, 31))
564657	29755650	Knockdown of UBA1A and B in these MLN7243-resistant lines dramatically increased sensitivity to the effects of the E1 inhibitor on cell viability and death (Figure 7B and 7C).	('sensitivity', 'MPA', (81, 92))	('MLN7243', 'Chemical', 'MESH:C000622638', (34, 41))	('UBA1A', 'Gene', '7317', (13, 18))	('increased', 'PosReg', (71, 80))	('MLN7243-resistant', 'Var', (34, 51))	('UBA1A', 'Gene', (13, 18))
564658	29755650	The level of UBA1 expression attained following siRNA-mediated knockdown in these resistant lines and the resulting susceptibility to MLN7243 were comparable to those in MLN7243-sensitive SCCRDEBMet cells (Figure 3 and 7B and 7C).	('MLN7243', 'Var', (134, 141))	('UBA1', 'Gene', '7317', (13, 17))	('MLN7243', 'Chemical', 'MESH:C000622638', (170, 177))	('knockdown', 'Var', (63, 72))	('UBA1', 'Gene', (13, 17))	('MLN7243', 'Chemical', 'MESH:C000622638', (134, 141))
564659	29755650	Consistent with inhibition of ubiquitin E1s, MLN7243 decreased the level of DTT-sensitive UBA1 species (UBA1-ubiquitin thioesters) along with high molecular weight ubiquitin conjugates and ubiquitinated histones H2A/H2B while the level of free monomeric ubiquitin was increased (Figure 7D).	('ubiquitinated', 'MPA', (189, 202))	('UBA1', 'Gene', '7317', (90, 94))	('DTT', 'Chemical', 'MESH:D004229', (76, 79))	('H2B', 'Gene', (216, 219))	('UBA1', 'Gene', (104, 108))	('MLN7243', 'Chemical', 'MESH:C000622638', (45, 52))	('UBA1', 'Gene', (90, 94))	('high molecular weight ubiquitin conjugates', 'MPA', (142, 184))	('H2B', 'Gene', '8349', (216, 219))	('MLN7243', 'Var', (45, 52))	('UBA1', 'Gene', '7317', (104, 108))	('thioesters', 'Chemical', '-', (119, 129))	('decreased', 'NegReg', (53, 62))
564660	29755650	These effects occurred at lower MLN7243 concentrations in sensitive SCCRDEBMet cells than in resistant SCCIC1 cells.	('MLN7243', 'Chemical', 'MESH:C000622638', (32, 39))	('MLN7243', 'Var', (32, 39))	('lower', 'NegReg', (26, 31))
564661	29755650	UBA1 knockdown in SCCIC1 cells reduced the concentration of MLN7243 required to attenuate ubiquitination.	('MLN7243', 'Chemical', 'MESH:C000622638', (60, 67))	('MLN7243', 'Var', (60, 67))	('reduced', 'NegReg', (31, 38))	('UBA1', 'Gene', (0, 4))	('knockdown', 'Var', (5, 14))	('ubiquitination', 'MPA', (90, 104))	('UBA1', 'Gene', '7317', (0, 4))	('attenuate', 'NegReg', (80, 89))
564662	29755650	In all circumstances cell death occurred at doses of MLN7243 that diminished ubiquitin conjugates.	('MLN7243', 'Var', (53, 60))	('MLN7243', 'Chemical', 'MESH:C000622638', (53, 60))	('cell death', 'CPA', (21, 31))	('diminished', 'NegReg', (66, 76))	('ubiquitin conjugates', 'MPA', (77, 97))
564663	29755650	These results indicate that UBA1 levels are a major determinant of the sensitivity of cSCC cells to MLN7243 due to their influence on the concentration of this agent required to inhibit ubiquitination.	('cSCC', 'Phenotype', 'HP:0006739', (86, 90))	('UBA1', 'Gene', (28, 32))	('inhibit', 'NegReg', (178, 185))	('MLN7243', 'Chemical', 'MESH:C000622638', (100, 107))	('ubiquitination', 'MPA', (186, 200))	('UBA1', 'Gene', '7317', (28, 32))	('MLN7243', 'Var', (100, 107))	('influence', 'Reg', (121, 130))
564665	29755650	Knockdown of UBA6 in MLN7243-resistant SCCIC1 and SCCRDEB3 cells did not alter their sensitivity to the E1 inhibitor (Supplementary Figure 8B and 8C).	('MLN7243', 'Chemical', 'MESH:C000622638', (21, 28))	('MLN7243-resistant', 'Var', (21, 38))	('UBA6', 'Gene', (13, 17))	('UBA6', 'Gene', '55236', (13, 17))
564666	29755650	This indicates that UBA6 protein levels are not a determinant of MLN7243 sensitivity in these cell lines.	('UBA6', 'Gene', (20, 24))	('UBA6', 'Gene', '55236', (20, 24))	('MLN7243', 'Chemical', 'MESH:C000622638', (65, 72))	('MLN7243', 'Var', (65, 72))
564668	29755650	In addition, knockdown of UBA6 alone and in combination with UBA1 did not alter high molecular weight ubiquitination in SCCRDEBMet cells (Supplementary Figure 9B).	('UBA1', 'Gene', (61, 65))	('UBA6', 'Gene', (26, 30))	('UBA1', 'Gene', '7317', (61, 65))	('UBA6', 'Gene', '55236', (26, 30))	('high molecular weight ubiquitination', 'MPA', (80, 116))	('knockdown', 'Var', (13, 22))
564669	29755650	Levels of ubiquitinated histone H2A/H2B were reduced by knockdown of UBA1 (Figure 7B and 7D and Supplementary Figure 9).	('H2B', 'Gene', '8349', (36, 39))	('reduced', 'NegReg', (45, 52))	('UBA1', 'Gene', (69, 73))	('H2B', 'Gene', (36, 39))	('UBA1', 'Gene', '7317', (69, 73))	('Levels of ubiquitinated', 'MPA', (0, 23))	('knockdown', 'Var', (56, 65))
564673	29755650	These bortezomib-resistant tumour cells can be sensitive to MLN7243.	('MLN7243', 'Chemical', 'MESH:C000622638', (60, 67))	('MLN7243', 'Var', (60, 67))	('tumour', 'Phenotype', 'HP:0002664', (27, 33))	('bortezomib', 'Chemical', 'MESH:D000069286', (6, 16))	('tumour', 'Disease', 'MESH:D009369', (27, 33))	('tumour', 'Disease', (27, 33))
564675	29755650	We provide evidence that c-MYC, NOXA and BAK are determinants of susceptibility to a pulse of proteasome inhibition and that low UBA1 expression confers susceptibility to MLN7243.	('BAK', 'Gene', (41, 44))	('expression', 'MPA', (134, 144))	('c-MYC', 'Gene', (25, 30))	('UBA1', 'Gene', '7317', (129, 133))	('MLN7243', 'Chemical', 'MESH:C000622638', (171, 178))	('BAK', 'Gene', '578', (41, 44))	('MLN7243', 'Var', (171, 178))	('NOXA', 'Gene', (32, 36))	('NOXA', 'Gene', '5366', (32, 36))	('low', 'NegReg', (125, 128))	('c-MYC', 'Gene', '4609', (25, 30))	('UBA1', 'Gene', (129, 133))
564694	29755650	Proteasome inhibition also increases c-MYC transcriptional activity towards the NOXA gene.	('c-MYC', 'Gene', '4609', (37, 42))	('increases', 'PosReg', (27, 36))	('NOXA', 'Gene', (80, 84))	('c-MYC', 'Gene', (37, 42))	('Proteasome', 'Protein', (0, 10))	('inhibition', 'Var', (11, 21))	('NOXA', 'Gene', '5366', (80, 84))
564696	29755650	We observed that low expression of both UBA1A and B isoforms is associated with MLN7243 sensitivity and high expression of UBA1A with MLN7243 resistance.	('UBA1A', 'Gene', (123, 128))	('expression', 'MPA', (109, 119))	('MLN7243 sensitivity', 'Var', (80, 99))	('expression', 'MPA', (21, 31))	('UBA1A', 'Gene', '7317', (40, 45))	('MLN7243 resistance', 'Var', (134, 152))	('UBA1A', 'Gene', '7317', (123, 128))	('UBA1A', 'Gene', (40, 45))	('MLN7243', 'Chemical', 'MESH:C000622638', (80, 87))	('MLN7243', 'Chemical', 'MESH:C000622638', (134, 141))
564697	29755650	Furthermore, knockdown of UBA1A and B confers MLN7243 sensitivity to resistant cSCC cells.	('MLN7243', 'Var', (46, 53))	('knockdown', 'Var', (13, 22))	('UBA1A', 'Gene', '7317', (26, 31))	('cSCC', 'Phenotype', 'HP:0006739', (79, 83))	('MLN7243', 'Chemical', 'MESH:C000622638', (46, 53))	('UBA1A', 'Gene', (26, 31))
564698	29755650	MLN7243-induced cell death is associated with a reduction in the level of ubiquitin conjugates.	('MLN7243', 'Chemical', 'MESH:C000622638', (0, 7))	('MLN7243-induced', 'Var', (0, 15))	('level of ubiquitin conjugates', 'MPA', (65, 94))	('reduction', 'NegReg', (48, 57))	('cell death', 'CPA', (16, 26))
564699	29755650	A lower concentration of MLN7243 is required to diminish ubiquitination in cSCC cells with low UBA1 expression.	('low', 'NegReg', (91, 94))	('UBA1', 'Gene', (95, 99))	('UBA1', 'Gene', '7317', (95, 99))	('MLN7243', 'Chemical', 'MESH:C000622638', (25, 32))	('cSCC', 'Phenotype', 'HP:0006739', (75, 79))	('MLN7243', 'Var', (25, 32))	('diminish', 'NegReg', (48, 56))	('ubiquitination', 'MPA', (57, 71))
564700	29755650	UBA1 protein levels may thus provide a marker for tumour sensitivity to MLN7243.	('tumour', 'Disease', 'MESH:D009369', (50, 56))	('UBA1', 'Gene', (0, 4))	('tumour', 'Disease', (50, 56))	('UBA1', 'Gene', '7317', (0, 4))	('MLN7243', 'Var', (72, 79))	('MLN7243', 'Chemical', 'MESH:C000622638', (72, 79))	('tumour', 'Phenotype', 'HP:0002664', (50, 56))	('protein', 'Protein', (5, 12))
564703	29755650	This may provide a means to enhance tumour sensitivity or increase the resistance of normal cells to MLN7243.	('MLN7243', 'Var', (101, 108))	('increase', 'PosReg', (58, 66))	('tumour', 'Disease', 'MESH:D009369', (36, 42))	('tumour', 'Disease', (36, 42))	('resistance', 'MPA', (71, 81))	('enhance', 'PosReg', (28, 35))	('tumour', 'Phenotype', 'HP:0002664', (36, 42))	('MLN7243', 'Chemical', 'MESH:C000622638', (101, 108))
564704	29755650	UBA1 and UBA6 are both inhibited by MLN7243.	('MLN7243', 'Var', (36, 43))	('UBA1', 'Gene', (0, 4))	('inhibited', 'NegReg', (23, 32))	('UBA6', 'Gene', '55236', (9, 13))	('UBA1', 'Gene', '7317', (0, 4))	('UBA6', 'Gene', (9, 13))	('MLN7243', 'Chemical', 'MESH:C000622638', (36, 43))
564705	29755650	While our study supports a pre-eminent role of UBA1 in determining the sensitivity of cSCC cells to MLN7243 under some circumstances suppression of UBA6 could contribute to the anti-tumour activity of this inhibitor.	('UBA1', 'Gene', (47, 51))	('cSCC', 'Phenotype', 'HP:0006739', (86, 90))	('MLN7243', 'Var', (100, 107))	('UBA6', 'Gene', '55236', (148, 152))	('tumour', 'Phenotype', 'HP:0002664', (182, 188))	('UBA1', 'Gene', '7317', (47, 51))	('tumour', 'Disease', 'MESH:D009369', (182, 188))	('MLN7243', 'Chemical', 'MESH:C000622638', (100, 107))	('UBA6', 'Gene', (148, 152))	('tumour', 'Disease', (182, 188))	('suppression', 'NegReg', (133, 144))	('contribute', 'Reg', (159, 169))
564709	29755650	These cancers may be highly sensitive to MLN7243.	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('MLN7243', 'Chemical', 'MESH:C000622638', (41, 48))	('MLN7243', 'Var', (41, 48))	('cancers', 'Phenotype', 'HP:0002664', (6, 13))	('cancers', 'Disease', 'MESH:D009369', (6, 13))	('cancers', 'Disease', (6, 13))
564718	29755650	Compounds used in this study were: bortezomib (B-1408: LC Laboratories Woburn, MA, USA), carfilzomib (S2853: Selleckchem, Houston, TX, USA), ixazomib (S2180: Selleckchem) and MLN7243 (CT-M7243: Chemietek, Indianapolis, IN, USA).	('S2853', 'Var', (102, 107))	('ixazomib', 'Chemical', 'MESH:C548400', (141, 149))	('S2180:', 'Var', (151, 157))	('MLN7243', 'Chemical', 'MESH:C000622638', (175, 182))	('MLN7243', 'Var', (175, 182))	('bortezomib', 'Chemical', 'MESH:D000069286', (35, 45))	('carfilzomib', 'Chemical', 'MESH:C524865', (89, 100))
564731	25084400	We also demonstrated that high expression of miR-21 could increase tumor cell proliferation, invasion, viability, and migration in GSQCLC cell line (YTMLC-90) and NSCLC cell line (NCI-H157).	('increase', 'PosReg', (58, 66))	('high expression', 'Var', (26, 41))	('miR-21', 'Gene', (45, 51))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('viability', 'CPA', (103, 112))	('NSCLC', 'Disease', (163, 168))	('migration', 'CPA', (118, 127))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('NCI-H157', 'CellLine', 'CVCL:0463', (180, 188))	('NSCLC', 'Disease', 'MESH:D002289', (163, 168))	('tumor', 'Disease', (67, 72))	('invasion', 'CPA', (93, 101))	('miR-21', 'Gene', '406991', (45, 51))	('NSCLC', 'Phenotype', 'HP:0030358', (163, 168))
564772	25084400	H460SM was kindly provided by Dr. Ming-Sound Tsao, Princess Margaret Cancer Centre, Toronto, Ontario, Canada.	('Cancer', 'Disease', 'MESH:D009369', (69, 75))	('H460SM', 'Var', (0, 6))	('Cancer', 'Phenotype', 'HP:0002664', (69, 75))	('Cancer', 'Disease', (69, 75))
564814	25084400	Interestingly, there was no significant difference in PTEN, RECK and Bcl-2 gene expression in miR-21 silenced YTMLC-90 cells when compared to miR-21 silenced NCI-H157 cells.	('miR-21', 'Gene', '406991', (142, 148))	('RECK', 'Gene', (60, 64))	('Bcl-2', 'Gene', (69, 74))	('NCI-H157', 'CellLine', 'CVCL:0463', (158, 166))	('Bcl-2', 'Gene', '596', (69, 74))	('PTEN', 'Gene', (54, 58))	('miR-21', 'Gene', (94, 100))	('miR-21', 'Gene', (142, 148))	('PTEN', 'Gene', '5728', (54, 58))	('silenced', 'Var', (101, 109))	('RECK', 'Gene', '8434', (60, 64))	('expression', 'MPA', (80, 90))	('miR-21', 'Gene', '406991', (94, 100))
564820	25084400	Altogether, these results showed silencing miR-21 could reduce NSCLC proliferation and viability.	('NSCLC', 'Disease', (63, 68))	('NSCLC', 'Disease', 'MESH:D002289', (63, 68))	('miR-21', 'Gene', '406991', (43, 49))	('viability', 'CPA', (87, 96))	('silencing', 'Var', (33, 42))	('NSCLC', 'Phenotype', 'HP:0030358', (63, 68))	('reduce', 'NegReg', (56, 62))	('miR-21', 'Gene', (43, 49))
564822	25084400	The results revealed that tumor cells with miR-21 knockdown rapidly closed the scratch wounds compared with the control cells (p<0.001) (Fig.	('scratch wounds', 'CPA', (79, 93))	('knockdown', 'Var', (50, 59))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('miR-21', 'Gene', '406991', (43, 49))	('closed', 'NegReg', (68, 74))	('miR-21', 'Gene', (43, 49))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))
564823	25084400	Moreover, the wounds of the miR-21 silenced YTMLC-90 cells were still open at 36 h at this time while miR-21 silenced NCI-H157 cells had almost closed the wounds at this time, which suggested that NCI-H157 cells with miR-21 knockdown have higher migratory potential relative to YTMLC-90 cells with miR-21 knockdown.	('migratory potential', 'CPA', (246, 265))	('miR-21', 'Gene', (102, 108))	('miR-21', 'Gene', (217, 223))	('miR-21', 'Gene', (298, 304))	('miR-21', 'Gene', (28, 34))	('higher', 'PosReg', (239, 245))	('NCI-H157', 'CellLine', 'CVCL:0463', (118, 126))	('miR-21', 'Gene', '406991', (102, 108))	('NCI-H157', 'CellLine', 'CVCL:0463', (197, 205))	('miR-21', 'Gene', '406991', (298, 304))	('miR-21', 'Gene', '406991', (217, 223))	('knockdown', 'Var', (224, 233))	('miR-21', 'Gene', '406991', (28, 34))
564825	25084400	6, miR-21 knockdown resulted in increased YTMLC-90 and NCI-H157 cell invasion rate compared with the control cells (p<0.05) (Table S3 in File S1).	('miR-21', 'Gene', (3, 9))	('NCI-H157 cell invasion rate', 'CPA', (55, 82))	('YTMLC-90', 'MPA', (42, 50))	('NCI-H157', 'CellLine', 'CVCL:0463', (55, 63))	('miR-21', 'Gene', '406991', (3, 9))	('increased', 'PosReg', (32, 41))	('knockdown', 'Var', (10, 19))
564826	25084400	These results clearly suggested that silencing miR-21 could inhibit migration and invasion of YTMLC-90 and NCI-H157 cells.	('inhibit', 'NegReg', (60, 67))	('miR-21', 'Gene', '406991', (47, 53))	('silencing', 'Var', (37, 46))	('NCI-H157', 'CellLine', 'CVCL:0463', (107, 115))	('migration', 'CPA', (68, 77))	('miR-21', 'Gene', (47, 53))
564827	25084400	In order to assess whether silencing miR-21 possesses proapoptotic properties, we transfected YTMLC-90 and NCI-H157 cells with pGCMV/EGFP-hsa-miR-21 interference or a negative control pGCMV/EGFP-hsa-miR-NC plasmid.	('miR-21', 'Gene', '406991', (142, 148))	('miR', 'Gene', '220972', (37, 40))	('silencing', 'Var', (27, 36))	('miR', 'Gene', (37, 40))	('miR-21', 'Gene', '406991', (37, 43))	('hsa-miR-21', 'Gene', '406991', (138, 148))	('miR', 'Gene', '220972', (199, 202))	('miR-21', 'Gene', (142, 148))	('miR', 'Gene', (199, 202))	('miR-21', 'Gene', (37, 43))	('miR', 'Gene', '220972', (142, 145))	('miR', 'Gene', (142, 145))	('NCI-H157', 'CellLine', 'CVCL:0463', (107, 115))	('hsa-miR-21', 'Gene', (138, 148))
564828	25084400	7A, silencing miR-21 caused a significant decrease in the number of apoptotic cells compared to the control cells.	('miR-21', 'Gene', '406991', (14, 20))	('decrease', 'NegReg', (42, 50))	('miR-21', 'Gene', (14, 20))	('silencing', 'Var', (4, 13))
564829	25084400	Furthermore, silencing miR-21 led to an increased rate of apoptosis in YTMLC-90 when compared with NCI-H157.	('miR-21', 'Gene', (23, 29))	('NCI-H157', 'CellLine', 'CVCL:0463', (99, 107))	('miR-21', 'Gene', '406991', (23, 29))	('apoptosis', 'CPA', (58, 67))	('silencing', 'Var', (13, 22))
564833	25084400	Next, transmission electron microscopy (TEM) investigated in detail the miR-21 knockdown-induced apoptotic cell death.	('miR-21', 'Gene', '406991', (72, 78))	('knockdown-induced', 'Var', (79, 96))	('miR-21', 'Gene', (72, 78))	('apoptotic', 'CPA', (97, 106))
564834	25084400	The ultrastructural analysis has shown that some morphological changes occurred when miR-21 was knocked down in YTMLC-90 and NCI-H157 cells.	('knocked', 'Var', (96, 103))	('NCI-H157', 'CellLine', 'CVCL:0463', (125, 133))	('miR-21', 'Gene', (85, 91))	('miR-21', 'Gene', '406991', (85, 91))
564836	25084400	Our data demonstrated that inhibition of miR-21 promoted YTMLC-90 and NCI-H157 cell apoptosis.	('YTMLC-90', 'CPA', (57, 65))	('NCI-H157 cell apoptosis', 'CPA', (70, 93))	('miR-21', 'Gene', (41, 47))	('NCI-H157', 'CellLine', 'CVCL:0463', (70, 78))	('inhibition', 'Var', (27, 37))	('miR-21', 'Gene', '406991', (41, 47))	('promoted', 'PosReg', (48, 56))
564837	25084400	Flow cytometric analysis of the cell cycle and DNA content was performed to determine the ability of miR-21 knockdown to induce cell cycle arrest in both YTMLC-90 and NCI-H157 cell lines.	('NCI-H157', 'CellLine', 'CVCL:0463', (167, 175))	('knockdown', 'Var', (108, 117))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (128, 145))	('induce', 'Reg', (121, 127))	('cell cycle arrest', 'CPA', (128, 145))	('miR-21', 'Gene', '406991', (101, 107))	('miR-21', 'Gene', (101, 107))
564839	25084400	Moreover, G2/M phase showed a significant increase in miR-21 silenced cells when compared to non-transfected cells or negative control cells (p<0.05).	('increase', 'PosReg', (42, 50))	('G2/M phase', 'CPA', (10, 20))	('miR-21', 'Gene', '406991', (54, 60))	('miR-21', 'Gene', (54, 60))	('silenced', 'Var', (61, 69))
564840	25084400	These results indicated that inhibition of miR-21 induced cell cycle arrest at G2/M phase in both YTMLC-90 and NCI-H157 cell lines.	('cell cycle arrest at G2/M phase', 'CPA', (58, 89))	('miR-21', 'Gene', '406991', (43, 49))	('NCI-H157', 'CellLine', 'CVCL:0463', (111, 119))	('miR-21', 'Gene', (43, 49))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (58, 75))	('inhibition', 'Var', (29, 39))
564866	25084400	Our flow cytometry data demonstrated that miR-21 silencing could induce apoptosis which was positively correlated with Bcl-2, but negatively correlated with PTEN and RECK in NSCLC cells.	('silencing', 'Var', (49, 58))	('NSCLC', 'Disease', 'MESH:D002289', (174, 179))	('miR-21', 'Gene', (42, 48))	('RECK', 'Gene', '8434', (166, 170))	('induce', 'PosReg', (65, 71))	('Bcl-2', 'Gene', '596', (119, 124))	('miR-21', 'Gene', '406991', (42, 48))	('NSCLC', 'Phenotype', 'HP:0030358', (174, 179))	('apoptosis', 'CPA', (72, 81))	('Bcl-2', 'Gene', (119, 124))	('PTEN', 'Gene', (157, 161))	('negatively', 'NegReg', (130, 140))	('RECK', 'Gene', (166, 170))	('PTEN', 'Gene', '5728', (157, 161))	('NSCLC', 'Disease', (174, 179))
564878	34007304	Potential Genes Associated with the Survival of Lung Adenocarcinoma Were Identified by Methylation Lung adenocarcinoma (LUAD) is the most common pathological type of lung cancer.	('Lung Adenocarcinoma', 'Disease', (48, 67))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('lung cancer', 'Disease', 'MESH:D008175', (166, 177))	('Lung adenocarcinoma', 'Phenotype', 'HP:0030078', (99, 118))	('cancer', 'Disease', (171, 177))	('Methylation', 'Var', (87, 98))	('Lung adenocarcinoma', 'Disease', (99, 118))	('Lung adenocarcinoma', 'Disease', 'MESH:D000077192', (99, 118))	('Lung Adenocarcinoma', 'Disease', 'MESH:D000077192', (48, 67))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('Lung Adenocarcinoma', 'Phenotype', 'HP:0030078', (48, 67))	('lung cancer', 'Disease', (166, 177))	('lung cancer', 'Phenotype', 'HP:0100526', (166, 177))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))
564889	34007304	In addition, the change of methylation state is an important factor leading to tumor genesis, including the decrease of the methylation level in the whole genome and the abnormal increase of the local methylation level in the CpG island, which leads to the instability of the genome and the nonexpression of tumor suppressor genes.	('tumor', 'Disease', (79, 84))	('change', 'Var', (17, 23))	('local methylation level', 'MPA', (195, 218))	('methylation', 'MPA', (27, 38))	('methylation level', 'MPA', (124, 141))	('tumor', 'Disease', 'MESH:D009369', (79, 84))	('tumor', 'Disease', 'MESH:D009369', (308, 313))	('tumor', 'Phenotype', 'HP:0002664', (308, 313))	('leading', 'Reg', (68, 75))	('decrease', 'NegReg', (108, 116))	('increase', 'PosReg', (179, 187))	('tumor', 'Disease', (308, 313))	('tumor', 'Phenotype', 'HP:0002664', (79, 84))	('instability', 'MPA', (257, 268))
564892	34007304	The COX model was used to further screen the predictive genes to obtain the genes related to the prognosis of LUAD and to identify the relationship between methylation drive and LUAD.	('COX', 'Gene', (4, 7))	('LUAD', 'Disease', (110, 114))	('LUAD', 'Disease', (178, 182))	('relationship', 'Interaction', (135, 147))	('COX', 'Gene', '1351', (4, 7))	('methylation', 'Var', (156, 167))
564907	32140187	Label-free quantitative identification of abnormally ubiquitinated proteins as useful biomarkers for human lung squamous cell carcinomas Ubiquitination is an important molecular event in lung squamous cell carcinoma (LSCC), which currently is mainly studied in nonsmall cell lung carcinoma cell models but lacking of ubiquitination studies on LSCC tissues.	('nonsmall cell lung carcinoma', 'Disease', 'MESH:D002289', (261, 289))	('lung squamous cell carcinomas', 'Disease', (107, 136))	('carcinoma', 'Phenotype', 'HP:0030731', (206, 215))	('carcinoma', 'Phenotype', 'HP:0030731', (280, 289))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (187, 215))	('nonsmall cell lung carcinoma', 'Disease', (261, 289))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (112, 136))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (107, 135))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (112, 135))	('human', 'Species', '9606', (101, 106))	('Ubiquitination', 'Var', (137, 151))	('lung squamous cell carcinomas', 'Disease', 'MESH:D002294', (107, 136))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (187, 215))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (107, 135))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (192, 215))	('carcinomas', 'Phenotype', 'HP:0030731', (126, 136))	('lung squamous cell carcinoma', 'Disease', (187, 215))
564917	32140187	The reason is that currently FDA-approved targeted drug therapies, such as epidermal growth factor receptor (EGFR) mutation or EML4-ALK fusion-based targeted therapies, are mainly suitable for lung adenocarcinoma (LUAD) but not for LSCC patients.	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (193, 212))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (193, 212))	('epidermal growth factor receptor', 'Gene', '1956', (75, 107))	('EML4', 'Gene', (127, 131))	('ALK', 'Gene', '238', (132, 135))	('EML4', 'Gene', '27436', (127, 131))	('lung adenocarcinoma', 'Disease', (193, 212))	('EGFR', 'Gene', '1956', (109, 113))	('UA', 'Chemical', 'MESH:C005460', (215, 217))	('epidermal growth factor receptor', 'Gene', (75, 107))	('EGFR', 'Gene', (109, 113))	('mutation', 'Var', (115, 123))	('ALK', 'Gene', (132, 135))	('carcinoma', 'Phenotype', 'HP:0030731', (203, 212))	('patients', 'Species', '9606', (237, 245))
564918	32140187	Although FGFR1 amplification and DDR2 mutation are nominated as "druggable" targets for LSCC patients, their clinical efficacy are still under clinical trials.	('FGFR1', 'Gene', '2260', (9, 14))	('amplification', 'Var', (15, 28))	('DDR2', 'Gene', (33, 37))	('DDR2', 'Gene', '4921', (33, 37))	('mutation', 'Var', (38, 46))	('FGFR1', 'Gene', (9, 14))	('patients', 'Species', '9606', (93, 101))	('LSCC', 'Disease', (88, 92))
564924	32140187	Thus, abnormal ubiquitination is associated with many diseases, including tumor, neurodegenerative disease, and inflammation.	('abnormal', 'Var', (6, 14))	('neurodegenerative disease', 'Disease', 'MESH:D019636', (81, 106))	('neurodegenerative disease', 'Disease', (81, 106))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('inflammation', 'Disease', 'MESH:D007249', (112, 124))	('associated', 'Reg', (33, 43))	('tumor', 'Disease', (74, 79))	('inflammation', 'Disease', (112, 124))	('ubiquitination', 'MPA', (15, 29))	('neurodegenerative disease', 'Phenotype', 'HP:0002180', (81, 106))
564928	32140187	Deregulation of E3 ligases contributes to cancer development, and overexpression of E3 ligases is often associated with poor prognosis.	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('E3 ligases', 'Protein', (16, 26))	('Deregulation', 'Var', (0, 12))	('contributes', 'Reg', (27, 38))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('overexpression', 'PosReg', (66, 80))
564952	32140187	The main parameters were set as trypsin for enzyme, four missed cleavages, 6 ppm for MS tolerance, 20 ppm for MS/MS tolerance, database uniprot_human_156639_20170105.fasta, carbamidomethyl for fixed modification, oxidation at Met residue, acetylation at protein N-term, and GlyGly at K residue for variable modification, reverse for decoy database pattern, true for included contaminants, FDR <= 0.01 for peptide, FDR <= 0.01 for ubiquitination site, FDR <= 0.01 for protein, and 2 min for time window (match between runs).	('human', 'Species', '9606', (144, 149))	('FDR <= 0.01', 'Var', (414, 425))	('FDR <= 0.01', 'Var', (451, 462))	('ubiquitination site', 'MPA', (430, 449))	('peptide', 'MPA', (405, 412))	('GlyGly', 'Var', (274, 280))
564960	32140187	The E3-substrate interaction network (http://ubibrowser.ncpsb.org/) was used to predict the E3s of VIM and ABCC1.	('VIM', 'Gene', '7431', (99, 102))	('VIM', 'Gene', (99, 102))	('ABCC1', 'Gene', (107, 112))	('E3s', 'Var', (92, 95))	('ABCC1', 'Gene', '4363', (107, 112))
564967	32140187	A representative MS/MS spectrum of ubiquitinated peptide 425ETNLDSLPLVDTHSK*R440 (precursor ion [M+2H]2+m/z = 969.9993, retention time RT = 86.77 min, and K* = ubiquitinated lysine residue) from vimentin (P08670) was shown (Fig.	('vimentin', 'Gene', (195, 203))	('P08670', 'Var', (205, 211))	('vimentin', 'Gene', '7431', (195, 203))	('lysine', 'Chemical', 'MESH:D008239', (174, 180))
564969	32140187	There is another representative MS/MS spectrum of 633RPVK*DGGGTNSITVR647 (precursor ion [M+3H]3+m/z = 557.6365, RT = 15.86 min, and K* = ubiquitinated lysine residue) from MRP1 (P33527) (Fig.	('633RPVK*', 'Var', (50, 58))	('lysine', 'Chemical', 'MESH:D008239', (151, 157))	('MRP1', 'Gene', (172, 176))	('MRP1', 'Gene', '4363', (172, 176))
564971	32140187	The results found that motifs A-X-K*, A-XX-K*, and A-XXX-K* (X = any amino acid residue, K* was the lysine residue that is prone to be ubiquitinated) were significantly prone to be ubiquitinated (Fig.	('ubiquitinated', 'MPA', (181, 194))	('lysine', 'Chemical', 'MESH:D008239', (100, 106))	('A-XX-K*', 'Var', (38, 45))	('prone', 'Reg', (169, 174))	('A-XXX-K*', 'Var', (51, 59))	('A-X-K*', 'Var', (30, 36))
564973	32140187	Comprehensive analysis of these functional clusters found those DUPs were involved in many cancer-related biological functions, such as cell-cell adhesion in cluster 1, regulation of the assemble of proteasome complex and UPS in clusters 2 and 3, transcriptional and translational regulations in cluster 6, cell signal transduction in cluster 2, and anti-tumor drug metabolism in cluster 8 (Table 2).	('tumor', 'Disease', 'MESH:D009369', (355, 360))	('tumor', 'Phenotype', 'HP:0002664', (355, 360))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('tumor', 'Disease', (355, 360))	('cell signal', 'CPA', (307, 318))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('cell-cell', 'CPA', (136, 145))	('transcriptional', 'MPA', (247, 262))	('DUPs', 'Var', (64, 68))	('involved', 'Reg', (74, 82))
564976	32140187	Their ubiquitination levels were significantly increased at residues K34 (ratio T/N = 2.27) in Rpn13; K293 (T+/N-) in Rpt2; K46 (ratio T/N = 4.96) in Rpt1; K372 (T+/N-) in Rpt5; K273 (T+/N-) in Rpt4; K346 (T+/N-), K330 (T+/N-), and K290 (T+/N-) in Rpt6; K194 (T+/N-), K328 (T+/N-), and K62 (ratio T/N = 2.37) in Rpt4; K273 (T+/N-) in Rpn3; K32 (T+/N-) in Rpn6; and K147 (T+/N-) in Rpn5.	('ubiquitination levels', 'MPA', (6, 27))	('K32', 'Gene', '3882', (340, 343))	('Rpn6', 'Gene', '5717', (355, 359))	('Rpn3', 'Gene', '5709', (334, 338))	('K19', 'Gene', '3880', (254, 257))	('K32', 'Gene', '3882', (268, 271))	('Rpn3', 'Gene', (334, 338))	('K34', 'Gene', (69, 72))	('K293', 'CellLine', 'CVCL:0045', (102, 106))	('K34', 'Gene', '3885', (200, 203))	('K46', 'Var', (124, 127))	('Rpn13', 'Gene', (95, 100))	('Rpn5', 'Gene', (381, 385))	('Rpn5', 'Gene', '5718', (381, 385))	('K32', 'Gene', (340, 343))	('Rpn6', 'Gene', (355, 359))	('K34', 'Gene', '3885', (69, 72))	('K32', 'Gene', (268, 271))	('K19', 'Gene', (254, 257))	('Rpn13', 'Gene', '36545', (95, 100))	('increased', 'PosReg', (47, 56))	('K34', 'Gene', (200, 203))	('K293', 'Var', (102, 106))
564977	32140187	Abnormal ubiquitinations in cell energy metabolism-related pathways might contribute to tumor metabolic reprogramming that is a hallmark of cancer.	('ubiquitinations', 'MPA', (9, 24))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('contribute', 'Reg', (74, 84))	('hallmark of cancer', 'Disease', (128, 146))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('Abnormal', 'Var', (0, 8))	('tumor', 'Disease', (88, 93))	('hallmark of cancer', 'Disease', 'MESH:D009369', (128, 146))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('cell energy metabolism-related pathways', 'Pathway', (28, 67))
564980	32140187	For glycolysis pathway, all 12 ubiquitination sites within 8 DUPs (including PKM, P14618, a rate-limiting enzyme) had the significantly increased ubiquitination levels; of these, ubiquitination at residue K270 in PKM was only detected in LSCC tissues, which indicated that ubiquitination might affect glycolysis (Supplemental Fig.	('PKM', 'Gene', (213, 216))	('glycolysis', 'MPA', (301, 311))	('PKM', 'Gene', '5315', (77, 80))	('K270', 'Chemical', '-', (205, 209))	('ubiquitination levels', 'MPA', (146, 167))	('PKM', 'Gene', (77, 80))	('affect', 'Reg', (294, 300))	('increased', 'PosReg', (136, 145))	('P14618', 'Var', (82, 88))	('glycolysis', 'Enzyme', (4, 14))	('PKM', 'Gene', '5315', (213, 216))	('LSCC', 'Disease', (238, 242))
564981	32140187	For fructose and mannose metabolism pathway, this study identified four DUPs, whose ubiquitination levels were significantly increased at residues K111 (ratio T/N = 3.84) and K200 (ratio T/N = 3.8) in P04075; K117 (T+/N-), K186 (ratio T/N = 16.91), K194 (ratio T/N = 2.67), and K215 (ratio T/N = 3.22) in P04406; K97 (T+/N-) in B3KXY9; and K168 (T+/N-) in P60174 (Supplemental Fig.	('K168 (T+/N-', 'Var', (340, 351))	('K19', 'Gene', '3880', (249, 252))	('K19', 'Gene', (249, 252))	('increased', 'PosReg', (125, 134))	('P04075; K117 (T+/N-', 'Var', (201, 220))	('mannose', 'Chemical', 'MESH:D008358', (17, 24))	('ubiquitination levels', 'MPA', (84, 105))	('K186', 'Var', (223, 227))	('fructose', 'Chemical', 'MESH:D005632', (4, 12))	('P60174', 'Var', (356, 362))
564982	32140187	For central carbon metabolism of cancer pathway, this study identified six DUPs, whose ubiquitination levels were significantly increased at K97 (T+/N-) in B3KXY9, K270 (T+/N-) in P14618, K178 (T+/N-) and K362 (ratio T/N = 7.19) in Q15758, K270 (ratio T/N = 110.93) and K502 (T+/N-) in Q59GX2, K19 (T+/N-) in Q01650, and K431 (T+/N-) in A0A024R8U1 (Supplemental Fig.	('K270', 'Chemical', '-', (164, 168))	('K19', 'Gene', (294, 297))	('B3KXY9', 'Var', (156, 162))	('P14618', 'Var', (180, 186))	('cancer', 'Disease', (33, 39))	('K270', 'Chemical', '-', (240, 244))	('K19', 'Gene', '3880', (294, 297))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('increased', 'PosReg', (128, 137))	('K270', 'Var', (240, 244))	('ubiquitination levels', 'MPA', (87, 108))	('central carbon metabolism', 'MPA', (4, 29))	('Q01650', 'Var', (309, 315))	('A0A024R8U1', 'Var', (337, 347))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('K178 (T+/N-', 'Var', (188, 199))	('carbon', 'Chemical', 'MESH:D002244', (12, 18))	('Q15758', 'Var', (232, 238))
564983	32140187	For carbon metabolism pathway, this study identified 10 DUPs, whose ubiquitination levels were significantly increased at K380 (T+/N-) and K57 (T+/N-) in O43175; K59 (ratio T/N = 2.66) and K377 (ratio T/N = 16.52) in P52209; K130 (T+/N-) in A0A140VK56; K81 (T+/N-) in A0A24R4F1; K111 (ratio T/N = 3.84) and K200 (ratio T/N = 3.8) in P04075; K117 (T+/N-), K215 (ratio T/N = 3.22), K194 (ratio T/N = 2.67), and K186 (ratio T/N = 16.91) in P04406; K97 (T+/N-) in B3KXY9; K216 (T+/N-) in P00558; K270 (T+/N-) in P14618; and K168 (T+/N-) in P60174 (Supplemental Fig.	('K19', 'Gene', '3880', (380, 383))	('K377', 'Var', (189, 193))	('K81', 'Gene', '3887', (253, 256))	('increased', 'PosReg', (109, 118))	('ubiquitination levels', 'MPA', (68, 89))	('P04406', 'Var', (437, 443))	('K270', 'Chemical', '-', (492, 496))	('K186', 'Var', (409, 413))	('P60174', 'Var', (536, 542))	('carbon', 'Chemical', 'MESH:D002244', (4, 10))	('K270', 'Var', (492, 496))	('K380', 'Var', (122, 126))	('K19', 'Gene', (380, 383))	('K215', 'Var', (355, 359))	('K216', 'Var', (468, 472))	('K200', 'Var', (307, 311))	('P00558; K270', 'Var', (484, 496))	('carbon', 'Enzyme', (4, 10))	('P52209; K130', 'Var', (217, 229))	('K81', 'Gene', (253, 256))	('K57', 'Var', (139, 142))	('O43175', 'Var', (154, 160))	('P14618', 'Var', (508, 514))
564984	32140187	For carbon metabolism pathway, this study identified eight DUPs, whose ubiquitination levels were significantly increased at K299 (T+/N-) in A0A0S2Z3S6; K502 (T+/N-) and K270 (ratio T/N = 110.93) in Q59GX2; K97 (T+/N-) in B3KXY9; K1033 (T+/N-) in P08069; K117 (T+/N-), K215 (ratio T/N = 3.22), K194 (ratio T/N = 2.67), and K186 (ratio T/N = 16.91) in P04406; K81 (T+/N-) in A0A024RF1; K111 (ratio T/N = 3.84) and K200 (ratio T/N = 3.8) in P04075; and K216 (T+/N-) in P00558 (Supplemental Fig.	('P04075', 'Var', (439, 445))	('K19', 'Gene', '3880', (294, 297))	('K19', 'Gene', (294, 297))	('carbon', 'Chemical', 'MESH:D002244', (4, 10))	('P08069', 'Var', (247, 253))	('K81', 'Gene', (359, 362))	('A0A0S2Z3S6; K502', 'Var', (141, 157))	('K215', 'Var', (269, 273))	('carbon', 'Enzyme', (4, 10))	('K81', 'Gene', '3887', (359, 362))	('K270', 'Chemical', '-', (170, 174))	('K111', 'Var', (385, 389))	('increased', 'PosReg', (112, 121))	('Q59GX2', 'Var', (199, 205))	('K270', 'Var', (170, 174))	('ubiquitination levels', 'MPA', (71, 92))	('K117', 'Var', (255, 259))	('K502', 'Var', (153, 157))
564985	32140187	For tight junction pathway, this study found that ubiquitination levels were significantly increased at residues K304 (T+/N-), K338 (ratio T/N = 9.37), K336 (ratio T/N = 21.89), K326 (ratio T/N = 5.07), K96 (ratio T/N = 4.74), and K60 (ratio T/N = 4.98) in tuba; K794 (T+/N-) in integrin; K13 (T+/N-) in PCNA; K62 (T+/N-) in PP2A (A0A140VJT0); K312 (T+/N-) in actin 4; K380 (T+/N-) in myosin (A0A024QZJ4); and K679 (T+/N-), K1410 (T+/N-), and K972 (ratio T/N = 5.40) in myosin (A0A024R1N1) and were significantly decreased at residues K151 (T-/N+), K360 (ratio T/N = 0.09), and K162 (ratio T/N = 0.14) in ERM; K620 (ratio T/N = 0.41) in myosin (P35580); K135 (ratio T/N = 0.32) in RhoA; K21 (ratio T/N = 0.48) in PP2A (A0A140VJS0); and K257 (ratio T/N = 0.05) and K239 (T-/N+) in claudin (Supplemental Fig.	('K360', 'Var', (549, 553))	('RhoA', 'Gene', (681, 685))	('tuba', 'Species', '185716', (257, 261))	('K338', 'Var', (127, 131))	('K60', 'Var', (231, 234))	('ubiquitination', 'MPA', (50, 64))	('K162', 'Var', (578, 582))	('K13', 'Var', (289, 292))	('K32', 'Gene', '3882', (178, 181))	('RhoA', 'Gene', '387', (681, 685))	('K336', 'Var', (152, 156))	('K257', 'Var', (736, 740))	('increased', 'PosReg', (91, 100))	('K620', 'Var', (610, 614))	('PP2A', 'Gene', '5524', (713, 717))	('PP2A', 'Gene', '5524', (325, 329))	('K21', 'Var', (687, 690))	('K1410', 'Var', (424, 429))	('K23', 'Gene', '25984', (764, 767))	('K794', 'Var', (263, 267))	('PP2A', 'Gene', (713, 717))	('decreased', 'NegReg', (513, 522))	('K135', 'Var', (654, 658))	('K32', 'Gene', (178, 181))	('PP2A', 'Gene', (325, 329))	('K972', 'Var', (443, 447))	('K23', 'Gene', (764, 767))
564986	32140187	For the adherens junction pathway, this study found that ubiquitination levels were significantly increased at residues K312 (T+/N-) in A0A024R694; K1033 (T+/N-) in P08069; K935 (T+/N-) in A0A024RC65; K119 (T+/N-) in A0A024R324; K749 (T+/N-), K676 (T+/N-), K810 (T+/N-), and K355 (ratio T/N = 4.99) in O60716; and K147 (T+/N-) in A0A024R1P2 and were significantly decreased at residues K161 (ratio T/N = 0.2) in A0A024RC65 and K135 (ratio T/N = 0.32) in A0A024R324 (Supplemental Fig.	('K81', 'Gene', (257, 260))	('decreased', 'NegReg', (364, 373))	('O60716', 'Var', (302, 308))	('K81', 'Gene', '3887', (257, 260))	('adherens', 'MPA', (8, 16))	('K135', 'Var', (427, 431))	('K355', 'Var', (275, 279))	('increased', 'PosReg', (98, 107))	('ubiquitination levels', 'MPA', (57, 78))
564988	32140187	For the PI3K-AKT pathway, 13 DUPs were identified, and the ubiquitination levels were significantly increased at residues K1033 (T+/N-) in IGFIR, K62 (T+/N-) in PP2A (A0A140VJT0), K517 (T+/N-) and K587 (T+/N-) in SYK, K95 (T+/N-) and K624 (T+/N-) in HSP90, K617 (T+/N-) in EPHA2, and K794 (T+/N-) in ITGB1 and were significantly decreased at residues K23 (ratio T/N = 0.15) in GNB2, K23 (ratio T/N = 0.12) in GNB1, K34 (T-/N+) in GNG12, K21 (ratio T/N = 0.48) in PP2A (A0A140VJS0), K106 (ratio T/N = 0.43) in 14-3-3, K11 (T-/N+) in GNB5, and K957 (T-/N+) in the extracellular matrix (ECM) (Supplemental Fig.	('K794', 'Var', (284, 288))	('K23', 'Gene', (383, 386))	('decreased', 'NegReg', (329, 338))	('PP2A', 'Gene', '5524', (161, 165))	('PP2A', 'Gene', '5524', (463, 467))	('HSP90', 'Gene', '3320', (250, 255))	('K587', 'Var', (197, 201))	('K62', 'Var', (146, 149))	('GNB2', 'Gene', (377, 381))	('K34', 'Gene', '3885', (415, 418))	('GNB5', 'Gene', (532, 536))	('increased', 'PosReg', (100, 109))	('ubiquitination levels', 'MPA', (59, 80))	('IGFIR', 'Gene', '3480', (139, 144))	('K106', 'Var', (482, 486))	('PP2A', 'Gene', (161, 165))	('PP2A', 'Gene', (463, 467))	('K624', 'Var', (234, 238))	('K957', 'Var', (542, 546))	('GNB5', 'Gene', '10681', (532, 536))	('EPHA2', 'Gene', (273, 278))	('SYK', 'Gene', (213, 216))	('K617', 'Var', (257, 261))	('ITGB1', 'Gene', (300, 305))	('K95', 'Var', (218, 221))	('GNB1', 'Gene', '2782', (409, 413))	('K23', 'Gene', '25984', (351, 354))	('GNB1', 'Gene', (409, 413))	('HSP90', 'Gene', (250, 255))	('K34', 'Gene', (415, 418))	('K23', 'Gene', '25984', (383, 386))	('EPHA2', 'Gene', '1969', (273, 278))	('SYK', 'Gene', '6850', (213, 216))	('K11', 'Var', (517, 520))	('K21', 'Var', (437, 440))	('K23', 'Gene', (351, 354))	('IGFIR', 'Gene', (139, 144))	('ITGB1', 'Gene', '3688', (300, 305))	('K517', 'Var', (180, 184))	('GNB2', 'Gene', '2783', (377, 381))
564989	32140187	For RAP1 signaling pathway, nine DUPs were identified, and the ubiquitination levels were significantly increased at residues K46 (T+/N-) in P04899; K147 (T+/N-) in A0A024R1P2; K92 (T+/N-) in P08754; K119 (T+/N-) in A0A024R324; K617 (T+/N-) in A0A024QZA8; K794 (T+/N-) in P05556; K749 (T+/N-); K676 (T+/N-), K406 (T+/N-), K810 (T+/N-), and K355 (ratio T/N = 4.99) in O60716; K91 (T+/N-) in P07737; and K1033 (T+/N-) in P08069 and were significantly decreased at residues K135 (ratio T/N = 0.32) in A0A024R324 (Supplemental Fig.	('decreased', 'NegReg', (449, 458))	('increased', 'PosReg', (104, 113))	('ubiquitination levels', 'MPA', (63, 84))	('RAP1', 'Gene', '5906', (4, 8))	('RAP1', 'Gene', (4, 8))	('K81', 'Gene', (322, 325))	('O60716', 'Var', (367, 373))	('K81', 'Gene', '3887', (322, 325))	('K92 (T+/N-', 'Var', (177, 187))	('K406 (T+/N-', 'Var', (308, 319))
564990	32140187	For the cGMP-PKG signaling pathway, this study identified eight DUPs, and the ubiquitination levels were significantly increased at residues K605 (T+/N-), K444 (T+/N-), K468 (ratio T/N = 22.88), K661 (T+/N-), K212 (T+/N-) in P05023; K128 (T+/N-) in A0A0S2Z3L2; K75 (T+/N-) in A0A024R968; K12 (T+/N-) in P21796; K12 (T+/N-) in Q9Y277; K46 (T+/N-) in P04899; K92 (T+/N-) in P08754; and K119 (T+/N-) in A0A024R324 and were significantly decreased at residue K135 (ratio T/N = 0.32) in A0A024R324 (Supplemental Fig.	('K75', 'Gene', (261, 264))	('cGMP', 'Chemical', 'MESH:D006152', (8, 12))	('P04899', 'Var', (349, 355))	('K75', 'Gene', '9119', (261, 264))	('K12', 'Gene', (233, 236))	('K444 (T+/N-', 'Var', (155, 166))	('K661 (T+/N-', 'Var', (195, 206))	('K12', 'Gene', '3859', (311, 314))	('decreased', 'NegReg', (434, 443))	('K468', 'Var', (169, 173))	('K12', 'Gene', (288, 291))	('K12', 'Gene', '3859', (288, 291))	('K12', 'Gene', (311, 314))	('ubiquitination levels', 'MPA', (78, 99))	('K212 (T+/N-', 'Var', (209, 220))	('cGMP-PKG', 'MPA', (8, 16))	('increased', 'PosReg', (119, 128))	('K12', 'Gene', '3859', (233, 236))
564991	32140187	A total of 44 molecules were identified as hub molecules with topology property degrees >= 10, among which 11.4% (5/44) molecules, including vimentin (VIM) (degree = 21), ACTC1 (degree = 18), YWHAE (degree = 14), ANXA5 (degree = 12), and UBE2N (degree = 11), had the decreased ubiquitination levels; 9.1% (4/44) molecules, including UBA52 (degree = 43), ATP5B (degree = 19), VCP (degree = 14), and ANXA1 (degree = 10), had at least two ubiquitination sites with inconsistent ubiquitination levels; and the rest of the molecules (35/44 = 79.5%) had an average degree of 17.7 and increased ubiquitination levels (Supplemental Table 3).	('hub', 'Gene', '1993', (43, 46))	('ACTC1', 'Gene', '70', (171, 176))	('ACTC1', 'Gene', (171, 176))	('UBE2N', 'Gene', (238, 243))	('YWHAE', 'Gene', (192, 197))	('increased', 'PosReg', (578, 587))	('YWHAE', 'Gene', '7531', (192, 197))	('UBA52', 'Gene', '7311', (333, 338))	('ATP5B', 'Gene', '506', (354, 359))	('ANXA1', 'Gene', (398, 403))	('ANXA5', 'Gene', '308', (213, 218))	('VIM', 'Gene', '7431', (151, 154))	('ubiquitination levels', 'MPA', (588, 609))	('ubiquitination', 'MPA', (436, 450))	('VCP', 'Gene', (375, 378))	('UBA52', 'Gene', (333, 338))	('degrees', 'Var', (80, 87))	('decreased', 'NegReg', (267, 276))	('VIM', 'Gene', (151, 154))	('ATP5B', 'Gene', (354, 359))	('vimentin', 'Gene', '7431', (141, 149))	('ANXA1', 'Gene', '301', (398, 403))	('vimentin', 'Gene', (141, 149))	('UBE2N', 'Gene', '7334', (238, 243))	('hub', 'Gene', (43, 46))	('VCP', 'Gene', '7415', (375, 378))	('ubiquitination levels', 'MPA', (277, 298))	('ANXA5', 'Gene', (213, 218))
564997	32140187	The abundances of vimentin and MRP1 were increased in the proteasome inhibitor MG132-treated LSCC cell lines (H520 and H226 for vimentin; H226 and Calu-1 for MRP1), indicating that vimentin and MRP1 were degraded through the UPS (Fig.	('vimentin', 'Gene', (181, 189))	('vimentin', 'Gene', '7431', (128, 136))	('vimentin', 'Gene', (18, 26))	('increased', 'PosReg', (41, 50))	('MRP1', 'Gene', '4363', (158, 162))	('vimentin', 'Gene', (128, 136))	('MG132', 'Chemical', 'MESH:C072553', (79, 84))	('MRP1', 'Gene', '4363', (31, 35))	('MRP1', 'Gene', (158, 162))	('H520', 'CellLine', 'CVCL:1566', (110, 114))	('MRP1', 'Gene', '4363', (194, 198))	('MRP1', 'Gene', (31, 35))	('abundances', 'MPA', (4, 14))	('degraded', 'NegReg', (204, 212))	('H226', 'Var', (138, 142))	('vimentin', 'Gene', '7431', (181, 189))	('MRP1', 'Gene', (194, 198))	('vimentin', 'Gene', '7431', (18, 26))
565001	32140187	The ubiquitination intensities at residues K129, K139, K168, K188, K223, K334, K402, K439, and K445 in vimentin were significantly decreased in LSCC tissues, with an average ratio = 0.38 (p < 0.01) (Fig.	('vimentin', 'Gene', '7431', (103, 111))	('vimentin', 'Gene', (103, 111))	('K439', 'Var', (85, 89))	('K223', 'Var', (67, 71))	('decreased', 'NegReg', (131, 140))	('LSCC', 'Disease', (144, 148))	('K334', 'Var', (73, 77))	('ubiquitination intensities', 'MPA', (4, 30))	('K402', 'Var', (79, 83))	('K188', 'Var', (61, 65))	('K139', 'Var', (49, 53))	('K168', 'Var', (55, 59))	('K12', 'Gene', (43, 46))	('K12', 'Gene', '3859', (43, 46))	('K445', 'Var', (95, 99))
565002	32140187	The ubiquitination intensities at residues K496, K498, and K636 in MRP1 were significantly increased in LSCC tissues with the average intensity of ubiquitination 3.8 x 107, while those three ubiquitination sites were only detected in LSCC tissues (Fig.	('K498', 'Var', (49, 53))	('K636', 'Var', (59, 63))	('ubiquitination intensities', 'MPA', (4, 30))	('LSCC', 'Disease', (104, 108))	('MRP1', 'Gene', '4363', (67, 71))	('increased', 'PosReg', (91, 100))	('K496', 'Var', (43, 47))	('MRP1', 'Gene', (67, 71))
565020	32140187	Ubiquitination-involved molecular network alterations not only reflect the roles of ubiquitination in the occurrence and development of LSCC, but also provide an important data to mine biomarkers for tumor diagnosis, prognosis, and new therapeutic targets from the components of UPS (such as E3 ligases and proteasome).	('tumor', 'Disease', 'MESH:D009369', (200, 205))	('tumor', 'Phenotype', 'HP:0002664', (200, 205))	('LSCC', 'Disease', (136, 140))	('alterations', 'Var', (42, 53))	('tumor', 'Disease', (200, 205))
565024	32140187	For example, Rpn10 and Rpn13 were important recognition receptors of ubiquitinated target proteins.	('Rpn13', 'Gene', (23, 28))	('Rpn13', 'Gene', '36545', (23, 28))	('Rpn10', 'Var', (13, 18))
565032	32140187	For example, GAPDH (P04406) was a glycolytic enzyme to specifically catalyze glyceraldehyde-3-phosphate (G-3-P) to D-glycerate 1, 3-bisphosphate.	('GAPDH', 'Gene', '2597', (13, 18))	('GAPDH', 'Gene', (13, 18))	('D-glycerate 1, 3-bisphosphate', 'Chemical', '-', (115, 144))	('glyceraldehyde-3-phosphate', 'Chemical', 'MESH:D005986', (77, 103))	('glyceraldehyde-3-phosphate', 'MPA', (77, 103))	('G-3-P', 'Chemical', 'MESH:D005986', (105, 110))	('P04406', 'Var', (20, 26))
565037	32140187	Pyruvate kinase (PK, P14618) was another cancer-related protein to catalyze the last irreversible reaction in the glycolytic pathway.	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('P14618', 'Var', (21, 27))	('cancer', 'Disease', (41, 47))
565039	32140187	Moreover, the overexpressed PK promoted tumor growth, and phosphorylation at residue Tyr105 in PKM2 might also contribute to the tumor growth.	('phosphorylation at residue Tyr105', 'Var', (58, 91))	('PKM2', 'Gene', (95, 99))	('PKM2', 'Gene', '5315', (95, 99))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('Tyr105', 'Chemical', '-', (85, 91))	('tumor', 'Disease', (40, 45))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('promoted', 'PosReg', (31, 39))	('contribute', 'Reg', (111, 121))	('tumor', 'Disease', (129, 134))
565040	32140187	Ubiquitinated K270 in PKM was only identified in LSCC tissues, which was important because it was both the substrate-binding site and transition state stabilizer site.	('PKM', 'Gene', '5315', (22, 25))	('K270', 'Chemical', '-', (14, 18))	('K270', 'Var', (14, 18))	('PKM', 'Gene', (22, 25))
565052	32140187	However, the effect of ubiquitination at residues K239 and K257 in CLDN18 remains unclear, and it is worth further exploring in the next step.	('K257', 'Var', (59, 63))	('K23', 'Gene', (50, 53))	('K23', 'Gene', '25984', (50, 53))	('CLDN18', 'Gene', (67, 73))	('ubiquitination', 'MPA', (23, 37))	('CLDN18', 'Gene', '51208', (67, 73))
565053	32140187	Another DUP, ITGB1 (P05556) belonged to the integrin family, which is linked with various proteins in ECM and actin cytoskeleton to support cell adhesion and anchorage, which was crucial for tissue maintenance and repair in their structural role.	('P05556', 'Var', (20, 26))	('ITGB1', 'Gene', '3688', (13, 18))	('belonged', 'Reg', (28, 36))	('ITGB1', 'Gene', (13, 18))
565061	32140187	Some molecules in these pathways were closely related to tumorigenesis, which were identified as DUPs, including Rac (A0A024R1P2), RhoA (A0A024R324), PP2A (A0A140VJT0, A0A140VJS0), ITGB1 (P05556), and IGF1R (P08069).	('PP2A', 'Gene', '5524', (150, 154))	('ITGB1', 'Gene', (181, 186))	('IGF1R', 'Gene', (201, 206))	('P05556', 'Var', (188, 194))	('RhoA', 'Gene', (131, 135))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('Rac', 'Gene', '207', (113, 116))	('IGF1R', 'Gene', '3480', (201, 206))	('A0A140VJT0', 'Var', (156, 166))	('ITGB1', 'Gene', '3688', (181, 186))	('A0A140VJS0', 'Var', (168, 178))	('PP2A', 'Gene', (150, 154))	('tumor', 'Disease', (57, 62))	('RhoA', 'Gene', '387', (131, 135))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('A0A024R324', 'Var', (137, 147))	('Rac', 'Gene', (113, 116))
565108	31636844	Females treated with 5-FU showed higher levels of toxicity such as nausea, vomiting, alopecia and leukopenia than males.	('alopecia', 'Disease', (85, 93))	('vomiting', 'Phenotype', 'HP:0002013', (75, 83))	('alopecia', 'Phenotype', 'HP:0001596', (85, 93))	('nausea', 'Disease', 'MESH:D009325', (67, 73))	('leukopenia', 'Phenotype', 'HP:0001882', (98, 108))	('vomiting', 'Disease', (75, 83))	('vomiting', 'Disease', 'MESH:D014839', (75, 83))	('alopecia', 'Disease', 'MESH:D000505', (85, 93))	('leukopenia', 'Disease', (98, 108))	('nausea', 'Phenotype', 'HP:0002018', (67, 73))	('nausea', 'Disease', (67, 73))	('leukopenia', 'Disease', 'MESH:D007970', (98, 108))	('toxicity', 'Disease', 'MESH:D064420', (50, 58))	('toxicity', 'Disease', (50, 58))	('5-FU', 'Var', (21, 25))
565111	31636844	For instance, male patients with lung adenocarcinoma showed 1.636-fold higher frequency of genetic alterations than female patients, and greater genetic alterations were related to worse overall survival in males.	('patients', 'Species', '9606', (19, 27))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (33, 52))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (33, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (43, 52))	('patients', 'Species', '9606', (123, 131))	('genetic alterations', 'Var', (91, 110))	('lung adenocarcinoma', 'Disease', (33, 52))
565120	31636844	Studies investigated the association between the risk of bladder cancer and hypomethylation of long interspersed nuclear element-1 (LINE-1).	('hypomethylation', 'Var', (76, 91))	('bladder cancer', 'Disease', 'MESH:D001749', (57, 71))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('bladder cancer', 'Disease', (57, 71))	('bladder cancer', 'Phenotype', 'HP:0009725', (57, 71))
565121	31636844	Hypomethylation of LINE-1 may be an effective biomarker for the risk of bladder cancer in females.	('Hypomethylation', 'Var', (0, 15))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('bladder cancer', 'Phenotype', 'HP:0009725', (72, 86))	('bladder cancer', 'Disease', 'MESH:D001749', (72, 86))	('bladder cancer', 'Disease', (72, 86))
565122	31636844	The lowest degree of LINE-1 methylation in females indicates a 2.5-fold significantly higher risk of bladder cancer.	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('bladder cancer', 'Disease', 'MESH:D001749', (101, 115))	('bladder cancer', 'Disease', (101, 115))	('methylation', 'Var', (28, 39))	('bladder cancer', 'Phenotype', 'HP:0009725', (101, 115))
565123	31636844	In males, however, there was no correlation between hypomethylation of LINE-1 and risk of bladder cancer.	('bladder cancer', 'Disease', (90, 104))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('LINE-1', 'Gene', (71, 77))	('bladder cancer', 'Phenotype', 'HP:0009725', (90, 104))	('hypomethylation', 'Var', (52, 67))	('bladder cancer', 'Disease', 'MESH:D001749', (90, 104))
565129	31636844	DNA from 251 primary tumors of Norwegian patients with colorectal carcinoma was analyzed using sequence-specific oligonucleotide probes for the presence of k-ras point mutations at codons 12 and 13.	('tumors of Norwegian', 'Disease', (21, 40))	('carcinoma', 'Phenotype', 'HP:0030731', (66, 75))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (55, 75))	('tumors', 'Phenotype', 'HP:0002664', (21, 27))	('patients', 'Species', '9606', (41, 49))	('tumors of Norwegian', 'Disease', 'MESH:C537312', (21, 40))	('k-ras', 'Gene', (156, 161))	('colorectal carcinoma', 'Disease', (55, 75))	('k-ras', 'Gene', '3845', (156, 161))	('point mutations', 'Var', (162, 177))	('tumor', 'Phenotype', 'HP:0002664', (21, 26))
565139	31636844	In 120 sporadic colorectal cancers, methylation-specific PCR was performed to determine whether the methylation of the CpG island in the 5' region of the p16INK4a tumor suppressor gene was associated with sex or other clinicopathological characteristics.	('colorectal cancers', 'Disease', (16, 34))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('tumor', 'Disease', 'MESH:D009369', (163, 168))	('tumor', 'Phenotype', 'HP:0002664', (163, 168))	('p16INK4a', 'Gene', (154, 162))	('associated', 'Reg', (189, 199))	('methylation', 'Var', (100, 111))	('cancers', 'Phenotype', 'HP:0002664', (27, 34))	('tumor', 'Disease', (163, 168))	('p16INK4a', 'Gene', '1029', (154, 162))	('colorectal cancer', 'Phenotype', 'HP:0003003', (16, 33))	('colorectal cancers', 'Disease', 'MESH:D015179', (16, 34))
565140	31636844	In female patients, methylation-positive cancer was 8.8-fold higher than in male patients, and methylation of p16INK4a was associated with poorly differentiated tumors.	('associated', 'Reg', (123, 133))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('p16INK4a', 'Gene', '1029', (110, 118))	('methylation', 'Var', (95, 106))	('tumors', 'Disease', (161, 167))	('tumors', 'Phenotype', 'HP:0002664', (161, 167))	('patients', 'Species', '9606', (81, 89))	('tumors', 'Disease', 'MESH:D009369', (161, 167))	('methylation-positive', 'MPA', (20, 40))	('tumor', 'Phenotype', 'HP:0002664', (161, 166))	('p16INK4a', 'Gene', (110, 118))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('patients', 'Species', '9606', (10, 18))
565141	31636844	Female patients with p16INK4a methylation may represent an important database of molecular alterations associated with sporadic colorectal cancers.	('methylation', 'Var', (30, 41))	('cancers', 'Phenotype', 'HP:0002664', (139, 146))	('colorectal cancer', 'Phenotype', 'HP:0003003', (128, 145))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('p16INK4a', 'Gene', (21, 29))	('colorectal cancers', 'Disease', 'MESH:D015179', (128, 146))	('p16INK4a', 'Gene', '1029', (21, 29))	('colorectal cancers', 'Disease', (128, 146))	('patients', 'Species', '9606', (7, 15))
565155	31636844	However, the 15 genes with a higher expression in female samples include cyclin dependent kinase 6 (CDK6), PROL2, FLJ20489, fibroblast growth factor receptor 2 (FGFR2), microfibrillar-associated protein 2 (MFAP), peroxiredoxin 3 (PRDX3), fibroblast growth factor receptor 3 (FGFR3), polyA site, and HSHRTPSN located on the autosome, and inactive X specific transcripts (XIST), ubiquitin specific peptidase 9 X-linked (USP9X), E1F1AX, ribosomal protein S4 X-linked (RPS4X), arylsulfatase E (ARSE), and DEAD-box helicase 3 X-linked (DDX3X) on the X chromosome.	('RPS4X', 'Gene', '6191', (465, 470))	('PROL2', 'Gene', (107, 112))	('microfibrillar-associated protein 2', 'Gene', (169, 204))	('DDX3X', 'Gene', (531, 536))	('fibroblast growth factor receptor 3', 'Gene', (238, 273))	('FGFR2', 'Gene', (161, 166))	('ARSE', 'Gene', (490, 494))	('DEAD-box helicase 3 X-linked', 'Gene', '1654', (501, 529))	('E1F1AX', 'Var', (426, 432))	('higher', 'PosReg', (29, 35))	('peroxiredoxin 3', 'Gene', '10935', (213, 228))	('FLJ20489', 'Var', (114, 122))	('peroxiredoxin 3', 'Gene', (213, 228))	('arylsulfatase E', 'Gene', '415', (473, 488))	('USP9X', 'Gene', '8239', (418, 423))	('XIST', 'Gene', (370, 374))	('cyclin dependent kinase 6', 'Gene', '1021', (73, 98))	('FGFR3', 'Gene', (275, 280))	('CDK6', 'Gene', '1021', (100, 104))	('DDX3X', 'Gene', '1654', (531, 536))	('FGFR2', 'Gene', '2263', (161, 166))	('MFAP', 'Gene', (206, 210))	('ARSE', 'Gene', '415', (490, 494))	('RPS4X', 'Gene', (465, 470))	('cyclin dependent kinase 6', 'Gene', (73, 98))	('ribosomal protein S4 X-linked', 'Gene', '6191', (434, 463))	('DEAD-box helicase 3 X-linked', 'Gene', (501, 529))	('fibroblast growth factor receptor 3', 'Gene', '2261', (238, 273))	('USP9X', 'Gene', (418, 423))	('FGFR3', 'Gene', '2261', (275, 280))	('PRDX3', 'Gene', '10935', (230, 235))	('XIST', 'Gene', '7503', (370, 374))	('arylsulfatase E', 'Gene', (473, 488))	('fibroblast growth factor receptor 2', 'Gene', (124, 159))	('PRDX3', 'Gene', (230, 235))	('ribosomal protein S4 X-linked', 'Gene', (434, 463))	('CDK6', 'Gene', (100, 104))	('ubiquitin specific peptidase 9 X-linked', 'Gene', '8239', (377, 416))	('fibroblast growth factor receptor 2', 'Gene', '2263', (124, 159))	('ubiquitin specific peptidase 9 X-linked', 'Gene', (377, 416))	('polyA', 'Chemical', 'MESH:C017937', (283, 288))	('microfibrillar-associated protein 2', 'Gene', '4237', (169, 204))	('PROL2', 'Gene', '10957', (107, 112))	('FLJ20489', 'Chemical', 'MESH:C035416', (114, 122))	('MFAP', 'Gene', '4237', (206, 210))	('expression', 'MPA', (36, 46))
565190	31636844	After treatment with carcinogens, large and diverse tumors were detected in the females with FOXA1/2 deficiency, whereas tumor growth in male mutants was reduced compared with the control.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('tumor', 'Disease', (52, 57))	('FOXA1/2', 'Gene', (93, 100))	('tumor', 'Disease', (121, 126))	('tumors', 'Disease', (52, 58))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('FOXA1/2', 'Gene', '3169;3170', (93, 100))	('detected', 'Reg', (64, 72))	('tumor', 'Disease', 'MESH:D009369', (52, 57))	('deficiency', 'Var', (101, 111))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
565195	31636844	These data suggest that Gnmt deficiency not only increases the expression of tumor genes but also induces a decrease in the expression of other tumor suppressor genes in the early stages of tumorigenesis in female rats, which explains the higher risk of hepatocellular carcinoma in female Gnmt-/- mice.	('hepatocellular carcinoma', 'Disease', 'MESH:D006528', (254, 278))	('tumor', 'Phenotype', 'HP:0002664', (190, 195))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('decrease', 'NegReg', (108, 116))	('deficiency', 'Var', (29, 39))	('hepatocellular carcinoma', 'Disease', (254, 278))	('Gnmt', 'Gene', (24, 28))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('mice', 'Species', '10090', (297, 301))	('tumor', 'Disease', (144, 149))	('carcinoma', 'Phenotype', 'HP:0030731', (269, 278))	('expression', 'MPA', (63, 73))	('increases', 'PosReg', (49, 58))	('tumor', 'Disease', (190, 195))	('tumor', 'Disease', 'MESH:D009369', (144, 149))	('rats', 'Species', '10116', (214, 218))	('tumor', 'Disease', 'MESH:D009369', (190, 195))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (254, 278))	('expression', 'MPA', (124, 134))	('tumor', 'Phenotype', 'HP:0002664', (144, 149))	('tumor', 'Disease', (77, 82))
565202	31636844	We believe that this variation may affect sex-specific cancer prognosis.	('affect', 'Reg', (35, 41))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('variation', 'Var', (21, 30))	('cancer', 'Disease', 'MESH:D009369', (55, 61))	('cancer', 'Disease', (55, 61))
565232	31416463	SCC Ag knockout reportedly increased the radiosensitivity of cervical tumor cell lines in vitro.	('cervical tumor', 'Phenotype', 'HP:0030159', (61, 75))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('increased', 'PosReg', (27, 36))	('tumor', 'Disease', (70, 75))	('SCC Ag', 'Gene', (0, 6))	('knockout', 'Var', (7, 15))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
565243	31416463	For patients with posttreatment SCC Ag levels < 1.15 ng/ml and >= 1.15 ng/ml, the 3-year OS rates were 90.7 and 36.6% (p < 0.001), and the 3-year progression-free survival (PFS) were 74.7 and 19.5% (p < 0.001), respectively.	('>= 1.15 ng/ml', 'Var', (63, 76))	('SCC Ag', 'Gene', (32, 38))	('< 1.15 ng/ml', 'Var', (46, 58))	('patients', 'Species', '9606', (4, 12))	('OS', 'Chemical', '-', (89, 91))
565287	29207685	In NSCLC (Non-small cell lung cancer), FDA has approved PD-1 inhibitor in first line setting in patients with high PDL-1 expression (PDL-1 expression >50 %).	('NSCLC', 'Disease', (3, 8))	('Non-small cell lung cancer', 'Phenotype', 'HP:0030358', (10, 36))	('NSCLC', 'Disease', 'MESH:D002289', (3, 8))	('expression', 'MPA', (121, 131))	('lung cancer', 'Phenotype', 'HP:0100526', (25, 36))	('Non-small cell lung cancer', 'Disease', 'MESH:D002289', (10, 36))	('high', 'Var', (110, 114))	('Non-small cell lung cancer', 'Disease', (10, 36))	('patients', 'Species', '9606', (96, 104))	('NSCLC', 'Phenotype', 'HP:0030358', (3, 8))	('PDL-1', 'Gene', (115, 120))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (14, 36))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))
565371	29207685	Stratification of tumor microenvironment based on the presence of PDL-1 and tumor infiltrating lymphocytes (TIL) has been proposed.	('tumor', 'Disease', (18, 23))	('tumor', 'Phenotype', 'HP:0002664', (76, 81))	('tumor', 'Disease', (76, 81))	('presence', 'Var', (54, 62))	('PDL-1', 'Gene', (66, 71))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('tumor', 'Disease', 'MESH:D009369', (76, 81))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))
565449	31379926	The gene sets identified by the other algorithms were related to different pathways such as "positive regulation of JNK cascade" (CoxPH), "central carbon metabolism in cancer" (Fisher score and Fscore), "O-glycan biosynthesis, mucin type core" (LLL21, RF, and XGBoost), "mitotic nuclear division" (Trace ratio), "regulation of gene silencing" (RFS), and "GPCR ligand binding" (SVM).	('JNK', 'Gene', '5599', (116, 119))	('cancer', 'Phenotype', 'HP:0002664', (168, 174))	('O-glycan', 'Chemical', '-', (204, 212))	('carbon', 'Chemical', 'MESH:D002244', (147, 153))	('Cox', 'Gene', (130, 133))	('Cox', 'Gene', '1351', (130, 133))	('cancer', 'Disease', 'MESH:D009369', (168, 174))	('cancer', 'Disease', (168, 174))	('JNK', 'Gene', (116, 119))	('gene silencing', 'Var', (327, 341))
565491	29426342	When the dosimetric parameters of the dose distributions for the treatment of patients with locally advanced stage III ESCC were compared between PBT and 3DCRT or IMRT, PBT enabled a significant reduction in the dose to the lung and heart, compared with 3DCRT or IMRT.	('dose', 'MPA', (212, 216))	('reduction', 'NegReg', (195, 204))	('patients', 'Species', '9606', (78, 86))	('PBT', 'Var', (169, 172))
565538	29426342	When the dosimetric parameters between the PBT and 3DCRT plans were compared, all the PBT domestic variables regarding the lung dose except for the lung V10 GyE and V15 GyE were significantly lower than those of the dummy 3DCRT plans (Table 3).	('GyE', 'Chemical', '-', (169, 172))	('V15', 'Gene', '28814', (165, 168))	('lower', 'NegReg', (192, 197))	('lung dose', 'MPA', (123, 132))	('V10 GyE', 'Var', (153, 160))	('GyE', 'Chemical', '-', (157, 160))	('V15', 'Gene', (165, 168))
565556	29426342	Actually, in a study comparing PBT with photon radiation therapy for esophageal cancer evaluated according to the tumor control probability (TCP) and the normal tissue complication probability (NTCP), the PBT plans were able to reduce the doses to structures of the lung and heart better like this study and appeared to have clear therapeutic advantages over photon radiation therapy.	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('esophageal cancer', 'Disease', (69, 86))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('PBT', 'Var', (205, 208))	('esophageal cancer', 'Disease', 'MESH:D004938', (69, 86))	('tumor', 'Disease', (114, 119))	('doses', 'MPA', (239, 244))	('reduce', 'NegReg', (228, 234))
565557	29426342	compared 4-dimensional computed tomography-based treatment plans with PBT or IMRT for distal esophageal cancer, and the application of PBT resulted in a more significant dose reduction to the lung than IMRT; however, no improvement in the dose to the heart was seen.	('dose', 'MPA', (170, 174))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('esophageal cancer', 'Disease', (93, 110))	('PBT', 'Var', (135, 138))	('esophageal cancer', 'Disease', 'MESH:D004938', (93, 110))	('reduction', 'NegReg', (175, 184))
565576	28052009	CAF-educated cells suppressed T cell proliferation more strongly than control cells, and the neutralization of TGF-beta IL-10, or arginase I significantly restored T cell proliferation.	('TGF-beta', 'Gene', '7040', (111, 119))	('neutralization', 'Var', (93, 107))	('IL-10', 'Gene', '3586', (120, 125))	('T cell proliferation', 'CPA', (30, 50))	('suppressed', 'NegReg', (19, 29))	('TGF-beta', 'Gene', (111, 119))	('restored', 'PosReg', (155, 163))	('IL-10', 'Gene', (120, 125))	('CAF', 'Gene', (0, 3))	('CAF', 'Gene', '8850', (0, 3))	('T cell proliferation', 'CPA', (164, 184))
565635	28052009	PFS and OS were significantly shorter in CAFs grade 3 cases than in CAFs grades 0-2 cases.	('CAF', 'Gene', (68, 71))	('CAF', 'Gene', '8850', (41, 44))	('OS', 'Chemical', '-', (8, 10))	('CAF', 'Gene', (41, 44))	('CAF', 'Gene', '8850', (68, 71))	('shorter', 'NegReg', (30, 37))	('grade 3', 'Var', (46, 53))
565652	28052009	Furthermore, CAF-educated cells significantly suppressed T cell proliferation, and the neutralization of IL-10, TGF-beta or arginase I restored the inhibitory effects of CAF-educated cells.	('CAF', 'Gene', (170, 173))	('inhibitory', 'MPA', (148, 158))	('T cell proliferation', 'CPA', (57, 77))	('CAF', 'Gene', (13, 16))	('CAF', 'Gene', '8850', (170, 173))	('IL-10', 'Gene', (105, 110))	('TGF-beta', 'Gene', '7040', (112, 120))	('neutralization', 'Var', (87, 101))	('CAF', 'Gene', '8850', (13, 16))	('TGF-beta', 'Gene', (112, 120))	('IL-10', 'Gene', '3586', (105, 110))	('suppressed', 'NegReg', (46, 56))
565681	28052009	The non-specific binding of antibodies to Fc receptors on the harvested cells was blocked using BD Fc Block  (BD Bioscience, San Jose, CA, USA) in accordance with the manufacturer's instructions, and cells were then stained with the following mouse anti-human antibodies in order to examine the expression of myeloid cell markers, HLA molecules, or co-regulatory molecules: HLA-DR, CD14, CD68, CD163, CD200R, CD206, CD80, CD86, HLA-G, B7H1/PD-L1, B7DC/PD-L2, or B7H3.	('CD86', 'Gene', '942', (422, 426))	('CD86', 'Gene', (422, 426))	('PD-L1', 'Gene', '29126', (440, 445))	('B7DC', 'Gene', '80380', (447, 451))	('B7H3', 'Gene', '80381', (462, 466))	('CD80', 'Gene', '941', (416, 420))	('HLA-G', 'Gene', (428, 433))	('CD200R', 'Gene', (401, 407))	('human', 'Species', '9606', (254, 259))	('CD80', 'Gene', (416, 420))	('B7H1', 'Gene', '29126', (435, 439))	('B7H3', 'Gene', (462, 466))	('CD163', 'Var', (394, 399))	('PD-L2', 'Gene', '80380', (452, 457))	('CD68', 'Var', (388, 392))	('B7H1', 'Gene', (435, 439))	('CD14', 'Gene', (382, 386))	('HLA-G', 'Gene', '3135', (428, 433))	('CD14', 'Gene', '929', (382, 386))	('mouse', 'Species', '10090', (243, 248))	('B7DC', 'Gene', (447, 451))	('PD-L2', 'Gene', (452, 457))	('CD200R', 'Gene', '131450', (401, 407))	('CD206', 'Gene', '4360', (409, 414))	('PD-L1', 'Gene', (440, 445))	('CD206', 'Gene', (409, 414))
565715	26840258	In terms of prognostic features, a survival analysis from KM-Plotter tool revealed that the high HMGB1 expression group exhibited poorer survival in lung adenocarcinoma (ADC) and overall NSCLC patients.	('patients', 'Species', '9606', (193, 201))	('high', 'Var', (92, 96))	('carcinoma', 'Phenotype', 'HP:0030731', (159, 168))	('lung adenocarcinoma', 'Disease', (149, 168))	('expression', 'MPA', (103, 113))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (149, 168))	('NSCLC', 'Disease', (187, 192))	('HMGB1', 'Gene', (97, 102))	('survival', 'MPA', (137, 145))	('NSCLC', 'Disease', 'MESH:D002289', (187, 192))	('HMGB1', 'Gene', '3146', (97, 102))	('poorer', 'NegReg', (130, 136))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (149, 168))
565740	26840258	Six microarray datasets (GSE19188, GSE21933, GSE30219, GSE40275, GSE51855 and GSE56044), which included both NSCLC patients and healthy people, were also collected from the GEO and ArrayExpress databases until September 2015 (Table 1).	('patients', 'Species', '9606', (115, 123))	('GSE40275', 'Var', (55, 63))	('NSCLC', 'Disease', 'MESH:D002289', (109, 114))	('GSE51855', 'Var', (65, 73))	('GSE30219', 'Var', (45, 53))	('GSE21933', 'Var', (35, 43))	('GSE19188', 'Var', (25, 33))	('GSE56044', 'Var', (78, 86))	('people', 'Species', '9606', (136, 142))	('NSCLC', 'Disease', (109, 114))
565745	26840258	Upon examining the HMGB1 expression in NSCLC patients in GSE30219 and GSE41271, we found some intriguing results.	('HMGB1', 'Gene', '3146', (19, 24))	('GSE41271', 'Var', (70, 78))	('patients', 'Species', '9606', (45, 53))	('NSCLC', 'Disease', (39, 44))	('HMGB1', 'Gene', (19, 24))	('NSCLC', 'Disease', 'MESH:D002289', (39, 44))
565746	26840258	In GSE30219, HMGB1 expression in ADC and SCC was found to be significantly different (Figure 3A, P=0.000); it was also found to be significantly different in tumor size (T stage, P=0.000), lymph node involvement (N stage P=0.000) and distant metastasis (M stage P=0.022) (Figure 3B-3D).	('tumor', 'Disease', (158, 163))	('expression', 'MPA', (19, 29))	('HMGB1', 'Gene', (13, 18))	('SCC', 'Gene', (41, 44))	('3B-3', 'Species', '1413326', (279, 283))	('HMGB1', 'Gene', '3146', (13, 18))	('SCC', 'Gene', '6317', (41, 44))	('GSE30219', 'Var', (3, 11))	('different', 'Reg', (145, 154))	('lymph node involvement', 'CPA', (189, 211))	('distant metastasis', 'CPA', (234, 252))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))	('different', 'Reg', (75, 84))
565747	26840258	In GSE41271, HMGB1 was observed to have a significant difference in final stage (P=0.0082) and histologic types (P=0.0091) (Figure 3E-3F).	('GSE41271', 'Var', (3, 11))	('HMGB1', 'Gene', '3146', (13, 18))	('HMGB1', 'Gene', (13, 18))	('final stage', 'CPA', (68, 79))
565748	26840258	Having examined HMGB1 expression in various histologic types and TNM stages from GSE30219 and GSE41271, we then associated the expression level of HMGB1 (low and high expressing groups) with clinicopathological parameters.	('TNM', 'Gene', '10178', (65, 68))	('HMGB1', 'Gene', (147, 152))	('HMGB1', 'Gene', '3146', (147, 152))	('GSE41271', 'Var', (94, 102))	('TNM', 'Gene', (65, 68))	('HMGB1', 'Gene', '3146', (16, 21))	('associated', 'Reg', (112, 122))	('HMGB1', 'Gene', (16, 21))
565751	26840258	Similarly, GSE41271 also showed an increase in the percentage of SCC subclass patients (60.49%), showing increased levels of HMGB1 greater than ADC (43.55%), and the final stage II (58.00%) and III-IV (57.61%) also indicated an increased percentage of patients with HMGB1 high expression compared to final stage I patients (42.11%) (see Table 3).	('HMGB1', 'Gene', (266, 271))	('patients', 'Species', '9606', (314, 322))	('SCC', 'Gene', (65, 68))	('GSE41271', 'Var', (11, 19))	('levels', 'MPA', (115, 121))	('patients', 'Species', '9606', (252, 260))	('HMGB1', 'Gene', '3146', (266, 271))	('patients', 'Species', '9606', (78, 86))	('SCC', 'Gene', '6317', (65, 68))	('HMGB1', 'Gene', (125, 130))	('HMGB1', 'Gene', '3146', (125, 130))	('increased', 'PosReg', (105, 114))
565763	26840258	Therefore, we used bioinformatics analysis techniques to analyze the pathway and gene information in GSE30219 during HMGB1 up-regulation.	('HMGB1', 'Gene', '3146', (117, 122))	('GSE30219', 'Var', (101, 109))	('HMGB1', 'Gene', (117, 122))	('up-regulation', 'PosReg', (123, 136))
565765	26840258	In ADC, 1672 genes were up-regulated and 1184 genes (see Supplementary Table 1) were down-regulated in the high HMGB1 expression group.	('HMGB1', 'Gene', (112, 117))	('HMGB1', 'Gene', '3146', (112, 117))	('down-regulated', 'NegReg', (85, 99))	('high', 'Var', (107, 111))	('up-regulated', 'PosReg', (24, 36))
565766	26840258	The mostly significant pathways for P-values from the KEGG pathway database included Metabolic, PI3K-Akt, cell cycle, pathways in cancer and others, and the pathways that possessed more enrichment scores were DNA replication, Staphylococcus aureus infection, complement and coagulation cascades and p53 signaling pathway.	('Akt', 'Gene', '207', (101, 104))	('p53', 'Gene', (299, 302))	('p53', 'Gene', '7157', (299, 302))	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('Staphylococcus aureus infection', 'Disease', (226, 257))	('cancer', 'Disease', (130, 136))	('Akt', 'Gene', (101, 104))	('Staphylococcus aureus infection', 'Disease', 'MESH:D013203', (226, 257))	('significant', 'Reg', (11, 22))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))	('P-values', 'Var', (36, 44))	('Staphylococcus aureus infection', 'Phenotype', 'HP:0002726', (226, 257))
565780	26840258	We also considered that the mutation of HMGB1 might lead to up-regulation in lung cancer, but the results from TCGA exclude this possibility.	('lung cancer', 'Phenotype', 'HP:0100526', (77, 88))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('HMGB1', 'Gene', (40, 45))	('HMGB1', 'Gene', '3146', (40, 45))	('up-regulation', 'PosReg', (60, 73))	('lung cancer', 'Disease', 'MESH:D008175', (77, 88))	('mutation', 'Var', (28, 36))	('lung cancer', 'Disease', (77, 88))
565782	26840258	Similar results from Liu PL showed that NSCLC patients with a high level of HMGB1 were associated with a poor clinical prognosis, but this article was limited by the number of cases (n=48).	('high level', 'Var', (62, 72))	('patients', 'Species', '9606', (46, 54))	('HMGB1', 'Gene', '3146', (76, 81))	('HMGB1', 'Gene', (76, 81))	('NSCLC', 'Disease', (40, 45))	('NSCLC', 'Disease', 'MESH:D002289', (40, 45))
565799	26840258	Mutations in RTK signaling are more frequent in ADC.	('frequent', 'Reg', (36, 44))	('RTK', 'Gene', '5979', (13, 16))	('ADC', 'Disease', (48, 51))	('Mutations', 'Var', (0, 9))	('RTK', 'Gene', (13, 16))
565805	26840258	Then, we performed a comprehensive bioinformatics analysis of DEGs and revealed possible central signal pathways (MAPK, apoptosis and cell cycle) and genes (PLCG2, PI3Ks, PKC and DGKZ) in the development of lung ADC.	('DGKZ', 'Gene', '8525', (179, 183))	('DGKZ', 'Gene', (179, 183))	('PLCG2', 'Gene', (157, 162))	('PI3Ks', 'Var', (164, 169))	('lung ADC', 'Disease', (207, 215))	('PKC', 'Gene', (171, 174))	('PKC', 'Gene', '112476', (171, 174))	('PLCG2', 'Gene', '5336', (157, 162))
565814	26840258	Finally, the GSE30219, GSE41271 datasets were chose because of the large number of NSCLC patient samples and correspondingly complete clinical information.	('patient', 'Species', '9606', (89, 96))	('GSE30219', 'Var', (13, 21))	('NSCLC', 'Disease', (83, 88))	('NSCLC', 'Disease', 'MESH:D002289', (83, 88))	('GSE41271', 'Var', (23, 31))
565821	26840258	The other web application, cBioPortal, was used to analyze the survival rate in HMGB1 high and HMGB1 low groups.	('HMGB1', 'Gene', (95, 100))	('HMGB1', 'Gene', '3146', (95, 100))	('HMGB1', 'Gene', '3146', (80, 85))	('HMGB1', 'Gene', (80, 85))	('high', 'Var', (86, 90))	('low', 'NegReg', (101, 104))
565823	26840258	We defined genetic alterations as HMGB1 mRNA over-expression if greater than the mean value.	('mRNA', 'MPA', (40, 44))	('HMGB1', 'Gene', (34, 39))	('over-expression', 'PosReg', (45, 60))	('HMGB1', 'Gene', '3146', (34, 39))	('alterations', 'Var', (19, 30))
565825	26840258	Affymetrix microarray dataset GSE30219 with the largest sample size within all NSCLC GEO datasets was selected to perform bioinformatics analysis.	('NSCLC', 'Disease', 'MESH:D002289', (79, 84))	('GSE30219', 'Var', (30, 38))	('NSCLC', 'Disease', (79, 84))
565835	32323889	Comprehensive genomic profiling obtained from liver metastases identified numerous genomic alterations including amplification of NTRK1.	('liver metastases', 'Disease', 'MESH:D009362', (46, 62))	('NTRK1', 'Gene', (130, 135))	('NTRK1', 'Gene', '4914', (130, 135))	('amplification', 'Var', (113, 126))	('liver metastases', 'Disease', (46, 62))
565837	32323889	Although larotrectinib is only approved for the treatment of cancers with NTRK gene fusions, treatment was started and led to a shrinkage of the primary tumor as well as the liver and lung metastases within 6 weeks according to RECIST criteria accompanied by tumor marker decrease.	('gene fusions', 'Var', (79, 91))	('liver and lung metastases', 'Disease', 'MESH:D009362', (174, 199))	('TRK', 'Gene', (75, 78))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('TRK', 'Gene', '4914', (75, 78))	('tumor', 'Disease', 'MESH:D009369', (259, 264))	('cancers', 'Disease', 'MESH:D009369', (61, 68))	('cancers', 'Phenotype', 'HP:0002664', (61, 68))	('tumor', 'Phenotype', 'HP:0002664', (259, 264))	('decrease', 'NegReg', (272, 280))	('tumor', 'Disease', (153, 158))	('cancers', 'Disease', (61, 68))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('shrinkage', 'NegReg', (128, 137))	('tumor', 'Disease', (259, 264))	('cancer', 'Phenotype', 'HP:0002664', (61, 67))	('larotrectinib', 'Chemical', 'MESH:C000609083', (9, 22))
565839	32323889	The use of comprehensive genomic profiling, specifically F1CDx, enabled the selection of a targeted therapy that led to a rapid reduction of the tumor and its metastases according to RECIST criteria.	('metastases', 'Disease', (159, 169))	('reduction of the tumor', 'Disease', 'MESH:D007022', (128, 150))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('metastases', 'Disease', 'MESH:D009362', (159, 169))	('reduction of the tumor', 'Disease', (128, 150))	('F1CDx', 'Var', (57, 62))	('F1CDx', 'Chemical', '-', (57, 62))
565843	32323889	Today, there is only limited knowledge about NTRK alterations in squamous epithelial carcinoma of the esophagus.	('TRK', 'Gene', (46, 49))	('TRK', 'Gene', '4914', (46, 49))	('squamous epithelial carcinoma', 'Disease', 'MESH:D002294', (65, 94))	('carcinoma of the esophagus', 'Phenotype', 'HP:0011459', (85, 111))	('alterations', 'Var', (50, 61))	('squamous epithelial carcinoma', 'Phenotype', 'HP:0002860', (65, 94))	('carcinoma', 'Phenotype', 'HP:0030731', (85, 94))	('squamous epithelial carcinoma', 'Disease', (65, 94))	('epithelial carcinoma', 'Phenotype', 'HP:0031492', (74, 94))
565850	32323889	Gene fusions lead to transcription of chimeric TRK oncoproteins that are constitutively active and serve as oncogenic drivers in a wide variety of cancers.	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('Gene fusions', 'Var', (0, 12))	('fusions', 'Var', (5, 12))	('lead to', 'Reg', (13, 20))	('transcription', 'MPA', (21, 34))	('TRK', 'Gene', (47, 50))	('TRK', 'Gene', '4914', (47, 50))	('cancers', 'Disease', 'MESH:D009369', (147, 154))	('cancers', 'Phenotype', 'HP:0002664', (147, 154))	('cancers', 'Disease', (147, 154))	('chimeric', 'Var', (38, 46))
565853	32323889	Larotrectinib is an orally available selective inhibitor of the TRK receptor family that has shown significant clinical benefit in pediatric and adult patients with NTRK gene fusion in recent years and is now approved in the European Union (EU) and the U.S. 3, 4.	('benefit', 'PosReg', (120, 127))	('TRK', 'Gene', (166, 169))	('TRK', 'Gene', '4914', (166, 169))	('TRK', 'Gene', (64, 67))	('TRK', 'Gene', '4914', (64, 67))	('patients', 'Species', '9606', (151, 159))	('Larotrectinib', 'Chemical', 'MESH:C000609083', (0, 13))	('gene fusion', 'Var', (170, 181))
565865	32323889	In a search of 879 cases with squamous cell carcinoma of the esophagus identified in the Foundation Medicine database, NTRK1 fusions were detected in none and gene amplification in two cases (0.2%).	('detected', 'Reg', (138, 146))	('carcinoma of the esophagus', 'Phenotype', 'HP:0011459', (44, 70))	('fusions', 'Var', (125, 132))	('gene amplification', 'Var', (159, 177))	('NTRK1', 'Gene', '4914', (119, 124))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (30, 53))	('NTRK1', 'Gene', (119, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (44, 53))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (30, 53))	('squamous cell carcinoma', 'Disease', (30, 53))
565866	32323889	Furthermore, to our knowledge, this is merely the second published case of a patient with NTRK gene amplification who received larotrectinib.	('TRK', 'Gene', (91, 94))	('TRK', 'Gene', '4914', (91, 94))	('larotrectinib', 'Chemical', 'MESH:C000609083', (127, 140))	('patient', 'Species', '9606', (77, 84))	('gene amplification', 'Var', (95, 113))
565878	32323889	FoundationOne CDx is a solid tumor genomic profiling test that detects clinically relevant mutations in cancer-associated genes and provides a comprehensive molecular tumor profile 13, 14, 15, 16.	('tumor', 'Disease', 'MESH:D009369', (29, 34))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('tumor', 'Phenotype', 'HP:0002664', (29, 34))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('FoundationOne CDx', 'Chemical', '-', (0, 17))	('mutations', 'Var', (91, 100))	('tumor', 'Disease', (29, 34))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))	('tumor', 'Disease', (167, 172))
565882	32323889	The microsatellite status was stable and the tumor mutational burden was classified as intermediate with 10 Muts/Mb.	('tumor', 'Disease', (45, 50))	('microsatellite', 'Var', (4, 18))	('tumor', 'Disease', 'MESH:D009369', (45, 50))	('tumor', 'Phenotype', 'HP:0002664', (45, 50))
565902	32323889	In numerous malignancies, mutations in NTRK gene family have been confirmed, although only fusions, in-frame deletions, and splice variations have been identified as oncogenic 1.	('TRK', 'Gene', (40, 43))	('TRK', 'Gene', '4914', (40, 43))	('mutations', 'Var', (26, 35))	('malignancies', 'Disease', 'MESH:D009369', (12, 24))	('malignancies', 'Disease', (12, 24))
565903	32323889	Very little has been reported about NTRK gene alterations in esophageal carcinoma.	('esophageal carcinoma', 'Disease', (61, 81))	('esophageal carcinoma', 'Disease', 'MESH:D004938', (61, 81))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('TRK', 'Gene', (37, 40))	('TRK', 'Gene', '4914', (37, 40))	('esophageal carcinoma', 'Phenotype', 'HP:0011459', (61, 81))	('alterations', 'Var', (46, 57))
565904	32323889	Considering our findings, NTRK1 alterations in squamous cell carcinoma occur at an extremely low frequency of 0.2%, as identified in the Foundation Medicine database.	('NTRK1', 'Gene', '4914', (26, 31))	('alterations', 'Var', (32, 43))	('carcinoma', 'Phenotype', 'HP:0030731', (61, 70))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (47, 70))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (47, 70))	('NTRK1', 'Gene', (26, 31))	('squamous cell carcinoma', 'Disease', (47, 70))
565915	32323889	Similar to ERBB2 gene amplification, which is a well-established class of driver gene alteration in breast and gastric cancer, protein overexpression of NTRK amplified tumors is inconsistent.	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('gastric cancer', 'Phenotype', 'HP:0012126', (111, 125))	('tumors', 'Disease', (168, 174))	('TRK', 'Gene', (154, 157))	('tumors', 'Disease', 'MESH:D009369', (168, 174))	('TRK', 'Gene', '4914', (154, 157))	('breast and gastric cancer', 'Disease', 'MESH:D001943', (100, 125))	('ERBB2', 'Gene', (11, 16))	('alteration', 'Var', (86, 96))	('ERBB2', 'Gene', '2064', (11, 16))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
565916	32323889	Recently, NTRK amplification (copy number >=4) was reported to result in a protein overexpression in 14.8% of patients 22.	('protein', 'MPA', (75, 82))	('amplification (copy number >=4', 'Var', (15, 45))	('TRK', 'Gene', (11, 14))	('TRK', 'Gene', '4914', (11, 14))	('overexpression', 'PosReg', (83, 97))	('result in', 'Reg', (63, 72))	('patients', 'Species', '9606', (110, 118))
565923	32323889	Additional investigation is needed to elucidate whether these genes mediate resistance to NTRK inhibition and if cotargeting them augments anti-NTRK antitumor activity.	('mediate', 'Reg', (68, 75))	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('augments', 'NegReg', (130, 138))	('TRK', 'Gene', (91, 94))	('TRK', 'Gene', '4914', (91, 94))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('genes', 'Var', (62, 67))	('TRK', 'Gene', (145, 148))	('TRK', 'Gene', '4914', (145, 148))
565925	32323889	NTRK1: neurotrophic receptor tyrosine kinase 1RK  CCND1: cyclin D1  CCND2: cyclin D2  CCND3: cyclin D3  EGFR: epidermal growth factor receptor  PIK3CA: phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha  CDK6: cyclin dependent kinase 6  HGF: hepatocyte growth factor  SOX2: SRY-box transcription factor 2  CDKN2A/B: cyclin dependent kinase inhibitor 2A/B  EPHB4: ePH receptor B4  FGF19: fibroblast growth factor 19  FGF3: fibroblast growth factor 3  FGF4: fibroblast growth factor 4  MCL1: MCL1 apoptosis regulator  PIM1: Pim-1 proto-oncogene, serine/threonine Kinase  TP53: tumor protein P53  VEGFA: vascular endothelial growth factor A  Conception/design: Dirk Hempel, Thomas Wieland, Beate Solfrank, Vera Grossmann, Johanna Steinhard, Andrea Frick, Louisa Hempel, Thomas Eberl, Andreas Gaumann  Provision of study material or patients: Dirk Hempel, Thomas Wieland, Beate Solfrank, Vera Grossmann, Johanna Steinhard, Andrea Frick, Louisa Hempel, Thomas Eberl, Andreas Gaumann  Manuscript writing: Dirk Hempel, Thomas Wieland, Beate Solfrank, Vera Grossmann, Johanna Steinhard, Andrea Frick, Louisa Hempel, Thomas Eberl, Andreas Gaumann  Final approval of manuscript: Dirk Hempel, Thomas Wieland, Beate Solfrank, Vera Grossmann, Johanna Steinhard, Andrea Frick, Louisa Hempel, Thomas Eberl, Andreas Gaumann  Vera Grossmann: Foundation Medicine Germany GmbH (E).	('PIM1', 'Gene', (536, 540))	('MCL1', 'Gene', (504, 508))	('PIM1', 'Gene', '5292', (536, 540))	('patients', 'Species', '9606', (849, 857))	('HGF', 'Gene', (257, 260))	('TP53', 'Gene', '7157', (589, 593))	('PIK3CA', 'Gene', '5290', (144, 150))	('tumor', 'Phenotype', 'HP:0002664', (595, 600))	('SOX2', 'Gene', '6657', (288, 292))	('CDK6', 'Gene', (224, 228))	('SOX2', 'Gene', (288, 292))	('CCND2', 'Gene', (68, 73))	('CCND1', 'Gene', '595', (50, 55))	('CCND3', 'Gene', '896', (86, 91))	('CCND2', 'Gene', '894', (68, 73))	('MCL1', 'Gene', (510, 514))	('Pim-1', 'Gene', (542, 547))	('phosphatidylinositol-4,5-bisphosphate', 'Chemical', 'MESH:D019269', (152, 189))	('MCL1', 'Gene', '4170', (504, 508))	('EGFR', 'Gene', (104, 108))	('CCND1', 'Gene', (50, 55))	('NTRK1', 'Gene', '4914', (0, 5))	('VEGFA', 'Gene', '7422', (614, 619))	('FGF3', 'Gene', (436, 440))	('FGF19', 'Gene', '9965', (400, 405))	('FGF19', 'Gene', (400, 405))	('FGF3', 'Gene', '2248', (436, 440))	('EPHB4', 'Gene', (376, 381))	('NTRK1', 'Gene', (0, 5))	('MCL1', 'Gene', '4170', (510, 514))	('PIK3CA', 'Gene', (144, 150))	('FGF4', 'Gene', (470, 474))	('vascular endothelial growth factor', 'Gene', '7422', (621, 655))	('serine', 'Chemical', 'MESH:D012694', (564, 570))	('2A/B', 'SUBSTITUTION', 'None', (330, 334))	('2A/B', 'Var', (330, 334))	('TP53', 'Gene', (589, 593))	('tumor', 'Disease', (595, 600))	('EGFR', 'Gene', '1956', (104, 108))	('CCND3', 'Gene', (86, 91))	('vascular endothelial growth factor', 'Gene', (621, 655))	('tumor', 'Disease', 'MESH:D009369', (595, 600))	('2A/B', 'SUBSTITUTION', 'None', (370, 374))	('2A/B', 'Var', (370, 374))	('HGF', 'Gene', '3082', (257, 260))	('CDK6', 'Gene', '1021', (224, 228))	('Pim-1', 'Gene', '5292', (542, 547))	('EPHB4', 'Gene', '2050', (376, 381))	('VEGFA', 'Gene', (614, 619))	('FGF4', 'Gene', '2249', (470, 474))
565930	31130944	In the current study, we performed a bioinformatics analysis to investigate whether C1q can serve as a potential prognostic marker for human carcinoma.	('carcinoma', 'Disease', 'MESH:D002277', (141, 150))	('carcinoma', 'Phenotype', 'HP:0030731', (141, 150))	('carcinoma', 'Disease', (141, 150))	('human', 'Species', '9606', (135, 140))	('C1q', 'Var', (84, 87))
565932	31130944	Our results showed that high levels of C1q have a favorable prognostic index in basal-like breast cancer for disease-free survival, and in HER2-positive breast cancer for overall survival, while it showed a pro-tumorigenic role of C1q in lung adenocarcinoma, and in clear cell renal cell carcinoma.	('HER2-positive breast cancer', 'Disease', (139, 166))	('carcinoma', 'Phenotype', 'HP:0030731', (288, 297))	('tumor', 'Disease', (211, 216))	('high', 'Var', (24, 28))	('clear cell renal cell carcinoma', 'Phenotype', 'HP:0006770', (266, 297))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('C1q', 'Var', (39, 42))	('breast cancer', 'Phenotype', 'HP:0003002', (91, 104))	('clear cell renal cell carcinoma', 'Disease', 'MESH:C538614', (266, 297))	('lung adenocarcinoma', 'Disease', (238, 257))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('breast cancer', 'Disease', 'MESH:D001943', (91, 104))	('breast cancer', 'Phenotype', 'HP:0003002', (153, 166))	('breast cancer', 'Disease', (91, 104))	('HER2-positive breast cancer', 'Disease', 'MESH:D001943', (139, 166))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (238, 257))	('clear cell renal cell carcinoma', 'Disease', (266, 297))	('renal cell carcinoma', 'Phenotype', 'HP:0005584', (277, 297))	('breast cancer', 'Disease', 'MESH:D001943', (153, 166))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (238, 257))	('carcinoma', 'Phenotype', 'HP:0030731', (248, 257))
565936	31130944	C1q associates with the Ca2+-dependent C1r2-C1s2 tetramer, of about 360 kDa, to form the soluble pentameric C1 complex.	('C1q', 'Var', (0, 3))	('Ca2+', 'Chemical', 'MESH:D000069285', (24, 28))	('C1r', 'Gene', '715', (39, 42))	('C1r', 'Gene', (39, 42))	('C1s', 'Gene', '716', (44, 47))	('C1s', 'Gene', (44, 47))	('associates', 'Interaction', (4, 14))
565942	31130944	C1q expressed in the stroma and vascular endothelium of several human malignant tumors acted as a tumor-promoting factor by favoring adhesion, migration and proliferation of cancer cells as well as angiogenesis and metastasis.	('malignant tumors', 'Disease', 'MESH:D018198', (70, 86))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('metastasis', 'CPA', (215, 225))	('tumor', 'Disease', (98, 103))	('adhesion', 'CPA', (133, 141))	('migration', 'CPA', (143, 152))	('proliferation', 'CPA', (157, 170))	('malignant tumors', 'Disease', (70, 86))	('C1q', 'Var', (0, 3))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('cancer', 'Disease', (174, 180))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('human', 'Species', '9606', (64, 69))	('favoring', 'PosReg', (124, 132))	('angiogenesis', 'CPA', (198, 210))	('tumor', 'Disease', (80, 85))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('tumors', 'Phenotype', 'HP:0002664', (80, 86))	('cancer', 'Disease', 'MESH:D009369', (174, 180))
565944	31130944	Recently, we demonstrated that C1q is abundantly present in malignant pleural mesothelioma (MPM), where it can combine with hyaluronic acid (HA), which is a principal component of the TME, and enhance the tumor growth by promoting cell adhesion and proliferation.	('malignant pleural mesothelioma', 'Disease', 'MESH:C562839', (60, 90))	('pleural mesothelioma', 'Phenotype', 'HP:0100002', (70, 90))	('C1q', 'Var', (31, 34))	('tumor', 'Disease', 'MESH:D009369', (205, 210))	('malignant pleural mesothelioma', 'Disease', (60, 90))	('HA', 'Chemical', 'MESH:D006820', (141, 143))	('hyaluronic acid', 'Chemical', 'MESH:D006820', (124, 139))	('promoting', 'PosReg', (221, 230))	('tumor', 'Phenotype', 'HP:0002664', (205, 210))	('tumor', 'Disease', (205, 210))	('cell adhesion', 'CPA', (231, 244))	('enhance', 'PosReg', (193, 200))	('combine', 'Interaction', (111, 118))
565947	31130944	In the current study, we performed a bioinformatics analysis, using Oncomine database and the survival analysis platforms Kaplan-Meier plotter, in order to investigate whether C1q can serve as a potential prognostic marker for human carcinoma, i.e., tumors of epithelial origin.	('carcinoma', 'Disease', (233, 242))	('C1q', 'Var', (176, 179))	('human', 'Species', '9606', (227, 232))	('carcinoma', 'Disease', 'MESH:D002277', (233, 242))	('tumors', 'Disease', (250, 256))	('tumors', 'Phenotype', 'HP:0002664', (250, 256))	('Oncomine', 'Chemical', '-', (68, 76))	('tumor', 'Phenotype', 'HP:0002664', (250, 255))	('tumors', 'Disease', 'MESH:D009369', (250, 256))	('carcinoma', 'Phenotype', 'HP:0030731', (233, 242))
565948	31130944	Our results showed that high levels of C1q have a favorable prognostic index in basal-like breast cancer (BLBC) and in HER-2 positive breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('breast cancer', 'Disease', (91, 104))	('breast cancer', 'Disease', (134, 147))	('breast cancer', 'Phenotype', 'HP:0003002', (91, 104))	('high levels', 'Var', (24, 35))	('breast cancer', 'Phenotype', 'HP:0003002', (134, 147))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('C1q', 'MPA', (39, 42))	('HER-2', 'Gene', '2064', (119, 124))	('HER-2', 'Gene', (119, 124))	('breast cancer', 'Disease', 'MESH:D001943', (91, 104))	('breast cancer', 'Disease', 'MESH:D001943', (134, 147))
565967	31130944	We only investigated carcinomas in which all the three C1q chains showed a significant prognostic effect by Kaplan-Meier plotter analysis.	('carcinomas', 'Phenotype', 'HP:0030731', (21, 31))	('carcinomas', 'Disease', (21, 31))	('carcinomas', 'Disease', 'MESH:D002277', (21, 31))	('C1q', 'Var', (55, 58))	('carcinoma', 'Phenotype', 'HP:0030731', (21, 30))
565969	31130944	These data appear to suggest that C1q can have pro- or anti-tumorigenic implications, depending on the carcinoma types (Table 1).	('carcinoma', 'Disease', (103, 112))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('tumor', 'Disease', (60, 65))	('carcinoma', 'Disease', 'MESH:D002277', (103, 112))	('C1q', 'Var', (34, 37))
565986	31130944	C1q is present in colon, lung, breast, pancreatic carcinoma, and melanoma.	('C1q', 'Var', (0, 3))	('lung', 'Disease', (25, 29))	('breast', 'Disease', (31, 37))	('carcinoma', 'Phenotype', 'HP:0030731', (50, 59))	('colon', 'Disease', (18, 23))	('melanoma', 'Disease', 'MESH:D008545', (65, 73))	('pancreatic carcinoma', 'Disease', (39, 59))	('melanoma', 'Phenotype', 'HP:0002861', (65, 73))	('melanoma', 'Disease', (65, 73))	('pancreatic carcinoma', 'Disease', 'MESH:C562463', (39, 59))
565987	31130944	C1q can promote adhesion, proliferation and migration of melanoma cells.	('C1q', 'Var', (0, 3))	('melanoma', 'Phenotype', 'HP:0002861', (57, 65))	('melanoma', 'Disease', (57, 65))	('adhesion', 'CPA', (16, 24))	('melanoma', 'Disease', 'MESH:D008545', (57, 65))	('migration', 'CPA', (44, 53))	('proliferation', 'CPA', (26, 39))	('promote', 'PosReg', (8, 15))
565989	31130944	C1q bound high and low molecular weight HA and acted as a tumor-promoting factor.	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', (58, 63))	('C1q', 'Var', (0, 3))	('bound', 'Interaction', (4, 9))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('high', 'Protein', (10, 14))	('HA', 'Chemical', 'MESH:D006820', (40, 42))
565990	31130944	In addition, C1q exerted a protective effect against apoptosis, suggesting an overall pro-tumorigenic activity.	('protective effect', 'CPA', (27, 44))	('apoptosis', 'CPA', (53, 62))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', (90, 95))	('C1q', 'Var', (13, 16))	('tumor', 'Disease', 'MESH:D009369', (90, 95))
565992	31130944	C1q was able to induce apoptosis and growth suppression of human prostate DU145 cells, through direct activation of the tumor suppressor WW-domain containing oxidoreductase (WOX1).	('human', 'Species', '9606', (59, 64))	('C1q', 'Var', (0, 3))	('DU145', 'CellLine', 'CVCL:0105', (74, 79))	('WOX1', 'Gene', (174, 178))	('apoptosis', 'CPA', (23, 32))	('WW-domain containing oxidoreductase', 'Gene', (137, 172))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('activation', 'PosReg', (102, 112))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('growth suppression', 'CPA', (37, 55))	('WW-domain containing oxidoreductase', 'Gene', '51741', (137, 172))	('tumor', 'Disease', (120, 125))	('WOX1', 'Gene', '51741', (174, 178))
565993	31130944	C1q also have a pro-apoptotic effect on an ovarian cell line, SKOV3, acting via a TNF-alpha induced apoptosis pathway that involves upregulation of Bax and Fas.	('Bax', 'Gene', (148, 151))	('apoptosis pathway', 'Pathway', (100, 117))	('C1q', 'Var', (0, 3))	('Fas', 'Protein', (156, 159))	('upregulation', 'PosReg', (132, 144))	('TNF-alpha', 'Gene', '7124', (82, 91))	('Bax', 'Gene', '581', (148, 151))	('TNF-alpha', 'Gene', (82, 91))	('SKOV3', 'CellLine', 'CVCL:0532', (62, 67))
565998	31130944	We selected the carcinomas that showed all the three chains of human C1q statistically significant for the prognosis; in several cases, the prognosis was differentially linked to the C1q chains, or limited to one or two C1q chains.	('human', 'Species', '9606', (63, 68))	('linked', 'Reg', (169, 175))	('carcinoma', 'Phenotype', 'HP:0030731', (16, 25))	('carcinomas', 'Phenotype', 'HP:0030731', (16, 26))	('carcinomas', 'Disease', (16, 26))	('carcinomas', 'Disease', 'MESH:D002277', (16, 26))	('C1q chains', 'Var', (183, 193))
566001	31130944	Our bioinformatics analysis highlighted that high levels of C1q have a favorable prognostic index in BLBCs for DFS and HER2+ breast cancer for OS, (Graphical Abstract) consistent with the in vivo studies by Bandini et al.	('BLBCs', 'Disease', (101, 106))	('high levels', 'Var', (45, 56))	('cancer', 'Phenotype', 'HP:0002664', (132, 138))	('breast cancer', 'Disease', 'MESH:D001943', (125, 138))	('C1q', 'Var', (60, 63))	('breast cancer', 'Disease', (125, 138))	('breast cancer', 'Phenotype', 'HP:0003002', (125, 138))	('OS', 'Chemical', '-', (143, 145))
566004	31130944	One possible explanation for the observed positive association between C1q expression and favorable prognostic index could be due to the correlation between the presence of C1q and dendritic cells (CD11c positive cells) in TME.	('CD11c', 'Gene', (198, 203))	('C1q', 'Gene', (173, 176))	('C1q', 'Gene', (71, 74))	('presence', 'Var', (161, 169))	('CD11c', 'Gene', '3687', (198, 203))
566005	31130944	High CD11c expression in BLBCs is associated with a significantly higher OS (p = 0.047) as compared to low CD11c expression.	('CD11c', 'Gene', (5, 10))	('High', 'Var', (0, 4))	('OS', 'Chemical', '-', (73, 75))	('CD11c', 'Gene', (107, 112))	('CD11c', 'Gene', '3687', (107, 112))	('higher', 'PosReg', (66, 72))	('CD11c', 'Gene', '3687', (5, 10))
566009	31130944	The analysis of publicly available data sets revealed that the genes encoding for the C1q chains were associated with a poor prognosis in BLBC using the TCGA dataset (504 patients).	('C1q', 'Var', (86, 89))	('BLBC', 'Disease', (138, 142))	('patients', 'Species', '9606', (171, 179))
566014	31130944	The expression of C1q in kidney cancer is increased as compared to normal kidney tissue (Figure 3A) and C1q has a negative prognostic effect in the case of CCRCC (Figure 3B); no association was evident for PRCC.	('increased', 'PosReg', (42, 51))	('PRCC', 'Gene', '5546', (206, 210))	('CCRCC', 'Phenotype', 'HP:0006770', (156, 161))	('kidney cancer', 'Disease', 'MESH:D007680', (25, 38))	('C1q', 'Var', (104, 107))	('C1q', 'Gene', (18, 21))	('PRCC', 'Gene', (206, 210))	('kidney cancer', 'Phenotype', 'HP:0009726', (25, 38))	('expression', 'MPA', (4, 14))	('negative', 'NegReg', (114, 122))	('kidney cancer', 'Disease', (25, 38))	('PRCC', 'Phenotype', 'HP:0006766', (206, 210))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('CCRCC', 'Disease', (156, 161))
566017	31130944	We can hypothesize that C1q can also participate in promoting angiogenic processes in this particular tumor.	('promoting', 'PosReg', (52, 61))	('C1q', 'Var', (24, 27))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('angiogenic processes', 'CPA', (62, 82))
566018	31130944	C1q has a negative prognostic value in lung tumors limited to adenocarcinomas, the most common form of lung cancer (Figure 3D).	('tumors', 'Phenotype', 'HP:0002664', (44, 50))	('C1q', 'Var', (0, 3))	('adenocarcinomas', 'Disease', 'MESH:D000230', (62, 77))	('lung cancer', 'Disease', 'MESH:D008175', (103, 114))	('lung tumors', 'Disease', (39, 50))	('adenocarcinomas', 'Disease', (62, 77))	('lung tumors', 'Phenotype', 'HP:0100526', (39, 50))	('cancer', 'Phenotype', 'HP:0002664', (108, 114))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('lung cancer', 'Disease', (103, 114))	('carcinomas', 'Phenotype', 'HP:0030731', (67, 77))	('lung cancer', 'Phenotype', 'HP:0100526', (103, 114))	('tumor', 'Phenotype', 'HP:0002664', (44, 49))	('lung tumors', 'Disease', 'MESH:D008175', (39, 50))
566022	31130944	C1q interaction with the ECM components can adversely interrupt its putative functions, as is the case with HA.	('C1q', 'Var', (0, 3))	('interaction', 'Interaction', (4, 15))	('ECM', 'Gene', '22915', (25, 28))	('HA', 'Chemical', 'MESH:D006820', (108, 110))	('ECM', 'Gene', (25, 28))	('putative functions', 'MPA', (68, 86))	('interrupt', 'NegReg', (54, 63))
566047	28086225	While some authors have also explored the potential correlation between its expression in squamous cell carcinoma and its lymphatic metastasis, we found that D2-40 was significantly expressed in the basal layer cells in the normal squamous epithelium but not in squamous cells above the basal layer.	('D2-40', 'Var', (158, 163))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (90, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('squamous cell carcinoma', 'Disease', (90, 113))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (90, 113))
566066	28086225	In patients with missing expression, the poloidal disorder of cells in the basal layer, was replaced by atypical tumor cells.	('tumor', 'Disease', (113, 118))	('missing expression', 'Var', (17, 35))	('patients', 'Species', '9606', (3, 11))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('poloidal disorder of', 'MPA', (41, 61))
566067	28086225	In lesions with non-continuous PDPN expression, the squamous epithelial layer was almost completely tumorized except a small number of residual basal layer cells were occasionally visible.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Disease', (100, 105))	('PDPN', 'Gene', '10630', (31, 35))	('PDPN', 'Gene', (31, 35))	('non-continuous', 'Var', (16, 30))	('tumor', 'Disease', 'MESH:D009369', (100, 105))
566104	28086225	Our study confirmed that displaying the basal layer with D2-40 clone of PDPN is a potential biomarker to identify the presence of any infiltration.	('rat', 'Species', '10116', (140, 143))	('PDPN', 'Gene', (72, 76))	('D2-40 clone', 'Var', (57, 68))	('PDPN', 'Gene', '10630', (72, 76))
566122	26590320	Malignant progression requires these genes, whose knockdown severely impairs tumor growth and prohibits progression from benign papillomas to SCCs.	('impairs tumor', 'Disease', 'MESH:D015417', (69, 82))	('knockdown', 'Var', (50, 59))	('benign papillomas', 'Disease', (121, 138))	('SCC', 'Gene', (142, 145))	('impairs tumor', 'Disease', (69, 82))	('prohibits', 'NegReg', (94, 103))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('SCC', 'Gene', '6317', (142, 145))	('benign papillomas', 'Disease', 'MESH:D010212', (121, 138))	('papillomas', 'Phenotype', 'HP:0012740', (128, 138))
566133	26590320	also show that over-active ETS2 is a major driver of squamous cell carcinoma.	('over-active', 'Var', (15, 26))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (53, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (67, 76))	('squamous cell carcinoma', 'Disease', (53, 76))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (53, 76))	('ETS2', 'Gene', (27, 31))
566134	26590320	Furthermore, ETS2 also increases the expression of genes that cause inflammation and promote the growth of cancers.	('cancers', 'Disease', (107, 114))	('cancers', 'Disease', 'MESH:D009369', (107, 114))	('ETS2', 'Var', (13, 17))	('promote', 'PosReg', (85, 92))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('inflammation', 'Disease', 'MESH:D007249', (68, 80))	('inflammation', 'Disease', (68, 80))	('increases', 'PosReg', (23, 32))	('expression of genes', 'MPA', (37, 56))	('cancers', 'Phenotype', 'HP:0002664', (107, 114))
566136	26590320	Furthermore, the experiments show that high levels of ETS2 are linked with poor outcomes for patients with head and neck squamous cell carcinoma, which is one of the most life-threatening cancers world-wide.	('neck squamous cell carcinoma', 'Disease', (116, 144))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('high', 'Var', (39, 43))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (116, 144))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (107, 144))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('cancers', 'Phenotype', 'HP:0002664', (188, 195))	('ETS2', 'Gene', (54, 58))	('cancers', 'Disease', (188, 195))	('cancers', 'Disease', 'MESH:D009369', (188, 195))	('patients', 'Species', '9606', (93, 101))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (121, 144))
566144	26590320	Moreover, the genes encoding lineage-specific TFs often themselves harbor SEs resulting in a stable feed-forward loop to fuel and maintain the lineage.	('TFs', 'Gene', (46, 49))	('SEs', 'Chemical', '-', (74, 77))	('SEs', 'Var', (74, 77))	('fuel', 'PosReg', (121, 125))
566168	26590320	The vast majority of chemically induced SCCs in mice have mutations in Hras, Kras or Rras2, and HRasG12V alone is sufficient to induce formation of benign tumors (papillomas).	('mutations', 'Var', (58, 67))	('Kras', 'Gene', '16653', (77, 81))	('papillomas', 'Disease', (163, 173))	('benign tumors', 'Disease', (148, 161))	('Hras', 'Gene', (71, 75))	('tumors', 'Phenotype', 'HP:0002664', (155, 161))	('induce', 'Reg', (128, 134))	('SCC', 'Gene', '6317', (40, 43))	('tumor', 'Phenotype', 'HP:0002664', (155, 160))	('Hras', 'Gene', '15461', (71, 75))	('SCC', 'Gene', (40, 43))	('benign tumors', 'Disease', 'MESH:D009369', (148, 161))	('Rras2', 'Gene', '66922', (85, 90))	('papillomas', 'Disease', 'MESH:D010212', (163, 173))	('Rras2', 'Gene', (85, 90))	('HRas', 'Gene', '15461', (96, 100))	('Kras', 'Gene', (77, 81))	('HRas', 'Gene', (96, 100))	('mice', 'Species', '10090', (48, 52))	('papillomas', 'Phenotype', 'HP:0012740', (163, 173))
566177	26590320	We then took advantage of the fact that when chromatin immunoprecipitation and high-throughput sequencing (ChIP-seq) is carried out for Mediator 1, H3K4me1, and H3K27ac, they generate highly overlapping patterns within SEs.	('rat', 'Species', '10116', (179, 182))	('SEs', 'Chemical', '-', (219, 222))	('H3K27ac', 'Var', (161, 168))	('H3K4me1', 'Var', (148, 155))
566178	26590320	Using H3K27ac as our paradigm, we performed ChIP-seq and delineated the SEs of our purified SCC-SCs.	('SCC', 'Gene', '6317', (92, 95))	('H3K27ac', 'Var', (6, 13))	('SEs', 'Chemical', '-', (72, 75))	('SCC', 'Gene', (92, 95))
566205	26590320	Notably, these putative binding sites occurred within epicenters, that is, small regions (1.5-3 kb) of SE chromatin that were particularly enriched for the H3K27ac mark.	('binding', 'Interaction', (24, 31))	('SE', 'Chemical', '-', (103, 105))	('H3K27ac', 'Var', (156, 163))
566217	26590320	For patients with high Elk3 and/or Ets2 expression, the median survival was ~3-6 fold less than that of patients with lower expression levels.	('expression', 'Var', (40, 50))	('Elk3', 'Gene', (23, 27))	('Ets2', 'Gene', (35, 39))	('high', 'Var', (18, 22))	('patients', 'Species', '9606', (4, 12))	('patients', 'Species', '9606', (104, 112))	('less', 'NegReg', (86, 90))
566232	26590320	Importantly, transduction of SCC-SCs with Ets2-shRNA also resulted in a loss of ETS2 protein as judged by immunolabeling of tumors derived from injecting these cells into host recipient mice (Figure 4B).	('ETS2', 'Gene', (80, 84))	('loss', 'NegReg', (72, 76))	('SCC', 'Gene', '6317', (29, 32))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('tumors', 'Disease', (124, 130))	('tumors', 'Disease', 'MESH:D009369', (124, 130))	('tumors', 'Phenotype', 'HP:0002664', (124, 130))	('mice', 'Species', '10090', (186, 190))	('protein', 'Protein', (85, 92))	('SCC', 'Gene', (29, 32))	('Ets2-shRNA', 'Var', (42, 52))
566234	26590320	Whether the SCC cells were transduced with Ets2 #649 or #985, tumor growth was markedly reduced relative to control virus (Figure 4C).	('#985', 'Var', (56, 60))	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('Ets2 #649', 'Var', (43, 52))	('tumor', 'Disease', (62, 67))	('SCC', 'Gene', (12, 15))	('reduced', 'NegReg', (88, 95))	('SCC', 'Gene', '6317', (12, 15))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
566236	26590320	Thus, while the tissue derived from Ets2 knockdown SCC cells was still disorganized, many of the classic signs of SCCs were lost without this SE-associated TF.	('SCC', 'Gene', (51, 54))	('SE', 'Chemical', '-', (142, 144))	('SCC', 'Gene', (114, 117))	('SCC', 'Gene', '6317', (51, 54))	('SCC', 'Gene', '6317', (114, 117))	('Ets2', 'Gene', (36, 40))	('knockdown', 'Var', (41, 50))
566238	26590320	Overall, the impeding effects on SCC tumor growth and morphology were seen irrespective of whether we knocked down Ets2 or Elk3.	('SCC tumor', 'Disease', (33, 42))	('knocked down', 'Var', (102, 114))	('SCC tumor', 'Disease', 'MESH:D009369', (33, 42))	('morphology', 'CPA', (54, 64))	('Ets2', 'Gene', (115, 119))	('Elk3', 'Gene', (123, 127))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))
566240	26590320	When SCC cells were transduced with both the Ets2-shRNA and the Ets2-cDNA harboring a mutated sequence in the shRNA targeting site (Ets2_mut) and then injected subcutaneously into host recipient mice, the Ets2_mut refractory to shRNA knockdown rescued the effects of Ets2-shRNA.	('SCC', 'Gene', '6317', (5, 8))	('mice', 'Species', '10090', (195, 199))	('mutated', 'Var', (86, 93))	('Ets2_mut', 'Var', (205, 213))	('SCC', 'Gene', (5, 8))	('effects', 'MPA', (256, 263))
566246	26590320	To test this hypothesis, we engineered a phosphomimetic T72D version of ETS2, thus bypassing the need for HRas/MAPK to make this modification .	('T72D', 'Mutation', 'p.T72D', (56, 60))	('T72D', 'Var', (56, 60))	('HRas', 'Gene', (106, 110))	('ETS2', 'Gene', (72, 76))	('MAPK', 'Gene', (111, 115))	('MAPK', 'Gene', '34780', (111, 115))	('HRas', 'Gene', '15461', (106, 110))
566248	26590320	When tested in transduced primary keratinocytes in vitro, expression of phosphomimetic T72D and wild-type ETS2 was markedly upregulated upon Doxycycline administration, where proteins, expressed at comparable levels, could be readily detected by ETS2 and Myc-antibodies (Figure 5:figure supplement 1B).	('Doxycycline', 'Chemical', 'MESH:D004318', (141, 152))	('expression', 'MPA', (58, 68))	('rat', 'Species', '10116', (36, 39))	('ETS2', 'Gene', (106, 110))	('rat', 'Species', '10116', (161, 164))	('upregulated', 'PosReg', (124, 135))	('T72D', 'Mutation', 'p.T72D', (87, 91))	('T72D', 'Var', (87, 91))
566256	26590320	By contrast, when the activated form (T72D) of ETS2 was induced, marked epidermal thickenings and invaginations were observed, accompanied by elevated immunolabeling for Ki67, a marker of actively proliferating cells (Figure 5E and Figure 5:figure supplement 1D).	('epidermal thickening', 'Phenotype', 'HP:0011368', (72, 92))	('epidermal thickenings', 'CPA', (72, 93))	('rat', 'Species', '10116', (204, 207))	('ETS2', 'Gene', (47, 51))	('Ki67', 'Gene', '17345', (170, 174))	('invaginations', 'CPA', (98, 111))	('epidermal thickenings', 'Phenotype', 'HP:0011368', (72, 93))	('T72D', 'Mutation', 'p.T72D', (38, 42))	('T72D', 'Var', (38, 42))	('elevated', 'PosReg', (142, 150))	('Ki67', 'Gene', (170, 174))
566259	26590320	Notably, T72D-ETS2 activated epithelium was also typified by expression of AP1 factors FOS and JUNB, as well as ELK3 (Figure 5F).	('T72D', 'Mutation', 'p.T72D', (9, 13))	('ELK3', 'Gene', (112, 116))	('JUNB', 'Gene', (95, 99))	('T72D-ETS2', 'Var', (9, 18))	('AP1', 'Gene', '16476', (75, 78))	('FOS', 'Protein', (87, 90))	('AP1', 'Gene', (75, 78))	('JUNB', 'Gene', '16477', (95, 99))
566265	26590320	Interestingly, T72D-ETS2 not only generated SCC-like hyperproliferation and invaginations, but also induced and/or up-regulated many genes which we had found to be strongly expressed in SCCs (Figures 6A and B).	('SCC', 'Gene', '6317', (44, 47))	('SCC', 'Gene', '6317', (186, 189))	('genes', 'Gene', (133, 138))	('invaginations', 'CPA', (76, 89))	('T72D', 'Mutation', 'p.T72D', (15, 19))	('up-regulated', 'PosReg', (115, 127))	('T72D-ETS2', 'Var', (15, 24))	('induced', 'Reg', (100, 107))	('SCC', 'Gene', (44, 47))	('SCC', 'Gene', (186, 189))	('rat', 'Species', '10116', (38, 41))	('rat', 'Species', '10116', (65, 68))
566268	26590320	Notably, many of the genes that were markedly up-regulated in T72D-ETS2 expressing skin epithelium also displayed SE in SCCs (highlighted in red in Figure 6A).	('T72D-ETS2', 'Var', (62, 71))	('SE', 'Chemical', '-', (114, 116))	('SCC', 'Gene', '6317', (120, 123))	('up-regulated', 'PosReg', (46, 58))	('T72D', 'Mutation', 'p.T72D', (62, 66))	('SCC', 'Gene', (120, 123))
566272	26590320	To test for direct binding of ETS2 to these SCC-SEs, we performed in vivo ETS2-CHIP-qPCR on induced T72D-ETS SCC-SCs.	('SCC', 'Gene', '6317', (44, 47))	('T72D', 'SUBSTITUTION', 'None', (100, 104))	('SCC', 'Gene', '6317', (109, 112))	('SEs', 'Chemical', '-', (48, 51))	('SCC', 'Gene', (44, 47))	('SCC', 'Gene', (109, 112))	('T72D', 'Var', (100, 104))
566273	26590320	Using ChIP immunoprecipitations with antibodies against both endogenous ETS2 and also the Myc-tag, we observed clear enrichment of representative SCC-SE epicenters that harbor ETS2 motifs (Figure 6G).	('motifs', 'Var', (181, 187))	('ETS2', 'Gene', (72, 76))	('ETS2', 'Gene', (176, 180))	('SCC', 'Gene', (146, 149))	('SE', 'Chemical', '-', (150, 152))	('SCC', 'Gene', '6317', (146, 149))
566275	26590320	To this end, we focused on the acetylation of lysine 27 of histone H3, which renders SE chromatin mutually exclusive for Polycomb (PcG)-mediated repression, typified by a trimethylation mark at this same residue.	('Polycomb', 'Gene', '12416', (121, 129))	('Polycomb', 'Gene', (121, 129))	('lysine 27', 'Var', (46, 55))	('lysine', 'Chemical', 'MESH:D008239', (46, 52))	('SE', 'Chemical', '-', (85, 87))	('PcG', 'Gene', '57390', (131, 134))	('PcG', 'Gene', (131, 134))	('acetylation', 'MPA', (31, 42))
566276	26590320	In this regard, it was intriguing that a small number of genes, including Cxcl1/2, Hmga2, Igf2bp2, and Vim, were PcG-repressed in normal skin progenitors, but they displayed H3K27ac-associated SEs in SCC-SCs (Figure 7A).	('SCC', 'Gene', '6317', (200, 203))	('Vim', 'Gene', (103, 106))	('H3K27ac-associated', 'Var', (174, 192))	('Hmga2', 'Gene', '15364', (83, 88))	('PcG', 'Gene', '57390', (113, 116))	('Hmga2', 'Gene', (83, 88))	('SEs', 'Chemical', '-', (193, 196))	('Igf2bp2', 'Gene', '319765', (90, 97))	('Cxcl1/2', 'Gene', (74, 81))	('SCC', 'Gene', (200, 203))	('Vim', 'Gene', '22352', (103, 106))	('Igf2bp2', 'Gene', (90, 97))	('PcG', 'Gene', (113, 116))
566284	26590320	To verify the functional significance, we knocked down Ets2 with our two different shRNAs and examined the consequences to Cxcl1 and Cxcl2 expression.	('Ets2', 'Gene', (55, 59))	('Cxcl2', 'Gene', '20310', (133, 138))	('Cxcl2', 'Gene', (133, 138))	('Cxcl1', 'Gene', (123, 128))	('Cxcl1', 'Gene', '14825', (123, 128))	('knocked', 'Var', (42, 49))
566285	26590320	As shown in Figure 7D, a significant reduction (>=2X) of Cxcl1 and Cxcl2 was seen upon transduction with Ets2 shRNA relative to the scrambled control shRNA.	('Cxcl1', 'Gene', (57, 62))	('reduction', 'NegReg', (37, 46))	('Cxcl1', 'Gene', '14825', (57, 62))	('Cxcl2', 'Gene', '20310', (67, 72))	('Cxcl2', 'Gene', (67, 72))	('Ets2 shRNA', 'Var', (105, 115))
566286	26590320	To further test a potential autocrine role of CXCL1 and CXCL2 in SCC progression, we knocked down Cxcr2 in HRasG12VTgfbr2-null keratinocytes and injected the scrambled shRNA-transduced and Cxcr2-shRNA transduced cells into host recipient mice to form allografts.	('CXCL2', 'Gene', '20310', (56, 61))	('Tgfbr2', 'Gene', (115, 121))	('Cxcr2', 'Gene', (189, 194))	('SCC', 'Gene', (65, 68))	('Cxcr2', 'Gene', '12765', (98, 103))	('rat', 'Species', '10116', (129, 132))	('knocked', 'Var', (85, 92))	('HRas', 'Gene', '15461', (107, 111))	('CXCL1', 'Gene', '14825', (46, 51))	('CXCL2', 'Gene', (56, 61))	('HRas', 'Gene', (107, 111))	('Tgfbr2', 'Gene', '21813', (115, 121))	('Cxcr2', 'Gene', '12765', (189, 194))	('SCC', 'Gene', '6317', (65, 68))	('mice', 'Species', '10090', (238, 242))	('Cxcr2', 'Gene', (98, 103))	('CXCL1', 'Gene', (46, 51))
566320	26590320	Indeed, it was recently shown that 86% of all skin SCCs induced by classical chemical carcinogenesis with 9,10-dimethyl-1,2-benzanthracene (DMBA) involve mutations in either HRas or KRas, and KRas is markedly upregulated even in SCCs that do not directly involve oncogenic HRas transformation.	('carcinogenesis', 'Disease', (86, 100))	('9,10-dimethyl-1,2-benzanthracene', 'Chemical', 'MESH:D015127', (106, 138))	('HRas', 'Gene', (273, 277))	('SCC', 'Gene', (51, 54))	('HRas', 'Gene', '15461', (174, 178))	('upregulated', 'PosReg', (209, 220))	('HRas', 'Gene', (174, 178))	('KRas', 'Gene', (192, 196))	('DMBA', 'Chemical', 'MESH:D015127', (140, 144))	('SCC', 'Gene', '6317', (51, 54))	('SCC', 'Gene', (229, 232))	('carcinogenesis', 'Disease', 'MESH:D063646', (86, 100))	('KRas', 'Gene', '16653', (192, 196))	('KRas', 'Gene', (182, 186))	('mutations', 'Var', (154, 163))	('KRas', 'Gene', '16653', (182, 186))	('SCC', 'Gene', '6317', (229, 232))	('HRas', 'Gene', '15461', (273, 277))
566339	26590320	Indeed, when we knocked down Cxcr2, tumor growth was severely impaired.	('impaired', 'NegReg', (62, 70))	('Cxcr2', 'Gene', '12765', (29, 34))	('tumor', 'Disease', 'MESH:D009369', (36, 41))	('tumor', 'Phenotype', 'HP:0002664', (36, 41))	('Cxcr2', 'Gene', (29, 34))	('knocked down', 'Var', (16, 28))	('tumor', 'Disease', (36, 41))
566344	26590320	Of additional relevance are the mutually exclusive H3K27 modifications of SEs and PcG-silencing that provide a powerful two-way switch for the cancer-normal SC balance.	('cancer', 'Phenotype', 'HP:0002664', (143, 149))	('H3K27', 'Protein', (51, 56))	('PcG', 'Gene', (82, 85))	('SEs', 'Chemical', '-', (74, 77))	('cancer', 'Disease', (143, 149))	('modifications', 'Var', (57, 70))	('cancer', 'Disease', 'MESH:D009369', (143, 149))	('PcG', 'Gene', '57390', (82, 85))
566351	26590320	Mice were maintained in the Association for Assessment and Accreditation of Laboratory Animal Care-accredited animal facility of The Rockefeller University (RU), and procedures were performed with Institutional Animal Care and Use Committee (IACUC)-approved protocols (#13622-H, #14693-H and #14765-H).	('#13622-H', 'Var', (269, 277))	('rat', 'Species', '10116', (80, 83))	('#14765-H', 'Var', (292, 300))	('Mice', 'Species', '10090', (0, 4))	('#14693-H', 'Var', (279, 287))
566353	26590320	For adenoviral infections with Ad-Cre-GFP and Ad-GFP (1010 pfu/ml; University of Iowa, Gene Transfer Vector Core Iowa), cells were plated in 6-well dishes at 200,000 cells/well and incubated with adenovirus at a MOI of 100 in the presence of polybrene (100 mg/ml) overnight.	('adenoviral infections', 'Disease', 'MESH:D007239', (4, 25))	('adenoviral infections', 'Disease', (4, 25))	('Ad-GFP', 'Var', (46, 52))	('polybrene', 'Chemical', 'MESH:D006583', (242, 251))
566367	26590320	The following antibodies were used for FACS: Integrin alpha6-PE (1:100, BD Biosciences), Integrin beta1-APC/Cy7 (1:200, Biolegend, San Diego, CA), CD34-eFluoro660 (1:100, eBiosciences, San Diego, CA) and Sca-1-PerCP-Cy5.5 (1:100, eBiosciences) and CD11b (1:200, eBiosciences).	('Integrin beta1', 'Gene', '16412', (89, 103))	('alpha6', 'Gene', '14399', (54, 60))	('Sca-1', 'Gene', (204, 209))	('Integrin beta1', 'Gene', (89, 103))	('alpha6', 'Gene', (54, 60))	('APC', 'Disease', 'MESH:D011125', (104, 107))	('APC', 'Disease', (104, 107))	('Sca-1', 'Gene', '110454', (204, 209))	('CD34-eFluoro660', 'Var', (147, 162))
566383	26590320	Chromatin immunoprecipitations were performed as described above with FACS-sorted populations from tumors, and anti-ETS2 antibody (Santa Cruz, Dallas, TX), anti-myc antibody (Abcam) and normal rabbit IgG (Cell Signaling, Danvers, MA) were used.	('myc', 'Gene', (161, 164))	('rabbit', 'Species', '9986', (193, 199))	('myc', 'Gene', '17869', (161, 164))	('tumors', 'Disease', (99, 105))	('anti-ETS2', 'Var', (111, 120))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('tumors', 'Phenotype', 'HP:0002664', (99, 105))	('tumors', 'Disease', 'MESH:D009369', (99, 105))
566398	26590320	Tissue microarrays comprising healthy human skin samples, human skin SCCs as well as head and neck SCCs (HNSCC) were obtained from US Biomax, Rockeville, MD: SK241, SK801b, SK811a, SK2081, and HN803a.	('SK811a', 'Var', (173, 179))	('SCC', 'Gene', '6317', (99, 102))	('SK801b', 'Var', (165, 171))	('human', 'Species', '9606', (58, 63))	('SCC', 'Gene', (69, 72))	('human', 'Species', '9606', (38, 43))	('SCC', 'Gene', (107, 110))	('SK2081', 'Var', (181, 187))	('SK2081', 'CellLine', 'CVCL:K843', (181, 187))	('SCC', 'Gene', '6317', (69, 72))	('SCC', 'Gene', '6317', (107, 110))	('SK241', 'Var', (158, 163))	('SCC', 'Gene', (99, 102))
566407	26590320	We tested the knockdown efficiency of 5-10 independent shRNAs for each gene and used the following clones and target sequence: The scramble shRNA (Sigma SHC002, CAACAAGATGAAGAGCACCAA), Ets2 (TRCN0000233985, CATTGATAAAGAGCCGTTATA; TRCN0000042649, CCGTCAATGTCAATTACTGTT), Elk3 (TRCN0000042643, GCTGAGATACTATTACGACAA; TRCN0000235780, ATCAGGTTTGTGACCAATAAA; TRCN0000235783, AGAGCGCTGAGATACTATTAC), Cxcr2 (TRCN0000026605, GCCTTGAATGCTACGGAGATT; TRCN0000026647, CGTTACAATTACAGTGAGATA).	('Cxcr2', 'Gene', (394, 399))	('TRCN0000042643', 'Var', (276, 290))	('Cxcr2', 'Gene', '12765', (394, 399))	('TRCN0000042649', 'Disease', (230, 244))	('TRCN0000026605', 'Var', (401, 415))	('TRCN0000042649', 'Disease', 'None', (230, 244))
566424	26590320	Based on the bioinformatics analysis on the H3K27ac ChIP-seq data and RNA-seq data, they identified both known and new cancer stem cell specific transcription factors under the super-enhancers.	('H3K27ac', 'Var', (44, 51))	('cancer', 'Disease', 'MESH:D009369', (119, 125))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))	('cancer', 'Disease', (119, 125))
566425	26590320	They functionally studied ETS family factors by both knocking down and ORF rescue experiments, and the ETS family factors played significant roles in driving squamous cell carcinoma stem cells.	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (158, 181))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (158, 181))	('knocking', 'Var', (53, 61))	('carcinoma', 'Phenotype', 'HP:0030731', (172, 181))	('squamous cell carcinoma', 'Disease', (158, 181))
566430	26590320	But, the follow up experiments are all on the functional study of Elk3 and Ets2 in tumorigenesis by knocking down and cDNA rescue, which cannot address the initial question.	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('Elk3', 'Gene', (66, 70))	('tumor', 'Disease', (83, 88))	('knocking down', 'Var', (100, 113))	('cDNA', 'MPA', (118, 122))	('Ets2', 'Gene', (75, 79))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
566441	26590320	Reviewer #2: Major concerns: 1) The authors performed H3K27ac ChIP-seq analysis on SCC-SC in comparison with the one in HF-SC, and identified cancer stem cell specific SEs and SEs associating genes.	('cancer', 'Disease', 'MESH:D009369', (142, 148))	('SCC', 'Gene', (83, 86))	('SEs', 'Chemical', '-', (176, 179))	('cancer', 'Phenotype', 'HP:0002664', (142, 148))	('SCC', 'Gene', '6317', (83, 86))	('H3K27ac', 'Var', (54, 61))	('SEs', 'Chemical', '-', (168, 171))	('cancer', 'Disease', (142, 148))
566449	26590320	To further validate our ETS2 overexpression model, we now also added data showing that expression of phosphomimetic constitutive-active ETS2 but not wild-type ETS2 induces hyperproliferation and marked epidermal thickening and invaginations.	('expression', 'Var', (87, 97))	('induces', 'Reg', (164, 171))	('rat', 'Species', '10116', (184, 187))	('epidermal thickening', 'Phenotype', 'HP:0011368', (202, 222))	('ETS2', 'Gene', (136, 140))	('hyperproliferation', 'CPA', (172, 190))
566513	32158625	A TP53-associated gene signature for prediction of prognosis and therapeutic responses in lung squamous cell carcinoma The tumor-suppressor gene tumor protein p53 (TP53) is one of the most commonly mutated genes in human lung cancer, and TP53 mutations are associated with a worsened prognosis and causes resistance to cancer therapy.	('p53', 'Gene', '7157', (159, 162))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (95, 118))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (90, 118))	('lung squamous cell carcinoma', 'Disease', (90, 118))	('cancer', 'Disease', (319, 325))	('TP53', 'Gene', '7157', (2, 6))	('lung cancer', 'Disease', (221, 232))	('cancer', 'Phenotype', 'HP:0002664', (319, 325))	('TP53', 'Gene', (164, 168))	('tumor', 'Disease', (123, 128))	('p53', 'Gene', (159, 162))	('tumor', 'Disease', (145, 150))	('TP53', 'Gene', '7157', (238, 242))	('cancer', 'Disease', 'MESH:D009369', (226, 232))	('tumor', 'Disease', 'MESH:D009369', (123, 128))	('human', 'Species', '9606', (215, 220))	('tumor', 'Disease', 'MESH:D009369', (145, 150))	('lung cancer', 'Disease', 'MESH:D008175', (221, 232))	('mutations', 'Var', (243, 252))	('cancer', 'Disease', 'MESH:D009369', (319, 325))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('lung cancer', 'Phenotype', 'HP:0100526', (221, 232))	('TP53', 'Gene', (2, 6))	('tumor', 'Phenotype', 'HP:0002664', (123, 128))	('TP53', 'Gene', '7157', (164, 168))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (90, 118))	('associated', 'Reg', (257, 267))	('tumor', 'Phenotype', 'HP:0002664', (145, 150))	('prognosis', 'CPA', (284, 293))	('causes', 'Reg', (298, 304))	('cancer', 'Disease', (226, 232))	('TP53', 'Gene', (238, 242))	('cancer', 'Phenotype', 'HP:0002664', (226, 232))
566514	32158625	RNA sequencing and TP53 mutation data were downloaded to determine specific TP53-associated signature based on differentially expressed genes between patients with lung squamous cell carcinoma (LUSC) with wild type (TP53 WT) and mutated (TP53MUT) TP53.	('mutated', 'Var', (229, 236))	('patients', 'Species', '9606', (150, 158))	('carcinoma', 'Phenotype', 'HP:0030731', (183, 192))	('TP53', 'Gene', '7157', (238, 242))	('TP53', 'Gene', (76, 80))	('TP53', 'Gene', (19, 23))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (164, 192))	('TP53', 'Gene', (216, 220))	('TP53', 'Gene', (247, 251))	('LUSC', 'Disease', (194, 198))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (169, 192))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (164, 192))	('lung squamous cell carcinoma', 'Disease', (164, 192))	('TP53', 'Gene', '7157', (76, 80))	('LUSC', 'Disease', 'MESH:D002294', (194, 198))	('LUSC', 'Phenotype', 'HP:0030359', (194, 198))	('TP53', 'Gene', '7157', (19, 23))	('TP53', 'Gene', '7157', (216, 220))	('TP53', 'Gene', '7157', (247, 251))	('TP53', 'Gene', (238, 242))
566516	32158625	In total, 1,556 differentially expressed genes were identified based on TP53 mutation status.	('TP53', 'Gene', (72, 76))	('mutation', 'Var', (77, 85))	('TP53', 'Gene', '7157', (72, 76))
566533	32158625	However, when mutated, loss of these functions results in abnormal cell proliferation and promotes cancer.	('mutated', 'Var', (14, 21))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('abnormal cell proliferation', 'Phenotype', 'HP:0031377', (58, 85))	('cancer', 'Disease', (99, 105))	('loss', 'NegReg', (23, 27))	('promotes', 'PosReg', (90, 98))	('cell proliferation', 'CPA', (67, 85))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))
566534	32158625	TP53 mutations, mainly missense mutations, are also the most common mutations in NSCLC, and are more prevalent in LUSC than in LUAD.	('missense mutations', 'Var', (23, 41))	('prevalent', 'Reg', (101, 110))	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('LUAD', 'Disease', 'MESH:D000077192', (127, 131))	('NSCLC', 'Phenotype', 'HP:0030358', (81, 86))	('LUSC', 'Phenotype', 'HP:0030359', (114, 118))	('mutations', 'Var', (5, 14))	('LUSC', 'Disease', 'MESH:D002294', (114, 118))	('LUSC', 'Disease', (114, 118))	('NSCLC', 'Disease', (81, 86))	('LUAD', 'Disease', (127, 131))	('NSCLC', 'Disease', 'MESH:D002289', (81, 86))	('LUAD', 'Phenotype', 'HP:0030078', (127, 131))
566535	32158625	Epidemiological studies have reported that TP53 mutations are closely related to smoking, and it occurring more frequently in patients with tobacco-associated lung cancer than in never-smokers.	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('lung cancer', 'Disease', 'MESH:D008175', (159, 170))	('tobacco', 'Species', '4097', (140, 147))	('lung cancer', 'Disease', (159, 170))	('patients', 'Species', '9606', (126, 134))	('lung cancer', 'Phenotype', 'HP:0100526', (159, 170))	('TP53', 'Gene', '7157', (43, 47))	('TP53', 'Gene', (43, 47))	('mutations', 'Var', (48, 57))
566536	32158625	An increasing body of literature suggests that TP53 mutations in lung cancer are associated with increased resistance to cancer therapies and poorer survival prognosis.	('mutations', 'Var', (52, 61))	('lung cancer', 'Disease', 'MESH:D008175', (65, 76))	('increased', 'PosReg', (97, 106))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('resistance to', 'CPA', (107, 120))	('lung cancer', 'Disease', (65, 76))	('lung cancer', 'Phenotype', 'HP:0100526', (65, 76))	('TP53', 'Gene', '7157', (47, 51))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('cancer', 'Disease', (121, 127))	('TP53', 'Gene', (47, 51))
566537	32158625	In addition, TP53 mutations are associated with higher vascular endothelial growth factor (VEGF) synthesis and angiogenesis.	('VEGF', 'Gene', '7422', (91, 95))	('angiogenesis', 'CPA', (111, 123))	('TP53', 'Gene', (13, 17))	('higher', 'PosReg', (48, 54))	('VEGF', 'Gene', (91, 95))	('vascular endothelial growth factor', 'Gene', (55, 89))	('TP53', 'Gene', '7157', (13, 17))	('vascular endothelial growth factor', 'Gene', '7422', (55, 89))	('mutations', 'Var', (18, 27))
566538	32158625	Recently, TP53 mutation status was associated with cancer-related microenvironment.	('mutation', 'Var', (15, 23))	('TP53', 'Gene', (10, 14))	('associated', 'Reg', (35, 45))	('cancer', 'Phenotype', 'HP:0002664', (51, 57))	('cancer', 'Disease', (51, 57))	('cancer', 'Disease', 'MESH:D009369', (51, 57))	('TP53', 'Gene', '7157', (10, 14))
566539	32158625	We hypothesized that the overall survival of patients with LUSC harboring TP53 mutations might be particularly influenced by the lung cancer microenvironment.	('lung cancer', 'Disease', (129, 140))	('lung cancer', 'Phenotype', 'HP:0100526', (129, 140))	('LUSC', 'Phenotype', 'HP:0030359', (59, 63))	('TP53', 'Gene', '7157', (74, 78))	('lung cancer', 'Disease', 'MESH:D008175', (129, 140))	('LUSC', 'Disease', 'MESH:D002294', (59, 63))	('patients', 'Species', '9606', (45, 53))	('cancer', 'Phenotype', 'HP:0002664', (134, 140))	('TP53', 'Gene', (74, 78))	('influenced', 'Reg', (111, 121))	('mutations', 'Var', (79, 88))	('LUSC', 'Disease', (59, 63))
566540	32158625	Therefore, we identified genes affected by TP53 mutation status, and established a three-gene gene signature that is a robust prognostic biomarker and predictive factor that can be used in the clinic.	('TP53', 'Gene', '7157', (43, 47))	('TP53', 'Gene', (43, 47))	('mutation', 'Var', (48, 56))	('affected', 'Reg', (31, 39))
566544	32158625	To obtain DEGs between patients with (n = 388) and without (n = 100) TP53 mutations in the TCGA LUSC cohort, the R package "edgeR" was used in the standard comparison mode.	('LUSC', 'Disease', 'MESH:D002294', (96, 100))	('LUSC', 'Disease', (96, 100))	('LUSC', 'Phenotype', 'HP:0030359', (96, 100))	('TP53', 'Gene', '7157', (69, 73))	('patients', 'Species', '9606', (23, 31))	('TP53', 'Gene', (69, 73))	('mutations', 'Var', (74, 83))
566545	32158625	To identify potential differences in biological functions between LUSC patients with and without TP53 mutations, GSEA annotation was performed using the R package "clusterProfiler".	('LUSC', 'Disease', 'MESH:D002294', (66, 70))	('LUSC', 'Phenotype', 'HP:0030359', (66, 70))	('differences', 'Reg', (22, 33))	('TP53', 'Gene', '7157', (97, 101))	('LUSC', 'Disease', (66, 70))	('patients', 'Species', '9606', (71, 79))	('TP53', 'Gene', (97, 101))	('mutations', 'Var', (102, 111))	('GSEA', 'Chemical', '-', (113, 117))
566564	32158625	According to TCGA, TP53 mutations were the most frequent, and were more prevalent in LUSC than LUAD (77% vs. 47%; Figure 1).	('LUAD', 'Phenotype', 'HP:0030078', (95, 99))	('LUAD', 'Disease', 'MESH:D000077192', (95, 99))	('TP53', 'Gene', '7157', (19, 23))	('TP53', 'Gene', (19, 23))	('LUSC', 'Phenotype', 'HP:0030359', (85, 89))	('mutations', 'Var', (24, 33))	('LUSC', 'Disease', 'MESH:D002294', (85, 89))	('LUSC', 'Disease', (85, 89))	('LUAD', 'Disease', (95, 99))	('prevalent', 'Reg', (72, 81))
566565	32158625	We also identified LUSC mutations in the ICGA database.	('LUSC', 'Disease', (19, 23))	('mutations', 'Var', (24, 33))	('LUSC', 'Phenotype', 'HP:0030359', (19, 23))	('LUSC', 'Disease', 'MESH:D002294', (19, 23))
566567	32158625	The high rate of TP53 mutations indicated that TP53 status was closely linked to LUSC.	('linked', 'Reg', (71, 77))	('mutations', 'Var', (22, 31))	('TP53', 'Gene', '7157', (47, 51))	('LUSC', 'Disease', 'MESH:D002294', (81, 85))	('LUSC', 'Phenotype', 'HP:0030359', (81, 85))	('TP53', 'Gene', '7157', (17, 21))	('TP53', 'Gene', (47, 51))	('TP53', 'Gene', (17, 21))	('LUSC', 'Disease', (81, 85))
566568	32158625	TP53 mutation status is a well-known clinically relevant molecular marker in lung cancer.	('lung cancer', 'Phenotype', 'HP:0100526', (77, 88))	('TP53', 'Gene', '7157', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('TP53', 'Gene', (0, 4))	('lung cancer', 'Disease', 'MESH:D008175', (77, 88))	('clinical', 'Species', '191496', (37, 45))	('mutation', 'Var', (5, 13))	('lung cancer', 'Disease', (77, 88))
566577	32158625	Consistent with the prognostic capacity of the three-gene signature, TP53 mutation status was also significantly correlated with the prognosis of patients with LUSC (Figure 4(a)).	('mutation', 'Var', (74, 82))	('TP53', 'Gene', '7157', (69, 73))	('TP53', 'Gene', (69, 73))	('LUSC', 'Disease', 'MESH:D002294', (160, 164))	('LUSC', 'Disease', (160, 164))	('LUSC', 'Phenotype', 'HP:0030359', (160, 164))	('correlated', 'Reg', (113, 123))	('patients', 'Species', '9606', (146, 154))
566581	32158625	To explore whether the three-gene signature was independent of TP53 mutation type, we performed prognostic analysis of the largest subgroup, which contained TP53 missense mutations.	('TP53', 'Gene', (157, 161))	('TP53', 'Gene', '7157', (63, 67))	('TP53', 'Gene', (63, 67))	('missense mutations', 'Var', (162, 180))	('TP53', 'Gene', '7157', (157, 161))
566582	32158625	Interestingly, the three-gene signature played a negative role, with high expression of these genes shortening the overall survival of patients with LUSC (Figure 4(e)).	('patients', 'Species', '9606', (135, 143))	('shortening', 'NegReg', (100, 110))	('LUSC', 'Disease', 'MESH:D002294', (149, 153))	('LUSC', 'Disease', (149, 153))	('LUSC', 'Phenotype', 'HP:0030359', (149, 153))	('high expression', 'Var', (69, 84))
566600	32158625	However, the mechanisms by which TP53 mutation affects the microenvironment and lung cancer prognosis.	('lung cancer', 'Disease', 'MESH:D008175', (80, 91))	('affects', 'Reg', (47, 54))	('microenvironment', 'MPA', (59, 75))	('TP53', 'Gene', '7157', (33, 37))	('lung cancer', 'Disease', (80, 91))	('lung cancer', 'Phenotype', 'HP:0100526', (80, 91))	('mutation', 'Var', (38, 46))	('TP53', 'Gene', (33, 37))	('cancer', 'Phenotype', 'HP:0002664', (85, 91))
566602	32158625	For the first time, this study has identified immune-related genes affected by TP53 mutation status, providing novel prognostic biomarkers and therapeutic targets for LUSC.	('TP53', 'Gene', '7157', (79, 83))	('affected', 'Reg', (67, 75))	('TP53', 'Gene', (79, 83))	('mutation status', 'Var', (84, 99))	('LUSC', 'Disease', 'MESH:D002294', (167, 171))	('LUSC', 'Disease', (167, 171))	('LUSC', 'Phenotype', 'HP:0030359', (167, 171))
566603	32158625	Generally, patients in the TP53 mutation group had worse clinical outcomes.	('TP53', 'Gene', '7157', (27, 31))	('TP53', 'Gene', (27, 31))	('clinical', 'Species', '191496', (57, 65))	('patients', 'Species', '9606', (11, 19))	('mutation', 'Var', (32, 40))
566609	32158625	PD-1 is a central regulator of T cells CD8 exhaustion and blockade of this inhibitory pathway enhances T cell immunity in several different types of cancers.	('T cell immunity', 'CPA', (103, 118))	('enhances', 'PosReg', (94, 102))	('cancers', 'Disease', (149, 156))	('CD8', 'Gene', (39, 42))	('CD8', 'Gene', '925', (39, 42))	('cancers', 'Phenotype', 'HP:0002664', (149, 156))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('blockade', 'Var', (58, 66))	('cancers', 'Disease', 'MESH:D009369', (149, 156))
566623	32158625	The three-gene signature could even distinguish the prognoses of patients with LUSC with different types of TP53 mutations.	('LUSC', 'Phenotype', 'HP:0030359', (79, 83))	('TP53', 'Gene', '7157', (108, 112))	('LUSC', 'Disease', (79, 83))	('TP53', 'Gene', (108, 112))	('mutations', 'Var', (113, 122))	('patients', 'Species', '9606', (65, 73))	('LUSC', 'Disease', 'MESH:D002294', (79, 83))
566627	32158625	Overall, for the first time, this study identifies a three-gene signature associated with TP53 mutation status that can independently predict the survival of patients with LUSC.	('LUSC', 'Disease', 'MESH:D002294', (172, 176))	('LUSC', 'Disease', (172, 176))	('LUSC', 'Phenotype', 'HP:0030359', (172, 176))	('TP53', 'Gene', '7157', (90, 94))	('TP53', 'Gene', (90, 94))	('predict', 'Reg', (134, 141))	('patients', 'Species', '9606', (158, 166))	('mutation', 'Var', (95, 103))
566634	31726654	In vivo and similar to cisplatin treatment, Sal-B significantly reduced tumor volume and increased the median survival when compared to tumor positive control mice group injected with Ehrlich solid carcinoma cell line (ESC).	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('tumor', 'Disease', (72, 77))	('median survival', 'CPA', (103, 118))	('carcinoma', 'Phenotype', 'HP:0030731', (198, 207))	('Sal-B', 'Chemical', 'MESH:C076944', (44, 49))	('tumor', 'Disease', 'MESH:D009369', (136, 141))	('Sal-B', 'Var', (44, 49))	('tumor', 'Phenotype', 'HP:0002664', (136, 141))	('cisplatin', 'Chemical', 'MESH:D002945', (23, 32))	('reduced', 'NegReg', (64, 71))	('mice', 'Species', '10090', (159, 163))	('Ehrlich solid carcinoma', 'Disease', (184, 207))	('increased', 'PosReg', (89, 98))	('tumor', 'Disease', 'MESH:D009369', (72, 77))	('tumor', 'Disease', (136, 141))	('Ehrlich solid carcinoma', 'Disease', 'MESH:D002286', (184, 207))
566659	31726654	Cisplatin provides its anticancer effect via crosslinking DNA and interfering with mitotic cell division.	('DNA', 'Protein', (58, 61))	('interfering', 'NegReg', (66, 77))	('crosslinking', 'Var', (45, 57))	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('Cisplatin', 'Chemical', 'MESH:D002945', (0, 9))	('mitotic cell division', 'CPA', (83, 104))	('cancer', 'Disease', (27, 33))	('cancer', 'Disease', 'MESH:D009369', (27, 33))
566723	31726654	Overall, these data suggest that modulating levels of ROS contributes to anticancer effect of Sal-B.	('Sal-B', 'Chemical', 'MESH:C076944', (94, 99))	('modulating', 'Var', (33, 43))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('ROS', 'Protein', (54, 57))
566759	31726654	Overexpression of COX-2 in oral mucosa has been shown to be associated with the increased risk of head and neck squamous cell carcinoma 13.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (112, 135))	('head and neck squamous cell carcinoma', 'Phenotype', 'HP:0012288', (98, 135))	('COX-2', 'Gene', '17709', (18, 23))	('Overexpression', 'Var', (0, 14))	('head and neck squamous cell carcinoma', 'Disease', 'MESH:C535575', (98, 135))	('carcinoma', 'Phenotype', 'HP:0030731', (126, 135))	('COX-2', 'Gene', (18, 23))	('associated', 'Reg', (60, 70))
566801	29484121	At the single cell level, we detected unique clonal mutation patterns for each of the two LUSC tumors, being initiated from clones carrying the mutant Igfbp7 and Trp53 genes, respectively.	('LUSC tumors', 'Disease', (90, 101))	('LUSC', 'Phenotype', 'HP:0030359', (90, 94))	('tumors', 'Phenotype', 'HP:0002664', (95, 101))	('Trp53', 'Gene', (162, 167))	('Igfbp7', 'Gene', (151, 157))	('Trp53', 'Gene', '22059', (162, 167))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('mutant', 'Var', (144, 150))	('Igfbp7', 'Gene', '29817', (151, 157))	('LUSC tumors', 'Disease', 'MESH:D009369', (90, 101))
566803	29484121	Lastly, we found that some of the mutant LUSC genes were associated with the significantly altered tumoral expression of inhibitory immune checkpoint genes such as PD-L1, VISTA, TIM3 and LAG3 in human LUSCs.	('tumor', 'Disease', (99, 104))	('TIM3', 'Gene', (178, 182))	('human', 'Species', '9606', (195, 200))	('LUSC', 'Phenotype', 'HP:0030359', (201, 205))	('LUSC genes', 'Gene', (41, 51))	('altered', 'Reg', (91, 98))	('tumor', 'Disease', 'MESH:D009369', (99, 104))	('PD-L1', 'Gene', (164, 169))	('tumor', 'Phenotype', 'HP:0002664', (99, 104))	('LUSC', 'Phenotype', 'HP:0030359', (41, 45))	('mutant', 'Var', (34, 40))	('associated', 'Reg', (57, 67))
566815	29484121	The 16 mouse LUSCs harbored 5,664 somatic coding mutations (mean = 354) that consisted of 2,885 missense, 106 nonsense, 2,426 silent mutations, 167 small insertions and deletions (indels) and 80 alterations residing in exon-exon boundaries (Supplementary Table 2 [Excel File]).	('missense', 'Var', (96, 104))	('deletions', 'Var', (169, 178))	('mouse', 'Species', '10090', (7, 12))	('LUSC', 'Phenotype', 'HP:0030359', (13, 17))	('nonsense', 'Var', (110, 118))
566828	29484121	Single-cell analysis by scRNA-seq was used to characterize the nonsilent somatic mutations in two mouse LUSC tumors, with a specific focus on the known cancer genes or the mutated genes identified by our exome-seq of mouse LUSC tumors.	('LUSC', 'Phenotype', 'HP:0030359', (104, 108))	('cancer', 'Disease', (152, 158))	('mouse', 'Species', '10090', (217, 222))	('LUSC tumors', 'Disease', (104, 115))	('cancer', 'Disease', 'MESH:D009369', (152, 158))	('tumors', 'Phenotype', 'HP:0002664', (109, 115))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('LUSC tumors', 'Disease', 'MESH:D009369', (223, 234))	('tumors', 'Phenotype', 'HP:0002664', (228, 234))	('mutations', 'Var', (81, 90))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('tumor', 'Phenotype', 'HP:0002664', (109, 114))	('mouse', 'Species', '10090', (98, 103))	('LUSC tumors', 'Disease', 'MESH:D009369', (104, 115))	('LUSC tumors', 'Disease', (223, 234))	('LUSC', 'Phenotype', 'HP:0030359', (223, 227))
566832	29484121	The details of the cancer gene mutations of the two mouse LUSC tumors can be seen in Supplementary Table 4.	('mutations', 'Var', (31, 40))	('LUSC', 'Phenotype', 'HP:0030359', (58, 62))	('cancer', 'Disease', 'MESH:D009369', (19, 25))	('mouse', 'Species', '10090', (52, 57))	('cancer', 'Disease', (19, 25))	('tumors', 'Phenotype', 'HP:0002664', (63, 69))	('LUSC tumors', 'Disease', 'MESH:D009369', (58, 69))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))	('LUSC tumors', 'Disease', (58, 69))
566834	29484121	For LUSC1, all the single tumor cells had the clonal mutation (R45P) in Igfbp7 and a subset of single tumor cells had the mutation (R2457S) in Igf2r (Figure 3A).	('Igfbp7', 'Gene', (72, 78))	('LUSC', 'Phenotype', 'HP:0030359', (4, 8))	('Igf2r', 'Gene', (143, 148))	('R45P', 'Mutation', 'p.R45P', (63, 67))	('R45P', 'Var', (63, 67))	('tumor', 'Disease', 'MESH:D009369', (26, 31))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('R2457S', 'Mutation', 'p.R2457S', (132, 138))	('tumor', 'Phenotype', 'HP:0002664', (26, 31))	('tumor', 'Disease', (26, 31))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('R2457S', 'Var', (132, 138))	('Igfbp7', 'Gene', '29817', (72, 78))
566836	29484121	In addition, the genes having somatic mutations in LUSC1 involve a number of transcription regulators such as Ahctf1, Notch4, Ncoa3, Nfe2l2 (Figure 3A).	('LUSC', 'Phenotype', 'HP:0030359', (51, 55))	('Notch4', 'Gene', (118, 124))	('Ncoa3', 'Gene', (126, 131))	('LUSC1', 'Gene', (51, 56))	('Ahctf1', 'Gene', (110, 116))	('Nfe2l2', 'Gene', (133, 139))	('involve', 'Reg', (57, 64))	('Notch4', 'Gene', '18132', (118, 124))	('mutations', 'Var', (38, 47))	('Ahctf1', 'Gene', '226747', (110, 116))	('Nfe2l2', 'Gene', '18024', (133, 139))
566837	29484121	The scRNA-seq of LUSC2 identified a Trp53 somatic missense mutation (Q97L) in all the tumor cells (Figure 3B).	('tumor', 'Phenotype', 'HP:0002664', (86, 91))	('LUSC', 'Phenotype', 'HP:0030359', (17, 21))	('Trp53', 'Gene', '22059', (36, 41))	('tumor', 'Disease', (86, 91))	('Q97L', 'Var', (69, 73))	('Q97L', 'Mutation', 'p.Q97L', (69, 73))	('Trp53', 'Gene', (36, 41))	('tumor', 'Disease', 'MESH:D009369', (86, 91))
566849	29484121	The risk group hazard ratio (HR) based on G80 module expression in the TCGA LUSC cohort was 10.2 (P = 1.7E-14), which was much greater than the HR values of the other three NSCLC cohorts (HR = 3.3, 3.5, 4.4, Figure 8).	('NSCLC', 'Phenotype', 'HP:0030358', (173, 178))	('LUSC', 'Phenotype', 'HP:0030359', (76, 80))	('NSCLC', 'Disease', (173, 178))	('NSCLC', 'Disease', 'MESH:D002289', (173, 178))	('G80 module', 'Var', (42, 52))
566855	29484121	The suppressed tumoral PD-L1 expression was significantly associated with mutations in eight genes (Figure 9, Supplementary Table 5): HIVEP3 (P = 2.8E-11), NKAIN2 (P = 2.9E-11), RUNX2 (P = 2.5E-09), MUC4(P = 2.3E-06), CUX1 (P = 9.0E-06), NIPBL (P = 6.1E-05), PLAGL2 (P = 0.0001), and NFE2L2 (P = 0.019).	('tumoral PD-L1', 'Disease', 'MESH:D010300', (15, 28))	('NKAIN2', 'Gene', '432450', (156, 162))	('RUNX2', 'Gene', (178, 183))	('NFE2L2', 'Gene', (284, 290))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('tumoral PD-L1', 'Disease', (15, 28))	('mutations', 'Var', (74, 83))	('PLAGL2', 'Gene', (259, 265))	('CUX1', 'Gene', (218, 222))	('suppressed', 'NegReg', (4, 14))	('CUX1', 'Gene', '13047', (218, 222))	('NKAIN2', 'Gene', (156, 162))	('NIPBL', 'Gene', '71175', (238, 243))	('NIPBL', 'Gene', (238, 243))	('RUNX2', 'Gene', '12393', (178, 183))	('expression', 'MPA', (29, 39))	('PLAGL2', 'Gene', '54711', (259, 265))
566856	29484121	The mutant NFE2L2 was associated with increased tumoral PD-L1 expression while the other seven mutant genes associated with decreased PD-L1 expression.	('tumor', 'Phenotype', 'HP:0002664', (48, 53))	('tumoral PD-L1', 'Disease', (48, 61))	('expression', 'MPA', (140, 150))	('mutant', 'Var', (4, 10))	('expression', 'MPA', (62, 72))	('decreased', 'NegReg', (124, 133))	('tumoral PD-L1', 'Disease', 'MESH:D010300', (48, 61))	('decreased PD', 'Phenotype', 'HP:0032198', (124, 136))	('NFE2L2', 'Gene', (11, 17))	('increased', 'PosReg', (38, 47))
566857	29484121	The tumoral VISTA expression was significantly decreased in the LUSCs with mutations in the KEAP1 (P = 0.0005), FANCA (P = 0.0076), and AFF3 (P = 0.008) genes while increased in the LUSCs with the mutant FLT1 gene (P = 0.02).	('tumor', 'Disease', (4, 9))	('AFF3', 'Gene', (136, 140))	('KEAP1', 'Gene', (92, 97))	('AFF3', 'Gene', '16764', (136, 140))	('LUSC', 'Phenotype', 'HP:0030359', (182, 186))	('FANCA', 'Gene', '14087', (112, 117))	('FANCA', 'Gene', (112, 117))	('FLT1', 'Gene', (204, 208))	('LUSC', 'Phenotype', 'HP:0030359', (64, 68))	('tumor', 'Disease', 'MESH:D009369', (4, 9))	('expression', 'MPA', (18, 28))	('mutations', 'Var', (75, 84))	('tumor', 'Phenotype', 'HP:0002664', (4, 9))	('increased', 'PosReg', (165, 174))	('decreased', 'NegReg', (47, 56))
566858	29484121	Moreover, tumoral TIM3 was significantly decreased in the mutant RET (P = 4.2E-10), FANCA (P = 0.0007), or ZMYND8 (P = 0.028) LUSC tumors while increased in the mutant DYNC1H1 (P = 0.027) LUSC tumors.	('mutant', 'Var', (58, 64))	('LUSC tumors', 'Disease', 'MESH:D009369', (188, 199))	('tumor', 'Disease', (131, 136))	('LUSC tumors', 'Disease', 'MESH:D009369', (126, 137))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('ZMYND8', 'Gene', (107, 113))	('tumor', 'Disease', (10, 15))	('decreased', 'NegReg', (41, 50))	('tumors', 'Phenotype', 'HP:0002664', (131, 137))	('RET', 'Gene', (65, 68))	('LUSC tumors', 'Disease', (188, 199))	('LUSC', 'Phenotype', 'HP:0030359', (188, 192))	('ZMYND8', 'Gene', '228880', (107, 113))	('tumor', 'Disease', (193, 198))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('LUSC', 'Phenotype', 'HP:0030359', (126, 130))	('LUSC tumors', 'Disease', (126, 137))	('FANCA', 'Gene', '14087', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('tumor', 'Disease', 'MESH:D009369', (193, 198))	('tumors', 'Phenotype', 'HP:0002664', (193, 199))	('increased', 'PosReg', (144, 153))	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('FANCA', 'Gene', (84, 89))	('tumor', 'Phenotype', 'HP:0002664', (193, 198))	('RET', 'Gene', '19713', (65, 68))
566859	29484121	The suppressed tumoral LAG3 expression was significantly associated with mutations in CUX1 (P = 6.9E-07), FANCA (P = 0.0005) or NOTCH4 (P = 0.028) genes.	('NOTCH4', 'Gene', (128, 134))	('tumor', 'Disease', 'MESH:D009369', (15, 20))	('CUX1', 'Gene', (86, 90))	('CUX1', 'Gene', '13047', (86, 90))	('expression', 'MPA', (28, 38))	('LAG3', 'Gene', (23, 27))	('tumor', 'Phenotype', 'HP:0002664', (15, 20))	('FANCA', 'Gene', '14087', (106, 111))	('suppressed', 'NegReg', (4, 14))	('tumor', 'Disease', (15, 20))	('FANCA', 'Gene', (106, 111))	('NOTCH4', 'Gene', '18132', (128, 134))	('mutations', 'Var', (73, 82))
566861	29484121	These data suggested that aberrant immune checkpoint gene expression could have significant impact on the survival outcome of LUSC patients.	('survival outcome', 'CPA', (106, 122))	('LUSC', 'Disease', (126, 130))	('patients', 'Species', '9606', (131, 139))	('aberrant', 'Var', (26, 34))	('aberrant immune checkpoint', 'Phenotype', 'HP:0002958', (26, 52))	('impact', 'Reg', (92, 98))	('LUSC', 'Phenotype', 'HP:0030359', (126, 130))	('immune checkpoint gene', 'Gene', (35, 57))
566866	29484121	BRAF mutated lung cancer is a genetically distinct subtype that accounts for about 5% of NSCLC.	('NSCLC', 'Disease', 'MESH:D002289', (89, 94))	('lung cancer', 'Disease', (13, 24))	('lung cancer', 'Phenotype', 'HP:0100526', (13, 24))	('NSCLC', 'Phenotype', 'HP:0030358', (89, 94))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('lung cancer', 'Disease', 'MESH:D008175', (13, 24))	('NSCLC', 'Disease', (89, 94))	('BRAF mutated', 'Var', (0, 12))
566870	29484121	The functional FLT1 variant and FLT1 mRNA expression are prognostic determinants of patient survival and recurrence in stage I-III NSCLC.	('stage I-III NSCLC', 'Disease', (119, 136))	('FLT1', 'Gene', (32, 36))	('FLT1', 'Gene', (15, 19))	('NSCLC', 'Phenotype', 'HP:0030358', (131, 136))	('variant', 'Var', (20, 27))	('patient', 'Species', '9606', (84, 91))
566871	29484121	ATR encoded protein kinase is a master regulator of the DNA-damage response and its genetic alteration was associated with lung cancer risk.	('lung cancer', 'Disease', (123, 134))	('protein kinase', 'Gene', '53859', (12, 26))	('associated', 'Reg', (107, 117))	('lung cancer', 'Phenotype', 'HP:0100526', (123, 134))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('lung cancer', 'Disease', 'MESH:D008175', (123, 134))	('genetic alteration', 'Var', (84, 102))	('protein kinase', 'Gene', (12, 26))
566886	29484121	IL2RB gene variants have been associated with human lung cancer risk in a large patient population.	('associated', 'Reg', (30, 40))	('IL2RB', 'Gene', (0, 5))	('lung cancer', 'Disease', 'MESH:D008175', (52, 63))	('variants', 'Var', (11, 19))	('lung cancer', 'Disease', (52, 63))	('human', 'Species', '9606', (46, 51))	('lung cancer', 'Phenotype', 'HP:0100526', (52, 63))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('IL2RB', 'Gene', '3560', (0, 5))	('patient', 'Species', '9606', (80, 87))
566889	29484121	A tumor typically arises from a single progenitor cell whose founder mutation gives it a growth advantage over the surrounding cells and helps it to evade the immune response.	('tumor', 'Disease', 'MESH:D009369', (2, 7))	('tumor', 'Phenotype', 'HP:0002664', (2, 7))	('evade', 'NegReg', (149, 154))	('mutation', 'Var', (69, 77))	('tumor', 'Disease', (2, 7))	('growth advantage', 'CPA', (89, 105))
566890	29484121	The mouse LUSC1 tumor was initiated from clonal cells having a mutant Igfbp7 gene, which may lead to an aberrant Igf-Igfr-Igfbp axis that is an important driver of cancer.	('mouse', 'Species', '10090', (4, 9))	('Igfbp7', 'Gene', '29817', (70, 76))	('Igfbp', 'Gene', '3490;29817', (122, 127))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('mutant', 'Var', (63, 69))	('tumor', 'Disease', 'MESH:D009369', (16, 21))	('Igfbp', 'Gene', (122, 127))	('Igfbp', 'Gene', '3490;29817', (70, 75))	('tumor', 'Phenotype', 'HP:0002664', (16, 21))	('Igfbp', 'Gene', (70, 75))	('cancer', 'Disease', (164, 170))	('cancer', 'Disease', 'MESH:D009369', (164, 170))	('LUSC', 'Phenotype', 'HP:0030359', (10, 14))	('tumor', 'Disease', (16, 21))	('lead to', 'Reg', (93, 100))	('Igfbp7', 'Gene', (70, 76))
566891	29484121	Igfbp7 is a tumor suppressor gene inactivated in lung cancer by DNA hypermethylation and it is regulated by p53.	('Igfbp7', 'Gene', '29817', (0, 6))	('lung cancer', 'Disease', 'MESH:D008175', (49, 60))	('DNA hypermethylation', 'Var', (64, 84))	('tumor', 'Disease', 'MESH:D009369', (12, 17))	('lung cancer', 'Disease', (49, 60))	('tumor', 'Phenotype', 'HP:0002664', (12, 17))	('lung cancer', 'Phenotype', 'HP:0100526', (49, 60))	('tumor', 'Disease', (12, 17))	('Igfbp7', 'Gene', (0, 6))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))
566892	29484121	Aberrant methylation and downregulation of IGFBP7 were frequently observed in NSCLCs.	('observed', 'Reg', (66, 74))	('Aberrant', 'Var', (0, 8))	('NSCLC', 'Phenotype', 'HP:0030358', (78, 83))	('IGFBP7', 'Gene', (43, 49))	('NSCLC', 'Disease', (78, 83))	('methylation', 'MPA', (9, 20))	('downregulation', 'NegReg', (25, 39))	('IGFBP7', 'Gene', '29817', (43, 49))	('NSCLC', 'Disease', 'MESH:D002289', (78, 83))
566893	29484121	Our findings provided evidence indicating that non-silent somatic mutations in IGFBP7 could be the important driver alteration leading to LUSCs.	('LUSC', 'Phenotype', 'HP:0030359', (138, 142))	('IGFBP7', 'Gene', (79, 85))	('IGFBP7', 'Gene', '29817', (79, 85))	('LUSCs', 'Disease', (138, 143))	('non-silent somatic mutations', 'Var', (47, 75))
566895	29484121	Mutations in NFE2L2 could cause the excessive intracellular accumulation of NFE2L2 protein and the subsequent activation of downstream oncogenes resulting in tumor growth promotion.	('tumor', 'Disease', (158, 163))	('cause', 'Reg', (26, 31))	('activation', 'PosReg', (110, 120))	('protein', 'Protein', (83, 90))	('NFE2L2', 'Gene', (13, 19))	('Mutations', 'Var', (0, 9))	('intracellular accumulation', 'MPA', (46, 72))	('tumor', 'Disease', 'MESH:D009369', (158, 163))	('NFE2L2', 'Gene', (76, 82))	('tumor', 'Phenotype', 'HP:0002664', (158, 163))
566896	29484121	For LUSC2, the founder clone was driven by mutant Trp53, the mouse homolog of the human TP53 gene that is a well known driver gene frequently mutated in the human LUSCs.	('Trp53', 'Gene', '22059', (50, 55))	('LUSC', 'Phenotype', 'HP:0030359', (163, 167))	('mutant', 'Var', (43, 49))	('mouse', 'Species', '10090', (61, 66))	('Trp53', 'Gene', (50, 55))	('LUSC', 'Phenotype', 'HP:0030359', (4, 8))	('human', 'Species', '9606', (157, 162))	('human', 'Species', '9606', (82, 87))
566897	29484121	In addition, a number of driver genes, such as Myh9, Kmt2d and Keap1, accumulated mutations in the subclones of LUSC2.	('Keap1', 'Gene', (63, 68))	('mutations', 'Var', (82, 91))	('LUSC', 'Phenotype', 'HP:0030359', (112, 116))	('Keap1', 'Gene', '50868', (63, 68))	('LUSC2', 'Gene', (112, 117))	('accumulated', 'PosReg', (70, 81))
566898	29484121	The mutations or abnormal expression of these genes have been linked to aberrant molecular events leading to cancer, such as the interruption of p53 stabilization (MYH9), abnormal chromatin/histone modification (KMT2D), and aberrant Keap1-Nrf2 pathway (KEAP1) activity.	('expression', 'MPA', (26, 36))	('chromatin/histone modification', 'MPA', (180, 210))	('p53', 'Protein', (145, 148))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('Keap1-Nrf2', 'Gene', '50868;18024', (233, 243))	('MYH9', 'Gene', '17886', (164, 168))	('cancer', 'Disease', (109, 115))	('interruption', 'NegReg', (129, 141))	('MYH9', 'Gene', (164, 168))	('mutations', 'Var', (4, 13))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('activity', 'MPA', (260, 268))	('Keap1-Nrf2', 'Gene', (233, 243))	('abnormal', 'Var', (17, 25))	('linked', 'Reg', (62, 68))
566901	29484121	Kmt2d serves as the key enzyme in histone lysine methyltransfer and thus is one of the important epigenetic regulators whose mutations could lead to the development of tumors with abnormal histone modifications.	('histone modifications', 'MPA', (189, 210))	('mutations', 'Var', (125, 134))	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('tumors', 'Disease', (168, 174))	('Kmt2d', 'Gene', (0, 5))	('tumors', 'Disease', 'MESH:D009369', (168, 174))	('lead to', 'Reg', (141, 148))	('lysine', 'Chemical', 'MESH:D008239', (42, 48))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
566902	29484121	Human studies revealed a high frequency of non-silent somatic mutations within KMT2D for LUSC tumors.	('Human', 'Species', '9606', (0, 5))	('non-silent somatic mutations', 'Var', (43, 71))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('LUSC tumors', 'Disease', 'MESH:D009369', (89, 100))	('tumors', 'Phenotype', 'HP:0002664', (94, 100))	('KMT2D', 'Gene', (79, 84))	('LUSC tumors', 'Disease', (89, 100))	('LUSC', 'Phenotype', 'HP:0030359', (89, 93))
566903	29484121	In human cancers, similar to NFE2L2, KEAP1 mutations would disrupt the normal combination of NFE2L2 and KEAP1 in tumors, resulting in accumulation of excessive intracellular NFE2L2 and activation of its downstream genes and the eventual promotion of tumor growth.	('tumors', 'Disease', (113, 119))	('human', 'Species', '9606', (3, 8))	('combination', 'Interaction', (78, 89))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('activation', 'PosReg', (185, 195))	('tumor', 'Disease', (250, 255))	('cancers', 'Phenotype', 'HP:0002664', (9, 16))	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('cancers', 'Disease', (9, 16))	('disrupt', 'NegReg', (59, 66))	('tumor', 'Disease', 'MESH:D009369', (250, 255))	('KEAP1', 'Gene', (104, 109))	('promotion', 'PosReg', (237, 246))	('NFE2L2', 'Gene', (93, 99))	('tumor', 'Disease', (113, 118))	('intracellular NFE2L2', 'MPA', (160, 180))	('tumor', 'Disease', 'MESH:D009369', (113, 118))	('tumor', 'Phenotype', 'HP:0002664', (250, 255))	('excessive', 'PosReg', (150, 159))	('KEAP1', 'Gene', (37, 42))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))	('cancers', 'Disease', 'MESH:D009369', (9, 16))	('genes', 'Gene', (214, 219))	('accumulation', 'PosReg', (134, 146))	('mutations', 'Var', (43, 52))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))
566908	29484121	Alteration of transcripts in these pathways may be a common mechanism involved in LUSC tumorigenesis and progression.	('tumor', 'Phenotype', 'HP:0002664', (87, 92))	('transcripts', 'MPA', (14, 25))	('Alteration', 'Var', (0, 10))	('tumor', 'Disease', (87, 92))	('LUSC', 'Phenotype', 'HP:0030359', (82, 86))	('involved', 'Reg', (70, 78))	('tumor', 'Disease', 'MESH:D009369', (87, 92))
566911	29484121	For example, IGFBP7 might be regulated by TP53 in lung cancer cells and mutant NFE2L2 or KEAP1 led to similar functional consequences in terms of causing NFE2L2 accumulation and aberrant Keap1-Nrf2 pathway activity in cancer cells.	('IGFBP7', 'Gene', '29817', (13, 19))	('lung cancer', 'Disease', 'MESH:D008175', (50, 61))	('NFE2L2', 'Gene', (79, 85))	('lung cancer', 'Phenotype', 'HP:0100526', (50, 61))	('activity', 'MPA', (206, 214))	('cancer', 'Disease', 'MESH:D009369', (218, 224))	('accumulation', 'PosReg', (161, 173))	('KEAP1', 'Gene', (89, 94))	('mutant', 'Var', (72, 78))	('cancer', 'Disease', (55, 61))	('NFE2L2', 'MPA', (154, 160))	('cancer', 'Phenotype', 'HP:0002664', (55, 61))	('causing', 'Reg', (146, 153))	('Keap1-Nrf2', 'Gene', (187, 197))	('Keap1-Nrf2', 'Gene', '50868;18024', (187, 197))	('IGFBP7', 'Gene', (13, 19))	('lung cancer', 'Disease', (50, 61))	('cancer', 'Disease', (218, 224))	('cancer', 'Phenotype', 'HP:0002664', (218, 224))	('cancer', 'Disease', 'MESH:D009369', (55, 61))
566912	29484121	Lastly, we found that the mutant LUSC genes could be associated with the significantly altered tumoral expression of inhibitory immune checkpoint genes such as PD-L1, VISTA, TIM3 and LAG3.	('altered', 'Reg', (87, 94))	('PD-L1', 'Gene', (160, 165))	('tumor', 'Disease', 'MESH:D009369', (95, 100))	('LUSC', 'Phenotype', 'HP:0030359', (33, 37))	('associated', 'Reg', (53, 63))	('tumor', 'Phenotype', 'HP:0002664', (95, 100))	('TIM3', 'Gene', (174, 178))	('mutant', 'Var', (26, 32))	('LAG3', 'Gene', (183, 187))	('LUSC genes', 'Gene', (33, 43))	('tumor', 'Disease', (95, 100))
566913	29484121	We observed both up- and down-regulated immune checkpoint gene expression patterns according to different mutant genes in LUSC tumors (Figure 9).	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('mutant', 'Var', (106, 112))	('tumors', 'Phenotype', 'HP:0002664', (127, 133))	('immune checkpoint gene', 'Gene', (40, 62))	('up-', 'PosReg', (17, 20))	('expression', 'MPA', (63, 73))	('down-regulated', 'NegReg', (25, 39))	('LUSC tumors', 'Disease', 'MESH:D009369', (122, 133))	('LUSC', 'Phenotype', 'HP:0030359', (122, 126))	('LUSC tumors', 'Disease', (122, 133))
566914	29484121	Notably, suppressed tumoral expression of immune checkpoint genes has been associated with mutated oncogenes in lung cancer.	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('lung cancer', 'Disease', (112, 123))	('lung cancer', 'Phenotype', 'HP:0100526', (112, 123))	('mutated', 'Var', (91, 98))	('tumor', 'Disease', 'MESH:D009369', (20, 25))	('lung cancer', 'Disease', 'MESH:D008175', (112, 123))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('suppressed', 'NegReg', (9, 19))	('immune checkpoint genes', 'Gene', (42, 65))	('associated', 'Reg', (75, 85))	('tumor', 'Disease', (20, 25))
566915	29484121	Particularly, the increased tumoral PD-L1 gene expression was significantly associated with the mutant NFE2L2 gene (Figure 9).	('increased', 'PosReg', (18, 27))	('tumoral PD-L1', 'Disease', (28, 41))	('mutant', 'Var', (96, 102))	('tumoral PD-L1', 'Disease', 'MESH:D010300', (28, 41))	('NFE2L2', 'Gene', (103, 109))	('tumor', 'Phenotype', 'HP:0002664', (28, 33))	('expression', 'MPA', (47, 57))
566916	29484121	This supported the finding that PD-L1 expression in LUSC tumor cells was associated with NFE2L2 mutations and indicated that LUSC patients carrying NFE2L2 mutations may be more responsive to anti-PD-L1 immunotherapy.	('LUSC', 'Phenotype', 'HP:0030359', (52, 56))	('LUSC', 'Phenotype', 'HP:0030359', (125, 129))	('mutations', 'Var', (155, 164))	('PD-L1', 'Gene', (32, 37))	('tumor', 'Disease', 'MESH:D009369', (57, 62))	('associated', 'Reg', (73, 83))	('NFE2L2', 'Gene', (89, 95))	('patients', 'Species', '9606', (130, 138))	('tumor', 'Phenotype', 'HP:0002664', (57, 62))	('more', 'PosReg', (172, 176))	('tumor', 'Disease', (57, 62))	('NFE2L2', 'Gene', (148, 154))	('mutations', 'Var', (96, 105))
566917	29484121	Similarly, the mutant FLT1 and DYNC1H1 genes associated with higher tumoral gene expression of VISTA and TIM3, respectively, suggesting that they may serve as biomarkers to predict the effectiveness of VISTA-targeted and TIM3-targeted antitumor immunotherapy for LUSC patients.	('tumor', 'Disease', (68, 73))	('VISTA', 'Gene', (95, 100))	('DYNC1H1', 'Gene', (31, 38))	('tumor', 'Disease', 'MESH:D009369', (239, 244))	('higher', 'PosReg', (61, 67))	('TIM3', 'Gene', (105, 109))	('tumor', 'Phenotype', 'HP:0002664', (239, 244))	('tumor', 'Disease', 'MESH:D009369', (68, 73))	('FLT1', 'Gene', (22, 26))	('LUSC', 'Phenotype', 'HP:0030359', (263, 267))	('tumor', 'Disease', (239, 244))	('tumor', 'Phenotype', 'HP:0002664', (68, 73))	('mutant', 'Var', (15, 21))	('patients', 'Species', '9606', (268, 276))
566955	27966448	A large number of studies have also shown that excessive ROS induce cell apoptosis or autophagy in cells, excessive ROS can cause cell necrosis.	('ROS', 'Var', (116, 119))	('autophagy in cells', 'CPA', (86, 104))	('ROS', 'Chemical', 'MESH:D017382', (116, 119))	('ROS', 'Chemical', 'MESH:D017382', (57, 60))	('cell apoptosis', 'CPA', (68, 82))	('necrosis', 'Disease', (135, 143))	('cause', 'Reg', (124, 129))	('necrosis', 'Disease', 'MESH:D009336', (135, 143))
566974	27966448	The result showed knockdown of PRDX3 inhibited the proliferation of Hep-2 cells compared with the si-NC transfectants (Figure 4C).	('knockdown', 'Var', (18, 27))	('proliferation of Hep-2 cells', 'CPA', (51, 79))	('inhibited', 'NegReg', (37, 46))	('Hep-2', 'CellLine', 'CVCL:1906', (68, 73))	('PRDX3', 'Gene', (31, 36))	('PRDX3', 'Gene', '10935', (31, 36))
566975	27966448	In addition, FITC-Annexin V/propidium iodide staining analysis was performed to determine PRDX3-induced apoptosis, and the percentage of apoptotic cells significantly increased in PRDX3 knockdown cells when compared to control (Figure 4D).	('PRDX3', 'Gene', (90, 95))	('knockdown', 'Var', (186, 195))	('Annexin V', 'Gene', '308', (18, 27))	('Annexin V', 'Gene', (18, 27))	('PRDX3', 'Gene', '10935', (90, 95))	('increased', 'PosReg', (167, 176))	('PRDX3', 'Gene', '10935', (180, 185))	('propidium iodide', 'Chemical', 'MESH:D011419', (28, 44))	('PRDX3', 'Gene', (180, 185))
566976	27966448	These results indicated that inhibition of PRDX3 expression can inhibit cell proliferation and induce cell apoptosis in vitro.	('cell apoptosis', 'CPA', (102, 116))	('PRDX3', 'Gene', (43, 48))	('PRDX3', 'Gene', '10935', (43, 48))	('inhibit', 'NegReg', (64, 71))	('cell proliferation', 'CPA', (72, 90))	('induce', 'Reg', (95, 101))	('inhibition', 'Var', (29, 39))
566979	27966448	As shown in Figure 5, compared with si-NC, Hep-2 cells with knockdown of PRDX3 migrated slower, suggesting that knockdown of PRDX3 inhibited the migration ability of laryngeal cancer Hep-2 cells.	('laryngeal cancer', 'Disease', 'MESH:D007822', (166, 182))	('PRDX3', 'Gene', (73, 78))	('migrated', 'CPA', (79, 87))	('Hep-2', 'CellLine', 'CVCL:1906', (43, 48))	('PRDX3', 'Gene', '10935', (73, 78))	('laryngeal cancer', 'Disease', (166, 182))	('cancer', 'Phenotype', 'HP:0002664', (176, 182))	('laryngeal cancer', 'Phenotype', 'HP:0012118', (166, 182))	('knockdown', 'Var', (112, 121))	('knockdown', 'Var', (60, 69))	('inhibited', 'NegReg', (131, 140))	('Hep-2', 'CellLine', 'CVCL:1906', (183, 188))	('PRDX3', 'Gene', '10935', (125, 130))	('slower', 'NegReg', (88, 94))	('PRDX3', 'Gene', (125, 130))
566986	27966448	Their data suggested that polymorphisms of PRDX 1, 2 and 6 were not associated with esophageal cancer.	('associated', 'Reg', (68, 78))	('polymorphisms', 'Var', (26, 39))	('esophageal cancer', 'Disease', (84, 101))	('esophageal cancer', 'Disease', 'MESH:D004938', (84, 101))	('PRDX 1, 2 and 6', 'Gene', '5052;7001;9588', (43, 58))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))
567006	27966448	CCK8 assay showed that knockdown of PRDX3 significantly inhibited the growth of Hep-2 cells.	('growth of Hep-2 cells', 'CPA', (70, 91))	('PRDX3', 'Gene', '10935', (36, 41))	('PRDX3', 'Gene', (36, 41))	('knockdown', 'Var', (23, 32))	('inhibited', 'NegReg', (56, 65))	('Hep-2', 'CellLine', 'CVCL:1906', (80, 85))
567009	27966448	Transwell assays indicated that knockdown of PRDX3 significantly inhibits Hep-2 cell migration, which may be due to an increase in apoptosis owing to downregulation of PRDX3.	('Hep-2 cell migration', 'CPA', (74, 94))	('inhibits', 'NegReg', (65, 73))	('downregulation', 'NegReg', (150, 164))	('knockdown', 'Var', (32, 41))	('PRDX3', 'Gene', '10935', (168, 173))	('PRDX3', 'Gene', (168, 173))	('increase', 'PosReg', (119, 127))	('apoptosis', 'CPA', (131, 140))	('PRDX3', 'Gene', (45, 50))	('PRDX3', 'Gene', '10935', (45, 50))	('Hep-2', 'CellLine', 'CVCL:1906', (74, 79))
567045	27966448	Hep-2 cells with transfection of si-NC or 2 PRDX3 shRNAs were seeded at 1x103 cells/well in 96-well plates.	('Hep-2', 'CellLine', 'CVCL:1906', (0, 5))	('PRDX3', 'Gene', (44, 49))	('si-NC', 'Var', (33, 38))	('PRDX3', 'Gene', '10935', (44, 49))
567048	27966448	In brief, Hep-2 cells, which were transfected with si-NC or 2 PRDX3 shRNAs, and normal Hep-2 cells without treatment were collected after dissociation with ethylenediaminetetraacetic acid (EDTA)-free trypsin and then washed with cold PBS.	('ethylenediaminetetraacetic acid', 'Chemical', 'MESH:D004492', (156, 187))	('PBS', 'Chemical', 'MESH:D007854', (234, 237))	('Hep-2', 'CellLine', 'CVCL:1906', (10, 15))	('Hep-2', 'CellLine', 'CVCL:1906', (87, 92))	('si-NC', 'Var', (51, 56))	('PRDX3', 'Gene', '10935', (62, 67))	('PRDX3', 'Gene', (62, 67))	('EDTA', 'Chemical', 'MESH:D004492', (189, 193))
567050	27966448	Hep-2 cells (2x105) transfected in si-NC or 2 PRDX3 shRNAs in 0.1 ml of serum-free DMEM medium were added to the upper compartment, and 0.6 ml of DMEM containing 10% fetal bovine serum was placed into the lower compartment.	('PRDX3', 'Gene', (46, 51))	('DMEM', 'Chemical', '-', (83, 87))	('DMEM medium', 'Chemical', '-', (83, 94))	('bovine', 'Species', '9913', (172, 178))	('Hep-2', 'CellLine', 'CVCL:1906', (0, 5))	('DMEM', 'Chemical', '-', (146, 150))	('si-NC', 'Var', (35, 40))	('PRDX3', 'Gene', '10935', (46, 51))
567091	32640732	Among markers with a significant difference, the estimated expression rates of CD205 were 0.650 (95% CI 0.461-0.801) and 0.958 (95% CI 0.757-0.994) in TC and TM type B3, respectively (Table 3).	('TM', 'Gene', '7063', (158, 160))	('CD205', 'Gene', (79, 84))	('expression', 'MPA', (59, 69))	('0.958', 'Var', (121, 126))	('CD205', 'Gene', '4065', (79, 84))
567096	32640732	Among these markers, the most effective positive and negative markers may be MUC1 and beta-5t, 0.932 (95% CI 0.686-0.988), 0.847 (95% CI 0.505-0.968), 46.251 ( 95% CI 11.634-183.877), 0.921 and 1.000 ( 95% CI 0.927-1.000), 1.000 (95% CI 0.942-1.000), 571.396 (95% CI 33.356-9788.053), 0.985), in sensitivity, specificity, diagnostic OR, and AUC on SROC, respectively; Table 4.	('0.985', 'Var', (285, 290))	('beta-5t', 'Gene', (86, 93))	('MUC1', 'Gene', (77, 81))	('MUC1', 'Gene', '4582', (77, 81))	('0.847', 'Var', (123, 128))	('beta-5t', 'Gene', '122706', (86, 93))	('0.932', 'Var', (95, 100))
567139	32323836	Furthermore, patients with pathological T1 stage and iCluster2 molecular subtype of LIHC expressed particularly low levels of E2F family genes.	('iCluster2', 'Var', (53, 62))	('E2F', 'Protein', (126, 129))	('LIHC', 'Disease', (84, 88))	('low', 'NegReg', (112, 115))	('patients', 'Species', '9606', (13, 21))	('LIHC', 'Disease', 'MESH:D006528', (84, 88))
567140	32323836	The present study demonstrated that hypo-DNA methylation, DNA amplification and TP53 mutation contributed to the high expression levels of E2F family genes in cancer cells.	('cancer', 'Disease', (159, 165))	('high expression levels', 'MPA', (113, 135))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('TP53', 'Gene', '7157', (80, 84))	('TP53', 'Gene', (80, 84))	('mutation', 'Var', (85, 93))	('E2F family genes', 'Gene', (139, 155))	('cancer', 'Disease', 'MESH:D009369', (159, 165))
567145	32323836	For example, E2F1 and E2F3 are increased in liver cancer, and the overexpression of E2F1 or E2F3 could induce spontaneous liver cancer development in mice.	('liver cancer', 'Disease', (44, 56))	('liver cancer', 'Disease', 'MESH:D006528', (122, 134))	('mice', 'Species', '10090', (150, 154))	('liver cancer', 'Phenotype', 'HP:0002896', (122, 134))	('liver cancer', 'Disease', (122, 134))	('E2F1', 'Var', (84, 88))	('E2F3', 'Var', (92, 96))	('E2F1', 'Var', (13, 17))	('E2F3', 'Var', (22, 26))	('induce', 'PosReg', (103, 109))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('liver cancer', 'Phenotype', 'HP:0002896', (44, 56))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('overexpression', 'PosReg', (66, 80))	('liver cancer', 'Disease', 'MESH:D006528', (44, 56))
567146	32323836	Furthermore, knockout of E2F8 could protect mice against the development of liver cancer.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('knockout', 'Var', (13, 21))	('liver cancer', 'Phenotype', 'HP:0002896', (76, 88))	('liver cancer', 'Disease', 'MESH:D006528', (76, 88))	('E2F8', 'Gene', (25, 29))	('mice', 'Species', '10090', (44, 48))	('liver cancer', 'Disease', (76, 88))
567151	32323836	Restoring the balance between E2F1 and E2F7 is a therapeutic strategy in head and neck squamous cell carcinomas.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (87, 110))	('head and neck squamous cell carcinomas', 'Phenotype', 'HP:0012288', (73, 111))	('carcinoma', 'Phenotype', 'HP:0030731', (101, 110))	('neck squamous cell carcinomas', 'Disease', 'MESH:D000077195', (82, 111))	('E2F1', 'Var', (30, 34))	('carcinomas', 'Phenotype', 'HP:0030731', (101, 111))	('E2F7', 'Gene', '144455', (39, 43))	('neck squamous cell carcinomas', 'Disease', (82, 111))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (87, 111))	('E2F7', 'Gene', (39, 43))
567191	32323836	Furthermore, the Kaplan-Meier survival analysis revealed that E2F1, E2F2, E2F4, E2F7 and E2F8 were all associated with overall survival in patients with LUAD (Fig.	('LUAD', 'Disease', 'MESH:D000077192', (153, 157))	('patients', 'Species', '9606', (139, 147))	('E2F2', 'Gene', (68, 72))	('E2F7', 'Gene', '144455', (80, 84))	('E2F4', 'Gene', (74, 78))	('LUAD', 'Disease', (153, 157))	('E2F2', 'Gene', '1870', (68, 72))	('LUAD', 'Phenotype', 'HP:0030078', (153, 157))	('associated with', 'Reg', (103, 118))	('E2F7', 'Gene', (80, 84))	('E2F1', 'Var', (62, 66))	('overall survival', 'MPA', (119, 135))	('E2F8', 'Var', (89, 93))	('E2F4', 'Gene', '1874', (74, 78))
567196	32323836	The Spearman's correlation test demonstrated a high correlation between E2F1, E2F7 and E2F8 in LIHC and LUAD expression datasets (Fig.	('LUAD', 'Disease', (104, 108))	('LUAD', 'Phenotype', 'HP:0030078', (104, 108))	('LIHC', 'Disease', (95, 99))	('LUAD', 'Disease', 'MESH:D000077192', (104, 108))	('E2F8', 'Var', (87, 91))	('E2F7', 'Gene', '144455', (78, 82))	('LIHC', 'Disease', 'MESH:D006528', (95, 99))	('E2F7', 'Gene', (78, 82))	('E2F1', 'Var', (72, 76))
567197	32323836	E2F2 was also highly correlated with E2F7 and E2F8 in LIHC and LUAD.	('E2F2', 'Gene', '1870', (0, 4))	('LUAD', 'Phenotype', 'HP:0030078', (63, 67))	('E2F8', 'Var', (46, 50))	('LUAD', 'Disease', (63, 67))	('LIHC', 'Disease', (54, 58))	('LIHC', 'Disease', 'MESH:D006528', (54, 58))	('E2F2', 'Gene', (0, 4))	('LUAD', 'Disease', 'MESH:D000077192', (63, 67))	('E2F7', 'Gene', '144455', (37, 41))	('correlated', 'Reg', (21, 31))	('E2F7', 'Gene', (37, 41))
567198	32323836	Additionally, E2F7 and E2F8 were correlated with each other (Fig.	('E2F7', 'Gene', (14, 18))	('E2F8', 'Var', (23, 27))	('E2F7', 'Gene', '144455', (14, 18))
567208	32323836	However, the expression levels of E2F5 and E2F8 in patients with T1 and T2 stage LIHC were not different.	('E2F5', 'Gene', '1875', (34, 38))	('E2F8', 'Var', (43, 47))	('E2F5', 'Gene', (34, 38))	('LIHC', 'Disease', (81, 85))	('patients', 'Species', '9606', (51, 59))	('LIHC', 'Disease', 'MESH:D006528', (81, 85))
567217	32323836	E2F2 and E2F8 were highly expressed in patients with T2 stage LUAD compared with patients with T1 stage (Fig.	('E2F2', 'Gene', '1870', (0, 4))	('E2F8', 'Var', (9, 13))	('patients', 'Species', '9606', (39, 47))	('LUAD', 'Phenotype', 'HP:0030078', (62, 66))	('LUAD', 'Disease', (62, 66))	('patients', 'Species', '9606', (81, 89))	('E2F2', 'Gene', (0, 4))	('LUAD', 'Disease', 'MESH:D000077192', (62, 66))
567220	32323836	Particularly LIHC, E2F2, E2F4, E2F5, E2F5 and E2F8 genes exhibited hypo-DNA methylation in tumor samples (Fig.	('E2F5', 'Gene', (37, 41))	('hypo-DNA methylation', 'MPA', (67, 87))	('E2F8', 'Var', (46, 50))	('E2F2', 'Gene', (19, 23))	('E2F4', 'Gene', '1874', (25, 29))	('E2F5', 'Gene', '1875', (31, 35))	('tumor', 'Disease', 'MESH:D009369', (91, 96))	('E2F5', 'Gene', (31, 35))	('E2F2', 'Gene', '1870', (19, 23))	('LIHC', 'Disease', (13, 17))	('E2F5', 'Gene', '1875', (37, 41))	('LIHC', 'Disease', 'MESH:D006528', (13, 17))	('tumor', 'Phenotype', 'HP:0002664', (91, 96))	('E2F4', 'Gene', (25, 29))	('tumor', 'Disease', (91, 96))
567224	32323836	It was revealed that the E2F1 and E2F3 genes were present in higher proportions of DNA amplification in BLCA (Fig.	('BLCA', 'Disease', 'MESH:D001749', (104, 108))	('E2F3', 'Var', (34, 38))	('DNA', 'MPA', (83, 86))	('BLCA', 'Disease', (104, 108))	('E2F1', 'Gene', (25, 29))
567226	32323836	TP53 is a driver of mutations in several types of tumor.	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Disease', (50, 55))	('mutations', 'Var', (20, 29))
567229	32323836	It was revealed that, except for E2F5, the other E2F family genes were all highly expressed in patients with TP53 mutant LIHC and LUAD, compared with those patients with TP53 wild-type LIHC and LUAD (Fig.	('mutant', 'Var', (114, 120))	('LUAD', 'Disease', (194, 198))	('LIHC', 'Disease', (185, 189))	('LUAD', 'Disease', (130, 134))	('LIHC', 'Disease', (121, 125))	('patients', 'Species', '9606', (156, 164))	('TP53', 'Gene', '7157', (109, 113))	('TP53', 'Gene', (170, 174))	('E2F5', 'Gene', (33, 37))	('highly expressed', 'PosReg', (75, 91))	('LIHC', 'Disease', 'MESH:D006528', (185, 189))	('LIHC', 'Disease', 'MESH:D006528', (121, 125))	('TP53', 'Gene', (109, 113))	('LUAD', 'Disease', 'MESH:D000077192', (194, 198))	('patients', 'Species', '9606', (95, 103))	('LUAD', 'Disease', 'MESH:D000077192', (130, 134))	('TP53', 'Gene', '7157', (170, 174))	('LUAD', 'Phenotype', 'HP:0030078', (194, 198))	('E2F5', 'Gene', '1875', (33, 37))	('LUAD', 'Phenotype', 'HP:0030078', (130, 134))
567230	32323836	Overall, the present study speculated that hypo-DNA methylation, DNA amplification and TP53 mutation were contributing to the high expression levels of E2F family genes in cancer cells.	('TP53', 'Gene', '7157', (87, 91))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('mutation', 'Var', (92, 100))	('high expression levels', 'MPA', (126, 148))	('TP53', 'Gene', (87, 91))	('E2F family genes', 'Gene', (152, 168))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('cancer', 'Disease', (172, 178))
567239	32323836	It was revealed that, compared with other tumor types, E2F2-4, E2F7 and E2F8 were all expressed at relatively low levels in LIHC tumors (Fig.	('LIHC', 'Disease', (124, 128))	('E2F8', 'Var', (72, 76))	('tumors', 'Disease', (129, 135))	('tumor', 'Disease', (42, 47))	('LIHC', 'Disease', 'MESH:D006528', (124, 128))	('E2F7', 'Gene', '144455', (63, 67))	('tumors', 'Disease', 'MESH:D009369', (129, 135))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('tumor', 'Disease', 'MESH:D009369', (129, 134))	('E2F2-4', 'Gene', '1870;1871;1874', (55, 61))	('E2F7', 'Gene', (63, 67))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('E2F2-4', 'Gene', (55, 61))	('tumor', 'Disease', 'MESH:D009369', (42, 47))	('tumor', 'Disease', (129, 134))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))
567243	32323836	E2F3 was highly expressed, while the expression levels of E2F7 and E2F8 were relatively lower in liver tissues (Fig.	('E2F8', 'Var', (67, 71))	('E2F7', 'Gene', '144455', (58, 62))	('E2F7', 'Gene', (58, 62))	('expression levels', 'MPA', (37, 54))	('lower', 'NegReg', (88, 93))	('E2F3', 'Gene', (0, 4))
567246	32323836	Similar to liver tissues, E2F3 was highly expressed, while the expression levels of E2F7 and E2F8 were relatively lower in normal lung or malignant tissues (Fig.	('expression levels', 'MPA', (63, 80))	('lower', 'NegReg', (114, 119))	('E2F7', 'Gene', '144455', (84, 88))	('E2F7', 'Gene', (84, 88))	('E2F8', 'Var', (93, 97))
567249	32323836	Similar to TCGA data, high expression levels of the E2F family genes E2F1, E2F2, E2F4, E2F7 and E2F8 were all associated with low overall survival in patients with lung cancer, while, high expression levels of E2F3, E2F5 and E2F6 were associated with an improved prognosis in patients with LUAD (Fig.	('patients', 'Species', '9606', (276, 284))	('E2F2', 'Gene', (75, 79))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('patients', 'Species', '9606', (150, 158))	('E2F3', 'Var', (210, 214))	('E2F2', 'Gene', '1870', (75, 79))	('E2F7', 'Gene', '144455', (87, 91))	('lung cancer', 'Disease', (164, 175))	('E2F5', 'Gene', (216, 220))	('E2F8', 'Var', (96, 100))	('E2F1', 'Gene', (69, 73))	('LUAD', 'Disease', 'MESH:D000077192', (290, 294))	('low', 'NegReg', (126, 129))	('E2F4', 'Gene', (81, 85))	('lung cancer', 'Disease', 'MESH:D008175', (164, 175))	('LUAD', 'Phenotype', 'HP:0030078', (290, 294))	('E2F5', 'Gene', '1875', (216, 220))	('E2F4', 'Gene', '1874', (81, 85))	('expression levels', 'MPA', (27, 44))	('lung cancer', 'Phenotype', 'HP:0100526', (164, 175))	('E2F7', 'Gene', (87, 91))	('E2F6', 'Gene', '1876', (225, 229))	('E2F6', 'Gene', (225, 229))	('overall survival', 'MPA', (130, 146))	('LUAD', 'Disease', (290, 294))
567253	32323836	Results derived from this dataset suggested a strong correlation among E2F1, E2F7 and E2F8 (Fig.	('E2F7', 'Gene', (77, 81))	('E2F8', 'Var', (86, 90))	('E2F7', 'Gene', '144455', (77, 81))	('E2F1', 'Var', (71, 75))
567254	32323836	E2F2 was also strongly correlated with E2F7 and E2F8.	('E2F2', 'Gene', '1870', (0, 4))	('correlated', 'Reg', (23, 33))	('E2F2', 'Gene', (0, 4))	('E2F7', 'Gene', '144455', (39, 43))	('E2F7', 'Gene', (39, 43))	('E2F8', 'Var', (48, 52))
567255	32323836	In addition, E2F7 and E2F8 were correlated with each other (Fig.	('E2F7', 'Gene', (13, 17))	('E2F7', 'Gene', '144455', (13, 17))	('E2F8', 'Var', (22, 26))
567257	32323836	Only E2F4 and E2F8 were independent prognostic markers (Fig.	('E2F4', 'Gene', '1874', (5, 9))	('E2F4', 'Gene', (5, 9))	('E2F8', 'Var', (14, 18))
567264	32323836	For example, higher E2F1, E2F3, E2F5, E2F7 and E2F8 expression levels were significantly associated with lower overall survival in patients with breast cancer.	('lower', 'NegReg', (105, 110))	('E2F7', 'Gene', '144455', (38, 42))	('patients', 'Species', '9606', (131, 139))	('E2F7', 'Gene', (38, 42))	('overall survival', 'MPA', (111, 127))	('E2F3', 'Var', (26, 30))	('higher', 'PosReg', (13, 19))	('expression', 'MPA', (52, 62))	('E2F8', 'Var', (47, 51))	('breast cancer', 'Disease', 'MESH:D001943', (145, 158))	('breast cancer', 'Phenotype', 'HP:0003002', (145, 158))	('E2F1', 'Var', (20, 24))	('E2F5', 'Gene', '1875', (32, 36))	('cancer', 'Phenotype', 'HP:0002664', (152, 158))	('breast cancer', 'Disease', (145, 158))	('E2F5', 'Gene', (32, 36))
567265	32323836	E2F1, E2F3 and E2F4 were significantly associated with unfavorable outcomes in patients with gastric cancer.	('gastric cancer', 'Disease', 'MESH:D013274', (93, 107))	('gastric cancer', 'Phenotype', 'HP:0012126', (93, 107))	('E2F4', 'Gene', (15, 19))	('E2F1', 'Var', (0, 4))	('associated', 'Reg', (39, 49))	('patients', 'Species', '9606', (79, 87))	('E2F3', 'Var', (6, 10))	('cancer', 'Phenotype', 'HP:0002664', (101, 107))	('E2F4', 'Gene', '1874', (15, 19))	('gastric cancer', 'Disease', (93, 107))
567269	32323836	In patients with LUAD, E2F1, E2F2, E2F4, E2F7 and E2F8, were significantly associated with unfavorable outcomes.	('E2F2', 'Gene', '1870', (29, 33))	('E2F8', 'Var', (50, 54))	('E2F7', 'Gene', '144455', (41, 45))	('E2F2', 'Gene', (29, 33))	('E2F7', 'Gene', (41, 45))	('E2F1', 'Var', (23, 27))	('E2F4', 'Gene', (35, 39))	('LUAD', 'Disease', 'MESH:D000077192', (17, 21))	('patients', 'Species', '9606', (3, 11))	('E2F4', 'Gene', '1874', (35, 39))	('LUAD', 'Phenotype', 'HP:0030078', (17, 21))	('associated', 'Reg', (75, 85))	('LUAD', 'Disease', (17, 21))
567273	32323836	The present study demonstrated that, in LIHC and LUAD patients, the hypomethylation of the E2F family genes in tumor samples may explain the high expression levels of these genes in the tumor tissues.	('hypomethylation', 'Var', (68, 83))	('tumor', 'Disease', 'MESH:D009369', (186, 191))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('LUAD', 'Phenotype', 'HP:0030078', (49, 53))	('LIHC', 'Disease', (40, 44))	('LUAD', 'Disease', (49, 53))	('tumor', 'Phenotype', 'HP:0002664', (186, 191))	('patients', 'Species', '9606', (54, 62))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('expression levels', 'MPA', (146, 163))	('tumor', 'Disease', (186, 191))	('tumor', 'Disease', (111, 116))	('E2F family genes', 'Gene', (91, 107))	('LIHC', 'Disease', 'MESH:D006528', (40, 44))	('LUAD', 'Disease', 'MESH:D000077192', (49, 53))
567279	32323836	The present study demonstrated that, except for E2F5, the E2F family genes were all highly expressed in patients with TP53 mutant LIHC and LUAD, compared with patients with TP53 wild-type LIHC and LUAD.	('E2F5', 'Gene', '1875', (48, 52))	('LUAD', 'Disease', (139, 143))	('TP53', 'Gene', (118, 122))	('LIHC', 'Disease', (130, 134))	('TP53', 'Gene', (173, 177))	('highly expressed', 'PosReg', (84, 100))	('E2F family', 'Gene', (58, 68))	('LIHC', 'Disease', 'MESH:D006528', (130, 134))	('LUAD', 'Disease', 'MESH:D000077192', (197, 201))	('LIHC', 'Disease', (188, 192))	('TP53', 'Gene', '7157', (118, 122))	('E2F5', 'Gene', (48, 52))	('TP53', 'Gene', '7157', (173, 177))	('LUAD', 'Phenotype', 'HP:0030078', (197, 201))	('patients', 'Species', '9606', (159, 167))	('patients', 'Species', '9606', (104, 112))	('LUAD', 'Disease', 'MESH:D000077192', (139, 143))	('LUAD', 'Phenotype', 'HP:0030078', (139, 143))	('LIHC', 'Disease', 'MESH:D006528', (188, 192))	('LUAD', 'Disease', (197, 201))	('mutant', 'Var', (123, 129))
567305	32104210	For example, ALK rearrangements are more common in non-smokers with adenocarcinoma than in smokers with adenocarcinoma or squamous cell carcinoma.	('rearrangements', 'Var', (17, 31))	('adenocarcinoma', 'Disease', (68, 82))	('ALK', 'Gene', (13, 16))	('adenocarcinoma', 'Disease', 'MESH:D000230', (68, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (73, 82))	('carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (122, 145))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (122, 145))	('men', 'Species', '9606', (26, 29))	('adenocarcinoma', 'Disease', (104, 118))	('ALK', 'Gene', '238', (13, 16))	('squamous cell carcinoma', 'Disease', (122, 145))	('carcinoma', 'Phenotype', 'HP:0030731', (136, 145))	('adenocarcinoma', 'Disease', 'MESH:D000230', (104, 118))	('common', 'Reg', (41, 47))
567306	32104210	Metabolic syndrome also has been linked to the development of lung adenocarcinoma, especially in never-smokers, as genome-wide association studies (GWASs) have demonstrated that EGFR, VTL1A, TNFRSF10C, C3ORF21 and hyper-methylations of TNFSF10C, BHLHB5 and BOLL are involved in both pathways.	('TNFSF10C', 'Gene', (236, 244))	('linked', 'Reg', (33, 39))	('BOLL', 'Gene', (257, 261))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (62, 81))	('carcinoma', 'Phenotype', 'HP:0030731', (72, 81))	('TNFRSF10C', 'Gene', '8794', (191, 200))	('Metabolic syndrome', 'Disease', 'MESH:D008659', (0, 18))	('BHLHB5', 'Gene', '27319', (246, 252))	('men', 'Species', '9606', (54, 57))	('C3ORF21', 'Gene', '152002', (202, 209))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (62, 81))	('involved', 'Reg', (266, 274))	('lung adenocarcinoma', 'Disease', (62, 81))	('BOLL', 'Gene', '66037', (257, 261))	('hyper-methylations', 'Var', (214, 232))	('TNFRSF10C', 'Gene', (191, 200))	('C3ORF21', 'Gene', (202, 209))	('Metabolic syndrome', 'Disease', (0, 18))	('BHLHB5', 'Gene', (246, 252))
567324	32104210	We estimate today that 5%-10% of all cancers are caused by inherited germline mutations, many of which are associated with known hereditary cancer syndromes.	('hereditary cancer syndromes', 'Disease', 'MESH:D009386', (129, 156))	('caused', 'Reg', (49, 55))	('cancers', 'Phenotype', 'HP:0002664', (37, 44))	('hereditary cancer syndromes', 'Disease', (129, 156))	('cancers', 'Disease', (37, 44))	('cancers', 'Disease', 'MESH:D009369', (37, 44))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))	('germline mutations', 'Var', (69, 87))
567327	32104210	Familial clustering of cancer may be explained by shared environmental factors, inherited mutation of moderate- and high-penetrance genes and/or inherited single nucleotide polymorphisms (SNPs).	('single nucleotide polymorphisms', 'Var', (155, 186))	('cancer', 'Disease', (23, 29))	('cancer', 'Disease', 'MESH:D009369', (23, 29))	('cancer', 'Phenotype', 'HP:0002664', (23, 29))	('men', 'Species', '9606', (64, 67))	('mutation', 'Var', (90, 98))
567350	32104210	Sellers et al estimated that segregation at this presumed lung cancer predisposition locus could be responsible for 69% of lung cancer cases at the age of 50 years, 47% at the age of 60 years and 22% at the age of 70 years, possibly as a reflection of an increasing proportion of tobacco exposure-related lung cancer in non-carriers.	('tobacco', 'Species', '4097', (280, 287))	('lung cancer', 'Disease', (123, 134))	('segregation', 'Var', (29, 40))	('lung cancer', 'Phenotype', 'HP:0100526', (123, 134))	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('lung cancer', 'Disease', (58, 69))	('lung cancer', 'Phenotype', 'HP:0100526', (58, 69))	('lung cancer', 'Disease', 'MESH:D008175', (305, 316))	('cancer', 'Phenotype', 'HP:0002664', (310, 316))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('lung cancer', 'Disease', 'MESH:D008175', (123, 134))	('responsible', 'Reg', (100, 111))	('lung cancer', 'Disease', (305, 316))	('lung cancer', 'Disease', 'MESH:D008175', (58, 69))	('lung cancer', 'Phenotype', 'HP:0100526', (305, 316))
567353	32104210	A meta-analysis of 1,018 publications describing 2,910 variants in 754 genes and loci was conducted to interpret genetic associations of common variants with lung cancer.	('variants', 'Var', (144, 152))	('lung cancer', 'Disease', (158, 169))	('lung cancer', 'Phenotype', 'HP:0100526', (158, 169))	('variants', 'Var', (55, 63))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('lung cancer', 'Disease', 'MESH:D008175', (158, 169))	('genetic associations', 'Disease', 'MESH:D030342', (113, 133))	('genetic associations', 'Disease', (113, 133))
567354	32104210	Credibility assessment of the accumulated epidemiological evidence from 246 eligible variants suggested that eight genetic variants (APEX1 rs1760944, AXIN2 rs2240308, CHRNA3 rs6495309, CXCR2 rs1126579, CYP2E1 rs6413432, HYKK rs931794, PON1 rs662 and REV3L rs462779) were strongly associated with the risk of lung cancer development, and ten (ATM rs189037, CD3EAP rs967591, CYP2A6 rs1801272, HIF1A rs11549467, PDCD5 rs1862214, PROM1 rs2240688, TP53 rs12951053, TP63 rs10937405, WWOX CNV-67048 and XRCC1 rs3213255) were moderately associated with this risk.	('rs3213255', 'Mutation', 'rs3213255', (502, 511))	('APEX1', 'Gene', '328', (133, 138))	('TP53', 'Gene', (443, 447))	('rs462779', 'Mutation', 'rs462779', (256, 264))	('rs662', 'Mutation', 'rs662', (240, 245))	('HYKK', 'Gene', (220, 224))	('cancer', 'Phenotype', 'HP:0002664', (313, 319))	('CYP2A6', 'Gene', '1548', (373, 379))	('CD3EAP', 'Gene', (356, 362))	('TP63', 'Gene', (460, 464))	('rs1126579', 'Mutation', 'rs1126579', (191, 200))	('CHRNA3', 'Gene', '1136', (167, 173))	('CYP2E1', 'Gene', '1571', (202, 208))	('AXIN2', 'Gene', (150, 155))	('WWOX', 'Gene', (477, 481))	('lung cancer', 'Disease', (308, 319))	('HIF1A', 'Gene', '3091', (391, 396))	('men', 'Species', '9606', (18, 21))	('ATM', 'Gene', (342, 345))	('rs1862214', 'Mutation', 'rs1862214', (415, 424))	('rs10937405', 'Var', (465, 475))	('PDCD5', 'Gene', '9141', (409, 414))	('CXCR2', 'Gene', (185, 190))	('rs6495309', 'Mutation', 'rs6495309', (174, 183))	('men', 'Species', '9606', (327, 330))	('XRCC1', 'Gene', '7515', (496, 501))	('rs11549467', 'Mutation', 'rs11549467', (397, 407))	('rs6413432', 'Mutation', 'rs6413432', (209, 218))	('PON1', 'Gene', (235, 239))	('TP63', 'Gene', '8626', (460, 464))	('rs931794', 'Mutation', 'rs931794', (225, 233))	('rs10937405', 'Mutation', 'rs10937405', (465, 475))	('rs1801272', 'Mutation', 'rs1801272', (380, 389))	('rs2240688', 'Mutation', 'rs2240688', (432, 441))	('PDCD5', 'Gene', (409, 414))	('rs2240308', 'Mutation', 'rs2240308', (156, 165))	('CXCR2', 'Gene', '3579', (185, 190))	('XRCC1', 'Gene', (496, 501))	('CHRNA3', 'Gene', (167, 173))	('TP53', 'Gene', '7157', (443, 447))	('CYP2E1', 'Gene', (202, 208))	('APEX1', 'Gene', (133, 138))	('rs967591', 'Mutation', 'rs967591', (363, 371))	('lung cancer', 'Disease', 'MESH:D008175', (308, 319))	('rs12951053', 'Mutation', 'rs12951053', (448, 458))	('rs189037', 'Mutation', 'rs189037', (346, 354))	('HYKK', 'Gene', '123688', (220, 224))	('PROM1', 'Gene', (426, 431))	('CYP2A6', 'Gene', (373, 379))	('WWOX', 'Gene', '51741', (477, 481))	('AXIN2', 'Gene', '8313', (150, 155))	('PROM1', 'Gene', '8842', (426, 431))	('REV3L', 'Gene', '5980', (250, 255))	('HIF1A', 'Gene', (391, 396))	('lung cancer', 'Phenotype', 'HP:0100526', (308, 319))	('rs1760944', 'Mutation', 'rs1760944', (139, 148))	('rs12951053', 'Var', (448, 458))	('ATM', 'Gene', '472', (342, 345))	('PON1', 'Gene', '5444', (235, 239))	('rs189037', 'Var', (346, 354))	('CD3EAP', 'Gene', '10849', (356, 362))	('REV3L', 'Gene', (250, 255))	('associated', 'Reg', (280, 290))
567355	32104210	An analysis based on the histological type of cancer revealed significant associations for 25 variants in the NSCLC group, eight of which (CHRNA5 rs16969968, CLPTM1L rs402710, CYP2E1 rs6413432, ERCC1 rs11615, FGFR4 rs351855, HYKK rs931794, MIR146A rs2910164 and TERT rs2736098) demonstrated strong cumulative epidemiological evidence.	('rs2910164', 'Var', (248, 257))	('CLPTM1L', 'Gene', '81037', (158, 165))	('rs11615', 'Mutation', 'rs11615', (200, 207))	('HYKK', 'Gene', '123688', (225, 229))	('rs6413432', 'Var', (183, 192))	('ERCC1', 'Gene', (194, 199))	('NSCLC', 'Disease', 'MESH:D002289', (110, 115))	('CHRNA5', 'Gene', '1138', (139, 145))	('associations', 'Interaction', (74, 86))	('CYP2E1', 'Gene', '1571', (176, 182))	('rs2910164', 'Mutation', 'rs2910164', (248, 257))	('FGFR4', 'Gene', (209, 214))	('type of cancer', 'Disease', (38, 52))	('CLPTM1L', 'Gene', (158, 165))	('CHRNA5', 'Gene', (139, 145))	('NSCLC', 'Disease', (110, 115))	('HYKK', 'Gene', (225, 229))	('rs351855', 'Mutation', 'rs351855', (215, 223))	('rs931794', 'Var', (230, 238))	('CYP2E1', 'Gene', (176, 182))	('MIR146A', 'Gene', '406938', (240, 247))	('rs402710', 'Var', (166, 174))	('ERCC1', 'Gene', '2067', (194, 199))	('rs351855', 'Var', (215, 223))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('rs11615', 'Var', (200, 207))	('type of cancer', 'Disease', 'MESH:D009369', (38, 52))	('rs2736098', 'Mutation', 'rs2736098', (267, 276))	('rs6413432', 'Mutation', 'rs6413432', (183, 192))	('rs16969968', 'Var', (146, 156))	('rs931794', 'Mutation', 'rs931794', (230, 238))	('MIR146A', 'Gene', (240, 247))	('rs16969968', 'Mutation', 'rs16969968', (146, 156))	('rs402710', 'Mutation', 'rs402710', (166, 174))	('TERT', 'Gene', (262, 266))	('TERT', 'Gene', '7015', (262, 266))	('FGFR4', 'Gene', '2264', (209, 214))
567356	32104210	Five variants in the SCLC group showed significant associations, but these associations were moderate (CHRNA5 rs16969968, CYP1A1 rs4646903 and NQO1 (rs1800566) and weak (GSTM1 present/null and XPC rs2228001), which may point to a greater contribution of genetic predisposition in patients with NSCLC than in those with SCLC.	('rs4646903', 'Mutation', 'rs4646903', (129, 138))	('associations', 'Interaction', (51, 63))	('NSCLC', 'Disease', 'MESH:D002289', (294, 299))	('NSCLC', 'Disease', (294, 299))	('rs16969968', 'Var', (110, 120))	('GSTM1', 'Gene', (170, 175))	('SCLC', 'Disease', 'MESH:D055752', (295, 299))	('rs16969968', 'Mutation', 'rs16969968', (110, 120))	('rs1800566', 'Var', (149, 158))	('XPC', 'Gene', '7508', (193, 196))	('rs4646903', 'Var', (129, 138))	('SCLC', 'Disease', 'MESH:D055752', (319, 323))	('patients', 'Species', '9606', (280, 288))	('CHRNA5', 'Gene', '1138', (103, 109))	('XPC', 'Gene', (193, 196))	('rs1800566', 'Mutation', 'rs1800566', (149, 158))	('CYP1A1', 'Gene', (122, 128))	('SCLC', 'Disease', (295, 299))	('SCLC', 'Disease', 'MESH:D055752', (21, 25))	('NQO1', 'Gene', '1728', (143, 147))	('SCLC', 'Disease', (319, 323))	('rs2228001', 'Mutation', 'rs2228001', (197, 206))	('CHRNA5', 'Gene', (103, 109))	('GSTM1', 'Gene', '2944', (170, 175))	('NQO1', 'Gene', (143, 147))	('SCLC', 'Disease', (21, 25))	('CYP1A1', 'Gene', '1543', (122, 128))
567358	32104210	These mutations occurred more frequently in genes associated with the DNA repair pathway, such as ATM (50%), followed by TP53, BRCA2, EGFR and PARK2.	('DNA repair pathway', 'Pathway', (70, 88))	('PARK2', 'Gene', '5071', (143, 148))	('BRCA2', 'Gene', '675', (127, 132))	('PARK2', 'Gene', (143, 148))	('TP53', 'Gene', '7157', (121, 125))	('ATM', 'Gene', (98, 101))	('TP53', 'Gene', (121, 125))	('occurred', 'Reg', (16, 24))	('ATM', 'Gene', '472', (98, 101))	('BRCA2', 'Gene', (127, 132))	('mutations', 'Var', (6, 15))
567362	32104210	In a GWAS reported in 2019, Hung et al detected three SNPs (rs31490, rs380286 and rs4975616), also mapped to the 5p15.33 CLPTM1-like TERT region, which were linked to genetic susceptibility to lung cancer in a European cohort of never-smokers.	('rs380286', 'Var', (69, 77))	('rs31490', 'Var', (60, 67))	('TERT', 'Gene', (133, 137))	('lung cancer', 'Disease', 'MESH:D008175', (193, 204))	('TERT', 'Gene', '7015', (133, 137))	('CLPTM1', 'Gene', '1209', (121, 127))	('CLPTM1', 'Gene', (121, 127))	('rs380286', 'Mutation', 'rs380286', (69, 77))	('rs4975616', 'Var', (82, 91))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('rs31490', 'Mutation', 'rs31490', (60, 67))	('rs4975616', 'Mutation', 'rs4975616', (82, 91))	('lung cancer', 'Disease', (193, 204))	('lung cancer', 'Phenotype', 'HP:0100526', (193, 204))
567365	32104210	The three alleles identified in the studies of Caucasian populations mentioned above were found to be rare in the Asian population, but the study demonstrated an increased risk of lung cancer associated with four other SNPs in 15q25 (rs2036534C > T, rs667282C > T, rs12910984G > A and rs6495309T > C).	('rs12910984G > A', 'Var', (265, 280))	('rs12910984G > A', 'DBSNP_MENTION', 'None', (265, 280))	('men', 'Species', '9606', (69, 72))	('rs6495309T > C', 'Var', (285, 299))	('lung cancer', 'Disease', 'MESH:D008175', (180, 191))	('cancer', 'Phenotype', 'HP:0002664', (185, 191))	('rs2036534C > T', 'DBSNP_MENTION', 'None', (234, 248))	('rs667282C > T', 'DBSNP_MENTION', 'None', (250, 263))	('lung cancer', 'Disease', (180, 191))	('rs667282C > T', 'Var', (250, 263))	('lung cancer', 'Phenotype', 'HP:0100526', (180, 191))	('rs2036534C > T', 'Var', (234, 248))	('rs6495309T > C', 'DBSNP_MENTION', 'None', (285, 299))
567366	32104210	In 2014, a GWAS of data from more than 20,000 cases and 40,000 controls revealed a strong association of the risk of squamous cell carcinoma development with rare variants of BRCA2-K3326X [rs11571833; odds ratio (OR) = 2.47, p = 4.74 x 10-20] and CHEK2-I157 (rs17879961; OR = 0.38, p = 1.27 x 10-13).	('rs11571833', 'Mutation', 'rs11571833', (189, 199))	('K3326X', 'Mutation', 'rs11571833', (181, 187))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (117, 140))	('rs17879961;', 'Var', (259, 270))	('squamous cell carcinoma', 'Disease', (117, 140))	('CHEK2', 'Gene', '11200', (247, 252))	('carcinoma', 'Phenotype', 'HP:0030731', (131, 140))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (117, 140))	('CHEK2', 'Gene', (247, 252))	('men', 'Species', '9606', (148, 151))	('BRCA2', 'Gene', (175, 180))	('rs17879961', 'Mutation', 'rs17879961', (259, 269))	('BRCA2', 'Gene', '675', (175, 180))
567367	32104210	For adenocarcinoma histology, the authors described a common variation at 3q28 (TP63; rs13314271; OR = 1.13, p = 7.22 x 10-10) previously associated with cancer only among Asians.	('TP63', 'Gene', (80, 84))	('carcinoma', 'Phenotype', 'HP:0030731', (9, 18))	('cancer', 'Disease', (154, 160))	('adenocarcinoma', 'Disease', (4, 18))	('associated with', 'Reg', (138, 153))	('cancer', 'Disease', 'MESH:D009369', (154, 160))	('rs13314271', 'Mutation', 'rs13314271', (86, 96))	('rs13314271', 'Var', (86, 96))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('adenocarcinoma', 'Disease', 'MESH:D000230', (4, 18))	('TP63', 'Gene', '8626', (80, 84))
567368	32104210	A study published in 2018 showed that chromosome 15q25 modifies lung cancer risk and is involved in the pathogenesis of this disease via activation of the neuroactive ligand receptor interaction pathway.	('lung cancer', 'Disease', (64, 75))	('lung cancer', 'Phenotype', 'HP:0100526', (64, 75))	('chromosome 15q25', 'Var', (38, 54))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('lung cancer', 'Disease', 'MESH:D008175', (64, 75))	('neuroactive ligand receptor interaction pathway', 'Pathway', (155, 202))	('activation', 'PosReg', (137, 147))	('modifies', 'Reg', (55, 63))
567370	32104210	Other variants associated with lung cancer susceptibility in GWASs are 6p21 and 5p15.	('lung cancer', 'Disease', 'MESH:D008175', (31, 42))	('5p15', 'Var', (80, 84))	('lung cancer', 'Disease', (31, 42))	('lung cancer', 'Phenotype', 'HP:0100526', (31, 42))	('cancer', 'Phenotype', 'HP:0002664', (36, 42))
567378	32104210	Case reports have described germline mutations in the kinase domain of the EGFR, such as R776G, R776H, T790M, V843I and P848L, which confer a greater risk of cancer development.	('T790M', 'Var', (103, 108))	('R776G', 'Var', (89, 94))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))	('P848L', 'Mutation', 'rs148934350', (120, 125))	('P848L', 'Var', (120, 125))	('R776H', 'Mutation', 'rs483352806', (96, 101))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('R776G', 'Mutation', 'p.R776G', (89, 94))	('V843I', 'Var', (110, 115))	('V843I', 'Mutation', 'rs146795390', (110, 115))	('cancer', 'Disease', (158, 164))	('R776H', 'Var', (96, 101))	('T790M', 'Mutation', 'rs121434569', (103, 108))	('men', 'Species', '9606', (172, 175))	('EGFR', 'Gene', (75, 79))
567379	32104210	Among these, T790M seems to be associated with a specific lung cancer syndrome targeting never-smokers.	('cancer', 'Phenotype', 'HP:0002664', (63, 69))	('associated with', 'Reg', (31, 46))	('lung cancer', 'Phenotype', 'HP:0100526', (58, 69))	('T790M', 'Mutation', 'rs121434569', (13, 18))	('T790M', 'Var', (13, 18))	('lung cancer syndrome', 'Disease', 'MESH:D008175', (58, 78))	('lung cancer syndrome', 'Disease', (58, 78))
567380	32104210	In various studies, Sanger sequencing has correlated familial clustering of lung cancer with a germline T790M mutation in EGFR.	('lung cancer', 'Disease', 'MESH:D008175', (76, 87))	('T790M', 'Var', (104, 109))	('EGFR', 'Gene', (122, 126))	('lung cancer', 'Disease', (76, 87))	('lung cancer', 'Phenotype', 'HP:0100526', (76, 87))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('T790M', 'Mutation', 'rs121434569', (104, 109))
567382	32104210	Although the presence of the EGFR T790M mutation seems to be sufficient to induce tumour formation in mouse models, this mutation is characterised as weakly oncogenic.	('tumour', 'Phenotype', 'HP:0002664', (82, 88))	('tumour', 'Disease', 'MESH:D009369', (82, 88))	('mouse', 'Species', '10090', (102, 107))	('T790M', 'Mutation', 'rs121434569', (34, 39))	('tumour', 'Disease', (82, 88))	('EGFR', 'Gene', (29, 33))	('T790M', 'Var', (34, 39))	('induce', 'PosReg', (75, 81))
567383	32104210	Seventy-three percent of patients with lung cancer and the germline T790M mutation have been found to carry a second activating mutation, most commonly the L858R mutation.	('lung cancer', 'Phenotype', 'HP:0100526', (39, 50))	('L858R', 'Mutation', 'rs121434568', (156, 161))	('lung cancer', 'Disease', (39, 50))	('T790M', 'Mutation', 'rs121434569', (68, 73))	('lung cancer', 'Disease', 'MESH:D008175', (39, 50))	('patients', 'Species', '9606', (25, 33))	('T790M', 'Var', (68, 73))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('L858R', 'Var', (156, 161))
567384	32104210	The germline T790M EGFR mutation is present in approximately 1% of NSCLC cases with a median age at diagnosis of 40 years, and the most common histology is adenocarcinoma.	('adenocarcinoma', 'Disease', (156, 170))	('adenocarcinoma', 'Disease', 'MESH:D000230', (156, 170))	('EGFR', 'Gene', (19, 23))	('T790M', 'Mutation', 'rs121434569', (13, 18))	('NSCLC', 'Disease', (67, 72))	('T790M', 'Var', (13, 18))	('carcinoma', 'Phenotype', 'HP:0030731', (161, 170))	('common', 'Reg', (136, 142))	('NSCLC', 'Disease', 'MESH:D002289', (67, 72))
567385	32104210	Although somatic mutations in EGFR are more common among patients from East Asia, the prevalence of germline mutations in lung cancer cases in Japan was lower than that in North America, and, to our knowledge, no case of germline T790M EGFR mutation in East Asia has been reported in the literature.	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('EGFR', 'Gene', (30, 34))	('lung cancer', 'Disease', (122, 133))	('lung cancer', 'Phenotype', 'HP:0100526', (122, 133))	('patients', 'Species', '9606', (57, 65))	('T790M', 'Mutation', 'rs121434569', (230, 235))	('lung cancer', 'Disease', 'MESH:D008175', (122, 133))	('mutations', 'Var', (17, 26))
567386	32104210	Sporadic EGFR mutation and germline T790M EGFR mutation are associated more frequently with female sex and non-smoking status.	('T790M', 'Mutation', 'rs121434569', (36, 41))	('EGFR', 'Gene', (42, 46))	('mutation', 'Var', (14, 22))	('EGFR', 'Gene', (9, 13))	('germline T790M', 'Var', (27, 41))	('associated', 'Reg', (60, 70))
567387	32104210	The screening of unselected populations has no proven benefit, but, as the germline T790M EGFR mutation is present in approximately 50% of patients with baseline T790M EGFR identified in pre-treatment evaluation, some authors have suggested that these patients should be referred for routine germline genotyping to identify carriers.	('T790M', 'Var', (162, 167))	('T790M', 'Mutation', 'rs121434569', (84, 89))	('men', 'Species', '9606', (196, 199))	('patients', 'Species', '9606', (139, 147))	('T790M', 'Var', (84, 89))	('patients', 'Species', '9606', (252, 260))	('EGFR', 'Gene', (90, 94))	('T790M', 'Mutation', 'rs121434569', (162, 167))
567389	32104210	Among the 105 participants, germline EGFR mutations were found in 63% of patients with EGFR T790M detected in lung cancer tissue at diagnosis, and in 62% (16 of 27) and 44% (4 of 9) of first- and second-degree relatives of germline carriers, respectively.	('lung cancer', 'Disease', 'MESH:D008175', (110, 121))	('T790M', 'Mutation', 'rs121434569', (92, 97))	('T790M', 'Var', (92, 97))	('EGFR', 'Gene', (87, 91))	('cancer', 'Phenotype', 'HP:0002664', (115, 121))	('lung cancer', 'Disease', (110, 121))	('lung cancer', 'Phenotype', 'HP:0100526', (110, 121))	('participants', 'Species', '9606', (14, 26))	('patients', 'Species', '9606', (73, 81))
567391	32104210	Tumour genotyping revealed somatic EGFR co-mutations in 94% of probands: 6 exon 19 del, 12 L858R, 6 G719X, 1 exon 19 del and G719R, 1 L861Q, 2 H773R and 1 V774M.	('L858R', 'Mutation', 'rs121434568', (91, 96))	('L861Q', 'Mutation', 'rs121913444', (134, 139))	('G719R', 'Var', (125, 130))	('EGFR', 'Gene', (35, 39))	('G719R', 'Mutation', 'rs28929495', (125, 130))	('V774M', 'Mutation', 'rs567477136', (155, 160))	('G719X', 'Mutation', 'p.G719X', (100, 105))	('H773R', 'Mutation', 'rs121913432', (143, 148))	('Tumour', 'Phenotype', 'HP:0002664', (0, 6))	('V774M', 'Var', (155, 160))	('L858R', 'Var', (91, 96))	('G719X', 'Var', (100, 105))	('H773R', 'Var', (143, 148))	('L861Q', 'Var', (134, 139))
567400	32104210	In an analysis of 555 lung adenocarcinoma cases from The Cancer Genome Atlas, 14 pathogenic mutations in five genes were identified.	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (22, 41))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (22, 41))	('carcinoma', 'Phenotype', 'HP:0030731', (32, 41))	('mutations', 'Var', (92, 101))	('lung adenocarcinoma', 'Disease', (22, 41))	('Cancer', 'Phenotype', 'HP:0002664', (57, 63))
567401	32104210	Among patients with TP53 mutations, the most common variants found were TP53 R267Q, TP53 P152L and TP53 R158L, all previously linked to LFS.	('patients', 'Species', '9606', (6, 14))	('TP53', 'Gene', (84, 88))	('mutations', 'Var', (25, 34))	('R267Q', 'Mutation', 'rs587780075', (77, 82))	('LFS', 'Disease', (136, 139))	('TP53', 'Gene', (20, 24))	('TP53', 'Gene', '7157', (72, 76))	('R158L', 'Mutation', 'rs587782144', (104, 109))	('P152L', 'Var', (89, 94))	('LFS', 'Disease', 'MESH:D016864', (136, 139))	('linked', 'Reg', (126, 132))	('TP53', 'Gene', (99, 103))	('R158L', 'Var', (104, 109))	('TP53', 'Gene', '7157', (84, 88))	('P152L', 'Mutation', 'rs587782705', (89, 94))	('R267Q', 'Var', (77, 82))	('TP53', 'Gene', '7157', (20, 24))	('TP53', 'Gene', (72, 76))	('TP53', 'Gene', '7157', (99, 103))
567402	32104210	In some reports, EGFR mutations have been detected in patients with LFS who develop lung cancer; the loss of p53 function may free the promoter of the EGFR gene and make the gene more susceptible to the occurrence of mutations.	('lung cancer', 'Disease', (84, 95))	('function', 'MPA', (113, 121))	('LFS', 'Disease', (68, 71))	('lung cancer', 'Phenotype', 'HP:0100526', (84, 95))	('EGFR', 'Gene', (151, 155))	('patients', 'Species', '9606', (54, 62))	('loss', 'Var', (101, 105))	('promoter', 'MPA', (135, 143))	('free', 'NegReg', (126, 130))	('LFS', 'Disease', 'MESH:D016864', (68, 71))	('p53', 'Gene', (109, 112))	('p53', 'Gene', '7157', (109, 112))	('lung cancer', 'Disease', 'MESH:D008175', (84, 95))	('susceptible', 'MPA', (184, 195))	('cancer', 'Phenotype', 'HP:0002664', (89, 95))
567403	32104210	BRCA mutations have always been associated more frequently with breast and ovarian cancer syndrome, but a 2017 study showed that the frequencies of other cancers were higher among subjects in hereditary than in non-hereditary branches of the families of patients eligible for BRCA testing, especially in the lung, kidney, liver and larynx.	('BRCA', 'Gene', (0, 4))	('cancers', 'Phenotype', 'HP:0002664', (154, 161))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('BRCA', 'Gene', '672', (276, 280))	('mutations', 'Var', (5, 14))	('higher', 'Reg', (167, 173))	('cancers', 'Disease', 'MESH:D009369', (154, 161))	('breast and ovarian cancer syndrome', 'Disease', 'MESH:D061325', (64, 98))	('BRCA', 'Gene', (276, 280))	('cancers', 'Disease', (154, 161))	('ovarian cancer', 'Phenotype', 'HP:0100615', (75, 89))	('cancer', 'Phenotype', 'HP:0002664', (154, 160))	('patients', 'Species', '9606', (254, 262))	('BRCA', 'Gene', '672', (0, 4))
567409	32104210	Such mutations are found in 1.6%-2.5% of NSCLC cases.	('NSCLC', 'Disease', (41, 46))	('NSCLC', 'Disease', 'MESH:D002289', (41, 46))	('mutations', 'Var', (5, 14))	('found', 'Reg', (19, 24))
567411	32104210	A Japanese study published in 2013 was the first to describe germline HER2 mutations in the transmembrane domain as conferring potential susceptibility to lung cancer.	('HER2', 'Gene', (70, 74))	('susceptibility', 'Reg', (137, 151))	('HER2', 'Gene', '2064', (70, 74))	('mutations in', 'Var', (75, 87))	('lung cancer', 'Disease', (155, 166))	('lung cancer', 'Phenotype', 'HP:0100526', (155, 166))	('cancer', 'Phenotype', 'HP:0002664', (160, 166))	('lung cancer', 'Disease', 'MESH:D008175', (155, 166))
567412	32104210	The germline variant G660D was identified through whole-exome sequencing in a Japanese family with a high rate of lung cancer.	('G660D', 'Mutation', 'rs1196929947', (21, 26))	('lung cancer', 'Disease', 'MESH:D008175', (114, 125))	('lung cancer', 'Disease', (114, 125))	('lung cancer', 'Phenotype', 'HP:0100526', (114, 125))	('G660D', 'Var', (21, 26))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
567415	32104210	With the hypothesis that mutations in the transmembrane domain of HER2 act as drivers, the researchers sequenced exon 17 of HER2 in samples of 315 sporadic NSCLCs, 253 of which were adenocarcinomas, and identified a novel non-synonymous somatic mutation, V659E, in one patient.	('V659E', 'Mutation', 'p.V659E', (255, 260))	('mutations', 'Var', (25, 34))	('HER2', 'Gene', '2064', (124, 128))	('HER2', 'Gene', '2064', (66, 70))	('adenocarcinomas', 'Disease', 'MESH:D000230', (182, 197))	('V659E', 'Var', (255, 260))	('adenocarcinomas', 'Disease', (182, 197))	('carcinoma', 'Phenotype', 'HP:0030731', (187, 196))	('NSCLCs', 'Disease', (156, 162))	('patient', 'Species', '9606', (269, 276))	('NSCLCs', 'Disease', 'MESH:D002289', (156, 162))	('HER2', 'Gene', (124, 128))	('HER2', 'Gene', (66, 70))
567419	32104210	In this family, individuals in whom YAP1 mutation was detected (smokers and never-smokers, aged 50-89 years) had been diagnosed with lung adenocarcinoma or were being monitored due to the detection of ground-glass opacities.	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (133, 152))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (133, 152))	('detected', 'Reg', (54, 62))	('mutation', 'Var', (41, 49))	('YAP1', 'Gene', (36, 40))	('YAP1', 'Gene', '10413', (36, 40))	('lung adenocarcinoma', 'Disease', (133, 152))	('carcinoma', 'Phenotype', 'HP:0030731', (143, 152))	('diagnosed', 'Reg', (118, 127))
567424	32104210	Exome analysis revealed non-synonymous homozygous mutations in CHEK2, FCGRT, INPP5J, MYO18B and SFI1.	('FCGRT', 'Gene', (70, 75))	('revealed', 'Reg', (15, 23))	('CHEK2', 'Gene', (63, 68))	('CHEK2', 'Gene', '11200', (63, 68))	('SFI1', 'Gene', (96, 100))	('INPP5J', 'Gene', (77, 83))	('FCGRT', 'Gene', '2217', (70, 75))	('SFI1', 'Gene', '9814', (96, 100))	('MYO18B', 'Gene', (85, 91))	('INPP5J', 'Gene', '27124', (77, 83))	('non-synonymous homozygous mutations', 'Var', (24, 59))	('MYO18B', 'Gene', '84700', (85, 91))
567425	32104210	The mutation in CHEK2 altered the tertiary structure of CHK2 by disrupting the salt bridge between p.R474 and p.E394, making it unstable.	('p.R474', 'Var', (99, 105))	('p.E394', 'Var', (110, 116))	('CHK2', 'Gene', '11200', (56, 60))	('salt bridge', 'MPA', (79, 90))	('disrupting', 'NegReg', (64, 74))	('tertiary structure', 'MPA', (34, 52))	('mutation', 'Var', (4, 12))	('CHEK2', 'Gene', '11200', (16, 21))	('altered', 'Reg', (22, 29))	('unstable', 'MPA', (128, 136))	('CHEK2', 'Gene', (16, 21))	('CHK2', 'Gene', (56, 60))
567427	32104210	However, further studies need to be performed to establish the pathogenic role of this CHEK2 mutation in human carcinogenesis.	('carcinogenesis', 'Disease', (111, 125))	('CHEK2', 'Gene', (87, 92))	('CHEK2', 'Gene', '11200', (87, 92))	('carcinogenesis', 'Disease', 'MESH:D063646', (111, 125))	('human', 'Species', '9606', (105, 110))	('mutation', 'Var', (93, 101))
567429	32104210	Among the 12 most highly mutated genes, as validated by a polymerase chain reaction and DNA sequencing, they identified five genes (ARHGEF5, ANKRD20A2, ZNF595, ZNF812 and MYO18B) with germline mutations potentially associated with lung cancer development.	('lung cancer', 'Disease', (231, 242))	('MYO18B', 'Gene', (171, 177))	('ZNF595', 'Gene', '152687', (152, 158))	('lung cancer', 'Phenotype', 'HP:0100526', (231, 242))	('ANKRD20A2', 'Gene', '441430', (141, 150))	('ZNF812', 'Gene', '729648', (160, 166))	('ZNF595', 'Gene', (152, 158))	('ANKRD20A2', 'Gene', (141, 150))	('ARHGEF5', 'Gene', (132, 139))	('men', 'Species', '9606', (250, 253))	('lung cancer', 'Disease', 'MESH:D008175', (231, 242))	('MYO18B', 'Gene', '84700', (171, 177))	('associated', 'Reg', (215, 225))	('cancer', 'Phenotype', 'HP:0002664', (236, 242))	('germline', 'Var', (184, 192))	('ZNF812', 'Gene', (160, 166))	('ARHGEF5', 'Gene', '7984', (132, 139))
567430	32104210	Some mutations in the MUC12, FOXD4L3 and FOXD4L5 genes occurred at greater frequencies in samples from subjects with the familial lung cancer or in lung cancer tissue compared with samples from healthy subjects.	('lung cancer', 'Phenotype', 'HP:0100526', (130, 141))	('familial lung cancer', 'Disease', 'MESH:D008175', (121, 141))	('FOXD4L3', 'Gene', (29, 36))	('lung cancer', 'Disease', 'MESH:D008175', (148, 159))	('MUC12', 'Gene', (22, 27))	('MUC12', 'Gene', '10071', (22, 27))	('mutations', 'Var', (5, 14))	('cancer', 'Phenotype', 'HP:0002664', (135, 141))	('lung cancer', 'Disease', 'MESH:D008175', (130, 141))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('lung cancer', 'Disease', (148, 159))	('familial lung cancer', 'Disease', (121, 141))	('FOXD4L5', 'Gene', '653427', (41, 48))	('FOXD4L5', 'Gene', (41, 48))	('lung cancer', 'Phenotype', 'HP:0100526', (148, 159))	('FOXD4L3', 'Gene', '286380', (29, 36))	('occurred', 'Reg', (55, 63))
567432	32104210	To evaluate genetic predisposition risk, germline variants from the 36 initial patients and 28 additional lung adenocarcinoma cases were analysed; the frequency of pathogenic and likely pathogenic germline mutations among young patients was 78.3%.	('patients', 'Species', '9606', (228, 236))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (106, 125))	('germline', 'Var', (197, 205))	('lung adenocarcinoma', 'Disease', 'MESH:C538231', (106, 125))	('patients', 'Species', '9606', (79, 87))	('carcinoma', 'Phenotype', 'HP:0030731', (116, 125))	('pathogenic', 'Reg', (164, 174))	('lung adenocarcinoma', 'Disease', (106, 125))
567433	32104210	The main germline mutations identified were BPIFB1 (rs6141383, p.V284M), CHD4 (rs74790047, p.D140E), PARP1 (rs3219145, p.K940R), NUDT1 (rs4866, p.V83M), RAD52 (rs4987207, p.S346*) and MFI2 (rs17129219, p.A559T).	('rs4866', 'Mutation', 'rs4866', (136, 142))	('rs74790047', 'Mutation', 'rs74790047', (79, 89))	('RAD52', 'Gene', (153, 158))	('p.K940R', 'Var', (119, 126))	('p.S346*', 'Var', (171, 178))	('MFI2', 'Gene', (184, 188))	('NUDT1', 'Gene', '4521', (129, 134))	('p.V83M', 'Mutation', 'rs4866', (144, 150))	('p.D140E', 'Mutation', 'rs74790047', (91, 98))	('rs4866', 'Var', (136, 142))	('PARP1', 'Gene', '142', (101, 106))	('p.D140E', 'Var', (91, 98))	('BPIFB1', 'Gene', '92747', (44, 50))	('BPIFB1', 'Gene', (44, 50))	('RAD52', 'Gene', '5893', (153, 158))	('p.A559T', 'Mutation', 'rs17129219', (202, 209))	('CHD4', 'Gene', (73, 77))	('rs6141383', 'Mutation', 'rs6141383', (52, 61))	('p.S346*', 'Mutation', 'rs4987207', (171, 178))	('rs4987207', 'Mutation', 'rs4987207', (160, 169))	('rs6141383', 'Var', (52, 61))	('rs3219145', 'Mutation', 'rs3219145', (108, 117))	('rs17129219', 'Mutation', 'rs17129219', (190, 200))	('rs17129219', 'Var', (190, 200))	('CHD4', 'Gene', '1108', (73, 77))	('MFI2', 'Gene', '4241', (184, 188))	('rs74790047', 'Var', (79, 89))	('rs3219145', 'Var', (108, 117))	('p.K940R', 'Mutation', 'rs3219145', (119, 126))	('p.V284M', 'Mutation', 'rs6141383', (63, 70))	('PARP1', 'Gene', (101, 106))	('NUDT1', 'Gene', (129, 134))	('rs4987207', 'Var', (160, 169))
567434	32104210	A TP53 missense germline mutation (rs121912664, p. R205H) was found in one individual with a tumour that appeared to be hypermutated relative to the others.	('R205H', 'SUBSTITUTION', 'None', (51, 56))	('tumour', 'Disease', (93, 99))	('tumour', 'Disease', 'MESH:D009369', (93, 99))	('R205H', 'Var', (51, 56))	('TP53', 'Gene', '7157', (2, 6))	('tumour', 'Phenotype', 'HP:0002664', (93, 99))	('rs121912664', 'Var', (35, 46))	('rs121912664', 'Mutation', 'rs121912664', (35, 46))	('TP53', 'Gene', (2, 6))
567439	32104210	Most commercial laboratories offer limited or no testing for hereditary lung cancer variants, and no guideline has been established for the best way to manage unaffected carriers of variants associated with lung cancer, such as germline EGFR T790M, HER2 and YAP1 mutations.	('hereditary lung cancer', 'Disease', (61, 83))	('T790M', 'Mutation', 'rs121434569', (242, 247))	('lung cancer', 'Disease', 'MESH:D008175', (207, 218))	('lung cancer', 'Phenotype', 'HP:0100526', (207, 218))	('HER2', 'Gene', (249, 253))	('YAP1', 'Gene', (258, 262))	('T790M', 'Var', (242, 247))	('mutations', 'Var', (263, 272))	('YAP1', 'Gene', '10413', (258, 262))	('HER2', 'Gene', '2064', (249, 253))	('EGFR T790M', 'Var', (237, 247))	('hereditary lung cancer', 'Disease', 'MESH:D009386', (61, 83))	('lung cancer', 'Phenotype', 'HP:0100526', (72, 83))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('lung cancer', 'Disease', (207, 218))	('lung cancer', 'Disease', 'MESH:D008175', (72, 83))	('cancer', 'Phenotype', 'HP:0002664', (212, 218))
567447	28925402	MDM2 SNP309G is a functional polymorphism that results in elevated levels of MDM2 (due to enhanced SP1 binding to the MDM2 promoter) thus decreasing p53 activity.	('levels', 'MPA', (67, 73))	('binding', 'Interaction', (103, 110))	('MDM2 SNP309G', 'Var', (0, 12))	('activity', 'MPA', (153, 161))	('enhanced', 'PosReg', (90, 98))	('SNP309', 'Chemical', '-', (5, 11))	('MDM2', 'MPA', (77, 81))	('SP1', 'Protein', (99, 102))	('p53', 'Enzyme', (149, 152))	('elevated', 'PosReg', (58, 66))	('SNP309G', 'Var', (5, 12))	('decreasing', 'NegReg', (138, 148))
567448	28925402	Mdm2SNP309G/G mice are more prone to spontaneous tumor formation than Mdm2SNP309T/T mice, providing direct evidence for the impact of this SNP in tumor development.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('mice', 'Species', '10090', (14, 18))	('tumor', 'Disease', (146, 151))	('prone', 'PosReg', (28, 33))	('tumor', 'Disease', (49, 54))	('Mdm2SNP309G/G', 'Var', (0, 13))	('mice', 'Species', '10090', (84, 88))	('tumor', 'Disease', 'MESH:D009369', (146, 151))
567449	28925402	We asked whether environmental factors impact SNP309G function and show that SNP309G cooperates with ionizing radiation to exacerbate tumor development.	('exacerbate', 'PosReg', (123, 133))	('tumor', 'Disease', 'MESH:D009369', (134, 139))	('SNP309', 'Chemical', '-', (46, 52))	('SNP309', 'Chemical', '-', (77, 83))	('tumor', 'Phenotype', 'HP:0002664', (134, 139))	('SNP309G', 'Var', (77, 84))	('tumor', 'Disease', (134, 139))
567450	28925402	Surprisingly, ultraviolet B light or Benzo(a)pyrene exposure of skin shows that SNP309G allele actually protects against squamous cell carcinoma susceptibility.	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (121, 144))	('protects', 'Reg', (104, 112))	('carcinoma', 'Phenotype', 'HP:0030731', (135, 144))	('squamous cell carcinoma', 'Disease', (121, 144))	('SNP309', 'Chemical', '-', (80, 86))	('Benzo(a)pyrene', 'Chemical', 'MESH:D001564', (37, 51))	('SNP309G', 'Var', (80, 87))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (121, 144))
567454	28925402	Our data show that E2F6 suppresses Mdm2 expression in cells harboring the SNP309G allele but not the SNP309T allele.	('SNP309G', 'Var', (74, 81))	('expression', 'MPA', (40, 50))	('E2F6', 'Gene', '50496', (19, 23))	('E2F6', 'Gene', (19, 23))	('suppresses', 'NegReg', (24, 34))	('Mdm2', 'Gene', '17246', (35, 39))	('SNP309', 'Chemical', '-', (101, 107))	('Mdm2', 'Gene', (35, 39))	('SNP309', 'Chemical', '-', (74, 80))
567455	28925402	Thus, Mdm2 SNP309G exhibits tissue-specific regulation and differentially impacts cancer risk.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('Mdm2', 'Gene', '17246', (6, 10))	('SNP309', 'Chemical', '-', (11, 17))	('impacts', 'Reg', (74, 81))	('SNP309G', 'Var', (11, 18))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('Mdm2', 'Gene', (6, 10))
567456	28925402	Functional SNPs in tumor suppressor pathways exist and mechanistic studies to determine how these genetic variants destabilize cell homeostasis and contribute to cancer risk may provide insight for prevention and treatment of human cancer.	('contribute', 'Reg', (148, 158))	('cancer', 'Disease', 'MESH:D009369', (162, 168))	('cancer', 'Disease', 'MESH:D009369', (232, 238))	('human', 'Species', '9606', (226, 231))	('variants', 'Var', (106, 114))	('destabilize', 'NegReg', (115, 126))	('cancer', 'Disease', (162, 168))	('cancer', 'Disease', (232, 238))	('tumor', 'Disease', 'MESH:D009369', (19, 24))	('tumor', 'Phenotype', 'HP:0002664', (19, 24))	('cancer', 'Phenotype', 'HP:0002664', (162, 168))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('tumor', 'Disease', (19, 24))	('cell homeostasis', 'MPA', (127, 143))
567460	28925402	Previous studies have illustrated the interrelationship between these two proteins; p53 transcriptionally activates the Mdm2 gene, which in turn produces a protein that binds and inhibits p53 activity creating a negative feedback loop.	('p53', 'Var', (84, 87))	('inhibits', 'NegReg', (179, 187))	('Mdm2', 'Gene', (120, 124))	('p53', 'Protein', (188, 191))	('binds', 'Interaction', (169, 174))	('activates', 'PosReg', (106, 115))	('activity', 'MPA', (192, 200))	('Mdm2', 'Gene', '17246', (120, 124))
567461	28925402	In addition, mouse models with Mdm2 deletion exhibit embryonic lethality, a phenotype that is completely rescued by p53 deletion.	('mouse', 'Species', '10090', (13, 18))	('deletion', 'Var', (36, 44))	('Mdm2', 'Gene', (31, 35))	('Mdm2', 'Gene', '17246', (31, 35))	('embryonic lethality', 'Disease', 'MESH:D020964', (53, 72))	('embryonic lethality', 'Disease', (53, 72))
567462	28925402	Moreover, tumor studies revealed a mutually exclusive relationship between MDM2 and p53; tumors harboring MDM2 amplification seldom carry TP53 mutations.	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('tumors', 'Disease', (89, 95))	('amplification', 'Var', (111, 124))	('tumors', 'Phenotype', 'HP:0002664', (89, 95))	('tumor', 'Disease', (10, 15))	('tumors', 'Disease', 'MESH:D009369', (89, 95))	('TP53', 'Gene', (138, 142))	('MDM2', 'Gene', (106, 110))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))
567463	28925402	MDM2 SNP309G is a functional polymorphism in the p53 pathway that associates with increased cancer risk in many cancer types, including lung, colon, pancreas, endometrium, and head and neck.	('colon', 'Disease', 'MESH:D015179', (142, 147))	('cancer', 'Disease', (92, 98))	('cancer', 'Disease', (112, 118))	('endometrium', 'Disease', (159, 170))	('pancreas', 'Disease', (149, 157))	('p53 pathway', 'Pathway', (49, 60))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('pancreas', 'Disease', 'MESH:D010190', (149, 157))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('colon', 'Disease', (142, 147))	('SNP309', 'Chemical', '-', (5, 11))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('lung', 'Disease', (136, 140))	('MDM2 SNP309G', 'Var', (0, 12))
567464	28925402	Furthermore, genetically engineered mice harboring the homozygous Mdm2 SNP309G allele are more susceptible to spontaneous tumor formation and exhibit a significantly lower overall survival compared to homozygous Mdm2 SNP309T mice.	('susceptible', 'Reg', (95, 106))	('Mdm2', 'Gene', (212, 216))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('Mdm2', 'Gene', '17246', (66, 70))	('lower', 'NegReg', (166, 171))	('Mdm2', 'Gene', (66, 70))	('mice', 'Species', '10090', (225, 229))	('mice', 'Species', '10090', (36, 40))	('SNP309', 'Chemical', '-', (71, 77))	('Mdm2', 'Gene', '17246', (212, 216))	('SNP309G', 'Var', (71, 78))	('more', 'PosReg', (90, 94))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumor', 'Disease', (122, 127))	('SNP309', 'Chemical', '-', (217, 223))
567465	28925402	Mechanistically the SNP309G sequence creates a stronger binding site for the transcription factor SP1 in the MDM2 P2 promoter, which results in elevated MDM2 expression leading to dampened p53 activity.	('MDM2', 'Gene', (153, 157))	('SNP309G sequence', 'Var', (20, 36))	('SNP309', 'Chemical', '-', (20, 26))	('stronger', 'PosReg', (47, 55))	('expression', 'MPA', (158, 168))	('activity', 'MPA', (193, 201))	('elevated', 'PosReg', (144, 152))	('binding', 'Interaction', (56, 63))	('p53', 'Enzyme', (189, 192))	('dampened', 'NegReg', (180, 188))
567466	28925402	However, recent studies have identified a protective role of SNP309G in some cancers.	('SNP309G', 'Var', (61, 68))	('cancers', 'Phenotype', 'HP:0002664', (77, 84))	('cancers', 'Disease', 'MESH:D009369', (77, 84))	('cancers', 'Disease', (77, 84))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('SNP309', 'Chemical', '-', (61, 67))
567467	28925402	For example, multiple studies associate the SNP309G allele with a decreased risk and late onset for prostate cancer compared to patients harboring the SNP309T allele.	('prostate cancer', 'Disease', 'MESH:D011471', (100, 115))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('prostate cancer', 'Phenotype', 'HP:0012125', (100, 115))	('SNP309', 'Chemical', '-', (151, 157))	('decreased', 'NegReg', (66, 75))	('prostate cancer', 'Disease', (100, 115))	('patients', 'Species', '9606', (128, 136))	('SNP309G', 'Var', (44, 51))	('SNP309', 'Chemical', '-', (44, 50))
567468	28925402	Thus, SNP309 appears to differentially impact cancer susceptibility in different cancers for reasons that are currently unknown.	('SNP309', 'Var', (6, 12))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('impact', 'Reg', (39, 45))	('cancer', 'Disease', 'MESH:D009369', (81, 87))	('cancer', 'Disease', (46, 52))	('SNP309', 'Chemical', '-', (6, 12))	('cancers', 'Phenotype', 'HP:0002664', (81, 88))	('cancer', 'Disease', (81, 87))	('cancers', 'Disease', (81, 88))	('cancers', 'Disease', 'MESH:D009369', (81, 88))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))
567469	28925402	Functional SNPs may exacerbate cancer risk by exposure to environmental factors, yet these mechanisms are also poorly defined.	('exacerbate', 'PosReg', (20, 30))	('cancer', 'Phenotype', 'HP:0002664', (31, 37))	('cancer', 'Disease', 'MESH:D009369', (31, 37))	('cancer', 'Disease', (31, 37))	('Functional SNPs', 'Var', (0, 15))
567470	28925402	Our current study tested the hypothesis that Mdm2 SNP309G allele cooperates with environmental factors to exacerbate spontaneous cancer risk.	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('Mdm2', 'Gene', '17246', (45, 49))	('exacerbate', 'PosReg', (106, 116))	('cancer', 'Disease', (129, 135))	('cancer', 'Disease', 'MESH:D009369', (129, 135))	('Mdm2', 'Gene', (45, 49))	('SNP309', 'Chemical', '-', (50, 56))	('SNP309G', 'Var', (50, 57))
567471	28925402	Low dose ionizing radiation (IR), a source of reactive oxygen species (ROS) and DNA damage, exacerbates spontaneous tumor formation in the Mdm2SNP309G/G mouse compared to Mdm2SNP309T/T mice.	('Mdm2SNP309G/G', 'Var', (139, 152))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (46, 69))	('mice', 'Species', '10090', (185, 189))	('tumor', 'Disease', 'MESH:D009369', (116, 121))	('exacerbates', 'PosReg', (92, 103))	('mouse', 'Species', '10090', (153, 158))	('tumor', 'Phenotype', 'HP:0002664', (116, 121))	('ROS', 'Chemical', 'MESH:D017382', (71, 74))	('Low dose ionizing radiation', 'Phenotype', 'HP:0011133', (0, 27))	('tumor', 'Disease', (116, 121))
567472	28925402	Conversely, exposure to ultraviolet B (UVB) light or Benzo(a)pyrene (B(a)P), a carcinogen found in tobacco products, increased tumor risk in the skin of Mdm2SNP309T/T mice compared to Mdm2SNP309G/G mice.	('tumor', 'Phenotype', 'HP:0002664', (127, 132))	('tobacco', 'Species', '4097', (99, 106))	('increased', 'PosReg', (117, 126))	('tumor', 'Disease', (127, 132))	('increased tumor risk in the skin', 'Phenotype', 'HP:0008069', (117, 149))	('B(a)P', 'Chemical', 'MESH:D001564', (69, 74))	('Benzo(a)pyrene', 'Chemical', 'MESH:D001564', (53, 67))	('mice', 'Species', '10090', (198, 202))	('tumor', 'Disease', 'MESH:D009369', (127, 132))	('Mdm2SNP309T/T', 'Var', (153, 166))	('mice', 'Species', '10090', (167, 171))
567473	28925402	Here our investigations show that SNP309G directly alters Mdm2 basal expression in a tissue-dependent manner.	('SNP309', 'Chemical', '-', (34, 40))	('SNP309G', 'Var', (34, 41))	('Mdm2', 'Gene', '17246', (58, 62))	('basal expression', 'MPA', (63, 79))	('Mdm2', 'Gene', (58, 62))	('alters', 'Reg', (51, 57))
567475	28925402	These findings suggest that the SNP309G allele cooperates with environmental and cellular factors to alter cancer risk in a tissue-dependent manner.	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('SNP309', 'Chemical', '-', (32, 38))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('alter', 'Reg', (101, 106))	('SNP309G', 'Var', (32, 39))	('cancer', 'Disease', (107, 113))
567477	28925402	Since SNP309G dampens p53 activity, we tested whether the SNP309G allele cooperates with low dose IR to increase spontaneous tumor risk in mice.	('increase', 'PosReg', (104, 112))	('SNP309G', 'Var', (58, 65))	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('dampens', 'NegReg', (14, 21))	('SNP309', 'Chemical', '-', (58, 64))	('p53', 'Protein', (22, 25))	('SNP309', 'Chemical', '-', (6, 12))	('tested', 'Reg', (39, 45))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('SNP309G', 'Var', (6, 13))	('tumor', 'Disease', (125, 130))	('mice', 'Species', '10090', (139, 143))	('activity', 'MPA', (26, 34))
567478	28925402	First, we treated Mdm2SNP309G/G and Mdm2SNP309T/T mice in a C57BL/6 background with a single dose of 1Gy IR 2 days postpartum, a regimen previously shown to activate acute p53 response in C57BL/6 mouse tissues, and analyzed p53 activity.	('Mdm2SNP309T/T', 'Var', (36, 49))	('activate', 'PosReg', (157, 165))	('mouse', 'Species', '10090', (196, 201))	('acute p53 response', 'MPA', (166, 184))	('Mdm2SNP309G/G', 'Var', (18, 31))	('mice', 'Species', '10090', (50, 54))
567481	28925402	Mdm2SNP309G/G mouse lymphatic tissues exhibit a delay in activation of apoptosis compared to Mdm2SNP309T/T after low-dose IR as measured by the number of cells staining positively for cleaved caspase-3 [Figure 1C, 1D].	('mouse', 'Species', '10090', (14, 19))	('apoptosis', 'CPA', (71, 80))	('caspase-3', 'Gene', '12367', (192, 201))	('Mdm2SNP309G/G', 'Var', (0, 13))	('caspase-3', 'Gene', (192, 201))
567484	28925402	We generated a cohort of irradiated Mdm2SNP309G/G and Mdm2SNP309T/T mice in a C57BL/6 background and monitored for tumor development.	('mice', 'Species', '10090', (68, 72))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('Mdm2SNP309G/G', 'Var', (36, 49))	('tumor', 'Disease', (115, 120))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('Mdm2SNP309T/T', 'Var', (54, 67))
567485	28925402	Tumors developed significantly more quickly in irradiated Mdm2SNP309G/G mice than in irradiated Mdm2SNP309T/T mice (p<0.001) [Figure 2A].	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('mice', 'Species', '10090', (110, 114))	('Tumors', 'Disease', (0, 6))	('Tumors', 'Disease', 'MESH:D009369', (0, 6))	('Tumors', 'Phenotype', 'HP:0002664', (0, 6))	('Mdm2SNP309G/G', 'Var', (58, 71))	('mice', 'Species', '10090', (72, 76))
567486	28925402	Mdm2SNP309G/G mice exhibited a median survival of 74 weeks; in contrast, the majority of Mdm2SNP309T/T mice survived without tumor development and thus the median survival could not be calculated.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('Mdm2SNP309T/T', 'Var', (89, 102))	('mice', 'Species', '10090', (103, 107))	('mice', 'Species', '10090', (14, 18))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('tumor', 'Disease', (125, 130))	('Mdm2SNP309G/G', 'Var', (0, 13))
567487	28925402	Mdm2SNP309G/G mice had a proclivity to develop lymphomas and sarcomas; however, a number of mice also developed other tumors, including mammary carcinomas, glioblastomas, and histiocytic sarcomas [Figure 2B and Table 1].	('mice', 'Species', '10090', (14, 18))	('tumors', 'Phenotype', 'HP:0002664', (118, 124))	('carcinoma', 'Phenotype', 'HP:0030731', (144, 153))	('mice', 'Species', '10090', (92, 96))	('developed', 'PosReg', (102, 111))	('carcinomas', 'Phenotype', 'HP:0030731', (144, 154))	('carcinomas', 'Disease', 'MESH:D002277', (144, 154))	('glioblastomas', 'Disease', (156, 169))	('sarcomas', 'Disease', 'MESH:D012509', (187, 195))	('tumor', 'Phenotype', 'HP:0002664', (118, 123))	('sarcomas', 'Phenotype', 'HP:0100242', (187, 195))	('Mdm2SNP309G/G', 'Var', (0, 13))	('lymphomas', 'Disease', (47, 56))	('sarcomas', 'Disease', (187, 195))	('tumors', 'Disease', (118, 124))	('sarcomas', 'Disease', 'MESH:D012509', (61, 69))	('glioblastomas', 'Disease', 'MESH:D005909', (156, 169))	('develop', 'PosReg', (39, 46))	('sarcomas', 'Phenotype', 'HP:0100242', (61, 69))	('sarcomas', 'Disease', (61, 69))	('lymphoma', 'Phenotype', 'HP:0002665', (47, 55))	('sarcoma', 'Phenotype', 'HP:0100242', (187, 194))	('tumors', 'Disease', 'MESH:D009369', (118, 124))	('sarcoma', 'Phenotype', 'HP:0100242', (61, 68))	('carcinomas', 'Disease', (144, 154))	('glioblastomas', 'Phenotype', 'HP:0012174', (156, 169))	('lymphomas', 'Disease', 'MESH:D008223', (47, 56))	('lymphomas', 'Phenotype', 'HP:0002665', (47, 56))
567488	28925402	In addition, Mdm2SNP309G/G mice treated with 1Gy IR had significantly increased tumor multiplicity compared to Mdm2SNP309T/T mice (p<0.001) [Figure 2C].	('tumor', 'Disease', 'MESH:D009369', (80, 85))	('increased', 'PosReg', (70, 79))	('mice', 'Species', '10090', (27, 31))	('tumor', 'Phenotype', 'HP:0002664', (80, 85))	('tumor', 'Disease', (80, 85))	('mice', 'Species', '10090', (125, 129))	('Mdm2SNP309G/G', 'Var', (13, 26))	('1Gy IR', 'Var', (45, 51))
567489	28925402	Only irradiated Mdm2SNP309G/G mice had three or more tumors per mouse.	('mice', 'Species', '10090', (30, 34))	('Mdm2SNP309G/G', 'Var', (16, 29))	('mouse', 'Species', '10090', (64, 69))	('tumor', 'Phenotype', 'HP:0002664', (53, 58))	('tumors', 'Phenotype', 'HP:0002664', (53, 59))	('tumors', 'Disease', 'MESH:D009369', (53, 59))	('tumors', 'Disease', (53, 59))
567491	28925402	Here, we observed that irradiated Mdm2SNP309G/G mice developed lymphomas significantly faster (p<0.001) compared to Mdm2SNP309T/T mice, of either T cell (CD3 marker) or B-cell (B220 marker) origin [Figure 2E].	('lymphomas', 'Disease', (63, 72))	('mice', 'Species', '10090', (130, 134))	('lymphomas', 'Disease', 'MESH:D008223', (63, 72))	('B220', 'Gene', (177, 181))	('lymphomas', 'Phenotype', 'HP:0002665', (63, 72))	('mice', 'Species', '10090', (48, 52))	('faster', 'PosReg', (87, 93))	('Mdm2SNP309G/G', 'Var', (34, 47))	('lymphoma', 'Phenotype', 'HP:0002665', (63, 71))	('B220', 'Gene', '19264', (177, 181))
567492	28925402	These experiments demonstrate that the SNP309G allele impacts p53 activity and exacerbates spontaneous tumor development after lowdose IR compared to the SNP309T allele.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('exacerbates', 'PosReg', (79, 90))	('impacts', 'Reg', (54, 61))	('tumor', 'Disease', (103, 108))	('activity', 'MPA', (66, 74))	('SNP309', 'Chemical', '-', (39, 45))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('p53', 'Protein', (62, 65))	('SNP309', 'Chemical', '-', (154, 160))	('SNP309G', 'Var', (39, 46))
567497	28925402	Isolated primary keratinocytes from Mdm2SNP309G/G and Mdm2SNP309T/T mouse epidermis were treated them with a single dose of UVB (100mJ/cm2), a dose previously shown to activate acute p53 response in skin tissue, and analyzed for p53 activity.	('mouse', 'Species', '10090', (68, 73))	('Mdm2SNP309G/G', 'Var', (36, 49))	('activate', 'PosReg', (168, 176))	('Mdm2SNP309T/T', 'Var', (54, 67))
567499	28925402	To further examine p53 activity in skin tissue, we treated 6-week old Mdm2SNP309G/G and Mdm2SNP309T/T mice with UVB and analyzed p21 expression.	('mice', 'Species', '10090', (102, 106))	('expression', 'MPA', (133, 143))	('p21', 'Gene', '12575', (129, 132))	('p21', 'Gene', (129, 132))	('analyzed', 'Reg', (120, 128))	('Mdm2SNP309T/T', 'Var', (88, 101))
567501	28925402	To examine skin cancer risk after UVB exposure, we generated a cohort of Mdm2SNP309G/G and Mdm2SNP309T/T mice in a FVB background and treated with an established UVB regimen (UVB radiation three times per week for 30 weeks) and monitored for spontaneous tumor development for squamous cell carcinoma (SCC).	('cancer', 'Phenotype', 'HP:0002664', (16, 22))	('tumor', 'Disease', (254, 259))	('skin cancer', 'Disease', (11, 22))	('skin cancer', 'Phenotype', 'HP:0008069', (11, 22))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (276, 299))	('squamous cell carcinoma', 'Disease', (276, 299))	('SCC', 'Phenotype', 'HP:0002860', (301, 304))	('skin cancer', 'Disease', 'MESH:D012878', (11, 22))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (276, 299))	('tumor', 'Disease', 'MESH:D009369', (254, 259))	('carcinoma', 'Phenotype', 'HP:0030731', (290, 299))	('Mdm2SNP309G/G', 'Var', (73, 86))	('mice', 'Species', '10090', (105, 109))	('tumor', 'Phenotype', 'HP:0002664', (254, 259))	('Mdm2SNP309T/T', 'Var', (91, 104))
567503	28925402	Thus, UV treatment led to a dampened p53 response and shorter tumor latency in Mdm2SNP309T/T mice compared to Mdm2SNP309G/G mice, in contrast to IR treatment.	('tumor', 'Phenotype', 'HP:0002664', (62, 67))	('Mdm2SNP309T/T', 'Var', (79, 92))	('tumor', 'Disease', (62, 67))	('mice', 'Species', '10090', (124, 128))	('mice', 'Species', '10090', (93, 97))	('dampened', 'NegReg', (28, 36))	('shorter', 'NegReg', (54, 61))	('p53 response', 'MPA', (37, 49))	('tumor', 'Disease', 'MESH:D009369', (62, 67))
567505	28925402	We therefore repeated the experiment using fibroblasts, a cell type that previously displayed higher basal Mdm2 levels in SNP309G than in SNP309T genotype.	('SNP309G', 'Var', (122, 129))	('Mdm2', 'Gene', '17246', (107, 111))	('SNP309', 'Chemical', '-', (138, 144))	('SNP309', 'Chemical', '-', (122, 128))	('Mdm2', 'Gene', (107, 111))	('higher', 'PosReg', (94, 100))
567506	28925402	Fibroblasts were treated with the same regimen of UVB and the results showed 1.9-fold higher (p=0.032) increase in Mdm2 expression 24 hours post UVB treatment in SNP309G compared to SNP309T fibroblasts [Figure 3D], suggesting that the contrasting differences were cell-type dependent.	('SNP309', 'Chemical', '-', (182, 188))	('increase', 'PosReg', (103, 111))	('expression', 'MPA', (120, 130))	('SNP309G', 'Var', (162, 169))	('Mdm2', 'Gene', '17246', (115, 119))	('SNP309', 'Chemical', '-', (162, 168))	('higher', 'PosReg', (86, 92))	('Mdm2', 'Gene', (115, 119))
567509	28925402	The epidermis of Mdm2SNP309G/G and Mdm2SNP309T/T mice was treated with either acetone (control) or B(a)P and total RNA was isolated 24-hour post treatment.	('B(a)P', 'Chemical', 'MESH:D001564', (99, 104))	('acetone', 'Chemical', 'MESH:D000096', (78, 85))	('mice', 'Species', '10090', (49, 53))	('Mdm2SNP309G/G', 'Var', (17, 30))	('Mdm2SNP309T/T', 'Var', (35, 48))
567511	28925402	To examine tumor risk following B(a)P exposure, we treated Mdm2SNP309G/G and Mdm2SNP309T/T mice to an established regimen of 317 nmol of B(a)P once a week for 30 weeks and monitored mice for spontaneous tumor formation.	('mice', 'Species', '10090', (91, 95))	('tumor', 'Phenotype', 'HP:0002664', (203, 208))	('tumor', 'Disease', (203, 208))	('tumor', 'Phenotype', 'HP:0002664', (11, 16))	('Mdm2SNP309T/T', 'Var', (77, 90))	('B(a)P', 'Chemical', 'MESH:D001564', (137, 142))	('tumor', 'Disease', (11, 16))	('mice', 'Species', '10090', (182, 186))	('tumor', 'Disease', 'MESH:D009369', (203, 208))	('tumor', 'Disease', 'MESH:D009369', (11, 16))	('B(a)P', 'Chemical', 'MESH:D001564', (32, 37))
567512	28925402	Tumor-free survival showed that B(a)P treated Mdm2SNP309T/T mice were more susceptible to squamous cell carcinoma than Mdm2SNP309G/G mice (p<0.001) [Figure 4A] with a median survival of 22 weeks compared to 25 weeks, respectively.	('mice', 'Species', '10090', (133, 137))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (90, 113))	('susceptible', 'Reg', (75, 86))	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('squamous cell carcinoma', 'Disease', (90, 113))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (90, 113))	('Mdm2SNP309T/T', 'Var', (46, 59))	('mice', 'Species', '10090', (60, 64))	('B(a)P', 'Chemical', 'MESH:D001564', (32, 37))
567514	28925402	Tumor development in male Mdm2SNP309G/G mice was significantly delayed (p<0.001) compared to the other groups.	('Tumor', 'Phenotype', 'HP:0002664', (0, 5))	('Mdm2SNP309G/G', 'Var', (26, 39))	('Tumor development', 'CPA', (0, 17))	('delayed', 'NegReg', (63, 70))	('mice', 'Species', '10090', (40, 44))
567517	28925402	Moreover, epidermal keratinocytes in skin samples from male Mdm2SNP309G/G mice displayed significantly higher number of cells staining positive for p21 (p=0.049) as compared to Mdm2SNP309T/T keratinocytes after B(a)P treatment [Figure 4E].	('Mdm2SNP309G/G', 'Var', (60, 73))	('p21', 'Gene', (148, 151))	('p21', 'Gene', '12575', (148, 151))	('higher', 'PosReg', (103, 109))	('mice', 'Species', '10090', (74, 78))	('B(a)P', 'Chemical', 'MESH:D001564', (211, 216))
567519	28925402	Thus, Mdm2SNP309G/G mice, particularly males, are more resistant to developing skin SCC in response to B(a)P treatment.	('mice', 'Species', '10090', (20, 24))	('B(a)P', 'Chemical', 'MESH:D001564', (103, 108))	('resistant', 'NegReg', (55, 64))	('Mdm2SNP309G/G', 'Var', (6, 19))	('SCC', 'Phenotype', 'HP:0002860', (84, 87))
567532	28925402	Sequence analysis of these cell lines showed that MCF10A cells harbor a homozygous SNP309T genotype and K562 cells harbor a SNP309T/G genotype [S5].	('MCF10A', 'Gene', (50, 56))	('SNP309T/G', 'Var', (124, 133))	('SNP309', 'Chemical', '-', (83, 89))	('MCF10A', 'CellLine', 'CVCL:0598', (50, 56))	('K562', 'CellLine', 'CVCL:0004', (104, 108))	('SNP309', 'Chemical', '-', (124, 130))	('SNP309T', 'Var', (83, 90))
567534	28925402	As expected, sorted cells expressing GFP and SP1 preferentially increased Mdm2 expression in SNP309G MEFs (p<0.001) [Figure 5C].	('SP1', 'Var', (45, 48))	('GFP', 'Var', (37, 40))	('expression', 'MPA', (79, 89))	('Mdm2', 'Gene', (74, 78))	('SNP309', 'Chemical', '-', (93, 99))	('SNP309G', 'Var', (93, 100))	('increased', 'PosReg', (64, 73))	('Mdm2', 'Gene', '17246', (74, 78))
567535	28925402	E2F4 transfection increased Mdm2 expression slightly, but there were no significant differences between genotypes [S6].	('transfection', 'Var', (5, 17))	('increased', 'PosReg', (18, 27))	('Mdm2', 'Gene', '17246', (28, 32))	('expression', 'MPA', (33, 43))	('Mdm2', 'Gene', (28, 32))	('E2F4', 'Gene', (0, 4))	('E2F4', 'Gene', '104394', (0, 4))
567536	28925402	E2F6 transfection statistically repressed Mdm2 levels in SNP309G MEFs compared to SNP309T MEFs (p<0.001) [Figure 5D].	('E2F6', 'Gene', (0, 4))	('SNP309', 'Chemical', '-', (82, 88))	('Mdm2', 'Gene', '17246', (42, 46))	('E2F6', 'Gene', '50496', (0, 4))	('SNP309', 'Chemical', '-', (57, 63))	('Mdm2', 'Gene', (42, 46))	('SNP309G', 'Var', (57, 64))
567538	28925402	No significant differences in expression of Fgf21 and Brca1 were observed in SNP309T MEFs compared to SNP309G MEFs, indicating similar transfection efficiencies.	('Brca1', 'Gene', (54, 59))	('SNP309', 'Chemical', '-', (102, 108))	('Brca1', 'Gene', '12189', (54, 59))	('Fgf21', 'Gene', '56636', (44, 49))	('SNP309', 'Chemical', '-', (77, 83))	('Fgf21', 'Gene', (44, 49))	('SNP309T', 'Var', (77, 84))
567539	28925402	We also examined protein levels of SP1 and E2F6 in thymus and keratinocytes harvested from Mdm2SNP309G/G and Mdm2SNP309T/T mice and showed that SP1 is expressed in thymus and not detectable in keratinocytes and vice versa E2F6 is clearly expressed in keratinocytes but not in thymus samples [Figure 5E].	('Mdm2SNP309T/T', 'Var', (109, 122))	('E2F6', 'Gene', '50496', (43, 47))	('E2F6', 'Gene', '50496', (222, 226))	('Mdm2SNP309G/G', 'Var', (91, 104))	('E2F6', 'Gene', (43, 47))	('E2F6', 'Gene', (222, 226))	('mice', 'Species', '10090', (123, 127))
567540	28925402	We next examined the binding specificity of E2F6 to the MDM2-P2 promoter in keratinocytes harvested from homozygous SNP309G and SNP309T newborn pups by performing chromatin immunoprecipitation assays (ChIP).	('SNP309G', 'Var', (116, 123))	('E2F6', 'Gene', '50496', (44, 48))	('SNP309', 'Chemical', '-', (128, 134))	('MDM2-P2', 'Gene', (56, 63))	('E2F6', 'Gene', (44, 48))	('SNP309T', 'Var', (128, 135))	('SNP309', 'Chemical', '-', (116, 122))
567541	28925402	ChIP assays using an E2F6 antibody showed that E2F6 bound more significantly (p<0.001) to the MDM2-P2 promoter in keratinocytes of SNP309G compared to SNP309T [Figure 5F].	('SNP309', 'Chemical', '-', (151, 157))	('E2F6', 'Gene', '50496', (47, 51))	('bound', 'Interaction', (52, 57))	('SNP309', 'Chemical', '-', (131, 137))	('E2F6', 'Gene', '50496', (21, 25))	('SNP309G', 'Var', (131, 138))	('E2F6', 'Gene', (47, 51))	('E2F6', 'Gene', (21, 25))
567542	28925402	We also performed ChIP assays on the Brca1 promoter, an establish target of E2F6, and saw no difference in E2F6 binding to SNP309G or SNP309T samples.	('binding', 'Interaction', (112, 119))	('SNP309', 'Chemical', '-', (123, 129))	('E2F6', 'Gene', '50496', (107, 111))	('SNP309G', 'Var', (123, 130))	('Brca1', 'Gene', '12189', (37, 42))	('E2F6', 'Gene', (107, 111))	('E2F6', 'Gene', (76, 80))	('E2F6', 'Gene', '50496', (76, 80))	('Brca1', 'Gene', (37, 42))	('SNP309', 'Chemical', '-', (134, 140))	('SNP309T', 'Var', (134, 141))
567544	28925402	Collectively, these data show that SNP309G regulates Mdm2 basal expression in a tissue-dependent manner utilizing alternative transcription factors.	('regulates', 'Reg', (43, 52))	('Mdm2', 'Gene', (53, 57))	('SNP309', 'Chemical', '-', (35, 41))	('SNP309G', 'Var', (35, 42))	('basal expression', 'MPA', (58, 74))	('Mdm2', 'Gene', '17246', (53, 57))
567547	28925402	Our study shows that the SNP309G allele further increased Mdm2 expression and dampened p53 activity in spleen and thymus post IR treatment compared to SNP309T allele and compared to non-irradiated mice, resulting in exacerbated tumor risk in Mdm2SNP309G/G mice compared to Mdm2SNP309T/T mice.	('tumor', 'Disease', 'MESH:D009369', (228, 233))	('exacerbated', 'PosReg', (216, 227))	('mice', 'Species', '10090', (197, 201))	('Mdm2', 'Gene', (242, 246))	('p53', 'Protein', (87, 90))	('SNP309', 'Chemical', '-', (25, 31))	('dampened', 'NegReg', (78, 86))	('Mdm2', 'Gene', (273, 277))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('Mdm2', 'Gene', (58, 62))	('SNP309', 'Chemical', '-', (246, 252))	('SNP309', 'Chemical', '-', (277, 283))	('SNP309', 'Chemical', '-', (151, 157))	('expression', 'MPA', (63, 73))	('activity', 'MPA', (91, 99))	('Mdm2', 'Gene', '17246', (242, 246))	('mice', 'Species', '10090', (287, 291))	('Mdm2', 'Gene', '17246', (273, 277))	('increased', 'PosReg', (48, 57))	('mice', 'Species', '10090', (256, 260))	('SNP309G', 'Var', (25, 32))	('Mdm2', 'Gene', '17246', (58, 62))	('tumor', 'Disease', (228, 233))
567548	28925402	These results are consistent with previous data, which show that the Mdm2SNP309G/G mice have increased susceptibility to tumors compared to Mdm2SNP309T/T mice, affirming that SNP309G is an 'at risk' allele for spontaneous tumor formation.	('susceptibility', 'MPA', (103, 117))	('mice', 'Species', '10090', (154, 158))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('tumor', 'Disease', 'MESH:D009369', (222, 227))	('SNP309G', 'Var', (175, 182))	('tumors', 'Disease', (121, 127))	('tumors', 'Phenotype', 'HP:0002664', (121, 127))	('tumor', 'Disease', (121, 126))	('SNP309', 'Chemical', '-', (73, 79))	('mice', 'Species', '10090', (83, 87))	('tumor', 'Disease', 'MESH:D009369', (121, 126))	('tumors', 'Disease', 'MESH:D009369', (121, 127))	('tumor', 'Phenotype', 'HP:0002664', (222, 227))	('tumor', 'Disease', (222, 227))	('Mdm2SNP309G/G', 'Var', (69, 82))	('SNP309', 'Chemical', '-', (144, 150))	('SNP309', 'Chemical', '-', (175, 181))
567550	28925402	Consequently, Mdm2SNP309T/T mice exhibit increased risk of skin squamous cell carcinoma compared to Mdm2SNP309G/G mice after UVB or B(a)P treatment.	('skin squamous cell carcinoma', 'Disease', (59, 87))	('skin squamous cell carcinoma', 'Disease', 'MESH:D002294', (59, 87))	('skin squamous cell carcinoma', 'Phenotype', 'HP:0006739', (59, 87))	('mice', 'Species', '10090', (28, 32))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('Mdm2SNP309T/T', 'Var', (14, 27))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (64, 87))	('mice', 'Species', '10090', (114, 118))	('B(a)P', 'Chemical', 'MESH:D001564', (132, 137))
567551	28925402	In this study, one irradiated Mdm2SNP309G/G C57BL/6 mouse presented with a squamous cell carcinoma, as well as histiocytic sarcoma and lymphoma; this squamous cell carcinoma represents only ~1% of all tumors present in irradiated Mdm2SNP309G/G C57BL/6 mice.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (150, 173))	('tumors', 'Disease', 'MESH:D009369', (201, 207))	('carcinoma', 'Phenotype', 'HP:0030731', (89, 98))	('squamous cell carcinoma', 'Disease', (75, 98))	('mice', 'Species', '10090', (252, 256))	('sarcoma', 'Disease', 'MESH:D012509', (123, 130))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (150, 173))	('sarcoma', 'Disease', (123, 130))	('lymphoma', 'Phenotype', 'HP:0002665', (135, 143))	('mouse', 'Species', '10090', (52, 57))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (75, 98))	('carcinoma', 'Phenotype', 'HP:0030731', (164, 173))	('tumors', 'Phenotype', 'HP:0002664', (201, 207))	('squamous cell carcinoma', 'Disease', (150, 173))	('sarcoma', 'Phenotype', 'HP:0100242', (123, 130))	('Mdm2SNP309G/G', 'Var', (30, 43))	('tumor', 'Phenotype', 'HP:0002664', (201, 206))	('lymphoma', 'Disease', (135, 143))	('tumors', 'Disease', (201, 207))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (75, 98))	('lymphoma', 'Disease', 'MESH:D008223', (135, 143))
567552	28925402	In comparison, a larger number of UVB and B(a)P treated mice showed both genotypes develop squamous cell carcinoma but Mdm2SNP309T/T mice were more susceptible.	('mice', 'Species', '10090', (133, 137))	('Mdm2SNP309T/T', 'Var', (119, 132))	('B(a)P', 'Chemical', 'MESH:D001564', (42, 47))	('develop', 'PosReg', (83, 90))	('mice', 'Species', '10090', (56, 60))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (91, 114))	('carcinoma', 'Phenotype', 'HP:0030731', (105, 114))	('squamous cell carcinoma', 'Disease', (91, 114))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (91, 114))
567553	28925402	A further examination of basal Mdm2 expression from different tissues harvested from SNP309 mice in a C57BL/6 background confirms that SNP309 regulates Mdm2 basal expression in a tissue-dependent manner.	('Mdm2', 'Gene', (152, 156))	('basal expression', 'MPA', (157, 173))	('SNP309', 'Var', (135, 141))	('Mdm2', 'Gene', '17246', (31, 35))	('SNP309', 'Chemical', '-', (135, 141))	('regulates', 'Reg', (142, 151))	('SNP309', 'Chemical', '-', (85, 91))	('Mdm2', 'Gene', '17246', (152, 156))	('Mdm2', 'Gene', (31, 35))	('mice', 'Species', '10090', (92, 96))
567555	28925402	Moreover, fibroblasts from FVB mice showed increased Mdm2 expression in SNP309G compared SNP309T fibroblast after UVB treatment, indicating that the phenotype is also not insult-dependent.	('SNP309', 'Chemical', '-', (89, 95))	('SNP309G', 'Var', (72, 79))	('expression', 'MPA', (58, 68))	('Mdm2', 'Gene', (53, 57))	('SNP309', 'Chemical', '-', (72, 78))	('mice', 'Species', '10090', (31, 35))	('increased', 'PosReg', (43, 52))	('Mdm2', 'Gene', '17246', (53, 57))
567556	28925402	Collectively, these data show that SNP309 contrastingly regulates basal Mdm2 expression levels and concomitantly affects p53 activity and cancer risk in a cell-type-specific manner.	('cancer', 'Disease', (138, 144))	('p53', 'Protein', (121, 124))	('SNP309', 'Var', (35, 41))	('affects', 'Reg', (113, 120))	('SNP309', 'Chemical', '-', (35, 41))	('activity', 'MPA', (125, 133))	('cancer', 'Phenotype', 'HP:0002664', (138, 144))	('Mdm2', 'Gene', '17246', (72, 76))	('regulates', 'Reg', (56, 65))	('expression levels', 'MPA', (77, 94))	('Mdm2', 'Gene', (72, 76))	('cancer', 'Disease', 'MESH:D009369', (138, 144))
567559	28925402	Moreover, a recent study demonstrated a decreased risk of developing oral squamous cell carcinoma (OSCC) for the MDM2 SNP309G group with pronounced susceptibility in the MDM2 SNP309T group, suggesting MDM2 SNP309G may be protective in a cell-dependent manner.	('SNP309', 'Chemical', '-', (206, 212))	('SCC', 'Phenotype', 'HP:0002860', (100, 103))	('carcinoma', 'Phenotype', 'HP:0030731', (88, 97))	('SNP309', 'Chemical', '-', (118, 124))	('oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (69, 97))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (74, 97))	('MDM2 SNP309G', 'Var', (113, 125))	('oral squamous cell carcinoma', 'Disease', (69, 97))	('decreased', 'NegReg', (40, 49))	('SNP309', 'Chemical', '-', (175, 181))
567561	28925402	The SP1 overexpression experiment supports previous mechanistic studies, both in human and mouse tissues, showing SP1 preferentially binds to SNP309G allele to increase Mdm2 expression.	('Mdm2', 'Gene', (169, 173))	('SP1', 'Gene', (114, 117))	('expression', 'MPA', (174, 184))	('preferentially', 'PosReg', (118, 132))	('SNP309', 'Chemical', '-', (142, 148))	('increase', 'PosReg', (160, 168))	('SNP309G', 'Var', (142, 149))	('binds', 'Interaction', (133, 138))	('Mdm2', 'Gene', '17246', (169, 173))	('human', 'Species', '9606', (81, 86))	('mouse', 'Species', '10090', (91, 96))
567562	28925402	In contrast, the E2F6 overexpression experiments show preferential repression of Mdm2 expression in the SNP309G allele, suggesting that this allele will elicit a more potent p53 response and protect mice harboring this SNP from tumor risk.	('repression', 'NegReg', (67, 77))	('p53 response', 'MPA', (174, 186))	('mice', 'Species', '10090', (199, 203))	('SNP309', 'Chemical', '-', (104, 110))	('E2F6', 'Gene', '50496', (17, 21))	('protect', 'Reg', (191, 198))	('SNP309G', 'Var', (104, 111))	('Mdm2', 'Gene', (81, 85))	('tumor', 'Disease', 'MESH:D009369', (228, 233))	('tumor', 'Phenotype', 'HP:0002664', (228, 233))	('tumor', 'Disease', (228, 233))	('more', 'PosReg', (162, 166))	('E2F6', 'Gene', (17, 21))	('elicit', 'Reg', (153, 159))	('Mdm2', 'Gene', '17246', (81, 85))
567564	28925402	The ChIP-seq data from ENCODE confirmed that E2F6 binds to MDM2-P2 promoter and our ChIP assay confirmed that E2F6 preferentially binds to the MDM2-P2 promoter in keratinocytes of SNP309G compared to SNP309T.	('preferentially', 'PosReg', (115, 129))	('E2F6', 'Gene', (45, 49))	('E2F6', 'Gene', (110, 114))	('MDM2-P2', 'Gene', (143, 150))	('SNP309', 'Chemical', '-', (180, 186))	('SNP309', 'Chemical', '-', (200, 206))	('E2F6', 'Gene', '50496', (45, 49))	('E2F6', 'Gene', '50496', (110, 114))	('SNP309G', 'Var', (180, 187))	('binds', 'Interaction', (130, 135))
567566	28925402	In summary, our data illustrates how SNP309G cooperates with environmental stress to exacerbate or protect cancer development in a tissue-dependent manner.	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('SNP309', 'Chemical', '-', (37, 43))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('protect', 'PosReg', (99, 106))	('cancer', 'Disease', (107, 113))	('exacerbate', 'PosReg', (85, 95))	('SNP309G', 'Var', (37, 44))
567568	28925402	The Mdm2SNP309G/G and Mdm2SNP309T/T mice in C57BL/6 strain have been previously characterized.	('Mdm2SNP309T/T', 'Var', (22, 35))	('Mdm2SNP309G/G', 'Var', (4, 17))	('mice', 'Species', '10090', (36, 40))
567570	28925402	Mdm2SNP309G/G and Mdm2SNP309T/T mice in C57BL/6 strain were treated with 1Gy IR 2 days after birth and monitored for tumor incidence and sacrificed upon tumor formation.	('tumor', 'Disease', 'MESH:D009369', (153, 158))	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('tumor', 'Disease', (117, 122))	('Mdm2SNP309T/T', 'Var', (18, 31))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumor', 'Disease', (153, 158))	('mice', 'Species', '10090', (32, 36))	('tumor', 'Disease', 'MESH:D009369', (117, 122))
567571	28925402	Six-week old Mdm2SNP309G/G and Mdm2SNP309T/T mice in FVB strain were treated with skin carcinogenesis protocols, including B[a]P and UVB, as previously described.	('skin carcinogenesis', 'Disease', (82, 101))	('mice', 'Species', '10090', (45, 49))	('skin carcinogenesis', 'Disease', 'MESH:D063646', (82, 101))	('Mdm2SNP309T/T', 'Var', (31, 44))
567579	28925402	Primary keratinocytes and early passage MEFs from Mdm2SNP309G/G and Mdm2SNP309T/T mice were generated as previously described.	('mice', 'Species', '10090', (82, 86))	('Mdm2SNP309T/T', 'Var', (68, 81))	('Mdm2SNP309G/G', 'Var', (50, 63))
567584	28925402	One hundred micrograms of lysate was resolved on 10% SDS-PAGE and immunoblotted with antibodies against SP1 (1:200; Sata Cruz, sc-59), E2F6 (1:200; Santa Cruz #E-20), and GAPDH (1:1000; Abcam, Cambridge, UK #ab9485).	('SP1', 'Gene', (104, 107))	('SDS', 'Chemical', 'MESH:D012967', (53, 56))	('1:200', 'Var', (109, 114))	('E2F6', 'Gene', (135, 139))	('GAPDH', 'Gene', '14433', (171, 176))	('GAPDH', 'Gene', (171, 176))	('E2F6', 'Gene', '50496', (135, 139))
567588	29228625	Recently, increasing evidence has suggested that long non-coding RNAs (lncRNAs) promote tumorigenesis in many cancer types.	('cancer', 'Disease', (110, 116))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('promote', 'PosReg', (80, 87))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumor', 'Disease', (88, 93))	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('long non-coding RNAs', 'Var', (49, 69))
567603	29228625	Accumulating evidence indicates that the majority of lncRNAs play key roles in cancer therapy through influencing cell cycle regulation, survival, cheomothrapy response, and various biological processes by modulating gene expression at the transcriptional, posttranscriptional and epigenetic regulation levels.	('influencing', 'Reg', (102, 113))	('survival', 'CPA', (137, 145))	('cancer', 'Phenotype', 'HP:0002664', (79, 85))	('biological processes', 'CPA', (182, 202))	('modulating', 'Reg', (206, 216))	('lncRNAs', 'Var', (53, 60))	('gene expression', 'MPA', (217, 232))	('cheomothrapy', 'Disease', (147, 159))	('cancer', 'Disease', (79, 85))	('cancer', 'Disease', 'MESH:D009369', (79, 85))	('cell cycle regulation', 'CPA', (114, 135))
567604	29228625	Dysregulation of lncRNAs contributes to cancer progression, and they are therefore considered as potential therapeutic targets.	('Dysregulation', 'Var', (0, 13))	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('contributes', 'Reg', (25, 36))	('cancer', 'Disease', (40, 46))	('lncRNAs', 'Protein', (17, 24))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))
567615	29228625	In addition, knockdown of hnRNP-U also contributes to cisplatin resistance through decreasing the expression of the apoptosis and DNA repair related gene GADD45A, similar to SFTA1P depletion induced effects.	('decreasing', 'NegReg', (83, 93))	('contributes', 'Reg', (39, 50))	('hnRNP-U', 'Gene', '3192', (26, 33))	('SFTA1P', 'Gene', (174, 180))	('hnRNP-U', 'Gene', (26, 33))	('GADD45A', 'Gene', (154, 161))	('cisplatin', 'Chemical', 'MESH:D002945', (54, 63))	('GADD45A', 'Gene', '1647', (154, 161))	('SFTA1P', 'Gene', '207107', (174, 180))	('knockdown', 'Var', (13, 22))	('cisplatin resistance', 'MPA', (54, 74))	('expression', 'MPA', (98, 108))
567638	29228625	Oppositely, knockdown of SFTA1P by transfecting SFTA1P-specific siRNA (Figure 3C) led to increased cell viability (Figure 3D).	('SFTA1P', 'Gene', '207107', (25, 31))	('SFTA1P', 'Gene', (48, 54))	('knockdown', 'Var', (12, 21))	('SFTA1P', 'Gene', (25, 31))	('increased', 'PosReg', (89, 98))	('cell viability', 'CPA', (99, 113))	('SFTA1P', 'Gene', '207107', (48, 54))
567658	29228625	These results demonstrated that LncRNA SFTA1P enhanced sensitivity of LSCC cell lines to cisplatin.	('LncRNA', 'Var', (32, 38))	('sensitivity', 'MPA', (55, 66))	('SFTA1P', 'Gene', '207107', (39, 45))	('enhanced', 'PosReg', (46, 54))	('cisplatin', 'Chemical', 'MESH:D002945', (89, 98))	('SFTA1P', 'Gene', (39, 45))	('LSCC', 'Phenotype', 'HP:0030359', (70, 74))
567667	29228625	And further Kaplan-Meier survival analysis showed that LSCC patients with high hnRNP-U expression had notably longer overall survival (OS) and progression-free survival (PFS) than those with low hnRNP-U expression in GSE50081 dataset (Figure 5C).	('longer', 'PosReg', (110, 116))	('high', 'Var', (74, 78))	('patients', 'Species', '9606', (60, 68))	('overall survival', 'CPA', (117, 133))	('hnRNP-U', 'Gene', '3192', (195, 202))	('hnRNP-U', 'Gene', (195, 202))	('hnRNP-U', 'Gene', '3192', (79, 86))	('LSCC', 'Disease', (55, 59))	('LSCC', 'Phenotype', 'HP:0030359', (55, 59))	('hnRNP-U', 'Gene', (79, 86))	('progression-free survival', 'CPA', (143, 168))
567670	29228625	The results showed that SFTA1P expression significantly increased hnRNP-U mRNA and protein levels in a dose-dependent manner (Figure 5E and 5F).	('SFTA1P', 'Gene', (24, 30))	('increased', 'PosReg', (56, 65))	('hnRNP-U', 'Gene', '3192', (66, 73))	('hnRNP-U', 'Gene', (66, 73))	('SFTA1P', 'Gene', '207107', (24, 30))	('expression', 'Var', (31, 41))
567683	29228625	As shown in Figure 6C, after hnRNP-U knockdown, GADD45A mRNA and protein expression was significantly down-regulated.	('down-regulated', 'NegReg', (102, 116))	('hnRNP-U', 'Gene', (29, 36))	('knockdown', 'Var', (37, 46))	('GADD45A', 'Gene', '1647', (48, 55))	('hnRNP-U', 'Gene', '3192', (29, 36))	('GADD45A', 'Gene', (48, 55))
567767	28081052	In recent years, molecular target therapies for lung AC, including tyrosine kinase inhibitor (gefitinib/erlotinib) against EGFR-sensitive mutants, crizotinib against ALK fusion, and bevacizumab against VEGF over-expression, have shown remarkable therapeutic efficacy.	('EGFR', 'Gene', (123, 127))	('erlotinib', 'Chemical', 'MESH:D000069347', (104, 113))	('mutants', 'Var', (138, 145))	('VEGF', 'Gene', '7422', (202, 206))	('ALK', 'Gene', '238', (166, 169))	('gefitinib', 'Chemical', 'MESH:D000077156', (94, 103))	('bevacizumab', 'Chemical', 'MESH:D000068258', (182, 193))	('crizotinib', 'Chemical', 'MESH:D000077547', (147, 157))	('EGFR', 'Gene', '1956', (123, 127))	('VEGF', 'Gene', (202, 206))	('ALK', 'Gene', (166, 169))	('lung AC', 'Disease', (48, 55))
567771	28081052	Hugl-l functions as a tumor suppressor, and the reduced expression of Hugl-1 shows an inverse correlation with lung SCC progression; inhibition of Hugl-1 contributes to the progression of lung squamous cell carcinoma.	('SCC', 'Gene', (116, 119))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (188, 216))	('lung squamous cell carcinoma', 'Disease', (188, 216))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (193, 216))	('inhibition', 'Var', (133, 143))	('SCC', 'Gene', '6317', (116, 119))	('carcinoma', 'Phenotype', 'HP:0030731', (207, 216))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('tumor', 'Disease', (22, 27))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (188, 216))	('Hugl-1', 'Gene', '3996', (147, 153))	('Hugl-1', 'Gene', (147, 153))	('Hugl-1', 'Gene', '3996', (70, 76))	('Hugl-1', 'Gene', (70, 76))
567773	28081052	Inhibition of the tumor-suppressive miR-29 family enhances cell invasion in lung SCC through direct regulation of oncogenic LOXL2.	('SCC', 'Gene', '6317', (81, 84))	('enhances', 'PosReg', (50, 58))	('tumor', 'Disease', (18, 23))	('cell invasion in', 'CPA', (59, 75))	('tumor', 'Disease', 'MESH:D009369', (18, 23))	('Inhibition', 'Var', (0, 10))	('SCC', 'Gene', (81, 84))	('LOXL2', 'Gene', (124, 129))	('tumor', 'Phenotype', 'HP:0002664', (18, 23))	('LOXL2', 'Gene', '4017', (124, 129))
567775	28081052	DNA methylation of PRDM5 promoter contributes to the development of lung SCC.	('PRDM5', 'Gene', '11107', (19, 24))	('contributes', 'Reg', (34, 45))	('SCC', 'Gene', (73, 76))	('methylation', 'Var', (4, 15))	('PRDM5', 'Gene', (19, 24))	('SCC', 'Gene', '6317', (73, 76))
567786	28081052	Two datasets were based on a platform of GPL6480 Agilent-014850 Whole Human Genome Microarray 4x44K; other datasets were based on platforms of GPL10558 Illumina HumanHT-12 V4.0 expression beadchip, GPL6947 Illumina HumanHT-12 V3.0 expression beadchip, GPL9053 Agilent-UNC-custom-4X44K, and GPL570 [HG-U133_Plus_2] Affymetrix Human Genome U133 Plus 2.0 Array.	('Human', 'Species', '9606', (161, 166))	('Human', 'Species', '9606', (325, 330))	('Human', 'Species', '9606', (70, 75))	('GPL10558', 'Var', (143, 151))	('GPL6947', 'Var', (198, 205))	('Human', 'Species', '9606', (215, 220))
567790	28081052	We collected six mRNA expression profiles (GSE60644, GSE40588, GSE33479, GSE23822, GSE17710, and GSE10245), including 167 lung SCC cases and 99 normal controls (Table 1).	('GSE17710', 'Var', (83, 91))	('SCC', 'Gene', (127, 130))	('GSE10245', 'Var', (97, 105))	('GSE60644', 'Var', (43, 51))	('SCC', 'Gene', '6317', (127, 130))	('GSE23822', 'Var', (73, 81))	('GSE40588', 'Var', (53, 61))	('GSE33479', 'Var', (63, 71))
567804	28081052	Over-expression of NFIC induces expression of E-cadherin and KLF4 in breast cancer, which maintains epithelial differentiation status, leads to inhibition of EMT, and migration and invasion in breast cancer cells.	('breast cancer', 'Disease', (193, 206))	('KLF4', 'Gene', '9314', (61, 65))	('epithelial', 'MPA', (100, 110))	('E-cadherin', 'Gene', (46, 56))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('E-cadherin', 'Gene', '999', (46, 56))	('breast cancer', 'Phenotype', 'HP:0003002', (69, 82))	('Over-expression', 'Var', (0, 15))	('induces', 'PosReg', (24, 31))	('breast cancer', 'Disease', 'MESH:D001943', (69, 82))	('breast cancer', 'Disease', (69, 82))	('NFIC', 'Gene', (19, 23))	('NFIC', 'Gene', '4782', (19, 23))	('expression', 'MPA', (32, 42))	('KLF4', 'Gene', (61, 65))	('breast cancer', 'Phenotype', 'HP:0003002', (193, 206))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('invasion', 'CPA', (181, 189))	('inhibition', 'NegReg', (144, 154))	('EMT', 'CPA', (158, 161))	('breast cancer', 'Disease', 'MESH:D001943', (193, 206))
567813	28081052	Mutations in this gene are responsible for approximately 40% of inherited breast cancers and 80% of inherited ovarian cancers.	('inherited breast cancers', 'Disease', 'MESH:D061325', (64, 88))	('cancers', 'Phenotype', 'HP:0002664', (81, 88))	('inherited ovarian cancers', 'Disease', (100, 125))	('cancer', 'Phenotype', 'HP:0002664', (81, 87))	('inherited breast cancers', 'Disease', (64, 88))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('Mutations', 'Var', (0, 9))	('responsible', 'Reg', (27, 38))	('ovarian cancers', 'Phenotype', 'HP:0100615', (110, 125))	('inherited ovarian cancers', 'Disease', 'MESH:D010051', (100, 125))	('breast cancers', 'Phenotype', 'HP:0003002', (74, 88))	('cancers', 'Phenotype', 'HP:0002664', (118, 125))	('breast cancer', 'Phenotype', 'HP:0003002', (74, 87))
567814	28081052	Mounting evidence shows that the expression of BRCA1 is associated with the natural prognosis and treatment prognosis in lung cancer.	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('lung cancer', 'Disease', 'MESH:D008175', (121, 132))	('BRCA1', 'Gene', (47, 52))	('expression', 'Var', (33, 43))	('associated', 'Reg', (56, 66))	('lung cancer', 'Disease', (121, 132))	('lung cancer', 'Phenotype', 'HP:0100526', (121, 132))	('BRCA1', 'Gene', '672', (47, 52))
567875	26098683	An MTT assay was carried out using wild type LKB1+/+ murine embryonic fibroblasts (MEFs) as a control, which was compared to LKB1-/- treated with a range of lovastatin concentrations of up to 25 muM for 48 and 72 hours.	('muM', 'Gene', '56925', (195, 198))	('murine', 'Species', '10090', (53, 59))	('lovastatin', 'Chemical', 'MESH:D008148', (157, 167))	('muM', 'Gene', (195, 198))	('LKB1+/+', 'Var', (45, 52))	('MTT', 'Chemical', 'MESH:C070243', (3, 6))
567876	26098683	Their data showed that LKB1+/+ cells (20% cell viability after 25 muM dose) were significantly more sensitive than LKB1-/- cells (90% cell viability in 25 muM) after 48 hours.	('LKB1+/+', 'Var', (23, 30))	('muM', 'Gene', '56925', (66, 69))	('muM', 'Gene', '56925', (155, 158))	('muM', 'Gene', (155, 158))	('muM', 'Gene', (66, 69))	('sensitive', 'MPA', (100, 109))
567892	26098683	With the western blots assay they found that monensin can inhibts phosphorylation status of EGFR and its downstream targets AKT and ERK proteins were assessed in SCC9 cells treated with 10mumol/L lovastatin for 24 hours.	('ERK', 'Gene', '5594', (132, 135))	('monensin', 'Chemical', 'MESH:D008985', (45, 53))	('inhibts', 'NegReg', (58, 65))	('phosphorylation status', 'MPA', (66, 88))	('lovastatin', 'Chemical', 'MESH:D008148', (196, 206))	('ERK', 'Gene', (132, 135))	('AKT', 'Gene', (124, 127))	('monensin', 'Var', (45, 53))	('EGFR', 'Gene', '1956', (92, 96))	('EGFR', 'Gene', (92, 96))	('AKT', 'Gene', '207', (124, 127))
567916	26098683	Interruption of this process in malignant cells results in inhibition of tumor growth and metastasis.	('inhibition', 'NegReg', (59, 69))	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('Interruption', 'Var', (0, 12))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Disease', (73, 78))
567941	31202631	Here we present CHASMplus, a computational method, that is uniquely capable of identifying driver missense mutations, including those specific to a cancer type, as evidenced by significantly superior performance on diverse benchmarks.	('cancer', 'Disease', (148, 154))	('cancer', 'Disease', 'MESH:D009369', (148, 154))	('missense mutations', 'Var', (98, 116))	('cancer', 'Phenotype', 'HP:0002664', (148, 154))	('CHASMplus', 'Disease', (16, 25))	('CHASMplus', 'Disease', 'None', (16, 25))
567942	31202631	Applied to 8,657 tumor samples across 32 cancer types in The Cancer Genome Atlas, CHASMplus identifies over 4,000 unique driver missense mutations in 240 genes, supporting a prominent role for rare driver mutations.	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('Cancer', 'Phenotype', 'HP:0002664', (61, 67))	('Cancer', 'Disease', (61, 67))	('tumor', 'Disease', (17, 22))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('Cancer', 'Disease', 'MESH:D009369', (61, 67))	('CHASMplus', 'Disease', (82, 91))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('missense mutations', 'Var', (128, 146))	('CHASMplus', 'Disease', 'None', (82, 91))
567945	31202631	Their analysis revealed that most driver mutations occur only in a few patients, presenting a challenge for precision medicine, and several cancer types will benefit from additional sequencing to identify these rare driver mutations.	('mutations', 'Var', (41, 50))	('patients', 'Species', '9606', (71, 79))	('cancer', 'Disease', (140, 146))	('cancer', 'Disease', 'MESH:D009369', (140, 146))	('cancer', 'Phenotype', 'HP:0002664', (140, 146))
567946	31202631	Cancer is a disease of the genome where certain somatic mutations drive the neoplastic process of cancer, while the majority of mutations are benign passengers.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('mutations', 'Var', (56, 65))	('neoplastic process', 'CPA', (76, 94))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('Cancer', 'Phenotype', 'HP:0002664', (0, 6))	('Cancer', 'Disease', (0, 6))	('cancer', 'Disease', (98, 104))	('drive', 'PosReg', (66, 71))	('Cancer', 'Disease', 'MESH:D009369', (0, 6))
567947	31202631	Missense mutations are the most common protein-coding mutation found in cancer genomes.	('cancer', 'Phenotype', 'HP:0002664', (72, 78))	('cancer', 'Disease', 'MESH:D009369', (72, 78))	('Missense mutations', 'Var', (0, 18))	('cancer', 'Disease', (72, 78))
567948	31202631	However, due to the large number of somatic mutations identified in DNA sequencing of human tumors, it has been logistically impossible to experimentally validate driver mutations at sufficiently large scale.	('tumors', 'Disease', 'MESH:D009369', (92, 98))	('human', 'Species', '9606', (86, 91))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('mutations', 'Var', (44, 53))	('tumors', 'Disease', (92, 98))	('tumors', 'Phenotype', 'HP:0002664', (92, 98))
567949	31202631	The task of identifying putative drivers from cancer sequencing studies has therefore depended on statistical models to identify genes with an excess number of mutations over expectation.	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('cancer', 'Disease', (46, 52))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('mutations', 'Var', (160, 169))
567950	31202631	The rationale is that because driver mutations provide a fitness advantage to cancer cells, they will be observed more often than expected by chance due to their contribution to carcinogenesis and, as such, leave a statistically detectable signal.	('cancer', 'Disease', (78, 84))	('carcinogenesis', 'Disease', 'MESH:D063646', (178, 192))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('mutations', 'Var', (37, 46))	('fitness', 'Disease', (57, 64))	('carcinogenesis', 'Disease', (178, 192))	('fitness', 'Disease', 'MESH:D012640', (57, 64))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))
567951	31202631	Based on such gene-level analyses, it has been hypothesized that cancer driver mutations exhibit a long tail phenomenon with few common drivers and many rare drivers, suggesting that numerous rare drivers remain to be discovered.	('cancer', 'Phenotype', 'HP:0002664', (65, 71))	('long tail', 'Phenotype', 'HP:0002831', (99, 108))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('mutations', 'Var', (79, 88))
567954	31202631	Overall, this highlights the critical importance of new methods that can identify putative driver missense mutations and separate them from passenger mutations even within known cancer genes, which could spur effective experimental validation.	('cancer', 'Disease', (178, 184))	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('missense mutations', 'Var', (98, 116))
567955	31202631	While many computational methods have been developed to predict whether a missense mutation is generally deleterious or pathogenic, there has not previously been a method to score the oncogenic impact of a missense mutation specifically by cancer type.	('missense mutation', 'Var', (206, 223))	('cancer', 'Phenotype', 'HP:0002664', (240, 246))	('cancer', 'Disease', 'MESH:D009369', (240, 246))	('missense mutation', 'Var', (74, 91))	('cancer', 'Disease', (240, 246))
567956	31202631	Although it is well known that missense mutations have different impacts in different cancer types, currently available computational methods either do not take it into consideration or fail at the task of distinguishing the differences.	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('missense mutations', 'Var', (31, 49))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('impacts', 'Reg', (65, 72))	('cancer', 'Disease', (86, 92))
567957	31202631	This indicates an unmet need, given the clinical relevance of mutations is increasingly understood to depend both on the particular mutation and cancer type.	('cancer', 'Disease', (145, 151))	('cancer', 'Disease', 'MESH:D009369', (145, 151))	('cancer', 'Phenotype', 'HP:0002664', (145, 151))	('mutations', 'Var', (62, 71))
567958	31202631	In this work, we introduce a machine learning method, CHASMplus, to predict the driver status of missense mutations in a cancer type-specific manner.	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('cancer', 'Disease', 'MESH:D009369', (121, 127))	('CHASMplus', 'Disease', (54, 63))	('CHASMplus', 'Disease', 'None', (54, 63))	('cancer', 'Disease', (121, 127))	('missense mutations', 'Var', (97, 115))
567960	31202631	We explore the emerging role for rare driver missense mutations in cancer and, when possible, relate predictions to supporting functional evidence.	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('missense mutations', 'Var', (45, 63))	('cancer', 'Disease', (67, 73))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))
567961	31202631	We provide an interactive resource for exploring driver missense mutations identified from the TCGA (http://karchinlab.github.io/CHASMplus) and a user-friendly tool (http://chasmplus.readthedocs.io/) to predict whether newly observed mutations from further sequencing are likely cancer drivers.	('cancer', 'Phenotype', 'HP:0002664', (279, 285))	('CHASMplus', 'Disease', (129, 138))	('CHASMplus', 'Disease', 'None', (129, 138))	('cancer', 'Disease', (279, 285))	('cancer', 'Disease', 'MESH:D009369', (279, 285))	('mutations', 'Var', (234, 243))
567962	31202631	Lastly, we examine the diversity of driver missense mutations across various types of cancer, which leads to a refined understanding of the likely trajectory of driver missense mutation discovery with further sequencing.	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('missense mutations', 'Var', (43, 61))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('cancer', 'Disease', (86, 92))
567963	31202631	We have developed a method named CHASMplus that uses machine learning to discriminate somatic missense mutations (referred to hereafter as missense mutations) as either cancer drivers or passengers (Figure 1a, Methods).	('cancer', 'Disease', (169, 175))	('cancer', 'Phenotype', 'HP:0002664', (169, 175))	('CHASMplus', 'Disease', (33, 42))	('CHASMplus', 'Disease', 'None', (33, 42))	('missense mutations', 'Var', (94, 112))	('cancer', 'Disease', 'MESH:D009369', (169, 175))
567968	31202631	In contrast, most previous methods provide a single impact score for each missense mutation, regardless of cancer type.	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('cancer', 'Disease', 'MESH:D009369', (107, 113))	('cancer', 'Disease', (107, 113))	('missense mutation', 'Var', (74, 91))
567971	31202631	First, a cancer type-specific model should accurately predict oncogenic effects of missense mutations in an appropriate cell line.	('missense mutations', 'Var', (83, 101))	('cancer', 'Disease', (9, 15))	('cancer', 'Disease', 'MESH:D009369', (9, 15))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))
567972	31202631	We therefore compared predictions of breast cancer-specific CHASMplus, CHASM, and CanDrA models in known breast cancer driver genes to a previous large-scale validation of 698 missense mutations in MCF10A (breast epithelium) cells that measured cell viability (Figure 2a, Methods).	('breast cancer', 'Disease', (37, 50))	('CHASM', 'Gene', '219537', (60, 65))	('breast cancer', 'Phenotype', 'HP:0003002', (37, 50))	('CHASMplus', 'Disease', 'None', (60, 69))	('MCF10A', 'CellLine', 'CVCL:0598', (198, 204))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('CHASM', 'Gene', (71, 76))	('CHASM', 'Gene', (60, 65))	('MCF10A', 'Gene', (198, 204))	('breast cancer', 'Disease', 'MESH:D001943', (105, 118))	('CHASM', 'Gene', '219537', (71, 76))	('missense mutations', 'Var', (176, 194))	('breast cancer', 'Disease', 'MESH:D001943', (37, 50))	('breast cancer', 'Disease', (105, 118))	('CHASMplus', 'Disease', (60, 69))	('cancer', 'Phenotype', 'HP:0002664', (44, 50))	('breast cancer', 'Phenotype', 'HP:0003002', (105, 118))
567981	31202631	Lastly, we reasoned that distinguishing cancer type-specificity of driver mutations within the same gene would be an even harder task to accomplish.	('cancer', 'Disease', 'MESH:D009369', (40, 46))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('mutations', 'Var', (74, 83))	('cancer', 'Disease', (40, 46))
567982	31202631	It has been previously documented that lung adenocarcinoma (LUAD) missense mutations in EGFR appear predominantly in its kinase domain, while GBM missense mutations appear in its extracellular domain.	('carcinoma', 'Phenotype', 'HP:0030731', (49, 58))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (39, 58))	('missense mutations', 'Var', (66, 84))	('EGFR', 'Gene', '1956', (88, 92))	('lung adenocarcinoma', 'Disease', (39, 58))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (39, 58))	('EGFR', 'Gene', (88, 92))
567983	31202631	We therefore scored TCGA missense mutations in the gene EGFR from LUAD patients and from GBM patients with CHASMplus, CanDrA, and CHASM (Figure 2c).	('CHASM', 'Gene', (107, 112))	('CHASM', 'Gene', '219537', (130, 135))	('CHASMplus', 'Disease', (107, 116))	('EGFR', 'Gene', '1956', (56, 60))	('patients', 'Species', '9606', (71, 79))	('CHASM', 'Gene', '219537', (107, 112))	('missense mutations', 'Var', (25, 43))	('CHASMplus', 'Disease', 'None', (107, 116))	('EGFR', 'Gene', (56, 60))	('CHASM', 'Gene', (130, 135))	('patients', 'Species', '9606', (93, 101))
567984	31202631	The CHASMplus GBM model correctly scores the missense mutations from GBM patients significantly higher than those from LUAD patients (p=0.004, two-sided t-test), and vice versa for the CHASMplus LUAD model (p=0.003, two-sided t-test).	('CHASMplus', 'Disease', (185, 194))	('CHASMplus', 'Disease', (4, 13))	('GBM', 'Disease', (69, 72))	('CHASMplus', 'Disease', 'None', (185, 194))	('CHASMplus', 'Disease', 'None', (4, 13))	('CHASMplus LUAD', 'Disease', 'None', (185, 199))	('CHASMplus LUAD', 'Disease', (185, 199))	('missense mutations', 'Var', (45, 63))	('higher', 'PosReg', (96, 102))	('patients', 'Species', '9606', (73, 81))	('patients', 'Species', '9606', (124, 132))
567985	31202631	In contrast, the CHASM GBM model and the CHASM LUAD model both score the mutations from LUAD patients higher than those from GBM patients (p=1e-5 and 5e-5, respectively, two-sided t-test).	('CHASM', 'Gene', (41, 46))	('score', 'PosReg', (63, 68))	('patients', 'Species', '9606', (129, 137))	('CHASM', 'Gene', '219537', (17, 22))	('higher', 'PosReg', (102, 108))	('CHASM', 'Gene', '219537', (41, 46))	('patients', 'Species', '9606', (93, 101))	('mutations', 'Var', (73, 82))	('CHASM', 'Gene', (17, 22))
567986	31202631	CanDrA does not have a LUAD model, but its GBM model scores mutations from LUAD patients higher than those from GBM patients (p=0.0002, two-sided t-test), which is significant in the wrong direction.	('mutations', 'Var', (60, 69))	('higher', 'PosReg', (89, 95))	('patients', 'Species', '9606', (116, 124))	('patients', 'Species', '9606', (80, 88))
567987	31202631	In summary, several lines of evidence suggest that CHASMplus, relative to other methods, has a substantial advantage in distinguishing between driver and passenger missense mutations, specifically by cancer type.	('driver', 'Var', (143, 149))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('CHASMplus', 'Disease', (51, 60))	('CHASMplus', 'Disease', 'None', (51, 60))	('cancer', 'Disease', 'MESH:D009369', (200, 206))	('cancer', 'Disease', (200, 206))
567989	31202631	This approach is useful because some cancer driver mutations do occur in many cancer types.	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('mutations', 'Var', (51, 60))	('cancer', 'Disease', (37, 43))	('cancer', 'Disease', (78, 84))	('cancer', 'Disease', 'MESH:D009369', (78, 84))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))
567990	31202631	The power to detect these mutations, particularly when they occur at low frequency in many cancer types, is increased when many cancer types are aggregated, known as a pan-cancer analysis.	('cancer', 'Disease', 'MESH:D009369', (128, 134))	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('cancer', 'Disease', (91, 97))	('increased', 'PosReg', (108, 117))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('mutations', 'Var', (26, 35))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('cancer', 'Phenotype', 'HP:0002664', (128, 134))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('cancer', 'Disease', (172, 178))	('cancer', 'Disease', (128, 134))
567993	31202631	A range of benchmarks was critical because missense mutations with the most established experimental support for a driver role tend to be in a few well-understood cancer driver genes.	('missense mutations', 'Var', (43, 61))	('cancer', 'Disease', (163, 169))	('cancer', 'Disease', 'MESH:D009369', (163, 169))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))
567995	31202631	These results suggest that CHASMplus improves on previous methods to predict driver missense mutations in a pan-cancer setting, as well as in a cancer type-specific manner.	('driver missense mutations', 'Var', (77, 102))	('cancer', 'Disease', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('CHASMplus', 'Disease', (27, 36))	('cancer', 'Disease', 'MESH:D009369', (144, 150))	('CHASMplus', 'Disease', 'None', (27, 36))	('cancer', 'Disease', (144, 150))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))
567998	31202631	Using cancer type-specific models, we found a wide range of putative driver missense mutations in various cancer types.	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('cancer', 'Disease', 'MESH:D009369', (106, 112))	('cancer', 'Disease', (106, 112))	('cancer', 'Disease', 'MESH:D009369', (6, 12))	('missense mutations', 'Var', (76, 94))	('cancer', 'Disease', (6, 12))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
568000	31202631	In total, 479 unique driver missense mutations were identified by the cancer type-specific analyses but missed by pan-cancer analysis.	('cancer', 'Disease', (118, 124))	('cancer', 'Phenotype', 'HP:0002664', (70, 76))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))	('missense mutations', 'Var', (28, 46))	('cancer', 'Disease', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (70, 76))	('cancer', 'Disease', 'MESH:D009369', (118, 124))
568001	31202631	The pan-cancer analysis identified 3,527 unique missense mutations as putative drivers (Table S3) and had substantial overlap with our earlier pan-cancer analysis (p<2.2e-16, one-sided Fisher's exact test).	('cancer', 'Phenotype', 'HP:0002664', (147, 153))	('cancer', 'Disease', (8, 14))	('cancer', 'Phenotype', 'HP:0002664', (8, 14))	('cancer', 'Disease', 'MESH:D009369', (147, 153))	('missense mutations', 'Var', (48, 66))	('cancer', 'Disease', (147, 153))	('cancer', 'Disease', 'MESH:D009369', (8, 14))
568002	31202631	Given the substantially different methodology, the overlap suggests the CHASMplus pan-cancer analysis identifies a core set of driver mutations with multiple distinct sources of evidence.	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('CHASMplus pan-cancer', 'Disease', 'MESH:D009369', (72, 92))	('CHASMplus pan-cancer', 'Disease', (72, 92))	('mutations', 'Var', (134, 143))
568004	31202631	Notably, the cancer type-specific analysis identified a substantial number of putative driver mutations not previously characterized in OncoKB (median overlap 53%).	('cancer', 'Disease', (13, 19))	('cancer', 'Disease', 'MESH:D009369', (13, 19))	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('mutations', 'Var', (94, 103))
568005	31202631	Altogether across the pan-cancer and cancer type-specific analyses, 4,006 unique driver missense mutations were identified by CHASMplus, of which 2,037 were neither found by OncoKB nor our earlier pan-cancer analysis, indicating a potentially expanded landscape of putative driver missense mutations of interest for further examination.	('cancer', 'Disease', 'MESH:D009369', (201, 207))	('CHASMplus', 'Disease', (126, 135))	('cancer', 'Disease', 'MESH:D009369', (37, 43))	('CHASMplus', 'Disease', 'None', (126, 135))	('cancer', 'Disease', (201, 207))	('cancer', 'Disease', (26, 32))	('cancer', 'Disease', (37, 43))	('cancer', 'Disease', 'MESH:D009369', (26, 32))	('cancer', 'Phenotype', 'HP:0002664', (201, 207))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('missense mutations', 'Var', (88, 106))
568010	31202631	These results suggest that CHASMplus has potential to discriminate driver and passenger mutations in both well-known and putative cancer driver genes, although follow up experiments are required for confirmation.	('cancer', 'Disease', 'MESH:D009369', (130, 136))	('cancer', 'Disease', (130, 136))	('CHASMplus', 'Disease', (27, 36))	('mutations', 'Var', (88, 97))	('CHASMplus', 'Disease', 'None', (27, 36))	('cancer', 'Phenotype', 'HP:0002664', (130, 136))
568011	31202631	Based on our mutation-level analysis, we observed that the spectrum of rare (<1% of cancer samples), intermediate (1-5%), and common (>5%) frequency driver missense mutations varied substantially among cancer types (Figure 3a).	('cancer', 'Disease', 'MESH:D009369', (84, 90))	('cancer', 'Phenotype', 'HP:0002664', (202, 208))	('cancer', 'Disease', (84, 90))	('cancer', 'Disease', 'MESH:D009369', (202, 208))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('cancer', 'Disease', (202, 208))	('missense mutations', 'Var', (156, 174))
568012	31202631	For example, uveal melanoma was dominated by common driver missense mutations (88%), while head and neck squamous cell carcinoma (HNSC) was dominated by rare driver missense mutations (63%).	('uveal melanoma', 'Disease', (13, 27))	('neck squamous cell carcinoma', 'Disease', (100, 128))	('melanoma', 'Phenotype', 'HP:0002861', (19, 27))	('missense mutations', 'Var', (59, 77))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (105, 128))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (100, 128))	('carcinoma', 'Phenotype', 'HP:0030731', (119, 128))	('uveal melanoma', 'Phenotype', 'HP:0007716', (13, 27))	('uveal melanoma', 'Disease', 'MESH:C536494', (13, 27))
568013	31202631	However, when we considered all cancer types together (pan-cancer), the overall proportion of rare driver missense mutations considered rare was slightly greater than for common (35.5% and 35.4%, respectively) and 4-fold greater than found by the cancer hotspots method (8%, P<2.2e-16, Fisher's exact test).	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('cancer', 'Phenotype', 'HP:0002664', (247, 253))	('missense mutations', 'Var', (106, 124))	('cancer', 'Disease', (32, 38))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('cancer', 'Disease', (247, 253))	('cancer', 'Disease', 'MESH:D009369', (247, 253))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))
568014	31202631	These results suggest that rare driver missense mutations have a greater role in many cancer types than previously suggested, but that this might not be the case for every cancer type.	('cancer', 'Phenotype', 'HP:0002664', (172, 178))	('cancer', 'Phenotype', 'HP:0002664', (86, 92))	('cancer', 'Disease', 'MESH:D009369', (172, 178))	('cancer', 'Disease', (172, 178))	('cancer', 'Disease', 'MESH:D009369', (86, 92))	('missense mutations', 'Var', (39, 57))	('cancer', 'Disease', (86, 92))
568015	31202631	We observed, after adjusting for sample size, that the average tumor mutation burden for a cancer type positively correlated with the prevalence of rare (but not common) driver missense mutations (R=0.63, P=4.7e-5, likelihood ratio test, Figure 3b).	('tumor', 'Disease', (63, 68))	('missense mutations', 'Var', (177, 195))	('cancer', 'Disease', (91, 97))	('cancer', 'Disease', 'MESH:D009369', (91, 97))	('tumor', 'Disease', 'MESH:D009369', (63, 68))	('cancer', 'Phenotype', 'HP:0002664', (91, 97))	('tumor', 'Phenotype', 'HP:0002664', (63, 68))
568016	31202631	While cancer types appear to have different proportions of rare, intermediate and common driver missense mutations across cancer types, this result could be confounded by differences in subtypes or cell-of-origin.	('cancer', 'Phenotype', 'HP:0002664', (6, 12))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (6, 12))	('missense mutations', 'Var', (96, 114))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('cancer', 'Disease', (6, 12))
568019	31202631	Fifty-five out of 223 genes (24.7%) contained putative driver missense mutations that were enriched in particular cancer subtypes (q-value<=0.1, chi-squared test, Figure 3c, Table S5, Figure S4).	('cancer', 'Disease', 'MESH:D009369', (114, 120))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('missense mutations', 'Var', (62, 80))	('cancer', 'Disease', (114, 120))
568020	31202631	Several genes showed strong specificity, consistent with prior literature, such as NFE2L2 mutations in esophageal cancers of squamous cell-of-origin, TP53 mutations in Human Papillomavirus-negative tumors in head and neck cancer, KIT mutations in testicular seminomas and PIK3CA mutations in the Luminal A subtype of breast cancer.	('cancers', 'Phenotype', 'HP:0002664', (114, 121))	('TP53', 'Gene', (150, 154))	('mutations', 'Var', (90, 99))	('cancers', 'Disease', (114, 121))	('breast cancer', 'Disease', 'MESH:D001943', (317, 330))	('breast cancer', 'Disease', (317, 330))	('tumor', 'Phenotype', 'HP:0002664', (198, 203))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('KIT', 'Gene', '3815', (230, 233))	('testicular seminomas', 'Phenotype', 'HP:0100617', (247, 267))	('Papillomavirus-negative tumors', 'Disease', 'MESH:D030361', (174, 204))	('mutations', 'Var', (279, 288))	('Papillomavirus-negative tumors', 'Disease', (174, 204))	('PIK3CA', 'Gene', (272, 278))	('NFE2L2', 'Gene', '4780', (83, 89))	('cancer', 'Phenotype', 'HP:0002664', (222, 228))	('neck cancer', 'Disease', 'MESH:D006258', (217, 228))	('TP53', 'Gene', '7157', (150, 154))	('neck cancer', 'Disease', (217, 228))	('cancers', 'Disease', 'MESH:D009369', (114, 121))	('seminomas', 'Disease', 'MESH:D018239', (258, 267))	('seminomas', 'Disease', (258, 267))	('cancer', 'Phenotype', 'HP:0002664', (324, 330))	('head and neck cancer', 'Phenotype', 'HP:0012288', (208, 228))	('NFE2L2', 'Gene', (83, 89))	('mutations', 'Var', (234, 243))	('KIT', 'Gene', (230, 233))	('mutations', 'Var', (155, 164))	('PIK3CA', 'Gene', '5290', (272, 278))	('breast cancer', 'Phenotype', 'HP:0003002', (317, 330))	('tumors', 'Phenotype', 'HP:0002664', (198, 204))
568021	31202631	It should be noted that in some cases these differences are confounded by the fact that subtypes were originally defined by mutation status (GBM or LGG with IDH1/IDH2 mutations).	('IDH2', 'Gene', '3418', (162, 166))	('IDH2', 'Gene', (162, 166))	('mutations', 'Var', (167, 176))	('IDH1', 'Gene', (157, 161))	('IDH1', 'Gene', '3417', (157, 161))
568022	31202631	For example, the protein phosphatase PPP2R1A, which has been implicated as a tumor suppressor gene in many tumor types, contained common driver missense mutations in our pan-cancer analysis at residue positions 179 and 183, which is located at the protein interface composing the phosphatase 2A complex (Figure 3d).	('PPP2R1A', 'Gene', '5518', (37, 44))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('missense mutations', 'Var', (144, 162))	('tumor', 'Disease', 'MESH:D009369', (77, 82))	('cancer', 'Phenotype', 'HP:0002664', (174, 180))	('cancer', 'Disease', (174, 180))	('cancer', 'Disease', 'MESH:D009369', (174, 180))	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('PPP2R1A', 'Gene', (37, 44))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('tumor', 'Disease', (77, 82))
568023	31202631	It also had a much broader set of rare driver mutations throughout the protein interface, such as R105Q and R459C.	('R105Q', 'Var', (98, 103))	('R105Q', 'Mutation', 'rs1489963266', (98, 103))	('R459C', 'Mutation', 'p.R459C', (108, 113))	('R459C', 'Var', (108, 113))
568024	31202631	Similarly, CHASMplus identified common driver missense mutations (S310A/F/Y) in the extracellular domain of the well-known oncogene ERBB2, but also finds rare driver missense mutations in both the extracellular and kinase domain (e.g., L313V and R678Q) (Figure 3e).	('R678Q', 'Var', (246, 251))	('ERBB2', 'Gene', (132, 137))	('S310A/F/Y', 'Var', (66, 75))	('S310A/F/Y', 'Mutation', 'rs1057519816', (66, 75))	('L313V', 'Mutation', 'p.L313V', (236, 241))	('CHASMplus', 'Disease', (11, 20))	('CHASMplus', 'Disease', 'None', (11, 20))	('L313V', 'Var', (236, 241))	('ERBB2', 'Gene', '2064', (132, 137))	('R678Q', 'Mutation', 'rs1057519862', (246, 251))
568025	31202631	This is supportive of previous experimental work implicating rare cancer driver mutations in commonly mutated cancer driver genes.	('cancer', 'Disease', (110, 116))	('mutations', 'Var', (80, 89))	('cancer', 'Phenotype', 'HP:0002664', (66, 72))	('cancer', 'Phenotype', 'HP:0002664', (110, 116))	('cancer', 'Disease', 'MESH:D009369', (66, 72))	('cancer', 'Disease', 'MESH:D009369', (110, 116))	('cancer', 'Disease', (66, 72))
568026	31202631	Truncating or likely loss-of-function mutations are typical hallmarks of tumor suppressor genes.	('tumor', 'Disease', 'MESH:D009369', (73, 78))	('loss-of-function', 'NegReg', (21, 37))	('tumor', 'Phenotype', 'HP:0002664', (73, 78))	('tumor', 'Disease', (73, 78))	('Truncating', 'Var', (0, 10))	('mutations', 'Var', (38, 47))
568027	31202631	However, the role of driver missense mutations may be under-characterized in tumor suppressor genes, since these mutations are more diverse and occur over a larger region than in oncogenes.	('tumor', 'Phenotype', 'HP:0002664', (77, 82))	('missense mutations', 'Var', (28, 46))	('tumor', 'Disease', (77, 82))	('tumor', 'Disease', 'MESH:D009369', (77, 82))
568028	31202631	As a case in point, the tumor suppressor gene CASP8 contains many truncating variants, while all of the putative driver missense mutations identified by CHASMplus were considered rare (Figure 3f).	('tumor', 'Phenotype', 'HP:0002664', (24, 29))	('variants', 'Var', (77, 85))	('tumor', 'Disease', (24, 29))	('tumor', 'Disease', 'MESH:D009369', (24, 29))	('CHASMplus', 'Disease', (153, 162))	('CASP8', 'Gene', (46, 51))	('CHASMplus', 'Disease', 'None', (153, 162))	('CASP8', 'Gene', '841', (46, 51))	('truncating', 'MPA', (66, 76))
568030	31202631	We explored functional evidence to support whether the rare driver missense mutations in CASP8, predicted by CHASMplus, behaved similarly to truncating variants.	('CHASMplus', 'Disease', 'None', (109, 118))	('CASP8', 'Gene', (89, 94))	('CASP8', 'Gene', '841', (89, 94))	('CHASMplus', 'Disease', (109, 118))	('missense mutations', 'Var', (67, 85))
568032	31202631	For 12 immune-related markers, we compared tumor samples with driver missense mutations or truncating mutations in CASP8 to control samples with no mutations in CASP8.	('CASP8', 'Gene', (161, 166))	('truncating mutations', 'Var', (91, 111))	('CASP8', 'Gene', '841', (161, 166))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('CASP8', 'Gene', (115, 120))	('CASP8', 'Gene', '841', (115, 120))	('missense mutations', 'Var', (69, 87))	('tumor', 'Disease', (43, 48))
568034	31202631	Conventional wisdom has suggested that because rare missense mutations in tumor suppressor genes do not tend to cluster in protein sequence, they are solely passenger events.	('tumor', 'Phenotype', 'HP:0002664', (74, 79))	('tumor', 'Disease', (74, 79))	('tumor', 'Disease', 'MESH:D009369', (74, 79))	('missense mutations', 'Var', (52, 70))
568035	31202631	However, our work suggests that rare driver missense mutations in CASP8 and perhaps in other tumor suppressor genes may be relevant to tumor immune-related phenotypes.	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('tumor', 'Phenotype', 'HP:0002664', (93, 98))	('missense mutations', 'Var', (44, 62))	('tumor', 'Disease', (93, 98))	('tumor', 'Disease', (135, 140))	('CASP8', 'Gene', (66, 71))	('tumor', 'Disease', 'MESH:D009369', (135, 140))	('CASP8', 'Gene', '841', (66, 71))	('tumor', 'Disease', 'MESH:D009369', (93, 98))
568040	31202631	Because PTEN mutations are found in many cancer types, we used CHASMplus pan-cancer predictions.	('CHASMplus pan-cancer', 'Disease', 'MESH:D009369', (63, 83))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('cancer', 'Disease', (77, 83))	('cancer', 'Disease', 'MESH:D009369', (77, 83))	('PTEN', 'Gene', (8, 12))	('PTEN', 'Gene', '5728', (8, 12))	('CHASMplus pan-cancer', 'Disease', (63, 83))	('found', 'Reg', (27, 32))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('mutations', 'Var', (13, 22))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))
568044	31202631	Next, we examined the lipid phosphatase activity and protein abundance for the PTEN mutations that we predicted as drivers in the TCGA.	('mutations', 'Var', (84, 93))	('PTEN', 'Gene', (79, 83))	('PTEN', 'Gene', '5728', (79, 83))
568045	31202631	We observed that these driver missense mutations, regardless of frequency, had significantly lower lipid phosphatase activity than other missense mutations in PTEN (common: p=0.008; intermediate: p=1.9e-9; rare: p=1.6e-18; Mann-Whitney U test, Figure 5e).	('PTEN', 'Gene', (159, 163))	('PTEN', 'Gene', '5728', (159, 163))	('missense mutations', 'Var', (30, 48))	('lipid phosphatase activity', 'MPA', (99, 125))	('lower', 'NegReg', (93, 98))
568046	31202631	A likely explanation is that greater decreases in PTEN lipid phosphatase activity may promote tumor growth and tumor clones with these mutations are positively selected in many patients.	('tumor', 'Disease', 'MESH:D009369', (94, 99))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('activity', 'MPA', (73, 81))	('tumor', 'Phenotype', 'HP:0002664', (94, 99))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('patients', 'Species', '9606', (177, 185))	('mutations', 'Var', (135, 144))	('PTEN', 'Gene', (50, 54))	('tumor', 'Disease', (94, 99))	('tumor', 'Disease', (111, 116))	('promote', 'PosReg', (86, 93))	('PTEN', 'Gene', '5728', (50, 54))	('decreases', 'NegReg', (37, 46))
568054	31202631	Based on our cancer type-specific models from CHASMplus, we found that the diversity and prevalence of driver missense mutations varied considerably across TCGA cancer types (Figure 6a, Methods).	('cancer', 'Phenotype', 'HP:0002664', (13, 19))	('cancer', 'Phenotype', 'HP:0002664', (161, 167))	('CHASMplus', 'Disease', (46, 55))	('cancer', 'Disease', (13, 19))	('cancer', 'Disease', 'MESH:D009369', (13, 19))	('cancer', 'Disease', 'MESH:D009369', (161, 167))	('CHASMplus', 'Disease', 'None', (46, 55))	('cancer', 'Disease', (161, 167))	('missense mutations', 'Var', (110, 128))	('TCGA', 'Disease', (156, 160))
568059	31202631	Are there substantially more cancer driver missense mutations yet to be discovered?	('missense mutations', 'Var', (43, 61))	('cancer', 'Disease', (29, 35))	('cancer', 'Disease', 'MESH:D009369', (29, 35))	('cancer', 'Phenotype', 'HP:0002664', (29, 35))
568062	31202631	Subsampling analysis showed all cancer types had a linear increase in the number of unique driver missense mutations identified (R2 > 0.5) with no evidence of saturation at current sample sizes (Figure S7a).	('S7', 'Gene', '6264', (202, 204))	('increase', 'PosReg', (58, 66))	('cancer', 'Disease', 'MESH:D009369', (32, 38))	('missense mutations', 'Var', (98, 116))	('cancer', 'Disease', (32, 38))	('cancer', 'Phenotype', 'HP:0002664', (32, 38))
568063	31202631	However, discovery of driver missense mutations, which occur in aggregate at a given prevalence (average number per cancer sample), varied substantially among cancer types (Figure 6b).	('cancer', 'Disease', (159, 165))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('missense mutations', 'Var', (29, 47))
568065	31202631	This resulted in only marginal increases in the overall prevalence of identified driver missense mutations, consistent with our predicted trajectory based only on TCGA samples (Methods, Table S7, Figure S7b).	('S7', 'Gene', '6264', (192, 194))	('missense mutations', 'Var', (88, 106))	('increases', 'PosReg', (31, 40))	('S7', 'Gene', '6264', (203, 205))
568066	31202631	In contrast, thymoma (THYM), uveal melanoma (UVM), and pancreatic ductal adenocarcinoma (PAAD) contained common driver missense mutations that could be detected based on only a few samples from the cohort, e.g., GTF2I L424H in THYM.	('thymoma', 'Gene', (13, 20))	('carcinoma', 'Phenotype', 'HP:0030731', (78, 87))	('uveal melanoma', 'Phenotype', 'HP:0007716', (29, 43))	('uveal melanoma', 'Disease', (29, 43))	('uveal melanoma', 'Disease', 'MESH:C536494', (29, 43))	('melanoma', 'Phenotype', 'HP:0002861', (35, 43))	('GTF2I', 'Gene', (212, 217))	('thymoma', 'Gene', '7063', (13, 20))	('thymoma', 'Phenotype', 'HP:0100522', (13, 20))	('GTF2I', 'Gene', '2969', (212, 217))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (55, 87))	('missense', 'Var', (119, 127))	('L424H', 'Mutation', 'p.L424H', (218, 223))	('pancreatic ductal adenocarcinoma', 'Disease', (55, 87))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (55, 87))
568067	31202631	In contrast, the prevalence of rare driver missense mutations increased substantially with sample size in breast cancer (BRCA), head and neck squamous cell carcinoma (HNSC), and colon adenocarcinoma (COAD).	('missense mutations', 'Var', (43, 61))	('carcinoma', 'Phenotype', 'HP:0030731', (156, 165))	('breast cancer', 'Disease', (106, 119))	('cancer', 'Phenotype', 'HP:0002664', (113, 119))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (142, 165))	('breast cancer', 'Phenotype', 'HP:0003002', (106, 119))	('neck squamous cell carcinoma', 'Disease', 'MESH:D000077195', (137, 165))	('colon adenocarcinoma', 'Disease', (178, 198))	('colon adenocarcinoma', 'Disease', 'MESH:D003110', (178, 198))	('carcinoma', 'Phenotype', 'HP:0030731', (189, 198))	('neck squamous cell carcinoma', 'Disease', (137, 165))	('breast cancer', 'Disease', 'MESH:D001943', (106, 119))
568068	31202631	These results suggest cancer types can be clustered by patterns of driver missense mutation diversity and prevalence (Figure 6a), in addition to well-established approaches to define cancer subtypes, such as by cell-of-origin.	('cancer', 'Disease', (183, 189))	('cancer', 'Disease', 'MESH:D009369', (22, 28))	('cancer', 'Disease', (22, 28))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('cancer', 'Phenotype', 'HP:0002664', (22, 28))	('driver missense mutation', 'Var', (67, 91))	('cancer', 'Disease', 'MESH:D009369', (183, 189))
568070	31202631	Future insights into cancer evolution and its relevance for clinical care will increasingly rely on the precise interpretation of whether individual mutations are cancer drivers.	('cancer', 'Phenotype', 'HP:0002664', (21, 27))	('mutations', 'Var', (149, 158))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('cancer', 'Disease', (21, 27))	('cancer', 'Disease', 'MESH:D009369', (21, 27))	('cancer', 'Disease', (163, 169))	('cancer', 'Disease', 'MESH:D009369', (163, 169))
568072	31202631	The long tail hypothesis posits that there are many rare driver mutations in human cancers.	('cancers', 'Disease', 'MESH:D009369', (83, 90))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('long tail', 'Phenotype', 'HP:0002831', (4, 13))	('mutations', 'Var', (64, 73))	('cancers', 'Phenotype', 'HP:0002664', (83, 90))	('cancers', 'Disease', (83, 90))	('human', 'Species', '9606', (77, 82))
568075	31202631	The observed diversity of driver mutations across patients' tumors may be influenced by tumor mutation burden, the type of gene (i.e., tumor suppressor genes), the functional strength of the mutation, and the mutation's subtype specificity.	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('tumor', 'Disease', 'MESH:D009369', (88, 93))	('patients', 'Species', '9606', (50, 58))	('tumor', 'Disease', 'MESH:D009369', (60, 65))	('tumor', 'Disease', (135, 140))	('influenced', 'Reg', (74, 84))	('mutations', 'Var', (33, 42))	('tumor', 'Disease', 'MESH:D009369', (135, 140))	('tumors', 'Disease', 'MESH:D009369', (60, 66))	('tumor', 'Phenotype', 'HP:0002664', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (88, 93))	('tumors', 'Phenotype', 'HP:0002664', (60, 66))	('tumor', 'Disease', (60, 65))	('tumor', 'Disease', (88, 93))	('tumors', 'Disease', (60, 66))
568076	31202631	The diversity of driver missense mutations supports the critical role of understanding the origins and overall contribution of rare driver mutations -- failure to capture and identify rare driver mutations, which occur in aggregate at reasonable prevalence, may result in crucial missed opportunities for interpreting a patient's cancer.	('missense mutations', 'Var', (24, 42))	('cancer', 'Phenotype', 'HP:0002664', (330, 336))	('patient', 'Species', '9606', (320, 327))	('cancer', 'Disease', 'MESH:D009369', (330, 336))	('cancer', 'Disease', (330, 336))
568078	31202631	We therefore have precomputed the score of every possible missense mutation across the genome, effectively an in silico saturation mutagenesis across all genes to score as of yet unobserved mutations that are potential cancer drivers.	('cancer', 'Disease', 'MESH:D009369', (219, 225))	('cancer', 'Phenotype', 'HP:0002664', (219, 225))	('missense mutation', 'Var', (58, 75))	('cancer', 'Disease', (219, 225))
568079	31202631	Although missense mutations are the most frequent protein-coding somatic alteration in cancer, CHASMplus only predicts missense mutations; but, in principle, our approach could be extended to other types of alterations.	('CHASMplus', 'Disease', (95, 104))	('cancer', 'Disease', (87, 93))	('CHASMplus', 'Disease', 'None', (95, 104))	('missense mutations', 'Var', (119, 137))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('missense mutations', 'Var', (9, 27))	('cancer', 'Disease', 'MESH:D009369', (87, 93))
568080	31202631	Lastly, while our study leverages the large sized TCGA cohorts to make informed judgements about driver missense mutations, inevitably these tumors may still miss important contexts for understanding cancer.	('tumor', 'Phenotype', 'HP:0002664', (141, 146))	('cancer', 'Phenotype', 'HP:0002664', (200, 206))	('tumors', 'Disease', 'MESH:D009369', (141, 147))	('tumors', 'Disease', (141, 147))	('tumors', 'Phenotype', 'HP:0002664', (141, 147))	('missense mutations', 'Var', (104, 122))	('cancer', 'Disease', 'MESH:D009369', (200, 206))	('cancer', 'Disease', (200, 206))
568082	31202631	For example, it is well known EGFR mutations in lung adenocarcinoma are more highly prevalent in Asian compared to Caucasian populations.	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (48, 67))	('EGFR', 'Gene', (30, 34))	('lung adenocarcinoma', 'Disease', (48, 67))	('prevalent', 'Reg', (84, 93))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (48, 67))	('EGFR', 'Gene', '1956', (30, 34))	('carcinoma', 'Phenotype', 'HP:0030731', (58, 67))	('mutations', 'Var', (35, 44))
568084	31202631	We expect that an increasingly complete catalog of driver missense mutations will be generated by a combination of improved computational methods and cumulative growth of available samples from cancer sequencing studies.	('missense mutations', 'Var', (58, 76))	('cancer', 'Phenotype', 'HP:0002664', (194, 200))	('cancer', 'Disease', (194, 200))	('cancer', 'Disease', 'MESH:D009369', (194, 200))
568085	31202631	However, for some cancer types in some populations, discovery of driver missense mutations may already be effectively saturated.	('cancer', 'Phenotype', 'HP:0002664', (18, 24))	('cancer', 'Disease', (18, 24))	('cancer', 'Disease', 'MESH:D009369', (18, 24))	('missense mutations', 'Var', (72, 90))
568086	31202631	By analyzing the trajectory of discovery at the level of driver missense mutations, we identified a more complicated pattern which depends on the cancer type.	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('missense mutations', 'Var', (64, 82))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))
568087	31202631	Future work will further elucidate a broader range of driver mutations, including those within non-coding regions of the genome, at different stages of carcinogenesis, such as in pre-cancerous lesions, and in response to therapeutic treatment.	('carcinogenesis', 'Disease', (152, 166))	('cancerous lesions', 'Disease', 'MESH:D009369', (183, 200))	('mutations', 'Var', (61, 70))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('cancerous lesions', 'Disease', (183, 200))	('carcinogenesis', 'Disease', 'MESH:D063646', (152, 166))
568090	31202631	We collected a set of 1,225,917 somatic mutations in 8,657 samples from The Cancer Genome Atlas (TCGA) somatic mutation calls from whole-exome sequencing (v0.2.8, https://synapse.org/MC3).	('Cancer', 'Phenotype', 'HP:0002664', (76, 82))	('MC3', 'Gene', (183, 186))	('MC3', 'Gene', '4159', (183, 186))	('mutations', 'Var', (40, 49))	('Cancer', 'Disease', (76, 82))	('Cancer', 'Disease', 'MESH:D009369', (76, 82))
568092	31202631	We identified hypermutated samples as having more mutations than 1.5 times the interquartile range above the third quartile (Tukey's condition) of samples within the same cancer type.	('mutations', 'Var', (50, 59))	('cancer', 'Disease', 'MESH:D009369', (171, 177))	('cancer', 'Phenotype', 'HP:0002664', (171, 177))	('cancer', 'Disease', (171, 177))
568095	31202631	Previous machine learning approaches for predicting driver mutations have been trained on a small positive class of bona fide driver missense mutations, which are highly prevalent in many cancer types.	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('missense mutations', 'Var', (133, 151))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('cancer', 'Disease', (188, 194))
568097	31202631	Driver genes have been labeled but the labels of missense mutations are inferred by cluster assumptions, e.g., driver missense mutations may occur together in known driver genes and in significantly mutated genes for a particular cancer type.	('cancer', 'Phenotype', 'HP:0002664', (230, 236))	('occur', 'Reg', (141, 146))	('cancer', 'Disease', (230, 236))	('cancer', 'Disease', 'MESH:D009369', (230, 236))	('missense mutations', 'Var', (118, 136))
568098	31202631	Mutations are assigned to the 'positive' class (driver-like) for a cancer type based on these assumptions, and all other mutations are assigned to the 'negative' class (passenger-like).	('cancer', 'Disease', 'MESH:D009369', (67, 73))	('Mutations', 'Var', (0, 9))	('cancer', 'Disease', (67, 73))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))
568099	31202631	To extend this approach to a pan-cancer prediction, all mutations from the positive class were merged into one group and a single classifier was trained.	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('mutations', 'Var', (56, 65))	('cancer', 'Disease', (33, 39))	('cancer', 'Disease', 'MESH:D009369', (33, 39))
568101	31202631	To test the assumptions of our training procedure, we rigorously evaluated CHASMplus on orthogonally labeled mutations based on in vitro experiments, in vivo experiments, and literature curation.	('CHASMplus', 'Disease', (75, 84))	('CHASMplus', 'Disease', 'None', (75, 84))	('mutations', 'Var', (109, 118))
568104	31202631	The positive class (likely-driver missense mutations) was selected by the following criteria: 1) missense mutations had to occur in a curated set of 125 pan-cancer driver genes; 2) for each of the 32 TCGA cancer types, missense mutations found in that cancer type had to occur in a significantly mutated gene for that cancer type according to MutSigCV v1.4.	('cancer', 'Disease', 'MESH:D009369', (318, 324))	('cancer', 'Phenotype', 'HP:0002664', (157, 163))	('cancer', 'Disease', 'MESH:D009369', (252, 258))	('cancer', 'Disease', 'MESH:D009369', (205, 211))	('cancer', 'Disease', (318, 324))	('v1.4', 'Gene', '28815', (352, 356))	('cancer', 'Disease', (252, 258))	('cancer', 'Disease', (205, 211))	('missense mutations', 'Var', (219, 237))	('cancer', 'Disease', 'MESH:D009369', (157, 163))	('cancer', 'Phenotype', 'HP:0002664', (318, 324))	('cancer', 'Disease', (157, 163))	('cancer', 'Phenotype', 'HP:0002664', (252, 258))	('cancer', 'Phenotype', 'HP:0002664', (205, 211))	('v1.4', 'Gene', (352, 356))
568106	31202631	Notably, MutSigCV v1.4 only assess the total number of mutations in a gene, and not any characteristics of those mutations; thus, we avoid making strong assumptions about the properties of a particular driver mutation; 3) missense mutations had to occur in samples with relatively low mutation rate (less than 500 mutations, half the minimum hypermutator threshold as defined above).	('missense mutations', 'Var', (222, 240))	('v1.4', 'Gene', '28815', (18, 22))	('v1.4', 'Gene', (18, 22))
568116	31202631	We used random forests, a machine learning technique, to predict whether a missense mutation is a cancer driver.	('missense mutation', 'Var', (75, 92))	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('cancer', 'Disease', (98, 104))	('cancer', 'Disease', 'MESH:D009369', (98, 104))
568118	31202631	Since missense mutations in the same gene may have overlapping feature representations which result in classifier overfitting, we performed prediction using a 10-fold gene hold-out cross-validation procedure for both CHASMplus and 20/20+.	('overfitting', 'PosReg', (114, 125))	('CHASMplus', 'Disease', (217, 226))	('CHASMplus', 'Disease', 'None', (217, 226))	('missense mutations', 'Var', (6, 24))	('result in', 'Reg', (93, 102))
568120	31202631	The CHASMplus score represents the fraction of decision trees which vote for the mutation being a driver.	('CHASMplus', 'Disease', (4, 13))	('mutation', 'Var', (81, 89))	('CHASMplus', 'Disease', 'None', (4, 13))
568125	31202631	Next, each simulated missense mutation and gene was scored with the CHASMplus and 20/20+ models that were previously trained on the observed data.	('missense mutation', 'Var', (21, 38))	('CHASMplus', 'Disease', (68, 77))	('CHASMplus', 'Disease', 'None', (68, 77))
568127	31202631	We compared CHASMplus to 12 other methods that were designed to prioritize likely cancer driver missense mutations or have been used for that purpose (VEST, CADD, FATHMM cancer, SIFT, MutationAssessor, REVEL, MCAP, ParsSNP, CHASM, Polyphen2, transFIC and CanDrA).	('cancer', 'Disease', 'MESH:D009369', (170, 176))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('MCAP', 'Gene', (209, 213))	('cancer', 'Disease', (170, 176))	('CHASM', 'Gene', (224, 229))	('CHASM', 'Gene', (12, 17))	('CHASM', 'Gene', '219537', (224, 229))	('cancer', 'Disease', (82, 88))	('CADD', 'Disease', (157, 161))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('cancer', 'Phenotype', 'HP:0002664', (170, 176))	('missense mutations', 'Var', (96, 114))	('CHASMplus', 'Disease', (12, 21))	('CHASMplus', 'Disease', 'None', (12, 21))	('CHASM', 'Gene', '219537', (12, 17))	('MCAP', 'Gene', '23476', (209, 213))
568138	31202631	Mutations were scored using the corresponding cancer type models of CHASMplus, CanDrA, and CHASM, along with two high-performing methods which are not cancer type-specific (ParsSNP and REVEL).	('CHASMplus', 'Disease', (68, 77))	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('CHASMplus', 'Disease', 'None', (68, 77))	('CHASM', 'Gene', '219537', (68, 73))	('cancer', 'Phenotype', 'HP:0002664', (151, 157))	('cancer', 'Disease', (46, 52))	('Mutations', 'Var', (0, 9))	('cancer', 'Disease', (151, 157))	('CHASM', 'Gene', (91, 96))	('cancer', 'Disease', 'MESH:D009369', (151, 157))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('CHASM', 'Gene', (68, 73))	('CHASM', 'Gene', '219537', (91, 96))
568140	31202631	To assess each method's ability to distinguish breast cancer-specific driver mutations, mutations that increased cell viability in known breast cancer driver genes were labeled as positive class.	('breast cancer', 'Disease', 'MESH:D001943', (137, 150))	('breast cancer', 'Phenotype', 'HP:0003002', (137, 150))	('breast cancer', 'Disease', (47, 60))	('increased', 'PosReg', (103, 112))	('breast cancer', 'Disease', (137, 150))	('breast cancer', 'Phenotype', 'HP:0003002', (47, 60))	('mutations', 'Var', (88, 97))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('cell viability', 'CPA', (113, 127))	('cancer', 'Phenotype', 'HP:0002664', (144, 150))	('breast cancer', 'Disease', 'MESH:D001943', (47, 60))
568141	31202631	Mutations that did not increase cell viability or increased cell viability but were not found in breast cancer-specific genes were labeled as negative class.	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('breast cancer', 'Disease', 'MESH:D001943', (97, 110))	('Mutations', 'Var', (0, 9))	('breast cancer', 'Phenotype', 'HP:0003002', (97, 110))	('breast cancer', 'Disease', (97, 110))
568143	31202631	Breast cancer-specific genes were labeled based on the Cancer Gene Census (CGC, genes marked as relevant to "breast" cancer and somatic missense mutations, COSMIC v79) or The Cancer Genome Atlas (TCGA).	('Cancer', 'Disease', (175, 181))	('missense mutations', 'Var', (136, 154))	('cancer', 'Phenotype', 'HP:0002664', (7, 13))	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('Breast cancer', 'Phenotype', 'HP:0003002', (0, 13))	('Cancer', 'Disease', 'MESH:D009369', (175, 181))	('Cancer', 'Phenotype', 'HP:0002664', (175, 181))	('Breast cancer', 'Disease', 'MESH:D001943', (0, 13))	('Cancer', 'Phenotype', 'HP:0002664', (55, 61))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('Cancer', 'Disease', (55, 61))	('cancer', 'Disease', (7, 13))	('cancer', 'Disease', 'MESH:D009369', (7, 13))	('cancer', 'Disease', (117, 123))	('Breast cancer', 'Disease', (0, 13))	('Cancer', 'Disease', 'MESH:D009369', (55, 61))
568145	31202631	We obtained all missense mutations from targeted sequencing with the MSK-IMPACT gene panel of 414 cancer-related genes originating from approximately 10,000 patients' tumors.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('missense mutations', 'Var', (16, 34))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('patients', 'Species', '9606', (157, 165))	('cancer', 'Disease', (98, 104))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('tumors', 'Disease', 'MESH:D009369', (167, 173))	('tumors', 'Disease', (167, 173))	('tumors', 'Phenotype', 'HP:0002664', (167, 173))
568147	31202631	For each cancer type, mutations were labeled as 'positive' class if they occurred in a cancer driver gene implicated for that cancer type and also a tumor of the same type.	('cancer', 'Disease', (87, 93))	('occurred', 'Reg', (73, 81))	('cancer', 'Disease', (9, 15))	('cancer', 'Disease', 'MESH:D009369', (87, 93))	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('tumor', 'Disease', 'MESH:D009369', (149, 154))	('tumor', 'Phenotype', 'HP:0002664', (149, 154))	('cancer', 'Phenotype', 'HP:0002664', (87, 93))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('cancer', 'Phenotype', 'HP:0002664', (9, 15))	('tumor', 'Disease', (149, 154))	('mutations', 'Var', (22, 31))	('cancer', 'Disease', 'MESH:D009369', (9, 15))
568154	31202631	We obtained all missense mutations from targeted sequencing with the MSK-IMPACT gene panel of 414 cancer-related genes, originating from approximately 10,000 patients' tumors.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('missense mutations', 'Var', (16, 34))	('tumors', 'Phenotype', 'HP:0002664', (168, 174))	('tumors', 'Disease', (168, 174))	('tumors', 'Disease', 'MESH:D009369', (168, 174))	('cancer', 'Disease', 'MESH:D009369', (98, 104))	('cancer', 'Disease', (98, 104))	('patients', 'Species', '9606', (158, 166))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
568156	31202631	The study selected mutations based on their presence in sequenced human tumors.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('human', 'Species', '9606', (66, 71))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('tumors', 'Disease', (72, 78))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('mutations', 'Var', (19, 28))
568159	31202631	We assessed each method's ability to distinguish TP53 mutations with low transactivation (positive class) versus all other TP53 mutations (negative class).	('TP53', 'Gene', '7157', (49, 53))	('TP53', 'Gene', (49, 53))	('transactivation', 'MPA', (73, 88))	('mutations', 'Var', (54, 63))	('low', 'NegReg', (69, 72))	('TP53', 'Gene', '7157', (123, 127))	('TP53', 'Gene', (123, 127))
568160	31202631	We evaluated all missense mutations (n=2,314) for TP53 from the IARC TP53 database.	('TP53', 'Gene', '7157', (69, 73))	('TP53', 'Gene', (69, 73))	('missense mutations', 'Var', (17, 35))	('TP53', 'Gene', '7157', (50, 54))	('TP53', 'Gene', (50, 54))
568161	31202631	Low transactivation was considered as less than 50% wildtype, as indicated by the median of 8 different targets (WAF1, MDM2, BAX, h1433s, AIP1, GADD45, NOXA, and P53R2).	('WAF1', 'Gene', (113, 117))	('transactivation', 'MPA', (4, 19))	('MDM2', 'Gene', '4193', (119, 123))	('GADD45', 'Gene', (144, 150))	('NOXA', 'Gene', (152, 156))	('MDM2', 'Gene', (119, 123))	('h1433s', 'Var', (130, 136))	('P53R2', 'Gene', '50484', (162, 167))	('AIP1', 'Gene', '23204', (138, 142))	('NOXA', 'Gene', '5366', (152, 156))	('BAX', 'Gene', (125, 128))	('WAF1', 'Gene', '1026', (113, 117))	('BAX', 'Gene', '581', (125, 128))	('GADD45', 'Gene', '1647', (144, 150))	('P53R2', 'Gene', (162, 167))	('AIP1', 'Gene', (138, 142))
568163	31202631	The experiment assumes that mutations that provide a growth advantage to cells with growth factors withdrawn reflect cancer drivers.	('cancer', 'Phenotype', 'HP:0002664', (117, 123))	('growth', 'MPA', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (117, 123))	('cancer', 'Disease', (117, 123))	('mutations', 'Var', (28, 37))
568164	31202631	We compared (pan-cancer) CHASMplus to the cancer hotspots method (v0.6), with respect to its sensitivity to identify driver missense mutations.	('cancer', 'Phenotype', 'HP:0002664', (42, 48))	('cancer', 'Disease', 'MESH:D009369', (17, 23))	('CHASMplus', 'Disease', (25, 34))	('CHASMplus', 'Disease', 'None', (25, 34))	('cancer', 'Disease', (42, 48))	('cancer', 'Disease', (17, 23))	('cancer', 'Disease', 'MESH:D009369', (42, 48))	('missense mutations', 'Var', (124, 142))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
568166	31202631	The sensitivity of CHASMplus to detect the OncoKB-labeled mutations was 0.83, which was significantly higher than the hotspot method (0.46, p<2.2e-16, McNemar's test, n=896).	('mutations', 'Var', (58, 67))	('CHASMplus', 'Disease', (19, 28))	('CHASMplus', 'Disease', 'None', (19, 28))	('higher', 'PosReg', (102, 108))
568167	31202631	To minimize potential gene bias, we also repeated the analysis after excluding all 389 TP53 mutations, yielding sensitivity of 0.76 for CHASMplus and 0.49 for hotspot detection, a difference which is still statistically significant (p<2.2e-16, McNemar's test, n=507) (Figure 7b).	('CHASMplus', 'Disease', 'None', (136, 145))	('TP53', 'Gene', '7157', (87, 91))	('TP53', 'Gene', (87, 91))	('mutations', 'Var', (92, 101))	('CHASMplus', 'Disease', (136, 145))
568174	31202631	We performed gene ontology analysis on the set of 75 genes (Table S4) containing at least one driver missense mutation from CHASMplus that did not overlap with previous genes from the Cancer Gene Census (COSMIC v79, annotated with somatic missense) or any driver genes from the TCGA PancanAtlas analysis.	('CHASMplus', 'Disease', (124, 133))	('CHASMplus', 'Disease', 'None', (124, 133))	('mutation', 'Var', (110, 118))	('Cancer', 'Phenotype', 'HP:0002664', (184, 190))	('Cancer', 'Disease', (184, 190))	('Cancer', 'Disease', 'MESH:D009369', (184, 190))
568175	31202631	Mutation frequency was calculated based on the fraction of cancer samples that contained a driver mutation in a particular cancer type.	('cancer', 'Phenotype', 'HP:0002664', (123, 129))	('mutation', 'Var', (98, 106))	('cancer', 'Phenotype', 'HP:0002664', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (123, 129))	('cancer', 'Disease', (123, 129))	('cancer', 'Disease', (59, 65))	('cancer', 'Disease', 'MESH:D009369', (59, 65))
568177	31202631	All mutations within a codon are then classified as rare (<1% of cancer samples), intermediate (1-5%), or common (>5%).	('mutations', 'Var', (4, 13))	('cancer', 'Disease', (65, 71))	('cancer', 'Disease', 'MESH:D009369', (65, 71))	('cancer', 'Phenotype', 'HP:0002664', (65, 71))
568183	31202631	gwCHASMplus scores were computed for each of these missense mutations.	('missense mutations', 'Var', (51, 69))	('gwCHASMplus', 'Disease', 'None', (0, 11))	('gwCHASMplus', 'Disease', (0, 11))
568186	31202631	We extended our comparison of the PTEN saturation mutagenesis experiment of lipid phosphatase activity to the two "runner-up" methods (CanDrA and ParsSNP), assessed in the five benchmarks in Figure 2d.	('activity', 'MPA', (94, 102))	('mutagenesis', 'Var', (50, 61))	('PTEN', 'Gene', (34, 38))	('PTEN', 'Gene', '5728', (34, 38))
568187	31202631	CHASMplus, CanDrA and ParsSNP were then compared to each other based on their specificity, sensitivity, precision and F1 score to identify mutations damaging to lipid phosphatase activity in PTEN.	('CHASMplus', 'Disease', (0, 9))	('CHASMplus', 'Disease', 'None', (0, 9))	('damaging', 'Reg', (149, 157))	('mutations', 'Var', (139, 148))	('PTEN', 'Gene', (191, 195))	('PTEN', 'Gene', '5728', (191, 195))	('lipid phosphatase activity', 'MPA', (161, 187))
568188	31202631	Most driver missense mutation prediction methods do not report p-values, but CHASMplus does compute a p-value.	('CHASMplus', 'Disease', 'None', (77, 86))	('missense mutation', 'Var', (12, 29))	('CHASMplus', 'Disease', (77, 86))
568191	31202631	We clustered TCGA cancer types according to two features, prevalence (fraction of samples mutated) and normalized diversity (normalized entropy) among predicted missense mutation drivers (q <= 0.01).	('cancer', 'Disease', (18, 24))	('cancer', 'Disease', 'MESH:D009369', (18, 24))	('missense mutation', 'Var', (161, 178))	('cancer', 'Phenotype', 'HP:0002664', (18, 24))
568193	31202631	To evaluate this possibility, we correlated the mean Variant Allele Fraction (VAF) for mutations in tumor samples in each cancer type with a variety of metrics summarizing our results.	('tumor', 'Phenotype', 'HP:0002664', (100, 105))	('tumor', 'Disease', (100, 105))	('cancer', 'Disease', (122, 128))	('cancer', 'Disease', 'MESH:D009369', (122, 128))	('cancer', 'Phenotype', 'HP:0002664', (122, 128))	('tumor', 'Disease', 'MESH:D009369', (100, 105))	('mutations', 'Var', (87, 96))
568195	31202631	We found no significant correlation between mean VAF for cancer types with: average number of predicted driver mutations per sample (Pearson r=0.26, p=0.14, correlation test), fraction of samples with predicted driver mutations (Pearson r=0.2, p=0.28, correlation test), unique number of significant mutations (Pearson r=0.04, p=0.82, correlation test), and normalized driver diversity (Pearson r=0.33, p=0.07, correlation test).	('mutations', 'Var', (111, 120))	('cancer', 'Disease', (57, 63))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))
568196	31202631	We performed driver missense mutation predictions on random subsamples of each of 9 representative cancer types (ACC, SARC, PRAD, THYM, UVM, PAAD, BRCA, HNSC, and COAD), using CHASMplus.	('missense mutation', 'Var', (20, 37))	('UVM', 'Disease', (136, 139))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('HNSC', 'Disease', (153, 157))	('CHASMplus', 'Disease', (176, 185))	('cancer', 'Disease', (99, 105))	('PRAD', 'Disease', (124, 128))	('THYM', 'Disease', (130, 134))	('BRCA', 'Disease', (147, 151))	('CHASMplus', 'Disease', 'None', (176, 185))	('ACC', 'Disease', (113, 116))	('SARC', 'Disease', (118, 122))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('PAAD', 'Disease', (141, 145))
568199	31202631	The number of unique driver missense mutations and overall driver prevalence (average number of driver missense mutations per cancer sample) were then calculated based on significant CHASMplus predictions (q<=0.01).	('cancer', 'Phenotype', 'HP:0002664', (126, 132))	('cancer', 'Disease', (126, 132))	('cancer', 'Disease', 'MESH:D009369', (126, 132))	('CHASMplus', 'Disease', (183, 192))	('missense mutations', 'Var', (28, 46))	('CHASMplus', 'Disease', 'None', (183, 192))
568200	31202631	Results were then ordered by increasing sample size to observe trends in the identification of driver missense mutations by CHASMplus.	('CHASMplus', 'Disease', (124, 133))	('CHASMplus', 'Disease', 'None', (124, 133))	('driver missense mutations', 'Var', (95, 120))
568203	31202631	Similar to statistical methods for driver gene detection, hotspot detection identifies an excess number of mutations compared to expectation using a large number of cancer samples.	('cancer', 'Disease', 'MESH:D009369', (165, 171))	('cancer', 'Disease', (165, 171))	('mutations', 'Var', (107, 116))	('cancer', 'Phenotype', 'HP:0002664', (165, 171))
568204	31202631	We assessed the number of samples required to detect driver missense mutations across a range of frequencies (proportion of tumor samples in which a mutation occurs) and somatic background mutation rates.	('missense mutations', 'Var', (60, 78))	('tumor', 'Phenotype', 'HP:0002664', (124, 129))	('tumor', 'Disease', (124, 129))	('tumor', 'Disease', 'MESH:D009369', (124, 129))
568205	31202631	In Figure 7a, each of the 32 TCGA cancer types is placed according to its sample size and background mutation rate, relative to six curves which represent the required sample size to detect driver missense mutations of a certain frequency, with 90% power, using hotspot detection (see Statistical Power Analysis).	('cancer', 'Disease', (34, 40))	('cancer', 'Phenotype', 'HP:0002664', (34, 40))	('missense mutations', 'Var', (197, 215))	('cancer', 'Disease', 'MESH:D009369', (34, 40))
568207	31202631	At current TCGA sample sizes, we found codon-based hotspot detection approaches were not well powered to identify driver missense mutations that occurred at less than 1% frequency in most cancer types.	('cancer', 'Disease', 'MESH:D009369', (188, 194))	('cancer', 'Phenotype', 'HP:0002664', (188, 194))	('missense mutations', 'Var', (121, 139))	('cancer', 'Disease', (188, 194))
568210	31202631	For these mutations, pan-cancer analysis using ~10,000 TCGA samples should enable detection of driver mutations at frequency as low as 0.1%.	('mutations', 'Var', (10, 19))	('cancer', 'Disease', (25, 31))	('cancer', 'Disease', 'MESH:D009369', (25, 31))	('cancer', 'Phenotype', 'HP:0002664', (25, 31))
568212	31202631	Interactive portal for exploring driver missense mutations in TCGA: https://karchinlab.github.io/CHASMplus.	('missense mutations', 'Var', (40, 58))	('CHASMplus', 'Disease', (97, 106))	('CHASMplus', 'Disease', 'None', (97, 106))
568213	31202631	Missense mutations are the most frequent type of protein-coding alteration in cancers and the most difficult to interpret.	('cancers', 'Phenotype', 'HP:0002664', (78, 85))	('cancers', 'Disease', 'MESH:D009369', (78, 85))	('cancers', 'Disease', (78, 85))	('cancer', 'Phenotype', 'HP:0002664', (78, 84))	('Missense mutations', 'Var', (0, 18))
568214	31202631	While many computational methods have been developed to predict whether genes are cancer drivers or whether missense mutations are generally deleterious or pathogenic, there has not previously been a method to score the oncogenic impact of a missense mutation specifically by cancer type, limiting adoption of computational missense mutation predictors in the clinic.	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('cancer', 'Disease', (276, 282))	('cancer', 'Disease', 'MESH:D009369', (276, 282))	('cancer', 'Disease', (82, 88))	('cancer', 'Disease', 'MESH:D009369', (82, 88))	('cancer', 'Phenotype', 'HP:0002664', (276, 282))	('missense', 'Var', (242, 250))
568217	31202631	We introduce a machine learning method honed for each cancer type, and a resource for fast lookup of the cancer-specific driver propensity of every possible missense mutation in the human exome.	('cancer', 'Disease', 'MESH:D009369', (54, 60))	('cancer', 'Disease', (105, 111))	('human', 'Species', '9606', (182, 187))	('cancer', 'Disease', 'MESH:D009369', (105, 111))	('cancer', 'Disease', (54, 60))	('cancer', 'Phenotype', 'HP:0002664', (105, 111))	('cancer', 'Phenotype', 'HP:0002664', (54, 60))	('missense mutation', 'Var', (157, 174))
568218	31202631	CHASMplus identifies driver missense mutations in a cancer type-specific manner Rare driver mutations are common in cancer when considered as a group In some cancers, further sequencing will yield insight into rare driver mutations Comprehensive resource of driver propensity for all possible missense mutations	('CHASMplus', 'Disease', (0, 9))	('CHASMplus', 'Disease', 'None', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (52, 58))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('cancers', 'Phenotype', 'HP:0002664', (158, 165))	('cancer', 'Disease', (158, 164))	('missense mutations', 'Var', (28, 46))	('cancers', 'Disease', (158, 165))	('cancers', 'Disease', 'MESH:D009369', (158, 165))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))	('cancer', 'Disease', (52, 58))	('cancer', 'Disease', 'MESH:D009369', (52, 58))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
568219	29286228	Effects of Damnacanthal and Nordamnacanthal on Proliferation, Apoptosis, and Migration of Oral Squamous Cell Carcinoma Cells Cancer is one of the most common causes of death in the developed world, with one-third of people diagnosed with cancer during their lifetime.	('Nordamnacanthal', 'Chemical', 'MESH:C465644', (28, 43))	('Oral Squamous Cell Carcinoma', 'Disease', 'MESH:D002294', (90, 118))	('cancer', 'Disease', (238, 244))	('cancer', 'Disease', 'MESH:D009369', (238, 244))	('people', 'Species', '9606', (216, 222))	('Carcinoma', 'Phenotype', 'HP:0030731', (109, 118))	('Oral Squamous Cell Carcinoma', 'Disease', (90, 118))	('Nordamnacanthal', 'Var', (28, 43))	('Cancer', 'Disease', (125, 131))	('cancer', 'Phenotype', 'HP:0002664', (238, 244))	('Migration', 'CPA', (77, 86))	('Cancer', 'Disease', 'MESH:D009369', (125, 131))	('Cancer', 'Phenotype', 'HP:0002664', (125, 131))	('Squamous Cell Carcinoma', 'Phenotype', 'HP:0002860', (95, 118))	('Apoptosis', 'CPA', (62, 71))	('Damnacanthal', 'Chemical', 'MESH:C079170', (11, 23))
568371	33990203	PUS3 homozygous variants are associated with intellectual disability.	('intellectual disability', 'Phenotype', 'HP:0001249', (45, 68))	('PUS3', 'Gene', '83480', (0, 4))	('PUS3', 'Gene', (0, 4))	('intellectual disability', 'Disease', (45, 68))	('homozygous variants', 'Var', (5, 24))	('associated', 'Reg', (29, 39))
568373	33990203	Additionally, catalytic null PUS10 plays a role in miRNA biogenesis.	('PUS10', 'Gene', '150962', (29, 34))	('miRNA biogenesis', 'MPA', (51, 67))	('PUS10', 'Gene', (29, 34))	('catalytic null', 'Var', (14, 28))
568443	33990203	EdU and colony-formation assays showed that knocking down or overexpressing PUS7 did not affect the growth of DLD1 and HCT-8 cells (Fig.	('HCT-8', 'CellLine', 'CVCL:2478', (119, 124))	('overexpressing', 'PosReg', (61, 75))	('knocking down', 'Var', (44, 57))	('PUS7', 'Gene', (76, 80))
568444	33990203	PUS7 silencing diminished the migration rates of DLD1 and SW480 cells, whereas the overexpression of PUS7 exhibited a contrasting trend.	('SW480', 'CellLine', 'CVCL:0546', (58, 63))	('silencing', 'Var', (5, 14))	('migration rates', 'CPA', (30, 45))	('diminished', 'NegReg', (15, 25))	('PUS7', 'Gene', (0, 4))
568449	33990203	KEGG enrichment data illustrated that PUS7 could alter multiple pathways, including the TNF signalling cascade, IL-17 signalling cascade, chemical carcinogenesis, glycolysis/gluconeogenesis, and complement and coagulation cascades, demonstrating the modulatory roles of PUS7 in CRC tumorigenesis (Fig.	('glycolysis/gluconeogenesis', 'MPA', (163, 189))	('CRC', 'Phenotype', 'HP:0003003', (278, 281))	('carcinogenesis', 'Disease', 'MESH:D063646', (147, 161))	('glycolysis/gluconeogenesis', 'Phenotype', 'HP:0005959', (163, 189))	('carcinogenesis', 'Disease', (147, 161))	('IL-17', 'Gene', (112, 117))	('TNF', 'Gene', (88, 91))	('IL-17', 'Gene', '3605', (112, 117))	('CRC tumorigenesis', 'Disease', (278, 295))	('alter', 'Reg', (49, 54))	('PUS7', 'Var', (38, 42))	('TNF', 'Gene', '7124', (88, 91))
568450	33990203	Consistent with RNA-seq results, KEGG enrichment analysis of differentially expressed proteins showed that PUS7 could also alter the TNF signalling cascade and IL-17 signalling cascade (Fig.	('PUS7', 'Var', (107, 111))	('alter', 'Reg', (123, 128))	('TNF', 'Gene', (133, 136))	('IL-17', 'Gene', (160, 165))	('IL-17', 'Gene', '3605', (160, 165))	('TNF', 'Gene', '7124', (133, 136))
568451	33990203	More importantly, PUS7 remarkably modulated multiple metastasis-related genes, including LASP1, S100P, and LCN2 (Fig.	('PUS7', 'Var', (18, 22))	('LCN2', 'Gene', (107, 111))	('S100P', 'Gene', (96, 101))	('LASP1', 'Gene', (89, 94))	('modulated', 'Reg', (34, 43))	('LCN2', 'Gene', '3934', (107, 111))	('metastasis-related genes', 'Gene', (53, 77))	('S100P', 'Gene', '6286', (96, 101))
568457	33990203	The forced expression of wild-type PUS7 (LV-PUS7WT) and mutant PUS7 (LV-PUS7MUT, with the D294A point-mutation attenuating the PUS7 enzymatic activity) was attained via lentiviral transfection into DLD1 and HCT-8 cells.	('D294A point-mutation', 'Var', (90, 110))	('attenuating', 'NegReg', (111, 122))	('mutant', 'Var', (56, 62))	('HCT-8', 'CellLine', 'CVCL:2478', (207, 212))	('D294A', 'Mutation', 'p.D294A', (90, 95))	('PUS7', 'MPA', (127, 131))	('PUS7', 'Gene', (63, 67))
568460	33990203	Furthermore, the decreased expression of LASP1 was rescued to control levels via stable expression of LV-PUS7WT or LV-PUS7MUT in DLD1 and SW480 PUS7-KD cells (Fig.	('SW480', 'CellLine', 'CVCL:0546', (138, 143))	('expression', 'MPA', (27, 37))	('LASP1', 'Gene', (41, 46))	('LV-PUS7WT', 'Var', (102, 111))	('LV-PUS7MUT', 'Var', (115, 125))
568462	33990203	To verify the key function of LASP1 in CRC metastasis, we conducted a LASP1 gain-and-loss of function study via transfection of shLASP1 into HCT8 cells and LV-LASP1 into DLD1 cells.	('transfection', 'Var', (112, 124))	('HCT8', 'CellLine', 'CVCL:2478', (141, 145))	('shLASP1', 'Gene', (128, 135))	('gain-and-loss', 'PosReg', (76, 89))	('LASP1', 'Gene', (70, 75))	('CRC', 'Phenotype', 'HP:0003003', (39, 42))
568492	33990203	Further, these data implied that PUS7 is important for the NMS-E973-induced repression of CRC metastasis in vivo and in vitro and that HSP90 inhibitors combined with PUS7 suppression exhibit an activity superior to that of monotherapy targeting HSP90.	('PUS7', 'Gene', (166, 170))	('inhibitors', 'Var', (141, 151))	('CRC', 'Phenotype', 'HP:0003003', (90, 93))	('CRC metastasis', 'Gene', (90, 104))	('activity', 'MPA', (194, 202))	('HSP90', 'Protein', (135, 140))	('NMS', 'Disease', 'MESH:D009459', (59, 62))	('repression', 'NegReg', (76, 86))	('NMS', 'Disease', (59, 62))
568496	33990203	Kaplan-Meier analysis data showed that patients with either HSP90/PUS7, PUS7/LASP1, or HSP90/LASP1 co-expression had the shortest OS times among all the subgroups.	('patients', 'Species', '9606', (39, 47))	('HSP90/PUS7', 'Var', (60, 70))	('OS times', 'MPA', (130, 138))	('HSP90/LASP1', 'Gene', (87, 98))	('shortest', 'NegReg', (121, 129))
568500	33990203	Similarly, high PUS7 positive staining was significantly linked to T classification, and high LASP1 positive staining was significantly linked to tumour size, T classification, and clinical stage.	('tumour', 'Disease', (146, 152))	('LASP1', 'Gene', (94, 99))	('T classification', 'Disease', (67, 83))	('high', 'Var', (89, 93))	('linked', 'Reg', (57, 63))	('tumour', 'Phenotype', 'HP:0002664', (146, 152))	('high PUS7', 'Protein', (11, 20))	('linked', 'Reg', (136, 142))	('tumour', 'Disease', 'MESH:D009369', (146, 152))
568506	33990203	Consistently, PUS7 expression was higher in HCT-116 and SW620 cells (with high metastatic ability) than in HCT-8 and SW480 cells (with low metastatic ability), indicating that PUS7 might be exclusively important for Grade IV CRC.	('expression', 'MPA', (19, 29))	('HCT-8', 'CellLine', 'CVCL:2478', (107, 112))	('higher', 'PosReg', (34, 40))	('HCT-116', 'CellLine', 'CVCL:0291', (44, 51))	('SW480', 'CellLine', 'CVCL:0546', (117, 122))	('SW620', 'CellLine', 'CVCL:0547', (56, 61))	('HCT-116', 'Var', (44, 51))	('CRC', 'Phenotype', 'HP:0003003', (225, 228))	('PUS7', 'Gene', (14, 18))	('SW620', 'Var', (56, 61))
568538	33197299	This approach revealed mutations in FBXW7, CTNNB1 and PIK3CA in the first case and FBXW7 and RB1 mutations in the second case.	('mutations', 'Var', (97, 106))	('PIK3CA', 'Gene', (54, 60))	('FBXW7', 'Gene', (36, 41))	('RB1', 'Gene', (93, 96))	('revealed', 'Reg', (14, 22))	('mutations', 'Var', (23, 32))	('FBXW7', 'Gene', (83, 88))	('CTNNB1', 'Gene', '12387', (43, 49))	('PIK3CA', 'Gene', '18706', (54, 60))	('CTNNB1', 'Gene', (43, 49))
568541	33197299	FBXW7 codifies the substrate recognition element of an ubiquitin ligase, and inactivating FBXW7 mutations lead to an exceptional accumulation of its target beta-catenin which results in overactivation of the Wnt-signalling pathway.	('beta-catenin', 'Gene', (156, 168))	('inactivating', 'Var', (77, 89))	('overactivation', 'PosReg', (186, 200))	('accumulation', 'PosReg', (129, 141))	('mutations', 'Var', (96, 105))	('FBXW7', 'Gene', (90, 95))	('Wnt-signalling pathway', 'Pathway', (208, 230))	('beta-catenin', 'Gene', '12387', (156, 168))
568542	33197299	In line with previously described hypotheses of de-differentiation of colon cells by enhanced Wnt-signalling, our data indicate a crucial role for mutant FBXW7 in the unusual morphological switch that determines these rare neoplasms.	('mutant', 'Var', (147, 153))	('neoplasms', 'Disease', 'MESH:D009369', (223, 232))	('neoplasms', 'Disease', (223, 232))	('FBXW7', 'Gene', (154, 159))	('neoplasm', 'Phenotype', 'HP:0002664', (223, 231))	('neoplasms', 'Phenotype', 'HP:0002664', (223, 232))
568553	33197299	Alongside accurate morphological evaluation, molecular classification of colorectal cancers with high grade morphology, via immunohistochemistry of mismatch repair proteins and mutational analyses of BRAF and other genes, has proven essential to provide best guidance for patient treatment and therapeutic outcome.	('mutational analyses', 'Var', (177, 196))	('BRAF', 'Gene', (200, 204))	('cancers', 'Phenotype', 'HP:0002664', (84, 91))	('colorectal cancer', 'Phenotype', 'HP:0003003', (73, 90))	('colorectal cancers', 'Disease', 'MESH:D015179', (73, 91))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('patient', 'Species', '9606', (272, 279))	('colorectal cancers', 'Disease', (73, 91))
568585	33197299	Next-generation sequencing analysis surveying hotspot regions of 50 oncogenes and tumour suppressor genes detected CTNNB1 (c.110C>G, p.Ser37Cys), PIK3CA (c.1173A>G, p.Ile391Met) and FBXW7 (c.1393C>T, p.Arg465Cys) mutations.	('c.110C>G', 'Mutation', 'rs121913403', (123, 131))	('p.Arg465Cys', 'Var', (200, 211))	('CTNNB1', 'Gene', (115, 121))	('FBXW7', 'Gene', (182, 187))	('PIK3CA', 'Gene', (146, 152))	('c.1393C>T', 'Mutation', 'rs867384286', (189, 198))	('tumour', 'Phenotype', 'HP:0002664', (82, 88))	('c.1173A>G', 'Mutation', 'rs2230461', (154, 163))	('c.1393C>T', 'Var', (189, 198))	('tumour', 'Disease', 'MESH:D009369', (82, 88))	('CTNNB1', 'Gene', '12387', (115, 121))	('tumour', 'Disease', (82, 88))	('p.Ile391Met', 'Mutation', 'rs2230461', (165, 176))	('c.1173A>G', 'Var', (154, 163))	('p.Ile391Met', 'Var', (165, 176))	('p.Ser37Cys', 'Mutation', 'rs121913403', (133, 143))	('PIK3CA', 'Gene', '18706', (146, 152))	('p.Arg465Cys', 'Mutation', 'rs867384286', (200, 211))	('c.110C>G', 'Var', (123, 131))
568603	33197299	The following staging was reported: pT4a, pN2a (5/19), cM1a (HEP), L1, V1, Pn0, R0, UICC-stage IVA.	('HEP', 'Gene', '109838', (61, 64))	('L1, V1', 'Gene', '23961;258186', (67, 73))	('HEP', 'Gene', (61, 64))	('Pn0', 'Var', (75, 78))	('pN2a', 'Disease', (42, 46))
568605	33197299	In addition, a RB1 (c.2284C>T, p.Gln762Ter) mutation was found.	('RB1', 'Gene', (15, 18))	('c.2284C>T', 'Mutation', 'c.2284C>T', (20, 29))	('p.Gln762Ter', 'Mutation', 'p.Q762X', (31, 42))	('p.Gln762Ter', 'Var', (31, 42))	('c.2284C>T', 'Var', (20, 29))
568611	33197299	The TCGA Nature 2012 Study, the updated TCGA Pan Cancer Atlas Study on CRC, and the MSKCC 2018 Cancer Cell Study for metastatic colorectal cancer [14, 15, 16, 17, 18] were screened for other cases with FBXW7, CTNNB, PIK3CA and RB1 mutations.	('colorectal cancer', 'Disease', 'MESH:D015179', (128, 145))	('PIK3CA', 'Gene', '18706', (216, 222))	('Cancer', 'Phenotype', 'HP:0002664', (95, 101))	('Cancer', 'Disease', (95, 101))	('RB1', 'Gene', (227, 230))	('mutations', 'Var', (231, 240))	('colorectal cancer', 'Phenotype', 'HP:0003003', (128, 145))	('Cancer', 'Disease', 'MESH:D009369', (95, 101))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('PIK3CA', 'Gene', (216, 222))	('Cancer', 'Phenotype', 'HP:0002664', (49, 55))	('FBXW7', 'Gene', (202, 207))	('colorectal cancer', 'Disease', (128, 145))	('Cancer', 'Disease', (49, 55))	('CTNNB', 'Gene', (209, 214))	('Cancer', 'Disease', 'MESH:D009369', (49, 55))
568612	33197299	Our search revealed 5-8% CTNNB1 mutations, 13-17% FBXW7 mutations, 20-28% PIK3CA mutations and 3-5% RB1 mutations, respectively.	('RB1', 'Gene', (100, 103))	('mutations', 'Var', (56, 65))	('mutations', 'Var', (104, 113))	('CTNNB1', 'Gene', '12387', (25, 31))	('FBXW7', 'Gene', (50, 55))	('CTNNB1', 'Gene', (25, 31))	('mutations', 'Var', (32, 41))	('mutations', 'Var', (81, 90))	('PIK3CA', 'Gene', '18706', (74, 80))	('PIK3CA', 'Gene', (74, 80))
568614	33197299	In addition, we screened for significant co-occurrences or mutual exclusivities between FBXW7, CTNNB1, PIK3CA and RB1 mutations in all three data sets, which mostly consist of classic adenocarcinoma cases, in order to explore possible mutational correlations that could potentially also occur in the scarce mixed neoplasms described here.	('CTNNB1', 'Gene', (95, 101))	('PIK3CA', 'Gene', '18706', (103, 109))	('FBXW7', 'Gene', (88, 93))	('RB1', 'Gene', (114, 117))	('neoplasms', 'Disease', 'MESH:D009369', (313, 322))	('neoplasms', 'Disease', (313, 322))	('mutations', 'Var', (118, 127))	('neoplasm', 'Phenotype', 'HP:0002664', (313, 321))	('PIK3CA', 'Gene', (103, 109))	('adenocarcinoma', 'Disease', (184, 198))	('neoplasms', 'Phenotype', 'HP:0002664', (313, 322))	('CTNNB1', 'Gene', '12387', (95, 101))	('carcinoma', 'Phenotype', 'HP:0030731', (189, 198))	('adenocarcinoma', 'Disease', 'MESH:D000230', (184, 198))
568617	33197299	In addition, mutations in the genes coding for APC and CTNNB1 as well as TP53 and PIK3CA related to the classical adenoma-carcinoma sequence were found to be mutually exclusive.	('APC', 'Disease', 'MESH:D011125', (47, 50))	('TP53', 'Gene', '22059', (73, 77))	('PIK3CA', 'Gene', (82, 88))	('CTNNB1', 'Gene', '12387', (55, 61))	('TP53', 'Gene', (73, 77))	('APC', 'Disease', (47, 50))	('adenoma-carcinoma', 'Disease', 'MESH:D000236', (114, 131))	('CTNNB1', 'Gene', (55, 61))	('carcinoma', 'Phenotype', 'HP:0030731', (122, 131))	('mutations', 'Var', (13, 22))	('PIK3CA', 'Gene', '18706', (82, 88))	('adenoma-carcinoma', 'Disease', (114, 131))
568618	33197299	Importantly, significant co-occurrence of FBXW7 and PIK3CA as well as FBXW7 and RB1 mutations, as was found in the scarce neoplasm type described here, was identified in two of the three data sets (Table 2).	('neoplasm', 'Disease', (122, 130))	('PIK3CA', 'Gene', '18706', (52, 58))	('neoplasm', 'Disease', 'MESH:D009369', (122, 130))	('neoplasm', 'Phenotype', 'HP:0002664', (122, 130))	('RB1', 'Gene', (80, 83))	('PIK3CA', 'Gene', (52, 58))	('mutations', 'Var', (84, 93))	('FBXW7', 'Gene', (70, 75))
568621	33197299	In the two cases of mixed large cell neuroendocrine and squamous cell carcinoma described here, and in contrast to MiNENs and classic adenocarcinomas, we noted the absence of APC, KRAS and TP53 mutations, as well as the occurrence of mutations in the FBXW7 gene in both tumours.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (56, 79))	('KRAS', 'Gene', (180, 184))	('APC', 'Disease', 'MESH:D011125', (175, 178))	('TP53', 'Gene', (189, 193))	('APC', 'Disease', (175, 178))	('TP53', 'Gene', '22059', (189, 193))	('KRAS', 'Gene', '16653', (180, 184))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (56, 79))	('absence', 'NegReg', (164, 171))	('tumours', 'Disease', (270, 277))	('tumours', 'Phenotype', 'HP:0002664', (270, 277))	('carcinoma', 'Phenotype', 'HP:0030731', (70, 79))	('squamous cell carcinoma', 'Disease', (56, 79))	('tumours', 'Disease', 'MESH:D009369', (270, 277))	('FBXW7', 'Gene', (251, 256))	('mutations', 'Var', (234, 243))	('adenocarcinomas', 'Disease', 'MESH:D000230', (134, 149))	('tumour', 'Phenotype', 'HP:0002664', (270, 276))	('adenocarcinomas', 'Disease', (134, 149))	('carcinoma', 'Phenotype', 'HP:0030731', (139, 148))	('carcinomas', 'Phenotype', 'HP:0030731', (139, 149))	('mutations', 'Var', (194, 203))
568622	33197299	The frequency of mutations in FBXW7 in particular was markedly lower (16-25%) in classic adenocarcinomas and MiNENs (Table 3), although we cannot exclude the existence of FBXW7 wild-type, mixed neuroendocrine and squamous cell carcinoma cases from our case report on only two individuals affected by this very rare tumour type.	('carcinoma', 'Phenotype', 'HP:0030731', (227, 236))	('squamous cell carcinoma', 'Disease', (213, 236))	('adenocarcinomas', 'Disease', 'MESH:D000230', (89, 104))	('tumour', 'Disease', 'MESH:D009369', (315, 321))	('carcinoma', 'Phenotype', 'HP:0030731', (94, 103))	('FBXW7', 'Gene', (30, 35))	('lower', 'NegReg', (63, 68))	('adenocarcinomas', 'Disease', (89, 104))	('carcinomas', 'Phenotype', 'HP:0030731', (94, 104))	('tumour', 'Disease', (315, 321))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (213, 236))	('mutations', 'Var', (17, 26))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (213, 236))	('tumour', 'Phenotype', 'HP:0002664', (315, 321))
568623	33197299	Given that tissue images of colorectal carcinoma cases with FBWX7 mutation were available via cBioPortal within the TCGA Nature 2012 study, these were screened for unusual morphology, such as squamous or neuroendocrine differentiation.	('colorectal carcinoma', 'Disease', 'MESH:D015179', (28, 48))	('carcinoma', 'Phenotype', 'HP:0030731', (39, 48))	('squamous or neuroendocrine differentiation', 'Disease', (192, 234))	('mutation', 'Var', (66, 74))	('FBWX7', 'Gene', (60, 65))	('colorectal carcinoma', 'Disease', (28, 48))
568624	33197299	Hence, other factors, such as the cell of tumour origin or epigenetic peculiarities might also be needed which, presumably in collaboration with mutant FBXW7, contribute to the occurrence of this very rare, mixed colorectal cancer entity.	('occurrence', 'Reg', (177, 187))	('tumour', 'Phenotype', 'HP:0002664', (42, 48))	('colorectal cancer', 'Disease', (213, 230))	('mutant', 'Var', (145, 151))	('cancer', 'Phenotype', 'HP:0002664', (224, 230))	('tumour', 'Disease', 'MESH:D009369', (42, 48))	('tumour', 'Disease', (42, 48))	('colorectal cancer', 'Disease', 'MESH:D015179', (213, 230))	('FBXW7', 'Gene', (152, 157))	('colorectal cancer', 'Phenotype', 'HP:0003003', (213, 230))
568626	33197299	This approach revealed a shared FBXW7 mutation and a lack of classical adenoma-carcinoma sequence mutations in both of our cases.	('FBXW7', 'Gene', (32, 37))	('adenoma-carcinoma', 'Disease', (71, 88))	('mutation', 'Var', (38, 46))	('carcinoma', 'Phenotype', 'HP:0030731', (79, 88))	('adenoma-carcinoma', 'Disease', 'MESH:D000236', (71, 88))
568645	33197299	Despite the young age of the patients, both carcinomas were microsatellite stable (MSS), excluding Lynch syndrome.	('patients', 'Species', '9606', (29, 37))	('Lynch syndrome', 'Disease', (99, 113))	('carcinomas', 'Disease', 'MESH:D009369', (44, 54))	('carcinomas', 'Phenotype', 'HP:0030731', (44, 54))	('carcinoma', 'Phenotype', 'HP:0030731', (44, 53))	('microsatellite', 'Var', (60, 74))	('carcinomas', 'Disease', (44, 54))	('Lynch syndrome', 'Disease', 'MESH:D003123', (99, 113))
568646	33197299	In one of the cases, we identified a CTNNB1 mutation, which is a key factor in the Wnt signalling pathway and well described in the development of colorectal carcinomas [29, 30].	('mutation', 'Var', (44, 52))	('colorectal carcinomas', 'Disease', (147, 168))	('CTNNB1', 'Gene', '12387', (37, 43))	('colorectal carcinomas', 'Disease', 'MESH:D015179', (147, 168))	('carcinoma', 'Phenotype', 'HP:0030731', (158, 167))	('CTNNB1', 'Gene', (37, 43))	('carcinomas', 'Phenotype', 'HP:0030731', (158, 168))
568647	33197299	In one of our cases, there was a mutation in the tumour suppressor gene RB1, which are present in 5.8% of all colorectal cancers (14, 15).	('mutation', 'Var', (33, 41))	('RB1', 'Gene', (72, 75))	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('tumour', 'Phenotype', 'HP:0002664', (49, 55))	('colorectal cancer', 'Phenotype', 'HP:0003003', (110, 127))	('tumour', 'Disease', 'MESH:D009369', (49, 55))	('colorectal cancers', 'Disease', 'MESH:D015179', (110, 128))	('colorectal cancers', 'Disease', (110, 128))	('cancers', 'Phenotype', 'HP:0002664', (121, 128))	('tumour', 'Disease', (49, 55))
568648	33197299	To date, no statistically significant impact of RB1 gene mutations on patient prognosis in colorectal cancer has been shown [31].	('RB1', 'Gene', (48, 51))	('colorectal cancer', 'Disease', (91, 108))	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('patient', 'Species', '9606', (70, 77))	('mutations', 'Var', (57, 66))	('colorectal cancer', 'Disease', 'MESH:D015179', (91, 108))	('colorectal cancer', 'Phenotype', 'HP:0003003', (91, 108))
568650	33197299	Mutations in PIK3CA can be detected in various cancer types and have been associated with more aggressive metastatic behaviour in colorectal cancer [32].	('colorectal cancer', 'Phenotype', 'HP:0003003', (130, 147))	('colorectal cancer', 'Disease', (130, 147))	('PIK3CA', 'Gene', (13, 19))	('aggressive metastatic behaviour', 'CPA', (95, 126))	('cancer', 'Disease', 'MESH:D009369', (47, 53))	('cancer', 'Phenotype', 'HP:0002664', (141, 147))	('more', 'PosReg', (90, 94))	('cancer', 'Disease', (47, 53))	('Mutations', 'Var', (0, 9))	('colorectal cancer', 'Disease', 'MESH:D015179', (130, 147))	('cancer', 'Disease', 'MESH:D009369', (141, 147))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('associated with', 'Reg', (74, 89))	('PIK3CA', 'Gene', '18706', (13, 19))	('cancer', 'Disease', (141, 147))
568651	33197299	However the PIK3CA (c.1173A>G, p.Ile391Met) mutation found here was a variant of uncertain significance (VUS) at the time of diagnosis but is now considered benign [33].	('p.Ile391Met', 'Var', (31, 42))	('c.1173A>G', 'Var', (20, 29))	('c.1173A>G', 'Mutation', 'rs2230461', (20, 29))	('p.Ile391Met', 'Mutation', 'rs2230461', (31, 42))	('PIK3CA', 'Gene', '18706', (12, 18))	('PIK3CA', 'Gene', (12, 18))
568652	33197299	Through analyses of PIK3CA mutations in three colorectal carcinoma data sets we detected a significant co-occurrence of PIK3CA and KRAS, which supports previous findings on that correlation [34].	('mutations', 'Var', (27, 36))	('PIK3CA', 'Gene', (120, 126))	('colorectal carcinoma', 'Disease', (46, 66))	('KRAS', 'Gene', (131, 135))	('PIK3CA', 'Gene', (20, 26))	('KRAS', 'Gene', '16653', (131, 135))	('carcinoma', 'Phenotype', 'HP:0030731', (57, 66))	('colorectal carcinoma', 'Disease', 'MESH:D015179', (46, 66))	('PIK3CA', 'Gene', '18706', (120, 126))	('co-occurrence', 'Interaction', (103, 116))	('PIK3CA', 'Gene', '18706', (20, 26))
568655	33197299	Loss of function FBXW7 mutations, like the R465C gene variant described here, occur in approximately 11% of colorectal cancers [37].	('cancers', 'Phenotype', 'HP:0002664', (119, 126))	('colorectal cancer', 'Phenotype', 'HP:0003003', (108, 125))	('Loss of function', 'NegReg', (0, 16))	('mutations', 'Var', (23, 32))	('R465C', 'Mutation', 'rs867384286', (43, 48))	('FBXW7', 'Gene', (17, 22))	('colorectal cancers', 'Disease', 'MESH:D015179', (108, 126))	('colorectal cancers', 'Disease', (108, 126))	('cancer', 'Phenotype', 'HP:0002664', (119, 125))
568656	33197299	Mono-allelic missense alterations, which affect crucial arginine residues, have been reported to be the most common mutant genotypes, even though bi-allelic inactivation mutations occur [38].	('affect', 'Reg', (41, 47))	('Mono-allelic', 'Var', (0, 12))	('arginine residues', 'MPA', (56, 73))	('arginine', 'Chemical', 'MESH:D001120', (56, 64))
568657	33197299	In 2017, Korphaisarn et al showed data suggesting a greater emphasis of FBXW7 missense mutation in comparison to other gene aberrations for patient outcome, linking these mutations, like those found in the above presented two cases, with a strong negative prognostic association [39].	('mutations', 'Var', (171, 180))	('missense mutation', 'Var', (78, 95))	('FBXW7', 'Gene', (72, 77))	('patient', 'Species', '9606', (140, 147))
568660	33197299	Therefore, we suppose that the detected FBXW7 mutation resulted in malfunctioning of beta-catenin depletion with subsequent beta-catenin accumulation in the nucleus, leading to extreme overactivation of Wnt-signalling.	('accumulation', 'PosReg', (137, 149))	('malfunctioning', 'MPA', (67, 81))	('beta-catenin', 'Gene', (124, 136))	('overactivation', 'PosReg', (185, 199))	('beta-catenin', 'Gene', '12387', (85, 97))	('FBXW7', 'Gene', (40, 45))	('beta-catenin', 'Gene', '12387', (124, 136))	('beta-catenin', 'Gene', (85, 97))	('mutation', 'Var', (46, 54))	('Wnt-signalling', 'Pathway', (203, 217))
568664	33197299	Of note, Wnt activating mutations in FBXW7 and CTNNB1 are not restricted to the rare colorectal cancer type identified here, but also occur in classical adenocarcinoma.	('CTNNB1', 'Gene', (47, 53))	('FBXW7', 'Gene', (37, 42))	('occur', 'Reg', (134, 139))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('colorectal cancer', 'Disease', (85, 102))	('mutations', 'Var', (24, 33))	('carcinoma', 'Phenotype', 'HP:0030731', (158, 167))	('CTNNB1', 'Gene', '12387', (47, 53))	('colorectal cancer', 'Disease', 'MESH:D015179', (85, 102))	('adenocarcinoma', 'Disease', (153, 167))	('adenocarcinoma', 'Disease', 'MESH:D000230', (153, 167))	('colorectal cancer', 'Phenotype', 'HP:0003003', (85, 102))
568667	33197299	Importantly, a study by Wang et al revealed that aberrant Wnt activation at an early stage of neurogenin three-dependent enteroendocrine cell differentiation induces small intestinal adenomas positive for serotonin expression in mice [50].	('induces', 'Reg', (158, 165))	('adenomas', 'Disease', (183, 191))	('aberrant', 'Var', (49, 57))	('serotonin', 'Chemical', 'MESH:D012701', (205, 214))	('mice', 'Species', '10090', (229, 233))	('adenomas', 'Disease', 'MESH:D000236', (183, 191))
568671	33197299	The underlying FBXW7 mutation might be the connecting element and the trigger for the crucial morphological switch, via overactivation of the canonical Wnt/beta-catenin signalling pathway.	('FBXW7', 'Gene', (15, 20))	('overactivation', 'PosReg', (120, 134))	('mutation', 'Var', (21, 29))	('beta-catenin', 'Gene', (156, 168))	('beta-catenin', 'Gene', '12387', (156, 168))
568673	33197299	Other genes related to neuroendocrine differentiation, like ASCL1, may also play a role in the development of the neuroendocrine component, especially since ASCL1 is involved in the Notch-Hes1 axis, which is analogous to the Wnt-beta catenin signalling pathway, altered by the FBXW7 mutation [51, 52, 53].	('mutation', 'Var', (283, 291))	('Hes1', 'Gene', '15205', (188, 192))	('FBXW7', 'Gene', (277, 282))	('beta catenin', 'Gene', (229, 241))	('altered', 'Reg', (262, 269))	('Hes1', 'Gene', (188, 192))	('ASCL1', 'Gene', '17172', (157, 162))	('ASCL1', 'Gene', '17172', (60, 65))	('beta catenin', 'Gene', '12387', (229, 241))	('ASCL1', 'Gene', (157, 162))	('ASCL1', 'Gene', (60, 65))
568681	33197299	Furthermore, we provide the histological and genetic evidence for a primary origin of this combined carcinoma in the colon and our data indicate that tumour development might occur via FBXW7 mutation-triggered tumorigenesis, and very intensive Wnt-signalling pathway enhancement.	('mutation-triggered', 'Var', (191, 209))	('carcinoma', 'Phenotype', 'HP:0030731', (100, 109))	('tumour', 'Disease', 'MESH:D009369', (150, 156))	('tumour', 'Phenotype', 'HP:0002664', (150, 156))	('carcinoma in the colon', 'Disease', (100, 122))	('tumour', 'Disease', (150, 156))	('carcinoma in the colon', 'Disease', 'MESH:D003110', (100, 122))	('enhancement', 'PosReg', (267, 278))	('Wnt-signalling pathway', 'Pathway', (244, 266))	('FBXW7', 'Gene', (185, 190))	('carcinoma in the colon', 'Phenotype', 'HP:0040276', (100, 122))	('tumorigenesis', 'CPA', (210, 223))
568688	30016460	A model is developed to link these to cancer development, where some mutations may be selected to facilitate cell division at rates dictated by Fenton reactions.	('mutations', 'Var', (69, 78))	('cancer', 'Phenotype', 'HP:0002664', (38, 44))	('cell division', 'CPA', (109, 122))	('cancer', 'Disease', 'MESH:D009369', (38, 44))	('cancer', 'Disease', (38, 44))	('facilitate', 'PosReg', (98, 108))	('Fenton', 'Chemical', '-', (144, 150))
568701	30016460	A variety of molecules can reduce Fe3+ to Fe2+, such as NAD(P)H, superoxide , S2-, and ascorbic acid, which can lead to repeated Fenton reactions, also called the Haber-Weiss reaction, giving rise to continuous production of  and OH- if the cellular environment is rich in such molecules.	('iron', 'Chemical', 'MESH:D007501', (253, 257))	('superoxide', 'Chemical', 'MESH:D013481', (65, 75))	('Fenton reactions', 'MPA', (129, 145))	('Fe3+', 'Chemical', '-', (34, 38))	('lead to', 'Reg', (112, 119))	('NAD(P)H', 'Chemical', '-', (56, 63))	('Fe2+', 'Chemical', 'MESH:C038178', (42, 46))	('S2-, and', 'Chemical', '-', (78, 86))	('ascorbic acid', 'Chemical', 'MESH:D001205', (87, 100))	('Fe3+', 'Var', (34, 38))	('Fenton', 'Chemical', '-', (129, 135))	('production', 'MPA', (211, 221))	('OH-', 'MPA', (230, 233))
568705	30016460	It is worth emphasizing that Fenton reaction, an inorganic reaction, is the result of increased concentrations of Fe2+ and H2O2 at a site enriched with macrophage, neutrophil and other innate immune cells, which does not require an enzyme to take place and hence is not regulated biologically, at least not actively.	('increased', 'PosReg', (86, 95))	('Fe2+', 'Chemical', 'MESH:C038178', (114, 118))	('Fenton reaction', 'Disease', (29, 44))	('Fenton', 'Chemical', '-', (29, 35))	('H2O2', 'Chemical', 'MESH:D006861', (123, 127))	('H2O2', 'Var', (123, 127))	('concentrations', 'MPA', (96, 110))
568710	30016460	We have predicted distinct roles of Fenton reactions in the two different subcellular locations of cancer cells: (i) cytosolic Fenton reactions can increase the intracellular pH that drives increased glycolytic ATP generation and nucleotide synthesis as a key response to the continuous production of OH-; and (ii) mitochondrial Fenton reactions give rise to two novel pathways for ATP production: an anaerobic respiration chain for ATP synthesis by using H2O2 rather than O2 as the final electron acceptor and another directly consuming protons within the mitochondrial inner membrane (or simply inside mitochondria), both leading to increased cross-membrane proton gradients and hence ATP synthesis.	('cross-membrane proton gradients', 'MPA', (645, 676))	('O2', 'Chemical', 'MESH:D013481', (458, 460))	('ATP', 'Gene', (382, 385))	('ATP', 'Gene', '51761', (211, 214))	('H2O2', 'Chemical', 'MESH:D006861', (456, 460))	('cancer', 'Disease', 'MESH:D009369', (99, 105))	('ATP', 'Gene', '51761', (433, 436))	('ATP', 'Gene', '51761', (687, 690))	('Fenton', 'Chemical', '-', (36, 42))	('O2', 'Chemical', 'MESH:D013481', (473, 475))	('Fenton', 'Chemical', '-', (329, 335))	('H2O2', 'Var', (456, 460))	('ATP', 'Gene', '51761', (382, 385))	('increased', 'PosReg', (635, 644))	('ATP', 'Gene', (211, 214))	('ATP', 'Gene', (433, 436))	('ATP', 'Gene', (687, 690))	('cancer', 'Disease', (99, 105))	('cancer', 'Phenotype', 'HP:0002664', (99, 105))	('Fenton', 'Chemical', '-', (127, 133))
568739	30016460	Hence the consumption of each glycolytic ATP generates one net H+ but not the respiration-generated ATP since ATP hydrolysis: ATP4- + H2O = ADP3- + HPO42- + H+ releases one net H+.	('ATP', 'Gene', (126, 129))	('ATP', 'Gene', '51761', (126, 129))	('ATP', 'Gene', (41, 44))	('ATP', 'Gene', (100, 103))	('ATP', 'Gene', '51761', (41, 44))	('net H+', 'MPA', (173, 179))	('ATP', 'Gene', '51761', (100, 103))	('H2O', 'Chemical', 'MESH:D014867', (134, 137))	('ADP3- + HPO42- + H+', 'Var', (140, 159))	('ATP', 'Gene', (110, 113))	('ATP', 'Gene', '51761', (110, 113))	('ATP4', 'Chemical', '-', (126, 130))
568754	30016460	Compared with the normal aerobic respiration chain with electrons going from NADH to O2 through ETC Complexes I-IV, mutations in mitochondrial DNA and/or other relevant genes in cancer may cause increased electron leak from Complexes I-III and decreased activity of Complex IV, hence reducing the normal electron flow through the entire ETC.	('activity', 'MPA', (254, 262))	('decreased', 'NegReg', (244, 253))	('electron leak', 'MPA', (205, 218))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))	('mitochondrial DNA', 'Gene', (129, 146))	('decreased activity of Complex IV', 'Phenotype', 'HP:0008347', (244, 276))	('Complex IV', 'Enzyme', (266, 276))	('normal electron flow', 'MPA', (297, 317))	('cause', 'Reg', (189, 194))	('cancer', 'Disease', (178, 184))	('mutations', 'Var', (116, 125))	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('O2', 'Chemical', 'MESH:D013481', (85, 87))	('increased', 'PosReg', (195, 204))	('reducing', 'NegReg', (284, 292))	('NADH', 'Chemical', 'MESH:D009243', (77, 81))
568796	30016460	Previous studies have shown that cancers occur with oncogenic mutations, and our study here has shown: there are deeper reasons beneath the mutations for the cells to divide.	('cancers', 'Phenotype', 'HP:0002664', (33, 40))	('cancers', 'Disease', (33, 40))	('cancers', 'Disease', 'MESH:D009369', (33, 40))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('mutations', 'Var', (140, 149))	('mutations', 'Var', (62, 71))
568797	30016460	Mutations in tumor suppressor genes might have been selected to help overcome these obstacles for the cells to remain viable.	('tumor', 'Disease', (13, 18))	('Mutations', 'Var', (0, 9))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))
568817	30016460	Our study strongly suggests that neutralizing cytosolic Fenton reaction-produced OH- may represent the cancer-defining stress that the affected cells must overcome.	('neutralizing', 'Var', (33, 45))	('cancer', 'Phenotype', 'HP:0002664', (103, 109))	('Fenton', 'Chemical', '-', (56, 62))	('cancer', 'Disease', (103, 109))	('cancer', 'Disease', 'MESH:D009369', (103, 109))
568864	28984820	In the human epidemiology of arsenic and cancer, the pattern of metabolism and excretion appears important, with a higher proportion of methylated arsenic in urine being a marker of higher risk of skin or urinary cancer.	('methylated', 'Var', (136, 146))	('arsenic', 'Chemical', 'MESH:D001151', (147, 154))	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('skin or urinary cancer', 'Disease', (197, 219))	('human', 'Species', '9606', (7, 12))	('cancer', 'Disease', 'MESH:D009369', (213, 219))	('arsenic', 'Chemical', 'MESH:D001151', (29, 36))	('cancer', 'Disease', (213, 219))	('cancer', 'Disease', (41, 47))	('skin or urinary cancer', 'Disease', 'MESH:D001749', (197, 219))	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('urinary cancer', 'Phenotype', 'HP:0010786', (205, 219))
568873	28984820	Arsenic concentrations were considered initially as <10 mug/L, >=10 <50 mug/L), >=50 <100 mug/L, and >=100 mug/L.	('Arsenic', 'Chemical', 'MESH:D001151', (0, 7))	('>=50 <100 mug/L', 'Var', (80, 95))	('>=100 mug/L', 'Var', (101, 112))
568904	28984820	It did, however, find that among those with a histological diagnosis of squamous cell carcinoma, those from high arsenic areas were more likely to have lesions classified as poorly differentiated.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (72, 95))	('carcinoma', 'Phenotype', 'HP:0030731', (86, 95))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (72, 95))	('high arsenic', 'Var', (108, 120))	('squamous cell carcinoma', 'Disease', (72, 95))	('arsenic', 'Chemical', 'MESH:D001151', (113, 120))
568920	28984820	If the higher grade is a reflection of longer standing disease, it might be, for example, that those from high arsenic areas were for some reason more likely to delay presentation, although the absence of a difference in age would not support that explanation.	('delay', 'NegReg', (161, 166))	('arsenic', 'Chemical', 'MESH:D001151', (111, 118))	('high arsenic', 'Var', (106, 118))
568937	27025651	Knocking down both HMGA1 and MALT1 by RNAi had a silencing effect on NF-kappaB-responsive genes similar to that caused by miR-26.	('silencing', 'NegReg', (49, 58))	('Knocking down', 'Var', (0, 13))	('HMGA1', 'Gene', '3159', (19, 24))	('miR', 'Gene', '220972', (122, 125))	('miR', 'Gene', (122, 125))	('MALT1', 'Gene', '10892', (29, 34))	('NF-kappaB-responsive genes', 'Gene', (69, 95))	('MALT1', 'Gene', (29, 34))	('HMGA1', 'Gene', (19, 24))
568951	27025651	Moreover, when the predicted miR-26 site in the 3' UTR of IL-6 mRNA was mutated, it had no effect on the translation of IL-6 in HeLa cells.	('mutated', 'Var', (72, 79))	('miR', 'Gene', '220972', (29, 32))	('miR', 'Gene', (29, 32))	('translation', 'MPA', (105, 116))	('IL-6', 'Gene', (58, 62))	('HeLa', 'CellLine', 'CVCL:0030', (128, 132))
568974	27025651	MicroRNA and control mimics were purchased from Sigma, including miR-26a (HMI0415), miR-26b (HMI0419) and control mimics (HMC0002).	('miR-26b', 'Gene', '407017', (84, 91))	('miR-26b', 'Gene', (84, 91))	('HMI0419', 'Var', (93, 100))
568977	27025651	miRNA mimic or siRNA) and plasmid DNA, cells were transfected with small RNAs first and then were transfected with plasmid DNA with or without small RNAs the next day.	('miR', 'Gene', (0, 3))	('miR', 'Gene', '220972', (0, 3))	('small RNAs', 'Var', (67, 77))
568986	27025651	We employed whole transcriptome RNA-seq to investigate changes of TNF-alpha responsiveness in response to alterations of miR-26 levels in a genome-wide fashion.	('TNF-alpha', 'Gene', '7124', (66, 75))	('TNF-alpha', 'Gene', (66, 75))	('miR', 'Gene', '220972', (121, 124))	('miR', 'Gene', (121, 124))	('alterations', 'Var', (106, 117))
568993	27025651	The results showed that either miR-26a or miR-26b mimic significantly reduced IL-6 mRNA levels in TNF-alpha-activated BEAS-2B cells (Supplementary Figure S1B) and IL-6 protein levels in the culture medium (Supplementary Figure S1C) to similar extents.	('IL-6 protein levels', 'MPA', (163, 182))	('reduced', 'NegReg', (70, 77))	('miR-26b', 'Gene', '407017', (42, 49))	('miR-26a', 'Var', (31, 38))	('IL-6 mRNA levels', 'MPA', (78, 94))	('TNF-alpha', 'Gene', '7124', (98, 107))	('BEAS-2B', 'CellLine', 'CVCL:0168', (118, 125))	('TNF-alpha', 'Gene', (98, 107))	('miR-26b', 'Gene', (42, 49))
568996	27025651	The results showed that the luciferase activity from the RL-IL-6 3' UTR reporter (which contains several potential RNA destabilizing elements) was dramatically lower than the RL 3' UTR control in BEAS-2B cells (Figure 1A).	('RL-IL-6', 'Var', (57, 64))	('BEAS-2B', 'CellLine', 'CVCL:0168', (196, 203))	('luciferase', 'Enzyme', (28, 38))	('activity', 'MPA', (39, 47))	('lower', 'NegReg', (160, 165))
569003	27025651	The dual-luciferase assay showed significantly lower activity from the RL-3x26(GW182) transcript in the presence of either miR-26a or miR-26b mimic than in the presence of the control mimic (Figure 1B, C, and Supplementary Figure S4A).	('lower', 'NegReg', (47, 52))	('miR-26b', 'Gene', (134, 141))	('GW182', 'Gene', '27327', (79, 84))	('miR-26b', 'Gene', '407017', (134, 141))	('activity', 'MPA', (53, 61))	('miR-26a', 'Var', (123, 130))	('GW182', 'Gene', (79, 84))
569004	27025651	In contrast, the respective luciferase activities derived from the RL 3' UTR, RL-IL-6 3' UTR, RL-IL-6 3' UTR(Delta26) and RL-3x26(IL-6) transcripts in the presence of miR-26 mimics were similar to the corresponding activities in the presence of a control mimic (Figure 1B, C, and Supplementary Figure S4A).	('miR', 'Gene', '220972', (167, 170))	('miR', 'Gene', (167, 170))	('RL-3x26', 'Var', (122, 129))	('luciferase', 'Enzyme', (28, 38))	('activities', 'MPA', (39, 49))	('Delta26', 'Mutation', 'c.del26', (109, 116))
569012	27025651	The dual-luciferase assay (Figure 2A) showed that while miR-26a mimic appreciably repressed the luciferase activity derived from the control RL-3x26(GW182) transcript, it had little effect on the activities from the transcripts containing either IL-6-5' UTR or IL-6-ORF.	('activities', 'MPA', (196, 206))	('IL-6-ORF', 'Var', (261, 269))	('activity', 'MPA', (107, 115))	("IL-6-5' UTR", 'Var', (246, 257))	('GW182', 'Gene', (149, 154))	('luciferase', 'Enzyme', (96, 106))	('GW182', 'Gene', '27327', (149, 154))
569016	27025651	The results showed that while the miR-26a and miR-26b mimics significantly reduced the stability of the positive control mRNA, MAP kinase 6 (MAPK6) transcript (Figure 2B), neither of them had a destabilizing effect on the IL-6 mRNA (Figure 2C).	('IL-6 mRNA', 'MPA', (222, 231))	('MAP kinase 6', 'Gene', (127, 139))	('stability', 'MPA', (87, 96))	('miR-26a', 'Var', (34, 41))	('miR-26b', 'Gene', (46, 53))	('MAPK6', 'Gene', (141, 146))	('MAP kinase 6', 'Gene', '5597', (127, 139))	('MAPK6', 'Gene', '5597', (141, 146))	('miR-26b', 'Gene', '407017', (46, 53))	('reduced', 'NegReg', (75, 82))
569037	27025651	We also performed parallel high-depth RNA-seq using RNA samples from cells treated with a miR-26 inhibitor (antagomir) to deplete endogenous miR-26 or with a control inhibitor.	('miR', 'Gene', '220972', (141, 144))	('inhibitor', 'Var', (97, 106))	('miR', 'Gene', (141, 144))	('miR', 'Gene', '220972', (90, 93))	('miR', 'Gene', (90, 93))	('deplete', 'NegReg', (122, 129))
569051	27025651	Therefore, we analysed the RNA-seq datasets to identify NF-kappaB signalling related factors whose mRNA levels were lowered by miR-26 mimics in both TNF-alpha-stimulated and non-stimulated cells.	('mimics', 'Var', (134, 140))	('TNF-alpha', 'Gene', '7124', (149, 158))	('lowered', 'NegReg', (116, 123))	('miR', 'Gene', '220972', (127, 130))	('miR', 'Gene', (127, 130))	('mRNA levels', 'MPA', (99, 110))	('NF-kappaB signalling', 'Gene', (56, 76))	('TNF-alpha', 'Gene', (149, 158))
569052	27025651	We first calculated Z-scores for genes from the differences in their RNA levels in non-stimulated BEAS-2B cells treated with either miR-26a mimic or a control mimic.	('BEAS-2B', 'CellLine', 'CVCL:0168', (98, 105))	('miR-26a mimic', 'Var', (132, 145))	('RNA levels', 'MPA', (69, 79))
569064	27025651	Moreover, knocking down either HMGA1 or MALT1 dramatically reduces the IL-6 mRNA levels in TNF-alpha-activated BEAS-2B cells (Figure 5C and D), indicating that both HMGA1 and MALT1 are required for a full TNF-alpha mediated induction of IL-6 expression in BEAS-2B cells.	('TNF-alpha', 'Gene', (91, 100))	('MALT1', 'Gene', (175, 180))	('knocking down', 'Var', (10, 23))	('BEAS-2B', 'CellLine', 'CVCL:0168', (256, 263))	('reduces', 'NegReg', (59, 66))	('HMGA1', 'Gene', (165, 170))	('IL-6 mRNA levels', 'MPA', (71, 87))	('HMGA1', 'Gene', '3159', (165, 170))	('HMGA1', 'Gene', (31, 36))	('TNF-alpha', 'Gene', '7124', (205, 214))	('MALT1', 'Gene', '10892', (40, 45))	('MALT1', 'Gene', '10892', (175, 180))	('TNF-alpha', 'Gene', (205, 214))	('BEAS-2B', 'CellLine', 'CVCL:0168', (111, 118))	('HMGA1', 'Gene', '3159', (31, 36))	('MALT1', 'Gene', (40, 45))	('TNF-alpha', 'Gene', '7124', (91, 100))
569066	27025651	We knocked down both HMGA1 and MALT1 simultaneously to an extent similar to that seen with miR-26a mimics in TNF-alpha-activated cells (Figure 6A), and the levels of IL-6 transcript were reduced to ~20% of the control levels (Figure 6B).	('MALT1', 'Gene', '10892', (31, 36))	('levels', 'MPA', (156, 162))	('HMGA1', 'Gene', (21, 26))	('MALT1', 'Gene', (31, 36))	('knocked', 'Var', (3, 10))	('reduced', 'NegReg', (187, 194))	('TNF-alpha', 'Gene', '7124', (109, 118))	('HMGA1', 'Gene', '3159', (21, 26))	('TNF-alpha', 'Gene', (109, 118))
569068	27025651	Fourteen of the 17 NF-kappaB-responsive genes (including IL-6) that were down-regulated by miR-26a were also down-regulated to a comparable extent by the knockdown of HMGA1 and MALT1 (Figure 6C).	('down-regulated', 'NegReg', (109, 123))	('HMGA1', 'Gene', (167, 172))	('HMGA1', 'Gene', '3159', (167, 172))	('MALT1', 'Gene', '10892', (177, 182))	('knockdown', 'Var', (154, 163))	('NF-kappaB-responsive genes', 'Gene', (19, 45))	('down-regulated', 'NegReg', (73, 87))	('MALT1', 'Gene', (177, 182))	('miR-26a', 'Gene', (91, 98))
569076	27025651	As our study uses a human bronchial epithelial cell line model, it is worth noting that both lung-related cancers (LUAD and LUSC) display a significant inverse relationship between miR-26a and HMGA1 mRNA levels (Figure 7A).	('HMGA1', 'Gene', (193, 198))	('bronchial epithelia', 'Disease', 'MESH:D001982', (26, 45))	('human', 'Species', '9606', (20, 25))	('miR-26a', 'Var', (181, 188))	('HMGA1', 'Gene', '3159', (193, 198))	('bronchial epithelia', 'Disease', (26, 45))	('LUAD', 'Phenotype', 'HP:0030078', (115, 119))	('LUAD', 'Disease', 'None', (115, 119))	('cancers', 'Phenotype', 'HP:0002664', (106, 113))	('LUAD', 'Disease', (115, 119))	('cancers', 'Disease', (106, 113))	('cancers', 'Disease', 'MESH:D009369', (106, 113))	('inverse', 'NegReg', (152, 159))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
569080	27025651	However, when we looked for the combined change of miR-26a levels and HMGA1 levels in a reverse manner (Figure 7B), we discovered that the survival rate of LUAD patients with high miR-26a levels and low HMGA1 mRNA levels (blue line, 50% survival at 53 months) is higher than that of the LUAD patients with low miR-26a levels and high HMGA1 mRNA levels (red line, 50% survival at 20 months).	('LUAD', 'Disease', 'None', (156, 160))	('high', 'Var', (175, 179))	('patients', 'Species', '9606', (292, 300))	('LUAD', 'Phenotype', 'HP:0030078', (287, 291))	('HMGA1', 'Gene', '3159', (334, 339))	('LUAD', 'Disease', (287, 291))	('HMGA1', 'Gene', (334, 339))	('HMGA1', 'Gene', '3159', (70, 75))	('HMGA1', 'Gene', (70, 75))	('LUAD', 'Phenotype', 'HP:0030078', (156, 160))	('patients', 'Species', '9606', (161, 169))	('HMGA1', 'Gene', '3159', (203, 208))	('low', 'Var', (199, 202))	('LUAD', 'Disease', 'None', (287, 291))	('survival', 'CPA', (139, 147))	('higher', 'PosReg', (263, 269))	('LUAD', 'Disease', (156, 160))	('HMGA1', 'Gene', (203, 208))	('miR-26a levels', 'MPA', (180, 194))
569081	27025651	At 120 months post prognosis, the difference between the two groups is even larger, with only 5% survival for tumours with low miR-26a expression and high HMGA1 expression versus 20% survival in the group with high miR-26a and low HMGA1 (Figure 7B).	('HMGA1', 'Gene', '3159', (231, 236))	('miR-26a', 'Gene', (127, 134))	('expression', 'MPA', (161, 171))	('low', 'NegReg', (123, 126))	('HMGA1', 'Gene', '3159', (155, 160))	('tumour', 'Phenotype', 'HP:0002664', (110, 116))	('high', 'Var', (150, 154))	('tumours', 'Phenotype', 'HP:0002664', (110, 117))	('expression', 'MPA', (135, 145))	('HMGA1', 'Gene', (155, 160))	('tumours', 'Disease', 'MESH:D009369', (110, 117))	('HMGA1', 'Gene', (231, 236))	('tumours', 'Disease', (110, 117))
569083	27025651	It is worth noting that at 120 months post prognosis, the difference became quite marked, with no survival for patients with tumours expressing low miR-26a and high MALT1 expression versus 20% patient survival with tumours expressing high miR-26a and low MALT1 expression (Figure 7C).	('high', 'Var', (160, 164))	('MALT1', 'Gene', (165, 170))	('MALT1', 'Gene', '10892', (255, 260))	('tumours', 'Phenotype', 'HP:0002664', (215, 222))	('tumours', 'Disease', (125, 132))	('tumours', 'Disease', 'MESH:D009369', (215, 222))	('tumour', 'Phenotype', 'HP:0002664', (125, 131))	('MALT1', 'Gene', (255, 260))	('tumours', 'Phenotype', 'HP:0002664', (125, 132))	('patients', 'Species', '9606', (111, 119))	('low miR-26a', 'Var', (144, 155))	('tumours', 'Disease', (215, 222))	('patient', 'Species', '9606', (111, 118))	('patient', 'Species', '9606', (193, 200))	('MALT1', 'Gene', '10892', (165, 170))	('tumour', 'Phenotype', 'HP:0002664', (215, 221))	('tumours', 'Disease', 'MESH:D009369', (125, 132))
569086	27025651	IL-6 mRNA levels were slightly higher in the low miR-26a LUAD patients than in the high miR-26a patients (data not shown).	('LUAD', 'Phenotype', 'HP:0030078', (57, 61))	('patients', 'Species', '9606', (96, 104))	('LUAD', 'Disease', 'None', (57, 61))	('higher', 'PosReg', (31, 37))	('LUAD', 'Disease', (57, 61))	('low miR-26a', 'Var', (45, 56))	('patients', 'Species', '9606', (62, 70))	('IL-6 mRNA levels', 'MPA', (0, 16))
569097	27025651	This finding is consistent with an earlier study which showed that mutating the predicted miR-26 site dose not change translation of IL-6 mRNA in HeLa cells.	('mutating', 'Var', (67, 75))	('HeLa', 'CellLine', 'CVCL:0030', (146, 150))	('miR', 'Gene', (90, 93))	('miR', 'Gene', '220972', (90, 93))
569103	27025651	Fourth, miR-26 mimics can destabilize MAPK6 (Figure 2B), HMGA1 and MALT1 transcripts (Figure 5B) but cannot destabilize the IL-6 mRNA (Figures 2C and 5B).	('IL-6 mRNA', 'MPA', (124, 133))	('HMGA1', 'Gene', (57, 62))	('destabilize', 'NegReg', (26, 37))	('HMGA1', 'Gene', '3159', (57, 62))	('MAPK6', 'Gene', '5597', (38, 43))	('MALT1', 'Gene', '10892', (67, 72))	('miR', 'Gene', '220972', (8, 11))	('MALT1', 'Gene', (67, 72))	('miR', 'Gene', (8, 11))	('MAPK6', 'Gene', (38, 43))	('mimics', 'Var', (15, 21))
569105	27025651	Our finding that miR-26 mimics repress the IL-6 promoter activity enough to account for the decrease in the steady-state level of IL-6 mRNA by miR-26 mimics in TNF-alpha-activated BEAS-2B cells (Figure 3A and B) not only further substantiates that miR-26 does not directly target IL-6 mRNA for rapid decay but also unravels the real mechanism underlying miR-26 mediated down-regulation of IL-6 production.	('mimics', 'Var', (150, 156))	('decrease', 'NegReg', (92, 100))	('repress', 'NegReg', (31, 38))	('miR', 'Gene', '220972', (17, 20))	('IL-6 promoter activity', 'MPA', (43, 65))	('miR', 'Gene', (17, 20))	('miR', 'Gene', (143, 146))	('miR', 'Gene', '220972', (143, 146))	('TNF-alpha', 'Gene', '7124', (160, 169))	('TNF-alpha', 'Gene', (160, 169))	('miR', 'Gene', '220972', (248, 251))	('miR', 'Gene', '220972', (354, 357))	('miR', 'Gene', (248, 251))	('miR', 'Gene', (354, 357))	('BEAS-2B', 'CellLine', 'CVCL:0168', (180, 187))
569106	27025651	Moreover, we demonstrated that miR-26 mimics can decrease TNF-alpha-mediated activation of a minimal promoter containing a DNA element responsive to NF-kappaB (Figure 3D), an essential modulator of transcription of many genes involved in cytokine and chemokine production (including IL-6) and cell survival and proliferation (e.g.).	('TNF-alpha', 'Gene', '7124', (58, 67))	('TNF-alpha', 'Gene', (58, 67))	('mimics', 'Var', (38, 44))	('miR', 'Gene', '220972', (31, 34))	('decrease', 'NegReg', (49, 57))	('miR', 'Gene', (31, 34))	('activation', 'MPA', (77, 87))
569108	27025651	The identification of HMGA1 mRNA as a direct target of miR-26 (Figure 5A, B, and Supplementary Figure S7) is consistent with a previous observation through dual-luciferase analysis, which showed that deletion of a predicted miR-26 recognition site in the 3' UTR of HMGA1 mRNA abolished miR-26-mediated gene silencing of HMGA1.	('deletion', 'Var', (200, 208))	('HMGA1', 'Gene', (22, 27))	('HMGA1', 'Gene', '3159', (22, 27))	('miR', 'Gene', '220972', (224, 227))	('abolished', 'NegReg', (276, 285))	('miR', 'Gene', (224, 227))	('HMGA1', 'Gene', '3159', (265, 270))	('miR', 'Gene', (55, 58))	('miR', 'Gene', '220972', (55, 58))	('HMGA1', 'Gene', (320, 325))	('miR', 'Gene', '220972', (286, 289))	('HMGA1', 'Gene', (265, 270))	('HMGA1', 'Gene', '3159', (320, 325))	('miR', 'Gene', (286, 289))
569112	27025651	Our data also show that miR-26 mimics can down-regulate MALT1 expression by promoting its mRNA decay (Figure 5B), a prominent mechanism of miRNA-mediated gene silencing.	('miR', 'Gene', '220972', (139, 142))	('miR', 'Gene', (139, 142))	('MALT1', 'Gene', '10892', (56, 61))	('MALT1', 'Gene', (56, 61))	('expression', 'MPA', (62, 72))	('promoting', 'PosReg', (76, 85))	('down-regulate', 'NegReg', (42, 55))	('mimics', 'Var', (31, 37))	('miR', 'Gene', '220972', (24, 27))	('miR', 'Gene', (24, 27))	('mRNA decay', 'MPA', (90, 100))
569117	27025651	Knocking down both HMGA1 and MALT1 had a silencing effect on many NF-kappaB-responsive genes, including IL-6, similar to that caused by miR-26 (Figure 6).	('silencing', 'NegReg', (41, 50))	('Knocking down', 'Var', (0, 13))	('HMGA1', 'Gene', '3159', (19, 24))	('miR', 'Gene', '220972', (136, 139))	('miR', 'Gene', (136, 139))	('MALT1', 'Gene', '10892', (29, 34))	('NF-kappaB-responsive genes', 'Gene', (66, 92))	('MALT1', 'Gene', (29, 34))	('IL-6', 'Gene', (104, 108))	('HMGA1', 'Gene', (19, 24))
569124	27025651	MALT1 can also activate NF-kappaB in an IKK-independent manner in lymphocyte by cleaving a NF-kappaB inhibitor, RelB, to facilitate DNA-binding by RelA or c-Rel-containing NF-kappaB complexes for transcriptional activation.	('RelB', 'Gene', '5971', (112, 116))	('MALT1', 'Gene', (0, 5))	('cleaving', 'Var', (80, 88))	('DNA-binding', 'Interaction', (132, 143))	('facilitate', 'PosReg', (121, 131))	('c-Rel', 'Gene', '5966', (155, 160))	('RelA', 'Gene', (147, 151))	('RelA', 'Gene', '5970', (147, 151))	('MALT1', 'Gene', '10892', (0, 5))	('c-Rel', 'Gene', (155, 160))	('RelB', 'Gene', (112, 116))	('activate', 'PosReg', (15, 23))
569142	33937330	The high expression of PERK was associated with a poor prognosis in KIRP, LGG, BRCA, and THCA and with a favorable prognosis in HNSC.	('HNSC', 'Phenotype', 'HP:0012288', (128, 132))	('BRCA', 'Gene', '672', (79, 83))	('BRCA', 'Gene', (79, 83))	('THCA', 'Phenotype', 'HP:0002890', (89, 93))	('KIRP', 'Disease', (68, 72))	('THCA', 'Disease', (89, 93))	('high', 'Var', (4, 8))	('PERK', 'Gene', (23, 27))	('LGG', 'Disease', (74, 77))	('PERK', 'Gene', '9451', (23, 27))	('BRCA', 'Phenotype', 'HP:0003002', (79, 83))
569145	33937330	Conclusion: The high expression of PERK could promote the infiltration of multiple immune cells in the tumor microenvironment and could deteriorate the outcomes of patients with breast and thyroid cancers, suggesting that PERK as well as tumor-infiltrating immune cells could be taken as potential biomarkers of prognosis.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('tumor', 'Phenotype', 'HP:0002664', (238, 243))	('infiltration', 'CPA', (58, 70))	('deteriorate', 'NegReg', (136, 147))	('thyroid cancer', 'Phenotype', 'HP:0002890', (189, 203))	('PERK', 'Gene', '9451', (222, 226))	('patients', 'Species', '9606', (164, 172))	('outcomes', 'CPA', (152, 160))	('high expression', 'Var', (16, 31))	('promote', 'PosReg', (46, 53))	('cancers', 'Phenotype', 'HP:0002664', (197, 204))	('tumor', 'Disease', (103, 108))	('PERK', 'Gene', (35, 39))	('tumor', 'Disease', (238, 243))	('cancer', 'Phenotype', 'HP:0002664', (197, 203))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('breast and thyroid cancers', 'Disease', 'MESH:D001943', (178, 204))	('tumor', 'Disease', 'MESH:D009369', (238, 243))	('PERK', 'Gene', '9451', (35, 39))	('PERK', 'Gene', (222, 226))
569174	33937330	Inhibitors augment T-cell activity by blocking programmed cell death protein 1 (PD-1) and PD-1 ligand (PD-L1) and show remarkable clinical effects (Topalian et al.,; Gordon et al.,).	('PD-L1', 'Gene', '29126', (103, 108))	('blocking', 'NegReg', (38, 46))	('programmed cell death protein 1', 'Gene', (47, 78))	('augment', 'PosReg', (11, 18))	('programmed cell death protein 1', 'Gene', '5133', (47, 78))	('Inhibitors', 'Var', (0, 10))	('PD-1', 'Gene', '5133', (90, 94))	('PD-L1', 'Gene', (103, 108))	('T-cell activity', 'CPA', (19, 34))	('PD-1', 'Gene', (90, 94))	('PD-1', 'Gene', (80, 84))	('PD-1', 'Gene', '5133', (80, 84))
569205	33937330	A previous study has shown that PERK inhibition by siRNA or GSK2656157 (a small molecule inhibitor against the PERK/elF2alpha/ATF4 pathway) might improve clinical prognosis and enhance the treatment of esophageal squamous cell carcinoma (ESCC) patients (Wang et al.,), but little research is reported in other types of cancers.	('ATF4', 'Gene', '468', (126, 130))	('cancers', 'Phenotype', 'HP:0002664', (319, 326))	('cancers', 'Disease', (319, 326))	('PERK', 'Gene', '9451', (111, 115))	('esophageal squamous cell carcinoma', 'Disease', (202, 236))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (213, 236))	('patients', 'Species', '9606', (244, 252))	('GSK2656157', 'Var', (60, 70))	('cancer', 'Phenotype', 'HP:0002664', (319, 325))	('inhibition', 'NegReg', (37, 47))	('clinical prognosis', 'CPA', (154, 172))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (202, 236))	('PERK', 'Gene', (32, 36))	('cancers', 'Disease', 'MESH:D009369', (319, 326))	('treatment', 'CPA', (189, 198))	('GSK2656157', 'Chemical', 'MESH:C000597302', (60, 70))	('improve', 'PosReg', (146, 153))	('enhance', 'PosReg', (177, 184))	('carcinoma', 'Phenotype', 'HP:0030731', (227, 236))	('PERK', 'Gene', (111, 115))	('ATF4', 'Gene', (126, 130))	('PERK', 'Gene', '9451', (32, 36))
569207	33937330	According to the PrognoScan database, the high expression of PERK was associated with a poor prognosis in brain cancer (shorter OS, p = 0.003) and soft tissue cancer (shorter DRFS, p = 0.008) and related to a favorable prognosis in lung cancer (longer OS and RFS, p < 0.05, Figure 3).	('soft tissue cancer', 'Phenotype', 'HP:0031459', (147, 165))	('cancer', 'Disease', (112, 118))	('lung cancer', 'Disease', 'MESH:D008175', (232, 243))	('high expression', 'Var', (42, 57))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('PERK', 'Gene', (61, 65))	('lung cancer', 'Phenotype', 'HP:0100526', (232, 243))	('cancer', 'Disease', (159, 165))	('cancer', 'Phenotype', 'HP:0002664', (159, 165))	('brain cancer', 'Phenotype', 'HP:0030692', (106, 118))	('cancer', 'Disease', (237, 243))	('PERK', 'Gene', '9451', (61, 65))	('brain cancer', 'Disease', 'MESH:D001932', (106, 118))	('cancer', 'Phenotype', 'HP:0002664', (237, 243))	('cancer', 'Disease', 'MESH:D009369', (112, 118))	('cancer', 'Disease', 'MESH:D009369', (159, 165))	('lung cancer', 'Disease', (232, 243))	('cancer', 'Disease', 'MESH:D009369', (237, 243))	('brain cancer', 'Disease', (106, 118))
569211	33937330	The high expression of PERK was associated with a favorable prognosis in bladder carcinoma (p = 0.006), esophageal squamous cell carcinoma (p = 0.0022), lung adenocarcinoma (p = 0.0054), rectum adenocarcinoma (p = 0.026), and thymoma (p = 0.039, Figure 4) and related to a poor prognosis in kidney renal papillary cell carcinoma (p = 0.014), liver hepatocellular carcinoma (p = 0.023), and thyroid carcinoma (p = 0.0036, Figure 4).	('bladder carcinoma', 'Phenotype', 'HP:0002862', (73, 90))	('thymoma', 'Disease', (226, 233))	('bladder carcinoma', 'Disease', 'MESH:D001749', (73, 90))	('high expression', 'Var', (4, 19))	('thymoma', 'Phenotype', 'HP:0100522', (226, 233))	('carcinoma', 'Phenotype', 'HP:0030731', (81, 90))	('kidney renal papillary cell carcinoma', 'Disease', (291, 328))	('rectum adenocarcinoma', 'Disease', (187, 208))	('carcinoma', 'Phenotype', 'HP:0030731', (199, 208))	('carcinoma', 'Phenotype', 'HP:0030731', (319, 328))	('PERK', 'Gene', '9451', (23, 27))	('lung adenocarcinoma', 'Disease', (153, 172))	('bladder carcinoma', 'Disease', (73, 90))	('esophageal squamous cell carcinoma', 'Disease', (104, 138))	('liver hepatocellular carcinoma', 'Disease', (342, 372))	('thyroid carcinoma', 'Disease', 'MESH:D013964', (390, 407))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (153, 172))	('thyroid carcinoma', 'Disease', (390, 407))	('kidney renal papillary cell carcinoma', 'Disease', 'MESH:C538614', (291, 328))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (153, 172))	('rectum adenocarcinoma', 'Disease', 'MESH:D012004', (187, 208))	('thyroid carcinoma', 'Phenotype', 'HP:0002890', (390, 407))	('renal papillary cell carcinoma', 'Phenotype', 'HP:0006766', (298, 328))	('hepatocellular carcinoma', 'Phenotype', 'HP:0001402', (348, 372))	('thymoma', 'Disease', 'MESH:D013945', (226, 233))	('carcinoma', 'Phenotype', 'HP:0030731', (163, 172))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:D000077277', (104, 138))	('carcinoma', 'Phenotype', 'HP:0030731', (129, 138))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (115, 138))	('PERK', 'Gene', (23, 27))	('liver hepatocellular carcinoma', 'Disease', 'MESH:D006528', (342, 372))
569215	33937330	According to the UALCAN database, the high expression of PERK was associated with a poor prognosis in kidney renal papillary cell carcinoma (KIRP) (p = 0.01), brain lower grade glioma (LGG) (p = 0.00016), and THCA (p = 0.017, Figure 5).	('renal papillary cell carcinoma', 'Phenotype', 'HP:0006766', (109, 139))	('THCA', 'Phenotype', 'HP:0002890', (209, 213))	('glioma', 'Disease', (177, 183))	('high expression', 'Var', (38, 53))	('THCA', 'Disease', (209, 213))	('glioma', 'Disease', 'MESH:D005910', (177, 183))	('kidney renal papillary cell carcinoma', 'Disease', (102, 139))	('carcinoma', 'Phenotype', 'HP:0030731', (130, 139))	('PERK', 'Gene', (57, 61))	('glioma', 'Phenotype', 'HP:0009733', (177, 183))	('kidney renal papillary cell carcinoma', 'Disease', 'MESH:C538614', (102, 139))	('PERK', 'Gene', '9451', (57, 61))
569216	33937330	Consistent with the results of the Kaplan:Meier plotter database, PERK expression in BRCA had a poor prognosis (OS < 4,000 days, ~130 months, p = 0.025, Figure 5).	('BRCA', 'Gene', (85, 89))	('PERK', 'Gene', (66, 70))	('expression', 'Var', (71, 81))	('PERK', 'Gene', '9451', (66, 70))	('BRCA', 'Phenotype', 'HP:0003002', (85, 89))	('BRCA', 'Gene', '672', (85, 89))
569218	33937330	Together, the high expression of PERK is associated with a poor prognosis in KIRP, LGG, BRCA, and THCA and with a favorable prognosis in HNSC.	('THCA', 'Phenotype', 'HP:0002890', (98, 102))	('THCA', 'Disease', (98, 102))	('PERK', 'Gene', (33, 37))	('HNSC', 'Disease', (137, 141))	('LGG', 'Disease', (83, 86))	('KIRP', 'Disease', (77, 81))	('high', 'Var', (14, 18))	('HNSC', 'Phenotype', 'HP:0012288', (137, 141))	('BRCA', 'Phenotype', 'HP:0003002', (88, 92))	('BRCA', 'Gene', '672', (88, 92))	('PERK', 'Gene', '9451', (33, 37))	('BRCA', 'Gene', (88, 92))
569251	33937330	Lung cancer was an exception where high levels of PERK expression showed a better prognosis.	('Lung cancer', 'Phenotype', 'HP:0100526', (0, 11))	('PERK', 'Gene', (50, 54))	('high levels', 'Var', (35, 46))	('Lung cancer', 'Disease', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (5, 11))	('PERK', 'Gene', '9451', (50, 54))	('Lung cancer', 'Disease', 'MESH:D008175', (0, 11))
569253	33937330	The UALCAN database analysis demonstrated that the high expression of PERK was associated with a poor prognosis in KIRP, LGG, THCA, and BRCA (Figure 5).	('KIRP', 'Disease', (115, 119))	('PERK', 'Gene', (70, 74))	('LGG', 'Disease', (121, 124))	('THCA', 'Phenotype', 'HP:0002890', (126, 130))	('THCA', 'Disease', (126, 130))	('PERK', 'Gene', '9451', (70, 74))	('BRCA', 'Gene', '672', (136, 140))	('high expression', 'Var', (51, 66))	('BRCA', 'Phenotype', 'HP:0003002', (136, 140))	('BRCA', 'Gene', (136, 140))
569256	33937330	Inhibition of CREB3L1 by genetic or pharmacological methods suppresses cancer cell invasion and metastasis (Feng et al.,).	('cancer', 'Disease', 'MESH:D009369', (71, 77))	('CREB3L1', 'Gene', '90993', (14, 21))	('cancer', 'Disease', (71, 77))	('suppresses', 'NegReg', (60, 70))	('Inhibition', 'Var', (0, 10))	('cancer', 'Phenotype', 'HP:0002664', (71, 77))	('CREB3L1', 'Gene', (14, 21))
569257	33937330	Another report showed that inhibition of the PERK-eIF2alpha-GRP94 signaling pathway silenced the epidermal growth factor receptor (EGFR) and then increased the radiosensitivity of both radiosensitive and radioresistant oropharyngeal squamous cell carcinoma (OSCC) cells (Zhang et al.,).	('radiosensitivity', 'CPA', (160, 176))	('epidermal growth factor receptor', 'Gene', '1956', (97, 129))	('EGFR', 'Gene', (131, 135))	('inhibition', 'Var', (27, 37))	('carcinoma', 'Phenotype', 'HP:0030731', (247, 256))	('squamous cell carcinoma', 'Disease', (233, 256))	('PERK', 'Gene', '9451', (45, 49))	('increased', 'PosReg', (146, 155))	('silenced', 'NegReg', (84, 92))	('OSCC', 'Phenotype', 'HP:0012182', (258, 262))	('GRP94', 'Gene', '7184', (60, 65))	('EGFR', 'Gene', '1956', (131, 135))	('eIF2alpha', 'Gene', (50, 59))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (233, 256))	('eIF2alpha', 'Gene', '83939', (50, 59))	('GRP94', 'Gene', (60, 65))	('oropharyngeal squamous cell carcinoma', 'Phenotype', 'HP:0012182', (219, 256))	('epidermal growth factor receptor', 'Gene', (97, 129))	('PERK', 'Gene', (45, 49))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (233, 256))
569276	33937330	Expansion of myeloid-derived suppressor cells (MDSCs) has emerged as a key mechanism of antitumor immune evasion and correlates with a poor clinical outcome and resistance to cancer immunotherapy (Lu et al.,).	('cancer', 'Phenotype', 'HP:0002664', (175, 181))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('cancer', 'Disease', (175, 181))	('cancer', 'Disease', 'MESH:D009369', (175, 181))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Disease', (92, 97))	('Expansion', 'Var', (0, 9))
569278	33937330	PERK deletion transformed MDSCs into myeloid cells that activated CD8+ T-cell-mediated immunity against cancer (Mohamed et al.,).	('PERK', 'Gene', (0, 4))	('deletion', 'Var', (5, 13))	('PERK', 'Gene', '9451', (0, 4))	('cancer', 'Phenotype', 'HP:0002664', (104, 110))	('CD8', 'Gene', (66, 69))	('CD8', 'Gene', '925', (66, 69))	('activated', 'PosReg', (56, 65))	('cancer', 'Disease', (104, 110))	('cancer', 'Disease', 'MESH:D009369', (104, 110))
569279	33937330	Another study showed that inhibition of PERK in CD8+ T cells abrogates mitochondrial ROS generation in PD-1+ CD8+ tumor-infiltrating lymphocytes (TILs), which boosts CD8+ TIL viability and enhances antitumor immunity (Hurst et al.,).	('abrogates', 'NegReg', (61, 70))	('boosts', 'PosReg', (159, 165))	('CD8', 'Gene', '925', (48, 51))	('ROS', 'Chemical', '-', (85, 88))	('CD8', 'Gene', '925', (166, 169))	('CD8', 'Gene', '925', (109, 112))	('tumor', 'Disease', (202, 207))	('inhibition', 'Var', (26, 36))	('tumor', 'Disease', (114, 119))	('mitochondrial ROS generation', 'MPA', (71, 99))	('tumor', 'Disease', 'MESH:D009369', (202, 207))	('tumor', 'Disease', 'MESH:D009369', (114, 119))	('PD-1', 'Gene', (103, 107))	('CD8', 'Gene', (48, 51))	('PERK', 'Gene', (40, 44))	('PD-1', 'Gene', '5133', (103, 107))	('enhances', 'PosReg', (189, 197))	('CD8', 'Gene', (166, 169))	('tumor', 'Phenotype', 'HP:0002664', (202, 207))	('CD8', 'Gene', (109, 112))	('tumor', 'Phenotype', 'HP:0002664', (114, 119))	('PERK', 'Gene', '9451', (40, 44))
569303	30181549	Nevertheless, unlike in other cancer types such as colon cancer, mutations in TGFBR2 and SMAD2/4 genes appear to be uncommon in NSCLC, according to previously reported studies and analysis of the catalog of somatic mutations in cancer (COSMIC), suggesting that additional mechanisms involved in maintaining constitutive activation of TGF-beta signaling cascades are to be revealed in NSCLC.	('cancer', 'Disease', (57, 63))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('NSCLC', 'Disease', (128, 133))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('colon cancer', 'Disease', 'MESH:D015179', (51, 63))	('TGF-beta', 'Gene', '7040', (334, 342))	('NSCLC', 'Phenotype', 'HP:0030358', (128, 133))	('SMAD2/4', 'Gene', '4087;4089', (89, 96))	('mutations', 'Var', (65, 74))	('colon cancer', 'Disease', (51, 63))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('TGF-beta', 'Gene', (334, 342))	('cancer', 'Disease', (228, 234))	('NSCLC', 'Disease', 'MESH:D002289', (384, 389))	('TGFBR2', 'Gene', '7048', (78, 84))	('cancer', 'Disease', (30, 36))	('cancer', 'Phenotype', 'HP:0002664', (228, 234))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('NSCLC', 'Disease', (384, 389))	('NSCLC', 'Phenotype', 'HP:0030358', (384, 389))	('NSCLC', 'Disease', 'MESH:D002289', (128, 133))	('colon cancer', 'Phenotype', 'HP:0003003', (51, 63))	('TGFBR2', 'Gene', (78, 84))	('SMAD2/4', 'Gene', (89, 96))	('cancer', 'Disease', 'MESH:D009369', (228, 234))
569305	30181549	While dysregulated expression of MYEOV transcript in cancer patients has been associated with its tumorigenic properties, the molecular mechanisms underlying MYEOV-mediated tumorigenesis are still largely unclear.	('dysregulated', 'Var', (6, 18))	('associated', 'Reg', (78, 88))	('MYEOV', 'Gene', '26579', (158, 163))	('expression', 'MPA', (19, 29))	('tumor', 'Disease', 'MESH:D009369', (173, 178))	('cancer', 'Disease', (53, 59))	('cancer', 'Disease', 'MESH:D009369', (53, 59))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('patients', 'Species', '9606', (60, 68))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('tumor', 'Disease', (173, 178))	('MYEOV', 'Gene', (33, 38))	('cancer', 'Phenotype', 'HP:0002664', (53, 59))	('MYEOV', 'Gene', '26579', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (173, 178))	('tumor', 'Disease', (98, 103))	('MYEOV', 'Gene', (158, 163))
569306	30181549	predicted Myc as the most affected transcriptional factor in response to knockdown of MYEOV using Integrated Motif Activity Response Analysis (ISMARA).	('MYEOV', 'Gene', (86, 91))	('MYEOV', 'Gene', '26579', (86, 91))	('Myc', 'Gene', '4609', (10, 13))	('Myc', 'Gene', (10, 13))	('knockdown', 'Var', (73, 82))
569322	30181549	In addition, the amplification status of MYEOV significantly correlated with high TNM clinical staging (P = 0.002), lymph nodes metastasis (P = 0.032), and metastasis status (P = 0.036) (Supplementary Table S1).	('MYEOV', 'Gene', (41, 46))	('MYEOV', 'Gene', '26579', (41, 46))	('metastasis status', 'CPA', (156, 173))	('amplification status', 'Var', (17, 37))	('lymph nodes metastasis', 'CPA', (116, 138))	('correlated', 'Reg', (61, 71))	('high', 'CPA', (77, 81))
569328	30181549	These results together indicate that MYEOV gene is amplified and overexpressed in NSCLC and MYEOV amplification predicts poor prognosis of NSCLC patients.	('patients', 'Species', '9606', (145, 153))	('NSCLC', 'Phenotype', 'HP:0030358', (139, 144))	('NSCLC', 'Phenotype', 'HP:0030358', (82, 87))	('overexpressed', 'PosReg', (65, 78))	('MYEOV', 'Gene', (37, 42))	('NSCLC', 'Disease', (139, 144))	('MYEOV', 'Gene', '26579', (37, 42))	('amplification', 'Var', (98, 111))	('MYEOV', 'Gene', (92, 97))	('MYEOV', 'Gene', '26579', (92, 97))	('NSCLC', 'Disease', 'MESH:D002289', (139, 144))	('NSCLC', 'Disease', (82, 87))	('poor', 'NegReg', (121, 125))	('NSCLC', 'Disease', 'MESH:D002289', (82, 87))
569331	30181549	Interestingly, analysis of the TCGA data sets revealed MYEOV copy number amplification was increased in subtypes of a number of tumor types, including esophageal squamous cell carcinoma, head and neck squamous cell carcinoma, ovarian serous cystadenocarcinoma, breast cancer, bladder carcinoma and gastric adenocarcinoma (Supplementary Figure S2a).	('head and neck squamous cell carcinoma', 'Disease', 'MESH:C535575', (187, 224))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('esophageal squamous cell carcinoma', 'Disease', 'MESH:C562729', (151, 185))	('breast cancer', 'Phenotype', 'HP:0003002', (261, 274))	('carcinoma', 'Phenotype', 'HP:0030731', (311, 320))	('bladder carcinoma', 'Phenotype', 'HP:0002862', (276, 293))	('carcinoma', 'Phenotype', 'HP:0030731', (284, 293))	('gastric adenocarcinoma', 'Disease', (298, 320))	('breast cancer', 'Disease', (261, 274))	('breast cancer', 'Disease', 'MESH:D001943', (261, 274))	('bladder carcinoma', 'Disease', 'MESH:D001749', (276, 293))	('carcinoma', 'Phenotype', 'HP:0030731', (215, 224))	('increased', 'PosReg', (91, 100))	('MYEOV', 'Gene', (55, 60))	('copy number', 'Var', (61, 72))	('MYEOV', 'Gene', '26579', (55, 60))	('ovarian serous cystadenocarcinoma', 'Disease', 'MESH:D010049', (226, 259))	('ovarian serous cystadenocarcinoma', 'Phenotype', 'HP:0012887', (226, 259))	('esophageal squamous cell carcinoma', 'Disease', (151, 185))	('tumor', 'Disease', (128, 133))	('bladder carcinoma', 'Disease', (276, 293))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (162, 185))	('ovarian serous cystadenocarcinoma', 'Disease', (226, 259))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (201, 224))	('gastric adenocarcinoma', 'Disease', 'MESH:D013274', (298, 320))	('cancer', 'Phenotype', 'HP:0002664', (268, 274))	('carcinoma', 'Phenotype', 'HP:0030731', (250, 259))	('carcinoma', 'Phenotype', 'HP:0030731', (176, 185))
569333	30181549	Taken together, these results suggest that amplification and overexpression of MYEOV gene may be an event frequently occurring in different types of cancers.	('cancers', 'Disease', (149, 156))	('MYEOV', 'Gene', '26579', (79, 84))	('cancers', 'Phenotype', 'HP:0002664', (149, 156))	('overexpression', 'PosReg', (61, 75))	('amplification', 'Var', (43, 56))	('cancer', 'Phenotype', 'HP:0002664', (149, 155))	('MYEOV', 'Gene', (79, 84))	('cancers', 'Disease', 'MESH:D009369', (149, 156))
569338	30181549	In following up with this notion, we further examined whether mutations of the AUG triplets in the 5'UTR of MYEOV transcript could restore the translation of MYEOV transcript.	('MYEOV', 'Gene', '26579', (158, 163))	('MYEOV', 'Gene', (108, 113))	('MYEOV', 'Gene', '26579', (108, 113))	('translation', 'MPA', (143, 154))	('restore', 'PosReg', (131, 138))	('mutations', 'Var', (62, 71))	('MYEOV', 'Gene', (158, 163))
569349	30181549	To elucidate whether MYEOV transcript operates as a ceRNA for miR-30c-2-3p in NSCLC progression, in vivo gain-of-function studies were performed by overexpressing wild-type full-length MYEOV cDNA (MYEOV-cDNA), MYEOV cDNA carrying mutation in the in-frame start codon (MYEOV-ATGmut), and MYEOV with mutation of all five predicted miR-30c-2-3p binding sites (MYEOV-miRmut), respectively, in A549, which expresses low-level endogenous MYEOV transcript (Fig.	('MYEOV', 'Gene', (432, 437))	('miR', 'Gene', '220972', (329, 332))	('MYEOV', 'Gene', '26579', (432, 437))	('miR', 'Gene', (363, 366))	('mutation', 'Var', (298, 306))	('MYEOV', 'Gene', (210, 215))	('MYEOV', 'Gene', '26579', (210, 215))	('miR-30c-2', 'Gene', '407032', (329, 338))	('miR-30c-2', 'Gene', (62, 71))	('MYEOV', 'Gene', (287, 292))	('MYEOV', 'Gene', '26579', (287, 292))	('NSCLC', 'Disease', (78, 83))	('NSCLC', 'Disease', 'MESH:D002289', (78, 83))	('miR', 'Gene', (329, 332))	('NSCLC', 'Phenotype', 'HP:0030358', (78, 83))	('MYEOV', 'Gene', (357, 362))	('miR-30c-2', 'Gene', (329, 338))	('MYEOV', 'Gene', '26579', (357, 362))	('MYEOV', 'Gene', (268, 273))	('miR', 'Gene', '220972', (62, 65))	('MYEOV', 'Gene', '26579', (268, 273))	('mutation', 'Var', (230, 238))	('MYEOV', 'Gene', (197, 202))	('MYEOV', 'Gene', '26579', (197, 202))	('miR-30c-2', 'Gene', '407032', (62, 71))	('MYEOV', 'Gene', (21, 26))	('miR', 'Gene', '220972', (363, 366))	('MYEOV', 'Gene', '26579', (21, 26))	('miR', 'Gene', (62, 65))	('MYEOV', 'Gene', (185, 190))	('MYEOV', 'Gene', '26579', (185, 190))
569353	30181549	In comparison, silencing endogenous MYEOV transcript in H1975 cells, which expressed MYEOV transcript at an elevated level with its DNA copy number amplified, could inhibit the metastatic ability of H1975 cells and increased animal survival (Fig.	('metastatic ability', 'CPA', (177, 195))	('silencing', 'Var', (15, 24))	('MYEOV', 'Gene', (36, 41))	('increased', 'PosReg', (215, 224))	('animal survival', 'CPA', (225, 240))	('inhibit', 'NegReg', (165, 172))	('MYEOV', 'Gene', '26579', (36, 41))	('MYEOV', 'Gene', (85, 90))	('MYEOV', 'Gene', '26579', (85, 90))
569354	30181549	Subcutaneous xenograft studies showed that A549-Vector or A549-MYEOV-miRmut cells formed well circumscribed tumor with clear edges, while tumors formed by A549-MYEOV-cDNA or A549-MYEOV-ATGmut cells exhibited highly invasive morphology with obscure boundary (Fig.	('tumor', 'Disease', (138, 143))	('tumor', 'Disease', (108, 113))	('tumors', 'Disease', 'MESH:D009369', (138, 144))	('miR', 'Gene', (69, 72))	('tumor', 'Disease', 'MESH:D009369', (138, 143))	('MYEOV', 'Gene', (63, 68))	('MYEOV', 'Gene', '26579', (63, 68))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('MYEOV', 'Gene', (160, 165))	('MYEOV', 'Gene', '26579', (160, 165))	('invasive morphology', 'CPA', (215, 234))	('tumor', 'Phenotype', 'HP:0002664', (138, 143))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('tumors', 'Phenotype', 'HP:0002664', (138, 144))	('MYEOV', 'Gene', (179, 184))	('MYEOV', 'Gene', '26579', (179, 184))	('A549-Vector', 'Var', (43, 54))	('tumors', 'Disease', (138, 144))	('miR', 'Gene', '220972', (69, 72))
569355	30181549	Meanwhile, silencing MYEOV transcript in H1975 inhibited subcutaneous tumor invasiveness (Fig.	('silencing', 'Var', (11, 20))	('tumor invasiveness', 'Disease', (70, 88))	('MYEOV', 'Gene', (21, 26))	('H1975', 'Var', (41, 46))	('inhibited', 'NegReg', (47, 56))	('MYEOV', 'Gene', '26579', (21, 26))	('tumor invasiveness', 'Disease', 'MESH:D009361', (70, 88))	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('subcutaneous tumor', 'Phenotype', 'HP:0001482', (57, 75))
569358	30181549	Meanwhile, silencing MYEOV transcript in SK-MES-1 and H1975 cells markedly weakened EMT and invasive capabilities of the cells (Fig.	('silencing', 'Var', (11, 20))	('MYEOV', 'Gene', (21, 26))	('MYEOV', 'Gene', '26579', (21, 26))	('weakened', 'NegReg', (75, 83))	('EMT', 'Gene', (84, 87))	('EMT', 'Gene', '3702', (84, 87))
569362	30181549	In agreement with the gain-of-function experiments, silencing MYEOV decreased the TGF-beta-driven luciferase reporter activity (Supplementary Figure S5b).	('MYEOV', 'Gene', (62, 67))	('decreased', 'NegReg', (68, 77))	('MYEOV', 'Gene', '26579', (62, 67))	('silencing', 'Var', (52, 61))	('TGF-beta', 'Gene', '7040', (82, 90))	('TGF-beta', 'Gene', (82, 90))
569367	30181549	In our in vivo experimental metastasis model, A549 cells with MYEOV transcript overexpressed formed more metastatic nodules and showed a shorter OS time as compared with the vector-control cells, whereas silencing MYEOV in H1975 cells remarkably decreased metastasis and increased animal survival (Fig.	('MYEOV', 'Gene', (62, 67))	('increased', 'PosReg', (271, 280))	('MYEOV', 'Gene', '26579', (62, 67))	('silencing', 'Var', (204, 213))	('metastasis', 'CPA', (256, 266))	('MYEOV', 'Gene', (214, 219))	('MYEOV', 'Gene', '26579', (214, 219))	('decreased', 'NegReg', (246, 255))	('metastatic nodules', 'CPA', (105, 123))	('animal survival', 'CPA', (281, 296))
569368	30181549	Notably, LY2109761 treatment significantly suppressed the metastatic capability of A549-MYEOV-cDNA and H1975-vector cells and prolonged animal survival, but had no obvious effects on A549-vector cells and H1975 cells with MYEOV knocked down (Fig.	('prolonged', 'PosReg', (126, 135))	('MYEOV', 'Gene', (88, 93))	('MYEOV', 'Gene', (222, 227))	('LY2109761', 'Var', (9, 18))	('MYEOV', 'Gene', '26579', (88, 93))	('MYEOV', 'Gene', '26579', (222, 227))	('metastatic capability', 'CPA', (58, 79))	('LY2109761', 'Chemical', 'MESH:C530108', (9, 18))	('animal survival', 'CPA', (136, 151))	('suppressed', 'NegReg', (43, 53))
569373	30181549	To demonstrate that miR-30c-2-3p directly targets TGFBR2 and USP15, we constructed luciferase reporters containing wild type (WT) or mutant (Mut) 3'-UTR of TGFBR2 and USP15 (Fig.	('TGFBR2', 'Gene', '7048', (50, 56))	('TGFBR2', 'Gene', '7048', (156, 162))	('miR-30c-2', 'Gene', (20, 29))	('USP15', 'Gene', '9958', (167, 172))	('USP15', 'Gene', '9958', (61, 66))	('miR-30c-2', 'Gene', '407032', (20, 29))	('TGFBR2', 'Gene', (50, 56))	('TGFBR2', 'Gene', (156, 162))	('USP15', 'Gene', (167, 172))	('mutant', 'Var', (133, 139))	('USP15', 'Gene', (61, 66))
569375	30181549	Meanwhile, the use of 3'-UTR reporters containing mutations in the miR-30c-2-3p binding sites showed that these mutations abolished the effect of deregulated miR-30c-2-3p on the luciferase reporter (Fig.	('miR-30c-2', 'Gene', (158, 167))	('mutations', 'Var', (50, 59))	('miR-30c-2', 'Gene', '407032', (67, 76))	('effect', 'MPA', (136, 142))	('mutations', 'Var', (112, 121))	('luciferase', 'Enzyme', (178, 188))	('miR-30c-2', 'Gene', '407032', (158, 167))	('miR-30c-2', 'Gene', (67, 76))	('abolished', 'NegReg', (122, 131))
569377	30181549	To investigate the functional significance of TGFBR2 and USP15 in the TGF-beta signaling and invasive capability of NSCLC cells, the effects of depleting TGFBR2 and USP15 were investigated.	('NSCLC', 'Disease', 'MESH:D002289', (116, 121))	('USP15', 'Gene', (165, 170))	('TGF-beta', 'Gene', '7040', (70, 78))	('depleting', 'Var', (144, 153))	('TGFBR2', 'Gene', '7048', (46, 52))	('TGFBR2', 'Gene', '7048', (154, 160))	('USP15', 'Gene', '9958', (57, 62))	('TGF-beta', 'Gene', (70, 78))	('USP15', 'Gene', '9958', (165, 170))	('NSCLC', 'Phenotype', 'HP:0030358', (116, 121))	('TGFBR2', 'Gene', (46, 52))	('NSCLC', 'Disease', (116, 121))	('USP15', 'Gene', (57, 62))	('TGFBR2', 'Gene', (154, 160))
569378	30181549	6d, e, individually silencing TGFBR2 or USP15 inhibited the transactivating activity of TGF-beta signaling and cell invasiveness.	('TGFBR2', 'Gene', '7048', (30, 36))	('silencing', 'Var', (20, 29))	('USP15', 'Gene', (40, 45))	('TGF-beta', 'Gene', '7040', (88, 96))	('USP15', 'Gene', '9958', (40, 45))	('TGF-beta', 'Gene', (88, 96))	('cell invasiveness', 'CPA', (111, 128))	('TGFBR2', 'Gene', (30, 36))	('inhibited', 'NegReg', (46, 55))	('transactivating activity', 'MPA', (60, 84))
569382	30181549	Moreover, the expression levels of TGFBR2 and USP15 were upregulated in cells ectopically expressing MYEOV-cDNA or MYEOV-ATGmut when compared with vector control cells, whereas introduction of mutant miRNAs binding sites of MYEOV attenuated this effect (Fig.	('miR', 'Gene', '220972', (200, 203))	('miR', 'Gene', (200, 203))	('expression levels', 'MPA', (14, 31))	('MYEOV', 'Gene', (101, 106))	('attenuated', 'NegReg', (230, 240))	('MYEOV', 'Gene', (115, 120))	('MYEOV', 'Gene', (224, 229))	('TGFBR2', 'Gene', (35, 41))	('MYEOV', 'Gene', '26579', (115, 120))	('MYEOV', 'Gene', '26579', (101, 106))	('USP15', 'Gene', (46, 51))	('MYEOV', 'Gene', '26579', (224, 229))	('mutant', 'Var', (193, 199))	('TGFBR2', 'Gene', '7048', (35, 41))	('USP15', 'Gene', '9958', (46, 51))	('upregulated', 'PosReg', (57, 68))
569386	30181549	IHC assays were performed in 160 cases clinical in NSCLC specimens and results exhibited that the protein expression levels of TGFBR2, USP15, and nuclear-localized SMAD3 were significantly higher in MYEOV transcript-high expression group than those in the MYEOV transcript-low expression group (Fig.	('NSCLC', 'Phenotype', 'HP:0030358', (51, 56))	('SMAD3', 'Gene', '4088', (164, 169))	('TGFBR2', 'Gene', (127, 133))	('transcript-high expression', 'Var', (205, 231))	('NSCLC', 'Disease', (51, 56))	('SMAD3', 'Gene', (164, 169))	('USP15', 'Gene', (135, 140))	('protein expression levels', 'MPA', (98, 123))	('NSCLC', 'Disease', 'MESH:D002289', (51, 56))	('TGFBR2', 'Gene', '7048', (127, 133))	('higher', 'PosReg', (189, 195))	('MYEOV', 'Gene', (256, 261))	('MYEOV', 'Gene', '26579', (256, 261))	('MYEOV', 'Gene', (199, 204))	('MYEOV', 'Gene', '26579', (199, 204))	('USP15', 'Gene', '9958', (135, 140))
569394	30181549	The accumulation of genetic changes as a hallmark of NSCLC development usually not only results in increased expression and/or overactivation of oncogenic genes but also represents useful prognostic markers or therapeutic targets.	('genetic changes', 'Var', (20, 35))	('NSCLC', 'Phenotype', 'HP:0030358', (53, 58))	('expression', 'MPA', (109, 119))	('oncogenic genes', 'Gene', (145, 160))	('overactivation', 'MPA', (127, 141))	('NSCLC', 'Disease', (53, 58))	('increased', 'PosReg', (99, 108))	('NSCLC', 'Disease', 'MESH:D002289', (53, 58))
569395	30181549	Notably, amplification of chr11q13.3 is frequently found and associated with poor clinical outcome in a wide spectrum of tumor types, including NSCLC.	('NSCLC', 'Disease', (144, 149))	('amplification', 'Var', (9, 22))	('tumor', 'Phenotype', 'HP:0002664', (121, 126))	('NSCLC', 'Disease', 'MESH:D002289', (144, 149))	('chr11q13.3', 'Gene', (26, 36))	('tumor', 'Disease', (121, 126))	('NSCLC', 'Phenotype', 'HP:0030358', (144, 149))	('associated', 'Reg', (61, 71))	('tumor', 'Disease', 'MESH:D009369', (121, 126))
569405	30181549	More interestingly, the biological effects of the MYEOV transcript were largely miR-30c-2-3p-dependent, as MYEOV cDNA and MYEOV cDNA carrying mutation in the in-frame start codon promoted invasion and metastasis of NSCLC, but not MYEOV with mutation of all five predicted miR-30c-2-3p binding sites.	('MYEOV', 'Gene', (50, 55))	('miR-30c-2', 'Gene', '407032', (272, 281))	('NSCLC', 'Disease', (215, 220))	('MYEOV', 'Gene', '26579', (50, 55))	('MYEOV', 'Gene', (230, 235))	('MYEOV', 'Gene', '26579', (230, 235))	('NSCLC', 'Phenotype', 'HP:0030358', (215, 220))	('miR-30c-2', 'Gene', '407032', (80, 89))	('miR-30c-2', 'Gene', (272, 281))	('promoted', 'PosReg', (179, 187))	('mutation', 'Var', (142, 150))	('MYEOV', 'Gene', (107, 112))	('MYEOV', 'Gene', '26579', (107, 112))	('metastasis', 'CPA', (201, 211))	('invasion', 'CPA', (188, 196))	('miR-30c-2', 'Gene', (80, 89))	('MYEOV', 'Gene', (122, 127))	('MYEOV', 'Gene', '26579', (122, 127))	('NSCLC', 'Disease', 'MESH:D002289', (215, 220))
569439	30181549	The 3'-UTRs of TGFBR2 and the USP15 genes containing the predicted potential miRNA binding sites were amplified and ligated downstream of the luciferase gene in a pGL3 control vector (Promega); the mutant 3'-UTRs of TGFBR2 and the USP15 carrying mutated sequences in the complementary sites in the seed region for miR-30c-2-3p were synthesized by Genewiz (Suzhou, China) and were cloned into the pGL3 control vector (Promega).	('miR', 'Gene', (77, 80))	('miR-30c-2', 'Gene', '407032', (314, 323))	('pGL3', 'Gene', (163, 167))	('TGFBR2', 'Gene', '7048', (216, 222))	('pGL3', 'Gene', '6391', (163, 167))	('USP15', 'Gene', (30, 35))	('miR', 'Gene', '220972', (314, 317))	('USP15', 'Gene', '9958', (30, 35))	('mutant', 'Var', (198, 204))	('miR-30c-2', 'Gene', (314, 323))	('miR', 'Gene', (314, 317))	('TGFBR2', 'Gene', (216, 222))	('TGFBR2', 'Gene', '7048', (15, 21))	('pGL3', 'Gene', (396, 400))	('USP15', 'Gene', (231, 236))	('pGL3', 'Gene', '6391', (396, 400))	('miR', 'Gene', '220972', (77, 80))	('USP15', 'Gene', '9958', (231, 236))	('TGFBR2', 'Gene', (15, 21))
569451	30181549	TGF-beta inhibitor, LY2109761 (Selleck Chemicals, Houston, TX), was administered orally at 50 mg kg-1 twice daily for five consecutive days followed by a 2-day rest (5 days on/2 days off) every week until the end of observation.	('LY2109761', 'Chemical', 'MESH:C530108', (20, 29))	('TGF-beta', 'Gene', '7040', (0, 8))	('LY2109761', 'Var', (20, 29))	('TGF-beta', 'Gene', (0, 8))
569474	29686221	Human papillomavirus-associated squamous cell carcinoma is a relatively common head and neck cancer, and the presence of HPV is associated with a good prognosis.	('relatively common head', 'Phenotype', 'HP:0004482', (61, 83))	('Human papillomavirus', 'Species', '10566', (0, 20))	('head and neck cancer', 'Phenotype', 'HP:0012288', (79, 99))	('carcinoma', 'Phenotype', 'HP:0030731', (46, 55))	('HPV', 'Species', '10566', (121, 124))	('cancer', 'Phenotype', 'HP:0002664', (93, 99))	('neck cancer', 'Disease', 'MESH:D006258', (88, 99))	('neck cancer', 'Disease', (88, 99))	('presence', 'Var', (109, 117))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (32, 55))	('squamous cell carcinoma', 'Disease', (32, 55))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (32, 55))
569488	29686221	Merkel cell and lymphoma were eliminated from the differential diagnosis with positive TTF1 (not shown) and cytokeratin staining, respectively.	('positive', 'Var', (78, 86))	('Merkel cell', 'Disease', (0, 11))	('lymphoma', 'Disease', 'MESH:D008223', (16, 24))	('lymphoma', 'Phenotype', 'HP:0002665', (16, 24))	('TTF1', 'Gene', (87, 91))	('TTF1', 'Gene', '7270', (87, 91))	('lymphoma', 'Disease', (16, 24))
569518	33033491	Loss-of-function assays showed circDENND2A knockdown suppressed cell growth via inducing cell cycle arrest and apoptosis and inhibited cell migration and invasion.	('arrest', 'Disease', 'MESH:D006323', (100, 106))	('circDENND2A', 'Gene', '27147', (31, 42))	('inducing', 'PosReg', (80, 88))	('arrest', 'Disease', (100, 106))	('knockdown', 'Var', (43, 52))	('cell growth', 'CPA', (64, 75))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (89, 106))	('inhibited', 'NegReg', (125, 134))	('circDENND2A', 'Gene', (31, 42))	('suppressed', 'NegReg', (53, 63))	('apoptosis', 'CPA', (111, 120))
569521	33033491	In addition, rescue assays demonstrated that restoration of CCNE1 significantly impaired the suppressive effects of circDENND2A silencing in terms of NSCLC growth, migration, and invasion.	('NSCLC', 'Disease', 'MESH:D002289', (150, 155))	('CCNE1', 'Gene', '898', (60, 65))	('circDENND2A', 'Gene', '27147', (116, 127))	('CCNE1', 'Gene', (60, 65))	('impaired', 'NegReg', (80, 88))	('silencing', 'Var', (128, 137))	('circDENND2A', 'Gene', (116, 127))	('suppressive effects', 'MPA', (93, 112))	('invasion', 'CPA', (179, 187))	('NSCLC', 'Disease', (150, 155))	('migration', 'CPA', (164, 173))
569526	33033491	For example, GIAT4RA was found to be a carcinoma inhibitor in NSCLC via offsetting Uchl3-induced de-ubiquitination of LSH.	('Uchl3', 'Gene', (83, 88))	('NSCLC', 'Disease', (62, 67))	('Uchl3', 'Gene', '7347', (83, 88))	('carcinoma', 'Disease', 'MESH:D009369', (39, 48))	('LSH', 'Gene', (118, 121))	('NSCLC', 'Disease', 'MESH:D002289', (62, 67))	('LSH', 'Gene', '3070', (118, 121))	('carcinoma', 'Phenotype', 'HP:0030731', (39, 48))	('offsetting', 'NegReg', (72, 82))	('GIAT4RA', 'Var', (13, 20))	('carcinoma', 'Disease', (39, 48))	('de-ubiquitination', 'MPA', (97, 114))
569532	33033491	CircHIPK3 regulated autophagy by MIR124-3p-STAT3-PRKAA/AMPKalpha signaling in lung cancer with mutated STK11 and retarded NSCLC apoptosis by sponging miR-149.	('CircHIPK3', 'Gene', (0, 9))	('cancer', 'Phenotype', 'HP:0002664', (83, 89))	('MIR124-3p', 'Gene', '406909', (33, 42))	('miR-149', 'Gene', (150, 157))	('lung cancer', 'Disease', (78, 89))	('PRKAA', 'Gene', (49, 54))	('autophagy', 'CPA', (20, 29))	('NSCLC', 'Disease', 'MESH:D002289', (122, 127))	('CircHIPK3', 'Gene', '10114', (0, 9))	('PRKAA', 'Gene', '5563', (49, 54))	('miR-149', 'Gene', '406941', (150, 157))	('retarded', 'NegReg', (113, 121))	('STK11', 'Gene', (103, 108))	('lung cancer', 'Disease', 'MESH:D008175', (78, 89))	('STAT3', 'Gene', (43, 48))	('NSCLC', 'Disease', (122, 127))	('lung cancer', 'Phenotype', 'HP:0100526', (78, 89))	('STAT3', 'Gene', '6774', (43, 48))	('mutated', 'Var', (95, 102))	('MIR124-3p', 'Gene', (33, 42))	('STK11', 'Gene', '6794', (103, 108))
569537	33033491	CircDENND2A, a new circRNA, was revealed to induce cell proliferation and migration but declined apoptosis in H9C2 cells.	('induce', 'PosReg', (44, 50))	('H9C2', 'CellLine', 'CVCL:0286', (110, 114))	('CircDENND2A', 'Var', (0, 11))	('declined', 'NegReg', (88, 96))	('migration', 'CPA', (74, 83))	('cell proliferation', 'CPA', (51, 69))	('apoptosis', 'CPA', (97, 106))
569589	33033491	However, knockdown of miR-34a enhanced CCNE1 expression in A549 and H1299 (Figure 5E).	('CCNE1', 'Gene', (39, 44))	('enhanced', 'PosReg', (30, 38))	('knockdown', 'Var', (9, 18))	('A549', 'CellLine', 'CVCL:0023', (59, 63))	('miR-34a', 'Gene', '407040', (22, 29))	('expression', 'MPA', (45, 55))	('miR-34a', 'Gene', (22, 29))	('H1299', 'CellLine', 'CVCL:0060', (68, 73))	('CCNE1', 'Gene', '898', (39, 44))
569606	33033491	CircDENND2A was a novel circRNA and promoted glioma progression.	('CircDENND2A', 'Var', (0, 11))	('glioma', 'Disease', 'MESH:D005910', (45, 51))	('glioma', 'Phenotype', 'HP:0009733', (45, 51))	('glioma', 'Disease', (45, 51))	('promoted', 'PosReg', (36, 44))
569615	33033491	CircDENND2A had been demonstrated to be an oncogene in glioma and enhanced glioma cell migration and invasion.	('glioma', 'Disease', (55, 61))	('glioma', 'Phenotype', 'HP:0009733', (75, 81))	('CircDENND2A', 'Var', (0, 11))	('glioma', 'Disease', (75, 81))	('enhanced', 'PosReg', (66, 74))	('glioma', 'Disease', 'MESH:D005910', (55, 61))	('glioma', 'Phenotype', 'HP:0009733', (55, 61))	('glioma', 'Disease', 'MESH:D005910', (75, 81))	('invasion', 'CPA', (101, 109))
569618	33033491	Ablated circDENND2A largely reduced biological performance of NSCLC cells.	('reduced', 'NegReg', (28, 35))	('NSCLC', 'Disease', (62, 67))	('NSCLC', 'Disease', 'MESH:D002289', (62, 67))	('circDENND2A', 'Gene', '27147', (8, 19))	('circDENND2A', 'Gene', (8, 19))	('Ablated', 'Var', (0, 7))
569629	33033491	Aberrant increased CCNE1 indeed enhanced CDK2 conversely resulting in substrate phosphorylation of pRb, thus causing peculiar cell viability.	('substrate phosphorylation', 'MPA', (70, 95))	('Aberrant', 'Var', (0, 8))	('CDK2', 'Gene', (41, 45))	('increased', 'PosReg', (9, 18))	('CDK2', 'Gene', '1017', (41, 45))	('resulting', 'Reg', (57, 66))	('pRb', 'Gene', '5925', (99, 102))	('pRb', 'Gene', (99, 102))	('enhanced', 'PosReg', (32, 40))	('causing', 'Reg', (109, 116))	('CCNE1', 'Gene', '898', (19, 24))	('CCNE1', 'Gene', (19, 24))
569646	32209571	We used CRISPR genome editing to delete multiple tumor suppressors in lung organoids derived from Cre-dependent SOX2 knock-in mice.	('tumor', 'Disease', 'MESH:D009369', (49, 54))	('mice', 'Species', '10090', (126, 130))	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('delete', 'Var', (33, 39))	('tumor', 'Disease', (49, 54))	('CRISPR', 'Gene', (8, 14))	('CRISPR', 'Gene', '70873', (8, 14))
569649	32209571	Using this genetically-defined mouse model and three-dimensional tumoroid culture system, we show that WEE1 inhibition induces DNA damage that primes the endogenous type I interferon and antigen presentation system in primary LSCC tumor cells.	('tumor', 'Disease', 'MESH:D009369', (231, 236))	('WEE1', 'Gene', (103, 107))	('tumor', 'Disease', (65, 70))	('primes', 'PosReg', (143, 149))	('LSCC tumor', 'Disease', (226, 236))	('LSCC', 'Phenotype', 'HP:0030359', (226, 230))	('LSCC tumor', 'Disease', 'MESH:D009369', (226, 236))	('mouse', 'Species', '10090', (31, 36))	('tumor', 'Phenotype', 'HP:0002664', (231, 236))	('DNA', 'MPA', (127, 130))	('tumor', 'Disease', (231, 236))	('tumor', 'Disease', 'MESH:D009369', (65, 70))	('inhibition', 'Var', (108, 118))	('tumor', 'Phenotype', 'HP:0002664', (65, 70))
569652	32209571	There are limited lung squamous cell carcinoma (LSCC) mouse models that recapitulate the co-occurring human LSCC mutations in genes encoding proteins operative in TP53, SOX2, PI3K and P16(INK4a) pathways.	('P16', 'Gene', '1029', (184, 187))	('INK4a', 'Gene', (188, 193))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (18, 46))	('INK4a', 'Gene', '1029', (188, 193))	('carcinoma', 'Phenotype', 'HP:0030731', (37, 46))	('LSCC', 'Phenotype', 'HP:0030359', (48, 52))	('SOX2', 'Pathway', (169, 173))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (18, 46))	('mutations', 'Var', (113, 122))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (23, 46))	('lung squamous cell carcinoma', 'Disease', (18, 46))	('mouse', 'Species', '10090', (54, 59))	('LSCC', 'Phenotype', 'HP:0030359', (108, 112))	('P16', 'Gene', (184, 187))	('human', 'Species', '9606', (102, 107))
569654	32209571	Moreover, unlike human lung adenocarcinomas harboring EGFR-activating mutations or ALK fusions, for which targeted inhibitors have achieved objective responses in up to 80% cases, no targeted therapies currently exist for LSCC patients.	('mutations', 'Var', (70, 79))	('ALK', 'Gene', '238', (83, 86))	('LSCC', 'Disease', (222, 226))	('human', 'Species', '9606', (17, 22))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (23, 42))	('carcinoma', 'Phenotype', 'HP:0030731', (33, 42))	('LSCC', 'Phenotype', 'HP:0030359', (222, 226))	('lung adenocarcinomas', 'Disease', (23, 43))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (23, 43))	('carcinomas', 'Phenotype', 'HP:0030731', (33, 43))	('ALK', 'Gene', (83, 86))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (23, 43))	('patients', 'Species', '9606', (227, 235))
569655	32209571	The extent to which LSCC mutations in these pathways contribute to tumorigenesis, shape the tumor microenvironment, and affect therapeutic responses remains unclear.	('mutations', 'Var', (25, 34))	('tumor', 'Disease', (67, 72))	('contribute', 'Reg', (53, 63))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('tumor', 'Disease', 'MESH:D009369', (67, 72))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('LSCC', 'Phenotype', 'HP:0030359', (20, 24))	('affect', 'Reg', (120, 126))	('shape', 'Reg', (82, 87))	('tumor', 'Disease', (92, 97))
569659	32209571	One strategy is to combine anti-PD-1 (pembrolizumab) with chemotherapy, which has been approved for first-line treatment of squamous NSCLC patients.	('patients', 'Species', '9606', (139, 147))	('squamous NSCLC', 'Disease', 'MESH:D002294', (124, 138))	('NSCLC', 'Phenotype', 'HP:0030358', (133, 138))	('anti-PD-1', 'Var', (27, 36))	('squamous NSCLC', 'Disease', (124, 138))	('pembrolizumab', 'Chemical', 'MESH:C582435', (38, 51))
569663	32209571	We and others have previously demonstrated that interference with the CDK1 negative regulator WEE1 via a selective small-molecule WEE1 kinase inhibitor activates CDK1, which potently induces DSB formation due to loss of control at the G2/M checkpoint, leading to lung cancer cell death.	('lung cancer', 'Disease', (263, 274))	('activates', 'PosReg', (152, 161))	('DSB formation', 'MPA', (191, 204))	('lung cancer', 'Phenotype', 'HP:0100526', (263, 274))	('leading to', 'Reg', (252, 262))	('cancer', 'Phenotype', 'HP:0002664', (268, 274))	('lung cancer', 'Disease', 'MESH:D008175', (263, 274))	('induces', 'Reg', (183, 190))	('loss', 'NegReg', (212, 216))	('interference', 'Var', (48, 60))	('CDK1', 'Gene', (162, 166))
569666	32209571	Here we show that CDK1 activation via WEE1 inhibition induces DNA damage that primes the endogenous type I interferon and antigen presentation system in primary mouse and human LSCC tumor cells.	('CDK1', 'Gene', (18, 22))	('inhibition', 'Var', (43, 53))	('human', 'Species', '9606', (171, 176))	('LSCC', 'Phenotype', 'HP:0030359', (177, 181))	('WEE1', 'Gene', (38, 42))	('DNA damage', 'Disease', (62, 72))	('activation', 'PosReg', (23, 33))	('LSCC tumor', 'Disease', (177, 187))	('induces', 'Reg', (54, 61))	('LSCC tumor', 'Disease', 'MESH:D009369', (177, 187))	('mouse', 'Species', '10090', (161, 166))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))	('primes', 'PosReg', (78, 84))
569667	32209571	We show in two mouse models, including our novel organoid-derived LSCC model, that WEE1 inhibition can enhance the anti-tumor activity of anti-PD-1 monotherapy by promoting cytotoxic NK cell-mediated clearance of tumor cells and decreasing immune-suppressive neutrophilic tumor infiltration.	('tumor', 'Disease', (213, 218))	('tumor', 'Phenotype', 'HP:0002664', (272, 277))	('WEE1', 'Gene', (83, 87))	('tumor', 'Disease', (272, 277))	('decreasing', 'NegReg', (229, 239))	('neutrophilic tumor', 'Disease', 'MESH:C564275', (259, 277))	('enhance', 'PosReg', (103, 110))	('promoting', 'PosReg', (163, 172))	('tumor', 'Disease', (120, 125))	('tumor', 'Disease', 'MESH:D009369', (120, 125))	('tumor', 'Disease', 'MESH:D009369', (213, 218))	('tumor', 'Disease', 'MESH:D009369', (272, 277))	('mouse', 'Species', '10090', (15, 20))	('tumor', 'Phenotype', 'HP:0002664', (120, 125))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))	('neutrophilic tumor', 'Disease', (259, 277))	('LSCC', 'Phenotype', 'HP:0030359', (66, 70))	('inhibition', 'Var', (88, 98))
569697	32209571	When tumor size reached a mean ~150 or 300mm3, mice were randomly stratified to treatment arms: vehicle, AZD1775 (20mg/kg), anti-PD-1 (200mug), anti-CD8a (200ug), carboplatin (40mg/kg) or combination therapies.	('200ug', 'Var', (155, 160))	('tumor', 'Disease', 'MESH:D009369', (5, 10))	('CD8a', 'Gene', '12525', (149, 153))	('tumor', 'Phenotype', 'HP:0002664', (5, 10))	('carboplatin', 'Chemical', 'MESH:D016190', (163, 174))	('AZD1775', 'Var', (105, 112))	('tumor', 'Disease', (5, 10))	('CD8a', 'Gene', (149, 153))	('mice', 'Species', '10090', (47, 51))	('AZD1775', 'Chemical', 'MESH:C549567', (105, 112))
569698	32209571	JH716 mice were treated up to 30 days, while KLN205 mice were treated up to 16 days.	('JH716', 'Chemical', '-', (0, 5))	('KLN205', 'Var', (45, 51))	('mice', 'Species', '10090', (6, 10))	('mice', 'Species', '10090', (52, 56))	('JH716', 'Var', (0, 5))
569715	32209571	Reasoning that multiple genetic alterations are required to potentiate LSCC, we developed a transgenic mouse to enable combined overexpression of SOX2 with deletion of distinct tumor suppressors, starting by crossing mice with inducible SOX2 and Cas9 genes (two copies, ++, each; Figure 1A).	('Cas9', 'Chemical', '-', (246, 250))	('SOX2', 'Gene', (237, 241))	('LSCC', 'Phenotype', 'HP:0030359', (71, 75))	('mice', 'Species', '10090', (217, 221))	('mouse', 'Species', '10090', (103, 108))	('Cas9', 'Gene', (246, 250))	('tumor', 'Disease', 'MESH:D009369', (177, 182))	('tumor', 'Phenotype', 'HP:0002664', (177, 182))	('expression', 'Species', '29278', (132, 142))	('tumor', 'Disease', (177, 182))	('deletion', 'Var', (156, 164))
569719	32209571	Transfected organoids express basal cell-specific markers such as cytokeratin 5 (CK5), p63, and EpCAM (Figure 1C).	('p63', 'Var', (87, 90))	('EpCAM', 'Gene', (96, 101))	('EpCAM', 'Gene', '17075', (96, 101))	('cytokeratin 5', 'Gene', (66, 79))	('cytokeratin 5', 'Gene', '110308', (66, 79))
569720	32209571	Using the Consortium of Genomic Analysis (TCGA) data from LSCC cohort, we next selected the top three tumor suppressor genes (TP53, PTEN and CDKN2A/p16) most frequently co-mutated with SOX2 amplification in human LSCC (Figure 1D-E).	('PTEN', 'Gene', (132, 136))	('TP53', 'Gene', (126, 130))	('LSCC', 'Disease', (213, 217))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('LSCC', 'Phenotype', 'HP:0030359', (213, 217))	('LSCC', 'Phenotype', 'HP:0030359', (58, 62))	('CDKN2A/p16', 'Gene', (141, 151))	('human', 'Species', '9606', (207, 212))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('co-mutated', 'Var', (169, 179))	('SOX2 amplification', 'Gene', (185, 203))
569722	32209571	We recognized that alternative splicing of exon 1 in CDKN2A could lead to two isoforms, p16 and p19(ARF), therefore, we specifically designed our guide to disrupt both isoforms.	('p19', 'Gene', (96, 99))	('CDKN2A', 'Gene', (53, 59))	('p19', 'Gene', '12581', (96, 99))	('p16', 'MPA', (88, 91))	('alternative splicing', 'Var', (19, 39))	('ARF', 'Disease', 'MESH:D058186', (100, 103))	('lead to', 'Reg', (66, 73))	('ARF', 'Disease', (100, 103))	('isoforms', 'MPA', (78, 86))
569723	32209571	Lentiviral infection of organoids did not alter the morphology of the organoid cultures compared to controls, but we did observe a modest growth advantage in the double and triple mutant organoids (Figure 1F and Figure S2A).	('viral infection', 'Disease', (5, 20))	('growth', 'CPA', (138, 144))	('double', 'Var', (162, 168))	('viral infection', 'Disease', 'MESH:D001102', (5, 20))	('advantage', 'PosReg', (145, 154))
569725	32209571	Furthermore, given that Pten is a negative regulator of PI3K signaling, we assessed whether loss of Pten resulted in upregulation of the PI3K pathway.	('Pten', 'Gene', (24, 28))	('Pten', 'Gene', (100, 104))	('loss', 'Var', (92, 96))	('PI3K pathway', 'Pathway', (137, 149))	('Pten', 'Gene', '19211', (100, 104))	('Pten', 'Gene', '19211', (24, 28))	('upregulation', 'PosReg', (117, 129))
569729	32209571	The double mutant organoids initially grew small tumors, but this growth eventually stalled.	('tumor', 'Phenotype', 'HP:0002664', (49, 54))	('tumors', 'Phenotype', 'HP:0002664', (49, 55))	('double mutant', 'Var', (4, 17))	('tumors', 'Disease', 'MESH:D009369', (49, 55))	('tumors', 'Disease', (49, 55))	('grew', 'CPA', (38, 42))
569732	32209571	SOX2 protein levels in triple mutant tumor cell lines were indeed elevated relative to human LSCC tumor cell lines (Figure 1L).	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('human', 'Species', '9606', (87, 92))	('tumor', 'Disease', 'MESH:D009369', (98, 103))	('tumor', 'Phenotype', 'HP:0002664', (98, 103))	('LSCC tumor', 'Disease', (93, 103))	('tumor', 'Disease', (37, 42))	('LSCC tumor', 'Disease', 'MESH:D009369', (93, 103))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('SOX2 protein levels', 'MPA', (0, 19))	('tumor', 'Disease', (98, 103))	('LSCC', 'Phenotype', 'HP:0030359', (93, 97))	('triple mutant', 'Var', (23, 36))	('elevated', 'PosReg', (66, 74))
569733	32209571	We also observed some cases of adeno-squamous cell carcinomas and well-differentiated adenocarcinomas arising from the triple mutants at earlier harvests (Figure S2C).	('adeno-squamous cell carcinomas', 'Disease', 'MESH:D002294', (31, 61))	('squamous cell carcinomas', 'Phenotype', 'HP:0002860', (37, 61))	('adenocarcinomas', 'Disease', 'MESH:D000230', (86, 101))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (37, 60))	('carcinomas', 'Phenotype', 'HP:0030731', (51, 61))	('triple mutants', 'Var', (119, 133))	('adenocarcinomas', 'Disease', (86, 101))	('carcinoma', 'Phenotype', 'HP:0030731', (91, 100))	('carcinomas', 'Phenotype', 'HP:0030731', (91, 101))	('carcinoma', 'Phenotype', 'HP:0030731', (51, 60))	('adeno-squamous cell carcinomas', 'Disease', (31, 61))
569735	32209571	To confirm the phenotype of the LSCC triple mutant tumors, we further performed immunohistochemistry (IHC) for markers used clinically to distinguish human lung SCC from ADC.	('human', 'Species', '9606', (150, 155))	('LSCC', 'Phenotype', 'HP:0030359', (32, 36))	('tumor', 'Phenotype', 'HP:0002664', (51, 56))	('tumors', 'Disease', (51, 57))	('tumors', 'Phenotype', 'HP:0002664', (51, 57))	('tumors', 'Disease', 'MESH:D009369', (51, 57))	('mutant', 'Var', (44, 50))
569747	32209571	We previously demonstrated that a selective small-molecule WEE1 kinase inhibitor potently induces DNA double-stranded break (DSB) formation leading to cell death in KRAS-mutant lung adenocarcinomas.	('lung adenocarcinomas', 'Disease', (177, 197))	('carcinoma', 'Phenotype', 'HP:0030731', (187, 196))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (177, 197))	('lung adenocarcinomas', 'Disease', 'MESH:D000077192', (177, 197))	('carcinomas', 'Phenotype', 'HP:0030731', (187, 197))	('cell death', 'CPA', (151, 161))	('induces', 'Reg', (90, 97))	('KRAS-mutant', 'Var', (165, 176))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (177, 196))
569749	32209571	AZD1775 reduced cell proliferation in all lines tested but to a greater extent in tumor cells compared to normal cells (IC50s: 300 nM versus >1310nM).	('AZD1775', 'Var', (0, 7))	('AZD1775', 'Chemical', 'MESH:C549567', (0, 7))	('tumor', 'Disease', 'MESH:D009369', (82, 87))	('reduced', 'NegReg', (8, 15))	('tumor', 'Phenotype', 'HP:0002664', (82, 87))	('tumor', 'Disease', (82, 87))	('cell proliferation', 'CPA', (16, 34))
569750	32209571	As expected, confocal microscopy confirmed that AZD1775 induced DSB formation as indicated by high levels of DSB marker gammaH2AX in treated-JH716 and PDX267 cells, supporting previous studies demonstrating cell death due to accumulation of DNA damage from mitotic catastrophe (Figure 2C).	('DSB', 'Disease', (64, 67))	('gammaH2AX', 'Gene', '15270', (120, 129))	('AZD1775', 'Var', (48, 55))	('JH716', 'Chemical', '-', (141, 146))	('AZD1775', 'Chemical', 'MESH:C549567', (48, 55))	('gammaH2AX', 'Gene', (120, 129))
569752	32209571	Inhibition of CDK1 has been shown to block mitotic entry and STAT1 activation.	('mitotic', 'CPA', (43, 50))	('STAT1', 'Gene', '20846', (61, 66))	('Inhibition', 'Var', (0, 10))	('block', 'NegReg', (37, 42))	('STAT1', 'Gene', (61, 66))	('CDK1', 'Gene', (14, 18))
569753	32209571	To investigate whether WEE1 inhibition increases STAT1 signaling by inducing CDK1 activation, we measured STAT1 phosphorylation at tyrosine 701 (pSTAT1 Y701) in mouse tumor cells treated with AZD1775 over a 24-hour time course.	('inducing', 'Reg', (68, 76))	('STAT1', 'Gene', '20846', (146, 151))	('STAT1', 'Gene', '20846', (49, 54))	('AZD1775', 'Chemical', 'MESH:C549567', (192, 199))	('CDK1', 'Gene', (77, 81))	('STAT1', 'Gene', (146, 151))	('STAT1', 'Gene', (49, 54))	('mouse', 'Species', '10090', (161, 166))	('tyrosine', 'Chemical', 'MESH:D014443', (131, 139))	('inhibition', 'Var', (28, 38))	('tumor', 'Disease', 'MESH:D009369', (167, 172))	('activation', 'PosReg', (82, 92))	('STAT1', 'Gene', '20846', (106, 111))	('tumor', 'Phenotype', 'HP:0002664', (167, 172))	('increases', 'PosReg', (39, 48))	('STAT1', 'Gene', (106, 111))	('tumor', 'Disease', (167, 172))
569754	32209571	Activation of pSTAT1 Y701 was observed in the treated AZD1775 cells after 24-hours, and this was correlated with reduced phosphorylation of CDK1 on the inhibitory residue Y15 and elevated gammaH2AX, suggesting that WEE1 inhibition may be promoting DSB-induced STAT1 activation via CDK1 activation (Figure 2E).	('gammaH2AX', 'Gene', (188, 197))	('Y701', 'Var', (21, 25))	('activation', 'PosReg', (266, 276))	('gammaH2AX', 'Gene', '15270', (188, 197))	('phosphorylation', 'MPA', (121, 136))	('CDK1', 'Protein', (140, 144))	('promoting', 'PosReg', (238, 247))	('STAT1', 'Gene', '20846', (15, 20))	('Activation', 'PosReg', (0, 10))	('STAT1', 'Gene', (15, 20))	('elevated', 'PosReg', (179, 187))	('STAT1', 'Gene', '20846', (260, 265))	('reduced', 'NegReg', (113, 120))	('STAT1', 'Gene', (260, 265))	('AZD1775', 'Chemical', 'MESH:C549567', (54, 61))	('DSB-induced', 'Disease', (248, 259))
569756	32209571	Consistent with STAT1 activation, expression of ISGs was significantly upregulated in both AZD1775-treated mouse and human LSCC lines (JH716, H157, PDX277 and H520; Figure 2F-G and S5A-B) compared to controls.	('expression', 'MPA', (34, 44))	('H520', 'Var', (159, 163))	('mouse', 'Species', '10090', (107, 112))	('human', 'Species', '9606', (117, 122))	('LSCC', 'Phenotype', 'HP:0030359', (123, 127))	('expression', 'Species', '29278', (34, 44))	('STAT1', 'Gene', '20846', (16, 21))	('JH716', 'Chemical', '-', (135, 140))	('ISGs', 'Gene', (48, 52))	('STAT1', 'Gene', (16, 21))	('AZD1775', 'Chemical', 'MESH:C549567', (91, 98))	('upregulated', 'PosReg', (71, 82))
569757	32209571	Similar trends were observed when cells were treated with additional small molecule WEE1 inhibitors, Wee1_II (on JH716 cells; Figure 2F), and PD0166285 (on H157 and H226 cells; Figure 2G-H) suggesting that these were 'on-target' effects.	('JH716', 'Chemical', '-', (113, 118))	('PD0166285', 'Var', (142, 151))	('H226', 'CellLine', 'CVCL:J621', (165, 169))	('WEE1', 'Gene', (84, 88))	('PD0166285', 'Chemical', 'MESH:C440869', (142, 151))
569761	32209571	AZD1775 treatment in vitro also significantly increased expression of orthologous genes in human lung cancer lines (H157, PDX277 and H520; Figure 2G right panel and S5A-B).	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('AZD1775', 'Var', (0, 7))	('AZD1775', 'Chemical', 'MESH:C549567', (0, 7))	('increased', 'PosReg', (46, 55))	('lung cancer', 'Disease', 'MESH:D008175', (97, 108))	('expression', 'Species', '29278', (56, 66))	('expression', 'MPA', (56, 66))	('lung cancer', 'Disease', (97, 108))	('lung cancer', 'Phenotype', 'HP:0100526', (97, 108))	('human', 'Species', '9606', (91, 96))
569762	32209571	Flow cytometry analysis showed that 72-hour treatment of AZD1775 or PD0166285 at 600nM significantly elevated expression of H-2Kb (MHC-I) by approximately two-fold but did not change PD-L1 or I-A/I-E (MHC-II) expression levels on the surface of JH716 tumor cells (Figure 2J and S5D).	('PD0166285', 'Var', (68, 77))	('elevated', 'PosReg', (101, 109))	('tumor', 'Disease', (251, 256))	('AZD1775', 'Chemical', 'MESH:C549567', (57, 64))	('expression', 'Species', '29278', (110, 120))	('PD0166285', 'Chemical', 'MESH:C440869', (68, 77))	('H-2Kb', 'Protein', (124, 129))	('expression', 'MPA', (110, 120))	('tumor', 'Disease', 'MESH:D009369', (251, 256))	('JH716', 'Chemical', '-', (245, 250))	('AZD1775', 'Var', (57, 64))	('tumor', 'Phenotype', 'HP:0002664', (251, 256))	('expression', 'Species', '29278', (209, 219))
569766	32209571	Given that our in vitro data demonstrated that WEE1 inhibition can increase expression of genes encoding antigen presentation molecules on lung squamous carcinoma models, we reasoned that combining AZD1775 with anti-PD-1 may enhance tumor cell killing by stimulating T cell activity.	('AZD1775', 'Chemical', 'MESH:C549567', (198, 205))	('carcinoma', 'Phenotype', 'HP:0030731', (153, 162))	('anti-PD-1', 'Gene', (211, 220))	('AZD1775', 'Var', (198, 205))	('tumor', 'Disease', (233, 238))	('expression', 'Species', '29278', (76, 86))	('tumor', 'Disease', 'MESH:D009369', (233, 238))	('inhibition', 'NegReg', (52, 62))	('lung squamous carcinoma', 'Phenotype', 'HP:0030359', (139, 162))	('T cell activity', 'CPA', (267, 282))	('increase', 'PosReg', (67, 75))	('squamous carcinoma', 'Phenotype', 'HP:0002860', (144, 162))	('enhance', 'PosReg', (225, 232))	('tumor', 'Phenotype', 'HP:0002664', (233, 238))	('lung squamous carcinoma', 'Disease', (139, 162))	('WEE1', 'Gene', (47, 51))	('stimulating', 'PosReg', (255, 266))	('expression', 'MPA', (76, 86))	('lung squamous carcinoma', 'Disease', 'MESH:D002294', (139, 162))
569767	32209571	To test this ex vivo, we first cultured fresh tumoroids from subcutaneous implants of JH716 cells and another lung SCC mouse model, KLN205, in 3D microfluidic culture systems.	('mouse', 'Species', '10090', (119, 124))	('tumor', 'Phenotype', 'HP:0002664', (46, 51))	('tumor', 'Disease', (46, 51))	('JH716', 'Chemical', '-', (86, 91))	('KLN205', 'Var', (132, 138))	('tumor', 'Disease', 'MESH:D009369', (46, 51))
569769	32209571	We observed that both single agent AZD1775 and anti-PD-1 treatment were insufficient to induce significant cell death; however, combined anti-PD-1 and AZD1775 synergistically induced cell death in both JH716- and KLN205-derived lung squamous tumoroids by 6 days co-treatment (Figure 3A-B).	('lung squamous tumoroids', 'Disease', 'MESH:D002294', (228, 251))	('AZD1775', 'Var', (151, 158))	('AZD1775', 'Chemical', 'MESH:C549567', (151, 158))	('AZD1775', 'Chemical', 'MESH:C549567', (35, 42))	('JH716', 'Chemical', '-', (202, 207))	('tumor', 'Phenotype', 'HP:0002664', (242, 247))	('induced', 'Reg', (175, 182))	('lung squamous tumoroids', 'Disease', (228, 251))	('anti-PD-1', 'Var', (137, 146))	('cell death', 'CPA', (183, 193))
569771	32209571	The addition of anti-IFNAR and BX-795 to combined AZD1775 and ICB therapy (triple combination) significantly reduced cell death of JH716 tumoroids treated with AZD1775 and ICB (p<0.0001; Figure 3C).	('tumor', 'Disease', (137, 142))	('tumor', 'Disease', 'MESH:D009369', (137, 142))	('ICB', 'Chemical', '-', (62, 65))	('IFNAR', 'Gene', (21, 26))	('tumor', 'Phenotype', 'HP:0002664', (137, 142))	('IFNAR', 'Gene', '15975', (21, 26))	('JH716', 'Chemical', '-', (131, 136))	('cell death', 'CPA', (117, 127))	('AZD1775', 'Var', (160, 167))	('reduced', 'NegReg', (109, 116))	('AZD1775', 'Chemical', 'MESH:C549567', (160, 167))	('AZD1775', 'Chemical', 'MESH:C549567', (50, 57))	('ICB', 'Chemical', '-', (172, 175))
569773	32209571	AZD1775 alone was not sufficient to reduce tumor growth in JH716 mice (Figure 3E and S6A-B).	('AZD1775', 'Var', (0, 7))	('JH716', 'Chemical', '-', (59, 64))	('AZD1775', 'Chemical', 'MESH:C549567', (0, 7))	('tumor', 'Disease', 'MESH:D009369', (43, 48))	('mice', 'Species', '10090', (65, 69))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('tumor', 'Disease', (43, 48))
569774	32209571	However, combined AZD1775 and anti-PD-1 treatment led to significant tumor regression compared to single agents or vehicle-treated control mice, showing 97% tumor growth inhibition and nearly 60% (3/5) complete tumor remissions (Figure 3E).	('tumor', 'Disease', (157, 162))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('tumor', 'Disease', 'MESH:D009369', (211, 216))	('tumor', 'Disease', (69, 74))	('tumor', 'Disease', 'MESH:D009369', (157, 162))	('AZD1775', 'Var', (18, 25))	('AZD1775', 'Chemical', 'MESH:C549567', (18, 25))	('tumor', 'Phenotype', 'HP:0002664', (211, 216))	('tumor', 'Disease', (211, 216))	('mice', 'Species', '10090', (139, 143))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
569778	32209571	We further validated whether AZD1775 complements PD-1 blockade in another myeloid-enriched syngeneic mouse model, KLN205, that is refractory to anti-PD-1 therapy and has lower tumor immune infiltrate (CD45+ cells) relative to JH716 tumors (Figure S6C).	('tumor', 'Phenotype', 'HP:0002664', (176, 181))	('JH716', 'Chemical', '-', (226, 231))	('tumors', 'Phenotype', 'HP:0002664', (232, 238))	('tumors', 'Disease', 'MESH:D009369', (232, 238))	('tumor', 'Disease', (176, 181))	('tumor', 'Disease', 'MESH:D009369', (232, 237))	('mouse', 'Species', '10090', (101, 106))	('tumor', 'Phenotype', 'HP:0002664', (232, 237))	('AZD1775', 'Var', (29, 36))	('KLN205', 'Var', (114, 120))	('lower', 'NegReg', (170, 175))	('tumor', 'Disease', (232, 237))	('AZD1775', 'Chemical', 'MESH:C549567', (29, 36))	('tumor', 'Disease', 'MESH:D009369', (176, 181))	('tumors', 'Disease', (232, 238))
569779	32209571	Similar to JH716 tumors, we observed KLN205 models were unresponsive to AZD1775 or anti-PD-1 alone but showed significant tumor growth inhibition in the combined treatment relative to anti-PD-1 or AZD1775 monotherapy, though we did not observe complete regressions (Figure 3F).	('tumor', 'Phenotype', 'HP:0002664', (17, 22))	('tumors', 'Phenotype', 'HP:0002664', (17, 23))	('tumor', 'Disease', (17, 22))	('AZD1775', 'Chemical', 'MESH:C549567', (197, 204))	('tumors', 'Disease', (17, 23))	('tumors', 'Disease', 'MESH:D009369', (17, 23))	('JH716', 'Chemical', '-', (11, 16))	('AZD1775', 'Chemical', 'MESH:C549567', (72, 79))	('tumor', 'Disease', 'MESH:D009369', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (122, 127))	('tumor', 'Disease', 'MESH:D009369', (17, 22))	('KLN205', 'Var', (37, 43))	('tumor', 'Disease', (122, 127))
569780	32209571	Given the potent anti-tumor effect of combined AZD1775 and ICB therapy, we next evaluated how this compared to chemotherapy and ICB dual therapy, which is currently FDA-approved for NSCLCs.	('ICB', 'Chemical', '-', (128, 131))	('AZD1775', 'Chemical', 'MESH:C549567', (47, 54))	('NSCLCs', 'Disease', 'MESH:D002289', (182, 188))	('tumor', 'Disease', 'MESH:D009369', (22, 27))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('tumor', 'Disease', (22, 27))	('NSCLC', 'Phenotype', 'HP:0030358', (182, 187))	('NSCLCs', 'Disease', (182, 188))	('AZD1775', 'Var', (47, 54))	('ICB', 'Chemical', '-', (59, 62))
569782	32209571	Survival analysis up to terminal tumor volume (20mm length) showed significant prolonged survival of mice (with 5/13 complete tumor regressions) in the AZD1775 and anti-PD-1 combination group compared to single-agent treated arms (Figure 3G).	('anti-PD-1', 'Gene', (164, 173))	('tumor', 'Disease', 'MESH:D009369', (33, 38))	('tumor', 'Phenotype', 'HP:0002664', (126, 131))	('prolonged', 'PosReg', (79, 88))	('AZD1775', 'Var', (152, 159))	('tumor', 'Phenotype', 'HP:0002664', (33, 38))	('tumor', 'Disease', 'MESH:D009369', (126, 131))	('mice', 'Species', '10090', (101, 105))	('tumor', 'Disease', (33, 38))	('AZD1775', 'Chemical', 'MESH:C549567', (152, 159))	('combination', 'Var', (174, 185))	('tumor', 'Disease', (126, 131))
569783	32209571	Similarly, combined carboplatin and anti-PD-1 also achieved significant survival benefit with 6/13 complete tumor regressions, suggesting that WEE1 inhibition may have comparable anti-tumor immunity as chemotherapy in our JH716-18 models.	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('inhibition', 'NegReg', (148, 158))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('tumor', 'Disease', (108, 113))	('carboplatin', 'Chemical', 'MESH:D016190', (20, 31))	('tumor', 'Disease', (184, 189))	('survival', 'CPA', (72, 80))	('anti-PD-1', 'Var', (36, 45))	('JH716', 'Chemical', '-', (222, 227))
569785	32209571	Consistently, we observed that combining WEE1 inhibition with ICB therapy markedly extended survival in treated KLN205 mice (Figure 3H).	('mice', 'Species', '10090', (119, 123))	('survival', 'CPA', (92, 100))	('inhibition', 'NegReg', (46, 56))	('WEE1', 'Protein', (41, 45))	('extended', 'PosReg', (83, 91))	('ICB', 'Chemical', '-', (62, 65))	('KLN205', 'Var', (112, 118))
569786	32209571	Multiplexed cytokine profiling of JH716-18 tumors after 1-week of treatment revealed that co-treatment with AZD1775 and anti-PD-1 downregulated levels of G-CSF, GM-CSF, CXCL2, and CXCL1, which are neutrophil chemoattractants, and increased levels of CCL5, which may enhance NK and T cell recruitment, relative to vehicle controls (Figure 3I).	('downregulated', 'NegReg', (130, 143))	('G-CSF', 'Gene', '100036204', (154, 159))	('AZD1775', 'Chemical', 'MESH:C549567', (108, 115))	('CXCL2', 'Gene', (169, 174))	('CXCL1', 'Gene', (180, 185))	('CXCL1', 'Gene', '14825', (180, 185))	('AZD1775', 'Var', (108, 115))	('CXCL2', 'Gene', '20310', (169, 174))	('T cell recruitment', 'CPA', (281, 299))	('enhance', 'PosReg', (266, 273))	('CCL5', 'Gene', (250, 254))	('tumors', 'Phenotype', 'HP:0002664', (43, 49))	('anti-PD-1', 'Gene', (120, 129))	('JH716', 'Chemical', '-', (34, 39))	('tumor', 'Phenotype', 'HP:0002664', (43, 48))	('increased', 'PosReg', (230, 239))	('tumors', 'Disease', (43, 49))	('GM-CSF', 'Gene', '12981', (161, 167))	('JH716-18', 'Gene', (34, 42))	('G-CSF', 'Gene', (154, 159))	('GM-CSF', 'Gene', (161, 167))	('CCL5', 'Gene', '20304', (250, 254))	('tumors', 'Disease', 'MESH:D009369', (43, 49))
569787	32209571	We next sought to determine how WEE1 inhibition and combined treatment may affect the quantity and subsequent recruitment of tumor-associated immune cell populations.	('tumor', 'Disease', 'MESH:D009369', (125, 130))	('inhibition', 'Var', (37, 47))	('WEE1', 'Protein', (32, 36))	('tumor', 'Phenotype', 'HP:0002664', (125, 130))	('quantity', 'CPA', (86, 94))	('tumor', 'Disease', (125, 130))	('affect', 'Reg', (75, 81))
569788	32209571	Using flow cytometry, we analyzed the tumor-infiltrating lymphoid and myeloid cell populations at 14 days post-treatment in JH716 mice (Figure 4A-I) and 9 days post-treatment in KLN205 mice (Figure 4J-Q).	('tumor', 'Phenotype', 'HP:0002664', (38, 43))	('tumor', 'Disease', (38, 43))	('mice', 'Species', '10090', (130, 134))	('KLN205', 'Var', (178, 184))	('JH716', 'Var', (124, 129))	('mice', 'Species', '10090', (185, 189))	('tumor', 'Disease', 'MESH:D009369', (38, 43))	('JH716', 'Chemical', '-', (124, 129))
569794	32209571	In KLN205 tumor-bearing mice, we also observed significantly increased CD8+ TILs in the combination-treated tumors compared to anti-PD-1 and isotype controls (Figure 4J).	('tumor', 'Phenotype', 'HP:0002664', (10, 15))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('CD8', 'Gene', '925', (71, 74))	('KLN205', 'Var', (3, 9))	('mice', 'Species', '10090', (24, 28))	('tumor', 'Disease', (10, 15))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('tumor', 'Disease', (108, 113))	('increased', 'PosReg', (61, 70))	('tumors', 'Disease', (108, 114))	('tumors', 'Disease', 'MESH:D009369', (108, 114))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))	('tumor', 'Disease', 'MESH:D009369', (10, 15))	('CD8', 'Gene', (71, 74))
569795	32209571	In fact, AZD1775 alone increased NK infiltration (Figure 4K).	('NK infiltration', 'CPA', (33, 48))	('AZD1775', 'Var', (9, 16))	('increased', 'PosReg', (23, 32))	('AZD1775', 'Chemical', 'MESH:C549567', (9, 16))
569796	32209571	Consistent with JH716 tumors, combined therapy had no significant effects on inflamed monocytes or dendritic cells, but significantly reduced TANs in KLN205 tumors relative to isotype controls (Figure 4N-Q).	('tumors', 'Phenotype', 'HP:0002664', (22, 28))	('KLN205', 'Var', (150, 156))	('tumors', 'Phenotype', 'HP:0002664', (157, 163))	('tumors', 'Disease', 'MESH:D009369', (22, 28))	('tumors', 'Disease', (157, 163))	('tumors', 'Disease', 'MESH:D009369', (157, 163))	('tumor', 'Phenotype', 'HP:0002664', (22, 27))	('TANs', 'MPA', (142, 146))	('reduced', 'NegReg', (134, 141))	('tumor', 'Phenotype', 'HP:0002664', (157, 162))	('TANs', 'Chemical', '-', (142, 146))	('tumors', 'Disease', (22, 28))	('JH716', 'Chemical', '-', (16, 21))
569798	32209571	In vivo interrogation of the function of genes implicated in tumorigenesis is limited by the resource-intensive need to generate and cross mice bearing multiple, distinct engineered inducible mutant alleles.	('mutant', 'Var', (192, 198))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('mice', 'Species', '10090', (139, 143))	('tumor', 'Disease', (61, 66))
569801	32209571	Here we demonstrate a successful organoid culture approach where lung squamous cell carcinoma is induced by CRISPR-Cas9-based multiplex editing of TP53, PTEN and CDKN2A (p16) tumor suppressor genes in lung epithelial cells derived from a SOX2-conditionally expressing transgenic mouse.	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (70, 93))	('tumor', 'Disease', (175, 180))	('TP53', 'Gene', (147, 151))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (65, 93))	('CRISPR', 'Gene', (108, 114))	('editing', 'Var', (136, 143))	('carcinoma', 'Phenotype', 'HP:0030731', (84, 93))	('mouse', 'Species', '10090', (279, 284))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (65, 93))	('lung squamous cell carcinoma', 'Disease', (65, 93))	('Cas9', 'Chemical', '-', (115, 119))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('CDKN2A (p16', 'Gene', (162, 173))	('CRISPR', 'Gene', '70873', (108, 114))	('induced by', 'Reg', (97, 107))
569805	32209571	In the last five years, clinical trials have demonstrated that inhibitors of PD-1 are effective in the treatment of squamous and non-squamous NSCLC.	('non-squamous NSCLC', 'Disease', 'MESH:D002294', (129, 147))	('inhibitors', 'Var', (63, 73))	('NSCLC', 'Phenotype', 'HP:0030358', (142, 147))	('non-squamous NSCLC', 'Disease', (129, 147))	('PD-1', 'Gene', (77, 81))
569810	32209571	Similar to the chemotherapeutics' reliance on DSB formation to drive tumor cell killing, we and others have previously shown that selective inhibition of WEE1, a negative regulator of a CDK1, leads to potent DSB formation due to exacerbated mitotic catastrophe in deregulated cancer cells.	('DSB formation', 'MPA', (208, 221))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('cancer', 'Disease', (276, 282))	('cancer', 'Disease', 'MESH:D009369', (276, 282))	('tumor', 'Disease', (69, 74))	('inhibition', 'Var', (140, 150))	('exacerbated', 'PosReg', (229, 240))	('cancer', 'Phenotype', 'HP:0002664', (276, 282))	('mitotic catastrophe', 'CPA', (241, 260))	('WEE1', 'Gene', (154, 158))	('tumor', 'Disease', 'MESH:D009369', (69, 74))
569812	32209571	Indeed, we show that AZD1775 and WEE1i treatment in vitro potently increases expression of antigen processing and presentation genes in both mouse and patient-derived LSCC xenograft cell lines, which correlates with DSB as measured by increased gammaH2AX foci formation in tumor cells.	('AZD1775', 'Var', (21, 28))	('expression', 'MPA', (77, 87))	('gammaH2AX', 'Gene', '15270', (245, 254))	('tumor', 'Disease', 'MESH:D009369', (273, 278))	('AZD1775', 'Chemical', 'MESH:C549567', (21, 28))	('LSCC', 'Phenotype', 'HP:0030359', (167, 171))	('patient', 'Species', '9606', (151, 158))	('increases', 'PosReg', (67, 76))	('increased', 'PosReg', (235, 244))	('gammaH2AX', 'Gene', (245, 254))	('DSB', 'Disease', (216, 219))	('mouse', 'Species', '10090', (141, 146))	('tumor', 'Phenotype', 'HP:0002664', (273, 278))	('tumor', 'Disease', (273, 278))	('antigen', 'MPA', (91, 98))	('WEE1i', 'Var', (33, 38))	('expression', 'Species', '29278', (77, 87))
569814	32209571	Consistent with this, we demonstrate that activation of CDK1 by AZD1775 treatment not only induces STAT1 phosphorylation at Y701 in a time-dependent manner, but also increases ISG expression in tumor cells, likely explaining their enhanced capacity for antigen presentation.	('AZD1775', 'Chemical', 'MESH:C549567', (64, 71))	('STAT1', 'Gene', '20846', (99, 104))	('tumor', 'Disease', 'MESH:D009369', (194, 199))	('Y701', 'Var', (124, 128))	('expression', 'Species', '29278', (180, 190))	('tumor', 'Phenotype', 'HP:0002664', (194, 199))	('increases', 'PosReg', (166, 175))	('STAT1', 'Gene', (99, 104))	('induces', 'Reg', (91, 98))	('activation', 'PosReg', (42, 52))	('tumor', 'Disease', (194, 199))	('AZD1775', 'Gene', (64, 71))	('ISG', 'Protein', (176, 179))	('CDK1', 'Gene', (56, 60))
569815	32209571	Along similar lines, Goel and colleagues recently showed that CDK4/6 inhibition induced cell cycle arrest that resulted in global upregulation of an IFN-driven transitional program and viral mimicry on breast cancer cells.	('CDK4/6', 'Gene', '12567;12571', (62, 68))	('viral mimicry', 'CPA', (185, 198))	('breast cancer', 'Disease', 'MESH:D001943', (202, 215))	('cell cycle arrest', 'Phenotype', 'HP:0011018', (88, 105))	('breast cancer', 'Disease', (202, 215))	('breast cancer', 'Phenotype', 'HP:0003002', (202, 215))	('IFN', 'Gene', '3439', (149, 152))	('upregulation', 'PosReg', (130, 142))	('CDK4/6', 'Gene', (62, 68))	('arrest', 'Disease', 'MESH:D006323', (99, 105))	('inhibition', 'Var', (69, 79))	('IFN', 'Gene', (149, 152))	('arrest', 'Disease', (99, 105))	('cancer', 'Phenotype', 'HP:0002664', (209, 215))
569816	32209571	For instance, Cribier and colleagues identified that CDK1 phosphorylates SAMHD1 at residue Thr592, directly inhibiting its antiviral restriction activity.	('CDK1', 'Gene', (53, 57))	('SAMHD1', 'Gene', '25939', (73, 79))	('antiviral restriction activity', 'MPA', (123, 153))	('Thr592', 'Var', (91, 97))	('inhibiting', 'NegReg', (108, 118))	('Thr592', 'Chemical', '-', (91, 97))	('SAMHD1', 'Gene', (73, 79))
569818	32209571	Depletion of SAMHD1 leads to enhanced antigen presentation and chronic type I IFN secretion upon HIV-1 infection and facilities T cell responses in co-culture models.	('HIV-1 infection', 'Disease', 'MESH:D015658', (97, 112))	('IFN', 'Gene', '3439', (78, 81))	('SAMHD1', 'Gene', (13, 19))	('facilities T cell responses', 'CPA', (117, 144))	('IFN', 'Gene', (78, 81))	('Depletion', 'Var', (0, 9))	('antigen presentation', 'MPA', (38, 58))	('SAMHD1', 'Gene', '25939', (13, 19))	('enhanced', 'PosReg', (29, 37))	('HIV-1 infection', 'Disease', (97, 112))
569819	32209571	Further studies will be necessary to carefully interrogate whether SAMHD1 or other interacting partners of CDK1 may be mediating the IFN response upon AZD1775 treatment, rendering the tumor microenvironment more permissive to T or NK cell infiltration.	('IFN', 'Gene', '3439', (133, 136))	('tumor', 'Disease', 'MESH:D009369', (184, 189))	('AZD1775', 'Var', (151, 158))	('AZD1775', 'Chemical', 'MESH:C549567', (151, 158))	('tumor', 'Phenotype', 'HP:0002664', (184, 189))	('IFN', 'Gene', (133, 136))	('mediating', 'Reg', (119, 128))	('SAMHD1', 'Gene', '25939', (67, 73))	('tumor', 'Disease', (184, 189))	('CDK1', 'Gene', (107, 111))	('more', 'PosReg', (207, 211))	('SAMHD1', 'Gene', (67, 73))
569823	32209571	Our in vivo efficacy studies demonstrate that co-treatment with anti-PD-1 and AZD1775 significantly reduces tumor growth and TAN infiltration post-combination treatment in JH716 and KLN205 tumors.	('AZD1775', 'Chemical', 'MESH:C549567', (78, 85))	('tumor', 'Disease', 'MESH:D009369', (108, 113))	('anti-PD-1', 'Gene', (64, 73))	('tumor', 'Disease', (189, 194))	('TAN', 'Chemical', '-', (125, 128))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('reduces', 'NegReg', (100, 107))	('JH716', 'Chemical', '-', (172, 177))	('tumors', 'Disease', (189, 195))	('tumor', 'Disease', (108, 113))	('tumors', 'Disease', 'MESH:D009369', (189, 195))	('tumors', 'Phenotype', 'HP:0002664', (189, 195))	('tumor', 'Disease', 'MESH:D009369', (189, 194))	('TAN infiltration', 'CPA', (125, 141))	('AZD1775', 'Gene', (78, 85))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('JH716', 'Var', (172, 177))
569824	32209571	Consistently, we found that treatment with AZD1775 in JH716 mice resulted in reduced levels of neutrophil chemoattractant G-CSF.	('JH716', 'Chemical', '-', (54, 59))	('AZD1775', 'Chemical', 'MESH:C549567', (43, 50))	('G-CSF', 'Gene', (122, 127))	('G-CSF', 'Gene', '100036204', (122, 127))	('reduced', 'NegReg', (77, 84))	('mice', 'Species', '10090', (60, 64))	('AZD1775', 'Var', (43, 50))
569828	32209571	Consistently, we observed an inverse correlation between TAN abundance and increased CD8+ T and NK cells in our JH716 and KLN205 tumors treated with dual therapy.	('KLN205', 'Var', (122, 128))	('tumors', 'Disease', (129, 135))	('tumors', 'Disease', 'MESH:D009369', (129, 135))	('CD8', 'Gene', (85, 88))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('CD8', 'Gene', '925', (85, 88))	('TAN', 'Chemical', '-', (57, 60))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('increased', 'PosReg', (75, 84))	('JH716', 'Chemical', '-', (112, 117))
569830	32209571	Given that emerging data suggest that neutrophils contribute to anti-PD-1 resistance, further studies are needed to delineate the mechanistic basis of how combined anti-PD-1 and AZD1775 reduces TAN infiltration.	('TAN', 'Chemical', '-', (194, 197))	('AZD1775', 'Chemical', 'MESH:C549567', (178, 185))	('anti-PD-1', 'Var', (164, 173))	('reduces', 'NegReg', (186, 193))	('TAN infiltration', 'MPA', (194, 210))	('AZD1775', 'Var', (178, 185))
569832	32209571	Thus, it would be interesting to examine whether AZD1775-induced DNA damage directly mediates neutrophil homeostasis by either deregulating signaling of its trafficking receptors (i.e., CXCR2) or apoptotic response.	('deregulating', 'NegReg', (127, 139))	('AZD1775', 'Chemical', 'MESH:C549567', (49, 56))	('signaling', 'MPA', (140, 149))	('apoptotic response', 'CPA', (196, 214))	('AZD1775-induced', 'Var', (49, 64))	('CXCR2', 'Gene', (186, 191))	('CXCR2', 'Gene', '12765', (186, 191))	('mediates', 'Reg', (85, 93))	('neutrophil homeostasis', 'MPA', (94, 116))
569833	32209571	In addition to the reduction of TANs, we also observed that AZD1775 combined with ICB therapy led to increased NK cell infiltration.	('NK cell infiltration', 'CPA', (111, 131))	('increased', 'PosReg', (101, 110))	('ICB', 'Chemical', '-', (82, 85))	('AZD1775', 'Var', (60, 67))	('TANs', 'Chemical', '-', (32, 36))	('AZD1775', 'Chemical', 'MESH:C549567', (60, 67))
569842	32209571	We generated two cell lines, JH715 and JH716, harboring SOX2;PTEN;CDKN2A;TP53 alterations.	('SOX2;PTEN;CDKN2A;TP53', 'Gene', (56, 77))	('CDKN2A;TP53', 'Gene', (66, 77))	('TP53', 'Gene', (73, 77))	('alterations', 'Var', (78, 89))	('JH716', 'Chemical', '-', (39, 44))	('PTEN;CDKN2A;TP53', 'Gene', (61, 77))
569845	32209571	Our work illustrates the challenges in understanding which cooperating mutations potentiate LSCC, since not all genotypes lead to LSCC in mice.	('LSCC', 'Disease', (92, 96))	('LSCC', 'Phenotype', 'HP:0030359', (92, 96))	('mice', 'Species', '10090', (138, 142))	('LSCC', 'Phenotype', 'HP:0030359', (130, 134))	('mutations', 'Var', (71, 80))	('potentiate', 'PosReg', (81, 91))
569846	32209571	Consistent with our data, Bern's group have also demonstrated that various combinations of genetic lesions can determine different cell fates and showed that SOX2;PTEN;CDKN2A transgenic mice gave rise to LSCC tumors in 7-9 months with a 73% penetrance, while FGFR;PTEN;CDKN2NA mice had 19% SCC penetrance.	('LSCC tumors', 'Disease', 'MESH:D009369', (204, 215))	('mice', 'Species', '10090', (277, 281))	('tumors', 'Phenotype', 'HP:0002664', (209, 215))	('LSCC tumors', 'Disease', (204, 215))	('LSCC', 'Phenotype', 'HP:0030359', (204, 208))	('transgenic', 'Var', (175, 185))	('mice', 'Species', '10090', (186, 190))	('transgenic mice', 'Species', '10090', (175, 190))	('SOX2', 'Var', (158, 162))	('tumor', 'Phenotype', 'HP:0002664', (209, 214))
569847	32209571	Sequencing of JH716 tumors also revealed mutations in genes not known to drive LSCC (data not shown).	('mutations', 'Var', (41, 50))	('tumors', 'Disease', 'MESH:D009369', (20, 26))	('tumors', 'Disease', (20, 26))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('JH716', 'Gene', (14, 19))	('JH716', 'Chemical', '-', (14, 19))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))	('LSCC', 'Phenotype', 'HP:0030359', (79, 83))
569848	32209571	We believe that the combined effects of deleting genes in the DNA damage repair/cell cycle machinery during long term in vivo culturing leads to accumulation of passenger mutations that help facilitate rapid LSCC tumorigenesis.	('LSCC', 'Phenotype', 'HP:0030359', (208, 212))	('accumulation', 'PosReg', (145, 157))	('LSCC tumor', 'Disease', (208, 218))	('deleting genes', 'Var', (40, 54))	('facilitate', 'PosReg', (191, 201))	('genes', 'Var', (49, 54))	('LSCC tumor', 'Disease', 'MESH:D009369', (208, 218))	('tumor', 'Phenotype', 'HP:0002664', (213, 218))
569851	32209571	We demonstrated for the first time that CDK1 activation via WEE1 inhibition can induce DSB-stimulated type I interferon signaling and antigen presentation in mouse and patient-derived LSCC tumors.	('CDK1', 'Protein', (40, 44))	('mouse', 'Species', '10090', (158, 163))	('DSB-stimulated type I interferon signaling', 'MPA', (87, 129))	('antigen presentation', 'MPA', (134, 154))	('tumor', 'Phenotype', 'HP:0002664', (189, 194))	('LSCC tumors', 'Disease', (184, 195))	('WEE1', 'Gene', (60, 64))	('patient', 'Species', '9606', (168, 175))	('tumors', 'Phenotype', 'HP:0002664', (189, 195))	('induce', 'PosReg', (80, 86))	('inhibition', 'Var', (65, 75))	('activation', 'PosReg', (45, 55))	('LSCC', 'Phenotype', 'HP:0030359', (184, 188))	('LSCC tumors', 'Disease', 'MESH:D009369', (184, 195))
569853	32209571	While we did observe some inhibitory activity in non-transformed cells treated with AZD1775, we believe that cancer cells with high replicative stress are more vulnerable and therefore we speculate that selectively activating CDK1 by AZD1775 may minimize the off-target side effects associated with chemotherapy while augmenting anti-tumor immunity.	('tumor', 'Disease', 'MESH:D009369', (334, 339))	('AZD1775', 'Var', (234, 241))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('stress', 'Disease', 'MESH:D000079225', (144, 150))	('tumor', 'Phenotype', 'HP:0002664', (334, 339))	('cancer', 'Disease', (109, 115))	('AZD1775', 'Chemical', 'MESH:C549567', (234, 241))	('tumor', 'Disease', (334, 339))	('CDK1', 'Gene', (226, 230))	('augmenting', 'NegReg', (318, 328))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('AZD1775', 'Chemical', 'MESH:C549567', (84, 91))	('stress', 'Disease', (144, 150))	('activating', 'PosReg', (215, 225))
569855	32209571	In fact, phase I trials (NCT00648648) of AZD1775 and chemotherapy showed responding patients with advanced solid tumors were mildly enriched for p53 mutations (response rate of 21% and 12% in p53 mutant and p53 wild-type, respectively), supporting the notion that patient selection may be necessary to obtain the maximum benefit from AZD1775 and ICB combination therapy.	('mutations', 'Var', (149, 158))	('tumors', 'Disease', (113, 119))	('p53', 'Gene', (145, 148))	('tumors', 'Disease', 'MESH:D009369', (113, 119))	('patients', 'Species', '9606', (84, 92))	('AZD1775', 'Chemical', 'MESH:C549567', (41, 48))	('AZD1775', 'Chemical', 'MESH:C549567', (334, 341))	('patient', 'Species', '9606', (84, 91))	('patient', 'Species', '9606', (264, 271))	('tumor', 'Phenotype', 'HP:0002664', (113, 118))	('p53', 'Gene', (192, 195))	('ICB', 'Chemical', '-', (346, 349))	('mutant', 'Var', (196, 202))	('tumors', 'Phenotype', 'HP:0002664', (113, 119))
569856	32209571	Yet another possibility is that relapsed p53 mutant tumors relying on G2/M checkpoint may be more responsive to AZD1775 and ICB combination therapy than tumors with intact G1 checkpoint.	('tumor', 'Phenotype', 'HP:0002664', (52, 57))	('relapsed', 'Disease', (32, 40))	('ICB', 'Chemical', '-', (124, 127))	('mutant', 'Var', (45, 51))	('AZD1775', 'Chemical', 'MESH:C549567', (112, 119))	('tumors', 'Phenotype', 'HP:0002664', (52, 58))	('responsive', 'MPA', (98, 108))	('tumors', 'Disease', (52, 58))	('tumors', 'Disease', 'MESH:D009369', (52, 58))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('tumors', 'Disease', (153, 159))	('tumors', 'Phenotype', 'HP:0002664', (153, 159))	('tumors', 'Disease', 'MESH:D009369', (153, 159))
569857	32209571	Future studies may also evaluate whether triple combinations such as AZD1775, PARPi and ICB therapies targeting both G1, G2, and immune checkpoints may reach improved efficacy.	('AR', 'Gene', '14149', (79, 81))	('AZD1775', 'Var', (69, 76))	('ICB', 'Chemical', '-', (88, 91))	('ICB', 'Gene', (88, 91))	('AZD1775', 'Chemical', 'MESH:C549567', (69, 76))
569860	31406302	Co-occurring genomic alterations in non-small cell lung cancer biology and therapy The impressive clinical activity of small molecule receptor tyrosine kinase inhibitors (TKIs) for oncogene-addicted subgroups of non-small cell lung cancer (NSCLC) [for example those driven by activating mutations in the gene encoding epidermal growth factor receptor (EGFR) or rearrangements in the genes encoding the receptor tyrosine kinases anaplastic lymphoma kinase (ALK), ROS proto-oncogene 1 (ROS1), and rearranged during transfection (RET)] has established an oncogene-centric molecular classification paradigm in this disease.	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (212, 238))	('tyrosine kinase', 'Gene', '7294', (143, 158))	('epidermal growth factor receptor', 'Gene', '1956', (318, 350))	('ROS1', 'Gene', (484, 488))	('non-small cell lung cancer', 'Disease', (36, 62))	('mutations', 'Var', (287, 296))	('lung cancer', 'Phenotype', 'HP:0100526', (51, 62))	('cancer', 'Phenotype', 'HP:0002664', (232, 238))	('lymphoma', 'Phenotype', 'HP:0002665', (439, 447))	('tyrosine kinase', 'Gene', (411, 426))	('ALK', 'Gene', '238', (456, 459))	('tyrosine kinase', 'Gene', '7294', (411, 426))	('RET', 'Gene', (527, 530))	('cancer', 'Phenotype', 'HP:0002664', (56, 62))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (212, 238))	('ALK', 'Gene', (456, 459))	('activating', 'PosReg', (276, 286))	('EGFR', 'Gene', (352, 356))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (36, 62))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (216, 238))	('lymphoma', 'Disease', (439, 447))	('NSCLC', 'Disease', 'MESH:D002289', (240, 245))	('lymphoma', 'Disease', 'MESH:D008223', (439, 447))	('rearrangements', 'Var', (361, 375))	('ROS proto-oncogene 1', 'Gene', '6098', (462, 482))	('ROS1', 'Gene', '6098', (484, 488))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (40, 62))	('non-small cell lung cancer', 'Disease', (212, 238))	('NSCLC', 'Disease', (240, 245))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (36, 62))	('anaplastic lymphoma', 'Phenotype', 'HP:0012193', (428, 447))	('lung cancer', 'Phenotype', 'HP:0100526', (227, 238))	('tyrosine kinase', 'Gene', (143, 158))	('EGFR', 'Gene', '1956', (352, 356))	('ROS proto-oncogene 1', 'Gene', (462, 482))	('epidermal growth factor receptor', 'Gene', (318, 350))	('RET', 'Gene', '5979', (527, 530))
569862	31406302	Co-occurring genomic alterations, particularly in tumor suppressor genes such as TP53 and LKB1 (also known as STK11), have emerged as core determinants of the molecular and clinical heterogeneity of oncogene-driven lung cancer subgroups through their effects on both tumor cell-intrinsic and non-cell-autonomous cancer hallmarks.	('lung cancer', 'Disease', (215, 226))	('tumor', 'Disease', 'MESH:D009369', (267, 272))	('TP53', 'Gene', '7157', (81, 85))	('STK11', 'Gene', '6794', (110, 115))	('cancer', 'Phenotype', 'HP:0002664', (312, 318))	('cancer hallmarks', 'Disease', (312, 328))	('lung cancer', 'Disease', 'MESH:D008175', (215, 226))	('tumor', 'Phenotype', 'HP:0002664', (267, 272))	('effects', 'Reg', (251, 258))	('lung cancer', 'Phenotype', 'HP:0100526', (215, 226))	('tumor', 'Disease', (50, 55))	('cancer hallmarks', 'Disease', 'MESH:D009369', (312, 328))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('LKB1', 'Gene', (90, 94))	('TP53', 'Gene', (81, 85))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('STK11', 'Gene', (110, 115))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Disease', (267, 272))	('alterations', 'Var', (21, 32))
569863	31406302	In this review, we discuss the impact of co-mutations on the pathogenesis, biology, micro-environmental interactions, and therapeutic vulnerabilities of NSCLC and assess the challenges and opportunities that co-mutations present for personalized anti-cancer therapy, as well as the expanding field of precision immunotherapy.	('cancer', 'Phenotype', 'HP:0002664', (251, 257))	('NSCLC', 'Disease', (153, 158))	('cancer', 'Disease', 'MESH:D009369', (251, 257))	('NSCLC', 'Disease', 'MESH:D002289', (153, 158))	('co-mutations', 'Var', (41, 53))	('cancer', 'Disease', (251, 257))
569866	31406302	The identification in 2004 of activating oncogenic mutations in the tyrosine kinase domain of epidermal growth factor receptor (EGFR) in a subset of patients with non-small cell lung cancer (NSCLC) that exhibited dramatic clinical responses to the first-generation EGFR tyrosine kinase inhibitor (TKI) gefitinib launched the field of targeted therapy in NSCLC and reinforced the concept of oncogene addiction as a pillar of modern cancer therapeutics.	('mutations', 'Var', (51, 60))	('non-small cell lung cancer', 'Disease', (163, 189))	('lung cancer', 'Phenotype', 'HP:0100526', (178, 189))	('gefitinib', 'Chemical', 'MESH:D000077156', (302, 311))	('cancer', 'Disease', (431, 437))	('epidermal growth factor receptor', 'Gene', (94, 126))	('NSCLC', 'Disease', (191, 196))	('cancer', 'Phenotype', 'HP:0002664', (431, 437))	('epidermal growth factor receptor', 'Gene', '1956', (94, 126))	('patients', 'Species', '9606', (149, 157))	('cancer', 'Disease', (183, 189))	('tyrosine kinase', 'Gene', (68, 83))	('EGFR', 'Gene', (128, 132))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (167, 189))	('NSCLC', 'Disease', 'MESH:D002289', (354, 359))	('non-small cell lung cancer', 'Phenotype', 'HP:0030358', (163, 189))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('EGFR', 'Gene', (265, 269))	('tyrosine kinase', 'Gene', '7294', (68, 83))	('activating', 'PosReg', (30, 40))	('cancer', 'Disease', 'MESH:D009369', (431, 437))	('NSCLC', 'Disease', (354, 359))	('non-small cell lung cancer', 'Disease', 'MESH:D002289', (163, 189))	('cancer', 'Disease', 'MESH:D009369', (183, 189))	('tyrosine kinase', 'Gene', (270, 285))	('EGFR', 'Gene', '1956', (128, 132))	('EGFR', 'Gene', '1956', (265, 269))	('NSCLC', 'Disease', 'MESH:D002289', (191, 196))	('tyrosine kinase', 'Gene', '7294', (270, 285))
569868	31406302	Since then, several additional driver events with robust transforming potential have been reported, including oncogenic ROS1, RET, NTRK1 and NRG1 fusions, oncogenic somatic mutations in BRAF (V600E and non-V600E), intragenic insertions in ERBB2 (also known as HER2) and exon 14 skipping mutations in the MET proto-oncogene.	('MET', 'Gene', (304, 307))	('ROS1', 'Gene', (120, 124))	('NTRK1', 'Gene', '4914', (131, 136))	('ERBB2', 'Gene', (239, 244))	('NTRK1', 'Gene', (131, 136))	('HER2', 'Gene', (260, 264))	('ERBB2', 'Gene', '2064', (239, 244))	('RET', 'Gene', '5979', (126, 129))	('insertions', 'Var', (225, 235))	('exon 14 skipping mutations', 'Var', (270, 296))	('fusions', 'Var', (146, 153))	('ROS1', 'Gene', '6098', (120, 124))	('mutations', 'Var', (173, 182))	('V600E', 'Mutation', 'rs113488022', (192, 197))	('HER2', 'Gene', '2064', (260, 264))	('NRG1', 'Gene', (141, 145))	('BRAF', 'Gene', (186, 190))	('NRG1', 'Gene', '3084', (141, 145))	('RET', 'Gene', (126, 129))	('V600E', 'Mutation', 'rs113488022', (206, 211))	('V600E', 'Var', (192, 197))
569873	31406302	In this review, we discuss the emerging role of co-occurring genomic alterations as major determinants of both tumor cell-intrinsic as well as non-cell-autonomous cancer hallmark traits, including their impact on the composition of the tumor microenvironment and response to systemic anti-cancer therapies.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('alterations', 'Var', (69, 80))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('cancer', 'Phenotype', 'HP:0002664', (289, 295))	('tumor', 'Disease', 'MESH:D009369', (236, 241))	('cancer', 'Phenotype', 'HP:0002664', (163, 169))	('tumor', 'Disease', (111, 116))	('tumor', 'Disease', (236, 241))	('tumor', 'Phenotype', 'HP:0002664', (236, 241))	('cancer', 'Disease', 'MESH:D009369', (289, 295))	('cancer', 'Disease', (163, 169))	('cancer', 'Disease', 'MESH:D009369', (163, 169))	('cancer', 'Disease', (289, 295))
569876	31406302	For example, KRAS-mutant lung adenocarcinomas (LUADs) demonstrate dual propensity towards either solid growth pattern with positivity for the NKX2-1 homeobox transcription factor (also known as TTF1) or, alternatively, invasive mucinous adenocarcinoma histology and corresponding lack of NKX2-1 expression.	('LUADs', 'Disease', (47, 52))	('carcinoma', 'Phenotype', 'HP:0030731', (35, 44))	('lung adenocarcinomas', 'Phenotype', 'HP:0030078', (25, 45))	('solid growth pattern', 'Disease', (97, 117))	('carcinoma', 'Phenotype', 'HP:0030731', (242, 251))	('carcinomas', 'Phenotype', 'HP:0030731', (35, 45))	('NKX2-1', 'Gene', (142, 148))	('invasive mucinous adenocarcinoma', 'Disease', (219, 251))	('lung adenocarcinomas', 'Disease', 'MESH:C538231', (25, 45))	('TTF1', 'Gene', '7270', (194, 198))	('KRAS-mutant', 'Var', (13, 24))	('invasive mucinous adenocarcinoma', 'Disease', 'MESH:D002288', (219, 251))	('LUADs', 'Disease', 'MESH:C538231', (47, 52))	('lung adenocarcinomas', 'Disease', (25, 45))	('TTF1', 'Gene', (194, 198))
569881	31406302	The pervasive diversity of this oncogenotype was aptly demonstrated in a study that applied affinity propagation clustering analysis to mRNA expression data from 106 genomically-annotated NSCLC cell lines; strikingly, variation in mRNA expression within KRAS-mutant NSCLC cell lines was equivalent to that observed across the entire cell line panel.	('mRNA expression', 'MPA', (231, 246))	('NSCLC', 'Disease', 'MESH:D002289', (188, 193))	('NSCLC', 'Disease', 'MESH:D002289', (266, 271))	('NSCLC', 'Disease', (266, 271))	('KRAS-mutant', 'Gene', (254, 265))	('KRAS-mutant', 'Var', (254, 265))	('NSCLC', 'Disease', (188, 193))
569884	31406302	Multiple studies have affirmed the favorable prognostic impact of exon 19 EGFR deletions compared with exon 21 L858R amino acid substitution, although the molecular basis for this association has not been conclusively determined.	('EGFR', 'Gene', '1956', (74, 78))	('EGFR', 'Gene', (74, 78))	('deletions', 'Var', (79, 88))	('L858R', 'Mutation', 'rs121434568', (111, 116))
569885	31406302	Furthermore, EGFR exon 20 in-frame insertion mutants are recalcitrant to all currently FDA-approved EGFR TKIs due to insertion-imposed steric hindrance of the drug binding pocket, but exhibit sensitivity to poziotinib - a smaller and more flexible inhibitor - in vitro and in vivo.	('EGFR', 'Gene', '1956', (100, 104))	('mutants', 'Var', (45, 52))	('EGFR', 'Gene', (100, 104))	('poziotinib - a', 'Chemical', '-', (207, 221))	('insertion mutants', 'Var', (35, 52))	('EGFR', 'Gene', '1956', (13, 17))	('EGFR', 'Gene', (13, 17))	('binding', 'Interaction', (164, 171))
569886	31406302	Among ALK-rearranged NSCLC, both the fusion partner as well as EML4-ALK fusion variantshave been considered candidate modifiers of transforming potential and response to ALK TKIs.	('ALK', 'Gene', '238', (6, 9))	('variantshave', 'Var', (79, 91))	('NSCLC', 'Disease', (21, 26))	('ALK', 'Gene', (68, 71))	('transforming potential', 'CPA', (131, 153))	('EML4', 'Gene', (63, 67))	('NSCLC', 'Disease', 'MESH:D002289', (21, 26))	('ALK', 'Gene', (6, 9))	('ALK', 'Gene', '238', (170, 173))	('ALK', 'Gene', '238', (68, 71))	('EML4', 'Gene', '27436', (63, 67))	('ALK', 'Gene', (170, 173))
569888	31406302	In addition, EML4-ALK variant 3 was associated with more frequent secondary resistance mutations (including the G1202R solvent front mutation) compared to EML4-ALK variant 1 and, consequently, longer progression-free survival with the 3rd generation ALK inhibitor lorlatinib, that is active against the EML4-ALKG1202R mutation.	('G1202R', 'Mutation', 'rs1057519783', (112, 118))	('EML4', 'Gene', (13, 17))	('ALK', 'Gene', (308, 311))	('EML4', 'Gene', '27436', (13, 17))	('G1202R', 'Mutation', 'rs1057519783', (311, 317))	('ALK', 'Gene', '238', (250, 253))	('ALK', 'Gene', (250, 253))	('G1202R', 'Var', (112, 118))	('EML4', 'Gene', (155, 159))	('solvent', 'Disease', (119, 126))	('EML4', 'Gene', '27436', (155, 159))	('longer', 'PosReg', (193, 199))	('ALK', 'Gene', '238', (18, 21))	('secondary resistance mutations', 'MPA', (66, 96))	('variant', 'Var', (22, 29))	('EML4-ALK variant 1', 'Gene', (155, 173))	('EML4', 'Gene', (303, 307))	('ALK', 'Gene', '238', (160, 163))	('progression-free survival', 'CPA', (200, 225))	('ALK', 'Gene', (18, 21))	('EML4', 'Gene', '27436', (303, 307))	('ALK', 'Gene', (160, 163))	('ALK', 'Gene', '238', (308, 311))	('EML4-ALK variant 1', 'Gene', '27436', (155, 173))	('lorlatinib', 'Chemical', 'MESH:C000590786', (264, 274))
569889	31406302	Similarly, in RET-rearranged NSCLC, non-KIF5B-RET fusions have been associated with significantly higher response rates to RXDX-105 (a RET and BRAF inhibitor) but not to the potent and selective RET inhibitor LOXO-292.	('KIF5B', 'Gene', (40, 45))	('RET', 'Gene', '5979', (195, 198))	('response rates', 'MPA', (105, 119))	('RET', 'Gene', '5979', (14, 17))	('RET', 'Gene', (46, 49))	('KIF5B', 'Gene', '3799', (40, 45))	('fusions', 'Var', (50, 57))	('RET', 'Gene', (195, 198))	('RXDX-105', 'Chemical', '-', (123, 131))	('RET', 'Gene', '5979', (46, 49))	('NSCLC', 'Disease', (29, 34))	('higher', 'PosReg', (98, 104))	('RET', 'Gene', '5979', (135, 138))	('RXDX-105', 'Gene', (123, 131))	('RET', 'Gene', (14, 17))	('LOXO-292', 'Chemical', '-', (209, 217))	('NSCLC', 'Disease', 'MESH:D002289', (29, 34))	('RET', 'Gene', (135, 138))
569890	31406302	Finally, distinct KRAS mutant alleles differentially engage downstream effectors with KRASG12C or KRASG12V preferentially activating RALA or RALB signaling and KRASG12D triggering increased PI3K-AKT and MAPK/ERKpathway activation.	('activating', 'PosReg', (122, 132))	('preferentially', 'PosReg', (107, 121))	('RALB', 'Gene', (141, 145))	('engage', 'Reg', (53, 59))	('PI3K-AKT', 'Pathway', (190, 198))	('increased', 'PosReg', (180, 189))	('RALA', 'Gene', (133, 137))	('RALA', 'Gene', '5898', (133, 137))	('KRASG12C', 'Var', (86, 94))	('MAPK/ERKpathway activation', 'Pathway', (203, 229))	('KRASG12D', 'Var', (160, 168))	('RALB', 'Gene', '5899', (141, 145))	('KRASG12V', 'Var', (98, 106))
569896	31406302	Although passenger mutations account for the largest fraction of this mutational burden, combinations of somatic mutations in bona fide cancer driver genes are identified in the majority of LUAD and a substantial fraction of LUSC, even when next generation sequencing platforms are limited to the evaluation of pre-defined sets of cancer-relevant genes.	('cancer', 'Phenotype', 'HP:0002664', (136, 142))	('cancer', 'Disease', (331, 337))	('cancer', 'Disease', 'MESH:D009369', (331, 337))	('cancer', 'Disease', 'MESH:D009369', (136, 142))	('LUAD', 'Disease', (190, 194))	('cancer', 'Disease', (136, 142))	('mutations', 'Var', (113, 122))	('LUAD', 'Disease', 'MESH:C538231', (190, 194))	('cancer', 'Phenotype', 'HP:0002664', (331, 337))	('LUSC', 'Chemical', '-', (225, 229))
569897	31406302	Importantly, large-scale profiling studies utilizing either whole exome sequencing or broad targeted sequencing panels in NSCLC tumors have revealed multiple non-random patterns of co-occurring or mutually exclusive mutations, which typically vary depending on the particular oncogenic driver mutation.	('NSCLC', 'Disease', 'MESH:D002289', (122, 127))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumors', 'Disease', (128, 134))	('tumors', 'Disease', 'MESH:D009369', (128, 134))	('tumors', 'Phenotype', 'HP:0002664', (128, 134))	('mutations', 'Var', (216, 225))	('NSCLC', 'Disease', (122, 127))
569900	31406302	For example, mutations in TP53 (which encodes p53) are under-represented among KRAS-mutant LUAD compared to other oncogene-driven subgroups, yet p53 inactivation is common and impactful in KRAS-mutant LUAD.	('TP53', 'Gene', (26, 30))	('p53', 'Gene', (145, 148))	('under-represented', 'NegReg', (55, 72))	('LUAD', 'Disease', (201, 205))	('LUAD', 'Disease', 'MESH:C538231', (201, 205))	('TP53', 'Gene', '7157', (26, 30))	('mutations', 'Var', (13, 22))	('LUAD', 'Disease', (91, 95))	('KRAS-mutant', 'Gene', (79, 90))	('LUAD', 'Disease', 'MESH:C538231', (91, 95))	('KRAS-mutant', 'Var', (79, 90))
569901	31406302	The importance of co-mutations as mediators of diverse NSCLC phenotypes has only recently attracted focus and their functional impact remains largely uncaptured within current molecular stratification frameworks.	('co-mutations', 'Var', (18, 30))	('NSCLC', 'Disease', 'MESH:D002289', (55, 60))	('NSCLC', 'Disease', (55, 60))
569908	31406302	For example in myeloproliferative disorders, the order in which mutations in JAK2 and TET2 arise in hematopoietic stem and progenitor cells can affect age of disease onset, influence the likelihood of the disease manifesting as polycythemia vera versus essential thrombocythemia and result in different propensities for development of thrombosis.	('JAK2', 'Gene', '3717', (77, 81))	('myeloproliferative disorders', 'Phenotype', 'HP:0005547', (15, 43))	('influence', 'Reg', (173, 182))	('thrombosis', 'Disease', 'MESH:D013927', (335, 345))	('polycythemia', 'Phenotype', 'HP:0001901', (228, 240))	('JAK2', 'Gene', (77, 81))	('myeloproliferative disorders', 'Disease', 'MESH:D009196', (15, 43))	('TET2', 'Gene', (86, 90))	('polycythemia vera versus essential thrombocythemia', 'Disease', 'MESH:D011087', (228, 278))	('age', 'MPA', (151, 154))	('mutations', 'Var', (64, 73))	('thrombocythemia', 'Phenotype', 'HP:0001894', (263, 278))	('affect', 'Reg', (144, 150))	('myeloproliferative disorders', 'Disease', (15, 43))	('polycythemia vera versus essential thrombocythemia', 'Disease', (228, 278))	('thrombosis', 'Disease', (335, 345))	('TET2', 'Gene', '54790', (86, 90))
569911	31406302	Certain recurrent oncogenic mutations, for example classical mutations in PIK3CA (which encodes a catalytic subunit of PI3K), occur within APOBEC deaminase trinucleotide motifs and are enriched in tumors with a high APOBEC mutational footprint.	('tumors', 'Disease', 'MESH:D009369', (197, 203))	('occur', 'Reg', (126, 131))	('PIK3CA', 'Gene', '5290', (74, 80))	('mutations', 'Var', (61, 70))	('tumors', 'Phenotype', 'HP:0002664', (197, 203))	('trinucleotide', 'Chemical', '-', (156, 169))	('tumor', 'Phenotype', 'HP:0002664', (197, 202))	('tumors', 'Disease', (197, 203))	('PIK3CA', 'Gene', (74, 80))
569912	31406302	While the full extent to which mutational processes account for unique combinations of somatic genomic alterations in NSCLC is currently unknown, there is evidence that APOBEC-mediated mutagenesis fuels sub-clonal diversification and branched evolution.	('APOBEC-mediated', 'Gene', (169, 184))	('mutagenesis', 'Var', (185, 196))	('sub-clonal diversification', 'CPA', (203, 229))	('NSCLC', 'Disease', (118, 123))	('branched evolution', 'CPA', (234, 252))	('NSCLC', 'Disease', 'MESH:D002289', (118, 123))
569915	31406302	Such immunoediting likely influences patterns of co-mutations in NSCLC and these associations warrant further study.	('influences', 'Reg', (26, 36))	('NSCLC', 'Disease', 'MESH:D002289', (65, 70))	('co-mutations', 'Var', (49, 61))	('NSCLC', 'Disease', (65, 70))
569916	31406302	On the other hand, imposition of a cold tumor immune microenvironment [G] as a result of tumor cell-intrinsic processes may relax immune selection and result in a more diverse spectrum of co-mutations.	('tumor', 'Disease', 'MESH:D009369', (40, 45))	('diverse spectrum of co-mutations', 'MPA', (168, 200))	('imposition', 'Var', (19, 29))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('tumor', 'Disease', (40, 45))	('immune selection', 'MPA', (130, 146))	('tumor', 'Phenotype', 'HP:0002664', (40, 45))	('relax', 'NegReg', (124, 129))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))	('result in', 'Reg', (151, 160))
569917	31406302	Activating mutations in KRAS are the most prevalent oncogenic driver event in both early-stage and metastatic LUAD, occurring in 25-32% of tumors.	('LUAD', 'Disease', (110, 114))	('Activating mutations', 'Var', (0, 20))	('LUAD', 'Disease', 'MESH:C538231', (110, 114))	('early-stage', 'Disease', (83, 94))	('tumor', 'Phenotype', 'HP:0002664', (139, 144))	('tumors', 'Disease', (139, 145))	('tumors', 'Disease', 'MESH:D009369', (139, 145))	('tumors', 'Phenotype', 'HP:0002664', (139, 145))	('KRAS', 'Gene', (24, 28))
569920	31406302	Remarkably, superimposition of somatic genetic alterations of key tumor suppressor genes revealed non-overlapping patterns of co-occurring genomic alterations in the three subgroups: one subgroup was dominated by co-occurring TP53 alterations (thereafter referred to as KP), whereas co-mutations or genomic loss in LKB1 (also known as STK11) were a hallmark of the second cluster (referred to as KL), that was further enriched in somatic mutations in KEAP1 and ATM.	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('LKB1', 'Gene', (315, 319))	('STK11', 'Gene', (335, 340))	('loss', 'NegReg', (307, 311))	('tumor', 'Disease', (66, 71))	('co-mutations', 'Var', (283, 295))	('mutations', 'Var', (438, 447))	('STK11', 'Gene', '6794', (335, 340))	('alterations', 'Var', (231, 242))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('alterations', 'Var', (47, 58))	('KEAP1', 'Gene', (451, 456))	('TP53', 'Gene', '7157', (226, 230))	('TP53', 'Gene', (226, 230))
569923	31406302	However, co-mutations in a set of core genes including LKB1, KEAP1, ATM and RBM10 are consistently enriched in KRAS-mutant LUAD (Figure 2).	('LUAD', 'Disease', 'MESH:C538231', (123, 127))	('KRAS-mutant', 'Var', (111, 122))	('RBM10', 'Gene', (76, 81))	('LKB1', 'Gene', (55, 59))	('LUAD', 'Disease', (123, 127))	('co-mutations', 'Var', (9, 21))
569925	31406302	Mutations in TP53 and inactivation of CDKN2A, CDKN2B or combined CDKN2A/CDKN2B loss due to bi-allelic deletion, are common and functionally relevant co-alterations, although they are not enriched in KRAS-mutant compared to other oncogene-driven subgroups.	('bi-allelic deletion', 'Var', (91, 110))	('loss', 'NegReg', (79, 83))	('TP53', 'Gene', (13, 17))	('CDKN2A/CDKN2B', 'Gene', (65, 78))	('CDKN2B', 'Gene', (46, 52))	('Mutations', 'Var', (0, 9))	('CDKN2A', 'Gene', (38, 44))	('TP53', 'Gene', '7157', (13, 17))	('inactivation', 'NegReg', (22, 34))
569926	31406302	Mutations in other established drivers within the receptor tyrosine kinase-RAS-RAF network including EGFR, ERBB2, BRAF, NF1, as well as ALK, ROS1 and RET rearrangementsare largely non-overlapping with KRAS, although the strength of their negative association varies depending on the individual gene.	('BRAF', 'Gene', (114, 118))	('RET', 'Gene', (150, 153))	('tyrosine kinase', 'Gene', '7294', (59, 74))	('EGFR', 'Gene', '1956', (101, 105))	('EGFR', 'Gene', (101, 105))	('NF1', 'Gene', (120, 123))	('ROS1', 'Gene', (141, 145))	('ALK', 'Gene', (136, 139))	('Mutations', 'Var', (0, 9))	('RET', 'Gene', '5979', (150, 153))	('ERBB2', 'Gene', (107, 112))	('tyrosine kinase', 'Gene', (59, 74))	('ROS1', 'Gene', '6098', (141, 145))	('NF1', 'Gene', '4763', (120, 123))	('ERBB2', 'Gene', '2064', (107, 112))	('KRAS', 'Disease', (201, 205))	('ALK', 'Gene', '238', (136, 139))
569927	31406302	Insights from genetically engineered mouse models and cell line studies have been pivotal towards elucidating the phenotypic sequelae of the most prominent KRAS co-mutations in NSCLC.	('KRAS', 'Gene', (156, 160))	('co-mutations', 'Var', (161, 173))	('NSCLC', 'Disease', (177, 182))	('mouse', 'Species', '10090', (37, 42))	('NSCLC', 'Disease', 'MESH:D002289', (177, 182))
569928	31406302	Somatic deletion of Lkb1 is insufficient for initiation of lung carcinogenesis in mice as a singular event but dramatically accelerates KrasG12D-driven carcinogenesis and fosters early metastatic dissemination.	('mice', 'Species', '10090', (82, 86))	('fosters', 'PosReg', (171, 178))	('carcinogenesis', 'Disease', (152, 166))	('carcinogenesis', 'Disease', 'MESH:D063646', (64, 78))	('initiation of lung carcinogenesis', 'Disease', (45, 78))	('carcinogenesis', 'Disease', (64, 78))	('early metastatic dissemination', 'CPA', (179, 209))	('Lkb1', 'Gene', (20, 24))	('accelerates', 'PosReg', (124, 135))	('carcinogenesis', 'Disease', 'MESH:D063646', (152, 166))	('deletion', 'Var', (8, 16))	('initiation of lung carcinogenesis', 'Disease', 'MESH:D063646', (45, 78))
569929	31406302	In addition, loss of Lkb1 results in epigenetic reprogramming and an expanded tumor histological repertoire, with high incidence of squamous or adenosquamous carcinomas, in agreement with data supporting enrichment of LKB1 mutations in human adenosquamous NSCLC.	('human', 'Species', '9606', (236, 241))	('NSCLC', 'Disease', 'MESH:D002289', (256, 261))	('expanded', 'PosReg', (69, 77))	('squamous or adenosquamous carcinomas', 'Disease', 'MESH:D018196', (132, 168))	('tumor', 'Disease', 'MESH:D009369', (78, 83))	('NSCLC', 'Disease', (256, 261))	('tumor', 'Disease', (78, 83))	('tumor', 'Phenotype', 'HP:0002664', (78, 83))	('LKB1', 'Gene', (218, 222))	('Lkb1', 'Gene', (21, 25))	('carcinoma', 'Phenotype', 'HP:0030731', (158, 167))	('squamous or adenosquamous carcinomas', 'Disease', (132, 168))	('epigenetic reprogramming', 'CPA', (37, 61))	('loss', 'NegReg', (13, 17))	('mutations', 'Var', (223, 232))	('carcinomas', 'Phenotype', 'HP:0030731', (158, 168))
569930	31406302	Epigenetic reprogramming upon LKB1 loss in KRAS-mutant cells is further fueled by a metabolic network, that promotes increased flux of glucose-derived carbon towards serine biosynthesis and the methionine salvage pathway, bolstering synthesis of S-adenosyl methionine (SAM), a critical substrate for DNA methylation.	('LKB1', 'Gene', (30, 34))	('methionine', 'Chemical', 'MESH:D008715', (194, 204))	('methionine salvage pathway', 'MPA', (194, 220))	('synthesis', 'MPA', (233, 242))	('loss', 'NegReg', (35, 39))	('carbon', 'Chemical', 'MESH:D002244', (151, 157))	('SAM', 'Chemical', 'MESH:D012436', (269, 272))	('glucose', 'Chemical', 'MESH:D005947', (135, 142))	('KRAS-mutant', 'Var', (43, 54))	('methionine', 'Chemical', 'MESH:D008715', (257, 267))	('S-adenosyl methionine', 'Chemical', 'MESH:D012436', (246, 267))	('promotes increased', 'PosReg', (108, 126))	('serine', 'Chemical', 'MESH:D012694', (166, 172))	('bolstering', 'PosReg', (222, 232))
569933	31406302	The unique metabolic phenotypes associated with combined expression of oncogenic KRAS and LKB1 inactivation - but not with mutations in either gene alone - may at least partially explain their preferential co-occurrence in human NSCLC.	('human', 'Species', '9606', (223, 228))	('LKB1', 'Gene', (90, 94))	('NSCLC', 'Disease', (229, 234))	('KRAS', 'Gene', (81, 85))	('NSCLC', 'Disease', 'MESH:D002289', (229, 234))	('inactivation', 'Var', (95, 107))
569934	31406302	Intricately linked with LKB1 inactivation is loss of KEAP1, an adaptor protein that mediates ubiquitination and proteasomal degradation of NRF2, a key transcription factor in cellular antioxidant, metabolic, cyto-protective, and anti-inflammatory pathways.	('LKB1', 'Gene', (24, 28))	('NRF2', 'Gene', '4780', (139, 143))	('loss', 'Var', (45, 49))	('NRF2', 'Gene', (139, 143))	('ubiquitination', 'MPA', (93, 107))	('KEAP1', 'Gene', (53, 58))	('inactivation', 'Var', (29, 41))
569935	31406302	Somatic mutations in LKB1 and KEAP1 significantly co-occur with mutant KRAS and with each other in NSCLC, .	('KRAS', 'Disease', (71, 75))	('LKB1', 'Gene', (21, 25))	('KEAP1', 'Gene', (30, 35))	('mutations', 'Var', (8, 17))	('NSCLC', 'Disease', (99, 104))	('mutant', 'Var', (64, 70))	('co-occur', 'Reg', (50, 58))	('NSCLC', 'Disease', 'MESH:D002289', (99, 104))
569936	31406302	In the conditional KrasG12D/+;Trp53Fl/FL mouse model, loss of Keap1 increases both tumor burden and the percent of high-grade lesions, pointing towards roles in both tumor initiation and progression.	('tumor', 'Disease', 'MESH:D009369', (166, 171))	('increases', 'PosReg', (68, 77))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('tumor', 'Phenotype', 'HP:0002664', (166, 171))	('Keap1', 'Gene', (62, 67))	('tumor', 'Disease', (83, 88))	('mouse', 'Species', '10090', (41, 46))	('tumor initiation', 'Disease', 'MESH:D009369', (166, 182))	('tumor', 'Disease', (166, 171))	('G12D', 'Mutation', 'rs121913529', (23, 27))	('loss', 'Var', (54, 58))	('tumor initiation', 'Disease', (166, 182))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
569937	31406302	At the cellular level KEAP1 loss results in increased cellular proliferation in vivo and an altered metabolic profile characterized by increased glucose-derived carbon flux towards the pentose phosphate and serine-glycine biosynthetic pathways with enhanced dependence on glutaminolysis for tricarboxylic acid (TCA) cycle anaplerosis, a dependence that is further enhanced by co-occurring LKB1 alterations.	('glucose-derived carbon flux towards', 'MPA', (145, 180))	('loss', 'NegReg', (28, 32))	('TCA', 'Chemical', 'MESH:D014233', (311, 314))	('cellular proliferation', 'CPA', (54, 76))	('increased', 'PosReg', (44, 53))	('pentose phosphate', 'Chemical', 'MESH:D010428', (185, 202))	('glucose', 'Chemical', 'MESH:D005947', (145, 152))	('increased glucose', 'Phenotype', 'HP:0003074', (135, 152))	('tricarboxylic acid', 'Chemical', 'MESH:D014233', (291, 309))	('serine', 'Chemical', 'MESH:D012694', (207, 213))	('dependence', 'MPA', (258, 268))	('altered', 'Reg', (92, 99))	('glycine', 'Chemical', 'MESH:D005998', (214, 221))	('metabolic profile', 'MPA', (100, 117))	('KEAP1', 'Gene', (22, 27))	('carbon', 'Chemical', 'MESH:D002244', (161, 167))	('increased', 'PosReg', (135, 144))	('LKB1', 'Gene', (389, 393))	('enhanced', 'PosReg', (249, 257))	('alterations', 'Var', (394, 405))
569938	31406302	Thus, NRF2- mediated metabolic reprogramming and regulation of redox homeostasis likely underpin the strong co-selection of KEAP1 with LKB1 and KRAS mutations in NSCLC at least partially because oncogenic KRAS itself promotes oxidative stress and anabolic metabolism and because KL NSCLC cells depend on the pentose phosphate pathway for NAPDH generation and for detoxification of reactive oxygen species because these cells have defective fatty acid oxidation, .	('fatty acid', 'Chemical', 'MESH:D005227', (440, 450))	('NRF2', 'Gene', (6, 10))	('mutations', 'Var', (149, 158))	('NSCLC', 'Disease', (282, 287))	('fatty acid oxidation', 'MPA', (440, 460))	('oxidative stress', 'Phenotype', 'HP:0025464', (226, 242))	('NSCLC', 'Disease', (162, 167))	('anabolic metabolism', 'MPA', (247, 266))	('promotes', 'PosReg', (217, 225))	('NSCLC', 'Disease', 'MESH:D002289', (162, 167))	('NSCLC', 'Disease', 'MESH:D002289', (282, 287))	('LKB1', 'Gene', (135, 139))	('defective', 'NegReg', (430, 439))	('reactive oxygen species', 'Chemical', 'MESH:D017382', (381, 404))	('pentose phosphate', 'Chemical', 'MESH:D010428', (308, 325))	('NRF2', 'Gene', '4780', (6, 10))	('oxidative stress', 'MPA', (226, 242))
569940	31406302	Potentiation of cellular anabolic, antioxidant and detoxification pathways collectively support the aggressive clinical phenotype of KEAP1-mutant NSCLC that is concordant with its role as an independent negative prognostic indicator.	('Potentiation', 'PosReg', (0, 12))	('NSCLC', 'Disease', (146, 151))	('NSCLC', 'Disease', 'MESH:D002289', (146, 151))	('cellular', 'Pathway', (16, 24))	('KEAP1-mutant', 'Var', (133, 145))
569941	31406302	Loss of p53 or expression of either dominant negative or dominant gain-of-function Trp53 mutants also co-operate with oncogenic Kras to induce LUADs with shortened latency and increased metastatic proclivity, although these tumors are less aggressive than those with Lkb1 loss.	('Trp53', 'Gene', (83, 88))	('tumor', 'Phenotype', 'HP:0002664', (224, 229))	('increased', 'PosReg', (176, 185))	('metastatic proclivity', 'CPA', (186, 207))	('LUADs', 'Disease', (143, 148))	('negative', 'NegReg', (45, 53))	('tumors', 'Disease', (224, 230))	('latency', 'CPA', (164, 171))	('tumors', 'Disease', 'MESH:D009369', (224, 230))	('LUADs', 'Disease', 'MESH:C538231', (143, 148))	('Loss', 'NegReg', (0, 4))	('tumors', 'Phenotype', 'HP:0002664', (224, 230))	('mutants', 'Var', (89, 96))	('gain-of-function', 'PosReg', (66, 82))	('induce', 'Reg', (136, 142))	('p53', 'Protein', (8, 11))
569943	31406302	This notion is further supported by identification of TP53 mutational inactivation as a clonal and predominantly early event in established NSCLC that precedes genome doubling and subsequent branched evolution.	('NSCLC', 'Disease', 'MESH:D002289', (140, 145))	('TP53', 'Gene', '7157', (54, 58))	('mutational inactivation', 'Var', (59, 82))	('TP53', 'Gene', (54, 58))	('NSCLC', 'Disease', (140, 145))
569944	31406302	In murine models the impact of Atm inactivation on Kras-driven lung carcinogenesis is context-dependent and varies according to the functional status of p53.	('Atm', 'Gene', (31, 34))	('lung carcinogenesis', 'Disease', (63, 82))	('inactivation', 'Var', (35, 47))	('lung carcinogenesis', 'Disease', 'MESH:D063646', (63, 82))	('murine', 'Species', '10090', (3, 9))	('Atm', 'Gene', '11920', (31, 34))
569945	31406302	In a p53-proficient setting, bi-allelic loss of Atm is tolerated but does not promote KrasG12D-initiated neoplasia.	('Atm', 'Gene', (48, 51))	('neoplasia', 'Phenotype', 'HP:0002664', (105, 114))	('neoplasia', 'Disease', (105, 114))	('bi-allelic loss', 'Var', (29, 44))	('Atm', 'Gene', '11920', (48, 51))	('neoplasia', 'Disease', 'MESH:D009369', (105, 114))
569946	31406302	In contrast, complete Atm inactivation is incompatible with cellular viability in the context of KrasG12D expression and bi-allelic Trp53 inactivation, suggesting that excessive DNA damage in this context removes incipient cancer cells from the proliferative pool.	('Atm', 'Gene', '11920', (22, 25))	('cancer', 'Phenotype', 'HP:0002664', (223, 229))	('inactivation', 'Var', (138, 150))	('Atm', 'Gene', (22, 25))	('cancer', 'Disease', 'MESH:D009369', (223, 229))	('Trp53', 'Gene', (132, 137))	('cancer', 'Disease', (223, 229))
569947	31406302	Interestingly, Kras-driven lung carcinogenesis is accelerated by incomplete Atm loss in a p53 deficient settingThus, data from genetically engineered mouse models (GEMMs) point towards a context-dependent, conditional haplo-insufficient role for Atm loss in KrasG12D-driven lung tumorigenesis.	('Atm', 'Gene', '11920', (76, 79))	('Atm', 'Gene', '11920', (246, 249))	('mouse', 'Species', '10090', (150, 155))	('tumor', 'Phenotype', 'HP:0002664', (279, 284))	('accelerated', 'PosReg', (50, 61))	('lung carcinogenesis', 'Disease', (27, 46))	('tumor', 'Disease', (279, 284))	('Atm', 'Gene', (76, 79))	('lung carcinogenesis', 'Disease', 'MESH:D063646', (27, 46))	('deficient settingThus', 'Disease', (94, 115))	('Atm', 'Gene', (246, 249))	('KrasG12D-driven', 'Var', (258, 273))	('tumor', 'Disease', 'MESH:D009369', (279, 284))	('deficient settingThus', 'Disease', 'None', (94, 115))
569948	31406302	Selection against complete ATM inactivation may explain the mutual exclusivity of ATM and TP53 mutations in human LUAD as well as the enrichment of ATM mutations in the KL subgroup.	('TP53', 'Gene', '7157', (90, 94))	('ATM', 'Gene', (82, 85))	('TP53', 'Gene', (90, 94))	('human', 'Species', '9606', (108, 113))	('mutations', 'Var', (95, 104))	('LUAD', 'Disease', (114, 118))	('LUAD', 'Disease', 'MESH:C538231', (114, 118))
569950	31406302	Intriguingly, analysis of patterns of co-occurrence and mutual exclusivity between a set of 505 pre-selected candidate functional genomic events in 6456 tumors from the Pan-Cancer TCGA Dataset using a novel algorithmic approach (SELECT algorithm) identified somatic mutations in RBM10 as the top-scoring KRAS co-occurrence motif in both NSCLC and colorectal adenocarcinoma.	('NSCLC', 'Disease', (337, 342))	('RBM10', 'Gene', (279, 284))	('colorectal adenocarcinoma', 'Disease', (347, 372))	('NSCLC', 'Disease', 'MESH:D002289', (337, 342))	('tumor', 'Phenotype', 'HP:0002664', (153, 158))	('mutations', 'Var', (266, 275))	('carcinoma', 'Phenotype', 'HP:0030731', (363, 372))	('tumors', 'Disease', (153, 159))	('tumors', 'Phenotype', 'HP:0002664', (153, 159))	('colorectal adenocarcinoma', 'Disease', 'MESH:D015179', (347, 372))	('tumors', 'Disease', 'MESH:D009369', (153, 159))	('Cancer', 'Phenotype', 'HP:0002664', (173, 179))
569951	31406302	In vivo depletion of Rbm10 in mice using CRISPR/Cas9- mediated gene editing concurrently with activation of endogenous oncogenic KrasG12D confers a modest fitness advantage that is lost when Trp53 or Lkb1 are also inactivated.	('mice', 'Species', '10090', (30, 34))	('depletion', 'Var', (8, 17))	('fitness advantage', 'CPA', (155, 172))	('Rbm10', 'Gene', '236732', (21, 26))	('G12D', 'Mutation', 'rs121913529', (133, 137))	('Rbm10', 'Gene', (21, 26))
569952	31406302	The precise phenotypic consequences of RBM10 inactivation in NSCLC and the mechanisms that underpin its oncogenic cooperation with KRAS remain incompletely understood.	('inactivation', 'Var', (45, 57))	('NSCLC', 'Disease', 'MESH:D002289', (61, 66))	('NSCLC', 'Disease', (61, 66))	('RBM10', 'Gene', (39, 44))
569953	31406302	Somatic genomic alterations in CDKN2A [encoding the p16 and p14ARF (p19ARF in the mouse) tumor suppressors] and CDKN2B (encoding p15) are observed in ~20% and ~12% of metastatic KRAS-mutant NSCLC respectively and bi-allelic loss of the CDKN2A/CDKN2B locus is a hallmark of the KC subgroup.	('p15', 'Gene', '12579', (129, 132))	('mouse', 'Species', '10090', (82, 87))	('p15', 'Gene', (129, 132))	('p16', 'Gene', '12578', (52, 55))	('CDKN2B', 'Gene', (112, 118))	('alterations', 'Var', (16, 27))	('p19ARF', 'Gene', '12578', (68, 74))	('tumor', 'Disease', 'MESH:D009369', (89, 94))	('NSCLC', 'Disease', (190, 195))	('p16', 'Gene', (52, 55))	('NSCLC', 'Disease', 'MESH:D002289', (190, 195))	('CDKN2A', 'Gene', (31, 37))	('loss', 'NegReg', (224, 228))	('tumor', 'Phenotype', 'HP:0002664', (89, 94))	('tumor', 'Disease', (89, 94))	('p19ARF', 'Gene', (68, 74))
569954	31406302	KC tumors are characterized by lack of NKX2-1 expression and frequent activation of a gastrointestinal transcriptional program (manifesting histologically as invasive mucinous carcinoma in some cases), enrichment for the KrasG12D mutation and poor prognosis.	('expression', 'MPA', (46, 56))	('tumors', 'Phenotype', 'HP:0002664', (3, 9))	('mucinous carcinoma', 'Phenotype', 'HP:0031495', (167, 185))	('tumor', 'Phenotype', 'HP:0002664', (3, 8))	('invasive mucinous carcinoma', 'Disease', (158, 185))	('invasive mucinous carcinoma', 'Disease', 'MESH:D002288', (158, 185))	('lack', 'NegReg', (31, 35))	('KC tumors', 'Disease', 'MESH:D009369', (0, 9))	('gastrointestinal transcriptional program', 'Pathway', (86, 126))	('KrasG12D', 'Var', (221, 229))	('NKX2-1', 'Enzyme', (39, 45))	('activation', 'PosReg', (70, 80))	('KC tumors', 'Disease', (0, 9))	('carcinoma', 'Phenotype', 'HP:0030731', (176, 185))
569957	31406302	Mechanistically, loss of NKX2-1 unleashes a hepatocyte nuclear factor 4-alpha (HNF4A)-driven gastric differentiation program whereas concomitant loss of HNF4A promotes de-repression of HMGA2.	('HNF4A', 'Gene', (79, 84))	('unleashes', 'NegReg', (32, 41))	('gastric differentiation program', 'CPA', (93, 124))	('HNF4A', 'Gene', '3172', (153, 158))	('loss', 'NegReg', (145, 149))	('HMGA2', 'Gene', '8091', (185, 190))	('hepatocyte nuclear factor 4-alpha', 'Gene', (44, 77))	('HNF4A', 'Gene', (153, 158))	('hepatocyte nuclear factor 4-alpha', 'Gene', '3172', (44, 77))	('HMGA2', 'Gene', (185, 190))	('HNF4A', 'Gene', '3172', (79, 84))	('de-repression', 'MPA', (168, 181))	('loss', 'Var', (17, 21))	('NKX2-1', 'Gene', (25, 31))
569959	31406302	The spectrum of enriched genomic co-alterations in advanced EGFR-mutant LUAD is dominated by recurrent mutations in a core set of genes including TP53 (54.6% % - 64.6%), RB1 (9.6%-10.33%), CTNNB1 (which encodes beta-catenin; 5.3%-9.6%), and PIK3CA (9%-12.4%) as well as amplifications involving EGFR itself (22% - 25.5%), NKX2-1 (12.2% - 16.7%), CDK4 (7%-10%), CDK6 and CCNE1 (Figure 2).	('CDK4', 'Gene', (346, 350))	('CTNNB1', 'Gene', (189, 195))	('mutations', 'Var', (103, 112))	('CCNE1', 'Gene', (370, 375))	('PIK3CA', 'Gene', (241, 247))	('TP53', 'Gene', (146, 150))	('EGFR', 'Gene', '1956', (60, 64))	('CDK4', 'Gene', '1019', (346, 350))	('EGFR', 'Gene', (295, 299))	('CCNE1', 'Gene', '898', (370, 375))	('beta-catenin', 'Gene', (211, 223))	('LUAD', 'Disease', (72, 76))	('RB1', 'Gene', (170, 173))	('beta-catenin', 'Gene', '1499', (211, 223))	('CDK6', 'Gene', '1021', (361, 365))	('EGFR', 'Gene', (60, 64))	('TP53', 'Gene', '7157', (146, 150))	('NKX2-1', 'Gene', (322, 328))	('LUAD', 'Disease', 'MESH:C538231', (72, 76))	('PIK3CA', 'Gene', '5290', (241, 247))	('RB1', 'Gene', '5925', (170, 173))	('EGFR', 'Gene', '1956', (295, 299))	('CDK6', 'Gene', (361, 365))
569960	31406302	The spectrum and prevalence of co-mutations does not appear to vary depending on the specific initiating EGFR mutation and is similar across the three most common subtypes (EGFR exon 19 deletion, EGFRL858R and EGFR exon 20 insertions).	('EGFR', 'Gene', (196, 200))	('EGFR', 'Gene', (210, 214))	('EGFR', 'Gene', '1956', (105, 109))	('EGFR', 'Gene', '1956', (173, 177))	('mutation', 'Var', (110, 118))	('EGFR', 'Gene', (105, 109))	('EGFRL858R', 'Mutation', 'rs121434568', (196, 205))	('EGFR', 'Gene', '1956', (196, 200))	('EGFR', 'Gene', (173, 177))	('EGFR', 'Gene', '1956', (210, 214))
569961	31406302	Mutations in PIK3CA and CTNNB1 are more frequent in advanced stage tumors compared with early stage LUADs, pointing towards functional roles in malignant progression and metastasis, whereas alterations in TP53 (62.5%), RB1 (9.5 -12.5%) and NKX2-1 (12.5%) appear to occur with comparable frequencies in early- and advanced-stage tumors, .	('PIK3CA', 'Gene', (13, 19))	('tumors', 'Disease', (328, 334))	('LUADs', 'Disease', 'MESH:C538231', (100, 105))	('frequent', 'Reg', (40, 48))	('tumors', 'Disease', 'MESH:D009369', (328, 334))	('TP53', 'Gene', '7157', (205, 209))	('malignant progression', 'CPA', (144, 165))	('Mutations', 'Var', (0, 9))	('tumors', 'Phenotype', 'HP:0002664', (67, 73))	('RB1', 'Gene', (219, 222))	('CTNNB1', 'Gene', (24, 30))	('tumor', 'Phenotype', 'HP:0002664', (67, 72))	('PIK3CA', 'Gene', '5290', (13, 19))	('LUADs', 'Disease', (100, 105))	('tumor', 'Phenotype', 'HP:0002664', (328, 333))	('tumors', 'Disease', (67, 73))	('tumors', 'Phenotype', 'HP:0002664', (328, 334))	('RB1', 'Gene', '5925', (219, 222))	('metastasis', 'CPA', (170, 180))	('TP53', 'Gene', (205, 209))	('tumors', 'Disease', 'MESH:D009369', (67, 73))
569963	31406302	TP53 mutations are mostly truncal events (present in all geographically distinct segments of the tumor) that occur early during tumor evolution and prior to whole genome doubling, and are frequently accompanied by truncal loss of heterozygosity at the TP53 locus, indicating strong selective pressure for complete TP53 inactivation in early stage LUADs.	('tumor', 'Disease', 'MESH:D009369', (97, 102))	('TP53', 'Gene', '7157', (0, 4))	('TP53', 'Gene', (0, 4))	('tumor', 'Disease', 'MESH:D009369', (128, 133))	('tumor', 'Phenotype', 'HP:0002664', (97, 102))	('LUADs', 'Disease', 'MESH:C538231', (347, 352))	('TP53', 'Gene', '7157', (314, 318))	('mutations', 'Var', (5, 14))	('tumor', 'Phenotype', 'HP:0002664', (128, 133))	('tumor', 'Disease', (97, 102))	('LUADs', 'Disease', (347, 352))	('TP53', 'Gene', (314, 318))	('tumor', 'Disease', (128, 133))	('TP53', 'Gene', '7157', (252, 256))	('TP53', 'Gene', (252, 256))	('loss of', 'NegReg', (222, 229))
569964	31406302	Furthermore, tumors bearing co-mutations in TP53 exhibit higher degrees of copy number genomic instability (aneuploidy), and a higher somatic mutation burden, both on the trunk and in the branches of the tumor phylogenetic tree.	('tumor', 'Disease', (13, 18))	('copy', 'MPA', (75, 79))	('aneuploidy', 'Disease', (108, 118))	('tumor', 'Disease', 'MESH:D009369', (204, 209))	('tumors', 'Disease', (13, 19))	('higher', 'PosReg', (57, 63))	('tumors', 'Disease', 'MESH:D009369', (13, 19))	('somatic mutation burden', 'CPA', (134, 157))	('tumors', 'Phenotype', 'HP:0002664', (13, 19))	('tumor', 'Phenotype', 'HP:0002664', (204, 209))	('tumor', 'Disease', (204, 209))	('tumor', 'Disease', 'MESH:D009369', (13, 18))	('TP53', 'Gene', '7157', (44, 48))	('higher', 'PosReg', (127, 133))	('aneuploidy', 'Disease', 'MESH:D000782', (108, 118))	('co-mutations', 'Var', (28, 40))	('tumor', 'Phenotype', 'HP:0002664', (13, 18))	('TP53', 'Gene', (44, 48))
569965	31406302	Therefore, TP53 co-mutations impact the natural history of EGFR-mutant NSCLC at least partially by allowing tolerance of a greater degree of genomic instability that results in both larger numbers of co-occurring truncal drivers as well as late sub-clonal diversification with focal emergence of high amplitude amplifications and deletions in mediators of therapeutic resistance.	('co-mutations', 'Var', (16, 28))	('EGFR', 'Gene', (59, 63))	('TP53', 'Gene', '7157', (11, 15))	('TP53', 'Gene', (11, 15))	('deletions', 'Var', (330, 339))	('NSCLC', 'Disease', (71, 76))	('larger', 'PosReg', (182, 188))	('amplifications', 'MPA', (311, 325))	('co-occurring truncal drivers', 'MPA', (200, 228))	('impact', 'Reg', (29, 35))	('EGFR', 'Gene', '1956', (59, 63))	('NSCLC', 'Disease', 'MESH:D002289', (71, 76))
569966	31406302	In keeping with a more complex genomic landscape and a larger burden of clonal or sub-clonal co-drivers, multiple clinical studies have identified TP53 co-alterations as a negative prognostic marker in EGFR-mutant LUAD and a consistent predictor of worse clinical outcomes following EGFR TKI therapy.	('EGFR', 'Gene', (202, 206))	('TP53', 'Gene', (147, 151))	('TP53', 'Gene', '7157', (147, 151))	('negative', 'NegReg', (172, 180))	('EGFR', 'Gene', '1956', (283, 287))	('LUAD', 'Disease', (214, 218))	('LUAD', 'Disease', 'MESH:C538231', (214, 218))	('EGFR', 'Gene', '1956', (202, 206))	('co-alterations', 'Var', (152, 166))	('EGFR', 'Gene', (283, 287))
569967	31406302	Mutational inactivation of RB1 is a clonal and early genetic event in 9.5%-12.5% of EGFR-mutant LUAD, .	('RB1', 'Gene', '5925', (27, 30))	('LUAD', 'Disease', (96, 100))	('LUAD', 'Disease', 'MESH:C538231', (96, 100))	('Mutational inactivation', 'Var', (0, 23))	('EGFR', 'Gene', '1956', (84, 88))	('EGFR', 'Gene', (84, 88))	('RB1', 'Gene', (27, 30))
569969	31406302	TP53 and RB1 co-mutations mark the earliest ancestors of EGFR-mutant LUAD that transform to small cell carcinoma following exposure to EGFR TKIs and dramatically increase the risk of small cell transformation, although loss of RB1 is insufficient to directly induce neuroendocrine trans-differentiation.. Alterations in other regulators of G1/S cell cycle transition including amplification of CDK4, CDK6 and CCNE1 are prevalent and appear to be enriched in tumors that express the EGFRT790M gatekeeper mutation that confers TKI resistance, although data regarding their preferential occurrence in EGFR-mutant compared to EGFR wild-type LUAD are less consistent between studies.	('TKI', 'Gene', (525, 528))	('LUAD', 'Disease', 'MESH:C538231', (69, 73))	('EGFR', 'Gene', '1956', (135, 139))	('EGFR', 'Gene', (598, 602))	('CDK4', 'Gene', (394, 398))	('tumors', 'Phenotype', 'HP:0002664', (458, 464))	('RB1', 'Gene', '5925', (9, 12))	('carcinoma', 'Phenotype', 'HP:0030731', (103, 112))	('mutation', 'Var', (503, 511))	('TP53', 'Gene', '7157', (0, 4))	('EGFR', 'Gene', (622, 626))	('CCNE1', 'Gene', (409, 414))	('tumor', 'Phenotype', 'HP:0002664', (458, 463))	('LUAD', 'Disease', (637, 641))	('EGFR', 'Gene', '1956', (482, 486))	('tumors', 'Disease', (458, 464))	('EGFR', 'Gene', (57, 61))	('CDK4', 'Gene', '1019', (394, 398))	('RB1', 'Gene', (227, 230))	('small cell carcinoma', 'Phenotype', 'HP:0030357', (92, 112))	('CCNE1', 'Gene', '898', (409, 414))	('EGFR', 'Gene', '1956', (598, 602))	('EGFR', 'Gene', (135, 139))	('LUAD', 'Disease', 'MESH:C538231', (637, 641))	('gatekeeper', 'Species', '111938', (492, 502))	('EGFR', 'Gene', '1956', (622, 626))	('tumors', 'Disease', 'MESH:D009369', (458, 464))	('CDK6', 'Gene', '1021', (400, 404))	('TP53', 'Gene', (0, 4))	('LUAD', 'Disease', (69, 73))	('RB1', 'Gene', (9, 12))	('small cell carcinoma', 'Disease', (92, 112))	('RB1', 'Gene', '5925', (227, 230))	('EGFR', 'Gene', '1956', (57, 61))	('EGFRT790M', 'Mutation', 'rs121434569', (482, 491))	('small cell carcinoma', 'Disease', 'MESH:D018288', (92, 112))	('CDK6', 'Gene', (400, 404))	('EGFR', 'Gene', (482, 486))
569970	31406302	Similarly, genomic alterations -most commonly deletion events - in the CDKN2A and CDKN2B genes are observed in ~24.6% and 20.2% of EGFR-mutant tumors and these alterations are typically truncal, further underscoring the significance of G1/S checkpoint dysregulation in the early stages of lung carcinogenesis driven by mutant EGFR, .	('mutant', 'Var', (319, 325))	('deletion', 'Var', (46, 54))	('tumors', 'Phenotype', 'HP:0002664', (143, 149))	('CDKN2A', 'Gene', (71, 77))	('tumors', 'Disease', (143, 149))	('tumors', 'Disease', 'MESH:D009369', (143, 149))	('lung carcinogenesis', 'Disease', (289, 308))	('EGFR', 'Gene', '1956', (131, 135))	('CDKN2B', 'Gene', (82, 88))	('EGFR', 'Gene', (131, 135))	('lung carcinogenesis', 'Disease', 'MESH:D063646', (289, 308))	('EGFR', 'Gene', '1956', (326, 330))	('tumor', 'Phenotype', 'HP:0002664', (143, 148))	('EGFR', 'Gene', (326, 330))
569971	31406302	Activating mutations in CTNNB1 represent one of the most consistently co-selected alterations in EGFR-mutant LUAD across different studies.	('Activating mutations', 'Var', (0, 20))	('EGFR', 'Gene', '1956', (97, 101))	('CTNNB1', 'Gene', (24, 30))	('EGFR', 'Gene', (97, 101))	('LUAD', 'Disease', (109, 113))	('LUAD', 'Disease', 'MESH:C538231', (109, 113))
569972	31406302	CTNNB1 mutations are rare in early-stage EGFR-mutant LUAD (1.8% in the TCGA cohort) but their prevalence increases in late-stage tumors (5.3% - 9.6%), in agreement with earlier studies that identified a central role for WNT signaling in LUAD metastasis and experimental data demonstrating increased invasive potential of EGFR and CTNNB1 co-mutated NSCLC cells in vitro, , .	('EGFR', 'Gene', (321, 325))	('EGFR', 'Gene', (41, 45))	('tumors', 'Phenotype', 'HP:0002664', (129, 135))	('LUAD', 'Disease', (237, 241))	('LUAD', 'Disease', 'MESH:C538231', (237, 241))	('CTNNB1', 'Gene', (0, 6))	('NSCLC', 'Disease', (348, 353))	('late-stage tumors', 'Disease', 'MESH:D007676', (118, 135))	('CTNNB1', 'Gene', (330, 336))	('tumor', 'Phenotype', 'HP:0002664', (129, 134))	('late-stage tumors', 'Disease', (118, 135))	('NSCLC', 'Disease', 'MESH:D002289', (348, 353))	('LUAD', 'Disease', (53, 57))	('EGFR', 'Gene', '1956', (321, 325))	('LUAD', 'Disease', 'MESH:C538231', (53, 57))	('EGFR', 'Gene', '1956', (41, 45))	('mutations', 'Var', (7, 16))
569973	31406302	However, in a mouse LUAD model driven by compound EgfrL858R/T790M mutations genetic deletion of Ctnnb1 reduced tumor burden indicating non-redundant functions in tumor initiation.	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (162, 167))	('LUAD', 'Disease', (20, 24))	('mouse', 'Species', '10090', (14, 19))	('deletion', 'Var', (84, 92))	('EgfrL858R', 'Mutation', 'rs121434568', (50, 59))	('LUAD', 'Disease', 'MESH:C538231', (20, 24))	('Ctnnb1', 'Gene', (96, 102))	('reduced', 'NegReg', (103, 110))	('tumor', 'Disease', (162, 167))	('tumor initiation', 'Disease', 'MESH:D009369', (162, 178))	('T790M', 'Mutation', 'rs121434569', (60, 65))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('tumor', 'Disease', (111, 116))	('tumor initiation', 'Disease', (162, 178))	('Ctnnb1', 'Gene', '12387', (96, 102))	('tumor', 'Disease', 'MESH:D009369', (162, 167))
569974	31406302	Interestingly, mutations in CTNNB1 have been reported to occur more frequently in LUAD with the EGFRT790M mutation following exposure to first or second generation EGFR TKIs suggesting enhanced genetic interaction in this setting.	('EGFR', 'Gene', (164, 168))	('EGFRT790M', 'Mutation', 'rs121434569', (96, 105))	('enhanced', 'PosReg', (185, 193))	('EGFR', 'Gene', (96, 100))	('mutations', 'Var', (15, 24))	('CTNNB1', 'Gene', (28, 34))	('LUAD', 'Disease', 'MESH:C538231', (82, 86))	('LUAD', 'Disease', (82, 86))	('EGFR', 'Gene', '1956', (164, 168))	('EGFR', 'Gene', '1956', (96, 100))
569975	31406302	Mutant EGFR has further been shown to directly tyrosine phosphorylate beta-catenin resulting in its stabilization and nuclear accumulation.	('nuclear accumulation', 'MPA', (118, 138))	('tyrosine', 'Chemical', 'MESH:D014443', (47, 55))	('EGFR', 'Gene', (7, 11))	('beta-catenin', 'Gene', (70, 82))	('beta-catenin', 'Gene', '1499', (70, 82))	('Mutant', 'Var', (0, 6))	('stabilization', 'MPA', (100, 113))	('EGFR', 'Gene', '1956', (7, 11))
569976	31406302	PIK3CA mutations, including classical kinase (H1074R and H1074L) and helical (E545K and E542K) domain mutations are observed in 9%-12.4% of advanced stage EGFR-mutant LUAD and, like CTNNB1 mutations, are encountered preferentially in advanced-stage tumors.	('tumors', 'Phenotype', 'HP:0002664', (249, 255))	('E545K', 'Var', (78, 83))	('tumors', 'Disease', 'MESH:D009369', (249, 255))	('EGFR', 'Gene', '1956', (155, 159))	('H1074L', 'Mutation', 'p.H1074L', (57, 63))	('H1074R', 'Mutation', 'p.H1074R', (46, 52))	('tumor', 'Phenotype', 'HP:0002664', (249, 254))	('E542K', 'Var', (88, 93))	('H1074L', 'Var', (57, 63))	('PIK3CA', 'Gene', (0, 6))	('EGFR', 'Gene', (155, 159))	('PIK3CA', 'Gene', '5290', (0, 6))	('H1074R', 'Var', (46, 52))	('E542K', 'Mutation', 'rs121913273', (88, 93))	('LUAD', 'Disease', (167, 171))	('LUAD', 'Disease', 'MESH:C538231', (167, 171))	('tumors', 'Disease', (249, 255))	('E545K', 'Mutation', 'rs104886003', (78, 83))
569977	31406302	In vitro, co-occurring PIK3CA mutations promote cellular invasion and migration whereas in vivo they are associated with worse overall survival in some studies but do not appear to impact response rates and progression-free survival with first or second line EGFR TKI therapy.	('promote', 'PosReg', (40, 47))	('PIK3CA', 'Gene', (23, 29))	('migration', 'CPA', (70, 79))	('cellular invasion', 'CPA', (48, 65))	('PIK3CA', 'Gene', '5290', (23, 29))	('EGFR', 'Gene', '1956', (259, 263))	('mutations', 'Var', (30, 39))	('EGFR', 'Gene', (259, 263))
569979	31406302	In mouse models of Kras-mutant LUAD, Nkx2-1 loss fosters metastasis and Nkx2-1 haplo-insufficiency promotes both initiation and progression of invasive mucinous adenocarcinomas; therefore, in this genomic background Nkx2-1 functions as a tumor suppressor gene.	('invasive mucinous adenocarcinomas', 'Disease', 'MESH:D002288', (143, 176))	('tumor', 'Phenotype', 'HP:0002664', (238, 243))	('LUAD', 'Disease', 'MESH:C538231', (31, 35))	('Nkx2-1', 'Gene', '21869', (216, 222))	('Nkx2-1', 'Gene', '21869', (72, 78))	('Nkx2-1', 'Gene', (37, 43))	('carcinoma', 'Phenotype', 'HP:0030731', (166, 175))	('invasive mucinous adenocarcinomas', 'Disease', (143, 176))	('loss fosters metastasis', 'Disease', (44, 67))	('Nkx2-1', 'Gene', '21869', (37, 43))	('promotes', 'PosReg', (99, 107))	('carcinomas', 'Phenotype', 'HP:0030731', (166, 176))	('tumor', 'Disease', (238, 243))	('mouse', 'Species', '10090', (3, 8))	('tumor', 'Disease', 'MESH:D009369', (238, 243))	('LUAD', 'Disease', (31, 35))	('Nkx2-1', 'Gene', (216, 222))	('Nkx2-1', 'Gene', (72, 78))	('haplo-insufficiency', 'Var', (79, 98))	('Kras-mutant', 'Var', (19, 30))	('loss fosters metastasis', 'Disease', 'MESH:D009362', (44, 67))
569980	31406302	In contrast, hemizygous Nkx2-1 loss suppresses EgfrL858R-driven lung carcinogenesis, indicating that sustained NKX2-1 expression is essential for tumor initiation downstream of mutant Egfr.	('Egfr', 'Gene', '1956', (47, 51))	('lung carcinogenesis', 'Disease', (64, 83))	('tumor initiation', 'Disease', 'MESH:D009369', (146, 162))	('lung carcinogenesis', 'Disease', 'MESH:D063646', (64, 83))	('Nkx2-1', 'Gene', (24, 30))	('tumor', 'Phenotype', 'HP:0002664', (146, 151))	('Egfr', 'Gene', (184, 188))	('Nkx2-1', 'Gene', '21869', (24, 30))	('Egfr', 'Gene', (47, 51))	('EgfrL858R', 'Mutation', 'rs121434568', (47, 56))	('mutant', 'Var', (177, 183))	('tumor initiation', 'Disease', (146, 162))	('Egfr', 'Gene', '1956', (184, 188))	('loss suppresses', 'NegReg', (31, 46))
569984	31406302	Interestingly, advanced-stage ALK-rearrangement -positive LUAD are enriched in somatic alterations in CDKN2A (32.5%) and CDKN2B (26.5%), but are less likely to harbor TP53 alterations (23.8%-26.5%) compared with other driver subgroups.	('ALK', 'Gene', (30, 33))	('alterations', 'Var', (87, 98))	('LUAD', 'Disease', (58, 62))	('LUAD', 'Disease', 'MESH:C538231', (58, 62))	('CDKN2A', 'Gene', (102, 108))	('ALK', 'Gene', '238', (30, 33))	('TP53', 'Gene', '7157', (167, 171))	('TP53', 'Gene', (167, 171))	('CDKN2B', 'Gene', (121, 127))
569985	31406302	TP53 co-mutations promote genomic instability and are an independent negative prognostic factor in ALK-re-arrangement-positive LUAD, regardless of the type of systemic therapy used.	('TP53', 'Gene', '7157', (0, 4))	('co-mutations', 'Var', (5, 17))	('TP53', 'Gene', (0, 4))	('ALK', 'Gene', (99, 102))	('LUAD', 'Disease', 'MESH:C538231', (127, 131))	('genomic instability', 'CPA', (26, 45))	('ALK', 'Gene', '238', (99, 102))	('LUAD', 'Disease', (127, 131))	('promote', 'PosReg', (18, 25))
569987	31406302	Similarly to LUAD with ALK fusions, both RET and ROS1 fusion-positive LUAD are characterized by high rates of concurrent CDKN2A loss (29.8% and 30.4% for RET and ROS1-rearranged tumors respectively) and CDKN2B loss (25% and 17.7% respectively) and relative paucity of TP53 mutations, although the frequency of TP53 mutations appears to be somewhat higher compared to ALK-rearranged tumors (34.6%-45.5% for RET-and 45.6% for ROS1- rearranged tumors).	('RET', 'Gene', (154, 157))	('ALK', 'Gene', (23, 26))	('tumors', 'Disease', 'MESH:D009369', (178, 184))	('TP53', 'Gene', (268, 272))	('LUAD', 'Disease', 'MESH:C538231', (70, 74))	('RET', 'Gene', '5979', (406, 409))	('tumors', 'Disease', (382, 388))	('CDKN2A', 'Gene', (121, 127))	('loss', 'NegReg', (210, 214))	('ROS1', 'Gene', '6098', (162, 166))	('ROS1', 'Gene', '6098', (424, 428))	('TP53', 'Gene', '7157', (310, 314))	('RET', 'Gene', (41, 44))	('ROS1', 'Gene', '6098', (49, 53))	('CDKN2B', 'Gene', (203, 209))	('ALK', 'Gene', '238', (367, 370))	('tumors', 'Disease', 'MESH:D009369', (382, 388))	('tumors', 'Phenotype', 'HP:0002664', (441, 447))	('RET', 'Gene', (406, 409))	('TP53', 'Gene', '7157', (268, 272))	('loss', 'NegReg', (128, 132))	('tumors', 'Phenotype', 'HP:0002664', (178, 184))	('ALK', 'Gene', (367, 370))	('tumor', 'Phenotype', 'HP:0002664', (441, 446))	('ROS1', 'Gene', (162, 166))	('RET', 'Gene', '5979', (154, 157))	('LUAD', 'Disease', (13, 17))	('tumor', 'Phenotype', 'HP:0002664', (178, 183))	('ROS1', 'Gene', (424, 428))	('tumors', 'Disease', (441, 447))	('tumor', 'Phenotype', 'HP:0002664', (382, 387))	('tumors', 'Disease', (178, 184))	('LUAD', 'Disease', (70, 74))	('ROS1', 'Gene', (49, 53))	('mutations', 'Var', (273, 282))	('TP53', 'Gene', (310, 314))	('ALK', 'Gene', '238', (23, 26))	('tumors', 'Phenotype', 'HP:0002664', (382, 388))	('LUAD', 'Disease', 'MESH:C538231', (13, 17))	('tumors', 'Disease', 'MESH:D009369', (441, 447))	('RET', 'Gene', '5979', (41, 44))
569988	31406302	The key finding that TP53 somatic mutations are underrepresented across LUAD driven by different oncogenic fusions was validated in a subsequent study that further identified frequent bi-allelic SETD2 deletions in this group.	('TP53', 'Gene', (21, 25))	('SETD2', 'Gene', '29072', (195, 200))	('LUAD', 'Disease', (72, 76))	('LUAD', 'Disease', 'MESH:C538231', (72, 76))	('SETD2', 'Gene', (195, 200))	('deletions', 'Var', (201, 210))	('TP53', 'Gene', '7157', (21, 25))
569990	31406302	A distinct pattern of co-occurring alterations is observed in LUAD driven by MET exon 14 skipping mutations.	('MET exon', 'Var', (77, 85))	('skipping mutations', 'Var', (89, 107))	('LUAD', 'Disease', (62, 66))	('LUAD', 'Disease', 'MESH:C538231', (62, 66))
569991	31406302	Specifically, these tumors are characterized by highly significant enrichment of MDM2 and CDK4 amplification (41.6%) compared with other driver oncogenes, as well as amplification of MET itself.	('tumors', 'Disease', (20, 26))	('CDK4', 'Gene', (90, 94))	('CDK4', 'Gene', '1019', (90, 94))	('tumors', 'Disease', 'MESH:D009369', (20, 26))	('tumors', 'Phenotype', 'HP:0002664', (20, 26))	('MDM2', 'Gene', '4193', (81, 85))	('MDM2', 'Gene', (81, 85))	('amplification', 'Var', (95, 108))	('tumor', 'Phenotype', 'HP:0002664', (20, 25))
569992	31406302	In contrast, mutations in TP53 (33.57%) are under-represented, whereas loss of CDKN2A (24.1%) and CDKN2B (17.5%) occur with similar frequencies to that in the overall population of patients with NSCLC.	('TP53', 'Gene', (26, 30))	('NSCLC', 'Disease', 'MESH:D002289', (195, 200))	('CDKN2A', 'Gene', (79, 85))	('patients', 'Species', '9606', (181, 189))	('loss', 'NegReg', (71, 75))	('CDKN2B', 'Gene', (98, 104))	('TP53', 'Gene', '7157', (26, 30))	('mutations', 'Var', (13, 22))	('NSCLC', 'Disease', (195, 200))
569993	31406302	The spectrum of co-occurring alterations in BRAF-mutant NSCLC mirrors the background frequency of alterations in TP53 (53.3%), LKB1 (16.2%), ATM (5.8%), NF1 (6.9%), PIK3CA (6.6%), KEAP1 (6.6%), MYC (10.8%), NKX2-1 (7.3%), although alterations in RB1, MDM2, CDKN2A (16.6%) and CDKN2B (11.2%) are less frequent within this molecular subgroup.	('MYC', 'Gene', '4609', (194, 197))	('NF1', 'Gene', (153, 156))	('PIK3CA', 'Gene', (165, 171))	('RB1', 'Gene', (246, 249))	('NSCLC', 'Disease', (56, 61))	('MDM2', 'Gene', '4193', (251, 255))	('NF1', 'Gene', '4763', (153, 156))	('MDM2', 'Gene', (251, 255))	('alterations', 'Var', (29, 40))	('NSCLC', 'Disease', 'MESH:D002289', (56, 61))	('MYC', 'Gene', (194, 197))	('TP53', 'Gene', '7157', (113, 117))	('RB1', 'Gene', '5925', (246, 249))	('PIK3CA', 'Gene', '5290', (165, 171))	('TP53', 'Gene', (113, 117))
569994	31406302	Finally, patients with ERBB2-mutant NSCLC exhibit preferential amplification of NKX2-1 (19.4%) and ERBB2 itself (14.4%) as well as frequent mutations in RB1 (8.9%), but the frequencies of co-mutations in TP53 (51.7%), CDKN2A (27.2%), CDKN2B (17.2%), PIK3CA (5%), CTNNB1 (4.4%) and MDM2 amplification (7.2%) are similar to that observed in the overall population of patients with NSCLC.	('patients', 'Species', '9606', (365, 373))	('ERBB2', 'Gene', '2064', (99, 104))	('NSCLC', 'Disease', 'MESH:D002289', (379, 384))	('RB1', 'Gene', '5925', (153, 156))	('TP53', 'Gene', (204, 208))	('PIK3CA', 'Gene', (250, 256))	('ERBB2', 'Gene', (23, 28))	('MDM2', 'Gene', (281, 285))	('NSCLC', 'Disease', (379, 384))	('NSCLC', 'Disease', 'MESH:D002289', (36, 41))	('ERBB2', 'Gene', '2064', (23, 28))	('MDM2', 'Gene', '4193', (281, 285))	('TP53', 'Gene', '7157', (204, 208))	('NSCLC', 'Disease', (36, 41))	('mutations', 'Var', (140, 149))	('patients', 'Species', '9606', (9, 17))	('PIK3CA', 'Gene', '5290', (250, 256))	('ERBB2', 'Gene', (99, 104))	('RB1', 'Gene', (153, 156))
569995	31406302	In addition to their impact on cell-autonomous cancer hallmarks, co-mutations can also shape the NSCLC microenvironment and determine its immune contexture (Figure 3).	('cancer hallmarks', 'Disease', 'MESH:D009369', (47, 63))	('shape', 'Reg', (87, 92))	('NSCLC', 'Disease', (97, 102))	('determine', 'Reg', (124, 133))	('co-mutations', 'Var', (65, 77))	('NSCLC', 'Disease', 'MESH:D002289', (97, 102))	('cancer', 'Phenotype', 'HP:0002664', (47, 53))	('cancer hallmarks', 'Disease', (47, 63))
569996	31406302	Inactivating LKB1 genomic alterations, present in ~25% of KRAS-mutant LUAD, have emerged as a major driver of the cold, non-T cell-inflamed microenvironment in NSCLC, characterized by paucity of infiltrating CD3+, CD4+ and CD8+ T-cells and low tumor cell expression of PD-L1, despite intermediate to high tumor mutational burden (TMB).	('LKB1', 'Gene', (13, 17))	('PD-L1', 'Gene', (269, 274))	('tumor', 'Phenotype', 'HP:0002664', (244, 249))	('tumor', 'Disease', (244, 249))	('LUAD', 'Disease', (70, 74))	('TMB', 'Chemical', '-', (330, 333))	('tumor', 'Disease', 'MESH:D009369', (305, 310))	('LUAD', 'Disease', 'MESH:C538231', (70, 74))	('Inactivating', 'Var', (0, 12))	('PD-L1', 'Gene', '29126', (269, 274))	('tumor', 'Disease', 'MESH:D009369', (244, 249))	('tumor', 'Phenotype', 'HP:0002664', (305, 310))	('KRAS-mutant', 'Gene', (58, 69))	('NSCLC', 'Disease', (160, 165))	('tumor', 'Disease', (305, 310))	('NSCLC', 'Disease', 'MESH:D002289', (160, 165))
569997	31406302	These findings are recapitulated in the KrasLSL-G12D/+; Lkb1Fl/Fl GEMM, where Cre-mediated Lkb1 ablation triggers marked influx of tumor-associated neutrophils with T cell suppressive properties including increased expression of Arginase 1 (ARG1) and Interleukin 10 (IL-10).	('Lkb1', 'Gene', (91, 95))	('Arginase 1', 'Gene', '383', (229, 239))	('increased', 'PosReg', (205, 214))	('tumor', 'Disease', (131, 136))	('influx', 'PosReg', (121, 127))	('increased expression of Arginase', 'Phenotype', 'HP:0500153', (205, 237))	('ARG1', 'Gene', (241, 245))	('tumor', 'Disease', 'MESH:D009369', (131, 136))	('IL-10', 'Gene', '3586', (267, 272))	('ablation', 'Var', (96, 104))	('expression', 'MPA', (215, 225))	('G12D', 'Mutation', 'rs121913529', (48, 52))	('IL-10', 'Gene', (267, 272))	('tumor', 'Phenotype', 'HP:0002664', (131, 136))	('ARG1', 'Gene', '383', (241, 245))	('T cell suppressive properties', 'CPA', (165, 194))	('Arginase 1', 'Gene', (229, 239))	('Interleukin 10', 'Gene', '3586', (251, 265))	('Interleukin 10', 'Gene', (251, 265))
569999	31406302	In addition, LKB1 inactivation induces epigenetic repression of STING (also known as TMEM173), thus promoting insensitivity to cytosolic dsDNA accumulation.	('LKB1', 'Gene', (13, 17))	('insensitivity to cytosolic dsDNA accumulation', 'MPA', (110, 155))	('TMEM173', 'Gene', '340061', (85, 92))	('inactivation', 'Var', (18, 30))	('promoting', 'PosReg', (100, 109))	('STING', 'Gene', '340061', (64, 69))	('epigenetic repression', 'MPA', (39, 60))	('STING', 'Gene', (64, 69))	('TMEM173', 'Gene', (85, 92))
570002	31406302	Finally, LKB1 inactivation has also been reported to impinge on non-immune components of the microenvironment of KrasG12D-mutant mouse tumors, including increased collagen deposition as a result of elevated lysyl oxidase (LOX) expression and effects on angiogenesis.	('tumor', 'Phenotype', 'HP:0002664', (135, 140))	('inactivation', 'Var', (14, 26))	('tumors', 'Disease', (135, 141))	('collagen deposition', 'CPA', (163, 182))	('lysyl oxidase', 'Gene', '16948', (207, 220))	('KrasG12D-mutant', 'Var', (113, 128))	('tumors', 'Disease', 'MESH:D009369', (135, 141))	('lysyl oxidase', 'Gene', (207, 220))	('angiogenesis', 'CPA', (253, 265))	('increased', 'PosReg', (153, 162))	('impinge', 'Reg', (53, 60))	('effects', 'Reg', (242, 249))	('LOX', 'Gene', '16948', (222, 225))	('LKB1', 'Gene', (9, 13))	('mouse', 'Species', '10090', (129, 134))	('LOX', 'Gene', (222, 225))	('elevated', 'PosReg', (198, 206))	('expression', 'MPA', (227, 237))	('tumors', 'Phenotype', 'HP:0002664', (135, 141))
570003	31406302	Inactivating mutations in KEAP1 have also been associated with an altered NSCLC immune microenvironment.	('KEAP1', 'Gene', (26, 31))	('Inactivating mutations', 'Var', (0, 22))	('NSCLC', 'Disease', (74, 79))	('NSCLC', 'Disease', 'MESH:D002289', (74, 79))	('associated', 'Reg', (47, 57))
570004	31406302	In a conditional GEMM of LUAD (Keap1Fl/Fl;PtenFl/Fl), co-deletion of Keap1 and Pten resulted in immunologically cold tumors, akin to Lkb1-mutant NSCLC.	('tumor', 'Phenotype', 'HP:0002664', (117, 122))	('LUAD', 'Disease', (25, 29))	('LUAD', 'Disease', 'MESH:C538231', (25, 29))	('tumors', 'Phenotype', 'HP:0002664', (117, 123))	('NSCLC', 'Disease', (145, 150))	('Keap1', 'Gene', (69, 74))	('tumors', 'Disease', (117, 123))	('Pten', 'Gene', (79, 83))	('tumors', 'Disease', 'MESH:D009369', (117, 123))	('NSCLC', 'Disease', 'MESH:D002289', (145, 150))	('Pten', 'Gene', '5728', (42, 46))	('Pten', 'Gene', (42, 46))	('Pten', 'Gene', '5728', (79, 83))	('co-deletion', 'Var', (54, 65))
570007	31406302	Finally, TP53 co-mutations are associated with an inflamed tumor immune microenvironment and increased tumor cell PD-L1 expression in KRAS-mutant NSCLC and GEMMs.	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('PD-L1', 'Gene', (114, 119))	('tumor', 'Disease', (59, 64))	('expression', 'MPA', (120, 130))	('increased', 'PosReg', (93, 102))	('tumor', 'Disease', (103, 108))	('NSCLC', 'Disease', (146, 151))	('PD-L1', 'Gene', '29126', (114, 119))	('KRAS-mutant', 'Var', (134, 145))	('TP53', 'Gene', '7157', (9, 13))	('TP53', 'Gene', (9, 13))	('NSCLC', 'Disease', 'MESH:D002289', (146, 151))	('tumor', 'Disease', 'MESH:D009369', (59, 64))	('co-mutations', 'Var', (14, 26))	('tumor', 'Disease', 'MESH:D009369', (103, 108))	('tumor', 'Phenotype', 'HP:0002664', (59, 64))
570009	31406302	The impact of co-mutations on other oncogene-driven subgroups of NSCLC, including those driven by EGFR mutations, ALK, ROS1 and RET translocations, as well as ERBB2 and MET exon 14 skipping mutations has not hitherto been determined and represents an area of active investigation.	('EGFR', 'Gene', (98, 102))	('mutations', 'Var', (103, 112))	('ROS1', 'Gene', '6098', (119, 123))	('ALK', 'Gene', '238', (114, 117))	('translocations', 'Var', (132, 146))	('RET', 'Gene', '5979', (128, 131))	('NSCLC', 'Disease', 'MESH:D002289', (65, 70))	('RET', 'Gene', (128, 131))	('EGFR', 'Gene', '1956', (98, 102))	('ALK', 'Gene', (114, 117))	('ERBB2', 'Gene', (159, 164))	('ERBB2', 'Gene', '2064', (159, 164))	('NSCLC', 'Disease', (65, 70))	('ROS1', 'Gene', (119, 123))
570010	31406302	This will be particularly pertinent for BRAF-mutant NSCLCs, which are characterized by high tumor cell PD-L1 expression and more favorable clinical response to PD-1 and PD-L1 inhibitors.	('PD-L1', 'Gene', (169, 174))	('PD-L1', 'Gene', '29126', (103, 108))	('NSCLC', 'Disease', (52, 57))	('PD-1', 'Gene', (160, 164))	('tumor', 'Disease', 'MESH:D009369', (92, 97))	('PD-L1', 'Gene', '29126', (169, 174))	('NSCLC', 'Disease', 'MESH:D002289', (52, 57))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('BRAF-mutant', 'Var', (40, 51))	('PD-L1', 'Gene', (103, 108))	('tumor', 'Disease', (92, 97))	('PD-1', 'Gene', '5133', (160, 164))
570013	31406302	Interestingly, logic models - generated using the LOBICO ("Logic Optimization for Binary Input to Continuous Output"computational approach- that combine multiple input features such as mutations in cancer genes, gene fusions, recurrent copy number aberrations and binarized pathway activity scores (derived from gene expression profiling outperform single-gene models for prediction of drug sensitivity.	('cancer', 'Disease', 'MESH:D009369', (198, 204))	('cancer', 'Disease', (198, 204))	('drug sensitivity', 'Phenotype', 'HP:0020174', (386, 402))	('copy number aberrations', 'Var', (236, 259))	('cancer', 'Phenotype', 'HP:0002664', (198, 204))	('outperform', 'PosReg', (338, 348))	('mutations', 'Var', (185, 194))
570018	31406302	Furthermore, LKB1 deficient cells are selectively vulnerable to inhibition of the ATP1A1 Na+/K+-ATPase by cardiac glycosides and to several structurally distinct inhibitors of the HSP90 family of molecular chaperones.	('LKB1', 'Gene', (13, 17))	('ATP1A1', 'Gene', '476', (82, 88))	('ATP1A1', 'Gene', (82, 88))	('inhibition', 'NegReg', (64, 74))	('glycosides', 'Chemical', 'MESH:D006027', (114, 124))	('deficient', 'Var', (18, 27))
570022	31406302	Finally, ATM co-alterations increase the sensitivity of KRAS and BRAF-mutant NSCLC cell lines to MEK inhibitor-induced apoptosis and genetic deletion of Atm is associated with increased sensitivity to poly(ADP-ribose) polymerase (PARP) and ATR inhibitors as well as to radiation therapy in mouse models of Kras-mutant LUAD.	('NSCLC', 'Disease', 'MESH:D002289', (77, 82))	('mouse', 'Species', '10090', (290, 295))	('Atm', 'Gene', '11920', (153, 156))	('increased', 'PosReg', (176, 185))	('MEK', 'Gene', '17242', (97, 100))	('sensitivity', 'MPA', (41, 52))	('PARP', 'Gene', (230, 234))	('PARP', 'Gene', '11545', (230, 234))	('genetic deletion', 'Var', (133, 149))	('MEK', 'Gene', (97, 100))	('Atm', 'Gene', (153, 156))	('LUAD', 'Disease', 'MESH:C538231', (318, 322))	('LUAD', 'Disease', (318, 322))	('sensitivity', 'MPA', (186, 197))	('NSCLC', 'Disease', (77, 82))	('poly(ADP-ribose) polymerase', 'Gene', (201, 228))	('increase', 'PosReg', (28, 36))	('poly(ADP-ribose) polymerase', 'Gene', '11545', (201, 228))
570023	31406302	In this setting signaling inputs from multiple co-altered RAS pathway genes coordinately contribute towards thresholds of oncogenic activity that are critical for transformation and tumor maintenance but also bestow therapeutic vulnerabilities; for example, co-mutations in NF1 and RASA1, encoding two critical RAS pathway GTPase-activating proteins (GAPs), drive addiction to the MEK-ERK signaling axis and confer enhanced sensitivity to MEK inhibitors in a subset of both LUAD and LUSC.	('LUSC', 'Chemical', '-', (483, 487))	('RASA1', 'Gene', (282, 287))	('tumor', 'Disease', (182, 187))	('MEK', 'Gene', (381, 384))	('LUAD', 'Disease', (474, 478))	('NF1', 'Gene', (274, 277))	('enhanced', 'PosReg', (415, 423))	('LUAD', 'Disease', 'MESH:C538231', (474, 478))	('addiction', 'MPA', (364, 373))	('NF1', 'Gene', '4763', (274, 277))	('MEK', 'Gene', '17242', (439, 442))	('co-mutations', 'Var', (258, 270))	('tumor', 'Disease', 'MESH:D009369', (182, 187))	('drive', 'PosReg', (358, 363))	('MEK', 'Gene', '17242', (381, 384))	('RASA1', 'Gene', '5921', (282, 287))	('tumor', 'Phenotype', 'HP:0002664', (182, 187))	('MEK', 'Gene', (439, 442))
570025	31406302	TP53 co-mutations have consistently been associated with shorter progression-free survival following upfront treatment with 1st or 2nd generation EGFR TKIs and there is further evidence that they adversely impact clinical outcomes with the third generation, mutant-selective EGFR TKIs, in patients whose tumors have acquired the EGFRT790M gatekeeper mutation.	('tumors', 'Disease', (304, 310))	('co-mutations', 'Var', (5, 17))	('mutant-selective', 'Var', (258, 274))	('EGFR', 'Gene', (146, 150))	('gatekeeper', 'Species', '111938', (339, 349))	('EGFRT790M', 'Mutation', 'rs121434569', (329, 338))	('EGFR', 'Gene', (329, 333))	('EGFR', 'Gene', '1956', (275, 279))	('TP53', 'Gene', '7157', (0, 4))	('tumors', 'Disease', 'MESH:D009369', (304, 310))	('clinical', 'MPA', (213, 221))	('patients', 'Species', '9606', (289, 297))	('EGFR', 'Gene', '1956', (146, 150))	('progression-free survival', 'CPA', (65, 90))	('tumor', 'Phenotype', 'HP:0002664', (304, 309))	('impact', 'Reg', (206, 212))	('EGFR', 'Gene', '1956', (329, 333))	('tumors', 'Phenotype', 'HP:0002664', (304, 310))	('shorter', 'NegReg', (57, 64))	('EGFR', 'Gene', (275, 279))	('TP53', 'Gene', (0, 4))
570026	31406302	In a study of 200 EGFR-mutant patients with extensive molecular profiling at baseline, pre-existing MET (present in 2% of cases) or ERBB2 (4% prevalence) amplification were also associated with significantly shorter progression-free survival with first-line 1st or 2nd generation EGFR TKI therapy, whereas among patients with acquired EGFRT790M mutation from a distinct cohort, co-mutations in RB1 and PTEN and amplification of MDM2 were independently associated with worse progression-free survival following treatment with 3rd generation EGFR TKIs.	('MDM2', 'Gene', '4193', (428, 432))	('EGFR', 'Gene', '1956', (540, 544))	('EGFR', 'Gene', (280, 284))	('co-mutations', 'Var', (378, 390))	('RB1', 'Gene', (394, 397))	('PTEN', 'Gene', (402, 406))	('EGFR', 'Gene', (18, 22))	('amplification', 'Var', (154, 167))	('patients', 'Species', '9606', (30, 38))	('EGFRT790M', 'Mutation', 'rs121434569', (335, 344))	('progression-free survival', 'CPA', (216, 241))	('RB1', 'Gene', '5925', (394, 397))	('PTEN', 'Gene', '5728', (402, 406))	('EGFR', 'Gene', (335, 339))	('EGFR', 'Gene', '1956', (280, 284))	('patients', 'Species', '9606', (312, 320))	('EGFR', 'Gene', (540, 544))	('shorter', 'NegReg', (208, 215))	('ERBB2', 'Gene', (132, 137))	('MDM2', 'Gene', (428, 432))	('EGFR', 'Gene', '1956', (18, 22))	('amplification', 'Var', (411, 424))	('ERBB2', 'Gene', '2064', (132, 137))	('EGFR', 'Gene', '1956', (335, 339))
570027	31406302	Co-alterations in BRAF, CDKN2A, CDKN2B, fibroblast growth factor receptor 3 (FGFR3) and amplification of MET and EGFR itself were all enriched in patients with acquired resistance to EGFR TKIs compared to pre-treatment tumors, indicating roles in mediating the drug resistant phenotype.	('tumor', 'Phenotype', 'HP:0002664', (219, 224))	('FGFR3', 'Gene', (77, 82))	('tumors', 'Disease', (219, 225))	('amplification', 'Var', (88, 101))	('tumors', 'Disease', 'MESH:D009369', (219, 225))	('EGFR', 'Gene', (183, 187))	('EGFR', 'Gene', '1956', (183, 187))	('CDKN2B', 'Gene', (32, 38))	('tumors', 'Phenotype', 'HP:0002664', (219, 225))	('fibroblast growth factor receptor 3', 'Gene', '2261', (40, 75))	('CDKN2A', 'Gene', (24, 30))	('Co-alterations', 'Var', (0, 14))	('EGFR', 'Gene', '1956', (113, 117))	('EGFR', 'Gene', (113, 117))	('FGFR3', 'Gene', '2261', (77, 82))	('patients', 'Species', '9606', (146, 154))	('BRAF', 'Gene', (18, 22))	('fibroblast growth factor receptor 3', 'Gene', (40, 75))
570028	31406302	Interestingly, co-mutations in PIK3CA don't impact response to first, second or third generation EGFR TKIs.	('co-mutations', 'Var', (15, 27))	('EGFR', 'Gene', '1956', (97, 101))	('impact', 'Reg', (44, 50))	('PIK3CA', 'Gene', (31, 37))	('EGFR', 'Gene', (97, 101))	('PIK3CA', 'Gene', '5290', (31, 37))	('response to first', 'MPA', (51, 68))
570029	31406302	Importantly, co-occurring clonal alterations in both TP53 and RB1, present in ~9 % of EGFR-mutant LUAD at baseline, substantially increase the risk of transformation to small cell carcinoma upon treatment with EGFR TKI; therefore co-occurring alterations can affect not only the likelihood and duration of response to targeted therapy but also impact mechanisms of acquired resistance.	('acquired resistance', 'MPA', (365, 384))	('EGFR', 'Gene', (210, 214))	('small cell carcinoma', 'Disease', (169, 189))	('affect', 'Reg', (259, 265))	('small cell carcinoma', 'Disease', 'MESH:D018288', (169, 189))	('impact', 'Reg', (344, 350))	('TP53', 'Gene', (53, 57))	('LUAD', 'Disease', (98, 102))	('RB1', 'Gene', '5925', (62, 65))	('EGFR', 'Gene', '1956', (86, 90))	('EGFR', 'Gene', '1956', (210, 214))	('LUAD', 'Disease', 'MESH:C538231', (98, 102))	('carcinoma', 'Phenotype', 'HP:0030731', (180, 189))	('alterations', 'Var', (33, 44))	('transformation', 'MPA', (151, 165))	('TP53', 'Gene', '7157', (53, 57))	('small cell carcinoma', 'Phenotype', 'HP:0030357', (169, 189))	('increase', 'Reg', (130, 138))	('EGFR', 'Gene', (86, 90))	('RB1', 'Gene', (62, 65))
570030	31406302	It is currently unknown whether the likelihood of acquisition of an EGFRT790M secondary resistance mutation can also be influenced by the co-mutation status of the tumor.	('tumor', 'Disease', (164, 169))	('EGFRT790M', 'Var', (68, 77))	('tumor', 'Disease', 'MESH:D009369', (164, 169))	('tumor', 'Phenotype', 'HP:0002664', (164, 169))	('EGFRT790M', 'Mutation', 'rs121434569', (68, 77))
570032	31406302	This is particularly evident in KRAS-mutant LUAD.	('KRAS-mutant', 'Var', (32, 43))	('LUAD', 'Disease', (44, 48))	('LUAD', 'Disease', 'MESH:C538231', (44, 48))
570033	31406302	Inactivating somatic mutations in LKB1, present in ~25% of KRAS-mutant LUAD, have emerged as a major genomic driver of primary resistance to PD-1 and PD-L1 inhibition, despite KL LUAD harboring intermediate to high TMB.	('LUAD', 'Disease', 'MESH:C538231', (179, 183))	('LKB1', 'Gene', (34, 38))	('Inactivating', 'Var', (0, 12))	('PD-L1', 'Gene', (150, 155))	('PD-1', 'Gene', (141, 145))	('PD-1', 'Gene', '5133', (141, 145))	('TMB', 'Chemical', '-', (215, 218))	('LUAD', 'Disease', (71, 75))	('PD-L1', 'Gene', '29126', (150, 155))	('LUAD', 'Disease', 'MESH:C538231', (71, 75))	('KRAS-mutant', 'Var', (59, 70))	('LUAD', 'Disease', (179, 183))
570035	31406302	Therefore, somatic genomic alterations may represent independent predictors of clinical outcomes with immune checkpoint inhibitors, in addition to previously established markers such as PD-L1 expression and TMB.	('PD-L1', 'Gene', (186, 191))	('PD-L1', 'Gene', '29126', (186, 191))	('alterations', 'Var', (27, 38))	('TMB', 'Chemical', '-', (207, 210))
570037	31406302	In contrast, KRAS-mutant tumors bearing co-mutations in TP53 exhibit high rates of clinical response to PD-1 axis immunotherapy and markedly improved progression-free and overall survival compared to KL.	('tumor', 'Phenotype', 'HP:0002664', (25, 30))	('progression-free', 'CPA', (150, 166))	('co-mutations', 'Var', (40, 52))	('tumors', 'Disease', (25, 31))	('TP53', 'Gene', '7157', (56, 60))	('tumors', 'Phenotype', 'HP:0002664', (25, 31))	('tumors', 'Disease', 'MESH:D009369', (25, 31))	('PD-1', 'Gene', (104, 108))	('improved', 'PosReg', (141, 149))	('TP53', 'Gene', (56, 60))	('PD-1', 'Gene', '5133', (104, 108))	('overall survival', 'CPA', (171, 187))
570038	31406302	In addition to LKB1, co-mutations in KEAP1 have also been implicated in de novo resistance to PD-1 blockade and both LKB1 and KEAP1 are associated with inferior clinical outcomes with chemo-immunotherapy with pemetrexed-carboplatin (or cisplatin)-pembrolizumab, particularly among PD-L1-positive and TMB-high tumors.	('PD-L1', 'Gene', (281, 286))	('pemetrexed', 'Chemical', 'MESH:D000068437', (209, 219))	('tumors', 'Disease', (309, 315))	('LKB1', 'Gene', (117, 121))	('co-mutations', 'Var', (21, 33))	('carboplatin', 'Chemical', 'MESH:D016190', (220, 231))	('tumors', 'Disease', 'MESH:D009369', (309, 315))	('TMB', 'Chemical', '-', (300, 303))	('PD-L1', 'Gene', '29126', (281, 286))	('tumors', 'Phenotype', 'HP:0002664', (309, 315))	('cisplatin', 'Chemical', 'MESH:D002945', (236, 245))	('PD-1', 'Gene', (94, 98))	('tumor', 'Phenotype', 'HP:0002664', (309, 314))	('PD-1', 'Gene', '5133', (94, 98))	('inferior', 'NegReg', (152, 160))	('pembrolizumab', 'Chemical', 'MESH:C582435', (247, 260))	('KEAP1', 'Var', (126, 131))
570039	31406302	In this context, double LKB1;KEAP1 mutant tumors exhibita particularly recalcitrant clinical response phenotype.	('tumors', 'Disease', (42, 48))	('tumors', 'Disease', 'MESH:D009369', (42, 48))	('tumors', 'Phenotype', 'HP:0002664', (42, 48))	('mutant', 'Var', (35, 41))	('double LKB1', 'Var', (17, 28))	('tumor', 'Phenotype', 'HP:0002664', (42, 47))	('KEAP1', 'Gene', (29, 34))
570040	31406302	Finally, mutations in PTEN have also been nominated as a candidate driver of primary resistance to immune checkpoint inhibition in NSCLC, in agreement with similar reports in melanoma, .	('NSCLC', 'Disease', (131, 136))	('mutations', 'Var', (9, 18))	('NSCLC', 'Disease', 'MESH:D002289', (131, 136))	('PTEN', 'Gene', (22, 26))	('melanoma', 'Disease', 'MESH:D008545', (175, 183))	('PTEN', 'Gene', '5728', (22, 26))	('melanoma', 'Phenotype', 'HP:0002861', (175, 183))	('melanoma', 'Disease', (175, 183))
570042	31406302	Co-occurring genomic alterations in oncogenic drivers and tumor suppressor genes have emerged as major tenets of the molecular diversity of NSCLC.	('oncogenic drivers', 'Gene', (36, 53))	('genomic alterations', 'Var', (13, 32))	('tumor', 'Disease', (58, 63))	('NSCLC', 'Disease', 'MESH:D002289', (140, 145))	('tumor', 'Phenotype', 'HP:0002664', (58, 63))	('tumor', 'Disease', 'MESH:D009369', (58, 63))	('NSCLC', 'Disease', (140, 145))
570043	31406302	Antecedent knowledge of a key set of major co-mutations may therefore allow more granular insights into NSCLC biology; facilitate development of improved clinical response prediction algorithms; anticipate and forestall the emergence of acquired resistance; and enable development of novel, highly personalized therapeutic approaches in the next wave of precision oncology clinical trials.	('NSCLC', 'Disease', (104, 109))	('co-mutations', 'Var', (43, 55))	('oncology', 'Phenotype', 'HP:0002664', (364, 372))	('NSCLC', 'Disease', 'MESH:D002289', (104, 109))	('acquired resistance', 'MPA', (237, 256))
570045	31406302	Immediate priorities and challenges for the future are to catalog, functionalize and systematically evaluate the therapeutic utility of the full spectrum of co-occurring alterations in NSCLC and, simultaneously, to expeditiously translate the most robust and critical insights into more precise therapeutic strategies that yield improved clinical outcomes for NSCLC patients.	('NSCLC', 'Disease', 'MESH:D002289', (360, 365))	('NSCLC', 'Disease', 'MESH:D002289', (185, 190))	('alterations', 'Var', (170, 181))	('patients', 'Species', '9606', (366, 374))	('NSCLC', 'Disease', (360, 365))	('NSCLC', 'Disease', (185, 190))
570051	31164631	STYK1 overexpression promoted NSCLC cells proliferation, migration, and invasion.	('NSCLC', 'Disease', 'MESH:D002289', (30, 35))	('STYK1', 'Gene', (0, 5))	('NSCLC', 'Disease', (30, 35))	('overexpression', 'Var', (6, 20))	('promoted', 'PosReg', (21, 29))	('migration', 'CPA', (57, 66))	('NSCLC', 'Phenotype', 'HP:0030358', (30, 35))	('invasion', 'CPA', (72, 80))
570052	31164631	STYK1 also induced epithelial-mesenchymal transition by E-cadherin downregulation and Snail upregulation.	('downregulation', 'NegReg', (67, 81))	('STYK1', 'Var', (0, 5))	('upregulation', 'PosReg', (92, 104))	('Snail', 'Gene', (86, 91))	('Snail', 'Gene', '6615', (86, 91))	('induced', 'Reg', (11, 18))	('E-cadherin', 'Gene', (56, 66))	('E-cadherin', 'Gene', '999', (56, 66))	('epithelial-mesenchymal transition', 'CPA', (19, 52))
570054	31164631	Further survival analyses showed that NSCLC patients with high STYK1 level and low SPINT2 level had the worst prognosis and survival.	('NSCLC', 'Disease', (38, 43))	('patients', 'Species', '9606', (44, 52))	('NSCLC', 'Disease', 'MESH:D002289', (38, 43))	('NSCLC', 'Phenotype', 'HP:0030358', (38, 43))	('low', 'Var', (79, 82))	('SPINT2', 'Gene', '10653', (83, 89))	('high STYK1 level', 'Var', (58, 74))	('SPINT2', 'Gene', (83, 89))
570055	31164631	These results indicated that STYK1 facilitated NSCLC progression via reducing SPINT2 expression.	('expression', 'MPA', (85, 95))	('NSCLC', 'Phenotype', 'HP:0030358', (47, 52))	('reducing', 'NegReg', (69, 77))	('SPINT2', 'Gene', (78, 84))	('SPINT2', 'Gene', '10653', (78, 84))	('NSCLC', 'Disease', (47, 52))	('NSCLC', 'Disease', 'MESH:D002289', (47, 52))	('STYK1', 'Var', (29, 34))	('facilitated', 'PosReg', (35, 46))
570080	31164631	IHC staining was performed on tissue microarray sections using the primary antibodies of anti-STYK1 (1:50, ab97451, abcam) and anti-SPINT2 (1:200, HPA011101, Sigma), and the standard protocols were followed as previously described.	('SPINT2', 'Gene', '10653', (132, 138))	('SPINT2', 'Gene', (132, 138))	('1:200', 'Var', (140, 145))
570099	31164631	Newly synthesized DNA in NSCLC cells was detected by the EdU fluorescence staining (C10638, Invitrogen) according to the manufacturer's directions.	('C10638', 'Var', (84, 90))	('NSCLC', 'Disease', (25, 30))	('NSCLC', 'Disease', 'MESH:D002289', (25, 30))	('EdU', 'Chemical', 'MESH:C031086', (57, 60))	('NSCLC', 'Phenotype', 'HP:0030358', (25, 30))
570108	31164631	Interestingly, the Kaplan-Meier plotter database (http://kmplot.com) analysis also showed the positive correlation between high STYK1 expression and poor prognosis of NSCLC patients (HR = 1.44, Logrank P = 0.034, Fig.	('NSCLC', 'Disease', 'MESH:D002289', (167, 172))	('expression', 'MPA', (134, 144))	('patients', 'Species', '9606', (173, 181))	('NSCLC', 'Phenotype', 'HP:0030358', (167, 172))	('high', 'Var', (123, 127))	('STYK1', 'Gene', (128, 133))	('NSCLC', 'Disease', (167, 172))
570115	31164631	Our Kaplan-Meier analysis results showed that NSCLC patients with high STYK1 expression were associated with worse overall survival (Logrank P < 0.001, Fig.	('STYK1', 'Gene', (71, 76))	('worse', 'NegReg', (109, 114))	('overall survival', 'MPA', (115, 131))	('NSCLC', 'Disease', (46, 51))	('NSCLC', 'Disease', 'MESH:D002289', (46, 51))	('high', 'Var', (66, 70))	('patients', 'Species', '9606', (52, 60))	('NSCLC', 'Phenotype', 'HP:0030358', (46, 51))
570117	31164631	The 3- and 5-year cumulative survival rates (27.3% and 16.9%, respectively) for NSCLC patient with high STYK1 expression were much lower than these (58.5% and 36.8%, respectively) with low STYK1 expression (Table 2).	('NSCLC', 'Phenotype', 'HP:0030358', (80, 85))	('high', 'Var', (99, 103))	('NSCLC', 'Disease', (80, 85))	('patient', 'Species', '9606', (86, 93))	('STYK1', 'Gene', (104, 109))	('NSCLC', 'Disease', 'MESH:D002289', (80, 85))	('lower', 'NegReg', (131, 136))
570118	31164631	After multivariate Cox survival analysis, STYK1 was found to be an independent prognostic factor for NSCLC patients (HR = 1.617, 95% CI: 1.254-2.084, P < 0.001, Table 3).	('Cox', 'Gene', (19, 22))	('NSCLC', 'Disease', (101, 106))	('STYK1', 'Var', (42, 47))	('NSCLC', 'Disease', 'MESH:D002289', (101, 106))	('Cox', 'Gene', '1351', (19, 22))	('patients', 'Species', '9606', (107, 115))	('NSCLC', 'Phenotype', 'HP:0030358', (101, 106))
570125	31164631	Consistent with the in vitro outcomes, we found that the mean volume of tumors of STYK1 OE group was 1.84-fold larger than that of NC group (Fig.	('tumor', 'Phenotype', 'HP:0002664', (72, 77))	('larger', 'PosReg', (111, 117))	('STYK1 OE', 'Var', (82, 90))	('tumors', 'Disease', 'MESH:D009369', (72, 78))	('tumors', 'Phenotype', 'HP:0002664', (72, 78))	('tumors', 'Disease', (72, 78))
570126	31164631	Moreover, the migratory and invasive potentials were also enhanced by STYK1 overexpression in both H1299 and Calu-1 cells.	('enhanced', 'PosReg', (58, 66))	('overexpression', 'Var', (76, 90))	('STYK1', 'Gene', (70, 75))	('H1299', 'CellLine', 'CVCL:0060', (99, 104))	('Calu-1', 'CellLine', 'CVCL:0608', (109, 115))
570127	31164631	To further detect the role of STYK1 on NSCLC cell lines from the primary sites, we then overexpressed the STYK1 in SK-LU-1 cells and found STYK1 overexpression also enhanced the migratory and invasive abilities in SK-LU-1 cells (supplementary Fig.	('NSCLC', 'Phenotype', 'HP:0030358', (39, 44))	('SK-LU-1', 'CellLine', 'CVCL:0629', (214, 221))	('enhanced', 'PosReg', (165, 173))	('NSCLC', 'Disease', (39, 44))	('STYK1', 'Var', (139, 144))	('NSCLC', 'Disease', 'MESH:D002289', (39, 44))	('SK-LU-1', 'CellLine', 'CVCL:0629', (115, 122))
570130	31164631	We then measured the EMT biomarkers E-cadherin and Snail expression by western blot, and we found STYK1 overexpression significantly decreased anti-EMT E-cadherin expression and increased pro-EMT Snail levels both in vitro and in vivo (Fig.	('E-cadherin', 'Gene', (152, 162))	('E-cadherin', 'Gene', '999', (152, 162))	('overexpression', 'Var', (104, 118))	('E-cadherin', 'Gene', (36, 46))	('Snail', 'Gene', (196, 201))	('Snail', 'Gene', '6615', (196, 201))	('E-cadherin', 'Gene', '999', (36, 46))	('anti-EMT', 'CPA', (143, 151))	('expression', 'MPA', (163, 173))	('Snail', 'Gene', (51, 56))	('Snail', 'Gene', '6615', (51, 56))	('increased', 'PosReg', (178, 187))	('decreased', 'NegReg', (133, 142))	('STYK1', 'Gene', (98, 103))
570133	31164631	Among these genes, we focused on SPINT2, whose expression was strongly downregulated by STYK1 overexpression (Fig.	('downregulated', 'NegReg', (71, 84))	('SPINT2', 'Gene', '10653', (33, 39))	('SPINT2', 'Gene', (33, 39))	('overexpression', 'Var', (94, 108))	('STYK1', 'Gene', (88, 93))	('expression', 'MPA', (47, 57))
570135	31164631	Decrease of SPINT2 mRNA level was further validated by qRT-PCR analysis in the STYK1 OE group compared with NC group in both H1299 and Calu-1 cells (P < 0.05, Fig.	('SPINT2', 'Gene', '10653', (12, 18))	('H1299', 'CellLine', 'CVCL:0060', (125, 130))	('Decrease', 'NegReg', (0, 8))	('SPINT2', 'Gene', (12, 18))	('Calu-1', 'CellLine', 'CVCL:0608', (135, 141))	('STYK1 OE', 'Var', (79, 87))
570141	31164631	Furthermore, the in vivo study showed that SPINT2 overexpression significantly decreased the mean volume of tumors in the H1299-STYK1 OE xenograft group (Fig.	('H1299-STYK1', 'Var', (122, 133))	('SPINT2', 'Gene', '10653', (43, 49))	('decreased', 'NegReg', (79, 88))	('tumor', 'Phenotype', 'HP:0002664', (108, 113))	('SPINT2', 'Gene', (43, 49))	('H1299', 'CellLine', 'CVCL:0060', (122, 127))	('tumors', 'Disease', (108, 114))	('tumors', 'Disease', 'MESH:D009369', (108, 114))	('tumors', 'Phenotype', 'HP:0002664', (108, 114))
570143	31164631	Interestingly, SPINT2 overexpression markedly reversed STYK1 OE-induced Akt phosphorylation in NSCLC cells (Supplementary Fig.	('Akt', 'Gene', '207', (72, 75))	('NSCLC', 'Disease', 'MESH:D002289', (95, 100))	('Akt', 'Gene', (72, 75))	('SPINT2', 'Gene', (15, 21))	('SPINT2', 'Gene', '10653', (15, 21))	('NSCLC', 'Phenotype', 'HP:0030358', (95, 100))	('STYK1', 'Var', (55, 60))	('NSCLC', 'Disease', (95, 100))	('reversed', 'NegReg', (46, 54))
570150	31164631	The high SPINT2 expression was negatively correlated to tumor invasion, distant metastasis, differentiation, and AJCC 8th stage (Table 1).	('SPINT2', 'Gene', (9, 15))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('negatively', 'NegReg', (31, 41))	('tumor', 'Disease', (56, 61))	('AJCC 8th', 'Disease', (113, 121))	('high', 'Var', (4, 8))	('SPINT2', 'Gene', '10653', (9, 15))	('differentiation', 'CPA', (92, 107))	('expression', 'MPA', (16, 26))	('tumor', 'Disease', 'MESH:D009369', (56, 61))	('distant metastasis', 'CPA', (72, 90))
570151	31164631	Furthermore, Kaplan-Meier survival curves indicated that NSCLC patients with high SPINT2 expression were associated with better prognosis (Fig.	('high', 'Var', (77, 81))	('better', 'PosReg', (121, 127))	('NSCLC', 'Phenotype', 'HP:0030358', (57, 62))	('SPINT2', 'Gene', (82, 88))	('SPINT2', 'Gene', '10653', (82, 88))	('patients', 'Species', '9606', (63, 71))	('NSCLC', 'Disease', (57, 62))	('NSCLC', 'Disease', 'MESH:D002289', (57, 62))
570152	31164631	The 3- and 5-year cumulative survival rates (63.1% and 45.2%, respectively) for NSCLC with high SPINT2 expression were much higher than NSCLC (29.5% and 13.7%, respectively) with low SPINT2 expression (Table 2).	('NSCLC', 'Disease', 'MESH:D002289', (136, 141))	('SPINT2', 'Gene', '10653', (183, 189))	('NSCLC', 'Phenotype', 'HP:0030358', (80, 85))	('SPINT2', 'Gene', (183, 189))	('high', 'Var', (91, 95))	('SPINT2', 'Gene', '10653', (96, 102))	('NSCLC', 'Disease', (80, 85))	('NSCLC', 'Phenotype', 'HP:0030358', (136, 141))	('NSCLC', 'Disease', 'MESH:D002289', (80, 85))	('higher', 'PosReg', (124, 130))	('NSCLC', 'Disease', (136, 141))	('SPINT2', 'Gene', (96, 102))
570157	31164631	In both high and low STYK1 level subgroups, patients with high SPITN2 level showed better prognosis than the low one (Fig.	('SPITN2', 'Gene', (63, 69))	('patients', 'Species', '9606', (44, 52))	('high', 'Var', (58, 62))
570158	31164631	Interestingly, in the NSCLC group and the LUAD subgroup, there was no statistically difference of patients' survival between the low STYK1/low SPINT2 group with high STYK1/high SPINT2 group (P > 0.05, Fig.	('SPINT2', 'Gene', (177, 183))	('SPINT2', 'Gene', '10653', (177, 183))	('low', 'Var', (129, 132))	('NSCLC', 'Phenotype', 'HP:0030358', (22, 27))	('patients', 'Species', '9606', (98, 106))	('SPINT2', 'Gene', '10653', (143, 149))	('NSCLC', 'Disease', (22, 27))	('SPINT2', 'Gene', (143, 149))	('NSCLC', 'Disease', 'MESH:D002289', (22, 27))
570164	31164631	In addition, multivariate Cox survival analysis indicated STYK1 was an independent prognostic factor for NSCLC patients.	('NSCLC', 'Disease', 'MESH:D002289', (105, 110))	('NSCLC', 'Phenotype', 'HP:0030358', (105, 110))	('STYK1', 'Var', (58, 63))	('Cox', 'Gene', (26, 29))	('NSCLC', 'Disease', (105, 110))	('Cox', 'Gene', '1351', (26, 29))	('patients', 'Species', '9606', (111, 119))
570166	31164631	Interestingly, our results based on larger cohort cases suggested that high STYK1 level was related to worse survival of both LUSC and LUAD patients.	('worse', 'NegReg', (103, 108))	('STYK1', 'MPA', (76, 81))	('patients', 'Species', '9606', (140, 148))	('high', 'Var', (71, 75))
570170	31164631	Additionally, the promotion of tumor growth by STYK1 was further confirmed in subcutaneous xenograft tumor nude mice model.	('tumor', 'Phenotype', 'HP:0002664', (31, 36))	('STYK1', 'Var', (47, 52))	('promotion', 'PosReg', (18, 27))	('tumor', 'Disease', (31, 36))	('tumor', 'Disease', (101, 106))	('tumor', 'Phenotype', 'HP:0002664', (101, 106))	('tumor', 'Disease', 'MESH:D009369', (31, 36))	('tumor', 'Disease', 'MESH:D009369', (101, 106))	('nude mice', 'Species', '10090', (107, 116))
570172	31164631	STYK1 has been previously reported as a potent EMT inducer and promotes several cancer metastasis such as liver cancer, cervical cancer, and gallbladder cancer.	('gallbladder cancer', 'Disease', (141, 159))	('gallbladder cancer', 'Disease', 'MESH:D005706', (141, 159))	('liver cancer', 'Disease', 'MESH:D006528', (106, 118))	('cancer', 'Phenotype', 'HP:0002664', (129, 135))	('liver cancer', 'Phenotype', 'HP:0002896', (106, 118))	('STYK1', 'Var', (0, 5))	('liver cancer', 'Disease', (106, 118))	('cancer', 'Phenotype', 'HP:0002664', (80, 86))	('promotes', 'PosReg', (63, 71))	('cervical cancer', 'Disease', (120, 135))	('cancer metastasis', 'Disease', (80, 97))	('cervical cancer', 'Disease', 'MESH:D002583', (120, 135))	('cancer', 'Phenotype', 'HP:0002664', (153, 159))	('cancer', 'Phenotype', 'HP:0002664', (112, 118))	('cancer metastasis', 'Disease', 'MESH:D009362', (80, 97))
570185	31164631	Consistent with previous studies, we found STYK1 overexpression could increase the Akt phosphorylation in NSCLC cells.	('STYK1', 'Var', (43, 48))	('NSCLC', 'Disease', 'MESH:D002289', (106, 111))	('increase', 'PosReg', (70, 78))	('Akt', 'Gene', (83, 86))	('NSCLC', 'Phenotype', 'HP:0030358', (106, 111))	('Akt', 'Gene', '207', (83, 86))	('overexpression', 'PosReg', (49, 63))	('NSCLC', 'Disease', (106, 111))
570195	31164631	When combining STYK1 and SPINT2 expression for further analyses, Kaplan-Meier survival curves showed that patients with high STYK1/low SPINT2 had the worst prognosis in NSCLC, LUAD and LUSC.	('NSCLC', 'Phenotype', 'HP:0030358', (169, 174))	('LUSC', 'Disease', (185, 189))	('SPINT2', 'Gene', '10653', (135, 141))	('NSCLC', 'Disease', (169, 174))	('LUAD', 'Disease', (176, 180))	('NSCLC', 'Disease', 'MESH:D002289', (169, 174))	('patients', 'Species', '9606', (106, 114))	('SPINT2', 'Gene', '10653', (25, 31))	('SPINT2', 'Gene', (25, 31))	('high STYK1/low', 'Var', (120, 134))	('SPINT2', 'Gene', (135, 141))
570200	31164631	Moreover, we found elevated STYK1 or decreased SPINT2 expression strongly correlated with NSCLC poor prognosis, and downregulation of SPINT2 involved in STYK1-mediated NSCLC progression (Fig.	('expression', 'MPA', (54, 64))	('downregulation', 'NegReg', (116, 130))	('SPINT2', 'Gene', '10653', (47, 53))	('NSCLC', 'Disease', (90, 95))	('NSCLC', 'Disease', 'MESH:D002289', (168, 173))	('SPINT2', 'Gene', (47, 53))	('SPINT2', 'Gene', (134, 140))	('STYK1', 'Var', (28, 33))	('elevated', 'PosReg', (19, 27))	('NSCLC', 'Disease', 'MESH:D002289', (90, 95))	('SPINT2', 'Gene', '10653', (134, 140))	('NSCLC', 'Phenotype', 'HP:0030358', (168, 173))	('correlated', 'Reg', (74, 84))	('NSCLC', 'Phenotype', 'HP:0030358', (90, 95))	('decreased', 'NegReg', (37, 46))	('NSCLC', 'Disease', (168, 173))
570202	30186308	A Novel Computational Method for the Identification of Potential miRNA-Disease Association Based on Symmetric Non-negative Matrix Factorization and Kronecker Regularized Least Square Increasing evidence has indicated that microRNAs (miRNAs) are associated with numerous human diseases.	('miR', 'Gene', '220972', (233, 236))	('numerous human diseases', 'Disease', 'MESH:D015658', (261, 284))	('miR', 'Gene', (233, 236))	('miR', 'Gene', '220972', (65, 68))	('microRNAs', 'Var', (222, 231))	('miR', 'Gene', (65, 68))	('numerous human diseases', 'Disease', (261, 284))	('associated', 'Reg', (245, 255))
570257	30186308	As shown in the results, the AUC values of global LOOCV, local LOOCV, and 5-fold cross validation of SNMFMDA reached 0.9007, 0.8426, and 0.8830 +- 0.0017 respectively, which verified the excellent prediction performance of SNMFMDA.	('0.8426', 'Var', (125, 131))	('SNMFMDA', 'Chemical', '-', (101, 108))	('SNMFMDA', 'Chemical', '-', (223, 230))	('0.8830', 'Var', (137, 143))
570363	29238207	It has been broadly accepted that inhibitory T-cell immune checkpoints contribute to tumor immune escape through negative immune regulatory signals (cytotoxic T-lymphocyte-associated antigen 4 [CTLA-4], programmed cell death 1 [PD-1], B7-H3, and B7-H4, etc).	('PD-1', 'Gene', (228, 232))	('tumor', 'Disease', (85, 90))	('cytotoxic T-lymphocyte-associated antigen 4', 'Gene', (149, 192))	('tumor', 'Disease', 'MESH:D009369', (85, 90))	('B7-H3', 'Var', (235, 240))	('tumor', 'Phenotype', 'HP:0002664', (85, 90))	('PD-1', 'Gene', '5133', (228, 232))	('cytotoxic T-lymphocyte-associated antigen 4', 'Gene', '397286', (149, 192))
570378	29238207	T-cells have been the primary focus of cancer immunotherapy primarily due to their ability to initiate diverse immunoreactions via CD4+ helper T-cells that provoke innate and adaptive immunity.	('CD4+ helper', 'Var', (131, 142))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('cancer', 'Disease', (39, 45))	('cancer', 'Disease', 'MESH:D009369', (39, 45))
570409	29238207	In vitro and in vivo studies have shown that deficiency of CTLA-4 in Tregs leads to systemic lymphoproliferation, fatal T-cell-mediated autoimmune disease, increased IgE production, and furthermore, potent tumor immunity.	('lymphoproliferation', 'Disease', 'MESH:C565232', (93, 112))	('tumor', 'Phenotype', 'HP:0002664', (206, 211))	('CTLA-4', 'Gene', (59, 65))	('autoimmune disease', 'Disease', (136, 154))	('tumor', 'Disease', (206, 211))	('increased', 'PosReg', (156, 165))	('autoimmune disease', 'Disease', 'MESH:D001327', (136, 154))	('IgE production', 'MPA', (166, 180))	('autoimmune disease', 'Phenotype', 'HP:0002960', (136, 154))	('lymphoproliferation', 'Disease', (93, 112))	('deficiency', 'Var', (45, 55))	('potent', 'PosReg', (199, 205))	('tumor', 'Disease', 'MESH:D009369', (206, 211))
570414	29238207	Malm et al showed that the PD-1 expression in healthy peripheral blood donors is generally under 15%, while the rate surged to over 50% of both the CD4+ and CD8+ T-cells among the PBLs, draining lymph nodes and TILs in the tumor microenvironment in HNSCC patients.	('tumor', 'Phenotype', 'HP:0002664', (223, 228))	('tumor', 'Disease', (223, 228))	('CD8', 'Gene', (157, 160))	('PD-1', 'Gene', (27, 31))	('HNSCC', 'Disease', (249, 254))	('CD8', 'Gene', '925', (157, 160))	('PD-1', 'Gene', '5133', (27, 31))	('patients', 'Species', '9606', (255, 263))	('HNSCC', 'Phenotype', 'HP:0012288', (249, 254))	('CD4+', 'Var', (148, 152))	('surged', 'PosReg', (117, 123))	('tumor', 'Disease', 'MESH:D009369', (223, 228))	('expression', 'MPA', (32, 42))
570451	29238207	Several studies have explored the association between oncogenesis and CTLA-4 single nucleotide polymorphisms (SNPs), namely +49A/G (rs231775), -1661A/G (rs4553808), -318C/T (rs5742909), -1722T/C (rs733618), and CT60G/A (rs3087243) SNPs, etc.	('rs231775', 'Var', (132, 140))	('oncogenesis', 'CPA', (54, 65))	('rs3087243', 'Var', (220, 229))	('CTLA-4', 'Gene', (70, 76))	('+49A/G', 'Mutation', 'rs231775', (124, 130))	('rs733618', 'Var', (196, 204))	('-1661A/G', 'Mutation', 'rs4553808', (143, 151))	('rs5742909', 'Var', (174, 183))	('rs4553808', 'Var', (153, 162))	('rs231775', 'Mutation', 'rs231775', (132, 140))	('-1722T/C', 'Mutation', 'rs733618', (186, 194))	('CT60G', 'Mutation', 'c.60CT>G', (211, 216))	('-318C/T', 'Mutation', 'rs5742909', (165, 172))	('rs5742909', 'Mutation', 'rs5742909', (174, 183))	('rs3087243', 'Mutation', 'rs3087243', (220, 229))	('rs733618', 'Mutation', 'rs733618', (196, 204))	('rs4553808', 'Mutation', 'rs4553808', (153, 162))
570452	29238207	Kammerer et al found that the genotype CTLA-4 (-1661A/G) was detected more frequently in patients with OSCC than in healthy controls, and that several combinations of SNPs were found only in patient tissues.	('OSCC', 'Disease', (103, 107))	('patient', 'Species', '9606', (89, 96))	('-1661A/G', 'Mutation', 'rs4553808', (47, 55))	('CTLA-4', 'Gene', (39, 45))	('patients', 'Species', '9606', (89, 97))	('patient', 'Species', '9606', (191, 198))	('-1661A/G', 'Var', (47, 55))
570469	29238207	Ipilimumab is currently being assessed in clinical trials in combination with cetuximab and intensity-modulated radiotherapy in patients with advanced HNSCC (NCT01860430 and NCT01935921).	('HNSCC', 'Phenotype', 'HP:0012288', (151, 156))	('advanced HNSCC', 'Disease', (142, 156))	('cetuximab', 'Chemical', 'MESH:D000068818', (78, 87))	('NCT01860430', 'Var', (158, 169))	('NCT01935921', 'Var', (174, 185))	('Ipilimumab', 'Chemical', 'MESH:D000074324', (0, 10))	('patients', 'Species', '9606', (128, 136))
570482	29238207	Some Phase II/III trials are underway to evaluate the clinical efficacy (ORR, response duration, and side effects) of pembrolizumab in R/M HNSCC (NCT02255097, NCT02252042).	('NCT02255097', 'Var', (146, 157))	('pembrolizumab', 'Chemical', 'MESH:C582435', (118, 131))	('HNSCC', 'Phenotype', 'HP:0012288', (139, 144))	('NCT02252042', 'Var', (159, 170))
570484	29238207	In patients with HNSCC refractory to platinum therapy, a randomized Phase III trial of nivolumab (NCT02105636) resulted in improved OS compared with treatment with the weekly methotrexate, docetaxel, or cetuximab (NCT02105636).	('HNSCC', 'Phenotype', 'HP:0012288', (17, 22))	('docetaxel', 'Chemical', 'MESH:D000077143', (189, 198))	('platinum', 'Chemical', 'MESH:D010984', (37, 45))	('NCT02105636', 'Var', (98, 109))	('nivolumab', 'Chemical', 'MESH:D000077594', (87, 96))	('patients', 'Species', '9606', (3, 11))	('improved', 'PosReg', (123, 131))	('cetuximab', 'Chemical', 'MESH:D000068818', (203, 212))	('methotrexate', 'Chemical', 'MESH:D008727', (175, 187))
570486	29238207	At present, representative antibodies targeting PD-L1 include BMS-936559 (also known as MDX1105), MPDL3280A, and durvalumab (MEDI-4736), which have been applied as monotherapy or adjuncts to conventional therapies in clinical trials for a variety of tumors.	('MPDL3280A', 'Var', (98, 107))	('tumors', 'Disease', (250, 256))	('durvalumab', 'Chemical', 'MESH:C000613593', (113, 123))	('tumors', 'Phenotype', 'HP:0002664', (250, 256))	('BMS-936559', 'Var', (62, 72))	('tumor', 'Phenotype', 'HP:0002664', (250, 255))	('PD-L1', 'Gene', (48, 53))	('tumors', 'Disease', 'MESH:D009369', (250, 256))
570487	29238207	Two ongoing Phase I trials, with anti-PD-L1 mAb (IgG1 isotype) MEDI-4736 (NCT01693562) and anti-PD-1 mAb (IgG4 isotype) MK-3475 (NCT01848834), have recruited cohorts of R/M HNSCC patients.	('PD-1', 'Gene', (96, 100))	('PD-1', 'Gene', '5133', (96, 100))	('R/M HNSCC', 'Disease', (169, 178))	('HNSCC', 'Phenotype', 'HP:0012288', (173, 178))	('NCT01693562', 'Var', (74, 85))	('NCT01693562', 'CellLine', 'None', (74, 85))	('patients', 'Species', '9606', (179, 187))	('MK-3475', 'Chemical', 'MESH:C582435', (120, 127))
570488	29238207	The disease control rate at 6 months was 15% (18% for PD-L1-positive vs 11% for PD-L1-negative), and the ORR in patients with HNSCC was 11%.	('patients', 'Species', '9606', (112, 120))	('HNSCC', 'Phenotype', 'HP:0012288', (126, 131))	('disease control', 'CPA', (4, 19))	('PD-L1-positive', 'Var', (54, 68))
570491	29238207	In another randomized Phase I/II trial to assess the combination of MEDI-4738 with either AZD9150 or AZD5069 in patients with metastatic squamous cell carcinoma of head and neck (NCT02499328), the clinical safety/efficacy and ORR are being evaluated.	('squamous cell carcinoma', 'Disease', (137, 160))	('combination', 'Interaction', (53, 64))	('AZD5069', 'Chemical', 'MESH:C000597960', (101, 108))	('patients', 'Species', '9606', (112, 120))	('AZD5069', 'Var', (101, 108))	('carcinoma of head and neck', 'Phenotype', 'HP:0012288', (151, 177))	('carcinoma', 'Phenotype', 'HP:0030731', (151, 160))	('AZD9150', 'Chemical', 'MESH:C000610954', (90, 97))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (137, 160))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (137, 160))	('MEDI-4738', 'Gene', (68, 77))	('AZD9150', 'Var', (90, 97))
570492	29238207	Some trials evaluating the utility of MEDI-4736 monotherapy alone or in conjunction with tremelimumab (anti-CTLA-4) compared to the standard treatment for first-line R/M HNSCC are ongoing (NCT02551159, NCT02369874, NCT02319044).	('NCT02319044', 'Var', (215, 226))	('NCT02369874', 'Var', (202, 213))	('NCT02551159', 'Var', (189, 200))	('tremelimumab', 'Chemical', 'MESH:C520704', (89, 101))	('HNSCC', 'Phenotype', 'HP:0012288', (170, 175))
570495	29238207	Blockades of immune checkpoints have proved to play a vital role in enhancing immune surveillance and tumor cell clearance, which provides oncologists with a significant set of antitumor therapies with promising potentials.	('tumor', 'Disease', (181, 186))	('Blockades', 'Var', (0, 9))	('enhancing', 'PosReg', (68, 77))	('tumor', 'Disease', 'MESH:D009369', (102, 107))	('tumor', 'Disease', 'MESH:D009369', (181, 186))	('tumor', 'Phenotype', 'HP:0002664', (102, 107))	('tumor', 'Disease', (102, 107))	('tumor', 'Phenotype', 'HP:0002664', (181, 186))	('immune surveillance', 'CPA', (78, 97))
570503	28423633	In ccRCC cell lines, SLINKY knockdown reduced cancer cell proliferation (with cell-cycle G1 arrest) and induced transcriptome changes enriched for cell proliferation and survival processes.	('cancer', 'Disease', 'MESH:D009369', (46, 52))	('reduced', 'NegReg', (38, 45))	('cancer', 'Disease', (46, 52))	('transcriptome changes', 'MPA', (112, 133))	('RCC', 'Disease', 'MESH:C538614', (5, 8))	('ccRCC', 'Phenotype', 'HP:0006770', (3, 8))	('RCC', 'Disease', (5, 8))	('SLINKY', 'Gene', (21, 27))	('cancer', 'Phenotype', 'HP:0002664', (46, 52))	('knockdown', 'Var', (28, 37))
570504	28423633	Notably, the genes affected by SLINKY knockdown in cell lines were themselves prognostic and correlated with SLINKY expression in the ccRCC patient samples.	('correlated', 'Reg', (93, 103))	('ccRCC', 'Phenotype', 'HP:0006770', (134, 139))	('patient', 'Species', '9606', (140, 147))	('RCC', 'Disease', 'MESH:C538614', (136, 139))	('knockdown', 'Var', (38, 47))	('RCC', 'Disease', (136, 139))
570520	28423633	Investigating its function, we found that SLINKY knockdown in ccRCC cell lines reduces cell proliferation, causes cell-cycle arrest, and alters gene expression programs related to cell growth and survival.	('knockdown', 'Var', (49, 58))	('cell-cycle arrest', 'CPA', (114, 131))	('alters', 'Reg', (137, 143))	('reduces', 'NegReg', (79, 86))	('cell proliferation', 'CPA', (87, 105))	('causes', 'Reg', (107, 113))	('RCC', 'Disease', 'MESH:C538614', (64, 67))	('ccRCC', 'Phenotype', 'HP:0006770', (62, 67))	('RCC', 'Disease', (64, 67))	('gene expression programs', 'MPA', (144, 168))
570528	28423633	SLINKY expression appeared to be cancer specific since it was not detected (RPKM < 0.001) in normal kidney samples (Figure 1F), but was measurable (RPKM > 0.001) in 59% of tumor samples (P < 0.001; Mann-Whitney U-test).	('tumor', 'Phenotype', 'HP:0002664', (172, 177))	('cancer', 'Disease', (33, 39))	('cancer', 'Disease', 'MESH:D009369', (33, 39))	('tumor', 'Disease', (172, 177))	('cancer', 'Phenotype', 'HP:0002664', (33, 39))	('SLINKY', 'Var', (0, 6))	('tumor', 'Disease', 'MESH:D009369', (172, 177))
570530	28423633	SLINKY expression did not correlate with the presence of either VHL or PBRM1 mutation (Supplementary Figure S1).	('VHL', 'Disease', 'MESH:D006623', (64, 67))	('PBRM1', 'Gene', (71, 76))	('men', 'Species', '9606', (93, 96))	('VHL', 'Disease', (64, 67))	('mutation', 'Var', (77, 85))	('PBRM1', 'Gene', '55193', (71, 76))
570539	28423633	For example, high SLINKY expression in patients with Stage III RCC was associated with an approximate 3-fold higher death rate compared to the low expression group (53% vs. 18%, P < 0.001).	('RCC', 'Disease', (63, 66))	('death', 'Disease', 'MESH:D003643', (116, 121))	('patients', 'Species', '9606', (39, 47))	('death', 'Disease', (116, 121))	('high', 'Var', (13, 17))	('SLINKY', 'Protein', (18, 24))	('RCC', 'Disease', 'MESH:C538614', (63, 66))
570540	28423633	For the stage I and II patients, high SLINKY levels were associated with more than double the risk of death (24% vs. 11%, P < 0.01).	('high', 'Var', (33, 37))	('death', 'Disease', 'MESH:D003643', (102, 107))	('death', 'Disease', (102, 107))	('patients', 'Species', '9606', (23, 31))	('SLINKY levels', 'MPA', (38, 51))
570542	28423633	The finding that SLINKY lincRNA was highly prognostic implies a possible mechanistic role in ccRCC development and/or progression.	('SLINKY', 'Var', (17, 23))	('RCC', 'Disease', 'MESH:C538614', (95, 98))	('RCC', 'Disease', (95, 98))	('ccRCC', 'Phenotype', 'HP:0006770', (93, 98))	('men', 'Species', '9606', (106, 109))
570544	28423633	The two most highly expressed SLINKY transcript variants (from the TCGA ccRCC data) both include the first exon, and therefore we designed two different siRNAs targeting distinct sequences within that exon (Figure 3A).	('RCC', 'Disease', 'MESH:C538614', (74, 77))	('variants', 'Var', (48, 56))	('ccRCC', 'Phenotype', 'HP:0006770', (72, 77))	('RCC', 'Disease', (74, 77))
570547	28423633	Using a Matrigel cell invasion assay, we observed that SLINKY knockdown did not affect cell invasion (Supplementary Figure S3).	('men', 'Species', '9606', (108, 111))	('knockdown', 'Var', (62, 71))	('cell invasion', 'CPA', (87, 100))	('SLINKY', 'Gene', (55, 61))
570550	28423633	However, SLINKY knockdown did not alter PIK3CG expression levels (which were not detectable at baseline), measured by RNA-seq (Supplementary Figure 4B).	('PIK3CG', 'Gene', '5294', (40, 46))	('knockdown', 'Var', (16, 25))	('men', 'Species', '9606', (133, 136))	('PIK3CG', 'Gene', (40, 46))	('expression', 'MPA', (47, 57))
570551	28423633	To better understand the role of SLINKY in ccRCC cells, we assayed whole-transcriptome changes (by RNA-seq) following SLINKY knockdown in 786-O and A-498 cells, using two different SLINKY siRNAs compared to non-targeting control.	('knockdown', 'Var', (125, 134))	('ccRCC', 'Phenotype', 'HP:0006770', (43, 48))	('A-498', 'CellLine', 'CVCL:1056', (148, 153))	('SLINKY', 'Gene', (118, 124))	('RCC', 'Disease', 'MESH:C538614', (45, 48))	('RCC', 'Disease', (45, 48))
570558	28423633	In a complementary approach, we used the 93 genes showing altered expression upon SLINKY knockdown in both ccRCC cell lines to cluster the TCGA patient samples.	('RCC', 'Disease', 'MESH:C538614', (109, 112))	('patient', 'Species', '9606', (144, 151))	('RCC', 'Disease', (109, 112))	('ccRCC', 'Phenotype', 'HP:0006770', (107, 112))	('knockdown', 'Var', (89, 98))	('men', 'Species', '9606', (11, 14))
570564	28423633	To evaluate the functional relevance of the SLINKY-HNRNPK interaction, we used siRNA to knockdown HNRNPK in the same ccRCC cell lines previously assessed for SLINKY knockdown.	('HNRNPK', 'Gene', (98, 104))	('HNRNPK', 'Gene', '3190', (98, 104))	('HNRNPK', 'Gene', (51, 57))	('HNRNPK', 'Gene', '3190', (51, 57))	('knockdown', 'Var', (88, 97))	('RCC', 'Disease', 'MESH:C538614', (119, 122))	('ccRCC', 'Phenotype', 'HP:0006770', (117, 122))	('RCC', 'Disease', (119, 122))
570565	28423633	Notably, HNRNPK knockdown led to reduced cell proliferation, at least comparable with SLINKY knockdown (Figure 5C).	('cell proliferation', 'CPA', (41, 59))	('HNRNPK', 'Gene', (9, 15))	('knockdown', 'Var', (16, 25))	('HNRNPK', 'Gene', '3190', (9, 15))	('reduced', 'NegReg', (33, 40))
570566	28423633	Moreover, the transcriptome changes induced by HNRNPK knockdown displayed a marked overlap (about one-third) with those observed with SLINKY knockdown, significantly more than expected by chance (P < 0.001; hypergeometric test; Figure 5D).	('transcriptome changes', 'MPA', (14, 35))	('HNRNPK', 'Gene', (47, 53))	('HNRNPK', 'Gene', '3190', (47, 53))	('knockdown', 'Var', (54, 63))
570567	28423633	Furthermore, in both cell lines, the altered genes common to SLINKY and HNRNPK knockdown exhibited significant enrichment for cell proliferation, cell survival and cell cycle functions by Ingenuity Pathway Analysis (Figure 5E).	('cell cycle functions', 'CPA', (164, 184))	('cell proliferation', 'CPA', (126, 144))	('HNRNPK', 'Gene', (72, 78))	('men', 'Species', '9606', (117, 120))	('HNRNPK', 'Gene', '3190', (72, 78))	('cell survival', 'CPA', (146, 159))	('knockdown', 'Var', (79, 88))
570569	28423633	We have identified SLINKY as a potentially significant lincRNA in ccRCC biology that could serve as an important biomarker of ccRCC prognosis.	('RCC', 'Disease', 'MESH:C538614', (128, 131))	('RCC', 'Disease', (128, 131))	('SLINKY', 'Var', (19, 25))	('ccRCC', 'Phenotype', 'HP:0006770', (126, 131))	('RCC', 'Disease', 'MESH:C538614', (68, 71))	('ccRCC', 'Phenotype', 'HP:0006770', (66, 71))	('RCC', 'Disease', (68, 71))
570578	28423633	HOTAIR is over-expressed in several RCC cell lines and knockdown of HOTAIR inhibits cell proliferation.	('HOTAIR', 'Gene', '100124700', (0, 6))	('knockdown', 'Var', (55, 64))	('RCC', 'Disease', 'MESH:C538614', (36, 39))	('RCC', 'Disease', (36, 39))	('HOTAIR', 'Gene', (68, 74))	('HOTAIR', 'Gene', (0, 6))	('cell proliferation', 'CPA', (84, 102))	('HOTAIR', 'Gene', '100124700', (68, 74))	('inhibits', 'NegReg', (75, 83))
570579	28423633	The lincRNAs MALAT-1and NBAT-1 have been identified in several malignancies and alteration of their expression levels has been shown to correlate with adverse outcomes in ccRCC.	('identified', 'Reg', (41, 51))	('RCC', 'Disease', (173, 176))	('expression levels', 'MPA', (100, 117))	('RCC', 'Disease', 'MESH:C538614', (173, 176))	('malignancies', 'Disease', 'MESH:D009369', (63, 75))	('MALAT-1', 'Gene', '378938', (13, 20))	('ccRCC', 'Phenotype', 'HP:0006770', (171, 176))	('NBAT-1', 'Gene', '729177', (24, 30))	('NBAT-1', 'Gene', (24, 30))	('malignancies', 'Disease', (63, 75))	('MALAT-1', 'Gene', (13, 20))	('alteration', 'Var', (80, 90))
570586	28423633	In our study, we find that SLINKY enhances cancer cell proliferation most likely through its interaction with HNRNPK.	('cancer', 'Disease', 'MESH:D009369', (43, 49))	('cancer', 'Disease', (43, 49))	('HNRNPK', 'Gene', (110, 116))	('interaction', 'Interaction', (93, 104))	('SLINKY', 'Var', (27, 33))	('enhances', 'PosReg', (34, 42))	('HNRNPK', 'Gene', '3190', (110, 116))	('cancer', 'Phenotype', 'HP:0002664', (43, 49))
570590	28423633	In our studies, knockdown of either SLINKY or HNRNPK leads to both the upregulation and downregulation of genes, so the possible recruitment of HNRNPK to gene loci (yet to be proven) might serve to either activate or repress genes.	('downregulation', 'NegReg', (88, 102))	('HNRNPK', 'Gene', '3190', (144, 150))	('knockdown', 'Var', (16, 25))	('HNRNPK', 'Gene', '3190', (46, 52))	('upregulation', 'PosReg', (71, 83))	('HNRNPK', 'Gene', (46, 52))	('activate', 'PosReg', (205, 213))	('genes', 'Gene', (225, 230))	('men', 'Species', '9606', (136, 139))	('HNRNPK', 'Gene', (144, 150))	('repress', 'NegReg', (217, 224))
570620	28423633	48 hrs following siRNA transfection, cells were seeded in serum-free DMEM media (20,000 cells/chamber), with 10% FBS in the lower chamber serving as a chemoattractant.	('FBS', 'Disease', 'MESH:D005198', (113, 116))	('transfection', 'Var', (23, 35))	('DMEM media', 'Chemical', '-', (69, 79))	('siRNA', 'Gene', (17, 22))	('FBS', 'Disease', (113, 116))
570662	27532037	Probes for the genes encoding NANOG (NM_024865.2), SALL4 (NM_020436.3) SOX2 (NM_003106.2), OCT4 (NM_002701.4), CD44 (NM_001001392.1), and STAT3 (NM_139276.2) and the housekeeping gene GUSB (NM_000181.1) were designed and manufactured by NanoString Technologies.	('NANOG', 'Gene', '79923', (30, 35))	('NANOG', 'Gene', (30, 35))	('NM_001001392.1', 'Var', (117, 131))	('GUSB', 'Gene', (184, 188))	('SALL4', 'Gene', '57167', (51, 56))	('CD44', 'Gene', '960', (111, 115))	('NM_002701.4', 'Var', (97, 108))	('CD44', 'Gene', (111, 115))	('STAT3', 'Gene', (138, 143))	('NM_020436.3', 'Var', (58, 69))	('OCT4', 'Gene', '5460', (91, 95))	('SOX2', 'Gene', (71, 75))	('SOX2', 'Gene', '6657', (71, 75))	('NM_003106.2', 'Var', (77, 88))	('STAT3', 'Gene', '6774', (138, 143))	('SALL4', 'Gene', (51, 56))	('GUSB', 'Gene', '2990', (184, 188))	('NM_139276.2', 'Var', (145, 156))	('OCT4', 'Gene', (91, 95))	('NM_024865.2', 'Var', (37, 48))
570664	27532037	The probes used for NANOG (NM_024865), SOX2 (NM_003106), SALL4 (NM_020436), STAT3 (NM_003150), and OCT4 (NM_002701) were obtained from Affymetrix.	('STAT3', 'Gene', '6774', (76, 81))	('NM_003150', 'Var', (83, 92))	('SALL4', 'Gene', '57167', (57, 62))	('NANOG', 'Gene', '79923', (20, 25))	('STAT3', 'Gene', (76, 81))	('OCT4', 'Gene', '5460', (99, 103))	('NM_003106', 'Var', (45, 54))	('SALL4', 'Gene', (57, 62))	('NANOG', 'Gene', (20, 25))	('NM_020436', 'Var', (64, 73))	('SOX2', 'Gene', '6657', (39, 43))	('NM_002701', 'Var', (105, 114))	('SOX2', 'Gene', (39, 43))	('OCT4', 'Gene', (99, 103))	('NM_024865', 'Var', (27, 36))
570716	26541825	Interestingly, very few cancer types harbor mutations in DDX3, which result in altered protein function rather than a loss of function.	('cancer', 'Phenotype', 'HP:0002664', (24, 30))	('altered', 'Reg', (79, 86))	('cancer', 'Disease', (24, 30))	('cancer', 'Disease', 'MESH:D009369', (24, 30))	('protein function', 'MPA', (87, 103))	('mutations', 'Var', (44, 53))	('DDX3', 'Gene', (57, 61))
570725	26541825	DEAD-box helicases are present in almost all organisms, conserved from human to yeast, and play a crucial role, as knockdown of these helicases are embryonically lethal.	('helicase', 'Gene', '164045', (9, 17))	('helicase', 'Gene', (9, 17))	('helicase', 'Gene', '164045', (134, 142))	('yeast', 'Species', '4932', (80, 85))	('helicase', 'Gene', (134, 142))	('human', 'Species', '9606', (71, 76))	('knockdown', 'Var', (115, 124))
570730	26541825	Deletion of DDX3Y causes azoospermia and cannot be rescued by the DDX3X homologue in humans.	('DDX3X', 'Gene', '1654', (66, 71))	('azoospermia', 'Disease', (25, 36))	('humans', 'Species', '9606', (85, 91))	('DDX3Y', 'Gene', '8653', (12, 17))	('DDX3Y', 'Gene', (12, 17))	('causes', 'Reg', (18, 24))	('azoospermia', 'Phenotype', 'HP:0000027', (25, 36))	('azoospermia', 'Disease', 'MESH:D053713', (25, 36))	('DDX3X', 'Gene', (66, 71))	('Deletion', 'Var', (0, 8))
570732	26541825	Deletion of DDX3 is embryonically lethal; however, Ded1P (Yeast orthologue) deletion can be rescued by human DDX3 or Belle (Drosophila orthologue), which underscores the conserved functionality across different species (Fig.	('deletion', 'Var', (76, 84))	('human', 'Species', '9606', (103, 108))	('Ded1P', 'Gene', '854379', (51, 56))	('Belle', 'Gene', '45826', (117, 122))	('Yeast', 'Species', '4932', (58, 63))	('DDX3', 'Gene', (12, 16))	('Belle', 'Gene', (117, 122))	('Drosophila', 'Species', '7227', (124, 134))	('Ded1P', 'Gene', (51, 56))	('Deletion', 'Var', (0, 8))
570742	26541825	Purine nucleobase stacks over phenyl group of Tyr 200.	('nucleobase', 'Chemical', '-', (7, 17))	('Tyr', 'Chemical', 'MESH:D014443', (46, 49))	('Tyr 200', 'Var', (46, 53))	('Purine nucleobase stacks', 'MPA', (0, 24))
570743	26541825	The adenine moiety of AMP interacts with amino acids in the Q motif (Arg 202 and Gln 207), whereas residues in the P-loop in motif I interact with the phosphate group (Gly 227, Ser228, Gly 229, Lys 230 and Thr 231).	('AMP', 'Gene', '353', (22, 25))	('Ser228', 'Chemical', '-', (177, 183))	('Lys', 'Chemical', 'MESH:D008239', (194, 197))	('Lys', 'Var', (194, 197))	('interact', 'Reg', (133, 141))	('Gly 227', 'Var', (168, 175))	('Arg 202', 'Var', (69, 76))	('interacts', 'Interaction', (26, 35))	('Ser228', 'Var', (177, 183))	('phosphate', 'Chemical', 'MESH:D010710', (151, 160))	('adenine', 'Chemical', 'MESH:D000225', (4, 11))	('AMP', 'Gene', (22, 25))	('Gly 229', 'Var', (185, 192))	('Arg', 'Chemical', 'MESH:D001120', (69, 72))	('Gly', 'Chemical', 'MESH:D005998', (168, 171))	('Gly', 'Chemical', 'MESH:D005998', (185, 188))	('Gln', 'Chemical', 'MESH:D005973', (81, 84))	('Thr', 'Chemical', 'MESH:D013912', (206, 209))	('Gln 207', 'Var', (81, 88))
570758	26541825	Stress granules and translation defects, initiated by Gle1A knockdown, are rescued by expression of DDX3, underlining the importance of DDX3 in stress granule dynamics.	('Gle1', 'Gene', '2733', (54, 58))	('DDX3', 'Gene', (100, 104))	('Gle1', 'Gene', (54, 58))	('knockdown', 'Var', (60, 69))	('translation', 'MPA', (20, 31))
570774	26541825	Strong stimulation of death receptors overcomes this antiapoptotic complex by inactivating GSK3 and cleaving DDX3 and cIAP-1, permitting progression of the apoptotic signal.	('inactivating', 'NegReg', (78, 90))	('stimulation', 'PosReg', (7, 18))	('cIAP-1', 'Gene', '329', (118, 124))	('DDX3', 'Gene', (109, 113))	('cleaving', 'Var', (100, 108))	('cIAP-1', 'Gene', (118, 124))	('GSK3', 'Protein', (91, 95))
570778	26541825	It was reported that DDX3 functions irrespective of p53 however, all hepatocellular cancer samples with enhanced DDX3 mRNA expression also harbored p53 mutations.	('hepatocellular cancer', 'Phenotype', 'HP:0001402', (69, 90))	('mutations', 'Var', (152, 161))	('p53', 'Gene', (148, 151))	('p53', 'Gene', (52, 55))	('p53', 'Gene', '7157', (52, 55))	('enhanced', 'PosReg', (104, 112))	('p53', 'Gene', '7157', (148, 151))	('hepatocellular cancer', 'Disease', 'MESH:D006528', (69, 90))	('cancer', 'Phenotype', 'HP:0002664', (84, 90))	('hepatocellular cancer', 'Disease', (69, 90))	('DDX3', 'Gene', (113, 117))	('mRNA expression', 'MPA', (118, 133))
570779	26541825	In contrast with these results, in lung cancer, it was shown that p53 inactivation (HPV or mutation) reduced DDX3 expression by transcriptional regulation.	('mutation', 'Var', (91, 99))	('lung cancer', 'Disease', 'MESH:D008175', (35, 46))	('p53', 'Gene', '7157', (66, 69))	('inactivation', 'NegReg', (70, 82))	('lung cancer', 'Disease', (35, 46))	('reduced', 'NegReg', (101, 108))	('lung cancer', 'Phenotype', 'HP:0100526', (35, 46))	('DDX3', 'Gene', (109, 113))	('expression', 'MPA', (114, 124))	('cancer', 'Phenotype', 'HP:0002664', (40, 46))	('p53', 'Gene', (66, 69))
570783	26541825	Paradoxically, in cells expressing mutant or non-functional p53, DDX3 inhibits apoptosis by reducing caspase 3 activation.	('reducing', 'NegReg', (92, 100))	('DDX3', 'Gene', (65, 69))	('non-functional', 'Var', (45, 59))	('caspase 3', 'Gene', (101, 110))	('mutant', 'Var', (35, 41))	('inhibits', 'NegReg', (70, 78))	('caspase 3', 'Gene', '836', (101, 110))	('p53', 'Gene', (60, 63))	('apoptosis', 'CPA', (79, 88))	('activation', 'MPA', (111, 121))	('p53', 'Gene', '7157', (60, 63))
570786	26541825	In contrast to the role of DDX3 in the stress response as described above, the H Lee group and Y-H Wu Lee group have reported that DDX3 reduces cell cycle progression via p53-DDX3-p21 regulation.	('p21', 'Gene', (180, 183))	('p21', 'Gene', '644914', (180, 183))	('DDX3', 'Var', (131, 135))	('reduces', 'NegReg', (136, 143))	('p53', 'Gene', (171, 174))	('cell cycle progression', 'CPA', (144, 166))	('p53', 'Gene', '7157', (171, 174))
570793	26541825	Like the epithelial-mesenchymal transition that occurred after overexpression of DDX3 in breast cancer cells, phosphorylated DDX5 interacted with nuclear beta-catenin and subsequently stimulated EMT via a Wnt-independent pathway.	('stimulated', 'PosReg', (184, 194))	('breast cancer', 'Disease', 'MESH:D001943', (89, 102))	('EMT', 'Gene', (195, 198))	('DDX5', 'Gene', (125, 129))	('cancer', 'Phenotype', 'HP:0002664', (96, 102))	('DDX5', 'Gene', '1655', (125, 129))	('EMT', 'Gene', '3702', (195, 198))	('breast cancer', 'Disease', (89, 102))	('Wnt-independent pathway', 'Pathway', (205, 228))	('beta-catenin', 'Gene', '1499', (154, 166))	('breast cancer', 'Phenotype', 'HP:0003002', (89, 102))	('phosphorylated', 'Var', (110, 124))	('interacted', 'Interaction', (130, 140))	('beta-catenin', 'Gene', (154, 166))
570795	26541825	Moreover, mutant DDX3 potentiates transactivation of the TCF promoter and enhances cell viability in combination with mutant, but not wild-type, beta-catenin.	('mutant', 'Var', (10, 16))	('enhances', 'PosReg', (74, 82))	('beta-catenin', 'Gene', (145, 157))	('cell viability', 'CPA', (83, 97))	('potentiates', 'PosReg', (22, 33))	('beta-catenin', 'Gene', '1499', (145, 157))	('TCF', 'Gene', '3172', (57, 60))	('DDX3', 'Gene', (17, 21))	('transactivation', 'MPA', (34, 49))	('TCF', 'Gene', (57, 60))
570796	26541825	Xenopus and C.elegans development depends on Wnt signaling, which was impaired by knockdown of DDX3.	('Wnt signaling', 'MPA', (45, 58))	('knockdown', 'Var', (82, 91))	('C.elegans', 'Species', '6239', (12, 21))	('Xenopus', 'Species', '8355', (0, 7))	('DDX3', 'Gene', (95, 99))	('impaired', 'NegReg', (70, 78))
570798	26541825	Another mechanism in which DDX3 can impair Wnt signaling is via translational control of Rac1.	('DDX3', 'Var', (27, 31))	('Rac1', 'Gene', '5879', (89, 93))	('Rac1', 'Gene', (89, 93))	('Wnt signaling', 'MPA', (43, 56))	('impair', 'NegReg', (36, 42))
570823	26541825	In public databases of RNA expression in cancer, high DDX3 level was a poor prognostic indicator in RNA sequencing analysis but not in microarray analysis (HR 2.06; p < 0.001).	('cancer', 'Disease', 'MESH:D009369', (41, 47))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('high', 'Var', (49, 53))	('cancer', 'Disease', (41, 47))
570827	26541825	For colon cancer specifically, the high frequency of both mutations in p53 and dysregulation of the Wnt pathway, in combination with the earlier described association of DDX3 with these oncogenic pathways, may explain why there appears to be a positive prognostic association with DDX3.	('mutations', 'Var', (58, 67))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('colon cancer', 'Phenotype', 'HP:0003003', (4, 16))	('p53', 'Gene', (71, 74))	('colon cancer', 'Disease', 'MESH:D015179', (4, 16))	('p53', 'Gene', '7157', (71, 74))	('Wnt pathway', 'Pathway', (100, 111))	('colon cancer', 'Disease', (4, 16))
570828	26541825	In gallbladder cancer as well, high DDX3 expression was related to worse survival both in squamous cell carcinoma, 13 vs 8 months (p = 0.003), as in adenocarcinoma, 15 vs 7 months (p < 0.001).	('adenocarcinoma', 'Disease', 'MESH:D000230', (149, 163))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (90, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (104, 113))	('squamous cell carcinoma', 'Disease', (90, 113))	('expression', 'MPA', (41, 51))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (90, 113))	('DDX3', 'Gene', (36, 40))	('adenocarcinoma', 'Disease', (149, 163))	('high', 'Var', (31, 35))	('carcinoma', 'Phenotype', 'HP:0030731', (154, 163))	('cancer', 'Phenotype', 'HP:0002664', (15, 21))	('worse', 'NegReg', (67, 72))	('gallbladder cancer', 'Disease', (3, 21))	('gallbladder cancer', 'Disease', 'MESH:D005706', (3, 21))
570833	26541825	showed that loss of DDX3 decreases Rac1 and beta-catenin proteins, leading to lower Wnt/beta-catenin target proteins.	('DDX3', 'Gene', (20, 24))	('decreases', 'NegReg', (25, 34))	('beta-catenin', 'Gene', (44, 56))	('loss', 'Var', (12, 16))	('beta-catenin', 'Gene', (88, 100))	('Rac1', 'Gene', '5879', (35, 39))	('beta-catenin', 'Gene', '1499', (44, 56))	('lower', 'NegReg', (78, 83))	('Rac1', 'Gene', (35, 39))	('beta-catenin', 'Gene', '1499', (88, 100))
570835	26541825	We obtained similar results which demonstrated that knockdown of DDX3 in cancer cells decreased metastatic load in the lungs in a preclinical model of breast cancer.	('cancer', 'Disease', (73, 79))	('cancer', 'Disease', 'MESH:D009369', (73, 79))	('DDX3', 'Gene', (65, 69))	('cancer', 'Disease', 'MESH:D009369', (158, 164))	('breast cancer', 'Disease', 'MESH:D001943', (151, 164))	('cancer', 'Phenotype', 'HP:0002664', (73, 79))	('breast cancer', 'Phenotype', 'HP:0003002', (151, 164))	('cancer', 'Disease', (158, 164))	('metastatic load in the lungs', 'CPA', (96, 124))	('breast cancer', 'Disease', (151, 164))	('decreased', 'NegReg', (86, 95))	('knockdown', 'Var', (52, 61))	('cancer', 'Phenotype', 'HP:0002664', (158, 164))
570841	26541825	Here it was shown that loss of DDX3 also led to a loss of E-cadherin as a possible explanation for the increase in metastatic events.	('metastatic events', 'CPA', (115, 132))	('increase', 'PosReg', (103, 111))	('DDX3', 'Gene', (31, 35))	('loss', 'NegReg', (50, 54))	('E-cadherin', 'Gene', (58, 68))	('E-cadherin', 'Gene', '999', (58, 68))	('loss', 'Var', (23, 27))
570846	26541825	As much as 50 % (16 of 32) of all Wnt associated medulloblastomas and 11 % (7 of 66) of all SHH associated medulloblastoma cases harbored mutations in DDX3.	('harbored', 'Reg', (129, 137))	('medulloblastoma', 'Disease', (107, 122))	('DDX3', 'Gene', (151, 155))	('medulloblastomas', 'Disease', 'MESH:D008527', (49, 65))	('SHH', 'Gene', '6469', (92, 95))	('medulloblastoma', 'Disease', 'MESH:D008527', (49, 64))	('medulloblastomas', 'Disease', (49, 65))	('medulloblastoma', 'Disease', 'MESH:D008527', (107, 122))	('SHH', 'Gene', (92, 95))	('medulloblastoma', 'Phenotype', 'HP:0002885', (49, 64))	('medulloblastoma', 'Phenotype', 'HP:0002885', (107, 122))	('medulloblastoma', 'Disease', (49, 64))	('mutations', 'Var', (138, 147))
570847	26541825	Through mapping of the mutations to its crystal structure, it seems that the mutations alter DDX3 - RNA binding and are likely to result in altered protein function, as opposed to loss of function.	('protein function', 'MPA', (148, 164))	('altered', 'Reg', (140, 147))	('DDX3 - RNA', 'Protein', (93, 103))	('Thr', 'Chemical', 'MESH:D013912', (0, 3))	('binding', 'Interaction', (104, 111))	('mutations', 'Var', (77, 86))	('alter', 'Reg', (87, 92))
570848	26541825	DDX3 mutations enhance cellular proliferation by potentiating the transactivation capacity of mutant beta-catenin.	('DDX3', 'Gene', (0, 4))	('cellular proliferation', 'CPA', (23, 45))	('beta-catenin', 'Gene', (101, 113))	('mutant', 'Var', (94, 100))	('mutations', 'Var', (5, 14))	('potentiating', 'PosReg', (49, 61))	('beta-catenin', 'Gene', '1499', (101, 113))	('transactivation capacity', 'MPA', (66, 90))	('enhance', 'PosReg', (15, 22))
570850	26541825	In head and neck cancer, missense mutations in DDX3 do occur but, the majority of genetic alterations are homozygous deletions, frame shift-, and nonsense- mutations, which is more supportive of loss of function.	('neck cancer', 'Disease', 'MESH:D006258', (12, 23))	('neck cancer', 'Disease', (12, 23))	('frame shift-', 'Var', (128, 140))	('nonsense- mutations', 'Var', (146, 165))	('missense mutations', 'Var', (25, 43))	('DDX3', 'Gene', (47, 51))	('head and neck cancer', 'Phenotype', 'HP:0012288', (3, 23))	('cancer', 'Phenotype', 'HP:0002664', (17, 23))
570851	26541825	Interestingly, all mutations were found in oropharyngeal cancer and deletions were found in oral squamous cell cancer.	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('oral squamous cell cancer', 'Disease', (92, 117))	('deletions', 'Var', (68, 77))	('cancer', 'Disease', (57, 63))	('squamous cell cancer', 'Phenotype', 'HP:0002860', (97, 117))	('cancer', 'Phenotype', 'HP:0002664', (111, 117))	('mutations', 'Var', (19, 28))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('found', 'Reg', (34, 39))	('cancer', 'Disease', (111, 117))	('cancer', 'Disease', 'MESH:D009369', (111, 117))	('found', 'Reg', (83, 88))	('oral squamous cell cancer', 'Disease', 'MESH:D002294', (92, 117))
570853	26541825	By mining the COSMIC database, we found only 12 % of genetic abnormalities of the DDX3 gene typical for tumor suppressor genes (nonsense mutation, deletions, frame shift or loss of heterozygosity), whereas 81 % of DDX3 genetic abnormalities are more typical for a gain of function (substitution missense mutations).	('tumor', 'Phenotype', 'HP:0002664', (104, 109))	('genetic abnormalities', 'Disease', 'MESH:D030342', (219, 240))	('genetic abnormalities', 'Disease', (53, 74))	('tumor', 'Disease', (104, 109))	('loss of', 'NegReg', (173, 180))	('frame shift', 'Var', (158, 169))	('tumor', 'Disease', 'MESH:D009369', (104, 109))	('deletions', 'Var', (147, 156))	('genetic abnormalities', 'Disease', 'MESH:D030342', (53, 74))	('genetic abnormalities', 'Disease', (219, 240))	('nonsense mutation', 'Var', (128, 145))	('substitution missense mutations', 'Var', (282, 313))	('gain of function', 'PosReg', (264, 280))	('DDX3', 'Gene', (82, 86))
570854	26541825	In conclusion, DDX3 mutations are found in different types of cancer and seem to induce altered protein function rather than a loss of function.	('cancer', 'Phenotype', 'HP:0002664', (62, 68))	('altered', 'Reg', (88, 95))	('protein function', 'MPA', (96, 112))	('cancer', 'Disease', (62, 68))	('cancer', 'Disease', 'MESH:D009369', (62, 68))	('DDX3', 'Gene', (15, 19))	('mutations', 'Var', (20, 29))
570855	26541825	In addition to the supporting evidence that DDX3 could act as a putative oncogene, there is an opposing view that loss of DDX3 promotes growth and could have potential tumor suppressor functions.	('DDX3', 'Gene', (122, 126))	('tumor', 'Disease', (168, 173))	('promotes', 'PosReg', (127, 135))	('loss', 'Var', (114, 118))	('tumor', 'Disease', 'MESH:D009369', (168, 173))	('growth', 'CPA', (136, 142))	('tumor', 'Phenotype', 'HP:0002664', (168, 173))
570857	26541825	Furthermore, the Lee group showed that loss of P53 decrease DDX3 expression, thus promoting tumor malignancy via the MDM2/Slug/E-cadherin pathway.	('tumor malignancy', 'Disease', 'MESH:D018198', (92, 108))	('Slug', 'Gene', '6591', (122, 126))	('Slug', 'Gene', (122, 126))	('MDM2', 'Gene', '4193', (117, 121))	('P53', 'Gene', (47, 50))	('P53', 'Gene', '7157', (47, 50))	('tumor', 'Phenotype', 'HP:0002664', (92, 97))	('E-cadherin', 'Gene', (127, 137))	('tumor malignancy', 'Disease', (92, 108))	('expression', 'MPA', (65, 75))	('decrease', 'NegReg', (51, 59))	('promoting', 'PosReg', (82, 91))	('loss', 'Var', (39, 43))	('DDX3', 'Gene', (60, 64))	('E-cadherin', 'Gene', '999', (127, 137))	('MDM2', 'Gene', (117, 121))
570858	26541825	This is in contrast with others who indicate that DDX3 does not activate p21 and loss of DDX3 impairs growth and proliferation.	('DDX3', 'Gene', (89, 93))	('p21', 'Gene', (73, 76))	('p21', 'Gene', '644914', (73, 76))	('impairs', 'NegReg', (94, 101))	('loss', 'Var', (81, 85))
570859	26541825	Furthermore, a recent paper showed that loss of DDX3 expression promotes metastasis in colorectal cancer.	('cancer', 'Phenotype', 'HP:0002664', (98, 104))	('promotes', 'PosReg', (64, 72))	('metastasis', 'CPA', (73, 83))	('DDX3', 'Gene', (48, 52))	('colorectal cancer', 'Phenotype', 'HP:0003003', (87, 104))	('loss', 'Var', (40, 44))	('colorectal cancer', 'Disease', (87, 104))	('colorectal cancer', 'Disease', 'MESH:D015179', (87, 104))
570861	26541825	that identified mutations in DDX3 as potential drivers of natural killer/T-cell lymphoma.	('lymphoma', 'Phenotype', 'HP:0002665', (80, 88))	('mutations', 'Var', (16, 25))	('DDX3', 'Gene', (29, 33))	('cell lymphoma', 'Phenotype', 'HP:0012191', (75, 88))	('T-cell lymphoma', 'Disease', 'MESH:D016399', (73, 88))	('T-cell lymphoma', 'Phenotype', 'HP:0012190', (73, 88))	('T-cell lymphoma', 'Disease', (73, 88))
570870	26541825	According to the X-ray crystallographic structure of DDX3 in complex with AMP, the interactions between DDX3 and AMP consist of six hydrogen bond interactions and one pi-pi interaction (Fig.	('AMP', 'Gene', (74, 77))	('AMP', 'Gene', (113, 116))	('DDX3', 'Gene', (104, 108))	('hydrogen bond interactions', 'MPA', (132, 158))	('AMP', 'Gene', '353', (74, 77))	('hydrogen', 'Chemical', 'MESH:D006859', (132, 140))	('AMP', 'Gene', '353', (113, 116))	('interactions', 'Interaction', (83, 95))	('pi-pi', 'Var', (167, 172))
570881	26541825	It will be exciting to see further target validation and in vivo activity of these potential DDX3 inhibitors as anticancer drugs.	('inhibitors', 'Var', (98, 108))	('cancer', 'Disease', (116, 122))	('cancer', 'Disease', 'MESH:D009369', (116, 122))	('DDX3', 'Gene', (93, 97))	('cancer', 'Phenotype', 'HP:0002664', (116, 122))
570887	26541825	RK-33 binds to DDX3, inhibits DDX3 helicase activity and cancer growth, and radiosensitizes lung cancer cells in a DDX3-dependent manner (Fig.	('lung cancer', 'Disease', (92, 103))	('lung cancer', 'Phenotype', 'HP:0100526', (92, 103))	('inhibits', 'NegReg', (21, 29))	('cancer', 'Disease', 'MESH:D009369', (57, 63))	('cancer', 'Disease', (97, 103))	('helicase', 'Gene', (35, 43))	('cancer', 'Disease', (57, 63))	('radiosensitizes', 'NegReg', (76, 91))	('activity', 'MPA', (44, 52))	('lung cancer', 'Disease', 'MESH:D008175', (92, 103))	('helicase', 'Gene', '164045', (35, 43))	('cancer', 'Phenotype', 'HP:0002664', (97, 103))	('cancer', 'Phenotype', 'HP:0002664', (57, 63))	('DDX3', 'Protein', (15, 19))	('RK-33', 'Var', (0, 5))	('binds', 'Interaction', (6, 11))	('cancer', 'Disease', 'MESH:D009369', (97, 103))
570897	26541825	Inhibition of DDX3 ATPase activity by ZINC00011012 was validated by measurement of Pi release from ATP in the mixture of purified His-DDX3 (6 muM) and varying concentrations of ZINC00011012.	('ATPase', 'Gene', (19, 25))	('ZINC00011012', 'Var', (38, 50))	('ATP', 'Chemical', 'MESH:D000255', (99, 102))	('ATP', 'Chemical', 'MESH:D000255', (19, 22))	('His', 'Chemical', 'MESH:D006639', (130, 133))	('Inhibition', 'NegReg', (0, 10))	('ZINC00011012', 'Chemical', '-', (177, 189))	('ZINC00011012', 'Chemical', '-', (38, 50))	('Pi release', 'MPA', (83, 93))	('ATPase', 'Gene', '1769', (19, 25))	('activity', 'MPA', (26, 34))
570909	26541825	DEAD/H Asp-Glu-Ala-Asp/His RNA Ribonucleic acid AzFa Azoospermia factor a ATPgammaS Adenosine 5'-[gamma-thio]-triphosphate ADP Adenosine diphosphate AMP Adenosine monophosphate Tyr Tyrosine Arg Arginine Gln L-glutamine Gly Glycine Ser Serine, Lys, lysine Thr Threonine HIF-1 Hypoxia inducible factor 1 HRE HIF-1 responsive elements PARP Poly ADP ribose polymerase DISC Death-inducing signaling complex FADD Fas associated with death domain protein TRAIL-R2 Tumor necrosis factor-related apoptosis-inducing ligand receptor 2 FLICE Caspase-8/FADD-like interleukin-1beta-converting enzyme cIAP-1 Cellular inhibitor of apoptosis protein-1 GSK3 Glycogen synthase kinase-3 HPV Human papillomavirus HCV Hepatitis C virus HBV Hepatitis B virus HIV-1 Human immunodeficiency virus 1 TCF Ternary complex factor CK1 Casein kinase 1 qPCR Quantitative polymerase chain reaction IHC Immunohistochemistry HR Hazard ratio OR Odds ratio OSCC Oral squamous cell carcinoma CI Confidence interval CRM1 Chromosome maintenance region 1, TAP, Tip-associated protein CML Chronic myeloid leukemia SHH Sonic hedgehog COSMIC Catalogue of somatic mutations in cancer REN Ring-expanded nucleoside	('Chronic myeloid leukemia', 'Phenotype', 'HP:0005506', (1046, 1070))	('necrosis', 'Disease', (463, 471))	('FADD', 'Gene', '8772', (402, 406))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (929, 952))	('Ser', 'Chemical', 'MESH:D012694', (235, 238))	('Hepatitis C', 'Disease', (696, 707))	('CRM1', 'Gene', (976, 980))	('cancer', 'Disease', 'MESH:D009369', (1131, 1137))	('TRAIL-R2', 'Gene', (448, 456))	('Thr', 'Chemical', 'MESH:D013912', (259, 262))	('FLICE', 'Gene', '841', (524, 529))	('Oral squamous cell carcinoma', 'Disease', 'MESH:D002294', (924, 952))	('SHH', 'Gene', (1071, 1074))	('Caspase-8', 'Gene', '841', (530, 539))	('cIAP-1', 'Gene', (586, 592))	('FADD', 'Gene', (402, 406))	('HIF-1', 'Gene', (269, 274))	('immunodeficiency', 'Phenotype', 'HP:0002721', (748, 764))	('Hepatitis', 'Phenotype', 'HP:0012115', (718, 727))	('AMP', 'Gene', (149, 152))	('Oral squamous cell carcinoma', 'Disease', (924, 952))	('cIAP-1', 'Gene', '329', (586, 592))	('Hypoxia', 'Disease', 'MESH:D000860', (275, 282))	('Gln', 'Chemical', 'MESH:D005973', (203, 206))	('Threonine', 'Chemical', 'MESH:D013912', (259, 268))	('cancer', 'Disease', (1131, 1137))	('HIF-1', 'Gene', (306, 311))	('Tip-associated protein', 'Gene', (1019, 1041))	('Hepatitis B', 'Disease', 'MESH:D006509', (718, 729))	('Azoospermia', 'Phenotype', 'HP:0000027', (53, 64))	('Casein kinase', 'Gene', '149420', (804, 817))	('Ala-Asp', 'Chemical', 'MESH:C038047', (15, 22))	('Arg', 'Chemical', 'MESH:D001120', (194, 197))	('TAP', 'Gene', '10482', (1014, 1017))	('mutations', 'Var', (1118, 1127))	('Tyr', 'Chemical', 'MESH:D014443', (177, 180))	('immunodeficiency', 'Disease', 'MESH:D007153', (748, 764))	('Chronic myeloid leukemia', 'Disease', 'MESH:D015464', (1046, 1070))	('Tumor', 'Phenotype', 'HP:0002664', (457, 462))	('papillomavirus', 'Disease', (677, 691))	('TCF', 'Gene', '3172', (773, 776))	('Arg', 'Chemical', 'MESH:D001120', (190, 193))	('FLICE', 'Gene', (524, 529))	('Gly', 'Chemical', 'MESH:D005998', (219, 222))	('REN', 'Chemical', '-', (1138, 1141))	('nucleoside', 'Chemical', 'MESH:D009705', (1156, 1166))	('ADP', 'Chemical', 'MESH:D000244', (123, 126))	('His', 'Chemical', 'MESH:D006639', (23, 26))	('Hepatitis C', 'Disease', 'MESH:D006526', (696, 707))	('TCF', 'Gene', (773, 776))	('Gly', 'Chemical', 'MESH:D005998', (223, 226))	('L-glutamine', 'Chemical', 'MESH:D005973', (207, 218))	('Arginine', 'Chemical', 'MESH:D001120', (194, 202))	('papillomavirus', 'Disease', 'MESH:D030361', (677, 691))	('carcinoma', 'Phenotype', 'HP:0030731', (943, 952))	('TRAIL-R2', 'Gene', '8795', (448, 456))	('ADP', 'Chemical', 'MESH:D000244', (342, 345))	('Azoospermia', 'Disease', (53, 64))	('Gly', 'Chemical', 'MESH:D005998', (640, 643))	('HIF-1', 'Gene', '3091', (269, 274))	('Adenosine diphosphate', 'Chemical', 'MESH:D000244', (127, 148))	('CK1', 'Species', '2498238', (800, 803))	('Thr', 'Chemical', 'MESH:D013912', (255, 258))	('FADD', 'Gene', '8772', (540, 544))	('Casein kinase', 'Gene', (804, 817))	('HIF-1', 'Gene', '3091', (306, 311))	('Hypoxia', 'Disease', (275, 282))	('Lys', 'Chemical', 'MESH:D008239', (243, 246))	('CML', 'Disease', 'MESH:D015464', (1042, 1045))	('cancer', 'Phenotype', 'HP:0002664', (1131, 1137))	('AMP', 'Gene', '353', (149, 152))	('Tyr', 'Chemical', 'MESH:D014443', (181, 184))	('PARP', 'Gene', (332, 336))	('CML', 'Disease', (1042, 1045))	('Caspase-8', 'Gene', (530, 539))	('TAP', 'Gene', (1014, 1017))	('Tip-associated protein', 'Gene', '10482', (1019, 1041))	('SHH', 'Gene', '6469', (1071, 1074))	('FADD', 'Gene', (540, 544))	('leukemia', 'Phenotype', 'HP:0001909', (1062, 1070))	('immunodeficiency', 'Disease', (748, 764))	('Tyrosine', 'Chemical', 'MESH:D014443', (181, 189))	('Serine', 'Chemical', 'MESH:D012694', (235, 241))	('Adenosine monophosphate', 'Chemical', 'MESH:D000249', (153, 176))	('Glycine', 'Chemical', 'MESH:D005998', (223, 230))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (1054, 1070))	('Hepatitis B', 'Disease', (718, 729))	('CML', 'Phenotype', 'HP:0005506', (1042, 1045))	('Chronic myeloid leukemia', 'Disease', (1046, 1070))	('Hepatitis', 'Phenotype', 'HP:0012115', (696, 705))	('Asp-Glu', 'Chemical', 'MESH:C038676', (7, 14))	('Ser', 'Chemical', 'MESH:D012694', (231, 234))	("Adenosine 5'-[gamma-thio]-triphosphate", 'Chemical', 'MESH:C022571', (84, 122))	('CRM1', 'Gene', '7514', (976, 980))	('lysine', 'Chemical', 'MESH:D008239', (248, 254))	('AzFa', 'Chemical', '-', (48, 52))	('ATPgammaS', 'Chemical', 'MESH:C022571', (74, 83))	('Azoospermia', 'Disease', 'MESH:D053713', (53, 64))	('necrosis', 'Disease', 'MESH:D009336', (463, 471))	('PARP', 'Gene', '142', (332, 336))
570912	33125142	However, it is not clear whether miR-7 has a regulatory effect on SP1 and TP53BP1 in NSCLC.	('NSCLC', 'Disease', (85, 90))	('NSCLC', 'Disease', 'MESH:D002289', (85, 90))	('TP53BP1', 'Var', (74, 81))	('miR-7', 'Gene', (33, 38))	('miR-7', 'Gene', '10859', (33, 38))	('SP1', 'Gene', (66, 69))
570915	33125142	Protein and mRNA abundance of SP1 and TP53BP1 were determined using western blotting and RT-qPCR, respectively, while miR-7 binding to SP1 was validated using a luciferase reporter assay.	('TP53BP1', 'Var', (38, 45))	('miR-7', 'Gene', (118, 123))	('mRNA', 'MPA', (12, 16))	('miR-7', 'Gene', '10859', (118, 123))
570932	33125142	Specific protein 1 (SP1) has been revealed to play critical roles in tumorigenesis, promote the repair of DNA double-strand breaks (DSBs) and regulate the radiosensitivity of tumors.	('tumors', 'Disease', (175, 181))	('tumors', 'Disease', 'MESH:D009369', (175, 181))	('tumor', 'Disease', (175, 180))	('tumors', 'Phenotype', 'HP:0002664', (175, 181))	('tumor', 'Phenotype', 'HP:0002664', (69, 74))	('promote', 'PosReg', (84, 91))	('tumor', 'Disease', (69, 74))	('tumor', 'Phenotype', 'HP:0002664', (175, 180))	('tumor', 'Disease', 'MESH:D009369', (175, 180))	('regulate', 'Reg', (142, 150))	('DSBs', 'Chemical', '-', (132, 136))	('DNA', 'Var', (106, 109))	('tumor', 'Disease', 'MESH:D009369', (69, 74))	('repair', 'MPA', (96, 102))
570933	33125142	Following SP1 silencing, cells were revealed to be more sensitive to DNA damage, and the foci degradation of gamma-H2AX was delayed.	('silencing', 'Var', (14, 23))	('sensitive', 'MPA', (56, 65))	('more', 'PosReg', (51, 55))	('foci degradation', 'MPA', (89, 105))	('delayed', 'NegReg', (124, 131))	('gamma-H2AX', 'Protein', (109, 119))	('SP1', 'Gene', (10, 13))	('gamma-H2AX', 'Chemical', '-', (109, 119))
570938	33125142	Additionally, it remains unclear whether miR-7 has a regulatory effect on SP1 and TP53BP1 in NSCLC.	('NSCLC', 'Disease', (93, 98))	('miR-7', 'Gene', (41, 46))	('NSCLC', 'Disease', 'MESH:D002289', (93, 98))	('miR-7', 'Gene', '10859', (41, 46))	('TP53BP1', 'Var', (82, 89))
570939	33125142	Herein, it was hypothesized that miR-7 increased radiosensitivity in NSCLC by downregulating SP1 and TP53BP1.	('TP53BP1', 'Var', (101, 108))	('NSCLC', 'Disease', (69, 74))	('radiosensitivity', 'MPA', (49, 65))	('miR-7', 'Gene', (33, 38))	('miR-7', 'Gene', '10859', (33, 38))	('NSCLC', 'Disease', 'MESH:D002289', (69, 74))	('increased', 'PosReg', (39, 48))	('increased radiosensitivity', 'Phenotype', 'HP:0010997', (39, 65))	('SP1', 'MPA', (93, 96))	('downregulating', 'NegReg', (78, 92))
570992	33125142	The predicted binding site between miR-7 and the 3'UTR of SP1 included the following bases: 1152-1159 and 4319-4325 (Fig.	('1152-1159', 'Var', (92, 101))	('miR-7', 'Gene', (35, 40))	('binding', 'Interaction', (14, 21))	('miR-7', 'Gene', '10859', (35, 40))	('SP1', 'Gene', (58, 61))	('4319-4325', 'Var', (106, 115))
570993	33125142	The wild-type (WT-3'UTR) and mutant (MT-3'UTR) sequences of the SP1 3'UTR were cloned into a luciferase plasmid, and the generated plasmids were transfected into 293T cells to investigate whether the 3'UTR of SP1 was a functional target of miR-7.	('miR-7', 'Gene', '10859', (240, 245))	('293T', 'CellLine', 'CVCL:0063', (162, 166))	('mutant', 'Var', (29, 35))	('SP1', 'Gene', (64, 67))	('miR-7', 'Gene', (240, 245))
571005	33125142	In contrast, inhibition of miR-7 increased the survival fraction (Fig.	('miR-7', 'Gene', (27, 32))	('survival fraction', 'CPA', (47, 64))	('inhibition', 'Var', (13, 23))	('miR-7', 'Gene', '10859', (27, 32))	('increased', 'PosReg', (33, 42))
571015	33125142	The aforementioned findings indicated that the depletion of SP1 enhanced radiosensitivity in NSCLC cells.	('NSCLC', 'Disease', (93, 98))	('radiosensitivity', 'CPA', (73, 89))	('depletion', 'Var', (47, 56))	('NSCLC', 'Disease', 'MESH:D002289', (93, 98))	('SP1', 'Gene', (60, 63))	('enhanced radiosensitivity', 'Phenotype', 'HP:0010997', (64, 89))	('enhanced', 'PosReg', (64, 72))
571017	33125142	The mRNA and protein expression levels of TP53BP1 were decreased after overexpression of miR-7 or downregulation of SP1 in both A549 and SK-MES-1 cells compared with control cells.	('miR-7', 'Gene', '10859', (89, 94))	('overexpression', 'PosReg', (71, 85))	('downregulation', 'NegReg', (98, 112))	('A549', 'CellLine', 'CVCL:0023', (128, 132))	('decreased', 'NegReg', (55, 64))	('SK-MES-1', 'CellLine', 'CVCL:0630', (137, 145))	('SP1', 'Gene', (116, 119))	('TP53BP1', 'Var', (42, 49))	('miR-7', 'Gene', (89, 94))
571019	33125142	The correlation between SP1 and TP53BP1 in LUAD, LUSC, and lung tissues from GEPIA revealed that SP1 was correlated with TP53BP1 in lung cancer tissue (Fig.	('cancer', 'Phenotype', 'HP:0002664', (137, 143))	('TP53BP1', 'Var', (121, 128))	('SP1', 'Var', (97, 100))	('lung cancer', 'Disease', 'MESH:D008175', (132, 143))	('correlated', 'Reg', (105, 115))	('lung cancer', 'Disease', (132, 143))	('lung cancer', 'Phenotype', 'HP:0100526', (132, 143))
571024	33125142	In human cervical carcinoma cells, miR-218 was revealed to promote radiation-induced apoptosis, increasing the radiosensitivity.	('carcinoma', 'Phenotype', 'HP:0030731', (18, 27))	('human', 'Species', '9606', (3, 8))	('carcinoma', 'Disease', (18, 27))	('radiosensitivity', 'CPA', (111, 127))	('radiation-induced apoptosis', 'CPA', (67, 94))	('miR-218', 'Var', (35, 42))	('promote', 'PosReg', (59, 66))	('increasing', 'PosReg', (96, 106))	('carcinoma', 'Disease', 'MESH:D009369', (18, 27))	('miR-218', 'Chemical', '-', (35, 42))
571045	33125142	Overexpression of miR-7 or depletion of SP1 inhibited the proliferation, migration, and invasion of NSCLC, which was enhanced by combination with irradiation.	('migration', 'CPA', (73, 82))	('proliferation', 'CPA', (58, 71))	('invasion', 'CPA', (88, 96))	('NSCLC', 'Disease', (100, 105))	('inhibited', 'NegReg', (44, 53))	('miR-7', 'Gene', '10859', (18, 23))	('SP1', 'Gene', (40, 43))	('NSCLC', 'Disease', 'MESH:D002289', (100, 105))	('enhanced', 'PosReg', (117, 125))	('depletion', 'Var', (27, 36))	('miR-7', 'Gene', (18, 23))
571046	33125142	Overexpression of miR-7 and silencing of SP1 had the same radiosensitization effect.	('miR-7', 'Gene', '10859', (18, 23))	('silencing', 'Var', (28, 37))	('SP1', 'Gene', (41, 44))	('radiosensitization', 'MPA', (58, 76))	('miR-7', 'Gene', (18, 23))
571057	33125142	The analysis of SP1 and TP53BP1 in LUAD and LUSC from GEPIA revealed that SP1 was correlated with TP53BP1 in lung cancer tissue.	('lung cancer', 'Disease', (109, 120))	('lung cancer', 'Phenotype', 'HP:0100526', (109, 120))	('SP1', 'Var', (74, 77))	('TP53BP1', 'Var', (98, 105))	('cancer', 'Phenotype', 'HP:0002664', (114, 120))	('correlated', 'Reg', (82, 92))	('lung cancer', 'Disease', 'MESH:D008175', (109, 120))
571078	32743577	ACE and ACE2 belong to the renin-angiotensin-aldosterone system, which regulates blood pressure and fluid-electrolyte balance; dysfunction of this system contributes to comorbidities in COVID-19.	('dysfunction', 'Var', (127, 138))	('comorbidities', 'Disease', (169, 182))	('ACE2', 'Gene', '59272', (8, 12))	('COVID-19', 'Disease', (186, 194))	('electrolyte balance', 'Phenotype', 'HP:0003111', (106, 125))	('aldosterone', 'Chemical', 'MESH:D000450', (45, 56))	('angiotensin-aldosterone system', 'Phenotype', 'HP:0000859', (33, 63))	('ACE2', 'Gene', (8, 12))	('COVID-19', 'Disease', 'MESH:C000657245', (186, 194))
571091	32743577	The combination of ENCODE chromatin modification marks (H3K4me1, H3K4me3, H3K27ac, and a cluster of DNase I hypersensitivity sites, Figure 1A) suggests that Ex1c, but not Ex1a and Ex1b, is located within a putative regulatory region that might affect gene expression.	('affect', 'Reg', (244, 250))	('Ex1c', 'Var', (157, 161))	('H3K4me1', 'Var', (56, 63))	('hypersensitivity', 'Disease', (108, 124))	('hypersensitivity', 'Disease', 'MESH:D004342', (108, 124))	('H3K4me3', 'Var', (65, 72))	('gene expression', 'MPA', (251, 266))	('H3K27ac', 'Var', (74, 81))
571095	32743577	Compared to the full-length ACE2 protein of 805 aa, the truncation eliminates 17 aa of the signal peptide (SigP) and 339 aa of the N-terminal peptidase domain (PD, Figure 1C).	('truncation', 'Var', (56, 66))	('peptide', 'Chemical', 'MESH:D010455', (98, 105))	('ACE2', 'Gene', (28, 32))	('N-terminal peptidase domain', 'MPA', (131, 158))	('signal peptide', 'MPA', (91, 105))	('eliminates', 'NegReg', (67, 77))	('ACE2', 'Gene', '59272', (28, 32))
571108	32743577	Compared to uninfected cells, dACE2-Ex1c expression was strongly induced by both viruses - by RV-A16 (2.58-fold; P = 2.52E-13) and RV-C15 (2.42-fold; P = 2.52E-12), while expression of ACE2-Ex1b was weakly induced only by RV-C15 (1.13-fold; P = 0.032) (Figure 3B).	('ACE2', 'Gene', '59272', (31, 35))	('RV-C15', 'Var', (131, 137))	('expression', 'MPA', (41, 51))	('RV-A16', 'Var', (94, 100))	('induced', 'PosReg', (65, 72))	('ACE2', 'Gene', (185, 189))	('infected', 'Disease', 'MESH:D007239', (14, 22))	('RV', 'Species', '12059', (222, 224))	('dACE2', 'Gene', (30, 35))	('dACE2', 'Gene', '41625', (30, 35))	('infected', 'Disease', (14, 22))	('ACE2', 'Gene', (31, 35))	('ACE2', 'Gene', '59272', (185, 189))	('RV', 'Species', '12059', (131, 133))	('RV', 'Species', '12059', (94, 96))
571155	32743577	The N-terminal truncation is also predicted to affect carboxypeptidase activity of dACE2, which is important for its ability to cleave angiotensin II, des-Arg9-bradykinin, and other substrates of ACE2.	('carboxypeptidase activity', 'MPA', (54, 79))	('ACE2', 'Gene', (196, 200))	('ACE2', 'Gene', '59272', (84, 88))	('angiotensin II', 'Gene', (135, 149))	('N-terminal truncation', 'Var', (4, 25))	('bradykinin', 'Gene', (160, 170))	('angiotensin II', 'Gene', '183', (135, 149))	('affect', 'Reg', (47, 53))	('ACE2', 'Gene', '59272', (196, 200))	('bradykinin', 'Gene', '3827', (160, 170))	('dACE2', 'Gene', '41625', (83, 88))	('ACE2', 'Gene', (84, 88))	('dACE2', 'Gene', (83, 88))
571161	32743577	Our findings highlight that in the presence of dACE2, ACE2 expression is likely to be misinterpreted when detected by methods such as 3'-scRNA-seq and gene-based assays that target shared dACE2 and ACE2 sequences.	('presence', 'Var', (35, 43))	('ACE2', 'Gene', '59272', (198, 202))	('dACE2', 'Gene', (47, 52))	('ACE2', 'Gene', '59272', (54, 58))	('ACE2', 'Gene', '59272', (48, 52))	('ACE2', 'Gene', (189, 193))	('ACE2', 'Gene', (48, 52))	('dACE2', 'Gene', '41625', (47, 52))	('dACE2', 'Gene', (188, 193))	('ACE2', 'Gene', '59272', (189, 193))	('dACE2', 'Gene', '41625', (188, 193))	('ACE2', 'Gene', (198, 202))	('ACE2', 'Gene', (54, 58))
571210	32743577	ACE2 with C-terminal GFP-tag (RG208442) and Myc-DDK tag (RC208442) were purchased from Origene.	('ACE2', 'Gene', (0, 4))	('RG208442', 'Chemical', '-', (30, 38))	('RC208442', 'Var', (57, 65))	('RG208442', 'Var', (30, 38))	('ACE2', 'Gene', '59272', (0, 4))
571248	32743577	Unless specified, bladder cancer cells (T24), in which no baseline expression of ACE2 or dACE2 was detected (Table S2), were used for transfections at 70-90% confluency in 12- or 6-well plates for 24 hrs.	('bladder cancer', 'Disease', 'MESH:D001749', (18, 32))	('ACE2', 'Gene', '59272', (90, 94))	('transfections', 'Var', (134, 147))	('bladder cancer', 'Disease', (18, 32))	('ACE2', 'Gene', (81, 85))	('dACE2', 'Gene', (89, 94))	('cancer', 'Phenotype', 'HP:0002664', (26, 32))	('ACE2', 'Gene', '59272', (81, 85))	('bladder cancer', 'Phenotype', 'HP:0009725', (18, 32))	('ACE2', 'Gene', (90, 94))	('dACE2', 'Gene', '41625', (89, 94))
571335	31289561	For example, Luo et al identified that the lncRNAs RP5-821D11.7, APCDD1L-AS1 and RP11-277P12.9 were associated with the prognosis of lung squamous cell carcinoma.	('APCDD1L-AS1', 'Gene', (65, 76))	('carcinoma', 'Phenotype', 'HP:0030731', (152, 161))	('RP11', 'Gene', '26121', (81, 85))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (138, 161))	('lung squamous cell carcinoma', 'Disease', 'MESH:D002294', (133, 161))	('lung squamous cell carcinoma', 'Disease', (133, 161))	('RP5-821D11.7', 'Var', (51, 63))	('associated with', 'Reg', (100, 115))	('APCDD1L-AS1', 'Gene', '149773', (65, 76))	('RP11', 'Gene', (81, 85))	('lung squamous cell carcinoma', 'Phenotype', 'HP:0030359', (133, 161))
571336	31289561	Overexpression of lncRNA MetaLnc9 in human NSCLC samples has been correlated with a poor prognosis, and has been revealed to promote migration and invasion of NSCLC cells in vitro, and enhance lung metastasis formation in vivo.	('NSCLC', 'Disease', (159, 164))	('enhance', 'PosReg', (185, 192))	('NSCLC', 'Phenotype', 'HP:0030358', (43, 48))	('lung metastasis formation', 'CPA', (193, 218))	('invasion', 'CPA', (147, 155))	('NSCLC', 'Disease', 'MESH:D002289', (159, 164))	('migration', 'CPA', (133, 142))	('Overexpression', 'Var', (0, 14))	('lncRNA MetaLnc9', 'Gene', (18, 33))	('human', 'Species', '9606', (37, 42))	('NSCLC', 'Disease', (43, 48))	('NSCLC', 'Phenotype', 'HP:0030358', (159, 164))	('promote', 'PosReg', (125, 132))	('NSCLC', 'Disease', 'MESH:D002289', (43, 48))
571342	31289561	For example, the lncRNA small nucleolar RNA host gene 20 has been demonstrated to promote NSCLC cell proliferation and migration by epigenetically silencing p21 expression.	('p21', 'Gene', (157, 160))	('p21', 'Gene', '644914', (157, 160))	('promote', 'PosReg', (82, 89))	('NSCLC', 'Disease', (90, 95))	('NSCLC', 'Disease', 'MESH:D002289', (90, 95))	('epigenetically silencing', 'Var', (132, 156))	('NSCLC', 'Phenotype', 'HP:0030358', (90, 95))	('migration', 'CPA', (119, 128))
571360	28039483	A multivariate analysis showed that, in a model adjusted for age, tumor site, p16 immunoexpression and tumor resectability, high expression of miR-21 remained an independent predictor of poor response to the organ preservation protocol (OR=5.69; 95%CI 1.27-25.58; p=0.023), together with clinical stage IV (OR=5.05; 95%CI 1.22-20.88; p=0.025).	('tumor', 'Phenotype', 'HP:0002664', (66, 71))	('tumor', 'Phenotype', 'HP:0002664', (103, 108))	('p16', 'Gene', (78, 81))	('tumor', 'Disease', (66, 71))	('miR-21', 'Gene', (143, 149))	('tumor', 'Disease', (103, 108))	('p16', 'Gene', '1029', (78, 81))	('miR-21', 'Gene', '406991', (143, 149))	('tumor', 'Disease', 'MESH:D009369', (66, 71))	('high', 'Var', (124, 128))	('tumor', 'Disease', 'MESH:D009369', (103, 108))
571361	28039483	Furthermore, considering the entire cohort, patients with high expression of miR-21 had worse survival.	('patients', 'Species', '9606', (44, 52))	('miR-21', 'Gene', '406991', (77, 83))	('survival', 'MPA', (94, 102))	('high expression', 'Var', (58, 73))	('worse', 'NegReg', (88, 93))	('miR-21', 'Gene', (77, 83))
571382	28039483	Clinical stage (CS) classification was T2/T3 in 46 cases (64.8%) and T4 in 25 cases (35.2%), N0/N1 in 35 cases (49.3%) and N2/N3 in 36 cases (50.7%).	('CS', 'Chemical', '-', (16, 18))	('T2/T3', 'Var', (39, 44))	('N0/N1', 'Var', (93, 98))
571396	28039483	Moreover, in a multivariate analysis, using a model adjusted for age, tumor site, p16 immunoexpression and tumor resectability, high expression of miR-21 remained as an independent predictor of poor response to the organ preservation protocol (OR=5.69; 95%CI 1.27-25.58; p=0.023), together with clinical stage IV (OR=5.05; 95%CI 1.22-20.88; p=0.025) (Table 2).	('tumor', 'Phenotype', 'HP:0002664', (70, 75))	('miR-21', 'Gene', (147, 153))	('tumor', 'Phenotype', 'HP:0002664', (107, 112))	('tumor', 'Disease', (107, 112))	('p16', 'Gene', (82, 85))	('tumor', 'Disease', (70, 75))	('p16', 'Gene', '1029', (82, 85))	('tumor', 'Disease', 'MESH:D009369', (107, 112))	('miR-21', 'Gene', '406991', (147, 153))	('high expression', 'Var', (128, 143))	('tumor', 'Disease', 'MESH:D009369', (70, 75))
571415	28039483	also found that tongue tumors with advanced clinical stages, poor differentiation or lymph node metastasis expressed higher levels of miR-21, suggesting that miR-21 is related to cancer progression.	('miR-21', 'Gene', (134, 140))	('higher', 'PosReg', (117, 123))	('tongue tumors', 'Disease', (16, 29))	('cancer', 'Phenotype', 'HP:0002664', (179, 185))	('poor', 'Var', (61, 65))	('levels', 'MPA', (124, 130))	('tongue tumors', 'Phenotype', 'HP:0100648', (16, 29))	('miR-21', 'Gene', '406991', (134, 140))	('tumor', 'Phenotype', 'HP:0002664', (23, 28))	('miR-21', 'Gene', '406991', (158, 164))	('related', 'Reg', (168, 175))	('cancer', 'Disease', 'MESH:D009369', (179, 185))	('tongue tumors', 'Disease', 'MESH:D014062', (16, 29))	('lymph node metastasis', 'CPA', (85, 106))	('tumors', 'Phenotype', 'HP:0002664', (23, 29))	('cancer', 'Disease', (179, 185))	('miR-21', 'Gene', (158, 164))
571429	28039483	Analysis in breast cancers demonstrated that decreased expression of miR-720 was correlated with lymph node metastasis, and re-expression of this miR/tRF in breast cancer cells inhibited cell invasion and migration.	('lymph node metastasis', 'CPA', (97, 118))	('cancers', 'Phenotype', 'HP:0002664', (19, 26))	('breast cancer', 'Phenotype', 'HP:0003002', (157, 170))	('miR', 'Gene', (69, 72))	('cancer', 'Phenotype', 'HP:0002664', (19, 25))	('miR', 'Gene', '220972', (146, 149))	('breast cancers', 'Disease', 'MESH:D001943', (12, 26))	('breast cancers', 'Disease', (12, 26))	('breast cancer', 'Disease', 'MESH:D001943', (157, 170))	('breast cancer', 'Disease', (157, 170))	('breast cancers', 'Phenotype', 'HP:0003002', (12, 26))	('miR', 'Gene', (146, 149))	('inhibited', 'NegReg', (177, 186))	('breast cancer', 'Phenotype', 'HP:0003002', (12, 25))	('expression', 'MPA', (55, 65))	('breast cancer', 'Disease', 'MESH:D001943', (12, 25))	('re-expression', 'Var', (124, 137))	('cancer', 'Phenotype', 'HP:0002664', (164, 170))	('decreased', 'NegReg', (45, 54))	('miR', 'Gene', '220972', (69, 72))
571440	28039483	Moreover, the high expression of miR-21 in this group of samples is associated with a better 5-year overall survival.	('miR-21', 'Gene', (33, 39))	('high', 'Var', (14, 18))	('miR-21', 'Gene', '406991', (33, 39))	('better', 'PosReg', (86, 92))
571478	33193699	Alterations at different regulatory layers often lead to the emergence of a cancerous phenotype.	('cancerous', 'Disease', (76, 85))	('Alterations', 'Var', (0, 11))	('cancer', 'Phenotype', 'HP:0002664', (76, 82))	('cancerous', 'Disease', 'MESH:D009369', (76, 85))	('lead to', 'Reg', (49, 56))
571480	33193699	For instance, genomic or epigenomic studies revealed how genetic mutations or epigenetic alterations may drive tumorigenesis.	('drive', 'PosReg', (105, 110))	('tumor', 'Disease', 'MESH:D009369', (111, 116))	('tumor', 'Phenotype', 'HP:0002664', (111, 116))	('genetic mutations', 'Var', (57, 74))	('epigenetic alterations', 'Var', (78, 100))	('tumor', 'Disease', (111, 116))
571489	33193699	The major molecular characterizations of cancer tissues/cells include NGS based techniques to quantify single nucleotide variants (SNVs), DNA methylation, copy number alterations (CNAs), and mRNA/miRNA expression.	('single nucleotide variants', 'Var', (103, 129))	('cancer', 'Phenotype', 'HP:0002664', (41, 47))	('mRNA/miRNA expression', 'MPA', (191, 212))	('copy number alterations', 'Var', (155, 178))	('cancer', 'Disease', (41, 47))	('cancer', 'Disease', 'MESH:D009369', (41, 47))
571490	33193699	Figure 1 represents an example of the mutational frequency of TP53 - a well-characterized tumor suppressor gene (TSG) across 32 TCGA cancer types.	('TP53', 'Gene', '7157', (62, 66))	('cancer', 'Disease', 'MESH:D009369', (133, 139))	('TP53', 'Gene', (62, 66))	('tumor', 'Disease', (90, 95))	('tumor', 'Phenotype', 'HP:0002664', (90, 95))	('tumor', 'Disease', 'MESH:D009369', (90, 95))	('cancer', 'Disease', (133, 139))	('cancer', 'Phenotype', 'HP:0002664', (133, 139))	('mutational', 'Var', (38, 48))
571502	33193699	The proteogenomic approach has shown much promise to reveal the latent effect of genomic and epigenomic alterations on the mRNA and protein levels which subsequently led to the acquisition of cancer hallmarks.	('alterations', 'Var', (104, 115))	('cancer', 'Phenotype', 'HP:0002664', (192, 198))	('led to', 'Reg', (166, 172))	('cancer', 'Disease', (192, 198))	('cancer', 'Disease', 'MESH:D009369', (192, 198))	('acquisition', 'Reg', (177, 188))
571503	33193699	For example, in colorectal cancer, the proteogenomic approach elucidated the consequence of chromosomal region 20q amplification which was not only restricted to altered mRNA levels but also reflected on the protein levels.	('cancer', 'Phenotype', 'HP:0002664', (27, 33))	('chromosomal region 20q amplification', 'Var', (92, 128))	('colorectal cancer', 'Disease', 'MESH:D015179', (16, 33))	('mRNA levels', 'MPA', (170, 181))	('altered', 'Reg', (162, 169))	('rectal cancer', 'Phenotype', 'HP:0100743', (20, 33))	('colorectal cancer', 'Phenotype', 'HP:0003003', (16, 33))	('colorectal cancer', 'Disease', (16, 33))
571504	33193699	The altered protein abundances of Hepatocyte-nuclear factor 4 alpha (HNF4A), Translocase of outer mitochondrial membrane (TOMM34), and SRC proto-oncogene and non-receptor tyrosine kinase (SRC) were directly caused by the 20q amplification event and are likely to play a crucial role in the acquisition of sustained proliferation.	('SRC', 'Gene', '6714', (135, 138))	('HNF4A', 'Gene', '3172', (69, 74))	('altered', 'Reg', (4, 11))	('SRC', 'Gene', (135, 138))	('HNF4A', 'Gene', (69, 74))	('TOMM34', 'Gene', '10953', (122, 128))	('Hepatocyte-nuclear factor 4 alpha', 'Gene', (34, 67))	('20q amplification event', 'Var', (221, 244))	('caused', 'Reg', (207, 213))	('protein abundances', 'MPA', (12, 30))	('SRC', 'Gene', (188, 191))	('TOMM34', 'Gene', (122, 128))	('SRC', 'Gene', '6714', (188, 191))	('Translocase', 'MPA', (77, 88))	('Hepatocyte-nuclear factor 4 alpha', 'Gene', '3172', (34, 67))
571515	33193699	It provides dynamic data visualization options and analysis platforms enabling the creation of an adaptable interface that allows the users to filter data based on disease site, cancer-type, demographic data material, treatment, mutational impact, etc.	('cancer', 'Disease', (178, 184))	('cancer', 'Disease', 'MESH:D009369', (178, 184))	('mutational', 'Var', (229, 239))	('cancer', 'Phenotype', 'HP:0002664', (178, 184))
571516	33193699	For instance, the survival curve of pancreatic ductal adenocarcinoma (PAAD) patients pre-stratified based on KRAS gene mutation is shown in Figure 4A.	('patients', 'Species', '9606', (76, 84))	('mutation', 'Var', (119, 127))	('pancreatic ductal adenocarcinoma', 'Disease', (36, 68))	('pancreatic ductal adenocarcinoma', 'Phenotype', 'HP:0006725', (36, 68))	('pancreatic ductal adenocarcinoma', 'Disease', 'MESH:D021441', (36, 68))	('KRAS', 'Gene', (109, 113))	('KRAS', 'Gene', '3845', (109, 113))	('carcinoma', 'Phenotype', 'HP:0030731', (59, 68))
571517	33193699	The analysis showed that patients with KRAS mutations have a poor prognosis compared to patients with wild-type KRAS.	('patients', 'Species', '9606', (88, 96))	('patients', 'Species', '9606', (25, 33))	('mutations', 'Var', (44, 53))	('KRAS', 'Gene', (39, 43))	('KRAS', 'Gene', (112, 116))	('KRAS', 'Gene', '3845', (39, 43))	('KRAS', 'Gene', '3845', (112, 116))
571520	33193699	Firebrowse can provide a list of genes that are associated with tumor stage, patient survival, gender, age, or ethnic background with respect to copy number alterations, methylation status, mRNA expression, and mutations.	('tumor', 'Disease', (64, 69))	('mRNA expression', 'MPA', (190, 205))	('associated', 'Reg', (48, 58))	('copy number alterations', 'Var', (145, 168))	('tumor', 'Disease', 'MESH:D009369', (64, 69))	('patient', 'Species', '9606', (77, 84))	('tumor', 'Phenotype', 'HP:0002664', (64, 69))	('methylation', 'Var', (170, 181))
571525	33193699	This web portal has an innovative way of representing multi-omics events like- mutation profiling, expression levels, copy number variations (CNV), methylation status, and miRNA-gene network across different cancers types.	('cancers', 'Phenotype', 'HP:0002664', (208, 215))	('cancers', 'Disease', (208, 215))	('copy number variations', 'Var', (118, 140))	('cancers', 'Disease', 'MESH:D009369', (208, 215))	('cancer', 'Phenotype', 'HP:0002664', (208, 214))
571529	33193699	Additionally, the highest mRNA expression level is found for tumor samples with copy number gain, whereas the lowest expression levels are observed for the normal samples.	('copy number gain', 'Var', (80, 96))	('mRNA expression level', 'MPA', (26, 47))	('tumor', 'Disease', 'MESH:D009369', (61, 66))	('tumor', 'Phenotype', 'HP:0002664', (61, 66))	('highest', 'Reg', (18, 25))	('tumor', 'Disease', (61, 66))
571539	33193699	The comparison of the protein progesterone receptor (PGR) abundance between MAP3K1 mutated and non-mutated samples in breast cancer (BRCA) is shown as an example (Figure 4F).	('MAP3K1', 'Gene', '4214', (76, 82))	('mutated', 'Var', (83, 90))	('progesterone receptor', 'Gene', '5241', (30, 51))	('cancer', 'Phenotype', 'HP:0002664', (125, 131))	('PGR', 'Gene', (53, 56))	('breast cancer', 'Disease', 'MESH:D001943', (118, 131))	('progesterone receptor', 'Gene', (30, 51))	('MAP3K1', 'Gene', (76, 82))	('breast cancer', 'Disease', (118, 131))	('PGR', 'Gene', '5241', (53, 56))	('breast cancer', 'Phenotype', 'HP:0003002', (118, 131))
571545	33193699	For instance, gene expression and copy number alterations of the APC gene have been shown as a heatmap pattern for tumor samples of rectal cancer (READ) (Figure 4H).	('cancer', 'Disease', 'MESH:D009369', (139, 145))	('rectal cancer', 'Phenotype', 'HP:0100743', (132, 145))	('READ', 'Disease', 'None', (147, 151))	('tumor', 'Phenotype', 'HP:0002664', (115, 120))	('copy number alterations', 'Var', (34, 57))	('APC', 'Gene', (65, 68))	('cancer', 'Phenotype', 'HP:0002664', (139, 145))	('tumor', 'Disease', (115, 120))	('APC', 'Gene', '324', (65, 68))	('READ', 'Disease', (147, 151))	('tumor', 'Disease', 'MESH:D009369', (115, 120))	('cancer', 'Disease', (139, 145))
571560	33193699	Recently an international collaboration based pan-cancer project of ICGC and TCGA called Pan-Cancer Analysis of Whole Genomes Consortium (PCAWG) examined the features and consequences of genomic variations by focusing on both coding and non-coding regions of 2,658 whole-cancer genomes.	('variations', 'Var', (195, 205))	('cancer', 'Disease', (50, 56))	('cancer', 'Disease', 'MESH:D009369', (50, 56))	('cancer', 'Phenotype', 'HP:0002664', (271, 277))	('pan', 'Gene', (46, 49))	('Pan', 'Gene', (89, 92))	('Pan', 'Gene', '51816', (89, 92))	('pan', 'Gene', '51816', (46, 49))	('Cancer', 'Phenotype', 'HP:0002664', (93, 99))	('cancer', 'Disease', 'MESH:D009369', (271, 277))	('cancer', 'Phenotype', 'HP:0002664', (50, 56))	('Cancer', 'Disease', (93, 99))	('cancer', 'Disease', (271, 277))	('Cancer', 'Disease', 'MESH:D009369', (93, 99))
571564	33193699	The highest mutation rate of the TP53 gene has been assigned to France (16.0%) followed by the United Kingdom (13.6%) whereas the lowest has been observed in Canada (7.8%) and China (4.9%) indicating the population-wise differences of the mutational burden of TP53 (Figure 5A).	('TP53', 'Gene', (260, 264))	('TP53', 'Gene', '7157', (33, 37))	('TP53', 'Gene', (33, 37))	('mutation', 'Var', (12, 20))	('TP53', 'Gene', '7157', (260, 264))
571565	33193699	The other countries (United States: 9.9%, and Germany: 8.9%) showed an intermediate range of mutational events in TP53.	('mutational events', 'Var', (93, 110))	('TP53', 'Gene', '7157', (114, 118))	('TP53', 'Gene', (114, 118))
571566	33193699	Moreover, the distributions of six different hotspot variants (Tyr163Cys, Cys176Trp, Met237Ile, Cys238Phe, Arg248Gln, and Arg273Cys) of TP53 with the highest frequency in prostate cancer for different countries are shown (Figure 5B).	('prostate cancer', 'Disease', 'MESH:D011471', (171, 186))	('prostate cancer', 'Phenotype', 'HP:0012125', (171, 186))	('Arg273Cys', 'Var', (122, 131))	('Cys238Phe', 'SUBSTITUTION', 'None', (96, 105))	('cancer', 'Phenotype', 'HP:0002664', (180, 186))	('Arg273Cys', 'SUBSTITUTION', 'None', (122, 131))	('Tyr163Cys', 'Var', (63, 72))	('Met237Ile', 'Var', (85, 94))	('Cys238Phe', 'Var', (96, 105))	('Arg248Gln', 'SUBSTITUTION', 'None', (107, 116))	('Met237Ile', 'SUBSTITUTION', 'None', (85, 94))	('Arg248Gln', 'Var', (107, 116))	('prostate cancer', 'Disease', (171, 186))	('Cys176Trp', 'Var', (74, 83))	('TP53', 'Gene', '7157', (136, 140))	('Cys176Trp', 'Chemical', '-', (74, 83))	('TP53', 'Gene', (136, 140))	('Tyr163Cys', 'SUBSTITUTION', 'None', (63, 72))
571567	33193699	Two mutational hotspots (Arg248Gln and Arg273Cys) with equal frequency (25%) were observed in France.	('Arg273Cys', 'Var', (39, 48))	('France', 'Disease', (94, 100))	('Arg273Cys', 'SUBSTITUTION', 'None', (39, 48))	('Arg248Gln', 'SUBSTITUTION', 'None', (25, 34))	('Arg248Gln', 'Var', (25, 34))
571578	33193699	Tier-1 CGC includes mutations in the tumor suppressor genes (TSGs) and oncogenes where the former typically are subjected to inactivating mutations and the latter serve as hotspots for missense mutations.	('TSGs', 'Gene', (61, 65))	('tumor', 'Disease', 'MESH:D009369', (37, 42))	('oncogenes', 'Gene', (71, 80))	('tumor', 'Phenotype', 'HP:0002664', (37, 42))	('tumor', 'Disease', (37, 42))	('mutations', 'Var', (20, 29))
571585	33193699	In addition, COSMIC provides a graphical representation of the mutational frequencies of a given gene in a particular cancer type.	('cancer', 'Disease', 'MESH:D009369', (118, 124))	('cancer', 'Disease', (118, 124))	('mutational', 'Var', (63, 73))	('cancer', 'Phenotype', 'HP:0002664', (118, 124))
571586	33193699	For instance, the missense mutations of TP53 (R248L) (Figure 6B) and PIK3CA (E545D) (Figure 6C) have the highest occurrence frequency in triple-negative BC.	('triple-negative BC', 'Disease', (137, 155))	('R248L', 'Mutation', 'rs11540652', (46, 51))	('E545D', 'Mutation', 'rs121913275', (77, 82))	('TP53', 'Gene', '7157', (40, 44))	('TP53', 'Gene', (40, 44))	('PIK3CA', 'Gene', (69, 75))	('E545D', 'Var', (77, 82))	('PIK3CA', 'Gene', '5290', (69, 75))	('missense mutations', 'Var', (18, 36))
571602	33193699	The survival analysis showed that high CDK1 expression has lower survival probability in liver cancer patients compared to patients with low CDK1 expression and thus CDK1 was classified as unfavorable while, in cervical cancer the high expression of the same gene CDK1 was associated with relatively higher survival probability compared to low expression of CDK1.	('lower', 'NegReg', (59, 64))	('patients', 'Species', '9606', (102, 110))	('cancer', 'Disease', 'MESH:D009369', (220, 226))	('higher', 'PosReg', (300, 306))	('survival', 'MPA', (65, 73))	('cancer', 'Disease', (95, 101))	('patients', 'Species', '9606', (123, 131))	('CDK1', 'Gene', '983', (358, 362))	('CDK1', 'Gene', '983', (264, 268))	('cancer', 'Phenotype', 'HP:0002664', (95, 101))	('CDK1', 'Gene', (358, 362))	('CDK1', 'Gene', (264, 268))	('liver cancer', 'Disease', 'MESH:D006528', (89, 101))	('cancer', 'Disease', (220, 226))	('CDK1', 'Gene', '983', (166, 170))	('CDK1', 'Gene', (166, 170))	('survival', 'MPA', (307, 315))	('liver cancer', 'Phenotype', 'HP:0002896', (89, 101))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('CDK1', 'Gene', '983', (39, 43))	('cancer', 'Disease', 'MESH:D009369', (95, 101))	('CDK1', 'Gene', (39, 43))	('liver cancer', 'Disease', (89, 101))	('high', 'Var', (34, 38))	('CDK1', 'Gene', (141, 145))	('CDK1', 'Gene', '983', (141, 145))
571618	33193699	PCAWG uncovered that the majority of the tumors (91%) harbored at least one well-characterized driver mutation, with an average of 4.6 driver mutations per tumor.	('tumor', 'Phenotype', 'HP:0002664', (41, 46))	('tumors', 'Phenotype', 'HP:0002664', (41, 47))	('tumor', 'Disease', (41, 46))	('mutation', 'Var', (102, 110))	('tumor', 'Disease', 'MESH:D009369', (156, 161))	('tumors', 'Disease', (41, 47))	('tumors', 'Disease', 'MESH:D009369', (41, 47))	('tumor', 'Phenotype', 'HP:0002664', (156, 161))	('tumor', 'Disease', 'MESH:D009369', (41, 46))	('tumor', 'Disease', (156, 161))	('harbored', 'Reg', (54, 62))
571619	33193699	Furthermore, PCAWG identified that chromothripsis - an event where clustered structural variants originate at a single time point, occurs in the early phase of tumor evolution in melanoma, and subsequently affect cancer-associated genes.	('cancer', 'Phenotype', 'HP:0002664', (213, 219))	('chromothripsis', 'Disease', (35, 49))	('tumor', 'Disease', 'MESH:D009369', (160, 165))	('cancer', 'Disease', 'MESH:D009369', (213, 219))	('tumor', 'Phenotype', 'HP:0002664', (160, 165))	('cancer', 'Disease', (213, 219))	('melanoma', 'Disease', 'MESH:D008545', (179, 187))	('melanoma', 'Phenotype', 'HP:0002861', (179, 187))	('variants', 'Var', (88, 96))	('melanoma', 'Disease', (179, 187))	('tumor', 'Disease', (160, 165))	('affect', 'Reg', (206, 212))
571628	33193699	For high-grade serous ovarian cancer (HGSC), the abundance profiles of proteins belonging to cell invasion and migration were found to be modulated by copy number alterations (CNA) indicating a possible role of CNA-driven proteogenomic events in attaining these hallmarks of cancer.	('migration', 'CPA', (111, 120))	('copy number alterations', 'Var', (151, 174))	('cancer', 'Disease', (275, 281))	('cancer', 'Phenotype', 'HP:0002664', (275, 281))	('cancer', 'Disease', (30, 36))	('abundance profiles of', 'MPA', (49, 70))	('cancer', 'Disease', 'MESH:D009369', (30, 36))	('cell invasion', 'CPA', (93, 106))	('cancer', 'Phenotype', 'HP:0002664', (30, 36))	('serous ovarian cancer', 'Disease', (15, 36))	('ovarian cancer', 'Phenotype', 'HP:0100615', (22, 36))	('cancer', 'Disease', 'MESH:D009369', (275, 281))	('serous ovarian cancer', 'Disease', 'MESH:D018284', (15, 36))	('proteins', 'Protein', (71, 79))	('modulated', 'Reg', (138, 147))
571631	33193699	For instance, in pediatric acute lymphoblastic leukemia, methylome and transcriptome datasets were analyzed separately to identify differentially methylated (DMGs) and differentially expressed genes (DEGs) followed by their integration revealed that the gene expression and methylation alterations occur in the same molecular pathways (Ras signaling pathway, PI3K-Akt signaling pathway, and Rap1 signaling pathway).	('Akt', 'Gene', (364, 367))	('occur', 'Reg', (298, 303))	('acute lymphoblastic leukemia', 'Phenotype', 'HP:0006721', (27, 55))	('acute lymphoblastic leukemia', 'Disease', (27, 55))	('lymphoblastic leukemia', 'Phenotype', 'HP:0005526', (33, 55))	('alterations', 'Var', (286, 297))	('Rap1', 'Gene', (391, 395))	('acute lymphoblastic leukemia', 'Disease', 'MESH:D054198', (27, 55))	('Akt', 'Gene', '207', (364, 367))	('methylation', 'MPA', (274, 285))	('Rap1', 'Gene', '5906', (391, 395))	('leukemia', 'Phenotype', 'HP:0001909', (47, 55))
571651	33193699	Integration of methylation, mRNA, and protein data from colorectal cancer patients using moCluster identified four molecular subtypes, including one with microsatellite instability and upregulation of immune-system related genes/proteins such as PDL1.	('colorectal cancer', 'Disease', 'MESH:D015179', (56, 73))	('PDL1', 'Gene', (246, 250))	('rectal cancer', 'Phenotype', 'HP:0100743', (60, 73))	('colorectal cancer', 'Phenotype', 'HP:0003003', (56, 73))	('patients', 'Species', '9606', (74, 82))	('cancer', 'Phenotype', 'HP:0002664', (67, 73))	('colorectal cancer', 'Disease', (56, 73))	('upregulation', 'PosReg', (185, 197))	('PDL1', 'Gene', '29126', (246, 250))	('microsatellite instability', 'Var', (154, 180))
571681	33193699	DNA analysis of liquid biopsy is based on the concept that clonal proliferation of tumor cells giving rise to tens of millions of cells carrying the identical mutated DNA, can serve as the template to be detected in blood samples.	('DNA', 'Gene', (167, 170))	('tumor', 'Phenotype', 'HP:0002664', (83, 88))	('mutated', 'Var', (159, 166))	('tumor', 'Disease', (83, 88))	('tumor', 'Disease', 'MESH:D009369', (83, 88))
571694	32110044	Interestingly, overexpression of R96Q, blunted the effects of FTO overexpression on cell proliferation and invasion.	('FTO', 'Gene', '79068', (62, 65))	('blunted', 'NegReg', (39, 46))	('FTO', 'Gene', (62, 65))	('R96Q', 'Var', (33, 37))	('invasion', 'CPA', (107, 115))	('cell proliferation', 'CPA', (84, 102))	('R96Q', 'Mutation', 'rs148771973', (33, 37))
571695	32110044	Through RNA sequencing analysis of A549 cells overexpressing FTO or R96Q and control A594 cells, 45 genes were identified as affected by m6A mRNA demethylation.	('FTO', 'Gene', '79068', (61, 64))	('R96Q', 'Mutation', 'rs148771973', (68, 72))	('FTO', 'Gene', (61, 64))	('A549', 'CellLine', 'CVCL:0023', (35, 39))	('m6A', 'Gene', (137, 140))	('R96Q', 'Var', (68, 72))	('affected', 'Reg', (125, 133))	('m6A', 'Gene', '56339', (137, 140))
571710	32110044	Several recent reports have indicated the potential association between aberrant m6A modification and lung cancer development.	('lung cancer', 'Phenotype', 'HP:0100526', (102, 113))	('cancer', 'Phenotype', 'HP:0002664', (107, 113))	('lung cancer', 'Disease', (102, 113))	('m6A', 'Gene', (81, 84))	('aberrant', 'Var', (72, 80))	('lung cancer', 'Disease', 'MESH:D008175', (102, 113))	('m6A', 'Gene', '56339', (81, 84))
571732	32110044	The R96Q mutation indicates that the Arg at position 96 of the FTO gene was replaced by a Gln.	('Gln', 'Chemical', 'MESH:D005973', (90, 93))	('Arg at', 'Var', (37, 43))	('FTO', 'Gene', '79068', (63, 66))	('R96Q', 'Mutation', 'rs148771973', (4, 8))	('Arg', 'Chemical', 'MESH:D001120', (37, 40))	('FTO', 'Gene', (63, 66))	('R96Q', 'Var', (4, 8))
571733	32110044	The FTO Arg96Gln mutation resulted in the loss of FTO demethylase activity.	('FTO', 'Gene', '79068', (4, 7))	('demethylase', 'Gene', (54, 65))	('FTO', 'Gene', (50, 53))	('Arg96Gln', 'Var', (8, 16))	('Arg96Gln', 'SUBSTITUTION', 'None', (8, 16))	('activity', 'MPA', (66, 74))	('demethylase', 'Gene', '8932', (54, 65))	('FTO', 'Gene', (4, 7))	('FTO', 'Gene', '79068', (50, 53))	('loss', 'NegReg', (42, 46))
571734	32110044	The R96Q plasmid was acquired by point mutation of the FTO plasmid.	('FTO', 'Gene', '79068', (55, 58))	('R96Q', 'Mutation', 'rs148771973', (4, 8))	('point mutation', 'Var', (33, 47))	('FTO', 'Gene', (55, 58))	('R96Q', 'Var', (4, 8))
571762	32110044	To examine the roles of FTO in LUAC, FTO was overexpressed or knocked down in A549 and H1299 cells.	('LUAC', 'Phenotype', 'HP:0030078', (31, 35))	('H1299', 'CellLine', 'CVCL:0060', (87, 92))	('FTO', 'Gene', (24, 27))	('FTO', 'Gene', (37, 40))	('FTO', 'Gene', '79068', (24, 27))	('A549', 'CellLine', 'CVCL:0023', (78, 82))	('knocked', 'Var', (62, 69))	('FTO', 'Gene', '79068', (37, 40))	('LUAC', 'Disease', (31, 35))	('LUAC', 'Disease', 'MESH:C538231', (31, 35))
571769	32110044	As expected, FTO knockdown suppressed cell proliferation, migration, colony formation, invasion, and apoptosis (Figure 3A-E).	('cell proliferation', 'CPA', (38, 56))	('invasion', 'CPA', (87, 95))	('FTO', 'Gene', (13, 16))	('suppressed', 'NegReg', (27, 37))	('FTO', 'Gene', '79068', (13, 16))	('knockdown', 'Var', (17, 26))	('apoptosis', 'CPA', (101, 110))	('colony formation', 'CPA', (69, 85))	('migration', 'CPA', (58, 67))
571772	32110044	Compared with those in control cells, FTO overexpression decreased mRNA m6A levels, whereas FTO knockdown increased m6A levels in A549 cells (Figure 3F).	('knockdown', 'Var', (96, 105))	('m6A', 'Gene', '56339', (116, 119))	('m6A', 'Gene', (72, 75))	('A549', 'CellLine', 'CVCL:0023', (130, 134))	('FTO', 'Gene', '79068', (38, 41))	('FTO', 'Gene', (92, 95))	('m6A', 'Gene', '56339', (72, 75))	('m6A', 'Gene', (116, 119))	('FTO', 'Gene', '79068', (92, 95))	('FTO', 'Gene', (38, 41))	('increased', 'PosReg', (106, 115))	('decreased', 'NegReg', (57, 66))
571774	32110044	To further verify the demethylase activity of FTO in LUAC, the FTO R96Q mutation was generated, and the mutated protein was expressed in A549 and H1299 cells.	('demethylase', 'Gene', (22, 33))	('H1299', 'CellLine', 'CVCL:0060', (146, 151))	('FTO', 'Gene', (46, 49))	('R96Q', 'Mutation', 'rs148771973', (67, 71))	('demethylase', 'Gene', '8932', (22, 33))	('LUAC', 'Disease', (53, 57))	('FTO', 'Gene', '79068', (63, 66))	('LUAC', 'Phenotype', 'HP:0030078', (53, 57))	('R96Q mutation', 'Var', (67, 80))	('FTO', 'Gene', '79068', (46, 49))	('LUAC', 'Disease', 'MESH:C538231', (53, 57))	('FTO', 'Gene', (63, 66))	('A549', 'CellLine', 'CVCL:0023', (137, 141))
571775	32110044	The R96Q missense mutation eliminated FTO demethylase activity.	('R96Q missense', 'Var', (4, 17))	('FTO', 'Gene', '79068', (38, 41))	('R96Q', 'Mutation', 'rs148771973', (4, 8))	('eliminated', 'NegReg', (27, 37))	('activity', 'MPA', (54, 62))	('demethylase', 'Gene', (42, 53))	('FTO', 'Gene', (38, 41))	('demethylase', 'Gene', '8932', (42, 53))
571776	32110044	Successful R96Q overexpression was confirmed at the mRNA and protein levels (Figure 2A and B).	('R96Q', 'Var', (11, 15))	('R96Q', 'Mutation', 'rs148771973', (11, 15))	('overexpression', 'PosReg', (16, 30))
571777	32110044	R96Q overexpression blunted the FTO-mediated promotion of cell proliferation, migration, colony-forming ability, invasion, and apoptosis (Figure 3A-E) but had no effect on the decrease in the cellular m6A level induced by FTO (Figure 3F).	('R96Q', 'Var', (0, 4))	('m6A', 'Gene', (201, 204))	('FTO', 'Gene', (32, 35))	('promotion', 'PosReg', (45, 54))	('invasion', 'CPA', (113, 121))	('colony-forming ability', 'CPA', (89, 111))	('cell proliferation', 'CPA', (58, 76))	('FTO', 'Gene', (222, 225))	('overexpression', 'PosReg', (5, 19))	('apoptosis', 'CPA', (127, 136))	('R96Q', 'Mutation', 'rs148771973', (0, 4))	('m6A', 'Gene', '56339', (201, 204))	('FTO', 'Gene', '79068', (32, 35))	('migration', 'CPA', (78, 87))	('blunted', 'NegReg', (20, 27))	('FTO', 'Gene', '79068', (222, 225))
571779	32110044	mRNA sequence analysis was performed on A594 cells overexpressing FTO or R96Q and control A594 cells.	('FTO', 'Gene', (66, 69))	('R96Q', 'Var', (73, 77))	('FTO', 'Gene', '79068', (66, 69))	('R96Q', 'Mutation', 'rs148771973', (73, 77))
571781	32110044	R96Q overexpression resulted in the upregulation of 94 genes.	('upregulation', 'PosReg', (36, 48))	('R96Q', 'Mutation', 'rs148771973', (0, 4))	('R96Q', 'Var', (0, 4))	('overexpression', 'PosReg', (5, 19))
571782	32110044	The genes upregulated by FTO overexpression but not R96Q overexpression were identified as gene affected by m6A mRNA demethylation.	('FTO', 'Gene', '79068', (25, 28))	('m6A', 'Gene', (108, 111))	('m6A', 'Gene', '56339', (108, 111))	('overexpression', 'Var', (29, 43))	('upregulated', 'PosReg', (10, 21))	('FTO', 'Gene', (25, 28))	('R96Q', 'Mutation', 'rs148771973', (52, 56))
571806	32110044	The overexpression of R96Q, an FTO missense mutant lacking demethylase activity, did not affect the cellular m6A level.	('R96Q', 'Mutation', 'rs148771973', (22, 26))	('FTO', 'Gene', '79068', (31, 34))	('lacking', 'NegReg', (51, 58))	('demethylase', 'Gene', (59, 70))	('m6A', 'Gene', (109, 112))	('FTO', 'Gene', (31, 34))	('demethylase', 'Gene', '8932', (59, 70))	('m6A', 'Gene', '56339', (109, 112))	('R96Q', 'Var', (22, 26))
571807	32110044	In this study, mRNA m6A levels were evaluated in A549 cells overexpressing FTO or R96Q and control A549 cells.	('A549', 'CellLine', 'CVCL:0023', (99, 103))	('m6A', 'Gene', '56339', (20, 23))	('FTO', 'Gene', (75, 78))	('R96Q', 'Mutation', 'rs148771973', (82, 86))	('A549', 'CellLine', 'CVCL:0023', (49, 53))	('R96Q', 'Var', (82, 86))	('FTO', 'Gene', '79068', (75, 78))	('m6A', 'Gene', (20, 23))
571808	32110044	FTO overexpression resulted in reduced m6A levels, but R96Q overexpression caused no such effect.	('reduced', 'NegReg', (31, 38))	('FTO', 'Gene', '79068', (0, 3))	('R96Q', 'Var', (55, 59))	('m6A', 'Gene', (39, 42))	('R96Q', 'Mutation', 'rs148771973', (55, 59))	('FTO', 'Gene', (0, 3))	('m6A', 'Gene', '56339', (39, 42))
571811	32110044	In contrast, R96Q had no effect on the cellular m6A level and impeded differentiation.	('differentiation', 'CPA', (70, 85))	('R96Q', 'Mutation', 'rs148771973', (13, 17))	('m6A', 'Gene', '56339', (48, 51))	('impeded', 'NegReg', (62, 69))	('R96Q', 'Var', (13, 17))	('m6A', 'Gene', (48, 51))
571814	32110044	Through mRNA sequential analysis of A594 cells overexpressing FTO or R96Q and control A594 cells, 45 genes were identified as affected by m6A mRNA demethylation.	('FTO', 'Gene', '79068', (62, 65))	('R96Q', 'Var', (69, 73))	('m6A', 'Gene', '56339', (138, 141))	('affected', 'Reg', (126, 134))	('FTO', 'Gene', (62, 65))	('R96Q', 'Mutation', 'rs148771973', (69, 73))	('m6A', 'Gene', (138, 141))
571818	32110044	LAMC2 overexpression increased the traction force, migration, and invasion of A549 cells, accompanied by cell epithelial-mesenchymal transition.	('traction force', 'CPA', (35, 49))	('increased', 'PosReg', (21, 30))	('migration', 'CPA', (51, 60))	('overexpression', 'Var', (6, 20))	('cell epithelial-mesenchymal transition', 'CPA', (105, 143))	('A549', 'CellLine', 'CVCL:0023', (78, 82))	('LAMC2', 'Gene', (0, 5))	('invasion', 'CPA', (66, 74))	('LAMC2', 'Gene', '3918', (0, 5))
571832	30834254	Poor prognosis was observed in patients with high platelet counts, PLR, NLR, and low lymphocyte percentage.	('PLR', 'Disease', (67, 70))	('low', 'Var', (81, 84))	('NLR', 'Disease', (72, 75))	('low lymphocyte percentage', 'Phenotype', 'HP:0001888', (81, 106))	('patients', 'Species', '9606', (31, 39))	('high platelet counts', 'Phenotype', 'HP:0001894', (45, 65))	('high platelet count', 'Phenotype', 'HP:0001894', (45, 64))
571881	30834254	At pretreatment and posttreatment, P values were, respectively, .018 for OS, .035 for TPD, and .012 for TM and .010 for OS, .042 for TPD, and .010 for TM.	('OS', 'Chemical', '-', (120, 122))	('OS', 'Chemical', '-', (73, 75))	('TPD', 'Disease', (86, 89))	('TPD', 'Chemical', '-', (133, 136))	('men', 'Species', '9606', (29, 32))	('TM', 'Chemical', '-', (151, 153))	('.012', 'Var', (95, 99))	('TPD', 'Chemical', '-', (86, 89))	('TM', 'Chemical', '-', (104, 106))	('men', 'Species', '9606', (11, 14))
571909	30834254	High platelet count is related to poor prognosis in various cancers.	('High platelet count', 'Phenotype', 'HP:0001894', (0, 19))	('cancers', 'Phenotype', 'HP:0002664', (60, 67))	('High', 'Var', (0, 4))	('cancers', 'Disease', (60, 67))	('cancers', 'Disease', 'MESH:D009369', (60, 67))	('cancer', 'Phenotype', 'HP:0002664', (60, 66))
571926	30834254	A high ALC during CCRT was associated with a high rate of pathologically complete remission for patients with esophageal cancer.	('cancer', 'Phenotype', 'HP:0002664', (121, 127))	('high', 'Var', (2, 6))	('esophageal cancer', 'Disease', (110, 127))	('ALC', 'MPA', (7, 10))	('patients', 'Species', '9606', (96, 104))	('esophageal cancer', 'Disease', 'MESH:D004938', (110, 127))
571931	30834254	reported a meta-analysis on the prognostic role of PLR in esophageal cancer: in a total of 6699 patients from 16 studies (17 cohorts), elevated PLR predicted poorer OS (HR, 1.389) and shorter disease-free survival (HR, 1.404).	('poorer', 'NegReg', (158, 164))	('disease-free survival', 'CPA', (192, 213))	('OS', 'Chemical', '-', (165, 167))	('esophageal cancer', 'Disease', (58, 75))	('cancer', 'Phenotype', 'HP:0002664', (69, 75))	('esophageal cancer', 'Disease', 'MESH:D004938', (58, 75))	('shorter', 'NegReg', (184, 191))	('patients', 'Species', '9606', (96, 104))	('PLR', 'Var', (144, 147))
571937	30834254	As per a previous study, inflammation may contribute to tumor initiation through genetic mutations, genomic instability, and epigenetic modifications.	('inflammation', 'Disease', (25, 37))	('tumor', 'Phenotype', 'HP:0002664', (56, 61))	('genomic instability', 'CPA', (100, 119))	('tumor', 'Disease', (56, 61))	('genetic mutations', 'Var', (81, 98))	('contribute', 'Reg', (42, 52))	('epigenetic modifications', 'Var', (125, 149))	('inflammation', 'Disease', 'MESH:D007249', (25, 37))	('tumor', 'Disease', 'MESH:D009369', (56, 61))
571947	27608841	The ratios of squamous cell carcinoma from CMUT, CMU1 and JMU were higher than the others, while it was the same for the ratio of large and small cell carcinoma in Takaoka and CMU1 (p<0.05).	('cell carcinoma', 'Disease', (146, 160))	('squamous cell carcinoma', 'Phenotype', 'HP:0002860', (14, 37))	('higher', 'PosReg', (67, 73))	('squamous cell carcinoma', 'Disease', (14, 37))	('squamous cell carcinoma', 'Disease', 'MESH:D002294', (14, 37))	('cell carcinoma', 'Disease', 'MESH:C538614', (146, 160))	('CMU1', 'Var', (49, 53))	('small cell carcinoma', 'Phenotype', 'HP:0030357', (140, 160))	('cell carcinoma', 'Disease', 'MESH:C538614', (23, 37))	('CMUT', 'Var', (43, 47))	('carcinoma', 'Phenotype', 'HP:0030731', (28, 37))	('carcinoma', 'Phenotype', 'HP:0030731', (151, 160))
571984	27608841	The patients from CMUT and CMU1 were younger than the other hospitals, while the patients from Takaoka were eldest in the 6 hospitals (Figure 2A, p<0.05).	('patients', 'Species', '9606', (81, 89))	('CMU1', 'Var', (27, 31))	('CMUT', 'Var', (18, 22))	('patients', 'Species', '9606', (4, 12))
571985	27608841	As indicated in Figure 2B, the proportion of male patients was comparatively higher in CMU1 and JMU than the other hospitals (p<0.05).	('higher', 'PosReg', (77, 83))	('patients', 'Species', '9606', (50, 58))	('CMU1', 'Var', (87, 91))
571996	27608841	The ratio of Ad was higher in female patients of Takaoka, CMUT, CMUS, CMU1, DMU and JMU than the male ones (Figure 3F, p<0.05).	('CMUT', 'Var', (58, 62))	('DMU', 'Chemical', '-', (76, 79))	('patients', 'Species', '9606', (37, 45))	('higher', 'PosReg', (20, 26))	('CMUS', 'Var', (64, 68))	('DMU', 'Var', (76, 79))	('CMU1', 'Var', (70, 74))
572027	27608841	Additionally, the economic level is higher in DMU than JMU, which determines the emphasis of health examination, and subsequently early finding, diagnosis and therapy at early clinicopathological staging.	('DMU', 'Chemical', '-', (46, 49))	('economic level', 'MPA', (18, 32))	('higher', 'Reg', (36, 42))	('DMU', 'Var', (46, 49))
572038	27608841	A research had showed that NOx and polycyclic aromatic hydrocarbons in the air were risk factors for lung cancer.	('sea', 'Disease', (4, 7))	('sea', 'Disease', 'MESH:D009041', (4, 7))	('lung cancer', 'Disease', 'MESH:D008175', (101, 112))	('NOx', 'Chemical', 'MESH:C024270', (27, 30))	('polycyclic aromatic hydrocarbons', 'Var', (35, 67))	('polycyclic aromatic hydrocarbons', 'Chemical', 'MESH:D011084', (35, 67))	('lung cancer', 'Phenotype', 'HP:0100526', (101, 112))	('lung cancer', 'Disease', (101, 112))	('cancer', 'Phenotype', 'HP:0002664', (106, 112))
572049	27608841	found that the increased risks of lung cancer incidence were associated with PM2.5 and ozone air pollution so that air pollution control would be effective for the prevention of lung cancer.	('lung cancer', 'Disease', (178, 189))	('lung cancer', 'Disease', (34, 45))	('lung cancer', 'Phenotype', 'HP:0100526', (178, 189))	('lung cancer', 'Phenotype', 'HP:0100526', (34, 45))	('cancer', 'Phenotype', 'HP:0002664', (183, 189))	('cancer', 'Phenotype', 'HP:0002664', (39, 45))	('lung cancer', 'Disease', 'MESH:D008175', (34, 45))	('lung cancer', 'Disease', 'MESH:D008175', (178, 189))	('PM2.5', 'Var', (77, 82))
572086	25520551	investigated several single-nucleotide polymorphisms (SNPs), the loci of genes that encode proteins on the DNA repair pathways (including the both excision repair [BER] pathway and the nucleotide excision repair [NER] pathway), to determine whether these SNPs are associated with non-small-cell lung cancer.	('non-small-cell lung cancer', 'Phenotype', 'HP:0030358', (280, 306))	('associated', 'Reg', (264, 274))	('lung cancer', 'Phenotype', 'HP:0100526', (295, 306))	('cancer', 'Phenotype', 'HP:0002664', (300, 306))	('SNPs', 'Var', (255, 259))	('non-small-cell lung cancer', 'Disease', (280, 306))	('non-small-cell lung cancer', 'Disease', 'MESH:D002289', (280, 306))	('small-cell lung cancer', 'Phenotype', 'HP:0030357', (284, 306))
572178	31417313	While advanced lung nonsquamous cell cancer has greatly benefited from the detection and targeting of oncogenic alterations, for instance ALK rearrangement and EGFR mutations, LUSC has been challenging in the identification and targeting of driving mutations.	('lung nonsquamous cell cancer', 'Disease', (15, 43))	('LUSC', 'Phenotype', 'HP:0030359', (176, 180))	('ALK', 'Gene', '238', (138, 141))	('lung nonsquamous cell cancer', 'Disease', 'MESH:D008175', (15, 43))	('EGFR', 'Gene', '1956', (160, 164))	('rearrangement', 'Var', (142, 155))	('cancer', 'Phenotype', 'HP:0002664', (37, 43))	('EGFR', 'Gene', (160, 164))	('ALK', 'Gene', (138, 141))	('mutations', 'Var', (165, 174))	('nonsquamous cell cancer', 'Phenotype', 'HP:0002860', (20, 43))
572179	31417313	MicroRNAs (miRs) are short noncoding RNA molecules, playing crucial roles in transcriptional regulation of gene expression through several mechanisms The deregulation of miRs has been shown to be associated with various cancers, including NSCLC.	('deregulation', 'Var', (154, 166))	('cancer', 'Phenotype', 'HP:0002664', (220, 226))	('NSCLC', 'Phenotype', 'HP:0030358', (239, 244))	('associated', 'Reg', (196, 206))	('miRs', 'Gene', (170, 174))	('cancers', 'Phenotype', 'HP:0002664', (220, 227))	('NSCLC', 'Disease', (239, 244))	('cancers', 'Disease', (220, 227))	('NSCLC', 'Disease', 'MESH:D002289', (239, 244))	('cancers', 'Disease', 'MESH:D009369', (220, 227))
572191	31417313	miR-6499-5p, miR-4746-5p, miR-1293, and miR-4664-3p were upregulated whereas miR-326, miR-30d-3p, and miR-30e-3p were downregulated in LUSC tissues (Figure 2).	('miR-30e-3p', 'Var', (102, 112))	('miR-30d', 'Gene', (86, 93))	('miR-1293', 'Gene', '100302220', (26, 34))	('miR-4664-3p', 'Var', (40, 51))	('miR-4746-5p', 'Var', (13, 24))	('miR-30d', 'Gene', '407033', (86, 93))	('LUSC', 'Phenotype', 'HP:0030359', (135, 139))	('miR-326', 'Gene', (77, 84))	('miR-1293', 'Gene', (26, 34))	('miR-326', 'Gene', '442900', (77, 84))	('downregulated', 'NegReg', (118, 131))	('miR-6499-5p', 'Var', (0, 11))	('upregulated', 'PosReg', (57, 68))
572193	31417313	We then applied a multivariate Cox proportional hazards regression analysis to identify seven miRs (Table 2) - miR-326, miR-6499-5p, miR-30d-3p, miR-4746-5p, miR-1293, miR-4664-3p, and miR-30e-3p - as independent prognostic factors (Figure 3A-G).	('miR-6499-5p', 'Var', (120, 131))	('miR-30d', 'Gene', '407033', (133, 140))	('miR-30e-3p -', 'Var', (185, 197))	('miR-326', 'Gene', (111, 118))	('miR-1293', 'Gene', '100302220', (158, 166))	('miR-326', 'Gene', '442900', (111, 118))	('miR-4746-5p', 'Var', (145, 156))	('miR-30d', 'Gene', (133, 140))	('miR-1293', 'Gene', (158, 166))	('miR-4664-3p', 'Var', (168, 179))
572194	31417313	Each patient was assigned one score for low expression of miR-6499-5p, miR-30d-3p, miR-4746-5p, and miR-30e-3p, respectively, and one score for high expression of miR-326, miR-1293, and miR-4664-3p, respectively.	('patient', 'Species', '9606', (5, 12))	('miR-4664-3p', 'Var', (186, 197))	('low', 'NegReg', (40, 43))	('miR-326', 'Gene', (163, 170))	('miR-30e-3p', 'Var', (100, 110))	('miR-30d', 'Gene', (71, 78))	('miR-326', 'Gene', '442900', (163, 170))	('miR-4746-5p', 'Var', (83, 94))	('miR-1293', 'Gene', '100302220', (172, 180))	('miR-1293', 'Gene', (172, 180))	('miR-30d', 'Gene', '407033', (71, 78))	('miR-6499-5p', 'Var', (58, 69))
572207	31417313	Tan et al proposed a five-miR (miR-210, miR-182, miR-486-5p, miR-30a, and miR-140-3p) signature for LUSC diagnosis and miR-31 for prognosis based on LUSCs from the People's Republic of China in 2011.	('miR-210', 'Gene', '406992', (31, 38))	('LUSC', 'Disease', (100, 104))	('miR-182', 'Gene', (40, 47))	('miR-30a', 'Gene', (61, 68))	('People', 'Species', '9606', (164, 170))	('miR-31', 'Gene', '407035', (119, 125))	('miR-140', 'Gene', '406932', (74, 81))	('LUSC', 'Phenotype', 'HP:0030359', (100, 104))	('miR-182', 'Gene', '406958', (40, 47))	('LUSC', 'Phenotype', 'HP:0030359', (149, 153))	('miR-30a', 'Gene', '407029', (61, 68))	('miR-210', 'Gene', (31, 38))	('miR-486-5p', 'Var', (49, 59))	('miR-140', 'Gene', (74, 81))	('miR-31', 'Gene', (119, 125))
572214	31417313	Wang et al suggested a seven-miR (miR-148b, miR-365, miR-32, miR-375, miR-21, miR-125b, and miR-155) prognostic signature for NSCLC including LUSC.	('miR-125b', 'Var', (78, 86))	('NSCLC', 'Disease', 'MESH:D002289', (126, 131))	('miR-155', 'Gene', (92, 99))	('miR-148b', 'Gene', (34, 42))	('miR-365', 'Var', (44, 51))	('miR-32', 'Gene', (53, 59))	('miR-21', 'Gene', '406991', (70, 76))	('LUSC', 'Disease', (142, 146))	('miR-375', 'Gene', '494324', (61, 68))	('miR-21', 'Gene', (70, 76))	('LUSC', 'Phenotype', 'HP:0030359', (142, 146))	('NSCLC', 'Phenotype', 'HP:0030358', (126, 131))	('miR-155', 'Gene', '406947', (92, 99))	('miR-148b', 'Gene', '442892', (34, 42))	('miR-375', 'Gene', (61, 68))	('miR-32', 'Gene', '407036', (53, 59))	('NSCLC', 'Disease', (126, 131))
572216	31417313	Among our seven miRs, miR-326 was identified as a tumor suppressor miR in various cancers and was downregulated in LUSC, but high expression of miR-326 was a high risk factor of LUSC in our study.	('downregulated', 'NegReg', (98, 111))	('cancer', 'Phenotype', 'HP:0002664', (82, 88))	('LUSC', 'Disease', (178, 182))	('cancers', 'Phenotype', 'HP:0002664', (82, 89))	('miR-326', 'Gene', '442900', (144, 151))	('LUSC', 'Disease', (115, 119))	('LUSC', 'Phenotype', 'HP:0030359', (115, 119))	('cancers', 'Disease', (82, 89))	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('miR-326', 'Gene', (22, 29))	('cancers', 'Disease', 'MESH:D009369', (82, 89))	('LUSC', 'Phenotype', 'HP:0030359', (178, 182))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('tumor', 'Disease', (50, 55))	('miR-326', 'Gene', '442900', (22, 29))	('miR-326', 'Gene', (144, 151))	('high', 'Var', (125, 129))
572219	31417313	Another study reported that exosomal miR-30e-3p was lung adenocarcinoma specific, rather than LUSC specific.	('lung adenocarcinoma', 'Disease', (52, 71))	('lung adenocarcinoma', 'Disease', 'MESH:D000077192', (52, 71))	('LUSC', 'Phenotype', 'HP:0030359', (94, 98))	('exosomal miR-30e-3p', 'Var', (28, 47))	('lung adenocarcinoma', 'Phenotype', 'HP:0030078', (52, 71))	('carcinoma', 'Phenotype', 'HP:0030731', (62, 71))
572220	31417313	However, our results indicated that miR-30e-3p in tumor tissue was a prognostic factor for LUSC.	('tumor', 'Disease', 'MESH:D009369', (50, 55))	('tumor', 'Phenotype', 'HP:0002664', (50, 55))	('LUSC', 'Phenotype', 'HP:0030359', (91, 95))	('miR-30e-3p', 'Var', (36, 46))	('LUSC', 'Disease', (91, 95))	('tumor', 'Disease', (50, 55))
572228	30326837	miRNAs have been implicated in many diseases, especially in various types of cancers, such as lung neoplasms, breast neoplasms, colonic neoplasms, etc.	('colonic neoplasms', 'Disease', 'MESH:D003110', (128, 145))	('cancers', 'Disease', 'MESH:D009369', (77, 84))	('cancers', 'Phenotype', 'HP:0002664', (77, 84))	('lung neoplasms', 'Disease', 'MESH:D008175', (94, 108))	('breast neoplasms', 'Disease', 'MESH:D001943', (110, 126))	('lung neoplasms', 'Phenotype', 'HP:0100526', (94, 108))	('cancers', 'Disease', (77, 84))	('colonic neoplasms', 'Phenotype', 'HP:0100273', (128, 145))	('colonic neoplasms', 'Disease', (128, 145))	('breast neoplasms', 'Disease', (110, 126))	('neoplasms', 'Phenotype', 'HP:0002664', (99, 108))	('neoplasms', 'Phenotype', 'HP:0002664', (136, 145))	('breast neoplasms', 'Phenotype', 'HP:0100013', (110, 126))	('cancer', 'Phenotype', 'HP:0002664', (77, 83))	('miRNAs', 'Var', (0, 6))	('implicated', 'Reg', (17, 27))	('lung neoplasms', 'Disease', (94, 108))	('neoplasms', 'Phenotype', 'HP:0002664', (117, 126))
572263	30326837	Moreover, the results showed many non-differentially expressed miRNAs had an important role in breast cancer.	('cancer', 'Phenotype', 'HP:0002664', (102, 108))	('non-differentially expressed', 'Var', (34, 62))	('breast cancer', 'Disease', (95, 108))	('breast cancer', 'Phenotype', 'HP:0003002', (95, 108))	('miRNAs', 'Protein', (63, 69))	('breast cancer', 'Disease', 'MESH:D001943', (95, 108))
572264	30326837	The known cancer mechanism-related pathways are significantly enriched, such as pathways in cancer, Prostate cancer, miRNAs in cancer, Pancreatic cancer, Chronic myeloid leukemia, Melanoma, the p53 signaling pathway, small cell lung cancer, colorectal cancer, acute myeloid leukemia, Transcriptional misregulation in cancer, Glioma and Non-small cell lung cancer.	('cancer', 'Disease', (146, 152))	('cancer', 'Disease', 'MESH:D009369', (252, 258))	('Glioma', 'Disease', (325, 331))	('cancer', 'Disease', 'MESH:D009369', (92, 98))	('cancer', 'Disease', 'MESH:D009369', (109, 115))	('Pancreatic cancer', 'Phenotype', 'HP:0002894', (135, 152))	('colorectal cancer', 'Disease', (241, 258))	('Non-small cell lung cancer', 'Disease', (336, 362))	('p53', 'Gene', (194, 197))	('Prostate cancer', 'Disease', (100, 115))	('lung cancer', 'Phenotype', 'HP:0100526', (351, 362))	('cancer', 'Phenotype', 'HP:0002664', (146, 152))	('small cell lung cancer', 'Disease', 'MESH:D055752', (340, 362))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (217, 239))	('cancer', 'Disease', (10, 16))	('cancer', 'Phenotype', 'HP:0002664', (10, 16))	('acute myeloid leukemia', 'Disease', (260, 282))	('Chronic myeloid leukemia', 'Phenotype', 'HP:0005506', (154, 178))	('cancer', 'Disease', 'MESH:D009369', (233, 239))	('cancer', 'Disease', (356, 362))	('Non-small cell lung cancer', 'Phenotype', 'HP:0030358', (336, 362))	('Melanoma', 'Disease', 'MESH:D008545', (180, 188))	('cancer', 'Disease', (127, 133))	('Pancreatic cancer', 'Disease', 'MESH:D010190', (135, 152))	('leukemia', 'Phenotype', 'HP:0001909', (274, 282))	('cancer', 'Disease', (317, 323))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (266, 282))	('Glioma', 'Disease', 'MESH:D005910', (325, 331))	('cancer', 'Disease', 'MESH:D009369', (146, 152))	('cancer', 'Phenotype', 'HP:0002664', (127, 133))	('cancer', 'Disease', (92, 98))	('colorectal cancer', 'Phenotype', 'HP:0003003', (241, 258))	('cancer', 'Disease', (252, 258))	('cancer', 'Disease', (109, 115))	('Pancreatic cancer', 'Disease', (135, 152))	('leukemia', 'Phenotype', 'HP:0001909', (170, 178))	('acute myeloid leukemia', 'Disease', 'MESH:D015470', (260, 282))	('Melanoma', 'Disease', (180, 188))	('myeloid leukemia', 'Phenotype', 'HP:0012324', (162, 178))	('cancer', 'Disease', 'MESH:D009369', (10, 16))	('small cell lung cancer', 'Phenotype', 'HP:0030357', (340, 362))	('cancer', 'Phenotype', 'HP:0002664', (109, 115))	('cancer', 'Phenotype', 'HP:0002664', (92, 98))	('Transcriptional misregulation', 'Var', (284, 313))	('small cell lung cancer', 'Disease', 'MESH:D055752', (217, 239))	('Prostate cancer', 'Disease', 'MESH:D011471', (100, 115))	('lung cancer', 'Phenotype', 'HP:0100526', (228, 239))	('Prostate cancer', 'Phenotype', 'HP:0012125', (100, 115))	('Chronic myeloid leukemia', 'Disease', (154, 178))	('Chronic myeloid leukemia', 'Disease', 'MESH:D015464', (154, 178))	('acute myeloid leukemia', 'Phenotype', 'HP:0004808', (260, 282))	('Glioma', 'Phenotype', 'HP:0009733', (325, 331))	('small cell lung cancer', 'Disease', (217, 239))	('Non-small cell lung cancer', 'Disease', 'MESH:D002289', (336, 362))	('cancer', 'Disease', 'MESH:D009369', (356, 362))	('Melanoma', 'Phenotype', 'HP:0002861', (180, 188))	('cancer', 'Disease', (233, 239))	('cancer', 'Disease', 'MESH:D009369', (127, 133))	('p53', 'Gene', '7157', (194, 197))	('colorectal cancer', 'Disease', 'MESH:D015179', (241, 258))	('cancer', 'Disease', 'MESH:D009369', (317, 323))